U.S. patent application number 12/881211 was filed with the patent office on 2011-03-24 for novel alkene oxindole derivatives.
Invention is credited to Li Chen, Lichun Feng, Mengwei Huang, Jia Li, Fajung Nan, Tao Pang, Lifang Yu, Mei Zhang.
Application Number | 20110071195 12/881211 |
Document ID | / |
Family ID | 43414813 |
Filed Date | 2011-03-24 |
United States Patent
Application |
20110071195 |
Kind Code |
A1 |
Chen; Li ; et al. |
March 24, 2011 |
NOVEL ALKENE OXINDOLE DERIVATIVES
Abstract
The present invention provides compounds of formula (I),
##STR00001## as well as pharmaceutical acceptable salt thereof,
wherein R.sup.1 to R.sup.7 have the significance given herein. The
compounds are useful in the treatment of prophylaxis of diseases
that are related to AMPK regulation.
Inventors: |
Chen; Li; (Shanghai, CN)
; Feng; Lichun; (Shanghai, CN) ; Huang;
Mengwei; (Shanghai, CN) ; Li; Jia; (Shanghai,
CN) ; Nan; Fajung; (Shanghai, CN) ; Pang;
Tao; (Rockville, MD) ; Yu; Lifang; (Chicago,
IL) ; Zhang; Mei; (Shanghai, CN) |
Family ID: |
43414813 |
Appl. No.: |
12/881211 |
Filed: |
September 14, 2010 |
Current U.S.
Class: |
514/339 ;
514/365; 514/414; 514/418; 546/277.7; 548/181; 548/468;
548/486 |
Current CPC
Class: |
A61P 3/10 20180101; A61P
35/00 20180101; C07D 417/06 20130101; A61P 3/06 20180101; C07D
409/06 20130101; C07D 401/06 20130101; A61P 3/04 20180101; A61P
43/00 20180101; C07D 209/34 20130101; A61P 3/00 20180101 |
Class at
Publication: |
514/339 ;
548/486; 546/277.7; 548/181; 548/468; 514/418; 514/365;
514/414 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; C07D 209/34 20060101 C07D209/34; C07D 401/06 20060101
C07D401/06; C07D 417/06 20060101 C07D417/06; C07D 409/06 20060101
C07D409/06; A61K 31/404 20060101 A61K031/404; A61K 31/427 20060101
A61K031/427; A61P 3/10 20060101 A61P003/10; A61P 3/00 20060101
A61P003/00; A61P 3/04 20060101 A61P003/04; A61P 35/00 20060101
A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 21, 2009 |
CN |
PCT/CN2009/074060 |
Claims
1. A compound of formula (I), ##STR00132## wherein R.sup.1 is
selected from the group consisting of: hydrogen, halogen, alkoxy,
cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl,
haloalkoxy and alkylcarbonyl; R.sup.2 is selected from the group
consisting of: hydrogen, halogen, alkoxy, cyano, haloalkyl,
alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and
alkylcarbonyl; R.sup.3 is selected from the group consisting of:
hydrogen, halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl,
aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl; R.sup.4
is selected from the group consisting of: hydrogen, halogen,
alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl,
alkylsulfonyl, haloalkoxy and alkylcarbonyl; R.sup.5 is selected
from the group consisting of: alkyl, hydroxyalkyl, cycloalkyl,
phenylalkyl, halophenylalkyl, phenyl, substituted phenyl,
thiophenyl and pyridinyl, wherein said substituted phenyl is phenyl
substituted with one to three substituents independently selected
from the group consisting of alkyl, alkoxy, halogen, cyano,
haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy
and alkylcarbonyl; R.sup.6 is selected from the group consisting
of: alkyl, hydroxyalkyl, cycloalkyl, phenylalkyl, halophenylalkyl,
phenyl, substituted phenyl, thiophenyl and pyridinyl, wherein said
substituted phenyl is phenyl substituted with one to three
substituents independently selected from the group consisting of
alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl,
aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl; R.sup.7
is selected from the group consisting of: substituted phenyl,
pyridinyl, substituted pyridinyl, thiazolyl, substituted thiazolyl
and carboxy, wherein said substituted phenyl is phenyl substituted
with one to three substituents independently selected from the
group consisting of alkyl, hydroxy, alkoxy, carboxy,
alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy,
alkoxycarbonyl, alkoxycarbonylalkoxy and
alkylsulfonylaminocarbonyl, and said substituted pyridinyl and said
substituted thiazolyl are, respectively, pyridinyl and thiazolyl
substituted with alkoxycarbonyl or carboxy; and n is 0 or 1; or a
pharmaceutically acceptable salt or ester thereof; with the
provisos that: R.sup.5 and R.sup.6 are not both methoxyphenyl at
the same time; and when one of R.sup.5 and R.sup.6 is phenyl and
the other one is phenyl, methylphenyl or alkoxyphenyl, R.sup.7 is
alkoxycarbonylphenyl.
2. A compound according to claim 1, wherein R.sup.1 is selected
from the group consisting of: hydrogen, halogen and alkoxy.
3. A compound according to claim 1, wherein R.sup.1 is selected
from the group consisting of: hydrogen, fluoro and chloro.
4. A compound according to claim 1, wherein R.sup.2 is selected
from the group consisting of: hydrogen, halogen and alkoxy.
5. A compound according to claim 1, wherein R.sup.2 is hydrogen or
fluoro.
6. A compound according to claim 1, wherein R.sup.3 is selected
from the group consisting of: hydrogen, halogen and alkoxy.
7. A compound according to claim 1, wherein R.sup.3 is selected
from the group consisting of: hydrogen, fluoro, chloro and
methoxy.
8. A compound according to claim 1, wherein R.sup.4 is selected
from the group consisting of: hydrogen, halogen and alkoxy.
9. A compound according to claim 1, wherein R.sup.4 is hydrogen or
fluoro.
10. A compound according to claim 1, wherein R.sup.5 is selected
from the group consisting of: alkyl, halophenylalkyl, phenyl,
substituted phenyl, thiophenyl and pyridinyl, wherein said
substituted phenyl is phenyl substituted with one to three
substituents independently selected from the group consisting of
alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl,
aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl.
11. A compound according to claim 1, wherein R.sup.5 is halophenyl
or cyanophenyl.
12. A compound according to claim 1, wherein R.sup.5 is
chlorophenyl or cyanophenyl.
13. A compound according to claim 1, wherein R.sup.6 is selected
from the group consisting of: alkyl, hydroxyalkyl, cycloalkyl,
phenyl and halophenyl.
14. A compound according to claim 1, wherein R.sup.6 is alkyl or
phenyl.
15. A compound according to claim 1, wherein R.sup.6 is isopropyl
or phenyl.
16. A compound according to claim 1, wherein R.sup.7 is selected
from the group consisting of: substituted phenyl, substituted
pyridinyl, substituted thiazolyl and carboxy, wherein said
substituted phenyl is phenyl substituted with one to three
substituents independently selected from the group consisting of
alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonylalkyl,
alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonyl,
alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, and said
substituted pyridinyl and said substituted thiazolyl are,
respectively, pyridinyl and thiazolyl substituted with
alkoxycarbonyl or carboxy.
17. A compound according to claim 1, wherein R.sup.7 is selected
from the group consisting of: carboxyphenyl, alkoxycarbonylphenyl
and carboxypyridinyl.
18. A compound according to claim 1, wherein R.sup.7 is selected
from the group consisting of: carboxyphenyl, methoxycarbonylphenyl
and carboxypyridinyl.
19. A compound according to claim 1 selected from the group
consisting of:
3-{2-Oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-benzoic
acid ethyl ester;
(3-{2-Oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-phenyl)-ac-
etic acid methyl ester;
2-Methyl-5-{2-oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-be-
nzoic acid methyl ester;
[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic acid;
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-(3-Benzhydrylidene-2-oxo-2,3-dihydro-indol-1-ylmethyl)-benzoic
acid methyl ester;
3-{3-[1-(4-Methoxy-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-i-
ndol-1-ylmethyl}-benzoic acid methyl ester;
3-{2-Oxo-3-[1-phenyl-1-p-tolyl-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylme-
thyl}-benzoic acid methyl ester;
3-{3-[1-(4-Chloro-phenyl)-1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,-
3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Cyano-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid methyl ester;
3-{2-Oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(3-Chloro-4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{2-Oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(3,4-Difluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(3-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(2-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(3,5-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(2,3-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid methyl ester;
4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3--
dihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(2-Bromo-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(2-Chloro-5-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2--
oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(3-Bromo-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(2-Methylsulfanyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{7-Chloro-3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2--
oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{2-Oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{2-Oxo-3-[1-phenyl-1-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(2-Methanesulfonyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{2-Oxo-3-[1-phenyl-1-thiophen-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol--
1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]--
2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
(4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-i-
ndol-1-ylmethyl}-phenoxy)-acetic acid ethyl ester;
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-N-isopropyl-benzamide;
6-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-nicotinic acid methyl ester;
2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-thiazole-4-carboxylic acid ethyl ester;
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(4-methoxy-benzyl)-1,-
3-dihydro-indol-2-one;
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trihydroxy-ben-
zyl)-1,3-dihydro-indol-2-one;
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trihydroxy-ben-
zyl)-1,3-dihydro-indol-2-one;
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(4-hydroxy-benzyl)-1,-
3-dihydro-indol-2-one;
3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Methoxy-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-i-
ndol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Chloro-phenyl)-1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,-
3-dihydro-indol-1-ylmethyl}-benzoic acid;
3-{2-Oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid;
3-{2-Oxo-3-[1-phenyl-1-(2-trifluoromethoxy-phenyl)-meth-(E)-ylidene]-2,3--
dihydro-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(3-Chloro-4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid;
3-{2-Oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(3-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(3,5-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(2,3-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid;
2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid;
4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3--
dihydro-indol-1-ylmethyl}-benzoic acid;
6-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-nicotinic acid;
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(2-Methylsulfanyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid;
3-{2-Oxo-3-[1-phenyl-1-pyridin-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-1-
-ylmethyl}-benzoic acid;
3-{3-[1-(2-Chloro-5-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2--
oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(3,5-Bis-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-
-2,3-dihydro-indol-1-ylmethyl}-benzoic acid;
3-{2-Oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid;
3-{2-Oxo-3-[1-phenyl-1-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]--
2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid;
(4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-i-
ndol-1-ylmethyl}-phenoxy)-acetic acid;
3-{3-[1-(4-Isopropyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(3,4-Difluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid;
3-{5-Chloro-3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(2-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid;
2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-thiazole-4-carboxylic acid;
3-{3-[4-Methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmet-
hyl}-benzoic acid methyl ester;
3-{3-[3,3-Dimethyl-1-phenyl-but-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-yl-
methyl}-benzoic acid methyl ester;
3-{3-[2-(4-Chloro-phenyl)-1-phenyl-eth-(Z)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[3,3-Dimethyl-1-phenyl-but-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-yl-
methyl}-benzoic acid methyl ester;
3-{3-[4-Methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmet-
hyl}-benzoic acid;
3-{3-[1-(4-Chloro-benzyl)-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Fluoro-phenyl)-eth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylme-
thyl}benzoic acid;
3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[2-Methyl-1-phenyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmet-
hyl}-benzoic acid methyl ester;
3-{3-[1-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Chloro-phenyl)-1-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[2-Methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Chloro-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3--
dihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Cyano-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid methyl ester;
3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid;
6-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-pyridine-2-carboxylic acid;
6-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-pyridine-2-carboxylic acid;
3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid;
6-{3-[1-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-pyridine-2-carboxylic acid;
3-{3-[2-Methyl-1-pyridin-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-
-ylmethyl}-benzoic acid;
3-{3-[1-(4-Chloro-phenyl)-1-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid;
3-{3-[2-Methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid;
3-{3-[2-Methyl-1-thiophen-3-yl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-
-1-ylmethyl}-benzoic acid;
3-{5-Chloro-3-[2-methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2--
oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid;
N-(3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoyl)-methanesulfonamide;
N-(3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dih-
ydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide; and
N-(3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dih-
ydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide; or a
pharmaceutically acceptable salt or ester thereof.
20. A compound according to claim 1 selected from the group
consisting of:
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid;
3-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid;
6-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-pyridine-2-carboxylic acid; and
6-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-pyridine-2-carboxylic acid; or a pharmaceutically
acceptable salt or ester thereof.
21. A pharmaceutical composition comprising a compound according to
claim 1 and a therapeutically inert carrier.
Description
PRIORITY TO RELATED APPLICATION(S)
[0001] This application claims the benefit of International Patent
Application No. PCT/CN2009/074060, filed Sep. 21, 2009, which is
hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The invention relates to compounds which are activators of
AMP-activated protein kinase (AMPK) and which are useful in the
treatment or prophylaxis of diseases that are related to AMPK
regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or
type 2 diabetes.
BACKGROUND OF THE INVENTION
[0003] Obesity and type 2 diabetes, hypertension and cardiovascular
disease, are diseases that feature serious disturbances in glucose
and lipid metabolism that severely affect the health and quality of
life of affected individuals. The increasing prevalence of these
diseases makes finding new drug targets for treating this syndrome
an urgent task.
[0004] AMP-activated protein kinase acts as a cellular energy
sensor and regulator. It is activated by an increase in the
cellular AMP:ATP ratio induced by metabolic stress. Once activated,
AMPK switches on catabolic pathways that generate ATP and switches
off ATP-consuming anabolic pathways by acute regulation of the
activity of key enzymes in metabolism and chronic regulation of the
expression of pivotal transcription factors (Hardie, D G. Nature
Reviews 8 (2007b), 774-785; Woods, A et al. Molecular and Cellular
Biology 20 (2000), 6704-6711). The growing evidence of AMPK
regulatory effects on glucose and lipid metabolism makes it a
potential drug target for treatment of diabetes and metabolic
syndrome (Carling, D. Trends Biochem Sci 29(2004), 18-24; Hardie, D
G. Annual Review of Pharmacology and Toxicology 47 (2007a),
185-210; Kahn, B B et al. Cell Metabolism 1 (2005), 15-25; Long, Y
C et al. The Journal of Clinical Investigation 116 (2006),
1776-1783).
[0005] At the physiological level, this concept has been supported
by two adipokines, leptin and adiponectin, both of which exert
excellent effects on glucose and lipid metabolism (Friedman, J M
and Halaas, J L. Nature 395 (1998), 763-770; Muoio, D M et al.
Diabetes 46 (1997), 1360-1363; Yamauchi, T et al. Nature Medicine 7
(2001), 941-946). Recent studies suggest that leptin and
adiponectin exert their antidiabetic effects by activating AMPK.
Leptin stimulates muscle fatty acid oxidation by activating AMPK
directly and through a hypothalamic-adrenergic pathway (Minokoshi,
Y et al. Nature 415 (2002), 339-343). Adiponectin stimulates
glucose uptake and fatty acid oxidation in vitro by activation of
AMPK. Furthermore, it exerts its hypoglycemic effect by decreasing
PEPCK and G6Pase expression, whereas the administration of dominant
negative .alpha.1 adenovirus reverses the effect in vivo (Yamauchi,
T et al. Nature Medicine 8 (2002), 1288-1295).
[0006] At the pharmacological level, the concept of AMPK as a
potential target for treating metabolic syndrome has been further
supported by the discovery of two major classes of existing
antidiabetic drugs: thiazolidinediones (rosiglitazone, troglitazone
and pioglitazone) and biguanides (metformin and phenformin)
activate AMPK in cultured cells and in vivo. Rosiglitazone is
traditionally considered to be a PPAR.gamma. agonist and exerts its
antidiabetic effects through differentiation of adipocytes (Semple,
R K et al. The Journal of clinical investigation 116 (2006),
581-589). Recent findings indicate that AMPK may be involved in the
antidiabetic effects of rosiglitazone (Brunmair, B et al. The
Journal of Biological Chemistry 277 (2002), 25226-25232; Kadowaki,
T et al. The Journal of Clinical Investigation 116(2006),
1784-1792). In the case of metformin, an existing antidiabetic
agent without a defined mechanism of action, recent studies
demonstrate that it could activate AMPK in vitro and in vivo by
inhibiting complex I (El-Mir, M Y et al. The Journal of Biological
Chemistry 275 (2000), 223-228; Owen, M R et al. The Biochemical
Journal 348 Pt 3 (2000), 607-614; Zhou, G et al. The Journal of
Clinical Investigation 108 (2001), 1167-1174), and the hypoglycemic
effect could be blocked completely by knockout of its upstream
kinase LKB1, confirming the key role of AMPK in mediating the
antidiabetic effect of metformin (Shaw, R J et al. Science (New
York) N.Y. 310 (2005), 1642-1646).
[0007] Most recently, Cool and coworkers have identified a small
direct AMPK activator, A-769662, which exerts antidiabetic effects
in vivo (Cool, B et al. Cell Metabolism 3 (2006), 403-416). Jia
Li's laboratory has identified a small AMPK activator, PT1, which
activates the inactive forms of AMPK .alpha.2398 and .alpha.1394
with micromolar activity and exerts some cellular effects (Pang, T
et al. The Journal of Biological Chemistry 283 (2008),
16051-16060).
[0008] It has been found that the compounds of the present
invention are potent AMPK activators. The compounds of the
invention are therefore useful in the treatment or prophylaxis of
diseases that are related to AMPK regulation, such as obesity,
dyslipidemia, hyperglycemia, type 1 or type 2 diabetes.
SUMMARY OF THE INVENTION
[0009] The present invention relates to a compound of formula
(I),
##STR00002##
[0010] wherein [0011] R.sup.1 is selected from the group consisting
of: hydrogen, halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl,
aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl; [0012]
R.sup.2 is selected from the group consisting of: hydrogen,
halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl,
alkylsulfonyl, haloalkoxy and alkylcarbonyl; [0013] R.sup.3 is
selected from the group consisting of: hydrogen, halogen, alkoxy,
cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl,
haloalkoxy and alkylcarbonyl; [0014] R.sup.4 is selected from the
group consisting of: hydrogen, halogen, alkoxy, cyano, haloalkyl,
alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and
alkylcarbonyl; [0015] R.sup.5 is selected from the group consisting
of: alkyl, hydroxyalkyl, cycloalkyl, phenylalkyl, halophenylalkyl,
phenyl, substituted phenyl, thiophenyl and pyridinyl, wherein said
substituted phenyl is phenyl substituted with one to three
substituents independently selected from the group consisting of
alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl,
aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl; [0016]
R.sup.6 is selected from the group consisting of: alkyl,
hydroxyalkyl, cycloalkyl, phenylalkyl, halophenylalkyl, phenyl,
substituted phenyl, thiophenyl and pyridinyl, wherein said
substituted phenyl is phenyl substituted with one to three
substituents independently selected from the group consisting of
alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl,
aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl; [0017]
R.sup.7 is selected from the group consisting of: substituted
phenyl, pyridinyl, substituted pyridinyl, thiazolyl, substituted
thiazolyl and carboxy, wherein said substituted phenyl is phenyl
substituted with one to three substituents independently selected
from the group consisting of alkyl, hydroxy, alkoxy, carboxy,
alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy,
alkoxycarbonyl, alkoxycarbonylalkoxy and
alkylsulfonylaminocarbonyl, and said substituted pyridinyl and said
substituted thiazolyl are, respectively, pyridinyl and thiazolyl
substituted with alkoxycarbonyl or carboxy; and [0018] n is 0 or 1;
or a pharmaceutically acceptable salt or ester thereof; with the
provisos that: [0019] R.sup.5 and R.sup.6 are not both
methoxyphenyl at the same time; and when one of R.sup.5 and R.sup.6
is phenyl and the other one is phenyl, methylphenyl or
alkoxyphenyl, R.sup.7 is alkoxycarbonylphenyl.
[0020] The invention also relates to a pharmaceutical composition
comprising a compound of formula I, or a pharmaceutically
acceptable salt or ester thereof, and a therapeutically inert
carrier.
[0021] The invention also relates to a process for the manufacture
of these novel compounds and medicaments containing them.
[0022] The compounds of the invention have an activation effect on
AMP (adenosine monophosphate)-activated protein kinase, which
results in lowered blood glucose. The invention thus also concerns
the use of such compounds for the treatment or prophylaxis of
diseases that are related to AMPK regulation, such as obesity,
dyslipidemia, hyperglycemia, type 1 or type 2 diabetes.
DETAILS DESCRIPTION OF THE INVENTION
[0023] The present invention relates to a compound of formula
(I),
##STR00003##
[0024] wherein [0025] R.sup.1 is selected from the group consisting
of: hydrogen, halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl,
aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl; [0026]
R.sup.2 is selected from the group consisting of: hydrogen,
halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl,
alkylsulfonyl, haloalkoxy and alkylcarbonyl; [0027] R.sup.3 is
selected from the group consisting of: hydrogen, halogen, alkoxy,
cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl,
haloalkoxy and alkylcarbonyl; [0028] R.sup.4 is selected from the
group consisting of: hydrogen, halogen, alkoxy, cyano, haloalkyl,
alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and
alkylcarbonyl; [0029] R.sup.5 is selected from the group consisting
of: alkyl, hydroxyalkyl, cycloalkyl, phenylalkyl, halophenylalkyl,
phenyl, substituted phenyl, thiophenyl and pyridinyl, wherein said
substituted phenyl is phenyl substituted with one to three
substituents independently selected from the group consisting of
alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl,
aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl; [0030]
R.sup.6 is selected from the group consisting of: alkyl,
hydroxyalkyl, cycloalkyl, phenylalkyl, halophenylalkyl, phenyl,
substituted phenyl, thiophenyl and pyridinyl, wherein said
substituted phenyl is phenyl substituted with one to three
substituents independently selected from the group consisting of
alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl,
aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl; [0031]
R.sup.7 is selected from the group consisting of: substituted
phenyl, pyridinyl, substituted pyridinyl, thiazolyl, substituted
thiazolyl and carboxy, wherein said substituted phenyl is phenyl
substituted with one to three substituents independently selected
from the group consisting of alkyl, hydroxy, alkoxy, carboxy,
alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy,
alkoxycarbonyl, alkoxycarbonylalkoxy and
alkylsulfonylaminocarbonyl, and said substituted pyridinyl and said
substituted thiazolyl are, respectively, pyridinyl and thiazolyl
substituted with alkoxycarbonyl or carboxy; and [0032] n is 0 or 1;
or a pharmaceutically acceptable salt or ester thereof; with the
provisos that: [0033] R.sup.5 and R.sup.6 are not both
methoxyphenyl at the same time; and when one of R.sup.5 and R.sup.6
is phenyl and the other one is phenyl, methylphenyl or
alkoxyphenyl, R.sup.7 is alkoxycarbonylphenyl.
[0034] The compounds of the invention have an activation effect on
AMP (adenosine monophosphate)-activated protein kinase, which
results in lowered blood glucose.
[0035] As used herein, the term "alkyl" alone or in combination
signifies a saturated, linear- or branched chain alkyl group
containing 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon
atoms, for example methyl, ethyl, propyl, isopropyl, 1-butyl,
2-butyl and tert-butyl. Preferred "alkyl" groups are methyl, ethyl,
isopropyl and tert-butyl.
[0036] The term "alkoxy" alone or in combination signifies a group
alkyl-O--, wherein the "alkyl" is as defined above; for example
methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy, 2-butoxy
and t-butoxy. Preferred alkoxy groups are methoxy and ethoxy and
more preferably methoxy.
[0037] The term "cycloalkyl" alone or in combination refers to a
saturated carbon ring containing from 3 to 7 carbon atoms,
preferably from 3 to 6 carbon atoms, for example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A preferred
cycloalkyl group is cyclohexyl.
[0038] The term "halogen" means fluorine, chlorine, bromine or
iodine. Halogen is preferably fluorine or chlorine.
[0039] The term "carboxy" alone or in combination refers to the
group --COOH.
[0040] The term "carbonyl" alone or in combination refers to the
group --C(O)--.
[0041] The term "amino" alone or in combination refers to primary
(--NH.sub.2--), secondary (--NH--) or tertiary amino (--N--).
[0042] The term "alkylsulfanyl" alone or in combination refers to
the group --S-alkyl.
[0043] The term "sulfonyl" alone or in combination refers to the
group --S(O).sub.2--.
[0044] The compounds according to the present invention may exist
in the form of their pharmaceutically acceptable salts. The term
"pharmaceutically acceptable salt" refers to conventional
acid-addition salts or base-addition salts that retain the
biological effectiveness and properties of the compounds of formula
(I) and are formed from suitable non-toxic organic or inorganic
acids or organic or inorganic bases. Acid-addition salts include
for example those derived from inorganic acids such as hydrochloric
acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic
acid, phosphoric acid and nitric acid, and those derived from
organic acids such as p-toluenesulfonic acid, salicylic acid,
methanesulfonic acid, oxalic acid, succinic acid, citric acid,
malic acid, lactic acid, fumaric acid, and the like. Base-addition
salts include those derived from ammonium, potassium, sodium and,
quaternary ammonium hydroxides, such as for example, tetramethyl
ammonium hydroxide. The chemical modification of a pharmaceutical
compound into a salt is a technique well known to pharmaceutical
chemists in order to obtain improved physical and chemical
stability, hygroscopicity, flowability and solubility of compounds.
It is for example described in Bastin R. J., et. al., Organic
Process Research & Development 2000, 4, 427-435; or in Ansel,
H., et. al., In: Pharmaceutical Dosage Forms and Drug Delivery
Systems, 6th ed. (1995), pp. 196 and 1456-1457. Preferred are the
sodium salts of the compounds of formula (I).
[0045] "Pharmaceutically acceptable esters" means that compounds of
formula (I) may be derivatised at functional groups to provide
derivatives which are capable of conversion back to the parent
compounds in vivo. Examples of such compounds include
physiologically acceptable and metabolically labile ester
derivatives, such as methoxymethyl esters, methylthiomethyl esters
and pivaloyloxymethyl esters. Additionally, any physiologically
acceptable equivalents of the compounds of general formula (I),
similar to the metabolically labile esters, which are capable of
producing the parent compounds of general formula (I) in vivo, are
within the scope of this invention. Preferred are the methyl and
ethyl esters of the compounds of formula (I).
[0046] Preferred is a compound according of formula (I) wherein
R.sup.1 is selected from the group consisting of: hydrogen, halogen
and alkoxy.
[0047] Further preferred is a compound of formula (I) wherein
R.sup.1 is selected from the group consisting of: hydrogen, fluoro
and chloro.
[0048] Still further preferred is a compound of formula (I) wherein
R.sup.1 is hydrogen.
[0049] A compound of formula (I) wherein R.sup.2 is selected from
the group consisting of: hydrogen, halogen and alkoxy is
preferred.
[0050] Also preferred is a compound of formula (I) wherein R.sup.2
is hydrogen or fluoro.
[0051] Also particularly preferred is a compound of formula (I)
wherein R.sup.3 is selected from the group consisting of: hydrogen,
halogen and alkoxy.
[0052] A compound of formula (I) wherein R.sup.3 is selected from
the group consisting of: hydrogen, fluoro, chloro and methoxy is
also preferred.
[0053] In particular, preferred is a compound of formula (I)
wherein R.sup.3 is hydrogen.
[0054] Furthermore, preferred is a compound of formula (I) wherein
R.sup.4 is selected from the group consisting of: hydrogen, halogen
and alkoxy.
[0055] A compound of formula (I) wherein R.sup.4 is hydrogen or
fluoro is preferred.
[0056] A compound of formula (I) wherein R.sup.5 is selected from
the group consisting of: alkyl, halophenylalkyl, phenyl,
substituted phenyl, thiophenyl and pyridinyl, wherein said
substituted phenyl is phenyl substituted with one to three
substituents independently selected from the group consisting of
alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl,
aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl is
further preferred.
[0057] In particular, preferred is a compound of formula (I)
wherein R.sup.5 is selected from the group consisting of: phenyl,
chlorophenyl, methoxyphenyl, methylphenyl, cyanophenyl,
trifluoromethylphenyl, chlorofluorophenyl, trimethoxyphenyl,
difluorophenyl, dichlorophenyl, bromophenyl,
chlorotrifluoromethylphenyl, methylsulfanylphenyl,
aminosulfonylphenyl, methylsulfonylphenyl, thiophenyl,
fluorophenyl, pyridinyl, bis(trifluoromethyl)phenyl,
isopropylphenyl, neopentyl, isopentyl, methylcarbonylphenyl and
tert-butyl.
[0058] Also preferred is a compound of formula (I) wherein R.sup.5
is halophenyl or cyanophenyl.
[0059] A compound of formula (I) wherein R.sup.5 is chlorophenyl or
cyanophenyl is also preferred.
[0060] Furthermore, preferred is a compound of formula (I) wherein
R.sup.6 is selected from the group consisting of: alkyl,
hydroxyalkyl, cycloalkyl, phenyl and halophenyl.
[0061] Moreover, a compound of formula (I) wherein R.sup.6 is alkyl
or phenyl is also preferred.
[0062] Further, a compound of formula (I) wherein R.sup.6 is
isopropyl or phenyl is also preferred.
[0063] In particular, preferred is a compound of formula (I)
wherein R.sup.6 is selected from the group consisting of: methyl,
phenyl, methoxyphenyl, chlorophenyl, neopentyl, isopropyl,
cyclohexyl, hydroxypropyl and tert-butyl.
[0064] Particularly preferred is a compound of formula (I) wherein
R.sup.7 is selected from the group consisting of: substituted
phenyl, substituted pyridinyl, substituted thiazolyl and carboxy,
wherein said substituted phenyl is phenyl substituted with one to
three substituents independently selected from alkyl, hydroxy,
alkoxy, carboxy, alkoxycarbonylalkyl, alkylaminocarbonyl,
carboxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy and
alkylsulfonylaminocarbonyl, and said substituted pyridinyl and said
substituted thiazolyl are, respectively, pyridinyl and thiazolyl
substituted with alkoxycarbonyl or carboxy.
[0065] Also particularly preferred is a compound of formula (I)
wherein R.sup.7 is selected from the group consisting of:
carboxyphenyl, alkoxycarbonylphenyl and carboxypyridinyl.
[0066] A compound according of formula (I) wherein R.sup.7 is
selected from the group consisting of: carboxyphenyl,
methoxycarbonylphenyl and carboxypyridinyl is further
preferred.
[0067] Further preferred is a compound of formula (I) wherein
R.sup.7 is selected from the group consisting of:
ethoxycarbonylphenyl, methoxycarbonylmethylphenyl, phenyl
substituted with methyl and methoxycarbonyl, carboxy,
methoxycarbonylphenyl, ethoxycarbonylmethoxyphenyl,
isopropylaminocarbonylphenyl, methoxycarbonylpyridinyl,
ethoxycarbonylthiazolyl, methoxyphenyl, trihydroxyphenyl,
hydroxyphenyl, carboxyphenyl, carboxymethoxyphenyl,
carboxythiazolyl, carboxypyridinyl and
methylsulfonylminocarbonylphenyl.
[0068] Also preferred is a compound of formula (I) wherein n is
1.
[0069] Particularly preferred is a compound of formula (I) selected
from the group consisting of: [0070]
3-{2-Oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-benzoic
acid ethyl ester; [0071]
(3-{2-Oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-phenyl)-ac-
etic acid methyl ester; [0072]
2-Methyl-5-{2-oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-be-
nzoic acid methyl ester; [0073]
[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic acid;
[0074]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dih-
ydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0075]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0076]
3-(3-Benzhydrylidene-2-oxo-2,3-dihydro-indol-1-ylmethyl)-benzoic
acid methyl ester; [0077]
3-{3-[1-(4-Methoxy-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-i-
ndol-1-ylmethyl}-benzoic acid methyl ester; [0078]
3-{2-Oxo-3-[1-phenyl-1-p-tolyl-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylme-
thyl}-benzoic acid methyl ester; [0079]
3-{3-[1-(4-Chloro-phenyl)-1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,-
3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0080]
3-{3-[1-(4-Cyano-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid methyl ester; [0081]
3-{2-Oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0082]
3-{3-[1-(3-Chloro-4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0083]
3-{2-Oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0084]
3-{3-[1-(3,4-Difluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid methyl ester; [0085]
3-{3-[1-(3-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester; [0086]
3-{3-[1-(2-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester; [0087]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0088]
3-{3-[1-(3,5-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid methyl ester; [0089]
3-{3-[1-(2,3-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid methyl ester; [0090]
4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester; [0091]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3--
dihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0092]
3-{3-[1-(2-Bromo-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid methyl ester; [0093]
3-{3-[1-(2-Chloro-5-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2--
oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0094]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0095]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0096]
3-{3-[1-(3-Bromo-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid methyl ester; [0097]
3-{3-[1-(2-Methylsulfanyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0098]
3-{7-Chloro-3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2--
oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0099]
3-{2-Oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0100]
3-{2-Oxo-3-[1-phenyl-1-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid methyl ester; [0101]
3-{3-[1-(2-Methanesulfonyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0102]
3-{2-Oxo-3-[1-phenyl-1-thiophen-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol--
1-ylmethyl}-benzoic acid methyl ester; [0103]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester; [0104]
3-{3-[1-(4-Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]--
2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester;
[0105]
(4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-i-
ndol-1-ylmethyl}-phenoxy)-acetic acid ethyl ester; [0106]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-N-isopropyl-benzamide; [0107]
6-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-nicotinic acid methyl ester; [0108]
2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-thiazole-4-carboxylic acid ethyl ester; [0109]
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(4-methoxy-benzyl)-1,-
3-dihydro-indol-2-one; [0110]
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trihydroxy-ben-
zyl)-1,3-dihydro-indol-2-one; [0111]
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trihydroxy-ben-
zyl)-1,3-dihydro-indol-2-one; [0112]
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(4-hydroxy-benzyl)-1,-
3-dihydro-indol-2-one; [0113]
3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid; [0114]
3-{3-[1-(4-Fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid; [0115]
3-{3-[1-(4-Methoxy-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-i-
ndol-1-ylmethyl}-benzoic acid; [0116]
3-{3-[1-(4-Chloro-phenyl)-1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,-
3-dihydro-indol-1-ylmethyl}-benzoic acid; [0117]
3-{2-Oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid; [0118]
3-{2-Oxo-3-[1-phenyl-1-(2-trifluoromethoxy-phenyl)-meth-(E)-ylidene]-2,3--
dihydro-indol-1-ylmethyl}-benzoic acid; [0119]
3-{3-[1-(3-Chloro-4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid; [0120]
3-{2-Oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid; [0121]
3-{3-[1-(3-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid; [0122]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid; [0123]
3-{3-[1-(3,5-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid; [0124]
3-{3-[1-(2,3-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid; [0125]
2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid; [0126]
4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid; [0127]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3--
dihydro-indol-1-ylmethyl}-benzoic acid; [0128]
6-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-nicotinic acid; [0129]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid; [0130]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid; [0131]
3-{3-[1-(2-Methylsulfanyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid; [0132]
3-{2-Oxo-3-[1-phenyl-1-pyridin-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-1-
-ylmethyl}-benzoic acid; [0133]
3-{3-[1-(2-Chloro-5-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2--
oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid; [0134]
3-{3-[1-(3,5-Bis-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-
-2,3-dihydro-indol-1-ylmethyl}-benzoic acid; [0135]
3-{2-Oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid; [0136]
3-{2-Oxo-3-[1-phenyl-1-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid; [0137]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid; [0138]
3-{3-[1-(4-Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]--
2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid; [0139]
(4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-i-
ndol-1-ylmethyl}-phenoxy)-acetic acid; [0140]
3-{3-[1-(4-Isopropyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid; [0141]
3-{3-[1-(3,4-Difluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid; [0142]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid; [0143]
3-{5-Chloro-3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid; [0144]
3-{3-[1-(2-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid; [0145]
2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-thiazole-4-carboxylic acid; [0146]
3-{3-[4-Methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmet-
hyl}-benzoic acid methyl ester; [0147]
3-{3-[3,3-Dimethyl-1-phenyl-but-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-yl-
methyl}-benzoic acid methyl ester; [0148]
3-{3-[2-(4-Chloro-phenyl)-1-phenyl-eth-(Z)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid methyl ester; [0149]
3-{3-[3,3-Dimethyl-1-phenyl-but-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-yl-
methyl}-benzoic acid methyl ester; [0150]
3-{3-[4-Methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmet-
hyl}-benzoic acid; [0151]
3-{3-[1-(4-Chloro-benzyl)-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid; [0152]
3-{3-[1-(4-Fluoro-phenyl)-eth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylme-
thyl}benzoic acid; [0153]
3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester; [0154]
3-{3-[2-Methyl-1-phenyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmet-
hyl}-benzoic acid methyl ester; [0155]
3-{3-[1-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester; [0156]
3-{3-[1-(4-Chloro-phenyl)-1-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid methyl ester; [0157]
3-{3-[2-Methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0158]
3-{3-[1-(4-Chloro-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3--
dihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0159]
3-{3-[1-(4-Cyano-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester; [0160]
3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-3-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid methyl ester; [0161]
3-{3-[1-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid methyl ester; [0162]
3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid methyl ester; [0163]
3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid; [0164]
3-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid; [0165]
6-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-pyridine-2-carboxylic acid; [0166]
6-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-pyridine-2-carboxylic acid; [0167]
3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid; [0168]
3-{3-[1-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid; [0169]
3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid; [0170]
3-{3-[1-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid; [0171]
6-{3-[1-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-pyridine-2-carboxylic acid; [0172]
3-{3-[2-Methyl-1-pyridin-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-
-ylmethyl}-benzoic acid; [0173]
3-{3-[1-(4-Chloro-phenyl)-1-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydr-
o-indol-1-ylmethyl}-benzoic acid; [0174]
3-{3-[2-Methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid; [0175]
3-{3-[2-Methyl-1-thiophen-3-yl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-
-1-ylmethyl}-benzoic acid; [0176]
3-{5-Chloro-3-[2-methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2--
oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid; [0177]
3-{3-[1-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid; [0178]
N-(3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoyl)-methanesulfonamide; [0179]
N-(3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dih-
ydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide; and [0180]
N-(3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dih-
ydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide; or a
pharmaceutically acceptable salt or ester thereof.
[0181] Also particularly preferred is a compound of formula (I)
selected from the group consisting of: [0182]
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid; [0183]
3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid; [0184]
3-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid; [0185]
6-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-pyridine-2-carboxylic acid; and [0186]
6-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-pyridine-2-carboxylic acid; or a pharmaceutically
acceptable salt or ester thereof.
[0187] The compounds of the present invention can be prepared by
any conventional means. Suitable processes for synthesizing these
compounds are provided in the examples. Generally, compounds of
formula (I) can be prepared according to the schemes illustrated
below.
[0188] In the following schemes, Ar is phenyl, substituted phenyl,
pyridinyl, substituted pyridinyl, thiazolyl or substituted
thiazolyl, wherein substituted phenyl is phenyl substituted with
one to three substituents independently selected from alkyl,
hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl,
alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonylalkoxy and
alkylsulfonylaminocarbonyl, wherein substituted pyridinyl and
substituted thiazolyl are pyridinyl and thiazolyl substituted with
alkoxycarbonyl or carboxy. R.sup.8 is independently selected from
the group consisting of alkyl, alkoxy, halogen, cyano, haloalkyl,
alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and
alkylcarbonyl as mono-substituent, bi-substituent or
tri-substituent. R.sup.1 to R.sup.7 are as defined above unless
otherwise indicated.
##STR00004##
[0189] One method for synthesizing a compound of the invention is
set forth in Scheme 1, wherein the oxindole Ia is prepared. In this
process, the condensation reaction between the substituted oxindole
II and the substituted acetophenone III gives the intermediate IV,
which subsequently undergoes coupling reaction in the presence of
copper salt catalyst to produce compound Ia.
[0190] In the first step outlined in Scheme 1, intermediate IV can
be prepared by a condensation reaction between the substituted
oxindole II and the substituted acetophenone III. The reaction can
be carried out in the presence of an organic base such as
piperidine or pyrrolidine, in an organic solvent such as methanol,
ethanol, toluene or the mixture thereof, under reflux
overnight.
[0191] The intermediate IV couples with the aryl halide V to afford
the compound of formula Ia. The coupling reaction can be carried
out in the presence of a copper catalyst such as copper(I) iodide
(CuI), in combination with a ligand such as 2,2'-bipyridine,
proline, N,N'-dimethyl glycine or ethylene glycol, and a suitable
base such as sodium carbonate, potassium carbonate, cesium
carbonate, sodium methoxide, sodium tert-butoxide, potassium
tert-butoxide, sodium hydride, triethylamine, or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable organic
solvent such as acetonitrile, dichloromethane, tetrahydrofuran,
toluene, benzene, 1,4-dioxane, N,N-dimethylformamide, dimethyl
sulfoxide, N-methylpyrrolidinone or a mixture thereof, at a
temperature between 100 and 180.degree. C. for 15 to 60 minutes
under microwave irradiation. Alternatively, the reaction can be
carried out at elevated temperature such as 80.degree. C. for a
longer reaction time without microwave irradiation (Ley, S. V. et
al., Angew. Chem. Int. Ed. 42 (2003) 5400).
##STR00005##
[0192] The compound of formula Ib can be prepared according to
Scheme 2. In this process, the condensation reaction between the
compound IV and the commercially available reagent VI gives the
intermediate VII, which subsequently undergoes a hydrolysis
reaction to afford the compound of formula Ib.
[0193] In the first step outlined in Scheme 2, starting material IV
can be obtained through the synthetic method illustrated in Scheme
1. The intermediate VII can be prepared by an alkylation reaction
between VI and IV when using base such as sodium hydride, potassium
carbonate or cesium carbonate in organic solvent such as
tetrahydrofuran, N,N-dimethylformamide or the mixture thereof, at
room temperature for several hours.
[0194] Finally, hydrolysis of the methyl ester VII affords the
compound Ib. Hydrolysis of the methyl ester can be carried out in
the presence of an aqueous inorganic base such as lithium
hydroxide, sodium hydroxide or potassium hydroxide in a solvent
such as methanol, 1,4-dioxane or tetrahydrofuran at room
temperature for several hours.
##STR00006##
[0195] The compound of formula Ic can be prepared according to
Scheme 3. This approach is based on a highly efficient
palladium-catalyzed synthesis of asymmetrically substituted
3-(diarylmethylenyl)indolinone from readily accessible starting
materials. This reaction can be carried out successfully in the
presence of catalytic amount of Pd(OAc).sub.2, using
N,N-dimethylformamide as solvent and NaOAc as a base. The reaction
usually takes place at 110.degree. C. and needs several hours to
complete (Artur Pinto et al., Org. Lett. 4927, 2006). The amide X
can be prepared by the coupling reaction between aniline VIII and
carboxylic acid IX in the presence of coupling reagent such as
1,3-dicyclohexylcarbodiimide.
[0196] Intermediate XII can be prepared by alkylation reaction
between XI and X. The reaction usually needs sodium hydride,
potassium carbonate or cesium carbonate as a base and is carried
out at room temperature for several hours in organic solvent such
as tetrahydrofuran or N,N-dimethylformamide.
##STR00007##
[0197] XIV can be prepared by the method described in Scheme 3.
Treatment of XIV with boron tribromide in dichloromethane
successfully affords Id.
##STR00008##
[0198] XV can be prepared by the method described in Scheme 3.
Hydrolysis of XV in a solvent such as methanol, 1,4-dioxane or
tetrahydrofuran at room temperature for several hours in the
presence of an aqueous inorganic base such as lithium hydroxide,
sodium hydroxide or potassium hydroxide successfully affords acid
Ie.
##STR00009##
[0199] The compounds of formula If and Ig can be prepared according
to Scheme 6. This approach is based on Nickel catalyzed
carboannulation reaction of zinc reagent XVII with unsaturated
compound XVI (Ruixue Deng, et al., Org. Lett. 5207, 2007).
[0200] The starting material XVI can be prepared according to the
method described in Scheme 3.
##STR00010##
[0201] The compounds of formula Ih and Ii can be prepared according
to Scheme 7. Hydrolysis of If and Ig in a solvent such as methanol,
1,4-dioxane or tetrahydrofuran at room temperature for several
hours in the presence of an aqueous inorganic base such as lithium
hydroxide, sodium hydroxide or potassium hydroxide successfully
affords acids Ih and Ii.
##STR00011##
[0202] The compounds of formula Ij can be prepared according to
Scheme 8. The key step is the palladium catalyzed
Heck-Carbocyclization/Suzuki-Coupling Reaction between iodide XVIII
and boronic acid XIX in the presence of catalytic amount of
Pd(PPh.sub.3).sub.4. This reaction proceeds smoothly when using CsF
or copper thiophene-2-carboxylic acid as base (Reiko, Y. et al., J.
Org. Chem. 70, 6972, 2005; Wing S. Cheung, et al., J. Org. Chem.
70, 3741, 2005).
[0203] Hydrolysis of XX in a solvent such as methanol, 1,4-dioxane
or tetrahydrofuran at room temperature for several hours in the
presence of an aqueous inorganic base such as lithium hydroxide,
sodium hydroxide or potassium hydroxide successfully affords acid
Ij.
[0204] The starting material XVIII can be prepared according to the
procedure described in Scheme 3.
##STR00012##
[0205] The compounds of formula Ik can be prepared according to
Scheme 9. The key step is the palladium catalyzed
Heck-Carbocyclization/Suzuki-Coupling Reaction between iodide XXVI
and boronic acid XXVII in the presence of catalytic amount of
Pd(PPh.sub.3).sub.4. This reaction proceeds smoothly when using CsF
or copper thiophene-2-carboxylic acid as base (Reiko, Y. et al., J.
Org. Chem. 70, 6972, 2005; Wing S. Cheung, et al., J. Org. Chem.
70, 3741, 2005).
[0206] The amide XXVI can be prepared by the alkylation between
amide XXIV and benzyl bromide XXV as described in Scheme 3. Amide
XXIV can be prepared by reacting isocyanate XXII with lithium
reagent XXIII generated from n-butyl lithium and acetylene. The
isocyanate XXII can be prepared by treating 2-iodo-anilines XXI
with triphosgene in organic solvent such as dichloromethane in the
presence of saturated aqueous sodium bicarbonate solution.
##STR00013##
[0207] The compounds of formula II can be prepared according to
Scheme 10. Hydrolysis of ester Ik in a solvent such as methanol,
1,4-dioxane or tetrahydrofuran at room temperature for several
hours in the presence of an aqueous inorganic base such as lithium
hydroxide, sodium hydroxide or potassium hydroxide successfully
affords acid I1.
##STR00014##
[0208] The compounds of formula Im can be prepared according to
Scheme 11. Treatment of acid I1 with methylsulfonamide in the
presence of coupling reagent such as
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and
organic base such as DMAP for hours successfully affords compound
Im.
[0209] The invention also relates to a process for the preparation
of a compound of formula (I) comprising one of the following
steps:
(a) the reaction of a compound according to formula (A)
##STR00015##
in the presence R.sup.7--X and a copper catalyst; (b) the reaction
of a compound according to formula (B)
##STR00016##
in the presence of R.sup.8--I and a palladium catalyst; (c) the
reaction of a compound according to formula (C)
##STR00017##
in the presence of boron tribromide; (d) the reaction of a compound
according to formula (D)
##STR00018##
in the presence of R.sup.6--ZnBr and a nickel catalyst; (e) the
reaction of a compound according to formula (E)
##STR00019##
in the presence of a base; (f) the reaction of a compound according
to formula (F)
##STR00020##
in the presence of R.sup.8--B(OH).sub.2 and a palladium catalyst;
(g) the reaction of a compound according to formula (G)
##STR00021##
in the presence of MeSO.sub.2NH.sub.2 and a coupling reagent;
wherein R.sup.1 to R.sup.7 are as defined above, wherein Ar is
selected from the group consisting of: phenyl, substituted phenyl,
pyridinyl and thiazolyl, wherein substituted phenyl is phenyl
substituted with one or two substituents independently selected
from the group consisting of: alkyl, hydroxy, alkoxy, carboxy,
alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy,
alkoxycarbonyl, alkoxycarbonylalkoxy and
alkylsulfonylaminocarbonyl, wherein R.sup.10 is phenyl substituted
with one to three substituents independently selected from the
group consisting of: alkyl, alkoxy, halogen, cyano, haloalkyl,
alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and
alkylcarbonyl, wherein R.sup.9 is alkyl, wherein R.sup.11 is alkyl
and wherein X is chloro or bromo.
[0210] R.sup.9 is preferably methyl or ethyl. R.sup.11 is
preferably selected from the group consisting of: C.sub.1-C.sub.4
alkyl, preferably methyl and ethyl, more preferably methyl.
[0211] The reaction of step (a) can be carried out in the presence
of coupling reagent, such as a copper catalyst, such as copper(I)
iodide (CuI), in combination with a ligand such as 2,2'-bipyridine,
proline, N,N'-dimethyl glycine or ethylene glycol, and a suitable
base such as sodium carbonate, potassium carbonate, cesium
carbonate, sodium methoxide, sodium tert-butoxide, potassium
tert-butoxide, sodium hydride, triethylamine, or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable organic
solvent such as acetonitrile, dichloromethane, tetrahydrofuran,
toluene, benzene, 1,4-dioxane, N,N-dimethylformamide, dimethyl
sulfoxide, N-methylpyrrolidinone or a mixture thereof. The reaction
temperature can be for example between 100 and 180.degree. C., e.g.
for 15 to 60 minutes under microwave irradiation. Alternatively,
the reaction can be carried out at a elevated temperature such as
80.degree. C. for a longer reaction time without microwave
irradiation.
[0212] The reaction of step (b) can be carried out in the presence
of catalytic amount of Pd(OAc).sub.2, using N,N-dimethylformamide
as solvent and NaOAc as a base. The reaction usually takes place at
110.degree. C. and may need several hours to complete.
[0213] Step (c) is preferably carried out in dichloromethane.
[0214] Step (e) can be carried out in a solvent such as methanol,
1,4-dioxane or tetrahydrofuran, e.g. at room temperature for
several hours. The base is preferably an aqueous inorganic base
such as lithium hydroxide, sodium hydroxide or potassium
hydroxide.
[0215] The reaction of step (f) can be carried out in the presence
of catalytic amount of Pd(PPh.sub.3).sub.4. A base is preferably
employed. This reaction proceeds smoothly when using CsF or copper
thiophene-2-carboxylic acid as base.
[0216] The reaction of step (g) can be achieved in the presence of
coupling reagent such as
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an
organic base such as DMAP.
[0217] The invention also relates to a compound of formula (I) for
use as therapeutically active substance.
[0218] The invention also relates to a pharmaceutical composition
comprising a compound of formula (I) and a therapeutically inert
carrier.
[0219] The use of a compound of formula (I) for the preparation of
medicaments useful in the treatment or prophylaxis diseases that
are related to AMPK regulation is an object of the invention.
[0220] The invention relates in particular to the use of a compound
of formula (I) for the preparation of a medicament for the
treatment or prophylaxis of obesity, dyslipidemia, hyperglycemia,
type 1 diabetes or type 2 diabetes, in particular type 2
diabetes.
[0221] Said medicaments, e.g. in the form of pharmaceutical
preparations, can be administered orally, e.g. in the form of
tablets, coated tablets, dragees, hard and soft gelatine capsules,
solutions, emulsions or suspensions. The administration can,
however, also be effected rectally, e.g. in the form of
suppositories, or parenterally, e.g. in the form of injection
solutions with an effective amount of a compound as defined
above.
[0222] The above-mentioned pharmaceutical composition can be
obtained by processing the compounds according to this invention
with pharmaceutically inert inorganic or organic carriers. Lactose,
corn starch or derivatives thereof, talc, stearic acids or its
salts and the like can be used, for example, can be used as such
carriers for tablets, coated tablets, dragees and hard gelatine
capsules. Suitable carriers for soft gelatine capsules are, for
example, vegetable oils, waxes, fats, semi-solid and liquid polyols
and the like. Depending on the nature of the active substance no
carriers are, however, usually required in the case of soft
gelatine capsules. Suitable carriers for the production of
solutions and syrups are, for example, water, polyols, glycerol,
vegetable oil and the like. Suitable carriers for suppositories
are, for example, natural or hardened oils, waxes, fats,
semi-liquid or liquid polyols and the like.
[0223] The pharmaceutical composition can, moreover, contain
preservatives, solubilizers, stabilizers, wetting agents,
emulsifiers, sweeteners, colorants, flavorants, salts for varying
the osmotic pressure, buffers, masking agents or antioxidants. They
can also contain still other therapeutically valuable
substances.
[0224] The dosage depends on various factors such as manner of
administration, species, age and/or individual state of health. The
doses to be administered daily are about 5-400 mg/kg, preferably
about 10-100 mg/kg, and can be taken singly or distributed over
several administrations.
[0225] A compound of formula (I) when manufactured according to the
above process is also an object of the invention.
[0226] Furthermore, the invention also relates to a method for the
treatment or prophylaxis of diseases that are related to AMPK
regulation, which method comprises administering an effective
amount of a compound of formula (I).
[0227] The invention further relates to a method for the treatment
or prophylaxis of obesity, dyslipidemia, hyperglycemia, type 1
diabetes or type 2 diabetes, in particular type 2 diabetes, which
method comprises administering an effective amount of a compound of
formula (I).
[0228] Furthermore, the invention also relates to a compound of
formula (I) for the preparation of medicaments useful in the
treatment of cancers that are related to AMPK regulation and
provides a method for the treatment of cancers that are related to
AMPK regulation.
[0229] The invention is illustrated by the following examples which
have no limiting character. Unless explicitly otherwise stated, all
reactions, reaction conditions, abbreviations and symbols have the
meanings well known to a person of ordinary skill in organic
chemistry.
EXAMPLES
[0230] Intermediates and final compounds were purified by flash
chromatography using one of the following instruments: i) Biotage
SP1 system and the Quad 12/25 Cartridge module, ii) ISCO
combi-fiash chromatography instrument. Silica gel Brand and pore
size: i) KP-SIL 60 .ANG., particle size: 40-60 uM; ii) CAS registry
NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel;
iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or
300-400.
[0231] Intermediates and final compounds were purified by
preparative HPLC on reversed phase column using X Bridge.TM. Perp
G8 (5 um, OBD.TM. 30.times.100 mm) column or SunFire.TM. Perp
C.sub.18 (5 um, OBD.TM. 30.times.100 mm) column.
[0232] LC/MS spectra were obtained using a MicroMass Plateform LC
(Waters.TM. alliance 2795-ZQ2000). Standard LC/MS conditions were
as follows (running time 6 min):
[0233] Acidic condition: A: 0.1% formic acid in H.sub.2O; B: 0.1%
formic acid in acetonitrile;
[0234] Basic condition: A: 0.01% NH.sub.3.H.sub.2O in H.sub.2O; B:
acetonitrile;
[0235] Neutral condition: A: H.sub.2O; B: acetonitrile.
[0236] Mass spectra (MS): generally only ions which indicate the
parent mass are reported, and unless otherwise stated the mass ion
quoted is the positive mass ion (M+H).sup.+.
[0237] The microwave assisted reactions were carried out in a
Biotage Initiator Sixty.
[0238] NMR spectra were obtained using Bruker Avance 400 MHz.
[0239] All reactions involving air-sensitive reagents were
performed under an argon atmosphere. Reagents were used as received
from commercial suppliers without further purification unless
otherwise noted.
[0240] In case a mixture of E and Z isomers is produced during a
reaction, these isomers are separated by methods described herein
or known to the man skilled in the art such as e.g. chromatography
or crystallization.
Example 1
3-[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-benzoic
acid ethyl ester
##STR00022##
[0241] 3-(1-Phenyl-ethylidene)-1,3-dihydro-indol-2-one
[0242] Oxindole (0.1332 g, 1 mmol) and acetophenone (1.4 ml, 1.2
mmol) were mixed in toluene; then pyrrolidine (0.17 ml, 2 mmol) was
added. The mixture refluxed for 3 hand monitored by TLC. When the
reaction was finished the solvent was removed under reduced
pressure. The residue was separated by flash chromatography column
(gradient elution, 10-25% ethyl acetate in petroleum ether) to give
3-(1-phenyl-ethylidene)-1,3-dihydro-indol-2-one as yellow powder
(200 mg, 85%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.70
(s, 3H) 5.96 (d, J=7.83 Hz, 1H) 6.51-6.57 (m, 1H) 6.77 (d, J=7.58
Hz, 1H) 7.00-7.10 (m, 1H) 7.30-7.37 (m, 2H) 7.44-7.58 (m, 3H) 10.54
(br. s., 1H). MS calcd. for C.sub.16H.sub.13NO 235, obsd.
(ESI.sup.+) [(M+H).sup.+]236.
3-[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-benzoic
acid ethyl ester
[0243] A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0
mol %), 3-(1-phenyl-ethylidene)-1,3-dihydro-indol-2-one (352.7 mg,
1.5 mmol), and K.sub.2CO.sub.3 (276 mg, 2.0 mmol), evacuated, and
backfilled with argon. N,N'-dimethylethylenediamine (11 uL, 0.10
mmol, 10 mol %), ethyl 3-iodobenzoate (278.8 mg, 1.01 mmol), and
acetonitrile (1.5 ml) were added under argon. The Schlenk tube was
sealed with a Teflon valve and the reaction mixture was stirred at
80.degree. C. for 23 h. The reaction was monitored by HPLC. When
the reaction was finished, the solvent was removed under reduced
pressure. The residue was separated by flash chromatography column
(gradient elution, 5-10% ethyl acetate in petroleum ether) to give
3-[2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-benzoic
acid ethyl ester as yellow powder (344 mg, 90%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.ppm 1.42 (t, J=7.20 Hz, 3H) 2.87 (s, 3H)
4.42 (q, J=7.07 Hz, 2H) 6.25 (d, J=7.58 Hz, 1H) 6.68-6.78 (m, 2H)
7.09 (t, J=7.71 Hz, 1H) 7.34-7.40 (m, 2H) 7.47-7.58 (m, 3H)
7.62-7.72 (m, 2H) 8.11-8.19 (m, 2H). MS calcd. for
C.sub.25H.sub.21NO.sub.3 383, obsd. (ESI.sup.+) [(M+H).sup.+]
383.9.
Example 2
(3-{2-Oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-phenyl)-ace-
tic acid methyl ester
##STR00023##
[0245] The title compound was prepared in analogy to Example 1
starting from (3-bromo-phenyl)-acetic acid methyl ester
(commercially available) and
3-[1-phenyl-eth-(E)-ylidene]-1,3-dihydro-indol-2-one. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.ppm 2.77 (s, 3H) 3.65 (s, 3H) 3.81
(s, 2H) 6.08 (d, J=7.33 Hz, 1H) 6.66-6.72 (m, 2H) 7.11 (t, J=7.33
Hz, 1H) 7.35-7.44 (m, 5H) 7.51-7.61 (m, 4H).
Example 3
2-Methyl-5-{2-oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-ben-
zoic acid methyl ester
##STR00024##
[0247] The title compound was prepared in analogy to Example 1
starting from 5-bromo-2-methyl-benzoic acid methyl ester
(commercially available) and
3-[1-phenyl-eth-(E)-ylidene]-1,3-dihydro-indol-2-one. .sup.1H NMR
(400 MHz, chloroform-d) .delta.ppm 2.71 (s, 3H) 2.86 (s, 3H) 3.91
(s, 3H) 6.24 (d, J=7.83 Hz, 1H) 6.67-6.75 (m, 2H) 7.08 (t, J=7.83
Hz, 1H) 7.34-7.37 (m, 2H) 7.43-7.47 (m, 1H) 7.49-7.56 (m, 4H) 8.05
(d, J=2.27 Hz, 1H).
Example 4
[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic
acid
##STR00025##
[0248] 3-(1-Phenyl-ethylidene)-1,3-dihydro-indol-2-one
[0249] The synthetic method of
3-(1-phenyl-ethylidene)-1,3-dihydro-indol-2-one is described in
Example 1.
[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic acid
methyl ester
[0250] 3-(1-Phenyl-ethylidene)-1,3-dihydro-indol-2-one (294 mg, 1
mmol) was dissolved in anhydrous DMF, then methyl bromoacetate (184
mg, 1.2 mmol) was added. Finally, Cs.sub.2CO.sub.3 (488 mg, 1.5
mmol) was added in one portion. The mixture was stirred at room
temperature overnight. The reaction was monitored by HPLC. When the
reaction was finished, the solvent was removed under reduced
pressure. The residue was separated by flash chromatography column
(gradient elution, 5-10% ethyl acetate in petroleum ether) to give
[2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic acid
methyl ester as yellow powder (230 mg, 75%). MS calcd. for
C.sub.19H.sub.17NO.sub.3 307, obsd. (ESI.sup.+) [(M+1).sup.+]
308.1.
[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic
acid
[0251]
[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic acid
methyl ester (50 mg, 0.16 mmol) was dissolved in menthol 1 ml; then
0.1 ml water was added. Finally, lithium hydroxide (10 mg) was
added. The mixture was stirred overnight. The reaction was
monitored by HPLC. When the reaction was finished, the solvent was
removed under reduced pressure. The residue was dissolved in 2 ml
DMF for prepared HPLC to give [2-oxo-3-(1-phenyl-ethylidene)-2,
3-dihydro-indol-1-yl]-acetic acid as white powder (11 mg). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.ppm 2.82 (s, 3H) 4.61 (s, 2H) 6.20
(d, J=7.58 Hz, 1H) 6.66-6.73 (m, 2H) 7.14 (t, J=7.58 Hz, 1H) 7.31
(s, 2H) 7.46-7.54 (m, 3H). MS calcd. for C.sub.18H.sub.15NO.sub.3
293, obsd. (ESI.sup.+) [(M+H).sup.+] 294.1.
Example 5
3-((3-((4-Chlorophenyl)(phenyl)meth-(E)-ylene)-2-oxoindolin-1-yl)methyl)be-
nzoic acid methyl ester
##STR00026##
[0252] 3-Phenyl-propynoic acid phenylamide
[0253] Phenylamine (1.86 g, 20 mmol) and phenylpropiolic acid (3.22
g, 22 mmol) were dissolved in dichloromethane (50 ml) and
1,3-dicyclohexylcarbodiimide (4.8 g, 23.2 mmol) was added in one
portion at 0.degree. C. The mixture was stirred room temperature
for 14 h. The mixture was poured into water and extracted with
dichloromethane (3.times.15 ml). The organic layers were combined,
dried over anhydrous sodium sulfate and concentrated in vacuo.
Purification by flash column chromatography on silica gel, eluting
with hexanes-EtOAc (6:1 and then 4:1) afforded 3-phenyl-propynoic
acid phenylamide 2.7 g (62%).
3-{[Phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl
ester
[0254] 3-Phenyl-propynoic acid phenylamide (951.4 mg, 4.3 mmol),
3-bromomethyl-benzoic acid methyl ester (1.2 g, 5.16 mmol) and
Cs.sub.2CO.sub.3 (2.1 g, 6.45 mmol) were dissolved in DMF (20 ml).
The mixture was stirred at room temperature for 16 h. The mixture
was poured into water and extracted with ethyl acetate, dried
overanhydrous sodium sulfate and concentrated under reduced
pressure. Purification was by flash column chromatography on silica
gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded
3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl
ester 1.03 g (65%).
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid methyl ester
[0255] To a solution of
3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl
ester (369.4 mg, 1 mmol) in THF (5 ml) were added palladium(II)
acetate (11.2 mg, 0.05 mmol), triphenylphosphine (26.2 mg, 0.1
mmol), 1-chloro-4-iodobenzene (262.3 mg, 1.1 mmol) and cesium
fluoride (456 mg, 3 mmol) at room temperature. The solution was
stirred for 3 h at 110.degree. C. under an argon atmosphere. After
being quenched with water, the mixture was extracted with ethyl
acetate, dried over magnesium sulfate and concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel eluting with (hexane/ethyl acetate=
5/1) to give
3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester, yield 297 mg (62%);
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. ppm 8.00 (s, 1H), 7.92
(d, 1H), 7.50 (d, 1H), 7.26-7.43 (m, 10H), 7.08 (dt, 1H), 6.71 (dt,
1H), 6.59 (d, 1H), 6.52 (d, 1H), 4.95 (s, 2H), 3.90 (s, 3H).
Example 6
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00027##
[0257] The title compound was prepared in analogy to Example 5
starting from 1-chloro-4-iodo-benzene (commercially available) and
3-{[(2-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic
acid methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm
3.88 (s, 3H), 5.11 (s, 2H), 6.22 (d, 1H), 6.61-6.67 (m, 1H),
6.82-6.89 (dd, 1H), 7.26-7.43 (m, 10H), 7.52 (d, 1H), 7.92 (d, 1H),
8.01 (s, 1H).
Example 7
3-(3-Benzhydrylidene-2-oxo-2,3-dihydro-indol-1-ylmethyl)-benzoic
acid methyl ester
##STR00028##
[0259] The title compound was prepared in analogy to Example 5
starting from iodo-benzene (commercially available) and
3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl
ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.01 (s, 1H),
8.00 (d, 1H), 7.93 (d, 1H), 7.33-7.52 (m, 12H), 7.05 (dt, 1H), 6.66
(m, 2H), 6.43 (d, 2H), 4.96 (s, 2H), 3.91 (s, 3H).
Example 8
3-{3-[1-(4-Methoxy-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester
##STR00029##
[0261] The title compound was prepared in analogy to Example 5
starting from 1-iodo 4-methoxy-benzene (commercially available) and
3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl
ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.01 (s, 1H),
7.94 (d, 1H), 7.49 (d, 1H), 7.26-7.38 (m, 8H), 7.06 (m, 1H), 6.94
(m, 2H), 6.63-6.70 (m, 3H), 4.97 (s, 2H), 3.91 (s, 3H), 3.88 (s,
3H).
Example 9
3-{2-Oxo-3-[1-phenyl-1-p-tolyl-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmet-
hyl}-benzoic acid methyl ester
##STR00030##
[0263] The title compound was prepared in analogy to Example 5
starting from 1-methyl-4-iodo-benzene (commercially available) and
3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl
ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.01 (s, 1H),
7.92 (d, 1H), 7.24-7.52 (m, 11H), 7.05 (t, 1H), 7.56-7.71 (m, 3H),
4.96 (s, 2H), 3.91 (s, 3H), 2.44 (s, 3H).
Example 10
3-{3-[1-(4-Chloro-phenyl)-1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-
-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00031##
[0265] The title compound was prepared in analogy to Example 5
starting from 1-chloro-4-iodo-benzene (commercially available) and
3-({[3-(2-methoxy-phenyl)-propynoyl]-phenyl-amino}-methyl)-benzoic
acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm
7.99 (s, 1H), 7.92 (d, 1H), 7.26-7.49 (m, 7H), 6.93-7.15 (m, 4H),
6.72 (t, 1H), 6.61-6.64 (m, 2H), 4.93 (dd, 2H), 3.90 (s, 3H), 3.63
(s, 3H).
Example 11
3-{3-[1-(4-Cyano-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indo-
l-1-ylmethyl}-benzoic acid methyl ester
##STR00032##
[0267] The title compound was prepared in analogy to Example 5
starting from 4-iodo-benzonitrile (commercially available) and
3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl
ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.00 (s, 1H),
7.93 (d, 1H), 7.74-7.76 (m, 2H), 7.35-7.51 (m, 9H), 7.10 (t, 1H),
6.56-6.72 (m, 2H), 6.35 (d, 1H), 4.95 (s, 2H), 3.91 (s, 3H)
Example 12
3-{2-Oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00033##
[0269] The title compound was prepared in analogy to Example 5
starting from 1-iodo-4-trifluoromethyl-benzene (commercially
available) and 3-{[phenyl-(3-phenyl
propynoyl)-amino]-methyl}-benzoic acid methyl ester. .sup.1H NMR
(300 Hz, CDCl.sub.3) .delta.ppm 3.91 (s, 3H), 4.96 (s, 2H), 6.37
(d, 1H), 6.67 (dd, 2H), 7.08 (t, 1H), 7.35-7.40 (m, 7H), 7.49 (d,
2H), 7.71 (d, 2H), 7.95 (d, 1H), 8.01 (s, 1H).
Example 13
3-{3-[1-(3-Chloro-4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00034##
[0271] The title compound was prepared in analogy to Example 5
starting from 2-chloro-1-fluoro-4-iodo-benzene (commercially
available) and 3-{[phenyl-(3-phenyl
propynoyl)-amino]-methyl}-benzoic acid methyl ester. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.ppm 8.00 (s, 1H), 7.93 (d, 1H), 7.50
(d, 1H), 7.22-7.42 (m, 9H), 7.09 (dt, 1H), 6.73 (dt, 1H), 6.66 (d,
1H), 6.51 (d, 1H), 4.95 (s, 2H), 3.91 (s, 3H).
Example 14
3-{2-Oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dih-
ydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00035##
[0273] The title compound was prepared in analogy to Example 5
starting from 5-Iodo-1,2,3-trimethoxy-benzene (commercially
available) and 3-{[phenyl-(3-phenyl
propynoyl)-amino]-methyl}-benzoic acid methyl ester. .sup.1H NMR
(300 Hz, CDCl.sub.3): .delta.ppm 3.76 (s, 6H), 3.91 (s, 3H), 3.94
(s, 3H), 4.96 (s, 2H), 6.55 (s, 2H), 6.61-6.71 (m, 4H), 7.06 (t,
1H), 7.38-7.40 (m, 5H), 7.53 (d, 1H), 7.91 (d, 1H), 8.02 (s,
1H).
Example 15
3-{3-[1-(3,4-Difluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00036##
[0275] The title compound was prepared in analogy to Example 5
starting from 1,2-difluoro-4-iodo-benzene (commercially available)
and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid
methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm 3.90 (s,
3H), 4.96 (s, 2H), 6.58 (d, 1H), 6.70 (m, 2H), 7.07-7.32 (m, 4H),
7.34-7.43 (m, 6H), 7.50 (d, 1H), 7.94 (d, 1H), 8.02 (s, 1H).
Example 16
3-{3-[1-(3-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid methyl ester
##STR00037##
[0277] The title compound was prepared in analogy to Example 5
starting from 1-chloro-3-iodo-benzene (commercially available) and
3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl
ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.01 (s, 1H),
7.93 (d, 1H), 7.50 (d, 1H), 7.26-7.46 (m, 10H), 7.08 (t, 1H), 6.70
(t, 1H), 6.65 (d, 1H), 6.44 (d, 1H), 4.96 (s, 2H), 3.90 (s,
3H).
Example 17
3-{3-[1-(2-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid methyl ester
##STR00038##
[0279] The title compound was prepared in analogy to Example 5
starting from 1-chloro-2-iodo-benzene (commercially available) and
3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl
ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.01 (s, 1H),
7.92 (d, 1H), 7.50-7.52 (m, 4H), 7.37-7.42 (m, 7H), 7.07 (t, 1H),
6.62-6.69 (m, 1H), 6.05 (d, 1H), 4.96 (dd, 2H), 3.91 (s, 3H).
Example 18
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00039##
[0281] The title compound was prepared in analogy to Example 5
starting from 1-chloro-4-iodo-benzene (commercially available) and
3-{[(4-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic
acid methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm
3.91 (s, 3H), 4.94 (s, 2H), 6.25 (dd, 1H), 6.54 (dd, 2H), 6.75-6.80
(m, 1H), 7.10 (d, 2H), 7.33-7.54 (m, 8H), 7.94 (d, 1H), 7.98 (s,
1H).
Example 19
3-{3-[1-(3,5-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00040##
[0283] The title compound was prepared in analogy to Example 5
starting from 1,3-dichloro-5-iodobenzene (commercially available)
and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid
methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm 3.92 (s,
3H), 4.95 (s, 2H), 6.47 (d, 1H), 6.65-6.78 (m, 2H), 7.13 (t, 2H),
7.33-7.43 (m, 8H), 7.52 (d, 1H), 7.93 (d, 1H), 8.01 (s, 1H).
Example 20
3-{3-[1-(2,3-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00041##
[0285] The title compound was prepared in analogy to Example 5
starting from 1,2-dichloro-3-iodobenzene (commercially available)
and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid
methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.00 (s,
1H), 7.92 (d, 1H), 7.33-7.54 (m, 9H), 7.23 (dd, 1H), 7.10 (t, 1H),
6.74 (t, 1H), 6.66 (d, 1H), 6.55 (d, 1H), 4.95 (s, 2H), 3.90 (s,
3H).
Example 21
4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid methyl ester
##STR00042##
[0287] The title compound was prepared in analogy to Example 5
starting from 1-chloro-4-iodobenzene (commercially available) and
4-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl
ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm 7.97 (d, 1H),
7.25-7.43 (m, 12H), 7.07 (dt, 1H), 6.71 (dt, 1H), 6.61 (d, 1H),
6.54 (d, 1H), 4.97 (s, 2H), 3.89 (s, 3H).
Example 22
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00043##
[0289] The title compound was prepared in analogy to Example 5
starting from 1-chloro-4-iodobenzene (commercially available) and
3-{[(4-methoxy-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic
acid methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm
3.49 (s, 3H), 3.91 (s, 3H), 4.92 (s, 2H), 6.10 (dd, 1H), 6.51 (d,
1H), 6.62 (dd, 1H), 7.25-7.50 (m, 11H), 7.93 (d, 1H), 7.99 (s,
1H).
Example 23
3-{3-[1-(2-Bromo-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indo-
l-1-ylmethyl}-benzoic acid methyl ester
##STR00044##
[0291] The title compound was prepared in analogy to Example 5
starting from 1-bromo-2-iodobenzene (commercially available) and
3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl
ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.01 (s, 1H),
7.93 (d, 1H), 7.71 (d, 1H), 7.30-7.53 (m, 11H), 7.04-7.09 (m, 2H),
6.62-7.04 (m, 3H), 6.42 (d, 1H), 6.02 (d, 1H), 4.88-5.05 (m, 2H),
3.91 (s, 3H).
Example 24
3-{3-[1-(2-Chloro-5-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-o-
xo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00045##
[0293] The title compound was prepared in analogy to Example 5
starting from 1-chloro-2-iodo-4-trifluoromethyl-benzene
(commercially available) and 3-{[phenyl-(3-phenyl
propynoyl)-amino]-methyl}-benzoic acid methyl ester. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.ppm 8.01 (s, 1H), 7.93 (d, 1H),
7.63-7.67 (m, 2H), 7.33-7.52 (m, 7H), 7.10 (t, 1H), 6.64-6.71 (m,
2H), 5.98 (d, 1H), 4.87-5.04 (m, 2H), 3.91 (s, 3H).
Example 25
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00046##
[0295] The title compound was prepared in analogy to Example 5
starting from 1-chloro-4-iodo-benzene (commercially available) and
3-{[(3-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic
acid methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm
4.97 (s, 2H), 6.39-6.51 (m, 2H), 7.25-7.45 (m, 11H), 7.53 (d, 1H),
7.99 (d, 1H), 8.00 (s, 1H).
Example 26
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00047##
[0297] The title compound was prepared in analogy to Example 5
starting from 1-chloro-4-iodo-benzene (commercially available) and
3-{[(3-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic
acid methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm
3.90 (s, 3H), 4.96 (s, 2H), 6.48 (d, 1H), 7.10 (d, 1H), 7.19 (d,
1H), 7.31-7.50 (m, 11H), 7.94 (d, 1H), 7.98 (s, 1H).
Example 27
3-{3-[1-(3-Bromo-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indo-
l-1-ylmethyl}-benzoic acid methyl ester
##STR00048##
[0299] The title compound was prepared in analogy to Example 5
starting from 1-bromo-3-iodobenzene (commercially available) and
3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl
ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.01 (s, 1H),
7.93 (d, 1H), 7.31-7.61 (m, 11H), 7.08 (t, 1H), 6.64-6.73 (m, 2H),
6.44 (d, 1H), 4.95 (s, 2H), 3.91 (s, 3H).
Example 28
3-{3-[1-(2-Methylsulfanyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dih-
ydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00049##
[0301] The title compound was prepared in analogy to Example 5
starting from 1-iodo-2-methylsulfanyl-benzene (commercially
available) and 3-{[phenyl-(3-phenyl
propynoyl)-amino]-methyl}-benzoic acid methyl ester. .sup.1H NMR
(300 Hz, CDCl.sub.3): .delta.ppm 2.31 (s, 3H), 3.90 (s, 3H), 5.00
(dd, 2H), 6.03 (d, 1H), 6.60-6.64 (m, 2H), 7.04 (t, 1H), 7.26-7.30
(m, 2H), 7.33-7.56 (m, 9H), 7.95 (d, 1H), 8.01 (s, 1H).
Example 29
3-{7-Chloro-3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-o-
xo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00050##
[0303] The title compound was prepared in analogy to Example 5
starting from 1-chloro-4-iodo-benzene (commercially available) and
3-{[(2-chloro-4-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoi-
c acid methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm
3.90 (s, 3H), 5.38 (s, 2H), 6.01 (dd, 1H), 6.80 (dd, 1H), 7.27-7.40
(m, 9H), 7.45-7.50 (m, 3H), 7.92 (m, 2H).
Example 30
3-{2-Oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00051##
[0305] The title compound was prepared in analogy to Example 5
starting from 1-iodo-3-trifluoromethyl-benzene (commercially
available) and 3-{[phenyl-(3-phenyl
propynoyl)-amino]-methyl}-benzoic acid methyl ester. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.ppm 8.01 (s, 1H), 7.95 (d, 1H), 7.72
(d, 1H), 7.50-7.63 (m, 3H), 7.36-7.42 (m, 4H), 7.08 (t, 1H),
6.64-6.68 (m, 2H), 6.42 (d, 1H), 4.96 (s, 2H), 3.91 (s, 3H).
Example 31
3-{2-Oxo-3-[1-phenyl-1-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro--
indol-1-ylmethyl}-benzoic acid methyl ester
##STR00052##
[0307] The title compound was prepared in analogy to Example 5
starting from 4-iodo-benzenesulfonamide (commercially available)
and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid
methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm 3.90 (s,
3H), 4.95 (s, 2H), 5.02 (s, 2H), 6.41 (d, 1H), 6.65-6.71 (m, 2H),
7.09 (t, 1H), 7.26-7.33 (m, 2H), 7.35-7.42 (m, 6H), 7.58-7.60 (m,
3H), 7.99 (d, 1H), 8.07 (s, 1H).
Example 32
3-{3-[1-(2-Methanesulfonyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00053##
[0309] The title compound was prepared in analogy to Example 5
starting from 1-iodo-2-methanesulfonyl-benzene (commercially
available) and 3-{[phenyl-(3-phenyl
propynoyl)-amino]-methyl}-benzoic acid methyl ester. .sup.1H NMR
(300 Hz, CDCl.sub.3): .delta.ppm 1.89 (s, 1.5H), 2.50 (s, 1.5H),
3.90 (s, 3H), 4.98 (dd, 2H), 5.98 (dd, 1H), 6.65-6.68 (m, 2H), 7.07
(m, 1H), 7.35-7.58 (m, 8H), 7.61 (t, 1H), 7.78 (t, 1H), 7.99 (d,
1H), 8.02 (d, 1H), 8.20 (d, 1H).
Example 33
3-{2-Oxo-3-[1-phenyl-1-thiophen-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-1-
-ylmethyl}-benzoic acid methyl ester
##STR00054##
[0311] The title compound was prepared in analogy to Example 5
starting from 3-iodo-thiophene (commercially available) and
3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl
ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm 3.91 (s, 3H),
4.96 (s, 2H), 6.65 (d, 1H), 6.76-6.82 (m, 2H), 7.06-7.11 (m, 2H),
7.33-7.43 (m, 8H), 7.50 (d, 1H), 7.92 (d, 1H), 8.01 (s, 1H).
Example 34
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid methyl ester
##STR00055##
[0313] The title compound was prepared in analogy to Example 5
starting from 1-chloro-4-iodo-benzene (commercially available) and
3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl
ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm 3.91 (s, 3H),
4.96 (s, 2H), 6.42 (d, 1H), 6.63-6.66 (m, 2H), 7.06 (t, 1H),
7.33-7.52 (m, 11H), 7.92 (d, 1H), 8.01 (s, 1H).
Example 35
3-{3-[1-(4-Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]-2-
-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00056##
[0315] The title compound was prepared in analogy to Example 5
starting from 1-iodo-4-trifluoromethyl-benzene (commercially
available) and
3-({[3-(4-chloro-phenyl)-propynoyl]-phenyl-amino}-methyl)-benzoic
acid methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm
3.91 (s, 3H), 4.96 (s, 2H), 6.37 (d, 1H), 6.66-6.71 (m, 2H), 7.08
(t, 1H), 7.26-7.52 (m, 9H), 7.73 (d, 2H), 7.94 (d, 1H), 8.01 (s,
1H).
Example 36
(4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-phenoxy)-acetic acid ethyl ester
##STR00057##
[0317] The title compound was prepared in analogy to Example 5
starting from 1-chloro-4-iodo-benzene (commercially available) and
(4-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-phenoxy)-acetic
acid ethyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm 1.28
(t, 3H), 4.26 (q, 2H), 4.57 (s, 2H), 4.84 (s, 2H), 6.51 (d, 1H),
6.67-6.71 (m, 2H), 6.83 (d, 2H), 7.08 (t, 1H), 7.24-7.42 (m,
11H).
Example 37
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-N-isopropyl-benzamide
##STR00058##
[0319] The title compound was prepared in analogy to Example 5
starting from 1-chloro-4-iodo-benzene (commercially available) and
N-isopropyl-3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzamide.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm 7.74 (s, 1H), 7.60 (d,
1H), 7.26-7.43 (m, 10H), 7.07 (dt, 2H), 6.70 (t, 1H), 6.68 (d, 1H),
6.53 (d, 1H), 5.99 (d, 1H), 4.94 (s, 2H), 4.26 (m, 1H), 1.26 (s,
3H), 1.24 (s, 3H).
Example 38
6-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-nicotinic acid methyl ester
##STR00059##
[0321] The title compound was prepared in analogy to Example 5
starting from 1-chloro-4-iodo-benzene (commercially available) and
6-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-nicotinic acid
methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm 3.93 (s,
3H), 5.10 (s, 2H), 6.54 (d, 1H), 6.57-6.75 (m, 2H), 7.08 (t, 1H),
7.28-7.44 (m, 10H), 8.20 (d, 1H), 9.16 (s, 1H).
Example 39
2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-thiazole-4-carboxylic acid ethyl ester
##STR00060##
[0323] The title compound was prepared in analogy to Example 5
starting from 1-chloro-4-iodo-benzene (commercially available) and
2-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-thiazole-4-carboxylic
acid ethyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm 1.39
(t, 3H), 4.44 (q, 2H), 5.27 (s, 2H), 6.58 (d, 1H), 6.78 (t, 1H),
6.88 (d, 1H), 7.13 (t, 1H), 7.31-7.43 (m, 9H), 8.10 (s, 1H).
Example 40
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(4-methoxy-benzyl)-1,3-
-dihydro-indol-2-one
##STR00061##
[0325] The title compound was prepared in analogy to Example 5
starting from 1-chloro-4-iodo-benzene (commercially available) and
3-phenyl-propynoic acid (4-methoxy-benzyl)-phenyl-amide. .sup.1H
NMR (300 Hz, CDCl.sub.3): .delta.ppm 3.77 (s, 3H), 4.88 (s, 2H),
6.53 (d, 1H), 6.67-6.71 (m, 2H), 6.80 (dd, 1H), 6.85-6.90 (m, 2H),
7.07 (t, 1H), 7.19-7.43 (m, 10H).
Example 41
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trihydroxy-benz-
yl)-1,3-dihydro-indol-2-one; and
Example 42
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trihydroxy-benz-
yl)-1,3-dihydro-indol-2-one
##STR00062##
[0326] 3-Phenyl-propynoic acid
phenyl-(3,4,5-trimethoxy-benzyl)-amide
[0327] 3-Phenyl-propynoic acid phenylamide (951.4 mg, 4.3 mmol),
5-bromomethyl-1,2,3-trimethoxy-benzene (1.35 g, 5.16 mmol), and
Cs.sub.2CO.sub.3 (2.1 g, 6.45 mmol) were dissolved in DMF (20 ml).
The mixture was stirred at room temperature for 16 h. The mixture
was poured into water and extracted with ethyl acetate, dried
overanhydrous sodium sulfate and concentrated under reduced
pressure. Purification was by flash column chromatography on silica
gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded
3-phenyl-propynoic acid phenyl-(3,4,5-trimethoxy-benzyl)-amide 1.03
g (65%).
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trimethoxy-benz-
yl)-1,3-dihydro-indol-2-one and
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trimethoxy-ben-
zyl)-1,3-dihydro-indol-2-one
[0328] To a solution of 3-phenyl-propynoic acid
phenyl-(3,4,5-trimethoxy-benzyl)-amide (401.5 mg, 1 mmol) in THF (5
ml) were added palladium(II) acetate (11.2 mg, 0.05 mmol),
triphenylphosphine (26.2 mg, 0.1 mmol), 1-chloro-4-iodobenzene
(262.3 mg, 1.1 mmol) and cesium fluoride (456 mg, 3 mmol) at room
temperature. The solution was stirred for 3 h at 110.degree. C.
under an argon atmosphere. After being quenched with water, the
mixture was extracted with ethyl acetate, dried over magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel eluting with
(hexane/ethyl acetate= 5/1) to give a mixture of
3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trimethoxy-ben-
zyl)-1,3-dihydro-indol-2-one and
3-[1-(4-chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trimethoxy-ben-
zyl)-1,3-dihydro-indol-2-one, yield 317 mg (62%);
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trihydroxy-benz-
yl)-1,3-dihydro-indol-2-one and
3-[1-(4-chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trihydroxy-ben-
zyl)-1,3-dihydro-indol-2-one
[0329] To a solution of
3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trimethoxy-ben-
zyl)-1,3-dihydro-indol-2-one and
3-[1-(4-chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trimethoxy-ben-
zyl)-1,3-dihydro-indol-2-one (317 mg, 0.62 mmol) in dichloromethane
(5 ml) was added a solution of boron tribromide (1M in
CH.sub.2Cl.sub.2, 3 ml) at room temperature. The mixture was
stirred at room temperature for 5 h. After being quenched by
pouring into ice water, the mixture was extracted with ethyl
acetate, dried over magnesium sulfate and concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel eluting with (hexane/ethyl acetate=
1/1) to give
3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trihydroxy-ben-
zyl)-1,3-dihydro-indol-2-one (60 mg). .sup.1H NMR (300 Hz,
CDCl.sub.3): .delta.ppm 4.66 (s, 2H), 5.60 (b, 1H), 6.31 (s, 2H),
6.56 (d, 1H), 6.67-6.82 (m, 2H), 7.00-7.23 (m, 8H), 7.38 (d, 2H);
and
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trihydroxy-ben-
zyl)-1,3-dihydro-indol-2-one (40 mg). .sup.1H NMR (300 Hz,
CDCl.sub.3): .delta.ppm 4.72 (s, 2H), 5.33 (b, 1H), 6.05 (b, 1H),
6.40 (s, 2H), 6.44 (d, 1H), 6.67 (t, 1H), 6.82 (d, 1H), 7.00 (d,
2H), 7.10-7.15 (m, 3H), 7.23-7.26 (m, 2H), 7.37-7.46 (m, 3H).
Example 43
3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(4-hydroxy-benzyl)-1,3-
-dihydro-indol-2-one
##STR00063##
[0331] The title compound was prepared in analogy to Example 41
starting from
3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(4-methoxy-benzy-
l)-1,3-dihydro-indol-2-one. .sup.1H NMR (300 Hz, CDCl.sub.3):
.delta.ppm 4.81 (s, 2H), 6.51 (d, 1H), 6.53-6.74 (m, 4H), 7.08-7.11
(m, 3H), 7.24-7.42 (m, 9H).
Example 44
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid
##STR00064##
[0333]
3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihy-
dro-indol-1-ylmethyl}-benzoic acid methyl ester (94 mg, 0.2 mmol)
was dissolved in THF (2 ml) and water (2 ml) and LiOH.H.sub.2O (42
mg, 1 mmol) was added in one portion. The mixture was stirred at
50.degree. C. for 16 h. The mixture was concentrated under reduced
pressure, and acidified to pH=3. Purification by preparative HPLC
afforded
3-((3-((4-chlorophenyl)(phenyl)meth-(E)-ylene)-2-oxoindolin-1-yl)methyl)b-
enzoic acid as light yellow powder. Yield 30 mg (70%). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.ppm 8.06 (s, 1H), 7.99 (d, 1H), 7.55
(d, 1H), 7.29-7.43 (m, 10H), 7.09 (t, 1H), 6.74-6.65 (m, 2H), 6.55
(d, 1H),
Example 45
3-{3-[1-(4-Fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid
##STR00065##
[0335] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihyd-
ro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.ppm 8.07 (s, 1H), 8.00 (d, 1H), 7.56
(d, 1H), 7.33-7.48 (m, 8H), 7.07-7.17 (m, 3H), 6.66-6.74 (m, 2H),
6.52 (d, 1H), 4.99 (s, 2H).
Example 46
3-{3-[1-(4-Methoxy-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid
##STR00066##
[0337] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(4-methoxy-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihy-
dro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.ppm 8.07 (s, 1H), 8.00 (d, 1H), 7.55
(d, 1H), 7.26-7.38 (m, 8H), 7.07 (m, 1H), 6.94 (m, 2H), 6.65-6.71
(m, 3H), 4.98 (s, 2H), 3.88 (s, 3H).
Example 47
3-{3-[1-(4-Chloro-phenyl)-1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-
-dihydro-indol-1-ylmethyl}-benzoic acid
##STR00067##
[0339] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(4-chloro-phenyl)-1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-o-
xo-2,3-dihydro-indol-1 ylmethyl}-benzoic acid methyl ester. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.04 (s, 1H), 7.99 (d, 1H),
7.54 (d, 1H), 7.32-7.44 (m, 6H), 7.07-7.15 (m, 2H), 6.93-7.01 (m,
2H), 6.73 (t, 1H), 6.64 (t, 2H), 4.95 (dd, 2H), 3.90 (s, 3H), 3.72
(s, 3H).
Example 48
3-{2-Oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid
##STR00068##
[0341] The title compound was prepared in analogy to Example 44
starting from
3-{2-oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]--
2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H
NMR (300 Hz, CDCl.sub.3): .delta.ppm 4.98 (s, 2H), 6.40 (d, 1H),
6.68 (dd, 2H), 7.10 (t, 1H), 7.35-7.55 (m, 9H), 7.71 (d, 2H), 7.99
(d, 1H), 8.07 (s, 1H).
Example 49
3-{2-Oxo-3-[1-phenyl-1-(2-trifluoromethoxy-phenyl)-meth-(E)-ylidene]-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid
##STR00069##
[0343] The title compound was prepared in analogy to Example 44
starting from
3-{2-oxo-3-[1-phenyl-1-(2-trifluoromethoxy-phenyl)-meth-(E)-ylidene]-
-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H
NMR (300 Hz, CDCl.sub.3): .delta.ppm 3.91 (s, 3H,), 5.96 (s, 2H),
6.37 (d, 1H), 6.64-6.72 (m, 2H), 7.07 (dt, 1H), 7.51-7.33 (m, H),
7.70 (d, 2H) 7.93 (d, 1H), 8.01 (s, 1H).
Example 50
3-{3-[1-(3-Chloro-4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid
##STR00070##
[0345] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(3-chloro-4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo--
2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.07 (s, 1H), 8.01 (d, 1H),
7.56 (d, 1H), 7.34-7.45 (m, 6H), 7.22-7.28 (m, 3H), 7.11 (dt, 1H),
6.74 (dt, 1H), 6.68 (d, 1H), 6.53 (d, 1H), 4.98 (s, 2H).
Example 51
3-{2-Oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dih-
ydro-indol-1-ylmethyl}-benzoic acid
##STR00071##
[0347] The title compound was prepared in analogy to Example 44
starting from
3-{2-oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2-
,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(300 Hz, CDCl.sub.3): .delta.ppm 3.79 (s, 6H), 3.94 (s, 3H), 4.98
(s, 2H), 6.55 (s, 2H), 6.61-6.72 (m, 4H), 7.08 (t, 1H), 7.40-7.45
(m, 5H), 7.58 (d, 1H), 7.99 (d, 1H), 8.07 (s, 1H).
Example 52
3-{3-[1-(3-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid
##STR00072##
[0349] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(3-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihyd-
ro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.ppm 8.07 (s, 1H), 7.90 (d, 1H), 7.56
(d, 1H), 7.26-7.50 (m, 10H), 7.09 (t, 1H), 6.66-6.70 (m, 2H), 6.45
(d, 1H), 4.98 (s, 2H).
Example 53
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid
##STR00073##
[0351] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo--
2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H
NMR (300 Hz, CDCl.sub.3): .delta.ppm 4.97 (s, 2H), 6.26 (dd, 1H),
6.55 (dd, 2H), 6.77-6.80 (m, 1H), 7.10 (d, 2H), 7.33-7.48 (m, 7H),
7.53 (d, 2H), 8.01 (d, 1H), 8.04 (s, 1H).
Example 54
3-{3-[1-(3,5-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid
##STR00074##
[0353] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(3,5-dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(300 Hz, CDCl.sub.3): .delta.ppm 4.96 (s, 2H), 6.48 (d, 1H),
6.65-6.78 (m, 2H), 7.13 (t, 2H), 7.33-7.43 (m, 8H), 7.56 (d, 1H),
7.98 (d, 1H), 8.08 (s, 1H).
Example 55
3-{3-[1-(2,3-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid
##STR00075##
[0355] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(2,3-dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.ppm 8.07 (s, 1H), 8.01 (d, 1H),
7.33-7.57 (m, 9H), 7.22-7.26 (m, 1H), 7.12 (t, 1H), 6.75 (t, 1H),
6.68 (d, 1H), 6.56 (d, 1H), 4.97 (s, 2H).
Example 56
2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid
##STR00076##
[0357] The title compound was prepared in analogy to Example 44
starting from
2-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihyd-
ro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.ppm 8.10 (d, 1H), 7.32-7.48 (m, 11H),
7.18 (d, 1H), 7.11 (t, 1H), 6.75 (t, 1H), 6.65 (d, 1H), 6.58 (d,
1H), 5.39 (s, 2H).
Example 57
4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid
##STR00077##
[0359] The title compound was prepared in analogy to Example 44
starting from
4-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihyd-
ro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.ppm 8.05 (d, 2H), 7.29-7.44 (m, 11H),
7.09 (t, 1H), 6.72 (t, 1H), 7.29 (d, 1H), 6.59 (d, 1H), 4.98 (s,
2H), 3.89 (s, 3H).
Example 58
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid
##STR00078##
[0361] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-
-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H
NMR (300 Hz, CDCl.sub.3): .delta.ppm 3.49 (s, 3H), 4.95 (s, 2H),
6.10 (dd, 1H), 6.51 (d, 1H), 6.64 (dd, 1H), 7.25-7.45 (m, 10H),
7.54 (d, 1H), 8.00 (d, 1H), 8.05 (s, 1H).
Example 59
6-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-nicotinic acid
##STR00079##
[0363] The title compound was prepared in analogy to Example 44
starting from
6-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihyd-
ro-indol-1-ylmethyl}-nicotinic acid methyl ester. .sup.1H NMR (300
Hz, CDCl.sub.3): .delta.ppm 5.19 (s, 2H), 6.56 (d, 1H), 6.58-6.77
(m, 2H), 7.09 (t, 1H), 7.28-7.44 (m, 10H), 8.30 (d, 1H), 9.26 (s,
1H).
Example 60
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid
##STR00080##
[0365] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo--
2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H
NMR (300 Hz, CDCl.sub.3): .delta.ppm 4.97 (s, 2H), 6.39-6.51 (m,
2H), 7.25-7.45 (m, 11H), 7.53 (d, 1H), 7.99 (d, 1H), 8.00 (s,
1H).
Example 61
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid
##STR00081##
[0367] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo--
2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H
NMR (300 Hz, CDCl.sub.3): .delta.ppm 4.88 (s, 2H), 6.40-6.429 (m,
1H), 7.08-7.10 (m, 1H), 7.20 (d, 1H), 7.31-7.38 (m, 10H), 7.42 (d,
1H), 7.90 (d, 1H), 7.94 (s, 1H).
Example 62
3-{3-[1-(2-Methylsulfanyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dih-
ydro-indol-1-ylmethyl}-benzoic acid
##STR00082##
[0369] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(2-methylsulfanyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2-
,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(300 Hz, CDCl.sub.3): .delta.ppm 2.31 (s, 3H), 5.00 (dd, 2H), 6.04
(d, 1H), 6.63-6.64 (m, 2H), 7.07 (t, 1H), 7.26-7.30 (m, 2H),
7.33-7.46 (m, 6H), 7.58-7.60 (m, 2H), 7.99 (d, 1H), 8.07 (s,
1H).
Example 63
3-{2-Oxo-3-[1-phenyl-1-pyridin-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-1--
ylmethyl}-benzoic acid
##STR00083##
[0371] The title compound was prepared in analogy to Example 44
starting from
3-{2-oxo-3-[1-phenyl-1-pyridin-3-yl-meth-(E)-ylidene]-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR (300 Hz,
CDCl.sub.3): .delta.ppm 4.98 (s, 2H), 6.40 (d, 1H), 6.65-6.68 (m,
2H), 7.07 (t, 1H), 7.35-7.42 (m, 8H), 7.58 (d, 2H), 7.69 (d, 1H),
7.99 (d, 1H), 8.04 (s, 1H).
Example 64
3-{3-[1-(2-Chloro-5-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-o-
xo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid
##STR00084##
[0373] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(2-chloro-5-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-yliden-
e]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.06 (s, 1H), 8.00 (d,
1H), 7.40-7.67 (m, 10H), 7.11 (t, 1H), 6.66-6.72 (m, 2H), 5.98 (d,
1H), 4.89-5.06 (m, 2H), 3.91 (s, 3H).
Example 65
3-{3-[1-(3,5-Bis-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo--
2,3-dihydro-indol-1-ylmethyl}-benzoic acid
##STR00085##
[0375] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(3,5-bis-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]--
2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.24 (s, 1H),
7.95-8.10 (m, 4H), 7.78-7.87 (m, 3H), 7.67 (d, 2H), 7.29-7.58 (m,
6H), 7.21 (t, 1H), 6.68-6.71 (m, 2H), 6.27 (d, 1H), 4.98 (s, 2H),
3.91 (s, 3H).
Example 66
3-{2-Oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid
##STR00086##
[0377] The title compound was prepared in analogy to Example 44
starting from
3-{2-oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]--
2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.08 (s, 1H), 8.01 (d, 1H),
7.72 (d, 1H), 7.64-7.56 (m, 4H), 7.35-7.54 (m, 4H), 7.10 (dt, 1H),
6.66-6.70 (m, 2H), 6.33 (dd, 1H), 4.98 (s, 2H).
Example 67
3-{2-Oxo-3-[1-phenyl-1-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro--
indol-1-ylmethyl}-benzoic acid
##STR00087##
[0379] The title compound was prepared in analogy to Example 44
starting from
3-{2-oxo-3-[1-phenyl-1-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR (300
Hz, CDCl.sub.3): .delta.ppm 4.97 (s, 2H), 5.17 (s, 2H), 6.42 (d,
1H), 6.64-6.71 (m, 2H), 7.08 (t, 1H), 7.26-7.60 (m, 11H), 7.97 (s,
1H), 8.00 (s, 1H).
Example 68
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid
##STR00088##
[0381] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihyd-
ro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR (300
Hz, CDCl.sub.3): .delta.ppm 4.96 (s, 2H), 6.42 (d, 1H), 6.63-6.66
(m, 2H), 7.06 (t, 1H), 7.33-7.52 (m, 11H), 7.92 (d, 1H), 8.01 (s,
1H).
Example 69
3-{3-[1-(4-Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]-2-
-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid
##STR00089##
[0383] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(4-chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-meth-(Z)-ylid-
ene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester.
.sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm 4.98 (s, 2H), 6.38 (d,
1H), 6.68-6.73 (m, 2H), 7.08 (t, 1H), 7.26-7.52 (m, 9H), 7.72 (d,
2H), 8.01 (d, 1H), 8.08 (s, 1H).
Example 70
(4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-phenoxy)-acetic acid
##STR00090##
[0385] The title compound was prepared in analogy to Example 44
starting from
(4-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihy-
dro-indol-1-ylmethyl}-phenoxy)-acetic acid methyl ester. .sup.1H
NMR (300 Hz, CDCl.sub.3): .delta.ppm 4.56 (s, 2H), 4.85 (s, 2H),
6.51 (d, 1H), 6.53-6.73 (m, 2H), 6.83 (d, 2H), 7.08 (t, 1H),
7.24-7.42 (m, 11H).
Example 71
3-{3-[1-(4-Isopropyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro--
indol-1-ylmethyl}-benzoic acid
##STR00091##
[0387] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(4-isopropyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR (300
Hz, CDCl.sub.3): .delta.ppm 1.31 (d, 6H), 2.94-3.01 (m, 1H), 4.99
(s, 2H), 6.56 (d, 1H), 6.67 (dd, 2H), 7.08 (t, 1H), 7.27 (s, 4H),
7.38-7.42 (m, 6H), 7.51 (d, 1H), 7.99 (d, 1H), 8.08 (s, 1H)
Example 72
3-{3-[1-(3,4-Difluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid
##STR00092##
[0389] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(3,4-difluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(300 Hz, CDCl.sub.3): .delta.ppm 4.97 (s, 2H), 6.51 (d, 1H), 6.71
(m, 2H), 7.08-7.26 (m, 4H), 7.34-7.43 (m, 6H), 7.56 (d, 1H), 8.00
(d, 1H), 8.05 (s, 1H).
Example 73
3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid
##STR00093##
[0391] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo--
2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H
NMR (300 Hz, CDCl.sub.3): .delta.ppm 5.13 (s, 2H), 6.32 (d, 1H),
6.63-6.67 (m, 1H), 6.82-6.89 (dd, 1H), 7.26-7.43 (m, 10H), 7.59 (d,
1H), 7.99 (d, 1H), 8.08 (s, 1H).
Example 74
3-{5-Chloro-3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid
##STR00094##
[0393] The title compound was prepared in analogy to Example 44
starting from
3-{5-chloro-3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo--
2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H
NMR (300 Hz, CDCl.sub.3): .delta.ppm 4.97 (s, 2H), 6.58 (m, 2H),
7.05 (dd, 1H), 7.20 (m, 1H), 7.27-7.46 (m, 9H), 7.52 (d, 1H), 8.01
(d, 1H), 8.04 (s, 1H).
Example 75
3-{3-[1-(2-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid
##STR00095##
[0395] The title compound was prepared in analogy to Example 44
starting from
3-{3-[1-(2-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihyd-
ro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.ppm 8.06 (s, 1H), 7.99 (d, 1H),
7.50-7.57 (m, 3H), 7.37-7.44 (m, 7H), 7.07 (t, 1H), 6.63-6.70 (m,
2H), 6.05 (d, 1H), 4.97 (dd, 2H).
Example 76
2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-thiazole-4-carboxylic acid
##STR00096##
[0397] The title compound was prepared in analogy to Example 44
starting from
2-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihyd-
ro-indol-1-ylmethyl}-thiazole-4-carboxylic acid methyl ester.
.sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm 5.27 (s, 2H), 6.59 (d,
1H), 6.78 (t, 1H), 6.87 (d, 1H), 7.15 (t, 1H), 7.31-7.43 (m, 9H),
8.22 (s, 1H).
Example 77
3-[3-(4-Methyl-1-phenyl-pent-(Z)-ylidene)-2-oxo-2,3-dihydro-indol-1-ylmeth-
yl]-benzoic acid methyl ester
##STR00097##
[0399] To a degassed refluxing solution of
3-{[(2-iodo-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic
acid methyl ester (100 mg, 0.2 mmol) and Ni(PPh.sub.3).sub.2I.sub.2
(16 mg, 0.02 mmol) in CH.sub.2Cl.sub.2 (8 ml) was added
3-methylbutylzinc bromide (151 mg, 0.7 mmol) in CH.sub.2Cl.sub.2 (1
ml). The reaction was stirred at 40.degree. C. for 6 h and then the
solution was cooled to room temperature. The resultant solution was
diluted with ethyl acetate (50 ml). The organic layer was washed
with aqueous HCl solution (4%, 10 ml), brine (3.times.10 ml). The
aqueous layer was back-extracted with ethyl acetate (3.times.10
ml). The combined organic layer was dried over anhydrous sodium
sulfate. After filtration, the solvent was removed under reduced
pressure and the residue was purified by column chromatography on
silica gel, eluting with petrol ether-ethyl acetate, to give
3-{3-[4-methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmet-
hyl}-benzoic acid methyl ester (24 mg, 28%) as light yellow solid.
.sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm 0.88 (d, 6H),
1.43-1.55 (m, 2H), 1.68-1.72 (m, 1H), 2.93-2.99 (m, 2H), 3.91 (s,
3H), 4.89 (s, 2H), 6.64 (d, 1H), 7.05 (t, 1H), 7.15 (t, 1H),
7.28-7.38 (m, 4H), 7.40-7.47 (m, 3H), 7.62 (d, 1H), 7.91 (d, 1H),
7.95 (s, 1H); and
3-{3-[4-methyl-1-phenyl-pent-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmet-
hyl}-benzoic acid methyl ester (29 mg, 33%) as light yellow solid.
.sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm 0.88 (d, 6H),
1.36-1.44 (m, 2H), 1.64-1.68 (m, 1H), 3.33-3.38 (m, 2H), 3.91 (s,
3H), 5.04 (s, 2H), 6.01 (d, 1H), 6.58-6.61 (m, 2H), 6.96-7.02 (t,
1H), 7.26-7.29 (m, 2H), 7.37 (t, 2H), 7.43-7.52 (m, 3H), 7.93 (d,
1H), 8.03 (s, 1H).
Example 78
3-{3-[3,3-Dimethyl-1-phenyl-but-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylm-
ethyl}-benzoic acid methyl ester
##STR00098##
[0401] The title compound was prepared in analogy to Example 77
starting from tert-butylzinc bromide (commercially available) and
3-{[(2-iodo-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic
acid methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm
0.80 (s, 9H), 2.74 (s, 2H), 3.90 (s, 3H), 5.67 (s, 2H), 6.98 (t,
1H), 7.12-7.52 (m, 10H), 7.93 (d, 1H), 8.03 (s, 1H).
Example 79
3-{3-[2-(4-Chloro-phenyl)-1-phenyl-eth-(Z)-ylidene]-2-oxo-2,3-dihydro-indo-
l-1-ylmethyl}-benzoic acid methyl ester
##STR00099##
[0403] The title compound was prepared in analogy to Example 77
starting from 4-chloro-benzylzinc bromide (commercially available)
and 3-{[(2-iodo-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic
acid methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm
3.92 (s, 3H), 4.73 (s, 2H), 5.07 (s, 2H), 5.99 (d, 1H), 6.58-6.65
(m, 2H), 7.08-7.20 (m, 7H), 7.37-7.43 (m, 4H), 7.52 (d, 1H), 7.93
(d, 1H), 8.06 (s, 1H).
Example 80
3-{3-[3,3-Dimethyl-1-phenyl-but-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylm-
ethyl}-benzoic acid methyl ester
##STR00100##
[0405] The title compound was prepared in analogy to Example 77
starting from tert-butylzinc bromide (commercially available) and
3-{[(2-iodo-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic
acid methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm
0.91 (s, 9H), 3.48 (s, 2H), 3.90 (s, 3H), 5.03 (s, 2H), 6.22 (d,
1H), 6.56-6.62 (m, 2H), 6.98 (t, 1H), 7.36-7.50 (m, 7H), 7.92 (d,
1H), 8.02 (s, 1H).
Example 81
3-[3-(4-Methyl-1-phenyl-pent-(Z)-ylidene)-2-oxo-2,3-dihydro-indol-1-ylmeth-
yl]-benzoic acid
##STR00101##
[0407]
3-{3-[4-Methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-
-ylmethyl}-benzoic acid methyl ester (24 mg, 0.05 mmol) was
dissolved in THF (1 ml) and water (1 ml) and LiOH.H.sub.2O (14 mg,
0.33 mmol) was added in one portion. The mixture was stirred at
50.degree. C. for 16 h. The mixture was concentrated under reduced
pressure and acidified to pH=3. Purification by preparative HPLC
afforded
3-[3-(4-methyl-1-phenyl-pent-(Z)-ylidene)-2-oxo-2,3-dihydro-indol-1-ylmet-
hyl]-benzoic acid 10 mg. .sup.1H NMR (300 Hz, CDCl.sub.3):
.delta.ppm 0.88 (d, 6H), 1.36-1.44 (m, 2H), 1.64-1.68 (m, 1H),
3.33-3.38 (m, 2H), 5.04 (s, 2H), 6.01 (d, 1H), 6.58-6.61 (m, 2H),
6.96-7.02 (t, 1H), 7.26-7.29 (m, 2H), 7.37 (t, 2H), 7.43-7.52 (m,
3H), 7.93 (d, 1H), 8.03 (s, 1H).
Example 82
3-{3-[1-(4-Chloro-benzyl)-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid
##STR00102##
[0409] The title compound was prepared in analogy to Example 81
starting from
3-{3-[1-(4-chloro-benzyl)-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihyd-
ro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR (300
Hz, CDCl.sub.3): .delta.ppm 1.14 (d, 6H), 3.62-3.71 (m, 1H), 4.577
(s, 2H), 5.018 (s, 2H), 6.82 (d, 1H), 7.04 (t, 1H), 7.21-7.26 (m,
5H), 7.43 (t, 1H), 7.53 (d, 1H), 7.63 (d, 1H), 8.01 (d, 1H), 8.07
(s, 1H).
Example 83
3-{3-[1-(4-Fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}--
benzoic acid
##STR00103##
[0410] But-2-ynoic acid (2-iodo-phenyl)-amide
[0411] A mixture of 2-iodo-phenylamine (10 g, 45.7 mmol) and
but-2-ynoic acid (4.6 g, 54.8 mmol) in dichloromethane (50 ml) was
cooled to 0.degree. C. Then 1,3-dicyclohexylcarbodiimide (14 g,
68.6 mmol) was added. After stirring for 3 hours at room
temperature, the mixture was washed with water (20 ml). The organic
layer was dried over sodium sulfate and concentrated to give the
crude product but-2-ynoic acid (2-iodo-phenyl)-amide (13.0 g, 100%)
as a yellow solid which was used in next step without purification.
MS calcd. for C.sub.10H.sub.8INO 285.1, obsd. (ESI.sup.+)
[(M+H).sup.+] 286.0.
3-{[(2-Iodo-phenyl)-(1-oxo-but-2-ynyl)-amino]-methyl}-benzoic acid
methyl ester
[0412] A mixture of but-2-ynoic acid (2-iodo-phenyl)-amide (2.85 g,
10 mmol) and cesium carbonate (4.89 g, 15 mmol) in DMF (20 ml) was
stirred for 10 minutes. 3-bromomethyl-benzoic acid methyl ester
(2.52 g, 11 mmol) was added. Then the mixture was stirred for 12
hours at room temperature. After removal of solids, the filtrate
was treated with water and extracted with ether. The organic layer
was dried over sodium sulfate and concentrated to give the residue
which was purified by flash chromatography, eluting with ethyl
acetate/hexane= 1:4 to afford the product
3-{[(2-iodo-phenyl)-(1-oxo-but-2-ynyl)-amino]-methyl}-benzoic acid
methyl ester as yellow solid (3.03, 70%). MS calcd. for
C.sub.19H.sub.16INO.sub.3 433.3, obsd. (ESP) [(M+H).sup.+]
434.1.
3-{3-[1-(4-Fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}--
benzoic acid methyl ester
[0413] A mixture of
3-{[(2-iodo-phenyl)-(1-oxo-but-2-ynyl)-amino]-methyl}-benzoic acid
methyl ester (0.5 g, 1.15 mmol), 4-fluorophenylboronic acid (0.32
g, 2.3 mmol), tetrakis (triphenylphosphine) palladium (0.13 g,
0.115 mmol) and copper thiophene-2-carboxylic acid (0.46 g, 2.42
mmol) in THF was stirred for 5 hours at 60.degree. C. After removal
of solvent, the residue was purified by flash chromatography,
eluting with ethyl acetate/hexane= 1:5 to afford the product
3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-
-benzoic acid methyl ester (0.28 g, 60%) as a yellow solid. MS
calcd. for C.sub.25H.sub.20FNO.sub.3 401.4, obsd. (ESP)
[(M+H).sup.+] 402.2.
3-{3-[1-(4-Fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}--
benzoic acid
[0414] A solution of
3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-
-benzoic acid methyl ester (0.33 g, 0.82 mmol) was dissolved in THF
5 ml. Then a solution of lithium hydroxide (0.35 g, 8.2 mmol) in
water (2.0 ml) was added. After stirring for 12 hours, the solvent
was removed under reduced pressure. The residue was dissolved in 2
ml DMF for prepared HPLC to give
3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-y-
lmethyl}-benzoic acid as yellow powder (100 mg). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.ppm 2.78 (s, 3H) 5.06 (s, 2H) 6.08 (d,
J=7.83 Hz, 1H) 6.68 (t, J=7.45 Hz, 1H) 6.92 (d, J=7.83 Hz, 1H) 7.11
(t, J=7.45 Hz, 1H) 7.38 (t, J=8.84 Hz, 2H) 7.43-7.51 (m, 1H) 7.46
(dd, 7=8.72, 5.68 Hz, 2H) 7.60 (d, J=7.58 Hz, 1H) 7.85 (d, J=7.83
Hz, 1H) 7.92 (s, 1H) 13.03 (s, 1H). MS calcd. for
C.sub.24H.sub.18FNO.sub.3 387.4, obsd. (ESI.sup.+) [(M+H).sup.+]
388.2.
Example 84
3-{3-[1-(4-Chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1--
ylmethyl}-benzoic acid methyl ester
##STR00104##
[0415] 1-Iodo-2-isocyanato-benzene
[0416] A solution of 2-iodo-phenylamine (30 g, 0.14 mol) in
dichloromethane (800 ml) was added triphosgene (14.6 g, 49.3 mmol)
and saturated sodium bicarbonate (544 ml) at 0.degree. C. The
resulted mixture was stirred for 4 hours. The organic layer was
washed with brine (200 ml) and dried over sodium sulfate. After
removal of solvent, the crude product 1-iodo-2-isocyanato-benzene
(32.3 g, 96%) was obtained as a yellow oil which was used in next
step without purification.
4-Methyl-pent-2-ynoic acid (2-iodo-phenyl)-amide
[0417] 3-Methyl-but-1-yne (11 g, 0.16 mol) in THF (100 ml) was
added n-BuLi (2.5M in hexane) (59 ml, 0.15 mol) at 0.degree. C. The
resulting mixture was stirred for 30 minutes. Then a solution of
1-iodo-2-isocyanato-benzene (33 g, 0.14 mol) in THF (100 ml) was
dropped into the mixture. After stirring for 2 hours at 0.degree.
C., the mixture was treated with brine (100 ml) and extracted with
ether (200 ml). The organic layer was dried over sodium sulfate and
concentrated to give the crude product 4-methyl-pent-2-ynoic acid
(2-iodo-phenyl)-amide (38 g, 90%) as a yellow oil which was used in
next step without purification. MS calcd. for C.sub.12H.sub.12INO
313.1, obsd. (ESP) [(M+H).sup.+]314.0.
3-{[(2-Iodo-phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic
acid methyl ester
[0418] A mixture of 4-methyl-pent-2-ynoic acid
(2-iodo-phenyl)-amide (21 g, 67.1 mmol) and cesium carbonate (33.0
g, 100.7 mmol) in DMF (170 ml) was stirred for 10 minutes.
3-bromomethyl-benzoic acid methyl ester (16.9 g, 73.8 mmol) was
added. Then the mixture was stirred for 12 hours at room
temperature. After removal of the solids, the filtrate was treated
with water and extracted with ether. The organic layer was dried
over sodium sulfate and concentrated to give the residue which was
purified by flash chromatography, eluting with ethyl
acetate/hexane= 1:4 to afford the product
3-{[(2-iodo-phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic
acid methyl ester as yellow solid (15.9 g, 51%). MS calcd. for
C.sub.21H.sub.20ClNO.sub.3 461.3, obsd. (ESP) [(M+H).sup.+]
461.9.
3-{3-[1-(4-Chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1--
ylmethyl}-benzoic acid methyl ester
[0419] A mixture of
3-{[(2-iodo-phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic
acid methyl ester (0.93 g, 2.02 mmol), 4-chlorophenylboronic acid
(0.63 g, 4.04 mmol), triphenylphosphine (53 mg, 0.202 mmol),
palladium acetate (23 mg, 0.10 mmol) and cesium fluoride (0.92 g,
6.06 mmol) in THF (15 ml) was stirred for 3 hours at 60.degree. C.
After removal of solvent, the residue was purified by flash
chromatography, eluting with ethyl acetate/hexane=1:5 to afford the
product
3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-
-ylmethyl}-benzoic acid methyl ester (0.40 g, 44%) as a yellow
solid. MS calcd. for C.sub.27H.sub.24ClNO.sub.3 445.5, obsd.
(ESI.sup.+) [(M+H).sup.+] 446.0. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.ppm 1.10 (d, 7=6.82 Hz, 6H) 3.91 (s, 3H) 4.99
(dt, J=13.71, 6.92 Hz, 1H) 5.06 (s, 2H) 5.73 (d, J=7.58 Hz, 1H)
6.62 (t, J=7.71 Hz, 1H) 6.73 (d, J=7.83 Hz, 1H) 7.05 (t, J=7.71 Hz,
1H) 7.19 (d, J=8.34 Hz, 2H) 7.46 (t, J=7.83 Hz, 1H) 7.55 (d, J=8.08
Hz, 3H) 7.94 (d, J=7.58 Hz, 1H) 8.02 (s, 1H) MS calcd. for
C.sub.27H.sub.24ClNO.sub.3 445.5, obsd. (ESI.sup.+) [(M+H).sup.+]
446.0.
Example 85
3-{3-[2-Methyl-1-phenyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmeth-
yl}-benzoic acid methyl ester
##STR00105##
[0421] The title compound was prepared in analogy to Example 84
starting from phenylboronic acid (commercially available) and
3-{[(2-iodo phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic
acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm
8.04 (s, 1H), 7.94 (d, 1H), 7.48-7.53 (m, 3H), 7.39 (t, 1H), 7.15
(dd, 2H), 6.99 (t, 1H), 6.59-6.61 (d, 1H), 6.55 (t, 1H), 5.59 (d,
2H), 5.00-5.05 (m, 3H), 3.97 (s, 3H), 1.11 (s, 3H), 1.09 (s,
3H).
Example 86
3-{3-[1-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid methyl ester
##STR00106##
[0423] The title compound was prepared in analogy to Example 84
starting from 4-acetyl-phenylboronic acid (commercially available)
and 3-{[(2-iodo
phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methyl
ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.03-8.11 (m,
4H), 7.94 (d, 1H), 7.71 (d, 1H), 7.52 (d, 1H), 7.40 (t, 1H), 7.29
(d, 2H), 7.00 (t, 1H), 6.61 (d, 1H), 6.54 (t, 1H), 5.61 (d, H),
5.02-5.07 (m, 3H), 3.90 (s, 3H), 2.70 (s, 3H), 1.19 (d, 3H), 1.17
(d, 3H).
Example 87
3-{3-[1-(4-Chloro-phenyl)-1-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00107##
[0425] The title compound was prepared in analogy to Example 84
starting from 4-chloro-phenylboronic acid (commercially available)
and
3-{[(3-cyclohexyl-propynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic
acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.ppm
8.02 (s, 1H), 7.93 (d, 1H), 7.47-7.51 (m, 13H), 7.39 (t, 1H), 7.10
(d, 2H), 7.01 (t, 1H), 6.59-6.63 (m, 2H), 5.71 (d, 2H), 5.02 (s,
2H), 4.62 (t, 1H), 3.91 (s, 3H), 1.44-1.76 (m, 6H), 1.01-1.18 (m,
4H).
Example 88
3-{3-[2-Methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00108##
[0427] The title compound was prepared in analogy to Example 84
starting from 4-trifluoromethyl-phenylboronic acid (commercially
available) and 3-{[(2-iodo
phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methyl
ester. .sup.1H NMR (DMSO, 300 MHz) .delta.ppm 7.90 (s, 1H),
7.79-7.86 (m, 2H), 7.58 (d, 1H), 7.48 (t, 1H), 7.42 (d, 1H), 7.09
(t, 1H), 7.00 (d, 1H), 6.89 (d, 1H), 6.65 (t, 1H), 5.65 (d, 1H),
5.03 (s, 2H), 4.84-4.93 (m, 1H), 3.57 (s, 3H), 0.96-1.06 (dd,
6H).
Example 89
3-{3-[1-(4-Chloro-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00109##
[0429] The title compound was prepared in analogy to Example 84
starting from 4-chloro-phenylboronic acid (commercially available)
and
3-{[(4-hydroxy-4-methyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benz-
oic acid methyl ester. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.ppm 1.30 (s, 6H) 3.83 (s, 3H) 5.14 (s, 2H) 5.43 (d, J=7.58
Hz, 1H) 6.68 (t, J=7.58 Hz, 1H) 7.01 (d, J=7.83 Hz, 1H) 7.12 (t,
J=7.45 Hz, 1H) 7.27 (d, J=8.34 Hz, 2H) 7.51 (t, J=7.71 Hz, 1H)
7.58-7.65 (m, 4H) 7.87 (d, J=7.58 Hz, 1H) 7.97 (s, 1H).
Example 90
3-{3-[1-(4-Cyano-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00110##
[0431] The title compound was prepared in analogy to Example 84
starting from 4-cyano-phenylboronic acid (commercially available)
and
3-{[(4-hydroxy-4-methyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benz-
oic acid methyl ester. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.ppm 1.33 (s, 6H) 3.85 (s, 3H) 5.15 (s, 2H) 5.35 (d, J=7.83
Hz, 1H) 6.68 (t, J=7.71 Hz, 1H) 7.03 (d, J=7.83 Hz, 1H) 7.15 (t,
J=7.71 Hz, 1H) 7.48-7.55 (m, 1H) 7.52 (d, J=7.58 Hz, 3H) 7.62 (d,
J=7.83 Hz, 1H) 7.89 (d, J=7.83 Hz, 1H) 7.99 (s, 1H) 8.05 (d, J=8.34
Hz, 2H).
Example 91
3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00111##
[0433] The title compound was prepared in analogy to Example 84
starting from 4-chloro-phenylboronic acid (commercially available)
and
3-{[(4,4-dimethyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic
acid methyl ester. .sup.1H NMR (400 MHz, MeOD) .delta.ppm 1.38 (s,
9H) 3.86 (s, 3H) 4.83 (d, 2H) 6.81 (d, J=7.83 Hz, 1H) 6.99 (d,
J=7.83 Hz, 2H) 7.10 (t, J=7.58 Hz, 1H) 7.22 (t, J=7.71 Hz, 1H)
7.33-7.42 (m, 4H) 7.84-7.88 (m, 2H) 7.93 (d, J=7.83 Hz, 1H).
Example 92
3-{3-[1-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro--
indol-1-ylmethyl}-benzoic acid methyl ester
##STR00112##
[0435] The title compound was prepared in analogy to Example 84
starting from 4-cyano-phenylboronic acid (commercially available)
and
3-{[(4,4-dimethyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic
acid methyl ester. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm
1.35 (s, 9H) 3.84 (s, 3H) 5.07 (s, 2H) 5.19 (d, J=7.83 Hz, 1H) 6.56
(t, J=7.71 Hz, 1H) 6.88 (d, J=7.83 Hz, 1H) 7.06 (t, J=7.71 Hz, 1H)
7.42 (d, J=8.08 Hz, 2H) 7.50 (t, J=7.71 Hz, 1H) 7.59 (d, J=7.58 Hz,
1H) 7.87 (d, J=7.58 Hz, 1H) 7.95-8.05 (m, 3H).
Example 93
3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid methyl ester
##STR00113##
[0437] The title compound was prepared in analogy to Example 84
starting from 4-chloro-phenylboronic acid (commercially available)
and
3-{[(4,4-dimethyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic
acid methyl ester. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm
1.36 (s, 9H) 3.84 (s, 3H) 5.07 (s, 2H) 5.30 (d, J=7.83 Hz, 1H) 6.57
(t, J=7.83 Hz, 1H) 6.88 (d, J=7.83 Hz, 1H) 7.05 (t, J=7.71 Hz, 1H)
7.21 (d, J=8.08 Hz, 2H) 7.51 (t, J=7.71 Hz, 1H) 7.57-7.64 (m, 2H)
7.87 (d, J=7.58 Hz, 1H) 7.97 (s, 1H).
Example 94
3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1--
ylmethyl}-benzoic acid
##STR00114##
[0439] A solution of
3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-
-ylmethyl}-benzoic acid methyl ester (0.40 g, 0.90 mmol) was
dissolved in THF 15 ml. Then a solution of lithium hydroxide (0.38
g, 9.0 mmol) in water (3.0 ml) was added. After stirring for 12
hours, the solvent was removed under reduced pressure. The residue
was dissolved in 2 ml DMF for prepared HPLC to give
3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-
-ylmethyl}-benzoic acid as a yellow powder (200 mg). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.ppm 1.00 (d, J=6.82 Hz, 6H)
4.90-4.99 (m, 1H) 5.05 (s, 2H) 5.59 (d, J=7.83 Hz, 1H) 6.64 (t,
J=7.71 Hz, 1H) 6.91 (d, J=7.83 Hz, 1H) 7.10 (t, J=7.71 Hz, 1H) 7.27
(d, J=8.34 Hz, 2H) 7.49 (t, J=7.58 Hz, 1H) 7.63 (d, J=8.34 Hz, 2H)
7.59 (d, J=7.58 Hz, 1H) 7.85 (d, J=7.58 Hz, 1H) 7.92 (s, 1H) 13.05
(s, 1H). MS calcd. for C.sub.26H.sub.22ClNO.sub.3 431.5, obsd.
(ESI.sup.+) [(M+H).sup.+] 432.0.
Example 95
3-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indo-
l-1-ylmethyl}-benzoic acid
##STR00115##
[0441] The title compound was prepared in analogy to Example 94
starting from
3-{3-[1-(4-cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydr-
oindol-1-ylmethyl} benzoic acid methyl ester. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.ppm 1.01 (d, J=6.82 Hz, 6H) 4.91-5.00 (m, 1H)
5.05 (s, 2H) 5.50 (d, J=7.83 Hz, 1H) 6.64 (t, J=7.58 Hz, 1H) 6.93
(d, J=7.83 Hz, 1H) 7.11 (t, J=7.58 Hz, 1H) 7.48 (d, J=7.58 Hz, 3H)
7.60 (d, J=7.58 Hz, 1H) 7.85 (d, J=7.33 Hz, 1H) 7.93 (s, 1H) 8.05
(d, J=8.08 Hz, 2H) 13.06 (br. s., 1H).
Example 96
6-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-pyridine-2-carboxylic acid
##STR00116##
[0443] The title compound was prepared in analogy to Example 94
starting from
6-{3-[1-(4-chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihyd-
ro-indol-1ylmethyl}-pyridine-2-carboxylic acid methyl ester.
.sup.1H NMR (400 MHz, MeOD) .delta.ppm 1.06 (d, 6H) 4.92-5.01 (m,
1H) 5.23 (s, 2H) 5.74 (d, 1H) 6.64 (t, 1H) 6.87 (d, 1H) 7.08 (t,
1H) 7.22 (d, 2H) 7.45 (d, 1H) 7.59 (d, 2H) 7.95 (t, 1H) 8.09 (d,
1H).
Example 97
6-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indo-
l-1-ylmethyl}-pyridine-2-carboxylic acid
##STR00117##
[0445] The title compound was prepared in analogy to Example 94
starting from
6-{3-[1-(4-cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydr-
oindol-1-ylmethyl}-pyridine-2-carboxylic acid methyl ester. .sup.1H
NMR (400 MHz, MeOD) .delta.ppm 1.06 (d, 6H) 4.95-5.08 (m, 1H) 5.25
(s, 2H) 5.64 (d, 1H) 6.63 (t, 1H) 6.89 (d, 1H) 7.09 (t, 1H) 7.46
(d, 3H) 7.90-8.00 (m, 3H) 8.09 (d, 1H).
Example 98
3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid
##STR00118##
[0447] The title compound was prepared in analogy to Example 94
starting from
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl-prop-(Z)ylidene]-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.ppm 1.32 (s, 9H) 4.86 (s, 2H) 6.95 (d,
J=7.58 Hz, 1H) 7.04 (d, J=8.59 Hz, 2H) 7.13 (t, 1H) 7.29 (t, 1H)
7.38-7.42 (m, 2H) 7.44 (d, J=5.05 Hz, 2H) 7.77-7.84 (m, 2H) 7.88
(d, J=7.83 Hz, 1H) 13.01 (s, 1H).
Example 99
3-{3-[1-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro--
indol-1-ylmethyl}-benzoic acid
##STR00119##
[0449] The title compound was prepared in analogy to Example 94
starting from
3-{3-[1-(4-cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-di-
hydro-indol-1ylmethyl}-benzoic acid methyl ester. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.ppm 1.35 (s, 9H) 5.06 (s, 2H) 5.19 (d,
J=7.83 Hz, 1H) 6.57 (t, J=7.45 Hz, 1H) 6.89 (d, J=7.58 Hz, 1H) 7.07
(t, J=7.45 Hz, 1H) 7.41-7.51 (m, 3H) 7.56 (d, 1H) 7.84 (d, J=7.58
Hz, 1H) 7.93 (s, 1H) 8.03 (d, J=8.34 Hz, 2H).
Example 100
3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid
##STR00120##
[0451] The title compound was prepared in analogy to Example 94
starting from
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.ppm 1.35 (s, 9H) 5.06 (s, 2H) 5.30
(d, J=7.83 Hz, 1H) 6.57 (t, 1H) 6.88 (d, J=7.83 Hz, 1H) 7.06 (t,
1H) 7.22 (d, J=8.08 Hz, 2H) 7.49 (t, 1H) 7.54-7.63 (m, 3H) 7.84 (d,
1H) 7.93 (s, 1H) 12.97 (s, 1H).
Example 101
3-{3-[1-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid
##STR00121##
[0453] The title compound was prepared in analogy to Example 94
starting from
3-{3-[1-(4-fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihyd-
ro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.ppm 1.01 (d, J=6.82 Hz, 6H) 4.87-4.99 (m,
1H) 5.05 (s, 2H) 5.54 (d, J=7.83 Hz, 1H) 6.63 (t, J=7.33 Hz, 1H)
6.90 (d, J=7.58 Hz, 1H) 7.09 (d, J=1.01 Hz, 1H) 7.24-7.31 (m, 2H)
7.40 (t, J=8.84 Hz, 2H) 7.49 (t, J=7.58 Hz, 1H) 7.59 (d, J=7.58 Hz,
1H) 7.85 (d, J=7.83 Hz, 1H) 7.92 (s, 1H) 13.03 (s, 1H).
Example 102
6-{3-[1-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-pyridine-2-carboxylic acid
##STR00122##
[0455] The title compound was prepared in analogy to Example 94
starting from
6-{3-[1-(4-fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihyd-
ro-indol-1-ylmethyl}pyridine-2-carboxylic acid methyl ester.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 1.01 (d, J=6.82 Hz,
6H) 4.86-5.00 (m, 1H) 5.16 (br. s., 2H) 5.56 (d, J=7.83 Hz, 1H)
6.63 (t, J=7.71 Hz, 1H) 6.85 (d, J=7.33 Hz, 1H) 7.06 (t, J=7.58 Hz,
1H) 7.29 (d, J=5.56 Hz, 2H) 7.27 (d, J=5.81 Hz, 1H) 7.41 (t, J=8.72
Hz, 2H) 7.81-7.98 (m, 2H).
Example 103
3-{3-[2-Methyl-1-pyridin-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1--
ylmethyl}-benzoic acid
##STR00123##
[0457] The title compound was prepared in analogy to Example 94
starting from
3-{3-[2-methyl-1-pyridin-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-in-
dol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR (400 MHz,
MeOD) .delta.ppm 1.13 (t, J=7.71 Hz, 6H) 5.01-5.14 (m, 1H) 5.10 (s,
2H) 5.59 (d, J=7.83 Hz, 1H) 6.62 (t, J=7.71 Hz, 1H) 6.83 (d, J=7.83
Hz, 1H) 7.11 (t, J=7.71 Hz, 1H) 7.47 (t, J=7.71 Hz, 1H) 7.59 (d,
J=7.58 Hz, 1H) 7.84 (br. s., 1H) 7.93-8.05 (m, 2H) 7.96 (s, 1H)
8.58 (br. s., 1H) 8.85 (br. s., 1H).
Example 104
3-{3-[1-(4-Chloro-phenyl)-1-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-
-indol-1-ylmethyl}-benzoic acid
##STR00124##
[0459] The title compound was prepared in analogy to Example 94
starting from
3-{3-[1-(4-chloro-phenyl)-1-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.ppm 8.09 (s, 1H), 8.02 (d, 1H), 7.57
(d, 1H), 7.41-7.50 (m, 3H), 7.11 (d, 2H), 7.03 (t, 1H), 6.60-6.64
(m, 2H), 5.73 (d, 1H), 5.05 (s, 2H), 4.63 (m, 1H), 1.44-1.81 (m,
6H), 1.01-1.18 (m, 4H).
Example 105
3-{3-[2-Methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-di-
hydro-indol-1-ylmethyl}-benzoic acid
##STR00125##
[0461] The title compound was prepared in analogy to Example 94
starting from
3-{3-[2-methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo--
2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.ppm 8.08 (s, 1H), 8.00 (d, 1H),
7.77 (d, 2H), 7.58 (d, 1H), 7.44 (t, 1H), 7.31 (d, 2H), 7.03 (t,
1H), 6.63 (d, 1H), 6.58 (t, 1H), 5.58 (d, 1H), 5.04-5.08 (m, 3H),
1.16 (s, 3H), 1.13 (s, 1H).
Example 106
3-{3-[2-Methyl-1-thiophen-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-
-ylmethyl}-benzoic acid
##STR00126##
[0463] The title compound was prepared in analogy to Example 94
starting from
3-{3-[2-methyl-1-thiophen-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-i-
ndol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.ppm 8.08 (s, 1H), 8.01 (d, 1H), 7.77
(d, 2H), 7.58 (d, 1H), 7.44 (t, 1H), 7.31 (d, 2H), 7.03 (t, 1H),
6.63 (d, 1H), 6.58 (t, 1H), 5.58 (d, 1H), 5.04-5.08 (m, 3H), 1.10
(s, 3H), 1.07 (s, 3H).
Example 107
3-{5-Chloro-3-[2-methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-o-
xo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid
##STR00127##
[0465] The title compound was prepared in analogy to Example 94
starting from 3-{5-chloro-3-[2-methyl-1-(4-trifluoromethyl
phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic
acid methyl ester. .sup.1H NMR (300 Hz, CDCl.sub.3): .delta.ppm
1.11 (d, 6H), 5.00-5.04 (m, 1H), 5.01 (s, 2H), 5.40 (d, 1H), 6.51
(d, 1H), 6.98 (dd, 1H), 7.28 (d, 2H), 7.42 (t, 1H), 7.56 (m, 1H),
7.81 (d, 2H), 8.01-8.04m, 2H).
Example 108
3-{3-[1-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-ind-
ol-1-ylmethyl}-benzoic acid
##STR00128##
[0467] The title compound was prepared in analogy to Example 94
starting from
3-{3-[1-(4-acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihyd-
ro-indol-1-ylmethyl}-benzoic acid methyl ester. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.ppm 8.00-8.12 (m, 3H), 7.72 (d, 1H),
7.57 (d, 1H), 7.44 (t, 1H), 7.29 (d, 2H), 7.02 (t, 1H), 6.62 (d,
1H), 6.55 (t, 1H), 5.63 (d, 2H), 5.04 (m, 3H), 2.70 (s, 3H), 1.10
(s, 3H), 1.08 (s, 3H).
Example 109
N-(3-{3-[1-(4-Chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-
-1-ylmethyl}-benzoyl)-methanesulfonamide
##STR00129##
[0469] A mixture of
3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-
-ylmethyl}-benzoic acid (0.22 g, 0.51 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.20
g, 1.02 mmol), methylsulfonamide (97 mg, 1.02 mmol), DMAP (12.2 mg,
0.10 mmol) in dichloromethane (20 ml) was stirred for 72 hours. The
organic solution washed with brine (10 ml) then dried over sodium
sulfate. After removal of solvent, the residue was dissolved in 2
ml DMF for prepared HPLC to give the product
N-(3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indo-
l-1-ylmethyl}-benzoyl)-methanesulfonamide (100 mg, 38%) as yellow
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.ppm 1.21 (d,
J=6.82 Hz, 6H) 3.50 (s, 3H) 5.00-5.12 (m, 1H) 5.17 (s, 2H) 5.52 (s,
1H) 5.84 (d, J=7.83 Hz, 1H) 6.75 (t, J=7.83 Hz, 1H) 6.85 (d, J=7.83
Hz, 1H) 7.17 (t, J=7.20 Hz, 1H) 7.28 (d, J=8.59 Hz, 2H) 7.60 (t,
J=7.71 Hz, 1H) 7.65 (d, J=8.34 Hz, 2H) 7.70 (d, J=7.83 Hz, 1H) 7.94
(d, J=7.83 Hz, 1H) 8.02 (s, 1H). MS calcd. for
C.sub.27H.sub.25ClN.sub.2O.sub.4S 508.5, obsd. (ESI.sup.+)
[(M+H).sup.+] 509.2.
Example 110
N-(3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihy-
dro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide
##STR00130##
[0471] The title compound was prepared in analogy to Example 109
starting from
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid. .sup.1H NMR (400 MHz, MeOD)
.delta.ppm 1.44 (s, 9H) 3.11 (s, 3H) 5.05 (s, 2H) 5.41 (d, J=7.83
Hz, 1H) 6.52 (t, 1H) 6.74 (d, J=7.58 Hz, 1H) 7.00 (t, 1H) 7.12-7.21
(m, 2H) 7.30-7.39 (m, 2H) 7.51-7.60 (m, 2H) 7.89-7.97 (m, 1H) 8.04
(s, 1H).
Example 111
N-(3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihy-
dro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide
##STR00131##
[0473] The title compound was prepared in analogy to Example 109
starting from
3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-d-
ihydro-indol-1-ylmethyl}-benzoic acid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.ppm 1.32 (s, 9H) 3.34 (s, 3H) 4.84 (s, 2H)
6.93 (d, J=7.83 Hz, 1H) 7.04 (d, J=8.34 Hz, 2H) 7.12 (t, J=7.33 Hz,
1H) 7.27 (t, J=7.45 Hz, 1H) 7.37-7.47 (m, 4H) 7.78-7.85 (m, 2H)
7.88 (d, J=8.08 Hz, 1H).
Example 112
Evaluation of AMPK Modulator by Analysis of AMPK and ACC
Phosphorylation
[0474] This method evaluates endogenous expression and
phosphorylation of AMP-activated protein kinase (AMPK) and acetyl
CoA carboxylase (ACC) in L6 cell line using Western blot analysis.
It is used to determine the potency and efficacy of small molecular
AMPK modulators. L6 cells (ATCC) are cultured and maintained at
DMEM (high glucose, Gibco, BRL) with 10% fetal bovine serum (FBS,
Hyclone). In an assay, cells are plated at 3.times.10.sup.6 per
plate in 10 ml on a 10 cm dish and they reach subconfluent of
70-80% within 24 hrs. The cells are serum starved overnight prior
to be treated with an AMPK modulator. The compound concentration
typically ranges from 0 to 100 uM and treat the cells for 1-4 hrs.
Once the incubation is completed, the medium is aspirated and the
cell layer is gently rinsed with 2 ml of ice-cold PBS. 500 .mu.l of
lysis buffer containing 150 mM NaCl, 5 mM EDTA, 2 mM EGTA, 25 mM
NaF, 2 mM Na.sub.3VO.sub.4, 1 mg/ml of Pefabloc, 1% Triton X-100,
and a Roche Complete Protease Inhibitor Tablet is added and
incubated on ice for 10 min. The cell lysate is harvested and
subsequently centrifugated at 12,000 rpm for 10 min at 4.degree. C.
The supernatant is saved and its protein concentration is
determined using Quick Start Bradford protein quantification kit
(Bio-Rad). 40 jug is loaded for 7.5% SDS-PAGE analysis and
subsequently blotted to PVDF membrane following a standard
procedure. The membrane is treated with a blocking buffer (5%
nonfat milk) for 1 h at room temperature in agitation. The levels
of phospho-AMPK and phospho-ACC are determined using
phospho-AMPK.alpha.(Thr172)(40H9) rabbit mAb (Cell Signaling) and
phospho-acetyl CoA carboxylase(Ser79) antibody (Cell Signaling) as
primary antibodies by incubating the blot at 4.degree. C.
overnight. The blots are stripped and re-probed using acetyl CoA
carboxylase (C83B10) rabbit mAb (Cell signaling), AMPK.alpha.(23A3)
rabbit mAb (Cell Signaling), and .beta.-actin antibody (Cell
Signaling) to determine the whole protein level of ACC, AMPK and
.beta.-actin, respectively. Each protein band in a blot is
visualized via ECL Plus Western blotting detection kit (Amersham)
and quantified by the scan analysis. The EC.sub.50 value, defined
as an activator concentration that produces half of the maximal
activation effect, and Emax, defined as the maximal activation
effect at the infinite activator concentration, are determined
semi-quantitatively and recorded. All the compounds of formula (I)
are active in the foregoing AMPK and ACC phosphorylation assay.
Example 113
Scintillation Proximity Assay
Preparation of Enzymes
[0475] Recombinant human AMPK .alpha.1.beta.1.gamma.1,
.alpha.2.beta.1.gamma.1 or AMPK .alpha. subunit truncations
al(1-335), .alpha.1(1-394) and .alpha.2(1-394) were constructed,
expressed and purified as described previously (Pang, T., Zhang, Z.
S., Gu, M., Qiu, B. Y., Yu, L. F., Cao, P. R., Shao, W., Su, M. B.,
Li, J. Y., Nan, F. J., and Li, J. (2008)). Rat liver AMPK
heterotrimer enzyme was obtained from Upstate (Billerica, Mass.,
U.S.A.).
Scintillation Proximity Assay
[0476] Before the Scintillation Proximity Assay (SPA) assay, 200 nM
recombinant AMPK proteins (.alpha.1.beta.1.gamma.1,
.alpha.2.beta.1.gamma.1, .alpha.1(1-335), .alpha.1(1-394) or
.alpha.2(1-394)) were fully phosphorylated as described previously
(Pang et al., 2008). SPA reactions were performed in 96-well plates
at a final volume of 50 .mu.l containing 20 mM Tris-HCl pH 7.5, 5
mM MgCl.sub.2, 1 mM DTT, 2 .mu.M biotin-SAMS, 2 .mu.M ATP, 0.2
.mu.Ci/well [.gamma.-.sup.33P]ATP, and various amount of activator.
Reactions were initiated by the addition of 50 nM recombinant AMPK
proteins to the reaction solutions and incubated at 30.degree. C.
for 2 hr. After that, reactions were terminated by the addition of
40 .mu.l stop solution containing 80 .mu.g streptavidin-coated SPA
beads per well, 50 mM EDTA, 0.1% Triton X-100 in PBS, pH 7.5 and
incubated for 1 hr. Finally, a 160 ul suspension solution
containing 2.4 M CsCl, 50 mM EDTA, and 0.1% Triton X-100 in PBS (pH
7.5) was added to the reaction solution to suspend SPA beads
completely. SPA signals were determined with a Wallac MicroBeta
plate counter (PerkinElmer) 30 min later for calculation of the
amount of product formed. The amount of products formed in 2 hr was
plotted against activator concentrations to determine the effective
concentration of the activator (EC50) required for 50% of maximal
enzyme activity. Compounds as described above have EC50 values
between 0.5 uM and 50 uM, preferred compounds have EC50 values
between 0.5 uM and 10 uM, particularly preferred compounds have
EC50 values between 0.5 uM and 1 uM. These results have been
obtained by using the foregoing Scintillation Proximity Assay (uM
means microMolar).
[0477] The EC50 of representative compounds of formula (I) are
reported in the following table.
TABLE-US-00001 Example No. EC50 (uM) 1 2.21 2 1.49 3 5.61 4 5.25 5
2.3 6 1.51 7 1.54 8 6.47 9 2.16 10 4.44 11 3.11 12 5.34 13 1.86 14
4.34 15 2.47 16 1.53 17 2.34 18 5.66 19 1 20 1.76 21 6.07 22 4.13
23 6.97 24 4.82 25 2.73 26 1.25 27 2.73 28 0.8 29 2.36 30 1.65 31
0.77 32 10.52 33 5.56 34 1.8 35 2.95 36 3.69 37 4.49 38 2.91 39
1.57 41 4.51 42 4.5 43 3.23 44 1.21 45 1.89 46 4.02 47 2.38 48 3.15
49 1.75 50 5.89 51 1.42 52 6.55 53 5.89 54 5.14 55 2.94 56 4.24 57
2.17 58 4.87 59 5.19 60 1.24 61 4.93 62 2.33 63 3.24 64 6.63 65
3.41 66 2.44 67 1.27 68 2.12 69 2.2 70 4.96 71 4.02 72 3.3 73 5.14
74 3.17 75 1.84 76 5.14 77 2.58 78 1.6 79 1.69 80 5.8 81 4.74 82
1.6 85 4.9 86 7.88 87 10.65 88 2.59 104 4.63 105 2.95 106 1.61 107
0.66 108 3.25
Example A
[0478] A compound of formula (I) can be used in a manner known per
se as the active ingredient for the production of tablets of the
following composition:
TABLE-US-00002 Per tablet Active ingredient 200 mg Microcrystalline
cellulose 155 mg Corn starch 25 mg Talc 25 mg
Hydroxypropylmethylcellulose 20 mg 425 mg
Example B
[0479] A compound of formula (I) can be used in a manner known per
se as the active ingredient for the production of capsules of the
following composition:
TABLE-US-00003 Per capsule Active ingredient 100.0 mg Corn starch
20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0
mg
* * * * *