Nitrogen-containing heterocyclic compound

Abstract

As a result of an effort made by us for the purpose of developing a therapeutic agent having a bone formation-stimulating effect by promoting the functions of osteoblasts, the present inventors discovered that a certain nitrogen-containing heterocyclic compound exhibits a potent bone formation-stimulating effect on the osteoblast and thus can serve as an excellent prophylactic or therapeutic agent against a metabolic bone disease, whereby establishing the present invention. Thus, the present invention provides a 3,6-disubstituted 1,2,4-triazolo[4,3-b]pyridazine compound or a pharmaceutically acceptable salt thereof as well as a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable carrier, especially a bone-forming agent.

1 . A nitrogen-containing heterocyclic compound represented by the formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 Ra and Rb: the same or different and each represents H; CO-lower alkyl; SO 2 -lower alkyl; an optionally substituted cycloalkyl; an optionally substituted aryl; or a lower alkyl which may have 1 to 3 substituents selected from the group consisting of an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring, CO-lower alkyl, SO 2 -lower alkyl, OR 1 , SR 1 , NR 1 R 2 , halogen, NO 2 , CN and COOR 1 ; provided that at least one of Ra and Rb represents a group other than H; or,  
 Ra and Rb taken together with an adjacent N atom represent a 4- to 8-membered saturated or partially unsaturated heterocyclic ring containing 1 to 2 nitrogen atoms as heteroatoms, said heterocyclic ring may be fused with a benzene ring or a cycloalkyl ring and may have a bridge and may form a spiro ring, and said heterocyclic ring may have 1 to 5 substituent,  
 E: a single bond, C 1-3  alkylene, vinylene (—C═C—), ethynylene (—C≡C—), CO, NR 3 , CH 2 -J, CONR 4  or NR 5 CO,  
 J: O, S, NR 6 , CO, SO or SO 2 ,  
 R: an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted 4- to 8-membered monocyclic saturated or partially saturated heterocyclic ring,  
 R 1  to R 6 : the same or different and each denotes H or lower alkyl;  
 with the proviso that the following compounds are excluded:  
 (1) a compound wherein Ra and Rb taken together with an adjacent N atom represent a piperidino, E is a single bond and R is a piperidino, unsubstituted phenyl, p-(trifluoromethyl)phenyl, p-chlorophenyl or o-nitrophenyl,  
 (2) a compound wherein Ra and Rb taken together with an adjacent N atom represent a 4-methyl-1-piperazinyl, E is a single bond, and R is an unsubstituted phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, m-chlorophenyl, p-chlorophenyl or m-nitrophenyl,  
 (3) a compound wherein R is an optionally substituted imidazolyl, 5-nitro-2-furyl or 5-nitro-2-thienyl,  
 (4) a compound wherein Ra is H, Rb is cyclopropyl, E is a single bond and R is a p-(trifluoromethyl)phenyl, and,  
 (5) a compound wherein Ra is a methyl, Rb is a 2-hydroxy-propyl, E is a single bond and R is a 3-pyridyl.  
 
     
     
         2 . A nitrogen-containing heterocyclic compound according to  claim 1  or a pharmaceutically acceptable salt thereof, 
 wherein —NRaRb forms a 4- to 8-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 N atoms as heteroatoms, which may be fused with a benzene ring or a cycloalkyl ring, which may have a bridge, or which may form a spiro ring, which may have 1 to 5 substituents selected from Group B; wherein Group B comprises a lower alkyl which may have 1 to 4 substituents selected from Group G, halogen, NR 1 R 2 , —NR 1 CO-lower alkyl, NO 2 , CN, OR 1 , —O-(lower alkyl having 1 to 4 substituents selected from Group G), SR 1 , —S-halogeno-lower alkyl, —O—CO-lower alkyl, COOR 1 , COR 1 , CONR 1 R 2 , SO-lower alkyl, SO 2 -lower alkyl, SO 2 NR 1 R 2 , P(═O) (OR 1 ) 2 , —O—CH 2 —O—, —O—(CH 2 ) 2 —O—, aryl which may have 1 to 4 substituents selected from Group D, heteroaryl which may have 1 to 4 substituents selected from Group D, —O-(aryl which may have 1 to 4 substituents selected from Group D), 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring which may have 1 to 4 substituents selected from Group D, cycloalkyl and —O-cycloalkyl; Group D comprises a lower alkyl, halogen, halogeno-lower alkyl, NR 1 R 2 , NO 2 , CN, OR 1  and SR 1 ; Group G comprises a halogen, NR 1 R 2 , CN, COOR 1 , OR 1 , SR 1 , 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring which may have 1 to 4 substituents selected from Group D, aryl which may have 1 to 4 substituents selected from Group D and heteroaryl which may have 1 to 4 substituents selected from Group D; E is a single bond, C 1-3  alkylene, vinylene, ethynylene, CONH, CH 2 NH, CH 2 O or CH 2 S; R is an aryl which may have 1 to 5 substituents selected from Group B or heteroaryl which may have 1 to 5 substituents selected from Group B.    
     
     
         3 . A nitrogen-containing heterocyclic compound according to  claim 2  or a pharmaceutically acceptable salt thereof, wherein E is a single bond, C 1-3  alkylene, vinylene or ethynylene; R is an aryl having 1 to 5 substituents selected from Group B1 or heteroaryl having 1 to 5 substituents selected from Group B1; Group B1 comprises a lower alkyl, halogeno-lower alkyl, halogen, NR 1 R 2 , NO 2 , CN, OR 1 , —O-halogeno-lower alkyl, SR 1 , COOR 1 , CONR 1 R 2 , SO 2 -lower alkyl, 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring, phenyl and phenoxy.  
     
     
         4 . A nitrogen-containing heterocyclic compound according to  claim 3  or a pharmaceutically acceptable salt thereof, wherein —NRaRb is a 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring which may have one N atom as a heteroatom and may have a bridge, and may have 1 to 2 substituents selected from a lower alkyl, halogen, OR 1  and COOR 1 ; E is a single bond; R is a phenyl having a substituent in its m-position selected from a halogen, O-lower alkyl and S-lower alkyl or a pyridyl having a substituent in its 6-position selected from a halogen, O-lower alkyl and S-lower alkyl.  
     
     
         5 . A nitrogen-containing heterocyclic compound according to  claim 1  or a pharmaceutically acceptable salt thereof selected from 6-azocan-1-yl-3-(6-methoxypyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine, 6-azepan-1-yl-3-(6-bromopyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine, 3-(3-methoxyphenyl)-6-(piperidin-1-yl)-1,2,14-triazolo[4,3-b]pyridazine, 3-(3-bromophenyl)-6-(piperidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine, 6-azepan-1-yl-3-(6-methoxypyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine, 6-(4-fluoropiperidin-1-yl)-3-(6-methoxypyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine, 6-(3-azabicyclo[3.2.1]octan-3-yl)-3-(6-methoxypyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine, 6-(4,4-difluoropiperidin-1-yl)-3-(6-methoxypyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine, 6-(3,3-difluoropiperidin-1-yl)-3-(6-methoxypyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine, 6-azocan-1-yl-3-(6-bromopyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine, and 6-(8-azabicyclo[3.2.1]octan-8-yl)-3-(6-bromopyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine.  
     
     
         6 . A pharmaceutical composition comprising a nitrogen-containing heterocyclic compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
     
     
         7 . A pharmaceutical composition according to  claim 6  which is a bone-forming agent.  
     
     
         8 . Use of a nitrogen-containing heterocyclic compound according to  claim 1  or a pharmaceutically acceptable salt thereof for the manufacture of a bone-forming agent for a mammalian animal.  
     
     
         9 . A method for stimulating bone formation in a mammalian animal, comprising administering an effective amount of a nitrogen-containing heterocyclic compound according to  claim 1  or a pharmaceutically acceptable salt thereof to the mammalian animal.