4-Oxo-4,5-dihydro-furan-2-carboxylic acid derivatives and methods of treatment of metabolic-related disorders thereof

Abstract

System for selecting a colour shade comprising a very small number of colour display cards with mixed shades of two or more colours. The system comprises means for selecting one shade among mixed shades, means for presenting the selected mixed shade as well as means for specifying the selected mixed shade for making paint in the desired colour tone.

1 . A compound of Formula (I):  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, hydrate or solvate thereof,  
     wherein: 
 R 1  is H or C 1-6  alkyl;  
 R 2  is H, halogen, C 1-6  alkyl or C 1-6  haloalkyl; and  
 A) R 3  is aryl, C 3-7  cycloalkyl, C 3-7  cycloalkenyl, heteroaryl, C 3-7  heterocycloalkyl or C 3-7  heterocycloalkenyl wherein each are optionally substituted with 1 to 5 substituents selected from the group consisting of C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylureyl, C 1-6  alkylamino, amino, aryl, substituted aryl, carbo-C 1-6 -alkoxy, carboxamide, cyano, C 3-7  cycloalkyl, C 2-6  dialkylamino, C 2-6  dialkylcarboxamide, C 2-6  dialkylsulfonamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, heteroaryl, substituted heteroaryl, hydroxyl, nitro and thiol; and 
 R 4  is selected from the group consisting of H, ethyl, n-propyl, C 4-6  alkyl and C 1-6  haloalkyl wherein each are optionally substituted with 1 to 5 substituents selected from the group consisting of C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6 alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylureyl, C 1-6  alkylamino, amino, carbo-C 1-6 -alkoxy, carboxamide, cyano, C 3-7  cycloalkyl, C 2-6  dialkylamino, C 2-6  dialkylcarboxamide, C 2-6  dialkylsulfonamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, hydroxyl, nitro and thiol; or  
 R 4  is C 3-6 -cycloalkyl optionally substituted with 1 to 5 substituents selected from the group consisting of C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylureyl, C 1-6  alkylamino, amino, carbo-C 1-6 -alkoxy, carboxamide, cyano, C 3-7  cycloalkyl, C 2-6  dialkylamino, C 2-6  dialkylcarboxamide, C 2-6  dialkylsulfonamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, hydroxyl, nitro and thiol;  
 
 or  
 B) R 3  is a substituted phenyl, 2-chlorophenyl, 3-chlorophenyl, naphthyl, C 3-7  cycloalkyl, C 3-7  cycloalkenyl, heteroaryl, C 3-7  heterocycloalkyl or C 3-7  heterocycloalkenyl wherein said 2-chlorophenyl, 3-chlorophenyl, naphthyl, C 3-7  cycloalkyl, C 3-7  cycloalkenyl, heteroaryl, C 3-7  heterocycloalkyl and C 3-7  heterocycloalkenyl are optionally substituted with 1 to 5 substituents selected from the group consisting of C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylureyl, C 1-6  alkylamino, amino, aryl, substituted aryl, carbo-C 1-6 -alkoxy, carboxamide, cyano, C 3-7  cycloalkyl, C 2-6  dialkylamino, C 2-6  dialkylcarboxamide, C 2-6  dialkylsulfonamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, heteroaryl, substituted heteroaryl, hydroxyl, nitro and thiol; and 
 R 4  is selected from the group consisting of H, C 1-6  alkyl, C 3-6 -cycloalkyl and C 1-6  haloalkyl wherein each are optionally substituted with 1 to 5 substituents selected from the group consisting of C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylureyl, C 1-6  alkylamino, amino, carbo-C 1-6 -alkoxy, carboxamide, cyano, C 3-7  cycloalkyl, C 2-6  dialkylamino, C 2-6  dialkylcarboxamide, C 2-6  dialkylsulfonamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, hydroxyl, nitro and thiol.  
 
 
   
   
       2 . The compound according to  claim 1  wherein R 1  is C 1-6  alkyl.  
   
   
       3 . The compound according to  claim 1  wherein R 1  is methyl or ethyl.  
   
   
       4 . The compound according to  claim 1  wherein R 1  is H.  
   
   
       5 . The compound according to  claim 1  wherein R 2  is H.  
   
   
       6 . The compound according to  claim 1  wherein R 4  is C 1-6  alkyl.  
   
   
       7 . The compound according to  claim 6  wherein R 4  is methyl.  
   
   
       8 . The compound according to  claim 6  wherein R 4  is ethyl.  
   
   
       9 . The compound according to  claim 1  wherein R 4  is C 1-6  haloalkyl.  
   
   
       10 . The compound according to  claim 9  wherein R 4  is trifluoromethyl.  
   
   
       11 . The compound according to  claim 1  wherein R 3  is substituted phenyl, 3-chlorophenyl, C 3-7  cycloalkyl, C 3-7  cycloalkenyl or heteroaryl, wherein said 3-chlorophenyl, C 3-7  cycloalkyl, C 3-7  cycloalkenyl and heteroaryl are optionally substituted with 1 to 5 substituents selected from the group consisting of C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, aryl, cyano, halogen, C 1-6  haloalkyl and heteroaryl.  
   
   
       12 . The compound according to  claim 1  wherein R 3  is thienyl optionally substituted with C 1-6  alkyl, halogen or C 1-6  haloalkyl.  
   
   
       13 . The compound according to  claim 1  wherein R 3  is thienyl optionally substituted with methyl, ethyl, F, Cl, Br, I or trifluoromethyl.  
   
   
       14 . The compound according to  claim 1  wherein R 3  is selected from the group consisting of biphenyl-3-yl, 3-thiophen-2-yl-phenyl, 3-bromo-phenyl, 3-iodo-phenyl, 3-chloro-phenyl, 3-fluoro-phenyl, 3,5-difluoro-phenyl, m-tolyl, 3-ethyl-phenyl, 3-trifluoromethyl-phenyl, 4-fluoro-phenyl, 2-fluoro-phenyl, 3,4-difluoro-phenyl, 2,4-difluoro-phenyl, 2,6-difluoro-phenyl, 2,5-dichloro-phenyl, 3-methoxy-phenyl, 3,5-dichloro-phenyl, 3-cyano-phenyl, 3-propenyl-phenyl, 3-hex-1-enyl-phenyl and 3-vinyl-phenyl.  
   
   
       15 . The compound according to  claim 1  wherein R 3  is selected from the group consisting of thiophen-3-yl, thiophen-2-yl, 4-bromo-thiophen-2-yl, 5-methyl-thiophen-2-yl, 5-chloro-thiophen-2-yl, 5-bromo-thiophen-3-yl, 5-chloro-thiophen-3-yl, 4-bromo-5-methyl-thiophen-2-yl, pyridin-3-yl, furan-2-yl, 4-methyl-thiophen-2-yl and 5-methyl-thiophen-3-yl.  
   
   
       16 . The compound according to  claim 1  wherein R 3  is selected from the group consisting of cyclohex-1-enyl, cyclopent-1-enyl and cyclopentyl.  
   
   
       17 . The compound according to  claim 1  wherein: 
 R 1  is H;    R 2  is H;    R 4  is C 1-6  alkyl or C 1-6  haloalkyl; and    R 3  is substituted phenyl, 3-chlorophenyl, C 3-7  cycloalkyl, C 3-7  cycloalkenyl or heteroaryl, wherein said 3-chlorophenyl, C 3-7  cycloalkyl, C 3-7  cycloalkenyl and heteroaryl are optionally substituted with 1 to 5 substituents selected from the group consisting of C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, aryl, cyano, halogen, C 1-6  haloalkyl and heteroaryl.    
   
   
       18 . The compound according to  claim 1  wherein: 
 R 1  is H;    R 2  is H;    R 4  is methyl, ethyl or trifluoromethyl; and    R 3  is selected from the group consisting of biphenyl-3-yl, 3-thiophen-2-yl-phenyl, 3-bromo-phenyl, 3-iodo-phenyl, 3-chloro-phenyl, 3-fluoro-phenyl, 3,5-difluoro-phenyl, m-tolyl, 3-ethyl-phenyl, 3-trifluoromethyl-phenyl, 3,4-difluoro-phenyl, 2,4-difluoro-phenyl, 2,6-difluoro-phenyl, 2,5-dichloro-phenyl, 3-methoxy-phenyl, 3,5-dichloro-phenyl, 3-cyano-phenyl, 3-propenyl-phenyl, 3-hex-1-enyl-phenyl and 3-vinyl-phenyl.    
   
   
       19 . The compound according to  claim 1  wherein: 
 R 1  is H;    R 2  is H;    R 4  is methyl, ethyl or trifluoromethyl; and    R 3  is thienyl optionally substituted with C 1-6  alkyl or halogen.    
   
   
       20 . The compound according to  claim 1  wherein: 
 R 1  is H;    R 2  is H;    R 4  is methyl, ethyl or trifluoromethyl; and    R 3  is selected from the group consisting of thiophen-3-yl, thiophen-2-yl, 4-bromo-thiophen-2-yl, 5-methyl-thiophen-2-yl, 5-chloro-thiophen-2-yl, 5-bromo-thiophen-3-yl, 5-chloro-thiophen-3-yl, 4-bromo-5-methyl-thiophen-2-yl, pyridin-3-yl, furan-2-yl, 4-methyl-thiophen-2-yl and 5-methyl-thiophen-3-yl.    
   
   
       21 . The compound according to  claim 1  selected from the group consisting of: 
 5-Cyclohex-1-enyl-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-Methyl-4-oxo-5-thiophen-3-yl-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-Methyl-4-oxo-5-thiophen-2-yl-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-(4-Bromo-thiophen-2-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-(4-Bromo-thiophen-2-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-Methyl-5-(5-methyl-thiophen-2-yl)-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-Methyl-5-(5-methyl-thiophen-2-yl)-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-(5-Chloro-thiophen-2-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl; ester;    5-Cyclopent-1-enyl-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-Biphenyl-3-yl-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-Methyl-4-oxo-5-(3-thiophen-2-yl-phenyl)-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-(3-Bromo-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-(3-Bromo-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-(3-Iodo-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-(3-Chloro-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-(3-Fluoro-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-(3,5-Difluoro-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-Methyl-4-oxo-5-m-tolyl-4,5-dihydro-furan-2-carboxylic acid;    5-(3-Ethyl-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-Methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-4,5-dihydro-furan-2-carboxylic acid;    5-(5-Chloro-thiophen-2-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid; and    5-Methyl-4-oxo-5-thiophen-2-yl-4,5-dihydro-furan-2-carboxylic acid; or 
 a pharmaceutically acceptable salt, hydrate or solvate thereof.  
   
   
   
       22 . The compound according to  claim 1  selected from the group consisting of: 
 5-(5-Bromo-thiophen-3-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-(5-Bromo-thiophen-3-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-(5-Chloro-thiophen-3-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-(5-Chloro-thiophen-3-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-(4-Bromo-5-methyl-thiophen-2-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-Methyl-4-oxo-5-thiophen-3-yl-4,5-dihydro-furan-2-carboxylic acid;    5-(4-Fluoro-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-Methyl-4-oxo-5-pyridin-3-yl-4,5-dihydro-furan-2-carboxylic acid;    5-Ethyl-4-oxo-5-phenyl-4,5-dihydro-furan-2-carboxylic acid;    5-(2-Fluoro-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    2-Methyl-3-oxo-2,3-dihydro-[2,2]bifuranyl-5-carboxylic acid;    5-(3,4-Difluoro-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-(2,4-Difluoro-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-(2,6-Difluoro-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-(2,5-Dichloro-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-(3-Methoxy-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-Methyl-4-oxo-5-m-tolyl-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-(3-Ethyl-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-Cyclohex-1-enyl-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-(3,5-Dichloro-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-(3,5-Dichloro-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-(3-Iodo-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-Cyclopentyl-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-Cyclopentyl-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-(3-Cyano-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-(3-Cyano-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-Methyl-4-oxo-5-[3-propenyl)-phenyl]-4,5-dihydro-furan-2-carboxylic acid;    5-(4-Bromo-5-methyl-thiophen-2-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-Biphenyl-3-yl-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-[3-Hex-1-enyl)-phenyl]-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-Methyl-5-(4-methyl-thiophen-2-yl)-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester;    5-Methyl-4-oxo-5-(3-vinyl-phenyl)-4,5-dihydro-furan-2-carboxylic acid;    5-Methyl-5-(4-methyl-thiophen-2-yl)-4-oxo-4,5-dihydro-furan-2-carboxylic acid;    5-Methyl-5-(5-methyl-thiophen-3-yl)-4-oxo-4,5-dihydro-furan-2-carboxylic acid; and    4-Oxo-5-phenyl-5-trifluoromethyl-4,5-dihydro-furan-2-carboxylic acid; or 
 a pharmaceutically acceptable salt, hydrate or solvate thereof.  
   
   
   
       23 . The compound according to  claim 1  wherein said compound is essentially the R enantiomer.  
   
   
       24 . The compound according to  claim 1  wherein said compound is essentially the S enantiomer.  
   
   
       25 . A pharmaceutical composition comprising a compound according to any one of claims  1  and  17  to  24  in combination with a pharmaceutically acceptable carrier.  
   
   
       26 . A pharmaceutical composition according to  claim 25  further comprising an agent selected from the group consisting of α-glucosidase inhibitor, aldose reductase inhibitor, biguanide, HMG-CoA reductase inhibitor, squalene synthesis inhibitor, fibrate, LDL catabolism enhancer, angiotensin converting enzyme inhibitor, insulin secretion enhancer and thiazolidinedione.  
   
   
       27 . 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 .  
   
   
       28 . The method according to  claim 27  wherein said metabolic-related disorder is selected from the group consisting of dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, obesity, impaired glucose tolerance, atheromatous disease, hypertension, stroke, Syndrome X, heart disease and type 2 diabetes.  
   
   
       29 . The method according to  claim 27  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 27  wherein said metabolic-related disorder is atherosclerosis.  
   
   
       31 . A method of modulating a RUP25 receptor comprising contacting said receptor with a compound according to  claim 1 .  
   
   
       32 . A method of modulating a RUP25 receptor for the treatment of a metabolic-related disorder in an individual in need of such modulation comprising contacting said receptor with a therapeutically-effective amount of a compound according to  claim 1 .  
   
   
       33 . The method according to  claim 32  wherein said compound is an agonist.  
   
   
       34 . The method according to  claim 33  wherein said agonist is a partial agonist.  
   
   
       35 . A method of raising HDL in an individual comprising administering to said individual a therapeutically-effective amount of a compound according to  claim 1 .  
   
   
       36 - 47 . (canceled)  
   
   
       48 . A method of producing a pharmaceutical composition comprising admixing a compound according to  claim 1  and a pharmaceutically acceptable carrier.