Hydroxamate derivatives of selected nonsteroidal antiinflammatory acyl residues and their use for cyclooxygenase and 5-lipoxygenase inhibition

The present invention is novel selected hydroxamic acid derivatives of acyl residues of selected NSAIDS, i.e. having 5-lipoxygenase and cyclooxygenase inhibiting properties, pharmaceutical compositions for treating conditions advantageously affected by the inhibition and methods for treating these conditions in mammals, including humans suffering therefor.

BACKGROUND OF THE INVENTION 
The present invention is novel hydroxamate analogs of acyl residues of 
selected nonsteroidal antiinflammatory drug(s) (NSAID(S)). Such NSAIDS 
include indomethacin and its analogs of U.S. Pat. No. 3,161,654; sulindac 
and its analogs of U.S. Pat. No. 3,654,349; tolmetin and its analogs of 
U.S. Pat. No. 3,752,826; and furofenac and its analogs of U.S. Pat. No. 
4,029,811; fentiazac and its analogs of U.S. Pat. No. 3,476,766; clidanac 
and its analogs of U.S. Pat. No. 3,565,943; ketorolac of U.S. Pat. No. 
4,089,969; oxepinac of British Pat. No. 1,476,214; fenclorac of U.S. Pat. 
No. 3,864,384; lonazolac of U.S. Pat. No, 4,146,721; metiazinic acid of 
U.S. Pat. Nos. 3,455,917 and 3,424,748; clopirac of Belgian Pat. No. 
777,207; clometacine of British Pat. No. 1,260,868; etodolac of U.S. Pat. 
No. 3,939,178; indoprofen of British Pat. No. 1,344,663; piriprofen of 
U.S. Pat. No. 3,641,040; carprofen of U.S. Pat. No. 3,896,145; oxaprozin 
of U.S. Pat. No. 3,578,671; pranoprofen of U.S. Pat. No. 3,931,205; 
suprofen of U.S. Pat. No. 4,035,376; miroprofen of U.S. Pat. No. 
3,978,071; tioxaprofen of U.S. Pat. No. 3,933,840; furaprofen of German 
Pat. No. DE 3026402 or furobufen of U.S. Pat. No. 3,728,349 or diclofenac 
of U.S. Pat. No. 3,558,690; and bucloxic acid of U.S. Pat. No. 3,754,021. 
The above patents are each incorporated by reference. 
Anthranilic acid derivatives of a fenamic acid series are previously known 
to include the generic compounds of the British Pat. No. 989,951 or 
formula 
##STR1## 
wherein Ar is .alpha.,.alpha.,.alpha.-trifluoro-m-tolyl; 2,3-xylyl, or 
2,6-dichloro-m-tolyl, also in U.S. Pat. No. 3,852,333. 
Of these, disclosures for unsubstituted hydroxamic acid of the acetyl 
residue of indomethacin are found in U.S. Pat. No. 3,624,103 and 
diclofenac are found in U.S. Pat. Nos. 4,092,430 and 4,173,577. However, 
no teaching to further substituted hydroxamic acids of indomethacin and 
diclofenac having the activity of the present invention compounds is 
found. 
Among related aminobenzhydroxamic acids also previously known are compounds 
of the formula 
##STR2## 
wherein R' is a saturated fatty hydrocarbon radical; phenyl, phenylalkyl, 
wherein the rings are optionally substituted by lower alkyl or lower 
alkoxy; or an aromatic heterocyclic group. This disclosure is in Japanese 
Application 24578/67 filed April 2, 1964 by the Takeda Chemical Industry 
Co., Ltd. as an o-aminobenzhydroxamic acid analgesic derivative having 
less toxicity and analgesic, anticatarrhic, and antifebrile activity. 
Other related disclosures include U.S. Pat. No. 4,029,815 to compounds of 
the formula 
##STR3## 
wherein X.sub.5 is trifluoromethyl, difluoromethyl, or nitro, X.sub.4 is 
H, Br, Cl, or nitro, and Q may be NHOH. These compounds have utility as 
antidiarrheal agents. 
Selected fenamic acid derivatives having an hydroxamic acid derived 
substituent are found in copending U.S. application Ser. No. 134725. 
Cyclized o-aminobenzhydroxamic-O-methylether of the formula 
##STR4## 
wherein R" is alkyl, aralkyl, or a basic side chain and R' is H, Cl, or 
Br; are disclosed by Wolf, E. and Kohl, H. in "Cyclisiarungareaktionen von 
am Aminostickstoff Substituierten 
o-Aminobenzhydroxamsaure-O-methyl-esteror," Ann. Chem. Liebigs. 1975, 
1245-1251. 
Wolf and Kohl also disclose an intermediate hydroxamic acid derivative from 
which the cyclized o-aminobenzhydroxamic-O-methylether are made. The 
intermediate is 
##STR5## 
wherein R.sub.c, R.sub.e, and R.sub.d are as defined below. 
Other cyclized o-aminobenzhydroxamic acids disclosed are 
##STR6## 
wherein R.sub.a is CH.sub.2 CO.sub.2 C.sub.2 H.sub.5, C.sub.6 H.sub.3 
Cl(p)NO.sub.2 (m) and suggesting that R.sub.a may also be SO.sub.2 C.sub.6 
H.sub.4 CH.sub.3 (p) and 
##STR7## 
wherein R.sub.b is H or phenyl; R.sub.c is H, CH.sub.2 C.sub.6 H.sub.5, 
C.sub.6 H.sub.4 Cl(p), CH.sub.2 C.sub.6 H.sub.4 Cl(p), C.sub.6 H.sub.5, or 
CH.sub.3 ; R.sub.e is H or NO.sub.2 ; and R.sub.d is H or Cl. However, 
Wolf and Kohl do not disclose activity for these cyclized compounds and, 
further, do not make obvious the present invention. 
Broadly, hydroxamic acid derivatives of selected aryl ring systems are 
disclosed in European Application Publication No. 0 196 184 and 196 674 
having surprisingly high potency particularly by inhalation, oral 
efficacy, and with a surprisingly long duration of action. However, these 
aryl ring systems are in no way related to the present NSAID type 
compounds. 
Two disclosures by Summers et al, (1) J. Med. Chem., 1987, 30, 574-80 and 
2121-2126 and (2) In Vivo Characterization of Hydroxamic Acid Inhibitors 
of 5-Lipoxygenase disclosed at a Poster session at a National ACS meeting 
(New Orleaans) meeting in September, 1987 (Abstract) disclose hydroxamic 
acids as inhibitors of 5-lipoxygenase, however, the disclosures do not 
extend beyond very limited representative examples not including any 
derivatives having the selected acyl residues of the present invention. 
Thus, the present invention are to selected novel derivatives of NSAIDS and 
pharmaceutically acceptable acid addition or base salts thereof, 
pharmaceutical compositions for treating allergy, psoriasis,inflammation, 
arthritis, pain, pyrrhia, and the methods for such treatment. 
SUMMARY OF THE INVENTION 
The present invention is a novel compound of the formula (I) 
##STR8## 
and pharmaceutically acceptable acid addition and base salts thereof; 
wherein 
##STR9## 
(ii) R.sub.1 is hydrogen, lower alkyl, or acyl; and (iii) R.sub.2 is H, 
lower alkyl, cycloalkyl of from three to twelve carbon atoms of which from 
three to seven are ring carbons, aryl, aralkyl or heteroaryl with the 
overall proviso that when the acyl residue is of the formula 
##STR10## 
wherein R.sub.4 is hydrogen or lower alkyl, then R.sub.3 is hydrogen, 
phenylmethyl, allyl, vinyl, isopropenyl, benzoyl, chlorobenzoyl, 
methoxybenzoyl, and thiomethylbenzoyl; and when the acyl residue is of the 
formula 
##STR11## 
wherein R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently H, 
chlorine, fluorine, or bromine, lower alkyl, lower alkoxy, or 
trifluoromethyl but when R.sub.4 is hydrogen then are not all hydrogen; 
and R.sub.4 is otherwise independently as defined above; then R.sub.1 and 
R.sub.2 cannot both be hydrogen. 
The present invention is also a pharmaceutical composition for the 
treatment of conditions advantageously affected by the inhibition of 
5-lipoxygenase and/or cyclooxygenase which comprises administering an 
amount effective for inhibiting 5-lipoxygenase and/or cyclooxygenase of a 
novel compound of the formula I as defined above; and a pharmaceutically 
acceptable carrier. 
Further, the present invention also provides a method of use for a 
composition of a compound of the formula I, as defined hereinbefore, or 
physiologically acceptable acid addition or base salt thereof for use to 
treat a condition which is advantageously affected by the inhibition of 
the lipoxygenase and cyclooxygenase enzymes of the mammalian, including 
human, arachidonic acid metabolism, which method comprises inhibition of 
such enzymes by administration to a mammal of a lipoxygenase and 
cyclooxygenase inhibiting amount of any such compound or salt in unit 
dosage form, and to use of any such compound or salt in the manufacture of 
lipoxygenase and/or cyclooxygenase inhibitor agents. 
Further, the present invention also provides any compound or composition of 
the formula I' or physiologically acceptable salt thereof, for use as a 
medical therapeutic or prophylactic agent, to methods of medical 
therapeutic or prophylactic treatment by administration to a mammal of a 
medically therapeutic or prophylactic effective amount of any such 
compound or salt, and to use of any such compound or salt in the 
manufacture of medical therapeutic or prophylactic agents. The kinds of 
medical therapy and prophylaxis pertinent to the foregoing and therefore 
in that sense comprising part of the present invention, are elaborated by 
way of example in the following paragraphs which are not intended to be 
construed as in any way limiting the scope of these aspects of said 
invention. 
DETAILED DESCRIPTION OF THE INVENTION 
In the compounds of formula I the term "lower alkyl" is meant to include a 
straight or branched alkyl group having one to six carbon atoms, such as, 
for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and isomers 
thereof. 
Lower alkoxy is O-alkyl or of from one to four carbon atoms as defined 
above for "lower alkyl". 
##STR12## 
substituted by a lower alkyl, fluoro, chloro, bromo, trifluoromethyl, 
hydroxy, or lower alkoxy; and wherein the lower alkyl is as defined above. 
Cycloalkyl of from three to ten carbons having from three to seven ring 
carbons includes cyclopropyl, cyclobutyl, methylcyclotrityl, 
ethylcyclobutyl, dimethylcyclobutyl, cyclopentyl, and the like. 
Aryl or aromatic radical is phenyl unsubstituted and substituted with from 
one to three substituents selected from the group consisting of hydroxy, 
lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, lower alkyl, CN, 
--S(O).sub.n -lower alkyl wherein n is as defined above, NO.sub.2, or 
NR.sub.9 R.sub.10 wherein R.sub.9 and R.sub.10 are independently hydrogen 
or lower alkyl. 
An aralkyl is an aryl as defined above attached through a lower alkylenyl 
wherein the alkylenyl, straight or branched chain, is of from one to four 
carbons such as methylenyl, 1,2-ethylenyl, 1,1-ethylenyl, propylenyl, and 
the like. 
Heterocycles includes derivatives of furan, thiophene, pyrrole, piperidine, 
dihydrofuran, pyridine, thiazole, piperazine, oxazole, benzofuran, 
tetrahydroquinoline, quinoline, indole, dihydroindole, benzothiophene, 
dihydrobenzothiophene, benzoxazole, and similar heterocyclic rings. 
The cycloalkyl and fused cycloalkyl groups may be mono or polycyclic and 
contain from three to twenty carbons. These groups include cyclopropyl, 
cyclopentyl, cyclohexyl, cycloheptyl, bornyl, norbornyl, indanyl and the 
like which are optionally substituted by lower alkyl up to a total of 
twelve carbons. 
Physiologically acceptable salts are meant to be synonymous with 
pharmacologically acceptable salts in this invention. 
An acyl residue of selected NSAIDS is RCO of the formula 
##STR13## 
in which R.sub.1a is selected from the group consisting of benzene, 
naphthalene, biphenyl and substituted benzene, naphthalene and biphenyl 
radicals in which said substituent is selected from the group consisting 
of halogen, lower alkyl, lower alkylthio, lower alkoxy, trifluoromethyl, 
phenoxy, lower alkyl phenoxy, lower alkoxy phenoxy, halogenophenoxy, 
trifluoroacetyl, difluoroacetyl, monofluoroacetyl, di-lower alkyl 
sulfamyl, lower alkanoyl, di-lower alkyl carboxamido, cyano, carb-lower 
alkoxy, trifluoromethylthio, lower alkyl sulfinyl, lower alkylsulfonyl, 
benzylthio, lower alkylbenzylthio, lower alkoxybenzylthio, 
halogenobenzylthio, mercapto, nitro, amino, di-(lower alkyl)amino, lower 
alkylamino, lower alkanoylamino, hydroxy, lower alkanoyloxy, 
trifluoroacetoxy, difluoroacetoxy, monofluoroacetoxy, benzyloxy, lower 
alkylbenzyloxy, lower alkoxylbenzyloxy, and halogenobenzyloxy; 
R.sub.2a is selected from the group consisting of hydrogen, lower alkenyl 
and lower alkyl; 
R.sub.3a is selected from the group consisting of hydrogen and lower alkyl; 
R.sub.4a is selected from the group consisting of hydrogen, lower alkyl, 
lower alkoxy, fluorine and trifluoromethyl; 
R.sub.5a is selected from the group consisting of hydrogen, hydroxy, lower 
alkyl, lower alkoxy, nitro, amino, lower alkylamino, di(lower alkyl) 
amino, lower alkanoylamino, lower alkanoyl, lower alkylamino, bis(hydroxy 
lower alkyl)amino, 1-pyrrolidino, 4-methyl-1-piperizinyl, 4-morpholinyl, 
cyano, amino lower alkyl, di-lower alkyl amino, lower alkyl, 
trifluoromethyl, halogen, di(lower alkyl)sulfamyl, benzylthio, lower 
alkylbenzylthio, lower alkoxybenzylthio, halogenobenzylthio, benzyloxy, 
lower alkylbenzyloxy, lower alkoxybenzyloxy, halogenobenzyloxy, lower 
alkenyl, lower alkenyloxy, 1-azacyclopropyl, cyclopropyl(lower alkoxy) 
methyoxy, and cyclobutyl(lower alkoxy)methyoxy. 
(The most preferred compound of the present invention is the compound of 
formula I.sub.a wherein RCO is the acyl residue of 
1-(4-chlorobenzoyl)-2-methyl-5-methoxy-3-indole acetic acid.) 
##STR14## 
wherein: R.sub.1b is hydrogen, lower alkyl or halogenated lower alkyl; 
R.sub.2b is hydrogen or alkyl; 
R.sub.3b, R.sub.4b, R.sub.5b and R.sub.6b each are hydrogen, lower alkyl, 
lower alkoxy, nitro, amino, lower alkylamino, lower dialkylamino, lower 
dialkylamino lower alkyl, sulfamyl, lower alkylthio, mercapto, hydroxy, 
hydroxy lower alkyl, lower alkylsulfonyl, halogen, carboxyl, carbo-lower 
alkoxy, carbamido, halogenoalkyl, cycloalkyl, or cycloalkoxy; 
R.sub.7b is lower alkylthio, alkylsulfinyl or alkylsulfonyl; 
R.sub.8b is hydrogen, halogen, hydroxy, alkoxy or haloalkyl. 
(The most preferred compound of teh formula I wherein RCO is defined in 
group (b) is the compound wherein RCO is I.sub.b wherein R.sub.1b is 
hydrogen; R.sub.2b is methyl; R.sub.3b is hydrogen; R.sub.4b is fluoro; 
R.sub.5b is hydrogen; R.sub.6b is hydrogen; R.sub.7b is p-methylsulfinyl; 
and R.sub.8b is hydrogen.) 
##STR15## 
wherein: Ar.sub.c represents a member selected from the group consisting 
of phenyl, thienyl, 5-methylthienyl, monosubstituted phenyl, disubstituted 
phenyl and trisubstituted phenyl, each substituent of said substituted 
phenyls being a member selected from the group consisting of halo, lower 
alkyl, trifluoromethyl, lower alkoxy, nitro, amino, methylthio and cyano; 
Ar.sub.lc represents a member selected from the group consisting of phenyl, 
monosubstituted phenyl, disubstituted phenyl and trisubstituted phenyl, 
each substituent of said substituted phenyls being a member selected from 
the group consisting of halo, lower alkyl and lower alkoxy; 
R.sub.c represents a member selected from the group consisting of hydrogen 
and lower alkyl; 
R.sub.1c represents a member selected from the group consisting of 
hydrogen, lower alkyl and benzyl; 
##STR16## 
R.sub.4c represents lower alkyl; R.sub.5c represents lower alkyl ; and 
R.sub.6c represents a member selected from the group consisting of hydrogen 
and lower alkyl. 
(The most preferred compound of the formula I wherein RCO is defined in 
group (c) is the compound wherein RCO is the acyl residue of 
5-(4-methylbenzoyl)-1-methylpyrrolo-2-acetic acid.) 
##STR17## 
wherein R.sub.d represents a group selected from: 
##STR18## 
wherein R.sup.1e and R.sup.2e are each radicals of the group consisting of 
thienyl, furyl, naphthyl, phenyl, and phenyl bearing from one to two 
substituents of the group consisting of (lower)aIkyl, (lower)alkoxy, 
chloro, bromo, fluoro, di-(lower alkyl)amino, nitro, amino and 
trifluoromethyl, and wherein R.sup.3e is a radical from the group 
consisting of --CH.sub.2 --CO, --CH.sub.2 --CH.sub.2 --CO, and 
--CH(CH.sub.3)--CO. 
(The most preferred compound of the formula I wherein RCO is defined in 
group (e) is the compound wherein RCO is I.sub.e wherein R.sup.1e is 
phenyl, R.sup.3e is --CH.sub.2 CO-- and R.sup.2e is p-chlorophenyl.) 
##STR19## 
wherein Y is hydrogen, chloro, bromo, fluoro, hydroxy, (lower)alkyl, 
(lower)alkoxy, mercapto, cyano, nitro, amino or (lower)alkylthio. 
(The most preferred compound of the formula I wherein RCO is defined in 
group (f) is the compound wherein RCO is the acyl residue of 
(.+-.)-6-chloro-5-cyclohexyl-1indancarboxylic acid.) 
##STR20## 
where R.sub.g represents hydrogen or a lower alkyl group having from one 
to four carbon atoms and R.sub.1g represents hydrogen, a lower alkyl group 
having from one to 4 carbon atoms, a lower alkoxy group having from one to 
four carbon atoms, chloro, fluoro or bromo, the R.sub.1g substitution 
being at the ortho, meta or para positions of the aroyl group. 
(The most preferred compound of the formula I wherein RCO is defined in 
group (g) is the compound wherein RCO is the acyl residue of 
5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid.) 
##STR21## 
wherein R.sub.1h represents a hydrogen or halogen atom or a trihalomethyl 
or lower alkoxy group; R.sub.2h represents a hydrogen atom or a lower 
alkyl group; 
##STR22## 
wherein R.sub.1i is a member selected from the group consisting of 
cycloalkyl with five to seven carbon atoms and lower alkyl substituted 
cycloalkyl; 
R.sub.2i is a member selected from the group consisting of halogen, nitro, 
cyano, trifluoromethyl and lower alkylsulfonyl; 
R.sub.3i is hydrogen; 
X.sub.i is halogen. 
(The most preferred compound of the formula I wherein RCO is defined in 
group (i) is the compound wherein RCO is the acyl residue of 
.alpha.,m-dichloro-p-cyclohexylphenylacetic acid.) 
##STR23## 
wherein R.sup.1ji and R.sup.2ji are selected from the group consisting of 
phenyl, halophenyl, lower alkylphenyl, dimethylphenyl, lower alkoxyphenyl, 
dimethoxyphenyl, lower alkylmercaptophenyl, trifluoromethylphenyl, furyl, 
thienyl, and naphthyl with the proviso that at least one of R.sup.1ji and 
R.sup.2ji is phenyl or substituted phenyl; 
##STR24## 
wherein R.sup.1jii is hydrogen, lower alkyl, phenyl, phenyl 
monosubstituted with lower alkyl, lower alkoxy or halogen, naphthyl, 
benzyl or benzyl wherein the phenyl ring thereof is monosubstituted with 
lower alkoxy or halogen; 
##STR25## 
wherein R.sup.1jiii is phenyl; R.sup.2jiii is phenyl, p-halogenophenyl, 
p-methylphenyl or furyl,; R.sup.3jiii is hydrogen, phenyl, or furyl; or 
##STR26## 
wherein R.sup.1jiv is phenyl, R.sup.2jiv is phenyl, p-halogenophenyl, 
p-methylphenyl, R.sup.3jiv is hydrogen or phenyl. 
(The most preferred compound of the formula I wherein RCO is defined in 
group (j) is the compound wherein RCO is the acyl residue of 
1-phenyl-3-(p-chlorophenyl)pyrazol-4-ylacetic acid.) 
##STR27## 
wherein R.sub.k represents hydrogen or methyl R.sub.1k represents 
hydrogen, methyl or ethyl, and represents hydrogen, halogen, or alkyl or 
alkoxy of 1 through 4 carbon atoms. 
(The preferred compounds of the formula I wherein RCO is defined in group 
(k) is the compound havin I.sub.k wherein R.sub.k is hydrogen or methyl, 
R.sub.1k is hydrogen, methyl or ethyl and Y.sub.k is hydrogen or methoxy, 
and the most preferred is the compound having I.sub.k wherein R.sub.k is 
methyl R.sub.1k is hydrogen and Y.sub.k is hydrogen.) 
##STR28## 
wherein R.sub.11 is a lower alkyl or lower alkyl substituted by cycloalkyl 
of from three to 12 carbons having from three to seven ring carbons, lower 
alkenylenyl, lower alkynylenyl, aryl, benzoyl, benzoyl substituted by 
halogen, lower alkyl, lower alkoxy or heterocycle, such as morpholinyl 
piperidinyl, furanyl, and thiophenyl; R.sub.2e and R.sub.3e are the same 
or different and are lower alkyl, aryl and R.sub.4e is hydrogen or lower 
alkyl. 
(The most preferred compound of the formula I wherein RCO is defined in 
group (1) is the compound wherein RCO is the group I.sub.1 wherein 
R.sub.21 and R.sub.31 are CH.sub.3, R.sub.41 is hydrogen and R.sub.11 is 
p-chlorophenyl.) 
##STR29## 
[in which A.sub.m represents a lower straight chain or branched alkylene 
group; 
R.sub.m represents a cyclohexyl or aromatic radical; 
R.sub.m.sup.' represents a halogen atom, trifluoromethyl radical, an alkoxy 
or alkyl radical containing 1 to 4 carbon atoms or a N,N-dialkylamino 
radical wherein each of the alkyl groups contain 1 to 4 carbon atoms] as 
well as alkyl esters thereof (in which the alkyl group in the alcoholic 
moiety contains 1 to 4 carbon atoms). 
(The most preferred compound of the formula I wherein RCO is defined in 
group (m) is the compound wherein RCO is the group I.sub.m wherein 
R.sub.m.sup.' is methoxy, A.sub.m is --CH.sub.2 --, and R.sub.m is 
p-chlorophenyl.) 
##STR30## 
in which R.sup.1n is selected from the group consisting of lower alkyl, 
lower alkenyl, lower alkynyl, lower cycloalkyl, phenyl, benzyl and 
2-thienyl, R.sup.2n, R.sup.3n, R.sup.4n and R.sup.5n are the same or 
different and are each selected from the group consisting of hydrogen and 
lower alkyl, R.sup.6an, R.sup.6bn, R.sup.6cn, and R.sup.6dn are the same 
or different and selected from the group consisting of hydrogen, lower 
alkyl, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro, halo, 
mercapto, lower alkylthio, trifluoromethyl, amino and sulfamoyl, R.sup.7n 
is selected from the group consisting of hydrogen, lower alkyl and lower 
alkenyl, X is selected from the group consisting of oxy and thio, Y is 
selected from the group consisting of carbonyl, 
##STR31## 
which each of R.sup.8n, R.sup.9n, R.sup.10n, R.sup.11n, R.sup.12n and 
R.sup.13n is hydrogen or lower alkyl. 
(The most preferred compound of the formula I wherein RCO is defined in 
group (n) is the compound wherein RCO is the acyl residue of 
1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid.) 
##STR32## 
wherein R.sub.o is hydrogen or lower alkyl. 
(The preferred compounds of the formula I wherein RCO is defined in group 
(o) is the compound I.sub.o wherein R.sub.o is CH.sub.3.) 
##STR33## 
in which R.sub.1p is hydrogen or lower alkyl R.sub.2p is hydrogen, alkyl, 
alkenyl three or four ring-membered cycloalkyl, cycloalkenyl or 
cycloalkyl-methyl cycloalkenyl-methyl; Ph is (i) 1,3- or 1,4-phenylene, 
(ii) (lower alkyl)-1,3- or 1,4-phenylene, (iii) (lower alkoxy)-1,3- or 
1,4-phenylene, (iv) mono- or di-(halogeno)-1,3- or 1,4-phenylene, (v) 
(trifluoromethyl)-1,3- or 1,4-phenylene, (vi) (nitro)-1,3- or 
1,4-phenylene, (vii) (amino)-1,3- or 1,4-phenylene, (viii) (di-lower 
alkylamino)-1,3- or 1,4-phenylene; and 
EQU A.sub.p N-- 
is monocyclic five to seven ring-membered lower alkyleneamino, piperazino, 
morpholino, thiamorpholino or N-(lower alkyl, hydroxy, lower alkyl, 
HPh-lower alkyl or HPh) piperazino; 
(The most preferred compound of the formula I wherein the RCO is defined in 
group I.sub.p wherein one of R.sub.1p is hydrogen and the R.sub.2p is 
methyl, Ph is -1,4-(3-chlorophenylene) and 
##STR34## 
wherein R.sub.q is hydrogen, halogen, hydroxy, cyano, lower alkyl, 
hydroxy-lower alkyl, lower alkoxy, acetyl, benzyloxy, lower alkylthio, 
trifluoromethyl, carboxy, carbo-lower alkoxy, nitro, amino, mono-lower 
alkylamino, di-lower alkylamino, sulfamoyl, di-lower alkylsulfamoyl or 
difluoromethylsulfonyl; R.sub.1q is halogen, cyano, hydroxy-lower alkyl, 
lower alkoxy, acetyl, acetamido, benzyloxy, lower alkylthio, 
trifluoromethyl, hydroxy, carboxy, carbo-lower alkoxy, nitro, amino, 
mono-lower alkylamino, di-lower alkylamino, sulfamoyl, di-lower 
alkylsulfamoyl or difluoromethylsulfonyl; or R.sub.q taken together with 
an adjacent R.sub.1q is also lower alkylenedioxy; R.sub.2q is 
##STR35## 
wherein Y.sub.q and X.sub.q, independently, are hydrogen or lower alkyl, 
and nq is one to seven and R.sub.3q is hydrogen, lower alkyl, lower 
alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, lower alkanoyl, 
halo-substituted lower alkanoyl, benzyl, halo-benzyl, benzoyl or 
halo-benzoyl; and when X.sub.q and Y.sub.q are different, their 
enantiomers. 
(The more preferred compounds of the formula I wherein RCO is defined by 
the group (q) is the compound wherein RCO is the acyl residue of racemic 
6-chloro-.alpha.-methylcarbazole-2-acetic acid.) 
##STR36## 
wherein each of the substituents R.sup.2r and R.sup.3r is a member of the 
group consisting of unsubstituted phenyl, naphthyl, thienyl and furyl 
radicals and phenyl radicals substituted by a substituent selected from 
the group consisting of halogen, lower alkyl, lower alkoxy, nitro and 
trifluoromethyl radicals; and wherein R.sup.1n is selected from the group 
consisting of carboxyalkyl- and carboxyalkenyl radicals each containing 
from two to five carbons. 
(The most preferred compound of the formula I wherein RCO is defined by the 
group (r) is the compound wherein RCO is the acyl residue of 
.beta.-(4,5-diphenyloxazol-2-yl)propionic acid.) 
##STR37## 
wherein each of X.sup.1s and X.sup.2s is a hydrogen atom, a halogen atom, 
an alkyl group having one to four carbon atoms or an alkoxy group having 
one to four carbon atoms; each of R.sup.1s and R.sup.2s is a hydrogen atom 
or an alkyl group having one to four carbon atoms; A.sup.s is carbonyl, 
methylene or alkylidene having two to four carbon atoms; Y.sub.s is --O--; 
and ring P.sub.s represents a pyridine or pyridine N-oxide ring. 
(The most preferred compound of the formula I wherein RCO is defined by the 
group (s) is the compound wherein RCO is the acyl residue of 
2-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)propionic acid.) 
##STR38## 
wherein: Ar.sub.t CO is an aroyl substituent the Ar.sub.t function of 
which is a member selected from the group consisting of 2-thienyl, 5-lower 
alkyl-2-thienyl, 5-halo-2-thienyl, 2-naphthyl and 3-pyridyl, said Ar.sub.t 
CO being in the meta- or para-position relative to the acetyl function; 
either of R.sub.t and R.sub.1t is hydrogen, the other being a member 
selected from the group consisting of hydrogen, halo and lower alkyl, 
provided that, when said R.sub.t is halo or lower alkyl, then said 
Ar.sub.t CO is in the aforementioned para-position, and when said R.sub.1t 
is halo or lower alkyl, then said Ar.sub.t CO is in the aforementioned 
meta-position, and further provided that when said R.sub.t or R.sub.1t is 
halo, then said Ar.sub.t is a member selected from the group consisting of 
2-thienyl, 5-lower alkyl-2-thienyl and 5-halo-2-thienyl; 
either of R.sub.2t and R.sub.3t is a member selected from the group 
consisting of hydrogen, allyl and lower alkyl, the other being a member 
selected from the group consisting of hydrogen and lower alkyl, provided 
that, when either of said R.sub.2t and R.sub.3t is allyl, the other is 
hydrogen, and when either of said R.sub.2t and R.sub.3t is lower alkyl, 
the other is a member selected from the group consisting of hydrogen and 
lower alkyl; 
R.sub.2t and R.sub.3t taken together, is an alkylene bridge attached to the 
c-carbon of the acetic acid function: 
##STR39## 
wherein n.sub.t is an integer from two to five; and wherein lower alkyl as 
above employed is a radical having from one to five carbon atoms; 
##STR40## 
wherein Ar.sub.ti CO is an aroyl substituent the function of which is a 
member selected from the group consisting of 2-thienyl, 
5-methyl-2-thienyl, 5-chloro-2-thienyl, 2-naphthyl and 3-pyridyl, said 
Ar.sub.ti CO being in the meta- or para-position relative to the acetic 
acid function; 
either of R.sub.ti and R.sub.1ti is hydrogen, the other being a member 
selected form the group consisting of hydrogen, chloro and methyl, 
provided that, when said R.sub.ti is chloro or methyl, then said Ar.sub.ti 
CO is in the aforementioned para-position, and when sai R.sub.1ti is 
chloro or methyl, then said Ar.sub.ti CO is in the aforementioned 
meta-position, and further provided that, when said R.sub.ti and R.sub.1ti 
is chloro, then said Ar.sub.ti is a member selected from the group 
consisting of 2-thienyl, 5-methyl-2-thienyl and 5-chloro-2-thienyl; 
either of R.sub.2ti and R.sub.3ti is a member selected from the group 
consisting of hydrogen, allyl and lower alkyl, the other being a member 
selected from the group consisting of hydrogen and lower alkyl, provided 
that, when either of said R.sub.2ti and R.sub.3ti is allyl, the other is 
hydrogen, and when either of said R.sub.2ti and R.sub.3ti is lower alkyl, 
the other is a member selected from the group consisting of hydrogen and 
lower alkyl; 
R.sub.2ti and R.sub.3ti, taken together, is an alkylene bridge attached to 
the .alpha.-carbon of the acetic acid function: 
##STR41## 
wherein n.sub.ti is an integer from two to five; and wherein lower alkyl 
as above employed is a radical having from one to five carbons; 
##STR42## 
wherein: Ar.sub.tii CO is an aroyl substituent the Ar.sub.tii function of 
which is a member selected from the group consisting of 2-thienyl, 5-lower 
alkyl-2-thienyl and 5-halo-2-thienyl, said Ar being in the meta- or 
para-position relative to the acetic acid function; 
either of R.sub.tii and R.sub.1tii is hydrogen, the other being a member 
selected from the group consisting of hydrogen, halo and lower alkyl, 
provided that, when said R.sub.tii is halo or lower alkyl, then said 
Ar.sub.tii CO is in the aforementioned para-position, and when said 
R.sub.1tii is halo or lower alkyl, then said Ar.sub.tii CO is in the 
aforementioned meta-position; 
either of R.sub.2tii and R.sub.3tii is a member selected from the group 
consisting of hydrogen, allyl and lower alkyl, the other being a member 
selected from the group consisting of hydrogen and lower alkyl, provided 
that, when either of said R.sub.2tii and R.sub.3tii is allyl, the other is 
hydrogen, and when said R.sub.2tii and R.sub.3tii is lower alkyl, the 
other is a member selected from the group consisting of hydrogen and lower 
alkyl; 
R.sub.2tii and R.sub.3tii together is also an alkylene bridge with the 
.alpha.-carbon of the acetic acid function: 
##STR43## 
wherein n.sub.tii is an integer from two to five; and wherein lower alkyl 
as above employed is a radical having from one to five carbon atoms; or 
##STR44## 
wherein: Ar.sub.tiii CO is an aroyl substituent the Ar.sub.tiii function 
of which is a member selected from the group consisting of 2-thienyl, 
5-methyl-2-thienyl and 5-chloro-2-thienyl, said Ar.sub.tiii CO being in 
the meta- or paraposition relative to the acetic acid function; 
either of R.sub.tiii and R.sub.1tiii is hydrogen, the other being a member 
selected from the group consisting of hydrogen, chloro and methyl, 
provided that, when said R.sub.tiii is chloro or methyl, then said 
Ar.sub.tiii CO is in the aforementioned para-position, and when said 
R.sub.1tiii is chloro or methyl, then said Ar.sub.tiii CO is in the 
aforementioned meta-position; 
either of R.sub.2tiii and R.sub.3tiii is a member selected from the group 
consisting of hydrogen, allyl and lower alkyl, the other being a member 
selected from the group consisting of hydrogen and lower alkyl, provided 
that, when either of said R.sub.2tiii and R.sub.3tiii is allyl, the other 
is hydrogen, and when either of said R.sub.2tiii and R.sub.3tiii is lower 
alkyl, the other is a member selected from the group consisting of 
hydrogen and lower alkyl; 
R.sub.2tiii and R.sub.3tiii is also an alkylene bridge with the 
.alpha.-carbon of the acetic acid function 
##STR45## 
wherein n.sub.tiii is an integer from two to five; and wherein lower alkyl 
as above employed is a radical having from one to five carbon atoms. 
(The most preferred compound of the formula I wherein RCO is defined by the 
group (t) is that of I.sub.ti wherein Ar.sub.t is 2-thienyl, R.sub.ti and 
R.sub.1ti are hydrogen, R.sub.2ti is hydrogen and R.sub.3ti is methyl.) 
##STR46## 
wherein each of R.sup.1u and R.sup.2u is a hydrogen atom or an alkyl group 
having one to four carbon atoms; each of X.sup.1u and X.sup.2u is a 
hydrogen atom, a halogen atom, an alkyl group having one to four carbon 
atoms or an alkoxy group having one to four carbon atoms; and Y.sub.u is 
CO. 
(The most preferred compound of the formula I wherein RCO is defined by the 
group (u) is that wherein X.sup.1u and X.sup.2u is hydrogen, R.sup.1u is 
hydrogen and R.sup.2u is methyl.) 
##STR47## 
wherein R.sub.2v and R.sub.3v each are phenyl or phenyl mono- or 
di-substituted by at least one member selected from the group consisting 
of alkyl, alkoxy, alkylmercapto, monoalkylamino, dialkylamino or 
alkanoylamino wherein the alkyl, alkoxy and alkanoyl each are of up to 
four carbon atoms, F, Cl, Br, I, CF.sub.3, OH, methylenedioxy, NH.sub.2 
and NO.sub.2, A.sub.v is C.sub.na H.sub.2na wherein na is an integer from 
one to ten inclusive or 
##STR48## 
and Z.sub.v is O or S. 
(The most preferred compound of the formula I wherein RCO is defined by the 
group I.sub.v wherein Z.sub.v is oxygen, A.sub.v is 
##STR49## 
R.sub.2v and R.sub.3v are each parachlorophenyl.) 
##STR50## 
wherein R.sub.1w, R.sub.2w, R.sub.3w and R.sub.4w are independently 
hydrogen, chlorine, fluorine, brominc, lower alkyl, lower alkoxy and 
R.sub.2w may additionally be trifluoromethyl, and R.sub.5w is H or lower 
alkyl with exclusion of R.sub.1w, R.sub.2w and R.sub.3w as hydrogen 
simultaneously. 
(The most preferred compound of the formula I wherein RCO is defined by the 
group (w) is that wherein R.sub.4w, R.sub.2w and R.sub.5w are hydrogen and 
R.sub.3w and R.sub.1w are each ortho-chloro.) 
(x) the acyl residue of 
(.+-.)-.alpha.-methyl-3-phenyl-7-benzofuranepropionic acid (I.sub.x). 
##STR51## 
R.sub..alpha.y and R.sub..beta.y are hydrogen or lower alkyl and R.sub.y 
is halo. 
(The most preferred compound of formula I wherein RCO is defined by the 
group (y) is a compound wherein RCO is the acyl residue of 
4-keto-4-(3'-chloro-4'-cyclohexyl)phenylbutyric acid.) 
Appropriate compounds of formula I are useful in the free base form, in the 
form of base salts where possible, and in the free acid form, or acid in 
the form of addition salts where possible The three forms are within the 
scope of the invention. In practice, use of the salt form amounts to use 
of the base form. Pharmaceutically acceptable salts within the scope of 
the invention may be those derived from mineral acids such as hydrochloric 
acid and sulfuric acid; and organic acids such as ethanesulfonic acid, 
benzenesulfonic acid, p-toluenesulfonic acid, and the like, giving the 
hydrochloride, sulfamate, ethanesulfonate, benzenesulfonate, 
p-toluenesulfonate, and the like, respectively or those derived from bases 
such as suitable organic and inorganic bases. Examples of pharmaceutically 
acceptable base addition salts with compounds of the present invention 
include organic bases which are nontoxic and strong enough to form such 
salts. These organic bases form a class whose limits are readily 
understood by those skilled in the art. Merely for purposes of 
illustration, the class may be said to include mono-, di-, and 
trialkylamines, such as methylamine, dimethylamine, and triethylamine; 
mono-, di-, or trihydroxyalkylamines such as mono-, di-, and 
triethanolamine; amino acids such as arginine, and lysine; guanidine; 
N-methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; 
morpholine; ethylenediamine; N-benzylphenethylamine; 
tris(hydroxymethyl)aminomethane; and the like. (See for example, 
"Pharmaceutical Salts," J. Pharm. Sci., 66(1):1-19 (1977).) 
The addition salts of said basic or acidic compounds are prepared either by 
dissolving the free base or acid of compound I in aqueous or aqueous 
alcohol solution or other suitable solvents containing the appropriate 
acid or base reagent and isolating the salt by evaporating the solution, 
or by reacting the free base of compound I with an acid as well as 
reacting compound I having an acid group thereon with a base such that the 
reactions are in an organic solvent, in which case the salt separates 
directly or can be obtained by concentration of the solution. 
The compounds of the invention may contain an asymmetric carbon atom. Thus, 
the invention includes the individual stereoisomers, and mixtures thereof. 
The individual isomers may be prepared or isolated by methods known in the 
art. 
By virtue of their lipoxygenase inhibitory properties, said compounds and 
salts find application in the treatment or prophylaxis of any condition 
where a lipoxygenase inhibitor is indicated, especially spasmogenic and 
allergic conditions, psoriasis, and as utility in cytoprotection. 
By virtue of their cyclooxygenase inhibitory properties, said compounds and 
salts find application in the treatment or prophylaxis of any condition 
where a cyclooxygenase inhibitor is indicated, especially pyrexia, pain, 
and inflammation. 
By virtue of both their lipoxygenase and cyclooxygenase inhibitory 
properties, said compounds and salts find application in the treatment or 
prophylaxis of any condition where a dual lipoxygenase/cyclooxygenase 
inhibitor is indicated, especially any condition involving blood platelet 
aggregation or inflammation. In the case of inflammation, the compounds 
and salts are particularly suited to the treatment or prophylaxis of 
conditions associated with infiltration of leukocytes into inflamed 
tissue. 
In determining when a lipoxygenase, cyclooxygenase, or dual 
lipoxygenase/cyclooxygenase inhibitor is indicated, of course inter alia, 
the particular condition in question and its severity, as well as, the 
age, sex, weight, and the like of the subject to be treated, must be taken 
into consideration and this determination is ultimately at the discretion 
of the attendant physician. 
Examples of the aforesaid spasmogenic conditions are those involving smooth 
muscle tissue, especially airway smooth muscle constriction such as 
intrinsic asthma--(including intrinsic or idiopathic bronchial asthma and 
cardiac asthma), bronchitis and arterial smooth muscle constriction such 
as coronary spasm (including that associated with myocardial infarction, 
which may or may not lead to left ventricular failure resulting in cardiac 
asthma) and cerebral spasm or `stroke`. Other examples include bowel 
disease caused by abnormal colonic muscular contraction such as may be 
termed `irritable bowel syndrome`, `spastic colon`, or `mucous colitis`. 
Examples of the aforesaid allergic conditions are extrinsic asthma (from 
which it will be appreciated that said compounds and salts are 
particularly favorable as antiasthmatic agents), allergic skin diseases 
such as eczema having a total or partial allergic origin, allergic bowel 
disease (including coeliac disease) and allergic eye conditions, hay 
fever, and allergic conjunctivitis. 
Examples of the aforesaid pyretic and painful conditions include fever 
associated with infections, trauma and injury, malignant disease, and 
diseases affecting the immune system (including autoimmune diseases). 
Examples of the aforesaid conditions involving blood platelet aggregation 
are those resulting from thrombosis, including `stroke` having a total or 
partial thrombotic origin, coronary thrombosis, phlebitis, and 
phlebothrombosis (the latter two conditions also possibly being associated 
with inflammation). 
Examples of the aforesaid conditions involving inflammation are 
inflammatory conditions of the lung, joints, eye, bowel, skin, and heart. 
Inflammatory lung conditions which may be so treated and/or prevented 
include asthma and bronchitis (vide supra) and cystic fibrosis (which may 
also or alternatively involve the bowel or other tissue). 
Inflammatory joint conditions which may be so treated and/or prevented 
include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, 
gouty arthritis, and other arthritic conditions. 
Inflammatory eye conditions which may be so treated and/or prevented 
include uveitis (including intis) and conjunctivitis (vide supra). 
Inflammatory bowel conditions which may be so treated and/or prevented 
include Crohn's disease, ulcerative colitis, and ischemic bowel disease. 
Inflammatory skin diseases which may be so treated and/or prevented include 
those associated with cell proliferation, such as psoriasis and eczema 
(vide supra) and dermatitis (whether or not of allergic origin). 
Inflammatory conditions of the heart which may be so treated and/or 
prevented include coronary infarct damage. 
Other inflammatory conditions which may be so treated and/or prevented 
include tissue necrosis of chronic inflammation and tissue rejection 
following transplant surgery. 
For medical use, the amount required of a compound of formula (I) or 
physiologically acceptable salt thereof--(hereinafter referred to as the 
active ingredient) to achieve a therapeutic effect will, of course, vary 
both with the particular compound, the route of administration and the 
mammal under treatment and the particular disorder or disease concerned. A 
suitable dose of a compound of formula (I) or physiologically acceptable 
salt thereof for a mammal suffering from, or likely to suffer from any 
condition as described hereinbefore is 0.1 .mu.g-500 mg of base per 
kilogram body weight. In the case of systemic administration, the dose may 
be in the range 0.5 to 500 mg of base per kilogram body weight, the most 
preferred dosage being 0.5 to 50 mg/kg of mammal body weight for Example 5 
to 25 mg/kg; administered two or three times daily. In the case of topical 
administration, e.g. to the skin or eye, a suitable dose may be in the 
range 0.1 ng-100 .mu.g of base per kilogram, typically about 0.1 .mu. 
g/kg. 
In the case of oral dosing for the treatment or prophylaxis of airway 
smooth muscle constriction, or asthma, or bronchitis in general, due to 
any course, a suitable dose of a compound of formula (I) or 
physiologically acceptable salt thereof, may be as specified in the 
preceding paragraph, but most preferably is from 1 mg to 10 mg of base per 
kilogram, the most preferred dosage being from 1 mg to 5 mg/kg of mammal 
body weight, for example from 1 to 2 mg/kg. In the case of pulmonary 
administration for the latter indications, the dose may be in the range of 
from 2 .mu.g to 100 mg, for example from 20 .mu.g to 0.5 mg, especially 
0.1 to 0.7 mg/kg. 
It is understood that the ordinarily skilled physician or veterinarian will 
readily determine and prescribe the effective amount of the compound to 
prevent or arrest the progress of the condition for which treatment is 
administered. In so proceeding, the physician or veterinarian could employ 
relatively low doses at first, subsequently increasing the dose until a 
maximum response is obtained. 
While it is possible for an active ingredient to be administered alone, it 
is preferable to present it as a pharmaceutical formulation comprising a 
compound of formula (I) or a pharmacologically acceptable acid addition 
salt thereof and a physiologically acceptable acid addition salt thereof 
and a physiologically acceptable carrier therefor. Such formulations 
constitute a further feature of the present invention. Conveniently, the 
active ingredient comprises from 0.1% to 99.9% by weight of the 
formulation. Conveniently, unit doses of a formulation contain between 0.1 
mg and 1 g of the active ingredient. For topical administration, the 
active ingredient preferably comprises from 1% to 2% by weight of the 
formulation but the active ingredient may comprise as much as 10% w/w. 
Formulations suitable for nasal or buccal administration, (such as 
self-propelling powder dispensing formulations described hereinafter), may 
comprise 0.1 to 20% w/w, for example 2% w/w of active ingredient. 
The formulations, both for veterinary and for human medical use, of the 
present invention comprise an active ingredient in association with a 
pharmaceutically acceptable carrier therefor and optionally other 
therapeutic ingredient(s). The carrier(s) must be `acceptable` in the 
sense of being compatible with the other ingredients of the formulations 
and not deleterious to the recipient thereof. 
The formulations include those in a form suitable for oral, pulmonary, 
ophthalmic, rectal, parenteral (including subcutaneous, intramuscular, and 
intravenous), intraarticular, topical, nasal, or buccal administration. 
The formulations may conveniently h=presented in unit dosage form and may 
be prepared by any of the methods well-known in the art of pharmacy. All 
methods include the step of bringing the active ingredient into 
association with the carrier which constitutes one or more accessory 
ingredients. In general, the formulations are prepared by uniformly and 
intimately bringing the active ingredient into association with a liquid 
carrier or a finely divided solid carrier or both, and then, if necessary, 
shaping the product into the desired formulation. 
Formulations of the present invention suitable for oral administration may 
be in the form of discrete units such as capsules, cachets, tablets, or 
lozenges, each containing a predetermined amount of the active ingredient; 
in the form of a powder or granules; in the form of a solution or a 
suspension in an aqueous liquid or nonaqueous liquid; or in the form of an 
oil-in-water emulsion or a water-in-oil emulsion. The active ingredient 
may also be in the form of a bolus, electuary, or paste. 
A tablet may be made by compressing or molding the active ingredient 
optionally with one or more accessory ingredients. Compressed tablets may 
be prepared by compressing, in a suitable machine, the active ingredient 
in a free-flowing form such as a powder or granules, optionally mixed with 
a binder, lubricant, inert diluent, surface active, or dispersing agent. 
Molded tablets may be made by molding, in a suitable machine, a mixture of 
the powdered active ingredient and a suitable carrier moistened with an 
inert liquid diluent. 
Formulations for rectal administration may be in the form of a suppository 
incorporating the active ingredient and a carrier such as cocoa butter, or 
in the form of an enema. 
Formulations suitable for parenteral administration conveniently comprise a 
sterile aqueous preparation of the active ingredient which is preferably 
isotonic with the blood of the recipient. 
Formulations suitable for intraarticular administration may be in the form 
of a sterile aqueous preparation of the active ingredient which may be in 
microcrystalline form, for example, in the form of an aqueous 
microcrystalline suspension. Liposomal formulations or biodegradable 
polymer systems may also be used to present the active ingredient for both 
intraarticular and ophthalmic administration. 
Formulations suitable for topical administration include liquid or 
semi-liquid preparations such as liniments, lotions, applications, 
oil-in-water or water-in-oil emulsions such as creams, ointments or 
pastes; or solutions or suspensions such as drops. For example, for 
ophthalmic administration, the active ingredient may be presented in the 
form of aqueous eye drops as, for example, a 0.1-1.0% solution. 
Formulations suitable for administration to the nose or buccal cavity 
include powder, self-propelling and spray formulations such as aerosols 
and atomizers. The formulations, when dispersed, preferably have a 
particle size in the range of 0.1 to 200 .mu.. 
A particularly valuable form of a pharmaceutical composition of the present 
invention, for use in the prophylaxis or treatment of airway smooth muscle 
constriction, or asthma or bronchitis in general, due to any cause, is one 
suitable for pulmonary administration via the buccal cavity. Preferably 
the composition is such that particles having a diameter of 0.5 to 7 .mu., 
most preferably 1 to 6 .mu., containing active ingredient, are delivered 
into the lungs of a patient. Such compositions are conveniently in the 
form of dry powders for administration from a powder inhalation device or 
self-propelling powder-dispensing containers, for example as a 
self-propelling aerosol composition in a sealed container; preferably the 
powders comprise particles containing active ingredient of which particles 
at least 98% by weight have a diameter greater than 0.5 .mu. and at least 
95% by number have a diameter less than 7 .mu.. Most desirably at least 
95% by weight of the particles have a diameter greater than 1 .mu. at 
least 90% by number of the particles have a diameter less than 6 .mu.. 
The compositions in the form of dry powders preferably include a solid fine 
powder diluent such as sugar and are conveniently presented in a permeable 
capsule, for example of gelatin. 
Self-propelling compositions of the invention may be either 
powder-dispensing compositions or compositions dispensing the active 
ingredient in the form of droplets of a solution or suspension. 
Self-propelling powder-dispensing compositions include a liquid propellant 
having a boiling point of below 65.degree. F. at atmospheric pressure. 
Generally the propellant may constitute 50 to 99.9% w/w of the composition 
whilst the active ingredient may constitute 0.1 to 20% w/w, for example 
about 2% w/w of the composition. The carrier in such compositions may 
include other constituents, in particular a liquid nonionic or solid 
anionic surfactant, or a solid diluent (preferably having a particle size 
of the same order as of the particles of active ingredient) or both. The 
surfactant may constitute from 0.01 up to 20% w/w, though preferably it 
constitutes below 1% w/w of the composition. 
Self-propelling compositions wherein the active ingredient is present in 
solution comprise an active ingredient, propellant, and co-solvent, and 
advantageously an antioxident stabilizer. The co-solvents may constitute 5 
to 40% w/w of the composition, though preferably less than 20% w/w of the 
composition. 
Compositions of the present invention may also be in the form of aqueous or 
dilute alcoholic solution, optionally a sterile solution, of the active 
ingredient for use in a nebulizer or atomizer. 
Formulations of the present invention may also be in the form of an aqueous 
or dilute alcoholic solution, optionally a sterile solution, of the active 
ingredient for use in a nebulizer or atomizer, wherein an accelerated air 
steam is used to produce a fine mist consisting of small droplets of the 
solution. Such formulations usually contain a flavoring agent such as 
saccharin sodium and a volatile oil. A buffering agent and a surface 
active agent may also be included in such a formulation which should also 
contain a preservative such as methylhydroxybenzoate. 
Other formulations suitable for nasal administration include a coarse 
powder having a particle size of 20 to 500 microns which is administered 
in the manner in which snuff is taken i.e. by rapid inhalation through the 
nasal passage from a container of the powder held close up to the nose. 
In addition to the aforementioned ingredients, the formulations of this 
invention may include one or more additional ingredients such as diluents, 
buffers, flavoring agents, binders, surface active agents, thickeners, 
lubricants, preservatives e.g. methylhydroxybenzoate (including 
antioxidants), emulsifying agents, and the like. Any other therapeutic 
ingredient may comprise one or more of the following: antibiotic (e.g. 
antibacterial), antifungal and antiviral agents, and antihistamines 
(particularly peripherally acting antihistamines). However, when such 
other agent(s) are also present, according to another aspect of the 
invention, the compound of formula (I) or physiologically acceptable salt 
thereof and the other agent(s), need not necessarily be present as a 
pharmaceutical formulation as hereinbefore defined, but merely in 
combination or intimate admixture, i.e. optionally, a pharmaceutically 
acceptable carrier need not be present. 
The combination with antihistamines is particularly favored for 
antiasthmatic use. Such an antihistamine may be selected from any compound 
described in European Patent Applications EP 0 859 949 A and EP 0 117 302 
A. The amount and dosage regime for such an antihistamine may be chosen 
from any of those recited in the latter two European Specifications. 
Especially preferred are the antihistamines 
(E)-3-(6-(3-pyrrolidino)-1-(4-tolyl)prop-lE-enyl(-2-pyridyl)) acrylic acid 
and (E)-3-(6-(3-pyrrolidino)-1-(4-tolyl)prop-lE-enyl 
(-2-pyridyl))propionic acid. Another preferred antihistamine is 
(E)-1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidinoprop-1-ene, otherwise 
known as typrolidine. 
Also preferred is the antihistamine known as Seldane. 
The compound of formula I and their salts may be prepared generally by one 
of two of the following processes and constitute a further aspect of the 
present invention 
For one of the preparations of compounds of the formula I as defined above, 
a compound of the formula 
EQU RCOOH 
wherein R is as defined above; 
is treated with a chloro- or bromo-generating compound, such as SOCl.sub.2, 
(COCl).sub.2, PBr.sub.3, preferably SOCl.sub.2 or (COCl).sub.2 under 
conditions analogous to those known in the art to obtain a compound of the 
formula 
EQU RCOQ 
wherein Q is chloro or bromo and R is as defined above, and then 
EQU RCOQ 
is treated with a compound of the formula 
##STR52## 
or its acid addition salt in the presence of a base to give the compund of 
the formula I. (See Scheme I) 
Where RCO is an acyl residue having s sulfinyl substituent, such as in 
I.sub.b, or an acyl residue having the definition of the formula of 
I.sub.w then the preparation with treatment by a chloro- or bromo- 
generating compound, such as SOCl.sub.2, (COCl).sub.2, or PBr.sub.3 
described above does not provide a desired product. For this definition of 
RCO, an alternate preparation is thus required. 
That is, surprisingly, for compounds having RCO defined by I.sub.b having a 
sulfoxide group among the definitions of its substituents, the sulfoxide 
reacts with the chloro- or bromo-of the generating compound so a product 
of the formula I having the sulfoxide as a substituent cannot be obtained. 
In other words, the acyl residue of sulindac does not provide the 
RCON(OR.sub.1)R.sub.2 desired by use of the above desired procedure. 
Further, in like manner, the compounds having the formula RCO of the 
structure I.sub.w cannot be treated with a chloro- or bromo- generating 
compound, such as SOCl.sub.2, (COCl).sub.2, or PBr.sub.3 to obtain the 
desired product of the above preparation because an intramolecular 
cyclization to oxindole occurs. For example, the acyl residue of methyl 
diclofenate as shown in U.S. Pat. No. 4,092,430 cannot be treated as 
described in the above preparation and reacted with the substituted 
hydroxyamine hydrogen chloride of the present invention contrary to the 
teaching of U.S. Pat. No. 4,092,430. 
Therefore, in these two instances use of the alternate preparation 
described hereinafter is critical. 
In an alternate preparation of the compound of the formula I as defined 
above a compound of the formula 
EQU RCOOH 
is treated with a coupling agent, such as 1,1'-carbonyldiimidazole, 
N-ethoxycarbonyl-2-ethoxy-1,3-dihydroquinoline, dicyclohexylcarbodiimide, 
dicyclohexylcarbodiimide/hydrox-vbenzenetriazole or the like, preferably 
1,1'-carbonyldiimidazole; and then further treated with a compound of the 
formula 
##STR53## 
or the acid addition salt thereof; wherein R.sub.1 and R.sub.2 are as 
defined above; to obtain the compound of formula I. (See Scheme II) 
##STR54## 
The reactions of Scheme II are carried out in organic solvents such as 
methylene chloride, DMF, THF and the like, preferably in methylene 
chloride. 
The hydroxamic acid formation is carried out at a temperature ranging from 
about 0.degree. C. to about 50.degree. C., preferably at about room 
temperature. 
One of skill in the art would recognize variations in the sequence and 
would recognize appropriate reaction conditions from analogous reactions 
which may be appropriately used in the processes to make the compounds of 
formula (I) herein. Further, the starting materials are known or can be 
prepared by known methods. 
Under certain circumstances it is necessary to protect either the N or O of 
intermediates in the above noted process with suitable protecting groups 
which are known. Introduction and removal of such suitable oxygen and 
nitrogen protecting groups are well-known in the art of organic chemistry; 
see for example "Protective Groups in Organic Synthesis," T. W. Greene, 
(Wiley-Interscience), New York, 1981. 
Examples of suitable oxygen protecting groups are benzyl, 
t-butyldimethylsilyl, ethoxyethyl, and the like. Protection of an N-H 
containing moiety is necessary for some of the processes described herein 
for the preparation of compounds of this invention. Suitable nitrogen 
protecting groups are benzyl, triphenylmethyl, trialkylsilyl, 
trichloroethylcarbamate, trichloroethoxycarbonyl, vinyloxycarbamate, and 
the like. 
Under certain circumstances it is necessary to protect two different 
oxygens with dissimilar protecting groups such that one can be selectively 
removed while leaving the other in place. The benzyl and 
t-butyldimethylsilyl groups are used in this way; either is removable in 
the presence of the other, benzyl being removed by catalytic 
hydrogenolysis, and t-butyldimethylsilyl being removed by reaction with, 
for example, tetra-n-butylammonium fluoride. 
In the process described herein for the preparation of compounds of this 
invention the requirements for protective groups are generally well 
recognized by one skilled in the art of organic chemistry, and accordingly 
the use of appropriate protecting groups is necessarily implied by the 
processes of the charts herein, although not expressly illustrated. 
The products of the reactions described herein are isolated by conventional 
means such as extraction, column chromatography, flash chromatography, and 
the like. 
The salts of the compounds of formula (I) described above are prepared by 
reacting the appropriate base or acid with a stoichiometric equivalent of 
the compounds of formula (I), respectively, to obtain pharmaceutically 
acceptable salts thereof. 
The invention is further elaborated by the representative examples as 
follows. Such examples are not meant to be limiting.

EXAMPLES 
EXAMPLE 1 
(Z)-6-fluoro-N-hydroxy-N,2-dimethyl-3-[[4-(methylsulfinyl)phenyl]methylene] 
-3H-indene-1-acetamide. 
A mixture of 
(Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3- 
acetic acid (sulindac, Sigma) (7.13 g, 0.02 mole) and 
1,1'-carbonyldiimidazole (4.9 g, 0.03 mole) in methylene chloride (200 ml) 
is stirred at room temperature for 30 minutes, then N-methyl-hydroxylamine 
hydrochloride (3.34 g, 0.04 mole) is added. After being stirred an 
additional 41 hours, the mixture is poured into cold 2 normal hydrochloric 
acid (1 l) and extracted with methylene chloride (400 ml). The organic 
solution is washed successively with 2 normal hydrochloric acid (1 l), 
water (3.times.1 l) and is dried over sodium sulfate. The solvent is 
removed under reduced pressure and the residue (8.2 g) is chromatographed 
on silica gel (225 g). Elution with 95:5 mixture of chloroform and 
methanol, gives 7.35 g of a solid. Recrystallization from ethyl 
acetate-hexane, then from methylene chloride-hexane, gives 5.5 g (75.3%) 
of analytically pure (Z)-6 
-fluoro-N-hydroxy-N,2-dimethyl-3-[[4-(methylsulfinyl)phenyl]methylene]-3H- 
indene-1-acetamide, m.p. 156.degree.-160.degree. C. 
EXAMPLE 2 
(Z)-6-fluoro-N-methoxy-2-methyl-3-[[4-(methylsulfinyl) 
phenyl]methylene]-3H-indene-1-acetamide. 
Prepared by the method described in Example 1, using appropriate starting 
materials. Recrystallization from methanol-ethyl acetate-hexane, gives 
analytically pure (Z)-6-fluoro-N-methoxy-2-methyl-3-[[4-(methylsulfinyl) 
phenyl]methylene]-3H-indene-1-acetamide in 50.8% yield, m.p. 
177.degree.-179.degree. C. 
EXAMPLE 2A 
(Z)-6-fluoro-N-hydroxy-2-methyl-3-[[4-(methylsulfinyl) 
phenYl]methylene]-3H-indene-1-acetamide. 
Prepared by the method described in Example 1, using appropriate starting 
materials. Recrystallization from methanol/ethyl acetate/hexane gives 
analytically pure (Z)-6-fluoro-N-hydroxy-2-methyl-3-[[4-(methylsulfinyl) 
phenyl]-methylene]-3H-indene-1-acetamide 28.9% yield, m.p. 
208.degree.-209.degree. C. dec. 
EXAMPL 2B 
(Z)-6-Fluoro-N-hydroxy-N-(1-methylethyl)-2-methyl-3-[[4-(methylsulfinyl)phe 
nyl]methylene]-3H-indene-1-acetamide. 
Prepared by the method described in Example 2, using appropriate starting 
materials. The crude product is flash chromatographed over silica gel 
using 5% CH.sub.3 OH-CHCl.sub.3 as eluent and obtained the pure analytical 
product as viscous oil in 94.8% yield. 
EXAMPLE 3 
1-(4-Chlorobenzoyl)-N-hydroxy-5-methoxy-N,2-dimethyl-1H-indole-3-acetamide. 
Oxalyl chloride (56.92 g, 0.448 mole) is added dropwise over 20 minutes 
with stirring to a solution of 
1(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (indomethacin, 
sigma) (64.2 g, 0.179 mole) in methylene chloride (500 ml) and 
dimethylformamide (13.12 g, 0.179 mole) at &lt;-2.degree. C. After being 
stirred for 80 minutes, this solution is added to a solution of 
N-methylhydroxylamine hydrochloride (59.9 g, 0.717 mole) and triethylamine 
(163.3 g, 1.61 mole) in tetrahydrofuran (200 ml) and water (100 ml). After 
being stirred for an additional 75 minutes, the mixture is poured into 
cold 2 normal hydrochloric acid (3 l) and extracted with methylene 
chloride (1.5 l). The organic layer is washed with water and dried over 
sodium sulfate. The solvent is removed under reduced pressure and the 
residue (68.7 g) is chromatographed on 663 g of silica gel. Elution with 
chloroform, then with 95:5 mixture of chloroform-methanol gives 63.1 g of 
a solid. Recrystallization from methanol, gives 55.49 g (80%) of 
analytically pure 
1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-N,2-dimethyl-1H-indole-3-acetamide 
, m.p. 170.degree.-171.degree. C. 
EXAMPLE 4 
1-(4-Chlorobenzoyl)-N,5-dimethoxy-2-methyl-1H-indole-3-acetamide. 
Prepared by the method described in Example 3 using appropriate starting 
materials. Recrystallization from methanol, gives analytically pure 
1-(4-chlorobenzoyl)-N,5-dimethoxy-2-methyl-1H-indole-3-acetamide in 73.7% 
yield, m.p. 184.degree.-185.degree. C. 
EXAMPLE 5 
1-(4-Chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-(1-methylethyl)-1H-indol 
e-3-acetamide. 
Prepared by the method described in Example 3 using appropriate starting 
materials. The crude product is chromatographed over silica gel using 
chloroform as eluant. Recrystallization from methanol gives analytically 
pure 
1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-(1-methylethyl)-1H-indo 
le-3-acetamide in 41.6% yield, m.p. 198.degree.-199.degree. C. 
EXAMPLE 6 
1-(4-Chlorobenzoyl)-N-cyclohexyl-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-a 
cetamide. 
Prepared by the method described in Example 3 using appropriate starting 
materials. The crude product is chromatographed on silica gel using 
chloroform as eluant. Recrystallization from methanol gives analytically 
pure 
1-(4-chlorobenzoyl)-N-cyclohexyl-N-hydroxy-5-methoxy-2-methyl-1H-indole-3- 
acetamide in 49.2% yield, m.p. 208.degree.-210.degree. C. 
EXAMPLE 6A 
1-(4-Chlorobenzoyl)-N,5-dimethoxy-N,2-dimethyl-1H-indole-3-acetamide. 
Prepared by the method described in Example 3 using appropriate starting 
materials. The crude product is flash chromatographed over silica gel 
using CHCl.sub.3 as eluent. Recrystallization from CH.sub.2 Cl.sub.2 
-isoPr.sub.2 O gives analytically pure product in 86.5% yield, m.p. 
155.degree.-157.degree. C. 
EXAMPLE 6B 
1-(4-Chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-phenyl-1H-indole-3-aceta 
mide. 
Prepared by the method described in Example 3 using appropriate starting 
materials. The crude product is flash chromatographed over silica gel 
using CHCl.sub.3 as eluent. Recrystallization of the purified product from 
methanol gives analytically pure product in 11.4% yield, m.p. 
173.degree.-174.degree. C. 
EXAMPLE 6C 
1-(4-Chlorobenzoyl)-N-benzyl-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-aceta 
mide. 
Prepared by the method described in Example 3 using appropriate starting 
materials. The crude product is flash chromatographed over silica gel 
using 5% CH.sub.3 OH-CH.sub.2 Cl.sub.2 as eluent. Recrystallization of the 
purified product from ethylacetate-ether gives analytically pure product 
in 27.6% yield, m.p. 188.degree.-189.degree. C. 
EXAMPLE 7 
N-Methoxy-2-[(2,6-dichlorophenyl)amino]-benzeneacetamide. 
A warm solution of 2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid (2.03 
g; 7 mmol) in CH.sub.2 Cl.sub.2 (100 mL) is treated with 
1,1'-carbonyl-diimidazole (1.75 g; 11 mmol) and the mixture is stirred at 
room temperature for 5.0 minutes when a clear solution is obtained. The 
solution is then treated with methoxylamine hydrochloride (1.50 g; 18 
mmol) and the reaction mixture stirred at room temperature for 108 hours. 
It is then decomposed with water, extracted with CH.sub.2 Cl.sub.2, dried 
over Na.sub.2 SO.sub.4 and then evaporated to dryness to give a solid. 
Fractional recrystallization of the crude product from a mixture of 
toluene-CH.sub.2 Cl.sub.2 gives off-white crystalline solid (1.27 g; 
55.8%); mp 177.degree.-178.degree. C. 
EXAMPLE 8 
N-Hydroxy-N-methyl-2-[(2,6-dichlorophenyl)amino]-benzeneacetamide. 
1,1'-Carbonyl-diimidazole (5.5 g; 34 mmol) is slowly added to a warm 
solution of 2-[(2,6-dichlorophenyl)-amino]-benzeneacetic acid (6.5 g; 22 
mmol) in CH.sub.2 Cl.sub.2 (600 mL) and stirred at room temperature for 
2.0 hours when a clear solution is formed. N-Methylhydroxylamine 
hydrochloride (5.5 g; 66 mmol) is slowly added to the solution and the 
mixture stirred at room temperature for 48 hours. It is decomposed with 
water, extracted with CH.sub.2 Cl.sub.2 and dried over Na.sub.2 SO.sub.4. 
The solvent is evaporated off and the residue flash chromatographed over 
silica gel (250 g) using 10% EtOH-CH.sub.2 Cl.sub.2 as eluant to give the 
pure product as white solid which is recrystallized from toluene-CH.sub.2 
Cl.sub.2. Yield 2.95 g (41.2%); mp 135.degree.-138.degree. C. 
The usefulness of the compounds of the present invention as inhibitors of 
the 5-lipoxygenase enzyme, cyclooxygenase, or other related biochemical 
actions may be demonstrated by their effectiveness in various standard 
test procedures. A description of each procedure follows. 
ARBL/ARBC Whole Cell 5-Lipoxygenase and Cyclooxygenase Assays 
Materials 
The rat basophilic leukemia cell line (RBL-1) was obtained from the 
American Type Culture Collection (Rockville, Md.). 
Radioimmuno assay (RIA) kits of LTB.sub.4 and PGF.sub.2.alpha. were 
obtained from Amersham (Arlington Heights, Ill.) and Seragen (Boston, 
Mass.) respectively. 
All tissue culture media were obtained from GIBCO (Grand Island, N.Y.). 
Method 
RBL-1 cells are grown in suspension culture in Eagle's minimum essential 
medium supplemented with 12% fetal bovine serum at 37.degree. C. in an 
incubator supplied with air-5% carbon dioxide. Cells are harvested by 
centrifugation. They are washed with cold phosphate buffered saline pH 7.4 
(PBS; NaCl, 7.1 g; Na.sub.2 PO.sub.4, 1.15 g; KH.sub.2 PO.sub.4, 0.2 g; 
and KCl, 0.2 g/l). Cells are finally suspended in PBS containing 1.0 mM 
calcium at a density of 2.times.10.sup.6 cells/ml. Cells are incubated 
with and without test agent (in DMSO) (1% DMSO is without effect on 
arachidonic acid metabolism) for ten minutes at room temperature. Calcium 
ionophore A23187 (5 .mu.M) is added and cells are incubated for seven 
minutes at 37.degree. C. The reaction is stopped by chilling the tubes on 
ice for ten minutes. Cells are separated by centrifugation and the 
supernatant is stored at -20.degree.. Aliquots (100 .mu.l) are analyzed 
for LTB.sub.4 and PGF.sub.2.alpha. using radioimmuno assay kits as 
provided by the supplier. 
Table 1 contains biochemical data obtained from this whole cell assay as 
IC.sub.50 s which are calculated as the amount of test compound causing 
50% inhibition of LTB.sub.4 or PGF.sub.2.alpha. formation. 
Carrageenan-Induced Rat Foot Paw Edema-2 (CFE-2) Assay: Protocol 
Carrageenan solution (1% w/v) is prepared by dissolving 100 mg carrageenan 
(Marine Colloidal Div., Springfield, N.J.) in 10 ml of sterile saline 
(0.9%) solution (Travenol). The solution is vortexed for thirty to 
forty-five minutes. Animals are dosed with compound one hour before 
carrageenan challenge. Foot paw edema is induced by injecting 0.05 ml of 
the 1% carrageenan subcutaneously into the plantar portion of the right 
hind paw of each rat under light anesthesia. Initial foot paw volume is 
measured immediately following carrageenan challenge using mercury 
plethysmography (Buxco Electronics). Edema is measured five hours after 
carrageenan. The difference between the five-hour and the initial paw 
volume is expressed as delta edema. The delta edema for each test group of 
animals is used to calculate the percent inhibition of edema achieved by 
the compound at the test dose compared with the vehicle control group. The 
ID.sub.25 (the dose at which swelling is inhibited by 25%) was calculated 
by probit analysis for the dose at which a result of 25 percent inhibition 
occurs. 
Mycobacterium - Induced Rat Footpad Edema Assay (MFE): Protocol 
Myobacterium butyricum (5 mg/ml) is suspended in paraffin oil by sonication 
for ten minutes in an ice bath. Footpad edema is induced on Day 0 by 
injecting 0.1 ml of the Mycobacterium mixture into the left hindpaw of 
lightly anesthetized rats. Swelling in the injected hindpaw is determined 
by mercury plethysmography seventy-two hours after injection. Groups of 
rats are treated with test compounds (suspended in 0.5% hydroxypropyl 
methylcellulose with 0.2% Tween-80) or vehicle one hour before 
Myobacterium injection and on Days 1 and 2. Inhibition of swelling is 
determined by comparing the change in hindpaw volume in compound- and 
vehicle-treated rats. An ID.sub.40 (the dose at which swelling is 
inhibited by 40%) was calculated by probit analysis. 
Gastric Ulcerogenicity (UD) Protocol 
Male outbred Wistar rats (100-250 gms) were fasted for twenty-four hours. 
After fasting, test compounds were administered orally (in 2 ml/Kg of 0.5% 
hydroxypropyl methylcellulose) and the rats were denied access to food and 
water for six more hours. The rats were then sacrificed with CO.sub.2 so 
that the stomachs could be removed, opened along the greater curvature, 
and evaluated for the presence of gastric ulcers. Results are expressed as 
the percent of rats with gastric ulcers at a given dose. 
The results of the CFE-2, MFE, and UD assays for each of the noted 
compounds is shown in the following Table 1 and Table 2. 
TABLE I 
__________________________________________________________________________ 
SULINDAC SERIES 
PD # X ARBC.sup.a /ARBL.sup.b 
RATIO.sup.c 
CFE.sup.d 
MFE.sup.e 
__________________________________________________________________________ 
SULINDAC 
Example 1 
COM(ME)OH 
0% @ 32*/1.0 
-- 15% @ 30 
30% @ 10 
Example 2 
CONHOME 0% @ 32*/26.4 
-- -- -- 
Example 2A 
CONHOH 0% @ 32*/12.9 
-- 31% @ 30 
53% @ 50 
__________________________________________________________________________ 
*Parent sulindac sulfoxides are not CO inhibitors, but converted to CO 
Inhibitory sulfides in vivo. 
.sup.a ARBC = RBL Whole Cell Cyclooxygenase Assay. IC50 (.mu.M) for 
PGF.sub.2.alpha. inhibition. 
.sup.b ARBL = RBL Whole Cell 5Lipoxygenase Assy. IC50 (.mu.M) for 
LTB.sub.4 inhibition. 
.sup.c RATIO = Selectivity of Inhibition. If &gt;1.0 compound is 
cyclooxygenase selective. If &lt;1.0 compound is 5lipoxygenase selective. 
.sup.d CFE = Carrageenan Footpad Edema Model. ID25 or % Inhibition @ Dose 
(mg/kg PO). 
.sup.3 MFE = Mycobacterium Footpad Edema Model. ID40 or % Inhibition @ 
Dose (mg/kg PO). 
TABLE 2 
__________________________________________________________________________ 
INDOMETHACIN SERIES 
Example # 
X ARBC.sup.a /ARBL.sup.b 
RATIO.sup.c 
CFE.sup.d 
MFE.sup.e 
UD50.sup.f 
__________________________________________________________________________ 
Indomethacin 
OH 0.5/&gt;100 &gt;200 36% @ 5 
0.21 
5.4 
Oxametacin 
NHOH 1.1/7.5 6.8 46% @ 30 103 
Example 3 
NMEOH 5.2/1.4 0.27 29% @ 10 
&lt;2 10% @ 100 
Example 4 
NHOME 0.2/24 120 40% @ 10 42 
Example 5 
N(iPR)OH 2.7/0.9 0.33 27% @ 10 
0.82 
N @ 100 
Example 6 
N(C--C.sub.6 H.sub.11)OH 
0.1/1.6 16.0 22% @ 10 
4.7 N @ 200 
__________________________________________________________________________ 
.sup.a ARBC = RBL Whole Cell Cyclooxygenase Assay. IC50 (.mu.M). 
.sup.b ARBL = RBL Whole Cell 5Lipoxygenase Assy. IC50 (.mu.M). 
.sup.c RATIO = Selectivity of Inhibition. If &gt;1.0 compound is 
cyclooxygenase selective. If &lt;1.0 compound is 5lipoxygenase selective. 
.sup.d CFE = Carrageenan Footpad Edema Model. ID25 or % Inhibition @ Dose 
(mg/kg PO). 
.sup.e MFE = Mycobacterium Footpad Edema Model. ID40 or % Inhibition @ 
Dose (mg/kg PO). 
.sup.f UD50 = Dose (mg/kg PO) causing ulcers in 50% of animals. 
Accordingly, the present invention is 
(a) a compound of formula I or an acid addition salt thereof; 
(b) a method for preparing a compound of formula I or a pharmacologically 
acceptable acid addition salt thereof; 
(c) a pharmaceutical formulation comprising a compound of formula (I) or a 
physiologically acceptable salt thereof and a pharmaceutically acceptable 
carrier therefor; 
(d) a method for preparing such formulations; 
(e) a method for the inhibition of the lipoxygenase and/or cyclooxygenase 
pathways of the arachidonic acid metabolism by use of a nontoxic, 
effective, inhibitory amount of a compound of formula I or a 
physiologically acceptable salt thereof; 
(f) a method for the prophylaxis or treatment of disease or condition in a 
mammal, including man, comprising the administration to said mammal of a 
nontoxic, therapeutically or prophylactically effective amount of a 
compound of formula I or a physiologically acceptable salt thereof; 
(g) a method for the prophylaxis or treatment of any individual condition 
described herein, in a mammal, including man, comprising the 
administration to said mammal of a nontoxic therapeutically or 
prophylactically effective amount of a compound of formula I or a 
physiologically acceptable salt thereof; 
(h) a method for the prophylaxis or treatment of inflammation, arthritis, 
pain or fever in a mammal, including man, comprising the administration to 
said mammal of a nontoxic, effective, antiinflammation, antiarthritic, 
analgesic, antipyretic amount of a compound of formula I or a 
physiologically acceptable salt thereof; 
(i) a method for the prophylaxis or treatment of asthma in a mammal, 
including man, comprising administration to said mammal of a nontoxic, 
effective, antiasthmatic amount of a compound of formula I or a 
physiologically acceptable salt thereof; 
(j) a compound of formula I or a physiologically acceptable salt thereof 
for use in medicine, especially as defined in (f)-(h) above; 
(k) use of a compound of formula I or a physiologically acceptable salt 
thereof in the manufacture of medical therapeutic agents, particularly 
those for use as defined in (f)-(k) above; and 
(l) any novel feature described herein.