Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-04-29
1999-10-26
MacMillan, Keith D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3147
Patent
active
059729562
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention concerns a method for inhibiting amyloidosis utilizing 9-acridinone compounds. The invention is a method for diagnosing and treating diseases characterized by amyloidosis.
BACKGROUND OF THE INVENTION
Amyloid plaque formation is found in a number of diseases, including Alzheimer's disease, scrapie, bovine spongiform encephalophy, Gerstmann-Straussler Syndrome, and the like. The amyloid plaques comprise proteins bound together in a fibrillous matrix. Amyloidosis is the general name given to diseases and conditions characterized by the presence of amyloid protein. A number of different types of amyloid protein are known, and all types are considered pathological, since no normally occurring amyloids are known. Accordingly, the presence of amyloid protein in a host is an indication of abnormal formation of fibrils and plaques. Amyloidosis has been clinically observed in a number of disease states, including certain mental illnesses, neurological diseases, and collagenosis. Indeed, the brains of subjects diagnosed with Alzheimer's disease have one thing in common, namely an abundance of amyloid in the form of plaques and tangles.
Alzheimer's disease is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgement, and emotional stability that gradually leads to mental deterioration and ultimately death. To date, only one clinically approved treatment is available, namely tacrine hydrochloride (Cognex.RTM., from the Parke-Davis Division of Warner-Lambert Company). Because Alzheimer's disease and related degenerative brain disorders are a major medical issue for an aging population, the need for new treatments and methods for diagnosing the disorders are needed.
We have now discovered that certain 9-acridinone compounds inhibit amyloid aggregation. The acridinone compounds are described as antibacterial and antitumor agents by Capps in U.S. Pat. No. 4,626,540. The compounds are also described as antitumor agents by Cholody, et al., in J. Med. Chem., 1990;33:49-52 and 1992;35:378-382. These references are incorporated herein by reference for their teaching of synthesis.
SUMMARY OF THE INVENTION
This invention provides a method for inhibiting amyloid aggregation in a mammal by administering a 9-acridinone compound. More particularly, the invention is a method for preventing amyloidosis comprising administering to a mammal an effective amount of a compound having the formula ##STR1## wherein:
R.sup.1 and R.sup.2 independently are hydrogen, halo, nitro, amino, hydroxy, trifluoromethyl, C.sub.1 -C.sub.4 alkyl-(O or S).sub.0 or 1, or R.sup.5 R.sup.6 N-alkylene-(O or S).sub.0 or 1 ; hydroxy C.sub.1 -C.sub.4 alkyl, or taken together with the nitrogen to which they are attached are piperidyl or pyrrolidinyl, and the pharmaceutically acceptable salts thereof.
A preferred method for inhibiting amyloid aggregation employs a compound of the above formula wherein R.sup.1 and R.sup.2 independently are hydrogen, hydroxy, C.sub.1 -C.sub.4 alkyl--O--, or C.sub.1 -C.sub.4 alkyl--S--.
Another preferred embodiment employs a compound of the above formula wherein R.sup.4 is --(CH.sub.2).sub.n --NR.sup.5 R.sup.6 ;
The most preferred method of the invention employs compounds of the above formula wherein R.sup.3 is hydrogen.
DETAILED DESCRIPTION OF THE INVENTION
In the above formula, R.sup.1 and R.sup.2 can be "C.sub.1 -C.sub.4 alkyl (O or S).sub.0 or 1 ". This term means a straight or branched alkyl group of up to 4 carbons, optionally bonded through oxygen or sulfur. Typical groups include methyl, methoxy, methylthio, ethoxy, ethylthio, isopropyl, isopropoxy, tert.-butoxy, and the like. R.sup.1 and R.sup.2 can additionally be "R.sup.5 R.sup.6 N-alkylene-(O or S).sub.0 or 1." This term means a C.sub.2 -C.sub.4 straight or branched alkylene group having attached to it an amino, substituted amino, or disubstituted amino group, and optionally bonded through an oxygen or sulfur atom. Examples include 2-aminoethyl, 3-aminopropoxy, 2-amino-1
REFERENCES:
patent: 4626540 (1986-12-01), Capps
Blanz, Jr., et al., A Systematic Investigation of Thioxanthen-9-ones and Analogs as Potential Antitumor Agents, Cancer Inst. vol. 6 (Mar. 1963) pp. 185-191.
Cholody et al., 5-[Aminoalkyl)amino]imidazo[4,5,1-de]acridin-6-ones as a Novel Class of Antineoplastic Agents. Synthesis and Biol. Activity, J. Med. Chem. (1990) vol. 33, pp. 49-52.
Cholody et al., Chromophore-Modified Antineoplastic Imidazoacridinones. Synthesis and and Activity against Murine Leukemias, J. Med. Chem. (1992) vol. 35, pp. 378-382.
Hays Sheryl Jeanne
LeVine, III Harry
Scholten Jeffery David
Ashbrook Charles W.
MacMillan Keith D.
Warner-Lambert & Company
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