Pharmaceutical compositions containing a compound of Formula I: ##STR1## wherein X is O, S, SO or SO.sub.2 and R.sub.2, R.sub.3, R.sub.4 and R.sub.5 may be positioned anywhere on the structure, or a pharmaceutically-acceptable salt thereof and certain novel benzo[a]phenothiazines, which compositions and compounds are useful in treating allergic conditions, asthma, cardiovascular disorders, inflammation and pain and are useful as cytoprotective agents.

Benzo[a]phenothiazine and hydro-derivatives and analogs thereof are useful 
as inhibitors of the biosynthesis of mammalian leukotrienes. As such, 
these compounds are useful therapeutic agents for treating allergic 
conditions, asthma, cardiovascular disorders, inflammation and pain. 
These compounds may 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 induced pancreatic or gastric 
damage; trauma- or stress-induced cell damage; and glycerol-induced renal 
failure. 
BACKGROUND OF THE INVENTION 
The leukotrienes are a novel group of biologically-active substances 
derived from arachidonic acid through the action of the 5-lipoxygenase 
enzyme system. There are two groups of leukotrienes derived from a 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. 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. See: D. M. Bailey and F. 
B. Casey, Ann. Rpts. Med. Chem. 17, 203 (1982). 
Because the leukotrienes have been implicated in numerous disease states, 
the inhibition of leukotriene biosynthesis and/or antagonism of 
leukotriene action, will provide a therapeutic benefit to patients 
suffering from these disease states. These disease states include, but are 
not limited to: asthma; allergic conditions, such as allergic rhinitis; 
skin diseases, including psoriasis and atopic dermatitis; inflammation; 
gouty arthritis; gall bladder spasms; and cardiovascular disorders, such 
as angina. 
Certain benzo[a]phenothiazine derivatives of general Formula A are known 
compounds: 
##STR2## 
Some of these compounds have been used (inter alia) as antioxidants, dyes, 
whitening agents, photosensitizers and polymerization retardants. See for 
example; T. G. Jackson et al., J. Org. Chem. 32 1190-1194 (1967), J. A. 
Van Allen et al., J. Organ. Chem. 34 1691-1694 (1969), T. G. Jackson et 
al. J. Med. Chem. 11 622-623 (1968), N. L. Agarwal et al., Aceta Chim. 
Acad. Sci. Hung. 92 89-97 (1977), R. L. Mital et al., J. Inst. Chem. 
(India) 40 286-287 (1977), J. P. Tiwari et al., Anorg. Chem., Org. Chem. 
33B 214-215 (1978), J. P. Tiwari et al., Indian J. Chem. Sect. B 17B 
408-409 (1979), Y. Ueno et al., J. Heterocycl. Chem. 19 167-169 (1982), S. 
Kikkawa et al., Chemical Abstracts 76 139757q (1972) and French Pat. No. 
1,541,977 (1968). 
It has been discovered that compounds of the Formula A type and analogs 
thereof are effective inhibitors of mammalian leukotriene biosynthesis and 
are thus useful in the treatment of leukotrienemediated conditions, such 
as asthma, allergies, inflammation, and the like in mammals, especially in 
humans. 
DESCRIPTION OF THE INVENTION 
The present invention relates to pharmaceutical compositions containing 
compounds of the Formula (I): 
##STR3## 
wherein X is O, S, SO or SO.sub.2 and R.sub.2, R.sub.3, R.sub.4 and 
R.sub.5 may be positioned anywhere on the structure; 
pharmaceutically-acceptable salts thereof; a method of treatment using 
compounds of Formula I; and certain novel compounds of Formula I. 
In one of its embodiments, the present invention relates to a 
pharmaceutical composition containing a compound of Formula I and a 
pharmaceutically-acceptable carrier: 
##STR4## 
wherein: X is O, S, SO or SO.sub.2 ; 
R.sub.1 is H; C.sub.1 to C.sub.6 -alkyl; C.sub.1 to C.sub.6 -acyl; C.sub.1 
to C.sub.6 -aminoacyl; C.sub.1 to C.sub.6 -acyloxy-C.sub.1 to C.sub.6 
-alkyl (e.g., --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 (e.g., --CH(CH.sub.3)OC.sub.2 H.sub.5); 
##STR5## 
where the substituents of substituted phenyl are as defined below among 
the definitions of R.sub.15 ; carbamoyl; 
##STR6## 
SO.sub.2 -C.sub.6 H.sub.4 -p-CH.sub.3 ; SO.sub.2 CH.sub.3 ; or R.sub.1 is 
an acyl group, such that R.sub.1 -OH is an essential amino acid, where 
alkyl indicates straight- or branched-chain and cycloalkyl groups, acyl is 
defined as alkanoyl, and essential amino acids are the naturally-occurring 
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; 
R.sub.2, R.sub.3, R.sub.4 and R.sub.5, all of which may be positioned 
anywhere on the structure, are independently selected from: 
(1) hydrogen; 
(2) alkyl having 1 to 6 carbon atoms; 
(3) alkenyl having 2 to 6 carbon atoms; 
(4) --(CH.sub.2).sub.n M, where n is 0 to 6 and M is 
(a) OR.sub.15 ; 
(b) halogen (F, Cl, Br or I); 
(c) CF.sub.3 ; 
(d) SR.sub.15, where R.sub.15 is H; C.sub.1 to C.sub.6 -alkoxy-C.sub.1 to 
C.sub.6 -alkyl; C.sub.1 to C.sub.6 -acyloxy-C.sub.1 to C.sub.6 -alkyl; 
C.sub.1 to C.sub.6 -alkyl; benzyl; --(CH.sub.2).sub.n COOR.sub.6, wherein 
n is 0 to 6; CN; formyl; C.sub.1 to C.sub.4 -perfluoroalkyl; CH.sub.2 
-R.sub.12, wherein R.sub.12 is C.sub.1 to C.sub.5 -alkyldimethylamino or 
phenyl; phenyl; substituted phenyl, wherein the substituents are C.sub.1 
to C.sub.3 -alkyl, halogen, CN, CF.sub.3, COOR.sub.6, CH.sub.2 COOR.sub.6, 
(CH.sub.2).sub.p NR.sub.8 R.sub.9, where p is 0 to 2, C.sub.1 to C.sub.3 
-alkoxy or OH; 
(e) phenyl or substituted phenyl, wherein the substituents of substituted 
phenyl are as defined in R.sub.15 ; 
(f) COOR.sub.6 ; 
##STR7## 
(h) tetrazole; 
##STR8## 
(j) --NR.sub.8 R.sub.9 ; (k) --NHSO.sub.2 R.sub.10 wherein R.sub.10 is OH, 
C.sub.1 to C.sub.6 -alkyl, C.sub.1 to C.sub.6 -alkoxy, or phenyl; 
##STR9## 
(m) --SOR.sub.11, wherein R.sub.11 is C.sub.1 to C.sub.6 -alkyl; phenyl; 
substituted phenyl, where the substituents of substituted phenyl are as 
defined in R.sub.15 ; (CH.sub.2).sub.m COOR.sub.6, wherein m is 1 to 6; 
CN; formyl or perfluoro-C.sub.1 to C.sub.4 -alkyl; 
(n) --CONR.sub.8 R.sub.9 ; 
(o) --SO.sub.2 NR.sub.8 R.sub.9 ; 
(p) --SO.sub.2 R.sub.13, wherein R.sub.13 is OH; C.sub.1 to C.sub.6 -alkyl; 
H; phenyl; substituted phenyl where the substituents of substituted phenyl 
are as defined in R.sub.15 ; (CH.sub.2).sub.m COOR.sub.6, wherein m is 1 
to 6; CN; formyl or perfluoro-C.sub.1 to C.sub.4 -alkyl; 
(q) NO.sub.2 ; 
##STR10## 
(t) --CN; (u) --OPO(OR.sub.6).sub.2 ; or 
(v) OR.sub.a, where R.sub.a is H; C.sub.1 to C.sub.5 -alkyl; C.sub.1 to 
C.sub.5 -acyl; C.sub.1 to C.sub.6 -alkoxy-C.sub.1 to C.sub.6 -alkyl; 
C.sub.1 to C.sub.6 -acyloxy-C.sub.1 to C.sub.6 -alkyl; C.sub.1 to C.sub.4 
-aminoacyl; carbamoyl; 
##STR11## 
wherein the substituents on substituted phenyl are as defined in R.sub.15 
; 
##STR12## 
where R.sub.c is C.sub.1 to C.sub.4 -alkyl; 
##STR13## 
where R.sub.d is C.sub.1 to C.sub.6 -alkyl or C.sub.1 to C.sub.6 
-acyloxy-C.sub.1 to C.sub.4 -alkyl (e.g., CH(CH.sub.3)OCOCH.sub.3); or is 
a structure such that --OR.sub.a is an ester of an essential amino acid, 
wherein essential amino acids are as defined above; and 
(5) --(CHR.sub.6).sub.q COOR.sub.6, where q is 0 to 4; 
where each R.sub.6 is independently H, phenyl or C.sub.1 to C.sub.6 -alkyl; 
each R.sub.7 is C.sub.1 to C.sub.6 -alkyl, benzyl, phenyl or C.sub.1 to 
C.sub.6 -acyloxy-C.sub.1 to C.sub.6 -alkyl; 
each R.sub.8 and each R.sub.9 is independently H, phenyl or substituted 
phenyl, where the substituents of substituted phenyl are as defined in 
R.sub.15, or C.sub.1 to C.sub.4 -alkyl, or an R.sub.8 and an R.sub.9 may 
be joined through the N to form a heterocycloalkyl of 5 to 8 ring atoms; 
each R.sub.14 is independently H, OH, (CH.sub.2).sub.q COOR.sub.6 where q 
is 0 to 4, C.sub.1 to C.sub.6 -alkyl, C.sub.1 to C.sub.6 -alkoxy, C.sub.1 
to C.sub.6 -acyloxy-C.sub.1 to C.sub.6 -alkoxy, phenyl or substituted 
phenyl wherein the substitutents of substituted phenyl are as defined in 
R.sub.15, C.sub.1 to C.sub.6 -aminoalkyl, or R.sub.14 is such that 
R.sub.14 CO.sub.2 H is an essential amino acid, as defined above; and 
the broken lines ( ) in ring A represent single or double bonds. 
Pharmaceutically-acceptable salts of the compounds described herein are 
also included within the scope of the present invention. Such salts may be 
prepared from pharmaceutically-acceptable non-toxic bases, including 
inorganic bases and organic bases when the compound is acidic. Salts 
derived from inorganic bases include sodium, potassium lithium, ammonium, 
calcium, magnesium, ferrous, zinc, copper, maganous, aluminum, ferric, 
maganic salts and the like. Particularly preferred are the potassium, 
sodium, calcium, and magnesium salts. Salts derived from 
pharmaceutically-acceptable organic non-toxic bases include salts of 
primary, secondary, and teriary amines, substituted amines, including 
naturally-occurring substituted amines, cyclic amines and basic ion 
exchange resins, such as isopropylamine, tri-methylamine, diethanolamine, 
diethylamine, triethylamine, tripropylamine ethanolamine, 
2-dimethylaminoethanol, 2-diethylaminoethanol, tomethamine, lysine, 
arginine, histidine, betaine, ethylenediamine, glucosamine, 
methylglucamine, theobromine, purines, piperazine, 
N,N'-dibenzylethylenediamine, piperidine, N-ethyl-piperidine, morpholine, 
N-ethylmorpholine, polyamine resins and the like. 
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-toluenesulfonic, acetic, benzoic, camphorsulfonic, 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 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. 
A preferred composition is comprised of compounds having the Formula II; 
##STR14## 
wherein: R.sub.1 is hydrogen, C.sub.1 to C.sub.4 -alkyl, C.sub.1 to 
C.sub.4 -acyl, C.sub.1 to C.sub.6 -aminoacyl, C.sub.1 to C.sub.6 
-acyloxy-C.sub.1 to C.sub.6 -alkyl (e.g., 
CH(CH.sub.3)OCOC(CH.sub.3).sub.3), or --COOR.sub.d ; 
R.sub.3, R.sub.4 and R.sub.5, all of which may be positioned anywhere on 
the structure, are each independently selected from hydrogen, halogen, 
CH.sub.3, CF.sub.3, COCH.sub.3, R.sub.b, SR.sub.6, CH.sub.2 OH, OR.sub.b, 
COOR.sub.b and CH.sub.2 COOR.sub.b, where each R.sub.b is independently 
selected from H and C.sub.1 to C.sub.4 -alkyl; 
X, R.sub.a, R.sub.d, R.sub.6, alkyl, acyl and halogen are as defined above, 
and OR.sub.a may be positioned anywhere on the structure. 
A more preferred composition is comprised of compounds of Formula III: 
##STR15## 
wherein: X is O or S; and 
R.sub.1, R.sub.3, R.sub.4, R.sub.5 (where R.sub.3, R.sub.4 and R.sub.5 may 
be positioned anywhere on the structure) and R.sub.a are as defined for 
Formula II compounds above. 
A still more preferred composition is comprised of compounds of Formula 
III, where X is S and the remaining substituents are as defined for 
Formula III, with the proviso that at least one of R.sub.1 or R.sub.a is 
not hydrogen. 
Another preferred embodiment of the present invention comprises the novel 
compounds of Formula IIIa: 
##STR16## 
wherein: X, R.sub.2, R.sub.3, R.sub.4, R.sub.5 (where R.sub.2, R.sub.3, 
R.sub.4 and R.sub.5 may be positioned anywhere on the structure) and 
R.sub.6 are as defined for Formula I. 
A particularly preferred series of novel compounds of Formula IIIa are 
those wherein: 
X is S; 
R.sub.2 is OH and is located at position 5; 
R.sub.6 is CH.sub.3 ; and 
R.sub.3, R.sub.4 and R.sub.5 are as defined for Formula I and may be placed 
anywhere on the structure. 
Examples of the Formula I compounds useful in the compositions of the 
present invention are tabulated below in Table I (the number preceding the 
R.sub.2 -R.sub.5 definitions signifying that group's position on the ring 
system). 
TABLE I 
__________________________________________________________________________ 
COMPOUNDS OF FORMULA I 
##STR17## (I) 
Compound.sup.a 
X Ring A 
R.sub.1 R.sub.2 R.sub.3 R.sub.4 
R.sub.5 
__________________________________________________________________________ 
1..sup.1 
S aromatic 
H 5-OH H H H 
2..sup.1 
S aromatic 
H 5-OCOCH.sub.3 6-Cl H H 
3. S aromatic 
H H H H H 
4. S aromatic 
H 5-OH 6-Cl H H 
5. S aromatic 
H 5-OH 6-Cl 9-Cl H 
6. S aromatic 
H 5-OH 6-Cl 9-OCH.sub.3 
H 
7. S aromatic 
H 5-OCOCH.sub.3 6-Cl 9-CH.sub.3 
H 
8..sup.1 
O aromatic 
H 5-OH H H H 
9..sup.1,2 
O aromatic 
H 5-OCOCH.sub.3 H H H 
10. SO aromatic 
H 5-OH H H H 
11..sup.1,2 
SO.sub.2 
aromatic 
H 5-OH H H H 
12. SO aromatic 
H H H H H 
13. SO.sub.2 
aromatic 
H H H H H 
14. SO aromatic 
COCH.sub.3 
H H H H 
15 S aromatic 
H 1-CO.sub.2 H H H H 
16. S aromatic 
CH.sub.3 2-Et H H H 
17. S aromatic 
COCH.sub.3 
2-COCH.sub.3 H H H 
18. S aromatic 
H 2-COCH.sub.3 H H H 
19. S aromatic 
H H H H 10-phenyl 
20. S aromatic 
H H H 8-CH.sub.3 
11-CH.sub.3 
21. S aromatic 
H H H H 10-COCH.sub.3 
22. S aromatic 
H 5-OH 6-NHCOCH.sub.3 
9-F H 
23. S aromatic 
H 5-OH 6-NHphenyl 
9-Cl H 
24. SO aromatic 
H 5-OAc 6-Cl H 10-CF.sub.3 
25. SO aromatic 
H 5-OCH.sub.2 Ph 
6-Cl H 10-CF.sub.3 
26. S aromatic 
H 5-OH 6-Cl 9-CH.sub.3 
11-CH.sub.3 
27. S aromatic 
H 5-OCH.sub.3 6-Cl 9-OCH.sub.3 
H 
28. SO.sub.2 
1,4-dihydro 
H 5-OH H H H 
29. SO.sub.2 
aromatic 
COCH.sub.3 
4-CH.sub.3 H 9-SCH.sub.3 
H 
30. O aromatic 
H H H 9-SO.sub.2 CF.sub.3 
H 
31. O aromatic 
H H H 11-CH.sub.3 
H 
32. S aromatic 
COCH.sub.3 
5-OCOMe H H H 
33. S aromatic 
CH.sub.2 OAc 
5-OH H H H 
34. S aromatic 
CH.sub.2 OAc 
5-OCOMe H H H 
35..sup.1 
S aromatic 
Me 5-OH H H H 
36..sup.1,2 
S aromatic 
H 5-OCOCH.sub.3 H H H 
37. S aromatic 
CH.sub.3 5-OCH.sub.3 H H H 
38. S aromatic 
CH.sub.3 5-OCOCH.sub.3 H H H 
39. S aromatic 
COCH.sub.3 
5-OH H H H 
40. S aromatic 
COCH.sub.3 
5-OCH.sub.3 H H H 
41..sup.1 
S aromatic 
H 5-OCOCH.sub.2 NH.sub.2 
H H H 
42..sup.1 
S 1,4-dihydro 
H 5-OH H H H 
43..sup.1 
S aromatic 
H 5-OCOCH(CH.sub.3).sub.2 
H H H 
44..sup.1 
S aromatic 
H 5-OCOC(CH.sub.3).sub.3 
H H H 
45..sup.1 
S aromatic 
H 5-OCOC.sub.6 H.sub.5 
H H H 
46..sup.1 
S aromatic 
H 5-OH 6-CH.sub.3 
H H 
47..sup.1 
S aromatic 
H 5-OCOCH.sub.3 6-CH.sub.3 
H H 
48. S aromatic 
H 5-OH 1-OH 6-CH.sub.3 
H 
49. S aromatic 
H 5-OCOCH.sub.3 1-OH 6-CH.sub.3 
H 
50. S aromatic 
H 5-OH 1-OCH.sub.3 
6-CH.sub.3 
H 
51. S aromatic 
H 5-OCOCH.sub.3 1-OCH.sub.3 
6-CH.sub.3 
H 
52. S aromatic 
H 5-OCOC(CH.sub.3).sub.3 
1-OCH.sub.3 
6-CH.sub.3 
H 
53. S 1,4-dihydro 
H 5-OCOCH.sub.3 H H H 
54. SO.sub.2 
1,4-dihydro 
H 5-OCOCH.sub.3 H H H 
55. SO aromatic 
H 5-OCOCH.sub.3 H H H 
56..sup.1,2 
SO.sub.2 
aromatic 
H 5-OCOCH.sub.3 H H H 
57. S aromatic 
H 5-OCH.sub.2 OCH.sub.3 
H H H 
58. S aromatic 
H 5-OCH.sub.3 H H H 
59. S aromatic 
H 5-OCOC.sub.6 H.sub.4p-OMe 
H H H 
60. S aromatic 
H 5-OCOC.sub.6 H.sub.4p-Cl 
H H H 
61. S aromatic 
H 5-OCOC.sub.6 H.sub.4p-NH.sub.2 
H H H 
62. S aromatic 
H 5-OCOC.sub.6 H.sub.4p-CO.sub.2 H 
H H H 
63. S aromatic 
H 5-OCOC.sub.6 H.sub.4 OCF.sub.3 
H H H 
64. S aromatic 
H 5-OCOC.sub.6 H.sub.4m-CN 
H H H 
65. S aromatic 
H 5-OCO(CH.sub.2).sub.2CO.sub.2 H 
H H H 
66. S aromatic 
H 5-OCO(CH.sub.2).sub.4CO.sub.2 H 
H H H 
67. S aromatic 
H 5-OCOCH(NH.sub.2)CH.sub.3 
H H H 
68. S aromatic 
H 5-OCOCH(NH.sub.2)CH.sub.2 C.sub.6 H.sub.5 
H H H 
69..sup.1,2 
S aromatic 
##STR18## 
5-OH H H H 
70..sup.1,2 
S aromatic 
##STR19## 
5-OAc H H H 
71. S aromatic 
##STR20## 
##STR21## H H H 
72. S aromatic 
H 
##STR22## H H H 
73. S aromatic 
H 5-OPO(OEt).sub.2 
H H H 
74. S aromatic 
H 5-OH 9-OMe H H 
75. S aromatic 
H 5-OAc 9-OMe H H 
76..sup.1 
S aromatic 
H 5-OH 9-Me H H 
77..sup.1 
S aromatic 
H 5-OAc 9-Me H H 
78. S aromatic 
H 5-OH 9-F H H 
79. S aromatic 
H 5-OAc 9-F H H 
80. S aromatic 
H 5-OH 6-OAc H H 
81. S aromatic 
H 5-OAc 6-OAc H H 
82. S aromatic 
Ac 5-OH 6-OH H H 
83. S aromatic 
Ac 5-OAc 6-OAc H H 
84. SO.sub.2 
aromatic 
H 5-OH 5-OH H H 
85..sup.1,2 
O aromatic 
##STR23## 
5-OH H H H 
86. SO.sub.2 
aromatic 
##STR24## 
5-OH H H H 
87..sup.1,2 
S aromatic 
##STR25## 
5-OH H H H 
88..sup.1 
S aromatic 
CO.sub.2 C.sub.2 H.sub.5 
5-OH H H H 
89..sup.1 
S aromatic 
CO.sub.2 CH(CH.sub.3).sub.2 
5-OH H H H 
90..sup.1,2 
S aromatic 
##STR26## 
5-OH H H H 
91..sup.1,2 
S aromatic 
##STR27## 
5-OH H H H 
92..sup.1,2 
S aromatic 
##STR28## 
5-OH 6-Cl H H 
93..sup.1,2 
S aromatic 
##STR29## 
5-OH 6-CF.sub.3 
H H 
94..sup.1,2 
S aromatic 
##STR30## 
5-OH 6-F H H 
__________________________________________________________________________ 
wherein Ac is acetyl, Et is ethyl, Me is methyl and Ph is phenyl. 
.sup.a The symbol 1 next to the number of a compound indicates which 
compounds are preferred and the symbol 2 next to the number of a compound 
indicates which compounds are also more preferred. 
Another embodiment of the present invention is novel compounds and their 
pharmaceutically-acceptable salts, encompassed by Formula I, examples of 
which are listed in Table II. The number preceding the R.sub.2 -R.sub.5 
definitions signifies that group's position on the ring system. 
TABLE II 
__________________________________________________________________________ 
NOVEL COMPOUNDS OF FORMULA I 
##STR31## (I) 
Compound.sup.a 
X Ring A 
R.sub.1 R.sub.2 R.sub.3 R.sub.4 
R.sub.5 
__________________________________________________________________________ 
1..sup.1 
S aromatic 
H 5-OCOCH.sub.3 
H H H 
2. S aromatic 
CH.sub.3 5-OCH.sub.3 
H H H 
3. S aromatic 
CH.sub.3 5-OCOCH.sub.3 
H H H 
4. S aromatic 
COCH.sub.3 
5-OH H H H 
5. S aromatic 
COCH.sub.3 
5-OCH.sub.3 
H H H 
6. S aromatic 
H 5-OCOCH.sub.2 NH.sub.2 
H H H 
7. S 1,4-dihydro 
H 5-OH H H H 
8. S aromatic 
H 5-OCOCH(CH.sub.3).sub.2 
H H H 
9. S aromatic 
H 5-OCOC(CH.sub.3).sub.3 
H H H 
10. S aromatic 
H 5-OCOC.sub.6 H.sub.5 
H H H 
11. S aromatic 
H 5-OH 6-CH.sub.3 
H H 
12. S aromatic 
H 5-OCOCH.sub.3 
6-CH.sub.3 
H H 
13. S aromatic 
H 5-OH 1-OH 6-CH.sub.3 
H 
14. S aromatic 
H 5-OCOCH.sub.3 
1-OH 6-CH.sub.3 
H 
15. S aromatic 
H 5-OH 1-OCH.sub.3 
6-CH.sub.3 
H 
16. S aromatic 
H 5-OCOCH.sub.3 
1-OCH.sub.3 
6-CH.sub.3 
H 
17. S aromatic 
H 5-OCOC(CH.sub.3).sub.3 
1-OCH.sub.3 
6-CH.sub.3 
H 
18. S 1,4-dihydro 
H 5-OCOCH.sub.3 
H H H 
19. SO aromatic 
H 5-OCOCH.sub.3 
H H H 
20..sup.1 
SO.sub.2 
aromatic 
H 5-OCOCH.sub.3 
H H H 
21. SO aromatic 
H 5-OH H H H 
22..sup.1 
SO.sub.2 
aromatic 
H 5-OH H H H 
23. S aromatic 
H 5-OCH.sub.2 OCH.sub.3 
H H H 
24. S aromatic 
H 5-OCH.sub.3 
H H H 
25 S aromatic 
COCH.sub.3 
5-OCOCH.sub.3 
H H H 
26. S aromatic 
CH.sub.3 5-OH H H H 
27..sup.1 
S aromatic 
##STR32## 
5-OH H H H 
28..sup.1 
S aromatic 
##STR33## 
5-OAc H H H 
29. S. aromatic 
##STR34## 
##STR35## 
H H H 
30. S aromatic 
H 
##STR36## 
H H H 
31. S aromatic 
H 5-OPO(OEt).sub.2 
H H H 
32. S aromatic 
H 5-OH 9-OMe H H 
33. S aromatic 
H 5-OAc 9-OMe H H 
34. S aromatic 
H 5-OH 9-Me H H 
35. S aromatic 
H 5-OAc 9-Me H H 
36. S aromatic 
H 5-OH 9-F H H 
37. S aromatic 
H 5-OAc 9-F H H 
38. S aromatic 
H 5-OH 6-OAc H H 
39. S aromatic 
H 5-OAc 6-OAc H H 
40. S aromatic 
Ac 5-OH 6-OH H H 
41. S aromatic 
Ac 5-OAc 6-OAc H H 
42. SO.sub.2 
aromatic 
H 5-OH 6-OH H H 
43. O aromatic 
H 5-OH H H H 
44..sup.1 
O aromatic 
H 5-OAc H H H 
45..sup.1 
O aromatic 
##STR37## 
5-OH H H H 
46. SO.sub.2 
aromatic 
##STR38## 
5-OH H H H 
47. S aromatic 
H 5-OH 9-OCH.sub.2 CO.sub.2 H 
H H 
48. S aromatic 
H 5-OH 6-Br 9-CH.sub.2 CO.sub.2 H 
H 
49..sup.1 
O aromatic 
##STR39## 
5-OH H H H 
50..sup.1 
S aromatic 
##STR40## 
5-OH H H H 
51. S aromatic 
CO.sub.2 C.sub.2 H.sub.5 
5-OH H H H 
52. S aromatic 
CO.sub.2 CH(CH.sub.3).sub.2 
5-OH H H H 
53..sup.1 
S aromatic 
##STR41## 
5-OH H H H 
54..sup.1 
S aromatic 
##STR42## 
5-OH H H H 
55. S aromatic 
##STR43## 
5-OH 6-Cl H H 
56..sup.1 
S aromatic 
##STR44## 
5-OH 6-CF.sub.3 
H H 
57..sup.1 
S aromatic 
##STR45## 
5-OH 6-F H H 
__________________________________________________________________________ 
.sup.a The symbol 1 next to the number of a compound indicates which 
compounds are preferred. 
The compounds of Formula I may be prepared by any process available to the 
skilled artisan. 
Several such processes are illustrated in Schemes I to IV below. 
##STR46## 
where: 
R.sub.d is C.sub.1 to C.sub.4 -alkyl or phenyl; 
R.sub.e is a residue such that the reagent 
##STR47## 
is a derivative of an essential amino acid; m is 1 or 2; 
n is 0 to 3; 
R.sub.f is hydrogen, C.sub.1 to C.sub.4 -alkyl, halogen, C.sub.1 l to 
C.sub.6 -acyloxy or hydroxy; 
R.sub.g is C.sub.1 to C.sub.5 -alkyl or benzyl; 
Z is Cl, Br, I, tosylate or mesylate. 
M.S.4.A is 4 Angstrom molecular sieves; and 
MCPBA is m-chloroperbenzoic acid. 
##STR48## 
Reaction of a napthoquinone (IV), optimally two equivalents, with a 
2-aminobenzenethiol (V), in a solvent such as acetic acid, acetic 
acid-water, or a lower alkanol at from -20.degree. to +60.degree. C. for 
0.25 to 6 hours, yields the benzo[a]phenothiazin-5-one (VI). Preferably, 
the solvent is methanol or ethanol, at 0.degree. to 25.degree. C. for 0.5 
to 2 hours. Reduction of VI to VII is carried out with a reducing agent, 
such as sodium hydrosulfite, in a suitable solvent system by stirring at 
from 10.degree. to 50.degree. C. (preferably at room temperature) for 1 to 
12 hours (preferably 1 to 4 hours). The solvent system may be a 
homogeneous one, such as dimethylformamide-water or dichloromethane-water 
(Scheme I). 
The O-acyl compounds (VIII) are prepared by reacting compound VII with the 
desired acid anhydride in pyridine at a temperature of from -25.degree. to 
+75.degree. C. (preferably at 0.degree. to 50.degree. C.) for from 1 hour 
to 24 hours (preferably 4 to 15 hours) (Scheme I). 
The O-aminoacyl compounds (IX) are prepared from VIII by reacting the 
latter with an N-blocked amino acid and dicyclohexylcarbodiimide (DCC), 
followed by removal of the blocking group by treatment with HCl (Scheme 
I). 
The N-acyl compound (X) may be prepared from VII by reacting the latter 
with an acyl halide, such as acetyl chloride, in a solvent, such as 
dimethyl formamide, at from 0.degree. to 50.degree. C. (preferably at room 
temperature) for from 0.5 to 4 hours, depending on the rate of reaction of 
the particular components (Scheme I). 
To obtain the N,O-dialkyl compounds (XI), compound VIII is reacted with an 
alkyl halide or a methyl sulfonate (preferably an alkyl iodide) in the 
presence of a strong base, such as sodium hydride or potassium t-butoxide, 
in a solvent, such as tetrahydrofuran or dimethylformamide, at 0.degree. 
to 60.degree. C. (preferably room temperature) for from 1 to 24 hours 
(preferably for from 1 to 10 hours). 
In this same reaction, some of the N-alkyl-O-acyl compound (XII) is also 
obtained, and is separated from compound XI by chromatography. The 
N-acyl-O-alkyl compounds (XIII) are prepared from compound X by a 
procedure similar to that used to prepare XI and XII (Scheme I). 
The sulfoxide derivative (XIV) (m=1) are prepared by treating VIII with 
peracid such as peracetic acid or meta-chloroperbenzoic acid (MCPBA), in a 
solvent, such as methylene chloride or methylene chloride-methanol, for 
0.5 to 4 hours at 0.degree. to 30.degree. C. The sulfones (XIV) (m=2) are 
obtained by reacting VIII with a peracid in methylene chloride-methanol, 
or preferably 1,2-dichloro-ethane-ethanol, at the reflux temperature of 
the mixture for from 12 to 24 hours, depending upon the rate of reaction. 
Hydrolysis of XIV to XV is carried out by reaction with a base (for 
example, LiOH, NaOH or KOH) in a mixed solvent, such as methanol-water or 
ethanol-water, at from 0.degree. to 60.degree. C. (preferably room 
temperature), for from 5 minutes to 180 minutes (preferably 10 minutes to 
90 minutes) (Scheme II). 
To prepare a carbamate derivative such as XVII, compound VII is reacted 
with the appropriate chloroformate reagent in a suitable solvent, such as 
tetrahydrofuran, dioxane or preferably acetonitrile, and the mixture 
heated to reflux for 4 to 24 hours. Reaction of the appropriate 
chloroalkylcarbamate (XVII) with a metal salt of a carboxylic acid then 
yields the acyloxyalkoxycarbonyl compound (XVIII). Preferred salts are 
those of silver, mercury (II) or sodium, using the corresponding free acid 
as a solvent, and heating the reaction mixture at 0.degree. to 100.degree. 
C., for from 10 minutes to 2 hours (Scheme III). 
The 1,4-dihydro series of compounds (XX) is prepared by condensing a 
2-amino benzenethiol (V) with diketone (XIX) under conditions similar to 
those used for the reaction between IV and V. Preparation of compounds XXI 
to XXVI is carried out by methodology very similar to that described in 
Scheme I to obtain compounds VIII to XIII (Scheme IV). 
Some of the benzo[a]-phenothiazin-5-one derivatives used as starting 
materials are described in our co-pending applications U.S. Ser. No. 
786,257, filed Oct. 10, 1985 and European Patent Application No. 115,394. 
The disclosure of these applications is hereby incorporated herein by 
reference. 
It will be evident to one skilled in the art that R.sub.2 must be chosen so 
as to be compatible with the reaction outlined in Schemes I to IV. 
Certain of the compounds of the present invention contain one or more 
centers of asymmetry. This invention is meant to include both the racemic 
and the resolved forms of such compounds. In addition, certain compounds 
of the present invention can exist as atropisomers. All such atropisomers 
represented by the two-dimensional representation of the structure are 
also meant to be included in the present invention. 
An X-ray crystallographic analysis of a representative compound of Formula 
I, 5-hydroxy-12-(1-acetoxyethoxycarbonyl)-12H-benzo[a]phenothiazine 
(XVIII; R.sub.2 =R.sub.f =H, R.sub.g =Me) indicates the following 
3-dimensional structure shown. 
##STR49## 
This compound exists as one isomer with the stereochemistry cis between 
the acetoxyethoxy group of the side-chain and the benzene ring A of the 
tetracyclic ring system. As shown, the asymmetric side-chain carbon center 
has the S configuration, however the mirror image of the indicated 
structure is also present in the crystal. 
A 250 MHz proton NMR spectrum of this compound, dissolved in 
dimethylformamide-d.sub.7 (DMF-d.sub.7), kept for one hour at room 
temperature, then cooled to -50.degree. C. to record the spectrum, shows a 
multiplicity of peaks in excess of what would be expected from such a 
structure. In particular, the methyl group of the acetyl unit appears as 
four sharp singlets, of approximately equal intensity, at 1.89, 1.91, 1.99 
and 2.28 parts per million (ppm). 
In another experiment, a sample of the crystalline compound was dissolved 
in DMF-d.sub.7, pre-cooled to -50.degree. C., and the NMR spectrum taken 
quickly at -50.degree. C. The resulting spectrum showed only two peaks for 
the acetyl methyl protons at 1.91 and 1.99 ppm. As the sample was warmed, 
these two signals coalesced to a singlet at about 30.degree. C. (1.91 
ppm); at about 80.degree. C., a second singlet appeared (2.04 ppm), and at 
170.degree. C., these two singlets began to coalesce. 
In another NMR study of the compound, five samples were dissolved in 
DMF-d.sub.7 at 25.degree. C., and then stored at -78.degree. C., after 
being held for 0, 5, 15, 30 and 60 minutes at 25.degree. C. The NMR 
spectra of these samples at -50.degree. C. showed that the two previously 
described peaks at 1.91 and 1.99 ppm were present initially, but that over 
time, the two additional peaks at 1.89 and 2.28 ppm gradually appeared, 
until after 60 minutes, all four peaks were present in approximately equal 
amounts. 
As a result of the x-ray and NMR studies, it is concluded that there is a 
single conformational isomer of compound XVIII present in the crystalline 
form, and that this isomer equilibrated, upon dissolution at room 
temperature, over a period of approximately one hour, to a mixture of at 
least four observable conformational isomers which may possibly be 
represented as follows: 
##STR50## 
A solid form of the compound containing all four conformational isomers may 
be obtained by rapid precipitation of the compound from solution with 
water. Suitable solvents from which to precipitate the compound include 
water-miscible protic and aprotic solvents, such as DMF, ethanol, acetone, 
dimethylsulfoxide (DMSO), polyethylene glycol-200 (PEG-200), PEG-400, 
acetic acid, 1,2-propanediol, and the like. The melting point of the solid 
thus obtained is somewhat variable because of its amorphous nature, but it 
is always lower than the melting point of the crystalline compound 
(195.degree.-196.degree. C.), in agreement with the presence of a mixture 
of isomers. Another suitable method for obtaining the compound in an 
amorphous form is by lyophilization from a suitable solvent, such as 
acetic acid, p-butanol, benzene, cyclohexane, carbon tetrachloride, 
chloroform, dioxane, and the like. 
The compounds of Formula I have unexpected activity as inhibitors of the 
mammalian biosynthesis of both 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 
slow-reacting substance of anaphylaxis (SRS-A). This inhibition of the 
biosynthesis of leukotrienes indicates that the compositions would be 
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 (5) cardiovascular conditions, such as angina and the like. 
Representative compounds of Formula I have been tested using one or more of 
the following assays to determine their mammalian leukotriene 
biosynthesis-inhibiting activity or their activity in assays relevant to 
the above disease conditions. 
Rat Peritoneal Polymorphonuclear (PMN) Leukocyte Assay 
Rats under ether anesthesia are injected (i.p.) with 8 ml of a suspension 
of sodium cascinate (6 grams in ca. 50 ml water). After 15-24 hr. The rats 
are sacrificed (CO.sub.2) and the cells from the peritoneal cavity are 
recovered by lavage with 20 ml of buffer (Eagles MEM containing 30 mM 
HEPES adjusted to pH 7.4 with NaOH). The cells are 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 are preincubated for 2 minutes at 37.degree. C., followed by 
the addition of 10 .mu.M A-23187. The suspension is 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 causes aggregation of the 
second PMN, which is measured as a change in light transmission. The size 
of the assay aliquot is chosen to give a submaximal transmission change 
(usually -70%) for the untreated control. The percentage inhibition of 
LTB.sub.4 formation is calculated from the ration of transmission change 
in the sample to the transmission change in the compound-free control. 
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 
Armad-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 injection (i.p.) 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.sup.-1 methylsergide. 
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.sup.-1 (intraperitoneally) or 10 
ml kg.sup.-1 (orally). 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. 
Following in Table III is data obtained using these various assays with 
representative compounds of Formula I. 
TABLE III 
__________________________________________________________________________ 
ASSAY RESULTS 
##STR51## 
Asth. Rat % 
Inhibition and 
PAF Induced Hyper- 
PMN IC.sub.50 
Dose (mg/kg) 
algesia % Inhibition and 
Ring A 
R.sub.1 
R.sub.a 
X (mg/ml) 
(p.o.) Dose (mg/kg) (p.o.) 
__________________________________________________________________________ 
aromatic 
H Ac S 0.025-0.05 
ED.sub.50 : 4 mg/kg 
ED.sub.50 : 0.145 mg/kg 
aromatic 
Me Me S 5 -- 80% (3) 
40% (1) 
aromatic 
Me Ac S 0.05 -- 30-60% (1) 
aromatic 
Ac H S 1-5 -- -- 
aromatic 
Ac Me S 5 -- -- 
aromatic 
H H S 0.02-0.1 
54% (1.5) 
-- 
aromatic 
H COCH.sub.2 NH.sub.2 
S 0.04-0.2 
44% (3) -- 
.HCl 21% (1.5) 
1,4-dihydro 
H H S 0.04 -- -- 
aromatic 
H CH.sub.2 OCH.sub.3 
S 1-5 -- -- 
aromatic 
H COPh S 0.5 18% (5) -- 
aromatic 
H COC(CH.sub.3).sub.3 
S 0.1-1 54% (5) -- 
aromatic 
H OR.sub.aH 
S 0.2-1 -- -- 
aromatic 
H Me S 0.1 -- -- 
aromatic 
H PO(OEt).sub.2 
S 0.2-1 -- -- 
aromatic 
Ac Ac S -- 47% (5) -- 
aromatic 
##STR52## 
H S 0.2-1 49% (1.5) 
60% (3) 
aromatic 
H H SO.sub.2 
0.2-1 67% (5) -- 
aromatic 
H Ac SO.sub.2 
0.2-1 42% (5) -- 
aromatic 
H Ac SO 0.2-1 -- -- 
aromatic 
H Ac O 0.05-0.5 
44% (5) -- 
__________________________________________________________________________ 
In certain biological tests, the amorphous mxiture of four isomers shows 
advantageous biological activity over the crystalline material. 
Representative results comparing the two forms of the compound are shown 
in the accompanying Table IV (where doses are in mg/kg, p.o.). 
TABLE IV 
______________________________________ 
Asthmatic Rat Assay Results on Compound XVIII 
(R.sub.2 = R.sub.f = H, R.sub.g = Me) 
Solid Form 
Vehicle Dose % Inhibition 
______________________________________ 
0.4% Tween 80/ 
5 81 
Crystalline (1 0.5% Methocel 
2 61 
Conformer) 1.5 49 ED.sub.50 = 1.5 
0.5 19 
1% Methocel 2 28 
0.4% Tween 80/ 
2 57 
Amorphous (4 0.5% Methocel 
1.5 52 ED.sub.50 = 1.0 
Conformers) 0.5 48 
1.5 59 
1% Methocel ED.sub.50 = 1.0 
0.5 36 
______________________________________ 
The pharmaceutical compositions will contain a sufficient amount of one or 
more of the compounds of Formula I in a dosage form suitable for 
inhibiting the mammalian biosynthesis of leukotrienes or, for the 
treatment desired. The effective concentration of Formula I compound in 
the composition will vary as required by the severity of the condition to 
be treated, the particular compound of Formula I, the mode of 
administration, dosage form and pharmacological effect and level desired. 
A general daily dosage of Formula I (for uses other than cytoprotection) 
will range from about 100 micrograms to 200 mg/kg of body weight. A 
preferred daily dosage range is from 1 mg/kg to 100 mg/kg and a most 
preferred dosage range is from 2 mg/kg to 50 mg/kg. 
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 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 of the 
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 addition to the common dosage forms set out above, the compound of 
Formula I may also be administered for the various utilities and 
indications or for inhibiting leukotriene synthesis 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. 
Dosage forms for application to treat the eye are also disclosed in 
4,348,398. 
In preparing suitable dosage forms, conventional compound procedures and 
ingredients, e.g., diluents, carriers, etc. may be used. 
Two assays may be used to measure cytoprotective ability. These assays are; 
(A) an ethanol-induced gastric ulcer 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 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. 
As cytoprotective agents, the compounds of Formula I may generally be 
administered at a dosage range of 0.02 mg/kg to 100 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 Formula I in avoiding future 
damage would be co-administration of a compound of the formula I with a 
non-steroidal antiinflammatory drug that might otherwise cause such damage 
(for example, indomethacin). For such use, the compound of Formula I is 
administered from 30 minutes prior to, 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 range from about 0.02 
mg/kg to about 100 mg/kg, preferably from about 0.02 mg/kg to about 30 
mg/kg. The dosage may be administered in single or divided individual 
doses, using various dosage forms, as described above. 
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 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. 
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 compounds 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 incorporated herein, by reference. 
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 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 are examples of representative pharmaceutical dosage forms 
for the compounds of Formula I: 
______________________________________ 
Injectable Suspension mg/ml 
Compound of Formula I 2.0 
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 
Tablet mg/tablet 
Compound of Formula I 25.0 
Microcrystalline Cellulose 
325.0 
Providone 14.0 
Microcrystalline Cellulose 
90.0 
Pregelatinized Starch 43.5 
Magnesium Stearate 2.5 
500 
Capsule mg/capsule 
Compound of Formula I 25 
Lactose Powder 573.5 
Magnesium Stearate 1.5 
600 
______________________________________ 
In addition to the compounds of Formula I, the pharmaceutical compositions 
of the present invention may 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, 
except in those cases where a beneficial synergism may be realized. 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 from about 
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. 
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 may 
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. 
Structurally-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 may 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: 
##STR53## 
which may bear a variety of substituents and in which the free --COOH 
group may be in the form of a pharmaceutically-acceptable salt group, 
e.g., --COO.sup.- Na.sup.+. 
The biphenylcarboxylic acid derivatives which may 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: 
##STR54## 
which may bear a variety of substituents and in which the free --COOH 
group may be in the form of a pharmaceutically-acceptable salt group, 
e.g., --COO.sup.- Na.sup.+. 
The oxicams which may 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: 
##STR55## 
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, ITC1, 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, 
SX1032, 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 other inhibitors of the biosynthesis of the leukotrienes, such as 
are disclosed in now-abandoned U.S. patent application Ser. No. 539,342, 
filed Oct. 5, 1983; Ser. No. 459,924, filed Jan. 21, 1983; and Ser. No. 
547,161, filed Oct. 31, 1983; which are incorporated herein by reference. 
The compounds of the Formula I may also be used in combination with 
leukotriene-antagonists, such as those disclosed in now-abandoned 
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 prostaglandinantagonists 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 H.sub.2 -receptor antagonist, 
such as, for instance, cimetidine, ranitidine, terfenadine, famotidine, 
aminothiadiazoles disclosed in EP Application No. 40,696 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 
application, U.S. Ser. No. 301,616, filed Sept. 14, 1981, abandoned. 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. 
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 reported in degrees Celsius 
(.degree.C.) and are uncorrected.

EXAMPLE 1 
Preparation of 5-acetoxy-12H-benzo[a]phenothiazine 
Acetic anhydride (2 ml) was added to a solution of 
5-hydroxy-12H-benzo[a]phenothiazine (1) (1.4 gm) in pyridine (10 ml) and 
stirred for 15 minutes. The reaction mixture was concentrated under vacuum 
and ice-water was added to the residue. The resulting precipitate was 
filtered, air-dried and washed with ethyl acetate to afford the title 
compound. 
m.p. 184.degree.-5.degree. Anal. C.sub.18 H.sub.13 NO.sub.2 S Calcd.: C, 
70.34; H, 4.26; N, 4.56; S, 10.43. Found: C, 70.28; H, 4.32; N, 4.53; S, 
10.51. Ref. (1): C.A. 70:69169z. S. African 6801,996. 
EXAMPLE 2 
Preparation of 5-methoxy-12-methyl-12H-benzo[a]phenothiazine and 
5-acetoxy-12-methyl-12H-benzo[a]phenothiazine 
Potassium tert. butoxide (1.3 gm) was added to a solution of 
5-acetoxy-12H-benzo[a]phenothiazine (from Example 1) (2.0 gm) and methyl 
iodide (4 ml) in DMF (20 ml). The reaction mixture was cooled with an 
ice-bath and stirred for 15 minutes. Diethyl ether (100 ml) was added to 
the reaction mixture followed by brine (100 ml). The ether layer was 
decanted, washed with brine, dried and evaporated to dryness. The 
resulting oily residue was chromatographed on silica gel (10% 
EtOAc/hexane) to afford 5-methoxy-12-methyl-12H-benzo[a]phenothiazine. 
M.P. 123.degree.-4.degree., Anal. C.sub.18 H.sub.15 NOS Calcd.: C, 76.69; 
H, 5.15; N, 4.77; S, 10.93. Found: C, 73.64; H, 5.30; N, 4.71; S, 11.00 
followed by 5-acetoxy-12-methyl-12H-benzo[a]phenothiazine. 
m.p. 109.degree.-110.degree. Anal. C.sub.19 H.sub.15 NO.sub.2 S Calcd.: C, 
71.01; H, 4.70; N, 4.36; S, 9.98. Found: C, 71.25; H, 4.90; N; 4.26; S, 
10.12. 
EXAMPLE 3 
Preparation of 12-acetyl-5-hydroxy-12H-benzo[a]phenothiazine 
Acetyl chloride (2 ml) was added to a solution of 
5-hydroxy-12H-benzo[a]phenothiazine (1) (2.65 gm) in DMF (10 ml) and 
stirred for 30 minutes. Diethyl ether (100 ml) was added to the reaction 
mixture followed by ice-water (50 ml). The aqueous layer was decanted and 
the organic layer containing a solid was evaporated to dryness. The 
resulting residue was treated with acetone and filtered to afford the 
title compound. 
m.p. 230.degree.. Anal. C.sub.18 H.sub.13 NO.sub.2 S. Calcd.: C, 70.34; H, 
4.26; N, 4.56; S, 10.43. Found: C, 70.43; H, 4.38; N, 4.55; S, 10.62. Ref. 
(1): C.A. 70:69169z. S. African 6801,966. 
EXAMPLE 4 
Preparation of 12-Acetyl-5-methoxy-12H-benzo[a]phenothiazine 
Potassium tert-butoxide (800 mg) was added to a solution of 
12-acetyl-5-hydroxy-12H-benzo[a]phenothiazine (950 mg) (from Example 3) 
and methyl iodide (1.5 ml) in DMF (10 ml) and stirred for 15 minutes. 
Water (80 ml) was added to the reaction mixture and the precipitate was 
filtered to afford the title compound. 
m.p. 208.degree.-9.degree. Anal. C.sub.19 H.sub.15 NO.sub.2 S Calcd.: C, 
71.01; H, 4.70; N, 4.36; S, 9.98. Found: C, 70.97; H, 4.84; N, 4.30; S, 
10.07. 
EXAMPLE 5 
Preparation of 5-aminoacetoxy-12H-benzo[a]phenothiazine-hydrochloride salt 
Dicyclohexylcarbodiimide (21 g) was added to a solution of 
5-hydroxy-12H-benzo[a]phenothiazine (4.2 g) and N-tert-butyloxycarbonyl 
glycine (8.4 g) in THF (150 ml) followed by the addition of DMAP (0.2 g). 
The reaction mixture was stirred for 15 minutes, filtered and the filtrate 
evaporated to dryness. The residue was dissolved in EtOAc, washed with a 
solution of NaHCO.sub.3, dried and evaporated to dryness. The resulting 
oily residue was chromatographed on silica gel (5% EtOAc/CH.sub.2 
Cl.sub.2) to afford 5-tert-butyloxycarbonylamino 
acetoxy-12H-benzo[a]phenothiazine. m.p. 175.degree. as an intermediate. 
The above intermediate (1 g) was dissolved in CH.sub.2 Cl.sub.2 (35 ml) 
cooled to 0.degree. and HCl (gas) was bubbled into the solution for 15 
minutes. The precipitate was filtered to afford the title compound. m.p. 
189.degree. Anal. C.sub.18 H.sub.13 N.sub.2 O.sub.2 S.HCl Calcd.: C, 
60.25; H, 4.21; N, 7.80; S, 8.93; Cl, 9.88. Found: C, 60.00; H, 4.30; N, 
7.90; S, 8.78; Cl, 10.16. 
EXAMPLE 6 
Preparation of 5-Hydroxy-1,4-dihydro-12H-benzo[a]phenothiazine 
A solution of 2-aminothiophenol (385 mg) in methanol (3 ml) was added to a 
solution of 4a, 5, 8, 8a-tetrahydro-1,4-naphtoquinone (Ref.: Ber. 62, 2361 
(1929)) (500 mg) in methanol (10 ml) and stirred for 1 hour. Then conc. 
HCl (2 ml) was added and the mixture was stirred for another 2 hours. 
Ethyl acetate was added to the reaction mixture followed by a solution of 
NaHCO.sub.3. The organic layer was decanted, dried and evaporated to 
dryness. The resulting oily residue was chromatographed on silica gel 
(CH.sub.2 Cl.sub.2) to afford the title compound. 
m.p. 166.degree. Anal. C.sub.16 H.sub.13 NOS Calcd.: C, 71.88; H, 4.90; N, 
5.23; S, 11.99. Found: C, 71.74; H, 4.88; N, 5.25; S, 12.17. 
EXAMPLE 7 
Preparation of 5-Hydroxy-6-methyl-12H-benzo[a]phenothiazine and 
5-acetoxy-6-methyl-12H-benzo[a]phenothiazine 
A solution of sodium hydrosulfite (40 g) in water (0.5 l) was added to a 
suspension of 6-methyl-5H-benzo[a]phenothiazine-5-one (10.4 g) in ethyl 
acetate (1 l) and stirred for 2 hours. The organic layer was decanted, 
dried and evaporated to dryness. The resulting residue was triturated with 
ether and filtered to afford 5-hydroxy-6-methyl-12H-benzo[a]phenothiazine 
as an air sensitive solid. 
The above compound (3 gm) was dissolved in a mixture of pyridine (20 ml) 
and acetic anhydride (10 ml) and stirred for 15 minutes. The reaction 
mixture was concentrated under vacuum and the residue triturated with 
diethyl ether and filtered. A sample was chromatographed on silica gel 
(CH.sub.2 Cl.sub.2) to afford the title compound, m.p. 170.degree., Anal. 
C.sub.19 H.sub.15 NO.sub.2 S Calcd.: C, 71.00; H, 4.70; N, 4.35; S, 9.97. 
Found: C, 70.95; H, 4.80; N, 4.24; S, 10.14. 
EXAMPLE 8 
Preparation of 5-Benzoyloxy-12H-benzo[a]phenothiazine 
Following the procedure of Example 1 but substituting benzoic anhydride for 
acetic anhydride, the title compound was obtained, m.p. 171.degree. C. 
Anal. C.sub.13 H.sub.15 NO.sub.2 S; Calcd.: C, 74.78; H, 4.09; N, 3.79; S, 
8.68. Found: C, 74.93; H, 4.22; N, 3.96; S, 8.57. 
EXAMPLE 9 
Preparation of 5-Trimethylacetoxy-12H-benzo[a]phenothiazine 
Following the procedure of Example 1 but substituting trimethyl acetic 
anhydride for acetic anhydride, the title compound was obtained, m.p. 
142.degree. C. Anal. C.sub.21 H.sub.19 NO.sub.2 S; Calcd.: C, 72.18; H, 
5.48; N, 4.01; S, 9.17. Found: C, 72.15; H, 5.46; N, 4.21; S, 9.34. 
EXAMPLE 10 
Preparation of 5-Methoxymethoxy-12H-benzo[a]phenothiazine 
Sodium hydride (75 mg) was added to a solution of 
5-hydroxy-12H-benzo[a]phenothiazine (1) (500 mg) and chloromethyl methyl 
ether (154 mg) in THF (10 ml) and the reaction mixture was stirred for 15 
minutes. Diethyl ether (60 ml) was added to the reaction mixture followed 
by water (60 ml). The ether layer was decanted, dried and evaporated to 
dryness. The resulting residue was chromatographed on silica gel (CH.sub.2 
Cl.sub.2 /hexane (7:3)) to afford the title compound, m.p. 103.degree. C. 
Anal. C.sub.18 H.sub.15 NO.sub.2 S; Calcd.: C, 69.87; H, 4.89; N, 4.53; S, 
10.36. Found: C, 69.75; H, 5.01; N, 4.41; S, 10.53. 
EXAMPLE 11 
Synthesis of 5-Acetoxy-12-acetyl-12H-benzo[a]phenothiazine 
To a mixture of 5-acetoxy-12H-benzo[a]phenothiazine (3.0 g) and powdered 4 
Angstrom molecular sieves (7.5 g) in 1,2-dichloroethane (75 ml) there was 
added slowly acetyl bromide (1.05 ml). The mixture was stirred at room 
temperature for 1 hour, then filtered. The filtrate was evaporated down to 
an oil which was triturated with a mixture of ether and hexane to afford 
solid title product (3 g), m.p. 141.degree.-142.degree. C. 
EXAMPLE 12 
Synthesis of 5-Methoxy-12H-benzo[a]phenothiazine 
To a solution of 5-hydroxy-12H-benzo[a]phenothiazine (2.65 g) and methyl 
iodide (2.5 ml) in DMF (dimethylformamide) (10 ml) there was added 
powdered potassium carbonate (2.0 g). The mixture was stirred at room 
temperature and after 15 minutes, another addition of potassium carbonate 
(2.0 g) and methyl iodide (2.0 ml) was done. The mixture was stirred for a 
further 20 minutes, then it was diluted with ethyl acetate (100 ml and 
washed with water (60 ml) twice, dried and evaporated down. The residue 
was triturated with ether to afford solid crude product which was filtered 
(1.7 g). This crude product was chromatographed on a column of silica gel, 
eluting with dichloromethane to afford pure title compound (1.33 g), m.p. 
168.degree.-170.degree. C. 
EXAMPLE 13 
Synthesis of Diethyl 12H-benzo[a]phenothiazin-5-yl phosphate 
To a solution of 5-hydroxy-12H-benzo[a]phenothiazine (1.5 g) and diethyl 
chlorophosphate (2 ml) in DMF (20 ml) there was added a powdered mixture 
of potassium carbonate (2 g) and potassium iodide (2 g). The reaction 
mixture was stirred at room temperature. After 30 minutes, a further 
addition of potassium carbonate and potassium iodide (2 g each) was made 
and stirring was continued. Two hours later more carbonate (2 g) and 
diethyl chlorophosphate (2 ml) were added, and then three hours later a 
final addition of carbonate (2 g) was made. The mixture was stirred for 3 
days then diluted with ethyl acetate (60 ml) and the insolubles filtered. 
The filtrate was washed with water, dried and evaporated down. This 
residue was crystallized from acetone, then chromatographed on a column of 
silica gel, eluting first with 1:1, then 3:1 mixtures of ethyl acetate and 
hexane to afford pure title compound (337 mg), m.p. 
162.degree.-163.degree. C. 
EXAMPLE 14 
Synthesis of 
5-hydroxy-12-(1-acetoxyethoxycarbonyl)-12H-benzo[a]phenothiazine 
Step 1 
Preparation of .alpha.-Chloroethyl chloroformate 
To a mixture of ethyl chloroformate (108.5 g) and sulfuryl chloride (138 
g), benzoyl peroxide (1 g) was added and it was refluxed for 20 hours. The 
reaction mixture was distilled and the liquid boiling above 110.degree. 
was collected. This was then fractionated using a 30 cm column packed with 
glass helices to give 32 g of pure alpha-chloroethyl chloroformate, b.p. 
118.degree.-119.degree.. 
Step 2 
Preparation of 
5-hydroxy-12-(.alpha.-chloroethoxycarbonyl)-12H-benzo[a]phenothiazine 
A mixture of 5-hydroxy-12H-benzo[a]phenothiazine (5 g) and 
.alpha.-chloroethyl chloroformate (10 g) in tetrahydrofuran (20 ml) was 
refluxed for 9 hours, then the volatile components were evaporated away 
and the residue chromatographed on a column of silica gel, eluting with a 
1:9 ethyl acetate-hexane mixture to afford the title compound (4 g) as an 
oil. 
Step 3 
Preparation of 
5-hydroxy-12-(1-acetoxyethoxycarbonyl)-12H-benzo[a]phenothiazine 
The product from Step 2 (4 g) and sodium acetate (6 g) were refluxed 
together in glacial acetic acid (60 ml) for 1 hour. The mixture was 
cooled, diluted with ethyl acetate (300 ml) and washed with water 
(3.times.100 ml), then with aqueous sodium bicarbonate and again with 
water, dried and evaporated down. The residue was chromatographed on a 
column of silica gel eluting with a 1:9 mixture of ethyl acetate-hexane to 
afford, after trituration in ether and filtration, the pure title compound 
(1.2 g), m.p. 195.degree.-196.degree. C. 
Step 4 
Conversion of crystalline 
5-hydroxy-12-(1-acetoxyethoxycarbonyl)-12H-benzo[a]phenothiazine into an 
amorphous solid of 4 conformers 
The crystalline material obtained in Step 3 (20 g) was dissolved in acetone 
(500 ml) and the solution evaporated to an oily residue. Residual acetone 
was removed by co-evaporation with absolute ethanol (50 ml), twice. The 
residual thick oil was dissolved in absolute ethanol (about 25 ml) and the 
mixture stirred vigorously during the rapid addition of water (1 L). The 
gummy precipitate, on further stirring, became a solid. The mixture was 
allowed to settle, the milky supernatant decanted and the solid stirred in 
water (600 ml) until a fine solid was obtained. It was filtered and dried, 
to afford 17 g of amorphous 
5-hydroxy-12-(1-acetoxyethoxycarbonyl)-12H-benzo[a]phenothiazine, m.p. 
102.degree.-112.degree. C. 
EXAMPLE 15 
Synthesis of 5-acetoxy-9-methoxy-12H-benzo[a]phenothiazine 
By following the procedures described in preparative Example 7, but 
substituting 9-methoxy-5H-benzo[a]phenothiazine-5-one for the 6-methyl 
analog as starting material, the title compound was obtained, m.p. 
156.degree.-158.degree. C. 
EXAMPLE 16 
Synthesis of 5-Acetoxy-9-methyl-12H-benzo[a]phenothiazine 
By following the procedures described in preparative Example 7, but 
substituting 9-methyl-5H-benzo[a]phenothiazine-5-one for the 6-methyl 
analog as starting material, the title compound was prepared, m.p. 
193.degree.-195.degree. C. 
EXAMPLE 17 
Synthesis of 5-Acetoxy-9-fluoro-12H-benzo[a]phenothiazine 
By following the procedures described in preparative Example 7, but 
substituting 9-fluoro-5H-benzo[a]phenothiazine-5-one for the 6-methyl 
analog as starting material, the title compound was obtained, m.p. 
196.degree.-198.degree. C. (dec). 
EXAMPLE 18 
Synthesis of 5-Acetoxy-12H-benzo[a]phenoxazine 
Applying the procedures described in preparative Example 7, but 
substituting 5H-benzo[a]phenoxazine-5-one for 
6-methyl-5H-benzo[a]phenothiazine-5-one, the title compound was 
synthesized, m.p. 152.degree.-155.degree. C. 
EXAMPLE 19 
Synthesis of 5,6-Diacetoxy-12H-benzo[a]phenothiazine 
By following the procedures described in preparative Example 7, but 
substituting 6-acetoxy-5H-benzo[a]phenothiazine-5-one for the 6-methyl 
analog as starting material there was obtained the title compound, m.p. 
206.degree.-207.degree. C. 
EXAMPLE 20 
Synthesis of 12-Acetyl-5,6-diacetoxy-12H-benzo[a]phenothiazine 
By following the procedure described in preparative Example 11, but 
substituting 5,6-diacetoxy-12H-benzo[a]phenothiazine for the 5-acetoxy 
analog as starting material, the title compound was obtained, m.p. 
213.degree.-214.degree. C. 
EXAMPLE 21 
Synthesis of 12-Acetyl-5,6-dihydroxy-12H-benzo[a]phenothiazine 
To a suspension of 12-acetyl-5,6-diacetoxy-12H-benzo[a]phenothiazine (450 
mg) in acetone (10 ml) there was added 2N aqueous sodium hydroxide 
solution (10 ml) and the resulting mixture was stirred at room temperature 
for 45 minutes. It was then made slightly acidic by the addition of 10% 
aqueous acetic acid solution and the insolubles filtered and washed with 
water. The solid was swished in ethyl acetate to afford pure title 
compound (100 mg), m.p. 258.degree.-260.degree. C. 
EXAMPLE 22 
Synthesis of 5-Acetoxy-12H-benzo[a]phenothiazine-7-oxide 
To a suspension of 5-acetoxy-12H-benzo[a]phenothiazine (10 g) in 
dichloromethane (125 cc) there was rapidly added a solution of 85% 
m-chloroperoxybenzoic acid (6.61 g) in methanol (125 ml). At first the 
solids dissolved, then after a few minutes a new solid separated out of 
solution. After 1 and 1/2 hours the mixture was filtered and the solid 
washed with dichloromethane. The title compound was thus obtained pure 
(8.76 g), m.p. 179.degree.-181.degree. C. 
EXAMPLE 23 
Synthesis of 5-Acetoxy-12H-benzo[a]phenothiazine-7,7-dioxide 
To a suspension of 5-acetoxy-12H-benzo[a]phenothiazine (10 g) in 
dichloromethane (125 ml) there was rapidly added a solution of 85% 
m-chloroperoxybenzoic acid (18 g) in methanol (125 ml). A solution 
resulted which rapidly began to deposit the sulfoxide. The mixture was 
heated to a gentle reflux and slowly the solid redissolved, then the 
sulfone began to crystallize out of solution. After 2 and 1/2 hours the 
mixture was allowed to cool down and it was filtered to afford nearly pure 
title product. A 1 gram sample was crystallized from THF (tetrahydrofuran) 
to afford pure product (504 mg), m.p. 284.degree.-287.degree. C. 
EXAMPLE 24 
Synthesis of 5-Hydroxy-12H-benzo[a]phenothiazine-7,7-dioxide 
To a suspension of 5-acetoxy-12H-benzo[a]phenothiazine-7,7-dioxide (6.6 g) 
in methanol (200 ml) there was added 2N aqueous sodium hydroxide solution 
(132 ml) and the mixture was stirred in the absence of air at room 
temperature for 7 minutes; at that point an amber solution had resulted. 
There was rapidly added 10% aqueous acetic acid solution (200 ml) causing 
precipitation of the title compound which was collected by filtration 
(5.68 g). A sample (500 mg) was crystallized from THF affording purified 
product (250 mg), m.p. 334.degree. C. (dec). 
EXAMPLE 25 
Synthesis of 5,6-Dihydroxy-12H-benzo[a]phenothiazine-7,7-dioxide 
To a suspension of 6-hydroxy-5H-benzo[a]phenothiazine-5-one-7,7-dioxide 
(430 mg) in water (10 cc) and ethyl acetate (10 ml) there was added sodium 
dithionite (1 g). The suspension was stirred vigorously at room 
temperature for 2 hours, then the insolubles were filtered and washed with 
water and ethyl acetate. There was obtained 346 mg of the title compound, 
m.p. 330.degree. C. 
EXAMPLE 26 
Synthesis of 
5-Acetoxy-12-(1-acetoxyethoxycarbonyl)-12H-benzo[a]phenothiazine 
By following the procedure of Example 1, but substituting the product of 
Example 14 for 5-hydroxy-12H-benzo[a]phenothiazine, the title compound was 
obtained, m.p. 76.degree.-78.degree.. 
EXAMPLE 27 
Synthesis of 5-Hydroxy-12-(1-acetoxyethoxycarbonyl)-12H-benzo[a]phenoxazine 
By following the procedure of Example 14, Steps 2 and 3, but substituting 
5-hydroxy-12H-benzo[a]phenoxazine for 5-hydroxy-12H-benzo[a]phenothiazine, 
the title compound is obtained. 
EXAMPLE 28 
Preparation of 
5-hydroxy-12-(1-pivaloyloxyethoxycarbonyl)-12H-benzo[a]phenothiazine 
Following the procedure of Example 14, Step 3, but substituting sodium 
pivaloate for sodium acetate, and pivaloic acid for acetic acid, the title 
compound is obtained. 
EXAMPLE 29 
Preparation of 5-hydroxy-12-ethoxycarbonyl-12H-benzo[a]phenothiazine 
Following the procedure of Example 14, Step 2, but substutiting ethyl 
chloroformate for .alpha.-chloroethylchloroformate, the title compound was 
obtained, m.p. 205.degree.-206.degree. C. 
EXAMPLE 30 
Preparation of 5-hydroxy-12-isopropyloxycarbonyl-12H-benzo[a]phenothiazine 
Following the procedure of Example 14, Step 2, but substituting 
isopropylchloroformate for .alpha.-chloroethylchloroformate, the title 
compound was obtained, m.p. 205.degree.-206.degree. C. 
Claims to the invention follow.