US2005203108A1PendingUtilityA1
Glucagon antagonists/inverse agonists
Priority: May 17, 1999Filed: Nov 3, 2004Published: Sep 15, 2005
Est. expiryMay 17, 2019(expired)· nominal 20-yr term from priority
Inventors:Jesper LauPeter MadsenChristian SamsCarsten BehrensJosef VagnerInge Thøger ChristensenBehrend Frederik LundtUlla Grove SidelmannHenning ThogersenAnthony Lai LingMichael Bruno PleweLarry Kenneth TruesdaleAnker JogensenJanos Tibor KodraShenghua Shi
C07D 333/70C07C 275/28C07D 487/04C07C 275/26C07D 277/72C07D 295/13C07C 275/42C07C 323/44C07D 213/75C07C 2601/02C07C 317/42C07D 333/60C07D 417/12C07D 409/12C07D 317/66C07C 237/36C07C 2602/10C07D 307/68C07C 243/38C07C 237/42C07D 319/20C07D 215/38C07D 257/06C07C 2603/94C07D 209/48C07D 319/18C07C 317/32C07C 275/34C07D 333/38C07D 211/58C07C 275/60C07C 2602/08C07D 231/40C07D 235/30C07B 2200/07C07D 333/20C07C 2601/08C07D 209/08C07C 317/22C07C 2601/14C07C 311/47C07C 271/58C07C 275/30C07C 2602/42C07C 275/36C07C 2603/68C07D 333/68C07C 275/38C07C 2603/18C07C 275/62C07C 271/56C07C 323/21C07C 275/24C07D 295/135
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Claims
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 glucagon-mediated conditions and diseases such as hyperglycemia, Type 1 diabetes, Type 2 diabetes and obesity.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I):
wherein
V is —C(O)OR 2 , —C(O)NR 2 R 3 , —C(O)NR 2 OR 3 , —S(O) 2 OR 2 ,
wherein
R 2 and R 3 independently are hydrogen or C 1-6 -alkyl,
R 4 is hydrogen, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , —OR 5 , —NR 5 R 6 or C 1-6 -alkyl,
wherein R 5 and R 6 independently are hydrogen or C 1-6 -alkyl,
A is
wherein
b is 0 or 1,
n is 0, 1, 2 or 3,
R 7 is hydrogen, C 1-6 -alkyl or C 3-8 -g-cycloalkyl-C 1-6 -alkyl,
R 8 and R 9 independently are hydrogen or C 1-6 alkyl,
Y is —C(O)—, —S(O) 2 —, —O— or a valence bond,
Z is phenylene 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 46 and R 47 selected from hydrogen, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , —OR 10 , —NR 10 R 11 and C 1-6 -alkyl,
wherein R 10 and R 11 independently are hydrogen or C 1-6 -alkyl,
or -A-Y-Z- together are
R 1 is 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 12 , R 13 , R 14 and R 15 independently are hydrogen or C 1-6 -alkyl,
D is
wherein
W is —O—, —S—, —S(O) 2 — or —NR 20 ,
W′ is ═CR 20′ — or ═N—,
R 16 , R 17 , R 18 and R 19 independently are
hydrogen, halogen, —CN, —CH 2 CN, —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —OS(O) 2 CF 3 , —SCF 3 , —NO 2 , —OR 21 , —NR 21 R 22 , —SR 21 , —NR 21 S(O) 2 R 22 , —S(O) 2 NR 21 R 22 , —S(O)NR 21 R 22 , —S(O)R 21 , —S(O) 2 R 21 , —OS(O) 2 R 21 , —C(O)NR 21 R 22 , —OC(O)NR 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 —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 21 , —NR 21 R 22 , —SR 21 , —S(O)R 21 , —S(O) 2 R 21 , —C(O)NR 21 R 22 , —OC(O)NR 21 R 22 , —NR 21 C(O)R 22 , —OCH 2 C(O)NR 21 R 22 , —C(O)R 21 and —C(O)OR 21 ,
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 or heterocyclyl-C 2-6 -alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from
—CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 21 , —NR 21 R 22 , —SR 21 , —S(O)R 21 , —S(O) 2 R 21 , —C(O)NR 21 R 22 , —OC(O)NR 21 R 22 , —NR 21 C(O)R 22 , —OCH 2 C(O)NR 21 R 22 , —C(O)R 21 and —C(O)OR 21 ,
C 1-6 -alkyl, C 2-6 -alkenyl and C 2-6 -alkynyl,
which may optionally be substituted with one or more substituents selected from —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 21 , —NR 21 R 22 , —SR 21 , —S(O)R 21 , —S(O) 2 R 21 , —C(O)NR 21 R 22 , —OC(O)NR 21 R 22 , —NR 21 C(O)R 22 , —OCH 2 C(O)NR 21 R 22 , —C(O)R 21 and —C(O)OR 21 ,
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 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl or heteroaryl-C 2-6 -alkynyl,
of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from
halogen, —CN, —CH 2 CN, —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —OS(O) 2 CF 3 , —SCF 3 , —NO 2 , —OR 21 , —NR 21 R 22 , —SR 21 , —NR 21 , S(O) 2 R 22 , —S(O) 2 NR 21 R 22 , —S(O)NR 21 R 22 , —S(O)R 21 , —S(O) 2 R 21 , —OS(O) 2 R 21 , —C(O)NR 21 R 22 , —OC(O)NR 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 and —C(O)OR 21 ,
C 1-6 -alkyl, C 2-6 -alkenyl and C 2-6 -alkynyl,
which may optionally be substituted with one or more substituents selected from —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 21 , —NR 1 R 22 , —SR 21 , —S(O)R 21 , —S(O) 2 R 21 , —C(O)NR 21 R 22 , —C(O)NR 21 R 22 , —NR 21 C(O)R 22 , —OCH 2 C(O)NR 21 R 22 , —C(O)R 21 and —C(O)OR 21 ,
wherein R 21 and R 22 independently are hydrogen, —CF 3 , C 1-6 -alkyl, tri-C 1-6 -alkylsilyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl or heteroaryl,
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 16 to R 19 when placed in adjacent positions together may form a bridge —(CR 16′ R 17′ ) a —O—(CR 18′ R 19′ ) c —O—,
wherein
a is 0, 1 or 2,
c is 1 or 2,
R 16′ , R 17′ , R 18′ and R 19′ independently are hydrogen, C 1-6 -alkyl or halogen,
R 20 and R 20′ independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 3-8 -cycloalkyl-C 1-6 -alkyl,
E is a 3 to 9 membered mono- or bicyclic ring which may optionally contain one or two double bonds and which may optionally contain one or two heteroatoms selected from nitrogen, oxygen and sulfur, wherein one or two groups R 23 and R 24 may be attached to the same or different ring carbon atoms and wherein a group R 31 may be attached to a ring nitrogen atom when present, 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,
R 23 and R 24 independently are
hydrogen, —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 36 , —NR 36 R 37 , —SR 36 , —S(O)R 36 , —S(O) 2 R 36 , —C(O)NR 36 R 37 , —OC(O)NR 36 R 37 , —NR 36 C(O)R 37 , —OCH 2 C(O)NR 36 R 37 , —C(O)R 36 or —C(O)OR 36 ,
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 —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 36 , —NR 36 R 37 , —SR 36 , —S(O)R 36 , —S(O) 2 R 36 , —C(O)NR 36 R 37 , —OC(O)NR 36 R 37 , —NR 36 C(O)R 37 , —OCH 2 C(O)NR 36 R 37 , —C(O)R 36 and —C(O)OR 36 ,
C 3-8 -cycloalkyl, C 3-8 -cycloalkylidene, C 4-8 -cycloalkenyl, heterocyclyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, 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 or heterocyclyl-C 2-6 -alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from
—CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 36 , —NR 36 R 37 , —SR 36 , —S(O)R 36 , —S(O) 2 R 36 , —C(O)NR 36 R 37 , —OC(O)NR 36 R 37 , NR 36 C(O)R 37 , —OCH 2 C(O)NR 3 R 37 , —C(O)R 36 and —C(O)OR 36 ,
C 1-6 -alkyl, C 2-6 -alkenyl and C 2-6 -alkynyl,
which may optionally be substituted with one or more substituents selected from —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 36 , NR 36 R 37 , SR 36 , —S(O)R 36 , —S(O) 2 R 36 , —C(O)NR 36 R 37 , —OC(O)NR 36 R 37 , NR 36 C(O)R 37 , —OCH 2 C(O)NR 36 R 37 , —C(O)R 36 and —C(O)OR 36 ,
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 aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from
halogen, —CN, —CH 2 CN, —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —OS(O) 2 CF 3 , —SCF 3 , —NO 2 , —OR 36 , —NR 36 R 37 , SR 36 , —NR 36 S(O) 2 R 37 , —S(O) 2 NR 36 R 37 , —S(O)NR 36 R 37 , —S(O)R 36 , —S(O) 2 R 36 , —OS(O) 2 R 36 , —C(O)NR 36 R 37 , —OC(O)NR 36 R 37 , —NR 36 C(O)R 37 , —CH 2 C(O)NR 36 R 37 , —CH 2 C(O)NR 36 R 37 , —CH 2 OR 36 , —CH 2 NR 36 R 37 , —OC(O)R 36 , —C(O)R 36 and —C(O)OR 36 ,
C 1-6 alkyl, C 2-6 -alkenyl and C 2-6 -alkynyl,
which may optionally be substituted with one or more substituents selected from —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , —OR 36 , —NR 36 R 37 , —SR 36 , —S(O)R 36 , —S(O) 2 R 36 , —C(O)NR 36 R 37 , —OC(O)NR 16 R 37 , —NR 36 C(O)R 37 , OCH 2 C(O)NR 36 R 37 , —C(O)R 36 and —C(O)OR 36 ,
wherein R 36 and R 37 independently are hydrogen, C 1-6 -alkyl or aryl,
of which the aryl moiety optionally may be substituted with one or more substituents selected from halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , —OR 38 , —NR 38 R 39 and C 1-6 -alkyl,
wherein R 38 and R 39 independently are hydrogen or C 1-6 -alkyl,
or R 36 and R 37 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 R 23 and R 24 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical —O—(CH 2 ) t —CR 40 R 41 —(CH 2 ) l —O—, —(CH 2 ) t —CR 40 R 41 —(CH 2 ) l — or —S—(CH 2 ) t —CR 40 R 41 —(CH 2 ) l —S—,
wherein
t and l independently are 0, 1, 2, 3, 4 or 5,
R 40 and R 41 independently are hydrogen or C 1-6 -alkyl,
R 25 to R 30 independently are hydrogen, halogen, —CN, —CF 3 , —NO 2 , —OR 42 , —NR 42 R 43 , C 1-6 -alkyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl,
wherein R 42 and R 43 independently are hydrogen or C 1-6 -alkyl, or
R 42 and R 43 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 31 , R 32 and R 33 independently are hydrogen or C 1-6 -alkyl,
R 34 and R 35 independently are
hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkanoyl, —C(O)NR 44 R 45 or —S(O) 2 R 45 ,
aryl, aroyl, aryl-C 1-6 -alkoxy, aryl-C 1-6 -alkanoyl or aryl-C 1-6 -alkyl,
of which the aryl moieties optionally may be substituted with one or more substituents selected from halogen, —CN, —CF 3 , —OCF 3 , —OR 44 , —NR 44 R 45 and C 1-6 -alkyl,
wherein R 44 and R 45 independently are hydrogen or C 1-6 -alkyl, or
R 34 and R 35 when attached to a carbon atom together with the said carbon atom may 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
R 34 and R 35 when attached to a 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 or sulfur, and optionally containing one or two double bonds,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof
2 . A compound according to claim 1 , wherein V is —C(O)OH, —S(O) 2 OH, —C(O)NHOH or 5-tetrazolyl.
3 . A compound according to claim 2 , wherein V is —C(O)OH.
4 . A compound according to claim 2 , wherein V is 5-tetrazolyl.
5 . A compound according to claim 1 , wherein A is
—CH 2 —NR 7 —, —(CH 2 ) 2 —NR 7 —, —NR 7 —, —(CH 2 ) 3 —, or —NR 7 —CH 2 —.
6 . A compound according to claim 5 , wherein A is
7 . A compound according to claim 5 , wherein A is
8 . A compound according to claim 5 , wherein A is
9 . A compound according to claim 5 , wherein A is
10 . A compound according to claim 1 , wherein Y is —C(O)—.
11 . A compound according to claim 1 , wherein Y is a valence bond.
12 . A compound according to claim 1 , wherein Z is
.
13 . A compound according to claim 12 , wherein Z is
14 . A compound according to claim 1 , wherein R 1 is hydrogen.
15 . A compound according to claim 1 , wherein R 1 is methyl.
16 . A compound according to claim 1 , wherein X is
.
17 . A compound according to claim 16 , wherein X is
wherein q is 0 or 1, r is 0 or 1, s is 0, 1 or 2, and R 13 is hydrogen or C 1-6 -alkyl.
18 . A compound according to claim 17 , wherein X is —C(O)NH—, —C(O)NHCH 2 —, —C(O)NHCH(CH 3 )—, —C(O)NHCH 2 CH 2 —, —C(O)CH 2 —, —C(O)CH═CH—, —(CH 2 ) s —, —C(O)—, —C(O)O— or —NHC(O)—, wherein s is 0 or 1.
19 . A compound according to claim 18 , wherein X is —C(O)NH—, —C(O)NHCH 2 —, —C(O)NHCH(CH 3 )—, —C(O)NHCH 2 CH 2 —, —C(O)CH 2 —, —CH 2 —, —C(O)— or —NHC(O)—.
20 . A compound according to claim 19 , wherein X is —C(O)NH—.
21 . A compound according to claim 19 , wherein X is —C(O)NHCH(CH 3 )—.
22 . A compound according to claim 1 , wherein D is
.
23 . A compound according to claim 22 , wherein D is
.
24 . A compound according to claim 23 , wherein D is
.
25 . A compound according to claim 24 , wherein R 16 and R 17 are both hydrogen and R 20 is C 1-6 -alkyl or C 3-8 -cycloalkyl-C 1-6 -alkyl.
26 . A compound according to claim 24 , wherein R 20 is cyclopropylmethyl, butyl or isopropyl.
27 . A compound according to claim 26 , wherein R 20 is isopropyl.
28 . A compound according to claim 23 , wherein D is
.
29 . A compound according to claim 23 , wherein D is
.
30 . A compound according to claim 22 , wherein R 16 , R 17 and R 18 independently are hydrogen, halogen, —CN, —NO 2 , —CF 3 , —OCF 3 , hydroxy, —SCF 3 , C 1-6 alkyl, C 1-6 alkyl substituted with hydroxy, C 1-6 alkyl substituted with —S(O) 2 R 21 , C 1 —alkoxy, —S—C 1 —alkyl, —C(O)OR 21 , —C(O)R 21 , —CH 2 (O)R 21 , —C(O)NR 21 R 22 , —S(O)R 21 , —S(O) 2 R 21 , —S(O) 2 CF 3 , —S(O) 2 NR 21 R 22 , C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkoxy, C 3-8 -cycloalkyl-C 1-6 -alkylthio or C 3-8 -cycloalkylthio,
wherein R 21 and R 22 independently are hydrogen, C 1-6 alkyl, tri-C 1-6 alkylsilyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 alkyl, phenyl, phenyl-C 1-6 alkyl, 2,3-dihydroindolyl or isoindolyl, or R 21 and R 22 together with the nitrogen atom to which they are attached form a piperidine ring, phenoxy, phenoxycarbonyl, phenyl, phenyl-C 1-6 alkoxy, phenyl-C 1-6 alkyl, furanyl, tetrazolyl, benzoxazolyl or oxadiazolyl, of which the ring systems optionally may be substituted with halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , —C(O)OR 21 , —OR 21 , —NR 21 R 22 or C 1-6 alkyl, wherein R 21 and R 22 independently are hydrogen or C 1-6 alkyl, or wherein R 16 and R 17 in adjacent positions form the radical —O—CH 2 —O—, —CF 2 —O—CF 2 —O— or —O—CF 2 —CF 2 —O—, and R 18 is hydrogen.
31 . A compound according to claim 30 , wherein R 16 , R 17 and R 18 independently are
hydrogen, halogen, —CN, —NO 2 , —CF 3 , —OCF 3 , —SCF 3 , C 1-6 -alkyl, C 14 -allyl substituted with hydroxy, C 1-6 -alkyl substituted with —S(O) 2 R 21 , C 1-6 -alkoxy, —S—C 1-6 -alkyl, —C(O)OR 21 , —C(O)R 21 , —CH 2 (O)R 21 , —C(O)NR 21 R 22 , —S(O)R 21 , —S(O) 2 R 21 , —S(O) 2 CF 3 , —S(O) 2 NR 21 R 22 , C 3-8 -cycloalkyl-C 1-6 -alkoxy, C 3-8 -cycloalkyl-C 1-6 -alkylthio or C 3-8 -cycloalkylthio, wherein R 21 and R 22 independently are hydrogen, C 1-6 -alkyl, tri-C 1-6 alkylsilyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, phenyl or 2,3-dihydroindolyl, or R 21 and R 22 together with the nitrogen atom to which they are attached form a piperidine ring, phenoxy, phenyl, benzyl, furanyl, tetrazolyl, benzoxazolyl or oxadiazolyl, of which the ring systems optionally may be substituted with halogen, —C(O)OR 21 or C 1-6 -alkyl, wherein R 21 is hydrogen or C 1-6 -alkyl, or wherein R 16 and R 17 in adjacent positions form the radical —CF 2 —O—CF 2 —O— or —O—CF 2 —CF 2 —O—, and R 18 is hydrogen.
32 . A compound according to claim 31 , wherein R 16 , R 17 and R 18 independently are
hydrogen, halogen, —CN, —NO 2 , —CF 3 , —OCF 3 , —SCF 3 , C 1-6 -alkyl, C 1-6 -alkyl substituted with hydroxy, C 1-6 -alkoxy, —S—C 1-6 -alkyl, —C(O)OR 21 , —C(O)R 21 , —CH 2 (O)R 21 , —C(O)NR 21 R 22 , —S(O) 2 R 21 , —(O) 2 CF 3 or —S(O) 2 NR 21 R 22 , wherein R 21 and R 22 independently are hydrogen, C 1-6 -alkyl, tri-C 1-6 -alkylsilyl, phenyl or 2,3-dihydro-indolyl, phenoxy, phenyl, benzyl, furanyl, tetrazolyl, benzoxazolyl or oxadiazolyl, of which the ring systems optionally may be substituted with halogen, —C(O)OR 21 or C 1-6 -alkyl, wherein R 21 is hydrogen or C 1-6 -alkyl, or wherein R 16 and R 17 in adjacent positions form the radical —CF 2 —O—CF 2 —O— or —O—CF 2 —CF 2 —O—, and R 18 is hydrogen.
33 . A compound according to claim 32 , wherein R 16 , R 17 and R 18 independently are hydrogen, halogen, —CN, —NO 2 , —CF 3 , —OCF 3 , —SCF 3 , C 1-6 -alkyl, C 1-6 -alkoxy, —S—C 1-6 -alkyl, —C(O)OC 1-6 -alkyl, —S(O) 2 C 1 —alkyl, —S(O) 2 CF 3 , —C(O)N(C 1-6 -alkyl)(C 1-6 -alkyl), —S(O) 2 N(phenyl)(C 1-6 -alkyl), —C(═O)C 1-6 -alkyl, —CH 2 OH, —CH 2 O(tri-C 1-6 -alkylsilyl), 2,3-dihydroindol-1-ylsulfonyl, phenoxy, phenyl, 4-chlorophenyl, 1,3,5-trimethylbenzyl, benzoxazolyl, 2-methyltetrazol-5-yl, 2-methyl-3-methoxycarbonylfuran-5-yl or 3-isopropyl-[1,2,4]oxadiazol-5-yl).
34 . A compound according to claim 30 , wherein one of R 16 to R 18 is hydrogen.
35 . A compound according to claim 30 , wherein two of R 16 to R 18 are hydrogen.
36 . A compound according to claim 30 , wherein R 16 and R 17 are both hydrogen and R 18 is —OCF 3 , —SCF 3 —CF 3 , —S(O) 2 CH 3 , phenyl, halogen, C 1-6 -alkyl, nitro, —S—C 6 -alkyl or —S(O) 2 NR 21 R 22 , wherein R 21 is C 1-6 -alkyl and R 22 is phenyl.
37 . A compound according to claim 30 , wherein R 16 and R 17 are both hydrogen and R 18 is —OCF 3 or halogen.
38 . A compound according to claim 30 , wherein R 16 is hydrogen and R 17 and R 18 are both halogen or are both —CF 3 .
39 . A compound according to claim 30 , wherein R 16 is hydrogen, R 17 is —CF 3 and R 18 is halogen, —CN, C 1-6 -alkoxy or —OCF 3 .
40 . A compound according to claim 30 , wherein R 16 is hydrogen, R 17 is —OCF 3 and R 18 is —S(O) 2 CH 3 , —CH 2 O-tri-C 1-6 -alkylsilyl, benzoxazolyl or —CH 2 OH.
41 . A compound according to claim 30 , wherein R 16 is hydrogen, R 17 is C 1-6 -alkyl and R 18 is —S(O) 2 NR 21 R 22 , wherein R 21 is C 1-6 -alkyl and R 22 is phenyl.
42 . A compound according to claim 30 , wherein R 16 , R 17 and R 18 are selected from hydrogen, —OCF 3 , —CF 3 , —Br, —F and —Cl.
43 . A compound according to claim 1 , wherein E is
.
44 . A compound according to claim 43 , wherein E is
.
45 . A compound according to claim 44 , wherein E is
1 .
46 . A compound according to claim 45 , wherein E is
.
47 . A compound according to claim 46 , wherein R 34 and R 35 independently are C 1-6 -alkyl, hydrogen or C 1-6 -alkoxy.
48 . A compound according to claim 47 , wherein R 34 and R 35 are both C 1-6 -alkyl.
49 . A compound according to claim 45 , wherein E is
.
50 . A compound according to claim 49 , wherein E is
.
51 . A compound according to claim 49 , wherein R 23 and R 24 independently are selected from hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkylidene, phenoxy, phenyl, —C(O)NR 36 R 37 and —OC(O)NH-phenyl, of which the phenyl moiety optionally may be substituted with —OCF 3 , wherein R 36 and R 37 are as defined in claim 1 , or R 23 and R 24 together form the radical —(CH 2 ) t —CR 40 R 41 —(CH 2 ) l —, —O—(CH 2 ) t —CR 40 R 41 —(CH 2 ) l —O—, —S—(CH 2 ) t —CR 40 R 41 —(CH 2 ) l —S.
52 . A compound according to claim 51 , wherein R 23 is hydrogen and R 24 is C 1-6 -alkyl such as tert-butyl or C 3-8 -cycloalkyl such as cyclohexyl, wherein R 23 and R 24 are both C 1-6 alkyl or wherein R 23 and R 24 together form the radical ——(CH 2 ) 5 —.
53 . A compound according to claim 46 , wherein E is
.
54 . A compound according to claim 53 , wherein E is
.
53 . A compound according to claim 53 , wherein R 25 , R 26 and R 27 independently are selected from hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, —CF 3 , —OCF 3 or —NR 42 R 43 .
56 . A compound according to claim 55 , wherein E is
wherein R 25 is —OCF 3 , —CF 3 , C 1-6 -alkyl, piperidyl, C 3-8 -cycloalkyl or C 4-8 -cycloalkenyl.
57 . A compound according to claim 46 , wherein E is
58 . A compound according to claim 57 , wherein E is
59 . A compound according to claim 1 of formula (I 1 ):
.
60 . A compound according to claim 1 of formula (I 2 ):
.
61 . A compound according to claim 1 of formula (I 3 ):
.
62 . A compound according to claim 1 of formula (I 4 ):
.
63 . A compound according to claim 1 of formula (I 5 ):
.
64 . A compound according to claim 1 of formula (I 6 ):
.
65 . A compound according to claim 1 of formula (I 7 ):
.
66 . A compound according to claim 1 of formula (I 8 ):
.
67 . A compound according to claim 1 of formula (I 9 ):
.
68 . A compound according to claim 59 , wherein R 46 and R 47 are both hydrogen.
69 . A compound according to claim 1 , which has an IC 50 value of no greater than 5 μM as determined by a Glucagon Binding Assay (I), Glucagon Binding Assay (II) or Glucagon Binding Assay (III).
70 . A compound according to claim 69 having a glucagon antagonistic activity as determined by the Glucagon Binding Assay (I), Glucagon Binding Assay (II) or Glucagon Binding Assay (III) corresponding to an IC 50 value of less than 1 μM.
71 . A compound according to claim 1 , which is an agent useful for treating an indication selected from the group consisting of hyperglycemia, impaired glucose tolerance (IGT), Type 2 diabetes, Type 1 diabetes and obesity.
72 - 86 . (canceled)
87 . A method for treating disorders or diseases mediated by a glucagon antagonistic action, the method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .
88 . The method according to claim 87 , wherein the effective amount of the compound is in the range of from about 0.05 mg to about 2000 mg.
89 . A pharmaceutical composition comprising, as an active ingredient, an effective amount of at least one compound of claim 1 together with one or more pharmaceutically acceptable carriers or excipients.
90 . The pharmaceutical composition of claim 89 in unit dosage form, comprising from about 0.05 mg to 1000 mg of the compound.
91 . The method of claim 87 , wherein the disorder or disease is hyperglycemia, impaired glucose tolerance (IGT), Type 2 diabetes, Type 1 diabetes or obesity.Cited by (0)
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