Tetrazole derivatives and methods of treatment of metabolic-related disorders thereof

Abstract

The present invention relates to certain tetrazole derivatives of Formula (I), and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists for the RUP25 receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of metabolic-related disorders, including dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, type 2 diabetes, Syndrome-X and the like. In addition, the present invention also provides for the use of the compounds of the invention in combination with other active agents such as those belonging to the class of α-glucosidase inhibitors, aldose reductase inhibitors, biguanides, HMG-CoA reductase inhibitors, squalene synthesis inhibitors, fibrates, LDL catabolism enhancers, angiotensin converting enzyme (ACE) inhibitors, insulin secretion enhancers and the like.

1 . A compound of Formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 X is NH or O;  
 R 1  is selected from the group consisting of H, halogen, hydroxy, thioxy, cyano, nitro, C 1-4  haloalkyl, amino, C 1-4  alkylamino, C 2-8  dialkylamino, C 1-4  alkyl, C 1-4  alkoxy, C 2-4  alkenyl, C 2-4  alkynyl, C 3-5  cycloalkyl, C 1-4  haloalkoxy, C 1-4  alkylthio, C 1-4  alkylsulfinyl, C 1-4  alkylsulfonyl, C 1-4  haloalkylthio, C 1-4  haloalkylsulfinyl and C 1-4  haloalkylsulfonyl;  
 R 2  is selected from the group consisting of H, halogen, hydroxy, thioxy, cyano, nitro, C 1-4  haloalkyl, amino, C 1-4  alkylamino, C 2-8  dialkylamino, C 1-4  alkyl, C 1-4  alkoxy, C 2-4  alkenyl, C 2-4  alkynyl, C 3-5  cycloalkyl, C 1-4  haloalkoxy, C 1-4  alkylthio, C 1-4  alkylsulfinyl, C 1-4  alkylsulfonyl, C 1-4  haloalkylthio, C 1-4  haloalkylsulfinyl and C 1-4  haloalkylsulfonyl; or R 2  is absent;  
    is a single bond when R 2  is present, or   is a double bond when R 2  is absent; and  
 Ring A is a 5, 6 or 7-membered carbocyclic ring or a 5, 6 or 7-membered heterocyclic ring optionally substituted with 1 to 4 substituents selected from the group consisting of halogen, hydroxy, thioxy, cyano, nitro, C 1-4  haloalkyl, amino, C 1-4  alkylamino, C 2-8  dialkylamino, C 1-4  alkyl, C 1-4  alkoxy, C 2-4  alkenyl, C 2-4  alkynyl, C 3-5  cycloalkyl, C 1-4  haloalkoxy, C 1-4  alkylthio, C 1-4  alkylsulfinyl, C 1-4  alkylsulfonyl, C 1-4  haloalkylthio, C 1-4  haloalkylsulfinyl and C 1-4  haloalkylsulfonyl; or  
 a pharmaceutically acceptable salt, solvate or hydrate thereof.  
 
   
   
       2 . The compound according to  claim 1  wherein: 
 X is NH;    R 1  is H or hydroxy;    R 2  is H or absent;       is a single bond when R 2  is H, or   is a double bond when R 2  is absent; and    Ring A is a 5-membered carbocyclic ring or a 5-membered heterocyclic ring optionally substituted with 1 to 4 substituents selected from the group consisting of halogen, C 1-4  alkyl, C 1-4  alkoxy and C 3-5  cycloalkyl; or    a pharmaceutically acceptable salt, solvate or hydrate thereof.    
   
   
       3 . The compound according to  claim 1  having Formula (If):  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is H or hydroxy; and  
 Ring A is optionally substituted with 1 or 2 substituents selected from the group consisting of halogen, C 1-4  alkyl, C 1-4  alkoxy and C 3-5  cycloalkyl; or  
 a pharmaceutically acceptable salt, solvate or hydrate thereof.  
 
   
   
       4 . The compound according to  claim 1  having Formula (Ih):  
     
       
         
         
             
             
         
       
     
     wherein: 
 Ring A is optionally substituted with 1 or 2 substituents selected from the group consisting of halogen, C 1-4  alkyl, C 1-4  alkoxy and C 3-5  cycloalkyl; or  
 a pharmaceutically acceptable salt, solvate or hydrate thereof.  
 
   
   
       5 . The compound according to  claim 1  having Formula (Ih):  
     
       
         
         
             
             
         
       
     
     wherein: 
 Ring A is unsubstituted or is substituted with ethyl; or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
 
   
   
       6 . The compound according to  claim 1  having Formula (Ih):  
     
       
         
         
             
             
         
       
     
     wherein: 
 Ring A is substituted with 1 or 2 substituents selected from the group consisting of halogen, n-propyl, n-butyl, C 1-4  alkoxy and C 3-5  cycloalkyl; or  
 a pharmaceutically acceptable salt, solvate or hydrate thereof.  
 
   
   
       7 . The compound according to  claim 1  that is 3-(1H-Tetrazol-5-yl)-2,4,5,6-tetrahydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       8 . The compound according to  claim 1  that is 3-(1H-Tetrazol-5-yl)-2,6-dihydro-4H-thieno[3,4-c]pyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       9 . The compound according to  claim 1  that is 6-Methyl-3-(1H-tetrazol-5-yl)-2,6-dihydro-4H-furo[3,4-c]pyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       10 . The compound according to  claim 1  that is 3-(1H-Tetrazol-5-yl)-2,4-dihydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       11 . The compound according to  claim 1  that is 3-(1H-Tetrazol-5-yl)-2,6-dihydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       12 . The compound according to  claim 1  that is 3-(1H-Tetrazol-5-yl)-2,6-dihydro-4H-furo[3,4-c]pyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       13 . The compound according to  claim 1  that is 5-Ethyl-3-(1H-tetrazol-5-yl)-2,4,5,6-tetrahydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       14 . The compound according to  claim 1  that is 5-Butyl-3-(1H-tetrazol-5-yl)-2,4,5,6-tetrahydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       15 . The compound according to  claim 1  that is 5-Methyl-3-(1H-tetrazol-5-yl)-2,6-dihydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       16 . The compound according to  claim 1  that is 5-Methyl-3-(1H-tetrazol-5-yl)-2,4-dihydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       17 . The compound according to  claim 1  that is 5-Propyl-3-(1H-tetrazol-5-yl)-2,4,5,6-tetrahydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       18 . The compound according to  claim 1  that is 5-Propoxy-3-(1H-tetrazol-5-yl)-2,4,5,6-tetrahydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       19 . The compound according to  claim 1  that is 5-Cyclopentyl-3-(1H-tetrazol-5-yl)-2,4,5,6-tetrahydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       20 . The compound according to  claim 1  that is 5-Fluoro-3-(1H-tetrazol-5-yl)-2,4,5,6-tetrahydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       21 . The compound according to  claim 1  that is 5-Isobutoxy-3-(1H-tetrazol-5-yl)-2,4,5,6-tetrahydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       22 . The compound according to  claim 1  that is 5-Butoxy-3-(1H-tetrazol-5-yl)-2,4,5,6-tetrahydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       23 . The compound according to  claim 1  that is 3-(1H-Tetrazol-5-yl)-2,4,5,6-tetrahydro-cyclopentapyrazol-6-ol or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       24 . The compound according to  claim 1  that is 5-Methoxy-3-(1H-tetrazol-5-yl)-2,4,5,6-tetrahydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       25 . The compound according to  claim 1  that is 5,5-Difluoro-3-(1H-tetrazol-5-yl)-2,4,5,6-tetrahydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       26 . The compound according to  claim 1  that is 5-Ethoxy-3-(1H-tetrazol-5-yl)-2,4,5,6-tetrahydro-cyclopentapyrazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
   
       27 . A pharmaceutical composition comprising a compound according to  claim 1  in combination with a pharmaceutically acceptable carrier.  
   
   
       28 . A method of treatment of a metabolic-related disorder comprising administering to an individual in need of such treatment a therapeutically-effective amount of a compound according to  claim 1 .  
   
   
       29 . The method according to  claim 28  wherein said metabolic-related disorder is selected from the group consisting of dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance and type 2 diabetes.  
   
   
       30 . The method according to  claim 28  wherein said metabolic-related disorder is atherosclerosis.  
   
   
       31 . A method of raising HDL in an individual comprising administering to said individual a therapeutically-effective amount of a compound according to  claim 1 .  
   
   
       32 . A compound according to  claim 1  for use in a method of treatment of the human or animal body by therapy.  
   
   
       33 . A compound according to  claim 1  for use in a method of treatment of a metabolic-related disorder of the human or animal body by therapy.  
   
   
       34 . A compound according to  claim 1  for use in a method of treatment of a metabolic-related disorder of the human or animal body by therapy wherein said metabolic-related disorder is selected from the group consisting of dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance and type 2 diabetes.  
   
   
       35 . A compound according to  claim 1  for use in a method of treatment of atherosclerosis of the human or animal body by therapy.  
   
   
       36 . A compound according to  claim 1  for use in a method of raising HDL of the human or animal body by therapy.  
   
   
       37 . Use of a compound according to  claim 1  for the manufacture of a medicament for use in the treatment of a metabolic-related disorder.  
   
   
       38 . Use of a compound according to  claim 1  for the manufacture of a medicament for use in the treatment of a metabolic-related disorder selected from the group consisting of dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance and type 2 diabetes.  
   
   
       39 . Use of a compound according to  claim 1  for the manufacture of a medicament for use in the treatment of atherosclerosis.  
   
   
       40 . Use of a compound according to  claim 1  for the manufacture of a medicament for use in raising HDL in an individual.  
   
   
       41 . A method of producing a pharmaceutical composition comprising admixing a compound according to  claim 1  and a pharmaceutically acceptable carrier.