U.S. patent application number 11/048037 was filed with the patent office on 2005-06-16 for substituted pyrazolyl benzenesulfonamides for the treatment of inflamation.
This patent application is currently assigned to G.D. Searle & Co.. Invention is credited to Bertenshaw, Stephen R., Carter, Jeffery S., Collins, Paul W., Docter, Stephen H., Graneto, Matthew J., Khanna, Ish K., Malecha, James W., Miyashiro, Julie M., Penning, Thomas D., Rogers, Roland S., Rogier, Donald J. JR., Talley, John J., Yu, Stella S..
Application Number | 20050131050 11/048037 |
Document ID | / |
Family ID | 32034548 |
Filed Date | 2005-06-16 |
United States Patent
Application |
20050131050 |
Kind Code |
A1 |
Talley, John J. ; et
al. |
June 16, 2005 |
Substituted pyrazolyl benzenesulfonamides for the treatment of
inflamation
Abstract
A class of pyrazolyl benzenesulfonamide compounds is described
for use in treating inflammation and inflammation-related
disorders. Compounds of particular interest are defined by Formula
II: 1 wherein R.sup.2 is selected from hydrido, alkyl, haloalkyl,
alkoxycaronyl, cyano, cyanoalkyl, carboxyl, aminocaronyl,
alkylaminocarbonyl, cycloalklaminocarbonyl, arylaminocarbonyl,
carboxyalkylaminocarbonyl, carboxyalkyl,
aralkoxycarbonylalkylaminocarbonyl, amioncarbonylalkyl,
alkoxycarbonylcyanoalkenyl and hydroxyalkyl; wherein R.sup.3 is
selected from hydrido, alkyl, cyano, hydroxyalkyl, cycloalkyl,
alkylsulfonyl and halo; and wherein R.sup.4 is selected from
aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic; wherein
R.sup.4 is optionally substituted at a substitutable position with
one or more radicals selected from halo alkylthio, alkylsulfonyl,
cyano, nitro, haloalkyl, alkyl, hydroxyl, alkenyl, hydroxyalkyl,
carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl,
aminocarbonyl, alkoxy, haloalkoxy, sulfamyl, heterocyclic and
amino; provided R.sup.2 and R.sup.3 are not both hydrido; further
provided that R.sup.2 is not carboxyl or methyl when R.sup.3 is
hydrido and when R.sup.4 is phenyl; further provided that R.sup.4
is not triazolyl when R.sup.2 is methyl; further provided that
R.sup.4 is not arakenyl when R.sup.2 is carboxyl, aminocarbonyl or
ethoxycarbonyl; further provided that R.sup.4 is not phenyl when
R.sup.2 is methyl and R.sup.3 is carboxyl; and further provided
that R.sup.4 is not unsubstituted thienyl when R.sup.2 is
trifluoromethyl; or a pharmaceutically-acceptable salt thereof.
Inventors: |
Talley, John J.; (St. Louis,
MO) ; Penning, Thomas D.; (Elmhurst, IL) ;
Collins, Paul W.; (Deerfield, IL) ; Rogier, Donald J.
JR.; (St. Louis, MO) ; Malecha, James W.;
(Libertyville, IL) ; Miyashiro, Julie M.;
(Chicago, IL) ; Bertenshaw, Stephen R.;
(Brentwood, MO) ; Khanna, Ish K.; (Vernon Hills,
IL) ; Graneto, Matthew J.; (St. Louis, MO) ;
Rogers, Roland S.; (Richmond Heights, MO) ; Carter,
Jeffery S.; (Chesterfield, MO) ; Docter, Stephen
H.; (Mt. Prospect, IL) ; Yu, Stella S.;
(Morton Grove, IL) |
Correspondence
Address: |
PHARMACIA CORPORATION
GLOBAL PATENT DEPARTMENT
POST OFFICE BOX 1027
ST. LOUIS
MO
63006
US
|
Assignee: |
G.D. Searle & Co.
chicago
IL
60680
|
Family ID: |
32034548 |
Appl. No.: |
11/048037 |
Filed: |
January 31, 2005 |
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11048037 |
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10700019 |
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10700019 |
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6586603 |
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6413960 |
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6156781 |
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08957345 |
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08648113 |
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5760068 |
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08648113 |
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PCT/US94/12720 |
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PCT/US94/12720 |
Nov 14, 1994 |
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08223629 |
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5521207 |
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Current U.S.
Class: |
514/406 ;
548/364.4; 548/371.1 |
Current CPC
Class: |
C07D 231/16 20130101;
C07D 495/04 20130101; C07D 231/54 20130101; C07D 405/04 20130101;
C07D 231/14 20130101; C07D 401/04 20130101; C07D 231/12 20130101;
C07D 409/04 20130101; C07D 403/04 20130101 |
Class at
Publication: |
514/406 ;
548/364.4; 548/371.1 |
International
Class: |
A61K 031/416; A61K
031/4152; C07D 045/02; C07D 231/10 |
Claims
1-21. (canceled)
22. A method for the preparation of
4-[5-(4-fluorophenyl)-3-trifluoromethy-
l)-1H-pyrazol-1-yl]benzenesulfonamide wherein the method comprises:
mixing ethyl trifluoroacetate with a base, contacting the ethyl
trifluoroacetate and base mixture with 4'-fluoroacetophenone to
form 4,4-trifluoro-1-[4-fluorophenyl]-butane-1,3-dione; and
contacting the 4,4-trifluoro-1-[4-(fluoro)phenyl]-butane-1,3-dione
with 4-sulphonamidophenyl hydrazine to produce
4-[5-(4-fluorophenyl)-3-(triflu-
oromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.
23. The method according to claim 22 wherein the base comprises an
alkoxide.
24. The method according to claim 23 wherein the alkoxide comprises
sodium methoxide.
25. The method according to claim 22 wherein the ethyl
trifluoroacetate and the base are mixed in the presence of a first
solvent.
26. The method according to claim 25 wherein the first solvent
comprises at least one compound selected from the group consisting
of an alcohol and an ether.
27. The method according to claim 26 wherein the first solvent
comprises an alcohol.
28. The method according to claim 26 wherein the alcohol is a
C.sub.1 to about C.sub.10 alcohol.
29. The method according to claim 25 wherein the first solvent
comprises an ether.
30. The method according to claim 29 wherein the ether is methyl
tert-butyl ether.
31. The method according to claim 22 wherein the
4,4-trifluoro-1-[4-(fluor- o)phenyl]-butane-1,3-dione and the
4-sulfonamidophenyl hydrazine are contacted in the presence of a
second solvent.
32. The method according to claim 31 wherein the second solvent
comprises an alcohol.
33. The method according to claim 31 wherein the alcohol is
ethanol.
34. The method according to claim 22 wherein the method comprises:
mixing ethyl trifluoroacetate with sodium methoxide and methanol,
contacting the ethyl trifluoroacetate, sodium methoxide, and
methanol mixture with 4'-fluoroacetophenone to form
4,4-trifluoro-1-[4-fluorophenyl]-butane-1,3- -dione; and contacting
the 4,4-trifluoro-1-[4-fluorophenyl]-butane-1,3-dio- ne with
4-sulphonamidophenyl hydrazine in the presence of ethanol under
reflux to produce
4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1--
yl]benzenesulfonamide.
Description
FIELD OF THE INVENTION
[0001] This invention is in the field of anti-inflammatory
pharmaceutical agents and specifically relates to compounds,
compositions and methods for treating inflammation and
inflammation-associated disorders, such as arthritis.
BACKGROUND OF THE INVENTION
[0002] Prostaglandins play a major role in the inflammation process
and the inhibition of prostaglandin production, especially
production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common
target of anti-inflammatory drug discovery. However, common
non-steroidal anti-inflammatory drugs (NSAIDS) that are active in
reducing the prostaglandin-induced pain and swelling associated
with the inflammation process are also active in affecting other
prostaglandin-regulated processes not associated with the
inflammation process. Thus, use of high doses of most common NSAIDs
can produce severe side effects, including life threatening ulcers,
that limit their therapeutic potential. An alternative to NSAIDs is
the use of corticosteroids, which have even more drastic side
effects, especially when long term therapy is involved.
[0003] Previous NSAIDs have been found to prevent the production of
prostaglandins by inhibiting enzymes in the human arachidonic
acid/prostaglandin pathway, including the enzyme cyclooxygenase
(COX). The recent discovery of an inducible enzyme associated with
inflammation (named "cyclooxygenase II (COX II)" or "prostaglandin
G/H synthase II") provides a viable target of inhibition which more
effectively reduces inflammation and produces fewer and less
drastic side effects.
[0004] Pyrazoles have been described for use in the treatment of
inflammation. U.S. Pat. No. 5,134,142 to Matsuo et al describes
1,5-diaryl pyrazoles, and specifically,
1-(4-fluorophenyl)-5-[4-(methylsu- lfonyl)phenyl]-3-trifluoromethyl
pyrazole, as having anti-inflammatory activity.
[0005] U.S. Pat. No. 3,940,418 to R. Hamilton describes tricyclic
4,5-dihydrobenz[g]indazoles as antiinflammatory agents. In
addition, R. Hamilton [J. Heterocyclic Chem., 13, 545 (1976)]
describes tricyclic 4,5-dihydrobenz[g]indazoles as antiinflammatory
agents. U.S. Pat. No. 5,134,155 describes fused tricyclic pyrazoles
having a saturated ring bridging the pyrazole and a phenyl radical
as HMG-CoA reductase inhibitors. European publication EP 477,049,
published Mar. 25, 1992, describes
[4,5-dihydro-1-phenyl-1H-benz[g]indazol-3-yl]amides as having
antipsychotic activity. European publication EP 347,773, published
Dec. 27, 1989, describes
[4,5-dihydro-1-phenyl-1H-benz[g]indazol-3-yl]propanam- ides as
immunostimulants. M. Hashem et al [J. Med. Chem., 19, 229 (1976)]
describes fused tricyclic pyrazoles, having a saturated ring
bridging the pyrazole and a phenyl radical, as antibiotics.
[0006] Certain substituted pyrazolyl-benzenesulfonamides have been
described in the literature as synthetic intermediates.
Specifically,
4-[5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl]benzenesulfonamide
has been prepared from a pyrazoline compound as an intermediate for
compounds having hypoglycemic activity [R. Soliman et al, J. Pharm.
Sci., 76, 626 (1987)].
4-[5-[2-(4-Bromophenyl)-2H-1,2,3-triazol-4-yl]-3-methyl-1H-pyraz-
ol)-1-yl]benzenesulfonamide has been prepared from a pyrazoline
compound and described as potentially having hypoglycemic activity
[H. Mokhtar, Pak. J. Sci. Ind. Res., 31, 762 (1988)]. Similarly,
4-[4-bromo-5-[2-(4-chlorophenyl)-2H-1,2,3-triazol-4-yl]-3-methyl-1H-pyraz-
ol-1-yl]benzenesulfonamide has been prepared [H. Mokhtar et al,
Pak. J. Sci. Ind. Res., 34, 9 (1991)].
[0007] The phytotoxicity of pyrazole derivatives is described [M.
Cocco et al, Il. Farmaco-Ed. Sci., 40, 272 (1985)], specifically
for
1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3,4-dicarboxylic
acid.
[0008] The use of styryl pyrazole esters for antidiabetes drugs is
described [H. Mokhtar et al, Pharmazie, 33, 649-651 (1978)]. The
use of styryl pyrazole carboxylic acids for antidiabetes drugs is
described [R. Soliman et al, Pharmazie, 33, 184-5 (1978)]. The use
of 4-[3,4,5-trisubstituted-pyrazol-1-yl]benzenesulfonamides as
intermediates for sulfonylurea anti-diabetes agents is described,
and specifically,
1-[4-(aminosulfonyl)phenyl]-3-methyl-5-phenyl-1H-pyrazole-4-carboxylic
acid [R. Soliman et al, J. Pharm. Sci., 72, 1004 (1983)]. A series
of 4-[3-substituted
methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamides has been
prepared as intermediates for anti-diabetes agents, and more
specifically,
4-[3-methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide [H.
Feid-Allah, Pharmazie, 36, 754 (1981)]. In addition,
1-(4-[aminosulfonyl]phenyl)-5-phenylpyrazole-3-carboxylic acid has
been prepared from the above described
4-[3-methyl-5-phenyl-1H-pyrazol-1-yl]be- nzenesulfonamide compound
[R. Soliman et al, J. Pharm. Sci., 70, 602 (1981)].
DESCRIPTION OF THE INVENTION
[0009] A class of compounds useful in treating inflammation-related
disorders is defined by Formula I: 2
[0010] wherein R.sup.1 is selected from aryl and heteroaryl,
wherein R.sup.1 is substituted at a substitutable position with one
or more radicals selected from sulfamyl, halo, alkyl, alkoxy,
hydroxyl, haloalkyl and 3
[0011] wherein R.sup.2 is selected from hydrido, halo, alkyl,
haloalkyl, cyano, nitro, formyl, carboxyl, alkoxy, aminocarbonyl,
alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino,
cyancamidino, cyanoalkyl, alkoxycarbonylcyanoalkenyl,
aminocarbonylalkyl, N-alkylaminocarbonyl, N-arylaminocarbonyl,
N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbony- l,
cycloalkylaminocarbonyl, heterocyclicaminocarbonyl,
carboxyalkylaminocarbonyl, aralkoxycarbonylalkylaminocarbonyl,
alkylcarbonyl, alkylcarbonylalkyl, hydroxyalkyl, haloaralkyl,
carboxyhaloalkyl, alkoxycarbonylhaloalkyl, aminocarbonylhaloalkyl,
alkylaminocarbonylhaloalkyl, N-alkylamino, N,N-dialkylamino,
N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,
N-alkyl-N-arylamino, aminoalkyl, N-alkylaminoalkyl,
N,N-dialkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,
N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalky- l, aryloxy,
aralkoxy, anylthio, aralkylthio, alkylthio, alkylsulfinyl,
alkylsulfonyl, N-alkylaminosulfanyl, N-arylaminosulfonyl,
arylsulfonyl, N,N-dialkylaminosulfonyl,
N-alkyl-N-arylaminosulfonyl, heterocyclic, 4
[0012] wherein R.sup.3 is selected from hydrido, alkyl, halo,
haloalkyl, cyano, nitro, formyl, carboxyl, alkoxycarbonyl,
carboxyalkyl, alkoxycarbonylalkyl, amidino, cyancamidino,
aminocarbonyl, alkoxy, N-alkylamino, N,N-dialkylamino,
aminocarbonylalkyl, N-alkylaminocarbonyl, N-arylaminocarbonyl,
N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbony- l,
alkylcarbonyl, alkylcarbonylalkyl, hydroxyalkyl, alkylthio,
alkylsulfinyl, alkylsulfonyl, N-alkylaminosulfonyl,
N-arylaminosulfonyl, arylsulfonyl, N,N-dialkylaminosulfonyl,
N-alkyl-N-arylaminosulfonyl, cycloalkyl, heterocyclic,
heterocyclicalkyl and aralkyl;
[0013] wherein R.sup.4 is selected from aralkenyl, aryl,
cycloalkyl, cycloalkenyl and heterocyclic; wherein R.sup.4 is
optionally substituted at a substitutable position with one or more
radicals selected from halo, alkylthio, alkylsulfinyl, alkyl,
alkenyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl,
aminocarbonyl, N-alkylaminocarbonyl, N-arylaminocarbonyl,
N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, haloalkyl,
hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl,
N-alklaminosulfonyl, amino, N-alkylamino, N,N-dialkylamino,
heterocyclic, cycloalkylalkyl, nitro, acylamino, 5
[0014] or wherein R.sup.3 and R.sup.4 together form 6
[0015] wherein m is 1 to 3, inclusive;
[0016] wherein A is selected from phenyl and five or six membered
heteroaryl;
[0017] wherein R.sup.5 is alkyl;
[0018] wherein R.sup.6 is one or more radicals selected from halo,
alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, carboxyl,
alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl,
N-arylaminocarbonyl, alkyl, alkenyl, N,N-dialkylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, haloalkyl, hydrido, hydroxyl, alkoxy,
hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylaminosulfonyl, amino,
N-alkylamino, N,N-dialkylamino, heterocyclic, cycloalkylalkyl,
nitro and acylamino; and
[0019] wherein R.sup.7 is selected from hydrido, alkyl, aryl and
aralkyl;
[0020] provided R.sup.2 and R.sup.3 are not identical radicals
selected from hydrido, carboxyl and ethoxycarbonyl; further
provided that R.sup.2 is not carboxyl or methyl when R.sup.3 is
hydrido and when R.sup.4 is phenyl; further provided that R.sup.4
is not triazolyl when R.sup.2 is methyl; further provided that
R.sup.4 is not aralkenyl when R.sup.2 is carboxyl, aminocarbonyl or
ethoxycarbonyl; further provided that R.sup.4 is not phenyl when
R.sup.2 is methyl and R.sup.3 is carboxyl; further provided that
R.sup.4 is not unsubstituted thienyl when R.sup.2 is
trifluoromethyl; and further provided that R.sup.4 is aryl
substituted with sulfamyl or R.sup.6 is sulfamyl, when R.sub.2 is
phenyl not substituted with sulfamyl;
[0021] or a pharmaceutically-acceptable salt thereof.
[0022] The phrase "further provided", as used in the above
description, is intended to mean that the denoted proviso is not to
be considered conjunctive with any of the other provisos.
[0023] Compounds of Formula I would be useful for, but not limited
to, the treatment of inflammation in a subject, and for treatment
of other inflammation-associated disorders, such as, as an
analgesic in the treatment of pain and headaches, or as an
antipyretic for the treatment of fever. For example, compounds of
Formula I would be useful to treat arthritis, including but not
limited to rheumatoid arthritis, spondyloarthropathies, gouty
arthritis, osteoarthritis, systemic lupus erythematosus and
juvenile arthritis. Such compounds of Formula I would be useful in
the treatment of asthma, bronchitis, menstrual cramps, tendinitis,
bursitis, and skin related conditions such as psoriasis, eczema,
burns and dermatitis. Compounds of Formula I also would be useful
to treat gastrointestinal conditions such as inflammatory bowel
disease, Crohn's disease, gastritis, irritable bowel syndrome and
ulcerative colitis and for the prevention of colorectal cancer.
Compounds of Formula I would be useful in treating inflammation in
such diseases as vascular diseases, migraine headaches,
periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's
disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia
gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,
polymyositis, gingivitis, hypersensitivity, conjunctivitis,
swelling occurring after injury, myocardial ischemia, and the like.
The compounds are useful as antiinflammatory agents, such as or the
treatment of arthritis, with the additional benefit of having
significantly less harmful side effects.
[0024] The present invention preferably includes compounds which
selectively inhibit cyclooxygenase II over cyclooxygenase I.
Preferably, the compounds have a cyclooxygenase II IC.sub.50 of
less than about 0.2 .mu.M, and also have a selectivity ratio of
cyclooxygenase II inhibition over cyclooxygenase I inhibition of at
least 50, and more preferably of at least 100. Even more
preferably, the compounds have a cyclooxygenase I IC.sub.50 of
greater than about 1 .mu.M, and more preferably of greater than 10
.mu.M. Such preferred selectivity may indicate an ability to reduce
the incidence of common NSAID-induced side effects.
[0025] A preferred class of compounds consists of those compounds
of Formula I wherein R.sup.1 is selected from aryl selected from
phenyl, naphthyl and biphenyl, and five- or six-membered
heteroaryl, wherein R.sup.1 is substituted at a substitutable
position with one or more radicals selected from sulfamyl, halo,
lower alkyl, lower alkoxy, hydroxyl, lower haloalkyl and 7
[0026] wherein R2 is selected from hydrido, halo, lower alkyl,
lower haloalkyl, cyano, nitro, formyl, carboxyl, lower
alkoxycarbonyl, lower carboxyalkyl, lower alkoxycarbonylalkyl,
amidino, cyanoamidino, lower cyanoalkyl, lower
alkoxycarbonylcyancalkenyl, aminocarbonyl, lower alkoxy, lower
aryloxy, lower aralkoxy, lower aminocarbonylalkyl, lower
N-alkylaminocarbonyl, N-arylaminocarbonyl, lower
N,N-dialkylaminocarbonyl- , lower N-alkyl-N-arylaminocarbonyl,
lower cycloalkylaminocarbonyl, lower heterocyclicaminocarbonyl,
lower carboxyalkylaminocarbonyl, lower
aralkoxycarbonylalkylaminocarbonyl, lower haloaralkyl, lower
carboxyhaloalkyl, lower alkoxycarbonylhaloalkyl, lower
aminocarbonylhaloalkyl, lower alkylaminocarbonylhaloalkyl, lower
alkylcarbonyl, lower alkylcarbonylalkyl, lower alkylamino, lower
N,N-dialkylamino, N-arylamino, lower N-aralkylamino, lower
N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino, lower
aminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl,
lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lower
N-alkyl-N-aralkylaminoalkyl, lower N-alkyl-N-arylaminoalkyl,
arylthio, lower aralkylthio, lower hydroxyalkyl, lower alkylthio,
lower alkylsulfinyl, lower alkylsulfonyl, lower
N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, lower
N,N-dialkylaminosulfonyl, lower N-alkyl-N-arylaminosulfonyl,
heterocyclic, 8
[0027] wherein R.sup.3 is selected from hydrido, lower alkyl, halo,
lower haloalkyl, cyano, nitro, formyl, carboxyl, lower
alkoxycarbonyl, lower carboxyalkyl, lower alkoxycarbonylalkyl,
amidino, cyanoamidino, aminocarbonyl, lower alkoxy, lower
N-alkylamino, lower N,N-dialkylamino, lower aminocarbonylalkyl,
lower N-alkylaminocarbonyl, lower N-arylaminocarbonyl, lower
N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower
alkylcarbonyl, lower alkylcarbonylalkyl, lower hydroxyalkyl, lower
alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower
N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, lower
N,N-dialkylaminosulfonyl, lower N-alkyl-N-arylaminosulfonyl, lower
cycloalkyl, heterocyclic, lower heterocyclicalkyl and lower
aralkyl;
[0028] wherein R.sup.4 is selected from lower aralkenyl, aryl,
lower cycloalkyl, lower cycloalkenyl and five to ten membered
heterocyclic; wherein R.sup.4 is optionally substituted at a
substitutable position with one or more radicals selected from
halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower
alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower
alkoxycarbonyl, aminocarbonyl, lower N-alkylaminocarbonyl,
N-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl- , lower
N-alkyl-N-arylaminocarbonyl, lower haloalkyl, hydroxyl, lower
alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, lower
N-alkylaminosulfonyl, amino, lower N-alkylamino, lower
N,N-dialkylamino, five- or six-membered heterocyclic, lower
cycloalkylalkyl, nitro, acylamino, 9
[0029] or wherein R.sup.3 and R.sup.4 together form 10
[0030] wherein m is 1 to 3, inclusive;
[0031] wherein A is selected from phenyl and five or six membered
heteroaryl;
[0032] wherein R.sup.5 is lower alkyl;
[0033] wherein R.sup.6 is one or more radicals selected from halo,
lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano,
carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower
N-alkylaminocarbonyl, N-arylaminocarbonyl, lower alkyl, lower
alkenyl, lower N,N-dialkylaminocarbonyl, lower
N-alkyl-N-arylaminocarbonyl, lower haloalkyl, hydrido, hydroxyl,
lower alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, lower
N-alkylaminosulfonyl, amino, lower N-alkylamino, lower
N,N-dialkylamino, five- or six membered heterocyclic, lower
cycloalkylalkyl, nitro and acylamino; and
[0034] wherein R.sup.7 is selected from hydrido, lower alkyl, aryl
and lower aralkyl;
[0035] or a pharmaceutically-acceptable salt thereof.
[0036] A more preferred class of compounds consists of those
compounds of Formula I wherein R.sup.1 is phenyl, wherein R.sup.1
is substituted at a substitutable position with one or more
radicals selected from sulfamyl, halo, lower alkyl, lower alkoxy,
hydroxyl, lower haloalkyl and 11
[0037] wherein R.sup.2 is selected from hydrido, lower alkyl, lower
haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, lower
carboxyalkyl, lower cyanoalkyl, lower alkoxycarbonylcyanoalkenyl,
lower haloaralkyl, lower carboxyhaloalkyl, lower
alkoxycarbonylhaloalkyl, lower aminocarbonylhaloalkyl, lower
alkylaminocarbonylhaloalkyl, lower N-alkylamino, lower
N,N-dialkylamino, N-arylamino, lower N-aralkylamino, lower
N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino, lower
aminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl,
lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lower
N-alkyl-N-aralkylaminoalkyl, lower N-alkyl-N-arylaminoalkyl,
aryloxy, lower aralkoxy, lower alkoxy, lower alkylthio, arylthio,
lower aralkylthic, aminocarbonyl, lower aminocarbonylalkyl, lower
N-alkylaminocarbonyl, N-arylaminocarbonyl, lower
N,N-dialkylaminocarbonyl- , lower N-alkyl-N-arylaminocarbonyl,
lower cycloalkylaminocarbonyl, lower carboxyalkylaminocarbonyl,
lower aralkoxycarbonylalkylaminocarbonyl, lower hydroxyalkyl,
12
[0038] wherein R.sup.3 is selected from hydrido, lower alkyl, halo,
cyano, lower hydroxyalkyl, lower alkylthio, lower alkylsulfinyl,
lower alkylsulfonyl, lower alkoxy, lower N-alkylamino, lower
N,N-dialkylamino, lower N-alkylaminosulfonyl, N-arylaminosulfonyl,
arylsulfonyl, lower N,N-dialkylaminosulfonyl, lower
N-alkyl-N-arylaminosulfonyl and lower cycloalkyl;
[0039] wherein R.sup.4 is selected from lower aralkenyl, aryl,
lower cycloalkyl, lower cycloalkenyl and five to ten membered
heterocyclic; wherein R.sup.4 is optionally substituted at a
substitutable position with one or more radicals selected from
halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower
alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower
alkoxycarbonyl, aminocarbonyl, lower haloalkyl, hydroxyl, lower
alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, lower
alkylaminosulfonyl, amino, lower N-alkylamino, lower
N,N-dialkylamino, five or six membered heterocyclic, lower
cycloalkylalkyl, nitro, 13
[0040] or wherein R.sup.3 and R.sup.4 together form 14
[0041] wherein m is 2;
[0042] wherein A is selected from phenyl and five or six membered
hetercaryl;
[0043] wherein R5 is lower alkyl;
[0044] wherein R.sup.6 is one or more radicals selected from halo,
lower alkylthio, lower alkylsulfinyl, lower alkyl, lower alkenyl,
lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl,
aminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower
hydroxyalkyl, lower haloalkoxy, sulfamyl, amino, lower
N-alkylamino, lower N,N-dialkylamino, lower cycloalkylalkyl and
nitro; and
[0045] wherein R.sup.7 is selected from hydrido, lower alkyl, aryl
and lower aralkyl;
[0046] or a pharmaceutically-acceptable salt thereof.
[0047] An even more preferred class of compounds consists of those
compounds of Formula I wherein R.sup.1 is phenyl, wherein R.sup.1
is substituted at a substitutable position with one or more
radicals selected from sulfamyl, halo, lower alkyl, lower alkoxy
and 15
[0048] wherein R.sup.2 is selected from hydrido, lower alkyl.,
lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, lower
carboxyalkyl, lower cyanoalkyl, lower alkoxycarbonylcyanoalkenyl,
lower haloaralkyl, lower carboxyhaloalkyl, lower
alkoxycarbonylhaloalkyl, lower aminocarbonylhaloalkyl, lower
alkylaminocarbonylhaloalkyl, lower N-alkylamino, lower
N,N-dialkylamino, N-arylamino, lower N-aralkylamino, lower
N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino, lower
aminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl,
lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lower
N-alkyl-N-aralkylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, lower
alkoxy, aryloxy, lower aralkoxy, lower alkylthio, arylthio, lower
aralkylthic, aminocarbonyl, lower aminocarbonylalkyl, lower
N-alkylaminocarbonyl, N-arylaminocarbonyl, lower
N,N-dialkylaminocarbonyl- , lower N-alkyl-N-arylaminocarbonyl,
lower cycloalkylaminocarbonyl, lower carboxyalkylaminocarbonyl,
lower heterocyclicaminocarbonyl, lower
aralkoxycarbonylalkylaminocarbonyl, lower hydroxyalkyl, 16
[0049] wherein R.sup.3 is selected from hydrido, lower alkyl, halo,
cyano, lower hydroxyalkyl, lower alkoxy, lower N-alkylamino, lower
N,N-dialkylamino, lower alkylthio, lower alkylsulfonyl and lower
cycloalkyl;
[0050] wherein R.sup.4 is selected from lower aralkenyl, aryl,
lower cycloalkyl, lower cycloalkenyl and five to ten membered
heterocyclic; wherein R.sup.4 is optionally substituted at a
substitutable position with one or more radicals selected from
halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower
alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower
alkoxycarbonyl, aminocarbonyl, lower haloalkyl, hydroxyl, lower
alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, amino,
lower N-alkylamino, lower N,N-dialkylamino, five or six membered
heterocyclic, lower cycloalkylalkyl, nitro, 17
[0051] or wherein R.sup.3 and R.sup.4 together form 18
[0052] wherein m is 2;
[0053] wherein A is selected from phenyl and five membered
heteroaryl;
[0054] wherein R.sup.5 is lower alkyl;
[0055] wherein R.sup.6 is one or more radicals selected from halo,
lower alkyl, lower alkylsulfonyl, lower haloalkyl, lower alkoxy,
sulfamyl, amino and nitro; and
[0056] wherein R.sup.7 is selected from hydrido, lower alkyl, aryl
and lower aralkyl;
[0057] or a pharmaceutically-acceptable salt thereof.
[0058] Within Formula I there is a subclass of compounds which
consists of compounds wherein R.sup.1 is phenyl substituted at a
substitutable position with one or more radicals selected from
halo, lower alkyl, sulfamyl and 19
[0059] wherein R.sup.2 is selected from hydrido, lower alkyl, lower
haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, lower
carboxyalkyl, lower cyanoalkyl, lower alkoxycarbonylcyanoalkenyl,
lower haloaralkyl, lower carboxyhaloalkyl, lower
alkoxycarbonylhaloalkyl, lower aminocarbonylhaloalkyl, lower
alkylaminocarbonylhaloalkyl, lower N-alkylamino, lower
N,N-dialkylamino, N-arylamino, lower N-aralkylamino,
lower-N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino, lower
aminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl,
lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lower
N-alkyl-N-aralkylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, lower
alkoxy aryloxy, lower aralkoxy, lower alkylthio, arylthio, lower
aralkylthio, aminocarbonyl, lower aminocarbonylalkyl, lower
N-alkylaminocarbonyl, N-arylaminocarbonyl, lower
N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower
cycloalkylaminocarbonyl, lower carboxyalkylaminocarbonyl, lower
aralkoxycarbonylalkylaminocarbonyl, lower hydroxyalkyl, 20
[0060] wherein R.sup.3 is selected from hydrido, lower alkyl, halo,
cyano, lower hydroxyalkyl, lower alkoxy, lower alkylthio, lower
N-alkylamino, lower N,N-dialkylamino, lower alkylsulfonyl and lower
cycloalkyl;
[0061] wherein R.sup.4 is selected from lower aralkenyl, aryl,
lower cycloalkyl, lower cycloalkenyl and five to ten membered
heterocyclic; wherein R.sup.4 is optionally substituted at a
substitutable position with one or more radicals selected from
halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower
alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower
alkoxycarbonyl, aminocarbonyl, lower haloalkyl, hydroxyl, lower
alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, lower
alkylaminocarbonyl, amino, lower N-alkylamino, lower
N,N-dialkylamino, five or six membered heterocyclic, lower
cycloalkylalkyl, nitro, 21
[0062] wherein R.sup.5 is lower alkyl; and
[0063] wherein R.sup.7 is selected from hydrido, lower alkyl, aryl
and lower aralkyl;
[0064] or a pharmaceutically-acceptable salt thereof.
[0065] A class of compounds of particular interest consists of
those compounds of Formula I wherein R.sup.1 is phenyl, substituted
at a substitutable position with one or more radicals selected from
fluoro, chloro, methyl, sulfamyl and 22
[0066] wherein R2 is selected from hydrido, methyl, ethyl,
isopropyl, tert-butyl, isobutyl, hexyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl, dichloropropyl, cyano, carboxyl,
methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,
tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, pentoxycarbonyl, acetyl, propionyl, butyryl,
isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,
trifluoroacetyl, cyanomethyl, ethoxycarbonylcyanoethenyl,
1,1-difluoro-1-phenyl-methyl, 1,1-difluoro-1-phenylethyl,
difluoroacetyl, methoxycarbonyldifluoromethyl- ,
difluoroacetamidyl, N,N-dimethyldifluoroacetamidyl,
N-phenyldifluoroacetamidyl, N-ethylamino, N-methylamino,
N,N-dimethylamino, N,N-diethylamino, N-phenylamino, N-benzylamino,
N-phenylethylamino, N-methyl-N-benzylamino, N-ethyl-N-phenylamino,
N-methyl-N-phenylamino, aminomethyl, N-methylaminomethyl,
N,N-dimethylaminomethyl, N-phenylaminomethyl, N-benzylaminomethyl,
N-methyl-N-benzylaminomethyl, N-methyl-N-phenylaminomethyl,
methoxy, ethoxy, phenoxy, benzyloxy, methylthio, phenylthic,
benzylthio, N-methylurea, N-methylthiourea, N-methylacetamidyl,
urea, ureamethyl, thiourea, thioureamethyl, acetamidyl,
N-phenylthioureamethyl, N-benzylthioureamethyl,
N-methylthioureamethyl, N-phenylureamethyl, N-benzylureamethyl,
N-methylureamethyl, N-phenylacetamidylmethyl,
N-benzylacetamidylmethyl, N-methylacetamidylmethyl, aminocarbonyl,
aminocarbonylmethyl, N-methylaminocarbonyl, N-ethylaminocarbonyl,
N-isopropylaminocarbonyl, N-propylaminocarbonyl,
N-butylaminocarbonyl, N-isobutylaminocarbonyl,
N-tert-butylaminocarbonyl, N-pentylaminocarbonyl,
N-phenylaminocarbonyl, N,N-dimethylaminocarbonyl,
N-methyl-N-ethylaminocarbonyl, N-(3-fluorophenyl)aminocarbonyl,
N-(4-methylphenyl)aminocarbonyl, N-(3-chlorophenyl)aminocarbonyl,
N-methyl-N-(3-chlorophenyl)aminocarbonyl,
N-(4-methoxyphenyl)aminocarbony- l, N-methyl-N-phenylaminocarbonyl,
cyclopentylaminocarbonyl, cyclohexylaminocarbonyl,
carboxymethylaminocarbonyl, benzyloxycarbonylmethylaminocarbonyl,
hydroxypropyl, hydroxymethyl, and hydroxypropyl;
[0067] wherein R.sup.3 is selected from hydrido, methyl, ethyl,
isopropyl, tert-butyl, isobutyl, hexyl, fluoro, chloro, bromo,
cyano, methoxy, methylthio, methylsulfonyl, N-methylamino,
N-ethylamino, N,N-dimethylamino, N,N-diethylamino, cyclopropyl,
cyclopentyl, hydroxypropyl, hydroxymethyl, and hydroxyethyl;
and
[0068] wherein R.sup.4 is selected from phenylethenyl, phenyl,
naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl,
1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl,
1-cyclopentenyl, 4-cyclopentenyl, benzofuryl,
2,3-dihydrobenzofuryl, 1,2,3,4-tetrahydronaphthyl, benzothienyl,
indenyl, indanyl, indolyl, dihydroindolyl, chromanyl, benzopyran,
thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl,
pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl; wherein
R.sup.4 is optionally substituted at a substitutable position with
one or more radicals selected from fluoro, chloro, bromo,
methylthio, methylsulfinyl, methyl, ethyl, propyl, isopropyl,
tert-butyl, isobutyl, hexyl, ethylenyl, propenyl, methylsulfonyl,
cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl,
isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl,
butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, aminocarbonyl,
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, bromodifluoromethyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,
dichloropropyl, hydroxyl, methoxy, methylenedioxy, ethoxy, propoxy,
n-butoxy, sulfamyl, methylaminosulfonyl, hydroxypropyl,
hydroxyisopropyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy,
amino, N-methylamino, N-ethylamino, N-ethyl-N-methylamino,
N,N-diethylamino, N,N-diethylamino, formylamino,
methylcarbonylamino, trifluoroacetamino, piperadinyl, piperazinyl,
morpholino, cyclohexylmethyl, cyclopropylmethyl, cyclopentylmethyl,
nitro, 23
[0069] and
[0070] wherein R.sup.7 is selected from hydrido, methyl, ethyl,
phenyl and benzyl;
[0071] or a pharmaceutically-acceptable salt thereof.
[0072] Within Formula I there is a second subclass of compounds of
high interest wherein R.sup.1 is phenyl substituted at a
substitutable position with sulfamyl; wherein R.sup.2 is selected
from lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, lower
carboxyalkyl, aminocarbonyl, lower N-alkylaminocarbonyl,
N-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lower
N-alkyl-N-arylaminocarbonyl, lower cycloalkylaminocarbonyl and
lower hydroxyalkyl; wherein R.sup.3 and R.sup.4 together form
24
[0073] wherein m is 2; wherein A is selected from phenyl and five
membered heteroaryl; and wherein R.sup.6 is one or more radicals
selected from halo, lower alkyl, lower alkylsulfonyl, lower
haloalkyl, lower alkoxy, amino and nitro; or a
pharmaceutically-acceptable salt thereof.
[0074] A class of compounds of particular interest consists of
those compounds of Formula I wherein R.sup.2 is selected from
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl,
cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl,
isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl,
butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, acetyl,
propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,
hexanoyl, trifluoroacetyl, aminocarbonyl, N-methylaminocarbonyl,
N-ethylaminocarbonyl, N-isopropylaminocarbonyl,
N-propylaminocarbonyl, N-butylaminocarbonyl,
N-isobutylaminocarbonyl, N-tert-butylaminocarbonyl,
N-pentylaminocarbonyl, N-phenylaminocarbonyl,
N,N-dimethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl,
N-(3-fluorophenyl)aminocarbonyl, N-(4-methylphenyl)aminocarbonyl,
N-(3-chlorophenyl)aminocarbonyl, N-(4-methoxyphenyl)aminocarbonyl,
N-methyl-N-phenylaminocarbonyl, cyclohexylaminocarbonyl,
hydroxypropyl, hydroxymethyl and hydroxyethyl; wherein A is
selected from phenyl, furyl and thienyl; and wherein R.sup.6 is one
or more radicals selected from fluoro, chloro, bromo,
methylsulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl,
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl,
methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy, amino, and
nitro; or a pharmaceutically-accept- able salt thereof.
[0075] Within Formula I there is a third subclass of compounds of
high interest wherein R.sup.1 is selected from phenyl, naphthyl,
biphenyl, and five- or six-membered heteroaryl, wherein R.sup.1 is
substituted at a substitutable position with one or more radicals
selected from halo, lower alkyl, lower alkoxy, hydroxyl and lower
haloalkyl; wherein R.sup.2 is selected from lower haloalkyl;
wherein R.sup.3 is hydrido; and wherein R.sup.4 is aryl substituted
at a substitutable position with sulfamyl; or a
pharmaceutically-acceptable salt thereof.
[0076] A class of compounds of particular interest consists of
those compounds of Formula I wherein R.sup.1 is selected from
phenyl, naphthyl, benzofuryl, benzothienyl, indolyl, benzodioxolyl,
benzodioxanyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl and
pyrazinyl; wherein R.sup.1 is substituted at a substitutable
position with one or more radicals selected from fluoro, chloro,
bromo, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichloropropyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,
methyl, ethyl, propyl, hydroxyl, methoxy., ethoxy, propoxy and
n-butoxy; wherein R.sup.2 is selected from fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, difluoroethyl, dichlorofluoromethyl,
difluoropropyl, dichloroethyl and dichloropropyl; wherein R.sup.3
is hydrido; and wherein R.sup.4 is phenyl substituted at a
substitutable position with sulfamyl; or a
pharmaceutically-acceptable salt thereof.
[0077] Within Formula I there is a subclass of compounds of high
interest represented by Formula II: 25
[0078] wherein R.sup.2 is selected from hydrido, alkyl, haloalkyl,
alkoxycarbonyl, cyano, cyanoalkyl, carboxyl, aminocarbonyl,
alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,
carboxyalkylaminocarbonyl, carboxyalkyl,
aralkoxycarbonylalkylaminocarbon- yl, aminocarbonylalkyl,
alkoxycarbonylcyanoalkenyl and hydroxyalkyl;
[0079] wherein R.sup.3 is selected from hydrido, alkyl, cyano,
hydroxyalkyl, cycloalkyl, alkylsulfonyl and halo; and
[0080] wherein R.sup.4 is selected from aralkenyl, aryl,
cycloalkyl, cycloalkenyl and heterocyclic; wherein R.sup.4 is
optionally substituted at a substitutable position with one or more
radicals selected from halo, alkylthio, alkylsulfonyl, cyano,
nitro, haloalkyl, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl,
cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl,
aminocarbonyl, alkoxy, haloalkoxy, sulfamyl, heterocyclic and
amino;
[0081] provided R.sup.2 and R.sup.3 are not both hydrido; further
provided that R.sup.2 is not carboxyl or methyl when R.sup.3 is
hydrido and when R.sup.4 is phenyl; further provided that R.sup.4
is not triazolyl when R.sup.2 is methyl; further provided that
R.sup.4 is not aralkenyl when R.sup.2 is carboxyl, aminocarbonyl or
ethoxycarbonyl; further provided that R.sup.4 is not phenyl when
R.sup.2 is methyl and R.sup.3 is carboxyl; and further provided
that R.sup.4 is not unsubstituted thienyl when R.sup.2 is
trifluoromethyl;
[0082] or a pharmaceutically-acceptable salt thereof.
[0083] A class of compounds of particular interest consists of
those compounds of Formula II wherein R.sup.2 is selected from
hydrido, lower alkyl, lower haloalkyl, lower alkoxycarbonyl, cyano,
lower cyanoalkyl, carboxyl, aminocarbonyl, lower
alkylaminocarbonyl, lower cycloalkylaminocarbonyl,
arylaminocarbonyl, lower carboxyalkylaminocarbon- yl, lower
aralkoxycarbonylalkylaminocarbonyl, lower aminocarbonylalkyl, lower
carboxyalkyl, lower alkoxycarbonylcyanoalkenyl and lower
hydroxyalkyl;
[0084] wherein R.sup.3 is selected from hydrido, lower alkyl,
cyano, lower hydroxyalkyl, lower cycloalkyl, lower alkylsulfonyl
and halo; and
[0085] wherein R.sup.4 is selected from aralkenyl, aryl,
cycloalkyl, cycloalkenyl and heterocyclic; wherein R.sup.4 is
optionally substituted at a substitutable position with one or more
radicals selected from halo, lower alkylthio, lower alkylsulfonyl,
cyano, nitro, lower haloalkyl, lower alkyl, hydroxyl, lower
alkenyl, lower hydroxyalkyl, carboxyl, lower cycloalkyl, lower
alkylamino, lower dialkylamino, lower alkoxycarbonyl,
aminocarbonyl, lower alkoxy, lower haloalkoxy, sulfamyl, five or
six membered heterocyclic and amino; or a
pharmaceutically-acceptable salt thereof.
[0086] A family of specific compounds of particular interest within
Formula I consists of compounds and pharmaceutically-acceptable
salts thereof as follows:
[0087]
4-[5-(4-(N-ethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0088]
4-[5-(4-(N-ethyl-N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyraz-
ol-1-yl]benzenesulfonamide;
[0089]
4-[5-(3-fluoro-4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyra-
zol-1-yl]benzenesulfonamide;
[0090]
4-[5-(3-chloro-4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyra-
zol-1-yl]benzenesulfonamide;
[0091]
4-[5-(3-methyl-4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyra-
zol-1-yl]benzenesulfonamide;
[0092]
4-[5-(4-(N,N-dimethylamino)-3-fluorophenyl)-3-(trifluoromethyl)-1H--
pyrazol-1-yl]benzenesulfonamide;
[0093]
4-[5-(3-chloro-4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H--
pyrazol-1-yl]benzenesulfonamide;
[0094]
4-[5-(4-(N,N-dimethylamino)-3-methylphenyl)-3-(trifluoromethyl)-1H--
pyrazol-1-yl]benzenesulfonamide;
[0095]
4-[5-(4-(N-ethyl-N-methylamino)-3-fluorophenyl)-3-(trifluoromethyl)-
-1H-pyrazol-1-yl]benzenesulfonamide;
[0096]
4-[5-(3-chloro-4-(N-ethyl-N-methylamino)phenyl)-3-(trifluoromethyl)-
-1H-pyrazol-1-yl]benzenesulfonamide;
[0097]
4-[5-(4-(N-ethyl-N-methylamino)-3-methylphenyl)-3-(trifluoromethyl)-
-1H-pyrazol-1-yl]benzenesulfonamide;
[0098]
4-[5-(4-(N,N-diethylamino)-3-fluorophenyl)-1H-(trifluoromethyl)-1H--
pyrazol-1-yl]benzenesulfonamide;
[0099]
4-[5-(4-(3-chloro-4-(N,N-diethylamino)phenyl)-3-(trifluoromethyl)-1-
H-pyrazol-1-yl]benzenesulfonamide;
[0100]
4-[5-(4-(N,N-diethylamino)-3-methylphenyl)-3-(trifluoromethyl)-1H-p-
yrazol-1-yl]benzenesulfonamide;
[0101]
N-[4-[1-[4-(aminosulfonyl)phenyl]-1H-(trifluoromethyl)-1H-pyrazol-5-
-yl]-3-fluorophenyl]-N-methylacetamide;
[0102]
N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5--
yl]-3-chlorophenyl]-N-methylacetamide;
[0103]
N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5--
yl]-3-methylphenyl]-N-methylacetamide;
[0104]
N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5--
yl]-3-fluorophenyl]-N-methylurea;
[0105]
N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5--
yl]-3-chlorophenyl]-N-methylurea;
[0106]
N-[4-[1-[4-(aminosulfonyl)phenyl]-1H-(trifluoromethyl)-1H-pyrazol-5-
-yl]-3-methylphenyl]-N-methylurea;
[0107]
N-[4-[1-[4-(aminosulfonyl)phenyl]-1H-(trifluoromethyl)-1H-pyrazol-5-
-yl]-3-fluorophenyl]-N-methylthiourea;
[0108]
N-[4-[1-[4-(aminosulfonyl)phenyl]3-1H-(trifluoromethyl)-1H-pyrazol--
5-yl]-3-chloropheryl]-N-methylthiourea;
[0109]
N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5--
yl]-3-methylphenyl]-N-methylthiourea;
[0110]
4-[5-(3-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
-yl]benzenesulfonamide;
[0111]
4-[5-(3-(N-ethyl-N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyraz-
ol-1-yl]benzenesulfonamide;
[0112]
4-[5-(4-chloro-3-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyra-
zol-1-yl]benzenesulfonamide;
[0113]
4-[5-(4-methyl-3-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyra-
zol-1-yl]benzenesulfonamide;
[0114]
N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5--
yl]phenyl]-N-methylacetamide;
[0115]
N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5--
yl]-4-fluorophenyl]-N-methylacetamide;
[0116]
N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5--
yl]-4-methylphenyl]-N-methylurea;
[0117]
N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5--
yl]-4-fluorophenyl]-N-methylthiourea;
[0118]
4-[5-(2-(N-ethyl-N-methylamino)-4-methylphenyl)-3-(trifluoromethyl)-
-1H-pyrazol-1-yl]benzenesulfonamide;
[0119]
N-[2-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5--
yl]-4-methylphenyl]-N-methylurea;
[0120]
N-[2-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5--
yl]-4-fluorophenyl]-N-methylthiourea;
[0121]
4-[5-(1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0122]
4-[5-(7-fluoro-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0123]
4-[5-(1-ethyl-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0124]
4-[5-(7-methyl-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0125]
4-[5-(7-chloro-1-methyl-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyraz-
ol-1-yl]benzenesulfonamide;
[0126]
4-[5-(2,3-dihydro-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-y-
l]benzenesulfonamide;
[0127]
4-[5-(7-fluoro-1-methyl-2,3-dihydro-1H-indol-5-yl)-3-(trifluorometh-
yl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0128]
4-[3-aminomethyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0129]
4-[3-(N-methylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonam-
ide;
[0130]
4-[3-(N,N-dimethylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulf-
onamide;
[0131]
4-[5-phenyl-3-(N-phenylamino)methyl-1H-pyrazol-1-yl]benzenesulfonam-
ide;
[0132]
4-[3-(N-benzylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonam-
ide;
[0133]
4-[3-(N-benzyl-N-methylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0134]
4-[3-(N-methyl-N-phenylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0135]
N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]ace-
tamide;
[0136]
N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N--
methylacetamide;
[0137]
N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N--
phenylacetamide;
[0138]
N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N--
benzylacetamide;
[0139]
N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]ure-
a;
[0140]
N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N--
methylurea;
[0141]
N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N--
phenylurea;
[0142]
N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N--
benzylurea;
[0143]
N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]thi-
ourea;
[0144]
N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N--
methylthiourea;
[0145]
N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl)-N--
phenylthioureau;
[0146]
N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N--
benzylthiourea;
[0147]
4-[4-methoxy-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0148]
4-[4-methylthio-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0149]
4-[4-(N-methylamino)-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0150]
4-[4-(N,N-dimethylamino)-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1--
yl]benzenesulfonamide;
[0151] 4-[3-methoxy-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
4-[3-ethoxy-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0152]
4-[3-phenoxy-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0153]
4-[3-benzyloxy-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0154]
4-[3-methylthio-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0155]
4-[3-benzylthio-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0156]
4-[3-(N-methylamino)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0157]
4-[3-(N,N-dimethylamino)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamid-
e;
[0158]
4-[3-(N-benzyl-N-methylamino)-5-phenyl-1H-pyrazol-1-yl]benzenesulfo-
namide;
[0159]
N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]acetamide;
[0160]
N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-methylac-
etamide;
[0161]
N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-benzylac-
etamide;
[0162]
N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]urea;
[0163]
N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-methylur-
ea;
[0164]
N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-benzylur-
ea;
[0165]
N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]thiourea;
[0166]
N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-methylth-
iourea;
[0167]
N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-benzylth-
iourea;
[0168]
4-[5-phenyl-3-(1,1-difluoro-1-phenylmethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide;
[0169]
4-[5-phenyl-3-(1,1-difluoro-2-phenylethyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide;
[0170]
1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-difluoroacetic
acid;
[0171] methyl
1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-difluoroa-
cetate;
[0172]
1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-difluoroacetamid-
e;
[0173]
N,N-dimethyl-1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-dif-
luoroacetamide;
[0174]
N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-difluor-
oacetamide;
[0175] 1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-acetic
acid;
[0176]
1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazole-3-difluor-
oacetic acid;
[0177]
1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazole-3-difluoro-
acetic acid;
[0178]
1-[4-(aminosulfonyl)phenyl]-4-chloro-5-(4-chlorophenyl)-1H-pyrazole-
-3-acetic acid;
[0179]
1-[4-(aminosulfonyl)phenyl)-4-bromo-5-phenyl-1H-pyrazole-3-acetic
acid;
[0180]
(R)-2-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]propano-
ic acid;
[0181]
(S)-2-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]propano-
ic acid;
[0182]
(R)-2-[1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazol-3-y-
l]propanoic acid;
[0183]
(S)-2-[1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazol-3-y-
l]propanoic acid;
[0184]
(R)-2-[1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazol-3-yl-
)propanoic acid;
[0185]
(S)-2-[1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazol-3-yl-
]propanoic acid;
[0186]
2-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-2-methylpr-
opanoic acid;
[0187]
2-[1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazol-3-yl]-2-
-methylpropanoic acid;
[0188]
2-[1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazol-3-yl]-2--
methylpropanoic acid;
[0189]
2-floro-4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulf-
onamide;
[0190]
3-fluoro-4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0191] 2-methyl-4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl
benzenesulfonamide;
[0192]
3-methyl-4-[S-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0193] ethyl
1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3--
carboxylate;
[0194] ethyl
1-[4-(aminosulfonyl)phenyl]-5-(4-methylphenyl)-1H-pyrazole-3--
carboxylate;
[0195] isopropyl
1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-
e-3-carboxylate;
[0196]
methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-aminophenyl)-1H-pyrazole-3--
carboxylate;
[0197]
1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carbox-
ylic acid;
[0198]
tert-butyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazo-
le-3-carboxylate;
[0199]
propyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-
-carboxylate;
[0200]
butyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3--
carboxylate;
[0201]
isobutyl-1-[4-(aminosulfonyl)phenyl)-5-(4-chlorophenyl)-1H-pyrazole-
-3-carboxylate;
[0202]
pentyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-
-carboxylate;
[0203]
methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-
-carboxylate;
[0204]
methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-methylphenyl)-1H-pyrazole-3-
-carboxylate;
[0205]
methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazole--
3-carboxylate;
[0206]
methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-bromophenyl)-1H-pyrazole-3--
carboxylate;
[0207]
methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-nitrophenyl)-1H-pyrazole-3--
carboxylate;
[0208]
methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-florophenyl)-1H-pyrazole-3--
carboxylate;
[0209]
methyl-1-[4-(aminosulfonyl)phenyl]-5-(3,5-dichloro-4-methoxyphenyl)-
-1H-pyrazole-3-carboxylate;
[0210]
methyl-1-[4-(aminosulfonyl)phenyl]-5-(3,5-difluoro-4-methoxyphenyl)-
-1H-pyrazole-3-carboxylate;
[0211]
N-[4-methylphenyl]-1-[4-(aminosulfonyl)phenyl)-5-(4-fluorophenyl)-1-
H-pyrazole-3-carboxamide;
[0212]
N-[3-chlorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1-
H-pyrazole-3-carboxamide;
[0213]
N-[3-fluorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1-
H-pyrazole-3-carboxamide;
[0214]
N-[3-fluorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1-
H-pyrazole-3-carboxamide;
[0215] phenylmethyl
N-[[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H--
pyrazol-3-yl]carbonyl]glycinate;
[0216]
1-[4-(aminosulfonyl)phenyl]-5-(4-bromophenyl)-1H-pyrazole-3-carboxa-
mide;
[0217]
1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carbox-
amide;
[0218]
N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-
-3-carboxamide;
[0219]
N-(4-methoxyphenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)--
1H-pyrazole-3-carboxamide;
[0220]
N-(4-methylphenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1-
H-pyrazole-3-carboxamide;
[0221]
N,N-dimethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyra-
zole-3-carboxamide;
[0222]
N-methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-
-3-carboxamide;
[0223]
N-methyl-N-ethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H--
pyrazole-3-carboxamide;
[0224]
N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-
-3-carboxamide;
[0225]
N-methyl-N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-
-pyrazole-3-carboxamide;
[0226]
N-ethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole--
3-carboxamide;
[0227]
N-isopropyl1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazo-
le-3-carboxamide;
[0228]
N-propyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-
-3-carboxamide;
[0229]
N-butyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole--
3-carboxamide;
[0230]
N-isobutyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazo-
le-3-carboxamide;
[0231]
N-tert-butyl1-[4-(aminosulfonyl)phenyl-5-(4-chlorophenyl)-1H-pyrazo-
le-3-carboxamide;
[0232]
N-pentyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-
-3-carboxamide;
[0233]
N-cyclohexyl-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyra-
zole-3-carboxamide;
[0234]
N-cyclopentyl-1-[4-(amincsulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyr-
azole-3-carboxamide;
[0235]
4-[5-(4-chlorophenyl)-3-(pyrrolidinocarboxamide)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0236]
4-[5-(4-chlorophenyl)-3-(piperidinocarboxamide)-1H-pyrazol-1-yl]ben-
zenesulfonamide;
[0237]
N-(3-chlorophenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1-
H-pyrazole-3-carboxamide;
[0238]
N-(2-pyridyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyr-
azole-3-carboxamide;
[0239]
N-methyl-N-(3-chlorophenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-chloro-
phenyl)-1H-pyrazole-3-carboxamide;
[0240]
1-[4-(aminosulfonyl)phenyl]-5-(4-nitrophenyl)-1H-pyrazole-3-carboxa-
mide;
[0241]
1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carbox-
amide;
[0242]
1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-carboxamide;
[0243]
1-[4-(aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-1H-pyrazol-
e-3-carboxamide;
[0244]
1-[4-(aminosulfonyl)phenyl]-5-(4-methylthiophenyl)-1H-pyrazole-3-ca-
rboxamide;
[0245]
1-[4-(aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazole-3-carbo-
xamide;
[0246]
1-[4-(aminosulfonyl)phenyl]-5-(4-methylphenyl)-1H-pyrazole-3-carbox-
amide;
[0247] N-methyl
1-[4-(aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazol-
e-3-carboxamide;
[0248]
N-[[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]-
carbonyl]glycine;
[0249]
1-[4-(aminosulfonyl)phenyl]-5-(3-bromo-4-methoxyphenyl)-1H-pyrazole-
-3-carboxamide;
[0250]
1-[4-(aminosulfonyl)phenyl]-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyr-
azole-3-carboxamide;
[0251]
4-[5-(4-bromophenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;
[0252] 4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl
benzenesulfonamide;
[0253]
4-[5-(4-chlorophenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;
[0254]
4-[3-cyano-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0255]
4-[3-cyano-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0256]
4-[3-cyano-5-(4-methylthiophenyl)-1H-pyrazol-1-yl]benzenesulfonamid-
e;
[0257]
4-[5-(3-chloro-4-methoxyphenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulf-
onamide;
[0258]
4-[5-(3,5-dichloro-4-methoxyphenyl)-3-cyano-1H-pyrazol-1-yl]benzene-
sulfonamide;
[0259]
4-[5-(3-bromo-4-methoxyphenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfo-
namide;
[0260] 4-[3-cyano-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0261]
4-[5-(4-nitrophenyl)-3-(cyano)-1H-pyrazol-1-yl]benzenesulfonamide;
[0262]
4-[4-chloro-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0263]
4-[4-chloro-5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0264]
4-4-bromo-5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0265] 4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0266] 4-[4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazol-1-yl
benzenesulfonamide;
[0267]
4-[4-bromo-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0268]
4-[4-chloro-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0269]
4-[4-chloro-5-(3-chloro-4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesul-
fonamide;
[0270]
4-[4-chloro-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0271]
4-[4-bromo-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0272]
4-[4-cyano-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0273]
4-[4-chloro-5-(3,5-difluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0274] 4-[4-methyl-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;
[0275] 4-[4-fluoro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0276]
4-[5-(4-chlorophenyl)-4-methylsulfonyl-1H-pyrazol-1-yl]benzenesulfo-
namide;
[0277]
4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0278]
4-[4-ethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulf-
onamide;
[0279]
4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0280]
4-[5-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl-
]benzenesulfonamide;
[0281]
4-[5-(4-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0282]
4-[5-(4-chlorophenyl)-4-ethyl-3-(trifluoromethyl)-1H-pyrazol]-1-yl]-
benzenesulfonamide;
[0283]
4-[4-ethyl-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0284]
4-[4-ethyl-5-(4-methoxy-3-methylphenyl)-3-(trifluoromethyl)-1H-pyra-
zol-1-yl]benzenesulfonamide;
[0285]
4-[4-ethyl-5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0286]
4-[4-cyclopropyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0287]
4-[4-ethyl-5-(3-fluoro-4-chlorophenyl)-3-(trifluoromethyl)-1H-pyraz-
ol-1-yl]benzenesulfonamide;
[0288]
4-[4-hydroxymethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ben-
zenesulfonamide;
[0289]
4-[5-(4-fluorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0290]
4-[4-methyl-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0291]
4-[4-fluoro-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0292]
4-[4-bromo-5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0293]
4-[4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-3-(difluoromethyl)-1H--
pyrazol-1-yl)benzenesulfonamide;
[0294]
4-[4-chloro-3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulf-
onamide;
[0295]
4-[4-bromo-3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfo-
namide;
[0296]
4-[4-chloro-3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0297]
4-[4-chloro-3-cyano-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0298]
4-[4-chloro-5-(4-chlorophenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfo-
namide;
[0299]
4-[4-chloro-3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfo-
namide;
[0300]
4-[4-bromo-3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfon-
amide;
[0301]
4-[4-bromo-3-cyano-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0302] ethyl
[1-(4-aminosulfonylphenyl)-4-bromo-5-(4-chlorophenyl)-1H-pyra-
zol-3-yl]carboxylate;
[0303] methyl
[1-(4-aminosulfonylphenyl)-4-chloro-5-phenyl-1H-pyrazol-3-yl-
]carboxylate;
[0304] methyl
1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyr-
azol-3-yl]carboxylate;
[0305] ethyl
[1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyr-
azol-3-yl]carboxylate;
[0306] methyl
[1-(4-aminosulfonylphenyl)-4-chloro-5-(4-fluorophenyl)-1H-py-
razol-3-yl]carboxylate;
[0307] methyl
[1-(4-aminosulfonylphenyl)-4-bromo-5-(4-fluorophenyl)-1H-pyr-
azol-3-yl]carboxylate;
[0308] methyl
[1-(4-aminosulfonylphenyl)-4-chloro-5-(3-chloro-4-methoxyphe-
nyl)-1H-pyrazol-3-yl]carboxylate;
[0309] methyl
[1-(4-aminosulfonylphenyl)-4-chloro-5-(3,5-dichloro-4-methox-
yphenyl)-1H-pyrazol-3-yl]carboxylate;
[0310] methyl
[1-(4-aminosulfonylphenyl)-5-(3-bromo-4-methoxyphenyl)-4-chl-
oro-1H-pyrazol-3-yl]carboxylate;
[0311]
[1-(4-aminosulfonylphenyl)-4-chloro-5-phenyl-1H-pyrazol-3-yl]carbox-
amide;
[0312]
[1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3-
-yl]carboxamide;
[0313]
[1-(4-aminosulfonylphenyl)-4-chloro-5-(4-fluorophenyl)-1H-pyrazol-3-
-yl]carboxamide;
[0314]
[1-(4-aminosulfonylphenyl)-4-bromo-5-(4-chlorophenyl)-1H-pyrazol-3--
yl]carboxamide;
[0315]
[1-(4-aminosulfonylphenyl)-4-bromo-5-phenyl-1H-pyrazol-3-yl]carboxa-
mide;
[0316]
[1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3-
-yl]carboxylic acid;
[0317]
[1-(4-aminosulfonylphenyl)-4-chloro-5-phenyl-1H-pyrazol-3-yl]carbox-
ylic acid;
[0318]
[1-(4-aminosulfonylphenyl)-4-chloro-5-(3,5-dichloro-4-methoxyphenyl-
)-1H-pyrazol-3-yl]carboxylic acid;
[0319]
4-[4-chloro-3-isopropyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide-
;
[0320]
4-[4-chloro-3-methyl-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;
[0321]
4-[4-chloro-3-hydroxymethyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfona-
mide;
[0322]
4-[4-chloro-5-(4-chlorophenyl)-3-hydroxymethyl-1H-pyrazol-1-yl]benz-
enesulfonamide;
[0323]
[1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3-
-yl]propanoic acid;
[0324]
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0325]
4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0326]
4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0327]
4-[5-(4-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0328]
4-[5-(2,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0329]
4-[5-(2,6-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0330]
4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide;
[0331]
4-[5-(3,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0332]
4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0333]
4-[5-(2,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0334]
4-[5-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0335]
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0336]
4-[5-(4-trifluoromethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl
benzenesulfonamide;
[0337]
4-[5-(4-trifluoromethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-
]benzenesulfonamide;
[0338]
4-[5-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0339]
4-[5-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0340]
4-[5-(2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0341]
4-[5-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0342]
4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0343]
4-[5-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0344]
4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0345]
4-[5-(4-ethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0346]
4-[5-(3,5-dimethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol--
1-yl]benzenesulfonamide;
[0347]
4-[5-(3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0348]
4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-
]benzenesulfonamide;
[0349]
4-[5-(4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0350]
4-[5-(4-chloro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0351]
4-[5-(4-ethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0352]
4-[5-(2,4-dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0353]
4-[5-(2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide;
[0354]
4-[5-(4-methoxy-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-
]benzenesulfonamide;
[0355]
4-[5-(3-bromo-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1--
yl]benzenesulfonamide;
[0356]
4-[5-(4-hydroxy-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-
]benzenesulfonamide;
[0357]
4-[5-(3-chloro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0358]
4-[5-(3,4-dimethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benz-
enesulfonamide;
[0359]
4-[5-(3-chloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-
]benzenesulfonamide;
[0360]
4-[5-(3-chloro-4-methoxy-5-methylphenyl)-3-(trifluoromethyl)-1H-pyr-
azol-1-yl]benzenesulfonamide;
[0361]
4-[5-(3-ethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0362]
4-[5-(4-fluoro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-
]benzenesulfonamide;
[0363]
4-[5-(4-hydroxymethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0364]
4-[5-(4-methoxy-3-(1-propenyl)phenyl)-3-(trifluoromethyl)-1H-pyrazo-
l-1-yl benzenesulfonamide;
[0365]
4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol--
1-yl]benzenesulfonamide;
[0366]
4-[5-(2,4-dimethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benz-
enesulfonamide;
[0367]
4-[5-(3-chloro-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-
benzenesulfonamide;
[0368]
4-[5-(4-methcxy-3-propylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-
]benzenesulfonamide;
[0369]
4-[5-(3,5-difluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol--
1-yl]benzenesulfonamide;
[0370]
4-[5-(3-fluoro-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
-yl]benzenesulfonamide;
[0371]
4-[5-(3-cyclopropylmethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-p-
yrazol-1-yl]benzenesulfonamide;
[0372]
4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-
benzoic acid;
[0373]
4-[5-(3-methyl-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
-yl]benzenesulfonamide;
[0374]
4-[5-(3-chloro-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
-yl]benzenesulfonamide;
[0375]
4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
-yl benzenesulfonamide;
[0376]
4-[5-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0377]
4-[5-(4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0378]
4-[5-(3-amino-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0379]
methyl-4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazo-
l-5-yl]benzoate;
[0380]
4-[1-[4-(aminosulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-
benzamide;
[0381]
4-[5-(3,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0382]
4-[5-(2,4,6-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0383]
4-[5-(2,6-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0384]
4-[5-(2,4,6-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0385]
4-[5-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide;
[0386]
4-[5-(3,4-dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0387]
4-[5-(1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]ben-
zenesulfonamide;
[0388]
4-[5-(2-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-
]benzenesulfonamide;
[0389]
4-[5-(2-chloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-
]benzenesulfonamide;
[0390]
4-[5-(4-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-
]benzenesulfonamide;
[0391]
4-[5-(2-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0392]
4-[5-(3-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benze-
nesulfonamide;
[0393]
4-[5-(2-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0394]
4-[5-(3-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0395]
4-[5-(4-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0396]
4-[5-(2-fluoro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0397]
4-[5-(4-fluoro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0398]
4-[5-(2-chloro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0399]
4-[5-(4-chloro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0400]
4-[5-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide;
[0401]
4-[5-(3,4-dihydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benz-
enesulfonamide;
[0402]
4-[5-(4-isopropylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0403]
N-[4-[1-[4-(aminosulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazol-5-yl-
)phenyl)acetamide;
[0404]
N-[4-[1-[4-(aminosulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazol-5-yl-
]phenyl]formamide;
[0405]
N-[4-[1-[4-(aminosulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazol-5-yl-
]phenyl]trifluoroacetamide;
[0406]
4-[5-(4-[N-methylaminosulfonyl]phenyl)-3-(trifluoromethyl)-1H-pyraz-
ol-1-yl]benzenesulfonamide;
[0407]
4-[5-(2,5-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0408]
4-[5-(4-n-butoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide;
[0409]
4-[5-(4-[aminosulfonyl]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0410]
4-[5-(2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0411]
4-[5-(2,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0412]
4-[5-(2,3,4-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0413]
4-[5-(3,4,5-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0414]
4-[5-(2,4,5-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0415]
4-[5-(2,5,6-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0416]
4-[5-(2,3,4,5-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y-
l]benzenesulfonamide;
[0417]
4-[5-(2,3,4,6-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y-
l)benzenesulfonamide;
[0418]
4-[5-(2,3,5,6-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y-
l]benzenesulfonamide;
[0419]
4-[5-(pentafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0420]
4-[5-(2,3,4-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0421]
4-[5-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0422]
4-[5-(2,4,5-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0423]
4-[5-(2,5,6-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl
benzenesulfonamide;
[0424]
4-[5-(2,3,4,5-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y-
l]benzenesulfonamide;
[0425]
4-[5-(2,3,4,6-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y-
l)benzenesulfonamide;
[0426]
4-[5-(2,3,5,6-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y-
l]benzenesulfonamide;
[0427]
4-[5-(2,3,4,5,6-pentachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
-yl]benzenesulfonamide;
[0428]
4-[5-(4-tert-butylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0429]
4-[5-(4-isobutylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzene-
sulfonamide;
n4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]ben-
zenesulfonamide;
[0430]
4-[5-(4-trifluoromethylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0431]
4-[5-(4-methylthiophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0432]
4-[5-(4-(1-morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0433]
4-[5-(4-methylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0434]
4-[5-phenyl-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0435]
4-[5-(4-methylthiophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0436]
4-[5-(3,4-dimethylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0437]
4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0438]
4-[1-[4-(aminosulfonyl)phenyl]-3-(difluoromethyl)-1H-pyrazol-5-yl]b-
enzoic acid;
[0439] methyl
4-[1-[4-(aminosulfonyl)phenyl]-3-(difluoromethyl)-1H-pyrazol-
-5-yl]benzoate;
[0440]
4-[1-(4-aminosulfonylphenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl]ben-
zamide;
[0441]
4-[5-(2-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0442]
4-[5-(4-cyanophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulf-
onamide;
[0443]
4-[5-(3-chloro-4-methylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0444]
4-[5-(3-chloro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0445]
4-[5-(4-chloro-3-methylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0446]
4-[5-(3,4-dimethoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0447]
4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-
-yl]benzenesulfonamide;
[0448]
4-[5-(3,5-difluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-
-yl]benzenesulfonamide;
[0449]
4-[5-(2-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0450]
4-[5-(3-bromo-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0451]
4-[5-(4-methylsulfonylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0452]
4-[5-(5-bromo-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide;
[0453]
4-[5-(5-chloro-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0454]
4-[5-(1-cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0455]
4-[5-(cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfona-
mide;
[0456]
4-[5-(biphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)benzenesulfonami-
de;
[0457]
4-[5-(1,4-benzodioxan-6-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benz-
enesulfonamide;
[0458]
4-[3-(difluoromethyl)-5-(4-methylcyclohexyl)-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0459]
4-[5-(methyl-1-cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]ben-
zenesulfonamide;
[0460]
4-[5-(2-methyl-1-cyclopentenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)-
benzenesulfonamide;
[0461]
4-[5-(benzofuran-2-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0462]
4-[5-(1,3-benzodioxol-5-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benz-
enesulfonamide;
[0463]
4-[5-(2-pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfon-
amide;
[0464]
4-[5-(4-(morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benz-
enesulfonamide;
[0465]
4-[5-(2,5-dimethyl-3-furyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benz-
enesulfonamide;
[0466]
4-[5-(5-methyl-2-furyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide;
[0467]
4-[5-(1-chloro-1-methyl-4-cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-
-1-yl]benzenesulfonamide;
[0468]
4-[5-(3,4-dibromo-4-methylcyclohexyl)-3-(difluoromethyl)-1H-pyrazol-
-1-yl]benzenesulfonamide;
[0469]
4-[5-(2-methoxycyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0470]
4-[5-(2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)benzenesulfonam-
ide;
[0471]
4-[5-(2,4-dimethyl-3-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0472]
4-[5-(2,5-dichloro-3-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0473]
4-[5-(benzofuran-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide;
[0474]
4-[5-(5-bromo-2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0475]
4-[5-(5-chloro-2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0476]
4-[5-(5-indanyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfona-
mide;
[0477]
4-[5-(5-methyl-2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0478]
4-[5-(2,3-dihydrobenzofuran-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1--
yl]benzenesulfonamide;
[0479]
4-[5-(1-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0480]
4-[5-(5-benzothienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0481]
4-[5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyra-
zol-1-yl]benzenesulfonamide;
[0482]
4-[5-(3,4-dihydro-2H-1-benzothiopyran-6-yl)-3-(trifluoromethyl)-1H--
pyrazol-1-yl]benzenesulfonamide;
[0483]
4-[5-(2-phenylethenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide;
[0484]
4-[5-(4-methyl-1,3-benzodioxol-6-yl)-3-(trifluoromethyl)-1H-pyrazol-
-1-yl]benzenesulfonamide;
[0485]
4-[5-(4-methyl-1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-
-1-yl benzenesulfonamide;
[0486]
4-(5-(2-pyrazinyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfo-
namide;
[0487]
4-[5-(biphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonam-
ide;
[0488]
4-[5-(1,2,3,4-tetrahydronaphth-6-yl])-3-(trifluoromethyl)-1H-pyrazo-
l-1-yl]benzenesulfonamide;
[0489]
4-[5-(2-naphthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfon-
amide;
[0490]
4-[(5-(2-thiazolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulf-
onamide;
[0491]
4-[5-(2-oxazolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfon-
amide;
[0492]
4-[5-(cyclohexyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfon-
amide;
[0493]
4-[5-(cyclopentyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfo-
namide;
[0494] 4-[5-(cycloheptyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl
benzenesulfonamide;
[0495]
4-[5-(1-cyclopentenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide;
[0496]
4-[5-(2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonami-
de;
[0497]
4-[5-(2-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfona-
mide;
[0498]
4-[5-(3-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfona-
mide;
[0499]
4-[5-(6-methyl-3-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze-
nesulfonamide;
[0500]
4-[5-(4-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfona-
mide;
[0501]
4-[5-(3-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0502]
4-[5-(4-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0503]
4-[5-(4-methylcyclohex-4-ene-1-yl)-3-(trifluoromethyl)-1H-pyrazol-1-
-yl]benzenesulfonamide;
[0504]
4-[5-(5-chloro-2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide;
[0505]
4-[5-(5-bromo-2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide;
[0506]
4-[5-(6-methoxy-2-naphthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]ben-
zenesulfonamide;
[0507]
4-[5-(4-chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl]benzene-
sulfonamide;
[0508]
4-[5-(4-chlorophenyl)-3-(chlorodifluoromethyl)-1H-pyrazol-1-yl]benz-
enesulfonamide;
[0509]
4-[5-(4-chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide;
[0510]
4-[5-(3-chloro-4-methoxyphenyl)-3-(chloromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0511]
4-[3-(chlorodifluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-
-1-yl]benzenesulfonamide;
[0512]
4-[5-(phenyl)-3-(fluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0513]
4-[3-(dichloromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0514]
4-[3-(bromodifluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol--
1-yl]benzenesulfonamide;
[0515]
4-[5-(4-chlorophenyl)-3-(fluoromethyl)-1H-pyrazol-1-yl]benzenesulfo-
namide;
[0516]
4-[5-(4-chlorophenyl)-3-(chloromethyl)-1H-pyrazol-1-yl]benzenesulfo-
namide;
[0517]
4-[5-(4-chlorophenyl)-3-(dichloromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0518]
4-[5-(4-chlorophenyl)-3-(dichlorofluoromethyl)-1H-pyrazol-1-yl]benz-
ene sulfonamide;
[0519]
4-[5-(4-fluorophenyl)-3-(trichloromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0520]
4-[5-(4-chlorophenyl)-3-(1,1-difluoroethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide;
[0521]
4-[5-(4-chlorophenyl)-3-(1,1-difluoropropyl)-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0522]
4-[5-(4-chlorophenyl)-3-(1,1-dichloroethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide;
[0523]
4-[5-(4-chlorophenyl)-3-(1,1-dichloropropyl)-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0524]
4-[5-(4-chlorophenyl)-3-nitro-1H-pyrazol-1-yl)benzenesulfonamide;
[0525]
4-[5-(4-chlorophenyl)-3-(amidino)-1H-pyrazol-1-yl]benzenesulfonamid-
e;
[0526]
4-[5-[(4-chlorophenyl)-3-(methylsulfonyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0527]
4-[5-(4-chlorophenyl)-3-(N-methyl-aminosulfonyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide;
[0528]
4-[5-(4-fluorophenyl)-3-(imidazolyl)-1H-pyrazol-1-yl)benzenesulfona-
mide;
[0529]
4-[5-(4-fluorophenyl)-3-(2-pyridyl)-1H-pyrazol-1-yl]benzenesulfonam-
ide;
[0530] 4-[5-(4-chlorophenyl)-3-(N-cyanoamidino)-1H-pyrazol-1-yl
benzenesulfonamide;
[0531]
4-[5-(4-chlorophenyl)-3-(tetrazolyl)-1H-pyrazol-1-yl]benzenesulfona-
mide;
[0532]
4-[5-(4-chlorophenyl)-3-(phenylsulfonyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0533]
4-[5-(4-chlorophenyl)-3-(N-phenylaminosulfonyl)-1H-pyrazol-1-yl]ben-
zenesulfonamide;
[0534]
4-[5-(4-chlorophenyl)-3-(N,N-dimethylaminosulfonyl)-1H-pyrazol-1-yl-
]benzenesulfonamide;
[0535]
4-(5-(4-chlorophenyl)-3-(N-methyl-N-phenylaminosulfonyl)-1H-pyrazol-
-1-yl]benzenesulfonamide;
[0536]
4-[5-(4-chlorophenyl)-3-(N-ethylaminosulfonyl)-1H-pyrazol-1-yl]benz-
enesulfonamide;
[0537]
4-[5-(4-chlorophenyl)-3-(N-isopropylaminosulfonyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0538]
4-[5-(4-chlorophenyl)-3-(N-methyl-N-ethylaminosulfonyl)-1H-pyrazol--
1-yl]benzenesulfonamide;
[0539] 4-[5-(4-chlorophenyl)-3-(N-methyl-N-(3-chlorophenyl)
aminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0540]
4-[5-(4-chlorophenyl)-3-(N-methyl-N-(2-pyridyl)aminosulfonyl)-1H-py-
razol-1-yl]benzenesulfonamide;
[0541] 4-[3-methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0542]
4-[3-isobutyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0543]
4-(3-(3-hydroxypropyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0544]
4-[5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0545]
4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(3-hydroxypropyl)-1H-pyrazol--
1-yl]benzenesulfonamide;
[0546]
4-[5-(4-methylphenyl)-3-(2-hydroxyisopropyl)-1H-pyrazol-1-yl]benzen-
esulfonamide;
[0547]
1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-propan-
oic acid;
[0548]
1-[4-(aminosulfonyl)phenyl]-S-(4-chlorophenyl)-1H-pyrazole-3-propan-
oic acid;
[0549]
1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-propan-
amide;
[0550] methyl
1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-
-propanoate;
[0551]
4-[3-(3-hydroxymethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0552]
4-[5-(4-chlorophenyl)-3-(3-hydroxymethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0553]
4-[3-(3-hydroxymethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide;
[0554]
4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(3-hydroxymethyl)-1H-pyrazol--
1-yl)benzenesulfonamide;
[0555]
4-[5-(3-chloro-4-methoxyphenyl)-3-(3-hydroxymethyl)-1H-pyrazol-1-yl-
]benzenesulfonamide;
[0556] ethyl
3-[1-(4-aminosulfonylphenyl)-5-(phenyl)-1H-pyrazol-3-yl]-2-cy-
ano-2-propenoate;
[0557]
4-[5-(4-chlorophenyl)-3-(chloro)-1H-pyrazol-1-yl]benzenesulfonamide-
;
[0558]
4-[5-(4-chlorophenyl)-3-(bromo)-1H-pyrazol-1-yl]benzenesulfonamide;
[0559]
4-[5-(4-chlorophenyl)-3-(fluoro)-1H-pyrazol-1-yl]benzenesulfonamide-
;
[0560]
4-[3-(difluoromethyl)-4,5-dihydro-7-methoxy-1H-benz[g]indazol-1-yl]-
benzenesulfonamide;
[0561]
4-[3-(diflucromethyl)-4,5-dihydro-7-methyl-1H-benz[g]indazol-1-yl]b-
enzenesulfonamide;
[0562]
4-[4,5-dihydro-7-methoxy-3-(trifluoromethyl)-1H-benz[g)indazol-1-yl-
]benzenesulfonamide;
[0563]
4-[4,5-dihydro-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesu-
lfonamide;
[0564]
4-[4,5-dihydro-7-methyl-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]-
benzenesulfonamide;
[0565]
4-[4,5-dihydro-6,8-dimethyl-3-(trifluoromethyl)-1H-benz[g]indazol-1-
-yl]benzenesulfonamide;
[0566]
4-[4,5-dihydro-6,8-dimethoxy-3-(trifluoromethyl)-1H-benz[g]indazol--
1-yl]benzenesulfonamide;
[0567]
methyl[1-(4-aminosulfonylphenyl)-4,5-dihydro-7-methoxy-1H-benz[g]in-
dazol-3-yl]carboxylate;
[0568]
4-[4,5-dihydro-3-trifluoromethyl-1H-thieno[3,2,g]indazol-1-yl]benze-
nesulfonamide;
[0569]
4-[1-phenyl-3-(difluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;
[0570]
4-[1-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl]benzenesul-
fonamide;
[0571]
4-[1-(4-fluorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl]benzenesul-
fonamide;
[0572]
4-[1-(4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl]benzenesu-
lfonamide;
[0573]
4-[1-phenyl-3-(trifluoromethyl)-2H-pyrazol-5-yl)benzenesulfonamide;
[0574] 4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl
benzenesulfonamide;
[0575]
4-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesu-
lfonamide; and
[0576]
4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenes-
ulfonamide.
[0577] A family of specific compounds of particular interest within
Formula II consists of compounds and pharmaceutically-acceptable
salts thereof as follows:
[0578]
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0579]
4-[(5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide-
;
[0580]
4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0581]
4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide;
[0582]
4-(5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
[0583] 4-[5-3-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl
benzenesulfonamide;
[0584]
4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0585] 4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl
benzenesulfonamide;
[0586]
4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0587]
4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide;
[0588]
4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
[0589]
4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
[0590]
4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-
]benzenesulfonamide;
[0591] 4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
[0592]
4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl]benzenesulf-
onamide; and
[0593]
4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
-yl]benzenesulfonamide.
[0594] The term "hydrido" denotes a single hydrogen atom (H). This
hydrido radical may be attached, for example, to an oxygen atom to
form a hydroxyl radical or two hydrido radicals may be attached to
a carbon atom to form a methylene (--CH.sub.2--) radical. Where the
term "alkyl" is used, either alone or within other terms such as
"haloalkyl" and "alkylsulfonyl", it embraces linear or branched
radicals having one to about twenty carbon atoms or, preferably,
one to about twelve carbon atoms. More preferred alkyl radicals are
"lower alkyl" radicals having one to about ten carbon atoms. Most
preferred are lower alkyl radicals having one to about six carbon
atoms. Examples of such radicals include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
iso-amyl, hexyl and the like. The term. "alkenyl" embraces linear
or branched radicals having at least one carbon-carbon double bond
of two to about twenty carbon atoms or, preferably, two to about
twelve carbon atoms. More preferred alkyl radicals are "lower
alkenyl" radicals having two to about six carbon atoms. Examples of
such radicals include ethenyl, n-propenyl, butenyl, and the like.
The term "halo" means halogens such as fluorine, chlorine, bromine
or iodine atoms. The term "haloalkyl" embraces radicals wherein any
one or more of the alkyl carbon atoms is substituted with halo as
defined above. Specifically embraced are monohaloalkyl, dihaloalkyl
and polyhaloalkyl radicals. A monohaloalkyl radical, for one
example, may have either an iodo, bromo, chloro or fluoro atom
within the radical. Dihalo and polyhaloalkyl radicals may have two
or more of the same halo atoms or a combination of different halo
radicals. "Lower haloalkyl" embraces radicals having 1-6 carbon
atoms. Examples of haloalkyl radicals include fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
The term "hydroxyalkyl" embraces linear or branched alkyl radicals
having one to about ten carbon atoms any one of which may be
substituted with one or more hydroxyl radicals. More preferred
hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one
to six carbon atoms and one or more hydroxyl radicals. Examples of
such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,
hydroxybutyl and hydroxyhexyl. The terms "alkoxy" and "alkoxyalkyl"
embrace linear or branched oxy-containing radicals each having
alkyl portions of one to about ten carbon atoms, such as methoxy
radical. More preferred alkoxy radicals are "lower alkoxy" radicals
having one to six carbon atoms. Examples of such radicals include
methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term
"alkoxyalkyl" also embraces alkyl radicals having two or more
alkoxy radicals attached to the alkyl radical, that is, to form
monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred
alkoxyalkyl radicals are "lower alkoxyalkyl" radicals having one to
six carbon atoms and one or two alkoxy radicals. Examples of such
radicals include methoxymethyl, methoxyethyl, ethoxyethyl,
methoxybutyl and methoxypropyl. The "alkoxy" or "alkoxyalkyl"
radicals may be further substituted with one or more halo atoms,
such as fluoro, chloro or bromo, to provide "haloalkoxyl" or
"haloalkoxyalkyl" radicals. Examples of such radicals include
fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy,
fluoroethoxy and fluoropropoxy. The term "aryl", alone or in
combination, means a carbocyclic aromatic system containing one,
two or three rings wherein such rings may be attached together in a
pendent manner or may be fused. The term "aryl" embraces aromatic
radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and
biphenyl. The term "heterocyclic" embraces saturated, partially
saturated and unsaturated heteroatom-containing ring-shaped
radicals, where the heteroatoms may be selected from nitrogen,
sulfur and oxygen. Examples of saturated heterocyclic radicals
include saturated 3 to 6-membered heteromonocylic group containing
1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl,
piperidino, piperazinyl, etc.]; saturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially
saturated heterocyclic radicals include dihydrothiophene,
dihydropyran, dihydrofuran and dihydrothiazole. The term
"heteroaryl" embraces unsaturated heterocyclic radicals. Examples
of unsaturated heterocyclic radicals, also termed "heteroaryl"
radicals include unsaturated 5 to 6 membered heteromonocyclic group
containing 1 to 4 nitrogen atoms, for example, pyrrolyl,
pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.]
tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.;
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen
atoms, for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,
tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl, etc.],
etc.; unsaturated 3 to 6-membered heteromonocyclic group containing
an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.;
unsaturated 5 to 6-membered heteromonocyclic group containing a
sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated
5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen
atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,
oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,5-oxadiazolyl, etc.]etc.; unsaturated condensed heterocyclic
group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms
[e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to
6-membered heteromonocyclic group containing 1 to 2 sulfur, atoms
and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl
[e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,
etc.] etc.; unsaturated condensed heterocyclic group containing 1
to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,
benzothiadiazolyl, etc.] and the like. The term also embraces
radicals where heterocyclic radicals are fused with aryl radicals.
Examples of such fused bicyclic radicals include benzofuran,
benzothiophene, and the like. Said "heterocyclic group" may have 1
to 3 substituents such as lower alkyl, hydroxy, oxo, amino and
lower alkylamino. Preferred heterocyclic radicals include five to
ten membered fused or unfused radicals. More preferred examples of
heteroaryl radicals include benzofuryl, 2,3-dihydrobenzofuryl,
benzothienyl, indolyl, dihydroindolyl, chromanyl, benzopyran,
thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl,
pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. The
term "sulfonyl", whether used alone or linked to other terms such
as alkylsulfonyl, denotes respectively divalent radicals
--SO.sub.2--.
[0595] "Alkylsulfonyl" embraces alkyl radicals attached to a
sulfonyl radical, where alkyl is defined as above. More preferred
alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having
one to six carbon atoms. Examples of such lower alkylsulfonyl
radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
The term "arylsulfonyl" embraces aryl radicals as defined above,
attached to a sulfonyl radical. Examples of such radicals include
phenylsulfonyl. The terms "sulfamyl," "aminosulfonyl" and
"sulfonamidyl," whether alone or used with terms such as
"N-alkylaminosulfonyl", "N-arylaminosulfonyl",
"N,N-dialkylaminosulfon- yl" and "N-alkyl-N-arylaminosulfonyl",
denotes a sulfonyl radical substituted with an amine radical,
forming a sulfonamide (--SO.sub.2NH.sub.2). The terms
"N-alkylaminosulfonyl" and "N,N-dialkylaminosulfonyl" denote
sulfamyl radicals substituted, respectively, with one alkyl
radical, or two alkyl radicals. More preferred alkylaminosulfonyl
radicals are "lower alkylaminosulfonyl" radicals having one to six
carbon atoms. Examples of such lower alkylaminosulfonyl radicals
include N-methylaminosulfonyl, N-ethylaminosulfonyl and
N-methyl-N-ethylaminosulfonyl. The terms "N-arylaminosulfonyl" and
"N-alkyl-N-arylaminosulfonyl" denote sulfamyl radicals substituted,
respectively, with one aryl radical, or one alkyl and one aryl
radical. More preferred N-alkyl-N-arylaminosulfonyl radicals are
"lower N-alkyl-N-arylsulfonyl" radicals having alkyl radicals of
one to six carbon atoms. Examples of such lower N-alkyl-N-aryl
aminosulfonyl radicals include N-methyl-phenylaminosulfonyl and
N-ethyl-phenylaminosulf- onyl The terms "carboxy" or "carboxyl",
whether used alone or with other terms, such as "carboxalkyl",
denotes --CO.sub.2H. The terms "alkanoyl" or "carboxyalkyl" embrace
radicals having a carboxy radical as defined above, attached to an
alkyl radical. The alkanoyl radicals may be substituted or
unsubstituted, such as formyl, acetyl, propionyl (propanoyl),
butanoyl (butyryl), isobutanoyl (isobutyryl), valeryl (pentanoyl),
isovaleryl, pivaloyl, hexanoyl or the like. The term "carbonyl",
whether used alone or with other terms, such as "alkylcarbonyl",
denotes --(C.dbd.O)--. The term "alkylcarbonyl" embraces radicals
having a carbonyl radical substituted with an alkyl radical. More
preferred alkylcarbonyl radicals are "lower alkylcarbonyl" radicals
having one to six carbon atoms. Examples of such radicals include
methylcarbonyl and ethylcarbonyl. The term "alkylcarbonylalkyl",
denotes an alkyl radical substituted with an "alkylcarbonyl"
radical. The term "alkoxycarbonyl" means a radical containing an
alkoxy radical, as defined above, attached via an oxygen atom to a
carbonyl radical. Preferably, "lower alkoxycarbonyl" embraces
alkoxy radicals having one to six carbon atoms. Examples of such
"lower alkoxycarbonyl" ester radicals include substituted or
unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
butoxycarbonyl and hexyloxycarbonyl. The term "alkoxycarbonylalkyl"
embraces radicals having "alkoxycarbonyl", as defined above
substituted to an alkyl radical. More preferred alkoxycarbonylalkyl
radicals are "lower alkoxycarbonylalkyl" having lower
alkoxycarbonyl radicals as defined above attached to one to six
carbon atoms. Examples of such lower alkoxycarbonylalkyl radicals
include methoxycarbonylmethyl, tert-butoxycarbonylethyl, and
methoxycarbonylethyl. The term "aminocarbonyl" when used by itself
or with other terms such as "aminocarbonylalkyl",
"N-alkylaminocarbonyl", "N-arylaminocarbonyl",
"N,N-dialkylaminocarbonyl", "N-alkyl-N-arylaminocarbonyl",
"N-alkyl-N-hydroxyaminocarbonyl" and
"N-alkyl-N-hydroxyaminocarbonylalkyl", denotes an amide group of
the formula --C(.dbd.O)N.sub.2. The terms "N-alkylaminocarbonyl"
and "N,N-dialkylaminocarbonyl" denote aminocarbonyl radicals which
have been substituted with one alkyl radical and with two alkyl
radicals, respectively. More preferred are "lower
alkylaminocarbonyl" having lower alkyl radicals as described above
attached to an aminocarbonyl radical. The terms
"N-arylaminocarbonyl" and "N-alkyl-N-arylaminocarbonyl" denote
aminocarbonyl radicals substituted, respectively, with one aryl
radical, or one alkyl and one aryl radical. The term
"aminocarbonylalkyl" embraces alkyl radicals substituted with
aminocarbonyl radicals. The term "N-cycloalkylaminocarbonyl"
denoted aminocarbonyl radicals which have been substituted with at
least one cycloalkyl radical. More preferred are "lower
cycloalkylaminocarbonyl" having lower cycloalkyl radicals of three
to seven carbon atoms, attached to an aminocarbonyl radical. The
term "aminoalkyl" embraces alkyl radicals substituted with amino
radicals. The term "alkylaminoalkyl" embraces aminoalkyl radicals
having the nitrogen atom substituted with an alkyl radical. The
term "amidino" denotes an --C(.dbd.NH)--NH.sub.2 radical. The term
"cyanoamidino" denotes an --C(.dbd.N--CN)--NH.sub.2 radical. The
term "heterocyclicalkyl" embraces heterocyclic-substituted alkyl
radicals. More preferred heterocyclicalkyl radicals are "lower
heterocyclicalkyl" radicals having one to six carbon atoms and a
heterocyclic radical. Examples include such radicals as
pyrrolidinylmethyl, pyridylmethyl and thienylmethyl. The term
"aralkyl" embraces aryl-substituted alkyl radicals. Preferable
aralkyl radicals are "lower aralkyl" radicals having aryl radicals
attached to alkyl radicals having one to six carbon atoms. Examples
of such radicals include benzyl, diphenylmethyl, triphenylmethyl,
phenylethyl and diphenylethyl. The aryl in said aralkyl may be
additionally substituted with halo, alkyl, alkoxy, halkoalkyl and
haloalkoxy. The terms benzyl and phenylmethyl are interchangeable.
The term "cycloalkyl" embraces radicals having three to ten carbon
atoms. More preferred cycloalkyl radicals are "lower cycloalkyl"
radicals having three to seven carbon atoms. Examples include
radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
and cycloheptyl. The term "cycloalkenyl" embraces unsaturated
cyclic radicals having three to ten carbon atoms, such as
cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The
term "alkylthio" embraces radicals containing a linear or branched
alkyl radical, of one to ten carbon atoms, attached to a divalent
sulfur atom. An example of "alkylthio" is methylthio,
(CH.sub.3--S--). The term "alkylsulfinyl" embraces radicals
containing a linear or branched alkyl radical, of one to ten carbon
atoms, attached to a divalent --S(.dbd.O)-- atom. The term
"aminoalkyl" embraces alkyl radicals substituted with amino
radicals. More preferred aminoalkyl radicals are "lower aminoalkyl"
having one to six carbon atoms. Examples include aminomethyl,
aminoethyl and aminobutyl. The term "alkylaminoalkyl" embraces
aminoalkyl radicals having the nitrogen atom substituted with at
least one alkyl radical. More preferred alkylaminoalkyl radicals
are "lower alkylaminoalkyl" having one to six carbon atoms attached
to a lower aminoalkyl radical as described above. The terms
"N-alkylamino" and "N,N-dialkylamino" denote amino groups which
have been substituted with one alkyl radical and with two alkyl
radicals, respectively. More preferred alkylamino radicals are
"lower alkylamino" radicals having one or two alkyl radicals of one
to six carbon atoms, attached to a nitrogen atom. Suitable
"alkylamino" may be mono or dialkylamino such as N-methylamino,
N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The
term "arylamino" denotes amino groups which have been substituted
with one or two aryl radicals, such as N-phenylamino. The
"arylamino" radicals may be further substituted on the aryl ring
portion of the radical. The term "aralkylamino" denotes amino
groups which have been substituted with one or two aralkyl
radicals, such as N-benzylamino. The "aralkylamino" radicals may be
further substituted on the aryl ring portion of the radical. The
terms "N-alkyl-N-arylamino" and "N-aralkyl-N-alkylamino" denote
amino groups which have been substituted with one aralkyl and one
alkyl radical, or one aryl and one alkyl radical; respectively, to
an amino group. The terms "N-arylaminoalkyl" and
"N-aralkylaminoalkyl" denote amino groups which have been
substituted with one aryl radical or one aralkyl radical,
respectively, and having the amino group attached to an alkyl
radical. More preferred arylaminoalkyl radicals are "lower
arylaminoalkyl" having the arylamino radical attached to one to six
carbon atoms. Examples of such radicals include N-phenylaminomethyl
and N-phenyl-N-methylaminomethy- l. The terms
"N-alkyl-N-arylaminoalkyl" and "N-aralkyl-N-alkylaminoalkyl" denote
N-alkyl-N-arylamino and N-alkyl-N-aralkylamino groups,
respectively, and having the amino group attached to alkyl
radicals. The term "acyl", whether used alone, or within a term
such as "acylamino", denotes a radical provided by the residue
after removal of hydroxyl from an organic acid. The term
"acylamino" embraces an amino radical substituted with an acyl
group. An examples of an "acylamino" radical is acetylamino or
acetamido (CH.sub.3C(.dbd.O)--NH--) where the amine may be further
substituted with alkyl, aryl or aralkyl. The term "arylthio"
embraces aryl radicals of six to ten carbon atoms, attached to a
divalent sulfur atom. An example of "arylthio" is phenylthio. The
term "aralkylthio" embraces aralkyl radicals as described above,
attached to a divalent sulfur atom. An example of "aralkylthio" is
benzylthio. The term "aryloxy" embraces aryl radicals, as defined
above, attached to an oxygen atom. Examples of such radicals
include phenoxy. The term "aralkoxy" embraces oxy-containing
aralkyl radicals attached through an oxygen atom to other radicals.
More preferred aralkoxy radicals are "lower aralkoxy" radicals
having phenyl radicals attached to lower alkoxy radical as
described above. The term "haloaralkyl" embraces aryl radicals as
defined above attached to haloalkyl radicals. The term
"carboxyhaloalkyl" embraces carboxyalkyl radicals as defined above
having halo radicals attached to the alkyl portion. The term
"alkoxycarbonylhaloalkyl" embraces alkoxycarbonyl radicals as
defined above substituted on a haloalkyl radical. The term
"aminocarbonylhaloalkyl" embraces aminocarbonyl radicals as defined
above substituted on a haloalkyl radical. The term
"alkylaminocarbonylhaloalkyl" embraces alkylaminocarbonyl radicals
as defined above substituted on a haloalkyl radical. The term
"alkoxycarbonylcyanoalkenyl" embraces alkoxycarbonyl radicals as
defined above, and a cyano radical, both substituted on an alkenyl
radical. The term "carboxyalkylaminocarbonyl" embraces
aminocarbonyl radicals substituted with carboxyalkyl radicals, as
defined above. The term "aralkoxycarbonylalkylaminocarbonyl"
embraces aminocarbonyl radicals substituted with aryl-substituted
alkoxycarbonyl radicals, as defined above. The term
"cycloalkylalkyl" embraces cycloalkyl radicals having three to ten
carbon atoms attached to an alkyl radical, as defined above. More
preferred cycloalkylalkyl radicals are "lower cycloalkylalkyl"
radicals having cycloalkyl radicals attached to lower alkyl
radicals as defined above. Examples include radicals such as
cyclopropylmethyl, cyclobutylmethyl, and cyclohexylethyl. The term
"aralkenyl" embraces aryl radicals attached to alkenyl radicals
having two to ten carbon atoms, such as phenylbutenyl, and
phenylethenyl or styryl.
[0596] The present invention comprises a pharmaceutical composition
for the treatment of inflammation and inflammation-associated
disorders, such as arthritis, comprising a
therapeutically-effective amount of a compound of Formula I in
association with at least one pharmaceutically-acceptable carrier,
adjuvant or diluent.
[0597] The present invention also comprises a therapeutic method of
treating inflammation or inflammation-associated disorders in a
subject, the method comprising administering to a subject having
such inflammation or disorder a therapeutically-effective amount of
a compound of Formula I.
[0598] Also included in the family of compounds of Formula I are
the pharmaceutically-acceptable salts thereof. The term
"pharmaceutically-acceptable salts" embraces salts commonly used to
form alkali metal salts and to form addition salts of free acids or
free bases. The nature of the salt is not critical, provided that
it is pharmaceutically-acceptable. Suitable
pharmaceutically-acceptable acid addition salts of compounds of
Formula I may be-prepared from an inorganic acid or from an organic
acid. Examples of such inorganic acids are hydrochloric,
hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric
acid. Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and
sulfonic classes of organic acids, example of which are formic,
acetic, propionic, succinic, glycolic, gluconic, lactic, malic,
tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,
aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic,
salicyclic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic
(pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic,
pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,
cyclohexylaminosulfonic, stearic, algenic, .beta.-hydroxybutyric,
salicyclic, galactaric and galacturonic acid. Suitable
pharmaceutically-acceptable base addition salts of compounds of
Formula I include metallic salts made from aluminum, calcium,
lithium, magnesium, potassium, sodium and zinc or organic salts
made from N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine. All of these salts may be prepared by conventional means
from the corresponding compound of Formula I by reacting, for
example, the appropriate acid or base with the compound of Formula
I.
General Synthetic Procedures
[0599] The compounds of the invention can be synthesized according
to the following procedures of Schemes I-VIII, wherein the
R.sup.1-R.sup.7 substituents are as defined for Formula I, above,
except where further noted. 26
[0600] Synthetic Scheme I shows the preparation of tetresubstituted
pyrazoles from starting material 1. In step 1 of synthetic Scheme
I, the phenyl-methyl ketone (1) is treated with a base and an
alkylating reagent (R.sup.3X, where X represents a leaving group
such as tosyl) to give the substituted ketone (2). In step 2, the
substituted ketone (2) is treated with base, such as sodium
methoxide, and an acylating reagent such as an ester
(R.sup.2CO.sub.2CH.sub.3), or ester equivalent (R CO-imidazole, to
give the intermediate diketone (3) in a procedure similar to that
developed by Reid and Calvin, J. Amer. Chem. Soc., 72, 2948-2952
(1950). In step 3, the diketone (3) is reacted with a substituted
hydrazine in acetic acid or an alcoholic solvent to give a mixture
of pyrazoles (4) and (5). Separation of the desired pyrazole (4)
can be achieved by chromatography or recrystallization. 27
[0601] Synthetic Scheme II shows the preparation of compounds
embraced by Formula I, where R.sup.3 is a hydrogen atom. In step 1,
ketone (1) is treated with a base, preferably NaOMe or NaH, and an
ester, or ester equivalent, to form the intermediate diketone (6)
which is used without further purification. In step 2, diketone (6)
in an anhydrous protic solvent, such as absolute ethanol or acetic
acid, is treated with the hydrochloride salt or the free base of a
substituted hydrazine at reflux for 10 to 24 hours to afford a
mixture of pyrazoles (7) and (8). Recrystallization from diethyl
ether/hexane or chromatography affords (7), usually as a light
yellow or tan solid. 28
[0602] Synthetic Scheme III shows the procedure for preparation of
4,5-dihydrobenz[g]indazole compounds embraced by Formula I. In step
1, ethyl trifluoroacetate is reacted with base, such as 25% sodium
methoxide in a protic solvent, such as methanol, and a 1-tetralone
derivative (9) to give the intermediate diketone (10). In step 2,
the diketone (10) in an anhydrous protic solvent, such as absolute
ethanol or acetic acid, is treated with the free base or
hydrochloride salt of a substituted hydrazine at reflux for 24
hours to afford a mixture of pyrazoles (11) and (12).
Recrystallization gives the 4,5-dihydro benz[g]indazolyl-benzen-
esulfonamide (11). 29
[0603] Synthetic Scheme IV shows the preparation of pyrazole
compounds (13), where R.sup.3 is chlorine, from the available
pyrazole compounds (7), where R.sup.3 is hydrogen. Chlorination
results from passing a stream of chlorine gas at room temperature
through a solution containing (7). 30
[0604] Synthetic Scheme V shows the preparation of substituted
ketones 18 which are not commercially available as used in Scheme
I. The ketones can be prepared by standard Friedel-Craft acylation
of the starting substituted benzenes 14 with acid chlorides or
anhydrides 15. Alternatively, the ketones can be prepared from
phenylcarbonitriles 16 by standard organometallic techniques where
M represents metals such as lithium, magnesium, and the like. An
alternative organometallic route is shown from the aldehydes 17
where M represents metals such as lithium, magnesium, and the like.
Oxidation with a suitable oxidizing agent, such as CrO.sub.3,
follows to produce the ketones. 31
[0605] Synthetic Scheme VI shows an alternative regioselective
method of constructing the pyrazole 21. Commercially available
enones 19 can be epoxidized to give epoxyketones 20, which are
treated with 4-sulfonamidophenylhydrazine hydrochloride to provide
the pyrazole 21. 32
[0606] Synthetic Scheme VII shows the preparation of pyrazoles 23
(where R.sup.4 is 3-amino-4-substituted phenyl) from starting
material 22. Appropriate 5-(4-substituted aryl)pyrazoles can be
nitrated next to the R-group under standard nitration conditions
and the nitro group reduced to the amino group, preferably with
hydrazine and Pd/C. The amino compounds can be further manipulated
by alkylation of the amino group. 33
[0607] Synthetic Scheme VIII shows the preparation of pyrazoles 26
from esters 24. Reduction of the ester 24 to the alcohol,
preferably with lithium aluminum hydride (LAH) followed by
oxidation, preferably with MnO.sub.2, gives the aldehyde 25.
Various nucleophiles (such as hydroxamates and 1,3-dicarbonyl
compounds) can be condensed with the aldehyde to give the desired
oximes or olefins 26.
[0608] The following examples contain detailed descriptions of the
methods of preparation of compounds of Formulas I-II. These
detailed descriptions fall within the scope, and serve to
exemplify, the above described General Synthetic Procedures which
form part of the invention. These detailed descriptions are
presented for illustrative purposes only and are not intended as a
restriction on the scope of the invention. All parts are by weight
and temperatures are in Degrees centigrade unless otherwise
indicated. HRMS is an abbreviation for High resolution mass
spectrometry. In the following tables, "ND" represents "not
determined".
Example 1
[0609] 34
4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonami-
de
Step 1: Preparation of
4,4,4-trifluoro-1-[4-(chloro)phenyl]-butane-1.3-dio- ne
[0610] Ethyl trifluoroacetate (23.52 g, 166 mmol) was placed in a
500 mL three-necked round bottom flask, and dissolved in methyl
tert-butyl ether (75 mL). To the stirred solution was added 25%
sodium methoxide (40 mL, 177 mmol) via an addition funnel over a 2
minute period. Next 4'-chloroacetophenone (23.21 g, 150 mmol) was
dissolved in methyl tert-butyl ether (20 mL), and added to the
reaction dropwise over 5 minutes. After stirring overnight (15.75
hours), 3N HCl (70 mL) was added. The organic layer was collected,
washed with brine (75 mL), dried over MgSO.sub.4, filtered, and
concentrated in vacuo to give a 35.09 g of yellow-orange solid. The
solid was recrystallized from iso-octane to give 31.96 g (85%) of
the dione: mp 66-67.degree. C.
Step 2: Preparation of
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazo-
l-1-yl]benzenesulfonamide
[0611] 4-Sulphonamidophenylhydrazine hydrochloride (982 mg, 4.4
mmol 1.1 equivalent) was added to a stirred solution of
4,4,4-trifluoro-1-(4-(chlo- ro)phenyl]-butane-1,3-dione from Step 1
(1.00 g, 4.0 mmol) in ethanol (50 mL). The reaction was heated to
reflux and stirred for 20 hours. (HPLC area percent showed a 96:3
ratio of 4-[5-(4-chlorophenyl)-3-(trifluoromet-
hyl)-1H-pyrazol-1-yl]benzenesulfonamide to its regioisomer
(4-[3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfona-
mide). After cooling to room temperature, the reaction mixture was
concentrated in vacuo. The residue was taken up in ethyl acetate,
washed with water and with brine, dried over MgSO.sub.4, filtered,
and concentrated in vacuo to give a light brown solid which was
recrystallized from ethyl acetate and iso-octane to give the
pyrazole (1.28 g, 80%, mp 143-145.degree. C.). HPLC showed that the
purified material was a 99.5:0.5 mixture of
4-[5-(4-chlorophenyl)-3-(trifluorometh-
yl)-1H-pyrazol-1-yl]benzenesulfonamide to its regioisomer. .sup.1H
NMR (CDCl.sub.3/CD.sub.3OD 10/1) d 5.2 (s, 2H), 6.8 (s, 1H), 7.16
(d, j =8.5 Hz, 2H), 7.35 (d, j=8.5 Hz, 2H), 7.44 (d, j=8.66, 2H),
7.91 (d, j=8.66, 2H); .sup.13C NMR (CDCl.sub.3/CD.sub.3OD 10/1) d
106.42 (d, j=0.03 Hz), 121.0 (q, j=276 Hz), 125.5, 126.9, 127.3,
129.2, 130.1, 135.7, 141.5, 143.0, 143.9 (q, =37 Hz), 144.0;
.sup.19F NMR (CDCl.sub.3/CD.sub.3OD 10/1) d -62.9. EI GC-MS
M+=401.
Example 2
[0612] 35
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonami-
de
Step 1: Preparation of
1-(4-methylopenyl)-4.4.4-trifluorobutane-1.3-dione
[0613] 4'-methylacetophenone (5.26 g, 39.2 mmol) was dissolved in
25 mL of methanol under argon and 12 mL (52.5 mmol) sodium
methoxide in methanol (25%) was added. The mixture was stirred for
5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added.
After refluxing for 24 hours, the mixture was cooled to room
temperature and concentrated. 100 mL 10% HCl was added and the
mixture extracted with 4.times.75 mL ethyl acetate. The extracts
were dried over MgSO.sub.4, filtered and concentrated to afford
8.47 g (94%) of a brown oil which was carried on without further
purification.
Step 2: Preparation of
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazo-
l-1-yl]benzenesulfonamide
[0614] To the dione from Step 1 (4.14 g, 18.0 mmol) in 75 mL
absolute ethanol was added 4.26 g (19.0 mmol)
4-sulphonamidophenylhydrazine hydrochloride. The reaction was
refluxed under argon for 24 hours. After cooling to room
temperature and filtering, the reaction mixture was concentrated to
afford 6.13 g of an orange solid. The solid was recrystallized from
methylene chloride/hexane to give 3.11 g (8.2 mmol, 46%) of the
product as a pale yellow solid: mp 157-159.degree. C.; Anal. calc'd
for C.sub.17H.sub.14N.sub.3O.sub.2SF.sub.3: C, 53.54; H, 3.70; N,
11.02. Found: C, 53.17; H, 3.81; N, 10.90.
Example 3
[0615] 36
4-[5-(3,5-Dichloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be-
nzenesulfonamide
Step 1: Preparation of 3.5-dichloro-4-methoxyacetophenone
[0616] To a cooled solution (0.degree. C.) of 7.44 g (55.8 mmol)
AlCl.sub.3 in 25 mL of CH.sub.2Cl.sub.2 under argon was added 2.5
mL of acetic anhydride dropwise. After stirring for 0.5 hours, 4.18
g (23.6 mmol) of 2,6-dichloroanisole was added dropwise. The
reaction was stirred at 0.degree. C. for 1 hour, warmed to room
temperature and stirred for 12 hours. The reaction was poured into
6 mL conc. hydrochloric acid/80 mL ice water. The aqueous phase was
extracted with ethyl acetate (3.times.75 mL). The combined organic
washes were dried over MgSO.sub.4, filtered, and stripped to afford
the crude product as a yellow oil. NMR analysis showed that
acylation only occured para to the methoxy. The crude oil was used
without any further purification.
Steps 2 and 3: Preparation of
4-[5-(3.5-dichloro-4-methoxyphenyl]-3-(trifl-
uoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
[0617] The title compound was prepared in the same manner as
Example 2, Steps 1 and 2 and was purified on a prep plate eluting
with 10:1 hexane/ethyl acetate to afford a yellow solid: Anal.
calc'd for C.sub.17H.sub.12N.sub.3O.sub.3SF.sub.3Cl.sub.2.H.sub.2O:
C, 42.16; H, 2.91; N, 8.68. Found: C, 42.03; H, 2.54; N, 8.45.
Example 4
[0618] 37
4-[5-(3-Ethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide
Step 1: Preparation of 3-ethyl-4-methoxyacetophenone
[0619] AlCl.sub.3 (4.9 g, 36.8 mmol) was added to a solution of
2-ethylanisole (2.5 g, 18.4 mmol) in methylene chloride (50 mL).
Acetyl chloride (1.3 mL, 18.4 mmol) was added dropwise to the
reaction mixture, which was then stirred at reflux for 0.5 hours.
After cooling to room temperature, the reaction was poured over
crushed ice and followed up with a methylene chloride/water
extraction. The organic layer was dried over magnesium sulfate,
filtered and concentrated. The crude product was chromatographed on
a 4000 micron chromatotron plate with 10% ethyl acetate/90% hexane
as eluant to afford 2.3 g of desired material.
Steps 2 and 3: Preparation of
4-[5-(3-ethyl-4-methoxyphenyl)-3-(trifluorom-
ethyl)-1H-pyrazol-1-yl]benzenesulfonamide
[0620] The title compound was prepared using the procedure
described in Example 2, Steps 1 and 2: Anal. calcd for
C.sub.19H.sub.18N.sub.3O.sub.3S- F.sub.3: C, 53.64; H, 4.26; N,
9.88. Found: C, 53.69; H, 4.36; N, 9.88.
Example 5
[0621] 38
4-[5-(3-Methyl-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]ben-
zenesulfonamide
Step 1: Preparation of 2-methylthioanisole
[0622] Methyl iodide (0.5 mL, 8.1 mmol) and potassium carbonate
(1.1 g, 8.1 mmol) were added to a solution of o-thiocresol (1.0 g,
8.1 mmol) in 10 mL of DMF. The reaction was stirred at 50.degree.
C. for 4 hours and poured into hexane and water. The organic layer
was separated, dried over magnesium sulfate and concentrated to
afford 1.1 g of desired material.
Steps 2, 3 and 4: Preparation of
4-[5-(3-methyl-4-methylthiophenyl)-3-(tri-
fluoromethyl)-1H-pyrazo]-1-yl]benzenesulfonamide
[0623] The title compound was prepared using the procedures found
in Example 4, Steps 1, 2 and 3: Anal. calcd. for
C.sub.18H.sub.16N.sub.3O.su- b.2S.sub.2F.sub.3: C, 50.58; H, 3.77;
N, 9.83. Found: C, 50.84; H, 3.62; N, 9.62.
Example 6
[0624] 39
4-[5-(3-(3-Propenyl)-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide
Step 1: Preparation of 3-allyl-4-methoxyacetophenone
[0625] Potassium hydroxide (3.2 g, 56.8 mmol) was added to a
solution of 3-allyl-4-hydroxyacetophenone (10 g, 56.8) in 125 mL
THF. Dimethyl sulfate (excess) was added and the reaction was
stirred at 50.degree. C. for 16 hours. The reaction was cooled,
concentrated and poured into EtOAc and water. The organic layer was
separated and washed with dilute sodium hydroxide to get rid of
unreacted starting material. The ethyl acetate layer was dried and
concentrated to afford 9.2 g of 3-allyl-4-methoxy acetophenone.
Steps 2 and 3: Preparation of
4-[5-(3-(3-propenyl)-4-methoxyphenyl)-3-(tri-
fluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
[0626] The title compound was prepared using the procedures
described in Example 2, Steps 1 and 2: Anal. calc'd for
C.sub.20H.sub.18N.sub.3F.sub.3- O.sub.3S: C, 54.92; H, 4.15; N,
9.61. Found: C, 54.70; H, 4.12; N, 9.43.
Example 7
[0627] 40
4-[5-(3-Propyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzen-
esulfonamide
Step 1: Preparation of 3-n-propyl-4-methoxyacetophenone
[0628] To a solution of the product in Example 6, Step. 1 (3 g,
17.0 mmol) in 50 mL of ethanol was added a catalytic amount of 4%
Pd/C. The reaction mixture was stirred in a Parr shaker at room
temperature at 5 psi hydrogen for 0.5 hours. The reaction was
filtered and concentrated to afford 4 g of pure 3-propyl-4-methoxy
acetophenone.
Steps 2 and 3: Preparation of
4-[5-(3-n-propyl-4-methoxyphenyl)-3-(trifluo-
romethyl)-1H-pyrazol-1-yl]benzenesulfonamide
[0629] The title compound was prepared using the procedures
described in Example 2, Steps 1 and 2: Anal. calcd. for
C.sub.20H.sub.20N.sub.3F.sub.3- O.sub.3S: C, 54.66; H, 4.59; N,
9.56. Found: C, 54.84; H, 4.65; N, 9.52.
Example 8
[0630] 41
4-[5-(3-Cyclopropylmethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol--
1-yl]benzenesulfonamide
Step 1: Preparation of
3-cyclopropylmethyl-4-methoxyacetophenone
[0631] To a solution of the product in Example 6, Step 1 (3 g, 17.0
mmol) and catalytic Pd(OAc).sub.2 in 20 mL Et.sub.2O was added
ethereal diazomethane until starting material was consumed. The
reaction was filtered, concentrated and chromatographed on a 4000
micron chromatotron plate (20% EA/80% hexane as eluant) to afford
2.5 g of desired ketone.
Steps 2 and 3: Preparation of
4-[5-(3-cyclopropylmethyl-4-methoxyohenyl)-3-
-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
[0632] The title compound was prepared using the procedures
described in Example 2, Steps 1 and 2: Anal. calc'd. for
C.sub.21H.sub.20N.sub.3F.sub.- 3SO.sub.3: C, 55.87; H, 4.47; N,
9.31. Found: C, 55.85; H, 4.27; N, 9.30.
Example 9
[0633] 42
4-[4-Methyl-3-nitrophenyl)-3-(trifluoromethyl-1H-pyrazol-1-yl]benzenesulfo-
namide
[0634] To a solution of the product of Example 2 (500 mg, 1.31
mmol) in 5 mL of sulfuric acid was added nitric acid (0.6 mL, 1.31
mmol) and the reaction was stirred at room temperature for 0.5
hours. The mixture was poured over ice, the solid precipitate was
filtered and chromatographed on a 4000 micron plate (20% EtoAc/80%
hexane as eluant) to afford 410 mg of desired material: Anal.
calc'd for C.sub.17H.sub.13N.sub.4O.sub.4SF.su- b.3: C, 47.89; H,
3.07; N, 13.14. Found: C, 47.86; H, 2.81; N, 13.15.
Example 10
[0635] 43
4-[5-(3-Amino-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide
[0636] A catalytic amount of 10% Pd/C was added to a solution of
hydrazine hydrate (0.022 mL, 0.7 mmol) in 10 mL of ethanol. The
reaction mixture was refluxed for 15 minutes before the addition of
the compound from Example 9 (100 mg, 0.23 mmol), and the resulting
reaction mixture was refluxed for another 2 hours. The reaction was
cooled, filtered through Celite and concentrated to afford 100 mg
of title compound: Anal. calc'd for
C.sub.17H.sub.15N.sub.4O.sub.2SF.sub.3.0.5 CO.sub.2: C, 50.24; H,
3.61; N, 13.39. Found: C, 50.49; H, 3.44; N, 13.37.
Example 11
[0637] 44
4-[5-(4-Hydroxymethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide
Step 1: Preparation of
4-[5-(4-bromomethylphenyl)-3-(trifluoromethyl)-1H-p-
yrazol-1-yl]benzenesulfonamide
[0638] The product from Example 2 (1.13 g, 3.0 mmol) and
N-bromosuccinimide (NBS, 0.64 g, 3.6 mmol) were dissolved in 40 mL
of benzene and irradiated with a UV lamp for 3 hours. The reaction
was cooled to room temperature and poured into 50 mL of H.sub.2O.
The organic phase was separated, washed with brine and dried over
MgSO.sub.4. The crude pyrazole was obtained as an amber oil. The
oil was purified via radical band chromatography eluting with 30%
ethyl acetate/70% hexane to afford the 4-bromomethyl compound as a
yellow oil which crystallized upon standing.
Step 2: Preparation of
4-[5-(4-hydroxymethylphenyl)-3-(trifluoromethyl)-1H-
-pyrazol-1-yl]benzenesulfonamide
[0639] The bromo methyl compound from Step 1 was dissolved in 30 mL
of acetone/4 mL of H.sub.2O and refluxed for 120 hours. The
reaction was concentrated and the residue dissolved in 50 mL of
ethyl acetate and dried over MgSO.sub.4. The crude product was
obtained as an amber oil. The oil was purified via radial band
chromatography eluting with 30% ethyl acetate/70% hexane to afford
the title compound as a yellow solid: Anal. calc'd for
C.sub.17H.sub.14N.sub.3O.sub.3SF.sub.3: C, 51.38; H, 3.55; N,
10.57. Found: C, 51.28; H, 3.59; N, 10.31.
Example 12
[0640] 45
4-[1-(4-(Aminosulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoic
acid
[0641] To the product from Example 11 in 2 mL of acetone was added
1.33 M Jones reagent until an orange color persisted. The reaction
was poured into 20 mL of ethyl acetate and 20 mL of H.sub.2O and
the organic layer separated, washed with saturated sodium bisulfite
and dried over MgSO.sub.4. The crude product was filtered through
silica gel/Celite to afford the title compound as a yellow solid:
HRMS m/z 411.0507 (calc'd for C17H.sub.12N.sub.3O.sub.4SF.sub.3,
411.0500).
[0642] The following compounds in Table I were prepared according
to procedures similar to that exemplified in Examples 1-12, with
the substitution of the appropriate acetophenone.
1TABLE I 46 Ex. A M.P. (.degree. C.) Analytical 13 4-Br 137-139
Calc. C, 43.07; H, 2.48; N, 9.42; Br, 17.91 Obs. C, 43.01; H, 2.32;
N, 9.39; Br, 17.62 14 3-Cl 154-155 Calc. C, 47.83; H, 2.76;N,
10.46; Cl, 8.82 Obs. C, .47.61; H, 2.85; N, 10.31; Cl, 8.43 15 2-Cl
159-160 Calc. C, 47.83: H, 2.76; N, 10.46 Obs. C, 47.47; H, 2.65;
N, 10.31 16 4-CF.sub.3 144-145 Calc. C, 46.90; H, 2.55; N, 9.65
Found: C, 46.98; H, 2.57; N, 9.61 17 4-F 168-169 Calc. C, 49.87; H,
2.88; N, 10.90 Found: C, 49.83; H, 2.89; N, 10.86 18 H 164-165
Calc. C, 52.31; H, 3.29; N, 11.43 Found: C, 52.14; H, 3.07; N,
11.34 19 4-OCH.sub.3 153-154 Calc. C, 51.38; H, 3.55; N, 10.57
Found: C, 51.00; H, 3.48; N, 10.24 20 4-OCF.sub.3 101-103 Calc. C,
45.24; H, 2.46; N, 9.31 Found: C, 45.22; H, 2.37; N, 9.29 21
2-CH.sub.3 126-128 Calc. C, 53.54; H, 3.70; N, 11.02 Found: C,
53.52; H, 3.55; N, 11.06 22 2,4-di-F 127-130 M + H 404 23 2,6-di-F
178-180 M + H 404 24 4-CN 196-197.5 25 3,4-di-Cl 145-147 Calc. C,
44.05; H, 2.31; N, 9.63; Cl, 16.25 Found: C, 44.00; H, 2.20; N,
9.63; Cl, 16.46 26 2,4-di-Cl 153-155 Calc.C, 43.87; H, 2.35; N,
9.59 Found: C, 43.78; H, 2.13; N, 9.56 27 4-NO.sub.2 169-172 (dec)
Calc. C, 46.61; H, 2.69; N, 13.59; S, 7.78 Obs. C, 46.52; H, 2.67;
N, 13.51; S, 7.84 28 2-F 165-166 Calc. C, 49.87; H, 2.88; N, 10.90
Found: C, 49.49; H, 2.62; N, 10.79 29 4-NH.sub.2 124-127 (dec)
HRMS: 382.0671 30 4-F, 2-CH.sub.3 170-171 Calc. C, 51.13; H, 3.28;
N, 10.52 Found: C, 50.83, H, 2.98; N, 10.55 31 3-CH.sub.3 135-137
Calc. C, 53.54; H, 3.70; N, 11.02 Found: C, 53.15; H, 3.58; N,
10.96 32 4-OCH.sub.2CH.sub.3 141-142 Calc. C, 51.43; H, 4.08; N,
9.99 Found: C, 51.49; H, 3.80; N, 10.08 33 4-OCH.sub.3,
3,5-di-CH.sub.3 143-144 Calc. C, 53.64; H, 4.26; N, 9.87 Found: C,
53.49; H, 4.39; N, 9.64 34 3-F 143-144 Calc. C, 49.87; H, 2.88; N,
10.90 Found: C, 49.80; H, 2.80; N, 10.84 35 4-OCH.sub.3, 3-F
155-156 Calc. C, 49.16; H, 3.15; N, 10.11 Found: C, 48.77; H, 2.93;
N, 9.96 36 4-SCH.sub.3 165-166 Calc. C, 49.39; H, 3.41; N, 10.16
Found: C, 49.48; H, 3.46; N, 10.26 37 4-Cl, 3-CH.sub.3 ND Calc. C,
49.10; H, 3.15; N, 10.11 Found: C, 49.00; H, 3.00; N, 10.10 38
4-CH.sub.2CH.sub.3 ND Calc. C, 54.68; H, 4.08; N, 10.63 Found: C,
54.54; H, 3.73; N, 10.67 39 2,4-di-CH.sub.3 ND Calc. C, 54.68; H,
4.08; N, 10.63 Found: C, 54.31; H, 4.32; N, 10.39 40 2-OCH.sub.3
167-168 Calc. C, 51.38; H, 3.55; N, 10.57 Found: C, 51.29; H, 3.34;
N, 10.52 41 4-OCH.sub.3, 3-CH.sub.3 146-147 42 4-SCH.sub.3, 3-Br
141-144 HRMS: 490.9595 43 4-CH.sub.3, 3-Cl 186-190 Calc. C, 49.10;
H, 3.15; N, 10.11 Found: C, 49.21;H, 3.17; N, 10.10 44
3,4-di-OCH.sub.3 192-193 Calc. C, 50.58; H, 3.77; N, 9.83 Found: C,
50.58; H, 3.83; N, 9.72 45 4-OCH.sub.3, 3-Cl 166-168 Calc. C,
47.29; H, 3.03; N, 9.73 Found: C, 47.21; H, 2.91; N, 9.55 46
4-OCH.sub.3, 3-Cl, 5-CH.sub.3 ND Calc. C, 48.49; H, 3.39; N, 9.42
Found: C, 48.27; H, 3.42; N, 9.22 47 2-OCH.sub.3, 4-F 163-164 Calc.
C, 49.16; H, 3.15; N, 10.12 Found: C, 49.32; H, 3.27; N, 10.18 48
2,4-di-OCH.sub.3 ND Calc. C, 50.58; H, 3.77; N, 9.83 Found: C,
50.40; H, 3.78; N, 9.83 49 4-F, 3-Cl ND Calc. C, 45.78; H, 2.40; N,
10.01 Found: C, 45.75; H, 2.34; N, 10.15 50 4-OCH.sub.3, 3,5-di-F
ND Calc. C, 47.12; H, 2.79; N, 9.70 Found: C, 46.72; H, 2.75; N,
9.54 51 4-SCH.sub.3, 3-F ND Calc. C, 47.33; H, 3.04; N, 9.74 Found:
C, 47.25; H, 3.39; N, 9.45 52 4-SCH.sub.3, 3-Cl ND Calc. C, 45.59;
H, 2.93; N, 9.38 Found: C, 45.56; H, 2.76; N, 9.52 53
4-N(CH.sub.3).sub.2 ND HRMS: 410.1016 54
4-N(CH.sub.2CH.sub.3).sub.2 ND HRMS: 438.1353
Example 55
[0643] 47
4-[5-(4-Hydroxy-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzen-
esulfonamide
[0644] To a solution of the product of Example 41 (240 mg, 0.58
mmol) in DMF (3 mL) was added NaSMe (205 mg, 2.9 mmol) and the
mixture heated to reflux for 2 hours. The mixture was cooled,
poured into 0.1N HCl and extracted with EtOAc (3.times.). The
combined extracts were dried over mgSO.sub.4 and concentrated.
Flash chromatography using 1:1 hexane/ethyl acetate provided 31 mg
of the title compound: Anal. calc'd for
C.sub.17H.sub.14N.sub.3O.sub.3SF.sub.3.0.25H.sub.2O: C, 50.80; H,
3.64; N, 10.45. Found: C, 50.71; H, 3.47; N, 10.39.
Example 56
[0645] 48
4-[5-(4-(N-Methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide
[0646] To a solution of the product from Example 53 (431 mg, 1.0
mmol) in 10 ml methanol was added 36 mg (0.17 mmol) ruthenium (III)
chloride hydrate, followed by 1.5 mL 30% hydrogen peroxide (14.7
mmol) over 2 hours. The reaction was quenched with 25 mL of 1M KOH
in methanol and concentrated to give 1.24 g of a brown solid. The
solid was purified on a prep plate eluting with 2/97/1
methanol/methylene chloride/ammonium chloride to give 52 mg (0.14
mmol, 12%) of the product as a yellow solid.
Example 57
[0647] 49
N-[4-[1-[4-(Aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-S-yl]phen-
yl]-N-methylacetamide
[0648] 19 mg (0.051 mmol) of the product from Example 56 was
treated with 0.03 mL acetic anhydride (0.32 mmol) and 0.03 mL
triethylamine (0.22 mmol) in 3 mL methylene chloride at room
temperrature for 12 hours. The reaction mixtured was concentrated
and the residue dissolved in 10 mL ethyl acetate. After washing
with brine (2.times.10 mL), the solution was dried over MgSO.sub.4,
filtered and concentrated to afford the title compound (18.4 mg,
74%) as a yellow solid: HRMS m/e 438.0976 (calc'd for
C.sub.19H.sub.17N.sub.4O.sub.3SF.sub.3, 438.0974).
Example 58
[0649] 50
4-[5-(4-Chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamid-
e
Step 1: Preparation of
4.4-difluoro-1-[4-(chloro)phenyl]-butane-1.3-dione.
[0650] Ethyl difluoroacetate (24.82 g, 200 mmol) was placed in a
500 mL three-necked round bottom flask, and dissolved in diethyl
ether (200 mL). To the stirred solution was added 25% sodium
methoxide in methanol (48 mL, 210 mmol) via an addition funnel over
a 2 minute period. Next, 4'-chloroacetophenone (25.94 g, 200 mmol)
was dissolved in diethyl ether (50 mL), and added to the reaction
dropwise over 5 minutes. After stirring overnight (18 hours), 1N
HCl (250 mL) and ether (250 mL) were added. The organic layer was
collected, washed with brine (250 mL), dried over MgSO4, filtered,
and concentrated in vacuo to give 46.3 g of a yellow solid. The
solid was recrystallized from methylene chloride and iso-octane to
give 31.96 g (69%) of the dione: mp 65-66.5.degree. C.
Step 2: Preparation of 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1
h-pyrazol-1-yl]benzenesulfonamide
[0651] 4-Sulphonamidophenylhydrazine hydrochloride (1.45 g, 6.5
mmol 1.3 equivalent) and
4,4-difluoro-1-[4-(chloro)phenyl]butane-1,3-dione from Step 1 (1.16
g, 5 mmol) were dissolved in ethanol (10 mL). The reaction was
heated to reflux and stirred for 20 hours. After cooling to room
temperature, the reaction mixture was concentrated in vacuo. The
residue was taken up in ethyl acetate (100 mL), washed with water
(100 mL) and with brine (100 mL), dried over MgSO.sub.4, filtered,
and concentrated in vacuo to give 1.97 g of a light brown solid
which was recrystallized from ethanol and water to give
4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyr-
azol-1-yl]benzenesulfonamide (1.6 g, 83%): mp 185-186.degree.
C.
Example 59
[0652] 51
4-[5-(3-Fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide
Step 1: Preparation of 3'-fluoro-4'-methoxyacetophenone.
[0653] Aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL)
were placed in a 2 L three-necked round bottom flask fitted with a
mechanical stirrer and cooled by means of an ice bath. To the
stirred solution acetyl chloride (51.0 g, 0.65 mol) was added
dropwise, maintaining the temperature between 5-10.degree. C. The
mixture was stirred for 10 minutes at 5.degree. C. before the
dropwise addition at 5-10.degree. C. of 2-fluoroanisole (62.6 g,
0.5 mol). The mixture was stirred at 0-10.degree. C. for 1 hour and
poured into ice (1 L). The resultant layers were separated and the
aqueous layer was extracted with dichloromethane (2.times.250 mL).
The combined organic layers were washed with water (2.times.150
mL), dried over anhydrous MgSO.sub.4, filtered and concentrated in
vacuo to a volume of 300 mL. Hexanes were added and a white solid
formed which was isolated by filtration and air dried. This
material was recrystallized from a mixture of dichloromethane and
hexanes to afford (77.2 g, 92%) of material suitable for use in the
next step: mp 92-94.degree. C.; .sup.1H NMR (DMSO-d.sub.6) 7.8 (m,
2H), 7.3 (t, 1H), 3.9 (s, 3H), 2.5 (s, 3H).
Step 2: Preparation of
4,4-difluoro-1-(3-fluoro-4-methoxyphenyl)-butane-1.- 3-dione.
[0654] Ethyl difluoroacetate (4.06 g, 32.7 mmol) was placed in a
250 mL Erlenmeyer flask, and dissolved in methyl tert-butyl ether
(50 mL). To the stirred solution was added 25% sodium methoxide
(7.07 g, 32.7 mmol) followed by 3'-fluoro-4'-methoxyacetophenone
from Step 1 (5.0 g, 29.7 mmol). After stirring for 16 hours, 1N HCl
(50 mL) was added. The organic layer was collected, washed with
water (2.times.50 mL), dried over anhydrous MgSO.sub.4, filtered,
and added to hexanes to precipitate a tan solid (7.0 g, 96%). mp
70-72.degree. C.; .sup.1H NMR (DMSO-d.sub.6) 8.0 (m, 3H), 7.3 (t,
1H), 6.9 (s, 1H), 6.5 (t, 1H), 3.9 (s, 3H).
Step 3: Preparation of
4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)--
1H-pyrazol-1-yl]benzenesulfonamide
[0655] 4,4-Difluoro-1-(3-fluoro-4-methoxyphenyl)butane-1,3-dione
from Step 2 (7.0 g, 28.4 mmol) was dissolved in ethanol (150 mL).
To the stirred mixture was added 4-sulphonamidophenylhydrazine
hydrochloride (7.4 g, 33 mmol) and stirred at reflux overnight (16
hours). The mixture was cooled and water was added until crystals
slowly appeared. The product was isolated by filtration and air
dried to provide the desired product as a light tan solid (9.8 g,
87%): mp 159-161.degree. C.; .sup.1H NMR (DMSO-d.sub.6) 7.85 (d,
2H), 7.5 (m, 6H), 7.3-6.9 (m, 5H), 3.8 (s 3H). Anal. Calc'd for
C.sub.17H.sub.14N.sub.3SO.sub.3F.sub.3: C, 51.38; H, 3.55; N,
10.57. Found: C, 51.46; H, 3.52; N, 10.63.
Example 60
[0656] 52
4-[3-Difluoromethyl-5-(4-methoxyphenyl)-1-H-pyrazol-1-yl]benzenesulfonamid-
e
Step 1. Preparation of
4.4.4-trifluoromethyl-1-(4-methoxyphenyl)butane-1,3- -dione
[0657] To a stirred solution of 4-methoxyacetophenone (11.43 g,
76.11 mmol) and ethyl difluoroacetate (8.4 mL, 10.4 g, 83.72 mmol)
in diethyl ether (300 mL) in a 500 mL round bottomed flask was
added sodium methoxide in methanol (18.2 mL of a 25% solution,
79.91 mmol). The solution became a dark lavender color within
thirty minutes, and then a gray suspension within 1.5 hours. The
reaction was stirred for 60 hours. Diethyl ether (300 mL) was added
and the mixture was acidified (pH 2) with 1N HCl. The mixture was
transferred to a separatory funnel, mixed and separated. The
ethereal phase was washed with water, dried over magnesium sulfate,
and filtered. Hexane was added causing precipitation of an orange
solid 5.25 g of 4,4,4-trifluoromethyl-1-(4-methoxyphenyl)but-
ane-1,3-dione. An additional 3.43 g of product was obtained by
recrystallization of the concentrated mother liquor from hexane:
.sup.1H NMR (CDCl.sub.3) 400 mHz 15.58 (br s, 1H), 7.94 (d, J=8.87
Hz, 2H), 6.98 (d, J=8.87 Hz, 2H), 6.49 (S., 1H), 6.00 (t, J=54.55
Hz, 1H), 3.89 (s, 3H).
Step 2. Preparation of
4-[5-(4-methoxyphenyl)-3-difluoromethyl-1-H-pyrazol-
-1-yl]benzenesulfonamide
[0658] A mixture of
4,4,4-trifluoromethyl-1-(4-methoxyphenyl)butane-1,3-di- one from
Step 1 (2.006 g, 8.79 mmol) and 4-sulfonamidophenylhydrazine
hydrochloride salt (2.065 g, 9.23 mmol) dissolved in ethanol (25
mL) was heated to reflux for 16 hours. The reaction was cooled to
room temperature, was concentrated and recrystallized from methanol
yielding
4-[5-(4-methoxyphenyl)-3-difluoromethyl-1-H-pyrazol-1-yl]benzenesulfonami-
de as fluffy tan crystals (1.49 g, 45%): mp 133-135.degree. C.;
.sup.1H NMR (CDCl.sub.3) 300 mHz 7.90 (d, J=8.863 Hz, 2H), 7.45 (d,
J=8.863 Hz, 2H), 7.14 (d, J=8.863 Hz, 2H), 6.88 (d, J=8.863 Hz,
2H), 6.77 (t, J=56.47 Hz, 1H), 6.68 (s, 1H), 4.96 (br s, 2H), 3.83
(s, 3H); .sup.19NMR (CDCl.sub.3) 300 mHz -112.70 (d, J=57.9 Hz).
High resolution mass spectrum Calc'd for
C.sub.17H.sub.15F.sub.2N.sub.3O.sub.3S: 379.0802. Found: 379.0839.
Elemental analysis calc'd for C.sub.17H.sub.15F.sub.2N.s-
ub.3O.sub.3S: C, 53.82; H, 3.99; N, 11.08. Found: C, 53.75; H,
3.99; N, 11.04.
[0659] The following compounds in Table II were obtained according
to procedures similar to that exemplified in. Examples 58-60, with
the substitution of the appropriate acetophenone.
2TABLE II 53 Ex. A M.P. (.degree. C.) Anal. 61 4-CF.sub.3 202-205 M
+ H 418 62 4-SCH.sub.3 157-158 63 4-(1-morpholino) 167-171 M + 434
64 4-CH.sub.3 158-159 Calc. C, 56.19; H, 4.16; N, 11.56 Obs. C,
56.25; H, 4.17; N, 11.61 65 3,4-di-CH.sub.3 168-171 Calc. C, 57.28;
H, 4.54; N, 11.13 Obs. C, 57.34; H, 4.59; N, 11.16 66
4-CO.sub.2CH.sub.3 157-158 Calc. C, 53.56; H, 3.09; N, 15.61 Obs.
C, 53.45; H, 3.11; N, 15.62 67 4-CONH.sub.2 235-236 HRMS: 393.0833
68 4-CO.sub.2H 258-260 (dec) HRMS: 394.0662 69 2-F, 4-OCH.sub.3
138-140 Calc. C, 51.38; H, 3.55; N, 10.57 Obs. C, 51.14; H, 3.48;
N, 10.40 70 4-CN 222-224 Calc. C, 54.54; H, 3.23; N, 14.97 Obs.: C,
54.58; H, 3.21; N, 15.06 71 3-Cl, 4-CH.sub.3 156-158 Calc. C,
51.32; H, 3.55; N, 10.56 Obs: C, 51.46; H, 3.53; N, 10.53 72 3-Cl,
4-OCH.sub.3 160 Calc. C, 49.34; H, 3.41; N, 10.15; Cl, 8.57; S,
7.75 Obs.: C, 49.41; H, 3.37; N, 10.17; Cl, 8.62; S, 7.67 73 4-Cl,
3-CH.sub.3 163-165 Calc. C, 51.32; H, 3.55; N, 10.56 Obs.: C,
51.42; H, 3.57; N, 10.53 74 3,4-di-OCH.sub.3 181-185 Calc. C,
52.81; H, 4.19; N, 10.26 Obs.: C, 52.86; H, 4.19; N, 10.20 75
3,5-di-Cl, 4-OCH.sub.3 170-173 Calc. C, 45.55; H, 2.92; N, 9.37
Obs.: C, 45.83; H, 3.05; N, 9.31 76 3,5-di-F, 4-OCH.sub.3 149-150
Calc. C, 49.16; H, 3.15; N, 10.12 Obs.: C, 49.24; H, 3.16; N, 10.13
77 2-OCH.sub.3 129-132 Calc. C, 53.82; H, 3.99; N, 11.08 Obs.: C,
53.82; H, 3.97; N, 11.15 78 3-Br, 4-OCH.sub.3 164 HRMS: 456.9883 79
4-SO.sub.2CH.sub.3 209-210 80 4-C.sub.6H.sub.5 167-170 M + 425 81 H
171-172 HRMS: 349.0737
Example 82
[0660] 54
4-[5-(1,3-Benzodioxol-5-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulf-
onamide
Step 1. Preparation of
1-(1.3-benzodioxol-5-yl)-4,4-difluorobutane-1.3-dio- ne.
[0661] Ethyl difluoroacetate (1.72 g, 11 mmol) was dissolved in
ether (25 mL). To the stirred solution was added 25% sodium
methoxide (2.38 g, 11 mmol) followed by
3',4'-(methylenedioxy)acetophenone (1.64 g, 10 mmol). After
stirring 16 hours, 1N HCl (25 mL) was added. The organic layer was
collected and washed with water (2.times.25 mL), dried over
magnesium sulfate, filtered, and concentrated. The resulting crude
dione was used in the next step without further purification or
characterization.
Step 2. Preparation of
5-(1.3-benzodioxol-5-yl)-4-[3-(difluoromethyl)-1H-p-
yrazol-1-yl]benzenesulfonamide
[0662] 1-(1,3-Benzodioxol-5-yl)-4,4-difluorobutane-1,3-dione from
Step 1 (2.4 g, 10 mmol) was dissolved in ethanol (100 mL). To the
stirred mixture was added 4-sulfonamidophenylhydrazine
hydrochloride (2.46 g, 11 mmol) and heated to reflux for 16 hours.
The mixture was cooled and water was added until crystals slowly
appeared. Filtration yielded a light tan solid (3.3 g, 84%): mp
214-218.degree. C.; .sup.1H NMR (D6-DMSO): 7.86 (d, J=8.7 Hz, 2H),
7.51 (d, J=8.7 Hz, 2H), 7.49 (brs, 2H), 7.3-6.7 (m, 5H), 6.06 (s,
2H). Anal. Calc'd for C.sub.17H.sub.13N.sub.3SO.sub.4F.sub.- 2: C,
51.91; H, 3.33; N, 10.68. Found: C, 51.90; H, 3.25; N, 10.65.
Example 83
[0663] 55
4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic
acid
Step 1: Preparation of
methyl-4-[4-(chloro)phenyl]-2.4-dioxo-butanoate
[0664] Dimethyl oxalate (23.6 g, 200 mmol) was placed in a 500 mL
three-necked round bottom flask, and dissolved in diethyl ether
(200 mL). To the stirred solution was added 25% sodium methoxide in
methanol (48 mL, 210 mmol) via an addition funnel over a 2 minute
period. Next, 4'-chloroacetophenone (25.94 g, 200 mmol) was
dissolved in diethyl ether (50 mL), and added to the reaction
dropwise over 3 minutes. After stirring overnight (18 hours), 1N
HCl (400 mL) and ethyl acetate (750 mL) were added. The organic
layer was collected, washed with brine (350 mL), dried over MgSO4,
filtered, and concentrated in vacuo to give 45.7 g of a yellow
solid. The solid was recrystallized from ethyl acetate and
iso-octane to give 23 g (48%) of the dione: mp 108.5-110.5.degree.
C.
Step 2: Preparation of
4-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-p-
yrazole-3-carboxylic acid
[0665] 4-Sulphonamidophenylhydrazine hydrochloride (1.45 g, 6.5
mmol, 1.3 equivalent) and
methyl-4-[4-(chloro)phenyl]-2,4-dioxobutanoate (1.2 g, 5 mmol) were
dissolved in ethanol (50 mL). The reaction was heated to reflux and
stirred for 20 hours. After cooling to room temperature, the
reaction mixture was concentrated in vacuo. The residue was taken
up in ethyl acetate (200 mL) and washed with water (100 mL) and
brine (100 mL), dried over MgSO.sub.4, filtered and concentrated in
vacuo to give 1.7 g of a light brown solid which was recrystallized
from methanol and water to yield 1.6 g (85%) of a white solid. This
material was dissolved in methanol (150 mL) and 3N NaOH (75 mL) and
stirred at reflux for 3 hours. The methanol was removed in vacuo
and the aqueous solution acidified with concentrated HCl. The
product was extracted into ethyl acetate (200 mL), which was washed
with brine (100 mL), dried over MgSO.sub.4 filtered and
concentrated to give
4-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-py-
razole-3-carboxylic acid, 1.4 g (74%): mp 135.degree. C. (dec).
Example 84
[0666] 56
Methyl
1-(4-aminosulfonylphenyl)-5-(3,5-difluoro-4-methoxyphenyl)-1-H-pyra-
zole-3-carboxylate
Step 1. Preparation of 3.5-difluoro-4-methoxyacetophenone.
[0667] To a stirred suspension of AlCl.sub.3 (24.05 g, 180.40 mmol)
in chloroform (300 mL, dried by passage through alumina) at
4.degree. C. (ice bath) under nitrogen was added acetyl chloride
(11.0 mL, 152.65 mmol) over 20 minutes. This chilled suspension was
stirred at 0.degree. C. for 30 minutes and 2,6-difluoro anisole was
added dropwise over 30 minutes. The resulting suspension was warmed
to room temperature and stirred overnight. The reaction was
quenched by slowly pouring it into a rapidly stirred ice/water
mixture. The water layer was extracted with methylene chloride
(2.times.50 mL) and the organic phases were combined and
concentrated in vacuo yielding a clear mobile oil. In a 50 mL round
bottomed flask was added the above clear oil, DMF (25 mL),
K.sub.2CO.sub.3 (15 g). Methyl iodide (6 mL) was added and the
suspension stirred at 45.degree. C. under nitrogen overnight. Water
(1 mL) was added and the mixture was heated for an additional 14
hours. The crude reaction mixture was cooled to room temperature,
diluted with water (250 mL) and extracted with diethyl ether
(3.times.100 mL). The ether phase was washed with sodium
bicarbonate saturated solution, potassium bisulfate (0.1 N
solution), dried over MgSO.sub.4, filtered and concentrated in
vacuo yielding a clear mobile liquid. This liquid was distilled
(30.degree. C., 1 mm) yielding 12.5 g of a clear liquid which was a
mixture of 3,5-difluoro-4-methoxyacetophenone and
3,5-difluoro-4-acetoxyacetophenone in an 85:15 ratio. The yield
based upon this ratio was 41%. This ketone was used as is.
Step 2. Preparation of methyl
1-(4-aminosulfonylhenyl)-5-(3.5-difluoro-4-m-
ethoxyphenyl)-1-H-pyrazole-3-carboxylate
[0668] To a stirred solution of 3,5-difluoro-4-methoxyacetophenone
from Step 1 (6.46 g, 34.70 mmol) and dimethyl oxalate (6.15 g,
52.05 mmol) in methanol (80 mL), was added sodium methoxide
solution (13.4 mL of 25% solution, 58.99 mmol) in one portion and
the reaction stirred overnight. The crude reaction was diluted with
methylene chloride, washed with potassium bisulfate (0.1N
solution), brine, dried over MgSO.sub.4, filtered, and concentrated
in vacuo yielding methyl
4-(3,5-difluoro-4-methoxyphenyl)-2,4-dioxo-butanoate as an off
white crystalline solid which was used as is. A mixture of
4-(3,5-difluoro-4-methoxyphenyl)-2,4-dioxo-butanoate and
4-sulfonamidophenylhydrazine hydrochloride salt (7.76 g, 34.70
mmol) dissolved in methanol was warmed to reflux for 9 hours. Upon
allowing the clear reaction to cool to room temperature, a
crystalline precipitate formed which was collected by vacuum
filtration yielding 5.45 g, (37% based upon the
3,5-difluoro-4-methoxyacetophenone) of methyl
1-(4-aminosulfonylphenyl)-5-(3,5-difluoro-4-methoxyphenyl)-1-H-pyrazole-3-
-carboxylate as an off-white solid: mp 185-190.degree. C.; .sup.1H
NMR (CDCl.sub.3/300 mHz) 7.95 (d, J=8.86, 2H), 7.49 (d, J=8.86,
2H), 7.02 (s, 1H), 6.77 (m, 2H), 4.99 (s, 2H), 4.04 (s, 3H), 3.98
(s, 3H); .sup.19F NMR (CDCl.sub.3/300 mHz) -126.66. Anal. Calc'd
for C.sub.17H.sub.13F.sub.2N.s- ub.3O.sub.3S: C, 51.06; H, 3.57; N,
9.92. Found: C, 51.06; H, 3.54, N, 9.99.
Example 85
[0669] 57
Methyl
[1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carb-
oxylate
Step 1. Preparation of methyl
4-[4-(chloro)phenyl]-2,4-dioxo-butanoate
[0670] Dimethyl oxalate (15.27 g, 0.129 mol) and
4'-chloroacetophenone (20.0 g, 0.129 mol) were charged to a 500 mL
round-bottom flask, with provisions made for magnetic stirring, and
diluted with methanol (300 mL). Sodium methoxide (25% in methanol,
70 mL) was added in one portion. The reaction was stirred at room
temperature for 16 hours. The reaction became an insoluble mass
during this time. The solid was mechanically broken up, then
concentrated hydrochloric acid (70 mL) was added, and the white
suspension was stirred vigorously at room temperature for sixty
minutes. The suspension was cooled to 0.degree. C. and held for 30
minutes. The soild was filtered, and the filter cake was washed
with cold water (100 mL). Upon drying, methyl
4-[4-(chloro)phenyl]-2,4-dioxobutanoa- te was obtained (16.94 g,
54.4%) as the enol: .sup.1H NMR (CDCl.sub.3/300 MHz) 7.94 (d,
J=8.66 Hz, 2H), 7.48 (d, J=8.66 Hz, 2H), 7.04 (s, 1H), 3.95 (s,
3H), 3.48 (s, 1H).
Step 2. Preparation of methyl
fl-(4-aminosulfonylthenyl)-5-(4-chlorophenyl-
)-1H-pyrazole-3-yl]carboxylate
[0671] A 100 mL round-bottomed flask equipped with magnetic stirrer
and nitrogen inlet was charged with methyl
4-[4-(chloro)phenyl]-2,4-dioxobuta- noate from Step 1 (5.0 g, 20.78
mmol), 4-sulfonamidylphenylhydrazine hydrochloride (5.11 g, 22.86
mmol) and methanol (50 mL). The reaction vessel was heated to
reflux and held for 16 hours. A precipitate formed overnight. The
suspension was cooled to 0.degree. C., held for 0.5 hour, filtered
and washed with cold water to provide, after air-drying, 7.91 g
(91%) of crude product. Recrystallized 3.50 g from boiling ethanol
to yield 3.14 g (97%) of pure methyl
[1-(4-aminosulfonylphenyl)-5-(4-chlorop-
henyl)-1H-pyrazole-3-yl]carboxylate: mp 227.degree. C.; .sup.1H NMR
(CDCl.sub.3/300 MHz) 7.91 (d, J=8.86 Hz, 2H), 7.44 (d, J=8.86 Hz,
2H), 7.33 (d, J=8.66 Hz, 2H), 7.14 (d, J=8.66 Hz, 2H), 7.03 (s,
1H), 3.96 (s, 3H). Mass Spectrum, MH.sup.+=392. Anal. Calc'd for
C.sub.17H.sub.14N.sub.3O.sub.4ClS: C, 52.11; H, 3.60; N, 10.72; Cl,
9.05; S, 8.18. Found: C, 52.07; H, 3.57; N, 10.76; Cl, 9.11; S,
8.27.
Example 86
[0672] 58
Ethyl
[1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carbo-
xylate
[0673] Methyl
[1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3--
yl]carboxylate (Example 85) (0.10 g) was dissolved in absolute
ethanol (10 mL) and a catalytic amount of 21% NaOEt/EtOH was added.
The reaction was stirred without temperature control for 72 hours,
then water (10 mL) was added. The product crystallized, the
suspension was cooled to 0.degree. C. and held for 30 minutes. The
product was filtered, washed with water (5 mL) and dried to yield
0.071 g (70%) of a white solid: Mass Spectrum: MH+=406. Anal.
Calc'd for C.sub.18H.sub.16N.sub.3O.sub.4ClS: C, 53.27; H, 3.97; N,
10.35; Cl, 8.74; S, 7.90. Found: C, 53.04; H, 4.00; N, 10.27; Cl,
8.69; S, 7.97.
[0674] The following compounds in Table III were prepared according
to procedures similar to that exemplified in Examples 83-86, with
the substitution of the appropriate reagents.
3TABLE III 59 Ex. A B M.P. (.degree. c.) Analytical. 87 4-NO.sub.2
--CH.sub.3 216-220 MH+ = 403 88 4-F --CH.sub.3 ND Calc. C, 54.40;
H, 3.76; N, 11.19; S, 8.54 Obs. C, 54.49; H, 3.70; N, 11.25; S,
8.50 89 4-NH.sub.2 --CH.sub.3 267-269 (dec) MH+ = 373 90 4-Br
--CH.sub.3 221-224 MH+ = 438 91 4-OCH.sub.3 --CH.sub.3 169-171
HRMS: 387.0930 92 4-CH.sub.3 --CH.sub.3 213-215 HRMS: 371.0965 93
4-CH.sub.3 --CH.sub.2CH.sub.3 219-220 Calc. C, 59.21; H, 4.97; N,
10.90 Obs. C, 58.73; H, 4.96; N, 10.78 94 4-Cl
--CH.sub.2CH.sub.2CH.sub.3 ND Calc. C, 54.35; H, 4.32; N, 10.01;
Cl, 8.44; 8, 7.64 Obs. C, 54.11; H, 4.28; N, 10.14; Cl, 8.54; 8,
7.64 95 3,5-di-Cl, 4-OCH.sub.3 --CH.sub.3 225-229
Example 96
[0675] 60
4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide
[0676]
4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carbox-
ylic acid (Example 83) (1.08 g, 2.86 mmol), HOBt (0.66 g, 4.3 mmol)
and EDC (0.66 g, 3.4 mmol) were dissolved in dimethylformamide
(DMF) (20 mL) and stirred at ambient temperature for 5 minutes. To
this solution was added NH.sub.4OH (30%, 2.9 mL) and the reaction
stirred for an additional 18 hours. This solution was then poured
into ethyl acetate (200 mL) and 1N HCl (200 mL), shaken and
separated. The organic layer was washed with saturated NaHCO.sub.3
(150 mL) and brine (150 mL), dried over MgSO.sub.4, filtered and
concentrated to yield 0.9 g of a white solid which was
recrystallized from ethyl acetate and iso-octane to yield
4-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide
(0.85 g, 79%): mp 108-110.degree. C.
Example 97
[0677] 61
[1-(Aminosulfonylphenyl)-5-(4-fluorophenyl-1H-pyrazol-3-yl]carboxamide
[0678] A 250 mL three-neck round-bottom flask, equipped with a
thermometer, gas sparging tube, reflux condenser and provisions for
magnetic stirring, was charged with
methyl[1-(4-aminosulfonylphenyl)-5-(4-
-fluorophenyl)-1H-pyrazol-3-yl]carboxylate (Example 88) (3.0 g,
7.99 mmol), methanol (100 mL), and a catalytic amount of sodium
cyanide. Anhydrous ammonia gas was sparged through the reaction
vessel for 16 hours without temperature control. The suspension
turned a deep-red during this time. The reaction was sparged with
anhydrous nitrogen at room temperature for 20 minutes, cooled to
0.degree. C. and held for 30 minutes. The solid was filtered and
washed with cold water (50 mL) to yield, upon drying, 1.87 g (65%)
of [1-(4-aminosulfonylphenyl)-5-(4-fluor-
ophenyl)-1H-pyrazol-3-yl]carboxamide as a white solid: mp
214-216.degree. C.; .sup.1H NMR (CDCl.sub.3/CD.sub.3OD/300 MHz)
7.64 (d, J=8.66 Hz, 2H), 7.14 (d, J=8.66 Hz, 2H), 6.95 (m, 2H),
6.82-6.67 (m, 6H), 6.39(s, 1H); .sup.19F NMR
(CDCl.sub.3/CD.sub.3OD/282.2 MHz)-112.00(m). Mass spectrum,
MH+=361. Anal. Calc'd for C.sub.16H.sub.13N.sub.4O.sub.3FS: C,
53.33; H, 3.64; N, 15.55; S, 8.90. Found: C, 53.41; H, 3.69; N,
15.52; S, 8.96.
Example 98
[0679] 62
N-(3-Chlorophenyl)-[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazo-
l-3-yl]carboxamide
Step 1. Preparation of methyl
4-[4-fluorophenyl]-2,4-dioxobutanoate
[0680] Dimethyl oxalate (18.80 g, 0.159 mol) and
4'-fluoroacetophenone (20.0 g, 0.145 mol) were charged to a 1000 mL
round-bottom flask and diluted with methanol (400 mL). The reaction
flask was placed in a sonication bath (Bransonic 1200), and sodium
methoxide (25% in methanol, 70 mL) was added over 25 minutes. The
reaction was sonicated at 45.degree. C. for 16 hours. The reaction
became an insoluble mass during this time. The solid was
mechanically broken up, then poured into a hydrochloric acid
solution (1N, 500 mL). A magnetic stirrer was added, and the white
suspension was stirred vigorously at room temperature for 60
minutes. The suspension was cooled to 0.degree. C. and held for 30
minutes. The solid was filtered, and the filter cake was then
washed with cold water (100 mL). Upon drying, methyl
4-[4-fluorophenyl]-2,4-diketobut- anoate was obtained (22.91 g,
70.6%) as the enol: .sup.1H NMR (CDCl.sub.3/300 MHz) 8.03 (ddd,
J=8.86 Hz, 3=8.66 Hz, J=5.03 Hz, 2H), 7.19 (dd, J=8.86 Hz, J=8.66
Hz, 2H), 7.04 (s, 1H), 3.95 (s, 3H). .sup.19F NMR (CDCl.sub.3/282.2
MHz)-103.9 (m).
Step 2. Preparation of methyl
4-[1-(4-aminosulfonylphenyl)-5-(4-fluorophen-
yl)-1H-pyrazol-3-yl]carboxylate
[0681] A 500 mL one-neck round-bottom flask equipped for magnetic
stirring was charged with methyl
4-[4-fluorophenyl]-2,4-diketobutanoate from Step 1 (1.00 mg, 44.61
mmol), 4-sulfonamidylphenylhyrazine hydrochloride (10.98 g, 49.07
mmol) and methanol (200 mL). The suspension was heated and held at
reflux for three hours, then cooled to room temperature. The
suspension was cooled to 0.degree. C., held for 30 minutes,
filtered, washed with water (100 mL), and dried to yield 14.4 g
(86%) of methyl
4-[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxyla-
te as a white solid: .sup.1H NMR (CDCl.sub.3/300 MHz) 7.85 (d,
J=8.66 Hz, 2H), 7.36 (d, J=8.66 Hz, 2H), 7.18 (ddd, J=8.66 Hz,
J=8.46 Hz, J=4.85 Hz, 2H), 7.00 (dd, J=8.66 Hz, J=8.46 Hz, 2H),
6.28 (s, 1H), 3.90(s, 3H). .sup.19F NMR (CDCl.sub.3/282.2 MHz):
-111.4(m). Mass spectrum, MH.sup.+=376. Anal. Calc'd for
C.sub.17H.sub.14N.sub.3O.sub.4FS: C, 54.40; H, 3.76; N, 11.19; S,
8.54. Found: C, 54.49; H, 3.70; N, 11.25; S, 8.50.
Step 3. Preparation of
[1-(4-aminosulfonylphenyl)-5-(4-fluorolphenyl)-1H-p-
yrazol-3-yl]carboxylic acid
[0682] A 500 mL one-neck round-bottom flask, equipped with
provisions for magnetic stirring, was charged with methyl
4-[1-(4-aminosulfonylphenyl)-5-
-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylate from Step 2 (10.0 g,
26.64 mmol) and tetrahydrofuran (200 mL). Aqueous sodium hydroxide
(2.5N, 27 mL) and water (25 mL) were added, and the suspension was
heated to reflux and held for 16 hours. The solids all dissolved
during this time. The reaction was cooled to room temperature, and
hydrochloric acid solution (1N, 110 mL) was added. The aqueous
suspension was extracted with methylene chloride (2.times.200 mL).
The combined organic soultion was dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo to an oil. Trituration
with 300 mL of methylene chloride yielded, upon filtration and
drying, 9.0 g, (94%) of [1-(4-aminosulfonylphenyl)-5--
(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylic acid as a white solid:
mp 138-142.degree. C. (dec); .sup.1H NMR (CD.sub.3OD/300 MHz) 7.93
(d, J=8.66 Hz, 2H), 7.51 (d, J=8.66 Hz, 2H), 7.31 (ddd, J=8.86 Hz,
J=8.66 Hz, J=4.83 Hz, 2H), 7.11 (dd, J=8.86 Hz, J=8.66 Hz, 2H),
7.06 (s, 1H). .sup.19F NMR (CD.sub.3OD/282.2 MHz): -114.01(m).
Step 4. Preparation of
N-(3-chlorophenyl)-[1-(4-aminosulfonylphenyl)-5-(4--
fluorophenyl)-1H-pyrazol-3-yl]carboxamide
[0683] A 100 mL one-neck round-bottom flask, equipped with
provisions for magnetic stirring, was charged with
[1-(4-aminosulfonylphenyl)-5-(4-fluor-
ophenyl)-1H-pyrazol-3-yl]carboxylic acid from Step 3 (0.500 g, 1.38
mmol), 1-hydroxybenzotriazole hydrate (0.206 g, 1.522 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.318
g, 1.66 mmol) and N,N-dimethylformamide (30 mL). The solution was
stirred at room temperature for forty minutes, then 3-chloroaniline
(0.154 mL, 1.453 mmol) was added. The reaction was held at room
temperature for sixteen hours, then poured into an aqueous solution
of citric acid (5%, 100 mL). The aqueous solution was extracted
with ethyl acetate (2.times.60 mL), and the combined organic
solutions were washed with aqueous citric acid (60 mL), saturated
sodium bicarbonate solution (2.times.60 mL) and 50% saturated
sodium chloride solution (2.times.60 mL). The organic solution was
dried over anhydrous magnesium sulfate, filtered, and concentrated
in vacuo to an oil. Trituration with 20 mL of dichloromethane
yielded, upon filtration and drying, 0.439 g (67%) of
N-(3-chlorophenyl)-[1-(4-aminosul-
fonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxamide as a
white solid: mp 207-212.degree. C.; .sup.1H NMR
(CDCl.sub.3/CD.sub.3OD/300 MHz) 8.90 (s, 1H), 7.86 (d, J=8.66 Hz,
2H), 7.79 (t, J=2.01 Hz, 1H), 7.46 (dd, J=7.05 Hz, J=2.01 Hz, 1H),
7.33 (d, J=8.86 Hz, 2H), 7.21-7.11 (m, 3H), 7.02-6.94 (m, 4H).
.sup.19F NMR (CDCl.sub.3/CD.sub.3OD/282.2 MHz): -111.38(m). Mass
spectrum, MH+=470. Anal. Calc'd for
C.sub.22H.sub.16N.sub.4O.sub.3ClFS: C, 56.11; H, 3.42; N, 11.90;
Cl, 6.81; S, 7.53. Found: C, 55.95; H, 3.50; N, 11.85; Cl, 6.82; S,
7.50.
[0684] The following compounds in Table IV were prepared according
to procedures similar to that exemplified in Examples 96-98, with
the substitution of the appropriate starting material.
4TABLE IV 63 Ex. A B M.P. .degree. C. Analytical 99 4-Br H 143-145
MH+ = 421 100 4-F phenyl- 233-236 MH+ = 436 101 4-NO.sub.2 H
278-281 MH+ = 387 102 4-F 4-CH.sub.3O-phenyl- 209-211 MH+ = 466 103
4-F 4-CH.sub.3-phenyl- 222-225 MH+ = 451 104 4-F cyclohexyl-
224-227 MH+ = 442 105 4-F 3-F-phenyl- 227 MH+ = 454 106 4-Cl
3-F-phenyl- 174-176 (dec) MH+ = 471 107 H H ND MH+ = 343 108
4-OCH.sub.3, 3-Cl H ND MH+ = 408 109 4-SCH.sub.3 H 115 (dec) HRMS:
389.0743 110 4-OCH.sub.3 H 115-140 Calc. C, 54.83; H, 4.33; N,
15.04 Obs. C, 54.76; H, 4.34; N, 14.98 111 4-CH.sub.3 H 139-140
HRMS.H2O: 356.0939 112 4-OCH.sub.3 --CH.sub.3 209 MH+ = 387 113
4-Cl glycine benzyl ester 136 MH+ = 525 114 4-Cl glycine 124-130
MH+ = 435 115 4-OCH.sub.3, 3-Br H ND M + Li = 457/459 116
4-OCH.sub.3, 3,5-di-Cl H 185 (dec) HRMS: 440.0113
Example 117
[0685] 64
4-[3-Cyano-5-(4-fluorophenyl-1H-pyrazol-1-yl]benzenesulfonamide
[0686] A dry 100 ml three-neck flask, equipped with a reflux
condenser, thermometer, pressure-equalizing addition funnel and
provisions for magnetic stirring was charged with anhydrous DMF (20
mL) and cooled to 0.degree. C. Oxalyl chloride (0.530 mL, 6.105
mmol) was added over twenty seconds, causing a 5.degree. C.
exotherm. The white precipitate formed dissolved as the reaction
cooled to 0.degree. C. The reaction was held at 0.degree. C. for
ten minutes, then a solution of [1-(4-aminosulfonylpheny-
l)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxamide (Example 97) in
anhydrous DMF was added to the vigorously stirring solution over
approximately two minutes. After fifteen minutes, pyridine (1.0 mL,
12.21 mmol) was added to quench the reaction. The mixture was
poured into dilute hydrochloric acid (IN, 100 mL) and extracted
with ethyl acetate (2.times.75 mL). The combined organic solution
was washed with 1N HCl (2.times.100 mL) and with 50% saturated NaCl
(3.times.100 mL). The organic solution was dried over magnesium
sulfate, filtered and concentrated in vacuo to a crude oil. The oil
was applied to a column of silica gel and eluted with ethyl acetate
and hexane (40% ethyl acetate) to obtain, upon concentration of the
appropriate fractions, 0.66 g (69%) of
4-[3-cyano-5-(4-fluorophenyl-1H-pyrazol-1-yl]benzenesulfonamide as
a white solid: mp 184-185.degree. C.; .sup.1H NMR (CDCl.sub.3/300
MHz) 7.94 (d, J=8.86 Hz, 2H), 7.44 (d, J=8.86 Hz, 2H), 7.23-7.07
(m, 4H), 6.87 (s, 1H), 4.88 (brs, 2H); .sup.19F NMR
(CDCl.sub.3/282.2 MHz) -109.90(m). Mass spectrum, MH+=343. Anal.
Calc'd for C.sub.16H.sub.11N.sub.4O.sub.2FS: C, 56.14; H, 3.24; N,
16.37; S, 9.36. Found: C, 56.19; H, 3.16; N, 16.39; S, 9.41.
[0687] The following compounds in Table V were prepared according
to procedures similar to that exemplified in Example 117, with the
substitution of the appropriate starting material.
5TABLE V 65 Ex. A M.P. (.degree. C.) Anal. 118 4-Br 156-157 HRMS:
401.9833 119 4-Cl 142-143 120 4-OCH.sub.3 ND HRMS: 354.0774 121
4-CH.sub.3 90-95 HRMS: 338.0849 122 4-SCH.sub.3 192-193 123
4-OCH.sub.3, 3-Cl 179 MH+ = 389 124 4-OCH.sub.3, 3,5-di-Cl 121-125
HRMS: 422.0051 125 4-OCH.sub.3, 3-Br 213 MH+ = 433 126 4-NO.sub.2
230-232 MH+ = 370 127 H ND MH+ = 325
Example 128
[0688] 66
4-[5-(4-Chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl]benzenesulfona-
mide
Step 1: Preparation of
4.4.5.5.6.6.6-heptafluoro-1-[4-(chloro)phenyl]hexan-
e-1.3-dione.
[0689] Ethyl heptafluorobutyrate (5.23 g, 21.6 mmol) was placed in
a 100 mL round bottom flask, and dissolved in ether (20 mL). To the
stirred solution was added 25% sodium methoxide (4.85 g, 22.4 mmol)
followed by 4-chloroacetophenone (3.04 g, 19.7 mmol). The reaction
was stirred at room temperature overnight (15.9 hours) and treated
with 3N HCl (17 mL). The organic layer was collected, washed with
brine, dried over MgSO.sub.4, concentrated in vacuo, and
recrystallized from iso-octane to give the diketone as a white
solid (4.27 g, 62%): mp 27-3.degree. C.; .sup.1H NMR (CDCl.sub.3)
300 MHz 15.20 (br s, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.7
Hz, 2H), 6.58 (S, 1H); .sup.19F NMR (CDCl.sub.3) 300 MHz: -80.94
(t), -121.01 (t), -127.17 (s); M+H 351.
Step 2: Preparation of
4-[5-(4-chlorophenyl)-3-(heptafluoropropyl)-1H-pyra-
zol-1-yl]benzenesulfonamide
[0690] The 4-sulfonamidophenylhydrazine hydrochloride (290 mg, 1.30
mmol) was added to a stirred solution of the diketone from Step 1
(400 mg, 1.14 mmol) in ethanol (5 mL). The reaction was heated to
reflux and stirred overnight (23.8 hours). The ethanol was removed
in vacuo, and the residue was dissolved in ethyl acetate, washed
with water and brine, dried over MgSO.sub.4, and concentrated in
vacuo to give a white solid which was passed through a column of
silica gel with ethyl acetate/hexane (40%) and recrystallized from
ethyl acetate/isooctane to give the pyrazole as a white solid (0.24
g, 42%): mp 168-71.degree. C.; .sup.1H NMR (CDCl.sub.3) 300 MHz
7.90 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.5 Hz,
2H), 7.19 (d, J=8.5 Hz, 2H), 6.79 (s, 1H), 5.20 (br s, 2H);
.sup.19F NMR (CDCl.sub.3) 300 MHz: -80.48 (t), -111.54 (t), -127.07
(s).
Example 129
[0691] 67
4-[5-(4-Chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide
Step 1: Preparation of
4-chloro-4.4-difluoro-1-[4-(chloro)phenyl]-butane-1- ,3-dione
[0692] Methyl 2-chloro-2,2-difluoroacetate (4.20 g, 29 mmol) was
placed in a 100 mL round bottom flask, and dissolved in ether (10
mL). To the stirred solution was added 25% sodium methoxide (6.37
g, 29 mmol) followed by 4'-chloroacetophenone (4.10 g, 26.5 mmol).
The reaction was stirred at room temperature overnight (20.4
hours), then poured into a separatory funnel and washed with 3N HCl
(15 mL), brine (20 mL), dried over MgSO.sub.4, and concentrated in
vacuo and recrystallized from iso-octane to give the diketone as a
yellow solid (3.78 g, 53%): mp 53-55.degree. C.; .sup.1H NMR
(CDCl.sub.3) 300 MHz 14.80 (br s, 1H), 7.87 (d, J=8.7 Hz, 2H), 7.50
(d, J=8.7 Hz, 2H), 6.49 (S, 1H); .sup.19F NMR (CDCl.sub.3) 300 MHz:
-66.03 (s); M+267.
Step 2: Preparation of
4-[5-(4-chlorophenyl)-3-(chloro-difluoromethyl)-1H--
pyrazol-1-yl]benzenesulfonamide
[0693] 4-Sulfonamidophenylhydrazine hydrochloride (1.39 g, 6.2
mmol) was added to a stirred solution of the diketone from Step 1
(1.43 g, 5.7 mmol) in ethanol (10 mL). The reaction was heated to
reflux and stirred overnight (15.75 hours). The ethanol was removed
in vacuo, and the residue was dissolved in ethyl acetate, washed
with water and brine, dried over MgSO.sub.4, and concentrated in
vacuo to give a white solid which was recrystallized from ethyl
acetate/isooctane to give the pyrazole as a white solid (0.32 g,
41%): mp 130-33.degree. C.; .sup.1H NMR (CDCl.sub.3) 300 MHz 7.90
(d, 3=8.9 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H),
7.19 (d, J=8.7 Hz, 2H), 6.76 (s, 1H), 5.13 (br s, 2H); .sup.19F NMR
(CDCl.sub.3) 300 MHz: -48.44 (s); M+ 417/419.
Example 130
[0694] 68
4-[3-(Dichloromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzene-
sulfonamide
Step 1. Preparation of 3'-fluoro-4'-methoxyacetophenone
[0695] Aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL)
were placed in a 2 L three-necked round bottom flask fitted with a
mechanical stirrer and cooled by means of an ice bath. To the
stirred solution was added acetyl chloride (51.0 g, 0.65 mol)
dropwise, maintaining the temperature between 5-10.degree. C. The
mixture was allowed to stir for 10 minutes. at 5.degree. C. before
the dropwise addition at 5-10.degree. C. of 2-fluoroanisole (63.06
g, 0.5 mol). The mixture was stirred at 0-10.degree. C. for 1 hour
and poured into ice (1 L). The resultant layers were separated and
the aqueous layer was extracted with methylene chloride
(2.times.250 mL). The combined organic layers were washed with
water (2.times.150 mL), dried over magnesium sulfate, and
concentrated to 300 mL. Hexanes were added and a white solid (77.2
g, 92%) was crystallized from the mixture: mp 92-94.degree. C.;
.sup.1H NMR (d.sub.6-DMSO) 7.8 (m, 2H), 7.3 (t, J=8.7 Hz, 1H), 3.9
(s, 3H), 2.5 (s, 3H).
Step 2. Preparation of
4.4-dichloro-1-(3-fluoro-4-methoxyphenyl)-butane-1.- 3-dione
[0696] Methyl dichloroacetate (1.57 g, 11 mmol) was dissolved ether
(25 mL). To the stirred solution was added 25% sodium methoxide
(2.38 g, 11 mmol) followed by 3'-fluoro-4'-methoxyacetophenone from
Step 1 (1.68 g, 10 mmol). After stirring 16 hours 1N HCl (25 mL)
was added. The organic layer was collected and washed with water
(2.times.25 mL), dried over magnesium sulfate, filtered, and
concentrated. The resulting crude dione was used in the next step
without further purification or characterization.
Step 3. Preparation of
4-[3-(dichloromethyl)-5-(3-fluoro-4-methoxyphenyl)--
1H-pyrazol-1-yl]benzenesulfonamide
[0697] 4,4-Dichloro-1-(3-fluoro-4-methoxyphenyl)butane-1,3-dione
from Step 2 (2.8 g, 10 mmol) was dissolved in ethanol (100 mL). To
the stirred mixture was added 4-sulfonamidophenylhydrazine
hydrochloride (2.46 g, 11 mmol) and heated to reflux for 16 hours.
The mixture was cooled and water was added until crystals slowly
appeared. Filtration yielded a light tan solid (2.7 g, 63%): mp
190-193.degree. C.; .sup.1H NMR (DMSO-d.sub.6) 7.84 (d, J=8.4 Hz,
2H), 7.53 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.47 (brs, 2H), 7.3-7.0
(m, 3H), 6.95 (s, 1H), 3.85 (s, 3H). Anal. Calc'd for
C.sub.17H.sub.14N.sub.3SO.sub.3FCl.sub.2: C, 47.45; H, 3.28; N,
9.76. Found: C, 47.68; H, 3.42; N, 10.04.
Example 131
[0698] 69
4-[3-Fluoromethyl-5-phenyl-1H-pyrazol-1-yl benzenesulfonamide
Step 1: Preparation methyl 4-phenyl-2.4-dioxo-butanoate
[0699] To a solution of dimethyl oxalate (11.81 g, 100 mmol) in
ether (200 mL) is added 24 mL of 25% sodium methoxide in methanol,
followed by a solution of acetophenone (12.02 g, 100 mmol) in ether
(20 mL) and the mixture stirred overnight at room temperature. The
mixture was partitioned between 1N HCl and EtOAc and the organic
layer was washed with brine, dried over MgSO.sub.4 and concentrated
to give 18.4 g of crude butanoate.
Step 2: Preparation of methyl 1-[(4-(aminosulfonyl)
phenyl]-5-phenyl-1H-pyrazole 3-carboxylate
[0700] The ester was prepared from the butanoate in Step 1 using
the procedure described in Example 2, Step 2.
Step 3: Preparation
4-.beta.-hydroxymethyl-5-phenyl-1H-pyrazol-1-yl]benzen-
esulfonamide
[0701] To a solution of ester in Step 2 (4.0 g, 10.4 mmol) in 50 mL
THF was added LiAlH.sub.4 (0.592 g, 15.6 mmol) in portions and the
mixture refluxed overnight. The reaction was cooled and quenched
with 1N NaHSO.sub.4 and extracted with ether (3.times.). The
combined extracts were dried over MgSO.sub.4 and concentrated to
give 3.5 g crude alcohol. Flash chromatography using 1:1
hexane/EtOAc provided the title compound.
Step 4: Preparation
4-[3-fluoromethyl-5-phenyl-1H-pyrazol-1-yl]benzenesulf- onamide
[0702] To a mixture of the alcohol from Step 3 (212 mg, 0.64 mmol)
in dichloromethane (4 mL) was added diethylaminosulfur trifluoride
(0.13 mL, 1.0 mmol). The reaction mixture was stirred at room
temperature for 3 hours and partitioned between water and
dichloromethane. The aqueous solution was extracted with
dichloromethane. The organic solution was washed with brine and
concentrated. The residue was chromatographed on silica (1:1
hexane:ethyl acetate) to give the desired product (72 mg, 34%): mp
162-163.degree. C.; Anal. calc'd for C.sub.16H.sub.14N.sub.3O.su-
b.2SF: C, 58.00; H, 4.26; N, 12.68. Found: C, 57.95; H, 4.03; N,
12.58.
[0703] The following compounds in Table VI were prepared according
to procedures similar to that exemplified in Examples 128-131, with
the substitution of the appropriate substituted acetyl and acetate
starting materials.
6TABLE VI 70 Ex. A R.sup.2 M.P. (.degree. C.) Anal. 132 4-Cl
--CF.sub.2CF.sub.3 145.5-150 133 4-Cl --CH.sub.2Cl 198-201 Calc. C,
50.27; H, 3.43; N, 10.99 Found C, 50.34; H, 3.43; N, 10.96 134
3-F,4-OCH.sub.3 --CF.sub.2Cl 120-124 Calc. C, 47.29; H, 3.04; N,
9.74 Found C, 47.28; H, 3.37; N, 9.88 135 3-F,4-OCH.sub.3
--CBrF.sub.2 120-122 Calc. C, 42.87; H, 2.75; N, 8.82 Found C,
42.99; H, 3.81; N, 9.92 136 3-Cl,4-OCH.sub.3 --CH.sub.2Cl ND Calc.
C, 49.53; H, 2.84; N, 8.66 Found C, 50.03; H, 3.81; N, 9.92
Example 137
[0704] 71
4-[5-(2-Pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
Step 1: Preparation of
4.4-difluoro-1-(2-pyrazinyl)butane-1.3-dione.
[0705] Ethyl difluoroacetate (2.23 g, 18 mmol) was placed in a 100
mL round bottom flask and dissolved in ether (10 mL). To the
stirred solution was added 25% sodium methoxide (4.68 g, 22 mmol)
followed by acetylpyrazine (2.00 g, 16 mmol). After two hours
stirring at room temperature, a precipitate formed and THF (10 mL)
was added to the reaction. The reaction was stirred an additional
25.9 hours, then treated with 3N HCl (10 mL). The organic layer was
collected, washed with brine (20 mL), dried over MgSO.sub.4, and
concentrated in vacuo and recrystallized from methylene
chloride/iso-octane to give the diketone as a brown solid (2.23 g,
68%); mp 103-110.degree. C.; .sup.1H NMR (CDCl.sub.3) 300 MHz 14.00
(br s, 1H), 9.31 (d, J=1.4 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.68
(dd, J=1.4 Hz 2.4 Hz, 1H), 7.20 (s, 1H), 6.03 (t, J=54.0 Hz, 1H);
.sup.19F NMR (CDCl.sub.3) 300 MHz: -127.16 (d); M+200.
Step 2. Preparation of
4-[5-(2-pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1--
yl]benzenesulfonamide
[0706] 4-Sulfonamidophenylhydrazine hydrochloride (0.37 g, 1.65
mmol) was added to a stirred suspension of the diketone from Step 1
(0.30 g, 1.50 mmol) in ethanol (10 mL). The reaction was heated to
reflux and stirred for 5.3 hours. The ethanol was removed in vacuo,
and the residue was dissolved in ethyl acetate, washed with water
(20 mL), brine (20 mL), dried over MgSO.sub.4, and concentrated in
vacuo to give a brown solid (0.36 g) which was recrystallized from
ethyl acetate/ethanol/isooctane to give the pyrazole as a brown
solid (0.20 g, 38%): mp 191-94.degree. C.; .sup.1H NMR (acetone d6)
300 MHz 8.94(d, J=1.4 Hz, 1H), 8.62 (d, J=2.4 Hz, 1H), 8.52 (dd,
J=1.4 Hz 2.4 Hz, 1H), 7.95 (d, J=8.7 Hz, 2H), 7.61 (d, J=8.7 Hz,
2H), 7.30 (s, 1H), 7.02 (t, J=54.6 Hz, 1H), 6.73 (br s, 2H);
.sup.19F NMR (acetone d.sub.6) 300 MHz: -113.67 (d); M+351.
Example 138
[0707] 72
4-[S-(4-methyl-1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide
Step 1: Preparation of 4-methyl-1.3-benzodioxole
[0708] 11.6-g Adogen 464 and 7 mL of dibromomethane were refluxed
in 50 mL of H.sub.2O for 0.5 hours under argon. 3-methylcatechol
(8.89 g, 71.6 mmol) was added over 2 hours and the mixture refluxed
for an additional 1 hour. Distillation of the product from the
reaction mixture afforded the title compound as a yellow oil: HRMS
m/e 136.0524 (calc'd for C.sub.8H.sub.8O.sub.2, 136.0524).
Step 2: Preparation of 5-acetyl-4-methyl-1.3-benzodioxole (A) and
6-acetyl-4-methyl-1.3-benzodioxole (B)
[0709] 13.8 g of polyphosphoric acid and 5 mL of acetic anhydride
were heated to 45.degree. C. under a drying tube of CaSO.sub.4
until liquified. The product from Step 1 was added and the reaction
was stirred at 45.degree. C. for 4.5 hours. The reaction was cooled
to room temperature and quenched with 150 mL of ice water. The
aqueous phase was washed with ethyl acetate (4.times.50 mL). The
combined organic extracts were dried over MgSO.sub.4 and filtered
to give the crude product as a red oil. The oil was chromatographed
on silica gel eluting with 10% ethyl acetate/90% hexane to afford
two products: A: Anal. calcd for C.sub.10H.sub.10O.sub.3: C, 67.07;
H, 5.66. Found: C, 67.41; H, 5.75, and B: MS, M+178.
Steps 3 and
4:4-[5-(4-methyl-1.3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H--
pyrazol-1-yl]benzenesulfonamide
[0710] The title compound was prepared from product A using the
procedures described in Example 2, Steps 1 and 2: White solid:
Anal. calcd for C.sub.18H.sub.14N.sub.3O.sub.4SF.sub.3: C, 50.82;
H, 3.22; N, 9.88. Found: C, 50.71; H, 3.34; N, 9.55.
[0711] The following compounds in Table VII were prepared according
to procedures similar to that exemplified in Examples 137-138, with
the substitution of the appropriate starting material.
7TABLE VII 73 Ex. A B M.P. (.degree. C.) Anal. 139
5-bromo-2-thienyl CF.sub.2H 168-169 M + Li 440/442 140 2-thienyl
CF.sub.2H 190-191 M + Li 367 141 5-chloro-2-thienyl CF.sub.2H
168-170 M+ 389/391 142 1-cyclohexenyl CF.sub.2H 160-161 M+ 353. 143
1,4-benzodioxan CF.sub.2H 115-119 Calc. C, 53.06; H, 3.71; N, 10.32
Obs. C, 52.40; H, 3.98; N, 9.96 144 4-methylcyclohex-3-ene-1-yl
CF.sub.2H 164-168 HRMS: 367.1194 145 2-methylcyclopenten-1-yl
CF.sub.2H 165-166 HRMS: 353.1033 146 2,5-dimethyl-3-thienyl
CF.sub.2H 125-127 Calc. C, 50.12; H, 3.94; N, 10.96 Obs. C, 50.21;
H, 3.92; N, 11.00 147 2,5-dimethyl-3-furyl CF.sub.2H 139-142 Calc.
C, 52.31; H, 4.12; N, 11.44 Obs. C, 52.07; H, 4.16; N, 11.37 148
5-methyl-2-furyl CF.sub.2H 177-179 Calc C, 50.99; H, 3.71; N, 11.89
Obs. C, 51.08; H, 3.68; N, 11.95 149 4-bromo-4-methylcyclohex-1-yl
CF.sub.2H 175-178 (dec) HRMS: 448.0520 150 4-methylcyclohex-1-yl
CF.sub.2H 190-192 HRMS: 369.1341 151 4-chloro-4-methylcyclohex-1-yl
CF.sub.2H 197-199 HRNS: 403.0958 152
3,4-dichloro-4-methylcyclohex-1-yl CF.sub.2H 172-173 153
2-methoxycyclohex-1-yl CF.sub.2H 177-179 HRMS: 386.1357 154
2-benzofuryl CF.sub.2H 215-217 Calc C, 55.52; H, 3.37; N, 10.79
Obs. C, 55.52; H, 3.32; N, 10.85 155 2,5-dichloro-3-thien-yl
CF.sub.2H 154-156 Calc. C, 39.63; H, 2.14; N, 9.90 Obs. C, 39.63;
H, 2.13; N, 9.89 156 2-benzofuryl CF.sub.3 227-228 Calc. C, 53.07;
H, 2.97; N, 10.31 Obs. C, 53.02; H, 2.96; N, 10.39 157
5-chloro-2-thienyl CF.sub.3 161-165 HRMS: 406.9784 158
5-bromo-2-thienyl CF.sub.3 ND Calc: C, 37.18; H, 2.01; N, 9.29; Br,
17.67 Found: C, 37.25; H, 1.93; N, 9.45; Br, 17.40 159 5-indanyl
CF.sub.3 118-120 Calc: C, 56.01; H, 3.96; N, 10.31 Found: C, 56.02;
H, 4.06; N, 10.22 160 5-methylthien-2-yl CF.sub.3 188-190 Calc. C,
46.51; H, 3.12; N, 10.85 Found: C, 46.17; H, 3.10; N, 10.75 161
2,3-dihydrobenzofuryl CF.sub.3 152-153 Calc. C, 52.81; H, 3.45; N,
10.26 Found: C, 52.67; H, 3.78; N, 10.13 162 1-cyclohexenyl
CF.sub.3 135-138 HRMS: 371.0918 163 6-tetrahydronaphthyl CF.sub.3
143-145 Calc. C, 57.00; H, 4.31; N, 9.97 Found: C, 56.72; H, 4.27;
N, 9.90 164 3-benzothienyl CF.sub.3 164-165 Calc. C, 51.06; H,
2.86; N, 9.92 Obs. C, 50.96; H, 2.73; N, 9.78 165
3,4-dihydrobenzopyranyl CF.sub.3 ND HRMS: 423.0855 166 styryl
CF.sub.3 166-167 Calc. C, 54.96; H, 3.59; N, 10.68 Obs. C, 54.77;
H, 3.59; N, 10.47 167 4-methyl-1,3-benzodioxol-6-yl CF.sub.3 ND
Calc. C, 50.82; H, 3.22; N, 9.88 Obs. C, 50.64; H, 3.35; N, 9.72
168 3-pyridyl CF.sub.3 202-204 Calc. C, 48.91; H, 3.01; N, 15.21
Obs. C, 48.97; H, 3.16; N, 14.96 169 3,4-dihydrobenzothiopyranyl
CF.sub.3 ND Calc. C, 51.95; H, 3.67; N, 9.56 Obs. C, 51.98; H,
3.78; N, 9.48
Example 170
[0712] 74
4-[5-(1-Cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
[0713]
4-[5-(1-Cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide (Example 142) (0.31 g, 0.88 mmol) was dissolved in ethanol
(15 mL), 10% palladium on charcoal was added, and the suspension
was stirred at room temperature under hydrogen (36 psi) for 18.25
hours. The reaction was filtered through celite, and the ethanol
removed in vacuo to give a white solid, which was recrystallized
from methylene chloride/isooctane (0.31 g, 99%): mp 199-203.degree.
C.; .sup.1H NMR (acetone-d.sub.6) 300 MHz 8.05 (d, J=8.7 Hz, 2H),
7.60 (d, J=8.5 Hz, 2H), 6.69 (t, J=55.0 Hz 1H), 6.47 (s, 1H), 5.02
(br s, 2H), 2.67 (m, 1H), 1.71-1.88(m, 5H), 1.24-1.43 (m, 5H);
.sup.19F NMR (acetone-d.sub.6) 300 MHz: -112.86 (d).
Example 171
[0714] 75
4-[5-(4-Chlorophenyl)-3-hydroxymethyl-1H-pyrazol-1-yl]benzenesulfonamide
[0715]
4-[4-(Aminosulfonyl)phenyl-5-(4-chlorophenyl)-1H-pyrazole-3-carboxy-
lic acid (Example 83) (3.8 g, 10 mmol) and tetrahydrofuran (100 mL)
were stirred at room temperature during the dropwise addition of
11.0M borane-tetrahydrofuran complex (30 mL, 30 mmol). The mixture
was heated to reflux for 16 hours. The solution was cooled and
methanol was added dropwise until gas evolution ceased. Ethyl
acetate (100 mL) was added and the mixture was washed successively
with 1N hydrochloric acid, brine, sat. aq. sodium bicarbonate
solution, and water, dried over magnesium sulfate, filtered and
concentrated. The resultant product was recrystallized from
ethanol:water to yield 2.6 g (71%) of a white solid: mp
192-194.degree. C.; .sup.1H NMR (d6-DMSO/300 MHz) 7.81 (d, J=8.7
Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.42 (brs, 2H), 7.40 (d, J=8.7 Hz,
2H), 7.26 (d, J=8.4 Hz, 2H), 6.63 (s, 1H), 5.35 (t, J=8.0 Hz, 1H),
4.50 (d, J=8.0 Hz, 2H). Anal. Calc'd for
C.sub.16H.sub.14N.sub.6SO.sub.2Cl: C, 52.82; H, 3.88; N, 11.55.
Found: C, 52.91; H, 3.88; N, 11.50.
Example 172
[0716] 76
4-[5-Phenyl-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide
[0717] A 60% dispersion of sodium hydride in mineral oil (4.0 g,
100 mmol) was twice washed with hexane (100 mL each) and dried
under a stream of nitrogen. Ether (300 mL) was added followed by
dropwise addition of ethanol (0.25 mL) and y-butyrolactone (4.0 mL,
52 mmol). The mixture was cooled to 10.degree. C. and acetophenone
(5.8 mL, 50 mmol) in ether (40 mL) was added dropwise over 1 hour.
The mixture was warmed to 25.degree. C. and stirred overnight. The
mixture was cooled to 0.degree. C. and quenched with ethanol (5 mL)
followed by 10% aqueous ammonium sulfate (100 mL). The organic
solution was separated, dried over Na.sub.2SO.sub.4 and
concentrated. The residue was chromatographed on silica gel with
1:1 hexane/ethyl acetate to give the desired diketone (3.4 g) as an
oil. Pyridine (0.34 mL, 4.2 mmol) and the diketone (700 mg, 3.4
mmol) in methanol (3 mL) were added to a slurry of
4-sulfonamidophenylhydrazine-HC- l (750 mg, 3.4 mmol) in methanol
(8 mL). The mixture was stirred at 25.degree. C. overnight and
concentrated in vacuo. The residue was dissolved in methylene
chloride and the solution washed with 1N HCl. The organic solution
was separated, dried and concentrated. The residue was
chromatographed on silica gel using ethyl acetate to give the
desired pyrazole (435 mg) as a solid: Anal. calc'd for
C.sub.18H.sub.19N.sub.3O.s- ub.3S: C, 60.49; H, 5.36; N, 11.75.
Found: C, 60.22; H, 5.63; N, 11.54.
Example 173
[0718] 77
4-[5-(4-Fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonami-
de
[0719] Following the procedure of Example 172, but substituting
4-fluoroacetophenone for acetophenone afforded
4-[5-(4-fluorophenyl)-3-(3-
-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide. Anal. calc'd
for C.sub.18H.sub.18N.sub.3O.sub.3SF.0.25H.sub.2O: C, 56.90; H,
4.91; N, 11.05. Found: C, 56.80; H, 4.67; N, 11.02.
Example 174
[0720] 78
4-[4-(Aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole]-3-propanoic
Acid
[0721] Jones reagent (0.64 mL of a 2.67 M solution) was added
dropwise to a solution of
4-[5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide from Example 173 (295 mg, 0.78 mmol) in acetone
(8 mL). The mixture was stirred at 25.degree. C. for 2 hours. The
solution was filtered and the filtrate concentrated in vacuo. The
residue was dissolved in ethyl acetate and washed with water
(3.times.). The organic solution was dried over MgSO.sub.4 and
concentrated. The residual oil was crystallized from ether/hexane
to give the desired acid (149 mg): mp 180-182.degree. C.; Anal.
calc'd for C.sub.18H.sub.16N.sub.3O.sub.4SF: C, 55.52; H, 4.14; N,
10.79. Found: C, 55.47; H, 4.22; N, 10.50.
Example 175
[0722] 79
4-(3-Isobutyl-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide
Step 1: Preparation of 2.3-epoxy-5-methyl-1-phenyl-3-hexanone
[0723] To a solution of 5-methyl-1-phenyl-1-hexen-3-one (2.0 g,
10.6 mmol) in 15 mL EtOH and 5 mL acetone was added a mixture of
30% hydrogen peroxide (2 mL) and 4 N NaOH (1.5 ML) dropwise and the
mixture stirred at 25.degree. C. for 1-3 hours. Water (50 mL) was
added and the precipitate filtered and dried at 40.degree. C. in
vacuo to provide 1.9 g of the epoxide as a white solid: Anal.
calc'd for C.sub.13H.sub.16O.sub.2.0.1H.s- ub.2O: C, 75.77; H,
7.92. Found: C, 75.47; H, 7.56.
Step 2: Preparation of
4-(3-isobutyl-5-phenyl-1H-pyrazol-1-yl)benzenesulfo- namide
[0724] The epoxide prepared above in Step 1 (1.26 g, 6.11 mmol) and
4-sulfonamidophenylhydrazine hydrochloride (1.38 g, 6.17 mmol) were
stirred in 20 mL EtOH with AcOH (0.5 mL) and the mixture refluxed
for 3 hours, cooled and quenched with 50 mL H.sub.2O. The aqueous
layer was extracted with ethyl acetate (3.times.50 mL), the
combined extracts were dried over MgSO.sub.4 and concentrated.
Flash chromatography using 70:30 hexane/ethyl acetate provided the
title compound (0.41 g, 19%) as a white solid: Calc'd for
C.sub.19H.sub.21N.sub.3O.sub.2S: C, 64.20; H, 5.96; N, 11.82.
Found: C, 64.31; H, 6.29; N, 11.73.
Example 176
[0725] 80
Ethyl
3-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-2-cyano-2-p-
ropenoate
Step 1: Preparation of
4-[3-formyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfona- mide
[0726] To a solution of the alcohol prepared in Example 131, Step 3
(1.1 g, 3.3 mmol) in ethyl acetate (20 mL) was added MnO.sub.2 (5
g, 60 mmol) and the mixture stirred at room temperature overnight.
The mixture was filtered through Celite and the solution was
concentrated to provide the crude aldehyde.
Step 2: Preparation of ethyl
3-[(1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-p-
yrazol-3-yl]-2-cyano-2-propenoate
[0727] To a solution of the aldehyde from Step 1 (1.2 g, 3.6 mmol)
in benzene (18 mL) was added ethyl cyanoacetate (0.38 mL, 3.6
mmol), ammonium acetate (50 mg, 0.7 mmol) and glacial acetic acid
(0.17 mL, 2.8 mmol). The solution was heated at reflux for 18
hours, cooled, and partitioned between water and ethyl acetate. The
organic solution was washed with a saturated aqueous sodium
bicarbonate solution, water and brine. The organic solution was
dried and concentrated. The residue was chromatographed on silica
(40% hexane in ethyl acetate) to give the desired product (1.0 g,
66%): Anal. calc'd for C.sub.21H.sub.18N.sub.4O.s- ub.4S: C, 59.82;
H, 4.30; N, 13.22. Found: C, 59.70; H, 4.29; N, 13.26.
Example 177
[0728] 81
4-[5-(4-Chlorophenyl)-3-[[(phenylmethoxy)imino]methyl]-1H-pyrazol-1-yl]ben-
zenesulfonamide
[0729] To a suspension of 220 mg (0.58 mmol)
4-[5-(4-chlorophenyl)-3-formy- l-1H-pyrazol-1-yl]benzenesulfonamide
(prepared as described in Example 176, Step 1) in dichloromethane
(3 mL) was added pyridine (0.12 mL, 1.3 mmol) and
O-benzylhyroxylamine hydrochloride (110 mg, 0.68 mmol) and the
reaction stirred at room temperature for 18 hours. The mixture was
partitioned between pH 7 buffer and dichloromethane and the organic
layer was washed with water, dried and concentrated. Flash
chromatography on silica gel (2:1 hexane/EtOAc) provided the title
compound (151 mg, 56%): mp 158-159.degree. C.; Anal. calc'd for
C.sub.23H.sub.19N.sub.4O.sub.3SCl- .0.25H.sub.2O: C, 58.59; H,
4.17; N, 11.88. Found: C, 58.43; H, 4.03; N, 11.85.
[0730] The following compounds in Table VIII were prepared
according to procedures similar to that exemplified in Examples
171-177, with the substitution of the appropriate starting
material.
8TABLE VIII 82 Ex. A R.sup.2 M.P. (.degree. C.) Anal. 178 H
--CH.sub.2OH 183-184 HRMS: 329.0845 179 4-OCH.sub.3 --CH.sub.2OH
140-142 Calc. C, 56.81; H, 4.77; N, 11.69 Found: C, 56.92; H, 4.76;
N, 11.64 180 3,5-di-Cl, 4-OCH.sub.3 --CH.sub.2OH 191-193 HRMS
427.0199 181 3-Cl, 4-OCH.sub.3 --CH.sub.2OH ND Calc. C, 51.84; H,
4.09; N, 10.67 Cl, 9.00; S, 8.14 Found: C, 51.77; H, 4.02; N,
10.73; Cl, 9.11; S, 8.03 182 4-CH.sub.3 --C(CH.sub.3).sub.2OH
178-179 183 4-Cl --(CH.sub.2).sub.2CO.sub.2H 156-159 184 4-Cl
--CH.sub.2CONH.sub.2 198-200 185 H --CH.sub.3 ND Calc. C, 60.46; H,
5.07; N, 13.21 Found: C, 60.48; H, 4.95; N, 13.19 186 4-Cl
--CH.sub.2CN 212-214 Calc. C, 54.77; H, 3.51 N, 15.03 Found: C,
54.94; H, 3.61; N, 14.88
Example 187
[0731] 83
4-[4,5-Dihydro-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonami-
de
Step 1: Preparation of 2-trifluoroacetyl-1-tetralone
[0732] A 250 mL one necked round bottomed flask equipped with a
reflux condenser, nitrogen inlet and provisions for magnetic
stirring was charged with ethyl trifluoroacetate (28.4 g, 0.2 mol)
and 75 mL of ether. To this solution was added 48 mL of 25% sodium
methoxide in methanol (0.21 mol). A solution of 1-tetralone (29.2
g, 0.2 mol) in 50 mL of ether was added over about 5 minutes. The
reaction mixture was stirred at room temperature for 14 hours and
was diluted wih 100 mL of 3N HCl. The phases were separated and the
organic layer was washed with 3N HCl, and with brine, dried over
anhydrous MgSO.sub.4, filtered and concentrated in vacuo. The
residue was taken up in 70 mL of boiling ethanol/water and cooled
to room temperature, whereupon crystals of 2-trifluoroacetyl-1-tet-
ralone formed which were isolated by filtration and air dried to
give pure compound (32 g, 81%): mp 48-49.degree. C.; .sup.1H NMR
CDCl.sub.3 .delta.2.8 (m, 2H), 2.9 (m, 2H), 7.2 (d, j=3.0 Hz, 1H),
7.36 (m, 1H), 7.50 (m, 1H), 7.98 (m, 1H); .sup.19F NMR CDCl.sub.3
.delta. -72.0. EI GC-MS M+=242.
Step 2: Preparation of
4-[4.5-dihydro-3-(trifluoromethyl)-1H-benz[a]indazo-
l-1-yl]benzenesulfonamide
[0733] A 100 mL one necked round bottomed flask equipped with
reflux condenser, nitrogen inlet and provisions for magnetic
stirring was charged with 2-trifluoroacetyl-1-tetralone from Step 1
(1.21 g, 5.0 mmol), 4-sulfonamidophenylhydrazine hydrochloride
(1.12 g, 5.0 mmol) and 25 mL of absolute ethanol. The solution was
warmed to reflux for 15 hours and concentrated in vacuo. The
residue was dissolved in ethyl acetate, washed with water, and with
brine, dried over anhydrous MgSO.sub.4, filtered and concentrated
in vacuo. The residue was recrystallized from a mixture of ethyl
acetate and isooctane to give 1.40 g, 71% of pure product: mp
257-258.degree. C.; .sup.1H NMR (CDCl.sub.3/CD.sub.3OD, 4:1)
.delta. 2.7 (m, 2H), 2.9 (m, 2H), 6.6 (m, 1H), 6.9 (m, 1H), 7.1 (m,
1H), 7.16 (m, 1H), 7.53 (m, 2H), 7.92 (m, 2H); .sup.19F NMR
(CDCl.sub.3) .delta. -62.5. FAB-MS M+H=394.
Example 188
[0734] 84
4-[4,5-Dihydro-7-methyl-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzene-
sulfonamide
Step 1. Preparation of 6-methyl-2-(trifluoroacetyl)tetralone
[0735] Ethyl trifluoroacetate (5.33 g, 37.5 mmol) was dissolved in
ether (50 mL) and treated with a sodium methoxide solution (25% in
methanol, 9.92 g, 45.9 mmol) followed by 6-methyltetralone (5.94 g,
37.1 mmol). The reaction was stirred at room temperature for 6.1
hours then treated with 3N HCl (20 mL). The organic layer was
collected, washed with brine, dried over MgSO.sub.4, and
concentrated in vacuo to give a brown oil (8.09 g) that was used in
the next step without further purification.
Step 2. Preparation of
4-[4.5-dihydro-7-methyl-3-(trifluoromethyl)-1H-benz
[g]indazol-1-yl]benzenesulfonamide
[0736] 4-Sulfonamidophenylhydrazine hydrochloride (1.80 g, 8.0
mmol) was added to a stirred solution of the diketone from Step 1
(1.86 g, 7.3 mmol) in ethanol (10 mL). The reaction was heated to
reflux and stirred for 14.8 hours. The reaction mixture was cooled
and filtered. The filtrate was concentrated in vacuo, dissolved in
ethyl acetate, washed with water and with brine, dried over
MgSO.sub.4 and reconcentrated in vacuo to give the pyrazole as a
brown solid (1.90 g, 64%):
[0737] mp 215-218.degree. C. .sup.1H NMR (acetone-d6) 300 MHz 8.10
(d, 2H), 7.80 (d, 2H), 7.24 (s, 1H), 6.92 (d, 1H), 6.79 (br s, 2H),
6.88 (d, 1H), 3.02 (m, 2H), 2.85 (m, 2H), 2.30 (s, 3H). .sup.19F
NMR (acetone-d.sub.6) 282 MHz -62.46 (s). High resolution mass
spectrum Calc'd. for C.sub.19H.sub.17F.sub.3N.sub.3O.sub.2S:
408.0994. Found: 408.0989.
[0738] The following compounds in Table IX were prepared according
to procedures similar to that exemplified in Examples 187-188, with
the substitution of the appropriate ester.
9TABLE IX 85 Ex. R.sup.2 R.sup.6 M.P. (.degree. C.) Anal. 189
--CHF.sub.2 6-OCH.sub.3 275-277 HRMS: 405.0961 190 --CHF.sub.2
7-CH.sub.3 240-241 HRMS: 390.1122 191 --CF.sub.3 6,8-CH.sub.3
284-288 HRMS: 422.1089 192 --CF.sub.3 7-OCH.sub.3 277-278 HRMS:
423.0838 193 --CF.sub.3 7;8-OCH.sub.3 269-275 HRMS: 453.1011 194
--CHF.sub.2 7-OCH.sub.3 256-257 195 --CO.sub.2CH.sub.3 7-OCH.sub.3
274-276 HRMS: 414.1117
Example 196
[0739] 86
4-[4,5-Dihydro-3-(trifluoromethyl)-1H
thieno[3,2-g]indazol-1-yl]benzenesul- fonamide
Step 1. Preparation of 4-keto-4,5,6,7-tetrahydrothianaphthene
[0740] 4-(2-Thienyl)butyric acid (28.42 g, 167 mmol) was placed in
a round bottom flask with acetic anhydride (30 mL) and phosphoric
acid (0.6 mL), and heated to reflux for 3.2 hours. The reaction
mixture was poured into 100 mL of water, extracted with ethyl
acetate, washed with brine, dried over MgSO.sub.4, and concentrated
in vacuo to give a brown oil (22.60 g) which was vacuum distilled
(1 mm Hg, 107-115.degree. C.) to give a white solid (13.08 g, 51%):
mp 34-40.degree. C.); .sup.1H NMR (CDCl.sub.3) 300 MHz 7.29 (d,
J=5.2 Hz, 1H), 6.99 (d, J=5.2 Hz, 1H), 2.95 (t, J=6.0 Hz, 2H),
2.47(m, 2H), 2.13(m, 2H). M+H=153.
Step 2. Preparation of
4-keto-4.5.6.7-tetrahydro-5-(trifluoroacetyl)thiana- phthene
[0741] Ethyl trifluoroacetate (11.81 g, 83.1 mmol) was dissolved in
ether (50 mL) and treated with a sodium methoxide solution (25% in
methanol, 18.35 g, 84.9 mmol) followed by
4-keto-4,5,6,7-tetrahydrothianaphthene from Step 1 (12.57 g, 82.6
mmol) dissolved in ether (25 mL). The reaction was stirred for 69.4
hours at room temperature, then treated with 3N HCl (40 mL). The
organic layer was collected, washed with brine, dried over
MgSO.sub.4, and concentrated in vacuo to give a brown solid which
was recrystallized from ether/hexane to give the diketone (10.77 g,
52%) as brown needles; mp 54-64.degree. C.; .sup.1NMR (CDCl.sub.3)
300 MHz 15.80 (s, 1H), 7.41 (d, J=5.2 Hz, 1H), 7.17 (d, J=5.2 Hz,
1H), 3.04 (m, 2H), 2.91 (m, 2H); .sup.19F NMR (CDCl.sub.3) 282 MHz
-70.37 (s). M+H=249.
Step 3. Preparation of
4-[4.5-dihydro-3-(trifluoromethyl)-1H-thieno[3.2-a]-
indazol-1-yl]benzenesulfonamide
[0742] 4-Sulfonamidophenylhydrazine hydrochloride (2.36 g, 10.6
mmol) was added to a stirred solution of the diketone from Step 2
(2.24 g, 9.0 mmol) in ethanol (20 mL). The reaction was heated to
reflux and stirred 14.7 hours. The reaction mixture was filtered
and washed with ethanol and with water to give the desired pyrazole
as a white solid (2.69 g, 75%): mp 288-290.degree. C.; .sup.1H NMR
(acetone-d6) 300 MHz 8.12 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz,
2H), 7.27 (d, J=5.2 Hz, 1H), 6.81 (br s, 2H), 6.59 (s, 3=5.4 Hz,
1H), 3.18 (m, 2H), 3.01 (m, 2H); .sup.19F NMR (acetone-d6) 282 MHz
-62.46 (s). High resolution mass spectrum Calc'd. for
C.sub.16H.sub.12F.sub.3N.sub.3O.sub.2S.sub.2: 399.0323. Found:
399.0280.
Example 197
[0743] 87
4-[5-(4-Chlorophenyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide
Step 1. Preparation of 3-[4-(chloro)phenyl]-propane-1,3-dione
[0744] Ethyl formate (8.15 g, 0.11 mol) and 4'-chloroacetophenone
(15.4 g, 0.1 mol) were stirred in ether (150 mL) at room
temperature. Sodium methoxide (25%) (23.77 g, 0.11 mol) was added
dropwise. The mixture was stirred at room temperature for 16 hours
and was then treated with 150 mL of 1N hydrochloric acid. The
phases were separated and the ethereal solution washed with brine,
dried over magnesium sulfate, filtered and concentrated in vacuo to
afford 18.3 g of a yellow oil. The resulting crude mixture was used
directly in the next step without purification.
Step 2. Preparation of
4-[5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfon- amide
[0745] 3-[4-(Chloro)phenyl]-propane-1,3-dione from Step 1 (18.3 g,
0.1 mol) and 4-sulfonamidophenylhydrazine hydrochloride (22.4 g,
0.1 mol) were dissolved in 150 mL of absolute ethanol and heated to
reflux for 16 hours. The solution was cooled to room temperature,
diluted with 100 mL of water and let stand, whereupon crystals of
pyrazole formed that were isolated by filtration to provide 8.4 g
(25%) of a white solid: mp 185-187.degree. C.; .sup.1H NMR
(CDCl.sub.3/300 MHz) 7.89 (d, J=8.7 Hz, 2H), 7.76 (d, J=1.8 Hz,
1H), 7.43 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7
Hz, 2H), 6.53 (d, J=1.8 Hz, 1H), 4.93 (brs, 2H). Anal. Calc'd for
C.sub.15H.sub.12N.sub.3SO.sub.2Cl: C, 53.97; H, 3.62; N, 12.59.
Found: C, 54.08; H, 3.57; N, 12.64.
Step 3. Preparation of
4-[5-(4-chlorophenyl)-4-chloro-1H-pyrazol-1-yl]benz-
enesulfonamide
[0746] 4-[5-(4-Chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide
from Step 2 (3.0 g, 9 mmol) was dissolved in 50 mL of acetic acid,
and 9 mL of 1M chlorine in acetic acid was added dropwise. The
mixture was stirred for 16 hours when sat. aq. sodium bicarbonate
solution was slowly added until the mixture was neutral to pH
paper. The mixture was extracted with ethyl acetate (3.times.50
mL), combined and washed with sat. aq. sodium bicarbonate and with
brine, dried over magnesium sulfate, filtered, and concentrated.
The resultant product was recrystallized from isopropanol to yield
2.6 g (78%) of a white solid: mp 168-171.degree. C. (dec); .sup.1H
NMR (DMSO-D6/300 MHz) 8.08 (s, 1H), 7.83 (d, J=8.7 Hz, 2H), 7.55
(d, J=8.7 Hz, 2H), 7.46 (brs, 2H), 7.44 (d, J=8.7 Hz, 2H), 7.35 (d,
J=8.7 Hz, 2H). Anal. Calc'd for
C.sub.15H.sub.11N.sub.3SO.sub.2Cl.sub.2: C, 48.93; H, 3.01; N,
11.41. Found: C, 49.01; H, 2.97; N, 11.41.
Example 198
[0747] 88
4-(4-4-(4-Fluoro-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide
Step 1: Preparation of 2-fluoroacetophenone
[0748] To a solution of 2-hydroxyacetophenone (2.5 g, 18.4 mmol) in
100 mL CH.sub.2Cl.sub.2 at -78.degree. C., was added triflic
anhydride (10 g, 35.4 mmol) followed by 2,6-lutidine (4.1 mL, 35.4
mmol) and the mixture stirred at -78.degree. C. for 50 minutes. The
mixture was poured into CH.sub.2Cl.sub.2 and water and the
CH.sub.2Cl.sub.2 layer separated, washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated to a peach solid. To a solution
of the crude triflate in 100 mL THF was added 35 mL of 1N
tetrabutylammonium fluoride in THF. The mixture was refluxed for 15
minutes, cooled and poured into ether and water. The ether layer
was separated, washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated. Flash chromatography on silica gel using 20:1
hexane/EtOAc furnished the .alpha.-fluoroketone (0.852 g,
33.5%).
Step 2: Preparation of
4-(4-fluoro-5-phenyl-1H-pyrazol-1-yl)benzenesulfona- mide
[0749] A solution of 2-fluoroacetophenone (200 mg, 1.45 mmol) in 2
mL dimethylformamide-dimethylacetal was refluxed for 18 hours. The
mixture was cooled and concentrated to give the crude
enaminoketone. Without further purification, the enaminoketone was
treated with 4-sulfonamidophenyl hydrazine hydrochloride (0.34 g,
1.52 mmol) in 10 mL EtOH at reflux for 17 hours. The mixture was
cooled, filtered and the filtrate concentrated to a yellow gum.
Flash chromatography using a gradient of 5:1 to 2:1 hexane/EtOAc
provided 0.11 g of a yellow solid: Recrystallization from
ether/hexane gave the product as a pale yellow solid, mp
194-194.5.degree. C.; Anal. calc'd for C.sub.15H.sub.12N.sub.3O-
.sub.2SF.0.2H.sub.2O: C, 56.14; H, 3.89; N, 13.09. Found: C, 55.99;
H, 3.65; N, 12.92.
Example 199
[0750] 89
4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-4-chloro-1H-pyrazol-1-yl]benzene-
sulfonamide
[0751] A 100 mL three-necked round-bottomed flask equipped with
reflux condenser, gas dispersion tube and provisions for magnetic
stirring was charged with
4-[5-(4-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benz-
enesulfonamide (Example 1)(500 mg, 1.2 mmol) and 50 mL of glacial
acetic acid. The solution was stirred at room temperature and
treated with a stream of chlorine gas for a period of 15 minutes.
The solution was then stirred at room temperature for 1.25 hours
and then diluted with 100 mL of water. The solution was then
extracted three times with ether and the combined ethereal phase
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated in vacuo to give a white solid that was recrystallized
from ether/petroleum ether to provide 390 mg (75%) of
4-[5-(4-chlorophenyl)-4-chloro-3-trifluoromethyl-1H-pyrazol-1-yl]benzenes-
ulfonamide: mp 180-182.degree. C.; .sup.1H NMR (CDCl.sub.3/300 MHz)
7.97 (d, J=6.6 Hz, 2H), 7.49 (d, J=6.3 Hz, 2H), 7.45 (d, J=6.3 Hz,
2H), 7.25 (d, J=6.6 Hz, 2H), 5.78 (brs, 2H).
Example 200
[0752] 90
4-[4-Fluoro-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamid-
e
Step 1: Preparation of 4.4.4-trifluoro-1-phenylbutane-1.3-dione
[0753] To a solution of 2-fluoroacetophenone from Step 1 of Example
198 (0.48 g, 3.4 mmol) in 25 mL THF at -78.degree. C., was added IN
lithium bis(trimethylsilyl)amide (4 mL) and the mixture stirred at
-78.degree. C. for 45 minutes. 1-(Trifluoroacetyl)imidazole (0.65
mL, 5.7 mmol) was added and the mixture stirred at -78.degree. C.
for 30 minutes and at 0.degree. C. for 30 minutes. The mixture was
quenched with 0.5 N HCl, poured into ether and water, and the ether
layer separated, washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated. Flash chromatography on silica gel using a gradient
of 10:1 to 4:1 hexane/EtOAc furnished the 1,3-diketone (0.34 g,
43%).
Step 2: Preparation of
4-[4-fluoro-5-phenyl-3-trifluoromethyl-1H-pyrazol-1-
-yl]benzenesulfonamide
[0754] The diketone from Step 1 (0.34 g, 1.45 mmol) was treated
with 4-sulfonamidophenyl hydrazine hydrochloride (0.35 g, 1.56
mmol) in 15 mL EtOH at reflux for 15 hours. The mixture was cooled,
filtered and the filtrate concentrated to a yellow gum. Flash
chromatography using 3:1 hexane/EtOAc provided 0.28 g of a yellow
solid. Recrystallization from CH.sub.2Cl.sub.2/hexane gave the
product as a pale yellow solid: Anal. calc'd for
C.sub.16H.sub.11N.sub.3O.sub.2SF.sub.4: C, 49.87; H, 2.88; N,
10.90. Found: C, 49.79; H, 2.88; N, 10.81.
Example 201
[0755] 91
4-[4-Methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamid-
e
Step 1: Preparation of
2-methyl-1-phenyl-4.4.4-trifluorobutane-1.3-dione
[0756] To a solution of propiophenone (965 mg, 7.2 mmol) in THF (20
mL) at -78.degree. C. was added sodium bis(trimethylsilyl)amide
(7.9 mL of a 1M solution in THF). The solution was kept at
-78.degree. C. for 0.5 hour and then warmed to -20.degree. C. over
1 hour. The solution was cooled to -78.degree. C. and
1-(trifluoroacetyl)imidazole (1.5 g, 9.1 mmol) in THF (4 mL) was
added via cannula. The solution was warmed to room temperature and
stirred overnight. The mixture was partitioned between 1N HCl and
ether. The organic solution was dried (Na.sub.2SO.sub.4) and
concentrated to give the crude diketone (1.9 g).
Step 2: Preparation of
4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-
-1-yl]benzenesulfonamide
[0757] The diketone from Step 1 was dissolved in absolute ethanol
(25 mL) and 4-sulfonamidophenylhydrazine hydrochloride (2.0 g, 9.0
mmol) was added. The mixture was heated at reflux for 19 hours.
Volatiles were removed in vacuo and the residue dissolved in ethyl
acetate. The organic solution was washed with water and brine,
dried and concentrated. The residue was chromatographed on silica
(2:1 hexane/ethyl acetate) to give the title pyrazole (1.52 g,
49%): mp 145-146.degree. C.; Calc'd for
C.sub.17H.sub.14N.sub.3O.sub.2SF.sub.3: C, 53.54; H, 3.70; N,
11.01. Found: C, 53.41; H, 3.66; N, 10.92.
Example 202
[0758] 92
4-[4-Ethyl-5-(3-methyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y-
l]benzenesulfonamide
Step 1: Preparation of 4-methoxy-3-methylbutyrophenone
[0759] To a suspension of aluminum chloride (10.3 g, 77.2 mmol) in
dichloromethane (40 mL) at 0.degree. C. was added dropwise a
solution of 2-methylanisole (5.0 mL, 35.3 mmol) and butyric
anhydride (5.8 mL, 35.3 mmol). The reaction solution was kept at
0.degree. C. for 2 hours and then warmed to room temperature and
stirred overnight. The reaction solution was poured into conc. HCl
(9 mL) and ice water (80 mL). The reaction was extracted with
dichloromethane and the organic layer was washed with 2N NaOH and
brine, dried and concentrated. The residue was chromatographed on
silica (9:1 hexane:ethyl acetate) to give the desired product (5.2
g, 77%).
Steps 2 and 3: Preparation of
4-[4-ethyl-5-(3-methyl-4-methoxyphenyl)-3-(t-
rifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
[0760] The title compound was prepared from the butyrophenone in
Step 1 using the procedure described in Example 201, Steps 1 and 2:
mp 135-136.degree. C.; Calc'd for
C.sub.20H.sub.20N.sub.3O.sub.3SF.sub.3: C, 54.66; H, 4.59; N, 9.56.
Found: C, 54.11; H, 4.38; N, 9.43.
Example 203
[0761] 93
0.4-[4-Cyclopropyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide
Step 1: Preparation of 2-cyclopropylacetophenone
[0762] To a suspension of sodium cyanide (1.8 g, 37.0 mmol) in
dimethyl sulfoxide (20 mL) at 60.degree. C. was added dropwise
(bromomethyl)cyclopropane (5.0 g, 37.0 mmol). The addition was done
at such a rate to keep the temperature of the reaction at
60.degree. C. After the addition was completed, the reaction
mixture was heated at 80.degree. C. for 15 minutes. The mixture was
cooled and partitioned between ether and water. The organic
solution was washed with 1N HCl and water, dried and concentrated.
The residue was dissolved in ether (5 mL) and added to a solution
of phenyl magnesium bromide (25 mL of a 3M solution in ether) in
ether (20 mL) and benzene (25 mL). The reaction mixture was stirred
at room temperature for 20 hours, then poured into a 1N HCl
solution and stirred for 1.5 hours. The organic solution was
separated and the aqueous solution extracted with dichloromethane.
The organic solution was dried and concentrated. The residue was
chromatographed on silica (9:1 hexane:ethyl acetate) to give the
desired product (2.0 g, 34%).
Steps 2 and 3: Preparation of
4-[4-cyclopronyl-5-phenyl-3-(trifluoromethyl-
)-1H-pyrazol-1-yl]benzenesulfonamide
[0763] The title compound was prepared from the acetophenone in
Step 1 using the procedure described in Example 201), Steps 1 and
2: mp 173-174.degree. C.; Calc'd for
C.sub.19H.sub.16N.sub.3O.sub.2SF.sub.3: C, 56.01; H, 3.96; N,
10.31. Found: C, 55.85; H, 3.78; N, 10.19.
Example 204
[0764] 94
4-[4-hydroxymethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide
Step 1: Preparation of
4-[4-bromomethyl-5-phenyl-3-(trifluoromethyl)-1H-py-
razol-1-yl]benzenesulfonamide
[0765] To a solution of
4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazo-
l-1-yl]benzenesulfonamide prepared in Example 201 (500 mg, 1.3
mmol) in carbon tetrachloride (9 mL) and benzene (4 mL) was added
N-bromosuccinimide (285 mg, 1.6 mmol). The mixture was irradiated
with a sunlamp for 3.5 hours. The reaction mixture was partitioned
between dichloromethane and water and the organic solution was
dried and concentrated to give the desired product, 412 mg
(69%).
Step 2: Preparation of
4-[4-formyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-
-1-yl]benzenesulfonamide
[0766] To a solution of the compound prepared in Step 1 (362 mg,
0.79 mmol) in dimethyl sulfoxide (7 mL) was added collidine (0.14
mL, 1.0 mmol). The solution was heated at 120.degree. C. for 3
hours and then kept at overnight at room temperature. The reaction
solution was partitioned between ethyl acetate and water and the
organic solution was washed with water, dried and concentrated. The
residue was chromatographed (1:1 hexane:ethyl acetate) to give the
desired product (205 mg, 66%).
Step 3: Preparation of
4-[4-hydroxymethyl-5-phenyl-3-(trifluoromethyl)-1H--
pyrazol-1-yl]benzenesulfonamide
[0767] To a solution of the aldehyde prepared in Step 2 (165 mg,
0.41 mmol) in methanol (3.5 mL) at 0.degree. C. was added sodium
borohydride (16 mg, 0.41 mmol). The reaction solution was kept at
0.degree. C. for 2.5 hours. The reaction was quenched with the
addition of an aqueous 1M KHSO.sub.4 solution (3 mL). The mixture
was extracted with dichloromethane and the organic solution dried
and concentrated. The residue was chromatographed on silica (1:1
hexane:ethyl acetate) to give the desired product (36 mg, 46%):
m.p. 179-180.degree. C.; .sup.1H NMR d 7.91 (m, 2H), 7.53-7.40 (m,
5H), 6.75 (s, 2H), 4.53 (d, 2h, 5.0 Hz), 4.30 (t, 1H, J=5.0
Hz).
Example 205
[0768] 95
4-(4-Chloro-3-isobutyl-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide
[0769] To a solution of the pyrazole prepared in Example 175 (0.15
g, 0.42 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added an excess of
sulfuryl chloride slowly at room temperature. The mixture was
stirred at room temperature for 2 hours, quenched with water and
the aqueous layer extracted three time with methylene chloride. The
combined organic layers were dried over MgSO.sub.4 and concentrated
to give an oil which was purified by flash chromatography on silica
gel using 70:30 hexane/ethyl acetate as eluent to give the desired
compound: HRMS m/z 389.0970 (calc'd for
C.sub.19H.sub.20ClN.sub.3SO.sub.2, 389.0965).
[0770] The following compounds in Table X were prepared according
to procedures similar to that examplified in Examples 197-205, with
the substitution of the appropriate starting material.
10TABLE X 96 Ex. R.sup.3 R.sup.2 A M.P. (.degree. C.) Analytical
206 Cl H 4-F 175-178 Calc C, 51.22; H, 3.15; N, 11.94 Obs. C,
51.43; H, 3.10; N, 11.82 207 Br H 4-Cl 209-210 Calc. C, 43.66; H,
2.69; N, 10.18 Obs. C,43.74; H,2.70; N,10.23 208 Cl H H 172-174
Calc. C, 53.98; H, 3.62; N, 12.59 Cl, 10.62; S, 9.60 Obs. C, 54.17;
H, 3.64, N, 12.45 Cl, 10.46; S, 9.42 209 Cl H 3,5-di-Cl,
4-OCH.sub.3 211-212 Calc. C, 44.41; H, 2.80; N, 9.71 Obs. C, 44.72;
H,3.04, N, 9.72 210 Br H 4-CH.sub.3 ND HRMS: 391.0003 211 Cl H
4-CH.sub.3 160-163 Calc. C, 55.25; H, 4.06; N, 12.08 Obs. C, 55.06;
H, 4.03, N, 12.02 212 Cl H 3-Cl, 4-OCH.sub.3 ND Calc. C, 48.25; H,
3.29; N, 10.55 Cl, 17.80; S, 8.05 Obs. C, 48.10; H, 3.31, N, 10.52
Cl, 17.70; S, 7.98 213 Cl H 4-OCH.sub.3 155-156 Calc. C, 52.82; H,
3.88; N, 11.55 Obs. C, 52.18; H, 3.93, N, 11.41 214 Br H
4-OCH.sub.3 130-132 215 CN H 4-OCH.sub.3 216-219 HRMS: 355.0860 216
Cl H 3,5-di-F, 4-OCH.sub.3 198-199 Calc. C, 48.07; H, 3.03; N,
10.51 Obs. C, 48.45; H, 3.55, N, 10.10 217 SO.sub.2CH.sub.3 H Cl
182-185 Calc. C, 46.66; H, 3.43; N, 10.20 Obs. C, 46.57; H, 3.49,
N, 10.39 218 C.sub.2H.sub.5 CF.sub.3 H 177-178 Calc. C, 54.68; H,
4.08; N, 10.62 Obs. C, 54.61; H, 4.10; N, 10.54 219 CH.sub.3
CF.sub.3 4-OCH.sub.3 158-159 Calc. C, 52.55; H, 3.92; N, 10.21 Obs.
C, 52.27; H, 4.00; N, 10.16 220 CH.sub.3 CF.sub.3 4-Cl 154-155
Calc. C, 49.10; H, 3.15; N, 10.10 Obs. C, 49.05; H, 3.02; N, 9.96
221 CH.sub.3 CF.sub.3 4-F 103-104 Calc. C, 51.13; H, 3.28; N, 10.52
Obs. C, 51.09; H, 3.26; N, 10.34 222 C.sub.2H.sub.5 CF.sub.3 4-Cl
ND Calc. C, 50.30; H, 3.52; N, 9.77 Obs. C, 50.40; H, 3.51; N, 9.72
223 CH.sub.3 CF.sub.3 4-CH.sub.3 144-145 Calc. C, 54.68; H, 4.08;
N, 10.62 Obs. C, 54.38; H, 3.87; N, 10.31 224 C.sub.2H.sub.5
CF.sub.3 4-CH.sub.3 142-143 Calc. C, 55.74; H, 4.43; N, 10.26 Obs.
C, 55.60; H, 4.37; N, 10.17 225 C.sub.2H.sub.5 CF.sub.3 4-OCH.sub.3
160-161 Calc. C, 53.64; H, 4.26; N, 9.87 Obs. C, 53.55; H, 4.23; N,
9.65 226 C.sub.2H.sub.5 CF.sub.3 3-F, 4-OCH.sub.3 156-157 Calc. C,
51.46; H, 3.86; N, 9.47 Obs. C, 51.27; H, 3.75; N, 9.33 227 Br
CHF.sub.2 4-Cl 224-226 Calc. C, 41.53; H, 2.40; N, 9.08 Obs. C,
41.50; H, 2.38; N, 9.00 228 Cl CHF.sub.2 3,5-di-Cl, 4-OCH.sub.3
92-102 (dec) Calc C, 42.30; H, 2.51; N, 8.70 Obs. C, 42.50; H,
2.67, N, 8.56 229 Cl CHF.sub.2 H 174-176 Calc. C, 50.07; H, 3.15;
N, 10.95 Obs. C, 50.07; H, 3.18, N, 10.98 230 Br CHF.sub.2 H
184-186 Calc C, 44.87; H, 2.82; N, 9.81 Obs. C, 44.98; H, 2.81, N,
9.64 231 Cl CHF.sub.2 4-OCH.sub.3 171-172 HRMS: 413.0351 232 Cl CN
H 174-177 (sub) Calc. C, 53.56; H, 3.09; N, 15.61; Cl, 9.98; S,
8.94 Obs. C, 53.81; H, 3.18; N, 15.43; Cl, 9.78; S, 8.91 233 Cl CN
4-Cl ND Calc. C, 48.87; H, 2.56; N, 14.25; Cl, 18.03; S, 8.15 Obs.
C, 48.99; H, 2.55; N, 14.30; Cl, 17.96; S, 8.08 234 Cl CN 4-F ND
Calc. C, 51.00; H, 2.68; N, 14.87; Cl, 9.41; S, 8.51 Obs. C, 51.19;
H, 2.73; N, 14.98; Cl, 9.22; S, 8.56 235 Br CN 4-F ND Calc. C,
45.62; H, 2.39; N, 13.30; Br, 18.97; S, 7.61 Obs. C, 45.51; H,
2.36; N, 13.21; Br, 19.09; S, 7.51 236 Br CN H ND Calc. C, 47.66;
H, 2.75; N, 13.89; Br, 19.81; S, 7.95 Obs. C, 47.62; H, 2.77; N,
13.77; Br, 19.74; S, 8.04 237 Br CO.sub.2C.sub.2H.sub.5 4-Cl ND
HRMS: 482.9707 238 Cl CO.sub.2CH.sub.3 H ND HRMS: 342.0495 239 Cl
CO.sub.2CH.sub.3 4-Cl ND HRMS: 426.0128 240 Cl
CO.sub.2C.sub.2H.sub.5 4-Cl ND HRMS: 440.0207 241 Cl
CO.sub.2CH.sub.3 4-F ND HRMS: 410.0391 242 Br CO.sub.2CH.sub.3 4-F
ND HRMS: 453.9880 243 Cl CO.sub.2CH.sub.3 4-OCH.sub.3, 3-Cl ND
Calc. C, 47.38; H, 3.31; N, 9.21; Cl, 15.54; S, 7.03 Obs. C, 47.10;
H, 3.26; N, 9.01; Cl, 15.74; S, 6.92 244 Cl CO.sub.2CH.sub.3
4-OCH.sub.3, 3,5-di-Cl 198-199 Calc. C, 44.06; H, 2.88; N, 8.56.
Obs. C, 43.59; H, 2.77; N, 8.44 245 Cl CO.sub.2CH.sub.3
4-OCH.sub.3, 3-Br ND Calc. C, 43.18, H, 3.02; N, 8.39; S, 6.40 Obs.
C, 43.25; H, 2.97; N, 8.40; S, 6.59 246 Cl CONH.sub.2 H ND HRMS:
377.0539 247 Cl CONH.sub.2 4-Cl ND HRMS: 411.0115 248 Cl CONH.sub.2
4-F ND HRMS: 395.0397 249 Br CONH.sub.2 4-F ND Calc. C, 43.75, H,
2.75; N, 12.75; Br, 18.19; S, 7.30 Obs. C, 43.65; H, 2.78; N,
12.66; Br, 18.13; S, 7.21 250 Br CONH.sub.2 H ND HRMS: 419.9920 251
Cl CO.sub.2H H ND HRMS: 377.0249 252 Cl CO.sub.2H 4-Cl ND Calc. C,
46.62, H, 2.69; N, 10.19; Cl, 17.20; S, 7.78 Obs. C, 46.59, H,
2.68; N, 10.21; Cl, 17.25; S, 7.73 253 Cl CO.sub.2H 4-OCH.sub.3,
3,5-di-Cl 220 (dec) Calc. C, 42.83; H, 2.54; N,8.81 Obs. C, 43.65;
H, 2.52; N, 8.78 254 Cl CH.sub.3 H ND Calc. C, 55.25; H, 4.06; N,
12.08 Obs. C, 55.24; H, 4.26; N, 12.17 255 Cl CH.sub.2OH H 195-197
HRMS: 363.0431 256 Cl CH.sub.2OH 4-Cl 203-204 Calc. C, 48.25; H,
3.29; N, 10.55 Obs. C, 48.36; H, 3.27; N, 10.50 257 Cl
(CH.sub.2).sub.2CO.sub.2H 4-Cl 212-214 Calc. C, 49.10; H, 3.43; N,
9.54 Obs. C, 49.23; H, 3.45; N, 9.49 258 OCH.sub.3 CF.sub.3 H
137-138 Calc. C, 51.38; H, 3.55; N, 10.57 Obs. C, 51.40; H, 3.47;
N, 10.47
Example 259
[0771] 97
4-[4-Chloro-3-cyano-5-[4-(fluoro)phenyl])-1H-pyrazol-1-yl]-N-[(dimethylami-
no)methylene] benzenesulfonamide
[0772] Increasing the polarity of the eluant used in the
purification in Example 234 to 60% ethyl acetate, upon
concentration of the appropriate fractions, yielded
4-[4-chloro-3-cyano-5-[4-(fluoro)phenyl])-1H-pyrazol-1-
-yl]-N-[(dimethylamino)methylene]benzenesulfonamide (0.485 g, 15%):
High Resolution Mass Spectrum (MLi+) calc'd: 438.0779. Found:
438.0714: Elemental analysis calc'd for
C.sub.19H.sub.15N.sub.5O.sub.2FClS: C, 52.84: H, 3.50: N, 16.22;
Cl, 8.21; S, 7.42. Found: C, 52.76; H, 3.52; N, 16.12; Cl, 8.11; S,
7.35.
Example 260
[0773] 98
4-[4-Bromo-3-cyano-5-phenyl-1H-pyrazol-1-yl]-N-[(dimethylamino)methylene]b-
enzenesulfonamide
[0774] Similarly,
4-[4-bromo-3-cyano-5-phenyl-1H-pyrazol-1-yl]-N-[(dimethy-
lamino)methylene]benzenesulfonamide was isolated from the
purification of Example 235 (0.153 g, 28%): High Resolution Mass
Spectrum (M+) calc'd: 457.0208. Found: 457.0157. Elemental analysis
calc'd for C.sub.19H.sub.16N.sub.5O.sub.2BrS: C, 49.79: H, 3.52: N,
15.28; Br, 17.43; S, 6.99. Found: C, 49.85; H, 3.56; N, 15.10; Br,
17.52; S, 6.87.
Example 261
[0775] 99
4-[1-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonami-
de
Step 1: Preparation of
N,N-bis(4-methoxybenzyl)-4-(aminosulfonyl)acetophen- one
[0776] To a solution of 4-(aminosulfonyl)acetophenone (2.0 g, 9.0
mmol) in dimethylsulfoxide (25 mL) was added sodium hydride (450
mg, 19.0 mmol). The reaction mixture was stirred for 45 minutes and
then 4-methoxybenzyl bromide (3.5 g, 19.0 mmol) in
dimethylsulfoxide (5 mL) was added via cannula. The mixture was
stirred at room temperature for 24 hours and partitioned between
ethyl acetate and pH 7 buffer. The aqueous solution was extracted
with ethyl acetate. The organic solution was dried (MgSO.sub.4) and
concentrated. The residue was chromatographed on silica (2:1
hexane:ethyl acetate) to give the desired product (815 mg,
21%).
Step 2: Preparation of
N,N-bis(4-methoxybenzyl)-4-[1-(4-fluorophenyl)-3-tr-
ifluoromethyl-1H-pyrazol-5-yl]benzenesulfonamide
[0777] To a 25% sodium methoxide solution in methanol (0.2 mL) was
added ethyl trifluoroacetate (75 mg, 0.53 mmol) and the protected
acetophenone from Step 1 (235 mg, 0.53 mmol). THF (0.5 mL) was
added and the reaction mixture was heated at reflux for 2 hours and
then stirred at room temperature overnight. The mixture was
partitioned between ether and 1N HCl solution. The organic solution
was dried and concentrated to give the crude diketone (279 mg),
which was diluted with absolute ethanol (2.5 mL). To this slurry
was added pyridine (49 mg, 0.62 mmol) and 4-fluorophenylhydrazine
hydrochloride (80 mg, 0.50 mmol). The mixture was stirred at room
temperature for 24 hours and concentrated in vacuo. The residue was
dissolved in methylene chloride and washed with 1N HCl. The organic
solution was dried and concentrated. The residue was
chromatographed on silica (3:1 hexane:ethyl acetate) to give the
protected pyrazole (159 mg, 51%).
Step 3: Preparation of
4-[1-(4-fluorophenyl)-3-trifluoromethyl-1H-pyrazol--
5-yl]benzenesulfonamide
[0778] To a solution of the protected pyrazole (50 mg, 0.08 mmol)
in acetonitrile (1 mL) and water (0.3 mL) was added ceric ammonium
nitrate (360 mg, 0.65 mmol). The reaction solution was kept at room
temperature for 16 hours. The solution was poured into water (15
mL) and extracted with ethyl acetate (2.times.25 mL). The combined
extracts were dried (MgSO.sub.4) and concentrated. The residue was
chromatographed on silica (2:1 hexane:ethyl acetate) to give the
desired product (13 mg, 42%): .sup.1H NMR (CD.sub.3OD) 7.88 (d,2H),
7.46 (d, 2H), 7.39 (dd, 2H), 7.21 (t, 2H), 7.06 (s, 1H).
Example 262
[0779] 100
4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonam-
ide
[0780] The title compound was prepared using the procedure
described in Example 261: HRMS m/z 397.0702 (calc'd for
C.sub.17H.sub.14N.sub.3O.sub.3- SF.sub.3, 397.0708).
Biological Evaluation
[0781] Rat Carrageenan Foot Pad Edema Test
[0782] The carrageenan foot edema test was performed with
materials, reagents and procedures essentially as described by
Winter, et al., (Proc. Soc. Exp. Biol. Med., 111, 544 (1962)). Male
Sprague-Dawley rats were selected in each group so that the average
body weight was as close as possible. Rats were fasted with free
access to water for over sixteen hours prior to the test. The rats
were dosed orally (1 mL) with compounds suspended in vehicle
containing 0.5% methylcellulose and 0.025% surfactant, or with
vehicle alone. One hour later a subplantar injection of 0.1 mL of
1% solution of carrageenan/sterile 0.9% saline was administered and
the volume of the injected foot was measured with a displacement
plethysmometer connected to a pressure transducer with a digital
indicator. Three hours after the injection of the carrageenan, the
volume of the foot was again measured. The average foot swelling in
a group of drug-treated animals was compared with that of a group
of placebo-treated animals and the percentage inhibition of edema
was determined (Otterness and Bliven, Laboratory Models for Testing
NSAIDS, in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino,
ed. 1985)). The % inhibition shows the % decrease from control paw
volume determined in this procedure and the data for selected
compounds in this invention are summarized in Table 1.
[0783] Rat Carrageenan-Induced Analgesia Test
[0784] The analgesia test using rat carrageenan was performed with
materials, reagents and procedures essentially as described by
Hargreaves, et al., (Pain, 32, 77 (1988)). Male Sprague-Dawley rats
were treated as previously described for the Carrageenan Foot Pad
Edema test. Three hours after the injection of the carrageenan, the
rats were placed in a special plexiglass container with a
transparent floor having a high intensity lamp as a radiant heat
source, positionable under the floor. After an initial twenty
minute period, thermal stimulation was begun on either the injected
foot or on the contralateral uninjected foot. A photoelectric cell
turned off the lamp and timer when light was interrupted by paw
withdrawal. The time until the rat withdraws its foot was then
measured. The withdrawal latency in seconds was determined for the
control and drug-treated groups, and percent inhibition of the
hyperalgesic foot withdrawal determined. Results are shown in Table
XI.
11TABLE XI RAT PAW EDEMA ANALGESIA % Inhibition % Inhibition
Examples @ 10 mg/kg body weight @ 30 mg/kg body weight 1 44 94 2 35
38 58 36 65 59 25 41 60 49 39 82 22* 86 42* 98 2* 117 32 129 47*
170 18* 171 14 37 188 32* 197 45* 27 199 35 *Assay performed at 30
mg/kg body weight
[0785] Evaluation of COX I and COX II Activity In Vitro
[0786] The compounds of this invention exhibited inhibition in
vitro of COX II. The COX II inhibition activity of the compounds of
this invention illustrated in the Examples was determined by the
following methods.
[0787] a. Preparation of Recombinant CoX Baculoviruses
[0788] A 2.0 kb fragment containing the coding region of either
human or murine COX-I or human or murine COX-II was cloned into a
BamHI site of the baculovirus transfer vector pVL1393 (Invitrogen)
to generate the baculovirus transfer vectors for COX-I and COX-II
in a manner similar to the method of D.R. O'Reilly et al
(Baculovirus Expression Vectors: A Laboratory Manual (1992)).
Recombinant baculoviruses were isolated by transfecting 4 pg of
baculovirus transfer vector DNA into SF9 insect cells
(2.times.10e8) along with 200 ng of linearized baculovirus plasmid
DNA by the calcium phosphate method. See M. D. Summers and G. E.
Smith, A Manual of methods for Baculovirus Vectors and Insect Cell
Culture Procedures, Texas Agric. Exp. Station Bull. 1555 (1987).
Recombinant viruses were purified by three rounds of plague
purification and high titer (10E7-10E8 pfu/ml) stocks of virus were
prepared. For large scale production, SF9 insect cells were
infected in 10 liter fermentors (0.5.times.10.sup.6/ml) with the
recombinant baculovirus stock such that the multiplicity of
infection was 0.1. After 72 hours the cells were centrifuged and
the cell pellet homogenized in Tris/Sucrose (50 mM: 25%, pH 8.0)
containing 1% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesul-
fonate (CHAPS). The homogenate was centrifuged at 10,000xG for 30
minutes, and the resultant supernatant was stored at -80.degree. C.
before being assayed for COX activity.
[0789] b. Assay for COX I and COX II Activity:
[0790] COX activity was assayed as PGE2 formed/.mu.g protein/time
using an ELISA to detect the prostaglandin released.
CHAPS-solubilized insect cell membranes containing the appropriate
COX enzyme were incubated in a potassium phosphate buffer (50 mM,
pH 8.0) containing epinephrine, phenol, and heme with the addition
of arachidonic acid (10 .mu.M). Compounds were pre-incubated with
the enzyme for 10-20 minutes prior to the addition of arachidonic
acid. Any reaction between the arachidonic acid and the enzyme was
stopped after ten minutes at 37.degree. C./room temperature by
transferring 40 .mu.l of reaction mix into 0.160 .mu.l ELISA buffer
and 25 .mu.M indomethacin. The PGE2 formed was measured by standard
ELISA technology (Cayman Chemical). Results are shown in Table
XII.
12TABLE XII Human COX II Human COX I Example ID.sub.50 .mu.M
ID.sub.50 .mu.M 1 <.1 18 2 <.1 15.0 3 <.1 >100 4 .6
37.5 5 <.1 6.3 6 .2 78.7 7 14 >100 8 37.7 >100 9 .1 55.2
10 2.7 >100 12 20 >100 55 22 77.9 56 <.1 11.7 57 47.9
>100 58 <.1 5.7 59 <.1 26.8 60 <.1 .8 82 <.1 1.1 84
<.1 65.5 85 73.6 >100 86 .5 >100 96 6.5 >100 97 96
>100 98 <.1 1.7 117 .3 >100 128 1.1 >100 129 <.1
13.5 130 3.6 12.5 131 .2 >100 138 .6 <.1 170 .1 >100 171
.8 >100 172 4.2 >100 173 4.7 >100 174 3.5 100 175 66.9
>100 176 .3 >100 187 1.1 13.6 188 .2 19.8 196 .6 4.1 197
<.1 3.4 198 4.2 56.5 199 <.1 <.1 200 <.1 .5 201 <.1
2.2 202 <.1 91 203 27 >100 204 6.7 >100 205 <.1 2.1 259
1.1 >100 260 1.1 >100 261 <.1 <.1 262 <.1 <.1
[0791] Also embraced within this invention is a class of
pharmaceutical compositions comprising one or more compounds of
Formula I in association with one or more non-toxic,
pharmaceutically acceptable carriers and/or diluents and/or
adjuvants (collectively referred to herein as "carrier" materials)
and, if desired, other active ingredients. The compounds of the
present invention may be administered by any suitable route,
preferably in the form of a pharmaceutical composition adapted to
such a route, and in a dose effective for the treatment intended.
The compounds and composition may, for example, be administered
intravascularly, intraperitoneally, subcutaneously, intramuscularly
or topically.
[0792] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or capsules.
The active ingredient may also be administered by injection as a
composition wherein, for example, saline, dextrose or water may be
used as a suitable carrier.
[0793] The amount of therapeutically active compound that is
administered and the dosage regimen for treating a disease
condition with the compounds and/or compositions of this invention
depends on a variety of factors, including the age, weight, sex and
medical condition of the subject, the severity of the disease, the
route and frequency of administration, and the particular compound
employed, and thus may vary widely. The pharmaceutical compositions
may contain active ingredient in the range of about 0.1 to 2000 mg,
preferably in the range of about 0.5 to 500 mg and most preferably
between about 1 and 100 mg. A daily dose of about 0.01 to 100 mg/kg
body weight, preferably between about 0.1 and about 50 mg/kg body
weight and most preferably from about 1 to 20 mg/kg body weight,
may be appropriate. The daily dose can be administered in one to
four doses per day.
[0794] For therapeutic purposes, the compounds of this invention
are ordinarily combined with one or more adjuvants appropriate to
the indicated route of administration. If administered per os, the
compounds may be admixed with lactose, sucrose, starch powder,
cellulose esters of alkanoic acids, cellulose alkyl esters, talc,
stearic acid, magnesium stearate, magnesium oxide, sodium and
calcium salts of phosphoric and sulfuric acids, gelatin, acacia
gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl
alcohol, and then tableted or encapsulated for convenient
administration. Such capsules or tablets may contain a
controlled-release formulation as may be provided in a dispersion
of active compound in hydroxypropylmethyl cellulose. Formulations
for parenteral administration may be in the form of aqueous or
non-aqueous isotonic sterile injection solutions or suspensions.
These solutions and suspensions may be prepared from sterile
powders or granules having one or more of the carriers or diluents
mentioned for use in the formulations for oral administration. The
compounds may be dissolved in water, polyethylene glycol, propylene
glycol, ethanol, corn oil, cottonseed-oil, peanut oil, sesame oil,
benzyl alcohol, sodium chloride, and/or various buffers. Other
adjuvants and modes of administration are well and widely known in
the pharmaceutical art.
[0795] Although this invention has been described with respect to
specific embodiments, the details of these embodiments are not to
be construed as limitations.
* * * * *