Ligands for metabotropic glutamate receptors and inhibitors of NAALADase

• US 6,528,499 B1
• Filed: 09/15/2000
• Issued: 03/04/2003
• Est. Priority Date: 04/27/2000
• Status: Expired due to Term

• Current Assignee: Georgetown University
• Original Assignee: Georgetown University
• Inventors: Nan, Fajun, Wroblewski, Jarda T., Kozikowski, Alan P.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): TRUONG, TAMTHOM NGO
• Application Number:
  US09/662,767
• Time in Patent Office: 900 Days
• Field of Search: 514/75, 514/574, 562/8, 562/10, 562/24
• US Class Current: 514/75
• 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 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 275/16 being further substituted by carboxyl groups
• CPC Class Codes: C07C 275/26 having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 323/59 with acylated amino groups bound to the carbon skeleton
• 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: C07D 257/04 Five-membered rings
• CPC Class Codes: C07F 9/301 Acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/303 Cycloaliphatic acids

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 structure 1:

wherein

X is selected from the group consisting of —

C(O)—

, —

C(S)—

, —

S(O)₂—

, —

C(R)(OR)—

, and —

C(R)(SR)—

;

Y is selected, independently for each occurrence, from the group consisting of (CR₂)_n, (NR)_n, and a bond;

Z is selected, independently for each occurrence, from the group consisting of C(R), C(NR₂), and C(NHacyl);

W is selected, independently for each occurrence, from the group consisting of (CR₂)_m, (NR)_m, and a bond;

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

COOH, —

SO₃H, —

P(O)(OH)₂, —

SR, and 2-R-tetrazol-5-yl;

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

also including a negative charge for instances of R bonded to a heteroatom;

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

the stereochemical configuration at any stereocenter of a compound represented by 1 is R, S, or a mixture of these configurations.

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

C(O)—

.

3. The compound of claim 1, wherein Y is independently for each occurrence (NR)_n.

4. The compound of claim 1, wherein Z is independently for each occurrence C(R).

5. The compound of claim 1, wherein W is independently for each occurrence (CR₂)_m.

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

COOH, —

SR, and 2-R-tetrazol-5-yl.

7. The compound of claim 1, wherein m and n are integers selected, independently for each occurrence, from 1 and 2.

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

C(O)—

; and

Y is independently for each occurrence (NR)_n.

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

C(O)—

; and

Z is independently for each occurrence C(R).

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

C(O)—

; and

W is independently for each occurrence (CR₂)_m.

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

C(O)—

; and

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

COOH, —

SR, and 2-R-tetrazol-5-yl.

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

C(O)—

;

Y is independently for each occurrence (NR)_n; and

Z is independently for each occurrence C(R).

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

C(O)—

;

Y is independently for each occurrence (NR)_n; and

W is independently for each occurrence (CR₂)_m.

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

C(O)—

;

Y is independently for each occurrence (NR)_n; and

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

COOH, —

SR, and 2-R-tetrazol-5-yl.

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

C(O)—

;

Y is independently for each occurrence (NR)_n;

Z is independently for each occurrence C(R); and

W is independently for each occurrence (CR₂)_m.

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

C(O)—

;

Y is independently for each occurrence (NR)_n;

W is independently for each occurrence (CR₂)_m; and

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

COOH, —

SR, and 2-R-tetrazol-5-yl.

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

C(O)—

;

Y is independently for each occurrence (NR)_n;

Z is independently for each occurrence C(R);

W is independently for each occurrence (CR₂)_m; and

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

COOH, —

SR, and 2-R-tetrazol-5-yl.

26. The compound of claim 1 or 18, wherein the compound is a single stereoisomer.

27. The compound of claim 1 or 18, wherein the compound is a ligand for a metabotropic glutamate receptor.

28. The compound of claim 1 or 18, wherein the compound is an agonist of a metabotropic glutamate receptor.

29. The compound of claim 1 or 18, wherein the compound is a antagonist of a metabotropic glutamate receptor.

30. The compound of claim 1 or 18, wherein the compound is a ligand for a single subtype of metabotropic glutamate receptor.

31. The compound of claim 1 or 18, wherein the compound is an agonist of a single subtype of metabotropic glutamate receptors.

32. The compound of claim 1 or 18, wherein the compound is an antagonist of a single subtype of metabotropic glutamate receptors.

33. The compound of claim 1 or 18, wherein the compound is an inhibitor of NAALADase.

34. A pharmaceutical composition, comprising a compound of claim 1 or 18;

and pharmaceutically acceptable excipient.

35. A method of inhibiting NAALADase in a mammal, comprising the step of administering to a mammal a therapeutically effective amount of a compound of claim 1 or 18.

36. A method of agonising a metabotropic glutamate receptor in a mammal, comprising the step of administering to a mammal a subject a therapeutically effective amount of a compound of claim 1 or 18.

37. A method of antagonising a metabotropic glutamate receptor in a mammal, comprising the step of administering to a mammal a therapeutically effective amount of a compound of claim 1 or 18.

38. A method of agonising a single subtype of metabotropic glutamate receptor in a mammal, comprising the step of administering to a mammal a therapeutically effective amount of a compound of claim 1 or 18.

39. A method of antagonising a single subtype of metabotropic glutamate receptor in a mammal, comprising the step of administering to a mammal a therapeutically effective amount of a compound of claim 1 or 18.

18. A compound represented by structure 2:

wherein

X is selected from the group consisting of —

C(O)—

, —

C(S)—

, —

P(O)(OR)—

, —

S(O)₂—

, —

C(R)(OR)—

, and —

C(R)(SR)—

;

Y is selected, independently for each occurrence, from the group consisting of (CR₂)_n, (NR)_n, and a bond;

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

COOH, —

SO₃H, —

P(O)(OH)₂, and 2-R-tetrazol-5-yl;

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

also including a negative charge for instances of R bonded to a heteroatom;

n is an integer selected, independently for each occurrence, from the range 0 to 3 inclusive; and

the stereochemical configuration at any stereocenter of a compound represented by 2 is R, S, or a mixture of these configurations.

19. The compound of claim 18, wherein X is —

C(O)—

.

20. The compound of claim 18, wherein Y is independently for each occurrence (NR)_n.

21. The compound of claim 18, wherein G is selected, independently for each occurrence, from the group consisting of —

COOH, —

SO₃H, —

P(O)(OH)₂, and 2-R-tetrazol-5-yl.

22. The compound of claim 18, wherein G is selected, independently for each occurrence, from the group consisting of —

COOH, and 2-R-tetrazol-5-yl.

23. The compound of claim 18, wherein X is —

C(O)—

; and

Y is independently for each occurrence (NR)_n.

24. The compound of claim 18, wherein X is —

C(O)—

;

Y is independently for each occurrence (NR)_n; and

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

COOH, —

SO₃H, —

P(O)(OH)₂, and 2-R-tetrazol-5-yl.

25. The compound of claim 18, wherein X is —

C(O)—

;

Y is independently for each occurrence (NR)_n; and

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

COOH, and 2-R-tetrazol-5-yl.