Substituted 1-benzyl-4-substituted piperazine analogues

• US 7,253,168 B2
• Filed: 04/06/2005
• Issued: 08/07/2007
• Est. Priority Date: 04/07/2004
• Status: Expired due to Fees

• Current Assignee: Neurogen Corporation (Ligand Pharmaceuticals, Inc.)
• Original Assignee: Neurogen Corporation (Ligand Pharmaceuticals, Inc.)
• Inventors: Lee, Kyungae, Hutchison, Alan J., Chenard, Bertrand L., Doller, Dario, Li, Guiying, Ghosh, Manuka, Luke, George P., Gustavson, Linda M., Pringle, Wallace C., Peterson, John M., Tarrant, James G., O'Donnell, Mary-Margaret E.
• Primary Examiner(s): Berch; Mark L.
• Assistant Examiner(s): Moore; Susanna
• Application Number:
  US11/100,355
• Publication Number:
  US 20060142301A1
• Time in Patent Office: 853 Days
• Field of Search: 544/349, 544/238, 544/295, 514/249, 514/252.02
• US Class Current: 514/249
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/08 Bridged systems

Abstract

Compounds of Formula I are provided, in which variables are as described herein:

Such compounds may be used to modulate MCH binding to MCH receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of metabolic, feeding and sexual disorders in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting MCH receptors (e.g., receptor localization studies).

Claims

1. A compound of the formula

2. A compound or salt of claim 1, wherein Q is CR₈ and X is CR₁₁.

3. A compound or salt of claim 2, wherein P is CR₇.

4. A compound or salt of claim 3, wherein R₇ is not hydrogen.

5. A compound or salt of claim 1, wherein R₁₁ is C₁-C₄alkoxy.

6. A compound or salt of claim 5, wherein U is CR₉ and T is CR₁₀.

7. A compound or salt of claim 1, wherein R₇ and R₈ are each chosen from C₁-C₄alkyl.

8. A compound or salt of claim 1, wherein V is C═

O.

9. A compound or salt of claim 1, wherein Z is CR₂.

10. A compound or salt of claim 9, wherein R₂ is halogen, cyano, amino, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄alkylthio, haloC₁-C₄alkyl, mono- or di-(C₁C₄alkyl)amino, (C₃-C₇cycloalkyl)C₀-C₄alkyl or (4- to 7-membered heterocycloalkyl)C₀-C₄alkyl, or R₂ is taken together with a R₁ to form a fused 5- or 6-membered carbocycle or heterocycle.

11. A compound or salt of claim 10, wherein R₂ is halogen, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, trifluoromethyl or mono- or di-methylamino.

12. compound or salt of claim 1, wherein the compound has the formula:

13. A compound or salt of claim 1, wherein the compound has the formula:

14. A pharmaceutical composition, comprising a compound or salt of claim 1, in combination with at least one physiologically acceptable carrier or excipient.

15. The pharmaceutical composition of claim 14, wherein the composition is formulated as an injectible fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup or a transdermal patch.

16. A packaged pharmaceutical preparation, comprising a pharmaceutical composition of claim 14 in a container;

and instructions for using the composition to treat a patient suffering from a disorder associated with MCH receptor activation.

17. The packaged phannaceutical preparation of claim 16, wherein the disorder is an eating disorder, a sexual disorder, obesity, diabetes, heart disease or stroke.

18. A method for treating obesity or diabetes type II, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt of claim 1.

19. The method of claim 18, wherein the compound or salt thereof is administered orally.

20. The method of claim 18, wherein the compound or salt thereof is achninistered intranasally, intravenously or topically.

21. The method of claim 18, wherein the patient is a human.

22. The method of claim 18 wherein the patient is a dog or a cat.

23. A compound or salt of claim 12, wherein R₇ is not hydrogen.

24. A compound or salt of claim 23, wherein R₈ is C₁-C₄alkyl.

25. A compound or salt of claim 13, wherein R₇ is not hydrogen.

26. A compound or salt of claim 25, wherein R₈ is C₁-C₄alkyl.