MGluR5 modulators VI

• US 20070259895A1
• Filed: 04/25/2007
• Published: 11/08/2007
• Est. Priority Date: 05/05/2006
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC), NPS Pharmaceuticals Incorporated (Shire plc)
• Inventors: Slassi, Abdelmalik, Isaac, Methvin, Xin, Tao, Edwards, Louise, Dove, Peter, Nagard, Mats, Stefanac, Tomislav
• Application Number:
  US11/790,424
• Publication Number:
  US 20070259895A1
• Time in Patent Office: Days
• US Class Current: 514/259.310
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• 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 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention is directed to novel compounds, to a process for their preparation, their use in therapy and pharmaceutical compositions comprising the novel compounds.

Claims

1. A compound of formula (I)

2. A compound according to claim 1, wherein R¹ is halogen or cyano.

3. A compound according to claim 2, wherein R¹ is chloro.

4. A compound according to claim 2, wherein R¹ is cyano.

5. A compound according to claim 1, wherein R² is hydrogen.

6. A compound according to claim 1, wherein R³ is hydrogen or fluoro.

7. A compound according to claim 1, wherein R⁴ is hydrogen or methyl.

8. A compound according to claim 1, wherein R⁵ is hydrogen, C₁-C₂ alkyl or C₁-C₂ alkoxy.

9. A compound according to claim 1, wherein R⁶ is hydrogen, C₁-C₂ alkyl or C₁-C₂ alkoxy.

10. A compound according to claim 1, wherein R⁷ is C₁-C₂ alkyl or C₁-C₂ alkoxy.

12. A compound according to claim 1 for use in therapy.

13. A pharmaceutical composition comprising a compound according to claim 1 as an active ingredient, together with a pharmacologically and pharmaceutically acceptable carrier.

14. Use of a compound according to claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations.

15. Use of a compound according to claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for treatment or prevention of gastroesophageal reflux disease.

16. Use of a compound according to claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for treatment or prevention of pain.

17. Use of a compound according to claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for treatment or prevention of anxiety.

18. Use of a compound according to claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for treatment or prevention of irritable bowel syndrome (IBS).

19. A method for the inhibition of transient lower esophageal sphincter relaxations whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such inhibition.

20. A method for the treatment or prevention of gastroesophageal reflux disease, whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such treatment or prevention.

21. A method for the treatment or prevention of pain, whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such treatment or prevention.

22. A method for the treatment or prevention of anxiety, whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such treatment or prevention.

23. A method for the treatment or prevention of irritable bowel syndrome (IBS), whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such treatment or prevention.

24. A combination comprising (i) at least one compound according to claim 1 and (ii) at least one acid secretion inhibiting agent.

25. A combination according to claim 24 wherein the acid secretion inhibiting agent is selected from cimetidine, ranitidine, omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole or leminoprazole.

11. A compound selected from

8-{[5-(3-Chlorophenyl)isoxazol-3-yl]methyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine;

8-{[5-(3-Chlorophenyl)isoxazol-3-yl]methyl}-3-(2-methoxypyridin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine; and

3-(3-{(R)-Methyl[3-(2-methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl]methyl} isoxazol-5-yl)benzonitrile

as well as pharmaceutically acceptable salts, hydrates, isoforms, tautomers and/or enantiomers thereof.

26. A compound selected from

3-[3-(1-hydroxyethyl)isoxazol-5-yl]benzonitrile;

1-[5-(3-Iodo-phenyl)-isoxazol-3-yl]-ethanol;

3-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-(3-iodo-phenyl)-isoxazole;

3-{3-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-isoxazol-5-yl}-benzonitrile; and

1-[5-(3-Cyanophenyl)isoxazol-3-yl]ethyl methanesulfonate.