U.S. patent application number 12/200164 was filed with the patent office on 2008-12-25 for substituted sulfonamide-indoles.
This patent application is currently assigned to Wyeth. Invention is credited to Baihua Hu.
Application Number | 20080319046 12/200164 |
Document ID | / |
Family ID | 34396268 |
Filed Date | 2008-12-25 |
United States Patent
Application |
20080319046 |
Kind Code |
A1 |
Hu; Baihua |
December 25, 2008 |
SUBSTITUTED SULFONAMIDE-INDOLES
Abstract
The present invention relates generally to substituted
sulfonamide indoles such as substituted sulfonamide indoles, and
methods of using them.
Inventors: |
Hu; Baihua; (Audubon,
PA) |
Correspondence
Address: |
WYETH;PATENT LAW GROUP
5 GIRALDA FARMS
MADISON
NJ
07940
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
34396268 |
Appl. No.: |
12/200164 |
Filed: |
August 28, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10947839 |
Sep 23, 2004 |
7442805 |
|
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12200164 |
|
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60505803 |
Sep 25, 2003 |
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Current U.S.
Class: |
514/419 ;
548/492 |
Current CPC
Class: |
A61P 35/00 20180101;
C07D 403/04 20130101; A61P 11/00 20180101; C07D 209/42 20130101;
A61P 9/10 20180101; A61P 25/28 20180101; A61P 7/02 20180101; A61P
13/12 20180101; A61P 3/10 20180101; A61P 9/04 20180101; A61P 15/00
20180101; A61P 43/00 20180101; A61P 9/00 20180101 |
Class at
Publication: |
514/419 ;
548/492 |
International
Class: |
A61K 31/405 20060101
A61K031/405; C07D 209/42 20060101 C07D209/42; A61P 3/10 20060101
A61P003/10 |
Claims
1. A compound having the formula: ##STR00008## or a
pharmaceutically acceptable salt or ester form thereof, wherein: X
is O or NH; R.sub.1 and R.sub.2 are independently, hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.7-C.sub.11 bicycloalkyl,
arylalkyl, carboxyalkyl, C.sub.6-C.sub.10 aryl, or heterocycle;
R.sub.3 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3 perfluoroalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.3-C.sub.8 cycloalkyl, or --C(.dbd.O)C.sub.1-C.sub.3 alkyl;
A.sub.1 is C.sub.6-C.sub.10 aryl or heterocycle; and A.sub.2 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.7-C.sub.11 bicycloalkyl,
C.sub.6-C.sub.10 aryl, or heterocycle; said alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, heterocycle groups or part of groups
being optionally substituted.
2. A compound of claim 1, having the formula: ##STR00009## or a
pharmaceutically acceptable salt or ester form thereof, wherein Aa
is an amino acid.
3. A compound of claim 2 wherein Aa is L-Leu or L-Phe.
4. A compound of claim 1 having the formula: ##STR00010## or a
pharmaceutically acceptable salt or ester form thereof.
5. A compound of claim 1 wherein R.sub.1 is hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.7-C.sub.11 bicycloalkyl,
carboxyalkyl, or C.sub.6-C.sub.10 aryl.
6. A compound of claim 1 wherein R.sub.1 is hydrogen,
C.sub.1-C.sub.6 alkyl, unsubstituted aralkyl, arylalkyl wherein the
ring of the aryl group is substituted with aryl or the alkyl group
of arylalkyl is substituted by aryl.
7. A compound of claim 6 wherein R.sub.1 is hydrogen, unsubstituted
benzyl, benzyl wherein the benzyl ring is substituted with phenyl,
unsubstituted C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkyl
substituted with benzhydryl.
8. A compound of claim 1 wherein A.sub.2 is alkyl, quinoline,
unsubstituted aryl or aryl substituted with OCF.sub.3, alkyl or
aryl.
9. A compound of claim 1 wherein R.sub.3 is hydrogen,
C.sub.1-C.sub.6 alkyl optionally substituted with halogen, --CN, or
C.sub.1-C.sub.3 alkoxy.
10. A compound of claim 1 that is
N-{[1-methyl-3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H--
indol-2-yl]carbonyl}-L-leucine or a pharmaceutically acceptable
salt or ester form thereof;
N-({5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1-methyl-3-phenyl-1H-indol-2-yl-
}carbonyl)-L-phenylalanine or a pharmaceutically acceptable salt or
ester form thereof;
N-({5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1-methyl-3-phenyl-1H-indol-2-yl-
}carbonyl)-L-leucine or a pharmaceutically acceptable salt or ester
form thereof;
N-[(5-{[(4-tert-butylphenyl)sulfonyl]amino}-1-methyl-3-phenyl-1H-
-indol-2-yl)carbonyl]-L-phenylalanine or a pharmaceutically
acceptable salt or ester form thereof or
N-[(5-{[(4-tert-butylphenyl)sulfonyl]amino}-1-methyl-3-phenyl-1H-indol-2--
yl)carbonyl]-L-leucine or a pharmaceutically acceptable salt or
ester form thereof.
11. A compound of claim 1 that is
1-benzyl-3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indo-
le-2-carboxylic acid or a pharmaceutically acceptable salt or ester
form thereof;
1-benzyl-3-phenyl-5-[(quinolin-8-ylsulfonyl)amino]-1H-indole-2-c-
arboxylic acid or a pharmaceutically acceptable salt or ester form
thereof;
1-benzyl-5-{[(4-tert-butylphenyl)sulfonyl]amino}-3-phenyl-1H-ind-
ole-2-carboxylic acid or a pharmaceutically acceptable salt or
ester form thereof;
1-benzyl-5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-3-phenyl-1H-indol-
e-2-carboxylic acid or a pharmaceutically acceptable salt or ester
form thereof or
1-methyl-3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indo-
le-2-carboxylic acid or a pharmaceutically acceptable salt or ester
form thereof.
12. A compound of claim 1 that is
5-{[(4-tert-butylphenyl)sulfonyl]amino}-1-methyl-3-phenyl-1H-indole-2-car-
boxylic acid or a pharmaceutically acceptable salt or ester form
thereof;
5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1-methyl-3-phenyl-1H-indole-2-carbo-
xylic acid or a pharmaceutically acceptable salt or ester form
thereof;
1-(1,1'-biphenyl-4-ylmethyl)-5-[(methylsulfonyl)amino]-3-phenyl-1H-indole-
-2-carboxylic acid or a pharmaceutically acceptable salt or ester
form thereof;
1-(1,1'-biphenyl-4-ylmethyl)-3-phenyl-5-[(phenylsulfonyl)amino]--
1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt
or ester form thereof; or
1-benzhydryl-5-[(methylsulfonyl)amino]-3-phenyl-1H-indole-2-carboxylic
acid or a pharmaceutically acceptable salt or ester form
thereof.
13. A compound of claim 1 that is
1-benzhydryl-3-phenyl-5-[(phenylsulfonyl)amino]-1H-indole-2-carboxylic
acid or a pharmaceutically acceptable salt or ester form thereof;
1-benzyl-3-(4-tert-butylphenyl)-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}-
amino)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable
salt or ester form thereof; 1-benzyl-5-[(phenylsulfonyl)amino]-1H,
1'H-3,5'-biindole-2-carboxylic acid or a pharmaceutically
acceptable salt or ester form thereof;
3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indole-2-carb-
oxylic or a pharmaceutically acceptable salt or ester form thereof
or
5-{[(4-tert-butylphenyl)sulfonyl]amino}-3-phenyl-1H-indole-2-carboxylic
acid or a pharmaceutically acceptable salt or ester form
thereof.
14. A compound of claim 1 that is
5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-3-phenyl-1H-indole-2-carboxylic
acid or a pharmaceutically acceptable salt or ester form
thereof.
15. A method of inhibiting PAI-1 activity comprising administering
to a subject in need thereof a therapeutically effective amount of
a compound of claim 1.
16. A method for treating a PAI-1 related disorder comprising
administering to a subject in need thereof a therapeutically
effective amount of a compound of claim 1.
17. The method of claim 16, wherein the PAI-1 related disorder is
impairment of the fibrinolytic system.
18. The method of claim 16, wherein the PAI-1 related disorder is
thrombosis, atrial fibrillation, pulmonary fibrosis, myocardial
ischemia, stroke, thromboembolic complication of surgery,
cardiovascular disease, atherosclerotic plaque formation, chronic
obstructive pulmonary disease, renal fibrosis, polycystic ovary
syndrome, diabetes, Alzheimer's disease, or cancer.
19. The method of claim 18 wherein the thrombosis is selected from
the group consisting of venous thrombosis, arterial thrombosis,
cerebral thrombosis, and deep vein thrombosis.
20. The method of claim 16 wherein the PAI-1 related disorder is
cardiovascular disease caused by noninsulin dependent diabetes
mellitus in a subject.
21. The method of claim 16 wherein the PAI-1 related disorder is
diabetes.
22. The method of claim 15 wherein the therapeutically effective
amount is from 25 mg/kg/day to 200 mg/kg/day.
23. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt or ester form thereof, and a
pharmaceutically acceptable excipient or carrier.
24. A method for treating thrombosis, atrial fibrillation,
pulmonary fibrosis, thromboembolic complication of surgery, stroke,
myocardial ischemia, atherosclerotic plaque formation, chronic
obstructive pulmonary disease, or renal fibrosis comprising
administering to a subject in need thereof a therapeutically
effective amount of a compound of claim 1.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. patent
application Ser. No. 10/947,839 filed Sep. 23, 2004 and U.S.
Provisional Application No. 60/505,803 filed Sep. 25, 2003, and the
entire disclosure of which is incorporated herein by reference.
BACKGROUND
[0002] The present invention relates generally to substituted
sulfonamide indoles and methods of using them.
[0003] The serine protease inhibitor PAI-1 is one of the primary
inhibitors of the fibrinolytic system. The fibrinolytic system
includes the proenzyme plasminogen, which is converted to the
active enzyme, plasmin, by one of two tissue type plasminogen
activators, t-PA or u-PA. PAI-1 is the principal physiological
inhibitor of t-PA and u-PA. One of plasmin's main responsibilities
in the fibrinolytic system is to digest fibrin at the site of
vascular injury. The fibrinolytic system, however, is not only
responsible for the removal of fibrin from circulation but is also
involved in several other biological processes including ovulation,
embryogenesis, intima proliferation, angiogenesis, tumorigenesis,
and atherosclerosis.
[0004] Elevated levels of PAI-1 have been associated with a variety
of diseases and conditions including those associated with
impairment of the fibrinolytic system. For example, elevated levels
of PAI-1 have been implicated in thrombotic diseases, e.g.,
diseases characterized by formation of a thrombus that obstructs
vascular blood flow locally or detaches and embolizes to occlude
blood flow downstream. (Krishnamurti, Blood, 69, 798 (1987);
Reilly, Arteriosclerosis and Thrombosis, 11, 1276 (1991);
Carmeliet, Journal of Clinical Investigation, 92, 2756 (1993),
Rocha, Fibrinolysis, 8, 294, 1994; Aznar, Haemostasis 24, 243
(1994)). Antibody neutralization of PAI-1 activity resulted in
promotion of endogenous thrombolysis and reperfusion (Biemond,
Circulation, 91, 1175 (1995); Levi, Circulation 85, 305, (1992)).
Elevated levels of PAI-1 have also been implicated in diseases such
as polycystic ovary syndrome (Nordt, Journal of clinical
Endocrinology and Metabolism, 85, 4, 1563 (2000)), bone loss
induced by estrogen deficiency (Daci, Journal of Bone and Mineral
Research, 15, 8, 1510 (2000)), cystic fibrosis, diabetes, chronic
periodontitis, lymphomas, diseases associated with extracellular
matrix accumulation, malignancies and diseases associated with
neoangiogenesis, inflammatory diseases, vascular damage associated
with infections, and diseases associated with increased uPA levels
such as breast and ovarian cancer.
[0005] In view of the foregoing, there exists a need for the
identification of inhibitors of PAI-1 activity and for methods of
using the identified inhibitors to modulate PAI-1 expression or
activity in a subject in order to treat disorders associated with
elevated PAI-1 levels.
SUMMARY
[0006] The present invention provides substituted sulfonamide
indoles and methods of using them. In certain embodiments,
substituted sulfonamide-1H-indoles are provided, including those of
the following formula:
##STR00001##
wherein:
[0007] X is O or NH;
[0008] R.sub.1 and R.sub.2 are independently, hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.7-C.sub.11 bicycloalkyl,
arylalkyl, carboxyalkyl, C.sub.6-C.sub.10 aryl, or heterocycle;
[0009] R.sub.3 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3 perfluoroalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.3-C.sub.8 cycloalkyl, or --C(.dbd.O)C.sub.1-C.sub.3
alkyl;
[0010] A.sub.1 is C.sub.6-C.sub.10 aryl or heterocycle; and
[0011] A.sub.2 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.7-C.sub.11 bicycloalkyl, C.sub.6-C.sub.10 aryl, or
heterocycle.
[0012] Such substituted sulfonamide indoles include
sulfonamide-1H-indoles of the following formulas:
##STR00002##
wherein Aa is an amino acid and X, R.sub.1, R.sub.2, R.sub.3,
A.sub.1, and A.sub.2 are defined as above for Formula 1.
[0013] The present invention also provides, inter alia,
pharmaceutically acceptable salt or ester forms of formulas
1-4.
[0014] The present invention further provides, inter alia, methods
of using substituted sulfonamide indoles. In one aspect of the
present invention, a therapeutically effective amount of one or
more substituted sulfonamide indole is administered to a subject in
order to treat a PAI-1 related disorder, e.g., by inhibiting PAI-1
activity in the subject. PAI-1 activity is associated with a number
of diseases and conditions. For example, in one embodiment of the
present invention, PAI-1 activity is associated with impairment of
the fibrinolytic system. In other embodiments, PAI-1 activity is
associated with thrombosis, e.g., venous thrombosis, arterial
thrombosis, cerebral thrombosis, and deep vein thrombosis, atrial
fibrillation, pulmonary fibrosis, thromboembolic complications of
surgery, cardiovascular disease, e.g., myocardial ischemia,
atherosclerotic plaque formation, chronic obstructive pulmonary
disease, renal fibrosis, polycystic ovary syndrome, Alzheimer's
disease, or cancer.
DETAILED DESCRIPTION
[0015] A. General Overview
[0016] The present invention provides compounds that inhibit PAI-1
activity, processes for preparing such compounds, pharmaceutical
compositions containing such compounds, and methods for using such
compounds in medical therapies. The compounds have properties that
are useful for the treatment, including the prevention and
inhibition, of a wide variety of diseases and disorders including
those involving the production and/or action of PAI-1. These
include disorders resulting from impairment of the fibrinolytic
system including, but not limited to, thrombosis, coronary heart
disease, renal fibrosis, atherosclerotic plaque formation,
pulmonary disease, myocardial ischemia, atrial fibrillation,
coagulation syndromes, thromboembolic complications of surgery,
peripheral arterial occlusion and pulmonary fibrosis. Other
disorders include, but are not limited to, polycystic ovary
syndrome, Alzheimer's disease, and cancer.
[0017] The terms "alkyl" and "alkylene," as used herein, whether
used alone or as part of another group, refer to substituted or
unsubstituted aliphatic hydrocarbon chains, the difference being
that alkyl groups are monovalent (i.e., terminal) in nature whereas
alkylene groups are divalent and typically serve as linkers. Both
include, but are not limited to, straight and branched chains
containing from 1 to about 12 carbon atoms, preferably 1 to about 6
carbon atoms, unless explicitly specified otherwise. For example,
methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are
encompassed by the term "alkyl." Specifically included within the
definition of "alkyl" are those aliphatic hydrocarbon chains that
are optionally substituted. In representative embodiments of the
present invention, optional substituents can include
C.sub.1-C.sub.6 alkyl, halogen, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8 cycloalkyl, aralkyl, aryl
optionally substituted with R.sub.4, heterocycle optionally
substituted with R.sub.4, hydroxy, C.sub.1-C.sub.6 alkoxy,
aryl-oxy, oxo (.dbd.O), --CN, --C(.dbd.O)H, --CO.sub.2H,
--OCO.sub.2C.sub.1-C.sub.6 alkyl, --CO.sub.2C.sub.1-C.sub.6 alkyl,
--CO.sub.2-aryl, --CO.sub.2(C.sub.1-C.sub.6 alkyl)aryl,
--OCO.sub.2-aryl, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHOH, amino,
alkylamino, dialkylamino, --NHC(.dbd.O)NH--C.sub.1-C.sub.6 alkyl,
--NHSO.sub.2--C.sub.1-C.sub.6 alkyl, --NHSO.sub.2-aryl, and
--NHSO.sub.2-heterocycle.
[0018] R.sub.4 is C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl,
halogen, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl,
hydroxyl, --C(.dbd.O)C.sub.1-C.sub.7 alkyl,
--SO.sub.2C.sub.1-C.sub.6 alkyl, --CO.sub.2C.sub.1-C.sub.6 alkyl,
or alkoxycarbonylalkyl. In some embodiments, R.sub.4 includes
C.sub.2-7 acyl.
[0019] The carbon number as used in the definitions herein refers
to carbon backbone and carbon branching, but does not include
carbon atoms of the substituents, such as alkoxy substitutions and
the like.
[0020] The term "alkenyl", as used herein, whether used alone or as
part of another group, refers to a substituted or unsubstituted
aliphatic hydrocarbon chain and includes, but is not limited to,
straight and branched chains having 2 to about 10 carbon atoms
(unless explicitly specified otherwise) and containing at least one
double bond. Preferably, the alkenyl moiety has 1 or 2 double
bonds. Such alkenyl moieties can exist in the E or Z conformations
and the compounds of this invention include both conformations.
Specifically included within the definition of "alkenyl" are those
aliphatic hydrocarbon chains that are optionally substituted. In
representative embodiments of the present invention, optional
substituents can include C.sub.1-C.sub.6 alkyl, halogen,
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8
cycloalkyl, aralkyl, aryl optionally substituted with R.sub.4,
heterocycle optionally substituted with R.sub.4, hydroxy,
C.sub.1-C.sub.6 alkoxy, aryl-oxy, oxo (.dbd.O), --CN, --C(.dbd.O)H,
--CO.sub.2H, --OCO.sub.2C.sub.1-C.sub.6 alkyl,
--CO.sub.2C.sub.1-C.sub.6 alkyl, --CO.sub.2-aryl,
--CO.sub.2(C.sub.1-C.sub.6 alkyl)aryl, --OCO.sub.2-aryl,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHOH, amino, alkylamino,
dialkylamino, --NHC(.dbd.O)NH--C.sub.1-C.sub.6 alkyl,
--NHSO.sub.2--C.sub.1-C.sub.6 alkyl, --NHSO.sub.2-aryl, and
--NHSO.sub.2-heterocycle. Heteroatoms, such as O or S attached to
an alkenyl should not be attached to a carbon atom that is bonded
to a double bond.
[0021] The term "alkynyl", as used herein, whether used alone or as
part of another group, refers to a substituted or unsubstituted
aliphatic hydrocarbon chain and includes, but is not limited to,
straight and branched chains having 2 to about 10 carbon atoms
(unless explicitly specified otherwise) and containing at least one
triple bond. Preferably, the alkynyl moiety has about 2 to about 7
carbon atoms. In certain embodiments, the alkynyl can contain more
than one triple bond and, in such cases, the alkynyl group must
contain at least three carbon atoms. Specifically included within
the definition of "alkynyl" are those aliphatic hydrocarbon chains
that are optionally substituted. In representative embodiments of
the present invention, optional substituents can include
C.sub.1-C.sub.6 alkyl, halogen, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8 cycloalkyl, aralkyl, aryl
optionally substituted with R.sub.4, heterocycle optionally
substituted with R.sub.4, hydroxy, C.sub.1-C.sub.6 alkoxy,
aryl-oxy, oxo (.dbd.O), --CN, --C(.dbd.O)H, --CO.sub.2H,
--OCO.sub.2C.sub.1-C.sub.6 alkyl, --CO.sub.2C.sub.1-C.sub.6 alkyl,
--CO.sub.2-aryl, --CO.sub.2(C.sub.1-C.sub.6 alkyl)aryl,
--OCO.sub.2-aryl, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHOH, amino,
alkylamino, dialkylamino, --NHC(.dbd.O)NH--C.sub.1-C.sub.6 alkyl,
--NHSO.sub.2--C.sub.1-C.sub.6 alkyl, --NHSO.sub.2-aryl,
--NHSO.sub.2-heterocycle. Heteroatoms, such as O or S attached to
an alkynyl should not be attached to the carbon that is bonded to a
triple bond.
[0022] The term "acyl", employed alone or in combination with other
terms, is defined herein as, unless otherwise stated, either an
arylalkyl, heteroarylalkyl, (C.sub.2-C.sub.10) straight chain, or
(C.sub.4-C.sub.11) branched-chain monovalent hydrocarbon moiety;
wherein the carbon atom, covalently linked to the defined chemical
structure, is oxidized to the carbonyl oxidation state. Such
hydrocarbon moieties may be mono or polyunsaturated, and may exist
in the E or Z configurations. The compounds of this invention are
meant to include all possible E and Z configurations. Examples of
acyl moieties include, but are not limited to, chemical groups such
as acetyl, propionyl, butyryl, 3,3-dimethylbutyryl,
trifluoroacetyl, pivaloyl, hexanoyl, hexenoyl, decanoyl, benzoyl,
nicotinyl, isonicotinyl, and homologs, isomers, and the like
[0023] The term "cycloalkyl" as used herein, whether alone or as
part of another group, refers to a substituted or unsubstituted
alicyclic hydrocarbon group having 3 to about 20 carbon atoms
(unless explicitly specified otherwise), preferably 3 to about 8
carbon atoms. Specifically included within the definition of
"cycloalkyl" are those alicyclic hydrocarbon groups that are
optionally substituted. In representative embodiments of the
present invention, optional substituents can include
C.sub.1-C.sub.6 alkyl, halogen, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8 cycloalkyl, aralkyl, aryl
optionally substituted with R.sub.4, heterocycle optionally
substituted with R.sub.4, hydroxy, C.sub.1-C.sub.6 alkoxy,
aryl-oxy, oxo (.dbd.O), --CN, --C(.dbd.O)H, --CO.sub.2H,
--OCO.sub.2C.sub.1-C.sub.6 alkyl, --CO.sub.2C.sub.1-C.sub.6 alkyl,
--CO.sub.2-aryl, --CO.sub.2(C.sub.1-C.sub.6 alkyl)aryl,
--OCO.sub.2-aryl, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHOH, amino,
alkylamino, dialkylamino, --NHC(.dbd.O)NH--C.sub.1-C.sub.6 alkyl,
--NHSO.sub.2--C.sub.1-C.sub.6 alkyl, --NHSO.sub.2-aryl, and
--NHSO.sub.2-heterocycle.
[0024] The term "aryl", as used herein, whether used alone or as
part of another group, is defined as a substituted or unsubstituted
aromatic hydrocarbon ring group having 5 to about 50 carbon atoms
(unless explicitly specified otherwise) with from about 6 (e.g.
phenyl) to about 10 atoms being preferred. The "aryl" group can
have a single ring or multiple, e.g. two or three, condensed rings.
The term "aryl" includes, but is not limited to phenyl,
.alpha.-naphthyl, .beta.-naphthyl, biphenyl, anthryl,
tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and
acenaphthenyl. Specifically included within the definition of
"aryl" are those aromatic groups that are optionally substituted.
For example, in representative embodiments of the present
invention, the, "aryl" groups are optionally substituted with from
1 to 5 substituents selected from the group consisting of acyloxy,
hydroxy, acyl, alkanoyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1
to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to
6 carbon atoms, substituted alkyl, substituted alkoxy, substituted
alkenyl, substituted alkynyl, aryl, amino, amino substituted by one
or two alkyl groups of from 1 to 6 carbon atoms, aminoacyl,
acylamino, azido, cyano, halo, nitro, thioalkoxy of from 1 to 6
carbon atoms, substituted thioalkoxy of from 1 to 6 carbon atoms,
and trihalomethyl. In an exemplary embodiment of the present
invention, the optional substituents include, for example,
C.sub.1-C.sub.6 alkyl, halogen, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8 cycloalkyl, aralkyl, aryl
optionally substituted with R.sub.4, heterocycle optionally
substituted with R.sub.4, hydroxy, C.sub.1-C.sub.6 alkoxy,
--O--C.sub.1-C.sub.3 perfluoroalkyl, --CN, --C(.dbd.O)H,
--CO.sub.2H, --OCO.sub.2C.sub.1-C.sub.6 alkyl,
--CO.sub.2C.sub.1-C.sub.6 alkyl, --CO.sub.2-aryl,
--CO.sub.2(C.sub.1-C.sub.6 alkyl)aryl, --OCO.sub.2-aryl,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHOH, amino, alkylamino,
dialkylamino, --NHC(.dbd.O)NH--C.sub.1-C.sub.6 alkyl,
--NHSO.sub.2--C.sub.1-C.sub.6 alkyl, --NHSO.sub.2-aryl, and
--NHSO.sub.2-heterocycle.
[0025] The term "alkoxy" as used herein, refers to the group
R.sub.a--O-- wherein R.sub.a is an alkyl group as defined above.
Specifically included within the definition of "alkoxy" are those
alkoxy groups that are optionally substituted
[0026] The term "aryl-oxy" as used herein, refers to the group
R.sub.b--O-- wherein R.sub.b is an aryl group as defined above.
[0027] The term "alkoxycarbonylalkyl", as used herein, refers to
the group R.sub.c--O--C(.dbd.O)R.sub.c--, wherein R.sub.c is an
alkyl group as defined above. Alkoxycarbonylalkyl of the present
invention have from about 3 to about 13 carbon atoms.
[0028] The term "arylalkyl" or "aralkyl" refers to the group
--R.sub.a--R.sub.b, where R.sub.a is an alkyl group as defined
above, substituted by R.sub.b, an aryl group, as defined above.
Preferably the alkyl group has from 1 to 6 carbon atoms. Examples
of arylalkyl moieties include, but are not limited to, benzyl,
1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and
the like.
[0029] The term "alkylamino", as used herein, refers to the group
R.sub.c--NH--, wherein R.sub.c is an alkyl group as defined above
preferably having from 1 to 6 carbon atoms.
[0030] The term "dialkylamino" as used herein refers to the group
--N(C.sub.1-C.sub.6 alkyl).sub.2.
[0031] The term "carboxyalkyl" as used herein refers to the group
--R.sub.c--COOH, wherein R.sub.c is an alkyl group as defined above
preferably having from 1 to 6 carbon atoms.
[0032] The term "alkanoyl" as used herein, refers to the group
--C(.dbd.O)-alkyl group wherein alkyl is defined as above.
Exemplary alkanoyl groups include, but are not limited to,
acetyl(ethanoyl), n-propanoyl, n-butanoyl, 2-methylpropanoyl,
n-pentanoyl, 2-methylbutanoyl, 3-methylbutanoyl,
2,2-dimethylpropanoyl, heptanoyl, and decanoyl. The alkyl moieties
of alkanoyl groups can be optionally substituted.
[0033] The term "--SO.sub.2--C.sub.1-C.sub.6 alkyl", as used
herein, refers to the group --S(O.sub.2)--R.sub.a, wherein R.sub.a
is an alkyl group of 1 to 6 carbons as defined above.
[0034] The term "bicycloalkyl" refers to an optionally substituted,
alkyl group having two bridged rings in its structure and having
from about 7 to about 20 carbon atoms (unless explicitly stated
otherwise) (and all combinations and subcombinations of ranges and
specific numbers of carbon atoms therein), with from about 7 to
about 11 carbon atoms being preferred. Exemplary bicycloalkyl-ring
structures include, but are not limited to, norbornyl, bornyl,
[2.2.2]-bicyclooctyl, cis-pinanyl, trans-pinanyl, camphanyl,
iso-bornyl, and fenchyl. Representative substituents include, for
example, C.sub.1-C.sub.6 alkyl, halogen, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8 cycloalkyl, aralkyl, aryl
optionally substituted with R.sub.4, heterocycle optionally
substituted with R.sub.4, hydroxy, C.sub.1-C.sub.6 alkoxy,
aryl-oxy, oxo (.dbd.O), --CN, --C(.dbd.O)H, --CO.sub.2H,
--OCO.sub.2C.sub.1-C.sub.6 alkyl, --CO.sub.2C.sub.1-C.sub.6 alkyl,
--CO.sub.2-aryl, --CO.sub.2(C.sub.1-C.sub.6 alkyl)aryl,
--OCO.sub.2-aryl, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHOH, amino,
alkylamino, dialkylamino, --NHC(.dbd.O)NH--C.sub.1-C.sub.6 alkyl,
--NHSO.sub.2--C.sub.1-C.sub.6 alkyl, --NHSO.sub.2-aryl, and
--NHSO.sub.2-heterocycle.
[0035] The term "heterocycle", as used herein, whether used alone
or as part of another group, refers to a stable 3 to about
50-member ring, preferably 5 to 10-member ring containing carbons
atoms and from 1 to 4 heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur. A heterocycle of this
invention can be either a monocyclic or bicyclic ring system, and
can be either saturated, unsaturated (including heteroaryl), or
partially saturated. A heterocycle can be optionally fused to a
phenyl ring. Heterocycle groups include, but are not limited to,
aziridinyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl,
piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,
thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl,
dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrofuranyl,
dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,
dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,
dihydropyrrazinyl, dihydropyrazolyl, dihydropyridinyl,
dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,
dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,
dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,
dihydro-1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl,
tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Preferred
heterocycle moieties include: (a) 6-membered saturated, partially
unsaturated, or unsaturated heterocycles containing 1-2 nitrogens,
optionally fused to a phenyl ring; (b) 5-membered saturated,
partially saturated, or unsaturated heterocycles containing 1-3
nitrogen, oxygen, or sulfur atoms, optionally fused to a phenyl
ring; (c) saturated, partially unsaturated, or unsaturated bicyclic
heterocycles containing 1-4 nitrogen, oxygen, or sulfur atoms; (d)
carbazole, dibenzofuran, and dibenzothiophene. Specifically
included in the definition of "heterocycle" are those heterocycles
that are optionally substituted. Representative substituents
include C.sub.1-C.sub.6 alkyl, halogen, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8 cycloalkyl, aralkyl, aryl
optionally substituted with R.sub.4, heterocycle optionally
substituted with R.sub.4, hydroxy, C.sub.1-C.sub.6 alkoxy,
aryl-oxy, oxo (.dbd.O), --CN, --C(.dbd.O)H, --CO.sub.2H,
--OCO.sub.2C.sub.1-C.sub.6 alkyl, --CO.sub.2C.sub.1-C.sub.6 alkyl,
--CO.sub.2-aryl, --CO.sub.2(C.sub.1-C.sub.6 alkyl)aryl,
--OCO.sub.2-aryl, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHOH, amino,
alkylamino, dialkylamino, --NHC(.dbd.O)NH--C.sub.1-C.sub.6 alkyl,
--NHSO.sub.2--C.sub.1-C.sub.6 alkyl, --NHSO.sub.2-aryl, and
--NHSO.sub.2-heterocycle.
[0036] The term "heteroaryl" as used herein is defined as a
substituted or unsubstituted aromatic heterocyclic ring system
(monocyclic or bicyclic). Heteroaryl groups can have, for example,
from about 3 to about 50 carbon atoms (unless explicitly specified
otherwise) with from about 4 to about 10 being preferred. In some
embodiments, heteroaryl groups are aromatic heterocyclic rings
systems having about 4 to about 14 ring atoms including carbon
atoms and 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen
or sulfur. Representative heteroaryl groups are furan, thiophene,
indole, azaindole, oxazole, thiazole, isoxazole, isothiazole,
imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine,
pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole,
1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole,
1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole,
benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole,
azabenzimidazole, indazole, quinazoline, quinoline, and
isoquinoline. Bicyclic aromatic heteroaryl groups include phenyl,
pyridine, pyrimidine or pyridizine rings that are (a) fused to a
6-membered aromatic (unsaturated) heterocyclic ring having one
nitrogen atom; (b) fused to a 5- or 6-membered aromatic
(unsaturated) heterocyclic ring having two nitrogen atoms; (c)
fused to a 5-membered aromatic (unsaturated) heterocyclic ring
having one nitrogen atom together with either one oxygen or one
sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated)
heterocyclic ring having one heteroatom selected from O, N or S.
Specifically included within the definition of "heteroaryl" are
those aromatic groups that are optionally substituted. Accordingly,
the heteroaryl groups (e.g., pyridinyl) described herein refer to
both unsubstituted or substituted groups. In representative
embodiments of the present invention, the, "heteroaryl" groups are
optionally substituted with 1 to 5 substituents selected from the
group consisting of acyloxy, hydroxy, acyl, alkyl of 1 to 6 carbon
atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon
atoms, alkynyl of 2 to 6 carbon atoms, substituted alkyl,
substituted alkoxy, substituted alkenyl, substituted alkynyl,
amino, amino substituted by one or two alkyl groups of from 1 to 6
carbon atoms, aminoacyl, acylamino, azido, cyano, halo, nitro,
thioalkoxy of from 1 to 6 carbon atoms, substituted thioalkoxy of
from 1 to 6 carbon atoms, and trihalomethyl.
[0037] The term "perfluoroalkyl", as used herein, whether used
alone or as part of another group, refers to a saturated aliphatic
hydrocarbon having 1 to 6 carbon atoms and two or more fluorine
atoms and includes, but is not limited to, straight or branched
chains, such as --CF.sub.3, --CH.sub.2CF.sub.3, --CF.sub.2CF.sub.3
and --CH(CF.sub.3).sub.2.
[0038] The term "halogen" or "halo" refers to chlorine, bromine,
fluorine, and iodine.
[0039] The term "treating" or "treatment" refers to any indicia of
success in amelioration of an injury, pathology, or condition,
including any objective or subjective parameter such as abatement;
remission; diminishing of symptoms or making the injury, pathology,
or condition more tolerable to the patient; slowing in the rate of
degeneration or decline; making the final point of degeneration
less debilitating; or improving a subject's physical or mental
well-being. The treatment or amelioration of symptoms can be based
on objective or subjective parameters; including the results of a
physical examination, neurological examination, and/or psychiatric
evaluation. "Treating" or "treatment of a PAI-1 related disorder"
includes preventing the onset of symptoms in a subject that may be
predisposed to a PAI-1 related disorder but does not yet experience
or exhibit symptoms of the disorder (prophylactic treatment),
inhibiting the symptoms of the disorder (slowing or arresting its
development), providing relief from the symptoms or side-effects of
the disorder (including palliative treatment), and/or relieving the
symptoms of the disorder (causing regression). Accordingly, the
term "treating" includes the administration of the compounds or
agents of the present invention to a subject to prevent or delay,
to alleviate, or to arrest or inhibit development of the symptoms
or conditions associated with PAI-1 related disorders, e.g., tumor
growth associated with cancer. A skilled medical practitioner will
know how to use standard methods to determine whether a patient is
suffering from a disease associated with enhanced levels and/or
activity of PAI-1, e.g., by examining the patient and determining
whether the patient is suffering from a disease known to be
associated with elevated PAI-1 levels or activity or by assaying
for PAI-1 levels in blood plasma or tissue of the individual
suspected of suffering from a PAI-1 related disease and comparing
PAI-1 levels in the blood plasma or tissue of the individual
suspected of suffering from a PAI-1 related disease to PAI-1 levels
in the blood plasma or tissue of a healthy individual. Increased
PAI-1 levels are indicative of disease. Accordingly, the present
invention provides, inter alia, methods of administering a compound
of the present invention to a subject and determining levels of
PAI-1 in the subject. The level of PAI-1 in the subject can be
determined before and/or after administration of the compound
[0040] In healthy individuals, PAI-1 is found at low levels in the
plasma (from about 5-26 ng/mL), but it is elevated in many PAI-1
related disorders, including, for example, atherosclerosis
(Schneiderman J. et. al, Proc Natl Acad Sci 89: 6998-7002, 1992)
deep vein thrombosis (Juhan-Vague I, et. al, Thromb Haemost 57:
67-72, 1987), and non-insulin dependent diabetes mellitus
(Juhan-Vague I, et. al, Thromb Haemost 78: 565-660, 1997). PAI-1
stabilizes both arterial and venous thrombi, contributing
respectively to coronary arterial occlusion in post-myocardial
infarction (Hamsten A, et. al. Lancet 2:3-9, 1987), and venous
thrombosis following post-operative recovery from orthopedic
surgery. (Siemens H J, et. al, J Clin Anesthesia 11: 622-629,
1999). Plasma PAI-1 is also elevated, for example, in
postmenopausal women, and has been proposed to contribute to the
increased incidence of cardiovascular disease in this population
(Koh K et. al, N Engl J Med 336: 683-690, 1997).
[0041] The term "PAI-1 related disorder or disease" refers to any
disease or condition that is associated with increased or enhanced
expression or activity of PAI-1 or increased or enhanced expression
or activity of a gene encoding PAI-1. Examples of such increased
activity or expression can include one or more of the following:
activity of the protein or expression of the gene encoding the
protein is increased above the level of that in normal subjects;
activity of the protein or expression of the gene encoding the
protein is in an organ, tissue or cell where it is not normally
detected in normal subjects (i.e. spatial distribution of the
protein or expression of the gene encoding the protein is altered);
activity of the protein or expression of the gene encoding the
protein is increased when activity of the protein or expression of
the gene encoding the protein is present in an organ, tissue or
cell for a longer period than in a normal subjects (i.e., duration
of activity of the protein or expression of the gene encoding the
protein is increased). A normal or healthy subject is a subject not
suffering from a PAI-1 related disorder or disease.
[0042] The term "pharmaceutically acceptable excipient" means an
excipient that is useful in preparing a pharmaceutical composition
that is generally safe, non-toxic, and desirable, and includes
excipients that are acceptable for veterinary use as well as for
human pharmaceutical use. Such excipients can be solid, liquid,
semisolid, or, in the case of an aerosol composition, gaseous.
[0043] "Pharmaceutically acceptable salts and esters" refers to
salts and esters that are pharmaceutically acceptable and have the
desired pharmacological properties. Such salts include, for
example, salts that can be formed where acidic protons present in
the compounds are capable of reacting with inorganic or organic
bases. Suitable inorganic salts include, for example, those formed
with the alkali metals or alkaline earth metals, e.g. sodium and
potassium, magnesium, calcium, and aluminum. Suitable organic salts
include, for example, those formed with organic bases such as the
amine bases, e.g. ethanolamine, diethanolamine, triethanolamine,
trimethamine, N methylglucamine, and the like. Pharmaceutically
acceptable salts can also include acid addition salts formed from
the reaction of basic moieties, such as amines, in the parent
compound with inorganic acids (e.g. hydrochloric and hydrobromic
acids) and organic acids (e.g. acetic acid, citric acid, maleic
acid, and the alkane- and arene-sulfonic acids such as
methanesulfonic acid and benzenesulfonic acid). Pharmaceutically
acceptable esters include esters formed from carboxy, sulfonyloxy,
and phosphonoxy groups present in the compounds, e.g. C.sub.1-6
alkyl esters. When there are two acidic groups present, a
pharmaceutically acceptable salt or ester can be a
mono-acid-mono-salt or ester or a di-salt or ester; and similarly
where there are more than two acidic groups present, some or all of
such groups can be salified or esterified. Compounds named in this
invention can be present in unsalified or unesterified form, or in
salified and/or esterified form, and the naming of such compounds
is intended to include both the original (unsalified and
unesterified) compound and its pharmaceutically acceptable salts
and esters. Also, certain compounds named in this invention can be
present in more than one stereoisomeric form, and the naming of
such compounds is intended to include all single stereoisomers and
all mixtures (whether racemic or otherwise) of such
stereoisomers.
[0044] "Inhibitors," "activators," and "modulators" of expression
or of activity are used to refer to inhibitory, activating, or
modulating molecules, respectively, identified using in vitro and
in vivo assays for expression or activity. Inhibitors of the
present invention are compositions that, inhibit expression of
PAI-1 or bind to, partially or totally block stimulation, decrease,
prevent, delay activation, inactivate, desensitize, or down
regulate the activity of PAI-1. Samples or assays comprising PAI-1
can be treated with a composition of the present invention and
compared to control samples without a composition of the present
invention. Control samples (untreated with compositions of the
present invention) can be assigned a relative activity value of
100%. In certain embodiments, inhibition of PAI-1 is achieved when
the activity value relative to the control is about 80% or less,
optionally 50% or 25, 10%, 5% or 1%.
[0045] The terms "pharmaceutically acceptable", "physiologically
tolerable" and grammatical variations thereof, as they refer to
compositions, carriers, diluents and reagents, are used
interchangeably and represent that the materials are capable of
administration to or upon a human without the production of
undesirable physiological effects such as nausea, dizziness,
gastric upset and the like which would be to a degree that would
prohibit administration of the compound.
[0046] A "therapeutically effective amount" or "pharmaceutically
effective amount" means the amount that, when administered to a
subject, produces effects for which it is administered. For
example, a "therapeutically effective amount," when administered to
a subject to inhibit PAI-1 activity, is sufficient to inhibit PAI-1
activity. A "therapeutically effective amount," when administered
to a subject for treating a disease, is sufficient to effect
treatment for that disease.
[0047] Except when noted, the terms "subject" or "patient" are used
interchangeably and refer to mammals such as human patients and
non-human primates, as well as experimental animals such as
rabbits, rats, and mice, and other animals. Accordingly, the term
"subject" or "patient" as used herein means any mammalian patient
or subject to which the compounds of the invention can be
administered. In an exemplary embodiment of the present invention,
to identify subject patients for treatment according to the methods
of the invention, accepted screening methods are employed to
determine risk factors associated with a targeted or suspected
disease or condition or to determine the status of an existing
disease or condition in a subject. These screening methods include,
for example, conventional work-ups to determine risk factors that
are associated with the targeted or suspected disease or condition.
These and other routine methods allow the clinician to select
patients in need of therapy using the methods and formulations of
the present invention.
[0048] When any variable occurs more than one time in any
constituent or in any formula, its definition in each occurrence is
independent of its definition at every other occurrence.
Combinations of substituents and/or variables are permissible only
if such combinations result in stable compounds.
[0049] B. Substituted Sulfonamide Indoles
[0050] The present invention provides substituted sulfonamide
indoles. Such compounds are preferably administered to inhibit
PAI-1 expression or activity in a subject and, ultimately, to treat
diseases or conditions associated with increased PAI-1 activity in
a subject, e.g., a PAI-1 related disorder.
[0051] In certain embodiments, substituted sulfonamide indoles of
the invention include those of the following formula:
##STR00003##
wherein:
[0052] X is O or NH;
[0053] R.sub.1 and R.sub.2 are independently, hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.7-C.sub.11 bicycloalkyl,
arylalkyl, carboxyalkyl, C.sub.6-C.sub.10 aryl, or heterocycle;
[0054] R.sub.3 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3 perfluoroalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.3-C.sub.8 cycloalkyl, or --C(.dbd.O)C.sub.1-C.sub.3
alkyl;
[0055] A.sub.1 is C.sub.6-C.sub.10 aryl or heterocycle; and
[0056] A.sub.2 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.7-C.sub.11 bicycloalkyl, C.sub.6-C.sub.10 aryl, or
heterocycle.
[0057] Such substituted sulfonamide indoles include
sulfonamide-1H-indoles of the following formulas:
##STR00004##
wherein Aa is an amino acid and X, R.sub.1, R.sub.2, R.sub.3,
A.sub.1, and A.sub.2 are defined as above for Formula 1.
[0058] Compounds of the present invention also include prodrugs,
stereoisomers, or pharmaceutically acceptable salt or ester forms
of formulas 1-4.
[0059] For use in the present invention, when the substituted
sulfonamide indole is represented by one of formulas 1 to 4,
R.sub.1 can be hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7
alkenyl, C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.7-C.sub.11 bicycloalkyl, arylalkyl, carboxyalkyl,
heterocycle, or aryl. In certain embodiments of the present
invention, R.sub.1 is alkyl, substituted aralkyl, unsubstituted
aralkyl, hydrogen, or benzhydryl. For example, in certain
embodiments, R.sub.1 is methyl. In other embodiments, R.sub.1 is
unsubstituted benzyl or benzyl substituted with phenyl. In even
other embodiments, R.sub.1 is hydrogen. In yet other embodiments,
R.sub.1 is benzhydryl. In such embodiments, X, R.sub.2, R.sub.3,
A.sub.1, and A.sub.2 are as defined herein. In some embodiments,
R.sub.1 can also be --CO.sub.2(C.sub.1-6)alkyl.
[0060] For use in the present invention, when the substituted
sulfonamide indole is represented by one of formulas 1 to 4,
R.sub.2 can be hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7
alkenyl, C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.7-C.sub.11 bicycloalkyl, arylalkyl, carboxyalkyl,
heterocycle, or aryl and X can be O or NH. In certain embodiments
of the present invention, X is O and R.sub.2 is hydrogen. In other
embodiments, X is NH and R.sub.2 is carboxyalkyl. For example X is
NH and R.sub.2 is carboxymethyl. In certain embodiments, the methyl
group of carboxymethyl is substituted with alkyl or arylalkyl. In
such embodiments, X, R.sub.1, R.sub.3, A.sub.1, and A.sub.2 are as
defined herein. In some embodiments, R.sub.1 can also be
--CO.sub.2(C.sub.1-6)alkyl.
[0061] In certain embodiments of the present invention, when the
substituted sulfonamide indole is represented by one of formulas 1
to 4, X and R.sub.2 together are an amino acid. The amino acids can
include, for example, alanine, arginine, asparagine, aspartic acid,
cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine,
leucine, lysine, methionine, phenylalanine, proline, serine,
threonine, tryptophan, tyrosine, and valine. In a preferred
embodiment, the amino acid is L-leucine or L-phenylalanine. In such
embodiments, R.sub.1, R.sub.3, A.sub.1, and A.sub.2 are as defined
herein.
[0062] When the substituted sulfonamide indole is represented by
one of formulas 1 to 4, R.sub.3 can be hydrogen, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 perfluoroalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.8 cycloalkyl, or
--C(.dbd.O)C.sub.1-C.sub.3 alkyl. In certain embodiments of the
present invention, R.sub.3 is C.sub.1-C.sub.6 alkyl optionally
substituted with halogen, --CN, or C.sub.1-C.sub.3 alkoxy. In
certain other embodiments, R.sub.3 is hydrogen. In such
embodiments, X, R.sub.1, R.sub.2, A.sub.1, and A.sub.2 are as
defined herein.
[0063] For use in the present invention, when the substituted
sulfonamide indole is represented by one of formulas 1 to 4,
A.sub.1 can be aryl or heterocycle. In some embodiments of the
present invention, A.sub.1 is unsubstituted aryl, aryl substituted
with alkyl, e.g., tert-butyl, or an indole ring. In such
embodiments, X, R.sub.1, R.sub.2, R.sub.3, and A.sub.2 are as
defined herein.
[0064] For use in the present invention, when the substituted
sulfonamide indole is represented by one of formulas 1 to 4,
A.sub.2 can be C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.7-C.sub.11 bicycloalkyl, heterocycle, or aryl. In certain
embodiments of the present invention, A.sub.2 is alkyl, quinoline,
unsubstituted aryl, or aryl substituted with --OCF.sub.3, alkyl or
aryl. For example, in some embodiments, A.sub.2 is phenyl
substituted with OCF.sub.3, tert-butyl, or phenyl. In such
embodiments, X, R.sub.1, R.sub.2, R.sub.3, and A.sub.1 are as
defined herein.
[0065] In certain preferred embodiments of the present invention,
the sulfonamide group is at position 5 of the indole ring.
[0066] Preferred compounds of the present invention include those
wherein
[0067] X is O or NH;
[0068] R.sub.1 and R.sub.2 are independently, hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.7-C.sub.11 bicycloalkyl,
arylalkyl, unsubstituted --CO.sub.2(C.sub.1-6 alkyl),
C.sub.6-C.sub.10 aryl, or heterocycle
[0069] wherein said C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.7-C.sub.11 bicycloalkyl, arylalkyl, --C.sub.6-C.sub.10 aryl,
or heterocycle groups are optionally substituted with unsubstituted
C.sub.1-C.sub.6 alkyl, halogen, unsubstituted C.sub.2-C.sub.7
alkenyl, unsubstituted C.sub.2-C.sub.7 alkynyl, unsubstituted
C.sub.3-C.sub.8 cycloalkyl, unsubstituted aralkyl, hydroxy,
unsubstituted C.sub.1-C.sub.6 alkoxy, unsubstituted aryl-oxy, oxo
(.dbd.O), --CN, --C(.dbd.O)H, --CO.sub.2H, unsubstituted
--OCO.sub.2C.sub.1-C.sub.6 alkyl, unsubstituted
--CO.sub.2C.sub.1-C.sub.6 alkyl, unsubstituted --CO.sub.2-- aryl,
unsubstituted --CO.sub.2(C.sub.1-C.sub.6 alkyl)aryl, unsubstituted
--OCO.sub.2-aryl, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHOH,
unsubstituted amino, unsubstituted alkylamino, unsubstituted
dialkylamino, unsubstituted --NHC(.dbd.O)NH--C.sub.1-C.sub.6 alkyl,
unsubstituted --NHSO.sub.2--C.sub.1-C.sub.6 alkyl, unsubstituted
--NHSO.sub.2-aryl, unsubstituted --NHSO.sub.2-heterocycle, aryl
(optionally substituted with unsubstituted C.sub.1-C.sub.6 alkoxy,
unsubstituted C.sub.1-C.sub.6 alkyl, halogen, unsubstituted
C.sub.2-C.sub.7 alkenyl, unsubstituted C.sub.2-C.sub.7 alkynyl,
hydroxy, unsubstituted --C(.dbd.O)C.sub.1-C.sub.7 alkyl,
unsubstituted --SO.sub.2C.sub.1-C.sub.6 alkyl, unsubstituted
--CO.sub.2C.sub.1-C.sub.6 alkyl, or unsubstituted
alkoxycarbonylalkyl) or heterocycle (optionally substituted with
unsubstituted C.sub.1-C.sub.6 alkoxy, unsubstituted C.sub.1-C.sub.6
alkyl, halogen, unsubstituted C.sub.2-C.sub.7 alkenyl,
unsubstituted C.sub.2-C.sub.7 alkynyl, hydroxy, unsubstituted
--C(.dbd.O)C.sub.1-C.sub.7 alkyl, unsubstituted
--SO.sub.2C.sub.1-C.sub.6 alkyl, unsubstituted
--CO.sub.2C.sub.1-C.sub.6 alkyl, or unsubstituted
alkoxycarbonylalkyl);
[0070] R.sub.3 is hydrogen, halogen, unsubstituted C.sub.1-C.sub.3
perfluoroalkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, unsubstituted
C.sub.3-C.sub.8 cycloalkyl, unsubstituted
--C(.dbd.O)C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.6 alkyl wherein
said alkyl group is optionally substituted with halogen, --CN, or
C.sub.1-C.sub.3 alkoxy;
[0071] A.sub.1 is C.sub.6-C.sub.10 aryl or heterocycle wherein said
aryl or heterocycle groups are optionally substituted with
unsubstituted C.sub.1-C.sub.6 alkyl, halogen, unsubstituted
C.sub.2-C.sub.7 alkenyl, unsubstituted C.sub.2-C.sub.7 alkynyl,
unsubstituted C.sub.3-C.sub.8 cycloalkyl, unsubstituted aralkyl,
hydroxy, unsubstituted C.sub.1-C.sub.6 alkoxy, unsubstituted
aryl-oxy, oxo (.dbd.O), --CN, --C(.dbd.O)H, --CO.sub.2H,
unsubstituted --OCO.sub.2C.sub.1-C.sub.6 alkyl, unsubstituted
--CO.sub.2C.sub.1-C.sub.6 alkyl, unsubstituted --CO.sub.2-- aryl,
unsubstituted --CO.sub.2(C.sub.1-C.sub.6 alkyl)aryl, unsubstituted
--OCO.sub.2-aryl, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHOH,
unsubstituted amino, unsubstituted alkylamino, unsubstituted
dialkylamino, unsubstituted --NHC(.dbd.O)NH--C.sub.1-C.sub.6 alkyl,
unsubstituted --NHSO.sub.2--C.sub.1-C.sub.6 alkyl, unsubstituted
--NHSO.sub.2-aryl, unsubstituted --NHSO.sub.2-heterocycle, aryl
(optionally substituted with unsubstituted C.sub.1-C.sub.6 alkoxy,
unsubstituted C.sub.1-C.sub.6 alkyl, halogen, unsubstituted
C.sub.2-C.sub.7 alkenyl, unsubstituted C.sub.2-C.sub.7 alkynyl,
hydroxy, unsubstituted --C(.dbd.O)C.sub.1-C.sub.7 alkyl,
unsubstituted --SO.sub.2C.sub.1-C.sub.6 alkyl, unsubstituted
--CO.sub.2C.sub.1-C.sub.6 alkyl, or unsubstituted
alkoxycarbonylalkyl) or heterocycle (optionally substituted with
unsubstituted C.sub.1-C.sub.6 alkoxy, unsubstituted C.sub.1-C.sub.6
alkyl, halogen, unsubstituted C.sub.2-C.sub.7 alkenyl,
unsubstituted C.sub.2-C.sub.7 alkynyl, hydroxy, unsubstituted
--C(.dbd.O)C.sub.1-C.sub.7 alkyl, unsubstituted
--SO.sub.2C.sub.1-C.sub.6 alkyl, unsubstituted
--CO.sub.2C.sub.1-C.sub.6 alkyl, or unsubstituted
alkoxycarbonylalkyl); and
[0072] A.sub.2 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.7-C.sub.11 bicycloalkyl, C.sub.6-C.sub.10 aryl, or
heterocycle
[0073] wherein said C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.7-C.sub.11 bicycloalkyl, --C.sub.6-C.sub.10 aryl, or
heterocycle groups are optionally substituted with unsubstituted
C.sub.1-C.sub.6 alkyl, halogen, unsubstituted C.sub.2-C.sub.7
alkenyl, unsubstituted C.sub.2-C.sub.7 alkynyl, unsubstituted
C.sub.3-C.sub.8 cycloalkyl, unsubstituted aralkyl, hydroxy,
unsubstituted C.sub.1-C.sub.6 alkoxy, unsubstituted aryl-oxy, oxo
(.dbd.O), --CN, --C(.dbd.O)H, --CO.sub.2H, unsubstituted
--OCO.sub.2C.sub.1-C.sub.6 alkyl, unsubstituted
--CO.sub.2C.sub.1-C.sub.6 alkyl, unsubstituted --CO.sub.2-- aryl,
unsubstituted --CO.sub.2(C.sub.1-C.sub.6 alkyl)aryl, unsubstituted
--OCO.sub.2-aryl, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHOH,
unsubstituted amino, unsubstituted alkylamino, unsubstituted
dialkylamino, unsubstituted --NHC(.dbd.O)NH--C.sub.1-C.sub.6 alkyl,
unsubstituted --NHSO.sub.2--C.sub.1-C.sub.6 alkyl, unsubstituted
--NHSO.sub.2-aryl, unsubstituted --NHSO.sub.2-heterocycle, aryl
(optionally substituted with unsubstituted C.sub.1-C.sub.6 alkoxy,
unsubstituted C.sub.1-C.sub.6 alkyl, halogen, unsubstituted
C.sub.2-C.sub.7 alkenyl, unsubstituted C.sub.2-C.sub.7 alkynyl,
hydroxy, unsubstituted --C(.dbd.O)C.sub.1-C.sub.7 alkyl,
unsubstituted --SO.sub.2C.sub.1-C.sub.6 alkyl, unsubstituted
--CO.sub.2C.sub.1-C.sub.6 alkyl, or unsubstituted
alkoxycarbonylalkyl) or heterocycle (optionally substituted with
unsubstituted C.sub.1-C.sub.6 alkoxy, unsubstituted C.sub.1-C.sub.6
alkyl, halogen, unsubstituted C.sub.2-C.sub.7 alkenyl,
unsubstituted C.sub.2-C.sub.7 alkynyl, hydroxy, unsubstituted
--C(.dbd.O)C.sub.1-C.sub.7 alkyl, unsubstituted
--SO.sub.2C.sub.1-C.sub.6 alkyl, unsubstituted
--CO.sub.2C.sub.1-C.sub.6 alkyl, or unsubstituted
alkoxycarbonylalkyl).
[0074] Exemplary substituted sulfonamide-indoles of the present
invention include, but are not limited to
1-Benzyl-3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indo-
le-2-carboxylic acid or a pharmaceutically acceptable salt or ester
form thereof;
1-Benzyl-3-phenyl-5-[(quinolin-8-ylsulfonyl)amino]-1H-indole-2-c-
arboxylic acid or a pharmaceutically acceptable salt or ester form
thereof;
1-Benzyl-5-1-{[(4-tert-butylphenyl)sulfonyl]amino}-3-phenyl-1H-i-
ndole-2-carboxylic acid or a pharmaceutically acceptable salt or
ester form thereof;
1-Benzyl-5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-3-phenyl-1H-indole-2-carbo-
xylic acid or a pharmaceutically acceptable salt or ester form
thereof;
1-Methyl-3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indo-
le-2-carboxylic acid or a pharmaceutically acceptable salt or ester
form thereof;
5-{[(4-tert-Butylphenyl)sulfonyl]amino}-1-methyl-3-phenyl-1H-ind-
ole-2-carboxylic acid or a pharmaceutically acceptable salt or
ester form thereof;
5-[(1,1'-Biphenyl-4-ylsulfonyl)amino]-1-methyl-3-phenyl-1H-indol-
e-2-carboxylic acid or a pharmaceutically acceptable salt or ester
form thereof;
N-{[1-Methyl-3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}a-
mino)-1H-indol-2-yl]carbonyl}-L-leucine or a pharmaceutically
acceptable salt or ester form thereof;
N-({5-[(1,1'-Biphenyl-4-ylsulfonyl)amino]-1-methyl-3-phenyl-1H-indol-2-yl-
}carbonyl)-L-phenylalanine or a pharmaceutically acceptable salt or
ester form thereof;
N-({5-[(1,1'-Biphenyl-4-ylsulfonyl)amino]-1-methyl-3-phenyl-1H-indol-2-yl-
}carbonyl)-L-leucine or a pharmaceutically acceptable salt or ester
form thereof;
N-[(5-{[(4-tert-Butylphenyl)sulfonyl]amino}-1-methyl-3-phenyl-1H-
-indol-2-yl)carbonyl]-L-phenylalanine or a pharmaceutically
acceptable salt or ester form thereof;
N-[(5-{[(4-tert-Butylphenyl)sulfonyl]amino}-1-methyl-3-phenyl-1H-indol-2--
yl)carbonyl]-L-leucine or a pharmaceutically acceptable salt or
ester form thereof;
1-(1,1'-Biphenyl-4-ylmethyl)-5-[(methylsulfonyl)amino]-3-phenyl--
1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt
or ester form thereof;
1-(1,1'-Biphenyl-4-ylmethyl)-3-phenyl-5-[(phenylsulfonyl)amino]-1H-indole-
-2-carboxylic acid or a pharmaceutically acceptable salt or ester
form thereof;
1-Benzhydryl-5-[(methylsulfonyl)amino]-3-phenyl-1H-indole-2-carb-
oxylic acid or a pharmaceutically acceptable salt or ester form
thereof;
1-Benzhydryl-3-phenyl-5-[(phenylsulfonyl)amino]-1H-indole-2-carboxylic
acid or a pharmaceutically acceptable salt or ester form thereof;
1-Benzyl-3-(4-tert-butylphenyl)-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}-
amino)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable
salt or ester form thereof;
1-Benzyl-5-[(phenylsulfonyl)amino]-1H,1'H-3,5'-biindole-2-carboxylic
acid or a pharmaceutically acceptable salt or ester form thereof;
3-Phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indole-2-carb-
oxylic or a pharmaceutically acceptable salt or ester form thereof;
5-{[(4-tert-Butylphenyl)sulfonyl]amino}-3-phenyl-1H-indole-2-carboxylic
acid or a pharmaceutically acceptable salt or ester form thereof;
and
5-[(1,1'-Biphenyl-4-ylsulfonyl)amino]-3-phenyl-1H-indole-2-carboxylic
acid or a pharmaceutically acceptable salt or ester form
thereof.
[0075] The present invention also provides compositions comprising
substituted sulfonamide indoles, including those compounds of
formulas 1-4 or a stereoisomer or pharmaceutically acceptable salt
thereof, and one or more pharmaceutically acceptable carriers,
excipients, or diluents. Such compositions include pharmaceutical
compositions for treating or controlling disease states or
conditions associated with increased PAI-1 activity. In certain
embodiments, the compositions comprise mixtures of one or more
substituted sulfonamide indoles.
[0076] Certain of the compounds of formulas 1-4 contain stereogenic
carbon atoms or other chiral elements and thus give rise to
stereoisomers, including enantiomers and diastereomers. The present
invention includes all of the stereoisomers of formulas 1-4, as
well as mixtures of the stereoisomers. Throughout this application,
the name of the product, where the absolute configuration of an
asymmetric center is not indicated, is intended to embrace the
individual stereoisomers as well as mixtures of stereoisomers.
[0077] Where an enantiomer is preferred, it can, in some
embodiments, be provided substantially free of the corresponding
enantiomer. Thus, an enantiomer substantially free of the
corresponding enantiomer refers to a compound that is isolated or
separated via separation techniques or prepared free of the
corresponding enantiomer. "Substantially free," as used herein,
means that the compound is made up of a significantly greater
proportion of one enantiomer. In preferred embodiments, the
compound is made up of at least about 90% by weight of a preferred
enantiomer. In other embodiments of the invention, the compound is
made up of at least about 99% by weight of a preferred enantiomer.
Preferred enantiomers can be isolated from racemic mixtures by any
method known to those skilled in the art, including high
performance liquid chromatography (HPLC) and the formation and
crystallization of chiral salts, or preferred enantiomers can be
prepared by methods described herein. Methods for the preparation
of preferred enantiomers are described, for example, in Jacques, et
al., Enantiomers, Racemates and Resolutions (Wiley Interscience,
New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977);
Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill,
N.Y., 1962); and Wilen, S. H. Tables of Resolving Agents and
Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame
Press, Notre Dame, Ind. 1972).
[0078] Exemplary salt forms of the compounds herein include, but
are not limited to, sodium salts and potassium salts. Other
exemplary salt forms of these compounds include, but are not
limited to, those formed with pharmaceutically acceptable inorganic
and organic bases or acids known in the art. The acids include, for
example, acetic, propionic, lactic, citric, tartaric, succinic,
fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric,
hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic,
naphthalenesulfonic, benzenesulfonic, toluenesulfonic,
camphorsulfonic, and similarly known acceptable aids when a
compound of this invention contains a basic moiety. Salt forms
prepared using inorganic bases include hydroxides, carbonates or
bicarbonates of the therapeutically acceptable alkali metals or
alkaline earth metals, such as sodium potassium, magnesium, calcium
and the like. Acceptable organic bases include amines, such as
benzylamine, mono-, di- and trialkylamines, preferably those having
alkyl groups of from 1 to 6 carbon atoms, more preferably 1 to 3
carbon atoms, such as methylamine, dimethylamine, trimethylamine,
ethylamine, diethylamine, triethylamine, mono-, di-, and
triethanolamine. Exemplary salts also include alkylene diamines
containing up to 6 carbon atoms, such as hexamethylenediamine;
cyclic saturated or unsaturated bases containing up to 6 carbon
atoms, including pyrrolidine, piperidine, morpholine, piperazine
and their N-alkyl and N-hydroxyalkyl derivatives, such as
N-methyl-morpholine and N-(2-hydroxyethyl)-piperidine, or pyridine.
Quaternary salts can also be formed, such as tetralkyl forms, such
as tetramethyl forms, alkyl-alkanol forms, such as
methyl-triethanol or trimethyl-monoethanol forms, and cyclic
ammonium salt forms, such as N-methylpyridinium,
N-methyl-N-(2-hydroxyethyl)-morpholinium,
N,N-di-methylmorpholinium,
N-methyl-N-(2-hydroxyethyl)-morpholinium, or
N,N-dimethyl-piperidinium salt forms. These salt forms can be
prepared using the acidic compound(s) of Formulas I-4 and
procedures known in the art.
[0079] Exemplary ester forms of the compounds of this invention
include, but are not limited to, straight chain alkyl esters having
from 1 to 6 carbon atoms or branched chain alkyl groups containing
1 to 6 carbon atoms, including methyl, ethyl, propyl, butyl,
2-methylpropyl and 1,1-dimethylethyl esters, cycloalkyl esters,
alkylaryl esters, benzyl esters, and the like. Other exemplary
esters include, but are not limited to, those of the formula
--COOR.sub.9 wherein R.sub.9 is selected from the formula:
##STR00005##
wherein R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are independently
selected from hydrogen, alkyl of from 1 to 10 carbon atoms, aryl of
6 to 12 carbon atoms, arylalkyl of from 6 to 12 carbon atoms;
heteroaryl or alkylheteroaryl wherein the heteroaryl ring is bound
by an alkyl chain of from 1 to 6 carbon atoms.
[0080] Preferred compounds of the present invention inhibit PAI-1
activity. Accordingly, the compounds can be used for the treatment,
including prevention, inhibition, and/or amelioration of PAI-1
related disorders in a subject, including, for example, in the
treatment of noninsulin dependent diabetes mellitus, in the
treatment of cardiovascular disease, and in the treatment of
thrombotic events associated with coronary artery and
cerebrovascular disease. Using the methods of the present
invention, a skilled medical practitioner will know how to
administer substituted sulfonamide indoles, including those
represented by formulas 1-4, to a subject suffering from any of the
diseases associated with increased PAI-1 activity or expression,
e.g., diabetes or cardiovascular disease, in order to effect
treatment for that disease.
[0081] In one exemplary embodiment, substituted sulfonamide indoles
are administered to a subject in order to treat disease processes
involving thrombotic and prothrombotic states which include, but
are not limited to, formation of atherosclerotic plaques, venous
and arterial thrombosis, myocardial ischemia, atrial fibrillation,
deep vein thrombosis, coagulation syndromes, pulmonary thrombosis,
cerebral thrombosis, thromboembolic complications of surgery (such
as joint or hip replacement), and peripheral arterial
occlusion.
[0082] Any disease or condition that is associated with increased
PAI-1 activity or expression in a subject can be treated with
substituted sulfonamide indoles of the present invention. Exemplary
diseases and conditions include stroke, e.g., stroke associated
with or resulting from atrial fibrillation; diseases associated
with extracellular matrix accumulation including, but not limited
to, renal fibrosis, chronic obstructive pulmonary disease,
polycystic ovary syndrome, restenosis, renovascular disease, and
organ transplant rejection; diseases associated with
neoangiogenesis, including, but not limited to, diabetic
retinopathy; Alzheimer's disease, e.g., by increasing or
normalizing levels of plasmin concentration in a subject;
myelofibrosis with myeloid metaplasia, e.g., by regulating stromal
cell hyperplasia and increases in extracellular matrix proteins;
diabetic nephropathy and renal dialysis associated with
nephropathy; malignancies or cancers, including, but not limited
to, leukemia, breast cancer and ovarian cancer; tumors, including,
but not limited to, liposarcomas and epithelial tumors; septicemia;
obesity; insulin resistance; proliferative diseases, including, but
not limited to, psoriasis; conditions associated with abnormal
coagulation homeostasis; low grade vascular inflammation;
cerebrovascular diseases; hypertension; dementia; osteoporosis;
arthritis; respiratory diseases, such as asthma; heart failure;
arrhythmia; angina, including, but not limited to, angina pectoris;
atherosclerosis and sequelae; kidney failure; multiple sclerosis;
osteoporosis; osteopenia; dementia; peripheral vascular disease;
peripheral arterial disease; acute vascular syndromes;
microvascular diseases including, but not limited to, nephropathy,
neuropathy, retinopathy and nephrotic syndrome; hypertension; Type
I and II diabetes and related diseases; hyperglycemia;
hyperinsulinemia; malignant lesions; premalignant lesions;
gastrointestinal malignancies; coronary heart disease, including,
but not limited to, primary and secondary prevention of myocardial
infarction, stable and unstable angina, primary prevention of
coronary events, and secondary prevention of cardiovascular events;
and inflammatory diseases, including, but not limited to, septic
shock and the vascular damage associated with infections.
[0083] The compounds of the present invention can also be
administered to a subject in combination with a second therapeutic
agent, including, but not limited to, prothrombolytic,
fibrinolytic, and anticoagulant agents, or in conjunction with
other therapies, for example, protease inhibitor-containing highly
active antiretroviral therapy (HAART) for the treatment of diseases
which originate from fibrinolytic impairment and
hyper-coagulability of HIV-1 infected patients. In certain
embodiments, the compounds of the present invention can be
administered in conjunction with and/or following processes or
procedures involving maintaining blood vessel patency, including,
but not limited to, vascular surgery, vascular graft and stent
patency, organ, tissue and cell implantation and transplantation.
The compounds of the present invention can also be used for the
treatment of blood and blood products used in dialysis, blood
storage in the fluid phase, especially ex vivo platelet
aggregation. The compounds of the present invention can also be
administered to a subject as a hormone replacement agent or to
reduce inflammatory markers or C-reactive protein. The compounds
can be administered to improve coagulation homeostasis, to improve
endothelial function, or as a topical application for wound
healing, e.g., the prevention of scarring. The compounds of the
present invention can be administered to a subject in order to
reduce the risk of undergoing a myocardial revascularization
procedure. The present compounds can also be added to human plasma
during the analysis of blood chemistry in hospital settings to
determine the fibrinolytic capacity thereof. In certain
embodiments, the compounds of the present invention can be used as
imaging agents for the identification of metastatic cancers.
[0084] C. Synthesis of Substituted Sulfonamide Indoles
[0085] Compounds of the present invention can be prepared by those
skilled in the art of organic synthesis employing conventional
methods that utilize readily available reagents and starting
materials. Representative compounds of the present invention can be
prepared using the following synthetic schemes. The skilled
practitioner will know how to make use of variants of these process
steps, which in themselves are well known in the art. In the
following reaction schemes, R.sub.1-R.sub.3, Aa, A.sub.2 and
A.sub.1 are selected from the groups defined above.
##STR00006##
[0086] Substituted indole 1 is first halogenated on the indole C-3
position with known halogenation agents such as chlorine, bromine,
N-chlorosuccinimide, N-bromosuccinimide and the like in a solvent
such as carbon tetrachloride, chloroform, dimethylformamide (DMF),
or N-methylpyrrolidinone (NMP) at temperatures of 0 to 30.degree.
C. Halo in compound 2 is chlorine, bromine or iodine. The C3-A1
group can be introduced by a Suzuki coupling reaction with boronic
acid in the presence of a base, preferably Na.sub.2CO.sub.3, and
Pd(PPh.sub.3).sub.4 in an inert solvent such as toluene at 80 to
100.degree. C. The 1H-indole intermediate 3 can be alkylated with
alkyl, benzyl, phenethyl, or naphthylmethyl iodide, bromide,
chloride, or triflate in the presence of a base, such as
K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, KOH or NaH, in an inert solvent,
such as THF, dioxane, pyridine, DMF, NMP, or DMSO, at -40 to
100.degree. C. The resulting nitro intermediate 4 can be reduced to
the amine 5 upon treatment with Raney.RTM. nickel in a mixture of
hydrazine and ethanol at temperature of 0 to 40.degree. C. This
amine can be converted to sulfonamide 6 upon treatment with a
sulfonyl halide, preferably alkyl, aryl, or Het sulfonyl chloride,
and a base such as N,N-diisopropylethylamine in an anhydrous
solvent such as dichloromethane for 0.5 to 24 hours at temperature
of 0 to 40.degree. C. The final acid 7 is obtained via a basic
hydrolysis of the corresponding ester 6 (Scheme 1). In this
reaction lithium hydroxide, sodium hydroxide, potassium hydroxide
and the like can be used as a base, and water or a mixture of water
with methanol, ethanol, THF, dioxane and the like can be used as a
solvent. The final products can be purified by recrystallization,
trituration, preparative thin layer chromatography, flash column
chromatography on silica gel, or high performance liquid
chromatography. Purification of intermediates can be achieved in
the same manner. A salt is optionally produced by the addition of
an acid or base, such as hydrogen chloride gas or hydrochloric
acid.
##STR00007##
[0087] Mono peptide derived from the acid 8 and amino acid and its
ester thereof, can be prepared by, for example, the following
synthetic scheme (Scheme 2). The carboxylic acid 8, which can be
readily prepared by basic hydrolysis of ester 4, is coupled to the
amine nitrogen of amino acid (ester), wherein the amino acid
(ester) means the carboxylic acid functionality of the amino acid
was protected as an ester. In this amide bond formation process
1,3-dicyclohexylcarbodiimide,
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide,
diisopropylcarbodiimide, 1,1'-carbonyldiimidazole,
6-chloro-2,4-dimethoxy-1,3,5-triazine and the like can be used as a
coupling agent and triethylamine, diisopropylethyl amine, N-methyl
morpholine and the like can be used as a base. At this time, as a
solvent, methylene chloride, diethyl ether, tetrahydrofuran,
dioxane and the like is used. Nitro reduction followed by
sulfonylation and ester hydrolysis, as previously described in
Scheme 1, furnishes the desired final product 12.
[0088] D. Substituted Sulfonamide Indoles as Pharmaceutical
Compositions
[0089] The present invention provides substituted sulfonamide
indoles as pharmaceuticals. In a preferred embodiment, substituted
sulfonamide indoles are formulated as pharmaceuticals to treat
diseases associated with increased PAI-1 activity, e.g., by
inhibiting PAI-1 activity in a subject.
[0090] In general, substituted sulfonamide indoles can be
administered as pharmaceutical compositions by any method known in
the art for administering therapeutic drugs including oral, buccal,
topical, systemic (e.g., transdermal, intranasal, or by
suppository), or parenteral (e.g., intramuscular, subcutaneous, or
intravenous injection). Compositions can take the form of tablets,
pills, capsules, semisolids, powders, sustained release
formulations, solutions, suspensions, emulsions, syrups, elixirs,
aerosols, or any other appropriate compositions; and comprise at
least one compound of this invention in combination with at least
one pharmaceutically acceptable excipient. Suitable excipients are
well known to persons of ordinary skill in the art, and they, and
the methods of formulating the compositions, can be found in such
standard references as Alfonso A R: Remington's Pharmaceutical
Sciences, 17th ed., Mack Publishing Company, Easton Pa., 1985.
Suitable liquid carriers, especially for injectable solutions,
include water, aqueous saline solution, aqueous dextrose solution,
and glycols. In some embodiments of the present invention
substituted sulfonamide indoles suitable for use in the practice of
this invention will be administered either singly or in combination
with at least one other compound of this invention. Substituted
sulfonamide indoles suitable for use in the practice of the present
invention can also be administered with at least one other
conventional therapeutic agent for the disease being treated.
[0091] Aqueous suspensions of the invention can contain a
substituted sulfonamide indole in admixture with excipients
suitable for the manufacture of aqueous suspensions. Such
excipients can include a suspending agent, such as sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethylene oxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
(e.g., polyoxyethylene sorbitol mono-oleate), or a condensation
product of ethylene oxide with a partial ester derived from fatty
acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan
mono-oleate). The aqueous suspension can also contain one or more
preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or
more coloring agents, one or more flavoring agents, and one or more
sweetening agents, such as sucrose, aspartame or saccharin.
Formulations can be adjusted for osmolarity.
[0092] Oil suspensions can be formulated by suspending a
substituted sulfonamide indole in a vegetable oil, such as arachis
oil, olive oil, sesame oil or coconut oil, or in a mineral oil such
as liquid paraffin; or a mixture of these. The oil suspensions can
contain a thickening agent, such as beeswax, hard paraffin or cetyl
alcohol. Sweetening agents can be added to provide a palatable oral
preparation, such as glycerol, sorbitol or sucrose. These
formulations can be preserved by the addition of an antioxidant
such as ascorbic acid. As an example of an injectable oil vehicle,
see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The
pharmaceutical formulations of the invention can also be in the
form of oil-in-water emulsions. The oily phase can be a vegetable
oil or a mineral oil, described above, or a mixture of these.
Suitable emulsifying agents include naturally-occurring gums, such
as gum acacia and gum tragacanth, naturally occurring phosphatides,
such as soybean lecithin, esters or partial esters derived from
fatty acids and hexitol anhydrides, such as sorbitan mono-oleate,
and condensation products of these partial esters with ethylene
oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion
can also contain sweetening agents and flavoring agents, as in the
formulation of syrups and elixirs. Such formulations can also
contain a demulcent, a preservative, or a coloring agent.
[0093] The compound of choice, alone or in combination with other
suitable components, can be made into aerosol formulations (i.e.,
they can be "nebulized") to be administered via inhalation. Aerosol
formulations can be placed into pressurized acceptable propellants,
such as dichlorodifluoromethane, propane, nitrogen, and the
like.
[0094] Formulations suitable for parenteral administration, such
as, for example, by intraarticular (in the joints), intravenous,
intramuscular, intradermal, intraperitoneal, and subcutaneous
routes, include aqueous and non-aqueous, isotonic sterile injection
solutions, which can contain antioxidants, buffers, bacteriostats,
and solutes that render the formulation isotonic with the blood of
the intended recipient, and aqueous and non-aqueous sterile
suspensions that can include suspending agents, solubilizers,
thickening agents, stabilizers, and preservatives. Among the
acceptable vehicles and solvents that can be employed are water and
Ringer's solution, an isotonic sodium chloride. In addition,
sterile fixed oils can conventionally be employed as a solvent or
suspending medium. For this purpose any bland fixed oil can be
employed including synthetic mono- or diglycerides. In addition,
fatty acids such as oleic acid can likewise be used in the
preparation of injectables. These solutions are sterile and
generally free of undesirable matter. Where the compounds are
sufficiently soluble they can be dissolved directly in normal
saline with or without the use of suitable organic solvents, such
as propylene glycol or polyethylene glycol. Dispersions of the
finely divided compounds can be made-up in aqueous starch or sodium
carboxymethyl cellulose solution, or in suitable oil, such as
arachis oil. These formulations can be sterilized by conventional,
well known sterilization techniques. The formulations can contain
pharmaceutically acceptable auxiliary substances as required to
approximate physiological conditions such as pH adjusting and
buffering agents, toxicity adjusting agents, e.g., sodium acetate,
sodium chloride, potassium chloride, calcium chloride, sodium
lactate and the like. The concentration of substituted sulfonamide
indoles in these formulations can vary widely, and will be selected
primarily based on fluid volumes, viscosities, body weight, and the
like, in accordance with the particular mode of administration
selected and the patient's needs. For IV administration, the
formulation can be a sterile injectable preparation, such as a
sterile injectable aqueous or oleaginous suspension. This
suspension can be formulated according to the known art using those
suitable dispersing or wetting agents and suspending agents. The
sterile injectable preparation can also be a sterile injectable
solution or suspension in a nontoxic parenterally-acceptable
diluent or solvent, such as a solution of 1,3-butanediol. The
formulations of commends can be presented in unit-dose or
multi-dose sealed containers, such as ampules and vials.
[0095] Injection solutions and suspensions can be prepared from
sterile powders, granules, and tablets of the kind previously
described.
[0096] Substituted sulfonamide indoles suitable for use in the
practice of this invention can be administered orally. The amount
of a compound of the present invention in the composition can vary
widely depending on the type of composition, size of a unit dosage,
kind of excipients, and other factors well known to those of
ordinary skill in the art. In general, the final composition can
comprise for example, from 0.000001 percent by weight (% w) to 10%
w of the substituted sulfonamide indoles, preferably 0.00001% w to
1% w, with the remainder being the excipient or excipients.
[0097] Pharmaceutical formulations for oral administration can be
formulated using pharmaceutically acceptable carriers well known in
the art in dosages suitable for oral administration. Such carriers
enable the pharmaceutical formulations to be formulated in unit
dosage forms as tablets, pills, powder, dragees, capsules, liquids,
lozenges, gels, syrups, slurries, suspensions, etc. suitable for
ingestion by the patient. Formulations suitable for oral
administration can consist of (a) liquid solutions, such as an
effective amount of the packaged nucleic acid suspended in
diluents, such as water, saline or PEG 400; (b) capsules, sachets
or tablets, each containing a predetermined amount of the active
ingredient, as liquids, solids, granules or gelatin; (c)
suspensions in an appropriate liquid; and (d) suitable
emulsions.
[0098] Pharmaceutical preparations for oral use can be obtained
through combination of the compounds of the present invention with
a solid excipient, optionally grinding a resulting mixture, and
processing the mixture of granules, after adding suitable
additional compounds, if desired, to obtain tablets or dragee
cores. Suitable solid excipients are carbohydrate or protein
fillers and include, but are not limited to sugars, including
lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat,
rice, potato, or other plants; cellulose such as methyl cellulose,
hydroxymethyl cellulose, hydroxypropylmethyl-cellulose or sodium
carboxymethylcellulose; and gums including arabic and tragacanth;
as well as proteins such as gelatin and collagen. If desired,
disintegrating or solubilizing agents can be added, such as the
cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt
thereof, such as sodium alginate. Tablet forms can include one or
more of lactose, sucrose, mannitol, sorbitol, calcium phosphates,
corn starch, potato starch, microcrystalline cellulose, gelatin,
colloidal silicon dioxide, talc, magnesium stearate, stearic acid,
and other excipients, colorants, fillers, binders, diluents,
buffering agents, moistening agents, preservatives, flavoring
agents, dyes, disintegrating agents, and pharmaceutically
compatible carriers. Lozenge forms can comprise the active
ingredient in a flavor, e.g., sucrose, as well as pastilles
comprising the active ingredient in an inert base, such as gelatin
and glycerin or sucrose and acacia emulsions, gels, and the like
containing, in addition to the active ingredient, carriers known in
the art.
[0099] The substituted sulfonamide indoles of the present invention
can also be administered in the form of suppositories for rectal
administration of the drug. These formulations can be prepared by
mixing the drug with a suitable non-irritating excipient which is
solid at ordinary temperatures but liquid at the rectal
temperatures and will therefore melt in the rectum to release the
drug. Such materials are cocoa butter and polyethylene glycols.
[0100] The compounds of the present invention can also be
administered by intranasal, intraocular, intravaginal, and
intrarectal routes including suppositories, insufflation, powders
and aerosol formulations (for examples of steroid inhalants, see
Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann.
Allergy Asthma Immunol. 75:107-111, 1995).
[0101] The substituted sulfonamide indoles of the present invention
can be delivered transdermally, by a topical route, formulated as
applicator sticks, solutions, suspensions, emulsions, gels, creams,
ointments, pastes, jellies, paints, powders, and aerosols.
Encapsulating materials can also be employed with the compounds of
the present invention and the term "composition" can include the
active ingredient in combination with an encapsulating material as
a formulation, with or without other carriers. For example, the
compounds of the present invention can also be delivered as
microspheres for slow release in the body. In one embodiment,
microspheres can be administered via intradermal injection of
drug-containing microspheres, which slowly release subcutaneously
(see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as
biodegradable and injectable gel formulations (see, e.g., Gao,
Pharm. Res. 12:857-863, 1995); or, as microspheres for oral
administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,
1997). Both transdermal and intradermal routes afford constant
delivery for weeks or months. Cachets can also be used in the
delivery of the compounds of the present invention, e.g.,
anti-atherosclerotic medicaments.
[0102] In another embodiment, the compounds of the present
invention can be delivered by the use of liposomes which fuse with
the cellular membrane or are endocytosed, i.e., by employing
ligands attached to the liposome, or attached directly to the
oligonucleotide, that bind to surface membrane protein receptors of
the cell resulting in endocytosis. By using liposomes, particularly
where the liposome surface carries ligands specific for target
cells, or are otherwise preferentially directed to a specific
organ, one can focus the delivery of the compound into the target
cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul.
13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995;
Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).
[0103] In other cases, the preferred preparation can be a
lyophilized powder which may contain, for example, any or all of
the following: 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7%
mannitol, at a pH range of 4.5 to 5.5, that is combined with buffer
prior to use
[0104] A pharmaceutical composition of the invention can optionally
contain, in addition to a substituted sulfonamide indoles, at least
one other therapeutic agent useful in the treatment of a disease or
condition associated with increased PAI-1 activity.
[0105] The pharmaceutical compositions are generally formulated as
sterile, substantially isotonic and in full compliance with all
Good Manufacturing Practice (GMP) regulations of the U.S. Food and
Drug Administration.
[0106] E. Determining Dosage Regimens for Substituted Sulfonamide
Indoles
[0107] The present invention provides methods of inhibiting PAI-1
activity in a subject for the treatment of diseases and conditions
associated with increased PAI-1 activity using substituted
sulfonamide indoles. In an exemplary embodiment of the present
invention, a skilled practitioner will treat a subject having a
disease associated with elevated PAI-1 levels and/or activity with
the compounds of the present invention.
[0108] For treatment purposes, the compositions or compounds
disclosed herein can be administered to the subject in a single
bolus delivery, via continuous delivery (e.g., continuous
transdermal, mucosal, or intravenous delivery) over an extended
time period, or in a repeated administration protocol (e.g., by an
hourly, daily or weekly, repeated administration protocol). The
pharmaceutical formulations of the present invention can be
administered, for example, one or more times daily, 3 times per
week, or weekly. In an exemplary embodiment of the present
invention, the pharmaceutical formulations of the present invention
are orally administered once or twice daily.
[0109] In this context, a therapeutically effective dosage of the
biologically active agent(s) can include repeated doses within a
prolonged treatment regimen that will yield clinically significant
results to alleviate one or more symptoms or detectable conditions
associated with increased PAI-1 activity. Determination of
effective dosages in this context is typically based on animal
model studies followed up by human clinical trials and is guided by
determining effective dosages and administration protocols that
significantly reduce the occurrence or severity of targeted
exposure symptoms or conditions in the subject. Suitable models in
this regard include, for example, murine, rat, porcine, feline,
non-human primate, and other accepted animal model subjects known
in the art. Alternatively, effective dosages can be determined
using in vitro models (e.g., immunologic and histopathologic
assays). Using such models, only ordinary calculations and
adjustments are typically required to determine an appropriate
concentration and dose to administer a therapeutically effective
amount of the biologically active agent(s) (e.g., amounts that are
intranasally effective, transdermally effective, intravenously
effective, or intramuscularly effective to elicit a desired
response). In alternative embodiments, an "effective amount" or
"therapeutically effective dose" of the biologically active
agent(s) will simply inhibit or enhance one or more selected
biological activity(ies) correlated with a disease or condition, as
set forth above, for either therapeutic or diagnostic purposes.
[0110] The actual dosage of biologically active agents will of
course vary according to factors such as the extent of exposure and
particular status of the subject (e.g., the subject's age, size,
fitness, extent of symptoms, susceptibility factors, etc), time and
route of administration, as well as other drugs or treatments being
administered concurrently. Dosage regimens can be adjusted to
provide an optimum prophylactic or therapeutic response. By
"therapeutically effective dose" herein is meant a dose that
produces effects for which it is administered. More specifically, a
therapeutically effective dose of the compound(s) of the invention
preferably alleviates symptoms, complications, or biochemical
indicia of diseases associated with increased PAI-1 activity. The
exact dose will depend on the purpose of the treatment, and will be
ascertainable by one skilled in the art using known techniques
(see, e.g., Lieberman, Pharmaceutical Dosage Forms (Vols. 1-3,
1992); Lloyd, 1999, The Art, Science, and Technology of
Pharmaceutical Compounding; and Pickar, 1999, Dosage Calculations).
A therapeutically effective dose is also one in which any toxic or
detrimental side effects of the active agent is outweighed in
clinical terms by therapeutically beneficial effects. It is to be
further noted that for each particular subject, specific dosage
regimens should be evaluated and adjusted over time according to
the individual need and professional judgment of the person
administering or supervising the administration of the
compound.
[0111] In an exemplary embodiment of the present invention, unit
dosage forms of the compounds are prepared for standard
administration regimens. In this way, the composition can be
subdivided readily into smaller doses at the physicians direction.
For example, unit dosages can be made up in packeted powders, vials
or ampoules and preferably in capsule or tablet form. The active
compound present in these unit dosage forms of the composition can
be present in an amount of, for example, from about one gram to
about fifteen grams or more, for single or multiple daily
administration, according to the particular need of the patient. By
initiating the treatment regimen with a minimal daily dose of about
one gram, the blood levels of PAI-1 and the patients symptomatic
relief analysis can be used to determine whether a larger or
smaller dose is indicated. Effective administration of the
compounds of this invention can be given at an oral dose of, for
example, from about 0.1 mg/kg/day to about 1,000 mg/kg/day.
Preferably, administration will be from about 10/mg/kg/day to about
600 mg/kg/day, more preferably from about 25 to about 200
mg/kg/day, and even more preferably from about 50 mg/kg/day to
about 100 mg/kg/day.
[0112] In certain embodiments, the present invention is directed to
prodrugs of compounds of formulas 1-4. The term "prodrug," as used
herein, means a compound that is convertible in vivo by metabolic
means (e.g. by hydrolysis) to a compound of formulas 1-4. Various
forms of prodrugs are known in the art such as those discussed in,
for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985);
Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press
(1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of
Prodrugs, Textbook of Drug Design and Development, Chapter 5,
113-191 (1991), Bundgaard, et al., Journal of Drug Delivery
Reviews, 8:1-38 (1992), Bundgaard, J. of Pharmaceutical Sciences,
77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as
Novel Drug Delivery Systems, American Chemical Society (1975).
[0113] F. Kits
[0114] After a pharmaceutical comprising a substituted sulfonamide
indole has been formulated in a suitable carrier, it can be placed
in an appropriate container and labeled for treatment of a PAI-1
related disorder, e.g., leukemia. Additionally, another
pharmaceutical comprising at least one other therapeutic agent
useful in the treatment of the PAI-1 related disorder can be placed
in the container as well and labeled for treatment of the indicated
disease. Alternatively, a single pharmaceutical comprising a
substituted sulfonamide indole and at least one other therapeutic
agent useful in the treatment of a PAI-1 related disorder can be
placed in an appropriate container and labeled for treatment. For
administration of pharmaceuticals comprising substituted
sulfonamide indoles and of pharmaceuticals comprising, in a single
pharmaceutical, substituted sulfonamide indoles and at least one
other therapeutic agent useful in the treatment of a PAI-1 related
disorder, such labeling would include, for example, instructions
concerning the amount, frequency and method of administration.
Similarly, for administration of multiple pharmaceuticals provided
in the container, such labeling would include, for example,
instructions concerning the amount, frequency and method of
administration of each pharmaceutical.
EXAMPLES
[0115] The syntheses of compounds 1-21 are described in examples
1-21 respectively.
Example 1
Synthesis of
1-benzyl-3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indo-
le-2-carboxylic acid
[0116] Step 1: A solution of ethyl
5-nitro-3-phenyl-1H-indole-2-carboxylate (1.0 g, 3.23 mmol) and
benzyl bromide (0.60 g, 3.5 mmol) in THF (50 mL) was treated with
Cs.sub.2CO.sub.3 (3.26 g, 10 mmol) and heated to a gentle reflux
for 16 h. After cooling to room temperature the reaction was
quenched by addition of water and then partitioned between water
and EtOAc. The organic phase was dried over MgSO.sub.4, and
concentrated to yield ethyl
1-benzyl-5-nitro-3-phenyl-1H-indole-2-carboxylate as a yellowish
solid (1.20 g, 93%): .sup.1H NMR (DMSO-d.sub.6) .delta. 0.93 (t,
J=7.0 Hz, 3H), 4.11 (q, J=7.0 Hz, 2H), 5.91 (s, 2H), 7.12 (d, J=8.3
Hz, 2H), 7.30-7.32 (m, 3H), 7.50-7.55 (m, 5H), 7.92 (d, J=9.2 Hz,
1H), 8.22 (dd, J=9.2, 2.0 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H); MS (EI)
m/z 400.1 (MH.sup.+); Anal. calcd for
C.sub.24H.sub.20N.sub.2O.sub.4: C, 71.99; H, 5.03; N, 7.00. Found:
C, 71.77; H, 5.14; N, 6.71.
[0117] Step 2: A large excess of Raney.RTM. nickel was added in
portions to a stirred solution of ethyl
1-benzyl-5-nitro-3-phenyl-1H-indole-2-carboxylate (1.20 g, 3 mmol)
and hydrazine (1.5 mL, 47.9 mmol) in 50 mL of ethanol. After
stirring at room temperature for 2 h the catalyst was then removed
by filtering through a short pad of Celite.RTM.521. The filtrate
was concentrated to give ethyl
5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate (1.0 g, 90%) as
an off-white solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 0.91 (t,
J=7.0 Hz, 3H), 4.03 (q, J=7.0 Hz, 2H), 4.77 (s, 2H), 5.71 (s, 2H),
6.61 (d, J=1.8 Hz, 1H), 6.75 (d, J=2.2 Hz, 1H), 7.21-7.45 (m, 11H);
MS (EI) m/z 371.2 (MH.sup.+).
[0118] Step 3: Ethyl
5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate (0.23 g, 0.67
mmol) was dissolved in 7 mL of methylene chloride. To the solution
was added diisopropylethylamine (0.5 mL, 2.9 mmol) and
4-trifluoromethoxy-benzenesulfonyl chloride (0.13 g, 0.5 mmol).
After being stirred at room temperature overnight the reaction was
concentrated and the residue was re-dissolved in 10 mL of 2:1:1
THF/MeOH/water. Lithium hydroxide monohydrate (0.15 g, 3.6 mmol)
was added and the mixture was stirred at 40.degree. C. overnight.
Most of the organic solvents was removed and the reaction mixture
was made acidic (pH 6) with glacial acetic acid, and the solid was
collected and purified by semi-preparative HPLC (Column: Phenomenex
C18 Luna 21.6 mm.times.60 mm, 5 .mu.M; Solvent A: Water (0.1% TFA
buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent
Gradient: Time 0: 0% B; 10 min: 100% B; Hold 100% B 5 min. Flow
Rate: 22.5 mL/min). The product was collected based on UV
absorption and concentrated to give the title compound as a pale
yellow solid (0.16 g, 45%): .sup.1H NMR (DMSO-d.sub.6) .delta. 5.78
(s, 2H), 7.00-7.10 (m, 4H), 7.20-7.30 (m, 5H), 7.30-7.45 (m, 3H),
7.50-7.60 (m, 3H), 7.75 (d, J=8.8 Hz, 2H), 10.02 (s, 1H), 13.03 (br
s, 1H); MS (ESI) m/z 565 [M-H].sup.-; HRMS calcd for
C.sub.29H.sub.22F.sub.3N.sub.2O.sub.5S, 567.1199; found
(ESI.sup.+): 567.1190; Anal. calcd for
C.sub.29H.sub.21F.sub.3N.sub.2O.sub.5S.0.25H.sub.2O: C, 61.00; H,
3.80; N, 4.91. Found: C, 60.67; H, 3.73; N, 5.09.
Example 2
Synthesis of
1-benzyl-3-phenyl-5-[(quinolin-8-ylsulfonyl)amino]-1H-indole-2-carboxylic
acid
[0119] The title compound was prepared from ethyl
5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate and
quinoline-8-sulfonyl chloride followed the procedure of Example 1
Step 3 as a pale yellow solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
5.66 (s, 2H), 6.90 (d, J=2.0 Hz, 1H), 6.95-7.05 (m, 5H), 7.15-7.28
(m, 3H), 7.30-7.45 (m, 4H), 7.64 (t, J=7.8 Hz, 1H), 7.75 (dd,
J=8.3, 4.1 Hz, 1H), 8.17 (dd, J=7.3, 1.3 Hz, 1H), 8.27 (dd, J=8.2,
1.2 Hz, 1H), 8.57 (dd, J=8.3, 1.7 Hz, 1H), 9.12 (dd, J=4.2, 1.6 Hz,
1H), 9.67 (s, 1H), 12.97 (br s, 1H); MS (ESI) m/z 534 (MH.sup.+);
MS (ESI) m/z 532 [M-H].sup.-; HRMS calcd for
C.sub.31H.sub.24N.sub.3O.sub.4S: 534.1477; found (ESI.sup.+):
534.1481; Anal. calcd for
C.sub.31H.sub.23N.sub.3O.sub.4S.0.25H.sub.2O: C, 69.19; H, 4.40; N,
7.81. Found: C, 69.28; H, 4.31; N, 7.73.
Example 3
Synthesis of
1-benzyl-5-{[(4-tert-butylphenyl)sulfonyl]amino}-3-phenyl-1H-indole-2-car-
boxylic acid
[0120] The title compound was prepared from ethyl
5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate and
4-tert-butylbenzene sulfonyl chloride followed the procedure of
Example 1 Step 3 as a pale yellow solid: .sup.1H NMR (DMSO-d.sub.6)
.delta. 1.25 (s, 9H), 5.76 (s, 2H), 7.05-7.15 (m, 4H), 7.20-7.30
(m, 5H), 7.30-7.45 (m, 3H), 7.50-7.60 (m, 5H); MS (ESI) m/z 537
[M-H].sup.-; HRMS calcd for C.sub.32H.sub.31N.sub.2O.sub.4S:
539.2002; found (ESI.sup.+): 539.1999.
Example 4
Synthesis of
1-benzyl-5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-3-phenyl-1H-indole-2-carbo-
xylic acid
[0121] The title compound was prepared from ethyl
5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate and
bisphenyl-4-sulfonyl chloride followed the procedure of Example 1
Step 3 as a pale yellow solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
5.76 (s, 2H), 7.02-7.15 (m, 4H), 7.18-7.48 (m, 10H), 7.49 (d, J=7.7
Hz, 2H), 7.53 (d, J=9.1 Hz, 2H), 7.65-7.75 (m, 4H), 7.83 (d, J=8.6
Hz, 2H), 9.95 (s, 1H), 13.00 (br s, 1H); MS (ESI) m/z 557
[M-H].sup.-; HRMS calcd for C.sub.34H.sub.27N.sub.2O.sub.4S:
559.1689; found (ESI.sup.+): 559.1674; Anal. calcd for
C.sub.34H.sub.26N.sub.2O.sub.4S. 05H.sub.2O: C, 71.94; H, 4.79; N,
4.93. Found: C, 71.84; H, 4.71; N, 5.02.
Example 5
Synthesis of
1-methyl-3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indo-
le-2-carboxylic acid
[0122] Step 1: A solution of ethyl
5-nitro-3-phenyl-1H-indole-2-carboxylate (1.0 g, 3.23 mmol) and
iodomethane (2.5 mL, 40.2 mmol) in DMF (25 mL) was treated with
Cs.sub.2CO.sub.3 (3.26 g, 10 mmol) and stirred for 16 h. The
reaction was quenched by addition of water and the solid was
collected and dried to yield ethyl
1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylate as a yellowish
solid (1.1 g, 100%): .sup.1H NMR (DMSO-d.sub.6) .delta. 1.03 (t,
J=7.0 Hz, 3H), 4.09 (s, 3H), 4.18 (q, J=7.0 Hz, 2H), 7.40-7.55 (m,
5H), 7.90 (d, J=9.2 Hz, 1H), 8.23 (dd, J=9.2, 2.3 Hz, 1H), 8.32 (d,
J=2.3 Hz, 1H); MS (EI) m/z 325.2 (MH.sup.+).
[0123] Step 2: The title compound was prepared from ethyl
1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylate and
4-trifluoromethoxy-benzenesulfonyl chloride followed the procedures
of Example 1 Step 2 & Step 3 as an off-white solid: .sup.1H NMR
(DMSO-d.sub.6) .delta. 3.95 (s, 3H), 6.98 (d, J=2.8 Hz, 1H), 7.11
(dd, J=8.8, 1.7 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H), 7.30-7.45 (m, 3H),
7.50-7.60 (m, 3H), 7.74 (d, J=8.7 Hz, 2H), 9.98 (s, 1H), 13.00 (br
s, 1H); MS (ESI) m/z 489[M-H].sup.-; HRMS calcd for
C.sub.23H.sub.18F.sub.3N.sub.2O.sub.5S: 491.0886; found
(ESI.sup.+): 491.0878; Anal. calcd for
C.sub.23H.sub.17F.sub.3N.sub.2O.sub.5S.0.4H.sub.2O: C, 55.51; H,
3.61; N, 5.63. Found: C, 55.61; H, 3.39; N, 5.77.
Example 6
Synthesis of
5-{[(4-tert-butylphenyl)sulfonyl]amino}-1-methyl-3-phenyl-1H-indole-2-car-
boxylic acid
[0124] The title compound was prepared from ethyl
1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylate and
4-tert-butylbenzene sulfonyl chloride followed the procedures of
Example 1 Step 2 & Step 3 as a pale yellow solid: .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.25 (s, 9H), 3.94 (s, 3H), 7.00-7.10 (m,
1H), 7.10-7.27 (m, 3H), 7.27-7.45 (m, 3H), 7.45-7.62 (m, 5H), 9.86
(s, 1H), 12.97 (br s, 1H); MS (ESI) m/z 461 [M-H].sup.-; HRMS calcd
for C.sub.26H.sub.27N.sub.2O.sub.4S: 463.1689; found (ESI.sup.+):
463.1681; Anal. calcd for
C.sub.26H.sub.26N.sub.2O.sub.4S.0.15H.sub.2O: C, 67.12; H, 5.70; N,
6.02. Found: C, 67.05; H, 5.42; N, 5.88.
Example 7
Synthesis of
5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1-methyl-3-phenyl-1H-indole-2-carbo-
xylic acid
[0125] The title compound was prepared from ethyl
1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylate and
bisphenyl-4-sulfonyl chloride followed the procedures of Example 1
Step 2 & Step 3 as a white solid: .sup.1H NMR (DMSO-d.sub.6)
.delta. 3.94 (s, 3H), 7.01 (d, J=1.8 Hz, 1H), 7.15-7.22 (m, 3H),
7.25-7.35 (m, 3H), 7.40-7.57 (m, 4H), 7.58-7.63 (m, 4H), 7.72 (d,
J=7.8 Hz, 2H), 9.90 (s, 1H), 12.96 (br s, 1H); MS (ESI) m/z
481[M-H].sup.-; HRMS calcd for C.sub.28H.sub.23N.sub.2O.sub.4S:
483.1376; found (ESI.sup.+): 483.1368; Anal. calcd for
C.sub.28H.sub.22N.sub.2O.sub.4S: C, 69.69; H, 4.60; N, 5.81. Found:
C, 69.37; H, 4.40; N, 5.64.
Example 8
Synthesis of
N-{[1-methyl-3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H--
indol-2-yl]carbonyl}-L-leucine
[0126] Step 1: 1-Methyl-5-nitro-3-phenyl-1H-indole-2-carboxylic
acid was prepared from ethyl
1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylate by KOH hydrolysis
as a yellowish solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 4.08 (s,
3H), 7.48-7.55 (m, 5H), 7.86 (d, J=9.2 Hz, 1H), 8.21 (dd, J=9.2,
2.3 Hz, 1H), 8.30 (d, J=2.3 Hz, 1H); MS (ESI) m/z 295 [M-H].sup.-;
HRMS calcd for C.sub.16H.sub.13N.sub.2O.sub.4: 297.0873; found
(ESI.sup.+): 297.0867; Anal. calcd for
C.sub.16H.sub.12N.sub.2O.sub.4.0.15H.sub.2O: C, 63.32; H, 4.25; N,
9.23. Found: C, 63.34; H, 3.87; N, 9.12.
[0127] Step 2: A mixture of
1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylic acid (0.56 g, 1.9
mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride
(0.47 g, 2.5 mmol), and L-leucine methyl ester hydrochloride (0.40
g, 2.2 mmol) was stirred in CH.sub.2Cl.sub.2 (20 mL).
N-methylmorpholine (1.01 g, 10 mmol) was added and the mixture was
stirred at room temperature overnight. The mixture was then washed
with 0.05 N HCl and water. The resulting solution was dried with
MgSO.sub.4 and concentrated. The residue was dissolved in 30 mL of
ethanol and a large excess of Raney.RTM. nickel and hydrazine (0.6
mL, 19 mmol) were added. After stirring at room temperature for 2 h
the catalyst was then removed by filtering through a short pad of
Celite.RTM.521. The filtrate was concentrated to give 0.65 g (87%)
of crude methyl
N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-leucinate
as a pale yellow solid: MS (ESI) m/z 394 (MH.sup.+); HRMS calcd for
C.sub.23H.sub.28N.sub.3O.sub.3: 394.2128; found (ESI.sup.+):
394.2121.
[0128] Step 3: The title compound was prepared from methyl
N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-leucinate
and 4-trifluoromethoxybenzenesulfonyl chloride followed the
procedure of Example 1 Step 3 as a brown solid: .sup.1H NMR
(DMSO-d.sub.6) .delta. 0.79 (d, J=6.3 Hz, 3H), 0.80 (d, J=6.3 Hz,
3H), 1.35-1.60 (m, 3H), 3.75 (s, 3H), 4.25-4.35 (m, 1H), 7.03 (dd,
J=8.8, 2.0 Hz, 1H), 7.24 (d, J=1.4 Hz, 1H), 7.25-7.40 (m, 5H), 7.47
(d, J=8.9 Hz, 1H), 7.55 (d, J=7.9 Hz, 2H), 7.77 (d, J=7.9 Hz, 2H),
8.77 (d, J=7.9 Hz, 1H), 9.99 (s, 1H), 12.64 (br s, 1H); MS (ESI)
m/z 604 (MH.sup.+), MS (ESI) m/z 602 [M-H].sup.-; HRMS calcd for
C.sub.29H.sub.29F.sub.3N.sub.3O.sub.6S: 604.1727; found
(ESI.sup.+): 604.1716; Anal. calcd for
C.sub.29H.sub.28F.sub.3N.sub.3O.sub.6S.0.4H.sub.2O: C, 57.02; H,
4.75; N, 6.96. Found: C, 56.70; H, 4.75; N, 6.94.
Example 9
Synthesis of
N-({5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1-methyl-3-phenyl-1H-indol-2-yl-
}carbonyl)-L-phenylalanine
[0129] Step 1: Ethyl
N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-phenylalaninate
was prepared from 1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylic
acid and L-phenylalanine ethyl ester hydrochloride followed the
procedure of Example 8 Step 2 as a pale
[0130] yellow solid: MS (ESI) m/z 442 (MH.sup.+); HRMS calcd for
C.sub.27H.sub.28N.sub.3O.sub.3: 442.2128; found (ESI.sup.+):
442.2122.
[0131] Step 2: The title compound was prepared from ethyl
N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-phenylalaninate
and bisphenyl-4-sulfonyl chloride followed the procedure of Example
8 Step 3 as a white solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 2.85
(dd, J=14.0, 10.9 Hz, 1H), 3.15 (dd, J=10.9, 4.1 Hz, 1H), 3.47 (s,
3H), 4.65 (ddd, J=14.0, 10.9, 4.1 Hz, 1H), 7.06 (dd, J=8.7, 2.0 Hz,
1H), 7.10-7.30 (m, 11H), 7.40-7.52 (m, 4H), 7.69-7.80 (m, 4H), 7.84
(d, J=8.6 Hz, 2H), 8.86 (d, J=8.2 Hz, 1H), 9.89 (s, 1H), 12.89 (br
s, 1H); MS (ESI) m/z 630 (MH.sup.+); MS (ESI) m/z 628 [M-H].sup.-;
HRMS calcd for C.sub.37H.sub.32N.sub.3O.sub.5S: 630.2060; found
(ESI.sup.+): 630.2053; Anal. calcd for
C.sub.37H.sub.31N.sub.3O.sub.5S.0.5H.sub.2O: C, 69.58; H, 5.05; N,
6.58. Found: C, 69.46; H, 4.93; N, 6.56.
Example 10
Synthesis of
N-({5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1-methyl-3-phenyl-1H-indol-2-yl-
}carbonyl)-L-leucine
[0132] The title compound was prepared from methyl
N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-leucinate
and bisphenyl-4-sulfonyl chloride followed the procedure of Example
1 Step 3 as a brown solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 0.77
(d, J=6.0 Hz, 3H), 0.78 (d, J=6.0 Hz, 3H), 1.30-1.60 (m, 3H), 3.73
(s, 3H), 4.25-4.35 (m, 1H), 7.08 (dd, J=8.9, 2.0 Hz, 1H), 7.20-7.32
(m, 6H), 7.40-7.52 (m, 4H), 7.71 (d, J=7.7 Hz, 2H), 7.72 (d, J=8.7
Hz, 2H), 7.85 (d, J=8.6 Hz, 2H), 8.74 (d, J=7.8 Hz, 1H), 9.92 (s,
1H), 12.32 (br s, 1H); MS (ESI) m/z 596 (MH.sup.+); MS (ESI) m/z
594 [M-H].sup.-; HRMS calcd for C.sub.34H.sub.34N.sub.3O.sub.5S:
596.2217; found (ESI.sup.+): 596.2207; Anal. calcd for
C.sub.34H.sub.33N.sub.3O.sub.5S.0.5H.sub.2O: C, 67.53; H, 5.67; N,
6.95. Found: C, 67.27; H, 5.62; N, 6.95.
Example 11
Synthesis of
N-[(5-{[(4-tert-butylphenyl)sulfonyl]amino}-1-methyl-3-phenyl-1H-indol-2--
yl)carbonyl]-L-phenylalanine
[0133] The title compound was prepared from ethyl
N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-phenylalaninate
and 4-tert-butylbenzenesulfonyl chloride followed the procedure of
Example 1 Step 3 as an off-white solid: .sup.1H NMR (DMSO-d.sub.6)
.delta. 1.24 (s, 9H), 2.85 (dd, J=13.9, 10.9 Hz, 1H), 3.16 (dd,
J=13.9, 4.2 Hz, 1H), 3.48 (s, 3H), 4.66 (ddd, J=13.9, 10.9, 4.2 Hz,
1H), 7.05 (dd, J=8.9, 2.0 Hz, 1H), 7.12-7.32 (m, 11H), 7.40 (d,
J=8.8 Hz, 1H), 7.53 (d, J=8.9 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 8.98
(d, J=8.2 Hz, 1H), 9.83 (s, 1H), 12.89 (br s, 1H); MS (ESI) m/z 610
(MH.sup.+); MS (ESI) m/z 608 [M-H].sup.-; HRMS calcd for
C.sub.35H.sub.36N.sub.3O.sub.5S: 610.2373; found (ESI.sup.+):
610.2362; Anal. calcd for
C.sub.35H.sub.35N.sub.3O.sub.5S.0.7H.sub.2O: C, 67.55; H, 5.90; N,
6.75. Found: C, 67.30; H, 5.93; N, 6.80.
Example 12
Synthesis of
N-[(5-{[(4-tert-butylphenyl)sulfonyl]amino}-1-methyl-3-phenyl-1H-indol-2--
yl)carbonyl]-L-leucine
[0134] The title compound was prepared from methyl
N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-leucinate
and 4-tert-butylbenzenesulfonyl chloride followed the procedure of
Example 1 Step 3 as an off-white solid: .sup.1H NMR (DMSO-d.sub.6)
.delta. 0.78 (d, J=6.3 Hz, 3H), 0.79 (d, J=6.0 Hz, 3H), 1.24 (s,
9H), 1.30-1.60 (m, 3H), 3.74 (s, 3H), 4.25-4.35 (m, 1H), 7.08 (dd,
J=8.8, 2.0 Hz, 1H), 7.25-7.32 (m, 4H), 7.33-7.40 (m, 2H), 7.45 (d,
J=7.9 Hz, 1H), 7.54 (d, J=7.8 Hz, 2H), 7.59 (d, J=8.7 Hz, 2H), 8.76
(d, J=7.8 Hz, 1H), 9.85 (s, 1H), 12.64 (br s, 1H); MS (ESI) m/z 576
(MH.sup.+); MS (ESI) m/z 574 [M-H].sup.-; HRMS calcd for
C.sub.32H.sub.38N.sub.3O.sub.5S: 576.2530; found (ESI.sup.+):
576.2518; Anal. calcd for
C.sub.32H.sub.37N.sub.3O.sub.5S.0.5H.sub.2O: C, 65.73; H, 6.55; N,
7.19. Found: C, 65.41; H, 6.45; N, 7.16.
Example 13
Synthesis of
1-(1,1'-biphenyl-4-ylmethyl)-5-[(methylsulfonyl)amino]-3-phenyl-1H-indole-
-2-carboxylic acid
[0135] Step 1: Ethyl
1-(1,1'-biphenyl-4-ylmethyl)-5-nitro-3-phenyl-1H-indole-2-carboxylate
was prepared from ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate
and 4-bromomethylbiphenyl according to the procedure of Example 1
Step 1 as a yellowish solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
0.95 (t, J=7.0 Hz, 3H), 4.13 (q, J=7.0 Hz, 2H), 5.96 (s, 2H),
7.30-7.32 (m, 14H), 7.62 (d, J=2.3 Hz, 1H), 8.25 (d, J=2.8 Hz, 1H),
8.36 (s, 1H); MS (ESI) m/z 477 (MH.sup.+); HRMS calcd for
C.sub.30H.sub.25N.sub.2O.sub.4: 477.1815; found (ESI.sup.+):
477.1806; Anal. calcd for C.sub.30H.sub.24N.sub.2O.sub.4: C, 75.62;
H, 5.08; N, 5.88. Found: C, 75.25; H, 5.18; N, 5.47.
[0136] Step 2: Ethyl
5-amino-1-(1,1'-biphenyl-4-ylmethyl)-3-phenyl-1H-indole-2-carboxylate
was prepared from ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate
followed the procedure of Example 1 Step 2 as a yellowish solid:
.sup.1H NMR (CDCl.sub.3) .delta. 0.96 (t, J=7.0 Hz, 3H), 4.12 (q,
J=7.0 Hz, 2H), 5.79 (s, 2H), 6.75-6.85 (m, 2H), 7.15-7.60 (m, 17H);
MS (ESI) m/z 447 (MH.sup.+).
[0137] Step 3: The title compound was prepared from ethyl
5-amino-1-(1,1'-biphenyl-4-ylmethyl)-3-phenyl-1H-indole-2-carboxylate
and methanesulfonyl chloride followed the procedure of Example 1
Step 3 as a white solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 2.86
(s, 3H), 5.87 (s, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.25 (dd, J=9.0, 2.1
Hz, 1H), 7.30-7.40 (m, 3H), 7.40-7.50 (m, 6H), 7.58-7.63 (m, 4H),
7.66 (d, J=9.0 Hz, 1H), 9.40 (s, 1H), 12.52 (br s, 1H); MS (ESI)
m/z 495 [M-H].sup.-; HRMS calcd for
C.sub.29H.sub.25N.sub.2O.sub.4S: 497.1533; found (ESI.sup.+):
497.1524; Anal. calcd for
C.sub.29H.sub.24N.sub.2O.sub.4S.0.5H.sub.2O.0.5 ACN: C, 68.49; H,
5.05; N, 6.66. Found: C, 68.05; H, 5.04; N, 7.04.
Example 14
Synthesis of
1-(1,1'-biphenyl-4-ylmethyl)-3-phenyl-5-[(phenylsulfonyl)amino]-1H-indole-
-2-carboxylic acid
[0138] The title compound was prepared from ethyl
5-amino-1-(1,1'-biphenyl-4-ylmethyl)-3-phenyl-1H-indole-2-carboxylate
and phenylsulfonyl chloride followed the procedure of Example 1
Step 3 as a pale yellow solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
5.81 (s, 2H); 7.05-7.10 (m, 1H), 7.16 (d, J=8.3 Hz, 2H), 7.27 (d,
J=8.3 Hz, 2H), 7.30-7.40 (m, 2H), 7.40-7.50 (m, 4H), 7.50-7.70 (m,
11H), 9.93 (s, 1H), 13.03 (br s, 1H); MS (ESI) m/z 557 [M-H].sup.-;
HRMS calcd for C.sub.34H.sub.27N.sub.2O.sub.4S: 559.1689; found
(ESI.sup.+): 559.1688; Anal. calcd for
C.sub.34H.sub.26N.sub.2O.sub.4S.0.5H.sub.2O: C, 71.94; H, 4.79; N,
4.94. Found: C, 71.81; H, 4.79; N, 5.07.
Example 15
Synthesis of
1-benzhydryl-5-[(methylsulfonyl)amino]-3-phenyl-1H-indole-2-carboxylic
acid
[0139] Step 1: Ethyl
1-benzhydryl-5-nitro-3-phenyl-1H-indole-2-carboxylate was prepared
from ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate and
bromodiphenylmethane according to the procedure of Example 1 Step 1
as a yellowish solid: .sup.1H NMR (CDCl.sub.3) .delta. 0.92 (t,
J=7.1 Hz, 3H), 4.08 (q, J=7.1 Hz, 2H), 6.86 (d, J=9.4 Hz, 1H),
7.20-7.50 (m, 15H), 7.89 (dd, J=9.3, 2.3 Hz, 1H), 7.97 (s, 1H),
8.47 (d, J=2.3 Hz, 1H), MS (ESI) m/z 477 (MH.sup.+); HRMS calcd for
C.sub.30H.sub.25N.sub.2O.sub.4: 477.1812; found (ESI.sup.+):
477.1808.
[0140] Step 2: Ethyl
5-amino-1-benzhydryl-3-phenyl-1H-indole-2-carboxylate was prepared
from ethyl 1-benzhydryl-5-nitro-3-phenyl-1H-indole-2-carboxylate
followed the procedure of Example 1 Step 2 as a yellowish solid MS
(ESI) m/z 447 (MH.sup.+).
[0141] Step 3: The title compound was prepared from ethyl
5-amino-1-benzhydryl-3-phenyl-1H-indole-2-carboxylate and
methanesulfonyl chloride followed the procedure of Example 1 Step 3
as an off-white solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 2.85 (s,
3H), 6.79 (d, J=9.0 Hz, 1H), 6.95 (dd, J=9.0, 2.0 Hz, 1H), 7.19 (d,
J=7.4 Hz, 4H), 7.30-7.50 (m, 12H), 7.91 (s, 1H), 9.37 (s, 1H),
13.21 (br s, 1H); MS (ESI) m/z 495 [M-H].sup.-; HRMS calcd for
C.sub.29H.sub.25N.sub.2O.sub.4S: 497.1533; found (ESI.sup.+):
497.1522; Anal. calcd for
C.sub.29H.sub.24N.sub.2O.sub.4S.0.7H.sub.2O: C, 68.41; H, 5.03; N,
5.50. Found: C, 68.32; H, 4.91; N, 5.70.
Example 16
Synthesis of
1-benzhydryl-3-phenyl-5-[(phenylsulfonyl)amino]-1H-indole-2-carboxylic
acid
[0142] The title compound was prepared from ethyl
5-amino-1-benzhydryl-3-phenyl-1H-indole-2-carboxylate and
phenylsulfonyl chloride followed the procedure of Example 1 Step 3
as a pale yellow solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 6.68 (d,
J=9.0 Hz, 1H), 6.78 (dd, J=9.2, 2.2 Hz, 1H), 7.04 (d, J=2.2 Hz,
1H), 7.13 (d, J=7.1 Hz, 4H), 7.25-7.30 (m, 2H), 7.30-7.40 (m, 7H),
7.40-7.55 (m, 4H), 7.58-7.68 (m, 3H), 7.84 (s, 1H), 9.93 (s, 1H),
13.19 (br s, 1H); MS (ESI) m/z 557 [M-H].sup.-; HRMS calcd for
C.sub.34H.sub.27N.sub.2O.sub.4S: 559.1689; found (ESI.sup.+):
559.1686; Anal. calcd for
C.sub.34H.sub.26N.sub.2O.sub.4S.0.6H.sub.2O: C, 71.71; H, 4.81; N,
4.92. Found: C, 71.51; H, 4.77; N, 5.11.
Example 17
Synthesis of
1-Benzyl-3-(4-tert-butylphenyl)-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}-
amino)-1H-indole-2-carboxylic acid
[0143] Step 1: A solution of N-bromosuccinimide (0.83 g, 4.7 mmol)
in DMF (5 mL) was added dropwise to a stirred solution of ethyl
5-nitro-1H-indole-2-carboxylate (1.0 g, 4.27 mmol) in DMF (5 mL) at
0-5.degree. C. After the addition was completed, the reaction was
warmed to room temperature and stirring was continued for an
additional 1.5 h. The reaction mixture was poured over ice water
and the resulting precipitate was collected and dried. The dried
solid was re-dissolved in DMF (10 mL) and benzyl bromide (0.68 g,
4.0 mmol) and Cs.sub.2CO.sub.3 (6.56 g, 20 mmol) were added
successively. The reaction was stirred for overnight and then
diluted with water. The product was extracted with ethyl acetate,
dried over magnesium sulfate. Recrystallization from ethyl acetate
and hexane gave 0.99 g (57%) of ethyl
1-benzyl-3-bromo-5-nitro-1H-indole-2-carboxylate as an off-white
solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 1.28 (t, J=7.0 Hz, 3H),
4.35 (q, J=7.0 Hz, 2H), 5.90 (s, 2H), 7.00-7.10 (m, 2H), 7.20-7.35
(m, 3H), 7.95 (d, J=9.3 Hz, 1H), 8.25 (dd, J=9.3, 2.0 Hz, 1H), 8.48
(d, J=2.0 Hz, 1H); MS (ESI) m/z 403/405 (MH.sup.+).
[0144] Step 2: A mixture of ethyl
1-benzyl-3-bromo-5-nitro-1H-indole-2-carboxylate (0.40 g, 1 mmol),
4-tert-butylbenzeneboronic acid (0.36 g, 2 mmol), 2 M aqueous
sodium carbonate (5 mL), tetrakis(triphenylphosphine)palladium (0)
(0.20 g, 0.17 mmol) in ethanol (5 mL) and toluene (5 ml) was heated
at 65.degree. C. for 16 h and then cooled. The reaction mixture was
diluted with 1 N hydrochloric acid and then extracted with ethyl
acetate. The organic extracts were washed with water, dried over
magnesium sulfate and concentrated. Flash silica gel chromatography
using 5-25% ethyl acetate/hexane gave 0.41 g (90%) of ethyl
1-benzyl-3-(4-tert-butylphenyl)-5-nitro-1H-indole-2-carboxylate as
a yellowish solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 0.92 (t,
J=7.0 Hz, 3H), 1.36 (s, 9H), 4.10 (q, J=7.0 Hz, 2H), 5.89 (s, 2H),
7.09 (d, J=8.4 Hz, 2H), 7.22-7.45 (m, 3H), 7.95 (d, J=7.6 Hz, 2H),
7.54 (d, J=8.5 Hz, 2H), 7.91 (d, J=11.2 Hz, 1H), 8.22 (dd, J=11.2,
2.1 Hz, 1H), 8.37 (d, J=2.1 Hz, 1H); MS (ESI) m/z 457 (MH.sup.+);
HRMS calcd for C.sub.28H.sub.29N.sub.2O.sub.4: 457.2128; found
(ESI.sup.+): 457.2114; Anal. calcd for
C.sub.28H.sub.28N.sub.2O.sub.4: C, 73.66; H, 6.18; N, 6.14. Found:
C, 73.48; H, 6.30; N, 5.97.
[0145] Step 3: Ethyl
5-amino-1-benzyl-3-(4-tert-butylphenyl)-1H-indole-2-carboxylate was
prepared from ethyl
1-benzyl-3-(4-tert-butylphenyl)-5-nitro-1H-indole-2-carboxylate
followed the procedure of Example 1 Step 2 as a pale yellowish
solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 0.89 (t, J=7.0 Hz, 3H),
1.34 (s, 9H), 4.03 (q, J=7.0 Hz, 2H), 4.77 (s, 2H), 5.69 (s, 2H),
6.60-6.65 (m, 1H), 6.74 (dd, J=8.8, 2.0 Hz, 2H), 7.06 (d, J=8.4 Hz,
2H), 7.20-7.32 (m, 5H), 7.44 (d, J=8.4 Hz, 2H); MS (ESI) m/z 427
(MH.sup.+); HRMS calcd for C.sub.28H.sub.31N.sub.2O.sub.2:
427.2386; found (ESI.sup.+): 427.2375.
[0146] Step 4: The title compound was prepared from ethyl
5-amino-1-benzyl-3-(4-tert-butylphenyl)-1H-indole-2-carboxylate and
4-trifluoromethoxy-benzenesulfonyl chloride followed the procedure
of Example 1 Step 3 as a slight colored solid: .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.34 (s, 9H), 5.76 (s, 2H), 7.00 (d, J=1.9
Hz, 1H), 7.07 (d, J=7.8 Hz, 4H), 7.15-7.35 (m, 5H), 7.42 (d, J=8.5
Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.75 (d, J=8.9 Hz, 2H), 9.95 (s,
1H), 12.50 (br s, 1H); MS (ESI) m/z 623 (MH.sup.+); MS (ESI) m/z
621 [M-H].sup.-; HRMS calcd for
C.sub.33H.sub.30F.sub.3N.sub.2O.sub.5S: 623.1825; found
(ESI.sup.+): 623.1813; Anal. calcd for
C.sub.33H.sub.29F.sub.3N.sub.2O.sub.5S.0.25H.sub.2O: C, 63.20; H,
4.74; N, 4.47. Found: C, 63.15; H, 4.58; N, 4.58.
Example 18
Synthesis of
1-benzyl-5-[(phenylsulfonyl)amino]-1H,1'H-3,5'-biindole-2-carboxylic
acid
[0147] Step 1: Ethyl
1-benzyl-5-nitro-1H,1'H-3,5'-biindole-2-carboxylate was prepared
from ethyl 1-benzyl-3-bromo-5-nitro-1H-indole-2-carboxylate and
indole-5-boronic acid followed the procedure of Example 17 Step 2
as a yellowish solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 0.90 (t,
J=7.1 Hz, 3H), 4.10 (q, J=7.1 Hz, 2H), 5.89 (s, 2H), 6.52 (t, J=1.1
Hz, 1H), 7.11 (d, J=8.4 Hz, 2H), 7.20 (dd, J=8.3, 1.7 Hz, 1H),
7.22-7.35 (m, 3H), 7.42 (t, J=2.7 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H),
7.66 (s, 1H), 7.90 (d, J=9.3 Hz, 1H), 8.21 (dd, J=9.2, 2.2 Hz, 1H),
8.40 (d, J=2.2 Hz, 1H), 11.23 (s, 1H); MS (ESI) m/z 440 (MH.sup.+);
MS (ESI) m/z 438 [M-H].sup.-; HRMS calcd for
C.sub.26H.sub.22N.sub.3O.sub.4: 440.1608; found (ESI.sup.+):
440.1596; Anal. calcd for
C.sub.26H.sub.21N.sub.3O.sub.4.0.25H.sub.2O: C, 70.34; H, 4.88; N,
9.47. Found: C, 70.23; H, 4.89; N, 9.58.
[0148] Step 2: Ethyl
5-amino-1-benzyl-1H,1'H-3,5'-biindole-2-carboxylate was prepared
from ethyl 1-benzyl-5-nitro-1H,1'H-3,5'-biindole-2-carboxylate
followed the procedure of Example 1 Step 2 as a white solid:
.sup.1H NMR (DMSO-d.sub.6) .delta. 0.89 (t, J=7.1 Hz, 3H), 4.06 (q,
J=7.1 Hz, 2H), 5.81 (s, 2H), 6.47 (t, J=2.0 Hz, 1H), 7.08 (d, J=7.1
Hz, 2H), 7.10-7.50 (m, 8H), 7.58 (s, 1H), 7.70 (d, J=8.9 Hz, 1H),
9.28 (br s, 2H), 11.18 (s, 1H); MS (ESI) m/z 410 (MH.sup.+); HRMS
calcd for C.sub.26H.sub.24N.sub.3O.sub.2: 410.1867 found
(ESI.sup.+): 410.1858; Anal. calcd for
C.sub.26H.sub.23N.sub.3O.sub.2 1.0 TFA: C, 64.24; H, 4.62; N, 8.03.
Found: C, 63.85; H, 4.77; N, 7.91.
[0149] Step 3: The title compound was prepared from ethyl
5-amino-1-benzyl-1H,1'H-3,5'-biindole-2-carboxylate and
phenylsulfonyl chloride followed the procedure of Example 1
[0150] Step 3 as a gray solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
5.75 (s, 2H), 6.46 (t, J=2.0 Hz, 1H), 6.99 (dd, J=
[0151] 8.3, 2.0 Hz, 1H), 7.00-7.10 (m, 4H), 7.18-7.32 (m, 3H),
7.36-7.46 (m, 3H), 7.45-7.55 (m, 3H), 7.60-7.68 (m, 3H), 9.88 (s,
1H), 11.14 (s, 1H), 12.80 (br s, 1H); MS (ESI) m/z 522 (MH.sup.+);
MS (ESI) m/z 520 [M-H].sup.-; HRMS calcd for
C.sub.30H.sub.24N.sub.3O.sub.4S: 522.1485; found (ESI.sup.+):
522.1473; Anal. calcd for
C.sub.30H.sub.23N.sub.3O.sub.4S.0.5H.sub.2O.0.5 ACN: C, 67.56; H,
4.66; N, 8.90. Found: C, 67.54; H, 4.57; N, 8.76.
Example 19
Synthesis of
3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indole-2-carb-
oxylic acid
[0152] The title compound was prepared from ethyl
5-nitro-3-phenyl-1H-indole-2-carboxylate and
4-trifluoromethoxy-benzenesulfonyl chloride followed the procedures
of Example 1 Step 2 & Step 3 as a dark brown solid: .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.01 (d, J=1.8 Hz, 1H), 7.06 (dd, J=8.7, 1.9
Hz, 1H), 7.28-7.42 (m, 6H), 7.50 (d, J=6.9 Hz, 2H), 7.74 (d, J=8.9
Hz, 2H), 9.94 (s, 1H), 11.84 (s, 1H), 12.89 (br s, 1H); MS (ESI)
m/z 475 [M-H].sup.-; HRMS calcd for
C.sub.22H.sub.16F.sub.3N.sub.2O.sub.5S: 477.0730; found
(ESI.sup.+): 477.0719; Anal. calcd for
C.sub.22H.sub.15F.sub.3N.sub.2O.sub.5S.0.15H.sub.2O: C, 55.15; H,
3.22; N, 5.85. Found: C, 54.95; H, 3.23; N, 5.93.
Example 20
Synthesis of
5-{[(4-tert-butylphenyl)sulfonyl]amino}-3-phenyl-1H-indole-2-carboxylic
acid
[0153] The title compound was prepared from ethyl
5-nitro-3-phenyl-1H-indole-2-carboxylate and 4-tert-butylbenzene
sulfonyl chloride followed the procedures of Example 1 Step 2 &
Step 3 as a gray solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 1.25 (s,
9H), 7.05 (d, J=1.8 Hz, 1H), 7.10 (dd, J=8.9, 2.0 Hz, 1H),
7.26-7.45 (m, 6H), 7.54 (d, J=8.9 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H),
9.81 (s, 1H), 11.79 (s, 1H), 12.42 (br s, 1H); MS (ESI) m/z 447
[M-H].sup.-; HRMS calcd for C.sub.25H.sub.25N.sub.2O.sub.4S:
449.1533; found (ESI.sup.+): 449.1524; Anal. calcd for
C.sub.25H.sub.24N.sub.2O.sub.4S.0.25H.sub.2O: C, 66.27; H, 5.45; N,
6.18. Found: C, 65.98; H, 5.34; N, 6.14.
Example 21
Synthesis of
5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-3-phenyl-1H-indole-2-carboxylic
acid
[0154] The title compound was prepared from ethyl
5-nitro-3-phenyl-1H-indole-2-carboxylate and bisphenyl-4-sulfonyl
chloride followed the procedures of Example 1 Step 2 & Step 3
as a gray solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 7.03 (d, J=1.9
Hz, 1H), 7.11 (dd, J=8.7, 2.1 Hz,
[0155] 1H), 7.25-7.55 (m, 9H), 7.68-7.75 (m, 4H), 7.84 (d, J=8.7
Hz, 2H), 9.86 (s, 1H), 11.80 (s, 1H), 12.86 (br s, 1H); MS (ESI)
m/z 467 [M-H].sup.-; HRMS calcd for
C.sub.27H.sub.19N.sub.2O.sub.4S: 467.1068; found (ESI.sup.-):
467.1062; Anal. calcd for
C.sub.27H.sub.20N.sub.2O.sub.4S.0.3H.sub.2O: C, 68.43; H, 4.38; N,
5.91. Found: C, 68.07; H, 4.27; N, 6.16
Example 22
Primary Screen for the PAI-1 Inhibition
[0156] Test compounds are dissolved in DMSO at a final
concentration of 10 mM, then diluted 100.times. in physiologic
buffer. The inhibitory assay is initiated by the addition of the
test compound (1-100 .mu.M final concentration, maximum DMSO
concentration of 0.2%) in a pH 6.6 buffer containing 140 nM
recombinant human plasminogen activator inhibitor-1 (PAI-1;
Molecular Innovations, Royal Oak, Mich.). Following a 1 hour
incubation at room temperature, 70 nM of recombinant human tissue
plasminogen activator (tPA) is added, and the combination of the
test compound, PAI-1 and tPA is incubated for an additional 30
minutes. Following the second incubation, Spectrozyme-tPA (American
Diagnostica, Greenwich, Conn.), a chromogenic substrate for tPA, is
added and absorbance read at 405 nm at 0 and 60 minutes. Relative
PAI-1 inhibition is equal to the residual tPA activity in the
presence of the test compound and PAI-1. Control treatments include
the complete inhibition of tPA by PAI-1 at the molar ratio employed
(2:1), and the absence of any effect of the test compound on tPA
alone.
Example 23
Assay for determining IC.sub.50 of Inhibition of PAI-1
[0157] This assay is based upon the non-SDS dissociable interaction
between tPA and active PAI-1. Assay plates are initially coated
with human tPA (10 .mu.g/ml). Test compounds of the present
invention are dissolved in DMSO at 10 mM, then diluted with
physiologic buffer (pH 7.5) to a final concentration of 1-50 .mu.M.
Test compounds are incubated with human PAI-1 (50 ng/ml) for 15
minutes at room temperature. The tPA-coated plate is washed with a
solution of 0.05% Tween 20 and 0.1% BSA, then the plate is blocked
with a solution of 3% BSA. An aliquot of the substituted
sulfonamide indole/PAI-1 solution is then added to the tPA-coated
plate, incubated at room temperature for 1 hour, and washed. Active
PAI-1 bound to the plate is assessed by adding an aliquot of a
1:1000 dilution of the 33B8 monoclonal antibody against human
PAI-1, and incubating the plate at room temperature for 1 hour
(Molecular Innovations, Royal Oak, Mich.). The plate is again
washed, and a solution of goat anti-mouse IgG-alkaline phosphatase
conjugate is added at a 1:50,000 dilution in goat serum. The plate
is incubated 30 minutes at room temperature, washed, and a solution
of alkaline phosphatase substrate is added. The plate is incubated
45 minutes at room temperature, and color development is determined
at OD.sub.405nm. The quantitation of active PAI-1 bound to tPA at
varying concentrations of the test compound is used to determine
the IC.sub.50. Results are analyzed using a logarithmic best-fit
equation. The assay sensitivity is 5 ng/ml of human PAI-1 as
determined from a standard curve ranging from 0-100 ng/ml.
[0158] The compounds of the present invention inhibited Plasminogen
Activator Inhibitor-1 as summarized in Table 1.
TABLE-US-00001 TABLE 1 Compound of IC.sub.50 % Inhibition @ 10 %
Inhibition @ 25 Example .mu.M .mu.M .mu.M 1 8.3 33 81 2 8 43 3 28.7
41 82 4 23.0 44 61 5 19 6 46 7 11 68 8 18 73 9 8 73 10 15 74 11 15
77 12 14 64 13 24 62 14 28.0 77 87 15 10 36 16 68 89 17 43 84 18 19
55 19 12 50 20 28.4 20 81 21 19.5 29 86
[0159] Although the foregoing invention has been described in
detail by way of example for purposes of clarity of understanding,
it will be apparent to the artisan that certain changes and
modifications are comprehended by the disclosure and can be
practiced without undue experimentation within the scope of the
appended claims, which are presented by way of illustration not
limitation.
[0160] All publications and patent documents cited above are hereby
incorporated by reference in their entirety for all purposes to the
same extent as if each were so individually denoted.
* * * * *