Substituted isoxazoles for the treatment of inflammation

A class of substituted isoxazolyl compounds is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula II ##STR1## wherein R.sup.1 is selected from hydroxyl, lower alkyl, carboxyl, lower carboxyalkyl, lower aminocarbonylalkyl, lower alkoxycarbonylalkyl, lower aralkyl, lower alkoxyalkyl, lower aralkoxyalkyl, lower alkylthioalkyl, lower aralkylthioalkyl, lower alkylaminoalkyl, lower aryloxyalkyl, lower arylthioalkyl, lower haloalkyl, lower hydroxylalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl; wherein R.sup.3 is selected from cycloalkyl, cycloalkenyl, aryl, and heteroaryl; wherein R.sup.3 is optionally substituted at a substitutable position with one or more radicals independently selected from lower alkylsulfinyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, lower arylamino, lower aminoalkyl, nitro, halo, lower alkoxy, aminosulfonyl, and lower alkylthio; and wherein R.sup.4 is selected from lower alkyl, hydroxyl and amino; or a pharmaceutically-acceptable salt thereof.

FIELD OF THE INVENTION 
This invention is in the field of antiinflammatory pharmaceutical agents 
and specifically relates to compounds, compositions and methods for 
treating inflammation and inflammation-associated disorders, such as 
arthritis. 
BACKGROUND OF THE INVENTION 
Prostaglandins play a major role in the inflammation process and the 
inhibition of prostaglandin production, especially production of 
PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common target of 
antiinflammatory drug discovery. However, common non-steroidal 
antiinflammatory drugs (NSAIDs) that are active in reducing the 
prostaglandin-induced pain and swelling associated with the inflammation 
process are also active in affecting other prostaglandin-regulated 
processes not associated with the inflammation process. Thus, use of high 
doses of most common NSAIDs can produce severe side effects, including 
life threatening ulcers, that limit their therapeutic potential. An 
alternative to NSAIDs is the use of corticosteroids, which have even more 
drastic side effects, especially when long term therapy is involved. 
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, show 
continuing efforts to find a safe and effective antiinflammatory agent. 
The novel isoxazoles disclosed herein are such safe and also effective 
antiinflammatory agents furthering such efforts. The invention's compounds 
are found to show usefulness in vivo as antiinflammatory agents with 
minimal side effects. The substituted isoxazolyl compounds disclosed 
herein preferably selectively inhibit cyclooxygenase-2 over 
cyclooxygenase-1. 
Isoxazoles have been described for various uses, including the treatment of 
inflammation. U.S. Pat. No. DE 4,314,966, published Nov. 10, 1994, 
describes 3-(2-hydroxyphenyl)isoxazoles for the treatment of inflammatory 
disorders. WO 92/05162, published Apr. 4, 1992, describes 
5-piperazinyl-3,4-diaryl-isoxazoles as having medicinal use. 
WO 92/19604, published Nov. 12, 1992, describes 
5-alkene-3,4-diaryl-isoxazoles as having cyclooxygenase inhibition 
activity. EP 26928, published Apr. 15, 1981, describes 
3,4-diaryl-isoxazole-5-acetic acids as having antiinflammatory activity. 
WO 95/00501, published Jan. 5, 1995, generically describes 
3,4-diaryl-isoxazoles as cyclooxygenase inhibitors. 
The invention's isoxazolyl compounds are found to show usefulness in vivo 
as antiinflammatory agents with minimal side effects. 
DESCRIPTION OF THE INVENTION 
A class of substituted isoxazolyl compounds useful in treating 
inflammation-related disorders is defined by Formula I: 
##STR2## 
wherein R.sup.1 is selected from hydroxyl, amino, alkyl, carboxyalkyl, 
alkoxycarbonyl, aminocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, 
carboxyl, alkoxy, haloalkoxy, aralkoxy, heteroaralkoxy, cycloalkylalkoxy, 
alkylthio, aralkylthio, heteroaralkylthio, cycloalkylalkylthio, 
alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl, aralkylthioalkyl, 
alkylaminoalkyl, aryloxyalkyl, arylthioalkyl, hydroxyalkyl, haloalkyl, 
cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, aryl, aralkyl, 
halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino, 
heteroaralkylamino, N-alkyl-N-heteroaralkylamino, 
N-alkyl-N-cycloalkylalkylamino, arylcarbonylthio, 
alkylaminocarbonylthioalkyl, arylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, 
alkylaminocarbonyloxyalkyl, alkoxycarbonylthioalkyl, and 
alkylaminocarbonylthioalkyl; 
wherein R.sup.2 is one or more radicals independently selected from alkyl, 
cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, 
haloalkoxy, amino, aminoalkyl, alkylamino, arylamino, nitro, alkoxyalkyl, 
alkylsulfinyl, halo, hydroxysulfonyl, alkylsulfonyl, aminosulfonyl, 
haloalkylsulfonyl, alkoxy and alkylthio; 
wherein R.sup.3 is selected from cycloalkyl, cycloalkenyl, aryl and 
heterocyclo; wherein R.sup.3 is optionally substituted at a substitutable 
position with one or more radicals independently selected from alkyl, 
cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, 
haloalkoxy, amino, aminoalkyl, alkylamino, arylamino, nitro, alkoxyalkyl, 
alkylsulfinyl, aminosulfonyl, halo, alkoxy and alkylthio; 
or a pharmaceutically-acceptable salt thereof. 
Compounds of Formula I would be useful for, but not limited to, the 
treatment of inflammation in a subject, and for treatment of other 
inflammation-associated disorders, such as, as an analgesic in the 
treatment of pain and headaches, or as an antipyretic for the treatment of 
fever. For example, compounds of Formula I would be useful to treat 
arthritis, including but not limited to rheumatoid arthritis, 
spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus 
erythematosus and juvenile arthritis. Such compounds of Formula I would be 
useful in the treatment of asthma, bronchitis, menstrual cramps, 
tendinitis, bursitis, and skin related conditions such as psoriasis, 
eczema, burns and dermatitis. Compounds of Formula I also would be useful 
to treat gastrointestinal conditions such as inflammatory bowel disease, 
Crohn's disease, gastritis, irritable bowel syndrome and ulcerative 
colitis and for the prevention of colorectal cancer. Compounds of Formula 
I would be useful in treating inflammation in such diseases as vascular 
diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic 
anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, 
myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, 
polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling 
occurring after injury, myocardial ischemia, and the like. The compounds 
are useful as anti-inflammatory agents, such as for the treatment of 
arthritis, with the additional benefit of having significantly less 
harmful side effects. Besides being useful for human treatment, these 
compounds are also useful for treatment of mammals, including horses, 
dogs, cats, rats, mice, sheep, pigs, etc. 
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, LTB.sub.4 
antagonists and LTA.sub.4 hydrolase inhibitors. 
Suitable LTB.sub.4 inhibitors include, among others, ebselen, Bayer 
Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-615, 
Lilly compound LY-293111, Ono compound ONO-4057, Terumo compound TMK-688, 
Lilly compounds LY-213024, 264086 and 292728, ONO compound ONO-LB457, 
Searle compound SC-53228, calcitrol, Lilly compounds LY-210073, LY223982, 
LY233469, and LY255283, ONO compound ONO-LB-448, Searle compounds 
SC-41930, SC-50605 and SC-51146, and SK&F compound SKF-104493. Preferably, 
the LTB4 inhibitors are selected from ebselen, Bayer Bay-x-1005, Ciba 
Geigy compound CGS-25019C, Leo Denmark compound ETH-615, Lilly compound 
LY-293111, Ono compound ONO-4057, and Terumo compound TMK-688. 
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 IC.sub.50 of less than about 0.5 .mu.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 
IC.sub.50 of greater than about 1 .mu.M, and more preferably of greater 
than 20 .mu.M. Such preferred selectivity may indicate an ability to 
reduce the incidence of common NSAID-induced side effects. 
Within Formula I there is a subclass of compounds of high interest 
represented by Formula II: 
##STR3## 
wherein R.sup.1 is selected from alkyl, carboxyalkyl, alkoxycarbonyl, 
aminocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl, alkoxy, 
haloalkoxy, aralkoxy, heteroaralkoxy, cycloalkylalkoxy, alkylthio, 
aralkylthio, heteroaralkylthio, cycloalkylalkylthio, alkoxyalkyl, 
aralkoxyalkyl, alkylthioalkyl, aralkylthioalkyl, alkylaminoalkyl, 
aryloxyalkyl, arylthioalkyl, hydroxyl, amino, hydroxyalkyl, haloalkyl, 
cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, aralkyl, halo, 
alkylamino, aralkylamino, N-alkyl-N-aralkylamino, heteroaralkylamino, 
N-alkyl-N-heteroaralkylamino, N-alkyl-N-cycloalkylalkylamino, 
arylcarbonyloxyalkyl, arylcarbonylthio, alkoxycarbonyloxyalkyl, 
alkylaminocarbonyloxyalkyl, alkoxycarbonylthioalkyl, and 
alkylaminocarbonylthioalkyl; 
wherein R.sup.3 is selected from cycloalkyl, cycloalkenyl, aryl and 
heterocyclo; wherein R.sup.3 is optionally substituted at a substitutable 
position with one or more radicals independently selected from alkyl, 
cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, 
haloalkoxy, amino, alkylamino, arylamino, aminoalkyl, nitro, alkoxyalkyl, 
alkylsulfinyl, alkylsulfonyl, aminosulfonyl, halo, alkoxy and alkylthio; 
and 
wherein R.sup.4 is selected from alkyl, hydroxyl, and amino; 
or a pharmaceutically-acceptable salt thereof. 
A preferred class of compounds consists of those compounds of Formula II 
wherein R.sup.1 is selected from hydroxyl, amino, lower alkyl, lower 
carboxyalkyl, lower alkoxycarbonyl, aminocarbonyl, carboxyl, lower 
aminocarbonylalkyl, lower alkoxycarbonylalkyl, lower alkoxy, lower 
haloalkoxy, lower aralkoxy, lower heteroaralkoxy, lower cycloalkylalkoxy, 
lower alkylthio, lower aralkylthio, lower heteroaralkylthio, lower 
cycloalkylalkylthio, lower alkoxyalkyl, lower aralkoxyalkyl, lower 
alkylthioalkyl, lower aralkylthioalkyl, lower alkylaminoalkyl, lower 
aryloxyalkyl, lower arylthioalkyl, lower hydroxyalkyl, lower haloalkyl, 
lower cycloalkyl, lower cycloalkylalkyl, 5- or 6-membered heterocyclo, 
lower heterocycloalkyl, lower aralkyl, halo, lower alkylamino, lower 
aralkylamino, lower N-alkyl-N-aralkylamino, lower heteroaralkylamino, 
lower N-alkyl-N-heteroaralkylamino, lower N-alkyl-N-cycloalkylalkylamino, 
lower arylcarbonyloxyalkyl, lower alkoxycarbonyloxyalkyl, lower 
alkylaminocarbonyloxyalkyl, lower alkoxycarbonylthioalkyl, and lower 
alkylaminocarbonylthioalkyl; wherein R.sup.3 is selected from cycloalkyl, 
cycloalkenyl, aryl, and heteroaryl; wherein R.sup.3 is optionally 
substituted at a substitutable position with one or more radicals 
independently selected from lower alkylsulfinyl, lower alkyl, cyano, 
carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower 
hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, lower arylamino, 
lower aminoalkyl, nitro, halo, lower alkoxy, lower alkylsulfonyl, 
aminosulfonyl, and lower alkylthio; and wherein R.sup.4 is selected from 
lower alkyl, hydroxyl and amino; or a pharmaceutically-acceptable salt 
thereof. 
A more preferred class of compounds consists of those compounds of Formula 
II wherein R.sup.1 is selected from hydroxyl, lower alkyl, carboxyl, lower 
carboxyalkyl, lower aminocarbonylalkyl, lower alkoxycarbonylalkyl, lower 
aralkyl, lower alkoxyalkyl, lower aralkoxyalkyl, lower alkylthioalkyl, 
lower aralkylthioalkyl, lower alkylaminoalkyl, lower aryloxyalkyl, lower 
arylthioalkyl, lower haloalkyl, lower hydroxylalkyl, cycloalkyl, 
cycloalkylalkyl, and aralkyl; wherein R.sup.3 is selected from cycloalkyl, 
cycloalkenyl, aryl, and heteroaryl; wherein R.sup.3 is optionally 
substituted at a substitutable position with one or more radicals 
independently selected from lower alkylsulfinyl, lower alkyl, cyano, 
carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower 
hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, lower arylamino, 
lower aminoalkyl, nitro, halo, lower alkoxy, aminosulfonyl, and lower 
alkylthio; and wherein R.sup.4 is selected from lower alkyl, hydroxyl and 
amino; or a pharmaceutically-acceptable salt thereof. 
A class of compounds of particular interest consists of those compounds of 
Formula II wherein R.sup.1 is selected from hydroxyl, methyl, ethyl, 
propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, neopentyl, hexyl, 
carboxyl, carboxypropyl, carboxymethyl, carboxyethyl, benzyl, phenethyl, 
aminocarbonylmethyl, methoxycarbonylmethyl, methoxycarbonylethyl, 
methoxymethyl, benzoxymethyl, phenylethoxymethyl, methylthiomethyl, 
benzylthiomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, 
phenyloxymethyl, phenylthiomethyl, fluoromethyl, difluoromethyl, 
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 
pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, 
difluoropropyl, dichloroethyl, dichloropropyl, hydroxylmethyl, 
hydroxylpropyl, hydroxylethyl, cyclohexyl, cyclobutyl, cyclopentyl, 
cycloheptyl, cyclohexylmethyl, cyclohexylethyl, cyclobutylethyl, 
cyclopentylmethyl, cycloheptylpropyl, and lower aralkyl selected form 
benzyl and phenylethyl, wherein the phenyl ring is optionally substituted 
at a substitutable position with fluoro, chloro, bromo, iodo, methyl, and 
methoxy; wherein R.sup.3 is selected from phenyl, naphthyl, biphenyl, 
cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 
3-cyclohexenyl, 4-cyclohexenyl, 1-cyclopentenyl, pyridyl, thienyl, 
thiazolyl, oxazolyl, furyl and pyrazinyl; wherein R.sup.3 is optionally 
substituted at a substitutable position with one or more radicals 
independently selected from trifluoromethoxy, N-methylamino, 
N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, 
N-methyl-N-ethylamino, phenylamino, N-methyl-N-phenylamino, 
methylsulfinyl, ethylsulfinyl, methyl, ethyl, isopropyl, butyl, 
tert-butyl, isobutyl, pentyl, hexyl, cyano, carboxyl, methoxycarbonyl, 
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, 
dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, 
fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, 
dichloropropyl, hydroxyl, hydroxymethyl, amino, nitro, fluoro, chloro, 
bromo, iodo, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, hexyloxy, 
methylenedioxy, aminosulfonyl, methylthio, ethylthio, butylthio, and 
hexylthio; and wherein R.sup.4 is selected from methyl, hydroxyl and 
amino; or a pharmaceutically-acceptable salt thereof. 
Within Formula I there is a subclass of compounds of high interest 
represented by Formula III: 
##STR4## 
wherein R.sup.1 is selected from hydroxyl, alkyl, carboxyalkyl, 
aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl, alkoxy, haloalkoxy, 
aralkoxy, heteroaralkoxy, cycloalkylalkoxy, alkylthio, heteroaralkylthio, 
cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl, 
aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl, 
hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, 
heterocycloalkyl, aralkyl, halo, alkylamino, aralkylamino, 
N-alkyl-N-aralkylamino, heteroaralkylamino, N-alkyl-N-heteroaralkylamino, 
alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio, 
alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl, 
alkoxycarbonylthioalkyl, and alkylaminocarbonylthioalkyl; and 
wherein R.sup.3 is selected from cycloalkyl, cycloalkenyl, aryl and 
heterocyclo; wherein R.sup.3 is optionally substituted at a substitutable 
position with one or more radicals independently selected from alkyl, 
cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyalkyl, haloalkoxy, 
amino, alkylamino, arylamino, aminoalkyl, nitro, alkoxyalkyl, 
alkylsulfinyl, aminosulfonyl, halo, alkoxy and alkylthio; or a 
pharmaceutically-acceptable salt thereof. 
A preferred class of compounds consists of those compounds of Formula III 
wherein R.sup.1 is selected from hydroxyl, lower alkyl, carboxyl, lower 
carboxyalkyl, lower aminocarbonylalkyl, lower alkoxycarbonylalkyl, lower 
aralkyl, lower alkoxyalkyl, lower aralkoxyalkyl, lower alkylthioalkyl, 
lower aralkylthioalkyl, lower alkylaminoalkyl, lower aryloxyalkyl, lower 
arylthioalkyl, lower haloalkyl, lower hydroxylalkyl, lower cycloalkyl, 
lower cycloalkylalkyl, and aralkyl; wherein R.sup.3 is selected from 
cycloalkyl, cycloalkenyl, aryl, and heteroaryl; and wherein R.sup.3 is 
optionally substituted at a substitutable position with one or more 
radicals independently selected from lower alkylsulfinyl, aminosulfonyl, 
lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, 
hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, 
lower arylamino, lower aminoalkyl, nitro, halo, lower alkoxy and lower 
alkylthio; or a pharmaceutically-acceptable salt thereof. 
A class of compounds of particular interest consists of those compounds of 
Formula III wherein R.sup.1 is selected from hydroxyl, methyl, ethyl, 
propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, neopentyl, hexyl, 
carboxyl, carboxypropyl, carboxymethyl, carboxyethyl, benzyl, phenethyl, 
aminocarbonylmethyl, methoxycarbonylmethyl, methoxycarbonylethyl, 
methoxymethyl, benzoxymethyl, phenylethoxymethyl, methylthiomethyl, 
benzylthiomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, 
phenyloxymethyl, phenylthiomethyl, fluoromethyl, difluoromethyl, 
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 
pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, 
difluoropropyl, dichloroethyl, dichloropropyl, hydroxylmethyl, 
hydroxylpropyl, hydroxylethyl, cyclohexyl, cyclobutyl, cyclopentyl, 
cycloheptyl, cyclohexylmethyl, cyclohexylethyl, cyclobutylethyl, 
cyclopentylmethyl, cycloheptylpropyl, and lower aralkyl selected from 
phenylethyl and benzyl optionally substituted at a substitutable position 
with fluoro, chloro, bromo, iodo, methyl, and methoxy; and wherein R.sup.3 
is selected from phenyl, naphthyl, biphenyl, cyclohexyl, cyclopentyl, 
cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 
4-cyclohexenyl, 1-cyclopentenyl, pyridyl, thienyl, thiazolyl, oxazolyl, 
furyl and pyrazinyl; wherein R.sup.3 is optionally substituted at a 
substitutable position with one or more radicals independently selected 
from trifluoromethoxy, N-methylamino, N,N-dimethylamino, N-ethylamino, 
N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, phenylamino, 
N-methyl-N-phenylamino, methylsulfinyl, ethylsulfinyl, methyl, ethyl, 
isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, cyano, carboxyl, 
methoxycarbonyl, fluoromethyl, difluoromethyl, trifluoromethyl, 
chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, 
heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, 
dichloroethyl, dichloropropyl, hydroxyl, hydroxymethyl, amino, 
aminomethyl, nitro, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy, 
n-butoxy, pentoxy, hexyloxy, methylenedioxy, methylthio, aminosulfonyl, 
ethylthio, butylthio, and hexylthio; or a pharmaceutically-acceptable salt 
thereof. 
A class of compounds of more particular interest consists of those 
compounds of Formula III wherein R.sup.1 is selected from methyl, ethyl, 
propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, neopentyl, hexyl, 
hydroxymethyl, hydroxypropyl, methoxymethyl, difluoromethyl, 
trifluoromethyl, chloromethyl, cyclohexyl, cyclohexylmethyl, 
4-chlorobenzyl, 3-chlorobenzyl, 4-methylbenzyl, 4-methoxybenzyl, carboxyl, 
carboxypropyl, carboxymethyl, carboxyethyl, methoxycarbonylmethyl, and 
ethoxycarbonylethyl; wherein R.sup.3 is phenyl; wherein R.sup.3 is 
optionally substituted at a substitutable position with one or more 
radicals independently selected from trifluoromethoxy, N-methylamino, 
N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, 
N-methyl-N-ethylamino, phenylamino, N-methyl-N-phenylamino, 
methylsulfinyl, ethylsulfinyl, aminosulfonyl, methyl, ethyl, isopropyl, 
butyl, tert-butyl, isobutyl, pentyl, hexyl, cyano, carboxyl, 
methoxycarbonyl, fluoromethyl, difluoromethyl, trifluoromethyl, 
chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, 
heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, 
dichloroethyl, dichloropropyl, hydroxyl, hydroxymethyl, amino, 
aminomethyl, nitro, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy, 
n-butoxy, pentoxy, hexyloxy, methylenedioxy, methylthio, ethylthio, 
butylthio, and hexylthio; or a pharmaceutically-acceptable salt thereof. 
Within Formula I there is a subclass of compounds of high interest 
represented by Formula IV: 
##STR5## 
wherein R.sup.1 is selected from alkyl and carboxyalkyl; and wherein 
R.sup.3 is selected from cycloalkyl, cycloalkenyl, aryl and heterocyclo; 
wherein R.sup.3 is optionally substituted at a substitutable position with 
one or more radicals independently selected from alkyl, cyano, carboxyl, 
alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, 
alkylamino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl, 
aminosulfonyl, halo, alkoxy and alkylthio; or a 
pharmaceutically-acceptable salt thereof. 
A family of specific compounds of particular interest within Formula I 
consists of compounds and pharmaceutically-acceptable salts thereof as 
follows: 
[3-(3-fluoro-4-methoxyphenyl)-4-phenyl-isoxazol-5-yl]propanoic acid; 
[3,4-diphenylisoxazol-5-yl]propanoic acid; 
3-(3-fluoro-4-methoxyphenyl)-5-methyl-4-phenylisoxazole; 
5-methyl-4-[4-(methylthio)phenyl]-3-phenylisoxazole; 
3-(3-fluoro-4-methoxyphenyl)-5-methyl-4-[4-(methylthio)phenyl]isoxazole; 
3-(3-chloro-4-methoxyphenyl)-5-methyl-4-[4 -(methylthio)phenyl]isoxazole; 
[4-[4-(methylthio)phenyl]-3-phenylisoxazol-5-yl]acetic acid; 
(3,4-diphenylisoxazol-5 -yl)acetic acid; 
[3-(3-fluoro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]isoxazol-5-yl]ace 
tic acid; 
[3-(3-chloro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]isoxazol-5-yl]ace 
tic acid; 
5-methyl-4-[4-(methylsulfonyl)phenyl]-3-phenyl-isoxazole; 
3-(3-chloro-4-methoxyphenyl)-5-methyl-4-[4-(methylsulfonyl)phenyl]isoxazole 
; 
3-(3-chloro-4-methoxyphenyl)-5-ethyl-4-[4-(methylsulfonyl)phenyl]isoxazole; 
3-(3-fluoro-4-methoxyphenyl)-5-ethyl-4-[4-(methylsulfonyl)phenyl]isoxazole; 
3-(3,4-dichlorophenyl)-5-methyl-4-[4-(methylsulfonyl)phenyl]isoxazole; 
3-(3,4-difluorophenyl)-5-methyl-4-[4-(methylsulfonyl)phenyl]isoxazole; 
3-(3,5-difluoro-4-methoxyphenyl)-5-methyl-4-[4-(methylsulfonyl)phenyl]isoxa 
zole; 
3-(4-methoxyphenyl)-5-methyl-4-[4-(methylsulfonyl)phenyl]isoxazole; 
3-(4-chlorophenyl)-5-methyl-4-[4-(methylsulfonyl)phenyl]isoxazole; 
3-(4-fluorophenyl)-5-methyl-4-[4-(methylsulfonyl)phenyl]isoxazole; 
3-(4-methylphenyl)-5-methyl-4-[4-(methylsulfonyl)phenyl]isoxazole; 
4-[5-ethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5propyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-isopropyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-butyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-isobutyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-cyclohexyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-neopentyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-cyclohexylmethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-(4-chlorophenyl)methyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-trifluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-chloromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonic acid; 
4-[5-propyl-3-phenylisoxazol-4-yl]benzenesulfonic acid; 
4-[5-methoxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-(3-hydroxypropyl)-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[3-(4-chlorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(4-fluorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(3-fluoro-4-methylphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(3-aminosulfonyl-4-methoxyphenyl)-5-methyl-isoxazol-4-yl]benzenesulfon 
amide; 
4-[3-(3-chloro-4-methylphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[5-methyl-3-(3-pyridyl)isoxazol-4-yl]benzenesulfonamide; 
4-[5-methyl-3-(4-pyridyl)-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(3-fluorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
[4-[4-(aminosulfonyl)phenyl]-3-phenylisoxazol-5-yl]carboxylic acid; 
4-[5-hydroxy-3-phenyl-4-isoxazolyl]benzenesulfonamide; 
4-[3-methyl-5-phenyl-isoxazol-4-yl]benzenesulfonamide; 
4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(3-fluoro-4-methoxyphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(4-methoxyphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(3,5-difluoro-4-methoxyphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonami 
de; 
4-[3-(3-chloro-4-methoxyphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(3,5-dichloro-4-methoxyphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonami 
de; 
4-[3-(4-methylphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[5-methyl-3-(4-trifluoromethoxyphenyl)-isoxazol-4-yl]benzenesulfonamide; 
4-[5-methyl-3-(4-trifluoromethylphenyl)-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(4-cyanophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(4-methylsulfinylphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(4-methylthiophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(4-hydroxymethylphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[5-ethyl-3-(3-fluoro-4-methoxyphenyl)isoxazol-4-yl]benzenesulfonamide; 
4-[5-benzyl-3-(3-fluoro-4-methoxyphenyl)isoxazol-4-yl]benzenesulfonamide; 
4-[3-(3-fluoro-4-methoxyphenyl)-5-methoxy-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(3-fluoro-4-methoxyphenyl)-5-phenoxymethyl-isoxazol-4-yl]benzenesulfon 
amide; 
4-[5-benzyloxymethyl-3-(3-fluoro-4-methoxyphenyl)-isoxazol-4-yl]benzenesulf 
onamide; 
4-[3-(3-fluoro-4-methoxyphenyl)-5-methoxymethyl-isoxazol-4-yl]benzenesulfon 
amide; 
4-[3-(3-fluoro-4-methoxyphenyl)-5-methylthiomethyl-isoxazol-4-yl]benzenesul 
fonamide; 
4-[3-(3-fluoro-4-methoxyphenyl)-5-(3-thienyl) 
methylthio-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(3-fluoro-4-methoxyphenyl)-5-methoxycarbonylmethyl-isoxazol-4-yl]benze 
nesulfonamide; 
4-[5-(aminocarbonylmethyl)-3-(3-fluoro-4-methoxyphenyl)-isoxazol-4-yl]benze 
nesulfonamide; 
4-[3-(3-fluoro-4-methoxyphenyl)-5-methylthio-isoxazol-4-yl]benzenesulfonami 
de; 
4-[3-(3-fluoro-4-methoxyphenyl)-5-(trifluoromethoxy)isoxazol-4-yl]benzenesu 
lfonamide; 
4-[3-(3-fluoro-4-methoxyphenyl)-5-(N-methylamino)isoxazol-4-yl]benzenesulfo 
namide; 
[4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]acetic acid; 
[4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]carboxamide; 
methyl [4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]acetate; 
[4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]propanoic acid; 
ethyl [4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]propanoate; and 
[4-[4-(aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)isoxazol-5-yl]prop 
anoic acid. 
A second family of specific compounds of particular interest within Formula 
I consists of compounds and pharmaceutically-acceptable salts thereof as 
follows: 
4-[5-ethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-propyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-isopropyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-butyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-isobutyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-cyclohexyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-neopentyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-cyclohexylmethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-(4-chlorophenyl)methyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-trifluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-chloromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonic acid; 
4-[5-propyl-3-phenylisoxazol-4-yl]benzenesulfonic acid; 
4-[5-methoxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[5-(3-hydroxypropyl)-3-phenylisoxazol-4-yl]benzenesulfonamide; 
4-[3-(4-chlorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(4-fluorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(3-fluoro-4-methylphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(3-aminosulfonyl-4-methoxyphenyl)-5-methyl-isoxazol-4-yl]benzenesulfon 
amide; 
4-[3-(3-chloro-4-methylphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[5-methyl-3-(3-pyridyl)isoxazol-4-yl]benzenesulfonamide; 
4-[5-methyl-3-(4-pyridyl)-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(3-fluorophenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 
[4-[4-(aminosulfonyl)phenyl]-3-phenylisoxazol-5-yl]carboxylic acid; 
4-[5-hydroxy-3-phenyl-4-isoxazolyl]benzenesulfonamide; 
4-[3-methyl-5-phenyl-isoxazol-4-yl]benzenesulfonamide; 
4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide; 
4-[3-(3-fluoro-4-methoxyphenyl)-5-methyl-isoxazol-4-yl]benzenesulfonamide; 
[3-(3-chloro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]isoxazol-5-yl]ace 
tic acid; 
5-methyl-4-[4-(methylsulfonyl)phenyl]-3-phenyl-isoxazole; 
3-(3-chloro-4-methoxyphenyl)-5-methyl 
-4-[4-(methylsulfonyl)phenyl]isoxazole; 
[4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]acetic acid; 
[4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]propanoic acid; 
ethyl [4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]propanoate; 
[4-[4-(aminosulfonyl)phenyl]-3-(3-fluoro-4-methoxyphenyl)isoxazol-5-yl]prop 
anoic acid; and 
[3-(3-fluoro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]isoxazol-5-yl]ace 
tic acid. 
The term "hydrido" denotes a single hydrogen atom (H). This hydrido radical 
may be attached, for example, to an oxygen atom to form a hydroxyl radical 
or two hydrido radicals may be attached to a carbon atom to form a 
methylene (--CH.sub.2 --) radical. Where used, either alone or within 
other terms such as "haloalkyl", "alkylsulfonyl", "alkoxyalkyl" and 
"hydroxyalkyl", the term "alkyl" embraces linear or branched radicals 
having one to about twenty carbon atoms or, preferably, one to about 
twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" 
radicals having one to about ten carbon atoms. Most preferred are lower 
alkyl radicals having one to about six carbon atoms. Examples of such 
radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 
sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. The term 
"cycloalkyl" embraces saturated carbocyclic radicals having three to 
twelve carbon atoms. More preferred cycloalkyl radicals are "lower 
cycloalkyl" radicals having three to about eight carbon atoms. Examples of 
such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 
The term "halo" means halogens such as fluorine, chlorine, bromine or 
iodine. The term "haloalkyl" embraces radicals wherein any one or more of 
the alkyl carbon atoms is substituted with halo as defined above. 
Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl 
radicals. A monohaloalkyl radical, for one example, may have either an 
iodo, bromo, chloro or fluoro atom within the radical. Dihalo and 
polyhaloalkyl radicals may have two or more of the same halo atoms or a 
combination of different halo radicals. "Lower haloalkyl" embraces 
radicals having 1-6 carbon atoms. Examples of haloalkyl radicals include 
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, 
dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, 
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, 
dichloroethyl and dichloropropyl. The terms "hydroxyalkyl" and 
"hydroxylalkyl" embrace linear or branched alkyl radicals having one to 
about ten carbon atoms any one of which may be substituted with one or 
more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower 
hydroxyalkyl" radicals having one to six carbon atoms and one or more 
hydroxyl radicals. Examples of such radicals include hydroxymethyl, 
hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms 
"alkoxy" and "alkoxyalkyl" embrace linear or branched oxy-containing 
radicals each having alkyl portions of one to about ten carbon atoms. More 
preferred alkoxy radicals are "lower alkoxy" radicals having one to six 
carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, 
butoxy and tert-butoxy. The term "alkoxyalkyl" also embraces alkyl 
radicals having two or more alkoxy radicals attached to the alkyl radical, 
that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. The "alkoxy" 
radicals may be further substituted with one or more halo atoms, such as 
fluoro, chloro or bromo, to provide haloalkoxy radicals. More preferred 
haloalkoxy radicals are "lower haloalkoxy" radicals having one to six 
carbon atoms and one or more halo radicals. Examples of such radicals 
include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, 
fluoroethoxy and fluoropropoxy. The term "cycloalkoxy" embraces radicals 
having cycloalkyl radicals, as defined above, attached to an alkoxy 
radical. The term "aryl", alone or in combination, means a carbocyclic 
aromatic system containing one, two or three rings wherein such rings may 
be attached together in a pendent manner or may be fused. The term "aryl" 
embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, 
indane and biphenyl. The terms "heterocyclic" and "heterocyclo" 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 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen 
atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); 
saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen 
atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 
6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 
3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially 
saturated heterocyclic radicals include dihydrothiophene, dihydropyran, 
dihydrofuran and dihydrothiazole. The term "heteroaryl" embraces 
unsaturated heterocyclic radicals. Examples of unsaturated heterocyclic 
radicals, also termed "heteroaryl" radicals include unsaturated 3 to 6 
membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for 
example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, 
pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 
1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g. 
1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed 
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 3 to 
6-membered heteromonocyclic group containing a sulfur atom, for example, 
thienyl, etc.; unsaturated 3-to 6-membered heteromonocyclic group 
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, 
oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 
1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed 
heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen 
atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 to 
6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 
3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; 
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms 
and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) 
and the like. The term also embraces radicals where heterocyclic radicals 
are fused with aryl radicals. Examples of such fused bicyclic radicals 
include benzofuran, benzothiophene, and the like. Said "heterocyclic 
group" may have 1 to 3 substituents such as lower alkyl, hydroxy, oxo, 
amino and lower alkylamino. The term "alkylthio" embraces radicals 
containing a linear or branched alkyl radical, of one to about ten carbon 
atoms attached to a divalent sulfur atom. More preferred alkylthio 
radicals are "lower alkylthio" radicals having alkyl radicals of one to 
six carbon atoms. Examples of such lower alkylthio radicals are 
methylthio, ethylthio, propylthio, butylthio and hexylthio. The term 
"alkylthioalkyl" embraces radicals containing an alkylthio radical 
attached through the divalent sulfur atom to an alkyl radical of one to 
about ten carbon atoms. More preferred alkylthioalkyl radicals are "lower 
alkylthioalkyl" radicals having alkyl radicals of one to six carbon atoms. 
Examples of such lower alkylthioalkyl radicals include methylthiomethyl. 
The term "cycloalkylalkylthio" embraces radicals having cycloalkyl 
radicals, as defined above, attached to an alkylthio radical. More 
preferred cycloalkylthio radicals are "lower cycloalkylalkylthio" radicals 
having cycloalkyl radicals of three to six carbon atoms. The term 
"alkylsulfinyl" embraces radicals containing a linear or branched alkyl 
radical, of one to ten carbon atoms, attached to a divalent --S(.dbd.O)-- 
radical. More preferred alkylsulfinyl radicals are "lower alkylsulfinyl" 
radicals having alkyl radicals of one to six carbon atoms. Examples of 
such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, 
butylsulfinyl and hexylsulfinyl. The term "sulfonyl", whether used alone 
or linked to other terms such as alkylsulfonyl, denotes respectively 
divalent radicals --SO.sub.2 --. "Alkylsulfonyl" embraces alkyl radicals 
attached to a sulfonyl radical, where alkyl is defined as above. More 
preferred alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having 
one to six carbon atoms. Examples of such lower alkylsulfonyl radicals 
include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The 
"alkylsulfonyl" radicals may be further substituted with one or more halo 
atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl 
radicals. The terms "sulfamyl", "aminosulfonyl" and "sulfonamidyl" denote 
NH.sub.2 O.sub.2 S--. The term "acyl" denotes a radical provided by the 
residue after removal of hydroxyl from an organic acid. Examples of such 
acyl radicals include alkanoyl and aroyl radicals. The terms "carboxy" or 
"carboxyl", whether used alone or with other terms, such as 
"carboxyalkyl", denotes --CO.sub.2 H. The term "carbonyl", whether used 
alone or with other terms, such as "alkoxycarbonyl", denotes 
--(C.dbd.O)--. The term "alkoxycarbonyl" means a radical containing an 
alkoxy radical, as defined above, attached via an oxygen atom to a 
carbonyl radical. Examples of such "alkoxycarbonyl" ester radicals include 
substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, 
propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The term 
"alkoxycarbonylalkyl" means a radical containing an alkoxycarbonyl 
radical, as defined above, attached to an alkyl radical. Examples of such 
"alkoxycarbonylalkyl" ester radicals include substituted or unsubstituted 
methoxycarbonylmethyl, butoxycarbonylmethyl and hexyloxycarbonylethyl. The 
terms "alkylcarbonyl", "arylcarbonyl" and "aralkylcarbonyl" include 
radicals having alkyl, aryl and aralkyl radicals, as defined above, 
attached via an oxygen atom to a carbonyl radical. Examples of such 
radicals include substituted or unsubstituted methylcarbonyl, 
ethylcarbonyl, phenylcarbonyl and benzylcarbonyl. The term "aralkyl" 
embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, 
triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in said aralkyl 
may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and 
haloalkoxy. The terms benzyl and phenylmethyl are interchangeable. The 
term "heterocycloalkyl" embraces heterocyclo-substituted alkyl radicals, 
such as pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, 
furanylethyl, tetrahydrofurylethyl and heteroaralkyl radicals. The term 
"heteroaralkyl" embraces heteroaryl-substituted alkyl radicals, such as 
pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and 
quinolylethyl. The heteroaryl in said heteroaralkyl may be additionally 
substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term 
"cycloalkylalkyl" embraces cycloalkyl-substituted alkyl radicals such as 
cyclohexylmethyl, cyclopentylethyl, cyclopentylmethyl, cyclohexylethyl, 
and cyclobutylpropyl. The term "aralkoxy" embraces aralkyl radicals 
attached through an oxygen atom to other radicals. The term 
"aralkoxyalkyl" embraces aralkoxy radicals attached through an oxygen atom 
to an alkyl radical. The term "aralkylthio" embraces aralkyl radicals 
attached to a sulfur atom. The term "aralkylthioalkyl" embraces 
aralkylthio radicals attached through a sulfur atom to an alkyl radical. 
The term "heteroaralkoxy" embraces heteroaralkyl radicals attached through 
an oxygen atom to other radicals. The term "heteroaralkylthio" embraces 
heteroaralkyl radicals attached through a sulfur atom to other radicals. 
The term "aminoalkyl" embraces alkyl radicals substituted with amino 
radicals. The term "alkylamino" denotes amino groups which have been 
substituted with one or two alkyl radicals. Suitable "alkylamino" may be 
mono or dialkylamino such as N-methylamino, N-ethylamino, 
N,N-dimethylamino, N,N-diethylamino or the like. The term 
"cycloalkylamino" denotes amino groups which have been substituted with 
one or two cycloalkyl radicals, as defined above. The term "arylamino" 
denotes amino groups which have been substituted with one or two aryl 
radicals, such as N-phenylamino. The "arylamino" radicals may be further 
substituted on the aryl ring portion of the radical. The term 
"aralkylamino" embraces aralkyl radicals attached through an nitrogen atom 
to other radicals. The term "heteroaralkylamino" embraces heteroaralkyl 
radicals, as defined above, attached through an nitrogen atom to other 
radicals. The term "aminocarbonyl" denotes an amide group of the formula 
--C(.dbd.O)NH.sub.2. The term "alkylcarbonylaminoalkyl" embraces radicals 
having one or more alkyl radicals attached to a carbonyl radical further 
attached to an aminoalkyl radical. The term "alkylaminoalkyl" embraces 
radicals having one or more alkyl radicals attached to an aminoalkyl 
radical. The term "aryloxyalkyl" embraces radicals having an aryl radicals 
attached to an alkyl radical through a divalent oxygen atom. The term 
"arylthioalkyl" embraces radicals having an aryl radicals attached to an 
alkyl radical through a divalent sulfur atom. 
The present invention comprises a pharmaceutical composition comprising a 
therapeutically-effective amount of a compound of Formulas I-IV in 
association with at least one pharmaceutically-acceptable carrier, 
adjuvant or diluent. 
The present invention also comprises a method of treating inflammation or 
inflammation-associated disorders in a subject, the method comprising 
administering to the subject having such inflammation or disorder a 
therapeutically-effective amount of a compound of Formulas I-IV. 
Also included in the family of compounds of Formulas I-IV are the 
pharmaceutically-acceptable salts thereof. The term 
"pharmaceutically-acceptable salts" embraces salts commonly used to form 
alkali metal salts and to form addition salts of free acids or free bases. 
The nature of the salt is not critical, provided that it is 
pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid 
addition salts of compounds of Formulas I-IV may be prepared from an 
inorganic acid or from an organic acid. Examples of such inorganic acids 
are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and 
phosphoric acid. Appropriate organic acids may be selected from aliphatic, 
cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and 
sulfonic classes of organic acids, example of which are formic, acetic, 
propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, 
ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, 
benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, 
mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, 
benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, 
sulfanilic, stearic, cyclohexylaminosulfonic, algenic, 
.beta.-hydroxybutyric, salicylic, galactaric and galacturonic acid. 
Suitable pharmaceutically-acceptable base addition salts of compounds of 
Formulas I-IV include metallic salts made from aluminum, calcium, lithium, 
magnesium, potassium, sodium and zinc or organic salts made from 
N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, 
ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these 
salts may be prepared by conventional means from the corresponding 
compound of Formulas I-IV by reacting, for example, the appropriate acid 
or base with the compound of Formulas I-IV. 
GENERAL SYNTHETIC PROCEDURES 
The compounds of the invention can be synthesized according to the 
following procedures of Schemes I-XIII, wherein the R.sup.1 -R.sup.4 
substituents are as defined for Formulas I-IV, above, except where further 
noted. 
##STR6## 
Scheme I illustrates the two step procedure used to prepare substituted 
desoxybenzoin derivatives 3. In step one, 4-methylthiophenylacetic acid 1 
is converted to the corresponding acid chloride 2 with thionyl chloride. A 
variety of aromatic compounds are then acylated with 2 in the presence of 
a Lewis acid such as aluminum chloride to provide the desired 
desoxybenzoins 3 in high yield. This Friedel Crafts acylation can be 
performed in an inert solvent, such as dichloromethane, chloroform, 
nitrobenzene, 1,2-dichloroethane, 1,2-dichlorobenzene and similar 
solvents. 
##STR7## 
Synthetic Scheme II shows the four step procedure which can be used to 
prepare substituted ketone compounds 7 from aldehyde 4 and acid 5. In step 
one, aldehyde 4 and substituted acetic acid 5 are heated together in 
acetic anhydride and triethylamine to form the 2,3-disubstituted acrylic 
acids 6 via a Perkin condensation. In step two, the addition of water 
produces the acids 6 free from any mixed acetic-acrylic anhydrides. In 
step three, the acrylic acids 6 are reacted with diphenylphosphorylazide 
(DPPA) and triethylamine in toluene at about 0.degree. C. and then at room 
temperature to form acylazides. In step four, the crude acylazides are 
heated to form a vinyl isocyanate via a Curtius rearrangement. The vinyl 
isocyanates are trapped with tert-butyl alcohol to produce 
N-tert-butoxycarbonyl enamine derivatives. Acidic hydrolysis using 
concentrated HCl provides the substituted ketone 7 intermediates. 
##STR8## 
Synthetic Scheme III illustrates an alternative approach which can be used 
to prepare substituted ketone intermediates 7 via the Claisen reaction of 
a substituted phenylacetonitrile 8 and a acid ester 9. In the first step, 
a mixture of substituted phenylacetonitrile 8 and acid ester 9 are treated 
with a base such as sodium methoxide in a protic solvent like methanol to 
provide the cyanoketone 10. In step two, the cyanoketone 10 is hydrolyzed 
in aqueous acid such as concentrated HBr to effect hydrolysis of the 
nitrile and decarboxylation of the incipient carboxylic acid to produce 
the substituted ketone intermediates 7. 
Other synthetic approaches are possible to form the desired ketones 7. 
These alternatives include reacting the appropriate Grignard or lithium 
reagents with Weinreb amides of substituted acids or acetic acids. The 
Weinreb methodology has been reported in Tetrahedron Letters, 4171 (1977). 
##STR9## 
Synthetic Scheme IV shows the procedure which can be used for the 
preparation of oxime intermediates 12. Treatment of ketone intermediates 7 
with hydroxylamine, generally prepared from hydroxylamine hydrochloride by 
potassium hydroxide, provides the oxime intermediates 12. A wide variety 
of solvents can be used for this reaction including ethanol, toluene and 
tetrahydrofuran. 
##STR10## 
Synthetic Scheme V shows the procedure which can be used for the 
preparation of hydrated isoxazole derivatives 13. The substituted oximes 
12 are treated with two equivalents of a base such as n-butyllithium in 
hexanes to produce a dianion which is subsequently acylated. Suitable 
acylating agents are anhydrides, acyl imidazoles, esters and the like. 
Upon quenching the reaction mixture with dilute aqueous acid, hydrated 
isoxazole derivatives 13 can be isolated by crystallization or 
chromatography. 
##STR11## 
Synthetic Scheme VI shows the procedure which can be used for the 
preparation of isoxazole analogs 14 by dehydration of the hydrated 
isoxazole derivatives 13. Substituted hydrated isoxazoles 13 are dissolved 
in an appropriate solvent such as toluene and then treated with a 
catalytic to stoichiometric amount of concentrated sulfuric acid to effect 
dehydration and thereby produce isoxazole derivatives 14. Other acids can 
also be employed to effect this transformation such as concentrated HCl, 
concentrated HBr and many others. 
##STR12## 
Synthetic Scheme VII shows the procedure which can be used for the 
preparation of substituted 4-[4-(methylsulfonyl)phenyl]isoxazole analogs 
16 from the corresponding 4-[4-(methylthio)phenyl]isoxazoles 15. The 
oxidation of an aromatic methythio derivative 15 to the corresponding 
aromatic methylsulfonyl compound 16 can be accomplished in a variety of 
ways such as with two equivalents of meta-chloroperoxybenzoic acid 
(MCPBA), two equivalents of Oxone.RTM. (potassium peroxymonosulfate) and 
many other oxidizing agents. 
##STR13## 
Synthetic Scheme VIII shows the procedure which can be used for the 
preparation of substituted 4-(4-aminosulfonyl)phenylisoxazole analogs 17 
from the corresponding 4-phenylisoxazoles 14. The procedure is a two step 
process for the direct introduction of the sulfonamide moiety into 
4-phenylisoxazoles 14 or hydrated isoxazoles 13. In step one, isoxazole 14 
or hydrated isoxazole 13 is treated at about 0.degree. C. with two or 
three equivalents of chlorosulfonic acid to form the corresponding 
sulfonyl chloride. In step two, the sulfonyl chloride thus formed is 
treated with concentrated ammonia to provide the sulfonamide derivative 
17. 
##STR14## 
Synthetic Scheme IX shows the three step procedure used to prepare 
sulfonamide antiinflammatory agents 17 from their corresponding methyl 
sulfones 16. In step one, a tetrahydrofuran solution (THF) of the methyl 
sulfones 16 are treated with an alkyllithium or alkylmagnesium (Grignard) 
reagent at -78.degree. C., such as n-propyl magnesium bromide. In step 
two, the anion generated in step one is treated with an organoborane, such 
as tri-n-butylborane at -78.degree. C. then warmed to room temperature and 
then heated to reflux. In step three, an aqueous solution of 
hydroxylamine-o-sulfonic acid is added to provide the corresponding 
sulfonamide antiinflammatory agents 17. This procedure is essentially that 
of Huang et. al., Tetrahedron Letters, 35, 7204 (1994). 
##STR15## 
Synthetic Scheme X shows the three step procedure used to prepare 
sulfonamide antiinflammatory agents 17 from their corresponding 
methylsulfinyl analogs 18. Methylsulfinyl derivatives 18 are available 
from the corresponding methylthio compounds 15 by oxidation with one 
equivalent of an oxidizing agent such as MCPBA. In step one, the 
methylsulfinyl compounds 18 are treated with trifluoroacetic anhydride to 
effect Pummerer rearrangement. In step two, the crude Pummerer 
rearrangement product dissolved in acetic acid is treated with chlorine 
gas to produce a sulfonyl chloride. In step three, the sulfonyl chloride 
is converted to the corresponding sulfonamide antiinflammatory agents 17 
by treatment with concentrated ammonia. This procedure was adapted from 
Kharash, J. Am. Chem. Soc., 73, 3240 (1951). 
##STR16## 
Synthetic Scheme XI shows the two step procedure used to prepare 
sulfonamide antiinflammatory agents 17 from their corresponding 4-phenyl 
isoxazole derivatives 14. In step one a mixture of sulfuryl chloride and 
dimethylformamide (DMF) are allowed to react at room temperature and then 
mixed with 4-phenylisoxazoles 14 and heated to about 100.degree. C. The 
sulfonyl chloride thus formed is then treated with an excess of 
concentrated ammonia to provide the antiinflammatory sulfonamides 17. 
##STR17## 
Synthetic Scheme XII shows the three step procedure used to prepare 
sulfonamide antiinflammatory agents 20 from 4-phenyl isoxazoles 19. In 
step one, the 4-phenylisoxazoles 19 are converted into the corresponding 
sulfonic acid by treatment with sulfur trioxide pyridine (pyridine) 
complex at about 100.degree. C. In step two, the sulfonic acid is 
converted into the sulfonyl chloride by the action of phosphorus 
oxychloride and in step three the sulfonyl chloride is treated with excess 
concentrated ammonia to provide the antiinflammatory sulfonamides 20. 
##STR18## 
Synthetic Scheme XIII shows the three step procedure used to prepare 
4,5-diphenylisoxazole antiinflammatory agents 24 from 
1,2-diphenylbutenones 21. In step one, the 1,2-diphenylketones 21 are 
converted to the corresponding oximes 22 by treatment with hydroxylamine 
in a manner similar to that shown in Scheme IV. In step two, the oxime 22 
is converted to the 4,5-diphenylisoxazole 23 in two steps. The oxime 22 is 
reacted with potassium iodide and iodine in the presence of base, such as 
sodium bicarbonate and heated to form the halo intermediate. Sodium 
bisulfite is added to form the isoxazole 23. The isoxazole 23 is converted 
to the sulfonamide by any of the procedures shown in Schemes VIII, XI or 
XII. 
The following examples contain detailed descriptions of the methods of 
preparation of compounds of Formulas I-IV. These detailed descriptions 
fall within the scope, and serve to exemplify, the above described General 
Synthetic Procedures which form part of the invention. These detailed 
descriptions are presented for illustrative purposes only and are not 
intended as a restriction on the scope of the invention. All parts are by 
weight and temperatures are in Degrees centigrade unless otherwise 
indicated. All compounds showed NMR spectra consistent with their assigned 
structures.