Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
WO 93/00094 21~ 0 ~ 7 ~ PCl'/GB92/010~3
~EDICAMENTS
The present invention relates to certain tetrahydro-
benzazepine derivatives for use in the treatment of disorderscharacterised by excessive vasodilatation, in particuIar the
treatment of portal hypertension and the treatment and
prophylaxis of migraine, and more generally to the use of
5-HT2 and 5-HTl-like receptor agonists in the treatment of
lo portal hypertension and to the use of 5-HT2 agonists in the
treatment and prophylaxis of migraine.
Portal hypertension, which is commonly associated with
. cirrhosis of the liver is characterised by increased portal
S venous blood flow, (which is caused by dilatation of
mesenteric arterioles~, and increased portal vascular
resistance. A serious complication of this condition is
rupture of esophageal varic~s or paraesophageal collaterals,
which develop to reduce portal pressure.
It has now been found that certain tetrahydro-
benzazepines known in the art for the treatment of
gastrointestinal motility disorders are agonists at 5-HT2
and/or 5-HT1-like-receptors and are expected to have utility
in the treatment of portal hypertension.
Migraine is a non-lethal disease suffered by one in ten
individuals. The main symptom is headache; other symptoms
include vomiting and photophobia. Currently, the most
widely used treatment for migraine involves administration of
ergotamine, dihydroergotamine or methysergide. All these
drugs are inter ~li~ agonists of 5HTl-like receptors but also
have other actions;.treatment with them is assoclated with a
number of adverse side effects. In addition, some pa~ients
experience a "withdrawal headache" following the cessation of
treatment with an ergot product, such as ergotamine, causing
them to repeat the treatment and resulting in a form of
addiction.
WO93~00094 ~ ~lS PCr/GB92/01083
2- `
In view of the foregoing, there is clearly a need for .:
the provision of effective and safe medicaments for the
treatment of migraine.
It has now been found that certain tetrahydro-
benzazepines known in the art for the treatment of
gastrointestinal motillty disorders are agonists at 5HT1-like
and/or 5HT2-receptors and are expected to have utility in the
treatment of migraine. ~
'' '
The present invention therefore provides compounds of
structure ~
R
'~N-R
Structure (I)
~':
in whiCh:
R iS hydrogen, C1_6alkyl or C3_salkenyl;
R1 iS NO2, cyano, halo, CoR3, SonR4 or
SOnNRSR6;
R2 iS hydrogen, hydroxy or C1_4alkoxy;
R3 is hydrogen, C1_4alkyl, oR5 or NR5R6;
R4 is C1_6alkyl or halo C1_6 alkyl;
R5 and R6 are hydrogen, C1_6alkyl or C3-6 cycloalkyl; and n
is 1 or 2;
25 and pharmaceutically acceptable salts thereof for use in the ~
manufacture of a medicament for th~ treatment of portal -
hypertension and/or migraine.
Suitably R is hydrogen, Cl_6alkyl or C3_salkenyl;
preferably R iS hydrogen.
21~0~75
W093/0~94 PCT/GB92/01083
~ 3 - :
Suitably Rl is nitro, cyano, halo, CoR3, SonR4 or
SonNR5R6; preferably R1 is SOnR~, nitro or haloi most
preferably Rl is SonR4.
Suitably n is 1 or 2; preferably n is 2.
Suitably R2 is hydrogen, hydroxy or Cl_4alkoxyi
preferably R2 is Cl_4alkoxy or hydroxy.
Suitably R3 is hydrogen, Cl_4alkyl, oR5 or NR5R6;
preferably R3 is C1_4alkyl, in particular methyl.
Preferably the group Rl is at the 8-position and the
grou~ R2 is at the 7-position of the ring of the compound of
structure (I).
Suitably R4 is Cl_6alkyl or halo C1_6 alkyl;
preferably R4 is C1_~alkyl, or Cl_6 alkyl substituted by 1 to
6 halogen atoms (eg. CF3). and most preferably R4 is methyl.
Suitably R5 and R6 are hydrogen or Cl_6alkyl, or C3-6
cycloalkyl. Preferably, when both groups represent C1_6
alkyl, they are the same.
C1_6alkyl groups, either alone or as part of another
group, can be straight or branched.
Suitable salts will be apparent to those skilled in the
art, and include, for example, acid addition salts such as
the hydrochloride, or the oxalate.
Suitable examples of compounds for u~e in the present
invention are as described in EP-0229510-B, for example :
3s 7-hydroxy-8-sulphamoyl-2,3,4,5-tetrahydro-lH-benzazepine, and
7-hydroxy-8-(N,N-dimethylsulphamoyl~-2,3,4,5-tetrahydro-lH-
benzazepine.
W093/0~94 ~ pcT/Gs92/olo8
In particular the present invention relates to the use
of a compound in which ~ is hydrogen, Rl is methylsulphonyl
and R2 is hydroxy, namely, 7-hydroxy-8-
methylsulphonyl-2,3,4,5--tetrahydro-lH-benzazepine, or a
5 pharmaceutically acceptable salt thereof in the manufacture ~:
of a medicament for the treatment of migraine.
Certain compounds falling within the scope of structure
(I) are themselves novel and as such form a further aspect of
the invention. These compounds are in particular:
7-methoxy-8-methylsulphinyl-2,3,4,5-tetrahydro-lH-
benzazepine oxalate;
7-methoxy-8-nitro-2,3,4,5-tetrahydro-lH-benzazepine
hydrochloride;
7-hydroxy-8-nitro-2,3,4,5-tetrahydro-lH-benzazepine :::
hydrochloride;
7-methoxy-8-bromo-2,3,4,5-tetrahydro-lH-benzazepine
hydrochloride;
7-hydroxy-8-bromo-2,3,4,5-tetrahydro-lH-benzazepine :~
20 hydrochloride; ::
7-methoxy-6-nitro-2,3,4,5-tetrahydro-lH-benzazepine
hydrochloride; ~:
6-bromo-7-methoxy-2,3,4,5-tetrahydro-lH-benzazepine
hydrochloride;
8-acetyl-7-hydroxy-2,3,4,5-tetrahydro-lH-benzazepine
hydrochloride;
7-hydroxy-8-methylsulphinyl-2,3,4,5-tetrahydro-lH-
benzazepine; and :;
7-hydroxy-8-trifluoromethylsulphonyl-2,3,4,5-tetrahydro-lH-
benzazepine.
~,''
Compounds of ~tructure (I) may be prepared by the
methods descxibed in EP 0229510-B, or by the following
methods
a) to prepare a compound of structure ~I) where R~
represents -SonR4, the reaction of a compound of structure
(II) :
wo 93/00094 2 1 1 G ~ 7 ~ PCT/GB92/01083
R~S
~ ~ 7 ~
R
Structure (II)
~wherein R2 and R4 are as hereinbefore defined and R7 is an
N-protecting group) with an oxidising agent, in the presence
of titanium trichloride;
~- to prepare a compound of structure (I) wherein R1
represents -CoR3, NO2 or halogen, the reaction of a compound
lo of structure (III) :
~--\ 7
~N-R
R
Structuxe (II')
(wherein R2, R3 and R7 are as hereinbefore defined) with an
appropriate acylating, nitrating or halogenating agent `
respectively; followed in each case by removal of the N-
protecting group, and if desired salt formation.
Suitable N-protecting groups R7 are well known in the
art and include acyl groups such as acetyl, trifluoroacetyl,
benzoyl, methoxycarbonyl, and benzyloxycarbonyl. N~
deprotection may be carried out by conventional methods. ~-
~.
2s In process ~a) the ox~dising agent may be for example
hydrogen peroxide or a peracid such as 3-chloroperbenzoic
acid, in a solvent such as acetic acid. It will be ;~
,
W093/O~g4 ~ 5 PCT/GB92/010X3
~ 6 -
appreciated that one equivalent of the oxidising agent will
produce a compound wherein n is l and two or more equivalents
will give a compound wherein n is 2.
In process (b) the acyla~ing agent may be for example
an acid chloride or acid anhydride corresponding to the group
R3Co-. The reaction is desirably effected in the presence of
tin tetrachloride. Nitration may be effected using
concentrated nitric acid in admixture with acetic anhydride,
O followed by neutralisation with e.g. sodium bicarbonate.
Halogenation may be carried out with an acidic solution of a
halogen e.g. Br2 in aeetic acid, followed by neutralisation
with e.g. sodi~m bicarbonate. In general the nitration and
halogenation reactions will result in a mixture of isomeric
compounds, substituted respectively at the 7,8 and 6,7
positions of the benzazepine ring, wh~ch may be separated for
example by chromatography, or crystallisation.
The compounds of structure (I) have been found to be
agonists at 5-HT2 andJor 5-HTl-like receptors and are
expected to have utility in medicine in the treatment ox ~
prophylaxis of portal hypertension. Whilst not wishing to ~-
be bound by theory, it is believed that 5-HTl-like agonists
and S-HT2-agonists are effective in portal hypertension
through constriction of mesenteric arterioles, and partial
constriction of paraesophageal collaterals with consequent
reduction of portal flow and portal pressure. Preferred
compounds for use according to the present ir,vention are
partial agonists at 5-HT2 receptors and/or 5-HTl-like
receptors.
It is believed that the use of 5-HT2 and 5-HTl-like-
receptor agonists in the treatment of portal hypertension has
not previously beeen described and hence represents a novel
use for these classes of compounds.In a further aspect
therefore the present invention provides 5-HT2 receptor
agonists and 5-HTl-like-agonists for use in the treatment of
portal hypertension. The invention also provides the use of
5-HT~ receptor agonists and 5-HTl-like-agonists in the
40 manufacture of a medicament for the treatment of portal
W093/0~94 2 ~ 7 5 PCT/GB92/01083
.
hypertension. Also provided is a method of treating portal
hypertension which comprises administering to a subject in
need thereof an effective amount of a 5-HT2-agonist or 5-HTl-
like-agonist. For use according to the present invention a
5-HT2-agonist or 5-HTl-like-agonist is preferably a partial
agonist at the said receptor. Most preferably, a compound
for use according to this invention is a partial agonist at
both 5-HT2 and 5-HTl-like receptors.
The compounds of structure (I) have been found to be
agonists at 5HTl-like and/or 5HT2 receptors and are expected
to have utility in medicine in the treatment or prophylaxis
of migraine. ~Whilst not wishing to be bound by theory, it
is believed that 5HTl-like agonists are effective in migra~ne
lS through constriction of cerebral arteries and that 5HT2
agonists constrict the superficial temporal artery.
Preferred compounds for use according to the present
invention are partial agonists at 5HTl-like andtor 5HT2
receptors.
It is believed that the use of 5-HT2-receptor agonists
in the treatment of migraine has not previously been
described and hence represents a novel use for this class of
compound. In a further aspect therefore the present
2s invention provides 5-HT2-receptor agonists for use in the
treatme~t of migraine. The invention also provides the use
of 5-HT2-receptor agonists in the manufacture of a medicament
for the treatment of migraine. Also provided is a method of ~`
treating migraine which comprises administering to a subject
in need thereof an effective amo~nt of a 5-HT2 agonist. For
use according to the present invention a 5-HT2-agonist is
preferably a partial a~onist at this receptor.
In therapeutic use the compounds are incorporated into
35 standard pharmaceutical compositions. They can be ~-~
administered orally, parenterally, rectally or transdermally.
.~.
The compounds of structure ~I) and their
pharmaceutically acceptable salts which are active when given
WO 93/00094 ~ 8 -- PCI~/GB92/01083
orally can be formulated as liqui~s, for example syrups,~
suspensions or emulsions, tablets, capsules and lozenges.
A liquid formulation will generally consist of a
s suspension or solution of the compound or pharmaceutically
acceptable salt in a suitable liquid carrier(s) for
example, ethanol, glycerine, non-aqueous solvent, for example
polyethylene glycol, oils, or water with a suspending agent,
preservative, flavouring or colouring agent.
A composition in the form of a tablet can be prepared
using any suitable pharmaceutical carrier(s) routinely used
for preparing solid formulations. Examples of such carriers
. include magnesium stearate, starch, lactose, sucrose and
cellulose.
A composition in the form of a capsule can be prepared -`
using routine encapsulation procedures. For example,
pellets containing the active ingredient can be prepared
using standard carriers and then filled into a hard gelatin
capsule; alternatively, a dispersion or suspension can be
prepared using any suitable pharmaceutical carrier(s), for
example aqueous gums, celluloses, silicates or oils and the
dispersion or suspension then filled into a soft gelatin
2s capsule.
The compounds of structure (I) and their
pharmaceutically acceptable salts which are active when
administered parenterally (i.e. by injection or infusion)
can be formulated as solutior.s or suspensions.
A composition for parentexal administration will
generally consist of a solution or suspension of the active
ingredient in a sterile aqueous carrier or parenterally
acceptable oil, for example polyethyleneglycol, polyvinyl
pyrrolidone, lecithin, arachis oil or sesame oil.
Alternatively, the solution can be lyophilised and then
reconstituted-with a suitable solvent just prior to
administration.
W093/0~94 2 1 ~ O .~ 7 5 PCT/GB92/01083
_ g _
A typical suppository composition comprises a compound
of formula ~I) or a pharmaceutically acceptable salt thereof
which is active when administered in this way, with a binding
and/~r lubricating agent such as polymeric glycols, gelatins
5 or cocoa butter or other l~w melting vegetable or synthetic -~
waxes or fats. ;
A typical transdermal formulation comprises a
conventional aqueous or non-aqueous vehicle, for example,
o a cream, ointment lotion or paste or in the form of a `
medicated plaster, patch or membrane.
Preferab~y the composition is in unit dose form. Each
dosage unit for oral administration contains preferably from
1 to 250 mg (and for parenteral administration contains
preferably from 0.1 to 150 mg) of a compound of the formula
(I) or a pharmaceutically acceptable salt thereof calculated
as the f ree base.
The daily dosage regimen for an adult patient may be,
for example, an oral dose of between 1 mg and 1000 mg,
preferably between 1 mg and 400 mg, for ex~mple between 10 -;
and 400 mg Qr an intravenous, subcutaneous, or intramuscular
dose of between 0.1 mg and 100 mg, preferably between 0.1 mg
and 30 mg, for example between 1 and 30 mg of the compound of
the formula (I) or a pharmaceutically acceptable salt thereof
calculated as the free base, the compound being administered
1 to 4 times per day. Suitably the compounds will be
administered for a period of continuous therapy.
- ~,
WOg3/0~94 PCT/GB92/01083
1 0 -
BIOLOGICAL DATA
5-~T1-lika Receptor Screen
Dog SaphQnous Vein
Helicoids of dog sapher.ous vein were set up at 37 C in
modified Krebs solution at a resting force of 10 mN. The
solution also contained 1 ~mol/l each of Xetanserin prazosin,
atropine and mepyramine, 6 ~mol/l cocaine and 200 ~mol/l
ascorbate. Nearly isomeric contractions were measured with
force transducers on a polygraph. The tissues were exposed
twice to 5-hydroxytryptamine ~5-HT) 2 ~mol/l followed by
washes. A cumulative concentration-effect curve to the test
compound was determined, followed by a curve to 5-HT in the
presence of the highest used concentration of test compound.
Contractions caused by the test compound were compared with
those caused by 5-HT. The intrinsic activity of the test
compound was calculated as the ratio of the maximum test
compound-induced effect over the effect caused by 2 ~mol/l
5-~T. The ECso of the test compound was estimated from the
corresponding effect curve. When appropriate equilibrium
dissociation constraints Kp were estimated by the method of
Marano & Kaumann (1976, J. Pharmacol. Exp. Ther. 198, 518-
525).
The compounds of structure (I) have been found to
demonstrate activity in this screen, for example:
7-hydroxy-8-methylsulphonyl-2,3,4,5-tetrahydro-lH-benzazepine
(prepared according to the procedures described in EP 229510-
B), was found to have an ECso of 0.2 ~M, and the compound of
Example 1 an ECso of 20 ~lM.
RABBIT BASILAR ARTERY `~
3s
MET~ODS
Experiments were performed in intracranial arteries
from rabbit isolated basilar artery in a similar method to
W093/0~94 2 1 ~ O ., 7 5 PCT/GB92/01083
one described previously (Parsons and Whalley, 1989. Eur J
Pharmacol 174, 189-196.). `
In brief, rabbits were killed by overdose with
anaesthetic (sodium pentobaxbitone). The whole brain was
quickly removed and immersed in ice cold modified Kreb's
solution and the basilar artery removed with the aid of a
dissecting microscope. The Krebs solution was of the
following composition (mM~ Na+ (120); K+ (5); Ca2+ (2.25); .
Mg2+ (0.5); Cl- (98.5); SO~~ (1); EDTA (0.04), equilibrated ~;
with 95% 02/5% CO2. The endothelium was removed by a gentle
rubbing of the lumen with a fine metal wire. Axteries were
then cut into ring segments (ca 4-5 mm wide) and set up for
. recording of isometric tension in 50 ml tissue baths in
modified Krebs solution with the additional supplement of
ImM); Na2+ (20?; fumarate (10); pyruvate ~5); L-glu~amate ~5)
and glucose (10~. The arteries were then placed under a
resting force of 3-4 mN maintained at 37C and the solution
bubbled with 95% 02/5% CO2.
After tests for initial reactivity with 90 mM KCl
depolarising solution and for lack of acetylcholine-induced
relaxation of 5-HT (10 mM) precontraction, cumulative
concentration-effect curves (2 nM-60 mM) to 5-HT were
constructed in the presence of ascorbate 200 mM, cocaine 6
mM, indomethacin 2.8 mM, ketanserin 1 mM and prazosin 1 mM.
.,
Following a- 45-60 min wash period, cumulative
concentration-effect curves to the test compounds or 5-HT ~as
a time match control) were constructed in the presence of
ascorbate, indomethacin, cocaine, ketanserin and prazosin.
5-~T2-Receptor Scr~en ~:
Rat Tail ArtQry (Kaumann A.J. & Frenken M. 1988, J.
Ph~rmacol. Exp. Pharmacol. 2~, 1010-1015)
;'~
The ventral caudal artery was used from rats pretreated
with reserpine 7mg/kg ip (~0 h). Five interconnected
arteri~l rings were prepared and set up to contract in
W093/00094 PCT/GB92/OtO83
~ 2 -
modified Krebs solution at 32.5C as follows. Resting force
of the rings was set to be 4 mN and the rings allowed to
relax thereafter without further readjustment. Three
cumulative concentration-effect curves were determined, the
first to 5-HT followed by washout, the second to the test
compound and the third to 5-HT in the presence of the highest
used concentration of test compound. The intrinsic activity
of the test compound was calculated as the ratio of the
maximum test compound-induced effect over maximum 5-HT-
lQ induced effect. The ECso of the test compound was estimated
from the corresponding concentration-effect curve.
Equilibrium dissociation constants Xp were estimated by the ;;
method of Marano & Kaumann (1~76, J. Pharmacol. Exp. Ther., ~;
. 198, 518-525).
The compounds of structure (I) have been found to
demonstrate activity in this screen, for example, 7-hydroxy-
8-methylsulphonyl-2,3,4,5-tetrahydro-lH- benzazepine was
found to have an ECso f 2 ~M, and the compound of Example 2
an EC50 f 1 ~M.
Portal ~ypertension - In vivo
The effect of 7 hydroxy-8-methylsulphonyl-2,3,4,5-
tetrahydro-lH-benzazepine was investigated on superior
mesenteric arterial flow in conscious normal and portal vein-
ligated rats (Sprague-~awley). Portal hypertension in portal
vein-ligated rats was produced as described ~roszmann et al.
1982). A Doppler flowmeter probe was implanted into the
superior mesenteric artery for chronic studies. Superior
mesenteric flow changes were observed during 4 days, followed
by 4 days' exposure to 7-hydroxy-8-methylsulphonyl-2,3,4,5-
tetrahydro-lH-benzazepine in the drinking water and another
period of 4 days without 7-hydroxy-8-methylsulphonyl-2,3,4,5-
tetrahydro-lH-benzazepine in the drinking water. 7-hydroxy-
8-methylsulphonyl-2,3,4,5-tetrahydro-lH-benzazepine
significantly reduced superior mesenteric flow in both sham-
operated and portal vein-ligated rats. The effect was
reversible during the last 4 day period without 7-hydroxy-8-
W093/0~94 21 ~ ~ ~ 7 5 PCT/GB92/01083
- 13 -
methylsulphonyl-2,3,4,5-tetrahydro-lH-benzazepine in the
drinking water.
Groszmann R J, Vorobioff J and Riley E ~1982). Splachnic
5 hemodynamics in portal hypertensive rats: measurement with
gamma-labelled microspheres. Am J Physiol 242: G156-G160,
WO 93/00094 ~ 14 - PCT ~l~B92/01083
P~CEUTICAL FORM~LATIONS
1. Formulation for intravenou~ infu~ion
Compound of structure ~I) 0.1 - 150 mg
Sodium hydroxide/hydrochloric acidto pH ca 7
polyethylene glycol 0 - 30 ml
propylene glycol 0 - 30 ml
alcohol 0 - 10 ml
water to 100 ml
2. Formulation for bolus injection
.:
Compound of structure (I) 0.1 - 150 mg
sodium hydroxide or hydrochloric acid to pH ca 7
polyethylene ~lycol 0 - 2.5 ml
alcohol 0 - 2.5 ml -~:
water to 5 ml :
A toxicity adjusting agent eg. sodium chloride,
dextrose or mannltol may also be added.
3. Tablet for oral administration
mg/tablet
Compound of structure (I) 50
lacatose 153 :
starch
crospovidone 12
microcrystalline cellulose 30
magnesium stearate __2
280
2t~ ~5~`
W093/00094 PCT/GB92/01083
- 15 - :.
Examples
Compounds within the scope of the present invention
(e.g. 7-hydroxy-8-methylsulphonyl-2,3,4,5-tetrahydro-
lH-3-benzazepine) can be prepared using the methods described
in EP-229510-B or the methods disclosed hereinbefore.
Example 1
7-Methoxy-8-methylsulphinyl-,3,4,5-tetrahydro~
benzazepinQ monooxalate
3-Acetyl-7-methoxy-8~methylthio-2, 3r 4,5-tetrahydro-
lH-benzazepine (3.04g) was dissolved in methanol ~500 ml) and
~lS treated with a 15% solution of titanium trichloride (11.8g), :
followed by 6% hydrogen peroxide solution ~18.0g~, dropwise,
with stirring, over 10 minutes at room temperature. After .
stirring for a further 30 minutes, the reaction mixture was .~`~
filtered, diluted with water and extracted with chloroform.
The latter extract was washed with aqueous sodium sulphite,
then water, dried, filtered, and evaporated to dryness
leaving 3-acetyl-7-methoxy-8-methylsulphinyl-,3, 4t 5-
tetrahydro-lH-benzazepine (3.21g) as a solid, m.p. 130-2C.
~ .
2s The above product (20mg) was hydrolyzed by refluxing a
solution in isopropanol (lml) with 40% aqueous sodium
hydroxide ~lml) for 60 hours. Most of the isopropanol was -~
evaporated.in vacuo, and the remaining solution was diluted
with water, and extracted with chloroform. The extracts
30 were combined, dried (MgS04) and evaporated to give 7- :
methoxy-8-methylsulphinyl-,3,4,5-tetrahydro-lH-benzazepine
117mg) which was converted to the monooxalate salt, m.p. 212-
~C.
W093/OOOg4 PCT/GB92/01~83
16 -
Example 2
7-Methoxy-8-~itro-2,3,4,5-tetrahydro-1~-banzazepino
hydrochloride
s
Concentrated nitric acid (0.6ml, 70~ w/w) wa~ added to
a stirred, ice-cooled solution of 3-acetyl-7-methoxy-
2,3,4,5-tetrahydro-lH-benzazepine (1.98g~ in acetic anhydride
(30ml) over 5-6 hours. The solution was allowed to warm to
room temperature and, after standing overnight, was added to
saturated aqueous sodium bicarbona~e. When all of the
excess acetic anhydride had reacted, the resulting mixture
was saturated with sodium chloride and extracted with ethyl
acetate. The combined extracts were washed with water,
dried (MgS04) and evaporated to a gum, which was purified by
chromatography (SiO2; C6H14/EtOAc) to give 3-acetyl-7-
methoxy-8-nitro-2,3,4,5-tetrahydro-lH-benzazepine ~0.93g),
m.p. 12?-132C, and 3-acetyl-6-nitro-7-methoxy-2,3,4,5-
tetrahydro-lH-benzazepine which was recrystallised from
benzene (0.16g), m.p. 143-149C.
The above product (3-acetyl-~-methoxy-8-nitro-
2,3,4,5-te~rahydro-lH-benzazepine) (0.9Og) was heated at
reflux in 3N.~Cl (54ml) for 16 hours. The resulting
solution was evaporated to dryness to leave a yellow solid
which was triturated with acetone and collected by
filtration. The beige solid thus obtained was dried over
P20s and recrystallised from methanol to give 7-methoxy-8-
nitro-2,3,4,5-tetrahydro-lH-benzazepine hydrochloride
(0.74g), m.p. 234-7C.
Example 3
~ .
7-~ydroxy-8-nitro-2,3,4,5-tatrahydro-lH-benzazepine
hydrochloride
7-Methoxy-8-nitro-2,3,4,5-tetrahydro-lH-benzazepine
hydrochloride (0.40g) was dissolved in 48% aqueous
hydrobromic acid, and the solution was heated to reflux for
24 hours. The solution was evaporated to dryness to leave a
wo 93/noo94 2 1 ~ ~ 7 5 PCr/GB92/OlU83
crude yellow solid which was basified and purified by
chromatography (SiO2; CHC13/MeOH~, then recrystallised from
methanol/conc. hydrochloric acid to give 7-hydroxy-8-nitro-
2,3,4,5-tetrahydro-lH-benzazepine hydrochloride tO.llg), m.p.
251-5C.
Example 4 ~
7-Methoxy-8-bromo-2,3,4,5-tetrahydro-1~-benzazepin~ ;
hydrochloride
3-Acetyl-7-methoxy-2,3,4,5-tetrahydro-lH-benzazepine
(5.0g) was dissolved in glacial acetic acid (70ml) and heated
to 70C. A l.OM solution of bromine in acetic acid was
s added over 20-30 minutes, and the resulting solution was
heated at 70C for a further hour. The solution was allowed ;
to cool overnight, during which a mass of beige crystals was
obtained. These were collected by filtration, basified and
purified by chromatography ~SiO2i CH2C12/EtOAc), followed by
crystallisation from ethyl acetate/ether to give 3-acetyl-7-
methoxy-8-bromo-2,3,4,5-tetrahydro-lH-benzazepine ~1.55g), ~
m.p. 123-125C, and 3-acetyl-6-bromo-7-methoxy-2,3,4,5- ;
tetrahydro-lH-benzazepine, m.p. 99-101C.
The above product (3-acetyl-7-methoxy-8-bromo-
2,3,4,5-tetrahydro-lH-benzazepine) (0.30g) was heated under
reflux in 3M HCl ~16.5ml) for 20 hours. The solution was ;~
evaporated to dryness in vacuo and triturated with acetone to
give 7-bromo-8-methoxy-2,3,4,5-
tetrahydro-lH-benzazepine hydrochloride as a white solid
(0.25g), m.p. 268-272C.
I Example 5
7-~ydroxy-8-bromo-2,3,4,5-tetrahydro-1~-benzazepine
hydrochloridQ
A solution of 3-acetyl-7-methoxy-8-bromo-2,3,4,5- `
tetrahydro-lH-benzazepine (0.5 g) in dichloromethane (12 ml)
40 was cooled in an acetone/dry ice bath. Boron tribromide
wo 93/00094 ~ ~ PCr/C~B92/01083
1 8 -
( 0 . 32 ml ) was added to the stirred solution in one portion,
and the mixture was allow~d to warm to room temperature over
1 hour. Stirring was continued for a further 30 minutes,
then water was added. The mixture was partitioned between
water and dichloromethane, and ~he aqueous layer was re-
extracted with dichloro-methane. The combined extracts were
washed with water and brine, dried (MgS04) and evaporated to
a solid, which was purified by chromatography (SiO2;
CHCl3/MeOH) to give 3-acetyl-7-hydroxy-8-bromo -2,3,4,5-
O tetrahydro-lH-benzazepine as a white solid (0.37 g).
The a~ove product (0.30 g~ was heated in 3~ HCl (50 ml)
to reflux over~ight. The resulting s~lution was evaporated
to dryness and triturated with acetone to give a white solid.
i5 This was recrystallised from n-pxopanol/ HCl to give the
title compound as white crystals (0.21 g), m.p. 277-281C.
Example ~
7-Methoxy-6-nitro-2,3,4,5-tetrahydro-lH-benzazQpine
hydrochloride
The title compound was prepared following the
procedures described in Example 2, by heating 3-acetyl-7-
methoxy-6-nitro-2,3,4,5-tetrahydro-lH-benzazepine
hydrochloride (0.15g) in 3N.HCl (9mL) at reflux. The
product, 7-methoxy-6-nitro-2,3,4,5-tetrahydro-lH-benzazepine
hydrochloride, was isolated as described, and recrystallised
from n-pxopanol to give small yellow crystals ~0.077g), m.p.
258-61C decomp.
Example 7
.
6-Bromo-7-methoxy-2,3i4,5-tetrahydro~ benzazepine ~`-
3s hydrochloride
The title compound was prepared following the
procedures described in Example 2, by heating 3-acetyl-6-
bromo-7-methoxy-2,3,4,5-tetrahydro-lH-benzazepine ~0.20g) in
3N.HCl (11 mL) at reflux. The product, 6-bromo-7-methoxy-
W093/0~94 21 ~ ~ 5 75 PCT~B9Z/01083
-- 19 -- ...
2,3,4,5-tetrahydro-lH-benzazepine hydrochloride, was isolated
as described and recrystallised from n-propanol to give white
needles (0.12g), m.p. 255-60C.
s Example 8
8-Acetyl-7-hydroxy-2,3,4,5-tetrahydro~ ba~zazapi~e
hydrochloride
Tin tetrachloride (2.4 mL) was added dropwise, with
stirring to a solution of acetyl chloride (1.46 mL) in CH2C12
(15 mL), at room temperature. Stirring was continued for a
further 1 hour, and then a solution of 7-methoxy~3-acetyl-
2,3,4,5-tetrahydro-lH-benzazepine hydrochloride (3.0g) in
lS CH2C12 (15 mL) was added over a period of 20 minutes. The
mixture was left to stir for 16 hours, and then partitioned
between 3~.HCl and CH2C12. The aqueous layer was re-
extracted and the combined organic layers were washed with
saturated sodium bicarbonate solution and then H20, dried
~MgS04) and evaporated. The residue was dissol~ed in
methanol and treated with charooal. The filtrate was
evaporated to dryness and the residue extracted twice with
boiling benzene, the extracts decanted combined and
evaporated to give a solid which was triturated with ether.
The product, 3,8-diacetyl-7-methoxy-2,3,4/5-tetrahydro-lH-
benzazepine, was obtained as an off-white solid (1.7g), m.p.
142-6C.
The 3,8-diacetyl-7-methoxy-2,3,4/5-tetrahydro-lH-
benzazepine (0.20g) was dissolved in CH2C12 (5 mL) and cooled
to ca -70C (acetone/solid C2 bath). Boron trichloride
(l.OM solution in CH2C12; 1.53 mL) was added from a syringe
over 10 minutes. The mixture was allowed to warm slowly to ~-
room temperature (1 hour) and then stirred for a further 30
minutes. The reaction was quenched by the addition of H20
and the mixture was partitioned between water and CH2C12.
The aqueous layer was re-extracted with CH2C12 and the
combined organic layers washed with water and brine, and
dried (MgS04). Evaporation gave a gum which was purified by
flash chromato~raphy (SiO2i CHC13/MeOH). The product, 3,8-
W093/0~94 ~ PCT/GB92/01083
diacetyl-7-hydroxy-2,3,9,5~tetrahydro-lH-benzazepine,
crystallised from ether as an off-white solid (0.129g), m~p.
131-4C.
The above diacetyl compound (0.121g) was heated at
reflux in 3M.HCl (3.7 mL) for 16 hours. The solution was
then evaporated to dryness, giving a yellow-orange
crystalline solid. This was recrystallised from n-propanol
containing dissolved HCl gas, to yield the product, 8-acetyl-
7-hydroxy-2,3,4,5-tetrahydro-lH-benzazepine hydrochloride, as -
small orange crystals (0.064g), m.p. 241-7C decomp.
Example 9
7-Hydroxy-8-~ethylsulphinyl-2,3,4,5-tetrahydro-lH-benza~api~e
Aluminium chloride (1.71 g) was added to
dichloromethane (50 ml) at room temperature, and a solution
of 3-acetyl-7-methoxy-8-methylsulphinyl-2,3,4,5-tetrahydro-
lH-benzazepine (0.90 g) in dichloromethane was added dropwise
with stirring over 3h. After leaving the mixture to stir
overnight at room temperature, the dichloromethane solution
was decanted from the precipitated gum. The latter was
digested with lM sodium hydroxide solution, and the resulting
aqueous solution was washed with dichloromethane, acidified ;~
to PH2 with conc. HCl and extracted ~3x) with chloroform.
The extract was dried (MgSO4), evaporated to an oil, and
purified by chromatography (SiO2; MeOH/CH2Cl2) to give 3-
acetyl-7-hydroxy-8-methylsulphinyl-2,3,4,5-tetrahydro-lH-
benzazepine (0.72 g). ~`
.
The above product (0.64 g) was heated with lM sodiumhydroxide solution (10 ml) at 100C overnight. After
cooling, the mixture was passed down an ion exehange column
(Amberlite CG~0; NH4~) and eluted with water. The resulting ~;
eluate was evaporated to dryness, extracted with hot
methanol, treated with activated charcoal, filtered and
' '.
W093/00094 ~1~ 0,~ 7 3 PCT/GB92/01083
~ 21 -
,
evaporated to a green gum. This crystallized on addition of
acetonitrile to give the title compound (0.45 g), mp 175-8C.
~xampl~ 10
7-~ydroxy-8-tri~luoromethylsulp~onyl-2, 314,? 5-tetrahydro-1~-
benzazepine
3-Acetyl-7-methoxy 2,3,4,5-tetrahydro-lH-benzazepine
(7.0 g) was dissolved in dry dichloromethane ~100 ml), cooled
in an ice bath, and treated dropwise with chlorosulphonic
acid ~13.9 g), with stirring. The mixture was stirred for a
further 2 1/2 h at room temperature and then poured carefully
~-~ onto ice. The resulting brown oil was partitioned between
dichloromethane and water, and the aqueous layer was
extracted further with dichloromethane. Combined organic
extracts were dried (MgSO4) and evaporated to give 3-acetyl-
7-methoxy-8-chlorosulphonyl-2,3,4,5-tetrahydro-lH-benzazepine
(4.5 g).
The above product (3.95 g) was dissolved in acetic acid
~75 ml), and stannous chloride dihydrate (11.2 g) and conc.
HCl (15 ml) were added. The mixture was stirred at 75C for
1 h then poured into ice water and shaken with ethyl acetate.
The solid thus produced was combined with the ethyl acetate
extracts and evaporated to dryness in vacuo. This crude
product was shaken with dry ethanol (200 ml) and filtered.
The resulting solid was stirred with lM NaOH solution (100
ml) for 30 min., filtered, acidified with conc. HCl and
extracted with chloroform. The extracts were combined, dried
(MgSO4) and evaporated to dryness to give 3-acetyl-7-methoxy-
8-mercapto-2,3,4,5-tetrahydro-lH-benzazepine (1.86 g).
.:
This product (1.22 g) was dissolved in dry DMF (50 ml)
35 and potassium carbonate (1.33 g) added. Trifluoromethyl -~
i~dide was bubbled through the solution, while irradiating ;-
with U.V. light, with cooling, for 5 h. Most of the DM~ was
removed under vacuum, and the residue was partitioned between
s~ ~
W093/00094 PCT/GB92/01083
- 22 -
chloroform and lM NaOH solution. The organic phase was dried
(MgS04) and evaporated to dryness. The residue was purified
by chromatography (SiO2; CHC13tMeOH) to give 3-acetyl-7-
methoxy-8-trifluoromethyl-2~3~4~5-tetrahydro-lH~benzazepine
(0.33 g).
The above product (1.0 g) was dissolved in 1,2-
dichloro-ethane (75 ml) and meta-chloro perbenzoic acid (2.26 .-
g) was added. The mixture wàs heated under reflux for 2 h.
o The resulting cooled solution was washed with lM NaOH
solution, dried tMgso4) and evaporated to dryness leaving 3-
acetyl-7-methoxy-8-trifluoromethylsulphonyl-2,3,4,~
tetrahydro-lH-benzazepine (0.95 g).
This product (0.50 g) was dissolved in dichloromethane :~
(100 ml) and boro~ tribromide (0.71 g) was added dropwise
with stirring at room temperature overnight. Methanol was :
added cautiously, dropwise, and the solvents were removed in
vacuo. The residual green oil consisting of the 7-hydroxy
compound was dissolved in chloroform and washed with lM NaOH ..
solution.
The aqueous phase was separated and heated at 100C for
40 h, cooled, and passed down an ion exchange column
~Amberlite CG-50(H). The relevant fractions were combined
and evaporated to dryness to leave a residue which was
chromatographed (SiO2; CHC13/MeOH~MH40H) to give a product
which was crystallized under acetonitrile to give the title
compound (0.12 g), mp >273C.
'.;"
