Novel glucagon antagonists/inverse agonists

Abstract

Novel compounds that act to antagonize the action of the glucagon peptide hormone on the glucagon receptor. More particularly, it relates to glucagon antagonists or inverse agonists.

1 . A compound of the general formula (I):  
     
       
         
         
             
             
         
       
       X is a valence bond, —CR 1 R 2 — or —NR 1 —,  
       Y is >CR 3 — or >N—,  
       R 1 , R 2  and R 3  independently are hydrogen or C 1-6 -alkyl, or R 1  and R 3  on adjacent atoms may be combined to form a double bond,  
       E is 
 C 1-10 -alkyl or C 2-10 -alkenyl,  
 C 3-10 -cycloaIkyl, C 3-10 -cycloalkenyl, C 7-10 -bicycloalkyl, C 3-10 -cycloalkyl-C 1-6 alkyl, C 3-10 -cycloalkenyl-C 1-6 -alkyl or C 7-10 -bicycloalkyl-C 1-6 -alkyl, wherein the rings may optionally be substituted with one or more substituents selected from halogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, —CF 3 , —OCF 3 , —SCF 3 , —OCHF 2  and —SCHF 2 ,  
 aryl, aryloxy, arylthio, heteroaryl, aryl-C 1-6 -alkyl, aryloxy-C 1-6 -alkyl, arylthio-C 1-6 -alkyl, heteroaryl-C 1-6 -alkyl, diaryl-C 1-6 -alkyl or (C 1-6 -alkyl)(aryl)-C 1-7 -alkyl, wherein the non-aromatic and aromatic rings may optionally be substituted with one or more substituents selected from halogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, —CF 3 , —OCF 3 , —SCF 3 , —OCHF 2 , —SCHF 2 , C 3-10 -cycloalkyl and C 3-10 -cyclo-alkenyl, or with two substituents on adjacent positions which are combined to form a bridge C 1-6 -alkylene, C 2-6 -alkenylene or —O—C 1-6 -alkylene-O—,  
                     
 
       R 8  is hydrogen, C 1-6 -alkyl or aryl, wherein aryl is optionally substituted with one or two substituents selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, —CF 3 , —OCF 3 , —SCF 3 , —OCHF 2 , —SCHF 2 , —SO 2 CF 3  and —SO 2 -C 1-6 -alkyl,  
       R 9  is hydrogen or C 1-6 -alkyl,  
       D is aryl or heteroaryl,  
       which may optionally be substituted with one or more substituents selected from 
 halogen, —CF 3 , —OCF 3 , —SCF 3 , —CN, —NO 2 , C 1-10 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy, C 1-6 -alkylthio, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, —SO 2 CF 3  and —SO 2 —C 1-6 -alkyl,  
 C 3-8 -cycloalkyl, C 3-8 -cycloalkenyl, aryl and aryl-C 1-6 -alkoxy, wherein the non-aromatic and aromatic rings optionally may be substituted with one to three substituents selected from halogen, —CF 3 , —OCF 3 , —SCF 3 , —CN, —NO 2 , C 1-10 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy and C 1-6 -alkylthio, or with two substituents on adjacent positions which are combined to form a bridge —O—(CH 2 ) m —O—(CH 2 ) p — or —O—(CF 2 ) m —O—(CF 2 ) p —, wherein m is an integer of from 1 to 6, and p is 0 or 1,  
 or with two substituents on adjacent positions which are combined to form a bridge —O—(CH 2 ) m —O—(CH 2 ) p — or —O—(CF 2 ) m —O—(CF 2 ) p —, wherein m is an integer of from 1 to 6, and p is 0 or 1,  
 
       or a substituent on B may be combined with a substiuent on D to form a —C(═O)— bridge,  
       as well as any diastereomer or enantiomer or tautomeric form or mixtures thereof of these or a pharmaceutically acceptable salt thereof.  
     
   
   
       2 . A compound A compound according to  claim 1 , wherein 
 E is 
 C 1-10 -alkyl or C 2-10 -alkenyl,  
 C 3-10 -cycloalkyl or C 3-10 -cycloalkenyl, which may optionally be substituted with one or two substituents selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, —CF 3 , —OCF 3 , —SCF 3 , —OCHF 2  and —SCHF 2 ,  
                     
   R 4  and R 5  independently are hydrogen, halogen, C 1-6 -alkyl, C 2-4 -alkenyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, —CF 3 , —OCF 3 , —SCF 3 , —OCHF 2 , —SCHF 2 , C 3-10 -cycloalkyl or C 3-10 -cyclo-alkenyl, alkenyl, or R 4  and R 5  on adjacent positions may be combined to form a bridge —O—C 1-6 -alkylene-O—, C 1-8 -alkylene or C 3-8 -alkenylene,    R 6  is C 1-6 -alkyl or aryl, wherein aryl may optionally be substituted with one or two substituents selected from halogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, —CF 3 , —OCF 3 , —SCF 3 , —OCHF 2  and —SCHF 2 ,    n is an integer of from 0 to 6,    Z is —O— or —S—,    W is —O—, —S—, or —NR 7 —,    R 7  is hydrogen or C 1-6 -alkyl,                          R 10 , R 11  and R 12  independentyl are 
 hydrogen, halogen, —CF 3 , —OCF 3 , —SCF 3 , —CN, —NO 2 , C 1-10 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy, C 1-6 -alkylthio, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, —SO 2 CF 3  or —SO 2 —C 1-6 -alkyl,  
 C 3-8 -cycloalkyl, C 3-8 -cycloalkenyl, aryl or aryl-C 1-6 -alkoxy, wherein the non-aromatic and aromatic rings optionally may be substituted with one to three substituents selected from halogen, —CF 3 , —OCF 3 , —SCF 3 , —CN, —NO 2 , C 1-10 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy and C 1-6 -alkylthio, or with two substituents on adjacent positions which are combined to form a bridge —O—(CH 2 ) m —O—(CH 2 ) p — or —O—(CF 2 ) m —O—(CF 2 ) p —, wherein m is an integer of from 1 to 6, and p is 0 or 1,  
 or two of R 10 , R 11  and R 12  on adjacent positions are combined to form a bridge —O—(CH 2 ) m —O—(CH 2 ) p — or —O—(CF 2 ) m —O—(CF 2 ) p —, wherein m is an integer of from 1 to 6, and p is 0 or 1,  
   X″ is —N═ or —CR 13 ═,    Y″ is —S—, —O— or —NR 14 —,    R 13  and R 15  independently are hydrogen, C 1-6 -alkyl or aryl, wherein aryl is optionally substituted with one or two substituents selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, —CF 3 , —OCF 3 , —SCF 3 , —OCHF 2  and —SCHF 2 ,    R 14  is hydrogen or C 1-6 -alkyl,    R 16 , R 17  and R 18  independently are hydrogen, halogen, —CF 3 , —OCF 3 , —SCF 3 , —CN, —NO 2 , C 1-10 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy and C 1-6 -alkylthio, or with two substituents on adjacent positions which are combined to form a bridge —O—(CH 2 ) q —O—(CH 2 ) r — or —O—(CF 2 ) q —O—(CF 2 ) r —, wherein q is an integer of from 1 to 6, and r is 0 or 1,                          R 8  and R 10  may be combined to form a bridge —C(═O)—,    as well as any diastereomer or enantiomer or tautomeric form thereof or mixtures thereof of these or a pharmaceutically acceptable salt thereof.    
   
   
       3 . A compound according to  claim 1 , wherein A is —(CH 2 ) 2 —COOH.  
   
   
       4 . A compound according to  claim 1 , wherein X is —CR 1 R 2 —, wherein R 1  and R 2  are as defined in  claim 1 .  
   
   
       5 . A compound according to  claim 4 , wherein X is —CH 2 —.  
   
   
       6 . A compound according to  claim 1 , wherein Y is >N—.  
   
   
       7 . A compound according to  claim 1 , wherein Y is >CH—.  
   
   
       8 . A compound according to  claim 1 , wherein B is  
     
       
         
         
             
             
         
       
     
     wherein X′ and Y′ are as defined in  claim 1 .  
   
   
       9 . A compound according to  claim 8 , wherein B is  
     
       
         
         
             
             
         
       
     
     wherein R 8  is as defined in  claim 1 .  
   
   
       10 . A compound according to  claim 9 , wherein R 8  is hydrogen, C 1-6 -alkyl or phenyl, wherein phenyl is optionally substituted as defined in  claim 1 .  
   
   
       11 . A compound according to  claim 10 , wherein R 8  is hydrogen, C 1-6 -alkyl or phenyl.  
   
   
       12 . A compound according to  claim 11 , wherein R 8  is hydrogen.  
   
   
       13 . A compound according to  claim 1 , wherein B is  
     
       
         
         
             
             
         
       
     
   
   
       14 . A compound according to  claim 1 , wherein E is 
 C 1-10 -alkyl,    C 3-10 -cycloalkyl, which may optionally be substituted as defined in  claim 1 ,                          wherein R 4  and R 5  are as defined in  claim 1 .    
   
   
       15 . A compound according to  claim 14 , wherein E is 
 C 1-10 -alkyl,    C 3-10 -cycloalkyl,                          wherein R 4  and R 5  independently are hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, —OCF 3 , —CF 3 , —SCF 3 , C 3-10 -cycloalkyl or C 3-10 -cycloalkenyl, or R 4  and R 5  on adjacent positions may be combined to form a bridge C 1-6 -alkylene or C 2-6 -alkenylene.    
   
   
       16 . A compound according to  claim 15 , wherein E is  
     
       
         
         
             
             
         
       
     
     wherein R 4  and R 5  independently are hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, —OCF 3 , —CF 3 , —SCF 3 , C 3-10 -cycloalkyl or C 3-10 -cycloalkenyl, or R 4  and R 5  on adjacent positions may be combined to form a bridge C 1-6 -alkylene or C 2-6 -alkenylene.  
   
   
       17 . A compound according to  claim 16  wherein E is  
     
       
         
         
             
             
         
       
     
     wherein R 4  and R 5  independently are hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, —OCF 3 , —CF 3 , —SCF 3 , cyclohexyl or cyclohex-1-enyl, or R 4  and R 5  on adjacent positions may be combined to form a bridge C 1-6 -alkylene.  
   
   
       18 . A compound according to  claim 17  wherein E is  
     
       
         
         
             
             
         
       
     
     wherein R 4  is hydrogen and R 5  is C 1-6 -alkyl, cyclohexyl, halogen, —CF 3  or cyclohex-1-enyl, 
 or R 4  and R 5  on adjacent positions may be combined to form a bridge C 1-6 -alkylene.  
 
   
   
       19 . A compound according to  claim 18  wherein E is  
     
       
         
         
             
             
         
       
     
   
   
       20 . A compound according to  claim 1 , wherein E is  
     
       
         
         
             
             
         
       
     
     wherein n is 1, 2 or 3, and R 4 , R 5  and R 6  are as defined in  claim 1 .  
   
   
       21 . A compound according to  claim 18 , wherein R 4  and R 5  independently are hydrogen, halogen, —OCF 3 , —CF 3 , C 1-6 -alkoxy or C 2-6 -alkenyl, or 
 R 4  and R 5  on adjacent atoms together form the bridge —O—CH 2 —O—.    
   
   
       22 . A compound according to  claim 1 , wherein D is  
     
       
         
         
             
             
         
       
     
     wherein R 10 , R 11 , R 12 , R 15 , R 16  R 17  and R 18  are as defined in  claim 1 .  
   
   
       23 . A compound according to  claim 1 , wherein D is  
     
       
         
         
             
             
         
       
     
     wherein R 10 , R 11  and R 12  are as defined in  claim 1 .  
   
   
       24 . A compound according to  claim 22 , wherein R 10 , R 11  and R 12  independently are hydrogen, halogen, —OCF 3 , —CF 3 , —NO 2 , di-C 1-6 -alkylamino, C 1-10 -alkyl, C 1-6 -alkoxy or —CN, 
 phenyl or phenyl-C 1-6 -alkoxy, which may optionally be substituted with one or two substituents as defined in  claim 1 ,    or two of R 10 , R 11  and R 12  in adjacent positions form a bridge —O—CH 2 —O—, —O—CH 2 —CH 2 —O—, —O—CH 2 —CH 2 —CH 2 —O—, —O—CF 2 —O—, —O—CF 2 —O—CF 2 — or —O—CF 2 —CF 2 —O—.    
   
   
       25 . A compound according to  claim 22 , wherein R 10 , R 11  and R 12  independently are hydrogen, halogen, —OCF 3 , —CF 3 , —NO 2 , di-C 1-6 -alkylamino, C 1-10 -alkyl, C 1-6 -alkoxy or —CN, 
 phenyl or phenyl-C 1-6 -alkoxy,    or two of R 10 , R 11  and R 12  in adjacent positions form a bridge —O—CH 2 —O—, —O—CH 2 —CH 2 —O— or —O—CH 2 —CH 2 —CH 2 —O—.    
   
   
       26 . A compound according to  claim 22 , wherein two of R 10  and R 11  are hydrogen, and and R 12  is halogen, —OCF 3 , —CF 3 , —NO 2 , di-C 1-6 -alkylamino, C 1-10 -alkyl, C 1-6 -alkoxy or —CN.  
   
   
       27 . A compound according to  claim 1 , wherein B and D together form  
     
       
         
         
             
             
         
       
     
     wherein Y′, R 11  and R 12  are as defined in  claim 1 .  
   
   
       28 . A compound according to  claim 27 , wherein B and D together form  
     
       
         
         
             
             
         
       
     
   
   
       29 . A compound of the general formula (I 1 ):  
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 8 , E and D are as defined in  claim 1 , 
 as well as any diastereomer or enantiomer or tautomeric form thereof or mixtures thereof of these or a pharmaceutically acceptable salt thereof.  
 
   
   
       30 . A compound according to  claim 1 , which has an IC 50  value of no greater than 5 μM as determined by the Glucagon Binding Assay (I) or Glucagon Binding Assay (II) disclosed herein.  
   
   
       31 . A compound according to  claim 30 , which has an IC 50  value of less than 1 μM, preferably of less than 500 nM and even more preferred of less than 100 nM as determined by the Glucagon Binding Assay (I) or Glucagon Binding Assay (II) disclosed herein.  
   
   
       32 . A method for the treatment of an indication selected from the group consisting of hyperglycemia, IGT, type 2 diabetes, type 1 diabetes, dyslipidemia and obesity comprising administering to a subject in need thereof an effective amount of a compound according to  claim 1 .  
   
   
       33 . A pharmaceutical composition comprising, as an active ingredient, at least one compound according to  claim 1  together with one or more pharmaceutically acceptable carriers or excipients.  
   
   
       34 . A pharmaceutical composition according to  claim 33  in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound.  
   
   
       35 . A method for the treatment of disorders or diseases, wherein a glucagon antagonistic action is beneficial, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to  claim 34 .  
   
   
       36 . The method according to  claim 35 , wherein the effective amount of the compound is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.