Novel dibenz[b,f]thiepin derivatives are employed in the treatment and control of allergic conditions such as allergic asthma.

BACKGROUND OF THE INVENTION 
This invention relates to new and useful compositions of matter 
classifiable in the field of organic chemistry as derivatives of 
dibenzthiepins. More particularly, the instant invention relates to a 
novel group of dibenz[b,f]thiepins having a fourth ring of five or six 
carbon atoms, fused to the main ring system e.g., 
benz[b]indeno[f]thiepins; to methods of preparing such compounds; and to 
the method of employing them in the treatment and control of allergic 
conditions such as asthma. 
SUMMARY OF THE INVENTION 
In its composition aspect, therefore, the instant invention may be 
described as residing in the concept of dibenz[b,f]thiepins characterized 
by having the following structural formulae: 
##STR1## 
wherein n is 1 or 2, the broken lines represents optional double bonds and 
Z is a member selected from the group consisting of thio, sulfinyl or 
sulfony; R.sub.2, R.sub.3 and R.sub.9 are each independently selected from 
the group consisting of hydrogen, halogen, nitro, loweralkyl, amino, 
N-loweralkylamino, N,N-diloweralkylamino, loweralkanoyl, hydroxy, 
loweralkoxy, loweracyloxy, loweralkylthio, trifluoromethylthio, 
loweralkylsulfinyl, loweralkylsulfonyl, trifluoromethyl or together 
R.sub.2 and R.sub.3 can be a doubly bonded oxygen; and R.sub.1 is a member 
selected from the groups consisting of: 
(a) 5-tetrazolyl, 5-tetrazolylmethyl, 3-hydroxy-1,2,5-thiadiazol-4-yl, 
4-hydroxy-.DELTA..sup.3 -pyrroline-3-yl-2,5-dione or 
##STR2## 
wherein m is an integer from 0-4 and R.sub.4 is a member selected from 
the group consisting of hydroxy, loweralkoxy, 
N,N-diloweralkylaminoloweralkoxy, hydroxyloweralkoxy, carboxyloweralkoxy, 
amino, N-loweralkylamino, N,N-diloweralkylamino, loweralkylsulfonylamino, 
carboxyloweralkylamino, carboxamidoloweralkylamino, 
2-imino-3-methylthiazolidine, loweracyloxyloweralkoxy or 
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxy; 
(b) --CHO or a prodrug derivative of an aldehyde having the formulae: 
##STR3## 
wherein R.sub.5 is a member selected from the group consisting of 
hydrogen, loweralkyl, aryl, hydroxy, loweralkoxy, loweracyloxy, amino or 
loweralkylamino; Y and Z are each independently oxygen, sulfur or NR.sub.6 
and R.sub.6 and R.sub.7 are each independently hydrogen or loweralkyl; R6 
and R7 may optionally be joined to form a ring of 5-8 members. 
(c) --(CH.sub.2)n-OR.sub.8 wherein n is 0-4 and R.sub.8 is a member 
selected from hydrogen loweracyl, loweralkylaminolacyl, loweralkylcarboxy, 
loweralkylcarboxamido, loweralkylcarboxamidoacyl or 
loweracyloxyloweralkyl; and the pharmaceutically acceptable salts thereof. 
DETAILED DESCRIPTION 
As used herein, the term, halogen, includes chlorine, bromine, iodine and 
fluorine. The terms, loweralkyl, loweracyl and loweralkoxy, wherever 
employed, include straight and branched chain alkyl, loweracyl and alkoxy 
groups having 1 to 5 carbon atoms in the alkyl, acyl or alkoxy moiety such 
as, for example, methyl, ethyl, isopropyl, butyl 2,2-dimethypropyl, 
ethoxy, propoxy and isobutoxy. The term, loweralkanoyl, includes straight 
and branched chain alkanoyl groups of 1 to 5 carbon atoms including, for 
example, formyl, acetyl, propanoyl, butyryl and 2,2-dimethylpropanoyl. 
The instant invention is based upon applicants' discovery that the 
dibenz[b,f]thiepins of Formulae Ia, Ib and Ic markedly antagonize the 
actions of contractile prostaglandins such as PGF.sub.2.alpha., PGG.sub.2, 
PGH.sub.2 and TXA.sub.2. The use of the dibenz[b,f]thiepins of this 
invention, which act as prostaglandin antagonists and biosynthesis 
inhibitors, offers a new approach to therapy in a variety of allergic 
conditions such as allergic asthma where excessive contractile activity of 
prostaglandins and prostaglandin biosynthetic intermediates occur. It is 
well known, for example, that prostaglandins such as PGF.sub.2.alpha., 
PGG.sub.2, TXA.sub.2 and PGH.sub.2 are potent contractants of bronchial 
muscle and that human asthmatics are especially sensitive to the bronchial 
constricting action of PGF.sub.2.alpha.. The antagonizing action of the 
dibenz[b,f]thiepins of this invention against the constricting actions of 
contractile prostaglandins has been confirmed in vitro and in vivo using 
standard pharmacological techniques. It is contemplated, therefore, that 
the dibenz[b,f]thiepins of this invention will be employed in dosage unit 
form as the essential active ingredient in pharmaceutical formulations 
intended for the treatment and control of allergic conditions such as 
asthma in humans and warm blooded animals. 
The dibenz[b,f]thiepin derivatives of this invention may be prepared in any 
manner available to the skilled artisan. One such method is presented in 
Scheme I. 
##STR4## 
5-Mercaptoindan is reacted with 4-carboxy-2-iodophenylacetic acid in the 
presence of a strong base such as potassium hydroxide affording an 
indanylthiophenylacetic acid compound. 
The indanyltniophenylacetic acid compound may be cyclized by treatment with 
(1) trifluoroacetic acid and (2) trifluoroacetic anhydride. Reduction of 
the 11-oxo compound to the 11-hydroxy compound is accomplished by 
conventional reducing agents, such as sodium borohydride. 
The 11-oxo compound may be converted to the compound 
2,3,10,11-tetrahydro-1H-benzo[b]indeno [5,6,-f]thiepin-7-carboxylic acid 
by treatment with potassium hydroxide and hydrazine hydrate. 
Dehydration of the 11-hydroxy compound may be accomplished by treatment 
with a strong acid such as sulfuric acid, affording the compound 
2,3-dihydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylic acid. 
Oxidation of the carboxylic acids using mild oxidation conditions affords 
the 5-oxide compound, while more vigorous conditions yield the 5,5-dioxide 
species. 
The carboxylic acids may be converted to a number of derivatives as 
discussed in greater detail below. 
In addition to the reactions outlined in Scheme I, the compounds of the 
present invention may be prepared as outlined in Scheme II. 
##STR5## 
3-Cyano-10,11-dihydrodibenz[b, f]thiepin (see compound XXVII, European 
Patent Appln. No. 11,067) may be reacted with dichloromethyl methylether 
to yield the 6-formyl- and 8-formyl-3-cyano compounds 
The formyl compounds may be reduced with sodium borohydride to produce the 
6-hydroxymethyl and 8-hydroxymethyl compounds. 
Bromination of the 6- or 8-hydroxymethyl compounds may be accomplished by 
treatment with phosphorus tribromide 
Reaction of the 6- or 8-bromo methyl compounds with diethyl malonate and 
sodium hydride, followed by (1) heating; (2) hydrolysis; and (3) 
cyclization, afforded the oxo-tetrahydro-1H-benz[b]indenothiepin compounds 
shown. 
Reduction of the 1-oxo group may be accomplished using a reducing agent 
such as sodium borohydride, affording the (.+-.) hydroxy derivatives. 
These compounds may then further be derivatized and/or resolved into the 
separate enantiomorphs. 
In addition to their therapeutic properties as noted above, the carboxylic 
acid derivatives of this invention serve as valuable intermediates in the 
preparation of other variously substituted and therapeutically useful 
dibenz[b,f]thiepins of formula Ia, Ib or Ic. Thus, the carboxylic acid of 
formula Ia, Ib or Ic may be converted readily into the corresponding acid 
halide, preferably the acid chloride, by treating the carboxylic acid with 
a thionyl halide, preferably thionyl chloride. The resulting 
halocarbonyldibenz[b,f]thiepin (i.e., the chlorocarbonylcompounds of 
formula Ia, Ib or Ic) then may be treated with various well-known reagents 
to form desired ester and amide derivatives 
Thus, for example, the chlorocarbonyl compounds of formula Ia, Ib or Ic may 
be treated: 
(a) with a loweralkanol such as, for example, methanol, ethanol, 
2-propanol, butanol and 2-butanol, to form the corresponding loweralkyl 
esters; 
(b) with ammonia to form the carboxamides; 
(c) with an N-loweralkylamine such as, for example, methylamine, 
ethylamine, propylamine, isopropylamine and butylamine, or an 
N,N-diloweralkylamine such as, for example, dimethylamine, diethylamine, 
dipropylamine and dibutylamine, to form the corresponding 
N-loweralkylcarboxamide or N,N-diloweralkylcarboxamide; 
(d) with a loweralkylsulphonamide such as for example, methanesulphonamide, 
ethanesulphonamide, propanesulphonamide and butanesulphonamide, to form 
the corresponding N-loweralkylsulfonylcarboxamide; 
(e) with 2-imino-3-methylthiazolidine to form the corresponding 
(3-methyl-2-thiazolidinylidene) carboxamide; 
(f) with a loweralkyldiol such as, for example ethylene glycol, 
trimethylene glycol and 1,4-butanediol, to form the corresponding 
hydroxyloweralkylester; 
(g) with an N,N-diloweralkylaminoloweralkanol such as, for example, 
N,N-dimethylethanolamine, N,N-diethylethanolamine, 
3-N,N-dimethylaminopropan-1-ol and 4-N,N-diethylaminobutan-1-ol, to form 
the corresponding N,N-diloweralkylaminolower-alkyl ester; 
(h) with an amino acid such as, for example, glycine, alanine and valine, 
to form the corresponding N-carboxyloweralkylcarboxamide; 
(i) with an alkali metal salt of a hydroxyloweralkanoic acid such as, for 
example, hydroxyacetic acid, 3-hydroxybutyric acid and 
.beta.-hydroxypropionic acid, to form the corresponding carboxyloweralkyl 
ester. 
Formation of the 5-oxide or the 5, 5-dioxide groups (e.g., preparation of 
the sulfinyl or sulfonyl compounds of the instant invention) conveniently 
is achieved by controlled oxidation techniques. Thus, for example, the 
carboxylic acid derivatives of formulae Ia, Ib or Ic may be oxidized with 
hydrogen peroxide in the presence of an acidic solvent such as acetic acid 
or with organic peroxides such as peroxy acids, for example, 
m-chloroperbenzoic acid and the like, in a stepwise fashion to form the 
corresponding sulfinyl derivative, formula Ia, Ib or Ic, and sulfonyl 
derivative, formulae Ia, Ib or Ic. The molar ratio of oxidant to reductant 
determines the oxidation level of the sulfur in the product. A 1:1 molar 
ratio, for example, results largely in the production of the sulfinyl 
derivative whereas a 2 to 3 molar excess of oxidant results in a yield 
predominantly comprising the sulfonyl derivative. 
As noted above, pharmaceutically acceptable salts of the novel 
dibenz[b,f]thiepins also are included within the scope of this invention. 
The term, pharmaceutically acceptable salts, is intended to include salts 
derived from pharmaceutically acceptable non-toxic acids and bases such 
as, for example, ammonium salts, alkali metal salts such as sodium and 
potassium salts, alkaline earth metal salts such as magnesium and calcium 
salts, salts of organic bases such as amine salts derived from mono-, di 
and triloweralkyl or loweralkanoyl amines such as trimethylamine, 
dimethylamine and triethanolamine, salts derived from heterocyclic amines 
such as piperidine, 1-methylpiperazine, piperazine and morpholine, and 
salts derived from pharmaceutically acceptable acids such as hydrochloric 
acid, sulfuric acid, tartaric acid and propionic acid. 
The dibenz[b,f]thiepins of formulae Ia, Ib and Ic are useful in the 
treatment and prophylaxis of human or warm-blooded animal disease 
conditions where excessive undesirable contractile activity of 
prostaglandins, such as PGF.sub.2.alpha., or prostaglandin biosynthetic 
intermediates contribute. In particular, they are of value in the 
treatment and control of allergic conditions such as asthma. 
The magnitude of a prophylactic or therapeutic dose of compound of formulae 
Ia, Ib and/or Ic will, of course, vary with the nature and the severity of 
the condition to be treated and with the particular compound of formulae 
Ia, Ib and Ic and its route of administration. In general, the dose range 
lies within the range of 0.2 mg to 100 mg per kg body weight per day. 
The pharmaceutical compositions of the present invention comprise a 
compound of formula Ia, Ib and/or Ic as an active ingredient, and may also 
contain pharmaceutically acceptable carrier and optionally other 
therapeutic ingredients. The compositions include compositions suitable 
for oral, rectal, opthalmic, 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 condition 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 is from 0.2 to 10 mg (preferably 1 to 8 mg) of a 
compound of formula Ia, Ib or Ic per kg of body weight per day. In the 
case where an oral composition is employed a suitable dosage range is 
about, e.g., 1 to 50 mg of a compound of formula Ia, Ib or Ic per kg of 
body weight per day, preferably from 10 to 40 mg/kg. 
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 tne 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 moulding, 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. Moulded tablets 
may be made by moulding in a suitable machine, a mixture of powdered 
compound moistened with an inert liquid diluent. Desirably, each tablet 
contains from 50 mg to 500 mg of the active ingredient and each cachet or 
capsule contains from 50 mg to 500 mg of the active ingredient 
The best mode contemplated by applicants for carrying out their invention 
is illustrated in the following working examples. No limitation, however, 
is intended except as set forth in the appended claims.

EXAMPLE 1 
4-Carboxy-2-(5-indanylthio)-phenylacetic acid 
To 50% aqueous potassium hydroxide solution (500 g) under argon was added 
5-mercaptoindan (30.0 g, 0.2 mole) and copper powder (16.3 g). Then 
4-carboxy-2-iodophenylacetic acid (38.25 g, 0.125 mole) was added with 
mechanical stirring and the reaction mixture was stirred under reflux 
(oil-bath 140.degree.-145.degree. C.) for 3 hours. The mixture was diluted 
with ice-water (800 ml), filtered, and the filtrate was treated with 
charcoal and refiltered. Acidification of the alkaline solution 
precipitated a solid which was collected, washed well with water and 
drained thoroughly on the filter. The solid was stirred with hexane (200 
ml) to remove mercaptoindane and was refiltered to yield 33.55 g. 
The product was recrystallized from acetic acid and then had a melting 
point of 225.degree.-228.degree. C. 
Analysis for C.sub.18 H.sub.16 O.sub.4 S: 
Requires: C 65.84, H 4.91, S 9.76; Found: C 65.64, H 4.97, S 9.70. 
EXAMPLE 2 
11-Oxo-2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f] thiepin-7-carboxylic 
acid 
4-Carboxy-2-(5-indanylthio)phenylacetic acid (33.55 g, 0.102 mole) was 
added to trifluoroacetic acid (200 ml) and to the stirred suspension was 
added, slowly with stirring, trifluoroacetic anhydride (200 ml). After 
stirring the mixture for 48 hours at room temperature, the mixture was 
poured slowly onto ice (200 g), and the slurry was diluted to about 1 
liter before collecting the crude product. The dried solid was stirred in 
suspension in acetonitrile for 45 minutes, refiltered and dried to yield 
24.95 g. 
The compound was recrystallized from dimethylformamide/acetonitrile and 
then had a melting point of 275.degree.-277.degree. C. dec. 
Analysis for C.sub.18 H.sub.14 O.sub.3 S: Requires: C 69.68, H 4.55, S 
10.32; Found: C 69.40, H 4.62, S 10.52. 
EXAMPLE 3 
11-Hydroxy-2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxyli 
c acid 
11-Oxo-2,3,10-11-tetrahydro-1H-benzo[b]indeno [5,6-f]thiepin-7-carboxylic 
acid (24.75 g, 0.0798 mole) was suspended in water (495 ml) and 5N sodium 
hydroxide (17.6 ml) was added with stirring. The resulting suspension of 
sodium salt was treated with sodium borohydride (9.10 g, 0.24 mole) in 1 g 
portions and the mixture was stirred at room temperature overnight. Then 
the mixture was acidified carefully (frothing) with 6N hydrochloric acid. 
The suspension was stirred for 20 minutes after completion of the 
acidification and the solid as collected, washed well with water, and 
dried to yield 24.44 g. 
The ammonium salt of the acid was crystallized from hot water and the title 
compound obtained by acidification of the salt had a melting point of 
202.degree.-203.degree. C. dec. 
Analysis for C.sub.18 H .sub.16 O.sub.3 S: Requires: C 69.21, H 5.16, S 
10.26; Found: C 69.52, H 5.33, S 10.14. 
EXAMPLE 4 
2,3-Dihydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylic acid 
11-Hydroxy-2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxyli 
c acid (11.3 g. 36.2 mmole) was suspended in acetic acid (225 ml) heated in 
an oil-bath at 115.degree. C. Concentrated sulfuric acid (22.5 ml) was 
added in a thin stream. The suspension was heated in the oil-bath for 1 
hour and allowed to cool. The crude product was filtered off and washed 
with methanol to yield 10.14 g. 
The title compound was purified by filtering a solution of the solid in a 
large volume of boiling acetic acid and evaporating the filtrate to a 
smaller volume, and the title compound had a melting point of 
268.degree.-271.degree. C. dec. 
Analysis for C.sub.18 H.sub.14 O.sub.2 S: Requires: C 73.44, H 4.79, S 
10.89; Found: C 73.23, H 5.01, S 10.78. 
The ethyl ester of the title compound had a melting point of 
103.degree.-104.degree. C. 
EXAMPLE 5 
2,3-Dihydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylic acid 5,5-dioxide 
2,3-Dihydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylic acid (2.97 g, 10.1 
mmole) was suspended in trifluoroacetic acid (60 ml) and the stirred 
suspension was treated at 0.degree.-5.degree. C. with 50% hydrogen 
peroxide in small increments. The formation of the 5-oxide and then of the 
5,5-oxide can be followed by thin layer chromatography. 
NOTE: Sulfone can be distinguished from sulfoxide and starting material on 
Quantum silica gel plates developed with 100:10:1 toluene/dioxane/acetic 
acid. Starting material was distinguished from sulfoxide and sulfone on 
Eastman silica gel sheet developed with the same solvent mixture. 
Sulfoxide and sulfone fluoresced differently. 
Conversion to the title compound requires about 1.8 ml of 50% hydrogen 
peroxide. The solution was evaporated to about 25 ml and poured into water 
(100 ml). The aqueous layer was decanted from the sticky precipitate which 
crystallized on stirring with hot acetic acid (10 ml) to afford 1.618 g of 
crude product. This was recrystallized from hot acetic acid to give the 
title compound 1.23 g with a melting point of 298.degree.-301.degree. C. 
dec. 
Analysis for C.sub.18 H.sub.14 O.sub.4 S: Requires: C 66.24, H 4.32, S 
9.82; Found: C 66.21, H 4.49, S 9.77. 
EXAMPLE 6 
2,3-Dihydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylic acid 5-oxide 
Repeating the procedure of Example 5 but using a little less than half of 
the equivalent amount of 50% hydrogen peroxide provides the title 
compound. 
EXAMPLE 7 
5-(2,3-Dihydro-1H-benzo[b]indeno[5,6-f]thiepin-7-yl)tetrazole 
STEP A Preparation of 
2,3-dihydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxamide 
A mixture of 2,3-dihydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylic acid 
(6.00 g, 20.4 mmole) and thionyl chloride (24 ml) was heated slowly to 
reflux during 30 minutes and maintained at reflux for another 30 minutes. 
Excess thionyl chloride was distilled off and the residue was evaporated 
twice with benzene. The crude acid chloride was suspended in dry ether 
(150 ml) and a concentrated solution of ammonia in dry ether was added 
slowly with stirring. Ammonia was passed through the mixture for one hour 
and the solid was collected. The solid was stirred in suspension in a 
solution of ammonia in methanol (30 ml) and refiltered to afford 4.66 g 
(78%) of the title compound as an extremely insoluble solid. 
STEP B Preparation of 
2,3-dihydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carbonitrile 
The crude amide from Step A (4.34 g, 14.8 mmole) in pyridine (43.5 ml) was 
treated slowly under cooling (ice-bath) with trifluoroacetic anhydride 
(8.7 ml). The mixture was stirred for 1 hour at ambient temperature and 
then poured into a mixture of ice (400 g) and concentrated hydrochloric 
acid (50 ml). The product was extracted into ether and the ethereal 
extract was washed with water, then with 10% sodium carbonate solution and 
finally with saturated sodium chloride solution. After drying (MgSO.sub.4) 
the solution was evaporated to a tan colored solid (3.22 g). The product 
was purified by chromatography on Merck silica gel using toluene as 
solvent to give 2.45 g of the title compound. Melting point 
142.degree.-143.degree. C. (from acetonitrile). 
Analysis for C.sub.18 H.sub.13 NS: Requires: C 78.51, H 4.76, N 5.09, S 
11.64; Found: C 78.36, H 4.71, N 5.30, S 11.27. 
STEP C Preparation of 
5-(2,3-dihydro-1H-benzo[b]indeno[5,6-f]thiepin-7-yl)tetrazole 
A solution of 2,3-dihydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carbonitrile 
(2.10 g, 7.625 mmole) in dimethylformamide (31.5 ml) stirred under reflux 
(oil-bath at 170.degree.-180.degree. C.) in an atmosphere of argon was 
treated with a mixture of sodium azide (743 mg, 11.44 mmole) and ammonium 
chloride (612 mg, 11.44 mmole). An equal portion of sodium azide and 
ammonium chloride was added after 1 hour and then at 30 minute intervals 
seven portions of a mixture of sodium azide (247 mg, 3.81 mmole) and 
ammonium chloride (204 mg, 391 mmole) were added. After heating for a 
further 1 hour the reaction mixture was allowed to cool, then it was 
diluted with water (150 ml) and acidified. An extraction with methylene 
chloride (250 ml) was performed. The methylene chloride solution was 
extracted with a mixture of water (100 ml) and 5N sodium hydroxide (10 ml) 
and after a further wash with water the combined aqueous extract on 
acidification yields 1.555 g of title compound. 
Work up of the methylene chloride solution gave 832 mg of unreacted nitrile 
which on recycling through the reaction affords another 426 mg of product. 
Thus the combined yield of 
5-(2,3-dihydro1H-benzo[b]indeno[5,6-f]thiepin-2-yl)tetrazole was 1.98 g 
(81%). The tetrazole was purified by suspending the solid in hot 50% 
aqueous methanol, adding sufficient ammonium hydroxide to dissolve the 
solid, treating the solution with charcoal and filtering and then 
acidifying the filtrate with acetic acid. The compound thus purified had a 
melting point of 238.degree.-240.degree. C. dec. 
Analysis for C.sub.18 H.sub.14 N.sub.4 S: Requires: C 67.90, H 4.43, N 
17.60, S 10.09; Found: C 67.75, H 4.76, N 17.48, S 10.14. 
EXAMPLE 8 
5-(2,3-Dihydro-5-oxido-1H-benzo[b]indeno[5,6-f]thiepin-7-yl)-tetrazole 
A suspension of 
5-(2,3-dihydro-1H-benzo[b]indeno[5,6-f]thiepin-7-yl)tertrazole (1.039 g, 
3.27 mmole) in acetic acid (40 ml) at 70.degree. C. was treated slowly 
with stirring with a solution of 50% hydrogen peroxide in acetic acid (68 
mg per ml). After the addition of 7.2 ml of oxidizing agent a barely 
detectable (by tlc) amount of starting material remained. The mixture was 
cooled and the solid was collected. It was purified by stirring in 
suspension in hot methanol (22 ml) and filtering hot to obtain the title 
compound, 781 mg (71%), m.p. 273.degree. dec. 
Analysis for C.sub.18 H.sub.14 N.sub.4 OS Required: C 64.65, H 4.22, N 
16.75, S 9.59; Found: C 64.81, H 4.26, N 16.66, S 9.55. 
EXAMPLE 9 
5-(2,3-Dihydro-5,5-dioxido-1H-benzo[b,f]thiepin-7-yl)-tetrazole 
Repeating the procedure of Example 8 but using a little more than twice the 
equivalent quantity of 50% hydrogen peroxide provides the title compound). 
EXAMPLE 10 
2,3,10,11-Tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylic acid 
A mixture of 
11-oxo-2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylic 
acid (10.0 g 34 mmole), 85% potassium hydroxide (7.5 g), 100% hydrazine 
hydrate (5 ml) and diethylene glycol (200 ml) was heated under nitrogen, 
in an oil-bath at 225.degree. C. for 4 hours. The cool reaction mixture 
was diluted with water and acidified with 6N hydrochloric acid. The solid 
was collected by filtration, and after drying on the filter it was stirred 
in suspension in a mixture of ethyl acetate (50 ml) and methanol (10 ml). 
The crude product was collected and dried. 9.47 g. 
Analytically pure title compound was obtained in about 70% yield by 
recrystallization of the crude product from a mixture of dimethylformamide 
and acetonitrile, and then had a m.p. of 264.degree. dec. 
Analysis for C.sub.18 H.sub.16 O.sub.2 S Require: C 72.94, H 5.44, S 10.82; 
Found: C 72.82, H 5.50, S 10.88. 
EXAMPLE 11 
2,3,10,11-Tetrahydro-1H-benzo[b]indeno[5,6-f]-thiepin-7-carboxylic acid 
5-oxide 
STEP A: Preparation of methyl 
2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]-thiepin-7-carboxylate 
A suspension of crude 
2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylic acid 
(8.276 g, 28 mmole) in methanol (200 ml) containing concentrated sulfuric 
acid was stirred under reflux for 20 hours. The suspension was evaporated, 
water was added and the product was extracted with chloroform. The crude 
ester was purified by chromatography (250 g Merck silica gel eluted with 
1:1 hexane/methylene chloride) The title compound had m.p. 
110.degree.-111.degree. C. (from acetonitrile). 
Analysis for C.sub.19 H.sub.18 O.sub.2 S Requires: C 73.52, H 5.84, S 
10.33; Found: C 73.79, H 6.17, S 9.99. 
STEP B: Preparation of methyl 
2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]-thiepin-7-carboxylate 
5-oxide 
To a solution of methyl 
2,3,10,11-tetrahydro1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylate (3.05 g; 
9.84 mmole) in methylene chloride (200 ml) stirred in a cooling bath at 
0.degree.-5.degree. C. was added 85% m-chloroperbenzoic acid (2.00 g; 9.85 
mmole) in small portions during 1 hour. After stirring the reaction 
mixture for 30 minutes at room temperature, more methylene chloride was 
added to get a clear solution and then calcium hydroxide (4 g) was added. 
The suspension was stirred for 25 minutes, filtered and evaporated. The 
crude product was purified by column chromatography (Merck silica gel 
eluted with 1:4 ethyl acetate/toluene) to yield 2.121 g (66%) of the title 
compound, m.p. 150.degree.-154.degree. C. (from MeCN). 
Analysis for C.sub.19 H.sub.18 O.sub.3 S Requires: C 69.91, H 5.56, S 9.82; 
Found: C 69.96, H 5.70, S 10.13. 
STEP C: Preparation of 
2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]-thiepin-7-carboxylic acid 
5-oxide 
Methyl 2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylate 
5-oxide (2.00 g; 6.13 mmole) was added to a solution of 85% potassium 
hydroxide (808 mg; 12.26 mmole) in a mixture of water (8 ml) and ethanol 
(40 ml) at room temperature. After 1 hour, the solution was filtered, 
evaporated to 15 ml and acidified to pH 2 with hydrochloric acid. The 
product was collected, washed with water and dried (finally at 105.degree. 
C./0.005 Torr) to yield 1.55 g (81%) with a m.p. 290.degree.-294.degree. 
dec. 
Analysis for C.sub.18 H.sub.16 O.sub.3 S Requires: C 69.21, H 5.16, S 
10.26; Found: C 69.13, H 5.17, S 10.31. 
EXAMPLE 12 
2,3,10,11-Tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylic acid 
5,5-dioxide 
STEP A: Preparation of methyl 
2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylate 
5,5-dioxide 
Repeating the procedure of Example 11, Step B, but using slightly more than 
the two equivalents of m-chloroperbenzoic acid and a correspondingly 
greater amount of calcium hydroxide, provides the title compound. 
STEP B: Preparation of 
2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]-thiepin-7-carboxylic acid 
5,5-dioxide 
Repeating the procedure of Example 11, Step C, but using methyl 
2,3,10-11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylate 
5,5-dioxide in place of methyl 
2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylate 
5-dioxide provides the title compound. 
EXAMPLE 13 
3-Cyano-6-formyl-10,11-dihydrodibenzo[b,f]thiepin and 
3-Cyano-8-formyl-10,11-dihydrodibenzo[b,f]thiepin 
Anhydrous aluminium chloride (37.8 g; 0.283 mole was added to a stirred 
solution of 3-cyano-10,11-dihydrodibenzo[b,f]thiepin (32.0 g; 0.135 mole) 
in dry 1,2-dichloroethane (325 ml) with cooling (ice-bath) under argon. 
After 5 minutes a solution of dichloromethyl methyl ether (17.08 g; 0.1485 
mole) in 1,2-dichloroethane (135 ml) was added slowly over 30 minutes and 
the reaction mixture was stirred for a further 30 minutes in the ice-bath 
before being poured into ice water (500 ml). The mixture was shaken 
thoroughly and the organic layer was separated. The aqueous layer was 
extracted with 200 ml of 1,2-dichloroethane and the combined organic 
layers were washed with water (2.times.250 ml), dried (MgSO.sub.4) and 
evaporated. The crude product 26.65 g (74.5%) consisted of a mixture of 
the two title compounds in the ratio of about 5:4 (by nmr). 
The solid was suspended in hot ethyl acetate (135 ml) and the suspension 
was allowed to stand for several hours before collecting the solid. 
Recrystallization of this solid from acetonitrile gave pure 
3-cyano-6-formyl-10,11-dihydrodibenzo[b,f]thiepin, m.p. 
168.degree.-9.degree. C. crystallized in the form of pale yellow prisms, 
nmr (CDCl.sub.3) 10.7 (s, CHO). Analysis for C.sub.16 H.sub.11 NOS 
Requires: C 72.43, H 4.18, N 5.28, S 12.08; Found: C 72.26, H 4.18, N 
5.27, S 11.96. 
Residue from the mother liquors were pooled and given a preliminary 
clean-up by chromatography on Merck silica gel using methylene chloride as 
solvent. The mixture of 6- and 8-formyl derivatives was separated by high 
pressure liquid chromatography on a Waters Prep Pak 500 instrument using 
methylene chloride. The 8-formyl derivative was the faster moving compound 
and complete separation was obtained with two recycles. 
3-Cyano-8-formyl-10,11-dihydrodibenzo[b,f]thiepin crystallized from 
acetonitrile in colorless needles, m.p. 133.degree.-134.degree. C., nmr 
(CDCl.sub.3) 9.90 (s, CHO). 
Analysis for C.sub.16 H.sub.11 NOS Requires: C 72.43, H 4.18, N 5.28, S 
12.08; Found: C 72.59, H 4.24, N 5.31, S 11.86. 
EXAMPLE 14 
Ethyl 3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-4-yl)-2-ethoxycarbonyl 
propenoate 
A mixture of 3-cyano-6-formyl-10,11-dihydrodibenzo[b,f]thiepin (3.71 g, 14 
mmole), diethyl malonate (2.285 g; 14.3 mmole), acetic acid (84 mg; 1.4 
mmole), piperidine (119 mg; 1.4 mmole) and benzene (140 ml) was heated 
under reflux under a Dean Starck Trap for 24 hours. A further 64 mg of 
diethyl malonate was added and reflux was continued for 10 hours. Tne 
benzene was evaporated off under vacuum and the residue was dissolved in 
methylene chloride (75 ml). The solution was washed with water, dried 
(MgSO.sub.4) and evaporated to a gum which soon crystallized. 6.521 g 
(theory 5.7 g). 
Purification of a sample of the crude product by preparative thin layer 
chromatography (Whatman silica gel/methylene chloride) gave a recovery 
equivalent to a 96% yield, m.p. 96.degree.-98.degree. C. 
Analysis for C.sub.23 H.sub.21 NO.sub.4 S Requires: C 67.79, H 5.19, N 
3.44, S 7.87; Found: C 67.69, H 5.39, N 3.42, S 8.08. 
EXAMPLE 15 
Ethyl 3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)-2-ethoxycarbonyl 
propenoate 
Substituting 3-cyano-6-formyl-10,11-dihydrodibenzo[b,f]thiepin in the 
foregoing example with 3-cyano-8-formyl-10,11-dihydro-dibenzo[b,f]thiepin 
provides the title compound in 77% yield after chromatography (Whatman 
silica gel/5% ethyl acetate in methylene chloride). The compound melted at 
132.degree.-133.degree. after recrystallization from ethyl 
acetate/isopropyl ether. 
Analysis for: C.sub.23 H.sub.21 NO.sub.4 S Requires: C 67.79, H 5.19, N 
3.44, S 7.87; Found: C 67.84, H 5.35, N 3.39, S 7.65. 
EXAMPLE 16 
Ethyl 3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)-2-ethoxycarbonyl 
propanoate 
A suspension of ethyl 
3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)-2-ethoxycarbonylpropenoa 
te (4.249 g; 10.44 mmole) in ethanol (130 ml) was treated with sodium 
borohydride (397 mg; 10.44 mole). The reaction mixture was stirred at room 
temperature until reduction is complete (ca 2 hours) and then it was 
acidified carefully with acetic acid. The solvent was evaporated and the 
residue was partitioned between water and methylene chloride. After 
washing the organic extract with saturated sodium chloride solution, it 
was evaporated to obtain an oil (4.125 g; 96%). The pure title compound 
was obtained by short path distillation of the crude product (oven 
temperature 230.degree. C./0.05 Torr). 
Analysis for: C.sub.23 H.sub.23 NO.sub.4 S Requires: C 67.46, H 5.66 , N 
3.43, S 7.83; Found: C 67.75, H 5.90, N 3.46, S 7.67. 
EXAMPLE 17 
Ethyl 3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-4-yl)-2-ethoxycarbonyl 
propanoate 
Substituting ethyl 
3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)-2-ethoxy carbonyl 
propenoate in the foregoing example with crude ethyl 
3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-4-yl)-2- ethoxycarbonyl 
propenoate provides the title compound in 69% yield m.p. 
81.degree.-83.degree. C. after chromatography on Merck silica gel (90 g) 
using 3% ethyl acetate in methylene chloride for elution. 
Analysis for C.sub.23 H.sub.23 NO.sub.4 S Requires: C 67.46, H 5.66, N 
3.43, S 7.83; Found: C 67.46, H 5.76, N 3.29, S 7.78. 
EXAMPLE 18 3-Cyano-6-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin and 
3-cyano-8-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin 
Sodium borohydride (42 mg; 1.1 mmole) was added portionwise to a mixture of 
3-cyano-6-formyl-10,11-dihydrodibenzo[b,f]thiepin and 
3-cyano-8-formyl-10,11-dihydrodibenzo[b,f]thiepin (from Example 13) (5:4 
ratio) (236 mg; 0.89 mmole) in methanol (2.5 ml) and dimethylformamide 
(2.5 ml) under nitrogen. The reaction mixture was stirred one hour at room 
temperature, then poured slowly into ice. The precipitate was filtered off 
and air-dried to afford quantitatively a mixture of the two title 
compounds which are separated by thin layer chromatography (toluene/ethyl 
acetate: 7/3). The less polar compound being the 
3-cyano-6-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin, m.p. 150.degree. 
C. and the more polar was the 
3-cyano-8-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin, m.p. 122.degree. 
C. 
EXAMPLE 19 
3-Cyano-8-bromomethyl-10,11-dihydrodibenzo[b,f]thiepin 
Phosphorous tribromide (0.2 ml) was added to a suspension of 
3-cyano-8-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin (500 mg; 1.87 
mmole) in ether (7 ml). The reaction mixture was stirred at room 
temperature for one hour, then poured onto ice, extracted with ether 
(3.times.50 ml), dried over Na.sub.2 SO.sub.4 and evaporated to afford 581 
mg (95%) of 3-cyano-8-bromomethyl-10,11-dihydrodibenzo[b,f]thiepin as an 
oil. 
EXAMPLE 20 
3-Cyano-6-bromomethyl-10,11-dihydrodibenzo[b,f]thiepin 
As described previously for the 
3-cyano-8-bromomethyl-10,11-dihydrodibenzo[b,f]thiepin, the title compound 
was prepared from 3-cyano-6-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin 
in 95% yield. 
EXAMPLE 21 
Ethyl 3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)-2-ethoxy carbonyl 
propanoate 
Diethylmalonate (0.69 ml; 4.5 mmoles) was added to a suspension of sodium 
hydride 50% in oil (220 mg; 4.58 mmoles) in dry dimethylformamide (3 ml) 
under nitrogen. The reaction mixture was stirred at room temperature for 
30 minutes and added dropwise to a solution of 
3-cyano-6-bromomethyl-10,11-dihydrodibenzo[b,f]thiepin (0.377 g; 0.8 
mmole) in dry dimethylformamide (3 ml). The reaction mixture was stirred 
overnight at room temperature then poured on ice and extracted with 
methylene chloride (3.times.50 ml). The organic layer was dried (Na.sub.2 
SO.sub.4) and evaporated to dryness. The crude product was purified by 
column chromatography (E. Merck silica gel eluting with methylene 
chloride) affording 12 mg (25%) of pure title compound. 
EXAMPLE 22 
Ethyl 3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-4-yl)-2-ethoxy carbonyl 
propanoate 
The title compound was obtained in 25% yield by the same route as the ethyl 
3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)-2-ethoxy carbonyl 
propanoate starting with 
3-cyano-8-bromomethyl-10,11-dihydrodibenzo[b,f]thiepin. 
EXAMPLE 23 
Ethyl 3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)propanoate 
A mixture of ethyl 
3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)-2-ethoxycarbonylpropanoa 
te (4.025 g; 4.84 mmole), water (354 mg; 19.7 mmole), sodium chloride (576 
mg) and dimethylsulfoxide (100 ml) are heated together under argon in an 
oil bath at 200.degree.-205.degree. C. for 3 hours. The cool reaction 
mixture was diluted with methylene chloride and the solution was extracted 
with water (3.times.100 ml), then dried (MgSO.sub.4) and evaporated to an 
oil (3.223 g; 97%). The pure title compound was obtained by short path 
distillation of the crude product (oven temperature 200.degree. C./0.05 
Torr). 
Analysis for: C.sub.20 H.sub.19 NO.sub.2 S Requires: C 71.19, H 5.68, N 
4.15, S 9.50; Found: C 71.18, H 5.91, N 4.10, S 9.47. 
EXAMPLE 24 
Ethyl 3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-4-yl)propanoate 
Substituting ethyl 
3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)-2-ethoxycarbonylpropanoa 
te in the foregoing example with an equivalent amount of ethyl 
3-(7-cyano-10,11-dihydrodibenzo[b,f]-thiepin-4-yl-2-ethoxycarbonylpropanoa 
te provided the title compound in 97% yield. The compound was purified by 
short-path distillation at an oven temperature of 190.degree./0.05 Torr 
and then has m.p. 61.degree.-62.degree. C. Analysis for: C.sub.20 H.sub.19 
NO.sub.2 S Requires: C 71.19, H 5.68, N 4.15, S 9.50; Found C 71.13, H 
5.80, N 4.09, S 9.42. 
EXAMPLE 25 
8-(2-Carboxyethyl)-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid 
A mixture of ethyl 
3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)-propanoate (1.50 g, 4.45 
mmole), ethanol (15 ml) and 40% potassium hydroxide solution (15 ml) was 
stirred under reflux under argon for 24 hours. The reaction mixture was 
diluted with water, acidified with hydrochloric acid and extracted with 
ethyl acetate (50 ml+2.times.25 ml). The extract was washed with water, 
then with saturated sodium chloride solution, dried (MgSO.sub.4) and 
evaporated. Recrystallization of the crude product from acetic acid 
provided the title compound, 1.27 g, (87%), m.p. 233.degree.-235.degree. 
C. 
Analysis for: C.sub.18 H.sub.16 O.sub.4 S Requires: C 65.84, H 4.91, S 
9.76; Found: C 65.61, H 4.77, S 9.53. 
EXAMPLE 26 
6-(2-Carboxyethyl)-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid 
Substituting ethyl 
3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)-propanoate in the 
foregoing Example 25 with an equivalent amount of ethyl 
3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-4-yl)-propanoate provided the 
title compound in 88% yield m.p. 265.degree.-270.degree. C. dec after 
recrystallization from acetic acid. Analysis for: C.sub.18 H.sub.16 
O.sub.4 S 
Requires: C 65.84, H 4.71, S 9.76; Found: C 65.68, H 5.02, S 9.48. 
EXAMPLE 27 
Methyl 
1-oxo-2,3,9,10-tetrahydro-1H-benz[b]indeno[5,4-f]thiepin-6-carboxylate 
6-(2-Carboxyethyl)-10,11-dihydrodibenz-[b,f]thiepin-3-carboxylic acid (328 
mg; 1 mmole) was treated with thionyl chloride (6 ml) and after heating 
the mixture under reflux for 2 hours excess thionyl chloride was removed 
under vacuum. The residue was dissolved in 1,2-dichloroethane and the 
solvent was evaporated off to remove the last traces of thionyl chloride. 
The crude acid chloride dissolved in 1,2-dichloroethane (5 ml) was treated 
at 0.degree.-5.degree. C. with anhydrous aluminum chloride (100 mg; 0.75 
mmole) in 1,2-dichloroethane (2 ml). The mixture was stirred in the 
ice-bath for 2 hours and then it was treated with methanol (4 ml). The 
mixture was stirred in the ice-bath for 5 minutes, then at room 
temperature for 30 minutes and finally at 50.degree. C. for 30 minutes. 
Ethyl acetate (20 ml) was added and the solution was washed in succession 
with 2N hydrochloric acid (2.times.6 ml), water (6 ml), N sodium 
(2.times.6 ml) and finally with water (6 ml). Evaporation of the dried 
(MgSO.sub.4) ethyl acetate solution gives 291 mg of crude product which on 
purification by column chromatography (10 g Merck silica gel eluted with 
3% ethyl acetate in methylene chloride) gave 228 mg (70%) of solid m.p. 
156.degree.-158.degree. C. 
The pure title compound crystallized from acetonitrile in prisms m.p. 
160.degree.-161.degree. C. 
EXAMPLE 28 
Methyl 
1-oxo-2,3,11,12-tetrahydro-1H-benz[b]indeno-[4,5-f]thiepin-8-carboxylate 
and methyl 
3-oxo-2,3,10,11-tetrahydro-1H-benz[b]indeno[5,6-f]thiepin-7-carboxylate 
Repetition of the procedure of Example 27 using an equivalent amount of 
8-(2-carboxyethyl)-10,11-dihydrodibenz[b,f]thiepin-3-carboxylic acid in 
place of 6-(2-carboxyethyl)-10,11-dihydrodibenz-[b,f]thiepin-3-carboxylic 
acid provides a mixture of the two title compounds which are separated by 
column chromatography (Merck silica gel eluted with 3% ethyl acetate in 
methylene chloride). The first keto ester to be eluted was methyl 
1-oxo-2,3,11,12-tetrahydro1H-benz[b]indeno[4,5-f]thiepin-8-carboxylate 
m.p. 162.degree. C. (33%) and the second was methyl 
3-oxo-2,3,10,11-tetrahydro-1H-benz[b]indeno[5,6-f]thiepin-7-carboxylate 
m.p. 218.degree.-220.degree. C. (20%). 
EXAMPLE 29 
1-Oxo-2,3,9,10-tetrahydro-1H-benz[b]indeno[5,4-f]thiepin-6-carboxylic acid 
A solution of 85% potassium hydroxide (6.59 g) in water (60 ml) was diluted 
with ethanol (325 ml) and dioxane (32.5 ml). 
Methyl 
1-oxo-2,3,9,10-tetrahydro-1H-benz[b]indeno[5,4-f]thiepin-6-carboxylate 
(160 mg, 0.5 mmole) was added to 4.1 ml of the potassium hydroxide 
solution described above and the mixture was stirred at room temperature 
under argon for 8 hours. Water (2 ml) was added and then 10% hydrochloric 
acid (0.3 ml) was added to precipitate the title compound 126 mg (81%), 
m.p. 298.degree.-302.degree. (dec.). 
EXAMPLE 30 
1-Oxo-2,3,11,12-tetrahydro-1H-benz[b]indeno[4,5-f]thiepin-8-carboxylic acid 
Repeating the procedure of Example 29 but using an equivalent amount of 
methyl 
1-oxo-2,3,11,12-tetrahydro-1H-benz[b]indeno[4,5-f]thiepin-8-carboxylate in 
place of methyl 
1-oxo-2,3,9,10-tetrahydro-1H-benz[b]indeno[5,4-f]thiepin-6-carboxylate 
provided the title compound in 79% yield, m.p. 267.degree.-270.degree. 
(dec.). 
EXAMPLE 31 
3-Oxo-2,3,10,11-tetrahydro-1H-benz[b]indeno[5,6-f]thiepin-7-carboxylic 
acid. 
Repeating the procedure of Example 29 but using an equivalent amount of 
methyl 
3-oxo-2,3,10,11-tetrahydro-1H-benz[b]indeno[5,6-f]thiepin-7-carboxylate in 
place of methyl 
1-oxo-2,3,9,10-tetrahydro-1H-benz[b]indeno[5,4-f]thiepin-6-carboxylate 
provided the title compound. 
EXAMPLE 32 
(.+-.)-1-Hydroxy-2,3,9,10-tetrahydro-1H-benzo[b]indeno-[5,4-f]thiepin-6-ca 
rboxylic acid 
A suspension of 
1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-carboxylic 
acid (3.10 g, 10 mmole) in water (60 ml) was stirred during the addition 
of 1N sodium hydroxide solution (10 ml). After stirring for 15 minutes the 
mixture was treated with sodium borohydride (0.95 g, 25 mmole) in portions 
and the reaction mixture was stirred at room temperature overnight. 
Careful acidification of the mixture with 10% hydrochloric acid 
precipitated the racemic title compound which was collected by filtration 
and washed well with water. 
EXAMPLE 33 
(.+-.)-1-Hydroxy-2,3,11,12-tetrahydro-1H-benzo[b]indeno-[4,5-f]thiepin-8-ca 
rboxylic acid 
Substituting an equivalent amount of 
1-oxo-2,3,11,12-tetrahydro-1H-benzo[b]indeno[4,5-f]-thiepin-8-carboxylic 
acid in Example 32 for 
1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-carboxylic 
acid provided the title compound. 
EXAMPLE 34 
(.+-.)-3-Hydroxy-2,3,10,11-tetrahydro-1H-benzo[b]indeno-[5,6-f]thiepin-7-ca 
rboxylic acid 
Substituting an equivalent amount of 
3-oxo-2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylic 
acid in Example 32 for 
1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-carboxylic 
acid provided the title compound. 
EXAMPLE 35 
(.+-.)-1.alpha.-Hydroxy 
4.alpha.-oxido-2,3,9,10-tetrahydro-1H-benzo-[b]indeno[5,4-f]thiepin-6-carb 
oxylic acid and 
(.+-.)-1.beta.-hydroxy-4.alpha.-oxido-2,3,9,10-tetrahydro-1H-benzo[b]-inde 
no-[5,4-f]thiepin-6-carboxylic acid 
STEP A: Preparation of methyl 
1-hydroxy-2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-carboxylat 
e 
A suspension of 
(.+-.)-1-hydroxy-2,3-9-10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-car 
boxylic acid (3.10 g; 10 mmole) in methanol (30 ml) at room temperature was 
treated with excess ethereal diazomethane solution in small portions with 
stirring. The completion of the reaction was indicated by the cessation of 
the evolution of nitrogen after adding more diazomethane and was confirmed 
by thin layer chromatography. Evaporation of the solvent provided the 
title compound. [Note: An alternative method of preparation was by 
reduction of methyl 
1-oxo-2,3,9,10-tetrahydro-1H-benzo-[b]indeno[5,4-f]thiepin-6-carboxylate.] 
STEP B: Preparation of methyl 
(.+-.)-1.alpha.-hydroxy-4.alpha.-oxido-2,3,9,10-tetrahydro-1H-benzo[b]inde 
no-[5,4-f]thiepin-6-carboxylate and methyl 
(.+-.)-1.beta.-hydroxy-4.alpha.-oxido-2,3,9,10-tetrahydro-1H-benzo[b]inden 
o[5,4-f]thiepin-6-carboxylate 
A solution of methyl 
(.+-.)-1-hydroxy-2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-car 
boxylate (1.40 g, 4 mmole) in methylene chloride (70 ml) was treated at 
0.degree.-5.degree. C. with 85% m-chloroperbenzoic acid (2.13 g, 4.2 
mmole) in small portions. After stirring the mixture for 2 hourscalcium 
hydroxide (4.25 g) was added and after another 20 mins. the solution was 
filtered. Evaporation of the solvent afforded a mixture of the 
diastereoisomeric methyl esters which are separated by column 
chromatography to provide the individual title compounds. 
STEP Ci: Preparation of 
(.+-.)-1.alpha.-hydroxy-4.alpha.-oxido-2,3,9,10-tetrahydro-1H-benzo[b]inde 
no[5,6-f]-thiepin-6-carboxylic acid 
Substituting an equivalent amount of methyl 
(.+-.)-1.alpha.-hydroxy-4.alpha.-oxido-2,3,9,10-tetrahydro-1H-benzo-[b]ind 
eno[5,4-f]thiepin-6-carboxylate in Example 29 for methyl 
1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]indeno [5,4-f]thiepin-6-carboxylate 
provided the title compound. 
STEP Cii: Preparation of 
(.+-.)-1.beta.-hydroxy-4.alpha.-oxido-2,3,9,10-tetrahydro-1H-benzo[b]inden 
o-[5,4-f]thiepin-6-carboxylic acid 
Substituting an equivalent amount of 
methyl(.+-.)-1.beta.-hydroxy-4.alpha.-oxido-2,3,9,10-tetrahydro-1H-benzo[b 
]indeno[5,4-f]thiepin-6-carboxylate in Example 29 for methyl 
1-oxo-2,3,9,10-tetrahydro-1H-benzo-[b]indeno[5,4-f]thiepin-6-carboxylate 
provided the diastereoisomer of the product from Step Ci. 
EXAMPLE 36 
(.+-.)-1.alpha.-Hydroxy-6.alpha.-oxido-2,3,11,12-tetrahydro-1H-benzo[b]inde 
no[4,5-f]thiepin-8-carboxylic acid and 
(.+-.)-1.beta.]Hydroxy-6.alpha.-oxido-2,3,11,12-tetrahydro-1H-benzo[b]-ind 
eno[4,5-f]thiepin-8-carboxylic acid 
Substituting an equivalent amount of 
(.+-.)-1-hydroxy-2,3,11,12-tetrahydro-1H-benzo[b]indeno[4,5-f]-thiepin-8-c 
arboxylic acid in Example 35, Step A, in place of 
(.+-.)-1-hydroxy-2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-car 
boxylic acid and then proceeding through Steps B, Ci and Cii provided the 
diastereoisomeric title compounds. 
EXAMPLE 37 
(.+-.)-3.alpha.-Hydroxy-5.alpha.-oxido-2,3,10,11-tetrahydro-1H-benzo[b]inde 
no[5,6-f]thiepin-7-carboxylic acid and 
(.+-.)-3.beta.-Hydroxy-5.alpha.-oxido-2,3,10,11-tetrahydro-1H-benzo[b]inde 
no[5,6-f]thiepin-7-carboxylic acid 
Substituting an equivalent amount of 
(.+-.)-3-hydroxy-2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-ca 
rboxylic acid in Example 35, Step A, in place of 
1-hydroxy-2,3,9,10-tetrahydro-1H-benzo 
[b]indeno[5,4-f]thiepin-6-carboxylic acid and then proceeding through 
Steps B, Ci and Cii provided the title compounds. 
EXAMPLE 38 
4-Oxido-1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]indeno-[5,4-f]thiepin-6-carbox 
ylic acid 
STEP A: Preparation of methyl 
4-oxido-1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-carbox 
ylate 
m-Chloroperbenzoic acid (85%) (10 mg; 0.05 mmole) was added to a solution 
of methyl 
1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-carboxylate 
(16 mg; 0.05 mmole) in methylene chloride (5 ml) stirred in an ice-bath. 
The reaction mixture was allowed to warm to 10.degree. C. and monitored by 
thin layer chromatography. A very small additional quantity of peracid was 
added to complete the oxidation. Calcium hydroxide (25 mg) was added and 
after stirring the mixture for 15 mins. it was filtered and evaporated to 
afford the title compound as a solid, m.p. 227.degree.-229.degree. C. dec. 
STEP B: Preparation of 
4-oxido-1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-5-carbox 
ylic acid 
Substituting an equivalent amount of methyl 
4-oxido-1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-carbox 
ylate in Example 29 in place of methyl 
1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]-indeno[5,4-f]thiepin-6-carboxylate 
provided the title compound. 
EXAMPLE 39 
6-Oxido-1-oxo-2,3,11,12-tetrahydro-1H-benzo[b]indeno[4,5-f]thiepin-8-carbox 
ylic acid 
Substituting an equivalent amount of methyl 
1-oxo-2,3,11,12-tetrahydro-1H-benzo[b]indeno[4,5-f]-thiepin-8-carboxylate 
in Example 38, Step A, in place of methyl 
1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]-indeno[5,4-f]thiepin-6-carboxylate 
and taking the product through Step B of this example provided the title 
compound. 
EXAMPLE 40 
5-Oxido-3-oxo-2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carbox 
ylic acid 
Substituting an equivalent amount of methyl 
3-oxo-2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-carboxylate in 
Example 38, Step A, in place of methyl 
1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]-indeno[5,4-f]thiepin-6-carboxylate 
and then taking the product through Step B of this example provided the 
title compound. 
EXAMPLE 41 
2,3,11,12-Tetrahydro-1H-benzo[b]indeno[4,5-f]thiepin-8-carboxylic acid 
1-Oxo-2,3,11,12-tetrahydro-1H-benzo[b]indeno[4,5-f]thiepin-8-carboxylic 
acid (50 mg; 0.16 mmole) was added in portions over a 3/4 hour period to a 
refluxing mixture of acetic acid (4 ml), concentrated hydrochloric acid 
(0.3 ml) and amalgamated "mossy" zinc (220 mg) under argon. After a 
further 3 hours under reflux no oxo-acid remained. The reaction mixture 
was filtered, evaporated to a small volume and diluted with a little water 
to afford 43 mg of the title compound. 
On esterification with diazomethane this acid gave a methyl ester of m.p. 
88.degree. C. 
EXAMPLE 42 
2,3,9,10-Tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-carboxylic acid 
Substituting an equivalent amount of 
1-oxo2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-carboxylic acid 
in Example 41 in place of 
1-oxo2,3,11,12-tetrahydro-1H-benzo[b]indeno[4,5-f]thiepin-8-carboxylic 
acid and heating under reflux for 9 hours instead of 3 hours yielded the 
title compound. 
The methyl ester of this product had a m.p. of 77.degree. C. 
Although the instant invention has been described in the foregoing 
specification in terms of the use of the novel oxathiepins disclosed 
herein in the treatment and control of human and warm-blooded animal 
disease conditions characterized by excessive undesirable contractile 
activity of prostaglandins and prostaglandin biosynthetic intermediates, 
and particularly of asthma, it will be recognized by those skilled in the 
art that, in addition to the involvement of contractile prostaglandins in 
chronic obstructive lung disease (e.g. asthma), prostaglandins play a role 
in other allergic conditions as well as in inflammation, diarrhea, 
hypertension, angina, platelet aggregation, cerebral spasm, premature 
abortion and dismenorrhea. Also the oxathiepins of this invention are 
potent TXA.sub.2 biosynthesis inhibitors, inhibiting platelet aggregation, 
and can be useful in diseases such as atherosclerosis, and myocardial 
infarction. Applicants consider application of the oxathiepins disclosed 
and claimed herein to the treatment and control of such disease conditions 
to be obvious equivalents to the invention as disclosed by applicants and 
to fall within the scope of the instant invention. 
For those compounds in which asymmetry is present, the present invention 
includes both the racemic forms and the separate optically active isomers 
thereof. 
The subject matter which applicants regard as their invention, and which is 
sought to be patented herein, is particularly pointed out and distinctly 
claimed as follows.