METHODS AND COMPOSITIONS FOR TREATING AMYLOID-RELATED DISEASES

• US 20100113591A1
• Filed: 11/05/2009
• Published: 05/06/2010
• Est. Priority Date: 06/23/2003
• Status: Active Grant

• Current Assignee: BHI Limited Partnership
• Original Assignee: Bellus Health (Interational) Limited (GSK plc)
• Inventors: Wu, Xinfu, Migneault, David, Kong, Xianqi, Gervais, Francine, Valade, Isabelle
• Granted Patent: US 8,642,801 B2
• Time in Patent Office: Days
• US Class Current: 514/487
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 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 2601/10 the ring being unsaturated
• 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 307/02 Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
• CPC Class Codes: C07C 309/13 containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
• CPC Class Codes: C07C 309/14 containing amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 309/15 the nitrogen atom of at least one of the amino groups being part of any of the groups , X being a hetero atom, Y being any atom
• CPC Class Codes: C07C 309/19 of a saturated carbon skeleton containing rings
• CPC Class Codes: C07C 309/23 of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings
• CPC Class Codes: C07C 309/46 having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
• CPC Class Codes: C07C 309/69 : of a carbon skeleton substituted by nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07C 311/32 : of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 311/46 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 323/25 : the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07C 323/58 : with amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 335/12 : the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 335/32 : having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
• CPC Class Codes: C07C 381/02 : Thiosulfates
• 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 209/14 : Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 209/18 : 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 209/20 : substituted additionally by nitrogen atoms, e.g. tryptophane
• 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 211/46 : having a hydrogen atom as the second substituent 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 217/04 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 217/10 : Quaternary compounds
• CPC Class Codes: C07D 235/28 : Sulfur atoms
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 295/084 : with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/088 : to an acyclic saturated chain
• CPC Class Codes: C07D 317/50 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 453/02 : containing not further condensed quinuclidine ring systems
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07F 9/1651 : with hydroxyalkyl compounds with further substituents on alkyl
• CPC Class Codes: C07F 9/2458 : of aliphatic amines
• CPC Class Codes: C07K 5/0812 : and aromatic or cycloaliphatic

Abstract

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

Claims

1. A compound of Formula V:

wherein;

A is nitrogen or oxygen;

R¹¹ is hydrogen, salt-forming cation, ester forming group, —

(CH₂)_x-Q, or when A is nitrogen, A and R¹¹ taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof, wherein A and R¹¹ taken together are not a leucine residue;

Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;

x is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

aa is a natural or unnatural amino acid residue;

m is 1, 2, or 3;

R¹⁴ is hydrogen or protecting group;

R¹⁵ is hydrogen, alkyl or aryl; and

pharmaceutically acceptable salts, esters, or prodrugs thereof;

wherein when A is oxygen, R¹¹ is hydrogen or a salt-forming cation, n is 2, m is 1, and R¹⁴ and R¹⁵ are both hydrogen, then aa is other than phenylalanine, and wherein when A is oxygen, R¹¹ is hydrogen or a salt-forming cation, n is 2, 3 or 4, m is 2, and R¹⁴ and R¹⁵ are both hydrogen, then aa is other than D-phenylalanine.

2. The compound of claim 1, wherein n is 2, 3 or 4.

3. The compound of claim 2, wherein n is 3.

4. The compound of claim 1, wherein m is 1 or 2.

5. The compound of claim 4, wherein m is 1.

6. The compound of claim 4, wherein m is 2.

7. The compound of claim 1, wherein A-R¹¹ is a residue of a natural amino acid, or a salt or ester thereof.

8. The compound of claim 7, wherein A-R¹¹ is a phenylalanine residue.

9. The compound of claim 1, wherein A is an oxygen and R¹¹ is a hydrogen or a salt-forming cation.

10. The compound of claim 1, wherein aa is a residue of a natural amino acid.

11. The compound of claim 1, wherein (aa)_m is a residue of phenylalanine, glycine, or phe-phe.

12. The compound of claim 1, wherein aa is a residue of an unnatural amino acid.

13. The compound of claim 1, wherein R¹⁵ is hydrogen or substituted alkyl.

14. The compound of claim 13, wherein R¹⁵ is arylalkyl.

15. The compound of claim 13, wherein R¹⁵ is hydrogen.

16. The compound of claim 1, wherein R¹⁴ and R¹⁵ are both hydrogen.

17. The compound of claim 1, wherein said compound is selected from the group consisting of:

and pharmaceutically acceptable salts, esters, or prodrugs thereof.

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

19. The method according to claim 18, wherein said amyloid-related disease or condition is Alzheimer'"'"'s disease, mild cognitive impairment, mild-to-moderate cognitive impairment, age-related cognitive decline, senile dementia, vascular dementia, cerebral amyloid angiopathy, inclusion body myositis, macular degeneration, or Down'"'"'s syndrome.

20. A pharmaceutical composition comprising a compound according to claim 1.

21. The pharmaceutical composition of claim 20, wherein said pharmaceutical composition comprises an effective amount of said compound and a pharmaceutically acceptable carrier.

22. The pharmaceutical composition of claim 21, wherein said effective amount is effective to treat or prevent an amyloid related disease or condition.

23. The pharmaceutical composition of claim 22, wherein said amyloid related disease or condition is Alzheimer'"'"'s disease, mild cognitive impairment, mild-to-moderate cognitive impairment, age-related cognitive decline, senile dementia, vascular dementia, cerebral amyloid angiopathy, inclusion body myositis, age-related macular degeneration, or Down'"'"'s syndrome.