Compounds, Compositions and Methods for the Treatment of Islet Amyloid Polypeptide (IAPP) Accumulation in Diabetes
First Claim
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1. A method of treating the formation, deposition, accumulation, or persistence of IAPP amyloid or amylin/IAPP fibrils, comprising treating the fibrils with an effective amount of a compound selected from the group consisting of:
- where R is selected from —
C(O)NR′
, sulfonamide, a five membered heteroaryl , tricycloalkyl or pharmaceutically acceptable esters or salts thereof, and where R′
is selected from H or CH3, and where R1, R2, R3, and R4 are OH, and when R is —
C(O)NR′ and
R′
is H and R1 and R2 are in the 3,4-position, R3 and R4 are not or when R3 and R4 are in the 3,4-position, R1 and R2 are not.
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Abstract
Dihydroxyaryl compounds and pharmaceutically acceptable esters, their synthesis, pharmaceutical compositions containing them, and their use in the treatment of IAPP or amylin fibril diseases, and the manufacture of medicaments for such treatment.
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Citations
28 Claims
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1. A method of treating the formation, deposition, accumulation, or persistence of IAPP amyloid or amylin/IAPP fibrils, comprising treating the fibrils with an effective amount of a compound selected from the group consisting of:
-
where R is selected from —
C(O)NR′
, sulfonamide, a five membered heteroaryl , tricycloalkyl or pharmaceutically acceptable esters or salts thereof, and where R′
is selected from H or CH3, and where R1, R2, R3, and R4 are OH, andwhen R is —
C(O)NR′ and
R′
is H and R1 and R2 are in the 3,4-position, R3 and R4 are not or when R3 and R4 are in the 3,4-position, R1 and R2 are not.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
2,3 dihydroxybenzoic acid 3,4 dihydroxyanilide; 3,4 dihydroxybenzoic acid 2,3 dihydroxyanilide; and 2,3 dihydroxybenzoic acid 2,3 dihydroxyanilide.
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5. The method of claim 2 where R′
- is CH3.
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6. The method of claim 2 where the compound is 3,4 dihydroxybenzoic acid 3,4 dihydroxy N-methyl anilide.
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7. The method of claim 1 where R is sulfonamide.
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8. The method of claim 7 where the sulfonamide is 3,4 dihydroxybenzenesulfonic acid 3,4 dihydroxysulfonamide.
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9. The method of claim 1 where R is a five membered heteroaryl.
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10. The method of claim 9 where the five membered heteroaryl is selected from the group consisting of imidazole, triazole, and pyrazole.
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11. The method of claim 9 where the five membered heteroaryl is selected from the group consisting of:
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2,4 bis(3,4 dihydroxyphenyl) imidazole; 3,5 bis(3,4 dihydroxyphenyl) 1,2,4 triazole ; and 3,5 bis(3,4 dihydroxyphenyl)pyrazole.
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12. The method of claim 1 where R is tricycloalkyl.
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13. The method of claim 12 where the tricycloalkyl is 1,3 bis(3,4 dihydroxyphenyl) adamantane.
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14. The method of claim 1 where the compound is selected from the group consisting of
(1) the compounds that are: -
2,3 dihydroxybenzoic acid 3,4 dihydroxyanilide, 3,4 dihydroxybenzoic acid 2,3 dihydroxyanilide, 2,3 dihydroxybenzoic acid 2,3 dihydroxyanilide, 3,4 dihydroxybenzoic acid 3,4 dihydroxy N-methyl anilide, 3,4 dihydroxybenzenesulfonic acid 3,4 dihydroxysulfonamide, 2,4 bis(3,4 dihydroxyphenyl) imidazole, 3,5 bis(3,4 dihydroxyphenyl) 1,2,4 triazole, 3,5 bis(3,4 dihydroxyphenyl)pyrazole, and 1,3 bis(3,4 dihydroxyphenyl) adamantane; (2) the methylenedioxy analogs and pharmaceutically acceptable esters thereof; and (3) the pharmaceutically acceptable salts of the compounds of (1) and (2).
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15. A method of treating type II diabetes in a mammal suffering therefrom, comprising administration to the mammal of a therapeutically effective amount of a compound selected from the group consisting of:
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where R is selected from —
C(O)NR′
, sulfonamide, a five membered heteroaryl , tricycloalkyl or pharmaceutically acceptable esters or salts thereof, and where R′
is selected from H or CH3, and where R1, R2, R3, and R4 are OH, andwhen R is —
C(O)NR′ and
R′
is H and R1 and R2 are in the 3,4-position, then R3 and R4 are not, or when R3 and R4 are in the 3,4-position, then R1 and R2 are not.- View Dependent Claims (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)
2,3 dihydroxybenzoic acid 3,4 dihydroxyanilide; 3,4 dihydroxybenzoic acid 2,3 dihydroxyanilide; and 2,3 dihydroxybenzoic acid 2,3 dihydroxyanilide.
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19. The method of claim 16 where R′
- is CH3.
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20. The method of claim 16 where the compound is 3,4 dihydroxybenzoic acid 3,4 dihydroxy N-methyl anilide.
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21. The method of claim 15 where R is sulfonamide.
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22. The method of claim 21 where the sulfonamide is 3,4 dihydroxybenzenesulfonic acid 3,4 dihydroxysulfonamide.
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23. The method of claim 15 where R is a five membered heteroaryl.
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24. The method of claim 23 where the five membered heteroaryl is selected from the group consisting of imidazole, triazole, and pyrazole.
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25. The method of claim 23 where the heteroaryl is selected from the group consisting of:
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2,4 bis(3,4 dihydroxyphenyl) imidazole; 3,5 bis(3,4 dihydroxyphenyl) 1,2,4 triazole ; and 3,5 bis(3,4 dihydroxyphenyl)pyrazole.
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26. The method of claim 15 where R is tricycloalkyl.
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27. The method of claim 26 where the tricycloalkyl is 1,3 bis(3,4 dihydroxyphenyl) adamantane.
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28. The method of claim 15 where the compound is selected from the group consisting of
(1) the compounds that are: -
2,3 dihydroxybenzoic acid 3,4 dihydroxyanilide, 3,4 dihydroxybenzoic acid 2,3 dihydroxyanilide, 2,3 dihydroxybenzoic acid 2,3 dihydroxyanilide, 3,4 dihydroxybenzoic acid 3,4 dihydroxy N-methyl anilide, 3,4 dihydroxybenzenesulfonic acid 3,4 dihydroxysulfonamide, 2,4 bis(3,4 dihydroxyphenyl) imidazole, 3,5 bis(3,4 dihydroxyphenyl) 1,2,4 triazole, 3,5 bis(3,4 dihydroxyphenyl)pyrazole, and 1,3 bis(3,4 dihydroxyphenyl) adamantane; (2) the methylenedioxy analogs and pharmaceutically acceptable esters thereof; and (3) the pharmaceutically acceptable salts of the compounds of (1) and (2).
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Specification