CA2373093A1 - Methods and compounds for inhibiting amyloid deposits - Google Patents

Methods and compounds for inhibiting amyloid deposits Download PDF

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CA2373093A1
CA2373093A1 CA002373093A CA2373093A CA2373093A1 CA 2373093 A1 CA2373093 A1 CA 2373093A1 CA 002373093 A CA002373093 A CA 002373093A CA 2373093 A CA2373093 A CA 2373093A CA 2373093 A1 CA2373093 A1 CA 2373093A1
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acid
iapp
independently
hydrogen
group
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CA2373093C (en
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Walter A. Szarek
Donald F. Weaver
Xianqi Kong
Ajay Gupta
David Migneault
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Bellus Health International Ltd
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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Abstract

Methods and compositions which are useful in the treatment of amyloidosis. I n particular, methods and compositions are provided for inhibiting, preventing and treating amyloid deposition, e.g., in pancreatic islets, wherein the amyloidotic deposits are islet amyloid polypeptide (IAPP)-associated amyloid deposition or deposits. The methods of the invention involve administering t o a subject a therapeutic compound which inhibits IAPP-associated amyloid deposits. Accordingly, the compositions and methods of the invention are useful for inhibiting IAPP-associated amyloidosis in disorders in which such amyloid deposition occurs, such as diabetes.

Claims (37)

1. Use of an LAPP-inhibiting compound of the formula wherein C is carbon, N is nitrogen, l, m, o, p and q are independently 0 or 1; n is an integer from 0 to 3; W is hydrogen or an anionic group at physiological pH; Y is an anionic group at physiological pH; R1 and R2 are independently hydrogen, alkyl, an anionic group at physiological pH, or R1 and R2, taken together with the nitrogen to which they are attached, may form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring; R3 is hydrogen, halogen, thiol or hydroxyl; R4, R5, and R6 are independently hydrogen or halogen; and A is hydrogen or C1 to C6 alkyl; or a pharmaceutically acceptable ester, acid or salt thereof; in the preparation of a medicament for treating a disease state characterized by IAPP-associated amyloid deposits; provided that said compound is not 2-hydmxyethylsulfamic acid sulfate, disodium salt; 3-hydroxypropylsulfamic acid sulfate, disodium salt; or N,N bis(2-hydroxyethyl)sulfamic acid disulfate, disodium salt.
2. The use according to claim 1, wherein said compound is selected from the group consisting of the compounds depicted in FIGs 10-14, and pharmaceutically acceptable esters, acids or salts thereof.
3. Use of an IAPP-inhibiting compound of the formula wherein A1, A2, A3, A4, A5 and A6 are independently alkyl, O, S, or -NH; m and n (for each individual A group) are independently 0 or 1; l, p and q are independently 0, 1, or 2; R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, alkyl, alicyclyl, heterocyclyl or aryl, and adjacent R groups may form an unsubstituted or substituted cyclic or heterocyclic ring; in the preparation of a medicament for treating a disease state characterized by IAPP-associated amyloid deposits.
4. The use according to claim 3, wherein said compound is selected from the group consisting of 1,2,3,4-tetrahydroisoquinoline, and the compounds depicted in FIGs 1-9.
5. The use according to either claim 1 or 3, wherein said IAPP-associated amyloid deposits occur in pancreatic islets.
6. The use according to either claim 1 or 3, such that IAPP fibrillogenesis is inhibited.
7. The use according to either claim 1 or 3, such that said IAPP-associated amyloid deposits are inhibited.
8. Use of an IAPP-inhibiting compound of the formula wherein C is carbon, N is nitrogen, l, m, o, p and q are independently 0 or 1; n is an integer from 0 to 3; W is hydrogen or an anionic group at physiological pH; Y is an anionic group at physiological pH; R1 and R2 are independently hydrogen, C1 to C4 alkyl, an anionic, group at physiological pH, or R1 and R2, taken together with the nitrogen to which they are attached, may form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring; R3 is hydrogen, halogen, thiol or hydroxyl; R4, R5, and R6 are independently hydrogen or halogen; and A is hydrogen or C1 to C6 alkyl; or a pharmaceutically acceptable ester, acid or salt thereof; in the preparation of a medicament for reducing IAPP-associated amyloid deposits; provided that said compound is not 2-hydroxyethylsulfamic acid sulfate, disodium salt; 3-hydroxypropylsulfamic acid sulfate, disodium salt; or N,N-bis(2-hydroxyethyl)sulfamic acid disulfate, disodium salt.
9. The use according to claim 8, wherein said IAPP inhibiting compound is selected from the group consisting of the compounds depicted in FIGs 10-14, and pharmaceutically acceptable esters, acids or salts thereof
10. Use of an IAPP-inhibiting compound of the formula wherein A1, A2, A3, A4, A5 and A6 are independently alkyl, O, S, or -NH; m and n (for each individual A group) are independently 0 or 1;1, p and q are independently 0, 1, or 2; R7, R8, R9, R10, R11, R12,R13, and R14 are independently hydrogen, alkyl, alicyclyl, heterocyclyl or aryl, and adjacent R groups may form an unsubstituted or substituted cyclic or heterocyclic ring; in the preparation of a medicament for reducing IAPP-associated amyloid deposits.
11. The use according to claim 10, wherein said compound is selected from the group consisting of the compounds depicted is FIGs 1-9.
12. The use according to any of claims 8 or 10, wherein said subject has IAPP-associated amyloid deposits in pancreatic islets.
13. Use of an IAPP-inhibiting compound of the formula whereon C is carbon, N is nitrogen, l, m, o, p and q are independently 0 or l; n is an integer from 0 to 3; W is hydrogen or an anionic group at physiological pH; Y is an anionic group at physiological pH; R1 and R2 are independently hydrogen, C1 to C4 alkyl, an anionic group at physiological pH, or R1 and R2, taken together with the nitrogen to which they are attached, may form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring; R3 is hydrogen, halogen, thiol or hydroxyl; R4, R5, and R6 are independently hydrogen or halogen; and A is hydrogen or C1 to C6 alkyl; or a pharmaceutically acceptable ester, acid or salt thereof, in the preparation of a medicament for inhibiting IAPP-associated amyloid deposits; provided that said compound is not 2-hydroxyethylsulfamic acid sulfate, disodium salt; 3-hydroxypropylsulfamic acid sulfate, disodium salt; or N,N bis(2-hydroxyethyl)sulfamic acid disulfate, disodium salt.
14. The use according to 13, wherein said IAPP inhibiting compound is selected from the group consisting of the compounds depicted in FIGs 10-14, and pharmaceutically acceptable esters, acids or salts thereof.
15. Use of an IAPP-inhibiting compound of the formula wherein A1, A2, A3, A4, A5 and A6 are independently alkyl, O, S, or -NH; m and n (for each individual A group) are independently 0 or 1;1, p and q are independently 0,1, or 2; R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, alkyl, alicyclyl, heterocyclyl or aryl, and adjacent R groups may form an unsubstituted or substituted cyclic or heterocyclic ring, in the preparation of a medicament for inhibiting IAPP-associated amyloid deposits,
16. The use according to claim 15 wherein said compound is selected from the group consisting of the compounds depicted in FIGS 1-9.
17. Use of an IAPP-inhibiting compound in treating a disease state characterized by IAPP-associated amyloid deposits of the formula wherein C is carbon, N is nitrogen, l, m, o, p and q are independently 0 or l; n is an integer from 0 to 3; W is hydrogen or as anionic group at physiological pH; Y is an anionic group at physiological pH; R1 and R2 are independently hydrogen, alkyl, an anionic group at physiological pH, ar R1 and R2, taken together with the nitrogen to which they are attached, may form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring; R3 is hydrogen, halogen, thiol or hydroxyl; R4, R5, and R6 are independently hydrogen or halogen; and A is hydrogen or C1 to C6 alkyl; or a pharmaceutically acceptable ester, acid or salt thereof;
provided that said compound is not 2-hydroxyethylsulfamic acid sulfate, disodium salt; 3-hydroxypropylsulfamic acid sulfate, disodium salt; or N,N-bis(2-hydroxyethyl)sulfamic acid disulfate, disodium salt.
18. The use according to claim 17, wherein said compound is selected from the group consisting of the compounds depicted in FIGs 10-14, and pharmaceutically acceptable esters, acids or salts thereof.
19. Use of an IAPP-inhibiting compound in treating a disease state characterized by IAPP-associated amyloid deposits of the formula wherein A1, A2, A3, A4, A5 and A6 are independently alkyl, O, S, or -NH; m and n (for each individual A group) are independently 0 or 1;l, p and q are independently 0, 1, or 2; R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, alkyl, alicyclyl, heterocyclyl or aryl, and adjacent R groups may form as unsubstituted or substituted cyclic or heterocyclic ring.
20. The use according to claim 19, wherein said compound is selected from the group consisting of 1,2,3,4-tetrahydroisoquinoline, and the compounds depicted in FIGS 1-9.
21. The use according to either claim 17 or 19, wherein said IAPP-associated amyloid deposits occur in pancreatic islets.
22. The use according to either claim 17 or 19, such that IAPP fibrillogenesis is inhibited.
23. The use according to either claim 17 or19, such that said IAPP-associated amyloid deposits are inhibited
24. Use of an IAPP-inhibiting compound in reducing IAPP-associated amyloid deposits of the formula wherein C is carbon, N is nitrogen, l, m, o, p and q are independently 0 or 1; n is an integer from 4 to 3; W is hydrogen or an anionic group at physiological pH; Y is an anionic group at physiological pH; R1 and R2 are independently hydrogen, C1 to C4 alkyl, an anionic group at physiological pH, or R1 and R2, taken together with the nitrogen to which they are attached, may form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring, R3 is hydrogen, halogen, thiol or hydroxyl; R4, R5, and R6 are independently hydrogen or halogen; and A is hydrogen or C1 to C6 alkyl; or a pharmaceutically acceptable ester, acid or salt thereof; provided that said compound is not 2-hydroxyethylsulfamic acid sulfate, disodium salt; 3-hydroxypropylsulfamic acid sulfate, disodium salt; or N,N-bis(2-hydroxyethyl)sulfamic acid disulfate, disodium salt.
25. The use according to claim 24, wherein said IAPP inhibiting compound is selected from the group consisting of the compounds depicted in FIGs 10-14, and pharmaceutically acceptable esters, acids or salts thereof,
26. Use of an IAPP-inhibiting compound in reducing IAPP-associated amyloid deposits of the formula wherein A1, A2, A3, A4, A5 and A6 are independently alkyl, O, S, or -NH; m and n (for each individual A group) are independently 0 or 1;l, p and q are indcpeadently 0, 1, or 2; R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, alkyl, alicyclyl, heterocyclyl or aryl, and adjacent R groups may form an unsubstituted or substituted cyclic or heterocyclic ring.
27. The use according to claim 26, wherein said compound is selected from the group consisting of the compounds depicted in FIGS 1-9.
28, The use according to claim 23, wherein. said subject has IAPP-associated amyloid deposits in pancreatic islets.
29. Use of an IAPP-inhibiting compound in inhibiting IAPP-associated amyloid deposits of the formula wherein C is carbon, N is nitrogen, l, m, o, p and q are independently 0 or 1; n is an integer from 0 to 3; W is hydrogen or an anionic group at physiological pH; Y is an anionic group at physiological pH; R1 and R2 are independently hydrogen, C1 to C4 alkyl; an anionic group at physiological ,pH, or R1 and R2, taken together with the nitrogen to which they are attached, may form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring; R3 is hydrogen, halogen, thiol or hydroxyl; R4, R5, and R6 are independently hydrogen or halogen; and A is hydrogen or C1 to C6 alkyl; or a pharmaceutically acceptable ester, acid or salt thereof; provided that said compound is not 2-hydroxyethylsulfamic acid sulfate, disodium salt; 3-hydroxypropylsulfamic acid sulfate, disodium salt; or N,N-bis(2-hydroxyethyl)sulfamic acid disulfate, disodium salt.
30. The use according to 29, wherein said IAPP inhibiting compound is selected from the group consisting of the compounds depicted in FIGs 10-14, and pharmaceutically acceptable esters, acids or salts thereof.
31. Use of an IAPP-inhibiting compound in inhibiting IAPP-associated amyloid deposits of the formula wherein A1, A2, A3, A4, A5 and A6 are independently alkyl, O, S, or -NH; m and n (for each individual A group) are independently 0 or 1;l, p and q are independently 0, 1, or 2; R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, alkyl, alicyclyl, heterocyclyl or aryl, and adjacent R groups may form an unsubstituted or substituted cyclic or heterocyclic ring.
32. The use according to claim 31, wherein said compound is selected from the group consisting of the compounds depicted in FIGs 1-9.
33. The use according to any of claims 1, 8, 13, 17, 24, or 29, wherein said compound is selected from 8-hydroxy-5-quinolinesulfonic acid; 8 hydroxy-7-iodo-5-quinolinesulfonic acid; 5-Chloro-8-quinolylmethylsulfonic acid, sodium salt; 5,8-Dibromo-6-quinolylmethylsulfonic acid, sodium salt; 8-Ethoxy 5-quinolinesulfonic acid, sodium salt; 5-Chloro-6-quinolylmethylsulfonic acid, sodium salt; Quinoline yellow; 5-Bromo-6-quinolylmethylsulfonic acid, sodium salt; 7-Bromo-8-hydroxy-5-quinolinesulfonic acid; 7-Chloro- 8-hydroxy-5-quinolinesulfonic acid; 5-Chloro-8-hydroxy-7-quinolinesulfonic acid; 5-Bromo-8-hydroxy-7-quinolinesulfonic acid; 8-hydroxy-2-methyl-5-quinolinesulfonic acid; 8-hydroxy-2-methyl-5,7-quinolinedisulfonic acid; 5-Chloro-8-hydroxy-2-methyl-7-quinolinesulfonic acid; 5-Bromo-8-hydroxy-2-methyl-7-quinolinesulfonic acid; 2,6-Quinolyldimethyldisulfonic acid, disodium salt;
5-Chloro-2,6-quinolyldimethyldisulfonic acid, disodium salt; 8-methoxy-5-quinolinesulfonic acid, sodium salt; 8-Methoxy-5-[N-(2-N',N'-diethylethylamino)]quinolinesulfonamide; 8-Methoxy-5-[N-(2-N',N'-indolineethylamino)]quinolinesulfonamide; Cyclohexylsulfamic acid, sodium salt; 3-[2-(1,2,3,4,5,6,7,8-Octahydroisoquinolinyl)]-1-propanesulfonic acid; 4-[2-(1,2,3,4,5,6,7,8-Octahydxoisoquinolinyl)]-1-butanesulfonic acid; Hexafluoroglutaric acid; 3,3-bis(trifluoromethyl)-2,2,4,4.tetrafluoro-1,5-pentanedioic acid; 2,2,3,3-tetrafluoro-1,4-butanedioic acid; 2,2,4,4; tetrafluoro-1,5-pentanedioic acid; hexafluoro-1,3-propanedisulfinic acid; 2,2-difluoro-1,3 propanedioic acid; or 3-hydroxyl-2,2,4,4,4 pentafluoro-3-phenylbutanoic acid.
34. The use according to any of claims 1, 8, 13,17, 24, or 29, wherein R1 and R2, taken together with the nitrogen to which they are attached, form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring,
35. The use according to any of claims 1, 8, 13, 17, 24, or 29, wherein at least one of R4, R5, or R6 is fluorine.
36. The use according to any of claims 1, 8, 13, 17, 24, or 29, wherein each of R1 and R2 is independently a substituted or unsubstituted alkyl group or a hydrogen, each of R3, R4, R5, and R6, if present, is hydrogen, and Y = -SO3H.
37. The use according to claim 36 wherein said substituted alkyl group is substituted with a hydroxyl group.
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US6562836B1 (en) 2003-05-13
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US20080227767A1 (en) 2008-09-18

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