Piperazine and piperidine compounds

Abstract

A group of new piperazine and piperidine compounds having interesting advantageous pharmacological properties and have the formula (a) wherein A represents a heterocyclic group having 5-7 ring atoms wherein 1-3 heteroatoms selected from the group O, N and S are present, R 1 is hydrogen or fluoro, R 2 is C 1-4 -alkyl, C 1-4 -alkoxy or an oxo group, and p is 0, 1 or 2, Z represents carbon or nitrogen, and the dotted line represents a single bond when Z is nitrogen, and represents a single or double bond when Z is carbon, R 3 and R 4 independently are hydrogen or C 1-4 -alkyl, n has the value 1 or 2, R 5 is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the meta-position with respect to the methylene bridge with a group Y, and optionally substituted with (R 6 )q, Y is a phenyl, furanyl or thienyl group, which groups may be substituted with 1-3 substituents from the group hydroxy, halogen, CF 3 , C 1-4 -alkoxy, C 1-4 -alkyl, cyano aminocarbonyl, mono- or di-C 1-4 -alkylaminocarbonyl, R 6 is halogen, hydroxy, C 1-4 -alkoxy or C 1-4 -alkyl, and q is 0, 1, 2 or 3 and salts thereof, are disclosed.

1. A compound having the formula (a) 
                 
 
       wherein
 A represents a heterocyclic group having 5-7 ring atoms wherein 1-3 heteroatoms selected from the group O, N and S are present,  
 R 1  is hydrogen or fluoro,  
 R 2  is C 1-4 -alkyl, C 1-4 -alkoxy or an oxo group, and p is 0, 1 or 2,  
 Z represents carbon or nitrogen, and the dotted line represents a single bond when Z is nitrogen, and represents a single or double bond when Z is carbon,  
 R 3  and R 4  independently are hydrogen or C 1-4 -alkyl, n has the value 1 or 2,  
 R 5  is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the meta-position with respect to the methylene bridge with a group Y, and optionally substituted with (R 6 )q,  
 Y is a phenyl, furanyl or thienyl group, which groups may be substituted with 1-3 substituents selected from the group hydroxy, halogen, CF 3 , C 1-4 -alkoxy, C 1-4 -alkyl, cyano, aminocarbonyl, mono- or di-C 1-4 -alkylaminocarbonyl,  
 R 6  is halogen, hydroxy, C 1-4 -alkoxy or C 1-4 -alkyl, and q is 0, 1, 2 or 3, or a pharmaceutically acceptable salt thereof.  
 
     
     
       2. A compound according to  claim 1 , wherein A together with the phenyl group represents a group having the formula b, c, d, e, f or g 
                 
 
       and wherein n is 1, and R 1 , (R 2 )p,  R 2 , R 3 , R 4 , R 5 , (R 6 )q,  R 6   , p, q,  Y and Z have the meanings given in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       3. A compound according to  claim 2 , wherein A together with the phenyl group represents a group of the formula (c) or (d), wherein R 5  has the meaning given in  claim 1 , Y is phenyl, R 3  and R 4  are hydrogen, R 6  is hydroxy, methoxy or halogen, q is 0 or 1 and Z is nitrogen, or a pharmaceutically acceptable salt thereof. 
     
     
       4. A compound according to  claim 3 , wherein A together with the phenyl group represents a group of the formula (d), wherein R 1 , (R 2 )p,  R 3  and R 4  are hydrogen, p is  0 , n is 1, Z is nitrogen, and R 5  is the group 5-(4-fluorophenyl)-pyrid-3-yl, or a pharmaceutically acceptable salt thereof. 
     
     
       5. A method for preparing a compound of the formula (a) according to  claim 1 , said method comprising
 a) reacting a compound of formula 
                 
 
 
       with a compound of the formula R 5 —CH 2 —X, wherein X is a leaving group; or
 b) reacting a compound of the formula 
                 
 
 
       wherein R 5 ′ has the same meaning as R 5  as given in  claim 1 , with the proviso that the bromine atom is at the meta-position with respect to the methylene bridge  R′ 5    is  2   - pyridyl,  3   - pyridyl or  4   - pyridyl substituted at the meta - position with respect to the methylene bridge with the bromine atom , with a compound of the formula B(OH) 2 —Y, in which each substituent has the meanings given in  claim 1 . 
     
     
       6. A pharmaceutical composition, said composition comprising a pharmaceutically effective amount of at least one compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       7. A method of preparing a pharmaceutical composition for treating a CNS disorder, said method comprising including in  adding to said composition a pharmaceutically effective amount of at least one compound of the formula (a) according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       8. A method of treating a CNS disorder, said method comprising administering to a host in need of said treatment an effective amount of a compound of formula (a) according to  claim 1 . 
     
     
       9. A compound of the formula 
                 
 
       wherein R 1 , (R 2 )p, Z, n, R 3  and R 4  have the meanings given in  claim 1 , and R 5 ′ has the same meaning as R 5  given in  claim 1 , with the proviso that the bromine atom is at the meta-position with respect to the methylene bridge  R′ 5    is  2   - pyridyl,  3   - pyridyl or  4   - pyridyl substituted at the meta - position with respect to the methylene bridge with the bromine atom.    
     
     
       10. A pharmaceutical composition, said composition comprising a pharmaceutically effective amount of at least one compound according to  claim 4  and a pharmaceutically acceptable carrier. 
     
     
       11. A method of preparing a pharmaceutical composition for treating a CNS disorder, said method comprising adding to said composition a pharmaceutically effective amount of at least one compound according to  claim 4  and a pharmaceutically acceptable carrier. 
     
     
       12. A method of treating a CNS disorder, said method comprising administering to a host in need of said treatment an effective amount of at least one compound according to  claim 4 .