OBTENTION D'AMINOALKYLTHIODIBENZTHIEPINES ET DE COMPOSES APPARENTES; SUBSTANCES PHARMACEUTIQUES ET A UTILISATION VETERINAIRE QUI EN CONTIENNENT

AMINOALKYLTHIODIBENZTHIEPINS AND RELATED COMPOUNDS, A METHOD OF PREPARING SAME AND PHARMACEUTICAL AND VETERINARY PREPARATIONS INCLUDING SAME

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
The present application concerns novel amino-
alkylthiodibenzthiepins of the formula I
<IMG> I
wherein X is hydrogen, Y is hydrogen or halogen, and Z
represent halogen or <IMG> wherein R1 is hydrogen, lower
alkyl, cyano, or phenoxycarbonyl and R2 is lower alkyl or
R1-N-R2 forms a morpholino or a N-lower alkyl substituted
piperazinyl; m is the integer 0 or 1; and n is an integer
of from 2 to 4; and the physiologically tolerable acid
addition salts thereof. The application is also directed
to a method of preparing these compounds and pharmeuctical
and veterinary preparations including them. The compounds
are useful as antidepressants, analgetics and anticonvulsant
agents.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of
the formula I
<IMG> I
wherein Z is hydrogen, Y is hydrogen, halogen or methylsulfonyl,
and X represents halogen or <IMG> wherein R1 is hydrogen, lower
alkyl, cyano or phenoxycarbonyl and R2is lower alkyl, or R1-
N-R2 forms a morpholino or a N-lower alkyl substituted piper-
azinyl; m is the integer 0 or 1; and n is an integer of from
2 to 4; and the physiologically tolerable acid addition salts
thereof,
in which
a) a compound of the formula II
<IMG> II
wherein X and Y are as defined in formula I and R3 and R4
are different and each is hydrogen or hydroxy, or R3 and R4
together are oxygen, is reacted with aminoalkylthiol of the
formula
<IMG>
wherein R1 and R2 are the same or different and each represents
lower alkyl in the presence of a catalyst/dehydrating agent
and a solvent to produce a compound of the formula Ia

<IMG> Ia
or
b) a compound of the formula Ia wherein R1 and R2 are each
methyl is reacted with cyanogen halide to obtain a mixture of
one compound of the formula Ib
<IMG> Ib
and another compound of the formula Ic
<IMG> Ic
wherein X, Y, m and n are as defined in the formula I and hal
is halogen, and each of the two compounds is isolated; or
c) a compound of the formula Ib is reacted with an appropriate
non-cyclic or cyclic amine to obtain the corresponding compound
of the formula Ia
<IMG> Ia
21

wherein X, Y, R1, R2, m and n are as defined in formula I; or
d) a compound of the formula Ia, wherein R1 and R2 are the
same or different and each is lower alkyl, and X, Y, m, n
are as defined in the formula I is reacted with an alkyl or
phenyl chloroformate to obtain a compound of the formula Ia
wherein R1 is alkoxy or phenoxy carbonyl and R2, X, Y, m and n
are as defined in formula I, or
e) a compound of the formula Ia, wherein X, Y, m and n are
as defined in formula I, R1 is lower alkoxy or phenoxy carbonyl
and R2 is a lower alkyl, is reacted with a base or an acid
medium to obtain a compound of the formula Ia wherein X, Y,
m and n are as defined in the formula I, R2 is as defined above
and R1 is hydrogen; or
f) a compound of the formula Ia, wherein X, Y, m and n are as
defined in formula I, R1 is hydrogen and R2 is lower alkyl
is reacted with a lower alkyl halide, to obtain a compound of
the formula Ia in which X, Y, m and n are as defined in the
formula I, R1 is lower alkyl, and R2 is lower alkyl.
2. A compound of the formula I as defined in claim 1,
whenever obtained according to a process as claimed in claim 1
or by an obvious chemical equivalent thereof.
22

3. A process for the preparation of 2-chloro-11-
[.beta.-(dimethylamino)ethylthio]dibenz[b,f]thiepin hydrochloride
in which 2-chloro-10,11-dihydro-11-oxodibenz[b,f]thiepin is
reacted with .beta.-dimethylaminoethanethiol hydrochloride in the
presence of boron trifluoride etherate in glacial acetic acid,
the product is isolated, treated with hydrochloric acid and the
resultant product is subsequently isolated.
4. 2-Chloro-11-[.beta.-(dimethylamino)ethylthio]dibenz[b,f]-
thiepin hydrochloride, whenever obtained according to a process
as claimed in claim 3 or by an obvious chemical equivalent
thereof.
5. A process for the preparation of 10-[.beta.-(dimethylamino)-
ethylthio]dibenz[b,f]thiepin hydrochloride in which 10,11-dihydro-
10-oxodibenz[b,f]thiepin is reacted with .beta.-dimethylaminoethane-
thiol hydrochloride in the presence of boron trifluoride etherate
and glacial acetic acid, the product is isolated, treated with
hydrochloric acid and the resultant product is subsequently
isolated.
6. 10-[.beta.-(Dimethylamino)ethylthio]dibenz[b,f]thiepin
hydrochloride, whenever obtained according to a process as
claimed in claim 5 or by an obvious chemical equivalent thereof.
7. A process for the preparation of 2-chloro-10,11-dihydro-
11-[.beta.-(dimethylamino)ethylthio ]dibenz[b,f]thiepin maleate in
which 2-chloro-10,11-dihydro-11-hydroxyspirodibenz[b,f]thiepin
is reacted with .beta.-dimethylaminoethanethiol hydrochloride in
the presence of boron trifluoride etherate in glacial acetic
23

acid, the product is isolated, treated with maleic acid and the
resultant product is subsequently isoiated.
8. 2-Chloro-10,11-dihydro-11-[.beta.-(dimethylamino)ethylthio]-
dibenz[b,f]thiepin maleate, whenever obtained according to a process
as claimed in claim 7 or by an obvious chemical equivalent thereof.
9. A process for the preparation of 10,11-dihydro-10-
[.beta.-(dimethylamino)ethylthio]dibenz[b,f]thiepin hydrochloride
in which 10,11-dihydro-10-hydroxydibenz[b,f]thiepin,
is reacted with .beta.-dimethylaminoethanethiol hydrochloride in
the presence of boron trifluoride etherate in glacial acetic
acid, the product is isolated, treated with hydrochloric acid
and the resultant product is subsequently isolated.
10. 10,11-Dihydro-10-[.beta.-(dimethylamino)ethylthio]dibenz-
[b,f]thiepin hydrochloride, whenever obtained according to a
process as claimed in claim 9 or by an obvious chemical
equivalent thereof.
11. A process for the preparation of 11-(.beta.-bromoethylthio)-
2-chloro-10,11-dihydrodibenz[b,f]thiepin in which 2-chloro-10,11-
dihydro-11-hydroxyspirodibenz[b,f]thiepin is reacted with
.beta.-dimethylaminoethanethiol hydrochloride in the presence of
boron trifluoride etherate in glacial acetic acid, 2-chloro-10,11-
dihydro-11-[.beta.-(dimethylamino)ethylthio]dibenz[b,f]thiepin is
isolated, dissolved in chloroform, the resultant solution is
added to a solution of a stoichiometric amount of cyanogen
bromide and an excess of potassium chloride in chloroform and
the resultant product is subsequently isolated.
24

12. 11-(.beta.-Bromoethylthio)-2-chloro-10,11-dihydrodibenz-
[b,f]thiepin, whenever obtained according to a process as
claimed in claim 11 or by an obvious chemical equivalent thereof.
13. A process for the preparation of 1-[.beta.-dimethylamino)-
ethylthio]-2-methylsulfonyldibenz[b,f]thiepin in which 10,11-
dihydro-2-methylsulfonyl-11-oxodibenz[b,f]thiepin is reacted
with dimethylaminoethanethiol hydrochloride in the presence of
boron trifluoride etherate in glacial acetic acid, and the
resultant product is subsequently isolated.
14. 11-[(.beta.-Dimethylamino)ethylthio]-2-methylsulfonyldibenz-
[b,f]thiepin, whenever obtained according to a process as claimed
in claim 13 or by an obvious chemical equivalent thereof.
15. A process for the preparation of 10-[.beta.-(methylamino)-
ethylthio]dibenz[b,f]thiepin hydrochloride in which 10,11-
dihydro-10-oxodibenz[b,f]thiepin is reacted with .beta.-dimethylamino-
ethanethiol hydrochloride in the presence of boron trifluoride
etherate in glacial acetic acid, a solution of the resultant
10-[.beta.-(dimethylamino)ethylthio]dibenz[b,f]thiepin hydrochloride
in ethylene glycol and potassium hydroxide is stirred, the
product is isolated, treated with hydrochloric acid and the
resultant product is subsequently isolated.
16. 10-[.beta.-(Methylamino)-ethylthio]dibenz[b,f]thiepin hydro-
chloride, whenever obtained according to a process as claimed
in claim 15 or by an obvious chemical equivalent thereof.

Description

l~lQ6Z5
The invention relates to novel aminoalkylthiodibenz-
thiepins and related compounds and to their physiological-
ly tolerable acid addition salts which are useful as anti-
depressant, analgetic and anticonvulsant agents, and to
pharmaceutical and veterinary compositions containing such
a compound as an essential active ingredient.
It is already known that Amethoclothepine of the
formula:
H V O(CH2)2N(CH3)2
~Cl
possesses central depressant activity by M. Protvia, et al.
II Farmaco XXI 98 (1966).
Japaneses Patent No. 47-28998 entitled "A Method
of Manufacturing Tricyclic Compounds Having an Enolic Ether
Bond" pertains to the preparation of compounds depicted
by the formula
O-Rl-N
~ \ R
15 in which A is an alkylimino group, an oxy radical, a thio
: group or a sulfonyl group, Rl is an alkylene group, R2 and
R3 each represent an alkyl group or may be bonded
cyclically either through the alkylimine or not through
the alkylimine group.
, ~
. .
' ~- ' ' . . ' -: , ' ': : - '

6Z5
,
- 3 - HOE 77/F 274
However, the compounds of the present invention possess
significant differences with respect to the aforesaid
prior art compounds. Furthermore, neither reference suggests
the unique methodology required for the preparation of the
compounds of the present invention.
The compounds of the present invention conform to the
general formula
~S- (CH2)n-Z
X~ ~ I ~
wherein X and Y are the same or different and each can be
hydrogen, halogen, trifluoromethyl, C1-C6-alkoxy, C1-C6-
alkyl, C1-C6alkylthio, Cl-C6alkylsulfonyl, C1-C6-alkylsul-
finyl, amino or nitro, Z is halogen or N~' wherein Ris hydrogen, straight or branched chain C1-C6alkyl, cyano,
cycloalkyl-C1-C6alkyl wherein the cycloalkyl ring contains
from 3 to 6 carbon atoms~ phenoxycarbonyl of the formula
; -C02- ~ , C1-C6-alkoxycarbonyl, C2-C6-alkenyl or C2-C6-
alkynyl, R2 is straight or branched chain C1-C6alkyl or cyc-
loalkyl-C1-C6-alkyl wherein the cycloalkyl ring contains
from 3 to 6 carbon atoms; and when R1 and R2 are taken to-
gether with the nitrogen atom to which they are attached,
the group R1-N-R2 forms a heterocycle which is morpholino,
piperidino, pyrrolidinyl, or N-substituted piperazinyl in
which the N-substituent is C1-C6alkyl; m is the integer O
or 1; and n is an integer of from 2 to 4; and a physiolo-
gically tolerable acid addition salt thereof.
~ ~ .
.
.. . . ..
~ ~, ,:,. ~ ., . . :
.. .. . ... .: ~. .
: . : .
.. . . . . .

l~Q625
, ~,
- 4 - ~OE 77/F 274
Acids useful for preparing the pharmaceutically
acceptable acid addition salts of the invention lncl~lde
inorganic acids such as hydrochloric, hydrobro~ic, sulfuric,
nit:ric, phosphoric and perchloric acids, as well as organic
5 acids such as tartaric, citric, acetic, succinic, ~aleic,
~u~aric, and oxalic acids.
Compounds of the invention are prepared by the me'~hods
given below. With the exceptions noted, X, Y, Z, R1, R2,
m and n are as defined earlier.
Method a)
A 10,11-dihydro-10-hydroxy- or -10-oxo-dibenz/ b,f 7
thiepin, of the Pormula
.~
R3 ~ 4
X ~ Y II
wherein X and Y are as defined in formula I and R3 and R4
are different and represent each hydrogen or hydroxy or to-
gether represent oxygen is reacted with aminoalkylthiol
of the formula
,Rl '
HS-(cl12~ N~R2 III
wherein R1 and R2 are the same or different and each can
be a straight or branched chain C1-C6alkyl to produce a com-
pound of the invention of the formula
Rl '
S- (CH2)
R~
,, , X~S ~Y
. ~ . .
,
.
.: . ' ' , :: : ~ ':, ',' : '

~llQ6Z5
~~ _ 5 ~ 771F 'l4
Method b)
A compound prepared in Method a) wherein
Rl and R2 are each methyl, can be treated with a cyano~en halide
such as cyanogen bromide in a suitable solvent and acld
5 scavenger to obtain a mixture of one compound of the invention
of the formula
S (C~2)nhal
X ~ y Ib
and another compound of the invention of the formula
S(CM2)n N\
X~ ~_ y
,
This reaction is carried out at a temperature of from about
' ambient to reflux. These two compounds of the invention may
be isolated and collected by column chromato~;raphy.
Method c)
A compound prepared in Method ~)of formula Ia can
be reacted in a known.fashion with a suitable amine to obtain .-
the corresponding compound of the invention. of the formula
~Rl '
~S- (CH,2)n-N\R2
Ia
.
,', ', ' , ' ,'' '',' '' '' "
', . ' , , ' '. ' , , ' ' '
~ ' " ~ ' .
.
'

~11~25
6 - HOE 77/F 274
wherein R is hydrogen, straight or branched chain Cl-C6al-
kyl, cycloalkyl-Cl-C6alkyl, C2-C6alkenyl or Cl-C6alkynyl;
R2 is straight or branched chain C1-C6alkyl; and when Rl
and R2 are taken together with the nitrogen atom to which
they are attached, the group R1-N-R2 forms a heterocycle
which is N-substituted piperazinyl, morpholino, piperidino
or pyrrolidinyl. A preferred method is carried out with a
dimethylformamide solvent, an acid scavenger such as sodium
bicarbonate and a reaction initiator such as potassium
iodide at a temperature of from ambient to the reflux tem-
perature of the reaction mixture.
Method d)
A compound prepared in Method a) 'canhe
treated with a chloroformate, e.g. an alkyl or phenyl
chloroformate, at a temperature of from 25 to 125C, in a
solvent such as methylene chloride, toluene or benzcne to
provide the corresponding compound o~ the inven~ion in w~lich Z
is N~R2 with R1 being C1-C6-alkoxy or phenoxy carbonyl.
Method e)
A co~pound prepared in Methodd) is treated ~ith a
base such as sodium or ~otassium hydroxide in a solvent such as
water, ethanol or ethylene ~lycol at a temperature o~ ~rom
ambient to reflux or with an acid medium such as hydrogen
bromide in glacial acetic acid at a temperature from about
ambient to reflux to provide the corresponding compound of
the invention in which Rl is hydrogen.
Method f)
A compound prepared in Method e is treated with a
straight or branched chain C1-c6alkyl halide, C2-C6 alky-
: '
,
~ ,

l~lQ6ZS
,_
- 7
nyl halide or cycloalkyl-Cl-C6alkyl halide under conditions
normal for such reactions to provide the corresponaing com-
pound of the invention in which Rl is straight or branched
chain Cl c6alkyl, C2-C6alkenyl, C2-C6alkynyl or cycloalkyl-
Cl-C6alkyl. A preferred method is to carry out this sub-
stitution in the presence of a solvent such as dimethyl-
formamide, an acid scavenger such as sodium bicarbonate
and a reaction initiator such as potassium iodide at the
reflux temperature of the solvent.
Method g)
A compound prepared in any of the above methods,
which includes a nitro group can be reduced by a convent-
ional method to produce the corresponding amino compound.
As is appreciated by those skilled in the art,
specific reaction conditions in any of the above methods
are dependent on and are a function of the ingredients
of each procedure.
The compounds of the invention are useful in the
treatment of depression in mammals which is evidenced by
their ability to inhibit tetrabenazine-induced depression
; in mice [International Journal of Neuropharmacology 8,
73 (1969)], a standard assay for useful antidepressant
properties
Compounds of the invention are furthex useful as
analgesic agents due to their ability to alleviate pain in
mammals which is demonstrated in the phenyl-p-quinone
writing assay in mice, a standard assay for analgesia [Proc.
Soc, Exptl. Biol. Med., 95, 729 (1957)].
,
.
: ' '. . ' ' ' ' ' ''
.
- . : , . : .
- .: : . . . ..
': :

6Z5
-~ 8
Compounds of the present invention are still further
useful as anticonvulsant agents for mammals, as evidenced
by the method of Woodbury, L.A. and Davenport, V.D. in
Arch. Int. Pharmacodynam, Vol. 92, (1952) at pages 97-107.
These compounds are useful, as any of the above
three categories of pharmaceutical agents, when administ-
ered in an amount ranging from about 0.1 to 100 mg per kg of
body weight per day.
Examples of compounds of the invention include:
11-[r-(dimethylamino)propylthio]-2-ethylsulfonyl-
dibenz[b,f]thiepin;
ll-[~-~bromo)ethylthio]-2-methoxy-10,11-dihydrodibenz-
[b,f]thiepin;
2-ethyl-11-[~-(methylamino)ethylthio]dibenz[b,f]
thiepin;
ll-[~-(ethylmethylar,lino)ethylthio]-2-methylsulfinyl-
dibenz[b,f]thiepin;
~ -(ethylmethylamino)ethylthio]-2-methylthiodibenz-
i [b,f]thiepin;
10,11-dihydro-10-[~-(piperidino)ethylthio]dibenz-
~b,f]thiepin;
10,11-dihydro-10-[~-(N-methylpiperazino)propylthio]-
dibenz[b,f]thiepin;
10,11-dihydro-10-[~-(piperidino)-n-butylthio]dibenz-
[b,f]thiepin;
10-[~-(pyrrolidino)ethylthio]dibenz[b,f]thiepin;
3-chloro-11-[~-(ethylmethylamino)ethylthio]dibenz-
[b,f]thiepin;
'
:, . .

fi~
, ~
ll-[~-(ethylamino)ethylthio]-10,11-dihydro-4-
nitrodibenz[b,f]thiepin;
ll-[~-(ethylamino)ethylthio]-3-trifluoromethyl-
dibenz[b,f]thiepin
2-amino-11-[~-(ethylamino)ethylthio]dibenz[b,f]-
thiepin;
ll-[~-(ethylamino)ethylthio]-3-methoxydibenz-
[b,f]thiepin;
ll-[~-(diethylamino)ethylthio]-2-n-propyldibenz-
[b,f]thiepin;
ll-[~-(methylamino)ethylthio]-3-methylthiodibenz-
[b,f]thiepin;
8-chloro-10,11-dihydro-10-[~-(dimethylamino)ethyl-
thio]-2-methyldibenz[b,f]thiepin; :
3-fluoro-11-[~-(methylamino)ethylthio]dibenz-
[b,f]thiepin;
2-bror,lo-7-fluoro-11-[~-tdimethylamino)ethylthio]-
: aibenz-[b,f]thiepin;
3-ethyl~ [~-(methylamino)ethylthio]dibenz[b,f]-
thiepin;
11-[ -(ethylamino)ethylthio]-4-nitrodibenz-
[b,f]thiepin;
2-methyl-11-~3-(N-meth~l-N-methoxycarbonylamino)-
ethylthio]dibenz[b,f]thiepin;
: 25 10-[~-(N-cyclopropylmethyl-N-methylamino)ethylthio]-
dibenz[b,f]thiepin;
10-[~-(N-allyl-N-methylamino)ethylthio]dibenz-
[b,f]thiepin; and
. :;:

6;~5
10-[~-(N-methyl-N-propargylamino)ethylthio]dibenz-
[b,f~thiepin.
Effective quantities of the compoundsof the invention
may be administered to a patient by any one of various
methods, for example, orally as in capsules or tablets,
parenterally in the form of sterile solutions or suspensions,
and in some cases intravenously in the form of sterile
solutions. The free base final products, while effective
themselves, may be formulated and administered in the form
of their pharmaceutically acceptable addition salts for
purposes of stability, convenience of crystallization,
increased solubility and the like.
The active compounds of the present invention may
be orally administered, for example, with an inert diluent
or with an edible carrier, or they may be enclosed in
gelatin capsules, or they may be compressed into tablets.
For the purpose of oral therapeutic administration, the
active compounds of the invention may be incorporated with
excipients and used in the form of tablets, troches,
capsules, elixiers, suspensions, syrups, wafers, chewing
gum and the like. These preparations should contain at
least 0.5% of active compound, but may be varied
depending upon the particular form and may conveniently
be between 4% to about 70% of the weight of the unit.
The amount of active compound in such compositions is
; such that a suitable dosage will be obtained. Preferred
compositions and preparations according to the present
invention are prepared so that an oral dosage unit form
~j, '. .

contains between 1.0-300 milligrams of active compound.
The tablets, pills, capsules, troches and the like
may also contain the following ingredients: a binder such
as microcrystalline cellulose, gum tragacanth or gelatin;
an excipient such as starch or lactose, a disintegrating
agent such as alginic acid, Primogel, corn starch and the
like; a lubricant such as magnesium stearate or Sterotex;
a glidant such as colloidal silicon dioxide; and a
sweetening agent such as sucrose or saccharin may be added
or a flavoring agent such as peppermint, methyl salicylate,
or orange flavoring. When the dosage unit form is a
capsule, it may contain, in addition to materials of the
above type, a liquid carrier such as a fatty oil. Other
dosage unit forms may contain other various materials
which modify the physical form of the dosage unit, for
example, as coatings. Thus, tablets or pills may be coated
with sugar, shellac, or other enteric coating agents. A
syrup may contain, in addition to the active compounds,
sucrose as a sweetening agent and certain preservatives,
dyes, colorings and flavors. Materials used in preparing
these various compositions should be pharmaceutically pure
and non-toxic in the amounts used.
For the purpose of parenteral therapeutic administr-
ation the active compounds of the invention may be
incorporated into a solution or suspension. These
preparations should contain at least 0.1% of active
compound, but may be varied to between 0.5% and about 30%
of the weight thereof. The amount of active compound in
'
' ' : ' ' ' ` ~ ' ~ '' ' ' ' "
' . ~ ' . ...

6Z5
12
in suc~l compositions is such that a suitable dosage will
be obtained. Preferred compositions and preparations
according to the present invention are prepared so that a
parenteral dosage unit contains between 0.5 to 100
milligrams of active compound.
The solutions or suspensions may also include the
following co~ponents: a sterile diluent such as water for
injection, saline solution, fixed oils, polyethylene
glycols, glycerine, propylene glycol or other synthetic
solvents; antibacterial agents such as benzyl alcohol or
methyl parabens; antioxidants such as ascorbic acid or
sodium bisulfite; chelating agents such as ethylenediamine-
tetraacetic acid; buffers such as acetates, citrates or
phosphates and agents for the adjustment of tonicity such
as sodium chloride or dextrose. The parenteral preparation
can be enclosed in ampuls, disposable syringes or multiple
dose vials made of glass or plastic.
Example 1
63 ml of boron trifluoride etherate are added to
a solution of 20.0 g of 2-chloro-10,11-dihydro-11-oxodibenz-
[b,f]thiepin, 21.8 g of ~-dimethylaminoethanethiol
hydrochloride and 218 ml of glacial acetic acid. After
total addition the reaction mixture is stirred for 30
minutes and then permitted to stand for 48 hours.
Thereafter, the mixture is poured into 1200 ml of a 10%
sodium hydroxide solution and the basified mixture is
extracted with methylene chloride. The combined
methylene chloride fractions are successi~ely washed with
. ~

6 Z 5
13
water, dried and filtered and the filtrate evaporated to
dryness leaving a red oil. The oil is column chromato-
graphed through a silica gel/methylene chloride column
with a 2-4% methanol in methylene chloride mixture as the
eluant. The purified product is converted to its
hydrogen chloride salt of 2-chloro-11-~-(dimethylamino)-
ethylthio]dibenzEb,f]thiepin hydrochloride.
Analysis:
Calculated for C18H18ClNS2-HCl: 56.24%C; 4.98~H; 3.64~N.
Found: 56.35%C; 5.17%H; 3.47%~.
Example 2
A sample of lO,ll-dihydro-lO-oxodibenz[b,r]thiepin
is treated according to the manipulative procedure of
Example l to provide 10-[~-(dimethylamino)ethylthio]-
dibenz[b,f]thiepin hydrochloride.
Example 3
To a mixture of 1.08 g of 6-dimethylaminoethanethiol
- hydrochloride and 2.5 ml of boron trifluoride etherate is
added dropwise a mixture of 1.0 g of 2-chloro-lO,ll-dihydro-
ll-hydroxyspirodiben~[b,f]thiepin in 8 ml of glacial acetic
; acid. After total addition, the reaction mixture is
stirred at ambient temperature for 30 minutes and then
permitted to stand for 24 hours. Thereafter, the reaction
is poured into 50 ml of a saturated potassium carbonate-
ice solution where it is extracted with ether. The
combined ether extracts are, successively, washed with a
dilute potassium carbonate solution and water and dried,
filtered and evaporated. The resulting oil is
. . ~
,
. : . . . : .
' . ~: ' . . ~ .
. ,: : . ~ ' ~ : .

~1$~5
"
14
chror.latographed through a silica gel/methylene chloride,
a 5% methyl alcohol is methylene chloride eluant and
then converted to the maleic acid salt, mp, 99-101C of
2-chloro-10,11-dihydro-11-[~-tdimethylamino)-ethylchio]-
dibenz[b,f]thiepin maleate.
Analysis:
Calculated or C18 20 2 C4 4 4
Found: 56.70%C; 5.29%H; 3.03%N.
Example 4
A sample of 10-E~-(dimethylamino)ethylthio]dibenz-
[b,f]thiepin, free base of Example 3, is treated according
to the manipulative procedure of Example 3 to provide 10,
ll-dihydro-10-[~-(dimethylamino)ethylthio]dibenzlb,f]thiepin
hydrochloride.
Example 5
A solution of 1.0 g of 2-chloro-11-[~-(dimethylamino)
-ethylthio]dibenz[b,f]thiepin, free base of Examyle 1, in
10 ml of methylene chloride is added dropwise to a
stirring solution of 0.5 g of cyanogen bromide and 1.0 g
o potassium carbonate in 7 ml of methylene chloride.
After total addition, the reaction is permitted to stand
with complete reaction occuring after about four hours.
After the reaction is completed the mixture is filtered
and the filtrate evaporated leaving an oil. The oil
is chromatographed through a silica gel/methylene
chloride column with methylene chloride as the eluant.
The desired fraction is evaporated to dryness leaving
: ~ .
:- .

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2-chloro-11-[~-(N-cyano-l~-methyl)ar.~inoethylthio]dibenz(b,f]-
thiepin, as a yellow oil -
Analysis:
Calculated for C18H15ClN2 2 6 3%C;
Found: 60.62%C; 4.19%H; 7.75%N.
Example 6
To a stirring solution of 0.50 g of phenyl
chloroformate and 0.2 g of sodium bicarbonate in 20 ml
of methylene chloride is added dropwise a solution of
0.95 g of 2-chloro-11-[~-(dimethylamino)ethylthio]dibenz-
[b,f]thiepin, free base of Example 1, in 10 ml of
methylene chloride. After total addition the reaction
is successively stirred at 25C for 24 hours, filtered,
diluted with 25 rnl of methylene chloride, washed with a
10% sodium hydroxide solution, washed with water, dried
and filtered. The filtrate is evaporated leaving a yellow
oil which is chromatographed through a silica gel/methylene
chloride column with methylene chloride as the eluant.
The purified product is the yellow oil of 2-chloro-11-
[~-(N-methyl-N-phenoxycarbonylamino)-ethylthio]dibenz[b,f]-
thiepin.
Analysis:
Calculated for C24H20ClNO2S2: 63.49~C; 4.44%H; 3.09%N.
Found: 63.76%C; 4.49~H; 2.90%N.
In a similar fashion a sample of 10-[~-(dimethyl-
amino)ethylthio]dibenz[b,f]thiepin, free base of Example
2, is treated to provide 10-[~-(N-methyl-N-phenoxycarbonyl-
amino)-ethylthio]dibenz[b,f]thiepin.
,,
..: . . .. . , :
. :: . :.' '. ~ ,;

6; :5
16
Example 7
A solution of 5.6 g of 2-chloro~ll-[~-(N-methyl-N-
phenoxycarbonylamino)ethylthio]dibenz[b,f]thiepin, Example
6, 127 ml of ethylene gylcol and 10.8 g of potassium
hydroxide is stirred at 150-155C for 30 minutes.
Thereafter the reaction mixture is poured onto 300 ml
of ice-water and the aqueous mixture is extracted with an
ether-toluene (1:1) mixture. The combined extracts,
successively, are washed well with water, dried and
filtered and the filtrate evaporated leaving an orange
oil. The oil is converted to its hydrogen chloride acid
salt which is recrystallized from a methanol-acetone-
ether mixture to give the product, mp 194-196C of
2-chloro-11-[~-(methylamino)ethylthio]dibenz[b,f]thiepin
hydrochloride.
Analysis:
Calculated for C17H16ClNS2 ~Cl: 55.13%C; 4.63%H; 3.78%N.
Found: 55.28%C; 4.71%H; 3.93%1~.
In a similar fashion, 10-[~-(N-methyl-N-
phenoxycarbonylamino)ethylthio]dibenz[b,f]thiepin,hereinabove described, is treated to provide 10-[~-(methyl-
amino)ethylthio]dibenz[b,f]thiepin hydrochloride.
Example 8
A solution of 2-chloro-lO,ll~dihydro-ll-[~-dimethyl-
ar.lino)ethylthio]dibenz[b,f]thiepin, free base of Example3, in 10 ml of chloroform is added dropwise to a solution
of a stoichiometric amount of cyanogen bromide and an
excess amount of potassium carbonate in 5 ml of chloroform.

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,,~~ . .
17
After total addition the reaction mixture is permitted to
stand for 10 minutes and then filtered. The filtrate is
concentrated to dryness leaving the product 11~
brornoethylthio)-2-chloro-10,11-dihydrodibenz[b,f]thiepin.
Example 9
A mixture of stoichiometric amounts of 2-chloro-11-
(~-bromoethylthio)-10,11-dihydrodibenz[b,f]thiepin,
Example 8, and N-methylpiperzine, an excess amount of
sodium bicarbonate, and 1.0 g of potassium iodide in 15
ml of dimethylformamide is stirred at 80C for 16 hours.
The mixture is permitted to cool before being diluted
with water. The biphasic mixture is extracted thrice with
100 ml portions of ether, the ether extracts are combined
and shaken vigorously with a large excess of 2N hydro-
chloric acid. The acidic solution is basified, liberating
the free amine which is extracted into benzene. The
benzene solution is dried and the benzene removed under
vacuum, leaving the product 2-chloro-10,11-dihydro-11[~-
(4-methylpiperazinyl-1-yl)ethylthio]dibenz[b,f]thiepin.
In a similar fashion, substituting morpholine for
N-methylpiperazine provides 2-chloro-10,11-dihydro-11-
(~-morpholinoethylthio)dibenz[b,f]thiepin.
Examples 10 & 11
By following the manipulative procedure of Example 2,
respectively substituting ~-diisopropylaminoethanethiol
hydrochloride, ~-diethylaminoethanethiol hydrochloride
for ~-dimethylaminoethanethiol hydrochloride provides
Example 10, 10-[~-(diisopropylamino)ethylthio]dibenz[b,f]-
.
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, . ~ . . .

~ 625
1~
thiepin hydrochloride and Example 11, 10~[~-(diethylamino)-
ethylthio]dibenz[b,f]thiepin hydrochloride.
Example 12
a. A solution of stoichiometric amounts of 2-(4-
methylsulfonylphenylthio)benzyl nitrile and 85% potassium
hydroxide in an alcohol-water mixture is stirred at 115C
for 24 hours, Thereafter the reaction mixture is concen-
trated to an oil. The oil is dissolved in water and the
aqueous solution is successively, washed ~.ith ether,
acidified with dilute hydrochloric acid again providing an
oil. This oil is dissolved in methylene chloride
and the solution, successively, is dried, filtered and
concentrated to dryness leaving the product 2-(4-methyl-
sulfonylphenylthio)phenylacetic acid.
b. A mixture of 1.0 g of 2-(4-methylsulfonyl-
phenylthio)phenyl acetic acid and 10 ml of polyphosphoric
acid under nitrogen is stirred at ~0-100C for 2 hours.
The reaction mixture is permitted to cool and then poured
into 100 ml of ice-water slurry. The aqueous solution is
basified with 20% sodium hydroxide before being extracted
with rnethylene chloride. The combined extracts are dried
and then evaporated to dryness leaving an oil. The oil
is chromatographed through a silica gel column with a 2%
methanol in methylene chloride eluant. The chromatographed solution
is evaporated to dryness providing 10,11-dihydro-2-
methylsulfonyl-ll-oxodibenz[b,f]thiepin.
.
.: ~
~ .

6Z5
,
19
c. A solution of stoichiometric amounts o 10,11-
dihydro-2-methylsulfonyl-11-oxodibenz[b,f]thiepin and
dirnethylaminoethanethiol hydrochloride and 15 ml of boron
trifluoride etherate in 37 ml of glacial acetic acid is
stirred until reaction is completed. Thereafter the
reaction mixture is poured into 300 ml of a cold sodium
hydroxide solution and the resulting solution is extracted
with methylene chloride. The combined extracts are
washed with water and dried before being filtered. The
filtrate is evaporated to dryness leaving an oil which is
chromatographed through a silica gel/methylene chloride
column with methanol (2-4~) in methylene chloride eluant.
The chromatographed solution is evaporated to dryness
leaving ll-[(~-dimethylamino)ethylthio]-2-methylsulonyldi-
benz[b,f]thiepin.
.: ~ .
' ' ' ~ .
.. . . . . .. . . .
.