Novel tricyclic compounds and drug compositions containing same

Abstract

Compounds having a β-3 adrenaline receptor agonist and are useful as drugs for the treatment and prevention of diabetes, obesity, hyperlipemia, etc., represented by a general formula (I) and salts thereof, and a process for producing these, and their intermediates, wherein R represents hydrogen or methyl; R 1 represents hydrogen, halogen, hydroxy, benzyloxy, amino, or hydroxymethyl; R 2 represents hydrogen, hydroxymethyl, NHR 3 , SO 2 NR 4 R 4′ , or nitro; R 6 represents hydrogen or lower alkyl; and X represents nitrogen, R 9 represents hydrogen, one of R 7 and R 8 represent hydrogen, and the other thereof represents hydrogen, amino, acetylamino, or hydroxy.

What is claimed is:  
     
         1 . A compound represented by the general formula (I) or a salt thereof:  
       
         
           
           
               
               
           
         
       
       in which R represents hydrogen atom or methyl, R 1  stands for hydrogen atom, halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl, R 2  stands for hydrogen atom, hydroxymethyl, NHR 3 , SO 2 NR 4 R 4′  or nitro, wherein R 3  is hydrogen atom, methyl, SO 2 R 5 , formyl or CONHR 6 , with R 5  being lower alkyl, benzyl or NR 4 R 4′  and R 6  being hydrogen atom or lower alkyl, and R 4  and R 4′  may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, R 6  represents hydrogen atom or lower alkyl, X is methylene, both R 7  and R 8  are hydrogen atom and R 9  stands for hydrogen atom, amino, acetyl amino or hydroxy, and  1 indicates an asymmetric carbon atom and  2 indicates that the carbon atom is asymmetric provided that R 6  is lower alkyl.  
     
     
         2 . A compound represented by the general formula (I) or a salt thereof as claimed in  claim 1:   
       
         
           
           
               
               
           
         
       
       in which R represents hydrogen atom, R 1  stands for hydrogen atom, halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl, R 2  stands for hydrogen atom, hydroxymethyl, NHR 3 , SO 2 NR 4 R 4′  or nitro, wherein R 3  is hydrogen atom, methyl, SO 2 R 5 , formyl or CONHR 6 , with R 5  being lower alkyl, benzyl or NR 4 , R 4  and R 6′  being hydrogen atom or lower alkyl, and R 4  and R 4′  may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, R 6  represents hydrogen atom or lower alkyl, X is methylene, both R 7  and R 8  are hydrogen atom and R 9  stands for hydrogen atom, amino, acetylamino or hydroxy, and  1 indicates an asymmetric carbon atom and  2 indicates that the carbon atom is asymmetric provided that R 6  is lower alkyl.  
     
     
         3 . A compound represented by the general formula (I) or a salt thereof as claimed in  claim 2:   
       
         
           
           
               
               
           
         
       
       in which R represents hydrogen atom, R 1  stands for hydrogen atom, fluorine atom, chlorine atom, hydroxy or benzyloxy, R 2  stands for hydrogen atom, hydroxymethyl, NHR 3 , SO 2 NR 4 R 4′  or nitro, wherein R 3  is hydrogen atom, methyl, SO 2 R 5 , formyl or CONHR 6′  and either one of R 4  and R 4′  is hydrogen atom and the other one is hydrogen atom, lower alkyl or benzyl, with R 5  being lower alkyl, benzyl or dimethylamino and R 6′  being hydrogen atom or lower alkyl, R 6  represents hydrogen atom or lower alkyl, X is methylene, both R 7  and R 8  are hydrogen atom, amino, acetylamino or hydroxy, and  1 indicates an asymmetric carbon atom and  2 indicates that the carbon atom is asymmetric provided that R 6  is lower alkyl.  
     
     
         4 . A compound represented by the general formula (I) or a salt thereof as claimed in  claim 2:   
       
         
           
           
               
               
           
         
       
       in which R represents hydrogen atom, R 1  stands for hydrogen atom, halogen atom, hydroxy or benzyloxy, R 2  stands for hydroxymethyl, NHR 3 , SO 2 NR 4 R 4  or nitro, wherein R 3  is hydrogen atom, methyl, SO 2 R 5 , formyl or CONHR 6′  and R 4  and R 4  may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, with R 5  being lower alkyl, benzyl or NR 4 R 4′  and R 6′  being hydrogen atom or lower alkyl, R 6  represents hydrogen atom or lower alkyl, X is methylene, both R 7  and R 8  are hydrogen atom and R 9  stands for hydrogen atom, amino, acetylamino or hydroxy, and  1 indicates an asymmetric carbon atom and  2 indicates that the carbon atom is asymmetric provided that R 6  is lower alkyl.  
     
     
         5 . A compound or a salt thereof as claimed in  claim 2 , wherein the general formula (I), both R and R 1  represent hydrogen atom, R 2  stands for hydroxymethyl, NHR 3  or SO 2 NR 4 R 4′ , wherein R 3  is hydrogen atom, methyl, SO 2 R 5 , formyl or CONHR 6  and R 4  and R 4  may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, with R 5  being lower alkyl, benzyl or NR 4 R 4′ .  
     
     
         6 . A compound or a salt thereof as claimed in  claim 2 , wherein, in the formula (I), R denotes hydrogen atom, R 1  stands for halogen atom or hydroxy, R 2  stands for NHSO 2 R 5  or SO 2 NR 4 R 4′ , wherein R 5  is lower alkyl, benzyl or NR 4 R 4  and R 4  and R 4′  may be identical with or different from each other and stand for hydrogen atom, lower alkyl or benzyl.  
     
     
         7 . A compound represented by the general formula (I) or a salt thereof as claimed in  claim 2:   
       
         
           
           
               
               
           
         
       
       wherein R represents hydrogen atom, R 1  stands for hydrogen atom, halogen atom-or hydroxy, R 2  stands for hydrogen atom, R 6  represents hydrogen atom or lower alkyl, X is methylene, both R 7  and R 8  are hydrogen atom, amino, acetylamino or hydroxy, and  1 indicates an asymmetric carbon atom and  2 indicates that the carbon atom is asymmetric provided that R 6  is lower alkyl.  
     
     
         8 . A compound represented by the general formula (I) or a salt thereof as claimed in  claim 1:   
       
         
           
           
               
               
           
         
       
       wherein R represents methyl, R 1  stands for hydrogen atom, halogen atom, hydroxy, amino or hydroxymethyl, R 2  stands for NHR 3  or SO 2 NR 4 R 4 , wherein R 3  represents SO 2 R 5 , with R 5  being lower alkyl, benzyl or NR 4 R 4′ , and R 4  and R 4  may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, R 6  represents hydrogen atom or lower alkyl, X is methylene, both R 7  and R 8  are hydrogen atom and R 9  stands for hydrogen atom, amino, acetylamino or hydroxy, and  1 indicates an asymmetric carbon atom and  2 indicates that the carbon atom is asymmetric provided that R 6  is lower alkyl.  
     
     
         9 . A pharmaceutical composition comprising as an effective component, a compound or a salt thereof as claimed in  claim 1 , in a physiologically or pharmacologically acceptable carrier.  
     
     
         10 . A medicament as claimed in  claim 1 , wherein it is a drug composition comprising, as an effective component, a compound or a salt thereof as claimed in  claim 1  and a carrier medicamentally acceptable for the effective component.  
     
     
         11 . A pharmaceutical composition as claimed in  claim 9 , in the form of a drug suitable for therapeutic treatment or preventive treatment of one of diabetes, obesity and hyperlipemia.  
     
     
         12 . A method for producing a compound represented by the general formula (I):  
       
         
           
           
               
               
           
         
       
       in which R represents hydrogen atom, R 1  stands for hydrogen atom, halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl, R 2  stands for hydrogen atom, hydroxymethyl, NHR 3 , SO 2 NR 4 R 4  or nitro, wherein R 3  is hydrogen atom, methyl, SO 2 R 5 , formyl or CONHR 6 , with R 5  being lower alkyl, benzyl or NR 4 R 4′  and R 6  being hydrogen atom or lower alkyl, and R 4  and R 4′  may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, R 6  represents hydrogen atom or lower alkyl, X is methylene, both R 7  and R 8  are hydrogen atom and R 9  stands for hydrogen atom, amino, acetylamino or hydroxy, and  1 indicates an asymmetric carbon atom and  2 indicates that the carbon atom is asymmetric provided that R 6  is lower alkyl, comprising the step of reacting a compound represented by the general formula (II):  
       
         
           
           
               
               
           
         
       
       in which R 6′  represents hydrogen atom, halogen atom, a protected hydroxyl group protected by a protecting group A, a protected amino group protected by acetyl group or a protected hydroxymethyl group protected by acetyl group, R 2′  stands for hydrogen atom, for a protected hydroxymethyl group in which the hydroxyl group is protected by a protecting group A′″, for NHR 3 , for SO 2 NR 1 R 4  or for nitro, wherein R 3′  represents a protecting group for the amino group, methyl, SO 2 R 5 , formyl or CONHR 6′ , with R 5  being lower alkyl, benzyl or NR 4 R 4′  and R 6′  being hydrogen atom or lower alkyl, R 4  and R 4′  may be identical with or different from each other and stand each for hydrogen atom, lower alkyl or benzyl, R 6  denotes hydrogen atom or lower alkyl, A′ represents a protecting group for the hydroxyl group, B is bromine atom or iodine atom and  1 indicates an asymmetric carbon atom with a compound represented by the general formula (III):  
       
         
           
           
               
               
           
         
       
       in which Y represents hydrogen atom, R 6  is hydrogen atom or lower alkyl, X is methylene, both R 7′  and R 8′  are hydrogen atom and R 9′  stands for hydrogen atom, acetylamino or a protected hydroxyl group protected by a protecting group A″, and  2 indicates that the carbon atom is asymmetric provided that R 6  is lower alkyl, 
 wherein the protecting groups A, A′, A″, and A′″ as well as the protecting group for the amino group in R 3′  and the protecting acetyl group in R 1′  are eliminated for protection with the proviso that the protecting group A is not eliminated if A is benzyl and R 1  is benzyloxy.  
 
     
     
         13 . A compound represented by the general formula (II):  
       
         
           
           
               
               
           
         
       
       in which R 6′  represents hydrogen atom, halogen atom, a protected hydroxy group protected by a protecting group A, a protected amino group protected by acetyl group or a protected hydroxymethyl group protected by acetyl group, R 2′  stands for SO 2 NR 4 R 4′  or nitro, A′ represents a protecting group for the hydroxy group, R 4  and R 4′  may be identical with or different from each other and stand for hydrogen atom, lower alky or benzyl, B is bromine atom or iodine atom and  1 indicates an asymmetric carbon atom with an absolute configuration of (R).  
     
     
         14 . A compound represented by the general formula (III):  
       
         
           
           
               
               
           
         
       
       in which Y represents hydrogen atom or a protecting group for the amino group, R 6  is hydrogen atom or lower alkyl, X is methylene, both R 7′  and R 8′  are hydrogen atom and R 9  stands for hydrogen atom, acetylamino or a protected hydroxyl group protected by a protecting group A″, and  2 indicates that the carbon atom is asymmetric provided that R 6  is lower alkyl.  
     
     
         15 . A compound represented by the general formula (IV):  
       
         
           
           
               
               
           
         
       
       in which R 1  represents hydrogen atom, halogen atom, a protected hydroxyl group protected by a protecting group A, a protected amino group protected by acetyl group or a protected hydroxymethyl group in which the hydroxyl group is protected by acetyl group, R 6  stands for hydrogen atom or lower alkyl, Y′ is hydrogen atom or a protecting group for the amino group, X is methylene, both R 7′  and R 8′  are hydrogen atom and R 9′  is hydrogen atom, acetylamino or a protected hydroxyl group protected by a protecting group A″, A′ represents a protecting group for the hydroxyl group,  1 indicates an asymmetric carbon atom and  2 indicates that the carbon atom is asymmetric provided that R 6  is lower alkyl.  
     
     
         16 . A compound or a salt thereof as claimed in  claim 2 , wherein the compound is selected from the group consisting of N-[5-[2-[2-(7-acetylaminofluoren-2-yloxy)-ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide; N-[5-[2-[2-(7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide; N-[3-[2-[2-(7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide; N-[3-[2-[2-(7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide; N-[5-[2-[2-(7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide; N′[5-[-2-[2-(7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide.  
     
     
         17 . A process for producing a compound represented by the general formula (II):  
       
         
           
           
               
               
           
         
       
       Wherein R 1′  represents a hydrogen atom, a halogen atom, a hydroxyl group protected by a protecting group A, an amino group protected by an acetyl group, or a hydroxymethyl group protected by an acetyl group, R 2′  represents SO 2 NR 4 R 4′  or a nitro group where R 4  and R 4′ , which may be identical or different, are independently a hydrogen atom, a lower alkyl group or a benzyl group, A′ represents a protecting group for hydroxyl group, B represents a bromine atom or an iodine atom,  1 indicates an asymmetric carbon atom with an absolute configures of (R), 
 said method comprising the following steps: 
 (1) subjecting a compound represented by the general formula (V):  
                     
  wherein R 1 , R 2 , R 4  and R 4  each are as defined above, to asymmetric reduction;  
 (2) optionally substituting an iodine atom for the bromine atom; and  
 (3) protecting the hydroxyl group formed in step (1) to form the compound of the formula (II).  
 
 
     
     
         18 . A process for producing a compound represented by the general formula (III′) or (III″):  
       
         
           
           
               
               
           
         
       
       wherein Y represents a protecting group for amine, RE represents a hydrogen atom or a lower alkyl group, and  2 indicates an asymmetric atom when R 6  is a lower alkyl group, X represents a secondary nitrogen atom, an oxygen atom, a sulfur atom, or a methylene group, and when X is a secondary nitrogen atom, oxygen atom or sulfur atom, then R 9′  is a hydrogen atom and one of R 7′  and R 8′  is a hydrogen atom and the other represents a hydrogen atom, an acetylamino group, or a hydroxyl group protected by a protecting group A″, or when X is a methylene group, then R 7′  and R 8′  each are a hydrogen atom, and R 9′  represents a hydrogen atom, an acetylamino group, or a hydroxyl group protected by a protecting group A″, 
 said method comprising the following steps of: 
 (1) reacting a compound represented by the general formula (VII):  
                     
  wherein Y, RE and  2 each are as defined above, with a compound represented by the general formula (VIII):  
                     
  wherein X, R 7 , R 8′  and R 9′  each are as defined above, to produce the compound of the formula (III′); and  
 (2) optionally deprotecting the protecting group for amine to form the compound of the formula (III′).  
 
 
     
     
         19 . A process for producing a compound represented by the general formula (IV′) or (IV):  
       
         
           
           
               
               
           
         
       
       wherein R 1′  represents a hydrogen atom, a halogen atom, a hydroxyl group protected by a protecting group A, an amino group protected by an acetyl group, or a hydroxymethyl group protected by an acetyl group, R 6  represents a hydrogen atom or a lower alkyl group, Y represents a hydrogen atom, A′ represents a protecting group for hydroxyl group,  1 indicates an asymmetric carbon atom,  2 indicates an asymmetric carbon atom when R 6  is a lower alkyl group, X represents a secondary nitrogen atom, an oxygen atom, a sulfur atom, or a methylene group, and when X is a secondary nitrogen atom, oxygen atom or sulfur atom, then R 9′  is a hydrogen atom and one of R 7′  and R 8′  is a hydrogen atom and the other represents a hydrogen atom, an acetylamino group or a hydroxyl group protected by a protecting group A″, or when X is a methylene group, then R 7′  and R 8′  each are a hydrogen atom, and R 9  represents a hydrogen atom, an acetylamino group, or a hydroxyl group protected by a protecting group A″; or  
       
         
           
           
               
               
           
         
       
       wherein Y′ represents a protecting group for amine, and R 1 , A′, R 6 , X, R 7′ , R 8′ , R 9′ ,  1 and  2 each are as defined above, 
 said method comprising the following steps of: 
 (1) reacting a compound represented by the general formula (II):  
                     
  wherein R 1 , A′ and  1 each are defined as above, R 2′  represents a nitro group, and B represents a bromine atom or iodine atom, with a compound represented by the general formula (III):  
                     
  wherein Y, R 6 , X, R 7′ , R 8′ , R 9′  and  2 each are defined as above, to form the compound of the formula (IV′); and  
 
 (2) optionally converting Y into a protecting group Y′ for amine to form the compound of the formula (IV).  
 
     
     
         20 . Either of the optical isomers of a compound represented by the general formula (XII)  
       
         
           
           
               
               
           
         
       
       wherein R 1′  is a halogen atom or a hydroxyl group protected by a protecting group A, R is a nitro group, and  1 represents an asymmetric carbon atom.