New compounds, their preparation and use

Abstract

The present invention relates to compounds of the general formula (I) The compounds are useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).

Claims:  
     
         1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein ring A and ring B, fused to the ring containing X and T, independently of each other represents a 5-6 membered cyclic ring, optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro, cyano, formyl, or C 1-12 -alkyl, C 4- 12 -alkenynyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C 1-12 -alkoxy, aryloxy, arylalkyl, arylalkoxy, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, acyl, acyloxy, hydroxyC 1-12 -alkyl, amino, acylamino, C 1-12 -alkyl-amino, arylamino, arylalkylamino, amino-C 1-12-alkyl, C   1-12 -alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, C 1-12 -alkoxyC 1-12 alkyl, aryloxyC 1-12 -alkyl, arylalkoxyC 1-12 -alkyl, C 1-12 -alkylthio, thioC 1-12 -alkyl, C 1-12 -alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, bicycloalkyl, (C 3-6 -cycloalkyl)C 1-6 -alkyl, C 1-6 -dialkylamino, C 1-6 -alkylsulfonyl, C 1-6 -monoalkylaminosulfonyl, C 1-6 -dialkylaminosulfonyl, arylthio, arylsulfonyl, C 1-6 -monoalkylaminocarbonyl, C 1-6 dialkylaminocarbonyl, —COR 6  or —SO 2 R 7 , wherein R 6  and R 7  independently of each other are selected from hydroxy, halogen, perhalomethyl, C 1-6 -alkoxy or amino optionally substituted with one or more C 1-6 -alkyl or perhalomethyl; or aryl , wherein the aryl optionally can be substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano; or heteroaryl, wherein the heteroaryl optionally can be substituted with halogen, amino hydroxy, C 1-6 -alkyl or C 1-6 -alkoxy; or heterocyclyl, wherein the heterocyclyl optionally can be substituted with halogen, amino, hydroxy, C 1-6 -alkyl or C 1-6 -alkoxy; 
 X is —O—, —S—or —(CHR 8 )- wherein R 8  is hydrogen, halogen, hydroxy, nitro, cyano, formyl, C 1-12 -alkyl, C 1-12 -alkoxy, aryl, aryloxy, arylalkyl, arylalkoxy, heterocyclyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, C 1-12 -alkyl-amino, arylamino, arylalkylamino, aminoC 1-12 -alkyl, C 1-12 -alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, C 1-12 -alkoxyC 1-12 -alkyl, aryloxyC 1-12 -alkyl, arylalkoxyC 1-12 -alkyl, C 1-12 -alkylthio, thioC 1-12 -alkyl, C 1-12 -alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, —COR 9  or —SO 2 R 10 , wherein R 9  and R 10  independently of each other are selected from hydroxy, halogen, C 1-6 -alkoxy, amino optionally substituted with one or more C 1-6 -alkyl, perhalomethyl or aryl;  
 T is N or CR 14 , wherein R 14  is hydrogen, C 1-12 -alkoxy, C 1-12 -alkyl, C 4-12 -alkenynyl, C 2-12 -alkenyl, C 2-12 -alkynyl, aryl or arylalkyl;  
 Y is C, O, S, CO, SO, SO 2  or NR 11 , wherein R 11  is hydrogen, C 1-6 -alkyl;  
 k is 1 or 2;  
   represents a single or a double bond;  
 Ar represents arylene, heteroarylene, 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 -alkoxy or aryl;  
 R 1  represents hydrogen, hydroxy, halogen, C 1-12 -alkoxy, C 1-12 -alkyl, C 4-12 -alkenynyl, C 2-12 -alkenyl, C 2-12 -alkynyl or arylalkyl; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano;  
 R 2  represents hydrogen, hydroxy, halogen, C 1-12 -alkoxy, C 1-12 -alkyl, C 4-12 -alkenynyl, C 2-12 -alkenyl, C 2-12 -alkynyl or arylalkyl; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano; or R 2  forms a bond together with R 3 ;  
 R 3  represents hydrogen, hydroxy, halogen, C 1-12 -alkoxy, C 1-12 -alkyl, C 4-12 -alkenynyl, C 2-12 -alkenyl, C 2-12 -alkynyl, acyl or arylalkyl; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano; or R 3  forms a bond together with R 2;    
 R 4  represents hydrogen, C 1-12 -alkyl, C 4-12 -alkenynyl, C 2-12 -alkenyl, C 2-12 -alkynyl, aryl, arylalkyl, heterocyclyl, heteroaryl or heteroarylalkyl groups; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano;  
 R 5  represents hydrogen, C 1-12 -alkyl, C 4-12 -alkenynyl, C 2-12 -alkenyl, C 2-12 -alkynyl, aryl, arylalkyl, heterocyclyl, heteroaryl or heteroarylalkyl groups; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano;  
 Z represents oxygen or NR 12 , wherein R 12  represents hydrogen C 1-12 -alkyl, aryl, hydroxyC 1-12  -alkyl or arylalkyl groups or when Z is NR  12 , R 4  and R 12  may form a 5 or 6 membered nitrogen containing ring, optionally substituted with one or more C 1-6 -alkyl;  
 Q represents oxygen or NR 13 , wherein R 13  represents hydrogen C 1-12 -alkyl, aryl, hydroxyC 1-12  -alkyl or arylalkyl groups or when Q is NR 13 , R 5  and R 13  may form a 5 or 6 membered nitrogen containing ring, optionally substituted with one or more C 1-6 -alkyl;  
 n is an integer ranging from 0 to 3;  
 m is an integer ranging from 0 to 1;  
 p is an integer ranging from 0 to 1;  
 or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.  
 
     
     
         2 . A compound according to  claim 1  wherein ring A and ring B, fused to the ring containing X and T independently of each other represents a 5-6 membered cyclic ring, optionally substituted with halogen, C 1-6 -alkyl or aryl, wherein the aryl can be substituted with one or more halogen or C 1-6 -alkyl; or heterocyclyl, wherein the heterocyclyl can be substituted with C 1-6 -alkyl.  
     
     
         3 . A compound according to any one of the preceding claims wherein ring A and ring B, fused to the ring containing X and T independently of each other represents a 5-6 membered cyclic ring.  
     
     
         4 . A compound according to any one of the preceding claims wherein ring A and ring B, fused to the ring containing X and T independently of each other represents aryl.  
     
     
         5 . A compound according to any one of the preceding claims wherein X is O.  
     
     
         6 . A compound according to any one of the preceding claims wherein T is N.  
     
     
         7 . A compound according to any one of the preceding claims wherein k is 2.  
     
     
         8 . A compound according to any one of the preceding claims wherein  represents a single bond.  
     
     
         9 . A compound according to any one of the preceding claims wherein Ar represents arylene.  
     
     
         10 . A compound according to any one of the preceding claims wherein R 1 , R 2  and R 3  represents hydrogen.  
     
     
         11 . A compound according to any one of the preceding claims wherein R 4  and R 5  represents hydrogen or methyl.  
     
     
         12 . A compound according to any one of the preceding claims wherein Z and Q represents O.  
     
     
         13 . A compound according to any one of the preceding claims wherein n is 1.  
     
     
         14 . A compound according to any one of the preceding claims wherein m is 1.  
     
     
         15 . A compound according to any one of the preceding claims wherein p is 0.  
     
     
         16 . The compound according to  claim 1  which is 
 2-{4-(2-Phenoxazine-10-yl-ethoxy)-benzyl]-malonic acid dimethyl ester,  
 2-{4-(2-Phenoxazine-10-yl-ethoxy)-benzyl]-malonic acid;  
 or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.  
 
     
     
         17 . A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.  
     
     
         18 . A composition according to  claim 17  in unit dosage form, comprising from about 0.05 to about 100 mg, preferably from about 0.1 to about 50 mg of the compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof.  
     
     
         19 . A pharmaceutical composition useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR), the composition comprising, as an active ingredient, a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.  
     
     
         20 . A pharmaceutical composition useful in the treatment and/or prevention of diabetes and/or obesity, the composition comprising, as an active ingredient, a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.  
     
     
         21 . A pharmaceutical composition according to any one of the claims  17 -  20  for oral, nasal, transdermal, pulmonary, or parenteral administration.  
     
     
         22 . A method for the treatment of ailments, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof, or of a composition according to any one of the preceding claims  17 -  21 .  
     
     
         23 . A method for the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR), the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof, or of a composition according to any one of the preceding claims  17 -  21 .  
     
     
         24 . A method for the treatment and/or prevention of diabetes and/or obesity, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof, or of a composition according to any one of the preceding claims  17 - 21 .  
     
     
         25 . The method according to claims  22 ,  23  or  24 , wherein the effective amount of the compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt or ester thereof is in the range of from about 0.05 to about 100 mg per day, preferably from about 0.1 to about 50 mg per day.  
     
     
         26 . Use of a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof for the preparation of a medicament.  
     
     
         27 . Use of a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof for the preparation of a medicament useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).  
     
     
         28 . Use of a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treatment and/or prevention of diabetes and/or obesity.