U.S. patent application number 11/640509 was filed with the patent office on 2007-04-26 for sulfonamide-substituted chalcone derivatives and their use to treat diseases.
This patent application is currently assigned to AtheroGenics, Inc.. Invention is credited to Charles Q. Meng, Liming Ni, James A. Sikorski, Jacob E. Simpson, M. David Weingarten, Kimberly J. Worsencroft, Zhihong Ye.
Application Number | 20070093453 11/640509 |
Document ID | / |
Family ID | 33511810 |
Filed Date | 2007-04-26 |
United States Patent
Application |
20070093453 |
Kind Code |
A1 |
Worsencroft; Kimberly J. ;
et al. |
April 26, 2007 |
Sulfonamide-substituted chalcone derivatives and their use to treat
diseases
Abstract
The invention relates to compounds, pharmaceutical compositions
and methods of using compounds of the general formula ##STR1## or
its pharmaceutically acceptable salt or ester, wherein the
substituents are defined in the application.
Inventors: |
Worsencroft; Kimberly J.;
(Alpharetta, GA) ; Ni; Liming; (Duluth, GA)
; Ye; Zhihong; (Lilburn, GA) ; Meng; Charles
Q.; (Alpharetta, GA) ; Weingarten; M. David;
(Cumming, GA) ; Simpson; Jacob E.; (Lawrenceville,
GA) ; Sikorski; James A.; (Atlanta, GA) |
Correspondence
Address: |
KING & SPALDING LLP
1180 PEACHTREE STREET
ATLANTA
GA
30309-3521
US
|
Assignee: |
AtheroGenics, Inc.
Alpharetta
GA
|
Family ID: |
33511810 |
Appl. No.: |
11/640509 |
Filed: |
December 15, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10863115 |
Jun 7, 2004 |
7173129 |
|
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11640509 |
Dec 15, 2006 |
|
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60476708 |
Jun 6, 2003 |
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Current U.S.
Class: |
514/63 ;
514/235.2; 514/252.13; 514/275; 514/326; 514/337; 514/342; 514/370;
514/378; 514/381; 514/406; 514/419; 544/146; 544/331; 544/379;
546/277.1; 548/110; 548/190; 548/247; 548/253; 548/465; 549/76 |
Current CPC
Class: |
A61K 31/4015 20130101;
A61K 31/55 20130101; A61K 31/18 20130101; A61K 31/397 20130101;
A61K 31/445 20130101 |
Class at
Publication: |
514/063 ;
514/275; 514/378; 514/381; 514/342; 514/370; 514/406; 514/337;
514/235.2; 514/252.13; 514/419; 514/326; 544/146; 544/379; 548/190;
548/247; 548/253; 548/110; 548/465; 549/076; 544/331;
546/277.1 |
International
Class: |
A61K 31/695 20060101
A61K031/695; A61K 31/5377 20060101 A61K031/5377; A61K 31/42
20060101 A61K031/42; A61K 31/506 20060101 A61K031/506; A61K 31/4439
20060101 A61K031/4439; A61K 31/41 20060101 A61K031/41; A61K 31/381
20060101 A61K031/381; C07D 413/02 20060101 C07D413/02; C07D 409/02
20060101 C07D409/02 |
Claims
1. A compound of Formula I ##STR715## or its pharmaceutically
acceptable salt, wherein: R.sup.1 is selected from the group
consisting of hydrogen, alkyl, lower alkyl, carbocyclic,
cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl,
heteroarylalkyl, acyl and heterocyclicalkyl, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, alkyl, lower alkyl, alkenyl,
cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,
amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8,
and --C(O)N(R.sup.2).sub.2; R.sup.2 is independently selected from
the group consisting of alkyl, lower alkyl, carbocyclic,
cycloalkyl, hydroxy, alkoxy, lower alkoxy, trialkylsilyloxy,
cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryl, heteroaryl,
heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and
heterocyclicalkyl, wherein all substituents may be optionally
substituted by one or more selected from the group consisting of
halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl,
hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,
--NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8,
--NR.sup.1R.sup.2 and --C(O)N(R.sup.2).sub.2; R.sup.1 and R.sup.2
may be taken together to form a 4- to 12-membered saturated or
unsaturated heterocyclic ring which can be optionally substituted
by one or more selected from the group consisting of halo, alkyl,
lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy,
hydroxyalkyl, heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8,
alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2; R.sup.7 and
R.sup.8 are independently selected from the group consisting of
alkyl, alkenyl and aryl and linked together forming a 4- to
12-membered monocyclic, bicylic, tricyclic or benzofused ring,
which may be optionally substituted by one or more selected from
the group consisting of halo, alkyl, lower alkyl, alkenyl,
cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,
amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2; R.sup.3 and R.sup.4 are independently
selected from hydroxy, alkoxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, cycloalkyloxy,
cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy,
heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy,
heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2; R.sup.5 is selected from the group
consisting of a carbon-carbon linked heteroaryl and a carbon-carbon
linked heterocyclic, which may be optionally substituted by one or
more selected from the group consisting of halo, alkyl, lower
alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2; with the proviso
that when R.sup.1 is hydrogen and R.sup.2 is 2-methyl propanoyl,
then R.sup.5 cannot be 5-benzo[b]thien-2-yl.
2. The compound of claim 1 or its pharmaceutically acceptable salt,
wherein: R.sup.1 is selected from the group consisting of hydrogen,
alkyl, and lower alkyl, wherein all substituents may be optionally
substituted by one or more selected from the group consisting of
halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl
and heteroaryl; R.sup.2 is independently selected from the group
consisting of alkyl, lower alkyl, alkoxy, lower alkoxy, heteroaryl,
heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, alkyl, lower alkyl, haloalkyl,
heterocyclic, --NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl,
alkoxycarbonyl and heteroaryl; R.sup.1 and R.sup.2 may be taken
together to form a 5- to 7-membered saturated or unsaturated
heterocyclic ring which can be optionally substituted by one or
more selected from the group consisting of halo, alkyl, lower
alkyl, haloalkyl, heterocyclic, --NR.sup.7R.sup.8, alkoxy, carboxy,
carboxyalkyl and alkoxycarbonyl; R.sup.7 and R.sup.8 are
independently selected from the group consisting of alkyl, alkenyl
and aryl and linked together forming a 5- to 10-membered
monocyclic, bicylic or benzofused ring, which may be optionally
substituted by one or more selected from the group consisting of
halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl and
alkoxycarbonyl; R.sup.3 and R.sup.4 are independently selected from
hydroxy, alkoxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, haloalkoxy,
heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,
heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, hydroxy,
hydroxyalkyl, heterocyclic, --NR.sup.7R.sup.8, alkoxy,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2; R.sup.5 is
selected from the group consisting of a carbon-carbon linked
heteroaryl and a carbon-carbon linked heterocyclic, which may be
optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8 and alkoxy.
3. The compound of claim 1 or its pharmaceutically acceptable salt,
wherein: R.sup.1 is selected from the group consisting of hydrogen
and lower alkyl; R.sup.2 is independently selected from the group
consisting of lower alkyl, lower alkoxy, heteroaryl, heterocyclic,
heteroarylalkyl, and heterocyclicalkyl, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8 and carboxy; R.sup.1 and R.sup.2 may be taken
together to form a 5- to 6-membered heterocyclic saturated ring
which can be optionally substituted by one or more selected from
the group consisting of halo, lower alkyl and carboxy; R.sup.7 and
R.sup.8 are independently selected from the group consisting of
alkyl and alkenyl, and linked together forming a 5- to 7-membered
monocyclic ring, which may be optionally substituted by one or more
selected from the group consisting of halo, lower alkyl, haloalkyl,
heterocyclic and carboxy; R.sup.3 and R.sup.4 are independently
selected from hydroxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, heteroaryl lower
alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower
alkoxy, --OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of hydroxy, hydroxyalkyl, heterocyclic,
--NR.sup.7R.sup.8, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2; R.sup.5 is selected from the group
consisting of a carbon-carbon linked heteroaryl and a carbon-carbon
linked heterocyclic, which may be optionally substituted by one or
more lower alkyl.
4. The compound of claim 1 or its pharmaceutically acceptable salt,
wherein: R.sup.1 is hydrogen; R.sup.2 is independently selected
from the group consisting of lower alkyl, heteroaryl,
heteroarylalkyl, and heterocyclicalkyl, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo and lower alkyl; R.sup.1 and R.sup.2 may
be taken together to form a 5- to 6-membered heterocyclic saturated
ring; R.sup.7 and R.sup.8 are independently alkyl and linked
together forming a 5- to 7-membered saturated monocyclic ring;
R.sup.3 and R.sup.4 are independently selected from hydroxy, lower
alkoxy and heterocyclic lower alkoxy; R.sup.5 is selected from the
group consisting of a carbon-carbon linked heteroaryl and a
carbon-carbon linked heterocyclic, which may be optionally
substituted by one or more lower alkyl.
5. The compound of claim 1 or its pharmaceutically acceptable salt,
wherein: R.sup.1 is hydrogen; R.sup.2 is independently selected
from the group consisting of lower alkyl, heteroaryl,
heteroarylalkyl, and heterocyclicalkyl, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo and lower alkyl; R.sup.3 and R.sup.4 are
independently selected from lower alkoxy and heterocyclic lower
alkoxy; R.sup.5 is a carbon-carbon linked heteroaryl, which may be
optionally substituted by one or more lower alkyl.
6. The compound of claim 1 or its pharmaceutically acceptable salt,
wherein the compound is selected from the group consisting of:
4-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)acryloyl]-N-(5-methylisoxazol-3--
yl)benzenesulfonamide;
3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-methylisoxazol-3-yl)b-
enzenesulfonamide sodium salt;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyrimidin-2-ylbenzene-
sulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(1-H-tetrazol-5-yl)be-
nzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyridin-2-ylbenzenesu-
lfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(1H-pyrazol-3-yl)benz-
enesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-isoxazol-3-ylbenzenes-
ulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-thiazol-2-ylbenzenesu-
lfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(3-methylisoxazol-5-y-
lbenzenesulfonamide;
N-(5-Chloropyridin-2-yl)-4-[3E-(2,4-dimethoxy-5-thien-2-ylphenyl)acryloyl-
]benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-fluoropyridin-2-yl-
)benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-trifluoromethylpyr-
idin-2-yl)benzenesulfonamide;
4-{3E-[2-(3-Hydroxy-2-hydroxymethylpropoxy)-4-methoxy-5-thien-2-ylphenyl]-
acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide;
4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thien-2-ylphenyl]acryloyl}-
-N-(5-methyl-isoxazol-3-yl)benzenesulfonamide hydrochloride;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(5-meth-
ylisoxazol-3-yl)benzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(5-meth-
ylisoxazol-3-yl)benzenesulfonamide sodium salt;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-pyridin-
-3-ylmethyl-benzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(2-morp-
holin-4-yl-ethyl)benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyridin-3-ylmethylben-
zenesulfonamide
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2-morpholin-4-yl-eth-
yl)benzenesulfonamide;
3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)-1-[4-(4-methylpiperazine-1-sulfonyl-
)phenyl]propenone;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-piperidin-1-ylbenzene-
sulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(3-imidazol-1-ylpropy-
l)benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2,2,2-trifluoroethyl-
)benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2,2,2-trifluoroethyl-
)benzenesulfonamide sodium salt;
{4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonylamino}ac-
etic acid;
2-{4-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)acryloyl]benzenesulfonylamino-
}-2-methylpropionic acid;
1-{4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonyl}piper-
idine-2-carboxylic acid;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-methyl--
benzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-methoxy-
benzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N,N-dimet-
hylbenzenesulfonamide;
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N,N-dimethylbenzen-
esulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(tert-b-
utyldimethylsiloxy)benzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]-acryloyl}-N-hydrox-
ybenzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-pyrol-2-yl)phenyl]acryloyl}-N-(5-meth-
yl-isoxazol-3-yl)benzenesulfonamide;
4-{3E-[2-(3-Hydroxy-propoxy)-4-methoxy-5-thien-2-ylphenyl]acryloyl}-N-(5--
methylisoxazol-3-yl)benzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-pyrol-2-yl)phenyl]acryloyl}-N-(5-meth-
yl-isoxazol-3-yl)benzenesulfonamide;
N-(3-Imidazol-1-yl-propyl)-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxy-phenyl]-
acryloyl}benzenesulfonamide;
(4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonylami-
no)acetic acid; and
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin-2-ylbenz-
enesulfonamide.
7. A compound of Formula III ##STR716## or its pharmaceutically
acceptable salt, wherein: R.sup.1 is selected from the group
consisting of hydrogen, alkyl, lower alkyl, carbocyclic,
cycloalkyl, alkoxy, lower alkoxy, cycloalkyloxy, cycloalkylalkoxy,
heterocyclicoxy, aryloxy, heteroaryloxy, aryl, heteroaryl,
heterocyclic, arylalkyl, heteroarylalkyl, --NR.sup.7R.sup.8,
--NHR.sup.2, --N(R.sup.2).sub.2, acyl and heterocyclicalkyl,
wherein all substituents may be optionally substituted by one or
more selected from the group consisting of halo, alkyl, lower
alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, --NHR.sup.2,
--N(R.sup.2).sub.2, alkoxy, oxo, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2; R.sup.2 is independently selected from the
group consisting of hydrogen, alkyl, lower alkyl, carbocyclic,
cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl,
heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl,
wherein all substituents may be optionally substituted by one or
more selected from the group consisting of halo, alkyl, lower
alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl,
--C(O)NR.sup.7R.sup.8, --NR.sup.1R.sup.2 and
--C(O)N(R.sup.2).sub.2; R.sup.7 and R.sup.8 are independently
selected from the group consisting of alkyl, alkenyl and aryl and
linked together forming a 4- to 12-membered monocyclic, bicylic,
tricyclic or benzofused ring, which may be optionally substituted
by one or more selected from the group consisting of halo, alkyl,
lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy,
hydroxyalkyl, heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8,
alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2; R.sup.3, R.sup.4
and R.sup.5 are independently selected from hydrogen, hydroxy,
alkoxy, lower alkoxy, --(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl,
cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,
heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,
heterocyclic, heteroaryl, NR.sup.7R.sup.8, heterocyclicoxy,
heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, N-linked heteroaryl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2; with the proviso
that at least one of R.sup.3, R.sup.4 or R.sup.5 is an N-linked
heteroaryl or --NR.sup.7R.sup.8.
8. The compound of claim 7 or its pharmaceutically acceptable salt,
wherein: R.sup.1 is selected from the group consisting of hydrogen,
alkyl, lower alkyl, alkoxy, lower alkoxy, cycloalkyloxy,
cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy,
heterocyclic, heteroarylalkyl, acyl and heterocyclicalkyl, wherein
all substituents may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
haloalkyl, heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8,
--NHR.sup.2, --N(R.sup.2).sub.2, alkoxy, carboxy, carboxyalkyl,
alkoxycarbonyl, and heteroaryl; R.sup.2 is independently selected
from the group consisting of alkyl, lower alkyl, heteroaryl,
heterocyclic, heteroarylalkyl, acyl and heterocyclicalkyl, wherein
all substituents may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
haloalkyl, heterocyclic, --NR.sup.7R.sup.8, alkoxy, carboxy,
carboxyalkyl, alkoxycarbonyl and heteroaryl; R.sup.7 and R.sup.8
are independently selected from the group consisting of alkyl,
alkenyl and aryl and linked together forming a 5- to 10-membered
monocyclic, bicylic or benzofused ring, which may be optionally
substituted by one or more selected from the group consisting of
halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl and
alkoxycarbonyl; R.sup.3, R.sup.4 and R.sup.5 are independently
selected from hydrogen, hydroxy, alkoxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, haloalkoxy,
heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,
heterocyclic, heteroaryl, NR.sup.7R.sup.8, heterocyclicoxy,
heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, hydroxy,
hydroxyalkyl, heterocyclic, N-linked heteroaryl, --NR.sup.7R.sup.8,
alkoxy, --C(O)NR.sup.7R.sup.8, and --C(O)N(R).sub.2; with the
proviso that at least one of R.sup.3, R.sup.4 or R.sup.5 is an
N-linked heteroaryl or --NR.sup.7R.sup.8.
9. The compound of claim 7 or its pharmaceutically acceptable salt,
wherein: R.sup.1 is selected from the group consisting of alkyl,
lower alkyl, alkoxy, and lower alkoxy, wherein all substituents may
be optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, amino, --NR.sup.7R.sup.8,
--NHR.sup.2, --N(R.sup.2).sub.2, aminoalkyl, alkoxy, carboxy,
carboxyalkyl, alkoxycarbonyl, and heteroaryl; R.sup.2 is
independently selected from the group consisting of lower alkyl,
heteroarylalkyl, and heterocyclicalkyl, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8 and carboxy; R.sup.7 and R.sup.8 are
independently selected from the group consisting of alkyl and
alkenyl, and linked together forming a 5- to 7-membered monocyclic
ring, which may be optionally substituted by one or more selected
from the group consisting of halo, lower alkyl, haloalkyl,
heterocyclic and carboxy; R.sup.3, R.sup.4 and R.sup.5 are
independently selected from hydrogen, hydroxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, heteroaryl lower
alkoxy, heterocyclic, heteroaryl, NR.sup.7R.sup.8, heterocyclicoxy,
heterocyclic lower alkoxy, --OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2,
and --OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of hydroxy, hydroxyalkyl, heterocyclic,
N-linked heteroaryl, --NR.sup.7R.sup.8, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2; with the proviso that at least one of
R.sup.3, R.sup.4 or R.sup.5 is an N-linked heteroaryl or
--NR.sup.7R.sup.8.
10. The compound of claim 7 or its pharmaceutically acceptable
salt, wherein: R.sup.1 is selected from the group consisting of
lower alkyl, and lower alkoxy, wherein all substituents may be
optionally substituted by one or more selected from the group
consisting of alkoxy, --NR.sup.7R.sup.8, --NHR.sup.2, and
--N(R.sup.2).sub.2; R.sup.2 is lower alkyl; R.sup.7 and R.sup.8 are
independently alkyl and linked together forming a 5- to 7-membered
saturated monocyclic ring; R.sup.3, R.sup.4 and R.sup.5 are
independently selected from hydrogen, hydroxy, lower alkoxy,
heterocyclic, heteroaryl, NR.sup.7R.sup.8 and heterocyclic lower
alkoxy; with the proviso that at least one of R.sup.3, R.sup.4 or
R.sup.5 is an N-linked heteroaryl or --NR.sup.7R.sup.8.
11. The compound of claim 7 or its pharmaceutically acceptable
salt, wherein: R.sup.1 is selected from the group consisting of
lower alkyl, and lower alkoxy; R.sup.7 and R.sup.8 are
independently alkyl and linked together forming a 5- to 7-membered
saturated monocyclic ring; R.sup.3, R.sup.4 and R.sup.5 are
independently selected from lower alkoxy, NR.sup.7R.sup.8 and
heterocyclic lower alkoxy; with the proviso that at least one of
R.sup.3, R.sup.4 or R.sup.5 is --NR.sup.7R.sup.8.
12. The compound of claim 7 or its pharmaceutically acceptable
salt, wherein the compound is
N-Butyryl-4-[3E-(2,4-dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesu-
lfonamide.
13. A compound of Formula III ##STR717## or its pharmaceutically
acceptable salt, wherein: R.sup.1 is selected from the group
consisting of hydrogen, alkyl, lower alkyl, carbocyclic,
cycloalkyl, alkoxy, lower alkoxy, cycloalkyloxy, cycloalkylalkoxy,
heterocyclicoxy, aryloxy, heteroaryloxy, aryl, heteroaryl,
heterocyclic, arylalkyl, heteroarylalkyl, --NR.sup.7R.sup.8,
--NHR.sup.2, --N(R.sup.2).sub.2, acyl and heterocyclicalkyl,
wherein all substituents may be optionally substituted by one or
more selected from the group consisting of halo, alkyl, lower
alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, --NHR.sup.2,
--N(R.sup.2).sub.2, alkoxy, oxo, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2; R.sup.2 is independently selected from the
group consisting of hydrogen, alkyl, lower alkyl, carbocyclic,
cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl,
heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl,
wherein all substituents may be optionally substituted by one or
more selected from the group consisting of halo, alkyl, lower
alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl,
--C(O)NR.sup.7R.sup.8, --NR.sup.1R.sup.2 and
--C(O)N(R.sup.2).sub.2; R.sup.7 and R.sup.8 are independently
selected from the group consisting of alkyl, alkenyl and aryl and
linked together forming a 4- to 12-membered monocyclic, bicylic,
tricyclic or benzofused ring, which may be optionally substituted
by one or more selected from the group consisting of halo, alkyl,
lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy,
hydroxyalkyl, heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8,
alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2; R.sup.3 and
R.sup.4 are independently selected from hydrogen, hydroxy, alkoxy,
lower alkoxy, --(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl,
cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,
heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,
heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, N-linked heteroaryl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2; R.sup.5 is
selected from the group consisting of a carbon-carbon linked
heterocyclic and a carbon-carbon linked heteroaryl, which may be
optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, --C(O)NR.sup.7R.sup.8, and
C(O)N(R.sup.2).sub.2; with the proviso that when R.sup.1 is
isopropyl, R.sup.5 cannot be 5-benzo[b]thien-2-yl.
14. The compound of claim 13 or its pharmaceutically acceptable
salt, wherein: R.sup.1 is selected from the group consisting of
hydrogen, alkyl, lower alkyl, alkoxy, lower alkoxy, cycloalkyloxy,
cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy,
heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, alkyl, lower alkyl, haloalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, --NHR.sup.2,
--N(R.sup.2).sub.2, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl,
and heteroaryl; R.sup.2 is independently selected from the group
consisting of alkyl, lower alkyl, heteroaryl, heterocyclic,
heteroarylalkyl, and heterocyclicalkyl, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, haloalkyl,
heterocyclic, --NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl,
alkoxycarbonyl and heteroaryl; R.sup.7 and R.sup.8 are
independently selected from the group consisting of alkyl, alkenyl
and aryl and linked together forming a 5- to 10-membered
monocyclic, bicylic or benzofused ring, which may be optionally
substituted by one or more selected from the group consisting of
halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl and
alkoxycarbonyl; R.sup.3 and R.sup.4 are independently selected from
hydroxy, alkoxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, haloalkoxy,
heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,
heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, hydroxy,
hydroxyalkyl, heterocyclic, --NR.sup.7R.sup.8, alkoxy,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2; R.sup.5 is
selected from the group consisting of a carbon-carbon linked
heteroaryl and a carbon-carbon linked heterocyclic, which may be
optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8 and alkoxy; with the proviso that when R.sup.1 is
isopropyl, R.sup.5 cannot be 5-benzo[b]thien-2-yl.
15. The compound of claim 13 or its pharmaceutically acceptable
salt, wherein: R.sup.1 is selected from the group consisting of
alkyl, lower alkyl, alkoxy, and lower alkoxy, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, alkyl, lower alkyl, amino,
aminoalkyl, --NR.sup.7R.sup.8, --NHR.sup.2, --N(R.sup.2).sub.2,
alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, and heteroaryl;
R.sup.2 is independently selected from the group consisting of
lower alkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, lower alkyl, haloalkyl,
heterocyclic, --NR.sup.7R.sup.8 and carboxy; R.sup.7 and R.sup.8
are independently selected from the group consisting of alkyl and
alkenyl, and linked together forming a 5- to 7-membered monocyclic
ring, which may be optionally substituted by one or more selected
from the group consisting of halo, lower alkyl, haloalkyl,
heterocyclic and carboxy; R.sup.3 and R.sup.4 are independently
selected from hydroxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, heteroaryl lower
alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower
alkoxy, --OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of hydroxy, hydroxyalkyl, heterocyclic,
--NR.sup.7R.sup.8, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2; R.sup.5 is selected from the group
consisting of a carbon-carbon linked heteroaryl and a carbon-carbon
linked heterocyclic, which may be optionally substituted by one or
more lower alkyl; with the proviso that when R.sup.1 is isopropyl,
R.sup.5 cannot be 5-benzo[b]thien-2-yl.
16. The compound of claim 13 or its pharmaceutically acceptable
salt, wherein: R.sup.1 is selected from the group consisting of
lower alkyl, and lower alkoxy, wherein all substituents may be
optionally substituted by one or more selected from the group
consisting of alkoxy, --NR.sup.7R.sup.8, --NHR.sup.2, and
--N(R.sup.2).sub.2; R.sup.2 is lower alkyl; R.sup.7 and R.sup.8 are
independently alkyl and linked together forming a 5- to 7-membered
saturated monocyclic ring; R.sup.3 and R.sup.4 are independently
selected from hydroxy, lower alkoxy and heterocyclic lower alkoxy;
R.sup.5 is selected from the group consisting of a carbon-carbon
linked heteroaryl and a carbon-carbon linked heterocyclic, which
may be optionally substituted by one or more lower alkyl; with the
proviso that when R.sup.1 is isopropyl, R.sup.5 cannot be
5-benzo[b]thien-2-yl.
17. The compound of claim 13 or its pharmaceutically acceptable
salt, wherein: R.sup.1 is selected from the group consisting of
lower alkyl, and lower alkoxy; R.sup.3 and R.sup.4 are
independently selected from lower alkoxy and heterocyclic lower
alkoxy; R.sup.5 is a carbon-carbon linked heteroaryl, which may be
optionally substituted by one or more lower alkyl; with the proviso
that when R.sup.1 is isopropyl, R.sup.5 cannot be
5-benzo[b]thien-2-yl.
18. The compound of claim 13 or its pharmaceutically acceptable
salt, wherein the compound is selected from the group consisting
of:
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-isobutyrylbenzen-
esulfonamide;
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-isobutyrylbenzen-
esulfonamide sodium salt;
N-Butyryl-4-{3E-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-
benzenesulfonamide;
N-Ethoxycarbonyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}be-
nzenesulfonamide potassium salt;
N-Ethoxycarbonyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}be-
nzenesulfonamide;
N-Acetyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesul-
fonamide;
N-Acetyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-
benzenesulfonamide sodium salt;
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-propionyl-benzen-
esulfonamide;
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-propionylbenzene-
sulfonamide sodium salt;
N-Butyryl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesu-
lfonamide; and
N-Butyryl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesu-
lfonamide sodium salt.
19. A compound of Formula I ##STR718## or its pharmaceutically
acceptable salt, wherein: R.sup.1 is selected from the group
consisting of hydrogen, alkyl, lower alkyl, carbocyclic,
cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl,
heteroarylalkyl, acyl and heterocyclicalkyl, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, alkyl, lower alkyl, alkenyl,
cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,
amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8,
and --C(O)N(R.sup.2).sub.2; R.sup.2 is independently selected from
the group consisting of alkyl, lower alkyl, carbocyclic,
cycloalkyl, hydroxy, alkoxy, lower alkoxy, trialkylsilyloxy,
cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryl, heteroaryl,
heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and
heterocyclicalkyl, wherein all substituents may be optionally
substituted by one or more selected from the group consisting of
halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl,
hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,
--NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8,
--NR.sup.1R.sup.2 and --C(O)N(R.sup.2).sub.2; R.sup.1 and R.sup.2
may be taken together to form a 4- to 12-membered saturated or
unsaturated heterocyclic ring which can be optionally substituted
by one or more selected from the group consisting of halo, alkyl,
lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy,
hydroxyalkyl, heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8,
alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2; R.sup.7 and
R.sup.8 are independently selected from the group consisting of
alkyl, alkenyl and aryl and linked together forming a 4- to
12-membered monocyclic, bicylic, tricyclic or benzofused ring,
which may be optionally substituted by one or more selected from
the group consisting of halo, alkyl, lower alkyl, alkenyl,
cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,
amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2; R.sup.3 and R.sup.4 are independently
selected from hydroxy, alkoxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, cycloalkyloxy,
cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy,
heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy,
heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2; R.sup.5 is selected from the group
consisting of a carbon-nitrogen linked heteroaryl and a
carbon-nitrogen linked heterocyclic, which may be optionally
substituted by one or more selected from the group consisting of
halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl,
hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,
--NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2.
20. The compound of claim 19 or its pharmaceutically acceptable
salt, wherein: R.sup.1 is selected from the group consisting of
hydrogen, alkyl, and lower alkyl, wherein all substituents may be
optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl
and heteroaryl; R.sup.2 is independently selected from the group
consisting of alkyl, lower alkyl, alkoxy, lower alkoxy, heteroaryl,
heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, alkyl, lower alkyl, haloalkyl,
heterocyclic, --NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl,
alkoxycarbonyl and heteroaryl; R.sup.1 and R.sup.2 may be taken
together to form a 5- to 7-membered saturated or unsaturated
heterocyclic ring which can be optionally substituted by one or
more selected from the group consisting of halo, alkyl, lower
alkyl, haloalkyl, heterocyclic, --NR.sup.7R.sup.8, alkoxy, carboxy,
carboxyalkyl and alkoxycarbonyl; R.sup.7 and R.sup.8 are
independently selected from the group consisting of alkyl, alkenyl
and aryl and linked together forming a 5- to 10-membered
monocyclic, bicylic or benzofused ring, which may be optionally
substituted by one or more selected from the group consisting of
halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl and
alkoxycarbonyl; R.sup.3 and R.sup.4 are independently selected from
hydroxy, alkoxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, haloalkoxy,
heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,
heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, hydroxy,
hydroxyalkyl, heterocyclic, --NR.sup.7R.sup.8, alkoxy,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2; R.sup.5 is
selected from the group consisting of a carbon-nitrogen linked
heteroaryl and a carbon-nitrogen linked heterocyclic, which may be
optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8 and alkoxy.
21. The compound of claim 19 or its pharmaceutically acceptable
salt, wherein: R.sup.1 is selected from the group consisting of
hydrogen and lower alkyl; R.sup.2 is independently selected from
the group consisting of lower alkyl, lower alkoxy, heteroaryl,
heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, lower alkyl, haloalkyl,
heterocyclic, heteroaryl, --NR.sup.7R.sup.8 and carboxy; R.sup.1
and R.sup.2 may be taken together to form a 5- to 6-membered
heterocyclic saturated ring which can be optionally substituted by
one or more selected from the group consisting of halo, lower alkyl
and carboxy; R.sup.7 and R.sup.8 are independently selected from
the group consisting of alkyl and alkenyl, and linked together
forming a 5- to 7-membered monocyclic ring, which may be optionally
substituted by one or more selected from the group consisting of
halo, lower alkyl, haloalkyl, heterocyclic and carboxy; R.sup.3 and
R.sup.4 are independently selected from hydroxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, heteroaryl lower
alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower
alkoxy, --OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of hydroxy, hydroxyalkyl, heterocyclic,
--NR.sup.7R.sup.8, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2; R.sup.5 is selected from the group
consisting of a carbon-nitrogen linked heteroaryl and a
carbon-nitrogen linked heterocyclic, which may be optionally
substituted by one or more lower alkyl.
22. The compound of claim 19 or its pharmaceutically acceptable
salt, wherein: R.sup.1 is hydrogen; R.sup.2 is independently
selected from the group consisting of lower alkyl, heteroaryl,
heteroarylalkyl, and heterocyclicalkyl, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, heterocyclic, heteroaryl, and lower
alkyl; R.sup.1 and R.sup.2 may be taken together to form a 5- to
6-membered heterocyclic saturated ring; R.sup.7 and R.sup.8 are
independently alkyl and linked together forming a 5- to 7-membered
saturated monocyclic ring; R.sup.3 and R.sup.4 are independently
selected from hydroxy, lower alkoxy and heterocyclic lower alkoxy;
R.sup.5 is selected from the group consisting of a carbon-nitrogen
linked heterocyclic, which may be optionally substituted by one or
more lower alkyl.
23. The compound of claim 19 or its pharmaceutically acceptable
salt, wherein: R.sup.1 is hydrogen; R.sup.2 is independently
selected from the group consisting of lower alkyl, heteroaryl,
heteroarylalkyl, and heterocyclicalkyl, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, heterocyclic, heteroaryl, and lower
alkyl; R.sup.3 and R.sup.4 are independently selected from lower
alkoxy and heterocyclic lower alkoxy; R.sup.5 is a carbon-nitrogen
linked heterocyclic.
24. The compound of claim 19 or its pharmaceutically acceptable
salt, wherein the compound is selected from the group consisting
of:
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-yl-phenyl)-acryloyl]-N-pyridin-2-yl-b-
enzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-pyridin-2-ylmeth-
ylbenzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-(3-imidazol-1-yl-
propyl)benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-[3-(4-methyl-pip-
erazin-1-yl)propyl]benzenesulfonamide; and
{4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonylami-
no}acetic acid.
25. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24,
together with one or more pharmaceutically acceptable carrier.
26. A method for the treatment or prophylaxis of an inflammatory
disorder, comprising administering an effective amount of a
compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 21, 22, 23 or 24.
27. The method of claim 26, wherein the disorder is arthritis.
28. The method of claim 26, wherein the disorder is rheumatoid
arthritis.
29. The method of claim 26, wherein the disorder is asthma.
30. The method of claim 26, wherein the treatment is disease
modifying for the treatment of rheumatoid arthritis.
31. The method of claim 26, wherein the disorder is allergic
rhinitis.
32. The method of claim 26, wherein the disorder is chronic
obstructive pulmonary disease.
33. The method of claim 26, wherein the disorder is
atherosclerosis.
34. The method of claim 26, wherein the disorder is restinosis.
35. A method for inhibiting the expression of VCAM-1, comprising
administering an effective amount of a compound of claim 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
22, 23 or 24.
36. A compound having the formula ##STR719## wherein X is --C(O)H
or --CH.sub.2OH; R.sup.3 and R.sup.4 are independently selected
from the group consisting of hydroxy, alkoxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, cycloalkyloxy,
cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy,
heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy,
heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.9).sub.2C(O)N(R.sup.9).sub.2, and
OC(R.sup.9).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents may
be optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.9).sub.2; Y.sup.1, Y.sup.2, Y.sup.3, and Y.sup.4 are
independently selected from the group consisting of hydrogen,
hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl,
acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,
--NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.9).sub.2, wherein all substituents, when possible may
be optionally substituted by one or more selected from the group
consisting of hydroxyl, halo, alkyl, lower alkyl, alkenyl,
cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,
amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8,
and --C(O)N(R.sup.2).sub.2. Y.sup.5 is selected from the group
consisting of hydrogen, alkyl, lower alkyl, acyl, and
alkoxycarbonyl wherein all substituents, when possible may be
optionally substituted by one or more selected from the group
consisting of hydroxyl, halo, alkyl, lower alkyl, alkenyl,
cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,
amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8,
and --C(O)N(R.sup.9).sub.2; R.sup.9 is independently selected from
the group consisting of alkyl, lower alkyl, carbocyclic,
cycloalkyl, hydroxy, alkoxy, lower alkoxy, trialkylsilyloxy,
cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryl, heteroaryl,
heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and
heterocyclicalkyl, wherein all substituents may be optionally
substituted by one or more selected from the group consisting of
halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl,
hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,
--NR.sup.7R.sup.8, --NHR.sup.9, --N(R.sup.9).sub.2, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl,
--C(O)NR.sup.7R.sup.8, --NR.sup.9R.sup.9 and
--C(O)N(R.sup.9).sub.2; R.sup.7 and R.sup.8 are independently
selected from the group consisting of alkyl, alkenyl and aryl and
linked together forming a 4- to 12-membered monocyclic, bicylic,
tricyclic or benzofused ring, which may be optionally substituted
by one or more selected from the group consisting of halo, alkyl,
lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy,
hydroxyalkyl, heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8,
alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.9).sub.2.
37. The compound of claim 36 wherein the compound is selected from
##STR720##
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional patent
application Ser. No. 60/476,708 filed Jun. 6, 2003.
FIELD OF THE INVENTION
[0002] The present invention is in the field of novel chalcone
derivatives, pharmaceutical compositions and methods for treating a
variety of diseases and disorders, including inflammation and
cardiovascular disease.
BACKGROUND OF THE INVENTION
[0003] Adhesion of leukocytes to the endothelium represents a
fundamental, early event in a wide variety of inflammatory
conditions, autoimmune disorders and bacterial and viral
infections. Leukocyte recruitment to endothelium is mediated in
part by the inducible expression of adhesion molecules on the
surface of endothelial cells that interact with counterreceptors on
immune cells. Endothelial cells determine which types of leukocytes
are recruited by selectively expressing specific adhesion
molecules, such as vascular cell adhesion molecule-1 (VCAM-1),
intercellular adhesion molecule-1 (ICAM-1), and E-selectin. VCAM-1
binds to the integrin VLA-4 expressed on lymphocytes, monocytes,
macrophages, eosinophils, and basophils but not neutrophils. This
interaction facilitates the firm adhesion of these leukocytes to
the endothelium. VCAM-1 is an inducible gene that is not expressed,
or expressed at very low levels, in normal tissues. VCAM-1 is
upregulated in a number of inflammatory diseases, including
arthritis (including rheumatoid arthritis), asthma, dermatitis,
psoriasis, cystic fibrosis, post transplantation late and chronic
solid organ rejection, multiple sclerosis, systemic lupus
erythematosis, inflammatory bowel diseases, autoimmune diabetes,
diabetic retinopathy, rhinitis, ischemia-reperfusion injury,
post-angioplasty restenosis, chronic obstructive pulmonary disease
(COPD), glomerulonephritis, Graves disease, gastrointestinal
allergies, conjunctivitis, atherosclerosis, coronary artery
disease, angina and small artery disease.
[0004] U.S. Pat. Nos. 5,750,351; 5,807,884; 5,811,449; 5,846,959;
5,773,231, and 5,773,209 to Medford, et al., as well as the
corresponding WO 95/30415 to Emory University indicate that
polyunsaturated fatty acids ("PUFAs") and their hydroperoxides
("ox-PUFAs"), which are important components of oxidatively
modified low density lipoprotein (LDL), induce the expression of
VCAM-1, but not intracellular adhesion molecule-1 (ICAM-1) or
E-selectin in human aortic endothelial cells, through a mechanism
that is not mediated by cytokines or other noncytokine signals.
This is a fundamental discovery of an important and previously
unknown biological pathway in VCAM-1 mediated immune responses. As
non-limiting examples, linoleic acid, linolenic acid, arachidonic
acid, linoleyl hydroperoxide (13-HPODE) and arachidonic
hydroperoxide (15-HPETE) induce cell-surface gene expression of
VCAM-1 but not ICAM-1 or E-selectin. Saturated fatty acids (such as
stearic acid) and monounsaturated fatty acids (such as oleic acid)
do not induce the expression of VCAM-1, ICAM-1 or E-selectin.
[0005] Chalcone (1,3-bis-aromatic-prop-2-en-1-ones) compounds are
natural products related to flavonoids. WO 99/00114
(PCT/DK98/00283) discloses the use of certain chalcones,
1,3-bis-aromatic-propan-1-ones (dihydrochalcones), and
1,3-bisaromatic-prop-2-yn-1-ones for the preparation of
pharmaceutical compositions for the treatment of prophylaxis of a
number of serious diseases including i) conditions relating to
harmful effects of inflammatory cytokines, ii) conditions involving
infection by Helicobacter species, iii) conditions involving
infections by viruses, iv) neoplastic disorders, and v) conditions
caused by microorganisms or parasites.
[0006] U.S. Pat. No. 4,085,135 to Kyogoku et al. discloses a
process for preparation of 2'-(carboxymethoxy)-chalcones having
antigastric and anti duodenal activities with low toxicity and high
absorptive ratio in the body.
[0007] European Patent No 307762 assigned to Hofmann-La Roche
discloses substituted phenyl chalcones.
[0008] Herencia, et al., in Synthesis and Anti-inflammatory
Activity of Chalcone Derivatives, Bioorganic & Medicinal
Chemistry Letters 8 (1998) 1169-1174, discloses certain chalcone
derivatives with anti-inflammatory activity.
[0009] Hsieh, et al., Synthesis and Antiinflammatory Effect of
Chalcones, J. Pharm. Pharmacol. 2000, 52; 163-171 describes that
certain chalcones have potent antiinflammatory activity.
[0010] Zwaagstra, et al., Synthesis and Structure-Activity
Relationships of Carboxylated Chalcones: A Novel Series of
CysLT.sub.1 (LT.sub.4) Receptor Antagonists; J. Med. Chem., 1997,
40, 1075-1089 discloses that in a series of 2-, 3-, and
4-(2-quinolinylmethoxy)- and 3- and
4-[2-(2-quinolinyl)ethenyl]-substituted, 2', 3', 4', or 5'
carboxylated chalcones, certain compounds are CysLT.sub.1 receptor
antagonists.
[0011] JP 63010720 to Nippon Kayaku Co., LTD discloses that
chalcone derivatives of the following formula (wherein R.sup.1 and
R.sup.2 are hydrogen or alkyl, and m and n are 0-3) are
5-lipoxygenase inhibitors and can be used in treating allergies.
##STR2##
[0012] JP 06116206 to Morinaga Milk Industry Co. Ltd, Japan,
discloses chalcones of the following structure as 5-lipoxygenase
inhibitors, wherein R is acyl and R.sup.1-R.sup.5 are hydrogen,
lower alkyl, lower alkoxy or halo, and specifically that in which R
is acyl and R.sup.1-R.sup.5 are hydrogen. ##STR3##
[0013] U.S. Pat. No. 6,046,212 to Kowa Co. Ltd. discloses
heterocyclic ring-containing chalcones of the following formula as
antiallergic agents. ##STR4##
[0014] Reported bioactivies of chalcones have been reviewed by
Dimmock, et al., in Bioactivities of Chalcones, Current Medicinal
Chemistry 1999, 6, 1125-1149; Liu, et al., Antimalarial Alkoxylated
and Hydroxylated Chalones: Structure-Activity Relationship
Analysis, J. Med. Chem. 2001, 44, 4443-4452; Herencia et al, Novel
Anti-inflammatory Chalcone Derivatives Inhibit the Induction of
Nitric Oxide Synthase and Cyclooxygenase-2 in Mouse Peritoneal
Macrophages, FEBS Letters, 1999, 453, 129-134; and Hsieh et al.,
Synthesis and Anti-inflammatory Effect of Chalcones and Related
Compounds, Pharmaceutical Research, 1998, Vol. 15, No. 1,
39-46.
[0015] U.S. patent application Ser. No. 09/866,348, filed Jun. 20,
2001 and Ser. No. 10/324,987, filed Dec. 19, 2002 both assigned to
AtheroGenics, Inc., and herein incorporated by reference, disclose
particular derivatives of chalcones suitable to treat diseases
mediated by VCAM-1.
[0016] Given that VCAM-1 is a mediator of chronic inflammatory
disorders, it is a goal of the present work to identify new
compounds, compositions and methods that can inhibit the expression
of VCAM-1. A more general goal is to identify selective compounds
and methods for suppressing the expression of redox sensitive genes
or activating redox sensitive genes that are suppressed. An even
more general goal is to identify selective compounds,
pharmaceutical compositions and methods of using the compounds for
the treatment of inflammatory diseases.
[0017] It is therefore an object of the present invention to
provide new compounds for the treatment of disorders mediated by
VCAM-1.
[0018] It is also an object to provide new pharmaceutical
compositions for the treatment of diseases and disorders mediated
by the expression of VCAM-1.
[0019] It is a further object of the invention to provide
compounds, compositions, and methods of treating disorders and
diseases mediated by VCAM-1, including cardiovascular and
inflammatory diseases.
[0020] Another object of the invention is to provide compounds,
compositions, and method of treating cardiovascular and
inflammatory diseases.
[0021] It is another object of the invention to provide compounds,
compositions and methods to treat arthritis.
[0022] Another object of the invention is to provide compounds,
compositions and methods to treat rheumatoid arthritis. The
inventions compounds, compositions and methods are also suitable as
disease modifying anti-rheumatoid arthritis drugs (DMARDs).
[0023] It is yet another object of the invention to provide
compounds, compositions and methods to treat asthma.
[0024] It is another object of the invention to provide compounds,
methods and compositions to inhibit the progression of
atherosclerosis.
[0025] It is still another object of the invention to provide
compounds, compositions, and methods to treat or prevent transplant
rejection.
[0026] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of lupus.
[0027] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
inflammatory bowel disease.
[0028] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of autoimmune
diabetes.
[0029] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of multiple
sclerosis.
[0030] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of diabetic
retinopathy.
[0031] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of diabetic
nephropathy.
[0032] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of diabetic
vasculopathy.
[0033] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
rhinitis.
[0034] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
ischemia-reperfusion injury.
[0035] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
post-angioplasty restenosis.
[0036] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of chronic
obstructive pulmonary disease (COPD).
[0037] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
glomerulonephritis.
[0038] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of Graves
disease.
[0039] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
gastrointestinal allergies.
[0040] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
conjunctivitis.
[0041] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
dermatitis.
[0042] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
psoriasis.
[0043] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of ocular
inflammation, including uveitis.
[0044] In a broader sense, an object of the present invention is to
provide compounds, methods and compositions that can be used as
adjunct or combination therapy both simultaneously, and and in
series.
SUMMARY OF THE INVENTION
[0045] It has been discovered that particular sulfonamide
substituted chalcone derivatives inhibit the expression of VCAM-1,
and thus can be used to treat a patient with a disorder mediated by
VCAM-1. Examples of inflammatory disorders that are mediated by
VCAM-1 include, but are not limited to arthritis, asthma,
dermatitis, cystic fibrosis, post transplantation late and chronic
solid organ rejection, multiple sclerosis, systemic lupus
erythematosis, inflammatory bowel diseases, autoimmune diabetes,
diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy,
rhinitis, ocular inflammation, uveitis, ischemia-reperfusion
injury, post-angioplasty restenosis, chronic obstructive pulmonary
disease (COPD), glomerulonephritis, Graves disease,
gastrointestinal allergies, conjunctivitis, atherosclerosis,
coronary artery disease, angina and small artery disease.
[0046] The compounds disclosed herein can also be used in the
treatment of inflammatory skin diseases that are mediated by
VCAM-1, as well as human endothelial disorders that are mediated by
VCAM-1, which include, but are not limited to psoriasis,
dermatitis, including eczematous dermatitis, Kaposi's sarcoma,
multiple sclerosis, as well as proliferative disorders of smooth
muscle cells.
[0047] In yet another embodiment, the compounds disclosed herein
can be selected to treat anti-inflammatory conditions that are
mediated by mononuclear leucocytes.
[0048] In one embodiment, the compounds of the present invention
are selected for the prevention or treatment of tissue or organ
transplant rejection. Treatment and prevention of organ or tissue
transplant rejection includes, but is not limited to treatment of
recipients of heart, lung, combined heart-lung, liver, kidney,
pancreatic, skin, spleen, small bowel, or corneal transplants. The
compounds can also be used in the prevention or treatment of
graft-versus-host disease, such as sometimes occurs following bone
marrow transplantation.
[0049] In an alternative embodiment, the compounds described herein
are useful in both the primary and adjunctive medical treatment of
cardiovascular disease. The compounds are used in primary treatment
of, for example, coronary disease states including atherosclerosis,
post-angioplasty restenosis, coronary artery diseases and angina.
The compounds can be administered to treat small vessel disease
that is not treatable by surgery or angioplasty, or other vessel
disease in which surgery is not an option. The compounds can also
be used to stabilize patients prior to revascularization
therapy.
[0050] Compounds of the present invention are of the formula
##STR5## or its pharmaceutically acceptable salt or ester, wherein
the substituents are defined herein.
[0051] A further embodiment of the invention is to supply
intermediates suitable for manufacturing compounds of the invention
that may have independent therapeutic value. Such intermediates
having the formulas ##STR6## wherein
[0052] X is --C(O)H or --CH.sub.2OH;
[0053] R.sup.3 and R.sup.4 are independently selected from the
group consisting of hydroxy, alkoxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, cycloalkyloxy,
cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy,
heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy,
heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.9).sub.2C(O)N(R.sup.9).sub.2, and
--OC(R.sup.9).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.9).sub.2;
[0054] Y.sup.1, Y.sup.2, Y.sup.3, and Y.sup.4 are independently
selected from the group consisting of hydrogen, hydroxyl, halo,
alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy,
hydroxyalkyl, heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8,
alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
heteroaryl, --C(O)NR.sup.7R.sup.8, and C(O)N(R.sup.9).sub.2,
wherein all substituents, when possible may be optionally
substituted by one or more selected from the group consisting of
hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl,
acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,
--NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2.
[0055] Y.sup.5 is selected from the group consisting of hydrogen,
alkyl, lower alkyl, acyl, and alkoxycarbonyl wherein all
substituents, when possible may be optionally substituted by one or
more selected from the group consisting of hydroxyl, halo, alkyl,
lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy,
hydroxyalkyl, heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8,
alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
heteroaryl, --C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.9).sub.2;
[0056] R.sup.9 is independently selected from the group consisting
of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy,
lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy,
heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl,
heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl,
wherein all substituents may be optionally substituted by one or
more selected from the group consisting of halo, alkyl, lower
alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, --NHR.sup.9,
--N(R.sup.9).sub.2, alkoxy, oxo, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8,
--NR.sup.9R.sup.9 and --C(O)N(R.sup.9).sub.2;
[0057] R.sup.7 and R.sup.8 are independently selected from the
group consisting of alkyl, alkenyl and aryl and linked together
forming a 4- to 12-membered monocyclic, bicylic, tricyclic or
benzofused ring, which may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.9).sub.2.
DETAILED DESCRIPTION OF THE INVENTION
[0058] It has been discovered that compounds of the invention
inhibit the expression of VCAM-1, and thus can be used to treat a
patient with a disorder mediated by VCAM-1. These compounds can be
administered to a host as monotherapy, or if desired, in
combination with another compound of the invention or another
biologically active agent, as described in more detail below.
[0059] In a 1.sup.st embodiment, the invention is represented by
Formula 1 ##STR7## or its pharmaceutically acceptable salt,
wherein:
[0060] R.sup.1 is selected from the group consisting of hydrogen,
alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl, heteroaryl,
heterocyclic, arylalkyl, heteroarylalkyl, acyl and
heterocyclicalkyl, wherein all substituents may be optionally
substituted by one or more selected from the group consisting of
halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl,
hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,
--NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2;
[0061] R.sup.2 is independently selected from the group consisting
of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy,
lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy,
heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl,
heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl,
wherein all substituents may be optionally substituted by one or
more selected from the group consisting of halo, alkyl, lower
alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl,
--C(O)NR.sup.7R.sup.8, --NR.sup.1R.sup.2 and
--C(O)N(R.sup.2).sub.2;
[0062] R.sup.1 and R.sup.2 may be taken together to form a 4- to
12-membered saturated or unsaturated heterocyclic ring which can be
optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2;
[0063] R.sup.7 and R.sup.8 are independently selected from the
group consisting of alkyl, alkenyl and aryl and linked together
forming a 4- to 12-membered monocyclic, bicylic, tricyclic or
benzofused ring, which may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2;
[0064] R.sup.3 and R.sup.4 are independently selected from hydroxy,
alkoxy, lower alkoxy, --(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl,
cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,
heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,
heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2;
[0065] R.sup.5 is selected from the group consisting of a
carbon-carbon linked heteroaryl and a carbon-carbon linked
heterocyclic, which may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and C(O)N(R.sup.2).sub.2;
[0066] with the proviso that when R.sup.1 is hydrogen and R.sup.2
is 2-methyl propanoyl, then R.sup.5 cannot be
5-benzo[b]thien-2-yl.
[0067] In a 2nd embodiment, the invention is represented by Formula
1 or its pharmaceutically acceptable salt, wherein:
[0068] R.sup.1 is selected from the group consisting of hydrogen,
alkyl, and lower alkyl, wherein all substituents may be optionally
substituted by one or more selected from the group consisting of
halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl
and heteroaryl;
[0069] R.sup.2 is independently selected from the group consisting
of alkyl, lower alkyl, alkoxy, lower alkoxy, heteroaryl,
heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, alkyl, lower alkyl, haloalkyl,
heterocyclic, --NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl,
alkoxycarbonyl and heteroaryl;
[0070] R.sup.1 and R.sup.2 may be taken together to form a 5- to
7-membered saturated or unsaturated heterocyclic ring which can be
optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl and
alkoxycarbonyl;
[0071] R.sup.7 and R.sup.8 are independently selected from the
group consisting of alkyl, alkenyl and aryl and linked together
forming a 5- to 10-membered monocyclic, bicylic or benzofused ring,
which may be optionally substituted by one or more selected from
the group consisting of halo, alkyl, lower alkyl, haloalkyl,
heterocyclic, --NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl and
alkoxycarbonyl;
[0072] R.sup.3 and R.sup.4 are independently selected from hydroxy,
alkoxy, lower alkoxy, --(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl,
haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower
alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower
alkoxy, --OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8 wherein all substituents may
be optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, hydroxy, hydroxyalkyl,
heterocyclic, --NR.sup.7R.sup.8, alkoxy, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2;
[0073] R.sup.5 is selected from the group consisting of a
carbon-carbon linked heteroaryl and a carbon-carbon linked
heterocyclic, which may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
haloalkyl, heterocyclic, --NR.sup.7R.sup.8 and alkoxy.
[0074] In a 3.sup.rd embodiment, the invention is represented by
Formula 1 or its pharmaceutically acceptable salt, wherein:
[0075] R.sup.1 is selected from the group consisting of hydrogen
and lower alkyl;
[0076] R.sup.2 is independently selected from the group consisting
of lower alkyl, lower alkoxy, heteroaryl, heterocyclic,
heteroarylalkyl, and heterocyclicalkyl, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8 and carboxy;
[0077] R.sup.1 and R.sup.2 may be taken together to form a 5- to
6-membered heterocyclic saturated ring which can be optionally
substituted by one or more selected from the group consisting of
halo, lower alkyl and carboxy;
[0078] R.sup.7 and R.sup.8 are independently selected from the
group consisting of alkyl and alkenyl, and linked together forming
a 5- to 7-membered monocyclic ring, which may be optionally
substituted by one or more selected from the group consisting of
halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
[0079] R.sup.3 and R.sup.4 are independently selected from hydroxy,
lower alkoxy, --(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl,
heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy,
heterocyclic lower alkoxy, --OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2,
and --OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of hydroxy, hydroxyalkyl, heterocyclic,
--NR.sup.7R.sup.8, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2;
[0080] R.sup.5 is selected from the group consisting of a
carbon-carbon linked heteroaryl and a carbon-carbon linked
heterocyclic, which may be optionally substituted by one or more
lower alkyl.
[0081] In a 4.sup.th embodiment, the invention is represented by
Formula 1 or its pharmaceutically acceptable salt, wherein:
[0082] R.sup.1 is hydrogen;
[0083] R.sup.2 is independently selected from the group consisting
of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl,
wherein all substituents may be optionally substituted by one or
more selected from the group consisting of halo and lower
alkyl;
[0084] R.sup.1 and R.sup.2 may be taken together to form a 5- to
6-membered heterocyclic saturated ring;
[0085] R.sup.7 and R.sup.8 are independently alkyl and linked
together forming a 5- to 7-membered saturated monocyclic ring;
[0086] R.sup.3 and R.sup.4 are independently selected from hydroxy,
lower alkoxy and heterocyclic lower alkoxy;
[0087] R.sup.5 is selected from the group consisting of a
carbon-carbon linked heteroaryl and a carbon-carbon linked
heterocyclic, which may be optionally substituted by one or more
lower alkyl.
[0088] In a 5.sup.th embodiment, the invention is represented by
Formula 1 or its pharmaceutically acceptable salt, wherein:
[0089] R.sup.1 is hydrogen;
[0090] R.sup.2 is independently selected from the group consisting
of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl,
wherein all substituents may be optionally substituted by one or
more selected from the group consisting of halo and lower
alkyl;
[0091] R.sup.3 and R.sup.4 are independently selected from lower
alkoxy and heterocyclic lower alkoxy;
[0092] R.sup.5 is a carbon-carbon linked heteroaryl, which may be
optionally substituted by one or more lower alkyl.
[0093] In a 6.sup.th embodiment, the invention is represented by
Formula 1 or its pharmaceutically acceptable salt, wherein the
compound is selected from [0094]
4-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)acryloyl]-N-(5-methylisoxazol-3--
yl)benzenesulfonamide; [0095]
3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-methylisoxazol-3-yl)b-
enzenesulfonamide sodium salt; [0096]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyrimidin-2-ylbenzene-
sulfonamide; [0097]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(1-H-tetrazol-5-yl)be-
nzenesulfonamide; [0098]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyridin-2-ylbenzenesu-
lfonamide; [0099]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(1H-pyrazol-3-yl)benz-
enesulfonamide; [0100]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-isoxazol-3-ylbenzenes-
ulfonamide; [0101]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-thiazol-2-ylbenzenesu-
lfonamide; [0102]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(3-methylisoxazol-5-y-
lbenzenesulfonamide; [0103]
N-(5-Chloropyridin-2-yl)-4-[3E-(2,4-dimethoxy-5-thien-2-ylphenyl)acryloyl-
]benzenesulfonamide; [0104]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-fluoropyridin-2-yl-
)benzenesulfonamide; [0105]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-trifluoromethylpyr-
idin-2-yl)benzenesulfonamide; [0106]
4-{3E-[2-(3-Hydroxy-2-hydroxymethylpropoxy)-4-methoxy-5-thien-2-ylphenyl]-
acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide; [0107]
4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thien-2-ylphenyl]acryloyl}-
-N-(5-methyl-isoxazol-3-yl)benzenesulfonamide hydrochloride; [0108]
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(5-meth-
ylisoxazol-3-yl)benzenesulfonamide; [0109]
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(5-meth-
ylisoxazol-3-yl)benzenesulfonamide sodium salt; [0110]
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-pyridin-
-3-ylmethylbenzenesulfonamide; [0111]
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(2-morp-
holin-4-yl-ethyl)benzenesulfonamide; [0112]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyridin-3-ylmethylben-
zenesulfonamide [0113]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2-morpholin-4-yl-eth-
yl)benzenesulfonamide; [0114]
3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)-1-[4-(4-methylpiperazine-1-sulfonyl-
)phenyl]propenone; [0115]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-piperidin-1-ylbenzene-
sulfonamide; [0116]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(3-imidazol-1-ylpropy-
l)benzenesulfonamide; [0117]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2,2,2-trifluoroethyl-
)benzenesulfonamide; [0118]
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2,2,2-trifluoroethyl-
)benzenesulfonamide sodium salt; [0119]
{4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonylamino}ac-
etic acid; [0120]
2-{4-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)acryloyl]benzenesulfonylamino-
}-2-methylpropionic acid; [0121]
1-{4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonyl}piper-
idine-2-carboxylic acid; [0122]
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-methyl--
benzenesulfonamide; [0123]
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-methoxy-
benzenesulfonamide; [0124]
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N,N-dimet-
hylbenzenesulfonamide; [0125]
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N,N-dimethylbenzen-
esulfonamide; [0126]
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(tert-b-
utyldimethylsiloxy)benzenesulfonamide; [0127]
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]-acryloyl}-N-hydrox-
ybenzenesulfonamide; [0128]
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-pyrol-2-yl)phenyl]acryloyl}-N-(5-meth-
yl-isoxazol-3-yl)benzenesulfonamide; [0129]
4-{3E-[2-(3-Hydroxy-propoxy)-4-methoxy-5-thien-2-ylphenyl]acryloyl}-N-(5--
methylisoxazol-3-yl)benzenesulfonamide; [0130]
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-pyrol-2-yl)phenyl]acryloyl}-N-(5-meth-
yl-isoxazol-3-yl)benzenesulfonamide; [0131]
N-(3-Imidazol-1-yl-propyl)-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxy-phenyl]-
acryloyl}benzenesulfonamide; [0132]
(4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonylami-
no)acetic acid; and [0133]
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin-2-ylbenz-
enesulfonamide.
[0134] In a 7.sup.th embodiment, the invention is represented by
Formula III ##STR8## or its pharmaceutically acceptable salt,
wherein:
[0135] R.sup.1 is selected from the group consisting of hydrogen,
alkyl, lower alkyl, carbocyclic, cycloalkyl, alkoxy, lower alkoxy,
cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryloxy,
heteroaryloxy, aryl, heteroaryl, heterocyclic, arylalkyl,
heteroarylalkyl, --NR.sup.7R.sup.8, --NHR.sup.2,
--N(R.sup.2).sub.2, acyl and heterocyclicalkyl, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, alkyl, lower alkyl, alkenyl,
cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,
amino, aminoalkyl, --NR.sup.7R.sup.8, --NHR.sup.2,
--N(R.sup.2).sub.2, alkoxy, oxo, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2;
[0136] R.sup.2 is independently selected from the group consisting
of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl,
heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl,
alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may
be optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8,
--NR.sup.1R.sup.2 and --C(O)N(R.sup.2).sub.2;
[0137] R.sup.7 and R.sup.8 are independently selected from the
group consisting of alkyl, alkenyl and aryl and linked together
forming a 4- to 12-membered monocyclic, bicylic, tricyclic or
benzofused ring, which may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2;
[0138] R.sup.3, R.sup.4 and R.sup.5 are independently selected from
hydrogen, hydroxy, alkoxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, cycloalkyloxy,
cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy,
heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclic,
heteroaryl, NR.sup.7R.sup.8, heterocyclicoxy, heterocyclicalkoxy,
heterocyclic lower alkoxy, --OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2,
and --OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, alkyl, lower alkyl, alkenyl,
cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,
amino, aminoalkyl, N-linked heteroaryl, --NR.sup.7R.sup.8, alkoxy,
oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2;
[0139] with the proviso that at least one of R.sup.3, R.sup.4 or
R.sup.5 is an N-linked heteroaryl or --NR.sup.7R.sup.8.
[0140] In an 8.sup.th embodiment, the invention is represented by
Formula III or its pharmaceutically acceptable salt, wherein:
[0141] R.sup.1 is selected from the group consisting of hydrogen,
alkyl, lower alkyl, alkoxy, lower alkoxy, cycloalkyloxy,
cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy,
heterocyclic, heteroarylalkyl, acyl and heterocyclicalkyl, wherein
all substituents may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
haloalkyl, heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8,
--NHR.sup.2, --N(R.sup.2).sub.2, alkoxy, carboxy, carboxyalkyl,
alkoxycarbonyl, and heteroaryl;
[0142] R.sup.2 is independently selected from the group consisting
of alkyl, lower alkyl, heteroaryl, heterocyclic, heteroarylalkyl,
acyl and heterocyclicalkyl, wherein all substituents may be
optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl
and heteroaryl;
[0143] R.sup.7 and R.sup.8 are independently selected from the
group consisting of alkyl, alkenyl and aryl and linked together
forming a 5- to 10-membered monocyclic, bicylic or benzofused ring,
which may be optionally substituted by one or more selected from
the group consisting of halo, alkyl, lower alkyl, haloalkyl,
heterocyclic, --NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl and
alkoxycarbonyl;
[0144] R.sup.3, R.sup.4 and R.sup.5 are independently selected from
hydrogen, hydroxy, alkoxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, haloalkoxy,
heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,
heterocyclic, heteroaryl, NR.sup.7R.sup.8, heterocyclicoxy,
heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, hydroxy,
hydroxyalkyl, heterocyclic, N-linked heteroaryl, --NR.sup.7R.sup.8,
alkoxy, --C(O)NR.sup.7R.sup.8, and --C(O)N(R).sub.2;
[0145] with the proviso that at least one of R.sup.3, R.sup.4 or
R.sup.5 is an N-linked heteroaryl or --NR.sup.7R.sup.8.
[0146] In a 9.sup.th embodiment, the invention is represented by
Formula III or its pharmaceutically acceptable salt, wherein:
[0147] R.sup.1 is selected from the group consisting of alkyl,
lower alkyl, alkoxy, and lower alkoxy, wherein all substituents may
be optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, amino, --NR.sup.7R.sup.8,
NHR.sup.2, --N(R.sup.2).sub.2, aminoalkyl, alkoxy, carboxy,
carboxyalkyl, alkoxycarbonyl, and heteroaryl;
[0148] R.sup.2 is independently selected from the group consisting
of lower alkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, lower alkyl, haloalkyl,
heterocyclic, --NR.sup.7R.sup.8 and carboxy;
[0149] R.sup.7 and R.sup.8 are independently selected from the
group consisting of alkyl and alkenyl, and linked together forming
a 5- to 7-membered monocyclic ring, which may be optionally
substituted by one or more selected from the group consisting of
halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
[0150] R.sup.3, R.sup.4 and R.sup.5 are independently selected from
hydrogen, hydroxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, heteroaryl lower
alkoxy, heterocyclic, heteroaryl, NR.sup.7R.sup.8, heterocyclicoxy,
heterocyclic lower alkoxy, --OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2,
and --OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of hydroxy, hydroxyalkyl, heterocyclic,
N-linked heteroaryl, --NR.sup.7R.sup.8, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2;
[0151] with the proviso that at least one of R.sup.3, R.sup.4 or
R.sup.5 is an N-linked heteroaryl or --NR.sup.7R.sup.8.
[0152] In a 10.sup.th embodiment, the invention is represented by
Formula III or its pharmaceutically acceptable salt, wherein:
[0153] R.sup.1 is selected from the group consisting of lower
alkyl, and lower alkoxy, wherein all substituents may be optionally
substituted by one or more selected from the group consisting of
alkoxy, --NR.sup.7R.sup.8, --NHR.sup.2, and --N(R.sup.2).sub.2;
[0154] R.sup.2 is lower alkyl;
[0155] R.sup.7 and R.sup.8 are independently alkyl and linked
together forming a 5- to 7-membered saturated monocyclic ring;
[0156] R.sup.3, R.sup.4 and R.sup.5 are independently selected from
hydrogen, hydroxy, lower alkoxy, heterocyclic, heteroaryl,
NR.sup.7R.sup.8 and heterocyclic lower alkoxy;
[0157] with the proviso that at least one of R.sup.3, R.sup.4 or
R.sup.5 is an N-linked heteroaryl or --NR.sup.7R.sup.8.
[0158] In an 11.sup.th embodiment, the invention is represented by
Formula III or its pharmaceutically acceptable salt, wherein:
[0159] R.sup.1 is selected from the group consisting of lower
alkyl, and lower alkoxy;
[0160] R.sup.7 and R.sup.8 are independently alkyl and linked
together forming a 5- to 7-membered saturated monocyclic ring;
[0161] R.sup.3, R.sup.4 and R.sup.5 are independently selected from
lower alkoxy, NR.sup.7R.sup.8 and heterocyclic lower alkoxy;
[0162] with the proviso that at least one of R.sup.3, R.sup.4 or
R.sup.5 is --NR.sup.7R.sup.8.
[0163] In the 12.sup.th embodiment, the invention is represented by
Formula III or its the compound is
N-Butyryl-4-[3E-(2,4-dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesu-
lfonamide.
[0164] In a 13.sup.th embodiment, the invention is represented by
Formula III ##STR9## or its pharmaceutically acceptable salt,
wherein:
[0165] R.sup.1 is selected from the group consisting of hydrogen,
alkyl, lower alkyl, carbocyclic, cycloalkyl, alkoxy, lower alkoxy,
cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryloxy,
heteroaryloxy, aryl, heteroaryl, heterocyclic, arylalkyl,
heteroarylalkyl, --NR.sup.7R.sup.8, --NHR.sup.2,
--N(R.sup.2).sub.2, acyl and heterocyclicalkyl, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, alkyl, lower alkyl, alkenyl,
cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,
amino, aminoalkyl, --NR.sup.7R.sup.8, --NHR.sup.2,
--N(R.sup.2).sub.2, alkoxy, oxo, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2;
[0166] R.sup.2 is independently selected from the group consisting
of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl,
heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl,
alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may
be optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8,
--NR.sup.1R.sup.2 and --C(O)N(R.sup.2).sub.2;
[0167] R.sup.7 and R.sup.8 are independently selected from the
group consisting of alkyl, alkenyl and aryl and linked together
forming a 4- to 12-membered monocyclic, bicylic, tricyclic or
benzofused ring, which may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2;
[0168] R.sup.3 and R.sup.4 are independently selected from
hydrogen, hydroxy, alkoxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, cycloalkyloxy,
cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy,
heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy,
heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, N-linked heteroaryl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2;
[0169] R.sup.5 is selected from the group consisting of a
carbon-carbon linked heterocyclic and a carbon-carbon linked
heteroaryl, which may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2;
[0170] with the proviso that when R.sup.1 is isopropyl, R.sup.5
cannot be 5-benzo[b]thien-2-yl.
[0171] In a 14.sup.th embodiment, the invention is represented by
Formula III or its pharmaceutically acceptable salt, wherein:
[0172] R.sup.1 is selected from the group consisting of hydrogen,
alkyl, lower alkyl, alkoxy, lower alkoxy, cycloalkyloxy,
cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy,
heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, alkyl, lower alkyl, haloalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, --NHR.sup.2,
--N(R.sup.2).sub.2, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl,
and heteroaryl;
[0173] R.sup.2 is independently selected from the group consisting
of alkyl, lower alkyl, heteroaryl, heterocyclic, heteroarylalkyl,
and heterocyclicalkyl, wherein all substituents may be optionally
substituted by one or more selected from the group consisting of
halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl
and heteroaryl;
[0174] R.sup.7 and R.sup.8 are independently selected from the
group consisting of alkyl, alkenyl and aryl and linked together
forming a 5- to 10-membered monocyclic, bicylic or benzofused ring,
which may be optionally substituted by one or more selected from
the group consisting of halo, alkyl, lower alkyl, haloalkyl,
heterocyclic, --NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl and
alkoxycarbonyl;
[0175] R.sup.3 and R.sup.4 are independently selected from hydroxy,
alkoxy, lower alkoxy, --(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl,
haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower
alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower
alkoxy, --OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, hydroxy,
hydroxyalkyl, heterocyclic, --NR.sup.7R.sup.8, alkoxy,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2;
[0176] R.sup.5 is selected from the group consisting of a
carbon-carbon linked heteroaryl and a carbon-carbon linked
heterocyclic, which may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
haloalkyl, heterocyclic, --NR.sup.7R.sup.8 and alkoxy;
[0177] with the proviso that when R.sup.1 is isopropyl, R.sup.5
cannot be 5-benzo[b]thien-2-yl.
[0178] In 15.sup.th embodiment, the invention is represented by
Formula III or its pharmaceutically acceptable salt, wherein:
[0179] R.sup.1 is selected from the group consisting of alkyl,
lower alkyl, alkoxy, and lower alkoxy, wherein all substituents may
be optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, amino, aminoalkyl,
--NR.sup.7R.sup.8, --NHR.sup.2, --N(R.sup.2).sub.2, alkoxy,
carboxy, carboxyalkyl, alkoxycarbonyl, and heteroaryl;
[0180] R.sup.2 is independently selected from the group consisting
of lower alkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, lower alkyl, haloalkyl,
heterocyclic, --NR.sup.7R.sup.8 and carboxy;
[0181] R.sup.7 and R.sup.8 are independently selected from the
group consisting of alkyl and alkenyl, and linked together forming
a 5- to 7-membered monocyclic ring, which may be optionally
substituted by one or more selected from the group consisting of
halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
[0182] R.sup.3 and R.sup.4 are independently selected from hydroxy,
lower alkoxy, --(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl,
heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy,
heterocyclic lower alkoxy, --OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2,
and --OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of hydroxy, hydroxyalkyl, heterocyclic,
--NR.sup.7R.sup.8, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2;
[0183] R.sup.5 is selected from the group consisting of a
carbon-carbon linked heteroaryl and a carbon-carbon linked
heterocyclic, which may be optionally substituted by one or more
lower alkyl;
[0184] with the proviso that when R.sup.1 is isopropyl, R.sup.5
cannot be 5-benzo[b]thien-2-yl.
[0185] In a 16.sup.th embodiment, the invention is represented by
Formula III or its pharmaceutically acceptable salt, wherein:
[0186] R.sup.1 is selected from the group consisting of lower
alkyl, and lower alkoxy, wherein all substituents may be optionally
substituted by one or more selected from the group consisting of
alkoxy, --NR.sup.7R.sup.8, --NHR.sup.2, and --N(R.sup.2).sub.2;
[0187] R.sup.2 is lower alkyl;
[0188] R.sup.7 and R.sup.8 are independently alkyl and linked
together forming a 5- to 7-membered saturated monocyclic ring;
[0189] R.sup.3 and R.sup.4 are independently selected from hydroxy,
lower alkoxy and heterocyclic lower alkoxy;
[0190] R.sup.5 is selected from the group consisting of a
carbon-carbon linked heteroaryl and a carbon-carbon linked
heterocyclic, which may be optionally substituted by one or more
lower alkyl;
[0191] with the proviso that when R.sup.1 is isopropyl, R.sup.5
cannot be 5-benzo[b]thien-2-yl.
[0192] In a 17.sup.th embodiment, the invention is represented by
Formula III or its pharmaceutically acceptable salt, wherein:
[0193] R.sup.1 is selected from the group consisting of lower
alkyl, and lower alkoxy;
[0194] R.sup.3 and R.sup.4 are independently selected from lower
alkoxy and heterocyclic lower alkoxy;
[0195] R.sup.5 is a carbon-carbon linked heteroaryl, which may be
optionally substituted by one or more lower alkyl;
[0196] with the proviso that when R.sup.1 is isopropyl, R.sup.5
cannot be 5-benzo[b]thien-2-yl.
[0197] In a 18.sup.th embodiment, the invention is represented by
Formula III or its pharmaceutically acceptable salt, wherein the
compound is selected from the group consisting of [0198]
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-isobutyrylbenzen-
esulfonamide; [0199]
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-isobutyrylbenzen-
esulfonamide sodium salt; [0200]
N-Butyryl-4-{3E-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-
benzenesulfonamide; [0201]
N-Ethoxycarbonyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}be-
nzenesulfonamide potassium salt; [0202]
N-Ethoxycarbonyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}be-
nzenesulfonamide; [0203]
N-Acetyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesul-
fonamide; [0204]
N-Acetyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesul-
fonamide sodium salt; [0205]
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-propionyl-benzen-
esulfonamide; [0206]
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-propionylbenzene-
sulfonamide sodium salt; [0207]
N-Butyryl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesu-
lfonamide; and [0208]
N-Butyryl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesu-
lfonamide sodium salt.
[0209] In a 19.sup.th embodiment, the invention is represented by
Formula I ##STR10## or its pharmaceutically acceptable salt,
wherein:
[0210] R.sup.1 is selected from the group consisting of hydrogen,
alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl, heteroaryl,
heterocyclic, arylalkyl, heteroarylalkyl, acyl and
heterocyclicalkyl, wherein all substituents may be optionally
substituted by one or more selected from the group consisting of
halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl,
hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,
--NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2;
[0211] R.sup.2 is independently selected from the group consisting
of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy,
lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy,
heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl,
heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl,
wherein all substituents may be optionally substituted by one or
more selected from the group consisting of halo, alkyl, lower
alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl,
--C(O)NR.sup.7R.sup.8, --NR.sup.1R.sup.2 and
--C(O)N(R.sup.2).sub.2;
[0212] R.sup.1 and R.sup.2 may be taken together to form a 4- to
12-membered saturated or unsaturated heterocyclic ring which can be
optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2;
[0213] R.sup.7 and R.sup.8 are independently selected from the
group consisting of alkyl, alkenyl and aryl and linked together
forming a 4- to 12-membered monocyclic, bicylic, tricyclic or
benzofused ring, which may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2;
[0214] R.sup.3 and R.sup.4 are independently selected from hydroxy,
alkoxy, lower alkoxy, --(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl,
cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,
heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy,
heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2;
[0215] R.sup.5 is selected from the group consisting of a
carbon-nitrogen linked heteroaryl and a carbon-nitrogen linked
heterocyclic, which may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2.
[0216] In a 20.sup.th embodiment, the invention is represented by
Formula I or its pharmaceutically acceptable salt, wherein:
[0217] R.sup.1 is selected from the group consisting of hydrogen,
alkyl, and lower alkyl, wherein all substituents may be optionally
substituted by one or more selected from the group consisting of
halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl
and heteroaryl;
[0218] R.sup.2 is independently selected from the group consisting
of alkyl, lower alkyl, alkoxy, lower alkoxy, heteroaryl,
heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of halo, alkyl, lower alkyl, haloalkyl,
heterocyclic, --NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl,
alkoxycarbonyl and heteroaryl;
[0219] R.sup.1 and R.sup.2 may be taken together to form a 5- to
7-membered saturated or unsaturated heterocyclic ring which can be
optionally substituted by one or more selected from the group
consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic,
--NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl and
alkoxycarbonyl;
[0220] R.sup.7 and R.sup.8 are independently selected from the
group consisting of alkyl, alkenyl and aryl and linked together
forming a 5- to 10-membered monocyclic, bicylic or benzofused ring,
which may be optionally substituted by one or more selected from
the group consisting of halo, alkyl, lower alkyl, haloalkyl,
heterocyclic, --NR.sup.7R.sup.8, alkoxy, carboxy, carboxyalkyl and
alkoxycarbonyl;
[0221] R.sup.3 and R.sup.4 are independently selected from hydroxy,
alkoxy, lower alkoxy, --(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl,
haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower
alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower
alkoxy, --OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2, and
--OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, hydroxy,
hydroxyalkyl, heterocyclic, --NR.sup.7R.sup.8, alkoxy,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.2).sub.2;
[0222] R.sup.5 is selected from the group consisting of a
carbon-nitrogen linked heteroaryl and a carbon-nitrogen linked
heterocyclic, which may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
haloalkyl, heterocyclic, --NR.sup.7R.sup.8 and alkoxy.
[0223] In a 21.sup.st embodiment, the invention is represented by
Formula I or its pharmaceutically acceptable salt, wherein:
[0224] R.sup.1 is selected from the group consisting of hydrogen
and lower alkyl;
[0225] R.sup.2 is independently selected from the group consisting
of lower alkyl, lower alkoxy, heteroaryl, heterocyclic,
heteroarylalkyl, and heterocyclicalkyl, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, lower alkyl, haloalkyl, heterocyclic,
heteroaryl, --NR.sup.7R.sup.8 and carboxy;
[0226] R.sup.1 and R.sup.2 may be taken together to form a 5- to
6-membered heterocyclic saturated ring which can be optionally
substituted by one or more selected from the group consisting of
halo, lower alkyl and carboxy;
[0227] R.sup.7 and R.sup.8 are independently selected from the
group consisting of alkyl and alkenyl, and linked together forming
a 5- to 7-membered monocyclic ring, which may be optionally
substituted by one or more selected from the group consisting of
halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
[0228] R.sup.3 and R.sup.4 are independently selected from hydroxy,
lower alkoxy, --(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl,
heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy,
heterocyclic lower alkoxy, --OC(R.sup.1).sub.2C(O)N(R.sup.2).sub.2,
and --OC(R.sup.1).sub.2C(O)NR.sup.7R.sup.8, wherein all
substituents may be optionally substituted by one or more selected
from the group consisting of hydroxy, hydroxyalkyl, heterocyclic,
--NR.sup.7R.sup.8, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2;
[0229] R.sup.5 is selected from the group consisting of a
carbon-nitrogen linked heteroaryl and a carbon-nitrogen linked
heterocyclic, which may be optionally substituted by one or more
lower alkyl.
[0230] In a 22.sup.nd embodiment, the invention is represented by
Formula I or its pharmaceutically acceptable salt, wherein:
[0231] R.sup.1 is hydrogen;
[0232] R.sup.2 is independently selected from the group consisting
of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl,
wherein all substituents may be optionally substituted by one or
more selected from the group consisting of halo, heterocyclic,
heteroaryl, and lower alkyl;
[0233] R.sup.1 and R.sup.2 may be taken together to form a 5- to
6-membered heterocyclic saturated ring;
[0234] R.sup.7 and R.sup.8 are independently alkyl and linked
together forming a 5- to 7-membered saturated monocyclic ring;
[0235] R.sup.3 and R.sup.4 are independently selected from hydroxy,
lower alkoxy and heterocyclic lower alkoxy;
[0236] R.sup.5 is selected from the group consisting of a
carbon-nitrogen linked heterocyclic, which may be optionally
substituted by one or more lower alkyl.
[0237] In a 23.sup.rd embodiment, the invention is represented by
Formula I or its pharmaceutically acceptable salt, wherein:
[0238] R.sup.1 is hydrogen;
[0239] R.sup.2 is independently selected from the group consisting
of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl,
wherein all substituents may be optionally substituted by one or
more selected from the group consisting of halo, heterocyclic,
heteroaryl, and lower alkyl;
[0240] R.sup.3 and R.sup.4 are independently selected from lower
alkoxy and heterocyclic lower alkoxy;
[0241] R.sup.5 is a carbon-nitrogen linked heterocyclic.
[0242] In a 24.sup.th embodiment, the invention is represented by
Formula I, wherein the compound is selected from the group
consisting of: [0243]
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-yl-phenyl)-acryloyl]-N-pyridin-2-yl--
benzenesulfonamide; [0244]
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-pyridin-2-ylmeth-
ylbenzenesulfonamide; [0245]
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-(3-imidazol-1-yl-
propyl)benzenesulfonamide; [0246]
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-[3-(4-methyl-pip-
erazin-1-yl)propyl]benzenesulfonamide; and [0247]
{4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonylami-
no}acetic acid.
[0248] In a 25.sup.th embodiment, the invention is a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24, together with one or
more pharmaceutically acceptable carrier.
[0249] In a 26.sup.th embodiment, the invention is represented by a
method for the treatment or prophylaxis of an inflammatory
disorder, comprising administering an effective amount of a
compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24.
[0250] In a 27.sup.th embodiment, the invention is represented by
embodiment 26, wherein the disorder is arthritis.
[0251] In a 28.sup.th embodiment, the invention is represented by
embodiment 26, wherein the disorder is rheumatoid arthritis.
[0252] In a 29.sup.th embodiment, the invention is represented by
embodiment 26, wherein the disorder is asthma.
[0253] In a 30.sup.th embodiment, the invention is represented by
embodiment 26, wherein the treatment is disease modifying for the
treatment of rheumatoid arthritis.
[0254] In a 31.sup.st embodiment, the invention is represented by
embodiment 26, wherein the disorder is allergic rhinitis.
[0255] In a 32.sup.nd embodiment, the invention is represented by
embodiment 26, wherein the disorder is chronic obstructive
pulmonary disease.
[0256] In a 33.sup.rd embodiment, the invention is represented by
embodiment 26, wherein the disorder is atherosclerosis.
[0257] In a 34.sup.th embodiment, the invention is represented by
embodiment 26, wherein the disorder is restinosis.
[0258] In a 35.sup.th embodiment, the invention is represented by
embodiment, the invention is represented by a method for inhibiting
the expression of VCAM-1, comprising administering an effective
amount of a compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24.
[0259] In further embodiments, the invention is represented by
intermediates used to make the final compounds of the invention.
Said intermediates are useful as starting materials for making the
compounds of the invention as well as having pharmaceutical
activity alone. Particular intermediates include the ones
represented by embodiment 36, represented by the formulas ##STR11##
wherein
[0260] X is --C(O)H or --CH.sub.2OH;
[0261] R.sup.3 and R.sup.4 are independently selected from the
group consisting of hydroxy, alkoxy, lower alkoxy,
--(O(CH.sub.2).sub.2).sub.1-3--O-lower alkyl, cycloalkyloxy,
cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy,
heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy,
heterocyclicalkoxy, heterocyclic lower alkoxy,
--OC(R.sup.9).sub.2C(O)N(R.sup.9).sub.2, and
--OC(R.sup.9).sub.2C(O)NR.sup.7R.sup.8, wherein all substituents
may be optionally substituted by one or more selected from the
group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,
haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino,
aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy,
carboxyalkyl, alkoxycarbonyl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.9).sub.2;
[0262] Y.sup.1, Y.sup.2, Y.sup.3, and Y.sup.4 are independently
selected from the group consisting of hydrogen, hydroxyl, halo,
alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy,
hydroxyalkyl, heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8,
alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
heteroaryl, --C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.9).sub.2,
wherein all substituents, when possible may be optionally
substituted by one or more selected from the group consisting of
hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl,
acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,
--NR.sup.7R.sup.8, alkoxy, oxo, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8, and
--C(O)N(R.sup.2).sub.2.
[0263] Y.sup.5 is selected from the group consisting of hydrogen,
alkyl, lower alkyl, acyl, and alkoxycarbonyl wherein all
substituents, when possible may be optionally substituted by one or
more selected from the group consisting of hydroxyl, halo, alkyl,
lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy,
hydroxyalkyl, heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8,
alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
heteroaryl, --C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.9).sub.2;
[0264] R.sup.9 is independently selected from the group consisting
of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy,
lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy,
heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl,
heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl,
wherein all substituents may be optionally substituted by one or
more selected from the group consisting of halo, alkyl, lower
alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, --NHR.sup.9,
--N(R.sup.9).sub.2, alkoxy, oxo, cyano, carboxy, carboxyalkyl,
alkoxycarbonyl, heteroaryl, --C(O)NR.sup.7R.sup.8,
--NR.sup.9R.sup.9 and --C(O)N(R.sup.9).sub.2;
[0265] R.sup.7 and R.sup.8 are independently selected from the
group consisting of alkyl, alkenyl and aryl and linked together
forming a 4- to 12-membered monocyclic, bicylic, tricyclic or
benzofused ring, which may be optionally substituted by one or more
selected from the group consisting of halo, alkyl, lower alkyl,
alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl,
heterocyclic, amino, aminoalkyl, --NR.sup.7R.sup.8, alkoxy, oxo,
cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, and --C(O)N(R.sup.9).sub.2.
[0266] In a 37.sup.th embodiment, the invention is represented by
embodiment 36 wherein the compound is selected from ##STR12##
[0267] Another embodiment of the invention includes the process for
making both the intermediates as well as the final compounds.
Definitions
[0268] A wavy line used as a bond "", denotes a bond which can be
either the E- or Z-geometric isomer.
[0269] When not used as a bond, the wavy line indicates the point
of attachment of the particular substituent.
[0270] The terms "alkyl" or "alk", alone or in combination, unless
otherwise specified, refers to a saturated straight or branched
primary, secondary, or tertiary hydrocarbon from 1 to 10 carbon
atoms, including, but not limited to methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, t-butyl, and sec-butyl. The term "lower
alkyl" alone or in combination refers to an alkyl having from 1 to
4 carbon atoms. The alkyl group may be optionally substituted with
any moiety that does not otherwise interfere with the reaction or
that provides an improvement in the process, including but not
limited to but limited to halo, haloalkyl, hydroxyl, carboxyl,
acyl, aryl, acyloxy, amino, amido, carboxyl derivatives,
alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano,
sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl,
sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl,
phosphoryl, phosphine, thioester, thioether, acid halide,
anhydride, oxime, hydrazine, carbamate, phosphonic acid,
phosphonate, either unprotected, or protected as necessary, as
known to those skilled in the art, for example, as taught in Greene
et al., Protective Groups in Organic Synthesis, John Wiley &
Sons, Second Edition, 1991, hereby incorporated by reference.
Specifically included are CF.sub.3 and CH.sub.2CF.sub.3.
[0271] The term "alkenyl", alone or in combination, means a
non-cyclic alkyl of 2 to 10 carbon atoms having one or more
unsaturated carbon-carbon bonds. The alkenyl group may be
optionally substituted with any moiety that does not otherwise
interfere with the reaction or that provides an improvement in the
process, including but not limited to but limited to halo,
haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido,
carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy,
aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl,
sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide,
phosphonyl, phosphinyl, phosphoryl, phosphine, thioester,
thioether, acid halide, anhydride, oxime, hydrazine, carbamate,
phosphonic acid, phosphonate, either unprotected, or protected as
necessary, as known to those skilled in the art, for example, as
taught in Greene et al., Protective Groups in Organic Synthesis,
John Wiley & Sons, Second Edition, 1991, hereby incorporated by
reference. Specifically included are CF.sub.3 and
CH.sub.2CF.sub.3.
[0272] The term "alkynyl", alone or in combination, means a
non-cyclic alkyl of 2 to 10 carbon atoms having one or more triple
carbon-carbon bonds, including but not limited to ethynyl and
propynyl. The alkynyl group may be optionally substituted with any
moiety that does not otherwise interfere with the reaction or that
provides an improvement in the process, including but not limited
to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl,
acyloxy, amino, amido, carboxyl derivatives, alkylamino,
dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic
acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl,
ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl,
phosphine, thioester, thioether, acid halide, anhydride, oxime,
hydrazine, carbamate, phosphonic acid, phosphonate, either
unprotected, or protected as necessary, as known to those skilled
in the art, for example, as taught in Greene et al., Protective
Groups in Organic Synthesis, John Wiley & Sons, Second Edition,
1991, hereby incorporated by reference. Specifically included are
CF.sub.3 and CH.sub.2CF.sub.3.
[0273] The terms "carboxy", "COOH" and "C(O)OH" are used
interchangeably.
[0274] The terms "alkoxycarbonyl" and "carboalkoxy" are used
interchangeably. Used alone or in combination, the terms mean refer
to the radical --C(O)OR, wherein R is alkyl that can be optionally
substituted as defined herein.
[0275] The term "thio", alone or in combination, means the radical
--S--.
[0276] The term "thiol", alone or in combination, means the radical
--SH.
[0277] The term "hydroxy", alone or in combination means the
radical --OH.
[0278] The term "sulfonyl", alone or in combination means the
radical --S(O).sub.2--.
[0279] The term "oxo" refers to an oxygen attached by a double bond
(.dbd.O).
[0280] The terms "carbocycle" and "carbocyclic", alone or in
combination, means any stable 3- to 7-membered monocyclic or
bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to
26-membered polycyclic carbon ring, any of which may be saturated,
partially unsaturated, or aromatic. Examples of such carbocyles
include, but are not limited to, cyclopropyl, cyclopentyl,
cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or
tetrahydronaphthyl (tetralin).
[0281] The term "cycloalkyl", alone or in combination, means a
saturated or partially unsaturated cyclic alkyl, having from 1 to
10 carbon atoms, including but not limited to mono- or bi-cyclic
ring systems such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexenyl, and cyclohexyl.
[0282] The term "aryl", alone or in combination, means a
carbocyclic aromatic system containing one, two or three rings
wherein such rings may be attached together in a pendent manner or
may be fused. The "aryl" group can be optionally substituted with
one or more of the moieties selected from the group consisting of
alkyl, alkenyl, alkynyl, heteroaryl, heterocyclic, carbocycle,
alkoxy, oxo, aryloxy, arylalkoxy, cycloalkyl, tetrazolyl,
heteroaryloxy; heteroarylalkoxy, carbohydrate, amino acid, amino
acid esters, amino acid amides, alditol, halogen, haloalkylthi,
haloalkoxy, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino,
aminoalkyl, aminoacyl, amido, alkylamino, dialkylamino, arylamino,
nitro, cyano, thiol, imide, sulfonic acid, sulfate, sulfonate,
sulfonyl, alkylsulfonyl, aminosulfonyl, alkylsulfonylamino,
haloalkylsulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic ester,
carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl,
thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid,
phosphate, phosphonate, phosphinate, sulfonamido, carboxamido,
hydroxamic acid, sulfonylimide or any other desired functional
group that does not inhibit the pharmacological activity of this
compound, either unprotected, or protected as necessary, as known
to those skilled in the art, for example, as taught in Greene, et
al., "Protective Groups in Organic Synthesis," John Wiley and Sons,
Second Edition, 1999. In addition, adjacent groups on an "aryl"
ring may combine to form a 5- to 7-membered saturated or partially
unsaturated carbocyclic, aryl, heteroaryl or heterocyclic ring,
which in turn may be substituted as above.
[0283] The term "heterocyclic", alone or in combination, refers to
a nonaromatic cyclic group that may be partially (containing at
least one double bond) or fully saturated and wherein the ring
contains at least one heteroatom selected from oxygen, sulfur,
nitrogen, or phosphorus. The terms "heteroaryl" or
"heteroaromatic", alone or in combination, refer to an aromatic
ring containing at least one heteroatom selected from sulfur,
oxygen, nitrogen or phosphorus. The heteroaryl or heterocyclic ring
may optionally be substituted by one or more substituent listed as
optional substituents for aryl. In addition, adjacent groups on the
heteroaryl or heterocyclic ring may combine to form a 5- to
7-membered carbocyclic, aryl, heteroaryl or heterocyclic ring,
which in turn may be substituted as above. Nonlimiting examples of
heterocyclics and heteroaromatics are pyrrolidinyl,
tetrahydrofuryl, tetrahydrofuranyl, pyranyl, purinyl,
tetrahydropyranyl, piperazinyl, piperidinyl, morpholino,
thiomorpholino, tetrahydropyranyl, imidazolyl, pyrrolinyl,
pyrazolinyl, indolinyl, dioxolanyl, or 1,4-dioxanyl, aziridinyl,
furyl, furanyl, pyridyl, pyridinyl, pyridazinyl, pyrimidinyl,
benzoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,3,4-thiadiazole, indazolyl, triazinyl, 1,3,5-triazinyl, thienyl,
isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl,
quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl,
indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl,
thiazolyl, benzothiazolyl, isothiazolyl, 1,2,4-thiadiazolyl,
isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrrolyl,
quinazolinyl, quinoxalinyl, benzoxazolyl, quinolinyl,
isoquinolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl,
pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole,
1,2,3-oxadiazole, thiazine, pyridazine, triazolopyridinyl or
pteridinyl wherein said heteroaryl or heterocyclic group can be
optionally substituted with one or more substituent selected from
the same substituents as set out above for aryl groups. Functional
oxygen and nitrogen groups on the heteroaryl group can be protected
as necessary or desired. Suitable protecting groups can include
trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and
t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups,
acyl groups such as acetyl and propionyl, methanesulfonyl, and
p-toluenesulfonyl.
[0284] The terms "thienyl" and "thien", alone or in combination,
refers to a five member cyclic group wherein the ring contains one
sulfur atom and two double bonds.
[0285] The term "benzothienyl", alone or in combination, refers to
a five member cyclic group wherein the ring contains one sulfur
atom and two double bonds fused to a phenyl ring.
[0286] The term "aryloxy", alone or in combination, refers to an
aryl group bound to the molecule through an oxygen atom.
[0287] The term "heteroaryloxy", alone or in combination, refers to
a heteroaryl group bound to the molecule through an oxygen
atom.
[0288] The term "aralkoxy", alone or in combination, refers to an
aryl group attached to an alkyl group which is attached to the
molecule through an oxygen atom.
[0289] The term "heterocyclearalkoxy" refers to a heterocyclic
group attached to an aryl group attached to an alkyl-O-- group. The
heterocyclic, aryl and alkyl groups can be optionally substituted
as described above.
[0290] The terms "halo" and "halogen", alone or in combination,
refer to chloro, bromo, iodo and fluoro.
[0291] The terms "alkoxy" or "alkylthio", alone or in combination,
refers to an alkyl group as defined above bonded through an oxygen
linkage (--O--) or a sulfur linkage (--S--), respectively.
[0292] The terms "lower alkoxy" or "lower alkylthio", alone or in
combination, refers to a lower alkyl group as defined above bonded
through an oxygen linkage (--O--) or a sulfur linkage (--S--),
respectively.
[0293] The term "acyl", alone or in combination, refers to a group
of the formula C(O)R', wherein R' is an alkyl, aryl, alkaryl or
aralkyl group, or substituted alkyl, aryl, aralkyl or alkaryl,
wherein these groups are as defined above.
[0294] The term "acetyl", alone or in combination, refers to the
radical --C(O)CH.sub.3.
[0295] The term "amino", alone or in combination, denotes the
radical --NH.sub.2 or --NH--.
[0296] The term "nitro", alone or in combination, denotes the
radical --NO.sub.2.
[0297] The term "substituted", means that one or more hydrogen on
the designated atom or substituent is replaced with a selection
from the indicated group, provided that the designated atom's
normal valency is not exceeded, and the that the substitution
results in a stable compound. When a substitutent is "oxo" (keto)
(i.e., .dbd.O), then 2 hydrogens on the atom are replaced.
[0298] As used herein, the term "patient" refers to warm-blooded
animals or mammals, and in particular humans, who are in need of
the therapy described herein. The term "host", as used herein,
refers to a unicellular or multicellular organism, including cell
lines and animals, and preferably a human.
Synthesis of the Active Compounds
[0299] The compounds of the present invention can be readily
prepared by those skilled in the art of organic synthesis using
commonly known methods, many of which are described by J, March, in
Advanced Organic Chemistry, 4.sup.th Edition (Wiley-Interscience,
New York, 1992) and D. N. Dnar in The Chemistry of Chalcones and
Related Compounds (Wiley-Interscience, New York, 1981),
incorporated herein by reference.
[0300] Compounds of the invention may be isolated as either
mixtures of cis (Z) and trans (E) geometric isomers or pure trans
(E) isomers. If desired, either the mixtures or the pure trans
isomers may be isomerized to the corresponding predominantly cis
(Z) iomers using methods well known in the literature.
[0301] The following schemes and examples will prove useful to
those skilled in the art in manufacturing the compounds of the
invention: ##STR13## ##STR14## ##STR15## ##STR16##
EXAMPLES
[0302] The following examples are understood to be illustrative
only and are not intended to limit the scope of the present
invention in any way. All intermediates and final products have
been characterized by conventional proton NMR, mass spectral
analyses and/or standard analytical methods known to those skilled
in the art.
Example 1
[0303] ##STR17##
4-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)acryloyl]-N-(5-methylisoxazol-3-y-
l)benzenesulfonamide
[0304] Ex-1A: 5-bromo-2,4-dimethoxybenzaldehyde (20.3 g, 83 mmol),
thiophene-2-boronic acid (11.6 g, 91 mmol) and THF (200 mL) were
sequentially charged into a clean reaction vessel fitted with a
reflux condenser, mechanical stirrer and nitrogen inlet adapter.
Nitrogen was bubbled into the resulting solution for 20 min
followed by the sequential addition of KF (10.1 g, 174 mmol), and
Pd(.sup.tBu.sub.3P).sub.2 (0.424 g, 0.83 mmol). The solution was
immediately heated to 60.degree. C. and aged for 1.5 h. The
reaction was diluted with H.sub.2O (200 mL) and transferred to a
separatory funnel containing EtOAc (200 mL) and H.sub.2O (200 mL).
The layers were cut and the aqueous layer was extracted with EtOAc
(100 mL). The combined organic cuts were filtered through a
pre-washed pad of solka floc (5 g). The pad of solka floc and spent
catalyst were washed with fresh EtOAc (200 mL) and this wash
combined with the batch. The resultant filtrate was concentrated to
dryness. The crude product was dissolved in THF (38 mL) and
crystallized upon heptane (152 mL) addition. The product was
filtered and then dried to a constant weight in the vacuum oven
(38.degree. C., 20 in Hg) affording 19.32 g (94%) of the desired
2,4-dimethoxy-5-thien-2-ylbenzaldehyde as a light off-white solid,
mp 125-126.degree. C. .sup.1H-NMR (300 MHz, CDCl.sub.3): 10.34 (s,
1H), 8.12 (s, 1H), 7.44 (dd, 1H, J=3.5 and 1.5 Hz), 7.31 (dd, 1H,
J=5.2 and 1.5 Hz), 7.07 (dd, 1H, J=5.2 and 3.5 Hz), 6.51 (s, 1H),
4.02 (s, 3H), 3.99 (s, 3H). HRMS (EI) Calcd. for
C.sub.13H.sub.12O.sub.3S: 248.0507 (M.sup.+); Found: 248.0504.
[0305] Ex-1B: To a solution of 3-amino-5-methylisoxazole (0.27 g,
2.75 mmol) in pyridine (1 mL) at 0.degree. C. was added a solution
of 4-acetylbenzenesulfonyl chloride (0.50 g, 2.29 mmol) in 1 mL
pyridine dropwise to the reaction. The resulting solution was
stirred at 0.degree. C. for 30 min and then warmed to room
temperature and stirred for an additional 18 h. The mixture was
diluted with water (100 mL), cooled to 0.degree. C., and stirred
for 1 h. The resulting precipitate was collected on filter paper
and rinsed with several portions of water. The filtrate was
acidified with 3 N HCl and the resulting precipitate was collected
and rinsed with water. The solids were combined and dried in vacuo
to afford 0.50 g (80%) of
4-acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide as a pale
green solid, mp 189-190.degree. C. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.14 (d, 2H, J=8.1 Hz), 7.98 (d, 2H, J=8.1
Hz), 6.16 (s, 1H), 2.62 (s, 3H), 2.30 (s, 3H). HRMS (EI) Calcd. for
C.sub.12H.sub.12N.sub.2O.sub.4S: 280.0518 (M.sup.+); Found:
280.0514. Anal. Calcd. for C.sub.12H.sub.12N.sub.2O.sub.4S: C,
51.42; H, 4.32; N, 9.99; S, 11.44; Found: C, 51.73; H, 4.39; N,
10.12; S, 11.30.
[0306] 4-Acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide
(Ex-1B, 2.50 g, 8.9 mmol) and
2,4-dimethoxy-5-thien-2-ylbenzaldehyde (Ex-1A, 2.20 g, 8.9 mmol)
were dissolved in a dimethylformamide-methanol solution (55 mL,
7:3). After complete dissolution, lithium methoxide (1.35 g, 35.6
mmol) was added and the resulting orange slurry was stirred in the
dark at room temperature for 1 h. Upon completion, as determined by
HPLC, the mixture was diluted with water (80 mL), acidified with a
1 N hydrochloric acid solution, and extracted with ethyl acetate
(3.times.40 mL). The combined organic extracts were dried over
sodium sulfate and evaporated to dryness. The crude oil was taken
up in ethanol (20 mL) and warmed to 60.degree. C. to obtain
complete dissolution and allowed to cool to room temperature. The
resulting precipitate was collected on filter paper and dried in
vacuo to yield 3.78 g (83%) of the title compound as an orange
solid, mp 202-203.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6)
8.31 (d, 2H, J=8.1 Hz), 8.27 (s, 1H), 8.08 (d, 1H, J=15.9 Hz), 8.01
(d, 2H, J=8.1 Hz), 7.88 (d, 1H, J=15.9 Hz), 7.66 (d, 1H, J=3.3 Hz),
7.53 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.3 Hz), 6.84 (s, 1H),
6.18 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 2.31 (s, 3H). Anal.
Calcd. for C.sub.25H.sub.22N.sub.2O.sub.6S.sub.2: C, 58.81; H,
4.34; N, 5.49; S, 12.56; Found: C, 58.68; H, 4.40; N, 5.61; S,
12.62. HRMS (EI) Calcd. for C.sub.25H.sub.22N.sub.2O.sub.6S.sub.2:
511.0997 (M.sup.+); Found: 511.0983.
Example 2
[0307] ##STR18##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-methylisoxazol-3-yl-
)benzenesulfonamide sodium salt
[0308] To a solution of
4-[3E-(2,4-dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-methyl-isoxazol-3--
yl)benzenesulfonamide (Ex-1, 0.50 g, 0.98 mmol) in tetrahydrofuran
(8 mL) was added sodium methoxide (0.061 g, 1.07 mmol) and the
reaction was stirred in the dark at room temperature for 1 h. The
resulting yellow solid was collected on filter paper and rinsed
with fresh portions of THF. The wet filtercake was dried in a
vacuum desiccator for 1 h then transferred to a flask and dried
further in vacuo for 18 h. The crude orange solid was taken up in
ethanol (6 mL) and stirred for 4 h at room temperature in the dark.
The solid was collected on filter paper and dried in vacuo to yield
0.30 g (60%) of the title compound as a yellow solid,
mp>260.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.26 (s,
1H), 8.11 (d, 2H, J=8.1 Hz), 8.04 (d, 1H, J=15.7 Hz), 7.88 (d, 1H,
J=15.7 Hz), 7.80 (d, 2H, J=8.1 Hz), 7.69 (d, 1H, J=3.3 Hz), 7.51
(d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.3 Hz), 6.83 (s, 1H), 5.80
(s,1H), 4.01 (s, 3H), 4.00 (s, 3H), 2.11 (s, 3H). Anal. Calcd. for
C.sub.25H.sub.21N.sub.2NaO.sub.6S.sub.2.1/4H.sub.2O: C, 55.91; H,
4.04; N, 5.22; S, 11.94; Found: C, 55.92; H, 3.98; N, 5.21; S,
11.95.
Example 3
[0309] ##STR19##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyrimidin-2-ylbenzenes-
ulfonamide
[0310] Ex-3A: 4-Acetyl-N-pyrimidin-2-ylbenzenesulfonamide was
prepared in an analogous fashion as Ex-1B using 2-aminopyrimidine,
30% yield, pale yellow solid, mp>240.degree. C. (dec).
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 8.50 (d, 2H, J=4.8 Hz),
8.07-8.14 (m, 4H), 7.05 (t, 1H, J=4.5 Hz), 2.61 (s, 3H). HRMS (ESI)
Calcd. for C.sub.12H.sub.11N.sub.3O.sub.3S: 278.0599 (M+H).sup.+;
Found: 278.0608.
[0311] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-pyrimidin-2-ylbenzenesulfonamide (Ex-3A), 70%
yield, yellow solid, mp 215.degree. C. (dec). .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) 8.27 (s, 1H), 8.12-8.16 (m, 4H), 8.06 (d, 1H, J=15.6
Hz), 7.95 (d, 2H, J=8.1 Hz), 7.90 (d, 1H, J=15.6 Hz), 7.68 (d, 1H,
J=3.6 Hz), 7.52 (d, 1H, J=4.8 Hz), 7.12-7.15 (m, 1H), 6.84 (s, 1H),
6.50 (t, 1H, J=5.1 Hz), 4.02 (s, 3H), 4.00 (s, 3H). Anal. Calcd.
for C.sub.25H.sub.21N.sub.3O.sub.5S.sub.2.3H.sub.2O: C, 53.46; H,
4.85; N, 7.48; S, 11.42; Found: C, 53.67; H, 4.71; N, 7.38; S,
11.76. HRMS (ESI) Calcd. for C.sub.25H.sub.21N.sub.3O.sub.5S.sub.2:
508.1001 (M+H).sup.+; Found: 508.1005.
Example 4
[0312] ##STR20##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(1-H-tetrazol-5-yl)ben-
zenesulfonamide
[0313] Ex-4A: 4-Acetyl-N-(1-H-tetrazol-5-yl)benzenesulfonamide was
prepared in an analogous fashion as Ex-1B using 5-aminotetrazole,
50% yield, off-white solid, mp 150-151.degree. C. .sup.1H-NMR (300
MHz, DMSO-d.sub.6) .delta. 8.98 (brs, 1H), 8.11 (d, 2H, J=8.1 Hz),
8.02 (d, 2H, J=8.1 Hz), 7.91 (brs, 1H), 2.64 (s, 3H). HRMS (EI)
Calcd. for C.sub.9H.sub.9N.sub.5O.sub.3S: 267.0426 (M.sup.+);
Found: 267.0425.
[0314] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-(1-H-tetrazol-5-yl)benzenesulfonamide
(Ex-4A), 55% yield, dark yellow solid, mp 185-186.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 8.29 (d, 2H, J=8.1 Hz),
8.27 (s, 1H), 8.07 (d, 1H, J=15.9 Hz), 8.03 (d, 2H, J=8.1 Hz), 7.88
(d, 1H, J=15.9 Hz), 7.66 (d, 1H, J=3.6 Hz), 7.52 (dd, 1H, J=5.4,
1.5 Hz), 7.13 (dd, 1H, J=5.4, 3.6 Hz), 6.85 (s, 1H), 4.02 (s, 3H),
4.00 (s, 3H). Anal. Calcd. for
C.sub.22H.sub.19N.sub.5O.sub.5S.sub.2.1/4EtOH: C, 53.09; H, 4.06;
N, 13.76; S, 12.60; Found: C, 53.39; H, 3.95; N, 13.51; S, 12.72.
HRMS (ESI) Calcd. for C.sub.22H.sub.19N.sub.5O.sub.5S.sub.2:
498.0906 (M+H).sup.+; Found: 498.0920.
Example 5
[0315] ##STR21##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyridin-2-ylbenzenesul-
fonamide
[0316] Ex-5A: 4-Acetyl-N-pyridin-2-ylbenzenesulfonamide was
prepared in an analogous fashion as Ex-1B using 2-aminopyridine,
77% yield, off-white solid, mp 198-199.degree. C. .sup.1H-NMR (300
MHz, DMSO-d.sub.6) .delta. 8.07 (d, 2H, J=8.1 Hz), 7.97 (d, 3H,
J=8.1 Hz), 7.75-7.80 (m, 1H), 7.22 (d, 1H, J=8.7 Hz), 6.86 (t, 1H,
J=6.9 Hz), 2.60 (s, 3H). HRMS (EI) Calcd. for
C.sub.13H.sub.12N.sub.2O.sub.3S: 276.0569 (M.sup.+); Found:
276.0563.
[0317] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A), 54%
yield, yellow solid, mp 141-143.degree. C. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) 8.26 (s, 1H), 8.24 (d, 2H, J=8.1 Hz), 8.06 (d, 1H,
J=15.6 Hz), 8.01 (d, 2H, J=8.1 Hz), 7.96-7.99 (m, 1H), 7.87 (d, 1H,
J=15.6 Hz), 7.75 (ddd, 1H, J=8.7, 6.7, 1.8 Hz), 7.66 (dd, 1H,
J=3.5, 1.5 Hz), 7.52 (d, 1H, J=5.4 Hz), 7.21 (d, 1H, J=8.7 Hz),
7.13 (dd, 1H, J=5.4, 3.5 Hz), 6.82-6.86 (m, 2H), 4.02 (s, 3H), 4.00
(s, 3H). Anal. Calcd. for
C.sub.26H.sub.22N.sub.2O.sub.5S.sub.2.1/2H.sub.2O: C, 60.78; H,
4.81; N, 5.35; S, 12.25; Found: C, 60.63; H, 4.55; N, 5.74; S,
12.32. HRMS (ESI) Calcd. for C.sub.26H.sub.22N.sub.2O.sub.5S.sub.2:
507.1048 (M+H).sup.+; Found: 507.1051.
Example 6
[0318] ##STR22##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(1H-pyrazol-3-yl)benze-
nesulfonamide
[0319] Ex-6A: 4-Acetyl-N-(1H-pyrazol-3-yl)benzenesulfonamide was
prepared in an analogous fashion as Ex-1B using 3-aminopyrazole
except that silica gel chromatography (ethyl acetate/hexanes, 1:1
to 3:1) was used, 15% yield, white solid. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) .delta. 10.60 (s, 1H), 8.09 (d, 2H, J=8.7 Hz), 7.90
(d, 2H, J=8.7 Hz), 7.56 (s, 1H), 5.98 (s, 1H), 2.61 (s, 3H). HRMS
(EI) Calcd. for C.sub.11H.sub.11N.sub.3O.sub.3S: 265.0521
(M.sup.+); Found: 265.0526.
[0320] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-(1H-pyrazol-3-yl)benzenesulfonamide (Ex-6A),
40% yield, yellow solid, mp 142-145.degree. C. .sup.1H-NMR (300
MHz, DMSO-d.sub.6) 10.60 (s, 1H), 8.25 (d, 3H, J=8.4 Hz), 8.08 (d,
1H, J=15.6 Hz), 7.93 (d, 2H, J=8.7 Hz), 7.87 (d, 1H, J=15.6 Hz),
7.67 (d, 1H, J=-3.6 Hz), 7.56 (d, 1H, J=2.1 Hz), 7.52 (d, 1H, J=5.4
Hz), 7.13 (dd, 1H, J=5.4, 3.6 Hz), 6.84 (s, 1H), 6.00 (d, 1H, J=1.8
Hz), 4.02 (s, 3H), 4.00 (s, 3H). HRMS (ESI) Calcd. for
C.sub.24H.sub.21N.sub.3O.sub.5S.sub.2: 496.1001 (M+H).sup.+; Found:
496.1022.
Example 7
[0321] ##STR23##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-isoxazol-3-ylbenzenesu-
lfonamide
[0322] Ex-7A: 4-Acetyl-N-isoxazol-3-ylbenzenesulfonamide was
prepared in an analogous fashion as Ex-1B using 3-aminoisoxazole,
71% yield, off-white solid, mp 165-166.degree. C. .sup.1H-NMR (300
MHz, DMSO-d.sub.6) .delta. 8.75 (d, 1H, J=1.5 Hz), 8.14 (d, 2H,
J=8.1 Hz), 8.00 (d, 2H, J=8.1 Hz), 6.45 (d, 1H, J=1.5 Hz), 2.62 (s,
3H). Anal. Calcd. for C.sub.11H.sub.10N.sub.2O.sub.4S: C, 49.62; H,
3.79; N, 10.52; S, 12.04. Found: C, 49.58; H, 3.63; N, 10.45; S,
12.14. HRMS (EI) Calcd. for C.sub.11H.sub.10N.sub.2O.sub.4S:
266.0361 (M.sup.+); Found: 266.0365.
[0323] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-isoxazol-3-ylbenzenesulfonamide (Ex-7A), 77%
yield, orange solid, mp 198-199.degree. C. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) 8.76 (d, 1H, J=2.7 Hz), 8.31 (d, 2H, J=8.1 Hz), 8.27
(s, 1H), 8.07 (d, 1H, J=15.6 Hz), 8.02 (d, 2H, J=8.1 Hz), 7.88 (d,
1H, J=15.6 Hz), 7.67 (d, 1H, J=3.6 Hz), 7.53 (d, 1H, J=5.4 Hz),
7.13 (dd, 1H, J=5.4, 3.6 Hz), 6.84 (s, 1H), 6.48 (d, 1H, J=2.7 Hz),
4.02 (s, 3H), 4.00 (s, 3H). Anal. Calcd. for
C.sub.24H.sub.20N.sub.2O.sub.6S.sub.2: C, 58.05; H, 4.06; N, 5.64;
S, 12.91; Found: C, 57.91; H, 4.16; N, 5.63; S, 12.71. HRMS (EI)
Calcd. for C.sub.24H.sub.20N.sub.2O.sub.6S.sub.2: 496.0763
(M.sup.+); Found: 496.0770.
Example 8
[0324] ##STR24##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-thiazol-2-ylbenzenesul-
fonamide
[0325] Ex-8A: 4-Acetyl-N-thiazol-2-ylbenzenesulfonamide was
prepared in an analogous fashion as Ex-1B using 2-aminothiazole,
68% yield, tan solid, mp 194-195.degree. C. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.08 (d, 2H, J=8.4 Hz), 7.92 (d, 2H, J=8.4
Hz), 7.29 (d, 1H, J=4.5 Hz), 6.87 (d, 1H, J=4.5 Hz), 2.60 (s, 3H).
HRMS (EI) Calcd. for C.sub.11H.sub.10N.sub.2O.sub.3S.sub.2:
282.0133 (M.sup.+); Found: 282.0131.
[0326] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-thiazol-2-ylbenzenesulfonamide (Ex-8A), 83%
yield, yellow solid, mp 220-221.degree. C. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) 8.24-8.26 (m, 3H), 8.06 (d, 1H, J=15.8 Hz), 7.95 (d,
2H, J=7.8 Hz), 7.88 (d, 1H, J=15.8 Hz), 7.66 (d, 1H, J=3.6 Hz),
7.52 (d, 1H, J=5.4 Hz), 7.29 (d, 1H, J=4.2 Hz), 7.13 (dd, 1H,
J=5.4, 3.6 Hz), 6.88 (d, 1H, J=4.5 Hz), 6.84 (s, 1H), 4.02 (s, 3H),
4.00 (s, 3H). HRMS (ESI) Calcd. for
C.sub.24H.sub.20N.sub.2O.sub.5S.sub.3: 513.0612 (M+H).sup.+; Found:
513.0633.
Example 9
[0327] ##STR25##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(3-methylisoxazol-5-yl-
benzenesulfonamide
[0328] Ex-9A: 4-Acetyl-N-(3-methylisoxazol-5-yl)benzenesulfonamide
was prepared in an analogous fashion as Ex-1B using
5-amino-3-methylisoxazole, 64% yield, tan solid, mp 144-145.degree.
C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 8.15 (d, 2H, J=8.7
Hz), 7.99 (d, 2H, J=8.7 Hz), 5.77 (s, 1H), 2.63 (s, 3H), 2.01 (s,
3H). HRMS (EI) Calcd. for C.sub.12H.sub.12N.sub.2O.sub.4S: 280.0518
(M.sup.+); Found: 280.0525.
[0329] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-(3-methylisoxazol-5-yl)benzenesulfonamide
(Ex-9A), 30% yield, orange solid, mp 138-140.degree. C. .sup.1H-NMR
(300 MHz, DMSO-d.sub.6) 8.28-8.34 (m, 3H), 8.08 (d, 1H, J=15.3 Hz),
8.02 (d, 2H, J=8.1 Hz), 7.90 (d, 1H, J=15.3 Hz), 7.66 (d, 1H,
J=-3.0 Hz), 7.51 (d, 1H, J=5.4 Hz), 7.13 (dd, 1H, J=5.4, 3.6 Hz),
6.85 (s, 1H), 5.80 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 2.11 (s,
3H). HRMS (ESI) Calcd. for C.sub.25H.sub.22N.sub.2O.sub.6S.sub.2:
510.0997 (M+H).sup.+; Found: 511.0991.
Example 10
[0330] ##STR26##
N-(5-Chloropyridin-2-yl)-4-[3E-(2,4-dimethoxy-5-thien-2-ylphenyl)acryloyl]-
benzenesulfonamide
[0331] Ex-10A: 4-Acetyl-N-(5-chloropyridin-2-yl)benzenesulfonamide
was prepared in an analogous fashion as Ex-1B using
2-amino-5-chloropyridine, 78% yield, tan solid, mp 181-182.degree.
C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 8.20 (d, 1H, J=3.3
Hz), 8.11 (d, 2H, J=8.4 Hz), 8.03 (d, 2H, J=8.4 Hz), 7.82 (dd, 1H,
J=9.0, 3.3 Hz), 7.09 (d, 1H, J=9.0 Hz), 2.62 (s, 3H). Anal. Calcd.
for C.sub.13H.sub.11ClN.sub.2O.sub.3S: C, 50.24; H, 3.57; Cl,
11.41; N, 9.01; S, 10.32. Found: C, 50.59; H, 3.62; Cl, 11.49; N,
9.34; S, 10.02. HRMS (ESI) Calcd. for
C.sub.13H.sub.11ClN.sub.2O.sub.3S: 311.0257 (M+H).sup.+; Found:
311.0264.
[0332] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-(5-chloropyridin-2-yl)benzenesulfonamide
(Ex-10A), 85% yield, orange solid, mp 228-229.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.27-8.30 (m, 3H), 8.22 (d, 1H,
J=2.4 Hz), 8.05-8.10 (m, 3H), 7.87 (d, 1H, J=16.0 Hz), 7.83 (dd,
1H, J=9.0, 2.4 Hz), 7.65 (d, 1H, J=3.6 Hz), 7.53 (d, 1H, J=5.4 Hz),
7.10-7.15 (m, 2H), 6.84 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H). Anal.
Calcd. for C.sub.26H.sub.21ClN.sub.2O.sub.5S.sub.2.1/6H.sub.2O: C,
57.40; H, 3.95; Cl, 6.52; N, 5.15; S, 11.79. Found: C, 57.18; H,
4.05; Cl, 6.25; N, 5.51; S, 11.60. HRMS (ESI) Calcd. for
C.sub.26H.sub.21ClN.sub.2O.sub.5S.sub.2: 541.0658 (M+H).sup.+;
Found: 541.0642.
Example 11
[0333] ##STR27##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-fluoropyridin-2-yl)-
benzenesulfonamide
[0334] Ex-11A: 4-Acetyl-N-(5-fluoropyridin-2-yl)benzenesulfonamide
was prepared in an analogous fashion as Ex-1B using
2-amino-5-fluoropyridine, 91% yield, light red solid, mp
151-152.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 8.17
(d, 1H, J=3.0 Hz), 8.11 (d, 2H, J=8.4 Hz), 8.02 (d, 2H, J=8.4 Hz),
7.82 (dt, 1H, J=9.1, 3.3 Hz), 7.09 (dd, 1H, J=9.1, 3.3 Hz), 2.61
(s, 3H). HRMS (ESI) Calcd. for C.sub.13H.sub.11FN.sub.2O.sub.3S:
295.0552 (M+H).sup.+; Found: 295.0563.
[0335] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-(5-fluoropyridin-2-yl)benzenesulfonamide
(Ex-11A), 81% yield, an orange solid, mp 194-195.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.29-8.31 (m, 3H), 8.18 (d, 1H,
J=2.1 Hz), 8.03-8.10 (m, 3H), 7.87 (d, 1H, J=15.6 Hz), 7.66-7.72
(m, 2H), 7.52 (d, 1H, J=3.0 Hz), 7.12-7.17 (m, 2H), 6.84 (s, 1H),
4.02 (s, 3H), 4.00 (s, 3H). Anal. Calcd. for
C.sub.26H.sub.21FN.sub.2O.sub.5S.sub.2.1/5H.sub.2O: C, 59.12; H,
4.08; F, 3.60; N, 5.30; S, 12.14. Found: C, 59.07; H, 4.07; F,
3.55; N, 5.53; S, 12.17. HRMS (ESI) Calcd. for
C.sub.26H.sub.21FN.sub.2O.sub.5S.sub.2: 525.0954 (M+H).sup.+;
Found: 525.0967.
Example 12
[0336] ##STR28##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-trifluoromethylpyri-
din-2-yl)benzenesulfonamide
[0337] Ex-12A:
4-Acetyl-N-(5-trifluoromethylpyridin-2-yl)benzenesulfonamide was
prepared in an analogous fashion as Ex-1B using
2-amino-5-(trifluoromethyl)pyridine, 75% yield, off-white solid, mp
179-180.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 8.52
(brs, 1H), 8.06-8.14 (m, 5H), 7.23 (d, 1H, J=9.0 Hz), 2.61 (s, 3H).
HRMS (ESI) Calcd. for C.sub.14H.sub.11F.sub.3N.sub.2O.sub.3S:
345.0520 (M+H).sup.+; Found: 345.0531.
[0338] The title compound was prepared in an analogous fashion as
Ex-1 using
4-acetyl-N-(5-trifluoromethylpyridin-2-yl)benzenesulfonamide
(Ex-12A), 85% yield, orange solid, mp 228-229.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.54 (brs, 1H), 8.29 (d, 2H,
J=8.4 Hz), 8.26 (s, 1H), 8.05-8.13 (m, 4H), 7.88 (d, 1H, J=15.9
Hz), 7.65 (d, 1H, J=3.6 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.24 (d, 1H,
J=8.7 Hz), 7.13 (dd, 1H, J=5.1, 3.6 Hz), 6.84 (s, 1H), 4.02 (s,
3H), 4.00 (s, 3H). Anal. Calcd. for
C.sub.27H.sub.21F.sub.3N.sub.2O.sub.5S.sub.2.1/4H.sub.2O: C, 56.00;
H, 3.74; F, 9.84; N, 4.84; S, 11.07. Found: C, 55.90; H, 3.90; F,
9.81; N, 5.09; S, 11.08. HRMS (ESI) Calcd. for
C.sub.27H.sub.21F.sub.3N.sub.2O.sub.5S.sub.2: 575.0922 (M+H).sup.+;
Found: 575.0925.
Example 13
[0339] ##STR29##
4-{3E-[2-(3-Hydroxy-2-hydroxymethylpropoxy)-4-methoxy-5-thien-2-ylphenyl]a-
cryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide
[0340] Ex-13A: To a solution of
3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)pr-
opan-1-ol (25.0 g, 74.3 mmol) and triethylamine (22.6 g, 223 mmol)
in dichloromethane (150 mL) at 0.degree. C. was added
methanesulfonyl chloride (12.8 g, 111 mmol) and the resulting
slurry was stirred at 0.degree. C. for 15 min and allowed to warm
to room temperature. The solution was stirred for an additional 3 h
at room temperature and diluted with water (130 mL) and ethyl
acetate (350 mL). The layers were separated and the aqueous was
extracted with ethyl acetate (150 mL). The combined organic
extracts were washed with a saturated sodium bicarbonate (200 mL),
a 50% sodium chloride solution (2.times.200 mL), dried over sodium
sulfate and concentrated to afford 29.5 g (97%) of methanesulfonic
acid
3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymeth-
yl)propyl ester as a yellow oil. .sup.1H-NMR (300 MHz, CDCl.sub.3)
.delta. 4.29 (d, 2H, J=5.7 Hz), 3.61-3.68 (m, 4H), 2.99 (s, 3H),
2.04-2.11 (m, 1H), 0.88 (s, 18H), 0.049 (s, 12H). HRMS (ESI) Calcd.
for C.sub.17H.sub.40O.sub.5SSi.sub.2: 413.2213 (M+H).sup.+; Found:
413.2226.
[0341] Ex-13B: 2-Hydroxy-4-methoxybenzaldehyde (6.0 g, 39 mmol) was
dissolved in dichloromethane (50 mL) and cooled to 0.degree. C.
using an ice-water bath. Bromine (6.8 g, 43 mmol) in
dichloromethane (2 mL) was added dropwise to the cooled solution
and stirred for 2 h at 0.degree. C. The mixture was warmed to room
temperature and stirred for an additional 1 h and the resulting
yellow precipitate was collected. Recrystallization (ethyl
acetate/hexanes) yielded 7.1 g (80%) of
5-bromo-2-hydroxy-4-methoxybenzaldehyde as white needles, mp
63-64.degree. C. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 11.43
(s, 1H), 9.69 (s, 1H), 7.68 (s, 1H), 6.48 (s, 1H), 3.95 (s, 3H).
Anal. Calcd. for C.sub.8H.sub.7BrO.sub.3: C, 41.59; H, 3.05; Found:
C, 41.86; H, 3.05.
[0342] Ex-13C: 5-Bromo-2-hydroxy-4-methoxybenzaldehyde (Ex-13B, 1.5
g, 6.5 mmol) and thiophene-2-boronic acid (0.91 g, 7.1 mmol) were
dissolved in tetrahydrofuran (15 mL). Nitrogen was bubbled into the
solution for 10 min followed by the sequential addition of
potassium fluoride (0.80 g, 14 mmol, spray-dried) and
bis(tri-t-butylphosphine)palladium (0) (0.033 g, 0.065 mmol). The
solution was immediately heated to 60.degree. C. and aged for 1.5
h. Upon completion, as determined by HPLC, the reaction was diluted
with water (25 mL) and extracted with ethyl acetate (3.times.30
mL). The combined organic extracts were dried over sodium sulfate
and concentrated to a brown solid. Silica gel chromatography (ethyl
acetate/hexanes, 1:3) gave 1.46 g (97%) of
2-hydroxy-4-methoxy-5-thien-2-ylbenzaldehyde as a yellow solid, mp
118-119.degree. C. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 11.48
(s, 1H), 9.79 (s, 1H), 7.72 (s, 1H), 7.37 (d, 1H, J=3.6 Hz), 7.31
(dd, 1H, J=5.1, 1.5 Hz), 7.08 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s,
1H), 3.98 (s, 3H). MS (ESI) m/z 235 ([M+H].sup.+, 100%). Anal.
Calcd. for C.sub.8H.sub.7O.sub.3S: C, 61.52; H, 4.30; S, 13.69;
Found: C, 61.12; H, 4.34; S, 13.56.
[0343] Ex-13D: To a solution of
2-hydroxy-4-methoxy-5-thien-2-ylbenzaldehyde (Ex-13C, 0.10 g, 0.43
mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate
(0.18 g, 1.3 mmol) and the resulting yellow slurry was heated to
80.degree. C. Methanesulfonic acid
3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)pr-
opyl ester (Ex-13A, 0.24 g, 1.3 mmol) was then added dropwise in
three equal portions with stirring at 1 h intervals. After the last
addition, the reaction was stirred for an additional 1 h at
80.degree. C. and cooled to room temperature. The mixture was
diluted with water (15 mL) and extracted with ethyl acetate
(3.times.15 mL). The combined organic phase was sequentially washed
with a saturated ammonium chloride solution (15 mL), water (15 mL),
and brine (15 mL), dried over sodium sulfate, and concentrated to a
brown oil. Silica gel chromatography (ethyl acetate/hexanes, 1:6)
gave 0.78 g (90%) of
2-[3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl-
)propoxy]-4-methoxy-5-thien-2-ylbenzaldehyde as a pale green solid,
mp 91-92.degree. C. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 10.34
(s, 1H), 8.13 (s, 1H), 7.41 (dd, 1H, J=3.6, 1.2 Hz), 7.28 (dd, 1H,
J=5.1, 1.2 Hz), 7.05 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 4.22
(d, 2H, J=5.7 Hz), 3.96 (s, 3H), 3.80 (d, 4H, J=5.7 Hz), 2.33
(pentet, 1H, J=5.7 Hz), 0.88 (s, 18H), 0.012 (s, 12H). HRMS (EI)
Calcd. for C.sub.28H.sub.46O.sub.5SSi.sub.2: 550.2604 (M+); Found:
550.2593.
[0344] Ex-13E: To a solution of
2-[3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl-
)propoxy]-4-methoxy-5-thien-2-ylbenzaldehyde (Ex-13D, 0.78 g, 1.41
mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium
fluoride (1 M in tetrahydrofuran, 3.0 mL, 2.9 mmol) and the mixture
was stirred at room temperature for 30 min. The reaction was
diluted with ethyl acetate (50 mL) and washed sequentially with a
50% ammonium chloride solution (30 mL), water (2.times.30 mL),
brine (30 mL), dried over sodium sulfate and concentrated to a
crude yellow solid. Silica gel chromatography afforded 0.37 g (99%)
of
2-(3-hydroxy-2-hydroxymethylpropoxy)-4-methoxy-5-thien-2-ylbenzaldehyde
as a pale yellow solid, mp 144-145.degree. C. .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta. 10.33 (s, 1H), 8.10 (s, 1H), 7.38 (dd, 1H,
J=3.6, 1.5 Hz), 7.30 (dd, 1H, J=5.1, 1.5 Hz), 7.07 (dd, 1H, J=5.1,
3.6 Hz), 6.59 (s, 1H), 4.35 (d, 2H, J=6.0 Hz), 4.02 (t, 4H, J=4.8
Hz), 3.96 (s, 3H), 2.33 (pentet, 1H, J=6.0 Hz), 1.89 (t, 2H, J=4.8
Hz). Anal. Calcd. for C.sub.16H.sub.18O.sub.5S: C, 59.61; H, 5.63;
S, 9.95; Found: C, 59.34; H, 5.75; S, 9.82.
[0345] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide
(Ex-13E), 57% yield, orange solid, mp 165-166.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.29 (d, 2H, J=8.7 Hz), 8.25
(s, 1H), 8.08 (d, 1H, J=15.9 Hz), 8.02 (d, 2H, J=8.7 Hz), 7.90 (d,
1H, J=15.9 Hz), 7.65 (d, 1H, J=3.6 Hz), 7.52 (d, 1H, J=5.1 Hz),
7.13 (dd, 1H, J=5.1, 3.6 Hz), 6.87 (s, 1H), 6.18 (s, 1H), 4.67
(brs, 2H), 4.23 (d, 2H, J=5.7 Hz), 4.01 (s, 3H), 3.57-3.59 (m, 4H),
2.31 (s, 3H), 2.11 (pentet, 1H, J=5.7 Hz). Anal. Calcd. for
C.sub.28H.sub.28N.sub.2O.sub.8S.sub.2: C, 57.52; H, 4.83; N, 4.79;
S, 10.97. Found: C, 57.58; H, 4.77; N, 4.67; S, 11.01. HRMS (ESI)
Calcd. for C.sub.28H.sub.28N.sub.2O.sub.8S.sub.2: 585.1365
(M+H).sup.+; Found: 585.1367.
Example 14
[0346] ##STR30##
4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thien-2-ylphenyl]acryloyl}--
N-(5-methyl-isoxazol-3-yl)benzenesulfonamide hydrochloride
[0347] Ex-14A:
4-Methoxy-2-(2-morpholin-4-ylethoxy)-5-thien-2-ylbenzaldehyde was
prepared in an analogous fashion as Ex-13D using
4-(2-chloroethyl)morpholine hydrochloride, 93% yield after silica
gel chromatography (80 to 100% ethyl acetate/hexanes then 5%
methanol/methylene chloride), off-white solid, mp 130-131.degree.
C. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 10.36 (s, 1H), 8.12
(s, 1H), 7.44 (dd, 1H, J=3.6, 1.5 Hz), 7.30 (dd, 1H, J=5.1, 1.5
Hz), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 6.53 (s, 1H), 4.27 (t, 2H, J=6.3
Hz), 4.00 (s, 3H), 3.72-3.76 (m, 4H), 2.89 (t, 2H, J=6.3 Hz),
2.60-2.63 (m, 4H). HRMS (EI) Calcd. for C.sub.18H.sub.21NO.sub.4S:
347.1191 (M.sup.+); Found: 347.1188.
[0348] 4-Acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide
(Ex-1B, 0.30 g, 0.86 mmol) and
4-methoxy-2-(2-morpholin-4-ylethoxy)-5-thien-2-ylbenzaldehyde
(Ex-14A, 0.24 g, 0.86 mmol) were dissolved in a
dimethylformamide-methanol solution (6.0 mL, 7:3). After complete
dissolution, lithium methoxide (0.13 g, 3.4 mmol) was added and the
resulting orange slurry was stirred in the dark at room temperature
for 1 h. Upon completion, as determined by HPLC, the mixture was
diluted with water (8.0 mL), acidified with a 1 N hydrochloric acid
solution, and extracted with ethyl acetate:tetrahydrofuran (1:1,
3.times.20 mL). The combined organic extracts were evaporated to
dryness. The crude oil was taken up in ethanol (10 mL) and warmed
to 60.degree. C. to obtain complete dissolution and allowed to cool
to room temperature. The resulting precipitate was collected on
filter paper and dried in vacuo to yield 0.46 g (88%) of the title
compound as a pale orange solid, mp>260.degree. C. .sup.1H-NMR
(300 MHz, DMSO-d.sub.6) 8.34 (d, 2H, J=9.0 Hz), 8.32 (s, 1H), 8.12
(d, 1H, J=15.9 Hz), 8.03 (d, 2H, J=9.0 Hz), 7.93 (d, 1H, J=15.9
Hz), 7.69 (d, 1H, J=3.3 Hz), 7.56 (d, 1H, J=5.4 Hz), 7.15 (dd, 1H,
J=5.4, 3.3 Hz), 6.92 (s, 1H), 6.18 (s, 1H), 4.65 (brs, 2H), 4.03
(s, 3H), 3.97 (brs, 4H), 3.69 (brs, 2H), 3.50-3.23 (brs, 4H), 2.31
(s, 3H). Anal. Calcd. for
C.sub.30H.sub.32ClN.sub.3O.sub.7S.sub.2.H.sub.2O: C, 54.25; H,
5.16; N, 6.33; S, 9.66; Found: C, 54.10; H, 4.91; N, 6.39; S, 9.68.
HRMS (ESI) Calcd. for C.sub.30H.sub.32ClN.sub.3O.sub.7S.sub.2:
610.1681 (--HCl) (M+H).sup.+. Found: 610.1673.
Example 15
[0349] ##STR31##
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(5-methy-
lisoxazol-3-yl)benzenesulfonamide
[0350] Ex-15A: 1-Methylindole (5.0 g, 38.1 mmol) was dissolved in
tetrahydrofuran (190 mL) and nitrogen was bubbled into the solution
for 15 min. The solution was then cooled to 0.degree. C. and
tert-butyllithium (1.6 M solution in pentane, 23.5 mL, 40.0 mmol)
was added dropwise and the mixture was stirred for 30 min at
0.degree. C. and then warmed to room temperature and stirred for an
additional 1 h. Triethylborane (1.0 M solution in THF, 45.7 mL,
45.7 mmol) was added, and the reaction mixture was stirred for 1 h
at room temperature. To the crude indolylborate, generated in situ,
was added 5-bromo-2,4-dimethoxybenzaldehyde (9.3 g, 38.1 mmol) and
bis(tri-t-butylphosphine)palladium (0) (0.48 g, 0.95 mmol). The
solution was immediately heated to 60.degree. C. and aged for 30
min. Upon completion, as determined by HPLC, the reaction was
treated with 10% aqueous sodium hydroxide (190 mL) and 30% hydrogen
peroxide (38 mL) with ice-cooling for 20 min. The mixture was
extracted with ethyl acetate (3.times.100 mL), and the combined
organic extracts were washed with brine (2.times.75 mL), dried over
sodium sulfate and concentrated to a brown oil. Silica gel
chromatography (ethyl acetate/hexanes, 1:3 to 3:1) gave 7.69 g
(77%) of 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde as a
yellow solid, mp 153-153.degree. C. .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta. 10.36 (s, 1H), 7.87 (s, 1H), 7.37 (d, 1H, J=7.5
Hz), 7.31 (d, 1H, J=9.0 Hz), 7.20-7.28 (m, 1H), 7.12 (t, 1H, J=6.8
Hz), 6.55 (s, 1H), 6.48 (s, 1H), 4.03 (s, 3H), 3.91 (s, 3H), 3.55
(s, 3H). Anal. Calcd. for C.sub.18H.sub.17NO.sub.3: C, 73.20; H,
5.80; N, 4.74; Found: C, 72.98; H, 5.89; N, 4.73.
[0351] The title compound was prepared in an analogous fashion as
Ex-1 using 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde
(Ex-15A), 66% yield, pale orange solid, mp 220.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.29 (d, 2H, J=8.7 Hz), 8.12
(d, 1H, J=15.8 Hz), 8.04 (s, 1H), 7.96 (d, 2H, J=8.7 Hz), 7.84 (d,
1H, J=15.8 Hz), 7.55 (d, 1H, J=7.5 Hz), 7.46 (d, 1H, J=8.1 Hz),
7.17 (t, 1H, J=7.5 Hz), 7.06 (t, 1H, J=7.8 Hz), 6.89 (s, 1H), 6.45
(s, 1H), 6.15 (s, 1H), 4.05 (s, 3H), 3.91 (s, 3H), 3.54 (s, 3H),
2.28 (s, 3H). Anal. Calcd. for C.sub.30H.sub.27N.sub.3O.sub.6S: C,
64.62; H, 4.88; N, 7.54; S, 5.75. Found: C, 64.42; H, 5.26; N,
7.46; S, 5.61. HRMS (ESI) Calcd. for
C.sub.30H.sub.27N.sub.3O.sub.6S: 558.1699 (M+H).sup.+; Found:
558.1685.
Example 16
[0352] ##STR32##
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(5-methy-
lisoxazol-3-yl)benzenesulfonamide sodium salt
[0353] The title compound was prepared in an analogous fashion as
Ex-2 from
4-{3-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(5--
methylisoxazol-3-yl)benzenesulfonamide (Ex-15) as a yellow solid,
mp 202-206.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.03-8.10
(m, 4H), 7.88 (d, 1H, J=15.9 Hz), 7.75 (d, 2H, J=8.1 Hz), 7.55 (d,
1H, J=7.5 Hz), 7.46 (d, 1H, J=8.4 Hz), 7.17 (t, 1H, J=7.5 Hz), 7.06
(t, 1H, J=7.8 Hz), 6.88 (s, 1H), 6.46 (s, 1H), 5.77 (s, 1H), 4.04
(s, 3H), 3.91 (s, 3H), 3.54 (s, 3H), 2.09 (s, 3H). Anal. Calcd. for
C.sub.30H.sub.26N.sub.3NaO.sub.6S.H.sub.2O.1/3EtOH: C, 60.09; H,
4.93; N, 6.86; S, 5.23; Found: C, 59.86; H, 4.89; N, 6.80; S,
5.14.
Example 17
[0354] ##STR33##
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-pyridin--
3-ylmethyl-benzenesulfonamide
[0355] Ex-17A: To a solution of 4-acetylbenzenesulfonyl chloride
(0.50 g, 2.3 mmol) in tetrahydrofuran (10 mL) was added
3-(aminomethyl)pyridine (0.58 g, 5.7 mmol) and the reaction was
stirred for 30 min at room temperature. The mixture was then
diluted with water (30 mL) and extracted with ethyl acetate
(3.times.20 mL). The combined organic layers were washed with brine
(2.times.25 mL), dried over sodium sulfate, and the solvent was
removed under reduced pressure. The resulting solid was dried in
vacuo to afford 0.67 g (99%) of
4-acetyl-N-pyridin-3-ylmethylbenzenesulfonamide as a white solid,
mp 143-144.degree. C. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.
8.50-8.52 (m, 1H), 8.41 (d, 1H, J=2.7 Hz), 8.06 (d, 2H, J=8.7 Hz),
7.95 (d, 2H, J=8.4 Hz), 7.6-7.63 (m, 1H), 7.21-7.25 (m, 1H), 5.05
(brs, 1H), 4.22 (d, 2H, J=5.7 Hz), 2.66 (s, 3H). HRMS (EI) Calcd.
for C.sub.14H.sub.14N.sub.2O.sub.3S: 290.0725 (M.sup.+); Found:
290.0726.
[0356] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide
(Ex-17A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde
(Ex-15A), 80% yield, yellow solid, mp 202-203.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.39-8.43 (m, 3H), 8.26 (d, 2H,
J=8.0 Hz), 8.13 (d, 1H, J=15.9 Hz), 8.06 (s, 1H), 7.89 (d, 2H,
J=8.0 Hz), 7.85 (d, 1H, J=15.9 Hz), 7.60-7.63 (m, 1H), 7.56 (d, 1H,
J=6.9 Hz), 7.46 (d, 1H, J=8.1 Hz), 7.27 (dd, 1H, J=7.2, 4.2 Hz),
7.17 (t, 1H, J=7.2 Hz), 7.06 (t, 1H, J=8.1 Hz), 6.90 (s, 1H), 6.46
(s, 1H), 4.07 (s, 2H), 4.06 (s, 3H), 3.93 (s, 3H), 3.55 (s, 3H).
Anal. Calcd. for C.sub.32H.sub.29N.sub.3O.sub.5S.1/4H.sub.2O: C,
67.17; H, 5.20; N, 7.34; S, 5.60; Found: C, 67.39; H, 5.41; N,
7.38; S, 5.54. HRMS (ESI) Calcd. for
C.sub.32H.sub.29N.sub.3O.sub.5S: 568.1906 (M+H).sup.+; Found:
568.1895.
Example 18
[0357] ##STR34##
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(2-morph-
olin-4-yl-ethyl)benzenesulfonamide
[0358] Ex-18A: 4-Acetyl-N-(2-morpholin-4-ylethyl)benzenesulfonamide
was prepared in an analogous fashion as Ex-17A using
4-(2-aminoethyl)morpholine, 99% yield, off-white solid, mp
128-129.degree. C. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.08
(d, 2H, J=8.7 Hz), 7.98 (d, 2H, J=8.7 Hz), 5.28 (brs, 1H),
3.61-3.64 (m, 4H), 3.05 (t, 2H, J=5.4 Hz), 2.66 (s, 3H), 2.42 (t,
2H, J=5.7 Hz), 2.27-2.31 (m, 4H). HRMS (ESI) Calcd. for
C.sub.14H.sub.20N.sub.2O.sub.4S: 313.1222 (M+H).sup.+; Found:
313.1215.
[0359] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide
(Ex-18A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde
(Ex-15A), 80% yield, yellow solid, mp 167-168.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.29 (d, 2H, J=8.7 Hz), 8.14
(d, 1H, J=15.3 Hz), 8.06 (s, 1H), 7.93 (d, 2H, J=8.7 Hz), 7.86 (d,
1H, J=15.3 Hz), 7.77 (brs, 1H), 7.56 (d, 1H, J=7.2 Hz), 7.46 (d,
1H, J=8.1 Hz), 7.18 (t, 1H, J=7.8 Hz), 7.06 (t, 1H, J=7.2 Hz), 6.90
(s, 1H), 6.46 (s, 1H), 4.06 (s, 3H), 3.93 (s, 3H), 3.55 (s, 3H),
3.42-3.48 (m, 4H), 2.89 (t, 2H, J=7.5 Hz), 2.22-2.31 (m, 6H). Anal.
Calcd. for C.sub.32H.sub.35N.sub.3O.sub.6S: C, 65.18; H, 5.98; N,
7.13; S, 5.44; Found: C, 65.05; H, 6.11; N, 7.09; S, 5.42. HRMS
(ESI) Calcd. for C.sub.32H.sub.35N.sub.3O.sub.6S: 590.2325
(M+H).sup.+; Found: 590.2334.
Example 19
[0360] ##STR35##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyridin-3-ylmethylbenz-
enesulfonamide
[0361] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-pyridin-3-ylmethylbenzenesulfonamide
(Ex-17A), 85% yield, yellow solid, mp 167-168.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.47 (brs, 1H), 8.40-8.43 (m,
2H), 8.27 (d, 3H, J=8.4 Hz), 8.10 (d, 1H, J=15.6 Hz), 7.94 (d, 2H,
J=8.4 Hz), 7.90 (d, 1H, J=15.6 Hz), 7.62-7.68 (m, 2H), 7.53 (d, 1H,
J=5.4 Hz), 7.29 (dd, 1H, J=7.5, 4.8 Hz), 7.14 (dd, 1H, J=5.4, 3.6
Hz), 6.85 (s, 1H), 4.10 (s, 2H), 4.02 (s, 3H), 4.01 (s, 3H). Anal.
Calcd. for C.sub.27H.sub.24N.sub.2O.sub.5S.sub.2: C, 62.29; H,
4.65; N, 5.38; S, 12.32; Found: C, 62.03; H, 4.87; N, 5.39; S,
12.10.
Example 20
[0362] ##STR36##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2-morpholin-4-yl-ethy-
l)benzenesulfonamide
[0363] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-(2-morpholin-4-ylethyl)benzenesulfonamide
(Ex-18A), 90% yield, yellow solid, mp 171-172.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.31 (d, 2H, J=9.0 Hz), 8.28
(s, 1H), 8.09 (d, 1H, J=15.6 Hz), 7.97 (d, 2H, J=9.0 Hz), 7.91 (d,
1H, J=15.6 Hz), 7.80 (brs, 1H), 7.67 (d, 1H, J=3.6 Hz), 7.53 (d,
1H, J=5.4 Hz), 7.13 (dd, 1H, J=5.4, 3.6 Hz), 6.85 (s, 1H), 4.02 (s,
3H), 4.01 (s, 3H), 3.47-3.50 (m, 4H), 2.91 (t, 2H, J=7.2 Hz),
2.24-2.33 (m, 6H). Anal. Calcd. for
C.sub.27H.sub.30N.sub.2O.sub.6S.sub.2: C, 59.76; H, 5.57; N, 5.16;
S, 11.82; Found: C, 59.39; H, 5.65; N, 5.11; S, 11.53.
Example 21
[0364] ##STR37##
3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)-1-[4-(4-methylpiperazine-1-sulfonyl)-
phenyl]propenone
[0365] Ex-21A: 1-[4-(4-Methylpiperazine-1-sulfonyl)phenyl]ethanone
was prepared in an analogous fashion as Ex-17A using
4-methylpiperazine, 99% yield, pale yellow solid, mp
118-119.degree. C. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.09
(d, 2H, J=9.3 Hz), 7.85 (d, 2H, J=9.3 Hz), 3.67 (t, 4H, J=4.8 Hz),
2.66 (s, 3H), 2.48 (t, 4H, J=4.8 Hz), 2.27 (s, 3H). HRMS (EI)
Calcd. for C.sub.13H.sub.18N.sub.2O.sub.3S: 282.1038 (M.sup.+);
Found: 282.1038.
[0366] The title compound was prepared in an analogous fashion as
Ex-1 using 1-[4-(4-methylpiperazine-1-sulfonyl)phenyl]ethanone
(Ex-21A), 30% yield after silica gel chromatography
(methanol/methylene chloride, 1:10), dark yellow solid, mp
133-135.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.31 (d, 2H,
J=8.7 Hz), 8.25 (s, 1H), 8.06 (d, 1H, J=15.0 Hz), 7.89 (d, 2H,
J=8.7 Hz), 7.82 (d, 1H, J=15.0 Hz), 7.63 (d, 1H, J=3.9 Hz), 7.48
(d, 1H, J=5.4 Hz), 7.09 (dd, 1H, J=5.4, 3.9 Hz), 6.81 (s, 1H), 4.00
(s, 3H), 3.98 (s, 3H), 3.90 (brs, 4H), 2.32-2.34 (m, 4H), 2.07 (s,
3H). HRMS (EI) Calcd. for C.sub.26H.sub.28N.sub.2O.sub.5S.sub.2:
512.1440 (M.sup.+); Found: 512.1427.
Example 22
[0367] ##STR38##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-piperidin-1-ylbenzenes-
ulfonamide
[0368] Ex-22A: 4-Acetyl-N-piperidin-1-ylbenzenesulfonamide was
prepared in an analogous fashion as Ex-17A using 1-aminopiperidine,
98% yield, pale yellow solid, mp 137-139.degree. C. .sup.1H-NMR
(300 MHz, CDCl.sub.3) .delta. 8.07 (s, 4H), 5.38 (brs, 1H), 2.67
(s, 3H), 2.54 (t, 4H, J=5.4 Hz), 1.47-1.55 (m, 4H), 1.30-1.33 (m,
2H). Anal. Calcd. for C.sub.13H.sub.18N.sub.2O.sub.3S: C, 55.30; H,
6.43; N, 9.92; S, 11.36; Found: C, 55.22; H, 6.40; N, 9.50; S,
11.38.
[0369] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-piperidin-1-ylbenzenesulfonamide (Ex-22A),
71% yield, orange solid, mp 174-176.degree. C. .sup.1H-NMR (300
MHz, DMSO-d.sub.6) 8.94 (s, 1H), 8.32 (d, 2H, J=8.7 Hz), 8.29 (s,
1H), 8.10 (d, 1H, J=15.0 Hz), 8.00 (d, 2H, J=8.7 Hz), 7.93 (d, 1H,
J=15.0 Hz), 7.67 (dd, 1H, J=3.6, 1.5 Hz), 7.53 (dd, 1H, J=5.4, 1.5
Hz), 7.14 (dd, 1H, J=5.4, 3.6 Hz), 6.85 (s, 1H), 4.02 (s, 3H), 4.01
(s, 3H), 2.44-2.47 (m, 4H), 1.38 (brs, 4H), 1.21-1.23 (m, 2H).
Anal. Calcd. for C.sub.26H.sub.28N.sub.2O.sub.5S.sub.2: C, 60.92;
H, 5.51; N, 5.46; S, 12.51; Found: C, 61.13; H, 5.71; N, 5.38; S,
12.35.
Example 23
[0370] ##STR39##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(3-imidazol-1-ylpropyl-
)benzenesulfonamide
[0371] Ex-23A: 4-Acetyl-N-(3-imidazol-1-ylpropyl)benzenesulfonamide
was prepared in an analogous fashion as Ex-17A using
1-(3-aminopropyl)imidazole, 89% yield, white solid, mp
142-144.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 8.14
(d, 2H, J=8.1 Hz), 7.89 (d, 2H, J=8.1 Hz), 7.54 (s, 1H), 7.09 (s,
1H), 6.85 (s, 1H), 3.96 (t, 2H, J=7.2 Hz), 3.31 (s, 3H), 2.70 (t,
2H, J=7.8 Hz), 1.80 (pentet, 2H, J=7.8 Hz). HRMS (EI) Calcd. for
C.sub.14H.sub.17N.sub.3O.sub.3S: 307.0991 (M.sup.+); Found:
307.0986.
[0372] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-(3-imidazol-1-ylpropyl)benzenesulfonamide
(Ex-23A), 70% yield, yellow solid, mp 160-162.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.31 (d, 2H, J=8.7 Hz), 8.29
(s, 1H), 8.10 (d, 1H, J=15.9 Hz), 7.93 (d, 3H, J=8.7 Hz), 7.91 (d,
1H, J=15.9 Hz), 7.67 (dd, 1H, J=3.6, 1.5 Hz), 7.55 (s, 1H), 7.54
(d, 1H, J=5.4 Hz), 7.13 (dd, 1H, J=5.4, 3.6 Hz), 7.10 (s, 1H), 6.85
(s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.97 (t, 2H, J=6.3 Hz),
2.70-2.76 (m, 2H), 1.81 (pentet, 2H, J=6.3 Hz). Anal. Calcd. for
C.sub.27H.sub.27N.sub.3O.sub.5S.sub.2: C, 60.32; H, 5.06; N, 7.82;
S, 11.93; Found: C, 59.76; H, 5.06; N, 7.60; S, 12.00.
Example 24
[0373] ##STR40##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2,2,2-trifluoroethyl)-
benzenesulfonamide
[0374] Ex-24A: 4-Acetyl-N-(2,2,2-trifluoroethyl)benzenesulfonamide
was prepared in an analogous fashion as Ex-17A using
2,2,2-trifluoroethylamine hydrochloride and triethylamine in a
tetrahydrofuran:water mixture (9:1), 73% yield, white solid, mp
180-181.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 8.85
(brs, 1H), 8.14 (d, 2H, J=8.1 Hz), 7.96 (d, 2H, J=8.1 Hz), 7.75 (q,
2H, J=10.0 Hz), 6.64 (s, 3H). HRMS (EI) Calcd. for
C.sub.10H.sub.10F.sub.3NO.sub.3S: 281.0333 (M.sup.+); Found:
281.0342.
[0375] The title compound was prepared in an analogous fashion as
Ex-1 using 4-acetyl-N-(2,2,2-trifluoroethyl)benzenesulfonamide
(Ex-24A), 43% yield, yellow solid, mp 167-168.degree. C.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) 8.87 (s, 1H), 8.31 (d, 2H,
J=5.6 Hz), 8.29 (s, 1H), 8.10 (d, 1H, J=10.4 Hz), 8.00 (d, 2H,
J=5.6 Hz), 7.92 (d, 1H, J=10.4 Hz), 7.67 (d, 1H, J=2.8 Hz), 7.53
(d, 1H, J=3.6 Hz), 7.14 (dd, 1H, J=3.6, 2.8 Hz), 6.85 (s, 1H), 4.02
(s, 3H), 4.01 (s, 3H), 3.78 (q, 2H, J=6.8 Hz). HRMS (ESI) Calcd.
for C.sub.23H.sub.20F.sub.3NO.sub.5S.sub.2: 512.0813 (M+H).sup.+;
Found: 512.0798.
Example 25
[0376] ##STR41##
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2,2,2-trifluoroethyl)-
benzenesulfonamide sodium salt
[0377] The title compound was prepared in an analogous fashion as
Ex-2, from
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2,2,2-trifluoro-
ethyl)benzenesulfonamide (Ex-24, 45% yield, yellow solid, mp
160-170.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.27 (s,
1H), 8.10 (d, 2H, J=8.1 Hz), 8.05 (d, 1H, J=15.7 Hz), 7.90 (d, 1H,
J=15.7 Hz), 7.71 (d, 3H, J=8.1 Hz), 7.52 (d, 1H, J=5.4 Hz), 7.13
(dd, 1H, J=3.3, 5.4 Hz), 6.84 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H),
3.28 (q, 2H, J=10.5 Hz). Anal. Calcd. for
C.sub.23H.sub.19F.sub.3NNaO.sub.5S.sub.2.2/3H.sub.2O.1/3EtOH: C,
50.68; H, 4.01; N, 2.50; S, 11.43; Found: C, 50.88; H, 4.35; N,
2.49; S, 10.99.
Example 26
[0378] ##STR42##
{4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonylamino}ace-
tic acid
[0379] Ex-26A: To a solution of 4-acetylbenzenesulfonyl chloride
(0.50 g, 2.3 mmol) in acetone (7.5 mL) was added a solution of
glycine (0.42 g, 5.7 mmol) in 5% aqueous sodium hydroxide (2.5 mL)
and the reaction was stirred for 30 min at room temperature. The
mixture was diluted with water (10 mL), acidified with a 1 N
hydrochloric acid solution, and extracted with ethyl acetate
(3.times.15 mL). The combined organic layers were washed with brine
(2.times.20 mL), dried over sodium sulfate, and the solvent was
removed under reduced pressure. The resulting solid was dried in
vacuo to afford 0.55 g (94%) of
(4-acetylbenzenesulfonylamino)acetic acid as a white solid, mp
213-215.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 8.28
(t, 1H, J=5.4 Hz), 8.12 (d, 2H, J=8.4 Hz), 7.92 (d, 2H, J=8.4 Hz),
3.64 (d, 2H, J=5.1 Hz), 2.64 (s, 3H). Anal. Calcd. for
C.sub.10H.sub.11NO.sub.5S: C, 46.69; H, 4.31; N, 5.44; S, 12.46;
Found: C, 46.76; H, 4.43; N, 5.39; S, 12.16.
[0380] The title compound was prepared in an analogous fashion as
Ex-1 using (4-acetylbenzenesulfonylamino)acetic acid (Ex-26A), 82%
yield, orange solid, mp 100-101.degree. C. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) 8.30 (d, 3H, J=8.1 Hz), 8.29(s, 1H), 8.10 (d, 1H,
J=15.0 Hz), 7.96 (d, 2H, J=8.1 Hz), 7.92 (d, 1H, J=15.0 Hz), 7.67
(dd, 1H, J=3.6, 1.2 Hz), 7.53 (d, 1H, J=5.4 Hz), 7.14 (dd, 1H,
J=5.4, 3.6 Hz), 6.85 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.66 (d,
2H, J=5.7 Hz). HRMS (ESI) Calcd. for
C.sub.23H.sub.21NO.sub.7S.sub.2: 488.0837 (M+H).sup.+; Found:
488.0847.
Example 27
[0381] ##STR43##
2-{4-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)acryloyl]benzenesulfonylamino}-
-2-methylpropionic acid
[0382] Ex-27A: 2-(4-Acetylbenzenesulfonylamino)-2-methylpropionic
acid was prepared in an analogous fashion as Ex-26A using
2-aminoisobutyric acid, 70% yield, white solid, mp 157-158.degree.
C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 8.21 (s, 1H), 8.10
(d, 2H, J=8.7 Hz), 7.92 (d, 2H, J=8.7 Hz), 3.63 (s, 3H), 1.27 (s,
6H). Anal. Calcd. for C.sub.12H.sub.15NO.sub.5S. 1/30H.sub.2O: C,
50.40; H, 5.31; N, 4.90; S, 11.21; Found: C, 50.12; H, 5.25; N,
5.15; S, 11.65. HRMS (ESI) Calcd. for C.sub.12H.sub.15NO.sub.5S:
286.0749 (M+H).sup.+; Found: 286.0756.
[0383] The title compound was prepared in an analogous fashion as
Ex-1 using 2-(4-acetylbenzenesulfonylamino)-2-methylpropionic acid
(Ex-27A), 80% yield, yellow solid, mp 205.degree. C. (dec).
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.29 (d, 2H, J=8.4 Hz), 8.28(s,
1H), 8.23 (s, 1H), 8.10 (d, 1H, J=15.3 Hz), 7.96 (d, 2H, J=8.4 Hz),
7.92 (d, 1H, J=15.3 Hz), 7.67 (d, 1H, J=3.6 Hz), 7.53 (d, 1H, J=5.4
Hz), 7.14 (dd, 1H, J=5.4, 3.6 Hz), 6.85 (s, 1H), 4.02 (s, 3H), 4.01
(s, 3H), 1.30 (s, 6H). Anal. Calcd. for
C.sub.25H.sub.25NO.sub.7S.sub.2.1/5H.sub.2O: C, 57.83; H, 4.93; N,
2.70; S, 12.35; Found: C, 57.81; H, 4.98; N, 3.08; S, 12.45.
Example 28
[0384] ##STR44##
1-{4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonyl}piperi-
dine-2-carboxylic acid
[0385] Ex-28A: 1-(4-Acetylbenzenesulfonyl)piperidine-2-carboxylic
acid was prepared in an analogous fashion as Ex-26A using
2-pipecolinic acid, 67% yield, white foam. .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta. 8.06 (d, 2H, J=8.4 Hz), 7.90 (d, 2H, J=8.4 Hz),
4.83 (d, 1H, J=3.9 Hz), 3.76-3.83 (m, 2H), 3.19 (dt, 1H, J=12.7,
3.0 Hz), 2.66 (s, 3H), 2.19-2.24 (m, 1H), 1.60-1.82 (m, 4H). HRMS
(ESI) Calcd. for C.sub.14H.sub.17NO.sub.5S: 312.0905 (M+H).sup.+;
Found: 312.0915.
[0386] The title compound was prepared in an analogous fashion as
Ex-1 using 1-(4-acetylbenzenesulfonyl)piperidine-2-carboxylic acid
(Ex-28A), 66% yield, yellow foam. .sup.1H-NMR (300 MHz, CDCl.sub.3)
8.08 (d, 1H, J=15.6 Hz), 8.05 (d, 2H, J=8.7 Hz), 8.00 (s, 1H), 7.91
(d, 2H, J=8.7 Hz), 7.86 (s, 1H), 7.51 (d, 1H, J=15.7 Hz), 7.41 (d,
1H, J=3.6 Hz), 7.31 (d, 1H, J=5.7 Hz), 7.09 (dd, 1H, J=5.7, 3.6
Hz), 6.54 (s, 1H), 4.81 (d, 1H, J=4.2 Hz), 3.99 (s, 3H), 3.98 (s,
3H), 3.80-3.83 (m, 2H), 3.23 (dt, 1H, J=12.0, 2.1 Hz), 2.17-2.21
(m, 1H), 1.65-1.73 (m, 4H). HRMS (ESI) Calcd. for
C.sub.27H.sub.27NO.sub.7S.sub.2: 542.1307 (M+H).sup.+; Found:
542.1298.
Example 29
[0387] ##STR45##
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-methyl-b-
enzenesulfonamide
[0388] Ex-29A: To a solution of 4-acetylbenzenesulfonyl chloride
(1.1 g, 5.0 mmol) in 25 ml of THF, methylamine (0.44 ml of 40%
solution in H.sub.2O, 5 mmol) was added dropwise, and the mixture
was stirred for 30 min. The reaction mixture was poured into water,
and the precipitate was filtered. Recrystallization from
EtOAc/hexanes gave 0.67 g (62.6%) of
4-acetyl-N-methyl-benzenesulfonamide as a white solid. .sup.1H-NMR
(300 MHz, CDCl.sub.3) .delta. 8.09 (d, J=8 Hz, 2H), 7.96 (d, J=8
Hz, 2H), 4.48 (br, 1H), 2.70 (d, J=4 Hz, 1H), 2.66 (s, 3H).
[0389] The title compound was prepared using in an analogous way as
Ex-1 using 4-acetyl-N-methyl-benzenesulfonamide (Ex-29A) and
2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 57%
yield, yellow solid, mp 129-131.degree. C. .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta. 8.17 (d, J=16 Hz, 1H), 8.10 (d, J=9 Hz, 2H),
7.95 (d, J=9 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=7 Hz, 1H), 7.47 (d,
J=16 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.22-7.26 (m, 1H), 7.14-7.16
(m, 1H), 6.59 (s, 1H), 6.51 (s, 1H), 4.42 (br s, 1H) 4.03 (s, 3H),
3.90 (s, 3H), 3.58 (s, 3H), 2.69 (d, J=6 Hz, 3H). HRMS (ESI) Calcd.
for C.sub.27H.sub.26N.sub.2O.sub.5S: 491.1641 (M+H).sup.+; Found:
491.1646.
Example 30
[0390] ##STR46##
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-methoxyb-
enzenesulfonamide
[0391] Ex-30A: To a solution of 4-acetylbenzenesulfonyl chloride
(2.18 g, 10.0 mmol) in 100 ml of THF at 0.degree. C., Et.sub.3N
(2.5 g, 25 mmol) was added followed by O-methyl hydroxyamine
hydrochloride (0.84 g, 10 mmol). The mixture was stirred for 1 hr
at room temperature and then poured into water, and the precipitate
was filtered and dried. Recrystallization from THF/hexanes gave 1.5
g (65.8%) of 4-acetyl-N-methoxybenzenesulfonamide as a white solid.
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.10 (d, J=8 Hz, 2H),
8.03 (d, J=8 Hz, 2H), 7.23 (brs, 1H), 3.82 (s, 3H), 2.66 (s,
3H).
[0392] The title compound was prepared in an analogous way as Ex-1
using 4-acetyl-N-methoxy-benzenesulfonamide (Ex-30A) and
2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 94%
yield, yellow solid, mp 214-216.degree. C. .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta. 8.17 (d, J=16 Hz, 1H), 8.11 (d, J=8 Hz, 2H),
8.03 (d, J=8 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=7 Hz, 1H), 7.48 (d,
J=16 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.25-7.26 (m, 1H), 7.11-7.16
(m, 2H), 6.59 (s, 1H), 6.50 (s, 1H), 4.03 (s, 3H) 3.90 (s, 3H),
3.84 (s, 3H), 3.58 (s, 3H). MS m/z: 506 ([M].sup.+, 30%), 476
(100%).
Example 31
[0393] ##STR47##
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N,N-dimeth-
ylbenzenesulfonamide
[0394] Ex-31A: 4-Acetyl-N,N-dimethylbenzenesulfonamide was prepared
in an analogous manner as Ex-29A using dimethylamine, 93% yield,
white solid. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.10 (d, J=8
Hz, 2H), 7.87 (d, J=8 Hz, 2H), 2.74 (s, 6H), 2.66 (s, 3H).
[0395] The title compound was prepared in an analogous manner as
Ex-1 using 4-acetyl-N,N-dimethyl-benzenesulfonamide (Ex-31A) and
2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 64%
yield, yellow solid, mp 120-122.degree. C. .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta. 8.18 (d, J=16 Hz, 1H), 8.12 (d, J=8 Hz, 2H),
7.88 (d, J=8 Hz, 2H), 7.69 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.48 (d,
J=16 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.22-7.27 (m, 1H), 7.11-7.16
(m, 1H), 6.59 (s, 1H), 6.50 (s, 1H), 4.11 (s, 3H), 3.90 (s, 3H),
3.59 (s, 3H), 2.74 (s, 6H). HRMS (ESI) Calcd. for
C.sub.28H.sub.28N.sub.2O.sub.5S: 505.1797 (M+H).sup.+; Found:
505.1797.
Example 32
[0396] ##STR48##
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N,N-dimethylbenzene-
sulfonamide
[0397] Ex-32A: 2-(5-Formyl-2,4-dimethoxyphenyl)indole-1-carboxylic
acid tert-butyl ester was prepared from
5-bromo-2,4-dimethoxybenzaldehyde and N-Boc-indole-2-boronic acid
in a similar manner as Ex-1A, 79% yield, yellow oil. .sup.1H-NMR
(300 MHz, CDCl.sub.3) .delta. 10.36 (s, 1H), 8.15 (d, J=8 Hz, 1H),
7.88 (s, 1H), 7.45 (d, J=8 Hz, 3H), 7.27-7.35 (m, 1H), 7.19-7.27
(m, 1H), 6.52 (s, 1H), 6.47 (s, 1H), 4.00 (s, 3H), 3.86 (s, 3H),
1.42 (s, 9H).
[0398] Ex-32B: 2-(5-Formyl-2,4-dimethoxyphenyl)indole-1-carboxylic
acid tert-butyl ester (Ex-32A, 2.0 g, 5.2 mmol) was dissolved in
100 ml of THF, and Bu.sub.4NF (6.86 g, 26 mmol) was added. The
reaction mixture was stirred at room temperature overnight. No
significant reaction occurred under these conditions by HPLC. Then,
additional Bu.sub.4NF (6.86 g, 26 mmol) was added to the mixture,
and the mixture was stirred at reflux for 4 days. The reaction
reached about 50% completion (HPLC). The reaction mixture was
poured into CH.sub.2Cl.sub.2, and washed with water and brine. The
organic phase was dried over MgSO.sub.4, and concentrated. The
residue was purified by column chromatography (EtOAc/hexanes, 2:1)
to give 0.45 g (30%) of
5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde. .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta. 10.37 (s, 1H), 9.25 (br, 1H), 8.28 (s, 1H),
7.63(d, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.08-7.20 (m, 2H),
6.92(d, J=2 Hz, 1H), 6.56 (s, 1H) 4.11(s, 3H), 4.00 (s, 3H). HMRS
(EI) calcd. for C.sub.17H.sub.15NO.sub.3: 281.1052 (M.sup.+);
Found: 281.1049.
[0399] The title compound was prepared in an analogous manner as
Ex-1 using 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde (Ex-32B) and
4-acetyl-N,N-dimethylbenzenesulfonamide (Ex-31A), 12% yield after
silica gel column chromatography (hexane/EtOAc, 2:1), yellow solid,
mp 158-162.degree. C. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.
9.39 (br, 1H), 8.15 (m, 2H), 8.08 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz,
2H), 7.64 (d, J=7 Hz, 1H), 7.57 (d, J=15 Hz, 1H), 7.42 (d, J=8 Hz,
1H), 7.09-7.21 (m, 2H), 6.87 (d, J=2 Hz, 1H), 6.60 (s, 1H), 4.10
(s, 3H), 4.01 (s, 3H), 2.76 (s, 6H). HRMS (ESI) Calcd. for
C.sub.27H.sub.26N.sub.2O.sub.5S: 491.1641 (M+H).sup.+; Found:
491.1638.
Example 33
[0400] ##STR49##
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(tert-bu-
tyldimethylsiloxy)benzenesulfonamide
[0401] Ex-33A: To a solution of
O-(tert-butyldimethylsilyl)hydroxylamine (0.74 g, 5 mmol) and
triethylamine (1.01 g, 10 mmol) in 25 ml THF,
4-acetylbenzenesulfonyl chloride (1.1 g, 5 mmol) was added at
0.degree. C. The mixture was stirred overnight and then poured into
H.sub.2O. The precipitate was filtered, dried, and recrystallized
from EtOAc/Hexene to give 1.3 g (76.8%) of
4-acetyl-N-(tert-butyldimethylsiloxy)benzenesulfonamide as a white
solid. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.11 (d, J=9 Hz,
2H), 8.01 (d, J=9 Hz, 2H), 6.59 (b, 1H), 2.67 (s, 3H), 0.89 (s,
9H), 0.20 (s, 6H).
[0402] The title compound was prepared in an analogous manner as
Ex-1 using 4-acetyl-N-(tert-butyldimethylsiloxy)benzenesulfonamide
(Ex-33A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde
(Ex-15A), 19% yield after preparative TLC (MeOH/CH.sub.2Cl.sub.2,
1:10), yellow solid, mp 129-131.degree. C. .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta. 8.18 (d, J=15 Hz, 1H), 8.12 (d, J=8 Hz, 2H),
8.02 (d, J=8 Hz, 2H), 7.69 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.47 (d,
J=15 Hz, 1H), 7.36 (d, J=7 Hz, 1H), 7.22-7.26 (m, 1H), 7.11-7.16
(m, 1H), 6.58 (s, 1H), 6.50-6.51 (m, 2H), 4.03 (s, 3H), 3.90 (s,
3H), 3.59 (s, 3H), 0.90 (s, 9H), 0.20 (s, 6H). HRMS (ESI) Calcd.
for C.sub.32H.sub.39N.sub.2O.sub.6SSi: 607.2298 (M+H).sup.+; Found:
607.2306.
Example 34
[0403] ##STR50##
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-hydroxyb-
enzenesulfonamide
[0404] The title compound was obtained as a side product from Ex-33
(37% yield after preparative TLC) as a yellow solid,
mp>260.degree. C. .sup.1H-NMR (300 MHz, CD.sub.3OD) .delta.
8.01-8.14 (m, 3H), 7.65-7.78 (m, 4H), 7.52 (d, J=7 Hz, 1H), 7.33
(d, J=8 Hz, 1H), 7.11-7.17 (m, 1H), 7.00-7.05 (m, 1H), 6.80(s, 1H),
6.40 (s, 1H), 4.05 (s, 3H), 3.91 (s, 3H), 3.55 (s, 3H). HRMS Calcd.
for C.sub.26H.sub.24N.sub.2O.sub.6S: 492.1355 (M.sup.+); Found:
493.1423.
Example 35
[0405] ##STR51##
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-isobutyrylbenzene-
sulfonamide
[0406] Ex-35A: To a solution of 4-acetylbenzenesulfonyl chloride in
acetone (30 mL) was added ammonia (28% in water, 8.2 mL, 57.3 mmol)
dropwise at 0.degree. C. The reaction mixture was allowed to stir
at 0.degree. C. for 30 min. The precipitate was filtered and the
residue was washed with water and dried in vacuo to afford
4-acetylbenzenesulfonamide as a white solid (3.54 g, 93%), mp
176-177.degree. C. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.10 (d, J=9
Hz, 2H), 8.03 (d, J=9 Hz, 2H), 4.86 (brs, 2H), 2.65 (s, 3H). HRMS
Calcd. for C.sub.8H.sub.9NO.sub.3S: 199.0303 (M.sup.+); Found:
199.0300.
[0407] Ex-35B: To a solution of 2,4-dimethoxybenzaldehyde (20.0 g,
120.4 mmol) in methanol (550 mL) was added iodine monochloride
(23.5 g in 60 mL methanol) dropwise over 20 min at ambient
temperature. The solution was allowed to stir at this temperature.
HPLC showed about 94% conversion after 3 hours. The reaction
mixture was then poured into a solution of HCl (0.5M, 600 mL). The
precipitate was collected by filtration, washed with water, dried
in vacuo (40.degree. C.) to give crude product of 33.02 g. The
crude product was further purified by recrystallization from
THF/heptane (1:1) to give 5-iodo-2,4-dimethoxybenzaldehyde as an
off-white solid (27.5 g, m.p 170-172.degree. C.). The mother liquid
was concentrated to dryness. The residual material was dissolved in
EtOH (100 mL) and acetone (20 mL) followed by addition of water (20
mL) to give additional product (3.12 g, m.p. 169-171.degree. C.).
Overall isolated yield of this reaction was 87.5%. .sup.1H NMR
(CDCl.sub.3) .delta. 10.20 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H),
3.97 (s, 3H), 3.95 (s, 3H). HRMS Calcd. for C.sub.9H.sub.9IO.sub.3:
291.9596 (M.sup.+); Found: 291.9602. Anal. Calcd. for
C.sub.8H.sub.9NO.sub.3S: C, 37.01; H, 3.11; I, 43.33; Found: C,
37.12; H, 3.15; I, 43.33.
[0408] Ex-35C: To a solution of 5-iodo-2,4-dimethoxybenzaldehyde
(Ex-35B, 11.7 g, 40 mmol) in 250 ml of THF,
PdCl.sub.2(PPh.sub.3).sub.2 (0.56 g, 0.8 mmol), CuI (0.3 g, 1.6
mmol), Et.sub.3N (6.06 g, 60 mmol), and
2-[(trimethylsilyl)ethynyl]aniline (7.92 g, 42 mmol) were added.
The mixture was stirred to a homogeneous solution, and then TBAF
(10.4 g, 40 mmol) was added. The reaction mixture was aged at room
temperature for 4 h and then filtered. The filtrate was
concentrated to about 50 ml, and the precipitate was filtered to
give first portion of
5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (8.5 g), as
light yellow crystals. The filtrate was concentrated, and the
residue was recrystallized from EtOAc/hexanes to give 1.85 g of
additional product (total 10.35 g, 92%), mp 180-181.degree. C.
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 10.30 (s, 1H), 7.99 (s,
1H), 7.36 (d, J=8 Hz, 1H), 7.11-7.17 (m, 1H), 6.69-6.75 (m, 2H),
6.46 (s, 1H), 4.41 (brs, 2H), 4.02 (s, 3H), 4.00 (s, 3H). HRMS
Calcd. for C.sub.17H.sub.15NO.sub.3: 281.1052 (M.sup.+); Found:
281.1056. Anal. Calcd. for C.sub.17H.sub.15NO.sub.3: C, 72.58; H,
5.37; N, 4.98; Found: C, 72.74; H, 5.38; N, 4.93.
[0409] Ex-35D:
4-{3E-[5-(2-Amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesulf-
onamide was prepared in a similar manner as Ex-1 using
4-acetylbenzenesulfonamide (Ex-35A) and
5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C), 82.6%
yield, yellow solid, mp 167-169.degree. C. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.27 (d, J=8 Hz, 2H), 8.20(s, 1H), 8.01 (d,
J=16 Hz, 1H), 7.94 (d, J=8 Hz, 2H), 7.84 (d, J=16 Hz, 1H), 7.53 (s,
2H), 7.15-7.17 (m, 1H), 7.02-7.08 (m, 1H), 6.77 (s, 1H), 6.72 (d,
J=8 Hz, 1H), 6.49-6.54 (m, 1H), 5.46 (br, 1H) 3.97 (s, 3H), 3.96
(s, 3H). MS m/z: 462 ([M+H].sup.+, 100%).
[0410] Ex-35E:
4-{3E-[5-(2-Aminophenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfo-
namide (Ex-35D, 0.91 g, 1.97 mmol) was dissolved in acetonitrile
(100 ml), heated to reflux, and then PdCl.sub.2 (0.035 g, 0.197
mmol) was added. The reaction mixture was kept at reflux for 10 min
and cooled to room temperature. Upon cooling, the mixture was
filtered to remove any solid material and the filtrate was treated
with 3-mercaptopropyl-functionalized silica gel (1.0 g) under
stirring for 0.5 h. The mixture was then filtered and concentrated
to give crude product, which was recrystallized from EtOAc/hexanes
to yield 0.75 g (83%) of
4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide
as a yellow solid, mp 185-187.degree. C. .sup.1H-NMR (DMSO-d.sub.6)
.delta. 11.15 (brs, 1H), 8.33(s, 1H), 8.24 (d, J=8 Hz, 2H), 8.07
(d, J=15 Hz, 1H), 7.98 (d, J=8 Hz, 2H), 7.80 (d, J=15 Hz, 1H),
7.41-7.55 (m, 4H), 7.03-7.08 (m, 1H), 6.93-6.99 (m, 2H), 6.83 (s,
1H), 4.04 (s, 3H), 3.99(s, 3H), MS m/z: 463 [M+H].sup.+.
[0411] To a suspension of
4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide
(Ex-35E, 1.84 g, 4 mmol) in 100 ml of THF, isobutyric anhydride
(1.26 g, 8 mmol), triethylamine (0.42 g, 4.2 mmol) and
N-dimethylaminopyridine (0.049 g, 0.4 mmol) were added. The mixture
was aged at room temperature overnight and then poured into water
(100 ml) and extracted with CH.sub.2Cl.sub.2 (3.times.100 ml). The
combined organic phases were washed with 0.5 N HCl, H.sub.2O and
brine, and concentrated. Recrystallization from EtOAc/hexanes gave
1.8 g (87%) of the title compound as a red solid, mp
243-245.degree. C. (dec.). .sup.1H-NMR (300 MHz,
CD.sub.3COCD.sub.3) .delta. 10.54 (brs, 1H), 8.35(s, 1H), 8.27 (d,
J=8 Hz, 2H), 8.18 (d, J=16 Hz, H), 8.15 (d, J=8 Hz, 2H), 7.90 (d,
J=16 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 6.91-7.07
(m, 4H), 4.10 (s, 3H), 4.05 (s, 3H), 2.58 (septet, J=6 Hz, 1H),
1.02 (d, J=6 Hz, 6H). HRMS (ESI) Calcd. for
C.sub.29H.sub.28N.sub.2O.sub.6S: 533.1746 (M+H).sup.+; Found:
533.1746.
Example 36
[0412] ##STR52##
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-isobutyrylbenzene-
sulfonamide sodium salt
[0413] To a solution of
4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-isobutyrylbenzen-
esulfonamide (Ex-35, 2.44 g, 4.6 mmol) in 100 ml of THF, NaOMe
(0.24 g, 4.4 mmol) was added. The mixture was stirred at room
temperature overnight. The resulting thick yellow mixture was
diluted with 150 ml of EtOAc/hexanes (1:1) and filtered. The yellow
solid was then dried in vacuo to afford 2.35 g (93%) of the title
compound as a red solid, mp 249-251.degree. C. (dec.). .sup.1H-NMR
(300 MHz, DMSO-d.sub.6) .delta. 11.16 (brs, 1H), 8.32 (s, 1H), 8.05
(d, J=8 Hz, 2H), 8.04 (d, J=15 Hz, 1H), 7.84 (d, J=15 Hz, 1H), 7.83
(d, J=8 Hz, 2H), 7.49 (d, J=8 Hz, 1H), 7.42 (d, J=8 Hz, 1H),
7.02-7.07(m, 1H), 6.93-6.97 (m, 2H), 6.83(s, 1H), 4.03 (s, 3H),
3.99 (s, 3H), 2.10 (septet, J=8 Hz, 1H), 0.84 (d, J=8 Hz, 6H). HRMS
(ESI) Calcd. for C.sub.29H.sub.27N.sub.2O.sub.6SNa: 531.1595
(M-Na).sup.+; Found: 531.1611.
Example 37
[0414] ##STR53##
N-Butyryl-4-{3E-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}b-
enzenesulfonamide
[0415] Ex-37A: To a solution of 4-acetylbenzenesulfonamide (Ex-35A,
0.20 g, 1 mmol) and
2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A, 0.30
g, 1 mmol) in DMF (25 ml) was added lithium methoxide (4 ml, 1.0 M
in methanol). The mixture was stirred at room temperature
overnight. It was poured into water (50 ml) and acidified to pH=1
with 3 N HCl. The yellow precipitate was filtered, washed with
water, and dried. Crystallization from EtOAc/hexanes gave
4-{3-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}benzenesulf-
onamide (0.43 g, 90%) as a yellow solid, mp 148-150.degree. C.
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.17 (d, J=16 Hz, 1H),
8.09 (d, J=9 Hz, 2H), 8.01 (d, J=9 Hz, 2H), 7.68 (s, 1H), 7.64 (d,
J=8 Hz, 1H), 7.47 (d, J=16 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 7.22-7.26
(m, 1H), 7.11-7.16 (m, 1H), 6.58 (s, 1H), 6.50 (s, 1H), 4.92 (brs,
2H), 4.02 (s, 3H), 3.90 (s, 3H), 3.58 (s, 3H). MS m/z=477
([M+H].sup.+, 100%).
[0416] To a suspension of
4-{3-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}benzenesulf-
onamide (Ex-37A, 1.5 g, 3.15 mmol) in 100 ml of THF, butyric
anhydride (1.0 g, 6.3 mmol), triethylamine (0.33 g, 3.3 mmol) and
4-dimethylaminopyridine (0.038 g, 0.32 mmol) were added. The
mixture was aged at room temperature overnight. The mixture was
poured into water (100 ml) and extracted with 3.times.100 ml of
CH.sub.2Cl.sub.2. The combined organic phase was washed with 0.5 N
HCl, H.sub.2O, and brine, and concentrated to give crude product.
Crystallization from EtOAc/hexanes gave 0.95 g (55%) of the title
compound as a yellow solid, mp 144-146.degree. C. .sup.1H-NMR (300
MHz, CD.sub.3COCD.sub.3) .delta. 8.27 (d, J=9 Hz, 2H), 8.21 (d,
J=16 Hz, 1H), 8.10 (d, J=9 Hz, 2H), 7.89 (s, 1H), 7.87 (d, J=16 Hz,
1H), 7.54 (d, J=8 Hz, 1H), 7.37 (d, J=8 Hz, 1H), 7.13-7.18 (m, 1H),
7.01-7.06 (m, 1H), 6.91 (s, 1H), 6.41 (s, 1H), 4.08 (s, 3H), 3.94
(s, 3H), 3.57 (s, 3H), 2.27 (t, J=7 Hz, 2H), 1.45-1.53 (m, 2H),
0.79 (t, J=8 Hz, 3H). HRMS (ESI) Calcd. for
C.sub.30H.sub.30N.sub.2O.sub.6S: 547.1903 (M+H).sup.+; Found:
547.1905.
Example 38
[0417] ##STR54##
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-yl-phenyl)acryloyl]-N-(5-methyl-isozax-
ol-3-yl)benzenesulfonamide
[0418] Ex-38A: Method A: A mixture of 2,4-dimethoxyaniline (1.0 g,
6.53 mmol), 1,4-dibromobutane (1.41 g, 6.53 mmol) and potassium
carbonate (3.61 g, 26.1 mmol) in N,N-dimethylformamide (70 mL) was
heated at 150.degree. C. overnight. The reaction mixture was
concentrated under reduced pressure. The residue was taken up in a
mixture of water and ethyl acetate. After the mixture was
partitioned, the aqueous solution was extracted with ethyl acetate.
The combined solution of ethyl acetate was washed with saturated
sodium bicarbonate, brine, dried over sodium sulfate and
concentrated. The residue was purified by flash chromatography.
Elution with ethyl acetate and hexane (1:2, v/v) gave
1'-pyrrolidin-1-yl-2,4-dimethoxybenzene as a brown oil (0.85 g,
63%). .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 6.76 (d, J=8.9 Hz,
1H), 6.49 (d, J=2.7 Hz, 1H), 6.41 (dd, J=2.7, 8.9 Hz, 1H), 3.84 (s,
3H), 3.78 (s, 3H), 3.18-3.14 (m, 4H), 1.95-1.90 (m, 4H). Method B:
Sodium tert-butoxide was charged to a mixture of
1-bromo-2,4-dimethoxybenzene (3.03 g, 14.0 mmol), pyrrolidine (1.75
mL, 20.9 mmol), tris(dibenzylideneacetone)dipalladium
(Pd.sub.2(dba).sub.3) (0.26 g, 0.28 mmol) and
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) (0.35 g,
0.56 mmol) in degassed toluene (60 mL). The reaction mixture was
heated at 100.degree. C. under N.sub.2 for 17 h. After cooling to
room temperature, the reaction mixture was diluted with water (60
mL) and partitioned. The aqueous solution was further extracted
with ethyl acetate. The combined ethyl acetate and toluene was
washed with saturated sodium bicarbonate, brine, dried over sodium
sulfate and concentrated. The crude product was purified by flash
chromatography with ethyl acetate and hexane (1:2, v/v) to give
1-pyrrolidin-1-yl-2,4-dimethoxybenzene as a brown oil (1.82 g,
63%).
[0419] Ex-38B: To a solution of
1-pyrrolidin-1-yl-2,4-dimethoxybenzene (Ex-38A, 1.82 g, 8.78 mmol)
and .alpha.,.alpha.-dichloromethyl methyl ether (1.6 mL, 17.6 mmol)
in dichloromethane (50 mL) was added titanium tetrachloride (1.0 M
in dichloromethane, 26.3 mL, 26.3 mmol) dropwise at 0.degree. C.
The solution was allowed to stir for 16 h at ambient temperature
and poured into ice/water. The aqueous solution was extracted with
dichloromethane. The combined dichloromethane was washed with
saturated sodium bicarbonate, brine, dried over sodium sulfate and
concentrated to give a crude product (0.67 g). The aqueous solution
was further treated with solid sodium hydroxide to pH 8. The
suspension was mixed with ethyl acetate. The insoluble solid was
removed by filtering through a pad of Celite. The filtrate was then
partitioned. The aqueous solution was further extracted with ethyl
acetate. The combined ethyl acetate was washed with saturated
sodium bicarbonate, brine, dried over sodium sulfate and
concentrated. The combined crude product (1.71 g) was purified by
flash chromatography. Elution with ethyl acetate and hexane (1:1,
v/v) gave 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde as a brown
oil (1.03 g, 50%): .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 10.25
(s, 1H), 7.26 (s, 3H), 6.44 (s, 1H), 3.93 (s, 3H), 3.89 (s, 3H),
3.20-3.16 (m, 4H), 1.93-1.89 (m, 4H). MS m/z: 235 (M.sup.+),
100%.
[0420] The title compound was prepared in a similar manner as Ex-1
using 4-acetyl-N-(5-methylisoxazol-3-yl)benzenesulfonamide (Ex-1B,
0.30 g, 1.07 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde
(Ex-38B, 0.25 g, 1.07 mmol) as a dark red solid, mp 164-165.degree.
C. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.09-7.93 (m, 4H),
7.35 (d, J=15.3 Hz, 1H), 7.05 (s, 1H), 6.48 (s, 1H), 6.24 (s, 1H),
3.92 (s, 3H), 3.90 (s, 3H), 3.29-3.18 (m, 4H), 2.38 (s, 3H),
2.02-1.91 (s 4H). MS m/z: 498 (M.sup.+), 100%.
Example 39
[0421] ##STR55##
4-{3E-[2-(3-Hydroxy-propoxy)-4-methoxy-5-thien-2-ylphenyl]acryloyl}-N-(5-m-
ethylisoxazol-3-yl)benzenesulfonamide
[0422] Ex-39A: A solution of
2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-13C, 500 mg,
2.13 mmol) in DMF (20 mL) was treated with potassium carbonate (589
mg, 4.26 mmol) followed by the addition of 3-bromo-propan-1-ol (356
mg, 2.56 mmol). The reaction mixture was heated to 80.degree. C.
for 2 h followed by another addition of potassium carbonate (294
mg, 2.13 mmol) and 3-bromo-propan-1-ol (296 mg, 2.13 mmol). The
reaction mixture was stirred for an additional 45 minutes, quenched
with water (15 mL), and extracted with ethyl acetate (2.times.25
ml). The organic phase was washed with brine, dried over sodium
sulfate, and concentrated to a beige oil. The oil was purified by
column chromatography (elution: 30, 50, and 80% ethyl acetate in
hexane) to yield 240 mg (38%) of
2-(3-hydroxypropoxy)-4-methoxy-5-thiophen-2-ylbenzaldehyde as an
off-white solid. .sup.1H-NMR (300 MHz, CDCl.sub.3) 10.21 (s, 1H),
8.02 (s, 1H), 7.41 (br d, 1H, J=3.9 Hz), 7.28 (d, 1H, J=5.10 Hz),
7.06 (dd, 1H, J=3.0, 5.7 Hz), 6.48 (s, 1H), 4.24 (t, 2H, J=7.0 Hz),
3.92 (s, 3H), 3.88 (br s, 2H), 2.11 (q, 2H, J=7.0 Hz).
[0423] The title compound was prepared in a analogous way as Ex-1
from 2-(3-hydroxypropoxy)-4-methoxy-5-thien-2-ylbenzaldehyde
(Ex-39A), 78% yield, red solid, mp 178-182.degree. C. .sup.1H-NMR
(300 MHz, DMSO-d.sub.6) 11.63 (brs, 1H), 8.23 (m, 3H), 8.04 (d, 1H,
J=16.0 Hz), 7.98 (d, 2H, J=9.0 Hz), 7.86 (d, 1H, J=16.0 Hz), 7.61
(d, 1H, J=4 Hz), 7.48 (d, 1H, J=5 Hz,), 7.09 (t, 1H), 6.81 (s, 1H),
6.14 (s, 1H), 4.62 (m, 1H), 4.62 (m, 1H), 4.24 (t, 2H), 3.96 (s,
3H), 3.59 (s, 2H), 2.27 (s, 3H), 1.95 (quintet, 2H). HRMS (ESI)
Calcd. for C.sub.27H.sub.26N.sub.2O.sub.7S.sub.2: 555.1260
(M+H).sup.+; Found: 555.1261.
Example 40
[0424] ##STR56##
N-Ethoxycarbonyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}ben-
zenesulfonamide potassium salt
[0425] To a solution of
4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide
(Ex-35E, 3.0 g, 6.5 mmol) in 250 mL of acetone were added ethyl
chloroformate (0.93 g, 8.6 mmol) and K.sub.2CO.sub.3 (2.3 g, 16.7
mmol). The mixture was heated to reflux overnight. The yellow
precipitate formed was filtered and washed with cold water to give
2.6 g (70%) of the title compound as a yellow solid, mp
220-222.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.
11.23 (br, 1H), 8.35 (s, 1H), 8.01-8.09 (m, 3H), 7.83-7.89 (m, 3H),
7.49 (d, J=7 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.02-7.07(m, 1H),
6.92-6.97 (m, 2H), 6.83 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 3.67
(q, J=8 Hz, 2H), 0.98(t, J=8 Hz, 3H). HRMS Calcd for
C.sub.28H.sub.25KN.sub.2O.sub.7S: 533.1382 ([M-K].sup.+); Found:
533.1378. Anal. Calcd for C.sub.28H.sub.25KN.sub.2O.sub.7S: C,
58.72; H, 4.40; N, 4.89; S, 5.60; Found: C, 58.62; H, 4.34; N,
4.83; S, 5.62.
Example 41
[0426] ##STR57##
N-Ethoxycarbonyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}ben-
zenesulfonamide
[0427] To a solution of
4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide
(Ex-35E, 3.0 g, 6.5 mmol) in 250 mL of acetone were added ethyl
chloroformate (0.93 g, 8.6 mmol) and K.sub.2CO.sub.3 (2.3 g, 16.7
mmol). The mixture was heated to reflux overnight. The yellow
precipitate formed was filtered. The filtrate was acidified to pH=1
with 3N HCl and extracted with CH.sub.2Cl.sub.2. The organic phase
was washed with water, dried over MgSO.sub.4, and concentrated. The
residue was further purified by passing a short silica gel column
eluted with EtOAc/hexenes (1:1) to give 30 mg of the title compound
as a yellow solid, mp 165-175.degree. C. .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta. 9.39 (br, 1H), 8.04-8.20 (m, 6H), 7.64 (d, J=7
Hz, 1H), 7.57 (d, J=15 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.12-7.07(m,
2H), 6.87 (s, 1H), 6.59 (s, 1H), 4.16 (q, J=7 Hz, 2H), 4.10 (s,
3H), 4.01 (s, 3H), 1.24 (t, J=7 Hz, 3H).
Example 42
[0428] ##STR58##
N-Acetyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulf-
onamide
[0429] To a solution of
4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide
(Ex-35E, 0.462 g, 1 mmol), DMAP (0.012 g, 0.1 mmol), and Et.sub.3N
(0.1 g, 1.05 mmol) in 50 ml of THF, was added Ac.sub.2O (0.204 g, 2
mmol). The reaction mixture was stirred at room temperature
overnight. The yellow solid precipitated was filtered and
redissolved in 50% ethanol in water (50 mL). The clear solution was
then adjusted to pH 1, and the solid formed was filtered and washed
with water to give 0.31 g (62%) the title compound as a red solid,
mp 218-220.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.
12.26 (br, 1H), 11.15 (s, 1H), 8.32 (s, 1H), 8.25 (d, J=8 Hz, 2H),
8.04-8.09 (m, 3H), 7.83 (d, J=15 Hz, 1H), 7.49 (d, J=7 Hz, 1H),
7.42 (d, J=8 Hz, 1H), 7.02-7.07 (m, 1H), 6.93-6.97(m, 2H), 6.82 (s,
1H), 4.03 (s, 3H), 3.99 (s, 3H), 1.94 (s, 3H). HRMS (EI) Calcd for
C.sub.27H.sub.24N.sub.2O.sub.6S: 504.1335 ([M].sup.+); Found:
504.1365.
Example 43
[0430] ##STR59##
N-Acetyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulf-
onamide sodium salt
[0431] To a solution of
N-acetyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesul-
fonamide (Ex-42, 0.17 g, 0.34 mmol) in THF (30 mL) was added NaOMe
(0.0174 g, 0.32 mmol). The solution was stirred overnight. The
reaction mixture was concentrated to about 5 mL and filtered to
give 0.17 g (96%) of the title compound as a red solid, mp
240-250.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.
11.17 (s, 1H), 8.30 (s, 1H), 8.00-8.06 (m, 3H), 7.80-7.86 (m, 3H),
7.49 (d, J=7 Hz, 1H), 7.42 (d, J=7 Hz, 1H), 7.02-7.04 (m, 1H),
6.93-6.96(m, 2H), 6.81 (s, 1H), 4.02 (s, 3H), 3.97 (s, 3H), 1.63
(s, 3H). Anal. Calcd for C.sub.27H.sub.23N.sub.2NaO.sub.6S.
5/4H.sub.2O: C, 59.06; H, 4.68; N, 5.10; S, 5.84; Found: C, 59.17;
H, 4.86; N, 5.04; S, 5.54.
Example 44
[0432] ##STR60##
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-pyrol-2-yl)phenyl]acryloyl}-N-(5-methy-
l-isoxazol-3-yl)benzenesulfonamide
[0433] Ex-44A: A solution of 5-bromo-2,4-dimethoxybenzaldehyde
(1.90 g, 7.77 mmol) and
trans-dichlorobis(triphenylphosphine)palladium(II) in dioxane (150
mL) was treated with 1-methyl-2-(tributylstannyl)-1H-pyrrole and
then refluxed for 68 h. The reaction mixture was quenched with 10%
potassium fluoride/ether (300 mL/100 mL) and filtered through
Celite. The organic phase was extracted with saturated ammonium
chloride solution (4.times.25 mL), dried over magnesium sulfate,
and concentrated to a brown solid. The solid was purified by column
chromatography (30% ethyl acetate/hexane) to yield 0.87 g (46%) of
2,4-dimethoxy-5-(1-methyl-1H-pyrol-2-yl)benzaldehyde as a white
solid. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 10.34 (s, 1H),
7.78 (s, 1H), 6.72 (m, 1H), 6.51 (s, 1H), 6.20 (m, 1H), 6.13
(m,1H), 4.01 (s, 3H), 3.92 (s, 3H), 3.46 (s, 3H).
[0434] The title compound was prepared in a similar manner as Ex-1
using 2,4-dimethoxy-5-(1-methyl-1H-pyrol-2-yl)benzaldehyde
(Ex-44A), yellow solid, mp 113-115.degree. C. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.13 (d, 1H, J=16.0 Hz), 8.05 (d, 2H, J=9.0
Hz), 7.95 (d, 2H, J=9.0 Hz), 7.57 (s, 1H), 7.41 (d, 1H, J=16.0
Hz,), 7.26 (s, 1H), 6.73 (t, 1H, J=3 Hz), 6.52 (s, 1H), 6.22 (m,
2H), 6.13 (m, 1H), 3.98 (s, 3H), 3.88 (s, 3H), 3.47 (s, 3H), 2.38
(s, 3H), HRMS (ESI) Calcd. for C.sub.26H.sub.25N.sub.3O.sub.6S:
507.1464 (M+H).sup.+; Found: 507.1477.
Example 45
[0435] ##STR61##
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-propionyl-benzene-
sulfonamide
[0436] To a solution of
4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide
(Ex-35E, 0.462 g, 1 mmol), DMAP (0.012 g, 0.1 mmol) and Et.sub.3N
(0.1 g, 1.05 mmol) in THF (50 mL) was added propionic anhydride
(0.26 g, 2 mmol). The reaction mixture was stirred at room
temperature overnight. The clear solution was poured into 100 ml of
H.sub.2O and extracted with CH.sub.2Cl.sub.2. The combined organic
phase was washed with water, dried over MgSO.sub.4, and
concentrated to dryness. Recrystallization from EtOAc/hexenes gave
0.42 g (81%) of the title compound as a red solid, mp
223-225.degree. C. .sup.1H-NMR (300 MHz, Acetone-d.sub.6) .delta.
10.54 (br, 1H), 8.35 (s, 1H), 8.27 (d, J=9 Hz, 2H), 8.13-8.20 (m,
3H), 7.89 (d, J=15 Hz, 1H), 7.52 (d, J=7 Hz, 1H), 7.39 (d, J=8 Hz,
1H), 6.97-7.05(m, 3H), 6.90 (s, 1H), 4.09 (s, 3H), 4.04 (s, 3H),
2.35 (q, J=8 Hz, 2H), 0.97(t, J=8 Hz, 3H). HRMS (EI) Calcd for
C.sub.28H.sub.26N.sub.2O.sub.6S: 518.1512 ([M].sup.+); Found:
518.1516.
Example 46
[0437] ##STR62##
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-propionylbenzenes-
ulfonamide sodium salt
[0438] To a solution of
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-propionylbenzene-
sulfonamide (Ex-45, 0.39 g, 0.75 mmol) in THF (50 mL) was added
NaOMe (0.039 g, 0.72 mmol). The solution was stirred overnight. The
reaction mixture was concentrated to about 5 mL, and filtered to
give 0.34 g (83%) of the title compound as a red solid,
mp>250.degree. C. .sup.1H-NMR (300 MHz, DMSO.sub.6) .delta.
11.18 (s, 1H), 8.30 (s, 1H), 8.00-8.06 (m, 3H), 7.80-7.86 (m, 3H),
7.49 (d, J=7 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.02-7.04 (m, 1H),
6.93-6.96(m, 2H), 6.81 (s, 1H), 4.02 (s, 3H), 3.97 (s, 3H), 1.90
(q, J=8 Hz, 2H), 0.82 (t, J=8 Hz, 3H). Anal. Calcd for
C.sub.28H.sub.25N.sub.2NaO.sub.6S.3/4H.sub.2O: C, 60.72; H, 4.78;
N, 5.06; S, 5.79; Found: C, 60.63; H, 4.76; N, 5.03; S, 5.68.
Example 47
[0439] ##STR63##
N-Butyryl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesul-
fonamide
[0440] To a solution of
4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide
(Ex-35E, 0.92 g, 2 mmol), DMAP (0.024 g, 0.2 mmol) and Et.sub.3N
(0.2 g, 2.1 mmol) in 100 ml of THF was added butyric anhydride
(0.64 g, 4 mmol). The reaction mixture was stirred at room
temperature overnight. The clear solution was then poured into 150
ml of H.sub.2O and extracted with CH.sub.2Cl.sub.2. The combined
organic phase was washed with water, dried over MgSO.sub.4, and
concentrated to dryness. Recrystallization from EtOAc/hexenes gave
0.80 g (75%) of the title compound as a red solid, mp
155-165.degree. C. .sup.1H-NMR (300 MHz, Acetone-d.sub.6) .delta.
10.55 (br, 1H), 8.35 (s, 1H), 8.27 (d, J=8 Hz, 2H), 8.13-8.20 (m,
3H), 7.89 (d, J=16 Hz, 1H), 7.52 (d, J=7 Hz, 1H), 7.39 (d, J=8 Hz,
1H), 7.02-7.07(m, 1H), 6.95-7.00 (m, 2H), 6.90 (s, 1H), 4.10 (s,
3H), 4.04 (s, 3H), 2.29 (t, J=8 Hz, 2H), 1.48-1.56 (m, 2H), 0.81(t,
J=8 Hz, 3H).
Example 48
[0441] ##STR64##
N-Butyryl-4-[3E-(2,4-dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesul-
fonamide
[0442] Ex-48A: To a solution of 4-acetylbenzenesulfonamide (Ex-35A,
0.13 g, 0.64 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde
(Ex-38B, 0.15 g, 0.64 mmol) in N,N-dimethylformamide (5 mL) was
added lithium methoxide (1.0 M in methanol, 1.6 mL, 1.6 mmol). The
solution was allowed to stir at ambient temperature for 13 h and
then at 40.degree. C. for 2 h. HPLC indicated no further change of
starting materials. The reaction mixture was then diluted with
water, acidified to pH 5. The resulting precipitate was collected
by filtration, washed with water, dried in vacuo. The crude product
was slurried in ethanol overnight. The solid was collected by
filtration, washed with ethanol, dried in vacuo to give
4-[3E-(2,4-dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonamide
(0.16 g, 59%) as a red solid, m.p. 220-222.degree. C. .sup.1H-NMR
(300 MHz, DMSO-d.sub.6) .delta. 8.22 (d, J=8.7 Hz, 2H), 8.04 (d,
J=16.1 Hz, 1H), 7.93 (d, J=8.7 Hz, 2H), 7.64 (d, J=16.1 Hz, 1H),
7.52 (s, 2H), 7.18 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.19-3.17
(m, 4H), 1.84-1.83 (m, 4H). HRMS Calcd for
C.sub.21H.sub.24N.sub.2O.sub.5S: 416.1408 (M.sup.+); Found:
416.1408.
[0443] The title compound was synthesized by reacting
4-[3E-(2,4-dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonamide
(Ex-48A, 137 mg, 0.33 mmol) with butyric anhydride (0.11 mL, 0.66
mmol) in the presence of triethylamine (0.048 mL, 0.35 mmol) and
4-(dimethylamino)pyridine (4 mg, 0.03 mmol) in a mixture of THF (5
mL) and DMF (0.7 mL) in a similar manner as Ex-35, dark red solid
(98 mg, 61%), mp 193-195.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 12.23 (brs, 1H), 8.26 (d, J=8.5 Hz, 2H),
8.11-8.03 (m, 3H), 7.66 (d, J=15.2 Hz, 1H), 7.02 (s, 1H), 6.71 (s,
1H), 3.90 (s, 6H), 3.15-3.25 (m, 4H), 2.20 (t, J=7.6 Hz, 2H),
1.92-1.81 (m, 4H), 1.46-1.39 (m, 2H), 0.76 (t, J=7.3 Hz, 3H).
Example 49
[0444] ##STR65##
N-Butyryl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesul-
fonamide sodium salt
[0445] To a solution of
N-butyryl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesu-
lfonamide (Ex-47, 0.40 g, 0.75 mmol) in 50 ml THF, was added NaOMe
(0.039 g, 0.72 mmol). The solution was stirred overnight. The
reaction mixture was concentrated to about 5 mL and filtered to
give 0.36 g (86%) of the title compound as a red solid, mp
191-193.degree. C. .sup.1H-NMR (300 MHz, DMSO.sub.6) .delta. 11.18
(s, 1H), 8.30 (s, 1H), 8.00-8.06 (m, 3H), 7.80-7.85 (m, 3H), 7.49
(d, J=7 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.02-7.04 (m, 1H),
6.93-6.96(m, 2H), 6.81 (s, 1H), 4.02 (s, 3H), 3.97 (s, 3H), 1.86
(t, J=7 Hz, 2H), 1.31-1.39 (m, 2H), 0.73 (t, J=8 Hz, 3H). Anal.
Calcd for C.sub.29H.sub.27N.sub.2NaO.sub.6S.2H.sub.2O: C, 58.97; H,
5.29; N, 4.74; S, 5.43; Found: C, 59.08; H, 5.52; N, 4.64; S,
5.16.
Example 50
[0446] ##STR66##
N-(3-Imidazol-1-yl-propyl)-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxy-phenyl]a-
cryloyl}benzenesulfonamide
[0447] Ex-50A: A solution of
4-acetyl-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (Ex-23A, 312
mg, 1.02 mmol) and
5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 287
mg, 1.02 mmol) in DMF (4.4 mL) and MeOH (1.9 mL) was treated with
lithium methoxide (155 mg, 4.08 mmol). The reaction mixture was
stirred at room temperature for 16 h under nitrogen. The reaction
mixture was quenched with water (25 mL) and extracted with (3:1)
ethyl acetate/THF (3.times.25 mL). The organic phase was brined,
dried over sodium sulfate, and concentrated to a yellow oil. The
crude material was purified by column chromatography (0-7.5% MeOH
in dichloromethane) to give
4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxy-phenyl]acryloyl}-N-(3-
-imidazol-1-ylpropyl)benzenesulfonamide (309 mg, 53%) as a yellow
oil. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.28 (d, 2H, J=7.80), 8.20
(s, 1H), 8.01 (d, 1H, J=15.0 Hz), 7.86 (m, 5H), 7.51 (s, 1H), 7.16
(d, 1H, J=7.5 Hz), 7.23 (m, 2H), 6.79 (d, 2H, J=10.8 Hz), 6.72 (d,
1H, J=8.1 Hz), 6.52 (t, 1H, J=7.2 Hz), 5.45 (m, 1H), 3.97 (s, 3H),
3.96 (s, 3H), 3.92 (m, 4H), 1.77 (quintet, 2H, J=6.6 Hz).
[0448] A suspension of
4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}-N-(3-imida-
zol-1-ylpropyl)benzenesulfonamide (Ex-50A, 210 mg, 0.37 mmol) in
acetonitrile (130 mL) was purged with nitrogen gas for 10 minutes.
Palladium(II) chloride (5.0 mg, 0.029 mmol) was added to the
reaction vessel. The reaction mixture was refluxed for 16 hrs. The
cooled reaction mixture was stirred with 3-mercaptopropyl
functionalized silica gel (500 mg) for 5 minutes. The filtrate was
collected via suction filtration and concentrated to an orange
solid to give 210 mg (100%) of the title compound, mp
197-200.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 11.19 (br s,
1H), 8.28 (m, 3H), 8.11 (m, 2H), 7.95 (m, 4H), 7.45 (m, 3H), 7.00
(m, 5H), 4.08 (s, 3H), 4.03 (s, 3H), 3.89 (m, 2H), 2.69 (br s, 2H),
1.78 (br s, 2H). HRMS (ESI) Calcd. for
C.sub.31H.sub.30N.sub.4O.sub.5S: 571.2015 [(M+H).sup.+]; Found:
571.2016.
Example 51
[0449] ##STR67##
(4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonylamin-
o)acetic acid
[0450] Ex-51A: A solution (4-acetylbenzenesulfonylamino)acetic acid
(Ex-26A, 238 mg, 1.01 mmol) in DMF (4.4 mL) and MeOH (1.9 mL) was
treated with lithium methoxide (153 mg, 4.04 mmol), followed by the
addition of 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde
(Ex-35C, 300 mg, 1.07 mmol). The reaction mixture was stirred at
room temperature for 23 h under nitrogen. It was quenched with
water (10 mL) and extracted with ethyl acetate (25 mL). The aqueous
phase was acidified with 6N HCl to pH3 and was extracted with (3:1)
ethyl acetate/THF (5.times.25 mL). The organic phase was brined,
dried over sodium sulfate, and concentrated to a yellow oil. The
crude material was purified by column chromatography (0-7.5% MeOH
in dichloromethane) to give
(4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesul-
fonylamino)acetic acid (188 mg, 36%) as an orange solid.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.23 (d, 2H, J=8.7), 8.19 (s,
1H), 7.99 (d, 1H, J=15.9 Hz), 7.92 (d, 2H, J=7.80 Hz), 7.82 (d, 1H,
J=16.5 Hz), 7.16 (d, 1H, J=6.6 Hz), 7.05 (t, 1H, J=8.1 Hz), 6.76
(s, 1H), 6.71 (d, 1H, J=7.8 Hz), 6.52 (t, 1H, J=7.2 Hz), 5.72 (s,
1H), 5.45 (br s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.41 (m, 2H).
[0451] A suspension of
(4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesul-
fonylamino)acetic acid (Ex-51A, 153 mg, 0.294 mmol) in acetonitrile
(130 mL) was purged with nitrogen gas for 10 minutes. Palladium
(II) chloride (5.2 mg, 0.029 mmol) was added to the reaction
vessel. The reaction mixture was refluxed for 2 h. The reaction
mixture was gravity filtered and yielded a red solid. The crude was
swished in ethanol to give 35 mg (23%) of the title compound as a
red solid, mp 189-190.degree. C. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) 11.18 (br s, 1H), 8.25 (m, 3H), 8.06 (d, 1H, J=15.3
Hz), 7.89 (m, 5H), 7.49 (d, 1H, J=7.8 Hz), 7.41 (d, 1H, J=8.1 Hz),
7.03 (t, 1H, J=6.6 Hz), 6.96 (m, 1H), 6.83 (s, 1H), 4.04 (s, 3H),
3.99 (s, 3H). MS (ESI, for C.sub.27H.sub.24N.sub.2O.sub.7S) Found:
520 [(M+H).sup.+].
Example 52
[0452] ##STR68##
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-yl-phenyl)-acryloyl]-N-pyridin-2-yl-be-
nzenesulfonamide
[0453] A solution 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A,
588 mg, 2.13 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde
(Ex-38B, 500 mg, 2.13 mmol) in DMF (9.3 mL) and MeOH (4.0 mL) was
treated with lithium methoxide (243 mg, 6.39 mmol) and stirred for
20 h at room temperature under nitrogen. The reaction mixture was
quenched with water (25 mL) and extracted ethyl acetate (3.times.50
mL). The product precipitated out of the organic phase to give 535
mg (51%) of the title compound as a red solid, mp 124-128.degree.
C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.16 (d, 2H, J=8.7), 8.02
(d, 1H, J=15.9 Hz), 7.95 (m, 3H), 7.70 (t, 1H, J=7.80 Hz), 7.61 (d,
1H, J=16.2 Hz), 7.18 (d, 1H, J=8.70 Hz), 7.15 (s, 1H), 6.83 (t, 1H,
J=6.0 Hz), 6.66 (s, 1H), 3.84 (s, 6H), 3.13 (m, 4H), 1.18 (m, 4H).
HRMS (ESI) Calcd. for C.sub.26H.sub.27N.sub.3O.sub.5S: 494.1750
[(M+H).sup.+]; Found: 494.1750.
Example 53
[0454] ##STR69##
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-pyridin-2-ylmethy-
lbenzenesulfonamide
[0455] Ex-53A: A solution of 4-acetyl-benzenesulfonyl chloride
(1.94 g, 8.89 mmol) and triethylamine (1.85 mL, 13.3 mmol) in
anhydrous THF (15 mL) was treated with 2-(aminomethyl)pyridine
(1.01 g, 9.34 mmol) at room temperature under nitrogen. The
reaction mixture was stirred for 5 minutes and a precipitate
formed. The reaction mixture was diluted with water (10 mL) and
suction filtration gave
4-acetyl-N-pyridin-2-ylmethylbenzenesulfonamide as a yellow solid
(1.36 g, 65%). .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 8.38 (m, 3H),
8.06 (d, 2H, J=9.0 Hz), 7.87 (d, 2H, J=7.8 Hz), 7.58 (d, 1H, J=8.7
Hz), 7.25 (dd, 1H, J=5.4, 4.5 Hz), 4.04 (d, 2H, J=3.9 Hz), 2.60 (s,
3H).
[0456] A solution 4-acetyl-N-pyridin-2-ylmethyl-benzenesulfonamide
(Ex-53A, 617 mg, 2.13 mmol) and
2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 500 mg, 2.13
mmol) in DMF (9.3 mL) and MeOH (4.0 mL) was treated with lithium
methoxide (162 mg, 4.26 mmol) and stirred for 20 h at room
temperature under nitrogen. The reaction mixture was quenched with
water (20 mL) and extracted ethyl acetate (3.times.50 mL). The
organic phase was brined, dried over sodium sulfate, and
concentrated to a red solid. Crystallization from hot ethanol (25
mL) and water (50 mL) gave the title compound as a red solid (626
mg, 58%), mp 112-116.degree. C. .sup.1H-NMR (300 MHz, DMSO-d.sub.6)
8.40 (m, 3H), 8.19 (d, 2H, J=9.0 Hz), 8.05 (d, 1H, J=15.9 Hz), 7.89
(d, 2H, J=9.0 Hz), 7.62 (m, 2H), 7.25 (dd, 1H, J=4.5, 5.7 Hz), 7.17
(s, 1H), 6.67 (s, 1H), 4.05 (d, 2H, J=5.7 Hz), 3.86 (s, 3H), 3.85
(s, 3H), 3.16 (br s, 4H), 1.82 (br s, 4H). HRMS (ESI) Calcd. for
C.sub.27H.sub.29N.sub.3O.sub.5S: 508.1906 [(M+H).sup.+]; Found:
508.1902.
Example 54
[0457] ##STR70##
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-(3-imidazol-1-ylp-
ropyl)benzenesulfonamide
[0458] A solution
4-acetyl-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (Ex-23A, 653
mg, 2.13 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde
(Ex-38B, 500 mg, 2.13 mmol) in DMF (9.3 mL) and MeOH (4.0 mL) was
treated with lithium methoxide (162 mg, 4.26 mmol) and stirred for
20 h at room temperature under nitrogen atmosphere. The reaction
mixture was quenched with water (75 mL) and extracted ethyl acetate
(3.times.50 mL). The organic phase was brined, dried over sodium
sulfate, and concentrated to a red solid. Crystallization from hot
ethanol (10 mL) and water (12 mL) gave 461 mg (41%) of the title
compound as a red solid, mp 140-143.degree. C. .sup.1H-NMR (300
MHz, DMSO-d.sub.6) 8.23 (d, 2H, J=8.7 Hz), 8.05 (d, 1H, J=15.3 Hz),
7.88 (d, 2H, J=9.3 Hz), 7.64 (d, 1H, J=15.3 Hz), 7.51 (s, 1H), 7.17
(s, 1H), 7.05 (s, 1H), 6.81 (s, 1H), 6.67 (s, 1H), 3.92 (t, 2H,
J=6.9 Hz), 3.86 (s, 6H), 3.15 (m, 4H), 2.68 (t, 2H, J=6.3 Hz), 1.80
(m, 6H). HRMS (ESI) Calcd. for C.sub.27H.sub.32N.sub.4O.sub.5S:
525.2172 (M+H).sup.+; Found: 525.2179.
Example 55
[0459] ##STR71##
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-[3-(4-methyl-pipe-
razin-1-yl)propyl]benzenesulfonamide
[0460] Ex-55A: A chilled solution of 4-acetyl-benzenesulfonyl
chloride (1.0 g, 4.57 mmol) and triethylamine (0.955 mL, 6.86 mmol)
in anhydrous THF (5 mL) was treated with
1-(3-aminopropyl)-4-methylpiperazine (755 mg, 4.80 mmol) under
nitrogen. The reaction mixture was stirred for 30 minutes, quenched
with water (30 mL) and extracted with ethyl acetate (3.times.25
mL). The combined organic phase was brined, dried over sodium
sulfate, and concentrated to
4-acetyl-N-[3-(4-methylpiperazin-1-yl)propyl]benzenesulfonamide as
a brown solid (1.18 g, 76%). .sup.1H-NMR (300 MHz, DMSO-d.sub.6)
8.10 (d, 2H, J=8.1 Hz), 7.86 (d, 2H, J=8.4 Hz), 7.77 (br s, 1H),
2.74 (quartet, 2H, J=5.4 Hz), 2.60 (s, 3H), 2.20-2.13 (m, 10H),
2.09 (s, 3H), 1.45 (quintet, 2H, J=7.2 Hz).
[0461] A solution
4-acetyl-N-[3-(4-methylpiperazin-1-yl)propyl]benzenesulfonamide
(Ex-55A, 830 mg, 2.44 mmol) and
2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde (Ex-38B, 575 mg, 2.44
mmol) in DMF (10.8 mL) and MeOH (4.4 mL) was treated with lithium
methoxide (278 mg, 7.32 mmol) and stirred for 20 h at room
temperature under nitrogen atmosphere. The reaction mixture was
quenched with water (75 mL) and extracted ethyl acetate (3.times.50
mL). The combined organic phase was brined, dried over sodium
sulfate, and concentrated to a red solid. Column chromatography (5%
MeOH in dichloromethane) gave 772 mg (57%) of the title compound as
a brown solid, mp 64-68.degree. C. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) 8.23 (d, 2H, J=8.7), 8.05 (d, 1H, J=15.3 Hz), 7.88
(d, 2H, J=7.5 Hz), 7.76 (t, 1H, J=4.8 Hz), 7.63 (d, 1H, J=15.3 Hz),
7.16 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.16 (br s, 4H), 2.76
(quartet, 2H, J=6.9 Hz), 2.15 (m, 10H), 2.06 (s, 3H), 1.80 (br s,
4H), 1.45 (quintet, 2H, J=6.9 Hz). HRMS (ESI) Calcd. for
C.sub.29H.sub.40N.sub.4O.sub.5S: 557.2798 [(M+H).sup.+]; Found:
557.2798.
Example 56
[0462] ##STR72##
{4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonylamin-
o}acetic acid
[0463] A solution of (4-acetylbenzenesulfonylamino)acetic acid
(Ex-26A, 226 mg, 0.878 mmol) and
2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde (Ex-38B, 216 mg, 0.922
mmol) in DMF (8.0 mL) and MeOH (3.6 mL) was treated with lithium
methoxide (140 mg, 3.69 mmol) and stirred for 21 h at room
temperature under nitrogen. The reaction mixture was quenched with
water (10 mL) and extracted ethyl acetate (2.times.20 mL). The
aqueous phase was acidified with 6N HCl to pH 3 and was extracted
with (3:1) ethyl acetate/THF (6.times.25 mL). The organic phase was
brined, dried over sodium sulfate, and concentrated to a red solid.
Precipitation from dichloromethane (5 mL) gave the title compound
(33 mg, 8%) as a brown solid, mp 155-158.degree. C. .sup.1H-NMR
(300 MHz, DMSO-d.sub.6) 12.06 (br s, 1), 8.22 (m, 3H), 8.04 (d, 1H,
J=15.3 Hz), 7.89 (d, 2H, J=7.8 Hz), 7.64 (d, 1H, J=15.3 Hz), 7.18
(s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.29 (br s, 2H), 3.16 (br s,
4H), 1.82 (br s, 4H). HRMS (ESI) Calcd. for
C.sub.23H.sub.26N.sub.2O.sub.7S: 475.1539 [(M+H).sup.+]; Found:
475.1547.
Example 57
[0464] ##STR73##
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin-2-ylbenze-
nesulfonamide
[0465] Ex-57A: A solution of
4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A, 451 mg, 1.63
mmol) and 5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde
(Ex-35C, 459 mg, 1.63 mmol) in DMF (10.0 mL) and MeOH (5.0 mL) was
treated with lithium methoxide (248 mg, 6.52 mmol). The reaction
mixture was stirred at room temperature for 3 h under nitrogen,
quenched with water (50 mL), and extracted with (3:1) ethyl
acetate/THF (4.times.30 mL). The combined organic phase was brined,
dried over sodium sulfate, and concentrated to a yellow oil. The
crude material was purified by column chromatography (2-5% MeOH in
dichloromethane) to give 735 mg (65%) of
4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin--
2-yl-benzenesulfonamide as a yellow oil. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) 8.21 (d, 2H, J=7.5), 8.18 (s, 1H), 8.00 (m, 4H), 7.81
(d, 1H, J=15.0 Hz), 7.74 (t, 2H, J=7.5 Hz), 7.17 (m, 2H), 7.05 (t,
2H, J=7.2 Hz), 6.80 (m, 3H), 6.52 (t, 1H, J=7.5 Hz), 5.43 (d, 1H,
J=6.9 Hz), 3.96 (s, 3H), 3.95 (s, 3H).
[0466] Ex-57B: ##STR74##
[0467] A solution of
5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 10.3 g,
36.7 mmol) in 500 ml of THF and 500 ml of MeOH was cooled to
0.degree. C. with an ice bath. To this solution was added
NaBH.sub.4 (2.8 g, 73.4 mmol) portion-wise. The mixture was stirred
at 0.degree. C. for 1 h. The reaction was quenched with 1N
H.sub.2SO.sub.4 slowly until no gas bubbling was observed. The
mixture was filtered and the filtrate was concentrated to about 100
ml. The precipitate was filtered to give 9.65 g (92.3%) of
[5-(2-aminophenylethynyl)-2,4-dimethoxyphenyl]methanol as a white
solid. .sup.1H-NMR (300 MHz, Acetone-d.sub.6) .delta. 7.44 (s, 1H),
7.19 (dd, J=8, 1 Hz, 1H), 7.00-7.5 (m, 1H), 6.74 (d, J=8 Hz, 1H),
6.70 (s, 1H), 6.52-6.57 (m, 1H), 5.15 (br, 2H), 4.53 (d, J=5 Hz,
2H), 3.92 (s, 3H), 3.87 (s, 3H).
[0468] Ex-57C: ##STR75##
[0469] To a solution of
[5-(2-aminophenylethynyl)-2,4-dimethoxyphenyl]methanol (Ex-57B,
9.65 g, 34 mmol) in 1 L of acetonitrile, was added PdCl.sub.2 (0.6
g, 3.4 mmol). The mixture was heated to reflux for about 0.5 h and
the reaction was complete as indicated by HPLC. The mixture was
cooled to room temperature and filtered. The filtrate was treated
with 20 g of 3-mercaptopropyl functional silica gel with stirring
for 30 min and then filtered. The filtrate was concentrated and the
residue was recrystallized from EtOAc/hexanes to give 6.25 g
(67.8%) of [5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]methanol as
off-white solid. .sup.1H-NMR (Acetone-d.sub.6) .delta. 10 50 (br,
1H), 7.84 (s, 1H), 7.48 (d, J=7 Hz, 1H), 7.37 (d, J=8 Hz, 1H),
6.91-7.03 (m, 2H), 6.79 (d, J=2 Hz, 1H), 6.77 (s, 1H), 4.59 (s,
2H), 3.98 (s, 3H), 3.88 (s, 3H).
[0470] Ex-57D: ##STR76##
[0471] To a solution of
[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]methanol (Ex-57C, 5.8 g, 20
mmol) in 250 ml of THF and 250 ml of CH.sub.2Cl.sub.2, was added
MnO.sub.2 (1.8 g, 20 mmol). The mixture was heated to reflux. The
reaction was pushed to completion by adding two more portions of
MnO.sub.2 (1.8 g each) within 48 h. The mixture was then cooled to
room temperature and filtered. The filtrate was concentrated and
the residue was recrystallized from EtOAc/Hexane to give 5.1 g
(88%) of 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde. .sup.1H-NMR
(300 MHz, DMSO-d.sub.6) .delta. 11.29 (br s, 1H), 10 24 (s, 1H),
8.10 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.37 (d, J=7 Hz, 1H), 7.01-7.05
(m, 1H), 6.91-6.95 (m, 1H), 6.85-6.86 (m, 2H), 4.06 (s, 3H), 3.99
(s, 3H). HRMS (EI) Calcd. for C.sub.17H.sub.15NO.sub.3: 281.1052
(M.sup.+); Found: 281.1046.
[0472] Ex-57DD: ##STR77##
[0473] A solution of PdCl.sub.2 (0.066 g, 0.373 mmol) in 200 ml of
acetonitrile was heated to reflux. To this solution was added
5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 1.4 g,
5 mmol) portion by portion slowly so that no cloudiness of the
solution occurred. After the addition, the reaction was kept at
reflux for another 10 min. Then the mixture was cooled to room
temperature and filtered. The filtrate was treated with 5 g of
3-mercaptopropyl functional silica gel with stirring for 30 min and
filtered. The filtrate was concentrated and the residue was
recrystallized from EtOAc/Hexane to give 0.84 g (60%) of
5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde, analytical dada
identical as in Ex-57D.
[0474] Ex-57E: ##STR78##
[0475] Pyridine (453 .mu.L, 5.61 mmol) was added to a suspension of
5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 750
mg, 2.67 mmol) in anhydrous methylene chloride (20 mL) and chilled
to 0.degree. C. The reaction mixture was treated dropwise with
acetyl chloride (9.25 mL, 75.1 mmol). Upon completion the reaction
was quenched with 1N HCl (10 mL) and the layers were separated. The
organic layer was washed with brine, dried over sodium sulfate, and
concentrated to dryness. The crude solid was purified by silica gel
chromatography (5% MeOH/CH.sub.2Cl.sub.2) to yield 671 mg (78%) of
N-[2-(5-formyl-2,4-dimethoxyphenylethynyl)phenyl]acetamide as an
off-white solid. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 10.15 (s, 1H),
9.23 (br s, 1H), 7.82 (m, 2H), 7.80 (s, 1H), 7.50 (dd, 1H, J=0.9,
7.8 Hz), 7.35 (dt, 1H, J=1.8, 9.3 Hz), 7.12 (t, 1H, J=7.8 Hz), 6.82
(s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 2.10 (s, 3H).
[0476] Ex-57F: ##STR79##
[0477] N-[2-(5-Formyl-2,4-dimethoxy-phenyl ethynyl)phenyl]acetamide
(Ex-57E, 535 mg, 1.6 mmol) was added to 150 mL of DMF (nitrogen
purged) at room temperature and the resulting solution was heated
to 80.degree. C. Palladium(II) chloride (22 mg) was added in one
portion. After 6 h the reaction mixture was poured into water (50
mL) and EtOAc (50 mL), and the layers were cut. The organic layer
was filtered through Celite, washed with brine, and concentrated to
an orange solid. The crude was purified by silica gel
chromatography (25% ethyl acetate/hexane) to yield 210 mg (39%) of
5-(1-acetyl-1H-indol-2-yl)-2,4-dimethoxybenzaldehyde as a white
solid. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 10.22 (s, 1H), 8.13 (d,
1H, J=8.1 Hz), 7.71 (s, 1H), 7.55 (d, 1H, J=6.3 Hz), 7.25 (m, 2H,
J=6.9 Hz), 6.84 (s, 1H), 6.64 (s, 1H), 4.01 (s, 3H), 3.87 (s, 3H),
2.13 (s, 3H).
[0478] Ex-57G: ##STR80##
[0479] Pyridine (12.6 mL, 156.24 mmol) was added to a suspension of
5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 20.90
g, 74.4 mmol) in anhydrous methylene chloride (572 mL) and chilled
to 0.degree. C. The reaction mixture was treated dropwise with
pivaloyl chloride (9.25 mL, 75.1 mmol) and then aged at room
temperature for 2 h. The reaction was quenched with 1N HCl (200 mL)
and the layers were cut. The organic layer was washed with brine,
dried over sodium sulfate, and concentrated to dryness to afford
21.47 g (79%) of
N-[2-(5-formyl-2,4-dimethoxyphenylethynyl)phenyl]-2,2-dimethylpropionamid-
e as a light brown solid. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 10.14
(s, 1H), 8.74 (br s, 1H), 7.89 (d, 1H, J=8.1 Hz), 7.80 (s, 1H),
7.50 (dd, 1H, J=1.2, 7.8 Hz), 7.35 (dt, 1H, 1.8, 9.3 Hz), 7.12 (t,
1H, J=9.0 Hz), 6.82 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 1.23 (s,
9H).
[0480] Ex-57H: ##STR81##
[0481]
N-[2-(5-Formyl-2,4-dimethoxy-phenylethynyl)phenyl]-2,2-dimethylpro-
pionamide (Ex-57G, 19.86 g, 54.4 mmol) was dissolved in
nitrogen-purged DMF (189 mL) and heated to 80.degree. C., followed
by the addition of palladium(II) chloride (754 mg). After 1 h, the
reaction mixture was diluted with water (300 mL) and extracted with
EtOAc (2.times.200 mL). The combined organic phase was brined,
dried over sodium sulfate, and concentrated to brown oil. The oil
was purified by silica gel chromatography (30 to 50% ethyl
acetate/hexane) to yield 14.31 g (72%) of
5-[1-(2,2-dimethylpropionyl)-1H-indol-2-yl]-2,4-dimethoxybenzaldehyde
as a light yellow solid. .sup.1H-NMR (300 z, CDCl.sub.3) 10.21 (s,
1H), 7.69 (s, 1H), 7.57 (d, 1H, J=37.8 Hz), 7.30 (d, 1H, J=8.10
Hz), 7.20 (t, 1H, J=6.9 Hz), 7.12 (t, 2H, J=6.9 Hz), 6.85 (s, 1H),
6.70 (s, 1H), 4.00 (s, 3H), 3.87 (s, 3H), 0.95 (s, 9H).
[0482] A suspension of
4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin--
2-ylbenzenesulfonamide (Ex-57A, 735 mg, 1.36 mmol) in acetonitrile
(100 mL) was purged with nitrogen for 10 minutes. Palladium(II)
chloride (24 mg, 0.14 mmol) was added and the reaction mixture was
refluxed for 3.5 hrs. The cooled reaction mixture was stirred with
3-mercaptopropyl functionalized silica gel (500 mg) for 5 minutes,
filtered, and concentrated. The crude material was purified by
column chromatography (2% MeOH in dichloromethane) to give 320 mg
(44%) of the title compound as a red solid, mp 206-208.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) 11.13 (br s, 1H), 8.31 (s, 1H),
8.19 (d, 2H, J=7.80 Hz), 8.05 (m, 3H), 7.94 (br s, 1H), 7.82 (d,
1H, J=15.0 Hz), 7.74 (t, 2H, J=7.2 Hz), 7.49 (d, 1H, J=8.1 Hz),
7.41 (d, 1H, J=7.5 Hz), 7.21 (d, 1H, J=8.4 Hz), 7.05 (t, 1H, J=7.5
Hz), 6.95 (m, 2H), 6.82 (s, 2H), 4.03 (s, 3H), 3.98 (s, 3H). HRMS
(ESI) Calcd. for C.sub.30H.sub.25N.sub.3O.sub.5S: 540.1593
(M+H).sup.+; Found: 540.1576.
[0483] Alternatively, 4-Acetyl-N-pyridin-2-ylbenzenesulfonamide
(Ex-5A, 1.52 g, 5.50 mmol),
5-[1-(2,2-dimethylpropionyl)-1H-indol-2-yl]-2,4-dimethoxybenzaldehyde
(Ex-57H, 2.0 g, 5.47 mmol), MeOH (7 mL) and DMF (14 mL) were
sequentially charged into a clean reaction vessel fitted with a
stir bar and nitrogen inlet adapter. LiOMe (0.42 g, 11.1 mmol) was
added and the resulting solution was aged for 45 min at room
temperature. The reaction was diluted with sat. NH.sub.4Cl (25 mL)
and transferred to a separatory funnel containing THF (50 mL),
EtOAc (50 mL) and H.sub.2O (50 mL). The layers were cut and the
organic layer was concentrated to dryness. The crude product was
suspended in EtOH (50 mL), filtered and then dried under vacuum to
afford 2.5 g (85% yield) of the title compound, analytical dada
identical as above. Similarly, the title compound could be prepared
from 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A) and
5-(1-acetyl-1H-indol-2-yl)-2,4-dimethoxybenzaldehyde (Ex-57F) or
5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde (Ex-57D or
Ex-57DD).
[0484] Using one or more of the preceding procedures or methods,
additional compounds of the inventions listed in the following
Tables can be prepared by one skilled in the art. TABLE-US-00001
TABLE 1a ##STR82## Ex. No. R.sup.2B 100 ##STR83## 101 ##STR84## 102
##STR85## 103 ##STR86## 104 ##STR87## 105 ##STR88## 106 ##STR89##
107 ##STR90## 108 ##STR91## 109 ##STR92## 110 ##STR93## 111
##STR94## 112 ##STR95## 113 ##STR96## 114 ##STR97## 115 ##STR98##
116 ##STR99## 117 ##STR100## 118 ##STR101## 119 ##STR102## 120
##STR103## 121 ##STR104## 122 ##STR105## 123 ##STR106## 124
##STR107## 125 ##STR108## 126 ##STR109## 127 ##STR110## 128
##STR111## 129 ##STR112##
[0485] TABLE-US-00002 TABLE 1b ##STR113## Ex. No. R.sup.4 130
##STR114## 131 ##STR115## 132 ##STR116## 133 ##STR117## 134
##STR118## 135 ##STR119## 136 ##STR120## 137 ##STR121## 138
##STR122## 139 ##STR123## 140 ##STR124## 141 ##STR125## 142
##STR126## 143 ##STR127## 144 ##STR128## 145 ##STR129## 146
##STR130## 147 ##STR131## 148 ##STR132## 149 ##STR133## 150
##STR134## 151 ##STR135## 152 ##STR136## 153 ##STR137## 154
##STR138## 155 ##STR139## 156 ##STR140## 157 ##STR141## 158
##STR142## 159 ##STR143##
[0486] TABLE-US-00003 TABLE 1c ##STR144## Ex. No. R.sup.5 160
##STR145## 161 ##STR146## 162 ##STR147## 163 ##STR148## 164
##STR149## 165 ##STR150## 166 ##STR151## 167 ##STR152## 168
##STR153## 169 ##STR154## 170 ##STR155## 171 ##STR156## 172
##STR157## 173 ##STR158## 174 ##STR159## 175 ##STR160## 176
##STR161## 177 ##STR162## 178 ##STR163## 179 ##STR164## 180
##STR165## 181 ##STR166## 182 ##STR167## 183 ##STR168## 184
##STR169## 185 ##STR170## 186 ##STR171## 187 ##STR172## 188
##STR173## 189 ##STR174##
[0487] TABLE-US-00004 TABLE 1d ##STR175## Ex. No. R.sup.5 190
##STR176## 191 ##STR177## 192 ##STR178## 193 ##STR179## 194
##STR180## 195 ##STR181## 196 ##STR182## 197 ##STR183## 198
##STR184## 199 ##STR185## 200 ##STR186## 201 ##STR187## 202
##STR188## 203 ##STR189## 204 ##STR190## 205 ##STR191## 206
##STR192## 207 ##STR193## 208 ##STR194## 209 ##STR195## 210
##STR196## 211 ##STR197## 212 ##STR198## 213 ##STR199## 214
##STR200## 215 ##STR201## 216 ##STR202## 217 ##STR203## 218
##STR204## 219 ##STR205##
[0488] TABLE-US-00005 TABLE 1e ##STR206## Ex. No. R.sup.5 220
##STR207## 221 ##STR208## 222 ##STR209## 223 ##STR210## 224
##STR211## 225 ##STR212## 226 ##STR213## 227 ##STR214## 228
##STR215## 229 ##STR216## 230 ##STR217## 231 ##STR218## 232
##STR219## 233 ##STR220## 234 ##STR221## 235 ##STR222## 236
##STR223## 237 ##STR224## 238 ##STR225## 239 ##STR226## 240
##STR227## 241 ##STR228## 242 ##STR229## 243 ##STR230## 244
##STR231## 245 ##STR232## 246 ##STR233## 247 ##STR234## 248
##STR235## 249 ##STR236##
[0489] TABLE-US-00006 TABLE 3f ##STR237## Ex. No. R.sup.2B 250
##STR238## 251 ##STR239## 252 ##STR240## 253 ##STR241## 254
##STR242## 255 ##STR243## 256 ##STR244## 257 ##STR245## 258
##STR246## 259 ##STR247## 260 ##STR248## 261 ##STR249## 262
##STR250## 263 ##STR251## 264 ##STR252## 265 ##STR253## 266
##STR254## 267 ##STR255## 268 ##STR256## 269 ##STR257## 270
##STR258## 271 ##STR259## 272 ##STR260## 273 ##STR261## 274
##STR262## 275 ##STR263## 276 ##STR264## 277 ##STR265## 278
##STR266## 279 ##STR267##
[0490] TABLE-US-00007 TABLE 1g ##STR268## Ex. No. R.sup.5 280
##STR269## 281 ##STR270## 282 ##STR271## 283 ##STR272## 284
##STR273## 285 ##STR274## 286 ##STR275## 287 ##STR276## 288
##STR277## 289 ##STR278## 290 ##STR279## 291 ##STR280## 292
##STR281## 293 ##STR282## 294 ##STR283## 295 ##STR284## 296
##STR285## 297 ##STR286## 298 ##STR287## 299 ##STR288## 300
##STR289## 301 ##STR290## 302 ##STR291## 303 ##STR292## 304
##STR293## 305 ##STR294## 306 ##STR295## 307 ##STR296## 308
##STR297## 309 ##STR298##
[0491] TABLE-US-00008 TABLE 2a ##STR299## Ex. No. R.sup.2B 310
##STR300## 311 ##STR301## 312 ##STR302## 313 ##STR303## 314
##STR304## 315 ##STR305## 316 ##STR306## 317 ##STR307## 318
##STR308## 319 ##STR309## 320 ##STR310## 321 ##STR311## 322
##STR312## 323 ##STR313## 324 ##STR314## 325 ##STR315## 326
##STR316## 327 ##STR317## 328 ##STR318## 329 ##STR319## 330
##STR320## 331 ##STR321## 332 ##STR322## 333 ##STR323## 334
##STR324## 335 ##STR325## 336 ##STR326## 33 ##STR327## 338
##STR328## 339 ##STR329##
[0492] TABLE-US-00009 TABLE 2b ##STR330## Ex. No. R.sup.4 340
##STR331## 341 ##STR332## 342 ##STR333## 343 ##STR334## 344
##STR335## 345 ##STR336## 346 ##STR337## 347 ##STR338## 348
##STR339## 349 ##STR340## 350 ##STR341## 351 ##STR342## 352
##STR343## 353 ##STR344## 354 ##STR345## 355 ##STR346## 356
##STR347## 357 ##STR348## 358 ##STR349## 359 ##STR350## 360
##STR351## 361 ##STR352## 362 ##STR353## 363 ##STR354## 364
##STR355## 365 ##STR356## 366 ##STR357## 367 ##STR358## 368
##STR359## 369 ##STR360##
[0493] TABLE-US-00010 TABLE 2c ##STR361## Ex. No. R.sup.5 370
##STR362## 371 ##STR363## 372 ##STR364## 373 ##STR365## 374
##STR366## 375 ##STR367## 376 ##STR368## 377 ##STR369## 378
##STR370## 379 ##STR371## 380 ##STR372## 381 ##STR373## 382
##STR374## 383 ##STR375## 384 ##STR376## 385 ##STR377## 386
##STR378## 387 ##STR379## 388 ##STR380## 389 ##STR381## 390
##STR382## 391 ##STR383## 392 ##STR384## 393 ##STR385## 394
##STR386## 395 ##STR387## 396 ##STR388## 397 ##STR389## 398
##STR390## 399 ##STR391##
[0494] TABLE-US-00011 TABLE 2d ##STR392## Ex. No. R.sup.5 400
##STR393## 401 ##STR394## 402 ##STR395## 403 ##STR396## 404
##STR397## 405 ##STR398## 406 ##STR399## 407 ##STR400## 408
##STR401## 409 ##STR402## 410 ##STR403## 411 ##STR404## 412
##STR405## 413 ##STR406## 414 ##STR407## 415 ##STR408## 416
##STR409## 417 ##STR410## 418 ##STR411## 419 ##STR412## 420
##STR413## 421 ##STR414## 422 ##STR415## 423 ##STR416## 424
##STR417## 425 ##STR418## 426 ##STR419## 427 ##STR420## 428
##STR421## 429 ##STR422##
[0495] TABLE-US-00012 TABLE 2e ##STR423## Ex. No. R.sup.5 430
##STR424## 431 ##STR425## 432 ##STR426## 433 ##STR427## 434
##STR428## 435 ##STR429## 436 ##STR430## 437 ##STR431## 438
##STR432## 439 ##STR433## 440 ##STR434## 441 ##STR435## 442
##STR436## 443 ##STR437## 444 ##STR438## 445 ##STR439## 446
##STR440## 447 ##STR441## 448 ##STR442## 449 ##STR443## 450
##STR444## 451 ##STR445## 452 ##STR446## 453 ##STR447## 454
##STR448## 455 ##STR449## 456 ##STR450## 457 ##STR451## 458
##STR452## 459 ##STR453##
[0496] TABLE-US-00013 TABLE 2f ##STR454## Ex. No. R.sup.2B 460
##STR455## 461 ##STR456## 462 ##STR457## 463 ##STR458## 464
##STR459## 465 ##STR460## 466 ##STR461## 467 ##STR462## 468
##STR463## 469 ##STR464## 470 ##STR465## 471 ##STR466## 472
##STR467## 473 ##STR468## 474 ##STR469## 475 ##STR470## 476
##STR471## 477 ##STR472## 478 ##STR473## 479 ##STR474## 480
##STR475## 481 ##STR476## 482 ##STR477## 483 ##STR478## 484
##STR479## 485 ##STR480## 486 ##STR481## 487 ##STR482## 488
##STR483## 489 ##STR484##
[0497] TABLE-US-00014 TABLE 2g ##STR485## Ex. No. R.sup.5 490
##STR486## 491 ##STR487## 492 ##STR488## 493 ##STR489## 494
##STR490## 495 ##STR491## 496 ##STR492## 497 ##STR493## 498
##STR494## 499 ##STR495## 500 ##STR496## 501 ##STR497## 502
##STR498## 503 ##STR499## 504 ##STR500## 505 ##STR501## 506
##STR502## 507 ##STR503## 508 ##STR504## 509 ##STR505## 510
##STR506## 511 ##STR507## 512 ##STR508## 513 ##STR509## 514
##STR510## 515 ##STR511## 516 ##STR512## 517 ##STR513## 518
##STR514## 519 ##STR515##
[0498] TABLE-US-00015 TABLE 3a ##STR516## Ex. No. R.sup.5 730
##STR517## 731 ##STR518## 732 ##STR519## 733 ##STR520## 734
##STR521## 735 ##STR522## 736 ##STR523## 737 ##STR524## 738
##STR525## 739 ##STR526## 740 ##STR527## 741 ##STR528## 742
##STR529## 743 ##STR530## 744 ##STR531## 745 ##STR532## 746
##STR533## 747 ##STR534## 748 ##STR535## 749 ##STR536## 750
##STR537##
[0499] TABLE-US-00016 TABLE 3b ##STR538## Ex. No. R.sup.5 751
##STR539## 752 ##STR540## 753 ##STR541## 754 ##STR542## 755
##STR543## 756 ##STR544## 757 ##STR545## 758 ##STR546## 759
##STR547## 760 ##STR548## 761 ##STR549## 762 ##STR550## 763
##STR551## 764 ##STR552## 765 ##STR553## 766 ##STR554## 767
##STR555## 768 ##STR556## 769 ##STR557## 770 ##STR558## 771
##STR559##
[0500] TABLE-US-00017 TABLE 3c ##STR560## Ex. No. R.sup.5 772
##STR561## 773 ##STR562## 774 ##STR563## 775 ##STR564## 776
##STR565## 777 ##STR566## 778 ##STR567## 779 ##STR568## 780
##STR569## 781 ##STR570## 782 ##STR571## 783 ##STR572## 784
##STR573## 785 ##STR574## 786 ##STR575## 787 ##STR576## 788
##STR577## 789 ##STR578## 790 ##STR579## 791 ##STR580## 792
##STR581##
[0501] TABLE-US-00018 TABLE 3d ##STR582## Ex. No. R.sup.5 793
##STR583## 794 ##STR584## 795 ##STR585## 796 ##STR586## 797
##STR587## 798 ##STR588## 799 ##STR589## 800 ##STR590## 801
##STR591## 802 ##STR592## 803 ##STR593## 804 ##STR594## 805
##STR595## 806 ##STR596## 807 ##STR597## 808 ##STR598## 809
##STR599## 810 ##STR600## 811 ##STR601## 812 ##STR602## 813
##STR603##
[0502] TABLE-US-00019 TABLE 3e ##STR604## Ex. No. R.sup.5 814
##STR605## 815 ##STR606## 816 ##STR607## 817 ##STR608## 818
##STR609## 819 ##STR610## 820 ##STR611## 821 ##STR612## 822
##STR613## 823 ##STR614## 824 ##STR615## 825 ##STR616## 826
##STR617## 827 ##STR618## 828 ##STR619## 829 ##STR620## 830
##STR621## 831 ##STR622## 832 ##STR623## 833 ##STR624## 834
##STR625##
[0503] TABLE-US-00020 TABLE 3f ##STR626## Ex. No. R.sup.5 835
##STR627## 836 ##STR628## 837 ##STR629## 838 ##STR630## 839
##STR631## 840 ##STR632## 841 ##STR633## 842 ##STR634## 843
##STR635## 844 ##STR636## 845 ##STR637## 846 ##STR638## 847
##STR639## 848 ##STR640## 849 ##STR641## 850 ##STR642## 851
##STR643## 852 ##STR644## 853 ##STR645## 854 ##STR646## 855
##STR647##
[0504] TABLE-US-00021 TABLE 3g ##STR648## Ex. No. R.sup.5 856
##STR649## 857 ##STR650## 858 ##STR651## 859 ##STR652## 860
##STR653## 861 ##STR654## 862 ##STR655## 863 ##STR656## 864
##STR657## 865 ##STR658## 866 ##STR659## 867 ##STR660## 868
##STR661## 869 ##STR662## 870 ##STR663## 871 ##STR664## 872
##STR665## 873 ##STR666## 874 ##STR667## 875 ##STR668## 876
##STR669##
[0505] TABLE-US-00022 TABLE 3h ##STR670## Ex. No. R.sup.5 877
##STR671## 878 ##STR672## 879 ##STR673## 880 ##STR674## 881
##STR675## 882 ##STR676## 883 ##STR677## 884 ##STR678## 885
##STR679## 886 ##STR680## 887 ##STR681## 888 ##STR682## 889
##STR683## 890 ##STR684## 891 ##STR685## 892 ##STR686## 893
##STR687## 894 ##STR688## 895 ##STR689## 896 ##STR690## 897
##STR691##
[0506] TABLE-US-00023 TABLE 3i ##STR692## Ex. No. R.sup.5 898
##STR693## 899 ##STR694## 900 ##STR695## 901 ##STR696## 902
##STR697## 903 ##STR698## 904 ##STR699## 905 ##STR700## 906
##STR701## 907 ##STR702## 908 ##STR703## 909 ##STR704## 910
##STR705## 911 ##STR706## 912 ##STR707## 913 ##STR708## 914
##STR709## 915 ##STR710## 916 ##STR711## 917 ##STR712## 918
##STR713##
Stereoisomerism and Polymorphism
[0507] It is appreciated that compounds of the present invention
having a chiral center may exist in and be isolated in optically
active and racemic forms. Some compounds may exhibit polymorphism.
It is to be understood that the present invention encompasses any
racemic, optically-active, diastereomeric, polymorphic, or
stereoisomeric form, or mixtures thereof, of a compound of the
invention, which possess the useful properties described herein, it
being well known in the art how to prepare optically active forms
(for example, by resolution of the racemic form by
recrystallization techniques, by synthesis from optically-active
starting materials, by chiral synthesis, or by chromatographic
separation using a chiral stationary phase).
[0508] Examples of methods to obtain optically active materials are
known in the art, and include at least the following. [0509] i)
physical separation of crystals--a technique whereby macroscopic
crystals of the individual enantiomers are manually separated. This
technique can be used if crystals of the separate enantiomers
exist, i.e., the material is a conglomerate, and the crystals are
visually distinct; [0510] ii) simultaneous crystallization--a
technique whereby the individual enantiomers are separately
crystallized from a solution of the racemate, possible only if the
latter is a conglomerate in the solid state; [0511] iii) enzymatic
resolutions--a technique whereby partial or complete separation of
a racemate by virtue of differing rates of reaction for the
enantiomers with an enzyme; [0512] iv) enzymatic asymmetric
synthesis--a synthetic technique whereby at least one step of the
synthesis uses an enzymatic reaction to obtain an enantiomerically
pure or enriched synthetic precursor of the desired enantiomer;
[0513] v) chemical asymmetric synthesis--a synthetic technique
whereby the desired enantiomer is synthesized from an achiral
precursor under conditions that produce asymmetry (i.e., chirality)
in the product, which may be achieved using chiral catalysts or
chiral auxiliaries; [0514] vi) diastereomer separations--a
technique whereby a racemic compound is reacted with an
enantiomerically pure reagent (the chiral auxiliary) that converts
the individual enantiomers to diastereomers. The resulting
diastereomers are then separated by chromatography or
crystallization by virtue of their now more distinct structural
differences and the chiral auxiliary later removed to obtain the
desired enantiomer; [0515] vii) first- and second-order asymmetric
transformations--a technique whereby diastereomers from the
racemate equilibrate to yield a preponderance in solution of the
diastereomer from the desired enantiomer or where preferential
crystallization of the diastereomer from the desired enantiomer
perturbs the equilibrium such that eventually in principle all the
material is converted to the crystalline diastereomer from the
desired enantiomer. The desired enantiomer is then released from
the diastereomer; [0516] viii) kinetic resolutions--this technique
refers to the achievement of partial or complete resolution of a
racemate (or of a further resolution of a partially resolved
compound) by virtue of unequal reaction rates of the enantiomers
with a chiral, non-racemic reagent or catalyst under kinetic
conditions; [0517] ix) enantiospecific synthesis from non-racemic
precursors--a synthetic technique whereby the desired enantiomer is
obtained from non-chiral starting materials and where the
stereochemical integrity is not or is only minimally compromised
over the course of the synthesis; [0518] x) chiral liquid
chromatography--a technique whereby the enantiomers of a racemate
are separated in a liquid mobile phase by virtue of their differing
interactions with a stationary phase. The stationary phase can be
made of chiral material or the mobile phase can contain an
additional chiral material to provoke the differing interactions;
[0519] xi) chiral gas chromatography--a technique whereby the
racemate is volatilized and enantiomers are separated by virtue of
their differing interactions in the gaseous mobile phase with a
column containing a fixed non-racemic chiral adsorbent phase;
[0520] xii) extraction with chiral solvents--a technique whereby
the enantiomers are separated by virtue of preferential dissolution
of one enantiomer into a particular chiral solvent; [0521] xiii)
transport across chiral membranes--a technique whereby a racemate
is placed in contact with a thin membrane barrier. The barrier
typically separates two miscible fluids, one containing the
racemate, and a driving force such as concentration or pressure
differential causes preferential transport across the membrane
barrier. Separation occurs as a result of the non-racemic chiral
nature of the membrane which allows only one enantiomer of the
racemate to pass through. Pharmaceutically Acceptable Salt
Formulations
[0522] In cases where compounds are sufficiently basic or acidic to
form stable nontoxic acid or base salts, administration of the
compound as a pharmaceutically acceptable salt may be appropriate.
The term "pharmaceutically acceptable salts" or "complexes" refers
to salts or complexes that retain the desired biological activity
of the compounds of the present invention and exhibit minimal
undesired toxicological effects.
[0523] Examples of pharmaceutically acceptable salts are organic
acid addition salts formed with acids, which form a physiological
acceptable anion, for example, tosylate, methanesulfonate, acetate,
citrate, malonate, tartarate, succinate, benzoate, ascorbate,
.alpha.-ketoglutarate and .alpha.-glycerophosphate. Suitable
inorganic salts may also be formed, including, sulfate, nitrate,
bicarbonate and carbonate salts. Alternatively, the
pharmaceutically acceptable salts may be made with sufficiently
basic compounds such as an amine with a suitable acid affording a
physiologically acceptable anion. Alkali metal (for example,
sodium, potassium or lithium) or alkaline earth metal (for example
calcium) salts of carboxylic acids can also be made.
[0524] Nonlimiting examples of such salts are (a) acid addition
salts formed with inorganic acids (for example, hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and
the like), and salts formed with organic acids such as acetic acid,
oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic
acid, benzoic acid, tannic acid, pamoic acid, alginic acid,
polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic
acid, and polygalacturonic acid; (b) base addition salts formed
with metal cations such as zinc, calcium, bismuth, barium,
magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium,
potassium, and the like, or with a cation formed from ammonia,
N,N-dibenzylethylenediamine, D-glucosamine, tetraethylammonium, or
ethylenediamine; or (c) combinations of (a) and (b); e.g., a zinc
tannate salt or the like. Also included in this definition are
pharmaceutically acceptable quaternary salts known by those skilled
in the art, which specifically include the quaternary ammonium salt
of the formula --NR.sup.+A.sup.-, wherein R is as defined above and
A is a counterion, including chloride, bromide, iodide, --O-alkyl,
toluenesulfonate, methylsulfonate, sulfonate, phosphate, or
carboxylate (such as benzoate, succinate, acetate, glycolate,
maleate, malate, citrate, tartrate, ascorbate, benzoate,
cinnamoate, mandeloate, benzyloate, and diphenylacetate).
[0525] Particular FDA-approved salts can be conveniently divided
between anions and cations (Approved Drug Products with Therapeutic
Equivalence Evaluations (1994) U.S. Department of Health and Human
Services, Public Health Service, FDA, Center for Drug Evaluation
and Research, Rockville, Md.; L. D. Bighley, S. M. Berge and D. C.
Monkhouse, Salt Forms of Drugs and Absorption, Encyclopedia of
Pharmaceutical Technology, Vol. 13, J. Swarbridk and J. Boylan,
eds., Marcel Dekker, NY (1996)). Among the approved anions include
aceglumate, acephyllinate, acetamidobenzoate, acetate,
acetylasparaginate, acetylaspartate, adipate, aminosalicylate,
anhydromethylenecitrate, ascorbate, aspartate, benzoate, besylate,
bicarbonate, bisulfate, bitartrate, borate, bromide, camphorate,
camsylate, carbonate, chloride, chlorophenoxyacetate, citrate,
closylate, cromesilate, cyclamate, dehydrocholate, dihydrochloride,
dimalonate, edentate, edisylate, estolate, esylate, ethylbromide,
ethylsulfate, fendizoate, fosfatex, fumarate, gluceptate,
gluconate, glucuronate, glutamate, glycerophosphate, glysinate,
glycollylarsanilate, glycyrrhizate, hippurate, hemisulfate,
hexylresorcinate, hybenzate, hydrobromide, hydrochloride,
hydroiodide, hydroxybenzenesulfonate, hydroxybenzoate,
hydroxynaphthoate, hyclate, iodide, isethionate, lactate,
lactobionate, lysine, malate, maleate, mesylate, methylbromide,
methyliodide, methylnitrate, methylsulfate, monophosadenine,
mucate, napadisylate, napsylate, nicotinate, nitrate, oleate,
orotate, oxalate, oxoglurate, pamoate, pantothenate, pectinate,
phenylethylbarbiturate, phosphate, pacrate, plicrilix, polistirex,
polygalacturonate, propionate, pyridoxylphosphate, saccharinate,
salicylate, stearate, succinate, stearylsulfate, subacetate,
succinate, sulfate, sulfosalicylate, tannate, tartrate,
teprosilate, terephthalate, teoclate, thiocyante, tidiacicate,
timonacicate, tosylate, triethiodide, triethiodide, undecanoate,
and xinafoate. The approved cations include ammonium, benethamine,
benzathine, betaine, calcium, carnitine, clemizole, chlorcyclizine,
choline, dibenylamine, diethanolamine, diethylamine,
diethylammonium diolamine, eglumine, erbumine, ethylenediamine,
heptaminol, hydrabamine, hydroxyethylpyrrolidone, imadazole,
meglumine, olamine, piperazine, 4-phenylcyclohexylamine, procaine,
pyridoxine, triethanolamine, and tromethamine. Metallic cations
include, aluminum, bismuth, calcium lithium, magnesium, neodymium,
potassium, rubidium, sodium, strontium and zinc.
[0526] A particular class of salts can be classified as organic
amine salts. The organic amines used to form these salts can be
primary amines, secondary amines or tertiary amines, and the
substituents on the amine can be straight, branched or cyclic
groups, including ringed structures formed by attachment of two or
more of the amine substituents. Of particular interest are organic
amines that are substituted by one or more hydroxyalkyl groups,
including alditol or carbohydrate moieties. These hydroxy
substituted organic amines can be cyclic or acyclic, both classes
of which can be primary amines, secondary amines or tertiary
amines. A common class of cyclic hydroxy substituted amines are the
amino sugars.
[0527] A particular class of acyclic organic amines are represented
by the formula ##STR714## wherein Y and Z are independently
hydrogen or lower alkyl or, may be taken together to form a ring, R
is hydrogen, alkyl or hydroxyloweralkyl, and n is 1, 2, 3, 4, or 5.
Among these hydroxylamines are a particular class characterized
when n is 4. A representative of this group is meglumine,
represented when Y is hydrogen, Z is methyl and R is methoxy.
Meglumine is also known in the art as N-methylglucamine, N-MG, and
1-deoxy-1-(methylamino)-D-glucitol.
[0528] The invention also includes pharmaceutically acceptable
prodrugs of the compounds. Pharmaceutically acceptable prodrugs
refer to a compound that is metabolized, for example hydrolyzed or
oxidized, in the host to form the compound of the present
invention. Typical examples of prodrugs include compounds that have
biologically labile protecting groups on a functional moiety of the
active compound. Prodrugs include compounds that can be oxidized,
reduced, aminated, deaminated, hydroxylated, dehydroxylated,
hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated,
deacylated, phosphorylated, dephosphorylated to produce the active
compound.
[0529] Any of the compounds described herein can be administered as
a prodrug to increase the activity, bioavailability, stability or
otherwise alter the properties of the compound. A number of prodrug
ligands are known. In general, alkylation, acylation or other
lipophilic modification of the compound will increase the stability
of the chalcone. Examples of substituent groups that can replace
one or more hydrogens on the compound are alkyl, aryl, steroids,
carbohydrates, including sugars, 1,2-diacylglycerol and alcohols.
Many are described in R. Jones and N. Bischofberger, Antiviral
Research, 27 (1995) 1-17. Any of these can be used in combination
with the disclosed compounds to achieve a desired effect.
[0530] The compounds of the present invention can be used to treat
any disorder that is mediated by VCAM-1. Inflammatory disorders
that are mediated by VCAM-1 include, but are not limited to
arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post
transplantation late and chronic solid organ rejection, multiple
sclerosis, systemic lupus erythematosis, inflammatory bowel
diseases, autoimmune diabetes, diabetic retinopathy, diabetic
nephropathy, diabetic vasculopathy, ocular inflammation, uveitis,
rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis,
chronic obstructive pulmonary disease (COPD), glomerulonephritis,
Graves disease, gastrointestinal allergies, conjunctivitis,
atherosclerosis, coronary artery disease, angina and small artery
disease.
[0531] The compounds disclosed herein can be used in the treatment
of inflammatory skin diseases that are mediated by VCAM-1, and in
particular, human endothelial disorders that are mediated by
VCAM-1, which include, but are not limited to, psoriasis,
dermatitis, including eczematous dermatitis, and Kaposi's sarcoma,
as well as proliferative disorders of smooth muscle cells.
[0532] In yet another embodiment, the compounds disclosed herein
can be selected to treat anti-inflammatory conditions that are
mediated by mononuclear leucocytes.
[0533] In yet another embodiment, the compounds of the present
invention can be selected for the prevention or treatment of tissue
or organ transplant rejection. Treatment and prevention of organ or
tissue transplant rejection includes, but are not limited to
treatment of recipients of heart, lung, combined heart-lung, liver,
kidney, pancreatic, skin, spleen, small bowel, or corneal
transplants. They are also indicated for the prevention or
treatment of graft-versus-host disease, which sometimes occurs
following bone marrow transplantation.
[0534] In an alternative embodiment, the compounds described herein
are useful in both the primary and adjunctive medical treatment of
cardiovascular disease. The compounds are used in primary treatment
of, for example, coronary disease states including atherosclerosis,
post-angioplasty restenosis, coronary artery diseases and angina.
The compounds can be administered to treat small vessel disease
that is not treatable by surgery or angioplasty, or other vessel
disease in which surgery is not an option. The compounds can also
be used to stabilize patients prior to revascularization
therapy.
[0535] In another aspect the invention the compounds can be used in
compositions including pharmaceutical compositions for the
treatment of diseases or disorders mediated by VCAM-1 wherein such
compositions comprise a VCAM-1 inhibiting amount of a compound of
the invention or a pharmaceutically acceptable salt thereof and/or
a pharmaceutically acceptable carrier.
[0536] Another aspect of the invention provides a method for
treating a disease or disorder mediated by VCAM-1 comprising
administering to a patient a VCAM-1 inhibiting effective amount of
a compound of the invention or a pharmaceutically acceptable salt
thereof.
[0537] In another aspect the invention provides a method for
treating cardiovascular and inflammatory disorders in a patient in
need thereof comprising administering to said patient an VCAM-1
inhibiting effective amount of a compound of the invention or a
pharmaceutically acceptable salt thereof.
[0538] In another aspect the invention provides a method and
composition for treating asthma or arthritis in a patient in need
thereof comprising administering to said patient an effective
amount of a compound of the invention or a pharmaceutically
acceptable salt thereof.
[0539] Nonlimiting examples of arthritis include rheumatoid (such
as soft-tissue rheumatism and non-articular rheumatism,
fibromyalgia, fibrositis, muscular rheumatism, myofascil pain,
humeral epicondylitis, frozen shoulder, Tietze's syndrome,
fascitis, tendinitis, tenosynovitis, bursitis), juvenile chronic,
spondyloarthropaties (ankylosing spondylitis), osteoarthritis,
hyperuricemia and arthritis associated with acute gout, chronic
gout and systemic lupus erythematosus.
[0540] Human endothelial disorders mediated by VCAM-1 include
psoriasis, eczematous dermatitis, Kaposi's sarcoma, as well as
proliferative disorders of smooth muscle cells.
[0541] In yet another embodiment, the compounds disclosed herein
can be selected to treat anti-inflammatory conditions that are
mediated by mononuclear leucocytes.
[0542] In one embodiment, the compounds of the present invention
are selected for the prevention or treatment of tissue or organ
transplant rejection. Treatment and prevention of organ or tissue
transplant rejection includes, but are not limited to treatment of
recipients of heart, lung, combined heart-lung, liver, kidney,
pancreatic, skin, spleen, small bowel, or corneal transplants. The
compounds can also be used in the prevention or treatment of
graft-versus-host disease, such as sometimes occurs following bone
marrow transplantation.
[0543] In an alternative embodiment, the compounds described herein
are useful in both the primary and adjunctive medical treatment of
cardiovascular disease. The compounds are used in primary treatment
of, for example, coronary disease states including atherosclerosis,
post-angioplasty restenosis, coronary artery diseases and angina.
The compounds can be administered to treat small vessel disease
that is not treatable by surgery or angioplasty, or other vessel
disease in which surgery is not an option. The compounds can also
be used to stabilize patients prior to revascularization
therapy.
[0544] In addition to inhibiting the expression of VCAM-1, some of
the compounds of the invention have the additional properties of
inhibiting monocyte chemoattractant protein-1 (MCP-1) and/or smooth
muscle proliferation. MCP-1 is a chemoattractant protein produced
by endothelial cells, smooth muscle cells as well as macrophages.
MCP-1 promotes integrin activation on endothelial cells thereby
facilitating adhesion of leukocytes to VCAM-1, and MCP-1 is a
chemoattractant for monocytes. MCP-1 has been shown to play a role
in leukocyte recruitment in a number of chronic inflammatory
diseases including atherosclerosis, rheumatoid arthritis, and
asthma. Its expression is upregulated in these diseases and as such
inhibition of MCP-1 expression represents a desirable property of
anti-inflammatory therapeutics. Furthermore, smooth muscle cell
hyperplasia and resulting tissue remodeling and decreased organ
function is yet another characteristic of many chronic inflammatory
diseases including atherosclerosis, chronic transplant rejection
and asthma. Inhibition of the hyperproliferation of smooth muscle
cells is another desirable property for therapeutic compounds.
Combination and Alternation Therapy
[0545] Any of the compounds disclosed herein can be administered in
combination or alternation with a second biologically active agent
to increase its effectiveness against the target disorder.
[0546] In combination therapy, effective dosages of two or more
agents are administered together, whereas during alternation
therapy an effective dosage of each agent is administered serially.
The dosages will depend on absorption, inactivation and excretion
rates of the drug as well as other factors known to those of skill
in the art. It is to be noted that dosage values will also vary
with the severity of the condition to be alleviated. It is to be
further understood that for any particular subject, specific dosage
regimens and schedules should be adjusted over time according to
the individual need and the professional judgment of the person
administering or supervising the administration of the
compositions.
[0547] The efficacy of a drug can be prolonged, augmented, or
restored by administering the compound in combination or
alternation with a second, and perhaps third, agent that induces a
different biological pathway from that caused by the principle
drug. Alternatively, the pharmacokinetics, biodistribution or other
parameter of the drug can be altered by such combination or
alternation therapy. In general, combination therapy is typically
preferred over alternation therapy because it induces multiple
simultaneous stresses on the condition.
[0548] Any method of alternation can be used that provides
treatment to the patient. Nonlimiting examples of alternation
patterns include 1-6 weeks of administration of an effective amount
of one agent followed by 1-6 weeks of administration of an
effective amount of a second agent. The alternation schedule can
include periods of no treatment. Combination therapy generally
includes the simultaneous administration of an effective ratio of
dosages of two or more active agents.
[0549] Illustrative examples of specific agents that can be used in
combination or alternation with the compounds of the present
invention are described below in regard to asthma and arthritis.
The agents set out below or others can alternatively be used to
treat a host suffering from any of the other disorders listed above
or that are mediated by VCAM-1 or MCP-1. Illustrative second
biologically active agents for the treatment of cardiovascular
disease are also provided below.
Asthma
[0550] In one embodiment, the compounds of the present invention
are administered in combination or alternation with heparin,
frusemide, ranitidine, an agent that effects respiratory function,
such as DNAase, or immunosuppressive agents, IV gamma globulin,
troleandomycin, cyclosporin (Neoral), methotrexate, FK-506, gold
compounds such as Myochrysine (gold sodium thiomalate), platelet
activating factor (PAF) antagonists such as thromboxane inhibitors,
leukotriene-D.sub.4-receptor antagonists such as Accolate
(zafirlukast), Ziflo (zileuton), leukotriene C.sub.1 or C.sub.2
antagonists and inhibitors of leukotriene synthesis such as
zileuton for the treatment of asthma, or an inducible nitric oxide
synthase inhibitor.
[0551] In another embodiment, the active compound is administered
in combination or alternation with one or more other prophylactic
agent(s). Examples of prophylactic agents that can be used in
alternation or combination therapy include but are not limited to
sodium cromoglycate, Intal (cromolyn sodium, Nasalcrom, Opticrom,
Crolom, Ophthalmic Crolom), Tilade (nedocromil, nedocromil sodium)
and ketotifen.
[0552] In another embodiment, the active compound is administered
in combination or alternation with one or more other
.beta..sub.2-adrenergic agonist(s) (.beta. agonists). Examples of
.beta..sub.2-adrenergic agonists (.beta. agonists) that can be used
in alternation or combination therapy include but are not limited
to albuterol (salbutamol, Proventil, Ventolin), terbutaline, Maxair
(pirbuterol), Serevent (salmeterol), epinephrine, metaproterenol
(Alupent, Metaprel), Brethine (Bricanyl, Brethaire, terbutaline
sulfate), Tornalate (bitolterol), isoprenaline, ipratropium
bromide, bambuterol hydrochloride, bitolterol meslyate, broxaterol,
carbuterol hydrochloride, clenbuterol hydrochloride, clorprenaline
hydrochloride, efirmoterol fumarate, ephedra (source of alkaloids),
ephedrine (ephedrine hydrochloride, ephedrine sulfate), etafedrine
hydrochloride, ethylnoradrenaline hydrochloride, fenoterol
hydrochloride, hexoprenaline hydrochloride, isoetharine
hydrochloride, isoprenaline, mabuterol, methoxyphenamine
hydrochloride, methylephedrine hydrochloride, orciprenaline
sulphate, phenylephrine acid tartrate, phenylpropanolamine
(phenylpropanolamine polistirex, phenylpropanolamine sulphate),
pirbuterol acetate, procaterol hydrochloride, protokylol
hydrochloride, psuedoephedrine (psuedoephedrine polixtirex,
psuedoephedrine tannate, psuedoephedrine hydrochloride,
psuedoephedrine sulphate), reproterol hydrochloride, rimiterol
hydrobromide, ritodrine hydrochloride, salmeterol xinafoate,
terbutaline sulphate, tretoquinol hydrate and tulobuterol
hydrochloride.
[0553] In another embodiment, the active compound is administered
in combination or alternation with one or more other
corticosteriod(s). Examples of corticosteriods that can be used in
alternation or combination therapy include but are not limited to
glucocorticoids (GC), Aerobid (Aerobid-M, flunisolide), Azmacort
(triamcinolone acetonide), Beclovet (Vanceril, beclomethasone
dipropionate), Flovent (fluticasone), Pulmicort (budesonide),
prednisolone, hydrocortisone, adrenaline, Alclometasone
Dipropionate, Aldosterone, Amcinonide, Beclomethasone Dipropionate,
Bendacort, Betamethasone (Betamethasone Acetate, Betamethasone
Benzoate, Betamethasone Dipropionate, Betamethasone Sodium
Phosphate, Betamethasone Valerate), Budesonide, Ciclomethasone,
Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate,
Clocortolone Pivalate, Cloprednol, Cortisone Acetate, Cortivazol,
Deflazacort, Deoxycortone Acetate (Deoxycortone Pivalate),
Deprodone, Desonide, Desoxymethasone, Dexamethasone (Dexamethasone
Acetate, Dexamethasone Isonicotinate, Dexamethasone Phosphate,
Dexamethasone Sodium Metasulphobenzoate, Dexamethasone Sodium
Phosphate), Dichlorisone Acetate, Diflorasone Diacetate,
Diflucortolone Valerate, Difluprednate, Domoprednate, Endrysone,
Fluazacort, Fluclorolone Acetonide, Fludrocortisone Acetate,
Flumethasone (Flumethasone Pivalate), Flunisolide, Fluocinolone
Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone
(Fluocortolone Hexanoate, Fluocortolone Pivalate), Fluorometholone
(Fluorometholone Acetate), Fluprednidene Acetate, Fluprednisolone,
Flurandrenolone, Fluticasone Propionate, Formocortal, Halcinonide,
Halobetasol Propionate, Halometasone, Hydrocortamate Hydrochloride,
Hydrocortisone (Hydrocortisone Acetate, Hydrocortisone Butyrate,
Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate,
Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate,
Hydrocortisone Valerate), Medrysone, Meprednisone,
Methylprednisolone (Methylprednisolone Acetate, Methylprednisolone,
Hemisuccinate, Methylprednisolone Sodium Succinate), Mometasone
Furoate, Paramethasone Acetate, Prednicarbate, Prednisolamate
Hydrochloride, Prednisolone (Prednisolone Acetate, Prednisolone
Hemisuccinate, Prednisolone Hexanoate, Prednisolone Pivalate,
Prednisolone Sodium Metasulphobenzoate, Prednisolone Sodium
Phosphate, Prednisolone Sodium Succinate, Prednisolone Steaglate,
Prednisolone Tebutate), Prednisone (Prednisone Acetate),
Prednylidene, Procinonide, Rimexolone, Suprarenal Cortex,
Tixocortol Pivalate, Triamcinolone (Triamcinolone Acetonide,
Triamcinolone Diacetate and Triamcinolone Hexacetonide).
[0554] In another embodiment, the active compound is administered
in combination or alternation with one or more other
antihistimine(s) (H.sub.1 receptor antagonists). Examples of
antihistimines (H.sub.1 receptor antagonists) that can be used in
alternation or combination therapy include alkylamines,
ethanolamines ethylenediamines, piperazines, piperidines or
phenothiazines. Some non-limiting examples of antihistamines are
Chlortrimeton (Teldrin, chlorpheniramine), Atrohist
(brompheniramine, Bromarest, Bromfed, Dimetane), Actidil
(triprolidine), Dexchlor (Poladex, Polaramine,
dexchlorpheniramine), Benadryl (diphenhydramine), Tavist
(clemastine), Dimetabs (dimenhydrinate, Dramamine, Marmine), PBZ
(tripelennamine), pyrilamine, Marezine (cyclizine), Zyrtec
(cetirizine), hydroxyzine, Antivert (meclizine, Bonine), Allegra
(fexofenadine), Hismanal (astemizole), Claritin (loratadine),
Seldane (terfenadine), Periactin (cyproheptadine), Nolamine
(phenindamine, Nolahist), Phenameth (promethazine, Phenergan),
Tacaryl (methdilazine) and Temaril (trimeprazine).
[0555] Alternatively, the compound of the present invention may be
administered in combination or alternation with [0556] (a)
xanthines and methylxanthines, such as Theo-24 (theophylline,
Slo-Phylline, Uniphyllin, Slobid, Theo-Dur), Choledyl
(oxitriphylline), aminophylline; [0557] (b) anticholinergic agents
(antimuscarinic agents) such as belladonna alkaloids, Atrovent
(ipratropium bromide), atropine, oxitropium bromide; [0558] (c)
phosphodiesterase inhibitors, including phosphodiesterase IV
inhibitors such as zardaverine; [0559] (d) calcium antagonists such
as nifedipine; [0560] (e) potassium activators such as cromakalim
for the treatment of asthma; [0561] (f) B-eotaxin chemokine
receptor, CCR3, antagonists; or [0562] (g) IL-5 antibodies, IL-13
antibodies, IL-13 antagonists, IL-4 receptor antagonists, and IgE
antibodies. Arthritic Disorders
[0563] In one embodiment, the compound of the present invention can
also be administered in combination or alternation with apazone,
amitriptyline, chymopapain, collegenase, cyclobenzaprine, diazepam,
fluoxetine, pyridoxine, ademetionine, diacerein, glucosamine, hylan
(hyaluronate), misoprostol, paracetamol, superoxide dismutase
mimics, IL-1 receptor antagonists, IL-2 receptor antagonists, IL-6
receptor antagonists, TNF.alpha. receptor antagonists, TNF.alpha.
antibodies, P38 MAP Kinase inhibitors, tricyclic antidepressents,
cJun kinase inhibitors or immunosuppressive agents, IV gamma
globulin, troleandomycin, cyclosporin (Neoral), methotrexate,
FK-506, gold compounds such as Myochrysine (gold sodium
thiomalate), platelet activating factor (PAF) antagonists such as
thromboxane inhibitors, MAPKAPK2 (MK2) Kinase inhibitors, CCR5
Receptor antagonists, Interleukin Converting Enzyme (ICE)
inhibitors, IKB Kinase (IKK1, IKK2) inhibitors, TNF-.alpha.
Convertase Enzyme (TACE) inhibitors, ICK Kinase inhibitors, Janus
Kinase 3 (JAK3) inhibitors, Kinase insert domain-containing
Receptor (KdR) Kinase inhibitors, and inducible nitric oxide
synthase (iNOS) inhibitors.
[0564] In another embodiment, the active compound is administered
in combination or alternation with one or more other
corticosteriod(s). Examples of corticosteriods that can be used in
alternation or combination therapy include but are not limited to
glucocorticoids (GC), Aerobid (Aerobid-M, flunisolide), Azmacort
(triamcinolone acetonide), Beclovet (Vanceril, beclomethasone
dipropionate), Flovent (fluticasone), Pulmicort (budesonide),
prednisolone, hydrocortisone, adrenaline, Alclometasone
Dipropionate, Aldosterone, Amcinonide, Beclomethasone Dipropionate,
Bendacort, Betamethasone (Betamethasone Acetate, Betamethasone
Benzoate, Betamethasone Dipropionate, Betamethasone Sodium
Phosphate, Betamethasone Valerate), Budesonide, Ciclomethasone,
Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate,
Clocortolone Pivalate, Cloprednol, Cortisone Acetate, Cortivazol,
Deflazacort, Deoxycortone Acetate (Deoxycortone Pivalate),
Deprodone, Desonide, Desoxymethasone, Dexamethasone (Dexamethasone
Acetate, Dexamethasone Isonicotinate, Dexamethasone Phosphate,
Dexamethasone Sodium Metasulphobenzoate, Dexamethasone Sodium
Phosphate), Dichlorisone Acetate, Diflorasone Diacetate,
Diflucortolone Valerate, Difluprednate, Domoprednate, Endrysone,
Fluazacort, Fluclorolone Acetonide, Fludrocortisone Acetate,
Flumethasone (Flumethasone Pivalate), Flunisolide, Fluocinolone
Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone
(Fluocortolone Hexanoate, Fluocortolone Pivalate), Fluorometholone
(Fluorometholone Acetate), Fluprednidene Acetate, Fluprednisolone,
Flurandrenolone, Fluticasone Propionate, Formocortal, Halcinonide,
Halobetasol Propionate, Halometasone, Hydrocortamate Hydrochloride,
Hydrocortisone (Hydrocortisone Acetate, Hydrocortisone Butyrate,
Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate,
Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate,
Hydrocortisone Valerate), Medrysone, Meprednisone,
Methylprednisolone (Methylprednisolone Acetate, Methylprednisolone,
Hemisuccinate, Methylprednisolone Sodium Succinate), Mometasone
Furoate, Paramethasone Acetate, Prednicarbate, Prednisolamate
Hydrochloride, Prednisolone (Prednisolone Acetate, Prednisolone
Hemisuccinate, Prednisolone Hexanoate, Prednisolone Pivalate,
Prednisolone Sodium Metasulphobenzoate, Prednisolone Sodium
Phosphate, Prednisolone Sodium Succinate, Prednisolone Steaglate,
Prednisolone Tebutate), Prednisone (Prednisone Acetate),
Prednylidene, Procinonide, Rimexolone, Suprarenal Cortex,
Tixocortol Pivalate, Triamcinolone (Triamcinolone Acetonide,
Triamcinolone Diacetate and Triamcinolone Hexacetonide).
[0565] In another embodiment, the active compound is administered
in combination or alternation with one or more other non-steroidal
anti-inflammatory drug(s) (NSAIDS). Examples of NSAIDS that can be
used in alternation or combination therapy are carboxylic acids,
propionic acids, fenamates, acetic acids, pyrazolones, oxicans,
alkanones, gold compounds and others that inhibit prostaglandin
synthesis, preferably by selectively inhibiting cylcooxygenase-2
(COX-2). Some nonlimiting examples of COX-2 inhibitors are Celebrex
(celecoxib), Bextra (valdecoxib), Dynastat (parecoxib sodium) and
Vioxx (rofacoxib). Some non-limiting examples of NSAIDS are aspirin
(acetylsalicylic acid), Dolobid (diflunisal), Disalcid (salsalate,
salicylsalicylate), Trisilate (choline magnesium trisalicylate),
sodium salicylate, Cuprimine (penicillamine), Tolectin (tolmetin),
ibuprofen (Motrin, Advil, Nuprin Rufen), Naprosyn (naproxen,
Anaprox, naproxen sodium), Nalfon (fenoprofen), Orudis
(ketoprofen), Ansaid (flurbiprofen), Daypro (oxaprozin),
meclofenamate (meclofanamic acid, Meclomen), mefenamic acid,
Indocin (indomethacin), Clinoril (sulindac), tolmetin, Voltaren
(diclofenac), Lodine (etodolac), ketorolac, Butazolidin
(phenylbutazone), Tandearil (oxyphenbutazone), piroxicam (Feldene),
Relafen (nabumetone), Myochrysine (gold sodium thiomalate), Ridaura
(auranofin), Solganal (aurothioglucose), acetaminophen, colchicine,
Zyloprim (allopurinol), Benemid (probenecid), Anturane
(sufinpyrizone), Plaquenil (hydroxychloroquine), Aceclofenac,
Acemetacin, Acetanilide, Actarit, Alclofenac, Alminoprofen,
Aloxiprin, Aluminium Aspirin, Amfenac Sodium, Amidopyrine,
Aminopropylone, Ammonium Salicylate, Ampiroxicam, Amyl Salicylate,
Anirolac, Aspirin, Auranofin, Aurothioglucose, Aurotioprol,
Azapropazone, Bendazac (Bendazac Lysine), Benorylate, Benoxaprofen,
Benzpiperylone, Benzydamine, Hydrochloride, Bornyl Salicylate,
Bromfenac Sodium, Bufexamac, Bumadizone Calcium, Butibufen Sodium,
Capsaicin, Carbaspirin Calcium, Carprofen, Chlorthenoxazin, Choline
Magnesium Trisalicylate, Choline Salicylate, Cinmetacin,
Clofexamide, Clofezone, Clometacin, Clonixin, Cloracetadol, Cymene,
Diacerein, Diclofenac (Diclofenac Diethylammonium Salt, Diclofenac
Potassium, Diclofenac Sodium), Diethylamine Salicylate,
Diethylsalicylamide, Difenpiramide, Diflunisal, Dipyrone, Droxicam,
Epirizole, Etenzamide, Etersalate, Ethyl Salicylate, Etodolac,
Etofenamate, Felbinac, Fenbufen, Fenclofenac, Fenoprofen Calcium,
Fentiazac, Fepradinol, Feprazone, Floctafenine, Flufenamic,
Flunoxaprofen, Flurbiprofen (Flurbiprofen Sodium), Fosfosal,
Furprofen, Glafenine, Glucametacin, Glycol Salicylate, Gold
Keratinate, Harpagophytum Procumbens, Ibufenac, Ibuprofen,
Ibuproxam, Imidazole Salicylate, Indomethacin (Indomethacin
Sodium), Indoprofen, Isamifazone, Isonixin, Isoxicam, Kebuzone,
Ketoprofen, Ketorolac Trometamol, Lithium Salicylate, Lonazolac
Calcium, Lomoxicam, Loxoprofen Sodium, Lysine Aspirin, Magnesium
Salicylate, Meclofenamae Sodium, Mefenamic Acid, Meloxicam, Methyl
Butetisalicylate, Methyl Gentisate, Methyl Salicylate, Metiazinic
Acid, Metifenazone, Mofebutazone, Mofezolac, Morazone
Hydrochloride, Morniflumate, Morpholine Salicylate, Nabumetone,
Naproxen (Naproxen Sodium), Nifenazone, Niflumic Acid, Nimesulide,
Oxametacin, Oxaprozin, Oxindanac, Oxyphenbutazone, Parsalmide,
Phenybutazone, Phenyramidol Hydrochloride, Picenadol Hydrochloride,
Picolamine Salicylate, Piketoprofen, Pirazolac, Piroxicam,
Pirprofen, Pranoprofen, Pranosal, Proglumetacin Maleate,
Proquazone, Protizinic Acid, Ramifenazone, Salacetamide,
Salamidacetic Acid, Salicylamide, Salix, Salol, Salsalate, Sodium
Aurothiomalate, Sodium Gentisate, Sodium Salicylate, Sodium
Thiosalicylate, Sulindac, Superoxide Dismutase (Orgotein,
Pegorgotein, Sudismase), Suprofen, Suxibuzone, Tenidap Sodium,
Tenoxicam, Tetrydamine, Thurfyl Salicylate, Tiaprofenic, Tiaramide
Hydrochloride, Tinoridine Hydrochloride, Tolfenamic Acid, Tometin
Sodium, Triethanolamine Salicylate, Ufenamate, Zaltoprofen,
Zidometacin and Zomepirac Sodium.
Cardiovascular Disease
[0566] Compounds useful for combining with the compounds of the
present invention for the treatment of cardiovascular disease
encompass a wide range of therapeutic compounds.
[0567] Ileal bile acid transporter (IBAT) inhibitors, for example,
are useful in the present invention, and are disclosed in patent
application no. PCT/US95/10863, herein incorporated by reference.
More IBAT inhibitors are described in PCT/US97/04076, herein
incorporated by reference. Still further IBAT inhibitors useful in
the present invention are described in U.S. application Ser. No.
08/816,065, herein incorporated by reference. More IBAT inhibitor
compounds useful in the present invention are described in WO
98/40375, and WO 00/38725, herein incorporated by reference.
Additional IBAT inhibitor compounds useful in the present invention
are described in U.S. application Ser. No. 08/816,065, herein
incorporated by reference.
[0568] In another aspect, the second biologically active agent is a
statin. Statins lower cholesterol by inhibiting of
3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, a key
enzyme in the cholesterol biosynthetic pathway. The statins
decrease liver cholesterol biosynthesis, which increases the
production of LDL receptors thereby decreasing plasma total and LDL
cholesterol (Grundy, S. M. New Engl. J. Med. 319, 24 (1988); Endo,
A. J. Lipid Res. 33, 1569 (1992)). Depending on the agent and the
dose used, statins may decrease plasma triglyceride levels and may
increase HDLc. Currently the statins on the market are lovastatin
(Merck), simvastatin (Merck), pravastatin (Sankyo and Squibb) and
fluvastatin (Sandoz). A fifth statin, atorvastatin
(Parke-Davis/Pfizer), is the most recent entrant into the statin
market. Any of these statins or thers can be used in combination
with the chalcones of the present invention.
[0569] MTP inhibitor compounds useful in the combinations and
methods of the present invention comprise a wide variety of
structures and functionalities. Some of the MTP inhibitor compounds
of particular interest for use in the present invention are
disclosed in WO 00/38725, the disclosure from which is incorporated
by reference. Descriptions of these therapeutic compounds can be
found in Science, 282, 23 Oct. 1998, pp. 751-754, herein
incorporated by reference.
[0570] Cholesterol absorption antagonist compounds useful in the
combinations and methods of the present invention comprise a wide
variety of structures and functionalities. Some of the cholesterol
absorption antagonist compounds of particular interest for use in
the present invention are described in U.S. Pat. No. 5,767,115,
herein incorporated by reference. Further cholesterol absorption
antagonist compounds of particular interest for use in the present
invention, and methods for making such cholesterol absorption
antagonist compounds are described in U.S. Pat. No. 5,631,365,
herein incorporated by reference.
[0571] A number of phytosterols suitable for the combination
therapies of the present invention are described by Ling and Jones
in "Dietary Phytosterols: A Review of Metabolism, Benefits and Side
Effects," Life Sciences, 57 (3), 195-206 (1995). Without
limitation, some phytosterols of particular use in the combination
of the present invention are Clofibrate, Fenofibrate, Ciprofibrate,
Bezafibrate, Gemfibrozil. The structures of the foregoing compounds
can be found in WO 00/38725.
[0572] Phytosterols are also referred to generally by Nes
(Physiology and Biochemistry of Sterols, American Oil Chemists'
Society, Champaign, Ill., 1991, Table 7-2). Especially preferred
among the phytosterols for use in the combinations of the present
invention are saturated phytosterols or stanols. Additional stanols
are also described by Nes (Id.) and are useful in the combination
of the present invention. In the combination of the present
invention, the phytosterol preferably comprises a stanol. In one
preferred embodiment the stanol is campestanol. In another
preferred embodiment the stanol is cholestanol. In another
preferred embodiment the stanol is clionastanol. In another
preferred embodiment the stanol is coprostanol. In another
preferred embodiment the stanol is 22,23-dihydrobrassicastanol. In
another embodiment the stanol is epicholestanol. In another
preferred embodiment the stanol is fucostanol. In another preferred
embodiment the stanol is stigmastanol.
[0573] Another embodiment the present invention encompasses a
therapeutic combination of a compound of the present invention and
an HDLc elevating agent. In one aspect, the second HDLc elevating
agent can be a CETP inhibitor. Individual CETP inhibitor compounds
useful in the present invention are separately described in WO
00/38725, the disclosure of which is herein incorporated by
reference. Other individual CETP inhibitor compounds useful in the
present invention are separately described in WO 99/14174,
EP818448, WO 99/15504, WO 99/14215, WO 98/04528, and WO 00/17166,
the disclosures of which are herein incorporated by reference.
Other individual CETP inhibitor compounds useful in the present
invention are separately described in WO 00/18724, WO 00/18723, and
WO 00/18721, the disclosures of which are herein incorporated by
reference. Other individual CETP inhibitor compounds useful in the
present invention are separately described in WO 98/35937 as well
as U.S. Pat. Nos. 6,313,142, 6,310,075, 6,197,786, 6,147,090,
6,147,089, 6,140,343, and 6,140,343, the disclosures of which is
herein incorporated by reference.
[0574] In another aspect, the second biologically active agent can
be a fibric acid derivative. Fibric acid derivatives useful in the
combinations and methods of the present invention comprise a wide
variety of structures and functionalities which have been reported
and published in the art.
[0575] The compounds of the present invention may also be used in
combination or alternation therapy with PPAR agonists including
PPAR.alpha./.gamma. dual agonists, PPAR.alpha. agonists, and
PPAR.gamma. agonists.
[0576] In another embodiment the present invention encompasses a
therapeutic combination of a compound of the present invention and
an antihypertensive agent. Hypertension is defined as persistently
high blood pressure. In another embodiment, the chalcone is
administered in combination with an ACE inhibitor, a beta
andrenergic blocker, alpha andrenergic blocker, angiotensin II
receptor antagonist, vasodilator and diuretic.
Pharmaceutical Compositions
[0577] Any host organism, including a patient, mammal, and
specifically a human, suffering from any of the above-described
conditions can be treated by the administration of a composition
comprising an effective amount of the compound of the invention or
a pharmaceutically acceptable salt thereof, optionally in a
pharmaceutically acceptable carrier or diluent.
[0578] The composition can be administered in any desired manner,
including oral, topical, parenteral, intravenous, intradermal,
intra-articular, intra-synovial, intrathecal, intra-arterial,
intracardiac, intramuscular, subcutaneous, intraorbital,
intracapsular, intraspinal, intrasternal, topical, transdermal
patch, via rectal, vaginal or urethral suppository, peritoneal,
percutaneous, nasal spray, surgical implant, internal surgical
paint, infusion pump, or via catheter. In one embodiment, the agent
and carrier are administered in a slow release formulation such as
an implant, bolus, microparticle, microsphere, nanoparticle or
nanosphere. For standard information on pharmaceutical
formulations, see Ansel, et al., Pharmaceutical Dosage Forms and
Drug Delivery Systems, Sixth Edition, Williams & Wilkins
(1995).
[0579] An effective dose for any of the herein described conditions
can be readily determined by the use of conventional techniques and
by observing results obtained under analogous circumstances. In
determining the effective dose, a number of factors are considered
including, but not limited to: the species of patient; its size,
age, and general health; the specific disease involved; the degree
of involvement or the severity of the disease; the response of the
individual patient; the particular compound administered; the mode
of administration; the bioavailability characteristics of the
preparation administered; the dose regimen selected; and the use of
concomitant medication. Typical systemic dosages for all of the
herein described conditions are those ranging from 0.1 mg/kg to 500
mg/kg of body weight per day as a single daily dose or divided
daily doses. Preferred dosages for the described conditions range
from 5-1500 mg per day. A more particularly preferred dosage for
the desired conditions ranges from 25-750 mg per day. Typical
dosages for topical application are those ranging from 0.001 to
100% by weight of the active compound.
[0580] The compound is administered for a sufficient time period to
alleviate the undesired symptoms and the clinical signs associated
with the condition being treated.
[0581] The active compound is included in the pharmaceutically
acceptable carrier or diluent in an amount sufficient to deliver to
a patient a therapeutic amount of compound in vivo in the absence
of serious toxic effects.
[0582] The concentration of active compound in the drug composition
will depend on absorption, inactivation, and excretion rates of the
drug as well as other factors known to those of skill in the art.
It is to be noted that dosage values will also vary with the
severity of the condition to be alleviated. It is to be further
understood that for any particular subject, specific dosage
regimens should be adjusted over time according to the individual
need and the professional judgment of the person administering or
supervising the administration of the compositions, and that the
dosage ranges set forth herein are exemplary only and are not
intended to limit the scope or practice of the claimed composition.
The active ingredient may be administered at once, or may be
divided into a number of smaller doses to be administered at
varying intervals of time.
[0583] A preferred mode of administration of the active compound
for systemic delivery is oral. Oral compositions will generally
include an inert diluent or an edible carrier. They may be enclosed
in gelatin capsules or compressed into tablets. For the purpose of
oral therapeutic administration, the active compound can be
incorporated with excipients and used in the form of tablets,
troches or capsules. Pharmaceutically compatible binding agents,
and/or adjuvant materials can be included as part of the
composition.
[0584] The tablets, pills, capsules, troches and the like can
contain any of the following ingredients, or compounds of a similar
nature: a binder such as microcrystalline cellulose, gum tragacanth
or gelatin; an excipient such as starch or lactose, a
disintegrating agent such as alginic acid, Primogel, or corn
starch; a lubricant such as magnesium stearate or Sterotes; a
glidant such as colloidal silicon dioxide; a sweetening agent such
as sucrose or saccharin; or a flavoring agent such as peppermint,
methyl salicylate, or orange flavoring.
[0585] When the dosage unit form is a capsule, it can contain, in
addition to material of the above type, a liquid carrier such as a
fatty oil. In addition, dosage unit forms can contain various other
materials which modify the physical form of the dosage unit, for
example, coatings of sugar, shellac, or other enteric agents.
[0586] The compound or its salts can be administered as a component
of an elixir, suspension, syrup, wafer, chewing gum or the like. A
syrup may contain, in addition to the active compounds, sucrose as
a sweetening agent and certain preservatives, dyes and colorings
and flavors.
[0587] The compound can also be mixed with other active materials
that do not impair the desired action, or with materials that
supplement the desired action. The compounds can also be
administered in combination with nonsteroidal antiinflammatories
such as ibuprofen, indomethacin, fenoprofen, mefenamic acid,
flufenamic acid, sulindac. The compound can also be administered
with corticosteriods.
[0588] Solutions or suspensions used for parenteral, intradermal,
subcutaneous, or topical application can include the following
components: a sterile diluent such as water for injection, saline
solution, fixed oils, polyethylene glycols, glycerine, propylene
glycol or other synthetic solvents; antibacterial agents such as
benzyl alcohol or methyl parabens; antioxidants such as ascorbic
acid or sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid; buffers such as acetates, citrates
or phosphates and agents for the adjustment of tonicity such as
sodium chloride or dextrose. pH can be adjusted with acids or
bases, such as hydrochloric acid or sodium hydroxide. The
parenteral preparation can be enclosed in ampoules, disposable
syringes or multiple dose vials made of glass or plastic.
[0589] If administered intravenously, preferred carriers are
physiological saline, bacteriostatic water, Cremophor EL.TM. (BASF,
Parsippany, N.J.) or phosphate buffered saline (PBS).
[0590] In a preferred embodiment, the active compounds are prepared
with carriers that will protect the compound against rapid
elimination from the body, such as a controlled release
formulation, including implants and microencapsulated delivery
systems. Biodegradable, biocompatible polymers can be used, such as
ethylene vinyl acetate, polyanhydrides, polyglycolic acid,
collagen, polyorthoesters and polylactic acid. Methods for
preparation of such formulations will be apparent to those skilled
in the art. The materials can also be obtained commercially from
Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal
suspensions (including liposomes targeted to infected cells with
monoclonal antibodies to viral antigens) are also preferred as
pharmaceutically acceptable carriers. These may be prepared
according to methods known to those skilled in the art, for
example, as described in U.S. Pat. No. 4,522,811 (which is
incorporated herein by reference in its entirety). For example,
liposome formulations may be prepared by dissolving appropriate
lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl
phosphatidyl choline, arachadoyl phosphatidyl choline, and
cholesterol) in an inorganic solvent that is then evaporated,
leaving behind a thin film of dried lipid on the surface of the
container. An aqueous solution of the compound is then introduced
into the container. The container is then swirled by hand to free
lipid material from the sides of the container and to disperse
lipid aggregates, thereby forming the liposomal suspension.
[0591] Suitable vehicles or carriers for topical application can be
prepared by conventional techniques, such as lotions, suspensions,
ointments, creams, gels, tinctures, sprays, powders, pastes,
slow-release transdermal patches, suppositories for application to
rectal, vaginal, nasal or oral mucosa. In addition to the other
materials listed above for systemic administration, thickening
agents, emollients and stabilizers can be used to prepare topical
compositions. Examples of thickening agents include petrolatum,
beeswax, xanthan gum, or polyethylene, humectants such as sorbitol,
emollients such as mineral oil, lanolin and its derivatives, or
squalene.
[0592] Any of the compounds described herein for combination or
alternation therapy can be administered as any derivative that upon
administration to the recipient, is capable of providing directly
or indirectly, the parent compound, or that exhibits activity
itself. Nonlimiting examples are the pharmaceutically acceptable
salts (alternatively referred to as "physiologically acceptable
salts"), and a compound which has been alkylated or acylated at an
appropriate position. The modifications can affect the biological
activity of the compound, in some cases increasing the activity
over the parent compound. This can easily be assessed by preparing
the derivative and testing its anti-inflammatory activity according
to known methods.
Biological Activity of Active Compounds
[0593] The ability of a compound described herein to inhibit the
expression of VCAM-1 or in the treatment of diseases in a host can
be assessed using any known method, including that described in
detail below.
In Vitro VCAM-1 Assay
[0594] Cell Culture and compound dosing: Cultured primary human
aortic (HAEC) or pulmonary (HPAEC) endothelial cells were obtained
from Clonetics, Inc., and were used below passage 9. Cells were
seeded in 96 well plates such that they would reach 90-95%
confluency by the following day. On the following day the cells
were stimulated with TNF-.alpha. (1 ng/ml) in the presence or
absence of compounds dissolved in DMSO such that the final
concentration of DMSO is 0.25% or less. To establish a dose curve
for each compound, four concentrations in 2- to 5-fold increments
were used. Cells were exposed to TNF-.alpha. and compounds for
approximately 16 hours. The next day the cells were examined under
microscope to score for visual signs of toxicity or cell
stress.
[0595] Following 16 hr exposure to TNF-.alpha. and compound the
media was discarded and the cells were washed once with Hanks
Balanced Salt Solution (HBSS)/Phosphate buffered saline (PBS)
(1:1). Primary antibodies against VCAM-1 (0.25 .mu.g/ml in
HBSS/PBS+5% FBS) were added and incubated for 30-60 minutes at
37.degree. C. Cells were washed with HBSS/PBS three times, and
secondary antibody Horse Radish Peroxidase (HRP)-conjugated goat
anti-mouse IgG (1:500 in HBSS/PBS+5% FBS) were added and incubated
for 30 minutes at 37.degree. C. Cells were washed with HBSS/PBS
four time and TMB substrate were added and incubated at room
temperature in the dark until there was adequate development of
blue color. The length of time of incubation was typically 5-15
minutes. 2N sulfuric acid was added to stop the color development
and the data was collected by reading the absorbance on a BioRad
ELISA plate reader at OD 450 nm. The results are expressed as
IC.sub.50 values (the concentration (micromolar) of compound
required to inhibit 50% of the maximal response of the control
sample stimulated by TNF-.alpha. only). Compounds exhibiting
IC.sub.50's of less than 5 micromolar are tabulated in Biological
Table 1. TABLE-US-00024 Biological TABLE 1 VCAM-1 Example IC50
Number (.mu.M) 1 <5 2 <5 3 <5 4 >10 5 <5 6 <5 7
<5 8 <5 9 <10 10 <10 11 <5 12 <10 13 >10 14
<5 15 <5 16 <5 17 <10 18 <10 19 <5 20 <5 21
<10 22 >10 23 <5 24 <5 25 <5 26 >10 27 <10 28
<10 29 <5 30 <10 31 <10 32 <5 33 >10 34 >10 35
<5 36 <5 37 <5 38 <5 39 <5 40 <5 41 <5 42
>10 43 <5 44 <5 45 <5 40 <5 46 <5 47 <5 48
<5 49 <5 50 >10 51 >10 52 <5 53 <5 54 >5 55
>10 56 >10 57 <5
[0596] Modifications and variations of the present invention
relating to compounds and methods of treating diseases will be
obvious to those skilled in the art from the foregoing detailed
description of the invention. Such modifications and variations are
intended to come within the scope of the appended claims.
* * * * *