Noncyclic 1,3-Dicarbonyl compounds as dual PPAR agonists with potent antihyperglycemic and antihyperlipidemic activity

Abstract

Disclosed are the preparation and pharmaceutical use of novel noncyclic 1,3-dicarbonyl compounds of formula I, wherein ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, Q, Ar and n are as defined in the specification. These compounds, as peroxisome proliferator-activated receptor (PPAR) dual agonists for both RXR/PPARgamma and RXR/PPARalpha heterodimers, are useful in the treatment and/or prevention of type 2 diabetes and associated metabolic syndrome such as hypertension, obesity, insulin resistance, hyperlipidemia, hyperglycemia, hypercholesterolemia, atherosclerosis, coronary artery disease, and other cardiovascular disorders.

1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 ring A, fused to ring B, represents a 5-6 membered cyclic ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms and may optionally be substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino; the ring A may be saturated or contain one or more double bonds;  
 ring B, fused to ring A, represents a 5-6 membered cyclic ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms and may optionally be substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino; the ring B may be saturated or contain one or more double bonds or may be aromatic;  
 X and Y are independently O, S, or NR 6  wherein R 6  represents hydrogen or C 1-3  alkyl;  
 Z represents O, S, or NR 7  wherein R 7  represents hydrogen, alkyl, aryl, or arylalkyl;  
 Q represents O, S, or NR 7  wherein R 7  represents hydrogen, alkyl, aryl, or arylalkyl;  
 R 1 , R 2  and R 3  are independently H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino;  
 R 4 , R 5  are independently H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl, or heteroaryl;  
 Ar represents arylene, hetero arylene, or a divalent heterocyclic group each of which can optionally be substituted with one or more halogen, C 1-6  alkyl, amino, hydroxy, C 1-6  alkoxyl or aryl; and  
 n is an integer ranging from 1 to 6.  
 
     
     
         2 . The compound of  claim 1 , wherein 
 ring A is a 6-membered cyclic ring;    ring B is a 6-membered aromatic ring;    X and Y are independently O;    Z is O or NR 7  wherein R 7  represents hydrogen, alkyl, aryl, or arylalkyl;    Q is O or NR 7  wherein R 7  represents hydrogen, alkyl, aryl, or arylalkyl;    R 1 , R 2  and R 3  are independently H or alkyl;    R 4  and R 5  are independently H or alkyl;    Ar is an arylene group;    n is 2;    
     
     
         3 . The compound of  claim 1 , wherein 
 ring A is a 6-membered cyclic ring;    ring B is benzene ring;    X and Y are independently O;    Z is O or NR 7  wherein R 7  represents hydrogen;    Q is O or NR 7  wherein R 7  represents hydrogen;    R 1 , R 2  and R 3  are independently H;    R 4  and R 5  are independently H or methyl;    Ar is benzene group;    n is 2;    
     
     
         4 . A compound of formula II wherein 
 ring A, ring B, X, Y, Ar and n are as defined in  claim 1 , and T is —CHO or —R 1 C═C(COOMe) 2  wherein R 1  is as defined in  claim 1 .                          
     
     
         5 . The compound according to  claim 4  wherein: 
 ring A is a 6-membered cyclic ring;    ring B is benzene ring;    X and Y are independently O;    Ar is benzene group;    n is 2;    
     
     
         6 . A process for the preparation of a compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 ring A, fused to ring B, represents a 5-6 membered cyclic ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms and may optionally be substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino; the ring A may be saturated or contain one or more double bonds;  
 ring B, fused to ring A, represents a 5-6 membered cyclic ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms and may optionally be substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino; the ring B may be saturated or contain one or more double bonds or may be aromatic;  
 X and Y are independently O, S, or NR 6  wherein R 6  represents hydrogen or C 1-3  alkyl;  
 Z represents O, S, or NR 7  wherein R 7  represents hydrogen, alkyl, aryl, or arylalkyl;  
 Q represents O, S, or NR 7  wherein R 7  represents hydrogen, alkyl, aryl, or arylalkyl;  
 R 1 , R 2  and R 3  are independently H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino;  
 R 4 , R 5  are independently H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl, or heteroaryl;  
 Ar represents arylene, hetero arylene, or a divalent heterocyclic group each of which can optionally be substituted with one or more halogen, C 1-6  alkyl, amino, hydroxy, C 1-6  alkoxyl or aryl;  
 n is an integer ranging from 1 to 6;  
 A stereoisomer, enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt thereof comprising the steps of:  
 a) changing the compound of formula 1 to the benzaldehyde derivative 2;  
                     
 b) changing the aldehyde 2 to the benzylidene 3 by Knoevenagel condensation;  
                     
 c) obtaining the dimethyl malonate 4 by catalytic hydrogenation of 3;  
                     
 d) changing the dimethyl malonate 4 to other 1,3-dicarbonyl compounds 5.  
                     
 
     
     
         7 . The process according to  claim 6  wherein: 
 (a) the benzaldehyde derivative 2 is prepared by the reaction of compound 1 with p-bromoethoxy benzaldehyde in the presence of potassium hydroxide;    (b) the Knoevenagel condensation is achieved by treating the benzaldehyde 2 with dimethyl malonate in the presence of a catalytic quantity of piperidinium acetate;    (c) the catalytic hydrogenation is achieved by treating the benzylidene 3 with H 2  in the presence of 5% palladium on carbon;    (d) the other 1,3-dicarbonyl compounds 5 are prepared from 4 by hydrolysis or other conventional reactions.    
     
     
         8 . A pharmaceutical composition for activating nuclear receptors comprising an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 ring A, fused to ring B, represents a 5-6 membered cyclic ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms and may optionally be substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino; the ring A may be saturated or contain one or more double bonds;  
 ring B, fused to ring A, represents a 5-6 membered cyclic ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms and may optionally be substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino; the ring B may be saturated or contain one or more double bonds or may be aromatic;  
 X and Y are independently O, S, or NR 6  wherein R 6  represents hydrogen or C 1-3  alkyl;  
 Z represents O, S, or NR 7  wherein R 7  represents hydrogen, alkyl, aryl, or arylalkyl;  
 Q represents O, S, or NR 7  wherein R 7  represents hydrogen, alkyl, aryl, or arylalkyl;  
 R 1 , R 2  and R 3  are independently H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino;  
 R 4 , R 5  are independently H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl, or heteroaryl;  
 Ar represents arylene, hetero arylene, or a divalent heterocyclic group each of which can optionally be substituted with one or more halogen, C 1-6  alkyl, amino, hydroxy, C 1-6  alkoxyl or aryl;  
 n is an integer ranging from 1 to 6; and  
 wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers or diluents.  
 
     
     
         9 . The pharmaceutical composition according to  claim 8 , wherein the nuclear receptors comprise the Retinoid X Receptor (RXR), and the Peroxisome Proliferator-Activated Receptors (PPAR).  
     
     
         10 . The pharmaceutical composition of  claim 9  in unit dosage form, comprising from about 0.05 to about 100 mg of the active compound.  
     
     
         11 . The pharmaceutical composition of  claim 10  in unit dosage form, comprising from about 0.1 to about 50 mg of the active compound  
     
     
         12 . The pharmaceutical composition of  claim 9  which is suitable for administration by an oral, nasal, transdermal, pulmonary, or parenteral route.  
     
     
         13 . A method of treating or preventing a condition mediated by at least one nuclear receptor, comprising administering to a subject in need thereof an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 ring A, fused to ring B, represents a 5-6 membered cyclic ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms and may optionally be substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino; the ring A may be saturated or contain one or more double bonds;  
 ring B, fused to ring A, represents a 5-6 membered cyclic ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms and may optionally be substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino; the ring B may be saturated or contain one or more double bonds or may be aromatic;  
 X and Y are independently O, S, or NR 6  wherein R 6  represents hydrogen or C 1-3  alkyl;  
 Z represents O, S, or NR 7  wherein R 7  represents hydrogen, alkyl, aryl, or arylalkyl;  
 Q represents O, S, or NR 7  wherein R 7  represents hydrogen, alkyl, aryl, or arylalkyl;  
 R 1 , R 2  and R 3  are independently H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino;  
 R 4 , R 5  are independently H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl, or heteroaryl;  
 Ar represents arylene, hetero arylene, or a divalent heterocyclic group each of which can optionally be substituted with one or more halogen, C 1-6  alkyl, amino, hydroxy, C 1-6  alkoxyl or aryl; and  
 n is an integer ranging from 1 to 6.  
 
     
     
         14 . The method according to  claim 13 , wherein the nuclear receptor is a Retinoid X Receptor (RXR) or a Peroxisome Proliferator-Activated Receptor (PPAR).  
     
     
         15 . A method of treating or preventing a condition mediated by reduced activity of at least one nuclear receptor, comprising administration to a subject in need thereof an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 ring A, fused to ring B, represents a 5-6 membered cyclic ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms and may optionally be substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino; the ring A may be saturated or contain one or more double bonds;  
 ring B, fused to ring A, represents a 5-6 membered cyclic ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms and may optionally be substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino; the ring B may be saturated or contain one or more double bonds or may be aromatic;  
 X and Y are independently O, S, or NR 6  wherein R 6  represents hydrogen or C 1-3  alkyl;  
 Z represents O, S, or NR 7  wherein R 7  represents hydrogen, alkyl, aryl, or arylalkyl;  
 Q represents O, S, or NR 7  wherein R 7  represents hydrogen, alkyl, aryl, or arylalkyl;  
 R 1 , R 2  and R 3  are independently H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino;  
 R 4 , R 5  are independently H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl, or heteroaryl;  
 Ar represents arylene, hetero arylene, or a divalent heterocyclic group each of which can optionally be substituted with one or more halogen, C 1-6  alkyl, amino, hydroxy, C 1-6  alkoxyl or aryl; and  
 n is an integer ranging from 1 to 6.  
 
     
     
         16 . A method according to  claim 15 , wherein the nuclear receptor is a Retinoid X Receptor (RXR) or a Peroxisome Proliferator-Activated Receptor (PPAR).  
     
     
         17 . A method according to  claim 15  wherein said condition is selected from the group consisting of type 1 diabetes, type 2 diabetes, dyslipidemia, syndrome X, cardiovascular disease, atherosclerosis, hypercholesteremia, and obesity.  
     
     
         18 . The method according to  claim 15 , wherein the effective amount of the compound is in the range of from about 0.05 to about 100 mg/kg body weight per day.  
     
     
         19 . The method according to  claim 15 , wherein the effective amount of the compound is in the range of from about 0.1 to about 50 mg/kg body weight per day.