US 6,613,942 B1 · Glucagon antagonists/inverse agonists

Abstract

Non-peptide compounds comprising a central hydrazide motif and methods for the synthesis thereof are disclosed. The compounds act to antagonize the action of the glucagon peptide hormone.

A compound of formula I:

wherein:
R1 and R2 together form a valence bond;
R3 is hydrogen or lower alkyl and R4 is hydrogen;
n is 0, 1, 2 or 3;
m is 0 or 1;
X is >C═O,
A is
wherein:
R8 is halogen, —CN, —F3, —OCF3, —OCH2CF3, —NO2, —OCOR13, —OSO2R13, -Olower alkyl, —Oaryl, —NR11R12, lower alkyl, aryl, —SCF3, —SR11, —CHF2, —OCHF2, —OSO2R11, —CONR11R12, —CH2OR11, —CH2NR11R12, —OCOR11, —CO2R13 or —OSO2CF3, and R9 is hydrogen, halogen, —CN, —CF3, —OCF3, —OCH2CF3, —NO2, —OR11, —NR11R12, lower alkyl, aryl, —SCF3, —SR11, —CHF2, —OCHF2, —OSO2R11, —CONR11R12, —CH2OR11, —CH2NR11R12, —OCOR11, —CO2R13 or —OSO2CF3, or R8 and R9 together form a bridge —OCH2O— or —OCH2CH2O—;
wherein R11 and R12 independently are hydrogen, —COR13, —SO2R13, lower alkyl or aryl;
wherein R13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
and
R10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
B is
wherein:
R14 and R15 independently are hydrogen, halogen, —CN, —CF3, —OCF3, —O(CH2)lCF3, —NO2, —OR16, —NR16R17, lower alkyl, aryl, aryl-lower alkyl, —SCF3, —SR16, —CHF2, —OCHF2, —OCF2CHF2, —OSO2CF3, —CONR16R17, —(CH2)lCONR16R17, —O(CH2)lCONR16R17, —(CH2)lCOR16, —(CH2)lCOR16, —(CH2)lOR16, —O(CH2)lOR16, —(CH2)lNR16R17, —O(CH2)lNR16R17, —OCOR16, —CO2R18, —O(CH2)lCO2R18, —O(CH2)lCN, —O(CH2)lCl, or R14 and R15 together form a bridge —O(CH2)lO— or —(CH2)l—;
wherein l is 1, 2, 3 or 4;
R16 and R17 independently are hydrogen, —COR18, —SO2R18, lower alkyl, aryl, or R16 and R17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
wherein R18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
W is CR19═;
Y is —CR20═;
Z is —CR21═;
and
V is —CR22═;
wherein:
R19, R20, R21 and R22 independently are hydrogen, halogen, —CN, —CF3, —OCF3, —OCH2CF3, —NO2, —OR24, —NR24R25, lower alkyl, aryl, aryl-lower alkyl, —SCF3, —SR24, —CHF2, 13 OCHF2, —OCF2CHF2, —OSO2CF3, —CONR24R25, —CH2CONR24R25, —OCH2CONR24R25, —CH2OR24, —CH2NR24R25, —OCOR24 or —COR2R24, or R19 and R20, R20 and R21, or R21 and R22 together form a bridge —OCH2O—;
wherein R24 and R25 independently are hydrogen, —COR26, —SO2R26, lower alkyl, aryl or aryl-lower alkyl;
and
wherein R26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
K is
wherein:
R3a, R3b, R4a and R4b independently are hydrogen, halogen, —CN, —CF3, —OCF3, —OCH2CF3, —NO2, —OR24n, —NR24nR25a, lower alkyl, aryl, aryl-lower alkyl, —SCF3, —SR24n, —CHF2, —OCH2, —OCF2CHF2, —OSO2CF3, —CONR24nR25a, —CH2CONR24aR25n, —OCH2CONR24aR25n, —CH2OR24n, —CH2NR24aR25n, —OCOR24n or —CO2R24n;
wherein R24n and R25a independently are hydrogen, —COR26n, —SO2R26a, lower alkyl, aryl or aryl-lower alkyl;
wherein R26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
or
R3n and R3b, R4n and R4b, or R3n and R4b together form a bridge —(CH2)i—;
wherein i is 1, 2, 3 or 4;
a, b, c and d independently are 0, 1, 2, 3 or 4;
e, f and p independently are 0 or 1;
q is 0, 1 or 2;
and
L and M independently are —O—, —S—, —CH═CH—, —C≡C—, —NR5a—, —CH2NR5a—, —CO—, —OCO—, —COO—, —CONR5a—, —CONR5b—, —NR5nCO—, —SO—, —SO2—, —OSO2—, —SO2NR5a—, —NR5nSO2—, —NR5aCON5b—, —CONR5aNR5b—, —NR5aCSNR5b—, —OCONR5b—, —CH2CONR5b—, —OCH2CONR5b, —P(O)(OR5a)O—, —NR5aC(O)O— or
wherein R5a and R5b independently are hydrogen, lower alkyl, —OH, —(CH2)kOR6n, —COR6n, —(CH2)k—CH(OR6n)z, —(CH2)k—CN, —(CH2)k—NR6aR6b, aryl, aryl-lower alkyl, —(CH2)E—COOR43 or —(CH2)E—CF3;
wherein k is 1, 2, 3 or 4;
R6a and R6b independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl;
g is 0, 1, 2, 3 or 4;
R43 is hydrogen or lower alkyl;
G″ is —OCH2CO—, —CH2CO—, —CO— or a valence bond;
and
E″ is —CH2—, —CH2CH2—, —CH═CH—, —CH2NH— or —CH2CH2NH—;
D is hydrogen,
wherein:
r is 0 or 1;
s is 0, 1, 2 or 3;
E, E′, F, G and G′ independently are —CHR38—, >C═O, >NR39, —O— or —S—;
F′ is >CR38— or >N—;
Y′is —N═ or —CR32═;
Z′ is —N═ or CR33═;
V′ is —N═ or —CR34═;
W′ is —N═ or —CR35═;
and
Q′ is —NR36—, —O— or —S—;
wherein:
R27, R28, R32, R33, R34 and R35 independently are hydrogen, halogen, —CN, —CF3, —O(CH2)yCF3, —(CH2)yNHCOCF3, —NO2, lower alkyl, aryl aryl-lower alkyl, —SCF3, —SR29, —CHF2, —OCHF2, —OCF2CHF2, —OSO2R29, —OSO2CF3, —(CH2)yCONR29R30, —O(CH2)yCONR29R30, —(CH2)yOR29, —(CH2)yNR29R30, —OCOR29, —COR29 or —CO2R29;
or
R27 and R28, R32 and R33, R33 and R34, or R34 and R35 together form a bridge —O(CH2)yO—;
wherein y is 0, 1, 2, 3 or 4;
and
R29 and R30 independently are hydrogen, —COR31, —CO2R31, —SO2R31, lower alkyl, aryl or aryl-lower alkyl;
wherein R31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R36 and R39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl;
and
R38 is hydrogen, —OR40, —NR40R41, lower alkyl, aryl, aryl-lower alkyl, —SCF3, —SR40, —CHF2, —OCHF2, —OCF2CHF2, —CONR40R41, —(CH2)xCONR40R41, —O(CH2)xCONR40R41, —(CH2)xOR40, —(CH2)xNR40R41, —OCOR40 or —CO2R40;
wherein x is 1, 2, 3 or 4;
R40 and R41 independently are hydrogen, —COR42, —SO2R42, lower alkyl, aryl or aryl-lower alkyl;
wherein R42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.

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Glucagon antagonists/inverse agonists

Life of this patent

Glucagon antagonists/inverse agonists

Life of this patent

Abstract

Claims50