Sulfinyl and sulfonyl substituted 2,3,4,5 tetrahydro-1H-3-benzazepines and their use in treating gastrointestinal motility disorders

Sulfinyl and sulfonyl substituted 3-benzazepine compounds are useful in treating gastrointestinal motility disorders and emesis. A particular compound of this invention is 7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

This invention relates to new sulfinyl and sulfonyl substituted benzazepine 
compounds, pharmaceutical compositions containing them and methods of 
treating gastrointestinal motility disorders and emesis by administering 
these compounds. 
The compounds of this invention have utility in the treatment of 
gastrointestinal diseases, in particular gastrointestinal motility 
disorders and emesis. The compounds are useful therapeutically for 
gastroesophageal reflux disease and disorders of delayed gastric emptying 
of various etiologies including diabetes, surgery, and idiopathic delayed 
emptying. The compounds may also be useful in treating disorders of upper 
GI motility, aspiration, early satiety, anorexia nervosa, and in 
diagnostic radiology or to facilitate intubation. 
The compounds of this invention are represented by the following formula 
(I): 
##STR1## 
in which: R is hydrogen, C.sub.1 -C.sub.6 alkyl or C.sub.3 -C.sub.5 
alkenyl; 
R.sup.1 is SOR.sup.3, SO.sub.2 R.sup.3 or SO.sub.1 NB.sub.4 R.sup.5 ; 
R.sup.2 is hydrogen, halogen, CF.sub.3, C.sub.1 -C.sub.6 alkyl or R.sup.6 
O--; 
R.sup.3 is C.sub.1 -C.sub.6 alkyl or CF.sub.3 ; 
R.sup.4 and R.sup.5 are hydrogen or C.sub.1 -C.sub.6 alkyl; and 
R.sup.6 is hydrogen, C.sub.1 -C.sub.6 alkyl or C.sub.1 -C.sub.6 alkanoyl, 
provided that when R.sup.1 is SO.sub.2 NH.sub.2 5 R.sup.2 is R.sup.6 O--, 
halogen, CF.sub.3 or C.sub.1 -C.sub.6 alkyl, 
or a pharmaceutically acceptable acid addition salt thereof. 
Particular compounds of formula (I) are those in which R.sup.1 is in the 
7-position. Further particular compounds of formula (I) are those in which 
R.sup.1 is in the 7-position and R.sup.2 is in the 8-position. 
A group of compounds of formula (I) is that in which R.sup.1 is SO.sub.2 
R.sup.3 or SO.sub.2 NR.sup.4 R.sup.5, R.sup.2 is hydrogen, alkoxy or 
hydroxy, R.sup.3 is methyl and R is hydrogen and, in addition, R.sup.1 may 
be in the 7-position and R.sup.2 may be in the 8-position. 
Specific compounds of this invention are: 
8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 
7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 
8-hydroxy-7-(N-methylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; 
8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 
6-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 
7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine. 
The process for preparing a compound of the formula (1) or a 
pharmaceutically acceptable acid-addition salt thereof, comprises: 
(a) for compounds where R.sup.1 is SOR.sup.3 and SO.sub.2 R.sup.3, reacting 
a compound of the formula (II): 
##STR2## 
wherein R.sup.3 is as hereinbefore defined, R.sup.7 is a N-protecting 
group, R.sup.8 is hydrogen, C.sub.1 -C.sub.6 alkyl, halogen with CF.sub.3 
or OR.sup.9 where R.sup.9 is an O-protecting group and R.sup.10 is 
hydrogen or bromo, with an oxidizing agent; 
(b) for compounds where R.sup.1 is SO.sub.2 R.sup.3 where R.sup.3 is 
C.sub.1 -C.sub.6 alkyl, reducing a compound of the formula (III): 
##STR3## 
wherein R.sup.7 and R.sup.8 are as hereinbefore defined and B.sup.10 is 
hydrogen or bromo, with sodium sulfite and reacting with a C.sub.1 
-C.sub.6 alkylating agent; or 
(c) for compounds where R.sup.1 is SO.sub.2 NR.sup.4 R.sup.5, reacting a 
compound of the formula (III) as hereinbefore defined with an amine: 
R.sup.4 R.sup.5 NH where R.sup.4 and R.sup.5 are as hereinbefore defined; 
and thereafter if necessary: 
(i) debrominating the benzazepine ring when R.sup.10 is bromo, 
(ii) removing a N-protecting group, 
(iii) alkylating or alkenylating the secondary amino group of the 
benzazepine ring, 
(iv) removing a O-protecting group, 
(v) alkylating or alkanoylating the hydroxy group of the benzazepine ring, 
(vi) forming a pharmaceutically acceptable acid addition salt. 
A compound of the formula (II) is suitably treated with an oxidizing agent 
such as hydrogen peroxide or a peracid such as 3-chloroperbenzoic acid, in 
a solvent such as acetic acid. One equivalent of the oxidizing agent gives 
the sulfinyl compounds and two equivalents gives the sulfonyl compounds. 
Suitably a compound of the formula (III) is treated with sodium sulfite in 
aqueous sodium bicarbonate and then with a C.sub.1 -C.sub.6 alkylating 
agent. Suitable alkylating agents include C.sub.1 -C.sub.6 alkyl halides, 
for example C.sub.1 -C.sub.6 alkyl bromides and iodides. 
A compound of the formula (III) is suitably reacted with an amine (R.sup.6 
R.sup.7 NH) in a solvent such as dichloromethane. When R.sup.6 and R.sup.7 
are hydrogen, preferably ammonium hydroxide is used. 
In the compounds of the formulae (II) and (III) the following combinations 
of substituents are preferable. 
R.sup.10 is hydrogen when the groups R.sup.8 and ClSO.sub.2 or R.sup.3 S 
are meta or para to each other. 
R.sup.10 is 9-bromo when R.sup.8 is in the 6-position and ClSO.sub.2 or 
R.sup.3 S is in the 7-position. 
R.sup.10 is 8-bromo when R.sup.8 is in the 7-position and ClSO.sub.2 or 
R.sup.3 S is in the 6-position. 
R.sup.10 is hydrogen when R.sup.8 is in the 8-position and ClSO.sub.2 or 
R.sup.3 S is in the 7-position. 
The subsequent steps of debromination, N-deprotection, N-alkylation, 
N-alkenylation, O-deprotection, O-alkylation and O-alkanoylation may be 
carried out by standard methods and may be carried out in various order of 
steps to prepare the desired compounds. 
Compounds of the formula (II) can be prepared by the following general 
routes: 
(a) for compounds where R.sup.3 is C.sub.1 -C.sub.6 alkyl, by treating a 
compound of the formula (IV) 
##STR4## 
where R.sup.7, R.sup.8 and R.sup.10 are as hereinbefore defined, with a 
C.sub.1 -C.sub.6 alkylating agent for example a C.sub.1 -C.sub.6 alkyl 
halide or a C.sub.1 -C.sub.6 dialkyl sulfate; 
(b) by treating a compound of the formula (V): 
##STR5## 
wherein R.sup.10 is bromo, R.sup.11 is R.sup.8 and R.sup.7 and R.sup.8 are 
as hereinbefore defined, with butyllithium and with either (R.sup.3 
S).sup.2 or R.sup.3 SCl; 
(c) for compounds where R.sup.8 is OR.sup.9, by treating a compound of the 
formula (V) wherein R.sup.11 is OH, R.sup.10 is hydrogen or bromo and 
R.sup.7 is as hereinbefore defined, with R.sup.3 SCl and then protecting 
the free hydroxyl group; 
(d) for compounds where R.sup.3 is trifluoromethyl, by treating a compound 
of the formula (II) wherein R.sup.3 is methyl, with chlorine in the 
presence of cumene and then with antimony trifluoride and antimony 
pentachloride. 
A compound of the formula (IV) can be prepared by reducing a compound of 
the formula (III). Suitably the reduction is performed with stannous 
chloride. 
Compounds of the formula (III) can be prepared as follows: 
(a) by treating a compound of the formula (V) where R.sup.10 is hydrogen or 
bromo, R.sup.11 is R.sup.8 and R.sup.7 and R.sup.8 are as hereinbefore 
defined with chlorosulfonic acid; and 
(b) by treating a compound of the formula (II) as hereinbefore defined with 
chlorine and aqueous acetic acid. 
Suitable N-protecting groups for compounds of the formulae (II), (III), 
(IV) and (V) include acyl groups such as acetyl, trifluoroacetyl, benzoyl, 
methoxycarbonyl or benzyloxycarbonyl. Suitable O-protecting groups for 
compounds of the formulae (II), (III), (IV) and (V) include C.sub.1 
-C.sub.6 alkyl and benzyl. These groups can be introduced in standard 
manner. 
The compounds of the formula (V) can be prepared using methods known in the 
art, for example by bromination of a compound of the formula (V) wherein 
R.sup.10 is hydrogen, or by the methods illustrated in Examples 1, 9 and 
10 hereinafter described. 
The compounds of formula (I) form pharmaceutically acceptable acid addition 
salts with organic or inorganic acids. Examples of these acids are 
hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, tartaric, citric, 
maleic, lactic, oxalic, succinic, methanesulfonic, and benzenesulfonic 
acids. The salts are formed according to methods known to the art. If the 
product is isolated as an acid addition salt, it may be treated with an 
inorganic or organic base, such as aqueous sodium hydroxide, sodium 
carbonate, triethylamine, etc., and converted to the corresponding free 
base. The base can then be treated with an appropriate acid, for example 
in an aqueous miscible solvent, such as a lower alkanol preferably 
methanol or ethanol, to give the desired salt. 
The effect of the pharmacologically active compounds of this invention on 
gastrointestinal motility is demonstrated in test procedures as follows: 
(1) an increase in resting pressure of the lower esophageal sphincter (LES) 
in dogs; and 
(2) an increase in the rate of gastric emptying in rats. 
Method for Determination of LES Pressure in the Anesthetized Dog 
Mongrel or beagle dogs, male and female,are anesthetized using sodium 
pentobarbital (35.0 mg/kg., i.v.). Sodium pentobarbital is then 
continuously infused (approximately 6.0 mg/kg/hr) to maintain deep 
anesthesia. Blood pressure is monitored via a catheter surgically 
implanted into the femoral artery and attached to a GouldStatham P23ID 
transducer. A catheter is also implanted into the femoral vein to 
administer test drugs. Respiration is maintained by an endotracheal tube 
attached to a respirator. A continuously perfused manometric catheter 
system including a Dent sleeve to measure sphincter pressure (Dent, 
Gastroenterology 71: 263-267, 1976) is inserted into the esophagus and 
positioned so that intraluminal pressure is recorded from the body of the 
esophagus, the lower esophageal sphincter (LES) and the fundus of the 
stomach. The Dent sleeve catheter is perfused at a rate of 0.5 ml of water 
per minute for each lumen of the catheter by using an Arndorfer Hydraulic 
Capillary Infusion System. A cannula is implanted into the gastric antrum 
to allow drainage of the perfusate solution and prevent intestinal 
distension. Continuous tracings of esophageal, LES and fundus pressure are 
monitored on a Grass Polygraph (Model 7D). Correct positioning of the Dent 
sleeve is verified by noting a high pressure zone at the LES and by 
administration of an intravenous dose of 5-hydroxytryptamine (usually 
10-15 mcg/kg) which contracts the LES while having little or no 
recordable effect on either the body of the esophagus or the fundus. After 
verification of placement of the sleeve, the animal is allowed to 
stabilize for approximately 30 minutes. 
Compounds are administered intravenously, intraduodenally or 
intragastrically. In most cases, succeeding doses of the same or different 
compounds are given only after the LES pressure has returned to 
approximate pre-dosing baseline values. In all cases, the magnitude of 
change in LES pressure is determined from the baseline pressure 
immediately prior to each treatment to the maximum pressure during 
treatment. Since the compounds used usually produce an immediate effect on 
LES pressure, no pretreatment time prior to measurement is necessary 
during this testing. 
Direct assay techniques are used to estimate an Effective Dose 20 
(ED.sub.20) for the test compound in individual animals. The mean 
ED.sub.20 and 95 PERCENT confidence limits are determined using the 
individual ED.sub.20 values from a group of animals (N=3) that received 
the same treatment. The ED.sub.20 is the dose which increases LES pressure 
20 mm Hg. The ED.sub.20 's of the 8-hydroxy-7-sulfamoyl, 
8-hydroxy-7-(N-methylsulfamoyl) and 8-hydroxy-7-methylsulfonyl compounds 
of Examples 1, 2 and 4 are 50.7, 4.0 and 27.0 mcg/kg, i.v., respectively. 
The ED.sub.20 's of the 7-methylsulfonyl-8-methoxy and 7-methylsulfonyl 
compounds are 33.9 and 40.3 mcg/kg, i.d. respectively. 
Gastric Emptying in the Rat 
Fasted rats are administered 0.5 Ci of Na.sub.2 51.sub.CrO (0.2 ml vol) 
into the stomach with an oral feeding tube. Compounds for evaluation or 
vehicle controls are administered either 15 minutes before (oral 
administration) or simultaneously with (intravenous administration) the 
test meal. After 35 minutes the rats are killed by cervical dislocation 
and the stomach is removed. Gastric emptying is measured from the amount 
of .sup.51 Cr remaining in the stomach at death. In this test, the 
compound of Example 4 at a dose of 0.5 mg/kg, i.v. doubled the rate of 
gastric emptying as compared to control. 
Method for Determination of the Anti-emetic Effect in the Conscious Dog 
Compounds are administered orally or parenterally to proven 
apomorphine-sensitive dogs of either sex. After the appropriate time has 
elapsed (determined by a peak time study), apomorphine hydrochloride (0.1 
mg/kg, s.c.) is administered and the frequency of emesis is observed and 
recorded for the next forty minutes. Emesis is defined as the actual 
expulsion of stomach contents. 
The control group of dogs, also apomorphine-sensitive, receive the test 
vehicle and apomorphine hydrochloride (0.1 mg/kg, s.c.) Emesis is recorded 
as with the test animals. 
The mean frequency of emesis for the control and test groups is calculated. 
A value for each test group is then obtained which expresses the 
percentage increase or decrease in frequency of emesis relative to 
controls. An effective dose-50% is calculated. The ED.sub.50 refers to the 
dose that decreases emesis induced by apomorphine by 50%. 
This invention also includes pharmaceutical compositions for treatment of 
gastrointestinal motility disorders comprising a compound of formula (I), 
6-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine, or 
7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine, or a pharmaceutically 
acceptable acid addition salt thereof and a pharmaceutically acceptable 
carrier. 
The pharmacologically active compounds of formula (I) can be administered 
orally or parenterally. Preferably, these compounds are administered in 
conventional dosage unit forms prepared by combining an appropriate dose 
of the compound with standard pharmaceutical carriers. The dosage units 
will contain the active ingredient in an effective amount selected from 
about 1 mg. to about 250 mg., preferably 10 mg. to 100 mg. 
The pharmaceutical carrier employed may be, for example, either a solid or 
liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, 
talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and 
the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, 
water and the like. Similarly, the carrier or diluent can include any time 
delay material well known to the art, such as glyceryl monostearate or 
glyceryl distearate alone or with a wax. 
A wide variety of pharmaceutical forms can be employed. Thus, if a solid 
carrier is used the preparation can be tableted, placed in a hard gelatin 
capsule in powder or pellet form or in the form of a trouche or lozenge. 
The amount of solid carrier will vary widely but preferably will be from 
about 25 mg. to about 1 g. If a liquid carrier is used, the preparation 
will be in the form of a syrup, emulsion, soft gelatin capsule, sterile 
injectable liquid such as an ampul or an aqueous or nonaqueous liquid 
suspension. 
The pharmaceutical compositions are prepared by conventional techniques 
involving procedures such as mixing, granulating and compressing when 
necessary or variously mixing and dissolving the ingredients as 
appropriate to the desired composition. 
The method of treating gastrointestinal motility disorders in accordance 
with this invention comprises administering internally to a subject in 
need of said particular treatment an effective amount of a compound of 
formula (I), in particular, 
7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 
6-sulfamoyl-2,3,4,5-tetrahydro- 1H-3-benzazepine, 
7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-henzazepine, or 
8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a 
pharmaceutically acceptable acid addition salt thereof. 
The method of treating and preventing emesis in accordance with this 
invention comprises administering internally to a subject in need of said 
treatment an effective amount of a compound of formula (I), in particular 
8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine. 
The compound will preferably be administered in a dosage unit form orally 
or parenterally. Advantageously equal doses will be administered one to 
four times daily with the daily dosage regimen being from about 1 mg. to 
about 1000 mg., preferably from 10 mg. to 400 mg. The method described 
above is useful for treating gastrointestinal motility disorders. 
One skilled in the art will recognize that in determininq the amounts of 
the compound needed to produce the desired pharmacological effect without 
toxic side effects, the activity of the particular compound as well as the 
size of the host animal must be considered.

The following examples illustrate the invention but are not to be construed 
as limiting the scope thereof. Temperatures are in degrees Centigrade 
unless otherwise stated. 
EXAMPLE 1 
8-Hydroxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine. 
A mixture of 3-methoxyphenylacetic acid (47.7 g, 0.287 m), thionyl chloride 
(50 ml) and N,N-dimethylformamide (6 drops) in toluene (500 ml) was 
stirred for 16 hours at 25.degree. and concentrated in vacuo to afford 
3-methoxyphenylacetyl chloride. The acetyl chloride was dissolved in 
chloroform (100 ml) and added to a solution of aminoacetaldehyde dimethyl 
acetal (32.1 g, 0.306 m) and triethylamine (32.4 g, 0.320 m) in chloroform 
(500 ml) stirred at 5.degree.. The mixture was stirred at 25.degree. for 
16 hours, washed with water, 1.5 N hydrochloric acid and water, dried with 
magnesium sulfate and concentrated in vacuo to give 
N-(2,2-dimethoxyethyl)-3-methoxybenzeneacetamide. 
A solution of the benzeneacetamide (70 g, 0.277 m) in acetic acid (180 ml) 
was added with stirring to concentrated hydrochloric acid (120 ml). The 
mixture was stirred for 16 hours, diluted with ice/water and filtered. The 
filter cake was dissolved in methylene chloride which was washed with 
water, dried with magnesium sulfate and concentrated in vacuo to give 
2,3-dihydro-8-methoxy-2-oxo-1H-3-benzazepine. 
A mixture of 2,3-dihydro-8-methoxy-2-oxo-1H-3-benzazepine (12 g, 0.063 m) 
and 10% palladium-on-carbon (1.2 g) in acetic acid (200 ml) was shaken in 
an atmosphere of hydrogen (60 psi), degassed, filtered and concentrated in 
vacuo. The residue was dissolved in methylene chloride, washed with water, 
dried with magnesium sulfate and concentrated in vacuo. The residue was 
triturated with ether and filtered to give 
8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine. 
A suspension of 8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine (20.4 
g, 0.105 m) in tetrahydrofuran (500 ml) was added to 1 M borane in 
tetrahydrofuran (300 ml) stirred at 5.degree.. The mixture was heated to 
reflux for 2 hours, cooled, treated with 3N hydrochloric acid (300 ml), 
concentrated in vacuo to remove tetrahydrofuran and heated to reflux for 1 
hour. The mixture was concentrated in vacuo, filtered and the filter cake 
was dissolved in methanol, heated to reflux, dried with magnesium sulfate 
and concentrated in vacuo to afford 
7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 
229.degree.-231.degree.. 
A mixture of 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride 
(4.3 g, 0.02 m) and sodium acetate (3.3 g, 0.04 m) in acetic anhydride (13 
ml) was refluxed and stirred for 16 hours, concentrated in vacuo and 
partitioned between methylene chloride and water. The organic phase was 
dried with magnesium sulfate, filtered and concentrated in vacuo to give 
3-acetyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 
89.degree.-90.degree.. 
3-Acetyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (2.3 g, 0.01 m) was 
added to chlorosulfonic acid (6 ml) which was stirred at 0.degree.; the 
mixture was allowed to warm to 25.degree. and stirred for 16 hours. The 
reaction was carefully poured into ice water and extracted with methylene 
chloride. The methylene chloride extracts were combined, washed, dried 
with magnesium sulfate and concentrated in vacuo to give 
3-acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, 
m.p. 153.degree.-160.degree.. 
3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (3 
g, 0.007 m) was treated with concentrated ammonium hydroxide (10 ml), 
stirred for 2 hours and filtered to give 
3-acetyl-8-methoxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 
260.degree.-263.degree.. 
The sulfonamide (2.3 g, 0.007 m) was suspended in 3N hydrochloric acid and 
heated to reflux for 16 hours. The mixture was concentrated in vacuo and 
the residue crystallized from methanol to give 
8-methoxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, 
m.p. 270.degree.-274.degree.. 
8-Methoxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride 
(1.5 g, 0.005 m) was dissolved in 48% hydrobromic acid (15 ml), refluxed 
for 2 hours and concentrated in vacuo. The residue was triturated with 
acetone and then recrystallized from methanol to give 
8-hydroxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, 
m.p. 315.degree.-320.degree. (decomp.). 
EXAMPLE 2 
8-Hydroxy-7-(N-methylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine 
3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (2 
g) was stirred with 10 ml of 40% aqueous methylamine, then was treated 
with hydrochloric acid and concentrated in vacuo to give 
8-methoxy-7-(N-methylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride. This 8-methoxy-7-(N-methylsulfamoyl) compound was treated 
with boron tribromide in methylene chloride and then with methanol to give 
8-hydroxy-7-(N-methylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrobromide, m.p. 130.degree.-135.degree. C. 
EXAMPLE 3 
8-Hydroxy-7-(N,N-dimethylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine 
By the procedure of Example 2, using dimethylamine in place of methylamine, 
8-methoxy-7-(N,N-dimethylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride was obtained which, on treatment with boron tribromide, gave 
8-hydroxy-7-(N,N-dimethylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrobromide, m.p. 195.degree.-197.degree. C. 
EXAMPLE 4 
8-Hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
Method A 
3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (18 
g, 0.056 m) was added in portions to a mixture of sodium sulfite (8.8 g, 
0.069 m) and sodium bicarbonate (10.8 g, 0.115 m) in water (36 ml) stirred 
at 70.degree. C. There was a vigorous evolution of gas after each 
addition. The mixture was stirred for fifteen minutes, treated with 
iodomethane (8.5 ml, 0.136 m) and refluxed for forty-five minutes. The 
mixture was partitioned between methylene chloride and water. The 
methylene chloride phase was washed with water, dried with sodium sulfate 
and concentrated in vacuo to give 
3-acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 
m.p. 159.degree.-162.degree. C. 
Method B 
3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (4 
g, 0.013 m) was dissolved in glacial acetic acid (80 ml), treated with 
stannous chloride dihydrate (11.6 g, 0.05 m) and concentrated hydrochloric 
acid (16 ml) and stirred at 75.degree. for 1 hour. The mixture was cooled, 
poured into ice water and extracted with ethyl acetate. The combined ethyl 
acetate extract was washed, dried with magnesium sulfate and concentrated 
in vacuo to give a mixture of 
3-acetyl-7-mercapto-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine and the 
corresponding disulfide. 
The crude mixture (3 g) was dissolved in ethanol and treated with sodium 
borohydride (2 g, 0.05 m) to effect reduction of the disulfide to the 
mercaptan. Methyl iodide (2 g, 0.014 m) was added and the reaction mixture 
was stirred at 25.degree. for 1 hour. The mixture was concentrated, 
partitioned between water and methylene chloride and the combined 
methylene chloride extract was washed, dried with magnesium sulfate and 
concentrated in vacuo to give 
3-acetyl-8-methoxy-7-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 
138.degree.-140.degree.. 
3-Acetyl-8-methoxy-7-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine (1.1 g, 
0.004 m) dissolved in chloride (10 ml) was treated with 3-chloromethylene 
perbenzoic acid (1.4 g, 0.008 m) and stirred for 1 hour. The mixture was 
extracted with 5% aqueous sodium carbonate, washed with water, dried with 
magnesium sulfate and concentrated in vacuo to give 
3-acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 
m.p. 162.degree.-164.degree.. 
3-Acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1 
g, 0.003 m), prepared as in Method A or B, in 48% hydrobromic acid (15 ml) 
was heated to reflux for 16 hours and concentrated in vacuo. The residue 
was triturated with acetone and recrystallized from methanol-water to give 
8-hydroxy-7-methylsulfonyl-2.3.4.5 -tetrahydro-1H-3-benzazepine 
hydrobromide, m.p. 300.degree. (decomp.). 
Alternatively, 
3-acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
was treated with 3N hydrochloric acid to give 
8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride, m.p. 228.5.degree.-229.5.degree.. Refluxing this compound 
with 48% hydrobromic acid gave 
8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrobromide. 
EXAMPLE 5 
8-Hydroxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
Following the general procedure of Example 4 Method B, 
3-acetyl-8-methoxy-7-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine is 
reacted with one equivalent of 3-chloroperbenzoic acid to give 
3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine. 
Following the procedure of Example 4, 
3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine is 
reacted with 3N hydrochloric acid to give 
8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride. This methoxy compound is treated with pyridine 
hydrochloride to give 
8-hydroxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride. 
EXAMPLE 6 
8-Hydroxy-3-methyl-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
A mixture of 8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride (1 g, 3.5 mmol), 37% aqueous formaldehyde (1.1 g) and 
platinum oxide (0.1 g) in ethanol (25 ml) was shaken under an atmosphere 
of hydrogen (60 psi). The mixture was degassed, filtered and concentrated 
at reduced pressure to give 
3-methyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride. 
Following the procedure of Example 4, 
3-methyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride was reacted with 48% hydrobromic acid to give 
8-hydroxy-3-methyl-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrobromide, m.p. 310.degree. (decomp.). 
EXAMPLE 7 
8-Hydroxy-7-trifluoromethylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 
8-hydroxy-7-trifluoromethylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
3-Acetyl-8-methoxy-7-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine (12 g, 
0.05 mol) prepared substantially as in Example 4, Method B, is dissolved 
in ethanol-free chloroform (250 ml) containing cumene (10 g) and stirred 
in the dark. Chlorine is passed through the solution for 48 hours and the 
mixture is concentrated in vacuo to give 
3-acetyl-8-methoxy-7-trichloromethylthio-2,3,4,5-tetrahydro-1H-3-benzazepi 
ne. 
3-Acetyl-8-methoxy-7-trichloromethylthio-2,3,4,5-tetrahydro-1H-3-benzazepin 
e (5.5 g, 0.016 mol), antimony trifluoride (15 g, 0.09 ml) and antimony 
pentachloride (1.5 g, 0.005 mol) are heated and stirred at 90.degree. for 
24 hours. The resulting mixture is partitioned between chloroform and 3N 
hydrochloric acid. The chloroform phase is concentrated in vacuo to give 
3-acetyl-8-methoxy-7-trifluoromethylthio-2,3,4,5-tetrahydro-1H-3-benzazepi 
ne. 
Following the procedure of Examples 4 Method B and 5, 
3-acetyl-8-methoxy-7-trifluoromethylthio-2,3,4,5-tetrahydro-1H-3-benzazepi 
ne is reacted with 3-chloroperbenzoic acid and then hydrolyzed with 3N 
hydrochloric acid to give: 
8-methoxy-7-trifluoromethylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride and 
8-methoxy-7-trifluoromethylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride. 
These 8-methoxy compounds are treated with 48% hydrobromic acid to give: 
8-hydroxy-7-trifluoromethylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrobromide and 
8-hydroxy-7-trifluoromethylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrobromide. 
EXAMPLE 8 
7-Hydroxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
A solution of 3-acetyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (2.3 
g, 0.01 m) in acetic acid (20 ml) was treated with a solution of bromine 
(1.8 g, 0.011 m) in acetic acid (10 ml). The mixture was warmed to 
70.degree. for 1.5 hours, concentrated in vacuo and partitioned between 
water and ethyl acetate. The ethyl acetate phase was washed, dried with 
sodium sulfate and concentrated in vacuo to give 
3-acetyl-8-bromo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine. NMR 
(CDCl.sub.3) 6.7, 7.3; aryl protons. 
Following the procedure of Example 1, 
3-acetyl-8-bromo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine is 
converted to 
3-acetyl-8-bromo-6-chlorosulfonyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzaz 
epine and by the procedure of Example 4, this chlorosulfonyl compound is 
converted to 
3-acetyl-8-bromo-7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzaz 
epine. 
A mixture of 
3-acetyl-8-bromo-7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzaz 
epine (3.7 g, 0.01 m) and 10% palladium-on-carbon (0.37 g) in methanol (50 
ml) is stirred in an atmosphere of hydrogen (60 psi) until uptake is 
complete. The mixture is degassed, filtered and concentrated in vacuo to 
give 
3-acetyl-7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine. 
Following the procedure of Example 4, 
3-acetyl-7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine is 
treated with hydrochloric acid to give 
7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride which is treated with 48% hydrobromic acid to give 
7-hydroxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrobromide. 
EXAMPLE 9 
8-Hydroxy-3-methyl-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 
6-hydroxy-3-methyl-8-methylsulfonyl-1H-3-benzazepine 
A mixture of 5-bromo-3-hydroxytoluene (93 g, 0.5 m) and sodium hydroxide 
(21 g, 0.5 m) in water (200 ml) is stirred at 10.degree., treated with 
dimethyl sulfate (63 g, 0.5 m) over 1 hour, refluxed for 2 hours and 
cooled. The mixture is diluted with water and extracted with ether. The 
ether extract is washed, dried with sodium sulfate and concentrated in 
vacuo to give 5-bromo-3-methoxytoluene. 
A mixture of 5-bromo-3-methoxytoluene (20 g, 0.1 m), N-bromosuccinimide 
(17.8 g, 0.1 m) and dibenzoyl peroxide in carbon tetrachloride (200 ml) is 
heated to reflux and irradiated with a sunlamp. The mixture is cooled, 
filtered and concentrated in vacuo to give 5-bromo-3-methoxybenzyl 
bromide. 
A mixture of the crude benzyl bromide and sodium cyanide (4.9 g, 0.1 m) in 
ethanol (500 ml) is stirred at 65.degree. for 16 hours. The mixture is 
cooled, filtered and concentrated in vacuo. The residue is partitioned 
between water and chloroform and the chloroform phase is washed, dried 
with sodium sulfate and concentrated in vacuo to afford 
5-bromo-3-methoxyphenylacetonitrile. 
A mixture of 5-bromo-3-methoxyphenylacetonitrile (22.6 g, 0.1 m) and 10% 
aqueous sodium hydroxide (300 ml) in ethanol (225 ml) is heated to 
95.degree. for 18 hours. The mixture is concentrated in vacuo, acidified 
with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl 
acetate extract is washed, dried with sodium sulfate and concentrated in 
vacuo to give 5-bromo-3-methoxyphenylacetic acid. 
Following the general procedure of Example 1, 5-bromo-3-methoxyphenylacetic 
acid is converted to a mixture of 
6-bromo-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine and 
8-bromo-6-methoxy-2,3,4,5-tetrahydro-1H-3benzazepine. The isomers are 
separated by preparative HPLC. 
Each isomer (2.6 g, 0.01 m) is dissolved in 98% formic acid (50 ml) and 37% 
aqueous formaldehyde (10 ml), then heated to 95.degree. for 5 hours, 
poured into ice water, basified with 10% aqueous sodium hydroxide and 
extracted with ethyl acetate. The ethyl acetate extract is washed, dried 
with sodium sulfate and concentrated in vacuo to give, individually 
6-bromo-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 
8-bromo-6-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine. 
A solution of 
6-bromo-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.7 g, 
0.01 m) in toluene (30 ml) is added to a solution of n-butyl lithium 
(0.044 m) in toluene (15 ml) stirred at -78.degree.. The mixture is 
stirred for thirty minutes, treated with a solution of methyl disulfide 
(8.2 g, 0.087 m) in toluene (10 ml), stirred for fifteen minutes and 
poured into water (125 ml). The mixture is acidified with 10% hydrochloric 
acid and the aqueous phase is washed with ether, made alkaline with 
aqueous sodium hydroxide and extracted with ethyl acetate. The ethyl 
acetate extract is washed, dried with sodium sulfate and concentrated in 
vacuo to give 
8-methoxy-3-methyl-6-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine. 
Following the procedure of Example 4, Method B, 
8-methoxy-3-methyl-6-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine is 
converted to 
8-methoxy-3-methyl-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride which is treated with hydrobromic acid to give 
8-hydroxy-3-methyl-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrobromide. 
By the same procedure, 
8-bromo-6-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is 
converted to 6-methoxy-3-methyl-8-methylsulfonyl-1H-3-benzazepine 
hydrochloride which is treated with 48% hydrobromic acid to give 
6-hydroxy-3-methyl-8-methylsulfonyl-1H-3-benzazepine hydrobromide. 
EXAMPLE 10 
6-Methoxy-9-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 
6-hydroxy-9-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
A mixture of 2,3-dimethylanisole (2 g, 0.014 m), N-bromosuccinimide (5.3 g, 
0.03 m) and dibenzoyl peroxide (8 mg) in carbon tetrachloride (50 ml) was 
heated to reflux and irradiated with a sunlamp for 45 minutes. The mixture 
was cooled, filtered and concentrated in vacuo to afford 
2,3-bis(bromomethyl)anisole which was triturated with methanol (m.p. 
70.degree.). 
A solution of 2,3-bis(bromomethyl)anisole (43 g, 0.146 m) in 
dimethylsulfoxide (150 ml) was added to a stirred mixture of sodium 
cyanide (28.7 g, 0.585 m) and dimethylsulfoxide (200 ml). The mixture was 
cooled so that the internal temperature did not exceed 60.degree. during 
addition of the dibromide. The mixture was stirred for one hour at 
50.degree., then poured into ice water and filtered to give 
3-methoxy-1,2-phenylene-diacetonitrile. 
A mixture of 3-methoxy-1,2-phenylenediacetonitrile (44 g, 0.236 m) and 
Raney nickel in ethanol saturated with ammonia was heated to 100.degree. 
in a hydrogen atmosphere (75 atm) for 2 hours. The mixture was cooled, 
deagassed, filtered, concentrated in vacuo and partitioned between 10% 
aqueous hydrochloric acid and ethyl acetate-ether (1:1). The aqueous phase 
was basified with 40% aqueous sodium hydroxide and extracted with ethyl 
acetate. The ethyl acetate extract was washed with brine, dried with 
magnesium sulfate and concentrated in vacuo. The residue was treated with 
maleic acid and crystallized from acetonitrile to give 6-methoxy-2,3,4 
5-tetrahydro-1H-3-benzazepine maleate, m.p. 153.degree.-155.degree.. 
Following the procedures of Examples 1 and 4, 
6-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine is converted via 
3-acetyl-6-methoxy-9-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine to 
6-methoxy-9-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride and then on treatment with hydrobromic acid to 
6-hydroxy-9-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrobromide. 
EXAMPLE 11 
6-Hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
Following the procedure of Examples 1 and 8, 
6-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine is converted via 
3-acetyl-6-methoxy-7-methylsulfonyl-9-bromo-2,3,4,5-tetrahydro-1H-3-benzaz 
epine to 6-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride which is treated with hydrobromic acid to give 
6-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrobromide. 
EXAMPLE 12 
8-Acetoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
A mixture of 8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrobromide (3.2 g, 0.01 m) in trifluoroacetic acid (25 ml) is stirred at 
25.degree. and treated with acetyl bromide (1.4 g, 0.011 m). The mixture 
is stirred at 25.degree. and concentrated in vacuo to give 
8-acetoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrobromide. 
EXAMPLE 13 
8-Hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
8-Hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide 
was treated with ammonium hydroxide. The resulting mixture was filtered to 
give 8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 
241.degree.-242.degree.. This was treated with methanesulfonic acid to 
give the methanesulfonate, m.p. 267.degree.-269.degree.. 
EXAMPLE 14 
3-Allyl-8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
Allyl bromide is added to a mixture of 
8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (one 
equivalent) in acetone containing potassium carbonate and the mixture is 
stirred at 5.degree., then at 25.degree. and finally at reflux. The 
mixture is then poured into water, extracted with ethyl acetate and 
treated with ethereal hydrogen chloride to give 
3-allyl-8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride. 
EXAMPLE 15 
7-Methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
Following the procedure of Examples 1 and 4, 
2,3,4,5-tetrahydro-1H-3-benzazepine was converted to 
3-acetyl-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine and then to 
3-acetyl-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine which was 
hydrolyzed with hydrochloric acid to give 
7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 
275.degree.-277.degree. C. 
EXAMPLE 16 
7-Methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
Following the procedure of Examples 4 and 5, 
3-acetyl-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine is converted 
to 3-acetyl-7-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine and then to 
3-acetyl-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine which is 
hydrolyzed with dilute hydrochloric acid to give 
7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. 
EXAMPLE 17 
8-Methyl-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3benzazepine and 
8-methyl-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
Following the procedure of Examples 1, 15 and 16, 3-methylphenylacetic acid 
is converted to 3-acetyl-7-methyl- 2,3,4,5-tetrahydro-1H-3-benzazepine and 
then to 
3-acetyl-8-methyl-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
which is converted to 
8-methyl-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride or 
8-methyl-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride. 
EXAMPLE 18 
8-Hydroxy-7-propylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
By the procedure of Example 4, Method B using propyl iodide in place of 
methyl iodide, 
3-acetyl-8-methoxy-7-propylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
was obtained which on treatment with hydrobromic acid gave 
8-hydroxy-7-propylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrobromide, m.p. 177.degree.-180.degree. C. 
EXAMPLE 19 
8-Chloro-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 
8-chloro-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
Following the procedure of Examples 15 and 16, 
7-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine is converted to 
3-acetyl-8-chloro-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 
then to 8-chloro-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride or 
8-chloro-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride. 
EXAMPLE 20 
8-Hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
methanesulfonate (10 mg) is mixed with 75 mg of lactose and 2 mg of 
magnesium stearate. The resulting mixture is filled into a hard gelatin 
capsule.