Piperidine Derivatives Useful as Modulators of Chemokine Receptor Activity

Abstract

The present invention relates to the compounds of formula (I): in which: and the remaining variables are defined herein. The present invention also relates to a process for preparing such compounds and use of such compounds in the treatment of a chemokine (such as CCR3) or H1 mediated disease state.

1 . A compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein: 
     
       
         
         
             
             
         
       
       n is 0 or 1; 
       X is CH 2 , C(O), O, S, S(O), S(O) 2  or NR 3 ; 
       Y is O; 
       R 1  is hydrogen, C 1-6  alkyl, aryl or heterocyclyl; 
       R 2  is C 3-7  cycloalkyl {optionally substituted by C 1-4  alkyl, aryl or oxo}, C 3-7  cycloalkenyl {optionally substituted by oxo, C 1-6  alkyl or aryl}, aryl or heterocyclyl; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, cyano, nitro, hydroxy, oxo, S(O) p R 4 , OC(O)NR 5 R 6 , NR 7 R 8 , NR 9 C(O)R 10 , NR 11 C(O)NR 12 R 13 , S(O) 2 NR 14 R 15 , NR 16 S(O) 2 R 17 , C(O)NR 18 R 19 , C(O)R 20 , CO 2 R 21 , NR 22 CO 2 R 23 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy(C 1-6 )alkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 1-6  alkoxy(C 1-6 )alkoxy, C 1-6  alkylthio, C 1-6  haloalkylthio, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl (optionally substituted by C 1-4  alkyl or oxo), methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C 1-4 )alkyl, phenoxy, phenylthio, phenyl(C 1-4 )alkoxy, heterocyclyl, heterocyclyl(C 1-4 )alkyl, heterocyclyloxy or heterocyclyl(C 1-4 )alkoxy; wherein any of the immediately foregoing phenyl and heterocyclyl moieties are optionally substituted with halogen, hydroxy, nitro, S(O) q (C 1-4  alkyl), S(O) 2 NH 2 , cyano, C 1-4  alkyl, C 1-4  alkoxy, C(O)NH 2 , C(O)NH(C 1-4  alkyl), C(O)N(C 1-4  alkyl) 2  (and these alkyl groups optionally being joined to form a ring as described for R 5  and R 6  below), CO 2 H, CO 2 (C 1-4  alkyl), NHC(O)(C 1-4  alkyl), NHS(O) 2 (C 1-4  alkyl), C(O)(C 1-4  alkyl), CF 3  or OCF 3 ; 
       M and T are, independently, hydrogen, halogen, cyano, nitro, hydroxy, oxo, S(O) p R 4 , OC(O)NR 5 R 6 , NR 7 R 8 , NR 9 C(O)R 10 , NR 11 C(O)NR 12 R 13 , S(O) 2 NR 14 R 15 , NR 16 S(O) 2 R 17 , C(O)NR 18 R 19 , C(O)R 20 , CO 2 R 21 , NR 22 CO 2 R 23 , C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy(C 1-6 )alkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 1-6  alkoxy(C 1-6 )alkoxy, C 1-6  alkylthio, C 1-6  haloalkylthio, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl (optionally substituted by C 1-4  alkyl or oxo), methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C 1-4 )alkyl, phenoxy, phenylthio, phenyl(C 1-4 )alkoxy, heterocyclyl, heterocyclyl(C 1-4 )alkyl, heterocyclyloxy or heterocyclyl(C 1-4 )alkoxy; wherein any of the immediately foregoing phenyl and heterocyclyl moieties are optionally substituted with halogen, hydroxy, nitro, S(O) q (C 1-4  alkyl), S(O) 2 NH 2 , cyano, C 1-4  alkyl, C 1-4  alkoxy, C(O)NH 2 , C(O)NH(C 1-4  alkyl), C(O)N(C 1-4  alkyl) 2  (and these alkyl groups optionally being joined to form a ring as described for R 5  and R 6  below), CO 2 H, CO 2 (C 1-4  alkyl), NHC(O)(C 1-4  alkyl), NHS(O) 2 (C 1-4  alkyl), C(O)(C 1-4  alkyl), CF 3  or OCF 3 ; 
       p and q are, independently, 0, 1 or 2; 
       R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 18 , R 19 , R 20 , R 21  and R 22  are, independently, hydrogen, C 1-6  alkyl (optionally substituted by halogen, hydroxy or C 3-10  cycloalkyl), CH 2 (C 2-6  alkenyl), phenyl (optionally substituted by halogen, hydroxy, nitro, NH 2 , NH(C 1-4  alkyl), N(C 1-4  alkyl) 2  (and these alkyl groups optionally being joined to form a ring as described for R 5  and R 6  below), S(O) 2 (C 1-4  alkyl), S(O) 2 NH 2 , cyano, C 1-4  alkyl, C 1-4  alkoxy, C(O)NH 2 , C(O)NH(C 1-4  alkyl), C(O)N(C 1-4  alkyl) 2  (and these alkyl groups optionally being joined to form a ring as described for R 5  and R 6  below), CO 2 H, CO 2 (C 1-4  alkyl), NHC(O)(C 1-4  alkyl), NHS(O) 2 (C 1-4  alkyl), C(O)(C 1-4  alkyl), CF 3  or OCF 3 ) or heterocyclyl (optionally substituted by halogen, hydroxy, nitro, NH 2 , NH(C 1-4  alkyl), N(C 1-4  alkyl) 2  (and these alkyl groups optionally being joined to form a ring as described for R 5  and R 6  below), S(O) 2 (C 1-4  alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4  alkyl), S(O) 2 N(C 1-4  alkyl) 2  (and these alkyl groups optionally being joined to form a ring as described for R 5  and R 6  below), cyano, C 1-4  alkyl, C 1-4  alkoxy, C(O)NH 2 , C(O)NH(C 1-4  alkyl), C(O)N(C 1-4  alkyl) 2  (and these alkyl groups optionally being joined to form a ring as described for R 5  and R 6  below), CO 2 H, CO 2 (C 1-4  alkyl), NHC(O)(C 1-4  alkyl), NHS(O) 2 (C 1-4  alkyl), C(O)(C 1-4  alkyl), CF 3  or OCF 3 ); 
       alternatively NR 5 R 6 , NR 7 R 8 , NR 12 R 13  or NR 14 R 15 , or NR 18 R 19 , independently, form a 4-7 membered heterocyclic ring, azetidine, pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter optionally substituted by C 1-4  alkyl on the distal nitrogen; 
       R 4 , R 17  and R 23  are, independently, C 1-6  alkyl (optionally substituted by halogen, hydroxy or C 3-10  cycloalkyl), CH 2 (C 2-6  alkenyl), phenyl (optionally substituted by halogen, hydroxy, nitro, NH 2 , NH(C 1-4  alkyl), N(C 1-4  alkyl) 2  (and these alkyl groups optionally being joined to form a ring as described for R 5  and R 6  above), S(O) 2 (C 1-4  alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4  alkyl), S(O) 2 N(C 1-4  alkyl) 2  (and these alkyl groups optionally being joined to form a ring as described for R 5  and R 6  above), cyano, C 1-4  alkyl, C 1-4  alkoxy, C(O)NH 2 , C(O)NH(C 1-4  alkyl), C(O)N(C 1-4  alkyl) 2  (and these alkyl groups optionally being joined to form a ring as described for R 5  and R 6  above), CO 2 H, CO 2 (C 1-4  alkyl), NHC(O)(C 1-4  alkyl), NHS(O) 2 (C 1-4  alkyl), C(O)(C 1-4  alkyl), CF 3  or OCF 3 ) or heterocyclyl (optionally substituted by halogen, hydroxy, nitro, NH 2 , NH(C 1-4  alkyl), N(C 1-4  alkyl) 2  (and these alkyl groups optionally being joined to form a ring as described for R 5  and R 6  above), S(O) 2 (C 14  alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4  alkyl), S(O) 2 N(C 1-4  alkyl) 2  (and these alkyl groups optionally being joined to form a ring as described for R 5  and R 6  above), cyano, C 1-4  alkyl, C 1-4  alkoxy, C(O)NH 2 , C(O)NH(C 1-4  alkyl), C(O)N(C 1-4  alkyl) 2  (and these alkyl groups optionally being joined to form a ring as described for R 5  and R 6  above), CO 2 H, CO 2 (C 1-4  alkyl), NHC(O)(C 1-4  alkyl), NHS(O) 2 (C 1-4  alkyl), C(O)(C 1-4  alkyl), CF 3  or OCF 3 ); and 
       R 24  is hydrogen, C 1-6  alkyl or benzyl; 
       or an N-oxide thereof; or a pharmaceutically acceptable salt thereof. 
     
   
   
       2 . A compound of formula (I) as claimed in  claim 1  wherein X is O. 
   
   
       3 . A compound of formula (I) as claimed in  claim 1  wherein R 24  is hydrogen. 
   
   
       4 . A compound of formula (I) as claimed in  claim 1  wherein R 1  is phenyl optionally substituted with fluorine, chlorine or C 1-4  alkyl. 
   
   
       5 . A compound of formula (I) as claimed in  claim 1  wherein R 2  is phenyl or heterocyclyl, either of which is optionally substituted by: halo, hydroxy, nitro, cyano, amino, C 1-4  alkyl (optionally substituted by S(O) 2 (C 1-4  alkyl) or S(O) 2 phenyl), C 1-4  alkoxy, S(O) p R 4  (wherein p is 0, 1 or 2), C(O)NH 2 , NHS(O) 2 (C 1-4  alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4  alkyl) or S(O) 2 N(C 1-4  alkyl) 2 ; and R 4  is C 1-4  alkyl, C 1-4  hydroxyalkyl, C 3-7  cycloalkyl or C 3-7  cycloalkyl(C 1-4  alkyl). 
   
   
       6 . A process for preparing a compound of formula (I) as claimed in  claim 1 , the process comprising:
 A. when Z is CHR 2 CO 2 R 24 :
 i. coupling a compound of formula (II): 
   
     
       
         
         
             
             
         
       
       
          with a compound of formula (III): 
       
     
     
       
         
         
             
             
         
       
       
          wherein L is a suitable leaving group, in a suitable solvent; or, 
         ii. reductive amination of a compound (II) with an ester compound of formula (IIIa): 
       
     
     
       
         
         
             
             
         
       
       
          in the presence of NaBH(OAc) 3  and acetic acid, followed optionally by removal of the ester group; or 
         iii. a three component coupling of a compound of formula (II) with compounds of formula (IIIb) and (IIlc): 
       
     
     
       
         
         
             
             
         
       
       B. when 
     
     
       
         
         
             
             
         
       
       
         a. when n is 1, reacting a compound of formula (II) with a compound of formula (XIV): 
       
     
     
       
         
         
             
             
         
       
       
          wherein L is a leaving group; 
         b. when n is 1, reacting a compound of formula (II) with a compound of formula (XVI): 
       
     
     
       
         
         
             
             
         
       
       
          under reductive amination conditions; and, 
         c. when n is 0, reacting a compound of formula (II) with a compound of formula (XV): 
       
     
     
       
         
         
             
             
         
       
     
     in the presence of potassium carbonate, in a suitable solvent at a suitable temperature. 
   
   
       7 . A pharmaceutical composition which comprises a compound of the formula (I), 
     or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , and a pharmaceutically acceptable adjuvant, diluent or carrier. 
   
   
       8 . A method comprising:
 treating a chemokine mediated disease state in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof as claimed in  claim 1 .