U.S. patent application number 10/191012 was filed with the patent office on 2004-12-09 for pyrazole substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors.
This patent application is currently assigned to Pharmacia Corporation. Invention is credited to Devadas, Balekudru, Graneto, Matthew J., Lu, Hwang-Fun, Norman, Bryan H., Sikorski, James A., Talley, John J..
Application Number | 20040248943 10/191012 |
Document ID | / |
Family ID | 23821199 |
Filed Date | 2004-12-09 |
United States Patent
Application |
20040248943 |
Kind Code |
A9 |
Talley, John J. ; et
al. |
December 9, 2004 |
Pyrazole substituted hydroxamic acid derivatives as
cyclooxygenase-2 and 5-lipoxygenase inhibitors
Abstract
This invention is in the field of antiinflammatory
pharmaceutical agents and specifically relates to compounds,
compositions and methods for treating disorders mediated by
cyclooxygenase-2 or 5-lipoxygenase, such as inflammation.
Inventors: |
Talley, John J.; (Cambridge,
MA) ; Sikorski, James A.; (Des Peres, MO) ;
Graneto, Matthew J.; (Chesterfield, MO) ; Norman,
Bryan H.; (Indianapolis, IN) ; Devadas,
Balekudru; (Chesterfield, MO) ; Lu, Hwang-Fun;
(Ballwin, MO) |
Correspondence
Address: |
SENNIGER POWERS LEAVITT AND ROEDEL
ONE METROPOLITAN SQUARE
16TH FLOOR
ST LOUIS
MO
63102
US
|
Assignee: |
Pharmacia Corporation
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 0073722 A1 |
April 17, 2003 |
|
|
Family ID: |
23821199 |
Appl. No.: |
10/191012 |
Filed: |
July 8, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10191012 |
Jul 8, 2002 |
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09878538 |
Jun 11, 2001 |
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6432999 |
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09878538 |
Jun 11, 2001 |
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08945840 |
Sep 14, 1998 |
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08945840 |
Sep 14, 1998 |
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PCT/US96/08314 |
May 31, 1996 |
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08945840 |
Sep 14, 1998 |
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08458545 |
Jun 2, 1995 |
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Current U.S.
Class: |
514/340 ;
514/357; 514/365; 514/372; 514/374; 514/378; 514/400; 514/406;
514/408; 514/471; 514/521; 514/575; 546/268.1; 546/330; 546/334;
548/204; 548/214; 548/236; 548/247; 548/338.1; 548/375.1; 549/498;
558/413; 562/621 |
Current CPC
Class: |
B60G 2400/102 20130101;
C07D 263/32 20130101; B64C 2027/004 20130101; B60G 2400/60
20130101; B64C 27/001 20130101; B60G 17/018 20130101; C07D 231/12
20130101; B60G 2400/206 20130101; B60G 2400/25 20130101; B60G
2400/91 20130101 |
Class at
Publication: |
514/340 ;
514/357; 514/365; 514/374; 514/400; 514/372; 514/378; 514/408;
514/406; 514/471; 514/521; 514/575; 546/268.1; 546/330; 546/334;
548/204; 548/214; 548/236; 548/247; 548/338.1; 548/375.1; 549/498;
558/413; 562/621 |
International
Class: |
C07D 277/30; C07D
275/02; C07D 263/34; C07D 261/06 |
Claims
What is claimed is:
1. A compound of Formula II 35wherein A is a ring substituent
selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl,
imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, cyclopentenyl,
phenyl, and pyridyl; wherein A is optionally substituted with a
radical selected from acyl, halo, hydroxyl, lower alkyl, lower
haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy,
aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower
cyanoalkyl, and lower hydroxyalkyl; wherein Y is selected from
lower alkyl, lower alkenyl and lower alkynyl; wherein R.sup.1 is
selected from 5- and 6-membered heterocyclo, lower cycloalkyl,
lower cycloalkenyl and aryl selected from phenyl, biphenyl and
naphthyl, wherein R.sup.1 is optionally substituted at a
substituable position with one or more radicals selected from lower
alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl,
hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower
alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower
alkylsulfinyl, halo, lower alkoxy and lower alkylthio; wherein
R.sup.2 is selected from lower alkyl and amino; and wherein R.sup.5
is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered
heterocyclo and lower cycloalkyl; provided R.sup.2 is amino when A
is pyrazolyl; or a pharmaceutically-acceptable salt thereof.
2. Compound of claim 1 wherein A is selected from thienyl,
oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl,
pyrazolyl, cyclopenzenyl, phenyl, and pyridyl, wherein A is
optionally substituted with a radical selected from formyl, fluoro,
chloro, bromo, methyl, trifluoromethyl, oxo, cyano, carboxyl,
methoxy, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl,
carboxypropyl, and hydroxymethyl; wherein Y is a radical selected
from methyl, ethyl, isooropyl, propyl, butyl, propenyl, butenyl,
propynyl and butynyl; wherein R.sup.1 is selected from thienyl,
oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl,
pyrazolyl, pyridyl, and phenyl, where R.sup.1 is optionally
substituced at a substitutable position with one or more radicals
selected from methyl, trifluoromethyl, hydroxyl, hydroxymethyl,
trifluoromethoxy, methoxymethyl, fluoro, chloro, bromo, methoxy and
methylthio; wherein R.sup.2 is methyl or amino; and wherein R.sup.5
is selected from hydrido, methyl, and phenyl; or a
pharmaceutically-acceptable salt thereof.
3. A compound according to claim 1 selected from
[1-[4-(aminosulfonyl)phen-
yl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]-N-hydroxy-N-methyl-ethanamide;
4-[[4-aminosulfonyl)phenyl]-5-(3,4-dichlorophenyl)-N-hydroxy-2-oxazolebut-
anamide; and
4-(4-fluorophenyl)-N-hydroxy-N-methyl-5-[(4-methylsulfonyl)ph-
enyl]-2-oxazolpropanamide.
4. A compound of Formula III 36wherein A is a ring substituent
selected from thienyl, oxazolyl furyl, pyrrolyl, thiazolyl,
imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, cyclopentenyl,
phenyl, and pyridyl; wherein A is optionally substituted with a
radical selected from acyl, halo, hydroxyl, lower alkyl, lower
haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy,
aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower
cyanoalkyl, and lower hydroxyalkyl; wherein Y is selected from
lower alkyl, lower alkenyl and lower alkynyl; wherein R.sup.1 is
selected from 5- and 6-membered heterocyclo, lower cycloalkyl,
lower cycloalkenyl and aryl selected from phenyl, biphenyl and
naphthyl, wherein R.sup.1 is optionally substituted at a
substitutable position with one or more radicals selected from
lower alkyl, lower haloalkyl, cyano, carboxyl, lower
alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy,
amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl,
lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
wherein R.sup.2 is selected from lower alkyl and amino; and wherein
R.sup.5 is selected from hydrido and alkyl; or a
pharmaceutically-accepta- ble salt thereof.
5. Compound of claim 4 wherein A is selected from thienyl,
oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl,
pyrazolyl, cyclopentenyl, phenyl, and pyridyl, wherein A is
optionally substituted with a radical selected from formyl, fluoro,
chloro, bromo, methyl, trifluoromethyl, oxo, cyaro, carboxyl,
methoxy, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl,
carboxypropyl, and hydroxymethyl; wherein Y is selected from
methyl, ethyl, isopropyl, propyl, butyl, propenyl, butenyl,
propynyl and butynyl; wherein R.sup.1 is selected from thienyl,
oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl,
pyrazolyl, pyridyl, and phenyl, where R.sup.1 is optionally
substituted at a substitutable position with one or more radicals
selected from methyl, trifuoromethyl, hydroxyl, hydroxymethyl,
trifluoromethoxy, methoxymethyl, fluoro, chloro, bromo, methoxy and
methylthio; wherein R.sup.2 is methyl or amino; and wherein R.sup.5
is selected from hydrido, and methyl; or a
pharmaceutically-acceptable salt thereof.
6. A compound according to claim 4 which is
N'-[[1-[4-(aminosulfonyl)pheny-
l]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]methyl]-N'-hydroxyurea.
7. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound of claim 1-6, or a
pharmaceutically-acceptable salt thereof.
8. Use of a compound of claim 1-6, or a pharmaceutically-acceptable
salt thereof for preparing a medica-ment for treating a condition
benefited by the in-hibition of 5-lipoxygenase, cyclooxygenase-2 or
both 5-lipoxygenase and cyclooxygenase-2.
9. Use according to claim 8 wherein the condition is inflammation
or an inflammation-associated disorder.
10. Use according to claim 9 wherein the condition is
inflammation.
11. The method of claim 9 wherein the condition is an
inflammation-associated disorder.
12. The method of claim 11 wherein the inflammation-associated
disorder is arthritis.
13. The method of claim 11 wherein the inflammation-associated
disorder is pain.
14. The method of claim 11 wherein the inflammation-associated
disorder is fever.
Description
FIELD OF THE INVENTION
[0001] This invention is in the field of antiinflammatory
pharmaceutical agents and specifically relates to compounds,
compositions and methods for treating disorders mediated by
cyclooxygenase-2 or 5-lipoxygenase, such as inflammation and
allergic conditions such as asthma.
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 antiinflammatory drug discovery. However, common
non-steroidal antiinflammatory 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-2 (COX-2)" 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] In another portion of the arachidonic acid pathway,
physiologically active leukotrienes, such as leukotriene B.sub.4
(LTB.sub.4), leukotriene C.sub.4 (LTC.sub.4) and leukotriene
D.sub.4 (LTD.sub.4) and other metabolites, are produced by the
5-lipoxygenase-mediated (5-LO) oxidation of arachidonic acid. These
leukotrienes have been implicated in various inflammation-related
disorders and allergic diseases, and thus compounds which inhibit
5-lipoxygenase are useful in the treatment of disease states in
which leukotrienes play an important role.
[0005] It is believed that selective dual inhibitors of both
cyclooxygenase-2 and 5-lipoxygenase, which affect the two enzymes
at low concentrations, will more completely and permanently affect
the damage caused by the various diseases and disorders mediated by
cyclooxygenase-2 and 5-lipoxygenase but without the
gastrointestinal side effects associated with traditional
NSAIDs.
[0006] The references below that disclose antiinflammatory
activity, show continuing efforts to find a safe and effective
antiinflammatory agent. The novel compounds disclosed herein are
such safe and also effective antiinflammatory agents furthering
such efforts. The compounds disclosed herein preferably selectively
inhibit cyclooxygenase-2 over cyclooxygenase-1.
[0007] Compounds which selectively inhibit cyclooxygenase-2 have
been described in U.S. Pat. Nos. 5,380,738, 5,344,991, 5,393,790
and WO documents WO94/15932, WO94/27980, WO95/00501, WO94/13635,
WO94/20480, and WO94/26731.
[0008] Compounds which inhibit 5-lipoxygenase have been described
in U.S. Pat. Nos. 5,364,877, 5,302,603, 5,234,950, 5,098,932 and
5,354,865, among others.
[0009] Compounds which inhibit both cyclooxygenase and
5-lipoxygenase have been described in U.S. Pat. Nos. 5,051,518,
5,298,521, 5,242,940, 5,234,939, and 5,356,898, among others.
However, these previous mixed inhibitors do not selectively inhibit
cyclooxygenase-2 and therefore still cause the gastrointestinal
side effects which substantially reduce their usage and
effectiveness.
[0010] The invention's compounds are found to show usefulness as
dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase with minimal
side effects.
DESCRIPTION OF THE INVENTION
[0011] A class of compounds useful in treating cyclooxygenase-2 and
5-lipoxygenase-mediated disorders is defined by Formula I: 1
[0012] wherein A is a 5- or 6-member ring substituent selected from
partially unsaturated or unsaturated heterocyclo and carbocyclic
rings, wherein A is optionally substituted with a radical selected
from acyl, halo, alkyl, haloalkyl, cyano, nitro, carboxyl, alkoxy,
oxo, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, and
hydroxyalkyl;
[0013] wherein Y is one or more radicals selected from alkyl,
alkynyl, alkenyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl,
arylaminoalkyl, acyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
heterocyclo and heterocycloalkyl;
[0014] wherein R.sup.1 is one or more substituents selected from
heterocyclo, cycloalkyl, cycloalkenyl and aryl, wherein R.sup.1 is
optionally substituted at a substitutable position with one or more
radicals selected from alkyl, haloalkyl, cyano, carboxyl,
alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,
alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo,
alkoxy and alkylthio;
[0015] wherein R.sup.2 is selected from alkyl and amino;
[0016] wherein R.sup.3 is a direct bond or a radical selected from
2
[0017] wherein R.sup.4 is selected from hydrido, hydroxyl, alkyl,
aryl, heterocyclo and cycloalkyl;
[0018] wherein R.sup.5 is selected from hydrido, alkyl, aryl,
heterocyclo and cycloalkyl; and
[0019] wherein R.sup.6 is selected from hydrido and hydroxyl;
provided R.sup.2 is amino when A is pyrazolyl;
[0020] or a pharmaceutically-acceptable salt thereof.
[0021] 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
the invention would be useful to treat arthritis, including but not
limited to rheumatoid arthritis, spondyloarthopathies, gouty
arthritis, osteoarthritis, systemic lupus erythematosus and
juvenile arthritis. Such compounds of the invention would be useful
in the treatment of asthma, bronchitis, menstrual cramps,
tendinitis, bursitis, skin-related conditions such as psoriasis,
eczema, burns and dermatitis, and from post-operative inflammation
including from ophthalmic surgery such as cataract surgery and
refractive surgery. Compounds of the invention 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 or treatment of cancer,
such as colorectal cancer. Compounds of the invention 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, neuromuscular junction disease including
myasthenia gravis, white matter disease including multiple
sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,
polymyositis, gingivitis, nephritis, hypersensitivity, swelling
occurring after injury, myocardial ischemia. and the like. The
compounds would also be useful in the treatment of ophthalmic
diseases, such as retinitis, retinopathies, uveitis, ocular
photophobia, and of acute injury to the eye tissue. The compounds
would also be useful in the treatment of pulmonary inflammation,
such as that associated with viral infections and cystic fibrosis.
The compounds would also be useful for the treatment of certain
central nervous system disorders such as cortical dementias
including Alzheimer's disease. The compounds of the invention are
useful as anti-inflammatory agents, such as for the treatment of
arthritis, with the additional benefit of having significantly less
harmful side effects. These compounds would also be useful in the
treatment of allergic rhinitis, syndrome, atherosclerosis and
central nervous system damage resulting from stroke, ischemia and
trauma. The compounds would also be useful in the treatment of
pain, but not limited to postoperative pain, dental pain, muscular
pain, and pain resulting from cancer.
[0022] Besides being useful for human treatment, these compounds
are also useful for treatment of mammals, including horses, dogs,
cats, rats, mice, sheep, pigs, etc.
[0023] The present compounds may also be used in co-therapies,
partially or completely, in place of other conventional
antiinflammatories, such as together with steroids, NSAIDs,
LTB.sub.4 antagonists and LTA.sub.4 hydrolase inhibitors.
[0024] Suitable LTB.sub.4 inhibitors include, among others,
ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo
Denmark compound ETH-615, Lilly compound LY-293111, Ono compound
ONO-4057, Terumo compound TMK-688, Lilly compounds LY-213024,
264086 and 292728, Ono compound ONO-LB457, Searle compound
SC-53228, calcitrol, Lilly compounds LY-210073, LY223982, LY233469,
and LY255283, ONO compound ONO-LB-448, Searle compounds SC-41930,
SC-50605 and SC-51146, and SK&F compound SKF-104493.
Preferably, the LTB.sub.4 inhibitors are selected from ebselen,
Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark
compound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057,
and Terumo compound TMK-688.
[0025] Suitable 5-LO inhibitors include, among others, masoprocol,
tenidap, zileuton, pranlukast, tepoxalin, rilopirox, flezelastine
hydrochloride, enazadrem phosphate, and bunaprolast.
[0026] The present invention preferably includes compounds which
selectively inhibit cyclooxygenase-2 over cyclooxygenase-1 as well
as inhibit the 5-lipoxygenase enzyme. Preferably, the compounds
have a cyclooxygenase-2 IC.sub.50 of less than about 10 .mu.M. and
also have a selectivity ratio of cyclooxygenase-2 inhibition over
cyclooxygenase-1 inhibition of at least 10, and more preferably of
at least 100, and inhibit 5-lipoxygenase at less than about 10
.mu.M. Even more preferably, the compounds have a cyclooxygenase-1
IC.sub.50 of greater than about 10 .mu.M, and more preferably of
greater than 20 .mu.m and have a 5-lipoxygenase IC.sub.50 of less
than about 1 .mu.M. Such preferred selectivity may indicate an
ability to reduce the incidence of common NSAID-induced side
effects.
[0027] A preferred class of compounds consists of those compounds
of Formula I wherein A is selected from thienyl, oxazolyl, furyl,
pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl,
pyrazolyl, cyclopentenyl, phenyl, and pyridyl, wherein A is
optionally substituted with a radical selected from acyl, halo,
lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower
alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl,
lower cyanoalkyi, and lower hydroxyalkyl; wherein Y is a radical
selected from lower alkyl, lower alkynyl, lower alkenyl, lower
hydroxyalkyl, lower aminoalkyl, lower alkylaminoalkyl, lower
arylaminoalkyl, lower acyl, aryl, lower aralkyl, lower cycloalkyl,
lower cycloalkylalkyl, 5- or 6-membered heterocyclo and lower
heterocycloalkyl; wherein R.sup.1 is one or more substituents
selected from 5- and 6-membered heterocyclo, lower cycloalkyl,
lower cycloalkenyl and aryl selected from phenyl, biphenyl and
naphthyl, where R.sup.1 is optionally substituted at a
substitutable position with one or more radicals selected from
lower alkyl, lower haloalkyl, cyano, carboxyl, lower
alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy,
amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl,
lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
wherein R.sup.2 is selected from lower alkyl and amino; wherein
R.sup.3 is a direct bond or a radical selected from 3
[0028] wherein R.sup.4 is selected from hydrido, hydroxyl, lower
alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl;
wherein R.sup.5 is selected from hydrido, lower alkyl, phenyl, 5-
and 6-membered heterocyclo and lower cycloalkyl; and wherein
R.sup.6 is selected from hydrido and hydroxyl; or a
pharmaceutically-acceptable salt thereof.
[0029] A class of compounds of particular interest consists of
those compounds of Formula I wherein A is a radical selected from
thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl,
isoxazolyl, pyrazolyl, cyclopentenyl, phenyl, and pyridyl, wherein
A is optionally substituted with a radical selected from formyl,
fluoro, chloro, bromo, methyl, trifluoromethyl, oxo, cyano,
carboxyl, methoxy, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl,
acetyl, carboxypropyl, and hydroxymethyl; wherein Y is a radical
selected from ethyl, propyl, isopropyl, butyl, 1-propynyl,
2-propynyl, 1-butyn-3-yl, 1-propenyl, 2-propenyl, acetyl,
dihydroxypropyl, hydroxyethyl, 1-amino-ethyl, 1-amino-propyl,
1-(N-methylamino)propyl, 1-(N,N-dimethylamino)propyl,
1-(N-phenylamino)propyl, triazolyl, thienyl, benzyl, phenylethyl,
cyclohexylmethyl, cyclopentylethyl, triazolylmethyl, thienylmethyl
and phenyl optionally substituted at a substitutable position with
one or more radicals selected from fluoro, chloro, bromo, hydroxyl,
methyl, and methoxy; wherein R.sup.1 is a substituent selected from
thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl,
isoxazolyl, pyrazolyl, pyridyl, and phenyl, where R.sup.1 is
optionally substituted at a substitutable position with one or more
radicals selected from methyl, trifluoromethyl, hydroxyl,
hydroxymethyl, trifluorometoxy, nitro, methoxymethyl, fluoro,
chloro, bromo, methoxy and methylthio; wherein R.sup.2 is methyl or
amino; wherein R.sup.3 is a direct bond or a radical selected from
4
[0030] wherein R.sup.4 is selected from hydrido, hydroxyl, methyl,
and phenyl; wherein R.sup.5 is selected from hydrido, methyl, and
phenyl; and wherein R.sup.6 is selected from hydrido and hydroxyl;
or a pharmaceutically-acceptable salt thereof.
[0031] Within Formula I there is a subclass of compounds of high
interest represented by Formula II: 5
[0032] wherein A is a ring substituent selected from thienyl,
oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl,
isoxazolyl, pyrazolyl, cyclopentenyl, phenyl, and pyridyl; wherein
A is optionally substituted with a radical selected from acyl,
halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro,
carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower
carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; wherein Y
is selected from lower alkyl, lower alkenyl and lower alkynyl;
wherein R.sup.1 is selected from 5- and 6-membered heterocyclo,
lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl,
biphenyl and naphthyl, wherein R.sup.1 is optionally substituted at
a substitutable position with one or more radicals selected from
lower alkyl, lower haloalkyl, cyano, carboxyl, lower
alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy,
amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl,
lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
wherein R.sup.2 is selected from lower alkyl and amino; and wherein
R.sup.5 is selected from hydrido, lower alkyl, phenyl, 5- and
6-membered heterocyclo and lower cycloalkyl; provided R.sup.2 is
amino when A is pyrazolyl; or a pharmaceutically-acceptable salt
thereof.
[0033] A class of compounds of particular interest consists of
those compounds of Formula II wherein A is selected from thienyl,
oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl,
pyrazolyl, cyclopentenyl, phenyl, and pyridyl, wherein A is
optionally substituted with a radical selected from formyl, fluoro,
chloro, bromo, methyl, trifluoromethyl, oxo, cyano, carboxyl,
methoxy, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl,
carboxypropyl, and hydroxymethyl; wherein Y is a radical selected
from methyl, ethyl, isopropyl, propyl, butyl, propenyl, butenyl,
propynyl and butynyl; wherein R.sup.1 is selected from thienyl,
oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl,
pyrazolyl, pyridyl, and phenyl, where R.sup.1 is optionally
substituted at a substitutable position with one or more radicals
selected from methyl, trifluoromethyl, hydroxyl, hydroxymethyl,
trifluoromethoxy, methoxymethyl, fluoro, chloro; bromo; methoxy and
methylthio; wherein R.sup.2 is methyl or amino; and wherein R.sup.5
is selected from hydrido, methyl, and phenyl; or a
pharmaceutically-acceptable salt thereof.
[0034] Within Formula I there is a second subclass of compounds of
high interest represented by Formula III: 6
[0035] wherein A is a ring substituent selected from thienyl,
oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl,
isoxazolyl, pyrazolyl, cyclopentenyl, phenyl, and pyridyl; wherein
A is optionally substituted with a radical selected from acyl,
halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro,
carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower
carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; wherein Y
is selected from lower alkyl, lower alkenyl and lower alkynyl;
wherein R.sup.1 is selected from 5- and 6-membered heterocyclo,
lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl,
biphenyl and naphthyl, wherein R.sup.1 is optionally substituted at
a substitutable position with one or more radicals selected from
lower alkyl, lower haloalkyl, cyano, carboxyl, lower
alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy,
amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl,
lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
wherein R.sup.2 is selected from lower alkyl and amino; and wherein
R.sup.5 is selected from hydrido and alkyl; or a
pharmaceutically-acceptable salt thereof.
[0036] A class of compounds of particular interest consists of
those compounds of Formula III wherein A is selected from thienyl,
oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl,
pyrazolyl, cyclopentenyl, phenyl, and pyridyl, wherein A is
optionally substituted with a radical selected from formyl, fluoro,
chloro, bromo, methyl, trifluoromethyl, oxo, cyano, carboxyl,
methoxy, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl,
carboxypropyl, and hydroxymethyl; wherein Y is selected from
methyl, ethyl, isopropyl, propyl, butyl, propenyl, butenyl,
propynyl and butynyl; wherein R.sup.1 is selected from thienyl,
oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl,
pyrazolyl, pyridyl, and phenyl, where R.sup.1 is optionally
substituted at a substitutable position with one or more radicals
selected from methyl, trifluoromethyl, hydroxyl, hydroxymethyl,
trifluoromethoxy, methoxymethyl, fluoro, chloro, bromo, methoxy and
methylthio; wherein R.sup.2 is methyl or amino; and wherein R.sup.5
is selected from hydrido, and methyl; or a
pharmaceutically-acceptable salt thereof.
[0037] A class of compounds of particular interest consists of
those compounds of Formula I
[0038]
[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]methyl-N-hydroxy-N-
-methyl-dithiocarbamate;
[0039]
[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]methyl-N-
-hydroxy-N-methyl-dithiocarbamate;
[0040]
[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]methyl-N-hydroxy-N-
-methyl-dithiocarbamate;
[0041]
[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]methyl-N-
-hydroxy-N-methyl-dithiocarbamate;
[0042]
[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]methyl-N-
-hydroxy-N-methyl-dithiocarbamate;
[0043]
[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]methyl--
N-hydroxy-N-methyl-dithiocarbamate;
[0044]
[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-oxazoly-
l]methyl-N-hydroxy-N-methyl-dithiocarbamate;
[0045]
[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxazoly-
l]methyl-N-hydroxy-N-methyl-dithiocarbamate;
[0046]
[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazolyl-
]methyl-N-hydroxy-N-methyl-dithiocarbamate;
[0047]
[4-[(4-methylsulfonyl)phenyl]-5-phenyl-2-oxazolyl]methyl-N-hydroxy--
N-methyl-dithiocarbamate;
[0048]
[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]methyl--
N-hydroxy-N-methyl-dithiocarbamate;
[0049]
[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]methyl-N-hydroxy--
N-methyl-dithiocarbamate;
[0050]
[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]methyl--
N-hydroxy-N-methyl-dithiocarbamate;
[0051]
[4-[(4-aminosulfonyl)phenyl]-3-phenyl-5-isoxazolyl]propyl-N-hydroxy-
-N-methyl-dithiocarbamate;
[0052]
[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-5-isoxazolyl]propyl-
-N-hydroxy-N-methyl-dithiocarbamate;
[0053]
[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-5-isoxazolyl]propyl-
-N-hydroxy-N-methyl-dithiocarbamate;
[0054]
[4-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-5-isoxazolyl]propy-
l-N-hydroxy-N-methyl-dithiocarbamate;
[0055]
[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxyphenyl)-5-isoxazo-
lyl]propyl-N-hydroxy-N-methyl-dithiocarbamate;
[0056]
[4-[(4-aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)-5-isoxazo-
lyl]propyl-N-hydroxy-N-methyl-dithiocarbamate;
[0057]
[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-fluorophenyl)-5-isoxazol-
yl]propyl-N-hydroxy-N-methyl-dithiocarbamate;
[0058]
[4-[(4-methylsulfonyl)phenyl]-3-phenyl-5-isoxazolyl]propyl-N-hydrox-
y-N-methyl-dithiocarbamate;
[0059]
[3-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-5-isoxazolyl]propy-
l-N-hydroxy-N-methyl-dithiocarbamte;
[0060]
[4-[(4-aminosulfonyl)phenyl]-3-phenyl-2-thienyl]propyl-N-hydroxy-N--
methyl-dithiocarbamate;
[0061]
[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-2-thienyl]propyl-N--
hydroxy-N-methyl-dithiocarbamate;
[0062]
[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-2-thienyl]propyl-N--
hydroxy-N-methyl-dithiocarbamate;
[0063]
[4-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-2-thienyl]propyl-N-
-hydroxy-N-methyl-dithiocarbamate;
[0064]
[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxyphenyl)-2-thienyl-
]propyl-N-hydroxy-N-methyl-dithiocarbamate;
[0065]
[4-[(4-aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)-2-thienyl-
]propyl-N-hydroxy-N-methyl-dithiocarbamate;
[0066]
[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-fluorophenyl)-2-thienyl]-
propyl-N-hydroxy-N-methyl-dithiocarbamate;
[0067]
[3-[(4-methylsulfonyl)phenyl]-4-phenyl-5-thienyl]propyl-N-hydroxy-N-
-methyl-dithiocarbamate;
[0068]
[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-5-thienyl]propyl-N-
-hydroxy-N-methyl-dithiocarbamate;
[0069]
[5-[(4-aminosulfonyl)phenyl]-6-phenyl-3-pyridyl]propyl-N-hydroxy-N--
methyl-dithiocarbamate;
[0070]
[5-[(4-aminosulfonyl)phenyl]-6-(4-chlorophenyl)-3-pyridyl]propyl-N--
hydroxy-N-methyl-dithiocarbamate;
[0071]
[5-[(4-aminosulfonyl)phenyl]-6-(4-fluorophenyl)-3-pyridyl]propyl-N--
hydroxy-N-methyl-dithiocarbamate;
[0072]
[5-[(4-aminosulfonyl)phenyl]-6-(4-methoxyphenyl)-3-pyridyl]propyl-N-
-hydroxy-N-methyl-dithiocarbamate;
[0073]
[6-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-3-pyridyl-
]propyl-N-hydroxy-N-methyl-dithiocarbamate;
[0074]
[6-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)-3-pyridyl-
]propyl-N-hydroxy-N-methyl-dithiocarbamate;
[0075]
[5-[(4-aminosulfonyl)phenyl]-6-(3-chloro-4-fluorophenyl)-3-pyridyl]-
propyl-N-hydroxy-N-methyl-dithiocarbamate;
[0076]
[5-[(4-methylsulfonyl)phenyl]-6-phenyl-3-pyridyl]propyl-N-hydroxy-N-
-methyl-dithiocarbamate;
[0077]
[5-(4-chlorophenyl)-6-[(4-methylsulfonyl)phenyl]-3-pyridyl]propyl-N-
-hydroxy-N-methyl-dithiocarbamate;
[0078]
[4-[(4-aminosulfonyl)phenyl]-3-phenyl-2-furyl]propyl-N-hydroxy-N-me-
thyl-dithiocarbamate;
[0079]
[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-2-furyl]propyl-N-hy-
droxy-N-methyl-dithiocarbamate;
[0080]
[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-2-furyl]propyl-N-hy-
droxy-N-methyl-dithiocarbamate;
[0081]
[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-furyl]propyl-N-h-
ydroxy-N-methyl-dithiocarbamate;
[0082]
[4-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-2-furyl]p-
ropyl-N-hydroxy-N-methyl-dithiocarbamate;
[0083]
[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-furyl]p-
ropyl-N-hydroxy-N-methyl-dithiocarbamate;
[0084]
[4-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-2-furyl]pr-
opyl-N-hydroxy-N-methyl-dithiocarbamate;
[0085]
[4-[(4-methylsulfonyl)phenyl]-3-phenyl-2-furyl]propyl-N-hydroxy-N-m-
ethyl-dithiocarbamate;
[0086]
[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-furyl]propyl-N-h-
ydroxy-N-methyl-dithiocarbamate;
[0087]
[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]-1-propyl-N-hydrox-
y-N-methyl-dithiocarbamate;
[0088]
[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]-1-propy-
l-N-hydroxy-N-methyl-dithiocarbamate;
[0089]
[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]-1-propyl-N-hydrox-
y-N-methyl-dithiocarbamate;
[0090]
[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]-1-propy-
l-N-hydroxy-N-methyl-dithiocarbamate;
[0091]
[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]-1-propy-
l-N-hydroxy-N-methyl-dithiocarbamate;
[0092]
[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]-1-prop-
yl-N-hydroxy-N-methyl-dithiocarbamate;
[0093]
[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-oxazoly-
l]-1-propyl-N-hydroxy-N-methyl-dithiocarbamate;
[0094]
[5-[(4-aninosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxazoly-
l]-1-propyl-N-hydroxy-N-methyl-dithiocarbamate;
[0095]
[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazolyl-
]-1-propyl-N-hydroxy-N-methyl-dithiocarbamate;
[0096]
[4-[4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]-1-propyl-N-hydrox-
y-N-methyl-dithiocarbamate;
[0097]
[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-1-prop-
yl-N-hydroxy-N-methyl-dithiocarbamate;
[0098]
[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]-1-propyl-N-hydro-
xy-N-methyl-dithiocarbamate;
[0099]
[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-1-prop-
yl-N-hydroxy-N-methyl-dithiocarbamate;
[0100]
3-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]-2-propenyl-N-hy-
droxy-N-methyl-dithiocarbamate;
[0101]
3-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]-2-pro-
penyl-N-hydroxy-N-methyl-dithiocarbamate;
[0102]
1-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]-2-propenyl-N-hy-
droxy-N-methyl-dithiocarbamate;
[0103]
3-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]-2-pro-
penyl-N-hydroxy-N-methyl-dithiocarbamate;
[0104]
3-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]-2-pro-
penyl-N-hydroxy-N-methyl-dithiocarbamate;
[0105]
3-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]-2-pr-
openyl-N-hydroxy-N-methyl-dithiocarbamate;
[0106]
3-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-oxazo-
lyl]-2-propenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0107]
3-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxazo-
lyl]-2-propenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0108]
3-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazol-
yl]-2-propenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0109]
3-[4-[(4-methylsulfonyl)phenyl]-5-phenyl-2-oxazolyl]-2-propenyl-N-h-
ydroxy-N-methyl-dithiocarbamate;
[0110]
3-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-2-pr-
openyl-N-hydroxy-N-methyl-dithiocarbamate;
[0111]
3-[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]-2-propenyl-N-h-
ydroxy-N-methyl-dithiocarbamate;
[0112]
3-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-2-pr-
openyl-N-hydroxy-N-methyl-dithiocarbamate;
[0113]
3-[1-[(4-aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-2-propenyl-
-N-hydroxy-N-methyl-dithiocarbamate;
[0114]
3-[1-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]--
2-propenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0115]
3-[3-[(4-aminosulfonyl)phenyl]-4-phenyl-1H-pyrazol-1-yl]-2-propenyl-
-N-hydroxy-N-methyl-dithiocarbamate;
[0116]
3-[3-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-1H-pyrazol-1-yl]--
2-propenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0117]
3-[1-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazol-3-yl]--
2-propenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0118]
3-[1-[(4-aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazol-3-yl]-
-2-propenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0119]
3-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-1H-pyra-
zol-3-yl]-2-propenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0120]
3-[1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)-1H-pyra-
zol-3-yl]-2-propenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0121]
3-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-1H-pyraz-
ol-3-yl]-2-propenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0122]
3-[1-[(4-methylsulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-2-propeny-
l-N-hydroxy-N-methyl-dithiocarbamate;
[0123]
3-[5-(4-chlorophenyl)-1-[(4-methylsulfonyl)phenyl]-1H-pyrazol-3-yl]-
-2-propenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0124]
3-[4-[(4-methylsulfonyl)phenyl]-3-phenyl-1H-pyrazol-1-yl]-2-propeny-
l-N-hydroxy-N-methyl-dithiocarbamate;
[0125]
3-[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-1H-pyrazol-1-yl]-
-2-propenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0126]
3-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]-2-propynyl-N-hy-
droxy-N-methyl-dithiocarbamate;
[0127]
3-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]-2-pro-
pynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0128]
3-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]-2-propynyl-N-hy-
droxy-N-methyl-dithiocarbamate;
[0129]
3-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]-2-pro-
pynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0130]
3-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]-2-pro-
pynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0131]
3-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]-2-pr-
opynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0132]
3-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-oxazo-
lyl]-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0133]
3-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxazo-
lyl]-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0134]
3-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazol-
yl]-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0135]
3-[4-[(4-methylsulfonyl)phenyl]-5-phenyl-2-oxazolyl]-2-propynyl-N-h-
ydroxy-N-methyl-dithiocarbamate;
[0136]
3-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-2-pr-
opynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0137]
3-[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]-2-propynyl-N-h-
ydroxy-N-methyl-dithiocarbamate;
[0138]
3-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-2-pr-
opynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0139]
3-[1-[(4-aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-2-propynyl-
-N-hydroxy-N-methyl-dithiocarbamate;
[0140]
3-(1-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]--
2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0141]
3-[3-[(4-aminosulfonyl)phenyl]-4-phenyl-1H-pyrazol-1-yl]-2-propynyl-
-N-hydroxy-N-methyl-dithiocarbamate;
[0142]
3-[3-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-1H-pyrazol-1-yl]--
2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0143]
3-[1-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazol-3-yl]--
2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0144]
3-[1-[(4-aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazol-3-yl]-
-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0145]
3-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-1H-pyra-
zol-3-yl]-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0146]
3-[(1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)-1H-pyr-
azol-3-yl]-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0147]
3-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-1H-pyraz-
ol-3-yl]-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0148]
3-[1-[(4-methylsulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-2-propyny-
l-N-hydroxy-N-methyl-dithiocarbamate;
[0149]
3-[5-(4-chlorophenyl)-1-[(4-methylsulfonyl)phenyl]-1H-pyrazol-3-yl]-
-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0150]
3-[4-[(4-methylsulfonyl)phenyl]-3-phenyl-1H-pyrazol-1-yl]-2-propyny-
l-N-hydroxy-N-methyl-dithiocarbamate;
[0151]
3-[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-1H-pyrazol-1-yl]-
-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0152]
3-[1-[(4-aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-1-methyl-2-
-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0153]
3-[1-[(4-aminosulfonyl)phenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]--
1-methyl-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0154]
3-[3-[(4-aminosulfonyl)phenyl]-4-phenyl-1H-pyrazol-1-yl]-1-methyl-2-
-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0155]
3-[3-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-1H-pyrazol-1-yl]--
1-methyl-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0156]
3-[1-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazol-3-yl]--
1-methyl-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0157]
3-[1-[(4-aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazol-3-yl]-
-1-methyl-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0158]
3-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-1H-pyra-
zol-3-yl]-1-methyl-2-propynyl-N-hydroxy-N-methyl
-dicthiocaroamate;
[0159]
3-[1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)-1H-pyra-
zol-3-yl]-1-methyl-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0160]
3-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-1H-pyraz-
ol-3-yl]-1-methyl-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0161]
3-[1-[(4-methylsulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-1-methyl--
2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0162]
3-[5-(4-chlorophenyl)-1-[(4-methylsulfonyl)phenyl]-1H-pyrazol-3-yl]-
-1-methyl-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0163]
3-[4-[(4-methylsulfonyl)phenyl]-3-phenyl-1H-pyrazol-1-yl]-1-methyl--
2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0164]
3-[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-1H-pyrazol-1-yl]-
-1-methyl-2-propynyl-N-hydroxy-N-methyl-dithiocarbamate;
[0165]
[[4-[(4-aminosulfonyl)phenyl]-3-phenyl-5-isoxazolyl]-1-methyl-2-pro-
penyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0166]
3-[[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-5-isoxazolyl]-1--
methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0167]
3-[[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-5-isoxazolyl]-1--
methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0168]
3-[[4-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-5-isoxazolyl]-1-
-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0169]
3-[[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxyphenyl)-5-isox-
azolyl]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0170]
3-[[4-[(4-aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)-5-isox-
azolyl]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0171]
3-[[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-fluorophenyl)-5-isoxa-
zolyl]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0172]
3-[[4-[(4-methylsulfonyl)phenyl]-3-phenyl-5-isoxazolyl]-1-methyl-2--
propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0173]
3-[[3-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-5-isoxazolyl]-1-
-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0174]
3-[[4-[(4-aminosulfonyl)phenyl]-3-phenyl-2-thienyl]-1-methyl-2-prop-
enyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0175]
3-[[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-2-thienyl]-1-met-
hyl-2-propenyl]-N-hydroxy-N-methyl-dithionarbamate;
[0176]
3-[[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-2-thienyl]-1-met-
hyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0177]
3-[[4-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-2-thienyl]-1-me-
thyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0178]
3-[[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxyphenyl)-2-thie-
nyl]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0179]
3-[[4-[(4-aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)-2-thie-
nyl]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0180]
3-[[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-fluorophenyl)-2-thien-
yl]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0181]
3-[[3-[(4-methylsulfonyl)phenyl]-4-phenyl-5-thienyl]-1-methyl-2-pro-
penyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0182]
3-[[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-5-thienyl]-1-me-
thyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0183]
3-[[5-[(4-aminosulfonyl)phenyl]-6-phenyl-3-pyridyl]-1-methyl-2-prop-
enyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0184]
3-[[5-[(4-aminosulfonyl)phenyl]-6-(4-chlorophenyl)-3-pyridyl]-1-met-
hyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0185]
3-[[5-[(4-aminosulfonyl)phenyl]-6-(4-fluorophenyl)-3-pyridyl]-1-met-
hyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0186]
3-[[5-[(4-aminosulfonyl)phenyl]-6-(4-methoxyphenyl)-3-pyridyl]-1-me-
thyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0187]
3-[[6-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-3-pyri-
dyl]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0188]
3-[[6-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)-3-pyri-
dyl]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0189]
3-[[5-[(4-aminosulfonyl)phenyl]-6-(3-chloro-4-fluorophenyl)-3-pyrid-
yl]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0190]
3-[[5-[(4-methylsulfonyl)phenyl]-6-phenyl-3-pyridyl]-1-methyl-2-pro-
penyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0191]
3-[[5-(4-chlorophenyl)-6-[(4-methylsulfonyl)phenyl]-3-pyridyl]-1-me-
thyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0192]
3-[[4-[(4-aminosulfonyl)phenyl]-3-phenyl-2-furyl]-1-methyl-2-propen-
yl]-N-hydroxy-N-methyl-dithiocarbamate;
[0193]
3-[[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-2-furyl]-1-methy-
l-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0194]
3-[[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-2-furyl]-1-methy-
l-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0195]
3-[[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-furyl]-1-meth-
yl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0196]
3-[[4-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-2-fury-
l]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0197]
3-[[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-fury-
l]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0198]
3-[[4-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-2-furyl-
]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0199]
3-[[4-[(4-methylsulfonyl)phenyl]-3-phenyl-2-furyl]-1-methyl-2-prope-
nyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0200]
3-[[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-furyl]-1-meth-
yl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0201]
3-[[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]-1-methyl-2-pro-
penyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0202]
3-[[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]-1-me-
thyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0203]
3-[[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]-1-methyl-2-pro-
penyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0204]
3-[[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]-1-me-
thyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0205]
3-[[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]-1-me-
thyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0206]
3-[[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]-1-m-
ethyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0207]
3-[[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-oxaz-
olyl]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0208]
3-[[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxaz-
olyl]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0209]
3-[[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazo-
lyl]-1-methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0210]
3-[[4-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]-1-methyl-2-pr-
openyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0211]
3-[[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-1-m-
ethyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0212]
3-[[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]-1-methyl-2-pr-
openyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0213]
3-[[4-(4-chilorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-1--
methyl-2-propenyl]-N-hydroxy-N-methyl-dithiocarbamate;
[0214]
3-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]phenyl-N-hydroxy-
-N-methyl-dithiocarbamate;
[0215]
3-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]phenyl-
-N-hydroxy-N-methyl-dithiocarbamate;
[0216]
3-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]phenyl-N-hydroxy-
-N-methyl-dithiocarbamate;
[0217]
4-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]phenyl-
-N-hydroxy-N-methyl-dithiocarbamate;
[0218]
4-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]phenyl-
-N-hydroxy-N-methyl-dithiocarbamate;
[0219]
4-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]pheny-
l-N-hydroxy-N-methyl-dithiocarbamate;
[0220]
4-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-oxazo-
lyl]phenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0221]
4-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxazo-
lyl]phenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0222]
4-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazol-
yl]phenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0223]
4-[4-[(4-methylsulfonyl)phenyl]-5-phenyl-2-oxazolyl]phenyl-N-hydrox-
y-N-methyl-dithiocarbamate;
[0224]
4-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]pheny-
l-N-hydroxy-N-methyl-dithiocarbamate;
[0225]
3-[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]phenyl-N-hydrox-
y-N-methyl-dithiocarbamate;
[0226]
3-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]pheny-
l-N-hydroxy-N-methyl-dithiocarbamate;
[0227]
4-[1-[(4-aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]phenyl-N-hy-
droxy-N-methyl-dithiocarbamate;
[0228]
4-[1-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]p-
henyl-N-hydroxy-N-methyl-dithiocarbamate;
[0229]
4-[3-[(4-aminosulfonyl)phenyl]-4-phenyl-1H-pyrazol-1-yl]phenyl-N-hy-
droxy-N-methyl-dithiocarbamate;
[0230]
3-[3-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-1H-pyrazol-1-yl]p-
henyl-N-hydroxy-N-methyl-dithiocarbamate;
[0231]
3-[1-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazol-3-yl]p-
henyl-N-hydroxy-N-methyl-dithiocarbamate;
[0232]
4-[1-[(4-aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazol-3-yl]-
phenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0233]
4-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-1H-pyra-
zol-3-yl]phenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0234]
3-[1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)-1H-pyra-
zol-3-yl]phenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0235]
4-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-1H-pyraz-
ol-3-yl]phenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0236]
4-[1-[(4-methylsulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]phenyl-N-h-
ydroxy-N-methyl-dithiocarbamate;
[0237]
4-[5-(4-chlorophenyl)-1-[(4-methylsulfonyl)phenyl]-1H-pyrazol-3-yl]-
phenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0238]
3-[4-[(4-methylsulfonyl)phenyl]-3-phenyl-1H-pyrazol-1-yl]phenyl-N-h-
ydroxy-N-methyl-dithiocarbamate;
[0239]
3-[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-1H-pyrazol-1-yl]-
phenyl-N-hydroxy-N-methyl-dithiocarbamate;
[0240]
5-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]1,2,3-triazol-4--
ylmethyl-N-hydroxy-N-methyl-dithiocarbamate;
[0241]
5-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]1,2,3--
triazol-4-ylmethyl-N-hydroxy-N-methyl-dithiocarbamate;
[0242]
5-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]1,2,3-triazol-4--
ylmethyl-N-hydroxy-N-methyl-dithiocarbamate;
[0243]
5-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]1,2,3--
triazol-4-ylmethyl-N-hydroxy-N-methyl-dithiocarbamate;
[0244]
5-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]1,2,3--
triazol-4-ylmethyl-N-hydroxy-N-methyl-dithiocarbamate;
[0245]
5-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]1,2,3-
-triazol-4-ylmethyl-N-hydroxy-N-methyl-dithiocarbamate;
[0246]
5-[5-[(4-am-nosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-oxazo-
lyl]1,2,3-triazol-4-ylmethyl-N-hydroxy-N-methyl-dithiocarbamate;
[0247]
5-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxazo-
lyl]1,2,3-triazol-4-ylmethyl-N-hydroxy-N-methyl-dithiocarbamate;
[0248]
5-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazol-
yl]1,2,3-triazol-4-ylmethyl-N-hydroxy-N-methyl-dithiocarbamate;
[0249]
5-[4-[(4-methylsulfonyl)phenyl]-5-cyclohexyl-2-oxazolyl]1,2,3-triaz-
ol-4-ylmethyl-N-hydroxy-N-methyl-dithiocarbamate;
[0250]
5-[5-4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]1,2,3--
triazol-4-ylmethyl-N-hydroxy-N-methyl-dithiocarbamate;
[0251]
5-[5-[(4-methylsulfonyl)phenyl]-4-cyclohexenyl-2-oxazolyl]1,2,3-tri-
azol-4-ylmethyl-N-hydroxy-N-methyl-dithiocarbamate;
[0252]
5-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]1,2,3-
-triazol-4-ylmethyl-N-hydroxy-N-methyl-dithiocarbamate;
[0253]
3-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]cyclohexyl-N-hyd-
roxy-N-methyl-dithiocarbamate;
[0254]
3-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]cycloh-
exyl-N-hydroxy-N-methyl-dithiocarbamate;
[0255]
3-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]cyclohexyl-N-hyd-
roxy-N-methyl-dithiocarbamate;
[0256]
4-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]cycloh-
exyl-N-hydroxy-N-methyl-dithiocarbamate;
[0257]
4-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]cycloh-
exyl-N-hydroxy-N-methyl-dithiocarbamate;
[0258]
4-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]cyclo-
hexyl-N-hydroxy-N-methyl-dithiocarbamate;
[0259]
4-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-oxazo-
lyl]cyclohexyl-N-hydroxy-N-methyl-dithiocarbamate;
[0260]
4-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxazo-
lyl]cyclohexyl-N-hydroxy-N-methyl-dithiocarbamate;
[0261]
4-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazol-
yl]cyclohexyl-N-hydroxy-N-methyl-dithiocarbamate;
[0262]
4-[4-[(4-methylsulfonyl)phenyl]-5-cyclohexyl-2-oxazolyl]cyclohexyl--
N-hydroxy-N-methyl-dithiocarbamate;
[0263]
4-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]cyclo-
hexyl-N-hydroxy-N-methyl-dithiocarbamate;
[0264]
3-[5-[(4-methylsulfonyl)phenyl]-4-cyclohexenyl-2-oxazolyl]cyclohexy-
l-N-hydroxy-N-methyl-dithiocarbamate;
[0265]
3-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]cyclo-
hexyl-N-hydroxy-N-methyl-dithiocarbamate;
[0266]
4-[(4-aminosulfonyl)phenyl]-5-(3,4-dichlorophenyl)-N-hydroxy-2-oxaz-
olebutanamide;
[0267]
4[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-5-phenyl-2-oxazolebut-
anamide;
[0268]
4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-N-hydroxy-2-oxazoleb-
utanamide;
[0269]
5-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-4-phenyl-2-oxazolebu-
tanamide;
[0270]
5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-N-hydroxy-2-oxazoleb-
utanamide;
[0271]
5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-N-hydroxy-N-methyl-2-
-oxazolebutanamide;
[0272]
5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-N-hydroxy-2-oxazole-
butanamide;
[0273]
5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-N-hydroxy--
2-oxazolebutanamide;
[0274]
5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-N-hydroxy--
N-methyl-2-oxazolebutanamide;
[0275]
5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-N-hydroxy-2-
-oxazolebutanamide;
[0276]
N-hydroxy-N-methyl-4-[4-methylsulfonyl)phenyl]-5-phenyl-2-oxazolebu-
tanamide;
[0277]
5-(4-chlorophenyl)-N-hydroxy-N-methyl-4-[(4-methylsulfonyl)phenyl]--
2-oxazolebutanamide;
[0278]
5-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl-4-phenyl-2-oxazoleb-
utanamide;
[0279]
4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-N-hydroxy-2-oxazole-
butanamide;
[0280]
1-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-5-phenyl-3-pyrazoleb-
utanamide;
[0281]
1-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-N-hydroxy-N-methyl-3-
-pyrazolebutanamide;
[0282]
1-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-N-hydroxy-N-methyl-3-
-pyrazolebutanamide;
[0283]
1-[(4-aminosulfonyl)phenyl]-5-(4-methyplhenyl)-N-hydroxy-N-methyl-3-
-pyrazolebutanamide;
[0284]
1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methylphenyl)-N-hydroxy-3-
-pyrazolebutanamide;
[0285]
1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methylphenyl)-N-hydroxy-3-
-pyrazolebutanamide;
[0286]
1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-N-hydroxy-3-
-pyrazolebutanamide;
[0287]
4-[(4-aminosulfonyl)phenyl]-N-hydroxy-3-phenyl-5-isoxazole-N-methyl-
-butanamide;
[0288]
4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-N-hydroxy-5-isoxazol-
e-N-methyl-butanamide;
[0289]
4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-N-hydroxy-5-isoxazol-
e-N-methyl-butanamide;
[0290]
4-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-N-hydroxy-5-isoxazo-
le-butanamide;
[0291]
4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxyphenyl)-N-hydroxy--
5-isoxazole-butanamide;
[0292]
4-[(4-aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)-N-hydroxy--
5-isoxazole-butanamide;
[0293]
4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-fluorophenyl)-N-hydroxy-5-
-isoxazole-butanamide;
[0294]
4-[(4-methylsulfonyl)phenyl]-N-hydroxy-3-phenyl-5-isoxazole-N-methy-
l-butanamide;
[0295]
3-(4-chlorophenyl)-N-hydroxy-N-methyl-4-[(4-methylsulfonyl)phenyl]--
5-isoxazolebutanamide;
[0296]
4-[(4-aminosulfonyl)phenyl]-3-(3,4-dichlorophenyl)-N-hydroxy-5-isox-
azole-N-methyl-butanamide;
[0297]
4-[(4-aminosulfonyl)phenyl]-3-(3-fluorophenyl)-N-hydroxy-5-isoxazol-
e-N-methyl-butanamide;
[0298]
4-[(4-aminosulfonyl)phenyl]-3-(3-fluorophenyl)-N-hydroxy-5-isoxazol-
e-butanamide;
[0299]
4-[(4-aminosulfonyl)phenyl]-3-(3,4-dichlorophenyl)-N-hydroxy-5-isox-
azole-butanamide;
[0300]
3-(3-fluorophenyl)-4-[(4-methylsulfonyl)phenyl]-N-hydroxy-5-isoxazo-
le-N-mehyl-butanamide;
[0301]
3-(3,4-dichlorophenyl)-N-hydroxy-4-[(4-methylsulfonyl)phenyl]-5-iso-
xazolebutanamide;
[0302]
4-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-3phenyl-2-thiopheneb-
utanamide;
[0303]
4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-N-hydroxy-N-methyl-2-
-thiophenebutanamide;
[0304]
4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-N-hydroxy-N-methyl-2-
-thiophenebutanamide;
[0305]
[4-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-N-hydroxy-N-methyl-
-2-thiophenebutanamide;
[0306]
[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxyphenyl)-N-hydroxy-
-2-thiophenebutanamide;
[0307]
[4-[(4-aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)-N-hydroxy-
-2-thiophenebutanamide;
[0308]
[4-[(4-aminosufonyl)phenyl]-3-(3-chloro-4-fluorophenyl)-N-hydroxy-2-
-thiophenebutanamide;
[0309]
[3-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl-4-phenyl-5-thiophe-
nebutanamide;
[0310]
[4-(4-chlorophenyl)-N-hydroxy-N-methyl-3-[(4-methylsulfonyl)phenyl]-
-5-thiophenebutanamide;
[0311]
[5-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-6-phenyl-3-pyridine-
butanamide;
[0312]
[5-[(4-aminosulfonyl)phenyl]-6-(4-chlorophenyl)-N-hydroxy-3-pyridin-
ebutanamide;
[0313]
(5-[(4-aminosulfonyl)phenyl]-6-(4-fluorophenyl)-N-hydroxy-N-methyl--
3-pyridinebutanamide;
[0314]
[5-[(4-aminosulfonyl)phenyl]-6-(4-methoxyphenyl)-N-hydroxy-N-methyl-
-3-pyridinebutanamide;
[0315]
[6-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-N-hydroxy-
-3-pyridinebutanamide;
[0316]
[6-[(4-aminosuifonyl)phenyl]-5-(3-fluoro-3-fluoro-4-methoxyphenyl)--
N-hydroxy-3-pyridinebutanamide;
[0317]
[5-[(4-aminosulfonyl)phenyl]-6-(3-chloro-4-fluorophenyl)-N-hydroxy--
N-methyl-3-pyridinebutanamide;
[0318]
[5-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl-6-phenyl-3-pyridin-
ebutanamide;
[0319]
[5-(4-chlorophenyl)-N-hydroxy-6-[(4-methylsulfonyl)phenyl]-3-pyridi-
nebutanamide;
[0320]
[4-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-3-phenyl-2-furanbut-
anamide;
[0321]
[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-N-hydroxy-2-furanbu-
tanamide
[0322]
[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-N-hydroxy-N-methyl--
2-furanbutanamide;
[0323]
[5-[(4-aminosulfonyl)phenyl]-N-hydroxy-4-(4-methoxyphenyl)-2-furanb-
utanamide;
[0324]
[4-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-N-hydroxy-
-2-furanbutanamide;
[0325]
[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-N-hydroxy-
-2-furanbutanamide;
[0326]
[4-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-N-hydroxy--
N-methyl-2-furanbutanamide;
[0327]
[4-[(4-methylsulfonyl)phenyl]-N-hydroxy-3-phenyl-2-furanbutanamide;
[0328]
[4-(4-chlorophenyl)-N-hydroxy-N-methyl-5-[(4-methylsulfonyl)phenyl]-
-2-furanbutanamide;
[0329]
4-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-5-phenyl-2-oxazolepr-
opanamide;
[0330]
4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-N-hydroxy-N-methyl-2-
-oxazolepropanamide;
[0331]
5-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-4-phenyl-2-oxazolepr-
opanamide;
[0332]
5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-N-hydroxy-N-methyl-2-
-oxazolepropanamide:
[0333]
5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-N-hydroxy-N-methyl-2-
-oxazolepropanamide;
[0334]
5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-N-hydroxy-N-methyl--
2-oxazolepropanamide;
[0335]
5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-N-hydroxy--
N-methyl-2-oxazolepropanamide;
[0336]
5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-N-hydroxy--
N-methyl-2-oxazolepropanamide;
[0337]
5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-N-hydroxy-N-
-methyl-2-oxazolepropanamide;
[0338]
N-hydroxy-N-methyl-4-[(4-mehylsulfonyl)phenyl]-5-phenyl-2-oxazolepr-
opanamide;
[0339]
5-(4-chlorophenyl)-N-hydroxy-N-methyl-4-[(4-methylsulfonyl)phenyl]--
2-oxazolepropanamide;
[0340]
5-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl-4-phenyl-2-oxazolep-
ropanamide;
[0341]
4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl--
2-oxazolepropanamide;
[0342]
1-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-5-phenyl-3-pyrazolep-
ropanamide;
[0343]
1-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-N-hydroxy-N-methyl-3-
-pyrazolepropanamide;
[0344]
1-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-N-hydroxy-N-methyl-3-
-pyrazolepropanamide;
[0345]
1-[(4-aminosulfonyl)phenyl]-5-(4-methylphenyl)-N-hydroxy-N-methyl-3-
-pyrazolepropanamide;
[0346]
1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methylphenyl)-N-hydroxy-N-
-methyl-3-pyrazolepropanamide;
[0347]
1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methylphenyl)-N-hydroxy-N-
-methyl-3-pyrazolepropanamide;
[0348]
1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-N-hydroxy-N-
-methyl-3-pyrazolepropanamide;
[0349]
4-[(4-aminosulfonyl)phenyl]-N-hydroxy-3-phenyl-5-isoxazole-N-methyl-
-propanamide;
[0350]
4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-N-hydroxy-5-isoxazol-
e-N-methyl-propanamide;
[0351]
4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-N-hydroxy-5-isoxazol-
e-N-methyl-propanamide;
[0352]
4-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-N-hydroxy-5-isoxazo-
le-N-methyl-propanamide;
[0353]
4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxyphenyl)-N-hydroxy--
5-isoxazole-N-methyl-propanamide;
[0354]
4-[(4-aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)-N-hydroxy--
5-isoxazole-N-methyl-propanamide;
[0355]
4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-fluorophenyl)-N-hydroxy-5-
-isoxazole-N-methyl-propanamide;
[0356]
4-[(4-methylsulfonyl)phenyl]-N-hydroxy-3-phenyl-5-isoxazole-N-methy-
l-propanamide;
[0357]
3-(4-chlorophenyl)-N-hydroxy-N-methyl-4-[(4-methylsulfonyl)phenyl]--
5-isoxazolepropanamide;
[0358]
4-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-3-phenyl-2-thiophene-
propanamide;
[0359]
4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-N-hydroxy-N-methyl-2-
-thiophenepropanamide;
[0360]
4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-N-hydroxy-N-methyl-2-
-thiophenepropanamide;
[0361]
[4-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-N-hydroxy-N-methyl-
-2-thiophenepropanamide;
[0362]
[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxyphenyl)-N-hydroxy-
-N-methyl-2-thiophenepropanamide;
[0363]
[4-[(4-aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)-N-hydroxy-
-N-methyl-2-thiophenepropanamide;
[0364]
[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-fluorophenyl)-N-hydroxy--
N-methyl-2-thiophenepropanamide;
[0365]
[3-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl-4-phenyl-5-thiophe-
nepropanamide;
[0366]
[4-(4-chlorophenyl)-N-hydroxy-N-methyl-3-[(4-methylsulfonyl)phenyl]-
-5-thiophenepropanamide;
[0367]
[5-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-6-phenyl-3-pyridine-
propanamide;
[0368]
[5-[(4-aminosulfonyl)phenyl]-6-(4-chlorophenyl)-N-hydroxy-N-methyl--
3-pyridinepropanamide;
[0369]
[5-[(4-aminosulfonyl)phenyl]-6-(4-fluorophenyl)-N-hydroxy-N-methyl--
3-pyridinepropanamide;
[0370]
[5-[(4-aminosulfonyl)phenyl]-6-(4-methoxyphenyl)-N-hydroxy-N-methyl-
-3-pyridinepropanamide;
[0371]
[6-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-N-hydroxy-
-N-methyl-3-pyridinepropanamide;
[0372]
[6-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-3-fluoro-4-methoxyphenyl)--
N-hydroxy-N-methyl-3-pyridinepropanamide;
[0373]
[5-[(4-aminosulfonyl)phenyl]-6-(3-chloro-4-fluorophenyl)-N-hydroxy--
N-methyl-3-pyridinepropanamide;
[0374]
[5-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl-6-phenyl-3-pyridin-
epropanamide;
[0375]
[5-(4-chlorophenyl)-N-hydroxy-N-methyl-6-[(4-methylsulfonyl)phenyl
-3-pyridinepropanamide;
[0376]
[4-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-3-phenyl-2-furanpro-
panamide;
[0377]
[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-N-hydroxy-N-methyl--
2-furanpropanamide;
[0378]
[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-N-hydroxy-N-methyl--
2-furanpropanamide;
[0379]
[5-[(4-aminosulfonyl)phenyl]-N-hydroxy-4-(4-methoxyphenyl)-N-methyl-
-2-furanpropanamide;
[0380]
[4-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-N-hydroxy-
y-N-methyl-9-furanpropanamide;
[0381]
[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-N-hydroxy-
-N-methyl-2-furanpropanamide;
[0382]
[4-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-N-hydroxy--
N-methyl-2-furanpropanamide;
[0383]
[4-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl-3-phenyl-2-furanpr-
opanamide;
[0384]
[4-(4-chlorophenyl)-N-hydroxy-N-methyl-5-[(4-methylsulfonyl)phenyl]-
-2-furanpropanamide;
[0385]
4-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-5-phenyl-2-oxazole-e-
thanamide;
[0386]
4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-N-hydroxy-N-methyl-2-
-oxazole-ethanamide; phenyl-2-oxazole-ethanamide;
[0387]
5-[(4-aminosultonyl)phenyl]-4-(4-chlorophenyl)-N-hydroxy-N-methyl-2-
-oxazole-ethanamide;
[0388]
5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-N-hydroxy-N-methyl-2-
-oxazole-ethanamide;
[0389]
5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-N-hydroxy-N-methyl--
2-oxazole-ethanamide;
[0390]
5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-N-hydroxy--
N-methyl-2-oxazole-ethanamide;
[0391] 5-[(4-aminnosulfonyl)phenyl
-4-(3-fluoro-4-methoxyphenyl)-N-hydroxy-
-N-methyl-2-oxazole-ethanamide;
[0392]
5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-N-hydroxy-N-
-methyl-2-oxazole-ethanamide;
[0393]
4-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl-5-phenyl-2-oxazole--
ethanamide;
[0394]
5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl--
2-oxazole-ethanamide;
[0395]
5-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl-4-phenyl-2-oxazole--
ethanamide;
[0396]
4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl--
2-oxazole-ethanamide;
[0397]
[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]-N--
hydroxy-N-methyl-ethanamide;
[0398]
1-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]-N-hydroxy-N-met-
hyl-2-propenamide;
[0399]
1-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]-N-hyd-
roxy-N-methyl-2-propenamide;
[0400]
1-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]-N-hydroxy-N-met-
hyl-2-propenamide;
[0401]
1-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]-N-hyd-
roxy-N-methyl-2-propenamide;
[0402]
1-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]-N-hyd-
roxy-N-methyl-2-propenamide;
[0403]
1-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]-N-hy-
droxy-N-methyl-2-propenamide;
[0404]
1-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-oxazo-
lyl]-N-hydroxy-N-methyl-2-propenamide;
[0405]
1-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxazo-
lyl]-N-hydroxy-N-methyl-2-propenamide;
[0406]
1-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazol-
yl]-N-hydroxy-N-methyl-2-propenamide;
[0407]
1-[4-[(4-methylsulfonyl)phenyl]-5-phenyl-2-oxazolyl]-N-hydroxy-N-me-
thyl-2-propenamide;
[0408]
1-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-N-hy-
droxy-N-methyl-2-propenamide;
[0409]
1-[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]-N-hydroxy-N-me-
thyl-2-propenamide;
[0410]
1-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-N-hy-
droxy-N-methyl-2-propenamide;
[0411]
1-[1-[(4-aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-hydroxy--
N-methyl-2-propenamide;
[0412]
1-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]-N-h-
ydroxy-N-methyl-2-propenamide;
[0413]
1-[3-[(4-aminosulfonyl)phenyl]-4-phenyl-1H-pyrazol-1-yl]-N-hydroxy--
N-methyl-2-propenamide;
[0414]
1-[3-[(4-aminosulfonyl)phenyl]-74-(4-chlorophenyl)-1H-pyrazol-1-yl]-
-N-hydroxy-N-methyl-2-propenamide;
[0415]
1-[1-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazol-3-yl]--
N-hydroxy-N-methyl-2-propenamide;
[0416]
1-[1-[(4-aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazol-3-yl]-
-N-hydroxy-N-methyl-2-propenamide;
[0417]
1-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-1H-pyra-
zol-3-yl]-N-hydroxy-N-methyl-2-propenamide;
[0418]
1-[1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)-1H-pyra-
zol-3-yl]-N-hydroxy-N-methyl-2-propenamide;
[0419]
1-[1-[(4aminosulfonyl)phenyl]-5-(3-chloro-4fluorophenyl)-1H-pyrazol-
-3-yl]-N-hydroxy-N-methyl-2-propenamide;
[0420]
1-[1-[(4-methylsulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-hydroxy-
-N-methyl-2-propenamide;
[0421]
1-[5-(4-chlorophenyl)-1-[(4-methylsulfonyl)phenyl]-1H-pyrazol-3-yl]-
-N-hydroxy-N-methyl-2-propenamide;
[0422]
1-[4-[(4-methylsulfonyl)phenyl-1-3-phenyl-1H-pyrazol-1-yl]-N-hydrox-
y-N-methyl-2-propenamide;
[0423]
1-[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-1H-pyrazol-1-yl]-
-N-hydroxy-N-methyl-2-propenaniide;
[0424]
1-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]-N-hydroxy-N-met-
hyl-2-propynamide;
[0425]
1-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]-N-hyd-
roxy-N-methyl-2-propynamide;
[0426]
1-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]-N-hydroxy-N-met-
hyl-2-propynamide;
[0427]
1-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]-N-hyd-
roxy-N-methyl-2-propynamide;
[0428]
1-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]-N-hyd-
roxy-N-methyl-2-propynamide;
[0429]
1-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]-N-hy-
droxy-N-methyl-2-propynamnide;
[0430]
1-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-oxazo-
lyl]-N-hydroxy-N-methyl-2-propynamide;
[0431]
1-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxazo-
lyl]-N-hydroxy-N-methyl-2-propynamide;
[0432]
1-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazol-
yl]-N-hydroxy-N-methyl-2-propynamide;
[0433]
1-[4-[(4-methylsulfonyl)phenyl]-5-phenyl-2-oxazolyl]-N-hydroxy-N-me-
thyl-2-propynamide;
[0434]
1-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-N-hy-
droxy-N-methyl-2-propynamide;
[0435]
1-[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]-N-hydroxy-N-me-
thyl-2-propynamide;
[0436]
1-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-N-hy-
droxy-N-methyl-2-propynamide;
[0437]
1-[1-[(4-aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-hydroxy--
N-methyl-2-propynamide;
[0438]
1-[1-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]--
N-hydroxy-N-methyl-2-propynamide;
[0439]
1-[3-[(4-aminosulfonyl)phenyl]-4-phenyl-1H-pyrazol-1-yl]-N-hydroxy--
N-methyl-2-propynamide;
[0440]
1-[3-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-1H-pyrazol-1-yl]--
N-hydroxy-N-methyl-2-propynamide;
[0441]
1-[1-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazol-3-yl]--
N-hydroxy-N-methyl-2-propynamide;
[0442]
1-[1-[(4-aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazol-3-yl]-
-N-hydroxy-N-methyl-2-propynamide;
[0443]
1-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-1H-pyra-
zol-3-yl]-N-hydroxy-N-methyl-2-propynamide;
[0444]
1-[1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)-1H-pyra-
zol-3-yl]-N-hydroxy-N-methyl-2-propynamide;
[0445]
1-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-1H-pyraz-
ol-3-yl]-N-hydroxy-N-methyl-2-propynamide;
[0446]
1-[1-[(4-methylsulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-hydroxy-
-N-methyl-2-propynamide;
[0447]
1-[5-(4-chlorophenyl)-1-[(4-methylsulfonyl)phenyl]-1H-pyrazol-3-yl]-
-N-hydroxy-N-methyl-2-propynamide;
[0448]
1-[4-[(4-methylsulfonyl)phenyl]-3-phenyl-1H-pyrazol-1-yl]-N-hydroxy-
-N-methyl-2-propynamide;
[0449]
1-[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-1H-pyrazol-1-yl]-
-N-hydroxy-N-methyl-2-propynamide;
[0450]
2-methyl-3-[4-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-5-phenyl-
-2-oxazolyl]-2-propynamide;
[0451]
2-methyl-3-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-N-hydrox-
y-N-methyl-2-oxazolyl]-2-propynamide;
[0452]
2-methyl-3-[5-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-4-phenyl-
-2-oxazolyll-2-propynamide;
[0453]
2-methyl-3-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-N-hydrox-
y-N-methyl-2-oxazolyl]-2-propynamide;
[0454]
2-methyl-3-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-N-hydrox-
y-N-methyl-2-oxazolyl]-2-propynamide;
[0455]
2-methyl-3-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-N-hydro-
xy-N-methyl-2-oxazolyl]-2-propynamide;
[0456]
2-methyl-3-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl-
)-N-hydroxy-N-methyl-2-oxazolyl]-2-propnamide;
[0457]
2-methyl-3-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl-
)-N-hydroxy-N-methyl-2-oxazolyl]-2-propynamide;
[0458]
2-methyl-3-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-
-N-hydroxy-N-methyl-2-oxazolyl]-2-propynamide;
[0459]
2-methyl-3-[N-hydroxy-N-methyl-4-[(4-methylsulfonyl)phenyl]-5-pheny-
l-2-oxazolyl]-2-propynamide;
[0460]
2-methyl-3-[5-(4-chlorophenyl)-N-hydroxy-N-methyl-4-[(4-methylsulfo-
nyl)phenyl]-2-oxazolyl]-2-propynamide;
[0461]
2-methyl-3-[5-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl-4-pheny-
l-2-oxazolyl]-2-propynamide;
[0462]
2-methyl-3-[4-4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-N-hydrox-
y-N-methyl-2-oxazolyl]-2-propynamide;
[0463]
2-methyl-3-[1-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-5-phenyl-
-1H-pyrazol-3-yl]-2-propynamide;
[0464]
2-methyl-3-[1-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-N-hydrox-
y-N-methyl-1H-pyrazol-3-yl]-2-propynamide;
[0465]
2-methyl-3-[1-[(4-aminosulfonyl)phenyl]-5-(4-fluoronhenyl)-N-hydrox-
y-N-methyl-1H-pyrazol-3-yl]-2-propynamide;
[0466]
2-methyl-3-[1-[(4-aminosulfonyl)phenyl]-5-(4-methylphenyl)-N-hydrox-
y-N-methyl-1H-pyrazol-3-yl]-2-propynamide;
[0467]
2-methyl-3-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methylphenyl)-
-N-hydroxy-N-methyl-1H-pyrazol-3-yl]-2-propynamide;
[0468]
2-methyl-3-[1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methylphenyl)-
-N-hydroxy-N-methyl-1H-pyrazol-3-yl]-2-propynamide;
[0469]
2-methyl-3-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-
-N-hydroxy-N-methyl-1H-pyrazol-3-yl]-2-propynamide;
[0470]
2-methyl-3-[4-[(4-aminosulfonyl)phenyl]-N-hydroxy-3-phenyl-5-isoxaz-
olyl]-N-methyl-2-propynamide;
[0471]
2-methyl-3-[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-N-hydrox-
y-5-isoxazolyl]-N-methyl-2-propynamide;
[0472]
2-methyl-3-[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-N-hydrox-
y-5-isoxazolyl]-N-methyl-2-propynamide;
[0473]
2-methyl-3-[4-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-N-hydro-
xy-5-isoxazolyl]-N-methyl-2-propynamide;
[0474]
2-methyl-3-[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxyphenyl-
)-N-hydroxy-5-isoxazolyl]-N-methyl-2-propynamide;
[0475]
2-methyl-3-[4-[(4-aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl-
)-N-hydroxy-5-isoxazolyl]-N-methyl-2-propynamide;
[0476]
2-methyl-3-[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-fluorophenyl)-
-N-hydroxy-5-isoxazolyl]-N-methyl-2-propynamide;
[0477]
2-methyl-3-[4-[(4-methylsulfonyl)phenyl]-N-hydroxy-3-phenyl-5-isoxa-
zolyl]-N-methyl-2-propynamide;
[0478]
2-methyl-3-[3-(4-chlorophenyl)-N-hydroxy-N-methyl-4-[(4-methylsulfo-
nyl)phenyl]-5-isoxazolyl]-2-propynamide;
[0479]
2-methyl-3-[4-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-3-phenyl-
-2-thienyl]-2-propynamide;
[0480]
2-methyl-3-[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-N-hydrox-
y-N-methyl-2-thienyl]-2-propynamide;
[0481]
2-methyl-3-[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-N-hydrox-
y-N-methyl-2-thienyl]-2-propynamide;
[0482]
2-methyl-3-[[4-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-N-hydr-
oxy-N-methyl-2-thienyl]-2-propynamide;
[0483]
2-methyl-3-[[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxypheny-
l)-N-hydroxy-N-methyl-2-thienyl]-2-propynamide;
[0484]
2-methyl-3-[[4-[(4-aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxypheny-
l)-N-hydroxy-N-methyl-2-thienyl]-2-propynamide;
[0485]
2-methyl-3-[[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-fluorophenyl-
)-N-hydroxy-N-methyl-2-thienyl]-2-propynamide;
[0486]
2-methyl-3-[[3-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl-4-phen-
yl-5-thienyl]-2-propynamide;
[0487]
2-methyl-3-[[4-(4-chlorophenyl)-N-hydroxy-N-methyl-3-[(4-methylsulf-
onyl)phenyl]-5-thienyl]-2-propynamide;
[0488]
2-methyl-3-[[5-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-6-pheny-
l-3-pyridyl]-2-propynamide;
[0489]
2-methyl-3-[[5-[(4-aminosulfonyl)phenyl]-6-(4-chlorophenyl)-N-hydro-
xy-N-methyl-3-pyridyl]-2-propynamide;
[0490]
2-methyl-3-[[5-[(4-aminosulfonyl)phenyl]-6-(4-fluorophenyl)-N-hydro-
xy-N-methyl-3-pyridyl]-2-propynamide;
[0491]
2-methyl-3-[[5-[(4-aminosulfonyl)phenyl]-6-(4-methoxyphenyl)-N-hydr-
oxy-N-methyl-3-pyridyl]-2-propynamide;
[0492]
2-methyl-3-[[6[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl-
)-N-hydroxy-N-methyl-3-pyridyl]-2-propynamide;
[0493]
2-methyl-3-[[6-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-3-fluoro-4-met-
hoxyphenyl)-N-hydroxy-N-methyl-3-pyridyl]-2-propynamide;
[0494]
2-methyl-3-[[5-[(4-aminosulfonyl)phenyl]-6-(3-chloro-4-fluorophenyl-
)-N-hydroxy-N-methyl-3-pyridyl]-2-propynamide;
[0495]
2-methyl-3-[[5-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl-6-phen-
yl-3-pyridyl]-2-propynamide;
[0496]
2-methyl-3-[[5-(4-chlorophenyl)-N-hydroxy-N-methyl-6-[(4-methylsulf-
onyl)phenyl]-3-pyridyl]-2-propynamide;
[0497]
2-methyl-3-[[4-[(4-aminosulfonyl)phenyl]-N-hydroxy-N-methyl-3-pheny-
l-2-furyl]-2-propynamide;
[0498]
2-methyl-3-[[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-N-hydro-
xy-N-methyl-2-furyl]-2-propynamide;
[0499]
2-methyl-3-[[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-N-hydro-
xy-N-methyl-2-furyl]-2-propynamide;
[0500]
2-methyl-3-[[5-[(4-aminosulfonyl)phenyl]-N-hydroxy-4-(4-methoxyphen-
yl)-N-methyl-2-furyl]-2-propynamide;
[0501]
2-methyl-3-[[4-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxypheny-
l)-N-hydroxy-N-methyl-2-furyl]-2-propynamide;
[0502]
2-methyl-3-[[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxypheny-
l)-N-hydroxy-N-methyl-2-furyl]-2-propynamide;
[0503]
2-methyl-3-[[4-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl-
)-N-hydroxy-N-methyl-2-furyl]-2-propynamide;
[0504]
2-methyl-3-[[4-[(4-methylsulfonyl)phenyl]-N-hydroxy-N-methyl-3-phen-
yl-2-furyl]-2-propynamide;
[0505]
2-methyl-3-[[4-(4-chlorophenyl)-N-hydroxy-N-methyl-5-[(4-methylsulf-
onyl)phenyl]-2-furyl]-2-propynamide;
[0506]
[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]-N-hydroxy-N-methy-
l-2-benzamide;
[0507]
[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]-N-hydro-
xy-N-methyl-2-benzamide;
[0508]
[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]-N-hydroxy-N-methy-
l-2-benzamide;
[0509]
[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]-N-hydro-
xy-N-methyl-2-benzamide;
[0510]
[5-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-2-oxazolyl]-N-hydro-
xy-N-methyl-2-benzamide;
[0511]
[5-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-2-oxazolyl]-N-hydr-
oxy-N-methyl-2-benzamide;
[0512]
[5-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxy-phenyl)-2-oxazol-
yl]-N-hydroxy-N-methyl-2-benzamide;
[0513]
[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxazoly-
l]-N-hydroxy-N-methyl-2-benzamide;
[0514]
[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazolyl-
]-N-hydroxy-N-methyl-2-benzamide;
[0515]
[4-[(4-methylsulfonyl)phenyl]-5-phenyl-2-oxazolyl]-N-hydroxy-N-meth-
yl-2-benzamide;
[0516]
[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-N-hydr-
oxy-N-methyl-3-benzamide;
[0517]
[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]-N-hydroxy-N-meth-
yl-3-benzamide;
[0518]
[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-N-hydr-
oxy-N-methyl-2-benzamide;
[0519]
[1-[(4-aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-hydroxy-N--
methyl-2-benzamide;
[0520]
[1-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]-N--
hydroxy-N-methyl-2-benzamide;
[0521]
[3-[(4-aminosulfonyl)phenyl]-4-phenyl-1H-pyrazol-1-yl]-N-hydroxy-N--
methyl-2-benzamide;
[0522]
[3-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-1H-pyrazol-1-yl]-N--
hydroxy-N-methyl-3-benzamide;
[0523]
[1-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazol-3-yl]-N--
hydroxy-N-methyl-3-benzamide;
[0524]
[1-[(4-aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N-
-hydroxy-N-methyl-4-benzamide;
[0525]
[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-1H-pyrazo-
l-3-yl]-N-hydroxy-N-methyl-2-benzamide;
[0526]
[1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazo-
l-3-yl]-N-hydroxy-N-methyl-2-benzamide;
[0527]
[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-1H-pyrazol-
-3-yl]-N-hydroxy-N-methyl-2-benzamide;
[0528]
[1-[(4-methylsulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-hydroxy-N-
-methyl-2-benzamide;
[0529]
[5-(4-chlorophenyl)-1-[(4-methylsulfonyl)phenyl]-1H-pyrazol-3-yl]-N-
-hydroxy-N-methyl-2-benzamide;
[0530]
[4-[(4-methylsulfonyl)phenyl]-3-phenyl-1H-pyrazol-1-yl]-N-hydroxy-N-
-methyl-2-benzamide;
[0531]
[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-1H-pyrazol-1-yl]-N-
-hydroxy-N-methyl-4-benzamide;
[0532]
5-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]-N-hydroxy-N-met-
hyl-1,2,3-triazol-4-ylethanamide;
[0533]
5-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]-N-hyd-
roxy-N-methyl-1,2,3-triazol-4-ylethanamide;
[0534]
5-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]-N-hydroxy-N-met-
hyl-1,2,3-triazol-4-ylethanamide;
[0535]
5-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]-N-hyd-
roxy-N-methyl-1, 2,3-triazol-4-ylethanamide;
[0536]
5-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]-N-hyd-
roxy-N-methyl-1,2,3-triazol-4-ylethanamide;
[0537]
5-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]-N-hy-
droxy-N-methyl-1,2,3-triazol-4-ylethanamide;
[0538]
5-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-oxazo-
lyl]-N-hydroxy-N-methyl-1,2,3-triazol-4-ylethanamide;
[0539]
5-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxazo-
lyl]-N-hydroxy-N-methyl-1,2,3-triazol-4-ylethanamide;
[0540]
5-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazol-
yl]-N-hydroxy-N-methyl-1,2,3-triazol-4-ylethanamide;
[0541]
5-[4-[(4-methylsulfonyl)phenyl]-5-cyclohexyl-2-oxazolyl]-N-hydroxy--
N-methyl-1,2,3-triazol-4-ylethanamide;
[0542]
5-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-N-hy-
droxy-N-methyl-1,2,3-triazol-4-ylethanamide;
[0543]
5-[5-[(4-methylsulfonyl)phenyl]-4-cyclohexenyl-2-oxazolyl]-N-hydrox-
y-N-methyl-1,2,3-triazol-4-ylethanamide;
[0544]
5-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-N-hy-
droxy-N-methyl-1,2,3-triazol-4-ylethanamide;
[0545]
3-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]-N-hydroxy-N-met-
hyl-3-cyclohexanamide;
[0546]
3-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]-N-hyd-
roxy-N-methyl-3-cyclohexanamide;
[0547]
3-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]-N-hydroxy-N-met-
hyl-3-cyclohexanamide;
[0548]
4-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]-N-hyd-
roxy-N-methyl-3-cyclohexanamide;
[0549]
4-(5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]-N-hyd-
roxy-N-methyl-3-cyclohexanamide;
[0550]
4-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]-N-hy-
droxy-N-methyl-3-cyclohexanamide;
[0551]
4-[(5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyohenyl)-2-oxaz-
olyl]-N-hydroxy-N-methyl-3-cyclohexanamide;
[0552]
4-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxazo-
lyl]-N-hydroxy-N-methyl-3-cyclohexanamide;
[0553]
4-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazol-
yl]-N-hydroxy-N-methyl-3-cyclohexanamide;
[0554]
4-[5-cyclohexyl-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-N-hydroxy--
N-methyl-3-cyclohexanamide;
[0555]
4-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-N-hy-
droxy-N-methyl-3-cyclohexanamide;
[0556]
3-[4-cyclohexenyl-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-N-hydrox-
y-N-methyl-3-cyclohexanamide;
[0557]
3-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]-N-hy-
droxy-N-methyl-3-cyclohexanamide;
[0558]
N'-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]methyl-N'-hydro-
xyrea;
[0559]
N'-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]methy-
l-N'-hydroxyrea;
[0560]
N'-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]methyl-N'-hydro-
xyurea;
[0561]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]methy-
l-N'-hydroxyurea;
[0562]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]methy-
l-N'-hydroxrea;
[0563]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]meth-
yl-N'-hydroxyurea;
[0564]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-oxaz-
olyl]methyl-N'-hydroxyurea;
[0565]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxaz-
olyl]methyl-N'-hydroxyurea;
[0566]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazo-
lyl]methyl-N'-hydroxyurea;
[0567]
N'-[4-[(4-methylsulfonyl)phenyl]-5-phenyl-2-oxazolyl]methyl-N'-hydr-
oxyurea;
[0568]
N'-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]meth-
yl-N'-hydroxyurea;
[0569]
N'-[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]methyl-N'-hydr-
oxyurea;
[0570]
N'[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]methy-
l-N'-hydroxyurea;
[0571]
N'-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]ethyl-N'-hydrox-
yurea;
[0572]
N'-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]ethyl-
-N'-hydroxyurea;
[0573]
N'-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]ethyl-N'-hydrox-
yurea;
[0574]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]ethyl-
-N'-hydroxyurea;
[0575]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]ethyl-
-N'-hydroxyurea;
[0576]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]ethy-
l-N'-hydroxyurea;
[0577]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-oxaz-
olyl]ethyl-N'-hydroxyurea;
[0578]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxaz-
olyl]ethyl-N'-hydroxyurea;
[0579]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazo-
lyl]ethyl-N'-hydroxyurea;
[0580]
N'-[4-[(4-methylsulfonyl)phenyl]-5-phenyl-2-oxazolyl]ethyl-N'-hydro-
xyurea;
[0581]
N'-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]ethy-
l-N'-hydroxyurea;
[0582]
N'-[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]ethyl-N'-hydro-
xyurea;
[0583]
N'-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]ethy-
l-N'-hydroxyurea;
[0584]
N'-[4-[(4-aminosulfonyl)phenyl]-3-phenyl-5-isoxazolyl]methyl-N'-hyd-
roxyurea;
[0585]
N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-5-isoxazolyl]met-
hyl-N'-hydroxyurea;
[0586]
N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-5-isoxazolyl]met-
hyl-N'-hydroxyurea;
[0587]
N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-5-isoxazolyl]me-
thyl-N'-hydroxyurea;
[0588]
N'-[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxyphenyl)-5-isox-
azolyl]methyl-N'-hydroxyurea;
[0589]
N'-[4-[(4-aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)-5-isox-
azolyl]methyl-N'-hydroxyurea;
[0590]
N'-[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-fluorophenyl)-5-isoxa-
zolyl]methyl-N'-hydroxyurea;
[0591]
N'-[4-[(4-methylsulfonyl)phenyl]-3-phenyl-5-isoxazolyl]methyl-N'-hy-
droxyrea;
[0592]
N'-[3-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-5-isoxazolyl]me-
thyl-N'-hydroxyurea;
[0593]
N'-[4-[(4-aminosulfonyl)phenyl]-3-phenyl-2-thienyl]methyl-N'-hydrox-
yurea;
[0594]
N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-2-thienyl]methyl-
-N'-hydroxyurea;
[0595]
N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-2-thienyl]methyl-
-N'-hydroxyurea;
[0596]
N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-2-thienyl]methy-
l-N'-hydroxyurea;
[0597]
N'-[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxyphenyl)-2-thie-
nyl]methyl-N'-hydroxyurea;
[0598]
N'-[4-[(4-aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)-2-thie-
nyl]methyl-N'-hydroxyurea;
[0599]
N'-[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-fluorophenyl)-2-thien-
yl]methyl-N'-hydroxyurea;
[0600]
N'-[3-[(4-methylsulfonyl)phenyl]-4-phenyl-5-thienyl]methyl-N'-hydro-
xyurea;
[0601]
N'-[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-5-thienyl]methy-
l-N'-hydroxyurea;
[0602]
N'-[5-[(4-aminosulfonyl)phenyl]-6-phenyl-3-pyridyl]methyl-N'-hydrox-
yurea;
[0603]
N'-[5-[(4-aminosulfonyl)phenyl]-6-(4-chlorophenyl)-3-pyridyl]methyl-
-N'-hydroxyurea;
[0604]
N'-[5-[(4-aminosulfonyl)phenyl]-6-(4-fluorophenyl)-3-pyridyl]methyl-
-N'-hydroxyurea;
[0605]
N'-[5-[(4-aminosulfonyl)phenyl]-6-(4-methoxyphenyl)-3-pyridyl]methy-
l-N'-hydroxyurea;
[0606]
N'-[6-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-3-pyri-
dyl]methyl-N'-hydroxyurea,
[0607]
N'-[6-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)-3-pyri-
dyl]methyl-N'-hydroxyurea;
[0608]
N'-[5-[(4-aminosulfonyl)phenyl]-6-(3-chloro-4-fluorophenyl)-3-pyrid-
yl]methyl-N'-hydroxyurea;
[0609]
N'-[5-[(4-methylsulfonyl)phenyl]-6-phenyl-3-pyridyl]methyl-N'-hydro-
xyurea;
[0610]
N'-[5-(4-chlorophenyl)-6-[(4-methylsulfonyl)phenyl]-3-pyridyl]methy-
l-N'-hydroxyurea;
[0611]
N'-[4-[(4-aminosulfonyl)phenyl]-3-phenyl-2-furyl]methyl-N'-hydroxyu-
rea;
[0612]
N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-2-furyl]methyl-N-
'-hydroxyurea;
[0613]
N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-2-furyl]methyl-N-
'-hydroxyurea;
[0614]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-furyl]methyl--
N'-hydroxyurea;
[0615]
N'-[4-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-2-fury-
l]methyl-N'-hydroxyurea;
[0616]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-fury-
l]methyl-N'-hydroxyurea;
[0617]
N'-[4-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-2-furyl-
]methyl-N'-hydroxyurea;
[0618]
N'-[4-[(4-methylsulfonyl)phenyl]-3-phenyl-2-furyl]methyl-N'-hydroxy-
urea;
[0619]
N'-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-furyl]methyl--
N'-hydroxyurea;
[0620]
N'-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]methyl-N'-hydro-
xyurea;
[0621]
N'-[4-[(4-aminnsulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]methy-
l-N'-hydroxyurea;
[0622]
N'-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]methyl-N'-hydro-
xyurea;
[0623]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]methy-
l-N'-hydroxyurea;
[0624]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]methy-
l-N'-hydroxyurea;
[0625]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]meth-
yl-N'-hydroxyurea;
[0626]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-oxaz-
olyl]methyl-N'-hydroxyurea;
[0627]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-oxaz-
olyl]methyl-N'-hydroxyurea;
[0628]
N'-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-oxazo-
lyl]methyl-N'-hydroxyurea;
[0629]
N'-[4-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]methyl-N'-hydr-
oxyurea;
[0630]
N'-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]meth-
yl-N'-hydroxyurea;
[0631]
N'-[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]methyl-N'-hydr-
oxyurea;
[0632]
N'-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]meth-
yl-N'-hydroxyurea;
[0633]
3-[N'-[1-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]-2-propen-
yl]-N'-hydroxyurea;
[0634]
3-[N'-[1-N'-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazo-
lyl]-2-propenyl]-N'-hydroxyurea;
[0635]
3-[N'-[1-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]-2-propen-
yl]-N'-hydroxyurea;
[0636]
3-[N'-[1-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl-
]-2-propenyl]-N'-hydroxyurea;
[0637]
3-[N'-[1-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl-
]-2-propenyl]-N'-hydroxyurea;
[0638]
3-[N'-[1-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazoly-
l]-2-propenyl]-N'-hydroxyurea;
[0639]
3-[N'-[1-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)--
2-oxazolyl]-2-propenyl]-N'-hydroxyurea;
[0640]
3-[N'-[1-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)--
2-oxazolyl]-2-propenyl]-N'-hydroxyurea;
[0641]
3-[N'-[1-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-
-oxazolyl]-2-propenyl]-N'-hydroxyurea;
[0642]
3-[N'-[1-[4-[(4-methylsulfonyl)phenyl]-5-phenyl-2-oxazolyl]-2-prope-
nyl]-N'-hydroxyurea;
[0643]
3-[N'-[1-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazoly-
l]-2-propenyl]-N'-hydroxyurea;
[0644]
3-[N'-[1-[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]-2-prope-
nyl]-N'-hydroxyurea;
[0645]
3-[N'-[1-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazoly-
l]-2-propenyl]-N'-hydroxyurea;
[0646]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-2-p-
ropenyl]-N'-hydroxyurea;
[0647]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-
-3-yl]-2-propenyl]-N'-hydroxyurea;
[0648]
3-[N'-[1-[3-[(4-aminosulfonyl)phenyl]-4-phenyl-1H-pyrazol-1-yl]-2-p-
ropenyl]-N'-hydroxyurea;
[0649]
3-[N'-[1-[3-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-1H-pyrazol-
-1-yl]-2-propenyl]-N'-hydroxyurea;
[0650]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazol-
-3-yl]-2-propenyl]-N'-hydroxyurea;
[0651]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazo-
l-3-yl]-2-propenyl]-N'-hydroxyurea;
[0652]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)--
1H-pyrazol-3-yl]-2-propenyl]-N'-hydroxurea;
[0653]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)--
1H-pyrazol-3-yl]-2-propenyl]-N'-hydroxyurea;
[0654]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-1-
H-pyrazol-3-yl]-2-propenyl]-N'-hydroxyurea;
[0655]
3-[N'-[1-[1-[(4-methylsulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-2--
propenyl]N'-hydroxyurea;
[0656]
3-[N'-[1-[5-(4-chlorophenyl)-1-[(4-methylsulfonyl)phenyl]-1H-pyrazo-
l-3-yl]-2-propenyl]-N'-hydroxyurea;
[0657]
3-[N'-[1-[4-[(4-methylsulfonyl)phenyl]-3-phenyl-1H-pyrazol-1-yl]-2--
propenyl]-N'-hydroxyurea;
[0658]
3-[N'-[1-[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-1H-pyrazo-
l-1-yl]-2-propenyl]-N'-hydroxyurea;
[0659]
3-[N'-[1-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]-2-propyn-
yl]-N'-hydroxyurea;
[0660]
3-[N'-[1-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl-
]-2-propynyl]-N'-hydroxyurea;
[0661]
3-[N'-1-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]-2-propeny-
l]-N'-hydroxyurea;
[0662]
3-[N'-(1-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl-
]-2-propynyl]-N'-hydroxyurea;
[0663]
3-[N'-[1-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl-
]-2-propynyl]-N'-hydroxyurea;
[0664]
3-[N'-[1-[5-[(4-aminosulfonylphenyl)-4-(4-methoxyphenyl)-2-oxazolyl-
]-2-propynyl]-N'-hydroxyurea;
[0665]
3-[N'-[1-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)--
2-oxazolyl]-2-propynyl]-N'-hydroxyurea;
[0666]
3-[N'-[1-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)--
2-oxazolyl]-2-propynyl]-N'-hydroxyurea;
[0667]
3-[N'-[1-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-
-oxazolyl]-2-propynyl]-N'-hydroxyurea;
[0668]
3-[N'-[1-[4-[(4-methylsulfonyl)phenyl]-5-phenyl-2-oxazolyl]-2-propy-
nyl]-N'-hydroxyurea;
[0669]
3-[N'-[1-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazoly-
l -2propynyl]-N'-hydroxyurea;
[0670]
3-[N'-[1-[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]-2-propy-
nyl]-N'-hydroxyurea;
[0671]
3-[N'-[1-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazoly-
l]-2-propynyl]-N'-hydroxyurea;
[0672]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-2-p-
ropynyl]-N'-hydroxyurea;
[0673]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(-4-chlorophenyl)-1H-pyrazo-
l-3-yl]-2-propynyl]-N'-hydroxyurea;
[0674]
3-[N'-[1-[3-[(4-aminosulfonyl)phenyl]-4-phenyl-1H-pyrazol-1-yl]-2-p-
ropynyl]-N'-hydroxyurea;
[0675]
3-[N'-[1-[3-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl;-1H-pyrazol-
-1-yl]-2-propynyl]-N'-hydroxyurea;
[0676]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazol-
-3-yl]-2-propynyl]-N'-hydroxurea;
[0677]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazo-
l-3-yl]-2-propynyl]-N'-hydroxyurea;
[0678]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)--
1H-pyrazol-3-yl]-2-propynyl]-N'-hydroxyurea;
[0679]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)--
1H-pyrazol-3-yl]-2-propynyl]-N'-hydroxyurea;
[0680]
3-[N'-1-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-1H-
-pyrazol-3-yl]-2-propynyl]-N'-hydroxyurea;
[0681]
3-[N'-[1-[1-[(4-methylsulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-2--
propynyl]-N'-hydroxcyurea;
[0682]
3-[N'-[1-[5-(4-chlorophenyl)-1-[(4-methylsulfonyl)phenyl]-1H-pyrazo-
l-3-yl]-2-propynyl]-N'-hydroxyurea;
[0683]
3-[N'-[1-[4[(4-methylsulfonyl)phenyl]-3-phenyl-1H-pyrazol-1-yl]-2-p-
ropynyl]-N'-hydroxyurea;
[0684]
3-[N'-[1-[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-1H-pyrazo-
l-1-yl]-2-propynyl]-N'-hydroxyurea;
[0685]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-1-m-
ethyl-2-propynyl]-N'-hydroxyurea;
[0686]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-
-3-yl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0687]
3-[N'-[1-[3-[(4-aminosulfonyl)phenyl]-4-phenyl-1H-pyrazol-1-yl]-1-m-
ethyl-2-propynyl]-N'-hydroxyurea;
[0688]
3-[N'-[1-[3-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-1H-pyrazol-
-1-yl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0689]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazol-
-3-yl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0690]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazo-
l-3-yl]-1-methyl-2-propenyl]-N'-hydroxyurea;
[0691]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)--
1H-pyrazol-3-yl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0692]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)--
1H-pyrazol-3-yl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0693]
3-[N'-[1-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-1-
H-pyrazol-3-yl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0694]
3-[N'-[1-[1-[(4-methylsulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-1--
methyl-2-propynyl]-N'-hydroxyurea;
[0695]
3-[N'-[1-[5-(4-chlorophenyl)-1-[(4-methylsulfonyl)phenyl]-1H-pyrazo-
l-3-yl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0696]
3-[N'-[1-[4-[(4-methylsulfonyl)phenyl]-3-phenyl-1H-pyrazol-1-yl]-1--
methyl-2-propynyl]-N'-hydroxyurea;
[0697]
3-[N'-[1-[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-1H-pyrazo-
l-1-yl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0698]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]-1-methyl-2--
propynyl]-N'-hydroxyurea;
[0699]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]-1-
-methyl-2-propynyl]-N'-hydroxyurea;
[0700]
3-[N'-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]-1-methyl-2--
propynyl]-N'-hydroxyurea;
[0701]
3-[N'-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]-1-
-methyl-2-propynyl]-N'-hydroxyurea;
[0702]
3-[N'-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]-1-
-methyl-2-propynyl]-N'-hydroxyurea;
[0703]
3-[N'-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]--
1-methyl-2-propynyl]-N'-hydroxyurea;
[0704]
3-[N'-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-o-
xazolyl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0705]
3-[N'-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-o-
xazolyl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0706]
3-[N'-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-ox-
azolyl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0707]
3-[N'-[4-[(4-methylsulfonyl)phenyl]-5-phenyl-2-oxazolyl]-1-methyl-2-
-propynyl-N'-hydroxyurea;
[0708]
3-[N'-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]--
1-methyl-2-propynyl]-N'-hydroxyurea;
[0709]
3-[N'-[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]-1-methyl-2-
-propynyl]-N'-hydroxyurea;
[0710]
3-[N'-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]--
1-methyl-2-propynyl]-N'-hydroxyurea;
[0711]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-phenyl-5-isoxazolyl]-1-methyl--
2-propynyl]-N'-hydroxyurea;
[0712]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-5-isoxazolyl]-
-1-methyl-2-propynyl]-N'-hydroxyurea;
[0713]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-5-isoxazolyl]-
-1-methyl-2-propynyl]-N'-hydroxyurea;
[0714]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-5-isoxazolyl-
]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0715]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxyphenyl)-5-i-
soxazolyl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0716]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)-5-i-
soxazolyl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0717]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-fluorophenyl)-5-is-
oxazolyl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0718]
3-[N'-[4-[(4-methylsulfonyl)phenyl]-3-phenyl-5-isoxazolyl]-1-methyl-
-2-propynyl]-N'-hydroxyurea;
[0719]
3-[N'-[3-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-5-isoxazolyl-
]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0720]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-phenyl-2-thienyl]-1-methyl-2-p-
ropynyl]-N'-hydroxyurea;
[0721]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-2-thienyl]-1--
methyl-2-propynyl]-N'-hydroxyurea;
[0722]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-2-thienyl]-1--
methyl-2-propynyl]-N'-hydroxyurea;
[0723]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-2-thienyl]-1-
-methyl-2-propynyl]-N'-hydroxyurea;
[0724]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-methoxyphenyl)-2-t-
hienyl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0725]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)-2-t-
hienyl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0726]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-(3-chloro-4-fluorophenyl)-2-th-
ienyl -1-methyl -2-propynyl]-N'-hydroxyurea;
[0727]
3-[N'-[3-[(4-methylsulfonyl)phenyl]-4-phenyl-5-thienyl]-1-methyl-2--
propynyl]-N'-hydroxyurea;
[0728]
3-[N'-[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-5-thienyl]-1-
-methyl-2-propynyl]-N'-hydroxyurea;
[0729]
3-[N'-[5-[(4-aminosulfonyl)phenyl]-6-phenyl-3-pyridyl]-1-methyl-2-p-
ropynyl]-N'-hydroxyurea;
[0730]
3-[N'-[5-[(4-aminosulfonyl)phenyl]-6-(4-chlorophenyl)-3-pyridyl]-1--
methyl-2-propynyl]-N'-hydroxyurea;
[0731]
3-[N'-[5-[(4-aminosulfonyl)phenyl]-6-(4-fluorophenyl)-3-pyridyl]-1--
methyl-2-propynyl]-N'-hydroxrurea;
[0732]
3-[N'-[5-[(4-aminosulfonyl)phenyl]-6-(4-methoxyphenyl)-3-pyridyl]-1-
-methyl-2-propynyl]-N'-hydroxyurea;
[0733]
3-[N'-[6-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-3-p-
yridyl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0734]
3-[N'-[6-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)-3-p-
yridyl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0735]
3-[N'-[5-[(4-aminosulfonyl)phenyl]-6-(3-chloro-4-fluorophenyl)-3-py-
ridyl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0736]
3-[N'-[5-[(4-methylsulfonyl)phenyl]-6-phenyl-3-pyridyl]-1-methyl-2--
propynyl]-N'-hydroxyurea;
[0737]
3-[N'-[5-(4-chlorophenyl)-6-[(4-methylsulfonyl)phenyl]-3-pyridyl]-1-
-methyl-2-propynyl]-N'-hydroxyurea;
[0738]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-phenyl-2-furyl]-1-methyl-2-pro-
pynyl]-N'-hydroxyurea;
[0739]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-chlorophenyl)-2-furyl]-1-me-
thyl-2-propynyl]-N'-hydroxyurea;
[0740]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-3-(4-fluorophenyl)-2-furyl]-1-me-
thyl-2-propynyl]-N'-hydroxyurea;
[0741]
3-[N'-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-furyl]-1-m-
ethyl-2-propynyl]N'-hydroxyurea;
[0742]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-2-f-
uryl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0743]
3-[N'-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-f-
uryl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0744]
3-[N'-[4-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-2-fu-
ryl]-1-methyl-2-propynyl]-N'-hydroxyurea;
[0745]
3-[N'-[4-[(4-methylsulfonyl)phenyl]-3-phenyl-2-furyl]-1-methyl-2-pr-
opynyl]-N'-hydroxyurea;
[0746]
3-[N'-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-furyl]-1-m-
ethyl-2-propynyl]-N'-hydroxyurea;
[0747]
N'-3-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]phenyl]-N'-hy-
droxyurea;
[0748]
N'-[3-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyliph-
enyl)-N'-hydroxyurea;
[0749]
N'-[3-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]phenyl)-N'-h-
ydroxyurea;
[0750]
N'-[4-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyllph-
enyl)-N'-hydroxyurea;
[0751]
N'-[4-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]ph-
enyl)-N'-hydroxyurea;
[0752]
N'-[4-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]p-
henyl]-N'-hydroxyurea;
[0753]
N'-[4-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-o-
xazolyl]phenyl]-N'-hydroxyurea;
[0754]
N'-[4[-5-[(4-aminosulfoonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2--
oxazolyl]phenyl]-N'-hydroxyurea;
[0755]
N'-[4-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-ox-
azolyl]phenyl]-N'-hydroxyurea;
[0756]
N'-[4-[4-[(4-methylsulfonyl)phenyl]-5-phenyl-2-oxazolyl]phenyl]-N'--
hydroxyurea;
[0757]
N'-[4-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]p-
henyl)-N'-hydroxyurea;
[0758]
N'-[3-[5-[(4-methylsulfonyl)phenyl]-4-phenyl-2-oxazolyl]phenyl]-N'--
hydroxyurea;
[0759]
N'-[3-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]p-
henyl]-N'-hydroxyurea;
[0760]
N'-[3-[1-[(4-aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]phenyl)-
-N'-hydroxyurea;
[0761]
N'-[2-[1-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3--
yl]phenyl)-N'-hydroxyurea;
[0762]
N'-[2-[1-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazol-3--
yl]phenyl)-N'-hydroxyurea;
[0763]
N'-[4-[1-[(4-aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazol-3-
-yl]phenyl]-N'-hydroxyurea;
[0764]
N'-[4-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-1H--
pyrazol-3-yl]phenyl]-N'-hydroxyurea;
[0765]
N'-[3-[1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)-1H--
pyrazol-3-yl phenyl]-N'-hydroxyurea;
[0766]
N'-[4-[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-1H-p-
yrazol-3-yl]phenyl]-N'-hydroxyurea;
[0767]
N'-[4-[1-[(4-methylsulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]phenyl-
]-N'-hydroxyurea;
[0768]
N'-[4-[5-(4-chlorophenyl)-1-[(4-methylsulfonyl)phenyl]-1H-pyrazol-3-
-yl]phenyl]-N'-hydroxyurea;
[0769]
N'-[3-[4-[(4-methylsulfonyl)phenyl]-3-phenyl-1H-pyrazol-1-yl]phenyl-
]-N'-hydroxyurea;
[0770]
N'-[3-[4-(4-chlorophenyl)-3-[(4-methylsulfonyl)phenyl]-1H-pyrazol-1-
-yl]phenyl]-N'-hydroxyurea;
[0771]
N'-5-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]1,2,3-triazol-
-4-ylmethyl]-N'-hydroxyurea;
[0772]
N'-[5-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]1,-
2,3-triazol-4-ylmethyl]-N'-hydroxyurea;
[0773]
N'[-5-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]1,2,3-triazo-
l-4-ylmethyl]-N'-hydroxyurea;
[0774]
N'-[5-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]1,-
2,3-triazol-4-ylmethyl]-N'-hydroxyurea;
[0775]
N'-[5-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]1,-
2,3-triazol-4-ylmethyl]-N'-hydroxyurea;
[0776]
N'-[5-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]1-
,2,3-triazol-4-ylmethyl]-N'-hydroxyurea;
[0777]
N'-[5-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-o-
xazolyl]1,2,3-triazol-4-ylmethyl]-N'-hydroxyurea;
[0778]
N'-[5-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-o-
xazolyl]1,2,3-triazol-4-ylmethyl]-N'-hydroxyurea;
[0779]
N'-[5-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-ox-
azolyl]1,2,3-triazol-4-ylmethyl]-N'-hydroxyurea;
[0780]
N'-[5-[4-[(4-methylsulfonyl)phenyl]-5-cyclohexyl-2-oxazolyl]1,2,3-t-
riazol-4-ylmethyl]-N'-hydroxyurea;
[0781]
N'-[5-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]1-
,2,3-triazol-4-ylmethyl]-N'-hydroxyurea;
[0782]
N'-[5-[5-[(4-methylsulfonyl)phenyl]-4-cyclohexenyl-2-oxazolyl]1,2,3-
-triazol-4-ylmethyl]-N'-hydroxyurea;
[0783]
N'-[5-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]1-
,2,3-triazol-4-ylmethyl]-N'-hydroxyurea;
[0784]
N'-[3-[4-[(4-aminosulfonyl)phenyl]-5-phenyl-2-oxazolyl]cyclohexyl]--
N'-hydroxyurea;
[0785]
N'-[3-[4-[(4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-2-oxazolyl]cy-
clohexyl]-N'-hydroxyurea;
[0786]
N'-[3-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-oxazolyl]cyclohexyl]--
N'-hydroxyurea;
[0787]
N'-[4-[5-[(4-aminosulfonyl)phenyl]-4-(4-chlorophenyl)-2-oxazolyl]cy-
clohexyl]-N'-hydroxyurea;
[0788]
N'-[4-[5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)-2-oxazolyl]cy-
clohexyl]-N'-hydroxyurea;
[0789]
N'-[4-[5-[(4-aminosulfonyl)phenyl]-4-(4-methoxyphenyl)-2-oxazolyl]c-
yclohexyl]-N'-hydroxyurea;
[0790]
N'-[4-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-methoxyphenyl)-2-o-
xazolyl]cyclohexyl]-N'-hydroxyurea;
[0791]
N'-[4-[5-[(4-aminosulfonyl)phenyl]-4-(3-fluoro-4-methoxyphenyl)-2-o-
xazolyl]cyclohexyl]-N'-hydroxyurea;
[0792]
N'-[4-[5-[(4-aminosulfonyl)phenyl]-4-(3-chloro-4-fluorophenyl)-2-ox-
azolyl]cyclohexyl]-N'-hydroxyurea;
[0793]
N'-[4-[4-[(4-methylsulfonyl)phenyl]-5-cyclohexyl-2-oxazolyl]cyclohe-
xyl]-N'-hydroxyurea;
[0794]
N'-[4-[5-(4-chlorophenyl)-4-[(4-methylsulfonyl)phenyl]-2-oxazolyl]c-
yclohexyl]-N'-hydroxyurea;
[0795]
N'-[3-[5-[(4-methylsulfonyl)phenyl]-4-cyclohexenyl-2-oxazolyl]cyclo-
hexyl]-N'-hydroxyurea;
[0796]
N'-[3-[4-(4-chlorophenyl)-5-[(4-methylsulfonyl)phenyl]-2-oxazolyl]c-
yclohexyl]-N'-hydroxyurea;
[0797]
N'-[[1-[(4-aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-
'-hydroxyurea;
[0798]
N'-[[1-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazol-3-yl-
]methyl]-N'-hydroxyurea;
[0799]
N'-[[1-[(4-aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazol-3-y-
l]methyl]-N'-hydroxyurea;
[0800]
N'-[[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-1H-py-
razol-3-yl]methyl]-N'-hydroxyurea;
[0801]
N'-[[1-[(4-aminosulfonyl)phenyl]-5-(3-fluoro-4-methoxyphenyl)-1H-py-
razol-3-yl]methyl]-N'-hydroxyurea;
[0802]
N'-[[1-[(4-aminosulfonyl)phenyl]-5-(3-chloro-4-fluorophenyl)-1H-pyr-
azol-3-yl]methyl'-N'-hydroxyurea;
[0803]
N'-[[1-[4-(aminosulfonyl)phenyl]-5-(4-methylphenyl)-1H-pyrazol-3-yl-
]methyl]-N'-hydroxyurea;
[0804]
N'-[[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl-
]ethyl]-N'-hydroxyurea;
[0805]
N'-[4-[1-[4-(aminosulfonyl)phenyl]-5-(4-methyl-3-chlorophenyl-1H-py-
razol-3-yl]phenyl]-N'-hydroxyurea;
[0806]
N'-[3-[1-[4-(aminosulfonyl)phenyl]-5-(4-methylphenyl)-1H-pyrazol-3--
yl]phenyl]-N'-hydroxyurea;
[0807]
N'-[5-[1-[4-(aminosulfonyl)phenyl]-5(4-3-chlorophenyl)-1H-pyrazol-3-
-yl]-2-thienyl]-N'-hydroxyurea;
[0808]
N'-[[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl-
]methyl]-N'-hydroxyurea; and
[0809]
4-(4-fluorophenyl)-N-hydroxy-N-methyl-5-[(4-methylsulfonyl)phenyl]--
2-oxazolepropanamide.
[0810] 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
used, either alone or within other terms such as "haloalkyl",
"alkylsulfonyl", "alkoxyalkyl", "aminoalkyl" and "hydroxyalkyl",
the term "alkyl" 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, one to about twelve
carbon atoms. More preferred alkenyl radicals are "lower alkenyl"
radicals having two to about six carbon atoms. Examples of alkenyl
radicals include ethenyl, propenyl, allyl, propenyl, butenyl and
4-methylbutenyl. The term "alkynyl" denotes linear or branched
radicals having two to about twenty carbon atoms or, preferably,
two to about twelve carbon atoms. More preferred alkynyl radicals
are "lower alkynyl" radicals having two to about ten carbon atoms.
Most preferred are lower alkynyl radicals having two to about six
carbon atoms. Examples of such radicals include propynyl,
propargyl, butynyl, and the like. The terms "alkenyl", and "lower
alkenyl" embrace radicals having, "cis" and "trans" orientations,
or alternatively, "E" and "Z" orientations. The term "cycloalkyl"
embraces saturated carbocyclic radicals having three to twelve
carbon atoms. More preferred cycloalkyl radicals are "lower
cycloalkyl" radicals having four to about eight carbon atoms.
Examples of such radicals include cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl. The term "cycloalkenyl" embraces
partially unsaturated carbocyclic radicals having three to twelve
carbon atoms. More preferred cycloalkenyl radicals are "lower
cycloalkenyl" radicals having four to about eight carbon atoms.
Examples of such radicals include cyclobutenyl, cyclopentenyl and
cyclohexenyl. The term "halo" means halogens such as fluorine,
chlorine, bromine or iodine. 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 "cyanoalkyl", embraces linear or
branched alkyl radicals having one to about ten carbon atoms any
one of which may be substituted with one or more cyano radicals.
More preferred cyanoalkyl radicals are "lower cyanoalkyl" radicals
having one to six carbon atoms and one or more cyano radicals.
Examples of such radicals include cyanomethyl, cyanoethyl,
cyanopropyl, cyanobutyl and cyanohexyl. 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. 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" embraces alkyl radicals having
one or more alkoxy radicals attached to the alkyl radical, that is,
to form monoalkoxyalkyl and dialkoxyalkyl radicals. The "alkoxy"
radicals may be further substituted with one or more halo atoms,
such as fluoro, chloro or bromo, to provide haloalkoxy radicals.
More preferred haloalkoxy radicals are "lower haloalkoxy" radicals
having one to six carbon atoms and one or more halo 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. Aryl moieties
may also be substituted at a substitutable position with one or
more substituents selected independently from alkyl, alkoxyalkyl,
alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,
aminocarbonylalkyl, alkoxy, aralkoxy, amino, halo, nitro,
alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and
aralkoxycarbonyl. The terms "heterocyclyl" and "heterocyclo"
embrace saturated, partially unsaturated and unsaturated
heteroatom-containing ring-shaped radicals, where the heteroatoms
may be selected from nitrogen, sulfur and oxygen. Examples of
saturated heterocyclo 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 unsaturated heterocyclo radicals include
dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
The term "heteroaryl" embraces unsaturated heterocyclo radicals.
Examples of unsaturated heterocyclo radicals, also termed
"heteroaryl" radicals include unsaturated 3 to 6 membered
heteromonocyclic group containing 1 to 4 nitrogen atoms, for
example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 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 heterocyclo 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, furyl, etc.; unsaturated 3 to
6-membered heteromonocyclic group containing a sulfur atom, for
example, thienyl, etc.; unsaturated 3- 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 heterocyclo group containing 1 to
2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl,
benzoxadiazolyl, etc.); unsaturated 3 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 heterocyclo 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 heterocyclo radicals are fused with aryl radicals.
Examples of such fused bicyclic radicals include benzofuran,
benzothiophene, and the like. Said "heterocyclo group" may also be
substituted at a substitutable position with one or more
substituents selected independently from alkyl, alkylaminoalkyl,
carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, hydroxyl,
alkoxy, aralkoxy, alkylaminoalkoxy, amino, halo, nitro, alkylamino,
acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and
aralkoxycarbonyl. The term "alkylthio" embraces radicals containing
a linear or branched alkyl radical, of one to about ten carbon
atoms attached to a divalent sulfur atom. More preferred alkylthio
radicals are "lower alkylthio" radicals having alkyl radicals of
one to six carbon atoms. Examples of such lower alkylthio radicals
are methylthio, ethylthio, propylthio, butylthio and hexylthio. 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)--radical. More preferred alkylsulfinyl
radicals are "lower alkylsulfinyl" radicals having alkyl radicals
of one to six carbon atoms. Examples of such lower alkylsulfinyl
radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and
hexylsulfinyl. The term "sulfonyl", whether used alone or linked to
other terms such as alkylsulfonyl, denotes respectively divalent
radicals --SO.sub.2--. "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 "alkylsulfonyl" radicals may be further
substituted with one or more halo atoms, such as fluoro, chloro or
bromo, to provide haloalkylsulfonyl radicals. The terms "sulfamyl",
"aminosulfonyl" and "sulfonamidyl" denote NH.sub.2O.sub.2S--. The
term "aralkyl" embraces aryl-substituted alkyl radicals. Preferred
aralkyl radicals are "lower aralkyl" radicals where the alkyl
radicals are of 1-6 carbons. Examples of such lower aralkyl
radiclas 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 "cycloalkylalkyl" embraces cycloalkyl-substituted alkyl
radicals. Preferred cycloalkylalkyl radicals are "lower
cycloalkylalkyl" radicals where the alkyl radicals are of 1-6
carbons. Examples of such radicals include cyclohexylmethyl,
cyclopentylmethyl, cyclobutylmethyl, cyclohexylethyl, and
cyclopentylpropyl. The term "heterocycloalkyl" embraces
heterocyclo-substituted alkyl radicals. Preferred heterocycloalkyl
radicals are "lower heterocycloalkyl" radicals where the alkyl
radicals are of 1-6 carbons and the heterocyclo radicals have 5- or
6-members. Examples of such radicals include triazolylmethyl,
triazolylethyl, thienylmethyl, furylethyl, and piperidinomethyl.
The heterocyclo in said heterocycloalkyl may be additionally
substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term "acyl" denotes a radical provided by the residue after
removal of hydroxyl from an organic acid. Examples of such acyl
radicals include alkanoyl and aroyl radicals. 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 terms "carboxy" or "carboxyl", whether used alone
or with other terms, such as "carboxyalkyl", denotes --CO.sub.2H.
The terms "carboxyalkyl" embrace radicals having a carboxy radical
as defined above, attached to an alkyl radical. More preferred
carboxyalkyl radicals are "lower carboxyalkyl" radicals having
alkyl portions of 1-6 carbons. The term "carbonyl", whether used
alone or with other terms, such as "alkoxycarbonyl", denotes
--(C.dbd.O)--. The term "alkoxycarbonyl" means a radical containing
an alkoxy radical, as defined above, attached via an oxygen atom to
a carbonyl radical. Examples of such "alkoxycarbonyl" ester
radicals include substituted or unsubstituted methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and
hexyloxycarbonyl. The terms "alkylcarbonyl", "arylcarbonyl" and
"aralkylcarbonyl" include radicals having alkyl, aryl and aralkyl
radicals, as defined above, attached via an oxygen atom to a
carbonyl radical. Examples of such radicals include substituted or
unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl and
benzylcarbonyl. The term "aminoalkyl" embraces alkyl radicals
substituted with amino radicals. More preferred are "lower
aminoalkyl" radicals. Examples of such radicals include
aminomethyl, aminoethyl, and the like. The term "alkylamino"
denotes amino groups which have been substituted with one or two
alkyl radicals. More preferred are "lower N-alkylamino" and "lower
N,N-dialkylamino". Examples of such radicals include N-methylamino,
N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like. The
term "arylamino" denotes amino groups which have been substituted
with one or more aryl radicals. Examples of such radicals include
N-phenylamino and N-naphthylamino. The "arylamino" radicals may be
further substituted on the aryl ring portion of the radical. The
term "alkylaminoalkyl" denotes aminoalkyl groups which have been
substituted with one or two alkyl radicals, as defined above. More
preferred are "lower N-alkylaminoalkyl" and "lower
N,N-dialkylaminoalkyl", where lower alkyl is defined above.
Examples of such radicals include N-methylaminoethyl,
N-ethylaminopropyl, N,N-dimethylaminoethyl, N,N-diethylaminomethyl,
and the like. The term "arylaminoalkyl" denotes aminoalkyl groups
which have been substituted with one or more aryl radicals, as
defined above. More preferred is "lower N-arylaminoalkyl", where
lower aminoalkyl is defined above. Examples of such radicals
include N-phenylaminoethyl and N-phenylaminopropyl. The
"arylaminoalkyl" radicals may be further substituted on the aryl
ring portion of the radical. The term "aminocarbonyl" denotes an
amide group of the formula --C(.dbd.O)NH.sub.2.
[0811] When the above radicals are included as linker moiety "Y" in
Formulas I-III, such radicals are divalent radicals. For terms such
as aralkyl, and heterocycloalkyl, the moiety may be linked to "A"
and "R.sup.3" through a divalent alkyl radical, or through the
alkyl radical at one end and the aryl or heteroaryl portion at the
other. The use of heterocyclo and aryl moieties includes divalent
attachment at substitutable sites.
[0812] The present invention comprises a pharmaceutical composition
comprising a therapeutically-effective amount of a compound of
Formulas I-III in association with at least one
pharmaceutically-acceptable carrier, adjuvant or diluent.
[0813] The present invention also comprises a method of treating
inflammation or inflammation-associated disorders in a subject, the
method comprising treating the subject having or susceptible to
such inflammation or disorder, with a therapeutically-effective
amount of a compound of Formulas I-III. The method includes
prophylactic or chronic treatment, especially in the case of
arthritis and other inflammatory conditions which can lead to
deterioration in the joints.
[0814] Also included in the family of compounds of Formula I are
the stereoisomers and tautomers thereof. Compounds of the present
invention can possess one or more asymmetric carbon atoms and are
thus capable of existing in the form of optical isomers as well as
in the form of racemic or nonracemic mixtures thereof. Accordingly,
some of the compounds of this invention may be present in racemic
mixtures which are also included in this invention. The optical
isomers can be obtained by resolution of the racemic mixtures
according to conventional processes, for example by formation of
diastereoisomeric salts by treatment with an optically active acid
or base. Examples of appropriate acids are tartaric,
diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and
camphorsulfonic acid and then separation-of the mixture of
diastereoisomers by crystallization followed by liberation of the
optically active bases from these salts. A different process for
separation of optical isomers involves the use of a chiral
chromatography column optimally chosen to maximize the separation
of the enantiomers. Still another available method involves
synthesis of covalent diastereoisomeric molecules by reacting an
amine functionality of precursors to compounds of Formula I with an
optically pure acid in an activated form or an optically pure
isocyanate. Alternatively, diastereomeric derivatives can be
prepared by reacting a carboxyl functionality of precursors to
compounds of Formula I with an optically pure amine base. The
synthesized diastereoisomers can be separated by conventional means
such as chromatography, distillation, crystallization or
sublimation, and then hydrolyzed to deliver the enantiomerically
pure compound. The optically active compounds of Formula I can
likewise be obtained by utilizing optimally active starting
materials. These isomers may be in the form of a free acid, a free
base, an ester or a salt.
[0815] 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, heterocyclo, 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, salicylic,
p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,
toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic,
cyclohexylaminosulfonic, algenic, .beta.-hydroxybutyric, salicylic,
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
[0816] The compounds of the invention can be synthesized according
to the following procedures of Schemes I-XXIV, wherein the
R.sup.1-R.sup.6 substituents are as defined for Formula I-III,
above, except where further noted. 7
[0817] Synthetic Scheme I shows the preparation of amide
derivatives 3, where one of Z or W is a leaving group. A
substituted hydroxylamine or equivalent 2, is dissolved in
anhydrous solvent such as THF or methylenie chloride. A solution of
sulfonylphenyl derivative 1 in anhydrous DMF is added and stirred
at about 0.degree. C. to provide the sulfonylphenyl amide
derivatives 3. In addition, hydroxydithiocarbamnates can be
prepared by the methods deciic in U.S. Pat. No. 5,298,521, and
N-hydroxyamides can be prepared by the procedures described in U.S.
Pat. No. 5,051,518, both of which are incorporated by reference.
8
[0818] Synthetic Scheme II shows the preparation of pyrazole
compounds embraced by Formula I where R is Z, (as defined in Scheme
I) and R.sup.a is a radical defined above for the subtituents
optionally substituted on A. In step 1, ketone 4 is treated with a
base, preferably NaOMe or NaH, and an ester, or ester equivalent,
to form the intermediate diketone 5 (in the enol form) which is
used without further purification. In step 2, diketone 5 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 15 hydrazine at reflux to afford a mixture of pyrazoles
6 and 7. Recrystallization from diethyl ether/hexane or
chromatography affords 6 usually as a solid. Similar pyrazoles can
be prepared by methods described in U.S. Pat. Nos. 4,146,721,
5,051,518, 5,134,142 and 4,914,121 which are incorporated by
reference. 9
[0819] Scheme III shows the four step procedure for forming
pyrazoles 11 of the present invention (where R.sup.b is alkyl) from
ketones 8. In step 1, ketone 8 is reacted with a base, such as
lithium bis(trimethylsilyl)amide or lithium diisopropylamide (LDA)
to form the anion. In step 2, the anion is reacted with an
acetylating reagent to provide diketone 9. In step 3, the reaction
of diketone 9 with hydrazine or a substituted hydrazine, gives
pyrazole 10. In step 4, the pyrazole 10 is oxidized with an
oxidizing reagent, such as Oxone.RTM. (potassium
peroxymonosulfate), 3-chloroperbenzoic acid (MCPBA) or hydrogen
peroxide, to give a mixture of the desired
3-(alkylsulfonyl)phenyl-pyrazole 11 and the
5-(alkylsulfonyl)phenyl-pyrazole isomer. The desired pyrazole 11,
usually a white or pale yellow solid, is obtained in pure form
either by chromatography or recrystallization.
[0820] Alternatively, diketone 9 can be formed from ketone 8 by
treatment with a base, such as sodium hydride, in a solvent, such
as dimethylformamide, and further reacting with a nitrile to form
an aminoketone. Treatment of the aminoketone with acid forms the
diketone 9. Similar pyrazoles can be prepared by methods described
in U.S. Pat. No. 3.984,431 which is incorporated by reference.
10
[0821] Diaryl/heteroaryl thiophenes (where T is S. and R.sup.b is
alkyl) can be prepared by the methods described in U.S. Pat. Nos.
4,427,693, 4,302,461, 4,381,311, 4,590,205, and 4,820,827, and PCT
documents WO 95/00501 and WO94/15932, which are incorporated by
reference. Similar pyrroles (where T is N), furanones and furans
(where T is 0) can be prepared by methods described in PCT
documents WO 95/00501 and WO94/15932. 11
[0822] Diaryl/heteroaryl oxazoles can be prepared by the methods
described in U.S. Pat. Nos. 3,743,656, 3,644,499 and 3,647,858, and
PCT documents WO 95/00501 and WO94/15932, which are incorporated by
reference. 12
[0823] Diaryl/heteroaryl isoxazoles can be prepared by the methods
described in PCT documents WO92/05162, and WO92/19604, and European
Publication EP 26928 which are incorporated by reference.
Sulfonamides 27 can be formed from the hydrated isoxazole 26 in a
two step procedure. First, hydrated isoxazole 26 is treated at
about 0.degree. C. with two or three equivalents of chlorosulfonic
acid to form the corresponding sulfonyl chloride. In step two, the
sulfonyl chloride thus 15 formed is treated with concentrated
ammonia to provide the sulfonamide derivative 27. 13
[0824] Scheme VII shows the three step preparation of the
substituted imidazoles 32 of the present invention. In step 1, the
reaction of substituted nitrites (R.sup.1CN) 28 with primary
phenylamines 29 in the presence of alkylaluminum reagents such as
trimethylaluminum, triethylaluminum, dimethylaluminum chloride,
diethylaluminum chloride in the presence of inert solvents such as
toluene, benzene, and xylene, gives amidines 30. In step 2, the
reaction of amidine 30 with 2-haloketones (where X is Br or Cl) in
the presence of bases, such as sodium bicarbonate, potassium
carbonate, sodium carbonate, potassium bicarbonate or hindered
tertiary amines such as N,N'-diisopropylethylamin- e, gives the
4,5-dihydroimidazoles 31 (where R.sup.c is hydroxyl, R.sup.d is
hydrido and R.sup.e is alkyl, halo or hydrido). Some of the
suitable solvents for this reaction are isopropanol, acetone and
dimethylformamide. The reaction may be carried out at temperatures
of about 20.degree. C. to about 90.degree. C. In step 3, the
4,5-dihydroimidazoles 31 may be dehydrated in the presence of an
acid catalyst such as 4-toluenesulfonic acid or mineral acids to
form the 1,2-disubstituted imidazoles 32 of the invention. Suitable
solvents for this dehydration step are e.g., toluene, xylene and
benzene. Trifluoroacetic acid can be used as solvent and catalyst
for this dehydration step.
[0825] In some cases (e.g., where YR=methyl or phenyl) the
intermediate 31 may not be readily isolable. The reaction, under
the conditions described above, proceeds to give the targeted
imidazoles directly.
[0826] Similarly, imidazoles can be prepared having the
sulfonylphenyl moiety attached at position 2 and R.sup.1 attached
at the nitrogen atom at position 1. Diaryl/heteroaryl imidazoles
can be prepared by the methods described in U.S. Pat. No.
4,822,805, and PCT document WO 93/14082, which are incorporated by
reference. 14
[0827] The subject imidazole compounds 39 of this invention may be
synthesized according to the sequence outlined in Scheme VIII.
Aldehyde 33 may be converted to the protected cyanohydrin 34 by
reaction with a trialkylsilyl cyanide, such as trimethylsilyl
cyanide (TMSCN) in the presence of a catalyst such as zinc iodide
(ZnI.sub.2) or potassium cyanide (KCN). Reaction of cyanohydrin 34
with a strong base followed by treatment with benzaldehyde 35
(where R.sup.2 is alkyl) and using both acid and base treatments,
in that order, on workup gives benzoin 36. Examples of strong bases
suitable for this reaction are lithium diisopropylamide (LDA) and
lithium hexamethyldisilazane. Benzoin 36 may be converted to benzil
37 by reaction with a suitable oxidizing agent, such as bismuth
oxide or manganese dioxide, or by a Swern oxidation using dimethyl
sulfoxide (DMSO) and trifluoroacetic anhydride. Benzil 37 may be
obtained directly by reaction of the anion of cyanohydrin 34 with a
substituted benzoic acid halide. Any of compounds 36 and 37 may be
used as intermediates for conversion to imidazoles 38 (where
R.sup.2 is alkyl) according to chemical procedures known by those
skilled in the art and described by M. R. Grimmett, "Advances in
Imidazole Chemistry" in Advances in Heterocyclic Chemistry, 12, 104
(1970). The conversion of 37 to imidazoles 38 is carried out by
reaction with ammonium acetate and an appropriate aldehyde (RYCHO)
in acetic acid. Benzoin 36 may be converted to imidazoles 38 by
reaction with formamide. In addition, benzoin 36 may be converted
to imidazoles by first acylating with an appropriate acyl group
(RYCO-) and then treating with ammonium hydroxide. Those skilled in
the art will recognize that the oxidation of the sulfide (where
R.sup.2 is methyl) to the sulfone may be carried out at any point
along the way beginning with compounds 35, and including oxidation
of imidazoles 38, using, for examples, reagents such as hydrogen
peroxide in acetic acid, m-chloroperoxybenzoic acid (MCPBA) and
potassium peroxymonosulfate (OXONE.RTM.).
[0828] Diaryl/heteroaryl imidazoles can be prepared by the methods
described in U.S. Pat. Nos. 3,707,475, 4,686,231, 4,503,065,
4,472,422, 4,372,964, 4,576,958, 3,901,908, European publication EP
372,445, and PCT document WO 95/00501, which are incorporated by
reference. 15
[0829] Diaryl/heteroaryl cyclopentenes can be prepared by the
methods described in U.S. Pat. No. 5,344,991, and PCT document WO
95/00501, which are incorporated by reference. 16
[0830] Similarly, Synthetic Scheme X shows the procedure for the
preparation of 1,2-diarylbenzene antiinflammatory agents 47 from
2-bromo-biphenyl intermediates 46 (prepared similar to that
described in Synthetic Scheme IX) and the appropriate substituted
phenylboronic acids. Using a coupling procedure similar to the one
developed by Suzuki et al. [Synth. Commun., 11, 513 (1981)],
intermediates 46 are reacted with the boronic acids in
toluene/ethanol at reflux in the presence of a Pd.sup.0 catalyst,
e.g., tetrakis(triphenylphosphine)palladium(0), and 2M sodium
carbonate to give the corresponding 1,2-diarylbenzene
antiinflammatory agents 47 of this invention. 17
[0831] Diaryl/heteroaryl thiazoles can be prepared by the methods
described in U.S. Pat. Nos. 4,051,250, 4,632,930, European
Application EP 592,-664, and PCT document WO 95/00501, which are
incorporated by reference. Isothiazoles can be prepared as
described in PCT document WO 95/00501. 18
[0832] Diaryl/heteroaryl pyridines can be prepared by the methods
described in U.S. Pat. Nos. 5,169,857, 4,011,328, and 4,533,666,
which are incorporated by reference. For example, Synthetic Scheme
XII shows the procedure used to prepare 3-alkylcarbonylaminoalkyl
pyridine antiinflammatory agents 53, 3-haloalkyl pyridine
antiinflammatory agents 55, 3-hydroxyalkyl pyridine
antiinflammatory agents 56, heteroatom substituted 3-alkyl pyridine
antiinflammatory agents 58 and 3-aryloxyalkyl pyridine
antiinflammatory agents 59 from the corresponding carbonitriles 51
(where R.sup.f is hydrido, halo, alkoxy, haloalkoxy, aryl,
alkylthio, alkylamino, aralkoxy, azido or allyloxy). The
3-alkylcarbonylaminoalkyl pyridine antiinflammatory agents 53
(where R' is alkyl) are prepared in a two step procedure from the
carbonitriles 51. In step one, the carbonitrile 51 is reduced using
reducing agents, such as diisobutyl aluminum hydride (DIBAL) in a
solvent such as toluene or boranes in a solvent such as
tetrahydrofuran at room temperature or reflux to form the
aminoalkyl pyridines 52. Additional reducing reagent may be added
to the solution. In step two, an acid chloride is added to the
aminoalkyl pyridines 52 in a solvent such as ethyl ether or
tetrahydrofuran and stirred to form the alkylcarbonylaminoalkyl
pyridines 53. The 3-haloalkyl pyridine antiinflammatory agents 55
are prepared in a two step procedure from the carbonitriles 51. In
step one, the carbonitriles 51 are reduced using agents, such as
diisobutyl aluminum hydride (DIBAL) in a solvent such as toluene,
at room temperature to form the aldehydes 54. The 3-hydroxyalkyl
pyridines 56 also can be isolated from this reaction. In step two,
a halogenating agent, such as diethylamino sulfur trifluoride
(DAST) is added to the aldehyde 54 to form the haloalkyl pyridines
55. Reduction of aldehydes 54 with agents such as diisobutyl
aluminum hydride (DIBAL) followed by methanol and water in methanol
to yield the 3-hydroxyalkyl pyridines 56. Compound 56 is
convertible to alkoxyalkyl and aralkoxyalkyl compounds 59 by
sequential treatment first with a base and then with an alkyl or
aralkyl halide. An example of a suitable base is sodium hydride.
Examples of alkyl and aralkyl halides are methyl iodide and benzyl
chloride. Alternatively, compound 56 may be converted to the
haloalkyl compound 57 using a suitable halogenating agent, such as
thionyl chloride. Under such circumstances, the hydrochloride salt
may be isolated. This in turn may be converted to compounds 58 by
reaction with the appropriate alcohol, thiol, or amine. It may be
advantageous to carry out this reaction in the presence of a base.
Examples of suitable alcohols are methanol, ethanol, benzyl alcohol
and phenol. Examples of suitable thiols are n-butyl mercaptan,
benzylthiol and thiophenol. Examples of suitable amines are
dimethylamine, benzylamine, N-methylbenzylamine, aniline,
N-methylaniline and diphenylamine. Examples of suitable bases are
sodium hydride and potassium carbonate. Alternatively, amines are
accessible by reaction of aldehyde 54 with a primary or secondary
amine in the presence of a reducing agent. Examples of suitable
primary amines are methyl amine and ethylamine. An example of a
suitable secondary amine is dimethylamine. Suitable reducing agents
include sodium cyanoborohydride and sodium borohydride. 19
[0833] Scheme XIII shows a method to form the alkylsulfonylphenyl
substituted compounds 61 of the current invention by oxidation of
alkylthio or alkylsulfinyl derivatives 60. Aqueous-hydrogen
peroxide (30%) is added to a suspension of a (methylthio)phenyl
substituted compound 60 in acetic acid. The mixture is stirred
while heating to about 100.degree. C. for about 2 hours.
Alternatively, m-chloroperoxybenzoic acid (MCPBA), and other
oxidizing agents [potassium peroxymonosulfate (OXONE.RTM.)] can be
used to form the sulfonyl radicals 61. 20
[0834] Synthetic Scheme XIV shows the three step procedure used to
prepare sulfonamide antiinflammatory agents 63 and the two step
procedure used to prepare fluoromethyl sulfone antiinflammatory
agents 64 from their corresponding methyl sulfones 62. In step one,
THF solutions of the methyl sulfones 62 at -78.degree. C. are
treated with an alkyllithium reagent, e.g., methyllithium,
n-butyllithium, etc. In step two, the anions generated in step one
are treated with an organoborane, e.g., triethylborane,
tributylborane, etc., at -78.degree. C. then allowed to warm to
ambient temperature prior to stirring at reflux. In step three, an
aqueous solution of sodium acetate and hydroxylamine-O-sulfonic
acid is added to provide the corresponding sulfonamide
antiinflammatory agents 63 of this invention. As an alternative to
the borane chemistry found in step two above, the base treated
sulfone is reacted with an alkylsilane, such as
(iodomethyl)trimethylsilane or (chloromethyl)trimethylsilane, at
room temperature to give a silylalkylsulfone. The silylalkylsulfone
is converted to a sulfinic acid salt by heating to about 90.degree.
C. with tetrabutylammoniumfluoride. Treatment proceeds as in step
three above to produce the sulfonamide.
[0835] Alternatively, the anion solutions generated in step one may
be warmed to 0.degree. C. and treated with
N-fluorodibenzenesulfonamide to provide the corresponding
fluoromethyl sulfone antiinflammatory agents 64 of this invention.
21
[0836] Synthetic Scheme XV shows a method of making the pyrazole
ureas 69 of the present invention. In step 1, the dione 66 is
formed from ketone 65 through the addition of a base, such as
lithium bis(trimethylsilyl)amide or lithium diisopropylamide (LDA),
followed by reacting with an appropriate acetylating reagent, such
as (CO.sub.2CH.sub.3).sub.2. Treatment of the dione 66 with a
phenylhydrazide yields the pyrazole ester 67. The pyrazole ester 67
is reduced to the alcohol 68 by treatment with base:and borane in
THF. In step four, the alcohol 68 is reacted with
triphenylphosphine, an alkyl azodicarboxylate (e.g. diisopropyl
azodicarboxylate (DIAD) and diethyl azodicarboxylate (DEAD)), and
bis(phenoxycarbonyl) hydroxylamine [prepared by the method of
Stewart and Brooks, J.Org.Chem., 57, 5020-23 (1992)] in a solvent
such as tetrahydrofuran (THF) at about 0.degree. C. to room
temperature. Aminolysis with ammonium hydroxide yields the
anti-inflammatory ureas 69 of the present invention. 22
[0837] Scheme XVI shows a procedure for forming an alkynyl oxazole
74 (where R.sup.2 is amino), similar to that shown in Scheme V
above. The ketone sulfonamide 71 is formed from ketone 70 through
chlorosulfonation and ammonolysis with ammonium hydroxide in a
solvent such as acetone. The ketone sulfonamide 71 is halogenated,
such as with HBr in acetic acid and bromine, to form the haloketone
sulfonamide 72. Substitution with butynoic acid in the presence of
K.sub.2CO.sub.3, a crown ether such as 18-Crown-6 and
dimethylacetamide (DMA) yields the alkynyl ketoester 73. Conversion
of the alkynyl ester 73 to the alkynyl oxazole 74 proceeds as
previously described in Scheme V. 23
[0838] Synthetic Scheme XVII shows the procedures for forming
heterocycloalkynyl ureas 76, heterocyclotriazole ureas 77 and
heterocycloalkyl ureas 78, from the corresponding alkynes 74. The
alkynes 74, such as formed in Scheme XVI, are halogenated, such as
with N-bromosuccinimide (NBS) and 2,2'-azobis(2-methylpropionitrile
(AIBN), to form the haloalkynes 75. The alkynyl halide 75 can be
converted into the urea by a three step procedure. In the first
step, the halide 75 is treated with
bis(phenoxycarbonyl)hydroxylamine. Aminolysis with ammonium
hydroxide yields the ureas 76 of the present invention. The alkynyl
ureas 76 can be converted to heterocyclo-containing ureas 77, such
as by treatment with azidotrimethylsilane, followed by acid.
Alternatively, the alkynyl ureas 76 can be reduced, such as with
hydrogen in the presence of catalyst (e.g., palladium) to yield the
heterocycloalkyl ureas 78. 24
[0839] Scheme XVIII shows a method of forming the alkenyl ureas 79,
and diols 80 of the present invention from the appropriate alkynyl
ureas 76. In Step one, treatment with diimide reduces the alkynyl
ureas 77 to the alkenyl ureas 79. Oxidation of the alkenyl urea 79,
such as with osmium tetraoxide and hydrogen peroxide, yields the
diols 80 of the present invention. 25
[0840] Scheme XIX shows the preparation of ureas 83 and amides 85
antiinflamnatory agents of the present invention. Esters 81 (where
R.sup.i is alkyl, as provided for in WO094/27980) can be converted
to the alcohols 82 by treatment with a reducing agent, such as
DIBAL-H. Alcohols 82 can be directly converted to the protected
urea by treating with triphenylphosphine, diethyl azodicarboxylate
(DEAD), and N,O-bis(phenoxycarbonyl)hydroxylamine. Aminolysis with
ammonium hydroxide yields the urea 83. Alternatively, the esters 81
can be hydrolyzed to the acids 84 with base such as LiOH. Amides 85
are formed from the acid 84 by treatment with oxalyl chloride to
form the corresponding acid chlorides, followed by substitution
with the hydroxylamines. 26
[0841] Scheme XX shows the preparation of the antiinflammatory
amides 88 of the present invention. Base treatment of ester 86,
such as with sodium hydride, followed by addition of an aralkyl
halide or heteroaralkyl halide forms the ester 87. Formation of the
amide 88 from the esters,87 occurs in a three step procedure.
Treatment with base, such as lithium hydroxide, and thionyl
chloride yields the acid chloride. Addition of a hydroxylamine
yields the amide 88. 27
[0842] Scheme XXI shows an alternative preparation of the alkynyl
alcohol 90 and alkynyl halides 91 previously described in Scheme
XVII. Cyclic halides 89 can be converted to the substituted alkynyl
alcohols 90 by reacting an alkynyl alcohol with the halides 89 in
the presence of base and
bis(triphenylphosphine)palladium(II)chloride. The alkynyl alcohol
90 can be converted to the alkynyl halide 91 by treatment with
triphenoxyphosphonium methyliodide. 28
[0843] Additional antiinflammatory agents containing various
substituted alkyl spacer radicals including hydroxyalkylureas 96
and aminoalkylureas 98, can be prepared from ketones 92, by the
procedures shown in Scheme XXII. The ketones 92 are halogenated to
form haloketones 93, such as by treatment with NBS in the presence
of AIBN. Treatment of the halides 93 with
bis(phenoxycarbonyl)hydroxylamine in the presence of base, such as
sodium hydride, generates the protected (ketoalkyl)hydroxylamines
94. The protected (ketoalkyl)hydroxylamines 94 can be converted to
the protected (hydroxyalkyl)hydroxylamines 95 by reducing the
carbonyl, such as with sodium borohydride. Deprotection, such as
with ammonium hydroxide, yields the hydroxyalkylureas 96. Amination
of the protected (ketoalkyl)hydroxylamines 94 by reaction with
ammonium acetate and sodium cyanoborohydride in the presence of
acetic acid generates the protected (aminoalkyl)hydroxylamines 97.
Deprotection, such as with ammonium hydroxide, yields the
aminoalkylureas 98. 29
[0844] Scheme XXIII shows a method for preparing oxazoles 103. A
solution of aldehyde 99 and zinc iodide in an organic solvent such
as dichloromethane is treated with trimethylsilylcyanide to give
the trimethylsilyl cyanohydrin. The trimethylsilyl cyanohydrin is
added to a solution of R.sup.1-magnesium bromide in diethyl ether
while,maintaining the temperature between 25-35.degree. C. to give
the benzoin 100. The benzoin 100, pyridine, and acid chloride are
reacted at room temperature to yield the benzoin ester 101.
Addition of ammonium acetate to the benzoin ester 101 yields the
oxazole 103. Alternatively, the hydroxy-oxazoline 102 is isolated.
Dehydration of the hydroxy-oxazoline 102 yields the oxazoles 103.
By reversing the positions of R.sup.1 and the phenyl group in
benzoin 100, oxazoles can be prepared where R.sup.1 is at position
4. 30
[0845] Scheme XXIV shows a method of preparing
oxazolylbenzenesulfonamides 106 of the present invention. The
oxazole 104 is stirred with chlorosulfonic acid at about 5.degree.
C. to give the sulfonyl chlorides 105. The sulfonyl chloride 105 is
reacted at about 5.degree. C. with ammonium hydroxide to give the
sulfonamides 106 of the current invention.
[0846] The following examples contain detailed descriptions of the
methods of preparation of compounds of Formulas I-III. 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. All compounds showed NMR spectra consistent with their
assigned structures.
EXAMPLE 1
[0847] 31
N'-[[1-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]methyl-
]-N'-hydroxyurea
[0848] Step 1. Preoaration of
methyl-4-(4-chlorophenyl)-2,4-dioxobutanoate
[0849] Dimethyl oxalate (15.27 g, 0.129 mol) and
4'-chloroacetophenone (20.0 g, 0.129 mol) were diluted with
methanol (300 mL) and sodium methoxide (25 wt % 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,
hydrochloric acid (conc. 70 mL) was added, and the white suspension
was stirred vigorously at room temperature for 1 hour. The
suspension was cooled to 0.degree. C. and held for 0.5 hour. The
solid was filtered, and the filter cake was washed with cold water
(100 mL). Upon drying,
methyl-4-[4-(chloro)phenyl]-2,4-dioxobutanoate was obtained (16.94
g, 54.-4%) as the enol: mp 108.5-110.5.degree. C. .sup.1H NMR
(CDCl.sub.3/300 MRz) .delta.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).
[0850] Step 2. Preparation of methyl
1-(4-aminosulfonylohenyl)-5-(4-chloro-
ohenyl)-1H-ovrazole-3-carboxylate
[0851] Methyl-4-[4-(chloro)phenyl]-2,4-dioxobutanoate from Step 1
(5.0 g, 20.78 mmol) was added to 4-sulfonamidylphenyl hydrazine
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 pyrazole.
Recrystallization of 3.50 g from boiling ethanol yielded .3.14 g
(90%) of pure methyl
1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-py-
razole-3-carboxylate: mp 227.degree. C.; .sup.1H NMR
(CDCl.sub.3/300 MHz) .delta.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+=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.
[0852] Step 3. Preparation of
!-(4-aminosulfonylohenyl)-5-(4-chlorophenyl)-
-1H-pyrazole-3-carboxylic acid
[0853] Methyl
1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-c-
arboxylate from Step 2 (1.0 g, 2.66 mmol) was added to
tetrahydrofuran (20 mL). Aqueous sodium hydroxide (2.5 N, 2.7 mL)
and water (2.5 mL) were added, and the suspension was heated to
reflux and held for 16 hours. The solids dissolved during this
time. The reaction was cooled to room temperature, and hydrochloric
acid solution (1 N, 11 mL) was added. The aqueous suspension was
extracted with methylene chloride (2.times.20 mL). The combined
organic solution was dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo to an oil. Trituration with 30
mL of dichloromethane yielded, upon filtration and drying,
1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic
acid (0.90 g (94%)) as a white solid: mp 126-128.degree. C.
[0854] Step 4. Preparation of
4-[5-(4-chlorophenyl)-3-hydroxymethyl-1H-pyr-
azol-1-yl]benzenesulfonamide.
[0855]
4-[4-(Amilinosulfonyl)phenyl-5-(4-chlorophenyl)-1H-pyrazole-3-carbo-
xylic acid from Step 3 (3.8 g, 10 mmol) and tetrahydrofuran (100
mL) was stirred at room temperature during the dropwise addition of
1.0 M 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 solution was washed with 1N
hydrochloric acid, brine, and sat. aq. sodium bicarbonate solution,
dried over magnesium sulfate, filtered and concentrated. The
resultant material was recrystallized from ethanol:water to yield
4-[5-(4-chlorophenyl)-3-hydroxymethyl-1H-pyrazol-1-
-yl]benzenesulfonamide (2.6 g, 71%) as a white solid: mp
192-194.degree. C.; .sup.1H NMR (DMSO-d.sub.6/300 MHz) .delta.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.3SO.sub.2Cl: C, 52.82; H, 3.88; N, 11.55.
Found: C, 52.91; H, 3.88; N, 11.50.
[0856] Step 5. Preparation of
[[1-[4-(aminosulfonyl)phenyl]-5-(4-chloroohe-
nyl)-1H-pyrazol-3-yl]methyl]-N,O-bis(phenoxycarbonyl)hydroxylamine.
[0857] A solution of
4-[5-(4-chlorophenyl)-3-hydroxymethyl-1H-pyrazol-1-yl-
]benzenesulfonamide from Step 4 (7.28 g, 0.02 mol),
triphenylphosphine (6.29 g, 0.024 mol) and
N,O-bis(phenoxycarbonyl)hydroxylamine prepared as described by A.
O. Stewart and D. W. Brooks, [J. Org. Chem., 57, 5020-5023
(1992)](6.01 g, 0.022 mol) in 250 mL of anhydrous tetrahydrofuran
(THF) was cooled to 0.degree. C. and treated with
diisopropylazo-dicarboxylate (3.75 g, 0.024 mol) dissolved in 25 mL
of THF. The solution was stirred at room temperature for 3 hours,
concentrated in vacuo and the residue purified by flash
chromatography on silica gel eluting with ethyl acetate/hexane
(2:3) to afford 9.30 g, 75% of the protected hydroxylamine as a
thick clear oil that was used directly in the next step.
[0858] Step 6. Preparation of N'-[[1-[4-(aminosulfonyl)
phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]methyl]-N'-hydroxyurea
[0859] The compound from Step 5 (6.0 g, 9.7 mmol) was dissolved in
150 mL of ethanol and the solution was saturated with ammonia. The
solution was let stand undisturbed overnight and then concentrated
in vacuo. The residue was dissolved in ethyl acetate, washed with 1
N HCl and brine, dried over anhyd. MgSO.sub.4, filtered and
concentrated in vacuo to afford
N'-[[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-y-
l]methyl]-N'-hydroxyurea as a white solid that was crystallized
from a mixture of ethyl acetate and hexane: mp 216-218.degree.
C.
EXAMPLE 2
[0860] 32
4-(4-Fluorophenyl)-N-hydroxy-N-methyl-5-[(4-methylsulfonyl)phenyl]-2-oxazo-
lepropanamide
[0861] A solution of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-oxa-
zoleproprionic acid (U.S. Pat. No. 5,380,738) (500 mg, 1.28 mmol)
was dissolved in 20 mL of dichloromethane containing 50 .mu.L of
dimethylformamide (DMF). This solution was cooled to 0.degree. C.
and treated with oxalyl chloride (130 .mu.L, 1.54 mmol, 1.2
equivalents). The solution was warmed to room temperature and
stirred for 3 hours, and concentrated in vacuo. The residue was
taken back up in dichloromethane and added dropwise to a solution
of N-methyl hydroxylamine hydrochloride (129 mg, 1.54 mmol, 1.2
equivalents) and triethylamine (390 .mu.L, 2.82 mmol, 2.2
equivalents) in 20 mL of dichloromethane at 0.degree. C. The
solution was stirred at room temperature for 1 hour and diluted
with water. The phases were separated and the dichloromethane layer
was washed with 1 N HCl, brine, dried over anhydrous MgSO.sub.4,
filtered and concentrated in vacuo to provide a yellow solid that
was recrystallized from a mixture of ethyl acetate and isooctane to
provide 4-(4-fluorophenyl)-N-hydroxy-N-methyl-5-[(4-methylsulfonyl)
phenyl]-2-oxazolepropanamide (455 mg, 85%): .sup.1H-NMR
(CDCl.sub.3, 300 MHz)-3.12 (s, 3H), 3.15 (t, 2H, J=6.6 Hz), 3.28
(s, 3H), 3.41 (t, 2H, J=6.6 Hz), 7.20 (t, 2H, J=8.5 Hz), 7.54 (m,
2H), 7.75 (d, 2H, J=8.5 Hz) and 7.97 (d, 2H, J=8.5 Hz). LRMS m/z
418 (M)+. HRMS calc'd. for C.sub.20H.sub.19N.sub.2O.sub.5FS:
418.0999. Found: 418.0987. Anal. calc'd. for
C.sub.20H.sub.19N.sub.2O.sub.5FS: C, 57.41; H, 4.58; N, 6.69.
Found: C, 56-.84; H, 4.50; N, 6.59.
EXAMPLE 3
[0862] 33
[1-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]-N-hydroxy-
-N-methyl-ethanamide
[0863] Step 1. Preparation of
4-[5-(4-chlorophenyl)-3-chloromethyl-1H-pyra-
zol-1-yl]benzenesulfonamide
[0864]
4-[5-(4-Chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl]benzenesulf-
onamide (Example 1 Step 4) (3.0 g, 8.2 mmol) was dissolved in 100
mL of dry tetrahydrofuran and treated with para-toluenesulfonyl
chloride (1.56 g, 8.2 mmol), lithium chloride (350 mg, 8.2 mmol),
and triethylamine (830 mg, 8.2 mmol). The solution was warmed to
reflux for 16 hours and diluted with 100 mL of ethyl acetate. The
solution was washed with 1 N hydrochloric acid, saturated aqueous
NaHCO.sub.3, and water, dried over anhydrous MgSO.sub.4, filtered
and concentrated in vacuo. The residue was purified by flash
chromatography over silica gel eluting with 1:1 (v:v) hexane/ethyl
acetate. The appropriate fractions were combined and concentrated
and the residue crystallized from ethanol/water to give pure
4-(5-(4-chlorophenyl)-3-chloromethyl-1H-pyrazol-1-yl]benzenesulfonamide
as a white solid (2.51 g, 80%): mp 198-201.degree. C. Anal. Calc'd.
for C.sub.16H.sub.13N.sub.3S.sub.1O.sub.2cl.sub.2: C, 50.27; H,
3.43; N, 10.99. Found: C, 50.34; H, 3.43; N, 10.96.
[0865] Step 2. Preparation of
4-[5-(4-chlororhenyl)-3-cyanomethyl-1-H-pyra-
zol-1-yl]benzenesulfonamide
[0866] A solution of
4-[5-(4-chlorophenyl)-3-chloromethyl-1H-pyrazol-1-yl]-
benzenesulfonamide from step 1 (350 mg, 0.9 mmol) and sodium
cyanide (200 mg), dissolved in 15 mL of dimethylsulfoxide, was
warmed to 100.degree. C. for 4 hours. The solution was cooled to
room temperature, diluted with water and extracted with ethyl
acetate. The ethyl acetate extracts were combined and washed with
water, dried over anhydrous MgSO.sub.4, filtered and concentrated
in vacuo. The residue was purified by flash chromatography over
silica gel eluting with 1:1 (v:v) hexane/ethyl acetate. The
appropriate fractions were combined and concentrated, and the
residue crystallized from ethanol/water to give
4-[5-(4-chlorophenyl)-3-cyanomethyl-1-H-pyrazol-1-yl]benzenesulfonamide
as a white solid (251 mg, 75%): mp 212-214.degree. C. Anal. Calc'd.
for C.sub.17H.sub.13ClN.sub.4O.sub.2S.sub.1: C, 54.77; H, 3.51; N,
15.03. Found: C, 54.94; H, 3.61; N, 14.88.
[0867] Step 3. Preparation of
[[1-[4-(aminosulfonyl)phenyl]-5-(4-chloroohe-
nyl)-1H-pyrazol-3-yl]acetic acid
[0868] To a solution of
4-(5-(4-chlorophenyl)-3-(cyanomethyl)-1H-pyrazol-1-
-yl]benzenesulfonamide from step 2 (0.340 g, 3.594 mmol) in ethanol
(250 mL) at -10.degree. C., HCl gas was added via a fritted gas
inlet tube over 6 hours. The reaction mixture was concentrated in
vacuo yielding an oil. The oil was dissolved in 50 mL of ethanol
and 15 mL of water, treated with LiOH until the pH was 12, and
stirred at room temperature overnight. The reaction was
concentrated in vacuo, diluted with water, acidified with dil HCl,
and extracted with ethyl acetate. The ethyl acetate phase was dried
over anhydrous MgSO.sub.4, filtered and concentrated yielding
[[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-
-pyrazol-3-yl]acetic acid as a brown solid (1.072 g, 76%): mp
120-122.degree. C. High resolution mass spectrum Calc'd. for
C.sub.17H.sub.15ClN.sub.3O.sub.4S (M+H): 392.0472. Found: 392.0467.
.sup.1H NMR (CDCl.sub.3 and CD.sub.3CO.sub.2D) 7.84 (d, J=8.66 Hz 2
H), 7.37 (d, J =8.66 Hz, 2 H), 7.31 (d, J=8.66 Hz, 2 H), 7.15 (d, J
=8.66 Hz, 2 H), 6.54 (s, 1H), 3.84 (s, 2H).
[0869] Step 4. Preparation of
[[1-[4-(aminosulfonyl)phenyl[-5-(4-chloroohe-
nyl)-1H-,pyrazol-3-yl]-N-hydroxy-N-methylacetamide
[0870] To a stirred solution of the
1-(4-aminosulfonylphenyl)-4-(4-chlorop- henyl)pyrazole-3-acetic
acid from step 3 (0.240 g, 0.613 mmol) in dioxane (6 mL) was added
N-hydroxysuccinimide (0.085 g, 0.735 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
(0.129 g, 0.674 mmol). After stirring overnight, the reaction
mixture was concentrated in vacuo and diluted with ethyl acetate.
The ethyl acetate phase was washed with KHSO.sub.4, NaHCO.sub.3,
and brine, dried over MgSO.sub.4, filtered and concentrated in
vacuo yielding the crude N-hydroxysuccinimide ester. This ester and
N-methylhydroxylamide HCl (0.056 g, 0.674 mmol) were dissolved in
dimethylformamide, (4 mL) and triethylamine (94 .mu.L, 0.068 g,
0.674 mmol) was added. The reaction was stirred at room temperature
for 56 hours, diluted with ethyl acetate, washed with KHSO.sub.4,
dried over anhydrous MgSo.sub.4, filtered and concentrated in vacuo
yielding a semi-solid. This solid was treated with isooctane and
ethyl acetate yielding [[1-[4-(aminosulfonyl)phenyl]-5-(4-c-
hlorophenyl)-1H-pyrazol-3-yl]-N-hydroxy-N-methyl acetamide as an
off-white powder (0.083 g, 32%): mp 110-135.degree. C. (dec).
.sup.1H NMR (CDCl.sub.3 and DMSO d.sub.6) 9.45 (s, 1 H exch), 7.86
(d, J=8.86 Hz, 2 H), 7.27-7.40 (m, 4 H), 7.12 (d, J=8.46 Hz, 2 H),
6.49, s, 1 H), 5.98 (s, 2H), 3.89 (s, 2 H), 3.25 (s, 3 H). LRMS:
M.sup.+obs at 421.
EXAMPLE 4
[0871] 34
4-[(4-Aminosulfonyl)phenyl]-5-(3,4-dichlorophenyl)-N-hydroxy-2-oxazole-but-
anamide
[0872] Step 1. Preparation of 2-(3
4-dichlorophenyl)-2-hydroxy-1-phenyleth- anone
[0873] Trimethylsilyl cyanide (14.6 g, 0.147 mol) was dissolved in
30 mL of methylene chloride and added to a solution of
3,4-dichlorobenzaldehyde (25 g, 0.143 mol) and zinc iodide (0.41 g,
1.28 mmol) in 100 mL of methylene chloride. The reaction mixture
was stirred at room temperature for 1 h and diluted with 200 mL of
methylene chloride. The organic layer was washed with saturated
sodium bicarbonate (2.times.150 mL), saturated brine (2.times.150
ML), dried over magnesium sulfate, filtered and concentrated to
give 38.4 g (98%) of a brown oil, which was used in the next
reaction without further purification. This trimethylsilyl
cyanohydrin (15 g, 0.0547 mol) was dissolved in 20 mL of diethyl
ether and added to phenylmagnesium bromide (19.5 mL of 3.0 M in
ether solution, 0.0585 mol) in 250 mL of ether. The reaction
mixture was stirred for 1.5 h at room temperature, then slowly
quenched with 100 mL of 3 N HCl. The organic layer was separated
and washed with saturated sodium bicarbonate (1.times.150 mL),
saturated brine (1.times.150 mL), dried over magnesium sulfate,
filtered and concentrated to give 13.0 g of a brown oil. A solution
of 9:1 trifluoroacetic acid in water (50 mL) was added to the
concentrated residue, and the mixture was stirred for 1.5 h at room
temperature. The reaction mixture was neutralized by adding solid
sodium carbonate. The resulting residue was partitioned between
water (200 mL) and ethyl acetate (300 mL). The organic layer was
separated and washed with saturated sodium bicarbonate (1.times.150
mL), saturated brine (1.times.150 mL), dried over magnesium
sulfate, filtered and concentrated. The concentrated residue was
crystallized from ethyl acetate and hexane to give 7.37 g (48%) of
2-(3,4-dichlorophenyl)-2-hydro- xy-1-(phenyl)ethanone as a yellow
solid: HRMS calcd. for C.sub.14H.sub.10O.sub.2Cl.sub.2 281.0136,
found 281.0112.
[0874] Step 2. Preparation of methyl
[(4-phenyl)-5-(3,4-dichlorophenyl)oxa- zolel-2-butanoate
[0875] 5-(Methoxycarbonyl)pentanoyl chloride (2.82 g, 0.017 mol)
and triethylamine (3.47 g, 0.034 mol) were added to a solution of
2-(3,4-dichlorophenyl)-2-hydroxy-1-[phenyl]ethanone (Step 1) (4.77
g, 0.017 mmol) in 40 mL of methylene chloride. The resulting
mixture was stirred overnight at room temperature. The reaction
mixture was diluted with 100 mL of methylene chloride. The organic
solution was washed with water (1.times.100 mL), saturated brine
(1.times.100 mL), dried over magnesium sulfate, filtered and
concentrated. The concentrated residue was dried under high vacuum,
then ammonium acetate (4.6 g, 0.06 mol) and 30 mL of acetic acid
were added. The reaction mixture was heated at 100.degree. C. for
2.5 h. The reaction mixture was cooled to room temperature, and the
excess acetic acid was removed under vacuum. The resulting residue
was partitioned between water (100 mL) and ethyl acetate (200 mL).
The organic layer was separated, washed with saturated aqueous
sodium bicarbonate (2.times.100 mL), saturated brine (1.times.100
mL), dried over magnesium sulfate, filtered and concentrated. The
concentrated residue was purified by flash chromatography on silica
gel (eluting with 1:9 ethyl acetate:hexane) to give 2.82 g (42.6%)
of methyl [(4-phenyl)-5-(3,4-dichlorophenyl)oxazole]-2-butanoate as
a yellow oil: HRMS calcd. for
C.sub.20H.sub.17N.sub.1O.sub.3Cl.sub.2 390.0664. Found
390.0648.
[0876] Step 3. Preparation of methyl
4-[(4-aminosulfonyl)phenyl]-5-(3.4-di-
chloro-phenyl)oxazole-2-butanoate.
[0877] Chlorosulfonic acid (28 g, 0.24 mol) was added to methyl
[(4-phenyl)-5-(3,4-dichlorophenyl)oxazole]-2-butanoate (Step 2)
(3.74 g, 9.58 mmol) at 5.degree. C. The ice bath was removed, and
the reaction was stirred for 3 h at room temperature. The reaction
mixture was diluted with 100 mL of methylene chloride and slowly
poured into ice. The organic layer was separated and washed with
saturated brine (1.times.100 mL). The organic layer was separated
and poured into 50 mL of concentrated ammonium hydroxide. The
reaction mixture was stirred for 30 minutes at room temperature.
The organic layer was separated and washed with water (1.times.100
mL), saturated brine (1.times.100 mL), dried over magnesium s
filtered and concentrated. The crude ester was crystallized from
methanol and water to give 1.7 g (38%) of methyl
4-[(4-aminosulfonyl)phen-
yl]-5-(3,4-dichloro-phenyl)oxazole-2-butanoate as a yellow solid:
m.p. 130.7-131.8.degree. C. HRMS calcd. for
C.sub.20H.sub.18N.sub.2O.sub.5SCl.- sub.2 469.0392. Found
469.0413.
[0878] Step 4. Preparation of
4-[(4-aminosulfonyl)phenyl]-5-(3.4-dichlorop-
henyl)-N-hydroxy-2-oxazolebutanamide
[0879] An aqueous solution of 50% N-hydroxylamine (1 g) was added
to methyl
4-[(4-aminosulfonyl)phenyl]-5-(3,4-dichlorophenyl)oxazole-2-butano-
ate (Step 3) (0.3 g, 0.64 mmol) in 10 mL of THF:methanol (1:1) The
resulting solution was stirred for 18 h at room temperature. An
additional amount of aqueous 50% N-hydroxylamine (2.7 g) was added,
and the resulting solution was stirred for 48 h at room
temperature. The solvents were removed under vacuum. Water (50 mL)
and ethyl acetate (50 mL) were added to the concentrated residue.
The resulting solid was collected by filtration, washed with water
and ether, and air-dried to give 0.14 g (46.5%) of
4-[(4-aminosulfonyl)phenyl]-5-(3,4-dichlorophenyl)-
-N-hydroxy-2-oxazolebutanamide as a white solid: m.p.
165.0-169.7.degree. C. .sup.1H NMR (CD.sub.3OD/300 MHz)
.delta.2.15-2.27 (m, 4H), 2.94 (t, 2H, J=7.05 Hz), 7.44-7.48 (m,
1H), 7.56-7.58 (m, 1H), 7.72-7.78 (m, 3H), 7.94-7.96 (m, 2H). HRMS:
calcd for C.sub.19H.sub.17N.sub.3O.sub.5SCl.sub.- 2 470.0344. Found
470.0340.
Biological Evaluation
[0880] Rat Carrageenan Foot Pad Edema Test
[0881] 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 Testina
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 I.
1TABLE I RAT PAW EDEMA % Inhibition Example @ 10 mg/kg body weight
2 2
[0882] Evaluation of COX-1 and COX-2 activity in vitro
[0883] The compounds of this invention exhibited inhibition in
vitro of COX-2. The COX-2 inhibition activity of the compounds of
this invention illustrated in the Examples was determined by the
following methods.
[0884] a. Preparation of Recombinant COX Baculoviruses
[0885] Recombinant COX-1 and COX-2 were prepared as described by
Gierse et al, (J. Biochem., 305, 479-84 (1995)]. A 2.0 kb fragment
containing the coding region of either human or murine COX-1 or
human or murine COX-2 was cloned into a BamH1 site of the
baculovirus transfer vector pVL1393 (Invitrogen) to generate the
baculovirus transfer vectors for COX-1 and COX-2 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 .mu.g of baculovirus
transfer vector DNA into SF9 insect cells (2.times.10.sup.8) 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 plaque purification and high titer
(10.sup.7-10.sup.8 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-propanesulfonate (CHAPS).
The homogenate was centrifuged at 10,000.times.G for 30 minutes,
and the resultant supernatant was stored at -80.degree. C. before
being assayed for COX activity.
[0886] b. Assay for COX-l and COX-2 activity
[0887] COX activity was assayed as PGE.sub.2 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 160 .mu.l ELISA buffer
and 25 .mu.M indomethacin. The PGE.sub.2 formed was measured by
standard ELISA technology (Cayman Chemical). Results are shown in
Table II.
Assay for 5-Lipoxygenase Activity
[0888] The 5-lipoxygenase (5-LO) activity of the compounds were
determined by the calcium ionophore-induced Leukotriene B4 (LTB4)
production in human whole blood. Venous blood was collected from
healthy human donors using heparin as an anti-coagulant. Human
blood samples (0.2 ml of a 1:4 dilution in RPMI 1640 medium) were
incubated in 96-well culture plates for 15 minutes at 37.degree. C.
with test compounds dissolved in ethanol (EtOH; final
concentration<1%), or vehicle. Typically 7 concentrations of
test compounds were examined in duplicate. A-23187 [Sigma] was
added to the blood to a final concentration of 20 .mu.g/ml, and the
mixtures were incubated for 10 minutes at 37.degree. C. The
reaction was stopped by placing the samples on ice. The samples
were then centrifuged at 800.times.g at 4.degree. C. for 10 minutes
to pellet the cells, and the supernatants were recovered for
quantitation of LTB4 by ELISA (Cayman Chemical Co.; sensitivity 3
pg/ml). IC.sub.50's were estimated from a four parameter logistic
model with two parameters fixed, the minimum (0% inhibition) and
maximum (100% inhibition). The ICSO value is the concentration that
produces 50% inhibition between the fixed values of the minimum and
maximum. Data is reported as the mean IC.sub.50 for each compound.
Results are shown in Table II.
2 TABLE II COX-2 COX-1 5-LO Example IC.sub.50 (.mu.M) IC.sub.50
(.mu.M) IC.sub.50 (.mu.M) 1 6.6 53.5 12.3 2 5.1 >100 0.05 4 0.3
12.5
[0889] Also embraced within this invention is a class of
pharmaceutical compositions comprising the active compounds of this
combination therapy 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 active 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 active compounds and composition may, for example, be
administered orally, intravascularly (IV), intraperitoneally,
subcutaneously, intramuscularly (IM) or topically.
[0890] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, hard or soft capsule,
lozenges, dispensable powders, 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.
[0891] The active ingredient may also be administered by injection
(IV, IM, subcutaneous or jet) as a composition wherein, for
example, saline, dextrose, or water may be used as a suitable
carrier. The pH of the composition may be adjusted, if necessary,
with suitable acid, base, or buffer. Suitable bulking, dispersing,
wetting or suspending agents, including mannitol and PEG 400, may
also be included in the composition. A suitable parenteral
composition can also include a compound formulated as a sterile
solid substance, including lyophilized powder, in injection vials.
Aqueous solution can be added to dissolve the compound prior to
injection.
[0892] The amount of therapeutically active compounds that are
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 inflammation
or inflammation related disorder, the route and frequency of
administration, and the particular compound employed, and thus may
vary widely. The prodrug compositions should include similar
dosages as for the parent compounds. The pharmaceutical
compositions may contain active ingredients in the range of about
0.1 to 1000 mg, preferably in the range of about 0.5 to 250 mg and
most preferably between about 1 and 60 mg. A daily dose of about
0.01 to 100 mg/kg body weight, preferably between about 0.05 and
about 20 mg/kg body weight and most preferably between about 0.1 to
10 mg/kg body weight, may be appropriate. The daily dose can be
administered in one to four doses per day.
[0893] In the case of skin conditions, it may be preferable to
apply a topical preparation of compounds of this invention to the
affected area two to four times a day.
[0894] For disorders of the eye or other external tissues, e.g.,
mouth and skin, the formulations are preferably applied as a
topical gel, spray, ointment or cream, or as a suppository,
containing the active ingredients in a total amount of, for
example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most
preferably 0.4 to 15% w/w. When formulated in an ointment, the
active ingredients may be employed with either paraffinic or a
water-miscible ointment base. Alternatively, the active ingredients
may be formulated in a cream with an oil-in-water cream base. If
desired, the aqueous phase of the cream base may include, for
example at least 30% w/w of a polyhydric alcohol such as propylene
glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene
glycol and mixtures thereof. The topical formulation may desirably
include a compound which enhances absorption or penetration of the
active ingredient through the skin or other affected areas.
Examples of such dermal penetration enhancers include
dimethylsulfoxide and related analogs. The compounds of this
invention can also be administered by a transdermal device.
Preferably topical administration will be accomplished using a
patch either of the reservoir and porous membrane type or of a
solid matrix variety. In either case, the active agent is delivered
continuously from the reservoir or microcapsules through a membrane
into the active agent permeable adhesive, which is in contact with
the skin or mucosa of the recipient. If the active agent is
absorbed through the skin, a controlled and predetermined flow of
the active agent is administered to the recipient. In the case of
microcapsules, the encapsulating agent may also function as the
membrane. The transdermal patch may include the compound in a
suitable solvent system with an adhesive system, such as an acrylic
emulsion, and a polyester patch.
[0895] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier, it may comprise a mixture
of at least one emulsifier with a fat or an oil or with both a fat
and an oil. Preferably, a hydrophilic emulsifier is included
together with a lipophilic emulsifier which acts as a stabilizer.
It is also preferred to include both an oil and a fat. Together,
the emulsifier(s) with or without stabilizer(s) make-up the
so-called emulsifying wax, and the wax together with the oil and
fat make up the so-called emulsifying ointment base which forms the
oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
present invention include Tween 60, Span 80, cetostearyl alcohol,
myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,
among others.
[0896] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties, since the
solubility of the active compound in most oils likely to be used in
pharmaceutical emulsion formulations is very low. Thus, the cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers straight or branched chain, mono- or dibasic alkyl
esters such as di-isoadipate, isocetyl stearate, propylene glycol
diester of coconut fatty acids, isopropyl myristate, decyl oleate,
isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a
blend of branched chain esters may be used. These may be used alone
or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[0897] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredients are dissolved
or suspended in suitable carrier, especially an aqueous solvent for
the active ingredients. The antiinflammatory active ingredients are
preferably present in such formulations in a concentration of 0.5
to 20%, advantageously 0.5 to 10% and particularly about 1.5%
w/w.
[0898] For therapeutic purposes, the active compounds of this
combination 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 hydroxy-propylmethyl
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.
[0899] Although this invention has been described with respect to
specific embodiments, the details of these embodiments are not to
be construed as limitations.
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