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US 6,649,641 B2Granted
Glucagon antagonists/inverse agonists
AssigneeNovo Nordisk A/S
InventorsCarsten Behrens, Jesper Lau, Peter Madsen
Life of this patent
Estimating the term…
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.
Claims55
A compound of formula (I):
- wherein
- R2 is hydrogen or C1-6-alkyl,
- B is
- R38 is hydrogen, —S(═O)2—C1-6-alkyl or —C(═O)—C1-6-alkyl,
- Z is arylene 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,
- X is
- wherein
- r is 0 or 1,
- q and s independently are 0, 1, 2 or 3,
- R11, R12, and R13 independently are hydrogen or C1-6-alkyl,
- D is
- wherein
- R15, R16, R17 and R18 independently are
- hydrogen, halogen, —CN, —CH2CN, —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —S(O)2CF3, —SCF3, —NO2, —OR21, —NR21R22, —SR21, —NR21S(O)2R22, —S(O)NR21R22, —S(O)R21, —S(O)2R21, —C(O)NR21R22, —OC(O)NR21R22, —NR21C(O)R22, —CH2C(O)NR21R22, —OCH2C(O)NR21R22, —CH2OR21, —CH2NR21R22, —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, C3-8-cycloalkylthio, 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-C1-6-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, —CN, —CF3, —OCF3, —NO2, —OR21, —NR21R22 and C1-6-alkyl,
- wherein R21 and R22 independently are hydrogen, C1-6-alkyl or aryl,
- 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 C3-8-cycloalkyl-C1-6-alkyl,
- E is
- wherein
- R27 and R28 independently are
- hydrogen, halogen, —CN, —CF3, —OCF3, —OR32, —NR32R33, C1-6-alkyl, C3-6-cycloalkyl, C4-8-cycloalkenyl or aryl,
- wherein the aryl group optionally may be substituted with one or more substituents selected from halogen, —CN, —CF3, —OCF3, —NO2, —OR32, —NR32R33 and C1-6-alkyl,
- wherein
- R32 and R33 independently are hydrogen or C1-6-alkyl,
- 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-C2-6-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, —CN, —CF3, —OCF3, —NO2, —OR34, —NR34R35 and C1-6-alkyl,
- wherein R34 and R35 independently are hydrogen, C1-6-alkyl or aryl,
- 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 and mixtures thereof or a pharmaceutically acceptable salt thereof.
42 more elements
Dependencies are inferred from the claim text.