Note: Descriptions are shown in the official language in which they were submitted.
CA 02221692 1997-11-19
W0961366~7 PCT~S9''0~2
S~BSTI~lu~l~K~ OXAZOLES FOR TH~ TREATMENT OF
INFT.AMM~TION
FIEhD OF THE lNY ~N'l'ION
This invention is in the field of anti-inflammatory
pharmaceutical agents and specifically relates to
compounds, c mpositions and methods for treating
inflammation and inflammation-associated disorders, such as
arthritis.
BA~KGRO~ND OF THE lNV ~-N'l'ION
Prostaglandins play a major role in the inflammation
process and the inhibition of prostaglandin production,
especially production of PGG2, PGH2 and PGE2, 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, inc~uding 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.
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.
The references below that disclose antiinflammatory
activity, si~w continuing efforts to find a safe and
effective antiinflammatory agent. The novel oxazoles
CA 02221692 1997-11-19
WO 96136617 PCTJUS9C/0(.~2
disclosed herein are such safe and also effective
antiinflammatory agents furthering such efforts. The
invention compounds are found to show usefulness in vivo as
antiinflammatory agents with mi nimAl side effects. The
substituted oxazoles disclosed herein preferably selectively
inhibit cyclooxygenase-2 over cyclooxygenase-1.
2,3-Diaryl-5-halo thiophenes are described in U.S.
Patent Mo. 4,590,205 as analgesic or antiin~lammatory
agents. More particularly, 2,3-diaryl-5-bromo thiophenes
are described in U.S. Patent No. 4,820,827 as having
antiinflammatory and prostaglandin synthetase inhibitory
activity for use in the treatment of inflammation and
dysmenorrhea. PCT publication WO94/15932 describes 4,5-
substitutedphenyl-thiophenes/furans and pyrroles as having
antiinflammatory activity.
Pyrazole derivatives having antiinflammatory activity
are described in U.S. Patent No. 5, 134,142, to Matsuo et
al.
U.S. Patent No. 3,578,671, to K. Brown, describes
antiinflammatory 4,5-diphenyloxazoles substituted in the 2-
position by a saturated or unsaturated aliphatic acid.
U.S. Patent No. 4,051,250, to J. Dahm et al, describes
oxazole, imidazole and thiazole compounds, including 2-
mercapto-4-(4-methylmercaptophenyl)-5-(4-
chlorophenyl)oxazole, as having antiphlogistic, analgesicand antipyretic activity. Other related diphenyloxazole
disclosures include U.S. Patent No. 4,001,228, to G.
Mattalia, for antiaggregating activity and U.S. Patent ~o.
3,895,024, to R. Hafeli, for intermediates in the
production of antiinflammatory agents. U. S. Patent No.
4,489,084, to F. Haviv and F.Kerdesky, describes
diphenyloxazolyl hydrazinoalkyl nitrile compounds for use
as antiinflammatory agents. U.S. Patent No. 4,143,047, to
R. Harrison, describes oxazole c~mpounds as reactants to
make 2-acylamino oxazole derivatives having anti-allergy
activity.
CA 0222l692 l997-ll-l9
WO 96/36617 PCrrUS9''069~)2
U.S. Patent Mo. 4,791,124, to Lutomski et al,
describes the pesticide activity of substituted bis(4-
halophenyl)oxazoles. U.S. Patent No. 4,775,687, to Meguro
et al describes the possible use of 4,5-phenyl oxazoles as
starting materials for antidiabetic compounds. WO
publication ~o. W092/21665, published December 9, 1992,
describes bis(halophenyl)oxazole derivatives as starting
materials for the preparation of antiinflammatory agents.
N. Meanwell et al [~.Med.Chem., 35, 3498 (1992)]
describe bis(substitutedphenyl)oxazoles as having ADP-
induced platelet aggregation inhibition activity.
U.S. Patent No. 4,812,470, to N. Rogers et al,
describes phenyl substituted oxazoles as having
antibacterial activity.
U.S. Patent No. 3.901,908, to K. Fitzi and R. Pfister,
describes 2-alkyl and 2-cycloalkyl-4,5-phenyloxazoles as
intermediates in the synthesis of imiaazoles having
analgesic and antipyretic activity. Specifically, 2-tert-
butyl-4-(4-methylsulfonylphenyl)-5-phenyloxazole is
described.
U.S. Pctent No. 4,632,930, to Carini et al, describes
antihypertensive alkyl and aryl substituted imidazole,
thiazole and oxazole derivatives. Specifically, 5-phenyl-
4-(4-methylsulfonylphenyl)-~a-
bis(trifluoromethyl)thiazole-2-methanol is described.
R. Cremylin et al describe the synthesis of
heterocyclic sulfonyl derivatives and specifically, 4',4"-
(2-methyl-4,S-oxazoldiyl)-bis-benzenesulfonamide (J.
Heterocycl.Chem., 22, 1211 (1985)).
T. van Es and O.G.Backeberg [J. Chem. Soc., 1363 (1963)]
describe the synthesis of 2-methyl-4,5-
substitutedphenyloxazoles, and specifically, 4-[5-(4-
chlorophenyl)-2-methyl-4-oxazolyl]benzenesulfonamide.
U.S. Patent No. 5,380,738, to Norman et al, describes
4-methylsulfonylphenyloxazoles for the treatment of
inflammatioI;. W094//27980, published Dec. 8, 1994,
describes substituted oxazoles for the treatment of
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WO 96/36617 PCT/US96/06992
inflammation. W095/00501, published Jan 5, 1995, describes
substituted oxazoles for the treatment of inflammation.
DESCRIPTION OF THE lNV ~1 ION
A class of substituted oxazolyl compounds useful in
treating inflammation-related disorders is defined by
Formula I:
~ - N
R2 ~
R3
wherein R is selected from hydrido, halo, mercapto,
hydroxyl, carboxyalkylthio, carboxyalkylthioalkyl,
carboxyalkoxy, carboxyalkoxyalkyl, haloalkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkoxy, aryloxy, aralkoxy,
alkylamino, aminocarbonyl, alkoxyalkyl, carboxy(haloalkyl),
alkyl, hydroxyalkyl, haloalkyl, alkenyl, hydroxyalkenyl,
alkynyl, hydroxyalkynyl, cycloalkyl, cycloalkylalkyl,
aminoalkyl, hydroxyalkoxyalkyl, alkylcarbonyl,
phosphonylalkyl, amino acid residue, heterocyclylalkyl,
cyanoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy,
carboxyalkyl, arylthioalkyl, aminocarbonylalkyl,
alkylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl,
aralkoxycar~onylaminoalkyl, aryl, heteroaryl, aralkyl,
aryloxyalkyl, aralkoxyalkyl, heteroaryloxyalkyl and
heteroarylalkoxyalkyli
wherein R1 is selec~ed from cycloalkyl, cycloalkenyl,
aryl and heterocyclyl, wherein R1 is optionally substituted
at a substitutable position by alkyl, alkylamino, alkoxy
and halo;
wherein R2 is selected from alkyl and aminoi and
wherein R3 is selected from hydrido and alkyli
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WO96/36617 PCT~S96106992
or a ph~rm~ceutically-acceptable salt thereof;
provided R is not methyl when R2 is amino and when Rl is
phenyl or 4-halophenyl; further provided R is haloalkyl
when R3 is alkyl; and ~urther provided that Rl is not
phenyl when R2 is methyl and R is isopropyl or tert-butyl.
The ph1-se "further provided", as used in the above
description, is intended to mean that the denoted proviso
is not to be considered conjunctive with the other
provl sos .
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, ~ursitis, and skin-related conditions such as
psoriasis, eczema, burns and dermatitis. 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 injur~, myocardial ischemia, and the like. The
compounds would also be useful in the treatment of
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WO 96/36617 PCT/US96/06992
ophth~lm,c diseases such as retinitis, retinopathies,
uveitis, conjunctivitis, and of acute injury to the eye
tissue. The compounds would also be useful in the
treatment of pulmonary inflammatio~, 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 Alzheimers disease. The compounds of the
invention are useful as anti-infla~matory 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, respiratory distress syndrome, endotoxin shock
syndrome, atl-erosclerosis and central nervous system damage
resulting ~rom stroke, ischemia and trauma.
Besides being useful for human treatment, these
compounds are also useful for veterinary treatment of
m~mm~l S, including companion ~nim~l S and farm animals, such
as, but not limited to, horses, dogs, cats, cows, sheep and
pigs.
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, 5-lipoxygenase inhibitors, LTB4 receptor
antagonists and LTA4 hydrolase inhibitors.
Suitable LTB4 receptor antagonists include, among
others, ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-
25019C, Leo Denmark compound ETH-615, Lilly compound LY-
293111, Ono ~ompound OMO-4057, Terumo compound TMK-688,
Lilly compounds LY-213024, 264086 and 292728, OMO com~ound
ONO-LB457, Searle compound SC-53228, calcitrol, Lilly
compounds LY-210073, LY223982, LY233469, and LY255283, OMO
compound ONO-LB-448, Searle compounds SC-41930, SC-50605
and SC-51146, and SK&F compound SKF-104493. Preferably, the
LTB4 receptor antagonists are selected from ebselen, Bayer
Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark
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WO96136617 PCT~S9~C'992
compound ETH-615, Lilly compound LY-293111, Ono compound
ONO-4057, and Terumo compound TMK-688.
The phrase "combination therapy" (or "co-therapy"), in
defining use of a cyclooxygenase-2 inhibitor agent and
another agent, is intended to embrace administration of
each agent in a se~uential manner in a regimen that will
provide beneficial effects of the drug combination, and is
intended as well to embrace co-a &inistration of these
agents in a substantially simultaneous manner, such as in a
single capsule having a fixed ratio of these active agents
or in multiple, separate capsules for each agent.
Suitable 5-LO inhibitors include, among others,
masoprocol, tenidap, zileuton, pranlukast, tepoxalin,
rilopirox, flezelastine hydrochloride, enazadrem phosphate,
and bunaprolast.
The present invention preferably includes compounds
which selectively inhibit cyclooxygenase-2 over
cyclooxygenase-1. Preferably, the compounds have a
cyclooxygenase-2 ICso of less than about 0.5 ~M, and also
have a selectivity ratio of cyclooxygenase-2 inhibition
over cyclooxygenase-1 inhibition of at least 50, and more
preferably of at least 100. Even more preferably, the
compounds have a cyclooxygenase-1 ICsa of greater than
about 1 ~M, and more preferably of greater than 20 ~M.
Such preferred selectivity may indicate an ability to
reduce the incidence of common ~SAID-induced side effects.
A preferred class of compounds consists of those
compounds of Formula I wherein R is selected from hydrido,
halo, mercapto, hydroxyl, lower carboxyalkylthio, lower
carboxyalkylthioalkyl, lower carboxyalkoxy, lower
carboxyalkoxyalkyl, lower haloalkoxy, lower alkylthio,
lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy,
aryloxy, lower aralkoxy, lower alkylamino, aminocarbonyl,
lower alkoxyalkyl, lower carboxy(haloalkyl), lower alkyl,
lower hydroxyalkyl, lower haloalkyl, lower alkenyl, lower
! hydroxyalkenyl, lower alkynyl, lower hydroxyalkynyl, lower
cycloalkyl, ~ower cycloalkylalkyl, lower aminoalkyl, lower
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WO 96/36617 PCT/US96/06992
hydroxyalkoxyalkyl, lower alkylcarbonyl, lower
phosphonylalkyl, amino acid residue, lower cyanoalkyl,
lower alkoxycarbonyl, lower alkoxycarbonylalkyl, carboxy,
lower carboxyalkyl, lower arylthioalkyl, lower
aminocarbonylalkyl, lower alkylcarbonylaminoalkyl, lower
alkoxycarbonylaminoalkyl, lower aralkoxycarbonylaminoalkyl,
aryl optionally substituted at a substitutable position by
carboxy, lower carboxyalkyl, lower alkyl, lower alkoxy and
halo, heteroaryl optionally substituted at a substitutable
position by carboxy, lower carboxyalkyl, lower alkyl, lower
alkoxy and halo, lower aralkyl optionally substituted at a
substitutable position on the aryl radical by carboxy,
lower carboxyalkyl, lower alkyl, lower alkoxy and halo,
lower heterocyclylalkyl optionally substituted at a
substitutable position on the heterocyclyl radical by
carboxy, lower carboxyalkyl, lower alkyl, lower alkoxy and
halo, lower aryloxyalkyl optionally substituted at a
substitutable position with halo, carboxy, lower
carboxyalkyl, lower alkyl and lower alkoxy, aralkoxyalkyl
optionally substituted at a substitutable position with
halo, carboxy, lower carboxyalkyl, lower alkyl and lower
alkoxy, heteroarylalkoxyalkyl optionally substituted at a
substitutable position with halo, carboxy, lower
carboxyalkyl, lower alkyl and lower alkoxy, and
heteroaryloxyalkyl optionally substituted at a
substitutable position with halo, carboxy, lower
carboxyalkyl, lower alkyl and lower alkoxyi wherein R1 is
selected from lower cycloalkyl, lower cycloalkenyl, aryl
and heteroaryl, wherein R1 is optionally substituted at a
substitutable position by lower alkyl, lower alkylamino,
lower alkoxy and halo; wherein R2 is selected from lower
alkyl and amino; and wherein R3 is selected from hydrido
and lower alkyl; or a pharmaceutically-acceptable salt
thereof.
A class of compounds of particular interest consists
of those compounds of Formula I wherein R is selected from
hydrido, chloro, fluoro, bromo, iodo, mercapto, hydroxyl,
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WO 96136617 PCTIUS9G~069~2
carboxymethylthio, carboxyethylthio, trifluoromethoxy,
methylthio, ethylthio, methylsulfinyl, methylsulfonyl,
methoxy, ethoxy, propoxy, butoxy, phenyloxy, benzyloxy, N-
methylamino, N,N-dimethylamino, N,N-diethylamino,
aminocarbonyl, methoxymethyl, ~-bromo-carboxymethyl,
methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl,
isobutyl, hydroxymethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, 1-
propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
hydroxyethenyl, hydroxypropenyl, ethynyl, 1-propynyl, 2-
propynyl, 1-butynyl, 2-butynyl, 3-butynyI, hydroxyethynyl,
hydroxypropynyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl,
cycloheptyImethyl, aminoethyl, aminopropyl,
bis(hydroxymethyl)methoxymethyl, methylcarbonyl, N-
benzyloxycarbonylaminomethyl, N-methoxycarbonylaminomethyl,
N-methoxycarbonylaminomethyl, cyanopentyl, phenyl
optionally substituted at a substitutable position by
fluoro, chloro, bromo, iodo, carboxy, carboxymethyl,
methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl,
isobutyl, methoxy, ethoxy, propoxy and butoxy, heteroaryl
selected from pyridyl, thienyl, thiazolyl, oxazolyl,
imidazolyl, pyrrolyl, furyl and quinolyl, optionally
substituted at a substitutable position by fluoro, chloro,
bromo, iodo, carboxy, carboxymethyl, methyl, ethyl, n-
propyl, isopropyl, butyl, tert-butyl, isobutyl, methoxy,
ethoxy, propoxy and butoxy, lower aralkyl selected from
benzyl, phenethyl, diphenylmethyl and phenylpropyl,
optionally substituted at a substitutable position on the
phenyl radical by fluoro, chloro, bromo, iodo, carboxy,
carboxymethy', methyl, ethyl, n-propyl, isopropyl, butyl,
tert-butyl, lsobutyl, methoxy, ethoxy, propoxy and butoxy,
lower heterocyclylalkyl selected from pyrrolidinylmethyl,
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WO 96/36617 . PCTIUS9G~;992
pyrrolidinylethyl, pyrrolylpropyl, pyrrolylethyl, (2-
methylimidazolyl)propynylphenylmethyl, piperidinylethyl,
and tetrazolylpentyl, optionally substituted at a
substitutable position by fluoro, chloro, bromo, iodo,
carboxy, carboxymethyl, methyl, ethyl, n-propyl, isopropyl,
butyl, tert-butyl, isobutyl, methoxy, ethoxy, propoxy and
butoxy, phenoxymethyl optionally substituted at a
substitutable position on the phenyl radical with fluoro,
chloro, bromo, iodo, carboxy, carboxymethyl, methyl, ethyl,
n-propyl, isopropyl, butyl, tert-butyl, isobutyl, methoxy,
ethoxy, propoxy and butoxy, benzyloxymethyl optionally
substituted at a substitutable position on the phenyl
radical with fluoro, chloro, bromo, iodo, carboxy,
carboxymeth~l, methyl, ethyl, n-propyl, isopropyl, butyl,
tert-butyl, isobutyl, methoxy, ethoxy, propoxy and butoxy,
heteroaryloxyalkyl selected from pyridyloxymethyl and
quinolyloxymethyl, optionally substituted at a
substitutable position with fluoro, chloro, bromo, iodo,
carboxy, carboxymethyl, methyl, ethyl, n-propyl, isopropyl,
butyl, tert-butyl, isobutyl, methoxy, ethoxy, propoxy and
butoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
butoxycarbonyl, methoxycarbonylmethyl,
ethoxycarbonylmethyl, methoxycarbonylethyl,
ethoxycarbonylethyl, carboxy, carboxymethyl, carboxyethyl,
carboxypropyl, carboxypentyl, carboxybutyl,
phenylthiomethyl, aminocarbonylmethyl, N-
methylaminocarbonylmethyl and N,N-
dimethylaminocarbonylmethyl; wherein Rl is selected from
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-
cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl,
cyclopentenyl, cycloheptenyl, phenyl, naphthyl, pyridyl,
thienyl, thiazolyl, oxazolyl, imidazolyl, furyl, ~uinolyl,
benzothiazolyl, 2,3-thianaphthalenyl, 2,3-
dihydrothianaphthalenyl, 2,3-benzofuryl, and 2,3-
dihydrobenzofuryl, wherein Rl is optionally substituted ata substitutable position by methyl, ethyl, n-propyl,
isopropyl, butyl, tert-butyl, isobutyl, amino, methoxy,
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WO96136617 PCT~S96/06992
ethoxy, propoxy, butoxy, N-methylamino, N,N-dimethylamino,
fluoro, chloro, bromo and iodo; wherein R2 is selected ~rom
methyl, and amino; wherein R3 is selected from hydrido, and
methyl.
Within Formula I there is a subclass of compounds of
high interest represented by Formula II:
R4
~N9_ 5 II
R2- S
o
wherein R2 is selected from lower alkyl and amino;
wherein R4 is selected from hydrido, alkyl, alkylamino,
alkoxy and halo; and wherein R5 is selected from halo,
mercapto, cz..boxyalkylthio, carboxyalkylthioalkyl,
carboxyalkoxy, carboxyalkoxyalkyl, haloalkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkoxy, aryloxy, alkylamino,
aminocarbonyl, alkoxyalkyl, carboxy(haloalkyl), aminoalkyl,
hydroxyalkoxyalkyl, alkylcarbonyl, phosphonylalkyl,
alkylcarbonylaminoalkyl, aralkoxycarbonylaminoalkyl, amino
acid residue, heterocyclylalkyl, and cyanoalkyli or a
pharmaceutically-acceptable salt thereof.
A preferred class of compounds consists of those
compounds of Formula II wherein R2 is selected from lower
alkyl and aminoi wherein R4 is selected from hydrido, lower
alkyl, lower alkylamino, lower alkoxy and halo; and wherein
R5 is selected ~rom halo, mercapto, lower carboxyalkylthio,
lower carboxyalkylthioalkyl, lower haloalkoxy, lower
alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower
alkoxy, aryl:xy, lower alkylamino, aminocarbonyl, lower
~ alkoxyalkyl, lower carboxy(haloalkyl), lower aminoalkyl,
lower hydroxyalkoxyalkyl, lower alkylcarbonyl, lower
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WO96/36617 PCT~S96/06992
phosphonylalkyl, lower alkylcarbonylaminoalkyl, lower
aralkoxycarbonylaminoalkyl, amino acid residue, lower
heterocyclylalkyl, and lower cyanoalkyl; or a
pharmaceutically-acceptable salt thereof.
A class of compounds of particular interest
consists of those compounds of Formula II wherein R2 is
selected from methyl and aminoi wherein R4 is selected
from hydrido, methyl, ethyl, n-propyl, isopropyl, butyl,
tert-butyl, isobutyl, amino, methoxy, ethoxy, propoxy,
butoxy, M-methylamino, N,N-dimethylamino, fluoro,
chloro, bromo and iodo; and wherein R5 is selected from
chloro, fluoro, bromo, iodo, mercapto,
carboxymethylthio, carboxyethylthio,
carboxyethylthiomethyl, trifluoromethoxy, methylthio,
ethylthio, methylsulfinyl, methylsulfonyl, methoxy,
ethoxy, propoxy, butoxy, phenyloxy, benzyloxy, N-
methylamino, N,N-dimethylamino, N,N-diethylamino,
aminocarbonyl, methoxymethyl, ~-bromo-carboxymethyl,
aminoethyl, bis(hydroxymethyl)methoxymethyl,
methylcarbonyl, N-methylcarbonylaminomethyl,
aminopropyl, pyrrolidinylmethyl, pyrrolidinylethyl,
pyrrolylpropyl, pyrrolylethyl,
methylcarbonylaminomethyl, N-
(benzyloxycarbonyl)aminomethyl, N-
(benzyloxycarbonyl)aminoethyl, N-
(benzyloxyc~rbonyl)aminopropyl, N-methyl-N-
(benzyloxycarbonyl)aminoethyl, [N-
(phenylmethoxycarbonyl)amino]methoxycarbonylpropyl, [N-
(phenylmethoxycarbonyl)amino]carboxypropyl,
piperidinylethyl, tetrazolylpentyl, and cyanopentyl; or
a pharmaceutically-acceptable salt thereof.
Within Formula I there is a subclass of
compounds of high interest represented by Formula III
CA 0222l692 l997-ll-l9
W~ 96136617 PCT/IJS96~06992
R4
6 III
R ' S
o
wherein R2 is selected ~rom lower alkyl and amino;
wherein R4 is selected from hydrido, lower alkyl, lower
alkylamino, lower alkoxy and halo; wherein R6 is -Y-Q
wherein Y is selected from aryl, heterocyclyl,
alkoxyalkyl, aryloxyalkyl, alkylaryloxyalkyl,
aralkoxyalkyl, alkylaralkoxyalkyl, aminoalkyl,
heterocyclylalkyl, alkylheterocyclyl,
alkylheterocyclylalkyl, alkylaralkyl, aralkyl,
alkynylaralk~l, alkyl, alkylsulfonylalkyl,
alkylthioalkyl, and alkylsulfonylaminoalkyl; and
wherein Q is an acidic moiety selected from carboxylic
acid, tetrazole, phosphorous-containing acids, sulfur-
containing acids, and the amide, ester and salt
derivatives of said acids; provided Y is not methyl
when Q is -P(O)(OH)2; and further provided Y is not
methyl or ethyl when Q is carboxyl; or a
pharmaceutically-acceptable salt thereof.
A preferred class of compounds consists of those
compounds of Formula III wherein R2 is selected from lower
alkyl and amino; wherein R4 is selected from hydrido, lower
alkyl, lower alkoxy and halo; wherein Y is selected from
phenyl, five and six membered heterocyclyl, lower
alkoxyalkyl, lower aminoalkyl, lower heterocyclylalkyl,
lower alkylheterocyclyl, lower alkylheterocyclylalkyl,
lower aryloxyalkyl, lower alkylaryloxyalkyl, lower
aralkoxyalkyl, lower alkylaralkoxyalkyl, lower
alkylaralkyl, lower alkynylaralkyl, lower aralkyl, lower
alkylsulfonylalkyl, lower alkylthioalkyl, alkyl, and lower
CA 02221692 1997-ll-lg
WO96/36617 PCT~S96/06992
14
alkylsulfonylaminoalkyl; wherein Q is selected from
carboxyl, lower alkoxycarbonyl, lower aralkoxycarbonyl,
tetrazolyl,
O O
- P - oR7 and - P - oR8
R7 oR8
and wherein each of R7 and R8 is independently selected
from hydrido, lower alkyl, lower cycloalkyl, phenyl and
lower aralkyl; or a pharmaceutically-acceptable salt
thereof.
A class of compounds of particular interest consists
of those compounds of Formula III wherein R2 is selected
from methyl and amino; wherein R4 is selected from hydrido,
methyl, methoxy, fluoro, chloro and bromo; wherein Y is
selected from phenyl, pyridyl, pyrrolyl, pyrrolidinyl,
imidazolyl, piperidinyl, methoxymethyl, 3-aminopropyl,
pyrrolylmethyl, pyrrolidinylmethyl, pyrrolylpropyl,
methylpyrrolyl, ethylphenylmethyl, methylphenylethyl,
phenoxymethyl, methylphenoxymethyl, benzyl,
ethylsulfonylmethyl, ethylthiomethyl, methylthiomethyl,
methylthioethyl, methyl, ethyl, propyl, pentyl, 2,2-
dimethylpropyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-
methylpropyl, butyl, and methylsulfonylaminopropyl; wherein
Q is selected from carboxyl, methoxycarbonyl,
ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl,
tetrazolyl,
O O
Il 11
- P - oR7 and - P - oR8
R7 oR8
and wherein each of R7 and R8 is independently selected
from hydrido, methyl, and ethyl; or a ph~r~ceutically-
acceptable salt thereof.
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WO 96136617 PCT)IJS~'/OG992
A family of specific compounds of particular interest
within Formulas I-III consists of compounds and
ph~rm~ceutically-acceptable salts thereof as follows:
4-[2-[[4-[3-(hydroxy)-1-propynyl]phenyl]methyl]-4-
phenyloxazol-5-yl]benzenesulfonamide;
4-[2-[[4-[3-(N,M-dimethylamino)-l-propynyl]phenyl]
methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;
4-[2-[[4-[3-(N,N-dimethylamino)propyl]phenyl]methyl]-4-
10phenyloxazol- 5 -yl ] benzenesulfonamidei
4-[2-[[4-[3-(hydroxy)-1-propynyl]phenyl]methyl]-4-
phenyloxazol-5-yl]benzenesulfonamide;
l,l-dimethylethyl [3-[4-[[5-[4-(aminosulfonyl)phenyl]-4-
phenyloxazol-2-yl]methyl]phenyl]-2-propynyl]carbamate;
154-[2-[[4-[3-(2-methyl-lH-imidazol-l-yl)-l-propyl~phenyl]
methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;
4-[2-[[4-[3-(amino)-1-propynyl]phenyl]methyl]-4-
phenyloxazol-5-ylJbenzenesulfonamide;
4-[2-[[4-[3-(tert-butylamino)-1-propynyl]phenyl]methyl]-
204-phenyloxazol-5-yl]benzenesulfonamide
phenylmethyl [2-[5-[4-(aminosulfonyl)phenyl]-4-
phenyloxazol-2-yl]methyl]carbamate;
phenylmethyl [2-[5-[4-(aminosulfonyl)phenyl]-4-
phenyloxazol-2-yl]ethyl]carbamate;
phenylmethyl [2-[5-[4-(aminosulfonyl)phenyl]-4-
phenyloxazol-2-yl]ethyl]methylcarbamate;
phenylmethyl [2-[5-[4-(aminosulfonyl)phenyl]-4-
phenyloxazol-2-yl]propyl]carbamate;
methyl 5-[4-(aminosulfonyl)phenyl]-~R-
[[(phenylmethoxy)carbonyl]aminno]-4-phenyloxazole-2-
butanoate;
5-[4-(aminosulfonyl)phenyl]-oR-
[[(phenylmethoxy)carbonyl]aminno]-4-phenyloxazole-2-
butanoic acid;
4-[4-(3-chloro-4-methoxyphenyl)-2-trifluoromethyl-5-
oxazolyl]benzenesulfonamide;
CA 02221692 1997-ll-l9
WO96/36617 PCT~S96/06992
16
4-phenyl-2-(benzyloxymethyl)-5-(4-
methylsulfonylphenyl)oxazole;
5-phenyl-2-(benzyloxymethyl)-4-(4-
methylsulfonylphenyl)oxazole;
[4-(3-fluoro-4-methoxyphenyl)-5-(aminosulfonylphenyl)-2-
oxazolyl]methanol;
4-[5-phenyl-2-methyl-4-oxazolyl]benzenesulfonamide;
4-[5-(4-brol~phenyl)-2-methyl- 4-
oxazolyl]benzenesulfonamide;
4-[5-(4-bromophenyl)-2-methoxymethyl-4-
oxazolyl]benzenesulfonamide;
4-[2-methoxymethyl-5-phenyl-4-
oxazolyl]benzenesulfonamide;
[5-(aminosulfonylphenyl)-4-phenyl-2-oxazolyl]-2-ethanol;
[5-(aminosulfonylphenyl)-4-phenyl-2-oxazolyl]-1-ethanol;
4-[4-(3-fluorophenyl)-2-methyl-5-
oxazolyl]benzenesulfonamide;
4-[4-(4-chlorophenyl)-2-methoxymethyl-5-
oxazolyl]benzenesulfonamide;
4-[4-(4-chlorophenyl)-2-methyl-5-
oxazolyl]benzenesulfonamide;
[4-(phenyl)-5-(aminosulfonylphenyl)-2-oxazolyl]-a,a-
dimethylme_hanol;
4-[4-(4-fluorophenyl)-2-methyl-5-
oxazolyl]benzenesulfonamide;
4-[4-(3-chlorophenyl)-2-methoxymethyl-5-
oxazolyl]benzenesulfonamide;
4-[4-(3-chlorophenyl)-2-ethyl-5-
oxazolyl]benzenesulfonamide;
[4-(3-chlorophenyl)-5-(aminosulfonylphenyl)-2-oxazolyl]-
2-methanol;
[4-(4-chlorophenyl)-5-(aminosulfonylphenyl)-2-oxazolyl]-
2-methanol;
4-[5-(4-chlorophenyl)-2-methoxymethyl-4-
oxazolyl]benzenesulfonamide;
4-[5-(3-chlorophenyl)-2-methoxymethyl-4-
oxazolyl]benzenesulfonamide;
CA 02221692 1997-11-19
WO 96136617 PCTmS9~;n)6992
4-[5-(3-chlorophenyl)-2-ethyl-4-
oxazolyl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-2-methoxymethyl-4-
oxazolyl]benzenesulfonamide;
4-[4-phenyl-2-(1-methyl-2-pyrrolyl)-5-
oxazolyl]benzenesulfonamide;
4-[4-phenyl-2-(methylcarbonylaminomethyl)-5-
oxazolyl]benzenesul~onamide;
4-[5-(4-chlorophenyl)-2-methyl-4-
oxazolyl]benzenesulfonamide;
4-[4-(3,4-dichlorophenyl)-2-ethyl-5-
oxazolyl]benzenesulfonamide;
[4-(3-chlorophenyl)-5-(aminosulfonylphenyl)-2-oxazolyl]-
~a-dimethylmethanol;
[5-(3-chlor--rhenyl)-4-(aminosulfonylphenyl)-2-oxazolyl]-
~a-dimethylmethanol;
[4-(phenyl)-5-(aminosulfonylphenyl)-2-oxazolyl]-2-
propanol;
(R) 4-[4-phenyl-2-[2-(1-pyrrolyl)ethyl]-5-
oxazolyl]benzenesulfonamide;
(S) 4-[4-phenyl-2-[2-(1-pyrrolyl)ethyl]-5-
oxazolyl]benzenesulfonamide;
4-[4-phenyl-2-(2-pyrrolyl)-5-
oxazolyl]benzenesulfonamide;
5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-pentanoic
acid;
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-
butanoate;
5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-butanoic
acidi
3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2-
yl]methyl]oxy]acetic acid;
5-[(4-aminosulfonyl)phenyl]-4-phenyl-~ dimethyloxazole-
2-butanoic acidi
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-
hexanoate;
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18
5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-hexanoic
acid;
diethyl [[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-
yl]propyl]phosphonate;
[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-
yl]propyl~phosphonic acid;
diethyl [[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-
yl]methyl]phosphonatei
ethyl [[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-
yl]methyl]phosphonate;
3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2- -
yl]methyl]sulfonyl]propanoic acid;
methyl 3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2-
yl]ethyl]thio]acetate;
3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2-
yl]ethyl]thio]acetic acid;
tert-butyl 3-[[[5-[4-aminosulfonyl)phenyl]-4-
phenyloxazol-2-yl]methyl]thio]acetate;
3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2-
yl]methyllthio]acetic acid;
5-[(4-aminosulfonyl)phenyl]-4-phenyl-~-methyloxazole-2-
butanoic acid;
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyl-~-
methyloxazole-2-butanoate;
4-[2-cyanopentyl-4-phenyloxazol-5-yl]benzenesulfonamide;
4-[(2-tetrazolyl)pentyl-4-phenyloxazol-5-
yl]benzenesulfonamide;
[[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2-
yl]methyl]-1-pyrrol-2-yl]carboxylic acid;
methyl [[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2-
yl]methyl]-1-pyrrol-2-yl]carboxylate;
[[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2-yl]-2-
pyrrol-1-yl]acetic acid;
ethyl [[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2-
yl]-2-pyrrol-1-yl~acetate;
methyl [[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2-
yl]methyl]-1-pyrrolidin-2-yl]carboxylate;
CA 02221692 1997-11-19
WO 96J366~7 ~C~TJUS96)D6992
19
methyl [[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2-
yl]propyl]aminosulfonyl]acetate;
5-[(4-aminosulfonyl)phenyl]-4-phenyl-~S-amino-oxazole-2-
butanoic acid;
[5-[(4-aminosulfonyl)phenyl]-4-phenyl-oxazol-2-
yl]ethyne;
4-[2-propargyl-4-phenyloxazol-5-yl~benzenesulfonamide;
[5-[(4-aminosulfonyl)phenyl]-4-phenyl-oxazol-2-
yl]et~n~m;ne;
4-[(1-piperidinyl)ethyl-4-phenyloxazol-5-
yl]benzenesulfon~mide;
4-[2-(1-pyrrolidinyl)methyl-4-phenyloxazol-5-
yl]benzenesulfonamide;-
4-[2-[bis(hydroxymethyl)methoxy]ethyl-4-phenyloxazol-5-
yl]benzenesul~onamide;
methyl [5-[(4-aminosulfonyl)phenyl]-4-(3,4-
dichlorophenyl)oxazole]-2-propanoate;
5-[(4-aminosulfonyl)phenyl]-4-(3,4-
dichlorophenyl)oxazole-2-propanoic acid;
methyl [5-[(4-aminosulfonyl)phenyl]-4-(3,4-
dichlorophenyl)oxazole]-2-butanoate;
5-[(4-aminosulfonyl)phenyl]-4-(3,4-
dichlorophenyl)oxazole-2-butanoic acid;
methyl [5-[(4-aminosulfonyl)phenyl]-4-(3,4-
dichlorophenyl~oxazole]-2-pentanoate;
5-[(4-aminosulfonyl)phenyl]-4-(3,4-
dichlorophenyl)oxazole-2-pentanoic acid;
4-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)oxazole-2-
pentanoic acid;
5-[(4-aminosulfonyl)phenyl]-4-(3,4-dichlorophenyl)-
~dimethyloxazole-2-butanoic acid;
4-[(4-methylsulfonyl)phenyl]-5-(3,4-
dichlorophenyl)oxazole-2-butanoic acid;
4-[(4-aminosulfonyl)phenyl]-5-(3,4-
dichlorophenyl)oxazole-2-butanoic acid;
5-[(4-aminosulfonyl)phenyl]-4-phenyl-~S-(lH-pyrrol-1-
yl)oxazole-2-butanoic acid;
CA 02221692 1997-11-19
WO 96136617 PCT/US9G/OG9~)2
2-[5-[~4-aminosulfonyl)phenyl]-4-phenyloxazol-2-
yl]ethan-2-one;
4-(2-etheny~?-4-phenyl-oxazol-5-yl]benzenesulfonamide
3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2-
yl]methyl]thio]propanoic acid;
3-[[[4-[4-aminosulfonyl)phenyl]-5-phenyloxazol-2-
yl]methyl]thio]propanoic acid;
4-[2-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-oxazol-2-
yl]methyl]benzenepropanoic acid;
methyl 4-[2-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-
oxazol-2-yl]methyl]benzenepropynoic acid;
5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)oxazole-2-
pentanoic acid;
4-[2-ethyl-4-(3-fluorophenyl)oxazol-5-
yl]benzenesulfonamide;
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-
pentanoate;
methyl 4-[(~-aminosulfonyl)phenyl]-5-(4-
fluorophenyl)oxazole-2-pentanoate;
methyl 5-[(4-aminosulfonyl)phenyl]-4-(3,4-
dichlorophenyl)-~,~-dimethyloxazole-2-butanoate;
methyl 4-[(4-methylsulfonyl)phenyl]-5-(3,4-
dichlorophenyl)oxazole-2-butanoate;
methyl 4-[(4-aminosulfonyl)phenyl]-5-(3,4-
dichlorophenyl)oxazole-2-butanoate;
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyl-aS-(lH-
pyrrol-1-yl)oxazole-2-butanoate;
tert butyl 3-[[[5-[4-aminosulfonyl)phenyl]-4-
phenyloxazol-2-yl]methyllthio]propanoate;
tert butyl 3-[[[4-[4-aminosulfonyl)phenyl]-5-
phenyloxazol-2-yl]methyl]thio]propanoate;
methyl 5-[(4-aminosulfonyl)phenyl]-4-(4-
fluorophe.nyl)oxazole-2-pentanoate;
ethyl [4-(4-aminosulfonylphenyl)-5-(3-fluoro-4-
methoxyphenyl)]-2-oxazoleacetate;
[4-(4-aminosulfonylphenyl)-5-cyclohexyl]-2-oxazoleacetic
acid;
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Wal 96/36617 PCTJlJS96~1)6992
[5-(4-aminosulfonylphenyl)-4-(4-chlorophenyl)]-2-
oxazoleacetic acid;
[4-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)]-2-
oxazoleacetic acid;
[4-(4-aminosulfonylphenyl)-5-(3-chloro-4-fluorophenyl)]-
2-oxazoleacetic acid;
[4-(4-aminosulfonylphenyl)-5-(3,4-dichlorophenyl)]-2-
oxazoleacetic acid;
[4-(4-aminosulfonylphenyl-5-(3,4-difluorophenyl)]-2-
oxazoleac~--ic acid;
[5-(3,4-difluorophenyl)-2-trifluoromethyl-4-
oxazolyl]benzenesulfonamide;
[5-(4-aminosulfonylphenyl)-4-phenyl]-2-oxazolepropanoic
acid;
4-[4-phenyl-5-oxazolyl]benzenesulfonamide;
4-[2-chloro-4-phenyl-5-oxazolyl]benzenesulfonamide;
4-[2-mercapto-4-phenyl-5-oxazolyl]benzenesulfonamide;
4-[2-(3-chlorophenoxy)-4-phenyl-5-
(oxazolyl]benzenesulfonamide;
5-(4-aminosulfonylphenyl)-4-phenyl-2-
oxazolemercaptoacetic acid;
4-[4-phenyl-2-(2,2,2-trifluoroethoxy-5-
oxazolyl]benzenesulfonamide;
4-[2-(methylthio)-4-phenyl-5-
oxazolyl]b~nzenesulfonamidei
4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide;
4-[2~methylsulfinyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-(methylsulfonyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-(2,3,4,5,6-pentafluorophenoxy)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-methoxy-4-phenyl-5-oxazolyl]benzenesulfonamide;
ethyl 2-[[5-(4-aminosulfonylphenyl)-4-phenyl-2-
oxazolyl]oxy]benzoate;
ethyl 3-[[5-(4-aminosulfonylphenyl)-4-phenyl-2-
oxazolyl]oxy]benzoate;
CA 02221692 1997-11-19
WO 96/36617 PCT/US~)C/1)6~!i2
4-[2-(N,N-dimethylamino)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-trifluoromethyl-4-
oxazolyl]benzenesulfonamide;
4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-
oxazolyl]benzenesulfonamide;
4-methyl-3-[5-phenyl-2-trifluoromethyl-4-
oxazolyl]benzenesulfonamide;
4-[4-(3-aminosulfonyl-4-methylphenyl)-2-trifluoromethyl-
5-oxazolyl]benzenesulfonamide;
4-methyl-3-[4-phenyl-2-trifluoromethyl-5-
oxazolyl]benzenesulfonamide;
4-[4-(N,N-dimethylamino)phenyl-2-trifluoromethyl-5-
oxazolyl]benzenesulfonamide;
[4-(4-aminosulfonylphenyl)-5-(3-fluoro-4-
methoxyphenyl)]-2-oxazoleacetic acid;
4-[4-aminosulfonylphenyl)-5-(3-fluoro-4-methoxyphenyl)-
2-oxazolylla-bromoacetic acid;
4-(4-methylphenyl)-5-(4-methylsulfonylphenyl)-2-
trifluoromethyloxazole;
4-[5-(3-fluoro-4-methoxyphenyl)-2-methyl-4-
oxazolyl]benzenesulfonamide;
5-(3-fluoro-4-methoxyphenyl)-4-(4-methylsulfonylphenyl)-
2-trifluoromethyloxazole;
4-[5-(3-bromo-4-methoxy-5-fluorophenyl)-2-
trifluoromethyl-4-oxazolyl]benzenesulfonamide
[5-(4-aminosulfonylphenyl)-4-phenyl]-2-
oxazolecarboxamide;
4-[2-methoxymethyl-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(phenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-fluorophenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-fluorophenyl)-4-
oxazolyl]benzenesulfonamide;
CA 02221692 1997-11-19
WO 961366~7 PCT)US9''DC992
23
4-[2-benzyl-5-(4-fluorophenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,4-difluorophenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,5-difluorophenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,6-difluorophenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3,4-difluorophenyl)-4-
oxazolyl]benzenesulfonamidei
4-[2-benzyl-5-(3,5-difluorophenyl)-4-
oxazolyl]b~nzenesulfonamide;
4-[2-benzyl-5-(2-chlorophenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-chlorophenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-chlorophenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,4-dichlorophenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,5-dichlorophenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,6-dichlorophenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3,4-dichlorophenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl--~-(3,5-dichlorophenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-methoxyphenyl)-4-
30 oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-methoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-methoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
3 5 4-[2-benzyl-5-(2,4-dimethoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
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WO 96/36617 PCT/US96/06992
24
4-[2-benzyl-5-(2,5-dimethoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,6-dimethoxyphenyl)-4-
oxazolyl]~enzenesulfonamide;
4-[2-benzyl-5-(3,4-dimethoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3,5-dimethoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-methylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-methylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-methylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,4-dimethylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,5-dimethylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-C-(2,6-dimethylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3,4-dimethylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3,5-dimethylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-chloro-4-methylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-chloro-4-methylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-chloro-2-methylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-chloro-6-methylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-chloro-2-methylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-chloro-3-methylphenyl)-4-
oxazolyl]benzenesulfonamide;
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4-[2-benzyl-5-(2-chloro-4-methoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-chloro-4-methoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-chloro-2-methoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-chloro-6-methoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-chloro-2-methoxyphenyl)-4-
oxazolyl]benzenesulfonamidei
4-[2-benzyl-5-(4-chloro-3-methoxyphenyl)-4-
oxazolyl]benzenesulfonamidei
4-[2-benzyl-5-(3,5-dichloro-4-methoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-fluoro-4-methylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-fluoro-4-methylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-fluoro-2-methylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-fluoro-6-methylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-fluoro-2-methylphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-.5-(4-fluoro-3-methylphenyl)-4-
oxazolyl]benzenesulfonamidei
4-[2-benzyl-5-(2-fluoro-4-methoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-fluoro-4-methoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-fluoro-2-methoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-fluoro-6-methoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-fluoro-2-methoxyphenyl)-4-
oxazolyl]benzenesulfonamide;
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26
4-[2-benzyl-5-(2-thienyl)-4-
oxazolyl]i~-nzenesulfonamide;
4-[2-benzyl-5-(5-chloro-2-thienyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(yl)-4-oxazolyl]benzenesulfonamide
4-[2-benzyl-5-(1-cyclohexenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-cyclohexenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-cyclohexenyl)-4-
oxazolyl]benzenesulfonamide;
2-benzyl-4-(4-methylsulfonylphenyl)-5-phenyloxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2-
fluorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3-
fluorophenyl)oxazole;
2-benzyl-4-~'-methylsulfonylphenyl)-5-(2,4-
difluorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,5-
difluorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2, 6 -
difluorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3,4-
difluorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3,5-
difluorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2-
chlorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3-
chlorophenyl)oxazole;
2-benzyl-4-(4-methylsul~onylphenyl)-5-(4-
chloropheIlyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,4-
dichlorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,5-
dichlorophenyl)oxazole;
CA 02221692 1997-11-19
WO 96136617 PCTJlJS~G/06~2
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,6-
dichlorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3,4-
dichlorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3,5-
dichlorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2-
metho~yph~:lyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3-
methoxyphenyl)oxazolei
2-benzyl-4-(4-methylsulfonylphenyl)-5-(4-
methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,4-
dimethoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,5-
dimethoxyphenyl)oxazolei
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,6-
dimethoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3,4-
dimethoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3,5-
dimethoxyphenyl)oxazole;
2-benzyl-4-~-methylsulfonylphenyl)-5-(2-
methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3-
methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(4-
methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,4-
dimethylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,5-
dimethylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,6-
dimethylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3,4-
r dimethylphenyl)oxazole;
CA 02221692 1997-11-19
WO 96/36617 PCT/US9''0'992
28
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3,5-
dimethylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2-chloro-4-
methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3-chloro-4-
methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3-chloro-2-
methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2-chloro-6-
methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(4-chloro-2-
methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(4-chloro-3-
methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2-chloro-4-
methoxyphenyl)oxazole;
2-benzyl-4-~4-methylsulfonylphenyl)-5-(3-chloro-4-
methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3-chloro-2-
methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2-chloro-6-
methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(4-chloro-2-
methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(4-chloro-3-
methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3,5-dichloro-
4-methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2-fluoro-4-
methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3-fluoro-4-
methylpheIlyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3-fluoro-2-
methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2-fluoro-6-
methylphenyl)oxazole;
CA 02221692 1997-11-19
WO 96/36617 PCr)US9611)6992
29
2-benzyl-4-(4-methylsulfonylphenyl)-5-(4-fluoro-2-
methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-~4-fluoro-3-
methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2-fluoro-4-
methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3-fluoro-4-
methoxyphelyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3-fluoro-2-
methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2-fluoro-6-
methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(4-fluoro-2-
methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2-
thienyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(5-chloro-2-
thienyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-
(cyclohexyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(1-
cyclohexenyl)oxazole;
2-benzyl-4-,4-methylsulfonylphenyl)-5-(2-
cyclohexenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3-
cyclohexenyl)oxazole;
2-(ethyl)-4-(4-methylsulfonylphenyl)-5-
phenyloxazole;
2-(trifluoromethyl)-4-(4-methylsulfonylphenyl)-5-
phenyloxazole;
2-(difluoromethyl)-4-(4-methylsulfonylphenyl)-5-
phenyloxazole;
2-(hydroxymethyl)-4-(4-methylsulfonylphenyl)-5-
phenyloxazole;
[4-(4-methylsulfonylphenyl)-5-phenyl]-2-
oxazolecarboxylic acid;
CA 02221692 1997-11-19
WO 96/36617 PCT/u~ 'OG992
methyl [4-(4-methylsulfonylphenyl)-5-phenyl]-2-
oxazolecarboxylate;
ethyl [4-(4-methylsulfonylphenyl)-5-phenyl]-2-
oxazolecarboxylate;
2-(propyl)-4-(4-methylsulfonylphenyl)-5-
phenyloxazole;
2-(benzyl)-4-(4-methylsulfonylphenyl)-5-
phenyloxazole;
2-(phenylthiomethyl)-4-(4-methylsulfonylphenyl)-5-
phenyloxazole;
2-(phenoxymethyl)-4-(4-methylsulfonylphenyl)-5-
phenyloxazole;
2-((4-chlorophenoxy)methyl)-4-(4-
methylsulfonylphenyl)-5-phenyloxazole;
2-((3-chlorophenoxy)methyl)-4-(4-
methylsul;onylphenyl)-5-phenyloxazole;
2-((2-chlorophenoxy)methyl)-4-(4-
methylsulfonylphenyl)-5-phenyloxazole;
2-((4-fluorophenoxy)methyl)-4-(4-
methylsulfonylphenyl)-5-phenyloxazole;
2-((3-fluorophenoxy)methyl)-4-(4-
methylsulfonylphenyl)-5-phenyloxazole;
2-((2-fluorophenoxy)methyl)-4-(4-
methylsulfonylphenyl)-5-phenyloxazole;
2-((4-carboxyphenoxy)methyl)-4-(4-
methylsulfonylphenyl)-5-phenyloxazole;
2-((3-carboxyphenoxy)methyl)-4-(4-
methylsulfonylphenyl)-5-phenyloxazole;
2-((2-carboxyphenoxy)methyl)-4-(4-
methylsulfonylphenyl)-5-phenyloxazole;
2-(2-pheneth~1)-4-(4-methylsulfonylphenyl)-5-
phenyloxazole;
2-(3-phenylpropyl)-4-(4-methylsulfonylphenyl)-5-
phenyloxazole;
[4-(4-methylsulfonylphenyl)-5-phenyl]-2-
oxazoleacetic acid;
CA 02221692 1997-11-19
WO9613~617 PCT~S96106992
ethyl [4-(4-methylsulfonylphenyl)-5-phenyl]-2-
oxazoleacetate;
methyl [4-(4-methylsulfonylphenyl)-5-phenyll-2-
oxazoleacetate;
[4-(4-methylsulfonylphenyl)-5-phenyl]-2-
oxazolepr~panoic a~id;
ethyl [4-(4-methylsulfonylphenyl)-5-phenyl]-2-
oxazolepropanoate;
methyl [4-(4-methylsulfonylphenyl)-5-phenyl]-2-
oxazolepropanoate;
[4-(4-methylsulfonylphenyl)-5-phenyl]-2-
oxazolebutanoic acid;
ethyl [4-(4-methylsulfonylphenyl)-5-phenyl]-2-
oxazolebutanoate;
methyl [4-(4-methylsulfonylphenyl)-5-phenyl]-2-
oxazolebutanoate;
2-(2-quinolyloxymethyl)-4-(4-methylsulfonylphenyl)-
5-phenyloxazole;
4-[2-(ethyl)-5-phenyl-4-oxazolyl]benzenesulfonamide;
4-[2-(trifluoromethyl)-5-phenyl-4-
oxazolyl]'-enzenesulfonamide;
4-[2-(difluoromethyl)-5-phenyl-4-
oxazolyl]benzenesulfonamidei
4-[2-(hydroxymethyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
[4-(4-aminosulfonylphenyl)-5-phenyl]-2-
oxazolecarboxylic acid;
methyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2-
oxazolecarboxylate;
ethyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2-
oxazolecarboxylate;
4-[2-(propyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
4-[2-(benzyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
4-[2-(phenyl~hiomethyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
CA 0222l692 l997-ll-l9
WO 96/36617 PCT/US96/06992
4-[2-(phenoxymethyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
4-[2-((4-chlorophenoxy)methyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
4-[2-((3-chlorophenoxy)methyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
4-[2-((2-chlorophenoxy)methyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
4-[2-((4-fluorophenoxy)methyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
4-[2-((3-fluorophenoxy)methyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
4-[2-((2-flu_rophenoxy)methyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
4-[2-((4-carboxyphenoxy)methyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
4-[2-((3-carboxyphenoxy)methyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
4-[2-((2-carboxyphenoxy)methyl)-5-phenyl-4-
oxazolyl]benzenesulfon~mide;
4-[2-(2-phenylethyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
4-[2-(3-phenylpropyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
[4-(4-aminosulfonylphenyl)-5-phenyl]-2-oxazoleacetic
acid;
methyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2-
oxazoleacetate;
ethyl [4-(4-aminosulfonylphenyl)-5-phenyl~-2-
oxazoleacetate;
[4-(4-aminosulfonylphenyl)-5-phenyl]-2-
oxazolepropanoic acid;
methyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2-
oxazolepropanoate;
ethyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2-
oxazolepropanoate;
CA 02221692 1997-11-19
WO 961366~7 PCTIUS96Jû6992
[4-(4-aminosulfonylphenyl)-5-phenyl]-2-
oxazolebutanoic acid;
methyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2-
oxazolebu'lnoatei
ethyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2-
oxazolebutanoate;
4-[2-(2-~uinolyloxymethyl)-5-phenyl-4-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-phenyl-5-oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-fluorophenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-fluorophenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-fluorophenyl)-5-
oxazolyl]benzenesulfonamide;
4-~2-benzyl-4-(2,4-di~luorophenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,5-difluorophenyl)-5-
oxazolyl],~nzenesulfonamide;
4-[2-benzyl-4-(2,6-difluorophenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,4-difluorophenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,5-difluorophenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-chlorophenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-chlorophenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-chlorophenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,4-dichlorophenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-'-(2,5-dichlorophenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,6-dichlorophenyl)-5-
oxazolyl]benzenesulfonamide;
CA 02221692 1997-11-19
WO 96/36617 PCTIUS95106~92
34
4-[2-benzyl-4-(3,4-dichlorophenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,5-dichlorophenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-methoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-methoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-methoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,4-dimethoxyphenyl)-5-
oxazolyl]~enzenesulfonamide;
4-[2-benzyl-4-(2,5-dimethoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,6-dimethoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,4-dimethoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,5-dimethoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-methylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-methylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-methylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-~-(2,4-dimethylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,5-dimethylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,6-dimethylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-( 3, 4-dimethylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,5-dimethylphenyl)-5-
oxazolyl]benzenesulfonamide;
CA 02221692 1997-11-19
WO 9613~617 P~Tm~;9~'0'992
4-[2-benzyl-4-(2-chloro-4-methylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-chloro-4-methylphenyl)-5-
oxazolyl]; ~nzenesulfonamide;
4-[2-benzyl-4-(3-chloro-2-methylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-chloro-6-methylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-chloro-2-methylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-chloro-3-methylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-chloro-4-methoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-chloro-4-methoxyphenyl)-5-
oxazolyl~benzenesulfonamide;
4-[2-benzyl-4-(3-chloro-2-methoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-l-(2-chloro-6-methoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-chloro-2-methoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-chloro-3-methoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,5-dichloro-4-methoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-fluoro-4-methylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-fluoro-4-methylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-fluoro-2-methylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-fluoro-6-methylphenyl)-5-
oxazolyl]~-nzenesulfonamide;
4-[2-benzyl-4-(4-fluoro-2-methylphenyl)-5-
oxazolyl]benzenesulfonamide;
CA 02221692 1997-11-19
WO 96/36617 PCT/U~ J'01;~9g2
4-[2-benzyl-4-(4-fluoro-3-methylphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-fluoro-4-methoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-fluoro-4-methoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-fluoro-2-methoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-fluoro-6-methoxyphenyl)-5-
oxazolyl],,~nzenesulfonamide;
4-[2-benzyl-4-(4-fluoro-2-methoxyphenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-thienyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(5-chloro-2-thienyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(cyclohexyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(1-cyclohexenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-cyclohexenyl)-5-
oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-cyclohexenyl)-5-
oxazolyl]benzenesulfonamide;
2 benzyl-5-';1.-methylsulfonylphenyl)-4-phenyloxazole
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-
fluorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-
fluorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,4-
difluorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,5-
difluorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,6-
difluorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,4-
difluorophenyl)oxazole;
CA 02221692 1997-11-19
WO 96/36617 PCT~US~CJ069~s2
2-benzyl-5~ methylsulfonylphenyl)-4-(3,5-
difluorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-
chlorophenyl)-4-oxazolyl]benzenesul~onamide;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-
chlorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-
chlorophenyl)-4-oxazolyl]benzenesulfonamide
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,4-
dichlorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,5-
dichlorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,6-
dichlorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,4-
dichloropl~nyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,5-
dichlorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-
methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-
methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-
methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,4-
dimethoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,5-
dimethoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,6-
dimethoxyphenyl)oxazole;
2-benzyl-5-'1-methylsulfonylphenyl)-4-(3,4-
dimethoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,5-
dimethoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-
methylphenyl)oxazole;
CA 02221692 1997-11-19
WO 96/36617 PCT/US96/OC9~)2
38
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-
methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-
methylphenyl)oxazolei
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,4-
dimethylphenyl)oxazole;
2-benzyl-5-'~-methylsulfonylphenyl)-4-(2,5-
dimethylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,6-
dimethylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,4-
dimethylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,5-
dimethylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-chloro-4-
methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-chloro-4-
methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-chloro-2-
methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-chloro-6-
methylphei~l)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-chloro-2-
methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-chloro-3-
methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-chloro-4-
methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-chloro-4-
methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-chloro-2-
methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-chloro-6-
methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-chloro-2-
methoxyphenyl)oxazolei
CA 02221692 1997-11-19
WC) 961366~7 PCTIUS96106992
39
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-chloro-3-
methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,5-dichloro-
4-methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-fluoro-4-
methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-fluoro-4-
methylphenyl)oxazolei
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-fluoro-2-
methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-fluoro-6-
methylphe~yl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-fluoro-2-
methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-fluoro-3-
methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-fluoro-4-
methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-fluoro-4-
methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-fluoro-2-
methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-fluoro-6-
methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-fluoro-2-
methoxyphenyl)oxazole;
2-benzyl-5-(~-methylsulfonylphenyl)-4-(2-
thienyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(5-chloro-2-
thienyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-
(cyclohexyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(1-
cyclohexenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-
cyclohexenyl)oxazole;
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WO96/36617 PCT~S96106992
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-
cyclohexenyl)oxazole;
2-(ethyl)-5-(4-methylsulfonylphenyl)-4-
phenyloxazole;
2-(trifluoromethyl)-5-(4-methylsulfonylphenyl)-4-
phenyloxa ~lei
2-(difluoromethyl)-5-(4-methylsulfonylphenyl)-4-
phenyloxazole;
2-(hydroxymethyl)-5-(4-methylsulfonylphenyl)-4-
phenyloxazole;
[5-(4-methylsulfonylphenyl)-4-phenyl]-2-
oxazolecarboxylic acid;
methyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2-
oxazolecarboxylate;
ethyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2-
oxazolecarboxylate;
2-(propyl)-5-(4-methylsulfonylphenyl)-4-
phenyloxazole;
2-(benzyl)-5-(4-methylsulfonylphenyl)-4-
phenyloxazole;
2-(phenylthlomethyl)-5-(4-methylsulfonylphenyl)-4-
phenyloxazole;
2-(phenoxymethyl)-5-(4-methylsulfonylphenyl)-4-
phenyloxazole;
2-((4-chlorophenoxy)methyl)-5-(4-
methylsulfonylphenyl)-4-phenyloxazole;
2-((3-chlorophenoxy)methyl)-5-(4-
methylsulfonylphenyl)-4-phenyloxazole;
2-((2-chlorophenoxy)methyl)-5-(4-
methylsulfonylphenyl)-4-phenyloxazole;
2-((4-fluorophenoxy)methyl)-5-(4-
methylsulfonylphenyl)-4-phenyloxazole;
2-((3-fluorophenoxy)methyl)-5-(4-
methylsulfonylphenyl)-4-phenyloxazole;
2-((2-fluorophenoxy)methyl)-5-(4-
methylsul~onylphenyl)-4-phenyloxazole;
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41
2-((4-carboxyphenoxy)methyl)-5-(4-
methylsulfonylphenyl)-4-phenyloxazole;
2-((3-carboxyphenoxy)methyl)-5-(4-
methylsulfonylphenyl)-4-phenyloxazole;
2-((2-carboxyphenoxy)methyl)-5-(4-
methylsulfonylphenyl)-4-phenyloxazole;
2-(2-phenethyl)-5-(4-methylsulfonylphenyl)-4-
phenyloxazole;
2-(3-phenylpropyl)-5-(4-methylsul~onylphenyl)-4-
phenyloxazole;
[5-(4-methylsulfonylphenyl)-4-phenyl]-2-
oxazoleac~ ic acid;
ethyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2-
oxazoleacetate;
methyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2-
oxazoleacetate;
[5-(4-methylsulfonylphenyl)-4-phenyl]-2-
oxazolepropanoic acid;
ethyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2-
oxazolepropanoate;
methyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2-
oxazolepropanoate;
[5-(4-methylsulfonylphenyl)-4-phenyl]-2-
oxazolebutanoic acid;
ethyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2-
oxazolebutanoate;
methyl [5-('--methylsulfonylphenyl)-4-phenyl]-2-
oxazolebutanoate;
2-(2-quinolyloxymethyl)-5-(4-methylsulfonylphenyl)-
4-phenyloxazole;
4-[2-(ethyl)-4-phenyl-5-oxazolyl]benzenesulfonamide;
4-[2-(trifluoromethyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-(difluoromethyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-(hydroxymethyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
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[5-(4-aminosulfonylphenyl)-4-phenyl]-2-
oxazoleca~boxylic acid;
methyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2-
oxazolecarboxylatei
ethyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2-
oxazolecarboxylatei
4-[2-~propyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide
4-[2-(benzyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-(phenylthiomethyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-(phenoxymethyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-((4-chlorophenoxy)methyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-((3-chl rophenoxy)methyl)-4-phenyl-5-
oxazolyl]benzenesulfonamidei
4-[2-((2-chlorophenoxy)methyl)-4-phenyl-5-
oxazolyl]benzenesulfonamidei
4-[2-((4-fluorophenoxy)methyl)-4-phenyl-5-
oxazolyl]benzenesulfonamidei
4-[2-((3-fluorophenoxy)methyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-((2-fluorophenoxy)methyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-((4-carboxyphenoxy)methyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-((3-carboxyphenoxy)methyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-((2-carboxyphenoxy)methyl)-4-phenyl-5-
oxazolyl]b-nzenesulfonamide;
4-[2-(2-phenethyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
4-[2-(3-phenylpropyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide;
,
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43
[5-(4-aminosulfonylphenyl)-4-phenyl]-2-oxazoleacetic
acid;
methyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2-
oxazoleacetate;
ethyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2-
oxazoleacetate;
[5-(4-aminosulfonylphenyl)-4-phenyl]-2-
oxazoleprGpanoic acidi
methyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2-
oxazolepropanoate;
ethyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2-
oxazolepropanoate;
[5-(4-aminosulfonylphenyl)-4-phenyl]-2-
oxazolebutanoic acidi
methyl [5-(4-aminosulfonylphenyl)-4-phenyl~-2-
oxazolebutanoate;
ethyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2-
oxazolebutanoate;
4-[2-(2-quinolyloxymethyl)-4-phenyl-5-
20oxazolyl]benzenesulfonamide;
5-(4-fluorophenyl)-2-methyl-4-[4-
(methylsulfonyl)phenyl]oxazole;
3-[5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]]-
2-oxazolepropanoic acid;
25methyl 3-[5-(4-fluorophenyl)-4-[4-
(methylsulfonyl)phenyl]]-2-oxazolepropanoate;
4-(4-fluorophenyl)-2-(2-phenylethyl)-5-(4-
(methylsulfonyl)phenyl)oxazole;
4-(4-fluorophenyl)-2-methyl-5-[4-
30(methylsulfonyl)phenyl]oxazole;
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-
phenyloxazole;
2-benzyl-4-(4-fluorophenyl)-5-(4-
(methylsulfonyl)phenyl)oxazole;
354-(4-fluorophenyl)-5-[4-methylsulfonylphenyl]-2-(3-
phenylpropyl)oxazole;
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44
4-( 4 - fluorophenyl)-5-[4-methylsulfonylphenyl]-2-
propyloxazole;
2-(tert-butyl)-4-( 4 -fluorophenyl)-5-[4-
methylsulfonylphenyl]oxazole;
4-(4-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-5-[4-
methylsulfonylphenyl]oxazole
4-(4-fluorophenyl)-2-[(3-methoxyphenyl)methyl]-5-[4-
methylsulfonylphenyl]oxazole;
2-(diphenylmethyl)-4-(4-fluorophenyl)-5- [4-
methylsulfonylphenyl]oxazole;
2-[4-(4-fluorophenyl)-5-[4-methylsulfonylphenyl]]-2-
oxazoleacetic acid;
ethyl 2-[4-~-fluorophenyl)-5-[4-
methylsulfonylphenyl]]-2-oxazoleacetate;
15 3-[4-(4-fluorophenyl)-5-[4-methylsulfonylphenyl]]-2-
oxazolepropanoic acid;
methyl 3-[4-(4-fluorophenyl)-5-[4-
methylsulfonylphenyl]]-2-oxazolepropanoate;
4-[4-(4-fluorophenyl)-5-[4-methylsulfonylphenyl]]-2-
oxazolebutanoic acid;
methyl 4-[4-(4-fluorophenyl)-5-[4-
methylsulfonylphenyl]]-2-oxazolebutanoate;
3-[4-(4-fluorophenyl)-5-[4-methylsulfonylphenyl]]-2-
oxazolepropanamide;
25 4-(4-fluorophenyl)-2-(cyclohexylethyl)-5-[4-
(methylsulfonyl)phenyl]oxazole;
4-(4-fluorophenyl)-2-(3-fluorophenoxymethyl)-5-[4-
(methylsu~fonyl)phenyl]oxazole;
4-(4-fluorophenyl)-2-(3-chlorophenoxymethyl)-5-[4-
(methylsulfonyl)phenyl]oxazole;
4- (4-fluorophenyl)-2-(pyridyloxymethyl)-5-[4-
(methylsulfonyl)phenyl]oxazole;
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-
phenoxymethyloxazole;
35 4-(4-fluorophenyl)-2-(2-hydroxyethyl)-5-[4-
(methylsul~onyl)phenyl]oxazole;
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4-(4-fluorophenyl)-2-(hydroxymethyl)-5-[4-
(methylsulfonyl)phenyl]oxazole;
4-(cyclohexyl)-2-phenyl-5-[4-
(methylsu~ onyl)phenyl]oxazole;
4-(4-fluorophenyl)-2-benzyloxymethyl-5-[4-
(methylsulfonyl)phenyl]oxazole;
4-(4-fluorophenyl)-2-cyclohexyl-5-[4-
(methylsulfonyl)phenyl]oxazole;
5-(4-fluorophenyl)-2-phenyl-4-[4-
(methylsulfonyl)phenyl]oxazole;
[5-(3,4-dichlorophenyl)-2-trifluoromethyl-4-
oxazolyl]benzenesulfonamide;
4-[4-(3-aminosulfonyl-5-fluoro-4-methoxyphenyl)-2-
trifluoromethyl-5-oxazolyl]benzenesulfonamide;
4-(3-fluoro-4-methoxyphenyl)-5-(4-methylsulfonylphenyl)-
2-trifluoromethyloxazole;
4-[4-(4-bromophenyl)-2-methyl-5-
oxazolyl],~enzenesulfonamide;
5-fluoro-4-methoxy-3-[5-phenyl-2-trifluoromethyl-4-
oxazolyl]benzenesulfonamide;
4-[4-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-5-
oxazolyllbenzenesulfonamidei
ethyl 4-[[5-(4-aminosulfonylphenyl)-4-phenyl-2-
oxazolyl]oxy]benzoate; and
4-[5-(3-chloro-4-fluorophenyl)-2-trifluoromethyl-4-
oxazolyl]benzenesulfonamide.
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 (-CH2-) radical. Where the term "alkyl" is used,
either alon~ or within other terms such as "haloalkyl",
"alkoxyalkyl" and "hydroxyalkyl~, embraces linear or
- branched radicals having one to about twenty carbon atoms
or, preferably, one to about twelve carbon atoms. More
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46
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, pre~erably, two to about twelve carbon atoms,
provided that the double bond does not directly bond to the
oxazole ring. More preferred alkenyl radicals are ~lower
alkenyl" ra~.cals having two to about six carbon atoms.
Examples of such radicals include ethenyl, n-propenyl,
butenyl, and the like. The term ~alkynyl~ embraces linear
or branched radicals having two to about twenty carbon
atoms or, preferably, two to about twelve carbon atoms, and
containing a carbon-carbon triple bond. The more preferred
"lower alkynyl" are radicals having two to ten carbons.
Examples of such radicals include ethynyl, 1- or 2-
propynyl, 1-, 2- or 3-butynyl and the like and isomers
thereof. 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 ~n 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. Il 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, di~luoropropyl,
dichloroethyl and dichloropropyl. The term "hydroxyalkyl"
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47
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 l'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 term "hydroxyalkenyl" embraces linear or branched
alkenyl radicals having three to about ten carbon atoms any
one of which may be substituted with one or more hydroxyl
radicals. The term "hydroxyalkynyl" embraces linear or
branched alkynyl radicals having three to about ten carbon
atoms any one of which may be substituted with one or more
hydroxyl radicals. The terms "alkoxy" and "alkoxyalkyl"
embrace linear or branched oxy-containing radicals each
having alkyl portions of one to about twelve carbon atoms.
More preferred alkoxy radicals are "lower alkoxy" radicals
having one ic 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" or "alkoxyalkyl" radicals may be further
substituted with one or more halo atoms, such as fluoro,
chloro or bromo, to provide haloalkoxy or haloalkoxyalkyl
radicals. The term "aryl" embraces aromatic radicals such
as phenyl, naphthyl and biphenyl. Preferred aryl radicals
are those consisting of one, two, or three benzene rings.
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, amino, halo, nitro, alkylamino, alkylcarbonylamino,
alkylsulfonyl, arylsulfonyl, alkynyl, hydroxyalkynyl,
aminoalkynyl, heteroarylalkynyl, heteroaralkyl, alkenyl,
acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and
alkylthio. The terms "heterocyclyl~ or "heterocyclic"
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48
embrace saturated, partially saturated and unsaturated
heteroatom-containing ring-shaped radicals, where the
heteroatoms may be selected from nitrogen, sulfur and
oxygen. Examples of saturated heterocyclic radicals include
saturated 5 to 7-membered heteromonocylic group containing
1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl,
piperidinyl, piperazinyl, tropanyl, homotropanyl, etc.];
saturated 5 to 7-membered heteromonocyclic group containing
1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
morpholinyl etc.]; saturated 5 to 7-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1
to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples
of partially saturated heterocyclic radicals include
dihydrothiophene, dihydropyran, oxazolinyl, dihydrofuran
and dihydrothiazole. Examples of unsaturated heterocyclic
radicals, also termed "heteroaryl" radicals include
unsaturated 5 to 7 membered heteromonocyclic group
containing 1 to 4 nitrogen atoms, for example, pyrrolyl,
pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl,
azepinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-
1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl,
etc.] tetrazolyl [e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.],
etc.; unsaturated condensed heterocyclic group containing 1
to 5 nitrogen atoms, for example, indolyl, isoindolyl,
indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,
indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,
tetrazolo[1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to
6-membered heteromonocyclic group containing an oxygen
atom, for example, pyranyl, furyl, etc.; unsaturated 5 to
7-membered heteromonocyclic group containing a sulfur atom,
for example, thienyl, etc.; unsaturated 5 to 7-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1
to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,
oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed
heterocyclic group containing 1 to 2 oxygen atoms and 1 to
3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl,
CA 02221692 1997-11-19
WO 96~36617 PCrflJS96J06992
49
etc.]; unsaturated 5 to 7-membered heteromonocyclic group
containing i 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.]
5 etc.; unsaturated condensed heterocyclic group containing 1
to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,
benzothiazolyl, benzothiadiazolyl, etc.] and the like. The
term also embraces radicals where heterocyclic radicals are
fused with aryl radicals. Examples of such fused bicyclic
10 radicals include benzofuryl, benzothienyl, and the like.
The heterocyclyl moieties may also be substituted at a
substitutable position with one or more substituents
selected independently from alkyl, alkoxyalkyl,
alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,
15 aminocarbonylalkyl, alkoxy, amino, halo, nitro, alkylamino,
alkylcarbon~lamino, alkylsulfonyl, alkynyl, alkenyl,
arylsulfonyl, acyl, cyano, carboxy, aminocarbonyl,
alkoxycarbonyl and alkylthio. The term "aralkyl" embraces
aryl-substituted alkyl radicals. Preferable aralkyl
20 radicals are ~lower aralkyl~ radicals having aryl radicals
attached to alkyl radicals having one to six carbon atoms.
Examples of such radicals include benzyl, diphenylmethyl,
triphenylmethyl, phenylethyl and diphenylethyl. The terms
benzyl and phenylmethyl are interchangeable. The term
25 "heterocyclylalkyl" embraces saturated and partially
unsaturated heterocyclyl-substituted alkyl radicals, such
as pyrrolidinylmethyl, and heteroaryl-substituted alkyl
radicals, such as pyridylmethyl, quinolylmethyl,
thienylmethyl, furylethyl, and quinolylethyl. The term
30 "aryloxy~ embrace oxy-containing aryl radicals attached
through an oxygen atom to other radicals. More preferred
aryloxy radlcals are "lower aryloxy" radicals having a
phenyl radical. An example of such radicals is phenoxy. The
term "aryloxyalkyl" embraces alkyl radicals having one or
35 more aryloxy radicals attached to the alkyl radical, that
r is ~ to form monoaryloxyalkyl and diaryloxyalkyl radicals.
The "aryloxy" or "aryloxyalkyl'l radicals may be further
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substituted on the aryl rings as defined above. The term
"aralkyloxy" embrace oxy-containing aralkyl radicals
attached through an oxygen atom to other radicals. The
"aralkoxy" radicals may be further substituted on the aryl
ring portion of the radical as described above. The term
"aralkyloxyalkyl" embraces alkyl radicals having one or
more aralkyloxy radicals attached to the alkyl radical,
that is, to form monoaralkyloxyalkyl and diaralkyloxyalkyl
radicals. The ~aralkyloxy~ or ~aralkyloxyalkyl" radicals
may be further substituted on the aryl ring portion of the
radical. The term "heteroaryloxyalkyl" embraces alkyl
radicals having one or more heteroaryloxy radicals attached
to the alkyl radical, that is, to form
monoheteroaryloxyalkyl and diheteroaryloxyalkyl radicals.
The "heteroaryloxy" radicals may be further substituted on
the heteroaryl ring portion of the radical. The term
l'arylthio" embraces radicals containing an aryl radical, as
described above, attached to a divalent sulfur atom, such
as a phenylthio radical. The term "arylthioalkyl" embraces
alkyl radicals substituted with one or more arylthio
radicals, as described above. The term "cycloalkyl"
embraces radicals having three to ten carbon atoms. More
preferred c~cloalkyl radicals are "lower cycloalkyl"
radicals having three to seven carbon atoms. Examples
include radicals such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl. The term
"cycloalkylalkyl" embraces alkyl radicals substituted with
cycloalkyl radicals having three to ten carbon atoms, such
as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl and
cycloheptylmethyl. The term "cycloalkenyl" embraces
unsaturated radicals having three to ten carbon atoms, such
as cylopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl
and cycloheptenyl. The term "sulfonyl", whether used alone
or linked to other terms such as alkylsulfonyl, denotes
respectively divalent radicals -SO2~ Alkylsulfonyl~
embraces alkyl radicals attached to a sulfonyl radical,
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where alkyl is defined as above. The "alkylsul~onyl"
radicals may be further substituted with one or more halo
atoms, such as fluoro, chloro or bromo, to provide
haloalkylsulfonyl radicals. The term "alkylsulfinyl"
embraces alkyl radicals attached to a sulfinyl (-S(O)-)
radical, where alkyl is defined as above. More preferred
alkylsulfinyl radicals are "lower alkylsulfinyl" radicals
having one to six carbon atoms. Examples of such lower
alkylsulfinyl radicals include methylsulfinyl,
ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term
"alkylthio" embraces alkyl radicals attached to a divalent
sulfur radical, where alkyl is defined as above. More
preferred alkylthio radicals are "lower alkylthio" radicals
having alkyi radicals of one to six carbon atoms Examples
o~ such lower alkylthio radicals are methylthio, ethylthio,
propylthio, butylthio and hexylthio. The terms "sulfamyl",
"aminosulfonyl" and ''sulfonamidylll denote a sulfonyl
radical substituted with an amine radical, forming a
sulfonamide (-SO2~H2). The terms "alkylcarbonyl",
"arylcarbonyl" and "aralkylcarbonyl" include radicals
having alkyl, hydroxylalkyl, aryl, arylalkyl and aryl-
hydroxylalkyl radicals, as defined herein, attached to a
carbonyl radical. Examples of such radicals include
substituted or unsubstituted methylcarbonyl, ethylcarbonyl,
propylcarbonyl, butylcarbonyl, pentylcarbonyI,
hydroxymethylcarbonyl, hydroxyethylcarbonyl,
phenylcarbonyl, benzylcarbonyl, and
phenyl(hydroxymethyl)carbonyl. The terms "carboxy" or
llcarboxyl'', whether used alone or with other terms, such as
~carboxyalkyl", denotes -CO2H. The term "carboxyalkyl"
embrace radicals having a carboxy radical as defined above,
attached to an alkyl radical, which may be substituted,
such as with halo radicals, or unsubstituted. More
preferred are "lower carboxyalkylll which embrace lower
alkyl radicals as defined above, and may be additionally
substituted on the alkyl radical with halo. Examples of
such lower carboxyalkyl radicals include carboxymethyl,
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carboxyethyl, carboxybutyl, carboxypentyl, carboxyhexyl and
carboxypropyl. 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. Examples of such alkanoyl radicals include
formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,
isovaleryl, ~ivaloyl, hexanoyl, and radicals formed from
succinic, glycolic, gluconic, lactic, malic, tartaric,
citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,
mandelic, pantothenic, ~-hydroxybutyric, galactaric and
galacturo~ic acids. The term "aroyl" embraces aryl
radicals with a carbonyl radical as defined below.
Examples of aroyl include benzoyl, naphthoyl, phenylacetyl,
and the like, and the aryl in said aroyl may be
additionally substituted, such as in p-hydroxybenzoyl, and
salicylyl. The term "carboxyalkylthio" embraces
carboxyalkyl radicals as defined above, connected to a
divalent sulfur atom. The term "alkoxycarbonyl" means a
radical containing an alkoxy radical, as defined above,
attached via an oxygen atom to a "carbonyl" (-C=O) radical.
Examples of such "alkoxycarbonyl" ester radicals include
substituted cr unsubstituted methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and
hexyloxycarbonyl. The term "alkoxycarbonylalkyl" embraces
alkyl radicals having one or more alkoxycarbonyl radicals
attached to the alkyl radical. The term llphosphonylalkyl"
describes alkyl radicals substituted with phosphonic acid
residues or esters thereof. The term llaminoalkyl" 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 "aminocarbonyl" embraces radicals having an
amino radical radicals attached to a carbonyl radical
forming -C(O)NH2. The term ~aminocarbonylalkyl" embraces
alkyl radicals having one or more aminocarbonyl radicals
attached to the alkyl radical. The term
"alkylaminocarbonylalkyl" embraces alkyl radicals having
CA 02221692 1997-11-19
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aminocarbonyl radlcals substituted with one or two alkyl
radicals. Examples o~ such include M-
alkylaminocarbonylalkyl and N,N-dialkylaminocarbonylalkyl
radicals such as N-methylaminocarbonylmethyl and N,N-
dimethylaminocarbonylmethyl. The term "alkylamino" denotesamino groups which have been substituted with one or two
alkyl radicals. More preferred alkylamino radicals are
~lower alkylamino" having alkyl radicals o~ one to six
carbon atoms attached to the nitrogen atom of an amine.
Suitable "lower alkylamino" may be mono or dialkylamino
such as N-methylamino, N-ethylamino, N,N-dimethylamino,
N,N-diethylamino or the like. "Amino acid residue" means
any of the naturally occurring alpha-, beta- and gamma-
amino carboxylic acids, including their D and L optical
isomers and -acemic mixtures thereof, synthetic amino
acids, and derivatives o~ these natural and synthetic amino
acids. The amino acid residue is bonded either through an
amino or an acid functional group of the amino acid. The
naturally occurring amino acids which can be incorporated
in the present invention include, but are not limited to,
alanine, arginine, asparagine, aspartic acid, cysteine,
glutamic acid, glutamine, glycine, histidine, isoleucine,
leucine, lysine, methionine, ornithine, phenylalanine,
proline, serine, threonine, cyclohexylalanine, tryptophan,
tyrosine, valine, ~-alanine, and ~-aminobutyric acid.
Derivatives of amino acids which can be incorporated in the
present invention include, but are not limited to amino
acids having protected and modified carboxylic acids,
including acid esters and amides, protected amines, and
substituted phenyl rings, including but not limited to
alkyl, alkoxy and halo substituted tyrosine and
phenylalanine.
The present invention comprises a p~rm~ceutical
composition for the treatment of inflammation and
inflammation-associated disorders, such as arthritis,
~ comprising a therapeutically-effective amount of a compound
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54
of Formula I in association with at least one
pharmaceutically-acceptable carrier, adjuvant or diluent.
The present invention also comprises a therapeutic
method of treating inflammation or inflammation-associated
5 disorders in a subject, the method comprising treating the
subject havi:~g such inflammation or disorder a
therapeutically-effective amount of a compound of Formula I.
The method of the present invention also
includes prophylactic treatment. A preferred method
of the invention is the administration of water
soluble compounds of Formulas III via injection.
Also included in the family of com~ounds of Formula I
are the ph~rm~ceutically-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 h~rochloric, hydrobromic, hydroiodic, nitric,
carbonic, sulfuric and phosphoric acid. Appropriate organic
acids may be selected from aliphatic, cycloaliphatic,
aromatic, araliphatic, heterocyclic, carboxylic and
sulfonic classes of organic acids, example of which are
formic, acetic, propionic, succinic, glycolic, gluconic,
lactic, malic, tartaric, citric, ascorbic, glucuronic,
maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,
anthranilic, mesylic, salicylic, p-hydroxybenzoic,
phenylacetic, mandelic, embonic (pamoic), methanesulfonic,
ethylsulfonic, benzenesulfonic, pantothenic,
toluenesul~onic, 2-hydroxyethanesulfonic, sulfanilic,
stearic, cyclohexylaminosulfonic, algenic, ~
-hydroxybutyric, salicylic, galactaric and galacturonic
acid. Suitable pharmaceutically-acceptable base addition
salts of com~ounds of Formula I include metallic salts made
from aluminum, calcium, lithium, magnesium, potassium,
CA 0222l692 l997-ll-l9
WO 96136617 PCTIUS96J06992
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
sodium and zinc or organic salts made from N,N'-
dibenzylethylenediamine, choline, chloroprocaine,
diethanolamine, ethylenediamine, meglumine (N-
methylglucamine) and procaine. All of these salts may beprepared 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.
Also included in the family of compounds of Formula I
are the stereoisomers thereof. Compounds of the present
invention can possess one or more asymmetric carbon atoms
and are thus capable o~ existing in the form of optical
isomers as well as in the form of racemic or nonracemic
~ mixtures thereof. Accordingly, some o~ the compounds of
this invention may be present in racemic mixtures which are
also included in this invention The optical isomers can
CA 0222l692 l997-ll-l9
WO 96/36617 PCT/US~ ;992
56
be obtained by resolution o~ the racemic mixtures according
to conventional processes, for example by formation of
active compounds of Formula I-III can likewise be obtained
by utilizing optically active starting materials. These
isomers may be in the form of a free acid, a free base, an
ester or a salt.
Additional methods for resolving optical isomers,
known to those skilled in the art may be used, for example,
those discussed by J. Jaques et al in Enantiomers
Racemates, and Resolutions, ~ohn Wiley and Sons, Mew York
(1981).
GENE ~ L SYNTHE~I~ PROCEDURES
The compounds of the invention can be synthesized
according to the following procedures of Schemes I-XI,
wherein the ~-R8 substituents are as de~ined ~or Formula
I-III, above, except where ~urther noted.
~cheme
R~SJ~H ~OH l.AC~O,Et3N, ~ OH
3. DPPA, EhN,
Ph-CH3,
O~C - ~
4. t-BuOH, HCl,
RT- A
R2 S~[~
Rl O
Synthetic Scheme I shows the four step procedure
which can be used to prepare the substituted ketone
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WO 96/3~617 PC~T)lJS96)(16992
compounds 4 from the substituted benzaldehyde 1 and acid
2, where R2 is alkyl. In step one, benzaldehyde 1 and
substituted acetic acid 2 are first heated in acetic
anhydride and triethylamine via a Perkin condensation.
In step two, hydrolysis produces the corresponding 2,3-
disubstituted acrylic acids 3. In step three, the
acrylic acids 3 are reacted with diphenylphosphorylazide
(DPPA) and t~iethylamine in toluene at 0~C and then
warmed to room temperature to form acylazides. In step
four, the crude acylazides are heated to form an
isocyanate via a Curtius rearrangement. The isocyanate
is trapped as the N-t-butyloxycarbonyl ~n~m; ne
derivative via the addition of tert-butanol. Acidic
hydrolysis, such as by using concentrated HCl, provides
the substituted ketone 4 intermediates.
S~heme II
SR2
6 ~ ~ ~
X=Cl, Br, F, OH
Synthetic Scheme II shows an alternative approach
which can be used to prepare substituted ketone
intermediates 7, isomers of 4 where R2 is alkyl, via the
use of Friedel-Crafts acylation. An acylating agent 5,
such as an acid chloride, is treated with aluminum
chloride in an inert solvent, such as methylene
chloride, chloroform, nitrobenzene, dichlorobenzene or
chlorobenzene, and reacted with alkylthiobenzene 6 to
form ketone 7.
Other synthetic approaches are possible to form the
desired ketones. These alternatives include reacting
appropriate Grignard or lithium reagents with
substituted acetic acids or corresponding esters.
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58
~cheme III
R~S~ Rl TBSCl 2 J~OTBS
MCPBA
OH TBSO
R202S~R~ R
RCOCl
Base
o
R~O~S~_Rl N~4OAc ~ ? N~--R
11 12
Scheme III shows the five step synthesis, as
described in U.S. Patent No. 3,647,858, which can be
used to prepare the 5-(4-alkylsulfonylphenyl)oxazoles 12
of Formula I from ketone 4 (prepared in Scheme I).
Preparation of the silyl enol ether 8 (where TBSCl is
ter~-butyl-dimethylsilyl chloride) is followed by
oxidation, such as with m-chloroperoxybenzoic acid
MCP3A), to give the appropriate silylated benzoin 9.
Desilylation of this silylated benzoin 9 is achieved
using a~ueous acid, such as trifluoroacetic acid, to
give the desired benzoin 10. Reaction of the benzoin 10
with the appropriate acid chloride in the presence of
base, such as pyridine, gives the benzoin esters 11
CA 02221692 1997-11-19
WO ~)6136617 P~)US9GJ3~9~2
59
which may be converted to the antiinflammatory oxazoles
12 of the present invention upon treatment with ammonium
acetate in acetic acid at reflux.
~ ~heme IV
7 TBSCl ~_l3
MC PBA
Rl r l5 . ~ T ~ SO~
14
RCOCl
sase
NH~OAc ~ O~ R
16 17
Scheme IV shows the five step synthesis, similar to
that described above in Scheme III, which can be used to
prepare the 4-(4-alkylsulfonylphenyl) oxazoles 17 of
Formula I from ketone 7 (prepared in Scheme II).
Preparation of the silyl enol ether 13 is followed by
- oxidation, such as with m-chloroperbenzoic acid, to give
the appropriate silylated benzoin 14. Desilylation of
this silylated benzoin 14 is achieved using aqueous acid,
such as trifluoroacetic acid to give the desired benzoin
15. Reaction of the benzoin 15 with the appropriate acid
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WO 96/36617 PCT/US96/06992
chloride in the presence of base, such as pyridine, gives
the benzoin esters 16 which may be converted to the
antiin~lammatory oxazoles 17 of the present invention upon
treatment with ammonium acetate in acetic acid at reflux.
~cheme V
R2 S~3~1 ) Br2, HBr, R2 S~
HOAc , ~, OH
Rl~O2 ) aq . acetone Rl~O
4 18
RCOCl
Base
R2 ~3 ~
\>_ NH4 OAc /HOAc R~O
~1 0
R2S~
19
Scheme V shows the four step synthesis which can be
used to prepare oxazoles 20 from ketones 4 (prepared in
Synthetic Scheme I). In step one, ketones 4 are readily
brominated via the addition of bromine in acetic acid to
form the 2-bromoethanone intermediates. In step two,
reaction of the bromoethanone with a~ueous acetone yields
the benzoin 18. In step three, reaction of the benzoin 18
with the appropriate acid chloride in the presence o~ base,
such as pyridine, gives the benzoin esters 19. In step
four, benzoin esters 19 are converted to the oxazoles 20
upon treatment with a~monium acetate in acetic acid at
reflux.
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WO96/36617 PCT~S~Gl0~9~2
61
S~heme VI
Rl ~rr
1 ) Br2, HBr,
R2S~bO 2 ) aq acetone
7 2
RCOC l
Base
.
R2S ~ Rl ~ R
\~ R ' NH~OAc/HOAc R2SJ~
23 22
Similarly, Scheme VI shows the four step synthesis
which can be used to prepare oxazoles 23 from ketones 7
(prepared in Synthetic Scheme II). In step one, ketones 7
are readily brominated via the addition of bromine in
acetic acid to form the 2-bromoethanone intermediates. In
step two, reaction of the bromoethanone with aqueous
acetone yields the benzoin 21. In step three, reaction of
the benzoin 21 with the appropriate acid chloride in the
presence of ~ase, such as pyridine, gives the benzoin
esters 22. In step four, benzoin esters 22 are converted
to the oxazoles 23 upon treatment with ammonium acetate in
acetic acid at reflux.
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WO 96/36617 PCTIIJS9C/06~2
~ cheme VI I
1~ N 1. MCPBA, CB2Cl2 ~ ~>--R
12
o 1. MCPBA, CB2Cl2 ~ R
23
17
An alternative synthesis of the
alkylsulfonylphenyloxazoles 12 and 17 is accomplished as
shown in Synthetic Scheme VII from oxazoles 20 and 23
(prepared in Schemes V and VI). Oxazoles 20 and 23, where
R2 is an alkyl radical, are oxidized, such as with MCPBA (2
equivalents) in methylene chloride to form the
antiinflammatory alkylsulfonyl oxazoles 12 and 17. Other
suitable oxidizing agents include Oxone~, hydrogen
peroxide, periodate, peracetic acid and the like.
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WO 96/36617 l:'~TIUS96/069~2
S cheme VI I I
ArlCHO 2 ) H~e ArlJ~ pyridine o~
24 25 a6 ~
~aOAc
/ HOAc
Rl)~ R -H2~ ArX~;
28 27
In a method similar to that shown in Scheme IV, Scheme
VIII shows a method for preparing oxazoles 28 where Ar
represents an aromatic or heteroaryl radical without a
sulfur substituent. A solution of aldehyde 24 and zinc
iodide in an organic solvent such as dichloromethane (100
mL) is treated with trimethylsilylcyanide to give the
trimethylsilyl cyanohydrin. The trimethylsilyl cyanohydrin
is added to a solution of Arl-magnesium bromide in diethyl
ether while maintaining the temperature between 25-35 ~C to
give the benzoin 25. The benzoin 25, pyridine, and acid
chloride are reacted at room temperature to yield the
benzoin ester 26. Addition of ammonium acetate to the
benzoin ester 26 yields the oxazole 28. Alternatively,
the hydroxy-oxazoline 27 is isolated. Dehydration of the
hydroxy-oxazoline 27 yields the oxazoles 28. By reversing
the positions of Rl and Arl in the keto-enol 25, oxazoles
can be prepared with Rl is at position 4.
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64
~cheme IX
,~
Ar-'-CH3 l.R~Li, THF, -78 C ~ Ar- -NH~
2.B(R")3~ ~
O o
3.H2NOSO3H,
29NaOAc, H~O 30
Synthetic Scheme VIII shows the three step procedure
used to prepare sulfonamide antiinflammatory agents 30
from their corresponding methyl sulfones 29. In step one,
a THF solution of the methyl sulfones 29 at about -78~C is
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 about -78~C then
allowed to warm to ambient temperature prior to stirring at
reflux. In step three, an aqueous solution of sodium
acetate and hydroxyamine-O-sulfonic acid is added to
provide the corresponding sulfonamide antiinflammatory
agents 30 of this invention.
~cheme X
Rl ~ O )NH40H ~ ~
~;" N~_ R
\V/ ~
NH2 S--Ar ~
Scheme X shows another method of preparing
oxazolylbenzenesulfonamides 33 of the present invention.
The oxazole 31 is stirred with chlorosulfonic acid at
CA 0222l692 l997-ll-l9
WO 96~36617 PCTllJ~396J~6992
about 5 ~C to give the sulfonyl chlorides 32. The
sulfonyl chloride 32 is reacted at about 5 ~C with
~mmnni um hydroxide to give the sulfonamides 33 of the
current invention. In addition, disulfonamides can be
5 ,formed ~y substitution on R1 where Rl is aryl or
heteroaryl.
~cheme XI
R1~0
~5 ClSO3H ~ NH40H ,13J
-78 C RT c~02sJ~ Acetone H2NO2S
34 35
HB}, HOAc, Br !
R1 ~
R1~0 0 ~f
H2N02SJ~o~R 18-Crown-6, Br
38
HOAc
NH40Ac
.~
Rl N
R
H2NO2s~f
39
~ ynthetic Scheme XI shows the five step procedure
which can be used to prepare the substituted
- oxazolebenzenesulfonamide compounds 39, from the
substituted ketone 34. The benzenesulfonamide 36 is
formed, such as by adding the ketone 34 to chlorosulfonic
acid at about -78 ~C, then w~rmi ng to room temperature to
form the sulfonyl chloride 35. The sulfonyl chloride 35 is
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WO 96/36617 PCTJUS9G/06~32
66
reacted with a~ueous ammonium hydroxide in a solvent, such
as acetone, at about 5 ~C, and then at room temperature to
form the sulfonamide 36. In step 3, the sul~onamide 36 is
selectively brominated, such as with a solution of 30% HBr
in acetic acid, acetic acid and bromine to form the
bromoketone 37. In Step 4, the bromoketone 37 is added to
an acid and potassium carbonate in dimethylacetamide to
give the desired crude ~-acyloxy ketone 38. In step 5,
acetic acid and ammonium acetate are added to the acyloxy
ketone 38, and heated, such as at about 100 ~C to give the
oxazole 39.
The following examples contain detailed descriptions
of the methods of preparation of compounds of Formula I-
III. These detailed descriptions ~all within the scope, and
serve to ex~mplify, 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.
The following abbreviations are used:
EtOAc - ethyl acetate
NaOAc - sodium acetate
MaH - sodium hydride
NH40Ac - ammoniuum acetate
HCl - hydrochloric acid
DMSO - dimethylsulfoxide
DMSOd6 - deuterated dimethylsulfoxide
CHC13 - chloroform
CD30D - deuterated methanol
MgS04 - magnesium sulfate
NaHCO3 - sodium bicarbonate
Na2S04 - sodium sulfate
DMF - dimethylformamide
CH3CM - acetonitrile
CuI - copper iodide
NaOH - sodium hydroxide
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67
Pd/C - palladium on carbon
HBr - hydrobromic acid
CO3 - potassium carbonate
MeOH - methanol
EtOH - ethanol
LioH - lithium hydroxide
CH2Cl2 - methylene chloride/dichloromethane
DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene
h - hour
min - minutes
THF - tetrahydrofuran
HRMS - high resolution mass spectrum
EXAMP LE
H3C O
4-(4-Fluorophenyl)-2-(2-phenylethyl)-5-(4-
(methylsulfonyl)phenyl)oxazole
Step 1: Preparation of 1-(4-fluoro~henyl)-2-hydroxY-2-
(methylsulfonyl)phenvl)ethanone
A suspension of 2.03 g sodium hydride in 125 mL
tetrahydrofuran (THF) was stirred at 0'C under a
nitrogen atmosphere as a solution containing 20.0 g of
1-(4-fluorophenyl)-2-[4-(methylthio)phenyl]ethanone, as
prepared in U.S. Patent No. 3,647,858, in 100 mL of THF
was added dropwise over 30 minutes. The reaction was
- allowed to warm to 25 C for 18 hours. A solution
containing 12.7 g (84.5 mmol) of tert-butyl-
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68
dimethylsilyl chloride (DBSCL) in 20 mL THF was added
over 5 minutes and the resulting solution stirred at
25~C for 18 hours. The reaction was quenched by pouring
into aqueous sodium bicarbonate. The mixture was
extracted with ethyl acetate and the combined organic
extracts dried over sodium sulfate. Concentration in
vacuo provides a yellow oil, which solidified on
standing to give 27.9 g of the silyl enol ether. NMR
spectra was consistent with the assigned structure. The
silyl enol ether was used without further purification.
A solution containing 27.9 g of the silyl enol
ether in 500 mL methylene chloride (CH2Cl2) was cooled
to O C under a nitrogen atmosphere while being stirred
mechanically. 77.lg of m-chloroperoxybenzoic acid
(technical grade, 50-60%) was added and the reaction was
stirred at O C for 2 hours and allowed to warm to 25 C
over 1 hour. The reaction mixture was washed with an
aqueous solution of sodium metabisulfite, followed by
aqueous sodium bicarbonate. The organic solution was
dried over sodium sulfate and concentrated in vacuo to
give 24.5 g of 1-(~-fluorophenyl)-2-tert-
butyldimethylsilyloxy-2-[4-
(methylsulfonyl)phenyl]ethanone. NMR spectra were
consistent with the assigned structure. This material
was used without further puri~ication.
The benzoin silyl ether was dissolved in 100 mL of
90% aqueous trifluoroacetic acid and stirred at 25 C for
18 hours. The reaction was quenched by slowly pouring
into saturated aqueous sodium bicarbonate solution. The
product was extracted with ethyl acetate and the
combined organic extracts were dried over sodium
sulfate. Concentration in vacuo provided an oily solid,
which was recrystallized from 50% ethyl
acetate/isooctane to give 15.5 g of a crystalline white
solid (mp 122-123-C) whose structure was assigned as 1-
(4-fluorophenyl)-2-hydroxy-2-
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69
(methylsulfonyl)phenyl)ethanone on the basis of its
spectral properties.
~ The isomeric benzoin, 2-(4-fluorophenyl)-2-hydroxy-
1-(4-(methylsulfonyl)phenyl)ethanone, was prepared
analogously from 2-(4-~luorophenyl)-1-[4-
(methylthio)phenyl ethanone.
Ste~ 2: Pre~aration of 4-(4-fluoro~henyl)-2-(2-
Dhenvlethvl)-5-(4-(methylsulfonvl)~henvl)oxazole.
A solution containing 5.00 g of 1-(4-fluorophenyl)-
2-hydroxy-2-(4-(methylsulfonyl)phenyl)ethanone in 100 mL
methylene chloride (CH2C12) was stirred at 25 C as 6.60
mL of pyridine was added, followed by 3.61 mL of
hydroci nn~moyl chloride.
The reaction was stirred at 25 C for 48 hours,
after which the organic solution was washed with lN HCl,
dried over sodium sulfate and concentrated in vacuo to
give an oily solid. This material was recrystallized
from 50% ethyl acetateJisooctane to give 4.40 g of a
beige crystalline solid (mp 152-153.5 C). NMR spectra
were consistent with the assigned structure of 1-(4-
fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-2-(2-
phenyl)propionyloxy ethanone. This material was
dissolved in 100 mL of glacial acetic acid and 7.70 g of
ammonium acetate was added. The reaction was heated to
reflux with stirring for 1.5 hours, after which it was
cooled to room temperature and poured into 100 mL of
water. The product was extracted with ethyl acetate and
the combined organic extracts washed with aqueous sodium
bicarbonate, dried over sodium sulfate and concentrated
in vacuo to give an oily solid which was recrystallized
from 50% ethyl acetate/isooctane to give 3.55 g o~ 4-(4-
fluorophenyl)-2-(2-phenylethyl)-5-(4-(methylsulfonyl)
phenyl)oxazole as a white crystalline solid (mp 117-
118-C). NMR spectra was consistent with the assigned
structure.
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EX;~MPLE 2
~ ~
CH302 S
54-(4-Fluorophenyl)-2-methyl-5-~4-
(methylsulfonyl)phenyl]oxazole
4-(4-Fluorophenyl)-2-methyl-5-[4-
(methylsulfonyl)phenyl]oxazole was prepared in an
analogous manner to that shown in Example 1. Melting
point: 158-159 ~C.
EXAMP LE 3
CH~SO ~ 1 ~
4-(4-Fluorophenyl)-5-~4-(methylsulfonyl)phenyl]-
2-phenyloxazole
4-(4-Fluorophenyl)-5-[4-(methylsulfonyl) phenyl~-2-
phenyloxazole was prepared in a manner analogous to
Example 1. Melting point: 204-205 C.
CA0222l692l997-ll-l9
WO96l36617 PCT~S9G10L~2
EXAMPI~E 4
; F ~
~3
\\S'~
H3C O
2-Benzyl-4-(4-fluorophenyl~-5-(4-
(methylsulfonyl)phenyloxazole
2-Benzyl-4-(4-fluorophenyl) -5- (4-
(methylsulfonyl)phenyloxazole was prepared in a manner
analogous to Example 1. The m/z 408 (M+H)+ was
consistent with the assigned structure.
EXAMPLE 5
o~
/S~
4-(4-Fluorophenyl)-5-t4-methylsulfonylphenyl]-2-
- (3-phenylpropyl)oxazole
4-(4-Fluorophenyl) -5- ~4-methylsulfonyl phenyl]-2-
(3-phenylpropyl)oxazole was prepared in a manner
analogous to Example 1. The m/z 436 (M+H)+ was
consistent with the assigned structure.
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WO96/36617 PCT~S96/06992
72
EXAMPI.E 6
~ 3N
~1~
~ ~
\~\S~
H3C 0
4-(4-Fluorophenyl)-5-[4-methylsulfonylphenyl]-2-
propyloxazole
4-(4-Fluorophenyl)- 5-[ 4-methylsulfonyl phenyl]-2-
propyloxazole was prepared in a manner analogous to
Example 1. The m/z 360 (M+H)+ was consistent with the
assigned structure.
EXAMPLE 7
~ 32\ ~
2-(tert-Butyl)-4-(4-fluorophenyl)-5-~4-
(methylsulfonyl)phenyl]oxazole
2-( Tert -butyl)-4-(4-fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]oxazole was prepared in a manner
analogous to Example 1. Melting point: 130-131-C.
CA 02221692 1997-11-19
WO 961366~7 PC:TlI)' ~unc~s2
EXAMP LE 8
F~f ~
~ ~ OCH3
CH3 S02
4-( 4-Fluorophenyl)-2-(4-methoxyphenyl)methyl-5-
[4-methylsulfonylphenyl]oxazole
4-(4-Fluorophenyl)-2-(4-methoxyphenyl)methyl-5-[4-
methylsulfonylphenyl]oxazole was prepared in a manner
analogous to Example 1. Melting point: 123-124 C.
EXAMP l.E 9
~ ~OCH3
CH3S02
4-(4-Fluorophenyl)-2-(3-methoxyphenyl)methyl-5-
[4-methylsul~onylphenyl~oxazole
4-(4-Fluorophenyl)-2-(3-methoxyphenyl)methyl-5-[4-
methylsulfonylphenyl]oxazole was prepared in a manner
analogous to Example 1. The m/z 437 (M+H)+ was
consistent with the assigned structure.
.,
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74
EXAMPLE 1 0
2-Diphenylmethyl-4-(4-fluorophenyl)-5-[4-
methylsulfonylphenyl]oxazole
2-Diphenylmethyl-4-(4-fluorophenyl) -5- [4-
methylsulfonylphenyl]oxazole was prepared in a manner
analogous to Example 1. Melting point: 155-156 C.
EXAMPLE 1 1
o~~
Ethyl 2-[4-(4-fluorophenyl)-5-(4-
methylsulfonylphenyl)]-2-oxazoleacetate
Ethyl 2-[4-(4-fluorophenyl)-5- (4-
methylsulfonylphenyl)-2-oxazoleacetate was prepared in a
manner analogous to Example 1. Melting point: 123-124-C.
CA 02221692 1997-11-19
WO 9613G617 PCTJUS9G1063~2
EXAMPLE 12
;~ ~o
Methyl 3-~4-(4-fluorophenyl)-5-(4-
methylsulfonylphenyl)]-2-oxazolepropanate
Methyl 3-[4-(4-fluorophenyl)- 5-[4-
methylsulfonylphenyl]oxazol-2-yl]propanate was prepared
in a manner analogous to Example 1. The m/z 404 (M+H)+
was consistent with the assigned structure.
EXAMPLE 13
~ N \\
~0~ \/~o
o~
~
Methyl 4-~4-(4-fluorophenyl)-5-(4-
methylsulfonyl)phenyl~]-2-oxazolebutanate
Methyl 4-[4-(4-fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]]-2-oxazole~utanate was prepared
in a manner analogous to Example 1. Melting point: 89-
91 ~C .
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76
EXAMPLE 14
CH302S ~--5 1~>--CH3
~ o
F ~
55-(4-Fluorophenyl)-2-methyl-4-[4-
(methylsul~onyl)phenyl]oxazole
5-( 4-Fluorophenyl)-2-methyl-4-[4-(methylsul~onyl)
phenyl]oxazole was prepared in a manner analogous to
Example 1 but with 2-(4-fluorophenyl)-1-[4-
(methylthio)phenyl]ethanone as the starting material.
The m/z 332 (M+H)+ was consistent with the assigned
structure.
EXAMPLE 15
~ '~
F ~
Methyl 3-~5-(4-fluorophenyl)-4-~4-
(methylsulfonyl)phenyl]]-2-oxazolepropanoate
Methyl 3-[5-(4-~luorophenyl)-4-[4- s
(methylsul~onyl)phenyl]]-2-oxazolepropanoate was
prepared in a manner analogous to Example 14. The m/z
404 (M+H)+ was consistent with the assigned structure.
CA 02221692 1997-11-19
WO 96~36617 PC~ 9CJ~.~2
EXAMPLE 1 6
~,
~ >~
O ~ HO
o
2-[4-(4-Fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]]-2-oxazoleacetic acid
2-[4-(~-Fluorophenyl)-5-[4-(methylsulfonyl)
phenyl]oxazol-2-yl]acetic acid was prepared ~rom Example
11 via alkaline hydrolysis using 1 N sodium hydroxide in
methanol and appropriate reaction conditions. Melting
point: 118-120-C.
EXAMPI.E 17
C~
3-t4-(4-Fluorophenyl)-5-[4-
(methylsul~onyl)phenyl]]-2-oxazolepropanoic acid
c
3-[4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)
phenyl]]-2-oxazolepropanoic acid was prepared from
Example 12 in a manner analogous to Example 17. Melting
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78
point: 197-198~C. The m/z 390 (M+H)+ was consistent with
the assigned structure.
:~:XAMPLE 1 8
>~
~ 11
\OH
4-[4-(4-Fluorophenyl)-5-~4-
(methylsulfonyl)phenyl]]-2-oxazolebutanoic acid
4-[4-(4-Fluorophenyl)-5-[4-(methylsul~onyl)
phenyl]]-2-oxazolebutanoic acid was prepared ~rom
Example 13 in a manner analogous to Example 17. Melting
point: 140-141~C. The m/z 404 (M+H)+ was consistent with
the assignea structure.
:~:XAMPL:~: 1 9
rl~ N ~
F
3-[5-(4-Fluorophenyl)-4-[4-
(methylsul~onyl)phenyl]]-2-oxazolepropanoic acid
=
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3-[5-(4-Fluorophenyl)-4-[4-(methylsulfonyl)
phenyl]]-2-oxazolpropanoic acid was prepared from
Example 15 in a manner analogous to Example 17 . The m/z
390 (M+H)+ was consistent with the assigned structure.
E~AMPLE 2 0
~ N ~
4-(4-Fluorophenyl)-2-(3-hydroxypropyl)-5-[4-
(methylsul~onyl)phenyl]oxazole
A solution containing 100 mg (0.239 mmol) of 3-[4-
(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-
yl]propanoic acid, methyl ester in 10 mL oftetrahydrofuran was cooled to 0~C with stirring under a
nitrogen atmosphere as 0.53 mL of diisobutylaluminum
hydride (lM in toluene, 0.523 mmol) was added dropwise
over 5 minutes. The reaction was allowed to warm to
25~C and poured into 100 mL of a saturated solution of
sodium potassium tartarate. Ethyl acetate (100 mL) was
added and the mixture was stirred until the layers
separated (approx. 1 hour). The organic layer was
separated and dried over sodium sulfate. Concentration
in vacuo gave an oily solid, which was recrystallized
from 50 % ethyl acetate-isooctane to give 75 mg of a
white crystalline solid (mp 123-124~C) which was
characterized on the basis of its spectral
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characteristics: lH-NMR (CDC13, 300 MHz) ~ 2.10 (m, 2H),
2.56 (bs, lH), 3.01 (t, 2H, J=7.0 Hz), 3.07 (s, 3H),
3.80 (t, 2H, J=5.9 Hz), 7.09 (t, 2H, J=8.5 Hz), 7.57
(dd, 2H, J=8.5 and 5.5 Hz), 7.73 (d, 2H, J=8.5 Hz) and
5 7.89 (d, 2H, J=8.5 Hz). 19F-NMR (CDCl3, 280 MHz) ~ -
-111.97. ~RMS m/z 376 (M + H)+. HRMS calc. for
C1gH18NO4FS: 376.1019. Observed: 376.1026. Analysis
calc. for C1gH18NO4FS-C: 60.79, H: 4.83, N: 3.73.
Observed-C: 60.53, H: 4.85, N: 3.66.
EXAMPLE 2 1
F~ ~
~ N ~2
,,~N~ ~
0~
~0
3-~4-(4- Fluorophenyl)-5-~4-
(methylsulfonyl)phenyl]]-2-oxazolepropanamide
3-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)
phenyl]]-2-oxazolepropanamide was prepared by treating
methyl 3-[4-(4-fluorophenyl)-5-(4-
(methylsulfonyl)phenyl)-2-oxazolepropanoic acid,
(Example 12) with excess ammonia in methanol for 5 days.
Melting point: 193-195-C. --
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81
EXAMPLE 2 2
~C025 ~? o
5-(4-Fluorophenyl)-2-phenyl-4-[4-
(methylsul~onyl)phenyl]oxazole
Step 1: Pre~aration of 5-(fluoro~henvl)-4-r4-
(methylthio)phenyll-2-~henvloxazole
A solution containing 560 mg (2.03 mmol) of 2-(4-
fluorophenyl)-2-hydroxy-1-[4-~methylthio)phenyl]
ethanone in 50 mL of methylene chloride was stirred at
25~C as 0.82 mL (10.15 mmol) of pyridihe was added,
followed by 0.28 mL ~2.44 mmol) of benzoyl chloride.
The reaction was stirred at 25~C for 2 days, after which
it was washed with lN HCl, dried over sodium sulfate and
concentrated in vacuo to give a crude oil which was
characterized as the benzoin ester on the basis of its
spectral characteristics: lH-NMR (CDCl3, 300 MHz) ~ 2.53
20 (s, 3H), 7.08 (s, lH), 7.12 (t, 2H, J=8.7 Hz), 7.27 (d,
2H, J=8.7 Hz/, 7.49 (t, 2H, J=7.7 Hz), 7.60 (m, 3H),
7.94 (d, 2H, J=8.7 Hz) and 8.14 (d, 2H, J=8.7 Hz). This
material was dissolved in 50 mL of glacial acetic acid
and 1.56 g (20.3 mmol) of ammonium acetate was added.
The reaction was heated at reflux for 2 hours, cooled to
25~C and poured into 100 mL of water. The aqueous
r solution was extracted with ethyl acetate and the
combined organic extracts were washed with water and
sodium bicarbonate solution, dried over sodium sulfate
and concentrated in vacuo. The crude solid was purified
by flash chromatography using a silica gel column and
50% ethyl acetate/hexane as the eluent to give a white
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.
82
solid which was recrystallized from 50% ethyl
acetate/isoh~tane to give 450 mg (61%) of a white
crystalline solid (mp 118-119~C) whose structure was
assigned as 5-(4-fluorophenyl)-4-[4-(methylthio)
phenyl]-2-phenyl oxazole on the basis of its spectral
characteristics: lH-NMR (CDC13, 300 MXz) ~ 2.52 (s, 3H),
7.10 (t, 2H, J=8.8 Hz), 7.28 (d, 2H, J=8.5 Hz), 7.47 (m,
3H), 7.62 (m, 4H) and 8.13 (m, 2H). 19F-NMR (CDC13, 280
MXz) ~ -111.96. hRMS m/z 361 (M)+. HRMS Calc'd. for
C22H16NOFS: 361.0937. Observed: 361.0970. Analysis
Calc'd. for C22H16MOFS: C, 71.51; H, 6.55i N, 3.79.
Observed: C, 72.85i H, 4.52i N, 3.84.
Ste~ 2: Preparation of 5-(4-fluorophenyl)-4-r4-
(methylsulfinvl)phenvll-2-~henvloxazole.
A solution containing 64 mg (O.173 mmol) of 5-(4-
fluoropheny')-4-[4-(methylthio)phenyl]-2-phenyloxazole
in 10 mL of methylene chloride was stirred at -78~C as
60 mg (0.173 mmol based on 50% purity) of m-
chloroperoxybenzoic acid was added all at once. Thereaction was stirred at -78~C ~or 1 hour. Thin-layer
chromatography (TLC) (silica, 50% hexane-ethyl acetate)
indicated that the reaction mixture consisted of mostly
sulfoxide, with a minor amount of sulfide and sulfone.
The reaction was poured into a solution of aqueous
sodium metabisulfite. The aqueous solution was
extracted using ethyl acetate and the organic layer was
washed with saturated sodium metabisulfite, saturated
sodium bicarbonate and brine. The resulting clear
solution was dried over sodium sulfate and concentrated
in vacuo to give a white solid which was purified by
flash chromatography on a silica gel column using 50%
ethyl acetate/hexane as the eluent. Recrystallization
from 50~ ethyl acetate/isooctane gave 48 mg (74%) of a
white crystalline solid (mp 164-165~C~ whose structure
was assigned as 5-(4-~luorophenyl)-4-[4-
(methylsulfinyl)phenyl]-2-phenyl oxazole on the basis of
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its spectral characteristics: 1H-NMR (CDC13, 300 MHz)
2.80 (s, 3H), 7.16 (t, 2H, ~=8.5 Hz), 7.54 (m, 3H),
~ 7.66-7.75 (m, 4H), 7.93 (d, 2H, J=8.5 Hz) and 8.19 (m,
2H) LRMS m/z 377 (M)+. HRMS Calc~d. for C22Hl6NO2FS:
377.0886. Observed: 377.0868. Analysis Calcld. for
C22H16NO2FS: C,70.01; H, 4.27; N, 3.71. Observed: C,
68.18; H, 4.19; N, 3.58.
SteD 3: Pre~aration of 5-(4-fluorophenvl)-4-r4-
10 (methvlsulfonyl~henyll-2-phenyloxazole.
A solution containing 64 mg (0.173 mmol) of 5-(4-
fluorophenyl)-4-[4-(methylthio)phenyl]-2-phenyloxazole
in 10 mL of methylene chloride was stirred at -78 ~C as
120 mg (0.346 mmol based on 50% purity) of m-
15 chloroperoxybenzoic acid was added all at once. The
reaction was stirred at -78 ~C for 1 hour and TLC
(silica, 50% hexane-ethyl acetate) indicated that the
reaction mixture consisted of mostly sulfone. The
reaction was poured into a solution of a~ueous sodium
20 metabisulfite. The a~ueous solution was extracted using
ethyl acetate and the organic layer was washed with
saturated sodium metabisulfite, saturated sodium
bicarbonate and brine. The resulting clear solution was
dried over sodium sulfate and concentrated in vacuo to
25 give a white solid which was purified by flash
chromatography on a silica gel column using 50% ethyl
acetate/hexane as the eluent. Recrystallization from
50% dichloromethane/isooctane gave 62 mg (91%) of a
white crystalline solid (mp 175-176~C) whose structure
30 was assigned as 5-(4-fluorophenyl)-4-[4-
(methylsulfonyl)phenyl]-2-phenyl oxazole on the basis of
r its spectral characteristics: 1H-NMR (CDCl3, 300 MHz) ~
3.13 (s, 3H), 7.19 (t, 2H, J=8.6 Hz), 7.55 (m, 3H), 7.69
(m, 2H), 8.00 (m, 2H), 8.17 (m, 2H). LRMS m/z 393 (M)+.
HRMS Calc~d. for C22Hl6NO3FS: 393.0835. Observed:
393.0865.
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EXAMPI.E 2 3
~ N~
H3C02 S
2-Cyclohexyl-4-(4-fluorophenyl)-5-~4-
(methylsulfonyl)phenyl]oxazole
2-Cyclohexyl-4-(4-fluorophenyl)-5-[4-
(methylsulfc-ryl)phenyl]oxazole was prepared in a manner
analogous to Example 1. Melting point: 127-128~C.
EXAMP I.E 2 4
F
~ N ~ O
2-Benzyloxymethyl-4-(4-fluorophenyl)-5-~4-
(methylsulfonyl)phenyl]oxazole
Ste~ 1: Pre~aration of the benzoin ester
A solution containing 2.07 g (6.71 mmol) of 1-(4-
fluorophenyl)-2-hydroxy-2-[4-
(methylsulfonylphenyl)ethanone in 100 mL of methylene
chloride was stirred at 25~C as 2 . 71 mL (33.55 mmol) of
pyridine was added, followed by the addition of 1.27 mL
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(8.05 mmol) of benzyloxyacetyl chlo~ide. The reaction
was stirred at 25~C for 48 hours, after which the
resulting yellow solution was washed with lN HCl, dried
- over sodium sul~ate and concentrated in vacuo. The oily
yellow solid was purified via flash chromatography on a
silica gel column using 20 % ethyl acetate/hexane as the
e]uent. This provided 2 . 22 g (73 %) of a white ~oam,
which was characterized as the benzoin ester on the
basis of its NMR spectra: lH-NMR (CDC13, 300 MXz) ~ 3.03
(s, 3H), 4.23 (d, lH, J=17.0 Hz), 4.33 (d, lH, J=17.0
Hz), 4.67 (s, 2H), 6.95 (s, lH), 7.13 (t, 2H, J=8.5 Hz),
7.35 (m, 5H), 7.66 (d, 2H, J=8.1 Hz) and 7.98 (m, 4H).
l9F-NMR (CDCl3, 280 MHz) ~ -102.5.
15 Step 2: Preparation of 2-benzvloxvmethyl-4-(4-
~luorophenyl)-5- r 4-(methylsul~onyl)phenylloxazole.
A solution containing 2.22 g (4.86 mmol) of
the benzoin ester and 3.74 g (48.6 mmol) of ammonium
acetate in 100 mL of acetic acid was heated to 80~C for
20 2 hours. The reaction was cooled to 25~C and poured
into water. The product was extracted into ethyl
acetate and the combined organic extracts washed with an
aqueous solution of sodium bicarbonate. The solution
was dried over sodium sul~ate and concentrated in vacuo
25 to give a yellow oil. This crude material was purified
by flash chromatography on a silica gel column using 25
% ethyl acetate/hexane as the eluent to give 1.92 g
(90%) of a clear oil, which was characterized as 2-
benzyloxymethyl-4-(4-~luorophenyl)-5-[4-
30 (methylsulfonyl)phenyl]oxazole on the basis of its
spectral properties: lH-NMR (CDCl3, 300 MHz) ~ 3.07 (s,
r 3H), 4.70 (s, 2H), 4.72 (s, 2H), 7.11 (t, 2H, J=8.8 Hz),
7.22-7.40 (m, 5H), 7.58 (m, 2H), 7.76 (d, 2H, J=8.8 Hz)
and 7.91 (d, 2H, J=8.8 Hz). 19F-NMR (CDC13, 280 MHz)
-111.88.
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EXAMPLE 2 5
\~ Ph
~0
H3CO2S ~J
4-(Cyclohexyl)-5-t4-(methylsul~onyl)phenyl]-2-
phenyloxazole
Ste~ 1: Preparation of 1-(cyclohexvl)-2-hydroxy-2-r4-
(methvlthio~henvl)ethanone
A 250 mL round bottomed flask was equipped with a
mechanical stirrer and reflux condenser and charged with
30 mL of absolute ethanol, 3,4-dimethyl-5-(2-
hydroxyethyl)thiazolium iodide (2.00 g, 7.0 mmol), 4-
methylthiobenzaldehyde (10.66 g, 70.0 mmol), and freshly
distilled cyclohexanecarboxaldehyde (7. 68 g, 70.1 mmol).
The solution was stirred vigorously, treated with
triethylamine (4.27 g, 42.2 mmol) and heated to reflux
for 24 hours. The solution was treated with additional
portions of 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium
iodide (2.05 g, 7.01 mmol), triethylamine (4.84 g, 48.0
mmol), and ~clohexanecarboxaldehyde (7.01 g, 62.5
mmol), and heated to reflux for an additional 42 hours.
The solution was concentrated in vacuo, the residue
dissolved in chloroform, washed with 3 N HC1, saturated
aqueous sodium bicarbonate, brine, dried over anhydrous
ma~nesium sulfate, filtered and concentrated in vacuo to
afford 18.75 g, (>100%) of a yellow oil that solidified
upon standing. The crude solid was purified by
trituratio~ with ether providing the desired compound in
pure form 15.80 g, (86%, mp 110-111.5~C) which was
characterized as 1-(cyclohexyl)-2-hydroxy-2-[4-
(methylthiophenyl)ethanone on the basis of its NMR
spectra. 1H-MMR (CDC13, 300 MHz) ~ 1.00-1.47 (m, 6H),
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1.60-1.95 (m, 4H), 2.45 (m, lH), 2.52 (s, 3H), 4.38(d,
J=3.9 Hz, lH), 7.55 (d, J=3.9 Hz, lH), 7.25 (m, 4H).
HRMS Calc'd. for ClsH20NO2S: 264.1184. Observed:
264.1207.
~te~ 2: Pre~aration o~ benzoin ester
A solution containing 162 mg (0.62 mmol) of 1-
(cyclohexyl)-2-hydroxy-2-[4-(methylthiophenyl) ethanone
in 10 mL of methylene chloride was stirred at 25~C as
251 ~L (31 mmol) of pyridine was added, ~ollowed by the
addition of 86 ~L (1.24 mmol) of benzoyl chloride. The
reaction was stirred at 25~C for 48 hours, after which
the resulting yellow solution was washed with lN HCl,
dried over sodium sul~ate and concentrated in vacuo.
The crude solid was purified via flash chromatography on
a silica gel column using 10 ~ ethyl acetate/hexane as
the eluent. This provided 131 mg (57 %) of a white
foam, which was characterized as the benzoin ester on
the basis of its NMR spectra: lH-NMR (CDCl3, 300 MXz) ~
1.03-1.48 (m, 6H), 1.56-1.88 (m, 3H), 2.03-2.14 (m, lH),
2.48 (s, 3H), 2.53 (m, lH), 6.28 (s, lH), 7.20-7.70 (m,
5H), 8.05-8.17 (m, 4H).
Step 3: Preparation of 4-cvclohexyl-5-r4-
25 (methvthio)~henYll-2-phenyloxazole
A solution cont~;ning 131 mg (0.355 mmol) of the
benzoin ester and 273 mg (35 mmol) of ammonium acetate
in 10 mL of acetic acid was heated to 80~C for 2 hours.
The reaction was cooled to 25~C and poured into water.
30 The product was extracted into ethyl acetate and the
combined organic extracts washed with an aqueous
r solution of sodium bicarbonate. The solution was dried
over sodium sulfate and concentrated in vacuo to give
the crude o~azole. This crude material was purified
35 crystallization from a mixture of dichloromethane and
isooctane to give 89 mg, (72%, mp 151-151.5~C) of
material, which was characterized as 4-(cyclohexyl)-5-
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[4-(methythio)phenyl]-2-phenyloxazole on the basis of
its spectral properties: lH-NMR (CDC13, 300 MHz) ~ 1.30-
1.45 (m, 3H), 1.70-1.94 (m, 7H), 2.54 (s, 3H), 2.80-2.90
(m, lH), 7.34 (d, J=8.5Hz, 2H), 7.42 (m, 3H), 7.55 (d,
J=8.5Hz, 2H), 8.08 (d, J=7.7Hz, 2H). HRMS Calc'd. for
C22H23NOS (M+H): 350.1579. Observed: 350.1597. The
material from this experiment was used directly in the
next step without further purification.
Ste~ 4: Pre~aration o~ 4-(c~clohexvl)-5-r4-
(methylsulfonvl)~henvll-2-~henyloxazole
A solution o~ 38 mg (0.11 mmol) of 2-phenyl-4-
(cyclohexyl)-5-[4-(methythio)phenyl]oxazole in 4 mL of
methylene chloride was stirred at -78~C as 75 mg (0.22
mmol based on 50% purity) of m-chloroperoxybenzoic acid
was added all at once. The reaction was stirred at
-78~C for 1 hour. Thin-layer chromatography (TLC)
(silica, 50% hexane/ethyl acetate) indicated the
reaction mixture consisted of mostly sulfone. The
reaction was poured into a solution of aqueous sodium
metabisulfite. The a~ueous solution was extracted using
ethyl acetate and the organic layer was washed with
saturated sodium metabisulfite, saturated sodium
bicarbonate ~nd brine. The resulting clear solution was
dried over sodium sulfate and concentrated in vacuo to
give a white solid which was purified by crystallization
from 50% dichloromethane/isooctane gave 26 mg (62%) of
pure product, whose structure was assigned as 4-
(cyclohexyl)-5-[4-(methylsulfonyl)phenyl]-2-
phenyloxazole on the basis of its spectralcharacteristics: mp 231~C. lH-NMR (CDC13, 300 MHz) ~
1.34-1.43 (m, 3H), 1.72-1.95 ~m, 7H), 2.84 (m, lH), 3.10
(s, 3H), 7.47 (m, 3H), 7.82 (d, J=8Hz, 2H), 8.03 (d,
J=8Hz, 2H), 8.10 (m, 2H). . LRMS m/z 382 (M)+. HRMS
Calcld. for C22H23NO3S: 382.1477. Observed: 382.1436.-
Analysis Calc~d. for C22H23NO3S: C, 69.27; H, 6.08; N,
3.67. Observed: C, 68.99i H, 6.07; N, 3.63.
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E~AMPI-E 2 6
F ~ N OH
~ 0
o~
~0
4-(4-Fluorophenyl)-2-(hydroxymethyl)-5-[4-
(~ethylsulfonyl)phenyl~oxazole
To a solution cont~ining 5.0 g (11.4 mmol) of 2-
benzyloxymethyl-4-(4-fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]oxazole (prepared in ~xample 24)
in 20 mL of 50 % THF-methanol, was added 100 mg of 10%
Pd on charcoal in a Fisher-Porter bottle. The reaction
vessel was evacuated and then charged with hydrogen at
50 psi for 24 hours. The Pd on carbon was removed by
filtration through diatomaceous earth and the filtrate
concentrated in vacuo to give 3.8 g (97 %) of a white
crystalline solid (mp 156-157~C) (recrystallized from
50% ethyl acetate/isooctane) whose structure was
assigned as 4-(4-fluorophenyl)-2-hydroxymethyl-5-[4-
(methylsulfonyl)phenyl]oxazole on the basis of its
spectral characteristics: lH-NMR (CDCl3, 300 MHz) ~ 3.07
(s, 3H), 3.21 (bs, lH), 4.81 (s, 2H), 7.10 (t, 2H, J=8.5
Hz), 7.56 (m, 2H), 7.72 (d, 2H, J=8.8 Hz) and 7.90 (d,
2H, J=8.8 Hz). 19F-NMR (CDC13, 280 MHz) ~ -111.5. LRMS
m/z 348 (M + H)+. HRMS Calc'd. for C17H14NO4FS:
348.0706. Observed: 348.0681. Analysis Calc'd. for
C17H14NO4FS: C:, 58.78; H, 4.06; N, 4.03. Observed: C,
58.67; H, 4.02; N, 4.01.
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EXAMPL.E 2 7
,~7 ~>~
CH302S
4-(4-Fluorophenyl)-2-(2-hydroxyethyl)-5-[4-
(methyl~ulfonyl)phenyl]oxazole
4-(4-Fluorophenyl)-2-(2-hydroxyethyl) -5- [4-
(methylsulfonyl)phenyl]oxazole was prepared in a manner
consistent with that described in Example 20. The m/z
362 (M+H)+ was consistent with the assigned structure.
EXAMPLE 2 8
~S~
~0
4-(4-Fluorophenyl)-5-~4-(methylsul~onyl)phenyl]-
2-phenoxymethyloxazole
A solution containing 1.69 g (4.87 mmol) of 4-(4-
fluorophenyl)-2-hydroxymethyl-5-[4-
(methylsulfonyl)phenyl]oxazole (Example 26) in 100 mL ofmethylene c~loride was stirred at 25~C as 1.36 mL (9.74
mmol) of triethylamine was added dropwise, followed by
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91
the addition of 560 uL (7.30 mmol) of methanesulfonyl
chloride. The reaction was stirred ~or 20 minutes,
after which the organic solution was washed with lN HCl,
dried over sodium sulfate and concentrated in vacuo to
give methyl [4-(4-fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]oxazol-2-yl]methanesulfonate as a
yellow oil which was characterized as the expected
mesylate by its NMR spectrum: 1H-MMR (CDCl3, 400 MHz)
3.08 (s, 3H), 3.17 (s, 3H), 5.37 (s, 2H), 7.12 (t, 2H,
J=8.8 Hz), 7.58 (m, 2H), 7.78 (d, 2H, J=8.8 Hz) and 7.94
(d, 2H, J=8.8 Hz). This material was used without
further puri~'ication. A solution containing 544 mg
(1.28 mmol) of methyl [4-(4-fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]oxazol-2-yl]methanesulfonate in
20 mL of DMF was stirred at 25~C as 353 mg (2.56 mmol)
o~ potassium carbonate and 240 mg (2.56 mmol) of phenol
were added. The reaction was stirred for 2 days at 25~C
and poured into 100 mL of water. To this mixture was
added 100 mL of ethyl acetate and the layers separated.
The organic layer was washed with water, dried over
sodium sulfate and concentrated in vacuo to give a crude
beige solid which was purified by flash chromatography
on a silica gel column using 25% ethyl acetate/hexane as
the eluent to give 475 mg (88~) of a white solid which
was recrystallized from 50% ethyl acetate/isooctane to
give a white crystalline solid (mp 168-169~C) whose
structure was assigned as 4-(4-fluorophenyl)-5-[4-
(methylsulfonyl)-phenyl]-2-phenoxymethyloxazole on the
basis of its spectral characteristics: 1H-NMR (CDC13,
300 MXz) ~ 3.07 (s, 3H), 5.23 (s, 2H), 6.98 (m, 5H),
7.33 (t, 2H, J=8.2 Hz), 7.60 (m, 2H), 7.77 (d, 2H, J=8.5
Hz) and 7.92 (d, 2H, J=8.5 Hz). 19F-NMR (CDC13, 280 MHz)
-111.9. Analysis calc. for C23H1gNO4FS- C: 65.24, H:
4.28, 3.31. Observed- C: 65.10, H: 4.29, N: 3.28.
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EXAMPLE 2 9
~ N ~ O ~ N
~3~/
4-(4-Fluorophenyl)-5-[4-(methyl~ulfonyl)phenyl]-
2-(pyridyloxymethyl)oxazole
4-(4-Fluorophenyl)-5-[4- (methylsulfonyl)phenyl] -2-
(pyridyloxyni~thyl)oxazole was prepared in a manner
consistent with Example 28. Melting point: 276-278~C.
EXAMPLE 3 0
~ ~ ~ Cl
~0
2-(3-Chlorophenoxymethyl)-4-(4-fluorophenyl)-5-
~4-(methylsul~onyl)phenyl~oxazole
A solution containing 612 mg (1.44 mmol) of methyl
20 [4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-
2-yl]methanesulfonate (as prepared in Example 28) in 20
CA 0222l692 lgg7-ll-l9
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93
mL of DMF was stirred at 25~C as 397 mg (2. 88 mmol) of
potassium carbonate and 0.3 mL (2.88 mmol) of 3-
" chlorophenol were added. The reaction was stirred for 2
_ days at 25~C and poured into 100 mL of water. To this
5 mixture was added 100 mL of ethyl acetate and the layers
separated. The organic layer was washed with water,
dried over sodium sul~ate and concentrated in vacuo to
give the crude solid which was purified by flash
chromatography on a silica gel column using 50% ethyl
acetate/hexa~le as the eluent to give 528 mg (80%) of a
white solid which was recrystallized from 50%
dichloromethane/isooctane to give a white crystalline
solid (mp 112-114~C) whose structure was assigned as 4-
(4-fluorophenyl)- 5 - [4 - (methylsulfonyl)phenyl]-2 - (3 -
chlorophenoxy)methyloxazole on the basis of its spectral
characteristics: lH-NMR (CDCl3, 300 MHz) ~ 3.08 (s, 3H),
5.22 (s, 2H), 7.08 (m, 2H), 7.13 (m, 3H), 7.26 (m, lH),
7.59 (dd, 2H, J=8.8, 5.4 Hz), 7.62 (dd, 2H, J=8.8, 5.4
Hz), 7.78 (d, 2H, J=8.8 Hz), 7.93 (d, 2H, J=8.8 Hz).
20 19F-NMR (CDCl3, 280 MHz) ~ -111.8. Analysis Calc~d. for
C23H17NO4FSCl: C, 60.33; H, 3.74; N, 3.06. Observed:
C, 60.19; H, 3 80; N, 3.03.
EXAMPLE 3 1
O
4-(4-Fluorophenyl)-2-(4-~luorophenoxymethyl)-5-
[4-(methyl~ulfonyl)phenyl]oxazole
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A solution containing 585 mg (1.37 mmol) of methyl
[4- (4- fluorophenyl)- 5 - [4 - ( methylsulfonyl)phenyl]oxazol-
2-yl]methanesulfonate (as prepared in Example 28) in 15
5 mL of DMF was stirred at 25~C as 380 mg (2.74 mmol) of
potassium carbonate and 308 mg (2.74 mmol) of 4-
fluorophenol are added. The reaction was stirred for 2
days at 25~C and poured into 100 mL of water. To this
mixture was added 100 mL of ethyl acetate and the layers
separated. The organic layer was washed with water,
dried over sodium sulfate and concentrated n vacuo to
give the crude solid which was purified by flash
chromatography on a silica gel column using 50% ethyl
acetate/hexane as the eluent to yive 528 mg (80%) of a
15 white solid which was recrystallized from 50%
dichloromethdne/isooctane to give a white crystalline
solid (mp 133-134~C) whose structure was assigned as 4-
(4-fluorophenyl) -5- [4- (methylsulfonyl)-phenyl] -2- [ (4-
~luorophenoxy)methyl]oxazole on the basis of its
20 spectral characteristics: lH-NMR (CDC13, 300 MHz) ~ 3.08
(s, 3H), 5.19 (s, 2H), 7.00 (m, 4H), 7.13 (m, 2H), 7.58
(dd, 2H, J=8.8, 5.2 Hz), 7.61 (dd, 2H, J=8.8, 5.2 Hz),
7.77 (d, 2H, J=8.7 Hz), 7.93 (d, 2H, J=8.7 Hz) . 19F-NMR
(CDC13, 280 MHz) ~ -111.8, -122.5. Analysis Calc'd. for
25 C23H17NO~F2S: C, 62.58i H, 3.88; N, 3.17. Observed: C,
62.44; H, 4.04; N, 3.11.
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EXAMPI.E 3 2
F
~ N
~~--~
2- (Cyclohexylethyl)-4-(4-:Eluorophenyl)-5-~4-
(methylsul~onyl)phenyl]oxazole
A solution containing 2.02 g (7.24 mmol) of 1-(4-
fluorophenyl)-2-hydroxy-2-[4-(methylthiophenyl?ethanone
in 100 mL of methylene chloride was stirred at 25~C as
1.76 mL (21.72 mmol) of pyridine was added, followed by
the addition o~ 1.52 g (8.69 mmol) of 2-
cyclohexylpropionyl chloride. The reaction was stirred
at 25~C for 48 hours, after which the resulting yellow
solution was washed with lN HCl, dried over sodium
sulfate and concentrated in vacuo. The crude solid was
purified via flash chromatography on a silica gel column
using 10 % ethyl acetate/hexane as the eluent. This
provided 2.87 g (96 %) of a white foam, which was
characterized as the benzoin ester on the basis of its
N~R spectra: lH-NMR (CDCl3, 300 MHz) ~ 0.80-0.96 (m,
2H), 1.10-1.25 (m, 4H), 1.45-1.78 (m, 7H), 2.40 (m, 2H),
2.43 (s, 3H), 6.75 (s, lH), 7.05 (m, 2H), 7.23 (d, 2H,
J=8 Hz), 7.35 (d, 2H, J=8 Hz) and 7.95 (m, 2H). 19F-NMR
(CDCl3, 280 MHz) ~ -104.4.
A solution containing 2.87 g (6.92 mmol) of the
benzoin ester and 5.3 g (69 mmol) of ammonium acetate in
100 mL of acetic acid was heated to 80~C for 2 hours.
The reactioIJ was cooled to 25~C and poured into water.
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The product was extracted into ethyl acetate and the
combined organic extracts washed with an aqueous
solution o~ sodium bicarbonate. The solution was dried
over sodium sulfate and concentrated in vacuo to give
the crude oxazole. This crude material was purified by
flash chromatography on a silica gel column using 25%
ethyl acetate/hexane as the eluent to give 1.87 g (68%)
of a clear oil, which was characterized as 2-(2-
cyclohexylethyl)-4-(4-fluorophenyl)-5-[4-
(methythio)phenyl]oxazole on the basis of its spectralproperties: lH-NMR (CDCl3, 400 MXz) ~ 0.90-1.02 (m,
2H), 1.10-1.40 (m, 4H), 1.62-1.82 (m, 7H), 2.49 (s, 3~),
2.84 (t, J=8.0 Hz, 2H), 7.03 (d, J-8.7Hz, lH), 7.06 (d,
J=8.7Hz, lH), 7.22 (d, J=8.6Hz, 2H), 7.45 (d, J=8.6Hz,
2H), 7.58 (d, J=5.4Hz, lH), 7.61 (d, J=5.4Hz, lH). The
material from this experiment was used directly in the
next step without further purification.
A solution of 1.87g (4.73 mmol) of 2-(2-
cyclohexylethyl)-4-(4-fluorophenyl)-5-[4-
(methythio)phenyl]oxazole in 100 m~ of methylenechloride was stirred at -78~C as 3.26 g (9.46 mmol based
on 50% purity) of m-chloroperoxybenzoic acid was added
all at once. The reaction was stirred at -78~C for 1
hour and TLC (silica, 50% hexane/ethyl acetate)
indicated that the reaction mixture consisted of mostly
sulfone. The reaction was poured into a solution of
aqueous sodium metabisulfite. The a~ueous solution was
extracted uslng ethyl acetate and the organic layer was
washed with saturated sodium metabisulfite, saturated
sodium bicarbonate and brine. The resulting clear
solution was dried over sodium sulfate and concentrated
in vacuo to give a white solid which was purified by
flash chromatography on a silica gel column using 50%
ethyl acetate/hexane as the eluent. Recrystallization
from 50% ethyl acetate/isooctane gave 1.76 g (87%) of a
low melting semi-solid whose structure was assigned as
2-(2-cyclohexylethyl)-4-(4-fluorophenyl)-5-[4-
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(methylsulfonyl)phenyl]oxazole on the basis of its
spectral characteristics: lH-NMR (CDC13, 300 MHZ) ~
0.90-1.06 (m, 2H), 1.11-1.40 (m, 7H), 2.87 (apparent t,
J=8.1HZ, 2H), 3.07 (S, 3H), 7.10 (t, J=8.7Hz, 2H), 7.59
(m, 2H), 7.'J (d, J=8.7Hz, 2H), 7.90 (d, J=8.7Hz, 2H).
19F-NMR (CDCl3, 280 ~z) ~ -112.49. LRMS m/z 427 (M)+.
HRMS Calc'd. for C24H26NO3FS: 421.1617. Observed:
421.1611. Analysis Calc'd. for C24H26NO3FS: C, 67. 43;
H, 6 .13; N, 3 . 28. Observed: c, 67.27; H, 6.15i N,
10 3 . 24 .
EXAMPLE 3 3
~~ >
~o~
Ethyl 2-t4-(4-~luorophenyl)-5-t4-(methylsul~onyl)
phenyl]-2-oxazolyl]-2-benzyl-acetate
Ste~ 1: Pre~aration of 2- (4-fluoro~henvl) -3- (4-
20 methvlthio~henvl)~ro~enoic acid
Acetic anhydride (500 mL), 4-
(methylthio)benzaldehyde (100.2 g, 0.66 mol), 4-
fluorophenylacetic acid (101.6 g, 0.66 mol), and
triethylamine (68.1 g, 0.67 mol) were placed in a 3 L
round bottom flask and heated to reflux for 1.75 hours.
The reaction was cooled to 110~C, and water (500 mL) was
added cauti~,_sly through an addition funnel. This
caused the solution to reflux vigorously and the
temperature to rise to 13 5~C. A yellow precipitate
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formed, and after cooling to room temperature, was
collected by filtration, washed with water, and
recrystallized from ethyl acetate/isooctane to provide
the diarylacrylic acid as yellow needles (135.2 g, 71%):
mp 172-176~C. lH NMR (acetone d6) 300 MHz 7.84 (s, lH),
7.03-7.28 (m, lOH), 2.46 (s, 3H). 19F MMR (acetone d6)
-116.11 (m). Mass spectrum M+ 288.
Step 2: Pre~aration of 1-(4-fluorophenyl)-2-(4-
methylthiophenyl)ethanone
The di~ryl acrylic acid (226.5 g, 0.78 mol) was
placed in a 2 L round bottom ~lask with anhydrous
toluene (800 mL) and triethylamine (81.2 g, 0.80 mol~.
After cooling to 0~C, diphenylphosphoryl azide (217.4 g,
0.79 mol) was added, the solution was stirred at 0~C for
20 minutes and at room temperature for 2.50 hours. The
reaction was poured into water, extracted with ether,
dried over maynesium sulfate, and concentrated in vacuo
to remove the ether. The r~m~ining toluene solution was
heated to reflux and a vigorous evolution of gas
occurred. After 1.25 hours, tert-butyl alcohol (80 mL,
0.84 mol) was added to the reaction. After an
additional 20 minutes, concentrated hydrochloric acid
(41 mL) was added slowly causing the reaction to foam.
The reaction was heated at 90~C overnight (14 hours) and
a white precipitate formed after cooling. The
precipitate was isolated by filtration, washed with cold
ether, and air dried to yield the desired intermediate
(182.7 g, 89%): mp 134.5-138~C. lH NMR (acetone d6) 300
MHz 8.16 (m, 2H), 7.24 (m, 6H), 4.34 (s, 2H), 2.46 (s,
3H). 19F NMR (acetone d6) -107.88 (m).
Ste~ 3: Preparation of 1-(4-fluoro~henvl)-2-(4-
methvlthiophenyl)-2-hydroxy-ethanone
A 1 L three necked round bottomed flask equipped
with reflux condenser, magnetic stir bar, thermometer
adapter, and constant pressure addition funnel was
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charged with the intermediate from Step 2, (55.5 g, 0.21
mol), acetic acid (250 mL) and 33% HBr in acetic acid
(120 mL). The solution was stirred and treated with
bromine (11.1 rnL, O.21 mol) from the addition funnel at
such a rate that the bromine color was discharged
rapidly, ca. 15 minutes. After an additional 10 minutes
at room temperature, the solution was filtered through a
Buchner funnel and the filtrate concentrated in vacuo to
give an orange solid. The crude bromoketone was
dissolved in dichloromethane and washed with lN NaHSO3,
dried over anhydrous MgS04, filtered and concentrated in
vacuo to give 68.8 g of 1-(4-fluorophenyl)-2-(4-
methylthiophenyl)-2-bromoethanone as a yellow solid
which was used directly without further purification.
The crude bromoketone was dissolved in 300 mL acetone
and 150 mL of water and heated to reflux for 2.5 hours.
~he solu~lon was concentrated in vacuo and the residue
taken up in dichloromethane, washed with saturated
aqueous sodi~lm bicarbonate, brine, dried over anhydrous
magnesium sulfate, ~iltered and reconcentrated n vacuo
to give a light yellow solid that was crystallized from
a mixture of dichloromethane and isooctane to provide
37.8 g (65%) of pure 1-(4-fluorophenyl)-2-(4-
methylthiophenyl)-2-hydroxy-ethanone: mp 90-92 ~C.
Step 4: Pre~aration of ethyl 2-r4-(4-fluorophenvl)-5-
r 4-methvlthio)phenylll-2-oxazoleacetate
A solution containing 8.00 g (29 mmol) of 1-(4-
fluorophenyl)-2-hydroxy-2-[4-(methylthiophenyl)ethanone
in 100 mL of methylene chloride was stirred at 25~C as
7.0 mL (31 mmol) of pyridine was added, ~ollowed by the
addition of 4.5 mL (35 mmol) of ethyl malonyl chloride.
The reaction was stirred at 25~C ~or 48 hours, after
which the r~~ulting yellow solution was washed with lN
c 35 HCl, dried over sodium sulfate and concentrated in
vacuo. The crude solid was purified via flash
chromatography on a silica gel column using 109~ ethyl
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100
acetate/hexane as the eluent. This provided 7.31 g
(64%) of a white foam, which was used directly without
further purification. The product from above (7.31 g,
18.7 mmol) and 7.2 g of ammonium acetate (93.5 mmol, 5
equivalents) in 50 mL of glacial acetic were heated to
reflux for 2 hours. The reaction mixture was cooled to
25~C and poured into 100 mL of water. The aqueous
solution was extracted with ethyl acetate and the
combined organic extracts were washed with water and
sodium bicarbonate solution, dried over sodium sulfate
and concentrated in vacuo. The crude solid was purified
by flash chl.-matography using a silica gel column and
20% ethyl acetate/hexane as the eluent to give a white
solid which was recrystallized from 50% ethyl
acetate/isooctane to give 5.55 g (80%) of a white solid
whose structure was assigned as ethyl 2-[4-(4-
fluorophenyl)-5-[4-methylthio)phenyl]oxazol-2-yl]acetate
and was judged suitable for taking onto the next step.
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Ste~ 5: Pre~aration of ethvl 2- r4- (4-fluoro~henvl)-5-
r4-methvlsulfonvl)~henvll-2-oxazolvll-2-benzvl-acetate
~ A solution of 755 mg (2.03 mmol) of ethyl 2-[4-(4-
- fluorophenyl)-5-[4-methylthio)phenyl]oxazol-2-yl]acetate
(from Step 4) was dissolved in 20 mL of anhydrous
tetrahydrofuran (THF) and cooled to -78~C and treated
with a solution o~ potassium bid(trimethylsilyl)amide
(2.44 mL. 1.2 equivalents, lM in THF via syringe. The
solution was maintained at -78~C for 15 minutes and
treated with a solution of 290 uL (2.44 mmol) of benzyl
bromide. The solution was warmed to room temperature
and poured into a saturated aqueous solution of ammonium
chloride The aqueous solution was extracted with ethyl
acetate, washed with brine, dried over anhydrous sodium
sulfate, filtered and concentrated in vacuo to give an
oil that was purified by flash chromatography on silica
gel eluting with 10% ethyl acetate/hexane to provide 396
mg of the d clkylated product and 182 mg (19~) of ethyl
2-[4-(4-fluorophenyl)-5-[4-methylthio)phenyl]oxazol-2-
yl]-1-benzyl-acetate that was used directly in the next
step. A solution of 182 mg (0.344 mmol) of ethyl 2-[4-
(4-fluorophenyl)-5-[4-methylthio)phenyl]oxazol-2-yl]-1-
benzyl-acetate in 5 mL of dichloromethane was cooled to
-78~C and treated with 272 mg (2 equivalents) of m-
chloroperoxybenzoic acid for 2 hours. The reaction waspoured into a solution of aqueous sodium metabisulfite.
The aqueous solution was extracted using ethyl acetate
and the organic layer was washed with saturated sodium
metabisulfite, saturated sodium bicarbonate and brine.
The resulting clear solution was dried over sodium
sulfate and concentrated in vacuo to give a transparent
oil which was purified by flash chromatography on a
silica gel (~lumn using 30% ethyl acetate/hexane as the
eluent. The purified material was an oil whose
structure was assigned as ethyl 2-[4-(4-fluorophenyl)-5-
[4-methylsulfonyl)phenyl]oxazol-2-yl]-2-benzyl-acetate
on the basis of its spectral characteristics: 1H-NMR
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102
(CDCl3, 300 MHz) ~ 1.20 (t, J= 7.0Hz, 3H), 3.07 (s, 3H),
3.53 (m, 2H), 4.19 (~, J= 7.0Hz, 2H), 4.23 (m, lH), 7.10
(d, J= 8.7Hz, 2H), 7.25 (m, 5H), 7.57 (m, 2H), 7.70 (d, J=
8.7Hz, 2H), 7.90 (d, J= 8.7Hz, 2H). 19F-NMR (CDCl3, 280
~Hz) ~ -112.15. LRMS m/z 493 (M)+. HRMS Calc'd. ~or
C27H24NosFS: 493.1359. Observed: 493.1371.
EXAMPLE 3 4
O~ "0
H2N ' ~
~N O
~0 OC H2C H3
H3C 0
F
Bthyl [4-(4-amino 8U 1 fonylphenyl)-5-(3-fluoro-4-
methoxyphenyl)]-2-oxazole]acetate
Ste~ 1. Pre~ar~tion of 2-hydroxy-2-(3-fluoro-4-
methoxy~henYl)-1-~henvlethanone
A solution of 3-fluoro-para-anisaldehyde (25.00 g, 162
mmol) and zinc iodide (0.27 g) in dichloromethane (100 mL)
was treated with a solution of trimethylsilylcyanide (22 mL,
165 mmol) in dichloromethane (20 mL). The solution was
stirred ~or 0.4 hours at room temperature, washed with
saturated NaHCO3, dried over Mg~04, and concentrated in vacuo
to give the trimethylsilyl cyanohydrin as an orange oil
(37.83 g). The trimethylsilyl-cyanohydrin was dissolved in
diethyl ether (50 mL) and added dropwise to a solution of
phenylmagnesium bromide (174 mmol) in diethyl ether (658 mL)
while maintaining the tempera~ure between 25-35 ~C with an
ice water bath. The reaction was stirred for 0.4 hours at
room temperature then ~uenched by adding 3N HCl. The
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103
reaction mixture was extracted with ethyl acetate, washed
with saturated NaHCO3 and brine, dried over MgSO4, and
concentrated in vacuo to give an orange oil (39.57 g). The
orange oil was dissolved in 9:1 trifluoroacetic acid/water
(80 mL) and stirred for 1.4 hours at room temperature. The
reaction was neutralized with solid sodium carbonate,
extracted with ethyl acetate, washed with 10% Na2CO3 and
brine, dried over MgSO4, and concentrated in vacuo to give a
brown solid which was recrystallized from diethyl
ether/hexane to give the benzoin (13.87 g, 33%): mp 76-79 ~C.
lH NMR (CDCl3) 300 MHz ~ 7.89 (d, J=7.3 Hz, 2H) 7.55 (m, lH)
7.42 (m, 2H) 7.05 (m, 2H) 6.90 (m, lH) 5.88 (br d, J=3.0 Hz,
lH) 4.50 (br d, lH). 19F NMR (CDCl3) 282 MHz -134.05 (m).
Ste~ 2 Esterification of 2-hYdroxv-2-(3-fluoro-4-
methoxv~henYl)-1-~henYlethanone
A solution of benzoin from Step 1 (3.25 g, 12.5 mmol),
pyridine (4.94 g, 62.5 mmol), and etnyl malonyl chlor~ide
(2 38 g, 15.8 mmol) in dichloromethane (20 mL) was stirred
for 94 hours at room temperature. The reaction mixture was
washed with 3N HCl, saturated NaHCO3 and water, dried over
MgSO4, concentrated in vacuo and passed through a column of
silica gel eluting with 25% ethyl acetate/hexane to give a
yellow oil (1.93 g, 41%): 1H NMR (CDCl3) 300 MHz ~ 7.89 (d,
J=7.7 Hz, 2H) 7.53 (m, lH) 7.41 (m, 2H) 7.16 (m, 2H) 6.92 (m,
lH) 6.84 (s, lH) 4.50 (~, J=7.0 Hz, 2H) 3.85 (d, J=1.0 Hz,
3H) 3.52 (s, 2H) 1.25 (t, J=7.0 Hz, 3H). 19F MMR (CDCl3) 282
MHz -133.67 (m). Mass spectrum: M+Li=381.
Ste~ 3. Pre~aration of ethvl r4-~hen~1-5-(3-fluoro-4
methoxv~henvl)l-2-oxazoleacetate.
The ketone from the Step 2 (1.83 g, 4.9 mmol) was
dissolved in acetic acid (25 mL), treated with ammonium
acetate (3.86 g, 50.0 mmol), and heated to reflux for 2.0
hours. The reaction mixture was diluted with ethyl acetate,
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104
washed with water, saturated NaHCO3, and brine, dried over
MgSO4, concentrated in vacuo, and passed through a column o~
silica gel eluting with 16~ ethyl acetate/hexane to give a
yellow solid (0.67 g, 39%): mp 85-86 ~C. 1H NMR (CDCl3) 300
MHz ~ 7.61 (d, J=7.5 Hz, 2H) 7.35 (m, SH) 6.93 (m, lH) 4.24
(q, J=7.1 Hz, 2H) 3.93 (s, 2H) 3.91 (s, 3H) 1.30 (t, J=7.1
Hz, 3H). 19F NMR (CDCl3) 282 MHz ~ 134.77 (m). High
resolution mass spectrum Calc~d. for C20H1gFNO4: 356.1298.
Found: 356.1303.
Ste~ 4. Pre~aration of ethvl ~4-(4-aminosulfonvl~henvl)-5-
(3-fluoro-4-methox~henvl)l-2-oxazoleacetate
The compound from Step 3 (0.63 g, 1.8 mmol) was stirred
with chlorosul~onic acid (15 mL) for 1.1 hours at 5 ~C. The
reaction mixture was slowly added to ice water, and extracted
with dichloromethane. The dichloromethane solution was
stirred at 5 ~C with ammonium hydroxide for 3.0 hours. The
organic layer was collected, washed with 3N HCl, dried over
MgSO4, concentrated in vacuo, and the residue recrystallized
from ethyl acetate/hexane to give a white solid (0.02 g,
2.6%): mp 127-130 ~C. 1H MMR (acetone-d6) 300 ~Hz ~ 7.90 (d,
J=8.7 Hz, 2H) 7.84 (d, J=8.7 Hz, 2H) 7.38 (m, 2H) 7.26 (m,
lH) 6.64 (br s, lH) 4.20 (q, J=7.0 Hz, 2H) 4.01 (s, 2H) 3.95
(s, 3H) 1.27 (t, J=7.0 Hz, 3H). 19F NMR (acetone-d6) 282 MHz
-135.76 (m). High resolution mass spectrum Calc~d. for
C20H2oFlN2c6sl: 435.1026. Found: 435.1036.
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105
EXAMPI.E 3 5
O~ ,p
H2N ~
~ ~ OH
[4-(4-Aminosul~onylphenyl)-5-cyclohexyl]-2-
oxazoleacetic acid
Step 1. Preparation of 2-hydroxy-2-cyclohexvl-1-
phenvlethanone
A solution of cyclohexanecarboxaldehyde (8.5 g, 76 mmol)
and zinc iodide (0.11 g) in dichloromethane (40 mL) was
treated with a solution of trimethylsilylcyanide (10 mL, 76
mmol) in dichloromethane (20 mL). The solution was stirred
for 0.33 hours at room temperature, washed with water and
saturated NaHCO3, dried over MgSO4, and concentrated in vacuo
to give the trimethylsilyl cyanohydrin as an orange oil
(13.02 g). The trimethylsilyl cyanohydrin was dissolved in
diethyl ether (50 mL) and added dropwise to a solution of
phenylmagnesium bromide (54 mmol) in diethyl ether (268 mL)
while maintaining the temperature between 25-35 ~C with an
ice water bath. The reaction was stirred for 0.67 hours at
room temperature then quenched by adding 3N HCl (60 mL). The
organic layer was collected, washed with saturated NaHCO3 and
brine, dried over MgSO4, and concentrated in vacuo to give a
white solid (12.96 g). The white solid was dissolved in 9:1
trifluoroacetic acid/water (50 mL) and stirred for 2.0 hours
at room temperature. The reaction was neutralized with solid
sodium carbonate, extracted with ethyl acetate, washed with
saturated Na~CO3 and brine, dried over MgSO4, concentrated in
.,
CA 02221692 1997-11-19
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106
~acuo and recrystallized ~rom diethyl ether/hexane to give
the benzoin (2.55 g, 25%): mp 87-92 ~C. 1H NMR (CDCl3) 300
MHz ~ 7.88 (d, J=7.1 Hz, 2H) 7.62 (m, lH) 7.50 (m, 2X) 4.93
(d, J=2.2 Hz lH) 3.60 (br s, lH) 1.52-1.82 (m, 6H) 1.02 1.24
(m, 5H). Mass spectrum: M+Li=225.
Ste~ 2 Esteri~ication of 2-hvdroxv-2-cvclohexvl-1-
~henvlethanone
The ethanone o~ Step 1 (2.55 g, 11.7 mmol) was dissolved
in THF (10 mL), 2,2-dimethyl-1,3-dioxane-4,6-dione (1.73 g,
12.0 mmol) ~dS added and the reaction was heated to reflux
for 17.3 hours. The reaction mixture was partitioned between
saturated NaHCO3 and diethyl ether. The aqueous layer was
acidified with concentrated HCl, extracted with diethyl
ether, washed with brine, dried over MgSO4, and concentrated
in vacuo to give a yellow oil (2.26 g) which was used in the
next step without further purification.
Ste~ 3. Pre~aration of 2-carboxvmethvl-4-hvdroxv-4-~henvl-5-
cvclohexvloxazoline
The ethanone ~rom the Step 2 (1.87 g, 6.1 mmol) was
dissolved in ethanol (20 mL), treated with ammonium acetate
(4.94 g,16.3 mmol), and heated to re~lux for 4.3 hours. The
reaction mixture was concentrated in vacuo, and the residue
was partitioned between saturated NaHCO3 and ethyl acetate.
The aqueous layer was acidi~ied with 3N HCl, extracted with
diethyl ether, washed with brine, dried over MgSO4, and
concentrated in vacuo dissolved in ethyl acetate, washed with
water, saturated NaHCO3, and brine, dried over MgSO4, and
concentrated in vacuo to give a white solid (0.75 g, 43%): mp
151-155 ~C dec. Mass spectrum: M~Li=310.
Ste~ 4. Pre~aration of ~4-(4-aminosulfonYl~henvl)-5-
cvclohexvll-2-oxazoleacetic acid
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The compound from Step 3 (0.47 g, 1.6 mmol) was stirred
with chlorosulfonic acid (2.5 mL) for 1.25 hours at 5 ~C.
The reaction mixture was slowly added to ice water, and
ex~racted with dichloromethane. The dichloromethane was
r 5 stirred at room temperature with ammonium hydroxide (20 mL)
for 23.1 hours. The aqueous layer was collected, acidified
with concentrated HCl, and filtered to give a white solid
(0.17 g, 28%): mp 223-230 ~C. lH NMR (acetone-d6) 300 MHz
7.95 (d, 2H) 7.85 (d, 2H) 6.60 (br s, 2H) 3.90 (s, 2H) 3.20
(m, lH) 1.20-1.95 (m, lOH). High resolution mass spectrum
Calc d- for C17H21N2~5S: 365-1171 Found: 365.1187.
EXA.MPIIE 3 6
H2N'S' ~OH
O' 'O
[5-(4-Aminosul~onylphenyl)-4-(4-chlorophenyl)]-2-
oxazoleacetic acid
Ste~ 1 Pre~aration of 2-hydroxy-2-phenvl-1-(4-
chloro~henyl)ethanone
The trimethylsilyl cyanohydrin of benzaldehyde, prepared
similar to that described in Example 34, Step 1, (10.18 g, 50
mmol) was dissolved in diethyl ether (10 mL) and added
dropwise to a solution of 4-chlorophenylmagnesium bromide (59
mmol) in diethyl ether (319 mL) while maintaining the
temperature between 23-35 ~C with an ice water bath. The
reaction was stirred for 1.2 hours at room temperature then
~uenched by adding 3N HCl (50 m~). The organic layer was
collected, washed with saturated NaHCO3 and brine, dried over
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MgSO4, and concentrated in vacuo to give a yellow oil (15.57
g). The yellow oil was dissolved in 9:1 trifluoroacetic
acid/water (30 mL) and stirred for 1.75 hours at room
temperature. The reaction was neutralized with solid sodium
carbonate, extracted with ethyl acetate, washed with 10%
Na2CO3 and brine, dried over MgSO4, concentrated in vacuo and
recrystallized from diethyl ether/hexane to give the benzoin
(5.76 g, 47%): mp 87-92 ~C.
Ste~ 2. Esterification of 2-hvdroxY-2-~henvl-1-(4-
chloro~henvl)ethanone
The ethanone from Step 1 (4.28 g,17.3 mmol) was
dissolved in THF (15 mL), 2,2 dimethyl-1,3-dioxane-4,6-dione
(2.52 g, 17.5 mmol) was added and the reaction heated to
reflux for 15.7 hours. The reaction mixture was partitioned
between saturated NaHCO3 and diethyl ether. The aqueous
layer was acidified with concentrated HCl, extracted with
diethyl ether, washed with brine, dried over MgSO4, and
concentrated in vacuo to give a yellow oil (4.55 g) which was
used in the next step without further purification: Mass
spectrum: M+Li=339.
Ste~ 3 Pre~aration of r4-(4-chloro~henvl)-5-~henvll-2-
oxazoleacetic acid
The ester from Step 2 (4.69 g, 14.1 mmol) was dissolved
in ethanol (20 mL), treated with ammonium acetate (10.87 g,
141.0 mmol), and heated to reflux for 4.75 hours. The
ethanol was removed in vacuo and the residue was dissolved in
water, acidified with 3N HCl, precipitated with diethyl ether
and hexane and filtered to give an orange solid (2.71 g,
61%): mp 158-160 ~C. lH MMR (DMSO-d6) 300 MHz ~ 14.8 (br s,
lH) 7.48 (m, 9H) 4.19 (s, 2H).
Ste~ 4. Pre~aration of r5-(4-aminosulfonvl~henvl)-4-(4-
chloro~henvl)l-2-oxazoleacetic acid
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The compound from Step 3 (1.71g, 5.4 mmol) was stirred
wi~h chlorosulfonic acid (7 mL) ~or 1.25 hours at 5 ~C. The
reaction mixture was added to ice water, and extracted with
~ dichloromethane. The dichloromethane was stirred with
ammonium hydroxide (30 mL) for 1.2 hours at room temperature.
The a~ueous layer was collected and acidified with
concentrated HCl, extracted with ethyl acetate, dried over
MgSO4, and concentrated in vacuo to give a white solid (0.11
g, 5%): 1H NMR (DMSO-d6) 300 MXz ~ 13.5 (br s, lH) 7.81 (d,
J=~.5 Hz, 2H) 7.62 (d, J=8.3 HZ, 2H) 7.47 (m, 6H) 3.90 (s,
2H).
EX;~MPLE 3 7
0~ "0
C I ~O~O H
[4-(4-Aminosulfonylphenyl)-5-(4-chlorophenyl)]-2-
oxazoleacetic acid
Ste~ 1. Pre~aration of 2-hvdroxY-2-(4-chloro~henvl)-1-
~henvlethanone.
A solution o~ 4-chlorobenzaldehyde (9. 86 g, 70 mmol) and
zinc iodide (0.18 g) in dichloromethane (40 mL) was treated
with a solution of trimethylsilylcyanide (9 mL, 71 mmol) in
dichloromethane (20 mL). The solution was stirred for 0.33
hours at room temperature, washed with water and saturated
NaHCO3, dried over MgSO4, and concentrated in vacuo to give
the trimethylsilyl cyanohydrin as an orange oil (13.90 g) .
> The trimethylsilyl cyanohydrin was dissolved in diethyl ether
~ 30 (50 mL) and added dropwise to a solution of phenylmagnesium
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bromide (69 mmol) in diethyl ether (269 mL) while maintaining
the temperature between 15-28 ~C with an ice water bath. The
reaction was stirred for 0.75 hours at room temperature then
quenched by adding 3N HCl (50 mL). The organic layer was
collected, washed with saturated NaHCO3 and brine, dried over
MgSO4, and concentrated in vacuo to give a yellow solid
(13.06 g). The yellow solid was dissolved in 9:1
trifluoroacetic acid/water (30 mL) and stirred for 1.6 hours
at room temperature. The reaction was neutralized with solid
sodium carboL-ate, extracted with ethyl acetate, washed with
10% Na2CO3 and brine, dried over MgSO4, concentrated in vacuo
to give a yellow solid (9.43 g) and used in the next step
without further purification.
Ste~ 2. Esterification of 2-hvdroxv-2-(4-chloro~henvl)-1-
Dhenvlethanone
The ethanone from Step 1 (4.34 g,17.6 mmol) was
dissolved in THF (40 mL), 2,2 dimethyl-1,3-dioxane-4,6-dione
(2.56 g, 17.8 mmol) was added and the reaction heated to
reflux for 18.3 hours. The reaction mixture was partitioned
between saturated NaHCO3 and diethyl ether. The aqueous
layer was acidified with concentrated HCl, extracted with
diethyl ether, washed with brine, dried over MgSO4, and
concentrated in vacuo to give a yellow oil (4.66 g, 68%): lH
NMR (CDC13) 300 MHz ~ 7.89 (d, J=8.5 Hz, 2H) 7.54 (m, lH) 7.35
(m, 6H) 6.90 (s, lH) 3.59 (s, 2H). Mass spectrum M+Li=339.
Ste~ 3. Pre~aration of r5-(4-chloro~henYl)-4-~henvll-2-
oxazoleacetic acid
The ester from Step 2 (2.88 g, 12.4 mmol) was dissolved
in ethanol (20 mL), treated with ammonium acetate (6.74 g,
87.4 mmol), and heated to reflux for 4.1 hours. The reaction
mixture was concentrated in vacuo, and the residue was
partitioned between water and diethyl ether. The aqueous
layer was acidified with 3N HCl, allowed stand at room
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temperature then filtered to give a white solid (0.75 g,
28%): mp 212.5-219 ~C. Mass spectrum: M+=313.
~ Ste~ 4. Pre~aration of r4-(4-aminosulfonYl~henYl)-5-(4-
chloro~henYl)l-2-oxazoleacetic acid
The compound from Step 3 (0.71 g, 2.3 mmol) was stirred
with chlorosulfonic acid (7 mL) at 5 ~C for 1.0 hour. The
reaction mixture was added to ice water, and extracted with
dichloromethane. The dichloromethane was stirred with
ammonium hydroxide for 1.3 hours at room temperature. The
aqueous layer was collected and acidified with concentrated
HC1, extracted with ethyl acetate, dried over MgSO4, and
concentrated in vacuo to give a white solid (0.18 g, 20~): mp
118-120 ~C (dec). lH NMR (DMSO-d6) 300 MHz ~ 7.86 (d, J=8.3
Hz, 2H) 7.66 (d, J=8.5 Hz, 2H) 7.56 (m, 4H) 4.15 (s, 2H).
EXAMPLE 3 8
~N o
H2N~SJ~ O H
o' 'o
[5-(4-Aminosulfonylphenyl)-4-phenyl]-2-oxazoleacetic
acid
SteD 1. Esterification of benzoin
Benzoin (33.32 g, 157 mmol) was dissolved in THF (65
mL), 2,2-dimethyl-1,3-dioxane-4,6-dione (22.85 g, 159 mmol)
was added and the reaction heated to reflux for 22.6 hours.
The reaction mixture was partitioned between saturated NaHCO3
and ethyl acetate. The aqueous layer was acidified with
concentrated HC1, extracted with diethyl ether, dried over
"
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MgS04, and concentrated in vacuo to give a yellow oil (35.08
g) which was used in the next step without further
purification.
Ste~ 2. Preparation of eth~l r4-hvdroxY-4,5-di~henvl-2-
oxazolinvllacetate.
The compound ~rom Step 1 (2.26 g, 7.6 mmol) was
dissolved in methanol (25 mL), treated with ammonium acetate
(1.26 g,l6.3 mmol), and heated to reflux. After 1.8 hours,
the reaction was cooled, acidified by adding concentrated
sulfuric acid and heated to reflux for an addi~ional 2.0
hours. The reaction mixture was concentrated in vacuo, and
the residue was dissolved in ethyl acetate, washed with
water, saturated NaHC03, and brine, dried over MgS04, and
concentrated in vacuo to give an orange oil (1.50 g) which
was used in the next step without further purification.
Ste~ 3. Pre~aration of ethvl r5-(4-aminosulfonvl~henvl)-4-
~henvll-2-oxazoleacetate.
The compound from Step 2 (1.32 g, 4.2 mmol) was stirred
with chlorosulfonic acid (13 mL) for 1.25 hours at 5 ~C. The
reaction mixture was slowly added to ice water, and extracted
with dichloromethane. The dichloromethane was stirred with
ammonium hydroxide (40 m~) for 1.9 hours at 5 ~C. The
organic layer was collected, washed with 3N HCl, dried over
MgS04, concen~rated in vacuo, and passed through a column of
silica gel eluting with 40% ethyl acetate/hexane to give a
white solid (0.30 g, 19~): mp 84-88 ~C. 1H NMR (aceto~e-d6)
300 MHz ~ 7.92 (d, J=8.5 Hz, 2H) 7.77 (d, ~=8.5 Hz, 2H) 7.63
(m, 2H) 7.41 (m, 3H) 6.71 (br s, 2H) 4.06 (s, 2H) 3.74 (s,
3H). High resolution mass spectrum Calc~d. for ClgH17N20sS:
373.0858. Found: 373.0833.
Ste~ 4. Pre~aration of ~5-(4-aminosul~onvl~henvl)-4-~henvll-
2-oxazoleacetic acid
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The ox~zole ester from Step 3 ( O . 65 g, 1 . 7 mmol) was
dissolved in methanol (10 mL), treated with NaOH (0.09 g
dissolved in 5 mL water, 2.2 mmol), and stirred at room
temperature. After 0. 33 hours, additional NaOH (0.10 g, 2 . 5
mmol) was added and stirring continued for 0. 4 hours. Water
was added and the reaction mixture was extracted with ethyl
acetate. The aqueous layer was acidified with concentrated
HCl and extracted with ethyl acetate. The ethyl acetate was
washed with brine, dried over MgSO4, and concentrated in
0 vacuo to give a yellow solid (0.43 g, 69%): mp 134-137 ~C
(dec). 1H NMR (acetone-d6) 300 MHz ~ 7.92 (d, J=8.5 Hz, 2H)
7.78 (d, J=8.7 Hz, 2H) 7.64 (m, 2H) 7.42 (m, 3H) 6.68 (br s,
lH) 4.03 (s, 2H). High resolution mass spectrum Calc'd. for
C17H15N2O5S: 359.0702. Found: 359.0722.
EXAMPI,E 3 9
o~ "~
H2N ~
N o
~ O ~ OH
F
Cl
~ 4-(4-Aminosulfonylphenyl)-5-(3-chloro-4-
fluorophenyl)]-2-oxazoleacetic acid
Ste~ 1 Pre~aration of 2-hYdroxv-2-(3-chloro-4-
fluoro~henvl)-l-~henvlethanone.
A solu~ion of 3-chloro-4-fluorobenzaldehyde (14.00 g, 89
mmol) and zinc iodide (0.16 g) in dichloromethane (50 mL) was
treated with a solution of trimethylsilylcyanide (12 mL, 90
mmol) in dichloromethane (15 mL). The solution was stirred
for 0.5 hours at room temperature, washed with saturated
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NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo
to give the trimethylsilyl cyanohydrin as an orange oil
(20.18 g). The trimethylsilyl cyanohydrin was dissolved in
diethyl ether (20 mL) and added dropwise to a solution of
phenylmagnesium bromide (90 mmol) in diethyl ether (200 mL)
while maintaining the temperature between 25-33 ~C with an
ice water bath. The reaction was stirred for 0.6 hours at
room tempera-ure then quenched by adding 3M HCl (90 mL). The
organic layer was collected, washed with saturated NaHCO3 and
brine, dried over MgSO4, and concentrated in vacuo to give
the an orange oil (24.13 g). The orange oil was dissolved in
9:1 trifluoroacetic acid/water (100 mL) and stirred for 1.5
hours at room temperature. The reaction was neutralized with
solid sodium carbonate, extracted with diethyl ether, washed
with saturated NaHCO3 and brine, dried over MgSO4, and
concentrated in vacuo to give a brown solid which was
recrystallized from diethyl ether/hexane to give the benzoin
(9.78 g, 41%): mp 58-63 ~C. lH NMR (CDC13) 300 MHz ~ 7.88 (d,
J=7.0 Hz, 2H) 7.57 (m, lH) 7.44 (m, 3H) 7.20 (m, lH) 7.08 (t,
J=8.7 Hz, lH) 5.92 (s, lH) 4.60 (br s, lH). 19F NMR (CDCl3)
282 MHz -115.88 (m).
Ste~ 2. Esterification of 2-hvdroxy-2-(3-chloro-4-
fluoro~henvl)ethanone
The ketone from Step 1 (5.54 g, 20.9 mmol) was dissolved
in THF (5 mL), 2,2 dimethyl-1,3-dioxane-4,6-dione (4.65 g,
32.2 mmol) was added and the reaction heated to reflux for
17.2 hours. The reaction mixture was partitioned between
saturated NaHCO3 and diethyl ether. The aqueous layer was
acidified with concentrated HCl, extracted with diethyl
ether, washed with brine, dried over MgSO4, and concentrated
in vacuo to give a brown oil (6.94 g) which was used in the
next step without further purification.
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Ste~ 3. Pre~aration of methvl r5-(3-chloro-4-fluoro~henYl)-
4-hvdroxv-4-~henvl-2-oxazolinvllacetate.
A solution of the ester ~rom Step 2 (6.86 g, 19.6 mmol)
~ dissolved in methanol (11 mL) was treated with ammonium
v 5 acetate (3.17 g, 41.1 mmol), and heated to reflux. After 1.9
hours, the reaction was cooled, additional methanol (65 mL)
was added, and the reaction mixture was acidified ~y adding
concentrated sulfuric acid and heated to reflux for an
additional 1.4 hours. The reaction mixture was concentrated
10 in vacuo, and the residue was dissolved in ethyl acetate,
washed with water, saturated NaHCO3, and brine, dried over
MgSO4, concentrated in vacuo, and passed through a column of
silica gel eluting with 50% ethyl acetate/hexane to give a
yellow oil (2.10 g, 29%): lH NMR (acetone-d6) 300 MHz ~ 8.30
15 (br s, lH) 8.18 (dd, J=7.3 Hz 2 2 Hz, lH) 8.12 (m, lH) 7.30-
7.50 (m, 6H) 6.60 (d, J= 6.8 Hz, lE) 3.65 (s, 3H) 3.41 (s,
2H). 19F N~ (acetone-d6) 282 MHz -109.78 (m). Mass
spectrum: M+Li=370.
Ste~ 4. Pre~aration of methyl r4-(4-aminosulfon~l~henvl)-5-
(3-chloro-4-fluoro~henvl)l-2-oxazoleacetate
The compound from Step 3 (2.05 g, 5.6 mmol) was stirred
with chlorosulfonic acid (10 mL) for 0.33 hours at room
temperature and then for 0.25 hours at 75 ~C. The reaction
was cooled, slowly added to ice water, and extracted with
dichloromethane. The dichloromethane layer was stirred with
ammonium hydroxide for one hour at room temperature. The
organic layer was concentrated in vacuo, dissolved in ethyl
acetate, washed with 3N HCl, brine, dried over MgSO4,
concentrated in vacuo and recrystallized from ethyl
acetate/hexane to give a white solid (0.58 g, 24%): mp 142-
144 ~C. 1H NMR (acetone-d6) 300 MHz ~ 7.92 (d, J=8.5 Hz, 2H)
7.85 (d, J=8.7 Hz, 2H) 7.78 (dd, J=7.1 Hz 2.2 Hz, lH) 7.62
(m, lH) 7.44 (t, J=8.8 Hz, lH) 6.66 (br s, lH) 4.06 (s, 2H)
3.75 (s, 3H). 19F NMR (acetone-d6) 282 MHz -115.94 (m).
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High resolution mass spectrum Calc'd. for C18H15ClFN2~5S:
425.0374. Found: 425.0379.
Ste~ 5. Pre~aration of r4-(4-aminosulfonvl~henvl)-5-(3-
chloro-4-fluoro~henvl)l-2-oxazoleacetic acid
The ester from Step 4 ~0.55 g, 1.3 mmol) was dissolved
in methanol (10 mL), treated with NaOH (0.09 g dissolved in 5
mL water, 2.2 mmol), and stirred at room temperature. After
1 hour, additional NaOH (0.10 g, 2.5 mmol) was added and
stirring was continued for 1.4 hours. Water was added and
the reaction mixture was extracted with ethyl acetate. The
aqueous layer was then acidified with concentrated HC1 and
extracted with ethyl acetate. The ethyl acetate was washed
with brine, dried over MgSO4, and concentrated in vacuo to
give a white solid (0.39 g, 74%): mp 222-223 ~C. 1H NMR
(acetone-d6) 300 MXz ~ 7.92 (d, J=8.5 Hz, 2H) 7.85 (d, J=8.6
Hz, 2H) 7.79 (dd, J=7.0 Hz 2.2 Hz, lX) 7.62 (m, lH) 7.44 (t,
J=8.9 Hz, lH) 6.67 (br s, lH) 4.04 (s, 2H). 19F NMR
(acetone-d6) 282 MHz -116.41 (m).
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EXAMPI.E 4 0
o~ ,P
.. ~
~4- (4-Aminosul:Eonylphenyl)-5-(3,4-aichlorophenyl)]-2-
oxazoleacetic acid
Ste~ 1. Pre~aration of 2-hYdroxv-2-(3,4-dichloro~henvl)-1-
~henvlethanone.
A solution of 3,4-dichlorobenzaldehyde ~25.35 g, 145
mmol) and zinc iodide (0.42 g) in dichloromethane (100 mL)
was treated with a solution of trimethylsilylcyanide (20 mL,
150 mmol) in dichloromethane (25 mL). The solution was
stirred for 0.33 hours at room temperature, washed with
saturated NaHCO3 and brine, dried over MgSO4, and
concentrated in vaCuo to give the trimethylsilyl cyanohydrin
as an orange oil (36.79 g). The trimethylsilyl cyanohydrin
was dissolved in diethyl ether (50 mL) and added dropwise to
a solution of phenylmagnesium bromide (144 mmol) in diethyl
ether (500 mL) while maintaining the temperature between 25-
33 ~C with an ice water bath. The reaction was allowed to
stir for 1.8 hours at room temperature then quenched by
adding 3N HCl (160 mL). The organic layer was collected,
washed with saturated NaHCO3 and brine, dried over MgSO4, and
concentrated in vacuo to give an orange oil (49.07g). The
orange oil was dissolved in 9:1 trifluoroacetic acid/water
(100 mL) and stirred for 1.5 hours at room temperature. The
reaction was neutralized with solid sodium carbonate,
extracted with diethyl ether, washed with brine, dried over
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MgSO4, and concentrated in vacuo to give a yellow solid which
was recrystallized from ethyl acetate/iso-octane to give the
benzoin (16.35 g, 37~): mp 68-71 ~C. 1H NMR (CDC13) 300 MHz
7.88 (d, J=7.5 Hz, 2H) 7.57 (m, lH) 7.44 (m, 3H) 7.37 (d,
J=8.3 Hz, lH) 7.07 (dd, J=8.3 Hz 2.0 Hz, lH) 5.92 (s, lH)
4.60 (br s, lH).
Ste~ 2. Esterification of 2-hYdroxv-2-(3,4-dichloro~henYl)-
1-~henvlethanone
The ketone from Step 1 (7.43 g, 26.4 mmol) was dissolved
in THF (8 mL), 2,2-dimethyl-1,3 dioxane-4,6-dione (5.92 g,
41.1 mmol) ~'.dS added and the reaction heated to reflux for
19.9 hours. The reaction mixture was partitioned between
saturated NaHC03 and diethyl ether. The aqueous layer was
acidified with concentrated HCl, extracted with diethyl
ether, washed with brine, dried over MgSO4, and concentrated
in vacuo to give a brown oil (6.67 g) which was used in the
next step without further purification.
Ste~ 3. Pre~aration of meth~l r5-(3,4-dichloro~henvl)-4-
hvdroxv-4-~henYl-2-oxazolinvllacetate
The ester from Step 2 (6.67 g, 18.2 mmol) was dissolved
in methanol (10 mL), treated with ammonium acetate (2.90 g,
37.6 mmol), and heated to reflux. After 2.0 hours, the
reaction was cooled, additional methanol (50 mL) was added,
and the reaction mixture was acidified by adding concentrated
sulfuric acid and heated to re~lux for an additional 0.6
hours. The reaction mixture was concentrated in vacuo, and
the residue was dissolved in ethyl acetate, washed with
water, saturated NaHCO3, and brine, dried over MgSO4, and
concentrated in vacuo to give an orange oil (4.38 g) which
was used in the next step without further purification.
Ste~ 4. Pre~aration of methvl r4-(4-aminosulfonvl~henvl)-5-
(3,4-dichloro~henvl)l-2-oxazoleacetate.
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The compound from Step 3 (4.32 g,ll.4 mmol) was stirred
with chlorosulfonic acid (13 mL) for 0.4 hours at room
temperature and then for 0.6 hours at 75 ~C. The reaction
was cooled, slowly added to ice water, and extracted with
dichloromethane. The dichloromethane was stirred with
ammonium hydloxide (20 mL) for 1.1 hours at room temperature.
The organic layer was concentrated in vacuo, dissolved in
ethyl acetate, washed with 3N HCl, brine, dried over MgSO4,
concentrated in vacuo, passed through a column of silica gel
eluting with 50% ethyl acetate/hexane, and recrystallized
from ethyl acetate/hexane to give a tan solid (1.20g, 24%):
mp 144-153 ~C. lH NMR (acetone-d6) 300 MHz 7.94 (d, J=8.5
Hz, 2H) 7.86 (d, J=8.3 Hz, 2H) 7.80 (d, J=1.8 Hz, lH) 7.67
(d, J=8.3 Hz, lH) 7.60 (dd, J=8.5 Hz 2.0 Hz, lH) 6.67 (br s,
lH) 4.07 (s, 2H) 3.75 (s, 3H). High resolution mass spectrum
Calc'd. for ClgHlsCl2N2OsS: 441.0079. Found: 441.0088.
Ste~ 5. Pre~aration of ~4-(4-aminosulfonYl~henvl)-5-(3,4-
dichloro~henvl)l-2-oxazoleacetic acid.
The oxazole ester from Step 4 (0.35 g, 0.8 mmol) was
dissolved in methanol (10 mL), treated with NaOH (0.07 g
dissolved in 5 mL water, 1.8 mmol), and stirred at room
temperature. After 1.1 hours, additional NaOH (0.10 g, 2.5
mmol) was added and stirring continued for 1.4 hours. Water
was added and the reaction mixture was extracted with ethyl
acetate. The aqueous layer was then acidified with
concentrated HCl and extracted with ethyl acetate. The ethyl
acetate was washed with brine, dried over MgSO4, and
concentrated in vacuo to give a yellow solid (0.33 g, 97%):
mp 204-209 ~C. 1H MMR (acetone-d6) 300 MHz ~ 7.94 (d, J=8.9
Hz, 2H) 7.87 (d, J=8.7 Hz, 2H) 7.82 (d, J=2.0 Hz, lH) 7.67
(d, J=8.3 Hz, lH) 7.60 (dd, J=8.5 Hz 2.2 Hz, lH) 6.68 (br s,
lH) 4.05 (s, 2H).
-
" 35 EXAMPI,E 41
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0~ ,P
~ ~ OH
[4-(4-Amino 8U l fonylphenyl-5-(3,4-difluorophenyl)]-2-
oxazoleacetic acid
Ste~ 1. Pre~aration of 2-hvdroxv-2-(3,4-difluoro~henvl)-1-
~henvlethanc,l~e.
A solution of 3,4-difluorobenzaldehyde (25.33 g, 178
mmol) and zinc iodide (0.13 g) in dichloromethane (100 mL)
was treated with a solution of trimethylsilylcyanide (24.5
mL, 184 mmol) in dichloromethane (20 mL). The solution was
stirred for 0.25 hours at room temperature, washed with
saturated NaHCO3 and brine, dried over MgSO4 and
concentrated in vacuo to give the trimethylsilyl cyanohydrin
as a yellow oil (41.03 g). The trimethylsilyl cyanohydrin
was dissolved in diethyl ether (50 mL) and added dropwise to
a solution of phenylmagnesium bromide (186 mmol) in diethyl
ether (560 mL) while maintaining the temperature between 25-
33 ~C with an ice water bath. The reaction was stirred for
0.5 hours at room temperature then quenched by adding 3N HCl
(150 mL). The organic layer was collected, washed withsaturated Na~CO3 and brine, dried over MgSO4, and
concentrated in vacuo to give an orange oil (49.71g). The
orange oil was dissolved in 9:1 trifluoroacetic acid/water
(100 mL) and stirred for 0.5 hours at room temperature. The
reaction was neutralized with solid sodium carbonate,
extracted with ethyl acetate, washed with brine, dried over
MgSO4, and concentrated in vacuo to give a brown solid which
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was recrystallized from diethyl ether/hexane to give the
benzoin (16.35 g, 37%): mp 68-71 ~C. 1H NMR (CDC13) 300 MHz
7.87 (d, J=7.1 Hz, 2~) 7.56 (m, lH) 7.42 (m, 2H) 7.07 (m, 3H)
5.92 (s, lH) 4.40 (br S, 1H) 19F NMR (CDC13) 282 MHz
-136.37 (m) -137.70 (m). Mass spectrum: M+Li=255.
Ste~ 2 Esterification of 2-hvdroxv-2-(3,4-difluoro~henvl)-
1-~henYlethanone
The ethanone from Step 1 (5.93 g, 23.9 mmol) was
dissolved in T~F (6 mL), 2,2-dimethyl-1,3-dioxane-4,6-dione
(3.70 g, 25.7 mmol) was added and the reaction heated to
reflux for 23.7 hours. Additional 2,2-dimethyl-1,3-dioxane-
4, 6-dione (1. 4 6 g, 10.1 mmol) was added and the reaction was
stirred at reflux an additional 19.7 hours. The reaction
mixture was partitioned between saturated NaHCO3 and diethyl
ether. The aqueous layer was acidified with concentrated
HC1, extracted with diethyl ether, washed with brine, dried
over MgSO4, and concentrated in vaCUo to give a yellow oil
(6.05 g) which was used in the next step without further
purification.
Ste~ 3 Pre~aration of methvl r5-(3,4-difluoro~henvl)-4-
hvdroxY-4-~henyl-2-oxazolinYllacetate
The ester from Step 2 (6.03 g, 18.0 mmol) was dissolved
in methanol (10 mL), treated with ~mmn~ium acetate (3.07 g,
39.8 mmol), and heated to reflux. After 2.4 hours, the
reaction was cooled, additional methanol (60 mL) was added,
and the reaction mixture was acidified by adding concentrated
sulfuric acid and heated to reflux for an additional 1.9
hours. The reaction mixture was concentrated in vacuo, and
the residue was dissolved in ethyl acetate, washed with
water, saturated NaHCO3, and brine, dried over MgSO4, and
concentrated in vacuo to give an orange oil (4.64 g, 74%)
which was used in the next step without further purification.
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Ste~ 4. Pre~aration of methYl-r4-(4-aminosulfonvl~henvl)-5-
(3,4-difluoro~henvl)l-2-oxazoleacetate.
The oxazoline from Step 3 (3.34 g, 9.6 mmol) was stirred
with chlorosulfonic acid (13 mL) for 0.4 hours at room
temperature and then for 0.75 hours at 75 %C. The reaction
was cooled, slowly added to ice water, and extracted with
dichloromethane. The dichloromethane was stirred at room
temperature with ammonium hydroxide (20 mL) for 1.1 hours.
The organic layer was concentrated in vacuo, dissolved in
ethyl acetate, washed with 3N HCl, brine, dried over MgSO4,
concentrated in vacuo, passed through a column of silica gel
eluting with 45% ethyl acetate/hexane, and recrystallized
from ethyl acetate/hexane to give a yellow solid (0.71 g,
27%): mp 144-149 ~C. lH NMR (acetone-d6) 300 MHz ~ 7.92 (d,
J=8.7 Hz, 2H; 7.84 (d, J=8.5 Hz, 2H) 7.58 (m, lH) 7.47 (m,
2H) 6.67 (br s, lH) 4.06 (s, 2H) 3.75 (s, 3H). 19F NMR
(acetone-d6) 282 MXz -138.46 (m) -138.79 (m). High
resolution mass spectrum Calc'd. for C18H15F2N2O5S:
409.0670. Found: 409.0686.
Ste~ 5. Pre~aration of ~4-(4-aminosulfonvl~henvl-5-(3,4-
difluoro~henvl)1-2-oxazoleacetate.
The oxazole ester from Step 4 (0.64 g, 1.3 mmol) was
dissolved in methanol (10 mL), treated with NaOH (0.07 g
dissolved in 5 mL water, 1.8 mmol), and stirred at room
temperature. After one hour, additional NaOH (0.11 g, 2.8
mmol) was added and stirring continued for 1.4 hours. Water
was added and the reaction mixture was extracted with ethyl
acetate. The a~ueous layer was acidified with concentrated
HCl and extracted with ethyl acetate. The ethyl acetate was
washed with Drine, dried over MgSO4, and concentrated in
vacuo to give a white solid (0.49 g, 80%): mp 223-227 ~C. lH
NMR (acetone-d6) 300 MHz ~ 7.92 (d, J=8.7 Hz, 2H) 7.85 (d,
J=8.7 Hz, 2H) 7.58 (m, lH) 7.48 (m, 2H) 6.66 (br s, lH) 4.04
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(s, 2H). 19F NMR (acetone-d6) 282 MXz -138.97 (m) -139.24
(m).
EXAMPI.E 4 2
O~ "0
H2N' ~
N
~ ~ CF3
F~ ~
F
[2-Trifluoromethyl-5-(3,4-difluorophenyl)-4-
oxazolyl]benzenesulfonamide
Ste~ 1 Pre~aration of 3-trifluoromethvl-4-~henvl-5-(3,4-
difluoro~henvl)oxazole.
A solution of 2-hydroxy-2-(3,4-difluorophenyl)-1-
phenylethanone (Example 41, Step 1) (3.48 g, 14.0 mmol) in
dimethylformamide (DMF) (15 mL) was added to a solution of
trifluoroacetonitrile (1.85 g, 19.5 mmol) in DMF (150 m~).
The reaction was cooled to 5 ~C, treated with 1,8-
diazabicyclo[5.4.0]undecane (DBU) (2.31 g, 15.2 mmol), and
stirred for L5.3 hours at room temperature and 3.5 hours at
90 ~C. The reaction mixture was diluted with ethyl acetate,
washed with 3N HCl, saturated MaHCO3, brine, dried over
MgSO4, concentrated in vacuo, and passed through a column of
silica gel eluting with 10% diethyl ether/hexane to give a
clear oil (2.35 g, 52%): 1H NMR (acetone-d6) 300 MHz ~ 7.66
(m, 3H) 7.47 (m, 5H). 19F MMR (acetone-d6) 282 MHz -67.02
(s) -137.15 (m) -138.58 (m).
Ste~ 2 Pre~aration of 4-~5-(3,4-difluoro~henvl)-2-
~rifluoromethvl-4-oxazolvllbenzenesulfonamide
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3-Trifluoromethyl-4-phenyl-5- (3,4-difluorophenyl)oxazole
from Step 1 (1. 02 g, 3.14 mmol) was stirred with
chlorosulforic acid (9.5 mL) for 0.9 hours at room
temperature and then for 2. 5 hours at 75 C. The reaction
5 was cooled, slowly added to ice water, and extracted with
dichloromethane. The dichloromethane was stirred with
ammonium hydroxide (100 mL) for 14.7 hours at room
temperature. The organic layer was concentrated in vacuo,
dissolved in ethyl acetate, washed with 3N HCl, brine, dried
over MgS04, concentrated in vacuo, and recrystallized from
ethyl acetate/hexane to give a tan solid (0. 87 g, 69~ ): mp
146-148 C lH NMR (acetone-d6) 300 MHz ~ 7.97 (d, J=8.5 HZ,
2H) 7.88 (d, J=8.7 HZ, 2H) 7.71 (m, 1~) 7.58 (m, 2H) 6.70 (br
S, lH) . 19F NMR (acetone-d6) 282 MHZ -67.04 (S) -136.52 (m)
15 -138 .30 (m). High resolution mass spectrum Calc'd. for
C16HloF5N2O3S: 405.0332. Found: 405.0323.
EXAMPLE 4 3
O~
NH2
~-~5-(4-Aminosulfonylphenyl)-4-phenyl]-2-
oxazolepropionic acid
4, 5-Diphenyl-2-oxazolepropionic acid (1.0 g, 34 mmol),
prepared as in U.S. Patent ~ 3,578,671, was added to
chlorosulfonic acid cooled to O ~C (25 mL), and the stirred
solution was warmed to room temperature for 1.0 hour. The
mixture was added dropwise to ice and dichloromethane t50 mL)
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with stirring. The resultant layers were separated, and the
organic layer was washed once with water and added to a 0 ~C
stirred solution of ammonium hydroxide (10 mL). The mix was
J stirred for 1.0 hour and extracted with dichloromethane (3 X
5 50 mL). The combined organic layers were washed with 1 N HCl
followed by brine and water, dried over MgSO4 and
concentrated. The crude product was purified by
recrystallization from ethyl acetate/hexane to afford a white
solid (0.6 g, 47.4%): mp 236-239 ~C. 1H NMR (3MSO-d6) 300
MHz ~ 12.15 (bs, lH) 7.84 (d, J=8.5 Hz, 2H) 7.68 (d, J=8.5 Hz,
2H) 7.4-7.5 (m, 7H) 3.07 (t, J=7.1 Hz, 2H) 2.78 (t, J=7.1 Hz,
2H). Anal. Calc~d. for C18H16N2O5S: C, 58.06; C, 58.22; H,
4.33; H, 4.52; N, 7.52; N, 7.30.
EXAMPLE 4 4
o ~~S~
NH2
4-[4-Phenyl-5-oxazolyl]benzenesul~onamide
Ste~ 1. Pre~aration of 4,5-di~henvloxazole
Benzoin (4.25 g, 20 mmol) was stirred at 0 ~C in
dichloromethane (150 mL) with triethylamine (2.23 g, 22
mmol). Methanesulfonyl chloride (2.52 g, 22 mmol) was added
dropwise. The solution was warmed to room temperature for
1.0 hour. Formamide (10 mL) was added and the mixture was
concentrated to remove dichloromethane. The residue was
heated to 50 ~C overnight, cooled, diluted with ether, washed
with 1 N HC1, brine, water dried over MgSO4, concentrated in
30 vacuo, and passed through a column of silica gel eluting with
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(1:16) ethyl acetate/hexane to give a clear oil (3.1 g, 70
~): 1H NMR (CDC13) 300 MHz 7.96 (s, lH) 7.60-7.70 (m, 4H)
7.31-7.41 (m, 6H). Anal. Calc~d. for C15H11NO-1.5 H2O: C,
80.20; H, 5.10; N, 6.24. Found: C, 80.20; H, 5.07; N, 6.25.
Ste~ 2. Pre~aration of 4-~4-~henvl-5-
oxazolvllbenzenesulfonamide
4,5-Diphenyloxazole from Step 1 (0.5 g, 2.3 mmol) was
added to chlorosulfonic acid cooled to 0 ~C (5 mL), and the
stirred solution was warmed to room temperature for 1.0 hour.
The mixture was added dropwise to ice and dichloromethane (50
mL) with stirring. The resultant layers were separated, and
the organic layer was washed once with water and added to a
0 ~C stirred solution of ammonium hydroxide (10 mL) and
stirred for l.0 hour and extracted with dichloromethane ~3 x
50 mL). The combined organic layers were washed with 1 N HCl
followed by brine and water, dried over MgSO4 and
concentrated. The residue was puri~ied by recrystallization
from ether/hexanes to give a white solid (0.3 g, 44 %) mp
122-125 ~C. lH NMR (acetone-d6) 300 MHz ~ 8.35 (s, lH) 7.88
(d, J=8.7 Hz, 2H) 7.79 (d, J=8.7 Hz, 2H) 7.64-7.70 (m, 2H)
7.40-7.5 (m, 3H) 6.68 (bs, 2H). Anal. Calc'd. for
C15H12N2O3S: C, 59.99i H, 4.03; N, 9.33. Found: C, 60.09;
H, 4.05; N, 9.27.
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EX~MPI,E 4 5
,, ~
~ \~CI
~\\~
O=S
NH2
4-~2-Chloro-4-phenyl-5-oxazolyl]benzene~ul~onamide
Ste~ 1 Pre~aration of 4,5-di~henvloxazolone.
senzoi. (31.8 g, O.lS mol) and urethane (42.79 g, 0.45
mol) were heated to reflux for 3.0 hours. The hot mixture
10 was poured into water (150 mL) Acetone (150 mL) was added
and heat was applied until the mixture dissolved. The
solution was cooled and filtered yielding a white solid which
was used in the next step without further purification: 1H
NMR (DMSO-d6) 300 MHz ~ 7.2-7.5 ~m, llH).
Ste~ 2 Pre~aration of 2-chloro-4,5-di~henYl-oxazole.
4,5-Diphenyloxazolone from Step 1 (30 g, 0.126 mol),
triethylamine (12.8 g, 0.126 mol), and phosphorous
oxychloride (96.6 g, 0.63 mol) were stirred at reflux for 4.0
20 hours. I~he mixture was concentrated in vacuo and dissolved
in ether (250 mL), washed with 1 N HCl, brine, water, dried
over MgSO4 and concentrated to a light yellow oil which was
used in the rext step without further purification or
characterization
Ste~ 3. Pre~aration of 4-r2-chloro-4-~henYl-5-
oxazolYllbenzenesulfonamide.
2-Chloro-4,5-diphenyl-oxazole from Step 2 (1.53 g, 6
mmol) was added to chlorosulfonic acid cooled to 0 ~C (20
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128
mL), and the stirred solution was warmed to room temperature
for 1.0 hour. The mixture was added dropwise to ice and
dichloromethane (50 mL) with stirring. The resultant layers
were separated, and the organic layer was washed once with
water and added to a 0 ~C stirred solution of ammonium
hydroxide (10 mL). The mixture was stirred for 1.0 hour and
extracted wich dichloromethane (3 X 50 mL). The combined
organic layers were washed with 1 N HCl followed by brine and
water, dried over MgSO4 and concentrated. Recrystallization
from ethyl acetate/hexanes gave a white solid (1.5 g, 75 %):
mp 158-159 ~C. 1H NMR (acetone-d6) 300 MHz ~ 7.98 (d, J=8.7
Hz, 2H) 7.78 (d, J=8.7 Hz, 2H) 7.64-7.70 (m, 2H) 7.42-7.5 (m,
3H) 6.72 (bs, 2H). Anal. Calc~d. for C15H11N2O3SCl: C,
53.82; H, 3.31; N, 8.37. Found: C, 53.92; H, 3.32; N, 8.33.
EXAMPLE 4 6
N
SH
o ~\~; C
NH2
4-[2-Mercapto-4-phenyl-5-oxazolyl]benzenesulfonamiae
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 45) (1.67 g, 5 mmol), dimethylsulfoxide (50 mL), and
sodium thiomethoxide (0.70 g, 10 mmol) were stirred at room
temperature for 16.0 hours. The mixture was diluted with
ethyl acetate (100 mL) washed with 1 N HCl, brine, water,
dried over MgSO4 and concentrated. Recrystallization from
ethyl acetate/hexanes gave the product as a brown solid (0.8
g, 48 %): mp 247-249 ~C. 1H NMR (acetone-d6) 300 MHz ~ 12.1
(bs, lH) 7.89 (d, J=8.7 Hz, 2H) 7.62-7.68 (m, 4H) 7.54-7.59
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(m, 3H) 6.7 (bs, 2H). Anal. Calc'd. for C15H12N203S2: C,
54.20; H, 3.64; N, 8.43. Found: C, 54.27; H, 3.68; N, 8.41.
EXAMPLE 4 7
o =~
NH2
4-~2-(3-Chlorophenoxy)-4-phenyl-5-
oxazolyl]benzenesulfonamide
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 45) (1.67 g, 5 mmol), DMF (20 mL), potassium
carbonate (1.38 g, 10 mmol), and 3-chlorophenol (0.64 g, 5
mmol) were stirred at room temperature for 16.0 hours,
diluted with ethyl acetate tlOO mL), washed with 1 N HCl,
brine and water, dried over MgS04 and concentrated. The
residue was dissolved in ethyl acetate/hexanes (1:1) and
filtered through silica The eluant was concentrated and the
residue recrystallized from ethyl acetate/hexanes to afford
the product as a light yellow solid (1.4 g, 66 %): mp 138-140
~C. lH NMR (acetone-d6) 300 MHz ~ 7.92 (d, J=8.9 Hz, 2H) 7.75
(d, J=8.9 Hz, 2H) 7.7 (m, lH) 7.60-7.65 (m, 2H) 7.54-7.56 (m,
2H) 7.38-7.46 (m, 4H) 6.90 (bs, 2H). Anal. Calc~d. for
C21H15N204SC1: C, 59.09; H, 3.54; N, 6.56. Found: C,
59.02; H, 3.55; N, 6.61.
EX;~MPLE 4 8
-
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130
~ ~ ~ OH
NH2
5-(4-Aminosulfonylphenyl)-4-phenyl-2-
oxazolemercaptoacetic acid
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 45) (1.67 g, 5 mmol), DMF (20 mL), sodium hydride
(1.32 g, 5.5 mmol), and mercaptoacetic acid, sodium salt
(0.63 g, 5.5 mmol) were stirred at room temperature for 16.0
hours. The solution was diluted with ethyl acetate (100 mL),
washed with 1 N HCl, brine and water, dried over MgSO4 and
concentrated. The residue was purified by flash column
chromatography eluting with ethyl acetate:methanol:water
(20:10:1) to provide the product as a light yellow solid (0.8
g, 41 %): mp 235-238 ~C. lH NMR (D2O) 300 MHz ~ 7.62 (d,
J=8.7 Hz, 2H) 7.43 (d, J=8.7 Hz, 2H) 7.32 (m, 5H) 3.76 (s,
2H). High resolution mass spectrum Calc~d. for
C17H15N2O5S2: 391.0422. Found: 391.0423.
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EXAMPI,E 4 9
N
~_o>--~ ~CF3
- o$~
NH2
4-[4-Phenyl-2-(2,2,2-trifluoroethoxy-5-
oxazolyl]benzenesulfonamide
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 45) (1.67 g, 5 mmol), DMF (20 mL), potassium
10 carbonate (38 g, 10 mmol), and 2,2,2-tri~luoroethanol (0.75
g, 7.5 mmol) were stirred at room temperature for 16.0 hours.
The solution was diluted with ethyl acetate (100 mL), washed
with 1 N HC1, brine and water, dried over MgSO4 and
concentrated. The residue was dissolved in ethyl
15 acetate/hexanes (1:1) and filtered through silica. The
eluant was concentrated and recrystallized from ethyl
acetate/hexanes to provide the product was a white solid (1. 4
g, 70 %) mp 180-182 ~C . 1H NMR (CDC13) 300 MHz ~ 7.85 (d,
J=8.5 HZ, 2H) 7.65 (d, J=8.5 HZ, 2H) 7.6 (m, 2H) 7. 4 (m, 3H)
20 4.9 (dd, J=8.1 HZ, 2H) 4.85 (bs, 2H) . Anal. Calc~d. for
C17H13N2O4S1F3: C, 51.26; H, 3.29; N, 7.03. Found: C,
51.32; H, 3.30; N, 7.01.
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132
EXAMPI.E 5 0
¢~o\>--SCH3
0=~~~
NH2
4-~2-(Methylthio)-4-phenyl-5-
oxazolyl]benzenesul~onamide
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 45) (1.67 g, 5 mmol), methanol (50 mL), and sodium
thiomethoxide (0.39 g, 5.5 mmol) were stirred a~ room
temperature for 16.0 hours. The solution was concentrated
and dissolved in ethyl acetate (100 mL), washed with 1 N HCl,
brine and water, dried over MgSO4 and concentrated. The
residue was recrystallized from ethyl acetate/hexanes to give
the product was a light yellow solid (1.4 g, 81 %): mp 162-
164 ~C. lH NMR (CDC13) 300 MHz ~ 7.85 (d, J=8.9 Hz, 2H) 7.68
(d, J=8.9 Hz, 2H) 7.6 (m, 2H) 7.4 (m, 3H) 4.85 (bs, 2H) 2.75
(s, 3H). Anal~ Calc'd- for C16H14N2~3S2 C, 55-48; H~
4.07; N, 8.09. Found: C, 55.56; H, 4.10; N, 8.15.
EXAMPLE 5 1
~ >--CH3
O=\SI ~
NH2
4-[2-Methyl-4-phenyl-5-oxazolyl]benzenesulfonamide
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133
Chlorosulfonic acid (25 mL) was cooled to -78 ~C with
stirring and 2-methyl-4,5-diphenyloxazole (Aldrich)(2.0 g,
8.5 mmol) was added, and the stirred solution was warmed to
room temperature for 4.0 hours. The mixture was then added
dropwise to ice and dichloromethane (100 mL) with stirring.
The resultant layers were separated, and the organic layer
was washed once with water and added to a 0 ~C stirred
solution of ammonium hydroxide (20 mL). The solution was
stirred for 1.0 hour and extracted with dichloromethane (3 X
50 mL). The combined organic layers were washed with 1 N HCl
followed by brine and water, dried over MgSO4 and
concentrated. The residue was purified by recrystallization
from ethanol'water to give the product as a white solid (1.6
g, 60 ~): mp 176-178 ~C. 1H NMR (acetone-d6) 300 MHz ~ 7.92
(d, J=8.7 Hz, 2H) 7.74 (d, J=8.7 Hz, 2H) 7.61-7.66 (m, 2H)
7.40-7.48 (m, 3H) 6.68 (bs, 2H) 2.53 (s, 3H). Anal. Calc~d.
~or C16H14N2O3S: C, 61.13; H, 4.49; N, 8.91. Found: C,
60.89; H, 4.53; N, 8.85.
Examp 1 e 5 2
¢~
~xo~cH3
S~
O~ O
2-[5-~(4-Aminosulfonyl)phenyl]-4-
phenyloxazol-2-yl]ethan-2-one
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134
Ste~ 1: Pre~aration of 2- r 5- r ( 4-AminosulfonYl)~henvll-4-
~henvloxazol-2-vll- (2-hvdroxY)ethane
A solution of 2-bromo-2-[(4-aminosulfonyl)phenyl]-1-
phenylethanone (O.5 g, 1.41 mmol) in 3 mL of anhydrous DMFwas added to a suspension of lactic acid sodium salt (0.16 g,
1.41 mmol) in 2 mL of anhydrous DMF, and the reaction mixture
was stirred for 18 h at room temperature. The DM~ was then
removed under vacuum. Ethyl acetate (50 mL) was added to the
concentrated residue, and the mixture was filtered. The
filtrate was concentrated and dried under vacuum. Acetic
acid (5 mL) and ammonium acetate (0.33 g, 4.28 mmol) were
added to this concentrated residue. This reaction mixture
was heated at 100 ~C for 3 h, cooled to room temperature,
and water (100 mL) was added to the cooled reaction mixture.
The aqueous solutio~ was extracted with ethyl acetate (1 x
150 mL). The organic phase was separated and washed with
water (2 x 100 mL), saturated sodium bicarbonate (2 x 100
mL), brine (2 x 100 mL) and dried over magnesium sulfate,
filtered and concentrated. The concentrated residue was
purified by flash chromatography on silica gel eluting with
45% ethyl acetate in hexane to give 0.26 g (57%) of 2-[5-[(4-
aminosulfonyl)-phenyl]-4-phenyl-oxazol-2-yl]-(2-
hydroxy)ethane as a yellow solid. 1H NMR (CDC13/300 MHz)
1.72 (d, 3H, J = 6.60 Hz), 2.69 (d, lH, J = 5.50 Hz), 4.87
(bs, 2H), 5.05-5.13 (m, lH), 7.41-7.43 (m, 3H), 7.56-7.60 (m,
2H), 7.72 (d, 2H, J = 8.40 Hz), 7.89 (d, 2H, J = 8.70 Hz).
HRMS (calcd for C17H16N204S1 345.0909) 345.0896.
Ste~ 2: Pre~aration of 2- r 5- r ( 4-aminosulfonvl)~henY11-4-
~henvloxazol-2-Yllethan-2-one
The 2-[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2-
yl](2-hydroxy)ethane (0.3 g, 0.87 mmol) from Step 1 was
suspended in 15 mL of methylene chloride. Pyridinium
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135
chlorochromate (0.3 g, 1.4 mmol) and molecular sieves (0.4 g)
were added, and the resulting mixture was stirred for 10
minutes at room temperature. Acetone (5 m~) was added, and
the reaction mixture was stirred for 48 h at room
temperature. The reaction mixture was filtered, and the
filtrate was concentrated. The concentrated residue was
crystalized from ethyl acetate and hexane to give 0.11 g
(30~) of 2-[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2-
yl]ethan-2-one as a white solid, m.p. 208.5-210.2 ~C. 1H
NMR(DMSO-d6/300 MHz) 2.65 (s, 3H), 7.45-7.52 (m, 5H), 7.59-
7.62 (m, 2H), 7.78 (d, 2H, J = 8.40 Hz), 7.90 (d, 2H, J =
8.40 HZ). HRMS (calcd. for C17H14N204S1 343.0753) 343.0728.
EXAMPI,E 5 3
~S
--0 CH3
o ~\~
NH2
4-~2-Methyl~ulfinyl)-4-phenyl-5-
oxazolyl]benzenecul~onamide
4-[2-Methylthio-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 50) (0.5 g, 1.44 mmol), ethanol (100 mL), water (50
mL), and Oxone~ (potassium peroxymonosulfate, 0.88 g, 1.44
mmol) were stirred at room temperature for 16.0 hours.
Sodium metabisulfite (5 g) and water (50 mL) were added and
the resulting mixture stirred for 0.25 hours before the
addition of ethyl acetate (200 mL). The organic layer was
separated and washed with brine and water, dried over MgSO4
and concentrated. The residue was purified by flash
chromatography eluting with ethyl acetate:hexanes (1:3). The
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first material collected was concentrated and recrystallized
to yield 4-[2-methylsulfonyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide as a white solid (0.3 g, 55 %):
mp 186-188 ~~. lH MMR (DMSO-d6) 300 MHz ~ 7.92 (d, J=8.5 Hz,
2H) 7.81 (d, J=8.5 Hz, 2H) 7.6 (m, 2H) 7.48 (m, 5H) 3.3 (s,
3H). Anal. Calc~d. for C16H14N2O5S2: C, 50.78; H, 3.73; N,
7.40. Found: C, 50.79; H, 3.72; N, 7.38. The second
material collected was concentrated and recrystallized to
yield 4-[2-methylsulfinyl)-4-phenyl-5-
oxazolyl]benzenesulfonamide as a white solid (0.16 g, 31 %):mp 174-176 ~C. lH NMR (DMSO-d6) 300 MHz ~ 7.9 (d, J=8.5 Hz,
2H) 7.8 (d, J=8.5 Hz, 2H) 7.6 (m, 2H) 7.48 (m, 5H) 3.2 (s,
3H). Anal. Calc'd. for C16H14N2O4S2: C, 53.03; H, 3.89; N,
7.73. Found: C, 53.08; H, 3.85; N, 7.66.
E~AMPLE 5 4
,~>~
NH2
4-~2-(2,3,4,5,6-Pentafluorophenoxy)-4-phenyl-5-
oxazolyl]benzenesulfonamide
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 45) (1.0 g, 3 mmol), DMF (20 mL), potassium
carbonate (0.83 g, 6 mmol), and pentafluorophenol (0.55 g, 3
mmol) were stirred at room temperature for 16.0 hours. The
solution was diluted with ethyl acetate (100 mL), washed with
1 N HCl, brine and water, dried over MgSO4 and concentrated.
The residue was dissolved in ethyl acetate/hexanes (1:1) and
filtered through silica and the eluant concentrated and
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recrystallized from ethyl acetate/hexanes to afford the
product was a white solid (0.4 g, 28 %): mp 146-148 ~C. 1H
NMR (DMSO-d6) 300 MHz ~ 7.88 (d, J=8.5 Hz, 2H) 7.71 (d, J=8.5
Hz, 2H) 7.56 (m, 2H) 7.42-7.48 (m, 5H).
EXAMPI.E 5 5
~ \~OCH3
O=S~~
NH2
4-[2-Methoxy-4-phenyl-5-oxazolyl~benzenesulfonamide
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 45) (1.0 g, 3 mmol), methanol (15 mL), and sodium
methoxide (25 % in methanol) (0.65 g, 6 mmol) were stirred at
room temperature for 16.0 hours. Water was added until
crystals appeared that were isolated by filtration to afford
the desired product as a white solid (0.6 g, 61 %): mp 180-
182 ~C. 1H NMR (DMSO-d6) 300 MHz ~ 7.81 (d, J=8.5 Hz, 2H)
7.62 (d, J=8.5 Hz, 2H) 7.57 (m, 2H) 7.38-7.46 (m, 5H) 4.12
(s, 3H). Anal. Calc~d. for C16H14N2O4S: C, 58.17; H, 4.27;
N, 8.48. Found: C, 58.12; H, 4.31; N, 8.44.
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EXAMPLE 5 6
,,~N~_
NH2
EthY12-~[5-(4-aminOSU1fOnY1PhenY1)-4-PhenY1-2
OXaZO1Y1]OXY]benZOate
4-[2-Chloro-4-phenyl -5 -oxazolyl]benzenesulfonamide
(Example 45) (1.0 g, 3 mmol), DMF (20 mL), potassium
carbonate (0.46 g, 3.3 mmol), and ethyl salicylate (0.55 g,
3.3 mmol) were stirred at room temperature for 16.0 hours,
diluted with ethyl acetate (100 mL), washed with 1 N HCl,
brine and water, dried over MgSO4 and concentrated. The
residue was dissolved in ethyl acetate/hexanes (1:1) and
filtered through silica. The eluant was concetltrated and
recrystallized from ethyl acetate/hexanes to give the product
was a white solid (0.7 g, 50 %): mp 183-184 ~C. 1H N~
(CDC13/CD3OD) 300 MHZ 8.12 (dd, J=1.8 HZ and J=7.8 HZ, lH)
7.86 (d, J=8.5 HZ, 2H) 7.62-7.72 (m, 3H) 7.38-7.54 (m, 7H)
4.35 (dd, J=7.2 HZ, 2H) 1.3 (t, J=7.2 HZ, 3H). Anal.
lc d- for C24H20N2O6S: C, 62.06; H, 4.34; N, 6 03 Found:
C, 61.85; H, 4.37; N, 5.91.
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EXAMPLE 5 7
0=~
NH2
5Ethyl 3-[[5-(4-aminosulfonylphenyl)-4-phenyl-2-
oxazolyl~oxy]benzoate
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesul~onamide
(Example 45) (1.0 g, 3 rnmol), DMF (20 mL), potassium
carbonate (0.46 g, 3.3 mmol), and ethyl 3-hydroxybenzoate
(0.5 5 g, 3.3 mmol) were stirred at room temperature ~or 16.0
hours. The solution was diluted with ethyl acetate (100 m~),
washed with 1 N HCl, brine and water, dried over MgSO4 and
concentrated. The residue was dissolved in ethyl
acetate/hexanes (1~ iltered through silica and the eluant
was concentrated and recrystallized ~rom ethyl
acetate/hexanes to give the product as a white solid (0. 6 g,
43 %): mp 157-158 ~C. lH NMR (CDC13/CF3CO2H) 300 MHz ~ 8.12
(dd, J=1.6 Hz and J=0 6 Hz, lH) 7.94-8.0 (dt, J=l.0 Hz and
20 J=7.8 Hz, lH) 7.89 (d, J=8.7 Hz, 2H) 7.72 (d, J=8.7 Hz, 2H)
7.67 (m, lH) 7.60 (m, 2H) 7.52 (m, lH) 7.4 (m, 3H) 4.56 (s,
2H) 4.4 (q, J=7.1 Hz, 2H) 1.4 (t, J=7.1 HZ, 3H). Anal.
d- ~or C24H20N2O6S: C, 62.06; H, 4.34; N, 6 03 Found:
C, 62.00; H, 4.36; N, 5.95.
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EXAMPLE 5 8
~ >--N~
o=\~
NH2
4-~2-(N,N-Dimethylamino)-4-phenyl-5-
oxazolyl]benzenesulfonamide
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 45) (1.0 g, 3 mmol) and 40 % aqueous dimethylamine
(25 mL) were stirred at room temperature for 16.0 hours,
diluted with ethyl acetate (100 mL), washed with brine and
water, dried over MgSO4 and concentrated. The residue was
recrystallized from ethyl acetate/hexanes to afford the
product as a light yellow/green solid (0.6 g, 58 %): mp 254-
256~C. lH NMR (DMSO-d6) 300 MHz 7.74 (d, J=8.7 Hz, 2H) 7.56
(m, 4H) 7.38-7.46 (m, 3H) 7.33 (bs, 2H) 3.08 (s, 6H). Anal.
alc d- for C17H17N3~3S: C, 57.31; H, 5.21; N, 11.79
Found: C, 57.32; H, 5.23; N, 11.73.
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E~AMPLE 5 9
o~ ,p
H2N-- ~\,
N
\~ CF3
~~
CIJ~
4-~5-(4-Chlorophenyl)-2-tri~luoromethyl-4-
oxazolyl]benzenesulfonamide
~te~ 1. Preparation of 2-hydroxv-2-(4-chloro~henvl)-1-
~henylethanone.
A solution of 4-chlorobenzaldehyde (9.86 g, 70 mmol) and
zinc iodide (0.18 g) in dichloromethane (40 mL) was treated
with a solution of trimethylsilylcyanide (9 mL, 71 mmol) in
dichloromethane (20 mL). The solution was stirred for 0.33
hours at room temperature, washed with water and saturated
NaHCO3, dried over MgSO4 and concentrated in vacuo to give
the trimethylsilyl cyanohydrin as an orange oil (13.90 g).
The trimethylsilyl cyanohydrin was dissolved in diethyl ether
(50 mL) and added dropwise to a solution of phenylmagnesium
bromide (69 mmol) in diethyl ether (269 mL) while maintaining
the temperature between 15-28 ~C with an ice water bath. The
reaction was stirred for 0.75 hours at room temperature then
quenched by adding 3N HCl (50 mL). The organic layer was
collected, washed with saturated NaHCO3 and brine, dried over
MgSO4, and concentrated in vacuo to give a yellow solid
(13.06 g). The yellow solid was dissolved in 9:1
~ trifluoroacetic acid/water (30 mL) and stirred for 1.6 hours
.~
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at room temperature. The reaction was neutralized with solid
sodium carbonate, extracted with ethyl acetate, washed with
10% Na2C03 and brine, dried over MgS04, concentrated in vacuo
to give a yellow solid (9.43 g) and used in the next step
without further purification.
Ste~ 2. Pre~aration of 2-trifluoromethyl-4-~henYl-5-(4-
chloro~henvl)oxazole.
Trifluoroacetonitrile (1.5 g, 15.8 mmol) was bubbled
into DMF (100 mL). This solution was cooled to 0 ~C and 4~-
chlorobenzoin (Example 37, Step 1) (2.5 g, 10 mmol) was
added. DBU (1.83 g, 12 mmol) was added and the solution was
warmed to room temperature for 4 hours. The reaction was
heated to approximately 100 ~C for an additional 4 hours.
The solution was cooled to room temperature, poured into 400
mL lN HCl and extracted with 500 mL ethyl acetate. The
organics were washed consecutively with lN HCl (400 mL),
NaHC03 (saturated) (400 mL) and brine (400 mL), dried over
Na2S04 and concentrated. The residue was purified by silica
gel chromatography eluting with 10% ether in hexane to give a
white solid (2.2 g, 67%): mp 53-53 ~C. Anal. Calc~d. for
C16HgMOClF3: C, 59.37; H, 2.80i N, 4.33. Found: C, 59.35;
H, 2.76; N, 4.25.
Ste~ 3. Pre~aration o~ 4-r2-tri~luoromethvl-5-(4-
chloro~henYl)-4-oxazolvllbenzenesulfonamide.
2-Trifluoromethyl-4-phenyl-5-(4-chlorophenyl)oxazole
(Step 2) (0.9 g, 2.8 mmol) was added to chlorosulfonic acid,
cooled to 0 ~C (25 mL), and the reaction was warmed to room
temperature for 5 hours. The solution was carefully poured
into ice water and extracted with three 75 mL portions of
dichloromethane. The combined organics were washed once with
brine (75 mL) and stirred over ice cold NH40H (125 mL) for 2
hours. The dichloromethane layer was separated, washed
consecutively with lM HCl (2 x 75 mL), NaHC03 (saturated) (75
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mL) and brine (75 mL), dried over Na2S04 and concentrated.
The crude material was crystallized from ethyl acetate/hexane
to yield 4-[5-(4-chlorophenyl)-2-trifluoromethyl-4-
oxazolyl]benzenesulfonamide (0.84 g, 75~): mp 167-168 ~C.
Anal. Calc~d. for C16HloN2O3SClF3: C, 47.71; H, 2.50; N,
6.96. Found: C, 47.62; H, 2.44; N, 6.88.
EXAMPLE 6 0
0~ ~0
H2N ' ~
\ N
~ 3
~~~-~
F
4-~5-(3-Fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-
oxazolyl~benzenesul~onamide
Ste~ 1. Pre~aration of 3-fluoro-p-anisaldehvde silvl
cvanohvdrin.
3-Fluoro-p-anisaldehyde (14.68 g, 95.2 mmol) was
dissolved in anhydrous methylene chloride (300 mL) and ZnI2
(0.4 g) was added. Trimethylsilyl cyanide (12.7 g, 95.2
mmol) and methylene chloride (75 mL) were added dropwise over
10 minutes. The reaction was stirred an additional 20
minutes and separated. The organics were washed
consecutively with water (350 mL), NaHCO3 (saturated) (300
- mL) and brine (300 mL). The methylene chloride was dried
over Na2SO4 and concentrated to yield silyl cyanohydrin
(24.52 g, 100%) which was used without further purification.
,.
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Ste~ 2. Pre~aration of 3'-fluoro-4'-methoxv benzoin.
3-Fluoro-p-anisaldehyde silyl cyanohydrin (from Step 1)
(24.52 g, 96.8 mmol) and diethyl ether (75 mL) added dropwise
to the solution of diethyl ether (250 mL) and phenyl
magnesium bromide (3M in ether, 34 mL) were added at such a
rate that the reaction temperature did not rise above 3Q ~C.
Upon complete addition, the reaction (which now contained a
gummy precipitate) was stirred an additional 15 minutes at
which time lN HC1 (400 mL) was added and the reaction stirred
until all solids were dissolved. The reaction was poured
into a lL separatory funnel and the layers separated. The
organics were washed with NaHC03 (saturated) (400 mL) and
brine (400 mL), dried over Na2SO4 and concentrated to yield a
mixture of benzoin and silyl benzoin. The crude product was
dissolved in 90% TFA (75 mL) and stirred for 15 minutes. The
TFA solution was poured into saturated NaHCO3(aq.). The
benzoin was extracted with ethyl acetate (350 mL) and washed
with NaHCO3 (saturated) (300 mL) and brine (300 mL).
Crystallization of crude benzoin from ether and hexane
yielded a first crop of crystals which were >99% pure (14.9
g): mp 84-85 ~C. Anal. Calc'd. for C15H13O3F: C, 69.22
H, 5.03. Found: C, 69.13; H, 5.07.
Ste~ 3 Pre~aration of 2-trifluoromethyl-4-~henvl-5-(3-
fluoro-4-methoxv~henvl)oxazole.
Trifluoroacetonitrile 0.92 g (9.7 mmol) was added to a
solution of ~MF (100 ml). This solution was cooled to 0 ~C
and 3'-fluoro-4~-methoxy benzoin from Step 2 (2.08 g, 8 mmol)
was added. DBU (1.45 g, 5.7 mmol) was added and the solution
was warmed to room temperature for 4 hours. The reaction was
heated to approximately 100 ~C for an additional 4 hours.
The solution was cooled to room temperature, poured into 400
mL lN HCl and extracted with 500 mL ethyl acetate. The
organics were washed consecutively with lN HCl (gO0 mL),
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NaHCO3 (saturated) (400 mL) and brine (400 mL) dried over
Na2SO4 and concentrated. The crystalline solid residue was
i
recrystallized from ether and hexane to yield analytically
pure oxazole (2.32 g, 86%): mp 75-76 ~C. Anal. Calc~d. for
C17H11NO2F4: C, 60.54; H, 3.29; N, 4.15. Found: C, 60.62;
~ H, 3.30; M, 4.18.
Ste~ 4. Pre~aration of 4-r5-(3-fluoro-4-methoxyphenvl)-2-
trifluoromethyl-4-oxazolyllbenzenesulfonamide
2-Trifluoromethyl-4-phenyl-5-(3-fluoro-4-methoxy
phenyl)oxazole from Step 3 (337 mg, 1 mmol) was added to
chlorosulfonic acid cooled to 0 ~C (10 mL) and the reaction
was warmed to room temperature for 3 hours. The solution was
carefully poured into ice water and extracted with three 75
mL portions of dichloromethane. The combined organics were
washed once with brine (75 mL) and stirred over ice cold
NH40H (125 mL) for 2 hours. The dichloromethane layer was
separated and washed consecutively with lN HCl (2 x 75 mL),
NaHCO3 (satu~ated) (75 mL) and brine (75 mL), dried over
Na2SO4 and concentrated. The crude material was
chromatographed over SiO2 eluting with a gradient ~rom 10% -
35% ethyl acetate in hexane to yield 4-[5-(3-fluoro-4-
methoxyphenyl)-2-trifluoromethyl-4-
oxazolyl]benzenesulfonamide (20 mg, 5%): mp 150-151 ~C. 1H
NMR (acetone-d6), 300 MHz ~ 3.99 (s, 3H), 6.69 (s, 2H), 7.32
(t, lH), 7.51 (m, 2H), 7.85 (d, J=8.3 Hz, 2H), 7.97 (d, J=8.3
Hz, 2H).
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EXAMPLE 6 1
H2N ~ />--CF3
~0
4-Methyl-3-~5-phenyl-2-trifluoromethyl-4-
oxazolyl]benzenesulfonamide
EXAMPLE 6 2
H3C ~
H2N - ~ / ~ CF3
~ O
H2N~ /~/
1/~ 0
~
4-~4-(3-Amino~ulfonyl-4-methylphenyl)-2-
trifluoromethyl-5-oxazolyl]benzenesulfonamide
Ste~ 1. Pre~aration of 2-hvdroxv-2-~henvl-1-(4-
methvl~henvl)ethanone.
The trimethylsilyl cyanohydrin of benzaldehyde Example
34, Step 1 (5.0 g, 24.4 mmol) was dissolved in diethyl ether
(50 m~) and added dropwise to a solution of ~-
methylphenylmagnesium bromide (29.3 mmol) in diethyl ether
-
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~130 mL) whi'e maintaining the temperature between 23-35 ~C
with an ice water bath. The reaction was stirred for 0.5
hours at room temperature. At this time lN HCl (100 mL) and
' ether (150 mL) were added and the layers separated. The
~ 5 organic layer was washed with saturated NaHC03 and brine,
dried over Na2S04, and concentrated in vacuo to give a yellow
oil. The yellow oil was dissolved in 9:1 trifluoroacetic
acid/water (30 mL) and stirred for 0.5 hours at room
temperature. The reaction was neutralized with solid sodium
bicarbonate, extracted with ethyl acetate, washed with
saturated NaHC03 and brine, dried over Na2S04, concentrated
in vacuo and recrystallized from diethyl ether/hexane to give
the benzoin (2.54 g, 46%): lH NMR (CDCl3) 300 MHz, ~ 2.35 (S,
3H), 4.45 (broad s, lH), 5.92 (s, lH), 7.19 (m, 2H), 7.32 (m,
15 3H), 7.82 (m, 2H) .
Ste~ 2. Pre~aration of 2-trifluoromethY1-4-(4-methvl
~henvl)-5-3hen~10xazole.
Trifluoroacetonitrile (0.84 g, 8.84 mmol) was added to
20 D~F (100 ml). This solution was cooled to 0 ~C and 4-
methylbenzoin from Step 1 (1. 36 g, 6 mmol) was added. DBU
(1.35 g, 8.84 mmol) was added and the solution was warmed to
room temperature for 4 hours. The reaction was then heated
to approximately 100 ~C for an additional 4 hours. The
25 solution was cooled to room temperature, poured into 400 mL
lN HCl and extracted with 500 mL ethyl acetate. The organics
were washed consecutively with lN HCl (400 mL), NaHC03
(saturated) (400 mL) and brine (400 mL), dried over Na2S04
and concentrated. The residue was purified by silica gel
30 chromatography eluting with 1% ether in hexane to give a
white solid (0.72 g, 40%): mp 49-50 ~C. Anal. Calc~d. for
C17H12NOF3: C, 67.33; H, 3.99; N, 4.62. Found: C, 67.27;
H, 3.99; N, 4. 58.
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Ste~ 3 Pre~aration of 2-trifluorometh~1-4-(4-methvl
~henvl)-5-~henvloxazole.
2-Trifluoromethyl-4-(4-methylphenyl)-5-phenyloxazole
from Step 2 (0.4 g) was added to chlorosulfonic acid (10 mL)
cooled to 0 ~C and the reaction was warmed to room
temperature for 2 hours. The solution was carefully poured
into ice water and extracted with three 75 mL portions of
dichloromethane. The combined organics were washed once with
brine (75 mL) and stirred over ice cold NH40H (125 mL) for 2
hours. The dichloromethane layer was separated and washed
consecutively with lN HCl (2 x 75 mL), NaHCO3 (saturated) (75
mL) and brine (75 mL), dried over Na2SO4 and concentrated.
The crude material was chromatographed, eluting with a
gradient from 10-60% ethyl acetate in hexane to yield 4-
methyl-3-[5-phenyl-2-trifluoromethyl-4-
oxazolyl]benzenesulfonamide (141 mg, 28%): mp 150-151 ~C
Anal. Calcld. for C17H13N2O3SF3: C, 53.40; H, 3.43; N,
7.27. Found: C, 53.33; H, 3.48; N, 7.27; and 4-[4-(3-
aminosulfonyl-4-methylphenyl)-2-trifluoromethyl-5-
oxazolyl]benzenesulfonamide (150 mg, 25%): mp 241-242 ~C;
Anal. Calc~d. for C17H14N3O5S2F3: C, 44.25; H, 3.06; N,
9.11; Found: C, 44.34; H, 3.07; N, 9.05.]
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EXAMPLE 6 3
~ ~,
N
>--CF3
1 ~1
~
~ NH2
O O
54-Methyl-3-[4-phenyl-2-trifluoromethyl-5-
oxazolyl]benzene~ul~onamide
Ste~ 1. Pre~aration of 2-hvdroxY-2-(4-methyl~henyl)-1-
phenylethanone.
10A solution of p-tolulylaldehyde (33.55 g, 279 mmol) and
trimethylsilylcyanide (38 mL, 285 mmol) in dichloromethane
(160 mL) was treated with zinc iodide (0.34 g). The solution
was stirred for 0. 33 hours at room temperature, washed with
water and saturated NaHCO3, dried over MgSO4 and
concentrated in vacuo to give the trimethylsilyl cyanohydrin
as a yellow oil (59.76 g). The trimethylsilyl cyanohydrin
was dissolved in diethyl ether (200 mL) and added dropwise to
a solution of phenylmagnesium bromide (285 mmol) in diethyl
ether (1095 mL) while maint~;ning the temperature between 25-
30 ~C with an ice water bath. The reaction was stirred for0.5 hours at room temperature then ~uenched by adding 3N HCl
(220 mL). The organic layer was collected, washed with
saturated NaHCO3 and brine, dried over MgSO4, and
concentrated in vacuo to give an orange oil (48.22 g). The
orange oil was dissolved in 9:1 trifluoroacetic acid/water
,. (100 mL) and stirred for 0. 67 hours at room temperature. The
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150
reaction was extracted with ethyl acetate, washed with 10~
Na2C03 and brine, dried over MgS04, and concentrated in vacuo
to give a brown solid which was recrystallized from diethyl
ether/hexane to give the benzoin (32.90 g, 52%~: mp 118-123
~C. 1H NMR (CDCl3) 300 MHz ~7.90 (d, J=7.1 Hz, 2H) 7.57 (m,
lH) 7.39 (m, 2H) 7.21 (d, J=8.1 Hz, 2H) 7.14 (d, J=7.9 Hz,
2H) 5.93 (s, lH) 4.50 (br s, lH) 2.29 (s, 3H).
Ste~ 2. Pre~aration of 2-trifluoromethvl-4-~henvl-5-(4-
methvl~henYl)oxazole.
Trifluoroacetonitrile (1.57 g (16.5 mmol) was added to
DMF (100 mL). This solution was cooled to 0 ~C and 4'-
methylbenzoin from Step 1 (3.05 g, 13.5 mmol) was added. DBU
(2.51 g, 16.5 mmol) was added and the solution was warmed to
room temperature for 4 hours. The reaction was heated to
approximately 100 ~C for an additional 4 hours. The solution
was cooled to room temperature and poured into 400 mL lN HCl
and extracted with 500 mL ethyl acetate. The organics were
washed cons~cutively with lN HCl (400 mL), NaHC03 (saturated)
(400 mL) and brine (400 mL), dried over Na2S04 and
concentrated. The residue was purified by silica gel
chromatography eluting with 5% ether in hexane to give a
white solid (1.28 g, 31%): mp 54-55 ~C. Anal. Calc'd. for
C17H12MOF3: C, 67.33; H, 3.99; N, 4.62. Found: C, 67.22;
H, 3.94; M, 4.55.
Ste~ 3. Pre~aration of 5-(3-aminosulfon~1-4-methvl~henvl)-4-
~henvl-2-trifluoromethvloxazole.
2-Trifluoromethyl-4-phenyl-5-(4-methylphenyl)oxazole
from Step 2 (0.34 g) was added to chlorosulfonic acid cooled
to 0 ~C (12 mL) and the reaction was warmed to room
temperature ~or 1.25 hours. The solution was carefully
poured into ice water and extracted with three 75 mL portions
of dichloromethane. The combined organics were washed once
with brine (75 mL) and stirred over ice cold MH40H (125 mL)
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for 2 hours. The dichloromethane layer was separated, washed
consecutively with lN HCl (2 x 75 mL), NaHCO3 (saturated) (75
mL) and brine (75 mL), dried over Na2S04 and concentrated.
The crude material was crystallized from ethyl acetate and
5 hexane to yield 2-trifluoromethyl-4-phenyl-5-(3-
aminosulfonyl-4-methylphenyl)oxazole (184 mg, 54 %): mp 156-
157 ~C. Anal. Calc'd- for C17H13N2~3SF3 C,
3.43; N, 7.33. Found: C, 53.23; H, 3.44; N, 7.31.
lo EXAMPLE 6 4
Q N
CF3
~ O
H2N
O O
4-~4-Phenyl-2-tri~luoromethyl-5-
15 oxazolyl]benzenesulfonamide
Step 1. Preparation o~ 2-trifluorQmethvl-4,5-di~henyl
oxazole.
Trifluoroacetonitrile (1.58 g, 16.5 mmol) was added to
20 DMF (100 ml). This solution was cooled to 0 ~C and benzoin
(2.87 g, 13.5 mmol) was added. DBU (2.51 g, 16.5 mmol) was
added and the solution was warmed to room temperature for 4
hours. The reaction was heated to approximately 100 ~C for
an additional 4 hours. The solution was cooled to room
25 temperature and poured into 400 mL lN HCl and extracted with
500 mL ethyl acetate. The organics were washed consecutively
- with lN HCl (400 mL), NaHCO3 (saturated) (400 mL) and brine
a (400 mL), dried over Na2SO4 and concentrated. The residue
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was purifie;. by silica gel chromatography eluting with 5%
ether in hexane to give a white solid (1.75 g, 45%): mp 70-71
~C. Anal. Calc~d. for C16H1oNOF3: C, 66.44; H, 3.48; N,
4.84. Found: C, 67.33; H, 3.52; N, 4.92.
Ste~ 2. Pre~aration of 4-r4-~hen~1-2-trifluoromethvl-5-
oxazolvllbenzenesulfonamide.
2-Trifluoromethyl-4,5-diphenyloxazole from Step 1
(0.77g, 2.8 mmol) was added to chlorosulfonic acid (25 mL)
(cooled to 0 ~C) and the reaction was stirred from 0 ~C to
room temperature for 5 hours. The solution was carefully
poured into ice water and extracted with three 75 mL portions
of dichloromethane. The combined organics were washed o~ce
with brine (75 mL) and stirred over ice cold NH40H (125 mL)
for 2 hours. The dichloromethane layer was separated and
washed conse:utively with lN HCl (2 x 75 mL), NaHCO3
(saturated) (75 mL) and brine (75 mL), dried over Na2SO4 and
concentrated. The crude material was crystallized from ethyl
acetate and hexane to yield 4-[4-phenyl-2-trifluoromethyl-5-
oxazolyl]benzenesulfonamide (0.56 g, 57%): mp 137-138 ~C.
Anal. Calc~d. for C16H1lN2O3SF3: C, 52.18; H, 3.01; N,
7.61. Found: C, 52.15; H, 2.98; ~, 7.52.
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EXAMPI~E 6 5
..
., ~ ~
N
- ~ CF3
~ O
H2N ~S
O O
4-~4-Dimethylaminophenyl-2-trifluoromethyl-5-
oxazolyl]benzenesulfonamide
Step 1. Preparation of 2-trifluoromethvl-4-(4-
dimethylamino~henyl)-5-~henyloxazole.
The oxazole was prepared as described in Example 32 with
the substitution of 4-dimethylaminobenzoin (3.06 g, 12 mmol)
to give a yellow solid (1.84 g, 46%): mp 120-121 ~C. Anal.
~ for C18H15M2~F3: C, 65.06; H, 4.55; N, 8 43 Found:
C, 65.96; H, 4.52; M, 8.42.
Step 2. Preparation of 4-~4-Dimethvlamino~henvl-2-
trifluoromethyl-5-oxazolYllbenzenesulfonamide
Example 33 was prepared from the oxazole of Step 1 as
described in Example 32, Step 2 (0.38 g, 62%): mp 159-160 ~C.
Anal. Calc~d. for C18H16N3O3SF3: C, 52.55; H, 3.92; N,
10.21. Found: C, 52.29; H, 3.98; N, 10.05.
-
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EXAMPLE 6 6
o~
H2N S~
~ Y
~ NyCO2H
~o
4-(4-Aminosulfonylphenyl)-5-(3-fluoro-4-
methoxyphenyl)-2-oxazoleacetic acid
Ethyl [4-(4-aminosulfonylphenyl)-5-(3-fluoro-4-
methoxyphenyl)]-2-oxazoleacetate (8.7 mg 0.021 mmol) (Example
10 34, Step 4) was dissolved in ethanol (1 mL), and a NaOH
solution (2. 5 N, 18 ml) was added. The reaction was stirred
for 0.25 hours at room temperature at which time HCl (aq.,
concentrated) was added to acidify the reaction. The aqueous
solution was extracted with ethyl acetate (dried over MgS04)
15 and concentrated to yield [4-(4-aminosulfonylphenyl)-5-(3-
fluoro-4-methoxyphenyl)]-2-oxazoleacetic acid (6.0 mg, 709~):
lH NMR (CD30D) 300 MHz ~ 3.91 (s, 3H), 3.97 (s, 2H), 7.19 (t,
lH), 7.31 (m, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.91 (d, J=8.7 Hz,
2H). 19F NMR (CD30D) 282 MHz d -132.8 (multiplet).
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EXAMPLE 6 7
o o
~/~
H2N-- ~\
~N~_~C02H
~~'~ Br
~ ~J
Cl~ ~~
4-[4-Amino~ul~onylphenyl)-5-(3-~luoro-4-
methoxyphenyl)-2-oxazolyl]a-bromoacetic acid
[4-(4-Aminosulfonylphenyl)-5-(4-chlorophenyl)-2-
oxazolyl]acetic acid (Example 66) (65 mg, 0.165 mmol) was
dissolved i~ chloro~orm (5 mL) and acetic acid (3 mL).
Bromine in acetic acid solution (1.1 M, 0.2 mL) was added and
the reaction was stirred for 16 hours. Sodium sulfite was
added until the orange color dissipated. lN HC1 (10 mL) was
added and the reaction concentrated to dryness. The residue
was suspended in acetone (2 mL), filtered through Celite~ and
concentrated to yield 4-[4-aminosulfonylphenyl)-5-(3-fluoro-
4-methoxyphenyl)-2-oxazolyl]~-bromoacetic acid (73 mg, 94%):
1H NMR (acetone-d6), 300 MHz ~ 4.57 (s, lH), 6.81 (s, 2H),
7.51 (d, J=8.5 HZ , 2H), 7.64 (d, J=8.5 HZ , 2H), 7.79 (d,
20 J=8.3 HZ, 2H), 7.94 (d, J=8.3 HZ, 2H) .
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EXAMPLE 6 8
H3C ~o~
bY ~
~_N
~ CF3
H3CO2S
4-(4-Methylphenyl)-5-(4-methylsulfonylphenyl)-2-
tri~luoromethyloxazole
Ste~ 1. Pre~aration of 2-hvdroxv-2-(4-methvlthio~henvl)-1-
(4-methvl~henvl)ethanone
A solution of p-thioanisaldehyde (15.22 g, 100 Irunol) and
zinc iodide (1 g) in dichloromethane (100 mL) was treated
with a solution of trimethylsilylcyanide (13.3 mL, 100 mmol)
in dichloromethane (S0 mL). The solution was stirred ~or 0. 5
hours at room temperature, washed with water and saturated
15 NaHCO3, dried over MgSO4 and concentrated in vacuo to give
the trimethylsilyl cyanohydrin as an orange oil (24.9 g).
The trimethylsilyl cyanohydrin (5.0 g, 20 mmol) was dissolved
in diethyl ether (50 mL) and added dropwise to a solution of
p-tolylmagnesium bromide ( 2 4 mmol) in diethyl ether ( 175 mL)
while maintaining the temperature at less than 30 ~C with an
ice water bath. The reaction was stirred for 0. 25 hours at
room temperature and then ~uenched by adding lN HCl (250 mL).
The organic layer was collected, washed with saturated NaHCO3
and brine, dried over MgSO4, and concentrated in vacuo to
give a yellow solid. The yellow solid was dissolved in 9:1
trifluoroacetic acid/water (30 mL) and stirred for 0 .25 hours
at room temperature. The reaction was neutralized with
saturated NaHCO3 solution, extracted with ethyl acetate,
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washed with .saturated NaHCO3 solution and brine, dried over
MgSO4, and concentrated in vacuo to give a yellow oil. The
oil was purified by SiO2 chromatography eluting with a
gradient from 20-30% ethyl acetate in hexane to yield 2-
hydroxy-2-(4-methylthiophenyl)-1-(4-methylphenyl)ethanone
(2.8 g, 51%): 1H NMR (CDC13) 300 MHz ~ 2.36 (s, 3H), 2.43 (s,
3H), 4.54 (d, J=6.0 Hz, lH), 5.89 (d, J=6.0 Hz, lH), 7.20
(m, 6H) 7.80 (d, J=8.3 Hz, 2H).
Step 2 Pre~aration of 4-(4-methvlphenY1)-5-(4-
methylthiophenyl)2-trifluoromethvl-oxazole.
The oxazole was prepared as in Example 64, Step 1, with
the substitution of 2-hydroxy-2-(4-methylthiophenyl)-1-(4-
methylphenyl)ethanone to give a white solid (0.6 g, 46%): mp
129-130 ~C. Anal. Calc'd. for Cl8H14NOSF3: C, 61.88; H,
4.04; N, 4.0l. Found: C, 61.81; H, 4.09; N, 3.92.
~te~ 3. 2-trifluoromethyl-4-(4-methyl~henyl)-5-(4-
methvlsulfonYl~henyl) oxazole.
4-(4-Methylphenyl)-5-(4-methylthiophenyl)-2-
trifluoromethyloxazole from Step 2 (350 mg, 1.0 mmol) was
dissolved in THF (20 mL), ethanol (20 mL) and water (20 mL).
Oxone~ (1.2 g, 2 mmol) was added and the reaction stirred for
3 hours. The reaction mixture was filtered and concentrated
to drYness. The residue was dissolved in ethyl acetate (200
mL), washed with water, NaHCO3 and brine, dried and
concentrated to yield a white crystalline product (350 mg)
which was recrystallized from ethanol and water to yield 4-
(4-methylphenyl)-5-(4-methylsulfonylphenyl)-2-
trifluoromethyl-oxazole (300 mg, 79~): mp 141-142 ~C. Anal.
d- for -18H14N~3SF3: C, 56.69; H, 3.70; N, 3 67
Found: C, 56.47; H, 3.79; N, 3.57.
- EX~MPLE 6 9
~ 35
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158
H2NO2S
\~\ N
CH3
--O
4-~5-(3-Fluoro-4-methoxyphenyl)-2-methyl-4-
oxazolyl]benzene~ulfonamide
Ste~ 1. Pre~aration of 5-(3-fluoro-4-methoxv~henYl)2-methYl-
4-~henYloxazole.
3-Fluoro-4-methoxybenzoin (Example 34, Step 1) (2.6 g,
10 mmol) and acetic anhydride (1.63 g, 16 mmol) were added to
THF (150 mL) and cooled to O ~C. DBU (1. 83 g, 12 mmol) was
added and the solu~ion was warmed to room temperature for 16
hours. The reaction was poured into 300 mL lN HCl and
extracted with 500 mL ethyl acetate. The organics were
washed consecutively with, NaHC03 (saturated) (400 mL) and
brine (400 mL) dried over Na2S04 and concentrated. Ammonium
aceta~e (6 g) and acetic acid (100 mL) were added to the
acetylated benzoin and the solution was heated to reflux for
2.5 hours. The reaction was concentrated to dryness and the
residue dissolved in ethyl acetate (250 mL), washed with lN
HCl, NaHC03 and brine, dried and concentrated to yield a
crystalline solid (2.37 g, 65%) which was used without
further purification.
Ste~ 2. Pre~aration of 5-(3-fluoro-4-methoxv~henvl-2-methYl-
4-oxazolYllbenzenesulfonamide
The oxazole of Step 1 was converted to the sulfonamide
by the method of Example 64, Step 2 to yield 4-[5-(3-fluoro-
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159
4-methoxyphenyl- 2 -methyl-4-oxazolyl]benzenesulfonamide ( 173
mg, 559~ H NMR (acetone d6), 300 MHz ~ 2.52 (s, 3H), 3.96
(s, 3H), 6.61 (s, 2H), 7.24 (m, lH), 7.37 (m, 2H), 7.81 (d,
J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H).
~ 5
J EX;~MPLE 7 0
H3CO2S ~,~
Il '1
\~ N
\>--CF3
~0
5-(3-Fluoro-4-methoxyphenyl)-4-(4-
methylsulfonylphenyl)-2-trifluoromethyloxazole
Ste~ 1. Pre~aration of 4-methvlthio-3~-fluoro-4~-methoxY
benzoin.
Magnesium (1.34 g, 55 mmol) was suspended in THF (300
mL) and a solution o~ 4-bromothioanisole (10.16 g, 50 mmol)
in THF (50 mL) was added dropwise over 0.5 hour maintaining
the temperature at less than 30 ~C. The reaction was stirred
an additional 0.5 hour once the addition was complete. 3-
Fluoro-p-anisaldehyde silyl cyanohydrin (Example 34, Step 1)
~12.7 g, 50 mmol) and diethyl ether (50 mL) were added
dropwise to ~he solution of Grignard at such a rate that the
reaction temperature did not rise above 30 ~C. Upon complete
addition, the reaction was stirred an additional 15 minutes
at which time lN HCl ( 400 mL) was added and the reaction
- stirred until all solids were dissolved. The organics were
washed with NaHC03 (saturated) (400 mL) and brine (400 mL),
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dried over Ma2SO4 and concentrated to yield a mixture of
benzoin and silyl benzoin. The crude product was dissolved
in TFA/H2O (9:1) (75 mL) and stirred for 15 minutes. The TFA
solution was poured into saturated NaHCO3 (aq.). The benzoin
was extracted with ethyl acetate (350 mL) and washed with
NaXCO3 (saturated) (300 mL) and brine (300 mL). The crude
benzoin was crystallized from ethyl acetate and hexane to
yield crystals of 4-methylthio-3~-fluoro-4~-methoxybenzoin
(4.9 g, 32%): 1H NMR (CDC13) 300 MHz ~ 2.45 (s, 3H), 3.81 (s,
3H), 5.8 (s, lH), 6.86 (m, lH), 7.01 (m, 2H), 7.17 (d, J=8.7
Hz, 2H), 7.79 (d, J=8.7 Hz, 2H); 19F MMR (CDCl3) 282 MHz
-134.0 (multiplet).
Step 2 Pre~aration of 2-trifluoromethvl-4-(4-
met~vlthio~henyl)-5-(3-fluoro-4-methoxyphenvl)oxazole.
5-(3-Fluoro-4-methoxyphenyl)-4-(4-methylthiophenyl)-2-
trifluoromethyloxazole was prepared from the benzoin o~ Step
1 by the method of Example 64, Step 1. The residue was
crystallized from ethanol and water to give a white solid
(0.26 g, 50%): 1H MMR (CDCl3) 300 MHz ~ 2.52 (s, 3H), 3.94
(s, 3H), 6.98 (t, J=8.7 Hz, lH), 7.26 (d, J=8.5 Hz, 2H), 7.36
(m, 2H), 7.55 (d, J=8.5 Hz, 2H); 19F NMR (CDC13) 282 MHz
-66.6 (s), -134 2 (s).
Ste~ 3 Pre~aration of 5-(3-fluoro-4-methoxv~henvl-4-(4-
methvlsulfonyl~henyl)2-trifluoromethvloxazole.
2-Trifluoromethyl-4-(4-methylthiophenyl)-5-(3-fluoro-4-
methoxyphenyl)oxazole from Step 2 (38 mg, 0.1 mmol) was
converted by the method of Example 68, Step 3 to yieid a
white crystalline product which was recrystallized from
ethanol and water to yield 5-(3-~luoro-4-methoxyphenyl)-4-(4-
methylsulfonylphenyl)-2-trifluoromethyloxazole (39 mg, 94%):
lH MMR (CDCl3) 300 MHz ~ 3.1 (s, 3H), 3.96 (s, 3H), 6.98 (t,
J=8.5 Hz, lH), 7.36 (m, 2H), 7.88 (d, J=8.5 Hz, 2H), 7.98
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(d, J=8.5 Hz, 2H); 19F NMR (CDC13) 282 MHz ~ -66.6 (s), -133.5
(s). FAB Mass spec. M + H 416.
EXAMPI,E 7 1
o~ ~o
H2N S ~
N
CF3
Br~~O
4-[5-(3-Bromo-4-methoxy-5-~luorophenyl)-2-
trifluoromethyl-4-oxazolyl]benzenesul~onamide
Ste~ 1. Preparation of 3-bromo-5-fluoro-4-
hydroxybenzaldehYde.
A solution o~ 3-fluoro-p-anisaldehyde (10.40 g, 67.5
mmol) in 1,2-dichloroethane (80 mL) was treated with bromine
(3.9 mL, 75.6 mmol) then cooled in ice while adding aluminum
chloride (11.87 g, 89.0 mmol). The reaction was stirred for
1.75 hours at room temperature and 1.3 hours at 60 ~C. The
excess bromlne was ~uenched by adding 10% sodium bisul~ite
solution. The reaction mixture was extracted with ethyl
acetate, washed with 3N HCl, brine, dried over MgSO4, and
concentrated in vacuo to give a white solid (14.84 g, 100%):
mp 136-138 ~C. 1H MMR (acetone-d6) 300 MXz ~ 10.30 (br s, lH)
f 9.86 (d, J=2.0 Hz, lH) 7.95 (t, J=1.6 Hz, lH) 7.70 (dd,
J=10.3 Hz 1.8 Hz, lH); 19F NMR (acetone-d6) 282 MHz -133.27
(m). Mass spectrum: M+H=219/221.
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Ste~ 2 Pre~aration of 3-bromo-5-fluoro-4-
methoxvbenzaldehvde.
A solution of 3-bromo-5-fluoro-4-hydroxybenzaldehyde
from Step 1 (6.01 g, 27.3 mmol) was treated with methyl
iodide (8.89 g, 62.6 mmol) and potassium carbonate (5.79 g,
41.9 mmol). The reaction was stirred for 15.1 hours at 50
~C, filtered and concentrated in vacuo. The residue was
dissolved in ethyl acetate, washed with water, 10% sodium
hydroxide, and brine. The organic layer was dried over MgSO4
and concentrated in vacuo to give a brown oil which was
crystallized from diethyl ether/hexane to give a white solid
(2.63 g, 41%): mp 47-49 ~C. 1H NMR (CDCl3) 300 MHz ~ 9.82 (d,
J=2.0 Hz, lH) 7.85 (t, J=1.6 Hz, lH) 7.58 (dd, J=11.1 Hz 2.0
Hz, lH) 4 . 09 (d, J=3.0 Hz, 3H); 19F NMR (CDCl3) 282 MHz
-125.92 (m). Mass spectrum: M+H=233/235.
Ste~ 3. Pre~aration of 3~-bromo-4~-methoxY-5~-fluorobenzoin.
A solution of 3-bromo-5-fluoro-4-hydroxybenzaldehyde
~rom Step 2 (2.63 g, 11.2 mmol) and zinc iodide (0.44 g) in
methylene c~loride (10 mL) was treated with trimethylsilyl
cyanide (1.7 mL, 12.7 mmol). The solution was stirred for
0.6 hours at room temperature, washed with saturated NaHCO3
and brine, dried over MgSO4 and concentrated in vacuo to
give the trimethylsilyl cyanohydrin as a yellow oil (3.04 g).
The trimethylsilyl cyanohydrin was dissolved in diethyl ether
(15 mL) and added dropwise to a solution of phenylmagnesium
bromide (13.8 mmol) in diethyl ether (90 mL) while
maintaining the temperature below 25 %C with an ice water
bath. The reaction was stirred for 1~2 hours at room
temperature then quenched by adding 3N HCl. The organic
layer was collected, washed with saturated NaHCO3 and brine,
dried over MgSO4, and concentrated in vacuo to give a yellow
oil (3.99 g). The yellow oil was dissolved in 9:1 -
trifluoroace~ic acid/water (20 mL) and stirred for 0.33 hours
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at room temperature. The reaction was neutralized with solid
potassium carbonate, extracted with ethyl acetate, washed
with 10% Na2CO3 and brine, dried over MgSO4, and concentrated
in vacuo to give the benzoin (3.15 g) as a yellow oil which
was used in the next step without further purification.
Ste~ 4. Pre~aration of 5-(3-bromo-4-methoxY-5-fluoro~henvl-
4-~henvl)-2-trifluoromethvl-oxazole.
5-(3-sromo-4-methoxy-5-fluorophenyl-4-phenyl)-2-
trifluoromethyloxazole was prepared by the method described
in Example 64, Step 1, substituting 3'-bromo-4'-methoxy-5'-
fluorobenzoin from Step 3. The crystalline solid residue was
recrystallized from ether and hexane to yield analytically
pure oxazole (1.9 g, 49%): 1H MMR (CDC13) 300 MHz ~ ~.03 (s,
3H), 7.32 (m, lH), 7.44 (m, 3H), 7.63 (m, 3H); 19F NMR
(CDC13) 282 MHz d -66.6 (s), -126.4 (s).
Ste~ 5. Pre~aration of 4-r5-(3-bromo-4-methoxv-5-
~luoro~henvl)-2-trifluoromethvl-4-oxazolvllbenzenesulfonamide
The oxazole of Step 4 was reacted as described in
Example 64, Step 2. The crude material was chromatographed
over SiO2 eluting with a gradie~t ~rom 10% - 50% ethyl
acetate in hexane to yield 4-[5-(3-bromo-4-methoxy-5-
fluorophenyl)-2-trifluoromethyl-4-oxazolyl]benzenesulfonamide
(0.25 g, 15%): lH NMR (CDC13) 300 MHz ~ 4.05 (s, 3H), 5.18
(s, 2H), 7.28 (m, lH), 7.61 (m, lH), 7.80 (d, J=8.5 Hz, 2H),
7.98 (d, J=8.5 Hz, 2H); 19F NMR (CDC13) 282 MHz ~ -66.6 (s),
-125.7 (s).
EXAMP~E 72
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164
~N
J~ CONH2
O
H2N
O O
5-(4-Aminosulfonylphenyl)-4-phenyloxazole-2-
carboxamide
Ste~ 1. Pre~aration of 4,5-diDhenyloxazole-2-acetic acid
methvl ester.
Benzoin (2.12 g, 10 mmol) was dissolved in THF (100 mL)
and the solution cooled to 0 ~C. Methyl oxalylchloride (1.47
g, 12 mmol) and triethylamine (1.67 mL, 12 mmol) were added
and the reac~-ion was warmed to room temperature for 2 hours.
Ether (150 mL) was added and the reaction mixture was
filtered and concentrated. Ammonium acetate (1.5 g) and
acetic acid (150 mL) were added to the acylated benzoin and
the solution was heated to reflux for 2.5 hours. The reaction
was concentrated to dryness, the residue was dissolved in
ethyl acetate (250 mL), washed with water, NaHCO3 and brine,
dried and concentrated to yield a crystalline solid which was
chromatographed over SiO2 eluting with a gradient ~rom 5% -
10~ ethyl acetate in hexane to yield the methyl ester (0.79g, 28%): 1H NMR (CDC13) 300 MHZ ~ 4.02 (s, 3H), 7.36 (m,
6H), 7.67 (m, 4H).
SteD 2. Preparation of 5-(4-aminosulfonvlphenyl)-4-phenyl-
oxazole-2-carboxamide.
4,5-Diphenyloxazole-2-acetic acid methyl ester from Step
1 (790 mg, 2.8 mmol) was added to chlorosulfonic acid cooled
to 0 ~C (25 mL) and the reaction was warmed to room
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temperature for 2 hours. The solution was carefully poured
into ice water and extracted with three 75 m~ portions of
dichloromethane. The combined organics were washed once with
brine (75 mL) and stirred over ice cold NH40H (125 mL) for
2.5 hours. The dichloromethane layer was separated and
washed consecutively with lN HCl (2 x 75 mL), NaHCO3
(saturated) (75 mL) and brine (75 mL), dried over Na2SO4 and
concentrated. The crude material was crystallized from a
m;n;mllm amount of boiling ethyl acetate to yield 5-(4-
aminosulfonylphenyl)-4-phenyl-oxazole-2-carboxamide (0.45
g,46%): lH MMR (acetone-d6) 300 MHz ~ 6.73 (broad s, 2H),
7.22 (broad s, 2H), 7.48 (m, 3H), 7.68 (m, 2H), 7.84 (d,
J=8.5 Hz, 2H), 7.98 (d, J=8.5 Hz, 2H). FAB Mass spec. M +
H 344.
EXAMPLE 7 3
~ />--
~ o
H2N--S/~/
//~
o o
204-~2-Methoxymethyl-4-phenyl-
oxazolyl]benzene~ulfonamide
Ste~ 1. Pre~aration of 2-methoxvmethvl-4,5-di~henvloxazole.
Benzoin (2.12 g, 10 mmol) was dissolved in THF (50 mL)
and the solution cooled to 0 ~C. Methoxy acetylchloride
(2.28 g, 21 mmol) and triethylamine (2.12 mL, 21 mmol) were
added and the reaction was warmed to room temperature for 32
hours. Ether (150 mL) was added and the reaction was
CA 02221692 1997-ll-l9
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166
filtered. The organics were washed with lN HCl, NaHC03 and
brine, drie~ over Na2S04 and concentrated. Ammonium acetate
(1.32 g, 17.1 mmol) and acetic acid (50 mL) were added to the
acylated benzoin and the solution was heated to reflux for 3
hours. The reaction was concentrated to dryness, residue was
dissolved in ethyl acetate (250 mL), washed with water,
NaHC03 and brine, dried and concentrated to yield a
crystalline solid (2.1 g) which was recrystallized from ethyl
acetate and hexane to yield 2-methoxymethyl-4,5-
diphenyloxazole (0.82 g, 36%): 1H NMR (CDCl3) 300 MHz d 3.53(s, 3H), 4.62 (s, 2H), 7.35 (m, 6H), 7.62 (m, 4H).
Step 2. Pre~aration of 4-r2-methoxymethyl-4-phenvl-
oxazolyllbenzenesulfonamide.
2-Methoxymethyl-4,5-diphenyloxazole from Step 1 (500 mg,
1.9 mmol) w2~ added to chlorosulfonic acid cooled to O ~C (25
mL) and the reaction allowed was warmed to room temperature
for 3 hours. The solution was carefully poured into ice
water and extracted with three 75 mL portions of
dichloromethane. The combined organics were washed once with
brine (75 mL) and stirred over ice cold NH40H (125 mL) for
2.5 hours. The dichloromethane layer was separated, washed
consecutively with lN HCl (2 x 75 mL), NaHC03 (saturated) (75
mL) and brine (75 m~), dried over Na2S04 and concentrated.
The crude material was chromatographed over SiO2 eluting with
a gradient from 50% - 75% ethyl acetate in hexane to yield 4-
[2-methoxymethyl-4-phenyl-oxazolyl]benzenesulfonamide (0.22
g, 34%): 1H NMR (acetone-d6) 300 MHz ~ 3.47 (s, 3H), 4.62 (s,
2H), 6.69 (s, 2H), 7.44 (m, 3H), 7.65 (m, 2H), 7.77 (d, J=8.7
Hz, 2H), 7.93 (d, J=8.7 Hz, 2H). FAB Mass spec. M + H 345.
EXAMPI,E 7 4
CA 02221692 1997-ll-l9
WO96/36617 PCT~S96/06992
167
G N
CF2H
, ~ O
~ 1' 11
H2N /~
O O
4-t2-Di~luoromethyl-4-phenyl-5-
oxazolyl~benzenesul~onamide
Ste~ 1. Preparation of 2-di~luoromethvl-4,5-di~henyloxazole.
Difluoroacetic acid was dissolved in ethanol containing
NaOH (4 mL, 2.5 N), and concentrated to dryness. The solid
was re-dissolved in EtOH (50 mL) and re-concentrated to
dryness. The salt was suspended in DMF (30 mL) and
desylbromide (2.75 g, 10 mmol) was added. The reaction was
stirred for 16 hours and concentrated. The residue was
dissolved in ethyl acetate (250 mL), washed with 0.lN HCl (75
mL), NaHCO3 (saturated) (75 mL) and brine (75 mL), dried over
Na2SO4 and concentrated to yield 3.09 g of a colorless oil.
Ammonium acetate (2.31 g, 30 mmol) and acetic acid (25 mL)
were added to the acylated benzoin and the solution was
heated to reflux for 3 hours. The reaction was concentrated
to dryness, the residue was dissolved in ethyl acetate (250
mL), washed with water, NaHC03 and brine, dried and
concentrated. The crude product was chromatographed over
SiO2, eluting with a gradient from 1% - 10% ether in hexane,
to yield 2-difluoromethyl-4,5-diphenyloxazole (0.35 g, 12%):
lH NMR (CDC13) 300 MHz ~ 6.74 (t, J 52.6 Hz, lH), 7.39 (m,
r 25 6H), 7.64 (m, 4H). 19F NMR (CDC13) 282 MHz ~ -118.6 (d, J
52.9 Hz). FAB Mass spec. M + H 272.
,.
,
CA 02221692 1997-11-19
WO 96136617 PCTJUS96106992
168
Ste~ 2. Pre~aration of 4-r2-difluoromethvl-4-~henvl-5-
oxazolvllben-enesulfonamide
2-Difluoromethyl-4,5-diphenyloxazole from Step 1 (320
mg, 1.18 mmol) was added to chlorosulfonic acid cooled to 0
~C (10 mL) and the reaction was warmed to room temperature
for 2 hours. The solution was carefully poured into ice
water and extracted with three 75 mL portions of
dichloromethane. The combined organics were washed once with
brine (75 mL) and stirred over ice cold NH40H (125 mL) for
2.5 hours. The dichloromethane layer was separated, washed
consecutively with lN HCl (2 x 75 mL), NaHCO3 (saturated) (75
mL) and brine (75 mL), dried over Na2SO4 and concentrated.
The crude material was chromatographed over SiO2, eluting
with a gradient from 20%-50% ethyl acetate in hexane, to
yield 4-[2-difluoromethyl-4-phenyl-5-
oxazolyl]benzenesulfonamide (0.26 g, 63%): 1H NMR (CD30D)
300 MHz ~ 6.99 (t, J 52.2 Hz, lH), 7.43 (m, 3H), 7.61 (m,
2H), 7.75 (d, J=6.8 Hz, 2H), 7.93 (d, J=6.8 Hz, 2H). 19F
NMR (CD30D) 282 MHz ~ -121.6 (d, J 52.2 Hz).
CA 02221692 1997-11-19
WO96/~6617 PCT~S9C~06~2
169
EXi~MPLE 7 5
~ > OH
~ O
H2N ~
//~
O O
4- [2-Hydroxymethyl-4-phenyl-5-
oxazolyl]benzene~ul~onamide
Deoxybenzoin (10 g, 51 mmol) was added to chlorosulfonic
acid cooled to 0 ~C (25 mL) and the reaction was warmed to
room temperature for 4 hours. The solution was carefully
poured into ice water, filtered and the a~ueous layer was
extracted with three 250 mL portions of dichloromethane. The
combined organics were washed once with brine (75 mL) and
stirred over ice-cold NH40H (125 mL) for 16 hours. The
dichloromethane layer was separated and washed consecutively
with lN HCl (2 x 75 mL), NaHCO3 (saturated) (75 mL) and brine
(75 mL), dried over Na2SO4 and concentrated. The crude
material (4.23 g) was suspended in acetic acid (75 mL) and
HBr/HOAc solution (33 u/V% HBr in HOAc, 25 mL) and Br2 (0 79
20 mL, 15.4 mmol) was added. After 0.25 hours at room
temperature the reaction was complete by TLC, and the
reaction was concentrated to remove the acetic acid. The
residue was dissolved in ethyl acetate (250 mL) and NaHSO3
(10%, 250 mL). The organics were washed with NaHCO3
25 (saturated) (75 mL) and brine (75 mL), dried over Na2SO4 and
concentrated yielding a crude 4-sulfonamido-desylbromide
,,
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170
which was used without purification. Glycolic acid mono
sodium salt (1.55 g, 15.8 mmol) and the 4-sulfonamido-
desylbromide were suspended in DMF (350 mL) and stirred at
room temperature for 16 hours. The reaction was concentrated
and the residue, along with ammonium acetate (2.31 g, 30
mmol) and acetic acid (25 mL), were heated to reflux for 3
hours. The reaction was concentrated to dryness. The residue
was dissolved in ethyl acetate (250 mL), washed with water,
MaHCO3 and brine, dried and concentrated. The crude product
was chromatographed over SiO2, eluting with a gradient from
50%-75% ethyl acetate in hexane, to yield 4-[2-hydroxymethyl-
4-phenyl-5-oxazolyl]benzenesulfonamide: lH MMR (acetone-d6)
300 MXz ~ 4.76 (m, 2H), 6.68 (s, 2H), 7.45 (m, 3H), 7 .65 (m,
2H), 7.77 (d, J=6.8 Hz, 2~), 7.94 (d, J=8.7 ~z, 2H).
Example 7 6
Q
Tl ~(CH2)4C02Na
o//S~_
5-~(4-Aminosulfonyl)phenyl]-4-phenyloxazole-
2-pentanoic acid, sodium salt.
Ste~ 1: Pre~aration of 2- r (4-chlorosulfonvl)~henvll-1-
~hen~lethanone
Deoxybenzoin (10 g, 0.051 mol) was added in portions to
neat chlorosulfonic acid (50 mL) at -78 ~C. The reaction
mixture was stirred at -78 ~C for 2 h, then warmed to room
temperature an~ stirred at room temperature for 1.5 h. The
reaction mixture was cooled to -78 ~C and was carefully
poured onto crushed ice. The resulting solid was collected
by filtration, washed with water, and dried to give 10.3 g
(68.5%) of the desired sulfonyl chloride as a yellow solid.
CA 02221692 1997-11-19
w~9~366~7 PCT~96106992
171
This crude material was used for the next reaction without
~urther puri~ication: HRMS: (calcd for C14HllO3SC1 295.0196)
295.0205.
Ste~ 2: Pre~aration of 2- r (4-aminosulfonvl)~henvll-1_
Dhenvlethanone
A solution of the sulfonyl chloride ~rom Step 1 (9 g,
0.03 mol) in tetrahydrofuran (100 mL) was slowly added to
ammonium hydroxide (100 mL) at 5 ~C. The reaction mixture
was stirred first for 1.5 h at 5 ~C and then for 30 minutes
at room temperature. The resulting solid was collected by
filtration, washed with excess water and hexane, and vacuum
dried to give 3.47 g (41.3%) of the desired sulfonamide as a
white solid: m.p. 259-261.5 ~C. lH-MMR (DMSO-d6/300 MHz) ~
4.52 (s, 2H), 7.30 (s, 2H), 7.43 (bd, 2H, J = 8.26 Hz), 7.54
(dd, 2H, J = 7.56 Hz), 7.65 (dd, lH, J = 7.35 Hz), 7.75 (d,
2H, J = 8.26 Hz), 8.04 (d, 2H, J = 7.45 Hz). HRMS (calcd for
Cl4Hl3NO3S 276.0694) 276.0709.
Ste~ 3: Pre~aration of 2-bromo-2- r (4-aminosulfonvl)
~henvll-l-Dhenvl-ethanone
The sulfonamide from Step 2 (5.0 g, 0.018 mol) was
suspended in dichloroethane (50 mL), then a solution of 30%
HBr in acetic acid (20 mL), acetic acid (70 mL) and bromine
(1 mL) was added at room temperature. The reaction mixture
was stirred for 40 minutes at room temperature and then was
concentrated in vacuo. Water (200 mL) was added to the
resulting concentrated residue, and the mixture was extracted
with ethyl acetate (2 x 250 mL). The combined ethyl acetate
extracts were washed with 5% sodium bicarbonate (2 x 250 mL),
and brine (2 x 250 mL), dried over magnesium sulfate,
filtered and concentrated under reduced pressure. Methylene
chloride (50 mL) was added to the concentrated residue, and a
solid precipitated. This solid was collected by filtration,
washed with cold methylene chloride and air-dried to give 3.5
g (54.9%) of 2-bromo-2-[(4-aminosulfonyl)phenyl]-1-
phenylethanone as a yellow solid: m.p. 153.6-155 ~C. lH-MMR
CA 02221692 1997-11-19
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172
(DMSO-d6/300 MXz) ~7.25 (s, lH), 7.38 (s, 2H), 7.54 (dd, 2H,
J = 7.55 Hz), 7.62-7.74 (m, 3H), 7.82 (d, 2H, J = 8.46 Hz),
8.07 (d, 2H, J = 8.66 Hz). HRMS (calcd for Cl~H12M03SBr
353.9800) 353.9824.
Ste~ 4: Preparation of methyl 5- r (4-aminosulfonyl)phenyl]_
4-phenyloxazole-2-~entanoa~e
An a~ueous solution of 2.5N NaOH (2.3 mL, 5.65 mmol) was
added to adipic acid monomethyl ester (0.9 g, 5.65 mmol) in
ethanol (10 mL), and the mixture was stirred for 15 min at
room temperature. The solvents were removed at reduced
pressure. Several mL of absolute ethanol were added to the
concentrated residue, and the mixture was again concentrated
at reduced pressure. This procedure was repeated three times
until a white .olid formed, which was dried under high
vacuum. The resulting carboxylic acid sodium salt was
suspended in 10 mL of anhydrous DMF. The bromoketone (2 g,
5.65 mmol) from Step 3 was dissolved in 10 mL of anhydrous
DMF and added at room temperature to the DMF solution of the
sodium carboxylate The reaction mixture was stirred for 18
h at room temperature, and then the DMF was removed at
reduced pressure. Ethyl acetate (100 mL) was added to the
concentrated residue, and the mixture was filtered. The
filtrate was concentrated and dried to give the desired crude
~-acyloxy ketone. Acetic acid (10 mL) and ammonium acetate
(1.32 g, 17.1 mmol) were added to this concentrated residue,
and this mixture was heated at 100 ~C for 3 h. The reaction
mixture was cooled to room temperature, and the excess acetic
acid was removed under vacuum. The resulting residue was
partitioned beiween water (100 mL) and ethyl acetate (200
mL). The organic layer was separated, washed with saturated
aqueous sodium bicarbonate (2 x 100 mL), saturated brine (1 x
100 mL), dried over magnesium sulfate, filtered and
concentrated. The concentrated residue was purified by flash
chromatography on silica gel (eluting with 4:1 ethyl
acetate:hexane) to give 0.73 g of a white solid which was
recrystallized ~rom methylene chloride and hexane to give
CA 02221692 1997-11-19
WO 96136617 PCTJUS9C~G~5~2
173
0.48 g (21~) of methyl 5-[(4-aminosulfonyl)phenyl]-4-
phenyloxazole-2-pentanoate as a white solid: m.p. 165.8-167.3
~C. lH-MMR (CDCl3/300 MHz) 1.78-1.89 (m, 4H), 2.40 (t, 2H, J
= 7.25 Hz), 2.90 (t, 2H, 7.35 Hz), 3.68 (s, 3H), 4.85 (s,
2H), 7.37-7.42 (m, 3H), 7.58-7.61 (m, 2H), 7.71 (d, 2H, J =
8.66 Hz), 7.88 ( d, 2H, J = 8.66 Hz). HRMS (calcd for
C21H22M2OsS 414.1249) 414.1259.
Ste~ 5: Pre~aration of 5- r (4-aminosulfonvl)~henvll-4_
~henvloxazole-2-~entanoic acid
Methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-
pentanoate (1.48 g, 3.57 mmol) (Step 4) and LiOH (0.45 g,
0.011 mmol) were dissolved in 1:1 tetrahydrofuran/methanol
(90 mL) containing 3 mL of water. The resulting mixture was
stirred for 48 h at room temperature. The solvents were
removed at reduced pressure, and the concentrated residue
was partitioned between ethyl acetate (150 mL) and 1 N HCl
(150 mL) in a separatory funnel and shaken vigorously. The
organic layer was separated and washed with saturated brine
(1 x 150 mL), dried over magnesium sulfate, filtered and
concentrated. The concentrated residue was vacuum dried to
give 1.03 g (72%) of 5-[(4-aminosulfonyl)phenyl]-4-
phenyloxazole-2-pentanoic acid as a white solid: mp. 157.2-
159 0 ~C lH-NMR ~CD30D/300 MHz) 1.70-1.80 (m, 2H), 1.86-1.94
(m, 2H), 2.38 (t, 2H, J = 7.25 Hz), 2.93 (t, 2H, J = 7.35
Hz), 7.42-7.45 (m, 3H), 7.55-7.58 (m, 2H), 7.69 (d, 2H, J =
8.66 Hz), 7.87 (d, 2H, J = 8.66 Hz). HRMS (calcd for
C20H20M2OsS 400.1093) 400.1087.
Ste~ 6: Pre~aration of 5- r (4-aminosulfonvl)~henvll-4_
~henvloxazole-2-~entanoic acid sodium salt
5-[(4-aminosulfonyl)phenyl)-4-phenyloxazole-2-pentanoic
acid (Step 5) (0.19 g, 0.47 mmol) was dissolved in 3 mL of
ethanol. 2.5 N Sodium hydroxide (2.4 mL, 0.47 mmol) was
added, and the solution was stirred for 5 min. at room
temperature. The solvents were removed, several mL of
absolute ethanol were added to the concentrated residue, and
CA 02221692 1997-11-19
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174
the mixture was again concentrated at reduced pressure. This
procedure was repeated twice until a white solid formed,
which was dried under high vacuum to give 0.19 g (96%) o~ 5-
[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-pentanoic acid,
sodium salt as a white solid: m.p. >250 ~C. 1H N~ (CD30D/300
MHz) 1.70-1.80 (m, 2H), 1.86-1.93 (m, 2H), 2.25 (t, 2H, J =
7.35 Hz), 2.93 (t, 2H, J = 7.45 Hz), 7.41-7.44 (m, 3H),
7.55-7.58 (m, 2H), 7.70 ( d, 2H, J = 8.86 Hz), 7.88 (d, 2H, J
= 8.66 Hz). HRMS (calcd for C20H1gN2O~SNa 423.0991) 423.0991.
Other representative examples prepared by similar
methods from 2-bromo-2-[(4-aminosulfonyl)phenyl]-1-phenyl-
ethanone are summarized in Table 1.
CA 02221692 1997-11-19
WO 96136617 ~ 75 PcTJl7s9cJl~659?
~D 00
~D ~
., ~ ~
~~ o o ~ ~ ~ ~ ~ o ~ co
o o o o 03 oo Lr) L~ ~ ,~ ~ ~ ~ ~ ~t ~ r--~-- o a~
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~-----~S~~--...........
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. . . ~ ~ . . . . . . . .
O ~ O V C~ ~ O ~r ~ 0 o f~ ~ o
~ ~ ~ ~ v ~ v ~ ~ ~ v ~ ~ ~ v ~ v ~ ~ ~
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CA 0222l692 l997-ll-l9
WO 96J36617 176 PCT/USg6'~C9~2
L~ O O~ t~ ~ ~ ~ ~ O ~ ~~
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CA 02221692 1997-ll-l9
WO 96t36617 ~ 77 PC~T)US9'10~992
~1 ~ ~ oo L-- o o
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V ~ V ~ V ~ ~ ~
r~ O ~ ~ ~ O ~ O
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1~ I
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CA 0222l692 l997-ll-l9
WO 96/36617 1 78 PCT/US9"069~2
o ~--~ ~ o
~D ~D ~ ~ Ln ~ ~ ~ ~ ~ O O
a~ ~ Ln 1~1 o o ~ ~ ~
oo ~ ~oooo
u~ ~ c~ ~P ~ a~ o~ o o ~ ~ ~ ~
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V ~ V ~ ~ ) ~ V ~ ~) ~
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CA 02221692 1997-11-19
W<:~ 96J3-~6~7 1 79 PCT~JS9CJ01~9
~q
a)o o ~--~ ~ ~ ~ ~ cs~ co ~ ~ Ln ~ ~ ~D O O
~C~ ~ ~ ~ Ln ~O Ln U~ O O ~ dl ~ r_ ~ c~ ~ o
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CA 02221692 1997-11-19
W O96136617 PCTrUS96/06992
180
Example 115
O O
~//
H N~S~
1~ ~CO2H
~ O
F~O
4-~(4-Amino~ul~onyl)phenyl]-5-(4-~luorophenyl)oxazole-
2-pentanoic acid
Ste~ 1: Preparation of 2-(4-fluoro~henvl)-2-hvdroxY-1-
phenvlethanone
4-Fluorobenzaldehyde (25 g, 0.2 mol) and zinc iodide
(0.14 g, 0.4 mmol) were mixed with 100 mL of methylene
chloride. Trimethylsilyl cyanide (20.6 g, 0.21 mol) was
dissolved in 30 mL of methylene chloride and added over 30
minutes. The reaction mixture was stirred at room
temperature ~or 1 h. The reaction mixture was diluted with
200 m~ of methylene chloride, and the organic phase was
washed with saturated aqueous sodium bicarbonate (1 x 150
mL), saturated brine (1 x 150 mL), dried over magnesium
sulfate, filtered, concentrated and vacuum dried to give 47.3
g of the desired trimethylsilyl cyanohydrin as a yellow
li~uid.
The trimethylsilyl cyanohydrin (45 g, 0.2 mol) was
diluted with 100 mL of ether and added to a solution of
phenylmagnesium bromide (72 mL of 3.0 M solution in ether,
0.215 mol) in 600 mL of diethyl ether over 1.5 h at room
temperature. The reaction mixture was stirred for 3 h at
room temperature and slowly quenched with 3 N HCl (300 mL).
The organic layer was separated and washed with saturated
sodium bicarbonate (1 x 300 mL), saturated brine (1 x 300
m~), dried over magnesium sulfate, filtered, concentrated,
and vacuum dried to give 43.2 g of a brown oil. This oil was
treated with 150 mL of 9:1 trifluoroacetic acid in water for
CA 02221692 1997-11-19
WO 96136617 PCTllJ~;~)C)065~2
181
3 h at room temperature. Excess saturated aqueous sodium
carbonate was slowly added to the reaction mixture, followed
by water (200 mL). The a~ueous solution was extracted with
ether (2 x 200 mL). The combined organic layers were washed
5 with saturated sodium bicarbonate (1 x 200 mL~, saturated
brine (1 x 200 mL), dried over magnesium sulfate, filtered
and concentrated. The crude material was crystallized from
ethyl acetate and hexane to give 17.4 g (38%) of 2-(4-
fluorophenyl)-2-hydroxy-1-phenylethanone as a yellow solid:
m.p. 91-94 ~C. HRMS (calcd for C14HllFO2 231.0831) 231.0835.
Ste~ 2 Preparation of methyl 4-~(4-aminosulfonyl)~henvll-
5-(4-fluoro~henyl)oxazole-2-pentanoate
5-(Methoxycarbonyl)pentanoyl chloride (6.5 g, 0.036 mol)
15 in 10 m~ of methylene chloride and triethylamine (7.1 g, 0.07
mol) was added to 2-(4-fluorophenyl)-2-hydroxy-1-
phenylethanone (Step 1) (8 g, 0.035 mol) in 100 mL of
methylene chloride. The resulting mixture was stirred for 2
h at room temperature, diluted with 200 mL of methylene
20 chloride, washed with water (1 x 100 mL), and saturated brine
(1 x 100 mL), dried over magnesium sulfate, filtered and
concentrated. The concentrated residue was dried under
vacuum to give 12.2 g of crude ester intermediate. Acetic
acid (50 mL) and ammonium acetate (10.2 g, 0.132 mol) were
25 added to this ester intermediate (12.2 g, 0.033 mol). The
resulting mixture was heated for 3 h at 100 ~C. The reaction
mixture was cooled to room temperature, and the excess acetic
acid was removed under vacuum. The resulting residue was
partitioned between water (150 mL) and ethyl acetate (300
30 mL). The organic layer was separated, washed with saturated
a~ueous sodium bicarbonate (2 x 150 mL), saturated brine (2 x
150 mL), dried over magnesium sul~ate, filtered and
concentrated. The concentrated residue was purified by flash
chromatography on silica gel (eluting with 1: 9 ethyl
J 35 acetate:hexane) to give 7 g (60%) of pure methyl 4-(phenyl)-
5-(4-fluorophenyl)oxazole-2-pentanoate as a yellow oil.
CA 0222l692 l997-ll-l9
WO 96/36617 PCT/US~-'06~:12
182
Chlorosulfonic acid (38.6 g, 0.33 mol) was slowly added
to methyl 4-(phenyl)-5-(4-fluorophenyl)oxazole-2-pentanoate
(4.7 g, 0.013 mol) at 5 ~C. The ice bath was removed, and
the reaction mixture was stirred ~or 3 h at room temperature.
The reaction mixture was diluted with methylene chloride (200
mL) and poured slowly into ice. The organic layer was
separated and added to ammonium hydroxide (50 mL) at room
temperature. The reaction mixture was stirred for 30 minutes
at room temperature. The organic layer was separated and
washed with water (1 x 200 mL), brine (1 x 200 mL), dried
over magnesium sulfate, filtered and concentrated. The
concentrated residue was puri~ied by ~lash chromatography on
silica gel (eluting with 9:11 ethyl acetate:hexane) to give
0.74 g (13%) of methyl 4-[(4-aminosul~onyl)phenyl]-5-(4-
fluorophenyl)-oxazole-2-pentanoate as a pale yellow solid:
m.p. 82.4-87.4 ~C. lH NMR (CDCl3/300 MHz) 1.74-1.95 (m, 4H),
2.40 (t, 2H, J = 7.25 Hz), 2.88 (t, 2H, J = 7.35 Hz), 3.67
(s, 3H), 4.93 (bs, 2H), 7.07-7.13 (m, 2H), 7.50-7.55 (m, 2H),
7.75 (d, 2H, J = 8.66 Hz), 7.89 (d, 2H, J = 8.66 Hz). 19F NMR
(CDCl3/300 MHz) -111.22 to -111.127 ppm. HRMS (calcd for
C21FH21N2OsS 433.1233) 433.1209.
Ste~ 3: Pre~aration of 4-~(4-aminosul~onvl)phenyl~-5-(4-
fluQro~henYl)-oxazole-2-pentanoic acid
Methyl 4-[(4-aminosulfonyl)phenyl]-5-~4-
fluorophenyl)oxazole-2-pentanoate (Step 2) (0.51 g, 1.2 mmol)
was dissolved in 30 mL of 1:1 THF/methanol. Lithium
hydroxide (0.2 g, 4.7 mmol) and 1 mL of water were added.
The reaction mixture was stirred for four days at room
30 temperature, then the solvents were removed at reduced
pressure. The concentrated residue was partitioned between
ethyl acetate (100 mL) and 3 N HCl (100 mL) in a separatory
funnel and shaken vigorously The organic layer was
separated and washed with saturated brine (1 x 100 mL), dried
35 over magnesium sulfate, filtered and concentrated. The a
concentrated residue was crystallized from ethyl acetate and
hexane to give 0.4 g (81%) of 4-[(4-aminosulfonyl)phenyl]-5-
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(4-~luorophenyl)oxazole-2-pentanoic acid as a white solid:
m.p. 153-154.5 ~C. lH NMR(CD30D/300 MXz) 1.69-1.79 (m, 2H),
1.85-1.95 (m, 2H), 2.38 (t, 2H, J = 7.15 Hz), 2.91 (t, 2H, J
= 7.35 Hz), 7.14-7.20 (m, 2H), 7.55-7.60 (m, 2H), 7.73 (d,
- 5 2H, J = 8.66 Hz), 7.90 (d, 2H, J = 8.46 Hz). 19F NMR
(CD3COD/300 MXz) -113.73 to -113.63 ppm. HRMS (calcd for
C20H1gN2OsFS 419.1077) 419.1083.
Example 116
0~;~
5-t(4-AminosulfonYl)phenyl]-4-(3~4-dichlorophenyl)
~,~-dimethyloxazole-2-butanoic acid
Ste~ 1: Pre~aration of methvl 5-(~henvl)-4-(3,4-
dichloro~henvl)-~ ~-dimethvloxazole-2-butanoate
2-sromo-2-(phenyl)-1-(3,4-dichlorophenyl)ethanone (3.00
g, 8.72 mmol), monomethyl 3,3-dimethylglutarate (3.0 g, 17.22
mmol), and powdered anhydrous potassium carbonate (1.79 g,
12.97 mmol) were mixed at room temperature in
dimethylformamide (40 mL) for 15 min. The dimethyl-formamide
solution was poured into ethyl acetate (200 mL). This
solution was extracted with water (2 x 100 mL), 10% aqueous
hydrochloric acid (2 x 100 mL), and finally extensively
extracted with saturated aqueous ammonium chloride (6 x 100
mL). The ethyl acetate layer was dried over anhydrous sodium
sulfate, and the solvent was removed at reduced pressure.
The resulting residue was purified by preparative silica gel
chromatography to give 2.78 g (73%) of the desired a-
acyloxyketone as a light yellow oil: lH MMR (CDCl3/300 MHz)
1.16 (s, 6H), 2.48 (s, 2H), 2.58 (AB, 2H, Jab = 15.0 Hz, ~v =
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26.0 Hz,), 3.61 (s, 3H), 6.70 (s, lH), 7.38-7.42 (m, 5H),
7.47 (d, lH, J = 8.1 Hz), 7.73 (dd, lH, J = 8.1 Hz, J = 2.0
Hz), 8.01 (d, lH, ~ = 2.0 Hz). FABMS m/z = 437 (m+H+). HRMS
(calcd for C22H22OsCl2 437.0923) 437.0905.
The a-acyloxyketone (2.53 g, 5.78 mmol) and ammonium
acetate (2.53 g, 32.8 mmol) were heated to reflux in acetic
acid (40 mL) for 8 h. The solution was poured into ethyl
acetate (200 mL) and extracted with water (2 x 200 mL),
saturated sodium bicarbonate (2 x 200 mL), and finally
saturated a~ueous ammonium chloride (1 x 200 mL). The ethyl
acetate layer was dried over anhydrous sodium sulfate, and
the solvent was removed at reduced pressure. The resulting
residue was purified by preparative silica gel chromatography
to give 1.57 g (65%) of methyl 5-(phenyl)-4-(3,4-dichloro-
phenyl)~ dimethyloxazole-2-butanoate as a yellow oil: lH
MMR (CDCl3/300 MXz) 1.10 (s, 6H), 2.44 (s, 2H), 2.95 (s, 2H),
3.67 (s, 3H), 7.37-7.56 (m, 7H), 7.79 (d, lH, J = 1.8 Hz).
FABMS m/z = 418 (m~H+). HRMS (calcd for C22H22C12N03 418.0977)
418.0969.
Ste~ 2: Pre~aration of methvl 5- r (4-aminosulfonYl)~henYll-
4-(3,4-dichloro~henvl)-~ ~-dimethyloxazole-2-butanoate
Methyl 5-(phenyl)-4-(3,4-dichlorophenyl)-
~dimethyloxazole-2-butanoate (Step 1) (980.0 mg, 2.34 mmol)
was cooled to -25 ~C in a dry ice/methanol bath.
Chlorosulfonic acid (15.0 mL) was added, and the solution was
warmed to room temperature over 1 h. The solution was
stirred for 6 h and slowly poured directly into ice (300 mL
in a 500 mL Erlenmeyer flask). The resulting heterogeneous
aqueous solution was poured into ethyl acetate (200 mL). The
ethyl acetate layer was collected, extracted with water (1 x
100 mL) and mixed with ammonium hydroxide solution (50 mL)
for 30 min. The ethyl acetate was collected, extracted with
saturated a~ueous ammonium chloride (2 x 100 mL), dried over
sodium sulfate and concentrated in vacuo to give 924 mg (79%)
of methyl 5-[(4-aminosulfonyl)-phenyl]-4-(3,4-
dichlorophenyl)-~,~-dimethyloxazcle-2-butanoate as a foam:
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m.p. 54-57 ~C. lH NMR (CDC13/300 MHz) 1.19 (s, 6H), 2.45 (s,
2H), 2.99 ( s, 2H), 3.68 (s, 3H), 4.89 (bs, 2H), 7.42-7.48
(m, 2H), 7.69 (d, 2H, J = 8.5 Hz), 7.76 (d, lH, J = 1.7 Hz),
7.92 (d, 2H, J = 8.5 Hz). FABMS m/z = 497 (m+H+). HRMS
(calcd for C22H22Cl2M2O5S 497.0705) 497.0681.
i
Ste~ 3: Pre~aration of 5-r(4-aminosulfonvl)~henvll-4-(3,4-
dichloro~henYl)-~ ~-dimethvloxazole-2-butanoic acid
Methyl 5-[(4-aminosulfonyl)phenyl]-4-(3,4-
dichlorophenyl)-~,~-dimethyloxazole-2-butanoate (Step 2)
(165.0 mg, 0.33 mmol) and lithium hydroxide mono hydrate
(15.0 mg, 0.36 mmol) were mixed in tetrahydrofuran-methanol-
water (5.0 mL, 7:2:1) and stirred at room temperature for 16
h. The solution was acidified with 10% aqueous hydrochloric
acid (pH = 1) and poured into ethyl acetate (50 mL). The
organic layer was extracted with brine (2 x 25 mL), dried
over sodium sulfate and concentrated at reduced pressure to
give 140 mg (87%) of 5-[(4-aminosulfonyl)phenyl]-4-(3,4-
dichlorophenyl)-~,~-dimethyloxazole-2-butanoic acid as a foam:
m.p. 82-85 ~C. lH NMR (CD30D/300 MHz) 1.20 (s, 6H), 2.41 (s,
2H), 3.02 (s, 2H), 7.53 (dd, lH, J = 8.4 Hz, J = 2.1 Hz),
7.57 (d, lH, J = 8.4 Hz), 7.72 (d, 2H, J = 8.7 Hz), 7.78 (d,
lH, J = 2.1 Hz), 7.94 (d, 2H, J = 8.7 Hz). FABMS m/z = 483
(m+H+). HRMS (calcd for C21H20C12N2O5S 483.0548) 483.0522.
Other representative examples prepared ~y similar methods
from 2-bromo-2-(phenyl)-1-(3,4-dichlorophenyl)-ethanone are
summarized in Table 2.
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Example 123
..
O
H,C~ \Q~ co2~
4-~(4-Methylsulfonyl)phenyl]-5-(3,4-
dichlorophenyl)oxazole-2-butanoic acid
Ste~ 1: Pre~aration of 2-(3,4-dichloro~henvl)-2-
hvdroxv-l- r (4-methvlthio)-~henvllethanone
Trimethylsilyl cyanide (14.6 g, 0.147 mol) was
diluted with 30 mL o~ methylene chloride and added to a
solution of 3, 4-dichlorobenzaldehyde (25 g, 0.143 mol)
in 100 mL of methylene chloride over 20 minutes. The
reaction mixture was stirred at room temperature for 1
h. The reaction mixture was diluted with 200 mL of
methylene chloride, and the organic solution was washed
with saturated sodium bicarbonate (2 x 150 mL),
saturated brine (2 x 150 mL), dried over magnesium
sulfate, filtered and concentrated to give 3 9 g of a
brown oil, which was used in the next reaction without
further purification.
Magnesium (1.8 g, 0. 073 mol) was suspended in ether
(20 mL), and iodomethane (0.1 mL) was added. 4 -
sromothioanisole (14.8 g, 0. 073 mol), dissolved in 100
mL of ether, was added over 50 min., and the reaction
mixture was stirred overnight at room temperature. The
cyanohydrin (10 g, 0.036 mol) was diluted with 100 mL of
ether and added to the pre-formed Griynard reagent over
a 1 h period. The reaction mixture was stirred for 3 h
3 0 at room temperature. The reaction was slowly quenched
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with 50 mL of 3 N HCl and the aqueous layer was removed
by separation. The organic layer was washed with water
(2 x 100 mL), saturated sodium bicarbonate (1 x 100 mL),
saturated brine (1 x 100 mL), dried over magnesium
sulfate, filtered and concentrated. A solution of 9:1
trifluoroacetic acid:water (50 mL) was added to the
concentrated r~sidue, and the mixture was stirred for
1.5 h at room temperature. The reaction mixture was
neutralized by adding solid sodium carbonate. Water
(300 mL) and ether (300 mL) were added. The ether layer
was separated and washed with saturated sodium
bicarbonate (2 X 150 mL), saturated brine (2 X 150 mL),
dried over magnesium sulfate, filtered and concentrated.
The crude material was purified by flash chromatography
on silica gel eluting with 1:9 ethyl acetate:hexane to
give 3.3 g (28%) of the desired benzoin as a yellow oil.
This yellow oil was crystallized from hexane and ethyl
acetate to give 0.46 g of 2-(3,4-dichlorophenyl)-2-
hydroxy-1-[(4-methylthio)phenyl]ethanone as a white
20 solid: m.p. 54-58 ~C. HRMS (calcd for C15H12O2SCl2
327 . 0013 ) 327 . 0024.
Step 2: Pre~aration of meth~l 4-~(4-
methYlthio)phenvll-5-(3,4-dichlorophenYl)oxazole-2-
hutanoate
5-(Methoxycarbonyl)pentanoyl chloride (1.63 g, 9.9
mmol) was diluted with 20 mL of methylene chloride and
was added to a solution of 2- (3, 4-dichloro-phenyl)-2-
hydroxy-1-[(4-methylthio)phenyl]ethanone (Step 1) ( 3 . 24
g, 9.9 mol) in 60 mL of methylene chloride containing
triethylamine (2 g, 0.02 mmol). The reaction mixture was
stirred for 1.5 h at room temperature. The reaction
mixture was diluted with 100 mL of methylene chloride
and washed with water (1 x 100 mL), saturated brine (1 x
100 mL), dried over magnesium sulfate, filtered,
concentrated and dried under high vacuum. Acetic acid
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(10 mL) and ammonium acetate (3.05 g, 0.04 mol) were
added to this concentrated residue, and the mixture was
heated at 100 ~C for 3 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 x 100 mL),
saturated brine (1 x 100 mL), dried over magnesium
sulfate, filtered and concentrated. The concentrated
residue was purified by flash chromatography on silica
gel (eluting with 1:4 ethyl acetate:hexane) to give 2.14
g (50%) of methyl 4-[(4-methylthio)phenyl]-5-(3,4-
dichlorophenyl)oxazole-2-butanoate as a yellow oil.
Ste~ 3: Preparation of methvl 4- r (4-
methylsulfonvl)phenyll-5-(3,4-dichlorophenyl)oxazole-2-
hutanoate
Methyl 4-[(4-methylthio)phenyl]-5-(3,4-
dichlorophenyl)oxazole-2-butanoate (1.7 g, 3.89 mmol)
from Step 2 was dissolved in 60 mL of methanol:water
(9:1), then Oxone~ (8.38 g, 0.014 mol) was added. The
reaction mixture was stirred for 3 h at room
temperature, and the solvents were removed under reduced
pressure. 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 x 100 mL), saturated brine (2 x
100 mL), dried over magnesium sulfate, filtered and
concentrated. The crude product was purified by flash
chromatography on silica gel (eluting with 3:7 ethyl
acetate:hexane) to give 0.6 g (33%) of methyl 4-[(4-
methylsulfonyl)phenyl]-5-(3,4-dichlorophenyl)oxazole-2-
~ butanoate as a clear oil: lH MMR (CDC13/300 MHz) 2.15-
2.25 (m, 2H), 2.52 (t, 2H, J = 7.35 Hz), 2.94 (t, 2H, J
= 7.35 Hz), 3.09 (s, 3H), 3.70 (s, 3H), 7.36 (dd, lH, J
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= 2.01 Hz), 7.46 (d, lH, J = 8.46 Hz), 7.69 (d, lH, J =
2.01 Hz), 7.85 ( d, 2H, J = 8.66 Hz), 7.96 (d, 2H, J =
8.46 Hz). HRMS (calcd ~or C21HlgNOsSCl2 468.0439)
468.0435
Step 4: PreDaration of 4- r (4-methylsulfonvl)~he~yll-5-
(3,4-dichlorophenyl)oxazole-2-butanoic acid
The methyl ester (0.5 g, 1.07 mmol) from Step 3 was
mixed with 15 mL of methanol, lithium hydroxide (O.18 g,
4.27 mmol) and 1 mL of water. The reaction mixture was
stirred for 1 h at room temperature and quenched with 15
mL of lN HCl. The solvents were removed, and the
resulting residue was partitioned between 1 N HCl (100
mL) and ethyl acetate (100 mL). The organic layer was
separated, washed with 1 N HCl (1 x 100 mL), saturated
brine (1 x 100 mL), dried over magnesium sulfate,
filtered and concentrated. The concentrated residue was
crystallized from methylene chloride and hexane to give
0.26 g (54%) o1~ 4-[(4-methylsulfonyl)phenyl]-5-(3,4-
dichlorophenyl)oxazole-2-butanoic acid as white
crystals: m.p. 181.7-182.9 ~C. lH NMR (CD30D/300 MHz)
2.10-2.20 (m, 2H), 2.48 (t, 2H, J = 7.15 Hz), 2.97 (t,
2H, J = 7.45 Hz), 3.16 (s, 3H), 7.46 (dd, lH, J = 2.11
Hz), 7.58 (d, lH, J = 8.46 Hz), 7.74 (d, lH, J = 2.01
Hz), 7.85 ( d, 2H, J = 8.66 Hz), 8.00 (d, 2H, J = 8.66
Hz). HRMS (calcd for C20H17NOsSCl2 454.0283) 454.0277.
Example 124
/~
H2N~ ~
~Ir~ CO2H
C~
Cl
-
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4-~(4-Aminosulfonyl)phenyl]-5-~3,4-
dichlorophenyl)oxazole-2-butanoic acid
r 5 Step 1: Pre~aration of 2-(3,4-dichlorophenyl)-2-
hvdroxy-l-phenylethanone
Trimethylsilyl cyanide (14.6 g, 0.147 mol) was
dissolved in 30 mL of methylene chloride and added over
20 minutes to a solution of 3,4-dichloro-benzaldehyde
(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. The reaction
mixture was diluted with 200 mL of methylene chloride
and the organic layer was washed with saturated sodium
bicarbonate (2 x 150 mL), saturated brine (2 x 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 over 15
minutes. 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 x 150 mL), saturated
brine (1 x 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, washed with saturated
sodium bicarbonate (1 x 150 mL), saturated brine (1 x
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192
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-hydroxy-1-(phenyl)ethanone as a
yellow solid: HRMS (calcd. for C14Hl0O2Cl2 281.0136)
281.0112.
Ste~ 2: Pre~aration of methvl r(4-~henyl)-5-(3,4-
~;chloro~henvl)oxazolel-2-butanoate
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-
l-[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 x 100 mL),
saturated brine (1 x 100 mL), dried over magnesium
sulfate, filtered, concentrated and dried under high
vacuum. Ammonium acetate (4.6 g, 0.06 mol) and 30 mL of
acetic acid were added. The reaction mixture was heated
at 100 ~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 x 100 mL),
saturated brine (1 x 10-0 mL), dried over magnesium
sulfate, filtered and concentrated. The concentrated
residue was purified by flash chromatography on silica
gel (eluting wi~h 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 C20H17NO3Cl2 390.0664) 390.0648.
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Ste~ 3: Pr~aration ~f methvl 4- r (4-
aminosulfonvl)Dhenvll-5-(3,4-dichloro~henyl)oxazole-2-
butanoate
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 ~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 x 100 mL). The organic layer was
separated, poured into 50 mL of concentrated ammonium
hydroxide and stirred for 30 minutes at room
temperature. The organic layer was separated, washed
15 with water (1 x 100 mL), saturated brine (1 x 100 mL),
dried over magnesium sulfate, filtered and concentrated.
The crude r,ateLial was cI-ys~allized from me~hanol and
water to give 1.7 g (38%) of methyl 4-[(4-
aminosulfonyl)phenyl]-5-(3,4-dichlorophenyl)oxazole-2-
20 butanoate as a yellow solid: m.p. 130.7-131.8 ~C. HRMS
(calcd. for C2oHlgN2oscl2 469.0392) 469.0413.
Ste~ 4: Pre~aration of 4- r (4-aminosulfonYl)~henvll-5-
(3,4-dichloro~henYl)oxazole-2-butanoic acid
Methyl 4-[(4-aminosulfonyl)phenyl]-5-(3,4-
dichlorophenyl)oxazole-2-butanoate (Step 3) (0.6 g, 1.28
mmol) was dissolved in 30 mL of 1:1 methanol/THF.
Lithium hydroxide (0.21 g, 5.11 mmol) and 3 mL of water
were added. The reaction mixture was stirred for 18 h
at room temperature. The solvents were removed, and the
resulting residue was partitioned between 1 N HCl (100
mL) and ethyl acetate (100 mL). The organic layer was
separated and washed with saturated sodium bicarbonate
- (1 x 100 mL). The aqueous layer was acidified by adding
35 excess 3M HCl and extracted with ethyl acetate (2 x 100
mL). The combined organic layers were washed with
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saturated brine (1 x 100 mL), dried over magnesium
sul~ate, ~iltered and concentrated to give 0.27 g (46%)
of 4-[(4-aminosulfonyl)phenyl]-5-(3,4-dichlorophenyl)-
oxazole-2-butanoic acid as a yellow solid: m.p. 168-171
~C. HRMS (calcd for C19H16N2OsSCl2 455.0235) 455.0197.
Example 12 5
~ \>~ CO2H
H2N~
O~ ~0
5-[4-~(Aminosulfonyl)phenyl]-4-phenyl-aS-(lH-
pyrrol-l-yl)oxazole-2-butanoic acid
SteD 1: Pre~aration of meth~l 5- r (4-
aminosulfonvl)~henYll-aS-
r r (~henYlmethoxY)carbonvllaminol-4-~hen~loxazole-2-
rbutanoate
A solution o~ 2-bromo-2-[(4-aminosulfonyl)phenyl]-
1-phenylethanone (1.0 g, 2.8 mmol) and N-Cbz-glutamic
acid a-methyl ester (0.92 g, 3.1 mmol) in
dimethylacetamide (5.0 mL) was treated with K2CO3 (0.27
g, 1.96 mmol) and 18-crown-6 (0.05 g), and stirred at
room temperature for 3.5 h. The reaction mixture was
poured into water (50 mL) and extracted with EtOAc (3 x
25 mL). The combined organic phase was washed with water
(2 x 25 mL), dried (Na2SO4), ~iltered, and concentrated
to give an amorphous pale yellow substance. This
material was dried in vacuo for 3 h, then dissolved in
glacial acetic acid (10 mL). A~ter adding NH40Ac (0.7 g,
9.1 mmol), the resulting mixture was heated at 100 ~C
for 2.5 h under a nitrogen atmosphere. The acetic acid
CA 0222l692 l997-ll-l9
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195
was removed in vacuo, and the residue was partitioned
between water (50 mL) and EtOAc (50 mL). The organic
phase was washed with water, dried (Na2SO4), filtered,
and concentrated under reduced pressure. The residue
was purified by silica gel flash chromatography (eluting
with 40% EtOAc in hexane) to give 0.9 g (58%) of methyl
5- [ ( 4-aminosulfonyl)phenyl]-aS-
[[(phenylmethoxy)carbonyl]amino]-4-phenyloxazole-2-
[butanoate as a white amorphous substance: 1H-MMR
(CD30D/300 MHz) 7.86 (d, 2H, J = 8 4 Hz), 7.66 (d, 2H, J
= 8.4 Hz), 7.54 (m, 2H), 7.4 (m, 3H), 7.3 (s, 5H), 5.05
(s, 2H), 4.4 (m, lH), 3.72 (s, 3H), 3.01 (t, 2H, J = 7.2
Hz), 2.42 (m lH), 2.21 (m, lH); FABMS: m/z = 550 (M+H+)
HRMS (calcd for C2gH2gN3O7S 550.1648) 550.1616.
Ste~ 2: Preparation of meth~l 5-r4-(aminosulfon~l)
~henyll-4-phenvl-aS-(lH-pyrrol-1-yl)oxazole-2-butanoate
A solution of methyl 5-[(4-aminosulfonyl)phenyl]-
aS-[[(phenylmethoxy)carbonyl]amino]-4-phenyloxazole-2-
[butanoate (Step 1) (1.0 g, 1.82 mmol) in EtOAc (20 mL)
was treated with 10% Pd/C (0.5 g) and hydrogenated at 50
psi ~or 3 h at room temperature. The catalyst was
removed by filtration, and the filtrate was
concentrated. The residue was dissolved in glacial
acetic acid (10 mL), then MaOAc (0.9 g) and 2,5-
dimethoxytetrahydrofuran (0.26 g, 2.0 mmol) were added,
and the mixture was heated at 100 ~C for 15 min under a
nitrogen atmosphere. The acetic acid was removed in
vacuo, and the residue was partitioned between water (25
mL) and EtOAc (30 mL). The organic phase was washed
with water, dried (Na2SO4), filtered, and concentrated.
The resulting material was purified by silica gel flash
chromatography eluting with 45% EtOAc in hexane, to give
0.35 g (41%) of methyl 5-[4-(aminosulfonyl)
phenyl]-4-phenyl-aS-(lH-pyrrol-1-yl)oxazole-2-butanoate
as a white amorphous material: lH-~MR (CD30D/300 MHz)
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7.87 (d, 2H, J = 8.7 Hz), 7.66 (d, 2H, J = 8.7 Hz),
7.54 (m, 2H), 7.42 (m, 3H), 6.79 (t, 2H, J = 2.1 Hz),
6.09 (t, 2H, J = 2.1 Hz), 4.95 (m, lH), 3.72 (s, 3H),
2.86-2.45 (m, 4H) FABMS m/z = 466 (M+H+). HRMS (calcd
for C24H24N3OsS 466.1437) 466.1458.
Ste~ 3: Pre~aration of 5-r4-r(Aminosulfonvl)phenvll-4-
~henyl-aS-(lH-pyrrol-1-yl)oxazole-2-butanoic aci~
A solution of methyl 5-[4-(aminosulfonyl)
phenyl]-4-phenyl-aS-(lH-pyrrol-1-yl)oxazol-2-butanoate
(Step 2) (0.2 g, 0.43 mmol) in MeOH (0.3 mL) and water
(0.3 mL) was treated with NaOH (0.026 g) and stirred at
room temperatu ~ for 1.5 h The reaction mixture was
diluted with 5% citric acid (10 mL) and extracted with
EtOAc (2 x 20 mL). The combined organic extracts were
washed with water, dried (Na2SO4), filtered, and
concentrated under reduced pressure. The resulting
substance was purified by reverse-phase HPLC (using 10-
90% CH3CN in water (30 min gradient)). The appropriate
fractions were combined and freeze-dried to give 0.15 g
(78%) of 5-[4-[(aminosulfonyl)phenyl]-4-phenyl-aS-(lH-
pyrrol-1-yl)oxazole-2-butanoic acid as a light brown
powder. m.p. 74-78 ~C. lH-NMR (CD30D/300 MHz) 7.87 (d,
2H, J = 8.7 Hz), 7.66 (d, 2H, J = 8.7 Hz), 7.55 (m, 2H),
7.44 (m, 3H), 6.79 (t, 2H, J = 2.1 Hz), 6.08 (t, 2H, J =
2.1 Hz), 4.91 (m, lH), 2.85-2.45 (m, 4H) FABMS m/z = 452
(M+H+) HRMS (calcd for C23H22N3O5S 452.1280) 452.1291.
Other representative examples prepared by similar
methods are summarized in Table 3.
CA 02221692 1997-11-19
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Wo 96/36617 197
o oo ~ Ln
o o o~
~n . . .
o~ o
V ~ ~ ~ ~,
X ~
~0
~ ~ V
o ~ ~ ~ ~
zC/?~
c~l O
~ ~, Z Z
I
X
CA022216921997-11-19
WO96136617 PCT~S96/06992
198
Example 12 9
~CI I~CH2
2~s~
54-(2-Ethenyl-4-phenyloxazol-5-
yl]benzenesul~onamide
Ste~ 1: Pre~aration of 2-r5-~(4-
aminosulfonvl)~henYll-4-~henvl-oxazQl-2-Yll-1-
10 hvdroxvethane
Lithium aluminum hydride (0.33 g, 8.6 mmol) was
suspended in 5 mL of anhydrous THF and cooled to -7 8
~C. Methyl 5-[(4-aminosulfonyl)phenyl]-4-
phenyloxazole-2-acetate (1.6 g, 4.3 mmol) (prepared
similar to that described in Example 38, step 3) was
dissolved in 15 mL of anhydrous THF and added at -78
~C. The reaction mixture was stirred at -78 ~C for
2 h, stirred at room temperature overnight, and
quenched with 50 mL of 1 N HCl. The aaueous
solution was extracted with ethyl acetate (2 x 100
mL). The combined organic extracts were washed with
saturated sodium bicarbonate (1 x 100 mL), saturated
brine (1 x 100 mL), dried over magnesium sulfate,
filtered and concentrated. The concentrated residue
was purified by flash chromatography on silica gel
(eluting with 3:2 ethyl acetate:hexane to 4:1 ethyl
acetate:hexane) to give 0.2 g (14%) of 2-[5-[(4-
aminosulfonyl)phenyl]-4-phenyl-oxazol-2-yl]-1-
hydroxyethane as a white solid: lH NMR(DMSO-d6/300
MHz) 2.98 (t, 2H, J = 6.45 Hz), 3.81-3.87 (m, 2H),
4.91 (t, lH, J = 5.4 Hz), 7.35-7.46 (m, 5H), 7.56
CA 02221692 1997-11-19
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(dd, 2H, J = 1.65 HZ), 7.68 (d, 2H, J = 8.7 Hz),
7.84 ~d, 2H, J = 8.7 Hz). HRMS (calcd for
C17H16N2O4S 345.0909) 345.0902.
Step 2: Pre~aration of 4-(2-ethenyl-4-
~henyloxazol-5-yllbenzenesulfonamide
2-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-oxazol-
2-yl]-1-hydroxyethane (Step 1) (0.2 g, 0.58 mmol) in
4 mL of dimethylacetamide (DMA) was added to NaH
suspended in 1 mL o~ DMA at 5 ~C. The reaction
mixture was stirred at 5 ~C for 30 minutes. 4-[4-
Bromomethylphenyl]-4-methoxytetrahydropyran (0.2 g,
0.70 mmol) was dissolved in 3 mL of DMA and added to
the reaction at 5 ~C. The reaction mixture was
stirred at 5 ~C for 1.5 h and at room temperature
overnight. The DMA was removed at reduced pressure,
and the concentrated residue was dissolved in 150 mL
of ethyl acetate. The organic solution was washed
with 1 N HCl (2 x 100 mL), saturated sodium
bicarbonate (2 x 100 mL), saturated brine (2 x 100
mL), dried over magnesium sulfate, filtered and
concentrated. The concentrated residue was filtered
through silica gel (eluting with 4:1 ethyl
acetate:hexane). The material recovered from this
column was purified by reverse phase HPLC (eluting
with a gradient from 10~ to 90% acetonitrile in
water with 0.1~ TFA) to give 15 mg (8%) of 4-(2-
ethenyl-4-phenyloxazol-5-yl]benzenesulfonamide as a
white solid: lH MMR(CD30D/300 MHz) 5.82 (d, 1 H, J
= 11.70 Hz), 6.38 (d, lH, J = 17.40 Hz), 6.71 (dd,
lH, J = 11.10 Hz), 7.43-7.45 (m, 3H), 7.57-7.60 (m,
2H), 7.74 (d, 2H, J = 8.70 Hz), 7.89 (d, 2H, J =
8.40 Hz) HRMS (calcd for C17H14N203S 327.0803)
- 327.0800.
CA 02221692 1997-11-19
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Example 13 0
~¢ ~ ~ CO2H
H2N~
0~ ~0
3-[[~5-[4-Aminosulfonyl)phenyl]-4-
phenyloxazol-2-yl~methyl]thio~propanoic acid
Example 131
0~//o
H2N~ ~X~S~CO2H
3-~[~4-~4-Aminosul~onyl)phenyl]-5-
phenyloxazol-2-yl]methyl]thio]propanoic acid
Ste~ 1: Pre~aration of tert-butvl 3- r (2-methoxy-2-
oxoethyl)thiolpropanoate
A solution of tert-butyl acrylate (3.7 g, 0.03
mol) and methyl thioglycolate (3.3 g, 0.31 mol ) in
CH2Cl2 (10 mL) was treated with DBU (0.3 g, 0.002
mol), and stirred at 10 ~C for 2 h. The reaction
mixture was diluted with CH2C12 (100 mL), washed
sequentially with 5% citric acid (2 x 50 mL), brine
(2 x 50 ml), and dried (Na2SO4). After the removal
of the solvent, the resulting liquid was purified by
silica gel flash chromatography (eluting with 30%
EtOAc in hexane) to give 6.0 g (90%) of tert-butyl
CA 02221692 1997-11-19
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201
3-[(2-meth~xy-2-oxoetllyl)-thio]propanoate as a
colorless liquid: lH-NMR (CDCl3/300 MHz) 3.75 (s,
3H), 3.26 (s, 2H), 2.87 (t, 2H, J = 6.9 Hz), 2.55
(t, 2H, J = 6.9 Hz), 1.46 (s, 9H).
Ste~ 2: Preparation of tert-butyl 3-
r ( carboxvmethvl)
thiolpro~anoate
A solution of tert-butyl 3-[(2-methoxy-2-
oxoethyl)thio]propanoate (Step 1) (2.0 g, 8.5 mmol)in MeOH (6.00 mL) and water (4.0 mL) was treated
with LioH (0.45 g, 10.8 mmol) and stirred at room
temperature for 2 h. The reaction mixture was
diluted with water (15 mL) and washed with EtOAc (2
x 10 mL). The aqueous phase was acidified with 5%
citric aci~ and extracted with EtOAc (2 x 15 mL).
The combined organic extracts were washed with
brine, dried (Na2SO4), filtered, and concentrated to
give 1.1 g (59%) of tert-butyl 3-
[(carboxymethyl)thio]propanoate as a colorlessli~uid which was used in the next step without
further purification: lH-NMR (CDCl3/300 MHz) 3.31
(s, 2H), 2.85 (t, 2H, J = 6.9 Hz), 2.58 (t, 2H, J =
6.9 Hz), 1.47 (s, 9H).
Ste~ 3: Pre~aration of tert-butyl 3- r r r5- r4-
aminosulfonvl)phenvll-4-phenvl-oxazol-2-vllmethyll-
thiolpropanoate and tert-butyl 3-rrr4-r4-
ami~osulfonvl)-phenyll- 5 -~henvloxazol-2-
yllmethyllthiolpropanoate
A mix~ure of 2-bromo-2-[(4-
aminosulfonyl)phenyl]-1-phenylethanone (1.3 g, 3.7
mmol), tert-butyl 3-[(carboxymethyl)thio]propanoate
- (Step 2) (1.0 g, 4.5 mmol), and K2CO3 (0.40 g, 2.9
mmol) in dimethylacetamide (5.0 mL) was stirred at
10 ~C for 2 h, and at room temperature for 1 h. The
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reaction mixture was diluted with water (50 mL), and
extracted with EtOAc (2 x 25 mL). The combined
organic extracts were washed with water (2 x 25 mL),
dried (Na2SO4), filtered, and concentrated to give
the desired a-acyloxy ketone. The resulting viscous
liquid (1.5 g) was used in the following reaction
without further purification.
This ~-acyloxy ketone (1.3 g) was dissolved in
acetic acid (20 mL), NH40Ac (0.8 g, 10.4 mmol) was
added, and the resulting mixture was heated at 100
~C for 2.5 h under a nitrogen atmosphere. The
acetic acid was distilled in vacuo, and the residue
was partitioned between water (25 mL) and EtOAc (30
mL). The organic phase was washed with water, dried
(Na2SO4), filtered, and concentrated under reduced
pressure. The resulting residue was purified by
silica gel flash chromatography (eluting with 40%
EtOAc in hexane) to give 0.45 g (36%) of a mixture
of tert-butyl 3-[[[5-[4-aminosulfonyl)phenyl]-4-
phenyl-oxazol-2-yl]methyl]thio]propanoate and tert-
butyl 3-[[ r 4-[4-amino-sulfonyl)phenyl]-5-
phenyloxazol-2-yl]methyl]-thio]propanoate oxazole
esters, as a light brown amorphous substance: m.p.
49-54 ~C. lH-NMR (CDCl3/300 MHz) 7.81 (d, 2H, J =
7.8 Hz), 7.66 (d, 2H, J = 7.8 Hz), 7.52 (m, 2H),
7.33 (m, 3H), 4.84 (s, 2H), 3.83 (s, 2H), 2.87 (t,
2H, J = 6.9 Hz), 2.53 (t, 2H, J = 6.9 Hz), 1.37 (s,
9H). HRMS (calcd for C23H27N2OsS2 475.1361) 475.1326.
Ste~ 4: Pre~aration of 3-rrr5-r4-
~minosulfonyl)~henyll-4-~henyloxazol-2-vll~eth
thiolpro~anoic a~i~ and 3-r r r4-r4-
~mi nosulfonyl)~henyll-5-~henyloxazol-2-
yllmethvllthiol~ro~anoic acid
A mixture of the oxazole esters (0.25 g, 5.2
mmol) Step 3, and p-toluenesulfonic acid (0.06 g 0.3
_
CA 0222l692 l997-ll-l9
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203
mmol) in acetonitrile (5.0 mL) was heated to re~lux
for 1.5 h under a nitrogen atmosphere. The reaction
mixture was concentrated under reduced pressure, and
~he residue was partioned between water (10 mL) and
~tOAc (20 mL). The organic phase was washed with
water, dried (Na2SO4), ~iltered, concentrated, and
~he resulting substance was purified by reverse-
phase HPLC (10-90% CH3CN/H2O) to give two isomeric
products: 3-[[[5-[4-aminosul~onyl)phenyl]-4-
phenyloxazol-2-yl]methyl]thio~propionic acid as a
white powder; (0.16 g (73~)) m.p. 170-173 ~C 1H-NMR
(CD30D/300 MHz) 7.9 (d, 2H, J = 8.7 Hz), 7.71 (d,
2H, J = 8.7 Hz), 7.57 (m, 2H), 7.42 (m, 3H), 3.98
(s, 2H), 2.95 (t, 2H, J = 7.2 Hz), 2.67 (t, 2H, J =
7.2 Hz); HRMS (calcd for C19H1gN2OsS2 419.0735) found
~19.0700;
3-[[[4-[4-aminosulfonyl)phenyl]-5-phenyl-oxazol-2-
yl]methyl]thio]propionic acid as a light brown
powder: (0.03 g (14%)) m.p. 171-175 ~C; lH-NMR
(CD30D/300 MHz) 7.91 (d, 2H, J = 8.4 Hz), 7.76 (d,
2H, J = 8.4 Hz), 7.56 (m, 2H), 7.43 (m, 3H), 3.97
(s, 2H), 2.94 (t, 2H, J = 6.9 Hz), 2.67 (t, 2H, J =
6.9 Hz); HRMS (calcd ~or C19H1gN2OsS2 419.0735)
419.0708.
ExaInple 13 2
~ /--C02H
~o~
~~
~s
H~N
-
4-tt5-t(4-Aminosulfonyl)phenyl]-4-phenyl-
oxazol-2-yl]methyl]benzenepropanoic acid
.
CA 0222l692 l997-ll-l9
WO 96t36617 PCTIUS9C/U~9!~2
204
Ste~ 1: Pre~aration of 5-~(4-
~ 1 n osulfonyl)~henyll-4-~henvl-2-~(4-iodo-
phenvl)methvlloxazole
A mixture of 2-bromo-2-[(4-
aminosulfonyl)phenyl]-1-phenylethanone (2.0 g, 5.65
mmol) and 4-iodophenylacetic acid (1.8 g, 6.9 mmol)
in dimethylacetamide (6.0 mL) was treated with
potassium carbonate (0.57 g, 4.13 mmol) and 18-
crown-6 (0.06 g) and stirred at room temperature for
4 h. The reaction mixture was diluted with cold
water (50 mL) and extracted with ethyl acetate (3 x
30 mL). The combined organic phases were washed
with water (2 x 25 mL), dried (Na2SO4), filtered,
and concentrated under reduced pressure. The
resulting material was purified by flash
chromatogr~phy on silica gel (eluting with 40% EtOAc
in hexane) to give the desired a-acyloxy ketone as
an amorphous substance, which was used in the next
reaction without ~urther puri~ication: lH-NMR
(CDCl3/300 MHz) 7.86 (m, 4H), 7.63 (d, 2H, J = 8.4
Hz), 7.59 (m, 3H), 7.41 (t, 2H, J = 7.8 Hz), 7.03
(d, 2H, J = 8.4 Hz), 6.89 (s, lH), 4.82 (s, 2H),
3.73 (~, 2H, J = 5.1 Hz). FABMS m/z = 536 (M~H+)
HRMS (calcd for C22H1gNOsSI 536.0029) 536.0023.
A mixture of this a-acyloxy ketone (2.2 g, 4.1
mmol), and ammonium acetate (1.3 g, 16.9 mmol) in
acetic acid (15.0 mL) was heated at 100 ~C under a
nitrogen atmosphere for 2.5 h. The reaction mixture
was concentrated in vacuo, and the residue was
partitioned between water (50 mL) and EtOAc (50 mL).
The organic phase was washed with water (2 x 30 mL),
dried (~a2SO4), filtered, and concentrated under
reduced pressure. The resulting solid was
tri~urated with methanol, cooled and filtered to
-
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205
give 1.1 g (52%) of 5-[(4-aminosulfonyl)phenyl]-4-
phenyl-2-[(4-iodophenyl)
methyl]oxazole as a pale yellow powder: m.p. 198-201
- ~C. lH-NMR (CDC13/ 300 MHz) 7.86 (d, 2H, J = 8.7
Hz), 7.7 (dd, 4H), 7.59 (m, 2H), 7.41 (m, 3H), 7.15
(d, 2H, J = 8.1 Hz), 4.81 (s, 2H), 4.16 (s, 2H).
FABMS m/z = 517 (M+H+) HRMS (calcd for C22HlgN2O3SI
517.0083) 517.0063.
Ste~ 2: Preparation of methyl 4-rr5-r(4-
~mi nosulfo~vl)~henyll-4-~henvl-oxazol-2
yllmethvllbenzenepropynoate
To a solution of 5-[(4-aminosulfonyl)phenyl]-4-
phenyl-2-[(4-iodophenyl)methyl]oxazole (Step 1) (0.3
g, 0.58 mmol) in dimethylacetamide (5.00 mL) was
added K2C03 (0.05 g, 0.3 mmol), 18-crown-6 (0.05 g),
PdCl2-(PPh3)2, methyl propiolate (0.32 g, 3.8 mmol)
and CuI (0.005 g), and the resulting mixture was
stirred at room temperature for 16 h under an argon
atmosphere. The reaction mixture was diluted with
water (10 mL) and extracted with EtOAc (2 x 25 mL).
The combined organic extracts were washed with
brine, dried (Na2SO4), filtered, and concentrated
under reduced pressure. This residue was purified
by silica gel flash chromatography (25% EtOAc in
hexane) to afford 0.11 g (40%) of methyl 4-[[5-[(4-
amino-sulfonyl)phenyl]-4-phenyl-oxazol-2-
yl]methyl]benzenepropynoate as a brown amorphous
powder: lH-NMR (CDCl3/300 MHz) 7.87 (d, 2H, J = 8.7
Hz), 7.68 (d, 2H, J = 8.7 Hz), 7.59 (m, 4H), 7.43
(m, 5H), 4.78 (s, 2H), 4.25 (s, 2H), 3.84 (s, 3H)
FABMS m/z = 473 (M+H+) HRMS (calcd for C26H21N2OsS
473.1171) 473.1181.
-
Step 3: Preparation of 4-~r5-~(4-
aminosulfonvl)phenyll
CA 02221692 1997-11-19
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206
-4-~henyl-oxazol-2-~llmethYllbenzene~ro~anoic acid
- A mixture of methyl 4-[[5-[(4-
aminosulfonyl)phenyl]
-4-phenyl-oxazol-2-yl]methyl]benzenepropynoate (Step
2) (0.12 g, 0.25 mmol) in MeOH (5 mL) was
hydrogenated in the presence of 10% Pd/C (0.13 g) at
50 psi for 3 h at room temperature. The catalyst
was removed by filtration, the filtrate was
concentrated, and the residue was stirred with lM
LioH (1 mL) in MeOH (0.7 mL) and water (0.3 mL) for
1 h. The reaction mixture was diluted with 5%
citric acid (10 mL) and extracted with EtOAc (2 x 20
mL). The combined organic extracts were washed with
water, dried (Na2SO4), filtered, and concentrated
under reduced pressure to afford 0.08 g (69%) of 4-
[[5-[(4-aminosulfonyl)phenyl]-4-phenyl-oxazol-2-
yl]methyl]benzenepropanoic acid as a light brown
amorphous powder: lH-NMR (CDCl3/300 MHz) 7.83 (d,
2H, J = 8.7 Hz), 7.66 (d, 2H, J = 8.7 Hz), 7.58 (m,
2H), 7.39 (m, 3H), 7.31 (d, 2H, J = 8.1 Hz), 7.19
(d, 2H, J = 8.1 Hz), 4.9 (s, 2H), 4.18 (s, 2H), 2.95
(t, 2H, J = 7.0 Hz), 2.68 (t, 2H, J = 7.0 Hz) FABMS
m/z = 463 (M+H+). HRMS (calcd for C2sH23N2OsS
463.1328) 463.1324.
other representative examples prepared by
similar methods from 5-[(4-aminosulfonyl)phenyl]-4-
phenyl-2-[(4-iodophenyl)methyl]oxazole are
summarize~ in Tables 3 and 4.
CA 02221692 1997-11-19
WO 96/36617 207 PCTfU!~96106992
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CA 02221692 1997-11-19
WO 96/36617 208 PCT/US9~ 'OG992
ra~
o o ~ ,,~
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CA 02221692 1997-11-19
WO 96~366I7 PCTJUS9~;J~)69~2
209 ~
ExaLmple 14 1
F
\~ ~--C02H
~fo
o//~
5-~(4-Aminosulfonyl)phenyl]-4-(4-
fluorophenyl)oxazole-2-pentanoic acid
Ste~ 1. Pre~aration of 2- r (4-aminosulfonYl)~henv~
fluoro~henvl)-ethanone.
Neat 2- (phenyl)-1-(p-fluorophenyl)ethanone (6.10 g,
28.54 mmol) was cooled to -78 ~C in a dry ice methanol
bath. Chlorosulfonic acid (15.0 mL) was added, and the
solution was warmed to room temperature over 1 h. The
solution was stirred for 2 h and poured directly into
ice. The resulting heterogenous a~ueous solution was
extracted with ethyl acetate (2 x 300 mL) The ethyl
acetate layers were combined, extracted with water (1 x
100 mL) and mixed with ammounium hydroxide solution (50
mL) for 1 h. The ethyl acetate was collected, extracted
with lN HCl (2 x 200 mL), brine (1 x 200 mL), and dried
over sodium sulfate. The solvent was removed to a volume
of 50 mL and crystals formed. The crystals were kept at
room temperature for 4 h and collected by vaccuum
filtration to give 3.1 g (37%) of 2-[(4-
aminosulfonyl)phenyl]-1-(p-fluorophenyl)ethanone: m.p.
198-204 ~C. lH NMR (CD30D/300 MHz) 4.46 (s, 2H), 7.23 (t,
2H, J = 8.8 Hz), 7.43 (d, 2H, J = 8.5 Hz), 7.85 (d, 2H, J
= 8.5 Hz). 8.10-8.20 (m, 2H). FABMS m/z = 294 (m+H+) HRMS
(calcd for C14H13FNO3S 294. 0600) 294. 0583.
CA 02221692 1997-11-19
WO 96/36617 . PCTIUS9''0~9~2
210
Ste~ 2: Pre~aration of 2-r (4-aminosulfonYl)Dhenvll-2-
bromo-1-(~-fluoro-~henvl)ethanone
To a solution of 2-[(4-aminosulfonyl)phenyl]-1-(p-
fluorophenyl)ethanone (Step 1) (2.93 g, 10.00 mmol) in
acetic acid (25 mL) at room temperature was added 33%
HBr in acetic acid (5.0 mL), followed by bromine (1.59 g,
10.00 mmol), and the solution was stirred at room
temperature for 1 h. The acetic acid was removed at
reduced pressure, and the resulting yellow li~uid was
poured into ethyl acetate (100 mL). This solution was
washed with saturated sodium bicarbonate (2 x 100 mL),
and brine (100 mL). The ethyl acetate layer was dried
over anhydrous sodium sulfate, filtered, and the solvent
was removed at reduced pressure to give 3.21 g (86%) of
2-[(4-aminosulfonyl)phenyl]-2-bromo-1-(p-
fluorophenyl)ethanone as a gummy foam: lH NMR (CDCl3/300
MXz) 5.05 (bs, 2H), 6.30 (s, lH), 7.16 (t, 2H, J - 8.6
Hz), 7.67 (d, 2H, J = 8.5 Hz), 7.92 (d, 2H, J = 8.5 Hz),
8.02-8.07 (m, 2H). FAsMS m/z = 389 (m+NH3+). HRMS (calcd
for C14H12BrF~O3S 371.9705) 371.9721.
Ste~ 3: Pre~aration of methvl 5- r (4-
aminosulfonvl)Dhenvll-4-(4-fluoro-~henyl)oxa~ole-2-
~entanoate
A mixture of 2-[(4-aminosulfonyl)phenyl]-2-bromo-1-
(p-fluorophenyl)ethanone (Step 2) (760 mg, 2.56 mmol) and
the sodium salt of adipic acid monomethyl ester (550 mg,
2.91 mmol) were combined in dimethyl~ormamide (5.0 mL)
and stirred at room temperature for 1 h. The solvent was
removed at reduced pressure, and the residue was taken up
in ethyl acetate (35 mL). This solution was washed with
saturated a~ueous ammonium chloride (2 x 25 mL), dried
over anhydrous sodium sulfate, and the solvent removed at
reduced pressure to give 924 mg (80%) of the desired a-
acyloxy ketone intermediate as a thick yellow oil: lH NMR(CDC13/300 MXz) 1.70-l.g5 (m, 4H), 2.31 ( t, 2H, J = 6.9
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Hz), 2.43-2.57 (m, 2H), 4.95 (bs, 2H), 6.85 (s, lH), 7.11
(t, 2H, J = 8.6 Hz), 7.60 (d, 2H, J = 8.3 Hz), 7.91 (d,
2H, J = 8.3 Hz), 7.95-8.00 (m, 2H). FABMS m/z = 452
(m~H+). HRMS (calcd for C21H23FN07S 452.1179) 452.1209.
This ~-acyloxy ketone intermediate (861 mg, 1.90
mmol) and ammonium acetate (1014 mg, 13.1 mmol) were
refluxed in acetic acid (5 mL) for 2 h. The solution was
poured into water (25 mL) and extracted with ethyl
acetate (3 x 25 mL). The ethyl acetate extracts were
combined and washed with saturated sodium bicarbonate (3
x 50 mL), and saturated aqueous sodium chloride (1 x 50
mL). The solution was dried over anhydrous sodium
sulfate, filtered, and the solvent was removed at reduced
pressure. The resulting residue was purified by flash
chromatography on silica gel to give 371 mg (45%) of
methyl 5-[(4-amino-sulfonyl)phenyl]-4-(4-fluorophenyl)-
oxazole-2-pentanoate as a gummy yellow semi-solid: lH NMR
(CD30D/300 Mhz) 1.64-1.99 (m, 4H), 2.41 (t, 2H, J = 7.2
Hz), 2.91 (t, 2H, J = 7.3 Hz), 3.65 (s, 3H), 7.17 (t, 2H,
J = 8.9 Hz), 7.57-7.61 (m, 2H), 7.67 (d, 2H, J = 8.6 Hz),
7.88 (d, 2H, J = 8.6 Hz). FABMS m/z = 433 (m+H+). HRMS
(calcd for C21H22FN2OsS 433.1233) 433.1213.
Ste~ 4: Pre~aration of 5-~(4-aminosulfonyl)~henvll-4-
(4-fluoro~henyl)-oxazole-2-~entanoic acid
Methyl 5-[(4-aminosulfonyl)phenyl]-4-(4-
fluorophenyl)oxazole-2-pentanoate (Step 3) (264.0 mg,
0.61 mmol) and lithium hydroxide monohydrate (100.0 mg,
2.40 mmol) were mixed in tetrahydrofuran/methanol/water
30 (10.0 mL, 7:2:1) at room temperature for 16 h. The
solution was acidified with 10% aqueous hydrochloric acid
(pH = 1 ) and poured into ethyl acetate (30 mL). The
solution was extracted with 10% aqueous hydrochloric acid
- (10 mL). The ethyl acetate layer was dried over sodium
sulfate, filtered, and the solvent was removed at reduced
pressure to give 251 mg (99%) of the desired product 5-
,
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[(4-aminosulfonyl)-phenyl]-4-(4-fluorophenyl)-oxazole-2-
pentanoic acid as a white solid: m.p. 164.0-165.6 ~C. lH
NMR (CD30D/300 MXz) 1.69-1.99 (m, 4H), 2.38 (t, 2H, J =
7.2 Hz), 2.92 (t, 2H, J = 7.3 Hz), 7.17 (t, 2H, J = 8.8
Hz), 7.57-7.61 (m, 2H), 7.68 (d, 2H, J = 8.6 Hz), 7.88
(d, 2H, J = 8.6 Hz). FABMS m/z = 419 (m+H+). HRMS (calcd
for C2oH2oFN2oss 419.1077) 419.1082.
Example 14 2
F
I~N~
o~~
NH2
4-~2-Ethyl-4-(3-~luorophenyl)-oxazol-5-
yl]benzenesul~onamide
Ste~ 1: Pre~aration of 1-(3-fluoro~henvl~-2-~henvl-
ethan-1-one
3-Fluorobenzaldehyde (10.0 g, 81 mmol),
dichloromethane (100 mL), and zinc iodide (5 mg) were
stirred at 0 ~C under nitrogen. Trimethylsilylcyanide
(8.83 g, 89 mmol) was added dropwise with a slight
exotherm. The cooling bath was removed and the reaction
proceeded for 2 hours when water (5 mL) was added
dropwise. The mixture was washed with brine (2 X 30 mL),
dried over magnesium sulfate, and concentrated under high
vacuum. The resulting oily residue was dissolved in
tetrahydroruran (150 mL) and cooled to -78 ~C under
nitrogen. Lithium diisopropylamine (2.0 M solution in
heptane/tetrahydrofuran/ethylbenzene, 45 mL, 90 mmol) was
added dropwise maintaining the ~emperature below -60 ~C.
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The reaction was stirred for 1/2 hour and benzyl bromide
was added (15.4 g, 90 mmol) all at once. The cooling
bath was removed and the mixture was stirred until the
temperature reached -15 ~C and poured into a stirred
solution of lN hydrochloric acid (150 mL) and
trifluoroacetic acid (10 mL). After one hour, the
mixture was extracted with ethyl acetate (2 X 50 mL),
combined, washed with brine (2 X 50 mL), and
concentrated. The resulting dark oily residue was
treated with 2.5 N sodium hydroxide, and a solid was
collected by filtration. Recrystallization from
ethanol/water resulted in 11.4 g of a light yellow solid:
mp 54.6-57.0 ~C. This material was used in the next step
without further purification or characterization.
Ste~ 2. Pre~aration of 1-(3-fluoro~henvl)-2-bromo-2-
~henyl-ethan-l-one
1-(3-Fluorophenyl)-2-phenyl-ethan-1-one (Step 1)
(4.28 g, 20 mmol), acetic acid (50 mL), 33% hydrobromic
acid in acetic acid (10 mL), and bromine (3.2 g, 20 mmol)
were stirred at room temperature for 2 hours. The
mixture was concentrated and ethyl acetate (150 mL) was
added. After washing with brine, drying over magnesium
sulfate, and concentrating, 5.3 g of a brown oil was
obtained. This material was used in the next step
without further purification or characterization.
Ste~ 3. Pre~aration of 2-ethyl-4-(3-fluoro~henvl)-5-
phenyloxazole.
1-(3-Fluorophenyl)-2-bromo-2-phenyl-ethan-1-one
(Step 2) (1.5 g, 5.15 mmol), N~,N~-dimethylformamide (25
mL), sodium hydroxide (60%, 0.23 mL, 5.67 mmol), and
propionic acid (0.33 g, 5.67 mmol) were stirred at room
- temperature overnight. After the addition of ethyl
acetate (100 mL), the mixture was washed successively
with lN hydrochloric acid, brine, and water. The organic
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solution was dried over magnesium sulfate and
concentrated. The resulting oily residue was dissolved
in acetic acid (50 mL) and ammonium acetate (6.0 g) was
added. After refluxing for 12 hours, the mixture was
S concentrated, dissolved in ethyl acetate (100 mL), washed
with brine, dried and concentrated. Purification by
flash column chromatography (eluting with hexanes:ethyl
acetate (20:1)) yielded 0.6 g of a light yellow oil
which formed an oily solid upon standing: lH NMR
(CDC13~300 MHz) 7.57 (m, 2H), 7.5-7.25 (m, 5H), 7.02 (m,
lH), 2.88 (q, J = 8.7 Hz, 2H), 1.42 (t, J = 8.7 Hz, 3H).
This material was used in the next step without further
purification or characterization.
Ste~ 4: Preparation of 4-r2-ethyl-4-(3-fluorophenyl~-
oxazol-5-yilbenzenesulfonamide
Chlorosulfonic acid (10 mL) was cooled to -78 ~C.
2-Ethyl-4-(3-fluorophenyl)-5-phenyloxazole (Step 3) (0.6
g, 22 mmol) was dissolved in a minimllm amount of
dichloromethane and added dropwise. The mixture was
stirred and warmed to room temperature over 5 hours, when
it was added dropwise to ice (500 mL). ~mm~;um
hydroxide (100 mL) and ethyl acetate (100 mL) were added
and the mixture was stirred overnight. The layers were
separated and the organic phase was washed with 1 N
hydrochloric acid, and brine. After drying over
magnesium sulfate and concentrating, 0.4 g of a light
yellow solid was recrystallized from ethanol water: mp
133.5-135.1 ~C. 1H MMR (aCetOne-d6/300 MHZ) 7.96 (d, ~ =
9.3 Hz, 2H), 7.78 (d, J = 9.3 Hz, 2H), 7.5-7.3 (m, 3H),
7.18 (m, lH), 6.70 (bs, 2H), 2.90 (q, J = 8.3 HZ, 2H),
1.40 (t, ~ = 8.3 Hz, 3H). FABHRMS m/z 347.0848. (M+H,
C17H15FN2O3S calcd 347.0866).
BIOLOGICAL EVALUATION
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Rat Carrageenan Foot Pad Edema Test
The carrageenan foot edema test was performed with
materials, reagents and procedures essentially as
described by Winter, et al., ( Proc . Soc . ~xp . Biol . Med .,
5 111, 544 (1962)). Male Sprague-Dawley rats were selected
in each group so that the average body weight was as
close as p~ssible. 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 ~nim~ls was compared with that o~ a group
of placebo-treated ~nim~ls and the percentage inhibition
of edema was determined (Otterness and Bliven, Laboratory
Models for restin~ NSAIDs, in Non-steroidal Anti-
Inflammator~ Dru~s, (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 6.
Rat Carrageenan-induced Analgesia Test
The analgesia test using rat carrageenan was
performed with materials, reagents and procedures
essentially as described by Hargreaves, et al., (Pain,
32, 77 (1988)). Male Sprague-Dawley rats were treated as
previously described for the Carrageenan Foot Pad Edema
test. Three hours after the injection of the
carrageenan, the rats were placed in a special plexiglass
container with a transparent floor having a high
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intensity lamp as a radiant heat source, positionable
under the floor. After an initial twenty minute period,
thermal stimulation was begun on either the injected foot
or on the contralateral uninjected foot. A photoelectric
cell turned off the lamp and timer when light was
interrupted by paw withdrawal. The time until the rat
withdraws its foot was then measured. The withdrawal
latency in seconds was determined for the control and
drug-treated groups, and percent inhibition of the
hyperalgesic foot withdrawal determined. Results are
shown in Table 6.
TABLE 6.
RAT PAW EDEMA ANALGE S IA
% Inhibition % Inhibition
~ lOmq/k~ body wei~ht ~20ma/k~ body weiaht
Example
1 41* 44
3 30
7 24
8 12
18
11 42
16 26
28 2
31 5
52 61
371
461
1 ~ 3Omg/kg body weight
* ~ 20ma/k~ body weiaht
Evaluation of COX I and COX II activity in vi tro
The compounds of this inven~ion exhibited inhibition
in vitro of COx-2. The COX-2 inhibition activity of the
-
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compounds of this invention illustrated in the Examples
was determined by the following methods.
re~aration of recombinant COX baculoviruses
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-l 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 ~or COX-l and COx-2 in a manner similar
to the method of D.R. O'Reilly et al (Baculovirus
Expression Vectors: A ~aboratory Manual (1992)).
Recombinant baculoviruses were isolated by trans~ecting 4
~g of baculovirus transfer vector DNA into SF9 insect
cells (2x108) 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
Baculovir~s Vectors and Insect Cell Culture Procedures,
Texas Agric. EXp . Station Bull. 1555 (1987). Recombinant
viruses were purified by three rounds of pla~ue
purification and high titer (107 - 108 pfu/ml) stocks of
virus were prepared. For large scale production, SF9
insect cells were infected in 10 liter fermentors (0.5 x
106/ml) with the recombinant baculovirus stock such that
the multiplicity of in~ection 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 centrifugedat 10,000xG for 30 minutes, and the resultant supernatant
was stored at -80~C before being assayed for COX
activity.
b. Assay for COX-1 and COX-2 activitv
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COX activity was assayed as PGE2 formed/~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 ~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~C/room temperature by transferring 40 ~l of
reaction mix into 160 ~l ELISA buffer and 25 ~M
indomethacin. The PGE2 formed was measured by standard
ELISA technology (Cayman Chemical). Results are shown in
Table 7.
TABLE 7.
COX-1 CoX-2
20 ~xam~le ID50_~M ID50_~M
1 6.9 cO.1
3 >10 <0.1
14 >30 >10
>30 0.2
>10 0.5
28 >100 cO.1
>100 <0 1
31 >100 <0.1
32 15.9 <0.1
72 7.9
36 24.7 1.4
38 72 <0.1
39 >100 79
26 <0.1
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TABLE 7. ( cont )
COX-l COX-2
Fxample IDso_~M IDso_~M
42 11.4 <0.1
51 14.0 <0.1
52 35 0.2
53 >100 0.5
58 31.0 <0.1
67 33 0.8
69 79 0.5
>100 <0.1
71 51 0.1
72 >100 2.2
73 47.5 ~0.1
>100 <0.1
76 >100 2.7
77 18 <0.1
78 >100 2.8
82 >100 0.5
83 33 1 6
>100 2.7
88 20.3 <0 1
89 >100 2.1
91 >100 6.2
92 28.3 0.2
93 >100 11.2
94 17.5 0.1
>100 1.9
96 17.5 0.1
100 >100 3.2
101 >100 3.0
103 11.3 <0.1
106 14.8 ~0.1
112 >100 2.7
113 >100 0.4
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TAsLE 7. (cont)
COX-1 COX-2
~xamDle ID50~M ID50~1M
115 >100 7.5
120 34 0-4
122 35.5 0.2
123 >100 1.5
124 >100 <0.1
130 >100 7.7
131 >100 8.~4
132 26.5 0.1
141 65.5 1.1
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.
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.
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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 adjlsted, if necessary, with suitable acid, base,
or buffer. Suitable bulking, dispersing, wetting or
suspending agents, including mannitol and PEG gO0, 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 in~ection vials. Aqueous solution
can be added to dissolve the compound prior to injection.
The amount o~ 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 ~actors,
including the age weight; sex and .m.edical conditisr~ of
the subject, the severity of the inflammation or
inflammation related disorder, the route and frequency of
administra~ion, 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.
n the case o~ 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.
For dlsorders of the eye or other external tissues,
e.g., mouth and skin, the formulations are preferably
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222
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 a~ueous 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
20 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 ddhesive, 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 ~low 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.
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
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223
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 emulsif'er 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-callea 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.
The choice of suitable oils or fats for the
formulatic.l 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
recIuired. Alternatively, high melting point lipids such
as white soft paraffin and/or liquid paraf~in or other
mineral oi s can be used.
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
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224
preferably present in such formulations in a
concentration o~ 0.5 to 20%, advantageously 0.5 to 10%
and particularly about 1.5% w/w.
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 hydroxypropylmethyl cellulose. Formulations
for parenteral administration may be in the form o~
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 ~ormulations 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.
Although this invention has been described with
respect to specific embodiments, the details of these
embodiments are not to be construed as limitations.
