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).

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 a valence bond, —(CHR 8 )—, —(CHR 8 )—CH 2 —, —CH═CH—, —O—(CHR 8 )—, —S—(CHR 8 )—, —(NR 8 )—CH 2 —, —(CHR 8 )—CH═CH—, —(CHR 8 )—CH 2 —CH 2 —, —(C═O)—, —O—CH 2 —O—, —(NR 8 )—S(O 2 )—, —CH═(CR 8 )—, —(CO)—(CHR 8 )—, —CH 2 —(SO)—, —(SO)—, —(SO 2 )—, —CH 2 —(SO 2 )—, —CH 2 —O—CH 2 —, 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 is 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  is 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  is 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  is 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  is 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  is 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 is 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 is 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 . The compound of  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 . The compound of  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 heterocyclyl, wherein the heterocyclyl can be substituted with C 1-6 -alkyl.  
     
     
         4 . The compound of  claim 1 , wherein ring A and ring B, fused to the ring containing X and T independently of each other represents aryl or pyridyl, optionally substituted with oxadiazolyl, wherein the oxadiazolyl can be substituted with C 1-4 -alkyl.  
     
     
         5 . The compound of  claim 1 , wherein X is a valence bond, —(CHR 8 )—, —(CHR 8 )—CH 2 —, —O—(CHR 8 )— or —S—(CHR 8 )—, wherein R 8  is hydrogen.  
     
     
         6 . The compound of  claim 1 , wherein X is a valence bond, —(CHR 8 )—CH 2 — or —S—(CHR 8 )—, wherein R 8  is hydrogen.  
     
     
         7 . The compound of  claim 1 , wherein T is N or CR 14 , wherein R 14  is hydrogen.  
     
     
         8 . The compound of  claim 1 , wherein Y is C, O or S.  
     
     
         9 . The compound of  claim 1 , wherein k is 2.  
     
     
         10 . The compound of  claim 1 , wherein   represents a single bond.  
     
     
         11 . The compound of  claim 1 , wherein Ar represents arylene.  
     
     
         12 . The compound of  claim 1 , wherein R 1 , R 2  and R 3  represents hydrogen.  
     
     
         13 . The compound of  claim 1 , wherein R 4  and R 5  represents hydrogen or methyl.  
     
     
         14 . The compound of  claim 1 , wherein Z and Q represents O.  
     
     
         15 . The compound of  claim 1 , wherein n is 1.  
     
     
         16 . The compound of  claim 1 , wherein m is 1.  
     
     
         17 . The compound of  claim 1 , wherein p is 0.  
     
     
         18 . The compound of  claim 1  which is 
 2-[4-(2-β-Carbolin-9-yl-ethoxy)-benzyl]-malonic acid dimethyl ester,  
 2-[4-(2-β-Carbolin-9-yl-ethoxy)-benzyl]-malonic acid,  
 2-{4-[2-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-ethoxy]-benzyl}-malonic acid dimethyl ester,  
 2-(4-{2-[3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-β-carbolin-9-yl]-ethoxy}-benzyl)-malonic acid ester dimethyl, 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.  
 
     
     
         19 . A pharmaceutical composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.  
     
     
         20 . The composition of  claim 19  in unit dosage form, wherein the compound comprises from about 0.05 to about 100 mg, preferably from about 0.1 to about 50 mg.  
     
     
         21 . The pharmaceutical composition of  claim 19 , for oral, nasal, transdermal, pulmonary, or parenteral administration.  
     
     
         22 . A method for the treatment and/or prevention of conditions mediated by Peroxisome Proliferator-Activated Receptors (PPAR), the method comprising administering to a subject in need thereof an effective amount of a compound according to  claim 1 .  
     
     
         23 . A method for the treatment of diabetes and/or obesity, the method comprising administering to a subject in need thereof an effective amount of the compound of  claim 1 .  
     
     
         24 . The method of  claim 23 , wherein the effective amount of the compound 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.