Nitrogen-containing heterocycle derivatives substituted with cyclic group

Abstract

It was found out that the nitrogen-containing heterocyclic derivative represented by the formula (I) specifically binds to a receptor of NR1/NR2B, and is used as a NR2B receptor antagonist. A compound represented by: wherein Z is N or CR 1 , A 1 is a nitrogen-containing aromatic monocyclic group which is optionally substituted, a nitrogen-containing aromatic fused cyclic group which is optionally substituted etc., A 2 is an aromatic hydrocarbon cyclic group or an aromatic heterocyclic group, each optionally having a substituent, R 1 , R 2 , R a , R b , R c and R d are each independently hydrogen, hydroxy, etc., w is 2 or 3, t is 1 or 2, X is —(CR 3 R 4 )m-, —CO(CR 3 R 4 )n-, —CONR 5 (CR 3 R 4 )n- etc., m is an integer of 1 to 4, n is an integer of 0 to 4, R 3 and R 4 are each independently hydrogen, halogen, hydroxy etc., and R 5 is hydrogen or lower alkyl, or a pharmaceutically acceptable salt, or a solvate thereof.

1 . A compound represented by the formula (I): 
       
         
           
           
               
               
           
         
         wherein Z is N or CR 1 ; 
         A 1  is a nitrogen-containing aromatic monocyclic group which is optionally substituted, or a nitrogen-containing aromatic fused cyclic group which is optionally substituted, the nitrogen-containing aromatic monocyclic group or the nitrogen-containing aromatic fused cyclic group satisfies at least one of the following conditions: 
         i) the group has at least one group selected from optionally substituted hydroxy, optionally protected amino and optionally substituted aminooxy, and 
         ii) the group contains —NH— in the ring; 
         A 2  is an aromatic hydrocarbon cyclic group which is optionally substituted, or an aromatic heterocyclic group which is optionally substituted; 
         R 1  and R 2  are each independently hydrogen, hydroxy or lower alkyl, or R 1  and R 2  may be taken together to form a single bond; 
         R a , R b , R c  and R d  are each independently hydrogen or lower alkyl and, when there are a plurality of R a s, a plurality of R b s, a plurality of R c s or a plurality of R d s, they may be different from each other; 
         w is 2 or 3; 
         t is 1 or 2; 
         X is: 
         —(CR 3 R 4 )m-, 
         —CO(CR 3 R 4 )n-, 
         —(CR 3 R 4 )mCO—, 
         —CONR 5 (CR 3 R 4 )n-, 
         —NR 5 CO(CR 3 R 4 )n-, 
         —(CR 3 R 4 )mNR 5 CO—, 
         —NR 5 CONR 6 (CR 3 R 4 )n-, 
         —C(═N—OR 7 )(CR 3 R 4 )n-, 
         —(CR 8 R 9 )rO(CR 3 R 4 )n-, 
         —(CR 8 R 9 )rS(CR 3 R 4 )n-, 
         —(CR 8 R 9 )rSO(CR 3 R 4 )n-, 
         —(CR 8 R 9 )rSO 2 (CR 3 R 4 )n-, 
         —CR 9 ═N—O(CR 3 R 4 )n-, 
         —C(═O)O(CR 3 R 4 )n-, 
         —(CR 3 R 4 )mC(═N—OR 8 )-, 
         —CH(OR 8 )(CR 3 R 4 )n-, 
         —(CR 3 R 4 )mCH(OR 8 )-, 
         NR 5 COCO(CR 3 R 4 )n-, 
         (CR 3 R 4 )mNR'COCO—, 
         —COCONR 5 (CR 3 R 4 )n-, 
         —NR 5 COCH(OR 8 )(CR 3 R 4 )n-, 
         —CH(OR 8 )(CR 3 R 4 )nNR 5 CO—, 
         —NR 5 (CR 3 R 4 )mCO—, 
         -A 3 -(CR 3 R 4 )n-, 
         —(CR 3 R 4 )m-A 3 -, 
         -A 3 -CR 10 ═CR 11 (CR 3 R 4 )n-, 
         —CR 10 ═CR 11 (CR 3 R 4 )n-A 3 -, 
         -A 3 -NR 6 (CR 3 R 4 )n-, 
         —(CR 3 R 4 )nNR 6 -A 3 - or 
         —NR 6 (CR 3 R 4 )m-A 3 -, 
         further, X may be 
         —CONR 5 (CR 3 R 4 )m-NR 6 —, 
         —(CR 3 R 4 )mCONR 5 —, 
         —(CR 3 R 4 )mNR 5 CONR 6 —, 
         —CO(CR 3 R 4 )mNR 5 —, or 
         -A 3 -(CR 3 R 4 )mNR 6 — when Z is CR 1 ; 
         m is an integer of 1 to 4; 
         n and r are an integer of 0 to 4; 
         A 3  is an aromatic hydrocarbon cyclic group which is optionally substituted, an aromatic heterocyclic group which is optionally substituted, or a non-aromatic heterocyclic group which is optionally substituted; 
         R 3  and R 4  are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, or optionally substituted lower alkoxy, and when there are a plurality of R 3 s and R 4 s, respectively, they may be different from each other; 
         R 5 , R 6 , R 7 , R 8 , R 9 , R 10  and R 11  are each independently hydrogen or lower alkyl, and when m or n is 1 or more, R 1  may be taken together with R 3  on CR 3 R 4  adjacent to a carbon atom to which R 1  binds, to form a single bond, 
         wherein the case where Z is N, A 1  is 
       
       
         
           
           
               
               
           
         
       
       and X is —NR 5 CO(CR 3 R 4 )n-, —NR 5 COCO(CR 3 R 4 )n- or —NR 5 (CR 3 R 4 )mCO— is excluded,
 or a pharmaceutically acceptable salt, or a solvate thereof. 
 
     
     
         2 . The compound according to  claim 1 , wherein w is 2 or 3, and t is 1, or a pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         3 . The compound according to  claim 1 , wherein X is —(CR 3 R 4 )m-, —CO(CR 3 R 4 )n-, —CONR 5 (CR 3 R 4 )n-, —(CR 3 R 4 )mCONR 5 —, —NR 5 CO(CR 3 R 4 )n-, —(CR 3 R 4 )mNR 5 CO—, —NR 5 CONR 6 (CR 3 R 4 )n-, —C(═N—OR 7 )(CR 3 R 4 )n-, —CH(OR 8 )(CR 3 R 4 )n-, —NR 5 COCO(CR 3 R 4 )n-, —NR 5 COCH(OR 8 )(CR 3 R 4 )n-, -A 3 -(CR 3 R 4 )n-, -A 3 -CR 10 ═(CR 3 R 4 )n-, —NR 5 (CR 3 R 4 )mCO— or -A 3 -(CR 3 R 4 )nNR 6 —, or a pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         4 . The compound according to  claim 1 , wherein A 1  is pyridyl substituted with at least hydroxy, quinolyl substituted with at least hydroxy, benzoxazolyl substituted with at least hydroxy, benzimidazolyl substituted with at least hydroxy, pyridyl substituted with at least optionally protected amino, imidazolyl in which ring constituting atoms other than —NH— may be substituted, pyrrolyl in which ring constituting atoms other than —NH— may be substituted, pyrazolyl in which ring constituting atoms other than —NH— may be substituted, benzpyrazolyl in which ring constituting atoms other than —NH— may be substituted, benzimidazolyl in which ring constituting atoms other than —NH— may be substituted, or indolyl in which ring constituting atoms other than —NH— may be substituted, or a pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         5 . The compound according to  claim 1 , wherein A 1  is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         6 . The compound according to  claim 1 , wherein X is —CO(CHR 3 )n-, —CONH(CHR 3 )n-, —NHCO(CHR 3 )n-, —NHCONH(CHR 3 )n-, —NHCOCO(CHR 3 )n- or —NR 5 (CR 3 R 4 )mCO— or a pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         7 . The compound according to  claim 1 , wherein X is —CO(CHR 3 ) 2 —, —CONHCHR 3 —, —CONH(CHR 3 ) 2 —, —NHCOCHR 3 —, —NHCO(CHR 3 ) 2 —, —NHCONH—, —NHCOCO— or —NHCH 2 CO— or a pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         8 . The compound according to  claim 1 , wherein Z is CR 1 , R 1  and R 2  are each independently hydrogen or hydroxy, or R 1  and R 2  are taken together to form a single bond and, when m or n is 1 or more, R 1  is taken together with R 3  on CR 3 R 4  adjacent to a carbon atom to which R 1  binds, to form a single bond, or a pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         9 . The compound according to  claim 1 , wherein Z is N, or a pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         10 . The compound according to  claim 1 , wherein A 2  is phenyl optionally substituted with one or more groups selected from halogen, cyano, lower alkyl, halogeno lower alkyl, lower alkoxy and halogeno lower alkoxy or pyridyl optionally substituted with one or more groups selected from halogen, cyano, lower alkyl, halogeno lower alkyl, lower alkoxy and halogeno lower alkoxy, or a pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         11 . The compound according to  claim 1 , wherein A 2  is para-substituted phenyl, meta and para-di-substituted phenyl or meta and para-tri-substituted phenyl, or a pharmaceutically acceptable salt, or a solvate thereof 
     
     
         12 . A pharmaceutical composition containing the compound according to  claim 1 , or a pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         13 . The pharmaceutical composition according to  claim 12 , which has the NMDA receptor antagonism. 
     
     
         14 . The pharmaceutical composition according to  claim 13 , which has the NR1/NR2B receptor antagonism.