U.S. patent application number 10/267477 was filed with the patent office on 2003-04-03 for nk1 receptor antagonists.
Invention is credited to Creswell, Mark Wallace, Higginbottom, Michael, Horwell, David Christopher, Lewthwaite, Russel Andrew, Pritchard, Martyn Clive, Raphy, Jennifer.
Application Number | 20030065007 10/267477 |
Document ID | / |
Family ID | 22345539 |
Filed Date | 2003-04-03 |
United States Patent
Application |
20030065007 |
Kind Code |
A1 |
Creswell, Mark Wallace ; et
al. |
April 3, 2003 |
NK1 receptor antagonists
Abstract
Non-peptide acetamide derivatives of Formula I are specific
NK.sub.1 antagonists, 1 where R is aryl, R.sup.1 and R.sup.2 are H
or alkyl, m, n and q are integers from 0 to 4, X is NR.sup.8 or
NHCONH, R.sup.3 and R.sup.9 are H or alkyl, R.sup.4 is naphthyl or
indolyl, R.sup.5 and R.sup.2 are H or alkyl, and R.sup.6 is aryl.
The compounds are useful agents for treating inflammatory and
allergic disorders, pain, anxiety, depression, schizophrenia and
emesis.
Inventors: |
Creswell, Mark Wallace;
(Chelsea, MI) ; Higginbottom, Michael;
(Cambridgeshire, GB) ; Horwell, David Christopher;
(Cambridge, GB) ; Lewthwaite, Russel Andrew;
(Cambridge, GB) ; Pritchard, Martyn Clive;
(Cambridgeshire, GB) ; Raphy, Jennifer; (Herts,
GB) |
Correspondence
Address: |
David R. Kurlandsky
Warner-Lambert Company
2800 Plymouth Road
Ann Arbor
MI
48105
US
|
Family ID: |
22345539 |
Appl. No.: |
10/267477 |
Filed: |
October 9, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10267477 |
Oct 9, 2002 |
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09868449 |
Jun 18, 2001 |
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6472418 |
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09868449 |
Jun 18, 2001 |
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PCT/US99/29592 |
Dec 14, 1999 |
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60112725 |
Dec 18, 1998 |
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Current U.S.
Class: |
514/307 ;
514/311; 514/357; 514/375; 514/394; 514/406; 514/408; 514/415;
514/438; 514/443; 514/469; 514/471; 514/563; 514/617; 546/146;
546/175; 546/336; 548/217; 548/309.7; 548/375.1; 548/494; 548/567;
549/467; 549/49; 549/76; 562/455; 564/161 |
Current CPC
Class: |
A61P 1/08 20180101; C07D
209/20 20130101; A61P 11/06 20180101; A61P 1/14 20180101; A61P
17/06 20180101; C07D 401/12 20130101; C07D 413/14 20130101; C07D
403/12 20130101; A61P 1/04 20180101; C07D 409/12 20130101; C07D
405/14 20130101; A61P 11/02 20180101; A61P 25/24 20180101; A61P
15/10 20180101; A61P 43/00 20180101; C07D 405/12 20130101; A61P
3/04 20180101; A61P 25/22 20180101; A61P 25/04 20180101; C07D
409/14 20130101; A61P 25/28 20180101; A61P 29/00 20180101; A61P
25/00 20180101; A61P 37/00 20180101; A61P 11/00 20180101; A61P
19/02 20180101; A61P 17/00 20180101 |
Class at
Publication: |
514/307 ;
514/357; 514/375; 514/311; 514/406; 514/394; 514/438; 514/415;
514/443; 514/469; 514/471; 514/563; 514/617; 546/146; 546/175;
546/336; 548/217; 548/309.7; 548/375.1; 548/494; 548/567; 549/49;
549/76; 549/467; 562/455; 564/161; 514/408 |
International
Class: |
C07D 333/52; C07D
333/22; C07D 217/06; C07D 217/12 |
Claims
We claim:
1. A compound of Formula I 43or a pharmaceutically acceptable salt
thereof, wherein .box-solid., .circle-solid., and and
.tangle-solidup. indicate all stereoisomers, R is: pyridyl,
thienyl, furyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl,
naphthyl, indolyl, benzofuryl, benzothiophenyl, benzimidazolyl, and
benzoxazolyl, wherein each of the foregoing is unsubstituted,
mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen,
--CF.sub.3, carboxy, sulfonamide, or nitro; R can also be:
44R.sup.1 and R.sup.2 are each independently H or C.sub.1-C.sub.4
alkyl; m is an integer from 0 to 3; X is NHCONH, or NR.sup.8 where
R.sup.8 is H or C.sub.1-C.sub.4 alkyl; R.sup.3 is hydrogen or
C.sub.1-C.sub.4 alkyl; n is an integer from 1 to 2; R.sup.4 is
naphthyl or indolyl, wherein said groups are unsubstituted, mono-,
di- or trisubstituted by alkyl, hydroxy or formyl; R.sup.9 is
hydrogen or C.sub.1-C.sub.4 alkyl; R.sup.5 and R.sup.7 are each
independently hydrogen or (CH.sub.2).sub.pR.sup.10 where: p is an
integer of 1 to 3, and R.sup.10 is H, CH.sub.3, CN, OH, OCH.sub.3,
CO.sub.2CH.sub.3, NH.sub.2, NHCH.sub.3, or N(CH.sub.3).sub.2; q is
an integer of 0 to 4; R.sup.6 is phenyl, pyridyl, thienyl, furyl,
pyrrolyl, pyrazolyl, imidazolyl, quinolyl, isoquinolyl, naphthyl,
indolyl, benzofuryl, benzothiophenyl, benzimidazolyl, or
benzoxazolyl, wherein each of the foregoing is unsubstituted,
mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen,
CF.sub.3, NO.sub.2, N(CH.sub.3).sub.2, OCF.sub.3, SONH.sub.2,
NH.sub.2, CONH.sub.2, CO.sub.2CH.sub.3, or CO.sub.2H, or R.sup.6
is: straight alkyl of from 1 to 3 carbons, branched alkyl of from 3
to 8 carbons, cycloalkyl of from 5 to 8 carbons, or
heterocycloalkyl, each of which can be substituted with up to one
or two substituents selected from OH, CO.sub.2H, N(CH.sub.3).sub.2,
NHCH.sub.3 and CH.sub.3; and R.sup.5 and R.sup.6, when joined by a
bond, can form a ring; R.sup.6 is also 45where X.sub.1 represents
the rest of the molecule.
2. A compound of claim I wherein R is selected from: pyridyl,
thienyl, furyl, quinolyl isoquinolyl naphthyl, indolyl, benzofuryl,
benzothiophenyl, benzimidazolyl, benzoxazolyl, wherein each of the
foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl,
hydroxy, alkoxy, halogen, or CF.sub.3, 46m is an integer from 1 to
3; R.sup.6 is phenyl pyridyl, thienyl, furyl, pyrrolyl, quinolyl,
isoquinolyl, naphthyl, indolyl, benzofuryl, benzothiophenyl,
benzimidazolyl, or benzoxazolyl, wherein each of the foregoing is
unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy,
alkoxy, halogen, CF.sub.3, NO.sub.2 N(CH.sub.3).sub.2, OCF.sub.3,
SONH.sub.2, NH.sub.2, CONH.sub.2, CO.sub.2CH.sub.3, or CO.sub.2H,
cycloalkyl of from 5 to 6 carbons or heterocycloalkyl, with up to
one or two substituents selected from OH, CO.sub.2H,
N(CH.sub.3).sub.2, NHCH.sub.3 and CH.sub.3; and R.sup.5 and R.sup.6
when joined by a bond can form a ring.
3. A compound according to claim 2 wherein R.sup.1 and R.sup.2 each
are hydrogen.
4. A compound according to claim 3 wherein X is NR.sup.8.
5. A compound according to claim 4 wherein R is pyridyl, thienyl,
furyl, quinolyl, naphthyl, benzofuryl, benzothiophenyl,
benzimidazolyl, or benzoxazolyl, where each of the foregoing is
unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy,
alkoxy, halogen, or --CF.sub.3, 47R.sup.1 and R.sup.2 are each H; m
is an integer from 1 to 3; X is NR.sup.8 or NHCONH, where R.sup.8
is H or methyl; R.sup.9 is hydrogen or alkyl of 1 to 3 carbon
atoms; R.sup.6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl,
benzimidazolyl, where each of the foregoing is unsubstituted,
mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen,
CF.sub.3, NO.sub.2, or N(CH.sub.3).sub.2; cyclohexyl or
heterocycloalkyl, with up to one or two substituents selected from
OH, CO.sub.2H, N(CH.sub.3).sub.2, NHCH.sub.3 and CH.sub.3; and
R.sup.5 and R.sup.6, when joined by a bond, can form a ring.
6. A compound of the Formula II 48wherein: R is benzofuryl,
benzoxazolyl, 3-cyanophenyl, 3-nitrophenyl, or
3-trifluoromethylphenyl; R.sup.3 is hydrogen or methyl; X is NH or
NHCONH; R.sup.5 and R.sup.7 independently are hydrogen or
CH.sub.2R.sup.10, where R.sup.10 is H, CH.sub.3 or OH; R.sup.6 is
phenyl, substituted phenyl, pyridyl, or, cyclohexyl; and the
pharmaceutically acceptable salts thereof.
7. A compound of claim 6 selected from:
2-[(Benzofuran-2-ylmethyl)-amino]--
3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide,
[R--(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl--
N-(1-pyridin-4-yl-ethyl)-propionamide,
[R--(R*,S*)]2-[(Benzofuran-2-ylmeth-
yl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-[1-(4-nitro-phenyl)-ethyl]-propion-
amide,
[R--(R*,R*)]2-[(Benzofuran-2-ylmethyl)-amino]-N-(2-hydroxy-1-phenyl-
-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide,
[R--(R*,R*)][R--(R*,S*)]2-
-[(Benzofuran-2-ylmethyl)-amino]-N-(1-cyclohexyl-ethyl)-3-(1H-indol-3-yl)--
2-methyl-propionamide
[R--(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H--
indol-3-yl)-2-methyl-N-(1-p-tolyl-ethyl)-propionamide
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-p-tolyl-ethyl)-p-
ropionamide,
[R--(R*,S*)]2-(3-Cyano-benzylamino)-3-(1H-indol-3-yl)-N-(1-ph-
enyl-ethyl)-propionamide,
[R--(R*,S*)]3-(1H-Indol-3-yl)-2-(3-nitro-benzyla-
mino)-N-(1-phenyl-ethyl)-propionamide,
[R--(R*,S*)]3-(1H-Indol-3-yl)-N-(1--
phenyl-ethyl)-2-(3-trifluoromethoxy-benzylamino)-propionamide,
[R--(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-pyri-
din-4-yl-ethyl)-propionamide,
[R--(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino-
]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide,
[R--(R*,S*)]2-[(Benzooxazol-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phe-
nyl-ethyl)-propionamide
2-(2-Benzofuran-2-yl-ethylamino)-3-(1H-indol-3-yl)-
-N-(1-phenyl-ethyl)-propionamide, [R--(R*,S*)] and
2-(3-Benzofuran-2-ylmet-
hyl-ureido)-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide,
[R--(R*,S*)].
8. A pharmaceutical formulation comprising a compound of claim I
admixed with a pharmaceutically acceptable diluent, carrier or
excipient.
9. A formulation according to claim 8 employing a compound of
Formula II 49wherein: R is benzofuryl, benzoxazolyl, 3-cyanophenyl,
3-nitrophenyl, or 3-trifluoromethylphenyl; R.sup.3 is hydrogen or
methyl; X is NH or NHCONH; R.sup.5 and R.sup.7 independently are
hydrogen or CH.sub.2R.sup.10, where R.sup.10 is H, CH.sub.3 or OH;
R.sup.6 is phenyl, substituted phenyl, pyridyl, or, cyclohexyl; or
a pharmaceutically acceptable salts thereof.
10. A formulation according to claim 9 employing a compound
selected from:
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl--
ethyl)-propionamide,
[R--(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-i-
ndol-3-yl)-2-methyl-N-(1-pyridin-4-yl-ethyl)-propionamide,
[R--(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl--
N-[1-(4-nitro-phenyl)-ethyl]-propionamide,
[R--(R*,R*)]2-[(Benzofuran-2-yl-
methyl)-amino]-N-(2-hydroxy-1-phenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-pro-
pionamide,
[R--(R*,R*)][R--(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-N-(1--
cyclohexyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide
[R--(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl--
N-(1-p-tolyl-ethyl)-propionamide
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-i-
ndol-3-yl)-N-(1-p-tolyl-ethyl)-propionamide,
[R--(R*,S*)]2-(3-Cyano-benzyl-
amino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide,
[R--(R*,S*)]3-(1H-Indol-3-yl)-2-(3-nitro-benzylamino)-N-(1-phenyl-ethyl)--
propionamide,
[R--(R*,S*)]3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-triflu-
oromethoxy-benzylamino)-propionamide,
[R--(R*,S*)]2-[(Benzofuran-2-ylmethy-
l)-amino]-3-(1H-indol-3-yl)-N-(1-pyridin-4-yl-ethyl)-propionamide,
[R--(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phen-
yl-ethyl)-propionamide,
[R--(R*,S*)]2-[(Benzooxazol-2-ylmethyl)-amino]-3-(-
1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide
2-(2-Benzofuran-2-yl-ethyla-
mino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide,
[R--(R*,S*)] and
2-(3-Benzofuran-2-ylmethyl-ureido)-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-
-ethyl)-propionamide, [R--(R*,S*)].
11. A method for antagonizing the NK.sub.1 receptor in a mammal
comprising administering a compound of claim 1.
12. A method for treating a CNS disorder in a mammal in need of
treatment comprising administering an effective amount of a
compound of claim 1.
13. A method according to claim 12 wherein the CNS disorder is
selected from pain, anxiety, depression or schizophrenia.
14. A method according to claim 12 wherein the CNS disorder is
selected from neuralgia, stress, sexual dysfunction, bipolar
disorders, movement disorders, cognitive disorders, obesity, and
addiction disorders.
15. A method for treating an allergic or inflammatory disorder in a
mammal in need of treatment comprising administering an effective
amount of a compound of claim 1.
16. A method according to claim 15 wherein the allergic or
inflammatory disorder is selected from arthritis, asthma,
bronchitis, psoriasis, eczema, rhinitis, colitis or Crohn's
disease.
17. A method for treating a neuropathological disorder in a mammal
in need of treatment comprising administering an effective amount
of a compound of claim 1.
18. A method according to claim 17 wherein the neuropathological
disorder is selected from scleroderma or emesis.
Description
BACKGROUND OF THE INVENTION
[0001] The neurokinins are a family of mammalian neuropeptides that
are involved with numerous biological activities such as pain
transmission, vasodilation, smooth muscle contraction,
bronchoconstriction, activation of the immune system, and
neurogenic inflammation. One such neuropeptide known as substance P
is widely distributed throughout the peripheral and central nervous
system of mammals, and is known to mediate a variety of biological
actions via interaction with three neurokinin (NK or tachykinin)
receptor types known as NK.sub.1, NK.sub.2, and NK.sub.3.
[0002] Substance P binds with higher affinity to the NK.sub.1
receptor than it does to the other receptors. Accordingly,
compounds capable of antagonizing the effects of substance P at the
NK.sub.1 receptor are useful for treating and controlling disorders
mediated by such interactions, including disorders such as anxiety,
pain, depression, schizophrenia, and emesis.
[0003] Since 1991, a number of high-affinity nonpeptide tachykinin
antagonists have been reported; for a review see Sprecher A, et al
(IDrugs, 1:73-91, 1998).
[0004] U.S. Pat. Nos. 5,594,022 and 5,716,979 describe nonpeptides
that are relatively specific NK.sub.1 antagonists.
[0005] Since substance P mediate various biological actions,
including smooth muscle contraction, pain transmission, neuronal
excitation, secretion of saliva, angiogenesis,
broncho-constriction, activation of the immune system and
neurogenic inflammation via an interaction with NK receptors,
preferably NK.sub.1, thus compounds capable of antagonising the
effects of substance P at NK.sub.1 receptors will be useful in
treating or preventing a variety of: brain disorders including pain
(inflammatory, surgical and neuropathic), anxiety, panic,
depression, schizophrenia, neuralgia, stress, sexual dysfunction,
bipolar disorders, movement disorders, cognitive disorders, obesity
and addiction disorders; inflammatory diseases such as arthritis,
asthma, bronchitis and psoriasis; gastrointestinal disorders
including colitis, Crohn's disease, irritable bowel syndrome, and
satiety; allergic responses such as eczema and rhinitis; vascular
disorders such as angina and migraine; neuropathological disorders
including scleroderma and emesis.
[0006] The compounds of the invention, NK.sub.1 receptor
antagonists, are useful as anti-angiogenic agents for the treatment
of conditions associated with aberrant neovascularization such as
rheumatoid arthritis, atherosclerosis and tumour cell growth. They
will also be useful as agents for imaging NK.sub.1 receptors in
vivo in conditions such as ulcerative colitis and Crohn's
disease.
SUMMARY OF THE INVENTION
[0007] This invention provides NK.sub.1 receptor antagonists
characterized as non-peptide acetamide derivatives. The compounds
of the invention differ from those of U.S. Pat. Nos. 5,716,979 or
5,594,022 in that the compounds of Formula I below are not
(N-substituted aryl-methyl) carbamates, i.e. they do not have a
--O--C(O)--N-- link in the backbone; certain final products being
more stable than known compounds, they should show improved oral
bioavailability and improved CNS penetration. The invention
compounds are defined by Formula I: 2
[0008] and the pharmaceutically acceptable salts thereof,
wherein
[0009] .box-solid., .circle-solid., and .tangle-solidup. indicate
all stereoisomers,
[0010] R is:
[0011] pyridyl,
[0012] thienyl,
[0013] furyl,
[0014] pyrrolyl,
[0015] pyrazolyl,
[0016] quinolyl,
[0017] isoquinolyl,
[0018] naphthyl,
[0019] indolyl,
[0020] benzofuryl,
[0021] benzothiophenyl,
[0022] benzimidazolyl, and
[0023] benzoxazolyl, wherein each of the foregoing is
unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy,
alkoxy, halogen, --CF.sub.3, carboxy, sulfonamide, or nitro;
[0024] R can also be: 3
[0025] R.sup.1 and R.sup.2 are each independently H or
C.sub.1-C.sub.4 alkyl;
[0026] m is an integer from 0 to 3;
[0027] X is NHCONH, or NR.sup.8 where R.sup.8 is H or
C.sub.1-C.sub.4 alkyl;
[0028] R.sup.3 is hydrogen or C.sub.1-C.sub.4 alkyl;
[0029] n is an integer from 1 to 2;
[0030] R.sup.4 is naphthyl or indolyl, wherein said groups are
unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy or
formyl;
[0031] R.sup.9 is hydrogen or C.sub.1-C.sub.4 alkyl;
[0032] R.sup.5 and R.sup.7 are each independently hydrogen or
(CH.sub.2).sub.pR.sup.10 where:
[0033] P is an integer of 1 to 3, and
[0034] R.sup.10 is H, CH.sub.3, CN, OH, OCH.sub.3,
CO.sub.2CH.sub.3, NH.sub.2, NHCH.sub.3, or N(CH.sub.3).sub.2;
[0035] q is an integer of 0 to 4;
[0036] R.sup.6 is
[0037] phenyl,
[0038] pyridyl,
[0039] thienyl,
[0040] furyl,
[0041] pyrrolyl,
[0042] pyrazolyl,
[0043] imidazolyl,
[0044] quinolyl,
[0045] isoquinolyl,
[0046] naphthyl,
[0047] indolyl,
[0048] benzofuryl,
[0049] benzothiophenyl,
[0050] benzimidazolyl, or
[0051] benzoxazolyl, wherein each of the foregoing is
unsubstituted, mono-, di- or
[0052] trisubstituted by
[0053] alkyl,
[0054] hydroxy,
[0055] alkoxy,
[0056] halogen,
[0057] CF.sub.3,
[0058] NO.sub.2,
[0059] N(CH.sub.3).sub.2,
[0060] OCF.sub.3,
[0061] SONH.sub.2,
[0062] NH.sub.2,
[0063] CONH.sub.2,
[0064] CO.sub.2CH.sub.3, or
[0065] CO.sub.2H,
[0066] or R.sup.6 is:
[0067] straight alkyl of from 1 to 3 carbons,
[0068] branched alkyl of from 3 to 8 carbons,
[0069] cycloalkyl of from 5 to 8 carbons or
[0070] heterocycloalkyl,
[0071] each of which can be substituted with up to one or two
substituents selected from
[0072] OH,
[0073] CO.sub.2H,
[0074] N(CH.sub.3).sub.2,
[0075] NHCH.sub.3 and
[0076] CH.sub.3; and
[0077] R.sup.5 and R.sup.6, when joined by a bond, can form a
ring;
[0078] R.sup.6 is also 4
[0079] where X.sub.1 represents the rest of the molecule.
[0080] Prodrugs of the above are also contemplated such as would
occur to one skilled in the art; see Bundgaard, et al, Acta Pharm
Suec, 1987; 24: 233-246. For example, a suitable moiety may be
attached to a nitrogen of the linker X, to the nitrogen of the
NR.sup.9 linker, or that of an indolyl radical of R.sup.4.
[0081] Preferred compounds of the invention are those of Formula I
above wherein
[0082] R is
[0083] pyridyl,
[0084] thienyl,
[0085] furyl,
[0086] quinolyl
[0087] isoquinolyl
[0088] naphthyl,
[0089] indolyl,
[0090] benzofuryl,
[0091] benzothiophenyl,
[0092] benzimidazolyl,
[0093] benzoxazolyl, wherein each of the foregoing is
unsubstituted, mono-, di- or
[0094] trisubstituted by alkyl, hydroxy, alkoxy, halogen, or
CF.sub.3, 5
[0095] m is an integer from 1 to 3;
[0096] R.sup.6 is
[0097] phenyl
[0098] pyridyl,
[0099] thienyl,
[0100] furyl,
[0101] pyrrolyl,
[0102] quinolyl,
[0103] isoquinolyl,
[0104] naphthyl,
[0105] indolyl,
[0106] benzofuryl,
[0107] benzothiophenyl,
[0108] benzimidazolyl, or
[0109] benzoxazolyl,
[0110] wherein each of the foregoing is unsubstituted, mono-, di-
or trisubstituted by
[0111] alkyl,
[0112] hydroxy,
[0113] alkoxy,
[0114] halogen,
[0115] CF.sub.3,
[0116] NO.sub.2
[0117] N(CH.sub.3).sub.2,
[0118] OCF.sub.3,
[0119] SONH.sub.2,
[0120] NH.sub.2,
[0121] CONH.sub.2,
[0122] CO.sub.2CH.sub.3, or
[0123] CO.sub.2H,
[0124] cycloalkyl of from 5 to 6 carbons or heterocycloalkyl, with
up to one or two substituents selected from OH,
[0125] CO.sub.2H,
[0126] N(CH.sub.3).sub.2,
[0127] NHCH.sub.3 and
[0128] CH.sub.3; and
[0129] R.sup.5 and R.sup.6 when joined by a bond can form a
ring.
[0130] More preferred compounds of the invention are those of
Formula I above wherein
[0131] R is
[0132] pyridyl,
[0133] thienyl,
[0134] furyl,
[0135] quinolyl,
[0136] naphthyl,
[0137] benzofuryl,
[0138] benzothiophenyl,
[0139] benzimidazolyl, or
[0140] benzoxazolyl, where each of the foregoing is unsubstituted,
mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, or
--CF.sub.3, 6
[0141] R.sup.1 and R.sup.2 are each H;
[0142] m is an integer from 1 to 3;
[0143] X is NR.sup.8 or NHCONH, where R.sup.8 is H or methyl;
[0144] R.sup.9 is hydrogen or alkyl of 1 to 3 carbon atoms;
[0145] R.sup.6 is
[0146] phenyl,
[0147] pyridyl,
[0148] thienyl,
[0149] furyl,
[0150] pyrrolyl,
[0151] benzimidazolyl, where each of the foregoing is
unsubstituted, mono-, di- or trisubstituted by
[0152] alkyl,
[0153] hydroxy,
[0154] alkoxy,
[0155] halogen,
[0156] CF.sub.3,
[0157] NO.sub.2,
[0158] N(CH.sub.3).sub.2;
[0159] cyclohexyl or heterocycloalkyl, with up to one or two
substituents selected from
[0160] OH,
[0161] CO.sub.2H,
[0162] N(CH.sub.3).sub.2,
[0163] NHCH.sub.3 and
[0164] CH.sub.3; and
[0165] R.sup.5 and R.sup.6, when joined by a bond, can form a
ring.
[0166] The most preferred compounds of the invention have Formula
II: 7
[0167] wherein:
[0168] R is
[0169] benzofuryl,
[0170] benzoxazolyl,
[0171] 3-cyanophenyl,
[0172] 3-nitrophenyl, or
[0173] 3-trifluoromethylphenyl;
[0174] R.sup.3 is hydrogen or methyl;
[0175] X is NH or NHCONH;
[0176] R.sup.5 and R.sup.7 independently are hydrogen or
CH.sub.2R.sup.10, where R.sup.10 is H, CH.sub.3 or OH;
[0177] R.sup.6 is
[0178] phenyl,
[0179] substituted phenyl,
[0180] pyridyl, or,
[0181] cyclohexyl;
[0182] and the pharmaceutically acceptable salts thereof
[0183] Most preferred compounds of the invention are:
[0184]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-p-
henyl-ethyl)-propionamide, [R--(R*,S*)]
[0185]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-p-
yridin-4-yl-ethyl)-propionamide, [R--(R*,S*)]
[0186] 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3
-yl)-2-methyl-N-[1-(4-nitro-phenyl)-ethyl]-propionamide,
[R--(R*,R*)]
[0187]
2-[(Benzofuran-2-ylmethyl)-amino]-N-(2-hydroxy-1-phenyl-ethyl)-3-(1-
H-indol-3-yl)-2-methyl-propionamide, [R--(R*,R*)]
[0188]
[R--(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-N-(1-cyclohexyl-ethyl-
)-3-(1H-indol-3-yl)-2-methyl-propionamide
[0189]
[R--(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-m-
ethyl-N-(1-p-tolyl-ethyl)-propionamide
[0190]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-p-tolyl-et-
hyl)-propionamide, [R--(R*,S*)]
[0191]
2-(3-Cyano-benzylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propio-
namide, [R--(R*,S*)]
[0192]
3-(1H-Indol-3-yl)-2-(3-nitro-benzylamino)-N-(1-phenyl-ethyl)-propio-
namide, [R--(R*,S*)]
[0193] 3-(1
H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-trifluoromethoxy-benzyla-
mino)-propionamide, [R--(R*,S*)]
[0194]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-pyridin-4--
yl-ethyl)-propionamide, [R--(R*,S*)]
[0195]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-eth-
yl)-propionamide, [R--(R*,S*)]
[0196]
2-[(Benzoxazol-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-eth-
yl)-propionamide
[0197]
2-(2-Benzofuran-2-yl-ethylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethy-
l)-propionamide, [R--(R*,S*)], and
[0198]
2-(3-Benzofuran-2-ylmethyl-ureido)-3-(1H-indol-3-yl)-2-methyl-N-(1--
phenyl-ethyl)-propionamide, [R--(R*,S*)].
[0199] The invention additionally provides pharmaceutical
formulations comprising a compound of Formula I admixed with a
pharmaceutically acceptable carrier, diluent or excipient therefor.
Especially preferred formulations comprise a compound of Formula
II. The invention also provides a method for antagonizing NK.sub.1
receptors in a mammal comprising administering to a mammal an
NK.sub.1 binding amount of a compound of Formula I. The invention
further provides a method for treating a CNS disorder including
pain, anxiety, depression, obesity, or schizophrenia; an allergic
or inflammatory disease; a gastrointestinal disorder; a vascular
disorder; or a neuropathological disorder including emesis;
comprising administering to a mammal in need of treatment an
effective amount of a compound of Formula I. An especially
preferred method of treatment utilizes a compound of Formula
II.
DETAILED DESCRIPTION OF THE INVENTION
[0200] Throughout this application, the following abbreviations
have the meanings listed below:
1 Boc tertiary butyloxycarbonyl DCE dichloroethane DCM
dichloromethane HBTU
O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate DIPEA N,N-diisopropylethylamine DMF
N,N-dimethylformamide DCC 1,3-dicyclohexylcarbodiimide EEDQ
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline EtOAc ethyl acetate
EtOH ethanol MeOH methanol KOH potassium hydroxide DIBAL
Diisobutylaluminium hydride NMM N-methyl-morpholine NMR nuclear
magnetic resonance Trp Tryptophan
[0201] The term "alkyl" means a straight or branched hydrocarbon
having from one to 12 carbon atoms and includes, for example,
methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,
n-pentyl, n-hexyl, n-heptyl, n-octyl, undecyl, dodecyl, and the
like unless stated specifically otherwise.
[0202] The term "cycloalkyl" means a saturated hydrocarbon ring
which contains from 3 to 12 carbon atoms, for example cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl except as otherwise stated.
[0203] The term "alkoxy" means an alkyl as described above attached
through an oxygen atom.
[0204] The term "halogen" is chlorine, bromine, fluorine or
iodine.
[0205] The ring formed by joining R.sup.5 and R.sup.6 is from 4 to
6 atoms total and is unsubstituted.
[0206] The compounds of Formula I are capable of forming
pharmaceutically acceptable acid addition salts. All of these forms
are within the scope of the present invention.
[0207] Pharmaceutically acceptable acid addition salts of the
compound of Formula I include salts derived from inorganic acids
such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic,
hydroiodic, hydrofluoric, phosphorous, and the like as well as the
salts derived from nontoxic organic acids, such as the aliphatic
mono- and dicarboxylic acids, phenyl-substituted alkanoic acids,
hydroxy-alkanoic acids, alkanedioic acids, aromatic acids,
aliphatic and aromatic sulfonic acids, etc. Such salts thus include
sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate,
phosphate, monohydrogenphosphate, dihydrogenphosphate,
metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride,
acetate, trifluoroacetate, propionate, caprylate, isobutyrate,
oxalate, malonate, succinate, suberate, sebacate, fumarate,
maleate, mandalate, benzoate, chlorobenzoate, methylbenzoate,
dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate,
phenylacetate, citrate, lactate, tartrate, methanesulfonate, and
the like. Also contemplated are salts of amino acids such as
arginate and the like. For example, see Berge S. M., et al.,
Pharmaceutical Salts, J. Pharm. Sci., 66:1-19 (1977) incorporated
herein by reference.
[0208] The acid addition salts of the compounds of Formula I are
prepared by contacting the free base form of the compound with a
sufficient amount of the desired acid to produce the salt in the
conventional manner. Preferably, a compound of Formula I can be
converted to an acidic salt by treating an aqueous solution of the
desired acid, such that the resulting pH is less than four. The
solution can be passed through a C18 cartridge to absorb the
compound, washed with copious amounts of water, the compound eluted
with a polar organic solvent such as, for example methanol,
acetonitrile, aqueous mixtures thereof, and the like, and isolated
by concentrating under reduced pressure followed by lyophilisation.
The free base form may be regenerated by contacting the salt form
with a base and isolating the free base in the conventional manner.
The free base forms differ from their respective salt forms
somewhat in certain physical properties such as solubility in polar
solvents, but otherwise the salts are equivalent to their
respective free base for the purpose of the present invention.
[0209] Certain of the compounds of the present invention can exist
in unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms, including hydrated forms are
equivalent to unsolvated forms and are intended to be encompassed
within the scope of the present invention.
[0210] Certain of the compounds of the present invention possess
one or more chiral centers and each center may exist in the R(D) or
S(L) configuration. The present invention includes all enantiomeric
and epimeric forms as well as the appropriate mixtures thereof
[0211] The compounds of the present invention can be prepared and
administered in a wide variety of oral and parenteral dosage forms.
Thus, the compounds of the present invention can be administered by
injection, that is intravenously, intramuscularly,
intracutaneously, subcutaneously, intraduodenally, or
intraperitoneally. In addition, the compounds of the present
invention can be administered by inhalation, for example
intranasally. Additionally, the compounds of the present invention
can be administered transdermally. It will be obvious to those
skilled in the art that the following dosage forms may comprise as
the active component, either a compound of Formula I or a
corresponding pharmaceutically acceptable salt of the compound of
Formula I.
[0212] For preparing pharmaceutical compositions from the compounds
of the present invention, pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
pills, tablets, capsules, cachets, suppositories and dispersible
granules. A solid carrier can be one or more substances that may
also act as diluents, flavouring agents, binders, preservatives,
tablet disintegrating agents, or an encapsulating material.
[0213] In powders, the carrier is a finely divided solid that is in
a mixture with the finely divided active component.
[0214] In tablets, the active component is mixed with the carrier
having the necessary binding properties in suitable proportions and
compacted in the shape and size desired.
[0215] The powders and tablets preferably contain from 5% or 10% to
about 70% of the active compound. Suitable carriers are magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin,
dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the
like. The term "preparation" is intended to include the formulation
of the active compound with encapsulating material as a carrier
providing a capsule in which the active component with or without
other carriers, is surrounded by a carrier, which is thus in
association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets, and lozenges can be
used as solid dosage forms suitable for oral administration.
[0216] For preparing suppositories, a low melting wax such as a
mixture of fatty acid glycerides or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogeneous mixture is then poured into
convenient sized moulds, allowed to cool, and thereby to
solidify.
[0217] Liquid form preparations include solutions, suspensions and
emulsions, for example, water or water propylene glycol solutions.
For parenteral injection, liquid preparations can be formulated in
solution in aqueous polyethylene glycol solution.
[0218] Aqueous solutions suitable for oral use can be prepared by
dissolving the active component in water and adding suitable
colorants, flavours, stabilizing and thickening agents as
desired.
[0219] Aqueous suspensions suitable for oral use can be made by
dispersing the finely divided active component in water with
viscous material, such as natural or synthetic gums, resins,
methylcellulose sodium carboxymethylcellulose, and other well-known
suspending agents.
[0220] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. These preparations may contain, in
addition to the active component, colorants, flavours, stabilizers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilising agents and the like.
[0221] The pharmaceutical preparation is preferably in unit dosage
form. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, such as packeted tablets,
capsules, and powders in vials or ampoules. Also, the unit dosage
form can be a capsule, tablet, cachet or lozenge itself, or it can
be the appropriate number of any of these in packaged form.
[0222] The quantity of active component in a unit dose preparation
may be varied or adjusted from 0.1 mg to 200 mg, preferably 0.5 mg
to 100 mg according to the particular application and the potency
of the active component. The composition can, if desired, also
contain other compatible therapeutic agents.
[0223] In therapeutic use, the highly selective and competitive
antagonists of the NK.sub.1 receptor and compounds utilized in the
pharmaceutical method of this invention are administered at the
initial dosage of about 0.01 mg/kg to about 500 mg/kg daily. A
daily dose range of about 0.01 mg/kg to about 100 mg/kg is
preferred. The dosages, however, may be varied depending upon the
requirements of the patient, the severity of the condition being
treated and the compound being employed. Determination of the
proper dosage for a particular situation is within the skill of the
art. Generally, treatment is initiated with smaller doses, which
are less than the optimum dose of the compound. Thereafter, the
dosage is increased by small increments until the optimum effect
under the circumstances is reached. For convenience, the total
daily dosage may be divided and administered in portions during the
day, if desired.
[0224] The compounds of Formula I can be prepared by any several
synthetic processes well known to those skilled in the art of
organic chemistry. 8
[0225] In a typical synthesis, a carboxylic acid of the formula
[0226] is coupled to an amine of the formula 9
[0227] The coupling can be achieved by routine acylation, e.g. by
converting the acid to an acid halide, followed by reaction with
the amine, or by utilizing a common coupling reagent such as 1,3
-dicyclohexylcarbodiimide (DCC) or
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroq- uinoline (EEDQ). The
synthesis can be carried out on racemic reactants, to provide
invention compounds in racemic form, which can then be resolved by
conventional methods, if desired. Alternatively, the invention
compounds can be prepared in optically active form by using
enantiomeric reactants.
[0228] In a typical synthesis, an optically active acetic acid is
first prepared by conventional methods. Schemes 1-5 illustrate the
preparation of intermediates utilized in Examples 1-5, which
illustrate the synthesis of specific compounds of Formula I in
optically active form. Scheme 1 describes the synthesis of
intermediates I and II, which are required for Examples 1 to 5. The
N-terminal benzofuran moiety is introduced by the reductive
amination of either tryptophan methyl ester or
alpha-methyl-tryptophan methyl ester with
benzofuran-2-carboxaldehyde and sodium triacetoxy borohydride in
DCM. The methyl ester is then hydrolyzed to the corresponding
carboxylic acid with lithium hydroxide.
[0229] Scheme 2 describes the synthesis of intermediate III.
3-Acetyl-l-methyl pyrrole is converted to the corresponding oxime
by reaction with hydroxylamine sulfate and potassium hydroxide in
water/methanol. The oxime is then reduced on palladium on
carbon.
[0230] Scheme 3 shows the synthesis of intermediate IV. This
compound was prepared from (R)-2-phenylglycinol, which was first
N-terminal protected as the carbobenzoxy (CBZ) analogue. The
alcohol was then treated with triethylamine and methane
sulfonylchloride, followed by dimethylamine to introduce the
tertiary amine. Removal of the CBZ protection with hydrogen over
Pearlman's catalyst gave the required intermediate.
[0231] Scheme 4 describes the synthesis of Examples 1 to 4. Each
was prepared by activation of the acid, intermediate I, with HBTU
in the presence of DIPEA and then reacting with the required amine
in DMF.
[0232] The synthesis of Example 5 is outlined in scheme 5.
Intermediate I was activated with HBTU in DMF and then coupled with
methoxybenzylamine. The methyl ether was then reduced with boron
tribromide in DCM. 10 11 12 13 14
EXAMPLE 1
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-methyl-1-
-phenyl-ethyl)-propionamide, (R)
[0233] Step 1
[0234] Alpha methyl tryptophan methyl ester (26.8 g, 0.115 mol) and
benzofuran-2-carboxaldehyde (17.57 g, 0.115 mol) were dissolved in
DCM (400 mL) under an atmosphere of nitrogen and sodium
triacetoxyborohydride (34.12 g, 0.161 mol) was added portionwise
over 20 min at 0.degree. C. The mixture was stirred at room
temperature for 2 h and then quenched by the addition of sat.
NaHCO.sub.3 (500 mL). The organic layer was collected and the
aqueous layer was extracted three times with EtOAc. The organics
were combined, dried (MgSO.sub.4), filtered, and evaporated to
dryness. The residue was crystallized from ether/heptane to give
the product (34.13 g, 82%); IR (film): 3410, 2948, 1724, 1455,
1253, 1104, 742cm.sup.-1; NMR (CDCl.sub.3).delta.1.48 (3H, s); 3.18
(1H, d, J=14 Hz); 3.21 (1H, d, J=14 Hz); 3.53 (3H, s); 3.85 (1H, d,
J=Hz); 3.92 (1H, d, J=14 Hz); 6.55 (1H, s); 7.04-7.59 (9H, m); 8.07
(1H, s); MS; ES+ 363, ES- 361.
[0235] Step 2. Intermediate I
[0236] The methyl ester from step one (24.94 g, 68.8 mmol) was
dissolved in dioxan (800 mL) and aq. LiOH (8.66 g, 206 mmol in 400
mL) was added. The reaction mixture was stirred overnight at room
temperature and then heated to 60.degree. C. for 5 h. The mixture
was reduced in vacuo to a volume of approximately 200 ml. Water
(1200 mL) was added and the reaction was stirred vigorously while
it was neutralized with 1N HCl. Ether (1200 mL) was added and the
mixture was stirred for two h, the precipitate was filtered off,
washed with water, ether and dried to give a white solid; (24.5 g,
100%); NMR (Dmso-d.sub.6) 1.28 (3H, s); 3.05 (1H, d, J=14 Hz); 3.07
(1H, d, J=14 Hz); 3.33 (2H, br s); 3.87 (2H, s); 6.72 (1H, s);
6.97-7.07 (3H, m); 7.14 (1H, d, J=2 Hz); 7.18-7.33 (3H, m);
7.50-7.58 (3H, m); 10.89 (1H, s); MS; ES+ 349, ES- 347.
[0237] Step 3
[0238] Intermediate I (0.348 g, 1 mmol), HBTU (0.379 g, 1 mmol),
DIPEA (0.35 mL, 2 mmol) and cumylamine (0.20 g, 1.48 mmol) were
stirred in DMF (25 mL) for 18 h. The reaction mixture was
evaporated and the residue taken up in EtOAc and washed with 10%
Na.sub.2CO.sub.3, and brine. Drying and purification by column
chromatography using 20% EtOAc/Heptane gave a white solid (0.285 g,
61%). mp=57-62.degree. C.; NMR (CDCl.sub.3): .delta.1.40 (3H, s);
1.70 (6H, s); 1.92 (1H, b s); 3.17 and 3.22 (2H, 2.times.d,
J=14.4,14.6); 3.82 and 3.89 (2H, 2.times.d, J=14.6, 14.1); 6.46
(1H, s); 7.02-7.68 (15H, m); 8.10 (1H, s); IR (film): 3317, 2987,
1661, 1506, 1455 cm.sup.-1; [.alpha.].sub.D.sup.23=26.1.degree.
(c=1, MeOH); MS(ES.sup.+) 466 (M+1); Analysis calculated for
C.sub.30H.sub.31N.sub.3O.sub.2. 0.25H.sub.2O: C, 76.65; H, 6.75; N,
8.94%. Found: C, 76.73; H, 6.54; N, 8.80%.
EXAMPLE 2
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-[1-(1-methy-
l- 1H-pyrrol-3-yl)-ethyl]-propionamide, [R--(R*,R*)] and
[R--(R*,S*)]
[0239] 15
[0240] Step 1
[0241] 3-Acetyl-1-methyl pyrrole (2.00 g, 16.2 mmol) was dissolved
in MeOH (60 mL) and treated with potassium hydroxide (4.10 g, 73
mmol) in water (10 mL) and hydroxylamine sulfate (4.00 g, 24.3
mmol) in water (10 mL) and stirred for 18 h. The methanol was
removed in vacuo and the residue was diluted with water and
extracted with EtOAc. Drying (MgSO.sub.4) and evaporation gave an
off-white solid (1.82 g, 81%). (E:Z=9:1); NMR (CDCl.sub.3):
.delta.2.17 (3H, s); 3.65 (3H, s); 3.69 (3H, s); 6.39 (1H, m); 6.46
(1H, m); 6.56 (1H, m); 6.58 (1H, m); 6.85 (1H, m); 7.59 (1H, m);
8.10 (1H, bs); IR(film): 3240, 2916, 1644, 1554, 1422, 1257,
892cm.sup.-1;
[0242] Step 2 Intermediate III
[0243] The oxime from step one (0.25 g, 1.8 mmol) was dissolved in
methanol and 10% Palladium on carbon (50 mg) was added. The mixture
was shaken under an atmosphere of hydrogen at 35 psi and at
30.degree. C. for 5 h. Filtering through Kieselguhr and evaporation
gave a colorless oil (220 mg) which was a mixture of starting
material and product .about.1:1. The crude, intermediate III was
used in step 3.
[0244] Step 3
[0245] Intermediate I (0.348 g, 1 mmol), HBTU (0.379 g, 1 mmol),
DIPEA (0.35 mL, 2 mmol) and the amine (Intermediate III) (220 mg,
1.8 mmol) were stirred in DMF (13 mL) for 18 h. The reaction
mixture was evaporated and the residue taken up in EtOAc and washed
with 10%Na.sub.2CO.sub.3, and brine. Drying and purification by
column chromatography using 20% EtOAc/Heptane followed by reverse
phase chromatography using 50-100% MeOH/H.sub.2O gave a white solid
(0.205 g, 45%); mp=53-57.degree. C.; NMR (CDCL.sub.3): .delta.1.35
and 1.43 (3H, 2.times.d, J=6.6 and 6.6 Hz); 1.45 (obs H.sub.2O) and
1.5 (3H, 2.times.s); 1.89 (1H, bs); 3.21 and 3.22 (2H, 2.times.s,);
3.49 and 3.54 (3H, 2.times.s); 3.72-3.86 (2H, 2.times.AB,
J=14.4,14.4); 5.05 (1H, m); 6.00 (1H, m); 6.34-7.72 (13H, m); IR
(film): 3278, 2969, 1648, 1507, 1455 cm.sup.-1; MS(ES.sup.+):
455(M+H) Analysis calculated for C.sub.28H.sub.30N.sub.4O.sub.4; C,
73.98; H, 6.65; N,12.32%. Found: C, 73.69; H, 6.44; N, 12.12%.
EXAMPLE 3
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin--
4-yl-ethyl) -propionamide, [R--(R*,S*)]
[0246] 16
[0247] Intermediate I (0.174 g, 0.5 mmol), HBTU (0.190 g, 0.5
mmol), DIPEA (0.348 mL, 2 mmol) and the amine (prepared as
described in U.S. Pat. No. 5,594,022) (252 mg, 0.6 mmol) were
stirred in DMF (25 mL) for 18 h. The reaction mixture was
evaporated and the residue taken up in EtOAc and washed with
10%Na.sub.2CO.sub.3, and brine. Drying and purification by column
chromatography using 3%MeOH/DCM gave a white solid (0.14 g, 62%).
mp=66-69.degree. C.; NMR (CDCl.sub.3): .delta.1.44(3H,d, J=7.2 Hz);
1.50 (3H, s); 1.96 (1H, bs) 3.12 (1H, d, J=14.4 Hz) and 3.23 (1H,
d, J=14.4 Hz); 3.80 (1H, d, J=14.2 Hz) and 3.92(1H, d, J=14.2 Hz);
5.02 (1H, m); 6.48 (1H, s); 6.89-8.00 (12H, m); 8.03 (1H, s);
8.46(2H, m); IR (film) 3326, 2978, 1660, 1602, 1505, 1455
cm.sup.-1; MS(ES.sup.+) 453 (M+1);
[.alpha.].sub.D.sup.23=-29.0.degree. (c=0.39, MeOH); Analysis
calculated for C.sub.28H.sub.28N.sub.4O.sub.2. 0.2H.sub.2O: C,
73.73; H, 6.28; N, 12.28% Found: C, 73.76; H, 6.2; N, 12.08%.
EXAMPLE 4
2-[(Benzofuran-2-ylmethyl)-amino]-N-(2-dimethylamino-1-phenyl-ethyl)-3-(1H-
-indol-3-yl)-2-methyl-propionamide, (R,R)
[0248] 17
[0249] Step 1
[0250] To a solution of (R)-2-phenyl glycinol (2.11 g, 15 mmol) and
benzyl chloroformate (2.35 mL, 16.5 mmol) in THF (30 mL) at
0.degree. C. was added triethylamine (2.30 mL, 16.5 mmol) in THF (5
mL). After stirring for 18 h at room temperature, the mixture was
filtered and evaporated to a white solid which was purified by
column chromatography on silica using 50% EtOAc/heptane, giving a
white solid (4.00 g, 98%); NMR (CDCl.sub.3): .delta.3.88 (2H, m);
4.85 (1H, m); 5.10 (2H, m); 5.48 (1H, m); 7.23-7.40 (10H, m); IR
(film): 3324, 2950, 1687, 1540, 1259 cm.sup.-1;
[0251] Step 2
[0252] To a solution of the alcohol from step one (1.00 g, 3.68
mmol) and triethylamine (1.16 mL, 8 mmol) in THF (20mL) was added a
solution of methane sulphonylchloride (0.31 mL, 4.0 mmol) in THF (3
mL). The mixture was stirred for 1 h. 2M dimethylamine in THF
solution. (1 7 mL, 34 mmol) was added and the sealed mixture was
stirred for 12 days. Evaporation of the solvent and purification by
column chromatography using 2% MeOH/DCM gave a yellow oil (0.399 g,
36%); NMR (CDCl.sub.3): .delta.2.23 (6H, s); 2.35-2.58 (2H, m);
4.64 (1H, bs); 5.06 (2H, m); 5.77 (1H, bs); 7.20-7.40 (10 H, m); IR
(film): 3330, 2945, 1716, 1538, 1246, 1050 cm.sup.-1.
[0253] Step 3 Intermediate IV
[0254] The protected amine from step one (0.226 g, 0.75 mmol) was
dissolved in methanol (30 mL) and Pearlman's catalyst (30 mg) was
added. The mixture was shaken for 2 h at 50 psi and then filtered
through kieselguhr. Evaporation gave a yellow syrup (0.127 g,
100%); NMR (CDCl.sub.3): .delta.2.22-2.51 (8H, m); 4.07 (1H, m);
7.22-7.39 (5H, m).
[0255] Step 4
[0256] Intermediate I (0.174 g, 0.5 mmol), HBTU (0.19 g, 0.5 mmol),
DIPEA (0.174 mL, 1.0 mmol) and the amine (Intermediate IV) (0.12
mg, 0.73 mmol) were stirred in DMF (15 mL) for 18 h. The reaction
mixture was evaporated and the residue taken up in EtOAc and washed
with 10% Na.sub.2CO.sub.3, and brine. Drying and purification by
column chromatography using 1% MeOH/DCM and reverse phase
chromatography using 40-100% MeOH/H.sub.2O gave a white solid (0.10
g, 40%). mp=130-134.degree. C.; NMR (CDCl.sub.3) .delta.1.44 (3H,
s); 2.16 (6H, s); 2.41 (1H, dd, J=5.6, 12.4 Hz) and 2.59 (1H, dd,
H=10.0, 12.4); 3.17 (2H, s); 3.86 (1H, d, 14.4 Hz) and 3.92 (1H, d,
J=14.6 Hz); 4.95 (1H, m); 6.55 (1H, s); 6.90 (1H, s); 7.09-7.67
(13H, m); 8.01 (1H, s); 8.18, d, J=6.6 Hz); IR (film) 3317, 2934,
1658, 1496, 1455 cm.sup.-1; MS(ES.sup.+) 482 (M+1);
[.alpha.].sub.D.sup.23=31.9 (c=0.72, MeOH); Analysis calculated for
C.sub.31H.sub.34N.sub.4O.sub.2: C, 75.28; H, 6.93; N, 11.33% Found:
C, 75.24; H, 6.92; N, 11.15%.
EXAMPLE 5
2-[(Benzofuran-2-ylmethyl)-amino]-N-(3-hydroxy-benzyl)-3-(1H-indol-3-yl)-2-
-methyl-propionamide, R
[0257] 18
[0258] Step 1
[0259] Intermediate I (0.348 g, 1 mmol), HBTU (0.379 g, 1 mmol),
DIPEA (0.35 mL, 2 mmol) and 3-methoxybenzylamine (0.206 g, 1.5
mmol) were stirred in DMF (17 mL) for 18 h. The reaction mixture
was evaporated and the residue taken up in EtOAc and washed with
10%Na.sub.2CO.sub.3, and brine. Drying and purification by column
chromatography using 40% EtOAc/Heptane gave a white solid (0.190 g;
41%). mp=42-47.degree. C.; NMR (CDCl.sub.3): .delta.1.50 (3H, s);
1.90 (1H, bs); 3.20 (1H, d, J=14.4 Hz) and 3.28 (1H, d, J=14.4 Hz);
3.72-3.82 (4H, m); 3.88 (1H, d, J=14.0 Hz); 4.37 (2H, d, J=6.0 Hz);
6.37 (1H, s); 6.75-7.70 (14H, m); 8.12 (1H, s); IR (film): 3322,
2920, 1654, 1602, 1455, 1256 cm.sup.-1; MS(ES.sup.+) 468 (M+1);
[.alpha.].sub.D.sup.23.5=-31.3.degree. (c=1.01, MeOH); Analysis
calculated for C.sub.29H.sub.29N.sub.3O.sub.3: C, 74.50; H, 6.25;
N, 8.99%; Found: C, 74.20; H, 6.24; N, 8.78%
[0260] Step 2
[0261] 1.0M Boron tribromide in dichloromethane (0.62 mL; 0.62
mmol) was added dropwise to a solution of the methoxy compound from
step one (0.146 g; 0.31 mmol) in dichloromethane at -70.degree. C.
under N.sub.2, warmed slowly to room temperature and stirred for 18
h. The mixture was poured onto 10 g crushed ice/2M HCl (15 mL) and
stirred for 10 min. Neutralizing with Na.sub.2CO.sub.3, extraction
with EtOAc and purification by column chromatography using 40%
EtOAc/heptane gave a white solid (0.115 g; 82%). mp=60-69.degree.
C.; NMR (CDCl.sub.3): .delta.1.53 (3H, s); 1.96 (1H, bs); 3.14 (1H,
d, J=14.4 Hz) and 3.37 (1H, d, J=14.4 Hz); 3.81 (1H, d, J=14.0 Hz)
and 3.93 (1H, d, J=14.0 Hz); 4.14-4.50 (2H, m); 5.23 (1H, bs);
6.32-7.82 (15H, m); 8.14 (1H, s); IR (film): 3333, 2907, 1645,
1599, 1520, 1455, 1254 cm.sup.-1; MS(ES.sup.+): 454 (M+1);
[.alpha.].sub.D.sup.23.5=-25.9.degree. (c=0.73, MeOH); Analysis
calculated for C.sub.28H.sub.27N.sub.3O.sub.3. 0.5 H.sub.2O: C,
72.71; H, 6.10; N, 9.08% Found: C, 72.83, 72.86; H, 6.03, 5.96; N,
8.81, 8.83%.
[0262] Scheme 6 describes the synthesis of intermediate V, which is
required for Examples 6to 17.
[0263] Boc-tryptophan was coupled to alpha-methylbenzylamine using
HBTU activation. The Boc group was removed using formic acid in DCM
to give Intermediate V.
[0264] Examples 6, 8 and 10 to 21 were prepared by a reductive
amination of the relative aldehydes and Intermediate V with sodium
triacetoxyborohydride as shown in scheme 7.
[0265] Scheme 8 outlines the synthesis of Example 7.
2-Benzofuranacetic acid was reacted with ethyl chloroformate in THF
and then reduced with lithium borohydride. The alcohol was then
converted to the corresponding mesylate and reacted with
Intermediate V to give Example7.
[0266] Scheme 9 describes the synthesis of Example 9.
2-Hydroxymethyl benzimidazole was reacted with
bis(4-nitrophenyl)carbonate in DMF to form the cyclic carbamate.
This compound was then reacted with intermediate V to give Example
9.
[0267] The synthesis of Intermediate VI is shown in scheme 10; the
intermediate was used to prepare Example 10.
Benzo[b]thiophene-2-carboxyl- ic acid was activated with ethyl
chloroformate and then coupled with N,O-dimethylhydroxylamine. The
Weinreb amide was then reduced to the corresponding aldehyde with
DIBAL.
[0268] The synthesis of Example 22 is described in scheme 11.
2-benzofurancarboxaldehyde was reacted with hydroxylamine in
aqueous potassium hydroxide/EtOH. The oxime was then reduced with
lithium aluminum hydride to give the amine. The corresponding
isocyanate, prepared by reacting the amine with triphosgene in
DCM/pyridine, was reacted with
2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propio-
namide to give Example 22.
[0269] Scheme 12 shows the synthesis of the key intermediate VII
that was used in the synthesis of Examples 192 to 308. This
N-carboxyanhydride was prepared by reacting intermediate I with
phosgene in toluene. 19 20
2 Example R.sup.1 R.sup.2 6 H 2-Benzofuran-CH.sub.2 8 H
2-(4,5-Dimethylfuran)-CH.sub.2 10 H 2-Benzothiophene-CH.sub.2 11 H
3-quinoline-CH.sub.2 12 H 2-(5-Cl-thiophene)-CH.sub.2 13 H
(3-SCF.sub.3--Ph)--CH.sub.2 14 H (3-CN--Ph)--CH.sub.2 15 H
(3-NO.sub.2--Ph)--CH.sub.2 16 H (3-OCF.sub.3--Ph)--CH.sub.2 17 H
(3-OH--Ph)--CH.sub.2 18 CH.sub.3 2-Benzofuran-CH.sub.2 19 CH.sub.3
3-Benzofuran-CH.sub.2 20 CH.sub.3 2-pyrrole-CH.sub.2 21 CH.sub.3
3-pyrazole-CH.sub.2
[0270] 21 22 23 24 25
EXAMPLE 6
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-pro-
pionamide, [R--(R*,S*)]
[0271] 26
[0272] Step 1. Intermediate V
[0273] To a stirred solution of Boc-(R)-Trp-OH (6.08 g, 0.02mol) in
DMF (50 mL) was added HBTU (7.59, 0.02 mol) and DIPEA (3.57 mL,
0.02 mol). After 5 min DIPEA (3.57 mL, 0.02 mol) and
(S)-(-)-.alpha.-methylbenzylami- ne in DMF (10 mL) was added. After
a further 60 min, the solvent was removed under reduced pressure.
The residue was taken up in EtOAc (250 mL) and washed with brine
(50 mL), 1N HCl (100 mL), saturated NaHCO.sub.3 (3.times.100 mL),
brine (50 mL), dried (MgSO.sub.4), filtered and the solvent was
removed under reduced pressure. The residue was dissolved in
CH.sub.2Cl.sub.2 (20 mL) and formic acid (30 mL). The reaction was
stirred over night at room temperature before refluxing for 4 h.
The solvent was removed under reduced pressure and the product was
crystallized from ether. Stirring in EtOAc (100 mL) for 4 h and
filtration gave pure product (4.17 g, 68%). The filtrate was
purified by chromatography using EtOAc and then
EtOAc/MeOH/NH.sub.3(aq) (95:5:0.5) as eluent. Crystallization from
ether gave white crystalline solid (0.98 g , 16%); mp
142-144.degree. C.; [.alpha..sub.D.sup.19=-83.9.degree. (c=1,
MeOH); IR (film): 3338, 3295, 3059, 2975, 2928, 1649, 1518, 1494,
1455, 1342, 1104, 894, 740 cm.sup.-1; NMR (CDCl.sub.3): .delta.1.44
(3H, d, J=7.1 Hz); 1.51 (2H, s); 2.95 (1H, d.d, J=14.4 and 8.5 Hz);
3.36 (1H, d,d, J=14.4 and 4.4 Hz); 3.74 (1H, d.d, J=8.5 and 4.4
Hz); 5.05-5.15 (1H, m); 6.95 (1H, d, J=2.2 Hz); 7.10-7.38 (8H, m);
7.48-7.52 (1H, m); 7.66-7.69 (1H, m); 7.98 (1H, s); MS m/e
(APCI.sup.+): 309.1 (20%), 308.1 (100%, M.sup.++H); Analysis
calculated for C.sub.19H.sub.21N.sub.3O: C, 74.24; H, 6.89; N,
13.66%. Found: C, 74.07; H, 6.87; N, 13.70%.
[0274] Step 2
[0275] To a stirred solution of 2-benzofurancarboxaldehyde (0.73 g,
5 mmol) in 1,2-dichloroethane (20 mL) was added intermediate V
(1.54 g, 5 mmol) followed by sodium triacetoxyborohydride (1.48 g,
7 mmol). After stirring for 3 h the reaction was cautiously
quenched with saturated NaHCO.sub.3 (20 mL) and extracted with
CH.sub.2Cl.sub.2 (3.times.50 mL). The combined organic phases were
dried (MgSO.sub.4) and the solvent was removed under reduced
pressure. The residue was purified by chromatography using 30%
EtOAc in heptane as eluent to give pure product as a glass (2.0 g,
91%); [.alpha..sub.D].sup.20=+34.0.degree. (c=0.5, MeOH); IR
(film): 3316, 3059, 2973, 2925, 1653, 1517, 1455, 1341, 1254, 1104,
1010, 909, 741 cm.sup.-1; NMR (CDCl.sub.3): .delta.1.38 (3H, d,
J=7.1 Hz); 1.93 (1H, s); 2.92 (1H, d.d, J=14.6 and 9.3 Hz);
3.29-3.35 (1H, m); 3.58 (1H, d.d, J=9.3 and 4.2 Hz); 3.75 (1H, d,
J=14.9 Hz); 3.82 (1H, d, J=14.9 Hz); 5.07-5.15 (1H, m); 6.36 (1H,
s); 6.87 (1H, d, J=2.2 Hz); 7.04-7.08 (1H, m); 7.15-7.35 (10H, m);
7.43-7.45 (1H, m); 7.58-7.64 (2H, m); 7.92 (1H, s); MS m/e
(APCI.sup.+): 439.9 (5%), 438.9 (34%), 437.9 (100%, M.sup.++H),
307.0 (9%); Analysis calculated for C.sub.28H.sub.27N.sub.3O.sub.2:
C, 76.86; H, 6.22; N, 9.60%. Found: C, 77.11; H, 6.31; N,
9.67%.
EXAMPLE 7
2-(2-Benzofuran-2-yl-ethylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-prop-
ionamide, [R--(R*,S*)]
[0276] 27
[0277] Step 1
[0278] A solution of N-methylmorpholine (NMM, 5.31 g, 52.5 mmol) in
THF (30 mL) was added dropwise over 15 min to a stirred solution of
2-benzofuranacetic acid (8.80 g, 50 mmol) and ethyl chloroformate
(5.70 g, 52.5 mmol) in THF (150 mL, anhydrous) at 0.degree. C. The
reaction mixture was stirred for 1 h at room temperature before
filtering off the precipitate of NMM.HCl. The filtrate was cooled
to 0.degree. C. and a solution of lithium borohydride (30 mL, 60
mmol, 2M in THF) was added dropwise over 30 min. The reaction was
allowed to reach room temperature and stirred over night before
being cautiously quenched with 1N HCl (100 mL)--vigorous
effervescence. The THF was removed under reduced pressure and the
aqueous phase was extracted with EtOAc (200 mL). The organic phase
was washed with 1N HCl, H.sub.2O, saturated NaHCO.sub.3 (.times.2),
brine, and dried (MgSO.sub.4). Removal of solvent under reduced
pressure gave intermediate VI (7.74 g, 93%). Used in the next step
without further purification. IR (film): 3347, 2957, 2887, 1603,
1587, 1455, 1422, 1317, 1252, 1167, 1105, 1049, 945, 926, 881, 854,
807, 751 cm.sup.-1; NMR (CDCl.sub.3): .delta.1.64 (1H, t, J=6.0
Hz); 3.05 (2H, t, J=6.2 Hz); 4.00 (2H, q, J=6.1 Hz); 6.51 (1H, d,
J=1.0 Hz); 7.17-7.25 (2H, m); 7.41-7.44 (1H, m); 7.49-7.52 (1H,
m).
[0279] Step 2
[0280] To an ice-cold solution of alcohol VI (1.62 g, 10 mmol) and
NEt.sub.3 (1.01 g, 10 mmol) in ether (50 mL, anhydrous) was added a
solution of methanesulphonyl chloride (1.20 g, 10.5 mmol) dropwise
over 5 min. The ice bath was removed and the reaction was stirred
at room temperature for 30 min before filtering off the
NEt.sub.3.HCl. The ether was removed under reduced pressure. To a
portion of the mesylate (240 mg, 1 mmol) dissolved in toluene (50
mL, anhydrous) was added amine V. The reaction was refluxed for 48
h, a further equivalent of NEt.sub.3 was added, and reflux was
continued for a further 48 h. The reaction mixture was cooled and
washed with 1N NaOH, the organic layer was dried (MgSO.sub.4), and
solvent removed under reduced pressure. The residue was purified by
chromatography on normal phase silica using 20% EtOAc in heptane as
eluent and then on reverse phase silica using 70% MeOH in H.sub.2O
as elan. Product crystallized on drying in vacuum oven to give pure
product (82 mg, 18%); mp 105-107.degree. C.;
[.alpha.].sub.D.sup.22=- -1.2.degree. (c=0.25, MeOH); IR (film):
3305, 3058, 2924, 2851, 1651, 1515, 1455, 1356, 1342, 1252, 1166,
1105,742 cm.sup.-1;NMR (CDCl.sub.3): .delta.1.37 (3H, d, J=7.1 Hz);
1.57 (1H, s); 2.72-2.97 (5H, m); 3.28-3.34 (1H, m); 3.44-3.48 (1H,
m); 5.07-5.15 (1H, m); 6.06 (1H, s); 6.75 (1H, d, J=2.2 Hz);
7.06-7.33 (11H, m); 7.40-7.44 (1H, m); 7.51 (1H, d, J=8.5 Hz);
7.62-7.65 (2H, m); MS m/e (ES.sup.+): 453.1 (33%), 452.2 (100%,
M.sup.++H); Analysis calculated for C.sub.29H.sub.29N.sub.3O.sub.2:
C, 77.14; H, 6.47; N, 9.31%. Found: C, 77.06; H, 6.48; N,
9.30%.
EXAMPLE 8
2-[(4,5-Dimethyl-furan-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-et-
hyl)-propionamide, [R--(R*,S*)]
[0281] 28
[0282] To a stirred solution of the 4,5-dimethyl-2-furaldehyde (124
mg, 1 mmol) in 1,2-dichloroethane (20 mL) was added intermediate V
(307 mg, 1 mmol) followed by sodium triacetoxyborohydride (424 mg,
2 mmol). After stirring over night the reaction was cautiously
quenched with saturated NaHCO.sub.3 (20 mL) and extracted with
CH.sub.2Cl.sub.2 (2.times.20 mL). The combined organic phases were
dried (MgSO.sub.4) and the solvent was removed under reduced
pressure. The residue was purified by chromatography on normal
phase silica using 25% EtOAc in heptane as eluent to give pure
product as a glass (196 mg, 47%);
[.alpha.].sub.D.sup.21=+18.6.degree. (c=0.5, MeOH); IR (film):
3312, 3059, 2971, 2922, 1651, 1516, 1455, 1342, 1220, 1106, 741
cm.sup.-1; NMR (CDCl.sub.3): .delta.1.44 (3H, d, J=6.8 Hz);
1.60-1.90 (1H, br.s); 1.83 and 2.06 (each 3H, s); 2.89 (1H, d,d,
J=14.6 and 9.3 Hz); 3.26-3.32 (1H, m); 3.49 (1H, d, J=14.4 Hz);
3.50-3.54 (1H, m); 3.58(1H, d, J=14.4 Hz); 5.08-5.16 (1H, m); 5.76
(1H, s); 6.89 (1H, d, J=2.2 Hz); 7.01-7.11 (1H, m); 7.17-7.36 (7H,
m); 7.62-7.65 (2H, m); 7.95 (1H, s); MS m/e (ES.sup.+): 417.3
(31%), 416.3 (100%, M.sup.++H), 308.3 (34%); Analysis calculated
for C.sub.26H.sub.29N.sub.3O.sub.2.0.2H.sub.2O: C, 74.51; H, 7.07;
N, 10.03%. Found: C, 74.43; H, 6.82; N, 10.03%.
EXAMPLE 9
2-[(1H-Benzoimidazol-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethy-
l)-propionamide, [R--(R*,S*)]
[0283] 29
[0284] Step 1
[0285] A solution of 2-hydroxymethyl benzimidazole (1.19 g, 8 mmol)
and bis(4-nitrophenyl)carbonate (2.43 g, 8 mmol) in DMF (20 mL,
anhydrous) was stirred for 12 h at room temperature. The DMF was
removed under reduced pressure and the residue stirred in ether (50
mL) for 2 h. Filtration and washing with ether (50 mL) gave
crystalline intermediate VII (1.04 g, 74%); IR (film): 1819, 1623,
1592, 1568, 1486, 1445, 1411, 1369, 1359, 1147, 1106, 1076, 1009,
997, 941, 862, 847, 765, 750, 741 cm.sup.-1; NMR (CDCl.sub.3):
.delta.5.49 (2H, s); 7.42-7.50 (2H, m); 7.79-7.84 (1H, m);
7.88-7.93 (1H, m).
[0286] Step 2
[0287] The product from step 1 (174 mg, 1 mmol) and intermediate V
(307 mg, 1 mmol) were dissolved in DMF (10 mL, anhydrous) and
stirred at 60.degree. C. for 10 h. The solvent was removed under
reduced pressure and the residue was purified by chromatography on
reverse phase silica using 60% MeOH in H.sub.2O as eluent. The
solvent was removed under reduced pressure and the residue was
crystallized from EtOAc to give pure product (396 mg, 91%); mp
148-152.5.degree. C.; [.alpha.].sub.D.sup.21=+2- 4.2.degree.
(c=0.5, MeOH); IR (film): 3300, 3058, 2923, 1651, 1520, 1455, 1340,
1271, 1235, 1218, 1109, 1013, 909, 739 cm.sup.-1; NMR (CDCl.sub.3):
.delta.1.31 (3H, d, J=7.1 Hz); 2.00-2.50 (1H, br.s); 3.04 (1H, d.d,
J=14.4 and 8.8 Hz); 3.29 (1H, d.d, J=14.4 and 5.2 Hz); 3.50 (1H,
d.d, J=8.8 and 5.2 Hz); 3.94 (1H, d, J=15.9 Hz); 4.04 (1H, d,
J=15.9 Hz); 5.03-5.10 (1H, m); 6.85 (1H, d, J=7.8 Hz); 6.99 (1H, d,
J=2.2 Hz); 7.10-7.30 (10H, m); 7.20-7.70 (1H, br.s); 7.42 (1H, d,
J=8.1 Hz); 7.66 (1H, d, J=7.8 Hz); 8.06 (1H, s); 8.80-9.20 (1H,
br.s); MS m/e (ES.sup.+): 439.3 (28%), 438.3 (100%, M.sup.++H);
Analysis calculated for C.sub.27H.sub.27N.sub.5O: C, 74.12; H,
6.22; N, 16.01%. Found: C, 74.04; H, 6.19; N, 15.95%.
EXAMPLE 10
2-[(Benzo[b]thiophen-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethy-
l)-propionamide
[0288] 30
[0289] Step 1
[0290] A solution of NMM (2.309 mL, 21 mmol) in THF (10 mL) was
added dropwise to a stirred ice cooled solution of
benzo[b]thiophene-2-carboxyl- ic acid (3.56 g, 20 mmol) and ethyl
chloroformate (2.008 mL, 21 mmol) in THF (150 mL) over 15 mins. The
reaction mixture was stirred at room temperature for 1 h before
adding N,O-dimethylhydroxylamine hydrochloride (2.146 g, 22 mmol)
and NMM (2.419 mL, 22 mmol). The reaction was stirred at room
temperature over night. The solvent was removed under reduced
pressure. The residue was taken up in EtOAc (100 mL) and washed
with 2N HCl (3.times.100 mL), 2N NaOH (100 mL), H.sub.2O, brine,
dried (MgSO.sub.4), and the solvent was removed under reduced
pressure. The residue was purified by chromatography on normal
phase silica using 30% EtOAc in heptane as eluent. Crystallization
from ether/heptane gave pure product (3.24 g, 73%).
[0291] To a stirred solution of the Weinreb amide (2.06 g, 9.3
mmol) in THF (100 mL, anhydrous) under nitrogen at 0.degree. C. was
added diisobutylaluminum hydride (11 mL, 11 mmol, 1M in
CH.sub.2Cl.sub.2) dropwise. After 20 min the reaction mixture was
poured onto ice cold 2N HCl and extracted with ether. The organic
phase was washed with brine, dried (MgSO.sub.4), and the solvent
was removed under reduced pressure. The residue was purified by
chromatography on normal phase silica using 5% EtOAc in heptane as
eluent to give solid benzo[b]thiophene-2-carboxald- ehyde
(Intermediate VI) (665 mg, 44%). IR (film): 1669, 1592, 1516, 1431,
1255, 1224, 1135, 840, 747, 725 cm.sup.-1; NMR (CDCl.sub.3):
.delta.7.42-7.54 (2H, m); 7.91 (1H, d, J=8.1 Hz); 7.95(1H, d, J=7.8
Hz); 8.04 (1H, s); 10.12 (1H, s).
[0292] Step 2
[0293] To a stirred solution of the
benzo[b]thiophene-2-carboxaldehyde (Intermediate VI) (162 mg, 1
mmol) in 1,2-dichloroethane (20 mL) was added intermediate V (307
mg, 1 mmol) followed by sodium triacetoxyborohydride (424 mg, 2
mmol). After stirring over night the reaction was cautiously
quenched with saturated NaHCO.sub.3 (20 mL) and extracted with
CH.sub.2Cl.sub.2 (2.times.20 mL).
[0294] The combined organic phases were dried (MgSO.sub.4) and the
solvent was removed under reduced pressure. The residue was
purified by chromatography on normal phase silica using 20% EtOAc
in heptane as eluent. Crystallization from ether/heptane gave pure
product (305 mg, 67%); mp 102-108.degree. C.;
[.alpha.].sub.D.sup.21=+51.4.degree. (c=0.5, MeOH); IR (film):
3311, 3059, 2925, 1651, 1515, 1456, 743 cm.sup.-1; NMR
(CDCl.sub.3): .delta.1.40 (3H, d, J=7.1 Hz); 1.97 (1H, s); 2.99
(1H, d.d, J=14.7 and 8.8 Hz); 3.35 (1H, d.d, J=14.4 and 4.2 Hz);
3.59 (1H, d.d, J=8.5 and 4.4 Hz); 3.94 (2H, m); 5.07-5.16 (1H, m);
6.91-6.93 (2H, m); 7.06-7.11 (1H, m); 7.17-7.37 (9H, m); 7.50 (1H,
d, J=8.5 Hz); 7.60 (1H, d.d, J=7.0 and 1.6 Hz); 7.65 (1H, d, J=8.1
Hz); 7.72-7.76 (1H, m); 7.95 (1H, s); MS m/e (ES.sup.+): 476.1
(60%, M.sup.++Na), 454.1 (100%, M.sup.++H), 402.2 (25%);
(ES.sup.-): 453.2 (25%), 452.1 (100%, M.sup.--H); Analysis
calculated for C.sub.28H.sub.27N.sub.3OS: C, 74.14; H, 6.00; N,
9.26; S, 7.07%. Found: C, 74.27; H, 6.16; N, 9.31; S, 7.11%.
EXAMPLE 11
3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-[(quinolin-3-ylmethyl)-amino]-propi-
onamide, [R--(R*,S*)]
[0295] 31
[0296] Method as for Example 10, step 2. The residue was purified
by chromatography on normal phase silica using 2% MeOH in
CH.sub.2Cl.sub.2 as eluent. Crystallization from EtOAc/heptane gave
pure product (340 mg, 76%); mp 161-163.degree. C.;
[.alpha.].sub.D.sup.22=+40.degree. (c=0.5, MeOH); IR (film): 3280,
3055, 2972, 2926, 1655, 1515, 1497, 1456, 1342, 1127, 742 cm.sup.-;
NMR (CDCl.sub.3): .delta.1.40 (3H, d, J=7.1 Hz); 1.90 (1H, s); 2.96
(1H, d.d, J=14.7 and 9.0 Hz); 3.36 (1H, d.d, J=14.5 and 4.5 Hz);
3.53-3.56 (1H, m); 3.78 (1H, d, J=13.7 Hz); 3.92 (1H, d, J=13.7
Hz); 5.08-5.16 (1H, m); 6.90 (1H, d, J=2.2 Hz); 7.03-7.08 (1H, m);
7.15-7.20 (1H, m); 7.23-7.37 (6H, m); 7.43 (1H,d J=8.3 Hz);
7.49-7.51 (1H, m); 7.59-7.72 (4H, m); 8.02 (1H, s); 8.04 (1H, d,
J=8.3 Hz); 8.66 (1H, d, J=2.2 Hz); MS m/e (ES.sup.+): 471.1 (31%,
M.sup.++Na), 449.1 (100%, M.sup.++H); Analysis calculated for
C.sub.29H.sub.28N.sub.4O: C, 77.65; H, 6.29; N, 12.49%. Found: C,
78.02; H, 6.30; N, 12.48%.
EXAMPLE 12
2-[(5-Chloro-thiophen-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-eth-
yl)-propionamide, [R--(R*,S*)]
[0297] 32
[0298] Method as for Example 10, step 2. The residue was dissolved
in aqueous acetonitrile and acidified using formic acid before
being purified by chromatography on reverse phase silica using 40%
CH.sub.3CN in H.sub.2O (0.1% formic acid in mobile phases) as
eluent. The solvent was removed under reduced pressure and the
residue was suspended between EtOAc and saturated NaHCO.sub.3. The
EtOAc was dried (MgSO.sub.4) and the solvent was removed under
reduced pressure to give pure product as a glass (245 mg, 56%);
[.alpha.].sub.D.sup.22=+26.2.degree. (c=0.5, MeOH); IR (film):
3307, 3059, 2973, 2925, 1652, 1515, 1455, 1342, 1230, 1105, 1061,
1000, 796, 742 cm.sup.-1; NMR (CDCl.sub.3): .delta.1.43 (3H, d,
J=6.8 Hz); 1.85 (1H, s); 2.96 (1H, d.d, J=14.7 and 8.5 Hz); 3.31
(1H, d.d, J=14.5 and 4.5 Hz); 3.49-3.53 (1H, m); 3.71-3.79 (2H, m);
5.07-5.15 (1H, m); 6.50 (1H, d, J=3.7 Hz); 6.65 (1H, d, J=3.9 Hz);
6.91 (1H, d, J=2.4 Hz); 7.09-7.14 (1H, m); 7.18-7.39 (8H, m); 7.63
(1H, d, J=7.6 Hz); 7.98 (1H, s); MS m/e (ES.sup.+): 437.9 (100%,
M.sup.++H); Analysis calculated for C.sub.24H.sub.24N.sub.3OSCl: C,
65.81; H, 5.52; N, 9.59; Cl, 8.09; S, 7.32%. Found: C, 65.54; H,
5.45; N, 9.40; Cl, 7.85; S, 7.42%.
EXAMPLE 13
3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-trifluoromethylsulfanyl-benzylam-
ino)-propionamide, [R--(R*,S*)]
[0299] 33
[0300] To a stirred solution of 3-(trifluoromethylthio)benzaldehyde
(72 mg, 0.55 mmol) in 1,2-dichloroethane (20 mL) was added
intermediate V (154 mg, 0.5 mmol) followed by sodium
triacetoxyborohydride (148 mg, 0.7 mmol). After stirring over night
the reaction was cautiously quenched with saturated NaHCO.sub.3 (20
mL) and extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The
combined organic phases were dried (MgSO.sub.4) and the solvent was
removed under reduced pressure. The residue was purified by
chromatography on normal phase silica using 30% EtOAc in heptane as
eluent. The solvent was removed under reduced pressure to give pure
product as a glass (193 mg, 77%); IR (film): 3306, 3058, 2972,
2923, 1651, 1516, 1456, 1342, 1114, 743 cm.sup.-1; NMR
(CDCl.sub.3): .delta.1.41 (3H, d, J=6.8 Hz); 1.60-1.90 (1H, br.s);
2.96 (1H, d.d, J=14.5 and 8.9 Hz); 3.32 (1H, d.d, J=14.4 and 4.4
Hz); 3.48 (1H, d.d, J=8.9 and 4.5 Hz); 3.62 (1H, d, J=13.9 Hz);
3.76 (1H, d, J=13.7 Hz); 5.08-5.16 (1H, m); 6.91 (1H, d, J=2.2 Hz);
7.07-7.48 (13H, m); 7.60 (1H, d, J=7.8 Hz); 7.97 (1H, s); MS m/e
(ES.sup.+): 499.4 (32%), 498.4 (100%, M.sup.++H); Analysis
calculated for C.sub.27H.sub.26N.sub.3OSF.sub.3.0.25- H.sub.2O: C,
64.59; H, 5.32; N, 8.37; S, 6.39%. Found: C, 64.69; H, 5.34; N,
8.30; S, 6.27%.
EXAMPLE 14
2-(3-Cyano-benzylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide,
[R--(R*,S*)]
[0301] 34
[0302] Method as for Example 13. Chromatography on normal phase
silica using 45% EtOAc in heptane as the eluent and subsequent
removal of the solvent under reduced pressure gave pure product as
a glass (130 mg, 62%); IR (film): 3312, 3059, 2973, 2924, 2229,
1652, 1516, 1456, 1342, 1231, 1101, 743 cm.sup.-1; NMR
(CDCl.sub.3): .delta.1.42 (3H, d, J=6.8 Hz); 1.87 (1H, s); 2.91
(1H, d.d, J=14.5 and 9.2 Hz); 3.32 (1H, d.d, J=14.5 and 4.0 Hz);
3.41 (1H, d.d, J=9.0 and 4.4 Hz); 3.58 (1H, d, J=14.2 Hz); 3.76
(1H, d, J=14.2 Hz); 5.08-5.17 (1H, m); 6.94 (1H, d, J=2.2 Hz);
7.07-7.12 (1H, m); 7.19-7.45 (12H, m); 7.58 (1H, d, J=8.1 Hz); 8.05
(1H, s); MS m/e (ES.sup.+): 424.4 (30%), 423.4 (100%, M.sup.++H);
(ES.sup.-): 422.3 (30%, M.sup.-), 421.3 (100%, M.sup.--H); Analysis
calculated for C.sub.27H.sub.26N.sub.4O: C, 76.75; H, 6.20; N,
13.26%. Found: C, 76.58; H, 6.14; N, 13.24%.
EXAMPLE 15
3-(1H-Indol-3-yl)-2-(3-nitro-benzylamino)-N-(1-phenyl-ethyl)-propionamide,
[R--(R*,S*)]
[0303] 35
[0304] To a stirred solution of 3-nitrobenzaldehyde (332 g, 2.2
mmol) in 1,2-dichloroethane (60 mL) was added intermediate V (614
mg, 2 mmol) followed by sodium triacetoxyborohydride (594 mg, 2.8
mmol). After stirring over night the reaction was cautiously
quenched with saturated NaHCO.sub.3 (20 mL) and extracted with
CH.sub.2Cl.sub.2 (3.times.50 mL). The combined organic phases were
dried (MgSO.sub.4) and the solvent was removed under reduced
pressure. The residue was purified by chromatography on normal
phase silica using 45% EtOAc in heptane as eluent. The solvent was
removed under reduced pressure to give pure product as a glass (648
mg, 73%); IR (film): 3317, 2925, 1652, 1526, 1456, 1349, 733
cm.sup.-1;NMR (CDCl.sub.3): .delta.1.43 (3H, d, J=6.8 Hz);
1.85-1.95 (1H, br.s); 2.90 (1H, d.d, J=14.5 and 9.1 Hz); 3.33 (1H,
d.d, J=14.4 and 4.4 Hz); 3.43 (1H, d.d, J=9.0 and 4.5 Hz); 3.65
(1H, d, J=14.2 Hz); 3.83 (1H, d, J=14.2 Hz); 5.09-5.17 (1H, m);
6.94 (1H, d, J=2.4 Hz); 7.06 (1H, t, J=7.5 Hz); 7.18 (1H, t, J=7.5
Hz); 7.22-7.40 (10H, m); 7.87 (1H, m); 7.97-8.10 (2H, m); MS m/e
(ES.sup.+): 444.4 (30%), 443.4 (100%, M.sup.++H); Analysis
calculated for C.sub.26H.sub.26N.sub.4O.sub.3: C, 70.57; H, 5.92;
N, 12.66%. Found: C, 70.55; H, 5.88; N, 12.67%.
EXAMPLE 16
3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-trifluoromethoxy-benzylamino)-pr-
opionamide, [R--(R*,S*)]
[0305] 36
[0306] Method as for Example 13. Chromatography on normal phase
silica using 35% EtOAc in heptane as the eluent and subsequent
removal of the solvent under reduced pressure gave pure product as
a glass (130 mg, 54%); IR (film): 3307, 3060, 2974, 2925, 1652,
1589, 1516, 1495, 1456, 1260, 1217, 1164, 1012, 743 cm.sup.-1; NMR
(CDCl.sub.3): .delta.1.40 (3H, d, J=6.8 Hz); 1.60-2.00 (1H, br.s);
2.97 (1H, d.d, J=14.7 and 8.8 Hz); 3.29-3.35 (1H, m); 3.48 (1H,
d.d, J=8.8 and 4.6 Hz); 3.62 (1H, d, J=13.9 Hz); 3.74 (1H, d,
J=13.9 Hz); 5.07-5.15 (1H, m); 6.91 (1H, d, J=2.2 Hz); 6.96-7.39
(13H, m); 7.63 (1H, d, J=7.8 Hz); 7.97 (1H, m); MS m/e (ES.sup.+):
483.4 (30%), 482.4 (100%, M.sup.++H); Analysis calculated for
C.sub.27H.sub.26N.sub.3O.sub.2F.sub.3: C, 67.35; H, 5.44; N, 8.73%.
Found: C, 67.31; H, 5.43; N, 8.67%.
EXAMPLE 17
2-(3-Hydroxy-benzylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamid-
e, [R--(R*,S*)]
[0307] 37
[0308] Method as for Example 13. Chromatography on normal phase
silica using 40% EtOAc in heptane as the eluent and subsequent
removal of the solvent under reduced pressure gave pure product as
a glass (94 mg, 45%); IR (film): 3317, 3059, 2975, 2926, 1645,
1589, 1520, 1456, 1266, 1159, 743 cm.sup.-1; NMR (CDCl.sub.3):
.delta.1.40 (3H, d, J=7.1 Hz); 1.70-1.90 (1H, br.s); 2.89 (1H, d.d,
J=14.5 and 9.4 Hz); 3.33 (1H, d.d, J=14.7 and 4.2 Hz); 3.49-3.54
(1H, m); 3.53 (1H, d, J=13.9 Hz); 3.69 (1H, d, J=13.9 Hz);
5.00-5.20 (2H, m); 6.28 (1H, d, J=1.7 Hz); 6.60 (1H, d, J=7.6 Hz);
6.65 (1H, d.d, J=7.9 and 2.0 Hz); 6.89 (1H, d, J=2.2 Hz); 7.06 (1H,
t, J=7.8 Hz); 7.09-7.13 (1H, m); 7.19-7.52 (7H, m); 7.54 (1H, d,
J=8.5 Hz); 7.64 (1H, d, J=8.5 Hz); 8.05 (1H, m); MS m/e (ES.sup.+):
415.4 (30%), 414.4 (100%, M.sup.++H); Analysis calculated for
C.sub.26H.sub.27N.sub.3O- .sub.2: C,75.52; H, 6.58; N, 10.16%.
Found: C, 75.28; H, 6.61; N, 10.03%.
EXAMPLE 18
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-e-
thyl)-propionamide, [R--(R*,S*)]
[0309] 38
[0310] To a stirred solution of 2-benzofurancarboxaldehyde (3.19 g,
21.8 mmol) in 1,2-dichloroethane (150 mL) was added
2-amino-3-(1H-indol-3-yl)--
2-methyl-N-(1-phenyl-ethyl)-propionamide (prepared as described by
Boyle S. et al., Bioorg. Med. Chem. 2:357, 1994) (5 g, 15.6 mmol),
followed by sodium triacetoxyborohydride (6.6 mg, 31.2 mmol). After
stirring over night the reaction was cautiously quenched with 2N
NaOH (150 mL) and extracted with CH.sub.2Cl.sub.2 (3.times.200 mL).
The combined organic phases were dried (MgSO.sub.4) and the solvent
was removed under reduced pressure. The residue was purified by
chromatography on normal phase silica using 30% EtOAc in heptane as
eluent and then on reverse phase silica using 70% MeOH in H.sub.2O
as eluent. Crystallization from ether gave pure product (5.55 g,
79%); mp 118-121.degree. C.: [.alpha.).sub.D.sup.20=+12.5.degree.
(c=1, MeOH); IR (film): 3329, 3059, 2975, 2926, 1652, 1506, 1455,
1371, 1354, 1342, 1255, 1170, 1105, 1010, 938, 743 cm.sup.-1; NMR
(CDCl.sub.3): .delta.1.47 (3H, s); 1.47 (3H, d, J=6.8 Hz); 1.89
(1H, s); 3.16 (2H, s); 3.78 (1H, br.d, J=12.9 Hz); 3.86 (1H, d,
J=14.4 Hz); 5.05-5.13 (1H, m); 6.43 (1H, s); 6.87 (1H, d, J=2.2
Hz); 7.09-7.40 (11H, m); 7.47-7.50 (1H, m); 7.65 (1H, d, J=7.8 Hz);
7.92 (1H, d, J=7.8 Hz); 7.96 (1H, s); MS m/e (ES.sup.+): 453.1
(30%), 452.1 (100%, M.sup.++H), 393.2 (15%); Analysis calculated
for C.sub.29H.sub.29N.sub.3O.sub.2: C, 77.14; H, 6.47; N, 9.30%.
Found: C, 77.14; H, 6.42; N, 9.36%.
EXAMPLE 19
2-[(Benzofuran-3-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-e-
thyl)-propionamide, [R--(R*,S*)]
[0311] 39
[0312] To a stirred solution of 3-benzofurancarboxaldehyde (146 mg,
1 mmol) (Ind. J. Chem., Vol. 31B, 1992, 526) in 1,2-dichloroethane
(10 mL) was added
2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionam-
ide (321 mg, 1 mmol) followed by sodium triacetoxyborohydride (424
mg, 2 mmol). After stirring over night at room temperature another
portion of sodium triacetoxyborohydride (424 mg, 2 mmol) was added.
The reaction was heated to reflux for 4 h. Cooled to room
temperature and cautiously quenched with saturated NaHCO.sub.3 (100
mL) and extracted with CH.sub.2Cl.sub.2 (3.times.20 mL). The
combined organic phases were dried (MgSO.sub.4) and the solvent was
removed under reduced pressure. The residue was purified by
chromatography on normal phase silica using 25% EtOAc in heptane as
eluent. Crystallization from ether/heptane gave pure product (232
mg, 51%); mp 104-106.degree. C.: [.alpha.].sub.D.sup.23=-13.-
4.degree. (c=1, MeOH); IR (film): 3418, 3314, 3058, 2976, 2927,
1652, 1505, 1452, 1371, 1354, 1341, 1279, 1266, 1186, 1095, 1010,
858, 743 cm.sup.-1; NMR (CDCl.sub.3): .delta.1.40 (3H, d, J=6.8
Hz); 1.52 (3H, s); 1.71 (1H, s); 3.15 (1H, d, J=14.4 Hz); 3.27 (1H,
d, J=14.4 Hz); 3.80 (1H, d, J=13.2 Hz); 3.88 (1H, d, J=13.2 Hz);
5.01-5.09 (1H, m); 6.79 (1H, d, J=2.2 Hz); 7.07-7.40 (12H, m); 7.44
(1H d,d, J=8.3 and 0.7 Hz); 7.65 (1H, d, J=7.8 Hz); 7.68 (1H, d,
J=8.1 Hz); 7.93 (1H, s); MS m/e (ES.sup.+): 452.1 (100%,
M.sup.++H); Analysis calculated for C.sub.29H.sub.29N.sub.3O-
.sub.2: C, 77.14; H, 6.47; N, 9.30%. Found: C, 76.91; H, 6.39; N,
9.26%.
EXAMPLE 20
3-(1H-Indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-2-[(1H-pyrrol-2-ylmethyl)-am-
ino]-propionamide, [R--(R*,S*)]
[0313] 40
[0314] To a stirred solution of 2-pyrrolecarboxaldehyde (71 mg,
0.75 mmol) in 1,2-dichloroethane (10 mL) was added
2-amino-3-(1H-indol-3-yl)-2-methy-
l-N-(1-phenyl-ethyl)-propionamide (161 mg, 0.5 mmol) followed by
sodium triacetoxyborohydride (424 mg, 2 mmol). After stirring over
night at room temperature the reaction was cautiously quenched with
saturated NaHCO.sub.3 (50 mL) and extracted with CH.sub.2Cl.sub.2
(2.times.50 mL). The combined organic phases were dried
(MgSO.sub.4) and the solvent was removed under reduced pressure.
The residue was purified by chromatography on normal phase silica
using 40% EtOAc in heptane as eluent. Crystallization from
ether/heptane gave pure product (50 mg, 25%); mp 123-133.degree.
C.; [.alpha.].sub.D.sup.23=(c=1, MeOH); IR (film): 3314, 2976,
2926, 2852, 1651, 1511, 1455, 909, 736 cm.sup.-1; NMR (CDCl.sub.3):
.delta.1.41 (3H, d, J=6.8 Hz); 1.45 (3H, s); 3.14 (1H, d, J=14.4
Hz); 3.29 (1H, d, J=14.4 Hz); 3.70 (1H, d, J=13.1 Hz); 3.76 (1H, d,
J=12.9 Hz); 5.02-5.10 (1H, m); 5.97 (1H, s); 6.07-6.09 (1H, m);
6.58-6.60 (1H, m); 6.74 (1H, d, J=2.2 Hz); 7.10-7.35 (8H, m); 7.41
(1H d, J=7.6 Hz); 7.65 (1H, d, J=7.8 Hz); 7.89 (2H, s); MS m/e
(ES.sup.+): 423.2 (20%, M.sup.++Na); 402.2 (30%); 401.2 (100%,
M.sup.++H); 322.2 (40%); Analysis calculated for
C.sub.25H.sub.28N.sub.4O: C, 74.97; H, 7.05; N, 13.99%. Found: C,
74.83; H, 7.05; N, 13.95%.
EXAMPLE 21
3-(1H-Indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-2-[(2H-pyrazol-3-ylmethyl)-a-
mino]-propionamide, [R--(R*,S*)]
[0315] 41
[0316] To a stirred solution of pyrazole-3-carboxaldehyde (96 mg, 1
mmol, supplied as dimer) in pyridine (10 mL) was added
2-amino-3-(1H-indol-3-yl-
)-2-methyl-N-(1-phenyl-ethyl)-propionamide (161 mg, 0.5 mmol)
followed by sodium triacetoxyborohydride (848 mg, 4 mmol). After
stirring over night at room temperature another portion of sodium
triacetoxyborohydride (424 mg, 2 mmol) was added. After stirring
over night at room temperature the pyridine was removed under
reduced pressure. The residue was taken up in CH.sub.2Cl.sub.2 (100
mL) and saturated NaHCO.sub.3. The aqueous phase was extracted with
CH.sub.2Cl.sub.2 (100 mL). The combined organic phases were washed
with brine (50 mL), dried (MgSO.sub.4), and the solvent was removed
under reduced pressure. The residue was initially purified by
chromatography on normal phase silica using 95% EtOAc in heptane as
eluent. The solvent was removed under reduced pressure and the
residue was dissolved in aqueous acetonitrile and acidified using
formic acid. Purification by chromatography on reverse phase silica
using 25% CH.sub.3CN in H.sub.2O (0.1% formic acid in mobile
phases) as eluent gave pure product. The solvent was removed under
reduced pressure and the residue was suspended between EtOAc and
saturated NaHCO.sub.3. The EtOAc was dried (MgSO.sub.4) and the
solvent was removed under reduced pressure to give pure product as
a glass (20 mg, 10%); IR (film): 3260, 3059, 2979, 2927, 1651,
1515, 1456, 1374, 1266, 1105, 1048, 1011, 932, 741 cm.sup.-1; NMR
(DMSO-d.sub.6): .delta.1.22 (3H, s); 1.35 (3H, d, J=6.8 Hz); 2.26
(1H, s); 2.96-3.05 (2H, m); 3.50-3.75 (2H, m); 4.93 (1H, s); 6.10
(1H, s); 6.89-6.93 (2H, m); 7.00-7.04 (1H, m); 7.18-7.32 (6H, m);
7.35 (0.5H, s); 7.52 (1H, d, J=7.8 Hz); 7.60 (0.5H, s); 8.05-8.20
(1H, m); 10.82 (1H, s); 12.52 (0.5H, s); 12.73 (0.5H, s); MS m/e
(ES.sup.+): 424.1 (27%); 402.1 (100%, M.sup.++H).
EXAMPLE 22
2-(3-Benzofuran-2-ylmethyl-ureido)-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl--
ethyl)-propionamide, [R--(R*,S*)]
[0317] 42
[0318] Step 1
[0319] To a stirred solution of potassium hydroxide (6.6 g, 100
mmol, 85%) and hydroxylamine (3.66, 52.5 mmol) in EtOH (100 mL,
95%) and water (100 mL) was added 2-benzofurancarboxaldehyde (7.34
g, 50 mmol). Stirred for 48 h before removing the EtOH under
reduced pressure. The aqueous phase was saturated with NaCl and
then extracted with EtOAc (2.times.300 mL). The combined organic
phases were dried (MgSO.sub.4) and the solvent removed under
reduced pressure. Crystallization from ether gave pure oxime (7.2
g, 89%). To an ice-cold solution of the oxime (3.22 g, 20 mmol) in
THF (150 mL, anhydrous) was added dropwise a solution of lithium
aluminum hydride (20 mL, 20 mmol, 1M in THF) under an atmosphere of
nitrogen. Reaction mixture allowed to reach room temperature and
stirred over night. Reaction mixture cautiously quenched using
water. Added 5N NaOH, and aqueous phase extracted with EtOAc
(2.times.100 mL). The combined organic layers were washed with
brine, dried (MgSO.sub.4), and the solvent was removed under
reduced pressure. The residue was purified by chromatography on
normal phase silica using EtOAc as eluent to give intermediate IX
(1.75 g, 59%).
[0320] Step 2
[0321] A solution of the amine prepared in step 1 (1.358 g, 9.23
mmol) and pyridine (1.46, 18.5 mmol) in CH.sub.2Cl.sub.2 (20 mL,
anhydrous) was added dropwise over 20 min to an ice cooled solution
of triphosgene (0.96, 3.23 mmol). Reaction mixture allowed to reach
room temperature. After 30 min, solvent removed under reduced
pressure. The residue was taken up in EtOAc, filtered, and solvent
removed under reduced pressure to give isocyanate (1.60 g, 100%).
IR (film): 2256 cm.sup.-1. A solution of the isocyanate (1.038 g, 6
mmol) and 2-amino-3-(1H-indol-3-yl)-2-methy-
l-N-(1-phenyl-ethyl)-propionamide (1.926 g, 6 mmol) in THF (50 mL,
anhydrous) was stirred at room temperature for 5 min. The solvent
was removed under reduced pressure. The residue was taken up in
EtOAc and washed with 1N HCl (3.times.20 mL), saturated
Na.sub.2CO.sub.3 (30 mL), brine (30 mL), dried MgSO.sub.4, and the
solvent removed under reduced pressure. The residue was purified by
chromatography on reverse phase silica using 65% MeOH in H.sub.2O
as eluent. Crystallization from MeOH/H.sub.2O gave pure product
(1.35 g, 45%). mp 176-178.degree. C.;
[.alpha.].sub.D.sup.22=+30.420 (c=1, MeOH); IR (film): 3321, 3058,
2978, 2932, 1645, 1558, 1506, 1495, 1445, 1253, 741 cm.sup.-1; NMR
(CDCl.sub.3): .delta.1.35 (3H, d, J=6.8 Hz); 1.61 (3H, s); 3.20
(1H, d, J=14.6 Hz); 3.54 (1H, d, J=14.6 Hz); 4.38 (1H, d.d, J=16.0
and 6.0 Hz); 4.45 (1H, d.d, J=15.9 and 6.1 Hz); 4.78 (1H, t, J=6.0
Hz); 4.97 (1H, s); 4.95-5.05 (1H, m); 6.49 (1H, s); 6.76 (1H, d,
J=2.4 Hz); 7.00 (1H, d, J=7.6 Hz); 7.05-7.10 (1H, m); 7.13-7.28
(9H, m); 7.38 (1H, d, J=8.1 Hz); 7.48-7.50 (1H, m); 7.57 (1H, d,
J=7.8 Hz); 7.74 (1H, s); MS m/e (APCI.sup.+): 496.3 (30%); 495.2
(100%, M.sup.++H); 477.2 (7%); 374.2 (7%); 322.3 (17%); Analysis
calculated for C.sub.30H.sub.30N.sub.4O.sub.3- : C, 72.85; H, 6.11;
N, 11.32%. Found: C, 73.09; H, 6.08; N, 11.35%.
EXAMPLES 23 TO 191
[0322] (See Table 2 Below)
Intermediate VII,
N-[b]benzofuranylmethyl-R-.alpha.-methyl-tryptophan-N-ca-
rboxyanhydride
[0323] Intermediate I (5.23 g, 15 mmol) was stirred in toluene (50
mL) under nitrogen and heated to 55.degree. C. Phosgene in toluene
(37 mL, 75 mmol) was added in one portion and as soon as the
temperature had returned to 55.degree. C. dry THF (150 mL) was
added rapidly dropwise. Stirring was continued for 30 min and the
reaction was then cooled, the solvent removed in vacuo. The residue
taken up in ether (50 mL) and filtered and evaporated to dryness
several times until a solid was obtained; (6.15 g, 100%); IR
(film): 3418, 1844, 1771, 1455, 1397, 1251, 986, 746 cm.sup.-1; NMR
(CDCl.sub.3) 1.64 (3H, s); 3.31 (1H, d, J=15 Hz); 3.44 (1H, d, J=15
Hz); 4.45 (1H, d J=16Hz); 4.81 (1H, d, J=16 Hz); 6.77 (1H, s); 6.94
(1H, d J=2.8 Hz); 7.14-7.58 (8H, m); 8.16 (1H, s).
[0324] General Procedure for Array Synthesis of Examples 23 to
191
[0325] A 40-well DTI synthesizer rack (U.S. Pat. No. 5,324,483) was
loaded with 40 DTI vials (12 mL). To each vial 0.15-0.21 mmol of an
amine or amine HCl salt was added. The rack was placed in a
Cyberlab Liquid Handling Robot and to each vial 0.10 mmol
N-[b]benzofuranylmethyl-R-.alph-
a.-methyl-tryptophan-N-carboxyanhydride (0.227 M in THF) was added.
To those vials that contained amine HCl salts, 0.15 mmol
triethylamine (0.254 M in THF) was added, in order to liberate the
free amines. THF was then added to each vial to make up the total
volume to 3 mL. The vials were placed in a 40-well DTI synthesizer
equipped with a heating block, 40 condensers and a nitrogen
manifold. The synthesizer was kept under a continuous flow of
nitrogen and was shaken at 65.degree. C. on an orbital shaker for 2
days. The reactions were monitored by TLC (10% CH.sub.3CN in
CH.sub.2Cl.sub.2). The vials in which the reaction had gone to
completion were taken out. To the remaining vials CH.sub.3CN (2 mL)
was added each and these were shaken at 85.degree. C. for 19 h. The
vials in which the reaction had gone to completion were taken out.
To the remaining vials pyridine (1 mL) was added each and these
were shaken at 105.degree. C. for 6 h followed by 15 h at
65.degree. C. The vials were then concentrated at reduced pressure
in a Speedvac and were purified by chromatography over a 12 mL
LC-Si SPE cartridge containing 2 g silica (elution with 10%
CH.sub.3CN in CH.sub.2Cl.sub.2 followed by 20% CH.sub.3CN in
CH.sub.2Cl.sub.2, 5% methanol in CH.sub.2Cl.sub.2, 10% methanol in
CH.sub.2Cl.sub.2, 20% methanol in CH.sub.2Cl.sub.2 and 50% methanol
in CH.sub.2Cl.sub.2, depending on the polarity of the products).
The products were subjected to LC-MS. Those products which did
contain the desired molecular ion, but were not sufficiently pure
(typically<85%) were further purified by prep HPLC on a C18
reversed phase preparative column. The HPLC-purified products were
re-analyzed by LC-MS to determine the purity. The 40 final products
were analyzed by .sup.1H NMR.
EXAMPLES 192 TO 308
[0326] (See Table 3 Below)
[0327] Intermediate II
[0328] Step 1
[0329] The compound was prepared as described for Intermediate I,
step 1; (20.5 g, 59%); NMR (CDCl.sub.3) 2.10 (1H, s); 3.18 (2H, m);
3.60 (3H, s); 3.80-4.00 (2H, m); 6.43 (1H, s); 7.03-7.60 (9H, m);
8.00 (1H, s).
[0330] Step 2
[0331] The compound was prepared as described for Intermediate I;
(7.02 g, 85%); NMR (DMSO-D.sub.6) 3.01-3.12 (2H, m); 3.52 (1H, m);
3.80 (1H, d, J=15 Hz); 3.80 (1H, d, J=14.8 Hz); 6.61 (1H, s);
6.93-7.54 (9H, m); 10.82 (1H, s).
[0332] General Procedure for Array Synthesis of Examples 192 to 308
(See Table 4 Below)
[0333] A 40-well DTI synthesizer rack was loaded with 40 Kimble
vials (10 mL). To each vial approximately 0.34 g (0.10 mmol)
N-[b]benzofuranylmethyl-R-tryptophan was added followed by 1.5
equivalent of an amine or amine HCl salt. The rack was placed in a
Cyberlab Liquid Handling Robot and to each vial 1.0 equivalent of
HBTU (0.4 M in DMF) was added followed by 1.5 equivalent of
diisopropylethylamine (0.5 M in DMF). To those vials, which
contained amine HCl salts, an additional equivalent of
diisopropylethylamine was added. DMF was added to make the total
volume up to 1.5 mL. The vials were capped and the rack was shaken
on an orbital shaker at room temperature for 3 h. To each vial,
water (1 mL) was added and the mixtures were purified on 3 mL LC-18
reversed phase SPE cartridges containing 500 mg of sorbent, using
an ASPEC XL4 robot. The cartridges were conditioned with methanol
(4 mL) followed by methanol/water 1:1 (4 mL). Water (1 mL) was
loaded onto the cartridges and the crude reaction mixtures were
loaded into the water layer. The cartridges were washed with water
(4 mL) and methanol/water 1:1 (4 mL) and were eluted with methanol
(4 mL). The methanol fractions were concentrated and the products
were subjected to LC-MS. Those products which did contain the
desired molecular ion, but were not sufficiently pure
(typically<90%) were further purified by prep HPLC on a C18
reversed phase preparative column. The HPLC-purified products were
re-analyzed by LC-MS to determine the purity. The 40 final products
were analyzed by .sup.1H NMR.
EXAMPLES 309 TO 405
[0334] (See Table 5 Below)
[0335] General Procedure for Array Synthesis of Examples 309 to
405
[0336] The N-terminal derivatives where prepared from
2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide,
prepared as described by Boyle S., et al., Bioorg. Med. Chem. 2:357
(1994), or from
2-amino-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide
(Intermediate V), using the procedure of Siegel M. G., et al., Tet.
Lett. 38: 3357, (1997).
[0337] Because the compounds are potent ligands to the NK.sub.1
receptor, they are effective at displacing substance P at that
position, and therefore are useful for treating biological
conditions otherwise mediated by substance P. Accordingly,
compounds capable of antagonising the effects of substance P at
NK.sub.1 receptors will be useful in treating or preventing a
variety of brain disorders including pain (inflammatory, surgical
and neuropathic), anxiety, panic, depression, schizophrenia,
neuralgia, stress, sexual dysfunction, bipolar disorders, movement
disorders, cognitive disorders, and addiction disorders;
inflammatory diseases such as arthritis, asthma, and psoriasis;
gastrointestinal disorders including colitis, Crohn's disease,
irritable bowel syndrome and satiety; allergic responses such as
eczema and rhinitis; vascular disorders such as angina and
migraine; neuropathological disorders including scleroderma and
emesis. The compounds of the invention, NK.sub.1 receptor
antagonists, are also useful as anti-angiogenic agents, for the
treatment of conditions associated with aberrant neovascularization
such as rheumatoid arthritis, atherosclerosis and tumour cell
growth. They will also be useful as agents for imaging NK.sub.1
receptors in vivo in conditions such as ulcerative colitis and
Crohn's disease.
[0338] The compounds of the present invention are highly selective
and competitive antagonists of the NK.sub.1 receptor. They have
been evaluated in an NK.sub.1-receptor binding assay which is
described below.
[0339] Human lymphoma IM9 cells were grown in RPMI 1640 culture
medium supplemented with 10% fetal calf serum and 2 mM glutamine
and maintained under an atmosphere of 5% CO.sub.2. Cells were
passaged every 3-4 days by reseeding to a concentration of
4-8.times.10.sup.6/40 ml per 175 cm.sup.2 flask. Cells were
harvested for experiments by centrifugation at 1000 g for 3 min.
Pelleted cells were washed once by resuspension into assay buffer
(50 mM Tris HCl pH 7.4, 3 mM MnCl.sub.2, 0.02% BSA, 40 mg/mL
bacitracin, 2 mg/mL chymostatin, 2 mM phosphoramidon, 4 mg/mL
leupeptin) and repeating the centrifugation step before
resuspending at a concentration of 2.5.times.10.sup.6 cells/mL
assay buffer. Cells (200 ml) were incubated with
[.sup.125I]Bolton-Hunter substance P (0.05-0.1 nM) in the presence
and absence of varying concentrations of test compounds for 50 min
at 21.degree. C. Non-specific binding (10% of the total binding
observed under these conditions) was defined by 1 mM [Sar.sup.9,
Met(0.sub.2).sup.11] substance P. Reactions were terminated by
rapid filtration under vacuum onto GF.backslash.C filters presoaked
in 0.2% PEI for 1-2 h, using a Brandel cell harvester. Filters were
washed with 6.times.1 ml ice-cold Tris HCl (50 mM, pH 7.4) and
radioactivity bound determined using a gamma counter. Results were
analyzed using iterative curve fitting procedures in RS1 or
Graphpad Inplot.
3TABLE 1 In Vitro Human NK.sub.1 Receptor Binding Assay NK.sub.1
binding Example No IC.sub.50 (nM) 1 591 2 23 3 6 4 1213 5 295 6 0.7
7 3.3 8 27 9 112 10 51 11 46 12 14 13 35 14 4.7 15 >10,000 16
9.1 17 344 18 4.4 19 58 20 815 21 1808 22 2.9
[0340] Similiar binding data are presented in Tables 2-5 for
specific invention compounds.
4TABLE 2 Examples 23-191 Yield Mol. Icms % Icms Rt IC.sub.50 (nM)
Ex. Name (mg) ion purity (min) hNK.sub.1 23
2-[(Benzofuran-2-ylmethyl)-amino]-3 19.7 439 100 3.07 1284
(1H-indol-3-yl)-2-methyl-N-pyridin-2 ylmethyl-propionamide 24
2-[(Benzofuran-2-ylmethyl)-amino]- 23.5 439 100 2.6 547
3-(1H-indol-3-yl)-2-methyl-N- pyridin-3-ylmethyl-propionamide 25
2-[(Benzofuran-2-ylmethyl)-amin- o]- 41.9 439 100 2.6 131
3-(1H-indol-3-yl)-2-methyl-N- pyridin-4-ylmethyl-propionamide 26
2-[(Benzofuran-2-ylmethyl)-amin- o]- 18.4 430 100 5.2 1011
N-cyclohexyl-3-(1H-indol-3-yl)-2- methyl-propionamide 27
2-[(Benzofuran-2-ylmethyl)-amino]- 24.6 444 100 5.81 311
N-cyclohexylmethyl-3-(1H-indol-3- yl)-2-methyl-propionamide 28
2-[(Benzofuran-2-ylmethyl)-amino]- 26.5 438 97 4.6 44
N-benzyl-3-(1H-indol-3-yl)-2- methyl-propionamide 29
2-[(Benzofuran-2-ylmethyl)-amino]- 43.1 468 82 3.22 7
N-(2-hydroxy-1-phenyl-ethyl)-3- (1H-indol-3-yl)-2-methyl-
propionamide 30 2-[(Benzofuran-2-ylmethyl)-amino ]- 43.3 486 74
5.81 17 N-[1-(4-chloro-phenyl)-ethyl]-3- (1H-indol-3-yl)-2-methyl-
propionamide 31 2-((Benzofuran-2-ylmethyl)-amino]- 29.4 502 100
6.05 >10,000 3-(1H-indol-3-yl)-2-methyl-N-(1-
naphthalen-1-yl-ethyl)-propionamide 32 2-[(Benzofuran-2-ylmethyl)--
amino]- 40.1 502 100 5.96 >10,000 3-(1H-indol-3-yl)-2-methyl-N--
(1- naphthalen-1-yl-ethyl)-propionamide 33
2-[(Benzofuran-2-ylmethyl)-amino]- 44.4 470 100 5.11 9
N-[1-(4-fluoro-phenyl)-ethyl]-3-(1H- indol-3-yl)-2-methyl-propion-
amide 34 2-[(Benzofuran-2-ylmethyl)-amino]- 23.8 497 100 5.07 14
3-(1H-indol-3-yl)-2-methyl-N-[1-(4- nitro-phenyl)-ethyl]-pro-
pionamide 35 2-[(Benzofuran-2-ylmethyl)-amino]- 27.8 482 100 4.86
31 3-(1H-indol-3-yl)-N-[1-(4-methoxy- phenyl)-ethyl]-2-methyl-
propionamide 36 N-[1-(2-Amino-phenyl)-ethyl]-2- 25.8 467 100 4.45
1620 [(benzofuran-2-ylmethyl)-amino]-3- (1H-indol-3-yl)-2-methyl-
propionamide 37 N-[1-(3-Amino-phenyl)-ethyl]-2- 25.5 467 100 3.7
364 [(benzofuran-2-ylmethyl)-amino]-3- (1H-indol-3-yl)-2-methyl-
propionamide 38 N-[1-(4-Amino-phenyl)-ethyl]-2- 22.5 467 100 3.2
141 [(benzofuran-2-ylmethyl)-amino]-3- (1H-indol-3-yl)-2-methyl-
propionamide 39 2-[(Benzofuran-2-ylmethyl)-amino]- 48.3 495 100
5.26 863 N-[1-(4-dimethylamino-phenyl)-
ethyl]-3-(1H-indol-3-yl)-2-methyl- propionamide 40
2-[(Benzofuran-2-ylmethyl)-amino]- 25.3 495 100 5.18 1065
N-[1-(3-dimethylamino-phenyl)- ethyl]-3-(1H-indol-3-yl)-2-methyl-
propionamide 41 2-[(Benzofuran-2-ylmethyl)-amino]- 17 458 100 4.89
19 3-(1H-indol-3-yl)-2-methyl-N-(1-
thiophen-3-yl-ethyl)-propionamide 42 2-[(Benzofuran-2-ylmethyl)-am-
ino]- 34.5 452 100 5.06 261 3-(1H-indol-3-yl)-2-methyl-N-(1-
phenyl-ethyl)-propionamide 43 2-{[2-[(Benzofuran-2-ylmethyl)- 28.5
500 10 9.4 3613 amino]-3-(1H-indol-3-yl)-2-methyl-
propionylamino]-methyl }-4- hydroxy-pyrimidine-5-carboxylic acid 44
2-[(Benzofuran-2-ylmethyl)-amino]- 43.9 453 90 6.85 151
3-(1H-indol-3-yl)-2-methyl-N-(1- pyridin-3-yl-ethyl)-prop- ionamide
45 2-[((Benzofuran-2-ylmethyl)-amino]- 43 453 95 7.15 913
3-(1H-indol-3-yl)-2-methyl-N-(2- pyridin-2-yl-ethyl)-prop- ionamide
46 2-[(Benzofuran-2-ylmethyl)-amino]- 49.5 506 95 10.2 1560
N-(2,4-dichloro-benzyl)-3-(1H- indol-3-yl)-2-methyl-propionamide 47
2-[(Benzofuran-2-ylmethyl)-am- ino]- 52.6 531 95 6.66 7616
3-(1H-indol-3-yl)-2-methyl-N-[2-(4- sulfamoyl-phenyl)-ethyl]-
propionamide 48 N-(2-Amino-6-fluoro-benzyl)-2- 49.3 471 95 8.68
6423 [(benzofuran-2-ylmethyl)-amino]-3- (1H-indol-3-yl)-2-methyl-
propionamide 49 2-[(Benzofuran-2-ylmethyl)-amino]- 4.9 460 95 8.22
1550 N-(2-hydroxy-cyclohexylmethyl)-3- (1H-indol-3-yl)-2-methyl-
propionamide 50 2-[(Benzofuran-2-ylmethyl)-amino]- 44.4 468 95 7.6
1333 N-(2-hydroxy-2-phenyl-ethyl)-3- (1H-indol-3-yl)-2-methyl-
propionamide 51 2-[(Benzofuran-2-ylmethyl)-amino]- 31.1 574 95
10.32 179 N-(3,5-bis-trifluoromethyl-benzyl)-
3-(1H-indol-3-yl)-2-methyl- propionamide 52
2-[(Benzofuran-2-ylmethyl)-amino]- 39.3 459 95 9.16 >10,000
3-(1H-indol-3-yl)-2-methyl-N-[2-(1- methyl-pyrrolidin-2-yl)-ethyl-
]- propionamide 53 2-[(Benzofuran-2-ylmethyl)-amino]- 42 452 90 8.9
262 3-(1H-indol-3-yl)-2-methyl-N- phenethyl-propionamide 54
2-[(Benzofuran-2-ylmethyl)-amino]- 23.2 466 90 9.95 834
N-(2,3-dimethyl-benzyl)-3-(1H- indol-3-yl)-2-methyl-propionamide 55
2-[(Benzofuran-2-ylmethyl)-am- ino]- 49 468 95 8.95 643
3-(1H-indol-3-yl)-N-(3-methoxy- benzyl)-2-methyl-propionamide 56
N-[2-(4-Amino-phenyl)-ethyl]-2- 49 467 90 7.31 3228
[(benzofuran-2-ylmethyl)-amino ]-3- (1H-indol-3-yl)-2-methyl-
propionamide 57 2-[(Benzofuran-2-ylmethyl)-amino] 7 458 95 10.73
290 N-(1-cyclohexyl-ethyl)-3-(1H-indol- 3-yl)-2-methyl-propionamide
58 2-[(Benzofuran-2-ylmethyl)-amino]- 27 466 90 9.95 624
3-(1H-indol-3-yl)-2-methyl-N-(1-p- tolyl-ethyl)-propionamide 59
2-[(Benzofuran-2-ylmethyl)-amino]- 46 522 90 9.61 >10,000
3-(1H-indol-3-yl)-2-methyl-N-(3- trifluoromethoxy-benzyl)-
propionamide 60 2-[(Benzofuran-2-ylmethyl)-amino]- 10 481 90 9.16
964 N-(4-dimethylamino-benzyl)-3-(1H-
indol-3-yl)-2-methyl-propionamide 61 2-[(Benzofuran-2-ylmethyl)-am-
ino ]- 48.4 456 90 8.74 61 N-(4-fluoro-benzyl)-3-(1H-indol-3-
yl)-2-methyl-propionamide 62 N-(4-Amino-benzyl)-2- 32.3 453 90 7.29
837 [(benzofuran-2-ylmethyl)-amino]-3- (1H-indol-3-yl)-2-methyl-
propionamide 63 2-[(Benzofuran-2-ylmethyl)-amino]- 21.6 466 75 9.95
58 3-(1H-indol-3-yl)-2-methyl-N-(1- phenyl-propyl)-propionamide 64
2-[(Benzofuran-2-ylmethyl)-amino]- 50.2 472 90 9.3 76
N-(4-chloro-benzyl)-3-(1H-indol-3- yl)-2-methyl-propionamide 65
2-[(Benzofuran-2-ylmethyl)-amino]- 43.9 516 90 9.43 700
N-(2-bromo-benzyl)-3-(1H-indol-3- yl)-2-methyl-propionamide 66
2-[(Benzofuran-2-ylmethyl)-amino]- 40.9 522 90 9.69 3444
3-(1H-indol-3-yl)-2-methyl-N-(4- trifluoromethoxy-benzyl)-
propionamide 67 2-[(Benzofuran-2-ylmethyl)-amino]- 18.8 466 92 9.94
3 3-(1H-indol-3-yl)-2-methyl-N-(1-p- tolyl-ethyl)-propionamide 68
2-[(Benzofuran-2-ylmethyl)-amino]- 48.9 468 90 8.41 312
3-(1H-indol-3-yl)-N-(4-methoxy- benzyl)-2-methyl-propionamide 69
2-[(Benzofuran-2-ylmethyl)-amino]- - 44.7 453 95 7.68 112
3-(1H-indol-3-yl)-2-methyl-N-(1- pyridin-2-yl-ethyl)-propionamide
70 2-[(Benzofuran-2-ylmethyl)-ami- no]- 38.1 458 90 10.45 216
N-(2-cyclohexyl-ethyl)-3-(1H-indol- 3-yl)-2-methyl-propionamide 71
2-[(Benzofuran-2-ylmethyl)-amin- o]- 40 452 90 9.13 144
3-(1H-indol-3-yl)-2-methyl-N-(4- methyl-benzyl)-propionamide 72
2-[(Benzofuran-2-ylmethyl)-amino]- 43.2 516 90 9.43 18
N-(3-bromo-benzyl)-3-(1H-indol-3- yl)-2-methyl-propionamide 73
2-[(Benzofuran-2-ylmethyl)-amino]- 35.2 468 90 7.56 1229
N-(2-hydroxy-2-phenyl-ethyl)-3- (1H-indol-3-yl)-2-methyl-
propionamide 74 2-[(Benzofuran-2-ylmethyl)-amino]- 16 506 90 9.51
12 3-(1H-indol-3-yl)-2-methyl-N-(3- trifluoromethyl-benzyl)-
propionamide 75 2-[(Benzofuran-2-ylmethyl)-amino]- 48.1 528 100
7.06 >10,000 N-(1,2-diphenyl-ethyl)-3-(1H-indol-
3-yl)-2-methyl-propionamide 76 2-[(Benzofuran-2-ylmethyl)-amino]-
28 405 50 2.01 3696 3-(1H-indol-3-yl)-2-methyl-N-(2-
methylamino-ethyl)-propionamide 77 2-[(Benzofuran-2-ylmethyl)-amin-
o ]- 20 472 100 6.19 17 N-(3-chloro-benzyl)-3-(1H-indol-3-
yl)-2-methyl-propionamide 78 2-[(Benzofuran-2-ylmethyl)-amino ]-
9.2 485 50 1.93 >10,000 3-(1H-indol-3-yl)-2-methyl-N-
(1,3,5-triaza-tricyclo[3.3.1.1 > 3,7]- dec-7-yl)-propionamide 79
2-[(Benzofuran-2-ylmethyl)-amino]- 30.1 534 100 6.84 >10,000
3-(1H-indol-3-yl)-2-methyl-N-[1- methyl-2-(3-trifluoromet-
hyl-phenyl)- ethyl]-propionamide 80 2-[(Benzofuran-2-ylmeth-
yl)-amino]- 22.4 529 100 5.9 >10,000 3-(1H-indol-3-yl)-2-methyl-
-N-(2- phenyl-2-pyridin-2-yl-ethyl)- propionamide 81
4-{[2-[(Benzofuran-2-ylmethyl)- 37.4 526 100 5.59 >10,000
amino]-3-(1H-indol-3-yl)-2-methyl- propionylamino]-methyl}-3-
methoxy-benzoic acid methyl ester 82 2-[(Benzofuran-2-ylmethyl-
)-amino]- 8.5 432 100 6.51 1144 3-(1H-indol-3-yl)-2-methyl-N-
(1,2,2-trimethyl-propyl)- propionamide 83
2-[(Benzofuran-2-ylmethyl)-amino]- 27.5 419 100 3.61 3519
N-(2-dimethylamino-ethyl)-3-(1H- indol-3-yl)-2-methyl-propionamid-
e 84 4-[2-[(Benzofuran-2-ylmethyl)- 5 544 100 1.62 >10,000
amino]-3-(1H-indol-3-yl)-2-methyl- propionylamino]-3-(4-chloro-
phenyl)-butyric acid 85 2-[(Benzofuran-2-ylmethyl)-amino]- 11.3 479
100 3.73 2443 3-(1H-indol-3-yl)-2-methyl-N-(3-
oxo-2,3-dihydro-1H-isoindol-1-yl)- propionamide 86
2-[(Benzofuran-2-ylmethyl)-amino]- 24.7 460 100 2.58 >10,000
oxo-imidazolidin-1-yl)-ethyl]- propionamide 87
2-[(Benzofuran-2-ylmethyl)-amino]- 38.9 551 100 4.63 >10,000
3-(1H-indol-3-yl)-2-methyl-N-[3-(4- pyridin-2-yl-piperazin-1-yl)--
propyl]- propionamide 88 2-[(Benzofuran-2-ylmethyl)-amino]- 33.4
515 100 4.58 >10,000 N-[4-(2.6-dimethyl-piperidin-1-yl)-
butyl]-3-(1H-indol-3-yl)-2-methyl- propionamide 89
2-[(Benzofuran-2-ylmethyl)-amino]- 21.2 527 100 8.88 6735
3-(1H-indol-3-yl)-2-methyl-N-(1- piperidin-1-ylmethyl-cyclohexyl)-
- propionamide 90 2-[(Benzofuran-2-ylmethyl)-amino]- 8.2 456 100
3.07 >10,000 N-[2-(1H-imidazol-4-yl)-1-methyl-
ethyl]-3-(1H-indol-3-yl)-2-methyl- propionamide 91
2-[(Benzofuran-2-ylmethyl)-amino]- 28.1 473 100 3.07 >10,000
3-(1H-indol-3-yl)-2-methyl-N-[3-(2- oxo-pyrrolidin-1-yl)-propyl]-
propionamide 92 2-[(Benzofuran-2-ylmethyl)-amino]- 17.6 390 100
4.96 2285 3-(1H-indol-3-yl)-N-isopropyl-2- methyl-propionamide 93
2-[(Benzofuran-2-ylmethyl)-amino]- 17.6 473 100 3.29 >10,000
3-(1H-indol-3-yl)-2-methyl-N-[1- methyl-2-(2-oxo-pyrrolidin-1-yl)-
ethyl]-propionamide 94 2-[(Benzofuran-2-ylmethyl)-amino]- 30.6 501
100 3.27 >10,000 N-[4-(2,5-dimethyl-pyrrolidin-1-yl)-
butyl]-3-(1H-indol-3-yl)-2-m- ethyl- propionamide 95
N-[2-(5-Amino-1H-imidazol-4-yl)- 19.2 471 100 3.5 >10,000
2-oxo-ethyl]-2-[(benzofuran-2- ylmethyl)-amino]-3-(1H-indol-3-yl)-
2-methyl-propionamide 96 2-[(Benzofuran-2-ylmethyl)-amino]- 4.6 461
100 2.26 >10,000 3-(1H-indol-3-yl)-2-methyl-N-[2-(2-
oxo-oxazolidin-3-yl)-ethyl]- propionamide 97
2-[(Benzofuran-2-ylmethyl)-amino]- 30 442 100 2.26 >10,000
N-[2-(1H-imidazol-4-yl)-ethyl]-3- (1H-indol-3-yl)-2-methyl-
propionamide 98 2-[(Benzofuran-2-ylmethyl)-amino]- 34.5 528 100
2.26 >10,000 N-(2,2-diphenyl-ethyl)-3-(1H-indol-
3-yl)-2-methyl-propionamide 99 2-[(Benzofuran-2-ylmethyl)-amino]-
17.9 459 100 2.26 >10,000 3-(1H-indol-3-yl)-2-methyl-N-[2-(2-
oxo-pyrrolidin-1-yl)-et- hyl]- propionamide 100
2-[(Benzofuran-2-ylmethyl)-amino]- 7.2 473 100 2.26 390
3-(1H-indol-3-yl)-2-methyl-N-(5- nitro-furan-2-ylmethyl)-
propionamide 101 2-[(Benzofuran-2-ylmethyl)-amino]- 19.4 456 100
2.27 >10,000 3-(1H-indol-3-yl)-2-methyl-N-[2-(5-
methyl-1H-imidazol-4-yl)-ethy- l]- propionamide 102
2-[(Benzofuran-2-ylmethyl)-amino]- 18.9 549 90 8.66 >10,000
N-[1-(3-dimethylamino-phenyl)- cyclopentylmethyl]-3-(1H-indol-3-
yl)-2-methyl-propionamide 103 2-[(Benzofuran-2-ylmethyl)-amino]-
0.4 478 77 0.05 74 N-(1H-benzoimidazol-2-ylmethyl)-
3-(1H-indol-3-yl)-2-methyl- propionamide 104
2-[(Benzofuran-2-ylmethyl)-amino]- 8.3 458 100 0.06 8
N-(1-cyclohexyl-ethyl)-3-(1H-indol- 3-yl)-2-methyl-propionamide 105
2-[(Benzofuran-2-ylniethyl)-amino]- - 13.2 510 69 0.05 >10,000
3-(1H-indol-3-yl)-2-methyl-N-(2- phenyl-[1,3]dioxolan-2-ylmethyl)-
propionamide 106 2-[(Benzofuran-2-ylmethyl)-amino]- 5.7 507 100
0.06 4630 3-(1H-indol-3-yl)-2-methyl-N-(2-
methyl-1,2,3,4-tetrahydro- isoquinolin-3-ylmethyl)- propionamide
107 2-[(Benzofuran-2-ylmethyl)-amino]- 14 464 100 0.05 4145
3-(1H-indol-3-yl)-2-methyl-N-(2- phenyl-cyclopropyl)-propionamide
108 2-[(Benzofuran-2-ylmethyl)-amino]- 0.6 493 100 0.05 4566
3-(1H-indol-3-yl)-2-methyl-N- (1,2,3,4-tetrahydro-isoquinolin-3- -
ylmethyl)-propionamide 109 2-[(Benzofuran-2-ylmethyl)-ami- no]-
30.3 512 100 0.06 279 N-(2,5-dichloro-thiophen-3-
ylmethyl)-3-(1H-indol-3-yl)-2- methyl-propionamide 110
2-[(Benzofuran-2-ylmethyl)-amino]- 19.7 478 100 0.05 1141
3-(1H-indol-3-yl)-2-methyl-N-(1- phenyl-cyclopropylmethyl)-
propionamide 111 2-[(Benzofuran-2-ylmethyl)-amino]- 1 478 100 0.08
>10,000 3-(1H-indol-3-yl)-2-methyl-N-
(1,2,3,4-tetrahydro-naphthalen-2-yl)- propionamide 112
2-[(Benzofuran-2-ylmethyl)-amino]- 3 483 100 0.06 12
3-(1H-indol-3-yl)-2-methyl-N-(3- nitro-benzyl)-propionamide 113
2-[(Benzofuran-2-ylmethyl)-amino]- 10.1 464 100 0.05 463
N-indan-2-yl-3-(1H-indol-3-yl)-2- methyl-propionamide 114
2-[(Benzofuran-2-ylmethyl)-amino]- 2.5 472 90 0.05 128
3-(1H-indol-3-yl)-2-methyl-N-(1- thiophen-2-yl-propyl)-propionami-
de 115 2-[(Benzofuran-2-ylmethyl)-amino ]- 11.5 442 95 0.05 154
N-(2-furan-2-yl-ethyl)-3-(1H-indol- 3-yl)-2-methyl-propionami- de
116 2-[(Benzofuran-2-ylmethyl)-amino]- 5.6 460 100 0.05 >10,000
N-(1-hydroxy-cyclohexylmethyl)-3- (1H-indol-3-yl)-2-methyl-
propionamide 117 2-[(Benzofuran-2-ylmethyl)-amino]- 14.2 482 100
0.06 >10,000 N-(1-furan-2-yl-cyclobutylmethyl)-
3-(1H-indol-3-yl)-2-methyl- propionamide 118
2-[(Benzofuran-2-ylmethyl)-amino]- 15 492 100 0.06 45
N-[1-(5-chloro-thiophen-2-yl)- ethyl]-3-(1H-indol-3-yl)-2-methyl-
propionamide 119 2-[(Benzofuran-2-ylmethyl)-amino ]- 4.1 483 100
0.07 89 3-(1H-indol-3-yl)-2-methyl-N-(4- nitro-benzyl)-propionamide
120 2-[(Benzofuran-2-ylmethyl)-amino]- 0.7 506 94 0.06 2652
N-[2-(1H-indazol-3-yl)-1-methyl- ethyl]-3-(1H-indol-3-yl)-2-methy-
l- propionamide 121 2-[(Benzofuran-2-ylmethyl)-amino]- 15 441 100
0.05 654 3-(1H-indol-3-yl)-2-methyl-N-(2-
pyrrol-1-yl-ethyl)-propionamide 122 2-[(Benzofuran-2-ylmethyl)-ami-
no]- 8.7 526 100 0.08 442 N-[1-(2,5-dichloro-thiophen-3-yl)-
ethyl]-3-(1H-indol-3-yl)-2-methyl- propionamide 123
2-[(Benzofuran-2-ylmethyl)-amino]- 7.3 499 63 0.04 >10,000
3-(1H-indol-3-yl)-2-methyl-N-[2- (octahydro-indol-1-yl)-ethyl]-
propionamide 124 2-[(Benzofuran-2-ylmethyl)-amino]- 2.6 497 100
0.07 92 3-(1H-indol-3-yl)-2-methyl-N-[1-(4-
nitro-phenyl)-ethyl]-propionamide 125 2-[(Benzofuran-2-ylmethyl)-a-
mino]- 29.5 459 97 0.04 >10,000 3-(1H-indol-3-yl)-2-methyl-N-(2-
- piperidin-1-yl-ethyl)-propionamide 126
2-[(Benzofuran-2-ylmethyl)-amino]- 28 448 95 0.07 6794
3-(1H-indol-3-yl)-2-methyl-N-(2- methyl-[1,3]dioxolan-2-ylmethyl)-
- propionamide 127 2-[(Benzofuran-2-ylmethyl)-amino]- 23.9 427 100
0.05 191 N-furan-2-ylmethyl-3-(1H-indol-3-
yl)-2-methyl-propionamide 128 2-[(Benzofuran-2-ylmethyl)-amino ]-
31.7 461 95 0.03 >10,000 3-(1H-indol-3-yl)-2-methyl-N-(2-
morpholin-4-yl-ethyl)-propionamide 129 2-[(Benzofuran-2-ylmethy-
l)-amino]- 37.7 452 100 0.06 43 3-(1H-indol-3-yl)-2-methyl-N-(3-
methyl-benzyl)-propionamide 130 2-[(Benzofuran-2-ylmethyl)-a-
mino]- 37.8 464 100 0.05 163 N-indan-1-yl-3-(1H-indol-3-yl)-2-
methyl-propionamide 131 2-[(Benzofuran-2-ylmethyl)-amino]- 31.6 487
100 0.08 >10,000 3-(1H-indol-3-yl)-2-methyl-N-(2-
methyl-2-piperidin-1-yl-propyl)- propionamide 132
2-[(Benzofuran-2-ylmethyl)-amino]- 24.6 476 97 0.02 6035
3-(1H-indol-3-yl)-2-methyl-N-[2-(2- thioxo-imidazolidin-1-yl)-eth-
yl]- propionamide 133 2-[(Benzofuran-2-ylmethyl)-amino]- 5 480 87
0.06 4479 3-(1H-indol-3-yl)-2-methyl-N-(2- methyl-2-phenyl-propyl)-
propionamide 134 2-[(Benzofuran-2-ylmethyl)-amino]- 27.3 456 100
0.02 5368 N-(3-imidazol-1-yl-propyl)-3-(1H-
indol-3-yl)-2-methyl-propionami- de 135
2-[(Benzofuran-2-ylmethyl)-amino]- 13.5 432 100 0.03 1205
3-(1H-indol-3-yl)-2-methyl-N- (tetrahydro-furan-2-ylmethyl)-
propionamide 136 2-[(Benzofuran-2-ylmethyl)-amino]- 26.6 446 95
0.02 >10,000 3-(1H-indol-3-yl)-2-methyl-N-(2-
methyl-tetrahydro-furan-2- ylmethyl)-propionamide 137
2-[(Benzofuran-2-ylmethyl)-amino]- 33.6 444 96 0.03 100
3-(1H-indol-3-yl)-2-methyl-N- thiophen-2-ylmethyl-propionamide 138
2-[(Benzofuran-2-ylmethyl)-amino]- 25.4 432 96 0.02 4867
3-(1H-indol-3-yl)-2-methyl-N- (tetrahydro-furan-2-ylmethyl)-
propionamide 139 2-[(Benzofuran-2-ylmethyl)-amino]- 41.7 474 93
0.05 99 N-(2,5-difluoro-benzyl)-3-(1H-indol-
3-yl)-2-methyl-propionamide 140 2-[(Benzofuran-2-ylmethyl)-amino]-
31.8 466 100 0.05 >10,000 3-(1H-indol-3-yl)-2-methyl-N-(2-
phenyl-propyl)-propionamide 141 N-(4-Amino-naphthalen-1- 11.6 503
95 0.03 2337 ylmethyl)-2-[(benzofuran-2-
ylmethyl)-amino]-3-(1H-indol-3-yl)- 2-methyl-propionamide 142
2-[(Benzofuran-2-ylmethyl)-amino]- 19.3 498 96 0.03 1961
N-(2,3-dimethoxy-benzyl)-3-(1H- indol-3-yl)-2-methyl-propionamide
143 2-[(Benzofuran-2-ylmethyl)-amino]- 32.9 468 96 0.02 >10,000
N-[2-(4-hydroxy-phenyl)-ethyl]-3- (1H-indol-3-yl)-2-methy- l-
propionamide 144 2-[(Benzofuran-2-ylmethyl)-amino]- 16.4 446 94
0.02 >10,000 N-(1-hydroxymethyl-cyclopentyl)-3-
(1H-indol-3-yl)-2-methyl- propionamide 145
2-[(Benzofuran-2-ylmethyl)-amino]- 35.9 453 97 0.01 1301
3-(1H-indol-3-yl)-2-methyl-N-(2- pyridin-3-yl-ethyl)-propionamide
146 2-[(Benzofuran-2-ylmethyl)-amino]- 0.8 444 90 0.02 3587
N-[1-(4,5-dihydro-furan-2-yl)-ethyl]- 3-(1H-indol-3-yl)-2-methyl- -
propionamide 147 2-[(Benzofuran-2-ylmethyl)-amino]- 18.5 460 98
0.02 >10,000 3-(1H-indol-3-yl)-2-methyl-N-(2-
piperazin-1-yl-ethyl)-propionamide 148 2-[(Benzofuran-2-ylmethyl)--
amino]- 34.7 478 93 0.03 >10,000 3-(1H-indol-3-yl)-2-methyl-N-
(1,2,3,4-tetrahydro-naphthalen-1-yl)- propionamide 149
2-[(Benzofuran-2-ylmethyl)-amino]- 31.8 490 75 0.02 >10,000
N-(2,5-dimethoxy-2,5-dihydro- furan-2-ylmethyl)-3-(1H-indol-3-yl-
)- 2-methyl-propionamide 150 2-[(Benzofuran-2-ylmethyl)-ami- no]-
32.4 466 95 0.04 2621 3-(1H-indol-3-yl)-2-methyl-N-(2-
phenyl-propyl)-propionamide 151 2-[(Benzofuran-2-ylmethyl)-amino]-
- 2.4 489 100 0.02 1213 3-(1H-indol-3-yl)-2-methyl-N-
quinolin-3-ylmethyl-propionamide 152 4-[2-[(Benzofuran-2-ylmethyl)-
- 9 510 94 0.01 >10,000 amino]-3-(1H-indol-3-yl)-2-methyl-
propionylamino]-3-phenyl-butyric acid 153
2-[(Benzofuran-2-ylmethyl)-amino]- 6.9 514 100 0.01 3555
N-[2-hydroxy-2-(4-hydroxy-3- methoxy-phenyl)-ethyl]-3-(1H-
indol-3-yl)-2-methyl-propionamide 154 2-[(Benzofuran-2-ylmethyl)--
amino]- 6.1 431 5 0.04 >10,000 3-(1H-indol-3-yl)-2-methyl-N-
pyrrolidin-3-ylmethyl-propionamide 155
2-[(Benzofuran-2-ylmethyl)-amino]- 25.2 445 93 0.02 >10,000
3-(1H-indol-3-yl)-2-methyl-N-(2- pyrrolidin-1-yl-ethyl)-propionam-
ide 156 2-[(Benzofuran-2-ylmethyl)-amino]- 1.4 445 3 0.05
>10,000 3-(1H-indol-3-yl)-2-methyl-N-
piperidin-4-ylmethyl-propionamide 157 2-[(Benzofuran-2-ylmethyl)-a-
mino]- 38.2 452 95 0.02 455 3-(1H-indol-3-yl)-2-methyl-N-(2-
methyl-benzyl)-propionamide 158 2-[(Benzofuran-2-ylmethyl)-amino-
]- 21.4 464 96 0.02 2567 N-indan-1-yl-3-(1H-indol-3-yl)-2-
methyl-propionamide 159 2-[(Benzofuran-2-ylmethyl)-amino]- 7 492 92
0.01 3757 3-(1H-indol-3-yl)-2-methyl-N-(1-
pyridin-3-yl-cyclobutylmethyl) propionamide 160
2-[(Benzofuran-2-ylmethyl)-amino]- 6.1 511 100 0.03 >10,000
3-(1H-indol-3-yl)-2-methyl-N-(1- thiophen-2-yl-cyclohexyl)-
propionamide 161 2-[Benzofuran-2-ylmethyl)amino]- 12.3 484 100 0.01
>10,000 N-[2-(3,4-dihydroxy-phenyl)-ethyl]-
3-(1H-indol-3-yl)-2-methyl- propionamide 162
2-[(Benzofuran-2-ylmethyl)-amino]- 8.7 466 95 0.02 42
3-(1H-indol-3-yl)-2-methyl-N-(1- phenyl-propyl)-propionamide 163
2-[(Benzofuran-2-ylmethyl)-amino]- 16.9 466 80 0.07 166
3-(1H-indol-3-yl)-2-methyl-N-(2- oxo-2-phenyl-ethyl)-propionamide
164 2-[(Benzofuran-2-ylmethyl)-amino]- 5.5 542 10 0.06 >10,000
N-(5-hydroxy-4-oxo-4H-pyran-2- ylmethyl)-3-(1H-indol-3-yl- )-2-
methyl-propionamide 165 2-[(Benzofuran-2-ylmethyl)-ami- no]- 38.1
456 100 0.08 >10,000 N-bicyclo[2.2.1]hept-2-ylmethyl-- 3-
(1H-indol-3-yl)-2-methyl- propionamide 166
2-[Benzofuran-2-ylmethyl)-amino]- 41.9 456 95 0.07 37
N-(3-fluoro-benzyl)-3-(1H-indol-3- yl)-2-methyl-propionamide 167
2-[(Benzofuran-2-ylmethyl)-amino]- 23.2 474 100 0.07 29
N-(3,4-difluoro-benzyl)-3-(1H-indol- 3-yl)-2-methyl-propionamide
168 2-[(Benzofuran-2-ylmethyl)-amino]- 42.8 490 95 0.08 230
N-(2-chloro-4-fluoro-benzyl)-3-(1H- indol-3-yl)-2-methyl-propion-
amide 169 2-[(Benzofuran-2-ylmethyl)-amino]- 11.2 467 100 0.06 6016
N-(4,6-dimethyl-pyridin-3- ylmethyl)-3-(1H-indol-3-yl)-2-
methyl-propionamide 170 2-[(Benzofuran-2-ylmethyl)-amino]- 49.6 533
100 0.08 2384 N-(5-bromo-2-hydroxy-benzyl)-3-
(1H-indol-3-yl)-2-methyl- propionamide 171
4-{[2-[(Benzofuran-2-ylmethyl)- 28.7 482 95 0.06 >10,000
amino]-3-(1H-indol-3-yl)-2-methyl- propionylamino]-methyl}-benzoi-
c acid 172 2-[(Benzofuran-2-ylmethyl)-amino]- 36.8 458 100 0.07 153
3-(1H-indol-3-yl)-2-methyl-N-(2- thiophen-2-yl-ethyl)-propionamide
173 2-[(Benzofuran-2-ylmethyl)-a- mino]- 36.3 475 90 0.06
>10,000 3-(1H-indol-3-yl)-2-methyl-N-(2- -
morpholin-4-yl-2-oxo-ethyl)- propionamide 174 N-Benzo[1,3
]dioxol-5-ylmethyl-2- 45.7 482 100 0.07 94
[(benzofuran-2-ylmethyl)-amino]-3- (1H-indol-3-yl)-2-methyl-
propionamide 175 2-[(Benzofuran-2-ylmethyl)-amino]- 21.4 507 90
0.08 96 N-(3,4-dichloro-benzyl)-3-(1H-
indol-3-yl)-2-methyl-propionamide 176 2-[2-[(Benzofuran-2-ylmethyl-
)- 44.3 453 100 0.07 1763 amino]-3-(1H-indol-3-yl)-2-methyl-
propionylamino]-3-(1H-imidazol-4- yl)-propionic acid methyl ester
177 2-[(Benzofuran-2-ylmethyl)-amino]- 24.6 490 100 0.08 444
N-(4-chloro-2-fluoro-benzyl)-3-(1H-
indol-3-yl)-2-methyl-propionamide 178 N-(3-Amino-benzyl)-2- 36.2
453 100 0.06 1373 [(benzofuran-2-ylmethyl)-amino]-3-
(1H-indol-3-yl)-2-methyl- propionamide 179
2-[(Benzofuran-2-ylmethyl)-amino]- 3.1 470 56 0.06 5917
N-(2,4-diamino-pyrimidin-5- ylmethyl)-3-(1H-indol-3-yl)-2-
methyl-propionamide 180 2-[Benzofuran-2-ylmethyl)-amino]- 42 456 95
0.07 266 N-(2-fluoro-benzyl)-3-(1H-indol-3-
yl)-2-methyl-propionamide 181 2-[(Benzofuran-2-ylmethyl)-amino]-
23.4 474 100 0.07 269 N-(2,4-difluoro-benzyl)-3-(1H-indol-
3-yl)-2-methyl-propionamide 182 2-[(Benzofuran-2-ylmethyl)amino]-
4.1 470 90 0.06 >10,000 N-(3,4-dihydroxy-benzyl)-3-(1H-
indol-3-yl)-2-methyl-propionamide 183 2-[(Benzofuran-2-ylmethyl)--
amino]- 1.7 472 33 0.05 >10,000 N-[1-hydroxymethyl-2-(1H-
imidazol-4-yl)-ethyl]-3-(1H-indol-3- yl)-2-methyl-propionamide 184
2-[(Benzofuran-2-ylmethyl)-amino]- 36.4 460 100 0.07 >10,000
N-(2-hydroxy-cyclohexylmethyl)-3- (1H-indol-3-yl)-2-methyl-
propionamide 185 2-[(Benzofuran-2-ylmethyl)-amino]- 28.5 475 100
0.06 >10,000 3-(1H-indol-3-yl)-2-methyl-N-(3-
morpholin-4-yl-propyl)- propionamide 186
2-[Benzofuran-2-ylmethyl)-amino]- 8.5 454 81 0.07 84
N-(2-hydroxy-benzyl)-3-(1H-indol- 3-yl)-2-methyl-propionamide 187
2-[(Benzofuran-2-ylmethyl)-amino]- 42.2 486 100 0.07 131
N-(3-fluoro-4-methoxy-benzyl)-3- (1H-indol-3-yl)-2-methyl-
propionamide 188 N-(2-Amino-methoxy-benzyl)-2- 10 483 96 0.06 2282
[(benzofuran-2-ylmethyl)-amino]-3- (1H-indol-3-yl)-2-methyl-
propionamide 189 2-[(Benzofuran-2-ylmethyl)-amino]- 47 472 94 0.07
1129 N-(2-chloro-benzyl)-3-(1H-indol-3- yl)-2-methyl-propionamide
190 2-[(Benzofuran-2-ylmethyl)-amino]- 41.6 474 97 0.07 3537
N-(2,6-difluoro-benzyl)-3-(1H-indol- 3-yl)-2-methyl-propionamide
191 2-[(Benzofuran-2-ylmethyl)-amino]- - 24.4 490 99 0.07 55
N-(3-chloro-4-fluoro-benzyl)-3-(1H-
indol-3-yl)-2-methyl-propionamide
[0341]
5TABLE 3 Examples 192-308 Yield Mol. Icms % Icms Rt IC.sub.50 (nM)
Ex. Name (mg) ion purity (min) hNK.sub.1 192
2-[(Benzofuran-2-ylmethyl)-amino]- 26 425 100 3.94 1981
3-(1H-indol-3-yl)-N-pyridin-2- ylmethyl-propionamide 193
2-[(Benzofuran-2-ylmethyl)-amino]- 27 446 94 1.04 >10,000
3-(1H-indol-3-yl)-N-(2-piperazin-1- yl-ethyl)-propionamide 194
2-[(Benzofuran-2-ylmethyl)-amino]- 41 464 100 5.63, 703
3-(1H-indol-3-yl)-N-(1,2,3,4- 5.80 tetrahydro-naphthalen-1-yl- )-
propionamide 195 2[(Benzofuran-2-ylmethyl)-amino]- 23 450 100 5.39
1750 N-indan-1-yl-3-(1H-indol-3-yl)- propionamide 196
2-[(Benzofuran-2-ylmethyl)-amino]- 36 458 100 5.67 92
3-(1H-indol-3-yl)-N-(1-thiophen-2- yl-propyl)-propionamide 197
2-[(Benzofuran-2-ylmethyl)-amino]- 44 488 99 6.77 933
3-(1H-indol-3-yl)-N-(1-naphthalen- 1-yl-ethyl)-propionamide 198
2-[(Benzofuran-2-ylmethyl)-amino]- 31 445 99 2.27 >10,000
3-(1H-indol-3-yl)-N-[2-(1-methyl-
pyrrolidin-2-yl)-ethyl]-propionamide 199 2-[(Benzofuran-2-ylmethyl-
)-amino]- 39 454 100 5.11 130 3-(1H-indol-3-yl)-N-(4-methoxy-
benzyl)-propionamide 200 2-[(Benzofuran-2-ylmethyl)-amino]- 34 508
96 6.19 355 3-(1H-indol-3-yl)-N-(3- trifluoromethoxy-benzyl)-
propionamide 201 2-[(Benzofuran-2-ylmethyl)-amino]- 21 442 100 1.22
>10,000 N-(3-imidazol-1-yl-propyl)-3-(1H-
indol-3-yl)-propionamide 202 2-[(Benzofuran-2-ylmethyl)-amino]- 6
417 98 4.3 2184 3-(1H-indol-3-yl)-N-pyrrolidin-3-
ylmethyl-propionamide 203 2-[(Benzofuran-2-ylmethyl)-amino]- 22 431
96 1.26 >10,000 3-(1H-indol-3-yl)-N-piperidin-4-
ylmethyl-propionamide 204 2-[(Benzofuran-2-ylmethyl)-amino]- 18 460
100 5.53 68 N-(2,5-difluoro-benzyl)-3-(1H-indol- 3-yl)-propionamide
205 2-[(Benzofuran-2-ylmethyl)-amino]- 10 475 97 4.27 2315
3-(1H-indol-3-yl)-N-quinolin-3- ylmethyl-propionamide 206
2-[(Benzofuran-2-ylmethyl)-amino]- 16 428 98 2.31 6681
N-[2-(1H-imidazol-4-yl)-ethyl]-3- (1H-indol-3-yl)-propionamide 207
2-[(Benzofuran-2-ylmethyl)-amino]- 43 489 98 6.76 591
3-(1H-indol-3-yl)-N-(1-naphthalen- 1-yl-ethyl)-propionamide 208
2-[(Benzofuran-2-ylmethyl)-amino]- 31 458 100 5.94 15
3-(1H-indol-3-yl)-N-[1-(5-methyl- thiophen-2-yl)-ethyl]-propional-
nide 209 2-[(Benzofuran-2-ylmethyl)-amino]- 35 438 100 5.74 82
3-(1H-indol-3-yl)-N-(4-methyl- benzyl)-propionamide 210
2-[(Benzofuran-2-ylmethyl)-amino]- 36 452 100 5.98 337
3-(1H-indol-3-yl)-N-(1-p-tolyl- ethyl)-propionamide 211
2-[(Benzofuran-2-ylmethyl)-amino]- 21 432 100 5 >10,000
N-(1-hydroxymethyl-cyclopentyl)-3- (1H-indol-3-yl)-propionamide 212
2-[(Benzofuran-2-ylmethyl)-amino]- 18 427 96 5.21 658
3-(1H-indol-3-yl)-N-(2-pyrrol-1-yl- ethyl)-propionamide 213
2-[(Benzofuran-2-ylmethyl)-amino]- 28 447 100 1.39 1256
3-(1H-indol-3-yl)-N-(2-morpholin-4- yl-ethyl)-propionamide 214
2-[(Benzofuran-2-ylmethyl)-amino]- 39 467 99 4.3 4015
N-(4-dimethylamino-benzyl)-3-(1H- indol-3-yl)-propionamide 215
2-[(Benzofuran-2-ylmethyl)-amino]- 9 498 97 6.61 70
N-(2,5-dichloro-thiophen-3- ylmethyl)-3-(1H-indol-3-yl)-
propionamide 216 2-[(Benzofuran-2-ylmethyl)-amino]- 2 459 11 5.07
>10,000 3-(1H-indol-3-yl)-N-(5-nitro-furan-
2-ylmethyl)-propionamide 217 2-[(Benzofuran-2-ylmethyl)-amino]- 44
481 99 4.46, 819 N-[1-(4-dimethylamino-phenyl)- 4.78
ethyl]-3-(1H-indol-3-yl)- propionamide 218
2-[(Benzofuran-2-ylmethyl)-amino]- 20 560 85 7.14 294
N-(3,5-bis-trifluoromethyl-benzyl)- 3-(1H-indol-3-yl)-propionamid-
e 219 2-[(Benzofuran-2-ylmethyl)-amino]- 17 502 96 6.96 31
N-(3-bromo-benzyl)-3-(1H-indol-3- yl)-propionamide 220
2-[(Benzofuran-2-ylmethyl)-amino]- 38 452 100 6.16 2
3-(1H-indol-3-yl)-N-(1-p-tolyl- ethyl)-propionamide 221
2-[(Benzofuran-2-ylmethyl)-amino]- 37 469 100 5.67 23
3-(1H-indol-3-yl)-N-(4-nitro- benzyl)-propionamide 222
2-[(Benzofuran-2-ylmethyl)-amino]- 30 431 100 1.64 >10,000
3-(1H-indol-3-yl)-N-(2-pyrrolidin-1- yl-ethyl)-propionamide 223
2-[(Benzofuran-2-ylmethyl)-amino]- 36 418 100 4.65 >10,000
3-(1H-indol-3-yl)-N-(tetrahydro- furan-2-ylmethyl)-propionamide 224
2-[(Benzofuran-2-ylmethyl)-amino]- 9 450 100 6.05 2902
3-(1H-indol-3-yl)-N-(2-phenyl- cyclopropyl)-propionamide 225
2-[(Benzofuran-2-ylmethyl)-amino]- 32 458 97 7.07 1341
N-(1-cyclohexyl-1-methyl-ethyl)-3- (1H-indol-3-yl)-propionamide 226
2-[(Benzofuran-2-ylmethyl)-amino]- 33 430 100 6.23 54
N-cyclohexylmethyl-3-(1H-indol-3- yl)-propionamide 227
2-[(Benzofuran-2-ylmethyl)-amino]- 41 481 96 5.05, 182
N-[1-(3-dimethylamino-phenyl)- 5.36 ethyl]-3-(1H-indol-3-yl)-
propionamide 228 2-[(Benzofuran-2-ylmethyl)-amino]- 31 492 100 6.63
82 3-(1H-indol-3-yl)-N-(3- trifluoromethyl-benzyl)- propionamide
229 2-[(Benzofuran-2-ylmethyl)-amino]- 39 476 98 6.4 33
N-(3-chloro-4-fluoro-benzyl)-3-(1H- indol-3-yl)-propionamide 230
2-[(Benzofuran-2-ylmethyl)-amino]- 38 441 100 5.54 21
3-(1H-indol-3-yl)-N-[1-(1-methyl- 1H-pyrrol-3-yl)-ethyl]-propiona-
mide 231 2-[(Benzofuran-2-ylmethyl)-amino]- 35 425 100 0.04 790
3-(1H-indol-3-yl)-N-pyridin-3- ylmethyl-propionamide 232
2-[(Benzofuran-2-ylmethyl)-amino]- 30 430 100 0.06 63
3-(1H-indol-3-yl)-N-thiophen-2- ylmethyl-propionamide 233
2-[(Benzofuran-2-ylmethyl)-amino]- 37 452 100 0.07 1998
3-(1H-indol-3-yl)-N-(2-phenyl- propyl)-propionamide 234
2-[(Benzofuran-2-ylmethyl)-amino]- 37 438 100 0.07 75
3-(1H-indol-3-yl)-N-(1-phenyl- ethyl)-propionamide 235
2-[(Benzofuran-2-ylmethyl)-amino]- 40 456 100 0.07 3
N-[1-(4-fluoro-phenyl)-ethyl]-3-(1H- indol-3-yl)-propionamide 236
2-[(Benzofuran-2-ylmethyl)-amino]- 41 444 100 0.07 7
3-(1H-indol-3-yl)-N-(1-thiophen-3- yl-ethyl)-propionamide 237
2-[(Benzofuran-2-ylmethyl)-amino]- 38 435 0 0.10 5341
3-(1H-indol-3-yl)-N-(2-oxo-2- phenyl-ethyl)-propionamide 238
2-[(Benzofuran-2-ylmethyl)-amino]- 34 442 100 0.07 89
N-(2-fluoro-benzyl)-3-(1H-indol-3- yl)-propionamide 239
2-[(Benzofuran-2-ylmethyl)-amino]- 36 450 100 0.07 243
N-indan-2-yl-3-(1H-indol-3-yl)- propionamide 240
2-[(Benzofuran-2-ylmethyl)-amino]- 33 425 100 0.04 196
3-(1H-indol-3-yl)-N-pyridin-4- ylmethyl-propionamide 241
2-[(Benzofuran-2-ylmethyl)-amino]- 29 444 100 0.07 2
N-(1-cyclohexyl-ethyl)-3-(1H-indol- 3-yl)-propionamide 242
2-[(Benzofuran-2-ylmethyl)-amino]- 39 438 100 0.07 170
3-(1H-indol-3-yl)-N-(2-methyl- benzyl)-propionamide 243
2-[(Benzofuran-2-ylmethyl)-amino]- 44 478 100 0.07 15
N-[1-(5-chloro-thiophen-2-yl)- ethyl]-3-(1H-indol-3-yl)-
propionamide 244 2-[(Benzofuran-2-ylmethyl)-amino]- 38 442 100 0.07
12 N-(4-fluoro-benzyl)-3-(1H-indol-3- yl)-propionamide 245
2-[(Benzofuran-2-ylmethyl)-amino]- 32 483 100 0.07 3
3-(1H-indol-3-yl)-N-[1-(4-nitro- phenyl)-ethyl]-propionamide 246
2-[(Benzofuran-2-ylmethyl)-amino]- 39 438 100 0.07 77
3-(1H-indol-3-yl)-N-phenethyl- propionamide 247
2-[(Benzofuran-2-ylmethyl)-amino]- 33 444 100 0.07 56
3-(1H-indol-3-yl)-N-(2-thiophen-2- yl-ethyl)-propionamide 248
2-[(Benzofuran-2-ylmethyl)-amino]- 37 442 100 0.07 6
N-(3-fluoro-benzyl)-3-(1H-indol-3- yl)-propionamide 249
2-[(Benzofuran-2-ylmethyl)-amino]- 43 454 100 0.06 607
N-(2-hydroxy-1-phenyl-ethyl)-3- (1H-indol-3-yl)-propionamide 250
2-[(Benzofuran-2-ylmethyl)-amino]- - 36 464 100 0.05 3413
N-(1H-benzoimidazol-2-ylmethyl)- 3-(1H-indol-3-yl)-propionamide 251
2-[(Benzofuran-2-ylmethyl)-amin- o]- 4 428 95 0.06 129
N-(2-furan-2-yl-ethyl)-3-(1H-indol- 3-yl)-propionamide 252
2-[(Benzofuran-2-ylmethyl)-amino]- 37 438 100 0.07 33
3-(1H-indol-3-yl)-N-(3-methyl- benzyl)-propionamide 253
2-[(Benzofuran-2-ylmethyl)-amino]- 25 464 81 0.07 3327
3-(1H-indol-3-yl)-N-(1,2,3,4- tetrahydro-naphthalen-2-yl)-
propionamide 254 2-[(Benzofuran-2-ylmethyl)-amino]- 37 424 100 0.06
22 N-benzyl-3-(1H-indol-3-yl)- propionamide 255
2-[(Benzofuran-2-ylmethyl)-amino]- 41 468 100 0.07 9
3-(1H-indol-3-yl)-N-[1-(4-methoxy- phenyl)-ethyl]-propionamide 256
2-[(Benzofuran-2-ylmethyl)-amino]- 5 440 68 0.05 >10,000
N-(2-hydroxy-benzyl)-3-(1H-indol- 3-yl)-propionamide 257
2-[(Benzofuran-2-ylmethyl)-amino]- 35 466 100 0.07 >10,000
3-(1H-indol-3-yl)-N-(2-methyl-2- phenyl-propyl)-propionamide 258
2-[(Benzofuran-2-ylmethyl)-amino]- 38 458 100 0.07 46
N-(4-chloro-benzyl)-3-(1H-indol-3- yl)-propionamide 259
2-[(Benzofuran-2-ylmethyl)-amino]- 39 452 100 0.07 21
3-(1H-indol-3-yl)-N-(1-phenyl- propyl)-propionamide 260
2-[(Benzofuran-2-ylmethyl)-amino]- 32 469 100 0.06 14
3-(1H-indol-3-yl)-N-(3-nitro- benzyl)-propionamide 261
2-[(Benzofuran-2-ylmethyl)-amino]- 31 414 100 0.06 406
N-furan-2-ylmethyl-3-(1H-indol-3- yl)-propionamide 262
2-[(Benzofuran-2-ylmethyl)-amino]- 41 450 100 0.07 86
N-indan-1-yl-13-(1H-indol-3-yl)- propionamide 263
2-[(Benzofuran-2-ylmethyl)-amino]- 36 458 100 0.07 9
N-(3-chloro-benzyl)-3-(1H-indol-3- yl)-propionamide 264
2-((Benzofuran-2-ylmethyl)-amino]- 44 472 100 0.07 7
N-[1-(4-chloro-phenyl)-ethyl]-3- (1H-indol-3-yl)-propionamide 265
2-[(Benzofuran-2-ylmethyl)-amino]- 41 452 96 0.07 328
3-(1H-indol-3-yl)-N-(1-methyl-1- phenyl-ethyl)-propionamide 266
2-[(Benzofuran-2-ylmethyl)-amino]- 39 442 100 0.07 633
N-bicyclo[2.2.1]hept-2-ylmethyl-3- (1H-indol-3-yl)-propionamide 267
N-Benzo[1,3]dioxol-5-ylmethyl-2- 40 468 100 0.06 55
[(benzofuran-2-ylmethyl)-amino]-3- (1H-indol-3-yl)-propionamide 268
2-[(Benzofuran-2-ylmethyl)-amino]- 39 460 91 0.07 10
N-(3,4-difluoro-benzyl)-3-(1H-indol- 3-yl)-propionamide 269
2-[(Benzofuran-2-ylmethyl)-amino]- 9 439 92 0.04 9
3-(1H-indol-3-yl)-N-(1-pyridin-4-yl- ethyl)-propionamide 270
2-[(Benzofuran-2-ylmethyl)-amino]- 19 432 100 0.04 >10,000
N-(2-hydroxy-cyclohexyl)-3-(1H- indol-3-yl)-propionamide 271
2-[(Benzofuran-2-ylmethyl)-amino]- 33 468 98 0.05 196
3-(1H-indol-3-yl)-N-[2-(4-methoxy- phenyl)-ethyl]-propionamide 272
2-[(Benzofuran-2-ylmethyl)-amino]- 42 468 99 0.05 336
N-(1-hydroxymethyl-2-phenyl- ethyl)-3-(1H-indol-3-yl)- propionamide
273 2-[(Benzofuran-2-ylmethyl)-amino]- 15 432 99 0.04 >10,000
N-(4-hydroxy-cyclohexyl)-3-(1H- indol-3-yl)-propionamide 274
2-[(Benzofuran-2-ylmethyl)-amino]- 21 456 97 0.05 264
N-[2-(2-fluoro-phenyl)-ethyl]-3-(1H- indol-3-yl)-propionamide 275
2-[(Benzofuran-2-ylmethyl)-amino]- 38 514 100 0.05 2157
N-(2-benzylsulfanyl-1- hydroxymethyl-ethyl)-3-(1H-indol-
3-yl)-propionamide 276 2-[(Benzofuran-2-ylmethyl)-amino]- 10 416 84
0.05 655 N-cyclohexyl-3-(1H-indol-3-yl)- propionamide 277
2-[(Benzofuran-2-ylmethyl)-amino]- 17 474 96 0.05 2198
N-(2-cyclohexyl-1-hydroxymethyl- ethyl)-3-(1H-indol-3-yl)-
propionamide 278 2-[(Benzofuran-2-ylmethyl)-amino]- 33 452 88 0.05
2379 3-(1H-indol-3-yl)-N-(3-phenyl- propyl)-propionamide 279
2-[(Benzofuran-2-ylmethyl)-amino]- 8 493 86 0.06 30
N-(3,4-dichloro-benzyl)-3-(1H- indol-3-yl)-propionamide 280
2-[(Benzofuran-2-ylmethyl)-amino]- 25 477 97 0.05 2540
3-(1H-indol-3-yl)-N-[2-(1H-indol-3- yl)-ethyl]-propionamide 281
2-[(Benzofuran-2-ylmethyl)-amino]- 28 483 93 0.05 51
3-(1H-indol-3-yl)-N-[2-(4-nitro- phenyl)-ethyl]-propionamide 282
2-[(Benzofuran-2-ylmethyl)-amino]- 30 487 98 0.06 833
N-[2-(4-chloro-phenyl)-1-methyl- ethyl]-3-(1H-indol-3-yl)-
propionamide 283 2-[(Benzofuran-2-ylmethyl)-amino]- 9 492 91 0.06
420 3-(1H-indol-3-yl)-N-(4- trifluoromethyl-benzyl)- propionamide
284 2-[(Benzofuran-2-ylmethyl)-amino]- 33 456 98 0.05 62
N-[2-(4-fluoro-phenyl)-ethyl]-3-(1H- indol-3-yl)-propionamide 285
2-[(Benzofuran-2-ylmethyl)-amino]- 32 483 99 0.05 246
3-(1H-indol-3-yl)-N-[1-(4-nitro- phenyl)-ethyl]-propionamide 286
4-{[2-[(Benzofuran-2-ylmethyl)-6 474 62 005 >10,000
amino]-3-(1H-indol-3-yl)- propionylamino]-methyl}-
cyclohexanecarboxylic acid 287 2-[(Benzofuran-2-ylmethyl)-amino]-
36 449 99 0.06 35 N-(cyano-phenyl-methyl)-3-(1H-
indol-3-yl)-propionamide 288 2-[(Benzofuran-2-ylmethyl)-amino]- 32
472 99 0.06 136 N-[2-(4-chloro-phenyl)-ethyl]-3-
(1H-indol-3-yl)-propionamide 289 2-[(Benzofuran-2-ylmethyl)-amino]-
35 468 99 0.05 209 N-(1-hydroxymethyl-2-phenyl-
ethyl)-3-(1H-indol-3-yl)- propionamide 290
2-[(Benzofuran-2-ylmethyl)-amino]- 37 517 100 0.06 8
N-[1-(4-bromo-phenyl)-ethyl]-3- (1H-indol-3-yl)-propionamide 291
2-[(Benzofuran-2-ylmethyl)-amino]- - 29 468 96 0.05 1337
3-(1H-indol-3-yl)-N-[2-(3-methoxy- phenyl)-ethyl]-propionamide 292
2-[(Benzofuran-2-ylmethyl)-amino]- 3 492 90 0.06 1126
3-(1H-indol-3-yl)-N-(2- trifluoromethyl-benzyl)- propionamide 293
2-[(Benzofuran-2-ylmethyl)-amino]- 33 456 96 0.05 55
N-[2-(3-fluoro-phenyl)-ethyl]-3-(1H- indol-3-yl)-propionamide 294
2-[(Benzofuran-2-ylmethyl)-amino]- 15 444 86 0.06 58
N-(1-cyclohexyl-ethyl)-3-(1H-indol- 3-yl)-propionamide 295
2-[(Benzofuran-2-ylmethyl)-amino]- 34 482 99 0.06 3531
3-(1H-indol-3-yl)-N-(1- methoxymethyl-2-phenyl-ethyl)- propionamide
296 2-[(Benzofuran-2-ylmethyl)-amino]- 16 484 98 0.06 1338
N-(2-benzylsulfanyl-ethyl)-3-(1H- indol-3-yl)-propionamide 297
2-[(Benzofuran-2-ylmethyl)-amino]- 36 491 100 0.05 3612
3-(1H-indol-3-yl)-N-[2-(1H-indol-3-
yl)-1-methyl-ethyl]-propionamide 298 2-[(Benzofuran-2-ylmethyl)-am-
ino]- 22 458 99 0.06 221 N-(2-chloro-benzyl)-3-(1H-indol-3-
yl)-propionamide 299 2-[(Benzofuran-2-ylmethyl)-amino]- 28 454 93
0.05 4 N-(2-hydroxy-1-phenyl-ethyl)-3- (1H-indol-3-yl)-propionamide
300 2-[(Benzofuran-2-ylmethyl)-amino]- - 10 452 98 0.06 256
3-(1H-indol-3-yl)-N-(2-p-tolyl- ethyl)-propionamide 301
2-[(Benzofuran-2-ylmethyl)-amino]- 12 460 98 0.06 53
N-(2,4-difluoro-benzyl)-3-(1H-indol- 3-yl)-propionamide 302
2-[(Benzofuran-2-ylmethyl)-amino]- 25 503 98 0.06 174
N-(2-bromo-benzyl)-3-(1H-indol-3- yl)-propionamide 303
2-[(Benzofuran-2-ylmethyl)-amino]- 7 510 88 0.06 17
N-(3-fluoro-5-trifluoromethyl- benzyl)-3-(1H-indol-3-yl)-
propionamide 304 [2-[(Benzofuran-2-ylmethyl)- 36 482 100 0.06 43
amino]-3-(1H-indol-3-yl)- propionylamino]-phenyl-acetic acid methyl
ester 305 2-[(Benzofuran-2-ylmethyl)-amino]- 30 454 99 0.06 400
3-(1H-indol-3-yl)-N-(2-phenoxy- ethyl)-propionamide 306
N-(4-Amino-benzyl)-2- 32 439 99 0.04 639
[(benzofuran-2-ylmethyl)-amino]-3- (1H-indol-3-yl)-propiona- mide
307 2-[(Benzofuran-2-ylmethyl)-amino]- 36 466 99 0.06 392
3-(1H-indol-3-yl)-N-(1-methyl-3- phenyl-propyl)-propionamide 308
2-[(Benzofuran-2-ylmethyl)-amino]- 6 440 94 0.05 731
N-(3-hydroxy-benzyl)-3-(1H-indol- 3-yl)-propionamide
[0342]
6TABLE 4 Examples 309-359 Yield Mol. Icms % Icms Rt IC.sub.50 (nM)
Ex. Name (mg) ion purity (min) hNK.sub.1 309
3-(1H-Indol-3-yl)-2-methyl-2- 30.51 462 50 6.44 169
[(naphthalen-2-ylmethyl)-amino]-N- (1-phenyl-ethyl)-propiona- mide
310 3-(1H-Indol-3-yl)-2-methyl-N-(1- 37.02 413 83 4.74 3325
phenyl-ethyl)-2-[(pyridin-2- ylmethyl)-amino]-propionamide 311
3-(1H-Indol-3-yl)-2-methyl-N-(1- 31.53 463 84 5.96 88
phenyl-ethyl)-2-[(quinolin-2- ylmethyl)-amino]-propionamide 312
2-[(Furan-3-ylmethyl)-amino]-3- 28 402 78 4.9 1820
(1H-indol-3-yl)-2-methyl-N-(1- phenyl-ethyl)-propionamide 313
3-(1H-Indol-3-yl)-2-methyl-N-(1- 41.02 452 8 6.02 50
phenyl-ethyl)-2-[(pyridin-4- ylmethyl)-amino]-propionamide 314
2-[(Furan-2-ylmethyl)-amino]-3- 27.6 402 74 4.82 141
(1H-indol-3-yl)-2-methyl-N-(1- phenyl-ethyl)-propionamide 315
3-(1H-Indol-3-yl)-2-methyl-N-(1- 3.13 463 12 3.78 1068
phenyl-ethyl)-2-[(quinolin-3- ylmethyl)-amino]-propionamide 316
2-[(1H-Benzoimidazol-2-ylmethyl)- 58.59 452 16 4.63 >10,000
amino]-3-(1H-indol-3-yl)-2-methyl- N-(1-phenyl-ethyl)-propionam-
ide 317 3-(1H-Indo1-3-yl)-2-[(5-methoxy- 33.16 482 75 7.29
>10,000 benzofuran-2-ylmethyl)-amino]-2-
methyl-N-(1-phenyl-ethyl)- propionamide 318
3-(1H-Indol-3-yl)-2-](isoquinolin-4- 8.84 463 55 3.28 1596
ylmethyl)-amino]-2-methyl-N-(1- phenyl-ethyl)-propionamide 319
3-(1H-Indol-3-yl)-2-](6-methoxy- 5.15 482 65 7.22 2098
benzofuran-2-ylmethyl)-amino]-2- methyl-N-(1-phenyl-ethyl)-
propionamide 320 3-(1H-Indol-3-yl)-2-methyl-N-(1- 20.2 413 72 2.51
5972 phenyl-ethyl)-2-[(pyridin-3- ylmethyl)-amino]-propionamide 321
2-{2-[2-(1,3-Dioxo-1,3-dihydro- 20.67 552 96 0.05 3040
isoindol-2-yl)-acetylamino]- ethylamino}-3-(1H-indol-3-yl)-2-
methyl-N-(1-phenyl-ethyl)- propionamide 322
2-(3-Furan-2-yl-allylamino)-3-(1H- 2.88 428 47 0.05 91
indol-3-yl)-2-methyl-N-(1-phenyl- ethyl)-propionamide 323
3-(1H-Indol-3-yl)-2-methyl-N-(1- 28.74 519 69 0.05 3183
phenyl-ethyl)-2-[2-(pyridin-2- ylmethoxy)-benzylamino]-
propionamide 324 3-(1H-Indol-3-yl)-2-methyl-N-(1- 32.96 519 88 0.04
2971 phenyl-ethyl)-2-[2-(pyridin-3- ylmethoxy)-benzylamino]-
propionamide 325 3-(1H-Indol-3-yl)-2-methyl-N-(1- 42.66 504 77 0.06
72 phenyl-ethyl)-2-[(5-styryl-furan-2-
ylmethyl)-amino]-propionamide 326 2-(4-Chloro-3-methylsulfamoyl-
8.05 539 83 0.05 4827 benzylamino)-3-(1H-indol-3-yl)-2-
methyl-N-(1-phenyl-ethyl)- propionamide 327
5-(4-{[2-(1H-Indol-3-yl)-1-methyl- 7.02 556 92 0.05 >10,000
1-(1-phenyl-ethylcarbamoyl)- ethylamino]-methyl}-phenoxy)-2,2-
dimethyl-pentanoic acid 328 3-(1H-Indol-3-yl)-2-methyl-2-{[4- 17.49
498 86 0.07 >10,000 (4-methyl-pent-2-enyl)-cyclohex-3-
enylmethyl]-amino}-N-(1-phenyl- ethyl)-propionamide 329
(2-{[2-(1H-Indol-3-yl)-1-methyl-1- 16.92 499 95 0.05 4188
(1-phenyl-ethylcarbamoyl)- ethylamino]-methyl}-phenyl)- carbamic
acid ethyl ester 330 2-(4-Chloro-2-methylsulfamoyl- 7.56 539 89
0.05 1100 benzylamino)-3-(1H-indol-3-yl)-2-
methyl-N-(1-phenyl-ethyl)- propionamide 331
2-[4-(2-Dimethylamino-ethoxy)- 24.9 499 65 0.03 >10,000
benzylamino]-3-(1H-indol-3-yl)-2- methyl-N-(1-phenyl-ethyl)-
propionamide 332 2-(2,3-Diphenyl-propylamino)-3- 10.84 516 98 0.06
4944 (1H-indol-3-yl)-2-methyl-N-(1- phenyl-ethyl)-propionamide 333
3-(1H-Indol-3-yl)-2-methyl-N-(1- 16.98 516 98 0.06 3606
phenyl-ethyl)-2-[(1-phenyl-1H- indol-2-ylmethyl)-amino]-
propionamide 334 3-(1H-Indol-3-yl)-2-methyl-N-(1- 19.88 527 74 0.06
>10,000 phenyl-ethyl)-2-[4-(4-phenyl-
piperidin-1-yl)-benzylamino]- propionamide 335
3-(1H-Indol-3-yl)-2-methyl-N-(1- 38.16 571 65 0.06 >10,000
phenyl-ethyl)-2-[4-(2-pyrrolidin-1- yl-ethoxy)-benzylamino]-
propionamide 336 2-(4-Chloro-3-sulfamoyl- 5.2 525 79 0.03 4229
benzylamino)-3-(1H-indol-3-yl)-2- methyl-N-(1-phenyl-ethyl)-
propionamide 337 4-{[2-(1H-Indol-3-yl)-1-methy1-1- 20.24 525 81
0.04 1920 (1-phenyl-ethylcarbamoyl)- ethylamino]-methyl}-benzoic
acid methyl ester 338 2-(2,3-Diphenyl-allylamino)-3-(1H- 20.13 470
99 0.05 >10,000 indol-3-yl)-2-methyl-N-(1-phenyl-
ethyl)-propionamide 339 2-(3-Benzo[1,3]dioxol-5-yl- 24.74 514 54
0.06 343 allylamino)-3-(1H-indol-3-yl)-2-
methyl-N-(1-phenyl-ethyl)- propionamide 340
2-[3-(4-Benzyloxy-phenyl)- 24.64 482 72 0.05 4912
allylamino]-3-(1H-indol-3-yl)-2- methyl-N-(1-phenyl-ethyl)-
propionamide 341 2-(4-Benzyloxy-benzylamino)-3- 32.02 544 62 0.06
>10,000 (1H-indol-3-yl)-2-methyl-N-(1-
phenyl-ethyl)-propionamide 342 Toluene-4-sulfonic acid 3-{[2-(1H-
20.65 518 96 0.06 5091 indol-3-yl)-1-methyl-1-(1-phenyl-
ethylcarbamoyl)-ethylamino]- methyl}-phenyl ester 343
2-[(Benzofuran-2-ylmethyl)-amino]- 23.9 582 93 0.06 13
3-(1H-indol-3-yl)-2-methyl-N-(1- phenyl-ethyl)-propionamide 344
2-(3-Benzyloxy-benzylamino)-3- 33.15 518 89 0.06 185
(1H-indol-3-yl)-2-methyl-N-(1- phenyl-ethyl)-propionamide 345
3-(1H-Indol-3-yl)-2-methyl-2-(4- 31.61 458 90 0.06 609
methylsulfanyl-benzylamino)-N-(1- phenyl-ethyl)-propionamide 346
2-[(Anthracen-9-ylmethyl)-amino]- 17.46 512 73 0.07 >10,000
3-(1H-indol-3-yl)-2-methyl-N-(1- phenyl-ethyl)-propionamide 347
3-(1H-Indol-3-yl)-2-methyl-2-(4- - 36.52 504 95 0.06 3382
phenoxy-benzylamino)-N-(1-phenyl- ethyl)-propionamide 348
2-[(Biphenyl-4-ylmethyl)-amino]-3- 30.82 488 93 0.06 5562
(1H-indol-3-yl)-2-methyl-N-(1- phenyl-ethyl)-propionamide 349
2-[(Benzo[1,3]dioxol-5-y1methyl)- 33.19 456 94 0.06 356
amino]-3-(1H-indol-3-yl)-2-methyl- N-(1-phenyl-ethyl)-propionamide
350 2-[2-(4-Chloro-phenylsulfanyl)- - 21.92 554 90 0.07 >10,000
benzylamino]-3-(1H-indol-3-yl)-2- methyl-N-(1-phenyl-ethyl)-
propionamide 351 3-(1H-Indol-3-yl)-2-methyl-N-(1- 22.24 514 88 0.07
>10,000 phenyl-ethyl)-2-(4-styryl- benzylamino)-propionamide 352
2-(2,6-Dimethyl-octa-2,6- 30.03 458 44 0.07 2212
dienylamino)-3-(1H-indol-3-yl)-2- methyl-N-(1-phenyl-ethyl)-
propionamide 353 3-(1H-Indol-3-yl)-2-methyl-2-{[5- 38.51 523 82
0.06 13 (4-nitro-phenyl)-furan-2-ylmethyl]-
amino}-N-(1-phenyl-ethyl)- propionamide 354
2-[(9H-Fluoren-2-ylmethyl)-amino]- 27.91 500 92 0.06 1731
3-(1H-indol-3-yl)-2-methyl-N-(1- phenyl-ethyl)-propionamide 355
3-(1H-Indol-3-yl)-2-[(1H-indol-3- 9.83 451 69 0.06 1047
ylmethyl)-amino]-2-methyl-N-(1- phenyl-ethyl)-propionamide 356
3-(1H-Indol-3-yl)-2-methyl-2-(2- 33.02 508 86 0.07 >10,000
pentyl-3-phenyl-allylamino)-N-(1- phenyl-ethyl)-propionamide 357
3-(1H-Indol-3-yl)-2-methyl-N-(1- 18.91 418 97 0.05 548
phenyl-ethyl)-2-[(thiophen-2- ylmethyl)-amino]-propionamide 358
3-(1H-Indol-3-yl)-2-methyl-N-(1- 18.79 418 99 0.05 598
phenyl-ethyl)-2-[(thiophen-3- ylmethyl)-amino]-propionamide 359
3-(1H-Indol-3-yl)-2-methyl-N-(1- 7.47 413 79 0.04 3712
phenyl-ethyl)-2-[(pyridin-4- ylmethyl)-amino]-propionamide
[0343]
7TABLE 5 Examples 360-405 Yield Mol. Icms % Icms Rt IC.sub.50 (nM)
Ex. (mg) ion purity (min) hNK.sub.1 360
2-(3-Furan-2-yl-allylamino)-3-(1H- 12.16 414 59 0.06 >10,000
indol-3-yl)-N-(1-phenyl-ethyl)- propionamide 361
3-(1H-Indol-3-yl)-N-(1-phenyl- 14.01 505 79 0.04 729
ethyl)-2-[2-(pyridin-3-ylmethoxy)- benzylamino]-propionamide 362
3-(1H-Indol-3-yl)-N-(1-phenyl- 39.92 490 36 0.08 >10,000
ethyl)-2-[(5-styryl-furan-2- ylmethyl)-amino]-propionamide 363
2-(4-Chloro-3-methylsulfamoyl- 18.8 526 86 0.06 490
benzylamino)-3-(1H-indol-3-yl)-N- (1-phenyl-ethyl)-propionamide 364
5-(4-{[2-(1H-Indol-3-yl)-1-(1- 12.49 543 79 0.07 1247
phenyl-ethylcarbamoyl)- ethylamino]-methyl}-phenoxy)-2,2-
dimethyl-pentanoic acid 365 2-{[4-(4-Hydroxy-4-methyl-pentyl)-
31.21 503 42 0.07 5278 cyclohex-3-enylmethyl]-amino}-3-
(1H-indol-3-yl)-N-(1-phenyl-ethyl)- propionamide 366
3-(1H-Indol-3-yl)-2-{[4-(4-methyl- 38.13 484 65 0.09 4046
pent-2-enyl)-cyclohex-3- enylmethyl]-amino}-N-(1-phenyl-
ethyl)-propionamide 367 (2-{[2-(1H-Indol-3-yl)-1-(1-phenyl- 4.86
485 82 0.07 236 ethylcarbamoyl)-ethylamino]-
methyl}-phenyl)-carbamic acid ethyl ester 368
2-(2-Chloro-4-morpholin-4-yl- 14.38 518 84 0.07 2239
benzylamino)-3-(1H-indol-3-yl)-N- (1-phenyl-ethyl)-propionamide 369
2-(4-Chloro-2-methylsulfamoyl- 53.07 526 83 0.06 450
benzylamino)-3-(1H-indol-3-yl)-N- (1-phenyl-ethyl)-propionamide 370
2-(2,3-Diphenyl-propylamino)-3- 11.18 502 73 0.08 534
(1H-indol-3-yl)-N-(1-phenyl-ethyl)- propionamide 371
3-(1H-Indol-3-yl)-2-[(4-oxo-4H- 16.18 466 66 0.07 >10,000
chromen-3-ylmethyl)-amino]-N-( 1- phenyl-ethyl)-propionamide 372
3-(1H-Indol-3-yl)-2-[(1-oxo-1,2,3,9- 9 523 26 0.08 >10,000
tetrahydro-4-thia-9-aza-fluoren-2- ylmethyl)-amino]-N-(1-phenyl- -
ethyl)-propionamide 373 3-(1H-Indol-3-yl)-2-[(5-methyl-4- 17.38 506
2 0.07 507 oxo-6-phenyl-4H-pyran-3-ylmethyl)-
amino]-N-(1-phenyl-ethyl)- propionamide 374
4-{[2-(1H-Indol-3-yl)-1-(1-phenyl- 33.82 456 95 0.06 1914
ethylcarbamoyl)-ethylamino]- methyl}-benzoic acid methyl ester 375
3-(1H-Indol-3-yl)-N-(1-phenyl- 28.55 495 76 0.05 165
ethyl)-2-[(2-propyl-5-pyrrol-1-yl- 3H-imidazol-4-ylmethyl)-amino]-
- propionamide 376 2-(2,3-Diphenyl-allylamino)-3-(1H- 14.27 500 76
0.08 >10,000 indol-3-yl)-N-(1-phenyl-ethyl)- propionamide 377
2-(3-Benzo[1,3]dioxol-5-yl- 14.52 468 57 0.07 593
allylamino)-3-(1H-indol-3-yl)-N-(1- phenyl-ethyl)-propionamide 378
2-[3-(4-Benzyloxy-phenyl)- 8.68 530 64 0.09 932
allylamino]-3-(1H-indol-3-yl)-N-(1- phenyl-ethyl)-propionamide 379
2-(4-Benzyloxy-benzylamino)-3- 15.05 504 80 0.08 587
(1H-indol-3-yl)-N-(1-phenyl-ethyl)- propionamide 380
3-(1H-Indol-3-yl)-2-(3-naphthalen- 11.18 476 46 0.08 500
1-yl-propylamino)-N-(1-phenyl- ethyl)-propionamide 381
Toluene-4-sulfonic acid 3-{[2-(1H- 24.84 568 92 0.08 >10,000
indol-3-yl)-1-(1-phenyl- ethylcarbamoyl)-ethylamino]-
methyl}-phenyl ester 382 2-(3-Benzyloxy-benzylamino)-3- 44.62 504
91 0.08 >10,000 (1H-indol-3-yl)-N-(1-phenyl-ethyl)- propionamide
383 3-(1H-Indol-3-yl)-2-(4- 39.33 444 69 0.07 252
methylsulfanyl-benzylamino)-N-(1- phenyl-ethyl)-propionamide 384
3-(1H-Indol-3-yl)-2-(4-phenoxy- 32.52 490 83 0.08 2350
benzylamino)-N-(1-phenyl-ethyl)- propionamide 385
2-[(Biphenyl-4-ylmethyl)-amino]-3- 24.28 474 90 0.08 1463
(1H-indol-3-yl)-N-(1-phenyl-ethyl)- propionamide 386
2.-[(Benzo[1,3]dioxol-5-ylmethyl)- 41.91 442 78 0.06 240
amino]-3-(1H-indol-3-yl)-N-(1- phenyl-ethyl)-propionamide 387
2-[2-(4-Chloro-phenylsulfanyl)- 48.88 541 96 0.09 201
benzylamino]-3-(1H-indol-3-yl)-N- (1-phenyl-ethyl)-propionamide 338
3-(1H-Indol-3-yl)-N-(1-phenyl- 12.14 500 66 0.09 >10,000
ethyl)-2-(4-styryl-benzylamino)- propionamide 389
2-(2,6-Dimethyl-octa-2,6- 50.41 444 5 0.08 2573
dienylamino)-3-(1H-indol-3-yl)-N- (1-phenyl-ethyl)-propionamide 390
3-(1H-Indol-3-yl)-2-{[5-(4-nitro- 7.86 509 44 0.07 50
phenyl)-furan-2-ylmethyl]-amino}- N-(1-phenyl-ethyl)-propionamide
391 2-[(9H-Fluoren-2-ylmethyl)-amino]- 37.84 486 85 0.08 846
3-(1H-indol-3-yl)-N-(1-phenyl- ethyl)-propionamide 392
2-[(2,5-Dimethyl-1-phenyl-1H- 5.27 491 3 0.08 >10,000
pyrrol-3-ylmethyl)-amino]-3-(1H-. indol-3-yl)-N-(1-phenyl-ethyl)-
propionamide 393 3-(1H-Indol-3-yl)-N-(1-phenyl- 03.2 399 71 0.04
802 ethyl)-2-[(pyridin-3-ylmethyl)- amino]-propionamide 394
3-(1H-Indol-3-yl)-2-[(naphthalen-2- 03.7 448 88 0.06 158
ylmethyl)-amino]-N-(1-phenyl- ethyl)-propionamide 395
3-(1H-Indol-3-yl)-N-(1-phenyl- 02.9 399 74 0.05 >10,000
ethyl)-2-[(pyridin-2-ylmethyl)- amino]-propionamide 396
3-(1H-Indol-3-yl)-N-(1-phenyl- 04.3 404 98 0.05 1073
ethyl)-2-[(thiophen-2-ylmethyl)- amino]-propionamide 397
2-(3,4-Dimethoxy-benzylamino)-3- 03.3 458 65 0.05 >10,000
(1H-indol-3-yl)-N-(1-phenyl-ethyl)- propionamide 398
2-(3,5-Bis-trifluoromethyl- 04.3 534 94 0.07 >10,000
benzylamino)-3-(1H-indol-3-yl)-N- (1-phenyl-ethyl)-propionamide 399
2-(3,5-Difluoro-benzylamino)-3- 03.5 434 92 0.06 140
(1H-indol-3-yl)-N-(1-phenyl-ethyl)- propionamide 400
2-(3-Chloro-benzylamino)-3-(1H- 03.4 432 86 0.06 13
indol-3-yl)-N-(1-phenyl-ethyl)- propionamide 401
2-(3-Fluoro-benzylamino)-3-(1H- 03.4 416 87 0.06 39
indol-3-yl)-N-(1-phenyl-ethyl)- propionamide 402
2-[(Furan-3-ylmethyl)-amino]-3- 03.0 388 84 0.05 881
(1H-indol-3-yl)-N-(1-phenyl-ethyl)- propionamide 403
3-(1H-Indol-3-yl)-N-(1-phenyl- 0.07 426 85 0.06 3907
ethyl)-2-(3-phenyl-propylamino)- propionamide 404
3-(1H-Indol-3-yl)-N-(1-phenyl- 03.2 404 81 0.05 2390
ethyl)-2-[(thiophen-3-ylmethyl)- amino]-propionamide 405
2-[(Furan-2-ylmethyl)-amino]-3- 03.2 388 86 0.06 429
(1H-indol-3-yl)-N-(1-phenyl-ethyl)- propionamide
[0344] As noted above, the compounds of formula I will be best
utilized in the form of pharmaceutical formulations. The following
examples further illustrate specific formulations that are provided
by the invention.
EXAMPLE 406
[0345]
8 Tablet Formulation Ingredient Amount
3-[(benzofuran-2-ylmethyl)-amino]-3 -(IH-indol-3-yl)-2- 50 mg
methyl-N-(1-phenyl-ethyl)-propionamide,[R-(R*, S*)] potato starch
100 mg talc 50 mg magnesium carbonate 20 mg dextrose 20 mg 240
mg
[0346] The above ingredients are blended to uniformity and pressed
into a tablet. Such tablets are administered to human subjects from
one to four times a day for treatment of pain, depression and
schizophrenia.
EXAMPLE 407
[0347]
9 Capsules Ingredient Amount The compound of Example 5 200 mg Corn
starch 100 mg Sodium benzoate 10 mg talc 50 mg 360 mg
[0348] The ingredients are blended to uniformity and encapsulated
into gelatin telescoping capsules. The capsules are administered to
a human at the rate of one to three each day for treatment of
rheumatoid arthritis, atheroclerosis, aberrant neovascularization,
and for the inhibition of tumor cell growth.
* * * * *