Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~2~ S
--1--
S Pharmaceutical Compositions and Method of Producing
~ ha2 Antayonism
This invention relates to pharmaceutical com-
positions and a method of producing alpha2 antagonism by
employing certain N-su~stituted 2,3,4,5-tetrahydro-lH-
3-benzazepines.
The pharmaceutical compositions and methods of
this invention produce alpha2 antagonism, a pharma-
cological action which is associated with the reduction of
intraocular pressure and a broad spectrum of cardio-
vascular activity. For example, the compounds of this
invention may be used for treating congestive heart
failure, angina pectoris, and thrombosis.
Advantageously, the compounds also produce a
reduction in blood pressure and are therefore useful as
antihypertensive agents. This invention also relates to a
method of producing antihypertensive activity by admin-
istering these compounds.
Reduction of intraocular pressure is of sig-
nificant ~nportance in the treatment of glaucoma which isa disease of the eye characterized by increased intra-
ocular pressure. Glaucoma is a leading cause of blindness
in people over forty. In poorly controlled glaucomat the
intraocular pressure is persistently increased and there
is a progressive retinal and optic nerve degeneration. If
untreated, a red painul eye may occur accompanied by
reduced vision and eventually blindness.
The three agents most commonly used in glaucoma
therapy are pilocarpiner timolol or epinephrine. Pilo-
carpine causes miosis and spasm of the ciliary musclewhich produces blurred vision and myopia. Epinephrine
dilates the pupil and blurs the vision as well as induces
--2--
1 hyperemia, macular edema and allergic reactions in the
eye. ~oreover, systemic absorption of epinephrine after
ocular instillation has produced cardiac arrhythmias.
Timolol has few notable ocular side effects but systemic
actions of the drug are a problem. Bradycardia, syncope,
exacerbation of borderline congestive heart failure and
bronchospasm have all been reported after topical timolol
administration.
A still further disadvantage associated with
epinephrine is that it is unstable to both air and light
and subject to chemical attack by many agents th~t are
conventionally used in pharmaceutical preparations.
Attempts made to overcome these disadvantages usually
resulted in compositions that were irritating to the body
tissues or formed biologically inactive derivatives
thereof.
It is therefore an object of this invention to
produce ophthalmic compositions and methods for lowering
intraocular pressure which lack direct effect on pupil
size, have no effect on heart rate or blood pressure in
normotensive animals, and minimal local or systemic
adverse effects upon instillation into the eye.
The no~el compositions and methods of using them
described hereafter have been found unexpectedly to reduce
intraocular pressure without the undesirable side effects
and disadvantages of the prior art agents noted above.
Description of Prior Art
United States Patents 4,210,749 and 4,233,217
disclose a broad class of benzazepines being useful as
analgesics, antihistaminics and narcotic antagonists.
However, there is no specific disclosure of the compounds
of Formula I. Moreover, there is no suggestion in these
patents that the compounds of Formula I would be useful as
alpha2 antagonists. One specific compound of Formula I,
6-chloro-3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine has
been disclosed as a chemical intermediate in United States
Patent 4,265,890. There is no suggestion in this patent
- 21~65
~3--
1 that the compound has any ~seful biological activity.
United States Patents 3,716,639 and 3,752,892 disclose
7-chloro and 6-chloro-2,3,4,5-tetrahydro-lH-3-benzazepines
as anorexigenic agents.
None of the above known art discloses the bio-
logical activities of the claimed compositions and methods.
Description of Invention
The N-substituted 2,3,4,5-tetrahydro-lH-3-
benzazepine compounds which are the active ingredients of
the pharmaceutical compositions of this invention are
represented by the rollowing formula: -
Formula I
l ~ N-R
in which:
R is lower alkyl of from 1 to 3 carbon atoms or
allyl; and
X is halogen such as chloro, bromo or fluoro,
and a pharmaceutically acceptable acid addition salt
thereof.
A particularly preferred compound in the pharma-
ceutical compositions and methods of this invention is a
compound of Formula I in which R is methyl and X is chloro
being the compound 6-chloro-2,3,4,5-tetrahydro~
3-methyl-lH-3-benzazepine.
The above compounds of Formula I which are the
3~ active ingredients in the compositions and method for pro-
ducing alpha2 antagonism are prepared by synthetic
methods familiar to the art. The most advantageous pro-
cedure is as follows:
8~
--4-
~ 1. SOCl ~
~ ~ 2. RNHCH2CH2OH ~ ~ CH2 2
~ CH2CO2H ~ ~ 2 ~O
_ 3 ~ 1. PCl~
~ ~ 2- AlC13,NH4Cl
~ -R
The terms X and R are as defined above.
According to the above procedure, a halophenyl
acetic acid is treated with thionyl chloride followed by
an appropriate amino alcohol. The resultant amide is
reduced by any well known agent such as, for example,
borane. The resultant amino alcohol is then converted to
the corresponding halide, such as chloride or bromide, and
cyclized under Friedel-Crafts conditions. The cyclization
step is carried out using Lewis acids~ such as, or
example, aluminum chloride, aluminum bromide, titanium
chloride and antimony chloride. Advantageously the
cyclization is carried QUt in a mel~ of aluminum chloride
and ammonium chloride at elevated temperatures.
The compounds of Formula I may also be prepared
by reacting a 3-benzazepine compound in which ~ is
hydrogen with an alkylating or acylating reagent which
will replace the hydrogen with the desired R group. Such
s
--5--
1 reagents include compounds of the formula RY and RCOY
wherein R is as defined above for Formula I and Y s
halogen, such as chloro or bromo. Other reagents could
include aldehydes or ketones.
When an aldehyde or ketone is used as the reagent
it is followed by reductive alkylation. The reduction can
be accomplished catalytically, such as with hydrogen and
platinum, or chemically, such as with sodium borohydride
or sodium cyanoborohydride.
When the reagent of the formula RCOY is employed,
the carbonyl moiet~ is subse~uently reduced with, for
example, lithium aluminum hydride.
The pharmaceutically acceptable acid addition
salts having the utility of the free bases of Formula I,
prepared by methods well known to the art, are formed with
both inorganic or organic acids, for example: maleic,
fumaric, benzoic, ascorbic, pamoic, succinic, bis-
methylenesalicylic, methanesulfonic, ethanedisulfonic,
acetic, oxalic, propionic, tartaric, salicylic, citric,
gluconic, aspartic, stearic, palmitic, itaconic, glycolic,
p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric,
hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and
nitric acids.
The activity of the compounds of Formula I is
demonstrated in vitro by determining the prejunctional
alpha2 anta~onist activity using the isolated superfused
guinea pig left atrium. Briefly, the heart is removed
from a pentobarbital-anesthetized male guinea pig. The
left atrium is removed, dissected free of extraneous
tissue and mounted in a 2 ml. superfusion chamber. The
tissue is paced at 60 pulse/minute and the sympachetic
nerves excited at 6 minute intervals by field stimu-
lation. The response to nerve stimulation is measured as
the difference in contractile force between the basal
contraction and peak contraction following a nerve stimu-
lation. A concentra~ion-response curve for clonidine
~alpha2 agonist) is prepared by administerins an
. ~
1 increasing concentration of clonidine following each
successive stimulation. The tissue is then superfused
with the alpha2 antagonist to be tested for thirty
minutes and the clonidine concentration-effect curve ~as
repeated in the presence of antagonist. The receptor
dissociation constant of the antagonist (KB) is defined
as the antagonist concentration required to shift the log
concentration-response curve of the agonist to the right
by a factor of 2.
Selectivity for the alpha2 vis-a-vis the
alphal-adrenoceptor is determined by comparing the KB
obtained as described above with the KB on the alphal
receptor determined in the rabbit ear artery segment as an
antagonist of the constrictor response induced by nor-
lS epinephrine. (Hieble and Pendleton, Arch. Pharmacol.,309, 217-224 (1979)~.
A preferred compound of this invention is
6-chloro-2,3,4,5-tetrahydro-3-methyl-lH-3-benzazepine
which has a KB value in the isolated perfused guinea pig
left atrium of 13 nM.
When substitution is present at the 7-position of
the benz-ring, a dramatic reduction in activity results.
For example, the 7-chloro-2,3,4,5-tetrahydro-3-methyl-
lH-3-benzazepine has a KB value of 150 nM, i.e., about
one tenth the alpha2 antagonist activity of the 6-chloro
derivative. Further, when a substituent such as amino is
present at the 6-position of the benz-ring, or the 6 and 7
positions are fused to a cyclopentane ring, the compounds
are completely inactive as alpha2 antagonists.
The antihypertensive activity of the compounds of
this invention is demonstrated in vivo as follows:
Male rats (300-450 g.) are anesthetized with
sodium brevital and the femoral vein and artery are
cannulated. Cannulas are run intradermally sc as to be
externalized in the dorso-sacral area of either side and
kept in place by wound clips. The rats are allowed to
regain consciousness after being placed in a small animal
6S
--7--
1 restrainer. The arterial cannula is connected to a
pressure transducer for constant blood pressure and heart
rate monitoring. Drugs are administered either orally via
gavage or i.v. via the femoral vein cannula at a rate of
0.06 ml./minute.
The above test is conducted on both normotensive
and hypertensive rats. DOCA Salt hypertensive rats are
prepared from male uninephrectomized Sprague-Dawley rats.
The rats, approximately six weeks of age, are lightly
anesthetized with ether and subcutaneously implanted with
a 25-mg. deoxycorticosterone acetate pellet in the left
dorso-sacral area. Six days later a second pellet is
implanted in the right dorso-sacral area. These rats are
fed a normal laboratory diet, but are given 1% saline
solution to drink in place of water. The rats are kept on
the saline drinking water for 22-24 days.
The following table sets forth the effect of
6-chloro-2,3,4,5-tetrahydro-3-methyl-lH-3-benzazepine on
blood pressure after i.v. administration to both normo-
tensive and hypertensive rats~
Table 1_.
Diastolic Blood Pressure
Type of Rats PreDrug Decrease BP(MMHg)
Q.5 mg./Kg. 1.0 mg./Kg. I.V.
. . __ _
Normotensive (control)95 + 7 MMHg 6 + 2 13 + 1
~Sprague-Dawley)
(n = 4)
DOCA Salt Hyper-
tensive (n = 4)135 + S MMHg27 + 3 33 + 4
Normotensive (control)
(Wistar-Kyoto)
(n = 4) 115 + 3 MMHg7 ~ 2 10 + 2
Spontaneously
Hypertensive (n = 7)167 + 3 MMHg 33 + 7 46 + 2
n = Number of rats
--8--
1 The data in Table 1 demonstrate that while
6-chloro-2,3,4,5-tetrahydro-3-methyl-lH-3-benzazepine has
little effect on diastolic blood pressure in normotensive
rats, it produced a marked drop in diastolic blood
pressure in both DOCA Salt and spontaneously hypertensive
rats. Moreover, comparison of the 0.5 mg./kg. and 1.0
mg./kg. doses shows that the antihypertensive effect is
dose-related.
The effect of the oral administration of 6-chloro-
2,3,4,5-tetrahydro-3-methyl-lH-3-benzazepine on blood
pressure in the DOCA-salt hypertensive rat was also
determined. Table 2 below sets forth the results of this
test.
Table 2
__ _ _. _ _
15 Dose Mean Arterial Pressure f~ BP
(PO) Pre-Druq Post-Druq (MM Hg)
~.,
~ mg/kg 148 + 11 ~31 + 12 17 + 3
5 mg~kg 160 + 7 127 + 5 34 + 4
10 mg/kg 167 ~ 8 99 i 4 68 i 8
In addition, for cardiovascular use, the com-
positions of this invention may be combined with thiazide
diuretics such as hydrochlorothiazide, triamterene, or
calcium channel blockers such as Verapamil or Nifedipine,
or B-adrenergic blockers such as propranolol. The amount
of the substituted 3-benzazepines in the com- positions of
this invention would be in the ranges noted above combined
with from about 2 mg. to about 250 mg. of the thiazide
component. When combined with triamterene, from about 5
mg. to about 250 mg. of triamterene would be present. When
a calcium channel blocker is employed in the compositions
of this invention, from about 1 mg. to about 500 ~g. would
be employed.
A further activity of the compounds of this
invention is demonstrated by their ability to red~ce intra-
ocular pressure. The measuremen~ of intraocular pressure
depends on subjecting the eye to a force that indents or
_9_
1 flattens it. Either the effect of a particular force or
the force for a given effect is measured. The specific
procedure employed for the compounds of this invention is
a normal rabbit intraocular pressure determination. A
solution of 0.5% proparacaine hydrochloride diluted 1:10
with physiological saline is instilled into the eye of a
rabbit. The lids are gently massaged over the cornea to
insure good distrlbution of the solution. The eye is
exposed by separating the lids and the tip of a probe is
slowly placed on the cornea at the point where the
curvature of the cornea is the greatest, i.e., on the
optic axis. Employiny an Alcon Applanation Pneumatono-
graph, the intraocular pressure is determined in each eye
until a stable reading is obtained. West, C., Capella, J.
and Kaufman, H., Am. J. Opthalmol. 74:505 (1972).
Nine rabbits are used in each study, three
animals for each dose in most circumstances. An initial,
t=0~ intraocular determination is made in both eyes.
Immediately following the initial reading, the formu-
lations to be tested, comprising concentrations of 0.01 to10~ of active ingredient, are instilled and pressure
readings are taken at 0.S, 1 t 2, 3~ 4, and 6 hours post-
instillation. The intraocular pressure is determined from
the value recorded on the pneumotonograph chart paper. A
mean intraocular pressure value is calculated at each time
point. A preferred compound of this invention,
6~chloro 2,3,4,5- tetrahydro-3-methyl-lH-3-benzazepine,
decreases intraocular pressure at one hour by 3.5 mm. of
mercury relative to the untreated eye.
When the chloro was placed on the 7-position of
the benzazepine nucleus and the compound was administered
at the same doses, there was no lowering of intraocular
pressure.
In summary, the structures of the compounds of
this invention are specifically identified by having the
halo at the 6-position of the benzazepine nucleus~ As
noted from the results of the test for alpha2 antagonism
~2~
--10-
1 and the lowering of intraocular pressure, this is a
critical feature of the compounds of this invention in
order to obtain the desired biological activity.
It was also unexpectedly discovered that when the
preferred compound, 6-chloro-2,3,4,5-tetrahydro-3-
methyl-lH-3-benzazepine, was given systemically and the
above procedure was followed, intraocular pressure was
lowered with no significant effect on systemic blood
pressure. For example, when 0.5 mg./kg. of the compound
was infused in the ear vein of conscious normotensive
rabbits, the compound decreased intraocular pressure at
one hour by between 4 and 5 mm. of mercury.
The pharmaceutical compositions used to carry out
the method of producing alpha2 antagonism and anti-
hypertensive activity comprise a pharmaceutical carrier
and, as the active ingredient, a benzazepine compound of
Formula I. The active ingredient will be present in the
compositions in an effective amount to produce alpha2
antagonism and antihypertensive activity.
Preferably, the compositions contain the active
ingredient of Formula I in an amount of from about 25 mg.
to about 500 mg., advantageously from about 50 mg. to
about 250 mg., per dosage unit.
The pharmaceutical carrier may be for example a
solid or a liquid. Exemplary of solid carriers arelactose, magnesium stearate, terra alba, sucrose, talc,
stearic acid, gelatin, agar, pectin or acacia. The amount
of solid carrier will vary widely but preferably will be
from about 25 mg. to about 1 gm. Exemplary of liquid
carriers are syrup, peanut oil, olive oil, sesame oil,
propylene glycol, polyethylene glycol (mol. wt. 200-400)
and water. The carrier or diluent may include a time
delay material well known to t~e art such as, for example,
glyceryl monosteara~e or glyceryl distearate alone or with
a wax.`
A wide variety of pharmaceutical forms can be
employed, for example, the preparation may take the form
--11--
1 tablets, capsules, powders, troches, lozenges, syrups,
emulsions, sterile injectable liquids or liquid sus~
pensions or solutions.
The pharmaceutical compositions are prepared by
5 conventional techniques involving procedures such as
mixing, granulating and compressing or dissolving the
ingredients as appropriate to the desired preparation.
Preferably, the compounds of Formula I are
administered in conventional dosage unit forms prepared by
combining an appropriate dose of the compound with
standard pharmaceutical carriers.
Preferably, the active ingredient of Formula I
will be administered in a daily dosage regimen of from
about 100 mg. to about 1~00 mg., most preferably from
about 200 m~. to about 500 mg. Advantageouslyr equal doses
will be administered preferably two to four times per
day.
The pharmaceutical compositions of this invention
which reduce intraocular pressure comprise a pharma-
ceutical carrier, preferably an ophthalmic vehicle, and asthe active ingredient an N-substituted 2,3,4,5-tetra-
hydro-lH-3-benzazepine of Formula 1. The active
ingredient will be pr~sent in the compositions of this
invention in an effective amount to reduce intraocular
pressure. Preferably, the compositions of this invention
contain from about 0.01% to about 5.0~ o~ the active
ingredient of Formula I, advantageously, ~rom about 0.03%
to about 3.0%.
The ophthalmic vehicle or carrier may be, for
example, a liquid or solid. Exemplary of liquid
ophthalmic carriers include standard 1.9% isotonic boric
acid, 0.9% sodi~m chloride, or sodium borate solutions.
Further, conventional phosphate buffer solutions such as
the Sorenson phosphate buffer having a pH of 6.8 may be
employed as the carrier. Exemplar~ of solid ophthalmic
carriers may be typical ointment bases such as petrolatum.
The compositions of the present invention can be
-12-
1 administered topically to the eye in dosage unit forms,
such as, for example, ophthalmic solutions, ointments,
creams, gels, or dispersions. When controlled release of
the compound is desired, it may alternatively be
incorporated into polymeric ocular insert systems which
are well known to the art such as, for example, U. ~.
Patent No. 4,052,505
The ophthalmic solutions are sterile and can
contain in addition to the compound of Formula I ant}-
microbrial agents. Exemplary of such agents are thequaternary ammonium germicides such as benzalkonium
chloride, benzethonium chloride or cetylpyridium
chloride. Other such agents that can be employed are
chlorobutanol or phenylmercuric nitrate. If antioxidants
are required, sodium sulfite, sodium ascorbate or other
ophthalmologically accepta~le antioxidants known to the
art such as oxime sulfate may be used.
The benzazepine compound is preferably admini-
stered in ophthalmological dosage unit forms prepared by
combining an appropriate dose of the compound with the
above noted ophthalmological ca~riers. Preferably the
ophthalmic dosage form is applied from two to four times
daily. When an ophthalmic solution is employed one to
five drops may be administered two to four times a day.
When the administration is carried out as
described above, alpha2 antagonism, antihypertensive
activity and a lowering of intraocular pressure is
produced.
The following examples are not limiting ~ut are
illustrative of the compounds of this invention and
processes for their preparation. The temperatures are in
degrees Centigrade~
Example 1
A mixture of 125 g. (0.73 mol) of O-chlorophenyl-
acetic acid, 155 g. (1.3 mol~ of thionyl chloride and 2-3
drops of dimethylformamide in 1500 ml. of toluene was
stirred at room temperature for three hours. The toluene
-13-
1 was evaporated under reduced pressure to give an oil which
was dissolved in 200 ml. of methylene chloride. This was
added dropwise to a solution of 165 y. (2.2 mol) of
N-methylamino ethanol in 1 liter of methylene chloride.
After addition was complete, the solution was stirred at
room temperature for three hours. The organic solution
was washed with water, dilute hydrochloric acid and
saturated sodium chloride, dried over magnesium sulfate,
filtered and evaporated to give 2-chloro-N-(2-hydroxy-
ethyl)-N-methylbenzeneacetamide as a crystalline solid,
m.p. 77.
To 400 ml. of a 1 mol solution of borane in
tetrahydrofuran was added dropwise a solution of 43 g. of
the above amide in 350 ml. of tetrahydrofuran at a rate
sufficient to maintain a gentle reflux. After addition
was complete, the solution was refluxed for two hours,
cooled in an ice bath and treated carefully with dilute
hydrochloric acid to destroy excess borane. The majority
of the solvent was removed under vacuum and the residue
heated on a steam bath for one hour. The mixture was
diluted with 300 ml. of water and extracted with ether.
The a~ueous layer was made basic with 40% sodium hydroxide
and extracted with ether. The combined basic extracts
were washed with water and saturated sodium chloride,
dried and evaporated to give 2-[[2-(2-chlorophenyl)-ethyl~-
methylamino]ethanol.
A suspension of 36 g. (0.173 mol~ of phosphorous
pentachloride in 300 ml. of methylene chloride was treated
dropwise with a solùtion o~ 37 g. (0.173 mol) of the
2-[[2-(2-chlorophenyl~ethyl]methylamino]ethanol in 150 ml.
of methylene chloride. After addition was complete, the
mixture was refluxed overnight, evaporated to dryness and
partitioned between dilute hydrochloric acid and ether.
The aqueous layer was made basic with 10~ sodium hydroxide
and extracted well with ether. The ether extracts were
washed with water and saturated sodium chloride, dried
over magnesium sulfate and filtered. Addition of a
-14-
1 saturated solution of ethereal hydrogen chloride gave a
solid precipitate which was removed by filtration, washed
with ether and dried to give 2-chloro-N-(2-chloroethyl)-
N-methylbenzene ethanamine hydrochloride, m.p. 110.
To a mixture of 41.5 g. (0.155 mol) of the above
chloro ethanamine hydrochloride and 6.26 g. (0.117 mol) of
ammonium chloride was added 41 y. of anhydrous aluminum
chloride. The reaction became homogenous, melted and
exothermed. It was placed in an oil bath which had been
heated to 175 and stirred for thirty minutes. An
additional 20 9. of aluminum chloride was added and the
mixture heated for another thirty minutes. A final 41 9.
portion of aluminum chloride was added and the reaction
heated for twenty hours. It was cooled to 140 and pourèd
into 3 1. of ice water containing 300 ml. of concentrated
hydrochloric acid and stirred for fifteen minutes. Sixty
grams of sodium potassium tartrate was added and stirred
until solution was effected~ It was made basic with 40%
sodium hydroxide, extracted twice with ether and the com-
bined extracts washed with water, and saturated sodiumchloride, dried and reduced in volume by half. Addition
of a solution of saturated ethereal hydrogen chloride gave
a solid precipitate which was collected, washed with ether
and dried to give a white solid. Crystallization from
methanol-ethyl acetate gave 6-chloro-3- methyl-2,3,4,5-
tetrahydro-lH-3-benzazepine hydrochloride, m.p. 268~270.
Example 2
A stirred solution of 1.2 9. of 6-chloro-3-methyl-
2,3,4,5-tetrahydro-iH-3-benzazepine in 30 ml. of toluene
was treated at 50 by dropwise addition with a solution of
0.7 g. cyanogen bromide in 25 ml. of toluene. Following
the addition~ the mixture was stirred and heated at 50
for one hour. A stream of nitrogen was passed over the
surface of the solution during the reaction. The mixture
was cooled, filtered and the filtrate concentrated in
vacuo to yield 6-chloro-3-cyano-2,3,4,5-tetrahydro-lH-3-
benzazepine melting at 81-82 from hexane-ether solution.
-15-
1 The 6-chloro-3-cyano-2,3,4,5-tetrahydro-lH-3-
benzazepine was refluxed for 19 hours in a mixture of 30
ml. of glacial acetic acid and 30 ml. of 6N hydrochloric
acid. The mixture was concentrated in vacuo to yield
6-chloro-2,3,4,5 tetrahydro-lH-3-benzazepine as the
hydrochloride salt of m.p. 214-215 from ethanol. This
salt in turn gave the base 6-chloro~2,3,4,5-tetrahydro-
lH-3-benzazepine on treatment with dilute sodium hydroxide
solution.
Example 3
A mixture of 0.52 g. of 6-chloro-2,3,4,5-tetra-
hydro-lH-3-benzazepine, 0.34 g. of allyl bromide, 0.6 g.
of potassium carbonate and 20 ml. of 90% ethanol was
stirred at room temperature for 17 hours. The mixture was
filtered and the filtrate concentrated in vacuo. The
residue was extracted with 35 ml. of ether and the
ethereal extract treated with isoproponolic hydrogen
chloride to precipitate 3-allyl-6-chloro-2,3,4,5-tetra-
hydro-lH-3-benzazepine hydrochloride. Recrystallization
of this salt from absolute ethanol gave 3-allyl-6-
chloro-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride
having a melting point of 248-249.
Example 4
A solution of 1.5 g. of 6-chloro-2,3,4,5-tetra-
hydro-lH-3-benzazepine, 2.0 g. o~ acetic anhydride and
20 ml. of pyridine was stirred at room temperature for 3
hours. The mixture was concentrated in vacuo and the
residue washed with 3N hydrochloric acid, then water, to
yield 3-acetyl-6-chloro-2,3,4,5-tetrahydro-lH-3-ben~aze-
pine melting at 64-66. This amide was reduced in ether
with a 50% excess of lithium aluminum hydride at reflux
for 6 hours. Upon decomposition of excess reducing agent,
the reaction mixture was filtered and the ethereal fil-
trate dried over magnesium sulfate. The filtrate was
treated with ethereal hydrogen chloride solution to pre-
cipitate 6-chloro-3-ethyl-~,3,4,5-tetrahydro-lH-3-benzaza-
pine as the hydrochloride salt which melted at 274-275
from absolute alcohol.
3L2~
-16-
1 Example 5
Following the procedure of Example 1 and sub-
stituting 2-[[2-(2-chlorophenyl)ethyl]ethylamino]ethanol
and 2-[[2-(2-chlorophenyl)ethyl]allylamino]ethanol for
2-[[2-(2-chlorophenyl)ethyl]methylamino]ethanol yields the
following respective products: 6-chloro-3-ethyl-2,3,4,5-
tetrahydro-lH-3-benzazepine and 6-chloro-3-allyl-2,3,4,5-
tetrahydro-lH-3-benzazepine.
Example 6
10 Ingredients % W/W
6-Chloro-2,3,4,5-Tetrahydro-3-
Methyl-lH-3-Benzazepine Hydrochloride 2.5 g.
Benzalkonium Chloride 0.02 g.
15 Sodium Bisulfite 0.10 g.
Sterile Sodium Chloride
Solution (0.9%) USP qs 100 ml.
The ingredients are dissolved in the sodium
chloride solution. The solution is sterilized by
filtration and aseptically packaged.
Two drops are instilled in the eye three times a
day.
Exam~le 7
Ingredients % W~W
.
6-Chloro-2,3,4,5-Tetrahydro-
3-Methyl~lH-3-Benzazepine 1.0 g.
Purified White Petrolatum, U.S.P. qs 100.0 g.
Under aseptic conditions, the benzazepine is
thoroughly incorporated in the petrolatum and packaged.
The ointment is applied topically to the eye four
times a day.
Example 8
Ingredient Amounts
6-Chloro-2,3,4,5-tetrahydro-3-methyl-
lH-3-benzazepine hydrochloride 150 mg.
Lactose 350 mg.
' :
~2~ ;5
-17-
1 The ingredients are mixed and filled into a hard
gelatin capsule.
One capsule is administered four times a day.
Example 9
Ingredients Amounts
6-Chloro-2,3,4,5-tetrahydro-3-methyl-
lH-3-benzazepine hydrochloride 200 mg.
Calcium sulfate dihydrate 150 mg.
Sucrose 25 mg.
10 Starch 15 mg.
Talc 5 mg.
Stearic Acid 3 mg.
The calcium sulfate dihydrate, sucrose and the
benzazepine are thoroughly mixed and granulated with 10
gelatin solution. The wet granules are screened, dried
and then mixed with the starch, talc and stearic acid,
screened and compressed into a tablet.
One tablet is administered three times a day.
