Method for treating amyloidosis

• US 5,840,294 A
• Filed: 10/13/1995
• Issued: 11/24/1998
• Est. Priority Date: 03/29/1993
• Status: Expired due to Term

• Current Assignee: BHI Limited Partnership
• Original Assignee: Queen's University At Kingston
• Inventors: Szarek, Walter, Kisilevsky, Robert, Weaver, Donald
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US08/542,997
• Time in Patent Office: 1,138 Days
• Field of Search: 424/450, 424/78.31, 424/78.35, 424/423, 424/427, 424/430, 424/434, 424/436, 424/441, 514/772.4, 526/286, 526/287
• US Class Current: 424/78.31
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/255 of sulfoxy acids or sulfur analogues thereof
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/737 Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate A61K31/727 takes precedence
• CPC Class Codes: A61K 31/795 Polymers containing sulfur
• CPC Class Codes: A61K 47/51 the non-active ingredient being a modifying agent
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/555 pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61L 33/08 Polysaccharides
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 11/00 Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof halo-sugars C07H5/02; thio-, seleno-, or telluro-sugars C07H5/08
• CPC Class Codes: C07H 15/04 attached to an oxygen atom of the saccharide radical

Abstract

Therapeutic compounds and methods for inhibiting amyloid deposition in a subject, whatever its clinical setting, are described. Amyloid deposition is inhibited by the administration to a subject of an effective amount of a therapeutic compound comprising an anionic group and a carrier molecule, or a pharmaceutically acceptable salt thereof, such that an interaction between an amyloidogenic protein and a basement membrane constituent is inhibited. Preferred anionic groups are sulfonates and sulfates. Preferred carrier molecules include carbohydrates, polymers, peptides, peptide derivatives, aliphatic groups, alicyclic groups, heterocyclic groups, aromatic groups and combinations thereof.

Claims

1. A method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound, the therapeutic compound comprising at least one sulfonate group covalently attached to a carrier molecule, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the therapeutic compound is administered orally.

3. The method of claim 1, wherein the carrier molecule is selected from the group consisting of a polymer, a peptide, a peptidomimetic, an aliphatic group, an alicyclic group, a heterocyclic group, and combinations thereof.

4. The method of claim 3, wherein the carrier molecule is an aliphatic group.

5. The method of claim 4, wherein the therapeutic compound is selected from the group consisting of ethanesulfonic acid, 1,2-ethanedisulfonic acid, 1-propanesulfonic acid, 1,3-propanedisulfonic acid, 1,4-butanedisulfonic acid, 1,5-pentanedisulfonic acid, 2-aminoethanesulfonic acid, 4-hydroxybutane-1-sulfonic acid, and pharmaceutically acceptable salts thereof.

6. The method of claim 1, wherein the therapeutic compound is selected from the group consisting of 1-butanesulfonic acid, 1-decanesulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid, 4-heptanesulfonic acid, and pharmaceutically acceptable salts thereof.

7. The method of claim 1, wherein the therapeutic compound is 1,7-dihydroxy-4-heptanesulfonic acid, or a pharmaceutically acceptable salt thereof.

16. The method of claim 1, wherein the carrier molecule comprises a targeting moiety.

21. The method of claim 1, wherein the carrier molecule is selected from the group consisting of an aromatic group, a carbohydrate, and combinations thereof.

8. A method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound, the therapeutic compound comprising at least one sulfate group covalently attached to a carrier molecule;

or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the therapeutic compound is administered orally.

10. The method of claim 8, wherein the carrier molecule is selected from the group consisting of a polymer, a peptide, a peptidomimetic, an aliphatic group, an alicyclic group, a heterocyclic group, and combinations thereof.

11. The method of claim 10, wherein the carrier molecule is an aliphatic group.

12. The method of claim 8, wherein the therapeutic compound is selected from the group consisting of 2-hydroxymethyl-1,3-propanediol disulfate, 2-hydroxymethyl-2-methyl-1,3-propanediol disulfate, 1,3-cyclohexanediol disulfate, and pharmaceutically acceptable salts thereof.

13. The method of claim 8, wherein the therapeutic compound is 2,3,4,3'"'"',4'"'"'-sucrose pentasulfate, or a pharmaceutically acceptable salt thereof.

14. The method of claim 8, wherein the therapeutic compound is selected from the group consisting of 2-hydroxyethylsulfamic acid disulfate, 3-hydroxypropylsulfamic acid sulfate, and pharmaceutically acceptable salts thereof.

15. The method of claim 8, wherein the therapeutic compound is selected from the group consisting of 1,3,5,7-heptanetetraol tetrasulfate and 1,3,5,7,9-nonanepentaol pentasulfate, and pharmaceutically acceptable salts thereof.

17. The method of claim 8, wherein the carrier molecule comprises a targeting moiety.

22. The method of claim 8, wherein the carrier molecule is selected from the group consisting of an aromatic group, a carbohydrate, and combinations thereof.

18. A method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound, the therapeutic compound comprising at least one tetrazole group covalently attached to a carrier molecule, or a pharmaceutically acceptable salt thereof.

19. The method of claim 18, wherein the therapeutic compound is selected from the group consisting of 3-(1H-tetrazol-5-yl)-9H-thioxanthen-9-one 10,10-dioxide, 5,5-dithiobis(1-phenyltetrazole), 1H-tetrazole, 5-phenyl-1H-tetrazole, and 5-(2-aminoethanoic acid)-1H-tetrazole, and pharmaceutically acceptable salts thereof.

20. The method of claim 18, wherein the carrier molecule comprises a targeting moiety.

23. A method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound, or a pharmaceutically acceptable salt thereof, such that amyloid deposition is inhibited, the therapeutic compound having the formula:

space="preserve" listing-type="equation">Q-- --Y.sup.- X.sup.+ !.sub.n

wherein Y^- is an anionic group at physiological pH;

Q is a carrier molecule;

X⁺ is a cationic group; and

n is an integer selected such that the biodistribution of the therapeutic compound for an intended target site is not prevented while maintaining activity of the therapeutic compound;

wherein the carrier molecule comprises a targeting moiety.

24. The method of claim 23, wherein the therapeutic compound is administered orally.

25. The method of claim 23 further comprising administering the therapeutic compound in a pharmaceutically acceptable vehicle.

26. The method of claim 23, wherein the carrier molecule is selected from the group consisting of a polymer, a peptide, a peptidomimetic, an aliphatic group, an alicyclic group, a heterocyclic group, and combinations thereof.

27. The method of claim 23, wherein the carrier molecule is selected from the group consisting of an aromatic group, a carbohydrate, and combinations thereof.

28. The method of claim 23, wherein n is an integer between 1 and 10.

29. The method of claim 23, wherein the anionic group is selected from the group consisting of a sulfonate group, a sulfate group, a carboxylate group, a phosphate group, a phosphonate group, ##STR3##

30. The method of claim 23, wherein the targeting moiety targets the therapeutic compound to the brain.

31. The method of claim 23, wherein the targeting moiety comprises an amino acid mimetic.

32. The method of claim 23, wherein the targeting moiety comprises a thyroxine mimetic.

33. The method of claim 23, wherein the targeting moiety allows transport of the therapeutic compound into cells by receptor-mediated endocytosis.

34. A method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a prodrug, or a pharmaceutically acceptable salt thereof, wherein the prodrug is converted in vivo to a therapeutic compound, such that amyloid deposition is inhibited, the therapeutic compound having the formula:

space="preserve" listing-type="equation">Q-- --Y.sup.- X.sup.+ !.sub.n

wherein Y^- is an anionic group at physiological pH;

Q is a carrier molecule;

X⁺ is a cationic group; and

n is an integer selected such that the biodistribution of the therapeutic compound for an intended target site is not prevented while maintaining activity of the therapeutic compound.

35. The method of claim 34, wherein the prodrug is administered orally.

36. The method of claim 34, further comprising administering the prodrug in a pharmaceutically acceptable vehicle.

37. The method of claim 34, wherein the carrier molecule is selected from the group consisting of a polymer, a peptide, a peptidomimetic, a carbohydrate, an aliphatic group, an alicyclic group, a heterocyclic group, and combinations thereof.

38. The method of claim 34, wherein the anionic group is selected from the group consisting of a sulfonate group, a sulfate group, a carboxylate group, a phosphate group, a phosphonate group, ##STR4##

39. The method of claim 34, wherein the prodrug is an ester of a sulfate or a sulfonate.

40. The method of claim 39, wherein the prodrug is a cyclic ester.

41. The method of claim 39, wherein the prodrug is cleaved in vivo reductively or hydrolytically when the prodrug is administered to the subject.

42. The method of claim 34, wherein the carrier molecule comprises a targeting moiety.

43. The method of claim 42, wherein the targeting moiety targets the therapeutic compound to the brain.

44. The method of claim 42, wherein the targeting moiety comprises an amino acid mimetic.

45. The method of claim 42, wherein the targeting moiety comprises a thyroxine mimetic.

46. The method of claim 42, wherein the targeting moiety allows transport of the therapeutic compound into cells by receptor-mediated endocytosis.

47. A pharmaceutical composition for treating amyloidosis comprising a therapeutic compound, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit amyloid deposition in a subject, and a pharmaceutically acceptable vehicle, the therapeutic compound having the formula:

space="preserve" listing-type="equation">Q-- --Y.sup.- X.sup.+ !.sub.n

wherein Y^- is an anionic group at physiological pH;

Q is a carrier molecule;

X⁺ is a cationic group; and

n is an integer selected such that the biodistribution of the therapeutic compound for an intended target site is not prevented while maintaining activity of the therapeutic compound;

wherein the carrier molecule comprises a targeting moiety.

48. The pharmaceutical composition of claim 47, wherein the carrier molecule is selected from the group consisting of a polymer, a peptide, a peptidomimetic, an aliphatic group, an alicyclic group, a heterocyclic group, and combinations thereof.

49. The pharmaceutical composition of claim 47, wherein the carrier molecule is selected from the group consisting of an aromatic group, a carbohydrate, and combinations thereof.

50. The pharmaceutical composition of claim 47, wherein n is an integer between 1 and 10.

51. The pharmaceutical composition of claim 47, wherein the anionic group is selected from the group consisting of a sulfonate group, a sulfate group, a carboxylate group, a phosphate group, a phosphonate group, ##STR5##

52. The pharmaceutical composition of claim 47, wherein the targeting moiety targets the therapeutic compound to the brain.

53. The pharmaceutical composition of claim 47, wherein the targeting moiety comprises an amino acid mimetic.

54. The pharmaceutical composition of claim 47, wherein the targeting moiety comprises a thyroxine mimetic.

55. The pharmaceutical composition of claim 47, wherein the targeting moiety allows transport of the therapeutic compound into cells by receptor-mediated endocytosis.

56. A pharmaceutical composition for inhibiting amyloid deposition in a subject comprising a prodrug, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit amyloid deposition in a subject, wherein the prodrug is converted in vivo to a therapeutic compound, the therapeutic compound having the formula:

space="preserve" listing-type="equation">Q-- --Y.sup.- X.sup.+ !.sub.n

wherein Y^- is an anionic group at physiological pH;

Q is a carrier molecule;

X⁺ is a cationic group; and

n is an integer selected such that the biodistribution of the therapeutic compound for an intended target site is not prevented while maintaining activity of the therapeutic compound;

and a pharmaceutically acceptable vehicle.

57. The pharmaceutical composition of claim 56, wherein the carrier molecule is selected from the group consisting of a polymer, a peptide, a peptidomimetic, a carbohydrate, an aliphatic group, an alicyclic group, a heterocyclic group, and combinations thereof.

58. The pharmaceutical composition of claim 56, wherein the anionic group is selected from the group consisting of a sulfonate group, a sulfate group, a carboxylate group, a phosphate group, a phosphonate group, ##STR6##

59. The pharmaceutical composition of claim 56, wherein the prodrug is an ester of a sulfate or a sulfonate.

60. The pharmaceutical composition of claim 59, wherein the prodrug is a cyclic ester.

61. The pharmaceutical composition of claim 56, wherein the prodrug is cleaved in vivo reductively or hydrolytically when the prodrug is administered to the subject.

62. The pharmaceutical composition of claim 56, wherein the carrier molecule comprises a targeting moiety.

63. The pharmaceutical composition of claim 62, wherein the targeting moiety targets the therapeutic compound to the brain.

64. The pharmaceutical composition of claim 62, wherein the targeting moiety comprises an amino acid mimetic.

65. The pharmaceutical composition of claim 62, wherein the targeting moiety comprises a thyroxine mimetic.

66. The pharmaceutical composition of claim 62, wherein the targeting moiety allows transport of the therapeutic compound into cells by receptor-mediated endocytosis.