Compounds for the treatment of CNS and amyloid associated diseases

• US 20060167057A1
• Filed: 11/16/2005
• Published: 07/27/2006
• Est. Priority Date: 11/16/2004
• Status: Abandoned Application

• Current Assignee: Bellus Health (Interational) Limited
• Original Assignee: Bellus Health (Interational) Limited
• Inventors: Wu, Xinfu, Kong, Xianqi, Gervais, Francine, Valade, Isabelle
• Application Number:
  US11/281,950
• Publication Number:
  US 20060167057A1
• Time in Patent Office: Days
• US Class Current: 514/338
• 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: C07D 233/84 Sulfur atoms
• CPC Class Codes: C07D 239/47 One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/56 One oxygen atom and one sulfur atom
• CPC Class Codes: C07D 249/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C07D 271/113 with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Methods, compounds, pharmaceutical compositions and kits are described for treating or preventing CNS and amyloid associated disease. Also described are methods, compounds, pharmaceutical compositions and kits for detecting, diagnosing, monitoring and treating or preventing CNS and amyloid associated disease.

Claims

1. A compound of Formula I:

A-Y-Q

wherein;

Q is a blood brain barrier transport vector;

Y is a direct bond or a linker group;

A is selected from the group consisting of hydrogen, alkyl, alkyloxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, carbocyclic, heterocyclic, bicyclic, aryl, heteroaryl, fused-ring aryl or heteroaryl, aryloxy, arylalkyl, arylalkyloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl,

each of which may be optionally substituted; and

R⁴ and R⁵ together with the nitrogen form a 5 or 6 membered heterocyclic ring, or are each independently selected from the group consisting of hydrogen, alkyl, alkyloxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkyl, aryl, aryloxy, arylalkyl, arylalkyloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl, each of which may be optionally substituted;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

2. The compound of claim 1, wherein Q is a large neutral amino acid moiety or analog thereof.

3. The compound of claim 1, wherein the compound is of Formula (II):

4. The compound of claim 3, wherein X is selected from the group consisting of oxygen, and nitrogen.

5. The compound of claim 3, wherein Z¹, Z², and Z³ are each independently N, C or CH.

6. The compound of claim 3, wherein Y is a direct bond.

7. The compound of claim 3, wherein Y is a linker group selected from the group consisting of a disulfide bond, an ether linkage, a thioether linkage, an alkylene or alkenylene linkage, an amino or a hydrozino linkage, an ester-based linkage, a thioester linkage, an amide bond, an acid-labile linkage, and a Schiff base linkage.

8. The compound of claim 3, wherein R¹ and R² are independently absent or hydrogen.

9. The compound of claim 3, wherein R³ is selected from the group consisting of hydrogen, arylamido, arylaminocarbonyl and arenesulfonyl, each of which may be optionally substituted.

10. The compound of claim 3, wherein each A is independently selected from the group consisting of

11. The compound of claim 3, wherein R⁴ and R⁵ are each independently selected from the group consisting of cycloalkyl, aryl, aryloxy, arylalkyl, arylalkyloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl, each of which may be optionally substituted.

12. The compound of claim 3, wherein R⁴ and R⁵ together with the nitrogen form a 6 membered ring optionally interrupted with one or more additional heteroatoms.

15. The compound of claim 1, wherein the compound is not a compound of Table 3.

16. The use of a compound according to claim 1, or a pharmaceutically acceptable salt, ester, or prodrug thereof, in the preparation of a medicament for the treatment or prevention of a CNS disease or an amyloid associated disease.

17. The use of a compound according to claim 1, or a pharmaceutically acceptable salt, ester, or prodrug thereof, in the preparation of a medicament for the treatment or prevention of Alzheimer'"'"'s disease or an amyloid associated disease.

18. A pharmaceutical composition for the treatment or prevention of a CNS disease or an amyloid associated disease comprising a compound according to claim 1, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

19. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

23. A kit for use in treating a CNS disease or an amyloid associated disease comprising a compound of claim 1 or depicted in the Tables, or a pharmaceutically acceptable salt, ester, or prodrug thereof, and instructions for use in the method of the instant invention.

24. A method of treating or preventing a CNS disease or an amyloid associated disease in a subject comprising administering to a subject in need thereof, a compound of claim 1 or depicted in the Tables, or a pharmaceutically acceptable salt, ester, or prodrug thereof, in an amount effective to treat or prevent a CNS disorder or an amyloid associated disease.

25. The method according to claim 24, wherein amyloid fibril formation or deposition, neurodegeneration, or cellular toxicity is reduced or inhibited upon administration of said compound.

26. The method according to claim 24, wherein said subject is a human.

27. A method for treating Alzheimer'"'"'s Disease in a subject comprising administering to a subject an effective amount of a therapeutic compound of claim 1 or depicted in the Tables, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that Alzheimer'"'"'s Disease is treated.

28. A method for treating an Aβ

-related disease in a subject having amyloid deposits, the method comprising administering to said subject an effective amount of a therapeutic compound of claim 1 or depicted in the Tables, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that the Aβ

-related disease is treated.

34. A method for preventing, slowing, or stopping disease progression comprising administering to a subject an effective amount of a compound of claim 1 or depicted in the Tables, or a pharmaceutically acceptable salt, ester, or prodrug thereof, such that said disease progression is prevented slowed, or stopped.

38. A method for treating a subject for a CNS disorder or an amyloid associated disease, comprising:

coadministration of any of the compounds of claim 1 or depicted in the Tables with an agent that enhances penetration of the blood brain barrier, such that the CNS disorder or amyloid associated disease is treated.

39. The method of claim 38, wherein the agent that enhances penetration of the blood brain barrier is L-arginine.

13. The compound of Formula (II), wherein said compound is at least one compound selected from the group consisting of compounds in Table 1, and pharmaceutically acceptable salts, esters, and prodrugs thereof.

14. A compound of Formula (II), wherein the compound is at least one compound selected from the group consisting of compounds in Table 2 and pharmaceutically acceptable salts, esters, and prodrugs thereof.

20-22. -22. (canceled)

29-33. -33. (canceled)

35. (canceled)

36. A bifunctional compound comprising a BBB transport vector and a moiety for the treatment of a CNS disorder or an amyloid associated disease, or a pharmacologically acceptable salt thereof.

37. The compound of claim 36, wherein the BBB transporter vector is a large neutral amino acid or a large neutral amino acid analog.