Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer's disease, type 2 diabetes and parkinson's disease
View Patent ↗Bis- and tris-dihydroxyaryl compounds and their methylenedioxy analogs and pharmaceutically acceptable esters, their synthesis, pharmaceutical compositions containing them, and their use in the treatment of amyloid diseases, especially Aβ amyloidosis, such as observed in Alzheimer's disease, IAPP amyloidosis, such as observed in type 2 diabetes, and synucleinopathies, such as observed in Parkinson's disease, and the manufacture of medicaments for such treatment.
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, where:
R is a C 4 -C 10 alkylene group, in which:
a) there are optionally 1 or 2 non-adjacent double bonds;
b) 2 non-adjacent methylene groups are replaced by NR′, where R′ is H or alkyl; and
c) 2 methylene groups not adjacent to the benzene ring are replaced by a carbonyl group.
2. The compound of claim 1 selected from:
or a pharmaceutically acceptable salt thereof.
3. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
4. A method of treating the formation, deposition, accumulation, or persistence of amyloid fibrils, comprising treating the fibrils with an effective amount of the compound of claim 1 .
5. The method of claim 4 , wherein the amyloid fibrils are Aβamyloid fibrils.
6. The method of claim 4 , wherein the amyloid fibrils are IAPP amyloid fibrils.
7. A method of treating the formation, deposition, accumulation, or persistence of synuclein fibrils, comprising treating the fibrils with an effective amount of the compound of claim 1 .
8. The method of claim 7 , wherein the synuclein fibrils are α- synuclein fibrils.
9. A method of inhibiting and/or relieving an amyloid disease or a synucleinopathy in a mammal suffering therefrom, comprising administration to the mammal of a therapeutically effective amount of the compound of claim 1 .
10. The method of claim 9 , wherein the amyloid disease is a disease associated with the formation, deposition, accumulation, or persistence of an amyloid protein selected from the group consisting of Aβ amyloid, AA amyloid, AL amyloid, IAPP amyloid, PrP amyloid, β 2 -microglobulin amyloid, transthyretin, prealbumin, and procalcitonin.
11. The method of claim 9 , wherein the amyloid disease is a disease associated with the formation, deposition, accumulation, or persistence of Aβamyloid.
12. The method of claim 9 , wherein the amyloid disease is a disease associated with the formation, deposition, accumulation, or persistence of IAPP amyloid.
13. The method of claim 9 , wherein the amyloid disease is selected from the group of diseases consisting of Alzheimer's disease, Down's syndrome, dementia pugilistica, multiple system atrophy, inclusion body myositosis, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, Nieman-Pick disease type C, cerebral β-amyloid angiopathy, dementia associated with cortical basal degeneration, the amyloidosis of type 2 diabetes, the amyloidosis of chronic inflammation, the amyloidosis of malignancy and Familial Mediterranean Fever, the amyloidosis of multiple myeloma and B-cell dyscrasias, the amyloidosis of the prion diseases, Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome, kuru, scrapie, the amyloidosis associated with carpal tunnel syndrome, senile cardiac amyloidosis, familial amyloidotic polyneuropathy, and the amyloidosis associated with endocrine tumors.
14. The method of claim 13 , wherein the amyloid disease is Alzheimer's disease.
15. The method of claim 9 , wherein the synucleinopathy is a disease associated with the formation, deposition, accumulation, or persistence of synuclein fibrils.
16. The method of claim 9 , wherein the synucleinopathy is a disease associated with the formation, deposition, accumulation, or persistence of α- synudein fibrils.
17. The method of claim 9 , wherein the synucleinopathy is selected from the group of diseases consisting of Parkinson's disease, familial Parkinson's disease, Lewy body disease, the Lewy body variant of Alzheimer's disease, dementia with Lewy bodies, multiple system atrophy, and the Parkinsonism-dementia complex of Guam.
18. The method of claim 17 , wherein the synucleinopathy is Parkinson's disease.
19. The method of claim 9 , wherein the mammal is a human.
20. The method of claim 9 , wherein the amount of the compound administered is between 0.1 mg/Kg/day and 1000 mg/Kg/day.
21. The method of claim 20 , wherein the amount of compound administered is between 1 mg/Kg/day and 100 mg/Kg/day.
22. The method of claim 21 , wherein the amount of compound administered is between 10 mg/Kg/day and 100 mg/Kg/day.