Naphthylazo inhibition of amyloidosis

Details Naphthylazo inhibition of amyloidosis Naphthylazo inhibition of amyloidosis

1998-04-29

1999-09-21

Leary, Louise N.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

534573, A01N 4342, C07C24500

Patent

active

059554720

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention concerns a method for inhibiting amyloidosis utilizing naphthylazo 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 fibrinous 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.
WO 9401116 describes the use of congo red, a biphenyl naphthylazo dye, to treat amyloidogenic diseases. We have now discovered that certain naphthylazo compounds inhibit amyloid aggregation for better than congo red. The naphthylazo compounds to be utilized in this invention are described as antiparasitic agents by Elslager, et al., in U.S. Pat. No. 3,218,309, which is incorporated herein by reference for its teaching of synthesis.


SUMMARY OF THE INVENTION

This invention provides a method for inhibiting amyloid aggregation in a mammal by administering a naphthylazo 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, C.sub.1 -C.sub.4 alkyl, hydroxy C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy-C.sub.2 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, or R.sup.1 and R.sup.2 taken together with the nitrogen to which they are attached complete a heterocyclic ring having from 4 to 12 carbon atoms; -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, phenoxy, benzyloxy, hydroxy-C.sub.1 -C.sub.4 alkyl, hydroxy-C.sub.1 -C.sub.4 alkoxy, NR.sup.1 R.sup.2, SO.sub.2 NR.sup.1 R.sup.2, R.sup.1 R.sup.2 N--CH.sub.2 (CH.sub.2).sub.n --(O or NH).sub.m where R.sup.1, R.sup.2, and n are as defined above, and m is 0 or 1, and R.sup.4 and R.sup.5 when attached to adjacent carbon atoms can be ##STR2## R.sup.6 and R.sup.7 independently are hydrogen, hydroxy, halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, or R.sup.1 R.sup.2 N-CH.sub.2 (CH.sub.2).sub.n --(O or NH).sub.m --where R.sup.1, R.sup.2, m, and n are as defined above; and the pharmaceutically acceptable acid addition salts thereof.
In a preferred embodiment, the amyloid aggregation inhibitors utilized have the formula ##STR3## where R.sup.1 and R.sup.2 independently are C.sub.1 -C.sub.4 alkyl and R.sup.4 is hydrogen, halo, SO.sub.2 NH.sub.2, benzyloxy, hydroxy C.sub.1 -C.sub.4 alkyl, NR.sup.1 R.sup.2, or R.sup.1 R.sup.2 N--CH.sub.2 (CH.sub.2).sub.n --(O or NH).sub.m --, and R.sup.4 is hydrogen or C.sub.1 -C.sub.4 alkoxy.
In a further preferred embodiment, the amyloid aggregation inhibitors utilized have the formula ##STR4## where R.sup.4 is hydrogen,

REFERENCES:
patent: 3218309 (1965-11-01), Elslager et al.
International Search Report PCT/US 96/16747.
Eislager et al; CA; vol. 64; p 19509, (1966) month not available.

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