Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-10-18
1998-06-16
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546105, A61K 31435, C07D21910
Patent
active
057671265
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/GB92/00828, filed on May 7, 1992, issued as WO92/22534 on Dec. 23, 1992.
DESCRIPTION
This invention relates to a method for treating Alzheimer's disease and similar cholinergic dysfunctions with polyhydroxylated and dehydrogenated derivatives of the compound 9-amino-1,2,3,4-tetrahydroacridine (Tacrine). Alzheimer's disease is a progressive deterioration of the brain resulting in loss of memory, cognitive deficits and depression. The illness has affected approximately 10% of the population by age 65 and its incidence increases by about 1% per year of the general population surviving from then. It is recognised as a major health care problem. The deterioration of the brain is known to cause a partial loss of the substance acetylcholine. The presence of this substance is essential for the proper functioning of memory so that certain drugs that cause its conservation will be of therapeutic benefit for Alzheimer's disease. Acetylcholine is destroyed in the brain by an enzyme known as acetylcholinesterase. The class of drugs that can prevent the action of this enzyme will cause the conservation of acetylcholine and thus are potentially able to restore the loss of memory.
Tacrine has been shown to prevent the action of acetylcholinesterase (P. N. Kaul, J. Pharm. Pharmacol. (1962), Vol 14, pages 237-242) and several studies most notably that by S. A. Eagger, R. Levy and B. J. Sahakian (Lancet (1991), Vol 337, pages 989-992) have demonstrated the effectiveness of Tacrine in restoring memory function in Alzheimer's disease. When Tacrine is withdrawn from the patient a relapse in cognitive function occurs so that continued administration would be necessary for effective therapy.
Unfortunately, as P. Hammell, D. Laney, J. Berman and others have shown Tacrine causes liver damage so that its prolonged use as a therapeutic agent is not possible (J. Clin. Gastroenterol (1990), Vol 12, pages 329-331).
According to the present invention certain compounds which result from the metabolism of Tacrine will not be toxic to the liver because it is their production in the liver itself which causes the damage to it. It is shown that such compounds retain their capacity to prevent the action of acetylcholinesterase provided that the carbon skeleton of the hydrogenated ring is not completely disrupted by metabolism. It is disclosed that the metabolism of Tacrine proceeds by dehydrogenation and hydroxylkation of the hydrogenated ring. It is also disclosed that polyhydroxylated and dehydrogenated derivatives retain their ability to prevent the action of acetylcholinesterase provided the carbon skeleton of the originally hydrogenated ring is not lost. The administration of such compounds will be of therapeutic benefit in the treatment of Alzheimer's disease because the hepatotoxic stages of the metabolism of Tacrine has been circumvented but the anticholinesterase activity conserved.
Embodiments of this invention will now be described with reference to the accompanying figure. ##STR1##
FIGURE Generic structure of metabolites of Tacrine. (In Tacrine itself X,Y, and Z all=hydrogen which is also the only and saturating substituent of carbon atoms numbered 1,2,3 & 4).
In this invention attached to at least two of the carbon atoms numbered 1,2,3 and 4 is a hydroxyl group and to the others either hydrogen, hydroxyl or double bonded oxygen, the residual valencies being occupied by hydrogen or double bonds between carbon atoms 1 and 2 and/or 3 and 4.
X is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, nitro, trifluoromethyl, NHCOR where R is lower alkyl, or NR' R' where R' is independently hydrogen or lower alkyl, Y is hydrogen or lower alkyl, Z is hydrogen, lower alkyl, diloweralkylaminoloweralkyl, arylloweralkyl, furylloweralkyl, thienylloweralkyl.
Throughout this specification and appended claims a given chemical formula or name shall encompass all stereo and optical isomers as exist as well as pharmaceutically acceptable acid addition salts and solvates which are useful in the formula
REFERENCES:
patent: 4985430 (1991-01-01), Morita
Huang Evelyn
Ivy C. Warren
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