Tripeptidyl peptidase inhibitors

Abstract

The present invention is concerned with novel compounds of formula (I) which are inhibitors of a membrane tripeptidyl peptidase responsible for the inactivation of endogenous neuropeptides such as cholecystokinis (CCKs). The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use as a medicine of said compounds. wherein n is an integer 0 or 1; X represents O; S; or —(CR 4 R 5 ) m — wherein m is an integer 1 or 2; R 4 and R 5 are each independently from each other hydrogen or C 1-4 alkyl; R 1 is C 1-6 alkylcarbonyl optionally substituted with hydroxy; C 1-6 alkyloxycarbonyl; aminoC 1-6 alkylcarbonyl wherein the C 1-6 alkyl group is optionally substituted with C 3-6 cycloalkyl; mono- and di(C 1-4 alkyl)aminoC 1-6 alkylcarbonyl; aminocarbonyl substituted with aryl; C 1-6 alkylcarbonyloxyC 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonylaminoC 1-6 alkylcarbonyl wherein the amino group is optionally substituted with C 1-4 alkyl; an amino acid; C 1-6 alkyl substituted with amino; or arylcarbonyl; R 2 is an optionally substituted 5-membered heterocycle, or R 2 is optionally substituted benzimidazole; R 3 is a bivalent radical —CH 2 CH 2 — optionally substituted with halo or phenylmethyl; or R 3 is a bivalent radical of formula

1 . A compound of formula (I)  
     
       
         
         
             
             
         
       
     
     a stereochemically isomeric form thereof, or a pharmaceutically acceptable addition salt thereof, wherein 
 n is an integer 0;  
 X represents —(CR 4 R 5 ) m — wherein m is 1; R 4  and R 5  are each independently from each other hydrogen or C 1-4 alkyl;  
 R 1  is C 1-6 alkylcarbonyl optionally substituted with hydroxy; 
 aminoC 1-6 alkylcarbonyl wherein the C 1-6 alkyl group is optionally substituted with C 3-6 cycloalkyl; mono- and di(C 1-4 alkyl)aminoC 1-6 alkylcarbonyl; aminocarbonyl substituted with aryl; C 1-6 alkylcarbonyloxyC 1-6 alkylcarbonyl;  
 C 1-6 alkyloxycarbonylaminoC 1-6 alkylcarbonyl wherein the amino group is optionally substituted with C 1-4 alkyl; an amino acid bound via the carbonyl group; C 1-6 alkyl substituted with amino; or arylcarbonyl;  
 
 R 2  is  
                     wherein m′ is an integer 1 to 2;    R 6  is hydrogen or C 1-4 alkyl;    R 7  is independently from each other halo; trifluoromethyl; C 1-6 alkyl; phenyl; aminocarbonyl; hydroxycarbonyl; or    C 1-4 alkyloxycarbonyl;    
 or R 2  is benzimidazole, or benzimidazole substituted with one or two substituents each independently selected from halo, trifluoromethyl, C 1-4 alkyl, hydroxy, hydroxycarbonyl, or C 1-4 alkyloxycarbonyl;  
 R 3  is a bivalent radical of formula  
                     wherein said (b-1) optionally can be substituted with one, two or three substituents each independently selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkyloxy, nitro, amino, cyano, trifluoromethyl, phenyl, or phenyl substituted with one or two subsitutents each independently selected from halo, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkyloxy, nitro, cyano, and trifluoromethyl;    
 aryl is phenyl, or phenyl substituted with amino, nitro or hydroxycarbonyl.  
 
   
   
       2 . A compound as claimed in  claim 1  wherein n is 0 and R3 is a radical of formula (b 1) optionally substituted with halo or methoxy.  
   
   
       3 . A compound as claimed in  claim 1  wherein n is 0, R3 is a radical of formula (b-1) optionally substituted with halo or methoxy, and X represents —CH2- or —CH2CH2-.  
   
   
       4 . A compound according to  claim 1  wherein R 2  is (a-2).  
   
   
       5 . A compound according to  claim 1  wherein R1 is C 1-6 alkylcarbonyl, aminoC 1-6 alkylcarbonyl or an amino acid.  
   
   
       6 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in  claim 1 .  
   
   
       7 . (canceled)  
   
   
       8 . (canceled)  
   
   
       9 . A process for preparing a compound of formula (I) wherein 
 a) an intermediate of formula (II) is reacted with an intermediate of formula (III) in a reaction-inert solvent and, optionally in the presence of a suitable base, thereby yielding compounds of formula (I-a), defined as compounds of formula (I) wherein R 1a  represents all R 1  substituents other than C 1-4 alkyl substituted with amino; or                          b) an intermediate of formula (II) is reacted with an intermediate of formula (IV), thereby yielding a compound of formula (I-a);                        wherein in the above reaction schemes the radicals R 1 , R 2 , R 3 , and the integer n, are as defined in  claim 1;       c) or, compounds of formula (I) are converted into each other following art-known transformation reactions; or if desired; a compound of formula (I) is converted into an acid addition salt, or conversely, an acid addition salt of a compound of formula (I) is converted into a free base form with alkali; and, if desired, preparing stereochemically isomeric forms thereof.    
   
   
       10 . A method for inhibiting a membrane tripeptidyl peptidase comprising administering an effective amount of a compound of Formula I as claimed in  claim 1 .  
   
   
       11 . A method of treating eating disorders, obesity, psychotic syndromes and associated psychiatric disorders comprising administering an effective amount of a compound of Formula I as claimed in  claim 1.