Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists

• US 7,112,595 B2
• Filed: 11/03/2003
• Issued: 09/26/2006
• Est. Priority Date: 08/19/1999
• Status: Expired due to Fees

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC), NPS Pharmaceuticals Incorporated (Shire plc)
• Inventors: Smith, Daryl L, Moe, Scott T, Sheehan, Susan M, Slassi, Abdelmalik, Egle, Ian, Isaac, Methvin, Xin, Tao, Stormann, Thomas M., Edwards, Louise, Arora, Jalaj, McLeod, Donald, Stefanac, Tomislav, Wagenen, Bradford Van, Michne, William
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US10/699,563
• Publication Number:
  US 20050154027A1
• Time in Patent Office: 1,058 Days
• Field of Search: 546/269.1, 514/340
• US Class Current: 514/340
• CPC Class Codes: C07D 213/55 Acids; Esters
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/78 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 213/79 Acids; Esters
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

Abstract

The present invention provides compounds and pharmaceutical compositions that act as antagonists at metabotropic glutamate receptors, and that are useful for treating neurological diseases and disorders. Methods of preparing the compounds also are disclosed.

Claims

1. A compound of Formula II or a pharmaceutically acceptable salt thereof:

2. The compound according to claim 1, wherein Ar² is substituted with one or more moieties selected from the group consisting of CF₃, Cl, F, Br, SCH₃, and CN.

3. The compound according to claim 1, wherein Ar¹ is substituted with one or more moieties selected from the group consisting of CF₃, Cl, F, Br, SCH₃, and CN.

4. The compound according to claim 1, wherein each of Ar¹ and Ar² is substituted with one or more moieties selected from the group consisting of CF₃, Cl, F, Br, SCH₃, and CN.

5. The compound according to claim 4, wherein the compound is one selected from the group consisting of:

3-(5-Cyano-2-pyridyl)-5-(3-bromophenyl)-1,2,4-oxadiazole (B59),

3-(5-Cyano-2-pyridyl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B60),

3-(5-Cyano-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (B61),

3-(5-Chloropyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B83),

3-(5-Chloropyrid-2-yl)-5-(3-cyano-5-chlorophenyl)-1,2,4-oxadiazole (B84),

3-(5-Chloropyrid-2-yl)-5-(3-chloro-5-fluorophenyl)-1,2,4-oxadiazole (B85),

3-(5-Fluoropyrid-2-yl)-5-(3-cyano-5-chlorophenyl)-1,2,4-oxadiazole (B87),

or pharmaceutically acceptable salts thereof.

6. The compound according to claim 4, wherein the compound is one selected from the group consisting of:

3-(2-pyridyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-oxadiazole (B28),

3-(5-chloropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B29)

3-(5-fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B30),

3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B31),

3-(3-fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B32),

3-(2-pyridyl)-5-(2,5,6-trifluorophenyl)-1,2,4-oxadiazole (B45),

or pharmaceutically acceptable salts thereof.

7. The compound according to claim 6, wherein the compound is 3-(5-fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B30) or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 6, wherein the compound is 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B31) or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 6, wherein the compound is 3-(3-fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B32) or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 5, wherein the compound is 3-(5-Cyano-2-pyridyl)-5-(3-bromophenyl)-1,2,4-oxadiazole (B59) or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 5, wherein the compound is 3-(5-Cyano-2-pyridyl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B60) or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 5, wherein the compound is 3-(5-Cyano-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (B61) or a pharmaceutically acceptable salt thereof.

21. A method for the treatment of a neurological disease whereby a compound according to any one of claims 1 thru 6 or 7 thru 12 is administered to a subject in need of such treatment.

22. A method for the treatment of a psychiatric disease whereby a compound according to any one of claims 1 thru 6 or 7 thru 12 is administered to a subject in need of such treatment.

23. A method for the treatment of a disease, selected from the group consisting of stroke, head trauma, anoxic injury, ischemic injury, hypoglycemia, epilepsy, pain, migraine headaches, Parkinson'"'"'s disease, senile dementia, Huntington'"'"'s Chorea, anxiety, and Alzheimer'"'"'s disease whereby a compound according to any one of claims 1 thru 6 or 7 thru 12 is administered to a subject in need of such treatment.

13. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula II or a pharmaceutically acceptable salt thereof:

14. The pharmaceutical composition according to claim 13, wherein the compound is one selected from the group consisting of:

3-(5-fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B30),

3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B31),

3-(3-fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B32),

3-(5-Cyano-2-pyridyl)-5-(3-bromophenyl)-1,2,4-oxadiazole (B59),

3-(5-Cyano-2-pyridyl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B60),

3-(5-Cyano-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (B61),

or pharmaceutically acceptable salts thereof.

15. The pharmaceutical composition according to claim 14, wherein the compound is 3-(5-fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B30) or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition according to claim 14, wherein the compound is 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B31) or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition according to claim 14, wherein the compound is 3-(3-fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B32) or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition according to claim 14, wherein the compound is 3-(5-Cyano-2-pyridyl)-5-(3-bromophenyl)-1,2,4-oxadiazole (B59) or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition according to claim 14, wherein the compound is 3-(5-Cyano-2-pyridyl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B60) or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition according to claim 14, wherein the compound is 3-(5-Cyano-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (B61) or a pharmaceutically acceptable salt thereof.