Glucagon antagonists/inverse agonists

A compound of the general formula (I):

• 650
• wherein
• R1, R2, R3, R4 and R5 independently are hydrogen or C1-6-alkyl,
• A is —C(O)—, —CH(OR6)— or —CHF—,
• wherein R6 is hydrogen or C1-6-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 R7 and R8 selected from halogen, —CN, —CF3, —OCF3, —NO2, —OR9, —NR9R10 and C1-6-alkyl,
• wherein R9 and R10 independently are hydrogen or C1-6-alkyl,
• 651
• wherein
• r is 0 or 1,
• q and s independently are 0, 1, 2 or 3,
• R11, R12, R13 and R14 independently are hydrogen, C1-6-alkyl or C3-8-cycloalkyl,
• 652
• wherein
• R15, R16, R17, and R18 independently are
• hydrogen, halogen, —CN, —CHF2, —CF3, —OCF3, —OCH2, —OCF2CHF2, —S(O)2CF3, —SCF3, —NO2, —OR21, —NR21R22, —SR21, —NR21S(O)2R22, —S(O)2NR21R22, —S(O)NR21R22, —S(O)R21, —S(O)2R21, —C(O)NR21R22, —OC(O)NR21R22, —NR21C(O)R22, —CH2C(O)NR21R22, —OCH2C(O)NR21R22, —OC(O)R21 or —C(O)OR21,
• C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
• which may optionally be substituted with one or more substituents selected from halogen, —CN, —CF3, —OCF3, —NO2, —OR21, —NR21R22 AND C1-6-alkyl,
• C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkoxy, C3-8-cycloalkyloxy, C3-8-cycloalkyl-C1-6-alkylthio, C3-8cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-16-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl,
• of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, —C(O)OR21, —CN, —CF3, —OCF3, —NO2, —OR21, —NR21R22 and C1-6-alkyl,
• wherein R21 and R22 independently are hydrogen, C1-6-alkyl, aryl-C1-16-alkyl or aryl,
• or R21 and R22 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 R15 to R18 when placed in adjacent positions together may form a bridge —(CR23R24)a—O(CR25R26)c—O—,
• wherein
• a is 0, 1 or 2,
• c is 1 or 2,
• R23, R24, R25 and R26 independently are hydrogen, C1-6-alkyl or fluorine,
• R19 and R20 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C3-4-cycloalkyl-C1-6-alkyl,
• 653
• wherein
• R27 and R28 independently are
• hydrogen, halogen, —CN, —CF3, —OR32, —NR32R33, C1-6-alkyl, C3-8-cycloalkyl, C4-8-cycloalkenyl or aryl,
• wherein the aryl group optionally may be substituted with one or more substituents selected from halogen, —CN, —CF3, —NO2, —OR32, —NR32R33 and C1-6-alkyl,
• wherein R32 and R33 independently are hydrogen or C1-6-alkyl, or
• R32 and R33 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,
• R29, R30 and R31 independently are
• hydrogen, halogen, —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR34, —NR34R35, —SR34, —S(O)R34, —S(O)2R34, —C(O)NR34R35, —OC(O)NR34R35, —NR34C(O)R35, —OCH2C(O)NR34R35, —C(O)R34 or —C(O)OR34,
• C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
• which may optionally be substituted with one or more substituents selected from halogen, —CN, —CF3, —OCF3, —NO2, —OR34, —NR34R35 and C1-6-alkyl,
• C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-4-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl,
• of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, —CN, —CF3, —OCF3, —NO2, —OR34, —NR34R35 and C1-6-alkyl,
• wherein R34 and R35 independently are hydrogen, C1-6-alkyl or aryl,
• or R34 and R35 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 R29, R30 and R31 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical —O—(CH2)t—CR36R37—(CH2)l—O—, —(CH2)t—CR36R37—(CH2)l— or —S—(CH2)t—CR36R37—(CH2)l—S—,
• wherein
• t and l independently are 0, 1, 2, 3, 4 or 5,
• R36 and R37 independently are hydrogen or C1-6-alkyl,
• as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.