Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-01-16
1999-04-06
Weddington, Kevin E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514311, 514 31, 514634, A61K 31535, A61K 3147, A61K 31155, A61K 3170
Patent
active
058918736
DESCRIPTION:
BRIEF SUMMARY
This invention relates to preparations of use in the prophylaxis and treatment of amyloidosis-based diseases, including amyloid encephalopathies such as non-senile dementias, in particular Alzheimer's disease.
Alzheimer's disease is a debilitating and eventually fatal disease of mature adults, typically in middle age. The causative agent is not yet understood, but it has similarities to other dementias, in particular scrapie in sheep and Creutzfeldt-Jakob and Gerstmann-Straussler-Scheinker syndromes and bovine spongiform encephalopathy (BSE). These diseases are characterised by the histopathological features of neural amyloidogenesis. Particular examples are the paired helical filaments that form the neurofibrillar tangles in Alzheimer's brains and the fibrils found in scrapie and other spongiform encephalopathies. These lesions are derived by modification of normal cellular proteins: tau in the case of Alzheimer's and the prion protein (PrP) in the case of the spongiform encephalopathies. The nature of the modification remains unknown, but leads to amyloid plaques, neuronal degeneration and vacuolation, together with astroglial proliferation.
Similarly, there is no known treatment for these diseases although it has been reported (You et al, Nature, 356, 598-601 (1992)) that the onset of scrapie is delayed in the present of the polyene antibiotic amphotericin B.
We have discovered that amphotericin B unexpectedly acts as an inhibitor for the Maillard reaction. Furthermore we have shown that glycation of soluble tau from Alzheimer's brains leads to the formation of amyloid filaments and that the Maillard reaction inhibitor aminoguanidine inhibits this aggregation. The Maillard reaction comprises the well known degradation of proteins in the presence of reductive sugars such as glucose to form glycosylated proteins which are implicated in the complications of diabetes such as cataract, nephropathy, retinopathy and atherosclerosis. Various classes of compounds are known to exhibit an inhibiting effect on the Maillard reaction and hence to be of use in the treatment or prophylaxis of the complications of diabetes and in diseases related to old age. Thus, for example, EP-A-0 433 679 describes 4-hydroxy-5,8-dioxoquinoline derivatives of the following formulae pharmaceutically acceptable salt thereof: ##STR1## wherein R.sub.1 and R.sub.2 are each hydrogen, methyl, trifluoromethyl, carboxy, methoxycarbonyl or ethoxycarbonyl, and R.sub.3 is hydrogen or hydroxy; pharmaceutically acceptable salt thereof: ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 are as defined hereinbefore; (c) a 3-oxophenoxazine derivative of the formula (III) or a pharmaceutically acceptable salt thereof: ##STR3## wherein R.sub.4 and R.sub.5 are each hydrogen or form by incorporation of optionally substituted with a hydroxyl group and/or a carboxyl group, and R.sub.6 is hydrogen or hydroxy; or acceptable salt thereof: ##STR4## wherein R.sub.4, R.sub.5 and R.sub.6 are as defined hereinbefore.
EP-A-0 430 045 similarly discloses ascorbic acid tocopheryl phosphate diesters having Maillard reaction--inhibiting action, namely compounds of the formula: ##STR5## wherein R.sub.1, R.sub.2 and R.sub.3 independently of one another denote hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
Also EP-A-0 325 936 describes aminoguanidine derivatives of the general formula: ##STR6## (wherein, R.sup.1b represents carbocyclic or heterocylic ring substituted or unsubstituted by from 1 to 3 group(s) selected from halogen atom, alkyl or alkoxy group of from 1 to 4 carbon atom(s), nitro group, phenoxy group, amino group, hydroxy group and acylamino group of from 2 to 4 carbon atom(s), X.sub.b represents single-bond, alkylene group of from 1 to 4 carbon atom(s) or alkenylene group of from 2 to 4 carbon atoms, or R.sup.1b together with X.sub.b represents alkyl group of from 1 to 4 carbon atom(s), R.sup.2b represents hydrogen atom, alkyl group of from 1 to 4 carbon atom(s) or phenyl group substituted or unsubstituted by from 1 to 3 group(s) selected from h
REFERENCES:
patent: 5112596 (1992-05-01), Malfroy-Camine
patent: 5202333 (1993-04-01), Berger et al.
patent: 5403861 (1995-04-01), Goldin et al.
patent: 5422360 (1995-06-01), Miyajima et al.
patent: 5453514 (1995-09-01), Niigata et al.
Agrimi, U. et al., Medical Hypotheses, (1993) 40:113-116.
Pocchiari, M. et al., "Amphotericin B: A Novel Class of Antiscrapie Drugs," J Infect Dis (1989) 160(5):795-802.
Brown, P., "A Therapeutic Panorama of the Spongiform Encephalopathies," Antiviral Chem Chemother (1990) 1(2):75-84.
You et al., "Amphotericin B Treatment Dissociates in Vivo Replicatioon of the Scrapie Agent from PrP Acummulation" Nature (1992) 356:598-601.
Colaco Camilo
Roser Bruce Joseph
Murashige Kate H.
Quadrant Holdings Cambridge Limited
Weddington Kevin E.
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