Note: Descriptions are shown in the official language in which they were submitted.
~2;25Z~3
This invention provides a series of novel chloro-
and dichlorotetrahydro-1~-2-benzazep;nes which are useful
as inhibitors or norepinephrine N-methyl transferase.
Tetrahyàro-2-benzazepines and tetrahydro-3-
benzazepines are both known in the art. von Braun and
Zobel, Ber. C6, 690, (1923) prepared both compounds as did
Deady, et al., J.C.C., Per.~in Trans 782 (1973) by a different
route. In addition, Deady et al (loc. cit.) prepaxed the
previously unreported 7-methyl derivati~-e of tetrahydro-
lH-2-benzazepine as well as 7-chlorotetrahydro-lH-2-
ben~azepine. No utility was given for any of these products.
According to Kasparek, writing in ~dvances in
Heterocyclic Chemis.ry, Vol. 17, pp. 4~ et seq. (Katritzky
and ~oulton, ed., Academic Press, 1974), 2-benzazepines ~ave
been tested as anti-hypertensives, adrenergic b}ockers, and
choline~terase innibitors. 3-Benzazepines have been tested
as h-ypoglycemics, analgesics, depressants, anorectics, and
ganglionic blocking agents. 1-3enzazepines have also been
found to nave analgesic, antidepressant, anti-fibrillant,
hypotensive, anti-neoplastic, diuretic, hypoglycemic, and
anti-arrhythmic ac~ivities. N-Substituted 'etrahydro-2-
benzazepines have been prepared [see for example, Chemical
.bstracts 74, 53575a tl971); 72, 66776a (1970); and 6~,
59453g (196~)1. Belleau prepared ~ -chloroethyl)-2-
benzazepine as an aaranergic blocking agent ~(~. Med._Pharm.
Chem. 1, 343 (1953)~. TAe compounà blocked epinephrine at ~ ;
a level about 2.5 times lower than did ibenamine.
X-~6~0 -~-
~ ,
~22~2~3
U.S. Patent 3,988,339 disclc es a number of 7-
and/or ~-substituted 1,2,3,4-tetrahydroisoquinolines, use~ul
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 DerCent 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-
~uinolines~
The active pressor principle cf suprarenal extracts
was named epinephrine by ~ble in 1899 and was synthesized
soon thexeafter by Stolz and Dakin. Epinephrine is the
major hormone produced by Ihe adrenal medulla. It is a
potent vasopressor and yields a rapid rise in blood pressure
upon intravenous injection. 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 signiricant 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 eleva~ed permanently or arrhyt~mias
may be inducea. Continued stress over long periods may
xesult in malignant hypertensicn or chronic heart disease.
X-46~0 -3- -`
~12;~5~8
The last stase in ~he biosynthesis or epinephrine
in the mammal is the methylation of the r.eurohumoral trans-
mitter for most sympathetic postganglionic fibers, nore-
pinephrine. The enzyme responsible ror this final synthetic
step is known as norepinephrine N-metnyl transIerase.
Inhibitors of this enzyme (~MT inhibitors) are useful in
~reventing the secretion by the adrenal into the blocd
stream of large quantities of epinephrine during periods of
stress by inhibiting the last step in the rormation of this
compound.
This invention provides novel chlorinated tat-a-
hydro-2-ben~azepines of the for~ula
I n3~
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 a~om
occupies the 3-position; and pharmaceutically-acceptable
acid addition salts the.reo~.
This invention also comprises novel and useful
pharmaceutical compositions valuable ror reducing the forma-
tion o~ epinephrine in a mammal whicn comprise a pharma-
ceutically-acceptable inert carrier and a compound of the
folmula
X-~6~0 -~-
~L~L22Si2~
~ 2 ~
Cl ~
\6~ \a 4/ II
wherein the chlorine atom occupies the 6, 7 or g position:
and pharmaceutically-acceptable acid addition salts thereof.
The compounds of Formulae I and II axe prepared
by reacting a compound of the formula
H H H H H
1~ /~ I I I I I :
t ~-C-!~I-C-C-C-Ha l o
C l ~
n ~ H H H H III
wherein n is as defined aDove, provided that none of the
chlorine atoms occupies a ~osition ortho to the side chain,
with a Friedel~Crafts catalyst of the Lewis acid type or
by reacting a compound of the formula
wherein n is as defined above, with àn azide in the presence
of a strong acid to pr~pare a compound of the formula
/~ / ~'~
C I n~
\~ / V
~l~22~
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 or
preparing a novel chlorinated tetrahydro-2-benzazepine of
the formula
lo ~ ~T, ~ I
wnerein n is l or 2, provided that no~e of the chlorine
atoms occupies the 9-position, that when n is 2, the chlorine
atoms are vicinal, and that, when n is l, 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-C-~C-C-C-Ha l o
2 0 \a~ I I I
wherein n ia 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 -
~lZ2~8
The pharmaceuticaily-acceptable acid addition
salts of compounds useful in the process of this invention
include salts derived from inorganic acids such as hydro-
ch}orlc acid, nitric acid, phosphoric acld, 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, hydroxyalkancic and alkandioic
acids, aromatic acids, aliphatic and aromatic sulfonic
acids, etc. Such pharmaceutically-acceptable salts thus
include sulfate, pyrosulfate, bisul~ate, 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, dinitrobenzoate,
hydroxybenzoate, methoxyben20ate, phthalate, terephthalate,
benzenesulfonate, toluenesulonate, chlorobenzenesulfonate,
xylenesulfonate, phenylacetate, phenylpropionate, phenyl-
butyrate, citrate, lactate, ~-hydroxybutyrate, glycollate,
malate, tartrate, methanesulfonate, propanesulfonate,
naphthalene-l-sulfonate, naphthalene-2-sulfonate and the
likP salts.
X-4680 -6~
~2~;2~
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 ormula III is reacted
with a Friedel-Crafts catalyst of the Lewis acid type,
preferably aluminl~m 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 Lewis 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 alXali
metal azide, or in the form of hydrazoic zcid. Whichever
~orm of the azide is prererred, the reaction of the compound
of formula IV is carried out in the presence o a strong
X-~6~0
3d
1~22~21~
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 nalogenated solvents are
particularly useful. Such halogenated solvents as chloro-
form, dichloromethane, the di~hloroethanes and the chlorinated
be~zenas are particularly useful. The te~perature of the
azide reaction is preferably from 0~C. to the ambient
temperatu-e.
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 a~ents, particularly lithium aluminum
hydride, may also be used. The reduction may be carried out
in any inert solvent, of which tetrahydrofuran is preferred.
Other ir.ert 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., pre~erably at the reflux temperature o 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 tnen cooled, and the cooled solution was diluted
X-46~0 -8-
with one liter of water. The aqueous mixture was made basic
with 2G0 ml. of 5N aqueous sodium hydroxide. 3-~o-~hloro-
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 witk saturated aqueous sodium chloride
solution. The ether e~tract was then dried and the ether
removed by evaporation in vacuo, yieldins a residue con-
sisting of 9% g. of a yellow llquid. Distillation of the
residue yielded 3-(o-chlorobenzylamino)propanol distilling
in th~ range 127-138C. at 0.1 mm/hg. Yield = 83.5 g.
~nalysis; ~alc.: C, 60.15; H, 7.07; N, 7.01; Cl, 17.75;
Found: C, 60.09; H, 7.01; ~, 6.99; Cl, 17.92
32.8 g. of 3-(_-chlorobenzylamino)propanol were
added slowly to 100 ml. of 48 percent aqueous hydrobromic
- acld and kept at about 0C. A 250 ml. round-bottom flas~
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
resldue remaining, containing 3-(o-chlorobenzylamino)propyl
bromide hydrobromide, was cooled. The resulting solid was
dissolved in acetore and the volatile constituents removed
by evaporation in vacuo. This operation was repeated twice
more and the resultirg residue was crystallized from ~00 ml.
of ethyl acetate and methanol to yield 38.76 g. of 3-~o-
chlorobenzylamino)propyl bromide hydrobromide formed in the
above reaction melting at 128-130C.
X-4680 _9_
~1 ~22~
nalysis; 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 --
~2;~21~
Example 1
Preparation of 6,7-dichloro-2,3,4,5-
tetrahydro-1~-2-benzazepine
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 sul uric acid were
added in dropwlse 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
.
3~
-- 11 --
1~2Z5Z~3
been completed and was then poured into an ice-water mixture.
The organic layer was separated and the separated layer
washed with 10 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 consisting 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
îormed in the above reaction. Ten g. OI the reac~ion
mixture containing the isomeric benzazepinones were dis-
solved in chloroform and the chloroform solution chromato-
graphed over 500 g. of silica gel (Woelm activitv 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 20-2~ were
found to contain predominately the 2-benzazepinone isomer.
Tho~e latter fractions were combined and recrystallized from
75 ml. of hot benzene. A yield o 1.422 g. o pure 6,7-
dicnloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one melting at
about 188-190C. was thus obtained.
Analysis; Calc.: C, 52.20; ~, 3.94; N, 6.09; Cl, 30.82;
Found: C, 52.18; d, 3.88; N, 6.00; Cl, 30.65
The structure of the isomer was verified by NMR.
1.30 g. or 6,7-dichloro-2,3,4,~-tetrahydro-lH-
2-benzazepine-3-one were slurried in 20 ml. of tetrahydro-
furan (THF). This suspension was added slowly to 20 ml. or
a 1 molar diborane solution in THF maintained at ambient
temperature. The consequent reaction mixtu_e was rerluxed
for 16 hours under a nitrogen atmos~here and then cooled.
X-4680 -12-
2~3
Excess diborane was destroyed with 2N aqueous hydrochloric
acid. The THF was evaporated and the aqueous residue was
made basic with 5N aqueous sodium hydroxlde and 6,7-
dichloro-2,3,4,5-tetrahydro-lH-2-~enzazepine being insoluble
in the alXaline layer was separated and extracted into
ether. The ether extract was washed with saturated aqueous
sodium chloride and dried. Evaporztion 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-2r3~a~5
tetrahydro-lH-2-benzazepine was formed by dissolving the
crystalline residue in ether and passing gaseous hydrogen
chloride through the _esulting 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.
~nalysis; Calc.: C, 47.55; H, 4.79; N, 5.55; C1, 42.11;
20Found: C, 47.53; H, ~.54; N, 5.48; C1, 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-tetralon~ was reacted with sodium azide in the
presence of sulfuric acid at 10C. to yield a mixtu-e of
7,8-dichloro-2,3,4,5-tetrahydro-1;~-2-benzazepine-3-one and
X-4680 -13-
~22~2~
7~-dichloro-1,~,4,5-tetrahydro-2H-3-benzazepine-2-one. The
isomer mixture was isolated by the procedure of Example 2
and its componerts separated by chromatography over silica
gel (Woelm acti~ity IV) using chloroform to develop the
chromatogram. The percentage of each lsomer 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 recxystallized from 125 ml. of
~enzene. The first fraction weighing 1.25 g. was shown by
NMR to contain 88 percen~ of the desired iSQmer. The second
rraction was obtained from the mo~her liquors and weighed
470 mg. It was shown 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,i-
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
~ollowing the procedure of Example 2, the 2-
ben~a2epine-3-one obtained as above was reduced with diborane
in THF solution. 860 mg. oI 7,8-dichloro-2,3,4,;-tetra-
hydro~lH-2-benzazepine were obtained. ~he free base was
converted to the hydrochloride salt by the procedure of
Example 2 and the salt recrystallized from an isopropanol-
methanol solvent mixture. 7,8-Dichloro-2,3,4,5-tetrahydro-
lH-2-benzazepine hydrochloride thus prepared sublimed at
250C; pKa = 8.4.
X-4680 -14-
~2Z52~
Analysis; Calc.: C, 47.55; H, 4.79; N, 5.55; Cl, 42011;
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-benzazeplne-3-one and
7-chloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one. The
isomer mixture was purified by the procedure of Example 2
- 15 -
~L~Z~2~
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
yielded ~aterial containing more than 80 percent o~ the
desired isomer. The 2-benzazepine-3-one free base was
further recrystallized from the cyclohexane~benzene solvent
mixture eventually yielding crystalline material shown to
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 hydrochloride from isopropanol yielded 1.5 g. of
crystalline material 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, 32.5};
Found: C, 54.95; H, 6.11; N, 6.25; Cl, 32.2b
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 extraCt-
~
X-4680 -16-
'' ~
sz~
with ethyl acetate. The ethyl acetate extract was separated,
washed successivel~ 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, 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-l-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 refluxed 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-
~L2Z5Z8
The dihydronaphthalene residue was mixed with
20 g. of 80 percent purity _-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 carbonate solution and dried.
E~aporation of the solvent yielded 6-chlorooxlrano[a]-2,3-
dihydronaphthzlere formed in the above reaction. The
compound was again used without further purification.
The crude oxirane was dissolved in b~nzene 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,i-tetrahydro-lH-2-benz-
azepine-3-one and 8-chloro-1,3,4,5-tetrahydro-2H-3-benz
azepine-2-one. The isomer mixture was partially separated
by chromatography over Woelm (activity IV) silica gel using
chloroform as an eluant. ~actions shown by ~R to con~ain
predominately the 2-benzazepine-3-one isomer were collected
and combined. ~vaporation of the solvent yielded 4.0 g. of
X-4680 -18-
1~22~i21~
solid which were recrystalliæed from 100 ml. of benzene.
2.93 g. of crystalline material containing predominately the
desired 2-henzazepine-3-one isomer were obtained. Following
the procedure of Example 2, the separated isomer was reduced
with diborane in TH~ 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 mPthod of Example 2. Recrystallization of the
hydrochloride salt from isopropanol yielded 1.88 g. of
108-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride
which sublimed at 260C.; pKa = 8.75.
Analysis; Calc.: C, i5.06; H, 6.01; N, 6.42; Cl, 32.51;
Found: C, 55.29; ~, 5.98; N, 6.23; Cl, 32.46
Example 5 -
Preparation o~ 6-chloro-2,3,4,5-tetra-
hydro-lH-2-benzazepine
Following the procedure of Example 2, 15.9 g. of
;-chloro-2-tetralone were reacted with 7.15 g. of sodium
azide and iO0 mL. of 36N sulfuric acid in 400 ml. of chlorororm
at 5-10C. The mixture was then allowed to warm to ambient
temperature over 30 minutes. The product of this r~action
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 chromatograp~y over silica gel
(Woelm Activity IV) using chloroform as the eluant and
taking ~00 ml. fractions. Fractions 9 and 10 were shown by
~MR to _onsist of 100 percent of the 3-benzazepine-2 one
isomer. Fractions 12-20, shown by ~MR to contain the
X-4680 -19-
Z~iZ8
2-ben~azepine-3-one isomer, were recrystallized from 175 ml.
of benzene. The first fraction was shown by NMR to be 97
percent pure ~-benzazepine-3-one isomer. Recrystallization
of this fraction from 125 ml. of benzene yielded 3.40 g. of
the desired isomer; mp = 18d-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~ 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; ~, 6.58; Cl, 32.24
The rompounds of this invention, either in the
form of the free base, or as a pharmaceutically-acceptable
acid addition salt thereo, are enzyme inhibitors. In
particular, as previously stated, they are inhibitors of
norepinephrine N-me~hyl 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 hypertension, an important aspect of the treatment of
this disease state.
X-4680 -20-
2SZ~
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 ~T was achieved. The negative
reciprocal logarithm (pI50) of this number was also cal-
culated as a useful index. Table 1, which ~ollows, 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-
1~22~ 8
C~ o o ,~
O ~
~n ~D
H
~ ~ O O 1 10 0
~ ~ x x X ~ x
5~
,~ ~r ~ u~ ,1 ,
O o
~ . ':
H
~1 N I I :
Q ~
I _ - 4 4
2 0 o
-- 4 ~ ~ 4 J~ 4
4 a~ 4 0 5~ ~ I O I
8 ~ o ' o , o ~ o
Z In ~1 1~'1 4 m 4
` O ` ~
`~ ` O ' O 4 ~ .4 a) 1 ~;
-~ O '- O ~::
b4 ~ ~4 ~ o ,~ S",,
S ~ S ~ .~ I N
X-~680 -22-
il2~8
The compounds of this invention are used as N~IT
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 ol these salts can be employed for parenteral
administration, with an isotonic solution being particuiarly
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-benzazapine of formula
I or II above. The amount of chlorinated tetrahydro-
2-benzazepine present is about iO-500 mg. per dosage unit.
The compounds are administered to mammals at concentrations
varving from about 1 to about 100 mg./kg. orally per day.
X-~680 -23-
