Lipoprotein lipase-activating compositions comprising benzene derivatives

Abstract

The present invention provides pharmaceutical compositions containing benzene compound(s) represented by General Formula (1) below and, particularly, LPL-activating compositions for use in hyperlipidemia therapeutic and preventive agents, anti-obesity agents, and the like: wherein R 1 , R 2 , R 3 and R 4 are as defined in the specification.

1 . A method for activating LPL in a patient in need of LPL activation treatment, comprising administering an effective amount of a benzene compound into the patient, the benzene compound being represented by General Formula (1): 
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, or phenyl lower alkyl; and 
         R 2  is hydrogen; lower alkyl; 1,2,3,4-tetrahydronaphthyl; cycloalkyl lower alkyl; phenyl; phenyl having one or two substituents selected from the group consisting of halogen, lower alkoxy, cyano, halogenated lower alkyl, and halogenated lower alkoxy; phenyl lower alkyl; phenyl lower alkyl having on the benzene ring one or two substituents selected from the group consisting of halogen, lower alkyl, halogenated lower alkyl, cyano, nitro, lower alkoxycarbonyl, carboxy, lower alkoxy, and halogenated lower alkoxy; or lower alkyl having one cycloalkyl and one phenyl or halogenated phenyl; or 
         R 1  and R 2  are joined to form —CH═C(Ph)- wherein Ph represents phenyl; 
         R 3  is hydrogen or lower alkoxy; and 
         Z is a group selected from (a) to (h) below: 
         (a) imidazo[2,1-b]thiazol-6-yl or imidazo[2,1-b]thiazol-6-yl having one lower alkyl substituent; 
         (b) benzimidazol-2-yl; 
         (c) benzothiazol-2-yl; 
         (d) imidazo[1,2-a]pyrimidin-2-yl; 
         (e) imidazol-4-yl having one phenyl or halogenated lower alkyl substituted phenyl; 
         (f) imidazo[1,2-a]pyridin-3-yl; 
         (g) imidazo[1,2-a]pyridin-5-yl; and 
         (h) a group represented by the formula below: 
       
       
         
           
           
               
               
           
         
         wherein R 4  is hydrogen, lower alkyl, or halogen; 
         R 5  is hydrogen, lower alkyl, halogen, hydroxy, lower alkoxy, phenyl lower alkoxy; 
         R 6  is hydrogen, lower alkyl, carboxy, or halogenated lower alkyl; 
         R 7  is hydrogen, lower alkyl, halogen, halogenated lower alkyl, lower alkoxycarbonyl, carboxy, cyano, carbamoyl, or phenyl; and 
         R 8  is hydrogen or lower alkyl, provided, however, that when Z is a group (e), R 1  is lower alkoxy, R 2  is phenyl lower alkyl, and R 3  is hydrogen. 
       
     
     
         2 . A method according to  claim 1  wherein the benzene compound is a compound of General Formula (1) wherein Z is a group (a). 
     
     
         3 . A method according to  claim 1  wherein the benzene compound is a compound of General Formula (1) wherein Z is a group (b). 
     
     
         4 . A method according to  claim 1  wherein the benzene compound is a compound of General Formula (1) wherein Z is a group (d). 
     
     
         5 . A method according to  claim 1  wherein the benzene compound is a compound of General Formula (1) wherein Z is a group (e). 
     
     
         6 . A method according to  claim 1  wherein the benzene compound is a compound of General Formula (1) wherein Z is a group (f), (g), or (h). 
     
     
         7 . A method according to  claim 1  wherein the benzene compound is a compound shown in any one of (1-1) to (1-4):
 (1-1) a compound of formula (1) wherein R 1  is lower alkoxy, and R 2  is phenyl, phenyl having one or two halogen atoms as substituents on the benzene ring, phenyl lower alkyl group, phenyl lower alkyl group having on the benzene ring one or two substituents selected from the group consisting of halogen, and cyano, or R 1  and R 2  are jointed to form —CH═C(Ph)- (wherein Ph is phenyl), and Z is a group (h); 
 (1-2) a compound of formula (1) wherein R 1  is lower alkoxy, R 2  is phenyl lower alkyl having one or two halogen atoms as substituents on the benzene ring, and Z is a group (a); 
 (1-3) a compound of formula (1) wherein R 1  is lower alkoxy, R 2  is phenyl lower alkyl, or phenyl lower alkyl having one or two halogen atoms as substituents on the benzene ring, and Z is a group (f); and 
 (1-4) a compound of formula (1) wherein R 1  is lower alkoxy, R 2  is phenyl lower alkyl, and Z is a group (e). 
 
     
     
         8 . A method according to  claim 1  wherein the patient in need of LPL activation treatment is a hyperlipidemia patient. 
     
     
         9 . A method according to  claim 1  wherein the patient in need of LPL activation treatment is an obese patient. 
     
     
         10 . A benzene compound represented by General Formula (1a) 
       
         
           
           
               
               
           
         
       
       wherein
 (2-1) R 1a  is lower alkoxy; R 2a  is phenyl lower alkyl having on the benzene ring one or two substituents selected from the group consisting of halogen, cyano, and nitro; and Z a  is a group (a); 
 (2-2) R 1a  is lower alkoxy; R 2a  is hydrogen, phenyl; phenyl having one or two lower alkoxy groups as substituents; phenyl lower alkyl; or phenyl lower alkyl having on the benzene ring one or two substituents selected from the group consisting of halogen, lower alkyl, halogenated lower alkyl, cyano, nitro, lower alkoxy, and halogenated lower alkoxy; and Z a  is a group (d), (f), or (g); 
 (2-3) R 1a  is lower alkoxy, R 2a  is phenyl lower alkyl, and Z a  is a group (e); or 
 (2-4) R 1a  is hydroxy or lower alkoxy, and R 2a  is 1,2,3,4-tetrahydronaphthyl, cycloalkyl lower alkyl, phenyl; phenyl having one or two substituents selected from the group consisting of halogen, lower alkoxy, cyano, halogenated lower alkyl, and halogenated lower alkoxy; phenyl lower alkyl having on the benzene ring one or two substituents selected from the group consisting of halogen, lower alkyl, halogenated lower alkyl, cyano, nitro, lower alkoxycarbonyl, carboxy, lower alkoxy, and halogenated lower alkoxy; or lower alkyl having one cycloalkyl and one phenyl or halogenated phenyl; or R 1a  and R 2a  are joined to form —CH═C(Ph)- (wherein Ph is phenyl), and Z a  is a group (h).