Ligands for metabotropic glutamate receptors and inhibitors of NAALAdase

• US 6,479,470 B1
• Filed: 04/27/2000
• Issued: 11/12/2002
• Est. Priority Date: 04/28/1999
• Status: Expired due to Term

• Current Assignee: Georgetown University
• Original Assignee: Georgetown University
• Inventors: Nan, Fajun, Kozikowski, Alan P., Wroblewski, Jarda T.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): TRUONG, TAMTHOM NGO
• Application Number:
  US09/559,978
• Time in Patent Office: 929 Days
• Field of Search: 514/75, 514/574, 562/8, 562/10, 562/24
• US Class Current: 514/75
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 335/08 of a saturated carbon skeleton
• CPC Class Codes: C07C 59/347 containing keto groups
• CPC Class Codes: C07C 69/716 Esters of keto-carboxylic acids or aldehydo-carboxylic acids
• CPC Class Codes: C07F 9/301 Acyclic saturated acids which can have further substituents on alkyl

Abstract

The present invention relates to novel compounds and formulations thereof which compounds are ligands, e.g., agonists or antagonists, for a metabotropic glutamate receptor or a NAALADase enzyme or both. The present invention also relates to methods of modulating the activity of a metabotropic glutamate receptor or a NAALADase enzyme or both, e.g., in a subject in need thereof, using a compound or formulation of the present invention. The present invention also relates to methods of treating a subject suffering from a chronic or acute disease, malady or condition due at least in part to an abnormality in the activity of an endogenous metabotropic glutamate receptor or a NAALADase enzyme or both, using a compound or formulation of the present invention.

Claims

1. A compound represented by generalized structure 1:

wherein

X is selected from the group consisting of —

C(O)—

, —

C(S)—

, —

P(O)(N(R)₂)—

, —

P(NR)(OR)—

, —

P(NR)(N(R)₂)—

, O, S, —

S(O)—

, —

S(O)₂—

, Se, —

Se(O)—

, —

Se(O)₂—

, —

C(R)(OR)—

, —

C(R)(SR)—

, —

C(NR)—

, —

NR(O)—

, and —

N(OR)—

;

Y is selected, independently for each occurrence, from the group consisting of (C(R)₂)_n, (NR)_n, (PR)_n, and a bond;

Z is selected, independently for each occurrence, from the group consisting of C(R), C(N(R)₂), C(NHacyl), N, and P;

W is selected, independently for each occurrence, from the group consisting of (C(R)₂)_m, (NR)_m, (PR)_m, and a bond;

G is selected, independently for each occurrence, from the group consisting of —

COOH, —

C(O)NHOH, —

C(O)NH₂, —

C(S)SH, —

SO₃H, —

SO₂H, —

SOH, —

SeO₃H, —

SeO₂H, —

SeOH, —

S(O)₂NH₂, —

P(O)(OH)₂, and —

P(OH)₂;

R is selected, independently for each occurrence, from the group consisting of H, alkyl, heteroalkyl, aryl, heteroaryl, and aralkyl;

or R is a negative charge for instances of R bonded to a heteroatom; and

m and n are integers selected, independently for each occurrence, from the range 0 to 3 inclusive.

2. The compound of claim 1, wherein X is selected from the group consisting of —

C(O)—

, —

C(S)—

, —

C(NR)—

, —

C(R)(OR)—

, —

C(R)(SR)—

, —

P(O)(N(R)₂)—

, —

P(NR)(OR)—

, and —

P(NR)(N(R)₂)—

.

3. The compound of claim 1, wherein X is —

P(O)(N(R)₂)—

.

4. The compound of claim 1, wherein Y is (C(R)₂)_n.

5. The compound of claim 1, wherein Y is (C(R)₂)_n;

and n is 1.

6. The compound of claim 1, wherein Z is selected, independently for each occurrence, from the group consisting of C(R), C(N(R)₂), and C(NHacyl).

7. The compound of claim 1, wherein Z is C(R).

8. The compound of claim 1, wherein W is (C(R)₂)_m.

9. The compound of claim 1, wherein W is (C(R)₂)_m;

and m is 2.

10. The compound of claim 1, wherein G is selected, independently for each occurrence, from the group consisting of —

COOH, —

C(O)NHOH, —

C(O)NH₂, —

SO₃H, —

SO₂H, —

S(O)₂NH₂, and —

P(O)(OH)₂.

11. The compound of claim 1, wherein G is selected, independently for each occurrence, from the group consisting of —

COOH, —

C(O)NHOH, —

SO₃H, and —

P(O)(OH)₂.

12. The compound of claim 1, wherein G is selected, independently for each occurrence, from the group consisting of —

COOH, and —

C(O)NHOH.

13. The compound of claim 1, wherein G is —

COOH.

14. The compound of claim 1, wherein m and n are integers selected, independently for each occurrence, from the range 1 to 2 inclusive.

15. The compound of claim 1, wherein X is selected from the group consisting of —

C(O)—

, —

C(S)—

, —

C(NR)—

, —

C(R)(OR)—

, —

C(R)(SR)—

, —

P(O)(N(R)₂)—

, —

P(NR)(OR)—

, and —

P(NR)(N(R)₂)—

; and

Y is (C(R)₂)_n.

16. The compound of claim 1, wherein X is selected from the group consisting of —

C(O)—

, —

C(S)—

, —

C(NR)—

, —

C(R)(OR)—

, —

C(R)(SR)—

, —

P(O)(N(R)₂)—

, —

P(NR)(OR)—

, and —

P(NR)(N(R)₂)—

;

Y is (C(R)₂)_n; and

Z is selected, independently for each occurrence, from the group consisting of C(R), C(N(R)₂), and C(NHacyl).

17. The compound of claim 1, wherein X is selected from the group consisting of —

C(O)—

, —

C(S)—

, —

C(NR)—

, —

C(R)(OR)—

, —

C(R)(SR)—

, —

P(O)(N(R)₂)—

, —

P(NR)(OR)—

, and —

P(NR)(N(R)₂)—

;

Y is (C(R)₂)_n;

Z is selected, independently for each occurrence, from the group consisting of C(R), C(N(R)₂), and C(NHacyl); and

W is (C(R)₂)_m.

18. The compound of claim 1, wherein X is selected from the group consisting of —

C(O)—

, —

C(S)—

, —

C(NR)—

, —

C(R)(OR)—

, —

C(R)(SR)—

, —

P(O)(N(R)₂)—

, —

P(NR)(OR)—

, and —

P(NR)(N(R)₂)—

;

Y is (C(R)₂)_n;

Z is selected, independently for each occurrence, from the group consisting of C(R), C(N(R)₂), and C(NHacyl);

W is (C(R)₂)_m; and

G is selected, independently for each occurrence, from the group consisting of —

COOH, —

C(O)NHOH, —

C(O)NH₂, —

SO₃H, —

SO₂H, —

S(O)₂NH₂, and —

P(O)(OH)₂.

19. The compound of claim 1, wherein X is selected from the group consisting of —

C(O)—

, —

C(S)—

, —

C(NR)—

, —

C(R)(OR)—

, —

C(R)(SR)—

, —

P(O)(N(R)₂)—

, —

P(NR)(OR)—

, and —

P(NR)(N(R)₂)—

;

Y is (C(R)₂)_n;

Z is selected, independently for each occurrence, from the group consisting of C(R), C(N(R)₂), and C(NHacyl);

W is (C(R)₂)_m;

G is selected, independently for each occurrence, from the group consisting of —

COOH, —

C(O)NHOH, —

C(O)NH₂, —

SO₃H, —

SO₂H, —

S(O)₂NH₂, and —

P(O)(OH)₂; and

m and n are integers selected, independently for each occurrence, from the range 1 to 2 inclusive.

20. The compound of claim 1, wherein X is —

P(O)(N(R)₂)—

; and

Y is (C(R)₂)_n.

21. The compound of claim 1, wherein X is —

P(O)(N(R)₂)—

;

Y is (C(R)₂)_n; and

Z is C(R).

22. The compound of claim 1, wherein X is —

P(O)(N(R)₂)—

;

Y is (C(R)₂)_n;

Z is C(R); and

W is (C(R)₂)_m.

23. The compound of claim 1, wherein X is —

P(O)(N(R)₂)—

;

Y is (C(R)₂)_n;

Z is C(R);

W is (C(R)₂)_m; and

G is selected, independently for each occurrence, from the group consisting of —

COOH, and —

C(O)NHOH.

24. The compound of claim 1, wherein X is —

P(O)(N(R)₂)—

;

Y is (C(R)₂)_n;

Z is C(R);

W is (C(R)₂)_m;

G is selected, independently for each occurrence, from the group consisting of —

COOH, and —

C(O)NHOH; and

m and n are integers selected, independently for each occurrence, from the range 1 to 2 inclusive.

55. The compound of any one of claims 1-54, wherein the compound is a ligand for a metabotropic glutamate receptor.

56. The compound of any one of claims 1-54, wherein the compound is an agonist of a metabotropic glutamate receptor.

57. The compound of any one of claims 1-54, wherein the compound is a antagonist of a metabotropic glutamate receptor.

58. The compound of any one of claims 1-54, wherein the compound is a ligand for a single subtype of metabotropic glutamate receptor.

59. The compound of any one of claims 1-54, wherein the compound is an agonist of a single subtype of metabotropic glutamate receptors.

60. The compound of any one of claims 1-54, wherein the compound is an antagonist of a single subtype of metabotropic glutamate receptors.

61. The compound of any one of claims 1-54, wherein the compound is an inhibitor of NAALADase.

62. A pharmaceutical composition comprising a compound of any one of claims 1-54.

63. A method of inhibiting NAALADase in a subject in need thereof, comprising the step of administering to the subject a composition comprising a compound of claim 61.

64. A method of agonising a metabotropic glutamate receptor in a mammal, comprising the step of administering to said mammal an effective amount of a compound of claim 56.

65. A method of antagonising a metabotropic glutamate receptor in a mammal, comprising the step of administering to said mammal an effective amount of a compound of claim 57.

66. A method of agonising a single subtype of metabotropic glutamate receptor in a mammal, comprising the step of administering to said mammal an effective amount of a compound of claim 59.

67. A method of antagonising a single subtype of metabotropic glutamate receptor in a mammal, comprising the step of administering to said mammal an effective amount of a compound of claim 60.

25. A compound represented by generalized structure 2:

wherein

X is selected from the group consisting of —

C(R)═

, —

C(OR)═

, —

C(SR)═

, and —

C(NR)═

,

Y is selected, independently for each occurrence, from the group consisting of (C(R)₂)_n, (NR)_n, (PR)_n, and a bond;

D is selected from the group consisting of ═

C(R)—

, ═

N—

, and ═

P—

;

Z is selected, independently for each occurrence, from the group consisting of C(R), C(N(R)₂), C(NHacyl), N, and P;

W is selected, independently for each occurrence, from the group consisting of (C(R)₂)_m, (NR)_m, (PR)_m, and a bond;

G is selected, independently for each occurrence, from the group consisting of —

COOH, —

C(O)NHOH, —

C(O)NH₂, —

C(S)SH, —

SO₃H, —

SO₂H, —

SOH, —

SeO₃H, —

SeO₂H, —

SeOH, —

S(O)₂NH₂, —

P(O)(OH)₂, and —

P(OH)₂;

R is selected, independently for each occurrence, from the group consisting of H, alkyl, heteroalkyl, aryl, heteroaryl, and aralkyl;

or R is a negative charge for instances of R bonded to a heteroatom; and

m and n are integers selected, independently for each occurrence, from the range 0 to 3 inclusive.

26. The compound of claim 25, wherein X is selected from the group consisting of —

C(OR)═

, and —

C(SR)═

.

27. The compound of claim 25, wherein X is —

C(SR)═

.

28. The compound of claim 25, wherein Y is (C(R)₂)_n.

29. The compound of claim 25, wherein the instance of Y bonded to D is a bond.

30. The compound of claim 25, wherein D is ═

C(R)—

.

31. The compound of claim 25, wherein D is ═

C(R)—

; and

the instance of Y bonded to D is a bond.

32. The compound of claim 25, wherein Z is selected, independently for each occurrence, from the group consisting of C(R), C(N(R)₂), and C(NHacyl).

33. The compound of claim 25, wherein Z is C(R).

34. The compound of claim 25, wherein W is (C(R)₂)_m.

35. The compound of claim 25, wherein W is (C(R)₂)_m;

and m is 2.

36. The compound of claim 25, wherein G is selected, independently for each occurrence, from the group consisting of —

COOH, —

C(O)NHOH, —

C(O)NH₂, —

SO₃H, —

SO₂H, —

S(O)₂NH₂, and —

P(O)(OH)₂.

37. The compound of claim 25, wherein G is selected, independently for each occurrence, from the group consisting of —

COOH, —

C(O)NHOH, —

SO₃H, and —

P(O)(OH)₂.

38. The compound of claim 25, wherein G is selected, independently for each occurrence, from the group consisting of —

COOH, and —

C(O)NHOH.

39. The compound of claim 25, wherein G is —

COOH.

40. The compound of claim 25, wherein m and n are independently for each occurrence 0, 1, or 2.

41. The compound of claim 25, wherein X is selected from the group consisting of —

C(OR)═

, and —

C(SR)═

, and Y is (C(R)₂)_n.

42. The compound of claim 25, wherein X is selected from the group consisting of —

C(OR)═

, and —

C(SR)═

; and

D is ═

C(R)—

.

43. The compound of claim 25, wherein X is selected from the group consisting of —

C(OR)═

, and —

C(SR)═

;

D is ═

C(R)—

; and

the instance of Y bonded to D is a bond.

44. The compound of claim 25, wherein X is selected from the group consisting of —

C(OR)═

, and —

C(SR)═

;

Y is (C(R)₂)_n; and

Z is selected, independently for each occurrence, from the group consisting of C(R), C(N(R)₂), and C(NHacyl).

45. The compound of claim 25, wherein X is selected from the group consisting of —

C(OR)═

, and —

C(SR)═

;

Y is (C(R)₂)_n;

Z is selected, independently for each occurrence, from the group consisting of C(R), C(N(R)₂), and C(NHacyl); and

W is (C(R)₂)_m.

46. The compound of claim 25, wherein X is selected from the group consisting of —

C(OR)═

, and —

C(SR)═

;

Y is (C(R)₂)_n;

Z is selected, independently for each occurrence, from the group consisting of C(R), C(N(R)₂), and C(NHacyl);

W is (C(R)₂)_m; and

G is selected, independently for each occurrence, from the group consisting of —

COOH, —

C(O)NHOH, —

C(O)NH₂, —

SO₃H, —

SO₂H, —

S(O)₂NH₂, and —

P(O)(OH)₂.

47. The compound of claim 25, wherein X is selected from the group consisting of —

C(OR)═

, and —

C(SR)═

;

Y is (C(R)₂)_n;

Z is selected, independently for each occurrence, from the group consisting of C(R), C(N(R)₂), and C(NHacyl);

W is (C(R)₂)_m;

G is selected, independently for each occurrence, from the group consisting of —

COOH, —

C(O)NHOH, —

C(O)NH₂, —

SO₃H, —

SO₂H, —

S(O)₂NH₂, and —

P(O)(OH)₂; and

m and n are independently for each occurrence 0, 1, or 2.

48. The compound of claim 25, wherein X is —

C(SR)═

; and

Y is (C(R)₂)_n.

49. The compound of claim 25, wherein X is —

C(SR)═

; and

D is ═

C(R).

50. The compound of claim 25, wherein X is —

C(SR)═

;

D is ═

C(R)—

; and

the instance of Y bonded to D is a bond.

51. The compound of claim 25, wherein X is —

C(SR)═

;

Y is (C(R)₂)_n; and

Z is C(R).

52. The compound of claim 25, wherein X is —

C(SR)═

;

Y is (C(R)₂)_n;

Z is C(R); and

W is (C(R)₂)_m.

53. The compound of claim 25, wherein X is —

C(SR)═

;

Y is (C(R)₂)_n;

Z is C(R);

W is (C(R)₂)_m; and

G is selected, independently for each occurrence, from the group consisting of —

COOH, and —

C(O)NHOH.

54. The compound of claim 25, wherein X is —

C(SR)═

;

Y is (C(R)₂)_n;

Z is C(R);

W is (C(R)₂)_m;

G is selected, independently for each occurrence, from the group consisting of —

COOH, and —

C(O)NHOH; and

m and n are independently for each occurrence 0, 1, or 2.