Melanin concentrating hormone receptor ligands: substituted 1-benzyl-4-aryl piperazine analogues

• US 6,953,801 B2
• Filed: 05/21/2002
• Issued: 10/11/2005
• Est. Priority Date: 05/22/2001
• Status: Expired due to Fees

• Current Assignee: Neurogen Corporation (Ligand Pharmaceuticals, Inc.)
• Original Assignee: Neurogen Corporation (Ligand Pharmaceuticals, Inc.)
• Inventors: Hutchison, Alan, Caldwell, Timothy M., Yoon, Taeyoung, Doller, Dario, Shen, Yiping, Gustavson, Linda M., Pringle, Wallace C., Peterson, John M., Steenstra, Cheryl
• Primary Examiner(s): Bernhardt, Emily
• Application Number:
  US10/152,189
• Publication Number:
  US 20050065162A1
• Time in Patent Office: 1,239 Days
• Field of Search: 544/350, 514/249
• US Class Current: 514/249
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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: C07D 209/86 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
• CPC Class Codes: C07D 211/52 having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 215/12 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 215/20 Oxygen atoms
• CPC Class Codes: C07D 243/08 not condensed with other rings
• CPC Class Codes: C07D 295/096 with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/108 to an acyclic saturated chain
• CPC Class Codes: C07D 311/18 substituted otherwise than in position 3 or 7
• CPC Class Codes: C07D 317/58 Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• 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
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

Melanin concentrating hormone receptor ligands (especially 1-benzyl-4-aryl-piperazines, 1-benzyl-4-aryl-piperidines and related compounds), capable of modulating MCH receptor activity, are provided. Such ligands 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

or a pharmaceutically acceptable salt thereof, wherein:

V is a bond or —

(C═

O)—

;

W is N;

X is selected from halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and (C₁-C₆)alkoxy;

Y and Z are each CH;

n is 1;

R₁ and R₂ are each independently selected from hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and (C₁-C₆)alkoxy;

with the proviso that if R₁ and R₂ are hydrogen, then V is —

C═

O)—

;

R₃ is joined with R₆ to form a heterocyclic group having 5 or 6 ring members, with one ring member being nitrogen and remaining ring atoms being carbon, wherein the heterocyclic group is substituted with 0, 1 or 2 substituents independently chosen from hydrogen, halogen, cyano, hydroxy, oxo, oxime, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkanoyl, C₁-C₆alkanoyloxy, C₁-C₆alkoxycarbonyl, halo(C₁-C₆)alkyl and halo(C₁-C₆)alkoxy;

R₄ is hydrogen, (C₁-C₆)alkyl or halo(C₁-C₆)alkyl;

R₅ is independently selected at each occurrence from hydrogen, halogen, hydroxy, nitro, cyano, amino, oxo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, mono- and di(C₁-C₆)alkylamino, and amino(C₁-C₆)alkyl;

R₇ is;

(i) selected from hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and (C₁-C₆)alkoxy;

or

(ii) joined with R₈ or R₁₂ to form a fused phenyl ring;

R₈ is;

(i) selected from hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and (C₁-C₆)alkoxy;

or

(ii) joined with R₇ or R₁₁ to form a fused phenyl ring;

U is CR₉;

T is CR₁₀;

R₉ is;

(i) selected from hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and (C₁-C₆)alkoxy;

or

(ii) joined with R₁₀ or R₁₁ to form a fused phenyl ring;

R₁₀ is;

(i) selected from hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and (C₁-C₆)alkoxy;

or

(ii) joined with R₃, R₈ or R₉ to form a fused phenyl ring;

R₁₁ is;

(i) selected from hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and (C₁-C₆)alkoxy;

or

(ii) joined with R₈ or R₉ to form a fused phenyl ring;

R₁₂ is;

(i) independently selected at each occurrence from hydrogen, halogen, hydroxy, nitro, cyano, amino, oxo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, mono- and di(C₁-C₆)alkylamino, and amino(C₁-C₆)alkyl;

or

(ii) joined with R₇ to form a fused phenyl ring.

2. A compound or salt according to claim 1, wherein X is a halogen, (C₁-C₃)alkyl, halo (C₁-C₃)alkyl, or (C₁-C₃)alkoxy.

3. A compound or salt according to claim 2, wherein R₁ is hydrogen.

4. A compound or salt according to claim 2, wherein R₁₁ is methoxy.

5. A compound or salt according to claim 2, wherein R₁₁ is halogen.

6. A compound or salt according to claim 1, wherein U is CR₉ and R₇, R₈, and R₉ are each independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy and halogen.

7. A compound or salt according to claim 1, wherein R₁₁ is halogen and R₈ is (C₁-C₆)alkoxy.

8. A compound or salt according to claim 1, wherein each R₅ is independently hydrogen or methyl.

9. A compound or salt according to claim 1, wherein V is a bond.

10. A compound or salt according to claim 1, wherein V is —

(C═

O)—

.

11. A compound or salt according to claim 1, of the formula:

wherein;

A and B are each independently selected from CR₁₃ and CHR₁₃, wherein R₁₃ is independently selected at each occurrence from hydrogen, halogen, cyano, hydroxy, oxo, oxime, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, halo(C₁-C₆)alkyl and halo(C₁-C₆)alkoxy;

R₄ is hydrogen or methyl;

the bond between A and B is a single bond or a double bond;

R₅ is independently selected at each occurrence from hydrogen and methyl; and

R₁₁ is hydrogen, halogen, or methoxy or hydroxy.

12. A compound or salt according to claim 11, wherein A and B are each CR₁₃.

13. A compound or salt according to claim 11, wherein R₇, R₈ and R₉ are each independently selected from hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy and halogen.

14. A compound or salt according to claim 1, wherein the compound is selected from the group consisting of:

2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;

2-(4-chloro-3-trifluoromethyl-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;

2-(4-chloro-3-methoxy-phenyl)-6-(3-fluoro, 4-methoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;

2-(4-fluoro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;

2-(4-fluoro-3-trifluoromethyl-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;

2-(4-chloro-3-methoxy-phenyl)-6-methoxy-naphthalen-2-yl)-octahydro-pyrido[1,2-a]pyrazine;

2-(4-chloro-3-methyl-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;

2-(4-methoxy-3-methyl-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;

2-(4-chloro-3-methoxy-phenyl)-6-(3-methoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;

2-(2,4-dibromo-5-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;

2-(3,4-dimethoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;

2-(4-chloro-3-fluoro-phenyl)-4-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;

1-(4-fluoro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;

2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-ol;

2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one;

2-(4-chloro-3-methoxy-phenyl)-6-(3-fluoro-4-methoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one;

2-(4-chloro-3-methoxy-phenyl)-6-(6-methoxy-naphthalen-2-yl)-octahydro-pyrido[1,2-a]pyrazin-8-one;

2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrrolo[1,2-a]pyrazine;

2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-1,3,4,6,9,9a-hexahydro-2H-pyrido[1,2-a]pyrazine; and

2-(4-chloro-3-methoxy-phenyl)-6-(3-methoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-ol.

15. A compound or salt according to claim 1, wherein the compound is [6-(3,4-dimethoxy-phenyl)octahydro-pyrido[1,2-a]pyrazin-2-yl]-(4-trifluoromethyl-phenyl)-methanone.

16. A compound or salt according to claim 1, wherein the compound is selected from the group consisting of:

(6R,10S)-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one;

(6R,10S)-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;

(6R,9S)-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrrolo[1,2-a]pyrazine;

(6R,10S)-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-ol;

(6R,10S)-[6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-(4-trifluoromethyl-phenyl)-methanone; and

(6R,10S)-2-(4-chloro-3-methoxy-phenyl)-6-(3-fluoro, 4-methoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine.

17. A pharmaceutical composition, comprising a compound or salt according to claim 1, in combination with a physiologically acceptable carrier or excipient.

18. pharmaceutical composition according to claim 17, 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.

19. A method for treating obesity in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound or salt according to claim 1.

20. A method according to claim 19, wherein the compound or salt is administered orally.

21. A method according to claim 19, wherein the patient is a human.

22. A method according to claim 19, wherein the patient is a dog or a cat.

23. A compound or salt according to claim 11, wherein:

A and B are CH₂;

R₄ is hydrogen;

R₇, R₈, R₉ and R₁₁ are each independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆alkoxy and halogen;

n is 1; and

each R₅ and R₁₂ are hydrogen.

24. A compound or salt according to claim 23, wherein:

Y and Z are each CH;

X is halogen, methoxy or trifluoromethyl; and

R₁ and R₂ are independently chosen from hydrogen, halogen, methyl, methoxy and di- and tri-fluoromethyl.

25. A compound or salt according to claim 24, wherein:

R₇ is hydrogen;

R₉ is hydrogen, C₁-C₆alkyl, C₁-C₆alkoxy or halogen; and

R₈ and R₁₁ are independently selected from C₁-C₆alkyl, C₁-C₆alkoxy and halogen.

26. A compound or salt according to claim 25, wherein:

R₁ is hydrogen; and

R₂ is halogen, methyl, methoxy or di- or tri-fluoromethyl.

27. A compound or salt according to claim 1, wherein R₇ is hydrogen, R₈ is methoxy, R₉ is hydrogen, R₁₀ is hydrogen and R₁₁ is methoxy.

28. A compound or salt according to claim 1, wherein R₇ is hydrogen, R₈ is a halogen, R₉ is hydrogen, R₁₀ is hydrogen and R₁₁ is methoxy.

29. A compound or salt according to claim 11, wherein R₇ is hydrogen, R₈ is methoxy, R₉ is hydrogen, R₁₀ is hydrogen and R₁₁ is methoxy.

30. A compound or salt according to claim 11, wherein R₇ is hydrogen, R₈ is a halogen, R₉ is hydrogen, R₁₀ is hydrogen and R₁₁ is methoxy.