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

{
  "publication_number": "US2013012555A1",
  "country": "US",
  "kind": "A1",
  "title": "Compounds, Compositions and Methods for the Treatment of Islet Amyloid Polypeptide (IAPP) Accumulation in Diabetes",
  "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 sulfonamide, a five membered heteroaryl, tricycloalkyl or pharmaceutically acceptable esters or salts thereof, and where R 1, R 2, R 3, and R 4 are OH, 2. The method of claim 1 where R is sulfonamide. 3. The method of claim 1 where the sulfonamide is 3,4 dihydroxybenzenesulfonic acid 3,4 dihydroxysulfonamide. 4. The method of claim 1 where R is a five membered heteroaryl. 5. The method of claim 1 where the five membered heteroaryl is selected from the group consisting of imidazole, triazole, and pyrazole. 6. The method of claim 1 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. 7. The method of claim 1 where R is tricycloalkyl. 8. The method of claim 1 where the tricycloalkyl is 1,3 bis(3,4-dihydroxyphenyl)adamantane. 9. The method of claim 1 where the compound is selected from the group consisting of (1) the compounds that are: 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). 10. 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 sulfonamide, a five membered heteroaryl, tricycloalkyl or pharmaceutically acceptable esters or salts thereof, and where R 1, R 2, R 3, and R 4 are OH. 11. The method of claim 10 where R is sulfonamide. 12. The method of claim 10 where the sulfonamide is 3,4 dihydroxybenzenesulfonic acid 3,4 dihydroxysulfonamide. 13. The method of claim 10 where R is a five membered heteroaryl. 14. The method of claim 10 where the five membered heteroaryl is selected from the group consisting of imidazole, triazole, and pyrazole. 15. The method of claim 10 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. 16. The method of claim 10 where R is tricycloalkyl. 17. The method of claim 10 where the tricycloalkyl is 1,3 bis(3,4 dihydroxyphenyl)adamantane. 18. The method of claim 10 where the compound is selected from the group consisting of (1) the compounds that are: 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)."
  ],
  "description_excerpt": "This invention relates to bis-dihydroxyaryl compounds and pharmaceutically acceptable salts, their synthesis, pharmaceutical compositions containing them, and their use in the treatment of islet amyloid polypeptide (IAPP) amyloid disease, such as observed in type 2 diabetes, and in the manufacture of medicaments for such treatment.\n\nA variety of human diseases demonstrate amyloid deposition and often involve systemic organs (i.e. organs or tissues lying outside the central nervous system), with the amyloid accumulation leading to organ dysfunction or failure. In these amyloid diseases, a single organ may be affected such as the pancreas in 90% of patients with type 2 diabetes. In this type of amyloid disease, the beta-cells in the islets of Langerhans in pancreas are believed to be destroyed by the accumulation of fibrillar amyloid deposits consisting primarily of a protein known as islet amyloid polypeptide (IAPP) or amylin. Specifically the islet is depleted in beta-cell mass due to beta-cell apoptosis and islet amyloid. In vitro studies have shown that amyloidogenic human IAPP is toxic to cultured beta-cells (Lorenzo, A., et al., Nature 368:756-760, 1994). In monkey's islet amyloid deposition has been temporally correlated with the onset of hyperglycemia (Howard, C. F. Diabetologia 29:301-306, 1986). A transgenic mouse model is available with increased human IAPP transgene expression which leads to beta-cell apoptosis and diabetes in the model animal (Matveyenkp A V and Butler P C. ILAR J. 47(3):225-233, 2006).",
  "cpc": [
    "A61K 31/18",
    "A61K 31/05",
    "A61K 31/167",
    "A61K 31/415",
    "A61K 31/4164",
    "A61K 31/4196",
    "A61P 3/10"
  ],
  "ipc": [
    "A61K 31/05",
    "A61K 31/18",
    "A61K 31/4155",
    "A61K 31/4164",
    "A61K 31/4196",
    "A61P 3/10",
    "A61K 31/415"
  ],
  "inventors": [
    "Thomas Lake",
    "Alan D. Snow"
  ],
  "filing_date": "2012-01-12",
  "publication_date": "2013-01-10",
  "priority_date": "2008-03-05",
  "application_number": "US-201213348945-A",
  "family_id": "41054309",
  "cited_by_count": 2
}