Compounds, Compositions and Methods for the Treatment of Islet Amyloid Polypeptide (IAPP) Accumulation in Diabetes

• US 20090227647A1
• Filed: 03/05/2009
• Published: 09/10/2009
• Est. Priority Date: 03/05/2008
• Status: Abandoned Application

• Current Assignee: Proteotech Inc
• Original Assignee: Proteotech Inc
• Inventors: Snow, Alan D., Lake, Thomas
• Application Number:
  US12/398,420
• Publication Number:
  US 20090227647A1
• Time in Patent Office: Days
• US Class Current: 514/383
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

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.

Claims

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.

2. The method of claim 1 where R is —

C(O)NR′ and

R′

is selected from H or CH₃ or pharmaceutically acceptable salts thereof.

3. The method of claim 2 where R′

is H.

4. The method of claim 2 where the compound is selected from the group consisting of:

2,3 dihydroxybenzoic acid 3,4 dihydroxyanilide;

3,4 dihydroxybenzoic acid 2,3 dihydroxyanilide; and

2,3 dihydroxybenzoic acid 2,3 dihydroxyanilide.

5. The method of claim 2 where R′

is CH₃.

6. The method of claim 2 where the compound is 3,4 dihydroxybenzoic acid 3,4 dihydroxy N-methyl anilide.

7. The method of claim 1 where R is sulfonamide.

8. The method of claim 7 where the sulfonamide is 3,4 dihydroxybenzenesulfonic acid 3,4 dihydroxysulfonamide.

9. The method of claim 1 where R is a five membered heteroaryl.

10. The method of claim 9 where the five membered heteroaryl is selected from the group consisting of imidazole, triazole, and pyrazole.

11. The method of claim 9 where the five membered heteroaryl is selected from the group consisting of:

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.

12. The method of claim 1 where R is tricycloalkyl.

13. The method of claim 12 where the tricycloalkyl is 1,3 bis(3,4 dihydroxyphenyl) adamantane.

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).

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:

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, then R₃ and R₄ are not, or when R₃ and R₄ are in the 3,4-position, then R₁ and R₂ are not.

16. The method of claim 15 where R is —

C(O)NR′ and

R′

is selected from H or CH₃ or pharmaceutically acceptable salts thereof.

17. The method of claim 16 where R′

is H.

18. The method of claim 16 where the compound is selected from the group consisting of:

2,3 dihydroxybenzoic acid 3,4 dihydroxyanilide;

3,4 dihydroxybenzoic acid 2,3 dihydroxyanilide; and

2,3 dihydroxybenzoic acid 2,3 dihydroxyanilide.

19. The method of claim 16 where R′

is CH₃.

20. The method of claim 16 where the compound is 3,4 dihydroxybenzoic acid 3,4 dihydroxy N-methyl anilide.

21. The method of claim 15 where R is sulfonamide.

22. The method of claim 21 where the sulfonamide is 3,4 dihydroxybenzenesulfonic acid 3,4 dihydroxysulfonamide.

23. The method of claim 15 where R is a five membered heteroaryl.

24. The method of claim 23 where the five membered heteroaryl is selected from the group consisting of imidazole, triazole, and pyrazole.

25. The method of claim 23 where the heteroaryl is selected from the group consisting of:

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.

26. The method of claim 15 where R is tricycloalkyl.

27. The method of claim 26 where the tricycloalkyl is 1,3 bis(3,4 dihydroxyphenyl) adamantane.

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).