U.S. patent application number 11/502473 was filed with the patent office on 2007-09-06 for novel triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors.
This patent application is currently assigned to ZENTARIS GmbH. Invention is credited to Damien BOEGLIN, Luc DEMANGE, Jean-Alain FEHRENTZ, Jean MARTINEZ, Aline MOULIN, Daniel PERRISSOUD.
Application Number | 20070208061 11/502473 |
Document ID | / |
Family ID | 35589641 |
Filed Date | 2007-09-06 |
United States Patent
Application |
20070208061 |
Kind Code |
A2 |
PERRISSOUD; Daniel ; et
al. |
September 6, 2007 |
NOVEL TRIAZOLE DERIVATIVES AS GHRELIN ANALOGUE LIGANDS OF GROWTH
HORMONE SECRETAGOGUE RECEPTORS
Abstract
The present invention provides novel triazole derivatives as
ghrelin analogue ligands of growth hormone secretagogue receptors
according to formula (I) that are useful in the treatment or
prophylaxis of physiological and/or pathophysiological conditions
in mammals, preferably humans, that are mediated by GHS receptors.
The present invention further provides GHS receptor antagonists and
agonists that can be used for modulation of these receptors and are
useful for treating above conditions, in particular growth
retardation, cachexia, short-, medium- and/or long term regulation
of energy balance; short-, medium- and/or long term regulation
(stimulation and/or inhibition) of food intake; adipogenesis,
adiposity and/or obesity; body weight gain and/or reduction;
diabetes, diabetes type I, diabetes type II, tumor cell
proliferation; inflammation, inflammatory effects, gastric
postoperative ileus, postoperative ileus and/or gastrectomy
(ghrelin replacement therapy).
Inventors: |
PERRISSOUD; Daniel; (Bad
Homburg, DE) ; MARTINEZ; Jean; (Caux, FR) ;
MOULIN; Aline; (Portes-les-Valence, FR) ; FEHRENTZ;
Jean-Alain; (St. Nazaire de Pezan, FR) ; BOEGLIN;
Damien; (Eguisheim, FR) ; DEMANGE; Luc;
(Orsay, FR) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
2314
US
|
Assignee: |
ZENTARIS GmbH
Weismuellerstrasse 50
Frankfurt
DE
D-60314
Le Centre National De La Recherche Scientifique
3 rue Michel Ange
Paris Cedex 16
FR
F-75794
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20070037857 A1 |
February 15, 2007 |
|
|
Family ID: |
35589641 |
Appl. No.: |
11/502473 |
Filed: |
August 11, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60/787,543 |
Mar 31, 2006 |
|
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60/707,941 |
Aug 15, 2005 |
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Current U.S.
Class: |
514/341 ;
514/383 |
Current CPC
Class: |
A61K 31/497 20130101;
A61P 1/02 20180101; A61P 9/02 20180101; A61P 15/08 20180101; A61P
7/04 20180101; A61P 35/00 20180101; A61P 37/00 20180101; A61P 37/06
20180101; A61P 25/24 20180101; A61K 31/4439 20130101; A61K 31/4439
20130101; A61P 3/00 20180101; A61P 7/08 20180101; A61P 25/20
20180101; A61K 31/4196 20130101; A61P 25/22 20180101; A61P 21/06
20180101; A61P 27/16 20180101; A61K 31/4427 20130101; A61P 9/12
20180101; A61P 15/14 20180101; A61P 27/02 20180101; A61P 5/38
20180101; A61P 11/00 20180101; A61K 31/4523 20130101; A61P 1/04
20180101; A61K 45/06 20130101; A61P 3/06 20180101; A61P 5/06
20180101; A61P 15/00 20180101; A61P 17/02 20180101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61P 3/10 20180101; A61P 5/50
20180101; A61P 17/14 20180101; A61P 5/00 20180101; A61P 5/08
20180101; A61P 3/04 20180101; A61P 25/00 20180101; A61P 37/04
20180101; C07D 401/14 20130101; A61P 13/12 20180101; A61P 25/18
20180101; A61P 9/04 20180101; A61P 21/00 20180101; A61P 19/08
20180101; A61P 19/10 20180101; A61P 31/18 20180101; C07D 403/06
20130101; A61K 31/4196 20130101; A61P 11/02 20180101; A61P 17/00
20180101; A61P 25/28 20180101; A61P 29/00 20180101; A61P 43/00
20180101; C07D 403/14 20130101; A61P 1/16 20180101; A61P 1/14
20180101; A61P 9/10 20180101 |
Class at
Publication: |
514/341 ;
514/383 |
International
Class: |
A61K 31/4439 20070101
A61K031/4439; A61K 31/4196 20070101 A61K031/4196 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 16, 2005 |
EP |
050177328 |
Claims
1. A method for the treatment or prophylaxis of at least one
physiological and/or pathophysiological condition in a mammal that
is mediated by GHS receptors, comprising administering to a mammal
in need of treatment or prophylaxis of at least one physiological
and/or pathophysiological condition that is mediated by GHS
receptors an effective amount of at least one compound according to
formula (I) ##STR192## wherein: R1 and R2 are independently of one
another selected from the group consisting of hydrogen atom, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,
alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl which are optionally
substituted in the alkyl, cycloalkyl, cycloalkylalkyl, aryl,
heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and/or
heterocyclylalkyl group by up to 3 substituents independently
selected from the group consisting of halogen, --F, --C, --Br, --I,
--N.sub.3, --CN, --NR7R8, --OH, --NO.sub.2, alkyl, aryl, arylalkyl,
--O-alkyl, --O-aryl, --O-arylalkyl; one of radicals R3 and R4 is a
hydrogen atom, whereas the other radical is selected from the group
consisting of hydrogen atom, alkyl, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -alkyl-O-aryl,
-alkyl-O-arylalkyl, -alkyl-O-heteroaryl, -alkyl-O-heteroarylalkyl,
-alkyl-O-heterocyclyl, alkyl-O-heterocyclylalkyl, -alkyl-CO-aryl,
-alkyl-CO-arylalkyl, -alkyl-CO-heteroaryl,
-alkyl-CO-heteroarylalkyl, -alkyl-CO-heterocyclyl,
-alkyl-CO-heterocyclylalkyl, -alkyl-C(O)O-aryl,
-alkyl-C(O)O-arylalkyl, -alkyl-C(O)O-heteroaryl,
-alkyl-C(O)O-heteroarylalkyl, -alkyl-C(O)O-heterocyclyl,
-alkyl-C(O)O-heterocyclylalkyl, -alkyl-CO--NH.sub.2, -alkyl-CO--OH,
-alkyl-NH.sub.2, -alkyl-NH--C(NH)--NH.sub.2, alkylsulfonyl,
arylsulfonyl, arylalkylsulfonyl, alkyl-5-alkyl, alkyl-S--H which
are optionally substituted in the aryl, heteroaryl, arylalkyl,
heteroarylalkyl, heterocyclyl and/or heterocyclylalkyl group by up
to 3 substituents independently selected from the group consisting
of halogen, --F, --Cl, --Br, --I, --N.sub.3, --CN, --NR7R8, --OH,
--NO.sub.2, alkyl, aryl, arylalkyl, --O-alkyl, --O-aryl,
--O-arylalkyl; R5 is selected from the group consisting of hydrogen
atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,
--CO-alkyl, --CO-cycloalkyl, --CO-cycloalkylalkyl, --CO-aryl,
--CO-arylalkyl, --CO-heteroaryl, --CO-heteroarylalkyl,
--CO-heterocyclyl, --CO-heterocyclylalkyl,
--CO--C*(R9R10)-NH.sub.2, --CO--CH.sub.2--C--(R9R10)-NH.sub.2,
--CQ-C*(R9R10)-CH.sub.2--NH.sub.2, alkylsulfonyl, arylsulfonyl,
arylalkylsulfonyl which are optionally substituted by up to 3
substituents independently selected from the group consisting of
halogen, --F, --Cl, --Br, --I, --N.sub.3, --CN, --NR7R8, --OH,
--NO.sub.2, alkyl, aryl, arylalkyl, --O-alkyl, --O-aryl,
--O-arylalkyl; R6 is selected from the group consisting of hydrogen
atom, alkyl, cycloalkyl, and cycloalkylalkyl; R7 and R8 are
independently of one another selected from the group consisting of
hydrogen atom, alkyl, cycloalkyl, and cycloalkylalkyl; R9 and R10
are independently of one another selected from the group consisting
of hydrogen atom, alkyl, natural alpha-amino acid side chain, and
unnatural alpha-amino acid side chain; m is 0, 1 or 2; and * means
a carbon atom of R or S configuration when chiral.
2. The method as claimed in claim 1, where R3 is selected from the
group consisting of -alkyl-CO-aryl, -alkyl-CO-arylalkyl,
-alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl,
-alkyl-CO-heterocyclyl, alkyl-CO-heterocyclylalkyl,
-alkyl-C(O)O-aryl, -alkyl-C(O)O-arylalkyl, -alkyl-C(O)O-heteroaryl,
-alkyl-C(O)O-heteroarylalkyl, -alkyl-C(O)O-heterocyclyl,
-alkyl-C(O)O-heterocyclylalkyl, -alkyl-CO--NH.sub.2, -alkyl-CO--OH,
-alkyl-NH--C(NH)--NH.sub.2, alkyl-5-alkyl, and alkyl-S--H.
3. The method as claimed in claims 1, where R4 is a hydrogen atom;
R5 is selected from the group consisting of hydrogen atom, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl,
arylsulfonyl, arylalkylsulfonyl, --CO-cycloalkyl,
--CO-cycloalkyl-alkyl, --CO-aryl, --CO-arylalkyl, --CO-heteroaryl,
--CO-heteroarylalkyl, --CO-heterocyclyl, --CO-heterocyclylalkyl;
with the proviso that if R5 is --CO-heteroarylalkyl, heteroaryl is
not imidazole; and with the proviso that if R5 is --CO-heterocyclyl
and heterocyclyl contains only nitrogen atoms as heteroatoms, that
at least two nitrogen atoms are contained in heterocyclyl; and with
the proviso that if R5 is --CO-heterocyclylalkyl and heterocyclyl
contains only nitrogen atoms as heteroatoms that in the case that
one or two nitrogen atoms are contained in heterocyclyl no nitrogen
atom is positioned at position 1 of heterocyclyl that is the atom
directly linking heterocyclyl to the carbonyl group --CO--; where
alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl,
arylsulfonyl, arylalkylsulfonyl, --CO-cycloalkyl,
--CO-cycloalkylalkyl, --CO-aryl, --CO-arylalkyl, --CO-heteroaryl,
--CO-heteroarylalkyl, --CO-heterocyclyl, and/or
--CO-heterocyclylalkyl are optionally substituted by up to 3
substituents independently selected from the group consisting of
halogen, --F, --Cl, --Br, --I, --N.sub.3, --CN, --NR7R8, --OH,
--NO.sub.2, alkyl, aryl, arylalkyl, --O-alkyl, --O-aryl,
--O-arylalkyl; with the proviso that if R5 is --CO-cycloalkyl or
--CO-cycloalkylalkyl, R5 is not substituted with NR7R8 at position
1 of cycloalkyl, that is the C atom directly linking cycloalkyl to
the carbonyl group --CO-- in case of R5=--CO-cycloalkyl or to the
alkyl in case R5=--CO-cycloalkylalkyl; and with the proviso that if
R5 is --CO-aryl or --CO-arylalkyl and aryl is phenyl/benzene and is
only substituted with one substituent, this one substituent is not
--NR7R8; R6 is a hydrogen atom; R7 and R8 are independently of one
another selected from the group consisting of hydrogen atom, alkyl,
cycloalkyl, cycloalkylalkyl; and m is 0, 1 or 2.
4. The method as claimed in claim 1, where R1 is selected from the
group consisting of hydrogen, methyl, (2-methoxyphenyl)-methyl,
(3-methoxyphenyl)-methyl, (4-methoxyphenyl)-methyl,
(3-methoxyphenyl)-ethyl, (4-methoxyphenyl)-ethyl, phenyl,
phenyl-methyl, phenyl-ethyl, (4-ethylphenyl)-methyl,
(4-methylphenyl)-methyl, (4-fluorophenyl)-methyl,
(4-bromophenyl)-methyl, (2,4-dimethoxyphenyl)-methyl,
(3,5-dimethoxyphenyl)-methyl, 2,2-diphenyl-ethyl,
naphthaline-1-yl-methyl, 1H-indole-3-yl-methyl,
2-(1H-indole-3-yl)-ethyl, 3-(1H-indole-3-yl)-propyl,
4-methyl-phenyl, 4-ethyl-phenyl, n-hexyl,
(3,4-dichlorophenyl)-methyl, (4-nitro-phenyl)-methyl,
(pyridine-2-yl)-methyl, (pyridine-3-yl)-methyl,
(pyridine-4-yl)-methyl, (thiophene-2-yl)-methyl,
(thiophene-3-yl)-methyl, (furan-2-yl)-methyl, (furan-3-yl)-methyl;
R2 is selected from the group consisting of methyl,
1H-indole-3-yl-methyl, 2-(1H-indole-3-yl)-ethyl,
3-(1H-indole-3-yl)-propyl, 2-phenyl-ethyl, 3-phenyl-propyl,
4-phenyl-butyl, 2-methoxy-phenylmethyl, 3-methoxy-phenylmethyl,
4-methoxy-phenylmethyl, 2-methoxy-phenylethyl,
3-methoxy-phenylethyl, 4-methoxy-phenylethyl; R3 is selected from
the group consisting of hydrogen atom, methyl, propan-2-yl,
2-methyl-propan-1-yl, butan-2-yl, butan-1-yl, --CH.sub.2--SH,
--(CH.sub.2).sub.2--S--CH.sub.3, 1H-indole-3-yl-methyl,
phenyl-methyl, 2-phenyl-ethyl, --CH.sub.2--OCH.sub.2-phenyl,
--CH.sub.2--CO--CH.sub.2-phenyl,
--(CH.sub.2).sub.2--CO--CH.sub.2-phenyl, --CH.sub.2--C(O)O-phenyl,
--(CH.sub.2).sub.2--C(O)O-phenyl, hydroxy-methyl,
1-hydroxy-ethan-1-yl, --CH.sub.2--CO--NH.sub.2,
--(CH.sub.2).sub.2--CO--NH.sub.2, (1-hydroxy-benzene-4-yl)-methyl,
--CH.sub.2--CO--OH, --(CH.sub.2).sub.2--CO--OH,
--(CH.sub.2).sub.4--NH.sub.2, (1H-imidazol-5-yl)-methyl,
--(CH.sub.2).sub.3--NH--C(NH)--NH.sub.2,
--(CH.sub.2).sub.3--NH.sub.2, and
--(CH.sub.2).sub.3--NH--CO--NH.sub.2; R4 is a hydrogen atom; R5 is
selected from the group consisting of hydrogen atom,
--CO--CH.sub.2--NH.sub.2 (Gly residue),
--CO--CH.sub.2--CH.sub.2--NH.sub.2 (beta-Ala residue),
--CO--CHCH.sub.3--NH.sub.2 (D- and/or L-alpha-Ala residue),
--CO-(pyrrolidine-2-yl) (D- and/or L-Pro residue),
2-amino-2-carbonyl-propane (2-amino-isobutyric acid/Aib residue),
4-carbonyl-1H-piperidine, 3-carbonyl-1H-piperidine,
R-(3-carbonyl-1H-piperidine), S-(3-carbonyl-1H-piperidine),
2-carbonyl-1H-piperidine, R-(2-carbonyl-1H-piperidine),
S-(2-carbonyl-1H-piperidine), 1-amino-2-carbonyl-benzene,
carbonyl-cyclohexane, 2-acetyl-pyridine, 3-acetyl-pyridine,
4-acetyl-pyridine, 2-propionyl-pyridine, 3-propionyl-pyridine,
4-propionyl-pyridine, (R-1-amino)-2-carbonyl-cyclohexane,
(S-1-amino)-2-carbonyl-cyclohexane, 2-carbonyl-1H-imidazole,
2-carbonyl-pyridine, 3-carbonyl-pyridine, 4-carbonyl-pyridine,
2-amino-3-carbonyl-pyridine, 2-carbonyl-pyrazine,
2-carbonyl-4-hydroxy-1H-pyrrolidine,
4-carbonyl-1H,3H-diazacyclohexane, methyl-sulfonyl, phenylsulfonyl,
1-carbonyl-1-amino-2-phenylethane, phenylmethyl,
1-carbonyl-4-azide-benzene, 2-carbonyl-2,5-dihydro-1H-pyrrole,
2-carbonyl-piperazine, 2-carbonyl-1H-pyrrolidine, 2-aminoethane,
carbonyl-benzene, 2-carbonyl-pyrazine, 3-carbonyl-pyrazine,
4-carbonyl-oxacyclohexane, 4-methyl-phenylsulfonyl,
phenylmethyl-sulfonyl; R6 is a hydrogen atom; and m is 0.
5. The method as claimed in claim 4, where R3 is selected from the
group consisting of --CH.sub.2--CO--CH.sub.27-phenyl,
--(CH.sub.2).sub.2--CO--CH.sub.2-phenyl, --CH.sub.2--CO--NH.sub.2,
--(CH.sub.2).sub.2--CO--NH.sub.2, --CH.sub.2--CO--OH,
--(CH.sub.2).sub.2--CO--OH,
--(CH.sub.2).sub.3--NH--C(NH)--NH.sub.2, --CH.sub.2--SH,
--(CH.sub.2).sub.2--S--CH.sub.3.
6. The method as claimed in claim 4, where R5 is selected from the
group consisting of hydrogen atom, methylsulfonyl, phenylsulfonyl,
carbonyl-cyclohexane, (R-1-amino)-2-carbonyl-cyclohexane,
(S-1-amino)-2-carbonyl-cyclohexane, 2-carbonyl-pyridine,
3-carbonyl-pyridine, 4-carbonyl-pyridine, 2-acetyl-pyridine,
3-acetyl-pyridine, 4-acetyl-pyridine, 2-propionyl-pyridine,
3-propionyl-pyridine, 4-propionyl-pyridine,
2-amino-3-carbonyl-pyridine, 2-carbonyl-1H-imidazole,
2-carbonyl-pyrazine, 4-carbonyl-1H,3H-diazacyclohexane.
7. The method as claimed in claim 1 where the compound is at least
one compound selected from the group consisting of: compound 1
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 2
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenethyl-4H-1,2,4-triazol-3-yl-
)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 3
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-phenethyl-4H-1,2,4-triazol-3-yl)-
-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 4
(R)--N-(1-(5-benzyl-4-(naphthalen-1-ylmethyl)-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 5
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(naphthalen-1-ylmethyl)-4H-1,2,4--
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 6
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 7
(R)--N-(1-(4-(3-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 8
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 9
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 10
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(3-methoxybenzyl)-4H-1,2,4-triaz-
ol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 11
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(naphthalen-1-ylmethyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 12
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 13
(R)--N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 14
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-bromobenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 15
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-hexyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 16
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-hexyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 17
(R)--N-(1-(4,5-bis(2-(1H-indol-3-yl)ethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 18
(S)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 19
(R)--N-(1-(4-(3-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 20
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 21
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3,5-dimethoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 22
(R)--N-(1-(4-(4-methoxybenzyl)-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-y-
l)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 23
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-methoxybenzyl)-4H-1,2,4-triaz-
ol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 24
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-5-(3-(1H-indol-3-yl)propyl)-4H-1,2,-
4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 25
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2-methoxy)benzyl)-4H-1,2,4-triaz-
ol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 26
(R)--N-(1-(4-(2-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 27
(R)--N-(2-(1H-indol-3-yl)-1-(4-(naphthalen-1-ylmethyl)-5-phenethyl-4H-1,2-
,4-triazol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 28
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3,4-dichlorobenzyl)-4H-1,2,4-tri-
azol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 29
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-fluorobenzyl)-4H-1,2,4-tria-
zol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 30
(R)--N-(1-(4-(4-fluorobenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 31
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4-carboxamide,
compound 32
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-3-carboxamide,
compound 33
(R)--N-(1-(4-(4-methylbenzyl)-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)-2-
-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 34
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methylbenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 36
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-2-carboxamide,
compound 37
(R)--N-(1-(4-(4-methylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 38
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminobenzamide, compound 39
(R)--N-(1-(5-benzyl-4-(pyridin-2-ylmethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 40
(2S,4R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl-
)-2-(1H-indol-3-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide,
compound 41
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)piperidine-3-carboxamide, compound 42
(R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)piperidine-3-carboxamide, compound 43
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 44
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)piperidine-4-carboxamide, compound 45
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4-carboxamide, compound
46
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide, compound 47
(R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide, compound 48
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)piperidine-2-carboxamide, compound 49
(R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)piperidine-2-carboxamide, compound 50
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,44-triazol-3-yl)-2-(1H--
indol-3-yl)ethyl)-2-aminoacetamide, compound 51
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide, compound 52
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-(pyridin-4-yl)acetamide, compound 53
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)cyclohexanecarboxamide, compound 54
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-4-carboxamide, compound 55
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-3-carboxamide, compound 56
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-3-aminopropanamide, compound 57
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)-2-aminopropanamide, compound 58
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-(pyridin-3-yl)acetamide, compound 59
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-3-(pyridin-3-yl)propanamide, compound 60
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide, compound 61
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide,
compound 62
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-4-carboxamide, compound 63
(R)--N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl-
)-2-(1H-indol-3-yl)ethyl)piperidine-2-carboxamide, compound 64
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)picolinamide, compound 65
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)isonicotinamide, compound 66
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)pyrazine-2-carboxamide, compound 67
(R)--N-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)piperazine-2-carboxamide, compound 68
(S)--N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl-
)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide, compound 69
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide,
compound 70
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2-
,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
compound 71
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrazine-2-carboxamide,
compound 72
(R)--N-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tri-
azol-3-yl)-2-(1H-indol-3-yl)ethyl)piperazine-2-carboxamide,
compound 73
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide, compound 74
(R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethanamine, compound 75
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-aminoacetamide, compound 76
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)pyrazine-2-carboxamide, compound 77
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)isonicotinamide, compound 78
(R)--N-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)piperazine-2-carboxamide, compound 79
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)picolinamide, compound 80
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide, compound 81
(R)--N-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)piperazine-2-carboxamide, compound 82
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide, compound 83
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)piperidine-4-carboxamide, compound 84
(R)--N-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)piperazine-2-carboxamide, compound 85
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)pyrazine-2-carboxamide, compound 86
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-cis-aminocyclohexanecarboxami-
de, compound 87
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,
24-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-3-carboxamide,
compound 88
(R)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-t-
riazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-2-carboxamide,
compound 89
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
compound 90
(R)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
compound 91
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide, compound
92
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-bromobenzyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound
93
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-phenylethyl)-2-amino-2-methylpropanamide, compound 94
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4-(thiophen-2-ylmethyl)-4H-1,2,4-
-triazol-3-yl)ethyl)piperidine-4-carboxamide, compound 95
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol--
3-yl)ethyl)-2-amino-2-methylpropanamide, compound 96
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 97
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 98
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
-yl)ethyl)-2-amino-2-methylpropanamide, compound 99
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 100
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-methyl-4H-1,2,4-triazol-3-yl)-2-(1H--
indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 101
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 102
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H--
indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 103
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 104
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-phenethyl-4H-1,2,4-triazol-3-yl)-2-
-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 105
(R)--N-(1-(5-benzyl-4-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)e-
thyl)-2-amino-2-methylpropanamide, compound 106
(R)--N-(1-(5-benzyl-4-(2,2-diphenylethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 107
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,2-diphenylethyl)-4H-1,2,4-tria-
zol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 108
(R)--N-(1-(4-(3,5-dimethoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 109
(R)--N-(1-(4,5-dibenzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2--
amino-2-methylpropanamide, compound 110
(R)--N-(1-(5-benzyl-4-hexyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl-
)-2-amino-2-methylpropanamide, compound 111
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 112
(S)--N-(1-(4-(2,4-dimethoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H--
indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 113
(R)--N-(1-(4-(3,5-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 114
(R)--N-(1-(4-(4-bromobenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol--
3-yl)ethyl)-2-amino-2-methylpropanamide, compound 115
(R)--N-(1-(4-(2-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 116
(S)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 117
(R)--N-(1-(4,5-diphenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
-2-amino-2-methylpropanamide, compound 118
(R)--N-(1-(4-(3,4-dichlorobenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 119
(R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethanamine, compound 120
(R)--N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-phenylet-
hyl)-2-amino-2-methylpropanamide, compound 121
(R)--N-(1-(4-(4-fluorobenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 122
(R)--N-(1-(4-(3,4-dichlorobenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 124
(R)--N-(1-(4-(4-methylbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 125
(S)--N-(1-(4-(4-methoxybenzyl)-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)--
2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 126
(S)--N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 128
N--((R)-1-(4-(4-nitrobenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 129
(S)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 130
(R)--N-(1-(4-(4-methoxyphenethyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 131
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4-(thiophen-2-ylmethyl)-4H-1,2,4-
-triazol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 132
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4-(pyridin-2-ylmethyl)-4H-1,
2,4-triazol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 133
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4-(pyridin-2-ylmethyl)-4H-1,
2,4-triazol-3-yl)ethyl)piperidine-3-carboxamide, compound 134
(S)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide, compound 135
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-aminoacetamide, compound 136
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-4-yl)acetamide, compound
137
(2R)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-2-carboxamide, compound 138
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)picolinamide, compound 139
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-aminopyridine-3-carboxamide, compound 140
(2S)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-aminopropanamide, compound 141
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)isonicotinamide, compound 142
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl)e-
thyl)piperidine-4-carboxamide, compound 143
(2S)--N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol--
3-yl)ethyl)pyrrolidine-2-carboxamide, compound 144
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl)e-
thyl)-2-aminoacetamide, compound 145
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl)e-
thyl)-2-(pyridin-2-yl)acetamide, compound 146
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl)e-
thyl)picolinamide, compound 147
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-ethylphenyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide, compound 148
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-ethylphenyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide, compound
149
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-ethylphenyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide, compound 150
(2S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-ethylphenyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
compound 152
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide, compound 153
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-trans-aminocyclohexanecarboxamide, compound 154
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-(pyridin-3-yl)acetamide, compound 155
(3S)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-3-carboxamide, compound 156
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-aminobenzamide, compound 157
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)picolinamide, compound 158
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-4-carboxamide, compound 159
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)picolinamide, compound 160
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide, compound 161
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)pyrazine-2-carboxamide, compound 162
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)-2-aminoacetamide, compound 163
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)piperidine-4-carboxamide, compound 164
N--((R)-1-(5-benzyl-4-((pyridin-2-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)picolinamide, compound 165
N--((R)-1-(5-benzyl-4-((pyridin-2-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-acetamide, compound 166
N--((R)-1-(5-benzyl-4-((pyridin-2-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)piperidine-4-carboxamide, compound 167
N--((R)-1-(5-benzyl-4-((pyridin-4-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 168
N--((R)-1-(5-(4-methoxybenzyl)-4-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 169
N--((R)-1-(5-benzyl-4-((pyridin-4-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)picolinamide, compound 170
N--((R)-1-(5-benzyl-4-((pyridin-4-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-acetamide, compound 171
(R)-benzyl-3-(2-aminoisobutyramido)-3-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-me-
thoxybenzyl)-4H-1,2,4-triazol-3-yl)-propanoate, compound 172
N--((R)-1-(5-benzyl-4-((pyridin-3-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 173
N--((R)-1-(4-benzyl-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)e-
thyl)-2-amino-2-methylpropanamide, compound 174
N--((R)-2-(1H-indol-3-yl)-1-(4-methyl-5-phenethyl-4H-1,2,4-triazol-3-yl)e-
thyl)picolinamide, compound 175
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 176
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)benzamide, compound 177
(R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)-N-phenylmethanesulfonylamine, compound 178
(R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)-N-tosylethanamine, compound 179
N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 180
N-1-((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)ethane-1,2-diamine, compound 181
N--((R)-1-(4-((furan-2-yl)methyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 182
N--((R)-1-(4-((furan-2-yl)methyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)picolinamide, compound 183
N--((R)-1-(4-((furan-2-yl)methyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)piperidine-4-carboxamide, compound 184
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-tetrahydro-2H-pyran-4-carboxamide, compound 185
N--((R)-1-(5-((1H-indol-3-yl)methyl)-4-(3-methoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 186
(2S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-
-(1H-indol-3-yl)ethyl)-2-amino-3-phenylpropanamide, compound 187
(R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)-N-tosylethanamine, compound 188
N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-4-azidobenzamide, compound 189
N-benzyl-(R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl-
)-2-(1H-indol-3-yl)ethanamine, compound 190
(2S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4--
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2,5-dihydro-1H-pyrrole-2-carboxamide-
.
8. The method as claimed in claim 1 where the treatment is achieved
by modulation of GHS receptors.
9. The method as claimed in claim 1 where the compound is a GHS
receptor antagonist.
10. The method as claimed in claim 7, where the compound is a GHS
receptor antagonist selected from the group consisting of: compound
1, 3, 12, 13, 14, 18, 20, 22, 23, 33, 36, 37, 38, 41, 46, 47, 48,
49, 50, 51, 52, 53, 57, 58, 59, 60, 61, 63, 64, 65, 66, 68, 69, 70,
71, 72, 73, 74, 75, 76, 77, 79, 80, 82, 85, 86, 87, 88, 89, 90, 91,
93, 101, 102, 109, 114, 116, 119, 134, 135, 136, 137, 138, 139,
140, 145, 146, 147, 148, 150, 152, 153, 154, 156, 157, 159, 160,
161, 164, 171, 174, 176, 178, 179, 182, 184, 186, 188 and/or
compound 190.
11. The method as claimed in claim 9 where the compound is a GHS
receptor agonist for GHS receptors selected from the group
consisting of GHS type 1 receptor, GHS-R 1a, GHS-R 1b, motilin
receptor, motilin receptor 1a, neurotensin receptor, TRH receptor,
GPR38 (FM1), GPR39 (FM2), FM3, GHS-R subtype, GHS binding site,
cardiac GHS-R, and mammary GHS-R.
12. The method as claimed in claim 9, where the GHS receptor
agonist is selected from the group consisting of: compound 2, 4, 5,
6, 7, 8, 9, 10, 11, 15, 16, 17, 19, 21, 24, 25, 26, 27, 28, 29, 30,
31, 32, 34, 39, 40, 42, 43, 44, 45, 54, 55, 56, 62, 67, 78, 81, 83,
84, 87, 92, 94, 99, 103, 104, 105, 106, 107, 108, 110, 111, 115,
117, 118, 121, 122, 124, 130, 131, 142, 155, 158, 163, 173, 175,
180, 181, 183, 185 and/or compound 187.
13. The method as claimed in claim 1 where the mammal is selected
from the group consisting of human, domestic animals, cattle,
livestock, pets, cow, sheep, pig, goat, horse, pony, donkey, hinny,
mule, hare, rabbit, cat, dog, guinea pig, hamster, rat, and
mouse.
14. The method as claimed in claim 1 where the compound is a GHS
receptor agonist for GHS receptors selected from the group
consisting of GHS type 1 receptor, GHS-R 1a, GHS-R 1b, motilin
receptor, motilin receptor 1a, neurotensin receptor, TRH receptor,
GPR38 (FM1), GPR39 (FM2), FM3, GHS-R subtype, GHS binding site,
cardiac GHS-R, and mammary GHS-R.
15. The method as claimed in claim 1 where the physiological and/or
pathophysiological conditions are selected from the group
consisting of acute fatigue syndrome and muscle loss following
election surgery, adipogenesis, adiposity, age-related decline of
thymic function, age-related functional decline (ARFD) in the
elderly, aging disorder in companion animals, Alzheimer's disease,
anorexia; anxiety, blood pressure (lowering), body weight
gain/reduction, bone fracture repair (acceleration), bone
remodeling stimulation, cachexia and protein loss reduction due to
chronic illness such as cancer or AIDS, cardiac dysfunctions,
cardiomyopathy, cartilage growth stimulation, catabolic disorders
in connection with pulmonary dysfunction and ventilator dependency,
catabolic side effects of glucocorticoids, catabolic state of
aging, central nervous system disorders (in combination with
antidepressants), chronic dialysis, chronic fatigue syndrome (CFS),
cognitive function improvement, complicated fractures,
complications associated with transplantation, congestive heart
failure (alone/in combination with corticotropin releasing factor
antagonists), Crohn's disease and ulcerative colits, Cushing's
syndrome, dementia, depressions, short-, medium- and/or long-term
regulation of energy balance, short-, medium- and/or long-term
regulation of food intake (stimulation and/or inhibition),
fraility, gastrectomy (ghrelin replacement therapy), gastric
postoperative ileus, glycemic control improvement, growth hormone
release stimulation in the elderly, growth hormone replacement in
stressed patients, growth promotion in livestock, growth
retardation associated with the Prader-Willi syndrome and Turner's
syndrome, growth retardation in connection with Crohn's disease,
growth retardation, hair/nail growth maintenance, hip fractures,
hunger, hypercortisolism, hyperinsulinemia including
nesidioblastosis, hypothermia, immune deficiency in individuals
with a depressed T4/T8 cell ratio, immune response improvement to
vaccination, immune system stimulation in companion animals, immune
system stimulation, immunosuppression in immunosuppressed patients,
inflammation or inflammatory effects, inflammatory bowel disease,
insulin resistance in the heart, insulin resistance in type 2
diabetic patients, insulin resistance including NIDDM, diabetes,
diabetes type I, diabetes type II, intrauterine growth retardation,
irritable bowel syndrome, lipodystrophy, metabolic homeostasis
maintenance, milk production increase in livestock, muscle
mass/strength increase, muscle mobility improvement, muscle
strength improvement, muscle strength/function maintenance in
elderly humans, muscular atrophy, musculoskeletal impairment (e.g.
in elderly), Noonan's syndrome, obesity and growth retardation
associated with obesity, osteoblast stimulation,
osteochondrodysplasias, osteoporosis, ovulation induction (adjuvant
treatment), physiological short stature including growth hormone
deficient children, postoperative ileus, protein catabolic response
attenuation after major surgery/trauma, protein kinase B activity
enhancement, psychosocial deprivation, pulmonary dysfunction and
ventilator dependency, pulmonary function improvement, pulsatile
growth hormone release induction, recovery of burn patients and
reducing hospitalization of burn patients (acceleration), renal
failure or insufficiency resulting from growth retardation, renal
homeostasis maintenance in the frail elderly, sarcopenia,
schizophrenia, sensory function maintenance, short bowel syndrome,
short stature associated with chronic illness, skeletal dysplasia,
skin thickness maintenance, sleep disorders, sleep quality
improvement, thrombocytopenia, thymic development stimulation,
tooth repair or growth, tumor cell proliferation, ventricular
dysfunction or reperfusion events, wasting in connection with AIDS,
wasting in connection with chronic liver disease, wasting in
connection with chronic obstructive pulmonary disease (COPD),
wasting in connection with multiple sclerosis or other
neurodegenerative disorders, wasting secondary to fractures, wool
growth stimulation in sheep, wound healing (acceleration) and/or
wound healing delay.
16. The method as claimed in claim 15 where physiological and/or
pathophysiological conditions are selected from the group
consisting of growth retardation, cachexia, short-, medium- and/or
long term regulation of energy balance; short-, medium- and/or long
term regulation (stimulation and/or inhibition) of food intake;
adipogenesis, adiposity and/or obesity; body weight gain and/or
reduction; diabetes, diabetes type I, diabetes type II, tumor cell
proliferation; inflammation, inflammatory effects, gastric
postoperative ileus, postoperative ileus and/or gastrectomy
(ghrelin replacement therapy)
17. The method as claimed in claim 1 further comprising
administering at least one additional pharmacologically active
substance.
18. The method as claimed in claim 17, further comprising
administering a GHS receptor antagonist and an endocannabinoid
receptor antagonist.
19. The method as claimed in claim 1 where the administration is
before and/or during and/or after treatment with at least one
additional pharmacologically active substance.
20. The method as claimed in claim 19, comprising administering a
GHS receptor antagonist and an endocannabinoid receptor
antagonist.
21. A triazole compound selected from the group consisting of:
compound 1
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 2
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenethyl-4H-1,2,4-triazol-3-yl)--
2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 3
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-phenethyl-4H-1,2,4-triazol-3-yl)-
-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 4
(R)--N-(1-(5-benzyl-4-(naphthalen-1-ylmethyl)-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 5
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(naphthalen-1-ylmethyl)-4H-1,2,4--
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 6
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 7
(R)--N-(1-(4-(3-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 8
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 9
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 10
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(3-methoxybenzyl)-4H-1,2,4-triaz-
ol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 11
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(naphthalen-1-ylmethyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 12
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 13
(R)--N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 14
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-bromobenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 15
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-hexyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 16
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-hexyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 17
(R)--N-(1-(4,5-bis(2-(1H-indol-3-yl)ethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 18
(S)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 19
(R)--N-(1-(4-(3-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 20
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 21
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3,5-dimethoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 22
(R)--N-(1-(4-(4-methoxybenzyl)-5-(3-phenylpropyl)-4H-1,24-triazol-3-yl-
)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 23
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-methoxybenzyl)-4H-1,2,4-triaz-
ol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 24
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-5-(3-(1H-indol-3-yl)propyl)-4H-1,2,-
4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 25
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2-methoxy)benzyl)-4H-1,2,4-triaz-
ol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 26
(R)--N-(1-(4-(2-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 27
(R)--N-(2-(1H-indol-3-yl)-1-(4-(naphthalen-1-ylmethyl)-5-phenethyl-4H-1,2-
,4-triazol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 28
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3,4-dichlorobenzyl)-4H-1,2,4-tri-
azol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 29
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-fluorobenzyl)-4H-1,2,4-tria-
zol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 30
(R)--N-(1-(4-(4-fluorobenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 31
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4-carboxamide,
compound 32
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-3-carboxamide,
compound 33
(R)--N-(1-(4-(4-methylbenzyl)-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)-2-
-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 34
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methylbenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 36
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-2-carboxamide,
compound 37
(R)--N-(1-(4-(4-methylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 38
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminobenzamide, compound 39
(R)--N-(1-(5-benzyl-4-(pyridin-2-ylmethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 40
(2S,4R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl-
)-2-(1H-indol-3-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide,
compound 41
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)piperidine-3-carboxamide, compound 42
(R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)piperidine-3-carboxamide, compound 43
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 44
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)piperidine-4-carboxamide, compound 45
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4-carboxamide, compound
46
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide, compound 47
(R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide, compound 48
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)piperidine-2-carboxamide, compound 49
(R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)piperidine-2-carboxamide, compound 50
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-aminoacetamide, compound 51
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide, compound 52
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-(pyridin-4-yl)acetamide, compound 53
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)cyclohexanecarboxamide, compound 54
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-4-carboxamide, compound 55
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-3-carboxamide, compound 56
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-3-aminopropanamide, compound 57
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)-2-aminopropanamide, compound 58
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-(pyridin-3-yl)acetamide, compound 59
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-3-(pyridin-3-yl)propanamide, compound 60
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide, compound 61
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide,
compound 62
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-4-carboxamide, compound 63
(R)--N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl-
)-2-(1H-indol-3-yl)ethyl)piperidine-2-carboxamide, compound 64
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)picolinamide, compound 65
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)isonicotinamide, compound 66
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)pyrazine-2-carboxamide, compound 67
(R)--N-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)piperazine-2-carboxamide, compound 68
(S)--N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl-
)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide, compound 69
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide,
compound 70
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2-
,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
compound 71
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrazine-2-carboxamide,
compound 72
(R)--N-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tri-
azol-3-yl)-2-(1H-indol-3-yl)ethyl)piperazine-2-carboxamide,
compound 73
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide, compound 74
(R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethanamine, compound 75
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-aminoacetamide, compound 76
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)pyrazine-2-carboxamide, compound 77
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)isonicotinamide, compound 78
(R)--N-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)piperazine-2-carboxamide, compound 79
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)picolinamide, compound 80
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide, compound 81
(R)--N-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)piperazine-2-carboxamide, compound 82
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide, compound 83
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)piperidine-4-carboxamide, compound 84
(R)--N-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)piperazine-2-carboxamide, compound 85
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)pyrazine-2-carboxamide, compound 86
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-cis-aminocyclohexanecarboxami-
de, compound 87
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-3-carboxamide,
compound 88
(R)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-2-carboxamide,
compound 89
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
compound 90
(R)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
compound 91
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide, compound
92
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-bromobenzyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound
93
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-phenylethyl)-2-amino-2-methylpropanamide, compound 94
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4-(thiophen-2-ylmethyl)-4H-1,2,4-
-triazol-3-yl)ethyl)piperidine-4-carboxamide, compound 95
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol--
3-yl)ethyl)-2-amino-2-methylpropanamide, compound 96
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 97
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 98
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
-yl)ethyl)-2-amino-2-methylpropanamide, compound 99
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 100
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-methyl-4H-1,2,4-triazol-3-yl)-2-(1H--
indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 101
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 102
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H--
indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 103
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 104
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-phenethyl-4H-1,2,4-triazol-3-yl)-2-
-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 105
(R)--N-(1-(5-benzyl-4-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)e-
thyl)-2-amino-2-methylpropanamide, compound 106
(R)--N-(1-(5-benzyl-4-(2,2-diphenylethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 107
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,2-diphenylethyl)-4H-1,2,4-tria-
zol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 108
(R)--N-(1-(4-(3,5-dimethoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 109
(R)--N-(1-(4,5-dibenzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2--
amino-2-methylpropanamide, compound 110
(R)--N-(1-(5-benzyl-4-hexyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl-
)-2-amino-2-methylpropanamide, compound 111
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 112
(S)--N-(1-(4-(2,4-dimethoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H--
indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 113
(R)--N-(1-(4-(3,5-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 114
(R)--N-(1-(4-(4-bromobenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol--
3-yl)ethyl)-2-amino-2-methylpropanamide, compound 115
(R)--N-(1-(4-(2-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 116
(S)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 117
(R)--N-(1-(4,5-diphenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
-2-amino-2-methylpropanamide, compound 118
(R)--N-(1-(4-(3,4-dichlorobenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 119
(R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethanamine, compound 120
(R)--N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-phenylet-
hyl)-2-amino-2-methylpropanamide, compound 121
(R)--N-(1-(4-(4-fluorobenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 122
(R)--N-(1-(4-(3,4-dichlorobenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 124
(R)--N-(1-(4-(4-methylbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 125
(S)--N-(1-(4-(4-methoxybenzyl)-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)--
2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 126
(S)--N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 128
N--((R)-1-(4-(4-nitrobenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 129
(S)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 130
(R)--N-(1-(4-(4-methoxyphenethyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 131
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4-(thiophen-2-ylmethyl)-4H-1,2,4-
-triazol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 132
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4-(pyridin-2-ylmethyl)-4H-1,
2,4-triazol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 133
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4-(pyridin-2-ylmethyl)-4H-1,
2,4-triazol-3-yl)ethyl)piperidine-3-carboxamide, compound 134
(S)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide, compound 135
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-aminoacetamide, compound 136
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-4-yl)acetamide, compound
137
(2R)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-2-carboxamide, compound 138
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)picolinamide, compound 139
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-aminopyridine-3-carboxamide, compound 140
(2S)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-aminopropanamide, compound 141
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)isonicotinamide, compound 142
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl)e-
thyl)piperidine-4-carboxamide, compound 143
(2S)--N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol--
3-yl)ethyl)pyrrolidine-2-carboxamide, compound 144
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl)e-
thyl)-2-aminoacetamide, compound 145
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl)e-
thyl)-2-(pyridin-2-yl)acetamide, compound 146
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl)e-
thyl)picolinamide, compound 147
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-ethylphenyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide, compound 148
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-ethylphenyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide, compound
149
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-ethylphenyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide, compound 150
(2S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-ethylphenyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
compound 152
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide, compound 153
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-trans-aminocyclohexanecarboxamide, compound 154
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-(pyridin-3-yl)acetamide, compound 155
(3S)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-3-carboxamide, compound 156
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-aminobenzamide, compound 157
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)picolinamide, compound 158
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-4-carboxamide, compound 159
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)picolinamide, compound 160
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide, compound 161
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)pyrazine-2-carboxamide, compound 162
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)-2-aminoacetamide, compound 163
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)piperidine-4-carboxamide, compound 164
N--((R)-1-(5-benzyl-4-((pyridin-2-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)picolinamide, compound 165
N--((R)-1-(5-benzyl-4-((pyridin-2-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-acetamide, compound 166
N--((R)-1-(5-benzyl-4-((pyridin-2-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)piperidine-4-carboxamide, compound 167
N--((R)-1-(5-benzyl-4-((pyridin-4-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 168
N--((R)-1-(5-(4-methoxybenzyl)-4-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 169
N--((R)-1-(5-benzyl-4-((pyridin-4-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)picolinamide, compound 170
N--((R)-1-(5-benzyl-4-((pyridin-4-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-acetamide, compound 171
(R)-benzyl-3-(2-aminoisobutyramido)-3-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-me-
thoxybenzyl)-4H-1,2,4-triazol-3-yl)-propanoate, compound 172
N--((R)-1-(5-benzyl-4-((pyridin-3-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 173
N--((R)-1-(4-benzyl-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)e-
thyl)-2-amino-2-methylpropanamide, compound 174
N--((R)-2-(1H-indol-3-yl)-1-(4-methyl-5-phenethyl-4H-1,2,4-triazol-3-yl)e-
thyl)picolinamide, compound 175
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 176
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)benzamide, compound 177
(R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)-N-phenylmethanesulfonylamine, compound 178
(R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)-N-tosylethanamine, compound 179
N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 180
N-1-((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)ethane-1,2-diamine, compound 181
N--((R)-1-(4-((furan-2-yl)methyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, compound 182
N--((R)-1-(4-((furan-2-yl)methyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)picolinamide, compound 183
N--((R)-1-(4-((furan-2-yl)methyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)piperidine-4-carboxamide, compound 184
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-tetrahydro-2H-pyran-4-carboxamide, compound 185
N--((R)-1-(5-((1H-indol-3-yl)methyl)-4-(3-methoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
compound 186
(2S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-
-(1H-indol-3-yl)ethyl)-2-amino-3-phenylpropanamide, compound 187
(R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)-N-tosylethanamine, compound 188
N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-4-azidobenzamide, compound 189
N-benzyl-(R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl-
)-2-(1H-indol-3-yl)ethanamine, compound 190
(2S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4--
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2,5-dihydro-1H-pyrrole-2-carboxamide-
.
22. A pharmaceutical composition comprising at least one compound
as claimed in claim 21 and pharmaceutically acceptable carrier
and/or excipient.
23. The pharmaceutical composition as claimed in claim 22, where
the active ingredient is present in a unit dose of from 0.001 mg to
100 mg per kg of a patient's bodyweight.
24. The pharmaceutical composition as claimed in claim 22, where
the composition comprises at least one further pharmacologically
active substance.
25. The pharmaceutical composition as claimed in claim 24, where
the further pharmacologically active substance is an
endocannabinoid receptor antagonist.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional
application 60/707,941 filed Aug. 15, 2005, U.S. provisional
application 60/787,543 filed Mar. 31, 2006, and European
application 05017732.8 filed Aug. 16, 2005, all of which are
incorporated herein by reference.
TECHNICAL FIELD
[0002] The invention relates to novel triazole derivatives that act
as ghrelin analogue ligands of growth hormone secretagogue
receptors. These compounds are useful in modulating growth hormone
plasma levels in mammals as well as in the treatment and/or
regulation of various physiological and pathophysiological
conditions, such as growth retardation, obesity, food intake,
energy balance, tumor cell proliferation, wound/burn healing,
metabolic disorders and inflammation.
BACKGROUND OF THE INVENTION
[0003] Ghrelin, a 28 amino acid peptide with a unique octanoyl
modification on Ser-3 (Kojima M et al., Nature 1999, 402: 656-660),
was identified as an endogenous ligand for the growth hormone
secretagogue receptor type 1a (GHS-R 1a), a G-protein coupled
receptor (Howard A D et al., Science 1996, 273: 974-977). Ghrelin
is essentially produced in the upper intestinal tract/stomach but
lower amounts were also detected in bowel, pancreas, kidney, the
immune system, placenta, testes, pituitary, lung and in the
hypothalamus (van der Lely A J et al., Endocrine Rev. 2004, 25:
426-457; Cowley M et al., Neuron 2003, 37: 649-661).
[0004] In humans, ghrelin stimulates growth hormone (GH) via a
pathway independent from GHRH receptor and in synergy with GHRH on
GH secretion (Arvat E et al., J. Clin. Endocrinol. Metab. 2001, 86:
1169-1174). Besides, it also stimulates ACTH, prolactin, cortisol,
aldosterone and epinephrine secretion (Arvat E et al., J. Clin.
Endocrinol. Metab. 2001, 86: 1169-1174; Nagaya N et al., Am. J.
Physiol. Regul. Integr. Comp. Physiol. 2001, 280: R1483-1487;
Takaya K et al., J. Clin. Endocrinol. Metab. 2000, 85:
4908-4911).
[0005] Ghrelin is thought to participate in metabolism regulation
and energy expenditure, so ghrelin expression and secretion into
the general circulation from the stomach is expected to be
influenced by metabolic hormones. In obese humans, plasma ghrelin
levels are reduced, suggesting that the elevated insulin or leptin
levels of obese subjects lower ghrelin secretion (Tschop M et al,
Diabetes 2001, 50: 707-709).
[0006] The release of growth hormone in humans and animals is
believed to treat physiological or pathophysiological conditions
characterized by a deficiency in growth hormone secretion as well
as to treat those conditions which are improved by the anabolic
effects of growth hormone.
[0007] Initially, clinical applications with GH were limited to
treatment of GH-deficient children, but the commercialization of
recombinant human growth hormone (rhGH) allowed many studies which
showed other potential clinical uses of GH (Strobl J S et al.,
Pharmacol. Rev. 1994, 46: 1-34; Torosian M H, J. Pediatr.
Endocrinol. 1993, 6: 93-97). rhGH has shown promise in the
treatment of patients with burns, wounds, bone fractures and more
recently in reversing the catabolic effects of glucocorticoids,
chemotherapy and AIDS as well as in modifying body composition
(Rudman D et al., N. Engl. J. Med. 1990, 323: 1-6; Papadakis M A et
al., Ann. Intern. Med. 1996, 124: 708-716; Welle S et al., J. Clin.
Endocrinol. Metab. 1996, 81: 3239-3243).
[0008] GH, synthesized and stored in the pituitary gland, is
released under the control of two known hypothalamic hormones:
growth hormone releasing hormone (GHRH) and the inhibitory hormone
somatostatin (SRIF). In most cases, GH deficiency is related to a
hypothalamic defect and not to a pituitary deficiency in GH.
Therefore, as an alternative treatment to rhGH, GH-deficient
patients could also be treated with any compound that releases
endogenous GH from the pituitary gland. This can either be
performed with GHRH which stimulates GH release but also with
synthetic growth hormone secretagogues (GHS).
[0009] Many synthetic, peptidyl and non-peptidyl GHS, such as GHRPs
1, 2 and 6, Hexarelin, MK-0677, EP-01572, were shown to
specifically bind to the then orphan receptor GHS receptor--several
of them long before ghrelin and ghrelin/GHS receptor were
discovered (see Camanni F et al., Front Neuroendocrinol. 1998, 19:
47-72; Casanueva F F et al., Trends Endocrinol. Metab. 1999, 10:
30-38; van der Lely A J et al., Endocrine Rev. 2004, 25: 426-457
for further references). GHS also show potent GH releasing action
and have the same biological activities as mentioned above for
ghrelin.
[0010] GHS were also disclosed in the following patents or patent
applications (not exhaustive list): U.S. Pat. No. 6,071,926, U.S.
Pat. No. 6,329,342, U.S. Pat. No. 6,194,578, US 2001/0041673, U.S.
Pat. No. 6,251,902, US 2001/0020012, US 2002/0013320, US
2002/0002137, WO 95/14666, WO 96/15148, WO 01/96300.
[0011] While the ghrelin/GHS induced GH secretion is mediated by
the activation of the ghrelin/GHS receptor type 1a (GHS-R 1a),
there is evidence so far that at least some of the other effects of
ghrelin and GHS are also mediated by different receptors of the GHS
receptor family or even different binding sites on a given GHS
receptor.
[0012] GHS receptors are concentrated in the hypothalamus-pituitary
area but appear also to be distributed in other central and
peripheral tissues (Hattori N et al., J. Clin. Endocrinol, Metab.
2001, 86: 4284-4291; Gnanapavan S et al., J. Clin, Endocrinol.
Metab. 2002, 87: 2988-2991; Muccioli G et al., J. Endocrinol. 2000,
157: 99-106; Muccioli G et al., Ann. Endocrinol. 2000, 61: 27-31;
Muccioli G et al., Eur. J. Pharmacol. 2002, 440: 235-254; Papotti M
et al., J. Clin. Endocrinol. Metab. 2000, 85: 3803-3807; Cassoni P
et al., J. Clin. Endocrinol, Metab. 2001, 86: 1738-1745; Guan X M
et al., Brain Res. Mol. Brain Res. 1997, 48: 23-29; Bluet-Pajot M T
et al., Endocrine 2001, 14: 1-8; Korbonits M et al., J. Clin,
Endocrinol. Metab, 1998, 83: 3624-3630).
[0013] Two GHS type 1 receptors have been identified, GHS-R 1a and
GHS-R 1b, that in human are presumably expressed by a single gene
and alternatively spliced (van der Lely A J et al., Endocrine Rev.
2004, 25: 426-457; Howard A D et al., Science 1996, 273: 974-977;
Smith R G et al., Endocr. Rev. 1997, 18: 621-645; Smith R G et al.,
Endocrine 2001, 14: 9-14; McKee K K et al., Mol. Endocrinol. 1997,
11: 415-423; Petersenn S, Minerva Endocrinol. 2002; 27: 243-256).
Among mammalian species a high degree of sequence identity has been
reported for GHS-R 1a (Petersenn S, Minerva Endocrinol. 2002; 27:
243-256: between 91.8% and 95.6%).
[0014] Motilin receptor, was discovered as a member of the GHS
receptor family, having 52% identity (Smith R G et al., Endocrine
2001, 14: 9-14; McKee K K et al., Genomics 1997, 46: 426-434).
Gastrointestinal motilin receptor 1a and GHS-R 1a show a high
similarity (Smith R G et al., Endocrine 2001, 14: 9-14; Feighner S
D et al., Science 1999, 284: 2184-2188).
[0015] Other GHS receptor family members appear to be neurotensin
receptor, TRH receptor, GPR38 (FM1), GPR39 (FM2) and FM3 (Smith R G
et al., Endocr. Rev. 1997, 18: 621-645; Smith R G et al., Horm.
Res. 1999, 51 (Suppl. 3): 1-8; Tan C P et al., Genomics 1998, 52:
223-229; Howard A D et al., Science 1996, 273: 974-977). Further
GHS receptor subtypes appear to exist in a wide variety of central
and peripheral tissues (van der Lely A J et al., Endocrine Rev.
2004, 25: 426-457). For instance, a cardiac GHS-R has been reported
(Bodart V et al., Circ. Res. 1999, 85: 796-802) with a predicted
sequence similar to that of CD36, a multifunctional receptor known
as glycoprotein IV (Bodart V et al., Circ. Res. 2002, 90: 844-849).
Cassoni et al. (J. Clin. Endocrinol. Metab. 2001, 86: 1738-1745)
report the existence of GHS-R subtypes in neoplastic mammary cells
that are activated by ligands binding to specific binding sites
different from the classical GHS-R type 1. Furthermore, data
gathered by these authors support the hypothesis that even
different binding site subtypes do exist for GHS-R in peripheral
organs, which are possibly due to their endocrine or non-endocrine,
but also on their normal or neoplastic nature.
[0016] The ubiquity of GHS binding sites explains that
independently from their strong growth hormone secretagogue
properties, ghrelin as well as synthetic GHS are implicated in
several important physiological and pathophysiological
conditions.
[0017] Accordingly, potential clinical applications include among
others [0018] a) Short-, medium- and long term regulation of energy
balance and/or food intake (Tschop M et al., Nature 2000, 407:
908-913; Asakawa A et al., Gut 2003, 52: 947-952; US 2001/0020012;
Kojima M et al., Curr. Opin. Pharmacol. 2002, 2: 665-668; Horvath T
L et al., Curr. Pharm. Des. 2003, 9: 1383-1395; Wren A M et al., J.
Clin. Endocrinol. Metab. 2001, 86: 5992-5995) [0019] Expression of
GHS-R1a has been shown on neurons of hypothalamus paraventricular
nucleus. These neurons send efferents onto key hypothalamic
circuits for the control of food intake, like the arcuate nucleus
which produces the mediator NPY. It is thought that the stimulation
of food intake by ghrelin and/or GHS is mediated by an increase of
NPY in the arcuate nucleus (Willesen M G et al., Neuroendocrin.
1999, 70: 306-316). Single administration (icv or ip) of
anti-ghrelin IgG suppressed acute feeding in lean rats (Bagnasco M
et al., Regul. Pept. 2003, 111: 161-167). Chronic twice-daily icv
administration of anti-ghrelin IgG reduced body weight over a
five-day period (Murakami N et al., J. Endocrinol. 2002, 174:
283-288). [0020] A recent study using a peptidic GHS-R 1a
antagonist, [D-Lys-3]-GHRP-6, showed a reduction of food intake and
body weight gain in diet induced obese mice (Asakawa A et al., Gut,
2003, 52: 947-952). The fact that peptidyl compounds, initially
characterized as growth hormone secretagogues, are able to
stimulate selectively food intake in rats without inducing growth
hormone secretion, suggests the existence of a GHS-R subtype
different from GHS-R 1a in the hypothalamus (Torsello A et al.,
Neuroendocrin. 2000, 72: 327-332; Torsello A et al., Eur. J.
Pharmacol. 1998, 360: 123-129). [0021] b) Treatment of
adipogenesis, adiposity and/or obesity and reduction of body weight
(Tschop M et al., Nature 2000, 407: 908-913; Asakawa A et al., Gut
2003, 52: 947-952) [0022] Chronic administration of ghrelin and/or
GHS in freely feeding mice and rats results in increased body
weight and decreased fat utilization (Tschop M et al., Nature 2000,
407: 908-913). Furthermore, it has been reported that ghrelin and
des-octanoyl ghrelin promote adipogenesis in vivo (Thompson N M et
al., Endocrinol. 2004, 145: 234-242) and inhibit
isoproterenol-induced lipolysis in rat adipocytes via a non-type
GHS-R 1a (Muccioli G et al., Eur. J. Pharmacol. 2004, 498: 27-35).
On the other hand, there is also a report describing that the
expression of the GHS-R1a in rat adipocytes increases with age and
during adipogenesis (Choi K et al., Endocrinol. 2003, 144,
754-759). [0023] c) Treatment of tumor cell proliferation [0024] As
in the case for other members of the hypothalamus-pituitary axis
which regulates the secretion of growth hormone, evidence is
emerging to indicate that ghrelin and GHS-receptors may play an
important autocrine/paracrine role in some cancers (Jeffery P L et
al., Cytokine Growth Factor Rev. 2003, 14: 113-122). Specific
binding sites for ghrelin, peptidyl- and non-peptidyl GHS are
present in tumoral tissues, like prostate cancer cell line PC3
(Jeffery P L et al., J. Endocrinology 2002, 172: R7-R11), thyroid
tissue (Cassoni P et al., J. Endocrinol. 2000, 165: 139-146), lung
carcinoma cells CALU-1 (Ghe C et al., Endocrinol. 2002, 143:
484-491) and breast carcinomas (Cassoni P et al., J. Clin.
Endocrinol. Metab. 2001, 86: 1738-1745). [0025] In the case of
breast, the specific binding sites for GHS were found in tumoral
tissue while the normal mammary parenchyma did not reveal such
receptors. Synthetic GHS have been reported to inhibit the
proliferation of lung carcinoma cells CALU-1 (Ghe C et al.,
Endocrinol. 2002, 143: 484-491) and that of breast carcinoma cell
lines (Cassoni P et al., J. Clin. Endocrinol. Metab. 2001, 86:
1738-1745). [0026] Both ghrelin and non-acylated ghrelin bind to
tumoral tissues. Because non-acylated ghrelin is unable to bind the
GHS-R1a, it is likely that the binding site of GHS to tumoral
tissues is different from the GHS-R1a. From these data, one can
anticipate that the binding site in tumoral tissues recognizes
ligands of the GHS-R1a and in addition other not yet characterized
chemical structures. Synthetic ligands of GHS-R1a may have
therefore the potential to inhibit the proliferation of tumor cells
expressing subtypes of GHS receptors. [0027] d) Treatment of
inflammation/anti-inflammatory effects [0028] The anti-inflammatory
effect of the ghrelin agonist growth hormone-releasing peptide-2
(GHRP-2) in chronic arthritis with clinical manifestations of
hypermetabolism and cachexia was demonstrated (Granado M et al.,
Am. J. Physiol. Endocrinol. Metab. 2005, 288: E486-492). These data
suggest that the anti-inflammatory action of GHRP-2 is mediated by
activation of ghrelin receptors expressed by immune competent
cells. [0029] e) Treatment of cachexia [0030] The anti-cachetic
effect of administered recombinant growth hormone in an animal
model of chachexia (Roubenoff R et al., Arthritis Rheum. 1997,
40(3): 534-539) could be demonstrated (Ibanez de Caceres I et al.,
J. Endocrin. 2000, 165(3): 537-544). The findings are also in line
with data of patients with rheumatoid arthritis (Roubenoff R et
al., J Clin Invest. 1994, 93(6): 2379-2386). [0031] f) Treatment of
gastrectomy (ghrelin replacement therapy) [0032] The gastric
hormone ghrelin was given to mice subjected to gastrectomy or sham
operation (Dornonville de la Cour C et al., Gut 2005, 54(7):
907-913). The results presented show that ghrelin replacement
therapy at least partially reverse gastrectomy induced reduction in
body weight and body fat. [0033] g) Treatment of (gastric)
postoperative ileus [0034] The effect of ghrelin on the motor
function of the gastrointestinal tract in rat was evaluated. It
could be shown that ghrelin reverses the delayed gastric evacuation
and is a strong prokinetic agent useful for the treatment/reversion
of postoperative gastric ileus (Trudel L et al., Am J Physiol
Gastrointest Liver Physiol 2002, 282(6): G948-G952). [0035] h)
Treatment of diabetes (diabetes type I and type II) [0036] The
effect of ablation of ghrelin in leptin-deficient mice was studied
(Sun et al., Cell Metabolism 2006, 3: 379-386). The results show
that deletion of ghrelin augments insulin secretion in response to
glucose challenge indicating that inhibition of ghrelin or
counteracting its activity may be a possible way for the treatment
of diabetes including its subtypes I and II (see also WO
03/051389).
[0037] Further fields of application comprise acceleration of
recovery of patients having undergone major surgery (e.g. U.S. Pat.
No. 6,194,578); accelerating the recovery of burn patients (e.g.
U.S. Pat. No. 6,194,578); attenuating protein catabolic response
after a major operation (e.g. U.S. Pat. No. 6,194,578); reducing
cachexia and protein loss due to acute or chronic illness (e.g.
U.S. Pat. No. 6,194,578); treating central nervous system disorders
of patients undergoing a medical procedure in combination with
antidepressants (e.g. US 2002/0002137 A1); acceleration of bone
fracture repair and cartilage growth (e.g. U.S. Pat. No.
6,194,578); treatment or prevention of osteoporosis; stimulation of
the immune system; accelerating wound healing (e.g. U.S. Pat. No.
6,194,578); treatment of growth retardation associated with the
Prader-Willi syndrome, Turner's syndrome and obesity; treatment of
intrauterine growth retardation, skeletal dysplasia,
hypercortisolism and Cushing's syndrome; treatment of
osteochondrodysplasias, Noonan's syndrome, schizophrenia,
depressions and Alzheimer's disease; treatment of pulmonary
dysfunction and ventilator dependency; treatment of
hyperinsulinemia including nesidioblastosis; adjuvant treatment for
ovulation induction; prevention of the age-related decline of
thymic function; improvement in muscle strength and mobility (e.g.
U.S. Pat. No. 6,194,578); maintenance of skin thickness (e.g. U.S.
Pat. No. 6,194,578); improvement of sleep quality (e.g. U.S. Pat.
No. 6,071,926); prevention of congestive heart failure alone (e.g.
U.S. Pat. No. 6,329,342; U.S. Pat. No. 6,194,578) and in
combination with corticotropin releasing factor antagonists (e.g.
US 2001/0041673); metabolic homeostasis or renal homeostasis (e.g.
in the frail elderly)(e.g. U.S. Pat. No. 6,194,578); improving
glycemic control (e.g. U.S. Pat. No. 6,251,902); treatment of
systemic lupus erythematosus and inflammatory bowel disease (e.g.
US 2002/0013320); treating or preventing frailty associated with
aging or obesity (e.g. U.S. Pat. No. 6,194,578); as well as
stimulation of osteoblasts.
[0038] Animals were not forgotten in potential applications such as
stimulation of food intake (Wren A M et al., Diabetes 2001, 50:
2540-2547), stimulation of the immune system in companion animals
and treatment of disorder of aging, growth promotion in livestock
and stimulation of wool growth in sheep.
[0039] Compounds containing triazole moieties have been widely
recognized in the medicinal chemistry due to their various
biological activities. The following patent families are all
directed to heterocyclic compounds that are said to show certain
biological action for use in different medicinal indications.
Triazole moieties are implicitly or explicitly contained. However,
neither of these patent families mentions ghrelin analogue ligands
of the GHS receptor family nor modulation of these receptors nor GH
secretagogue properties or the like.
[0040] WO 2004/111015 discloses modulators of the glucocorticoid
receptor. WO 2004/052280 describes anti-agiogenic compounds as
inhibitors of tyrosine kinase activity of VEGF receptors and their
use in cancer. WO 2004/096795 also discloses tyrosine kinase
inhibitors, preferably C-FMS inhibitors, WO 03/011831 and WO
03/011210 both describe heteroarylheteroalkylamine derivatives as
inhibitors of nitric oxide synthase. WO 02/00651 is directed to
Factor XA inhibitors for use in thromboembolic disorders. WO
01/94318 and WO 01/94317 both describe chemical libraries of
substituted azole derivatives and methods of their synthesis for
use in drug discovery high-throughput screening. However, they fail
to provide any biological activity or any medicinal use nor do they
name specific compounds. WO 00/76971 and WO 00/76970 both claim
serine protease inhibitors useful as antithrombotic agents. WO
01/36395 discloses triazole derivatives as farnesyl transferase
inhibitors. WO 96/33176 and U.S. Pat. No. 5,703,092 are directed to
hydroxamic acid compounds as metalloprotease and TNF inhibitors. WO
93/09095 describes 2-heterocyclicethylamine derivatives and their
use in neurological and neurodegenerative disorders. WO 2004/103270
claims compounds for the treatment of thrombosis, in particular
Factor XIa inhibitors. WO 98/38177, U.S. Pat. No. 6,506,782, U.S.
Pat. No. 6,849,650 and US 2003/0130188 all describe heterocyclic
compounds as inhibitors of beta-amyloid peptide release or its
synthesis for use in Alzheimer's disease.
[0041] Heterocyclic compounds that may be useful as GHS have also
been described in the literature.
[0042] WO 00/54729, for instance, discloses heterocyclic aromatic
compounds as GH secretagogues which are said to stimulate
endogenous production and/or release of GH and can also contain
triazole moieties. In addition, a method for increasing levels of
endogenous GH or increasing the endogenous production or release of
GH administering such GHS is described. Furthermore, a method is
provided for preventing or treating osteoporosis (improving bone
density and/or strength), or treating obesity, or increasing muscle
mass and/or muscle strength and function in elderly humans, or
reversal or prevention of frailty in elderly humans administering
such GHS.
[0043] However, although claiming in vivo GH release WO 00/54729
fails to actually prove such effect. Neither in vitro nor in vivo
data are contained that demonstrate any stimulation of or increase
in endogenous production and/or release of GH.
[0044] Besides, WO 00/54729 fails to describe and show action of
those claimed compounds on any biological target, i.e. claimed
compounds are not shown/described to be ligands of one or more
specific receptors, for instance of a receptor family, that bind to
them and modulate their activity.
[0045] Furthermore, WO 00/54729 fails to describe and demonstrate
inhibitory and/or antagonistic activity of claimed compounds. As a
matter of fact, such compounds are not shown to decrease levels of
endogenous GH and/or inhibit or decrease endogenous production
and/or release of GH. Nor is an inhibitory action on any receptor
mentioned nor made obvious.
[0046] U.S. Pat. No. 6,525,203, U.S. Pat. No. 6,518,292 U.S. Pat.
No. 6,660,760 are members of the same patent family as WO 00/54729
that, however, do not comprise triazole moieties as claimed subject
matter any more. With regard to biological activity, the above
stated facts as for WO 00/54729 apply.
[0047] WO 2004/021984 describes heterocyclic aromatic compounds GH
secretagogues which are said to be useful in stimulating endogenous
production or release of GH. However, claimed compounds consists of
bi- to tetracylic aromatic rings and do not contain triazoles.
[0048] Analogous to WO 00/54729 in vivo GH release is claimed, but
neither in vitro nor in vivo data are contained that demonstrate
any stimulation of or increase in endogenous production and/or
release of GH. With regard to biological activity, the same stated
facts as for WO 00/54729 apply.
[0049] WO 97/23508 claims compounds of peptide mimetic nature as
GHS and are said to act directly on pituitary cells in vitro to
release GH therefrom and show improved properties, such as improved
resistance to proteolytic degradation and improved bioavailability.
In addition, claimed compounds could also be administered in vivo
to increase GH release. The compounds are peptide derivatives and
do not explicitly contain triazole moieties.
[0050] However, once again and in analogy to above WO 00/54729 and
WO 2004/021984, WO 97/23508 fails to exhibit any in vitro or in
vivo data that demonstrate the claimed effects such as direct
action on pituitary cells, GH release therefrom and improved
properties. Furthermore, with regard to biological targets and
inhibitory/antagonistic activity, the above stated facts as for WO
00/54729 apply.
[0051] U.S. Pat. No. 6,127,391, U.S. Pat. No. 5,977,178 and U.S.
Pat. No. 6,555,570 are members of the same patent family as WO
97/23508. The facts as stated for WO 97/23508 do apply.
BRIEF DESCRIPTION OF THE Invention
[0052] The present invention has as one object to provide novel
compounds which can be employed for the treatment of physiological
and/or pathophysiological conditions in mammals, in particular
humans, that are mediated by GHS receptors. It is another object of
the underlying invention to provide compounds for the above
treatment where the treatment is achieved by modulation of GHS
receptors. A further object of the present invention is to provide
antagonists of GHS receptors for those treatments. It is yet
another object of the underlying invention to provide agonists of
GHS receptors for those treatments.
[0053] The object of the invention has been surprisingly solved in
one aspect by providing compounds according to formula (I)
##STR1##
[0054] wherein: [0055] R1 and R2 are independently of one another
selected from the group consisting of hydrogen atom, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,
alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl which are optionally
substituted in the alkyl, cycloalkyl, cycloalkylalkyl, aryl,
heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and/or
heterocyclylalkyl group by up to 3 substituents independently
selected from the group consisting of halogen, --F, --Cl, --Br,
--I, --N.sub.3, --CN, --NR7R8, --OH, --NO.sub.2, alkyl, aryl,
arylalkyl, --O-alkyl, --O-aryl, --O-arylalkyl; and preferably are
selected from the group consisting of alkyl, aryl, heteroaryl,
arylalkyl, heteroarylalkyl optionally being substituted by up to 3
substituents independently selected from the group consisting of
halogen, --F, --Cl, --Br, --I, --N.sub.3, --CN, --NR7R8, --OH,
--NO.sub.2, alkyl, aryl, arylalkyl, --O-alkyl, --O-aryl,
--O-arylalkyl; [0056] one of radicals R3 and R4 is a hydrogen atom,
whereas the other radical is selected from the group consisting of
hydrogen atom, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,
heterocyclyl, heterocyclylalkyl, -alkyl-O-aryl, -alkyl-O-arylalkyl,
-alkyl-O-heteroaryl, -alkyl-O-heteroarylalkyl,
-alkyl-O-heterocyclyl, alkyl-O-heterocyclylalkyl, -alkyl-CO-aryl,
-alkyl-CO-arylalkyl, -alkyl-CO-heteroaryl,
-alkyl-CO-heteroarylalkyl, -alkyl-CO-heterocyclyl,
-alkyl-CO-heterocyclylalkyl, -alkyl-C(O)O-aryl,
-alkyl-C(O)O-arylalkyl, -alkyl-C(O)O-heteroaryl,
-alkyl-C(O)O-heteroarylalkyl, -alkyl-C(O)O-heterocyclyl,
-alkyl-C(O)O-heterocyclylalkyl, -alkyl-CO--NH.sub.2, -alkyl-CO--OH,
-alkyl-NH.sub.2, -alkyl-NH--C(NH)--NH.sub.2, alkylsulfonyl,
arylsulfonyl, arylalkylsulfonyl, alkyl-5-alkyl, alkyl-S--H which
are optionally substituted in the aryl, heteroaryl, arylalkyl,
heteroarylalkyl, heterocyclyl and/or heterocyclylalkyl group by up
to 3 substituents independently selected from the group consisting
of halogen, --F, --Cl, --Br, --I, --N.sub.3, --CN, --NR7R8, --OH,
--NO.sub.2, alkyl, aryl, arylalkyl, --O-alkyl, --O-aryl,
--O-arylalkyl; and preferably are selected from the group
consisting of arylalkyl, heteroarylalkyl, heterocyclylalkyl,
-alkyl-O-aryl, -alkyl-O-arylalkyl, -alkyl-O-heteroaryl,
-alkyl-O-heteroarylalkyl, -alkyl-O-heterocyclyl,
alkyl-O-heterocyclylalkyl, -alkyl-CO-aryl, -alkyl-CO-arylalkyl,
-alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl,
-alkyl-CO-heterocyclyl, alkyl-CO-heterocyclylalkyl,
-alkyl-C(O)O-aryl, -alkyl-C(O)O-arylalkyl, -alkyl-C(O)O-heteroaryl,
-alkyl-C(O)O-heteroarylalkyl, -alkyl-C(O)O-heterocyclyl,
-alkyl-C(O)O-heterocyclylalkyl, -alkyl-CO--NH.sub.2, -alkyl-CO--OH,
-alkyl-NH.sub.2, -alkyl-NH--C(NH)--NH.sub.2, optionally being
substituted in the aryl, heteroaryl, arylalkyl, heteroarylalkyl,
heterocyclyl and/or heterocyclylalkyl group by up to 3 substituents
independently selected from the group consisting of halogen, --F,
--Cl, --Br, --I, --N.sub.3, --CN, --NR7R8, --OH, --NO.sub.2, alkyl,
aryl, arylalkyl, --O-alkyl, --O-aryl, --O-arylalkyl; [0057] R5 is
selected from the group consisting of hydrogen atom, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, heterocyclyl, heterocyclylalkyl, --CO-alkyl,
--CO-cycloalkyl, --CO-cycloalkylalkyl, --CO-aryl, --CO-arylalkyl,
--CO-heteroaryl, --CO-heteroarylalkyl, --CO-heterocyclyl,
--CO-heterocyclylalkyl, --CO--C*(R9R10)-NH.sub.2,
--CO--CH.sub.2--C*(R9R10)-NH.sub.2,
--CO--C*(R9R10)-CH.sub.2--NH.sub.2, alkylsulfonyl, arylsulfonyl,
arylalkylsulfonyl which are optionally substituted by up to 3
substituents independently selected from the group consisting of
halogen, --F, --Cl, --Br, --I, --N.sub.3, --CN, --NR7R8, --OH,
--NO.sub.2, alkyl, aryl, arylalkyl, --O-alkyl, --O-aryl,
--O-arylalkyl; and preferably is selected from the group consisting
of hydrogen atom, --CO-alkyl, --CO-cycloalkyl, --CO-aryl,
--CO-heteroaryl, --CO-arylalkyl, --CO-heteroarylalkyl,
--CO-heterocyclyl, --CO--C*(R9R10)-NH.sub.2,
--CO--CH.sub.2--C*(R9R10)-NH.sub.2,
--CO--C*(R9R10)-CH.sub.2--NH.sub.2, optionally being substituted by
up to 3 substituents independently selected from the group
consisting of halogen, --F, --Cl, --Br, --I, --N.sub.3, --CN,
--NR7R8, --OH, --NO.sub.2, alkyl, aryl, arylalkyl, --O-alkyl,
--O-aryl, --O-arylalkyl; [0058] R6 is selected from the group
consisting of hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl and
preferably is a hydrogen atom; [0059] R7 and R8 are independently
of one another selected from the group consisting of hydrogen atom,
alkyl, cycloalkyl, cycloalkylalkyl and preferably are a hydrogen
atom; [0060] R9 and R10 are independently of one another selected
from the group consisting of hydrogen atom, alkyl natural
alpha-amino acid side chain, unnatural alpha-amino acid side chain
and preferably are selected from the group consisting of hydrogen
atom, alkyl; [0061] m is 0, 1 or 2 and preferably is 0; and [0062]
* means a carbon atom of R or S configuration when chiral;
[0063] that can be used for the manufacture of a medicament for the
treatment or prophylaxis of physiological and/or pathophysiological
conditions in mammals that are mediated by GHS receptors.
BRIEF DESCRIPTION OF THE DRAWINGS
[0064] FIGS. 1-13 show the measured competition plots of the GHS-R
1a receptor-ligand binding assay with .sup.125I-His.sup.9-ghrelin
and selected compounds 9, 31, 39, 45, 50, 62, 64, 71, 73, 74, 79,
81 and 90 as described in II) of the example section.
[0065] FIGS. 14-40 show the calculated dose-response plots of the
in vitro intracellular Calcium release assay with human GHS-R 1a
transfected CHO cells of the selected compounds 1, 9, 12, 20, 22,
31, 39, 41, 42, 45, 46, 47, 48, 49, 50, 51, 55, 62, 64, 67, 71, 73,
74, 79, 81, 90 and ghrelin as described in III) of the example
section as well as EC.sub.50 and KI values for GHS receptor
agonists and IC.sub.50 and Kb values for GHS receptor
antagonists.
[0066] FIGS. 41-46 show the effects of selected compounds 9, 38,
50, 64, 74, 81 on the isoprorerenol-induced lipolysis inhibition
curve of unacylated ghrelin (UAG) in primary adipocytes from mice
under diet-induced obesity as described in VIII) of the example
section.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0067] In a preferred embodiment compounds according to above
formula (I) are provided, where [0068] R3 is selected from the
group consisting of -alkyl-CO-aryl, -alkyl-CO-arylalkyl,
-alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl,
-alkyl-CO-heterocyclyl, alkyl-CO-heterocyclylalkyl,
-alkyl-C(O)O-aryl, -alkyl-C(O)O-arylalkyl, -alkyl-C(O)O-heteroaryl,
-alkyl-C(O)O-heteroarylalkyl, -alkyl-C(O)O-heterocyclyl,
-alkyl-C(O)O-heterocyclylalkyl, -alkyl-CO--NH.sub.2, -alkyl-CO--OH,
-alkyl-NH--C(NH)--NH.sub.2, alkyl-5-alkyl, alkyl-S--H, and
preferably is selected from the group consisting of
-alkyl-CO-arylalkyl, -alkyl-C(O)O-arylalkyl, -alkyl-CO--NH.sub.2,
-alkyl-CO--OH;
[0069] that can be used for the manufacture of a medicament for the
treatment or prophylaxis of physiological and/or pathophysiological
conditions in mammals that are mediated by GHS receptors.
[0070] In another preferred embodiment compounds according to above
formula (I) are provided, where [0071] R4 is a hydrogen atom;
[0072] R5 is selected from the group consisting of hydrogen atom,
alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl,
arylsulfonyl, arylalkylsulfonyl, --CO-cycloalkyl,
--CO-cycloalkylalkyl, --CO-aryl, --CO-arylalkyl, --CO-heteroaryl,
--CO-heteroarylalkyl, --CO-heterocyclyl, --CO-heterocyclylalkyl;
[0073] with the proviso that if R5 is --CO-heteroarylalkyl,
heteroaryl is not imidazole; and [0074] with the proviso that if R5
is --CO-heterocyclyl and heterocyclyl contains only nitrogen atoms
as heteroatoms, that at least two nitrogen atoms are contained in
heterocyclyl; and [0075] with the proviso that if R5 is
--CO-heterocyclylalkyl and heterocyclyl contains only nitrogen
atoms as heteroatoms that in the case that one or two nitrogen
atoms are contained in heterocyclyl no nitrogen atom is positioned
at position 1 of heterocyclyl that is the atom directly linking
heterocyclyl to the carbonyl group --CO--; [0076] where alkyl,
cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl,
arylsulfonyl, arylalkylsulfonyl, --CO-cycloalkyl,
--CO-cycloalkylalkyl, --CO-aryl, --CO-arylalkyl, --CO-heteroaryl,
--CO-heteroarylalkyl, --CO-heterocyclyl, and/or
--CO-heterocyclylalkyl are optionally substituted by up to 3
substituents independently selected from the group consisting of
halogen, --F, --Cl, --Br, --I, --N.sub.3, --CN, --NR7R8, --OH,
--NO.sub.2, alkyl, aryl, arylalkyl, --O-alkyl, --O-aryl,
--O-arylalkyl; [0077] with the proviso that if R5 is
--CO-cycloalkyl or --CO-cycloalkylalkyl, R5 is not substituted with
NR7R8 at position 1 of cycloalkyl, that is the C atom directly
linking cycloalkyl to the carbonyl group --CO-- in case of
R5=--CO-cycloalkyl or to the alkyl in case R5=--CO-cycloalkylalkyl;
and [0078] with the proviso that if R5 is --CO-aryl or
--CO-arylalkyl and aryl is phenyl/benzene and is only substituted
with one substituent, this one substituent is not --NR7R8; [0079]
R6 is a hydrogen atom; [0080] R7 and R8 are independently of one
another selected from the group consisting of hydrogen atom, alkyl,
cycloalkyl, cycloalkylalkyl and preferably are a hydrogen atom; and
[0081] m is 0, 1 or 2, and more preferably is 0;
[0082] that can be used for the manufacture of a medicament for the
treatment or prophylaxis of physiological and/or pathophysiological
conditions in mammals that are mediated by GHS receptors.
[0083] In a further aspect, the object of the invention has
surprisingly been achieved by providing compounds according to
formula (I), where [0084] R1 is selected from the group consisting
of hydrogen, methyl, (2-methoxyphenyl)-methyl,
(3-methoxyphenyl)-methyl, (4-methoxyphenyl)-methyl,
(3-methoxyphenyl)-ethyl, (4-methoxyphenyl)-ethyl, phenyl,
phenyl-methyl, phenyl-ethyl, (4-ethylphenyl)-methyl,
(4-methylphenyl)-methyl, (4-fluorophenyl)-methyl,
(4-bromophenyl)-methyl, (2,4-dimethoxyphenyl)-methyl,
(3,5-dimethoxyphenyl)-methyl, 2,2-diphenyl-ethyl,
naphthaline-1-yl-methyl, 1H-indole-3-yl-methyl,
2-(1H-indole-3-yl)-ethyl, 3-(1H-indole-3-yl)-propyl,
4-methyl-phenyl, 4-ethyl-phenyl, n-hexyl,
(3,4-dichlorophenyl)-methyl, (4-nitro-phenyl)-methyl,
(pyridine-2-yl)-methyl, (pyridine-3-yl)-methyl,
(pyridine-4-yl)-methyl, (thiophene-2-yl)-methyl,
(thiophene-3-yl)-methyl, (furan-2-yl)-methyl, (furan-3-yl)-methyl;
[0085] R2 is selected from the group consisting of methyl,
1H-indole-3-yl-methyl, 2-(1H-indole-3-yl)-ethyl,
3-(1H-indole-3-yl)-propyl, 2-phenyl-ethyl, 3-phenyl-propyl,
4-phenyl-butyl, 2-methoxy-phenylmethyl, 3-methoxy-phenylmethyl,
4-methoxy-phenylmethyl, 2-methoxy-phenylethyl,
3-methoxy-phenylethyl, 4-methoxy-phenylethyl; [0086] R3 is selected
from the group consisting of hydrogen atom, methyl, propan-2-yl,
2-methyl-propan-1-yl, butan-2-yl, butan-1-yl, --CH.sub.2--SH,
--(CH.sub.2).sub.2--S--CH.sub.3, 1H-indole-3-yl-methyl,
phenyl-methyl, 2-phenyl-ethyl, --CH.sub.2--O--CH.sub.2-phenyl,
--CH.sub.2--CO--CH.sub.2-phenyl,
--(CH.sub.2).sub.2--CO--CH.sub.2-phenyl, --CH.sub.2--C(O)O-phenyl,
--(CH.sub.2).sub.2--C(O)O-phenyl, hydroxy-methyl,
1-hydroxy-ethan-1-yl, --CH.sub.2--CO--NH.sub.2,
--(CH.sub.2).sub.2--CO--NH.sub.2, (1-hydroxy-benzene-4-yl)-methyl,
--CH.sub.2--CO--OH, --(CH.sub.2).sub.2--CO--OH,
--(CH.sub.2).sub.4--NH.sub.2, (1H-imidazol-5-yl)-methyl,
--(CH.sub.2).sub.3--NH--C(NH)--NH.sub.2,
--(CH.sub.2).sub.3--NH.sub.2, --(CH.sub.2).sub.3--NH--CO--NH.sub.2,
and preferably is selected from the group consisting of
1H-indole-3-yl-methyl, --CH.sub.2--CO--CH.sub.2-phenyl,
--(CH.sub.2).sub.2--CO--CH.sub.2-phenyl, --CH.sub.2--C(O)O-phenyl,
--(CH.sub.2).sub.2--C(O)O-phenyl; [0087] R4 is a hydrogen atom;
[0088] R5 is selected from the group consisting of hydrogen atom,
--CO--CH.sub.2--NH.sub.2 (Gly residue),
--CO--CH.sub.2--CH.sub.2--NH.sub.2 (beta-Ala residue),
--CO--CHCH.sub.3--NH.sub.2 (D- and/or L-alpha-Ala residue),
--CO-(pyrrolidine-2-yl) (D- and/or L-Pro residue),
2-amino-2-carbonyl-propane (2-amino-isobutyric acid/Aib residue),
4-carbonyl-1H-piperidine, 3-carbonyl-1H-piperidine,
R-(3-carbonyl-1H-piperidine), S-(3-carbonyl-1H-piperidine),
2-carbonyl-1H-piperidine, R-(2-carbonyl-1H-piperidine),
S-(2-carbonyl-1H-piperidine), 1-amino-2-carbonyl-benzene,
carbonyl-cyclohexane, 2-acetyl-pyridine, 3-acetyl-pyridine,
4-acetyl-pyridine, 2-propionyl-pyridine, 3-propionyl-pyridine,
4-propionyl-pyridine, (R-1-amino)-2-carbonyl-cyclohexane,
(S-1-amino)-2-carbonyl-cyclohexane, 2-carbonyl-1H-imidazole,
2-carbonyl-pyridine, 3-carbonyl-pyridine, 4-carbonyl-pyridine,
2-amino-3-carbonyl-pyridine, 2-carbonyl-pyrazine,
2-carbonyl-4-hydroxy-1H-pyrrolidine,
4-carbonyl-1H,3H-diazacyclohexane, methylsulfonyl, phenylsulfonyl,
1-carbonyl-1-amino-2-phenylethane, phenylmethyl,
1-carbonyl-4-azide-benzene, 2-carbonyl-2,5-dihydro-1H-pyrrole,
2-carbonyl-piperazine, 2-carbonyl-1H-pyrrolidine, 2-aminoethane,
carbonyl-benzene, 2-carbonyl-pyrazine, 3-carbonyl-pyrazine,
4-carbonyl-oxacyclohexane, 4-methyl-phenylsulfonyl,
phenylmethyl-sulfonyl [0089] R6 is a hydrogen atom; and [0090] m is
0;
[0091] that can be used for the manufacture of a medicament for the
treatment or prophylaxis of physiological and/or pathophysiological
conditions in mammals that are mediated by GHS receptors.
[0092] In a preferred embodiment compounds according to above
formula (I) are provided, where [0093] R3 is selected from the
group consisting of --CH.sub.2--CO--CH.sub.2-phenyl,
--(CH.sub.2).sub.2--CO--CH.sub.2-phenyl, --CH.sub.2--CO--NH.sub.2,
--(CH.sub.2).sub.2--CO--NH.sub.2, --CH.sub.2--CO--OH,
--(CH.sub.2).sub.2--CO--OH,
--(CH.sub.2).sub.3--NH--C(NH)--NH.sub.2, --CH.sub.2--SH,
--(CH.sub.2).sub.2--S--CH.sub.3;
[0094] that can be used for the manufacture of a medicament for the
treatment or prophylaxis of physiological and/or pathophysiological
conditions in mammals that are mediated by GHS receptors.
[0095] In another preferred embodiment compounds according to above
formula (I) are provided, where [0096] R5 is selected from the
group consisting of hydrogen atom, methylsulfonyl, phenylsulfonyl,
carbonyl-cyclohexane, (R-1-amino)-2-carbonyl-cyclohexane,
(S-1-amino)-2-carbonyl-cyclohexane, 2-carbonyl-pyridine,
3-carbonyl-pyridine, 4-carbonyl-pyridine, 2-acetyl-pyridine,
3-acetyl-pyridine, 4-acetyl-pyridine, 2-propionyl-pyridine,
3-propionyl-pyridine, 4-propionyl-pyridine,
2-amino-3-carbonyl-pyridine, 2-carbonyl-1H-imidazole,
2-carbonyl-pyrazine, 4-carbonyl-1H,3H-diazacyclohexane;
[0097] that can be used for the manufacture of a medicament for the
treatment or prophylaxis of physiological and/or pathophysiological
conditions in mammals that are mediated by GHS receptors.
[0098] In a further aspect, the object of the invention has
surprisingly been achieved by providing novel triazole compounds
selected from the group consisting of:
compound 1
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4-
H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0099] ##STR2##
compound 2
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenethyl-4H-1,2,4-tria-
zol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0100] ##STR3##
compound 3
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-phenethyl-4H-1,2,4-tri-
azol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0101] ##STR4##
compound 4
(R)--N-(1-(5-benzyl-4-(naphthalen-1-ylmethyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0102] ##STR5##
compound 5
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(naphthalen-1-ylmethyl)-
-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamid-
e,
[0103] ##STR6##
compound 6
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3-methoxybenzyl)-4H-1,-
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0104] ##STR7##
compound 7
(R)--N-(1-(4-(3-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)--
2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0105] ##STR8##
compound 8
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0106] ##STR9##
compound 9
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-benzyl-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0107] ##STR10##
compound 10
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(3-methoxybenzyl)-4H-1,2,4-triaz-
ol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0108] ##STR11##
compound 11
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(naphthalen-1-ylmethyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0109] ##STR12##
compound 12
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0110] ##STR13##
compound 13
(R)--N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0111] ##STR14##
compound 14
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-bromobenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0112] ##STR15##
compound 15
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-hexyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0113] ##STR16##
compound 16
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-hexyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0114] ##STR17##
compound 17
(R)--N-(1-(4,5-bis(2-(1H-indol-3-yl)ethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0115] ##STR18##
compound 18
(S)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0116] ##STR19## ##STR20##
compound 20
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0117] ##STR21##
compound 21
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3,5-dimethoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0118] ##STR22##
compound 22
(R)--N-(1-(4-(4-methoxybenzyl)-5-(3-phenylpropyl)-4H-1,2,4-thiazol-3-yl)--
2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0119] ##STR23##
compound 23
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-methoxybenzyl)-4H-1,2,4-triaz-
ol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0120] ##STR24##
compound 24
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-5-(3-(1H-indol-3-yl)propyl)-4H-1,2,-
4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0121] ##STR25##
compound 25
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2-methoxy)benzyl)-4H-1,2,4-triaz-
ol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0122] ##STR26##
compound 26
(R)--N-(1-(4-(2-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-3-
-yl)-2-amino-2-methylpropanamide,
[0123] ##STR27##
compound 27
(R)--N-(2-(1H-indol-3-yl)-1-(4-(naphthalen-1-ylmethyl)-5-phenethyl-4H-1,2-
,4-triazol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0124] ##STR28##
compound 28
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3,4-dichlorobenzyl)-4H-1,2,4-tri-
azol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0125] ##STR29##
compound 29
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-fluorobenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0126] ##STR30##
compound 30
(R)--N-(1-(4-(4-fluorobenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0127] ##STR31##
compound 31
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4-carboxamide,
[0128] ##STR32##
compound 32
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-3-carboxamide,
[0129] ##STR33##
compound 33
(R)--N-(1-(4-(4-methylbenzyl)-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)-2-
-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0130] ##STR34##
compound 34
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methylbenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0131] ##STR35##
compound 36
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-2-carboxamide,
[0132] ##STR36##
compound 37
(R)--N-(1-(4-(4-methylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0133] ##STR37##
compound 38
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminobenzamide,
[0134] ##STR38##
compound 39
(R)--N-(1-(5-benzyl-4-(pyridin-2-ylmethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0135] ##STR39##
compound 40
(2S,4R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl-
)-2-(1H-indol-3-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide,
[0136] ##STR40##
compound 41
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)piperidine-3-carboxamide,
[0137] ##STR41##
compound 42
(R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)piperidine-3-carboxamide,
[0138] ##STR42##
compound 43
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0139] ##STR43##
compound 44
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)piperidine-4-carboxamide,
[0140] ##STR44##
compound 45
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4-carboxamide,
[0141] ##STR45##
compound 46
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
[0142] ##STR46##
compound 47
(R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
[0143] ##STR47##
compound 48
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)piperidine-2-carboxamide,
[0144] ##STR48##
compound 49
(R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)piperidine-2-carboxamide,
[0145] ##STR49##
compound 50
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-aminoacetamide,
[0146] ##STR50##
compound 51
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide,
[0147] ##STR51##
compound 52
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,24-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-(pyridin-4-yl)acetamide,
[0148] ##STR52##
compound 53
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)cyclohexanecarboxamide,
[0149] ##STR53##
compound 54
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-4-carboxamide,
[0150] ##STR54##
compound 56
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-3-aminopropanamide,
[0151] ##STR55##
compound 57
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)-2-aminopropanamide,
[0152] ##STR56## ##STR57##
compound 58
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-(pyridin-3-yl)acetamide,
[0153] ##STR58##
compound 59
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-3-(pyridin-3-yl)propanamide,
[0154] ##STR59##
compound 60
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide,
[0155] ##STR60##
compound 61
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide,
[0156] ##STR61##
compound 62
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-4-carboxamide,
[0157] ##STR62##
compound 63
(R)--N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl-
)-2-(1H-indol-3-yl)ethyl)piperidine-2-carboxamide,
[0158] ##STR63##
compound 64
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)picolinamide,
[0159] ##STR64##
compound 65
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)isonicotinamide,
[0160] ##STR65##
compound 66
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)pyrazine-2-carboxamide,
[0161] ##STR66##
compound 67
(R)--N-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)piperazine-2-carboxamide,
[0162] ##STR67##
compound 68
(S)--N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl-
)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
[0163] ##STR68##
compound 69
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide,
[0164] ##STR69##
compound 70
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2-
,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
[0165] ##STR70##
compound 71
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrazine-2-carboxamide,
[0166] ##STR71##
compound 72
(R)--N-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tri-
azol-3-yl)-2-(1H-indol-3-yl)ethyl)piperazine-2-carboxamide,
[0167] ##STR72##
compound 73
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide,
[0168] ##STR73##
compound 74
(R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethanamine,
[0169] ##STR74##
compound 75
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-aminoacetamide,
[0170] ##STR75##
compound 76
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,24-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)pyrazine-2-carboxamide,
[0171] ##STR76##
compound 77
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)isonicotinamide,
[0172] ##STR77##
compound 78
(R)--N-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,24-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)piperazine-2-carboxamide,
[0173] ##STR78##
compound 79
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)picolinamide,
[0174] ##STR79##
compound 80
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide,
[0175] ##STR80##
compound 81
(R)--N-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)piperazine-2-carboxamide,
[0176] ##STR81##
compound 82
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide,
[0177] ##STR82##
compound 83
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)piperidine-4-carboxamide
[0178] ##STR83##
compound 84
(R)--N-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)piperazine-2-carboxamide,
[0179] ##STR84##
compound 85
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)pyrazine-2-carboxamide,
[0180] ##STR85##
compound 86
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-cis-aminocyclohexanecarboxami-
de,
[0181] ##STR86##
compound 87
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-3-carboxamide,
[0182] ##STR87##
compound 88
(R)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-2-carboxamide,
[0183] ##STR88##
compound 89
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
[0184] ##STR89##
compound 90
(R)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
[0185] ##STR90##
compound 91
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide,
[0186] ##STR91##
compound 92
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-bromobenzyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0187] ##STR92##
compound 93
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-phenylethyl)-2-amino-2-methylpropanamide,
[0188] ##STR93##
compound 94
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4-(thiophen-2-ylmethyl)-4H-1,24--
triazol-3-yl)ethyl)piperidine-4-carboxamide,
[0189] ##STR94##
compound 95
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol--
3-yl)ethyl)-2-amino-2-methylpropanamide,
[0190] ##STR95##
compound 96
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0191] ##STR96##
compound 97
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0192] ##STR97##
compound 98
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
-yl)ethyl)-2-amino-2-methylpropanamide,
[0193] ##STR98##
compound 99
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0194] ##STR99##
compound 100
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-methyl-4H-1,2,4-triazol-3-yl)-2-(1H--
indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0195] ##STR100##
compound 101
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0196] ##STR101##
compound 102
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H--
indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0197] ##STR102##
compound 103
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(2,4-dimethoxybenzyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0198] ##STR103##
compound 104
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-phenethyl-4H-1,2,4-triazol-3-yl)-2-
-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0199] ##STR104##
compound 105
(R)--N-(1-(5-benzyl-4-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)e-
thyl)-2-amino-2-methylpropanamide,
[0200] ##STR105##
compound 106
(R)--N-(1-(5-benzyl-4-(2,2-diphenylethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0201] ##STR106##
compound 107
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,2-diphenylethyl)-4H-1,2,4-tria-
zol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0202] ##STR107##
compound 108
(R)--N-(1-(4-(3,5-dimethoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H--
indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0203] ##STR108##
compound 109
(R)--N-(1-(4,5-dibenzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2--
amino-2-methylpropanamide,
[0204] ##STR109##
compound 110
(R)--N-(1-(5-benzyl-4-hexyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl-
)-2-amino-2-methylpropanamide,
[0205] ##STR110##
compound 111
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0206] ##STR111##
compound 112
(S)--N-(1-(4-(2,4-dimethoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H--
indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0207] ##STR112##
compound 113
(R)--N-(1-(4-(3,5-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0208] ##STR113##
compound 114
(R)--N-(1-(4-(4-bromobenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol--
3-yl)ethyl)-2-amino-2-methylpropanamide,
[0209] ##STR114##
compound 115
(R)--N-(1-(4-(2-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0210] ##STR115##
compound 116
(S)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0211] ##STR116##
compound 117
(R)--N-(1-(4,5-diphenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
-2-amino-2-methylpropanamide,
[0212] ##STR117##
compound 118
(R)--N-(1-(4-(3,4-dichlorobenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0213] ##STR118##
compound 119
(R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethanamine,
[0214] ##STR119##
compound 120
(R)--N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-phenylet-
hyl)-2-amino-2-methylpropanamide,
[0215] ##STR120##
compound 121
(R)--N-(1-(4-(4-fluorobenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0216] ##STR121##
compound 122
(R)--N-(1-(4-(3,4-dichlorobenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0217] ##STR122##
compound 124
(R)--N-(1-(4-(4-methylbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0218] ##STR123##
compound 125
(S)--N-(1-(4-(4-methoxybenzyl)-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)--
2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0219] ##STR124##
compound 126
(S)--N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0220] ##STR125##
compound 128
N--((R)-1-(4-(4-nitrobenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0221] ##STR126##
compound 129
(S)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0222] ##STR127##
compound 130
(R)--N-(1-(4-(4-methoxyphenethyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0223] ##STR128##
compound 131
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4-(thiophen-2-ylmethyl)-4H-1,2,4-
-triazol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0224] ##STR129##
compound 135
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-aminoacetamide,
[0225] ##STR130##
compound 136
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-4-yl)acetamide,
[0226] ##STR131##
compound 137
(2R)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-2-carboxamide,
[0227] ##STR132##
compound 132
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4-(pyridin-2-ylmethyl)-4H-1,
2,4-triazol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0228] ##STR133##
compound 133
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4-(pyridin-2-ylmethyl)-4H-1,
2,4-triazol-3-yl)ethyl)piperidine-3-carboxamide,
[0229] ##STR134##
compound 134
(S)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
[0230] ##STR135##
compound 138
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)picolinamide,
[0231] ##STR136##
compound 139
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-aminopyridine-3-carboxamide,
[0232] ##STR137##
compound 140
(2S)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-aminopropanamide,
[0233] ##STR138##
compound 141
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)isonicotinamide,
[0234] ##STR139##
compound 142
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl)e-
thyl)piperidine-4-carboxamide,
[0235] ##STR140##
compound 143
(2S)--N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol--
3-yl)ethyl)pyrrolidine-2-carboxamide,
[0236] ##STR141##
compound 144
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl)e-
thyl)-2-aminoacetamide,
[0237] ##STR142##
compound 145
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl)e-
thyl)-2-(pyridin-2-yl)acetamide,
[0238] ##STR143##
compound 146
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl)e-
thyl)picolinamide,
[0239] ##STR144##
compound 147
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-ethylphenyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide,
[0240] ##STR145##
compound 148
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-ethylphenyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide,
[0241] ##STR146##
compound 149
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-ethylphenyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide,
[0242] ##STR147##
compound 150
(2S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-ethylphenyl)-4H-1,
2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,
[0243] ##STR148##
compound 152
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide,
[0244] ##STR149##
compound 153
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-trans-aminocyclohexanecarboxamide,
[0245] ##STR150##
compound 154
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-(pyridin-3-yl)acetamide,
[0246] ##STR151##
compound 155
(3S)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-3-carboxamide,
[0247] ##STR152##
compound 156
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-aminobenzamide,
[0248] ##STR153##
compound 157
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)picolinamide,
[0249] ##STR154##
compound 158
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)piperidine-4-carboxamide,
[0250] ##STR155##
compound 159
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)picolinamide,
[0251] ##STR156##
compound 160
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide,
[0252] ##STR157##
compound 161
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)pyrazine-2-carboxamide,
[0253] ##STR158##
compound 162
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)-2-aminoacetamide,
[0254] ##STR159##
compound 163
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-phenethyl-4H
-1,2,4-triazol-3-yl)ethyl)piperidine-4-carboxamide,
[0255] ##STR160##
compound 164
N--((R)-1-(5-benzyl-4-((pyridin-2-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)picolinamide,
[0256] ##STR161##
compound 165
N--((R)-1-(5-benzyl-4-((pyridin-2-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-acetamide,
[0257] ##STR162##
compound 166
N--((R)-1-(5-benzyl-4-((pyridin-2-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)piperidine-4-carboxamide,
[0258] ##STR163##
compound 167
N--((R)-1-(5-benzyl-4-((pyridin-4-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0259] ##STR164##
compound 168
N--((R)-1-(5-(4-methoxybenzyl)-4-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0260] ##STR165##
compound 169
N--((R)-1-(5-benzyl-4-((pyridin-4-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)picolinamide,
[0261] ##STR166##
compound 170
N--((R)-1-(5-benzyl-4-((pyridin-4-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-acetamide,
[0262] ##STR167##
compound 171
(R)-benzyl-3-(2-aminoisobutyramido)-3-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-me-
thoxybenzyl)-4H-1,2,4-triazol-3-yl)-propanoate,
[0263] ##STR168##
compound 172
N--((R)-1-(5-benzyl-4-((pyridin-3-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0264] ##STR169##
compound 173
N--((R)-1-(4-benzyl-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)e-
thyl)-2-amino-2-methylpropanamide,
[0265] ##STR170##
compound 174
N--((R)-2-(1H-indol-3-yl)-1-(4-methyl-5-phenethyl-4H-1,2,4-triazol-3-yl)e-
thyl)picolinamide,
[0266] ##STR171##
compound 175
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0267] ##STR172##
compound 176
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)benzamide,
[0268] ##STR173##
compound 177
(R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)-N-phenylmethanesulfonylamine,
[0269] ##STR174##
compound 178
(R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)-N-tosylethanamine,
[0270] ##STR175##
compound 179
N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0271] ##STR176##
compound 180
N-1-((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)ethane-1,2-diamine,
[0272] ##STR177##
compound 181
N--((R)-1-(4-((furan-2-yl)methyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0273] ##STR178##
compound 182
N--((R)-1-(4-((furan-2-yl)methyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)picolinamide,
[0274] ##STR179##
compound 183
N--((R)-1-(4-((furan-2-yl)methyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)piperidine-4-carboxamide,
[0275] ##STR180##
compound 184
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-tetrahydro-2H-pyran-4-carboxamide,
[0276] ##STR181##
compound 185
N--((R)-1-(5-((1H-indol-3-yl)methyl)-4-(3-methoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,
[0277] ##STR182##
compound 186
(2S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-
-(1H-indol-3-yl)ethyl)-2-amino-3-phenylpropanamide,
[0278] ##STR183##
compound 187
(R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)-N-tosylethanamine,
[0279] ##STR184##
compound 188
N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-4-azidobenzamide,
[0280] ##STR185##
compound 189
N-benzyl-(R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl-
)-2-(1H-indol-3-yl)ethanamine,
[0281] ##STR186##
compound 190
(2S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4--
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2,5-dihydro-1H-pyrrole-2-carboxamide-
,
[0282] ##STR187##
[0283] For the avoidance of doubt, if chemical name and chemical
structure of the above illustrated compounds do not correspond by
mistake, the chemical structure is regarded to unambigously define
the compound.
[0284] In a preferred embodiment these compounds can be used for
the manufacture of a medicament for the treatment or prophylaxis of
physiological and/or pathophysiological conditions in mammals that
are mediated by GHS receptors.
[0285] In a further preferred embodiment all triazole compounds as
illustrated herein, i.e. generically (by above formula (I) and
different R radicals) and explicitly, in the following referred to
as the compounds of the (present) invention, can be used for the
manufacture of a medicament for the treatment or prophylaxis of
physiological and/or pathophysiological conditions in mammals that
are mediated by GHS receptors and where the treatment is achieved
by modulation of GHS receptors.
[0286] In yet another preferred embodiment all compounds of the
invention are antagonists of GHS receptors.
[0287] More preferably, antagonists of GHS receptors are compounds
selected from the group consisting of:
[0288] compound 1, 3, 12, 13, 14, 18, 20, 22, 23, 33, 36, 37, 38,
41, 46, 47, 48, 49, 50, 51, 52, 53, 57, 58, 59, 60, 61, 63, 64, 65,
66, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79, 80, 82, 85, 86, 87,
88, 89, 90, 91, 93, 101, 102, 109, 114, 116, 119, 134, 135, 136,
137, 138, 139, 140, 145, 146, 147, 148, 150, 152, 153, 154, 156,
157, 159, 160, 161, 164, 171, 174, 176, 178, 179, 182, 184, 186,
188 and/or compound 190.
[0289] In yet a further preferred embodiment all compounds of the
invention are agonists of GHS receptors.
[0290] More preferably, agonists of GHS receptors are compounds
selected from the group consisting of:
[0291] compound 2, 4, 5, 6, 7, 8, 9, 10, 11, 15, 16, 17, 19, 21,
24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 39, 40, 42, 43, 44, 45, 54,
55, 56, 62, 67, 78, 81, 83, 84, 87, 92, 94, 99, 103, 104, 105, 106,
107, 108, 110, 111, 115, 117, 118, 121, 122, 124, 130, 131, 142,
155, 158, 163, 173, 175, 180, 181, 183, 185 and/or compound
187.
[0292] The terms indicated for explanation of the above compounds
of formula (I) always, unless indicated otherwise in the
description or in the claims, have the following meanings:
[0293] The term substituted means that the corresponding radical or
group has one or more substituents. Where a radical has a plurality
of substituents, and a selection of various substituents is
specified, the substituents are selected independently of one
another and need not be identical. The term unsubstituted means
that the corresponding group has no substituent. The term
optionally substituted means that the corresponding group is either
unsubstituted or substituted by one or more substituents. The term
substituted by up to 3 substituents means that the corresponding
radical or group is substituted either by one or by two or three
substituents.
[0294] The term alkyl includes for the purposes of this invention
acyclic saturated hydrocarbons having C1-C12 carbon atoms, which
may be straight-chain or branched. The term alkyl preferably stands
for alkyl chains of 1 to 8, particularly preferably 1 to 6, carbon
atoms. Examples of suitable alkyl radicals are methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl. sec-butyl, tert-butyl,
n-pentyl, tert-pentyl, 2- or 3-methyl-pentyl, n-hexyl, isohexyl,
n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl.
[0295] The term cycloalkyl stands for a saturated or partially
unsaturated non-aromatic cyclic hydrocarbon group/radical,
containing 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl
and tricyclic alkyl, and containing a total of 3 to 20 carbon atoms
forming the rings, preferably 3 to 10, most preferably
(C3-C8)-cycloalkyl. Examples of suitable cycloalkyl radicals are
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl,
cyclooctadienyl.
[0296] The term cycloalkylalkyl refers to a radical in which the
cycloalkyl group is linked via an alkyl group, where the alkyl and
cycloalkyl groups have the meanings defined herein, preferably a
(C3-C8)-cycloalkyl-(C1-C4)-alkyl radical. Examples thereof are
cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl,
cyclohexenylethyl.
[0297] The term alkenyl includes for the purposes of this invention
acyclic unsaturated or partially unsaturated hydrocarbons having
C2-C12 carbon atoms, which may be straight-chain or branched and
contain one or more double bonds. The term alkenyl preferably
stands for alkenyl chains of 2 to 8, particularly preferably 2 to
6, carbon atoms. Examples are vinyl, propenyl, butenyl, pentenyl,
hexenyl, and octadienyl and the like.
[0298] The term alkynyl refers to acyclic unsaturated or partially
unsaturated hydrocarbons having C2-C12 carbon atoms, which may be
straight-chain or branched and contain one or more triple bonds.
The term alkynyl preferably stands for alkynyl chains of 2 to 8,
particularly preferably 2 to 6, carbon atoms. Examples are
propynyl, butynyl, pentynyl, hexynyl.
[0299] The term aryl refers to aromatic hydrocarbon systems having
3 to 14, preferably 5 to 14, carbon atoms, which may also be fused
to further saturated, (partially) unsaturated or aromatic cyclic
systems. Examples of aryl are inter alia phenyl, biphenyl, naphthyl
and anthracenyl, but also indanyl, indenyl, or
1,2,3,4-tetrahydronaphthyl.
[0300] The term heteroaryl refers to a 5-, 6- or 7-membered cyclic
aromatic radical which comprises at least 1, where appropriate also
2, 3, 4 or 5 heteroatoms, preferably nitrogen, oxygen and/or
sulfur, where the heteroatoms are identical or different. The
number of nitrogen atoms is preferably between 0 and 3, and that of
the oxygen and sulfur atoms is between 0 and 1. The term heteroaryl
also includes systems in which the aromatic cycle is part of a bi-
or polycyclic system, such as were the aromatic cycle is fused to
an aryl, cycloalkyl, heteroaryl or heterocyclyl group as defined
herein via any desired and possible ring member of the heteroaryl
radical. Examples of heteroaryl include pyrrolyl, thienyl, furyl,
imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,
pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl,
and isoquinolinyl.
[0301] The terms arylalkyl and heteroarylalkyl refer to radicals in
which the aryl or heteroaryl radical is linked via an alkyl group,
where the alkyl, aryl and heteroaryl groups have the meanings
defined herein. Preferred arylalkyl groups are
phenyl-(C.sub.1-C.sub.4)-alkyl radicals, preferably benzyl or
phenylethyl radicals. Preferred heteroarylalkyl groups are
indolyl-(C.sub.1-C.sub.4)-alkyl radicals, preferably
1H-indole-3-yl-methyl or 2(1H-indole-3-yl)-ethyl.
[0302] The term heterocyclyl refers to a mono- or polycyclic system
of 3 to 14, preferably 5 or 6 to 14 ring atoms which may be
exclusively carbon atoms. However, the cyclic system may also
comprise 1, 2, 3, 4, or 5 heteroatoms, in particular nitrogen,
oxygen and/or sulfur. The cyclic system may be saturated, mono- or
polyunsaturated but may not be aromatic. In the case of a cyclic
system consisting of at least two rings the rings may be fused or
spiro- or otherwise connected. The heterocyclyl radical may be
attached at any carbon or heteroatom which results in the creation
of a stable structure. Examples include pyrrolidinyl,
thiapyrrolidinyl, piperidinyl, piperazinyl, oxapiperazinyl,
oxapiperidinyl and oxadiazolyl.
[0303] The term heterocyclylalkyl refers to radicals in which the
heterocyclyl group is linked via an alkyl group, where the alkyl
and heterocyclyl groups have the meanings defined herein.
[0304] The terms alkylsulfonyl, arylsulfonyl and arylalkylsulfonyl
refer to radicals in which the alkyl, aryl or arylalkyl group is
linked via a --SO.sub.2-- group, where the alkyl, aryl and
arylalkyl groups have the meanings defined herein. Examples are
methylsulfonyl and phenylsulfonyl.
[0305] The term halogen, halogen atom or halogen substituent (Hal-)
refers to one, where appropriate, a plurality of fluorine (F,
fluoro), bromine (Br, bromo), chlorine (Cl, chloro), or iodine (I,
iodo) atoms. The designations dihalogen, trihalogen and perhalogen
refer respectively to two, three and four substituents, where each
substituent can be selected independently from the group consisting
of fluorine, chlorine, bromine and iodine. Halogen preferably means
a fluorine, chlorine or bromine atom.
[0306] The term natural alpha-amino acid side chain for the purpose
of the present invention refers to all side chains of the known 20
proteinogenic alpha-amino acids as well as to side chains of
naturally occurring (i.e. in any biological systems) alpha-amino
acids, such as for instance selenocystein, pyrrolysine, citrulline,
ornithine, homocysteine, N-methylariginine, N-acetyllysine,
gamma-carboxyglutamate, 5-hydroxylysine, 3-methylhistidine and/or
N,N,N,-trimethyllysine. In this connection side chain refers to the
residue that is attached to the alpha-carbon atom, e.g. methyl in
case of an Ala side chain or benzyl in case of a Phe side
chain.
[0307] The term unnatural alpha amino acid side chain for the
purpose of the present invention refers to all side chains of known
alpha-amino acids that are not proteinogenic nor are known to occur
naturally (i.e. in any biological systems). Examples are
norleucine, cyclohexylglycine, 2-naphthylalanine, substituted
alpha-amino acids (e.g. halogen substituted Tyr or Phe) as well as
protected alpha-amino acid side chains, where a protection group
such as Fmoc, Boc, Z, CBZ, Aloc, trityl, acetyl and/or benzyl is
directly attached/reacted to a functionalization (e.g. amino,
hydroxy and/or carboxy residue). In this connection side chain is
referred to as for natural alpha amino acid side chains.
[0308] Above embodiments of radicals R1 to R10 that possess
functionalization (e.g. amino, hydroxy and/or carboxy residues),
such as alkyl-CO--NH.sub.2, -alkyl-CO--OH, -alkyl-NH.sub.2,
-alkyl-NH--C(NH)--NH.sub.2, --CO--C*(R9R10)-NH.sub.2,
--CO--CH.sub.2--C*(R9R10)-NH.sub.2,
--CO--C*(R9R10)-CH.sub.2--NH.sub.2 and/or
2-amino-2-carbonyl-propane (2-amino-isobutyric acid/Aib residue),
may be protected with protection groups as mentioned above. Such
protection group carrying embodiments are regarded as belonging
to/within the scope and spirit of the invention.
[0309] All stereoisomers of the compounds of the invention are
contemplated, either in a mixture or in pure or substantially pure
form. The compounds of the present invention can have asymmetric
centers at any of the carbon atoms including any one of the R
radicals. Consequently, compounds of the invention can exist in the
form of their racemates, in the form of the pure enantiomers and/or
diastereomers or in the form of mixtures of these enantiomers
and/or diastereomers. The mixtures may have any desired mixing
ratio of the stereoisomers. All these different stereochemical
forms and mixtures are within the scope of the present
invention.
[0310] Thus, for example, the compounds of the invention which have
one or more centers of chirality and which occur as racemates or as
diastereomer mixtures can be fractionated by methods known per se
into their optical pure isomers, i.e. enantiomers or diastereomers.
The separation of the compounds of the invention can take place by
column separation on chiral or nonchiral phases or by
recrystallization from an optionally optically active solvent or
with use of an optically active acid or base or by derivatization
with an optically active reagent such as, for example, an optically
active alcohol, and subsequent elimination of the radical.
[0311] Where possible, the compounds of the invention may be in the
form of the tautomers.
[0312] It is likewise possible for the compounds of the invention
to be in the form of any desired prodrugs such as, for example,
esters, carbonates or phosphates, in which cases the actually
biologically active form is released only through metabolism. Any
compound that can be converted in vivo to provide the bioactive
agent (i.e. a compound of the invention) is a prodrug within the
scope and spirit of the invention.
[0313] Various forms of prodrugs are well known in the art and are
described for instance in: [0314] (i) The Practice of Medicinal
Chemistry (Wermuth C G et al., Chapter 31, Academic Press 1996);
[0315] (ii) Design of Prodrugs (editor: Bundgaard H, Elsevier
1985); and [0316] (iii) A Textbook of Drug Design and Development
(Krogsgaard-Larson P and Bundgaard H, eds., Chapter 5: 113-191,
Harwood Academic Publishers 1991).
[0317] Said references are incorporated herein by reference.
[0318] It is further known that chemical substances are converted
in the body into metabolites which may where appropriate likewise
elicit the desired biological effect--in some circumstances even in
more pronounced form.
[0319] Any biologically active compound that was converted in vivo
by metabolism from any compound of the invention is a metabolite
within the scope and spirit of the invention.
[0320] The compounds of the invention can, if they have a
sufficiently basic group such as, for example, a primary, secondary
or tertiary amine, be converted with inorganic and organic acids
into salts. The pharmaceutically acceptable salts of the compounds
of the invention are preferably formed with hydrochloric acid,
hydrobromic acid, iodic acid, sulfuric acid, phosphoric acid,
methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic
acid, acetic acid, sulfoacetic acid, trifluoroacetic acid, oxalic
acid, malonic acid, maleic acid, succinic acid, tartaric acid,
racemic acid, malic acid, embonic acid, mandelic acid, fumaric
acid, lactic acid, citric acid, taurocholic acid, glutaric acid,
stearic acid, glutamic acid or aspartic acid. The salts which are
formed are, inter alia, hydrochlorides, chlorided, hydrobromides,
bromides, iodides, sulfates, phosphates, methanesulfonates,
tosylates, carbonates, bicarbonates, formates, acetates,
sulfoacetates, triflates, oxalates, malonates, maleates,
succinates, tartrates, malates, embonates, mandelates, fumarates,
lactates, citrates, glutarate, stearate, aspartates and glutamates.
The stoichiometry of the salts formed from the compounds of the
invention may moreover be an integral or non-integral multiple of
one.
[0321] The compounds of the invention can, if they contain a
sufficiently acidic group such as, for example, the carboxy,
sulfonic acid, phosphoric acid or a phenolic group, be converted
with inorganic and organic bases into their physiologically
tolerated salts. Examples of suitable inorganic bases are ammonium,
sodium hydroxide, potassium hydroxide, calcium hydroxide, and of
organic bases are ethanolamine, diethanolamine, triethanolamine,
ethylenediamine, t-butylamine, t-octylamine, dehydroabietylamine,
cyclohexylamine, dibenzylethylene-diamine and lysine. The
stoichiometry of the salts formed from the compounds of the
invention can moreover be an integral or non-integral multiple of
one.
[0322] It is likewise possible for the compounds of the invention
to be in the form of their solvates and, in particular, hydrates
which can be obtained for example by crystallization from a solvent
or from aqueous solution. It is moreover possible for one, two,
three or any number of solvate or water molecules to combine with
the compounds of the invention to give solvates and hydrates.
[0323] It is known that chemical substances form solids which exist
in different order states which are referred to as polymorphic
forms or modifications. The various modifications of a polymorphic
substance may differ greatly in their physical properties. The
compounds of the invention can exist in various polymorphic forms,
and certain modifications may moreover be metastable. All these
polymorphic forms of the compounds of the invention are to be
regarded as belonging to the invention.
[0324] The triazole derivatives (compounds of the invention) as
illustrated herein are ghrelin analogue ligands of GHS receptors.
Thus, the aforementioned compounds of the invention are suitable
for the treatment or prophylaxis of physiological and/or
pathophysiological conditions mediated by GHS receptors and/or
physiological and/or pathophysiological conditions which can be
influenced by modulation of these receptors, and thus prevented,
treated and/or alleviated.
[0325] For the purpose of the present invention, the term treatment
is also intended to include prophylactic treatment or
alleviation.
[0326] The term ghrelin analogue ligand or ligand is intended to
refer for the purposes of the present invention to every compound
which binds in any way to a receptor (the receptors in the present
invention being GHS receptors) and induces either activation,
inhibition and/or another conceivable effect at this receptor. The
term ghrelin analogue ligand or ligand thus includes agonists,
antagonists, partial agonists/antagonists, inverse agonists and
other ligands which cause an effect at the receptor which is
similar to the effect of agonists, antagonists, partial
agonists/antagonists or inverse agonist.
[0327] For the purpose of the present invention, the term GHS
receptor antagonist or antagonist of GHS receptors refers to
compounds of the invention that bind to GHS receptors but do not
elicit a proper activation of the receptors as assessed by
recording an increase of intracellular calcium which is
characteristic for activation of G-protein coupled receptors
(GPCRs).
[0328] The ability to properly activate the receptors is assessed
for any compound of the invention by comparing the degree of
activation (increase of intracellular calcium) of GHS-R 1a by the
compound to be tested (at 10.sup.-6 M concentration) to the degree
of activation (increase of intracellular calcium) of GHS-R 1a by
10.sup.-6 M ghrelin (100%) and to the basal level (0%). Such
assessment can be readily performed by the skilled artisan due to
his expert knowledge. The output is a percentage value for each
compound to be tested.
[0329] Any compound of the invention that does not show a degree of
activation (increase of intracellular calcium) of GHS-R 1a of at
least 20% as assessed in accordance with above specification is
regarded as not eliciting a proper activation and therefore as GHS
receptor antagonist. Preferably such compounds do show an
antagonizing effect (counteraction/decrease) on ghrelin and/or
other GHS stimulated intracellular calcium increase, prevent such
stimulation or even act as inverse agonists (an inverse agonists is
an ligand which binds to the same receptor binding-site as an
agonist or antagonist but causes an inhibition of the
basal/constitutive activity of the receptor, in principle an
agonists with a negative intrinsic activity). Such compounds may
furthermore exhibit an inhibitory activity on GH secretion and/or
on other physiological or pathophysiological conditions or effects,
such as food intake or lipogenesis. Their effects may be
dissociated. Thus, they may have no impact at all on GH secretion
while inhibiting other physiological effects. They may even
stimulate other physiological effects.
[0330] For the purpose of the present invention, the term GHS
receptor agonist or agonist of GHS receptors refers to compounds of
the invention that bind to GHS receptors and elicit a proper
activation of the receptor as assessed by recording an increase of
intracellular calcium which is characteristic for activation of
G-protein coupled receptors.
[0331] Any compound of the invention that shows a degree of
activation (increase of intracellular calcium) of GHS-R 1a of at
least 20% as assessed in accordance with above specification is
regarded as eliciting a proper activation and therefore as GHS
receptor agonist. Such compounds may mimic the effects of ghrelin
and/or GHS on GH secretion and for instance food intake or
lipogenesis. Like for antagonists, the effects of agonist compounds
may be dissociated from the GH secretory effect. Such compounds may
even antagonize (counteract/decrease) ghrelin and/or other GHS
stimulated intracellular calcium increase.
[0332] The term GHS receptor or GHS-R is intended to comprise for
the purposes of the present invention receptors that bind at least
one known peptidyl and/or non-peptidyl GHS and/or ghrelin. The term
GHS receptor or GHS-R is also intended to comprise different GHS
binding sites in the various tissues and/or organs as illustrated
herein, that bind at least one known peptidyl and/or non-peptidyl
GHS and/or ghrelin and which are probably not yet characterized
GHS-R subtypes.
[0333] Binding of a given known peptidyl and/or non-peptidyl GHS
and/or ghrelin can be easily verified by the skilled artisan on the
basis of his expert knowledge, e.g. by appropriate binding assays
which represent only routine experimentation.
[0334] Such GHS receptors may be stimulated/activated by ghrelin
(ghrelin responsive) or may not be stimulated/activated by ghrelin
(ghrelin non-responsive)--with regard to both acylated and
non-acylated ghrelin, respectively. Stimulation/activation of such
receptors may cause but does not compulsorily have to elicit GH
production and/or GH secretion and/or increase GH plasma
levels.
[0335] Preferably such GHS receptors are selected from the group
consisting of GHS type 1 receptor, GHS-R 1a, GHS-R 1b, motilin
receptor, motilin receptor 1a, neurotensin receptor, TRH receptor,
GPR38 (FM1), GPR39 (FM2), FM3, GHS binding site, GHS-R subtype,
cardiac GHS-R, mammary GHS-R.
[0336] More preferably, such GHS receptors are selected from the
group consisting of GHS type 1 receptor, GHS-R 1a, GHS-R 1b and
most preferably are GHS-R 1a.
[0337] As discussed herein, GHS receptors (including GHS binding
sites and GHS-R sub-types) are known to be concentrated in the
hypothalamus-pituitary area but also appear to be distributed in
other central and peripheral tissues. Furthermore, they are also
expressed in various tumoral tissues, even in tumoral tissues from
organs that do not express these receptors under physiological
conditions.
[0338] For the purposes of the present invention, all these GHS
receptor (including GHS binding sites and GHS-R subtypes)
expressing organs and/or tissues are intended to be comprised by
the scope of the present invention. Expression of GHS receptors
(including GHS binding sites and GHS-R subtypes) in a given organ
and/or tissue can be easily verified by the skilled artisan on the
basis of his expert knowledge, e.g. by appropriate molecular
biologic assays, such as immunofluorescence or immunoprecipitation
assays, which represent only routine experimentation.
[0339] Preferably, such GHS receptors are located in tissues and/or
organs selected from the group consisting of endocrine tissue,
exocrine tissue, peripheral tissue, adipose/fat tissue, brain,
hypothalamus, thalamus, hippocampus, striatum, cortex, pituitary,
central nervous system, spinal cord, gland, adrenal gland, thyroid
gland, salivary gland, mammary gland, neuron, bowel, intestine,
stomach, heart, liver, pancreas, kidney, bile, gall, bladder,
prostate, spleen, muscle, skeletal muscle, aorta, artery, vein,
immune cell, leukocyte, lymphocyte, T cell, B cell, granulocyte,
monocyte, macrophage, dendritic cell, mast cell, NK cell,
neutrophil, eosinophil, basophil, lymph node, bone, bone marrow,
tonsil, thymus, placenta, testes, ovary, uterus, lung, adipocyte,
tumor/cancer cell, carcinoma cell, prostate cancer cell, thyroid
cancer cell, lung cancer cell, breast cancer cell.
[0340] As illustrated supra, the compounds of the invention are
ghrelin analogue ligands of GHS receptors. They can be administered
to various mammalian species, including human, for the treatment or
prophylaxis of physiological and/or pathophysiological condition in
such mammals.
[0341] For the purpose of the present invention, all mammalian
species are regarded as being comprised. Preferably, such mammals
are selected from the group consisting of human, domestic animals,
cattle, livestock, pets, cow, sheep, pig, goat, horse, pony,
donkey, hinny, mule, hare, rabbit, cat, dog, guinea pig, hamster,
rat, mouse. More preferably, such mammals are human.
[0342] The compounds of the invention being non-peptidic ghrelin
analogue ligands of GHS receptors are surprisingly characterized by
a strong binding affinity to such receptors. Such compounds for
instance may preferably exhibit an IC.sub.50 value of less than
1000 nM for binding to GHS-R 1a. More preferably, such compounds
may exhibit an IC.sub.50 value of less than 500 nM, even more
preferably of less than 300 nM and most preferably of less than 100
nM for binding to GHS-R 1a.
[0343] Due to their surprisingly strong receptor binding, the
compounds of the invention can be advantageously administered at
lower doses compared to other less potent binders while still
achieving equivalent or even superior desired biological effects.
In addition, such a dose reduction may advantageously lead to less
or even no medicinal adverse effects. Further, the high binding
specificity of the compounds of the invention may translate into a
decrease of undesired side effects on its own regardless of the
dose applied.
[0344] Furthermore, the compounds of the invention, being of
non-peptidic nature, are resistant to degradation by enzymes of the
gastrointestinal tract. Hence, they offer the advantage to be given
by oral route. They surprisingly display an improved metabolic
stability and/or an improved bioavailability. Hence, again an
advantageous dose reduction may be achievable which may cause less
or even no side effects.
[0345] The compounds of the invention can either be antagonists or
agonists of GHS receptors as illustrated and defined herein.
[0346] GHS receptor antagonists of the present invention can for
instance be employed for the inhibition of GHS receptors stimulated
by ghrelin and/or other GHS thus decreasing and/or blocking GH
production and/or secretion and/or GH plasma levels. In addition,
such GHS receptor antagonists may also be employed for the
inhibition or prevention of physiological or pathophysiological
effects of ghrelin which are not related to GH production and/or GH
secretion.
[0347] Therefore, GHS receptor antagonists of the present invention
are suitable for the treatment and/or prophylaxis of various
physiological and pathophysiological conditions as disclosed
herein, in particular for the short-, medium- and/or long term
regulation of energy balance, the short-, medium- and/or long term
regulation (stimulation and/or inhibition) of food intake, the
treatment of adipogenesis, adiposity and/or obesity, body weight
gain and/or reduction and the treatment of tumor cell
proliferation.
[0348] In contrast, GHS receptor agonists of the present invention
can for instance be employed for the activation of GHS receptors
and stimulation/increase of GH production and/or GH secretion and
would thus have similar effects or uses as growth hormone itself,
ghrelin and/or known GHS.
[0349] Thus, GHS receptor agonists of the present invention are
suitable for the treatment and/or prophylaxis of various
physiological and pathophysiological conditions as disclosed
herein, in particular for growth retardation, cachexia,
inflammation, inflammatory effects, gastric postoperative ileus,
postoperative ileus and/or gastrectomy (ghrelin replacement
therapy).
[0350] For the purpose of the present invention, all physiological
and/or pathophysiological conditions are intended to be comprised
that are known to be mediated by GHS receptors.
[0351] Preferably, these physiological and/or pathophysiological
conditions are selected from the group consisting of acute fatigue
syndrome and muscle loss following election surgery, adipogenesis,
adiposity, age-related decline of thymic function, age-related
functional decline (ARFD) in the elderly, aging disorder in
companion animals, Alzheimer's disease, anorexia (e.g. associated
with cachexia or aging); anxiety, blood pressure (lowering), body
weight gain/reduction, bone fracture repair (acceleration), bone
remodeling stimulation, cachexia and protein loss reduction due to
chronic illness such as cancer or AIDS, cardiac dysfunctions (e.g.
associated with valvular disease, myocarial infarction, cardiac
hypertrophy or congestive heart failure), cardiomyopathy, cartilage
growth stimulation, catabolic disorders in connection with
pulmonary dysfunction and ventilator dependency, catabolic side
effects of glucocorticoids, catabolic state of aging, central
nervous system disorders (in combination with antidepressants),
chronic dialysis, chronic fatigue syndrome (CFS), cognitive
function improvement (e.g. in dementia, Alzheimer's disease),
complicated fractures (e.g. disctraction osteogenesis),
complications associated with transplantation, congestive heart
failure (alone/in combination with corticotropin releasing factor
antagonists), Crohn's disease and ulcerative colits, Cushing's
syndrome, dementia, depressions, short-, medium- and/or long-term
regulation of energy balance, short-, medium- and/or long-term
regulation of food intake (stimulation and/or inhibition), fraility
(e.g. in elderly humans), gastrectomy (ghrelin replacement
therapy), gastric postoperative ileus, glycemic control
improvement, growth hormone release stimulation in the elderly,
growth hormone replacement in stressed patients, growth promotion
in livestock, growth retardation associated with the Prader-Willi
syndrome and Turner's syndrome, growth retardation in connection
with Crohn's disease, growth retardation, hair/nail growth
maintenance, hip fractures, hunger, hypercortisolism,
hyperinsulinemia including nesidioblastosis, hypothermia, immune
deficiency in individuals with a depressed T4/T8 cell ratio, immune
response improvement to vaccination, immune system stimulation in
companion animals, immune system stimulation, immunosuppression in
immunosuppressed patients, inflammation or inflammatory effects,
inflammatory bowel disease, insulin resistance in the heart,
insulin resistance in type 2 diabetic patients, insulin resistance
including NIDDM, diabetes, diabetes type I, diabetes type II,
intrauterine growth retardation, irritable bowel syndrome,
lipodystrophy (e.g. HIV-induced), metabolic homeostasis
maintenance, milk production increase in livestock, muscle
mass/strength increase, muscle mobility improvement, muscle
strength improvement, muscle strength/function maintenance in
elderly humans, muscular atrophy, musculoskeletal impairment (e.g.
in elderly), Noonan's syndrome, obesity and growth retardation
associated with obesity, osteoblast stimulation,
osteochondrodysplasias, osteoporosis, ovulation induction (adjuvant
treatment), physiological short stature including growth hormone
deficient children, postoperative ileus, protein catabolic response
attenuation after major surgery/trauma, protein kinase B activity
enhancement, psychosocial deprivation, pulmonary dysfunction and
ventilator dependency, pulmonary function improvement, pulsatile
growth hormone release induction, recovery of burn patients and
reducing hospitalization of burn patients (acceleration), renal
failure or insufficiency resulting from growth retardation, renal
homeostasis maintenance in the frail elderly, sarcopenia,
schizophrenia, sensory function maintenance (e.g. hearing, sight,
olefaction and taste), short bowel syndrome, short stature
associated with chronic illness, skeletal dysplasia, skin thickness
maintenance, sleep disorders, sleep quality improvement,
thrombocytopenia, thymic development stimulation, tooth repair or
growth, tumor cell proliferation, ventricular dysfunction or
reperfusion events, wasting in connection with AIDS, wasting in
connection with chronic liver disease, wasting in connection with
chronic obstructive pulmonary disease (COPD), wasting in connection
with multiple sclerosis or other neurodegenerative disorders,
wasting secondary to fractures, wool growth stimulation in sheep,
wound healing (acceleration), wound healing delay. More preferably
these physiological and/or pathophysiological conditions are
selected from the group consisting of growth retardation, cachexia,
short-, medium- and/or long term regulation of energy balance;
short-, medium- and/or long term regulation (stimulation and/or
inhibition) of food intake; adipogenesis, adiposity and/or obesity;
body weight gain and/or reduction; diabetes, diabetes type I,
diabetes type II, tumor cell proliferation; inflammation,
inflammatory effects, gastric postoperative ileus, postoperative
ileus and/or gastrectomy (ghrelin replacement therapy).
[0352] In a further aspect of the present invention, the compounds
of the invention may be used in combination with at least one
additional pharmacologically active substance.
[0353] Such additional pharmacologically active substance may be
other compounds of the present invention and/or other suitable
therapeutic agents useful in the treatment and/or prophylaxis of
the aforementioned physiological and/or pathophysiological
conditions. The additional pharmacologically active substance may
be an antagonist of GHS receptors and/or an agonist of GHS
receptors depending on the purpose of the combined use. Selection
and combination of the additional pharmacologically active
substance(s) can be easily performed by the skilled artisan on the
basis of his expert knowledge and depending on the purpose of the
combined use and physiological and/or pathophysiological conditions
targeted.
[0354] In a preferred embodiment, the compounds of the invention
are used for the treatment and/or prophylaxis of the aforementioned
physiological and/or pathophysiological conditions in the form of a
medicament, where such medicament comprises at least one additional
pharmacologically active substance.
[0355] In another preferred embodiment, the compounds of the
invention are used for the treatment and/or prophylaxis of the
aforementioned physiological and/or pathophysiological conditions
in the form of a medicament, where the medicament is applied before
and/or during and/or after treatment with at least one additional
pharmacologically active substance.
[0356] The above mentioned suitable therapeutic agents include:
GHS, anti-diabetic agents; anti-osteoporosous agents; anti-obesity
agents; anti-inflammatory agents; anti-anxiety agents;
anti-depressants; anti-hypertensive agents; anti-platelet agents;
antithrombotic and thrombolytic agents; cardiac glycosides;
cholesterol/lipid lowering agents; mineralocorticoid receptor
antagonists; phosphodiesterase inhibitors; protein tyrosine kinase
inhibitors; thyroid mimetics (including thyroid receptor
antagonists); anabolic agents; HIV or AIDS therapies; therapies
useful in the treatment of Alzheimer's disease and other cognitive
disorders; therapies useful in the treatment of sleeping disorders;
anti-proliferative agents; anti-tumor agents; anti-ulcer and
gastroesopheageal reflux disease agents; progestin receptor
agonists (PRA); estrogen; testosterone; a selective estrogen
receptor modulator; a selective androgen receptor modulator;
parathyroid hormone; and/or bisphosphonate, and preferably, a
suitable therapeutic agents is selected of the group consisting of
this agents.
[0357] Examples of suitable GHS for use in combination with the
compounds of the present invention include GHRP-6, GHRP-1 as
described in U.S. Pat. No. 4,411,890; and publications WO 89/07110
and WO 89/07111 and B-HT920 or growth hormone releasing factor and
its analogs or growth hormone and its analogs or somatomedins
including IGF-1 and IGF-2 as well as GHS described in WO
01/96300.
[0358] Examples of suitable anti-diabetic agents for use in
combination with the compounds of the present invention include
biguanides (e.g. metformin), glucosidase inhibitors (e.g.
acarbose), insulins (including insulin secretagogues or insulin
sensitizers), meglitinides (e.g. repaglinide), sulfonylureas (e.g.,
glimepiride, glyburide and glipizide), biguanide/glyburide
combinations (e.g., glucovance), thiozolidinediones (e.g.
troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists,
PPAR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2
inhibitors, inhibitors of fatty acid binding protein (aP2) such as
those disclosed in U.S. Pat. No. 6,548,529, glucagon-like peptide-1
(GLP-1), and dipeptidyl peptidase IV (DP4) inhibitors.
[0359] Examples of suitable anti-osteoporosous agents for use in
combination with the compounds of the present invention include
alendronate, risedronate, raloxifene, calcitonin, non-steroidal
progestin receptor agonists, RANK ligand agonists, calcium sensing
receptor antagonists, TRAP inhibitors, selective estrogen receptor
modulators (SERM), estrogen and AP-1 inhibitors.
[0360] Examples of suitable anti-obesity agents for use in
combination with the compounds of the present invention include
endocannabinoid receptor antagonists, e.g. CB1 receptor antagonists
such as rimonabant (1H-Pyrazole-3-carboxamide,
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-,
monohydrochloride; CAS Registry Number: 158681-13-1; SR-141716A;
U.S. Pat. No. 5,624,941), aP2 inhibitors such as those disclosed in
U.S. Pat. No. 6,548,529, PPAR gamma antagonists, PPAR delta
agonists, and orlistat.
[0361] Examples of suitable antinflammatory agents for use in
combination with the compounds of the present invention include
prednisone, dexamethasone, Enbrel, cyclooxygenase inhibitors (i.e.,
COX-1 and/or COX-2 inhibitors such as NSAIDs, aspirin,
indomethacin, ibuprofen, piroxicam, Naproxen, Celebrex, Vioxx),
CTLA4-Ig agonists/antagonists, CD40 ligand antagonists, integrin
antagonists, alpha4 beta7 integrin antagonists, cell adhesion
inhibitors, interferon gamma antagonists, ICAM-1, tumor necrosis
factor (TNF) antagonists (e.g., infliximab, OR1384), prostaglandin
synthesis inhibitors, budesonide, clofazimine, CNI-1493, CD4
antagonists (e.g., priliximab), p38 mitogen-activated protein
kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKK
inhibitors, and therapies for the treatment of irritable bowel
syndrome (e.g., zelmac and Maxi-K openers such as those disclosed
in U.S. Pat. No. 6,184,231).
[0362] Examples of suitable anti-anxiety agents for use in
combination with the compounds of the present invention include
diazepam, lorazepam, buspirone, oxazepam, and hydroxyzine
pamoate.
[0363] Examples of suitable anti-depressants for use in combination
with the compounds of the present invention include citalopram,
fluoxetine, nefazodone, sertraline, and paroxetine.
[0364] Examples of suitable anti-hypertensive agents for use in
combination with the compounds of the present invention include
beta adrenergic blockers, calcium channel blockers (L-type and
T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and
mybefradii), diruetics (e.g., chlorothiazide, hydrochlorothiazide,
flumethiazide, hydroflumethiazide, bendroflumethiazide,
methylchlorothiazide, trichloromethiazide, polythiazide,
benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,
furosemide, musolimine, bumetamide, triamtrenene, amiloride,
spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril,
zofenopril, fosinopril, enalapril, ceranopril, cilazopril,
delapril, pentopril, quinapril, ramipril, lisinopril), AT-1
receptor antagonists (e.g., losartan, irbesartan, valsartan), ET
receptor antagonists (e.g., sitaxsentan, atrsentan and compounds
disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265, Dual ET/All
antagonist (e.g., compounds disclosed in WO 00/01389), neutral
endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual
NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and
nitrates.
[0365] Examples of suitable anti-platelet agents for use in
combination with the compounds of the present invention include
GPIIb/IIIa blockers (e.g., abciximab, eptifibatide, tirofiban),
P2Y12 antagonists (e.g., clopidogrel, ticlopidine, CS-747),
thromboxane receptor antagonists (e.g., ifetroban), aspirin, and
PDE-III inhibitors (e.g., dipyridamole) with or without
aspirin.
[0366] Examples of suitable cardiac glycosides for use in
combination with the compounds of the present invention include
digitalis and ouabain.
[0367] Examples of suitable cholesterol/lipid lowering agents for
use in combination with the compounds of the present invention
include HMG-CoA reductase inhibitors [e.g., pravastatin lovastatin,
atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, or
nisvastatin or nisbastatin] and ZD-4522 (a.k.a. rosuvastatin, or
atavastatin or visastatin)), squalene synthetase inhibitors,
fibrates, bile acid sequestrants, ACAT inhibitors, MTP inhibitors,
lipooxygenase inhibitors, choesterol absorption inhibitors, and
cholesterol ester transfer protein inhibitors (e.g.,
CP-529414).
[0368] Examples of suitable mineralocorticoid receptor antagonists
for use in combination with the compounds of the present invention
include spironolactone and eplerinone.
[0369] Examples of suitable phosphodiesterase inhibitiors for use
in combination with the compounds of the present invention include
PDE III inhibitors such as cilostazol, and PDE V inhibitors such as
sildenafil.
[0370] Examples of suitable thyroid mimetics for use in combination
with the compounds of the present invention include thyrotropin,
polythyroid, KB-130015, and dronedarone.
[0371] Examples of suitable anabolic agents for use in combination
with the compounds of the present invention include testosterone
and SARMs.
[0372] Examples of suitable HIV or AIDS therapies for use in
combination with the compounds of the present invention include
indinavir sulfate, saquinavir, saquinavir mesylate, amprenavir,
ritonavir, lopinavir, ritonavir/lopinavir combinations, lamivudine,
zidovudine, lamivudine/zidovudine combinations, zalcitabine,
didanosine, stavudine, and megestrol acetate.
[0373] Examples of suitable therapies for treatment of Alzheimer's
disease and cognitive disorders for use in combination with the
compounds of the present invention include donepezil, tacrine,
revastigmine, 5HT6, gamma secretase inhibitors, beta secretase
inhibitors, SK channel blockers, Maxi-K blockers, and KCNQs
blockers.
[0374] Examples of suitable therapies for treatment of sleeping
disorders for use in combination with the compounds of the present
invention include melatonin analogs, melatonin receptor
antagonists, ML1B agonists, and GABA/NMDA receptor antagonists.
[0375] Examples of suitable anti-proliferative agents for use in
combination with the compounds of the present invention include
cyclosporin A, taxol, FK 506, and adriamycin.
[0376] Examples of suitable anti-tumor agents for use in
combination with the compounds of the present invention include
taxol, adriamycin, epothilones, cisplatin and carboplatin.
[0377] Examples of suitable a selective estrogen receptor modulator
for use in combination with the compounds of the present invention
include tamoxifen and raloxifene.
[0378] Examples of suitable a selective androgen receptor modulator
for use in combination with the compounds of the present invention
include such disclosed in Edwards, J. P. et al., Bio. Med. Chem.
Let., 9, 1003-1008 (1999) and Hamann, L. G. et al., J. Med. Chem.,
12, 210-212 (1999).
[0379] Examples of suitable a bisphosphonate for use in combination
with the compounds of the present invention include MK-217
(alendronate).
[0380] The above other therapeutic agents, when employed in
combination with the compounds of the present invention, may be
used, for example, in those amounts indicated in the Physicians'
Desk Reference (PDR) or as otherwise determined by one of ordinary
skill in the art.
[0381] In a preferred embodiment, the compounds of the invention
are used for the treatment and/or prophylaxis of the aforementioned
physiological and/or pathophysiological conditions in the form of a
medicament, where such medicament comprises as additional
pharmacologically active substance an endocannabinoid receptor
antagonist, preferably a CB1 receptor antagonist, most preferably
rimonabant (1H-Pyrazole-3-carboxamide,
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-,
monohydrochloride; CAS Registry Number: 158681-13-1; SR-141716A;
U.S. Pat. No. 5,624,941) and as compound of the invention a GHS-R
antagonist.
[0382] In another preferred embodiment, the compounds of the
invention are used for the treatment and/or prophylaxis of the
aforementioned physiological and/or pathophysiological conditions
in the form of a medicament, where the medicament is applied before
and/or during and/or after treatment with at least one additional
pharmacologically active substance, where such additional
pharmacologically active substance is an endocannabinoid receptor
antagonist, preferably a CB1 receptor antagonist, most preferably
rimonabant (1H-Pyrazole-3-carboxamide,
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-,
monohydrochloride; CAS Registry Number: 158681-13-1; SR-141716A;
U.S. Pat. No. 5,624,941) and the compound of the invention is a
GHS-R antagonist.
[0383] The compounds of the present invention can be administered
in a known manner. The route of administration may thereby be any
route which effectively transports the active compound to the
appropriate or desired site of action, for example orally or
non-orally, in particular topically, transdermally, pulmonary,
rectally, intravaginally, nasally or parenteral or by implantation.
Oral administration is preferred.
[0384] The compounds of the invention are converted into a form
which can be administered and are mixed where appropriate with
pharmaceutically acceptable carriers or diluents. Suitable
excipients and carriers are described for example in Ullman's
Encyclopedia of Technical Chemistry, Vol. 4, (1953), 1-39; Journal
of Pharmaceutical Sciences, Vol. 52 (1963), 918 et seq.; H. v.
Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie and angrenzende
Gebiete; Pharm. Ind. 2, 1961, 72 et seq.; Dr. H. P. Fiedler,
Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende
Gebiete, Cantor K G, Aulendorf in Wurttemberg, 1971.
[0385] Oral administration can take place for example in solid form
as tablet, capsule, gel capsule, coated tablet, granulation or
powder, but also in the form of a drinkable solution. The compounds
of the invention can for oral administration be combined with known
and ordinarily used, physiologically tolerated excipients and
carriers such as, for example, gum arabic, talc, starch, sugars
such as, for example, mannitol, methylcellulose, lactose, gelatin,
surface-active agents, magnesium stearate, cyclodextrins, aqueous
or nonaqueous carriers, diluents, dispersants, emulsifiers,
lubricants, preservatives and flavorings (e.g. essential oils). The
compounds of the invention can also be dispersed in a
microparticulate, e.g. nanoparticulate, composition.
[0386] Non-oral administration can take place for example by
intravenous, subcutaneous, intramuscular injection of sterile
aqueous or oily solutions, suspensions or emulsions, by means of
implants or by ointments, creams or suppositories. Administration
as sustained release form is also possible where appropriate.
Implants may comprise inert materials, e.g. biodegradable polymers
or synthetic silicones such as, for example, silicone rubber.
Intravaginal administration is possible for example by means of
vaginal rings. Intrauterine administration is possible for example
by means of diaphragms or other suitable intrauterine devices.
Transdermal administration is additionally provided, in particular
by means of a formulation suitable for this purpose and/or suitable
means such as, for example, patches.
[0387] The dosage may vary within a wide range depending on type
and/or severity of the physiological and/or pathophysiological
condition, the mode of administration, the age, gender, bodyweight
and sensitivity of the subject to be treated. It is within the
ability of a skilled worker to determine a pharmacologically
effective amount of a compound of the invention and/or additional
pharmacologically active substance. Administration can take place
in a single dose or a plurality of separate dosages.
[0388] A suitable unit dose is, for example, from 0.001 mg to 100
mg of the active ingredient, i.e. at least one compound of the
invention and, where appropriate, at least one additional
pharmacologically active substance, per kg of a patient's
bodyweight.
[0389] In another aspect, the present invention relates to a
pharmaceutical composition comprising a pharmacologically active
amount of at least one triazole compound selected from the group
consisting of: compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,
31, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,
49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65,
66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,
83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,
100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112,
113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 124, 125, 126,
128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140,
141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 152, 153, 154,
155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167,
168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180,
181, 182, 183, 184, 185, 186, 187, 188, 189 and/or compound
190.
[0390] In a further aspect, such a pharmaceutical composition may
additionally comprise at least one pharmaceutically acceptable
carrier and/or excipient and/or may comprise at least one further
pharmacologically active substance.
[0391] In a preferred embodiment, such further pharmacologically
active substance is an endocannabinoid receptor antagonist,
preferably a CB1 receptor antagonist, most preferably rimonabant
[1H-Pyrazole-3-carboxamide,
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-,
monohydrochloride].
[0392] Concerning the pharmaceutical compositions of the invention,
at least one of the triazole compounds as listed above is present
in a pharmacologically effective amount, preferably in a unit dose,
e.g. the aforementioned unit dose, specifically and preferably in
an administration form which makes oral administration possible.
Furthermore, reference may be made to that already said in
connection with the possible uses and administrations of the
compounds of the invention.
General Syntheses Schemes
[0393] The compounds of the present invention may be prepared
according to the following general synthetic schemes, as well as
relevant published literature procedures that are known to the one
skilled in the art (e.g. WO 00/54729 and cited references
therein).
[0394] Exemplary reagents and procedures for these reactions appear
hereinafter and in the working examples. Unless otherwise
specified, the various substituents (radicals) of the compounds
have the meanings as defined for formula (I) herein.
[0395] Amide bond formation (peptide coupling) is conducted under
standard peptide coupling procedures known in the prior art.
Optimally, the reaction is conducted in a solvent such as
dichloromethane (DCM) at room temperature using
benzotriazol-1-yl-oxytris(dimethylamino)phosphonium-hexafluoorophosphate
(BOP) (Castro B et al. Tetrahedron Lett. 1975, 14:1219-1222) and a
base, for example N-methyl-morpholine or diisopropylethylamine.
[0396] Thionation of the formed amide was performed using
Lawesson's reagent (Pons J F et al., Tetrahedron Lett. 2000, 41:
4965-4968).
[0397] Cyclisation: the obtained thioamide was then submitted to
the conditions reported by Hitosuyanagi et al. (Hitotsuyanagi Y. et
al., J. Org. Chem. 2002, 67: 3266-3271) which were slightly
modified (5 eq. of hydrazide and 1.1 eq. of mercury (II) acetate in
acetonitrile). Cyclisation into triazoles was generally achieved
within three hours. When the hydrazide was not commercially
available, it was prepared by known methods from its acid or methyl
ester precursors.
[0398] Deprotection of the tert-butyloxycarbonyl group (Boc) was
performed at room temperature in acidic medium as usually
described. ##STR188##
[0399] For R5=--CO-alkyl, --CO-cycloalkyl, --CO-cycloalkylalkyl,
--CO-aryl, --CO-arylalkyl, --CO-heteroaryl, --CO-heteroarylalkyl,
--CO-heterocyclyl, --CO-heterocyclylalkyl,
--CO--C*(R9R10)-NH.sub.2, --CO--CH.sub.2--C*(R9R10)-NH.sub.2,
--CO--C*(R9R10)-CH.sub.2--NH.sub.2 (R): ##STR189##
[0400] For R5=alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl (R):
##STR190##
[0401] For R5=alkyl-SO.sub.2--, aryl-SO.sub.2--,
arylalkyl-SO.sub.2-- (R=alkyl, aryl, arylalkyl): ##STR191##
[0402] The compounds of the invention, especially compounds 1 to
190 were named from the drawn formula using the Chem Draw Ultra 8
software (CambridgeSoft Corporation, Cambridge, USA).
[0403] The contents of all cited references and patents are hereby
incorporated by reference. The invention is explained in more
detail by means of the following examples without, however, being
restricted thereto.
EXAMPLES
I) Synthesis of Compounds of the Invention
Example 1
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tri-
azol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide
(Compound 1)
[0404] Compound 1 was obtained from Boc-(D)-Trp (10 mmoles),
(2,4-dimethoxyphenyl)-methanamine, 3-(1H-indol-3-yl)propane
hydrazide and Boc-2-amino-2-methylpropanoic acid according to the
general synthetic schemes with a total yield after purification by
HPLC of 35%.
[0405] .sup.1H NMR (400 MHz, 300.degree. K, DMSO-d.sup.6):
[0406] .delta. 1.32 (3H, s, CH.sub.3 Aib), 1.36 (3H, s, CH.sub.3
Aib), 2.93 (2H, m, CH.sub.2--CH.sub.2-indole), 2.97 (2H, m,
CH.sub.2--CH.sub.2-indole), 3.31 (1H, dd, J=14.5, J=6.1, 1H C.sub.2
.beta.Trp), 3.38 (1H, dd, J=14.5, J=9.1, 1H C.sub.2 .beta.Trp),
3.66 (3H, s, o-OCH.sub.3), 3.72 (3H, s, p-OCH.sub.3), 4.93 (1H, d,
J=16.9, 1H C.sub.2 o,p-dimethoxybenzyl), 5.10 (1H, d, J=16.9, 1H
C.sub.2 o,p-dimethoxybenzyl), 5.23 (1H, m, C.alpha.H Trp), 6.31
(1H, dd, J=8.5, J=1.7, H.sub.5 o,p-dimethoxybenzyl), 6.45 (1H, d,
J=8.5, H.sub.6 o,p-dimethoxybenzyl), 6.59 (1H, d, J=1.7, H.sub.3
o,p-dimethoxybenzyl), 6.88 (1H, t, J=7.5, H.sub.5 Trp), 6.94 (1H,
t, J=7.5, H.sub.5 indole), 7.04 (1H, t, H.sub.6 Trp), 7.06 (1H, t,
H.sub.6 indole), 7.08 (1H, s, H.sub.2 indole), 7.11 (1H, s, H.sub.2
Trp), 7.18 (1H, d, J=7.9, H.sub.4 Trp), 7.33 (3H, H.sub.4, H.sub.7
indole, H.sub.7 Trp), 8.05 (2H, s, NH.sub.2 Aib), 8.95 (1H, d,
J=7.9, NH Trp), 10.80 (1H, s, NH indole), 10.82 (1H, s, NH indole
Trp).
[0407] .sup.13C NMR (400 MHz, DMSO-d.sup.6):
[0408] .delta. 22.4 (CH.sub.2--CH.sub.2 indole), 23.2 (CH.sub.3
Aib), 23.3 (CH.sub.3 Aib), 25.4 (CH.sub.2--CH.sub.2 indole), 28.7
(C.beta. Trp), 41.3 (CH.sub.2-o,p-dimethoxybenzyl), 45.3 (C.alpha.
Trp), 55.2 (p-OCH.sub.3), 55.4 (o-OCH.sub.3), 56.3 (Cq Aib), 98.6
(C.sub.3 o,p-dimethoxybenzyl), 104.7 (C.sub.5 o,p-dimethoxybenzyl),
109.5 (C.sub.3 Trp), 111.3 (C.sub.7 Trp, C.sub.7 indole), 112.9
(C.sub.3 indole), 115.2 (C.sub.1 o,p-dimethoxybenzyl), 117.8
(C.sub.4 indole), 117.9 (C.sub.4 Trp), 118.2 (C.sub.5 Trp, C.sub.5
indole), 120.9 (C.sub.6 Trp, C.sub.6 indole), 122.4 (C.sub.2
indole), 124.3 (C.sub.2 Trp), 126.8 (C.sub.9 Indole), 126.9
(C.sub.9 Trp), 127.5 (C.sub.6 o,p-dimethoxybenzyl), 136.0 (C.sub.8
Trp), 136.2 (C.sub.8 indole), 154.6 (2Cq triazole), 157.3 (C.sub.2
o,p-dimethoxybenzyl), 160.4 (C.sub.4 o,p-dimethoxybenzyl), 171.3
(CO Aib).
[0409] ESI-MS: found: m/z 606.3 [M+H].sup.+/calculated: 604.3
g/mol
Example 2
(R)--N-(1-(5-benzyl-4-(naphthalen-1-ylmethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 4)
[0410] Compound 4 was obtained from Boc-(D)-Trp (10 mmoles),
naphthalen-1-yl-methanamine, 2-phenylacetohydrazide and
Boc-2-amino-2-methylpropanoic acid according to the general
synthetic schemes with a total yield after purification by HPLC of
42%.
[0411] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0412] .delta.(ppm) 1.18 (3H, s, CH.sub.3 Aib), 1.24 (3H, s,
CH.sub.3 Aib), 3.17 (1H, dd, J=14 Hz and 5 Hz, CH.sub.2 .beta.Trp),
3.36 (1H, dd, J=14 and 9 Hz, CH.sub.2 .beta.Trp), 4.05 (2H, m,
CH.sub.2-benzyl), 4.90 (1H, m, CH .alpha.Trp), 5.65 (1H, d, J=18
Hz, CH.sub.2-naphtyl), 5.81 (1H, d, J=18 Hz, CH.sub.2-naphtyl),
6.12 (1H, d, J.sub.o=7 Hz, H.sub.2 naphtyl), 6.38 (1H, t, J.sub.o=7
Hz, H.sub.5 Trp), 6.47 (1H, d, J.sub.o=8 Hz, H.sub.4 Trp), 6.85
(1H, t, J.sub.o=8 Hz, H.sub.6 Trp), 7.03 (1H, d, J.sub.m=2 Hz,
H.sub.2 Trp), 7.05-7.12 (5H, m, CHar benzyl), 7.15 (1H, d,
J.sub.o=8 Hz, H.sub.7 Trp), 7.19 (1H, d, J.sub.o=8 Hz, H.sub.3
naphtyl), 7.58 (2H, m, H.sub.6 and H.sub.7 naphtyl), 7.81 (1H, d,
J.sub.o=8 Hz, H.sub.4 naphtyl), 7.89-8.01 (5H, m, NH.sub.2 Aib,
H.sub.5 and H.sub.8 naphtyl), 8.92 (1H, d, J=8 Hz, NH amide), 10.73
(1H, s, NH indole Trp).
[0413] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0414] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.6 (CH.sub.3 Aib), 29.2
(CH.sub.2 .beta.Trp), 30.5 (CH.sub.2-benzyl), 44.0
(CH.sub.2-naphtyl), 45.6 (CH .alpha.Trp), 56.6 (Cq Aib), 109.7
(C.sub.3 Trp), 111.7 (C.sub.7 Trp), 117.9 (C.sub.4 Trp), 118.4
(C.sub.5 Trp), 121.1 (C.sub.6 Trp), 122.1 (C.sub.2 naphtyl), 122.8
(C.sub.8 naphtyl), 124.9 (C.sub.2 Trp), 125.7 (C.sub.3 naphtyl),
126.7 (C.sub.6 naphtyl), 126.9 (C.sub.9 Trp), 127.0 (C.sub.7
naphtyl), 128.2 (C.sub.4 benzyl), 128.7-129.1 (C.sub.2, C.sub.3,
C.sub.5 and C.sub.6 benzyl, C.sub.4 and C.sub.5 naphtyl), 129.9
(C.sub.9 naphtyl), 131.5 (C.sub.1 naphtyl), 133.5 (C.sub.10
naphtyl), 136.2 (C.sub.1 benzyl), 136.4 (C.sub.8 Trp), 154.2 (Cq
triazole), 155.7 (Cq triazole), 171.9 (CO Aib).
[0415] ESI-MS: found: m/z 543.4 [M+H].sup.+/calculated: 542.2
g/mol
Example 3
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(naphthalen-1-ylmethyl)-4H-1,2,4-t-
riazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide
(Compound 5)
[0416] Compound 5 was obtained from Boc-(D)-Trp (10 mmoles),
naphthalen-1-yl-methanamine, 3-(1H-indol-3-yl)propane hydrazide and
Boc-2-amino-2-methylpropanoic acid according to the general
synthetic schemes with a total yield after purification by HPLC of
33%.
[0417] .sup.1H NMR (400 MHz, DMSO-d.sup.6, 300.degree. K):
[0418] .delta.(ppm) 1.25 (3H, s, CH.sub.3 Aib), 1.28 (3H, s,
CH.sub.3 Aib), 2.93 (2H, m, CH.sub.2--CH.sub.2-indole), 3.01 (2H,
m, CH.sub.2--CH.sub.2-indole), 3.30 (1H, dd, .sup.3J=14.3 and 5.8
Hz, CH.sub.2 .beta.Trp), 3.40 (1H, dd, .sup.3J=14.3 and 8.8 Hz,
CH.sub.2 .beta.Trp), 5.03 (1H, m, CH .alpha.Trp), 5.62 (1H, d,
J=18.0 Hz, CH.sub.2-naphtyl), 5.76 (1H, J=18.0 Hz,
CH.sub.2-naphtyl), 3.36 (1H, d, J.sub.o=7.2 Hz, H.sub.2 naphtyl),
6.51 (1H, t, J.sub.o=7.4 Hz, H.sub.5 Trp), 6.72 (1H, d, J.sub.o=7.9
Hz, H.sub.4 Trp), 6.76 (1H, t, J.sub.o=7.5 Hz, H.sub.5 indole),
6.92 (1H, t, J.sub.o=7.5 Hz, H.sub.6 Trp), 7.0 (1H, t, J.sub.o=7.5
Hz, H.sub.6 indole), 7.02 (1H, d, J=2.0 Hz, H.sub.2 indole), 7.09
(1H, d, J=2.0 Hz, H.sub.2 Trp), 7.13 (1H, d, J.sub.o=7.9 Hz,
H.sub.4 indole), 7.26 (1H, J.sub.o=7.9 Hz, H.sub.7 Trp), 7.27 (1H,
t, J.sub.o=8.2 Hz, H.sub.3 naphtyl), 7.29 (1H, d, H.sub.7 indole),
7.58-7.64 (2, m, H.sub.6 and H.sub.7 naphtyl), 7.88 (1H, d,
J.sub.o=8.2 Hz, H.sub.4 naphtyl), 7.93 (1H, d, J.sub.o=7.9 Hz,
H.sub.8 naphtyl), 7.98 (3H, brs, NH.sub.2 Aib), 8.03 (1H, d,
J.sub.o=8.2 Hz, H.sub.5 naphtyl), 8.96 (1H, d, J.sub.o=7.9 Hz, NH
Trp), 10.75 (1H, brs, NH indole), 10.77 (1H, brs, NH indole
Trp).
[0419] .sup.13C NMR (100 MHz, DMSO-d.sup.6, 300.degree. K):
[0420] .delta.(ppm) 22.6 (CH.sub.2--CH.sub.2-indole), 23.1
(CH.sub.3 Aib), 23.2 (CH.sub.3 Aib), 25.3
(CH.sub.2--CH.sub.2-indole), 28.8 (CH.sub.2 .beta.Trp), 43.3
(CH.sub.2-naphtyl), 45.3 (CH .alpha.Trp), 56.2 (Cq Aib), 109.4
(C.sub.3 Trp), 111.2 (C.sub.7 indole and C.sub.7 Trp), 112.9
(C.sub.3 indole), 117.5 (C.sub.4 Trp), 117.8 (C.sub.4 indole),
118.0 (C.sub.5 Trp), 118.1 (C.sub.5 indole), 120.7 (C.sub.6 Trp),
120.8 (C.sub.6 indole), 121.6 (C.sub.2 naphtyl), 122.5 (C.sub.2
indole and C.sub.8 naphtyl), 124.4 (C.sub.2 Trp), 125.4 (C.sub.3
naphtyl), 126.3 (C.sub.6 naphtyl), 126.6 (C.sub.9 indole, C.sub.9
Trp and C.sub.7 naphtyl), 127.9 (C.sub.4 naphtyl), 128.6 (C.sub.5
naphtyl), 129.5 (C.sub.9 naphtyl), 131.4 (C.sub.1 naphtyl), 133.1
(C.sub.10 naphtyl), 135.9 (C.sub.8 Trp), 136.1 (C.sub.8 indole),
154.7 (2 Cq triazole), 171.4 (CO Aib).
[0421] ESI-MS: found: m/z 596.4 [M+H].sup.+/calculated: 595.3
g/mol
Example 4
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3-methoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide
(Compound 6)
[0422] Compound 6 was obtained from Boc-(D)-Trp (10 mmoles),
(3-methoxyphenyl)-methanamine, 3-(1H-indol-3-yl)propane hydrazide
and Boc-2-amino-2-methylpropanoic acid according to the general
synthetic schemes with a total yield after purification by HPLC of
25%.
[0423] .sup.1H NMR (400 MHz, DMSO-d.sup.6):
[0424] .delta.(ppm) 1.28 (3H, s, CH.sub.3 Aib), 1.30 (3H, s,
CH.sub.3 Aib), 2.92 (2H, m, CH.sub.2--CH.sub.2-indole), 2.98 (2H,
m, CH.sub.2--CH.sub.2-indole), 3.33 (1H, dd, J=14.5, J=6.2, 1H
C.sub.2 .beta.Trp), 3.40 (1H, dd, J=14.5, J=8.8, 1H C.sub.2
.beta.Trp), 3.66 (3H, s, OCH.sub.3), 5.09 (2H, m, CH.sub.2
m-methoxybenzyl), 5.22 (1H, m, C.alpha.H Trp), 6.38 (1H, d, J=7.5,
H.sub.6 m-methoxybenzyl), 6.59 (1H, s, H.sub.2 m-methoxybenzyl),
6.86 (1H, t, H.sub.5 Trp), 6.87 (1H, d, H.sub.4 m-methoxybenzyl),
6.92 (1H, t, J=7.5, H.sub.5 indole), 7.03 (1H, t, J=7.9, H.sub.6
Trp), 7.05 (1H, t, H.sub.6 indole), 7.07 (1H, s, H.sub.2 indole),
7.11 (1H, s, H.sub.2 Trp), 7.18 (1H, t, H.sub.5 m-methoxybenzyl),
7.19 (1H, d, H.sub.4 Trp), 7.31 (1H, H.sub.4 indole), 7.32 (2H,
H.sub.7 Trp, H.sub.7 indole), 8.00 (2H, s, NH.sub.2 Aib), 8.96 (1H,
d, J=8.1, NH Trp), 10.78 (1H, s, NH indole), 10.80 (1H, s, NH
indole Trp).
[0425] .sup.13C NMR (400 MHz, DMSO-d.sup.6):
[0426] .delta.(ppm) 22.4 (CH.sub.2--CH.sub.2 indole), 23.1
(CH.sub.3 Aib), 23.3 (CH.sub.3 Aib), 25.4 (CH.sub.2--CH.sub.2
indole), 28.7 (C.beta. Trp), 45.3 (CH.sub.2 m-methoxybenzyl), 45.4
(C.alpha. Trp), 55.0 (OCH.sub.3), 56.3 (Cq Aib), 109.5 (C.sub.3
Trp), 111.3 (C.sub.7 Trp, C.sub.7 indole), 112.0 (C.sub.2
m-methoxybenzyl), 113.0 (C.sub.4 m-methoxybenzyl, C.sub.3 indole),
117.8 (C.sub.4 Trp, C.sub.6 m-methoxybenzyl), 118.0 (C.sub.4
indole), 118.2 (C.sub.5 indole), 118.3 (C.sub.5 Trp), 120.8
(C.sub.6 indole), 120.9 (C.sub.6 Trp), 122.4 (C.sub.2 indole),
124.3 (C.sub.2 Trp), 126.7 (C.sub.9 indole), 126.9 (C.sub.9 Trp),
130.0 (C.sub.5 m-methoxybenzyl), 136.0 (C.sub.8 indole), 136.1
(C.sub.8 Trp), 137.2 (C.sub.1 m-methoxybenzyl), 154.3 (2Cq
triazole), 159.6 (C.sub.3 m-methoxybenzyl), 171.4 (CO Aib).
[0427] ESI-MS: found: m/z 576.6 [M+H].sup.+/calculated: 575.3
g/mol
Example 5
(R)--N-(1-(4-(3-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 7)
[0428] Compound 7 was obtained from Boc-(D)-Trp (10 mmoles),
(3-methoxyphenyl)-methanamine, 2-phenylacetohydrazide and
Boc-2-amino-2-methylpropanoic acid according to the general
synthetic schemes with a total yield after purification by HPLC of
30%.
[0429] .sup.1H NMR (400 MHz, DMSO-d.sup.6):
[0430] .delta.(ppm) 1.25 (3H, s, CH.sub.3 Aib), 1.29 (3H, s,
CH.sub.3 Aib), 3.24 (1H, dd, J=14.3, J=5.8, 1H CH.sub.2 .beta.Trp),
3.38 (1H, dd, J=14.3, J=9.1, 1H C.sub.2 .beta.Trp), 3.61 (3H, s,
m-OCH.sub.3), 4.04 (2H, m, CH.sub.2 benzyl), 5.07 (1H, d, J=17.4,
1H C.sub.2 m-methoxybenzyl), 5.13 (1H, d, J=17.4, 1H C.sub.2
m-methoxybenzyl), 5.14 (1H, m, C.alpha.H Trp), 6.32 (1H, d, J=7.8,
H.sub.6 m-methoxybenzyl), 6.40 (1H, m, H.sub.2 m-methoxybenzyl),
6.82 (1H, t, H.sub.5 Trp), 6.83 (1H, d, J=7.8, H.sub.4
m-methoxybenzyl), 7.01 (1H, t, J=8.2, H.sub.6 Trp), 7.04 (1H, d,
J=8.2, H.sub.4 Trp), 7.06 (1H, d, J=2.0, H.sub.2 Trp), 7.12 (2H, m,
H.sub.2, H.sub.6 Benzyl), 7.13 (1H, t, J=7.9, H.sub.5
m-methoxybenzyl), 7.20 (1H, m, H.sub.4 benzyl), 7.24 (2H, m,
H.sub.3, H.sub.5 benzyl), 7.29 (1H, d, J=8.2, H.sub.7 Trp), 7.99
(2H, s, NH.sub.2 Aib), 8.92 (1H, d, J=8.2, NH Trp), 10.77 (1H, s,
NH indole Trp).
[0431] .sup.13C NMR (400 MHz, DMSO-d.sup.6):
[0432] .delta.(ppm) 23.0 (CH.sub.3 Aib), 23.3 (CH.sub.3 Aib), 28.6
(C.sub.1 Trp), 30.1 (CH.sub.2 benzyl), 45.2 (C.alpha. Trp), 45.6
(CH.sub.2-- m-methoxybenzyl), 54.9 (m-OCH.sub.3), 56.2 (Cq Aib),
109.4 (C.sub.3 Trp), 111.2 (C.sub.7 Trp), 111.7 (C.sub.2
m-methoxybenzyl), 113.1 (C.sub.4 m-methoxybenzyl), 117.9 (C.sub.4
Trp, C.sub.6 m-methoxybenzyl), 118.2 (C.sub.5 Trp), 120.8 (C.sub.6
Trp), 124.3 (C.sub.2 Trp), 126.6 (C.sub.4 benzyl), 126.8 (C.sub.9
Trp), 128.3 (C.sub.3, C.sub.5 benzyl), 128.4 (C.sub.2, C.sub.6
benzyl), 129.9 (C.sub.5 m-methoxybenzyl), 135.9 (C.sub.1 benzyl,
C.sub.8 Trp), 137.0 (C.sub.1 m-methoxybenzyl), 153.5 (Cq triazole),
154.8 (Cq triazole), 159.5 (C.sub.3 m-methoxybenzyl), 171.3 (CO
Aib).
[0433] ESI-MS: found: m/z 523.3 [M+H].sup.+/calculated: 522.3
g/mol
Example 6
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 8)
[0434] Compound 8 was obtained from Boc-(D)-Trp (10 mmoles),
phenylmethanamine, 3-(1H-indol-3-yl)propane hydrazide and
Boc-2-amino-2-methylpropanoic acid according to the general
synthetic schemes with a total yield after purification by HPLC of
45%.
[0435] .sup.1H NMR (400 MHz, DMSO-d.sup.6):
[0436] .delta.(ppm) 1.29 (3H, s, CH.sub.3 Aib), 1.30 (3H, s,
CH.sub.3 Aib), 2.88 (2H, m, CH.sub.2--CH.sub.2-indole), 2.97 (2H,
m, CH.sub.2--CH.sub.2-indole), 3.37 (2H, m, CH.sub.2 .beta.Trp),
5.11 (2H, s, CH.sub.2 benzyl), 5.21 (1H, m, C.alpha.H Trp), 6.86
(1H, t, J=7.4, H.sub.5 Trp), 6.88 (2H, H.sub.2, H.sub.6 benzyl),
6.92 (1H, t, J=7.6, H.sub.5 indole), 7.03 (1H, t, J=7.6, H.sub.6
Trp), 7.05 (2H, H.sub.6 indole, H.sub.2 indole), 7.09 (1H, d,
J=1.8, H.sub.2 Trp), 7.17 (1H, d, J=7.9, H.sub.4 Trp), 7.26 (2H,
H.sub.3, H.sub.5 benzyl), 7.27 (1H, H.sub.4 benzyl), 7.30 (1H,
H.sub.4 indole), 7.32 (2H, H.sub.7 Trp, H.sub.7 indole), 8.03 (2H,
brs, NH.sub.2 Aib), 8.95 (1H, d, J=8.1, NH Trp), 10.77 (1H, s, NH
indole), 10.81 (1H, s, NH indole Trp).
[0437] .sup.13C NMR (400 MHz, DMSO-d.sup.6):
[0438] .delta.(ppm) 22.4 (CH.sub.2--CH.sub.2 indole), 23.1
(CH.sub.3 Aib), 23.3 (CH.sub.3 Aib), 25.4 (CH.sub.2--CH.sub.2
indole), 28.7 (C.beta. Trp), 45.3 (C.alpha. Trp, CH.sub.2-benzyl),
56.3 (Cq Aib), 109.5 (C.sub.3 Trp), 111.3 (C.sub.7 Trp, C.sub.7
indole), 113.0 (C.sub.3 indole), 117.8 (C.sub.4 Trp), 118.0
(C.sub.4 indole), 118.2 (C.sub.5 indole), 118.3 (C.sub.5 Trp),
120.9 (C.sub.6 Trp, C.sub.6 indole), 122.4 (C.sub.2 indole), 124.3
(C.sub.2 Trp), 125.9 (C.sub.2, C.sub.6 benzyl), 126.7 (C.sub.9
Indole), 126.9 (C.sub.9 Trp), 127.6 (C.sub.4 benzyl), 128.8
(C.sub.3, C.sub.5 benzyl), 135.7 (C.sub.1 benzyl), 136.0 (C.sub.8
Trp), 136.1 (C.sub.8 indole), 154.3 (Cq triazole), 154.5 (Cq
triazole), 171.4 (CO Aib).
[0439] ESI-MS: found: m/z 546.3 [M+H].sup.+/calculated: 545.3
g/mol
Example 7
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(-
1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 9)
[0440] Compound 9 was obtained from Boc-(D)-Trp (10 mmoles),
phenylmethanamine, 4-(1H-indol-3-yl)butanehydrazide and
Boc-2-amino-2-methylpropanoic acid according to the general
synthetic schemes with a total yield after purification by HPLC of
38%.
[0441] .sup.1H NMR (400 MHz, DMSO-d.sup.6):
[0442] .delta.(ppm) 1.29 (3H, s, CH.sub.3 Aib), 1.31 (3H, s,
CH.sub.3 Aib), 1.90 (2H, m, CH.sub.2--CH.sub.2--CH.sub.2-indole),
2.61 (2H, m, CH.sub.2--CH.sub.2--CH.sub.2-indole), 2.69 (2H, m,
CH.sub.2--CH.sub.2--CH.sub.2-indole), 3.37 (2H, m, CH.sub.2
.beta.Trp), 5.09 (2H, s, CH.sub.2 benzyl), 5.20 (1H, m, C.alpha.H
Trp), 6.85 (3H, m, H.sub.2, H.sub.6 benzyl, H.sub.5 Trp), 6.94 (1H,
t, J=7.5, H.sub.5 indole), 7.01 (1H, s, H.sub.2 indole), 7.02 (1H,
t, J=7.8, H.sub.6 Trp), 7.05 (1H, t, J=8, H.sub.6 indole), 7.08
(1H, d, J=2.0, H.sub.2 Trp), 7.14 (1H, d, J=8.0, H.sub.4 Trp), 7.25
(3H, m, H.sub.3, H.sub.4, H.sub.5 benzyl), 7.31 (1H, d, J=8.0,
H.sub.7 Trp), 7.32 (1H, d, J=8.0, H.sub.7 indole), 7.42 (1H, d,
J=7.8, H.sub.4 indole), 8.03 (2H, s, NH.sub.2 Aib), 8.95 (1H, d,
J=8.1, NH Trp), 10.73 (1H, s, NH indole), 10.80 (1H, d, J=2.0, NH
indole Trp).
[0443] .sup.13C NMR (400 MHz, DMSO-d.sup.6):
[0444] .delta.(ppm) 23.1 (CH.sub.3 Aib), 23.3 (CH.sub.3 Aib), 23.8
(CH.sub.2--CH.sub.2--CH.sub.2-indole), 24.1
(CH.sub.2--CH.sub.2--CH.sub.2-indole), 27.2
(CH.sub.2--CH.sub.2--CH.sub.2-indole), 28.7 (C.beta. Trp), 45.4
(C.alpha. Trp), 45.5 (CH.sub.2 benzyl), 56.3 (Cq Aib), 109.4
(C.sub.3 Trp), 111.3 (C.sub.7 Trp, C.sub.7 indole), 113.6 (C.sub.3
indole), 117.8 (C.sub.4 Trp), 118.0 (C.sub.5 indole), 118.2
(C.sub.4 indole), 118.3 (C.sub.5 Trp), 120.8 (C.sub.6 indole,
C.sub.6 Trp), 122.2 (C.sub.2 indole), 124.3 (C.sub.2 Trp), 125.9
(C.sub.2, C.sub.6 benzyl), 126.8 (C.sub.9 Trp), 127.0 (C.sub.9
indole), 127.7 (C.sub.4 benzyl), 128.7 (C.sub.3, C.sub.5 benzyl),
135.5 (C.sub.1 benzyl), 136.0 (C.sub.8 Trp), 136.2 (C.sub.8
indole), 154.3 (Cq triazole), 154.7 (Cq triazole), 171.4 (CO
Aib).
[0445] ESI-MS: found: m/z 560.4 [M+H].sup.+/calculated: 559.3
g/mol
Example 8
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(3-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide
(Compound 10)
[0446] Compound 10 was obtained from Boc-(D)-Trp (10 mmoles),
(3-methoxyphenyl)-methanamine, 4-(1H-indol-3-yl)butanehydrazide and
Boc-2-amino-2-methylpropanoic acid according to the general
synthetic schemes with a total yield after purification by HPLC of
25%.
[0447] .sup.1H NMR (400 MHz, DMSO-d.sup.6):
[0448] .delta.(ppm) 1.27 (3H, s, CH.sub.3 Aib), 1.30 (3H, s,
CH.sub.3 Aib), 1.92 (2H, m, CH.sub.2--CH.sub.2--CH.sub.2-indole),
2.62 (2H, m, CH.sub.2--CH.sub.2--CH.sub.2-indole), 2.68 (2H, m,
CH.sub.2--CH.sub.2--CH.sub.2-indole), 3.24 (1H, dd, J=14.5, J=5.8,
1H C.sub.2 .beta.Trp), 3.39 (1H, dd, J=14.5, J=9.0, 1H C.sub.2
.beta.Trp), 3.66 (3H, s, m-OCH.sub.3), 5.07 (2H, s, CH.sub.2
m-methoxybenzyl), 5.18 (1H, m, C.alpha.H Trp), 6.35 (1H, d, J=7.5,
H.sub.6 m-methoxybenzyl), 6.54 (1H, bs, H.sub.2 m-methoxybenzyl),
6.84 (1H, t, J=7.5, H.sub.5 Trp), 6.87 (1H, dd, J=8.0, J=2.1,
H.sub.4 m-methoxybenzyl), 6.94 (1H, t, J=7.3, H.sub.5 indole), 7.02
(1H, t, H.sub.6 Trp), 7.02 (1H, s, H.sub.2 indole), 7.05 (1H, t,
J=7.8, H.sub.6 indole), 7.08 (1H, d, J=2.1, H.sub.2 Trp), 7.13 (1H,
d, J=8.1, H.sub.4 Trp), 7.17 (1H, t, J=8.1, H.sub.5
m-methoxybenzyl), 7.30 (1H, d, H.sub.7 Trp), 7.32 (1H, d, J=8,
H.sub.7 indole), 7.42 (1H, d, J=7.6, H.sub.4 indole), 7.98 (2H, s,
NH.sub.2 Aib), 8.93 (1H, d, J=8.2, NH Trp), 10.71 (1H, s, NH
indole), 10.77 (1H, s, NH indole Trp).
[0449] .sup.13C NMR (400 MHz, DMSO-d.sup.6):
[0450] .delta.(ppm) 23.1 (CH.sub.3 Aib), 23.3 (CH.sub.3 Aib), 23.9
(CH.sub.2--CH.sub.2--CH.sub.2-indole), 24.3
(CH.sub.2--CH.sub.2--CH.sub.2-indole), 27.4
(CH.sub.2--CH.sub.2--CH.sub.2 indole), 28.8 (C.beta. Trp), 45.2
(CH.sub.2-- m-methoxybenzyl), 45.4 (C.alpha. Trp), 55.1
(m-OCH.sub.3), 56.3 (Cq Aib), 109.5 (C.sub.3 Trp), 111.3 (C.sub.7
Trp, C.sub.7 indole), 111.8 (C.sub.2 m-methoxybenzyl), 113.0
(C.sub.4 m-methoxybenzyl), 113.8 (C.sub.3 indole), 117.8 (C.sub.6
m-methoxybenzyl), 117.9 (C.sub.4 Trp), 118.1 (C.sub.5 indole),
118.2 (C.sub.5 Trp, C.sub.4 indole), 120.8 (C.sub.6 Trp), 120.9
(C.sub.6 indole), 122.2 (C.sub.2 indole), 124.3 (C.sub.2 Trp),
126.8 (C.sub.9 Trp), 127.0 (C.sub.9 Indole), 130.0 (C.sub.5
m-methoxybenzyl), 136.0 (C.sub.8 Trp), 136.2 (C.sub.8 indole),
137.4 (C.sub.1 m-methoxybenzyl), 154.3 (Cq triazole), 154.6 (Cq
triazole), 159.7 (C.sub.3 m-methoxybenzyl), 171.4 (CO Aib).
[0451] ESI-MS: found: m/z 590.3 [M+H].sup.+/calculated: 589.3
g/mol
Example 9
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(naphthalen-1-ylmethyl)-4H-1,2,4--
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide
(Compound 11)
[0452] Compound 11 was obtained from Boc-(D)-Trp (10 mmoles),
naphthalen-1-ylmethanamine, 4-(1H-indol-3-yl)butanehydrazide and
Boc-2-amino-2-methylpropanoic acid according to the general
synthetic schemes with a total yield after purification by HPLC of
22%.
[0453] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0454] .delta.(ppm) 1.20 (3H, 5, CH.sub.3 Aib), 1.25 (3H, s,
CH.sub.3 Aib), 1.93 (2H, m, CH.sub.2--CH.sub.2--CH.sub.2-indole),
2.66 (4H, m, CH.sub.2--CH.sub.2--CH.sub.2-indole), 3.25 (1H, dd,
J=14 Hz and 5 Hz, CH.sub.2 .beta.Trp), 3.40 (1H, dd, J=14 Hz and 9
Hz, CH.sub.2 .beta.Trp), 4.95 (1H, m, CH .alpha.Trp), 5.66 (1H, d,
J=18 Hz, CH.sub.2-naphtyl), 5.81 (1H, d, J=18 Hz,
CH.sub.2-naphtyl), 6.37 (1H, d, J.sub.o=7 Hz, H.sub.2 naphtyl),
6.43 (1H, t, J.sub.o=7 Hz, H.sub.5 Trp), 6.59 (1H, d, J.sub.o=8 Hz,
H.sub.4 Trp), 6.86 (3H, m, H.sub.5 and H.sub.6 indole, H.sub.6
Trp), 6.95 (1H, d, J=2 Hz, H.sub.2 indole), 7.00 (1H, d, J.sub.o=8
Hz, H.sub.4 indole), 7.06 (1H, d, J=2 Hz, H.sub.2 Trp), 7.20-7.33
(4H, m, H.sub.4 and H.sub.7 indole, H.sub.7 Trp, H.sub.3 naphtyl),
7.60 (2H, m, H.sub.6 and H.sub.7 naphtyl), 7.87 (1H, d, J.sub.o=8
Hz, H.sub.4 naphtyl), 7.99 (5H, m, NH.sub.2 Aib, H.sub.5 and
H.sub.8 naphtyl), 8.95 (1H, d, J=8 Hz, NH amide), 10.70 (1H, s, NH
indole), 10.77 (1H, s, NH indole Trp).
[0455] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0456] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.6 (CH.sub.3 Aib), 24.1
(CH.sub.2--CH.sub.2--CH.sub.2-indole), 24.5
(CH.sub.2--CH.sub.2--CH.sub.2-indole), 27.6
(CH.sub.2--CH.sub.2--CH.sub.2-indole), 29.1 (CH.sub.2 .beta.Trp),
44.1 (CH.sub.2-naphtyl), 45.7 (CH .alpha. Trp), 56.7 (Cq Aib),
109.7 (C.sub.3 Trp), 111.7 (C.sub.7 indole and C.sub.7 Trp), 113.9
(C.sub.3 indole), 117.9 (C.sub.4 Trp), 118.5 (C.sub.4 indole,
C.sub.5 Trp), 118.6 (C.sub.5 indole), 121.1 (C.sub.6 Trp), 121.2
(C.sub.6 indole), 122.1 (C.sub.2 naphtyl), 122.7 (C.sub.2 indole),
122.9 (C.sub.8 naphtyl), 125.0 (C.sub.2 Trp), 125.9 (C.sub.3
naphtyl), 126.8 (C.sub.6 naphtyl), 127.0 (C.sub.9 indole), 127.1
(C.sub.7 naphtyl), 127.4 (C.sub.9 Trp), 128.5 (C.sub.4 naphtyl),
129.2 (C.sub.5 naphtyl), 129.9 (C.sub.9 naphtyl), 131.6 (C.sub.1
naphtyl), 133.6 (C.sub.10 naphtyl), 136.4 (C.sub.8 Trp), 136.7
(C.sub.8 indole), 155.4 (Cqs triazole), 171.9 (CO Aib).
[0457] ESI-MS: found: m/z 610.3 [M+H].sup.+/calculated: 609.3
g/mol
Example 10
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide
(Compound 12)
[0458] Compound 12 was obtained from Boc-(D)-Trp (10 mmoles),
(4-methoxyphenyl)-methanamine, 3-(1H-indol-3-yl)propane hydrazide
and Boc-2-amino-2-methylpropanoic acid according to the general
synthetic schemes with a total yield after purification by HPLC of
28%.
[0459] .sup.1H NMR (400 MHz, DMSO-d.sup.6):
[0460] .delta.(ppm) 1.30 (3H, s, CH.sub.3 Aib), 1.33 (3H, s,
CH.sub.3 Aib), 2.91 (2H, m, CH.sub.2--CH.sub.2-indole), 2.97 (2H,
m, CH.sub.2--CH.sub.2-indole), 3.37 (2H, d, CH.sub.2 .beta.Trp),
3.71(3H, s, OCH.sub.3), 5.02 (2H, s, CH.sub.2 p-methoxybenzyl),
5.23 (1H, m, C.alpha.H Trp), 6.78 (4H, m, CHar p-methoxybenzyl),
6.87 (1H, t, J=7.5, H.sub.5 Trp), 6.93 (1H, t, J=7.5, H.sub.5
indole), 7.03 (1H, t, H.sub.6 Trp), 7.05 (1H, t, H.sub.6 indole),
7.07 (1H, s, H.sub.2 indole), 7.09 (1H, s, H.sub.2 Trp), 7.21 (1H,
d, J=8, H.sub.4 Trp), 7.32 (3H, H.sub.4 indole, H.sub.7 Trp,
H.sub.7 indole), 8.02 (2H, s, NH.sub.2 Aib), 8.97 (1H, d, J=8.1, NH
Trp), 10.77 (1H, s, NH indole), 10.80 (1H, s, NH indole Trp).
[0461] .sup.13C NMR (400 MHz,DMSO-d.sup.6):
[0462] .delta.(ppm) 22.4 (CH.sub.2--CH.sub.2 indole), 23.1
(CH.sub.3 Aib), 23.4 (CH.sub.3 Aib), 25.5 (CH.sub.2--CH.sub.2
indole), 28.9 (C.beta. Trp), 44.9 (CH.sub.2 p-methoxybenzyl), 45.3
(C.alpha. Trp), 55.0 (OCH.sub.3), 56.3 (Cq Aib), 109.5 (C.sub.3
Trp), 111.3 (C.sub.7 Trp, C.sub.7 indole), 113.0 (C.sub.3 indole),
114.1 (C.sub.3, C.sub.5 p-methoxybenzyl), 117.9 (C.sub.4 Trp),
118.0 (C.sub.4 indole), 118.2 (C.sub.5 indole), 118.3 (C.sub.5
Trp), 120.9 (C.sub.6 indole, C.sub.6 Trp), 122.0 (C.sub.2 indole),
124.4 (C.sub.2 Trp), 126.7 (C.sub.9 indole), 126.9 (C.sub.9 Trp),
127.3 (C.sub.2, C.sub.6 p-methoxybenzyl), 127.4 (C.sub.1
p-methoxybenzyl), 135.9 (C.sub.8 Trp), 136.1 (C.sub.8 indole),
154.2 (Cq triazole), 154.5 (Cq triazole), 158.4 C.sub.4
p-methoxybenzyl), 171.4 (CO Aib).
[0463] ESI-MS: found: m/z 576.3 [M+H].sup.+/calculated: 575.3
g/mol
Example 11
(R)--N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 13)
[0464] Compound 13 was obtained from Boc-(D)-Trp (10 mmoles),
(4-methoxyphenyl)-methanamine, 2-phenylacetohydrazide and
Boc-2-amino-2-methylpropanoic acid according to the general
synthetic schemes with a total yield after purification by HPLC of
37%.
[0465] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0466] .delta.(ppm) 1.24 (3H, s, CH.sub.3 Aib), 1.28 (3H, s,
CH.sub.3 Aib), 3.26 (1H, dd, .sup.3J=14 Hz and 6 Hz, CH.sub.2
.beta.Trp), 3.31 (1H, dd, .sup.3J=14 Hz and 9 Hz, CH.sub.2
.beta.Trp), 3.67 (3H, s, OCH.sub.3), 3.99 (2H, s, CH.sub.2-benzyl),
4.99 (2H, s, CH.sub.2-p-methoxybenzyl), 5.12 (1H, m, CH
.alpha.Trp), 6.67 (4H, m, CHar p-methoxybenzyl), 6.80 (1H, t,
J.sub.o=8 Hz, H.sub.5 Trp), 6.98 (1H, t, J.sub.o=8 Hz, H.sub.6
Trp), 7.02-7.06 (4H, m, H.sub.2 and H.sub.6 benzyl, H.sub.2 and
H.sub.4 Trp), 7.12-7.25 (3H, m, H.sub.3, H.sub.4 and H.sub.5
benzyl), 7.26 (1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 8.01 (3H, brs,
NH.sub.2 Aib), 8.92 (1H, d, J=8 Hz, NH Trp), 10.77 (1H, s, NH
indole Trp).
[0467] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0468] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.7 (CH.sub.3 Aib), 29.1
(CH.sub.2 .beta.Trp), 30.6 (CH.sub.2-benzyl), 45.7
(CH.sub.2-p-methoxybenzyl), 45.7 (CH .alpha.Trp), 55.5 (OCH.sub.3),
56.7 (Cq Aib), 109.8 (C.sub.3 Trp), 111.7 (C.sub.7 Trp), 114.5
(C.sub.3 and C.sub.5 p-methoxybenzyl), 118.3 (C.sub.4 Trp), 118.7
(C.sub.5 Trp), 121.3 (C.sub.6 Trp), 124.8 (C.sub.2 Trp), 127.1
(C.sub.2 and C.sub.6 benzyl), 127.3 (C.sub.9 Trp), 127.6 (C.sub.1
p-methoxybenzyl), 127.8 (C.sub.2 and C.sub.6 p-methoxybenzyl),
128.8 (C.sub.3, C.sub.4 and C.sub.5 p-methoxybenzyl), 136.3
(C.sub.1 benzyl), 136.4 (C.sub.8 Trp), 153.8 (Cq triazole), 155.2
(Cq triazole), 159.1 (C.sub.4 p-methoxybenzyl), 171.9 (CO Aib).
[0469] ESI-MS: found: m/z 524.1 [M+H].sup.+/calculated: 522.3
g/mol
Example 12
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-hexyl-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 15)
[0470] Compound 15 was obtained from Boc-(D)-Trp (10 mmoles),
hexan-1-amine, 3-(1H-indol-3-yl)propane hydrazide and
Boc-2-amino-2-methylpropanoic acid according to the general
synthetic schemes with a total yield after purification by HPLC of
28%.
[0471] .sup.1H NMR (400 MHz, DMSO-d.sup.6):
[0472] .delta.(ppm) 0.77 (3H, t, J=7.2 (CH.sub.2).sub.5--CH.sub.3),
1.01 (4H, m, 2CH.sub.2), 1.11 (2H, m, CH.sub.2--CH.sub.3), 1.14
(1H, m, 1H N--CH.sub.2--CH.sub.2), 1.33 (1H, m, 1H
N--CH.sub.2--CH.sub.2), 1.40 (3H, s, CH.sub.3 Aib), 1.42 (3H, s,
CH.sub.3 Aib), 3.05 (2H, m, CH.sub.2--CH.sub.2-indole), 3.10 (2H,
m, CH.sub.2--CH.sub.2-indole), 3.37 (1H, dd, J=14.2, J=7.6, 1H
C.sub.2 .beta.Trp), 3.44 (1H, dd, J=14.2, J=7.6, 1H C.sub.2
.beta.Trp), 3.58 (1H, m, 1H N--CH.sub.2), 3.71 (1H, m, 1H
N--CH.sub.2), 5.21 (1H, m, C.alpha.H Trp), 6.96 (1H, H.sub.5 Trp),
6.97 (1H, H.sub.5 indole), 7.06 (2H, H.sub.6 Trp, H.sub.6 indole),
7.09 (1H, s, H.sub.2 Trp), 7.13 (1H, s, H.sub.2 indole), 7.34 (2H,
H.sub.7 Trp, H.sub.7 indole),7.48 (1H, d, H.sub.4 indole), 7.50
(1H, H.sub.4 Trp), 8.14 (2H, s, NH.sub.2 Aib), 9.08 (1H, d, J=7.8,
NH Trp), 10.84 (1H, s, NH indole), 10.88 (1H, s, NH indole
Trp).
[0473] .sup.13C NMR (400 MHz, DMSO-d.sup.6):
[0474] .delta.(ppm) 13.7 (CH.sub.2).sub.5--CH.sub.3), 21.7
(CH.sub.2--CH.sub.3), 22.4 (CH.sub.2--CH.sub..quadrature.indole),
23.1 (CH.sub.3 Aib), 23.3 (CH.sub.3 Aib), 25.1
(CH.sub.2--CH.sub...quadrature.indole), 25.5
(CH.sub.3--CH.sub.2--CH.sub.2--CH.sub.2), 29.1 (C.beta. Trp), 29.3
(N--CH.sub.2--CH.sub.2), 30.4 (CH.sub.3--CH.sub.2--CH.sub.2), 42.6
(N--CH.sub.2--CH.sub.2), 45.6 (C.alpha. Trp), 56.3 (Cq Aib), 109.2
(C.sub.3 Trp), 111.4-111.5 (C.sub.7 Trp, C.sub.7 indole), 112.8
(C.sub.3 indole), 117.7 (C.sub.4 Trp), 118.0 (C.sub.5 indole),
118.2 (C.sub.4 indole), 118.4 (C.sub.5 Trp), 120.9 (C.sub.6 indole,
C.sub.6 Trp), 122.6 (C.sub.2 indole), 124.3 (C.sub.2 Trp), 126.8
(C.sub.9 Trp), 126.9 (C.sub.9 indole), 136.0 (C.sub.8 Trp), 136.2
(C.sub.8 indole), 154.0 (Cq triazole), 154.1 (Cq triazole), 171.4
(CO Aib). ESI-MS: found: m/z 540.3 [M+H].sup.+/calculated: 539.3
g/mol
Example 13
(S)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tri-
azol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide
(Compound 18)
[0475] Compound 18 was obtained from Boc-(L)-Trp (10 mmoles),
(2,4-dimethoxyphenyl)-methanamine, 3-(1H-indol-3-yl)propane
hydrazide and Boc-2-amino-2-methylpropanoic acid according to the
general synthetic schemes with a total yield after purification by
HPLC of 30%.
[0476] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0477] .delta.(ppm) 1.27 (3H, s, CH.sub.3 Aib), 1.31 (3H, s,
CH.sub.3 Aib), 2.89 (2H, m, CH.sub.2CH.sub.2-indole), 2.93 (2H, m,
CH.sub.2CH.sub.2-indole), 3.27 (2H, m, CH.sub.2 .beta.Trp), 3.62
(3H, s, o-OCH.sub.3), 3.68 (3H, s, p-OCH.sub.3), 4.89 (1H, d,
.sup.3J=17 Hz, CH.sub.2-o,p-dimethoxybenzyl), 5.06 (1H, d,
.sup.3J=17 Hz, CH.sub.2-o,p-dimethoxybenzyl), 5.18 (1H, m, CH
.alpha.Trp), 6.27 (1H, dd, J.sub.o=8 Hz and J.sub.p=2 Hz, H.sub.5
o,p-dimethoxybenzyl), 6.40 (1H, d, 8 Hz, H.sub.6
o,p-dimethoxybenzyl), 6.56 (1H, d, J.sub.p=2 Hz, H.sub.3
o,p-dimethoxybenzyl), 6.83 (1H, t, J.sub.o=7 Hz, H.sub.5 Trp), 6.90
(1H, t, J.sub.o=7 Hz, H.sub.5 indole), 7.02 (1H, t, H.sub.6 Trp),
7.04 (1H, t, H.sub.6 indole), 7.07 (1H s, H.sub.2 indole), 7.08
(1H, s, H.sub.2 Trp), 7.12 (1H, d, J.sub.o=8 Hz, H.sub.4 Trp), 7.29
(3H, H.sub.4 and H.sub.7 indole, H.sub.7 Trp), 8.00 (3H, brs,
NH.sub.2 Aib), 8.93 (1H, d, J=8 Hz, NH amide), 10.76 (1H, s, NH
indole), 10.79 (1H, s, NH indole Trp).
[0478] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0479] .delta.(ppm) 22.9 (CH.sub.2CH.sub.2-indole), 23.6 (CH.sub.3
Aib), 23.7 (CH.sub.3 Aib), 25.8 (CH.sub.2CH.sub.2-indole), 29.2
(CH.sub.2 .beta.Trp), 41.4 (CH.sub.2-o,p-dimethoxybenzyl), 45.7
(C.alpha.Trp), 55.7 (p-OCH.sub.3), 55.9 (o-OCH.sub.3), 56.7 (Cq
Aib), 99.0 (C.sub.3 o,p-dimethoxybenzyl), 105.1 (C.sub.5
o,p-dimethoxybenzyl), 109.9 (C.sub.3 Trp), 111.8 (C.sub.7 Trp,
C.sub.7 indole), 113.4 (C.sub.3 indole), 115.6 (C.sub.1
o,p-dimethoxybenzyl), 118.3 (C.sub.4 indole), 118.4 (C.sub.4 Trp),
118.6 (C.sub.5 Trp, C.sub.5 indole), 121.3 (C.sub.6 Trp, C.sub.6
indole), 122.6 (C.sub.2 indole), 124.4 (C.sub.2 Trp), 127.2
(C.sub.9 indole), 127.3 (C.sub.9 Trp), 128.0 (C.sub.6
o,p-dimethoxybenzyl), 136.4 (C.sub.8 Trp), 136.6 (C.sub.8 indole),
155.0 (2 Cq triazole), 157.7 (C.sub.2 o,p-dimethoxybenzyl), 160.9
(C.sub.4 o,p-dimethoxybenzyl), 171.6 (CO Aib).
[0480] ESI-MS: found: m/z 606.2 [M+H].sup.+/calculated: 605.3
g/mol
Example 14
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide
(Compound 23)
[0481] Compound 23 was obtained from Boc-(D)-Trp (10 mmoles),
(4-methoxyphenyl)-methanamine, 4-(1H-indol-3-yl)butanehydrazide and
Boc-2-amino-2-methylpropanoic acid according to the general
synthetic schemes with a total yield after purification by HPLC of
25%.
[0482] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0483] .delta.(ppm) 1.27 (3H, s, CH.sub.3 Aib), 1.30 (3H, s,
CH.sub.3 Aib), 1.84 (2H, m, CH.sub.2CH.sub.2CH.sub.2-indole), 2.58
(2H, m, CH.sub.2CH.sub.2CH.sub.2-indole), 2.65 (2H, m,
CH.sub.2CH.sub.2CH.sub.2-indole), 3.34 (2H, d, .sup.3J=7 Hz,
CH.sub.2 .beta.Trp), 3.67 (3H, s, OCH.sub.3), 4.96 (2H, s,
CH.sub.2-p-methoxybenzyl), 5.19 (1H, m, CH .alpha.Trp), 6.71 (4H,
s, CH ar p-methoxybenzyl), 6.89 (1H, t, J.sub.o=7 Hz, H.sub.5 Trp),
6.92 (1H, t, J.sub.o=7 Hz, H.sub.5 indole), 7.02 (1H, s, H.sub.2
indole), 7.05 (1H, s, H.sub.2 Trp), 7.14 (1H, d, J.sub.o=8 Hz,
H.sub.4 Trp), 7.33 (3H, H.sub.4 indole, H.sub.7 Trp, H.sub.7
indole), 8.02 (3H, brs, NH.sub.2 Aib), 7.90 (1H, d, J=8 Hz, NH
amide), 10.73 (1H, s, NH indole), 10.79 (1H, s, NH indole Trp).
[0484] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0485] .delta.(ppm) 23.6 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 24.3
(CH.sub.2CH.sub.2CH.sub.2-indole), 24.8
(CH.sub.2CH.sub.2CH.sub.2-indole), 27.7
(CH.sub.2CH.sub.2CH.sub.2-indole), 29.1 (C.beta. Trp), 45.5
(N--CH.sub.2-p-methoxybenzyl), 45.8 (C.alpha.Trp), 55.5
(OCH.sub.3), 56.8 (Cq Aib), 109.8 (C.sub.3 Trp), 111.7 (C.sub.7
Trp, C.sub.7 indole), 114.0 (C.sub.3 indole), 114.5 (C.sub.3,
C.sub.5 p-methoxybenzyl), 118.3 (C.sub.4 indole, C.sub.4 Trp),
118.5 (C.sub.5 indole), 118.8 (C.sub.5 Trp), 121.3 (C.sub.6 indole,
C.sub.6 Trp), 127.3 (C.sub.9 indole), 127.4 (C.sub.9 Trp), 127.6
(C.sub.1 p-methoxybenzyl), 127.9 (C.sub.2, C.sub.6 p-methoxybenzyl,
C.sub.2 Trp, C.sub.2 indole), 136.1 (C.sub.8 indole), 136.4
(C.sub.8 Trp), 154.7 (Cq triazole), 155.1 (Cq triazole), 159.2
(C.sub.4 p-methoxybenzyl), 171.9 (CO Aib).
[0486] ESI-MS: found: m/z 590.0 [M+H].sup.+/calculated: 589.3
g/mol
Example 15
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2-methoxy)benzyl)-4H-1,2,4-triazo-
l-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide
(Compound 25)
[0487] Compound 25 was obtained from Boc-(D)-Trp (10 mmoles),
(2-methoxyphenyl)-methanamine, 3-(1H-indol-3-yl)propane hydrazide
and Boc-2-amino-2-methylpropanoic acid according to the general
synthetic schemes with a total yield after purification by HPLC of
28%.
[0488] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0489] .delta.(ppm) 1.27 (3H, s, CH.sub.3 Aib), 1.29 (3H, s,
CH.sub.3 Aib), 2.90 (2H, m, CH.sub.2--CH.sub.2-indole), 2.96 (2H,
m, CH.sub.2--CH.sub.2-indole), 3.29 (2H, m, CH.sub.2 .beta.Trp),
3.65 (3H, s, OCH.sub.3), 5.09 (3H, m, CH.sub.2-o-methoxybenzyl and
CH .alpha.Trp), 6.49 (1H, d, J.sub.o=8 Hz, H.sub.3
o-methoxybenzyl), 6.76 (1H, t, J.sub.o=8 Hz, H.sub.5 Trp), 6.81
(1H, t, J.sub.o=8 Hz, H.sub.5 indole), 6.89 (1H, t, J.sub.o=7 Hz,
H.sub.6 Trp), 6.96 (1H, t, J.sub.o=8 Hz, H.sub.6 indole), 6.98 (1H,
s, H.sub.2 indole), 7.02 (3H, m, H.sub.4, H.sub.5 and H.sub.6
o-methoxybenzyl), 7.07 (1H, d, J.sub.o=6 Hz, H.sub.4 Trp), 7.18
(1H, m, H.sub.4 indole), 7.29 (2H, m, H.sub.7 indole and H.sub.7
Trp), 8.07 (3H, brs, NH.sub.2 Aib), 8.97 (1H, d, J=8 Hz, NH amide),
10.80 (1H, s, NH indole), 10.82 (1H, s, NH indole Trp).
[0490] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0491] .delta.(ppm) 22.8 (CH.sub.2--CH.sub.2-indole), 23.6
(CH.sub.3 Aib), 23.7 (CH.sub.3 Aib), 25.8
(CH.sub.2--CH.sub.2-indole), 29.1 (CH.sub.2 .beta.Trp), 42.3
(CH.sub.2-o-methoxybenzyl), 45.7 (CH .alpha. Trp), 55.8
(OCH.sub.3), 56.7 (Cq Aib), 109.8 (C.sub.3 Trp), 111.5 (C.sub.3
o-methoxybenzyl), 111.8 (C.sub.7 indole and C.sub.7 Trp), 113.2
(C.sub.3 indole), 118.2 (C.sub.4 Trp), 118.4 (C.sub.4 indole),
118.7 (C.sub.5 indole and C.sub.5 Trp), 121.0 (C.sub.6 indole),
121.3 (C.sub.6 Trp), 121.4 (C.sub.5 o-methoxybenzyl), 123.0
(C.sub.2 indole and C.sub.2 Trp), 123.3 (C.sub.1 o-methoxybenzyl),
127.0 (C.sub.4 o-methoxybenzyl), 127.1 (C.sub.9 indole), 127.3
(C.sub.9 Trp), 129.8 (C.sub.6 o-methoxybenzyl), 136.4 (C.sub.8
indole), 136.6 (C.sub.8 Trp), 155.2 (Cq triazole), 171.9 (CO
Aib).
[0492] ESI-MS: found: m/z 576.1 [M+H].sup.+/calculated: 575.3
g/mol
[0493] Data on further exemplary embodiments that were synthesized
according to the general sysnthesis schemes are compiled below
(please refer also to Table 1):
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-phenethyl-4H-1,2,4-triazol-3-yl)--
2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound
3)
[0494] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0495] .delta.(ppm) 1.32 (s, 3H, CH.sub.3 Aib), 1.37 (s, 3H,
CH.sub.3 Aib), 1.86 (2H, m, CH.sub.2--CH.sub.2--CH.sub.2-indole),
2.38 (2H, m, CH.sub.2--CH.sub.2--CH.sub.2-indole), 2.65 (4H, m,
CH.sub.2--CH.sub.2--CH.sub.2-indole and CH.sub.2--CH.sub.2-phenyl),
3.38 (2H, m, CH.sub.2--CH.sub.2-phenyl), 3.74 (1H, m, CH.sub.2
.beta.Trp), 3.92 (1H, m, CH.sub.2 .beta.Trp), 5.23 (1H, m, CH
.alpha.Trp), 6.78 (2H, m, H.sub.5 indole and H.sub.5 Trp), 6.93
(1H, t, J.sub.o=8 Hz, H.sub.6 Trp), 7.01 (3H, m, H.sub.6 indole,
H.sub.2 and H.sub.6 phenyl), 7.05 (1H, d, J=2 Hz, H.sub.2 Trp),
7.08 (1H, d, J=2 Hz, H.sub.2 indole), 7.15 (3H, m, H.sub.3, H.sub.4
and H.sub.5 phenyl), 7.29 (1H, d, J.sub.o=8 Hz, H.sub.4 Trp), 7.31
(1H, d, Jo=8 Hz, H.sub.7 Trp), 7.44 (1H, d, J.sub.o=8 Hz, H.sub.7
indole), 7.46 (1H, d, J.sub.o=8 Hz, H.sub.4 indole), 8.06 (3H, brs,
NH.sub.2 Aib), 9.05 (1H, d, 8 Hz, NH amide), 10.76 (1H, s, NH
indole), 10.85 (1H, d, J=2 Hz, NH indole Trp).
[0496] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0497] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.6
(CH.sub.2--CH.sub.2--CH.sub.2-indole), 23.9 (CH.sub.3 Aib), 24.5
(CH.sub.2--CH.sub.2--CH.sub.2-indole), 27.3
(CH.sub.2--CH.sub.2--CH.sub.2-indole), 29.4 (CH.sub.2 .beta.Trp),
35.7 (CH.sub.2--CH.sub.2-phenyl), 44.5 (CH.sub.2--CH.sub.2-phenyl),
46.1 (CH .alpha.Trp), 56.8 (Cq Aib), 109.6 (C.sub.3 Trp), 111.8
(C.sub.7 indole), 111.9 (C.sub.7 indole), 113.9 (C.sub.3 indole),
118.3 (C.sub.4 Trp), 118.6 (C.sub.5 indole), 118.7 (C.sub.4
indole), 118.9 (C.sub.5 Trp), 121.3 (C.sub.6 Trp), 121.4 (C.sub.6
indole), 122.8 (C.sub.2 indole and C.sub.2 Trp), 127.1 (C.sub.4
phenyl), 127.3 (C.sub.9 Trp), 127.5 (C.sub.9 indole), 128.8
(C.sub.2 and C.sub.6 phenyl), 129.1 (C.sub.3 and C.sub.5 phenyl),
136.5 (C.sub.1 phenyl), 136.8 (C.sub.8 Trp), 137.2 (C.sub.8
indole), 154.7 (Cq triazole), 172.0 (CO Aib).
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-hexyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 16)
[0498] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0499] .delta.(ppm) 0.74 (3H, t, J=6 Hz,
CH.sub.3--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2), 0.95
(4H, brs,
CH.sub.3--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2), 1.06
(3H, m, CH.sub.3--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2
and 1H N--CH.sub.2--CH.sub.2), 1.38 (7H, s, CH.sub.3 Aib and 1H
N--CH.sub.2--CH.sub.2), 1.97 (2H, m,
CH.sub.2--CH.sub.2--CH.sub.2-indole), 2.71 (4H, m,
CH.sub.2--CH.sub.2--CH.sub.2-indole), 3.37 (2H, m, CH.sub.2
.beta.Trp), 3.56 (2H, m, N--CH.sub.2), 5.15 (1H, m, CH .alpha.Trp),
6.91 (2H, m, H.sub.5 indole and H.sub.5 Trp), 7.00 (2H, m, H.sub.6
indole and H.sub.6 Trp), 7.07 (2H, s, H.sub.2 indole and H.sub.2
Trp), 7.29 (2H, d, J.sub.o=8 Hz, H.sub.7 indole and H.sub.7 Trp),
7.45 (2H, d, J.sub.o=7 Hz, H.sub.4 indole and H.sub.4 Trp), 8.15
(3H, brs, NH.sub.2 Aib), 9.10 (1H, d, J=6 Hz, NH amide), 10.77 (1H,
s, NH indole), 10.85 (1H, s, NH indole Trp).
[0500] .sup.13C NMR (75 MHz, DMSO-D.sup.6, 300.degree. K):
[0501] .delta.(ppm) 14.2
(CH.sub.3--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2), 22.2
(CH.sub.3--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2 and
CH.sub.2--CH.sub.2--CH.sub.2-indole), 23.6 (CH.sub.3 Aib), 23.7
(CH.sub.3 Aib), 24.5 (CH.sub.2--CH.sub.2--CH.sub.2-indole), 25.9
(CH.sub.3--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2), 27.5
(CH.sub.2 .beta.Trp and CH.sub.2--CH.sub.2--CH.sub.2-indole), 29.7
(N--CH.sub.2--CH.sub.2), 30.8
(CH.sub.3--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2), 43.2
(N--CH.sub.2), 46.1 (CH .alpha.Trp), 56.8 (Cq Aib), 109.5 (C.sub.3
Trp), 111.8 (C.sub.7 Trp), 111.9 (C.sub.7 indole), 113.9 (C.sub.3
indole), 118.1 (C.sub.4 Trp), 118.5 (C.sub.5 indole), 118.6
(C.sub.4 indole), 118.9 (C.sub.5 Trp), 121.3 (C.sub.6 indole and
C.sub.6 Trp), 122.8 (C.sub.2 indole and C.sub.2 Trp), 127.3
(C.sub.9 Trp), 127.4 (C.sub.9 indole), 136.5 (C.sub.8 Trp), 136.8
(C.sub.8 indole), 154.7 (Cq triazole), 172.0 (CO Aib).
(R)--N-(1-(4,5-bis(2-(1H-indol-3-yl)ethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 17)
[0502] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0503] .delta.(ppm) 1.30 (3H, s, CH.sub.3 Aib), 1.37 (3H, s,
CH.sub.3 Aib), 2.50 (2H, m, N--CH.sub.2--CH.sub.2-indole), 2.68
(2H, t, J.sub.o=8 Hz, C--CH.sub.2--CH.sub.2-indole), 2.91 (2H, t,
J.sub.o=8 Hz, C--CH.sub.2--CH.sub.2-indole), 3.34 (2H, m,
N--CH.sub.2--CH.sub.2-indole), 3.93 (2H, m, CH.sub.2 .beta.Trp),
5.25 (1H, m, CH .alpha.Trp), 6.72-6.94 (4H, m, H.sub.5 and H.sub.6
Trp, H.sub.5 indole from C--CH.sub.2--CH.sub.2-indole and H.sub.5
indole from N--CH.sub.2--CH.sub.2-indole), 6.98-7.04 (4H, m,
H.sub.2 Trp, H.sub.6 indole from C--CH.sub.2--CH.sub.2-indole,
H.sub.2 and H.sub.6 indole from N--CH.sub.2--CH.sub.2-indole), 7.11
(1H, s, H.sub.2 indole from C--CH.sub.2--CH.sub.2-indole), 7.19
(1H, d, J.sub.o=8 Hz, H.sub.4 indole from
N--CH.sub.2--CH.sub.2-indole), 7.28 (3H, m, H.sub.4 and H.sub.7
Trp, H.sub.7 indole from N--CH.sub.2--CH.sub.2-indole), 7.40 (1H,
d, J.sub.o=8 Hz, H.sub.7 indole from C--CH.sub.2--CH.sub.2-indole),
7.44 (1H, d, J.sub.o=8 Hz, H.sub.4 indole from
C--CH.sub.2--CH.sub.2-indole), 8.04 (3H, brs, NH.sub.2 Aib), 9.69
(1H, d, J=8 Hz, NH amide), 10.73 (1H, s, NH indole from
C--CH.sub.2--CH.sub.2-indole), 10.82 (1H, d, J=2 Hz, NH indole
Trp), 10.84 (1H, s, NH indole from
N--CH.sub.2--CH.sub.2-indole).
[0504] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0505] .delta.(ppm) 22.7 (C--CH.sub.2--CH.sub.2-indole), 23.6
(CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 25.4
(C--CH.sub.2--CH.sub.2-indole), 26.0
(N--CH.sub.2--CH.sub.2-indole), 29.6 (CH.sub.2 .beta.Trp), 43.9
(N--CH.sub.2--CH.sub.2-indole), 46.0 (CH .alpha.Trp), 56.8 (Cq
Aib), 109.5 (C.sub.3 indole from N--CH.sub.2--CH.sub.2-indole),
109.9 (C.sub.3 Trp), 111.7 (C.sub.7 Trp), 111.9 (C.sub.7 indole
from N--CH.sub.2--CH.sub.2-indole and C.sub.7 indole from
C--CH.sub.2--CH.sub.2-indole), 113.5 (C.sub.3 indole from
C--CH.sub.2--CH.sub.2-indole), 118.3 (C.sub.4 indole from
N--CH.sub.2--CH.sub.2-indole), 118.4 (C.sub.4 Trp), 118.5 (C.sub.5
indole from C--CH.sub.2--CH.sub.2-indole), 118.7 (C.sub.4 indole
from C--CH.sub.2--CH.sub.2-indole), 118.9 (C.sub.5 Trp), 119.0
(C.sub.5 indole from N--CH.sub.2--CH.sub.2-indole), 121.3 (C.sub.6
Trp), 121.5 (C.sub.6 indole from C--CH.sub.2--CH.sub.2-indole and
C.sub.6 indole from N--CH.sub.2--CH.sub.2-indole), 122.8 (C.sub.2
Trp, C.sub.2 indole from C--CH.sub.2--CH.sub.2-indole and indole
from N--CH.sub.2--CH.sub.2-indole), 127.1 (C.sub.9 Trp), 127.2
(C.sub.9 indole from C--CH.sub.2--CH.sub.2-indole), 127.4 (C.sub.9
indole from N--CH.sub.2--CH.sub.2-indole), 136.5 (C.sub.8 Trp and
C.sub.8 indole from C--CH.sub.2--CH.sub.2-indole), 136.6 (C.sub.8
indole from N--CH.sub.2--CH.sub.2-indole), 154.5 (Cq triazole),
154.8 (Cq triazole), 171.8 (CO amide).
(R)--N-(1-(4-(3-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 19)
[0506] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0507] .delta.(ppm) 1.24 (3H, s, CH.sub.3 Aib), 1.27 (3H, s,
CH.sub.3 Aib), 2.82 (4H, m, CH.sub.2--CH.sub.2-phenyl), 3.32 (2H,
m, CH.sub.2.beta.Trp), 3.63 (3H, s, OCH.sub.3), 5.08 (2H, m,
CH.sub.2-m-methoxybenzyl), 5.18 (1H, m, CH .alpha.Trp), 6.35 (1H,
d, J.sub.o=8 Hz, H.sub.6 m-methoxybenzyl), 6.57 (1H, s, H.sub.2
m-methoxybenzyl), 6.82 (1H, t, J.sub.o=8 Hz, H.sub.5 Trp), 6.84
(1H, d, J.sub.o=8 Hz, H.sub.4 m-methoxybenzyl), 6.99 (1H, t,
J.sub.o=8 Hz, H.sub.6 Trp), 7.08 (1H, m, H.sub.4 phenyl), 7.11-7.16
(5H, m, H.sub.2 and H.sub.4 Trp, H.sub.2 and H.sub.6 phenyl,
H.sub.5 m-methoxybenzyl), 7.20 (2H, m, H.sub.3 and H.sub.5 phenyl),
7.27 (1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 8.01 (3H, brs, NH.sub.2
Aib), 8.96 (1H, d, J=8 Hz, NH amide), 10.81 (1H, d, J=2 Hz, NH
indole).
[0508] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0509] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 26.4
(CH.sub.2--CH.sub.2-phenyl), 29.1 (CH.sub.2 .beta.Trp), 32.7
(CH.sub.2--CH.sub.2-phenyl), 45.7 (CH .alpha.Trp), 45.8
(CH.sub.2-m-methoxybenzyl), 55.5 (OCH.sub.3), 56.7 (Cq Aib), 109.8
(C.sub.3 Trp), 111.8 (C.sub.7 Trp), 112.5 (C.sub.2
m-methoxybenzyl), 113.5 (C.sub.4 m-methoxybenzyl), 118.2 (C.sub.4
Trp), 118.4 (C.sub.6 m-methoxybenzyl), 118.7 (C.sub.5 Trp), 121.3
(C.sub.6 Trp), 124.8 (C.sub.2 Trp), 126.5 (C.sub.4 phenyl), 127.3
(C.sub.9 Trp), 128.7 (C.sub.2, C.sub.3, C.sub.5 and C.sub.6
phenyl), 130.5 (C.sub.5 m-methoxybenzyl), 136.4 (C.sub.8 Trp),
137.7 (C.sub.1 m-methoxybenzyl), 170.9 (C.sub.1 phenyl), 154.6 (Cq
triazole), 154.9 (Cq triazole), 160.1 (C.sub.3 m-methoxybenzyl),
171.9 (CO amide).
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 20)
[0510] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0511] .delta.(ppm) 1.28 (3H, s, CH.sub.3 Aib), 1.32 (3H, s,
CH.sub.3 Aib), 2.46 (2H, m, CH.sub.2--CH.sub.2-phenyl), 2.82 (2H,
m, CH.sub.2--CH.sub.2-phenyl), 3.35 (2H, d, J=7 Hz, CH.sub.2
.beta.Trp), 3.68 (3H, s, OCH.sub.3), 5.02 (2H, s,
CH.sub.2-p-methoxybenzyl), 5.22 (1H, m, CH .alpha.Trp), 6.73-6.81
(4H, m, CHar p-methoxybenzyl), 6.84 (1H, t, J.sub.o=7 Hz, H.sub.5
Trp), 7.00 (1H, t, J.sub.o=7 Hz, H.sub.6 Trp), 7.05-7.11 (4H, m,
H.sub.2 and H.sub.6 phenyl, H.sub.2 and H.sub.4 Trp), 7.14-7.22
(3H, m, H.sub.3, H.sub.4 and H.sub.5 phenyl), 7.29 (1H, d,
J.sub.o=8 Hz, H.sub.7 Trp), 8.09 (3H, brs, NH.sub.2 Aib), 8.99 (1H,
d, J=8 Hz, NH amide), 10.83 (1H, s, NH indole Trp).
[0512] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0513] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 26.5
(CH.sub.2--CH.sub.2-phenyl), 29.1 (CH.sub.2 .beta.Trp), 32.6
(CH.sub.2--CH.sub.2-phenyl), 45.5 (CH.sub.2-p-methoxybenzyl), 45.7
(CH .alpha.Trp), 55.5 (OCH.sub.3), 56.8 (Cq Aib), 109.7 (C.sub.3
Trp), 111.8 (C.sub.7 Trp), 114.6 (C.sub.3 and C.sub.5
p-methoxybenzyl), 118.3 (C.sub.4 Trp), 118.7 (C.sub.5 Trp), 121.3
(C.sub.6 Trp), 124.9 (C.sub.2 Trp), 126.6 (C.sub.2 and C.sub.6
phenyl), 127.3 (C.sub.9 Trp), 127.6 (C.sub.1 p-methoxybenzyl),
128.0 (C.sub.2 and C.sub.6 p-methoxybenzyl), 128.7 (C.sub.3,
C.sub.4 and C.sub.5 phenyl), 136.4 (C.sub.8 Trp), 140.8 (C.sub.1
phenyl), 154.5 (Cq triazole), 154.8 (Cq triazole), 159.2 (C.sub.4
p-methoxybenzyl), 172.0 (CO Aib).
(R)--N-(1-(4-(4-methoxybenzyl)-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)-2-
-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound
22)
[0514] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree.K):
[0515] .delta.(ppm) 1.27 (3H, s, CH.sub.3 Aib), 1.31 (3H, s,
CH.sub.3 Aib), 1.73 (2H, m, CH.sub.2--CH.sub.2--CH.sub.2-phenyl),
2.47 (2H, m, CH.sub.2--CH.sub.2--CH.sub.2-phenyl), 2.52 (2H, t,
.sup.3J=7 Hz, CH.sub.2--CH.sub.2--CH.sub.2-phenyl), 3.35 (2H, d,
J=7 Hz, CH.sub.2 .beta.Trp), 3.68 (3H, s, OCH.sub.3), 4.98 (2H, s,
CH.sub.2-p-methoxybenzyl), 5.20 (1H, m, CH .alpha.Trp), 6.75 (4H,
m, CHar p-methoxybenzyl), 6.82 (1H, t, J.sub.o=7 Hz, H.sub.5 Trp),
6.99 (1H, t, J.sub.o=7 Hz, H.sub.6 Trp), 7.04-7.07 (4H, m, H.sub.2
and H.sub.6 phenyl, H.sub.2 and H.sub.4 Trp), 7.13-7.24 (3H, m,
H.sub.3, H.sub.4 and H.sub.5 phenyl), 7.29 (1H, d, J.sub.o=8 Hz,
H.sub.7 Trp), 8.03 (3H, brs, NH.sub.2 Aib), 8.96 (1H, d, J=8 Hz, NH
amide), 10.80 (1H, d, J=2 Hz, NH indole Trp).
[0516] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0517] .delta.(ppm) 23.6 (CH.sub.3 Aib), 23.6 (CH.sub.3 Aib), 24.06
(CH.sub.2--CH.sub.2--CH.sub.2-phenyl), 28.5
(CH.sub.2--CH.sub.2--CH.sub.2-phenyl),29.2 (CH.sub.2 .beta.Trp),
34.7 (CH.sub.2--CH.sub.2--CH.sub.2-phenyl), 45.5
(CH.sub.2-p-methoxybenzyl), 45.8 (CH .alpha.Trp), 55.5 (OCH.sub.3),
56.8 (Cq Aib), 109.8 (C.sub.3 Trp), 111.8 (C.sub.7 Trp), 114.6
(C.sub.3 and C.sub.5 p-methoxybenzyl), 118.3 (C.sub.4 Trp), 118.7
(C.sub.5 Trp), 121.3 (C.sub.6 Trp), 124.9 (C.sub.2 Trp), 126.2
(C.sub.2 and C.sub.6 phenyl), 127.3 (C.sub.9 Trp), 127.8 (C.sub.1
p-methoxybenzyl), 127.9 (C.sub.2 and C.sub.6 p-methoxybenzyl),
128.7 (C.sub.3, C.sub.4 and C.sub.5 phenyl), 136.4 (C.sub.8 Trp),
141.7 (C.sub.1 phenyl), 154.8 (Cq triazole), 159.2 (C.sub.4
p-methoxybenzyl), 171.9 (CO Aib).
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-5-(3-(1H-indol-3-yl)propyl)-4H-1,2,4-
-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide
(Compound 24)
[0518] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0519] .delta.(ppm) 1.29 (3H, s, CH.sub.3 Aib), 1.35 (3H, s,
CH.sub.3 Aib), 1.78 (2H, m, CH.sub.2--CH.sub.2--CH.sub.2-indole),
2.34 (2H, m, CH.sub.2--CH.sub.2--CH.sub.2-indole), 2.48 (2H, m,
N--CH.sub.2--CH.sub.2-indole), 2.80 (2H, m,
CH.sub.2--CH.sub.2--CH.sub.2-indole), 3.34 (2H, m,
N--CH.sub.2--CH.sub.2-indole), 3.94 (2H, m, CH.sub.2 .beta.Trp),
5.27 (1H, m, CH .alpha.Trp), 6.73-6.94 (4H, m, H.sub.5 and H.sub.6
Trp, H.sub.5 indole from N--CH.sub.2--CH.sub.2-indole and H.sub.5
indole from CH.sub.2--CH.sub.2--CH.sub.2-indole), 6.99-7.04 (5H, m,
H.sub.2 Trp, H.sub.2 and H.sub.6 indole from
N--CH.sub.2--CH.sub.2-indole, H.sub.2 and H.sub.6 indole from
CH.sub.2--CH.sub.2--CH.sub.2-indole), 7.20 (1H, d, J.sub.o=8 Hz,
H.sub.4 indole from N--CH.sub.2--CH.sub.2-indole), 7.29 (3H, m,
H.sub.4 and H.sub.7 Trp, H.sub.7 indole from
N--CH.sub.2--CH.sub.2-indole), 7.40 (1H, d, J.sub.o=8 Hz, H.sub.7
indole from CH.sub.2--CH.sub.2--CH.sub.2-indole), 7.44 (1H, d,
J.sub.o=8 Hz, H.sub.4 indole from
CH.sub.2--CH.sub.2--CH.sub.2-indole), 8.05 (3H, brs, NH.sub.2 Aib),
9.07 (1H, d, J=8 Hz, NH amide), 10.75 (1H, s, NH indole from
CH.sub.2--CH.sub.2--CH.sub.2-indole), 10.86 (1H, s, NH indole Trp),
10.90 (1H, s, NH indole from N--CH.sub.2--CH.sub.2-indole).
[0520] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0521] .delta.(ppm) 23.6 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 24.5
(CH.sub.2--CH.sub.2--CH.sub.2-indole), 25.8
(CH.sub.2--CH.sub.2--CH.sub.2-indole), 27.2
(CH.sub.2--CH.sub.2--CH.sub.2-indole), 29.4 (CH.sub.2 .beta.Trp),
44.1 (N--CH.sub.2--CH.sub.2-indole), 46.0 (CH .alpha.Trp), 52.9
(N--CH.sub.2--CH.sub.2-indole), 56.8 (Cq Aib), 109.7 (C.sub.3 Trp
and C.sub.3 indole from N--CH.sub.2--CH.sub.2-indole), 111.8
(C.sub.7 Trp), 111.9 (C.sub.7 indole from
N--CH.sub.2--CH.sub.2-indole and C.sub.7 indole from
CH.sub.2--CH.sub.2--CH.sub.2-indole), 114.0 (C.sub.3 indole from
CH.sub.2--CH.sub.2--CH.sub.2-indole), 118.2 (C.sub.4 indole from
N--CH.sub.2--CH.sub.2-indole), 118.3 (C.sub.4 Trp), 118.5 (C.sub.5
indole from CH.sub.2--CH.sub.2--CH.sub.2-indole), 118.6 (C.sub.4
indole from CH.sub.2--CH.sub.2--CH.sub.2-indole), 118.9 (C.sub.5
Trp), 119.0 (C.sub.5 indole from N--CH.sub.2--CH.sub.2-indole),
121.3 (C.sub.6 Trp), 121.4 (C.sub.6 indole from
CH.sub.2--CH.sub.2--CH.sub.2-indole), 121.6 (C.sub.6 indole from
N--CH.sub.2--CH.sub.2-indole), 122.7 (C.sub.2 Trp, C.sub.2 indole
from N--CH.sub.2--CH.sub.2-indole and C.sub.2 indole from
CH.sub.2--CH.sub.2--CH.sub.2-indole), 127.1 (C.sub.9 Trp), 127.4
(C.sub.9 indole from N--CH.sub.2--CH.sub.2-indole and C.sub.9
indole from CH.sub.2--CH.sub.2--CH.sub.2-indole), 136.4 (C.sub.8
Trp), 136.5 (C.sub.8 indole from
CH.sub.2--CH.sub.2--CH.sub.2-indole), 136.7 (C.sub.8 indole from
N--CH.sub.2--CH.sub.2-indole), 154.7 (2 Cq triazole), 171.9 (CO
amide).
(R)--N-(1-(4-(2-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 26)
[0522] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0523] .delta.(ppm) 1.26 (3H, s, CH.sub.3 Aib), 1.29 (3H, s,
CH.sub.3 Aib), 2.78-2.92 (4H, m, CH.sub.2--CH.sub.2-phenyl), 3.29
(2H, m, CH.sub.2 .beta.Trp), 3.65 (3H, s, OCH.sub.3), 4.97-5.21
(3H, m, CH .alpha.Trp and CH.sub.2-o-methoxybenzyl), 6.52 (1H, d,
J.sub.o=7 Hz, H.sub.3 o-methoxybenzyl), 6.78 (1H, t, J.sub.o=7 Hz,
H.sub.5 Trp), 6.82 (1H, t, J.sub.o=8 Hz, H.sub.6 Trp), 6.84-7.04
(3H, m, H.sub.4, H.sub.5 and H.sub.6 o-methoxybenzyl), 7.15 (1H, d,
J.sub.o=7 Hz, H.sub.4 Trp), 7.19-7.29 (4H, m, H.sub.3, H.sub.4 and
H.sub.5 phenyl, H.sub.7 Trp), 8.03 (3H, brs, NH.sub.2 Aib), 8.94
(1H, d, J=8 Hz, NH amide), 10.82 (1H, s, NH indole Trp).
[0524] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0525] .delta.(ppm) 23.6 (CH.sub.3 Aib), 23.7 (CH.sub.3 Aib), 26.3
(CH.sub.2--CH.sub.2-phenyl), 29.0 (CH.sub.2 .beta.Trp), 32.5
(CH.sub.2--CH.sub.2-phenyl), 42.3 (CH.sub.2-o-methoxybenzyl), 45.7
(CH .alpha.Trp), 55.8 (OCH.sub.3), 56.7 (Cq Aib), 109.7 (C.sub.3
Trp), 111.5 (C.sub.7 Trp), 111.8 (C.sub.3 o-methoxybenzyl), 118.2
(C.sub.4 Trp), 118.7 (C.sub.5 Trp), 121.0 (C.sub.6 Trp), 121.3
(C.sub.5 o-methoxybenzyl), 123.2 (C.sub.1 o-methoxybenzyl), 124.9
(C.sub.2 Trp), 126.6 (C.sub.2 and C.sub.6 phenyl), 127.2 (C.sub.9
Trp and C.sub.4 o-methoxybenzyl), 128.7 (C.sub.3, C.sub.4 and
C.sub.5 phenyl), 129.9 (C.sub.6 o-methoxybenzyl), 136.4 (C.sub.8
Trp), 140.6 (C.sub.1 phenyl), 154.8 (Cq triazole), 155.2 (Cq
triazole), 156.7 (C.sub.2 o-methoxybenzyl), 171.9 (CO Aib).
(R)--N-(2-(1H-indol-3-yl)-1-(4-(naphthalen-1-ylmethyl)-5-phenethyl-4H-1,2,-
4-triazol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 27)
[0526] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0527] .delta.(ppm) 1.21 (3H, s, CH.sub.3 Aib), 1.25 (3H, s,
CH.sub.3 Aib), 2.46 (2H, m, CH.sub.2--CH.sub.2-phenyl), 2.88 (2H,
m, CH.sub.2--CH.sub.2-phenyl), 3.26 (2H, dd, .sup.3J=14 Hz and 6
Hz, CH.sub.2 .beta.Trp), 3.36 (2H, dd, .sup.3J=14 Hz and 9 Hz,
CH.sub.2 .beta.Trp), 4.99 (1H, m, CH .alpha.Trp), 5.65 (1H, d,
.sup.3J=18 Hz, CH.sub.2-naphtyl), 5.78 (1H, d, .sup.3J=18 Hz,
CH.sub.2-naphtyl), 6.29 (1H, d, J.sub.o=7 Hz, H.sub.2 naphtyl),
6.45 (1H, t, J.sub.o=7 Hz, H.sub.5 Trp), 6.62 (1H, d, J.sub.o=8 Hz,
H.sub.4 Trp), 6.88 (1H, t, J.sub.o=8 Hz, H.sub.6 Trp), 7.04-7.06
(4H, m, H.sub.2 and H.sub.7 Trp, H.sub.2 and H.sub.6 phenyl),
7.07-7.25 (H.sub.3 naphtyl, H.sub.3, H.sub.4 and H.sub.5 phenyl),
7.57-7.60 (2H, m, H.sub.6 and H.sub.7 naphtyl), 7.86 (1H, d,
J.sub.o=8 Hz, H.sub.4 naphtyl), 7.98-8.00 (4H, m, H.sub.5 and
H.sub.8 naphtyl, NH.sub.2 Aib), 8.96 (1H, d, J=8 Hz, NH amide),
10.77 (1H, s, NH indole Trp).
[0528] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0529] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.6 (CH.sub.3 Aib), 26.3
(CH.sub.2CH.sub.2-phenyl), 29.2 (CH.sub.2 .beta.Trp), 32.6
(CH.sub.2--CH.sub.2-phenyl), 43.8 (CH.sub.2-naphtyl), 45.6 (CH
.alpha.Trp), 56.7 (Cq Aib), 109.7 (C.sub.3 Trp), 111.7 (C.sub.7
Trp), 117.9 (C.sub.4 Trp), 118.4 (C.sub.5 Trp), 121.1 (C.sub.6
Trp), 122.1 (C.sub.2 naphtyl), 123.0 (C.sub.8 naphtyl), 124.9
(C.sub.2 Trp), 125.9 (C.sub.3 naphtyl), 126.5 (C.sub.6 naphtyl),
126.9 (C.sub.2 and C.sub.6 phenyl), 127.0 (C.sub.9 Trp and C.sub.7
naphtyl), 127.1 (C.sub.4 naphtyl), 128.4 (C.sub.5 naphtyl), 128.7
(C.sub.3, C.sub.4 and C.sub.5 phenyl), 130.0 (C.sub.9 naphtyl),
131.7 (C.sub.1 naphtyl), 133.6 (C.sub.10 naphtyl), 136.4 (C.sub.8
Trp), 140.8 (C.sub.1 phenyl), 154.8 (Cq triazole), 155.3 (Cq
triazole), 171.9 (CO Aib).
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3,4-dichlorobenzyl)-4H-1,2,4-tria-
zol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide
(Compound 28)
[0530] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0531] .delta.(ppm) 1.26 (6H, s, CH.sub.3 Aib), 2.87 (2H, m,
CH.sub.2--CH.sub.2-indole), 2.96 (2H, m,
CH.sub.2--CH.sub.2-indole), 3.32 (2H, m, CH.sub.2 .beta.Trp), 5.13
(3H, m, CH .alpha.Trp and CH.sub.2-m,p-dichlorobenzyl), 6.58 (1H,
d, J.sub.o=8 Hz, H.sub.6 m,p-dichlorobenzyl), 6.85 (1H, t,
J.sub.o=7 Hz, H.sub.5 Trp), 6.96 (1H, t, J.sub.o=7 Hz, H.sub.5
indole), 7.01 (2H, m, H.sub.6 indole and H.sub.6 Trp), 7.04 (1H, s,
H.sub.2 Trp), 7.08 (1H, s, H.sub.2 indole), 7.13 (1H, d, J.sub.o=8
Hz, H.sub.5 m,p-dichlorobenzyl), 7.20-7.30 (4H, m, H.sub.4 and
H.sub.7 indole, H.sub.7 Trp and H.sub.2 m,p-dichlorobenzyl), 7.36
(1H, d, J.sub.o=8 Hz, H.sub.4 Trp), 8.08 (3H, brs, NH.sub.2 Aib),
8.98 (1H, d, J=8 Hz, NH amide), 10.80 (1H, s, NH indole), 10.82
(1H, s, NH indole Trp).
[0532] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0533] .delta.(ppm) 22.8 (CH.sub.2--CH.sub.2-indole), 23.4
(CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 25.8
(CH.sub.2--CH.sub.2-indole), 29.0 (CH.sub.2 .beta.Trp), 44.8
(CH.sub.2-m,p-dichlorobenzyl), 45.6 (CH .alpha.Trp), 56.8 (Cq Aib),
109.7 (C.sub.3 indole), 111.8 (C.sub.7 indole and C.sub.7 Trp),
118.1 (C.sub.4 Trp), 118.4 (C.sub.5 indole), 118.6 (C.sub.4 indole
and C.sub.5 Trp), 121.3 (C.sub.6 indole and C.sub.6 Trp), 123.0
(C.sub.2 indole and C.sub.2 Trp), 126.4 (C.sub.6
m,p-dichlorobenzyl), 127.1 (C.sub.9 Trp), 127.3 (C.sub.9 indole),
128.6 (C.sub.2 m,p-dichlorobenzyl), 130.9 (C.sub.4
m,p-dichlorobenzyl), 131.3 (C.sub.5 m,p-dichlorobenzyl), 132.0
(C.sub.3 m,p-dichlorobenzyl), 136.4 (C.sub.8 Trp), 136.6 (C.sub.8
indole), 137.2 (C.sub.1 m,p-dichlorobenzyl), 154.7 (Cq triazole),
155.1 (Cq triazole), 172.0 (CO Aib).
(R)--N-(1-(4-(4-fluorobenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol--
3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 30)
[0534] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0535] .delta.(ppm) 1.27 (3H, s, CH.sub.3 Aib), 1.29 (3H, s,
CH.sub.3 Aib), 3.33 (2H, m, CH.sub.2 .beta.Trp), 4.02 (2H, s,
CH.sub.2-benzyl), 5.10 (3H, m, CH.sub.2-p-fluorobenzyl and CH
.alpha.Trp), 6.71 (2H, m, H.sub.3 and H.sub.5 p-fluorobenzyl), 6.80
(1H, t, J.sub.o=8 Hz, H.sub.5 Trp), 6.90 (2H, d, J.sub.o=8 Hz,
H.sub.2 and H.sub.6 p-fluorobenzyl), 6.94 (1H, t, J.sub.o=8 Hz,
H.sub.6 Trp), 6.99-7.10 (4H, m, H.sub.2 and H.sub.4 Trp, H.sub.2
and H.sub.6 benzyl), 7.20 (3H, m, H.sub.3, H.sub.4 and H.sub.5
benzyl), 7.27 (1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 8.09 (3H, brs,
NH.sub.2 Aib), 8.97 (1H, d, J=8 Hz, NH amide), 10.79 (1H, s, NH
indole Trp).
[0536] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0537] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 29.0
(CH.sub.2 .beta.Trp), 31.1 (CH.sub.2-benzyl), 45.7
(CH.sub.2-p-fluorobenzyl), 45.8 (CH .alpha.Trp), 56.8 (Cq Aib),
109.6 (C.sub.3 Trp), 111.8 (C.sub.7 Trp), 115.6 and 115.9 (C.sub.3
and C.sub.5 p-fluorobenzyl), 118.2 (C.sub.4 Trp), 118.7 (C.sub.5
Trp), 121.3 (C.sub.6 Trp), 124.8 (C.sub.2 Trp), 127.1 (C.sub.4
benzyl), 127.2 (C.sub.9 Trp), 128.8 and 128.9 (C.sub.2 and C.sub.6
p-fluorobenzyl), 129.4 (C.sub.2, C.sub.3, C.sub.5 and C.sub.6
p-fluorobenzyl), 131.6 (C.sub.1 p-fluorobenzyl), 135.9 (C.sub.1
benzyl), 136.4 (C.sub.8 Trp), 154.0 (C.sub.4 p-fluorobenzyl), 155.3
(Cq triazole), 172.0 (CO amide).
(R)--N-(1-(4-(4-methylbenzyl)-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 33)
[0538] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0539] .delta.(ppm) 1.25 (3H, s, CH.sub.3 Aib), 1.28 (3H, s,
CH.sub.3 Aib), 1.73 (2H, m, CH.sub.2--CH.sub.2--CH.sub.2-phenyl),
2.23 (3H, s, CH.sub.3 p-methylbenzyl), 2.49-2.54 (4H, m,
CH.sub.2--CH.sub.2--CH.sub.2-phenyl), 3.33 (2H, m, CH.sub.2
.beta.Trp), 5.04 (2H, s, CH.sub.2-p-methylbenzyl), 5.16 (1H, m, CH
.alpha.Trp), 6.74 (2H, d, J.sub.o=8 Hz, H.sub.3 and H.sub.5
p-methylbenzyl), 6.80 (1H, t, J.sub.o=7 Hz, H.sub.5 Trp), 6.98 (1H,
t, J.sub.o=7 Hz, H.sub.6 Trp), 7.03 (1H, d, J=2 Hz, H.sub.2 Trp),
7.06 (5H, m, CHar phenyl), 7.14 (1H, d, J.sub.o=7 Hz, H.sub.4 Trp),
7.20 (2H, d, J.sub.o=7 Hz, H.sub.2 and H.sub.6 p-methylbenzyl),
7.27 (1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 8.01 (3H, brs, NH.sub.2
Aib), 8.95 (1H, d, J=8 Hz, NH amide), 10.80 (1H, d, J=2 Hz, NH
indole Trp).
[0540] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0541] .delta.(ppm) 21.0 (CH.sub.3 p-methylbenzyl), 23.5 (CH.sub.3
Aib), 23.8 (CH.sub.3 Aib), 24.0
(CH.sub.2--CH.sub.2--CH.sub.2-phenyl), 28.5
(CH.sub.2--CH.sub.2--CH.sub.2-phenyl), 29.1 (CH.sub.2 .beta.Trp),
34.7 (CH.sub.2--CH.sub.2--CH.sub.2-phenyl), 45.7 (CH .alpha.Trp),
45.8 (CH.sub.2-p-methylbenzyl), 56.8 (Cq Aib), 109.8 (C.sub.3 Trp),
111.8 (C.sub.7 Trp), 118.3 (C.sub.4 Trp), 118.7 (C.sub.5 Trp),
121.3 (C.sub.6 Trp), 124.9 (C.sub.2 Trp), 126.2 (C.sub.4 phenyl),
126.4 (C.sub.3 and C.sub.5 p-methylbenzyl), 127.3 (C.sub.9 Trp),
128.7 (C.sub.2, C.sub.3, C.sub.5 and C.sub.6 phenyl), 129.8
(C.sub.2 and C.sub.6 p-methylbenzyl), 133.0 (C.sub.1
p-methylbenzyl), 136.4 (C.sub.8 Trp), 137.5 (C.sub.4
p-methylbenzyl), 141.7 (C.sub.1 phenyl), 154.8 (Cq triazole), 171.9
(CO Aib).
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methylbenzyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound
34)
[0542] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0543] .delta.(ppm) 1.25 (3H, s, CH.sub.3 Aib), 1.28 (3H, s,
CH.sub.3 Aib), 2.23 (3H, s, CH.sub.3-p-methylbenzyl), 2.84-2.97
(4H, m, CH.sub.2--CH.sub.2-indole), 3.32 (2H, m, CH.sub.2
.beta.Trp), 5.04 (2H, s, CH.sub.2-p-methylbenzyl), 5.16 (1H, m, CH
.alpha.Trp), 6.79-6.86 (4H, m, CH ar p-methylbenzyl), 6.99-7.05
(4H, m, H.sub.5 and H.sub.6 indole, H.sub.5 and H.sub.6 Trp), 7.08
(3H, m, H.sub.2 indole, H.sub.2 and H.sub.4 Trp), 7.25-7.30 (3H, m,
H.sub.4 and H.sub.7 indole, H.sub.7 Trp), 8.00 (3H, brs, NH.sub.2
Aib), 8.94 (1H, d, J=8 Hz, NH amide), 10.76 (1H, s, NH indole),
10.78 (1H, s, NH indole Trp).
[0544] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0545] .delta.(ppm) 21.0 (CH.sub.3-p-methylbenzyl), 22.8
(CH.sub.2--CH.sub.2-indole), 23.8 (CH.sub.3 Aib), 23.9 (CH.sub.3
Aib), 25.9 (CH.sub.2--CH.sub.2-indole), 28.5 (CH.sub.2 .beta.Trp),
45.7 (CH.sub.2-p-methylbenzyl and CH .alpha.Trp), 56.7 (Cq Aib),
109.9 (C.sub.3 Trp), 111.8 (C.sub.7 indole and C.sub.7 Trp), 113.4
(C.sub.3 indole), 118.1 (C.sub.4 Trp), 118.3 (C.sub.4 indole),
118.5 (C.sub.5 indole), 118.7 (C.sub.5 Trp), 120.9 (C.sub.6 indole
and C.sub.6 Trp), 121.3 (C.sub.2 indole and C.sub.2 Trp), 126.3
(C.sub.3 and C.sub.5 p-methylbenzyl), 127.2 (C.sub.9 indole), 127.3
(C.sub.9 Trp), 129.8 (C.sub.2 and C.sub.6 p-methylbenzyl), 133.1
(C.sub.1 p-methylbenzyl), 135.8 (C.sub.8 indole, C.sub.8 Trp),
136.4 (C.sub.4 p-methylbenzyl), 154.8 (Cq triazole), 155.0 (Cq
triazole), 171.9 (CO Aib).
(R)--N-(1-(4-(4-methylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 37)
[0546] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0547] .delta.(ppm) 1.25 (3H, s, CH.sub.3 Aib), 1.28 (3H, s,
CH.sub.3 Aib), 2.23 (3H, s, CH.sub.3 p-methylbenzyl), 2.83 (4H, m,
CH.sub.2--CH.sub.2-phenyl), 3.32 (2H, m, CH.sub.2 .beta.Trp), 5.05
(2H, s, CH.sub.2-p-methylbenzyl), 5.18 (1H, m, CH .alpha.Trp), 6.75
(2H, d, J.sub.o=8 Hz, H.sub.3 and H.sub.5 p-methylbenzyl), 6.82
(1H, t, J.sub.o=8 Hz, H.sub.5 Trp), 6.99 (1H, t, J.sub.o=8 Hz,
H.sub.6 Trp), 7.02-7.11 (6H, m, H.sub.2 Trp and CHar phenyl), 7.15
(1H, d, J.sub.o=7 Hz, H.sub.4 Trp), 7.20 (2H, d, J.sub.o=7 Hz,
H.sub.2 and H.sub.6 p-methylbenzyl), 7.28 (1H, d, J.sub.o=8 Hz,
H.sub.7 Trp), 8.01 (3H, brs, NH.sub.2 Aib), 8.93 (1H, d, J=8 Hz, NH
amide), 10.77 (1H, s, NH indole Trp).
[0548] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0549] .delta.(ppm) 21.0 (CH.sub.3 p-methylbenzyl), 23.6 (CH.sub.3
Aib), 23.8 (CH.sub.3 Aib), 26.5 (CH.sub.2--CH.sub.2-phenyl), 29.1
(CH.sub.2 .beta.Trp), 32.7 (CH.sub.2--CH.sub.2-phenyl), 45.7 (CH
.alpha.Trp and CH.sub.2-p-methylbenzyl), 56.8 (Cq Aib), 109.8
(C.sub.3 Trp), 111.8 (C.sub.7 Trp), 118.3 (C.sub.4 Trp), 118.7
(C.sub.5 Trp), 121.3 (C.sub.6 Trp), 124.8 (C.sub.2 Trp), 126.4
(C.sub.3 and C.sub.5 p-methylbenzyl), 126.6 (C.sub.4 phenyl), 127.3
(C.sub.9 Trp), 128.7 (C.sub.2, C.sub.3, C.sub.5 and C.sub.6
phenyl), 129.8 (C.sub.2 and C.sub.6 p-methylbenzyl), 133.0 (C.sub.1
p-methylbenzyl), 136.4 (C.sub.8 Trp), 137.5 (C.sub.4
p-methylbenzyl), 140.9 (C.sub.1 phenyl), 154.5 (Cq triazole), 154.9
(Cq triazole), 171.9 (CO amide).
(R)--N-(1-(5-benzyl-4-(pyridin-2-ylmethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 39)
[0550] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0551] .delta.(ppm) 1.23 (3H, s, CH.sub.3 Aib), 1.27 (3H, s,
CH.sub.3 Aib), 3.34 (1H, dd, J=14 Hz and 6 Hz, CH.sub.2 .beta.Trp),
3.43 (1H, dd, J=14 Hz and 9 Hz, CH.sub.2 .beta.Trp), 4.13 (2H, s,
CH.sub.2-benzyl), 5.22 (1H, s, CH .alpha.Trp), 5.35 (2H, s,
CH.sub.2-o-pyridyl), 6.80 (1H, t, J.sub.o=8 Hz, H.sub.5 Trp), 6.92
(1H, t, J.sub.o=8 Hz, H.sub.5 pyridyl), 6.97 (1H, t, J.sub.o=8 Hz,
H.sub.6 Trp), 7.04 (1H, d, J.sub.o=8 Hz, H.sub.4 Trp), 7.07 (1H, d,
J=2 Hz, H.sub.2 Trp), 7.10-7.16 (5H, m, CHar benzyl), 7.19 (1H, s,
H.sub.3 o-pyridyl), 7.26 (1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 7.57
(1H, t, J.sub.o=9 Hz, H.sub.4 o-pyridyl), 8.16 (3H, brs, NH.sub.2
Aib), 8.36 (1H, d, J.sub..alpha..beta.=5 Hz, H.sub.6 o-pyridyl),
9.01 (1H, d, J=8 Hz, NH amide), 10.85 (1H, s, NH indole Trp).
[0552] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0553] .delta.(ppm) 23.4 (CH.sub.3 Aib), 23.7 (CH.sub.3 Aib), 28.6
(CH.sub.2 .beta.Trp), 30.4 (CH.sub.2-benzyl), 45.7 (CH .alpha.Trp),
47.7 (CH.sub.2-o-pyridyl), 56.7 (Cq Aib), 109.8 (C.sub.3 Trp),
111.8 (C.sub.7 Trp), 118.3 (C.sub.4 Trp), 118.6 (C.sub.5 Trp),
121.2 (C.sub.6 Trp), 121.7 (C.sub.3 o-pyridyl), 123.3 (C.sub.5
o-pyridyl), 124.8 (C.sub.2 Trp), 127.1 (C.sub.4 benzyl), 127.3
(C.sub.9 Trp), 128.8 (C.sub.2 and C.sub.6 benzyl), 129.0 (C.sub.3
and C.sub.5 benzyl), 135.6 (C.sub.1 benzyl), 136.4 (C.sub.8 Trp),
137.5 (C.sub.4 o-pyridyl), 149.5 (C.sub.6 o-pyridyl), 154.1 (Cq
triazole), 154.2 (Cq triazole), 155.7 (C.sub.2 o-pyridyl), 172.0
(CO amide).
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 43)
[0554] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0555] .delta.(ppm) 1.10 (3H, t, J=8 Hz, CH.sub.3--CH.sub.2
p-ethylbenzyl), 1.25 (3H, s, CH.sub.3 Aib), 1.28 (3H, s, CH.sub.3
Aib), 2.53 (2H, q, J=8 Hz, CH.sub.3--CH.sub.2 p-ethylbenzyl), 2.83
(4H, m, CH.sub.2--CH.sub.2-phenyl), 3.34 (2H, m, CH.sub.2
.beta.Trp), 5.07 (2H, s, CH.sub.2-p-ethylbenzyl), 5.19 (1H, m, CH
.alpha.Trp), 6.77 (2H, d, J.sub.o=8 Hz, H.sub.3 and H.sub.5
p-ethylbenzyl), 6.81 (1H, t, J.sub.o=7 Hz, H.sub.5 Trp), 6.99 (1H,
t, J.sub.o=8 Hz, H.sub.6 Trp), 7.05-7.10 (7H, m, CHar phenyl,
H.sub.2 and H.sub.6 p-ethylbenzyl), 7.13 (1H, d, J=2 Hz, H.sub.2
Trp), 7.20 (1H, d, J.sub.o=7 Hz, H.sub.4 Trp), 7.28 (1H, d,
J.sub.o=8 Hz, H.sub.7 Trp), 8.03 (3H, brs, NH.sub.2 Aib), 8.94 (1H,
d, J=8 Hz, NH amide), 10.79 (1H, s NH indole Trp).
[0556] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0557] .delta.(ppm) 15.9 (CH.sub.3--CH.sub.2 p-ethylbenzyl), 23.5
(CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 26.5
(CH.sub.2--CH.sub.2-phenyl), 28.1 (CH.sub.3--CH.sub.2
p-ethylbenzyl), 29.1 (CH.sub.2 .beta.Trp), 32.7
(CH.sub.2--CH.sub.2-phenyl), 45.7 (CH .alpha.Trp), 45.8
(CH.sub.2-p-ethylbenzyl), 56.8 (Cq Aib), 109.8 (C.sub.3 Trp), 111.8
(C.sub.7 Trp), 118.3 (C.sub.4 Trp), 118.7 (C.sub.5 Trp), 121.3
(C.sub.6 Trp), 124.9 (C.sub.2 Trp), 126.5 (C.sub.3 and C.sub.5
p-ethylbenzyl), 126.6 (C.sub.4 phenyl), 127.3 (C.sub.9 Trp), 128.6
(C.sub.2 and C.sub.6 p-ethylbenzyl, C.sub.2, C.sub.3, C.sub.5 and
C.sub.6 phenyl), 133.1 (C.sub.1 p-ethylbenzyl), 136.5 (C.sub.8
Trp), 140.8 (C.sub.1 phenyl), 143.8 (C.sub.4 p-ethylbenzyl), 154.6
(Cq triazole), 154.9 (Cq triazole), 171.9 (CO amide).
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)piperidine-4-carboxamide (Compound 44)
[0558] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0559] .delta.(ppm) 1.42 (m, 2H, H.sub.3 and H.sub.5 piperidyl),
1.55 (m, 1H, H.sub.5 piperidyl), 2.23 (m, 1H, H.sub.4 piperidyl),
2.75 (m, 5H, H.sub.2 piperidyl and CH.sub.2--CH.sub.2-phenyl), 3.04
(m, 1H, H.sub.6 piperidyl), 3.13 (m, 1H, H.sub.2 piperidyl), 3.32
(m, 2H, CH.sub.2 .beta.Trp), 3.66 (s, 3H, OCH.sub.3), 4.97 (m, 2H,
CH.sub.2-p-methoxybenzyl), 5.23 (m, 1H, CH .alpha.Trp), 6.70 (s,
4H, CHar p-methoxybenzyl), 6.87 (t, 1H, J.sub.o=8 Hz, H.sub.5 Trp),
7.00 (m, 2H, H.sub.2 and H.sub.6 Trp), 7.07 (d, 2H, J.sub.o=8 Hz,
H.sub.2 and H.sub.6 phenyl), 7.14 (d, 1H, J.sub.o=7 Hz, H.sub.4
Trp), 7.18-7.30 (m, 4H, H.sub.7 Trp, H.sub.3, H.sub.4 and H.sub.5
phenyl), 8.16 and 8.46 (2 m, 2H, NH piperidyl TFA salt), 8.66 (d
1H, J=8 Hz, NH amide), 10.75 (1H, s, NH indole Trp).
[0560] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0561] .delta.(ppm) 24.9 (C.sub.3 piperidyl), 25.4 (C.sub.5
piperidyl), 26.5 (CH.sub.2--CH.sub.2-phenyl), 29.2 (CH.sub.2
.beta.Trp), 32.7 (CH.sub.2--CH.sub.2-phenyl), 38.7 (C.sub.4
piperidyl), 42.7 (C.sub.2 and C.sub.6 piperidyl), 44.7 (CH Trp),
45.3 (CH.sub.2-p-methoxybenzyl), 55.5 (OCH.sub.3), 110.2 (C.sub.3
Trp), 111.7 (C.sub.7 Trp), 114.4 (C.sub.3 and C.sub.5
p-methoxybenzyl), 118.5 (C.sub.4 Trp), 118.7 (C.sub.5 Trp), 121.3
(C.sub.6 Trp), 124.4 (C.sub.2 Trp), 126.5 (C.sub.2 and C.sub.6
phenyl), 127.5 (C.sub.9 Trp), 127.8 (C.sub.1, C.sub.2 and C.sub.6
p-methoxybenzyl), 128.7 (C.sub.3, C.sub.4 and C.sub.5 phenyl),
136.4 (C.sub.8 Trp), 140.8 (C.sub.1 phenyl), 155.3 (Cq triazole),
155.4 (Cq triazole), 159.1 (C.sub.4 p-methoxybenzyl), 173.1 (CO
amide).
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4-carboxamide (Compound
45)
[0562] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0563] .delta.(ppm) 1.41 (m, 2H, H.sub.3 and H.sub.5 piperidyl),
1.54 (dd, 1H, J=13 Hz and 2 Hz, H.sub.5 piperidyl), 2.23 (m, 1H,
H.sub.4 piperidyl), 2.72 (m, 2H, H.sub.2 and H.sub.6 piperidyl),
2.77-2.93 (m, 4H, CH.sub.2--CH.sub.2-indole), 3.06 (m, 2H, H.sub.2
and H.sub.6 piperidyl), 3.32 (m, 2H, CH.sub.2 .beta.Trp), 3.65 (s,
3H, OCH.sub.3), 4.94 (s, 2H, CH.sub.2-p-methoxybenzyl), 5.22 (m,
1H, CH .alpha.Trp), 6.68 (s, 4H, CHar p-methoxybenzyl), 6.87 (m,
3H, H.sub.5 and H.sub.6 Trp, H.sub.5 indole), 6.98 (m, 4H, H.sub.2
and H.sub.6 indole, H.sub.2 and H.sub.4 Trp), 7.20-7.33 (m, 3H,
H.sub.4 and H.sub.7 indole, H.sub.7 Trp), 8.15 and 8.46 (2 m, 2H,
NH piperidyl TFA salt), 8.64 (d, 1H, J=8 Hz, NH amide), 10.74 (s,
2H, NH indole and NH indole Trp).
[0564] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0565] .delta.(ppm) 22.9 (CH.sub.2--CH.sub.2-indole), 24.9 (C.sub.3
piperidyl), 25.4 (C.sub.5 piperidyl), 26.0
(CH.sub.2--CH.sub.2-indole), 29.3 (CH.sub.2 .beta.Trp), 39.1
(C.sub.4 piperidyl), 42.7 (C.sub.2 and C.sub.6 piperidyl), 44.7 (CH
.alpha.Trp), 45.3 (CH.sub.2-p-methoxybenzyl), 55.5 (OCH.sub.3),
109.5 (C.sub.3 Trp), 111.7 (C.sub.7 indole and C.sub.7 Trp), 113.5
(C.sub.3 indole), 114.4 (C.sub.3 and C.sub.5 p-methoxybenzyl),
118.5 (C.sub.4 indole and C.sub.4 Trp), 118.6 (C.sub.5 indole and
C.sub.5 Trp), 121.2 (C.sub.6 indole), 121.3 (C.sub.6 Trp), 122.9
(C.sub.2 indole and C.sub.2 Trp), 127.2 (C.sub.9 indole), 127.6
(C.sub.9 Trp, C.sub.2 and C.sub.6 p-methoxybenzyl), 127.9 (C.sub.1
p-methoxybenzyl), 136.4 (C.sub.8 Trp), 136.6 (C.sub.8 indole),
154.9 (Cq triazole), 155.2 (Cq triazole), 159.0 (C.sub.4
p-methoxybenzyl), 173.0 (CO amide).
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-aminoacetamide (Compound 50)
[0566] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0567] .delta.(ppm) 2.78 (m, 4H, CH.sub.2--CH.sub.2-phenyl), 3.26
(1H, dd, J=14 Hz and 7 Hz, CH.sub.2 .beta.Trp), 3.39 (m, 3H,
CH.sub.2 .beta.Trp and CH.sub.2--NH.sub.2), 3.65 (s, 3H,
OCH.sub.3), 4.95 (m, 2H, CH.sub.2-p-methoxybenzyl), 5.20 (m, 1H, CH
.alpha.Trp), 6.63 (s, 4H, CHar p-methoxybenzyl), 6.86 (t, 1H,
J.sub.o=7 Hz, H.sub.5 Trp), 6.99 (s, 1H, H.sub.2 Trp), 7.02 (t, 1H,
J.sub.o=7 Hz, H.sub.6 Trp), 7.10 (m, 2H, H.sub.2 and H.sub.6
phenyl), 7.15 (d, 1H, J.sub.o=7 Hz, H.sub.4 Trp), 7.23 (m, 3H,
H.sub.3, H.sub.4 and H.sub.5 Trp), 7.31 (d, 1H, J.sub.o=8 Hz,
H.sub.7 Trp), 7.95 (brs, 3H, NH.sub.2 Gly, TFA salt), 9.20 (d, 1H,
J=8 Hz, NH amide), 10.82 (s, 1H, NH indole Trp).
[0568] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0569] .delta.(ppm) 26.5 (CH.sub.2--CH.sub.2-phenyl), 29.8
(CH.sub.2 .beta.Trp), 32.7 (CH.sub.2--CH.sub.2-phenyl), 39.0
(CH.sub.2--NH.sub.2), 45.3 (CH.sub.2-p-methoxybenzyl), 45.4 (CH
.alpha.Trp), 55.4 (OCH.sub.3), 109.7 (C.sub.3 Trp), 111.8 (C.sub.7
Trp), 114.5 (C.sub.3 and C.sub.5 p-methoxybenzyl), 118.3 (C.sub.4
Trp), 118.9 (C.sub.5 Trp), 121.4 (C.sub.6 Trp), 124.6 (C.sub.2
Trp), 126.5 (C.sub.2 and C.sub.6 phenyl), 127.3 (C.sub.9 Trp),
127.7 (C.sub.1 p-methoxybenzyl), 127.8 (C.sub.2 and C.sub.6
p-methoxybenzyl), 128.7 (C.sub.3, C.sub.4 and C.sub.5 phenyl),
136.4 (C.sub.8 Trp), 140.9 (C.sub.1 phenyl), 154.3 (Cq triazole),
154.8 (Cq triazole), 159.0 (C.sub.4 p-methoxybenzyl), 166.1 (CO
amide).
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide (Compound 51)
[0570] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0571] .delta.(ppm) 2.77-2.88 (m, 4H, CH.sub.2--CH.sub.2-phenyl),
3.37 (m, 2H, CH.sub.2 .beta.Trp), 3.64 (s, 3H, OCH.sub.3), 3.74 (m,
2H, CH.sub.2-o-pyridyl), 5.03 (m, 2H, CH.sub.2-p-methoxybenzyl),
5.24 (m, 1H, CH .alpha.Trp), 6.65 (s, 4H, CHar p-methoxybenzyl),
6.85 (t, 1H, J.sub.o=7 Hz, H.sub.5 Trp), 7.01 (m, 2H, H.sub.2 and
H.sub.6 Trp), 7.08 (d, 2H, J.sub.o=7 Hz, H.sub.2 and H.sub.6
phenyl), 7.15 (d, 1H, J.sub.o=7 Hz, H.sub.4 Trp), 7.21 (m, 3H,
H.sub.3, H.sub.4 and H.sub.5 phenyl), 7.27-7.36 (m, 2H, H.sub.7 Trp
and H.sub.3 o-pyridyl), 7.58 (t, 1H, J=6 Hz, H.sub.5 o-pyridyl),
8.04 (t, 1H, J.sub.o=8 Hz, H.sub.4 o-pyridyl), 8.62 (d, 1H,
J.sub..alpha..beta.=5 Hz, H.sub.6 o-pyridyl), 9.17 (d, 1H, J=8 hz,
NH amide), 10.81 (s, 1H, NH indole Trp).
[0572] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0573] .delta.(ppm) 26.4 (CH.sub.2--CH.sub.2-phenyl), 29.2
(CH.sub.2 .beta.Trp), 32.4 (CH.sub.2--CH.sub.2-phenyl), 41.7
(CH.sub.2-o-pyridyl), 45.3 (CH .alpha.Trp), 45.7
(CH.sub.2-p-methoxybenzyl), 55.5 (OCH.sub.3), 109.7 (C.sub.3 Trp),
111.8 (C.sub.7 Trp), 114.4 (C.sub.3 and C.sub.5 p-methoxybenzyl),
118.4 (C.sub.4 Trp), 118.8 (C.sub.5 Trp), 121.4 (C.sub.6 Trp),
124.1 (C.sub.3 o-pyridyl), 124.6 (C.sub.2 Trp), 126.4 (C.sub.5
o-pyridyl), 126.6 (C.sub.2 and C.sub.6 phenyl), 127.2 (C.sub.9
Trp), 127.4 (C.sub.1 p-methoxybenzyl), 127.9 (C.sub.2 and C.sub.6
p-methoxybenzyl), 128.7 (C.sub.3, C.sub.4 and C.sub.5 phenyl),
136.4 (C.sub.8 Trp), 140.5 (C.sub.1 phenyl), 142.1 (C.sub.4
o-pyridyl), 145.3 (C.sub.6 o-pyridyl), 153.0 (C.sub.2 o-pyridyl),
154.5 (Cq triazole), 155.3 (Cq triazole), 159.1 (C.sub.4
p-methoxybenzyl), 167.9 (CO amide).
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)picolinamide (Compound 64)
[0574] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0575] .delta.(ppm) 2.83 (m, 2H, CH.sub.2--CH.sub.2-phenyl), 2.90
(m, 2H, CH.sub.2--CH.sub.2-phenyl), 3.48 (m, 2H, CH.sub.2
.beta.Trp), 3.57 (s, 3H, OCH.sub.3), 3.61 (s, 3H, OCH.sub.3), 4.97
(d, 1H, J=17 Hz, CH.sub.2-o,p-dimethoxybenzyl), 5.09 (d, 1H, J=17
Hz, CH.sub.2-o,p-dimethoxybenzyl), 5.56 (m, 1H, CH .alpha.Trp),
6.18 (dd, 1H, J.sub.o=8 Hz and J.sub.m=2 Hz, H.sub.5
o,p-dimethoxybenzyl), 6.41 (d, 1H, J.sub.m=2 Hz, H.sub.3
o,p-dimethoxybenzyl), 6.55 (d, 1H, J.sub.o=8 Hz, H.sub.6
o,p-dimethoxybenzyl), 6.87 (t, 1H, J.sub.o=8 Hz, H.sub.5 Trp), 7.01
(t, 1H, J.sub.o=8 Hz, H.sub.6 Trp), 7.08 (m, 3H, H.sub.2 Trp,
H.sub.2 and H.sub.6 phenyl), 7.14 (d, 1H, J.sub.o=7 Hz, H.sub.4
Trp), 7.19-7.31 (m, 4H, H.sub.7 Trp, H.sub.3, H.sub.4 and H.sub.5
phenyl), 7.56 (t, 1H, J=8 Hz, NH amide), 7.91 (m, 2H, H.sub.4 and
H.sub.5 o-pyridyl), 8.57 (d, 1H, J.sub..alpha..beta.=5 Hz, H.sub.6
o-pyridyl), 9.16 (d, 1H, J.sub.o=8 Hz, H.sub.3 o-pyridyl), 10.80
(s, 1H, NH indole Trp).
[0576] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0577] .delta.(ppm) 26.2 (CH.sub.2--CH.sub.2-phenyl), 28.8
(CH.sub.2 .beta.Trp), 32.1 (CH.sub.2--CH.sub.2-phenyl), 43.0
(CH.sub.2-o,p-dimethoxybenzyl), 45.5 (CH .alpha.Trp), 55.6
(OCH.sub.3), 55.8 (OCH.sub.3), 98.9 (C.sub.3 o,p-dimethoxybenzyl),
105.0 (C.sub.5 o,p-dimethoxybenzyl), 109.5 (C.sub.3 Trp), 111.8
(C.sub.7 Trp), 114.4 (C.sub.1 o,p-dimethoxybenzyl), 118.4 (C.sub.4
Trp), 118.8 (C.sub.5 Trp), 121.4 (C.sub.6 Trp), 122.4 (C.sub.3
o-pyridyle), 124.4 (C.sub.2 Trp), 126.7 (C.sub.6
o,p-dimethoxybenzyl), 127.2 (C.sub.5 o-pyridyle), 127.5 (C.sub.9
Trp), 128.6-128.8 (C.sub.2, C.sub.3, C.sub.4, C.sub.5 and C.sub.6
phenyl), 136.4 (C.sub.8 Trp), 138.1 (C.sub.4 o-pyridyle), 140.2
(C.sub.1 phenyl), 148.8 (C.sub.6 o-pyridyle), 149.3 (C.sub.2
o-pyridyle), 155.2 (Cq triazole), 155.4 (Cq triazole), 157.9
(C.sub.2 o,p-dimethoxybenzyl), 161.0 (C.sub.4 o,p-dimethoxybenzyl),
163.9 (CO amide).
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)pyrazine-2-carboxamide (Compound 66)
[0578] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0579] .delta.(ppm) 2.87 (m, 4H, CH.sub.2--CH.sub.2-phenyl), 3.51
(m, 2H, CH.sub.2 .beta.Trp), 3.58 (s, 3H, OCH.sub.3), 3.59 (s, 3H,
OCH.sub.3), 4.97 (d, 1H, J=17 Hz, CH.sub.2-o,p-dimethoxybenzyl),
5.08 (d, 1H, J=17 Hz, CH.sub.2-o,p-dimethoxybenzyl), 5.56 (s, 1H,
CH .alpha.Trp), 6.10 (dd, 1H, J.sub.o=8 Hz and J.sub.m=2 Hz,
H.sub.5 o,p-dimethoxybenzyl), 6.36 (d, 1H, J.sub.m=2 Hz, H.sub.3
o,p-dimethoxybenzyl), 6.40 (d, 1H, J.sub.o=8 Hz, H.sub.6
o,p-dimethoxybenzyl), 6.87 (t, 1H, J.sub.o=8 Hz, H.sub.5 Trp), 7.00
(t, 1H, J.sub.o=7 Hz, H.sub.6 Trp), 7.09 (m, 3H, H.sub.2 Trp,
H.sub.2 and H.sub.6 phenyl), 7.15 (d, 1H, J.sub.o=7 Hz, H.sub.4
Trp), 7.19-7.28 (m, 3H, H.sub.3, H.sub.4 and H.sub.5 phenyl), 7.36
(d, 1H, J.sub.o=8 Hz, H.sub.7 Trp), 8.61 (t, 1H, J=2 Hz, H.sub.3
o-pyrazinyl), 8.78 (d, 1H, J=2 Hz, H.sub.5 o-pyrazinyl), 8.94 (d,
1H, J=1 Hz, H.sub.6 o-pyrazinyl), 9.26 (d, 1H, J=8 Hz, NH amide),
10.78 (s, 1H, NH indole Trp).
[0580] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0581] .delta.(ppm) 26.1 (CH.sub.2--CH.sub.2-phenyl), 28.4
(CH.sub.2 .beta.Trp), 32.1 (CH.sub.2--CH.sub.2-phenyl), 42.9
(CH.sub.2-o,p-dimethoxybenzyl), 45.5 (CH .alpha.Trp), 55.5
(OCH.sub.3), 55.8 (OCH.sub.3), 98.7 (C.sub.3 o,p-dimethoxybenzyl),
104.9 (C.sub.5 o,p-dimethoxybenzyl), 109.7 (C.sub.3
o,p-dimethoxybenzyl), 111.8 (C.sub.7 Trp), 114.5 (C.sub.1
o,p-dimethoxybenzyl), 118.5 (C.sub.4 Trp), 118.8 (C.sub.5 Trp),
121.4 (C.sub.6 Trp), 124.4 (C.sub.2 Trp), 126.7 (C.sub.6
o,p-dimethoxybenzyl), 127.5 (C.sub.9 Trp), 128.1 (C.sub.4 phenyl),
128.7-128.8 (C.sub.2, C.sub.3, C.sub.5 and C.sub.6 phenyl), 136.4
(C.sub.8 Trp), 140.3 (C.sub.1 phenyl), 141.2 (C.sub.6
o,p-dimethoxybenzyl), 144.2 (C.sub.2 o-pyrazinyl), 144.3 (C.sub.3
o-pyrazinyl), 146.8 (C.sub.5 o-pyrazinyl), 155.2 (Cqs triazole),
157.7 (C.sub.2 o,p-dimethoxybenzyl), 160.7 (CO amide), 162.9
(C.sub.4 o,p-dimethoxybenzyl).
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,-
4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide
(Compound 70)
[0582] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0583] .delta.(ppm) 1.40 (m, 1H, H.sub.3 Pro), 1.53 (m, 1H, H.sub.4
Pro), 1.71 (m, 1H, H.sub.4 Pro), 2.09 (m, 1H, H.sub.3 Pro), 2.90
(m, 4H, CH.sub.2--CH.sub.2-indole), 3.06 (t, 2H, J=6 Hz, H.sub.5
Pro), 3.28 (m, 2H, CH.sub.2 .beta.Trp), 3.40(s, 3H, OCH.sub.3),
3.80(s, 3H, OCH.sub.3), 3.80(m, 1H, CH .alpha.Pro), 4.80(d, 1H,
J=17 Hz, CH.sub.2-o,p-dimethoxybenzyl), 5.4 (d, 1H, J=17 Hz,
CH.sub.2-o,p-dimethoxybenzyl), 5.1 (m, 1H, CH .alpha.Trp), 6.26
(dd, 1H, J.sub.o=8 Hz and J.sub.m=2 Hz, H.sub.5
o,p-dimethoxybenzyl), 6.38 (d, 1H, J.sub.o=8 Hz, H.sub.6
o,p-dimethoxybenzyl), 6.53 (d, 1H, J.sub.m=2 Hz, H.sub.3
o,p-dimethoxybenzyl), 6.84 (t, 1H, H.sub.5 indole), 6.91 (t, 1H,
J.sub.o=8 Hz, H.sub.5 Trp), 6.93-7.07 (m, 4H, H.sub.2 and H.sub.6
indole, H.sub.2 and H.sub.6 Trp), 7.16 (d, 1H, J.sub.o=8 Hz,
H.sub.4 Trp), 7.29 (m, 3H, H.sub.4 and H.sub.7 indole, H.sub.7
Trp), 8.39 and 9.10 (2 m, 2H, NH Pro TFA salt), 9.22 (d, 1H, J=8
Hz, NH amide), 10.76 (s, 1H, NH indole), 10.80 (s, 1H, NH indole
Trp).
[0584] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0585] .delta.(ppm) 22.9 (CH.sub.2--CH.sub.2-indole), 23.5 (C.sub.4
Pro), 25.8 (CH.sub.2--CH.sub.2-indole), 29.6 (CH.sub.2 .beta.Trp),
29.8 (C.sub.3 Pro), 41.9 (CH.sub.2-o,p-dimethoxybenzyl), 45.2 (CH
.alpha.Trp), 46.0 (C.sub.5 Pro), 55.7 (OCH.sub.3), 55.9
(OCH.sub.3), 59.3 (CH .alpha.Pro), 99.0 (C.sub.3
o,p-dimethoxybenzyl), 105.1 (C.sub.5 o,p-dimethoxybenzyl), 109.7
(C.sub.3 Trp), 111.8 (C.sub.7 indole and C.sub.7 Trp), 113.4
(C.sub.3 indole), 115.6 (C.sub.1 o,p-dimethoxybenzyl), 118.4
(C.sub.4 indole and C.sub.4 Trp), 118.7 (C.sub.5 indole and C.sub.5
Trp), 121.4 (C.sub.6 indole and C.sub.6 Trp), 123.0 (C.sub.2 indole
and C.sub.2 Trp), 127.2 (C.sub.9 indole), 127.3 (C.sub.9 Trp),
128.1 (C.sub.6 o,p-dimethoxybenzyl), 136.5 (C.sub.8 Trp), 136.6
(C.sub.8 indole), 155.0 (Cq triazole), 157.8 (C.sub.2
o,p-dimethoxybenzyl), 160.9 (C.sub.4 o,p-dimethoxybenzyl), 168.1
(CO amide).
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tri-
azol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrazine-2-carboxamide (Compound
71)
[0586] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0587] .delta.(ppm) 3.01 (m, 2H, CH.sub.2--CH.sub.2-indole), 3.10
(m, 2H, CH.sub.2--CH.sub.2-indole), 3.51 (m, 2H, CH.sub.2
.beta.Trp), 3.55 (s, 3H, OCH.sub.3), 3.57 (s, 3H, OCH.sub.3), 5.15
(d, 2H, J=7 Hz, CH.sub.2-o,p-dimethoxybenzyl), 5.63 (m, 1H, CH
.alpha.Trp), 6.08 (dd, 1H, J.sub.o=8 Hz and J.sub.m=2 Hz, H.sub.5
o,p-dimethoxybenzyl), 6.35 (d, 1H, J.sub.m=2 Hz, H.sub.3
o,p-dimethoxybenzyl), 6.53 (d, 1H, J.sub.o=8 Hz, H.sub.6
o,p-dimethoxybenzyl), 6.89 (m, 2H, H.sub.5 indole and H.sub.5 Trp),
6.99 (m, 2H, H.sub.6 indole and H.sub.6 Trp), 7.08 (m, 2H, H.sub.2
indole and H.sub.2 Trp), 7.29 (m, 3H, H.sub.4 Trp, H.sub.4 and
H.sub.7 indole), 7.41 (d, 1H, J.sub.o=8 Hz, H.sub.7 Trp), 8.61 (t,
1H, J=2 Hz, H.sub.3 o-pyrazine), 8.79 (d, 1H, J=2 Hz, H.sub.5
o-pyrazine), 8.94 (d, 1H, J=1 Hz, H.sub.6 o-pyrazine), 9.43 (d, 1H,
J=8 Hz, NH amide), 10.84 (s, 2H, NH indole and NH indole Trp).
[0588] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0589] .delta.(ppm) 22.0 (CH.sub.2--CH.sub.2-indole), 25.3
(CH.sub.2--CH.sub.2-indole), 27.9 (CH.sub.2 .beta.Trp), 44.1
(CH.sub.2-o,p-dimethoxybenzyl), 45.5 (CH .alpha.Trp), 55.5
(OCH.sub.3), 55.8 (OCH.sub.3), 98.8 (C.sub.3 o,p-dimethoxybenzyl),
104.9 (C.sub.5 o,p-dimethoxybenzyl), 109.3 (C.sub.3 Trp), 111.8
(C.sub.7 indole and C.sub.7 Trp), 112.1 (C.sub.3 indole), 113.4
(C.sub.1 o,p-dimethoxybenzyl), 118.4 (C.sub.4 indole), 118.5
(C.sub.4 Trp), 118.8 (C.sub.5 indole and C.sub.5 Trp), 121.5
(C.sub.6 indole and C.sub.6 Trp), 127.0 (C.sub.9 indole), 127.4
(C.sub.9 Trp), 136.4 (C.sub.8 Trp), 136.6 (C.sub.8 indole), 141.2
(C.sub.6 o-pyrazine), 144.1 (C.sub.2 o-pyrazine), 144.3 (C.sub.3
o-pyrazine), 146.8 (C.sub.5 o-pyrazine), 155.4 (Cq triazole), 156.0
(Cq triazole), 157.8 (C.sub.2 o,p-dimethoxybenzyl), 161.0 (CO
amide), 163.2 (C.sub.4 o,p-dimethoxybenzyl).
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tri-
azol-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide (Compound 73)
[0590] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0591] .delta.(ppm) 2.94 (m, 4H, CH.sub.2--CH.sub.2-indole), 3.47
(m, 2H, CH.sub.2 .beta.Trp), 3.57 (s, 3H, OCH.sub.3), 3.60 (s, 3H,
OCH.sub.3), 5.05 (m, 2H, CH.sub.2-o,p-dimethoxybenzyl), 5.56 (m,
1H, CH .alpha.Trp), 6.14 (dd, 1H, J.sub.o=8 Hz and J.sub.m=2 Hz,
H.sub.5 o,p-dimethoxybenzyl), 6.41 (d, 1H, J.sub.m=2 Hz, H.sub.3
o,p-dimethoxybenzyl), 6.52 (d, 1H, J.sub.o=8 Hz, H.sub.6
o,p-dimethoxybenzyl), 6.88 (t, 2H, J.sub.o=7 Hz, H.sub.5 indole and
H.sub.5 Trp), 6.99 (t, 1H, J.sub.o=8 Hz, H.sub.6 Trp), 7.01 (t, 1H,
J.sub.o=8 Hz, H.sub.6 indole), 7.04 (d, 1H, J=2 Hz, H.sub.2 Trp),
7.07 (d, 1H, J=2 Hz, H.sub.2 indole), 7.27-7.33 (m, 4H, H.sub.4 and
H.sub.7 Trp, H.sub.4 and H.sub.7 indole), 7.55 (m, 1H, NH amide),
7.90 (m, 2H, H.sub.4 and H.sub.5 o-pyridyl), 8.57 (d, 1H,
J.sub..alpha..beta.=4 Hz, H.sub.6 o-pyridyl), 9.15 (d, 1H, J=8 Hz,
H.sub.3 o-pyridyl), 10.78 (brs, 2H N indole and NH indole Trp).
[0592] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0593] .delta.(ppm) 22.3 (CH.sub.2--CH.sub.2-indole), 25.6
(CH.sub.2--CH.sub.2-indole), 28.9 (CH.sub.2 .beta.Trp), 43.1
(CH.sub.2-o,p-dimethoxybenzyl), 45.5 (CH .alpha.Trp), 55.5
(OCH.sub.3), 55.8 (OCH.sub.3), 98.9 (C.sub.3 o,p-dimethoxybenzyl),
105.0 (C.sub.5 o,p-dimethoxybenzyl), 109.5 (C.sub.3 Trp), 111.8
(C.sub.7 indole and C.sub.7 Trp), 112.8 (C.sub.3 indole), 114.4
(C.sub.1 o,p-dimethoxybenzyl), 118.4 (C.sub.4 indole and C.sub.4
Trp), 118.7 (05 indole), 118.8 (C.sub.5 Trp), 121.4 (C.sub.6 indole
and C.sub.6 Trp), 122.5 (C.sub.2 indole and C.sub.3 o-pyridyl),
123.1 (C.sub.2 Trp), 127.1 (C.sub.5 o-pyridyl), 127.2 (C.sub.9
indole), 127.5 (C.sub.9 Trp), 128.6 (C.sub.6 o,p-dimethoxybenzyl),
136.4 (C.sub.8 Trp), 136.6 (C.sub.8 indole), 139.1 (C.sub.4
o-pyridyl), 146.6 (C.sub.6 o-pyridyl), 150.6 (C.sub.2 o-pyridyl),
155.5 (Cq triazole), 155.6 (Cq triazole), 157.8 (C.sub.2
o,p-dimethoxybenzyl), 161.0 (C.sub.4 o,p-dimethoxybenzyl), 163.9
(CO amide).
(R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethanamine (Compound 74)
[0594] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0595] .delta.(ppm) 2.79 (m, 2H, CH.sub.2--CH.sub.2-indole), 2.86
(m, 2H, CH.sub.2--CH.sub.2-indole), 3.30 (dd, 1H, .sup.3J=14 Hz and
5 Hz, CH.sub.2 .beta.Trp), 3.38 (dd, 1H, .sup.3J=14 Hz and 6 Hz,
CH.sub.2.beta.Trp), 3.62 (s, 3H, OCH.sub.3), 3.63 (s, 3H,
OCH.sub.3), 4.47 (d, 1H, .sup.3J=17 Hz,
CH.sub.2-o,p-dimethoxybenzyl), 4.59 (d, 1H, .sup.3J=17 Hz,
CH.sub.2-o,p-dimethoxybenzyl), 6.11 (dd, 1H, J.sub.o=8 Hz and
J.sub.m=2 Hz, H.sub.5 o,p-dimethoxybenzyl), 6.20 (d, 1H, J.sub.o=8
Hz, H.sub.6 o,p-dimethoxybenzyl), 6.45 (d, 1H, J.sub.m=2 Hz,
H.sub.3 o,p-dimethoxybenzyl), 6.87 (t, 1H, J.sub.o=8 Hz, H.sub.5
Trp), 6.91 (t, 1H, J.sub.o=8 Hz, H.sub.5 indole), 7.00-7.04 (m, 2H,
H.sub.6 indole and H.sub.6 Trp), 7.07 (s, 1H, H.sub.2 indole), 7.09
(s, 1H, H.sub.2 Trp), 7.17-7.35 (m, 4H, H.sub.4 and H.sub.7 indole,
H.sub.4 and H.sub.7 Trp), 8.75 (brs, 3H, NH.sub.2 TFA salt), 10.78
(s, 1H, NH indole), 11.00 (s, 1H, NH indole Trp).
[0596] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0597] .delta.(ppm) 22.9 (CH.sub.2--CH.sub.2-indole), 25.7
(CH.sub.2--CH.sub.2-indole), 29.9 (CH.sub.2 .beta.Trp), 41.5
(CH.sub.2-o,p-dimethoxybenzyl), 46.5 (CH .alpha.Trp), 55.6
(OCH.sub.3), 55.9 (OCH.sub.3), 98.8 (C.sub.3 o,p-dimethoxybenzyl),
105.0 (C.sub.5 o,p-dimethoxybenzyl), 107.4 (C.sub.3 Trp), 111.8
(C.sub.7 indole and C.sub.7 Trp), 113.4 (C.sub.3 indole), 115.1
(C.sub.1 o,p-dimethoxybenzyl), 118.0 (C.sub.4 indole), 118.4
(C.sub.4 Trp), 118.6 (C.sub.5 Trp), 119.0 (C.sub.5 indole), 121.3
(C.sub.6 Trp), 121.6 (C.sub.6 indole), 122.9 (C.sub.2 indole),
125.4 (C.sub.2 Trp), 127.1 (C.sub.9 indole and C.sub.9 Trp), 128.5
(C.sub.6 o,p-dimethoxybenzyl), 136.5 (C.sub.8 Trp), 136.6 (C.sub.8
indole), 152.3 (Cq triazole), 155.6 (Cq triazole), 157.6 (C.sub.2
o,p-dimethoxybenzyl), 160.8 (C.sub.4 o,p-dimethoxybenzyl).
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)picolinamide (Compound 79)
[0598] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0599] .delta.(ppm) 2.85 (m, 4H, CH.sub.2--CH.sub.2-phenyl), 3.51
(m, 2H, CH.sub.2 .beta.Trp), 3.59 (s, 3H, OCH.sub.3), 5.11 (d, 1H,
J=17 Hz, CH.sub.2-p-methoxybenzyl), 5.23 (d, 1H, J=17 Hz,
CH.sub.2-p-methoxybenzyl), 5.51 (m, 1H, CH .alpha.Trp), 6.59 (d,
2H, J.sub.o=8 Hz, H.sub.3 and H.sub.5 p-methoxybenzyl), 6.73 (d,
2H, J.sub.o=8 Hz, H.sub.2 and H.sub.6 p-methoxybenzyl), 6.87 (t,
1H, J.sub.o=8 Hz, H.sub.5 Trp), 7.01 (t, 1H, J.sub.o=8 Hz, H.sub.6
Trp), 7.06 (m, 2H, H.sub.2 and H.sub.6 phenyl), 7.10 (d, 1H, J=2
Hz, H.sub.2 Trp), 7.14 (d, 1H, J.sub.o=7 Hz, H.sub.4 Trp), 7.24 (m,
3H, H.sub.3, H.sub.4 and H.sub.5 phenyl), 7.34 (d, 1H, J.sub.o=8
Hz, H.sub.7 Trp), 7.55 (m, 1H, NH amide), 7.88 (m, 2H, H.sub.4 and
H.sub.5 o-pyridyl), 8.56 (d, 1H, J.sub..alpha..beta.=4 Hz, H.sub.6
o-pyridyl), 9.20 (d, 1H, J.sub.o=8 Hz, H.sub.3 o-pyridyl), 10.80
(s, 1H, NH indole Trp).
[0600] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0601] .delta.(ppm) 26.2 (CH.sub.2--CH.sub.2-phenyl), 28.6
(CH.sub.2 .beta.Trp), 32.1 (CH.sub.2--CH.sub.2-phenyl), 45.5 (CH
.alpha.Trp), 46.2 (CH.sub.2-p-methoxybenzyl), 55.4 (OCH.sub.3),
109.6 (C.sub.3 Trp), 111.8 (C.sub.7 Trp), 114.3 (C.sub.3 and
C.sub.5 p-methoxybenzyl), 118.5 (C.sub.4 Trp), 118.8 (C.sub.5 Trp),
121.4 (C.sub.6 Trp), 122.5 (C.sub.3 o-pyridyl), 124.5 (C.sub.2
Trp), 127.2 (C.sub.2 and C.sub.6 phenyl), 127.4 (C.sub.9 Trp and
C.sub.1 p-methoxybenzyl), 127.8 (C.sub.5 o-pyridyl), 128.7 (C.sub.2
and C.sub.6 p-methoxybenzyl), 128.8 (C.sub.3, C.sub.4 and C.sub.5
phenyl), 136.4 (C.sub.6 Trp), 138.1 (C.sub.4 o-pyridyl), 140.3
(C.sub.1 phenyl), 148.7 (C.sub.6 o-pyridyl), 149.3 (C.sub.2
o-pyridyl), 155.0 (Cq triazole), 155.3 (Cq triazole), 159.0
(C.sub.4 p-methoxybenzyl), 164.1 (CO amide).
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide (Compound 80)
[0602] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0603] .delta.(ppm) 2.95 (m, 4H, CH.sub.2--CH.sub.2-indole), 3.48
(m, 2H, CH.sub.2 .beta.Trp), 3.58 (s, 3H, OCH.sub.3), 5.16 (m, 2H,
CH.sub.2-p-methoxybenzyl), 5.50 (m, 1H, CH .alpha.Trp), 6.57 (d,
2H, J.sub.o=8 Hz, H.sub.3 and H.sub.5 p-methoxybenzyl), 6.72 (d,
2H, J.sub.o=8 Hz, H.sub.2 and H.sub.6 p-methoxybenzyl), 6.87 (t,
2H, J.sub.o=8 Hz, H.sub.5 Trp and H.sub.5 indole), 6.96-7.07 (m,
5H, H.sub.2 and H.sub.6 indole, H.sub.2, H.sub.4 and H.sub.6 Trp),
7.27-7.34 (m, 3H, H.sub.4 and H.sub.7 indole, H.sub.7 Trp), 7.55
(m, 1H, NH amide), 7.88 (m, 2H, H.sub.4 and H.sub.5 o-pyridyl),
8.56 (d, 1H, J.sub..alpha..beta.=4 Hz, H.sub.6 o-pyridyl), 9.18 (d,
1H, J.sub.o=8 Hz, H.sub.3 o-pyridyl), 10.77 (brs, 2H, NH indole Trp
and NH indole).
[0604] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0605] .delta.(ppm) 22.4 (CH.sub.2--CH.sub.2-indole), 25.7
(CH.sub.2--CH.sub.2-indole), 28.9 (CH.sub.2 .beta.Trp), 45.5 (CH
.alpha.Trp), 46.2 (CH.sub.2-p-methoxybenzyl), 55.4 (OCH.sub.3),
109.7 (C.sub.3 Trp), 111.8 (C.sub.7 Trp and C.sub.7 indole), 112.6
(C.sub.3 indole), 114.3 (C.sub.3 and C.sub.5 p-methoxybenzyl),
118.4 (C.sub.4 Trp and C.sub.4 indole), 118.7 (C.sub.5 indole),
118.8 (C.sub.5 Trp), 121.4 (C.sub.6 Trp and C.sub.6 indole), 122.4
(C.sub.3 o-pyridyl and C.sub.2 indole), 124.5 (C.sub.2 Trp), 126.7
(C.sub.9 indole), 127.1 (C.sub.9 Trp), 127.2 (C.sub.5 o-pyridyl),
127.5 (C.sub.1 p-methoxybenzyl), 127.7 (C.sub.2 and C.sub.6
p-methoxybenzyl), 136.4 (C.sub.8 Trp), 136.6 (C.sub.8 indole),
138.1 (C.sub.4 o-pyridyl), 148.7 (C.sub.6 o-pyridyl), 149.3
(C.sub.2 o-pyridyl), 155.3 (Cq triazole), 159.0 (C.sub.4
p-methoxybenzyl), 164.0 (CO amide).
(R)--N-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)piperazine-2-carboxamide (Compound
81)
[0606] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0607] .delta.(ppm) 2.18 (m, 2H, NH piperazine), 2.96 (m, 6H,
H.sub.2, H.sub.5 and H.sub.6 piperazine), 3.34 (d, 2H, J=7 Hz,
CH.sub.2 .beta.Trp), 3.57 (m, 4H, CH.sub.2--CH.sub.2-indole), 3.61
(s, 3H, OMe), 3.64 (m, 1H, H.sub.3 piperazine), 4.82 (m, 2H,
CH.sub.2-p-methoxybenzyl), 5.40 (m, 1H, CH .alpha.Trp), 6.45 (d,
2H, J.sub.o=8 Hz, H.sub.3 and H.sub.5 p-methoxybenzyl), 6.51 (d,
2H, J.sub.o=8 Hz, H.sub.2 and H.sub.6 p-methoxybenzyl), 6.65-7.47
(m, 10H, CHar, indole and indole Trp), 8.95 (m, 1H, NH amide),
10.88 (d, 1H, J=2 Hz, NH indole), 10.91 (s, 1H, NH indole Trp).
[0608] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0609] .delta.(ppm) 22.5 (CH.sub.2--CH.sub.2-indole), 25.6
(CH.sub.2--CH.sub.2-indole), 31.3 (CH.sub.2 .beta.Trp), 41.9
(CH.sub.2-p-methoxybenzyl), 47.7 (CH .alpha.Trp, C.sub.5 and
C.sub.6 piperazine), 55.5 (OCH.sub.3 and C.sub.2 piperazine), 61.1
(C.sub.3 piperazine), 109.3 (C.sub.3 Trp), 111.7 (C.sub.7 indole
and C.sub.7 Trp), 114.0 (C.sub.3 indole), 114.3 (C.sub.3 and
C.sub.5 p-methoxybenzyl), 118.6 (C.sub.4 indole), 118.7 (C.sub.4
Trp), 118.9 (C.sub.5 indole and C.sub.5 Trp), 121.4 (C.sub.6
indole), 121.5 (C.sub.6 Trp), 123.9 (C.sub.2 indole and C.sub.2
Trp), 127.0 (C.sub.9 indole), 127.2 (C.sub.9 Trp), 127.7 (C.sub.1
p-methoxybenzyl), 128.1 (C.sub.2 and C.sub.6 p-methoxybenzyl),
136.3 (C.sub.8 Trp), 136.5 (C.sub.8 indole), 155.5 (Cq triazole),
162.2 (C.sub.4 p-methoxybenzyl), 171.1 (CO amide).
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide
(Compound 89)
[0610] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0611] .delta.(ppm) 1.42 (m, 1H, H.sub.3 Pro), 1.52 (m, 1H, H.sub.4
Pro), 1.72 (m, 1H, H.sub.4 Pro), 2.07 (m, 1H, H.sub.3 Pro), 2.94
(m, 4H, CH.sub.2--CH.sub.2-indole), 3.05 (t, 2H, J=6 Hz, H.sub.5
Pro), 3.30 (m, 2H, CH.sub.2 .beta.Trp), 3.67 (s, 3H, OCH.sub.3),
3.96 (m, 1H, CH .alpha.Pro), 5.02 (s, 2H,
CH.sub.2-p-methoxybenzyl), 5.19 (m, 1H, CH .alpha.Trp), 6.73 (s,
4H, CHar p-methoxybenzyl), 6.84 (t, 1H, J.sub.o=8 Hz, H.sub.5
indole), 6.90 (t, 1H, J.sub.o=8 Hz, H.sub.5 Trp), 6.93-7.06 (m, 4H,
H.sub.2 and H.sub.6 indole, H.sub.2 and H.sub.6 Trp), 7.17 (d, 1H,
J.sub.o=8 Hz, H.sub.4 Trp), 7.29 (d, 3H, J.sub.o=8 Hz, H.sub.4 and
H.sub.7 indole, H.sub.7 Trp), 8.39 and 9.10 (2 m, 2H, NH Pro TFA
salt), 9.25 (d, 1H, J=8 Hz, NH amide), 10.76 (s, 1H, NH indole),
10.80 (d, 1H, J=2 Hz, NH indole Trp).
[0612] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0613] .delta.(ppm) 22.8 (CH.sub.2--CH.sub.2-indole), 23.5 (C.sub.4
Pro), 25.8 (CH.sub.2--CH.sub.2-indole), 29.4 (CH.sub.2 .beta.Trp),
29.8 (C.sub.3 Pro), 45.2 (CH .alpha.Trp), 45.5
(CH.sub.2-p-methoxybenzyl), 46.0 (C.sub.5 Pro), 55.5 (OCH.sub.3),
59.3 (CH .alpha.Pro), 109.6 (C.sub.3 Trp), 111.8 (C.sub.7 indole
and C.sub.7 Trp), 113.4 (C.sub.3 indole), 114.6 (C.sub.3 and
C.sub.5 p-methoxybenzyl), 118.4 (C.sub.4 indole), 118.5 (C.sub.4
Trp), 118.7 (C.sub.5 indole and C.sub.5 Trp), 121.4 (C.sub.6 indole
and C.sub.6 Trp), 123.0 (C.sub.2 Trp), 124.7 (C.sub.2 indole),
127.2 (C.sub.9 indole), 127.3 (C.sub.9 Trp), 127.7 (C.sub.1
p-methoxybenzyl), 127.8 (C.sub.2 and C.sub.6 p-methoxybenzyl),
126.5 (C.sub.8 Trp), 136.6 (C.sub.8 indole), 154.8 (Cq triazole),
154.9 (Cq triazole), 159.2 (C.sub.4 p-methoxybenzyl), 168.2 (CO
amide).
(R)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-tr-
iazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide
(Compound 90)
[0614] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0615] .delta.(ppm) 1.23 (m, 1H, H.sub.3 Pro), 1.52 (m, 1H, H.sub.4
Pro), 1.74 (m, 1H, H.sub.4 Pro), 2.08 (m, 1H, H.sub.3 Pro), 2.81
(m, 2H, H.sub.5 Pro), 2.90-3.14 (m, 4H, CH.sub.2--CH.sub.2-indole),
3.31 (dd, 1H, J=14 Hz and 7 Hz, CH.sub.2 .beta.Trp), 3.41 (dd, 1H,
J=14 Hz and 8 Hz, CH.sub.2 .beta.Trp), 3.63 (s, 3H, OCH.sub.3),
4.05 (m, 1H, CH .alpha.Pro), 4.86 (s, 2H,
CH.sub.2-p-methoxybenzyl), 5.21 (m, 1H, CH .alpha.Trp), 6.63 (s,
4H, CHar p-methoxybenzyl), 6.88 (t, 2H, J.sub.o=7 Hz, H.sub.5
indole and H.sub.5 Trp), 7.02 (m, 4H, H.sub.2 and H.sub.6 indole,
H.sub.2 and H.sub.6 Trp), 7.26-7.34 (m, 4H, H.sub.4 and H.sub.7
indole, H.sub.4 and H.sub.7 Trp), 8.51 and 9.18 (2 m, 2H, NH Pro,
TFA salt), 9.27 (d, 1H, J=8 Hz, NH amide), 10.73 (s, 1H, NH
indole), 10.80 (s, 1H, NH indole Trp).
[0616] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0617] .delta.(ppm) 22.8 (CH.sub.2--CH.sub.2-indole), 23.8 (C.sub.4
Pro), 25.9 (CH.sub.2--CH.sub.2-indole), 29.7 (CH.sub.2 .beta.Trp
and C.sub.3 Pro), 45.4 (CH.sub.2-p-methoxybenzyl), 45.8 (CH
.alpha.Trp), 46.1 (C.sub.5 Pro), 55.5 (OCH.sub.3), 59.2 (CH
.alpha.Pro), 109.7 (C.sub.3 Trp), 111.8 (C.sub.7 Trp), 111.9
(C.sub.7 indole), 113.4 (C.sub.3 indole), 114.4 (C.sub.3 and
C.sub.5 p-methoxybenzyl), 118.3 (C.sub.4 indole), 118.5 (C.sub.4
Trp), 118.6 (C.sub.5 indole), 118.9 (C.sub.5 Trp), 121.4 (C.sub.6
indole and C.sub.6 Trp), 122.9 (C.sub.2 indole and C.sub.2 Trp),
127.2 (C.sub.9 indole), 127.4 (C.sub.9 Trp), 127.6 (C.sub.1,
C.sub.2 and C.sub.6 p-methoxybenzyl), 136.5 (C.sub.8 Trp), 136.6
(C.sub.8 indole), 154.4 (Cq triazole), 155.0 (Cq triazole), 159.1
(C.sub.4 p-methoxybenzyl), 168.3 (CO amide).
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-bromobenzyl)-4H-1,2,4-triazol-3-
-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound
92)
[0618] .sup.1H NMR (400 MHz, DMSO-d.sup.6):
[0619] .delta.(ppm) 1.28 (3H, s, CH.sub.3 Aib), 1.30 (3H, s,
CH.sub.3 Aib), 2.90 (2H, m, CH.sub.2--CH.sub.2-indole), 3.00 (2H,
m, CH.sub.2--CH.sub.2-indole), 3.37 (2H, m, CH.sub.2 .beta.Trp),
5.10 (2H, s, CH.sub.2 4-bromobenzyl), 5.13 (1H, m, C.alpha.H Trp),
6.75 (2H, d, J=8.1, H.sub.2, H.sub.6 4-bromobenzyl), 6.88 (1H, t,
J=7.3, H.sub.5 Trp), 6.93 (1H, t, J=7.5, H.sub.5 indole), 7.03 (1H,
t, J=7.0, H.sub.6 Trp), 7.05 (1H, H.sub.6 indole), 7.07 (1H, d,
J=1.7, H.sub.2 indole), 7.09 (1H, d, J=1.8, H.sub.2 Trp), 7.12 (1H,
d, J=8.2, H.sub.4 Trp), 7.28 (1H, d, J=7.9, H.sub.4 indole), 7.32
(2H, d, J=8.2, H.sub.7 Trp, H.sub.7 indole), 7.41 (2H, d, J=8.1,
H.sub.3, H.sub.5 4-bromobenzyl), 8.01 (2H, s, NH.sub.2 Aib), 8.95
(1H, d, J=7.9, NH Trp), 10.77 (1H, brs, NH indole), 10.80 (1H, brs,
NH indole Trp).
[0620] .sup.13C NMR (400 MHz,DMSO-d.sup.6):
[0621] .delta.(ppm) 22.4 (CH.sub.2--CH.sub...quadrature.-indole),
23.1 (CH.sub.3 Aib), 23.4 (CH.sub.3 Aib), 25.4
(CH.sub.2--CH.sub...quadrature.indole), 28.7 (C.beta. Trp), 44.8
(CH.sub.2 4-bromobenzyl), 45.2 (C.alpha. Trp,), 56.3 (Cq Aib),
109.4 (C.sub.3 Trp), 111.3 (C.sub.7 Trp, C.sub.7 indole), 113.0
(C.sub.3 indole), 117.8 (C.sub.4 Trp), 118.0 (C.sub.4 indole),
118.2 (C.sub.5 indole), 118.3 (C.sub.5 Trp), 120.8 (C.sub.4
4-bromobenzyl), 120.9 (C.sub.6 Trp, C.sub.6 indole), 122.5 (C.sub.2
indole), 124.4 (C.sub.2 Trp), 126.7 (C.sub.9 Indole), 126.8
(C.sub.9 Trp), 128.0 (C.sub.2, C.sub.6 4-bromobenzyl), 131.6
(C.sub.3, C.sub.5 4-bromobenzyl), 135.1 (C.sub.1 4-bromobenzyl),
136.1 (C.sub.8 Trp, C.sub.8 indole), 154.2 (Cq triazole), 154.5 (Cq
triazole), 171.4 (CO Aib).
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-
-3-yl)-2-phenylethyl)-2-amino-2-methylpropanamide (Compound 93)
[0622] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0623] .delta.(ppm) 1.18 (3H, s, CH.sub.3 Aib), 1.27 (3H, s,
CH.sub.3 Aib), 2.91 (4H, m, CH.sub.2--CH.sub.2-indole), 3.19 (2H,
m, CH.sub.2 .beta.Phe), 3.69 (3H, s, OCH.sub.3), 5.05 (2H, m,
CH.sub.2-p-methoxybenzyl), 5.20 (1H, m, CH .alpha.Phe), 6.82 (2H,
d, J.sub.o=8 Hz, H.sub.3 and H.sub.5 p-methoxybenzyl), 6.88 (2H, d,
J.sub.o=8 Hz, H.sub.2 and H.sub.6 p-methoxybenzyl), 6.92 (1H, t,
J.sub.o=8 Hz, H.sub.5 indole), 7.02 (1H, t, J.sub.o=7 Hz, H.sub.6
indole), 7.03 (1H, d, J=2 Hz, H.sub.2 indole), 7.11-7.20 (5H, m,
CHar Phe), 7.29 (2H, d, J.sub.o=8 Hz, H.sub.4 and H.sub.7 indole),
7.99 (3H, brs, NH.sub.2 Aib), 8.93 (1H, d, J=8 Hz, NH amide), 10.77
(1H, s, NH indole).
[0624] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0625] .delta.(ppm) 22.8 (CH.sub.2--CH.sub.2-indole), 23.5
(CH.sub.3 Aib), 23.9 (CH.sub.3 Aib), 25.9
(CH.sub.2--CH.sub.2-indole), 38.7 (CH.sub.2 .beta.Phe), 45.7
(CH.sub.2-p-methoxybenzyl), 46.4 (CH .alpha.Phe), 55.6 (OCH.sub.3),
56.8 (Cq Aib), 111.8 (C.sub.7 indole), 113.4 (C.sub.3 indole),
114.7 (C.sub.3 and C.sub.5 p-methoxybenzyl), 118.5 (C.sub.4 Trp),
118.6 (C.sub.5 Trp), 121.4 (C.sub.6 Trp), 123.0 (C.sub.2 Trp),
127.0 (C.sub.4 phenyl), 127.2 (C.sub.9 indole), 127.9 (C.sub.1
p-methoxybenzyl), 128.1 (C.sub.2 and C.sub.6 phenyl), 128.5
(C.sub.3 and C.sub.5 phenyl), 129.8 (C.sub.2 and C.sub.6
p-methoxybenzyl), 136.6 (C.sub.8 indole), 137.7 (C.sub.1 phenyl),
155.2 (Cq triazole), 154.4 (Cq triazole), 159.3 (C.sub.4
p-methoxybenzyl), 171.7 (CO Aib).
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
-yl)ethyl)-2-amino-2-methylpropanamide (Compound 95)
[0626] .sup.1H NMR (400 MHz, DMSO-d.sup.6):
[0627] .delta.(ppm) 1.29 (3H, s, CH.sub.3 Aib), 1.35 (3H, s,
CH.sub.3 Aib), 2.85 (1H, m, 1H N--CH.sub.2--CH.sub.2--In), 2.89
(1H, m, 1H, --N--CH.sub.2--CH.sub.2--In), 3.28 (1H, dd, J=14.2,
J=6.8, 1H C.sub.2.beta. Trp), 3.40 (1H, dd, J=14.2, J=8.4, 1H
C.sub.2.beta. Trp), 4.10 (2H, m, --N--CH.sub.2--CH.sub.2--In), 5.25
(1H, m, CH.alpha. Trp), 6.85 (1H, d, J=2.0, H.sub.2 indole),
6.90-6.98 (2H, m, H.sub.5 indole), 7.01 (1H, d, J=2.0, H.sub.2
indole), 7.02-7.12 (2H, m, H.sub.6 indole), 7.30 (1H, d, J=8.2,
H.sub.7 indole), 7.33 (1H, d, J=8.3, H.sub.7 indole), 7.40 (1H, d,
J=7.9, H.sub.4 indole), 7.47 (1H, d, J=7.8, H.sub.4 indole), 8.04
(2H, brs, NH.sub.2 Aib), 8.42 (1H, s, H triazole), 9.01 (1H, d,
J=8.0, NH Trp), 10.81 (1H, s, NH indole), 10.90 (1H, s, NH
indole).
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 96)
[0628] .sup.1H NMR (400 MHz, DMSO-d.sup.6):
[0629] .delta.(ppm) 1.20 (3H, s, CH.sub.3 Aib), 1.28 (3H, s,
CH.sub.3 Aib), 3.32 (3H, d, N--CH.sub.3), 3.30-3.45 (2H, m,
CH.sub.2.beta. Trp), 4.22 (2H, s, --CH.sub.2--In), 5.30 (1H, m,
CH.alpha. Trp), 6.91 (1H, t, J=7.5, Hg indole), 6.94 (1H, d, J=7.5,
H.sub.5 indole), 7.02 (1H, t, J=7.9, He indole), 7.05 (1H, t,
J=7.9, H.sub.6 indole), 7.08 (1H, d, J=1.9, H.sub.2 indole), 7.12
(1H, d, J=1.9, H.sub.2 indole), 7.29 (1H, d, J=8.1, H.sub.7
indole), 7.33 (1H, d, J=8.2, H.sub.7 indole), 7.48 (1H, d, J=7.9,
H.sub.4 indole), 7.57 (1H, d, J=7.9H.sub.4 indole), 8.00 (2H, brs,
NH.sub.2 Aib), 8.85 (1H, d, J=8.2, NH Trp), 10.82 (1H, s, NH
indole), 10.98 (1H, s, NH indole).
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 97)
[0630] .sup.1H NMR (400 MHz, DMSO-d.sup.6):
[0631] .delta.(ppm) 1.30 (3H, s, CH.sub.3 Aib), 1.40 (3H, s,
CH.sub.3 Aib), 3.00-3.20 (4H, m, --CH.sub.2--CH.sub.2--In), 3.36
(3H, s, N--CH.sub.3), 3.45-3.50 (2H, m, CH.sub.2.beta. Trp), 5.30
(1H, m, CH.alpha. Trp), 6.95-7.04 (2H, t, H.sub.5 indole),
7.06-7.13 (2H, m, H.sub.6 indole), 7.18 (2H, brs, H.sub.2 indole),
7.34 (1H, d, J=8.0, H.sub.7 indole), 7.36 (1H, d, J=8.0, H.sub.7
indole), 7.48 (1H, d, J=7.8, H.sub.4 indole), 7.58 (1H, d, J=7.8,
H.sub.4 indole), 8.10 (2H, brs, NH.sub.2 Aib), 8.95 (1H, d, J=8.1,
NH Trp), 10.95 (1H, s, NH indole), 10.96 (1H, s, NH indole).
[0632] .sup.13C NMR (100 MHz,DMSO-d.sup.6):
[0633] .delta.(ppm) 22.9-25.9 (--CH.sub.2--CH.sub.2-indole), 24.1
(CH.sub.3 Aib), 24.3 (CH.sub.3 Aib), 28.8 (CH.sub.2.beta. Trp),
30.7 (--NCH.sub.3), 46.2 (CH.alpha. Trp), 57.2 (Cq Aib), 110.2
(C.sub.3 indole), 112.3 (2C.sub.7 indole), 113.5 (C.sub.3 indole),
118.9-119.2 (2C.sub.5, 2C.sub.4 indole), 121.9 (2C.sub.6 indole),
123.6 (C.sub.2 indole), 125.3 (C.sub.2 indole), 127.7 (C.sub.9
indole), 128.0 (C.sub.9 indole), 136.9 (C.sub.8 indole), 137.1
(C.sub.8 indole), 155.3 (Cq triazole), 155.8 (Cq triazole), 172.2
(CO Aib).
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3--
yl)ethyl)-2-amino-2-methylpropanamide (Compound 98)
[0634] .sup.1H NMR (400 MHz, DMSO-d.sup.6):
[0635] .delta.(ppm) 1.31 (3H, s, CH.sub.3 Aib), 1.42 (3H, s,
CH.sub.3 Aib), 3.19 (1H, dd, J=14.5, J=9.6, 1H CH.sub.2 .beta.Trp),
3.35 (1H, dd, J=14.5, J=5.3, 1H C.sub.2 .beta.Trp), 4.15 (2H, s,
CH.sub.2 indole), 5.26 (1H, m, C.alpha.H Trp), 6.95 (1H, t, H.sub.5
Trp), 6.96 (1H, t, H.sub.5 indole), 7.05 (1H, t, H.sub.6 Trp), 7.06
(1H, s, H.sub.2 Trp), 7.07 (1H, t, H.sub.6 indole), 7.21 (1H, s,
H.sub.2 indole), 7.32 (1H, d, H.sub.7 Trp), 7.37 (1H, d, H.sub.7
indole), 7.51 (1H, d, J=7.8, H.sub.4 indole), 7.58 (1H, d, J=7.8,
H.sub.4 Trp), 8.00 (2H, s, NH.sub.2 Aib), 8.64 (1H, d, J=8.7, NH
Trp), 10.77 (1H, s, NH indole Trp), 10.92 (1H, s, NH indole).
[0636] .sup.13C NMR (400 MHz,DMSO-d.sup.6):
[0637] .delta.(ppm) 22.9 (CH.sub.2 indole), 23.2 (CH.sub.3 Aib),
23.3 (CH.sub.3 Aib), 29.4 (C.beta. Trp), 48.3 (C.alpha. Trp), 56.3
(Cq Aib), 109.7 (C.sub.3 indole), 110.3 (C.sub.3 Trp), 111.2
(C.sub.7 Trp), 111.3 (C.sub.7 indole), 118.1 (C.sub.4 Trp, C.sub.5
Trp), 118.3 (C.sub.4 indole), 118.4 (C.sub.5 indole), 120.7
(C.sub.6 Trp), 121.0 (C.sub.6 indole), 123.4 (C.sub.2 indole),
123.6 (C.sub.2 Trp), 126.8 (C.sub.9 indole), 127.1 (C.sub.9 Trp),
136.0 (C.sub.8 Trp), 136.2 (C.sub.8 indole), 157.5 (Cq triazole),
161.7 (Cq triazole), 170.8 (CO Aib).
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-tria-
zol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide
(Compound 99)
[0638] .sup.1H NMR (400 MHz, DMSO-d.sup.6):
[0639] .delta.(ppm) 1.27 (3H, s, CH.sub.3 Aib), 1.29 (3H, s,
CH.sub.3 Aib), 3.25 (1H, dd, J=14.3, J=5.6, 1H CH.sub.2 .beta.Trp),
3.38 (1H, dd, J=14.3, J=9.1, 1H C.sub.2 .beta.Trp), 3.68 (3H, s,
OCH.sub.3), 3.72 (3H, s, OCH.sub.3), 4.10 (1H, d, J=16.5, 1H
C.sub.2 indole), 4.16 (1H, d, J=16.5, 1H C.sub.2 indole), 4.96 (1H,
d, J=16.8, 1H C.sub.2 o,p-dimethoxybenzyl), 5.12 (1H, d, J=16.8, 1H
C.sub.2 o,p-dimethoxybenzyl), 5.16 (1H, m, C.alpha.H Trp), 6.21
(1H, dd, J=8.5, J=2.1, H.sub.5 o,p-dimethoxybenzyl), 6.27 (1H, d,
J=8.5, H.sub.6 o,p-dimethoxybenzyl), 6.57 (1H, d, J=2.1, H.sub.3
o,p-dimethoxybenzyl), 6.83 (1H, t, H.sub.5 Trp), 6.94 (1H, t,
H.sub.5 indole), 7.02 (1H, t, H.sub.6 Trp), 7.05 (1H, t, H.sub.2
indole), 7.06 (1H, t, H.sub.6 indole), 7.07 (1H, s, H.sub.2 Trp),
7.07 (1H, t, H.sub.4 Trp), 7.31 (1H, d, H.sub.7 Trp), 7.33 (1H, d,
H.sub.7 indole), 7.36 (1H, d, J=7.8, H.sub.4 indole), 8.00 (2H, br
s, NH.sub.2 Aib), 8.92 (1H, d, J=8.2, NH Trp), 10.79 (1H, s, NH
indole Trp), 10.89 (1H, s, NH indole).
[0640] .sup.13C NMR (400 MHz,DMSO-d.sup.6):
[0641] .delta.(ppm) 21.2 (CH.sub.2indole), 23.1 (CH.sub.3 Aib),
23.2 (CH.sub.3 Aib), 28.6 (C.beta. Trp), 41.4 (N--CH.sub.2
o,p-dimethoxybenzyl), 45.1 (C.alpha. Trp), 55.2 (OCH.sub.3), 55.4
(OCH.sub.3), 56.2 (Cq Aib), 98.5 (C.sub.3 o,p-dimethoxybenzyl),
104.6 (C.sub.5 o,p-dimethoxybenzyl), 107.9 (C.sub.3 indole), 109.5
(C.sub.3 Trp), 111.2 (C.sub.7 Trp), 111.3 (C.sub.7 indole), 115.1
(C.sub.1 o,p-dimethoxybenzyl), 117.8 (C.sub.4 Trp), 118.1 (C.sub.5
Trp), 118.3 (C.sub.4 indole), 118.4 (C.sub.5 indole), 120.8
(C.sub.6 Trp), 121.1 (C.sub.6 indole), 123.5 (C.sub.2 indole),
124.3 (C.sub.2 Trp), 126.6 (C.sub.9 indole), 126.8 (C.sub.9 Trp),
127.2 (C.sub.6 o,p-dimethoxybenzyl), 136.0 (C.sub.8 Trp), 136.2
(C.sub.8 indole), 157.5 (Cq triazole), 154.9 (Cq triazole), 157.2
(C.sub.2 o,p-dimethoxybenzyl), 160.3 (C.sub.4 o,p-dimethoxybenzyl),
171.2 (CO Aib).
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound
101)
[0642] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0643] .delta.(ppm) 1.22 (3H, s, CH.sub.3 Aib), 1.25 (3H, s,
CH.sub.3 Aib), 3.22 (1H, dd, J=14 Hz and 6 Hz, CH.sub.2 .beta.Trp),
3.34 (1H, dd, J=14 Hz and 9 Hz, CH.sub.2 .beta.Trp), 3.68 (3H, s,
OCH.sub.3), 4.11 (2H, m, CH.sub.2-indole), 5.09 (3H, m, CH
.alpha.Trp and CH.sub.2-p-methoxybenzyl), 6.70 (4H, s, CHar
p-methoxybenzyl), 6.78 (2H, m, H.sub.5 indole and H.sub.5 Trp),
6.93 (2H, m, H.sub.6 indole and H.sub.6 Trp), 7.01-7.06 (3H, m,
H.sub.2 indole, H.sub.2 and H.sub.4 Trp), 7.31 (3H, m, H.sub.4 and
H.sub.7 indole, H.sub.7 Trp), 7.98 (3H, brs, NH.sub.2 Aib), 8.92
(1H, d, J=8 Hz, NH amide), 10.77 (1H, s, NH indole), 10.89 (1H, s,
NH indole Trp).
[0644] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0645] .delta.(ppm) 21.7 (CH.sub.2-indole), 23.5 (CH.sub.3 Aib),
23.7 (CH.sub.3 Aib), 28.9 (CH.sub.2 .beta.Trp), 45.6 (CH
.alpha.Trp), 45.8 (CH.sub.2-- p-methoxybenzyl), 55.5 (OCH.sub.3),
56.7 (Cq Aib), 108.1 (C.sub.3 indole), 109.7 (C.sub.3 Trp), 111.7
(C.sub.7 Trp), 111.9 (C.sub.7 indole), 114.5 (C.sub.3 and C.sub.5
p-methoxybenzyl), 118.3 (C.sub.4 Trp), 118.7 (C.sub.4 indole),
118.8 (C.sub.5 indole), 118.9 (C.sub.5 Trp), 121.3 (C.sub.6
indole), 121.6 (C.sub.6 Trp), 124.2 (C.sub.2 indole), 125.3
(C.sub.2 Trp), 127.1 (C.sub.9 indole), 127.2 (C.sub.9 Trp), 127.6
(C.sub.1 p-methoxybenzyl), 127.8 (C.sub.2 and C.sub.6
p-methoxybenzyl), 136.4 (C.sub.8 Trp), 136.7 (C.sub.8 indole),
154.2 (Cq triazole), 155.2 (Cq triazole), 159.2 (C.sub.4
p-methoxybenzyl), 171.9 (CO Aib).
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 102)
[0646] .sup.1H NMR (400 MHz, DMSO-d.sup.6):
[0647] .delta.(ppm) 1.30 (3H, s, CH.sub.3 Aib), 1.33 (3H, s,
CH.sub.3 Aib), 3.26 (1H, dd, J=14.2, J=5.9, 1H CH.sub.2 .beta.Trp),
3.38 (1H, dd, J=14.2, J=8.7, 1H C.sub.2 .beta.Trp), 3.69 (3H, s,
OCH.sub.3), 3.72 (3H, s, OCH.sub.3), 4.02 (2H, s, CH.sub.2 benzyl),
4.87 (1H, d, J=16.7, 1H C.sub.2 o,p-dimethoxybenzyl), 5.08 (1H, d,
J=16.7, 1H C.sub.2 o,p-dimethoxybenzyl), 5.17 (1H, m, C.alpha.H
Trp), 6.24 (1H, dd, J=8.4, J=1.7, H.sub.5 o,p-dimethoxybenzyl),
6.28 (1H, d, J=8.4, H.sub.6 o,p-dimethoxybenzyl), 6.56 (1H, d,
J=1.7, H.sub.3 o,p-dimethoxybenzyl), 6.85 (1H, t, J=7.5, H.sub.5
Trp), 7.02 (1H, t, H.sub.6 Trp), 7.07 (2H, m, H.sub.2, H.sub.6
benzyl), 7.08 (1H, s, H.sub.2 Trp), 7.09 (1H, d, H.sub.4 Trp),
7.16-7.29 (3H, m, H.sub.3, H.sub.4, H.sub.5 benzyl), 7.31 (1H, d,
J=8.2, H.sub.7 Trp), 8.01 (2H, s, NH.sub.2 Aib), 8.92 (1H, d,
J=7.9, NH Trp), 11.79 (1H, s, NH indole Trp).
[0648] .sup.13C NMR (400 MHz,DMSO-d.sup.6):
[0649] .delta.(ppm) 23.2 (2CH.sub.3 Aib), 28.7 (C.beta. Trp), 30.2
(CH.sub.2-benzyl), 41.3 (CH.sub.2-- o,p-dimethoxybenzyl), 45.2
(C.alpha. Trp), 55.2 (OCH.sub.3), 55.4 (OCH.sub.3), 56.2 (Cq Aib),
98.5 (C.sub.3 o,p-dimethoxybenzyl), 104.7 (C.sub.5
o,p-dimethoxybenzyl), 109.$ (C.sub.3 Trp), 111.3 (C.sub.7 Trp),
115.1 (C.sub.1 o,p-dimethoxybenzyl), 117.8 (C.sub.4 Trp), 118.2
(C.sub.5 Trp), 120.8 (C.sub.6 Trp), 124.3 (C.sub.2 Trp), 126.5
(C.sub.2, C.sub.6 benzyl), 126.8 (C.sub.9 Trp), 127.3 (C.sub.6
o,p-dimethoxybenzyl), 128.3 (C.sub.3, C.sub.4, C.sub.5 Benzyl),
135.8 (C.sub.1 benzyl), 136.0 (C.sub.8 Trp), 153.4 (Cq triazole),
155.0 (Cq triazole), 157.2 (C.sub.2 o,p-dimethoxybenzyl), 160.3
(C.sub.4 o,p-dimethoxybenzyl), 171.3 (CO Aib).
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-phenethyl-4H-1,2,4-triazol-3-yl)-2--
(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound
104)
[0650] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0651] .delta.(ppm) 1.27 (3H, s, CH.sub.3 Aib), 1.29 (3H, s,
CH.sub.3 Aib), 2.39-2.53 (4H, m, CH.sub.2--CH.sub.2-phenyl), 3.74
(1H, m, CH.sub.2 .beta.Trp), 3.92 (1H, m, CH.sub.2 .beta.Trp), 3.99
(2H, s, CH.sub.2-indole), 5.21 (1H, m, CH .alpha.Trp), 6.74 (2H, m,
H.sub.5 indole and H.sub.5 Trp), 6.90 (1H, t, J.sub.o=8 Hz, H.sub.6
Trp), 6.92 (1H, t, J.sub.o=8 Hz, H.sub.6 indole), 7.01-7.06 (4H, m,
H.sub.2 and H.sub.6 phenyl, H.sub.2 indole and H.sub.2 Trp), 7.16
(3H, m, H.sub.3, H.sub.4 and H.sub.5 phenyl), 7.27 (1H, d,
J.sub.o=8 Hz, H.sub.4 Trp), 7.32 (1H, d, J.sub.o=8 Hz, H.sub.7
Trp), 7.36 (1H, d, J.sub.o=8 Hz, H.sub.7 indole), 7.50 (1H, d,
J.sub.o=8 Hz, H.sub.4 indole), 7.99 (3H, brs, NH.sub.2 Aib), 9.02
(1H, s, J=8 Hz, NH amide), 10.79 (1H, s, NH indole Trp), 10.94 (1H,
s, NH indole).
[0652] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0653] .delta.(ppm) 21.4 (CH.sub.2-indole), 23.5 (CH.sub.3 Aib),
23.8 (CH.sub.3 Aib), 29.5 (CH.sub.2 .beta.Trp), 35.8
(CH.sub.2--CH.sub.2-phenyl), 44.5 (CH.sub.2--CH.sub.2-phenyl), 45.8
(CH .alpha.Trp), 56.7 (Cq Aib), 108.5 (C.sub.3 indole), 109.9
(C.sub.3 Trp), 114.0 (C.sub.7 indole and C.sub.7 Trp), 118.4
(C.sub.4 Trp), 118.8 (C.sub.4 indole and C.sub.5 Trp), 119.0
(C.sub.5 indole), 121.4 (C.sub.6 Trp), 121.7 (C.sub.6 indole),
124.0 (C.sub.2 indole and C.sub.2 Trp), 127.1 (C.sub.4 phenyl),
127.7 (C.sub.9 indole and C.sub.9 Trp), 128.8 (C.sub.2 and C.sub.6
phenyl), 129.1 (C.sub.3 and C.sub.5 phenyl), 136.5 (C.sub.8 Trp),
136.6 (C.sub.8 indole), 137.5 (C.sub.1 phenyl), 153.6 (Cq
triazole), 155.0 (Cq triazole), 171.8 (CO Aib).
(R)--N-(1-(5-benzyl-4-(2,2-diphenylethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 106)
[0654] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0655] .delta.(ppm) 1.29 (3H, s, CH.sub.3 Aib), 1.34 (3H, s,
CH.sub.3 Aib), 3.37 (4H, m, CH.sub.2 .beta.Trp and
CH.sub.2-benzyl), 3.74 (1H, t, J=7 Hz, CH.sub.2--CH(Phe).sub.2),
4.21 (1H, dd, J=14 Hz and 8 Hz, CH.sub.2--CH(Phe).sub.2), 4.51 (1H,
dd, J=14 Hz and 8 Hz, CH.sub.2--CH(Phe).sub.2), 5.08 (1H, m, CH
.alpha.Trp), 6.72 (2H, m, H.sub.2 and H.sub.6 benzyl), 6.86-6.93
(5H, m, H.sub.3, H.sub.4 and H.sub.5 benzyl, H.sub.5 and H.sub.6
Trp), 7.03 (1H, s, H.sub.2 Trp), 7.06-7.25 (CHar phenyl from
CH(Phe).sub.2), 7.33 (1H, d, J.sub.o=8 Hz, H.sub.4 Trp), 7.47 (1H,
d, J.sub.o=8 Hz, H.sub.7 indole), 8.10 (3H, brs, NH.sub.2 Aib),
8.98 (1H, d, J=8 Hz, NH amide), 10.94 (1H, s, NH indole Trp).
[0656] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0657] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.7 (CH.sub.3 Aib), 29.4
(CH.sub.2 .beta.Trp), 30.1 (CH.sub.2-benzyl), 46.0 (CH .alpha.Trp),
47.7 (CH.sub.2--CH(Phe).sub.2), 51.3 (CH(Phe).sub.2), 56.8 (Cq
Aib), 109.8 (C.sub.3 Trp), 112.0 (C.sub.7 Trp), 118.5 (C.sub.4
Trp), 119.0 (C.sub.5 Trp), 121.5 (C.sub.6 Trp), 124.8 (C.sub.2
Trp), 127.1 (C.sub.4 phenyl from CH(Phe).sub.2), 127.4 (C.sub.9
Trp, C.sub.2 and C.sub.6 benzyl), 128.3 (C.sub.2 and C.sub.6 phenyl
from CH(Phe).sub.2), 128.8-129.1 (C.sub.3 and C.sub.5 phenyl from
CH(Phe).sub.2, C.sub.3, C.sub.4 and C.sub.5 benzyl), 136.2 (C.sub.1
benzyl), 136.5 (C.sub.8 Trp), 141.0 (C.sub.1 phenyl from
CH(Phe).sub.2), 153.5 (Cq triazole), 155.1 (Cq triazole), 172.0 (CO
Aib)
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,2-diphenylethyl)-4H-1,2,4-triaz-
ol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide
(Compound 107)
[0658] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0659] .delta.(ppm) 1.34 (3H, s, CH.sub.3 Aib), 1.38 (3H, s,
CH.sub.3 Aib), 2.06 (1H, m, CH.sub.2--CH.sub.2-indole), 2.30 (1H,
m, CH.sub.2--CH.sub.2-indole), 2.78 (2H, m,
CH.sub.2--CH.sub.2-indole), 3.35 (1H, dd, J=14 Hz and 7 Hz,
CH.sub.2 .beta.Trp), 3.46 (1H, dd, J=14 Hz and 9 Hz, CH.sub.2
.beta.Trp), 3.58 (1H, t, J=7 Hz, CH.sub.2--CH(Phe).sub.2), 4.14
(1H, dd, J=14 Hz and 8 Hz, CH.sub.2--CH(Phe).sub.2), 4.39 (1H, dd,
J=14 Hz and 7 Hz, CH.sub.2--CH(Phe).sub.2), 5.12 (1H, m, CH
.alpha.Trp), 6.50 (2H, m, H.sub.5 indole and H.sub.5 Trp), 6.76
(2H, m, H.sub.6 indole and H.sub.6 Trp), 6.87 (2H, m, H.sub.2
indole and H.sub.2 Trp), 6.89-6.96 (2H, m, H.sub.4 phenyl),
7.03-7.15 (8H, m, H.sub.2, H.sub.3, H.sub.5 and H.sub.6 phenyl),
7.33 (3H, m, H.sub.4 indole, H.sub.4 and H.sub.7 Trp), 7.47 (1H, d,
J=8 Hz, H.sub.7 indole), 8.11 (3H, brs, NH.sub.2 Aib), 9.04 (1H, d,
J=8 Hz, NH amide), 10.76 (1H, s, NH indole), 10.96 (1H, s, NH
indole Trp).
[0660] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0661] .delta.(ppm) 22.4 (CH.sub.2--CH.sub.2-indole), 23.6
(CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 24.9
(CH.sub.2--CH.sub.2-indole), 29.6 (CH.sub.2 .beta.Trp), 46.1 (CH
.alpha.Trp), 47.5 (CH.sub.2--CH(Phe).sub.2), 51.5
(CH.sub.2--CH(Phe).sub.2), 56.8 (Cq Aib), 109.8 (C.sub.3 Trp),
111.8 (C.sub.7 Trp), 112.1 (C.sub.7 indole), 113.5 (C.sub.3
indole), 118.4 (C.sub.4 Trp), 118.7 (C.sub.4 and C.sub.5 indole),
119.0 (C.sub.5 Trp), 121.4 (C.sub.6 indole and C.sub.6 Trp), 122.8
(C.sub.2 indole), 125.0 (C.sub.2 Trp), 127.2 (C.sub.9 indole and
C.sub.9 Trp), 127.3 (C.sub.4 phenyl), 128.2 (C.sub.2 and C.sub.6
phenyl), 128.7 (C.sub.3 and C.sub.5 phenyl), 136.6 (C.sub.8 indole
and C.sub.8 Trp), 141.0 (C.sub.1 phenyl), 154.6 (2 Cq triazole),
172.0 (CO Aib).
(R)--N-(1-(4,5-dibenzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-a-
mino-2-methylpropanamide (Compound 109)
[0662] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0663] .delta.(ppm) 1.23 (3H, s, CH.sub.3 Aib), 1.26 (3H, s,
CH.sub.3 Aib), 3.23 (1H, dd, J=14 Hz and 6 Hz, CH.sub.2 .beta.Trp),
3.35 (1H, dd, J=14 Hz and 9 Hz, CH.sub.2 .beta.Trp), 3.99 (2H, s,
C--CH.sub.2-phenyl), 5.10 (3H, m, N--CH.sub.2-phenyl and CH
.alpha.Trp), 6.77 (3H, m, H.sub.5 Trp, H.sub.2 and H.sub.6 phenyl
from N--CH.sub.2-phenyl), 6.99 (2H, m, H.sub.2 and H.sub.6 Trp),
7.01-7.07 (3H, m, H.sub.4 Trp, H.sub.2 and H.sub.6 from
C--CH.sub.2-phenyl), 7.15-7.23 (6H, m, H.sub.3, H.sub.4 and H.sub.5
phenyl from N--CH.sub.2-phenyl and from C--CH.sub.2-phenyl), 7.25
(1H, d, J=8 Hz, H.sub.7 Trp), 8.01 (3H, brs, NH.sub.2 Aib), 8.91
(1H, d, J=8 Hz, NH amide), 10.78 (1H, s, NH indole Trp).
[0664] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0665] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.7 (CH.sub.3 Aib), 29.0
(CH.sub.2 .beta.Trp), 30.6 (C--CH.sub.2-phenyl), 45.7 (CH
.alpha.Trp), 46.1 (N--CH.sub.2-phenyl), 56.7 (Cq Aib), 109.8
(C.sub.3 Trp), 111.7 (C.sub.7 Trp), 118.3 (C.sub.4 Trp), 118.7
(C.sub.5 Trp), 121.2 (C.sub.6 Trp), 124.8 (C.sub.2 Trp), 126.3
(C.sub.2 and C.sub.6 phenyl from N--CH.sub.2-phenyl), 127.0
(C.sub.2 and C.sub.6 phenyl from C--CH.sub.2-phenyl), 127.2
(C.sub.9 Trp), 128.0 (C.sub.4 phenyl from N--CH.sub.2-phenyl),
128.8 (C.sub.3, C.sub.4 and C.sub.5 phenyl from
C--CH.sub.2-phenyl), 128.9 (C.sub.3 and C.sub.5 phenyl from
N--CH.sub.2-phenyl), 135.8 (C.sub.1 phenyl from
N--CH.sub.2-phenyl), 136.2 (C.sub.1 phenyl from
C--CH.sub.2-phenyl), 136.4 (C.sub.8 Trp), 153.9 (Cq triazole),
155.3 (Cq triazole), 171.9 (CO Aib).
(R)--N-(1-(5-benzyl-4-hexyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
-2-amino-2-methylpropanamide (Compound 110)
[0666] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0667] .delta.(ppm) 0.71 (3H, t, .sup.3J=7 Hz,
(CH.sub.2).sub.5--CH.sub.3), 0.87 (4H, m, 2 CH.sub.2), 0.95 (2H, m,
CH.sub.2--CH.sub.3), 1.00 (2H, m, N--CH.sub.2--CH.sub.2), 1.36 (6H,
s, CH.sub.3 Aib), 3.36 (1H, dd, .sup.3J=14 Hz and 7 Hz, CH.sub.2
.beta.Trp), 3.41 (1H, dd, .sup.3J=14 Hz and 7 Hz, CH.sub.2
.beta.Trp), 3.50 (1H, m, N--CH.sub.2), 3.65 (1H, m, N--CH.sub.2),
4.11 (2H, s, CH.sub.2-benzyl), 5.14 (1H, m, CH .alpha.Trp), 6.90
(1H, t, J.sub.o=7 Hz, H.sub.5 Trp), 7.01 (1H, t, J.sub.o=7 Hz,
H.sub.6 Trp), 7.04 (1H, s, H.sub.2 Trp), 7.09 (2H, m, H.sub.2 and
H.sub.6 benzyl), 7.17-7.29 (4H, m, H.sub.4 Trp, H.sub.3, H.sub.4
and H.sub.5 benzyl), 7.47 (1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 8.10
(3H, brs, NH.sub.2 Aib), 9.05 (1H, d, J=7 Hz, NH amide), 10.84 (1H,
s, NH indole Trp).
[0668] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0669] .delta.(ppm) 14.1 ((CH.sub.2).sub.5--CH.sub.3), 22.1
(CH.sub.2--CH.sub.3), 23.8 (CH.sub.3 Aib), 23.5 (CH.sub.3 Aib),
25.8 (CH.sub.3--CH.sub.2--CH.sub.2--CH.sub.2), 29.5 (CH.sub.2
.beta.Trp), 30.3 (N--CH.sub.2--CH.sub.2), 30.8 (CH.sub.2-benzyl and
CH.sub.3--CH.sub.2--CH.sub.2), 43.3 (N--CH.sub.2--CH.sub.2), 46.1
(CH .alpha.Trp), 56.8 (Cq Aib), 109.6 (C.sub.3 Trp), 111.9 (C.sub.7
Trp), 118.2 (C.sub.4 Trp), 118.8 (C.sub.5 Trp), 121.4 (C.sub.6
Trp), 124.7 (C.sub.2 Trp), 127.2 (C.sub.2 and C.sub.6 benzyl),
127.3 (C.sub.9 Trp), 128.8 (C.sub.3, C.sub.4 and C.sub.5 benzyl),
136.2 (C.sub.1 benzyl), 136.5 (C.sub.8 Trp), 153.1 (Cq triazole),
155.1 (Cq triazole), 171.9 (CO Aib).
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 111)
[0670] .sup.1H NMR (400 MHz, DMSO-d.sup.6, 300.degree. K):
[0671] .delta.(ppm) 1.31 (3H, s, CH.sub.3 Aib), 1.35 (3H, s,
CH.sub.3 Aib), 2.51 (2H, m, CH.sub.2--CH.sub.2-indole), 3.37 (2H,
m, CH.sub.2 .beta.Trp), 3.76-3.90 (4H, m, CH.sub.9-benzyl and
CH.sub.2--CH.sub.2-indole), 5.25 (1H, m, CH .alpha.Trp), 6.88 (2H,
t, J.sub.o=7 hz, H.sub.5 indole and H.sub.5 Trp), 6.95 (2H, t,
J.sub.o=7 Hz, H.sub.6 indole and H.sub.6 Trp), 7.03 (4H, m, H.sub.2
Trp, H.sub.2 indole, H.sub.2 and H.sub.6 benzyl), 7.16 (2H, d,
J.sub.o=8 Hz, H.sub.4 indole and H.sub.4 Trp), 7.20-7.30 (4H, 3,
H.sub.7 indole, H.sub.3, H.sub.4 and H.sub.5 benzyl), 7.47 (1H, d,
J.sub.o=8 Hz, H.sub.7 Trp), 8.05 (3H, brs, NH.sub.2 Aib), 9.05 (1H,
d, J=8 Hz, NH amide), 10.83 (1H, s, NH indole), 10.88 (1H, s, NH
indole Trp).
[0672] .sup.13C NMR (100 MHz, DMSO-d.sup.6, 300.degree. K):
[0673] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.7 (CH.sub.3 Aib), 29.6
(CH.sub.2 .beta.Trp), 30.3 (CH.sub.2-benzyl and
CH.sub.2-CH.sub.2-indole), 44.1 (CH.sub.2--CH.sub.2-indole), 46.1
(CH .alpha.Trp), 56.8 (Cq Aib), 109.8 (C.sub.3 Trp), 109.9 (C.sub.3
indole), 111.9 (C.sub.7 indole and C.sub.7 Trp), 118.3 (C.sub.4
Trp), 118.4 (C.sub.4 indole), 118.9 (C.sub.5 indole and C.sub.5
Trp), 121.3 (C.sub.6 Trp), 121.5 (C.sub.6 indole), 123.7 (C.sub.2
indole), 124.7 (C.sub.2 Trp), 127.0 (C.sub.9 indole), 127.2
(C.sub.2 and C.sub.6 benzyl), 127.4 (C.sub.9 Trp), 128.8 (C.sub.3
and C.sub.5 benzyl), 129.0 (C.sub.4 benzyl), 136.3 (C.sub.1
benzyl), 136.4 (C.sub.8 indole and C.sub.8 Trp), 153.1 (Cq
triazole), 155.3 (Cq triazole), 171.8 (CO Aib).
(S)--N-(1-(4-(2,4-dimethoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-i-
ndol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 112)
[0674] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0675] .delta.(ppm) 1.26 (3H, s, CH.sub.3 Aib), 1.29 (3H, s,
CH.sub.3 Aib), 3.24 (1H, dd, J=14 Hz and 6 Hz, CH.sub.2 .beta.Trp),
3.33 (1H, dd, J=14 Hz and 9 Hz, CH.sub.2 .beta.Trp), 3.64 (3H, s,
OCH.sub.3), 3.68 (3H, s, OCH.sub.3), 3.99 (2H, s, CH.sub.2 phenyl),
4.84 (1H, d, J=17 Hz, CH.sub.2-o,p-dimethoxybenzyl), 5.05 (1H, d,
J=17 Hz, CH.sub.2-o,p-dimethoxybenzyl), 5.13 (1H, m, CH
.alpha.Trp), 6.24 (2H, m, H.sub.5 and H.sub.6 o,p-dimethoxybenzyl),
6.52 (1H, d, J.sub.m=2 Hz, H.sub.3 o,p-dimethoxybenzyl), 6.83 (1H,
t, J.sub.o=7 Hz, H.sub.5 Trp), 7.01 (1H, t, J.sub.o=8 Hz, H.sub.6
Trp), 7.04 (1H, s, H.sub.2 Trp), 7.05-7.23 (6H, m, H.sub.4 Trp and
CHar phenyl), 7.27 (1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 8.01 (3H,
brs, NH.sub.2 Aib), 8.90 (1H, d, J=8 Hz, NH amide), 10.77 (1H, d,
J=2 Hz, NH indole Trp).
[0676] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0677] .delta.(ppm) 23.6 (CH.sub.3 Aib), 29.1 (CH.sub.2 .beta.Trp),
30.6 (CH.sub.2-phenyl), 41.9 (CH.sub.2-o,p-dimethoxybenzyl), 45.7
(CH .alpha.Trp), 55.7 (OCH.sub.3), 55.9 (OCH.sub.3), 56.7 (Cq Aib),
99.9 (C.sub.3 o,p-dimethoxybenzyl), 105.1 (C.sub.5
o,p-dimethoxybenzyl), 109.9 (C.sub.3 Trp), 111.7 (C.sub.7 Trp),
115.5 (C.sub.1 o,p-dimethoxybenzyl), 118.3 (C.sub.4 Trp), 118.6
(C.sub.5 Trp), 121.3 (C.sub.6 Trp), 124.2 (C.sub.2 Trp), 127.0
(C.sub.6 o,p-dimethoxybenzyl), 127.3 (C.sub.9 Trp), 127.8 (C.sub.4
phenyl), 128.8 (C.sub.2, C.sub.3, C.sub.5 and C.sub.6 phenyl),
136.2 (C.sub.8 Trp), 136.4 (C.sub.1 phenyl), 153.9 (Cq triazole),
155.5 (Cq triazole), 157.6 (C.sub.2 o,p-dimethoxybenzyl), 160.8
(C.sub.4 o,p-dimethoxybenzyl), 171.8 (CO amide).
(R)--N-(1-(4-(3,5-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 113)
[0678] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0679] .delta.(ppm) 1.24 (3H, s, CH.sub.3 Aib), 1.27 (3H, s,
CH.sub.3 Aib), 2.83 (4H, s, CH.sub.2--CH.sub.2-phenyl), 3.32 (2H,
m, CH.sub.2 .beta.Trp), 3.61 (6H, s, OCH.sub.3), 5.02 (2H, m,
CH.sub.2-m-dimethoxybenzyl), 5.18 (1H, m, CH .alpha.Trp), 6.07 (2H,
d, J.sub.m=2 Hz, H.sub.2 and H.sub.6 m-dimethoxybenzyl), 6.42 (1H,
brs, H.sub.4 m-dimethoxybenzyl), 6.83 (1H, t, J.sub.o=7 Hz, H.sub.5
Trp), 6.99 (1H, t, J.sub.o=8 Hz, H.sub.6 Trp), 7.08 (1H, d, J=2 Hz,
H.sub.2 Trp), 7.13 (3H, t, J.sub.o=8 Hz, H.sub.3, H.sub.4 and
H.sub.5 phenyl), 7.20 (3H, d, J.sub.o=7 Hz, H.sub.2 and H.sub.6
phenyl, H.sub.4 Trp), 7.28 (1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 7.99
(3H, brs, NH.sub.2 Aib), 8.92 (1H, d, J=8 Hz, NH amide), 10.77 (1H,
s, NH indole).
[0680] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0681] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 26.5
(CH.sub.2--CH.sub.2-phenyl), 29.2 (CH.sub.2 .beta.Trp), 32.7
(CH.sub.2--CH.sub.2-phenyl), 45.6 (CH .alpha.Trp), 45.8 (CH.sub.2--
m-dimethoxybenzyl), 55.6 (OCH.sub.3), 56.8 (Cq Aib), 99.6 (C.sub.4
m-dimethoxybenzyl), 104.6 (C.sub.2 and C.sub.6 m-dimethoxybenzyl),
109.9 (C.sub.3 Trp), 111.8 (C.sub.7 Trp), 118.2 (C.sub.4 Trp),
118.7 (C.sub.5 Trp), 121.3 (C.sub.6 Trp), 124.8 (C.sub.2 Trp),
126.5 (C.sub.4 phenyl), 127.3 (C.sub.9 Trp), 128.7 (C.sub.2,
C.sub.3, C.sub.5 and C.sub.6 phenyl), 136.4 (C.sub.8 Trp), 138.6
(C.sub.4 m-dimethoxybenzyl), 140.9 (C.sub.1 phenyl), 154.6 (Cq
triazole), 154.8 (Cq triazole), 161.4 (C.sub.3 and C.sub.5
m-dimethoxybenzyl), 171.8 (CO amide).
(R)--N-(1-(4-(4-bromobenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
-yl)ethyl)-2-amino-2-methylpropanamide (Compound 114)
[0682] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0683] .delta.(ppm)1.23 (3H, s, CH.sub.3 Aib), 1.25 (3H, s,
CH.sub.3 Aib), 3.26 (1H, dd, .sup.3J=14 Hz and 6 Hz, CH.sub.2 Trp),
3.34 (1H, dd, .sup.3J=14 Hz and 9 Hz, CH.sub.2 .beta.Trp), 4.01
(2H, m, CH.sub.2-benzyl), 5.01 (1H, m, CH .alpha.Trp), 5.08 (2H, s,
CH.sub.2-p-bromobenzyl), 6.59 (2H, d, J.sub.o=8 Hz, H.sub.2 and
H.sub.6 p-bromobenzyl), 6.81 (1H, t, J.sub.o=7 Hz, H.sub.5 Trp),
6.94 (1H, s, H.sub.2 Trp), 6.98 (1H, t, J.sub.o=7 Hz, H.sub.6 Trp),
7.06 (2H, m, H.sub.2 and H.sub.6 benzyl), 7.12 (1H, d, J.sub.o=7
Hz, H.sub.4 Trp), 7.16-7.20 (3H, m, H.sub.3, H.sub.4 and H.sub.5
benzyl), 7.26 (1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 7.29 (2H, d,
J.sub.o=8 Hz, H.sub.3 and H.sub.5 benzyl), 8.00 (3H, brs, NH.sub.2
Aib), 8.92 (1H, d, J=8 Hz, NH amide), 10.78 (1H, s, NH indole
Trp).
[0684] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0685] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 29.0
(CH.sub.2 .beta. Trp), 30.5 (CH.sub.2-benzyl), 45.6
(CH.sub.2-p-bromobenzyl), 45.7 (CH .alpha. Trp), 56.7 (Cq Aib),
109.7 (C.sub.3 Trp), 111.8 (C.sub.7 Trp), 118.2 (C.sub.4
tryptophae), 118.7 (C.sub.5 Trp), 121.2 (C.sub.4 p-bromobenzyl),
121.3 (C.sub.6 Trp), 124.9 (C.sub.2 typtophane), 127.0 (C.sub.2 and
C.sub.6 benzyl), 127.2 (C.sub.9 Trp), 128.4 (C.sub.2 and C.sub.6
p-bromobenzyl), 128.9 (C.sub.3, C.sub.4 and C.sub.5 benzyl), 131.9
(C.sub.3 and C.sub.5 p-bromobenzyl), 135.2 (C.sub.1 p-bromobenzyl),
136.2 (C.sub.8 Trp), 136.4 (C.sub.1 benzyl), 153.9 (Cq triazole),
155.3 (Cq triazole), 171.9 (CO Aib).
(R)--N-(1-(4-(2-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 115)
[0686] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0687] .delta.(ppm) 1.24 (3H, s, CH.sub.3 Aib), 1.27 (3H, s,
CH.sub.3 Aib), 3.20 (1H, dd, J=14 Hz and 5 Hz, CH.sub.2 .beta.Trp),
3.33 (1H, dd, J=14 Hz and 9 Hz, CH.sub.2 .beta.Trp), 3.68 (3H, s,
OCH.sub.3), 4.00 (2H, s, CH.sub.2-phenyl), 4.95 (1H, d, J=17 Hz,
CH.sub.2-o-methoxybenzyl), 5.07 (1H, m, CH .alpha.Trp), 5.18 (1H,
d, J=17 Hz, CH.sub.2-o-methoxybenzyl), 6.27 (1H, d, J.sub.o=8 Hz,
H.sub.3 o-methoxybenzyl), 6.67 (1H, t, J.sub.o=7 Hz, H.sub.5 Trp),
6.77 (1H, t, J.sub.o=6 Hz, H.sub.6 Trp), 6.92-7.05 (6H, m, H.sub.2
Trp, H.sub.2 and H.sub.6 phenyl, H.sub.4, H.sub.5 and H.sub.6
o-methoxybenzyl), 7.14-7.26 (5H, m, H.sub.4 and H.sub.7 Trp,
H.sub.3, H.sub.4 and H.sub.5 phenyl), 8.03 (3H, brs, NH.sub.2 Aib),
8.91 (1H, d, J=8 Hz, NH amide), 10.78 (1H, s, NH indole Trp).
[0688] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0689] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.6 (CH.sub.3 Aib), 29.1
(CH.sub.2 .beta. Trp), 30.5 (CH.sub.2-phenyl), 42.1
(CH.sub.2-o-methoxybenzyl), 45.7 (CH .alpha. Trp), 55.9
(OCH.sub.3), 56.7 (Cq Aib), 109.8 (C.sub.3 Trp), 111.3 (C.sub.3
o-methoxybenzyl), 111.7 (C.sub.7 Trp), 118.2 (C.sub.4 Trp), 118.7
(C.sub.5 Trp), 120.9 (C.sub.5 o-methoxybenzyl), 121.2 (C.sub.6
Trp), 123.3 (C.sub.1 o-methoxybenzyl), 124.8 (C.sub.2 Trp), 126.6
(C.sub.2 and C.sub.6 phenyl), 127.1 (C.sub.4 o-methoxybenzyl),
127.2 (C.sub.9 Trp), 128.8 (C.sub.3, C.sub.4 and C.sub.5 phenyl),
129.5 (C.sub.6 o-methoxybenzyl), 136.0 (C.sub.1 phenyl), 136.4
(C.sub.8 Trp), 154.0 (Cq triazole), 155.6 (Cq triazole), 156.5
(C.sub.2 o-methoxybenzyl), 171.8 (CO Aib).
(S)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 116)
[0690] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0691] .delta.(ppm) 1.28 (3H, s, CH.sub.3 Aib), 1.32 (3H, s,
CH.sub.3 Aib), 2.81 (4H, m, CH.sub.2--CH.sub.2-phenyl), 3.30 (2H,
t, CH.sub.2 .beta.Trp), 3.61 (3H, s, OCH.sub.3), 3.69 (3H, s,
OCH.sub.3), 4.87 (1H, d, J=17 Hz, CH.sub.2-o,p-dimethoxybenzyl),
5.03 (1H, d, J=17 Hz, CH.sub.2-o,p-dimethoxybenzyl), 5.20 (1H, m,
CH .alpha.Trp), 6.29 (1H, dd, J.sub.o=8 Hz and J.sub.m=2 Hz,
H.sub.5 o,p-dimethoxybenzyl), 6.43 (1H, d, J.sub.o=8 Hz, H.sub.6
o,p-dimethoxybenzyl), 6.55 (1H, d, J.sub.m=2 Hz, H.sub.3
o,p-dimethoxybenzyl), 6.83 (1H, t, J.sub.o=8 Hz, H.sub.5 Trp), 6.99
(1H, t, J.sub.o=8 Hz, H.sub.6 Trp), 7.06 (1H, d, J=2 Hz, H.sub.2
Trp), 7.09-7.25 (6H, m, H.sub.4 Trp and CHar phenyl), 7.28 (1H, d,
J.sub.o=8 Hz, H.sub.7 Trp), 8.04 (3H, brs, NH.sub.2 Aib), 8.92 (1H,
d, J=8 Hz, NH amide), 10.79 (1H, s, NH indole Trp).
[0692] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0693] .delta.(ppm) 23.6 (CH.sub.3 Aib), 23.7 (CH.sub.3 Aib), 26.5
(CH.sub.2--CH.sub.2-phenyl), 29.1 (CH.sub.2 .beta.Trp), 32.7
(CH.sub.2--CH.sub.2-phenyl), 41.8 (CH.sub.2-o,p-dimethoxybenzyl),
45.7 (CH .alpha.Trp), 55.7 (OCH.sub.3), 55.9 (OCH.sub.3), 56.8 (Cq
Aib), 99.1 (C.sub.3 o,p-dimethoxybenzyl), 105.2 (C.sub.5
o,p-dimethoxybenzyl), 109.9 (C.sub.3 Trp), 111.8 (C.sub.7 Trp),
115.6 (C.sub.1 o,p-dimethoxybenzyl), 118.3 (C.sub.4 Trp), 118.7
(C.sub.5 Trp), 121.3 (C.sub.6 Trp), 124.4 (C.sub.2 Trp), 126.6
(C.sub.4 phenyl), 127.3 (C.sub.9 Trp), 128.2 (C.sub.6
o,p-dimethoxybenzyl), 128.7 (C.sub.2, C.sub.3, C.sub.5 and C.sub.6
phenyl), 136.4 (C.sub.8 Trp), 140.9 (C.sub.1 phenyl), 154.6 (Cq
triazole), 155.0 (Cq triazole), 157.8 (C.sub.2
o,p-dimethoxybenzyl), 160.9 (C.sub.4 o,p-dimethoxybenzyl), 171.8
(CO Aib).
(R)--N-(1-(4,5-diphenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)--
2-amino-2-methylpropanamide (Compound 117)
[0694] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0695] .delta.(ppm) 1.32 (3H, s, CH.sub.3 Aib), 1.37 (3H, s,
CH.sub.3 Aib), 2.59 (4H, m, C--CH.sub.2--CH.sub.2-phenyl), 2.83
(2H, t, J=8 Hz, N--CH.sub.2--CH.sub.2-phenyl), 3.38 (2H, m,
N--CH.sub.2--CH.sub.2-phenyl), 3.84 (1H, m, CH.sub.2 .beta.Trp),
3.94 (1H, m, CH.sub.2 .beta.Trp), 5.23 (1H, m, CH .alpha.Trp), 6.84
(2H, m, H.sub.4 phenyl from C--CH.sub.2--CH.sub.2-phenyl and
H.sub.4 phenyl from N--CH.sub.2--CH.sub.2-phenyl), 6.93 (1H, t,
J.sub.o=8 Hz, H.sub.5 Trp), 7.00 (1H, t, J.sub.o=8 Hz, H.sub.6
Trp), 7.07 (1H, d, J=2 Hz, H.sub.2 Trp), 7.11-7.27 (9H, m, H.sub.2,
H.sub.3, H.sub.5 and H.sub.6 phenyl from
C--CH.sub.2--CH.sub.2-phenyl, H.sub.2, H.sub.3, H.sub.5 and H.sub.6
phenyl from N--CH.sub.2--CH.sub.2-phenyl and H.sub.4 Trp), 7.50
(1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 8.07 (3H, brs, NH.sub.2 Aib),
9.04 (1H, d, J=8 Hz, NH amide), 10.85 (1H, s, NH indole Trp).
[0696] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0697] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 25.9
(C--CH.sub.2--CH.sub.2-phenyl), 29.5 (CH.sub.2 .beta.Trp), 32.4
(C--CH.sub.2--CH.sub.2-phenyl), 35.8
(N--CH.sub.2--CH.sub.2-phenyl), 44.2
(N--CH.sub.2--CH.sub.2-phenyl), 45.9 (CH .alpha.Trp), 56.8 (Cq
Aib), 109.7 (C.sub.3 Trp), 111.9 (C.sub.7 Trp), 118.4 (C.sub.4
Trp), 118.9 (C.sub.5 Trp), 121.4 (C.sub.6 Trp), 124.8 (C.sub.2
Trp), 126.6 (C.sub.4 phenyl from C--CH.sub.2--CH.sub.2-phenyl),
127.2 (C.sub.4 phenyl from N--CH.sub.2--CH.sub.2-phenyl), 127.4
(C.sub.9 Trp), 128.7 (C.sub.2 and C.sub.6 phenyl from
C--CH.sub.2--CH.sub.2-phenyl, C.sub.2 and C.sub.6 phenyl from
N--CH.sub.2--CH.sub.2-phenyl), 128.8 (C.sub.3 and C.sub.5 phenyl
from C--CH.sub.2--CH.sub.2-phenyl, C.sub.3 and C.sub.5 phenyl from
N--CH.sub.2--CH.sub.2-phenyl), 136.5 (C.sub.1 phenyl from
N--CH.sub.2--CH.sub.2-phenyl), 137.5 (C.sub.1 phenyl from
C--CH.sub.2--CH.sub.2-phenyl), 140.8 (C.sub.8 Trp), 154.1 (Cq
triazole), 154.7 (Cq triazole), 171.9 (CO Aib).
(R)--N-(1-(4-(3,4-dichlorobenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 118)
[0698] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0699] .delta.(ppm) 1.24 (3H, s, CH.sub.3 Aib), 1.25 (3H, s,
CH.sub.3 Aib), 3.33 (2H, m, CH.sub.2 .beta.Trp), 4.04 (2H, s,
CH.sub.2-benzyl), 5.05 (1H, m, CH .alpha.Trp), 5.12 (2H, s,
CH.sub.2-m,p-dichlorobenzyl), 6.49 (1H, dd, J.sub.o=8 Hz and
J.sub.m=2 Hz, H.sub.6 m,p-dichlorobenzyl), 6.80 (1H, t, J.sub.o=8
Hz, H.sub.5 Trp), 6.87 (1H, d, J.sub.m=2 Hz, H.sub.2 Trp), 6.98
(1H, t, J.sub.o=7 Hz, H.sub.6 Trp), 7.02-7.10 (3H, m, H.sub.2 and
H.sub.6 benzyl, H.sub.5 m,p-dichlorobenzyl), 7.18 (3H, m, H.sub.3,
H.sub.4 and H.sub.5 benzyl), 7.26 (2H, m, H.sub.4 and H.sub.7 Trp),
8.04 (3H, brs, NH.sub.2 Aib), 8.94 (1H, d, J=9 Hz, NH amide), 10.81
(1H, s, NH indole Trp).
[0700] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0701] .delta.(ppm) 23.4 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 29.0
(CH.sub.2 .beta.Trp), 30.4 (CH.sub.2-benzyl), 45.1
(CH.sub.2-m,p-dichlorobenzyl), 45.6 (CH .alpha.Trp), 56.7 (Cq Aib),
109.6 (C.sub.3 Trp), 111.8 (C.sub.7 Trp), 118.1 (C.sub.4 Trp),
118.6 (C.sub.5 Trp), 121.3 (C.sub.6 Trp), 124.9 (C.sub.2 Trp),
126.4 (C.sub.6 m,p-dichlorobenzyl), 127.0 (C.sub.2
m,p-dichlorobenzyl), 127.2 (C.sub.9 Trp), 128.4 (C.sub.2 and
C.sub.6 benzyl), 130.7 (C.sub.4 and C.sub.5 m,p-dichlorobenzyl),
131.8 (C.sub.3 m,p-dichlorobenzyl), 136.0 (C.sub.1 benzyl), 136.4
(C.sub.8 Trp), 136.7 (C.sub.1 m,p-dichlorobenzyl), 154.1 (Cq
triazole), 155.2 (Cq triazole), 172.0 (CO Aib).
(R)--N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-phenyleth-
yl)-2-amino-2-methylpropanamide (Compound 120)
[0702] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0703] .delta.(ppm) 1.18 (3H, s, CH.sub.3 Aib), 1.26 (3H, s,
CH.sub.3 Aib), 3.09 (1H, dd, J=14 Hz and 6 Hz, CH.sub.2 .beta.Phe),
3.18 (1H, dd, J=14 Hz and 9 Hz, CH.sub.2 .beta.Phe), 3.99 (2H, d,
J=4 Hz, CH.sub.2-phenyl), 4.95 (1H, d, J=16 Hz,
CH.sub.2-p-methoxybenzyl), 5.06 (1H, d, J=16 Hz,
CH.sub.2-p-methoxybenzyl), 5.13 (1H, m, CH .alpha.Phe), 6.78 (4H,
s, CHar p-methoxybenzyl), 7.02-7.08 (4H, m, H.sub.2 and H.sub.6
phenyl, H.sub.2 and H.sub.6 Phe), 7.12-7.25 (6H, m, H.sub.3,
H.sub.4 and H.sub.5 phenyl, H.sub.3, H.sub.4 and H.sub.5 Phe), 7.99
(3H, brs, NH.sub.2 Aib), 8.92 (1H, d, J=8 Hz, NH amide).
[0704] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0705] .delta.(ppm) 23.4 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 30.7
(CH.sub.2-phenyl), 38.7 (CH.sub.2 .beta.Phe), 45.9
(CH.sub.2-p-methoxybenzyl), 46.4 (CH .alpha.Phe), 55.6 (OCH.sub.3),
56.7 (Cq Aib), 114.6 (C.sub.3 and C.sub.5 p-methoxybenzyl), 126.9
and 127.1 (C.sub.4 phenyl and C.sub.4 Phe), 127.7 (C.sub.1
p-methoxybenzyl), 128.2 (C.sub.2 and C.sub.6 Phe), 128.5 (C.sub.3
and C.sub.5 Phe), 128.9 (C.sub.2, C.sub.3, C.sub.5 and C.sub.6
phenyl), 129.7 (C.sub.2 and C.sub.6 p-methoxybenzyl), 136.3
(C.sub.1 phenyl), 137.6 (C.sub.1 Phe), 154.0 (Cq triazole), 154.9
(Cq triazole), 159.2 (C.sub.4 p-methoxybenzyl), 171.7 (CO
amide).
(R)--N-(1-(4-(4-fluorobenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-ind-
ol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 121)
[0706] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0707] .delta.(ppm) 1.27 (3H, s, CH.sub.3 Aib), 1.28 (3H, s,
CH.sub.3 Aib), 2.82 (4H, m, CH.sub.2--CH.sub.2-phenyl), 3.34 (2H,
m, CH.sub.2 .beta.Trp), 5.06 (2H, s, CH.sub.2-p-fluorobenzyl), 5.16
(1H, m, CH .alpha.Trp), 6.85 (3H, m, H.sub.5 Trp, H.sub.3 and
H.sub.5 p-fluorobenzyl), 6.98-7.04 (4H, m, H.sub.2 and H.sub.6 Trp,
H.sub.2 and H.sub.6 phenyl), 7.09-7.11 (2H, m, H.sub.2 and H.sub.6
p-fluorobenzyl), 7.15 (1H, d, J.sub.o=6 Hz, H.sub.4 Trp), 7.19 (3H,
t, J.sub.o=8 Hz, H.sub.3, H.sub.4 and H.sub.5 phenyl), 7.29 (1H, d,
J.sub.o=8 Hz, H.sub.7 Trp), 8.01 (3H, brs, NH.sub.2 Aib), 8.94 (1H,
d, J=8 Hz, NH amide), 10.78 (1H, s, NH indole Trp).
[0708] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0709] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 26.5
(CH.sub.2--CH.sub.2-phenyl), 29.2 (CH.sub.2 .beta.Trp), 32.7
(CH.sub.2--CH.sub.2-phenyl), 45.4 (CH.sub.2-p-fluorobenzyl), 45.7
(CH .alpha.Trp), 56.8 (Cq Aib), 109.8 (C.sub.3 Trp), 111.8 (C.sub.7
Trp), 115.9 and 116.2 (C.sub.3 and C.sub.5 p-fluorobenzyl), 118.3
(C.sub.4 Trp), 118.7 (C.sub.5 Trp), 121.3 (C.sub.6 Trp), 124.8
(C.sub.2 Trp), 126.5 (C.sub.4 phenyl), 127.3 (C.sub.9 Trp), 128.5
(C.sub.2 and C.sub.6 p-fluorobenzyl), 128.7 (C.sub.2, C.sub.3,
C.sub.5 and C.sub.6 phenyl), 132.2 (C.sub.1 p-fluorobenzyl), 136.4
(C.sub.8 Trp), 140.9 (C.sub.1 phenyl), 154.5 (Cq triazole), 154.7
(Cq triazole), 160.3 (C.sub.4 p-fluorobenzyl), 171.9 (CO
amide).
[0710] NMR .sup.19F (282 MHz, DMSO-d.sup.6, 300.degree. K):
[0711] .delta.(ppm)-114.9 (1F, m, p-fluorobenzyl).
(R)--N-(1-(4-(3,4-dichlorobenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 122)
[0712] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0713] .delta.(ppm) 1.25 (3H, s, CH.sub.3 Aib), 1.26 (3H, s,
CH.sub.3 Aib), 2.84 (4H, m, CH.sub.2--CH.sub.2-phenyl), 3.34 (2H,
d, J=7 Hz, CH.sub.2 .beta.Trp), 5.11 (3H, m, CH .alpha.Trp and
CH.sub.2-m,p-dichlorobenzyl), 6.63 (1H, dd, J.sub.o=8 Hz and
J.sub.m=2 Hz, H.sub.6 m,p-dichlorobenzyl), 6.83 (1H, t, J.sub.o=8
Hz, H.sub.5 Trp), 6.99 (1H, t, J.sub.o=8 Hz, H.sub.6 Trp), 7.05
(1H, d, J=2 Hz, H.sub.2 Trp), 7.12 (5H, m, CHar phenyl), 7.17 (1H,
d, J.sub.o=8 Hz, H.sub.4 Trp), 7.21 (1H, s, H.sub.2
m,p-dichlorobenzyl), 7.27 (1H, d, J.sub.o=8 Hz, H.sub.5
m,p-dichlorobenzyl), 7.39 (1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 8.02
(3H, brs, NH.sub.2 Aib), 8.94 (1H, d, J=8 Hz, NH amide), 10.78 (1H,
s, NH indole Trp).
[0714] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0715] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 26.4
(CH.sub.2--CH.sub.2-phenyl), 29.1 (CH.sub.2 .beta.Trp), 32.6
(CH.sub.2--CH.sub.2-phenyl), 44.7 (CH.sub.2-m,p-dichlorobenzyl),
45.6 (CH .alpha.Trp), 56.7 (Cq Aib), 109.7 (C.sub.3 Trp), 111.8
(C.sub.7 Trp), 118.1 (C.sub.4 Trp), 118.7 (C.sub.5 Trp), 121.3
(C.sub.6 Trp), 124.9 (C.sub.2 Trp), 126.5 (C.sub.4 phenyl and
C.sub.6 m,p-dichlorobenzyl), 127.2 (C.sub.9 Trp), 128.7 (C.sub.2,
C.sub.3, C.sub.5 and C.sub.6 phenyl, C.sub.2 m,p-dichlorobenzyl),
130.9 (C.sub.4 m,p-dichlorobenzyl), 131.4 (C.sub.5
m,p-dichlorobenzyl), 132.0 (C.sub.3 m,p-dichlorobenzyl), 136.4
(C.sub.8 Trp), 137.2 (C.sub.1 m,p-dichlorobenzyl), 140.8 (C.sub.1
phenyl), 154.5 (Cq triazole), 154.7 (Cq triazole), 171.9 (CO
amide).
(R)--N-(1-(4-(4-methylbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol--
3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 124)
[0716] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0717] .delta.(ppm) 1.22 (3H, s, CH.sub.3 Aib), 1.27 (3H, s,
CH.sub.3 Aib), 2.22 (3H, s, CH.sub.3 p-methylbenzyl), 3.22 (1H, dd,
J=14 Hz and 6 Hz, CH.sub.2 .beta.Trp), 3.33 (1H, dd, J=14 Hz and 9
Hz, CH.sub.2 .beta.Trp), 3.99 (2H, s, CH.sub.2-benzyl), 5.04 (2H,
s, CH.sub.2-p-methylbenzyl), 5.09 (1H, m, CH .alpha.Trp), 6.64 (2H,
d, J.sub.o=8 Hz, H.sub.3 and H.sub.5 p-methylbenzyl), 6.78 (1H, t,
J.sub.o=7 Hz, H.sub.5 Trp), 6.98 (4H, t, J.sub.o=7 Hz, H.sub.6 Trp,
H.sub.3, H.sub.4 and H.sub.5 benzyl), 7.01 (1H, d, J=2 Hz, H.sub.2
Trp), 7.07 (2H, d, J.sub.o=7 Hz, H.sub.2 and H.sub.6
p-methylbenzyl), 7.20 (3H, m, H.sub.4 Trp, H.sub.2 and H.sub.6
benzyl), 7.26 (1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 7.98 (3H, brs,
NH.sub.2 Aib), 8.89 (1H, d, J=8 Hz, NH amide), 10.74 (1H, s, NH
indole Trp).
[0718] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0719] .delta.(ppm) 21.0 (CH.sub.3 p-methylbenzyl), 23.5 (CH.sub.3
Aib), 23.7 (CH.sub.3 Aib), 29.1 (CH.sub.2 .beta.Trp), 30.6
(CH.sub.2-benzyl), 45.7 (CH .alpha.Trp), 46.0
(CH.sub.2-p-methylbenzyl), 56.7 (Cq Aib), 109.8 (C.sub.3 Trp),
111.7 (C.sub.7 Trp), 118.3 (C.sub.4 Trp), 118.6 (C.sub.5 Trp),
121.2 (C.sub.6 Trp), 124.8 (C.sub.2 Trp), 126.3 (C.sub.3 and
C.sub.5 p-methylbenzyl), 127.0 (C.sub.4 benzyl), 127.2 (C.sub.9
Trp), 128.9 (C.sub.2, C.sub.3, C.sub.5 and C.sub.6 benzyl), 129.7
(C.sub.2 and C.sub.6 p-methylbenzyl), 132.9 (C.sub.1
p-methylbenzyl), 136.3 (C.sub.4 p-methylbenzyl), 136.4 (C.sub.8
Trp), 137.4 (C.sub.1 benzyl), 153.9 (Cq triazole), 155.3 (Cq
triazole), 171.8 (CO amide).
(S)--N-(1-(4-(4-methoxybenzyl)-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)-2-
-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound
125)
[0720] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0721] .delta.(ppm) 1.27 (3H, s, CH.sub.3 Aib), 1.31 (3H, s,
CH.sub.3 Aib), 1.74 (2H, m, (CH.sub.2--CH.sub.2--CH.sub.2-phenyl),
2.52 (4H, t, J=7 Hz, CH.sub.2--CH.sub.2--CH.sub.2-phenyl), 3.35
(2H, d, J=7 Hz, CH.sub.2 .beta.Trp), 3.68 (3H, s, OCH.sub.3), 4.98
(2H, s, CH.sub.2-p-methoxybenzyl), 5.20 (1H, m, CH .alpha.Trp),
6.75 (4H, s, CHar p-methoxybenzyl), 6.83 (1H, t, J.sub.o=8 Hz,
H.sub.5 Trp), 6.99 (1H, t, J.sub.o=7 Hz, H.sub.6 Trp), 7.06 (3H, m,
H.sub.2 and H.sub.6 phenyl, H.sub.2 Trp), 7.14 (1H, d, J.sub.o=7
Hz, H.sub.4 Trp), 7.19 (3H, t, J.sub.o=8 Hz, H.sub.3, H.sub.4 and
H.sub.5 phenyl), 7.29 (1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 8.01 (3H,
brs, NH.sub.2 Aib), 8.94 (1H, d, J=8 Hz, NH amide), 10.79 (1H, d,
J=2 Hz, NH indole Trp).
[0722] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0723] .delta.(ppm) 23.6 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 24.1
(CH.sub.2--CH.sub.2--CH.sub.2-phenyl), 28.5
(CH.sub.2--CH.sub.2--CH.sub.2-phenyl), 29.2 (CH.sub.2 .beta.Trp),
34.7 (CH.sub.2--CH.sub.2--CH.sub.2-phenyl), 45.5
(CH.sub.2-p-methoxybenzyl), 45.8 (CH .alpha.Trp), 55.5 (OCH.sub.3),
56.8 (Cq Aib), 109.8 (C.sub.3 Trp), 111.8 (C.sub.7 Trp), 114.6
(C.sub.3 and C.sub.5 p-methoxybenzyl), 118.3 (C.sub.4 Trp), 118.7
(C.sub.5 Trp), 121.3 (C.sub.6 Trp), 124.9 (C.sub.2 Trp), 126.2
(C.sub.4 phenyl), 127.3 (C.sub.9 Trp), 127.8 (C.sub.1
p-methoxybenzyl), 127.9 (C.sub.3, C.sub.4 and C.sub.5 phenyl),
128.7 (C.sub.2 and C.sub.6 p-methoxybenzyl), 136.4 (C.sub.8 Trp),
141.7 (C.sub.1 phenyl), 154.7 (Cq triazole), 154.8 (Cq triazole),
159.2 (C.sub.1 p-methoxybenzyl), 171.9 (CO amide).
(S)--N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 126)
[0724] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0725] .delta.(ppm) 1.25 (3H, s, CH.sub.3 Aib), 1.28 (3H, s,
CH.sub.3 Aib), 3.26 (1H, dd, J=14 Hz and 6 Hz, CH.sub.2 .beta.Trp),
3.34 (1H, dd, J=14 Hz and 8 Hz, CH.sub.2 .beta.Trp), 3.99 (2H, s,
CH.sub.2-phenyl), 4.98 (2H, s, CH.sub.2-p-methoxybenzyl), 5.13 (1H,
m, CH .alpha.Trp), 6.68 (4H, s, CHar p-methoxybenzyl), 6.80 (1H, t,
J.sub.o=8 Hz, H.sub.5 Trp), 6.99 (1H, t, J.sub.o=8 Hz, H.sub.6
Trp), 7.02-7.06 (4H, m, H.sub.2 and H.sub.4 Trp, H.sub.2 and
H.sub.6 phenyl), 7.20 (3H, m, H.sub.3, H.sub.4 and H.sub.5 phenyl),
7.27 (1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 8.00 (3H, s, NH.sub.2
Aib), 8.91 (1H, d, J=8 Hz, NH amide), 10.76 (1H, s, NH indole
Trp).
[0726] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0727] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.7 (CH.sub.3 Aib), 29.1
(CH.sub.2 .beta.Trp), 30.6 (CH.sub.2-phenyl), 45.7 (CH .alpha.Trp
and CH.sub.2-p-methoxybenzyl), 55.5 (OCH.sub.3), 56.7 (Cq Aib),
109.8 (C.sub.3 Trp), 111.7 (C.sub.7 Trp), 114.5 (C.sub.3 and
C.sub.5 p-methoxybenzyl), 118.3 (C.sub.4 Trp), 118.7 (C.sub.5 Trp),
121.3 (C.sub.6 Trp), 124.8 (C.sub.2 Trp), 127.1 (C.sub.4 phenyl),
127.3 (C.sub.9 Trp), 127.6 (C.sub.1 p-methoxybenzyl), 127.8
(C.sub.2 and C.sub.6 p-methoxybenzyl), 128.8 (C.sub.2 and C.sub.6
phenyl), 128.9 (C.sub.3 and C.sub.5 phenyl), 136.3 (C.sub.8 Trp),
136.4 (C.sub.1 phenyl), 153.8 (Cq triazole), 155.2 (Cq triazole),
159.2 (C.sub.4 p-methoxybenzyl), 171.9 (CO amide).
N--((R)-1-(4-(4-nitrobenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indo-
l-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 128)
[0728] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0729] .delta.(ppm) 1.28 (3H, s, CH.sub.3 Aib), 1.29 (3H, s,
CH.sub.3 Aib), 2.77-2.94 (4H, m, CH.sub.2--CH.sub.2-phenyl), 3.28
(1H, dd, .sup.3J=14 Hz and 8 Hz, CH.sub.2 .beta.Trp), 3.43 (1H, dd,
.sup.3J=14 Hz and 7 Hz, CH.sub.2 .beta.Trp), 5.05 (1H, m, CH
.alpha.Trp), 5.25 (2H, d, J=7 Hz, CH.sub.2-p-nitrobenzyl), 6.72
(1H, t, J.sub.o=7 Hz, H.sub.5 Trp), 6.89 (2H, d, J.sub.o=9 Hz,
H.sub.2 and H.sub.6 p-nitrobenzyl), 6.92 (1H, t, J.sub.o=7 Hz,
H.sub.6 Trp), 7.00 (1H, d, J.sub.m=2 Hz, H.sub.2 Trp), 7.08-7.15
(4H, m, H.sub.4 and H.sub.7 Trp, H.sub.2 and H.sub.6 phenyl), 7.17
(2H, J.sub.o=7 hz, H.sub.3 and H.sub.5 phenyl), 7.24 (1H, t,
J.sub.o=8 Hz, H.sub.4 phenyl), 7.92 (2H, d, J.sub.o=9 Hz, H.sub.3
and H.sub.5 p-nitrobenzyl), 8.06 (3H, brs, NH.sub.2 Aib), 8.98 (1H,
d, J=8 Hz, NH amide), 10.79 (1H, s, NH indole Trp).
[0730] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0731] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 26.4
(CH.sub.2--CH.sub.2-phenyl), 29.1 (CH.sub.2 .beta.Trp), 32.6
(CH.sub.2--CH.sub.2-phenyl), 45.3 (CH.sub.2-p-nitrobenzyl), 45.7
(CH .alpha.Trp), 56.8 (Cq Aib), 109.6 (C.sub.3 Trp), 111.8 (C.sub.7
Trp), 118.1 (C.sub.4 Trp), 118.5 (C.sub.5 Trp), 121.2 (C.sub.6
Trp), 124.1 (C.sub.2 and C.sub.5 p-nitrobenzyl), 124.8 (C.sub.2
Trp), 126.5 (C.sub.2 and C.sub.5 phenyl), 127.2 (C.sub.9 Trp,
C.sub.1 and C.sub.6 p-nitrobenzyl), 128.7 (C.sub.3, C.sub.4 and
C.sub.5 phenyl), 136.4 (C.sub.8 Trp), 140.8 (C.sub.1 phenyl), 143.5
(C.sub.1 p-nitrobenzyl), 154.5 (Cq triazole), 154.8 (Cq triazole),
172.0 (CO Aib).
(S)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 129)
[0732] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0733] .delta.(ppm) 1.27 (3H, s, CH.sub.3 Aib), 1.30 (3H, s,
CH.sub.3 Aib), 2.81 (4H, m, CH.sub.2--CH.sub.2-phenyl), 3.34 (2H,
d, J=7 Hz, CH.sub.2 .beta.Trp), 3.68 (3H, s, OCH.sub.3), 4.99 (2H,
s, CH.sub.2-p-methoxybenzyl), 5.20 (1H, m, CH .alpha.Trp), 6.75
(4H, m, CHar p-methoxybenzyl), 6.83 (1H, t, J.sub.o=7 Hz, H.sub.5
Trp), 7.03 (1H, t, J.sub.o=8 Hz, H.sub.6 Trp), 7.04 (1H, d, J=2 Hz,
H.sub.2 Trp), 7.10 (2H, d, J.sub.o=7 Hz, H.sub.2 and H.sub.6
phenyl), 7.13 (1H, d, J.sub.o=8 Hz, H.sub.4 Trp), 7.19 (3H, t,
J.sub.o=7 Hz, H.sub.3, H.sub.4 and H.sub.5 phenyl), 7.29 (1H, d,
J.sub.o=8 Hz, H.sub.7 Trp), 8.01 (3H, brs, NH.sub.2 Aib), 8.94 (1H,
d, J=8 Hz, NH amide), 10.78 (1H, d, J=2 Hz, NH indole Trp).
[0734] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0735] .delta.(ppm) 23.6 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 26.6
(CH.sub.2--CH.sub.2-phenyl), 29.2 (CH.sub.2 .beta.Trp), 32.7
(CH.sub.2--CH.sub.2-phenyl), 45.3 (CH.sub.2-p-methoxybenzyl), 45.7
(CH .alpha.Trp), 55.5 (OCH.sub.3), 56.8 (Cq Aib), 109.9 (C.sub.3
Trp), 111.8 (C.sub.7 Trp), 114.6 (C.sub.3 and C.sub.5
p-methoxybenzyl), 118.3 (C.sub.4 Trp), 118.7 (C.sub.5 Trp), 121.3
(C.sub.6 Trp), 124.8 (C.sub.2 Trp), 126.5 (C.sub.4 phenyl), 127.3
(C.sub.9 Trp and C.sub.1 p-methoxybenzyl), 127.9 (C.sub.2 and
C.sub.6 p-methoxybenzyl), 128.7 (C.sub.2, C.sub.3, C.sub.5 and
C.sub.6 p-methoxybenzyl), 136.5 (C.sub.8 Trp), 140.9 (C.sub.1
phenyl), 154.4 (Cq triazole), 154.7 (Cq triazole), 159.2 (C.sub.4
p-methoxybenzyl), 171.9 (CO amide).
(R)--N-(1-(4-(4-methoxyphenethyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-
-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 130)
[0736] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0737] .delta.(ppm) 1.30 (3H, s, CH.sub.3 Aib), 1.35 (3H, s,
CH.sub.3 Aib), 2.55 (4H, m, CH.sub.2--CH.sub.2-phenyl and
CH.sub.2--CH.sub.2-p-methoxybenzyl), 2.83 (2H, t, J=8 Hz,
CH.sub.2--CH.sub.2-phenyl), 3.37 (2H, m,
CH.sub.2--CH.sub.2-p-methoxybenzyl), 3.65 (3H, s, OCH.sub.3), 3.77
(1H, m, CH.sub.2 .beta.Trp), 3.89 (1H, m, CH.sub.2 .beta.Trp), 5.20
(1H, m, CH .alpha.Trp), 6.72 (4H, s, CHar p-methoxybenzyl), 6.94
(1H, t, J.sub.o=7 Hz, H.sub.5 Trp), 7.02 (1H, t, J.sub.o=8 Hz,
H.sub.6 Trp), 7.05 (1H, d, J=2 Hz, H.sub.2 Trp), 7.11 (2H, d,
J.sub.o=7 Hz, H.sub.2 and H.sub.6 phenyl), 7.16 (1H, d, J.sub.o=7
Hz, H.sub.4 Trp), 7.25 (3H m, H.sub.3, H.sub.4, H.sub.5 phenyl),
7.50 (1H, d, J.sub.o=8 Hz, H.sub.7 Trp), 8.05 (3H, brs, NH.sub.2
Aib), 9.02 (1H, d, J=8 hz, NH amide), 10.83 (1H, d, J=2 Hz, NH
indole Trp).
[0738] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0739] .delta.(ppm) 23.5 (CH.sub.3 Aib), 23.8 (CH.sub.3 Aib), 26.0
(CH.sub.2--CH.sub.2-phenyl), 29.5 (CH.sub.2 .beta.Trp), 32.5
(CH.sub.2--CH.sub.2-phenyl), 35.0
(CH.sub.2--CH.sub.2-p-methoxybenzyl), 44.4
(CH.sub.2--CH.sub.2-p-methoxybenzyl), 45.8 (CH .alpha.Trp), 55.4
(OCH.sub.3), 56.8 (Cq Aib), 109.9 (C.sub.3 Trp), 111.9 (C.sub.7
Trp), 114.2 (C.sub.3 and C.sub.5 p-methoxybenzyl), 118.4 (C.sub.4
Trp), 118.9 (C.sub.5 Trp), 121.4 (C.sub.6 Trp), 124.7 (C.sub.2
Trp), 126.5 (C.sub.4 phenyl), 127.4 (C.sub.9 Trp), 128.7 (C.sub.2,
C.sub.3, C.sub.5 and C.sub.6 phenyl), 129.4 (C.sub.1
p-methoxybenzyl), 130.3 (C.sub.2 and C.sub.6 p-methoxybenzyl),
136.5 (C.sub.8 Trp), 141.0 (C.sub.1 phenyl), 154.0 (Cq triazole),
154.5 (Cq triazole), 158.6 (C.sub.4 p-methoxybenzyl), 171.8 (CO
amide).
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4-(pyridin-2-ylmethyl)-4H-1,2,4-t-
riazol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 132)
[0740] .sup.1H NMR (300 MHz, DMSO-d.sup.6, 300.degree. K):
[0741] .delta.(ppm) 1.26 (3H, s, CH.sub.3 Aib), 1.29 (3H, s,
CH.sub.3 Aib), 2.95 (4H, m, CH.sub.2--CH.sub.2-phenyl), 3.40 (2H,
m, CH.sub.2 .beta.Trp), 5.26 (1H, m, CH .alpha.Trp), 5.37 (2H, s,
CH.sub.2-o-pyridyl), 6.83 (1H, t, J.sub.o=7 Hz, H.sub.5 Trp), 6.98
(1H, t, J.sub.o=8 Hz, H.sub.6 Trp), 7.11-7.30 (10H, m, H.sub.2,
H.sub.4 and H.sub.7 Trp, CHar phenyl, H.sub.3 and H.sub.5
o-pyridyl), 7.71 (1H, t, J.sub.o=7 Hz, H.sub.4 o-pyridyl), 8.22
(3H, brs, NH.sub.2 Aib), 8.42 (1H, d, J.sub..alpha..beta.=4 Hz,
H.sub.6 o-pyridyl), 9.05 (1H, d, J=8 Hz, NH amide), 10.87 (1H, s,
NH indole Trp).
[0742] .sup.13C NMR (75 MHz, DMSO-d.sup.6, 300.degree. K):
[0743] .delta.(ppm) 23.4 (CH.sub.3 Aib), 23.7 (CH.sub.3 Aib), 26.4
(CH.sub.2--CH.sub.2-phenyl), 28.6 (CH.sub.2 .beta.Trp), 32.5
(CH.sub.2--CH.sub.2-phenyl), 45.7 (CH .alpha.Trp), 47.6 (CH.sub.2
o-pyridyl), 56.8 (Cq Aib), 109.8 (C.sub.3 Trp), 111.8 (C.sub.7
Trp), 118.3 (C.sub.4 Trp), 118.6 (C.sub.5 Trp), 121.2 (C.sub.6
Trp), 122.0 (C.sub.3 o-pyridyl), 123.6 (C.sub.5 o-pyridyl), 126.3
(C.sub.2 Trp), 126.6 (C.sub.4 phenyl), 127.3 (C.sub.9 Trp), 128.7
(C.sub.2, C.sub.3, C.sub.5 and C.sub.6 phenyl), 136.4 (C.sub.8
trypophane), 137.7 (C.sub.4 o-pyridyl), 140.7 (C.sub.1 phenyl),
150.1 (C.sub.6 o-pyridyl), 154.9 (Cq triazole), 155.2 (Cq
triazole), 158.7 (C.sub.2 o-pyridyl), 172.0 (CO amide).
N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1-
H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 179)
[0744] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0745] .delta.(ppm) 1.26 (s, 3H, CH.sub.3 Aib), 1.30 (s, 3H,
CH.sub.3 Aib), 2.82 (m, 4H, CH.sub.2--CH.sub.9-phenyl), 3.29 (t,
2H, J=8 Hz, CH.sub.2 .beta.Trp), 3.61 (s, 3H, OCH.sub.3), 3.68 (s,
3H, OCH.sub.3), 4.85 (d, 1H, J=17 Hz,
CH.sub.2-o,p-dimethoxybenzyl), 5.02 (d, 1H, J=17 Hz,
CH.sub.2-o,p-dimethoxybenzyl), 5.18 (m, 1H, CH .alpha.Trp), 6.29
(dd, 1H, J.sub.o=8 Hz and J.sub.m=2 Hz, H.sub.5
o,p-dimethoxybenzyl), 6.40 (d, 1H, J.sub.o=8 Hz, H.sub.6
o,p-dimethoxybenzyl), 6.55 (d, 1H, J.sub.m=2 Hz, H.sub.3
o,p-dimethoxybenzyl), 6.82 (t, 1H, J.sub.o=8 Hz, H.sub.5 Trp), 6.99
(t, 1H, J.sub.o=8 Hz, H.sub.6 Trp), 7.05 (s, 1H, H.sub.2 Trp),
7.09-7.24 (m, 6H, H.sub.4 Trp and CHar phenyl), 7.27 (d, 1H,
J.sub.o=8 Hz, H.sub.7 Trp), 7.99 (s, 3H, large, NH.sub.2 Aib TFA
salt), 8.89 (d, 1H, J=8 Hz, NH amide), 10.77 (s, 1H, NH indole
Trp).
[0746] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0747] .delta.(ppm) 23.6 (CH.sub.3 Aib), 23.7 (CH.sub.3 Aib), 26.5
(CH.sub.2--CH.sub.2-phenyl), 29.2 (CH.sub.2 .beta.Trp), 32.7
(CH.sub.2--CH.sub.2-phenyl), 41.6 (CH.sub.2-o,p-dimethoxybenzyl),
45.7 (CH .alpha.Trp), 55.7 (OCH.sub.3), 55.9 (OCH.sub.3), 56.7 (Cq
Aib), 99.1 (C.sub.3 o,p-dimethoxybenzyl), 105.2 (C.sub.5
o,p-dimethoxybenzyl), 110.0 (C.sub.3 Trp), 111.8 (C.sub.7 Trp),
115.7 (C.sub.1 o,p-dimethoxybenzyl), 118.3 (C.sub.4 Trp), 118.7
(C.sub.5 Trp), 121.3 (C.sub.6 Trp), 126.5 (C.sub.2 Trp and C.sub.6
o,p-dimethoxybenzyl), 127.3 (C.sub.9 Trp), 128.1 (C.sub.4 phenyl),
128.7 (C.sub.2, C.sub.3, C.sub.5 and C.sub.6 phenyl), 136.4
(C.sub.6 Trp), 140.9 (C.sub.1 phenyl), 154.5 (Cq triazole), 155.0
(Cq triazole), 157.8 (C.sub.2 o,p-dimethoxybenzyl), 160.9 (C.sub.4
o,p-dimethoxybenzyl), 171.7 (CO amide).
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-in-
dol-3-yl)ethyl)-tetrahydro-2H-pyran-4-carboxamide (Compound
184)
[0748] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0749] .delta.(ppm) 1.20 (m, 1H, H.sub.5 tetrahydropyrane), 1.30
(m, 3H, H.sub.3 and H.sub.5 tetrahydropyrane), 2.17 (m, 1H, H.sub.4
tetrahydropyrane), 2.82 (m, 4H, CH.sub.2--CH.sub.2-phenyl), 3.16
(m, 2H, H.sub.2 and H.sub.6 tetrahydropyrane), 3.31 (dd, 1H, J=14
Hz and 8 Hz, CH.sub.2 .beta.Trp), 3.35 (dd, 1H, J=14 Hz and 7 Hz,
CH.sub.2 .beta.Trp), 3.66 (s, 3H, OCH.sub.3), 3.72 (m, 2H, H.sub.2
and H.sub.6 tetrahydropyrane), 5.08 (m, 2H,
CH.sub.2-p-methoxybenzyl), 5.26 (m, 1H, CH .alpha.Trp), 6.73 (s,
4H, CHar p-methoxybenzyl), 6.87 (t, 1H, J.sub.o=8 Hz, H.sub.5 Trp),
7.02 (m, 2H, H.sub.2 and H.sub.6 Trp), 7.07 (d, 2H, J.sub.o=7 Hz,
H.sub.2 and H.sub.6 phenyl), 7.18 (m, 3H, H.sub.3, H.sub.4 and
H.sub.5 phenyl), 7.30 (m, 2H, H.sub.4 and H.sub.7 Trp), 8.52 (d,
1H, J=8 Hz, NH amide), 10.77 (s, 1H, NH indole Trp).
[0750] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0751] .delta.(ppm) 26.3 (CH.sub.2--CH.sub.2-phenyl), 28.8 (C.sub.3
and C.sub.5 tetrahydropyrane), 29.2 (CH.sub.2 .beta.Trp), 32.2
(CH.sub.2--CH.sub.2-phenyl), 40.7 (C.sub.4 tetrahydropyrane), 44.8
(CH .alpha.Trp), 45.9 (CH.sub.2-p-methoxybenzyl), 55.5 (OCH.sub.3),
66.6 (C.sub.2 and C.sub.6 tetrahydropyrane), 109.8 (C.sub.3 Trp),
111.7 (C.sub.7 Trp), 114.5 (C.sub.3 and C.sub.5 p-methoxybenzyl),
118.4 (C.sub.4 Trp), 118.7 (C.sub.5 Trp), 121.3 (C.sub.6 Trp),
124.5 (C.sub.2 Trp), 126.7 (C.sub.4 phenyl), 127.2 (C.sub.9 Trp),
127.5 (C.sub.1 p-methoxybenzyl), 128.8 (C.sub.2 and C.sub.6
phenyl), 128.7 (C.sub.3 and C.sub.5 phenyl), 127.9 (C.sub.2 and
C.sub.6 p-methoxybenzyl), 136.4 (C.sub.8 Trp), 140.4 (C.sub.1
phenyl), 154.7 (Cq triazole), 155.7 (Cq triazole), 159.2 (C.sub.4
p-methoxybenzyl), 174.2 (CO amide).
N--((R)-1-(5-((1H-indol-3-yl)methyl)-4-(3-methoxybenzyl)-4H-1,2,4-triazol--
3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound
185)
[0752] .sup.1H NMR (300 MHz, DMSO d.sup.6, 300.degree. K):
[0753] .delta.(ppm) 1.19 (s, 3H, CH.sub.3 Aib), 1.23 (s, 3H,
CH.sub.3 Aib), 3.14 (dd, 1H, J=14 Hz and 5 Hz, CH.sub.2 .beta.Trp),
3.34 (dd, 1H, J=14 Hz and 9 Hz, CH.sub.2 .beta.Trp), 3.46 (s, 3H,
OCH.sub.3), 3.72 (m, 2H, CH.sub.2-indole), 5.06 (m, 1H, CH
.alpha.Trp), 5.14 (m, 2H, CH.sub.2-m-methoxybenzyl), 6.31 (s, 1H,
H.sub.2 m-methoxybenzyl), 6.32 (d, 1H, J.sub.o=7 Hz, H.sub.6
m-methoxybenzyl), 6.77 (m, 3H, H.sub.5 indole, H.sub.5 Trp and
H.sub.4 m-methoxybenzyl), 6.92 (m, 2H, H.sub.6 indole and H.sub.6
Trp), 7.02 (m, 2H, H.sub.2 indole and H.sub.2 Trp), 7.26-7.30 (m,
3H, H.sub.5 m-methoxybenzyl, H.sub.4 and H.sub.7 indole, H.sub.4
Trp), 7.41 (d, 1H, J.sub.o=8 Hz, H.sub.7 Trp), 7.94 (brs, 3H,
NH.sub.2 Aib TFA salt), 8.87 (d, 1H, J=8 Hz, NH amide), 10.73 (d,
1H, J=2 Hz, NH indole), 10.85 (s, 1H, NH indole Trp).
[0754] .sup.13C NMR (75 MHz, DMSO d.sup.6, 300.degree. K):
[0755] .delta.(ppm) 21.7 (CH.sub.2-indole), 23.5 (CH.sub.3 Aib),
23.7 (CH.sub.3 Aib), 28.9 (CH.sub.2 .beta.Trp), 45.5 (CH
.alpha.Trp), 46.2 (CH.sub.2-m-methoxybenzyl), 55.2 (OCH.sub.3),
56.7 (Cq Aib), 108.2 (C.sub.3 indole), 109.8 (C.sub.3 Trp), 111.7
(C.sub.7 Trp), 111.9 (C.sub.7 indole and C.sub.2 m-methoxybenzyl),
113.7 (C.sub.4 m-methoxybenzyl), 118.2 (C.sub.6 m-methoxybenzyl),
118.4 (C.sub.4 Trp), 118.6 (C.sub.4 indole), 118.9 (C.sub.5 indole
and C.sub.5 Trp), 121.2 (C.sub.6 indole), 121.6 (C.sub.6 Trp),
127.1 (C.sub.9 indole), 127.2 (C.sub.9 Trp), 136.4 (C.sub.8 Trp),
136.7 (C.sub.8 indole), 137.5 (C.sub.1 m-methoxybenzyl), 154.2 (Cq
triazole), 155.3 (Cq triazole), 160.0 (C.sub.3 m-methoxybenzyl),
171.8 (CO amide). TABLE-US-00001 TABLE 1 Further exemplary
embodiments with synthetic sequence and MS data (compounds no. 2,
3, 14, 16, 17, 19-22, 24, 26-35, 36-122, 124-126, 128-150,
152-190): Chemical name ESI-MS ESI-MS No. (Chem Draw Ultra 8)
(calculated) [found (M + H)+] 2
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4- 559.3 560.4
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)-2-amino-2-methylpropanamide 3
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4- 573.3 574.3
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)-2-amino-2-methylpropanamide 14
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4- 637.2 638.1
bromobenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-amino-2- methylpropanamide 16
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-hexyl- 553.3 554.4
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 17
(R)--N-(1-(4,5-bis(2-(1H-indol-3-yl)ethyl)-4H- 598.3 599.2
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
amino-2-methylpropanamide 19
(R)--N-(1-(4-(3-methoxybenzyl)-5-phenethyl- 536.3 537.1
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 20
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl- 536.3 537.3
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 21
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3,5- 605.3 606.4
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide 22
(R)--N-(1-(4-(4-methoxybenzyl)-5-(3- 550.3 551.3
phenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-amino-2- methylpropanamide 24
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-5-(3-(1H- 612.3 612.8
indol-3-yl)propyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide 26
(R)--N-(1-(4-(2-methoxybenzyl)-5-phenethyl- 536.3 537.1
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 27
(R)--N-(2-(1H-indol-3-yl)-1-(4-(naphthalen-1- 556.3 557.2
ylmethyl)-5-phenethyl-4H-1,2,4-triazol-3-
yl)ethyl)-2-amino-2-methylpropanamide 28
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3,4- 613.2 614.2
dichlorobenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-amino-2- methylpropanamide 29
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 563.3 564.1
fluorobenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-amino-2- methylpropanamide 30
(R)--N-(1-(4-(4-fluorobenzyl)-5-benzyl-4H- 510.3 511.0
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
amino-2-methylpropanamide 31
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4- 631.3 632.0
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)piperidine-4- carboxamide 32
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4- 631.3 631.8
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)piperidine-3- carboxamide 33
(R)--N-(1-(4-(4-methylbenzyl)-5-(3- 534.3 535.4
phenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-amino-2- methylpropanamide 34
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 559.7 559.9
methylbenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-amino-2- methylpropanamide 36
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4- 631.3 631.8
dimethoxybenzyl)- 4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)piperidine-2- carboxamide 37
(R)--N-(1-(4-(4-methylbenzyl)-5-phenethyl- 520.3 521.0
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 38
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4- 639.3 639.8
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)-2-aminobenzamide 39
(R)--N-(1-(5-benzyl-4-(pyridin-2-ylmethyl)- 493.3 493.9
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 40
(2S,4R)--N--((R)-1-(4-(4-methoxybenzyl)-5- 564.3 565.0
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)-4-hydroxypyrrolidine-2- carboxamide 41
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5- 562.3 563.0
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)piperidine-3-carboxamide 42
(R)--N--((R)-1-(4-(4-methoxybenzyl)-5- 562.3 562.9
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)piperidine-3-carboxamide 43
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H- 534.3 535.0
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
amino-2-methylpropanamide 44
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl- 562.3 563.0
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperidine-4-carboxamide 45
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 601.3 602.0
methoxybenzyl)- 4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)piperidine-4-carboxamide 46
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5- 548.3 548.9
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)pyrrolidine-2-carboxamide 47
(R)--N--((R)-1-(4-(4-methoxybenzyl)-5- 548.3 548.9
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)pyrrolidine-2-carboxamide 48
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5- 562.3 563.0
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)piperidine-2-carboxamide 49
(R)--N--((R)-1-(4-(4-methoxybenzyl)-5- 562.3 562.9
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)piperidine-2-carboxamide 50
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl- 508.3 508.9
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)- 2-aminoacetamide 51
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl- 570.3 571.2
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-(pyridin-2-yl)acetamide 52
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl- 570.3 570.9
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-(pyridin-4-yl)acetamide 53
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl- 561.3 562.4
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)cyclohexanecarboxamide 54
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl- 571.3 572.5
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperidine-4-carboxamide 55
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl- 571.3 572.4
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperidine-3-carboxamide 56
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl- 522.3 523.3
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)- 3-aminopropanamide
57 (S)--N--((R)-1-(4-(4-methoxybenzyl)-5- 522.3 523.3
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)-2-aminopropanamide 58
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl- 570.3 571.2
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-(pyridin-3-yl)acetamide 59
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl- 584.3 585.3
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
3-(pyridin-3-yl)propanamide 60
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl- 579.3 580.2
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-(pyridin-2-yl)acetamide 61
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4- 639.3 640.5
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)-2-(pyridin-2- yl)acetamide 62
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5- 592.3 593.3
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)piperidine-4-carboxamide 63
(R)--N-((R)-1-(4-(2,4-dimethoxybenzyl)-5- 592.3 593.3
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)piperidine-2-carboxamide 64
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5- 586.3 587.2
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)picolinamide 65 (R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-
586.3 587.2 phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)isonicotinamide 66 (R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-
587.3 588.2 phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)pyrazine-2-carboxamide 67
(R)--N-1-(4-(2,4-dimethoxybenzyl)-5- 593.3 594.2
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)piperazine-2-carboxamide 68
(S)--N--((R)-1-(4-(2,4-dimethoxybenzyl)-5- 578.3 579.4
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)pyrrolidine-2-carboxamide 69
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4- 577.3 578.0
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)-2-aminoacetamide 70
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4- 617.3 618.0
(2,4-dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-
2-(1H-indol-3-yl)ethyl)pyrrolidine-2- carboxamide 71
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4- 626.3 627.2
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)pyrazine-2-carboxamide 72
(R)--N-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4- 632.3 633.2
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)piperazine-2- carboxamide 73
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4- 625.3 626.3
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)picolinamide 74
(R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4- 520.3 520.8
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethanamine 75 (R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-
538.3 539.3 phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)-2-aminoacetamide 76
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl- 557.3 558.0
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)pyrazine-2-carboxamide 77
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl- 556.3 556.9
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3- yl)ethyl)isonicotinamide 78
(R)--N-1-(4-(4-methoxybenzyl)-5-phenethyl- 563.3 564.0
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperazine-2-carboxamide 79
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl- 556.3 557.3
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3- yl)ethyl)picolinamide 80
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 595.3 596.2
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)picolinamide 81
(R)--N-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 602.3 603.3
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)piperazine-2-carboxamide 82
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H- 568.3 569.3
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
(pyridin-2-yl)acetamide 83
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H- 560.3 561.3
1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperidine-4-carboxamide 84
(R)--N-1-(4-(4-ethylbenzyl)-5-phenethyl-4H- 561.3 562.2
1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperazine-2-carboxamide 85
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H- 555.3 556.2
1,2,4-triazol-3-yl)-2-(1H-indol-3- yl)ethyl)pyrazine-2-carboxamide
86 (R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4- 645.3 646.2
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)-2-cis- aminocyclohexanecarboxamide 87
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 601.3 601.9
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)piperidine-3-carboxamide 88
(R)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 601.3 602.2
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)piperidine-2-carboxamide 89
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 587.3 588.2
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)pyrrolidine-2-carboxamide 90
(R)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 587.3 588.0
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)pyrrolidine-2-carboxamide 91
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 609.3 610.0
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide 92
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 623.2 624.1
bromobenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-amino-2- methylpropanamide 93
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 536.3 536.9
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
phenylethyl)-2-amino-2-methylpropanamide 94
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4- 538.3 538.8
(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-
yl)ethyl)piperidine-4-carboxamide 95
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-4H-1,2,4- 455.2 456.2
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino- 2-methylpropanamide
96 (R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-methyl- 455.2 456.4
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 97
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-methyl- 469.3 470.2
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 98
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4H-1,2,4- 441.3 442.1
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino- 2-methylpropanamide
99 (R)--N-(1-(5-((1H-ndol-3-yl)methyl)-4-(2,4- 591.3 592.1
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide 100
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-methyl- 476.3 477.4
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 101
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4-(4- 561.3 562.3
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-amino-2- methylpropanamide 102
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-benzyl- 552.3 553.2
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 103
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(2,4- 619.3 620.2
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide 104
(R)--N-(1-(5-((1H-indol-3-yl)methyl)-4- 545.3 546.4
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)-2-amino-2-methylpropanamide 105
(R)--N-(1-(5-benzyl-4-phenethyl-4H-1,2,4- 506.3 507.4
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino- 2-methylpropanamide
106 (R)--N-(1-(5-benzyl-4-(2,2-diphenylethyl)-4H- 582.3 583.3
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
amino-2-methylpropanamide 107
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,2- 635.3 636.4
diphenylethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-amino-2- methylpropanamide 108
(R)--N-(1-(4-(3,5-dimethoxybenzyl)-5-benzyl- 552.3 553.3
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 109
(R)--N-(1-(4,5-dibenzyl-4H-1,2,4-triazol-3-yl)- 492.3 493.3
2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide 110
(R)--N-(1-(5-benzyl-4-hexyl-4H-1,2,4-triazol- 486.3 487.4
3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide 111
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-5-benzyl- 545.3 546.2
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 112
(S)--N-(1-(4-(2,4-dimethoxybenzyl)-5-benzyl- 552.3 553.1
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 113
(R)--N-(1-(4-(3,5-dimethoxybenzyl)-5- 566.3 567.3
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)-2-amino-2-methylpropanamide 114
(R)--N-(1-(4-(4-bromobenzyl)-5-benzyl-4H- 570.2 571.0
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
amino-2-methylpropanamide 115
(R)--N-(1-(4-(2-methoxybenzyl)-5-benzyl-4H- 522.3 523.0
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
amino-2-methylpropanamide 116 (S)--N-(1-(4-(2,4-dimethoxybenzyl)-5-
566.3 567.0 phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)-2-amino-2-methylpropanamide 117
(R)--N-(1-(4,5-diphenethyl-4H-1,2,4-triazol-3- 520.3 521.1
yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide 118
(R)--N-(1-(4-(3,4-dichlorobenzyl)-5-benzyl- 560.2 561.3
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 119
(R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4- 451.3 452.1
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethanamine 120
(R)--N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H- 483.3 484.0
1,2,4-triazol-3-yl)-2-phenylethyl)-2-amino-2- methylpropanamide 121
(R)--N-(1-(4-(4-fluorobenzyl)-5-phenethyl-4H- 524.3 524.9
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
amino-2-methylpropanamide 122
(R)--N-(1-(4-(3,4-dichlorobenzyl)-5-phenethyl- 574.2 574.9
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 124
(R)--N-(1-(4-(4-methylbenzyl)-5-benzyl-4H- 506.3 507.3
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
amino-2-methylpropanamide 125 (S)--N-(1-(4-(4-methoxybenzyl)-5-(3-
550.3 551.3 phenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-amino-2- methylpropanamide 126
(S)--N-(1-(4-(4-methoxybenzyl)-5-benzyl- 522.3 523.4
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
amino-2-methylpropanamide 128
(R)--N-(1-(4-(4-nitrobenzyl)-5-phenethyl-4H- 551.3 551.9
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
amino-2-methylpropanamide 129
(S)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl- 536.3 537.0
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 130
(R)--N-(1-(4-(4-methoxyphenethyl)-5- 550.3 551.0
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)-2-amino-2-methylpropanamide 131
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4- 512.2 512.8
(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-
yl)ethyl)-2-amino-2-methylpropanamide 132
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4- 507.3 508.4
(pyridin-2-ylmethyl)-4H-1,2,4-triazol-3-
yl)ethyl)-2-amino-2-methylpropanamide 133
(R)--N-(-2-(1H-indol-3-yl)-1-(5-phenethyl-4- 533.3 534.0
(pyridin-2-ylmethyl)-4H-1,2,4-triazol-3-
yl)ethyl)piperidine-3-carboxamide 134
(S)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl- 546.3 547.3
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)pyrrolidine-2-carboxamide 135
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H- 506.3 507.3
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2- aminoacetamide 136
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 609.3 610.4
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-(pyridin-4-yl)acetamide 137
(2R)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl- 560.3 561.3
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperidine-2-carboxamide 138
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H- 554.3 555.3
1,2,4-triazol-3-yl)-2-(1H-indol-3- yl)ethyl)picolinamide 139
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H- 569.3 570.3
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
aminopyridine-3-carboxamide 140
(2S)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl- 520.3 521.2
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)- 2-aminopropanamide
141 N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H- 554.3 555.4
1,2,4-triazol-3-yl)-2-(1H-indol-3- yl)ethyl)isonicotinamide 142
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4- 518.3 519.3
phenyl-4H-1,2,4-triazol-3-yl)ethyl)piperidine- 4-carboxamide 143
(2S)--N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl- 504.3 505.1
4-phenyl-4H-1,2,4-triazol-3- yl)ethyl)pyrrolidine-2-carboxamide 144
N((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4- 464.3 465.1
phenyl-4H-1,2,4-triazol-3-yl)ethyl)-2- aminoacetamide 145
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4- 526.3 527.2
phenyl-4H-1,2,4-triazol-3-yl)ethyl)-2-(pyridin- 2-yl)acetamide 146
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4- 512.3 513.4
phenyl-4H-1,2,4-triazol-3- yl)ethyl)picolinamide 147
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 579.3 580.1
ethylphenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)picolinamide 148
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 593.3 594.2
ethylphenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide 149
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 531.3 532.2
ethylphenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-aminoacetamide 150
(2S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 571.3 572.4
ethylphenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)pyrrolidine-2-carboxamide 152
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 547.3 548.0
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-aminoacetamide 153
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl- 576.3 577.2
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-trans-aminocyclohexanecarboxamide 154
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H- 568.3 569.3
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
(pyridin-3-yl)acetamide 155
(3S)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl- 560.3 561.5
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperidine-3-carboxamide 156
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H- 568.3 569.1
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2- aminobenzamide 157
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl- 551.3 552.2
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3- yl)ethyl)picolinamide 158
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl- 557.3 558.1
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperidine-4-carboxamide 159
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4- 572.3 573.4
dimethoxyphenyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)ethyl)picolinamide 160
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4- 586.3 587.3
dimethoxyphenyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide 161
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4- 573.3 574.2
dimethoxyphenyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)ethyl)pyrazine-2-carboxamide 162
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4- 524.3 525.3
dimethoxyphenyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)ethyl)-2-aminoacetamide 163
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4- 578.3 579.4
dimethoxyphenyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)ethyl)piperidine-4-carboxamide 164
N--((R)-1-(5-benzyl-4-((pyridin-2-yl)methyl)- 513.3 514.3
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3- yl)ethyl)picolinamide 165
N--((R)-1-(5-benzyl-4-((pyridin-2-yl)methyl)- 465.3 466.4
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)- 2-amino-acetamide
166 N--((R)-1-(5-benzyl-4-((pyridin-2-yl)methyl)- 519.3 520.2
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperidine-4-carboxamide 167
N--((R)-1-(5-benzyl-4-((pyridin-4-yl)methyl)- 493.3 494.3
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 168
N--((R)-1-(5-(4-methoxybenzyl)-4-phenethyl- 536.3 537.3
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 169
N--((R)-1-(5-benzyl-4-((pyridin-4-yl)methyl)- 513.3 514.2
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3- yl)ethyl)picolinamide 170
N--((R)-1-(5-benzyl-4-((pyridin-4-yl)methyl)- 465.3 466.1
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3- yl)ethyl)2-amino-acetamide
171 (R)-benzyl-3-(2-aminoisobutyramido)-3-(5- 594.3 595.2
(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-
4H-1,2,4-triazol-3-yl)-propanoate 172
N--((R)-1-(5-benzyl-4-((pyridin-3-yl)methyl)- 493.3 494.3
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide
173 N--((R)-1-(4-benzyl-5-phenethyl-4H-1,2,4- 506.3 507.3
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino- 2-methylpropanamide
174 N--((R)-2-(1H-indol-3-yl)-1-(4-methyl-5- 450.3 451.3
phenethyl-4H-1,2,4-triazol-3- yl)ethyl)picolinamide 175
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl- 531.3 532.4
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 176
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl- 555.3 556.2
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3- yl)ethyl)benzamide 177
(R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl- 635.3 637.0
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-N-
phenylmethanesulfonylamine 178
(R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl- 635.3 636.3
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-N- tosylethanamine 179
N--((R)-1-(4-(2,4-dimethoxybenzyl)-5- 566.3 567.2
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)-2-amino-2-methylpropanamide 180
N-1-((R)-1-(4-(2,4-dimethoxybenzyl)-5- 524.3 525.2
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)ethane-1,2-diamine 181
N--((R)-1-(4-((furan-2-yl)methyl)-5-phenethyl- 496.3 497.1
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
2-amino-2-methylpropanamide 182
N--((R)-1-(4-((furan-2-yl)methyl)-5-phenethyl- 516.3 517.1
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3- yl)ethyl)picolinamide 183
N--((R)-1-(4-((furan-2-yl)methyl)-5-phenethyl- 522.3 523.2
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperidine-4-carboxamide 184
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl- 563.3 564.2
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-
tetrahydro-2H-pyran-4-carboxamide 185
N--((R)-1-(5-((1H-indol-3-yl)methyl)-4-(3- 561.3 562.2
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2-amino-2- methylpropanamide 186
(2S)--N--((R)-1-(4-(4-methoxybenzyl)-5- 598.3 599.1
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)-2-amino-3-phenylpropanamide 187
(R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4- 674.3 675.0
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)-N-tosylethanamine 188
N--((R)-1-(4-(2,4-dimethoxybenzyl)-5- 626.3 627.3
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-
3-yl)ethyl)-4-azidobenzamide 189
N-benzyl-(R)-1-(4-(2,4-dimethoxybenzyl)-5- 571.3 572.3
phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol- 3-yl)ethanamine 190
(2S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4- 585.3 586.2
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-
indol-3-yl)ethyl)-2,5-dihydro-1H-pyrrole-2- carboxamide
II) GHS-R 1a Receptor-Ligand Binding Assay (Membrane Preparations
from Transfected LLC PK-1 Cells)
[0756] The GHS-R 1a receptor binding/affinity studies were
performed according to Guerlavais et al. (J. Med. Chem. 2003, 46:
1191-1203).
[0757] Isolated plasma membranes from LLC PK-1 cells, a renal
epithelial cell line originally derived from porcine kidneys (ECACC
No. 86121112) (10 .mu.g of protein), that were transiently
transfected with human GHS-R 1a cDNA (Guerlavais et al., J. Med.
Chem. 2003, 46: 1191-1203), were incubated in homogenization buffer
HB [50 mM Tris (pH 7,3), 5 mM MgCl.sub.2, 2,5 mM EDTA, and 30
.mu.g/mL bacitracin (Sigma)] for 60 min at 25.degree. C.
(steady-state conditions) with 60 pM .sup.125I-His.sup.9-ghrelin
(Amersham) in the presence or absence of competing compounds
(compounds of the invention).
[0758] The binding affinity for each compound to be tested for the
human GHS-R 1a was measured by displacement of the radiolabelled
ghrelin with increasing concentrations of the test compound
(10.sup.-11M to 10.sup.-2M) (each experiment being performed in
triplicates).
[0759] Nonspecific binding was defined using an excess (10.sup.-6
M) of ghrelin. The binding reaction was stopped by addition of 4 mL
of ice-cold HB followed by rapid filtration over Whatman GP/C
filters presoaked with 0.5% polyethyleneimine to prevent excessive
binding of radioligand to the filters. Filters were rinsed three
times with 3 mL of ice-cold wash buffer [50 mM Tris (pH 7.3), 10 mM
MgCl.sub.2, 2.5 mM EDTA, and 0.015% (w/v) X-100 Triton], and the
radioactivity bound to membranes was measured in a gamma-counter
(Kontron Analytical Gamma Matic, Automatic gamma counting
system).
[0760] The concentration of test compounds required to inhibit
radiolabelled ghrelin binding by 50% (IC.sub.50) was determined by
fitting competitive binding curves using non-linear regression
(PRISM 3.0, Graph Pad San Diego, USA).
[0761] In the following table 2 results obtained for selected
compounds of the invention are presented in comparison to an
example of the prior art. IC.sub.50 values given are the mean of at
least two independent experiments performed in triplicates.
[0762] FIGS. 1-13 show the measured competition plots of the GHS-R
1a Receptor-ligand binding assay with .sup.125I-His.sup.9-ghrelin
and the selected compounds 9, 31, 39, 45, 50, 62, 64, 71, 73, 74,
79, 81 and 90. TABLE-US-00002 TABLE 2 GHS-R 1a Receptor-ligand
binding assay test results (IC.sub.50 values for a number of
selected exemplary compounds) GHS-R 1a No. IC.sub.50 [nM] Chemical
name 1 160 (R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)-2-amino-2-methylpropanamide 2 81
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide
3 14 (R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-phenethyl-4H-
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-
methylpropanamide 4 220
(R)--N-(1-(5-benzyl-4-(naphthalen-1-ylmethyl)-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide
5 125 (R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(naphthalen-1-
ylmethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
amino-2-methylpropanamide 6 18
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3-methoxybenzyl)-
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-
methylpropanamide 7 120
(R)--N-(1-(4-(3-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-
3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide 8 18
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide
9 46 (R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-benzyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide
10 32 (R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(3-
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)-2-amino-2-methylpropanamide 11 137
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(naphthalen-1-
ylmethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
amino-2-methylpropanamide 12 6
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-
methylpropanamide 13 138
(R)--N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-
3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide 14 150
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-bromobenzyl)-
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-
methylpropanamide 15 120
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-hexyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide
16 240 (R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-hexyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide
17 156 (R)--N-(1-(4,5-bis(2-(1H-indol-3-yl)ethyl)-4H-1,2,4-triazol-
3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide 18 83
(S)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)-2-amino-2-methylpropanamide 19 78
(R)--N-(1-(4-(3-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide
20 14 (R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide
21 203 (R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3,5-
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)-2-amino-2-methylpropanamide 22 12
(R)--N-(1-(4-(4-methoxybenzyl)-5-(3-phenylpropyl)-4H-
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-
methylpropanamide 23 37
(R)--N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)-2-amino-2-methylpropanamide 24 29
(R)--N-(1-(4-(2-(1H-indol-3-yl)ethyl)-5-(3-(1H-indol-3-
yl)propyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-
amino-2-methylpropanamide 25 96
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2-methoxy)benzyl)-
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-
methylpropanamide 26 56
(R)--N-(1-(4-(2-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide
27 126 (R)--N-(2-(1H-indol-3-yl)-1-(4-(naphthalen-1-ylmethyl)-5-
phenethyl-4H-1,2,4-triazol-3-yl)ethyl)-2-amino-2- methylpropanamide
28 79 (R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(3,4-
dichlorobenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)-2-amino-2-methylpropanamide 29 66
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-fluorobenzyl)-4H-
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-
methylpropanamide 30 171
(R)--N-(1-(4-(4-fluorobenzyl)-5-benzyl-4H-1,2,4-triazol-3-
yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide 31 0.5
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperidine-4-carboxamide 32 10.3
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperidine-3-carboxamide 33 30
(R)--N-(1-(4-(4-methylbenzyl)-5-(3-phenylpropyl)-4H-
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-
methylpropanamide 34 28
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methylbenzyl)-
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-
methylpropanamide 36 53
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperidine-2-carboxamide 37 136
(R)--N-(1-(4-(4-methylbenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide
38 112 (R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)-2-aminobenzamide 40 249
(2S,4R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-4-
hydroxypyrrolidine-2-carboxamide 41 16
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-3- carboxamide 42 7
(R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-3- carboxamide 43
44 (R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-
3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide 44 0.6
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4- carboxamide 45
0.3 (R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4-
carboxamide 46 12
(S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2- carboxamide 47
27 (R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2- carboxamide 48
11 (S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-2- carboxamide 49
23 (R)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-2- carboxamide 50
56 (R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide 51 3
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-2- yl)acetamide 53
18 (R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3- yl)ethyl)cyclohexanecarboxamide 54 35
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4- carboxamide 55
11 (R)--N-1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-3- carboxamide 56
59 (R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-3-aminopropanamide 57 140
(S)--N-((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminopropanamide 58 29
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-3- yl)acetamide 59
173 (R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-3-(pyridin-3- yl)propanamide
60 61 (R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-benzyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-2- yl)acetamide 61
34 (R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)-2-(pyridin-2-yl)acetamide 62 0.9
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4- carboxamide 63
210 (R)--N-((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-2-
carboxamide 64 1.1
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide 65 58
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)isonicotinamide 66 8
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrazine-2- carboxamide 67 35
(R)--N-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-piperazine-2- carboxamide 68
44 (S)--N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-
carboxamide 69 38 (R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)-2-aminoacetamide 70 6
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)pyrrolidine-2-carboxamide 71 19
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)pyrazine-2-carboxamide 72 32
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)-piperazine-2-carboxamide 73 1.8
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)picolinamide 75 140
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide 76 14
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrazine-2- carboxamide 77 119
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)isonicotinamide 78 54
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-piperazine-2- carboxamide 79
0.7 (R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide 80 1.9
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide 81 18
(R)--N-(1-(5-((1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-piperazine-2-
carboxamide 82 51
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-
3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-2-yl)acetamide 83 19
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-
3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4-carboxamide 84 247
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-
3-yl)-2-(1H-indol-3-yl)ethyl)-piperazine-2-carboxamide 85 89
(R)--N-(1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-
3-yl)-2-(1H-indol-3-yl)ethyl)pyrazine-2-carboxamide 86 143
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-
dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)-2-cis-aminocyclohexanecarboxamide 87 10
(S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperidine-3-carboxamide 88 29
(R)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)piperidine-2-carboxamide
89 9 (S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)pyrrolidine-2-carboxamide 90 28
(R)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)pyrrolidine-2-carboxamide 91 11
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-2-
yl)acetamide 92 200
(R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-bromobenzyl)-
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-
methylpropanamide 94 255
(R)--N-(2-(1H-indol-3-yl)-1-(5-phenethyl-4-(thiophen-2-
ylmethyl)-4H-1,2,4-triazol-3-yl)ethyl)piperidine-4- carboxamide 108
250 (R)--N-(1-(4-(3,5-dimethoxybenzyl)-5-benzyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide
136 106 (R)--N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-4-
yl)acetamide 138 44
N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-triazol-
3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide 146 105
N--((R)-2-(1H-indol-3-yl)-1-(5-phenethyl-4-phenyl-4H-
1,2,4-triazol-3-yl)ethyl)picolinamide 147 49
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-ethylphenyl)-4H-
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide 148 96
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-ethylphenyl)-4H-
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-(pyridin-2-
yl)acetamide 152 138
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2- aminoacetamide
155 188 (3S)--N--((R)-1-(4-(4-ethylbenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-3- carboxamide 157
160 N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide 158 70
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4- carboxamide 159
33 N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-
phenethyl-4H-1,2,4-triazol-3-yl)ethyl)picolinamide 160 121
N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-
phenethyl-4H-1,2,4-triazol-3-yl)ethyl)-2-(pyridin-2- yl)acetamide
163 63 N--((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimethoxyphenyl)-5-
phenethyl-4H-1,2,4-triazol-3-yl)ethyl)piperidine-4- carboxamide 164
207 N--((R)-1-(5-benzyl-4-((pyridin-2-yl)methyl)-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide 173 114
N--((R)-1-(4-benzyl-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-
(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide 175 140
N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-phenyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide
176 80 N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)benzamide 179 62
N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- methylpropanamide
180 189 N-1-((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)ethane-1,2- diamine 182
81 N--((R)-1-(4-((furan-2-yl)methyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide 184 5.9
N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-tetrahydro-2H-pyran-4-
carboxamide 186 175
(2S)--N--((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-3-
phenylpropanamide 187 66
(R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-N-tosylethanamine 188 87
N--((R)-1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-4-azidobenzamide 190 12
(2S)--N--((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-
yl)ethyl)-2,5-dihydro-1H-pyrrole-2-carboxamide Example 39 ca. 5000
(R)--N-(1-(5-(tert-butylthio)-4-(furan-2-ylmethyl)-4H-1,2,4- from
triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2- WO 00/54729
methylpropanamide A2 Example 8 from ca. 20000
(S)--N-(1-(4-benzyl-5-(tert-butylthio)-1,2,4-triazol-3-yl)-2- WO
00/54729 (benzyloxy)ethyl)-2-amino-2-methylpropanamide A2 Example 3
from ca. 3000
(R)--N-(1-(1-methylpropanoate-tetrazol-5-yl)-2-(1H-indol- WO
00/54729 3-yl)ethyl)-2-amino-2-methylpropanamide A2 Example from
ca. 25000 (S)--N-(1-(1-benzyl-tetrazol-5-yl)-2-(benzyloxy)ethyl)-2-
page 175, amino-2-methylpropanamide WO 00/54729 A2
III) In Vitro Intracellular Calcium Release Assay using Human GHS-R
1a Transfected CHO Cells
[0763] The potential of the compounds of the invention to modulate
GHS receptor activity was assessed by an in vitro intracellular
Calcium release assay employing CHO cells that were transfected
with human GHS-R 1a.
[0764] Release of intracellular calcium or inhibition thereof was
measured using the fluorescent calcium indicator assay (FLIPR) and
Fluo-4 AM.
[0765] CHO cells (CHO-KI Chinese Hamster Ovary cell line, ATCC No.
CCL-61) were transiently transfected with human GHS-R 1a cDNA by
electroporation and plated into 96-well black bottom plates
(Corning 3603) (80,000 cells/well). Transient transfections were
performed using the Easyject Optima Electroporator (Equibio),
according to the manufacturer's instructions.
[0766] Transfected cells were grown in Dulbecco's modified Eagle's
medium without phenol red, supplemented with 10% (v/v)
non-essential amino acids, 2 nM glutamine and
streptomycin-penicillin (250 .mu.g/ml-250 u/ml) (all purchased from
Cambrex) at 37.degree. C., 5% CO.sub.2 in a humidified atmosphere
for 24 hours.
[0767] After incubation, transfected cells were washed with 150
.mu.l Buffer A [Hanks' balanced salt solution (Sigma H-6648), 0.5%
(v/v) BSA (Sigma A-7906), 20 mM CaCl.sub.2, 2.5 mM probenecid (pH
7.4, dissolved in 1M NaOH) (Sigma P-8761)] and were then loaded
with fluorescent calcium indicator Fluo-4 AM (10.sup.-6 M)
(Interchim UP72972) prepared in Buffer A, additionally containing
0.06% pluronic acid (Molecular probes P-6867) (a mild-ionic
detergent which facilitates Fluo-4AM ester loading).(Loading: 100
.mu.l per well of Buffer A containing 120 .mu.l/ml Pluronic Acid
and 1 .mu.M Fluo-4AM was added to the cells).
[0768] After loading with Fluo-4 AM, transfected cells were
incubated for 1 hour in the dark at 37.degree. C.
[0769] Compounds to be tested were dissolved in Buffer A in
triplicates at a concentration of 10.sup.-6 M and distributed into
another 96-well plate (Fisher Labosi A1210500).
[0770] Following incubation, excess Fluo-4AM was removed, 100 .mu.l
of Buffer A was added to each well at room temperature and
immediately removed by aspiration. This was then repeated, before
adding 50 .mu.l Buffer A to each well.
[0771] Transfected cells were further incubated room temperature
for 30 min to allow complete de-esterification of intracellular
Fluo-4AM esters.
[0772] Subsequently, both plates, the black-bottom plate containing
transfected cells and the microtiter plate containing the compounds
to be tested, were then placed into a temperature-regulated
(25.degree. C.) FlexStation machine (benchtop scanning fluorometer
Flex Station II, Molecular Devices, Sunnyvale, Calif., USA) for
fluorescence output measurements.
[0773] Since Fluo-4AM exhibits a large fluorescence intensity
increase upon binding of calcium, fluorescence output can be used
directly as a proportional measure of intracellular calcium
release.
[0774] Basal fluorescence output from the transfected cells was
measured for 15 sec and then 50 .mu.l of the compounds to be tested
were automatically distributed into the wells containing the
transfected cells. The fluorescence output was then recorded for a
further 45 sec.
[0775] Excitation and emission wavelengths were 485 nm and 525 nm,
respectively. Basal fluorescence intensity of Fluo-4AM-loaded
transfected cells without compounds to be tested varied between
800-1200 arbitrary units, whereas maximal fluorescence output of
dye-loaded transfected cells upon incubation with the compounds to
be tested varied between 5000-7000 arbitrary units and was
equivalent to that achieved by stimulation of dye-loaded
transfected cells with 10.sup.-6 M ghrelin.
[0776] For each compound to be tested change in fluorescence output
upon addition of the respective compound was compared with the
basal fluorescence output measured with a negative control, i.e.
addition 50 .mu.l of buffer A to transfected cells only.
[0777] The ability and extent to which each compound to be tested
caused calcium release was determined relative to the basal level
(0%) and the maximum level (100%) achieved with 1 .mu.M
ghrelin.
[0778] For the compounds to be tested that were identified as GHS
receptor agonists, EC.sub.50 and KI values were determined using a
dose-response curve.
[0779] As for the compounds to be tested that were identified as
GHS receptor antagonists, IC.sub.50 and Kb (antagonist dissociation
constant) values were determined using antagonist inhibition curves
in the presence of 10.sup.-7 M ghrelin (submaximal concentration).
IC.sub.50 values were calculated as the molar concentration of GHS
receptor antagonist that reduced the maximal response of ghrelin by
50%. Kb values were estimated using the Cheng-Prusoff Equation
(Lazareno S and Birdsall N J, Trends Pharmacol Sci. 1993,
14(6):237-239).
[0780] FIGS. 14-40 show the calculated dose-response plots of the
in vitro intracellular Calcium release assay with human GHS-R 1a
transfected CHO cells of the selected compounds 1, 9, 12, 20, 22,
31, 39, 41, 42, 45, 46, 47, 48, 49, 50, 51, 55, 62, 64, 67, 71, 73,
74, 79, 81, 90 and ghrelin as well as individual EC.sub.50 and KI
values for agonistic compounds and IC.sub.50 and Kb values for
antagonistic compounds.
IV) Assaying In Vivo GH Concentration in the Plasma of Male Rat
Pups
[0781] GH plasma concentrations of male rat pubs were assayed to
characterize the modulation effect (antagonistic or agonistic) of
the compounds of the invention being GHS receptor analogue
ligands.
[0782] In principle, assaying in vivo GH concentration in rat
plasma was performed according to Torsello et al. (Eur. J.
Pharmacol. 1998, 360: 123-129).
[0783] Male Sprague-Dawley rat pups (Charles River, Calco, Italy)
were separated on postnatal day seven from their mothers and
randomly redistributed to the dams, so that each one nurtured ten
to twelve pups. On postnatal day ten, the pups were again separated
from their mothers.
[0784] The compounds to be tested were dissolved in solvent [DMSO
(0.4% of total volume), distilled water (4% of total volume),
brought to the final volume with physiological saline].
[0785] One hour after separation from their mothers, the pups were
given isovolumetric amounts of the compounds to be tested (160
.mu.g/kg body weight s.c.) at time -10 min and then administered
with hexarelin (80 .mu.g/kg body weight s.c.) or solvent at time 0
min before being killed 15 min later by decapitation. Trunk blood
was collected, immediately centrifuged and plasma samples were
stored at -20.degree. C. until assayed for the determination of GH
concentrations.
[0786] Plasma GH concentrations were measured using a rat growth
hormone enzyme immunoassay kit (SPIbio, France, cat. no. 589601)
according to the manufacturer's instructions. Values are expressed
in terms of NIDDK rat-GH-RP2 standard (potency 2 IU/mg) as ng/mL of
plasma
[0787] The limit of detection calculated as the concentration
producing 15% displacement of initial tracer was 0.5 ng/ml;
intra-assay and inter-assay coefficient of variation are 4% (n=24)
and 14% (n=9).
[0788] In the following table 3 results obtained for selected
compounds of the invention are presented. TABLE-US-00003 TABLE 3
Relative GH concentration in rat plasma after treatment with
selected compounds of the invention (160 .mu.g/kg body weight s.c.)
and/ or hexarelin (80 .mu.g/kg body weight s.c.) and/or solvent
Treatment GH concentration (ng/mL) solvent 4,008 .+-. 0,469
hexarelin 162,839 .+-. 21,095 compound 1 n.d. compound 1 +
hexarelin 80.22 .+-. 18.66 compound 12 4.0 .+-. 0.12 compound 12 +
hexarelin 200.0 .+-. 19.7 compound 20 5.27 .+-. 0.59 compound 20 +
hexarelin 220.51 .+-. 15.52 compound 22 4.88 .+-. 0.33 compound 22
+ hexarelin 239.91 .+-. 19.75 compound 47 5,658 .+-. 1,192 compound
47 + hexarelin 160,857 .+-. 13,52 compound 39 5,509 .+-. 1,950
compound 39 + hexarelin 82,481 .+-. 11,530 compound 31 119,937 .+-.
33,054 compound 31 + hexarelin 103,528 .+-. 14,094 compound 48
6,096 .+-. 2,091 compound 48 + hexarelin 145,946 .+-. 12,159
compound 44 87,520 .+-. 15,066 compound 44 + hexarelin 100,52 .+-.
12,112 solvent 2,237 .+-. 0,073 hexarelin 170,101 .+-. 13,226
compound 9 13,016 .+-. 1,960 compound 9 + hexarelin 183.562 .+-.
16.729 compound 39 5.509 .+-. 1.95 compound 39 + hexarelin 82.481
.+-. 11.53 compound 50 9.852 .+-. 1.040 compound 50 + hexarelin
164.459 .+-. 4.443 compound 64 13.056 .+-. 2.169 compound 64 +
hexarelin 138.394 .+-. 14.580 solvent 10,729 .+-. 2,027 hexarelin
253,820 .+-. 12,268 compound 71 15,326 .+-. 1,355 compound 71 +
hexarelin 173,611 .+-. 18,444 compound 74 10,571 .+-. 0,791
compound 74 + hexarelin 194,564 .+-. 7,658 compound 81 18,634 .+-.
2,933 compound 81 + hexarelin 216,575 .+-. 19,734 compound 90
16,857 .+-. 2,152 compound 90 + hexarelin 218,844 .+-. 19,723
V) Assaying the Feeding Behavior (Food Intake) of Young-Adult Male
Rats
[0789] The impact of compounds of the invention being GHS receptor
analogue ligands on the feeding behaviour, i.e. food intake, of
young-adult male rats was assayed.
[0790] In principle, assaying the feeding behavior (food intake) of
young-adult male rats was performed according to Torsello et al.
(Eur. J. Pharmacol. 1998, 360: 123-129).
[0791] For the assay, young-adult male Sprague-Dawley rats (Charles
River, Calco, Italy), weighing 200-250 g, were used.
[0792] Rats had 1 week of acclimation in individual home cages, and
animal room conditions (22.+-.2.degree. C., 65% humidity,
artificial light from 08.00 to 20.00 h). The following week, they
were daily trained to mimic the experimental procedure. Rats
maintained free access to dry pellets and tap water throughout the
whole experimental period. At the end of training, rats were
administered (around 10.00-11.00 a.m.) subcutaneously with the
compounds to be tested (160 .mu.g/kg body weight) and/or hexarelin
(80 .mu.g/kg body weight) and/or solvent [DMSO (0.4% of total
volume), distilled water (4% of total volume), brought to the final
volume with physiological saline].
[0793] Hexarelin was used to study the effects of the compounds to
be tested on stimulated feeding behavior. Immediately after the
injections, the animals were returned to their home cages, which
contained a known amount of standard rat chow and ad libitum water.
Every hour for the following 6 hours, the remaining food was
carefully collected and weighed to the nearest 0.1 g. Food intake
was normalized for the body weight of the rats and expressed as
grams of food eaten per 100 g body weight of rats.
[0794] In the following table 4 results obtained for selected
compounds of the invention are presented. TABLE-US-00004 TABLE 4
Cumulative food intake (g food/100 g body weight) of young-adult
rats after 2 hours and 6 hours and after treatment with selected
compounds of the invention (160 .mu.g/kg body weight s.c.) and/or
hexarelin (80 .mu.g/kg body weight s.c.) and/or solvent Cumulative
Cumulative food intake food intake Treatment (after 2 hours) (after
6 hours) solvent 0.003 .+-. 0.0015 0.017 .+-. 0.0026 hexarelin
0.533 .+-. 0.194 1.0014 .+-. 0.1973 compound 1 0.02 .+-. 0.002 0.06
.+-. 0.03 compound 1 + hexarelin 0.06 .+-. 0.02 0.33 .+-. 0.21
compound 12 0.034 .+-. 0.011 0.06 .+-. 0.019 compound 12 +
hexarelin 0.13 .+-. 0.07 0.48 .+-. 0.22 compound 20 0.01 0.2 .+-.
0.19 compound 20 + hexarelin 0.53 .+-. 0.21 0.63 .+-. 0.19 compound
22 0.01 0.44 .+-. 0.2 compound 22 + hexarelin 0.67 .+-. 0.12 0.86
.+-. 0.18 compound 47 0.006 .+-. 0.002 0.02 .+-. 0 compound 47 +
hexarelin 0.35 .+-. 0.201 0.47 .+-. 0.1943 compound 44 0.43 .+-.
0.0721 0.7075 .+-. 0.1471 compound 44 + hexarelin 1.2667 .+-.
0.1319 1.4033 .+-. 0.1177 solvent 0.184 .+-. 0.111 0.497 .+-. 0.183
hexarelin 0.536 .+-. 0.176 0.549 .+-. 0.169 compound 9 0.01 .+-. 0
0.01 .+-. 0 compound 9 + hexarelin 0.0104 .+-. 0.0032 0.0231 .+-.
0.0032 solvent 0.184 .+-. 0.111 0.497 .+-. 0.183 hexarelin 1.060
.+-. 0.143 1.138 .+-. 0.114 compound 13 0.057 .+-. 0.057 0.167 .+-.
0.167 compound 13 + hexarelin 0.731 .+-. 0.318 0.792 .+-. 0.337
solvent 0.184 .+-. 0.111 0.497 .+-. 0.183 hexarelin 1.060 .+-.
0.143 1.138 .+-. 0.114 compound 17 0.001 .+-. 0.001 0.2661 .+-.
0.166 compound 17 + hexarelin 0.0501 .+-. 0.049 0.846 .+-. 0.411
solvent 0.184 .+-. 0.111 0.497 .+-. 0.183 hexarelin 0.428 .+-.
0.192 0.588 .+-. 0.303 compound 24 0.008 .+-. 0.008 0.215 .+-.
0.200 compound 24 + hexarelin 0.586 .+-. 0.252 0.912 .+-. 0.359
solvent 0.184 .+-. 0.111 0.497 .+-. 0.183 hexarelin 0.627 .+-.
0.211 0.778 .+-. 0.218 compound 30 0.264 .+-. 0.244 0.277 .+-.
0.246 compound 30 + hexarelin 1.350 .+-. 0.177 1.449 .+-. 0.213
solvent 0.184 .+-. 0.018 0.399 .+-. 0.201 hexarelin 0.278 .+-.
0.078 0.883 .+-. 0.259 compound 38 0.001 .+-. 0 0.076 .+-. 0.096
compound 38 + hexarelin 0.002 .+-. 0.002 0.478 .+-. 0.141 solvent
0.184 .+-. 0.111 0.497 .+-. 0.183 hexarelin 0.26 .+-. 0.13 0.78
.+-. 0.25 compound 49 0.004 .+-. 0.004 0.004 .+-. 0.004 compound 49
+ hexarelin 0.057 .+-. 0.037 0.558 .+-. 0.212 solvent 0.184 .+-.
0.111 0.497 .+-. 0.183 hexarelin 0.536 .+-. 0.176 0.594 .+-. 0.169
compound 50 0.012 .+-. 0.008 0.039 .+-. 0.011 compound 50 +
hexarelin 0.003 .+-. 0.002 0.017 .+-. 0.001 solvent 0.184 .+-.
0.111 0.497 .+-. 0.183 hexarelin 0.427 .+-. 0.16 0.688 .+-. 0.203
compound 64 0.012 .+-. 0.008 0.039 .+-. 0.011 compound 64 +
hexarelin 0.012 .+-. 0.004 0.021 .+-. 0.007 solvent 0.184 .+-.
0.111 0.497 .+-. 0.183 hexarelin 0.696 .+-. 0.267 0.74 .+-. 0.27
compound 71 0.522 .+-. 0.283 0.53 .+-. 0.28 compound 71 + hexarelin
0.117 .+-. 0.074 0.20 .+-. 0.01 solvent 0.184 .+-. 0.111 0.497 .+-.
0.183 hexarelin 0.70 .+-. 0.116 1.221 .+-. 0.06 compound 72 0.008
.+-. 0.003 0.011 .+-. 0 compound 72 + hexarelin 0.634 .+-. 0.33
0.746 .+-. 0.31 solvent 0.184 .+-. 0.111 0.497 .+-. 0.183 hexarelin
1.031 .+-. 0.219 1.455 .+-. 0.192 compound 80 0.145 .+-. 0.143
0.346 .+-. 0.159 compound 80 + hexarelin 0.475 .+-. 0.196 0.733
.+-. 0.238 solvent 0.184 .+-. 0.111 0.497 .+-. 0.183 hexarelin
0.696 .+-. 0.267 0.74 .+-. 0.27 compound 81 0.017 .+-. 0.004 0.03
.+-. 0 compound 81 + hexarelin 0.024 .+-. 0.0101 0.116 .+-. 0.077
solvent 0.184 .+-. 0.111 0.497 .+-. 0.183 hexarelin 0.412 .+-.
0.173 0.68 .+-. 0.29 compound 81 0.034 .+-. 0.003 0.346 .+-. 0.179
compound 81 + hexarelin 1.4 .+-. 0.35 1.665 .+-. 0.345 solvent
0.184 .+-. 0.111 0.497 .+-. 0.183 hexarelin 0.323 .+-. 0.131 0.45
.+-. 0.17 compound 90 0.014 .+-. 0.001 0.035 .+-. 0.003 compound 90
+ hexarelin 0.054 .+-. 0.041 0.069 .+-. 0.041
VI) Motilin Receptor-Ligand Binding Assay (Using Human Recombinant
HEK-293 Cells)
[0795] Motilin Receptor binding/affinity studies were performed as
described by Feighner S D et al. (Science 1999, 284: 2184-2188).
The assays were run under the following conditions:
[0796] Source: Human recombinant HEK-293 cells [Motilin-Receptor 1a
(MTL-R1a)]
[0797] Ligand: 0.1 nM [.sup.125I] Motilin (human, porcine)
[0798] Vehicle: 1% DMSO
[0799] Incubation Time/Temperature: 2.5 hours at 25.degree. C.
[0800] Incubation Buffer: 50 mM Tris, pH 7, 4, 10 mM MgCl.sub.2,
0.5% BSA
[0801] Non-Specific Ligand: 1 .mu.M Motilin (human, porcine)
[0802] Compounds of the invention were tested in concentrations
comprising 0.01 .mu.M, 0.1 .mu.M, 1 .mu.M and 10 .mu.M.
[0803] IC.sub.50 values were determined by a non-linear, least
square regression analysis using Data Analysis Toolbox (MDL
Information Systems, USA).
[0804] In the following table 5 results obtained for selected
compounds of the invention are presented. TABLE-US-00005 TABLE 5
Motilin Receptor-ligand binding assay test results (IC.sub.50
values for a number of selected exemplary compounds) MTL-R 1a No.
IC.sub.50 [.mu.M] Chemical name 44 1,61
(R)--N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-
1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4-
carboxamide, 64 1,39
(R)--N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-
4H-1,2,4-triazol-3-yl)-2-(1H-indol-3- yl)ethyl)picolinamide,
VII) Study of Anti-Cachectic Effects in an Adjuvant-Induced
Arthritis Model System
[0805] The effectiveness of compounds of the invention in the
treatment of cachexia was investigated according to Ibanez de
Caceres I et al. (J Endocrinol. 2000, 165(3): 537-544) using a
cachexia model system (Roubenoff R et al., Arthritis Rheum. 1997,
40(3): 534-539).
[0806] Table 6 shows the anti-cachetic effect of compound 44 (0.1
.mu.g/kg/day s.c. injection) in arthritic rats in comparison to
adjuvant induced arthritis without medical treatment.
TABLE-US-00006 TABLE 6 Body weight change in gram (mean of 6
animals per group) Day 3 Day 6 Day 10 Day 13 Day 15 Day 17 Rats
with -3.02 2.95 11.97 9.32 -2.78 -8.27 adjuvant induced arthritis +
vehicle Arthritic rats + -5.32 2.98 14.92 19.08 7.05 1.47 treatment
with compound 44 (0.1 .mu.g/kg/day s.c.)
VIII) Study of Anti-Inhibitory Effects of Isoproterol-Induced
Lipolysis in Adipocyte Models
[0807] The effectiveness of compounds of the invention in the
inhibition of the unacylated ghrelin-induced inhibition of
isoproterol-induced lipolysis was investigated using adipocyte
models.
Isolation of Primary Mouse Adipocytes
[0808] Mice were fed with high fat diet induce obesity (60% of
lipids) starting at 4 weeks of age for 12 and 18 weeks.
[0809] White adipose tissue from epididymal fat was minced and
digested in Krebs-Ringer-Bicarbonate-Hepes (KRBH) buffer (20 mM
Hepes pH 7.4, 120 mM NaCl, 4.7 mM KCl, 1.2 mM K.sub.2HPO.sub.4, 2.5
mM CaCl.sub.2, 1.2 mM MgSO.sub.4, 24 mM NaHCO.sub.3) satured with
CO.sub.2 containing glucose (1 mg/mL), 1% BSA and collagenase (2
mg/g tissue). The digestion was made under constant shaking (250
rpm) at 37.degree. C. for 45 minutes.
[0810] The cell suspension was filtered through a nylon mesh to
separate the adipocytes from tissue fragments, and washed three
times in 3 mL of warm KRBH 1% BSA.
[0811] The cells was resuspended in KRBH 1% BSA and incubated in
shaker (75 rpm) at 37.degree. C. for 30 minutes.
Lipolysis Assay
[0812] Lipolysis in primary adipocytes cells was induced with 30 nM
of isoproterenol in KRBH 4% BSA for 90 minutes with constant (125
rpm) shaking at 37.degree. C.
[0813] Lipolysis in differentiated cells was induced with 30 nM of
isoproterenol in DMEM FBS free for 90 minutes at 37.degree. C. with
shaking every 15 minutes.
[0814] The inhibitory effect of unacylated ghrelin (UAG) on
isoproterenol induced lipolysis was documented with increasing
concentration of UAG from 10.sup.-11 M to 10.sup.-6 M in presence
or in absence of selected compounds of the invention at 10.sup.-7
M.
[0815] The lipolysis index was assessed by measuring glycerol
release following triglyceride hydrolysis.
[0816] The antagonistic effect was determined as follows: pA
.times. .times. 2 = - log .times. [ concentration .times. .times.
of .times. .times. competitor .times. .times. ( M ) ] Ratio - 1
##EQU1## with ##EQU1.2## Ratio = EC .times. .times. 50 .times.
.times. in .times. .times. presence .times. .times. of .times.
.times. competitor .times. .times. ( M ) EC .times. .times. 50
.times. .times. in .times. .times. absence .times. .times. of
.times. .times. competitor .times. .times. ( M ) ##EQU1.3##
[0817] FIGS. 41-46 show the effects of selected compounds 9, 38,
50, 64, 74, 81 on the isoprorerenol-induced lipolysis inhibition
curve of unacylated ghrelin (UAG) in primary adipocytes from mice
under diet-induced obesity.
[0818] The above written description of the invention provides a
manner and process of making and using it such that any person
skilled in this art is enabled to make and use the same, this
enablement being provided in particular for the subject matter of
the appended claims, which make up a part of the original
description.
[0819] As used herein, the phrases "selected from the group
consisting of," "chosen from," and the like include mixtures of the
specified materials. Terms such as "contain(s)" and the like as
used herein are open terms meaning `including at least` unless
otherwise specifically noted.
[0820] All references, patents, applications, tests, standards,
documents, publications, brochures, texts, articles, etc. mentioned
herein are incorporated herein by reference. Where a numerical
limit or range is stated, the endpoints are included. Also, all
values and subranges within a numerical limit or range are
specifically included as if explicitly written out.
[0821] The above description is presented to enable a person
skilled in the art to make and use the invention, and is provided
in the context of a particular application and its requirements.
Various modifications to the preferred embodiments will be readily
apparent to those skilled in the art, and the generic principles
defined herein may be applied to other embodiments and applications
without departing from the spirit and scope of the invention. Thus,
this invention is not intended to be limited to the embodiments
shown, but is to be accorded the widest scope consistent with the
principles and features disclosed herein.
[0822] The invention method, compounds and compositions are
preferably used by subjects desirous of the benefits noted herein,
subjects "in need of" these benefits. Such subjects are typically
suffering from physiological and/or pathophysiological conditions
such as those selected from the group consisting of acute fatigue
syndrome and muscle loss following election surgery, adipogenesis,
adiposity, age-related decline of thymic function, age-related
functional decline (ARFD) in the elderly, aging disorder in
companion animals, Alzheimer's disease, anorexia; anxiety, blood
pressure (lowering), body weight gain/reduction, bone fracture
repair (acceleration), bone remodeling stimulation, cachexia and
protein loss reduction due to chronic illness such as cancer or
AIDS, cardiac dysfunctions, cardiomyopathy, cartilage growth
stimulation, catabolic disorders in connection with pulmonary
dysfunction and ventilator dependency, catabolic side effects of
glucocorticoids, catabolic state of aging, central nervous system
disorders (in combination with antidepressants), chronic dialysis,
chronic fatigue syndrome (CFS), cognitive function improvement,
complicated fractures, complications associated with
transplantation, congestive heart failure (alone/in combination
with corticotropin releasing factor antagonists), Crohn's disease
and ulcerative colits, Cushing's syndrome, dementia, depressions,
short-, medium- and/or long-term regulation of energy balance,
short-, medium- and/or long-term regulation of food intake
(stimulation and/or inhibition), fraility, gastrectomy (ghrelin
replacement therapy), gastric postoperative ileus, glycemic control
improvement, growth hormone release stimulation in the elderly,
growth hormone replacement in stressed patients, growth promotion
in livestock, growth retardation associated with the Prader-Willi
syndrome and Turner's syndrome, growth retardation in connection
with Crohn's disease, growth retardation, hair/nail growth
maintenance, hip fractures, hunger, hypercortisolism,
hyperinsulinemia including nesidioblastosis, hypothermia, immune
deficiency in individuals with a depressed T4/T8 cell ratio, immune
response improvement to vaccination, immune system stimulation in
companion animals, immune system stimulation, immunosuppression in
immunosuppressed patients, inflammation or inflammatory effects,
inflammatory bowel disease, insulin resistance in the heart,
insulin resistance in type 2 diabetic patients, insulin resistance
including NIDDM, diabetes, diabetes type I, diabetes type II,
intrauterine growth retardation, irritable bowel syndrome,
lipodystrophy, metabolic homeostasis maintenance, milk production
increase in livestock, muscle mass/strength increase, muscle
mobility improvement, muscle strength improvement, muscle
strength/function maintenance in elderly humans, muscular atrophy,
musculoskeletal impairment (e.g. in elderly), Noonan's syndrome,
obesity and growth retardation associated with obesity, osteoblast
stimulation, osteochondrodysplasias, osteoporosis, ovulation
induction (adjuvant treatment), physiological short stature
including growth hormone deficient children, postoperative ileus,
protein catabolic response attenuation after major surgery/trauma,
protein kinase B activity enhancement, psychosocial deprivation,
pulmonary dysfunction and ventilator dependency, pulmonary function
improvement, pulsatile growth hormone release induction, recovery
of burn patients and reducing hospitalization of burn patients
(acceleration), renal failure or insufficiency resulting from
growth retardation, renal homeostasis maintenance in the frail
elderly, sarcopenia, schizophrenia, sensory function maintenance,
short bowel syndrome, short stature associated with chronic
illness, skeletal dysplasia, skin thickness maintenance, sleep
disorders, sleep quality improvement, thrombocytopenia, thymic
development stimulation, tooth repair or growth, tumor cell
proliferation, ventricular dysfunction or reperfusion events,
wasting in connection with AIDS, wasting in connection with chronic
liver disease, wasting in connection with chronic obstructive
pulmonary disease (COPD), wasting in connection with multiple
sclerosis or other neurodegenerative disorders, wasting secondary
to fractures, wool growth stimulation in sheep, wound healing
(acceleration) and/or wound healing delay, such as by self
diagnosis or medical diagnosis, or are at recognized and
appreciated risk of developing such conditions and who use the
invention methods and compositions to combat these effects.
Naturally, one using the invention as disclosed will use an amount
of the invention compounds and compositions effective to obtain the
desired results. Such amount is inclusive of the amounts described
herein.
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