Amidine derivatives for treating amyloidosis

• US 20050182118A1
• Filed: 01/23/2004
• Published: 08/18/2005
• Est. Priority Date: 01/23/2004
• Status: Active Grant

• Current Assignee: Bellus Health (Interational) Limited (GSK plc)
• Original Assignee: Neurochem (International) Limited (GSK plc)
• Inventors: Wu, Xinfu, Migneault, David, Kong, Xianqi
• Granted Patent: US 7,262,223 B2
• Time in Patent Office: Days
• US Class Current: 514/400
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/4172 Imidazole-alkanecarboxylic acids, e.g. histidine

Abstract

The present invention relates to the use of amidine compounds in the treatment of amyloid-related diseases. In particular, the invention relates to a method of treating or preventing an amyloid-related disease in a subject comprising administering to the subject a therapeutic amount of an amidine compound. Among the compounds for use according to the invention are those according to the following Formula, such that, when administered, amyloid fibril formation, neurodegeneration, or cellular toxicity is reduced or inhibited:

Claims

1. A method of treating or preventing an amyloid-related disease in a subject comprising administering to a subject a therapeutically effective amount of a compound, wherein said compound is selected from the group consisting of

N-(6-aminoheptyl)-4-bromobenzamidine (compound #145),

4-bromo-N-{7-[(4-bromobenzimidoyl)-amino]-heptyl}-benzamide (compound #146),

N-hydroxy-4-(9-hydroxyaminononyloxy)-benzamidine (compound #147),

N-[7-(4-carbamimidoylbenzoylamino)-heptyl]-terephthalamic acid ethyl ester (compound #148),

N-[9-(4-carbamimidoyl-benzoylamino)-nonyl]-terephthalamic acid ethyl ester (compound #149),

4,4′

-(pentamethylenediamidino)di(p-bromobenzene) (compound #150),

4,4′

-(nonamethylenediamidino)di(p-bromobenzene) (compound #151),

4,4′

-(nonamethylenediamidino)di(p-methoxybenzene) (compound #152),

4-methoxy-N-{2-[2-(4-methoxyphenyl)-4,5-dihydroimidazol-1-yl]-ethyl}-benzamidine (compound #153),

4,4′

-(pentamethylenediamidino)di(p-methoxybenzene) (compound #154),

2,2′

-(p-amidinophenylcarboxamido)-N,N-diethyl-p-amidinobenzamide (compound #155),

{4-[5-(p-aminophenoxy)-pentyloxy]-phenyl}-(4,5-dihydro-1H-imidazol-2-yl)-amine (compound #156),

4,4′

-(nonamethylenedisulfamyl)di(amidinobenzene) (compound #158),

3,3′

-(pentamethylenediaminocarbonyl)di(amidinobenzene) (compound #159),

4,4′

-(tetramethylenediaminocarbonyl)di(amidinobenzene) (compound #160), and

pharmaceutically acceptable salts thereof.

2. The method according to claim 1, wherein said subject is in need of treating or preventing of said amyloid-related disease.

3. The method according to claim 2, wherein said amyloid-related disease is associated with IAPP.

4. The method according to claim 2, wherein said amyloid-related disease is associated with β

-amyloid.

5. The method according to claim 2, wherein said amyloid-related disease is, Alzheimer'"'"'s disease, Down'"'"'s syndrome, type II diabetes, Mild Cognitive Impairment, age-related macular degeneration, or cerebral amyloid angiopathy.

6. The method according to claim 2, wherein said compound is adapted to be administered orally.

7. The method according to claim 2, where said subject is a human.

8. A chemical compound selected from the group consisting of:

23. A pharmaceutical composition comprising a compound according to claim 8.

24. The composition according to claim 23, further comprising a pharmaceutically acceptable vehicle.

25. A pharmaceutical composition for the treatment or prevention of an amyloid-related disease comprising a therapeutically effective amount of a compound according to claim 8.

26. The composition according to claim 25, wherein said amyloid-related disease is Alzheimer'"'"'s disease, Down'"'"'s syndrome, type II diabetes, Mild Cognitive Impairment, age-related macular degeneration, or cerebral amyloid angiopathy.

9-22. -22. (canceled)