Note: Descriptions are shown in the official language in which they were submitted.
~llg592
This inventlon provides a series of novel chloro-
and dichlorotetrahydro-lH-2-benzazepines which are useful
as inhibitors of norepinephrine N-methyl transferase.
Tetrahydro-2-benzazepines and tetrahydro-3-
benzazepines are both known in the art. von Braun and
Zobel, Ber. _, 69G, (1923) prepared both compounds as did
Deady, et al., J.C.S., Perkin Trans 782 (1973) by a different
route. In addition, Deady et al (loc. cit.) prepared the
previously unreported 7-methyl derivative of tetrahydro-
lH-2-benzazepine as well as 7-chlorotetrahydro-lH-2-
benzazepine. No utility was given for any of these products.
According to Kasparek, writing in Advances in
Heterocyclic Chemistry, Vol. 17, pp. 45 _ ~. (Katritzky
and Boulton, ed., Academic Press, 1974), 2-benzazepines have
been tested as anti-hypertensives, adrenergic blockers, and
cholinesterase inhibitors. 3-Benzazepines have been tested
as hypoglycemics, analgesics, depressants, anorectics, and
ganglionic blocking agents. l-Benzazepines have also been
found to have analgesic, antidepressant, anti-fibrillant,
hypotensive, anti-neoplastic, diuretic, hypoglycemic, and
anti-arrhythmic activities. N-Substituted tetrahydro-2-
benzazepines have been prepared [see for example, Chemical
Abstracts 74, 53575a (1971); 72, 66776a (1970); and 68,
59453g (1968)]. ~elleau prepared N-(~-chloroethyl)-2-
benzazepine as an adrenergic blocking agent [(J. Med. Pharm.
Chem. 1, 343 (1959)]. The compound blocked epinephrine at
a level about 2.5 times lower than did dibenamine.
X-46~0 _~_
~19S92
U.S. Patent 3,988,3~9 discloses a number of 7-
and/or 8-substituted 1,2,3,4-tetrahydroisoquinolines, useful
as phenylethanolamine N-methyl transferase inhibitors (NMT
inhibitors, also referred to as norepinephrine N-methyl
transferase inhibitors). 7,8-Dichloro-1,2,3,4-tetrahydro-
isoquinoline was said to inhibit NMT by 50 percent at a
concentration of 1.2 x 10 7 molar. U.S. Patent 3,939,164,
the parent of U.S. Patent 3,988,399, discloses a
limited group of 7- and 8-halo-substituted tetrahydroiso-
quinoiines.
The active pressor principle of suprarenal extracts
was named epinephrine by Able in 1899 and was synthesized
soon thereafter by Stolz and Dakin. Epinephrine is the
major hormone produced by the adrenal medulla. It is a
potent vasopressor and yields a rapid rise in blood pressure
upon intravenous in~ection. It constricts the smaller
arterioles and precapillary sphincters as well as veins and
large arteries. Epinephrine is a powerful cardiac stimu-
lant; the compound can also cause cardiac arrhythmias.
Epinephrine is released in significant quantities
into the blood stream during periods of stress. It is this
burst of epinephrine which enables mammals, including
humans, to take immediate evasive action. Continuous stress
and therefore continuous injection of epinephrine into the
blood stream, however, nas a deleterious effect in that
blood pressure may be elevated permanently or arrhythmias
may be induced. Continued stress over long periods may
result in malignant hypertension or chronic heart disease.
X-46~0 -3-
~,,~ ~=, ,),,,
~1959;~
The last stage in the biosynthesis of epinephrinein the mammal is the methylation of the neurohumoral trans-
mitter for most sympathetic postganglionic fibers, nore-
pinephrine. The enzyme responsible for this final synthetic
step is known as norepinephrine N-methyl transferase.
Inhibitors of this enzyme (NMT inhibitors) are useful in
preventing the secretion by the adrenal into the blood
stream of large quantities of epinephrine during periods of
stress by inhibiting the last step in the formation of this
compound.
This invention provides novel chlorinated tetra-
hydro-2-benzazepines of the formula
~/~ j1-2~
\~j \5 ~
wherein n is 1 or 2, provided that when n is 2, the chlorine
atoms are vicinal, and that, when n is 1, the chlorine atom
occupies the 8-position; and pharmaceutically-acceptable
acid addition salts thereof.
This invention also comprises novel and useful
pharmaceutical compositions valuable for reducing the forma-
tion of epinephrine in a mammal which comprise a pharma-
ceutically-acceptable inert carrier and a compound of the
formula
X-4680 -4-
~1~3159Z
Cl - ~ ~
\6~ 4 II
wherein~t~e chlorine atom occupies the 6, 7 or 9 position;
and pharmaceutically-acceptable acid addition salts thereof.
The compounds of Formulae I and II are prepared
by reacting a compound of the formula
H H H H H
1~ /~ IIIII
~-C-N-C-C-C-Ha l o
III
. .
wherein n is as defined a~ove, provided that none of the
chlorine atoms occupies a position ortho to the side chain,
with a Friedel-Crafts catalyst of the Lewis acid type or
by reacting a compound of the formula
C~n~\ ~
. . ~ ,
wherein n is as defined above, with an azide in the presence
of a strong acid to prepare a compound of the formula
V
,~ _ 5 _
~19159Z
and reacting the compound of formula V with a reducing agent;
and if desired recovering the compound of Formula I or II
in the form of a pharmaceutically-acceptable salt.
This invention also comprises a process for
preparing a novel chlorinated tetrahydro-2-benzazepine of
the formula
lo n~\ ~
wherein n is 1 or 2, provided that none of the chlorine
atoms occupies the 9-position, that when n is 2, the chlorine
atoms are vicinal, and that, when n is 1, the chlorine atom
occupies the 8-position; and pharmaceutically-acceptable acid
addition salts thereof; which process is characterized by
reacting a compound of the formula
H H H H H
/~ I I I I I
R t-c-N-c-c-c-Ha l o
\~
wherein n is as defined above, provided that none of the
chlorine atoms occupies a position ortho to the side chain,
with a Friedel-Crafts catalyst of the Lewis acid type.
~ - 5a -
~959;2
The pharmaceutically-acceptable acid addition
. salts of compounds useful in the process of this invention
~ include salts derived from inorganic acids such as hydro-
i chloric acid, nitric acid, phosphoric acid, sulfuric acid,
hydrobromic acid, hydriodic acid, nitrous acid and phos-
phorous acid, as well as salts derived from nontoxic organic
acids such as aliphatic mono and dicarboxylic acids, phenyl-
substituted alkanoic acids, hydroxyalkanoic and alkandioic
acids, aromatic acids, aliphatic and aromatic sulfonic
acids, etc. Such pharmaceutically-acceptable salts thus
include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,
nitrate, phosphate, monohydrogenphosphate, dihydrogenphos-
phate, metaphosphate, pyrophosphate, chloride, bromide,
iodide, acetate, propionate, decanoate, caprylate, acrylate,
formate, isobutyrate, caproate, heptanoate, propiolate,
oxalate, malonate, succinate, suberate, sebacate, fumarate,
maleate, mandelate, butyn-1,4-dioate, hexyn-1,6-dioate,
benzoate, chlorobenzoate, methylbenzoate, dlnitrobenzoate,
hydroxybenzoate, methoxybenzoate, phthalate, terephthalate,
benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate,
xylenesulfonate, phenylacetate, phenylpropionate, phenyl-
butyrate, citrate, lactate, ~-hydroxybutyrate, glycollate,
malate, tartrate, methanesulfonate, propanesulfonate,
naphthalene-l-sulfonate, naphthalene-2-sulfonate and the
like salts.
X-4680 -6-
.~.~
~5~;~
When a starting compound of formula III is used,the halo atom at the end of the side chain is preferably
bromine. The starting compound of formula III is reacted
with a Friedel-Crafts catalyst of the Lewis acid type,
preferably aluminum chloride. Such other metal halides as
aluminum bromide, zinc chloride, boron trifluoride, boron
trichloride, boron tribromide, titanium tetrachloride,
stannic chloride, bismuth trichloride and ferric chloride
are also well known ~ewis acid Friedel-Crafts catalysts and
are useful in the present reaction.
The reaction may be carried out in a solvent or
without one. If a solvent is used, it should be a high-
boiling solvent such as decalin, because the reaction
should be carried out at a high temperature from 100C. to
200C. If aluminum chloride is the catalyst, it is possible
to use no solvent and to carry out the reaction at or above
the fusion temperature.
When the process begins with a starting compound
of formula IV, the first step is to react the starting
compound with an azide. The azide may be supplied in the
form of an azide salt, particularly and preferably an alkali
metal azide, or in the form of hydrazoic acid. Whichever
form of the azide is preferred, the reaction of the compound
of formula IV is carried out in the presence of a strong
X-4680
i - 7
~1~959Z
acid. Sulfuric acid is preferred, but other typical strong
acids such as phosphoric acid and trifluoroacetic acid may
also be used. The reaction of the starting compound of
Formula IV with an azide is carried out in a solvent which
is inert to the reactants. The halogenated solvents are
particularly useful. Such halogenated solvents as chloro-
form, dichloromethane, the dichloroethanes and the chlorinated
benzenes are particularly useful. The temperature of the
azide reaction is preferably from 0C. to the ambient
temperature.
The intermediate compound of Formula V is then
reduced to prepare the compound of Formulae I or II. The
preferred reducing agent is diborane (B2H6). Other typical
effective reducing agents, particularly lithium aluminum
hydride, may also be used. The reduction may be carried out
in any inert solvent, of which tetrahydrofuran is preferred.
Other inert solvents, such as diethyl ether and 1,2-dimethoxy-
ethane may also be effectively used. The reduction is best
carried out at a temperature from the ambient temperature to
100C., preferably at the reflux temperature of the reaction
mixture.
Preparation 1
A solution was prepared from 90 g. of o-chloro-
benzyl chloride in 200 ml. of 3-aminopropanol. The solution
immediately became hot, and external heating was applied
slowly until reflux temperature was reached. The reaction
mixture was then cooled, and the cooled solution was diluted
X-4680 -8-
~lg592
with one liter of water. The aqueous mixture was made basic
with 200 ml. of 5N aqueous sodium hydroxide. 3~ Chloro-
benzylamino)propanol formed in the above reaction, being
insoluble in aqueous base, separated and was extracted into
ether. The ether extract was separated, washed twice with
water and once with saturated aqueous sodium chloride
solution. The ether extract was then dried and the ether
removed by evaporation in vacuo, yielding a residue con-
sisting of 98 g. of a yellow liquid. Distillation of the
residue yielded 3-(_-chlorobenzylamino)propanol distilling
in the range 127-138C. at 0.1 mm/hg. Yield = 83.5 g.
Analysis; Calc.: C, 60.15; H, 7.07; N, 7.01; Cl, 17.75;
Found: C, 60.09; H, 7.01; N, 6.99; Cl, 17.92
32.8 g. of 3-(o-chlorobenzylamino)propanol were
added slowly to 100 ml. of 48 percent aqueous hydrobromic
acid and kept at about 0C. A 250 ml. round-bottom flask
fitted with a mechanical stirrer and a distillation head was
used as a reaction vessel. After the addition had been
completed, the reaction mixture was heated to refluxing
temperature and then to a temperature of about 127C. in
order to remove constant boiling hydrobromic acid. The
residue remaining, containing 3-(_-chlorobenzylamino)propyl
bromide hydrobromide, was cooled. The resulting solid was
dissolved in acetone and the volatile constituents removed
by evaporation in vacuo. This operation was repeated twice
more and the resulting residue was crystallized from 400 ml.
of ethyl acetate and methanol to yield 38.76 g. of 3-(_-
chlorobenzylamino)propyl bromide hydrobromide formed in the
above reaction melting at 128-130C.
X-4680 _9_
~9592
Analysis; Calc.: C, 34.97; H, 4.11; N, 4.08; Cl, 10.32;
Br, 46.12;
Found: C, 34.76; H, 3.94; N, 3.99; Cl, 10.12;
Br, 46.41
~ - 10 - .
3 119592
Example 1
Preparation of 6,7-dichloro-2,3,4,5-
tetrahydro-lH-2-benzaæepine
A solution of 10.1 g. of 5,6-dichloro-2-tetralone
in 200 ml. of chloroform was prepared. 3.57 g. of sodium
azide were added while the reaction mixture was being cooled
to about 15C. 50 ml. of 36N aqueous sulfuric acid were
added in dropwise fashion while maintaining the temperature
in the range 15-20C. The reaction mixture was stirred for
an additional 15 minutes after the addition of the acid had
3Q
-- 11 --
~lg~92
been completed and was then poured into an ice-water mixture.
The organic layer was separated and the separated layer
washed with lO percent aqueous sodium carbonate and saturated
aqueous sodium chloride. After drying, evaporation of the
volatile constituents from the organic layer yielded 10.42 g.
of a greenish oil consi5ting of a 50:50 mixture of 6,7-
dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one and
6,7-dichloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one
formed in the above reacti~n. Ten g. of the reaction
mixture containing the isomeric benzazepinones were dis-
solved in chloroform and the chloroform solution chromato-
graphed over 500 g. of silica gel (Woelm activity IV). The
chromatogram was developed with chloroform; 500 ml. fractions
were taken. Fractions 17-18 were found to contain 100
percent of the 3-benzazepinone and fractions 20-25 were
found to contain predominately the 2-benzazepinone isomer.
Those latter fractions were combined and recrystallized from
75 ml. of hot benzene. A yield of 1.422 g. of pure 6,7-
dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one melting at
about 188-190C. was thus obtained.
Analysis; Calc.: C, 52.20; H, 3.94; N, 6.09; Cl, 30.82;
Found: C, 52.18; H, 3.88; N, 6.00; Cl, 30.65
The structure of the isomer was verified by NMR.
1.30 g. of 6,7-dichloro-2,3,4,5-tetrahydro-lH-
2-benzazepine-3-one were slurried in 20 ml. of tetrahydro-
furan (THF~. This suspension was added slowly to 20 ml. of
a 1 molar diborane solution in THF maintained at ambient
temperature. The consequent reaction mixture was refluxed
for 16 hours under a nitrogen atmosphere and then cooled.
X-4680 -12-
1592
Excess diborane was destroyed with 2N aqueous hydrochloric
acid. The THF was evaporated and the aqueous residue was
made basic with 5~ aqueous sodium hydroxide and 6,7-
dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine being insoluble
in the alkaline layer was separated and extracted into
ether. The ether extract was washed with saturated aqueous
sodium chloride and dried. Evaporation of the ether yielded
1.21 g. of a clear oily residue of 6,7-dichloro-2,3,4,5-
tetrahydro-lH-2-benzazepine which crystallized upon standing.
10The hydrochloride salt of 6,7-dichloro-2,3,4,5-
tetrahydro-lH-2-benzazepine was formed by dissolving the
crystalline residue in ether and passing gaseous hydrogen
chloride through the resulting solution. The hydrochloride
salt, being insoluble in ether, separated and was collected
by filtration. Recrystallization of the filter cake from a
1:3 ethyl acetate/isopropanol solvent mixture yielded
1.12 g. of 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine
hydrochloride melting at 231-233C.
Analysis; Calc.: C, 47.55; H, 4.79; N, 5.55; Cl, 42.11;
20Found: C, 47.53; H, 4.54; N, 5.48; Cl, 41.85
Example 2
Preparation of 7,8-dichloro-2,3,4,5-tetra-
hydro-lH-2-benzazepine
Following the procedure of Example 2, 6,7-
dichloro-2-tetralone was reacted with sodium azide in the
presence of sulfuric acid at 10C. to yield a mixture of
7,8-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one and
X-4680 -13-
959Z
7~-dichloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one. The
~- isomer mixture was isolated by the procedure of Example 2
and i~ components separated by chromatography over silica
gel (Woelm activity IV) using chloroform to develop the
chromatogram. The percentage of each isomer in fractions
shown to contain the compounds was determined by NMR.
Fractions containing predominately the 2-benzazepine-3-one
isomer (weight 2.4 g.) were recrystallized from 125 ml. of
benzene. The first fraction weighing 1.25 g. was shown by
NMR to contain 88 percent of the desired isomer. The second
fraction was obtained from the mother liquors and weighed
470 mg. It was æhown to contain 85 percent of the desired
isomer. Further recrystallization of these combined fractions
from benzene yielded 1.258 g. of 7,8-dichloro-2,3,4,5-
tetrahydro-lH-2-benzazepine-3-one melting at 199-204C.
shown to be 97 percent pure of the desired isomer by NMR.
Analysis; Calc.: C, 52.20; H, 3.94; N, 6.09; Cl, 30.82;
Found: C, 52.10; H, 3.73; N, 6.37: Cl, 30.74
Following the pro~edure of Example 2, the 2-
benzazepine-3-one obtained as above was reduced with diborane
in THF solution. 860 mg. of 7,8-dichloro-2,3,4,5-tetra-
hydro-lH-2-benzazepine were obtained. The free base was
converted to the hydrochloride salt by the procedure o~
Example 2 and the salt recrystallized from an isopropanol-
methanol solvent mixture. 7,8-Dichloro-2,3,4,5-tetrahydro-
lH-2-benzazepine hydrochlorid~ thu8 prepared sublimed at
250C; pKa = 8 ~.
X-~680 -14-
~19592
Analysis; Calc.: C, 47.55; ~, 4.79; N, 5.55; Cl, 42.11;
Found: C, 47.73; H, 4.58; N, 5.80; Cl, 42.08
Example 3
Preparation of 7-chloro-2,3,4,5-tetrahydro-
lH-2-benzazepine
Following the procedure of Example 2, 22.6 g. of
6-chloro-2-tetralone was reacted with sodium azide in the
presence of sulfuric acid at 15C. to yield a mixture of
7-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one and
lQ 7-chloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one. The
isomer mixture was purified by the procedure of Example 2
- 15 -
, ,
592
~and chromatographed over Woelm activity IV silica gel using
a chloroform-benzene mixture and pure chloroform as eluants.
Fractions shown to be rich in the 2-benzazepine-3-one isomer
by NMR were collected and recrystallized from a 3:1 benzene/
cyclohexane solvent mixture. The first recrystallization
yieldçd m~terial,containing more than 80 percent of the
desired isomer. The 2-benzazepine-3-one free base was
further recrystallized from the cyclohexane/benzene solvent
mixture e~entually yielding crystalline material shown to
~10 contain in excess of 95 percent of the desired isomer by
NMR.
The,7-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine-
3-one was reduced with diborane in THF according to the
procedure of Example 2. 7-Chloro-2,3,4,5-tetrahydro-lH-
2-benzazepine,thus prepared was purified and converted to
the hydrochloride salt by the procedure of Example 2. Re-
crystallization of 7-chloro-2,3,4,5-tetrahydro-lH-2-benz-
azepine hyd,rochloride from isopropanol yielded 1.5 g. of
crystalline matçrial melting at 246-249C. which was shown
by,NMR to be a pure isomer; pka 8.8.
Analysis; Calc.: C, 55.06; H, 6.01; N, 6.42; Cl, 32.51;
Found: C, 54.95; H, 6.11; N, 6.25; Cl, 32.28
Preparation 2
39.8 Grams of 4-(_-chlorophenyl)butyric acid were
heated with 500 g. of polyphosphoric acid at 100C. for 4
hours, The reaction mixture was poured over ice and 7-
chloro-l-tetralone formed in the above reaction was extracted
X-4680 -16-
~llg~2
with ethyl acetate. The ethyl acetate extract was separated,
washed successively with water, 10 percent sodium carbonate
and saturated aqueous sodium chloride and then dried.
Evaporation of the solvent yielded a yellow solid residue
comprising 7-chloro~l-tetralone. The compound melted at
94-96C. after recrystallization from hexane.
Analysis; Calc.: C, 66.49; H, 5.02; Cl, 19.63;
Found: C, 66.30; H, 4.89; Cl, 19.65
16 Grams of 7-chloro-1-tetralone were added to a
slurry of 7.8 g. of sodium borohydride in 250 ml. of anhydrous
ethanol at about 0C. The reaction mixture was stirred at
ambient temperature for about 20 hours r and was worked up in
standard fashion to yield 16 g. of 7-chloro-1-tetralol.
Infrared spectrum showed an absence of peaks attributable to
a carbonyl function indicating the reduction to the tetralol
was substantially complete.
16 Grams of 7-chloro-1-tetralol were dissolved in
250 ml. of benzene and the solution placed in a 500 ml.
round-bottom flask fitted with Dean-Stark evaporator and
condenser. 1.0 g. of _-toluene sulfonic acid was added and
the reaction mixture was reflu~ed overnight. 1.8 ml. of
water were collected indicating that the dehydration reaction
to form 7-chloro-3,4-dihydronaphthalene had proceeded to
completion. The reaction mixture was cooled, and the
benzene layer washed twice with 10 percent aqueous sodium
bicarbonate and once with saturated aqueous sodium chloride.
The benzene layer was dried and the benzene removed by
evaporation in vacuo. The dihydronaphthalene derivative
remaining as a residue was used without purification.
X-4680 -17-
3S92
The dihydronaphthalene residue was mixed with
20 g. of 80 percent purity m-chloroperbenzoic acid in
250 ml. of chloroform at 0C. The reaction mixture was
stirred at about 30C. for 18 hours, and then washed twice
with 10 percent sodium car~onate solution and dried.
Evaporation of the solvent yielded 6-chlorooxirano[a]-2,3-
dihydronaphthalene formed in the above reaction. The
compound was again used without further purification.
The crude oxirane was dissolved in benzene and the
solution was cooled to 0C. and then saturated with
anhydrous boron trifluoride. The reaction mixture was
stirred at ambient temperature for 1.5 hrs.; 19.3 g. of
7-chloro-2-tetralone were formed and were obtained as a
residual dark pale liquid after a standard purification
procedure.
Example 4
Preparation of 8-chloro-2,3,4,5-tetra-
hydro-lH-2-benzazepine
Following the procedure of Example 2, 14.3 g. of
7-chloro-2-tetralone were reacted with sodium azide in the
presence of sulfuric acid at 5-10C. to yield 13.25 g. of a
50-50 mixture of 8-chloro-2,3,4,5-tetrahydro-lH-2-benz-
azepine-3-one and 8-chloro-1,3,4,5-tetrahydro-2H-3-benz-
azepine-2-one. The icomer mixture was partially separated
by chromatography over Woelm (activity IV) silica gel using
chloroform as an eluant. Fractions shown by NMR to contain
predominately the 2-benzazepine-3-one isomer were collected
and combined. Evaporation of the solvent yielded 4.0 g. of
X-4680 -18-
'.~
~1~9S92
solid which were recrystallized from 100 ml. of benzene.
2.g3 g. of crystalline material containing predominately the
desired 2-benzazepine-3-one isomer were obtained. Following
the procedure of Example 2, the separated isomer was reduced
with diborane in THF to yield 8-chloro-2,3,4,5-tetrahydro-
lH-2-benzazepine. The product was isolated and purified and
the purified free base converted to the hydrochloride salt
by the method of Example 2. Recrystallization of the
hydrochloride salt from isopropanol yielded 1.88 g. of
8-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride
which sublimed at 260C.; pKa = 8.75.
Analysis; Calc.: C, 55.06; H, 6.01; N, 6.42; Cl, 32.51;
Found: C, 55.29; H, 5.98; N, 6.23; C1, 32.46
Example 5
Preparation of 6-chloro-2,3,4,5-tetra-
hydro-lH-2-benzazepine
Following the procedure of Example 2, 15.9 g. of
5-chloro-2-tetralone were reacted with 7.15 g. of sodium
azide and 100 ml. of 36N sulfuric acid in 400 ml. of chloroform
at 5-10C. The mixture was then allowed to warm to ambient
temperature o~er 30 minutes. The product of this reaction
was shown by NMR to consist of equal amounts of 6-chloro-
2,3,4,5-tetrahydro-lH-2-benzazepine-3-one and 6-chloro-
1,3,4,5-tetrahydro-2H-3-benzazepine-2-one. The isomer
mixture was separated by chromatography over silica gel
(Woelm Activity IV) using chloroform as the eluant and
taking 500 ml. fractions. Fractions 9 and 10 were shown by
NMR to consist of 100 percent of the 3-benzazepine-2-one
isomer. Fractions 12-20, shown by NMR to contain the
X-4680 -19-
lll~S92
2-benzazepine~3-one isomer, were recrystallized from 175 ml.
of benzene. The first fraction was shown by NMR to be 97
percent pure 2-benzazepine-3-one isomer. Recrystallization
of this fraction from 125 ml. of benzene yielded 3.40 g. of
the desired isomer; mp = 184-187C.; shown by NMR to be 100
percent pure.
Analysis; Calc.: C, 61.39; H, 5.15; N, 7.16; Cl, 18~12;
Found: C, 61.35; H, 5.23; N, 7.19; Cl, 17.99
Reduction of the 6-chloro-2,3,4,5-tetrahydro-lH-
2-benzazepine-3-one with diborane by the procedure of Example
2 yielded 6-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine which
was purified as the hydrochloride salt; mp = 235-8C. pKa =
8.75.
Analysis; Calc.: C, 55.06; H, 6.01; N, 6.42; Cl, 32.51;
Found: C, 54.84; H, 5.98; N, 6.58; Cl, 32.24
The compounds of this invention, either in the
form of the free base, or as a pharmaceutically-acceptable
acid addition salt thereof, are enzyme inhibitors. In
particular, as previously stated, they are inhibitors of
norepinephrine N-methyl transferase ~NMT or phenethanol-
amine N-methyl transferase--see Axelod, J. Bio. Chem. 237,
1657 (1962)]. Compounds which inhibit the conversion of
norepinephrine to epinephrine are capable of lowering a high
epinephrine-norepinephrine ratio in mammals, a physiological
condition frequently associated with essential hypertension.
The compounds of this invention are thus capable of ameli-
orating the epinephrine-norepinephrine imbalance in essen-
tial hypert~nsion, an important aspect of the treatment of
this disease state.
X-4680 -20-
gZ
The effectiveness of the compounds as N-methyl
transferase inhibitors has been measured in vitro using NMT
from rabbit adrenals. By using a series of decreasing
concentrations of the inhibiting amine, usually starting
with 1 x 10 4M continuing with 3 x 10 5M, 1 x 10 5M, etc.,
it was possible to determine a concentration at which
the 50 percent inhibition of NMT was achieved. The negative
reciprocal logarithm (pI50) of this number was also cal-
culated as a useful index. Table 1, which follows, summarizes
the information thus obtained; i.e., the determination of
enzyme inhibition activity for the compounds of this invention.
In the table, column 1 gives the name of the compound,
column 2, the concentration at which 50 percent inhibition
of NMT is obtained and column 3, the pI50.
X-4680 -21-
`~
59Z
,,~ o o ,1
o a ~9 ~ ~ co
~D, In ~ o~ D
L~
o
In
~ ~ ~o ~o , ~o ~o
10 a) ~ ,, ~ o ~ ~1
O X X, X ,~.. ..
o O I ,~
- .4
H
I I ~ ,
~ I ~ O O
o o o ,~ ~
~ ~ ~ o ~ o I o I o
n~ ~ S O ~ ~.C ~.C
~J ~ ~ o
Z ~ In ~ h n~l
` O `~
~,~ ~ a) ~
.C ~ O ~ O
O ~ I ~ ~ ~ Q
O ~ O N O N I rl N ~1 N
..C ~ ,.C N ,5 N I I N I N
I ~
~ Q r~ ~
X-4680 -22-
....,. ~
I
~1~95~Z
The compounds of this invention are used as NMT
inhibitors, preferably in the form of an acid addition salt.
These salts can be mixed with one or more standard pharma-
ceutical excipients and loaded into empty telescoping
gelatin capsules or compressed into tablets. Aqueous
solutions of these salts can be employed for parenteral
administration, with an isotonic solution being particularly
adapted for IV use. The compounds can be administered in
dosage unit form for oral administration comprising an
amount effective to inhibit epinephrine N-methyl transferase
comprising a pharmaceutical carrier and as the active
ingredient a chlorinated tetrahydro-2-benzazepine of formula
I or II above. The amount of chlorinated tetrahydro-
2-benzazepine present is about 50-500 mg. per dosage unit.
The compounds are administered to mammals at concentrations
varying from about 1 to about 100 mg./kg. orally per day.
X-4680 -23-
959;~:
SUPPLEMENTARY DISCLOSURE
Further investigations into the processes
of making chlorinated tetrahydro-2-benzazepines
according to the invention have confirmed that all
compounds of the invention can be produced by reacting
a suitable compound of the formula
\ ~ \./ IV
with an azide in the presence of a strong acid to prepare
a compound of the formula
Cln~ I ~
v
and reacting the compound of formula V with a reducing
agent, as described previously. However, it has also
been found that nqt all the compounds of the invention ~ -
can be produded in any significant amount by reacting
a compound of the formula
H H H H H
~!-C-~C-C-C-Ha l o
\~ III
with a Friedel-Crarts catalyst.
When compounds of formula III which have
a chlorine atom in ortho-position to the side chain
are reacted with a Friedel-crafts catalyst none or very
- SD 24 -
`` ~119S92
little 9-chloro- or 8,9-dichloro-2,3,4,5-tetrahydro-
lH-2-benzazepine are produced. It appears that the
presence of the ortho-chloro substituent in compounds
of formula III activates a molecular rearrangement
in which the halogen moiety, which preferably is a
bromine moiety, of the benzylaminopropylhalogenide
starting material is moved one carbon atom down the
chain, thus forming the corresponding 8-chloro- or
7,~-dichloro-4-methyl-1,2,3,4-tetrahydroiso~uinoline.
Compounds of formula III which have no
chlorine atom in ortho-position to the side chain
will form, when reacted with a Friedel-Crafts catalyst
according to the process of the invention, chlorinated
tetrahydro-2-benzazepines.
This invention then, in a further aspect, provides
a process for preparing a novel chlorinated tetrahydro-2-
benzazepine of the formula
Cl
`1'~ ' ~
i7
and pharmaceutically-acceptable acid addition salts
thereof. The process is characterized by reacting a compound
of the formula
Cl / ~
~ IV
\ ,,' \~/
~herein n is as defined above, with an azide in the
presence of a stron~ acid to prepare a compound of the
formula
~ r ,~
- SD 25 -
111~5~Z
Cl
Cl ~ --~ H
Il I . >~ V~
and reacting the compound of formula V' with a reducing
agent; and if desired recovering the compound of Formula I'
in the form of a pharmaceutically-acceptable salt.
This invention further provides the novel compound
8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine and its pharm-
aceutically acceptable acid addition salts.
The invention is further illustrated by the follow-
ing examples.
Example 6
Preparation of 9-chloro-2,3,4,5-tetrahydro-
lH-2-benzazepine
In a 500 ml. three-neck, round-bottom flask equipped
with magnetic stirrer, drying tube, thermometer, and addition
funnel were placed 15 g. of 8-chloro-2-tetralone, 6 g. of
sodium azide and 200 ml. of chloroform. The reaction mixture
was cooled to about 15C. 50 Milliliters of 18N sulfuric acid
were added thereto in dropwise fashion while keeping the temper-
ature of the reaction between 15 and 20C. After the sulfuric
acid had all been added, the reaction mixture was stirred at
room temperature for two hours. It was then poured into a
mixture of ice and water. The chloroform layer was separated
and the aqueous layer extracted three times with chloroform.
The chloroform ex~racts were combined and the combined extracts
washed with both 10 percent aqueous sodium carbonate and satur-
ated aqueous sodium chloride and were then dried. Evaporation
of the chloroform in vacuo yielded 16.4 g. of a solid com-
30 prising a mixture of 9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepin-
3-one and the corresponding 3-benzazepine-2-one isomer. Six
- SD26 -
1119~92
recrystallizations from toluene yielded 3.23 g~ of 9-chloro-
2,3,4,5-tetrahydro-lH-2-benzazepin-3-one substantially free of
its 3-benzazepin-2-one isomer. The compound melted at about
197-199C.
Analysis: Calc.: C, 61.39; H, 5.15; N, 7.16;
Cl, 18.12
Found: C, 61.53; H, 5.09; N, 7.40;
CL, 18.37
Following the procedure of Example 2 following,
3.3 g. of 9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepin-3-one
were reduced with diborane in tetrahydrofuran (THF) solution to
yield 9-chloro-2,3,4,5-lH-2-benzazepine. 2.95 Grams of base
were obtained following the purification procedure of Example 2.
The free base was converted to the corresponding hydrochloride
salt which melted at about 244-246C. with decomposition
after recrystallization from a 95:5 ethyl acetatemethanol
solvent mixture; yield = about 2.2 g.
Analysis' Calc.: C, 55.06; H, 6.01; N, 6.42;
Cl, 32.51
Found: C, 54.75; H, 5.74; N, 9.46;
Cl, 32.68
Alternatively, the mixture of 9-chloro-2,3,4,5-
tetrahydro-lH-2-benzazepin-3-one and its 3-benzazepine-2-one
isomer can be reduced with diborane in THF to a mixture of
the corresponding benzazepines. This isomer mixture can be
readily separated via high pressure liquid chromatography with
better yields than are found by crystallization of the
benzazepinones from toluene. The HPLC system employed was
a waters prep. l.c. system 500 with one silica 500 prep pack
cartridge. The solvent used was an 8 1 gradient, consisting of
4 1 100% CHC13 and 4 1 of 98% CHC13-2% MeOH with 20 ml 14 N
NH40H. Thirty 250 ml fractions were collected at a flow rate
~ - SD27 -
~19SgZ
of 250 ml/min. The effluent was monitored by absorbance at
280 mm.
Example 7
Preparation of 8,9-Dichloro-2,3,4,5-
Tetrahydro-lH-2-benzacepine
In a 4 liter beaker equipped with mechanical
stirrer were placed 370 ml. of 12N aqueous hydrochloric acid.
162 Grams of 2,3-dichloroaniline were added with stirring.
The solution of the hydrochloride salt thus formed was cooled
to about 0C. with an ice bath. Next, a solution of 73 g. of
sodium nitrite in 200 ml. of water was added while maintaining
the temperature below about 5C. After all of the sodium
nitrite solution had been added, the diazotization reaction
was stirred for an additional 45 minutes by which time all of
the aniline hydrochloride had dissolved. The diazonium chloride
solution was then neutralized by the addition of solid sodium
carbonate. During the addition, the reaction temperature
was maintained below about 5C. The reaction mixture foamed
and, from the solution upon reaching neutrality, a precipitate
separated. About 150 g. of sodium carbonate were used.
While the diazotization reaction was being carried
out, in a separate 4 1. beaker equipped with mechanical
stirrer were placed 138 g. of 90 percent cuprous chloride in
750 ml. of water. 160 Grams of sodium cyanide were added.
The reaction temperature rose to about 70C. The reaction mix-
ture containing cuprous cyanide thus formed was cooled to room
temperature.
Next, the cuprous cyanide solution was cooled
to about 0C. and 500 ml. of toluene were added thereto.
The neutral diazonium solution formed as above was added
slowly to the cuprous cyanide solution with vigorous stirring
while maintaining the temperature below about 5C. by adding
- -SD28-
ll~g59Z
ice to the reaction mixture as needed. The reaction tempera-
ture was maintained in the range 0 to 5C. for about 30
minutes. After all of the diazonium carbonate solution had
been added, the reaction temperature was allowed to warm to
room temperature overnight. The reaction mixture was then
heated to about 50C. and was then cooled. The reaction mixture
was extracted three times with toluene, the toluene extracts
were combined and insoluble material removed therefrom by
filtration. The combined toluene extracts were washed twice
with water and once with saturated aqueous sodium chloride solu-
tion, and were then dried. The solvent was removed therefrom
in vacuo. Distillation of the residue in vacuo yielded 2,3-
dichlorophenylcyanide formed in the above reaction boiling in
the range 108-116C. at 7 torr; weight = 98.8 g. 2,3-Dichloro-
phenylcyanide thus prepared was crystallized from hexane to
yield 87 g. of a white crystalline material melting at 59-60C.
~nalysis Calc~: C, 48.88; H, 1.76; N, 8.14;
Cl, 41.72
Found: C, 48.65; H, 1.83; N, 8.28;
Cl, 42.04(41.94)
One mole of methyl magnesium bromide in ethyl
ether was placed in a 2 1., three-necked, round-bottom flask
equipped with magnetic stirrer, condenser, calcium sulfate
drying tube, and addition funnel under a nitrogen atmosphere.
87 Grams of 2,3-dichlorophenylcyanide were dissolved in 210
ml. of tetrahydrofuran. This solution was added in dropwise
fashion to the methyl Grignard reagent at a rate such as to
maintain gentle reflux of the ether. Reflux 2 hrs. after addi-
tion was complete. The reaction mixture refluxed for 2 hrs.
after the addition had been completed and was then cooled and
poured into 400 ml. of a mixture of ice and 12N aqueous
hydrochloric acid. The acidic reaction mixture was allowed to
- SD29-
111~59Z
remain a~ room temperature overnight after which time it was
extracted three times with ether. The ether extracts were
combined and the combined extracts washed with water, 10 percent
aqueous sodium carbonate and saturated aqueous sodium chloride.
The ether solution was dried and the solvent removed from the
dried solution in vacuo. 96 Grams of a reddish oil, constituting
2,3-dichloroacetophenone remained as a residue in the flask.
Distillation of the residue yielded about 88.9 g. of 2,3-di-
chloroacetophenone boiling in the range 77-84C. at .05 torr.
Next, 2,3-dichloroacetophenone was transformed to the
corresponding phenyl acetic acid via a Willgerodt reaction as
follows: 26.6 g. of 2,3-dichloroacetophenone were placed in a
200 ml., round-bottom flask equipped with magnetic stirrer,
condenser, and drying tube. 10 Grams of sulfur were added plus
27.5 ml. of morpholine. The reaction mixture was heated in an
oil bath to about 130C. overnight and was then cooled. The
cooled mixture was poured into a mixture of toluene and water.
This consequent mixture was stirred until most of the solid
material had dissolved. The mixture was then filtered through
super cel to remove remaining insoluble matter. The toluene
layer was separated and the aqueous layer extracted twice more
with toluene. The toluene layers were combined and the combined
layers washed with water followed by a saturated aqueous sodium
chloride wash. The toluene solution was dried and the toluene
removed by evaporation in vacuo. 33.2 Grams of a solid compris-
ing N-(2,3-dichlorophenylthioacetyl)morpholine were obtained.
This solid was refluxed overnight with a 15 percent aqueous
potassium hydroxide solution (88 g. of 85 percent KOH plus 500
ml. of water). The hydrolysis mixture was cooled and the cool-
ed mixture extracted 3 times with ether. These ether extractswere discarded. The alkaline aqueous layer was then made acidic
by the addition of 2N aqueous hydrGchloric acid. The acidic
:~ 7'
-SD30-
,
1119592
layer was extracted 3 times with ether. The ether extracts were
combined and the combined extracts washed with satura~ed aqueous
sodium chloride. The ether extracts were dried and the ether
removed therefrom by evaporation in vacuo. The residue weighing
about 13.6 g. comprised 2,3-dichlorophenylacetic acid formed in
the above reaction. The acid was recrystallized from water after
decolorization with carbon. 6.4 Grams of 2,3-dichlorophenylacetic
acid melting at about 126-128C were obtained.
In a 500 ml., round-bottom flask equipped with magnetic
stirrer, condenser, and drying tube were placed 14.156 g. of 2,
3-dichlorophenylacetic acid and 200 ml. of carbon tetrachloride.
To this solution were added in dropwise fashion 29.5 ml. of oxalyl
chloride. The reaction mixture was heated to refluxing tempera-
ture for about 3 hours after which time it was cooled. Excess
oxalyl chloride and carbon tetrachloride were removed by evapora-
tion in vacuo. Distillation of the residue at 6 torr. yielded
12.8 g. of 2,3-dichlorophenylacetylchloride formed in the above
reaction boiling at 126-127C.
A mixture of 15.2g. of anhydrous aluminum chloride
and 200 ml. of methylene dichloride was placed in a 500 ml. four-
neck, round-bottom flask equipped with magnetic stirrer, drying
tube, thermometer, addition funnel, and sintered glass ethylene
inlet under a nitrogen atmosphere. The mixture was cooled to
about 5C. 12.8 Grams of 2,3-dichlorophenylacetylchloride in
50 ml. of methylenedichloride were added thereto in dropwise
fashion while keeping the temperature below 5C. After the
addition had been completed, ethylene was bubbled into the reac-
tion mixture while still maintaining the temperature below about
10C. The stream of ethylene was bubbled in slowly for a period
of about 6 hours. The reaction mixture was then stirred over-
night at room temperature after which time it was poured onto
ice. The methylenedichloride layer was separated and the aqueous
-SD31-
1~1959Z
mixture extracted twice more with methylenedichloride. The
methylenedichloride extracts were combined and the combined ex-
tracts washed with saturated aqueous sodium chloride solution and
dried. Evaporation of the methylenedichloride yield as a residue
24.7 g. of an oil comprising 7,8-dichloro-~-tetralone formed in
the above reaction. The residual oil solidified on cooling and
was recrystallized from ether to yield 6.67 g. of the dichloro-
tetralone melting at about 68-70C.
In a 500 ml., three-neck, round bottom flask equipped
with magnetic stirrer, drying tube, thermometer, and addition
funnel were placed 13.7 g. of 7,8-dichloro-2-tetralone, 4,6 g.
sodium azide and 200 ml. of chloroform. The reaction mixture
was cooled to about 15C. and 50 ml. of 18N sulfuric acid were
added thereto in dropwise fashion, while keeping the reaction
temperature between 15 and 20C. After the addition of the
sulfuric acid had been completed, the reaction mixture was
stirred at room temperature for an additional two hours, after
which time it was poured onto ice. The chloroform layer was
separated and the aqueous mixture extracted three more times
with chloroform. The chloroform extracts were combined and the
combined extracts washed with 10 percent aqueous sodium carbonate
and saturated aqueous sodium chloride solution and were then
dried. Evaporation of the chloroform in vacuo yielded as a
residue 14.4 g. of a mixture of 8,9-dichloro-3-benzazepin-2-one
and 8,9-dichloro-2-benzazepin-3-one. The desired 2-benzazepin-
3-one isomer was obtained by recrystallization from toluene. A
five-fold recrystallization yielded pure 8,9-dichloro-2-
benzazepin-3-one melting at about 192-194C; yield = 1.8 g.
Thin layer chromatography indicated that none of the 8,9-di-
chloro-3-benzazepin-2-one was present.
Analysis; Calc.: C, 52.20; H, 3.94; N, 6.09
Found: C, 52.45; H, 4.06; N, 5.94
-SD32-
ll:l9S~;2
Following the procedure of Example 2, 1.7 g. of 8,9-
dichloro-2-benzazepin-3-one were reduced with 23 ml. of a lM
diborane ~olution in THF. 8,9-Dichloro-2,3,4,5-tetrahydro-lH-
2-benzazepine formed in the above reaction was purified by the
procedure of Example 2 and was obtained as a white solid melting
at about 61-63C.; yield = 1.667 g.
The corresponding hydrochloride salt was prepared in
ether. Recrystallization of the ether-insoluble precipitate
from a mixture of isopropanol and methanol (90:10) yielded
1.237 g. of 8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine
hydrochloride melting 259-261C.
Analysis; Calc.: C, 47.55; H, 4.79; N, 5.55;
Cl, 42.11
Found: C, 47.79; H, 5.03; N, 5.65;
Cl, 42.21
- SD 32a -
~gS9Z
The compounds of the invention including
the 9-chloro and 8,9-chloro compounds are, as previously
stated, inhibitors of norepinephrine N-methyl transferase
(NMT). The effectiveness of 9-chloro- and 8,9-dichloro-
2,3,4,5-tetrahydro-lH-2-benzazepine and their
pharmaceutically acceptable acid addition salts have
been measured in the same way as described above.
Table 2, which follows, summarizes the results.
In the table, column 1 gives the name of the compound,
column 2, the concentration at which 50% inhibition
of NMT is obtained and column 3, pI50.
Table 2
i
Name 50~ Inhibitory pI50
Concentration
9-Chloro-2,3,4,5-tetrahydro-
lH-2-benzazepine maleate 1.0 x 10 6 5.98
2.0 x 10 6 5.70*
8,9-dichloro-2,3,4,5-
tetrahydro-lH-2-benzazepine 7
hydrochloride 1.5 x 10 6.81
7.8 x 10 8 7.11*
* - NMT from rat brain
As previously stated, the compounds are
preferably administered in the form of an acid addition
salt mixed with 1 or more standard pharmaceutical
excipients.
-~ - SD 33
