Inhibition of the 5-lipoxygenase pathway

A method of inhibiting the 5-lipoxygenase pathway in an animal in need thereof which comprises administering an effective, 5-lipoxygenase pathway inhibiting amount of a diaryl- substituted imidazole fused to a thiazole pyrrolidine, thiazide or piperidine ring to such animal.

BACKGROUND OF THE INVENTION 
This invention relates to novel compounds, pharmaceutical compositions and 
a method of inhibiting the 5-lipoxygenase pathway of arachidonic acid 
metabolism in an animal in need thereof which comprises administering to 
such animal an effective, 5-lipoxygenase pathway inhibiting amount of a 
diaryl-substituted imidazole fused to a thiazole, pyrrolidine, thiazine or 
piperidine ring or a pharmaceutically acceptable salt thereof. 
Ciba-Geigy AG., U.K. Patent Application GB 2,039,882, published Aug. 20, 
1980, discloses compounds of the formula 
##STR1## 
wherein the 1,3-diazacyclopent-2-ene ring may have a further double bond, 
Alk represents lower alkylene that separates the sulfur atom from the 
nitrogen atom by 2 to 4 carbon atoms, Ar.sub.1 and Ar.sub.2 represent, 
independently of one another, an optionally substituted phenyl, pyridyl or 
thienyl radical and n is 0, 1 or 2, provided that at least one of the 
radicals Ar.sub.1 and Ar.sub.2 is not phenyl when Alk represents ethylene 
and the 1,3-diazacyclopent-2-ene ring represents an imidazole ring, and 
the salts thereof. Compound 1 is not specifically disclosed. The 
Ciba-Geigy reference alleges that such compounds exhibit anti-inflammatory 
and antiexudation effects in the rat kaolin paw-oedema test or in the rat 
turpentine pleuritis test; that the unsaturated compounds in particular 
exhibit an excellent effect in the adjuvant arthritis test; and that such 
compounds also have an analgesic effect as shown in the 
phenyl-p-benzoquinone test in mice; inhibit prostaglandin synthetase in 
vitro; protect against fatal pulmonary embolism in rabbits (i.e., are 
anti-thrombotic); and that the tetrahydro compounds exhibit a strong 
effect in the pertussis oedema test. The rat kaolin paw oedema test and 
the rat turpentine pleuritis test are useful in detecting compounds which 
are cyclooxygenase inhibitors but are of no known utility in detecting or 
suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. 
The adjuvant arthritis test is useful for detecting compounds which are 
inhibitors of prostanoid synthesis, but is of no utility for disclosing or 
suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. 
The phenyl-p-benzoquinone test is useful for detecting compounds which are 
cyclooxygenase inhibitors, but is of no known utility in detecting or 
suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. 
The observation that compounds of the Ciba-Geigy reference inhibit 
prostaglandin synthetase in vitro (cyclooxygenase) is of no utility in 
detecting or suggesting compounds which are inhibitors of the 
5-lipoxygenase pathway. The observation that the compounds of the 
Ciba-Geigy reference are anti-thrombotic in rabbits is of no known utility 
in detecting or suggesting compounds which are inhibitors of the 
5-lipoxygenase pathway. The pertussis oedema test is useful in detecting 
compounds which are cyclooxygenase inhibitors, but is of no known utility 
in detecting or suggesting compounds which are inhibitors of the 
5-lipoxygenase pathway. 
Bender et al., U.S. Pat. No. 4,175,127, issued Nov. 20, 1979 disclose 
compounds of the formula 
##STR2## 
in which R.sub.1 and R.sub.2 are the same or different, but one of which 
always being pyridyl, are pyridyl or phenyl optionally monosubstituted by 
a lower alkoxy, lower alkyl, lower alkylthio, chloro, fluoro, bromo, or 
trifluoromethyl or a pharmaceutically acceptable acid addition salt or 
oxide derivative thereof. Bender et al. also discloses that such compounds 
have utility as antiarthritic agents. Such antiarthritic activity is 
disclosed as the result of test results from adjuvant-induced 
polyarthritis in rats. Although not claimed, the Bender patent also 
suggests, at column 3, lines 66-68, that compounds of Formula A also have 
antiinflammatory or immunoregulatory properties in addition to their 
antiarthritic activity. The Bender patent states, at column 4, lines 
47-50, that such anti-inflammatory activity is produced by some of the 
Formula A compounds in the carrageenan-induced rat paw edema test. The 
Bender patent also states, at column 4, lines 51-65, that species of the 
Formula A compounds have the ability to regulate cell-mediated immunity as 
shown in procedures such as the oxazolone-induced contact sensitivity test 
procedure in which mouse paw volume is measured. 
Lantos et al., J. Med. Chem., 27, 72-75 (1984), also disclose that certain 
5,6-diaryl-2,3-dihydroimidazo [2,1-b]thiazoles have antiinflammatory 
activity in the carrageenan-induced rat paw edema and adjuvant arthritis 
assay in rats. Both the adjuvant-induced polyarthritis assay in rats and 
the carrageenan-induced rat paw edema test are useful in detecting 
compounds which are inhibitors of prostanoid synthesis, mediated by the 
prostanoids formed by the enzyme cyclooxygenase, but are of no known 
utility in detecting or suggesting compounds which are inhibitors of the 
generation of 5-lipoxygenase products (such as HETES, LTB.sub.4 and 
peptidoleukotrienes). The oxazolone-induced contact sensitivity test in 
which mouse paw volume is measured is useful in detecting compounds which 
are immunostimulatory, but is of no known utility in detecting or 
suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. 
Lantos et al., U.S. Ser. No. 737,137, filed May 29, 1985, disclose an 
improved method for the preparation of compounds of the formula: 
##STR3## 
in which R is H, halo, C.sub.1-2 -alkyl, C.sub.1-2 -alkoxy or 
trifluoromethyl. Lantos et al. state that such compounds have 
antiarthritic activity. There is no further statement in this reference as 
to how such antiarthritic activity was determined. Such a blanket 
statement of anti-arthritic utility does not disclose to one of skill in 
the art that such compounds have 5-lipoxygenase pathway inhibiting 
activity. Lantos et al. also disclose compounds of the formula: 
##STR4## 
in which: R is H, halo, C.sub.1-2 alkyl, C.sub.1-2 alkoxy or 
trifluoromethyl; 
R.sup.2 is H or 
##STR5## 
R is C.sub.1-8 alkyl, C.sub.1-8 alkoxy, phenyl, phenoxy, benzyl or 
benzyloxy. 
Cherkofsky et al., U.S. Pat. No. 4,064,260, issued Dec. 20, 1977 discloses 
compounds of the formula 
##STR6## 
in which n is 0, 1 or 2, and R and R.sup.1 are independently selected from 
monosubstituted phenyl wherein said substituent is selected from C.sub.1-4 
alkoxy. Cherkofsky et al. also disclose that such compounds have utility 
as antiinflammatory agents as demonstrated by their activity in the 
established adjuvant-induced arthritis assay in rats or the phenylquinone 
writhing test in mice. As stated above, the adjuvant arthritis test is of 
no utility for disclosing or suggesting compounds which are inhibitors of 
the 5-lipoxygenase pathway. The phenylquinone writhing test is useful for 
detecting compounds which are inhibitors of prostanoid synthesis but is of 
no known utility for disclosing or suggesting compounds which are 
inhibitors of the 5-lipoxygenase pathway. 
Bender et al., U.S. Pat. No. 4,263,311 issued Apr. 21, 1981, discloses 
compounds of the formula 
##STR7## 
wherein n is 0, 1 or 2, and R.sup.1 and R.sup.2 are independently selected 
from (a) monosubstituted phenyl wherein said substituent is selected from 
lower alkoxy, chloro, fluoro, bromo, trifluoromethyl, amino, di-N-N-lower 
alkylamino or (b) 3,4-methylenedioxyphenyl. Bender et al. also disclose 
that such compounds have utility (a) in the treatment of arthritis based 
on their activity in the adjuvant-induced arthritis test in rats and in 
the carrageenan-induced rat paw edema test; and (b) as immunoregulatory 
agents based on their activity in the oxazolone-induced contact 
sensitivity test in which mouse paw volume is measured. As stated above, 
none of the adjuvant arthritis test, carrageenan edema test or oxazalone 
sensitivity test have any known utility in detecting or suggesting 
compounds which are inhibitors of the 5-lipoxygenase pathway. 
Bender et al., U.S. Pat. No. 4,186,205, issued Jan. 29, 1980, disclose 
compounds of the formula 
##STR8## 
wherein R is 4-monosubstituted phenyl and said substituent is selected 
from C.sub.1-4 alkoxy or chloro, or a non-toxic, pharmaceutically 
acceptable salt thereof. Bender et al. also disclose that such compounds 
are useful as (a) antiarthritic agents based on their activity in the 
adjuvant-induced arthritis assay in rats; and (b) regulators of 
cell-mediated immunity based on their activity in the oxazolone-induced 
contact sensitivity test in which mouse paw volume is measured. As stated 
above, neither the adjuvant arthritis test nor the oxazolone sensitivity 
test are of any known utility in disclosing or suggesting compounds which 
are inhibitors of the 5-lipoxygenase pathway. 
Bender et al., J. Med. Chem., 28, 1169-1177 (1985), disclose compounds of 
the formula 
##STR9## 
wherein n is 0, 1 or 2, and R and R.sup.1 are independently selected from 
(a) monosubstituted phenyl wherein said substituent is selected from 
C.sub.1-4 alkoxy, halo, 4-amino, 4-acetamido, 4-trifluoromethyl, 
4-N(ethyl)-acetamido, 4-ethylamino, and 4-ethyl(methyl)amino; or (b) 
3,4-methylenedioxyphenyl. Bender et al. also disclose that some of such 
compounds are useful as immunoregulatory, anti-inflammatory and 
antiarthritic agents based on their activity in the adjuvant-induced 
arthritis test and the mouse subliminal oxazolone-induced contact 
sensitivity assay. As stated above, the adjuvant arthritis assay is of no 
utility in detecting or suggesting compounds which are inhibitors of the 
5-lipoxygenase pathway. The mouse subliminal oxazolone sensitivity assay 
is useful in detecting compounds which are immunostimulatory but is of no 
known utility in detecting compounds which are inhibitors of the 
5-lipoxygenase pathway. 
Baetz et al., U.S. Pat. No. 4,110,460, issued Aug. 29, 1978, discloses 
compounds of the formula 
##STR10## 
wherein R and R.sup.1 are independently selected from monosubstituted 
phenyl wherein said substituent is selected from chloro, bromo, C.sub.1-4 
alkoxy, or a pharmaceutically acceptable acid addition salt thereof. Baetz 
et al. also disclose that such compounds have anti-inflammatory activity 
based on their activity in the carrageenan-induced edema assay in rats, 
cotton-induced granuloma assay in rats, ultraviolet induced erythema assay 
in guinea pigs, and Freund-adjuvant induced arthritis assay in rats. All 
of such assays are useful for detecting compounds which are inhibitors of 
prostanoid synthesis, but none of such assays is of any known utility for 
disclosing or suggesting compounds which are inhibitors of the 
5-lipoxygenase pathway. Baetz et al. also disclose that such compounds 
have utility as antipyretic agents based on their activity in an assay in 
which hyperthermia was induced in rats by subcutaneous infection with 
yeast. Such assay is useful for detecting compounds which are 
cyclooxygenase inhibitors but is of no known utility in detecting or 
suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. 
Baetz et al. also disclose that such compounds have analgesic activity 
based on their activity in the acetic acid writhing test in mice. The 
acetic acid writhing test is useful for detecting compounds which are 
cyclooxygenase inhibitors but is of no known utility in detecting 
compounds which are inhibitors of the 5-lipoxygenase pathway. 
Bender et al., U.S. Pat. No. 4,153,706, issued May 8, 1979, disclose 
compounds of the formula 
##STR11## 
wherein R.sup.1 is 4-substituted phenyl wherein said substituent is 
selected from lower alkoxy, lower alkylthio, fluoro, chloro, bromo or 
trifluoromethyl; and R.sup.2 is 4-substituted phenyl wherein said 
substituent is an election withdrawing group, in particular, fluoro, 
chloro, bromo or trifluoromethyl. Bender et al. also state that such 
compounds have antiarthritic activity as measured in the adjuvant-induced 
polyarthritis assay in rats; and immunoregulatory activity as measured by 
the oxazolone-induced contact sensitivity test in mice. As stated above, 
such assays do not disclose or suggest that such compounds have 
5-lipoxygenase pathway inhibiting activity. 
Davidson et al., U.S. Pat. No. 4,507,481, issued Mar. 26, 1985, disclose 
compounds of the formula 
##STR12## 
wherein X is O or S(O)n; 
n is 0, 1 or 2; 
R.sub.1 can be H; 
R.sub.2 can be H; 
A is CH.sub.2 or CH.sub.2 CH.sub.3 ; 
R.sub.3 and R.sub.4 are independently selected from phenyl substituted with 
lower alkyl, lower alkylamino, lower alkoxy or halogen; 
R.sub.5 and R.sub.6 are each H or join to form a double bond at the 
2,3-position. 
Davidson et al. also disclose that such compounds are immunostimulants or 
immunosuppresants based on (a) their inhibiting or stimulating activity in 
a chemotaxis assay which measures the ability of a drug substance to 
influence the movement of murine macrophages responding to complement; (b) 
their immunosuppressing or activating activity in the Kennedy plaque assay 
in which an animal's humoral immune system is depressed artificially with 
6-mercaptopyrine. Such chemotaxis assay is no known utility for detecting 
or suggesting compounds which are inhibitors of the 5-lipoxygenase 
pathway. Such Kennedy plaque assay is of no known utility for detecting or 
suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. 
Davidson et al. also disclose that such compounds have antiinflammatory 
activity as determined by the carrageenan-induced paw edema assay in rats. 
As stated above, such assay has no known utility in detecting or 
suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. 
Davidson et al. also disclose that such compounds have antiviral activity 
in mice with hepatitis; but such activity is of no known utility in 
detecting or suggesting compounds which are inhibitors of the 
5-lipoxygenase pathway. 
SUMMARY OF THE INVENTION 
This invention relates to a compound of the formula 
##STR13## 
wherein: X is CH.sub.2 or S(O).sub.n ; 
n is 0, 1 or 2; 
A is CH.sub.2 or CH.sub.2 CH.sub.2 ; 
B and C are independently selected from H, methyl, ethyl or dimethyl; 
One of R.sup.a or R.sup.b must be selected from 2-pyridyl, 3-pyridyl, 
4-pyridyl, monosubstituted phenyl wherein said substituent is selected 
from C.sub.1-3 dialkylamino, C.sub.1-3 alkylamino, N-(azacyclo C.sub.5-6 
alkyl), cyano, 2,2,2-trihaloethoxy, N-C.sub.1-3 alkanamido, N-(C.sub.1-3 
alkyl)-(C.sub.1-3 alkanamido) or prop-2-ene-1-oxy; or disubstituted phenyl 
wherein said substituents are independently selected from C.sub.1-4 alkyl 
or C.sub.1-3 alkoxy or the disubstituents together form a methylenedioxy 
group; and the other of R.sup.a or R.sup.b is selected from: 
1) pyridyl; 
2) phenyl; 
3) monosubstituted phenyl wherein said substituent is selected from 
C.sub.1-3 alkoxy, halo, CF.sub.3, C.sub.1-3 alkylthio, C.sub.1-4 alkyl, 
2,2,2-trihaloethoxy, prop-2-ene-1-oxy, C.sub.1-3 alkylamino, C.sub.1-3 
dialkylamino, cyano or N-(azacyclo C.sub.5-6 alkyl); 
4) disubstituted phenyl wherein said substituents are independently 
selected from C.sub.1-4 alkyl or C.sub.1-3 alkoxy or the disubstituents 
together form a methylene dioxy group; or 
5) 3,4,5-trimethoxyphenyl; 
provided that: 
(a) when X is CH.sub.2, both of R.sup.a and R.sup.b are other than pyridyl; 
(b) when X is CH.sub.2 or S, both of R.sup.a and R.sup.b are other than 
phenyl substituted in the 2,3,5 or 6 position with C.sub.1-3 alkylamino; 
C.sub.1-3 dialkylamino; or N-(azacyclo C.sub.5-6 alkyl); 
(c) when X is S(O).sub.n only one of R.sup.a or R.sup.b is C.sub.1-3 
alkylaminophenyl; 
(d) when X is S(O).sub.n only one of R.sup.a or R.sup.b is C.sub.1-3 
dialkylaminophenyl; 
(e) when either of R.sup.a or R.sup.b is disubstituted phenyl the other 
must be 4-pyridyl; 
(f) when either of R.sup.a or R.sup.b is cyanophenyl the other must be 
cyanophenyl or 4-pyridyl; 
(g) when X is S(O).sub.n and either of R.sup.a or R.sup.b is phenyl 
substituted in the 2,3,5 or 6 position with C.sub.1-3 alkylamino, 
C.sub.1-3 dialkylamino or N-(azacyclo C.sub.5-6 alkyl), the other must be 
4-pyridyl; 
(h) when X is S(O).sub.n only one of R.sup.a or R.sup.b is 
4-(prop-2-ene-1-oxy)phenyl; 
(i) when X is S(O).sub.n only one of R.sup.a or R.sup.b is 
4-(2,2,2-trifluoroethoxy)phenyl; 
(j) when X is S(O).sub.n only one of R.sup.a or R.sup.b is 
3,4-methylenedioxyphenyl; 
or a pharmaceutically acceptable salt thereof. 
The term "N-(azacyclo C.sub.5-6 alkyl)" is used herein at all occurrences 
to mean pyrrolidino or piperidino. 
This invention also relates to a pharmaceutical composition comprising a 
pharmaceutically acceptable carrier or diluent and an effective, non-toxic 
5-lipoxygenase pathway inhibiting amount of a compound of 
##STR14## 
wherein: X is CH.sub.2 or S(O).sub.n ; 
n is 0, 1 or 2; 
A is CH.sub.2 or CH.sub.2 CH.sub.2 ; 
B and C are independently selected from H, methyl, ethyl or dimethyl; 
One of R.sup.c or R.sup.d must be selected from 2-pyridyl, 3-pyridyl, 
4-pyridyl, monosubstituted phenyl wherein said substituent is selected 
from C.sub.1-3 dialkylamino, C.sub.1-3 alkylamino, N-(azacyclo C.sub.5-6 
alkyl), cyano, 2,2,2-trihaloethoxy, N-C.sub.1-3 alkanamido, N-(C.sub.1-3 
alkyl)-(C.sub.1-3 alkanamido) or prop-2-ene-1-oxy; or disubstituted phenyl 
wherein said substituents are independently selected from C.sub.1-4 alkyl 
or C.sub.1-3 alkoxy or the disubstituents together form a methylenedioxy 
group; and the other of R.sup.c or R.sup.d is selected from: 
1) pyridyl; 
2) phenyl; 
3) monosubstituted phenyl wherein said substituent is selected from 
C.sub.1-3 alkoxy, halo, CF.sub.3, C.sub.1-3 alkylthio, C.sub.1-4 alkyl, 
2,2,2-trihaloethoxy, prop-2-ene-1-oxy, C.sub.1-3 alkylamino, C.sub.1-3 
dialkylamino, cyano or N-(azacyclo C.sub.5-6 alkyl); 
4) disubstituted phenyl wherein said substituents are independently 
selected from C.sub.1-4 alkyl or C.sub.1-3 alkoxy or the disubstituents 
together form a methylene dioxy group; or 
5) 3,4,5-trimethoxyphenyl; 
provided that: 
(a) when X is CH.sub.2, both of R.sup.c and R.sup.d are other than pyridyl 
and when X is; S(O).sub.n and n is 0, both of R.sup.c and R.sup.d are not 
simultaneously 2-, 3-, or 4-pyridyl; when n is 1, and one of R.sup.c or 
R.sup.d is 2-pyridyl or 3-pyridyl the other of R.sup.c or R.sup.d is not 
2-pyridyl or 3-pyridyl; when n is 2, and one of R.sup.c and R.sup.d is 
2-pyridyl the other of R.sup.c and R.sup.d is not 2-pyridyl; and when n is 
0 and one of R.sup.c and R.sup.d is phenyl the other of R.sup.c and 
R.sup.d is not 2-, 3-, or 4-pyridyl; 
(b) when X is CH.sub.2 or S, both of R.sup.c and R.sup.d are other than 
phenyl substituted in the 2,3,5 or 6 position with C.sub.1-3 alkylamino; 
C.sub.1-3 dialkylamino; or N-(azacyclo C.sub.5-6 alkyl); 
(c) when X is S(O).sub.n only one of R.sup.c or R.sup.d is C.sub.1-3 
alkylaminophenyl; 
(d) when X is S(O).sub.n only one of R.sup.c or R.sup.d is C.sub.1-3 
dialkylaminophenyl; 
(e) when either of R.sup.c or R.sup.d is disubstituted phenyl the other 
must be 4-pyridyl; 
(f) when either of R.sup.c or R.sup.d is cyanophenyl the other must be 
cyanophenyl or 4-pyridyl; 
(g) when X is S(O).sub.n and either of R.sup.c or R.sup.d is phenyl 
substituted in the 2,3,5 or 6 position with C.sub.1-3 alkylamino; 
C.sub.1-3 dialkylamino or N-(azacyclo C.sub.5-6 alkyl), the other must be 
4-pyridyl; 
(h) when X is S(O).sub.n only one of R.sup.c or R.sup.d is 
4-(prop-2-ene-1-oxy)phenyl; 
(i) when X is S(O).sub.n only one of R.sup.c or R.sup.d is 
4-(2,2,2-trifluoroethoxy)phenyl; 
(j) when X is S(O).sub.n only one of R.sup.c or R.sup.d is 
3,4-methylenedioxyphenyl; 
(k) when X is S(O).sub.n, and n is 0, and one of R.sup.c or 4-pyridyl, the 
other is not 4-pyridyl, phenyl, 4-methoxyphenyl, 4-fluorophenyl, 
4-methylthiophenyl, 2-bromophenyl, 3-chlorophenyl, 
4-trifluoromethylphenyl, 4-methylphenyl, 4-ethylphenyl, [or] 
3-isopropoxyphenyl, 4-methoxyphenyl or 4-ethoxyphenyl; and 
(l) when R.sup.d is N-(C.sub.1-3 alkanamido) or N-(C.sub.1-3 
alkyl)-N-(C.sub.1-3 alkanamido), R.sup.c must be 4-pyridyl; 
(m) when X is S(O).sub.n, and n is 1, and one of R.sup.c or R.sup.d is 
4-pyridyl, the other is not 4-pyridyl, phenyl, or phenyl mono-substituted 
by 4-methoxy, 4-ethoxy, or 4-fluoro; 
(n) when X is S(O)n, and n is 0, 1 or 2, and one of R.sup.a or R.sup.b is 
phenyl, the other is not a phenyl di-substituted with methoxy; 
or a pharmaceutically acceptable salt thereof. 
This invention also relates to a method of treating rheumatoid arthritis in 
an animal in need thereof which comprises administering to such animal an 
effective, non-toxic 5-lipoxygenase pathway inhibiting amount of a 
compound of Formula (IC) or a pharmaceutically acceptable salt thereof. 
This invention also relates to a method of treating a 5-lipoxygenase 
pathway mediated disease in an animal in need thereof, provided that such 
animal is in need of treatment of a 5-lipoxygenase pathway mediated 
disease other than, or in addition to, rheumatoid arthritis, which 
comprises administering to such animal an effective, non-toxic 
5-lipoxygenase pathway inhibiting amount of a compound of the formula 
##STR15## 
wherein: X is CH.sub.2 or S(O)n; 
n is 0, 1 or 2; 
A is CH.sub.2 or CH.sub.2 CH.sub.2 ; 
B and C are independently selected from H, methyl, ethyl or dimethyl; 
R.sup.1 and R are independently selected from 
(a) pyridyl, provided that when either or both of R and R.sup.1 are pyridyl 
X is other than CH.sub.2 ; 
(b) phenyl; 
(c) monosubstituted phenyl wherein said substituent is selected from 
C.sub.1-3 alkoxy, halo, CF.sub.3, C.sub.1-3 alkylthio, C.sub.1-4 alkyl, 
2,2,2-trihaloethoxy, prop-2-ene-1-oxy, C.sub.1-3 alkylamino, C.sub.1-3 
dialkylamino, cyano, or N-(azacyclo C.sub.5-6 alkyl); 
(d) disubstituted phenyl wherein said substituents are independently 
selected from C.sub.1-4 alkyl or C.sub.1-3 alkoxy or the disubstituents 
together form a methylene dioxy group; 
(e) 3,4,5-trimethoxyphenyl; provided that: 
(1) when X is CH.sub.2, both of R and R.sup.1 are other than phenyl 
substituted in the 2 or 6 position with C.sub.1-3 alkylamino; C.sub.1-3 
dialkylamino or N-(azacyclo C.sub.5-6 alkyl); 
(2) when X is CH.sub.2, both of R and R.sup.1 are other than pyridyl; 
(3) when either of R or R.sup.1 is cyanophenyl the other must be 
cyanophenyl or 4-pyridyl; 
(4) when X is S(O).sub.n and R or R.sup.1 is phenyl substituted in the 
2,3,5 or 6 position with C.sub.1-3 alkylamino; C.sub.1-3 dialkylamino or 
N-(azacyclo C.sub.5-6 alkyl), the other must be 4-pyridyl); 
or a pharmaceutically acceptable salt thereof. 
This invention also relates to a compound of the formula 
##STR16## 
wherein: X.sup.3 is S; 
A is CH.sub.2 or CH.sub.2 CH.sub.2 ; 
B and C are independently selected from H, methyl, ethyl or dimethyl; and 
R.sup.6 is selected from: 
(a) phenyl or monosubstituted phenyl wherein said substituent is selected 
from C.sub.1-3 alkanamido, dialkylamino, N-(azacyclo C.sub.5-6 alkyl), 
halo, cyano, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, C.sub.1-4 alkyl, 
CF.sub.3 or H; 
(b) disubstituted phenyl wherein said substituents are independently 
selected from C.sub.1-4 alkyl or C.sub.1-3 alkoxy, or the disubstituents 
together form a methylene dioxy group; or 
(c) 3,4,5-trimethoxyphenyl; 
provided that when A is CH.sub.2 and B and C are H, R.sup.6 is other than 
phenyl or monosubstituted phenyl wherein said substituent is halo, 
C.sub.1-3 alkoxy, C.sub.1-4 alkyl, CF.sub.3 or C.sub.1-3 alkylthio, 
or a pharmaceutically acceptable salt thereof. 
This invention also relates to a compound of the formula: 
##STR17## 
wherein: X.sup.3 is CH.sub.2 or S; 
A is CH.sub.2 or CH.sub.2 CH.sub.2 ; 
B and C are independently selected from H, methyl, ethyl or dimethyl; and 
One of R.sup.4 and R.sup.5 must be H and the other is selected from: 
(a) monosubstituted phenyl wherein said substituent is selected from 
C.sub.1-3 alkanamido, N-(C.sub.1-3 alkyl)-C.sub.1-3 alkanamido, amino, 
hydroxy, cyano, C.sub.1-3 dialkylamino, N-(azacyclo C.sub.5-6 alkyl), 
halo, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, C.sub.1-4 alkyl, CF.sub.3, 
prop-2-ene-1-oxy or 2,2,2-trihaloethoxy; 
(b) disubstituted phenyl wherein said substituents are independently 
selected from C.sub.1-4 alkyl or C.sub.1-3 alkoxy, or the disubstituents 
together form a methylenedioxy group; or 
(c) 3,4,5-trimethoxyphenyl; provided that: 
(i) when X.sup.3 is CH.sub.2 ; R.sup.5 must be H; 
(ii) when A is CH.sub.2, B and C are H, X.sup.3 is S, and R.sup.4 is H, 
R.sup.5 is other than 2-, 3- or 4-methoxyphenyl, 2,4-dimethoxyphenyl, 
4-hydroxyphenyl, 4-methylphenyl, 4-butylphenyl, 4-chlorophenyl or 
4-bromophenyl; and 
(iii) when A is CH.sub.2 CH.sub.2, B and C are H, X.sup.3 is S, and R.sup.4 
is H, R.sup.5 is other than 4-bromophenyl, 4-chlorophenyl or 
4-methylphenyl; 
or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION 
As used herein, the term "Formula (IA)" will refer to compounds of the 
formula: 
##STR18## 
wherein: X is CH.sub.2 or S(O).sub.n ; 
n is 0, 1 or 2; 
A is CH.sub.2 or CH.sub.2 CH.sub.2 ; 
B and C are independently selected from H, methyl, ethyl or dimethyl; 
R.sup.2 and R.sup.3 are independently selected from 
(a) pyridyl, 
(b) phenyl or monosubstituted phenyl wherein said substituent is selected 
from C.sub.1-3 dialkylamino, C.sub.1-3 alkylamino, N-(azacyclo C.sub.5-6 
alkyl), cyano, 2,2,2-trihaloethoxy, prop-2-ene-1-oxy, N-(C.sub.1-3 
alkyl)-(C.sub.1-3 alkanamido), C.sub.1-3 alkanamido, amino, hydroxy, 
C.sub.1-3 alkylthio, C.sub.1-4 alkyl, halo, or CF.sub.3 ; 
(c) disubstituted phenyl wherein said substituents are independently 
selected from C.sub.1-4 alkyl or C.sub.1-3 alkoxy, or the disubstituents 
together form a methylenedioxy group; or 
(d) 3,4,5-trimethoxyphenyl; provided that: 
(1) when X is CH.sub.2, both of R.sup.2 and R.sup.3 are other than pyridyl; 
and 
(2) when R.sup.3 is cyanophenyl, R.sup.2 must be either cyanophenyl or 
4-pyridyl; 
or a pharmaceutically acceptable salt thereof. 
All the compounds of Formula (IA) can be prepared by the following 
synthetic route: 
##STR19## 
It will be apparent to one of skill in the art that all the compounds of 
Formula (I), Formula (IB) and Formula (IC) are encompassed by the scope of 
Formula (IA). 
It will also be apparent to one of skill in the art that all of the 
compounds of Formula (IC) are embraced by the scope of Formula (I). All of 
the compounds of Formula (I) are useful as inhibitors of the 
5-lipoxygenase pathway of arachidonic acid metabolism and some compounds 
of Formula (I) are also useful as intermediates in the production of 
compounds of Formula (I) and/or Formula (IB). All of the compounds of 
Formula (IB) are useful as inhibitors of the 5-lipoxygenase pathway of 
arachidonic acid metabolism and/or serve as intermediates in the 
production of compounds of Formula (IB) and/or Formula (I). All of the 
compounds of Formula (IC) are useful as inhibitors of the 5-lipoxygenase 
pathway of arachidonic acid metabolism and some compounds of Formula (IC) 
are also useful as intermediates in the production of compounds of Formula 
(I) and/or Formula (IB). All the compounds of Formula (III), Formula 
(IIIA) and Formula (V) are useful as intermediates in the production of 
compounds of Formula (I) and/or Formula (IB). 
All the required compounds necessary to produce the compounds of Formula 
(IA), i.e., the compounds of Formulas (II), (IIIA), (III), (IV), (V), 
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV) and (IA), can be obtained 
from commercial sources or can be prepared by techniques described herein. 
Moreover, any necessary compounds of Formula (V) and Formula (IIIA) where 
X.sup.3 is CH.sub.2 and of Formula (III) where R.sup.4 is H can be 
prepared according to the method of Bender et al., U.S. Ser. No. 856,926, 
titled "Inhibitors of the 5-lipoxygenase pathway", filed simultaneously 
with this application; the disclosure of which is hereby incorporated by 
reference; and any necessary compounds of Formula (IV) and of Formula (V) 
where X.sup.3 is S can be prepared according to the method of Bender et 
al., U.S. Ser. No. 856,246, titled "Process for preparing 
pyridyl-substituted imidazo [2,1-b] thiazoles and thiazines", filed 
simultaneously with this application, the disclosure of which is hereby 
incorporated by reference. 
Compounds of Formula (IA) wherein X is S; A is CH.sub.2 or CH.sub.2 
CH.sub.2 ; B and C are independently selected from H, methyl, or ethyl; 
and R and R.sup.1 are independently mono, di or tri-substituted phenyl, 
are prepared from either (a) the corresponding Formula (IX) compounds or 
(b) the corresponding Formula (XI) compounds. 
In the first procedure, the Formula (IX) compound is treated with the 
corresponding 1,2-dihaloethane or 1,3-dihalopropane and potassium 
carbonate by the method described by Bender et al, J. Med. Chem., 28, 1169 
(1985) (therein designated as method B). The requisite Formula (IX) 
compounds wherein R.sup.9 and R.sup.10 are independently selected from (a) 
monosubstituted phenyl where said substituent is selected from C.sub.1-3 
dialkylamino, N-(azacyclo C.sub.5-6 alkyl), C.sub.1-3 alkoxy, 
2,2,2-trihaloethoxy, prop-2-ene-1-oxy, C.sub.1-4 alkyl, C.sub.1-3 
alkylthio, N-C.sub.1-3 alkanamido, N-(C.sub.1-3 alkyl)-C.sub.1-3 
alkanamido, halo, H or CF.sub.3, (b) disubstituted phenyl wherein said 
substitutents are independently selected from C.sub.1-4 alkyl or C.sub.1-3 
alkoxy or the disubstitutents together form a methylenedioxy group, or (c) 
3,4,5-trimethoxyphenyl are prepared by treating the corresponding Formula 
(VIII) compound with thiourea by the method described in Bender et al, 
ibid, (therein designated as the general method for preparation of 
4,5-diarylimidazole-2-thiones). The Formula (VIII) compounds are prepared 
from the corresponding aryl carboxaldehydes employing the benzoin 
condensation catalyzed by cyanide (see, Ide et al., in "Organic 
Reactions", Wiley, (1948), Chapter 5) or the Stetter catalyst [Stetter et 
al., Synthesis, 733 (1975)]. 
Alternatively, compounds of Formula (IX) may be prepared from the 
corresponding ethanones of Formula (X) by reaction with hydroxylamine to 
afford the oximes of Formula (XII). Subsequent treatment of the Formula 
(XII) compounds with tosyl chloride and pyridine gives the oxime tosylates 
of Formula (XIII). Reaction of the Formula (XIII) compounds with strong 
base affords the 2-aminoethan-1-ones of Formula (XIV). Treatment of the 
Formula (XIV) compounds with sodium thiocyanate and hydrochloric acid by 
the method described in Ciba-Geigy AG., U.K. Patent Application Number GB 
2,039,882 for the conversion of 2-phenyl-1-pyridyl-ethan-1-one into the 
5-phenyl-4-pyridyl-2-mercaptoimidazole. The required ethanones of Formula 
(X) wherein R.sup.7 and R.sup.8 are independently selected from (a) 
monosubstituted phenyl where said substitutent is selected from C.sub.1-3 
alkoxy, 2,2,2-trihaloethoxy, prop-2-ene-1-oxy, C.sub.1-4 alkyl, C.sub.1-3 
alkylthio, N-C.sub.1-3 alkanamido, halo, H or CF.sub.3, (b) disubstituted 
phenyl wherein said substituents are independently selected from C.sub.1-4 
alkyl or C.sub.1-3 alkoxy or the disubstituents together form a 
methylenedioxy group, (c) 3,4,5-trimethoxyphenyl, or (d) R.sup.7 and 
R.sup.8 are both CN, are obtained by (a) Friedel-Crafts acylation of the 
substituted phenylacetyl chloride of the corresponding benzene, (b) 
Curtius rearrangement of the substituted stilbenecarbonyl azides derived 
from Perkin condensation of a substituted benzaldehyde with the 
substituted phenylacetic acid ester (by the method of Hill, et al., 13th 
Mid-American Regional Meeting of the American Chemical Society, March 
1979; ORG 21), (c) reduction of the corresponding benzoin with zinc or tin 
by the method of Kohler et al., J. Amer. Chem. Soc., 52, 4133 (1930), and 
(d) Claisen condensation of a substituted phenylacetonitrile with a 
substituted aryl carboxylic acid ester (see, Magnani et al., Org. Syn. 
Coll., 3, 251 (1955). 
In the second procedure for the preparation of Formula (IA) compounds 
wherein X is S; A is CH.sub.2 or CH.sub.2 CH.sub.2 ; B and C are 
independently selected from H, methyl or ethyl; and R.sup.3 and R.sup.2 
are independently mono, di or trisubstituted, a 2-halo-ethan-1-one of 
Formula (XI) wherein R.sup.11 and R.sup.12 are independently selected from 
(a) monosustituted phenyl and said substitutent is selected from C.sub.1-4 
alkyl, halo (preferably chloro or bromo), H, CF.sub.3, C.sub.1-3 alkoxy, 
C.sub.1-3 alkylthio, 2,2,2-trihaloethoxy, prop-2-ene-1-oxy, C.sub.1-3 
alkanamido, or (b) disubstituted phenyl wherein said substituents are 
independently selected from C.sub.1-4 alkyl or C.sub.1-3 alkoxy or the 
disubstituents together form a methylenedioxy group, is treated with a 
correspondingly substituted 2-amino-thiazoline or 
2-amino-4,5-dihydro[1,3]thiazine by the method described in Bender, et 
al., J. Med. Chem., 28, 1169 (1985) (therein designated as method A). The 
Formula (XI) compounds where halo is Br are prepared preferably by 
bromination of the corresponding Formula (X) compounds by the method 
described in Bender et al, ibid (therein designated as the general method 
for alpha-bromination of desoxybenzoins), or alternately the alpha-chloro 
Formula (XI) compounds are prepared from the corresponding Formula (VIII) 
compounds by treatment with SOCl.sub.2 by the method of Fieser et al., J. 
Org. Chem., 27, 2247 (1962). 
Compounds of Formula (IA) where X is CH.sub.2 ; A is CH.sub.2 or CH.sub.2 
CH.sub.2 ; B and C are independently H, methyl or ethyl; and R and R.sup.1 
are both monosubstituted phenyl are prepared by the method described in 
Bender et al., U.S. Pat. No. 4,186,205, from the corresponding Formula 
(XI) compounds, prepared as described above, and the substituted 
2-iminopyrrolidine or 2-iminopiperidine. The unsubstituted (B,C.dbd.H) and 
alkyl-substituted (B,C.dbd.C.sub.1-3 alkyl) 2-iminopyrrolidines and 
piperidines are prepared by O-alkylation of the corresponding 
2-pyrrolidones and 2-piperidones with dimethyl sulfate by the procedure of 
Wick et al., Helv. Chim. Acta, 54, 513 (1971), and subsequent treatment of 
the cyclic imidates with ammonium chloride in absolute alcohol by the 
method of Etienne et al., Compt. Rend., 259, 2660 (1964). Unsubstituted 
2-iminopyrrolidine and 2-iminopiperidine are preferably prepared from 
4-chlorobutyronitrile and 5-chlorovaleronitrile, respectively as described 
by Moriconi et al., J. Org. Chem., 33, 2109 (1968), as their hydrohalide 
salts and liberated to the free bases with concentrated aqueous sodium 
hydroxide. 
Alternatively, compounds of Formula (IA) wherein X is CH.sub.2 and R and 
R.sup.1 are both monosubstituted phenyl are prepared from the 
corresponding Formula (V) compound wherein X.sup.3 is CH.sub.2 wherein 
R.sup.7 and R.sup.8 are independently selected from (a) monosubstituted 
phenyl where said substitutent is selected from C.sub.1-3 alkoxy, 
2,2,2-trihaloethoxy, prop-2-ene-1-oxy, C.sub.1-4 alkyl, C.sub.1-3 
alkylthio, N-C.sub.1-3 alkanamido, halo, H or CF.sub.3, (b) disubstituted 
phenyl wherein said substituents are independently selected from C.sub.1-4 
alkyl or C.sub.1-3 alkoxy or the disubstituents together form a 
methylenedioxy group, (c) 3,4,5-trimethoxyphenyl, or (d) R.sup.7 and 
R.sup.8 are both CN. 
Treatment of the Formula (III) compounds wherein X.sup.3 is CH.sub.2 with 
bromine, by the procedure of Kano, Yakugaku Zasshi, 92, 51 (1972), results 
in bromination at the R.sup.3 position to afford the compounds of Formula 
(V). Formula (III) compounds where X.sup.3 is CH.sub.2 are prepared in two 
steps from the corresponding Formula (IIIA) and Formula (II) compounds. 
The Formula (IIIA) compounds are prepared by treatment of the 
corresponding Formula (II) a-haloacetophenones with the appropriately 
substituted 2-iminopyrrolidine or 2-iminopiperidine in an inert solvent, 
such as chloroform or alcohol, and filtration of the product. Reflux of 
the Formula (IIIA) product in an aqueous or aqueous alcohol solvent until 
cyclodehydration is complete affords the Formula (III) compounds on 
neutralization with aqueous base. Compounds of Formula (V) wherein X.sup.3 
is CH.sub.2 are obtained by bromination of the corresponding Formula (III) 
compounds, and are treated with n-butyl lithium (n-BuLi) in THF to afford 
3-lithio derivatives by halogen-metal interchange. Transmetallation of the 
3-lithio compounds with MgBr.sub.2 affords the corresponding magnesium 
compounds, according to the method of Negishi et al., J. Org. Chem., 42, 
1821, (1977), which are coupled with the corresponding substituted 
bromobenzene in the presence of PdCl.sub.2 
(bis(diphenylphosphino)C.sub.1-4 alkylene) catalyst using the method of 
Kumada et al., Tetrahedron Letters, 22, 5319 (1981), to afford the Formula 
(IA) compounds. 
Compounds of Formula (IA) wherein X is S; A is CH.sub.2 or CH.sub.2 
CH.sub.2 ; B and C are independently selected from H, methyl, or ethyl; 
and one of R.sup.2 or R.sup.3 is pyridyl and the other is mono-, di-, or 
trisubstituted phenyl are prepared from the corresponding Formula (IX) 
compounds by alkylation with the appropriate C.sub.2-3 dihaloalkane and 
sodium hydride in DMF followed by addition of potassium carbonate and 
subsequent cyclization upon heating (using the procedure of Lantos et al., 
J. Med. Chem., 27, 72 (1984) for the preparation of compounds 13 and 14 
therein). The resulting two isomeric 6-aryl-5-pyridyl and 5-aryl-6-pyridyl 
Formula (IA) compounds are separated chromatographically (Lantos et al., 
cited above). The Formula (IX) compounds are prepared from either the 
corresponding (a) Formula (VIII) 2-hydroxy ethanones or (b) Formula (XIV) 
2-amino ethanones. Formula (IX) compounds where at least one of R.sup.9 or 
R.sup.10 is pyridyl and the other is selected from (a) monosubstituted 
phenyl where said substituent is selected from C.sub.1-3 alkoxy, 
2,2,2-trihaloethoxy, prop-2-ene-1-oxy, C.sub.1-4 alkyl, C.sub.1-3 
alkylthio, N-C.sub.1-3 alkanamido, halo, H or CF.sub.3, (b) disubstituted 
phenyl wherein said substitutents are independently selected from 
C.sub.1-4 alkyl or C.sub.1-3 alkoxy or the disubstitutents together form a 
methylenedioxy group, (c) 3,4,5-trimethoxyphenyl, or (d) pyridyl are 
prepared from the corresponding Formula (VIII) compounds by the same 
procedure as described above for the substituted diphenyl Formula (IX) 
compounds. Formula (VIII) compounds where one of R.sup.9 or R.sup.10 is 
4-pyridyl are prepared by the method described in Bender et al., U.S. Pat. 
No. 4,175,127, by treatment of 4-pyridine carboxaldehyde cyanohydrin 
benzoate and a substituted benzaldehyde in t-butanol with sodium or 
potassium hydride. 
Alternatively, pyridyl containing Formula (IX) compounds may be prepared 
from the corresponding Formula (X) ethanones in 4 steps by successive 
conversion of the Formula (X) compounds to the corresponding Formula 
(XII), Formula (XIII), and Formula (XIV) compounds by the method described 
in Ciba-Geigy AG., U.K. Patent Application Number GB 2,039,882, for the 
conversion of 2-phenyl-1-(3-pyridyl)-ethan-1-one into 
5-phenyl-4-(3-pyridyl)-2-mercaptoimidazole. The requisite Formula (X) 
ethanones wherein U.S.S.N. at least one of R.sup.7 and R.sup.8 is pyridyl 
and the other is independently selected from (a) monosubstituted phenyl 
where said substitutent is selected from C.sub.1-3 alkoxy, 
2,2,2-trihaloethoxy, prop-2-ene-1-oxy, C.sub.1-4 alkyl, C.sub.1-3 
alkylthio, N-alkanamido, halo, H or CF.sub.3, (b) disubstituted phenyl 
wherein said substituents are independently selected from C.sub.1-4 alkyl 
or C.sub.1-3 alkoxy or the disubstituents together form a methylenedioxy 
group, or (c) 3,4,5-trimethoxyphenyl, are preferably prepared by Claisen 
condensation of a substituted phenylacetonitrile with a 2-, 3-, or 
4-picolinic acid ester (see Cherkofsky et al., U.S. Pat. No. 4,199,592), 
or alternatively by reaction of the picolyl sodium or lithium and the 
appropriately substituted benzoic acid ester by the method described in 
Brust et al., Belgian Patent Number 668,701 (1966); Chem. Abstr., 65, 
5446c (1966). 
The Formula (IA) compounds where both R.sup.2 and R.sup.3 are pyridyl and X 
is S are prepared in two steps from the corresponding Formula (VIII) 
2-hydroxy-ethan-1-ones and the corresponding Formula (IX) compounds by the 
methods described above for the corresponding Formula (VIII), Formula (IX) 
and Formula (IA) compounds where the aryl groups are both substituted 
phenyl. The precursor dipyridyl Formula (VIII) compounds are prepared by 
the benzoin condensation as described above for the corresponding diphenyl 
Formula (VIII) compounds with the exception that thiourea must be added in 
the condensation of 4-pyridine carboxaldehyde. 
Compounds of Formula (IA) where R.sup.1 is 4-pyridyl and R is substituted 
phenyl are preferably prepared in two steps by the method described in 
Lantos et al., U.S. Ser. No. 737,137, filed May 29, 1985, the disclosure 
of which is hereby incorporated by reference, and the method described in 
Bender et al., U.S. Ser. No. 856,246, titled "Process for preparing 
pyridyl-substituted Imidazo [2,1-b] thiazoles and thiazines", which was 
filed simultaneously with this application, the disclosure of which is 
hereby incorporated by reference, from their corresponding Formula (III) 
and Formula (IV) compounds. The Formula IV compounds wherein A is CH.sub.2 
or CH.sub.2 CH.sub.2, B and C are independently selected from H, methyl, 
ethyl, or dimethyl; X.sup.2 is N-Z-carbonyl-1,4-dihydro-4-pyridyl, Z is 
C.sub.1-8 alkyl, C.sub.1-8 alkoxy, phenyl, phenoxy, benzyl or benzyloxy, 
and X.sup.1 is (a) monosubstituted phenyl and said substituent is selected 
from H, C.sub.1-3 alkoxy, halo, CF.sub.3, C.sub.1-3 alkylthio, C.sub.1-4 
alkyl, N-(azacyclo C.sub.5-6 alkyl), N-(C.sub.1-3 alkyl)-(C.sub.1-3 
alkanamido), C.sub.1-3 dialkylamino, cyano, 2,2,2-trihaloethoxy 
prop-2-ene-1-oxy or disubstituted phenyl wherein said substituents are 
independently selected from C.sub.1-4 alkyl or C.sub.1-3 alkoxy or the 
disubstituents together form a methylene dioxy group, are prepared from 
the corresponding Formula (III) compounds. In the first step, the Formula 
(III) compound is treated at 5.degree.-25.degree. C. with pyridine and an 
acyl halide such as an alkylchloroformate (preferably ethylchloroformate) 
or an arylcarbonyl halide such as benzoylchloride in a solvent in which 
the reactants are soluble and inert, such as methylene chloride, to form 
the corresponding Formula (IV) compound. Compounds of Formula (IC) serve 
as intermediates in the preparation of the compounds of Formula (A). In 
the second step, the Formula (IV) compound, an N-acyldihydropyridine 
product, is deacylated and aromatized either with a mild oxidizing agent 
such as sulfur in refluxing decalin, tetralin or p-cymene or preferably 
with oxygen and excess potassium t-butoxide in t-butanol, to afford the 
compounds of Formula (A). The compounds of Formula (III) are prepared in 
two steps from the corresponding Formula (II) and Formula (IIIA) compounds 
by the method of Lantos et al., U.S. Ser. No. 737,137, cited above. 
Formula (IIIA) compounds are prepared by treatment of the appropriately 
substituted Formula (II) phenacyl halide with the correspondingly 
substituted 2-amino-3,4-dihydrothiazole or 
2-amino-4,5-dihydro(1,3)thiazine in a chlorinated hydrocarbon or 
preferably an alcoholic solvent. The hydrohalide salt of the Formula 
(IIIA) compound which precipitates is refluxed in water or aqueous alcohol 
until cyclodehydration is complete. Neutralization with aqueous base 
affords the corresponding Formula (III) compound. The substituted Formula 
(IIIA) compounds are prepared from the corresponding acetophenones by 
treatment with bromine or alternatively prepared by acylating the 
corresponding mono- or disubstituted benzene by Friedel Crafts reaction 
with 2-chloroacetylchloride and AlCl.sub.3, by the method of Joshi et al., 
J. Het. Chem., 16, 1141 (1979). 
The 2,2,2-trihaloethoxyphenyl and prop-2-en-1-oxyphenyl Formula (IA), 
Formula (III), and Formula (V) compounds are prepared by alkylation of the 
corresponding Formula (IA), Formula (III), and Formula (V) hydroxyphenyl 
compounds with a 2,2,2-trihaloalkylester of trifluoromethane sulfonic acid 
and 2-propenyl bromide respectively by the method described in Bender et 
al., J. Med. Chem., 28, 1169-1177 (1985) for the preparation of compounds 
No. 23 and 33 described therein. The hydroxyphenyl Formula (IA), Formula 
(III), and Formula (V) compounds are prepared by treatment of the 
corresponding methoxyphenyl compounds with HBr in refluxing acetic acid or 
alternatively with BBr.sub.3 in CH.sub.2 Cl.sub.2. N-(C.sub.1-3 
alkanamido) and N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido) phenyl 
substituted acetophenones, and in some cases the Formula (III), and 
Formula (IA) compounds, are prepared by acylation of the corresponding 
amino and N-(C.sub.1-3 alkylamino) compounds with the alkanoic acid 
anhydride or chloride in pyridine. Another alternative preparation of the 
N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido) phenyl carboxaldehydes, 
substituted Formula (III) and Formula (IA) compounds employs the 
alkylation of the corresponding N-(C.sub.1-3 alkanamido) phenyl 
substituted carboxaldehydes, Formula (III) and Formula (IA) compounds with 
sodium hydride and a C.sub.1-3 alkyl bromide or iodide in dimethyl 
formamide. 
Aminophenyl substituted Formula (III) and Formula (IA) compounds are 
prepared by hydrolysis of the corresponding N-(C.sub.1-3 alkanamido) 
compounds in refluxing 6N mineral acid. 
N-(C.sub.1-3 alkylamino) phenyl substituted Formula (III), Formula (V), and 
Formula (IA) compounds are preferably prepared by acid catalyzed 
hydrolysis of the corresponding N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 
alkanamido) compounds as described above for the aminophenyl substituted 
compounds, or alternatively by reduction of the corresponding N-(C.sub.1-3 
alkanamido) phenyl Formula (III), Formula (V) or Formula (IA) compounds 
with borane or borane dimethylsulfide complex in THF by the method of 
Brown, "Organic Synthesis via Boranes", John Wiley and Sons, (1975). 
N,N-(C.sub.1-3 dialkylamino) phenyl substituted Formula (III) and Formula 
(IA) compounds were alternatively prepared by reduction of the 
corresponding N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido) compounds with 
borane as described above for the N-(C.sub.1-3 alkylamino) phenyl 
substituted compounds. 
N-(azacyclo C.sub.5-6 alkyl) phenyl substituted Formula (III) and Formula 
(IA) compounds are alternatively prepared by cyclodialkylation of the 
corresponding aminophenyl compounds with dibromobutane or dibromopentane 
and anhydrous potassium carbonate in an inert solvent such as 
dimethylformamide. 
Compounds of Formula (I) where X is S(O).sub.n and n is 1 or 2 are prepared 
by oxidation with one or two equivalents of an organic peracid as 
described in Bender et al., U.S. Pat. No. 4,263,311 and Bender et al., 
U.S. Pat. No. 4,175,127. 
Compounds of Formula (I) where at least one of R and R.sup.1 is pyridyl, X 
is S(O).sub.n and n=2 are preferably prepared by oxidation of 1 equivalent 
of an acid salt of X=S(O).sub.n, n is 1, with 2/3 equivalent of an aqueous 
solution of KMn04 according to the method of Chatterway et al., J. Chem. 
Soc., 1352 (1930). 
Compounds of Formula (I) where X is S(O).sub.n, n is 1 or 2, and where at 
least one of R.sup.1 and R is C.sub.1-3 alkylaminophenyl, C.sub.1-3 
dialkylaminophenyl, or N-(azacyclo C.sub.5-6 alkyl)phenyl are preferably 
prepared by treating the immediate precursor alkanamidophenyl compound 
with an oxidizing agent (as described above for preparation of compounds 
of Formula (I) where X is S(O).sub.n and n is 1 or 2) followed by 
hydrolysis of the alkanamide to the primary or secondary amine. The 
primary or secondary amine may then be further alkylated as described 
above to afford the tertiary amine S(O).sub.n compounds where n is 1 or 2. 
Pharmaceutically acceptable salts and their preparation are well known to 
those skilled in pharmaceuticals. Pharmaceutically acceptable salts of the 
compounds of Formula (IA) and the corresponding compounds of Formula 
(III), Formula (IIIA) and Formula (V) which are useful in the present 
invention include, but are not limited to, maleate, fumarate, lactate, 
oxalate, methanesulfonate, ethane-sulfonate, benzenesulfonate, tartrate, 
citrate, hydrochloride, hydrobromide, sulfate and phosphate salts. The 
preparation of such salts of some of the compounds of Formula (IA) is 
disclosed in Bender et al., U.S. Pat. No. 4,175,127; Bender et al., U.S. 
Pat. No. 4,263,311; Baetz, U.S. Pat. No. 4,110,460; Ciba Geigy, U.K. 
Patent Application No. GB 2,039,882-A; and Bender et al., U.S. Pat. No. 
4,186,205, the disclosures of all of which are hereby incorporated by 
reference, and such disclosures are also relevant to the preparation of 
the pharmaceutically acceptable salts of Formula (III), Formula (IIIA) and 
Formula (V) compounds. Preferred pharmaceutically acceptable salts of the 
compounds of Formula (IA) include the hydrochloride and hydrobromide 
salts. 
Some of the compounds of Formula (IA) can form covalent hydrates i.e., the 
compounds of Formula (IA) where R.sup.3 is other than pyridyl, R.sup.2 is 
2- or 4-halo, CF.sub.3 or cyano substituted phenyl and X is S will form 
covalent hydrates where an OH group is attached to the carbon atom 
attached to R.sup.3 and an H is attached to the carbon atom attached to 
R.sup.2. The preparation of such hydrates is disclosed by Bender et al., 
U.S. Pat. No. 4,153,706, issued May 8, 1979, the disclosure of which is 
hereby incorporated by reference, which claims compounds of the formula 
##STR20## 
wherein R.sup.1 is 4-substituted phenyl wherein said substituent is 
selected from lower alkoxy, lower alkylthio, fluoro, chloro, bromo or 
trifluoro methyl; and R.sup.2 is 4-substituted phenyl wherein said 
substituent is an electron withdrawing group, in particular, fluoro, 
chloro, bromo or trifluoromethyl. At least some of the hydrates disclosed 
by Bender et al. have 5-lipoxygenase inhibiting activity as determined by 
the assays set forth in the Examples. Therefore, the scope of the 
compounds of Formula (IA) includes such hydrates, described in Bender et 
al., which have 5-lipoxygenase pathway inhibiting activity or which are 
useful to prepare other compounds of Formula (IA) which have 
5-lipoxygenase pathway inhibiting activity. 
It is known that some of the compounds of Formula (I) are useful for 
inhibiting the cyclooxygenase pathway of arachidonic acid metabolism. It 
has now been discovered that all the compounds of Formula (I) are useful 
for treating disease states mediated by the 5-lipoxygenase pathway of 
arachidonic acid metabolism by inhibiting such pathway. The discovery that 
the compounds of Formula (I) are inhibitors of the 5-lipoxygenase pathway 
or are dual inhibitors of the cyclooxygenase and 5-lipoxygenase pathways 
is based on the effects of the compounds of Formula (I) on tissue 
inflammation in vivo and on the production of cyclooxygenase products and 
5-lipoxygenase products by inflammatory cells in vitro in assays which are 
described in the Examples. In summary, such assays reveal that the 
compounds of Formula (I) inhibit the infiltration of polymorphonuclear 
leukocytes into inflammatory lesions in mice (carrageenan-induced 
peritonitis) and rats (air pouch inflammation induced by arachidonic 
acid). In addition, the compounds of Formula (I) display anti-inflammatory 
activity in arachidonic acid-induced inflammation in the mouse ear and rat 
paw models. The cyclooxygenase inhibitor, indomethacin, did not reduce 
inflammation or cell infiltration in these assays. These data, together 
with previous observations on the anti-edematous effects of the compounds 
of Formula (I) in inflammatory lesions caused by cyclooxygenase-generated 
products, reveal that the compounds of Formula (I) inhibit either the 
5-lipoxygenase pathway or both the 5-lipoxygenase and cyclooxygenase 
pathways of arachidonic acid metabolism. The 5-lipoxygenase pathway 
inhibitory action of the compounds of Formula (I) was confirmed by showing 
that such compounds (a) impaired the production of 5-lipoxygenase products 
such as leukotriene B.sub.4 (di-HETE) and 5-HETE production by RBL-1 
cells, (b) impaired the production of LTC.sub.4 by human monocytes, and 
(c) that peritoneal exudate cells harvested from Formula (I) compound 
treated mice exhibited a reduced capacity to produce LTB.sub.4 in vitro. 
The pathophysiological role of arachidonic acid metabolites has been the 
focus of recent intensive studies. In addition to the well-described 
phlogistic activity (i.e. general inflammatory activity) of 
prostaglandins, the more recent description of similar activity for 
eicosanoids has broadened the interest in these products as mediators of 
inflammation [See, O'Flaherty, Lab. Invest., 47, 314-329 (1982)]. The 
reported discovery of potent chemotactic and algesic activity for 
LTB.sub.4 [see, Smith, Gen. Pharmacol., 12, 211-216 (1981) and Levine et 
al., Science, 225, 743-745 (1984)], together with known LTC.sub.4 and 
LTD.sub.4 -mediated increase in capillary permeability [see, Simmons et 
al., Biochem. Pharmacol., 32, 1353-1359 (1983), Veno et al., 
Prostaglandins, 21, 637-647 (1981), and Camp et al., Br. J. Pharmacol., 
80, 497-502 (1983)], has led to their consideration as targets for 
pharmacological intervention in both the fluid and cellular phases of 
inflammatory diseases. 
The pharmacology of several inflammatory model systems has attested to the 
effectiveness of corticosteroids in reducing the cellular infiltration. 
These results, and the observation that corticosteroids inhibit the 
generation of both cyclooxygenase and lipoxygenase products, suggest that 
such dual inhibitors may effectively reduce both the fluid and cellular 
phases of the inflammatory response since selective cyclooxygenase 
inhibitors do not reliably inhibit cell influx into inflammatory sites 
[See, Vinegar et al., Fed. Proc., 35, 2447-2456 (1976), Higgs et al., 
Brit. Bull., 39, 265-270 (1983), and Higgs et al., Prostaglandins, 
Leukotrienes and Medicine, 13, 89-92 (1984)]. The observations outlined 
above cogently argue that a dual inhibitor of arachidonic acid metabolism 
would be a more effective anti-inflammatory agent than an inhibitor of 
cyclooxygenase only. Under optimal conditions, it is likely that an agent 
with preferential lipoxygenase inhibitory activity would not share the 
ulcerogenic liability of cyclooxygenase inhibitors or the toxicity of 
corticosteroids. 
Recent clinical data also support the enthusiasm for dual inhibitors of 
arachidonic acid metabolism in a variety of inflammatory diseases in which 
granulocyte and/or monocyte infiltration is prominent. The reported 
demonstration of elevated levels of LTB.sub.4 in rheumatoid arthritic 
joint fluid [See, Davidson et al., Ann. Rheum. Dis., 42, 677-679 (1983)] 
also suggests a contributing role for arachidonic acid metabolites in 
rheumatoid arthritis. The recently reported preliminary observation of 
efficacy, including remission, reported with sulfasalazine treatment of 
rheumatoid arthritic patients [See Neumann et al., Brit. Med. J., 287, 
1099-1102 (1983)] illustrates the utility of inhibitors of the 
5-lipoxygenase pathway in rheumatoid arthritis. 
Sulfasalazine, which is used for treatment of ulcerative colitis, has been 
reported to inhibit LTB.sub.4 and 5-HETE production in vitro [See, 
Stenson et al., J. Clin. Invest., 69, 494-497 (1982)]. This observation, 
coupled with the fact that it has been reported that inflamed 
gastrointestinal mucosa from inflammatory bowel disease patients showed 
increased production of LTB.sub.4 [See, Sharon et al., Gastroenterol., 84, 
1306 (1983)], suggests that sulfasalazine can be effective by virtue of 
inhibition of production of chemotactic eicosanoids (such as the 
5-lipoxygenase pathway product known as LTB.sub.4). The observations serve 
to underscore utility of inhibitors of the 5-lipoxygenase pathway in 
inflammatory bowel disease. 
Another area of utility for an inhibitor of the 5-lipoxygenase pathway is 
in the treatment of psoriasis. It was demonstrated that involved psoriatic 
skin had elevated levels of LTB.sub.4 [See, Brain et al., Lancet, 19, Feb. 
19, 1983]. The promising effect of benoxaprofen on psoriasis [See, Allen 
et al., Brit. J. Dermatol., 109, 126-129 (1983)], a compound with in vitro 
lipoxygenase inhibitory activity on psoriasis, lends support to the 
concept that 5-lipoxygenase pathway inhibitors can be useful in the 
treatment of psoriasis. 
Lipoxygenase products have been identified in exudate fluids from gouty 
patients. This disorder is characterized by massive neutrophil 
infiltration during the acute inflammatory phases of the disease. Since a 
major 5-lipoxygenase product, LTB.sub.4, is produced by neutrophils, it 
follows that inhibition of the synthesis of LTB.sub.4 can block an 
amplification mechanism in gout. 
Another area in which inhibitors of the 5-lipoxygenase pathway can have 
utility is in myocardial infarction. Studies in dogs with the dual 
cyclooxygenase and 5-lipoxygenase inhibitor, BW755-C, demonstrated that 
the area of infarction following coronary occlusion was reduced, and such 
reduction was attributed to inhibition of leukocyte infiltration into the 
ischaemic tissue [See, Mollane et al., J. Pharmacol. Exp. Therap., 228, 
510-522 (1984)]. 
Yet another area of utility for inhibitors of the 5-lipoxygenase pathway is 
in the area of prevention of rejection of organ transplants. [See, e.g., 
Foegh et al., Adv. Prostaglandin, Thromboxane, and Leukotriene Research, 
13, 209-217 (1983)]. 
Furthermore, another area of utility for inhibitors of the 5-lipoxygenase 
pathway is in the treatment of inflammatory reaction in the central 
nervous system, including multiple sclerosis. [See, e.g., MacKay et al., 
Clin. Exp. Immunol., 15, 471-482 (1973)]. Formula (I) compounds, but not 
indomethacin, show efficacy in inhibiting experimental allergic 
encephalomyelitis (EAE) in rats. 
Yet another utility for inhibitors of the 5-lipoxygenase pathway is in the 
treatment of tissue trauma. [See, e.g., Denzlinger et al., Science, 230 
(4723), 330-332 (1985)]. 
A further area of utility for inhibitors of the 5-lipoxygenase pathway is 
in the treatment of asthma. [See, e.g., Ford-Hutchinson, J. Allerg. Clin. 
Immunol., 74, 437-440 (1984)]. 
Compounds of Formula (I) which are preferred because of their potent 
5-lipoxygenase pathway inhibiting activity, as evidenced by their ability 
to inhibit the 5-lipoxygenase products known as 5-HETE, LTB.sub.4 and/or 
LTC.sub.4, are listed in Table A, below. 
This invention also relates to a pharmaceutical composition comprising a 
pharmaceutically acceptable carrier or diluent and an effective, 
5-lipoxygenase pathway inhibiting amount of a compound of Formula (IC) or 
a pharmaceutically acceptable salt thereof. 
The compounds of Formula (I) and (IC) are administered in conventional 
dosage forms prepared by combining a therapeutically effective amount 
(i.e., a 5-lipoxygenase pathway inhibiting amount) of a compound of 
Formula (I) or (IC) ("active ingredient") with standard pharmaceutical 
carriers or diluents according to conventional procedures. These 
procedures may involve mixing, granulating and compressing or dissolving 
the ingredients as appropriate to the desired preparation. 
TABLE A 
__________________________________________________________________________ 
##STR21## Formula (I) 
Compound 
Number 
R.sup.1 R X A n 
__________________________________________________________________________ 
3 4-(pyrrolidin-1-yl)phenyl 
4-(pyrrolidin-1-yl)phenyl 
S(O)n 
CH.sub.2 
0 
6 4-fluorophenyl 
4-dimethylaminophenyl 
S(O)n 
CH.sub.2 
0 
9 4-diethylaminophenyl 
4-diethylaminophenyl 
S(O)n 
CH.sub.2 
0 
14 4-fluorophenyl 
4-methoxyphenyl 
S(O)n 
CH.sub.2 
0 
17 4-ethylaminophenyl 
4-ethylaminophenyl 
S(O)n 
CH.sub.2 
0 
24 4-pyridyl 4-(pyrrolidin-1-yl)phenyl 
S(O)n 
CH.sub.2 
0 
27 4-pyridyl 4-fluorophenyl 
S(O)n 
CH.sub.2 
1 
28 4-pyridyl 4-fluorophenyl 
S(O)n 
CH.sub.2 
2 
1 4-pyridyl 4-fluorophenyl 
S(O)n 
CH.sub.2 
0 
2 4-pyridyl 4-(1-propylamino)phenyl 
S(O)n 
CH.sub.2 
0 
4 4-(piperidin-1-yl)phenyl 
4-(piperidin-1-yl)phenyl 
S(O)n 
CH.sub.2 
0 
7 3,4-(methylenedioxy)phenyl 
4-pyridyl CH.sub.2 
CH.sub.2 
-- 
15 4-trifluoromethylphenyl 
4-trifluoromethylphenyl 
S(O)n 
CH.sub.2 
0 
16 3,4-(methylenedioxy)phenyl 
3,4-(methylenedioxy)phenyl 
S(O)n 
CH.sub.2 
0 
17 4-ethylaminophenyl 
4-ethylaminophenyl 
S(O)n 
CH.sub.2 
0 
18 4-pyridyl 4-methoxyphenyl 
S(O)n 
CH.sub.2 
0 
19 4-fluorophenyl 
4-fluorophenyl 
S(O)n 
CH.sub.2 
0 
21 4-methoxyphenyl 
4-methoxyphenyl 
S(O)n 
CH.sub.2 
0 
20 4-methoxyphenyl 
4-methoxyphenyl 
S(O)n 
CH.sub.2 CH.sub.2 
0 
22 4-methoxyphenyl 
4-methoxyphenyl 
CH.sub.2 
CH.sub.2 
-- 
11 4-pyridyl 4-pyridyl S(O)n 
CH.sub.2 
0 
__________________________________________________________________________ 
The pharmaceutical carrier employed may be, for example, either a solid or 
liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, 
talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and 
the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, 
water and the like. Similarly, the carrier or diluent may include time 
delay material well known to the art, such as glyceryl monostearate or 
glyceryl distearate alone or with a wax. 
A wide variety of pharmaceutical forms can be employed. Thus, if a solid 
carrier is used, the preparation can be tableted, placed in a hard gelatin 
capsule in powder or pellet form or in the form of atroche or lozenge. The 
amount of solid carrier will vary widely but preferably will be form about 
25 mg. to about 1 g. If a liquid carrier is used, the preparation will be 
in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable 
liquid such as an ampule or nonaqueous liquid suspension. 
To obtain a stable water soluble dose form, a pharmaceutically acceptable 
salt of a compound of Formula (I) or (IC) is dissolved in an aqueous 
solution of an organic or inorganic acid, such as a 0.3M solution of 
succinic acid, or, preferably, citric acid. 
Preferably, each parenteral dosage unit will contain the active ingredient 
in an amount of from about 50 mg. to about 500 mg. Preferably each oral 
dosage unit will contain the active ingredient in an amount of from about 
100 mg to about 1,000 mg. 
This invention relates to a method of treating a disease state which is 
mediated by the 5-lipoxygenase pathway in an animal in need thereof, 
including humans and other mammals, provided that such animal is in need 
of treatment of a 5-lipoxygenase pathway mediated disease other than, or 
in addition to, rheumatoid arthritis, which comprises administering to 
such animal an effective, 5-lipoxygenase pathway inhibiting amount of a 
Formula (I) compound or a pharmaceutically acceptable salt thereof. By the 
term "treating" is meant prophylactic or therapeutic therapy. By the term 
"mediated" is meant caused by or exacerbated by. This invention also 
relates to a method of treating rheumatoid arthritis in a animal in need 
thereof, including humans and other mammals, which comprises administering 
to such animal an effective, 5-lipoxygenase pathway inhibiting amount of a 
compound of Formula (IC) or a pharmaceutically acceptable salt thereof. By 
the term "treating" is meant prophylactic or therapeutic therapy. The 
Formula (I) compound is administered to an animal in need of treatment of 
a 5-lipoxygenase pathway mediated disease state, other than or in addition 
to rheumatoid arthritis, in an amount sufficient to inhibit the 
5-lipoxygenase pathway. The Formula (IC) compound is administered to an 
animal in need of treatment of rheumatoid arthritis in an amount 
sufficient to inhibit the 5-lipoxygenase pathway. Such Formula (I) or (IC) 
compound can be administered to such animal in a conventional dosage form 
prepared by combining the Formula (I) or (IC) compound with a conventional 
pharmaceutically acceptable carrier or diluent according to known 
techniques. It will be recognized by one of skill in the art that the form 
and character of the pharmaceutically acceptable carrier or diluent is 
dictated by the amount of active ingredient with which it is to be 
combined, the route of administration and other well-known variables. As 
stated above, it will be apparent to one of skill in the art that all the 
compounds of Formula (IC) are embraced by the scope of Formula (I), and as 
such, all the following disclosure regarding appropriate pharmaceutical 
composition dosage forms and preferred dosage ranges are applicable to 
both Formula (I) and Formula (IC) compounds which will hereafter be 
collectively referred to as "Formula (I)" compound(s). The route of 
administration of the Formula (I) compound may be oral, parenteral, by 
inhalation or topical. The term parenteral as used herein includes 
intravenous, intramuscular, subcutaneous, rectal, vaginal or 
intraperitoneal administration. The subcutaneous and intramuscular forms 
of parenteral administration are generally preferred. The daily parenteral 
dosage regimen for a compound will preferably be from about 50 mg to about 
1,000 mg per day. The daily oral dosage regimen will preferably be from 
about 150 mg to about 2,000 mg. 
The compounds for Formula (I) may also be administered by inhalation. By 
"inhalation" is meant intranasal and oral inhalation administration. 
Appropriate dosage forms for such administration, such as an aerosol 
formulation or a metered dose inhaler, may be prepared by conventional 
techniques. The preferred daily dosage amount of a compound of Formula (I) 
administered by inhalation is from about 10 mg to about 100 mg per day. 
The compounds of Formula (I) may also be administered topically to a mammal 
in need of the inhibition of the 5-lipoxygenase pathway of arachidonic 
acid metabolism. Thus, the compounds of Formula (I) may be administered 
topically in the treatment of inflammation in an animal, including man and 
other mammals, and may be used in the relief of rheumatoid arthritis, 
rheumatoid spondylitis, osteoarthritis, gouty arthritis and other 
arthritic conditions, inflammed joints, eczema, psoriasis or other 
inflammatory skin conditions such as sunburn; inflammatory eye conditions 
including conjunctivitis; pyresis, pain and other conditions associated 
with inflammation. 
The amount of a compound of Formula (I) (hereinafter referred to as the 
active ingredient) required for therapeutic effect on topical 
administration will, of course, vary with the compound chosen, the nature 
and severity of the inflammatory condition and the animal undergoing 
treatment, and is ultimately at the discretion of the physician. A 
suitable anti-inflammatory dose of an active ingredient is 0.5 mg to 500 
mg of base per kilogram bodyweight for topical administration, the most 
preferred dosage being 0.5 to 50 mg/kg of animal bodyweight, for example 5 
to 25 mg/kg; administered two or three times daily. For application to the 
skin, from 1 .mu.g to several mg of active ingredient may be applied per 
application, preferably from 10 to 100 .mu.g per application. 
By topical administration is meant non-systemic administration and includes 
the application of a compound of Formula (I) externally to the epidermis, 
to the buccal cavity and instillation of such a compound into the ear, eye 
and nose, and where the compound does not significantly enter the blood 
stream. By systemic administration is meant oral, intravenous, 
intraperitoneal and intramuscular administration. 
While it is possible for an active ingredient to be administered alone as 
the raw chemical, it is preferable to present it as a pharmaceutical 
formulation. The active ingredient may comprise, for topical 
administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of 
the formulation although it may comprise as much as 10% w/w but preferably 
not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the 
formulation. 
The topical formulations of the present invention, both for veterinary and 
for human medical use, comprise an active ingredient together with one or 
more acceptable carrier(s) therefore and optionally any other therapeutic 
ingredient(s). The carrier(s) must be `acceptable` in the sense of being 
compatible with the other ingredients of the formulation and not 
deleterious to the recipient thereof. 
Formulations suitable for topical administration include liquid or 
semi-liquid preparations suitable for penetration through the skin to the 
site of inflammation such as: liniments, lotions, creams, ointments or 
pastes, and drops suitable for administration to the eye, ear or nose. 
Drops according to the present invention may comprise sterile aqueous or 
oily solutions or suspensions and may be prepared by dissolving the active 
ingredient in a suitable aqueous solution of a bactericidal and/or 
fungicidal agent and/or any other suitable preservative, and preferably 
including a surface active agent. The resulting solution may then be 
clarified by filtration, transferred to a suitable container which is then 
sealed and sterilized by autoclaving or maintaining at 
98.degree.-100.degree. C. for half an hour. Alternatively, the solution 
may be sterilized by filtration and transferred to the container by an 
aseptic technique. Examples of bactericidal and fungicidal agents suitable 
for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), 
benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable 
solvents for the preparation of an oily solution include glycerol, diluted 
alcohol and propylene glycol. 
Lotions according to the present invention include those suitable for 
application to the skin or eye. An eye lotion may comprise a sterile 
aqueous solution optionally containing a bactericide and may be prepared 
by methods similar to those for the preparation of drops. Lotions or 
liniments for application to the skin may also include an agent to hasten 
drying and to cool the skin, such as an alcohol or acetone, and/or a 
moisturizer such as glycerol or an oil such as castor oil or arachis oil. 
Creams, ointments or pastes according to the present invention are 
semi-solid formulations of the active ingredient for external application. 
They may be made by mixing the active ingredient in finely-divided or 
powered form, alone or in solution or suspension in an aqueous or 
non-aqueous fluid, with the aid of suitable machinery, with a greasy or 
non-greasy basis. The basis may comprise hydrocarbons such as hard, soft 
or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil 
of natural origin such as almond, corn, arachis, castor or olive oil; wool 
fat or its derivatives, or a fatty acid such as steric or oleic acid 
together with an alcohol such as prolylene glycol or macrogols. The 
formulation may incorporate any suitable surface active agent such as an 
anionic, cationic or non-ionic sulfactant such as sorbitan esters or 
polyoxyethylene derivatives thereof. Suspending agents such as natural 
gums, cellulose derivatives or inorganic materials such as silicaceous 
silicas, and other ingredients such as lanolin, may also be included. 
It will be recognized by one of skill in the art that the optimal quantity 
and spacing of individual dosages of the Formula (I) compound will be 
determined by the nature and extent of the condition being treated, the 
form, route and site of administration, and the particular animal being 
treated, and that such optimums can be determined by conventional 
techniques. It will also be appreciated by one of skill in the art that 
the optimal course of treatment, i.e., the number of doses of the Formula 
(I) compound given per day for a defined number of days, can be 
ascertained by those skilled in the art using conventional course of 
treatment determination tests. 
EXAMPLES 
Without further elaboration, it is believed that one skilled in the art 
can, using the preceding description, utilize the present invention to its 
fullest extent. The following examples are, therefore, to be construed as 
merely illustrative and not a limitation of the scope of the present 
invention in any way. 
As used herein, the term "Compound 1" refers to the compound of Formula (I) 
wherein R.sup.1 is 4-pyridyl, R is 4-fluorophenyl, A is CH.sub.2, X is 
S(O)n, and n is 0. 
Temperature is in degrees Centigrade (.degree.C.). 
SYNTHESIS EXAMPLES 
EXAMPLE 1 
5,6-bis(4-N,N-diethylaminophenyl)-2,3-dihydroimidazo [2,1-b]thiazole, 
Formula (I) compound 
Compounds of Formula (I) wherein X is S; A is CH.sub.2 or CH.sub.2 CH.sub.2 
; B and C are independently selected from H, methyl, or ethyl; and R and 
R.sup.1 are independently mono, di or tri-substituted phenyl, are prepared 
by the method described in Bender et al., U.S. Pat. No. 4,263,311, and 
Bender et al., J. Med. Chem., 28, 1169-1177 (1985). Reduction of 
6-(alkanamidophenyl) compounds with two to three equivalents of borane or 
borane-dimethylsulfide complex in tetrahydrofuran at room temperature 
affords the 6-(N-alkylaminophenyl) derivatives. Using this procedure, 
5,6-bis(4-N-ethyl-acetamidophenyl)-2,3-dihydroimidazo(2,1-b)thiazole, 
prepared as described in Bender et al., ibid, was reduced to 
5,6-bis(4-diethylaminophenyl)-2,3-dihydroimidazo[2,1-b]thiazole by 
employing 6 equivalents of borane-dimethylsulfide complex by the method of 
Brown et al., J. Org. Chem., 38, 2786 (1973). This product was isolated by 
chromatography on alumina (methylene chloride:chloroform, 1:1) and 
recrystallized from methanol. It had a melting point (mp) of 
168.degree.-169.degree. C., and was analyzed for C.sub. 25 H.sub.32 
N.sub.4 S; Calcd.: C, 71.39; H, 7.67; N, 13.32; Found: C, 71.38; H, 7.72; 
N, 13.31. 
EXAMPLE 2 
5,6-bis(4-(1-piperidinyl)phenyl)-2,3-dihydroimidazo[2,1-b] thiazole, 
Formula (I) compound 
A mixture of 1.3 g (4.2 mmoles) of 
5,6-bis(4-aminophenyl)-2,3-dihydroimidazo[2,1-b]thiazole, prepared as 
described in Bender et al., J. Med. Chem., 28, 1169-1177 (1985), 2.2 g 
(9.7 mmoles) of 1,5-dibromopentane, and 2.7 g (19.4 mmoles) of powdered 
potassium carbonate in 25 ml of dry DMF was heated to reflux for 1 hour. 
Another 2.7 g of powdered potassium carbonate and 2.2 g of 
1,5-dibromopentane were added and refluxed for an additional 2 hours. 
Water was added and the mixture acidified and washed with CH.sub.2 
Cl.sub.2. The aqueous phase was made alkaline and the product extracted 
into CH.sub.2 Cl.sub.2. The organic phase was dried over potassium 
carbonate and concentrated in vacuo. The residue was column 
chromatographed on silica and the product eluted with CH.sub.3 
CN--CH.sub.2 Cl.sub.2 (1:1). The solvent was removed in vacuo, and the 
residue was dissolved in methanol. Addition of ethereal HCl gave the title 
Formula (I) compound, mp 280.degree.-285.degree. C. Analyzed for C.sub.27 
H.sub.32 N.sub.4 S.3HCl.1H.sub.2 O, Calculated, C: 56.58, H: 6,25, N: 
9.84; Found, C: 56.69, H: 5.99, N: 9.79. 
EXAMPLE 3 
5,6-bis(4-(1-pyrrolidinyl)phenyl)-2,3-dihydroimidazo[2,1-b] thiazole, 
Formula (I) compound 
A mixture of 1.3 g (4.2 mmoles) of 
5,6-bis(4-aminophenyl)-2,3-dihydroimidazo(2,1-b)thiazole, prepared as 
described in Example 2, 2.1 g (9.7 mmoles) of 1,4-dibromobutane, and 2.7 g 
(19.4 mmoles) of powdered potassium carbonate in 25 ml of dry DMF was 
refluxed for 2 hours under argon. The reaction mixture was poured into 
water, acidified and washed with CH.sub.2 Cl.sub.2. The aqueous phase was 
made basic and extracted with CH.sub.2 Cl.sub.2. The organic layer was 
dried over potassium carbonate, concentrated and column chromatographed on 
silica, eluting the product with ethyl acetate/CH.sub.2 Cl.sub.2 (2:10). 
The solvent was evaporated and the solid residue recrystallized from 
CH.sub.2 Cl.sub.2 --CH.sub.3 OH to afford the title Formula (I) compound, 
mp 235.degree.-237.degree. C. Analyzed for C.sub.25 H.sub.28 N.sub.4 
S.CH.sub.3 OH, Calculated, C; 69.60, H: 7.19, N: 12.49; Found, C: 69.53, 
H: 7.01, N: 12.68. 
EXAMPLE 4 
5-(4-Dimethylaminophenyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]-thia 
zole and 
6-(4-dimethylaminophenyl)-5-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thia 
zole, Formula (I) compounds 
A solution of 0.40 g (1.28 mmoles) of 
4-(4-dimethylaminophenyl)-5-(4-fluorophenyl)-2-mercaptoimidazole, a 
Formula (IV) compound, [obtained by treatment of the corresponding Formula 
(VIII) compound (prepared from 4-dimethylaminobenzaldehyde and 
4-fluorobenzaldehyde as described by Ide et al., in "Organic Reactions"; 
John Wiley and Sons, (1948) Chapter 5) with thiourea in DMF by the method 
described in Bender et al., J. Med. Chem., 28, 1169 (1985) (therein 
designated as the general method for preparation of 
4,5-diarylimidazole-2-thiones)] in 15 ml of dry DMF was treated with 0.061 
g (1.28 mmoles) of a 50% sodium hydride dispersion. 0.18 g (1.28 mmoles) 
of 1-bromo-2-chloroethane was added after 0.5 hours stirring at ambient 
temperature. After an additional 12 hours stirring, 0.18 g (1.28 mmoles) 
of powdered potassium carbonate was added, and the mixture heated to 
150.degree. C. for 2 hours. The solvent was removed in vacuo and the 
residue extracted with chloroform. The solution was washed with water, 
dried over MgSO.sub.4 and concentrated in vacuo. Column chromatography on 
silica afforded two isomers eluting with 10% and 20% CH.sub.3 CN in 
CH.sub.2 Cl.sub.2. Evaporation of the solvents followed by 
recrystallization from methanol gave 
5-(4-dimethylaminophenyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thia 
zole, mp 163.degree.-164.5.degree. C., (TLC, silica, 10% CH.sub.3 CN in 
CH.sub.2 Cl.sub.2, Rf 0.17) and 
6-(4-dimethylaminophenyl)-5-(4-fluorophenyl)-2,3-dihydroimid 
azo[2,1-b]thiazole, mp 195.degree.-201.degree. C., (TLC, silica, 10% 
CH.sub.2 CN in CH.sub.2 Cl.sub.2, Rf 0.3). 
EXAMPLE 5 
5-(2-pyridinyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole and 
5-(4-fluorophenyl)-6-(2-pyridinyl)-2,3-dihydroimidazo[2,1-b]thiazole, 
Formula (I) compounds 
a) 1-(2-Pyridinyl)-2-(4-fluorophenyl)ethanone (Formula (X) compound) 
To a solution of 40.8 g (0.60 mol) of sodium ethoxide in 200 ml absolute 
ethanol was added a mixture of 60.5 g (0.40 mol) of ethyl picolinate and 
54.1 g (0.40 mol) of 4-fluorophenylacetonitrile. The solution was refluxed 
10 minutes, then cooled to ambient temperature. The solids were dissolved 
by the addition of 330 ml of water. Then, 50 ml 12N hydrochloric acid was 
added dropwise. The solid was collected by filtration, washed with water, 
and dried overnight (30.degree. C. in vacuo) to give 
1-(2-pyridinyl)-2-cyano-2-(4-fluorophenyl)-ethen-1-ol. This compound was 
dissolved in 250 ml 48% hydrobormic acid and refluxed for 17 hours. Upon 
cooling, aqueous ammonium hydroxide was added until the reaction mixture 
was basic. The aqueous solution was extracted three times with chloroform. 
The combined organic extracts were washed with water, dried (MgSO.sub.4), 
and concentrated. The resulting solid was chromatographed on silica gel 
with ether-petroleum ether (1:3) as eluant, and recrystallized from 
2-propanol-hexane to give the title Formula (X) compound, m.p. 
56.58.degree. C. 
b) 1-(2-Pyridinyl)-2-(4-fluorophenyl)ethanone, oxime (Formula (XII) 
compound) 
A solution of 18.5 g (0.086 mol) of 
1-(2-pyridinyl)-2-(4-fluorophenyl)-ethanone, prepared as described in part 
a, 52.7 g (0.387 mol) of sodium acetate trihydrate, and 19.6 g (0.282 mol) 
of hydroxylamine hydrochloride in 280 ml methanol-water (1:1) was refluxed 
for 1 hour. Upon cooling to 5.degree. C., the precipitate was collected by 
filtration, washed with water, and dried overnight (30.degree. C. in 
vacuo). The title Formula (XII) compound was recrystallized from 
methanol-water, m.p. 106.degree. C. 
c) 1-(2-Pyridinyl)-2-(4-fluorophenyl)ethanone, 
0-[(4-methylphenyl)sulfonyl]oxime (Formula (XIII) compound) 
To a solution of 19.6 g (0.085 mol) of 
1-(4-pyridinyl)-2-(4-fluorophenyl)-ethanone, oxime, prepared as described 
in part b, in 100 ml of dry pyridine at 0.degree. C. under argon was added 
20.3 g (0.106 mol) of p-toluenesulfonyl chloride. The mixture was stirred 
at 25.degree. C. for 20 hours, and then poured into ice/water. The solid 
was collected by filtration and dried (25.degree. C. in vacuo to give the 
title Formula (XIII) compound, m.p. 120.degree.-122.degree. C. 
d) 4-(2-Pyridinyl)-5-(4-fluorophenyl)imidazole-2-thione (Formula (IX) 
compound) 
A suspension of 30.7 g (0.08 mol) of 
1-(2-pyridinyl)-2-(4-fluorophenyl)-ethanone, 0-[(4-methylphenyl) 
sulfonyl]oxime, prepared as described in part c, in 170 ml absolute 
ethanol at 5.degree. C. under argon was treated with a solution of 8.6 g 
(0.10 mol) of potassium ethoxide in 90 ml of absolute ethanol. The 
suspension was stirred at 5.degree. C. for 1 hour. Then, 260 ml of ether 
was added, and the reaction mixture was stirred for an additional 90 
minutes. The suspension was then filtered and washed with ether. The 
ethereal solution was washed four times with 10% hydrochloric acid. The 
combined aqueous acid extracts were concentrated in vacuo, then 
redissolved in 150 ml water. Then 15.5 g (0.16 mol) potassium thiocyanate 
was added, and the reaction was refluxed for 1 hour. After cooling, the 
reaction mixture was poured into 5% sodium bicarbonate solution. The solid 
was collected by filtration and dried overnight (30.degree. C. in vacuo) 
to give the title Formula (IX) compound, m.p. 248.degree.-250.degree. C. 
e) 5-(2-Pyridinyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo [2,1-b]thiazole 
5-(4-fluorophenyl)-6-(2-pyridinyl)-2,3-dihydroimidazo[2,1-b]thiazole 
(Formula (I) compounds) 
A solution of 9.76 g (0.036 mol) of 
4-(2-pyridinyl)-5-(4-fluorophenyl)-imidazole-2-thione, prepared as 
described in part d, in 250 ml of dry N,N-dimethylformamide was treated 
with 3.52 g (0.073 mol) of a 50% oil dispersion of sodium hydride. The 
solution was stirred for 30 minutes, followed by the addition of 13.95 g 
(0.074 mol) of 1,2-dibromoethane. The reaction mixture was stirred for 3 
hours, and then poured into ice/water. The aqueous suspension was 
extracted several times with methylene chloride. The combined organic 
layers were washed with water, dried (MgSO.sub.4), and concentrated. The 
products were separated by chromatography on silica gel with 10% 
acetonitrile in methylene chloride and 25% acetonitrile in methylene 
chloride as eluants. Each product was recrystallized from 
acetonitrile-hexane to give the title Formula (I) compounds 
5-(2-pyridinyl)-6-(4-fluoro-phenyl)-2,3-dihydroimidazo[2,1-b]thiazole, 
m.p. 152.degree.-154.degree. C., and 
5-(4-fluorophenyl)-6-(2-pyridinyl)-2,3-dihydroimidazo[ 2,1-b]thiazole, 
m.p. 164.degree.-166.degree. C. 
EXAMPLE 6 
6-(4-pyridyl)-5-(3,4-methylenedioxyphenyl)-2,3-dihydroimidazo 
[2,1-b]thiazole and 
4-(4-pyridyl)-6-(3,4-methylenedioxyphenyl)-2,3-dihydroimidazo 
[2,1-b]thiazole (Formula (I) compounds) 
The compounds of Formula (I) described in Example 5, as well as 
monosubstituted phenyl compounds of Formula (I) where the phenyl 
substituent is C.sub.1-3 alkanamido, may be prepared by the method 
described in Bender et al., U.S. Pat. No. 4,175,127, starting from the 
pyridine carboxyaldehyde cyanohydrin benzoate and the corresponding 
substituted benzaldehyde. Using this method with 
3,4-methylenedioxybenzaldehyde and 4-pyridine carboxyaldehyde cyanohydrin 
benzoate afforded a mixture of 
5/6-(4-pyridyl)-6/5-(3,4-methylenedioxypheny)-2,3-dihydroimidazo[2,1-b]thi 
azole isomers which were separated by chromatography on silica 
(methanol-methylene chloride, 2:98). The 6-pyridyl isomer eluted first, 
and was recrystallized from methanol to give the 6-(4-pyridyl) product, mp 
213.5.degree.-214.5.degree. C. Analyzed for C.sub.17 H.sub.13 N.sub.3 
O.sub.2 S; Calcd: C, 63.14; H, 4.05; N, 12.99; Found: C, 63.12; H, 4.10; 
N, 12.91. The 5-(4-pyridyl) product eluted next, and was also 
recrystallized from methanol, mp 177.5.degree.-178.5.degree. C. Analyzed 
for C.sub.17 H.sub.13 N.sub.3 O.sub.2 S; Calcd: C, 63.14; H, 4.05; N, 
12.99; Found: C, 63.24; H, 4.20; N, 12.90. 
EXAMPLE 7 
5-(4-pyridyl)-6-(4-acetamidophenyl)-2,3-dihydroimidazo (2,1-b)thiazole and 
6-(4-pyridyl)-5-(4-acetamidophenyl)-2,3-dihydroimidazo[2,1-b]thiazole 
Formula (I) compounds 
Employing the procedure of Example 6, and using 4-acetamidobenzaldehyde and 
4-pyridine carboxaldehyde cyanohydrin benzoate as the starting materials, 
afforded a mixture of 
5/6-(4-pyridyl)-6/5-(4-acetamidophenyl)-2,3-dihydroimidazo[2,1-b]thiazole 
isomers which were separated by chromatography on silica 
(methanol-methylene chloride, 2:98). The 5-(4-pyridyl) product eluted 
before the 6-(4-pyridyl) product. 
EXAMPLE 8 
5-(4-pyridyl)-6-(4-(pyrrolidin-1-yl)phenyl)-2,3-dihydroimida 
zo[2,1-b]thiazole Formula (I) compound 
a) 6-(4-pyrrolidin-1-yl)-phenyl)-2,3-dihydroimidazo[2,1-b]thiazole (Formula 
(III) compound) 
To 250 ml of KOH dried pyridine was added 50 g (0.37 mole) of 
p-aminoacetophenone and 39.6 g of acetic anhydride. After one and a half 
hours of stirring at room temperature, the solution had become a thick 
suspension of a white solid. Filtration and drying gave 44 g of 
p-acetamidoacetophenone. This solid (44 g, 0.25 mole) was then suspended 
in 500 ml methylene chloride and treated with 44 g Br.sub.2 (0.275 mole). 
The reaction was allowed to proceed overnight whereupon it was stripped 
and dried under high vacuum, then suspended in 200 ml absolute EtOH and 
treated with 60 g 2-amino-2-thiazoline (0.59 mole). The reaction was 
stirred for 2 days then stripped, taken up in water and extracted with 
methylene chloride. The organic phase was washed with water, brine and was 
dried with sodium sulfate. Flash column chromatography with 2% MeOH/98% 
CH.sub.2 Cl.sub.2 gave 10.2 g (0.039 mole) of the Formula (III) compound, 
6-acetamidophenyl-2,3-dihydroimidazo[2,1-b]thiazole. 
The amide described above (10.2 g, 0.039 mole) was refluxed in 200 ml of 6N 
HCl for one hour, cooled, neutralized and extracted with methylene 
chloride. The organic layer was washed with brine, dried over sodium 
sulfate and evaporated to give 6.8 g of the Formula (III) compound 
6-aminophenyl-2,3-dihydroimidazo[2,1-b]thiazole. 
To 6.8 g (0.034 mole) of the amine described above in 150 ml of dry DMF was 
added 8.4 g (0.039 mole) 1,4-dibromobutane and 15.5 g K.sub.2 CO.sub.3 
(0.112 mole). The reaction was stirred at room temperature overnight, the 
DMF removed under high vacuum and the residue flash chromatographed on 
silica with 3% MeOH/97% CH.sub.2 Cl.sub.2 to give (after recrystallization 
from MeOH) 0.88 g of the title Formula (III) compound, m.p. 
218.degree.-220.degree. C. (dec.). Analyzed for C.sub.15 H.sub.17 N.sub.3 
S, Calculated, C: 66:39, H: 6.31, N: 15.48; Found, C: 66.30, H: 6.32, N: 
15.27. 
b) 
5-(4-pyridyl)-6-(4-(pyrrolidin-1-yl)-phenyl)-2,3-dihydroimidazo[2,1-b]thia 
zole (Formula (I) compound) 
The procedure of Lantos et al., ibid, can be utilized to add a 4-pyridyl 
substituent at C-5 to either the tertiary amide, N-(C.sub.1-3 
alkyl)-alkanamidophenyl-2,3-dihydroimidazo[2,1-b]thiazole, or the tertiary 
amine, 6-(4-pyrrolidin-1-yl)phenyl-2,3-dihydroimidazo[2,1-b]thiazole. 
5-(4-pyridyl)-6-(4-N-pyrrolidinophenyl)-2,3-dihydroimidazo[2,1-b]thiazole 
was prepared by this route and isolated by chromatography twice on silica 
(1. methanol-methylene chloride, 1.5:98.5, 2. ethyl acetate) to afford a 
glass. Analyzed for C.sub.20 H.sub.20 N.sub.4 S.O.875H.sub.2 O; Calcd.: C, 
65.95; H, 6.01; N, 15.38; Found: C, 65.98; H, 5.77; N, 15.16. 
EXAMPLE 9 
5-(4-pyridyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole-S-dioxid 
e Formula (I) compound 
Compounds of Formula (I) where X is S(O).sub.n and n is 1 or 2 are prepared 
by oxidation with one or two equivalents of an organic peracid as 
described in Bender et al., U.S. Pat. No. 4,263,311 and Bender et al., 
U.S. Pat. No. 4,175,127. Compounds of Formula (I) where at least one of R 
and R.sup.1 is pyridyl, X is S(O).sub.n and n=2 are preferably prepared by 
oxidation of 1 equivalent of an acid salt of X=S(O).sub.n, n is 1, with 
2/3 equivalent KMnO4 aqueous in solution according to the method of 
Chatterway et al., J. Chem. Soc., 1352 (1930. Using this procedure, 
5-(4-pyridyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole-S-oxide 
, prepared as described in Bender et al., U.S. Pat. No. 4,175,127, was 
cleanly oxidized to give the cyclic sulfone, after recrystallization from 
methanol, mp 250 dec. (Rf 0.73, silica, methanol-methylene chloride, 
5:95). Analyzed for C.sub.16 H.sub.12 FN.sub.3 SO.sub.2 ; Calcd.: C, 
58.35; H, 3.67; N, 12.76; Found: C, 58.69; H, 3.86; N, 12.79. 
EXAMPLE 10 
5,6-bis(4-cyanophenyl)-2,3-dihydroimidazo[2,1-b]thiazole Formula (I) 
compound 
a) 2-Oxo-1,2-di(4-cyanophenyl)ethane 
To a solution of 25 g of p-cyanobenzaldehyde in 50 ml of ethanol was added 
5 g of potassium cyanide in 10 ml of water. The mixture was heated at 
reflux for 1 hr, cooled, and the crystalline product was filtered and 
washed with cold ethanol. Recrystallization from acetic acid afforded 4.7 
g of the part (a) title compound, mp. 209.degree.-215.degree. C. 
b) 1-Bromo-2-oxo-1,2-di(4-cyanophenyl)ethane 
A mixture of 3.8 g of 2-oxo-1,2-di(4-cyanophenyl) ethane, prepared as 
described above in part (a), and 7.2 g of cuprous bromide in 500 ml of 
ethylacetate and 500 ml of chloroform was refluxed for 31/2 hours. The 
mixture was cooled, filtered through celite and the filtrate was 
evaporated to dryness. The residue was redissolved in ethyl acetate, 
washed with water, dried over magnesium sulfate and evaporated to dryness. 
The residue was titrated with ether to afford a crystalline product which 
was recrystallized from methanol-ester to afford the part (b) title 
compound, 3.9 g, mp. 167.degree.-170.degree.. 
c) 5,6-bis(4-cyanophenyl)-2,3-dihydroimidazo[2,1-b]thiazole (Formula (I) 
compound) 
A mixture of 3.8 g of 1-bromo-2-oxo-1,2-di(4-cyanophenyl)ethane, prepared 
as described above in part (b) and 3.8 g of 2-aminothiazoline in 70 ml of 
DMF was stirred at room temperature for 18 hours. The reaction mixture was 
diluted with cold water, and the precipitated product was filtered and 
dried in vacuum. The material was suspended in 200 ml of toluene, 125 mg 
of p-toluenesulfonic acid was added, and the mixture was refluxed for 2 
hours with removal of water. After cooling, the crude product was filtered 
and recrystallized twice from acetic acid to afford the part (c) title 
compound, 1.3 g, m.p. 255.degree.-260.degree.; Analysis: C.sub.19 H.sub.12 
N.sub.4 S.0.5AcO; Theory; C 67.03%, H 3.91%, N 15.64%; found C: 67.03% H: 
3.96%, N: 15.04%. 
EXAMPLE 11 
6-(4-(1-Propylamino)phenyl)-5-(4-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole 
Formula (I) compound 
a) 6-(4-N-propylacetamido)phenyl-2,3-dihydroimidazo[2,1-b]thiazole (Formula 
(III) compound) 
6-acetamidophenyl-2,3-dihydroimidazo[2,1-b]thiazole (1.0 g, 0.0038 mole), 
prepared as described in Example 8, was suspended in 25 ml dry DMF, and 
NaH (50% in oil, 0.21 g, 0.0046 mole) was added. The suspension slowly 
dissolved and after stirring at room temperature for 30 min., 
n-propylbromide (0.522 g, 0.0042 mole) was added to the reaction. The 
reaction was heated to 80.degree. C. for one hour whereupon the DMF was 
removed under reduced pressure. The residue was then flash chromatographed 
(5% MeOH/95% CH.sub.2 Cl.sub.2) to give 0.6 g of 
6-(4-(N-propylacetamido)phenyl)-2,3-dihydro-imidazo[2,1-b]thiazole 
(Formula (III) compound) (TLC: R.sub.f =0.31 2.5% MeOH/97.5% CH.sub.2 
Cl.sub.2). 
b) 
6-(4-(1-propylamino)phenyl)-5-(4-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazol 
e (Formula (I) compound) 
The N-propylacetamido Formula (III) compound (0.60 g, 0.002 mole), prepared 
as described above in part a, was then suspended in CH.sub.2 Cl.sub.2 (10 
ml) and dry pyridine (0.47 ml, 0.006 mole) was added. The suspension was 
heated to aid in dissolving the solid, then cooled to ice-bath 
temperature. Ethyl chloroformate (0.72 ml, 0.648 g, 0.006 mole) in 2 ml 
CH.sub.2 Cl.sub.2 was added dropwise to this mixture over a one hour 
period. The solution was stirred at room temperature for one hour and then 
heated at reflux for 10 min. The reaction was then cooled to 10.degree. C. 
and an additional equivalent of pyridine (161 .mu.l) and ethyl 
chloroformate (240 .mu.l) was added. After heating at reflux for 10 min., 
the reaction was left to stir at room temperature overnight. The reaction 
was then washed with water (3.times.100 ml) and the organic layer stripped 
then decalin (5 ml) and sulfur (0.063 g, 0.002 mole) were added and the 
mixture was heated to 170.degree. C. This temperature was maintained for 
one hour. The reaction was then diluted with CH.sub.2 Cl.sub.2 and 
extracted with a 12% HCl solution. The acidic layer was basified with 
solid K.sub.2 CO.sub.3 and then extracted with CH.sub.2 Cl.sub.2. After 
treating with brine and MgSO.sub.4, the CH.sub.2 Cl.sub.2 was removed, and 
the residue was flash chromatographed (0.10% MeOH/100-90% CH.sub.2 
Cl.sub.2) to give 0.2 g of a (Formula (I) compound), 
6-4-(N-propylacetamido)phenyl)-5-(4-pyridyl)-2,3-dihydroimidazo[2,1-b]thia 
zole (TLC: R.sub.f =0.22 5% MeOH/95% CH.sub.2 Cl.sub.2. 
The N-propylacetamido Formula (IB) compound (0.10 g, 0.26 mmole) was 
refluxed in 10 ml of 6N HCl for one hour, cooled, neutralized and 
extracted with methylene chloride. The organic layer was washed with 
brine, dried over sodium sulfate and evaporated to give 0.082 g of 
(6-(4-(N-propylamino)-phenyl)-5-(4-pyridyl)2,3-dihydro-imidazo[2,1-b]thiaz 
ole, (Formula (I) compound), as a glassy material (TLC: R.sub.f =0.35 8% 
MeOH/92% CH.sub.2 Cl.sub.2, MS indicates presence of title compound, 
(M+H).sup.+ at 337). 
EXAMPLE 12 
5,6-Bis(4-pyridyl)-2,3-dihydroimidazo(2,1-b) thiazole Formula (I) compound 
10 g (0.10 mole) of 4-pyridine carboxaldehyde was slowly added to a 
solution of 7.6 g (0.1 mole) of thiourea and 2.0 g (0.03 mole) in 50 ml 
water at 0.degree. C. The solution was stirred at 0.degree. C. for one 
hour, and then at ambient temperature overnight. A yellow precipitate of 
4-pyridoin formed, which was filtered, dried and used without further 
purification. 
A mixture of 1.1 g (5.4 mmoles) of the 4-pyridoin, prepared as described 
above, and 0.7 g (9.2 mmoles) of the thiourea was heated in 20 ml of 
dimethylacetamide at reflux for 6 hours. 
4,5-Bis-(4-pyridyl)-2-mercaptoimidazole, a compound of Formula (IX), 
precipitated after dilution with water. 
A solution of 2.90 g (11.5 mmoles) of the 2-mercaptoimidazole described 
above in 50 ml of DMF was treated with 1.64 g (11.5 mmoles) of 
1-bromo-2-chloroethane, stirred at 100.degree. C. for 1 hour. After 
treatment with a second 1.64 g of the dihaloethane, the reaction mixture 
was heated at 120.degree. C. for an additional hour and then cooled. 4.2 g 
(30.4 mmoles) of powdered potassium carbonate was added and the mixture 
heated to reflux for one hour. The reaction mixture was concentrated in 
vacuo to 40 ml, diluted with cold water, and extracted into CH.sub.2 
Cl.sub.2. The organic phase was dried over sodium carbonate and 
concentrated in vacuo. The residue was column chromatographed on alumina 
and eluted with CHCl.sub.3. Evaporation of the solvent gave an oil which 
crystallized on trituration with ether to afford the title Formula (I) 
compound, mp 219.degree.-222.degree. C. Analyzed for C.sub.15 H.sub.12 
N.sub.4 S, Calculated, C: 64.26, H: 4.31, N: 19.98; Found C: 63.81, H: 
4.57, N: 19.87. 
UTILITY EXAMPLES 
In the following Examples where mice were used, they were male Balb/c mice 
(20-28 g), and where rats were used, they were male Lewis rats (180-210 
g). All mice and rats were obtained from Charles River Breeding 
Laboratories, Kingston, N.Y. Within a single experiment, mice and rats 
were sex and age matched. 
In the following examples, reagents used were employed as follows: 
Auranofin, phenidone, indomethacin, naproxen, and ibuprofen were each used 
as the free base. The compounds of Formula (I) were used either as the 
free base or in the appropriate salt form. Levamisole was used as the 
hydrochloride salt. The compounds were homogenized in 0.5% tragacanth. 
Compounds were administered by gavage at the indicated dose in a final 
volume of 10 ml/kg. Nordihydroguaiaretic acid (NDGA) was solubilized in 
dimethylacetamide and diluted with olive oil for subcutaneous 
administration. 
For in vitro experiments, compounds were dissolved at appropriate 
concentrations in ethanol or DMSO (dimethylsulfoxide) (final 
concentration.ltoreq.1.0%) and then diluted to final concentrations using 
the buffers indicated in the text. 
I. METHODS 
Mouse Carrageenan Peritonitis 
Mice were pretreated with either the test compound or vehicle one hour 
before the intraperitoneal injection of a 1.0% carrageenan suspension in 
saline (0.2 ml/mouse). Mice were sacrificed by cervical dislocation two 
hours after injection, and 3.0 ml of phosphate buffered saline, without 
Ca.sup.++ or Mg.sup.++, was injected into the peritoneum. Following 
massage, a 2.0 ml aliquot of the lavage fluid was removed, and the total 
cell count determined on a Coulter counter and differential cell count 
determined by microscopic examination of Giesma-stained slides. 
Arachidonic Acid-Induced Mouse Ear Inflammation 
Arachidonic acid in acetone (20 mg/20 .mu.l) was applied to the inner 
surface of the left ear. The thickness of both ears was then measured with 
a dial micrometer one hour after treatment, and the data were expressed as 
the change in thickness (10.sup.-3 cm) between treated and untreated ears. 
Test compounds were given orally in 0.5% tragacanth at the times indicated 
in the text prior to the topical application of arachidonic acid. 
Parenteral administration of compound was accomplished by subcutaneous 
injection of solution as indicated. 
Arachidonic Acid-Induced Rat Paw Swelling 
After determining pretreatment paw volumes by plethysmography by the method 
of Webb and Griswold, J. Pharmacol. Methods, 12, 149-153 (1984), rats were 
given test compound or vehicle one hour prior to the subplantar injection 
of 0.1 ml of 1 mg/ml arachidonic acid. Paw volumes were then remeasured 
and compared to pretreatment values and the increase in paw volume was 
expressed as mean values .+-. S.D. 
Carrageenan and Arachidonic Acid-Induced Air Pouch Inflammation 
Rats were shaved on the dorsal flank, and then injected subcutaneously one 
day later with 20 ml of air to form a defined pouch, by the method of 
Sedgwick et al., J. Pathology, 141, 483-495 (1983). The air pouch was 
reinflated as necessary over the next 6 days. To assay anti-inflammatory 
activity, animals were treated orally with test compound or vehicle (10 
ml/kg) one hour before injection of 2.0 ml of a 2.0% carrageenan 
suspension containing 200 .mu./ml penicillin and 100 g/ml streptomycin 
into the air pouch. In other experiments, 5 ml of 0.1% arachidonic acid in 
0.2M bicarbonate buffer was injected two hours after drug treatment. 
Animals were sacrificed using CO.sub.2 three hours after instillation of 
irritant. The exudate was then aspirated from the pouch and neutrophil 
count and differential cell count were measured. 
PGE.sub.2 Production by Peritoneal Macrophages 
Mice were injected intraperitoneally with 350 .mu.g Corynebacterium parvum 
and the peritoneal exudate cell population was harvested 12-14 days later 
by peritoneal lavage with cold phosphate-buffered saline, and resuspended 
in Eagles minimal essential medium supplemented with 5% fetal calf serum. 
The recovered cells, representing 95% macrophages as determined by 
morphology, phagocytic capacity and reactivity with a macrophage-specific 
monoclonal antibody [Koestler et al., Proc. Natl. Acad. Sci., USA, 81, 
4504 (1984)], were placed in wells of 24-well microtiter plate (10.sup.6 
cells/900 .mu.l) and allowed to adhere for 1 hour at 37.degree. C. Test 
compounds were added (100 .mu.l) to bring the final volume to 1.0 ml. 
Lipopolysaccharide (5 .mu.g/ml) was then added to stimulate PGE.sub.2 
synthesis. After incubation at 37.degree. C. for 2 hours, cell-free 
supernatants were harvested, placed in polypropylene tubes and frozen at 
-20.degree. C. until assayed for their PGE.sub.2 content using a 
commercial radioimmunoassay kit. 
Assay of 5-Lipoxygenase and Cyclooxygenase Activities 
The activities of these enzymes in extracts of RBL-1 cells were assayed 
using the method of Jakschik and Lee, Nature, 287, 51-52 (1980). RBL-1 
cells were obtained from the American Type Culture Collection (#CRL 1378) 
and were grown at 37.degree. C. (5% CO.sub.2 in air) in spinner culture in 
MEM supplemented with 10% heat inactivated fetal calf serum. Harvested 
cells were washed with 50 mM sodium phosphate buffer, pH 7.0, containing 1 
mM EDTA and 0.1% gelatin, resuspended in fresh buffer (5.times.10.sup.7 
cells/ml) and disrupted by nitrogen cavitation using the Parr bomb at 750 
psi for 10 min. The broken cell extract was then centrifuged at 
10,000.times. g for 20 minutes (min) and the supernatant centrifuged at 
100,000 xIg for 60 min. Aliquots (0.25 mls) of the supernatant were 
preincubated with or without drugs for 10 min, after which 10 .mu.l 
CaCl.sub.2 (50 mM) was added and the reaction was initiated with 2.5 .mu.l 
of 2.5 mM arachidonic acid-1-.sup.14 C (final concentration was 25 .mu.M; 
specific activity 20,000 dpm/nmole). After incubation for 3 min at 
37.degree. C., the reaction was terminated by addition of 2 volumes (0.5 
ml) ice cold acetone and the sample was allowed to deproteinize on ice for 
10 min prior to centrifugation at 1,000.times. g for 10 min. The 
deproteinized supernatant was adjusted to pH 3.5 with 2N formic acid and 
extracted with 2 volumes of ice cold ethyl acetate. The extracted samples 
were dried under argon, redissolved in ethyl acetate and applied to 
Whatman LK5D thin layer chromatography (TLC) plates which were developed 
using the A-9 solvent system [organic phase of ethyl acetate: 
2,2,5-trimethylpentane:acetic acid: water (110:50:20:10)] described by 
Hamberg and Samuelsson, J. Biol. Chem., 241, 257-263 (1966). Arachidonic 
acid, 5-HETE, LTB.sub.4 and PGD.sub.2 were quantified with a Berthold LB 
2832 autoscanner. 
The 5-lipoxygenase and LTA.sub.4 synthetase activities were further studied 
under the following conditions. An additional centrifugation of the RBL-1 
supernatant was run at 100,000.times. g for 60 min, to remove the 
particulate cyclooxygenase activity. Sample incubation was done under 
conditions similar to those described above, i.e., 2 mM CaCl.sub.2 and 25M 
arachidonic acid-1-.sup.14 C, however, with an incubation time of 5 min at 
5.degree. C. Under these conditions, only the 5-lipoxygenase pathway 
metabolites were detectable. The 5-HETE and di-HETEs were formed at a 
linear rate, and substantial amounts of the arachidonic acid-1-.sup.14 C 
substrate were utilized. 
Drug-induced effects on enzyme activities are described as the 
concentration of drug causing a 50% inhibition of metabolite synthesis 
(IC.sub.50). 
Ex Vivo Production of LTB.sub.4 from Peritoneal Exudate Cells 
Carrageenan-induced peritoneal exudate cells from normal or drug-treated 
mice were washed and suspended in 2.2 ml of phosphate buffered saline. 
Aliquots of 1-1.5.times.10.sup.7 cells were suspended in 15 ml centrifuge 
tubes containing 5 ml of phosphate buffer (1.2 mM Ca.sup.++). After 
incubation at room temperature for 30 minutes, cells were treated with the 
calcium ionophore A23187 (10 .mu.M) for 5 minutes. The cell preparation 
was centrifuged at 1500 rpm for 10 min and the supernatant was extracted 
using a C-18 silica column. LTB.sub.4 was separated by isocratic reverse 
phase high performance liquid chromatography using an Altex C-18 5 .mu.M 
column attached to a Beckman Series 112 pump and a Beckman 254 detector 
set at 280 nm/0.01 AUFS. A tetrahydrofuran, methanol, water, acetic acid 
(25:30:45: 0.1) solvent system, adjusted to pH 5.5 with ammonium 
hydroxide, was used at a flow rate of 0.7 ml/min. Cell derived LTB.sub.4 
was quantified utilizing standard curves constructed with known amounts of 
synthetic LTB.sub.4. 
Experimental Allergic Encephalomyelitis Induced in Female Lewis Rats 
The effect of Compound 1 and indomethacin on hindleg paralysis in 
experimental allergic encephalomyelitis induced in female Lewis rats was 
evaluated according to the following protocol. EAE is induced in Female 
(Charles River) Lewis rats by a single intradermal injection of 0.1 ml of 
an encephalitogenic emulsion consisting of equial parts of a 50% w/v 
homogenate of guinea pig spinal cord and mid-brain in 0.5% aqueous phenol 
and Freund's complete adjuvant (4 mg/ml killed, dried M. butyricum) into a 
hindpaw (left) footpad. Within 9-11 days, the animals exhibit tail 
limpness, hindleg weakness, and decrease in body weight. By day 16, the 
animals develop complete hindleg paralysis and exhibit a further decrease 
in body weight. Any animal which becomes paralyzed during the course of 
the experiment is considered to have developed EAE whether or not the 
paralysis is permanent. Test compounds are administered daily beginning on 
the day of injection, for 19 days, exclusive of days 5, 6 12 and 13. Drug 
activity is determined by comparing the indicidence of EAE (paralysis) of 
the treated group with a control (vehicle) group. The level of significant 
difference between the treated groups and control groups is determined by 
a Chi-square test using a 2.times.2 contingency table. Body weight changes 
from day 0 are also statistically compared to the control group using a 
Student "t" test. 
LTC.sub.4 Production by Human Monocytes 
The compounds of Formula (I) were evaluated for their ability to inhibit 
the production of LTC.sub.4 by human monocytes according to the following 
assay. Human monocytes were prepared from whole blood supplied by the 
American Red Cross. The blood was fractinated by a two-step procedure 
employing sedimentation on Ficoll followed by sedimentation on Percoll. 
The mononuclear cell fraction recovered was composed of 80-90% monocytes 
with the remainder of the cells being predominantly lymphocytes. The 
monocytes were plated at 1.times.10.sup.6 cells per well in a costar 24 
well tissue culture plate and allowed to adhere for 1 hour at 37.degree. 
C. Non-adherent cells were removed by washing. The cells were stimulated 
with 1 .mu.M A23187 calcium ionophore for 3 hours at 37.degree. C. to 
induce LTC.sub.4 production. When drugs were evaluated, they were added to 
the cells 30 minutes prior to the A23187. Supernatants were collected, 
clairified by centrifugation and stored frozed at -20.degree. C. until 
assay. The LTC.sub.4 content was determined by using a New England Nuclear 
Leukotriene C-4 (.sup.3 H) RIA Kit as per instructions. 
II. RESULTS 
The Effects of Compound 1 on Leukocyte Infiltration into Inflammatory 
Lesions 
The effect of Compound 1 on the infiltration of cells into inflammatory 
lesions was examined in several assay systems. As shown in Table 1, the 
infiltration of polymorphonuclear leukocytes induced by intraperitoneal 
injection of carrageenan in mice is reduced dramatically by oral 
administration of Compound 1. The inhibition is dose-related, with an 
ED.sub.50 of 43.9 mg/kg, p.o. Also, the leukotriene synthesis inhibitors 
phenidone (Table 1), NDGA and dexamethasone (Table 2) were effective in 
PMN infiltration in this peritonitis model. In contrast, the 
cyclooxygenase inhibitors indomethacin (10 mg/kg, p.o.) and naproxen (100 
mg/kg, p.o.), the organo-gold compound auranofin (2 mg Au/kg, p.o.) and 
levamisole (100 mg/kg, p.o.) did not impair inflammatory cell infiltration 
in this assay system despite the use of near maximally tolerated doses 
(Table 3). Compound 1 also produced significant inhibition of 
polymorphonuclear leukocyte infiltration into rat air pouch inflammatory 
lesions induced by carrageenan (Table 4). The reduction in PMN 
infiltration was accompanied by a relative increase in mononuclear cell 
counts. A reduction in the PMN count and the PMN:mononuclear cell ratio 
was also produced by phenidone (100 mg/kg, p.o.) and a high dose of 
indomethacin (5 mg/kg, p.o.). Unlike the mouse carrageenan model, this 
assay system was sensitive to the anti-inflammatory activity of 
indomethacin. 
The Effect of Compound 1 on Arachidonic Acid-induced Inflammation 
In order to help define the anti-inflammatory properties of Compound 1, 
inflammatory lesions were induced using arachidonic acid. As shown in 
Table 5, Compound 1 and phenidone significantly reduced PMN and 
mononuclear cell infiltration into arachidonic acid-induced inflammation 
in the rat air pouch but indomethacin had no significant effect on cell 
infiltration. Further elucidation of the anti-inflammatory activity of 
Compound 1 was achieved in models of arachidonic acid-induced edema in 
mice and rats. The mouse ear edematous response to arachidonic acid has 
been shown to be sensitive to agents that inhibit both lipoxygenase and 
cyclooxygenase-generated mediators or that selectively inhibit 
lipoxygenase, but not cyclooxygenase, enzyme activity [See, Young et al., 
J. Invest. Dermatol., 82, 367-371 (1984)]. The inflammatory response 
induced in rat paws by arachidonic acid injection was inhibited 
significantly by both Compound 1 and phenidone, but not by indomethacin 
(Table 6). Similarly, Compound 1 produced marked inhibition of the 
edematous response normally seen 1 hour after the application of 2 mg of 
arachidonic acid to the ear (ED.sub.50 of 19.5 mg/kg, p.o.). The 
anti-inflammatory activity of Compound 1 in this assay is greater than for 
phenidone (ED.sub.50 =44.0 mg/kg, p.o.) and for dexamethasone which was 
only moderately effective. The cyclooxygenase inhibitors, indomethacin (10 
mg/kg, p.o.), ibuprofen (250 mg/kg, p.o.) and naproxen (100 mg/kg, p.o.) 
did not exhibit detectable anti-inflammatory activity in this assay, 
despite use at near maximally tolerated doses (Table 7). Table 7A 
represents the results of testing other compounds of Formula (I) in the 
arachidonic acid-induced ear swelling assay. Such results indicate that 
the compounds of Formula (I) exhibit antiinflammatory activity in an assay 
in which selective cyclooxygenase inhibitors do not exhibit such activity. 
Collectively, these findings indicate that Compound 1 is a potent inhibitor 
of both the cellular and edematous responses of inflammation in rats and 
mice. These inflammatory responses were also inhibited by agents that 
inhibit lipoxygenase activity but not by selective cyclooxygenase 
inhibitors. 
The Effect of Compound 1 on Arachidonic Acid Metabolism 
The generation of the 5-lipoxygenase product, LTB.sub.4, and the generation 
of the cyclooxygenase product, PGD.sub.2, by RBL-1 cell extracts can be 
distinguished as shown by the inhibition of PGD.sub.2 production by 
indomethacin (IC.sub.50 =2.5 .mu.M) and the inhibition of 5-HETE synthesis 
by phenidone (IC.sub.50 =10 .mu.M) (Table 8). The generation of both 
enzyme products was inhibited, however, by Compound 1, with IC.sub.50 
values of 75 .mu.M and 100 .mu.M for 5-HETE and PGD.sub.2, respectively. 
The effect of other compounds of Formula (I) on the inhibition of 5-HETE 
is presented in Table 8A which indicates that compounds of Formula (I) are 
inhibitors of the 5-lipoxygenase pathway as evidenced by their ability to 
inhibit 5-HETE a 5-lipoxygenase pathway product. 
Additional experiments using a soluble extract preparation of RBL-1 cells 
containing only lipoxygenase activity (LTB.sub.4 production by RB1-cells) 
confirmed the inhibitory effects of Compound 1 on eicosanoid formation 
(IC.sub.50 =7.5 .mu.M) (Table 9). Indomethacin at concentrations up to 
10.sup.-4 M was inactive. 
Table 9A represents the testing of compounds of Formula (I) for their 
ability to inhibit 5-lipoxygenase activity. The results presented in Table 
9A indicate that the compounds of Formula (I) possess 5-lipoxygenase 
pathway inhibiting activity as evidenced by their ability to inhibit 
LTB.sub.4, a 5-lipoxygenase pathway product. 
The production of PGE.sub.2 by inflammatory macrophages is inhibited by 
Compound 1 (Table 10). The IC.sub.50 value of 0.7 .mu.M in this assay is 
comparable to those exhibited by the non-steroidal anti-inflammatory 
agents, ibuprofen and naproxen (IC.sub.50 =0.5 .mu.M and 1.8 .mu.M, 
respectively) and higher than that of indomethacin (IC.sub.50 =0.04 
.mu.M). Phenidone proved much less active in inhibiting PGE.sub.2 
production by inflammatory macrophages (IC.sub.50 =28 .mu.M). 
To establish whether Compound 1 at doses shown to be effective in 
inhibiting inflammatory responses in vivo inhibited LTB.sub.4 synthesis by 
inflammatory cells, the ability of peritoneal exudate cells obtained from 
drug-treated animals to produce LTB.sub.4 in vitro was determined. 
Impairment of LTB.sub.4 production was observed in peritoneal exudate 
cells obtained from animals treated with Compound 1 (100 mg/kg, p.o.), as 
compared to those from vehicle-treated controls. Under the same 
experimental conditions, phenidone exhibited a weaker but inhibition of 
LTB.sub.4 synthesis, whereas naproxen was inactive (Table 11). 
The Effect of Compound 1 on Hindleg Paralysis in Experimental Allergic 
Encephalomyelitis Induced in Female Lewis Rats 
As shown in Table 12, Compound 1, but not indomethacin, was efficacious in 
inhibiting experimental allergic encephalomyelitis (EAE) in rats. 
LTC.sub.4 Inhibition Assay 
As shown in Table 13, compounds of Formula (I) were efficacious in 
inhibiting LTC.sub.4 production by human monocytes. These data confirm the 
ability of compounds of Formula (I) to inhibit the 5-lipoxygenase pathway, 
as evidenced by their ability to inhibit LTC.sub.4, a 5-lipoxygenase 
pathway product. 
As seen in Table 7A not all compounds of Formula (I) significantly 
inhibited arachidonic acid-induced ear swelling, but such non-significant 
inhibitors of ear swelling did significantly inhibit the production of 
5-HETE by RBL-1 high speed supernatant (Table 8A), the production of 
LTB.sub.4 by RBL-1 high speed supernatant (Table 9A) and/or the production 
of LTC.sub.4 by human monocytes (Table 13) indicating that such compounds 
are inhibitors of the 5-lipoxygenase pathway. 
TABLE 1 
______________________________________ 
The Effect of Compound 1 and Phenidone on the 
Infiltration of Polymorphonuclear Leukocytes into 
Sites of Carrageenan-Induced Inflammation 
PMN .times. 10.sup.-5/ml 
Treatment.sup.a 
(mean .+-. S.D.) 
% Change 
______________________________________ 
Vehicle 10.90 .+-. 0.89 
-- 
Compound 1 
100 mg/kg, p.o. 
2.48 .+-. 0.98 
-77.sup.b 
50 mg/kg, p.o. 
4.84 .+-. 3.01 
-56.sup.c 
25 mg/kg, p.o. 
7.92 .+-. 4.15 
-27.sup.e 
Phenidone 
200 mg/kg, p.o. 
0.66 .+-. 0.53 
-94.sup.b 
100 mg/kg, p.o. 
6.97 .+-. 3.81 
-36.sup.d 
50 mg/kg, p.o. 
5.30 .+-. 2.25 
-51.sup.c 
______________________________________ 
.sup.a Mice were pretreated with the compounds indicated one hour prior t 
the i.p. injection of carrageenan, and cellular infiltration was measured 
two hours later as described in the Methods. The data represent mean 
values (.+-. S.D.) derived from measurements on five animals in each 
treatment group. 
.sup.b Statistically significant: P &lt; 0.001. 
.sup.c Statistically significant: P &lt; 0.01. 
.sup.d Statistically significant: P &lt; 0.05. 
.sup.e Not Significant. 
TABLE 2 
______________________________________ 
The Effect of Dexamethasone and NDGA on the 
Infiltration of Polymorphonuclear Leukocytes into Sites of 
Carrageenan-Induced Inflammation 
PMN .times. 10.sup.-5 /ml 
Treatment.sup.a 
(mean .+-. S.D.) 
% Change 
______________________________________ 
Experiment 1 
Vehicle, p.o. 19.8 .+-. 3.2 
-- 
Dexamethasone 
50 mg/kg, p.o. 
6.1 .+-. 1.5 -69.sup.b 
25 mg/kg, p.o. 
8.8 .+-. 2.6 -55.sup.b 
12.5 mg/kg, p.o. 
9.1 .+-. 2.0 -54.sup.b 
Experiment 2 
Vehicle, s.c. 9.7 .+-. 3.1 
-- 
NDGA 5.7 .+-. 2.1 
41.sup.c 
50 mg/kg, s.c. 
______________________________________ 
.sup.a Mice were pretreated with the compounds indicated one hour prior t 
the i.p. injection of carrageenan, and cellular infiltration was measured 
two hours later as described in the Methods. The data represent mean 
values (.+-. S.D.) derived from measurements on 5 animals in each 
treatment group. 
.sup.b Statistically significant at a P &lt; 0.001. 
.sup.c Statistically significant at a P &lt; 0.01. 
TABLE 3 
______________________________________ 
The Effect of Indomethacin, Naproxen, Levamisole 
and Auranofin on the Infiltration of Polymorpho- 
nuclear Leukocytes into Sites of Carrageenan- 
Induced Inflammation 
Dosage PMN .times. 10.sup.-5 /ml 
Treatment.sup.a 
mg/kg, p.o. (Mean .+-. S.D.) 
% Change 
______________________________________ 
Indomethacin 
10 8.20 .+-. 2.65 
-12.sup.b 
Naproxen 100 10.28 .+-. 2.49 
-11.sup.b 
Levamisole 
100 5.88 .+-. 2.70 
-37.sup.b 
Auranofin 
2 (mg Au/kg) 
7.50 .+-. 1.57 
-6.sup.b 
______________________________________ 
.sup.a Experiments were conducted using the protocol described in Table 1 
The results represent mean values (.+-. S.D.) derived from measurements o 
5 animals/group. Control values for these experiments ranged from 7.8 .+- 
2.59 to 11.49 .+-. 3.56 PMN .times. 10.sup.-5 /ml. 
.sup.b Not statistically significant. 
TABLE 4 
______________________________________ 
The Effect of Compound 1, Phenidone and 
Indomethacin on Carrageenan-Induced 
Cellular Infiltration into the Rat "Air 
Pouch.".sup.a 
Exudate 
Cellular Infiltrate (Total .times. 10.sup.-6) 
Volume PMN/MN 
Treatment 
(ml) PMN.sup.b MN.sup.c 
Ratio 
______________________________________ 
Control 1.8 .+-. 0.8 
6.3 .+-. 4.0.sup. 
2.8 .+-. 0.7 
2.21 .+-. 1.09.sup. 
Phenidone 
1.5 .+-. 0.8 
1.7 .+-. 0.6.sup.d 
3.5 .+-. 1.4 
0.52 .+-. 0.13.sup.d 
(100 mg/kg) 
Compound 1 
1.0 .+-. 0.9 
2.6 .+-. 1.3.sup.d 
.sup. 5.5 .+-. 3.8.sup.e 
0.50 .+-. 0.14.sup.d 
(100 mg/kg) 
Indomethacin 
2.0 .+-. 0.5 
2.8 .+-. 0.7.sup.d 
4.0 .+-. 0.8 
0.69 .+-. 0.19.sup.d 
(5 mg/kg) 
______________________________________ 
.sup.a Cell infiltration was measured 3 hours after injection of 
carrageenan into a preformed air pouch as described in the Methods. The 
results represent mean values (.+-. S.D.) derived from measurements on 8 
animals. 
.sup.b Polymorphonuclear leukocytes. 
.sup.c Mononuclear leukocytes. 
.sup.d Statistically significant at a P &lt; 0.01. 
.sup.e Statistically significant at a P &lt; 0.05. 
TABLE 5 
______________________________________ 
The Effect of Compound 1, Phenidone and 
Indomethacin on Arachidonic Acid-Induced Cellular 
Infiltration into the Rat "Air Pouch.".sup.a 
Exudate 
Cellular Infiltrate (Total .times. 10.sup.-6) 
Volume PMN/MN 
Treatment (ml) PMN.sup.b MN.sup.c 
Ratio 
______________________________________ 
Control 2.8 .+-. 0.7 
4.4 .+-. 3.7.sup. 
9.8 .+-. 4.7.sup. 
0.65 .+-. 0.62 
Compound 1 
2.6 .+-. 0.8 
1.2 .+-. 0.7.sup.e 
1.5 .+-. 1.1.sup.d 
1.20 .+-. 0.88 
(100 mg/kg) 
Phenidone 2.8 .+-. 0.4 
1.3 .+-. 0.8.sup.e 
2.2 .+-. 1.5.sup.d 
0.74 .+-. 0.39 
(100 mg/kg) 
Indomethacin 
2.5 .+-. 0.8 
5.0 .+-. 3.8.sup. 
7.0 .+-. 6.4.sup. 
0.94 .+-. 0.83 
(5 mg/kg) 
______________________________________ 
.sup.a Cell infiltration was measured 3 hours after injection of 
arachidonic acid into a preformed air pouch as described in the Methods. 
The results represent mean values (.+-. S.D.) derived from measurement of 
6 to 8 animals. 
.sup.b Polymorphonuclear leukocytes. 
.sup.c Mononuclear leukocytes. 
.sup.d Statistically significant at a P &lt; 0.01. 
.sup.e Statistically significant at a P &lt; 0.05. 
TABLE 6 
______________________________________ 
The Effect of Compound 1, Phenidone and 
Indomethacin on Arachidonic Acid-Induced Rat Paw 
Edema..sup.a 
Change in Paw Volume (ml) 
Treatment (% Inhibition) 
______________________________________ 
Control 0.27 .+-. 0.05.sup. 
Compound 1 0.06 .+-. 0.05.sup.b 
(100 mg/kg) (78) 
Phenidone 0.13 .+-. 0.05.sup.b 
(100 mg/kg) (52) 
Indomethacin 
0.29 .+-. 0.06.sup. 
(5 mg/kg) (0) 
______________________________________ 
.sup.a Animals were treated with the indicated compounds one hour before 
subplantar injection of arachidonic acid. The results represent mean 
values (.+-. S.D.) derived from measurements on 8 animals read at 2 hours 
post arachidonic acid injection. 
.sup.b Statistically significant at a P &lt; 0.01. 
TABLE 7 
______________________________________ 
The Effect of Compound 1, Phenidone and Selected 
Compounds on Arachidonic Acid-Induced Inflam- 
mation of the Mouse Ear..sup.a 
Increase in Ear 
Thickness at 
Dose 1 Hour 
Treatment (mg/kg, p.o.) 
(.times. 10-3 cm) 
% Change 
______________________________________ 
Compound 1 50 10.0 .+-. 1.5 
-67.sup.b 
Phenidone 50 12.2 .+-. 1.6 
-57.sup.b 
Dexamethasone 
25 18.2 .+-. 4.1 
-35.sup.c 
Indomethacin 
10 24.4 .+-. 0.8 
-5 
Naproxen 100 26.4 .+-. 2.6 
+3 
Ibuprofen 250 30.8 .+-. 2.0 
+20.sup.b 
______________________________________ 
.sup.a Compounds were administered 15 minutes (dexamethasone was 
pretreated at 2 hrs) before application of arachidonic acid to the ear as 
described in the Methods. The results represent mean values (.+-. S.D.) 
derived from measurements on 5 animals. Control values for these 
experiments ranged from 28.1 .+-. 0.8 to 30.0 .+-. 1.3. 
.sup.b Statistically significant at a P &lt; 0.001. 
.sup.c Statistically significant at a P &lt; 0.0005. 
TABLE 7A 
__________________________________________________________________________ 
The Effect of Compounds of Formula I on Arachidonic Acid-Induced Ear 
Swelling 
##STR22## Formula (I) 
% Inhibition.sup.(a,b) 
Compound of Ear 
Number 
R.sup.1 R X A n Swelling 
__________________________________________________________________________ 
2 4-pyridyl 4-(1-propylamino)phenyl 
S(O)n 
CH.sub.2 
0 23* 
3 4-(pyrrolidin-1-yl)phenyl 
4-(pyrrolidin-1-yl)phenyl 
S(O)n 
CH.sub.2 
0 44*** 
4 4-(piperidin-1-yl)phenyl 
4-(piperidin-1-yl)phenyl 
S(O)n 
CH.sub.2 
0 22* 
5 4-pyridyl 3,4-(methylenedioxy)phenyl 
S(O)n 
CH.sub.2 
0 NS 
6 4-fluorophenyl 4-dimethylaminophenyl 
S(O)n 
CH.sub.2 
0 48*** 
7 3,4-(methylenedioxy)phenyl 
4-pyridyl S(O)n 
CH.sub.2 
0 62*** 
8 4-fluorophenyl 4-fluorophenyl CH.sub.2 
CH.sub.2 
-- 
40***(p.o.) 
9 4-diethylaminophenyl 
4-diethylaminophenyl 
S(O)n 
CH.sub.2 
0 17* (p.o.) 
10 4-dimethylaminophenyl 
4-fluorophenyl S(O)n 
CH.sub.2 
0 7* 
11 4-pyridyl 4-pyridyl S(O)n 
CH.sub.2 
0 29*** 
12 4-fluorophenyl 4-pyridyl S(O)n 
CH.sub.2 
0 58*** 
13 4-cyanophenyl 4-cyanophenyl S(O)n 
CH.sub.2 
0 50*** 
14 4-fluorophenyl 4-methoxyphenyl 
S(O)n 
CH.sub.2 
0 64*** 
15 4-trifluoromethylphenyl 
4-trifluoromethylphenyl 
S(O)n 
CH.sub.2 
0 NS (p.o.) 
16 3,4-methylenedioxyphenyl 
3,4-methylenedioxyphenyl 
S(O)n 
CH.sub.2 
0 32***(p.o.) 
17 4-ethylaminophenyl 
4-ethylaminophenyl 
S(O)n 
CH.sub.2 
0 38*** 
18 4-pyridyl 4-methoxyphenyl 
S(O)n 
CH.sub.2 
0 40***(p.o.) 
19 4-fluorophenyl 4-fluorophenyl S(O)n 
CH.sub.2 
0 34***(p.o.) 
20 4-methoxyphenyl 
4-methoxyphenyl 
S(O)n 
CH.sub.2 CH.sub.2 
0 47*** 
21 4-methoxyphenyl 
4-methoxyphenyl 
S(O)n 
CH.sub.2 
-- 
NS (p.o.) 
22 4-methoxyphenyl 
4-methoxyphenyl 
CH.sub.2 
CH.sub.2 
-- 
15* 
23 2-pyridyl 4-fluorophenyl S(O)n 
CH.sub.2 
0 65*** 
24 4-fluorophenyl 2-pyridyl S(O)n 
CH.sub.2 
0 69*** 
25 4-pyridyl 4-(pyrrolidin-1-yl)phenyl 
S(O)n 
CH.sub.2 
0 17* (p.o.) 
26 4-fluorophenyl 4-fluorophenyl(hydrate) 
S(O)n 
CH.sub.2 
0 NT 
27 4-fluoromethylphenyl 
4-trifluoromethylphenyl 
S(O)n 
CH.sub.2 
0 NT 
(hydrate) 
28 4-pyridyl 4-fluorophenyl S(O)n 
CH.sub.2 
1 69*** 
29 4-pyridyl 4-fluorophenyl S(O)n 
CH.sub.2 
2 67*** (p.o.) 
30 4-fluorophenyl 4-fluorophenyl S(O)n 
CH.sub.2 
1 NT 
31 4-fluorophenyl 4-fluorophenyl S(O)n 
CH.sub.2 
2 NT 
32 4-methylthiophenyl 
4-methylthiophenyl 
S(O)n 
CH.sub.2 
0 NS (p.o.) 
33 phenyl phenyl S(O)n 
CH.sub.2 
0 NT 
34 4-methylphenyl 4-methylphenyl S(O)n 
CH.sub.2 
0 NT 
35 4-(prop-2-ene-1-oxy)phenyl 
4-(prop-2-ene-1-oxy)phenyl 
S(O)n 
CH.sub.2 
0 NT 
36 4-(2,2,2-trifluoroethoxy) 
4-(2,2,2-trifluoroethyoxy) 
S(O)n 
CH.sub.2 
0 NT 
phenyl phenyl 
37 3,4,5-trimethoxyphenyl 
3,4,5-trimethoxyphenyl 
S(O)n 
CH.sub.2 
0 NT 
38 4-pyridyl 4-acetamidophenyl 
S(O)n 
CH.sub.2 
0 NT 
__________________________________________________________________________ 
.sup.a) Screened at 50 mg/kg s.c. or i.p. unless indicated as oral dosing 
(p.o.). 
.sup.b) * = p .05, ** = p .01, ***p .001, NS = not siginificant, NT = not 
tested 
TABLE 8 
______________________________________ 
The Effect of Compound 1, Phenidone and 
Indomethacin on Cyclooxygenase and 
5-Lipoxygenase Activities in RBL-1 Cells..sup.a 
IC.sub.50 (mM) 
Treatment Cyclooxygenase 
5-Lipoxygenase 
______________________________________ 
Compound 1 100 75 
Phenidone Inactive @ 100 
10 
Indomethacin &gt;2.5 Inactive @ 30 
______________________________________ 
aEnzyme activities were measured by the amount of PGD.sub.2 and 5HETE 
produced from .sup.14 Clabeled arachidonic acid incubated with the 10,000 
.times. g supernatant of RBL1 cells as described in the Methods. 
TABLE 8A 
__________________________________________________________________________ 
The Effect of Compounds of Formula I on 5-HETE Production 
##STR23## Formula (I) 
Compound 5-HETE.sup.a b 
Number 
R.sup.1 R X A n IC.sub.50 
__________________________________________________________________________ 
(.mu.M) 
2 4-pyridyl 4-(1-propylamino)phenyl 
S(O)n 
CH.sub.2 
0 12 
3 4-(pyrrolidin-1-yl)phenyl 
4-(pyrrolidin-1-yl)phenyl 
S(O)n 
CH.sub.2 
0 .23 
4 4-(piperidin-1-yl)phenyl 
4-(piperidin-1-yl)phenyl 
S(O)n 
CH.sub.2 
0 1.2 
5 4-pyridyl 3,4-(methylenedioxy)phenyl 
S(O)n 
CH.sub.2 
0 10 
6 4-fluorophenyl 4-dimethylaminophenyl 
S(O)n 
CH.sub.2 
0 .80 
7 3,4-(methylenedioxy)phenyl 
4-pyridyl S(O)n 
CH.sub.2 
0 10 
8 4-fluorophenyl 4-fluorophenyl CH.sub.2 
CH.sub.2 
-- 
12 
9 4-diethylaminophenyl 
4-diethylaminophenyl 
S(O)n 
CH.sub.2 
0 .35 
10 4-dimethylaminophenyl 
4-fluorophenyl S(O)n 
CH.sub.2 
0 5 
11 4-pyridyl 4-pyridyl S(O)n 
CH.sub.2 
0 110 
12 4-fluorophenyl 4-pyridyl S(O)n 
CH.sub.2 
0 16 
13 4-cyanophenyl 4-cyanophenyl S(O)n 
CH.sub.2 
0 16 
14 4-fluorophenyl 4-methoxyphenyl 
S(O)n 
CH.sub.2 
0 2 
15 4-trifluoromethylphenyl 
4-trifluoromethylphenyl 
S(O)n 
CH.sub.2 
0 10 
16 3,4-methylenedioxyphenyl 
3,4-methylenedioxyphenyl 
S(O)n 
CH.sub.2 
0 3.8 
17 4-ethylaminophenyl 
4-ethylaminophenyl 
S(O)n 
CH.sub.2 
0 .10 
18 4-pyridyl 4-methoxyphenyl 
S(O)n 
CH.sub.2 
0 5.4 
19 4-fluorophenyl 4-fluorophenyl S(O)n 
CH.sub.2 
0 8.6 
20 4-methoxyphenyl 
4-methoxyphenyl 
S(O)n 
CH.sub.2 CH.sub.2 
0 5.6 
21 4-methoxyphenyl 
4-methoxyphenyl 
S(O)n 
CH.sub.2 
0 3.9 
22 4-methoxyphenyl 
4-methoxyphenyl 
CH.sub.2 
CH.sub.2 
0 4.0 
23 2-pyridyl 4-fluorophenyl S(O)n 
CH.sub.2 
0 90 
24 4-fluorophenyl 2-pyridyl S(O)n 
CH.sub.2 
0 37 
25 4-pyridyl 4-(pyrrolidin-1-yl)phenyl 
S(O)n 
CH.sub.2 
0 .5 
26 4-fluorophenyl 4-fluorophenyl(hydrate) 
S(O)n 
CH.sub.2 
0 &gt;10(C) 
27 4-trifluoromethylphenyl 
4-trifluoromethylphenyl 
S(O)n 
CH.sub.2 
0 28 
(hydrate) 
28 4-pyridyl 4-fluorophenyl S(O)n 
CH.sub.2 
1 1000 
29 4-pyridyl 4-fluorophenyl S(O)n 
CH.sub.2 
2 100 
30 4-fluorophenyl 4-fluorophenyl S(O)n 
CH.sub.2 
1 70 
31 4-fluorophenyl 4-fluorophenyl S(O)n 
CH.sub.2 
2 33 
32 4-methylthiophenyl 
4-methylthiophenyl 
S(O)n 
CH.sub.2 
0 &gt;10(D) 
33 phenyl phenyl S(O)n 
CH.sub.2 
0 NT 
34 4-methylphenyl 4-methylphenyl S(O)n 
CH.sub.2 
0 NT 
35 4-(prop-2-ene-1-oxy)phenyl 
4-(prop-2-ene-1-oxy)phenyl 
S(O)n 
CH.sub.2 
0 NT 
36 4-(2,2,2-trifluoroethoxy)phenyl 
4-(2,2,2-trifluoroethoxy) 
S(O)n 
CH.sub.2 
0 NT 
phenyl 
37 3,4,5-trimethoxyphenyl 
3,4,5-trimethoxyphenyl 
S(O)n 
CH.sub. 2 
0 NT 
38 4-pyridyl 4-acetamidophenyl 
S(O)n 
CH.sub.2 
0 69 
__________________________________________________________________________ 
.sup.a IC.sub.50 determined on 5HETE reduction by RBL1 high speed 
supernatant 
.sup.b NT = not tested 
(C) 46% inhibition at 10 .mu.M 
(D) 35-40% inhibition at 10 .mu.M 
TABLE 9 
______________________________________ 
The Effect of Compound 1 on the Production of 
Di-HETE and 5-HETE by the High Speed 
Supernatant of RBL-1 Cells..sup.a 
Di-HETE % 5-HETE % 
Treatment 
(nM/ml) Control (nM/ml) Control 
______________________________________ 
Control 1.94 .+-. 0.11 
-- 10.15 .+-. 0.65 
-- 
Compound 1 
1 .mu.M 1.56 .+-. 0.06 
19.7.sup.b 
8.86 .+-. 0.31 
12.7.sup.b 
3.3 .mu.M 
1.34 .+-. 0.12 
30.9.sup.b 
7.63 .+-. 0.44 
24.9.sup.b 
10 .mu.M 
0.88 .+-. 0.21 
54.8.sup.b 
5.57 .+-. 0.35 
45.1.sup.b 
33 .mu.M 
0.40 .+-. 0.08 
79.6.sup.b 
3.36 .+-. 0.07 
67.9.sup.b 
100 .mu.M 
0.03 .+-. 0.04 
98.3.sup.b 
1.08 .+-. 0.13 
89.4.sup.b 
______________________________________ 
.sup.a Enzyme activities were measured by the production of 5HETE and 
DiHETE from .sup.14 Clabeled arachidonic acid incubated with a high speed 
supernatant of RBL1 cells (see Methods for details). The results represen 
mean values (.+-. S.D.) derived from measurements on 4 replicate analyses 
.sup.b Statistically significant from Control at a P &lt; 0.01 or better. 
TABLE 9A 
__________________________________________________________________________ 
The Effect of Compounds of Formula I on Lipoxygenase Activity 
(LTB.sub.4 Production) 
##STR24## Formula (I) 
Compound 5-LO.sup.(a)(b) 
Number 
R.sup.1 R A X n IC.sub.50 (.mu.M) 
__________________________________________________________________________ 
2 4-pyridyl 4-(1-propyl)aminophenyl 
CH.sub.2 
S(O)n 
0 7 
3 4-(pyrrolidin-1-yl)phenyl 
4-(pyrrolidin-1-yl)phenyl 
CH.sub.2 
S(O)n 
0 0.1 
4 4-(piperidin-1-yl)phenyl 
4-(piperidin-1-yl)phenyl 
CH.sub.2 
S(O)n 
0 0.6 
5 4-pyridyl 3,4-(methylenedioxy)phenyl 
CH.sub.2 
S(O)n 
0 10.0 
6 4-fluorophenyl 4-dimethylaminophenyl 
CH.sub.2 
S(O)n 
0 0.6 
7 3,4-(methylenedioxy)phenyl 
4-pyridyl CH.sub.2 
S(O)n 
0 10.0 
8 4-fluorophenyl 4-fluorophenyl 
CH.sub.2 
S(O)n 8.0 
9 4-diethylaminophenyl 
4-diethylaminophenyl 
CH.sub.2 
S(O)n 
0 0.16 
10 4-dimethylaminophenyl 
4-fluorophenyl 
CH.sub.2 
S(O)n 
0 1.5 
11 4-pyridyl 4-pyridyl CH.sub.2 
S(O)n 
0 33.0 
12 4-fluorophenyl 4-pyridyl CH.sub.2 
S(O)n 
0 17.0 
13 4-cyanophenyl 4-cyanophenyl CH.sub.2 
S(O)n 
0 15.0 
14 4-fluorophenyl 4-methoxyphenyl 
CH.sub.2 
S(O)n 
0 0.6 
15 4-trifluoromethylphenyl 
4-trifluoromethylphenyl 
CH.sub.2 
S(O)n 
0 10.0 
16 3,4-methylenedioxyphenyl 
3,4-methylenedioxyphenyl 
CH.sub.2 
S(O)n 
0 1.5 
17 4-ethylaminophenyl 
4-ethylaminophenyl 
CH.sub.2 
S(O)n 
0 0.1 
18 4-pyridyl 4-methoxyphenyl 
CH.sub.2 
S(O)n 
0 1.9 
19 4-fluorophenyl 4-fluorophenyl 
CH.sub.2 
S(O)n 
0 5.0 
20 4-methoxyphenyl- 
4-methoxyphenyl 
CH.sub.2 CH.sub.2 
S(O)n 
0 5.6 
21 4-methoxyphenyl 
4-methoxyphenyl 
CH.sub.2 
S(O)n 
0 2.8 
22 4-methoxyphenyl 
4-methoxyphenyl 
CH.sub.2 
CH.sub.2 
NT 
23 2-pyridyl 4-fluorophenyl 
CH.sub.2 
S(O)n 
0 42 
24 4-fluorophenyl 2-pyridyl CH.sub.2 
S(O)n 
0 20 
25 4-pyridyl 4-(pyrrolidin-1-yl)phenyl 
CH.sub.2 
S(O)n 
0 0.5 
26 4-fluorophenyl 4-fluorophenyl(hydrate) 
CH.sub.2 
S(O)n 
0 &gt;10 
27 4-trifluoromethylphenyl 
4-trifluoromethylphenyl 
CH.sub.2 
S(O)n 
0 NT 
(hydrate) 
28 4-pyridyl 4-fluorophenyl 
CH.sub.2 
S(O)n 
1 1000 
29 4-pyridyl 4-fluorophenyl 
CH.sub.2 
S(O)n 
2 &gt;100 
30 4-fluorophenyl 4-fluorophenyl 
CH.sub.2 
S(O)n 
1 60 
31 4-fluorophenyl 4-fluorophenyl 
CH.sub.2 
S(O)n 
2 &lt;33 
32 4-methylthiophenyl 
4-methylthiophenyl 
CH.sub.2 
S(O)n 
0 &gt;100 
33 phenyl phenyl CH.sub.2 
S(O)n 
0 NT 
34 4-methylphenyl 4-methylphenyl 
CH.sub.2 
S(O)n 
0 NT 
35 4-(prop-2-ene-oxy)phenyl 
4-(prop-2-ene-oxy)phenyl 
CH.sub.2 
S(O)n 
0 NT 
36 4-(2,2,2-trifluoroethoxy)phenyl 
4-(2,2,2-trifluoroethoxy) 
CH.sub.2 
S(O)n 
0 NT 
phenyl 
37 3,4,5-trimethoxyphenyl 
3,4,5-trimethoxyphenyl 
CH.sub.2 
S(O)n 
0 NT 
38 4-pyridyl 4-acetamidophenyl 
CH.sub.2 
S(O)n 
0 30 
__________________________________________________________________________ 
.sup.(a) IC.sub.50 determined on LTB.sub.4 production by RBL.sup.-1 high 
speed supernatant. 
.sup.(b) Not tested 
TABLE 10 
______________________________________ 
The Effect of Compound 1, Indomethacin, 
Ibuprofen, Naproxen and Phenidone on the 
Production of PGE.sub.2 by Mouse Peritoneal 
Exudate Cells 
Compound IC.sub.50 (.mu.M) 
______________________________________ 
Compound 1 0.7 
Indomethacin 0.04 
Ibuprofen 0.5 
Naproxen 1.8 
Phenidone 28.0 
______________________________________ 
.sup.a Release of PGE.sub.2 was measured by RIA of cell free supernatants 
from LPSstimulated, C. parvum-elicited peritoneal exudate cells as 
described in the Methods. 
TABLE 11 
______________________________________ 
The Effect of Compound 1 on the Production of 
LTB.sub.4 by Peritoneal Exudate Cells from Animals 
Treated with Anti-Inflammatory Agents 
% Inhibition of 
LTB.sub.4 
Synthesis.sup.a 
Experiment: 
Treatment 1 2 3 
______________________________________ 
Compound 1 (100 mg/kg/p.o.) 
90 23 100 
Phenidone (200 mg/kg/p.o.) 21 33 
Naproxen (50 mg/kg/p.o.) 
0 15 0 
______________________________________ 
.sup.a Peritoneal exudate cells, harvested from control and drugtreated 
mice, were incubated in vitro with the calcium ionophore A23187 to 
stimulate LTB.sub.4 production as described in the Methods. The results 
are expressed as the percentage inhibition of LTB.sub.4 production in 
cells from drugtreated animals versus untreated control animals. 
Measurements were made on ten animals in each group for each experiment. 
Cells not exposed to A23187 did not release detectable LTB.sub.4. 
TABLE 12 
______________________________________ 
Effect of Compound 1 on Hindleg Paralysis in 
Experimental Allergic Encephalomyelitis Induced 
in Lewis Female Rats 
HINDLEG ALYSIS - 
COMPOUND CUMULATIVE INCIDENCE 
(DOSE)* DAY 9 TO 13 DAY 14 TO 18 
______________________________________ 
Compound 1 10/12 0/11** 
(60) 
INDOMETHACIN 6/11 10/11 
(2) 
METHOTREXATE 0/11** 0/11** 
(0.3) 
CONTROL 12/16 14/16 
______________________________________ 
*Mg/kg/day, p.o. days 0-4, 7-11, 14-18. 
**Significantly different from control (p &lt; 0.01). 
TABLE 13 
__________________________________________________________________________ 
Effect of Compounds of Formula (I) in Inhibiting LTC.sub.4 Production 
##STR25## Formula I 
Compound IC.sub.50.sup.(a)(b) 
Number 
R.sup.1 R A X n (.mu.M) 
__________________________________________________________________________ 
1 4-pyridyl 4-fluorophenyl CH.sub.2 
S(O)n 
0 1.8.sup.(c) 
2 4-pyridyl 4-(1-propyl)aminophenyl 
CH.sub.2 
S(O)n 
0 NT 
3 4-(pyrrolidin-1-yl)phenyl 
4-(pyrrolidin-1-yl)phenyl 
CH.sub.2 
S(O)n 
0 NT 
4 4-(piperidin-1-yl)phenyl 
4-(piperidin-1-yl)phenyl 
CH.sub.2 
S(O)n 
0 NT 
5 4-pyridyl 3,4-(methylenedioxy)phenyl 
CH.sub.2 
S(O)n 
0 NT 
6 4-fluorophenyl 4-dimethylaminophenyl 
CH.sub.2 
S(O)n 
0 NT 
7 3,4-(methylenedioxy)phenyl 
4-pyridyl CH.sub.2 
S(O)n 
0 NT 
8 4-fluorophenyl 4-fluorophenyl CH.sub.2 
CH.sub.2 
0 NT 
9 4-dimethylaminophenyl 
4-diethylaminophenyl 
CH.sub.2 
S(O)n 
0 NT 
10 4-dimethylaminophenyl 
4-fluorophenyl CH.sub.2 
S(O)n 
0 NT 
11 4-pyridyl 4-pyridyl CH.sub.2 
S(O)n 
0 NT 
12 4-fluorophenyl 4-pyridyl CH.sub.2 
S(O)n 
0 NS 
13 4-cyanophenyl 4-cyanophenyl CH.sub.2 
S(O)n 
0 NT 
14 4-fluorophenyl 4-methoxyphenyl 
CH.sub.2 
S(O)n 
0 NT 
15 4-trifluoromethylphenyl 
4-trifluoromethylphenyl 
CH.sub.2 
S(O)n 
0 NT 
16 3,4-methylenedioxyphenyl 
3,4-methylenedioxyphenyl 
CH.sub.2 
S(O)n 
0 NT 
17 4-ethylaminophenyl 
4-ethylaminophenyl 
CH.sub.2 
S(O)n 
0 1.2 
18 4-pyridyl 4-methoxyphenyl 
CH.sub.2 
S(O)n 
0 9.9 
19 4-fluorophenyl 4-fluorophenyl CH.sub.2 
S(O)n 
0 NT 
20 4-methoxyphenyl- 
4-methoxyphenyl 
CH.sub.2 
S(O)n 
0 NT 
21 4-methoxyphenyl 
4-methoxyphenyl 
CH.sub.2 
S(O)n 
0 NT 
22 4-methoxyphenyl 
4-methoxyphenyl 
CH.sub.2 
CH.sub.2 
0 NT 
23 4-pyridyl 4-(pyrrolidin-1-yl)phenyl 
CH.sub.2 
S(O)n 
0 NT 
24 4-fluorophenyl 4-fluorophenyl(hydrate) 
CH.sub.2 
S(O)n 
0 NT 
25 4-trifluoromethylphenyl 
4-trifluoromethylphenyl 
CH.sub.2 
S(O)n 
0 NT 
(hydrate) 
26 2-pyridyl 4-fluorophenyl CH.sub.2 
S(O)n 
0 NT 
27 4-fluorophenyl 2-pyridyl CH.sub.2 
S(O)n 
0 NT 
28 4-pyridyl 4-fluorophenyl CH.sub.2 
S(O)n 
1 0.5 
29 4-pyridyl 4-fluorophenyl CH.sub.2 
S(O)n 
2 0.5 
30 4-fluorophenyl 4-fluorophenyl CH.sub.2 
S(O)n 
1 NT 
31 4-fluorophenyl 4-fluorophenyl CH.sub.2 
S(O)n 
2 NT 
32 4-methylthiophenyl 
4-methylthiophenyl 
CH.sub.2 
S(O)n 
0 NT 
33 phenyl phenyl CH.sub.2 
S(O)n 
0 NT 
34 4-methylphenyl 4-methylphenyl CH.sub.2 
S(O)n 
0 NT 
35 4-(prop-2-ene-oxy)phenyl 
4-(prop-2-ene-oxy)phenyl 
CH.sub.2 
S(O)n 
0 NT 
36 4-(2,2,2-trifluoroethoxy)phenyl 
4-(2,2,2-trifluoroethoxy) 
CH.sub.2 
S(O)n 
0 NT 
phenyl 
37 3,4,5-trimethoxyphenyl 
3,4,5-trimethoxyphenyl 
CH.sub.2 
S(O)n 
0 NT 
38 4-pyridyl 4-acetamedophenyl 
CH.sub.2 
S(O)n 
0 NT 
__________________________________________________________________________ 
.sup.(a) NT = not tested; NS = not significant 
.sup.(b) IC.sub.50 determined on LTB.sub.4 production by human monocytes 
.sup.(c) average value based on 4 separate tests 
COMPOSITION EXAMPLES 
Example A 
Capsule Composition 
A pharmaceutical composition of this invention in the form of a capsule is 
prepared by filling a standard two-piece hard gelatin capsule with 50 mg 
of a compound of Formula (IC), in powdered form, 110 mg of lactose, 32 mg 
of talc and 8 mg of magnesium stearate. 
Example B 
Injectable Parenteral Composition 
A pharmaceutical composition of this invention in a form suitable for 
administration by injection is prepared by stirring 1.5% by weight of a 
compound of Formula (IC) in 10% by volume propylene glycol and water. The 
solution is sterilized by filtration. 
Example C 
Ointment Composition 
Compound of Formula (IC) 1.0 g 
White soft paraffin to 100.0 g 
The compound of Formula (IC) is dispersed in a small volume of the vehicle 
and gradually incorporated into the bulk of the vehicle to produce a 
smooth, homogeneous product. Collapsible metal tubes are then filled with 
the dispersion. 
Example D 
Topical Cream Composition 
Compound of Formula (IC) 1.0 g 
Polawax GP 200 20.0 g 
Lanolin Anhydrous 2.0 g 
White Beeswax 2.5 g 
Methyl hydroxybenzoate 0.1 g 
Distilled Water to 100.0 g 
The polawax, beeswax and lanolin are heated together at 60.degree. C. A 
solution of methyl hydroxybenzoate is added and homogenization is achieved 
using high speed stirring. The temperature is then allowed to fall to 
50.degree. C. The compound of Formula (IC) is then added and dispersed 
throughout, and the composition is allowed to cool with slow speed 
stirring. 
Example E 
Topical Lotion Composition 
Compound of Formula (IC) 1.0 g 
Sorbitan Monolaurate 0.6 g 
Polysorbate 20 0.6 g 
Cetostearyl Alcohol 1.2 g 
Glycerin 6.0 g 
Methyl Hydroxybenzoate 0.2 g 
Purified Water B.P. to 100.00 ml 
The methyl hydroxybenzoate and glycerin are dissolved in 70 ml of the water 
at 75.degree.. The sorbitan monolaurate, polysorbate 20 and cetostearyl 
alcohol are melted together at 75.degree. C. and added to the aqueous 
solution. The resulting emulsion is homogenized, allowed to cool with 
continuous stirring and the compound of Formula (IC) is added as a 
suspension in the remaining water. The whole suspension is stirred until 
homogenized. 
Example F 
Eye Drop Composition 
Compound of Formula (IC) 0.5 g 
Methyl Hydroxybenzoate 0.01 g 
Propyl Hydroxybenzoate 0.04 g 
Purified Water B.P. to 100.00 ml 
The methyl and propyl hydroxybenzoates are dissolved in 70 ml purified 
water at 75.degree. C. and the resulting solution is allowed to cool. The 
compound of Formula (IC) is then added, and the solution is made up to 100 
ml with purified water. The solution is sterilized by filtration through a 
membrane filter (0.22 mu m pore size) and packed aseptically into suitable 
sterile containers. 
Example G 
Composition for Administration by Inhalation 
For an aerosol container with a capacity of 15-20 ml: Mix 10 mg of a 
compound of Formula (IC) with 0.1-0.2% of a lubricating agent, such as 
Span 85 or oleic acid, and disperse such mixture in a propellant (c.a.), 
such as freon, preferably in a combination of freon 114 and freon 12, and 
put into an appropriate aerosol container adapted for either intranasal or 
oral inhalation administration. 
Example H 
Composition for Administration by Inhalation 
For an aerosol container with a capacity of 15-20 ml: Dissolve 10 mg of a 
compound of Formula (IC) in ethanol (6-8 ml), add 0.1-0.2% of a 
lubricating agent, such as Span 85 or oleic acid; and disperse such in a 
propellant (c.a.), such as freon, preferably a combination of freon 114 
and freon 12, and put into an appropriate aerosol container adapted for 
either intranasal or oral inhalation administration.