Chemical compounds

1. A method for the treatment of emesis 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 )qR 7 or a (CH 2 )rCO(CH 2 )pR 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 represent independently hydrogen or C 1-4 alkyl optionally substituted by hydroxy or by amino;

R 10 is hydrogen, a C1-4 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.

2. The method according to claim 1 , wherein said mammal is a human.

3. The method according to claim 1 , wherein said emesis is delayed emesis.

4. The method according to claim 1 , wherein said emesis is anticipatory emesis.

5. The method according to claim 1 , wherein said emesis is induced by cancer chemotherapeutic agents.

6. The method according to claim 5 , wherein said cancer chemotherapeutic agent is selected from the group consisting of cyclophosphamide, carmustine, lomustine, chlorambucil, dactinomycin, doxorubicin, mitomycin-C, bleomycin, cytarabine, methotrexate, 5-fluorouracil, etoposide, vinblastine, vincristine, cisplatin, dacarbazine, procarbazine and hydroyurea.

7. The method according to claim 1 , wherein said emesis is induced by radiation sickness or radiation therapy.

8. The method according to claim 1 , wherein said emesis is induced by pregnancy.

9. The method according to claim 1 , wherein said emesis is induced by post-operative sickness.

10. The method according to claim 1 , wherein said emesis is induced by migraine.

11. The method according to claim 1 , wherein said emesis is induced by opiod analgesics.

12. A method for the treatment of emesis 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-3-methyl-phenyl)-piperazine-1-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-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-amide;

2-(2-Methyl-4-Fluoro-phenyl)-6-Methyl-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;

4-(2-Amino-acetyl)-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)-4-(piperidine-4-carbonyl)-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-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.

13. The method according to claim 12 , wherein said mammal is a human.

14. The method according to claim 12 , wherein said emesis is delayed emesis.

15. The method according to claim 12 , wherein said emesis is anticipatory emesis.

16. The method according to claim 12 , wherein said emesis is induced by cancer chemotherapeutic agents.

17. The method according to claim 16 , wherein said cancer chemotherapeutic agent is selected from the group consisting of cyclophosphamide carmustine, lomustine, chlorambucil, dactinomycin, doxorubicin, mitomycin-C, bleomycin, cytarabine, methotrexate, 5-fluorouracil, etoposide, vinblastine, vincristine, cisplatin, dacarbazine, procarbazine and hydroyurea.

18. The method according to claim 12 , wherein said emesis is induced by radiation sickness or radiation therapy.

19. The method according to claim 12 , wherein said emesis is induced by pregnancy.

20. The method according to claim 12 , wherein said emesis is induced by post-operative sickness.

21. The method according to claim 12 , wherein said emesis is induced by migraine.

22. The method according to claim 12 , wherein said emesis is induced by opiod analgesics.

23. The method according to claim 1 , further comprising administering an effective amount of a 5-HT3 antagonist.

24. The method according to claim 23 , wherein said 5-HT3 antagonist is selected from the group consisting of ondansetron, granisetron and metoclopramide.

25. The method according to claim 12 , further comprising administering an effective amount of a 5-HT3 antagonist.

26. The method according to claim 25 , wherein said 5-HT3 antagonist is selected from the group consisting of ondansetron, granisetron and metoclopramide.

27. A method for the treatment of emesis in a mammal comprising administering to said mammal an effective amount of 2-(S)-(4-Fluoro-2-methyl-phenyl)-4-(piperidine-4-carbonyl)-piperazine-1carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride.

28. A method for the treatment of emesis 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.

29. A method for the treatment of emesis 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 methanesulphonate.

30. A method for the treatment of emesis 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.

31. A method for the treatment of emesis 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 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.