Agents for treating neurodegenerative diseases

• US 20070078144A1
• Filed: 08/02/2006
• Published: 04/05/2007
• Est. Priority Date: 01/29/2003
• Status: Abandoned Application

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Inventors: Stockwell, Brent, Hoffstrom, Benjamin, Varma, Hemant
• Application Number:
  US11/498,110
• Publication Number:
  US 20070078144A1
• Time in Patent Office: Days
• US Class Current: 514/254.110
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/452 Piperidinium derivatives pancuronium A61K31/58
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Abstract

The present invention relates to compounds effective in preventing neuronal cell death, which may be used in the treatment of neurodegenerative diseases. It is based, at least in part, on the discovery that particular compounds were effective in preventing neuronal death in model systems of Huntington'"'"'s Disease.

Claims

1. A sterile pharmaceutical composition comprising a compound having a formula selected from the group consisting of Formula I and Formula II, in an amount effective in inhibiting neuronal cell death:

where A is a substituted or unsubstituted cycloalkyl, aryl, or heterocyclyl;

where B is a substituted tetrahydrofuran-2-one;

and where R¹ is an alkylheterocyclyl group having the formula (CH₂)_n-D, where n=1-3 and D is selected from the group consisting of substituted or unsubstituted quinoline;

substituted or unsubstituted isoquinoline;

substituted or unsubstituted piperidine;

substituted or unsubstituted piperazine; and

substituted or unsubstituted pyrrolidine.

2. The composition of claim 1, which further comprises a pharmaceutical carrier.

3. A sterile pharmaceutical composition comprising a compound having Formula III in an amount effective in inhibiting neuronal cell death:

where R² is selected from the group consisting of H, methyl, alkyl,and cycloalkyl;

where R³ is selected from the group consisting of H, methyl, alkyl, and cycloalkyl;

where R⁴ is (CH₂)_m-E, where m=1 -3 and E is selected from the group consisting of substituted or unsubstituted quinoline;

substituted or unsubstituted isoquinoline, substituted or unsubstituted piperidine;

substituted or unsubstituted piperazine; and

substituted or unsubstituted pyrrolidine.

4. The composition of claim 3, further comprising a pharmaceutical carrier.

5. A sterile pharmaceutical composition comprising a compound having Formula IV in an amount effective in inhibiting neuronal cell death:

where R¹ may be absent (in which case the bond to oxygen is a double bond) or is selected from the group consisting of H, (C_1-4)alkyl, (C_1-4)alkenyl, (C_1-4)alkylcarbonyl(C_1-4)alkyl, (C_1-4)alkenylcarbonyl(C_1-4)alkyl, (C_1-4)alkylcarbonyl(C_1-4)alkenyl, (C_1-4)alkylaryl, and (C_1-4)alkylcarbonyl(C_1-4)alkenylary;

where R⁹ is selected from the group consisting of H and (C_1-4)alkyl;

where R¹⁰ may be absent or is selected from the group consisting of H, (C_1-4)alkyl, (C_1-4)alkylcarbonyl(C_1-4)alkyl, (C_1-4)alkylhydroxyl, and (C_1-4)alkylhydroxyl(C_1-4)alkyl; and

where R¹¹ is H or (C_1-4)alkyl.

6. The composition of claim 5, further comprising a pharmaceutical carrier.

7. A sterile pharmaceutical composition comprising a compound having Formula V in an amount effective in inhibiting neuronal cell death:

wherein F comprises one or two ring structures containing 10 carbon atoms.

8. The composition of claim 7, further comprising a pharmaceutical carrier.

9. A sterile pharmaceutical composition comprising a compound having Formula VI in an amount effective in inhibiting neuronal cell death:

wherein R¹² is selected from the group consisting of H, (C_1-4)alkyl, amide, (C_1-4)alkylamide;

(C_1-4)alkylcarbonyl, (C_1-4)alkoxycarbonyl, and sulfonyl; and

wherein R¹³ is selected from the group consisting of H, (C_1-4)alkyl, NO₂, (C_1-4)alkylcarbonyl, (C_1-4)alkoxycarbonyl and sulfonyl.

10. The composition of claim 9, further comprising a pharmaceutical carrier.

11. A sterile pharmaceutical composition comprising a compound having Formula VII in an amount effective in inhibiting neuronal cell death:

where R¹⁴ and R¹⁵ may be the same or different, and are selected from the group consisting of H, (C_1-4)alkyl, oxy, (C_1-4)alkoxy, and (C_1-4)alkoxycarbonyl;

where R¹⁶ is selected from the group consisting of H, (C_1-4)alkyl, (C_1-4)alkoxy, (C_1-4)alkoxyalkyl, and (C_1-4)alkoxycarbonyl;

where R¹⁷ is selected from the group consisting of H or (C_1-4)alkyl;

where R¹⁸ may be absent or is selected from the group consisting of H and methyl; and

where R¹⁹ is selected from the group consisting of (C_1-4)alkylcarbonyl(C_1-4)alkyl, (C_1-4)alkylcarbonylaryl, (C_1-4)alkylcarbonyl(C_1-4)alkenylaryl, amido(C_1-4)alkylaryl and amido(C_1-4)alkylheteroaryl.

12. The composition of claim 11 where R¹⁹ is (CH₂)_ocarbonyl-G-J, where o=1-3, G is selected from the group consisting of (C_1-4)alkyl, (C_1-4)alkenyl, and (C_1-4)alkylhydroxy, and J is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrrole, substituted or unsubstituted furan, substituted or unsubstituted isoxazole, and substituted or unsubstituted isothiazole.

13. The composition of claim 11, further comprising a pharmaceutical carrier.

14. The composition of claim 12, further comprising a pharmaceutical carrier.

15. A sterile pharmaceutical composition comprising a compound having Formula VIII in an amount effective in inhibiting neuronal cell death:

where R²⁰ is selected from the group consisting of H, (C_1-4)alkyl, and (C_1-4)alkoxy;

wherein R²¹ is selected from the group consisting of H, (C_1-4)alkyl, and (C_1-4)alkoxy;

wherein R²² is selected from the group consisting of H, (C_1-4)alkyl, (C_1-4)alkoxy, (C_1-4)alkyl(4-7)cyclo(C_1-4)alkyl, (C_1-4)alkylaryl, (C_1-4)alkylheteroaryl, and (C_1-4)alkylhetero(4-7)cyclyl.

16. The composition of claim 15 wherein R²² is an alkylheterocyclyl where the heterocyclic group is selected from the group consisting of a substituted or unsubstituted piperidine, a substituted or unsubstituted piperazine, a substituted or unsubstituted pyrrolidine, a substituted or unsubstituted phenyl, a sustituted or unsubstituted pyrazine, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, a substituted or unsubstituted pyrrole and a substituted and unsubstituted furan.

17. The composition of claim 15, further comprising a pharmaceutical carrier.

18. The composition of claim 16, further comprising a pharmaceutical carrier.

19. A sterile pharmaceutical composition comprising a compound having Formula IX in an amount effective in inhibiting neuronal cell death:

wherein R²³ and R²⁴ may be the same or different and are selected from the group consisting of H, (C_1-4)alkyl, hydroxy, and (C_1-4)alkoxy;

wherein R²⁵ is selected from the group consisting of H, (C_1-4)alkyl, (C_1-4)alkoxy, hydroxy, and halogen.

20. The composition of claim 19, further comprising a pharmaceutical carrier.

21. A sterile pharmaceutical composition comprising a compound having Formula X in an amount effective in inhibiting neuronal cell death:

wherein R²⁶ is a heterocyclyl group of 4, 5, 6, or 7 members comprising N.

22. The composition of claim 21, where R²⁶ is a heterocyclyl comprising O in an epoxide linkage, and substituted with R²⁷, where R²⁷ is selected from the group consisting of (C_1-4)alkyl or aryl.

23. The composition of claim 21, further comprising a pharmaceutical carrier.

24. The composition of claim 22, further comprising a pharmaceutical carrier.

25. A sterile pharmaceutical composition comprising a compound having Formula XI in an amount effective in inhibiting neuronal cell death:

wherein r is 0, 1, or 2;

wherein R²⁸ is selected from the group consisting of NH and S;

wherein R²⁹ is selected from the group consisting of hydroxy, a 4-7 member heterocyclyl group, and carbamidoyl (—

C(═

NH)—

NH2);

wherein R³³ and R³⁴ are selected from the group consisting of H and (C_1-4)alkyl.

26. The composition of claim 25, where R²⁹ is a 4-7 member substituted heterocyclyl group where the heteroatom is N, and where the substitutions are R³⁰, R³¹ , and R³²;

wherein R³⁰, R³¹, and R³² are selected from the group consisting of H, hydroxy, and (C_1-4)alkyl.

27. The composition of claim 25, where R²⁹ is a substituted carbamidoyl group (—

C(═

N¹H)—

N²H2) where the substitution may be on N¹ or ² and where the substitution is selected from the group consisting of (C_1-4)alkyl, aryl, or C_1-4 alkylaryl.

28. The composition of claim 25, further comprising a pharmaceutical carrier.

29. The composition of claim 26, further comprising a pharmaceutical carrier.

30. The composition of claim 27, further comprising a pharmaceutical carrier.

31. A sterile pharmaceutical composition comprising a compound having Formula XII in an amount effective in inhibiting neuronal cell death:

wherein R³⁵ is selected from the group consisting of H, (C_1-4)alkyl, I, F, and Br;

wherein R³⁶ is selected from the group consisting of hydroxy and keto;

wherein t is a single bond or a double bond;

wherein u is 0 or 1;

wherein R³⁷ is selected from the group consisting of Br, F, I, and a 4-7 member heterocyclyl group.

32. The composition of claim 31, where R³⁷ is a 4-7 member heterocyclyl group substituted with (C_1-4)alkyl.

33. The composition of claim 31, further comprising a pharmaceutical carrier.

34. The composition of claim 32, further comprising a pharmaceutical carrier.

35. A method of inhibiting neuronal cell death comprising administering, to a neuronal cell, an effective amount of a compound having a formula selected from the group consisting of Formula I and Formula II:

where A is a substituted or unsubstituted cycloalkyl, aryl, or heterocyclyl;

where B is a substituted tetrahydrofuran-2-one;

and where R¹ is an alkylheterocyclyl group having the formula (CH₂)_n-D, where n=1-3 and D is selected from the group consisting of substituted or unsubstituted quinoline;

substituted or unsubstituted isoquinoline;

substituted or unsubstituted piperidine;

substituted or unsubstituted piperazine; and

substituted or unsubstituted pyrrolidine.

36. A method of inhibiting neuronal cell death comprising administering, to a neuronal cell, an effective amount of a compound having Formula III:

where R² is selected from the group consisting of H, methyl, alkyl,and cycloalkyl;

where R³ is selected from the group consisting of H, methyl, alkyl, and cycloalkyl;

where R⁴ is (CH₂)_m-E, where m=1-3 and E is selected from the group consisting of substituted or unsubstituted quinoline;

substituted or unsubstituted isoquinoline, substituted or unsubstituted piperidine;

substituted or unsubstituted piperazine; and

substituted or unsubstituted pyrrolidine.

37. A method of inhibiting neuronal cell death comprising administering, to a neuronal cell, an effective amount of a compound having Formula IV:

where R⁸ may be absent (in which case the bond to oxygen is a double bond) or is selected from the group consisting of H, (C_1-4)alkyl, (C_1-4)alkenyl, (C_1-4)alkylcarbonyl(C_1-4)alkyl, (C_1-4)alkenylcarbonyl(C_1-4)alkyl, (C_1-4)alkylcarbonyl(C_1-4)alkenyl, (C_1-4)alkylaryl, and (C_1-4)alkylcarbonyl(C_1-4)alkenylary;

where R⁹ is selected from the group consisting of H and (C_1-4)alkyl;

where R¹⁰ may be absent or is selected from the group consisting of H, (C_1-4)alkyl, (C_1-4)alkylcarbonyl(C_1-4)alkyl, (C_1-4)alkylhydroxyl, and (C_1-4)alkylhydroxyl(C_1-4)alkyl; and

where R¹¹ is H or (C_1-4)alkyl.

38. A method of inhibiting neuronal cell death comprising administering, to a neuronal cell, an effective amount of a compound having Formula V:

wherein F comprises one or two ring structures containing 10 carbon atoms.

39. method of inhibiting neuronal cell death comprising administering, to a neuronal cell, an effective amount of a compound having Formula VI:

wherein R¹² is selected from the group consisting of H, (C_1-4)alkyl, amide, (C_1-4)alkylamide;

(C₁₄)alkylcarbonyl, (C_1-4)alkoxycarbonyl, and sulfonyl; and

wherein R¹³ is selected from the group consisting of H, (C_1-4)alkyl, NO₂, (C_1-4)alkylcarbonyl, (C_1-4)alkoxycarbonyl and sulfonyl.

40. A method of inhibiting neuronal cell death comprising administering, to a neuronal cell, an effective amount of a compound having Formula VII:

where R¹⁴ and R¹⁵ may be the same or different, and are selected from the group consisting of H, (C_1-4)alkyl, oxy, (C_1-4)alkoxy, and (C_1-4)alkoxycarbonyl;

where R¹⁶ is selected from the group consisting of H, (C_1-4)alkyl, (C_1-4)alkoxy, (C_1-4)alkoxyalkyl, and (C_1-4)alkoxycarbonyl;

where R¹⁷ is selected from the group consisting of H or (C_1-4)alkyl;

where R¹⁸ may be absent or is selected from the group consisting of H and methyl; and

where R¹⁹ is selected from the group consisting of(C_1-4)alkylcarbonyl(C_1-4)alkyl, (C_1-4)alkylcarbonylaryl, (C_1-4)alkylcarbonyl(C_1-4)alkenylaryl, amido(C_1-4)alkylaryl and amido(C_1-4)alkylheteroaryl.

41. The method of claim 40 where R¹⁹ is (CH₂)_ocarbonyl-G-J, where o=1-3, G is selected from the group consisting of(C_1-4)alkyl, (C_1-4)alkenyl, and (C_1-4)alkylhydroxy, and J is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrrole, substituted or unsubstituted furan, substituted or unsubstituted isoxazole, and substituted or unsubstituted isothiazole.

42. A method of inhibiting neuronal cell death comprising administering, to a neuronal cell, an effective amount of a compound having Formula VIII:

where R²⁰ is selected from the group consisting of H, (C_1-4)alkyl, and (C_1-4)alkoxy;

wherein R²¹ is selected from the group consisting of H, (C_1-4)alkyl, and (C_1-4)alkoxy;

wherein R²² is selected from the group consisting of H, (C_1-4)alkyl, (C_1-4)alkoxy, (C_1-4)alkyl(4-7)cyclo(C_1-4)alkyl, (C_1-4)alkylaryl, (C_1-4)alkylheteroaryl, and (C_1-4)alkylhetero(4-7)cyclyl.

43. The method of claim 42 wherein R²² is an alkylheterocyclyl where the heterocyclic group is selected from the group consisting of a substituted or unsubstituted piperidine, a substituted or unsubstituted piperazine, a substituted or unsubstituted pyrrolidine, a substituted or unsubstituted phenyl, a sustituted or unsubstituted pyrazine, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, a substituted or unsubstituted pyrrole and a substituted and unsubstituted furan.

44. A method of inhibiting neuronal cell death comprising administering, to a neuronal cell, an effective amount of a compound having Formula IX:

wherein R²³ and R²⁴ may be the same or different and are selected from the group consisting of H, (C_1-4)alkyl, hydroxy, and (C_1-4)alkoxy;

wherein R²⁵ is selected from the group consisting of H, (C_1-4)alkyl, (C_1-4)alkoxy, hydroxy, and halogen.

45. A method of inhibiting neuronal cell death comprising administering, to a neuronal cell, an effective amount of a compound having Formula X:

wherein R²⁶ is a heterocyclyl group of 4, 5, 6, or 7 members comprising N.

46. The method of claim 45, where R²⁶ is a heterocyclyl comprising O in an epoxide linkage, and substituted with R²⁷, where R²⁷ is selected from the group consisting of (C_1-4)alkyl or aryl.

47. A method of inhibiting neuronal cell death comprising administering, to a neuronal cell, an effective amount of a compound having Formula XI:

wherein r is 0, 1, or 2;

wherein R²⁸ is selected from the group consisting of NH and S;

wherein R²⁹ is selected from the group consisting of hydroxy, a 4-7 member heterocyclyl group, and carbamidoyl (—

C(═

NH)—

NH2);

wherein R³³ and R³⁴ are selected from the group consisting of H and (C_1-4)alkyl.

48. The method of claim 47, where R²⁹ is a 4-7 member substituted heterocyclyl group where the heteroatom is N, and where the substitutions are R³⁰, R³¹, and R³²;

wherein R³⁰, R³¹, and R³² are selected from the group consisting of H, hydroxy, and (C_1-4)alkyl.

49. The method of claim 47, where R²⁹ is a substituted carbamidoyl group (—

C(═

N¹H)—

N²H2) where the substitution may be on N¹ or ² and where the substitution is selected from the group consisting of (C_1-4) alkyl, aryl, or C_1-4 alkylaryl.

50. A method of inhibiting neuronal cell death comprising administering, to a neuronal cell, an effective amount of a compound having Formula XII:

wherein R³⁵ is selected from the group consisting of H, (C_1-4)alkyl, I, F, and Br;

wherein R³⁶ is selected from the group consisting of hydroxy and keto;

wherein t is a single bond or a double bond;

wherein u is 0 or 1;

wherein R³⁷ is selected from the group consisting of Br, F, I, and a 4-7 member heterocyclyl group.

51. The method of claim 50, where R³⁷ is a 4-7 member heterocyclyl group substituted with (C_1-4)alkyl.

52. A sterile pharmaceutical composition comprising a compound having Formula XIII in an amount effective in inhibiting neuronal cell death:

where R⁴⁰ may be may be a substituted or unsubstituted aromatic, substituted or unsubstituted diaromatic, or C₁-C₁₀ alkyl;

wherein substituent groups may be H, halogen, C₁-C₄ alkyl groups, or alkoxy groups; and

wherein the number of substituents may be one, two, or more than two;

R⁴¹ may be a (C_1-4)alkyl, alkoxy, aromatic ring, or dimethyl group;

Ring 1 may be additionally substituted, wherein R⁴² and R⁴³ may be H or a halogen, preferably flourine or chlorine; and

R⁴² and R⁴³ may be the same or may be different substituent groups.

53. The composition of claim 52 further comprising a pharmaceutical carrier.

54. A sterile pharmaceutical composition comprising a compound having Formula XIV in an amount effective in inhibiting neuronal cell death:

wherein R⁴⁴ and R⁴⁵ may be C₁-C₄ alkoxy groups;

“

—

X—

”

may be a single or double bond or an amide bond.

R⁴⁶ may be absent or, for example, one of the following substituent groups;

or may be a substituted aromatic rin or heterocyclic (optionally aromatic ring);

R⁴⁷ may be absent or may be hydrogen or methyl (in which case the N is a quaternary ammonium ion); and

R⁴⁸may be C or N or O.

55. The composition of claim 54 further comprising a pharmaceutical carrier.

56. A method of inhibiting neuronal cell death comprising administering, to a neuronal cell, an effective amount of a compound having Formula XIII:

where R⁴⁰ may be may be a substituted or unsubstituted aromatic, substituted or unsubstituted diaromatic, or C₁-C₁₀ alkyl;

wherein substituent groups may be H, halogen, C₁-C₄ alkyl groups, or alkoxy groups; and

wherein the number of substituents may be one, two, or more than two;

R⁴¹ may be a (C_1-4)alkyl, alkoxy, aromatic ring, or dimethyl group;

Ring 1 may be additionally substituted, wherein R⁴² and R⁴³ may be H or a halogen, preferably flourine or chlorine; and

R⁴² and R⁴³ may be the same or may be different substituent groups.

57. A method of inhibiting neuronal cell death comprising administering, to a neuronal cell, an effective amount of a compound having Formula XIV:

wherein R⁴⁴ and R⁴⁵ may be C₁-C₄ alkoxy groups;

“

—

X—

”

may be a single or double bond or an amide bond.

R⁴⁶ may be absent or, for example, one of the following substituent groups;

or may be a substituted aromatic ring or heterocyclic (optionally aromatic ring);

R⁴⁷ may be absent or may be hydrogen or methyl (in which case the N is a quaternary ammonium ion); and

R⁴⁸ may be C or N or O.