Treating emesis in a mammal
AssigneeSmithKline Beecham Corporation
InventorsGiuseppe Alvaro, Romano Di Fabio, Riccardo Giovannini, Giuseppe Guercio, Yves St-Denis, Antonella Ursini
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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.
Claims31
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 C1-4 alkyl group;
- R1 is hydrogen or a C1-4 alkyl group;
- R2 is hydrogen, a C1-4 alkyl, C2-6 alkenyl or a C3-7 cycloalkyl group;
- or R1 and R2 together with nitrogen and carbon atom to which they are attached respectively represent a 5-6 membered heterocyclic group;
- R3 is a trifluoromethyl, a C1-4 alkyl, a C1-4 alkoxy, a trifluoromethoxy or a halogen group;
- R4 is hydrogen, a (CH2)qR7 or a (CH2)rCO(CH2)pR7 group;
- R5 is hydrogen, a C1-4 alkyl or a COR6 group;
- R6 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;
- R7 is hydrogen, hydroxy or NR8R9 wherein R8 and R9 represent independently hydrogen or C1-4 alkyl optionally substituted by hydroxy or by amino;
- R10 is hydrogen, a C1-4 alkyl group or R10 together with R2 represents a C3-7 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 R1 and R2 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, B 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.
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-carboxytic acid [(3,5-bis-trifluoromethyl-phenyl)-cyclopropyl-methyl]-methyl-amide;
- or an enantiomer, or pharmaceutically acceptable salt or solvate thereof.
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.
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.
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.
A method for the treatment of emesis in a mammal comprising administering to said mammal an effective amount of 2-(S)-(4-Flouro-2-methyl-phenyl-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide acetate.
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 or an enantiomer or pharmaceutically acceptable salt or solvate thereof.
Dependencies are inferred from the claim text.