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 diseases and disorders, wherein a glucagon antagonistic action is beneficial, such as hyperglycemia, Type 1 diabetes, Type 2 diabetes, disorders of the lipid metabolism and obesity.

1 . A method of promoting glucagon antagonistic action in a subject comprising administering to the subject a glucagon antagonist composition consisting essentially of (a) a compound of the general formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 2  is hydrogen or C 1-6 -alkyl,  
 Z is arylene 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 7  and R 8  selected from halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , —OR 9 , —NR 9 R 10  and C 1-6 -alkyl,  
 wherein R 9  and R 10  independently are hydrogen or C 1-6 -alkyl,  
 
 X is  
                     
 wherein  
 r is 0 or 1,  
 q and s independently are 0, 1, 2 or 3,  
 R 11 , R 12 , R 13  and R 14  independently are hydrogen or C 1-6 -alkyl,  
 D is  
                     
 wherein  
 R 15 , R 16 , R 17  and R 18  independently are 
 hydrogen, halogen, —CN, —CH 2 CN, —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —S(O) 2 CF 3 , —SCF 3 , —NO 2 , —OR 21 , NR 21 R 22 , —SR 21 , —NR 21 S(O)R 22 , —S(O) 2 NR 21 R 22 , —S(O)NR 21 R 22 , —S(O)R 21 , —S(O) 2 R 21 , —C(O)NR 21 R 22 , —OC(O)N 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 halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , —OR 21 , —NR 21 R 22  and C 1-6 -alkyl,  
 
 C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, heterocyclyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -cyclo-alkyl-C 1-6 -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 4-8 -cycloalkenyl-C 2-6 -alkenyl, C 4-8 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, 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 2-6 -alkyl, heteroaryl-C 2-6 -alkenyl or heteroaryl-C 2-6 -alkynyl, 
 of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , —OR 21 , —NR 21 R 22  and C 1-6 -alkyl,  
 wherein R 21  and R 22  independently are hydrogen, C 1-6 -alkyl or aryl,  
 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 15  to R 18  when placed in adjacent positions together may form a bridge —(CR 23 R 24 ) a —O—(CR 25 R 26 ) c —O—, 
 wherein  
 a is 0, 1 or 2,  
 c is 1 or 2,  
 R 23 , R 24 , R 25  and R 26  independently are hydrogen, C 1-6 -alkyl or fluorine, R 19  and R 20  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 3-8 -cyclo-alkyl-C 1-6 -alkyl,  
 E is  
                     
 wherein  
 
 R 27  and R 28  independently are  
 hydrogen, halogen, —CN, —CF 3 , —OCF 3 , —OR 32 , —NR 32 R 33 , C 1-6 -alkyl, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl or aryl,  
 wherein the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , —OR 32 , —NR 32 R 33  and C 1-6 -alkyl,  
 wherein 
 R 32  and R 33  independently are hydrogen or C 1-6 -alkyl, or  
 R 32  and R 33  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 2 , R 30  and R 3  lindependently are 
 hydrogen, halogen, —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 34 , —NR 34 R 35 , —SR 34 , —S(O)R 34 , —S(O) 2 R 34 , —C(O)NR 34 R 35 , —OC(O)NR 34 R 35 , —NR 34 C(O)R 35 , —OCH 2 C(O)NR 34 R 35 , —C(O)R 34  or —C(O)OR 34 ,  
 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 halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , —OR 34 , —NR 34 R 35  and C 1-6 -alkyl,  
 
 C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, heterocyclyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -cyclo-alkyl-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, heterocyclyl-C 2-6 -alkynyl, 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 cyclic moieties optionally may be substituted with one or more substituents selected from halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , —OR 34 , —NR 34 R 35  and C 1-6 -alkyl,  
 wherein R 34  and R 35  independently are hydrogen, C 1-6 -alkyl or aryl,  
 or R 34  and R 35  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 29 , R 30  and R 31  when attached to the same ring carbon atom or different ring carbon atoms together may form a radical —O—(CH 2 ) t —CR 36 R 37 —(CH 2 ) l —O—, —(CH 2 ) t —CR 36 R 37 —(CH 2 ) l — or —S—(CH 2 ) t —CR 36 R 37 —(CH 2 ) l —S—, 
 wherein  
 t and l independently are 0, 1, 2, 3, 4 or 5,  
 R 36  and R 37  independently are hydrogen or C 1-6 -alkyl;  
 
 (b) an optical isomer, geometric isomer, or tautomeric form thereof; (c) a mixture of any combination of compounds provided by (b); (d) a pharmaceutically acceptable salt of any compound provided by (a) or (b); or (e) a combination of any of compounds provided by any of (a)-(d), in an amount effective for antagonizing glucagon.  
 
     
     
         2 . The method of  claim 1 , wherein the subject is diagnosed as having or being at risk of developing a condition for which glucagon antagonistic action is likely to be therapeutically or prophylactically beneficial.  
     
     
         3 . The method of  claim 2 , wherein the method comprises administering about 0.05 mg to about 2000 mg of the glucagon antagonist composition to the subject per day.  
     
     
         4 . The method of  claim 3 , wherein the method comprises administering about 0.1 mg to about 1000 mg of the glucagon antagonist composition to the subject per day.  
     
     
         5 . The method of  claim 4 , wherein the method comprises administering about 0.5 mg to about 500 mg of the glucagon antagonist composition to the subject per day.  
     
     
         6 . The method of  claim 2 , wherein the subject is diagnosed as having hyperglycemia and the method is performed as a treatment for hyperglycemia.  
     
     
         7 . The method of  claim 2 , wherein the subject is diagnosed as being at risk of developing hyperglycemia and the method is performed to prevent the development of hyperglycemia in the subject.  
     
     
         8 . The method of  claim 1 , wherein the composition is administered in an amount and under conditions such that the subject's blood glucose level is detectably lowered.  
     
     
         9 . The method of  claim 8 , wherein the subject has been diagnosed as having a condition wherein the reduction of blood glucose level is therapeutically desirable.  
     
     
         10 . The method of  claim 2 , wherein the subject is diagnosed as having impaired glucose tolerance and the method is performed as a treatment for impaired glucose tolerance.  
     
     
         11 . The method of  claim 2 , wherein the subject is diagnosed as having Type 2 diabetes and the method is performed as a treatment for Type 2 diabetes.  
     
     
         12 . The method of  claim 2 , wherein the subject is diagnosed as being at risk of developing Type 2 diabetes and the method is performed to prevent the development of Type 2 diabetes in the subject.  
     
     
         13 . The method of  claim 2 , wherein the subject has been diagnosed as having impaired glucose tolerance and the method is performed to prevent a progression from impaired glucose tolerance to Type 2 diabetes in the subject.  
     
     
         14 . The method of  claim 11 , wherein the method is performed to prevent the progression from non-insulin-requiring Type 2 diabetes to insulin-requiring Type 2 diabetes.  
     
     
         15 . The method of  claim 2 , wherein the subject has been diagnosed as having Type 1 diabetes and the method is performed as a treatment for Type 1 diabetes.  
     
     
         16 . The method of  claim 11 , wherein the method further comprises administering an antidiabetic agent to the subject, wherein the glucagon antagonist composition and antidiabetic agent are administered in amounts and under conditions suitable for treating diabetes in the subject.  
     
     
         17 . The method of  claim 1 , further comprising administering an antiobesity agent to said subject.  
     
     
         18 . The method of  claim 1 , further comprising administering an antihypertensive agent to said subject.