Piperazine derivatives as tachykinin antagonists

Abstract

This invention relates to piperazine derivatives of the formula: wherein each symbol is as defined in the description, and its pharmaceutically acceptable salt, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a use of the same for treating or Tachykinin-mediated diseases in human being or animals.

1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 Y is bond or lower alkylene,  
 R 1  is aryl which may have suitable substituent(s),  
 R 2  is aryl or indolyl each of which may have suitable substituent(s),  
 R 3  is hydrogen or lower alkyl,  
 R 4  is chloro(lower)alkenyl; 
 chloro(lower)alkynyl;  
 pyridyl(lower)alkylamino(lower)alkyl;  
 pyridyl(lower)alkylamino(lower)alkenyl;  
 N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl;  
 triazolylamino(lower)alkyl;  
 lower alkoxy(lower)alkylamino(lower)alkyl;  
 bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl;  
 N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino (lower)alkyl;  
 hydroxy(lower)alkyl;  
 lower alkylsulfonyloxy(lower)alkyl;  
 phenyl(lower)alkyl which may have lower alkanoyl,  
 amino, lower alkanoylamino,  
 di(lower)alkylaminocarbonyl or nitro;  
 lower alkoxyphenyl(lower)alkylcarbonyl;  
 lower alkanoylbenzoyl;  
 benzoyl(lower)alkyl which has lower alkyl, chlorine or di(lower)alkylamino;  
 benzoyl(lower)alkyl which has halogen and lower alkyl;  
 dihalobenzoyl(lower)alkyl;  
 di(lower)alkylbenzoyl(lower)alkyl;  
 3-fluorobenzoyl(lower)alkyl;  
 3-(4-fluorobenzoyl)propyl;  
 4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;  
 piperazinylcarbonyl(lower)alkyl which has cyclopentyl or halophenyl;  
 (2-pyridyl)(lower)alkyl;  
 (3-pyridyl)propyl;  
 (3-pyridyl)(lower)alkynyl;  
 imidazolyl(lower)alkyl which may have lower alkyl;  
 pyrazolyl(lower)alkyl which may have lower alkyl;  
 thiomorpholinylcarbonyl(lower)alkyl;  
 (3-azabicyclo[3.2.2]non-3-yl)carbonyl(lower)alkyl; or  
 thienylcarbonyl(lower)alkyl,  
 1,2,3,6-tetrahydropyridyl(lower)alkyl,  
 1,2,3,6-tetrahydropyridyl(lower)alkynyl,  
 1,2,3,4-tetrahydroisoquinolyl(lower)alkyl,  
 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower)alkyl,  
 saturated heterocyclic(lower)alkyl,  
 saturated heterocyclic(lower)alkenyl,  
 saturated heterocyclic(lower)alkynyl,  
 saturated heterocyclicamino(lower)alkyl,  
 saturated heterocyclicamino(lower)alkenyl or  
 saturated heterocyclicamino(lower)alkynyl, each of which may have suitable substituent(s),  
 and a pharmaceutically acceptable salt thereof.  
 
 
     
     
         2 . The compound of  claim 1 , in which 
 Y is lower alkylene,    R 1  is C 6 -C 10  aryl which may have 1 to 3 mono(or di or tri)halo(lower)alkyl,    R 2  is C 6 -C 10  aryl or indolyl, each of which may have 1 to 3 suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl and halogen,    R 3  is hydrogen, and    R 4  is chloro(lower)alkenyl; 
 chloro(lower)alkynyl;  
 pyridyl(lower)alkylamino(lower)alkyl;  
 pyridyl(lower)alkylamino(lower)alkenyl;  
 N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl;  
 triazolylamino(lower)alkyl;  
 lower alkoxy(lower)alkylamino(lower)alkyl;  
 bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl;  
 N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino (lower) alkyl;  
 hydroxy(lower)alkyl;  
 lower alkylsulfonyloxy(lower)alkyl;  
 phenyl(lower)alkyl which may have lower alkanoyl, amino, lower alkanoylamino,  
 di(lower)alkylaminocarbonyl or nitro;  
 lower alkoxyphenyl(lower)alkylcarbonyl;  
 lower alkanoylbenzoyl;  
 benzoyl(lower)alkyl which has lower alkyl, chlorine or di(lower)alkylamino;  
 benzoyl(lower)alkyl which has halogen and lower alkyl;  
 dihalobenzoyl(lower)alkyl;  
 di(lower)alkylbenzoyl(lower)alkyl;  
 3-fluorobenzoyl(lower)alkyl;  
 3-(4-fluorobenzoyl)propyl;  
   4 , 4 -ethylenedioxy-4-(4-fluorophenyl)butyl;  
 piperazinylcarbonyl(lower)alkyl which has cyclopentyl or halophenyl;  
 (2-pyridyl)(lower)alkyl;  
 (3-pyridyl)propyl;  
 (3-pyridyl)(lower)alkynyl;  
 imidazolyl(lower)alkyl which may have lower alkyl;  
 pyrazolyl(lower)alkyl which may have lower alkyl;  
 thiomorpholinylcarbonyl(lower)alkyl;  
 (3-azabicyclo[3.2.2]non-3-yl)carbonyl(lower)alkyl; or  
 thienylcarbonyl(lower)alkyl,  
 1,2,3,6-tetrahydropyridyl(lower)alkyl,  
 1,2,3,6-tetrahydropyridyl(lower)alkynyl,  
 1,2,3,4-tetrahydroisoquinolyl(lower)alkyl, 4,5,6,7-tetrahydrothieno [3,2-c]pyridinyl(lower)alkyl,  
 saturated heterocyclic(lower)alkyl,  
 saturated heterocyclic(lower)alkenyl,  
 saturated heterocyclic(lower)alkynyl,  
 saturated heterocyclicamino(lower)alkyl,  
 saturated heterocyclicamino(lower)alkenyl or  
 saturated heterocyclicamino(lower)alkynyl [wherein “saturated heterocyclic moiety” is saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s);  
 saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s);  
 saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s); or  
 saturated heterocyclic group of the formula:  
                     
  each of which may have 1 to 3 suitable substituent(s) selected from the group consisting of cyclo(lower)alkyl, lower alkanoyl, lower alkyl, mono(or di or tri)halo(lower)alkyl, lower alkoxy, lower alkoxy(lower)alkyl, halogen, C 6 -C 10  aryl, cyano, oxo and bivalent group of the formula:  
                     
   
     
     
         3 . The compound of  claim 2 , in which 
 Y is lower alkylene,    R 1  is phenyl which may have 1 or 2 mono(or di or tri)halo(lower)alkyl,    R 2  is phenyl, naphthyl or indolyl, each of which may have 1 or 2 suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl and halogen,    R 3  is hydrogen, and    R 4  is chloro(lower)alkenyl; 
 chloro(lower)alkynyl;  
 pyridyl(lower)alkylamino(lower)alkyl;  
 pyridyl(lower)alkylamino(lower)alkenyl;  
 N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl;  
 triazolylamino(lower)alkyl;  
 lower alkoxy(lower)alkylamino(lower)alkyl;  
 bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl;  
 N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino (lower)alkyl;  
 hydroxy(lower)alkyl;  
 lower alkylsulfonyloxy(lower)alkyl;  
 phenyl(lower)alkyl which may have lower alkanoyl, amino, lower alkanoylamino, di(lower)alkylaminocarbonyl or nitro;  
 lower alkoxyphenyl(lower)alkylcarbonyl;  
 lower alkanoylbenzoyl;  
 benzoyl(lower)alkyl which has lower alkyl, chlorine or di(lower)alkylamino;  
 benzoyl(lower)alkyl which has halogen and lower alkyl;  
 dihalobenzoyl(lower)alkyl;  
 di(lower)alkylbenzoyl(lower)alkyl;  
 3-fluorobenzoyl(lower)alkyl;  
 3-(4-fluorobenzoyl)propyl;  
 4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;  
 piperazinylcarbonyl(lower)alkyl which has cyclopentyl or halophenyl;  
 (2-pyridyl)(lower)alkyl;  
 (3-pyridyl) propyl;  
 (3-pyridyl)(lower)alkynyl;  
 imidazolyl(lower)alkyl which may have lower alkyl;  
 pyrazolyl(lower)alkyl which may have lower alkyl;  
 thiomorpholinylcarbonyl(lower)alkyl;  
 (3-azabicyclo[3.2.2]non-3-yl)carbonyl(lower)alkyl; or  
 thienylcarbonyl(lower)alkyl,  
 1,2,3,6-tetrahydropyridyl(lower)alkyl,  
 1,2,3,6-tetrahydropyridyl(lower)alkynyl,  
 1,2,3,4-tetrahydroisoquinolyl(lower)alkyl, 4,5,6,7-tetrahydrothieno [3,2-c]pyridinyl(lower)alkyl,  
 saturated heterocyclic(lower)alkyl,  
 saturated heterocyclic(lower)alkenyl,  
 saturated heterocyclic(lower)alkynyl,  
 saturated heterocyclicamino(lower)alkyl,  
 saturated heterocyclicamino(lower)alkenyl or  
 saturated heterocyclicamino(lower)alkynyl [wherein “saturated heterocyclic moiety” is pyrrolidinyl, piperidyl, piperazinyl, hexamethyleneimino, morpholinyl, homomorpholinyl, thiomorpholinyl or 3-azabicyclo[3.2.2]non-3-yl], each of which may have 1 or 2 suitable substituent(s) selected from the group consisting of cyclo(lower)alkyl, lower alkanoyl, lower alkyl, mono(or di or tri)halo(lower)alkyl, lower alkoxy, lower alkoxy(lower)alkyl, halogen, phenyl, cyano, oxo and bivalent group of the formula:  
                     
   
     
     
         4 . The compound of  claim 3 , in which 
 Y is lower alkylene,    R 1  is phenyl which may have 1 or 2 mono(or di or tri)halo(lower)alkyl,    R 2  is phenyl which may have 1 or 2 suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl and halogen, naphthyl or indolyl,    R 3  is hydrogen, and    R 4  is (2-pyridyl)(lower)alkyl; 
 (3-pyridyl)propyl;  
 (3-pyridyl)(lower)alkynyl;  
 imidazolyl(lower)alkyl which may have lower alkyl;  
 pyrazolyl(lower)alkyl which may have lower alkyl;  
 pyridyl(lower)alkylamino(lower)alkyl;  
 pyridyl(lower)alkylamino(lower)alkenyl;  
 N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl;  
 triazolylamino(lower)alkyl;  
 lower alkoxy(lower)alkylamino(lower)alkyl;  
 bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl;  
 N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino(lower)alkyl;  
 1,2,3,6-tetrahydropyridyl(lower)alkyl;  
 1,2,3,6-tetrahydropyridyl(lower)alkynyl;  
 1,2,3,4-tetrahydroisoquinolyl(lower)alkyl; or  
   4 , 5 , 6 , 7 -tetrahydrothieno[3,2-c]pyridinyl(lower) alkyl.  
   
     
     
         5 . The compound of  claim 3 , in which 
 Y is lower alkylene,    R 1  is phenyl which may have 1 or 2 mono(or di or tri)halo(lower)alkyl,    R 2  is phenyl which may have 1 or 2 suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl and halogen, naphthyl or indolyl,    R 3  is hydrogen, and    R 4  is morpholinyl(lower)alkyl which may have 1 or 2 lower alkyl; 
 homomorpholinyl(lower)alkyl;  
 rhiomorpholinyl(lower)alkyl;  
 (hexamethyleneimino)(lower)alkyl;  
 (3-azabicyclo[3.2.2]non-3-yl)(lower)alkyl;  
 piperazinyl(lower)alkyl which may have phenyl or cyclo(lower)alkyl;  
 inorpholinyl(lower)alkenyl which may have 1 or 2 lower alkyl;  
 morpholinyl(lower)alkynyl which may have 1 or 2 lower alkyl, lower alkoxy(lower)alkyl or mono(or di or tri)halo(lower)alkyl;  
 thiomorpholinyl(lower) alkenyl;  
 thiomorpholinyl(lower)alkynyl;  
 pyrrolidinyl(lower)alkynyl which may have lower alkoxy(lower)alkyl;  
 piperazinyl(lower)alkynyl which may have cyclo (lower)alkyl;  
 morpholinylamino(lower)alkyl;  
 morpholinylamino(lower)alkenyl;  
 morpholinylamino(lower)alkynyl;  
 [spiro[indan-1,4′-piperidinel-1′-yl](lower)alkyl;  
 piperidyl(lower)alkyl which has phenyl, lower alkoxy, lower alkanoyl, piperidyl or oxo; or  
 piperidyl(lower)alkyl which has phenyl and cyano.  
   
     
     
         6 . The compound of  claim 5 , in which 
 Y is lower alkylene,    R 1  is phenyl which may have 1 or 2 mono(or di or tri) halo(lower)alkyl,    R 2  is phenyl which may have 1 or 2 suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl and halogen, naphthyl or indolyl,    R 3  is hydrogen, and    R 4  is morpholinyl(lower)alkyl which may have 1 or 2 methyl; 
 homomorpholinyl(lower)alkyl;  
 thiomorpholinyl(lower)alkyl;  
 (hexamethyleneimino)(lower)alkyl;  
 (3-azabicyclo[3.2.2]non-3-yl)(lower)alkyl;  
 piperazinyl(lower)alkyl which has phenyl or cyclohexyl;  
 morpholinyl(lower)alkenyl which may have 1 or 2 methyl;  
 morpholinyl(lower)alkynyl which may have 1 or 2 methyl, methoxymethyl or fluoromethyl;  
 thiomorpholinyl(lower)alkenyl;  
 thiomorpholinyl(lower)alkynyl;  
 pyrrolidinyl(lower)alkynyl which may have methoxymethyl;  
 piperazinyl(lower)alkynyl which may have cyclohexyl;  
 morpholinylamino(lower)alkyl;  
 morpholinylamino(lower)alkenyl;  
 morpholinylamino(lower)alkynyl;  
 [spiro[indan-1,4′-piperidine]-1′-yl](lower)alkyl;  
 piperidyl(lower)alkyl which has phenyl, methoxy, acetyl, piperidyl or oxo; or  
 piperidyl(lower)alkyl which has phenyl and cyano.  
   
     
     
         7 . The compound of  claim 6 , in which 
 Y is methylene,    R 1  is bis(trifluoromethyl)phenyl,    R 2  is phenyl or naphthyl, each of which may have 1 or 2 suitable substituent(s) selected from the group consisting of methyl, methoxy, trifluoromethyl and fluorine, or indolyl,    R 3  is hydrogen, and    R 4  is thiomorpholinyl(C 1 -C 4 )alkyl; 
 morpholinyl(C 2 -C 4 )alkenyl which may have 1 or 2 methyl;  
 morpholinyl(C 2 -C 5 )alkynyl which may have 1 or 2 methyl, methoxymethyl or fluoromethyl; or  
 morpholinylamino(C 1 -C 4 )alkyl.  
   
     
     
         8 . The compound of  claim 7 , which is selected from the group consisting of 
 (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3 -ylmethyl)-4-(3-thiomorpholinopropyl)- piperazine,    (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(4-morpholino-2 -butynyl)-2-(2-naphthylmethyl) piperazine,    (3) (2R)-4-(4-Morpholino-2-butynyl)-1-[3,5-bis (trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) piperazine,    (4) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4 -[3-(morpholinoamino)propyl]piperazine and    (5) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4 -[(E)-4-morpholino-2-butenyl]piperazine,    or a pharmaceutically acceptable salt thereof.    
     
     
         9 . A process for the preparation of compound of the following general formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 Y is bond or lower alkylene,  
 R 1  is aryl which may have suitable substituent(s),  
 R 2  is aryl or indolyl each of which may have suitable substituent(s),  
 R 3  is hydrogen or lower alkyl,  
 R 4  is chloro(lower)alkenyl; 
 chloro(lower)alkynyl;  
 pyridyl(lower)alkylamino(lower)alkyl;  
 pyridyl(lower)alkylamino(lower)alkenyl;  
 N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl;  
 triazolylamino(lower)alkyl;  
 lower alkoxy(lower)alkylamino(lower)alkyl;  
 bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl;  
 N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino (lower) alkyl;  
 hydroxy(lower)alkyl;  
 lower alkylsulfonyloxy(lower)alkyl;  
 phenyl(lower)alkyl which may have lower alkanoyl, amino, lower alkanoylamino, di(lower)alkylaminocarbonyl or nitro;  
 lower alkoxyphenyl(lower)alkylcarbonyl;  
 lower alkanoylbenzoyl;  
 benzoyl(lower)alkyl which has lower alkyl, chlorine or di(lower)alkylamino;  
 benzoyl(lower)alkyl which has halogen and lower alkyl;  
 dihalobenzoyl(lower)alkyl;  
 di(lower)alkylbenzoyl(lower)alkyl;  
 3-fluorobenzoyl(lower)alkyl;  
 3-(4-fluorobenzoyl)propyl;  
 4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;  
 piperazinylcarbonyl(lower)alkyl which has cyclopentyl or halophenyl;  
 (2-pyridyl)(lower)alkyl;  
 (3-pyridyl)propyl;  
 (3-pyridyl)(lower)alkynyl;  
 imidazolyl(lower)alkyl which may have lower alkyl;  
 pyrazolyl(lower)alkyl which may have lower alkyl;  
 thiomorpholinylcarbonyl(lower)alkyl;  
 (3-azabicyclo[3.2.2]non-3-yl)carbonyl(lower)alkyl; or  
 thienylcarbonyl(lower)alkyl,  
 1,2,3,6-tetrahydropyridyl(lower)alkyl,  
 1,2,3,6-tetrahydropyridyl(lower)alkynyl,  
 1,2,3,4-tetrahydroisoquinolyl(lower)alkyl,  
 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower) alkyl,  
 saturated heterocyclic(lower)alkyl,  
 saturated heterocyclic(lower)alkenyl,  
 saturated heterocyclic(lower)alkynyl,  
 saturated heterocyclicamino(lower)alkyl,  
 saturated heterocyclicamino(lower)alkenyl or  
 saturated heterocyclicamino(lower)alkynyl, each of which may have suitable substituent(s), or  
 a salt thereof,  
 which comprises  
 
 (1) reacting a compound of the formula:  
                     
  or its reactive derivative at the imino group or a salt thereof with a compound of the formula 
 W 1 -R 4   
  or a salt thereof to provide a compound of the formula:  
                     
  or a salt thereof, in the above formulas, 
 Y, R 1 , R 2 , R 3  and R 4  are each as defined above, and  
 W 1  is a leaving group, or  
 
 (2) reacting a compound of the formula:  
                     
  or its reactive derivative at the imino group or a salt thereof with a compound of the formula:  
                     
  or its reactive derivative at the carboxy group or a salt thereof to provide a compound of the formula:  
                     
  or a salt thereof, in the above formulas, 
 Y, R 1 , R 2  and R 3  are each as defined above, and  
 R 5  is lower alkoxyphenyl(lower)alkyl or lower alkanoylphenyl, or  
 
 (3) reacting a compound of the formula:  
                     
  or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula: 
 H-R 6   
  or a salt thereof to provide a compound of the formula:  
                     
  or a salt thereof, in the above formulas, 
 Y, R 1 , R 2  and R 3  are each as defined above,  
 X is lower alkylene, and  
 R 6  is piperazinyl which has cyclopentyl or halophenyl; or thiomorpholinyl, or  
 
 (4) subjecting a compound of the formula:  
                     
  or a salt thereof to an acylation reaction to provide a compound of the formula:  
                     
  or a salt thereof, in the above formulas, 
 X, Y, R 1 , R 2  and R 3  are each as defined above, and  
 R 7  is acyloxy, or  
 
 (5) reacting a compound of the formula:  
                     
  or a salt thereof with a compound of the formula: 
 H-R 8    
  or a salt thereof to provide a compound of the formula:  
                     
  or a salt thereof, in the above formulas, 
 X, Y, R 1 , R 2  and R 3  are each as defined above, and  
 R 8  is pyridyl(lower)alkylamino; 
 N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino;  
 triazolylamino; morpholinoamino;  
 lower alkoxy(lower)alkylamino;  
 bis[(lower)alkoxy(lower)alkyl]amino;  
 N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino;  
 imidazolyl; pyrazolyl; or  
 1,2,3,6-tetrahydropyridyl,  
 1,2,3,4-tetrahydroisoquinolyl,  
 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl or saturated heterocyclic, each of which may have suitable substituent(s), or  
 
 
 (6) subjecting a compound of the formula:  
                     
  or a salt thereof to a reduction reaction to provide a compound of the formula:  
                     
  or a salt thereof, in the above formulas, 
 X, Y, R 1 , R 2  and R 3  are each as defined above, or  
 
 (7) reacting a compound of the formula:  
                     
  or a salt thereof with a compound of the formula: 
 W 2 -R 9    
  or a salt thereof to provide a compound of the formula:  
                     
  or a salt thereof, in the above formulas, 
 X, Y, R 1 , R 2  and R 3  are each as defined above,  
 W 2  is a leaving group, and  
 R 9  is lower alkanoyl.  
 
 
     
     
         10 . A pharmaceutical composition which comprises, as an active ingredient, a compound of  claim 1  or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.  
     
     
         11 . A use of a compound of  claim 1  as a medicament.  
     
     
         12 . A method for treating or preventing Tachykinin-mediated diseases which comprises administering an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof to human being or animals.  
     
     
         13 . A compound of  claim 1  for use as a medicament.  
     
     
         14 . Use of a compound of  claim 1  for manufacture of a medicament for treating or preventing Tachykinin-mediated diseases.