Methods and compositions for treating amyloid-related diseases

• US 20060223855A1
• Filed: 12/21/2005
• Published: 10/05/2006
• Est. Priority Date: 12/22/2004
• Status: Active Grant

• Current Assignee: BHI Limited Partnership
• Original Assignee: Neurochem (International) Limited
• Inventors: Wu, Xinfu, Migneault, David, Delorme, Daniel, Kong, Xianqi, Samim, Bita, Bouzide, Abderrahim, Bachand, Benoit, Gervais, Francine, Atfani, Mohamed, Valade, Isabelle, Levesque, Sophie
• Granted Patent: US 8,044,100 B2
• Time in Patent Office: Days
• US Class Current: 514/315
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• 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 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/18 with a ring being at least seven-membered
• CPC Class Codes: C07C 2602/08 the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 2602/42 : the bicyclo ring system containing seven carbon atoms
• CPC Class Codes: C07C 2603/74 : Adamantanes
• CPC Class Codes: C07C 309/14 : containing amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 309/19 : of a saturated carbon skeleton containing rings
• CPC Class Codes: C07C 309/21 : containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
• CPC Class Codes: C07C 309/24 : of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 309/26 : containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
• CPC Class Codes: C07D 207/12 : Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/333 : Radicals substituted by oxygen or sulfur atoms
• CPC Class Codes: C07D 209/08 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/16 : Tryptamines
• CPC Class Codes: C07D 209/36 : in position 3, e.g. adrenochrome
• CPC Class Codes: C07D 209/44 : Iso-indoles; Hydrogenated iso-indoles
• CPC Class Codes: C07D 209/48 : with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 209/86 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
• CPC Class Codes: C07D 211/06 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 211/14 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/18 : with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 211/34 : with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/48 : having an acyclic carbon atom attached in position 4
• CPC Class Codes: C07D 211/52 : having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 211/58 : attached in position 4
• CPC Class Codes: C07D 211/64 : having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 211/70 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 211/82 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 213/04 : having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 213/20 : Quaternary compounds thereof
• CPC Class Codes: C07D 213/50 : Ketonic radicals
• CPC Class Codes: C07D 213/75 : Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 217/04 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 219/10 : attached in position 9
• CPC Class Codes: C07D 231/44 : Oxygen and nitrogen or sulfur and nitrogen atoms
• CPC Class Codes: C07D 233/54 : having two double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 235/28 : Sulfur atoms
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 275/06 : with hetero atoms directly attached to the ring sulfur atom
• CPC Class Codes: C07D 277/66 : with aromatic rings or ring systems directly attached in position 2
• CPC Class Codes: C07D 295/073 : with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/088 : to an acyclic saturated chain
• CPC Class Codes: C07D 307/14 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 317/58 : Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 327/04 : Five-membered rings
• CPC Class Codes: C07D 327/06 : Six-membered rings
• CPC Class Codes: C07D 327/08 : [b,e]-condensed with two six-membered carbocyclic rings
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 333/34 : Sulfur atoms
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/08 : Bridged systems
• CPC Class Codes: C07K 5/06 : Dipeptides

Abstract

Methods, compounds, pharmaceutical compositions and kits are described for treating or preventing amyloid-related disease.

Claims

1. A compound of the formula (VIII):

63. A kit for use in treating amyloid related disease comprising a compound of claim 1 and instructions for use in the method of the instant invention.

64. A method of treating or preventing an amyloid-related disease in a subject comprising administering to a subject in need thereof a compound of claim 1, Table 2A, or Table 2B in an amount effective to treat or prevent an amyloid related disease.

65. The method according to claim 64, wherein said amyloid-related disease is Alzheimer'"'"'s disease, cerebral amyloid angiopathy, inclusion body myositis, macular degeneration, MCI, or Down'"'"'s syndrome.

67. The method according to claim 64, wherein amyloid fibril formation or deposition, neurodegeneration, cellular toxicity, or microglial inflammatory response, is reduced or inhibited upon administration of said compound.

68. The method according to claim 64, wherein said amyloid-related disease is diabetes, AA amyloidosis, AL amyloidosis, or hemodialysis related amyloidosis (β

₂M).

70. The method of claim 64, wherein said subject has Alzheimer'"'"'s disease, Mild Cognitive Impairment, or cerebral amyloid angiopathy, and stabilization of cognitive function, prevention of a further decrease in cognitive function, or prevention, slowing, or stopping of disease progression occurs in said patient upon administration.

76. A method for inhibiting amyloid deposition in a subject comprising administering to a subject an effective amount of a therapeutic compound of claim 1, Table 2A, Table 2B, or a pharmaceutically acceptable salt thereof, such that amyloid deposition is inhibited.

83. A method for reducing amyloid deposits in a subject having amyloid deposits, the method comprising administering to a subject an effective amount of a compound of claim 1, Table 2A, Table 2B, or a pharmaceutically acceptable salt thereof, such that amyloid deposits are reduced in the subject.

85. The use of a compound according to claim 64, in the preparation of a medicament for the treatment or prevention of an amyloid-related disease.

86. A pharmaceutical composition for the treatment or prevention of an amyloid-related disease comprising a compound according to claim 1, Table 2A, or Table 2B.

87. A pharmaceutical composition comprising a compound according to claim 1, Table 2A, or Table 2B.

88. A pharmaceutical composition for treating amyloidosis comprising a compound of claim 1, Table 2A, Table 2B, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit amyloid deposition in a subject.

182. A method for inhibiting amyloid deposition in a subject comprising contacting a body fluid with a compound of claim 1, Table 2A, Table 2B, or a pharmaceutically acceptable salt thereof, and administering said body fluid to said subject, such that amyloid deposition in said subject is inhibited.

194. A method for preventing, slowing, or stopping disease progression comprising administering to a subject an effective amount of a compound of claim 1, Table 2A, or Table 2B, such that said disease progression is prevented slowed, or stopped.

196. A method for treating a subject for an amyloid-related disease, comprising:

administering a cognitive test to a subject prior to administration of a compound of claim 1, Table 2A, or Table 2B;

administering an effective amount of the compound to the subject, and administering a cognitive test to the subject subsequent to administration of said compound, such that said subject is treated for said amyloid-related disease, wherein the subject'"'"'s score on said cognitive test is improved.

205. A method for reducing or preventing the deposition of amyloid protein, comprising administering to a subject in need thereof a compound of claim 1, Table 2A, or Table 2B, wherein said amyloid protein is AA amyloid protein, AL amyloid protein, amyloid λ

, amyloid κ

, amyloid κ

IV, amyloid γ

, or amyloid γ

1.

206. A method for reducing the rate of change of organ function due to amyloid deposition, comprising administering to a subject in need thereof a compound of claim 1, Table 2A, or Table 2B, such that the rate of change of organ function to amyloid deposition is reduced.

207. A method for inhibiting fibril formation, comprising administering to a subject an effective amount of a compound of claim 1, Table 2A, or Table 2B, wherein said effective amount is effective to inhibit protein-protein interactions, such that fibril formation is inhibited.

208. A method for treating CAA or hereditary cerebral hemorrhage, comprising administering an effective amount of a compound of claim 1, Table 2A, or Table 2B, wherein said effective amount is effective to prevent or decrease the recurrence of hemorrhagic stroke.

209. A method for inhibiting amyloid deposition in a subject comprising administering to a subject an effective amount of a therapeutic compound of claim 1, Table 2A, Table 2B, or a pharmaceutically acceptable salt thereof, such that said therapeutic compound inhibits a protein-protein interaction between amyloidogenic proteins.

210. A method for inhibiting amyloid fibril formation, comprising administering to a subject an effective amount of a therapeutic compound of claim 1, Table 2A, Table 2B, or a pharmaceutically acceptable salt thereof, such that clearance or catabolism of the amyloid protein is increased or the amyloid concentration is reduced.

216. A method of treating Alzheimer'"'"'s Disease in a subject, comprising administering to a subject in need thereof a compound of claim 1, Table 2A, or Table 2B in an amount effective to treat Alzheimer'"'"'s Disease.

217. A method of treating Mild Cognitive Impairment in a subject, comprising administering to a subject in need thereof a compound of claim 1, Table 2A, or Table 2B in an amount effective to treat Mild Cognitive Impairment.

218. A method of treating neurotoxicity associated with Aβ

amyloid in a subject, comprising administering to a subject in need thereof a compound of claim 1, Table 2A, or Table 2B in an amount effective to treat neurotoxicity associated with Aβ

amyloid.

220. A method for providing neuroprotection to a subject having an Aβ

-amyloid related disease, comprising administering to a subject in need thereof a compound of claim 1, Table 2A, or Table 2B in an amount effective to provide neuroprotection.

2-16. -16. (canceled)

17. A compound of the formula (IX):

18-22. -22. (canceled)

23. A compound of the formula (X):

24-34. -34. (canceled)

35. A compound of the formula (XI):

36-42. -42. (canceled)

43. A compound of the formula (XII):

44-53. -53. (canceled)

54. A compound of the formula (XIII):

55-57. -57. (canceled)

58. A compound of the formula (XIV):

59. (canceled)

60. A compound of the formula (XV):

61. (canceled)

62. A compound of Table 3A or Table 3B, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

69. (canceled)

71-75. -75. (canceled)

77-82. -82. (canceled)

84. (canceled)

89-181. -181. (canceled)

183-193. -193. (canceled)

195. (canceled)

197-204. -204. (canceled)

211-215. -215. (canceled)

219. A pharmaceutical composition comprising a compound selected from the group consisting of the compounds in Tables 3A and 3B and a pharmaceutically acceptable carrier.