Note: Descriptions are shown in the official language in which they were submitted.
334
1 This invention comprises a new group of chemical compounds
which are l-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepines having three
substituents on the benz-ring of the nucleus, one of which is pre-
ferably a 6-lower alkylthio group. The compounds have utility as
~- 5 dopaminergic agents with pronounced activity at central nervous
system receptors.
Exemplary of the compounds of this invention are those
represented by the following structural formula:
; 10 R
HO
HO ~ -R
3 3 R2
I
in which:
R and R3 are hydrogen, lower alkylthio of 1-5 carbon atoms.' ~0
or trifluoromethylthio, at least one of R and R3 being a group
other than hydrogen;
Rl is hydrogen, lower alkyl of 1-5 carbons, hydroxyethyl,
lower alkenyl of 3-5 carbons, benzyl, phenethyl, carbobenzoxy
or lower al~anoyl of 1-5 carbons; and
~5
R2 is hydrogen, halo such as fluoro, chloro, bromo or iodo,
trifluoromethyl, methyl, methoxy or hydroxy.
. The compounds in which Rl is benzyl, phenethyl, carbobenzoxy
or lower alkanoyl or the higher alkoxy or acyloxy containing compounds
` are of utility particularly for intermediate use in the preparation of
other more active compounds.
- 2 -
` -- lt~O33~,
Also included in this invention are the S-oxidized
derivatives of the compounds of Formula I that is the 6 or 9-lower
alkylsulfonyl, lower alkylsulfinyl, trifluoromethylsulfonyl, tri-
fluoromethylsulfinyl or dimethylsulfonium halide containing compounds.
These are the compounds defined in Formula I in which at least one of
R and R3 is a methyl or trifluoromethyl sulfoxide or sulfonyl group
together with the sulfonium derivatives (those in which R or R3 are
-(CH3)2S02X where X is a pharmaceutically acceptable anion such as
chloride, bromide, iodide, tosylate or mesylate).
- 10 A subgeneric group of compounts with within the above illustrative
group are those of Formula I in which R is methylthio or trifluoro-
methylthio, Rl and R3 are hydrogen. In this group individual compounds
of note are those in which R2 is hydrogen, chloro, methyl, trifluoro-
methyl, methoxy or hydroxy. The 9-methylthio containing compounds
while less potent than the 6-methylthio compounds have fewer side effects.
2he 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,
bismethylenesalicylic, 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. Similarly the quarternary salts including the
sulfonium derivatives as defined above include those prepared from
organic halides such as lower alkyl halides, for example, methyl
bromide, methyl iodide, ethyl iodide, benzyl chloride, as well as
methyl tosylate or mesylate and the like.
,''- -
.. -- 3 --
L J
`; - ~
33'~
. .
1 Certain l-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepines havebeen described in U.S. Patent 3,393,192; 3,795,683; British Patent
Specification 1,118,688; and Swiss Patent 555,831, including general
methods of preparation. However these references disclose no benz-
` 5 trisubstituted compounds of the type here claimed, no 6-methylthio
substituted compounds of any kind and no advantage to such 6-methylthio
substitution in the structures. These references do disclose 7,8-
dihydroxy substltuted-l-phenyl-3-benzazepines and various intermediates
therefor, some of which serve a~ starting materials for preparing the
compounds of this invention.
It will be obvious to one skilled in the art that the compounds
of Formula I may be present as diastereo isomers which may be resolved
into t or 1 optical isomers. Resolution of the optical isomers may be
conveniently accomplished by factional crystallization of their salts
with optically active acids from appropriate solvents. Unless otherwise
specified herein or in the claims, it is intended to include all isomers,
whether separated or mixtures thereof. Wherc iso~ers are separated, the
desired pharmacological activity will often predominate in one of the
isomers usually in the d-isomer.
The compound~ of Formula I contain as one skilled in the
art will recognize two functional hydroxy groups at positions 7 and 8
which may be optionally converted to the lower alkoxy derlvatives of
1-5 carbons in each alkoxy group such as methoxy, ethoxy, butoxy or
isoamyloxy or the lower alkanoyloxy derivatives of 2-5 carbons such as
O-acetyl, O-propionyl or O-valeryl. The dimethoxy or diacetoxy
derivatives are most useful but are of somewhat lower level of general
; biological activity. The diacyloxy derivatives in general have sub-
stantial oral activity.
The lower alkyl or lower alkanoyl derivatives of the compounds
of Formula I are prepared by alkylation-acylation methods which are
- 4 -
. .
.
)33'.~
1 conventional to the art. One skilled in the art, however, would
recognize that the use of lower alkyl halides as alkylating agents,
- for example, in addition to O-alkylation would also form the lower
alkylsulfonium halides at the sulfur atom during the alkylation.
For example, the dimethylsulfonium bromide would form during reaction
with methyl bromide. These sulfonium salts can optionally be re-
converted to the parent thio compound without affecting the O-alkyl
groups by conventional methods such as heating in 1 N hydrobromic
acid, in brine or another source of bromide or chloride ions.
The compounds of Formula I may be prepared by the cyclization
reactions described in U.S. Patent No. 3,393,192 using as starting
` materials an appropriate 2-lower alkylthio-3,4-dimethoxyphenethylamine `~
or the corresponding phenethylaminomethylbenzyl alcohol. The N-
substituted derivatives of Formula I may also be prepared using the
appropriate tertiary amino alcohol in the cyclization reaction. A
preferred method of preparation, however, is to reac~ a 7,8-dione of
the formula:
. .
. o~--~
O ~ N-Rl .
,, `I
'
¦ ~ R
.' ~
II
with the deslred mercaptan (RSH) in a suitable inert organic solvent
. such as an alcoholic solvent, methanol or ethanol, at about room
,- temperature to give a compound of the following structure:
.'
-- 5 --
,. .
. .
33~
R
` HO
HO ~ j -R
- I ~ 2
~/ - ,
- III
In the addition reaction no~ed above the 9-isomer is also
obtained, however, the mixture is easily separated into the 6 and 9-
` isomers by methods described hereafter. Also the mixture of mono-
sub~tituted isomers can be alternatively used to prepare the 6,9-
disubstituted congeners as described immediately hereafter.
A second lower alkylthio substituent can optionally be
introduced into the 9-position by oxidation of III (or into 6 via
the 9-isomer) with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone followed
by reactlon once more with the desired mercaptan. In the intermediates
. .
` of Formulas II and III, R, Rl and R2 are as defined for compounds of
Formula I.
The important 7,8-dialkoxy derivatives are also conventiently
prepared by reacting a 6-lithium derivative corresponding to Formula I
:~ (R - Li) with the appropriate lower alkyl or trifluoromethyldisulfide
in an inert organic solvent in which the reactants are soluble such
as ether or tetrahydrofuran at ambient or elevated temperature under
anhydrous conditions. The important 7,8-dimethoxy derivatives may be
optionally prepared by reaction of the 7,8-dihydroxy congener with
~, diazomethane. Of course the dialkoxy derivaeives are also convenientlyprepared by the conventional cyclization reaction mentioned above.
The sulfonyl derivatives of the co~pounds of Formula I
[I in which R and/or R3 are lower alkyl or trifluoromethyl sulfonyl
-- 6
)33~
1 ~alkS02- or CF3S02-)] are prepared by oxidizing the corresponding
sulfide optionally protectet at the N or 3-position by an inert group
such as trifluoroacetyl or carbobenzoxy using a sulfonyl producing
oxidizing agent such as excess hydrogen peroxide, m-chloroperbenzoic
acid, peracetic acid or perbenzoic acid. The 6-sulfinyl derivatives
of the compounds of Formula I ~I in which R and/or R3 are lower alkyl
or trifluoromethyl sulfinyl (alkS0- or CF3S~)] are prepared using a
sulfoxide producing oxidizing agent such as sodium periodate usually
in neutral solution or one equivalent of hydrogen peroxide or
0 m-chloroperbenzoic acid at low temperatures.
. The compounds of Formula I, their lower alkyl ethers or
esters and their nontoxic pharmaceutically acceptable addition salts
have a novel dopaminergic effect. It is well known that dopaminergic
compounds have a dual effect on dopamine receptors in the central
nervous system notably tha brain as well as on peripheral dopamine
receptors such as tho~e affecting the peripheral cardiovascular system.
;.-
The latter effect results in increased renal blood flow with
~ a resulting hypotensive effect. It is often measured by admlnistering
; the compound by infusion i.v. lncrementally at five minute intervals
to the anesthetized normotensive dog with measurement of various
cardiovascular parameters. The effect on renal vasculator resistance
; can be calculated from any change in renal blood flow and arterial
blood pressure. The effect is quantified as an ED15 values which is
; the cumulative dose which produces a 15% decrease in renal vascular
i 8.P. in mm/Hg.
resi~tance (R = B.F. ml/min. ).
, _ .
; The 6-lower alkylthio containing benzazepine compounds of
Formula I especially have antiparkinsonism activity due to central
~, dopaminergic activity as demonstrated by employing a modified standard
animal pharmacological test procedure reported by Ungerstedt et al.,
- 30 in Brain Research 24, 1970, 485-493. This procedure is based on a drug
- 7 -
,
3~4
induced rotation of rats having extensive unilateral lesions of
the substantia nigra. Briefly, the test comprises the quantitative
recording of rotational behavior in rats in which 6-hydroxydopamine
lesions of the nigrostriatal dopamine system have been produced.
A unilaterial brain lesion in the left substantia nigra causes the
dopamine receptor in the left caudate to become hypersensitive
following the resulting degeneration of the nigral cell bodies.
These lesions destroy the source of the neutrotransmitter dopamine
in the caudate but leave the caudate cell bodies and their dopamine
receptors intact. Activation of these receptors by drugs which
produce contralateral rotation, with respect to the lesioned side
of the brain, is used as a measure of central dopaminergic acti~ity
of the drug.
Compounds which are known to be clinically effective in
controlling parkinsonism, such as, for example, L-dopa and apomorphine,
are also effective in this rate turning model. These compounds
directly activate the dopamine receptors and cause contralateral
rotation of the le~ioned rat.
Rotational activity is defined as the ability of a compound
to produce 500 contralateral rotations during a two-hour period after
administration, usually intraperitoneally. The dose corresponding
to 500 contralateral rotations per two hours is obtained and assigned ~
a9 the RD500 value.
~ The unexpected nature of the biological spectrum of the
- 25 dopaminergic compounds of Formula I is a shift from activity at
peripheral receptors to central activity. For example, 7-8-dihydroxy-
6-methylthio-l-phenyl-2,3,4,5-tetrahydro-3-lH-benzazepine hydrobromide
has an RD500 of 0.18 t0.06-0.29) mg/Kg [0.14 mg/Kg base] which is 8
times more potent than is its 6-hydrogen analog with a faster onset
and longer duration of activity. The ED15 of this compound is 372
- 8 -
)33~
1 which is 10 times less potent than the 6-hydrogen analog. 7,8-
Dihydroxy-9-methylthio-1-phenyl-2,3,4,5-tetrahydro-3-lH-benzazepine
hydrobromide has an RD500 of 4.8 mg/Kg [3.8 base] which is 3 times
more potent than the 6-hydrogen analog. The higher alkylthio, i.e.
those other than methylthio as well as the 6,9-disubstituted congeners
were less potent in the rotation test than the preferred methylthio
- containing compounds.
The pharmaceutical compositions of this invention having
dopaminergic activity are prepared in conventional dosage unit forms
0 by incorporating a compound of Formula I, an isomer or a pharmaceuti-
cally acceptable acid addition salt thereof, with a nontoxic pharma-
. ceutical carrier according to accepted procedures in a nontoxic amount
sufficient to produce the desired pharmacodynamic activity in a subject,
animal or human. Preferably the composition will contain the active
ingredient in an active but nontoxic amount selected from about 2.5 mg
to about 1000 mg of active ingredient per dosage unit but this quantity
depends on the specific biological activity desired and the conditions
of patient. The most desirable object of the compositions and methods
is in the treatment of Parkinson's disease to ameliorate or prevent
i''20 the attacks common with patients suffering from this central nervous
' system abnormality.
The pharmaceutical carrier employed may be, for example,
either a solid or liquid. Exemplary of solid carriers are lactose,
terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium
. .
~5 stearate, stearic acid, and the like. Exemplary of liquid carriers --
are syrup, peanut oil, olive oil, water and the like. Similarly the
. .
,~ carrier or diluent may include any time delay material well known to
, .
the art, such as glyceryl monostearate or glyceryl distearate alone
or with a wax.
_ g _
33~
A wide variety of pharmaceutical forms can be employed.
Thus, if a solid carrier is used the preparation can be tableted,
placed in a hard gelatin capsule in powder or pellet form, or in
the form of a troche or lozenge. The amount of solid carrier will
vary widely but preferably will be from about 25 mg to about 1 g.
If a liquid carrier is used, the preparation will be in the form of
a syrup, emulsion, soft gelatin capsule, sterile injectable liquid
such as an ampul, or an aqueous or nonaqueous liquid suspension.
The pharmaceutical preparations are made following the
conventional techniques of the pharmaceutical chemist involving
mixing, granulating and compressing when necessary, or variously
mixing and dissolving the ingredients as appropriate to give the
desiret end product.
The method of producing dopaminergic activity in accordance
with this invention as described above comprises administering in-
ternally to a sub~ect in need of such activity a compound of Formula I
or a pharmaceutically acceptable acid addition salt thereof, usually
combined with a pharmaceutical carrier, in a nontoxic amount sufficient
to produce said activity as described above. The route of adminis-
tration may be any route which effectively transports the active
compouud to the dopamine receptors which are to be stimulated such as
orally or parenterally, the oral route being preferred. Advantageously,
equal doses will be administered several times such as two or three
times a day with the daily dosage regimen being selected from about
~5 150 mg. to about 1.5 g. When the method described above is carried --
out anti-parkinsonism activity is produced with a minimum of side
effects.
The following examples are designed to teach those skilled
in the art the preparation and use of the invention. Other modifi-
cations of the synthetic procedures and of the structural variations
-- 10 --
. .
. :
()33~
1 possible will be obvious beyond the teaching of the examples. All
temperatures are in degrees Centigrade.
; EXAMPLE 1
To a suspension of 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-
lH-3-benzazepine hydrobromide (34 g, .lOl mole, U.S. Patent No.
3,393,192) in methanol (275 ml) was added a solution of 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (25.2 g, .111 mole) in methanol (125 ml).
The addition was carriad out rapidly with stirring at 0 under an
argon atmosphere. After stlrring at 0 for 1 hour the reaction mixture
was filtered and the orange precipitate was washed with cold meth&nol
(75 ml), ethyl acetate (100 ml) and then diethyl ether (100 ml). After
~, drying at room temperature under vacuum, l-phenyl-2,3,4,5-tetrahydro-
-:~ lH-3-benzazepine-7,8-dione hydrobromide (32.8 g, 0.98 mole, 97%) was
obtained, mp 164-165 (dec.).
Anal. Calc'd for C16H15N02 HBr 1/4H20 C, 56-34;
Found: C, 55.02; H, 4.76; N, 4.01.
Into a stirred suspension of l-phenyl-2,3,4,5-tetrahydro-lH-
- 3-benzazepine-7,8-dione (5 g, ;015 mole,generated from the salt above)
in methanol (150 ml) was rapidly bubbled an excess of methyl mercaptan.
The orange quinone quickly dissolved to give a pale yellow solution
~ which was evaporatet to a residue (5.5 g) which was a mixture of 7,8-
$~ dihydroxy-6-methylthio and 9-methylthio-1-phenyl-2,3~4,5-tetrahydro-lH-
3-benzazepine hydrobromides. The 9-isomer could be directly crystallized
by dissolving the residue in mathanol and diluting to the cloud point
with ethyl acetate; however, this material (2.2 g) contained a small
amount of the 6-isomer. A more efficient separation was achieved by
; chromatography on silica gel. A mixture of the isomers (3.3 g) was
dissolved in 3.2 ml of methanol and diluted to 80 ml with chloroform.
This solution was applied to a silica gel column (100 g, 4.5 x 15 cm)
and eluted with a linear gradient composed of chloroform containing an
'''
., -- 11 --
.
,:
''
3033~
1 increasing concentration of methanol (1000 ml, 5~ to 20% methanol).
The 6-isomer was elutet first followed by a mixture of 6- and 9-
isomers and then the 9-isomer. Fractions containing the pure 6-
isomer were combined and evaporated to a residue (1.4 g) which was
crystallized from ethanol-ethyl acetate to give 0.64 g (.0017 mole,
11%), mp 258 (dec.).
Anal. Calc'd for C17HlgN02S HBr: C, 53.41; H, 5.27; N, 3-66;
Found: C, 53.41; H, 5.10; N, 3.55; S, 8.64.
- Fractions containing the pure 9-isomer were evaporated to a residue
.' 10
and combined with the 2.2 g obtained by direct crystallization. Re-
crystallization from methanol-ethyl acetate gave the pure 9-isomer
tl-25 g, .0034 mole, 22%), mp 270 (dec.).
Anal. Calc~d for C17HlgN02S ~Br: C, 53.41; H, 5-27; N, 3-66;
; 15 Found: C, 53.15; ~, 5.33; N, 3.58; S, 8.24.
EXAMPLE 2
PreParation of 6- and 9-lower alkylthio-7,8-dihydroxy-2,3,4,5-
tetrahYdro-l-phenyl-3-lH-benzazepines
A 1 1. 3-necked, round bottom flask was equipped with a
magnetic stirrer, argon gas inlet and outlet tubes, and a powder
addition funnel. The outlet tube was arranged so the exit gas
bubbled through a solution of sotium hypochlorite (CLOROX~) to
remove entrained mercaptan. To a stirred solution of 3-3.7 ml
(0.041-0.07 moles) of the appropriate alkylmercaptan in 300 ml
of methanol was added 10 grams (0.03 moles) of 1-phenyl-7,8-dione-
2,3,4,5-tetrahydro-3-lH-benzazepine hydrobromide by means of the
powder addition funnel. Addition was carried out in portions at
such a rate that the initial intensity brick red color of the solution
. changed ~o light orange before each subsequent addition. This process
` normally takes about 10 minutes to complete. The resulting yellowish
- 12 -
' :
. . .
. " .
334
solution was stirred for an addltional 15-30 minutes and was then
evaporated under reduced pressure. The oily residue was chromato-
graphed on silica gel, the products being eluted with a gradient of
- 5-15% methanol in chloroform. The ratio of 6- and 9-isomers is about
1:2 and the 6-isomer is eluted first. However, repeated chromatography
is usually necessary in order to obtain a complete separation. Thus,
although the crude yield is quite high, the isolated yields of pure
isomers are relatively low.
The melting points, analytical values and isolated yields of
o the separated isomers as the hydrobromide salts are tabulated below.
Compounds m.p. Calcd.Found Yield
9-n-BuS- 191-2 C 56.6056.42 14.9%
H 6.18 6.31
N 3.30 3.22
6-n-BuS~ 197 C 56.6056.94 9.6%
H 6.18 6.29
N 3.30 3.45
9-i-PrS- 245-6 C 55.0754.72 25.6%
H 5.95 5.79
N 3.38 3.30
6-i-PrS 269-70 C 55.6155.38 18.7%
H 5.89 6.16
N 3.41 3.34
9-EtS- 287C(d) C 54.5554.32 13.4%
H 5.59 5.71
N 3.53 3.20
6-EtS- 215-7(d) C 54.4454.42 15.1%
X 5.59 5.72
; N 3.53 3.21
A mixture of 10 g. of trifluoromethyldisulfide, a stoichio-
metric quantity of dithioerythritol in methanol is allowed to stand at
~5 room temperature until the reaction is complete. The mixture is then
used as the source of trifluoromethylthio in the general procedure
outlined above to protuce 6-trifluoromethylthio-i,8-dihydroxy-1-phenyl-
2,3,4,5-tetrahydro~3-lH-benzazepine hydrobromide.
The bases of the noted salts are obtained by shaking each
~0 salt in a bicarbonate-methylene dichloride mixture, separating the
- 13 -
, .
334
1 organic layer and evaporating the tried organic extract in vacuo.
EXAMPLE 3
A 3.7 g (0.0145 mole) sample of 7,8-dihydroxy-1-phenyl-
2,3,4,5-tetrahydro-lH-3-benzazepine free base was slurried in 25 ml.
of acetone and 0.07 g (.016 mole, 10% excess) of ethylene oxide was
added and the mixture placed in a pressure bottle and stirred at
- ambien~ temperature for ca. 40 hours. The reaction mixture was
heated to 60-80 for thirty minutes, cooled and filtered. Concen-
tration of the filtrate gave 4.5 g of crystalline solid. This was
taken up in ethyl acetate, reprecipitated by the addition of ether
and converted to its hydrochloride salt by solution in ethanol, addition ~`
of ethereal hydrogen chloride and precipitation of the salt by additional
ether to give 3.0 g (yield 60~) on drying. Recrystallization from ~-
ethanol-ether gave 1.9 g (yield 38%), mp 136-137 of 7,8-dihydroxy-3-
~; 15 (2-hydroxyethyl)-1-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydro-
chloride.
The 2-hydroxyethyl compound (1.5 g) is reacted with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone in methanol as in Example 1 to
give 3-(2-hydroxyethyl)-1-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine-
7,8-dione hydrobromide. The (1 g) is reacted w~th methylmercaptan in
methanol as in Example 1 to give 6-methylthio-7,8-dihydroxy-3-(2-
hydroxyethyl)-l-phenyl-2,3,4,5-tetrahydro-1~-3-benzazepine hydrobromide.
EXAMPLE 4
A 25 g (0.0874 mole) quantity of 2-methoxy-2-(m-trifluoro-
methylphenyl)ethyl bromide (U.S. Patent 3,226,440) and 75 ml. of
2-(3,4-dimethoxyphenyl)ethylamine were heated at 90-95 for two hours
with stirring under nitrogen. Cooling caused crystallization of
21.3 g of 2-(3,4-dimethoxyphenyl)-ethylamine hydrobromide. This was
filtered and the filtrate fractionally distilled under vacuum. The
fraction boiling at 207-232C. (1.3-2.0 mm) was collected and the
- - 14 -
-
,~ : . , " . : `
033~
1 hydrochloride salt formed in ether. This was recrystallized from
acetonitrile/ether to give 14.5 g (40% yield) of N-[2-methoxy-2-
(m-trifluoromethylphenyl)ethyl]-N-2-(3',4'-dimethoxyphenyl)-ethylamine
hydrochloride, m.p. 157-160.
A 1.0 g (0.00238 mole) sample of this material was added to
20 ml 48% hydrobromic acid and the mixture heated at reflux for one
hour with stirring under nitrogen. The solution was cooled, con-
centrated to dryness under reduced pressure and the residue triturated
with ether to give 1.0 g of crystalline solid (yield, 89%). This was
recrystallized from ethanol/ether to give 7,8-dihydroxy-1-(m-trifluoro-
methylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine hydrobromide of mp
153 (forms glass).
The base (1 g) is reacted with 2,3-dichloro-5,6-dicyano-1,4-
- benzoquinone in methanol to give the dione which (0.5 g) is reacted
with methyl mercaptan to give 6-methylthio-7,8-dihydroxy-1-(m-trifluoro-
methylphenyl)-2,3,4,5-tetrahydro-1~-3-benzazepine hyarobromide.
EXAMPLE 5
Sodium hydride (57Z) (4.84 g., 0.115 mole) previously washed
with hexane was stirred with dry dimethylsulfoxide (70 ml) at 65-70
for 2 hours under argon. The mixture was tilutet with dry T~F (70 ml),
cooled to -5 and trimethylsulfonium iodide (23.5 g, 0.115 mole)
in 100 ml of dry DMS0 was added over a period of 3 minutes. After
stirring for one minute o-tolualdehyde (11.5 g, 0.0926 mole) was added
at a moderate rate whlle keeping the reaction mixture at 0 to -5.
The mixture was stirred at 0 for 5 minutes and at room temperature
for 1 hour, diluted with 500 ml of ice water and extracted three times
with ether. The ether solution was washed with saturated sodium
;-- chloride, dried with sodium sulfate and evaporated to an oil which was
distilled under reduced pressure (~ .25-.50 mm) to give 10.25 g (83Z)
of o-methylstyrene oxide as a clear liquid (b.p. 35-38).
- 15 -
:
:,
33~
1 Homoveratrylamine (13.6 g, 0.0753 mole) and o-methylstyrene
oxide (10.1 g, 0.0753 mole) were stirred at 100 under argon for 16
hours and then diluted with benzene and hexane and cooled in ice.
The solid which precipitated was filtered and recrystallized from
benzene-hexane to give 8.6 g (36%) of 2-methyl--[N-(3,4-dimethoxy-
phenethyl)aminomethyl]benzyl alcohol, mp 91-94.
2-Methyl--~N-(3,4-dimethoxyphenethyl)aminomethyl~-benzyl -
alcohol, (8.5 g, 0.0269 mole), was refluxed in 48% HBr (58 ml) for
2 hours under argon. After cooling the product was filtered off and
recrystallized once from ethanol-ethyl acetate to give 6.7 g (69%)
of 1-(2-methylphenyl)-7,8-dihydroxy-2,3,4,5-tetrahydro-lH-3-benzazepine
hydrobromide which analyzed for a 1/2 hydrate, mp 232-233C.
This compound (5 g) is oxidized using the 1,4-benzoquinone
as in Example 1 to give 1-(2-methylphenyl)-2,3,4,5-tetrahydro-lH-3-
benzazepine-7,8-dione which (2 g) is reacted with methylmercaptan
in methanol to give 6-methylehio-7,8-dihydroxy-1-(2-methylphenyl)-
2,3,4,5-tetrahydro-lH-3-benzazepine hydrobromide.
Using m-methylstyrene oxide gives the 7,8-dihydroxy compound
(mp 108-110), the 7,8-dione and finally 6-methylthio-7,8-dihydroxy-1-
(3-methylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine hydrobromide.
Using m-methoxystyrene oxide gives the 7,8-dihydroxy-m-
hydroxyphenyl compound tmp 285 as the hydrobromide), the 7,8-dione
and finally 6-methylthio-7,8-tihydroxy-1-(3-hydroxyphenyl)-2,3,4,5-
tetrahydro-lH-3-benzazepine.
Using ~-chlorostyrene oxide gives the 7,8-dihydroxy ~
(mp 156-164), the dione and finally 6-methylthio-7,8-dihydroxy-1-
(p-chlorophenyl)-2,3,45-tetrahydro-lH-3-benzazepine hydrobromide.
Using p-trifluoromethylstyrene oxide gives the 7,8-dihydroxy,
the dione and finally 6-methylthio-7,8-dihydroxy-l-(p-trifluorometh
phenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine hydrobromide.
- 16 -
`" 1(~033~
::`
`~ EXAMPLE 6
l A 3.3 g tO.019 mole) quantity of 7,8-dihydroxy-1-phenyl-
:~ 2,3,4,5-tetrahydro-lH-3-benzazepine tfree base) was slurried in 40
ml of dry acetone ant 4.0 g of anhydrous potassium carbonate was
added. The mixture was stirred under nitrogen, a small amount of
ascorbic acid was added as antioxidant and the mixture chilled to 0
and 1.57 g (0.0129 mole) of allyl bromide was added. The mixture
was stirred two to three hours in the cold and allowed to warm to
- ambient temperature and stir an additional twelve hours. The
` mixture was then heated to reflux for thirty minutes and cooled,
poured into water and extracted with three portions of ethyl acetate.
Concentration of the combined extracts gave 2.7 g of solid (71% crude
yield). This was taken up in boiling ether and the solution allowed
to stand for several hours. Filtration removed a small amount of
precipitate and ethereal hydrogen chloride was then added to the
filtrate to precipitate the hydrochloride salt which was isolated as
an amorphous but non-hygroscopic solid, 2.0 g on filtration and
drying. Trituration of the solid with hot ethyl acetate followed by
recrystallization from ethanol-ethyl acetate gave 0.85 g of crystalline
.~
3-allyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine
hydrochloride, mp 232-234 (dec.).
This compound is reacted with quinone to give the 7,8-
dione then with methylmercaptan in methanol to give 3-allyl-6-
methylthio-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine.
Substituting the 3-methyl, 3-butyl (mp 231-234 as the
hydrobromide) and 3-benzyl compounds gives 3-methyl-6-methylthio-7,8-
dihydroxy-l-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine, 3-butyl-6-
methylthio-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine
and 3-benzyl-6-methylthio-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-
lH-3-benzazepine substituting phenethyl bromide gives the 3-phenethyl-
6-methylthio compound.
.,
:
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()33~
. .
EXA~PLE 7
6-Methylthio-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-
lH-3-benzazepine (5 g) is oxidized with 2,3-dichloro-4,5-dicyano-1,4-
benzoquinone in methanol at room temperature as in Example 1 to give
6-methylthio-1-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine-7,8-dione
which (1 g) is reacted with methylmercaptan in methanol to give
6,9-dimethylthio-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine.
EXAMPLE_8 ~- -
7,8-Dimethoxy-l-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine
(280 g, 0.75 mole) was d~ssolved in 1700 cc of acetic acid. Bromine
(280 g, 1.75 mole) was added in a thin stream. The reaction was
stirred for two hours. The precipitate, which formed after 1 hour,
was collected and washed wlth ether. It was dissolved in boiling
methanol and acetone was added to destroy the bromine excess.
6-Bromo-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine
hydrobromide was allowed to crystallize from the methanol and a
second crop was obtained by adding ether to the mother liquor. Yield
298 g, 77% m.p. 236-238%. Thi~ bromination may be applied to any
:,; .
7,8-dialkoxy or alkanoyloxybenzazepine having a free 6-position.
The hydrobromide was shaken in a mixture of excess 10%
sodium hytroxide and methylene chloride. The organic layer was
separatet, dried and evaporated to give a solid base which was
crystallized from toluene-hexane; m.p. 125-128, yield 238 g (97%).
6-Bromo-7,8-dimethoxy-1-phenyl-3-trifluoro-acetyl-2,3,4,5- ~ -
tetrahydro-lH-3-benzazepine (5 g, prepared by reaction of trifluoro-
acetic anhydride in be~zene on the N-hydrogen compound prepared
: above3 is reacted with an excess of butyl lithium in ether at -78 ~-
to give the 6-lithium salt-3-~rifluoroacetylbutyl-lithium adduct.
This intermediate is reacted without isolation with an excess of
dimethyldisulfide in ether at reflux overnight. After hydrolysis
- 18 -
~)9()334
..
with water, 6-methylthio-7,8-dimethoxy-I-phenyl-2,3,4,5-tetrahydro-
lH-3-benzazepine is obtained. Other disulfides especially di(tri-
- fluoromethyl)disulfide may be substituted as well as other N-alkylated
or N-acylated benzazepines.
EXA~PLE 9
2-(2-Methylthio-3,4-dimethoxyphenyl)-ethylamine was prepared
from 2-chloroveratraldehyde [L.C. ~aiford and R.P. Perry, J. Org.
Chem., 7, 354 (1942)] by first forming the ethylene acetal (from
ethylene glycol with acid catalysis and azeotropic removal of water)
0 and then the Grignard reagent (magnesium and dibromoethane in
refluxing benzene) which was reacted with dimethyldisulfide in
refluxing benzene. Hydrolysis of the acetal (refluxing aqueous acetic
acid) gave 2-methylthioveratraldehyde which was condensed with
nitromethane and then reduced with lithium aluminum hydride to
; 15 give the desired phenethylamine.
2-(2-Methylthio-3,4-dimethoxyphenyl)ethylamine (26 g)
is heated to 115 in an oil bath. Styrene oxide (14.4 g) is
added and the reaction is heated for 1 hour. After cooling, to
.. ~
` ~30, hexane-ethyl acetate is used to produce N-~(2-hydroxy-2-
phenylethyl)]-N-[2-(2'-methylthio-3',4'-dimethoxyphenyl)ethyl]amine.
;~ The methylthio containing hydroxyphenethylamine (15 g)
is dissolved in a 2:1 mixture of acetic acid/conc. hydrochloric acid.
The reaction is refluxed 2 hours. After cooling most of the volatiles
are stripped off and the residue is poured into water. It is made
basic with 50% sodiu~ bicarbonate and extracted with ethyl acetate --
twice; The extracts are washed with brine, dried and evaporated
to give 6-methylthio-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-
lH-3-benzazepine.
.', . . `
-- 19 --
"
()33~
1 EXA~PLE 10
7,8-Dihydroxy-6-methylthio-1-phenyl-2,3,4,5-tetrahydro-
lH~3-benzazepine (5.0 g) is suspended in 50 ml of benzene. Tri-
fluoroacetic anhydride (15 g) is added dropwise rapidly. The
solution is stirred an additional hour and then the volatiles are
stripped off, leaving the ~,0,0-tris-trifluoroacetyl derivatives.
This is added directly to 50 ml of methanol and hydrogen chloride
gas is bubbled in for a few minutes. The reaction is stirred for
2 hours and the solvent stripped off, leaving a residue of 7,8- -
o dihydroxy-6-methylthio-1-phenyl-3-trifluoroacetyl-2,3,4,5-tetrahydro-
lH-3-benzazepine.
The N-trifluoroacetyldihydroxy compound (3 g) is reacted -
with an excess of methyl iodide in the presence of sodium carbonate
in aqueous ethanol at room temperature. The crude 7,8-dimethoxy-
6-dimethyl sulfonium iodide is isolated by evaporation then heated
-~ at reflux in brine solution for 2 hours. The folatiles are
, .~ . .
evaporated and the residue recrystallized to give 7,8-dimethoxy-6-
methylthio-l-phenyl-3-trifluoroacetyl-2,3,4,5-tetrahydro-lH-3-
benzazepine. The N-acyl group is removed by treatment with 5%
.... .
sodium hydroxide in aqueous methanol at room temperature to give
7,8-dimethoxy-6-methylthio-1-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine.
EXAMPLE 11
. 7,8-Dihydroxy-6-methylthio-1-phenyl-2,3,4,5-tetra-lH-3-
benzazepine hydrobromide (5 g) is dissolvet in trifluoroacetic acid
2- and reacted with a stoichiometric quantity of acetyl chloride in
:~ the cold. The reaction mixture is quenched in brine and extracted
with ethyl acetate to give the desired 7,8-diacetoxy derivative.
Substituting other alkanoyl anhydrides or chlorides gives various
.
. 7,8-dialkanoyl derivative.
:,
'
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?33~
1 E~AMPLE 12
` A solution of 7.10 g (18.6 mmoles) of 7,8-dihydroxy-1-
phenyl-6-methylthio-2,3,4,5-tetrahydro-lH-3-benzazepine, hydrobromide
in 120 ml of aqueous dimethyl-formamide at 0 under an argon atmosphere
is basified to pH 10.0 with 10% sodium hydroxide solution. To this
cold mixture is added 13.0 g (76 mmoles) of carbobenzoxy chloride in
small portions over 15 minutes with concomitant addition of 10%
alkali so as to maintain a pH of 10 to 10.5. The reaction is allowed
to warm to room temperature after stirring at 0 for 1-1/2 hours.
The mixture is diluted with saturated salt and extracted with three
portions of ethyl acetate. The combined organic extract is backwashed
twice with saturated salt. The dried extract is concentrated in vacuo
and heated at 75/0.1 mm Hg to remove any benzyl alcohol.
The residue is taken up in 50 ml of glacial acetic acid,
1 cooled to 15 and treated with 14 ml of 40% peracetic acid over 5
minutes at 10-15. The solution is allowed to warm to room temperature.
, Further treatment with portions of 40% peracetic acid to complete
~i. conversion to the sulfone are often neeted. The reaction is quenched
in 800 ml of water and extracted with three portions of ethyl acetate.
.:,
i` The combined organic layers are washed with two portions of saturated
` 20
salt, three portions of 5% bicarbonate and two portions of saturated
salt. The extracts are dried, treated with decolorizing charcoal,
~ .
concentrated in vacuo ant pumped free of solvent to give 12 g of
N-carbobenzoxy 6-methylsulfonyl compound.
` This protected sulfone is treated with 70 ml of 38%
hydrobromic acid in glacial acetic acid at room temperature for
2 hours. The solution is added dropwise into 1 1. of rapidly
stirred anhydrous diethyl ether over 40 minutes. The solids
are allowed to settle and the supernatant decanted. The precipitate
` is washed several times with fresh ether and dried under a nitrogen
- 30
- 21 -
.
S(~33~
stream to give the hydrobromide salt of 7,8-dihydroxy-6-methylsulfonyl-
l-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine.
Using variations of this method with other starting
materials the 6-trifluoromethylsulfonyl containing compound and
other products of this invention can be prepared.
EXAMPLE 13
A solution of 8.6 g (20 mm) of 3-acetyl-7,8-diacetoxy-1-
phenyl-6-methylthio-2,3,4,5-tetrahydro-1~-3-benzazepine tprepared
by reacting the dihydroxy parent with an excess of acetic anhydride
in pyridine at room temperature) in 40,ml of methanol at -5 is
` treated with 40 ml of 0.52 M sodium periotate (20.8 mm) dropwise
over 15 minutes at 0. The mixture is cooled overnight, then filtered
to give a solid which is washed with methylene chloride. The organic
extracts are combined, dried and evaporated in vacuo. The residue
'`` 15 is heated at reflux in ethanolic hydrochloric acid overnight. The ''
I volatiles are removed and the residue taken up in water. Neutralization
with ammonia and extraction with ethyl acetate gives the desired
' 7,8-dihydroxy-6-methylsulfinyl-1-phenyl-2,3,4,5-tetrahydro-lH-3- ~'
benzazepine. The hydrochloride salt is formed by treatment with
ethereal hydrogen chloride.
., .
.
..
- 22 -
,: ' . : .
,',. ' - .
334
1 EXAMPLE 14
Ingredients Mg. per Capsule
6-Methylthio-7,8-dihydroxy-1-phenyl-125 tfree base)
2,3,4,5-tetrahydro-lH-3-benzazepine
(as an acid addition salt)
S Magnesium stearate 2
Lactose 200
The above ingredients are thoroughly mixed and placed into hard
gelatin capsules. Such capsules are administered orally to subjects
in need of treatment from 1-5 times daily to induce dopaminergic
; 1O or antiparkinsonism activity.
EXAMPLE 15
InRredients Mg. per Tablet
9-Methylthio-7,8-dihydroxy-1-phenyl)-200 (free base)
2,3,4,5-tetrahydro-lH-3-benzazepine
"15 (as an acid addition salt)
Corn starch 30
Polyvinyl pyrrolidone 12
Corn ~tarch 16
Magnesium stearate 3
The first two ingredients are thoroughly mixed and granulated.
The granules obtained are dried, mixed with the remaining corn
starch and magnesium stearate, and compressed into tablets.
The capsules or tablets thusly prepared are administered
orally to an animal or human requiring stimulation of central
dopamine receptors such as to treat the symptom of Parkinson's disease
within the dose ranges set forth hereinabove. Similarly other
compounds of Formula I and the illustrative examples can be
formulated in the same manner to give pharmaceutical compositions
useful in the methods of this invention based on the chemical
characteristics and relative biological activtty using the test
:, ~0
methods outlined.
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