US2004229899A1PendingUtilityA1

Compounds useful in the treatment of conditions mediated by peroxisome proliferator-activated receptors (PPAR)

52
Priority: Oct 21, 1998Filed: Jan 6, 2004Published: Nov 18, 2004
Est. expiryOct 21, 2018(expired)· nominal 20-yr term from priority
Inventors:Lone JeppesenPaul Stanley BuryPer Sauerberg
C07C 2603/32C07D 313/12C07C 69/734C07D 321/12A61P 5/48A61P 3/10C07D 263/52C07D 337/12C07C 217/22C07C 59/72
52
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Claims

Abstract

The present invention relates to compounds of formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Ar, X, Q, A, Y and Z are as defined in the specification. These compounds are useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A compound of formula (Ia)  
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , and R 4  independently of each other represent hydrogen, 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, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyC 1-12 alkyl, amino, acylamino, C 1-12 alkyl-amino, arylamino, aralkylamino, aminoC 1-12 alkyl, C 1-12 alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, C 1-12 alkoxyC 1-12 alkyl, aryloxyC 1-12 alkyl, aralkoxyC 1-12 alkyl, C 1-12 alkylthio, thioC 1-12 alkyl, C 1-12 alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, —COR 11 , or —SO 2 R 12 , wherein R 11  and R 12  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, perhalomethyl or aryl; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano;  
         or R 1  and R 2 , R 2  and R 3  and/or R 3  and R 4 , together with the carbon atoms to which they are attached, may form a cyclic ring containing from 5 to 7 carbon atoms optionally substituted with one or more C 1-6 -alkyl;  
         ring A 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, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyC 1-12 alkyl, amino, acylamino, C 1-12 alkyl-amino, arylamino, aralkylamino, aminoC 1-12 alkyl, C 1-12 alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, C 1-12 alkoxyC 1-12 alkyl, aryloxyC 1-12 alkyl, aralkoxyC 1-12 alkyl, C 1-12 alkylthio, thioC 1-12 alkyl, C 1-12 alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, —COR 11 , or —SO 2 R 12 , wherein R 11  and R 12  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, perhalomethyl or aryl; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano;  
         X is —O—, —(NR 9 )—CH 2 —, —(C═O)—, —(NR 9 )—S(O 2 )—, —(NR 9 )—, —(CO)—(CHR 9 )—, —S—, —(SO)—, —(SO 2 )—, —CH 2 —O—CH 2 —, wherein R 9  is hydrogen, halogen, hydroxy, nitro, cyano, formyl, C 1-12 alkyl, C 1-12 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, C 1-12 alkyl-amino, arylamino, aralkylamino, aminoC 1-12 alkyl, C 1-12 alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, C 1-12 alkoxyC 1-12 alkyl, aryloxyC 1-12 alkyl, aralkoxyC 1-12 alkyl, C 1-12 alkylthio, thioC 1-12 alkyl, C 1-12 alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, —COR 13 , or —SO 2 R 14 , wherein R 13  and R 14  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;  
         Z is —CH 2 —, —O—, —S—, >SO 2, , >NR 15 , wherein R 15  is hydrogen, halogen, hydroxy, nitro, cyano, formyl, C 1-12 alkyl, C 1-12 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, C 1-12 alkyl-amino, arylamino, aralkylamino, aminoC 1-12 alkyl, C 1-12 alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, C 1-12 alkoxyC 1-12 alkyl, aryloxyC 1-12 alkyl, aralkoxyC 1-12 alkyl, C 1-12 alkylthio, thioC 1-12 alkyl, C 1-12 alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, —COR 16 , or —SO 2 R 17 , wherein R 15  and R 17  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;  
         Q is —O—, —S—, >NR 18  wherein R 18  is hydrogen or C 1-6 -alkyl;  
         Ar represents arylene, heteroarylene, or a divalent heterocyclic group optionally substituted with one or more C 1-6 -alkyl or aryl;  
         R 5  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 aralkyl; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano; or R 5  forms a bond together with R 6 ;  
         R 6  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 aralkyl; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano; or R 6  forms a bond together with R 5 ;  
         R 7  represents hydrogen, C 1-12 alkyl, C 4-12 -alkenynyl, C 2-12 -alkenyl, C 2-12 -alkynyl, aryl, aralkyl, C 1-12 alkoxyC 1-12 alkyl, C 1-12 alkoxycarbonyl, aryloxycarbonyl, C 1-12 alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano;  
         R 8  represents hydrogen, C 1-12 alkyl, C 4-12 -alkenynyl, C 2-12 -alkenyl, C 2-12 -alkynyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano;  
         Y represents oxygen, sulphur or NR 10 , where R 10  represents hydrogen, C 1-12 alkyl, aryl, hydroxyC 1-12 alkyl or aralkyl groups or when Y is NR 10 , R 8  and R 10  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 1 to 4;  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         2 . A compound of  claim 1  wherein R 1 , R 2 , R 3 , and R 4  independently of each other represent hydrogen, halogen, perhalomethyl, hydroxy, cyano, or C 1-7 alkyl, C 4-7 -alkenynyl, C 2-7 -alkenyl, C 2-7 -alkynyl, C 1-7 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyC 1-7 alkyl, amino, acylamino, C 1-7 alkylamino, arylamino, aralkylamino, aminoC 1-7 alkyl, C 1-7 alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, C 1-7 alkoxyC 1-7 alkyl, aryloxyC 1-7 alkyl, aralkoxyC 1-7 alkyl, C 1-7 alkylthio, thioC 1-7 alkyl, C 1-7 alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, —COR 11 , or —SO 2 R 12 , wherein R 11  and R 12  independently of each other are selected from hydroxy, perhalomethyl, C 1-6 -alkoxy or amino optionally substituted with one or more C 1 -alkyl, perhalomethyl or aryl; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano; 
 or R 1  and R 2 , R 2  and R 3  and/or R 3  and R 4  may form a cyclic ring containing from 5 to 7 carbon atoms optionally substituted with one or more C 1-6 alkyl.  
 
     
     
         3 . A compound of  claim 1  wherein R 1 , R 2 , R 3 , and R 4  independently of each other represent hydrogen, halogen, perhalomethyl, hydroxy, cyano, or C 1-7 alkyl, C 4-7 -alkenynyl, C 2-7 -alkenyl, C 2-7 -alkynyl, C 1-7 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, hydroxyC 1-7 alkyl, amino, acylamino, C 1-7 alkyl-amino, arylamino, aralkylamino, aminoC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, aryloxyC 1-7 alkyl, aralkoxyC 1-7 alkyl, C 1-7 alkylthio, thioC 1-7 alkyl, C 1-7 alkoxycarbonylamino, aryloxycarbonylamino or aralkoxycarbonylamino.  
     
     
         4 . A compound of  claim 1  wherein R 1 , R 2 , R 3 , and R 4  independently of each other represent hydrogen, halogen, perhalomethyl, hydroxy, cyano, or C 1-7 alkyl, C 4-7 -alkenynyl, C 2-7 -alkenyl, C 2-7 -alkynyl, C 1-7 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, acyl, hydroxyC 1-7 alkyl, amino, C 1-7 alkyl-amino, arylamino, aralkylamino, C 1-7 alkoxyC 1-7 alkyl, aryloxyC 1-7 alkyl, aralkoxyC 1-7 alky or C 1-7 alkylthio.  
     
     
         5 . A compound of  claim 1  wherein R 1 , R 2 , R 3 , and R 4  independently of each other represent hydrogen, halogen, perhalomethyl, or C 1-7 alkyl, C 4-7 -alkenynyl, C 2-7 -alkenyl, C 2-7 -alkynyl, aryl, aralkyl, hydroxyC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, aryloxyC 1-7 alkyl or aralkoxyC 1-7 alkyl.  
     
     
         6 . A compound of  claim 1  wherein R 1 , R 2 , R 3 , and R 4  independently of each other represent hydrogen, halogen or C 1-7 alkyl.  
     
     
         7 . A compound of  claim 1  wherein R 1 , R 2 , R 3 , and R 4  independently of each other represent hydrogen, chlorine or methyl.  
     
     
         8 . A compound of  claim 1  wherein ring A represents a 5-6 membered cyclic ring, optionally substituted with one or more halogen, perhalomethyl, hydroxy, cyano or C 1-7 alkyl, C 4-7 -alkenynyl, C 2-7 -alkenyl, C 2-7 -alkynyl, C 1-7 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyC 1-7 alkyl, amino, acylamino, C 1-7 alkyl-amino, arylamino, aralkylamino, aminoC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, aryloxyC 1-7 alkyl, aralkoxyC 1-7 alkyl, C 1-7 alkylthio, thioC 1-7 alkyl, C 1-7 alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, —COR 11 , or —SO 2 R 12 , wherein R 11  and R 12  independently of each other are selected from hydroxy, perhalomethyl, C 1-6 -alkoxy or amino optionally substituted with one or more C 1-6 -alkyl, perhalomethyl or aryl; optionally substituted with one or more halogen, perhalomethyl, hydroxy or cyano.  
     
     
         9 . A compound of  claim 1  wherein ring A represents a 5-6 membered cyclic ring, optionally substituted with one or more halogen, perhalomethyl, hydroxy, cyano, or C 1-7 alkyl, C 4-7 -alkenynyl, C 2-7 -alkenyl, C 2-7 -alkynyl, C 1-7 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, hydroxyC 1-7 alkyl, amino, acylamino, C 1-7 alkyl-amino, arylamino, aralkylamino, aminoC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, aryloxyC 1-7 alkyl, aralkoxyC 1-7 alkyl, C 1-7 alkylthio, thioC 1-7 alkyl, C 1-7 alkoxycarbonylamino, aryloxycarbonylamino or aralkoxycarbonylamino.  
     
     
         10 . A compound of  claim 1  wherein ring A represents a 5-6 membered cyclic ring, optionally substituted with one or more halogen, perhalomethyl, hydroxy, cyano, or C 1-7 alkyl, C 4-7 -alkenynyl, C 2-7 -alkenyl, C 2-7 -alkynyl, C 1-7 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, acyl, hydroxyC 1-7 alkyl, amino, C 1-7 alkyl-amino, arylamino, aralkylamino, C 1-7 alkoxyC 1-7 alkyl, aryloxyC 1-7 alkyl, aralkoxyC 1-7 alkyl or C 1-7 alkylthio.  
     
     
         11 . A compound of  claim 1  wherein ring A represents a 5-6 membered cyclic ring, optionally substituted with one or more halogen, perhalomethyl or C 1-7 alkyl, C 4-7 -alkenynyl, C 2-7 -alkenyl, C 2-7 -alkynyl, C 1-7 alkoxy, aryl, aralkyl, hydroxyC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, aryloxyC 1-7 alkyl or aralkoxyC 1-7 alkyl.  
     
     
         12 . A compound of  claim 1  wherein ring A represents a 5-6 membered cyclic ring, optionally substituted with one or more chlorine or methyl groups.  
     
     
         13 . A compound of  claim 1  wherein X is —O—, —(NR 9 )—CH 2 —, —(C═O)—, —(NR 9 )—S(O 2 )—, —(NR 9 )—, —(CO)—(CHR 9 )—, —S—, —(SO)—, —(SO 2 )—, or —CH 2 —O—CH 2 —, wherein R 9  is hydrogen, halogen, hydroxy, C 1-7 alkyl, C 1-7 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, hydroxyalkyl, amino, acylamino, C 1-7 alkyl-amino, arylamino, aralkylamino, aminoC 1-7 alkyl, C 1-7 alkoxyC 1-12 alkyl, aryloxyC 1-7 alkyl, aralkoxyC 1-7 alkyl, C 1-12 alkylthio, thioC 1-7 alkyl, C 1-7 alkoxycarbonylamino, aryloxycarbonylamino or aralkoxycarbonylamino.  
     
     
         14 . A compound of  claim 1  wherein X is —O—, —(NR 9 )—CH 2 —, —(C═O)—, —(NR 9 )—S(O 2 )—, —(NR 9 )—, —(CO)—(CHR 9 )—, —S—, —(SO)—, —(SO 2 )—, or —CH 2 —O—CH 2 —, wherein R 9  is hydrogen, halogen, hydroxy, C 1-7 alkyl, aryl, aralkyl, C 1-7 alkoxyC 1-12 alkyl, aryloxyC 1-7 alkyl or aralkoxyC 1-7 alkyl.  
     
     
         15 . A compound of  claim 1  wherein X is —O—, —(NR 9 )—CH 2 —, —(C═O)—, —(NR 9 )—S(O 2 )—, —(NR 9 )—, —(CO)—(CHR 9 )—, —S—, —(SO)—, —(SO 2 )—, or —CH 2 —O—CH 2 —, wherein R 9  is hydrogen.  
     
     
         16 . A compound of  claim 1  wherein Z is —CH 2 —, —O—, —S—, >NR 15 , wherein R 15  is hydrogen, C 1-12 alkyl, C 1-7 alkoxy, aralkyl, aralkoxy, hydroxyalkyl, aminoC 1-7 alkyl, C 1-12 alkoxyC 1-7 alkyl, aryloxyC 1-7 alkyl or aralkoxyC 1-7 alkyl.  
     
     
         17 . A compound of  claim 1  wherein Z is —CH 2 —, —O—, —S— or >NR 15 , wherein R 15  is hydrogen.  
     
     
         18 . A compound of  claim 1  wherein Z is —O—.  
     
     
         19 . A compound of  claim 1  wherein Q is —O—, —S— or >NR 18  wherein R 18  is hydrogen or methyl.  
     
     
         20 . A compound of  claim 1  wherein Q is —O— or >NR 18  wherein R 18  is methyl.  
     
     
         21 . A compound of  claim 1  wherein Ar represents arylene optionally substituted with one or more C 1-6 -alkyl or aryl.  
     
     
         22 . A compound of  claim 1  wherein Ar is phenyl.  
     
     
         23 . A compound of  claim 1  wherein R 5  is hydrogen, hydroxy, halogen, C 1-7 alkoxy, C 1-7 alkyl, C 4-7 -alkenynyl, C 2-7 -alkenyl, C 2-7 -alkynyl or aralkyl, or R 5  forms a bond together with R 6 .  
     
     
         24 . A compound of  claim 1  wherein R 5  is hydrogen or R 5  forms a bond together with R 6 .  
     
     
         25 . A compound of  claim 1  wherein R 5  is hydrogen, hydroxy, halogen, C 1-7 alkoxy, C 1-7 alkyl, C 4-7 -alkenynyl, C 2-7 -alkenyl, C 2-7 -alkynyl or aralkyl, or R 5  forms a bond together with R 6 .  
     
     
         26 . A compound of  claim 1  wherein R 5  is hydrogen or R 5  forms a bond together with R 6 .  
     
     
         27 . A compound of  claim 1  wherein R 7  is hydrogen, C 1-7 alkyl, C 4-7 -alkenynyl, C 2-7 -alkenyl, C 2-7 -alkynyl, aryl, aralkyl, C 1-7 alkoxyC 1-7 alkyl, C 1-7 alkoxycarbonyl, aryloxycarbonyl, C 1-7 alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl.  
     
     
         28 . A compound of  claim 1  wherein R 7  is hydrogen, C 1-7 alkyl, C 4-7 -alkenynyl, C 2-7 -alkenyl or C 2-7 -alkynyl.  
     
     
         29 . A compound of  claim 1  wherein R 7  is C 1-2 alkyl.  
     
     
         30 . A compound of  claim 1  wherein R 8  is hydrogen, C 1-7 alkyl, C 4-7 -alkenynyl, C 2-7 -alkenyl, C 2-7 -alkynyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano.  
     
     
         31 . A compound of  claim 1  wherein R 8  is hydrogen, C 1-7 alkyl, C 4-7 -alkenynyl, C 2-7 -alkenyl, C 2-7 -alkynyl, aryl or aralkyl.  
     
     
         32 . A compound of  claim 1  wherein R 8  is hydrogen or C 1-2 alkyl.  
     
     
         33 . A compound of  claim 1  wherein Y is oxygen, sulphur or NR 10 , where R 10  is hydrogen, C 1-7 alkyl, aryl, hydroxyC 1-7 alkyl or aralkyl.  
     
     
         34 . A compound of  claim 1  wherein Y is oxygen.  
     
     
         35 . A compound of  claim 1  wherein n is an integer ranging from 2 to 3.  
     
     
         36 . A compound of  claim 1  wherein A is benzo.  
     
     
         37 . A compound of  claim 1  wherein A is a five membered ring containing S.  
     
     
         38 . A compound of  claim 1  wherein Q is —O—.  
     
     
         39 . A compound of  claim 1  wherein Q is —S—.  
     
     
         40 . A compound of  claim 1  wherein Q is >NR 18 , wherein R 18  is C 1-6 -alkyl.  
     
     
         41 . A compound of  claim 1  wherein Z is —O—.  
     
     
         42 . A compound of  claim 1  wherein n is 2.  
     
     
         43 . A compound of  claim 1  wherein Q is —O—.  
     
     
         44 . A compound of  claim 1  wherein Ar is phenylene.  
     
     
         45 . A compound of  claim 1  wherein R 5  is H.  
     
     
         46 . A compound of  claim 1  wherein R 6  is H.  
     
     
         47 . A compound of  claim 1  wherein R 7  is ethyl.  
     
     
         48 . A compound of  claim 1  wherein R 8  is H.  
     
     
         49 . A pharmaceutical composition comprising, as an active ingredient, an effective amount of a compound of  claim 1  together with a pharmaceutically acceptable carrier or diluent.  
     
     
         50 . The pharmaceutical composition of  claim 49  in unit dosage form, comprising from about 0.05 to about 100 mg of the compound.  
     
     
         51 . The pharmaceutical composition of  claim 49  wherein the route of administration is oral, nasal, transdermal, pulmonal, or parenteral.  
     
     
         52 . A method of treating or preventing conditions mediated the Peroxisome Proliferator-Activated Receptors (PPAR), the method comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .  
     
     
         53 . A method of treating or preventing diabetes or obesity, the method comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .  
     
     
         54 . The method of  claim 52 , wherein the effective amount of the compound is in the range of from about 0.05 to about 100 mg per day.

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