Compounds of the Formula I: ##STR1## are inhibitors of the mammalian 5-lipoxygenase enzyme system of the arachidonic acid cascade. As such, these compounds are useful therapeutic agents for treating allergic conditions, asthma, cardiovascular disorders and inflammation.

This invention is directed to inhibitors of the 5-lipoxygenase enzyme 
system of the arachidonic acid cascade. Inhibition of 5-lipoxygenase 
prevents the biosynthesis of the leukotrienes. 
The leukotrienes are a novel group of biologically active mediators derived 
from arachidonic acid through the action of lipoxygenase enzyme systems. 
There are two groups of leukotrienes derived from the common unstable 
precursor Leukotriene A.sub.4. The first of these are the peptido-lipid 
leukotrienes, the most important being Leukotrienes C.sub.4 and D.sub.4. 
These compounds collectively account for the biologically active material 
known as the slow reacting substance of anaphylaxis. 
The leukotrienes are potent smooth muscle contracting agents, particularly 
on respiratory smooth muscle but also on other tissues (e.g. gall 
bladder). In addition, they promote mucous production, modulate vascular 
permeability changes and are potent inflammatory agents in human skin. The 
most important compound in the second group of leukotrienes is Leukotriene 
B.sub.4, a dihydroxy fatty acid. This compound is a potent chemotactic 
agent for neutrophils and eosinophils and in addition, may modulate a 
number of other functions of these cells. It also effects other cell types 
such as lymphocytes and for example may modulate the action of 
T-suppressor cells and natural killer cells. When injected in vivo, in 
addition to promoting the accumulation of leukocytes, Leukotriene B.sub.4 
is also a potent hyperalgesic agent and can modulate vascular permeability 
changes through a neutrophil dependent mechanism. Both groups of 
leukotrienes are formed following oxygenation of arachidonic acid through 
the action of a 5-lipoxygenase enzyme. See for example, D. M. Bailey et 
al., Ann. Rpts. Med. Chem. 17 203 (1982). 
The leukotrienes are potent spasmogens of human trachea, bronchus and lung 
parenchymal strips, and when administered to normal volunteers as aerosols 
are 3,800 times more potent that histamine at inducing a 50% decrease in 
air flow at 30% of vital capacity. They mediate increases in vascular 
permeability in animals and promote mucous production in human bronchial 
explants. In addition, Leukotriene B.sub.4 may also mediate mucous 
production and could be an important mediator of neutrophil and eosinophil 
accumulation in asthamatic lungs. 5-Lipoxygenase products are also thought 
to be regulators of mast cell degranulation and recent studies with human 
lung mast cells have suggested that 5-lipoxygenase inhibitors, but not 
corticosteroids, may suppress antigen-induced mast cell degranulation. In 
vitro studies have shown that antigen challenge of human lung results in 
the release of leukotrienes and in addition purified human mast cells can 
produce substantial amount of leukotrienes. There is therefore good 
evidence that leukotrienes are important mediators of human asthma. 
5-Lipoxygenase inhibitors would therefore be a new class of drugs for the 
treatment of asthma. 
Psoriasis is a human skin disease which effects between two and six percent 
of the population. There is no adequate therapy for psoriasis and related 
skin conditions. The evidence for leukotriene involvement in these 
diseases is as follows. One of the earliest events in the development of 
prepapillary lesions is the recruitment of leukocytes to the skin site. 
Injection of Leukotriene B.sub.4 into human skin results in a pronounced 
neutrophil accumulation. There are gross abnormalities in arachidonic acid 
metabolism in human psoriatic skin. In particular, highly elevated levels 
of free arachidonic acid can be measured as well as large amount of 
lipoxygenase products. Leukotriene B.sub.4 has been deteected in psoriatic 
lesions, but not in uninvolved skin, in biologically significant amounts. 
Leukotrienes can be measured in nasal washings from patients with allergic 
rhinitis and are greatly elevated following antigen challenge. 
Leukotrienes may mediate this disease through their ability to regulate 
mast cell degranulation, by modulating mucous production and mucocillary 
clearance and by mediating the accumulation of inflammatory leukocytes. 
Leukotrienes can also mediate other diseases. These include atopic 
dermatitis, gouty arthritis and gall bladder spasms. In addition, they may 
have a role in cardiovascular disease because leukotrienes C.sub.4 and 
D.sub.4 act as coronary and cerebral arterial vasoconstrictors and these 
compounds may also have negative inotropic effects on the myocardium. In 
addition, the leukotrienes are important mediators of inflammatory 
diseases through their ability to modulate leukocyte and lymphocyte 
function. See, for example, B. Samuelson, Science, 220, 568 (1983). 
Several compounds having the Formula A (especially wherein Z=S) are taught 
in the literature as pesticides and herbicides: 
##STR2## 
see for example: S. D. Carter et al., Tetrahedron 33 827 (1977); G. W. H. 
Cheeseman et al., Tetrahedron 36 2681 (1980); C. O. Okafor, Het. Chem. 18 
405-407 and 1445-1449 (1981); and U.S. Pat. Nos. 3,663,543; 3,746,707; 
3,808,208; 3,821,213 and 3,845,044. None of the compounds of Formula A are 
taught to have 5-lipoxygenase inhibiting properties. 
It has been discovered that compounds of the Formula A are effective 
inhibitors of leukotriene biosynthesis via inhibition of the mammalian 
5-lipoxygenase enzyme system. Thus, these compounds are useful therapeutic 
agents for treating conditions such as asthma, allergies, cardiovascular 
disorders such as angina and inflammation, and skin diseases such as 
psoriasis. 
The compounds of the present invention may also be used to treat or prevent 
mammalian (especially human) disease states such as erosive gastritis; 
erosive esophagitis; inflammatory bowel disease; ethanol-induced 
hemorrhagic erosions; hepatic ischemia; noxious agent induced damage or 
necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver 
parenchymal damage caused by hepatoxic agents such as CCl.sub.4 and 
D-galactosamine; ischemic renal failure; disease-induced hepatic damage; 
bile salt incuded pancreatic or gastric damage; trauma- or stress-induced 
cell damage; and glycerol-induced renal failure. 
The present invention relates to pharmaceutical compositions containing a 
compound of the Formula I: 
##STR3## 
or a pharmaceutically acceptable salt thereof, a method of treatment using 
said composition and novel compounds encompassed by Formula I. 
One embodiment of the present invention is a pharmaceutical composition 
useful for inhibiting leukotriene biosynthesis or action containing a 
compound of the Formula I: 
##STR4## 
or a pharmaceutically acceptable salt thereof and a pharmaceutically 
acceptable carrier, wherein: 
Z is O, NCN, S, SO or SO.sub.2 ; 
R.sub.1 is H, C.sub.1 to C.sub.6 alkyl, benzyl, C.sub.1 to C.sub.6 acyl, 
C.sub.1 to C.sub.6 lower aminoacyl, C.sub.1 to C.sub.6 
alkylacyloxy-C.sub.1 to C.sub.6 alkyl (for example, 
--CH(CH.sub.3)OCOC(CH.sub.3).sub.3), C.sub.1 to C.sub.6 alkoxy-C.sub.1 to 
C.sub.6 alkyl (for example, --CH(CH.sub.3)OC.sub.2 H.sub.5), 
--(CH.sub.2).sub.n COOR.sub.6 wherein n is 0 to 4, CN, C.sub.1 to C.sub.6 
alkylacyloxy-C.sub.1 to C.sub.6 alkoxycarbonyl (e.g. --COOCH(O.sub.2 
CCH.sub.3)CH.sub.3), --C(R.sub.7).dbd.C(R.sub.7)COOR.sub.6 or SO.sub.2 
R.sub.10 ; R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are each independently 
selected from: 
(1) hydrogen; 
(2) C.sub.1 to C.sub.6 alkyl; 
(3) C.sub.2 to C.sub.6 alkenyl; 
(4) --(CH.sub.2).sub.n M wherein: 
n is 0 to 6 and 
M is 
(a) OR.sub.16 ; 
(b) halogen; 
(c) CF.sub.3 ; 
(d) SR.sub.16 ; 
(e) phenyl; 
(f) substituted phenyl wherein substituted phenyl is as defined in the 
definition of R.sub.16 ; 
(g) COOR.sub.6 ; 
(h) 
##STR5## 
(i) tetrazole; (j) 
##STR6## 
(k) NR.sub.8 R.sub.9 ; (l) NHSO.sub.2 R.sub.10 ; 
(m) 
##STR7## 
(n) SOR.sub.11 wherein R.sub.11 is C.sub.1 to C.sub.6 alkyl, phenyl, 
substituted phenyl wherein substituted phenyl is as defined in the 
definition of R.sub.16, (CH.sub.2).sub.m COOR.sub.6 wherein m is 1 to 6, 
or CF.sub.3 ; 
(o) CONR.sub.8 R.sub.9 ; 
(p) SO.sub.2 NR.sub.8 R.sub.9 ; 
(q) SO.sub.2 R.sub.13 wherein R.sub.13 is OH, C.sub.1 to C.sub.6 alkyl, H, 
phenyl, substituted phenyl wherein substituted phenyl is as defined in the 
definition of R.sub.16, (CH.sub.2).sub.m COOR.sub.6 wherein m is 1 to 6, 
or CF.sub.3 ; 
(r) NO.sub.2 ; 
(s) 
##STR8## 
(t) 
##STR9## 
(u) 
##STR10## 
(v) --CN: each R.sub.16 is independently H; C.sub.1 to C.sub.6 
-alkoxy-C.sub.1 to C.sub.6 alkyl; C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 
to C.sub.6 alkyl; C.sub.1 to C.sub.6 alkyl; substituted phenyl wherein the 
substituents are C.sub.1 to C.sub.3 alkyl, halogen, CN, C.sub.1 to C.sub.3 
alkoxy, OH, (CH.sub.2).sub.n NR.sub.8 R.sub.9 wherein n is 0 to 2, 
CF.sub.3, COOR.sub.6, CH.sub.2 COOR.sub.6 ; --(CH.sub.2).sub.m COOR.sub.6 
wherein m is 0 to 6; CN: C.sub.1 to C.sub.5 alkylacyl; C.sub.1 to C.sub.4 
perfluoroalkyl; phenyl; benzyl; or CH.sub.2 --R.sub.12 wherein R.sub.12 is 
C.sub.1 to C.sub.5 alkyldimethylamino; 
each R.sub.6 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl or 
phenyl; 
each R.sub.14 is independently H, C.sub.1 to C.sub.6 
alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to 
C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxy, 
(CH.sub.2).sub.n COOR.sub.6 wherein n is 0 to 4, phenyl, substituted phenyl 
wherein substituted phenyl is as defined in the definition of R.sub.16, or 
is such that R.sub.14 COOH is an essential amino acid; 
each R.sub.8 and R.sub.9 is independently H, phenyl, substituted phenyl 
wherein substituted phenyl is as defined in the definition of R.sub.16, or 
C.sub.1 to C.sub.4 alkyl, or R.sub.8 and R.sub.9 may be joined through the 
N to form a heterocycloalkyl of 5 to 8 ring atoms (for example, 
pyrrolidino, piperidino); and 
each R.sub.7 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl, phenyl 
or C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxy; 
each R.sub.10 is indpendently OH, C.sub.1 to C.sub.6 alkyl, C.sub.1 to 
C.sub.6 alkoxy, phenyl or p-tolyl; 
or any two of R.sub.1, R.sub.2, R.sub.3, R.sub.4 or R.sub.5 may be joined 
to form an additional ring of 5 to 7 members, said ring optionally 
containing a carbonyl group as a substituent, optionally containing a 
hydroxyl group as a substituent, and optionally having 1 or 2 double 
bonds, wherein if R.sub.1 is a constituent of the ring, one member is 
nitrogen and the others are carbon and if R.sub.1 is not a constituent of 
the ring, all the members are carbon; and 
T is hydrogen or OR.sub.15 wherein R.sub.15 is hydrogen, C.sub.1 to C.sub.6 
alkyl, C.sub.1 to C.sub.6 alkylacyl, phenyl-C.sub.1 to C.sub.8 -alkylacyl, 
SO.sub.2 R.sub.10, arylsulfonyl, --CO-phenyl or substituted phenyl wherein 
substituted phenyl is as defined in the definition of R.sub.16. 
A preferred embodiment of the Formula I compounds is one wherein Z is O, S, 
SO or SO.sub.2 and wherein n is 0 or 1 in the unit --(CH.sub.2).sub.n M. A 
more preferred embodiment is wherein Z is O, S, SO or SO.sub.2 and wherein 
n is 0 (zero) in the unit --(CH.sub.2).sub.n M. In both of these 
embodiments, the remaining substituents are as defined for Formula I. 
Another preferred embodiment of the Formula I compounds is one wherein: 
Z is O or S; 
R.sub.1 is H, C.sub.1 to C.sub.6 alkyl, C.sub.1 C.sub.6 acyl, 
--(CH.sub.2).sub.n COOR.sub.6 wherein n is 0 to 4, C.sub.1 to C.sub.6 
alkylacyloxy-C.sub.1 to C.sub.6 alkoxycarbonyl (e.g. --COOCH(O.sub.2 
CCH.sub.3)CH.sub.3), --C(H).dbd.C(H)COOR.sub.6, or SO.sub.2 R.sub.10 ; 
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are each independently selected from: 
(1) hydrogen; 
(2) C.sub.1 to C.sub.6 alkyl; 
(3) --(CH.sub.2).sub.n M wherein: 
n is 0 and 
M is 
(a) OR.sub.16 ; 
(b) halogen 
(c) CF.sub.3 ; 
(d) NO.sub.2 ; 
(e) 
##STR11## 
(f) 
##STR12## 
(g) 
##STR13## 
each R.sub.16 is independently H; C.sub.1 to C.sub.6 -alkoxy-C.sub.1 to 
C.sub.6 alkyl; C.sub.1 to 
C.sub.6 alkylacyloxy-C.sub.1 to C .sub.6 alkyl; 
Cl to C6 alkyl; benzyl; phenyl; substituted phenyl wherein the substituents 
are C.sub.1 to C.sub.3 alkyl, halogen, CN, C.sub.1 to C.sub.3 alkoxy, OH, 
(CH.sub.2).sub.n NR.sub.8 R.sub.9 wherein n is 0 to 2, CF.sub.3, 
COOR.sub.6, CH.sub.2 COOR.sub.6 ; --(CH.sub.2).sub.m COOR.sub.6 wherein m 
is 0 to 6; CN; C.sub.1 to C.sub.5 alkylacyl; C.sub.1 to C.sub.4 
perfluoroalkyl; or CH.sub.2 --R.sub.12 wherein R.sub.12 is C.sub.1 to 
C.sub.5 alkyldimethylamino; 
each R.sub.6 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl or 
phenyl; 
each R.sub.14 is independently H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to 
C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxy, 
(CH.sub.2).sub.n COOR.sub.6 wherein n is 0 to 4, phenyl, substituted 
phenyl wherein substituted phenyl is as defined in the definition of 
R.sub.16, or is such that R.sub.14 COOH is an essential amino acid; 
each R.sub.8 and R.sub.9 is independently H, phenyl, substituted phenyl 
wherein substituted phenyl is as defined in the definition of R.sub.16 or 
C.sub.1 to C.sub.4 alkyl, or R.sub.8 and R.sub.9 may be joined through the 
N to form a heterocycloalkyl of 5 to 8 ring atoms (for example, 
pyrrolidino, piperidino); and 
each R.sub.7 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl, phenyl 
or C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxy; and 
each R.sub.10 is independently OH, C.sub.1 to C.sub.6 alkyl, C.sub.1 to 
C.sub.6 alkoxy, phenyl or p-tolyl; 
T is hydrogen or OR.sub.15 wherein R.sub.15 is hydrogen, C.sub.1 to C.sub.6 
alkyl, C.sub.1 to C.sub.6 alkylacyl, phenyl-C.sub.1 to C.sub.8 -alkylacyl, 
SO.sub.2 R.sub.10, arylsulfonyl, --CO-phenyl or substituted phenyl wherein 
substituted phenyl is as defined in the definition of R.sub.16 ; 
with the proviso that there is a group OR.sub.16 located at one of the 6, 
7, 8 or 9-positions. 
The term alkyl, as used herein, includes straight chain, branched chain and 
cyclic groups. 
The term aryl, as used herein, includes phenyl, naphthyl, anthracenyl, and 
the like. 
The term heteroaryl includes 5- and 6-membered rings containing at least 
one heteroatom selected from N, O, S, for example, furyl, thienyl, 
pyrrolyl, pyridyl. 
The term essential amino acid is employed to include the following amino 
acids; lysine, tryptophan, histidine, phenylalanine, leucine, isoleucine, 
threonine, methionine, valine, arginine, alanine, proline, glycine, 
serine, cysteine, tyrosine, asparagine, glutamine, aspartic acid and 
glutamic acid. 
Whenever possible, appropriate pharmaceutically acceptable salts of Formula 
I are included within the definitions given above. These include 
carboxylic or mineral acid addition salts where Formula I is basic and 
salts of pharmaceutically acceptable bases when Formula I is acidic. Salts 
derived from inorganic bases include sodium, potassium, lithium, ammonium, 
calcium, magnesium, ferrous, zinc, copper, manganous, aluminum, ferric, 
manganic salts and the like. Particularly preferred are the ammonium, 
potassium, sodium, calcium and magnesium salts. Salts derived from 
pharmaceutically acceptable organic non-toxic bases include salts of 
primary, secondary and tertiary amines, substituted amines including 
naturally occurring substituted amines, cyclic amines and basic ion 
exchange resins, such as isopropylamine, trimethylamine, diethylamine, 
triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 
2-diethylaminoethanol, trimethamine, lysine, arginine, histidine, 
caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, 
glucosamine, methylglucamine, theobromine, purines, piperazine, 
piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly 
preferred organic non-toxic bases are isopropylamine, diethylamine, 
ethanolamine, piperidine, trimethamine, choline and caffeine. 
When the compound is basic, salts may be prepared from pharmaceutically 
acceptable non-toxic acids, including inorganic and organic acids. Such 
acids include hydrochloric, hydrobromic, sulfuric, nitric, isethionic, 
methanesulfonic, ethanesulfonic, benzenesulfonic, p-tolueuesulfonic, 
acetic, benzoic, comphorsulfonic, citric, fumaric, gluconic, glutamic, 
lactic, malic, maleic, mandelic, mucic, pamoic, pantothenic, phosphoric, 
succinic; tartaric acid and the like. Particularly preferred are 
hydrochloric, hydrobromic, citric, maleic, phosphoric, sulfuric and 
tartaric acids. 
For a helpful discussion of pharmaceutical salts see S. M. Berge et al., 
Journal of Pharmaceutical Sciences, 66, 1-19 (1977), the disclosure of 
which is hereby incorporated herein by reference. 
The compounds of the present invention are prepared by a series of 
reactions as illustrated in Scheme I. An initial condensation reaction 
between a vicinal dihalopyrazine (III) with an appropriately substituted 
aminobenzenethiol (IV) affords the compound (V). 
Compound (V) is cyclized in the presence of a base, such as triethylamine 
and an inert solvent such as dimethylformamide (DMF) to afford the 
compound of Formula I wherein Z=S. 
Compounds of Formula I wherein Z=S may be oxidized by contacting the 
Formula I compounds with 30-35% hydrogen peroxide in an acidic solvent for 
several hours at a temperature of from about 75.degree. to 80.degree. C. 
In some cases, higher peroxide concentrations, higher temperatures and/or 
more prolonged contact times may be required, especially when the sulfone 
is the desired product. Acetic acid is generally a useful solvent, but 
other acids, such as trifluoroacetic acid, can also be employed. 
Similarly, the compounds of Formula I wherein Z=O or NCN may be produced by 
following Scheme I, but substituting the appropriate compound 
corresponding to Formula (IV) for the aminobenzenethiol shown. 
It will be obvious to the skilled artisan that the substituents present in 
the compounds of formulae III, IV and V must be such that they are 
compatible with the reaction conditions used in the preparation of Formula 
I. 
##STR14## 
An alternative procedure for preparing compounds of Formula I substituted 
at position 10 is illustrated in Scheme II. Thus, an alkylating agent is 
reacted with a compound of Formula VI in the presence of a base in an 
inert solvent to yield compounds of Formula I. A side product of Formula 
VII, resulting from alkylation at position I is sometimes obtained in this 
reaction. 
##STR15## 
The compounds of the Formula I have unexpected activity as inhibitors of 
the mammalian biosynthesis of leukotriene B.sub.4, as well as leukotrienes 
C.sub.4, D.sub.4, E.sub.4 and F.sub.4, the active elements of the slow 
reacting substance of anaphylaxis (SRS-A). The compounds of Formula I act 
as inhibitors of the mammalian 5-lipoxygenase enzyme system of the 
arachidonic acid cascade. This inhibition of the mammalian biosynthesis of 
leukotrienes indicates that the compositions are useful to treat, prevent 
or ameliorate, in mammals and especially in humans (1) pulmonary 
conditions including diseases such as asthma, (2) allergies and allergic 
reactions such as allergic rhinitis, contact dermatitis, allergic 
conjunctivitis and the like, (3) inflammation such as arthritis, (4) pain, 
(5) skin conditions such as psoriasis and the like and (6) cardiovascular 
conditions such as angina and the like.

Examples of the Formula I compounds useful in the present compositions are 
tabulated in Table I. The number preceding the R.sub.2 -R.sub.5 and T 
definitions signifies that group's position on the ring system. 
TABLE I 
__________________________________________________________________________ 
##STR16## 
Compound 
Z R.sub.1 R.sub.2 
R.sub.3 
R.sub.4 
R.sub.5 
T 
__________________________________________________________________________ 
1 S H H H H H H 
2 S CH.sub.3 H H H H H 
3 S CH.sub.2 Ph 
H H H H H 
4 S H 3-NO.sub.2 
H H H H 
5 S H 2-Cl 
3-Cl 
H H H 
6 S H 3-NO.sub.2 
7-NO.sub.2 
H H H 
7 S CH.sub.3 2-NO.sub.2 
H H H H 
8 S CH.sub.3 3-NO.sub.2 
H H H H 
9 S n-C.sub.3 H.sub.7 
2-Cl 
3-Cl 
H H H 
10 S n-C.sub.6 H.sub.13 
2-Cl 
3-Cl 
H H H 
11 S CH.sub.2 Ph 
2-Cl 
3-Cl 
H H H 
12 SO H H H H H H 
13 SO CH.sub.3 H H H H H 
14 SO H 2-Cl 
3-Cl 
H H H 
15 SO H 3-NO.sub.2 
7-NO.sub.2 
H H H 
16 SO.sub.2 
CH.sub.3 H H H H H 
17 SO.sub.2 
CH.sub.2 Ph 
H H H H H 
18 SO.sub.2 
CH.sub.2 Ph 
2-Cl 
3-Cl 
H H H 
19 O H H H H H H 
20 O H 2-F 3-F H H H 
21 O H 2-Cl 
3-Cl 
H H H 
22 O H 2-Br 
3-Br 
H H H 
23 O H 2-Cl 
3-Cl 
8-CH.sub.3 
H H 
24 NCN H H H H H H 
25 NCN CH.sub.3 2-CH.sub.3 
3-CH.sub.3 
H H H 
26 NCN CH.sub.3 H H H H 7-OCH.sub.3 
27 S H 2-Cl 
H H H H 
28 S H 3-Cl 
H H H H 
29 S H 8-Cl 
H H H H 
30 S H 2-CH.sub.3 
H H H H 
31 S H H H H H 7-OCH.sub.3 
32 S H H H H 8-Cl 
7-OCH.sub.3 
33 S CH.sub.3 H H H 8-Cl 
7-OCH.sub.3 
34 S CH.sub.3 H H H 8-Cl 
7-OH 
35 S CH.sub.3 H H H H 7-OCH.sub.3 
36 S H H H H H 7-OH 
37 S CH.sub.3 H H H H 7-OH 
38 SO H H H H H 7-OCH.sub.3 
39 SO CH.sub.3 H H H H 7-OCH.sub.3 
40 S SO.sub.2 Php-Me 
H H H H 7-OCH.sub.3 
41 SO.sub.2 
H H H H H 7-OCH.sub.3 
42 S COCH.sub.3 
H H H H 7-OCH.sub.3 
43 S COCH.sub.3 
H H H H H 
44 SO.sub.2 
H H H H H H 
45 S CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 
H H H H H 
46 S CH.sub.2 CO.sub.2 H 
H H H H H 
47 S CO.sub.2 CH.sub.3 
H H H H H 
48 S CHCHCO.sub.2 CH.sub.3 
H H H H H 
__________________________________________________________________________ 
Representative compounds of Formula I have been tested using one or more of 
the following assays to determine their mammalian leukotriene biosynthesis 
inhibiting activity and other relevant biological activities. 
Rat Polymorphonuclear Leukocyte (P.M.N.) Assay 
Rats under ether anesthesia were injected (i.p.) with 8 ml of a suspension 
of sodium caseinate (6 grams in ca. 50 ml water). After 15-24 hours the 
rats were sacrificed (CO.sub.2) and the cells from the peritoneal cavity 
were recovered by lavage with 20 ml of buffer (Eagles MEM containing 30 mM 
HEPES adjusted to pH 7.4 with NaOH). The cells were pelleted (350.times.g, 
5 min.), resuspended in buffer with vigorous shaking, filtered through 
lens paper, recentrifuged and finally suspended in buffer at a 
concentration of 10 cells/ml. A 500 .mu.l aliquot of PMN suspension and 
test compound were preincubated for 2 minutes at 37.degree. C., followed 
by the addition of 10 .mu.M A-23187. The suspension was stirred for an 
additional 4 minutes then bioassayed for LTB.sub.4 content by adding an 
aliquot to a second 500 .mu.l portion of the PMN at 37.degree. C. The 
LTB.sub.4 produced in the first incubation caused aggregation of the 
second PMN, which was measured as a change in light transmission. The size 
of the assay aliquot was chosen to give a submaximal transmission change 
(usually -70%) for the untreated control. The percentage inhibition of 
LTB.sub.4 formation was calculated from the ratio of transmission change 
in the sample to the transmission change in the compound-free control. 
Antigen Challenge `in vitro` Assay 
Male guinea pigs weighing 300-350 g were sensitized by injecting (I.P.) 0.5 
ml of a suspension containing 0.4 mg of egg albumin (Ovalbumin, Grade V, 
Sigma Chemical Co.) and 4.0 g aluminum hydroxide in 19.6 ml of saline. Two 
weeks were permitted for sensitization to occur. 
Three sensitized guinea pigs were stunned and exsanguinated. The tracheas 
were removed, freed of adhering tissue and divided longitudinally by 
cutting through the cartilaginous tissue directly opposite the muscle 
insertion. Each opened trachea was then transected between every second 
cartilage. Four of the cut sections were tied together, end to end, in a 
series with No. 7 silk thread ensuring that the tracheal muscles were all 
in the same vertical plane. Thus, each chain consisted of tissue from 
three different animals. 
The chain so formed was then suspended under 1 g of tension (by silk ties 
at each end) in a 20 ml organ bath containing 10 ml of modified.sup.1 
Krebs-Henseleit buffer solution gassed with 95% O.sub.2 and 5% CO.sub.2 at 
37.degree. C. Mepyramine (0.55 .mu.g/ml) and indomethacin (2.67 .mu.g/ml) 
were added to the buffer to avoid the contribution of histamine receptors 
and cyclooxygenase products to the contraction. To record responses one 
end of the tracheal chain was attached to a Gould-Statham UC-2 force 
displacement transducer which was connected to a Beckman Type R-dynograph. 
The preparations were allowed to equilibrate for one hour during which 
time the tissues were automatically washed (10 ml volume displacement) 
every 6 minutes. 
FNT .sup.1 modified Krebs solution in grams/liter and (mM): NaCl--6.87 (120); 
glucose--2.1 (11); NaHCO.sub.3 --2.1 (25); KCl--0.32 (4.72); CaCl.sub.2 
--0.28 (2.5); MgSO.sub.4. 7 H.sub.2 O--0.11 (0.5); KH.sub.2 PO.sub.4 
--0.16(1.2); pH at bathing solution=7.35.+-.0.05. 
After the equilibration period the tissues were primed with methacholine (3 
.mu.g/ml; 1.5.times.10.sup.-5 M), washed and allowed to recover to 
baseline. The tissues were treated again with a second dose of 
methacholine, washed, allowed to return to baseline and washed for an 
additional hour. 
Two chains were used as a control. These were incubated in a concentration 
of egg albumin sufficient to induce an average contraction of 50-80% of 
the methacholine response. 
Each compound to be tested was added to two other baths (at a final 
concentration in each bath of 10 .mu.g/ml) 15 minutes prior to challenging 
the fresh chains with egg albumin. 
The response of the challenged tissue was expressed as a percentage of the 
methacholine maximum. The percentage inhibition for each compound was then 
calculated. Compounds which at 10 .mu.g/ml (final conc.) inhibited the egg 
albumin response by 50% or more were retested at a lower concentration. 
Asthmatic Rat Assay 
Rats were obtained from an inbred line of asthmatic rats. Both female and 
male rats from 200 to 300 g were used. 
Egg albumin (EA), grade V, crystallized and lyophilized, was obtained from 
Sigma Chemical Co., St. Louis. Bordetella pertussis vaccine, containing 
30.times.10.sup.9 killed bacteria per ml was obtained from the Institut 
Armand-Frappier, Laval des Rapides, Quebec. Aluminum hydroxide was 
obtained from the Regis Chemical Company, Chicago. 
The challenge and subsequent respiratory recordings were carried out in a 
clear plastic box with internal dimensions 10.times.6.times.4 inches. The 
top of the box was removable; in use, it was held firmly in place by four 
clamps and an airtight seal was maintained by a soft rubber gasket. 
Through the center of each end of the chamber a Devilbiss nebulizer (No. 
40) was inserted via an airtight seal and each end of the box also had an 
outlet. A Fleisch No. 0000 pneumotachograph was inserted into one end of 
the box and coupled to a Grass volumetric pressure transducer (PT5-A) 
which was then connected to a Beckman Type R Dynograph through appropriate 
couplers. While aerosolizing the antigen, the outlets were open and the 
pneumotachograph was isolated from the chamber. The outlets were closed 
and the pneumotachograph and the chamber were connected during the 
recording or the respiratory patterns. For challenge, 2 ml of a 3% 
solution of antigen in saline was placed into each nebulizer and the 
aerosol was generated with air from a small Potter diaphragm pump 
operating at 10 psi and a flow of 8 liters/minute. 
Rats were sensitized by injecting (s.c.) 1 ml of a suspension containing 1 
mg EA and 200 mg aluminum hydroxide in saline. Simultaneously, they 
received an intraperitoneal (i.p.) injection of 0.5 ml of B. pertussis 
vaccine. They were used between days 14 and 18 postsensitization. In order 
to eliminate the serotonin component of the response, rats were pretreated 
intravenously 5 minutes prior to aerosol challenge with 30 gm/kg 
methylserzide. Rats were then exposed to an aerosol of 3% EA in saline for 
exactly 1 minute, then their respiratory profiles were recorded for a 
further 25-30 minutes. The duration of continuous dyspnoea was measured 
from the respiratory recordings. 
Compounds were generally administered either intraperitoneally 1 hour prior 
to challenge or orally 11/2 hours prior to challenge. They were either 
dissolved in dimethylsulfoxide or suspended in 0.1% methocel and 0.5% 
Tween 80. The volume injected was 2 ml/kg (intraperitoneally) or 10 ml/kg 
(orally (p.o.)). Prior to oral treatment rats were starved overnight. 
Their activity was determined in terms of their ability to decrease the 
duration of symptoms of dyspnoea in comparison with a group of 
vehicle-treated controls. Usually, a compound was evaluated at a series of 
doses and an ED.sub.50 was determined. This was defined as the dose 
(mg/kg) which would inhibit the duration of symptoms by 50%. 
PAF-Induced Hyperalgesia Assay 
Female Sprague-Dawley rats, 35-40 g were fasted overnight. Platelet 
activating factor, PAF, (L-lecithin B-acetyl O-alkyl) 1 .mu.g/0.1 ml was 
given by subplantar injection in the rat paw. The compounds to be 
evaluated were homogenized in Aqueous Vehicle (0.9% benzyl alcohol, 0.5% 
Tween 80 and 0.4% methylcellulose) and administered orally in a volume of 
0.1 ml, 30 minutes prior to PAF. 
Animals were tested 1, 2, 3 and 4 hours after PAF administration. The 
vocalization threshold, defined as the pressure (mmHg) needed to evoke a 
squeak response, was recorded for both the injected and contralateral paw. 
No animal was subjected to pressure greater than 60 mmHg. Hyperalgesia is 
defined as a decrease in vocalization threshold as compared to a normal 
paw. Percent inhibition of hyperalgesia was calculated as the proportion 
of animals with vocalization thresholds greater than 200% of controls. 
Tables II and III below show data obtained using the above described assays 
with representative compounds of Formula I. 
TABLE II 
______________________________________ 
Assay Results 
Antigen 
PMN Challenge 
I.sub.50 % Inhibition 
Compound .mu.g/ml and .mu.g/ml 
______________________________________ 
##STR17## 5 85% (10) 
##STR18## 0.2 
##STR19## 1-5 -- 
##STR20## 0.05-0.5 42% (3) 
##STR21## 1-5 71% (3) 
##STR22## -- 14% (3) 
##STR23## -- 22% (3) 
##STR24## 5 -- 
##STR25## 1 -- 
##STR26## 0.5-1 35% (3) 
______________________________________ 
TABLE III 
______________________________________ 
Asthmatic 
Rat % PAF % 
Inhibition, 
Inhibition, 
Compound Dose Dose 
______________________________________ 
##STR27## 30% 5 mg/kg, p.o. 
70% 10 mg/kg, i.p. 
##STR28## 47% 5 mg/kg, p.o. 
-- 
##STR29## 43% 3 mg/kg, p.o. 
-- 
##STR30## 39% 3 mg/kg, p.o. 
-- 
##STR31## 25% 3 mg/kg, p.o. 
-- 
______________________________________ 
The cytoprotective activity of a compound may be observed in both animal 
and man by noting the increased resistance of the gastrointestinal mucosa 
to the noxious effects of strong irritants, for example, the ulcerogenic 
effects of aspirin or indomethacin. In addition to lessening the effect of 
non-steroidal anti-inflammatory drugs on the gastrointestinal tract, 
animal studies show that cytoprotective compounds will prevent gastric 
lesions induced by oral administration of strong acids, strong bases, 
ethanol, hypertonic saline solutions and the like. 
Two assays can be used to measure cytoprotective ability. These assays are; 
(A) an ethanol-induced lesion assay and (B) an indomethacin-induced ulcer 
assay. 
A. Ethanol-Induced Gastric Ulcer Assay 
Twenty-four hour fasted Sprague-Dawley (S.D.) rats are perorally (p.o.) 
dosed with 1.0 ml absolute ethanol. Fifteen to thirty minutes prior to 
ethanol administration, groups of rats each receive either an aqueous 
vehicle (aqueous methylcellulose 5% wt.) or the test compound at various 
doses perorally. One hour later, the animals are sacrificed and stomach 
mucosae are examined for resulting lesions. 
B. Indomethacin-Induced Ulcer Assay 
Indomethacin, 10 mg/kg p.o., is used to induce ulcers in 24 hour fasted 
S.D. rats. Fifteen minutes prior to indomethacin administration, groups of 
rats each receive either an aqueous vehicle (5% by weight methylcellulose) 
or the test compound at various doses perorally. Four hours later the 
animals are sacrificed and stomach mucosae are examined for resulting 
ulcers. 
The magnitude of a prophylactic or therapeutic dose of a compound of 
Formula I will, of course, vary with the nature of the severity of the 
condition to be treated and with the particular compound of formula I and 
its route of administration. In general, the daily dose range for 
anti-asthmatic, anti-allergic or anti-inflammatory use and, generally, 
uses other than cytoprotection, lies within the range of from about 10 
micrograms to about 20 mg per kg body weight of a mammal. This dosage may 
be administered in single or divided individual doses. 
As cytoprotective agents, the leukotriene inhibitors of Formula I may 
generally be administered at a dosage range of 0.01 mg/kg to 20 mg/kg of 
body weight. The exact amount of inhibitor to be used will depend on, 
inter alia, whether it is being administered to heal damaged cells or to 
avoid future damage, on the nature of the damaged cells (e.g., 
gastro-intestinal ulcerations vs. nephrotic necrosis), and on the nature 
of the causative agent. An example of the use of a compound of the Formula 
I in avoiding future damage would be co-administration of a compound of 
the Formula I with a non-steroidal antiinflammatory drug (NSAID) that 
might otherwise cause such damage (for example, indomethacin). For such 
use, the compound of Formula I is administered from 30 minutes prior up to 
30 minutes after administration of the NSAID. Preferably, it is 
administered prior to or simultaneously with the NSAID (for example, in a 
combination dosage form). 
The effective daily dosage level for compounds of Formulae I inducing 
cytoprotection in mammals, especially humans, will generally range from 
about 0.01 mg/kg to about 20 mg/kg, preferably from about 0.01 mg/kg to 
about 10 mg/kg. The dosage may be administered in single or divided 
individual doses. 
Any suitable route of administration may be employed for providing a 
mammal, especially a human with an effective dosage of a leukotriene 
inhibitor. For example, oral, rectal, transdermal, parenteral, 
intramuscular, intravenous and the like may be employed. Dosage forms 
include tablets, troches, dispersions, suspensions, solutions, capsules 
and the like. 
The pharmaceutical compositions of the present invention comprise a 
compound of formula I as an active ingredient or a pharmaceutically 
acceptable salt thereof, and may also contain a pharmaceutically 
acceptable carrier and optionally other therapeutic ingredients. The 
compositions include compositions suitable for oral, rectal, ophthalmic, 
pulmonary, nasal, dermal, topical or parenteral (including subcutaneous, 
intramuscular and intravenous) administration, although the most suitable 
route in any given case will depend on the nature and severity of the 
conditions being treated and on the nature of the active ingredient. They 
may be conveniently presented in unit dosage form and prepared by any of 
the methods well-known in the art of pharmacy. 
For use where a composition for intravenous administration is employed, a 
suitable dosage range for anti-asthmatic, anti-inflammatory or 
anti-allergic use is from about 0.01 mg to about 20 mg (preferably from 
about 0.1 mg to about 10 mg) of a compound of formula I per kg of body 
weight per day and for cytoprotective use from about 0.01 mg to about 20 
mg (preferably from about 0.1 mg to about 10 mg) of a compound of Formula 
I per kg of body weight per day. In the case where an oral composition is 
employed, a suitable dosage range for anti-asthmatic, anti-inflammatory or 
anti-allergic use is, e.g. from about 0.1 to about 20 mg of a compound of 
formula I per kg of body weight per day, preferably from about 1 mg to 
about 10 mg per kg and for cytoprotective use from about 0.01 mg to about 
20 mg (preferably from about 0.1 mg to about 10 mg) of a compound of 
Formula I per kg of body weight per day. 
For treating pulmonary conditions such as asthma, the mode of 
administration may be oral, parenteral, by inhalation, by suppository and 
the like. Suitable oral dosage forms are tablets, elixirs, emulsions, 
solutions, capsules, including delayed or sustained release capsules and 
the like. Parenteral dosage forms include solutions, emulsions and the 
like. Dosage forms for administration by inhalation including sprays, 
aerosols and the like. These inhalation formulations may be administered 
in metered doses ranging from about 0.1 micrograms to about 200 
micrograms, administered as needed. 
For administration by inhalation, the compounds of the present invention 
are conveniently delivered in the form of an aerosol spray presentation 
from pressurized packs or a nebuliser. The preferred composition for 
inhalation is a powder which may be formulated as a cartridge from which 
the powder composition may be inhaled with the aid of a suitable device. 
In the case of a pressurized aerosol, the dosage unit may be determined by 
providing a valve to deliver a metered amount. 
For treating allergies or allergic reactions, such as allergic 
conjunctivitis, allergic rhinitis and the like, the Formula I compound may 
be administered by any conventional mode, e.g., orally, parenterally, 
topically, subcutaneously, by inhalation and the like. The oral and 
parenteral dosage forms are the same type as for the pulmonary treatment. 
The topical application dosage forms include ointments, salves, controlled 
release patches, emulsions, solutions, thixotropic formulations, powders, 
sprays and the like. For topical application, the percent by weight active 
ingredient (Formula I compound) may vary from about 0.001 to about 10%. 
For treating inflammation the mode of administration may be oral, 
parenteral, by suppository and the like. The various dosage forms are the 
same as those described above. 
For treating skin diseases such as psoriasis, atopic dermatitis and the 
like, oral, topical or parenteral administration is useful. For topical 
application to the diseased area salves, patches, controlled release 
patches, emulsions, etc., are convenient dosage forms. 
For use as an analgesic, i.e., for treating pain, any suitable mode of 
administration may be used, e.g., oral, parenteral, by insufflation, by 
suppository and the like. 
For treating cardiovascular conditions such as angina pectoris, etc., any 
suitable mode of administration, e.g. oral, parenteral, topical, 
insufflation, etc. and dosage form e.g. pills, liquid formulations, 
controlled release capsules, controlled release skin patches, etc. may be 
used. 
In practical use, leukotriene inhibitors of Formula I can be combined as 
the active ingredient in intimate admixture with a pharmaceutical carrier 
according to conventional pharmaceutical compounding techniques. The 
carrier may take a wide variety of forms depending on the form of 
preparation desired for administration, e.g., oral or intravenous. In 
preparing the compositions for oral dosage form, any of the usual 
pharmaceutical media may be employed, such as, for example, water glycols, 
oils, alcohols, flavoring agents, preservatives, coloring agents and the 
like in the case of oral liquid preparations, such as, for example, 
suspensions, elixirs and solutions; or carriers such as starches, sugars, 
diluents, granulating agents, lubricants, binders, disintegrating agents 
and the like in the case of oral solid preparations such as, for example, 
powders, capsules and tablets. Because of their ease of administration, 
tablets and capsules represent the most advantageous oral dosage unit 
form, in which case solid pharmaceutical carriers are obviously employed. 
If desired, tablets may be sugar coated or enteric coated by standard 
techniques. 
In addition to the common dosage forms set out above, the leukotriene 
inhibitors of Formula I may also be administered by controlled release 
means and/or delivery devices such as those described in U.S. Pat. Nos. 
3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719, the 
disclosure of which is hereby incorporated herein by reference. 
Dosage forms for application to treat the eye are also disclosed in U.S. 
Pat. No. 4,348,398. 
Pharmaceutical compositions of the present invention suitable for oral 
administration and by inhalation in the case of asthma therapy may be 
presented as discrete units such as capsules, cachets or tablets each 
containing a predetermined amount of the active ingredient, as a powder or 
granules or as a solution or a suspension in an aqueous liquid, a 
non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid 
emulsion. Such compositions may be prepared by any of the methods of 
pharmacy but all methods include the step of bringing into association the 
active ingredient with the carrier which constitutes one or more necessary 
ingredients. In general, the compositions are prepared by uniformly and 
intimately admixing the active ingredient with liquid carriers or finely 
divided solid carriers or both, and then, if necessary, shaping the 
product into the desired presentation. For example, a tablet may be 
prepared by compression or molding, optionally with one or more accessory 
ingredients. Compressed tablets may be prepared by compressing in a 
suitable machine, the active ingredient in a free-flowing form such as 
powder or granules, optionally mixed with a binder, lubricant, inert 
diluent, lubricating, surface active or dispersing agent. Molded tablets 
may be made by molding in a suitable machine, a mixture of the powdered 
compound moistened with an inert liquid diluent. Desirably, each tablet 
contains from about 25 mg to about 500 mg of the active ingredient and 
each cachet or capsule contains from about 25 to about 500 mg of the 
active ingredient. 
The following, prepared by conventional compounding procedures, are 
examples of representative pharmaceutical dosage forms: 
______________________________________ 
Injectible Suspension 
mg/mL 
______________________________________ 
Compound of Formula I 
1-100 
Methylcellulose 5.0 
Tween 80 0.5 
Benzyl alcohol 9.0 
Methyl paraben 1.8 
Propyl paraben 0.2 
Water for injection to a total volume of 1 ml 
______________________________________ 
______________________________________ 
Aerosol for Oral Inhibition 
mg/can (200 doses/can) 
______________________________________ 
Compound of Formula I 
2-40 
Oleic Acid 0.2-4.0 
Trichloromonofluoro methane 
5,000-8,000 To a total 
Dichloromonofluoro methane 
15,000-12,400 of 20,400 
______________________________________ 
______________________________________ 
Cream mg/g 
______________________________________ 
Compound of Formula I 1-100 
Cetyl alcohol 130.0 
Sodium Lauryl Sulfate 15.0 
Propylene Glycol 100.0 
Methyl paraben 1.8 
Propyl paraben 1.2 
Purified Water of sufficient quantity to 
make total 1 g 
______________________________________ 
______________________________________ 
Ointment mg/g 
______________________________________ 
Compound of Formula I 
1-100 
Methyl paraben 1.8 
Propyl paraben 1.2 
Petrolatum of sufficient quantity to 
make total 1 g 
______________________________________ 
______________________________________ 
Tablet mg/tablet 
______________________________________ 
Compound of Formula I 
0.2-350 
Microcrystalline Cellulose 
0-349.8 
Providone 14.0 
Microcrystalline Cellulose 
90.0 
Pregelatinized Starch 
43.5 
Magnesium Stearate 2.5 
500 
______________________________________ 
______________________________________ 
Capsule mg/capsule 
______________________________________ 
Compound of Formula I 
0.2-350 
Lactose Powder 248.5-598.3 
Magnesium Stearate 
1.5 
600 
______________________________________ 
In addition to the compounds of Formula I, the pharmaceutical compositions 
can also contain other active ingredients, such as cyclooxygenase 
inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), peripheral 
analgesic agents such as zomepirac diflunisal and the like. The weight 
ratio of the compound of the Formula I to the second active ingredient may 
be varied and will depend upon the effective dose of each ingredient. 
Generally, an effective dose of each will be used. Thus, for example, when 
a compound of the Formula I is combined with an NSAID, the weight ratio of 
the compound of the Formula I to the NSAID will generally range from about 
1000:1 to about 1:1000, preferably 200:1 to about 1:200. Combinations of a 
compound of the Formula I and other active ingredients will generally also 
be within the aforementioned range, but in each case, an effective dose of 
each active ingredient should be used. 
Combinations of a compound of the Formula I and other active ingredients 
will generally be in the aforementioned ratios. 
NSAIDs can be characterized into five groups: 
(1) the propionic acid derivatives; 
(2) the acetic acid derivatives; 
(3) the fenamic acid derivatives; 
(4) the biphenylcarboxylic acid derivatives; and 
(5) the oxicams 
or a pharmaceutically acceptable salt thereof. 
The propionic acid derivatives which may be used comprise: ibuprofen, 
ibuprufen aluminum, indoprofen, ketoprofen, naproxen, benoxaprofen, 
flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, 
carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, 
alminoprofen, tiaprofenic acid, fluprofen and bucloxic acid. Structurally 
related propionic acid derivatives having similar analgesic and 
anti-inflammatory properties are also intended to be included in this 
group. 
Thus, "propionic acid derivatives" as defined herein are non-narcotic 
analgesics/non-steroidal anti-inflammatory drugs having a free 
--CH(CH.sub.3)COOH or --CH.sub.2 CH.sub.2 COOH group (which optionally can 
be in the form of a pharmaceutically acceptable salt group, e.g., 
--CH(CH.sub.3)COO.sup.- Na.sup.+ or --CH.sub.2 CH.sub.2 COO.sup.- 
Na.sup.+), typically attached directly or via a carbonyl function to a 
ring system, preferably to an aromatic ring system. 
The acetic acid derivatives which may be used comprise: indomethacin, which 
is a preferred NSAID, sulindac, tolmetin, zomepirac, diclofenac, 
fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, 
zidometacin, acemetacin, fentiazac, clidanac, oxpinac, and fenclozic acid. 
Structually related acetic acid derivatives having similar analgesic and 
antiinflammatory properties are also intended to be encompassed by this 
group. 
Thus, "acetic acid derivatives" as defined herein are non-narcotic 
analgesics/non-steroidal anti-inflammatory drugs having a free --CH.sub.2 
COOH group (which optionally can be in the form of a pharmaceutically 
acceptable salt group, e.g. --CH.sub.2 COO.sup.- Na.sup.+), typically 
attached directly to a ring system, preferably to an aromatic or 
heteroaromatic ring system. 
The fenamic acid derivatives which may be used comprise: mefenamic acid, 
meclofenamic acid, flufenamic acid, niflumic acid and tolfenamic acid. 
Structurally related fenamic acid derivatives having similar analgesic and 
anti-inflammatory properties are also intended to be encompassed by this 
group. 
Thus, "fenamic acid derivatives" as defined herein are non-narcotic 
analgesics/non-steroidal anti-inflammatory drugs which contain the basic 
structure: 
##STR32## 
which can bear a variety of substituents and in which the free --COOH 
group can be in the form of a pharmaceutically acceptable salt group, 
e.g., --COO.sup.- Na.sup.+. 
The biphenylcarboxylic acid derivatives which can be used comprise: 
diflunisal and flufenisal. Structurally related biphenylcarboxylic acid 
derivatives having similar analgesic and anti-inflammatory properties are 
also intended to be encompassed by this group. 
Thus, "biphenylcarboxylic acid derivatives" as defined herein are 
non-narcotic analgesics/non-steroidal anti-inflammatory drugs which 
contain the basic structure: 
##STR33## 
which can bear a variety of substituents and in which the free --COOH 
group can be in the form of a pharmaceutically acceptable salt group, 
e.g., --COO.sup.- Na.sup.+. 
The oxicams which can be used in the present invention comprise: piroxicam, 
sudoxicam, isoxicam and 4-hydroxyl-1,2-benzothiazine 1,1-dioxide 
4-(N-phenyl)-carboxamide. Structurally related oxicams having similar 
analgesic and anti-inflammatory properties are also intended to be 
encompassed by this group. 
Thus, "oxicams" as defined herein are non-narcotic analgesics/non-steroidal 
anti-inflammatory drugs which have the general formula: 
##STR34## 
wherein R is an aryl or heteroaryl ring system. 
The following NSAIDs may also be used: acemetacin, alminoprofen, amfenac 
sodium, aminoprofen, anitrazafen, antrafenine, auranofin, bendazac 
lysinate, benzydamine, beprozin, broperamole, bufezolac, carprofen, 
cinmetacin, ciproquazone, clidanac, cloximate, dazidamine, deboxamet, 
delmetacin, detomidine, dexindoprofen, diacerein, di-fisalamine, 
difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole, 
etersalate, etodolac, etofenamate, fanetizole mesylate, fenclofenac, 
fenclorac, fendosal, fenflumizole, fentiazac, feprazone, floctafenine, 
flunixin, flunoxaprofen, fluproquazone, fopirtoline, fosfosal, 
furcloprofen, furofenac, glucametacin, guaimesal, ibuproxam, isofezolac, 
isonixim, isoprofen, isoxepac, isoxicam, lefetamine HCl, leflunomide, 
lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysin clonixinate, 
meclofenamate sodium, meseclazone, miroprofen, nabumetone, nictindole, 
nimesulide, orpanoxin, oxametacin, oxapadol, oxaprozin, perisoxal citrate, 
pimeprofen, pimetacin, piproxen, pirazolac, pirfenidone, pirprofen, 
pranoprofen, proglumetacin maleate, proquazone, pyridoxiprofen, sudoxicam, 
suprofen, talmetacin, talniflumate, tenoxicam, thiazolinobutazone, 
thielavin B, tiaprofenic acid, tiaramide HCl, tiflamizole, timegadine, 
tioxaprofen, tolfenamic acid, tolpadol, tryptamid, ufenamate, and 
zidometacin. 
The following NSAIDs, designated by company code number, may also be used: 
480156S, AA861, AD1491, AD1590, AFP802, AFP860, AHR6293, AI77B, AP504, 
AU8001, BAYo8276, BPPC, BW540C, BW755C, CHINOIN 127, CN100, CO893XX, CPP, 
D10242, DKA9, DV17, EB382, EGYT2829, EL508, F1044, FZ, GP53633, GP650, 
GV3658, HG/3, ITCl, ITF, ITF182, KB1043, KC8973, KCNTEI6090, KME4, LA2851, 
LT696, LU20884, M7074, MED15, MG18311, MR714, MR897, MY309, NO164, 
ONO3144, PR823, PV102, PV108, QZ16, R830, RS2131, RU16029, RU26559, 
RUB265, SCR152, SH440, SIR133, SIR136, SIR92, SPAS510, SQ27239, ST281, SX 
1032, SY6001, SaH46798, TA60, TAI901, TEI615, TVX2706, TVX960, TZI615, 
U60257, UR2310, WY23205, WY41770, YM09561, YM13162, YS1033, and ZK31945. 
Finally, NSAIDs which may also be used include the salicylates, 
specifically aspirin, and the phenylbutazones, and pharmaceutically 
acceptable salts thereof. 
Pharmaceutical compositions comprising the Formula I compounds may also 
contain inhibitors of the biosynthesis of the leukotrienes such as are 
disclosed in pending U.S. patent applications Ser. Nos. 539,342, filed 
Oct. 5, 1983, 459,924, filed Jan. 21, 1983, 539,215, filed Oct. 5, 1983, 
and 547,161, filed Oct. 31, 1983, which are hereby incorporated herein by 
reference. 
The compounds of the Formula I may also be used in combination with 
leukotriene antagonists such as those disclosed in copending applications 
U.S. Ser. Nos. 520,051 and 520,052, filed Aug. 5, 1983 which are hereby 
incorporated herein by reference and others known in the art such as those 
disclosed in European Patent Application Nos. 56,172 and 61,800; and in 
U.K. Patent Specification No. 2,058,785, which are hereby incorporated 
herein by reference. 
Pharmaceutical compositions comprising the Formula I compounds may also 
contain as the second active ingredient, antihistaminic agents such as 
benadryl, dramamine, histadyl, phenergan and the like. Alternatively, they 
may include prostaglandin antagonists such as those disclosed in European 
Patent Application No. 11,067 or thromboxane antagonists such as those 
disclosed in U.S. Pat. No. 4,237,160. They may also contain histidine 
decarboxyase inhibitors such as .alpha.-fluoromethylhistidine, described 
in U.S. Pat. No. 4,325,961. The compounds of the Formula I may also be 
advantageously combined with an H.sub.1 or H2-receptor antagonist, such as 
for instance cimetidine, ranitidine, terfenadine, famotidine, 
aminothiadiazoles disclosed in EP No. 81102976.8 and like compounds, such 
as those disclosed in U.S. Pat. Nos. 4,283,408; 4,362,736; 4,394,508; 
European Patent Application No. 40,696 and a pending U.S. application Ser. 
No. 301,616, filed Sept. 14, 1981. The pharmaceutical compositions may 
also contain a K.sup.+ /H.sup.+ ATPase inhibitor such as omeprazole, 
disclosed in U.S. Pat. No. 4,255,431, and the like. Each of the references 
referred to in this paragraph is hereby incorporated herein by reference. 
Another embodiment of the present invention are certain novel compounds 
encompassed by Formula I. These compounds are shown in Table IV. 
##STR35## 
TABLE IV 
______________________________________ 
NOVEL COMPOUNDS 
Z R.sub.1 R.sub.2 
R.sub.3 
R.sub.4 
R.sub.5 
T 
______________________________________ 
S H H H H H 7-OCH.sub.3 
S H H H H 8-Cl 7-OCH.sub.3 
S CH.sub.3 H H H 8-Cl 7-OCH.sub.3 
S CH.sub.3 H H H 8-Cl 7-OH 
S CH.sub.3 H H H H 7-OCH.sub.3 
S H H H H H 7-OH 
S CH.sub.3 H H H H 7-OH 
SO H H H H H 7-OCH.sub.3 
SO CH.sub.3 H H H H 7-OCH.sub.3 
S SO.sub.2 Ph--p-Me 
H H H H 7-OCH.sub.3 
SO.sub.2 
H H H H H 7-OCH.sub.3 
S COCH.sub.3 H H H H 7-OCH.sub.3 
S COCH.sub.3 H H H H H 
SO.sub.2 
H H H H H H 
S CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 
H H H H H 
S CH.sub.2 CO.sub.2 H 
H H H H H 
S CO.sub.2 CH.sub.3 
H H H H H 
S CH.dbd.CHCO.sub.2 CH.sub.3 
H H H H H 
______________________________________ 
The following examples are provided to aid in the interpretation of the 
claims appearing below. They are not intended as a limitation upon the 
scope of said claims. All temperatures are in degrees Celsius. 
EXAMPLE 1 
Preparation of 1,4-diazaphenoxazine Step A: Sodium (1.15 g) was dissolved 
in iso-propanol (250 ml) with brief refluxing. The solution was cooled to 
room temperature and 2,3-dichloropyrazine (7.45 g) and ortho aminophenol 
(5.45 g) were added. The mixture was heated at reflux for 4 hours, cooled 
to room temperature and evaporated to about one-quarter volume in vacuo. 
To the black solution was added water (200 ml) with stirring. A solid 
precipitate was collected by filtration. The brown solid was 
recrystallized from MeOH/H.sub.2 O (2:1) to yield 6.3 g of fluffy brown 
needles. A second recrystallization afforded off-white needles, m.p. 
88.degree.-89.degree.. 
Analysis, Calculated: C, 54.19; H, 3.64; N, 18.96; Cl, 15.99. Observed: C, 
54.25; H, 3.54; N, 18.60; Cl, 15.76. 
Step B: A mixture of the compound from Step A (1 g) in pyridine (20 ml) was 
refluxed for 4 hours. DBU (2 ml) was added and the solution refluxed an 
additional 5 hours. The reaction mixture was diluted by the slow addition 
of water (100 ml). The resulting precipitate was collected by filtration, 
washed with water and air dried. Recrystallization from ethanol afforded 
the title compound, m.p. 230.degree.-232.degree.. 
Analysis, Calculated: C, 64.86; H, 3.81; N, 22.69. Observed: C, 64.93; H, 
3.80; N, 22.44. 
EXAMPLE 2 
1,4-Diazaphenothiazine 
Step A: Preparation of ortho-(2-chloro-3-pyrazinyl)thioaniline 
To a solution of 2,3-dichloropyrazine (7.45 g, 50 mmoles) and 
ortho-aminothiophenol (6.25 g, 50 mmoles) in tetrahydrofuran (50 ml) was 
added dropwise a solution of triethylamine (6 g) in THF (25 ml) over a 
period of 10 minutes. A cold water bath was used to control the modest 
exotherm and maintain the temperature below 20.degree.. The triethylamine 
chloride was removed by filtration and the filtrate was evaporated to 
yield a solid that was slurried for 1 hour in methanol (75 ml). The solid 
thus obtained was recrystallized from methanol to yield the title 
compound, m.p. 130.degree.-135.degree. (dec.). 
Analysis, Calculated: C, 50.53; N, 3.39; N, 17.68; S, 13.49; Cl, 14.91. 
Observed: C, 50.68; N, 3.37; N, 17.56; S, 13.38; Cl, 14.54. 
Step B: Preparation of 1,4-diazaphenothiazine 
1,4-Diazaphenothiazine can be prepared by heating the title compound of 
Step A of this example with DBU in pyridine. 
It was also prepared according to Cheeseman, Tetrahedron 33 827 (1973) to 
yield 1,4-diazaphenothiazine m.p. 190.degree.-193.degree.. Lit. 
190.degree.-192.degree.. 
EXAMPLE 3 
7-Methoxy-1,4-diaza-10H-phenothiazine 
5-Methoxy-2-aminothiophenol (5.5 g, 35.4 mmole) 2,3-dichloropyrazine (5.4 
g, 36.2 mmoles), sodium carbonate (7.8 g, 73.6 mmoles) in 30 ml 
o-dichlorobenzene was refluxed until a vigorous reaction took place. 
Heating was stopped, the reaction mixture was cooled to room temperature, 
poured in water (50 ml), stirred for 30 minutes, filtered, washed with 
water and air-dried to yield the title compound, m.p. 
210.degree.-211.degree. after recrystallization from ethanol-acetone. 
Analysis, Calculated: C, 57.13; H, 3.92; N, 18.17; S, 13.86. Observed: C, 
57.23; H, 3.82; N, 17.94; S, 14.04. 
EXAMPLE 4 
7-Methoxy-1,4-diaza-10-methylphenothiazine 
10H-7-Methoxy-1,4-diazaphenothiazine (2.3 g, 10 mmoles) in glyme (50 ml) 
was heated with NaH (500 mg) when N.sub.2 evolution subsided within 30 
minutes, a red solution was obtained and treated with excess CH.sub.3 I (5 
ml). Reflux was maintained for 15 minutes. The mixture was absorbed on 
silica gel and elution with 30% EtOAc in hexane yield successively 1.8 g 
of the title compound, m.p. 109.degree.-111.degree. and 0.23 g of the 
isomeric 7-methoxy-1-methyl-1,4-ciazaphenothiazine, m.p. 
128.degree.-130.degree.. 
Title compound: 
Analysis, Calculated: C, 58.76; H, 4.52; N, 17.13; S, 13.07. Observed: C, 
58.64; H, 4.48; N, 17.00; S, 12.92. 
Isomeric compound: 
Analysis, Calculated: C, 58,76; H, 4.52; N, 17.13; S, 13.07. Observed: C, 
58.87; H, 4.68; N, 17.03; S, 13.15. 
EXAMPLE 5 
7-Hydroxy-1,4-diaza-10H-phenothiazine 
Sodium hydride (60 mg, 2.5 mmoles) was added to ethanethiol (124 mg, 2 
mmoles) in dry DMF (2 ml) under argon. 
7-Methoxy-1,4-diaza-10H-phenothiazine (462 mg, 2 mmoles) was then added 
and the reaction mixture was refluxed for 3 hours. The mixture was poured 
into 0.5N HCl (50 ml). The solid was collected, washed with methanol and 
air-dried to yield starting material. Extraction of the filtrate with 
ethyl acetate gave 100 mg of a mixture that was chromatographed on silica 
gel, eluting with 40% ethyl acetate in hexane to yield 25 mg of the title 
compound. 
Analysis, Calculated: C, 55.19; H, 3.25; N, 19.34; S, 14.76. Observed: C, 
55.19; H, 3.37; N, 19.12; S, 14.86. 
EXAMPLE 6 
7-Hydroxy-1,4-diaza-10-methylphenothiazine 
Following a procedure identical to that described in Example 5, 
7-methoxy-1,4-diaza-10-methylphenothiazine was converted to the title 
compound, m.p. 207-208.5.degree.. 
Analysis, Calculated: C, 57.13; H, 3.92; N, 18.17; S, 13.86. Observed: C, 
57.16; H, 3.97; N, 18.26; S, 13.81. 
EXAMPLE 7 
7-Methoxy-1,4-diaza-10H-10-acetyl phenothiazine 
A mixture of 7-methoxy-1,4-diaza-10H-phenothiazine (4.62 g, 20 mmoles) and 
sodium acetate (2.5 g) in acetic anhydride (50 ml) was refluxed for 18 
hours. The reaction mixture was cooled to room temperature. The resulting 
crystals were filtered, washed with dilute acetic acid and air dried to 
yield 5.0 g of the title compound, m.p. 221.degree.-223.degree.. 
EXAMPLE 8 
7-Methoxy-1,4-diaza-10-methylphenothiazine 
To a suspension of sodium hydride (0.5 g, 20.8 mmoles) in dimethoxy ethane 
(50 ml) was added 7-methoxy-1,4-diaza-10H-phenothiazine (2.3 g, 10 
mmoles). After stirring for 30 minutes, a deep red colored solution of the 
anion was obtained and was quenched by adding excess methyl iodide (5 ml). 
The reaction mixture was poured on ice and the resulting mixture was 
extracted with ethyl acetate, washed with brine, dried (Na.sub.2 SO.sub.4) 
and evaporated to dryness. The residue was chromatographed on silica gel, 
yielding 1.8 g of the title compound, m.p. 109.degree.-111.degree.. 
Also obtained was 0.28 g of isomeric 
3-methoxy-6,9-diaza-9-methylphenothiazine, m.p. 128.degree.-130.degree.. 
EXAMPLE 9 
1,4-Diaza-10-methylphenothiazine 
Similarly, using the procedure of Example 8, substituting 
1,4-diaza-10H-phenothiazine for 3-methoxy-1,4-diaza-10H-phenothiazine, the 
title compound, m.p. 101.degree.-102.degree., was obtained. 
The isomeric 1,4-diaza-1-methylphenothiazine, m.p. 101.degree.-102.degree. 
was also obtained. 
EXAMPLE 10 1,4-Diazaphenothiazine-5-oxide 
To 1,4-diaza-10H-phenothiazine (1 g, 5 mmoles) in acetic acid (15 ml) was 
added 50% hydrogen peroxide (1 ml). The mixture was stirred at 55.degree. 
for 30 minutes. The mixture was evaporated to a small volume and the title 
compound crystallized out. The crystals were filtered, washed with acetic 
acid and air dried to yield 983 mg of the title compound, m.p. 
261.degree.-263.degree.. 
EXAMPLE 11 
7-Methoxy-1,4-diazaphenothiazine-5-oxide 
Similarly, as in Example 10, but substituting 
7-methoxy-1,4-diazaphenothiazine for 1,4-diazaphenothiazine, the title 
compound, m.p. 240.degree.-241.degree., was obtained in an 87% yield. 
EXAMPLE 12 
1,4-Diazaphenothiazine-5,5-dioxide 
Similarly, by carrying out the reaction described in Example 10, but at 
80.degree. instead of 55.degree., the title compound, m.p. 
316.degree.-318.degree., was obtained. 
EXAMPLE 13 
7-Methoxy-1,4-diazaphenothiazine-5,5-dioxide 
Similarly, as in Example 10, but substituting 
7-methoxy-1,4-diazaphenothiazine for 1,4-diazaphenothiazine and carrying 
out the reaction at 80.degree. instead of 55.degree., the title compound, 
m.p. 293.degree.-294.degree., was obtained. 
EXAMPLE 14 
7-Methoxy-10-methyl-1,4-diazaphenothiazine-5-oxide 
Similarly, as in Example 10, but substituting 
7-methoxy-10-methyl-1,4-diazaphenothiazine for 1,4-diazaphenothiazine, the 
title compound, m.p. 229.degree.-231.degree. was obtained in 67% yield. 
EXAMPLE 15 
1,4-Diaza-10-carboethoxymethylphenothiazine 
Following the conditions of Example 4 but substituting ethyl bromoacetate 
for methyl iodide, the title compound, m.p. 115.degree.-117.degree., was 
obtained. 
The isomeric 1,4-diaza-1-carboethoxymethyl phenothiazine m.p. 
157.degree.-158.degree., was also obtained. 
EXAMPLE 16 
1,4-Diaza-10-carboxymethylphenothiazine 
1,4-Diaza-10-carboethoxymethylphenothiazine (862 mg, 3 mmoles) in methanol 
(17 ml) was treated with 5N sodium hydroxide (1 ml). The mixture was 
refluxed for 2 hours. Water (17 ml) was added and the solution was 
acidified with 6N hydrochloric acid (1 ml). The title compound, m.p. 
197.degree.-198.degree., was isolated by filtration in a yield of 84%. 
EXAMPLE 17 
10-Acetyl-1,4-diazaphenothiazine 
By following the conditions of Example 7, but substituting 
1,4-diazaphenothiazine for 3-methoxy-1,4-diazaphenothiazine, the title 
compound, m.p. 174.degree.-175.degree., was obtained in an 89% yield. 
EXAMPLE 18 
10-Carbomethoxy-1,4-diazaphenothiazine 
By following the conditions of Example 4, but substituting 
1,4-diazaphenothiazine for 7-methoxy 1,4-diazaphenothiazine and 
methylchloroformate for methyl iodide, the title compound, m.p. 
137.degree.-138.degree. was obtained in a 23% yield. 
EXAMPLE 19 8-Chloro-1,4-diaza-7-methoxyphenothiazine 
Following the conditions of Cheeseman et al., (Tetrahedron 33, 827 (1977)), 
the reaction of 2,3-dichloropyrazine with 
2-amino-4-chloro-5-methoxythiophenol gave the title compound, in a 25% 
yield. 
Analysis, Calculated: C, 4972; H, 3.03; N, 15.81; S, 13.34. Observed: C, 
49.70; H, 2.83; N, 15.84; S, 13.54. 
EXAMPLE 20 
8-Chloro-7-methoxy-1,4-diaza-10-methylphenothiazine 
By following the conditions of Example 4, but substituting 
8-chloro-7-methoxy-1,4-diaza-phenothiazine for 
7-methoxy-1,4-diazaphenothiazine, the title compound was obtained in a 50% 
yield. 
Analysis, Calculated: C, 51.52; H, 3.60; N, 15.02; Cl, 12.67; S, 11.46. 
Observed: C, 51.66; H, 3.79; N, 14.84; Cl, 12.61; S, 11.71. 
EXAMPLE 21 
8-Chloro-7-hydroxy-1,4-diaza-10-methylphenothiazine 
By following the conditions of Example 5, but substituting 
8-chloro-7-methoxy-1,4-diaza-10-methyl-phenothiazine for 
7-methoxy-1,4-diazaphenothiazine, the title compound was obtained in a 90% 
yield. 
Analysis, Calculated: C, 49.72; H, 3.03; N, 15.81; S, 12.07, Cl, 13.34. 
Observed: C, 49.60; H, 3.19; N, 15.75; S, 12.11; Cl, 13.21. 
EXAMPLE 22 
10-(2-Carbomethoxyvinyl)-1,4-diazaphenothiazine 
To a suspension of sodium hydride (0.1 g, 4.2 mmoles) in dimethoxyethane 
(10 ml) was added 1,4-diazaphenothiazine (200 mg, 1 mmole). After stirring 
for 30 minutes a deep red solution of the anion was obtained and this was 
treated with methylpropiolate (85 .mu.l, 1.0 mmole). Stirring was 
maintained for 30 minutes. The mixture was evaporated to dryness and the 
residue was purified by chromatography. Elution with 40% EtOAc/hexane gave 
the desired product as on orange solid, m.p. 165.degree.-169.degree.. NMR 
analysis showed the product to be a mixture of trans and cis isomers in a 
ratio of 4 to 1. 
EXAMPLE 23 
7-Methoxy-10-p-toluenesulfonyl-1,4-diazaphenothiazine 
To a cooled, stirred suspension of 1,4-diazaphenothiazine (2.31 g, 10 
mmole) in glyme (23 ml) was added portionwise sodium hydride (300 mg). 
After stirring the mixture at room temperature for one hour, the mixture 
was again cooled in an ice-bath and p-tosylchloride (1.9 g, 10 mmole) was 
added in portions. An additional 200 mg of sodium hydride was added and 
the solution stirred at room temperature for one hour. Water was 
cautiously added, and the phases were separated. The organic phase was 
washed with water and dried. The title compound slowly crystallized from 
the organic solvent. The crude title compound was recrystallized from 
ethyl acetate/diisopropyl ether (2:1). 
Analysis Calculated: C, 56.09; H, 3.92; H, 10.90; S, 16.64. Observed: C, 
56.03; H, 4.00; N, 10.83 S, 16.81. 
EXAMPLE 24 
9-Oxo-10-trifluoroacetyl-9,10-dihydro-pyrazino[2,3-b]pyrrolo[1,2,3-d,e][1,4 
]benzothiazine 
A suspension of the acid from Example 16 (2.59 g, 10 mmole) in methylene 
chloride (78 ml) was treated with trifluoroacetic anhydride (1.55 ml, 2.31 
g, 11.0 mmole). The mixture was stirred at room temperature overnight, and 
then evaporated. The residue was dissolved in ethylene chloride and the 
solution evaporated onto silica gel (13 g). The solid was placed on a 
column of silica gel (100 g) and elution with 1:1 ethyl acetate/hexane 
gave 878 mg of title compound. 
Analysis, Calculated: C, 49.86; H, 1.79; N, 12.46; S, 9.50; F, 16.90. 
Observed: C, 49.69; H, 2.02; N, 12.22; S, 10.07; F: 16.67. 
In those instances where asymmetric centers are present, more than one 
stereoisomer is possible, and all possible isomeric forms are deeded to be 
included within the planar structural representation shown. Optically 
active (R) and (S) isomers may be resolved using conventional techniques 
known to the skilled artisan.