US 6,503,949 B1 · Glucagon antagonists/inverse agonists

Abstract

Disclosed is a novel class of compounds of formula (I) wherein V, A, Y, Z, R1, E, X and D are as defined in the specification. These compounds act to antagonize the action of the glucagon hormone on the glucagon receptor. Owing to their antagonizing effect of the glucagon receptor, the compounds are suitable for treating or preventing glucagon-mediated conditions and diseases such as hyperglycemia, Type 1 diabetes, Type 2 diabetes and obesity.

A compound of formula (I):

wherein
V is —COOH
A is
—NR7CH2—,
wherein
b is 0 or 1,
n is 0, 1, 2 or 3,
R7 is hydrogen, C1-6-alkyl or C3-8-cycloalkyl-C1-6-alkyl,
R8 and R9 independently are hydrogen or C1-6-alkyl,
Y is —C(O)—,
Z is
wherein R46 and R47 independently are selected from hydrogen, halogen, —CN, —CF3, —OCF3, —NO2, —OR10, —NR10R11 and C1-6-alkyl,
wherein R10 and R11 independently are hydrogen or C1-6-alkyl,
R1 is hydrogen or C1-6-alkyl,
X is
wherein
r is 0 or 1,
q and s independently are 0, 1, 2 or 3,
R12, R13, and R14 independently are hydrogen or C1-6-alkyl,
D is
wherein
R16, R17, R18 and R19 independently are
hydrogen, halogen, —CN, —CH2CN, —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —OS(O)2CF3, —SCF3, —NO2, —OR21, —NR21R22, —SR21, —NR21S(O)2R22, —S(O)2NR21R22, —S(O)NR21R22, —S(O)R21, —S(O)2R21, —OS(O)2R21, —C(O)NR21R22, —OC(O)NR21R22, —NR21C(O)R22, —CH2C(O)NR21R22, —OCH2C(O)NR21R22, —CH2OR21, —CH2NR21R22, —OC(O)R21, —C(O)R21 or —C(O)OR21,
C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
optionally substituted with one or more substituents selected from —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR21, —NR21R22, —SR21, —S(O)R21, —S(O)2R21, —C(O)NR21R22, —OC(O)NR21R22, —NR21C(O)R22, —OCH2C(O)NR21R22, —C(O)R21 and —C(O)OR21,
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-C1-6alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocycle-C2-6-alkenyl or heterocyclyl-C2-6alkynyl,
of which the cyclic moieties optionally are substituted with one or more substituents selected from
—CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR21, —NR21R22, —SR21, —S(O)R21, —S(O)2R21, —C(O)NR21R22, —OC(O)NR21R22, —NR21C(O)R22, —OCH2C(O)NR21R22, —C(O)R21 and —C(O)OR21,
C1-6-alkyl, C2-6-alkenyl and C2-6-alkynyl,
optionally substituted with one or more substituents selected from —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR21, —NR21R22, —SR21, —S(O)R21, —S(O)2R21, —C(O)NR21R22, —OC(O)NR21R22, —NR21C(O)R22, —OCH2C(O)NR21R22, —C(O)R21 and —C(O)OR21,
aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl,
of which the aryl and heteroaryl moieties optionally are substituted with one or more substituents selected from
halogen, —CN, —CH2CN, —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —OS(O)2CF3, —SCF3, —NO2, —OR21, —NR21R22, —SR21, —NR21S(O)2R22, —S(O)2NR21R22, —S(O)NR21R22, —S(O)R21, —S(O)2R21, —OS(O)2R21, —C(O)NR21R22, —OC(O)NR21R22, —NR21C(O)R22, —CH2C(O)NR21R22, —OCH2C(O)NR21R22, —CH2OR21, —CH2NR21R22, —OC(O)R21, —C(O)R21 and —C(O)OR21,
C1-6-alkyl, C2-6-alkenyl and C2-6-alkynyl,
optionally substituted with one or more substituents selected from —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR21, —NR21R22, —SR21, —S(O)R21, —S(O)2R21, —C(O)NR21R22, —OC(O)NR21R22, —NR2C(O)R22, —OCH2C(O)NR21R22, —C(O)R21 and —C(O)OR21,
wherein R21 and R22 independently are hydrogen, —CF3, C1-6-alkyl, tri-C1-6-alkylsilyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, aryl, aryl-C1-6-alkyl or heteroaryl,
or R21 and R22 when attached to the same nitrogen atom together 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 R16 to R19 when placed in adjacent positions together form a bridge —(CR16′R17′)a—O—(CR18′R19′)c—O—,
wherein
a is 0, 1 or 2,
c is 1 or 2,
R16′, R17′, R18′ and R19′ independently are hydrogen, C1-6-alkyl or halogen,
E is a 3 to 9 membered mono- or bicyclic ring optionally containing one or two double bonds wherein one or two groups R23 and R24 are attached to the same or different ring carbon atoms 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,
R23 and R24 independently are
hydrogen, —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR36, —NR36R37, —SR36, —S(O)R36, —S(O)2R36, —C(O)NR36R37, —OC(O)NR36R37, —NR36C(O)R37, —OCH2C(O)NR36R37, —C(O)R36 or —C(O)OR36,
C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
optionally substituted with one or more substituents selected from —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR36, —NR36R37, —SR36, —S(O)R36, —S(O)2R36, —C(O)NR36R37, —OC(O)NR36R37, —NR36C(O)R37, —OCH2C(O)NR36R37, —C(O)R36 and —C(O)OR36,
C3-8-cycloalkyl, C3-8-cycloalkylidene, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6alkyl, 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-C1-6alkyl, heterocyclyl-C2-6-alkenyl or heterocyclyl-C2-6-alkynyl,
of which the cyclic moieties optionally are substituted with one or more substituents selected from
—CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR36, —NR36R37, —SR36, —S(O)R36, —S(O)2R36, —C(O)NR36R37, —OC(O)NR36R37, —NR36C(O)R37, —OCH2C(O)NR36R37, —C(O)R36 and —C(O)OR36,
C1-6-alkyl, C2-4-alkenyl and C2-6-alkynyl,
optionally substituted with one or more substituents selected from —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR36, —NR36R37, —SR36, —S(O)R36, —S(O)2R36, —C(O)NR36R37, —OC(O)NR36R37, —NR36C(O)R37, —OCH2C(O)NR36R37, —C(O)R36 and —C(O)OR36,
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 aryl and heteroaryl moieties optionally are substituted with one or more substituents selected from
halogen, —CN, —CH2CN, —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —OS(O)2CF3, —SCF3, —NO2, —OR36, —NR36R37, —SR36, —NR36S(O)2R37, —S(O)2NR36R37, —S(O)NR36R37, —S(O)R36, —S(O)2R36, —OS(O)2R36, —C(O)NR36R37, —OC(O)NR36R37, —NR36C(O)R37, —CH2C(O)NR36R37, —CH2C(O)NR36R37, —CH2OR36, —CH2NR36R37, —OC(O)R36, —C(O)R36 and —C(O)OR36,
C1-6-alkyl, C2-6-alkenyl and C2-6-alkynyl,
optionally substituted with one or more substituents selected from —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —OR36, —NR36R37, —SR36, —S(O)R36, —S(O)2R36, —C(O)NR36R37, —OC(O)NR36R37, —NR36C(O)R37, —OCH2C(O)NR36R37, —C(O) R36 and —C(O)OR36,
wherein R36 and R37 independently are hydrogen, C1-6alkyl or aryl,
of which the aryl moiety optionally is substituted with one or more substituents selected from halogen, —CN, —CF3, —OCF3, —NO2, —OR38, —NR38R39 and C1-6-alkyl,
wherein R38 and R39 independently are hydrogen or C1-6-alkyl,
or R36 and R37 when attached to the same nitrogen atom together 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 R23 and R24 when attached to the same ring carbon atom or different ring carbon atoms together form a radical —O—(CH2)t—CR40R41—(CH2)l—O—, —(CH2)t—CR40R41—(CH2)l— or —S—(CH2)t—CR40R41—(CH2)l—S—,
wherein
t and l independently are 0, 1, 2, 3, 4 or 5,
R40 and R41 independently are hydrogen or C1-6-alkyl,
R25 to R30 independently are hydrogen, halogen, —CN, —CF3, —NO2, —OR42, —NR42R43, C1-6-alkyl, C3-8-cycloalkyl or C4-8-cycloalkenyl,
wherein R42 and R43 independently are hydrogen or C1-6-alkyl, or
R42 and R43 when attached to the same nitrogen atom together 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,
R31, R32 and R33 independently are hydrogen or C1-6-alkyl,
R34 and R35 independently are
hydrogen, C1-6-alkyl, C1-6-alkoxy, C1-6-alkanoyl, —C(O)NR44R45 or —S(O)2R45,
aryl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkanoyl or aryl-C1-6-alkyl,
of which the aryl moieties optionally are substituted with one or more substituents selected from halogen, —CN, —CF3, —OCF3, —OR44, —NR44R45 and C1-6-alkyl,
wherein R44 and R45 independently are hydrogen or C1-6-alkyl, or
R34 and R35 when attached to a carbon atom together 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
R34 and R35 when attached to a nitrogen atom together 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 or a pharmaceutically acceptable salt thereof.

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Glucagon antagonists/inverse agonists

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Glucagon antagonists/inverse agonists

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Abstract

Claims56