Glucagon Antagonists/Inverse Agonists

Abstract

A novel class of compounds, which act to antagonize the action of the glucagon hormone on the glucagon receptor. Owing to their antagonizing effect of the glucagon receptor the compounds may be suitable for the treatment and/or prevention of any glucagon-mediated conditions and diseases such as hyperglycemia, Type 1 diabetes, Type 2 diabetes and obesity.

1 . A compound of the general formula (I): 
     
       
         
         
             
             
         
       
     
     wherein
 V is —C(O)OR 2 , —C(O)NR 2 R 3 , —C(O)NR 2 OR 3 ; —S(O) 2 OR 2 , 
 
     
       
         
         
             
             
         
       
     
     wherein
 R 2  and R 3  independently are hydrogen or C 1-6 -alkyl, 
 R 4  is hydrogen, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , —OR 5 , —NR 5 R 6  or C 1-6 -alkyl, 
 wherein R 5  and R 6  independently are hydrogen or C 1-6 -alkyl, 
 A is 
 
     
       
         
         
             
             
         
       
     
     wherein
 b is 0 or 1, 
 n is 0, 1, 2 or 3, 
 R 7  is hydrogen, C 1-6 -alkyl or C 3-8 -cycloalkyl-C 1-6 -alkyl, 
 R 8  and R 9  independently are hydrogen or C 1-6 -alkyl, 
 Y is —C(O)—, —S(O) 2 —, —O— or a valence bond, 
 Z is phenylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur,
 which may optionally be substituted with one or two groups R 46  and R 47  selected from hydrogen, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , —OR 10 , —NR 10 R 11  and C 1-6 -alkyl, 
 wherein R 10  and R 11  independently are hydrogen or C 1-6 -alkyl, 
 
 or -A-Y-Z- together are 
 
     
       
         
         
             
             
         
       
       R 1  is hydrogen or C 1-6 -alkyl, 
       X is 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein
 r is or 1, 
 q and s independently are 0, 1, 2 or 3, 
 R 12 , R 13 , R 14  and R 15  independently are hydrogen or C 1-6 -alkyl, 
 D is 
 
     
       
         
         
             
             
         
       
     
     wherein
 W is —O—, —S—, —S(O) 2 — or —NR 20 —, 
 W′ is ═CR 20′ — or ═N—, 
 R 16 , R 17 , R 18  and R 19  independently are
 hydrogen, halogen, —CN, —CH 2 CN, —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —OS(O) 2 CF 3 , —SCF 3 , —NO 2 , —OR 21 , —NR 21 R 22 , —SR 21 , —NR 21 S(O) 2 R 22 , —S(O) 2 NR 21 R 22 , —S(O)NR 21 R 22 , —S(O)R 21 —S(O) 2 R 21 , —OS(O) 2 R 21 , —C(O)NR 21 R 22 , —OC(O)NR 21 R 22 , —NR 21 C(O)R 22 , —CH 2 C(O)NR 21 R 22 , —OCH 2 C(O)NR 21 R 22 , —CH 2 OR 21 , —CH 2 NR 21 R 22 , OC(O)R 21 , —C(O)R 21  or —C(O)OR 21 , 
 C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl,
 which may optionally be substituted with one or more substituents selected from —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 21 , —NR 21 R 22 , —SR 21 , —S(O)R 21 , —S(O) 2 R 21 , —C(O)NR 21 R 22 , —OC(O)NR 21 R 22 , —NR 21 C(O)R 22 , —OCH 2 C(O)NR 21 R 22 , —C(O)R 21  and —C(O)OR 21 , 
 
 C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, heterocyclyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -cycloalkyl-C 1-16 -alkoxy, C 3-8 -cycloalkyloxy, C 3-8 -cycloalkyl-C 1-6 -alkylthio, C 3-8 -cycloalkylthio, C 3-8 -cycloalkyl-C 2-6 -alkenyl, C 3-8 -cycloalkyl-C 2-6 -alkynyl, C 4-8 -cycloalkenyl-C 1-6 -alkyl, C 4-4 -cycloalkenyl-C 2-6 -alkenyl, C 4-8 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl or heterocyclyl-C 2-6 -alkynyl,
 of which the cyclic moieties optionally may be substituted with one or more substituents selected from 
 —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 21 , —NR 21 R 22 , SR 21 , —S(O)R 21 , —S(O) 2 R 21 , —C(O)NR 21 R 22 , —OC(O)NR 21 R 22 , —NR 21 C(O)R 22 , —OCH 2 C(O)NR 21 R 22 , —C(O)R 21  and —C(O)OR 21 , 
 C 1-6 -alkyl, C 2-6 -alkenyl and C 2-6 -alkynyl,
 which may optionally be substituted with one or more substituents selected from —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 21 , —NR 21 R 22 , —SR 21 , —S(O)R 21 , —S(O) 2 R 21 , —C(O)NR 21 R 22 , —OC(O)NR 21 R 22 , —NR 21 C(O)R 22 , —OCH 2 C(O)NR 21 R 22 , —C(O)R 21  and —C(O)OR 21 , 
 
 
 aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C 1-6 -alkoxy, aryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl or heteroaryl-C 2-6 -alkynyl,
 of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from 
 halogen, —CN, —CH 2 CN, —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —OS(O) 2 CF 3 , —SCF 3 , —NO 2 , —OR 21 , —NR 21 R 22 , —SR 21 , —NR 21 S(O) 2 R 22 , —S(O) 2 NR 21 R 22 , —S(O)NR 21 R 22 , —S(O)R 21 , —S(O) 2 R 21 , —OS(O) 2 R 21 , —C(O)NR 21 R 22 , —OC(O)NR 21 R 22 , —NR 21 C(O)R 22 , —CH 2 C(O)NR 21 R 22 , —OCH 2 C(O)NR 21 R 22 , —CH 2 OR 21 , —CH 2 NR 21 R 22 , —OC(O)R 21 , —C(O)R 21  and —C(O)OR 21 , 
 C 1-6 -alkyl, C 2-6 -alkenyl and C 2-6 -alkynyl,
 which may optionally be substituted with one or more substituents selected from —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 21 , —NR 21 R 22 , —SR 21 , —S(O)R 21 C(O)NR 21 R 22 , —OC(O)NR 21 R 22 , —NR 21 C(O)R 22 , —OCH 2 C(O)NR 21 R 22 , —C(O)R 21  and —C(O)OR 21 , 
 
 
 
 wherein R 21  and R 22  independently are hydrogen, —CF 3 , C 1-6 -alkyl, tri-C 1-6 -alkylsilyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl or heteroaryl, 
 or R 21  and R 22  when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, 
 or two of the groups R 16  to R 19  when placed in adjacent positions together may form a bridge —(CR 16′ R 17′ ) a —O—(CR 18′ R 19′ ) c —O—, 
 
     wherein
 a is 0, 1 or 2, 
 c is 1 or 2, 
 R 16′ , R 17′ , R 18′  and R 19′  independently are hydrogen, C 1-6 -alkyl or halogen, 
 R 20  and R 20′  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 3-8 -cycloalkyl-C 1-6 -alkyl, 
 E is a 3 to 9 membered mono- or bicyclic ring which may optionally contain one or two double bonds and which may optionally contain one or two heteroatoms selected from nitrogen, oxygen and sulfur, wherein one or two groups R 23  and R 24  may be attached to the same or different ring carbon atoms and wherein a group R 31  may be attached to a ring nitrogen atom when present, or 
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein
 m and p independently are 0, 1, 2, 3 or 4, with the proviso that when both m and p are present in the same formula at least one of m and p is different from 0, 
 R 23  and R 24  independently are
 hydrogen, —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 36 , —NR 36 R 37 , —SR 36 , —S(O)R 36 , —S(O) 2 R 36 , —C(O)NR 36 R 37 , —OC(O)NR 36 R 37 , —NR 36 C(O)R 37 , —OCH 2 C(O)NR 36 R 37 , —C(O)R 36  or —C(O)OR 36    
 C 1-6 -alkyl, C 2-4 -alkenyl or C 2-6 -alkynyl,
 which may optionally be substituted with one or more substituents selected from —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 36 , —NR 36 R 37 , —SR 36 , —S(O)R 36 —S(O) 2 R 36 , —C(O)NR 36 R 37 , —OC(O)NR 36 R 37 , —NR 36 C(O)R 37 , —OCH 2 C(O)NR 36 R 37 , —C(O)R 36  and —C(O)OR 36 , 
 
 C 3-8 -cycloalkyl, C 3-8 -cycloalkylidene, C 4-8 -cycloalkenyl, heterocyclyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -cycloalkyl-C 2-6 -alkenyl, C 3-8 -cycloalkyl-C 2-6 -alkynyl, C 4-8 -cycloalkenyl-C 1-6 -alkyl, C 4-8 -cycloalkenyl-C 2-6 -alkenyl, C 4-8 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl or heterocyclyl-C 2-6 -alkynyl,
 of which the cyclic moieties optionally may be substituted with one or more substituents selected from 
 —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 36 , —NR 36 R 37 , —SR 36 , —S(O)R 36 , —S(O) 2 R 36 , —C(O)NR 36 R 37 , —OC(O)NR 36 R 37 , —NR 36 C(O)R 37 , —OCH 2 C(O)NR 36 R 37 , —C(O)R 36  and —C(O)OR 36 , 
 C 1-6 -alkyl, C 2-6 -alkenyl and C 2-6 -alkynyl,
 which may optionally be substituted with one or more substituents selected from —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , SCF 3 , OR 36 NR 36 R 37 , —SR 36 —S(O)R 36 , —S(O) 2 R 36 , —C(O)NR 36 R 37 , —OC(O)NR 36 R 37 , —NR 36 C(O)R 37 , —OCH 2 C(O)NR 36 R 37 , —C(O)R 36  and —C(O)OR 36 , 
 
 
 aryl, aryloxy, aroyl, aryl-C 1-6 -alkoxy, aryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl or heteroaryl-C 2-6 -alkynyl,
 of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from 
 halogen, —CN, —CH 2 CN, —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —OS(O) 2 CF 3 , —SCF 3 , —NO 2 , —OR 36 , —NR 36 R 37 , —SR 36 —NR 36 S(O) 2 R 37 , —S(O) 2 NR 36 R 37 , —S(O)NR 36 R 37 , —S(O)R 36 , —S(O) 2 R 36 , —OS(O) 2 R 36 , —C(O)NR 36 R 37 , —OC(O)NR 36 R 37 , —NR 36 C(O)R 37 , —CH 2 C(O)NR 36 R 37 , —CH 2 C(O)NR 36 R 37 , —CH 2 OR 36 , —CH 2 NR 36 R 37 , —OC(O)R 36 , —C(O)R 36  and —C(O)OR 36 , 
 C 1-6 -alkyl, C 2-6 -alkenyl and C 2-6 -alkynyl,
 which may optionally be substituted with one or more substituents selected from —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 36 , NR 36 R 37 , —SR 36 , —S(O)R 36 , —S(O) 2 R 36 , —C(O)NR 36 R 37 , —OC(O)NR 36 R 37 , —NR 36 C(O)R 37 , —OCH 2 C(O)NR 36 R 37 , —C(O)R 36  and —C(O)OR 36 , 
 
 
 
 wherein R 36  and R 37  independently are hydrogen, C 1-6 -alkyl or aryl,
 of which the aryl moiety optionally may be substituted with one or more substituents selected from halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , —OR 38 , —NR 38 R 39  and C 1-6 -alkyl, 
 
 wherein R 38  and R 39  independently are hydrogen or C 1-6 -alkyl, 
 or R 36  and R 37  when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, 
 or R 23  and R 24  when attached to the same ring carbon atom or different ring carbon atoms together may form a radical —O—(CH 2 ) t —CR 40 R 41 —(CH 2 )—O—, —(CH 2 ) t —CR 40 R 41 —(CH 2 ) l — or —S—(CH 2 ) t —CR 40 R 41 —(CH 2 ) l —S—, 
 
     wherein
 t and l independently are 0, 1, 2, 3, 4 or 5, 
 R 40  and R 41  independently are hydrogen or C 1-6 -alkyl, 
 R 25  to R 30  independently are hydrogen, halogen, —CN, —CF 3 , —NO 2 , —R 42 , —NR 42 R 43 , C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl, 
 wherein R 42  and R 43  independently are hydrogen or C 1-6 -alkyl, or 
 R 42  and R 43  when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, 
 R 31 , R 32  and R 33  independently are hydrogen or C 1-6 -alkyl, 
 R 34  and R 35  independently are
 hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkanoyl, —C(O)NR 44 R 45  or —S(O) 2 R 45 , 
 aryl, aroyl, aryl-C 1-6 -alkoxy, aryl-C 1-6 -alkanoyl or aryl-C 1-6 -alkyl,
 of which the aryl moieties optionally may be substituted with one or more substituents selected from halogen, —CN, —CF 3 , —OCF 3 , —OR 44 , —NR 44 R 45  and C 1-6 -alkyl, 
 
 
 wherein R 44  and R 45  independently are hydrogen or C 1-6 -alkyl, or 
 R 34  and R 35  when attached to a carbon atom together with the said carbon atom may form a 3 to 8 membered cyclic ring optionally containing one or two heteroatoms selected from nitrogen, oxygen or sulfur, and optionally containing one or two double bonds, or 
 R 34  and R 35  when attached to a nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen or sulfur, and optionally containing one or two double bonds, 
 
     as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof. 
   
   
       2 . A compound according to  claim 1 , wherein V is —C(O)OH, —S(O) 2 OH, —C(O)NHOH or 5-tetrazolyl. 
   
   
       3 . A compound according to  claim 2 , wherein V is —C(O)OH. 
   
   
       4 . A compound according to  claim 2 , wherein V is 5-tetrazolyl. 
   
   
       5 . A compound according to any one of the  claims 1  to  4 , wherein A is 
     
       
         
         
             
             
         
       
     
     wherein R 7  is as defined in  claim 1 . 
   
   
       6 . A compound according to  claim 5 , wherein A is 
     
       
         
         
             
             
         
       
     
   
   
       7 . A compound according to  claim 5 , wherein A is 
     
       
         
         
             
             
         
       
     
   
   
       8 . A compound according to  claim 5 , wherein A is 
     
       
         
         
             
             
         
       
     
   
   
       9 . A compound according to  claim 5 , wherein A is 
     
       
         
         
             
             
         
       
     
   
   
       10 . A compound according to any one of the  claims 1  to  9 , wherein Y is —C(O)—. 
   
   
       11 . A compound according to any one of the  claims 1  to  9 , wherein Y is a valence bond. 
   
   
       12 . A compound according to any one of the  claims 1  to  11 , wherein Z is 
     
       
         
         
             
             
         
       
     
     wherein R 46  and R 47  are as defined in  claim 1 . 
   
   
       13 . A compound according to  claim 12 , wherein Z is 
     
       
         
         
             
             
         
       
     
   
   
       14 . A compound according to any one of the  claims 1  to  13 , wherein R 1  is hydrogen. 
   
   
       15 . A compound according to any one of the  claims 1  to  13 , wherein R 1  is methyl. 
   
   
       16 . A compound according to any one of the  claims 1  to  15 , wherein X is 
     
       
         
         
             
             
         
       
     
     wherein q, r, s, R 12 , R 13  and R 14  are as defined in  claim 1 . 
   
   
       17 . A compound according to  claim 16 , wherein X is 
     
       
         
         
             
             
         
       
     
     wherein q is 0 or 1, r is 0 or 1, s is 0, 1 or 2, and R 13  is hydrogen or C 1-6 -alkyl. 
   
   
       18 . A compound according to  claim 17 , wherein X is —C(O)NH—, —C(O)NHCH 2 —, —C(O)NHCH(CH 3 )—, —C(O)NHCH 2 CH 2 —, —C(O)CH 2 —, —C(O)CH═CH—, —(CH 2 ) 2 —, —C(O)—, —C(O)O— or —NHC(O)—, wherein s is 0 or 1. 
   
   
       19 . A compound according to  claim 18 , wherein X is —C(O)NH—, —C(O)NHCH 2 —, —C(O)NHCH(CH 3 )—, —C(O)NHCH 2 CH 2 —, —C(O)CH 2 —, —CH 2 —, —C(O)— or —NHC(O)—. 
   
   
       20 . A compound according to  claim 19 , wherein X is —C(O)NH—. 
   
   
       21 . A compound according to  claim 19 , wherein X is —C(O)NHCH(CH 3 )—. 
   
   
       22 . A compound according to any one of the  claims 1  to  21 , wherein D is 
     
       
         
         
             
             
         
       
     
     wherein R 16 , R 17 , R 18 , R 19  and R 20  are as defined in  claim 1 . 
   
   
       23 . A compound according to  claim 22 , wherein D is 
     
       
         
         
             
             
         
       
     
     wherein R 16 , R 17 , R 18  and R 20  are as defined in  claim 1 . 
   
   
       24 . A compound according to  claim 23 , wherein D is 
     
       
         
         
             
             
         
       
     
     wherein R 16 , R 17  and R 20  are as defined in  claim 1 . 
   
   
       25 . A compound according to  claim 24 , wherein R 16  and R 17  are both hydrogen and R 20  is C 1-6 -alkyl or C 3-8 -cycloalkyl-C 1-6 -alkyl. 
   
   
       26 . A compound according to  claim 24  or  25 , wherein R 20  is cyclopropylmethyl, butyl or isopropyl. 
   
   
       27 . A compound according to  claim 26 , wherein R 20  is isopropyl. 
   
   
       28 . A compound according to  claim 23 , wherein D is 
     
       
         
         
             
             
         
       
     
     wherein R 16  and R 17  are as defined in  claim 1 . 
   
   
       29 . A compound according to  claim 23 , wherein D is 
     
       
         
         
             
             
         
       
     
     wherein R 16 , R 17  and R 18  are as defined in  claim 1 . 
   
   
       30 . A compound according to any one of the  claims 22 ,  23 ,  28  or  29 , wherein R 16 , R 17  and R 18  independently are
 hydrogen, halogen, —CN, —NO 2 , —CF 3 , —OCF 3 , hydroxy, —SCF 3 , C 1-6 -alkyl, C 1-6 -alkyl substituted with hydroxy, C 1-6 -alkyl substituted with —S(O) 2 R 21 , C 1-6 -alkoxy, —S—C 1-6 -alkyl, —C(O)OR 21 , —C(O)R 21 , —CH 2 (O)R 21 , —C(O)NR 21 R 22 , —S(O)R 21 , —S(O) 2 R 21 , —S(O) 2 CF 3 , —S(O) 2 NR 21 R 22 , C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkoxy, C 3-8 -cycloalkyl-C 1-6 -alkylthio or C 3-8 -cycloalkylthio,   wherein R 21  and R 22  independently are hydrogen, C 1-6 -alkyl, tri-C 1-6 -alkylsilyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, phenyl, phenyl-C 1-6 -alkyl, 2,3-dihydroindolyl or isoindolyl, or R 21  and R 22  together with the nitrogen atom to which they are attached form a piperidine ring,   phenoxy, phenoxycarbonyl, phenyl, phenyl-C 1-6 -alkoxy, phenyl-C 1-6 -alkyl, furanyl, tetrazolyl, benzoxazolyl or oxadiazolyl, of which the ring systems optionally may be substituted with halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , —C(O)OR 21 , —OR 21 , —NR 21 R 22  or C 1-6 -alkyl, wherein R 21  and R 22  independently are hydrogen or C 1-6 -alkyl, or   wherein R 16  and R 17  in adjacent positions form the radical —O—CH 2 —O—, —CF 2 —O—CF 2 —O— or —O—CF 2 —CF 2 —O—, and R 18  is hydrogen.   
   
   
       31 . A compound according to  claim 30 , wherein R 16 , R 17  and R 18  independently are
 hydrogen, halogen, —CN, —NO 2 , —CF 3 , —OCF 3 , —SCF 3 , C 1-6 -alkyl, C 1-6 -alkyl substituted with hydroxy, C 1-6 -alkyl substituted with —S(O) 2 R 21 , C 1-6 -alkoxy, —S—C 1-6 -alkyl, —C(O)OR 21 , —C(O)R 21 , —CH 2 (O)R 21 , —C(O)NR 21 R 22 , —S(O)R 21 , —S(O) 2 R 21 , —S(O) 2 CF 3 , —S(O) 2 NR 21 R 22 , C 3-8 -cycloalkyl-C 1-6 -alkoxy, C 3-8 -cycloalkyl-C 1-6 -alkylthio or C 3-8 -cycloalkylthio,   wherein R 21  and R 22  independently are hydrogen, C 1-6 -alkyl, tri-C 1-6 -alkylsilyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, phenyl or 2,3-dihydroindolyl, or R 21  and R 22  together with the nitrogen atom to which they are attached form a piperidine ring,   phenoxy, phenyl, benzyl, furanyl, tetrazolyl, benzoxazolyl or oxadiazolyl, of which the ring systems optionally may be substituted with halogen, —C(O)OR 21  or C 1-6 -alkyl, wherein R 21  is hydrogen or C 1-6 -alkyl, or   wherein R 16  and R 17  in adjacent positions form the radical —CF 2 —O—CF 2 —O— or —O—CF 2 —CF 2 —O—, and R 18  is hydrogen.   
   
   
       32 . A compound according to  claim 31 , wherein R 16 , R 17  and R 18  independently are
 hydrogen, halogen, —CN, —NO 2 , —CF 3 , —OCF 3 , —SCF 3 , C 1-6 -alkyl, C 1-6 -alkyl substituted with hydroxy, C 1-6 -alkoxy, —S—C 1-6 -alkyl, —C(O)OR 21 , —C(O)R 21 , —CH 2 (O)R 21 —C(O)NR 21 R 22 , —S(O) 2 R 21 , —(O) 2 CF 3  or —S(O) 2 NR 21 R 22 ,   wherein R 21  and R 22  independently are hydrogen, C 1-6 -alkyl, tri-C 1-16 -alkylsilyl, phenyl or 2,3-dihydroindolyl,   phenoxy, phenyl, benzyl, furanyl, tetrazolyl, benzoxazolyl or oxadiazolyl, of which the ring systems optionally may be substituted with halogen, —C(O)OR 21  or C 1-6 -alkyl, wherein R 21  is hydrogen or C 1-6 -alkyl, or   wherein R 16  and R 17  in adjacent positions form the radical —CF 2 —O—CF 2 —O— or —O—CF 2 —CF 2 —O—, and R 18  is hydrogen.   
   
   
       33 . A compound according to  claim 32 , wherein R 16 , R 17  and R 18  independently are hydrogen, halogen, —CN, —NO 2 , —CF 3 , —OCF 3 , —SCF 3 , C 1-6 -alkyl, C 1-6 -alkoxy, —S—C 1-6 -alkyl, —C(O)OC 1-6 -alkyl, —S(O) 2 C 1-6 -alkyl, —S(O) 2 CF 3 , —C(O)N(C 1-6 -alkyl)(C 1-6 -alkyl), —S(O) 2 N(phenyl)(C 1-6 -alkyl), —C(═O)C 1-6 -alkyl, —CH 2 OH, —CH 2 O(tri-C 1-6 -alkylsilyl), 2,3-dihydroindol-1-ylsulfonyl, phenoxy, phenyl, 4-chlorophenyl, 1,3,5-trimethylbenzyl, benzoxazolyl, 2-methyltetrazol-5-yl, 2-methyl-3-methoxycarbonylfuran-5-yl or 3-isopropyl-[1,2,4]oxadiazol-5-yl). 
   
   
       34 . A compound according to any one of the  claims 30  to  33 , wherein one of R 16  to R 18  is hydrogen. 
   
   
       35 . A compound according to any one of the  claims 30  to  33 , wherein two of R 16  to R 18  are hydrogen. 
   
   
       36 . A compound according to  claim 30 , wherein R 16  and R 17  are both hydrogen and R 18  is —OCF 3 , —SCF 3 —CF 3 , —S(O) 2 CH 3 , phenyl, halogen, C 1-6 -alkyl, nitro, —S—C 1-6 -alkyl or —S(O) 2 NR 21 R 22 , wherein R 21  is C 1-6 -alkyl and R 22  is phenyl. 
   
   
       37 . A compound according to  claim 30 , wherein R 16  and R 17  are both hydrogen and R 18  is —OCF 3  or halogen. 
   
   
       38 . A compound according to  claim 30 , wherein R 16  is hydrogen and R 17  and R 18  are both halogen or are both —CF 3 . 
   
   
       39 . A compound according to  claim 30 , wherein R 16  is hydrogen, R 17  is —CF 3  and R 18  is halogen, —CN, C 1-6 -alkoxy or —OCF 3 . 
   
   
       40 . A compound according to  claim 30 , wherein R 16  is hydrogen, R 17  is —OCF 3  and R 18  is —S(O) 2 CH 3 , —CH 2 O-tri-C 1-6 -alkylsilyl, benzoxazolyl or —CH 2 OH. 
   
   
       41 . A compound according to  claim 30 , wherein R 16  is hydrogen, R 17  is C 1-6 -alkyl and R 18  is —S(O) 2 NR 21 R 22 , wherein R 21  is C 1-6 -alkyl and R 22  is phenyl. 
   
   
       42 . A compound according to  claim 30 , wherein R 16 , R 17  and R 18  are selected from hydrogen, —OCF 3 , —CF 3 , —Br, —F and —Cl. 
   
   
       43 . A compound according to any one of the preceding claims, wherein E is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein
 m, p and R 23  to R 35  are as defined in  claim 1 . 
 
   
   
       44 . A compound according to  claim 43 , wherein E is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein m, p and R 23  to R 35  are as defined in  claim 1 . 
   
   
       45 . A compound according to  claim 44 , wherein E is 
     
       
         
         
             
             
         
       
     
     wherein p, R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 34  and R 35  are as defined in  claim 1 . 
   
   
       46 . A compound according to  claim 45 , wherein E is 
     
       
         
         
             
             
         
       
     
     wherein R 23 , R 24 , R 25 , R 26 , R 27 , R 34  and R 35  are as defined in  claim 1 . 
   
   
       47 . A compound according to  claim 46 , wherein R 34  and R 35  independently are C 1-6 -alkyl, hydrogen or C 1-6 -alkoxy. 
   
   
       48 . A compound according to  claim 47 , wherein R 34  and R 35  are both C 1-6 -alkyl. 
   
   
       49 . A compound according to  claim 45 , wherein E is 
     
       
         
         
             
             
         
       
     
     wherein R 23  and R 24  are as defined in  claim 1 . 
   
   
       50 . A compound according to  claim 49 , wherein E is 
     
       
         
         
             
             
         
       
     
     wherein R 23  and R 24  are as defined in  claim 1 . 
   
   
       51 . A compound according to  claim 49  or  50 , wherein R 23  and R 24  independently are selected from hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkylidene, phenoxy, phenyl, —C(O)NR 36 R 37  and —OC(O)NH-phenyl, of which the phenyl moiety optionally may be substituted with —OCF 3 , wherein R 36  and R 37  are as defined in  claim 1 , or R 23  and R 24  together form the radical —(CH 2 ) t —CR 40 R 41 —(CH 2 ) l —, —O—(CH 2 ) t —CR 40 R 41 —(CH 2 )—O—, —S—(CH 2 ) t —CR 40 R 41 —(CH 2 ) l —S—, wherein t, l, R 40  and R 41  are as defined in  claim 1 . 
   
   
       52 . A compound according to  claim 51 , wherein R 23  is hydrogen and R 24  is C 1-6 -alkyl such as tert-butyl or C 3-8 -cycloalkyl such as cyclohexyl, wherein R 23  and R 24  are both C 1-6 -alkyl or wherein R 23  and R 24  together form the radical —(CH 2 ) 5 —. 
   
   
       53 . A compound according to  claim 46 , wherein E is 
     
       
         
         
             
             
         
       
     
     wherein R 25 , R 26  and R 27  are as defined in  claim 1 . 
   
   
       54 . A compound according to  claim 53 , wherein E is 
     
       
         
         
             
             
         
       
     
     wherein R 25 , R 26  and R 27  are as defined in  claim 1 . 
   
   
       55 . A compound according to  claim 53  or  54 , wherein R 25 , R 26  and R 27  independently are selected from hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, —CF 3 , —OCF 3  or —NR 42 R 43 , wherein R 42  and R 43  are as defined in  claim 1 . 
   
   
       56 . A compound according to  claim 55 , wherein E is 
     
       
         
         
             
             
         
       
     
     wherein R 25  is —OCF 3 , —CF 3 , C 1-6 -alkyl such as tert-butyl, piperidyl, C 3-8 -cycloalkyl such as cyclohexyl or C 4-8 -cycloalkenyl such as cyclohexenyl. 
   
   
       57 . A compound according to  claim 46 , wherein E is 
     
       
         
         
             
             
         
       
     
   
   
       58 . A compound according to  claim 57 , wherein E is 
     
       
         
         
             
             
         
       
     
   
   
       59 . A compound according to  claim 1  of the general formula (I 1 ): 
     
       
         
         
             
             
         
       
     
     wherein V, A, R 46 , R 47 , R 1 , E, X and D are as defined in  claim 1  or in any one of the preceding claims. 
   
   
       60 . A compound according to  claim 1  of the general formula (I 2 ): 
     
       
         
         
             
             
         
       
     
     wherein V, A, R 46 , R 47 , R 1 , E, X and D are as defined in  claim 1  or in any one of the preceding claims. 
   
   
       61 . A compound according to  claim 1  of the general formula (I 3 ): 
     
       
         
         
             
             
         
       
     
     wherein V, A, R 46 , R 47 , R 1 , E, X and D are as defined in  claim 1  or in any one of the preceding claims. 
   
   
       62 . A compound according to  claim 1  of the general formula (I 4 ): 
     
       
         
         
             
             
         
       
     
     wherein V is —C(O)OR 2 , —C(O)NR 2 R 3  or —C(O)NR 2 OR 3 , and R 1 , R 2 , R 3 , E, X and D are as defined in  claim 1  or in any one of the preceding claims. 
   
   
       63 . A compound according to  claim 1  of the general formula (I 5 ): 
     
       
         
         
             
             
         
       
     
     wherein R 46 , R 47 , R 1 , E, X and D are as defined in  claim 1  or in any one of the preceding claims. 
   
   
       64 . A compound according to  claim 1  of the general formula (I 6 ): 
     
       
         
         
             
             
         
       
     
     wherein R 46 , R 47 , R 1 , E, X and D are as defined in  claim 1  or in any one of the preceding claims. 
   
   
       65 . A compound according to  claim 1  of the general formula (I 7 ): 
     
       
         
         
             
             
         
       
     
     wherein R 46 , R 47 , R 1 , E, X and D are as defined in  claim 1  or in any one of the preceding claims. 
   
   
       66 . A compound according to  claim 1  of the general formula (I 8 ): 
     
       
         
         
             
             
         
       
     
     wherein R 46 , R 47 , R 1 , E, X and D are as defined in  claim 1  or in any one of the preceding claims. 
   
   
       67 . A compound according to  claim 1  of the general formula (I 9 ): 
     
       
         
         
             
             
         
       
     
     wherein R 46 , R 47 , R 1 , E, X and D are as defined in  claim 1  or in any one of the preceding claims. 
   
   
       68 . A compound according to anyone of the  claims 59  to  61  or  63  to  67 , wherein R 46  and R 47  are both hydrogen. 
   
   
       69 . A compound according to any one of the preceding claims, which has an IC 50  value of no greater than 5 μM as determined by the Glucagon Binding Assay (I), Glucagon Binding Assay (II) or Glucagon Binding Assay (III) disclosed herein. 
   
   
       70 . A compound according to  claim 69  characterized by having a glucagon antagonistic activity as determined by the Glucagon Binding Assay (I), Glucagon Binding Assay (II) or Glucagon Binding Assay (III) disclosed herein corresponding to an IC 50  value of less than 1 μM, preferably of less than 500 nM and even more preferred of less than 100 nM. 
   
   
       71 . A compound according to any one of the preceding claims, which is an agent useful for the treatment and/or prevention of an indication selected from the group consisting of hyperglycemia, IGT, Type 2 diabetes, Type 1 diabetes and obesity. 
   
   
       72 . A compound according to any one of the  claims 1  to  71  for use as a medicament. 
   
   
       73 . A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the  claims 1  to  71  together with one or more pharmaceutically acceptable carriers or excipients. 
   
   
       74 . A pharmaceutical composition according to  claim 73  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 according to any one of the  claims 1  to  71 . 
   
   
       75 . Use of a compound according to any one of the  claims 1  to  71  for the preparation of a medicament for the treatment and/or prevention of disorders or diseases, wherein a glucagon antagonistic action is beneficial. 
   
   
       76 . Use of a compound according to any one of the  claims 1  to  71  for the preparation of a medicament for the treatment and/or prevention of glucagon-mediated disorders and diseases. 
   
   
       77 . Use of a compound according to any one of the  claims 1  to  71  for the manufacture of a medicament for the treatment and/or prevention of hyperglycemia. 
   
   
       78 . Use of a compound according to any one of the  claims 1  to  71  for the manufacture of a medicament for lowering blood glucose in a mammal. 
   
   
       79 . Use of a compound according to any one of the  claims 1  to  71  for the preparation of a medicament for the treatment and/or prevention of IGT. 
   
   
       80 . Use of a compound according to any one of the  claims 1  to  71  for the preparation of a medicament for the treatment and/or prevention of Type 2 diabetes. 
   
   
       81 . Use according to  claim 80  for the preparation of a medicament for the delaying or prevention of the progression from IGT to Type 2 diabetes. 
   
   
       82 . Use according to  claim 80  for the preparation of a medicament for the delaying or prevention of the progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes. 
   
   
       83 . Use of a compound according to any one of the  claims 1  to  71  for the preparation of a medicament for the treatment and/or prevention of Type 1 diabetes. 
   
   
       84 . Use according to any one of the  claims 75  to  83  in a regimen which additionally comprises treatment with another antidiabetic agent. 
   
   
       85 . Use of a compound according to any one of the  claims 1  to  71  for the preparation of a medicament for the treatment and/or prevention of obesity. 
   
   
       86 . Use of a compound according to any one of the  claims 1  to  71  for the preparation of a medicament for the treatment and/or prevention of obesity in a regimen which additionally comprises treatment with another antiobesity agent. 
   
   
       87 . A method for the treatment and/or prevention of disorders or diseases mediated by a glucagon antagonistic action, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of the  claims 1  to  71  or a pharmaceutical composition according to  claim 73  or The. 
   
   
       88 . The method according to  claim 87 , 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.