Antiarrhythmic agents, compositions and method of use thereas

An antiarrhythmic agent of the formula ##STR1## or a pharmaceutically acceptable salt thereof; wherein R.sup.1 is H, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; PA0 X is O, ##STR2## or a direct link; and R.sup.2 and R.sup.3, which are the same or different, are each C.sub.1 -C.sub.4 alkyl, with the proviso that when X is ##STR3## R.sup.2 and R.sup.3 are the same.

This invention relates to certain benzazepine sulfonamides which are 
antiarrhythmic agents, and to intermediates therefor. 
The antiarrhythmic compounds of the invention prolong the duration of the 
action potential in cardiac muscle and conducting tissue, and thereby 
increase refractoriness to premature stimuli. Thus, they are Class III 
antiarrhythmic agents according to the classifications of Vaughan Williams 
(Anti-Arrhythmic Action, E. M. Vaughan Williams, Academic Press, 1980). 
They are effective in atria, ventricles and conducting tissue both in 
vitro and in vivo and are therefore useful for the prevention and 
treatment of a wide variety of ventricular and supraventricular 
arrhythmias including atrial and ventricular fibrillation. Because they do 
not alter the speed at which impulses are conducted, they have less 
propensity than current drugs (mostly Class I) to precipitate or aggravate 
arrhythmias, and also produce less neurological side effects. Some of the 
compounds also have some positive inotropic activity and therefore are 
particularly beneficial in patients with impaired cardiac pump function. 
Thus the invention provides the compounds of the formula: 
##STR4## 
and their pharmaceutically acceptable salts, wherein R.sup.1 is H, C.sub.1 
-C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; 
X is O, 
##STR5## 
or a direct link; and R.sup.2 and R.sup.3, which are the same or 
different, are each C.sub.1 -C.sub.4 alkyl, with the proviso that when X 
is --NHCO--, R.sup.2 and R.sup.3 are the same. 
These compounds of the formula (I) are antiarrhythmic agents. 
The preferred alkyl and alkoxy groups are methyl and methoxy. 
R.sup.1 is preferably H, methyl or methoxy. R.sup.1 is most preferably H. 
R.sup.2 and R.sup.3 are preferably the same and are also preferably 
methyl. X is preferably O or a direct link. 
Most preferably, R.sup.1 is H, R.sup.2 and R.sup.3 are methyl, and X is O 
or a direct link. 
The preferred individual compound has the formula: 
##STR6## 
The compounds will be named as derivatives of: 
##STR7## 
which is 1,2,4,5-tetrahydro-3H-3-benzazepine. 
In addition, the invention includes the intermediates of the formula: 
##STR8## 
wherein R.sup.1 is as defined for formula (I) and either (a) X is as 
defined for formula (I) and R.sup.a and R.sup.b, which are the same, are 
--NO.sub.2 or --NH.sub.2 or (b) X is O or a direct link, R.sup.a is 
--NO.sub.2 and R.sup.b is --NH.sub.2. 
Also within the scope of the invention are the intermediates of the 
formulae: 
##STR9## 
where R.sup.c is --NO.sub.2, --NH.sub.2 or --NHSO.sub.2 (C.sub.1 -C.sub.4 
alkyl); and 
##STR10## 
where R.sup.2 is as defined for formula (I). 
The compounds of the formula (I) in which R.sup.2 and R.sup.3 are the same 
can be prepared by the acylation of the corresponding di-amino compounds 
according to the following reaction sequence: 
##STR11## 
The acylation is typically carried out in a suitable organic solvent, e.g. 
methylene chloride, pyridine or N-methylmorpholine, at about room 
temperature and optionally in the presence of an acid acceptor such as 
triethylamine, potassium carbonate, sodium bicarbonate, pyridine or 
N-methylmorpholine. It is in fact preferred to carry out the acylation 
using a C.sub.1 -C.sub.4 alkanesulphonic anhydride or sulphonyl chloride 
in pyridine or N-methylmorpholine as these function both as the solvent 
and the acid acceptor. Clearly at least two equivalents of the acylating 
agent must be used. The product of the formula (I) can then be separated 
and purified conventionally. 
The starting materials of the formula (II) can be prepared by conventional 
methods as are illustrated in detail in the following Preparations. These 
routes can be illustrated schematically as follows: 
(a) The starting materials of the formula (II) in which X is O or a direct 
link can be prepared by the following route: 
##STR12## 
In the above, R.sup.1 is as defined for formula (I) and X is O or a direct 
link. 
In the second stage of the above reaction scheme, the use of the sodium 
iodide catalyst is preferred but not essential. Other leaving groups than 
halogen, e.g. methanesulphonyloxy, benzenesulphonyloxy or 
toluenesulphonyloxy, can also be used. The presence of an acid acceptor 
such as potassium carbonate is preferred. Other acid acceptors such as 
sodium carbonate or bicarbonate can also be used. 
(b) The starting materials of the formula (II) in which X is O or a direct 
link can also be prepared via the following route: 
##STR13## 
In the above, R.sup.1 is as defined for formula (I) and X is O or a direct 
link. 
(c) The starting materials of the formula (II) in which X is --NHCO-- can 
be prepared by the following route: 
##STR14## 
In the above, R.sup.1 is as defined for formula (I). 
The compounds of the formula (I) in which X is O or a direct link and 
R.sup.2 and R.sup.3 are the same or different can be prepared via the 
following general scheme: 
##STR15## 
Clearly this method can be used to prepare compounds of the formula (I) in 
which the alkanesulphonamido groups are the same or different. 
In the above, R.sup.1, R.sup.2, R.sup.3 are as defined for formula (I), X 
is O or a direct link, and Q is a leaving group. Typical leaving groups 
include chloro, bromo, iodo, methanesulphonyloxy, benzenesulphonyloxy and 
toluenesulphonyloxy. 
The reaction is typically carried out in the presence of an acid acceptor 
such as triethylamine, sodium or potassium bicarbonate or carbonate in a 
suitable organic solvent, e.g. ethanol, methanol or acetonitrile, at up to 
the reflux temperature. The product can then be isolated and purified by 
conventional means. 
The preparation of 
7-methanesulphonamido-1,2,4,5-tetrahydro-3H-3-benzazepine is described in 
Preparations 1 and 18 to 21. The higher alkanesulphonamido derivatives 
(III) can be prepared analogously using the appropriate alkanesulphonyl 
chloride in the penultimate step. The starting materials (IV) are either 
known compounds (see e.g. EP-A-0245997) or can be prepared by conventional 
techniques as will be known to those skilled in the art. 
The pharmaceutically acceptable salts of the compounds of the formula (I) 
include acid addition salts formed from acids which form non-toxic acid 
addition salts containing pharmaceutically acceptable anions, such as 
hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, 
phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, 
tartrate, citrate, gluconate, benzoate, methanesulphonate, besylate and 
p-toluenesulphonate salts. The compounds also form metal salts, preferred 
examples of which are the alkaline earth and alkali metal salts. The 
sodium and potassium salts are most preferred. The salts are preparable by 
conventional techniques. 
For assessment of effects of the compounds on atrial refractoriness, guinea 
pig right hemiatria are mounted in a bath containing physiological salt 
solution, and one end is connected to a force transducer. Tissues are 
stimulated at 1 Hz using field electrodes. Effective refractory period 
(ERP) is measured by introducing premature stimuli (S.sub.2) after every 
8th basic stimulus (S.sub.1). The S.sub.1 S.sub.2 coupling interval is 
gradually increased until S.sub.2 reproducibly elicits a propagated 
response. This is defined as the ERP. The concentration of compound 
required to increase ERP by 25% (ED.sub.25) is then determined. ERP is 
also measured in guinea pig right papillary muscles incubated in 
physiological salt solution. Muscles are stimulated at one end using 
bipolar electrodes and the propagated electrogram is recorded at the 
opposite end via a unipolar surface electrode. ERP is determined as above 
using the extrastimulus technique. Conduction time is obtained from a 
digital storage oscilloscope by using the interval between the stimulus 
artefact and the peak of the electrogram (i.e. the time required for the 
impulse to travel along the length of the muscle). 
Atrial and ventricular ERP's are also measured in anaesthetised or 
conscious dogs by the extrastimulus technique whilst the atrium or right 
ventricle is being paced at a constant rate. 
The compounds of the formula (I) can be administered alone but will 
generally be administered in admixture with a pharmaceutical carrier 
selected with regard to the intended route of administration and standard 
pharmaceutical practice. They can be administered both to patients 
suffering from arrhythmias and also prophylactically to those likely to 
develop arrhythmias. For example they may be administered orally in the 
form of tablets containing such excipients as starch or lactose, or in 
capsules either alone or in admixture with excipients, or in the form of 
elixirs or suspensions containing flavouring or colouring agents. They may 
be injected parenterally, for example, intravenously, intramuscularly or 
subcutaneously. For parenteral administration, they are best used in the 
form of a sterile aqueous solution which may contain other solutes, for 
example, enough salts or glucose to make the solution isotonic. 
For administration to man in the curative or prophylactic treatment of 
cardiac conditions such as ventricular and supraventricular arrhythmias, 
including atrial and ventricular fibrillation, it is expected that oral 
dosages of the compounds of the formula (I) will be in the range from 1 to 
75 mg daily, taken in up to 4 divided doses per day, for an average adult 
patient (70 kg). Dosages for intravenous administration would be expected 
to be within the range 0.5 to 10 mg per single dose as required. A severe 
cardiac arrythmia is preferably treated by the i.v. route in order to 
effect a rapid conversion to the normal rhythm. Thus for a typical adult 
patient individual tablets or capsules might for example contain 1 to 25 
mg of active compound, in a suitable pharmaceutically acceptable vehicle 
or carrier. Variation may occur depending on the weight and condition of 
the subject being treated as will be known to medical practitioners. 
Thus the present invention provides a pharmaceutical composition comprising 
a compound of the formula (I) as defined above or a pharmaceutically 
acceptable salt thereof, together with a pharmaceutically acceptable 
diluent or carrier. 
The invention also provides a method of preventing or reducing cardiac 
arrhythmias in a human being, which comprises administering to said human 
an effective amount of a compound of the formula (I) or pharmaceutically 
acceptable salt thereof, or of a pharmaceutical composition as defined 
above. 
The invention yet further provides a compound of the formula (I) or a 
pharmaceutically acceptable salt thereof, for use as a medicament, 
particularly for use as an antiarrhythmic agent. 
The invention also provides the use of a compound of the formula (I), or of 
a pharmaceutically acceptable salt thereof, for the manufacture of a 
medicament for the prevention or reduction of cardiac arrhythmias.

The following Examples, in which all temperatures are in .degree. C., 
illustrate the preparation of the compounds of the formula (I): 
EXAMPLE 1 
7-Methanesulphonamido-3-(2-[4-methanesulphonamidophenoxy]ethyl)-1,2,4,5-tet 
rahydro-3H-3-benzazepine, free base and hydrochloride 
Method (A) (Free Base) 
##STR16## 
Methanesulphonic anhydride (0.2) was added to a solution of 
7-amino-3-(2-[4-aminophenoxy]ethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine 
(0.37 g) in pyridine (30 ml) cooled to 0.degree. and the mixture was then 
stirred at room temperature for 72 hours. The solvent was evaporated in 
vacuo and the residue taken up in methylene chloride, washed three times 
with aqueous sodium bicarbonate and three times with brine. The organic 
layer was dried (Na.sub.2 SO.sub.4), filtered and evaporated in vacuo to 
give an oil which was purified by column chromatography on silica eluting 
with methylene chloride containing methanol (0% up to 5%). The 
product-containing fractions were combined and evaporated to give a 
semi-solid which was triturated with ether, filtered and dried to give the 
title compound as an amorphous powder, yield 0.19 g, m.p. indistinct. 
Analysis %: Found: C,53.05; H,6.1; N,8.9; Calculated for C.sub.20 H.sub.27 
N.sub.3 O.sub.5 S.sub.2 : C,53.0; H,6.00; N,9.3. 
.sup.1 H-N.m.r. (CDCl.sub.3):.delta.=7.2 (d, 2H); 7.05 (q, 2H); 7.00 (s, 
1H); 6.9 (d, 2H); 4.1 (t, 2H); 3.00 (t, 2H); 3.00 (s, 3H); 2.95 (s, 3H); 
2.9 (m, 4H); 2.8 (m, 4H). 
The above reaction was also repeated using methanesulphonyl chloride and 
triethylamine in ethanol at room temperature with silimar results. 
Method (B) (Hydrochloride) 
##STR17## 
Methanesulphonyl chloride (70.3 g) was added dropwise over 45 minutes to a 
stirred solution of 
7-amino-3-(2-[4-aminophenoxy]-ethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine 
(83 g) in N-methylmorpholine (700 ml) cooled to 0.degree.. The reaction 
was allowed to warm to 15.degree. and further methanesulphonyl chloride 
(14.6 g) was added. The solvent was decanted from the heavy precipitate 
into water (3000 ml). The aqueous solution was extracted with ethyl 
acetate (2.times.500 ml). The precipitate was taken up in the combined 
organic extracts, washed with water (2.times.500 ml), dried (MgSO.sub.4) 
and evaporated in vacuo. The resulting oil was taken up in methanol (500 
ml) containing 2.5M sodium hydroxide (400 ml) and stirred at 40.degree. 
for 1/2 hour. The methanol was evaporated in vacuo and the aqueous layer 
was washed twice with methylene chloride. The aqueous layer was diluted 
with water (1000 ml) and adjusted to pH 6.5 with concentrated hydrochloric 
acid. The resulting precipitate was granulated, filtered, washed with 
water then dried in vacuo at 60.degree., yield 110.4 g. The product was 
recrystallised from industrial methylated spirits (1100 ml) and methanol ( 
1320 ml) to give the title compound, yield 73.5 g, m.p. 221.degree.. 
Analysis %: Found: C,48.9; H,5.8; N,8.6; S,13.0; Calculated for C.sub.20 
H.sub.27 N.sub.3 O.sub.5 S.sub.2. HCl: C,49.0; H,5.8; N,8.6; S,13.1. 
EXAMPLE 2 
7-Methanesulphonamido-3-(4-methanesulphonamidophenethyl)-1,2,4,5-tetrahydro 
-3H-3-benzazepine 
The title compound, m.p. 184.degree.-7.degree., was prepared similarly to 
Example 1 Method (A) by the acylation of the corresponding di-amino 
compound with methanesulphonic anhydride except that the reaction time was 
18 hours. The solvate was detected and quantified by .sup.1 H-n.m.r. 
spectroscopy. 
##STR18## 
Analysis %: Found: C,53.9; H,6.0; N,9.3; Calculated for C.sub.20 H.sub.27 
N.sub.3 O.sub.4 S.sub.2. 1/10 CH.sub.2 C1.sub.2 : C,54.1; H,6.15; N,9.4. 
.sup.1 H-N.m.r. (DMSO d.sub.6): .delta. =9.55 (br s, 2H); 7.1 (q, 4H); 7.05 
(d, 1H); 6.95 (s, 1H); 6.90 (d, 1H); 2.95 (s, 6H); 2.8 (br s, 4H); 2.65 
(m, 8H). 
EXAMPLE 3 
7-Methanesulphonamido-3-[2-(4-methanesulphonamido-2-methoxybenzamido)ethyl] 
-1,2,4,5-tetrahydro-3H-3-benzazepine 
##STR19## 
Methanesulphonyl chloride (0.155 ml) was added dropwise to a solution of 
7-amino-3-[2-(4-amino-2-methoxybenzamido)ethyl]-1,2,4,5-tetrahydro-3H-3-be 
nzazepine in pyridine cooled to 0.degree., and the reaction mixture was 
stirred for a further 18 hours at room temperature. The solvent was 
evaporated in vacuo and the residue taken up in methylene chloride, washed 
three times with aqueous sodium bicarbonate and three times with brine. 
The organic layer was dried (Na.sub.2 SO.sub.4), filtered and evaporated 
to give an oil, in which thin layer chromatography detected the presence 
of some unreacted starting material. The oil was therefore taken up in 
pyridine and treated with methanesulphonyl chloride (0.05 ml), and the 
reaction mixture was stirred at room temperature for 72 hours. The solvent 
was then evaporated in vacuo and the residue taken up in methylene 
chloride, washed three times with aqueous sodium bicarbonate and three 
times with brine. The organic layer was dried (Na.sub.2 SO.sub.4), 
filtered and evaporated to give an oil. The resulting oil was then 
purified by column chromatography on silica eluting with methylene 
chloride containing methanol (0% up to 5%) and the product-containing 
fractions were combined and evaporated in vacuo to give the title compound 
as a colourless foam, yield 0.32 g. 
Analysis %: Found: C,51.7; H,6.0; N,10.6; Calculated for C.sub.22 H.sub.30 
N.sub.4 O.sub.6 S.sub.2 : C,51.7; H,5.9; N,11.0. 
.sup.1 H-N.m.r. (CDC1.sub.3).delta.=8.4 (br s, 1H); 8.25 (d, 1H); 7.1 
(d,1H); 7.05 (s, 2H); 7.0 (d, 1H); 6.8 (d, 1H); 4.0 (s, 3H); 3.6 (m, 2H); 
3.1 (s, 3H); 3.05 (s, 3H); 2.95 (br s, 4H); 2.7 (br s, 6H). 
EXAMPLE 4 
7-Methanesulphonamido-3-[2-(4-methanesulphonamido-3-methylphenoxy)ethyl]-1, 
2,4,5-tetrahydro-3H-3-benzazepine 
##STR20## 
Methanesulphonyl chloride (0.18 ml) was added dropwise to a solution of 
7-amino-3-[2-(4-amino-3-methylphenoxy)ethyl]-1,2,4,5-tetrahydro-3H-3-benza 
zepine (0.36 g) in pyridine (30 ml) cooled to 0.degree., and the mixture 
was then stirred at room temperature for 72 hours. The solvent was 
evaporated in vacuo and the residue was taken up in methylene chloride and 
washed three times with saturated aqueous sodium bicarbonate and three 
times with brine. The organic layer was dried (Na.sub.2 SO.sub.4), 
filtered and evaporated in vacuo to give an oil which was triturated with 
methylene chloride to give a solid. Recrystallisation of the solid from 
ethanol/ethyl acetate gave the title compound, yield 0.28 g, m.p. 
173.degree.-174.degree.. 
Analysis %: Found: C,54.3; H,6.3; N,8.7; Calculated for C.sub.21 H.sub.29 
N.sub.3 O.sub.5 S.sub.2 : C,53.9; H,6.25; N,9.0. 
.sup.1 H-N.m.r. (DMSO d.sub.6): .delta. =7.15 (d, 1H); 7.05 (d, 1H); 6.95 
(s, 1H); 6.90 (d, 1H); 6.85 (d, 1H); 6.75 (dd, 1H); 4.05 (t, 2H); 2.95 (s, 
3H); 2.90 (s, 3H); 2.85 (t, 2H); 2.8 (br s, 4H); 2.7 (br s, 4H); 2.3 (s, 
3H). 
EXAMPLE 5 
Preparation of 
7-methanesulphonamido-3-(4-methanesulphonamidophenethyl)-1,2,4,5-tetrahydr 
o-3H-3-benzazepine 
##STR21## 
7-Methanesulphonamido-1,2,4,5-tetrahydro-3H-3-benzazepine (0.21 g), 
4-[2-(methanesulphonyloxy)ethyl]methanesulphonanilide (0.26 g) (see 
EP-A-0245997, Preparation 7) and triethylamine (0.12 ml) were heated at 
reflux temperature in ethanol for 24 hours. The solvent was removed in 
vacuo and the residue taken up in methylene chloride, washed with aqueous 
sodium bicarbonate, brine and then water. The organic layer was dried 
(Na.sub.2 SO.sub.4), evaporated in vacuo and the residue purified by 
column chromatography on silica eluting with methylene chloride containing 
methanol (0% up to 5%). The product-containing fractions were combined and 
evaporated to give a solid which was recrystallised to give the title 
compound, yield 0.05 g, m.p. 190.degree.-193.degree.. 
Analysis %: Found: C,55.1; H,6.3; N,9.4; Calculated for C.sub.20 H.sub.27 
N.sub.3 O.sub.4 S.sub.2 : C,54.9; H,6.2; N,9.6. 
The following Preparations illustrate the preparation of certain of the 
starting materials used in the previous Examples. All temperatures are in 
.degree.C: 
Preparation 1 
##STR22## 
7-Nitro-1,2,4,5-tetrahydro-3H-3-benzazepine 
1,2,4,5-Tetrahydro-3H-3-benzazepine (1 g) (see P. Ruggli et al., Helv. 
Chem. Acta, 18, 1388 [1935]) was added slowly, dropwise to stirred fuming 
nitric acid (25 ml. density 1.5 gm/ml) cooled to -10.degree.. Stirring was 
continued at -10.degree. for 1 hour, and the reaction mixture was then 
poured onto ice, the precipitate collected by filtration and dried to give 
the title compound as the nitrate salt, yield 1.4 g. A sample was 
recrystallised from water, m.p. 203.degree.-204.degree.. 
Analysis %: Found: C,46.9; H,5.4; N,16.6; Calculated for C.sub.10 H.sub.12 
N.sub.2 O.sub.2.HNO.sub.3 : C,47.05; H,5.1; N,16.5. 
The bulk of the nitrate salt was suspended in water, chilled and 
neutralised with 5M sodium hydroxide and the precipitate collected by 
filtration, recrystallised from water and dried to give the title 
compound, yield 0.6 g, m.p. 53.degree.-56.degree.. 
Analysis %: Found: C,62.9; H,6.45; N,14.8; Calculated for C.sub.10 H.sub.12 
N.sub.2 O.sub.2 : C,62.5; H,6.3; N,14.6. 
Preparation 2 
7-Nitro-3-(2-[4-nitrophenoxy]ethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine 
##STR23## 
7-Nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (0.7 g), 
2-[4-nitrophenoxy]ethyl chloride (0.73 g) (see C. A. [1955], 49, 3163e), 
sodium iodide (0.5 g) and potassium carbonate in acetonitrile (50 ml) were 
heated under reflux for 3 days. After cooling, the solvent was removed in 
vacuo, the residue dissolved in ethyl acetate and washed once with water, 
once with sodium carbonate and twice with brine. The organic layer was 
dried (Na.sub.2 SO.sub.4) and evaporated in vacuo to give an oil which was 
purified by column chromatography on silica eluting with methylene 
chloride containing methanol (0% up to 1%). The product-containing 
fractions were combined and evaporated in vacuo to give the product as an 
orange oil, yield 1.0 g. 
Analysis %: Found: C,60.5; H,5.5; N,11.9; Calculated for C.sub.18 H.sub.19 
N.sub.3 O.sub.5 : C,60.5; H,5.4; N,11.8. 
Preparation 3 
7-Nitro-3-(4-nitrophenethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine 
hemihydrate 
##STR24## 
The title compound was prepared similarly to Preparation 2 by the reaction 
of 7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (0.5 g) and 
4-nitrophenethyl bromide (0.6 g), which, after 18 hours reflux, gave the 
title compound as an oil, yield 0.29 g. 
Analysis %: Found: C,61,7; H,5.5; N,12.1; Calculated for C.sub.18 H.sub.19 
N.sub.3 O.sub.4 : 2/3H.sub.2 O:C,61.7; H,5.75; N,12.0. 
Preparation 4 
7-Amino-3-(2-[4-aminophenoxy]ethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine 
##STR25## 
7-Nitro-3-(2-[4-nitrophenoxy]ethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine 
(0.42 g) was stirred at room temperature under a hydrogen atmosphere 
[344.7 kPa (50 p.s.i.)] in ethyl acetate containing 5% Pd/C for 4 hours. 
The catalyst was then removed by filtration and the filtration evaporated 
in vacuo to give the title compound as an oil, which was used directly 
without further purification, yield 0.3 g. 
.sup.1 H-N.m.r. (CDC1.sub.3):.delta.=6.9 (d, 1H); 6.7 (q, 4H); 6.45 (q, 
2H); 4.05 (t, 2H); 2.95 (t, 2H); 2.80 (m, 8H). 
Preparation 5 
7-Amino-3-(4-aminophenethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine 
The title compound was prepared similarly to Preparation 4 by the 
hydrogenation of the corresponding di-nitro compound. 
.sup.1 H-N.m.r. (CDC1.sub.3);.delta.=7.02 (d, 2H); 6.9 (d, 1H); 6.65 (d, 
2H); 6.5 (s, 1H); 6.45 (d, 1H); 2.9 (br s, 4H); 2.7 (br s, 8H). 
Preparation 6 
2-Methanesulphonyloxyethyl azide 
##STR26## 
A solution of methanesulphonyl chloride (5.7 g) in methylene chloride (20 
ml) was added dropwise to a stirred solution of 2-azidoethanol (4.3 g) and 
triethylamine (5.0 g) in methylene chloride (80 ml). After 2 hours 
stirring at room temperature the reaction mixture was washed with water, 
dried (MgSO.sub.4) and evaporated to dryness in vacuo to give the title 
compound as a yellow oil, yield 7 g, which was used directly without 
further purification. 
.sup.1 H-N.m.r. (CDC1.sub.3):.delta.=4.25 (t, 2H); 3.5 (t, 2H); 3.0 (s, 
3H). 
Preparation 7 
3-(2-Azidoethyl)-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine 
##STR27## 
7-Nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (1.1 g), 
2-methanesulphonyloxyethyl azide (0.92 g) and potassium carbonate (0.76 g) 
were heated under reflux in acetonitrile for 18 hours. The solvent was 
evaporated in vacuo and the residue taken up in ethyl acetate then washed 
three times with aqueous sodium carbonate and three times with brine. The 
organic layer was dried, filtered and evaporated in vacuo to give an oil 
which was purified by chromatography on silica eluting with ethyl 
acetate/hexane (1:1). The product-containing fractions were combined and 
evaporated to give the title compound as an oil, yield 0.65 g, which was 
used without further purification. 
I.R. .nu.=2100 cm.sup.-1 (azide). 
.sup.1 H-N.m.r. (CDC1.sub.3):.delta.=8.05 (d, 1H); 8.05 (s, 1H); 7.3 (d, 
1H); 3.4 (t, 2H); 3.1 (m, 4H); 2.75 (m, 6H). 
Preparation 8 
3-(2-Aminoethyl)-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine 
##STR28## 
Triphenylphosphine (0.71 g) was added to a solution of 
3-(2-azidoethyl)-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (0.68 g) in 
dry tetrahydrofuran under a nitrogen atmosphere and the reaction mixture 
was then stirred at room temperature for 18 hours and heated at 50.degree. 
for 5 hours. After cooling, water was added and the mixture was stirred at 
room temperature for 3 days. The solvent was then evaporated in vacuo and 
the residue was diluted with 2M hydrochloric acid and washed three times 
with ethyl acetate. The aqueous layer was made alkaline (pH=12) with 5M 
sodium hydroxide and extracted three times with ethyl acetate. The latter 
organic extracts were combined and dried (Na.sub.2 SO.sub.4), filtered and 
evaporated in vacuo to give the title compound as an oil, yield 0.56 g, 
which was used without further purification. 
Preparation 9 
7-Nitro-3-(2-[2-methoxy-4-nitrobenzamido]ethyl-1,2,4,5-tetrahydro-3H-3-benz 
azepine 
##STR29## 
A solution of 2-methoxy-4-nitrobenzoyl chloride (0.56 g) in methylene 
chloride was added dropwise to a stirred solution of 
3-(2-aminoethyl)-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (0.56 g) in 
methylene chloride cooled to 0.degree., and stirring was continued at room 
temperature for 1 hour. The solvent was then evaporated in vacuo, the 
residue triturated with ether, and filtered. The precipitate was suspended 
in aqueous sodium carbonate and extracted three times with methylene 
chloride. The organic layers were combined and then washed three times 
with brine, dried (Na.sub.2 SO.sub.4), filtered and evaporated in vacuo. 
The residue was purified by column chromatography on silica eluting with 
methylene chloride containing methanol (0% up to 2%). The 
product-containing fractions were combined and evaporated in vacuo to give 
the title compound, yield 0.55 g, m.p. 138.degree.-140.degree.. 
Analysis %: Found: C,58.05; H,5.5; N,13.1; Calculated for C.sub.20 H.sub.22 
N.sub.4 O.sub.6 : C,58.0; H,5.35; N,13.5. 
Preparation 10 
7-Amino-3-(2-[4-amino-2-methoxybenzamido]ethyl)-1,2,4,5-tetrahydro-3H-3-ben 
zazepine 
##STR30## 
7-Nitro-3-(2-[2-methoxy-4-nitrobenzamido]ethyl)-1,2,4,5-tetrahydro-3H-3-ben 
zazepine (0.52 g) was stirred under a hydrogen atmosphere [344.7 kPa (50 
p.s.i.)] in an ethanol/methanol (1:1) solution at room temperature for 3 
hours. The catalyst was then removed by filtration and the filtrate 
evaporated in vacuo to give the title compound as a foam, yield 0.42 g, 
which was used directly without further purification. 
.sup.1 H-N.m.r. (CDC1.sub.3):.delta.=8.4 (br, s, 1H); 8.1 (d, 1H); 6.95 (d, 
1H); 6.5 (s, 2H); 6.45 (d, 1H); 6.35 (q, 1H); 6.25 (d, 1H); 4.0 (s, 2H); 
3.95 (s, 3H); 3.6 (s, 2H); 2.9 (m, 4H); 2.7 (m, 2H). 
Preparation 11 
2-Methoxy-4-nitrobenzoyl chloride 
##STR31## 
Oxalyl chloride (0.81 ml) in methylene chloride (10 ml) was added dropwise 
to a solution of 2-methoxy-4-nitrobenzoic acid monohydrate (1 g) in 
methylene chloride (40 ml) and dimethylformamide (1 drop) and the reaction 
mixture was stirred at room temperature for 1 hour after gas evolution 
ceased. The solvent was then evaporated in vacuo to give an oil which was 
crystallised from cold ethyl acetate/hexane to give the title compound, 
yield 0.7 g. 
This low melting compound was used directly without further purification. 
Preparation 12 
2-(4-Nitrophenoxy)ethyl chloride 
##STR32## 
A mixture of 4-nitrophenol (139 g, 1 mole), 2-(benzenesulphonyloxy)ethyl 
chloride (220.5 g, 1 mole--see Ber. (1920), 53, 1836) and anhydrous 
potassium carbonate (138 g, 1 mole) in methyl ethyl ketone ("MEK"--1000 
ml) was stirred at reflux for 16 hours. After cooling, the mixture was 
poured onto water and the organic layer was separated. Following two 
further extractions with methyl ethyl ketone, the combined organic 
fractions were dried (MgSO.sub.4), filtered and evaporated. The resultant 
solid was crystallised from ethanol to give the title compound, (165.8 g), 
m.p. 60.degree.. 
Analysis %: Found: C,47.65; H,4.0; N,7.0; Calculated for C.sub.8 H.sub.8 
C1NO.sub.3 : C,47.7; H,4.0; N,7.0. 
Preparation 13 
4-(2-Chloroethoxy)-2-methylacetanilide 
##STR33## 
A mixture of 4-hydroxy-2-methylacetanilide (33 g), 
2-toluenesulphonyloxyethyl chloride (46.9 g) and potassium carbonate 
(23.6) were heated under reflux in butan-2-one (200 ml) for 6 hours. The 
reaction mixture was then cooled, diluted with water and the precipitate 
collected by filtration, washed with water and recrystallised from ethanol 
to give the title compound, yield 22 g, m.p. 127.degree.-129.degree.. 
Analysis %: Found: C,58.0; H,6.2; N,6.15; Calculated for C.sub.11 H.sub.14 
C1NO.sub.2 : C,58.2; H,6.3; N,6.4. 
Preparation 14 
3-[2-(4-Acetylamino-3-methylphenoxy)ethyl]-7-nitro-1,2,4,5-tetrahydro-3H-3- 
benzazepine 
##STR34## 
7-Nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (1.69 g), 
2-methyl-4-(2-chloroethoxy)acetanilide (2 g), potassium carbonate (1.21 g) 
and sodium iodide (1.32 g) were heated at reflux in acetonitrile for 5 
days. After cooling the solvent was removed in vacuo and the residue was 
diluted with sodium carbonate solution and extracted three times with 
methylene chloride. The combined organic extracts were washed three times 
with brine, dried (Na.sub.2 SO.sub.4) and evaporated to give a semi-solid 
which was triturated with ether to give a solid. Recrystallisation of the 
solid from ethyl acetate/hexane gave the title compound, yield 1.6 g, m.p. 
132.degree.-134.degree.. 
Analysis %: Found: C,65.9; H,6.7; N,11.0; Calculated for C.sub.21 H.sub.25 
N.sub.3 O.sub.4 : C,65.8; H,6.6; N,11.0. 
Preparation 15 
3-[2-(4-Amino-3-methylphenoxy)ethyl]-7-nitro-1,2,4,5-tetrahydro-3H-3-benzaz 
epine dihydrochloride 
##STR35## 
3-[2-(4-Acetylamino-3-methylphenoxy)ethyl]-7-nitro-1,2,4,5-tetrahydro-3H-3- 
benzazepine (1 g) was stirred in 6M hydrochloric acid (20 ml) at 90.degree. 
for 18 hours. After cooling, the precipitate was collected by filtration 
and recrystallised from ethanol to give the title compound, yield 0.65 g, 
m.p. 253.degree.-256.degree.. 
Analysis %: Found: C,53.9; H,6.6; N,9.1; Calculated for C.sub.19 H.sub.23 
N.sub.3 O.sub.2.2HC1.1/2H.sub.2 0.1/2C.sub.2 H.sub.5 OH*: C,53.8; H,6.3; 
N,9.4. 
FNT *1/2 Mole of ethanol in the sample was detected and quantified by .sup.1 
H-n.m.r. 
.sup.1 H-n.m.r. (CDC1.sub.3).delta.=8.0 (s, 1H); 8.0 (d, 1H); 7.5 (d, 1H); 
7.3 (d, 1H); 6.9 (s, 1H); 6.9 (q, 2H); 4.1 (t, 2H); 3.05 (m, 6H); 2.8 (br 
s, 4H); 2.25 (s, 3H); 2.2 (s, 3H). 
Preparation 16 
3-[2-(4-Amino-3-methylphenoxy)ethyl]-7-nitro-1,2,4,5-tetrahydro-3H-3-benzaz 
epine 
##STR36## 
3-[2-(4-Amino-3-methylphenoxy)ethyl]-7-nitro-1,2,4,5-tetrahydro-3H-3-benzaz 
epine dihydrochloride hemihydrate (0.62 g) was dissolved in saturated 
aqueous sodium carbonate (20 ml) and extracted three times with ethyl 
acetate (30 ml). The combined organic extracts were dried (Na.sub.2 
SO.sub.4) and evaporated in vacuo to give the title compound as an oil, 
yield 0.5 g, which was used directly without further purification. 
Preparation 17 
7-Amino-3-[2-(4-amino-3-methylphenoxy)ethyl]-1,2,4,5-tetrahydro-3H-3-benzaz 
epine 
##STR37## 
3-[2-(4-Amino-3-methylphenoxy)ethyl]-7-nitro-1,2,4,5-tetrahydro-3H-3-benzaz 
epine (0.5 g) was stirred at room temperature under a hydrogen atmosphere 
[344.7 kPa (50 p.s.i.)]in ethyl acetate (20 ml) and methanol (20 ml) 
containing 5% Pd/C (0.075 g) for 3 hours. The catalyst was then removed by 
filtration and the filtrate was evaporated in vacuo to give the title 
compound as an oil, yield 0.385 g, which was used directly without further 
purification. 
.sup.1 H-N.m.r. (CDC1.sub.3):.delta.=6.9 (d, 1H); 6.7 (s, 1H); 6.6 (s, 2H); 
6.5 (s, 2H); 4.05 (t, 2H); 2.95 (t, 2H); 2.8 (m, 8H); 2.2 (s, 3H). 
Preparation 18 
3-Tertiary-butoxycarbonyl-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine 
##STR38## 
A solution of di-t-butyldicarbonate (2.18 g) in dry methylene chloride (15 
ml) was added dropwise to a stirred solution of 
7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (1.92 g) in dry methylene 
chloride (40 ml) cooled to 0.degree.. After stirring for 18 hours at room 
temperature the solvent was removed in vacuo to give an oil which was 
dissolved in methylene chloride, then washed twice with aqueous sodium 
bicarbonate, three times with 1M hydrochloric acid and finally twice with 
brine. The methylene chloride solution was dried (Na.sub.2 SO.sub.4) and 
evaporated in vacuo to give an oil which was triturated with hexane to 
give the title compound, yield 2.33 g, m.p. 106-108. 
Analysis %: Found: C,61.7; H,7.0; N,9.6; Calculated for C.sub.15 H.sub.20 
N.sub.2 O.sub.4 : C,61.6; H,6.9; N,9.6. 
Preparation 19 
7-Amino-3-tertiary-butoxycarbonyl-1,2,4,5-tetrahydro-3H-3-benzazepine 
##STR39## 
A solution of 
3-tertiary-butoxycarbonyl-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (2.1 
g) was stirred under a hydrogen atmosphere (50 p.s.i. equivalent to 344.7 
kPa) in ethanol (20 ml) and methanol (20 ml) solution containing 5% Pd/C 
(0.21 g) for 3 hours. The catalyst was removed by filtration and the 
solvent evaporated to give the title compound as an oil, yield 2.0 g. 
A sample (100 mg) of this oil was chromatographed on silica eluting with 
methylene chloride containing methanol (0% up to 2%). The 
product-containing fractions were combined and evaporated in vacuo to give 
the title compound as a low melting solid (.about.30.degree.), yield 58 
mg. 
Analysis %: Found: C,69.0; H,8.6; N,10.3; Calculated for C.sub.15 H.sub.22 
N.sub.2 O.sub.2 : C,68.7; H,8.45; N,10.7. 
Preparation 20 
7-Methanesulphonamido-3-tertiary-butoxycarbonyl-1,2,4,5-tetrahydro-3H-3-ben 
zazepine 
##STR40## 
Methanesulphonyl chloride (0.56 ml) was added dropwise to a solution of 
7-amino-3-tertiary-butoxycarbonyl-1,2,4,5-tetrahydro-3H-3-benzazepine (1.9 
g) in pyridine (40 ml) cooled to 0.degree.. Stirring was continued at room 
temperature for 18 hours. The solvent was removed by evaporation to give 
an oil which was taken up in methylene chloride, washed three times with 
aqueous sodium bicarbonate and three times with brine, then dried 
(Na.sub.2 SO.sub.4) and evaporated in vacuo. The residue was purified by 
column chromatography on silica eluting with methylene chloride containing 
methanol (0% up to 5%). The product-containing fractions were combined and 
evaporated in vacuo to give a semi-solid which was triturated with ether 
to give the title compound, yield 1.2 g, m.p. 153.degree.-154.degree.. 
Analysis %: Found: C,56.6; H,67.05; N,8.2; Calculated for C.sub.16 H.sub.24 
N.sub.2 O.sub.4 S: C,56.45; H,7.1; N,8.2. 
Preparation 21 
7-Methanesulphonamido-1,2,4,5-tetrahydro-3H-3-benzazepine 
##STR41## 
3-Tertiary-butoxycarbonyl-7-methanesulphonamido-1,2,4,5-tetrahydro-3H-3-ben 
zazepine (0.6 g) and 98% formic acid (10 ml) were stirred together at room 
temperature for 2 hours. The solvent was evaporated in vacuo to give an 
oil which was basified with aqueous sodium bicarbonate. The aqueous 
solution was evaporated in vacuo and the residue was triturated with hot 
isopropanol. The isopropanol was decanted and evaporated in vacuo to give 
a solid which was recrystallised from ethyl acetate/hexane to give the 
title compound, yield 0.22 g. 
Analysis %: Found: C,54.7; H,7.0; N,11.4; Calculated for C.sub.11 H.sub.16 
N.sub.2 O.sub.2 S: C,55.0; H,6.7; N,11.7.