IP Library › Granted Patent US 6,951,861

Granted Patent B1

US 6,951,861 · App. 10/089,964 · Granted Oct 4, 2005

Chemical compounds

Assignee: SmithKline Beechan Corporation

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Quick Facts

Patent No.: US 6,951,861
App. No.: 10/089,964
Granted: Oct 4, 2005
Kind: B1

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Abstract

The invention relates to piperazine derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to their medical use. The novel compounds are antagonists of tachykinins, including substance P and other neurokinins.

Claims (301)

1. A compound of formula (I)

wherein

R is a halogen atom or a C 1-4 alkyl group;

R 1 is hydrogen or a C 1-4 alkyl group;

R 2 is hydrogen, a C 1-4 alkyl, C 2-6 alkenyl or a C 3-7 cycloalkyl group; or R 1 and R 2 together with nitrogen and carbon atom to which they are attached respectively are a 5-6 membered heterocyclic group;

R 3 is a trifluoromethyl, a C 1-4 alkyl, a C 1-4 alkoxy, a trifluoromethoxy, or a halogen group;

R 4 is hydrogen, a (CH 2 ) q R 7 or a (CH 2 ) r CO(CH 2 ) p R 7 group;

R 5 is hydrogen, a C 1-4 alkyl or a COR 6 group;

R 6 is hydrogen, hydroxy, amino, methylamino, dimethylamino, a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen or a 6 membered heteroaryl group containing 1 to 3 nitrogen atoms;

R 7 is hydrogen, hydroxy or NR 8 R 9 wherein R 8 and R 9 are independently hydrogen or C 1-4 alkyl optionally substituted by hydroxy, or by amino;

R 10 is hydrogen, a C 1-4 alkyl 1 group or

R 10 together with R 2 is a C 3-7 cycloalkyl group;

m is zero or an integer from 1 to 3; n is zero or an integer from 1 to 3; both p and r are independently zero or an integer from 1 to 4; q is an integer from 1 to 4; provided that, when R 1 and R 2 together with nitrogen and carbon atom to which they are attached respectively are a 5 to 6 membered heterocyclic group, i) m is 1 or 2; ii) when m is 1, R is not fluorine and iii) when m is 2, the two substituents R are not both fluorine,

or a pharmaceutically acceptable salt or solvate thereof.

2. A compound as claimed in claim 1 wherein n is 2 and R 3 is trifluoromethyl both at the 3 and 5 position.

3. A compound as claimed in claim 1 wherein R is selected independently from halogen or a C 1-4 alkyl group and m is 1 or 2.

4. A compound as claimed in claim 1 wherein m is 2, R is selected independently from halogen or methyl group at 2 or 4 position.

5. A compound as claimed in claim 1 wherein R 5 is hydrogen or a methyl group.

6. A compound as claimed in claim 1 wherein R 1 is hydrogen or a methyl group.

7. A compound as claimed in claim 1 wherein R 4 is hydrogen, a (CH 2 ) r CO(CH 2 ) p R 7 or CH 2 ) q R 7 group, wherein R 7 represents an amine, both p and r are independently zero or 1; and q is 1 or 2.

8. A compound as claimed in claim 1 wherein R is selected independently from halogen or methyl, R 3 is trifluoromethyl both at the 3 and 5 position, R 1 is hydrogen or methyl, R 2 is hydrogen, methyl, 2-propenyl or a cyclopropyl group or together with R 1 is a 3,6-dihydro-2H-pyridin-1-yl, a piperidin-1-yl or a pyrrolidin-1-yl group, R 10 represents hydrogen, a methyl or R 10 together with R 2 is a cyclopropyl group, R 4 is hydrogen, an aminoacetyl or amino ethyl group and R 5 is hydrogen or a methyl group.

9. A compound as claimed in claim 1 wherein R is selected independently from halogen or methyl and m is 2, R 3 is trifluoromethyl both at the 3 and 5 position, R 1 and R 2 are independently hydrogen or methyl, R 4 is hydrogen and R 5 is hydrogen.

10. A compound selected from:

2-(4-fluoro-2-methyl-phenyl)piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amine;

2-(2-isopropyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)methyl-amide;

2-(4-fluoro-3-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

2-(2,4-difluoro-phenyl)-piperazine-1-caboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amide;

2-(4-fluoro-phenyl)-piperazine-1-carboxylic acid (3,4-bis-trifluoromethyl-benzyl)methyl-amide;

2-phenyl-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

2-(2,4-dichloro-phenyl)-piperazine-1-carboxylic acid (3,5-bistrifluoro methyl-benzyl)-methyl-amide:

2-(3,4-dichloro-phenyl)-piperazine-1-carboxylic acid (3,5-bistrifluoro methyl-benzyl)-methyl-amide;

2-(4-fluoro-2-methyl-phenyl)-3-methyl-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amine;

2-(2-methyl-4-fluoro-phenyl)-6-methyl-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amine;

4-(2-amino-acetyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifuoromethyl-benzyl)-methyl-amide;

4-(2-amino-ethyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [(1-3,5-bis-trifluoromethyl-phenyl)-cyclopropyl]-methyl-amide;

[2-(3,5-bis-trifluoromethyl-phenyl)-pyrrolidin-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;

[2-(3,5-bis-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridyn-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl-piperazin-1-yl]-methanone;

2-(3,5-bis-trifluoromethyl-phenyl)-piperidin-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl)-methanone;

2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-but-3-enyl]-methyl-amide;

2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propyl]-methyl-amide;

2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [(3,5-bis-trifluoromethyl-phenyl)cyclopropyl-methyl]-methyl-amide;

and enantiomers, pharmaceutically acceptable salts, and solvates thereof.

11. 4-(2-amino-acetyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)methyl-amide hydrochloride.

12. 2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide methanesulphonate.

13. 2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide acetate.

14. A process (A) for the preparation of a compound as claimed in claim 1 , wherein R 4 is hydrogen or a (CH 2 ) q R 7 group, provided that when R 5 is a C 1-4 alkyl or a COR 6 group, R 5 is not in the 3 position of the piperazine ring, which comprises reduction of a compound of formula (II), wherein (R 4 ) a is hydrogen or a suitable nitrogen protecting group or (R 4 ) u is a (CH 2 ) q R 7 group or protecting derivatives thereof; or

a process (B) for the preparation of a compound as claimed in claim 1 , wherein R 4 is hydrogen or a (CH 2 ) r CO(CH 2 ) p R 7 group which comprises the reaction of a compound of formula (VIII), wherein (R 4 ) b represents a nitrogen protecting group or (R 4 ) b is (CH 2 ) r CO(CH 2 ) p R 7 or a protecting group thereof with triphosgene and an organic base followed by addition of the amine (V)

followed where necessary or desired by one or more of the following steps:

(i) removal of any protecting group;

(ii) Isolation of the compound as salt thereof;

(iii) separation of a compound of formula (I) or derivative thereof into the enantiomers thereof.

15. A pharmaceutical composition comprising a compound as claimed in claim 1 in admixture with one or more physiologically acceptable carriers or excipients.

16. The pharmaceutical composition according to claim 15 further comprising a serotonin reuptake inhibitor.

17. The pharmaceutical composition according to claim 16 , wherein said serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.

18. The pharmaceutical composition according to claim 15 , wherein said compound of formula (I) is 2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amide or an enantiomer or pharmaceutically acceptable salt or solvate thereof.

19. The pharmaceutical composition according to claim 18 , further comprising a serotonin reuptake inhibitor.

20. The pharmaceutical composition according to claim 19 , wherein said serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.

21. The pharmaceutical composition according to claim 15 further comprising a dopaminergic antidepressant.

22. The pharmaceutical composition according to claim 21 , wherein said dopaminergic antidepressant is selected from the group consisting of buproprion and amineptine.

23. The pharmaceutical composition according to claim 18 further comprising a dopaminergic antidepressant.

24. The pharmaceutical composition according to claim 23 wherein said dopaminergic antidepressant is selected from the group consisting of buproprion and amineptine.

25. A method for the treatment of a depressive state in a mammal comprising administering to said mammal an effective amount of a compound of formula (I):

wherein:

R is a halogen atom or a C 1-4 alkyl group;

R 1 is hydrogen or a C 1-4 alkyl group;

R 2 is hydrogen, a C 1-4 alkyl, C 2-8 alkenyl or a C 3-7 cycloalkyl group; or R 1 and R 2 together with nitrogen and carbon atom to which they are attached respectively represent a 5-6 membered heterocyclic group;

R 3 is a trifluoromethyl, a C 1-4 alkyl, a C 1-4 alkoxy, a trifluoromethoxy or a halogen group;

R 4 is hydrogen, a (CH 2 ) q R 7 or a (CH 2 )CO(CH 2 ) p R 7 group;

R 5 is hydrogen, a C 1-4 alkyl or a COH 6 group;

R 6 is hydrogen, hydroxy, amino, methylamino, dimethylamino a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen or a 6 membered heteroaryl group containing 1 to 3 nitrogen atoms;

R 7 is hydrogen, hydroxy or NR 8 R 9 wherein R 8 and R 9 represent independently hydrogen or C 1-4 alkyl optionally substituted by hydroxy or by amino;

R 10 is hydrogen, a C 1-4 alkyl group or R 10 together with R 2 represents a C 3-7 cycloalkyl group;

m is zero or an integer from 1 to 3;

n is zero or an integer from 1 to 3;

both p and r are independently zero or an integer from 1 to 4:

q is an integer from 1 to 4;

provided that, when R 1 and R 2 together with nitrogen and carbon atom to which they are attached respectively represent a 5 to 6 membered heterocyclic group,

i) m is 1 or 2;

ii) when m is 1, R is not fluorine and

iii) when m is 2, the two substituents R are not both fluorine,

or a pharmaceutically acceptable salt or solvate thereof.

26. The method according to claim 25 , wherein said mammal is man.

27. The method according to claim 25 , wherein said depressive state is selected from the group consisting of bipolar depression, unipolar depression, single major depressive episodes, recurrent major depressive episodes, dysthymic disorder, neurotic depression, social phobia, dementia of Alzheimer's type, vascular dementia with depressed mood, mood disorders induced by alcohol, mood disorders induced by amphetamines, mood disorders induced by cocaine, mood disorders induced by hallucinogens, mood disorders induces by inhalants, mood disorders induced by opioids, mood disorders induced by phencyclidine, mood disorders induced by sedatives, mood disorders induced by hypnotics, mood disorders induced by anxiolytics and schizoaffective disorder of the depressed type.

28. The method according to claim 25 , wherein said depressive state is selected from the group consisting of bipolar depression and unipolar depression.

29. The method according to claim 25 , further comprising administering an effective amount of a serotonin reuptake inhibitor.

30. The method according to claim 29 , wherein said serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.

31. The method according to claim 25 , further comprising administering an effective amount of a dopaminergic antidepressant.

32. The method according to claim 31 , wherein said dopaminergic antidepressant is selected from the group consisting of buproprion and amineptine.

33. A method for the treatment of a depressive state in a mammal comprising administering to said mammal an effective amount of a compound selected from the group consisting of

2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amine;

2-(2-isopropyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)methyl-amide;

2-(4-Fluoro-3-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amine;

2-(2,4-Difluoro-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)methyl-amide;

2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amide;

2-(4-Fluoro-phenyl)-piperazine-1-carboxylic acid (3,4-bis-trifluoromethyl-benzyl)-methyl-amide;

2-Phenyl-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

2-(2,4-dichloro-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoro-methyl-benzyl)-methyl-amide;

2-(3,4-dichloro-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoro-methyl-benzyl)-methyl-amide;

2-(4-Fluoro-2-methyl-phenyl)-3-methyl-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)methyl-amine;

2-(2-Methyl-4-Fluoro-phenyl)-6-Methyl-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amine;

4-(2-Amino-acetyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

4-(2-Amino-ethyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [(1,3,5-bis-trifluoromethyl-phenyl)-cyclopropyl]-methyl-amide;

[2-(3,5-Bis-trifluoromethyl-phenyl)-pyrrolidin-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;

[2-(3,5-Bis-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;

2-(3,5-Bis-trifluoromethyl-phenyl)-piperidin-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;

2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-but-3-enyl]-methyl-amide;

2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propyl]-methyl-amide;

2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [(3,5-bis-trifluoromethyl-phenyl)-cyclopropyl-methyl]-methyl-amide;

or an enantiomer, or pharmaceutically acceptable salt or solvate thereof.

34. The method according to claim 33 , wherein said mammal is man.

35. The method according to claim 33 , wherein said depressive state is selected from the group consisting of bipolar depression and unipolar depression.

36. The method according to claim 33 , further comprising administering an effective amount of a serotonin reuptake inhibitor.

37. The method according to claim 36 , wherein said serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.

38. The method according to claim 33 , further comprising administering an effective amount of a dopaminergic antidepressant.

39. The method according to claim 38 , wherein said dopaminergic antidepressant is selected from the group consisting of buproprion end amineptine.

40. A method for the treatment of a depressive state in a mammal comprising administering to said mammal an effective amount of 4-(2-Amino-acetyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride.

41. A method for the treatment of a depressive state in a mammal comprising administering to said mammal an effective amount of 2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amide or an enantiomer or pharmaceutically acceptable salt or solvate thereof.

42. The method according to claim 41 , wherein said depressive state is selected from the group consisting of bipolar depression and unipolar depression.

43. A method for the treatment of a depressive state in a mammal comprising administering to said mammal an effective amount of 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide methansulphonate.

44. The method according to claim 43 , wherein said depressive state is selected from the group consisting of bipolar depression and unipolar depression.

45. A method for the treatment of a depressive state in a mammal comprising administering to said mammal an effective amount of 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide acetate.

46. The method according to claim 45 , wherein said depressive state is selected from the group consisting of bipolar depression and unipolar depression.

47. A method for the treatment of anxiety in a mammal comprising administering to said mammal an effective amount of a compound of formula (I):

wherein:

R is a halogen atom or a C 1-4 alkyl group;

R 1 is hydrogen or a C 1-4 alkyl group;

R 2 is hydrogen, a C 1-4 alkyl, C 2-6 alkenyl or a C 3-7 cycloalkyl group; or R 1 and R 2 together with nitrogen and carbon atom to which they are attached respectively represent a 5-6 membered heterocyclic group;

R 3 is a trifluoromethyl, a C 1-4 alkyl, a C 1-4 alkoxy, a trifluoromethoxy or a halogen group;

R 4 is hydrogen, a (CH 2 ) q R 7 or a (CH 2 )CO(CH 2 ) q R 7 group;

R 5 is hydrogen, a C 1-4 alkyl or a COR 6 group;

R 7 is hydrogen, hydroxy or NR 8 R 9 wherein R 8 and R 9 represent independently hydrogen or C 1-4 alkyl optionally substituted by hydroxy or by amino;

R 10 is hydrogen, a C 1-4 alkyl group or R 10 together with R 2 represents a C 3-7 cycloalkyl group:

m is zero or an integer from 1 to 3;

n is zero or an integer from 1 to 3;

both p and r are independently zero or an integer from 1 to 4;

q is an integer from 1 to 4;

provided that, when R 1 and R 2 together with nitrogen and carbon atom to which they are attached respectively represent a 5 to 6 membered heterocyclic group,

i) m is 1 or 2;

ii) when m is 1, R is not fluorine and

iii) when m is 2, the two substituents R are not both fluorine,

or a pharmaceutically acceptable salt or solvate thereof.

48. The method according to claim 47 , wherein said mammal is a human.

49. The method according to claim 47 , further comprising administering an effective amount of a serotonin reuptake inhibitor.

50. The method according to claim 49 , wherein said serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.

51. The method according to claim 47 , further comprising administering an effective amount of a dopaminergic antidepressant.

52. The method according to claim 51 , wherein said dopaminergic antidepressant is selected from the group consisting of buproprion and amineptine.

53. A method for the treatment of anxiety in a mammal comprising administering to said mammal an effective amount of a compound selected from the group consisting of

2-(4-fluoro-2-methyl-phenyl)-pipe rboxylic acid (3,5-bis-trifluoromethyl-benzyl)-ethyl-amide;

2-(2-Isopropyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

2-(4-Fluoro-3-methyl-phenyl)piperazine-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)methyl-amide;

2-(2,4-Difluoro-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

2-(4-fluoro-2-methylphenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amide;

2-(4-Fluoro-phenyl)-piperazine-1-carboxylic acid (3,4-bis-trifuoromethyl-benzyl)methyl-amide;

2-Phenyl-piperazin 1-carboxylic acid (3,5-bis-trifuoromethyl-benzyl)-methyl amide;

2-(2,4-dichloro-phenyl)-piperazine-1-Carboxylic acid (3,5-bis-trifluoro-methyl-benzyl)-methyl-amide;

2-(3,4-dichloro-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoro-methyl-benzyl)-methyl-amide;

2-(4-Fluoro-2-methyl-phenyl)-3-methyl-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amine;

2-(2-Methyl-4-Fluoro-phenyl)-6-Methyl-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amine;

4-(2-Amino-acetyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

4-(2-Amino-ethyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [(1-3,5-bis-trifluoromethyl-phenyl)cyclopropyl-methyl-amide;

[2-(3,5-Bis-trifluoromethyl-phenyl)-pyrrolidin-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;

[2-(3,5-Bis-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridyn-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;

2-(3,5-Bis-trifluoromethyl-phenyl)-piperidine-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;

2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-but-3-enyl]methyl-amide;

2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethylphenyl)-2-methyl-propyl]-methyl-amide;

2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [(3,5-bis-trifluoromethyl-phenyl)-cyclopropyl-methyl]-methyl-amide;

or an enantiomer, or pharmaceutically acceptable salt or solvate thereof.

54. The method according to claim 53 , wherein said mammal is a human.

55. The method according to claim 53 , further comprising administering an effective amount of a serotonin reuptake inhibitor.

56. The method according to claim 55 , wherein said serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.

57. The method according to claim 53 , further comprising administering an effective amount of a dopaminergic antidepressant.

58. The method according to claim 57 , wherein said dopaminergic antidepressant is selected from the group consisting of buproprion and amineptine.

59. A method for the treatment of anxiety in a mammal comprising administering to said mammal an effective amount of 4-(2-Amino-acetyl)-2-(S)-(4-fluoro-2-methyl-phenyl)piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride.

60. A method for the treatment of anxiety in a mammal comprising administering to sail mammal an effective amount of 2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifuoromethyl-phenyl)ethyl]-methyl-amide or an enantiomer or pharmaceutically acceptable salt or solvate thereof.

61. A method for the treatment of anxiety in a mammal comprising administering to said mammal an effective amount of 2-(S)-(4-Fluoro 2-methyl-phenyl)-piperazin-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amide methanesulphonate.

62. A method for the treatment of anxiety in a mammal comprising administering to said mammal an effective amount of 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]methyl-amide acetate.

63. A method for the treatment of a panic disorder in a mammal comprising administering to said mammal an effective amount of a compound of formula (I):

wherein:

R is a halogen atom or a C 1-4 alkyl group;

R 1 is hydrogen or a C 1-4 alkyl group;

R 2 is hydrogen, a C 1-4 alkyl, C 2-6 , alkenyl or a C 3-7 cycloalkyl group; or R 1 and R 2 together with nitrogen and carbon atom to which they are attached respectively represent a 5-6 membered heterocyclic group;

R 3 is a trifluoromethyl, a C 1-4 alkyl, a C 1-4 alkoxy, a trifluoromethoxy or a halogen group;

R 4 is hydrogen, a (CH 2 ) q R 7 or a (CH 2 )CO(CH 2 ) p R 7 group;

R 5 is hydrogen, a C 1-4 alkyl or a COR 6 group;

R 7 is hydrogen, hydroxy or NR 8 R 9 wherein R 8 and R 9 represent independently hydrogen or C 1-4 alkyl optionally substituted by hydroxy or by amino;

R 10 is hydrogen, a C 1-4 alkyl group or together with R 2 represents a C 1-7 cycloalkyl group;

m Is zero or an integer from 1 to 3;

n is zero or an integer from 1 to 3;

both p and r are independently zero or an integer from 1 to 4;

q is an integer from 1 to 4;

provided that, when R 1 and R 2 together with nitrogen and carbon atom to which they are attached respectively represent a 5 to 6 membered heterocyclic group,

i) m is 1 or 2;

ii) when m is 1, R is not fluorine and

iii) when m is 2, the two substituents R are not both fluorine,

or a pharmaceutically acceptable salt or solvate thereof.

64. The method according to claim 63 , wherein said mammal is a human.

65. The method according to claim 63 , further comprising administering an effective amount of a serotonin reuptake inhibitor.

66. The method according to claim 65 , wherein said serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.

67. The method according to claim 63 , further comprising administering an effective amount of a dopaminergic antidepressant.

68. The method according to claim 67 , wherein said dopaminergic antidepressant is selected from the group consisting of buproprion and amineptine.

69. A method for the treatment of a panic disorder in a mammal comprising administering to said mammal an effective amount of a compound selected from the group consisting of

2-(4-fluoro-2-methyl-phenyl)piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

2-(2-isopropyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

2-(4-Fluoro-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amine;

2-(2,4-Difluoro-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

2-(4-fluoro-2-methyl-phenyl)piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amide;

2-(4-Fluoro-phenyl)-piperazine-1-carboxylic acid (3,4-bis-trifluoromethyl-benzyl)-methyl-amide;

2-Phenyl-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;

2-(2,4-dichloro-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoro-methyl-benzyl)methyl-amide;

2-(3,4-dichloro-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoro-methyl-benzyl)methyl-amide;

2-(4-Fluoro-2-methylphenyl)-3-methyl-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amine;

2-(2-Methyl-4-Fluoro-phenyl)-6-Methyl-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amine;

2-(2-Amino-acetyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)methyl-amide;

4-(2-Amino-ethyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)methyl-amide;

2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [(1-3,5-bis-trifluoromethyl-phenyl)-cyclopropyl]-methyl-amide;

[2-(3,5-Bis-trifluoromethyl-phenyl)-pyrrolidin-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)piperazin-1-yl]-methanone;

[2-(3,5-Bis-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridyn-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;

2-(3,5-Bis-trifluoromethyl-phenyl)-piperidin-1-yl]-[2-(S)(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;

2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-but-3-enyl]-methyl-amide;

2-(4-Fluoro-1-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propyl]-methyl-amide;

2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [(3,5-bis-trifluoromethyl-phenyl)-cyclopropyl-methyl]-methyl-amide;

or an enantiomer, or pharmaceutically acceptable salt or solvate thereof.

70. The method according to claim 69 , wherein said mammal is a human.

71. The method according to claim 69 , further comprising administering an effective amount of a serotonin reuptake inhibitor.

72. The method according to claim 71 , wherein said serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.

73. The method according to claim 69 , further comprising administering an effective amount of a dopaminergic antidepressant.

74. The method according to claim 73 , wherein said dopaminergic antidepressant is selected from the group consisting of buproprion and amineptine.

75. A method for the treatment of a panic disorder in a mammal comprising administering to said mammal an effective amount of 4-(2-Amino-acetyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)methyl-amide hydrochloride.

76. A method for the treatment of a panic disorder In a mammal comprising administering to said mammal an effective amount of 2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amide or an enantiomer or pharmaceutically acceptable salt or solvate thereof.

77. A method for the treatment of a panic disorder in a mammal comprising administering to said mammal an effective amount of 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide methansulphonate.

78. A method for the treatment of a panic disorder in a mammal comprising administering to said mammal an effective amount of 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide acetate.

79. A method for the treatment of a gastrointestinal disorder in a mammal comprising administering to said mammal an effective amount of a compound of formula (I):

wherein:

R is a halogen atom or a C 1-4 alkyl group;

R 1 is hydrogen or a C 1-4 alkyl group;

R 2 is hydrogen, a C 1-4 alkyl, C 2-4 alkenyl or a C 3-7 cycloalkyl group; or R 1 and R 2 together with nitrogen and carbon atom to which they are attached respectively represent a 5-6 membered heterocyclic group;

R 3 is a trifluoromethyl, a C 1-4 alkyl, a C 1-4 alkoxy, a trifluoromethoxy or a halogen group;

R 4 is hydrogen, a (CH 2 ) q R 7 or a (CH 2 )CO(CH 2 ) p R 7 group;

R 5 is hydrogen, a C 1-4 alkyl or a COR 6 group;

R 7 is hydrogen, hydroxy or NR 8 R 9 wherein R 8 and R 9 represent independently hydrogen or C 1-4 alkyl optionally substituted by hydroxy or by amino;

R 10 is hydrogen, a C 1-4 alkyl group or R 10 together with R 2 represents a C 3-7 cycloalkyl group;

m is zero or an integer from 1 to 3;

n is zero or an integer from 1 to 3;

both p and r are independently zero or an Integer from 1 to 4;

q is an integer from 1 to 4;

provided that, when R 1 and R 2 together with nitrogen and carbon atom to which they are attached respectively represent a 5 to 6 membered heterocyclic group,

i) m is 1 or 2;

li) when m is 1, R is not fluorine and

iii) when m is 2, the two substituents R are not both fluorine,

or a pharmaceutically acceptable salt or solvate thereof.

80. The method according to claim 79 , wherein said mammal is a human.

81. The method according to claim 79 , wherein said gastrointestinal disorder is irritable bowel syndrome.

82. The method according to claim 79 , further comprising administering an effective account of a 5HT3 antagonist.

83. The method according to claim 82 , wherein said 5HT3 antagonist is selected from the group consisting of ondansetron, granisetron and metoclopramide.

84. A method for the treatment of a gastrointestinal disorder in a mammal comprising administering to said mammal an effective amount of a compound selected from the group consisting of