Aroyl-piperazine derivatives, their preparation and their use as tachykinin antagonists

Abstract

This invention relates to piperazine derivatives of formula (I), wherein Y is bond or lower alkylene, R1 is aryl which may have substituent(s), R2 is aryl or indolyl, each of which may have substituent(s), R3 is hydrogen or lower alkyl, and R4 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 preventing Tachykinin-mediated diseases in human beings or animals.

1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 Y is bond or lower alkylene,  
 R 1  is aryl which may have substituent(s),  
 R 2  is aryl or indolyl, each of which may have substituent(s),  
 R 3  is hydrogen or lower alkyl,  
 R 4  is pyridyl(lower)alkylamino(lower)alkynyl; 
 N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino-(lower)alkyl;  
 hydroxy(lower)alkoxy(lower)alkyl;  
 lower alkanoyl(lower)alkoxy(lower)alkyl;  
 phenyl(lower)alkyl which has hydroxy(lower)alkyl or morpholinyl(lower)alkyl;  
 ar(lower)alkoxycarbonyl;  
 (2-pyridyl)(lower)alkyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono(or di or tri)halo(lqwer)alkyl and halogen;  
 (3-pyridyl)propyl which may have lower alkoxy or amino;  
 (3-pyridyl)butyl which may have lower alkoxy or amino;  
 pyridyl(lower)alkenyl which may have lower alkoxy or amino;  
 (2-pyridyl)(lower)alkynyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono(or di or tri)halo(lower)alkyl and halogen;  
 (3-pyridyl)(lower)alkynyl which may have lower alkoxy or amino;  
 pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have substituent(s);  
 imidazolyl(lower)alkyl which may have 1 or 2 substituent(s) selected from the group consisting of lower alkyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen;  
 pyrazolyl(lower)alkyl which may have hydroxy(lower)alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, morpholinyl(lower)alkyl or morpholinylcarbonyl(lower)alkyl;  
 thiazolyl(lower)alkyl which may have lower alkyl;  
 piperidyl(lower)alkyl which may have hydroxy(lower)alkyl or lower alkoxy;  
 morpholinyl(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy(lower)alkyl;  
 morpholinyl(lower)alkyl which has lower alkyl and lower alkoxy(lower)alkyl;  
 (3,5-dimethylmorpholino)(lower)alkyl; morpholino(lower)alkenyl which may have lower alkyl or lower alkoxy(lower)alkyl;  
 (2- or 3-morpholinyl)(lower)alkenyl which may have lower alkoxycarbonyl;  
 pyrrolidinyl(lower)alkynyl which may have lower alkoxy(lower)alkyl;  
 morpholinyl(lower)alkynyl which may have 1 or 2 substituent(s) selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl and halo(lower)alkyl;  
 morpholinyl(lower)alkynyl which has methyl and lower alkoxy;  
 (dimethylmorpholino)(lower)alkynyl;  
 homomorpholinyl(lower)alkynyl which have halogen;  
 (morpholinylamino)propyl which may have lower alkanoyl;  
 thiomorpholinyl(lower)alkynyl which may have substituent(s);  
 homomorpholinylamino(lower)alkyl;  
 thiomorpholinylamino(lower)alkyl; or  
 saturated heterocyclicimino(lower)alkyl, saturated heterocyclicaminocarbonyl(lower)alkyl or saturated heterocyclic(lower)alkoxy(lower)alkyl, each of which may have substituent(s),  
 provided that when  
 
 R 4  is 2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl, 
 3-(3-pyridyl)propyl,  
 3-(3-pyridyl)-2-propynyl,  
 4-[(2-methoxymethyl)pyrrolidino]-2-butynyl,  
 4-thiomorpholino-2-butynyl,  
 3-(morphlinoamino)propyl,  
 4-morpholino-2-butenyl,  
 4-morpholino-2-butynyl, or  
 4-(3,3-dimethylmorpholino)-2-butynyl, then  
 
 R 1  is not 3,5-bis(trifluoromethyl)phenyl, and a 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 or 2 substituent(s) selected from the group consisting of mono(or di or tri)halo(lower)alkyl, halogen, lower alkylamino, di(lower)alkylamino and nitro,    R 2  is C 6 -C 10  aryl or indolyl, each of which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, mono(or di or tri)halo(lower)alkyl, lower alkylenedioxy, hydroxy, hydroxy(lower)alkyl, lower alkoxy, lower alkylamino and di(lower)alkylamino,    R 3  is hydrogen, and    R 4  is pyridyl(lower)alkylamino(lower)alkynyl; 
 (2-pyridyl)propyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono(or di or tri)halo(lower)alkyl and halogen;  
 pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have 1 or 2 substituent(s) selected from the group consisting of lower alkyl, ar(lower)alkyl and pyridyl(lower)alkyl;  
 imidazolyl(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of lower alkyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen;  
 (2-methyl-1H-imidazol-4-yl)(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of isopropyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen;  
 (5-methyl-1H-imidazol-4-yl)(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of isopropyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen;  
 piperidyl(lower)alkyl which may have hydroxy(lower)alkyl or lower alkoxy;  
 morpholinyl(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy(lower)alkyl;  
 morpholinyl(lower)alkyl which has lower alkyl and lower alkoxy(lower)alkyl;  
 (3,5-dimethylmorpholino)(lower)alkyl;  
 morpholino(lower)alkenyl which may have lower alkyl or lower alkoxy(lower)alkyl;  
 (2- or 3-morpholinyl)(lower)alkenyl which may have lower alkoxycarbonyl;  
 pyrrolidinyl(lower)alkynyl which may have lower alkoxy(lower)alkyl;  
 morpholinyl(lower)alkynyl which may have 1 or 2 substituent(s) selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl and halo(lower)alkyl;  
 morpholinyl(lower)alkynyl which has methyl and lower alkoxy(lower)alkyl;  
 (dimethylmorpholino)(lower)alkynyl; or  
 homomorpholinyl(lower)alkynyl which may have halogen.  
   
     
     
         3 . The compound of  claim 2 , in which 
 Y is lower alkylene,    R 1  is phenyl which has 1 or 2 substituent(s) selected from the group consisting of trihalo(lower)alkyl, halogen, lower alkylamino, di(lower)alkylamino and nitro,    R 2  is phenyl or indolyl, each of which have 1 or 2 substituent(s) selected from the group consisting of lower alkyl, trihalo(lower)alkyl, lower alkylenedioxy, hydroxy, hydroxy(lower)alkyl, lower alkoxy, lower alkylamino and di(lower)alkylamino,    R 3  is hydrogen, and    R 4  is (2-pyridyl)propyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl and halogen; 
 morpholinyl(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy(lower)alkyl;  
 morpholinyl(lower)alkynyl which may have 1 or 2 substituent(s) selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl and halo(lower)alkyl.  
   
     
     
         4 . A compound of  claim 3 , which is selected from the group consisting of 
 (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(4-((3S)-3-ethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]piperazine,    (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((2S)-2-methoxymethyl-morpholino)ethyl]piperazine,    (3) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((3R)-3-methoxymethyl-morpholino)ethyl]piperazine,    (4) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl[-2-(3,4-dimethylbenzyl)-4-[2-((2R)-2-methoxymethyl-morpholino)ethyl]piperazine,    (5) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[2-((2S)-2-methoxymethyl-morpholino)ethyl]piperazine, and    (6) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-((3R)-3-ethylmorpholino)ethyl]-2-[(1H-indol-3-yl)-methyl]piperazine    or a pharmaceutically acceptable salt thereof.    
     
     
         5 . A process for the preparation of the compound of  claim 1  or a salt thereof, which comprises, 
 (1) reacting a compound of the formula (II):  
                     
 wherein R 1 , R 2   1  R 3  and Y are each as defined in  claim 1 , or a salt thereof, with a compound of the formula (III): 
 W 1 -R 4   (IV) 
 wherein R 4  is as defined in  claim 1  and  
 W 1  is a leaving group,  
 or a salt thereof to give a compound of the formula (I):  
                     
 wherein R 1   1  R 2 , R 3 , R 4  and Y are each as defined in  claim 1 , or a salt thereof,  
 (2) subjecting a compound of the formula (Ia):  
                     
 wherein R 1 , R 2 , R 3  and Y are each as defined above,  
 R 5  is 2-pyridyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono(or di or tri)halo(loweralkyl and halogen; or 3-pyridyl which may have lower alkoxy or amino, and  
 Z 1  is lower alkynylene,  
 or a salt thereof to a reduction reaction to give a compound of the formula (Ib):  
                     
 wherein R 1 , R 2 , R 3 , Y and R 5  are each as defined above, and  
 X 1  is lower alkylene,  
 or a salt thereof,  
 (3) reacting a compound of the formula (III):  
                     
 wherein R 1   1  R 2 , R 3  and Y are each as defined above, and  
 X 2  is lower alkylene,  
 or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula (V): 
 H 2 N—R 6   (V) 
 wherein R 6 is saturated heterocyclic which may have substituent(s),  
 or a salt thereof to give a compound (Ic):  
                     
 wherein R 1 , R 2 , R 3 , R 6 , X 2  and Y are each as defined above,  
 (4) reacting a compound of the formula (VI):  
                     
 wherein R 1 , R 2 , R 3  and Y are each as defined above,  
 X 3  is lower alkylene and  
 W 2  is a leaving group,  
 or a salt thereof with a compound of the formula (VII): 
 H—R 7   (VII) 
 wherein  
 R 7  is pyridyl(lower)alkylamino; 
 N-(lower alkyl)-N-(pyridyl(lower)alkyl]-amino;  
 1-imidazolyl which may have 1 or 2 substituent(s) selected from the group consisting of lower alkyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, rmono(or di or tri)halo(lower)alkyl and halogen;  
 1-pyrazolyl which may have hydroxy(lower)alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, morpholinyl(lower)alkyl or morpholinylcarbonyl(lower)alkyl;  
 piperidino which may have hydroxy(lower)alkyl or lower alkoxy;  
 morpholino which has 1 or 2 substituent(s) selected from the group consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy-(lower)alkyl;  
 morpholino which has lower alkyl and lower alkoxy(lower)alkyl;  
 3,5-dimethylmorpholino;  
 morpholinylamino which may have lower alkanoyl;  
 homomorpholinylamino; or  
 thiomorpholinylamino,  
 or a salt thereof to give a compound of the formula (Id):  
                     
 wherein R 1 , R 2 , R 3 , R 7 , X 3  and Y are each as defined above,  
 or a salt thereof,  
 
 (5) reacting a compound of the formula (VIII):  
                     
 wherein R 1   1 , R 2 , R 3  and Y are each as defined above,  
 Z 2  is lower alkenylene, and  
 W 3  is a leaving group,  
 or a salt thereof with a compound of the formula (IX): 
 H—R 8   (IX) 
 wherein R 8  is morpholino which may have lower alkyl or lower alkoxy(lower)alkyl,  
 or a salt thereof to give a compound of the formula (Ie):  
                     
 wherein R 1 , R 2 , R 3 , R 8 , Y and Z 2  are as defined as above,  
 or a salt thereof,  
 (6) reacting compound of the formula (X):  
                     
 wherein  
 R 1 , R 2 , R 3  and Y are each as defined above,  
 Z 3  is a lower alkynylene and  
 W 4  is a leaving group,  
 or a salt thereof with a compound of the formula (XI): 
 H—R 9   (XI) 
 wherein R 9  is pyrrolidino which may have lower alkoxy(lower)alkyl; 
 morpholino which may have 1 or 2 substituent(s) selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl and halo(lower)alkyl;  
 morpholino which has methyl and lower alkoxy;  
 dimethylmorpholino; or  
 homomorpholino which has halogen,  
 or a salt thereof to give a compound of the formula (If):  
                     
 wherein R 1 , R 2 , R 3 , R 9 , Y and Z 3  are each as defined above,  
 or a salt thereof.  
 
 
     
     
         6 . 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.  
     
     
         7 . A compound of  claim 1  for use as a medicament.  
     
     
         8 . 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.  
     
     
         9 . A compound of  claim 1  for use as Tachykinin antagonist.  
     
     
         10 . Use of a compound of  claim 1  for manufacture of a medicament for treating or preventing Tachykinin-mediated diseases.