PROCESS FOR THE MANUFACTURE OF AZATETRACYCLIC COMPOUNDS

TRADUCTION NON-DISPONIBLE

English Abstract

ABSTRACT OF THE DISCLOSURE

Process for the manufacture of new azatetracyclic compounds of
the formula

Image (I)

wherein
R1 represents hydrogen, lower alkyl, cycloalkyl-lower alkyl of not more than 10
carbon atoms, lower alkenyl, lower alkynyl, (di-lower alkylamino)-lower alkyl,
hydroxy lower alkyl, alkoxy lower alkyl, alkanoyloxy lower alkyl, lower
alkylthio-lower alkyl, phenyl-lower alkyl, or phenyl-lower alkyl substituted
by halogen with an atomic number up to 35, lower alkyl, lower alkoxy,
methylenedioxy, or trifluoromethyl,
the ring A is unsubstituted or substituted by halogen with an atomic number
up to 35, lower alkyl, hydroxyl, lower alkoxy, alkanoyloxy, lower alkylthio,
trifluoromethyl or cyano,
Y represents a direct bond, Z represents vinylene and X represents O, S,
methylene, a direct bond or a divalent radical of the partial formula

Image (Ia)


in which R3 represents hydrogen or lower alkyl, or Y represents a direct
bond, Z represents S and X represents a direct bond or S, and acid addition
salts thereof. The novel compounds possess valuable pharmaceutical
properties and can be used as tranquillizing, antipsychotic and excitation-
inhibiting compounds for the treatment of states of agitation.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the manufacture of azatetracyclic compounds of
the formula

Image (I)

wherein
R1 represents hydrogen, lower alkyl, cycloalkyl-lower alkyl of not more than
10 carbon atoms, lower alkenyl, lower alkynyl, (di-lower alkylamino)-lower
alkyl, hydroxy lower alkyl, alkoxy lower alkyl, alkanoyloxy lower alkyl, lower
alkylthio-lower alkyl, phenyl-lower alkyl, or phenyl-lower alkyl substituted by
halogen with an atomic number up to 35, lower alkyl, lower alkoxy, methylene-
dioxy, or trifluoromethyl,
the ring A is unsubstituted or substituted by halogen with an atomic number
up to 35, lower alkyl, hydroxyl, lower alkoxy, alkanoyloxy, lower alkylthio,
trifluoromethyl or cyano,
Y represents a direct bond, Z represents vinylene, and
X represents O, S, methylene, a direct bond or a divalent radical of the
partial formula

Image (Ia)

m which R3 represents hydrogen or lower alkyl, or Y represents a direct bond,
Z represents S and X represents a direct bond or S, and acid addition salts
thereof, which process consists in

68


a) reacting a reactive diester of a diethanol of the formula

Image (II)

with a compound fo the formula

Image (III)

or
b) for the manufacture of compounds of the formula I in which R1 represents
the group R? , with the exception of alkanoyloxy-lower alkyl, reducing a
compound of the formula

Image (IV)

wherein at least one of the symbols Q1 and Q2 represents an oxygen atom and
the other can represent 2 hydrogen atoms, and, when a compound of formula I

69


is required in which R1 has a meaning other than hydrogen, con-
verting R1 in a compound of formula I in which R1 is hydrogen to
a meaning other than hydrogen, and when a compound of formula I
is required in which R1 is alkanoyloxy lower alkyl, converting
the hydroxy-lower alkyl group R1 in a resulting compound of
formula I into alkanoyloxy lower alkyl by acylation, and when
a compound of formula I is required in which R1 is hydrogen,
converting the phenyl lower alkyl group R1 in a resulting compound
of formula I, into hydrogen by hydrogenolysis, and when a compound
of formula I is required in which X represents a divalent radical
of the partial formula

Image (Ia)

in which R3 represents lower alkyl, alkylating a compound of
formula I in which R3 is hydrogen, and when a free compound
of formula I is required, converting a resulting salt into the
free compound, and when a pharmaceutically acceptable acid
addition salt of a compound of formula I is required, converting
a resulting free compound into a pharmaceutically acceptable
acid addition salt, and when an optical antipode is required,
separating a resulting racemate into the optical antipodes.

2. A process according to claim 1 for the manufacture
of compounds of the formula I, wherein R1 represents hydrogen,



lower alkyl, cycloalkyl-lower alkyl of not more than 8 carbon
atoms, lower alkenyl, lower alkynyl, (di-lower alkylamino)-lower
alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, alkanoyl-
oxy-lower alkyl, lower alkylthio-lower alkyl or phenyl-lower
alkyl, and the ring A is unsubstituted or monosubstituted by
halogen with an atomic number up to 35, lower alkyl, hydroxy,
lower alkoxy, alkanoyloxy, lower alkylthio, trifluoromethyl or
cyano, X represents O, S, methylene, a

71


direct bond or the divalent radical of the partial formula

Image (Ia)

in which R3 represents hydrogen or lower alkyl, Z represents vinylene and Y
represents a direct bond.

3. A process according to claim 1 for the manufacture of compounds of
the formula I, wherein R1 represents hydrogen, lower alkyl, cycloalkyl-lower
alkyl of 4 to 8 carbon atoms, lower alkenyl, lower alkynyl, (di-lower
alkylamino)-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,
alkanoyloxy-lower alkyl, lower alkylthio-lower alkyl or phenyl-lower alkyl,
the ring A is unsubstituted or substituted by halogen with an atomic number
up to 35, lower alkyl, hydroxy, lower alkoxy, alkanoyloxy, lower alkylthio,
trifluoromethyl or cyano, X represents O, S, methylene, a direct bond or the
divalent radical of the partial formula Ia

Image (Ia)

in which R3 represents hydrogen or lower alkyl of not more than 4 carbon
atoms, Z represents vinylene and Y represents a direct bond.

4. A process according to claim 1 for the manufacture of compounds
of the formula I, wherein R1 represents hydrogen, lower alkyl, cycloalkyl
lower alkyl of 4 to 8 carbon atoms, lower alkenyl, lower alkynyl, (di-lower
alkylamino)-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,
alkanoyloxy-lower alkyl, lower alkylthio-lower alkyl or phenyl-lower alkyl,

72


the ring A is unsubstituted or substituted by chlorine, bromine, methyl,
hydroxy, methoxy, methylthio or cyano, X represents O, S, methylene or the
divalent radical of the partial formula Ia

Image (Ia)

in which R3 represents hydrogen, methyl or ethyl, and Y represents a direct
bond and Z represents vinylene.

5. A process according to claim 1, for the manufacture of compounds
of the formula I, wherein R1 represents lower alkyl or cyclopentylmethyl and
the ring A is unsubstituted or substituted by chlorine, methyl, methoxy or
cyano, X represents O, S, methylene or the divalent radical of the partial
formula

Image (Ia)

in which R3 represents hydrogen, methyl or ethyl, and Y represents a direct
bond and Z represents vinylene.

6. A process according to claim 1 for the manufacture of 3-Methyl-
2,3,4,5-tetrahydro-1H-dibenzo[2,3:6,7] thiepino [4,5-d] azepine.

7. A process according to claim 1 for the manufacture of 3-Methyl-
2,3,4,5-tetrahydro-1H-dibenzo [2,3:6,7] oxepino[4,5-d] azepine.

8. A process according to claim 1 for the manufacture of 3-Methyl-
7-cyano-2,3,4,5-tetrahydro-1H-dibenzo [2,3:6,7]thiepino [4,5-d]azepine.

73


9. A process according to claim 1 for the manufacture of 3-Methyl-
1,2,3,4,5,10-hexahydro-dibenzo[3,4:6,7]cyclohepta[1,2-d]azepine.

10. A process according to claim 1, for the manufacture of 3-(2,3,4,
5-Tetrahydro-1H-dibenzo[2,3:6,7]thiepino[4,5-d]azepin-3-yl)-propanol.

11. Azatetracyclic compounds of the formula I as defined in claim 1,
whenever prepared by a process as claimed in claim 1.

12. 3-Methyl-2,3,4,5-tetrahydro-1H-dibenzo[2,3:6,7]thiepino[4,5-d]
azepine whenever prepared by a process as claimed in claim 6.

13. 3-Methy1-2,3,4,5-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-d]
azepine whenever prepared by a process as claimed in claim 7.

74

Description

i;6~ ~

The present invention relates to novel azatetracyclic compounds
and their acid addition salts having useful pharmacologi.cal properties, a
process for their manufacture, and also to pharmaceutical compositions which
contain the novel compounds as active ingredient, and to their use.
The azatetracyclic compounds of ~he present invention have the
formula



N .~:
Y~


wherein
Rl represents hydrogenl lower alkyl, cycloalkyl-lower alkyl of not more than
10 carbon atoms, lower alkenyl, lower alkynyl, ~di-lower alkylamino)-lower
alkyl, hydroxy lower alk~l, alkoxy lower alkyl, alkanoyloxy lower alkyl, lower
alkylthio-lower alkyl, phenyl-lower alkyl, or phenyl-lower alkyl substituted
by halogen with an atomic number up to 35~ lower a~lkyl, lower alkoxy,
methylenedioxy, or trifluoromethyl,
the ring A is unsubstituted or substituted by halogen with an atomic number
up to 35, lower alkyl, hydroxyl, lower alkoxy, alkanoyloxy, lower alkylthio,
trifluoromethyl or cyano, :
Y represents a direct bond, Z represents vinylene, and X represents 0, S,
methylene, a direct bond or a divalent radical of the partial formula

~ ~
Nl ~Ia)
R3
J

~ 2-
~., ~
. . . .
. - . : , :

.. ,' .


in which R3 represents hydrogen or lower alkyl, or Y represents a direct bond,
Z represents S and ~ represents a direct bond or S.
The subject matter o-E the invention also comprises the acid
addition salts of the compounds of the formula I, in particwlar the pharma-
ceutically acceptable acid additlon salts.
In the abo~e definition of the formula I and throughout this
specification, the term "lower" used to qualify organic groups and radicals
denotes that these contain not more than 8, preferably not more than 4, carbon
atoms.
lQ Lower alkyl radicals represented by Rl pre$erably contain 1 to 6
carbon atoms. These lo~er alkyl radicals, which can be straight-chain or
branched, are for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl
or tert. butyl.
~ cycloalkyl-lower alkyl radical represented by Rl contains
preferably 4 to 8 carbon atoms and is, for example, cyclopropylmethyl,
cyclobutylmethyl and, in particular, cyclopentylmethyl, cyclohexylmethyl,
and also, for example cyclo-




~ ~ ,

~ ;~s~

pxo?ylethyl., cyc~ol~utyl.ethyl~ cyclopen~ylethyl, cyc~ohexyl~ethyl.
~ lower a.lkenyl radical Rl contains prefera~ly 3 ~o 4
and, in particular, 3 carbon atoms, a.nd is ~or exarnple a~.lyl
or 2-methylallyl.
A lower allcynyl radical Rl is in particular pro-
pargyl.
In a(di-lower alkylamino)~lower al.ky]. radical P~l5 the
nitrogen atom i.s separated from the ring n:itrogen atom by at:
leas~ 2 carbon atoms. This radieal con~a.in.s prefer~.bly not
more than 10, iTI particular ~rom 4 to ~, carborl atoms, I.'he
lower alkyl moieties in this substituent are preferab:l.y
straight-chain. The entire radic.al is for example diethyl-
aminobutyl, diethylaminopropyl or di.ethylaminoethyl, dimethyl-
aminobutyl, dimethylaminoethyl and, in particuLar, dim2thyl~ ~:
aminopropyl.
The hydroxyl group in a hydroxy-lower alkyl radical
Rl is separatecl from the ring nitrogen atom by at least 2
carbon atoms. This radical con~ains 2 to ~, preferably 2 to 6,
carbon atoms, can be straight-chain O-L- branched~ and is for
example l-methyl-2-hydroxyethyl, 2-hydroxypropyl, 1. or 2-
methyl-2-hydroxypropyl and, in particular, 2-hydroxyethyl and
3 hydroxypro~yl.
The oxygen atom in a lower alkoxy-lower alkyi
radical Rl ;s separated from the rîng nitrogen atom by at least
.

~ $



2 carbon ator.ls~ '3`h:is radicaJ contai.ns ~or example 3 to 10, ;~
preferably 3 to 69 carbon atoms, and i~s for example 2~meth.o~y-
propyl, 2- or 3-etho~ypropyl, 2- or 3-propoxyprbp-~1, 3-iso-
pxopoxypropyl and~ in parti.cular) 2 methoxyethyl or 2-ethcxy~
ethyl and~ preferably, 3~methoxypropyl,
The oxygen atom ln an alkanoyloxy-lo~er alkyl radical
Rl is separat:ed from the ring nitrogen atom by at lPast 2
carbon atoms, This radical contains for example 3 to 21,
preferably 4 to 11, carbon atoms, and i5 for example 2-formyl-
ethyl~ 2~acetyloxyethyl, 2-propionyloxyethyl, 2-acetyloxy
propyl, 2~ ethyl-3-acetyloxypropyl or 2- or 3~propionyluxypropyl
and, in par~:icular, 3-acetyloxypropyl and 3-oc-t~noyloxypropyl, ...
The sulphur atom in a lower alkylthi.o-lower alky:l
raclical Rl is separated from the ring nitrogerl atom by at
least 2 carbon atoms. This radical contains for exalnple 3 to
lOj preferably 3 to 6, carbon atoms, and ;s in paxt:;cular
methylthioethyl or 3 meth~lthiopropyl.
As unsubst:ituted or substituted phenyl-lower a].k.yl
i.n the phenyl ring, Rl contains for e~ample halogen with an
a~ornic number up to 35, lower alkyL and lower al.koxy~
methylenedi.oxy and trifluorometllyl~ in particulax chlorine~
methyl and methoxy,
The ring A can be mono~ or polysubstituted. However,
it is preferably monosubstitu~ed by halog n with an ato~nic
n~tmber up to 35, preferably by chlorine; lower alkyl of not


~.~
-- 5 --


. ~
., .



.
. . .


more than 4 carbon atoms, such as ethyl, propyl, isopropyl,
butyl, isohutyl, ~ert.-butyl and especially methyl; hydroxyl~
lo~er alkoxy of at most ~ carbon atoms, such as ethox~ pro~
poxy, isopropoxy, butoxy, isobutoxy and especially rueLhoxy;
alkanoyloxy, such as formyloxy, propionyloxy and especially
acetyloxy; lower alkylthio of at most 4 carbon atonis9 such as
ethylthio3 propylthio, isopropylthio, butylthio, and especi.ally
methylthio, as well as by trifluoromethyl or cyano.
If X represents ~he divalent radical of the partial

formula Ia
I /
N
¦ (Ia)
R3


then R3 is preferably hydrogen or lower alkyl o~ no~ more than
4 carbon atoms, such as propyl, butyl, isobut~Jl and, in
particul.ar, methyl or ethyl.
Preferably, Y represents a direct bond and Z repre
sen~s vi.nylene or epi.thio.
Salts of compounds of the formula I are primarily
acid addition salts, in particular pharmaceutically acceptable
acid addition salts, for exa~lple with inorganic acids~ such
as hydrochloric acid, hydrobromi.c acidg sulphuric acid or
phosphoric acid, or with organic acids, such as organic
carboxylic and sulphonic acids, for exarnple meLhanesulphonic
acid, ethanesulphonic acid~ 2-hydroxyethanesulphonic acid,

~ .
6 -

:




.
, . ; . ~ . ~

-, ' ~ . ~


acetic aclcl~ malic acid~ tarta~ic ac:;~, cltri.c acid, lact.ic
acid, oxal:i.c acid, succinic acid, fumaric acid~ maleîc aci.d,
ben~o:;c acid, salicylic acid, ph-?.nylacetic acid, rrandelic
acid or embonic acid.
The novel azatetracycllc compounds of the formula X
and the acid addition salts thereof have useful pharma-
cological properties which a.ct, for example~ on the central
nervous systeml They revea.l in particular a damping effect
on the central nervous system and excitation-inhibiting -.
e~fects (amplletamine-inhi~iti.llg effects) 9 as can be
demonstratcd ~y means of pharrnacological tes~s. When adminis-
tere(l ~o rats in the amphetamine antagonism test in a dosage
range from 0~1 to 25 mg/kg i.p. or per os LNiemegeers and
Jal~ssen, Arzneimittelforschung, VolO ~4, page 45~ 1~974)3 9
they thlls show excitation inhiblting effects. Compared with
the amphetamine antagonistic e~fect, the cataleptic e~fect
is relative].y s.l.ight. The novel azatetracyclic compounds and
~:he pharmaceu~:ically acceptable acid addition salts thereof
can therefore be used as tranquillising, antipsychot-ic and
excitation-inhibîting compounds for the treatment of states
of ag:itati.onG
The invention relates in particular to cornpounds
of the formula I, wherein Rl represents hydrogen~ l.ower alkyl,
cy~loalkyl-lower alkyl of not more than 8 carbon atoms, lower
alkenyl~ lower alkynyl,(di-lower alkylamino~lower alhyl,



-- 7 ~


,................ . ~, .
.
.. .


.

s~
:

hydroxy-lower alkyl, lower alkoxy-lower al]cyl, alkanoyloxy-lower :
alkyl, lower alkylthio-lower alkyl or phenyl-lower alkyl, and the
riny A is unsubstituted or monosubstituted by halogen with an
atomic number up to 35, lower alkyl, hydroxy, lower alkoxy,:
alkanoyloxy, lower alkylthio, trifluoromethyl or cyano, X repre-
sents epoxy, epithio, methylene, a direct bond or the divalent
radical of the paxtial formula




(Ia) ~;~

::
in which R3 represents hydrogen or lower alkyl, Z represents
vinylene and ~ represents a direct bond, and pharmaceutically
acceptable acid addition salts thereo.
The invention accordingly provides compounds of the
formula I, wherein R1 represents hydrogen, lower alkyl, for example
methyl, ethyl, isopropyl and n-butyl, cycloalkyl-lower alkyl of
4 to 8 carbon atoms, for example cyclopentylmethyl and cyclohexyl~
methyl, lower alkenyl, for example allyl, lower alkynyl, for
example propargyl, (di-lower alkylamino)-lower alkyl, for example
dimethylaminoethyl and 3-dimethylaminopropyl, hydroxy-lower :alkyl,
for example 2 hydroxyethyl and 3-hydroxypropyl, lower alkoxy-

lower alkyl, for example 3-methoxypropyl and 3-ethoxypropyl,
aIkanoyloxy-lower alkyl, for example 3-acetyloxypropyl and 3-
octanoyloxypropyl, lower
'~; .
'~'`

- 8 - ~ :
r~ :
.. ~ ~
~.




,:


alkylthio-lower alkyl, for example 2-methylthioethyl and 2-
ethylthioethyl, 3-methylthiopropyl and 2-ethylthiopropyl or phenyl-
lower alkyl, for example ben~yl and phenylethyl, the ring A is
unsubstituted or substikuted by halo~en with an atomic number
up to 35, lower alkyl, hydroxy, lower alkoxy, alkanoyloxy, lower
alkylthio, trifluoromethyl or cyano, X represents epoxy, epithio,
methylene, a direct bond or the divalent radical of the partial
formula Ia

\/
(Ia)
R3




in whlch R3 represents hydrogen or lower alkyl of not more than
4 carbon atoms, preferably methyl or ethyl, and Z represents
vinylene and Y represents a direct bond, and pharmaceutically
acceptable acid addition salts thereof.
The invention provides in particular compounds of the
formula I, wherein Rl represents hydroyen, lower alkyl, for
example methyl or ethyl; cycloalkyl-lower alkyl of ~ to 8 carbon
atoms, for example cyclopentylmethyl and cyclohexylmethyl; lower
alkenyl, for example allyl; lower alkynyl, for example propargyl;
tdi-lower alkylamino)-lower alkyl, for example dimethylaminoethyl
and 3-dimethylaminopropyl; hydroxy-lower alkyl, for example 2-
hydroxyethyl and 3-hydroxypropyl; lower alkoxy-lower alkyl, for
example 3-methoxypropyl;


g



:



alkanoyloxy-lower alkyl, for example acetoxypropyl and octanoyl-
oxypropyl; lower alkylthio-lower alkyl, for example 2-methyl-
thioethyl and 3-methylthiopropyl; or phenyl-lower alkyl, for
example benzyl and phenylethyl; the ring A is unsubstltuted or
substituted by chlorine, bromine, methyl, hydroxy, methoxy, ~:
methylthio or cyano, X represents epoxy, epithio, methylene or
the divalent radical of the partial formula Ia




(Ia)
R3



wherein R3 represents hydrogen, methyl or ethyl, and Y represents
a direct bond and Z represents vinylene, and pharmaceutically
acceptable acid addition salts thereo~. ;
The preferred compounds are those of the formula I
wherein Rl represents lower alkyl, for example methyl or ethyl
or cyclopentylmethyl, and the ring A is unsubstituted or sub- :
stituted by chlorine, methyl, methoxy or cyano, preferably in
the 7-position in the ring A of compounds in which Z represents
vinylene, X represents epoxy, epithio, or methylene, or the
divalent radical of the partial formula Ia

\ / :'
N
I (Ia) -i
R3



wherein R3 represents hydrogen, methyl or ethyl and Y represents
a direct bond,


- 10 -- ~
D

.. . . . . . .


. ~ . .. ..
... . . ~ ..
. ` ~; ` .

such as 3~methyl-2,3,4,5-tetrahydro-lH~dibenzo[2,3:6,7] thiepino-
[4,5-d]azepine r 3-methyl-2,3,4,5-tetrahydro-lH dibenzo[2,3:6,7]-
oxepino[4,5-d]azepine, 3-methyl-7-cyano-2,3,4,5-tetrahydro-lH-
dibenzo[2,3:6,7]thiepino[4,5-d]azepine, 3-methyl-1,2,3,4,5,10-
hexahydro-dibenzo[3,4:6,7]cyclohepta[1,2~d]azepine or 2,3,4,5-
tetrahydro-lH-dibenzo[2,3:6,73thiepino[4,5-d]azepin-propanol,
and pharmaceutically acceptable acid addition salts thereof.
The compounds of the formula I are obtained in a manner
which is known per se. Thus they are obtained, for example,
by reacting a reac-tive diester of a diethanol of the formula



HO - Cfl2 CH2 - O~I
CH2\ / E12




with a compound of the formula




/ N \ (III)
H H




- 11 -




:. ,
:
: ,:


.

:
As reac~ive cliesters of a diethclnol of t11c ormula II
it is possible to use e.sters of strong il~Ol::galliC acitls~ for
e~a;nple este-rs o:E ~is-hydroc111.or.; c acil d, bis hytlroioc1ic acid
or, i n pa.rticular~ esters of bis--hydrob-l-omic acid or hydr;:)-
brom:;c-11ydroch.lorlc acid~ Fuxtherrnore~ correspol1di.ng dle~te-rs
OI stron~; organ:i.c acids, for exan!ple of sul.phcJT1;.c acic1s, such
as metha1~esulphorl:ic acid, benzenesulphonic acid, p~ch.loro or
p~bromobf~nz.enesul~honic acid or p- toluenes~1}.phonic a.cid? car
also be useda These diesters of compounds of the formuLa XI
are preferably reacl~ed in a su:i.tab:l e inert solvent at
reaction temperatuxe bet~een 20 and 13()C, E~amples of
sui.table inext solvent~s are: hydrocarbons, such as ber1zene
or toluene, halogenal:ed hyclro~arbons, sueh as chloro:orm,
lo~er alcohols, such as ethanol and~ parl:icular~ me~thano1
ethereal liquids, such as et:her or dioxan~ as well as lower ;~
al~;anones, for example acetone, methyl ethyl !cetone or diethyl
ketone, or mixtures o~ such solvents, for exar.lple benzene-
meth2nol..
During the reaf l ion o:E one molar equivalent: of a
diester of a diethclnol of the formula II with one ntolar
equivalent o:E a :~ree base of the formula LII two molar
equivalents o:E acid, which are preferably bonded to an acid
accep~ox~ are split off. Examples of suitable acid ac:ceptors
are alka.li carbonat:es~ such as potassium carbonate9 or alkali
hydroxides, for exat~ple soc1ium hydroxide ox potassium hydro~
xide, or excess base o the formula III, and also tertiary

-- 1 2 ~

- . . . . ~ :
.

. . -
. ~ .. . . ..

.



organic bases, such ~lS pyrid1ne and especial1y triethy1amine
or N- e~hyl d:iisopropylami.ne .
'rhe direct starting m~teriaLs, i.e. the reactive
dlesters of the formula II, can be obtained frorn the
corresponding dietllanols by esterif1catiorl or rep1acement of
the hydroxy1 groups by halogen by conventional mathods. The
diethanols car ~e obtai7led in turn from the corresponding
dimethyl acetates by reduction with lithlurn aluminium hydride.
The ~nethyl cliacetates can be obtained from the correspon~ing
diacetonitriles with methanol ~ncl 2 molar e~luivalents of
wateL- by intro~ucill~ hvclro~,en chloride. The diacetonitriles
can be obtained in turn from the corresponding bis~(bromoe~hvl)
compounds with sodium cyanide.
h further process gives compounds of ~he orm~l1a I
in which R1 represents the group R1 which has the same
meanin~ as R1, with the exception of esterified hydroxy-lower
a]~yl, by reducing a compound of the formu1a


I
~2~ / N \ ~ Q1
J . ~
~Sx~z3 : ~


~ 13 - ~
'

: ',, ' . ~ ~ .
.
- -


herei~ at le~st one the symbv'!.~ Q-l ancl ~2 represents an
oxy~er~ at:om and th.e other can repre~ellt 2 hydrogen atomsO
Th.e reclltction is advantageously carried ou~ with
a comyle~ ~hydrlde~ such as lithit~ ai.umin:iu[ri hydride or
diborane or al~rmini~lm hydride} The prefer~ed solvent i5 an
ethereal liquld~ such as cliethyl ether, tetrahydrofuLan,
~io~an, e'chylene glycol dimetllyl ether or cliethylelle glycvl
climethyl ether The reaction, ternperature is preferably bet~een
approx050 and 100C, or the boill,ng temperature o:E the
reaction rnedium employed. The diborane can eit.her l.~e prepared
separately and introduced or formed ln SitU from sodiu~n '.
Ior~n'l.lydrid.e ancl boron trifluoLi.de etheral:e,~ It is possib'l.e to
use ad~litlonally an acti.vator, such as aluminium ~hlorJ.cle, for
the reaction with lithium alum,inium hydride.
The N-substituted lactam and imide compounds as
~tarting materials of the formula IV can be prepared by ''
substitu~ion of the corresponding compounds o~ the formula IV
which are not N-substitutedO This N-~ubstitution can be
effected by known methods~ for example with a reacti.ve ester
of a correspolld:ing hydxoxy compound of the forrrrula R.l-OH, in
which Rl i9 as de~ined above with the exception of hydrogen~
The imides of the formula IV ~hich are not N-subs~l-
~uted can be obtained from the compounds of the formula VII,
namely by formation of the azepine ring with hydrogen bromide
and subsequent treatment with wa.ter and dirnethyl formamide.


.~ .

~ 6




The correspondi.ng lactamsc~ be obtain d from these imides by
partial reduction with a c.omplex anhydride in an ethereal
solvent, such as diethyl ether or tetrahydro~aran,
Subsequent to the reactions according to the
invention, a number of conversions can he effected to convert
the compounds of the form~la I into other compo~mds o~ the
formula I.
If desired, a compound of the ormula I~ whose
radical Rl represents hydrogen, can be converted into a
product whose radical Rl has one of the other meanings.
. Thus, for example, a N-substitu~ion can be effected
either with a rea.ctive ester o a corresponding alcohol o the
formula RlV-OH, in which RlV has the same meaning as R] in
formula I with the exception o hydrogen, or by a reaction
with corresponding aldehydes or ketones under reducing
conditions.
The reaction of compounds oE the form~lla I, irl~which
Rl rep~esents hydrogen, with a reactive ester of a h-ydroxy
compound o~ the formula RIV OH,is preferably carried out in a
solvent at a reaction temperature between 20 and 130C, in
particular at the boiling temperature of the solvelltO
E~amples of suitable reactive esters are: halides J ~ :
such as chlorides or bromides, also sulphonates, such as methyl
or ethyl ortho- or para-toluenesulphonate, or sulphates, for
example dimethyl or diethyl sulphate~ Suitable acid acceptors




: - 15 -


, ~ , . .

.

:`, . .
.

S~

are alkali metal car~onates, for example potassium carbonate,
or alkali hydroxides, for example sodium hydroxide, or tertiary
organic bases, for example pyridine or N-ethyl diisopropylamineO
Suitable solvents are those which are inert under the reaction
conditions, for example 'nydrocarbons, such as benzene or toluene~
and alkanols, for example methanol, or ethanol, or alkanones,
such as acetone or methyl ethyi ketone.
Aldehydes and ketones which correspond to the
alcohols of the formula RlV OH are for example lower aliphatic
aldehydes or ketones, lower free, esterified or etherified
hydroxyoxoa~esor esterified oxoalkanecarboxylic acids. The
reaction product obtained during the reaction of these
aldehydes or ketones with the compounds of the rormula I can
be reduced in the same process step or subsequently.
The aldehydes, for example formaldehyde or acetal-
dehyde, or the ke~ones, for example acetone, are heated for
example with the compounds of the formula I in an inert solverlt
t.o approx, 30 - 100C, and simultaneously or subsequently the
reaction mixture is hydrogenated with hydrogen in the presence
of a catalyst. Examples of suitable solvents are alkanols,
such as methanol or ethanol, and suitable catalysts are noble
metal catalysts, such as palladium on charcoal or alloy
skeleton catalysts, such as Raney nicke].
Instead of using hydrogen in the presence of a
catalyst, it i5 also possible to use other reducing a~ents,
for example formic acid, for the reductive a]kylatiotl. In
this modification of the process, the compounds of the
_ l6 -

. , . : .

, , : ,.


formula I are heated with forrQic acid and the~ ~ypes of
aldehydes or ketones r:e~erred to above, in particular forrnal
dehyde, pre~erabl~ wit]~out a solvent.
Thi~ N-alkyla~ion can also be performPd by lirst
acylating the process product in which thc-~ radical Rl repre-
sents h~drogen and then acylatirlg the carbonyl group~ This
reduction is advantageously carried out with a romplex hydride,
such as lithium aluminium hydride or di1~orane The pre~erred
solvent ls an ethere~ liquid, such as dlethyl ether, tetra-
hydrofuran, dioxan, ethylene glycol dimethyl ether or diethyl-
~ne glycol dimethyl ether. I'he react:ion temperature ls pre~e~
rably between approxO 0 and 100C or the boiling tempe~ature
oi the reaction medium employed. The dlborane can be px:epaled
separately and introduced or formed in 9itU from so~ium
bor~ydride and boron trifluoride etherate.
If desired, a compound of the ~ormula I 5 in which
the radical Rl represerlt~ a hydroxy-lower alkyl group, can be
acylated to give a compound in which the rad;cal Rl repre-

sents an esterified hydroxy-lower alkyl group. ~`
The acylation can be carried out ~or example with
a carboxylic acid anhydride or with a corresponding carbonyl
halide at a reaction temperature betweerl approx. 20 and 100C.
Since the condensation takes place accompanied by elimination
of acid, it is advan~ageous to add an acid acceptor, for
example a tertiary organic base, such as pyridine, to the
reaction mixture. Excess tertiary organic base can also be

- 17 -

,............ : . ,

'

,~ .
. .

~ ~f~ ti~



used as solve~ 0 l: is also possible to use a hydrocarbon~
for exalr.ple benzen~ or toluene~ ur a halngena.ted hydrocar~on~
or eY.ample chloroforrn~ as solventc
In addition~ a compound ~f the formula I, in whicl
tne ra.dical Rl represents a phenyl-lower alkyl group 9 can be
subjected to h~dro~,enolys;s to give a process product in which
the radical Rl represents hydrogen.
The hydrogenolysis can be carried out using
conventional hydrogenation catalyst.s, for example nable metal
catalysts, StlCh as palladi.um on caL~bon or platinum o~ide, ox
rhodium cataly3ts, such as rhodium on carbon or on alumlnium
oxide~ or of alloy ske~eton catalys~s, sucll as Raney ni.ckel~
in an inert organic solvent, such as methanol, ethanol or
dioxan, at room temperature and normal pressure cr at :~
moderately elevated temperature ~o appro~. 100C and~or
elevated pressure up to approx. 100 ~ar~
Further!nore~ a compound of the formula I, in whicn
X represents a divalent radical of the partial formula .
\N/




(Ia)


in which R3 represen.ts hydrogen, can optionally be converted

i.nto another process produc~ in which the radica]. R3 repre- ~:

sents lower alkyl.

This conversion is advantageously carried out i.n

- 1.8

:,.. . .


. :
' ': '. ' ' ' . '


such a manner th2i: t~-le a~ove process produc~ 1~ reacted in the ~ .
presence of solvents and ba.s.ic conden~a.ti.on agents ~ith a
r~active lower alkyl ester~
Examples of reactlve esters which. can be u~ed are:
halidesg s~tch ~s chlorides or bromid~ and s~].pllona~es, such
as methyl or ethyl ortho or para toluenesulphonate, or
sulphates, for example dimethyl or diethyl sulpllate. Suitable ~.
basic condensation agents axe alkali. metal alkanolates, such
as potassium tert.-butylate, or correspondlng amides, such as
sodium amide, or metal hydrides~ such as sodium or lithium
hydrideO Suitable solvents are those which are iner~ under the
reaction condit:ic)ns, ~or example hydrocarbons, such as benzelle
or toluene, and e~hereal l.i.quids, for example ~etrahydrouran,
dioxan, ethylelle glycol di.methyl ether, or amides~ such as
phosphoric he~amethyl triamide or dimethyl formamide~
This conversion can, however, be carried ~ut in such
a manner that the process product is fir5t acylated and ~he
carbonyl group then reduced.
This reduction is prefe.rably carr;ed out with a
hydrideO The preerred hydride is cliborane in an ethereal
reac~ion medium, such as tetrahydrofuran, cl:ioxaII~ e~hylene
glycol dimethyl ether or diethylene glycol dimethyl ether~
The reaction temperature is preferably between -2~ and +~0~5
preferably between 0C and room temperature. The diborane is
formed for ex.ample from boron trifluoride etherate and 50d~um


,. .




'~

borohydL-ide either separately, for example i.n tlle solvent: used
~or the reduction~ and used as a solution, or, for example9
formed in diet:hylene g:Lycol dimethyl ether and introduced into
the react~on mixt~lre in gaseous form~ or else formed in situ.
Depending on the process con.ditions and the s~tarting
materials, the inal products are obtained in the free orm
or i.n the form of their salts, which can be converted i.nto
eacll other or i.nto other salts in conventional mannerO Thus :
free compounds of the formula I are formed from resul.tarlt
acid addition salts, for example b~ treatment with base~ or
- ion exchangers, whilst free ~ases o the formula I are
converted illtO acid addition salts, for e~ample by reaction
wi~h organi~ or i.norganic acids, in par~icula.r those which are
suitable for the ~ormation of pharmacologically a~epta~le salts,
such as those mentioned above.
Salts of the novel compounds can also be used for ;~:
purification purposes, for example by converting the free
compounds into their salts, isolating these andopt-onally:
purifying and converLing them again into the free compo~1nds.
Beeause of the close relationship between the novel compounds
in ~h~ free form and in the form of their salts, what is stated
in this specification in respect of the free compounds applîes
by analogy also to the corresponding salts.
The i.nvention also relate~ to those modifications
of the pro~ess in which a compound ob,ainable in any stage as


~, .
20 -




;~
, '

~ ~J ~ '3


i.ntcxn;edia~e~ :i.s tsed as sta~ting mat~ricll and the m:issing
proce.ss steps are c~rr:iecl out~ or the proeess i.s discontinued
at any stage, or in wllich a starti ng mate:cial is ~ormed under
tlle reacti.on collditi.ons o~ in whjch a reaction compon2nt is
op~ional.ly in the form of a.d~rivat:ive, for example in the
orm o.~ a sal~7
It is advantageous to use for earrying OLlt the
reactions of t.he present invention those s~arting mai:exi.als
which resLllt in the groups of end products par,icularly
referred to at the outset and espeeia].ly in the end products
described or cingled out for special mention.
The novel compounds ean be used Eor exarrlple in the
form o~ pll~.rmace~ttiecll ccmpositions whieh colltain ~n ef~ective
amount of the active substanee, if appropriate to~e~her with
i.norgan-le or organie, solid or liquid pharmaeeut.ieally useful
earriers suitable for enteral, ~or example oral, or parenteral
admin~stratjon. '~ablets or gelatin capsules are therefore
used whieh cont~in the aetive substanee tog~ther wi~h diluents,
for example lactose~ dextrose~ suerose, rnannitol, sorbitolS
ee~.'lu'lose an.dtor glyein, and lubrieants, for example siliGa~
tale~ stearie aeid or salts thereo~, sueh as magnesium or
ealeium stearate, and/or polyethyïene glyeol. Tablets also
contai.n binding agents, for example magnesium aluminium sili.eate,
starehes, such as maize, eorn, riee or arrow root starchl
gelat.ins, tragacanth, methyl eellulose, soditlm car~oxymethyl

,
21



.:
, ~
.


~v~

cellulose and/or poly-vinyl pyrrolidone~ and, if desired,
disintegr~tors, for example starches, agar, aLginic acid or
a salt thereof, such as sodium alginate, al~d/or ef~e~vescellt
mixtures, or adso ption agents~ dye~, flavouring m~tters c~nd
sweetencrsO It is also pos.sible to use the novel pharma-
cologically active co~lpounds in the ~orm of compositions ~or
parent~ral administrPtion or o infusion solu~ions Such
solutiorls are preferabl~ isotonic aqueous solutions or sus-
pensions which can be prepared before ~lse, for example
frvm lyophilised preparations that contain the active subs~ance
alone or together ~ith a carrier~ for example mamlitol.
The pharmaceutical compositions can be sterilised and¦or contain
adjuvants~ ~or example preservatives, stab~lis~rs, wetting
a~ents and/or emulsifiers, solubility promoters, salts ~or re-

gula~ing the osmotic pressure and/or buffersO ~le pharmaceu~ -
;
tical composit:ions which, if desired, can contain further
pharmacologically useful ~ubs~ances, are manufactured in
kno~n manner, for example using conventional mixing, graIlul~
... ~
ating9 con~ect:ioning, dissolving or lyophilising methods,
and they contaill from abou~ 0.1 % to 100 %, especi.ally from
about 1 % ~o about 50 %, of lyophilisates up to lOO % oI the
active substance.
The dosage depends on the mode o~ applicaticn,
species~ age, and on the individual condition. The dailv doses
of the free bases or of pharmaceutically acceptablP salts


- ~2



: .

..
.

~ 5 ~



thereoI are be~ween approx. 0.1 m~/kg and approx~ 10 mg/kg ~or
warm- blooded animal~ in ~eneral, and be~wcen approxJ 0.01 g
and approx. O.S g for warlllblooded an:imclls haviIl~ a weight of
approx, 70 kg.
The :invent.:i.on is illustrated by the following
ExamplesO




- 23




' ,~

,


~ le 1

To a solution o~ 21~8 g (0.05 mole3 o ].0,11-bis-[2
(met'hylsul~?hon~loxy)-ethyl~-5H-d:LbenzoLaad~cycloh.eptene ln
200 ml of absolute ethanol are added 35 m:L (~G g, 0~06 n-LoLe~
of a 7.4 % ethanolic ethylaluine solution and 15,5 g (0.125 mol.e~
of diisopropyl ethylc~mine. The reaction mixture i~ refluxed
for 18 hours, then concentrated in a water jet ~acuum. ~he
residue is dissolved in 300 ml of methylene chloride and the
solutlon is washed in succession with 100 ml of 2N sodium ~-
hydro~ide ~olution and 100 ml of waterO The methylene chlorlde
solutlon is concen~ra~ed in a ~ater jet vacuum to approx.
50 ml and treatecl wi~h 15 ~ll o~ 4N ethereal hydrogen chlor:ide
solutioll, whereupon the 3-ethyl-1,2~3,4,5,10-hexahydro-d.ibenzo
~3,4:6,7jcyclohe.pt2~1,2-d~azepine hydrochloride with a meltlng
point of 29G-2~39C orystallises out. Melting point; ~f the ~ ~ -
methanesulphonate: 220-221C~
T~le starting material can be prepared in the ~ollowing ~ -
manner in accordance with the particulars of E~ample 5:
dimethyl 5H-dibenzo~a,d]cycloheptene 10,1l--diacetate, m~p.
104-106C (fro~n hexane)~ star~ing from 27 g (0.1 mole~ of
5H-dibenzo~a,d]cycloheptene-10,11-diace~onitrile~ 400 ml of
metnanol, 3.8 ml G~ water and dry hydrogen chloride5
5H-dibenæo[a,d]cycloheptene-lO,ll-diethanol, mOp. 154D-156~C
(from acetone), starting rom 33 6 g ~0~1 mole) o dimethyl
5H-dibenzoLa~d~cycloheptene lO,ll~diacetate and 7.6 g (002 lllole3


-- 2~ ~ ~
':




, . : ~ , : - .
-
, .

- : : - . :. :, ~ :

11J~

OL li~hi.um alumi.niu~ hydride in 1 li~re of abs, diethyl ether~
To a solu~ioll of 2~ g (0~10 mole~ o SH dibenzc)[a~,d3
cycloheptelle-lO,ll~dietha,nol i.n 120 ml of pyricllne are added
dropt~ise 1608 ml (,'5~2 g, 0~2~ mo'le) o:E l~ethanesulphonyl
chloride at room temperc~tureD Ihe reaction mixture is there~
ater s~irred for 30 minutes at 0C an(l then ~or 1 hVUr at
15~25C, then together with 600 ml of methylene chloride -ls
extracted in a separating f~mnel in succes.sion with 400 ml of
5N hydrochloric a.cid and 400 ml of ice~water. The methylene
chl,oride sol~ltion is æp~.~d,dric~lover magne.si.um sulphate and
concentrated in a ~.ater jet vacu1lm, to give as resi~ue lOg'll-
bis~-[2-~Methyls~lphonyloxy)-etllyl]--SH-clibenzo[a~dJcyclolleptene
in the ~urm of a colourless oil.
The following compounds can be prepared in analogous
mann~Qr:
3-methyl-1,2,3,4,5~10-hexahydro~dibenzo~3,4:6,73cyclohepta[1,2-
d]azepine rnethanesulphonate, m.p. 189-191C, starting ~orn
21~8 g (0.05 mole) of 10,11-~is~[2-(methylsulphorlyloxy)-ethyl]-
SH-dibenzo~a,d~cycloheptane, 30 ml (1.9 g~ 0~06 rr.ole) o a
6.3 % e~hanolic methy'lamine solution ~nd 15,5 g (0~125 mole~
of diisopro~yl ethvlamine. ~ '
3-Benzyl-1,23~3,4,5,10-he~ahydro-dibenzo[3,4:6,7~cyclohepta[1~2
d~azepine hydrochloride, m~pO 265-27~C, starting f-~om 21.~ g
(OO0S mole) of 10,11-bis~2-~methyls~.llphorlyloxy~-ethyl}-SH-
dibenzo~a,dleycloheptene, 602 g (0006 mole) of benæylamille

.,
- ~5 ~


and 15,S g (0 125 mole) o diisopL^cpyl ethylamine.




F.xample 2

A suspension o~ 19.4 g (0~05 mole~ of 3 benæyl-1,2,
3,4,5,10-he~.ahydro-diben~o[3,~:6,7]cyclohep~a~152 d]azepine
hydrochloride and ~ g o~ 5 % palladium on charcoal ~atalyst
in 900 ml of methanol is hydrogenated at ncrm~l pressure and
40-50C until 770 ml o h~drogell llave been taken up, The
catalyst is then removed by suetion filtration and the filtrate
i5 concentr~ted in a water iet vacuum.
The resi-lual crucle 152~3,4~5,10-hexahydro-diberlzo~3
4:G~7]cyclohepta[1,2-d]a~epine hydrochloride is r~crystallised
~rom ethanol~ Melting point: 295-300C,
The base is set free ~y suspendirlg th hydroch~o-~ide~
in 250 mol of methylene chloride and extraction with 100 ml
of conc~ ammonia solution. The methylene chloxide solution is
separated and concentrated until the onset o~ cry9~allisationO
Then hexarle is added, whereupon the 1,2~3,4,5~10-hexahydro-di-
benzo[3,4:6,7]cyclohepta[1,2~d]a~epine with a mel~in~ point o
190-191C crystallises ou~.
For co~v~rsion into ~he methanesulphonate, the free
base is dlssolved in methylene chloride and a~ter addition
of the theoxeti~al amount of methanesulphonic acid the 1,2,3,
4,5,10-hexahydro-di~enzo~3,4:6~7~cyclohepta~1,2-d]azeplne


- 26 -




':.~ ` ;

~ 5 ~ ~ :


methanesulphonate i.s pre.cip:itated with ether~ Meltirlg point:
269~-~71Q~. : ;




~ 3

To a solution of 43~6 g (OD 1 mole) of lO,ll-bis~~2- .
~methylsulphonyloxy)-ethyl]--5H-diben~o[a,d~cycloheptane in
400 ml of ~bsolute ethanol are added 11.9 g (0.12 mole) of ~.
(aminomethyl)~cyclopentane and 32.3 g ~0.25 mole) of dii~o
propyl ethylamine. The reaction mixture is ~hen concentratecl
in a water jet vacuum, the residue dissolved i.n 150 ml of
methylene chloride and 500 ml of pentane, and the solut;io
washed in succession wi~h 200 ml of 2M sodium hydroxide
solut.ion and 200 ml of water. The organi.c phase is subsequently
treated with 2.00 ml of 2N hydrochloric acid and the hydro~
chloride precipitates in crystals. The crystals are collected:
with suc~ion and the base is set free by suspending the hydro~
chloride in 300 ml of methylene chloride a.nd extraction with
100 ml of conc. ammonia solutionO
The methylene chloricle solution is separated and
concentraLed until the onset of crystallisation. After the
addition o~ hexane, the 3-(cyclopentyl-methyl)~1,2,3,4,.5,10-
hexahydro-dibenzoL3,4:6,7]cyclohepta~1,2-d]azepine with a
melting poinc of 141-142C crystallises outO For conversio~l
into the methanesulphonateg:the base is dissolved:-Lll methylene


: '

~'; , :
,, .. . ~ .

chloride, the solutivn ls acidifled ~:ith the theoret:ical amourlt
o me~h~nesulphonic acid, and the 3 (cyclope-~tylmethyl~ 2,~3,
4~5jlO~hexah.ydrv dibenzo[3~4:6~7]cyelohepta~:l,2-d¦azepine
methanesulphonate is precipitated with etherO ..
Melting point: 248 249C

`;, ~ ' ..
F ample

With ice cooling, 2601 g (0.1 mo~e) o:~ 1,753,4,5,10- `
hexahydrv-dibenzQ[3,4:6~7]cyclohepta~1,2~d3azepine (prepared ~:
in accordance with Example 2) are treated with 92 g (2 moles~ of
~ormic a~id and 20 g (0,2 moLe) of 30 % :Eormaldeh~de and the
reaction m:i~tuxe is stirred ~or 1 hour at 95-:L00C~ The
mix~ure is then poured onto ice wate~ and mada alkaline with
lON sodium hydroxide solution.~ The precipitated base is ~aken
:
Up in methylene c.hlor:ide and ~he methylene c~.loride solution~
is concentrated until. the onset of crystalli~ation. Ihen
hexane is added, whereupon:the 3-methyl-1,2,3,4,5,10-he~ahy~ro-
~dihenzo[3~4:6,7~cyclohep~a:[1,2-d]azepine with a melting point
ox L44~ &~ crys~allises ou~. For conversion into ~he
methanesu ~ onate, the base is dissolved iII meth~1enP ch1oride~
tlle solution is treated wlth the theoretical amount of me~hane-
~:sulphonic acid, and the 3 methyl 1,2~3,4,5510-hexah~ro-


- : :
dibenzo~3,4:6,7]cyclQhepta[1,2-dJazepine methanesulphonate

: lS precipitated with ether~ Melting point: lS9-191C.

, ~
.~ ~. 28
,,




.

:

5~

E.~am~e 5

To a soluLion of 4~56 g (0cOL mole) of 10511-bis~2-
(meth.ylsul.phon~loxy)-ethyl]-dibel~zo~b~]thiepine in 50 ml o~
absolute ethanol are added 113 g (00012 mole) of benzylamine
and 3.25 g (0.0125 mole) of dlisoprop~Tl ethylamine and the
reactlon mixtu-~e is refluxed for 18 hoursO Af~er cooling
with an ice bath, crystals precipitate znd are collected with
suction and washed with a sn~all flmo~mt ol isoproparlol and
pentane, The fi.lter cal~e con3ists of 3~benzyl-2~3~4,5-tetra~
'nydro~lH d:ibenzGE2~3:6~7]thiepino~4~5-dJ~azepine Wi~}l a mel~ing
pOill~ 0~ 9-]50Co




`1~ . . ~. Cl3


M
'~'\~3 '


For conversion into the h~drochloride, 3 g of the
base are dissolved in acetone and 2,2 ml of a 4N hydrogen
chloride solution in ethe re ac1ded to tnis sol~tior1.c Then
ether is added until the solution becomes slightly turbld and

- :.




. . . . -
.

.~ :, :, . : ' ' ' ' :

~ J ~



the 3-bellzyl-2,3,4,5~tetra~1~1-dicenzo[2~3:6,7Jthiep-Lno[4,5-d]~
azepine hydrochlorlde crysta:llises out~ Melting point: ::
2 ~1 2 ~r ') C
The sta~ing material can be prepared as follows:
With stirri.ng, 5S g (0,2 mole) of dibenzo[b,~th:i.epi.ne-10,11~
diacetonitrile ar~ susperide~ in 800 ml of metllanol and 7~5 ml
o~ water and the susperlgiorl i5 cooled ln an. ice bath to 0 5C.
Then c]ry hydrogerl chloride is introduced in the course o L
hour ancl a clear so].ution forms. (During ~.hi.s in.troduction
the temperat.~1re should be kept at 5-20C). The reactiorl
mi.xture is further st:irred fo~ 1 hour at room temperature and
thell or ~ ho~lrs cl~ re~lux and therea,~,er completely evapora~ed
to dryness by rotar~ e~aporatior!l The re.sldue is dissolved -in
ether and the ethereal solution is washe~l with water and ?.
sodium carbonate sol-ltion~ dried over sodium sulphat~, and
completely evaporatect to dryness. The oily residue;is
dissolved in me~hanol and the solution is cooled to 0~
whereupon methyl dibenzo~b,f~thiepine-10~11 diacet~e
cry5tal~.-lges outO The product is collect-ed with suc~ion an.d
dried at 50C under reduced pressure~ Melting point: S4D~86~C~
With stirring and exc,lusion of moisture~ a solution
of 3504 g (0cl mole) of dimethyl dibenzo~b,f]thiepine--10,11
diacetate in 1 litre of absolute diethyl ether is ad.ded
; dropw:ise, in a nitrogen ~tmosph.ere and in the course of 1
hour, to a suspension of 7O5 g (0~2 mole) of llthium aluminium
: ;
~ 30 ~
; ' '

~: : - -- . - - . .


- . . -

. , -. .'. ~ , '' . :

~ 5 ~



hydride Irl 4~0 ml of absoluke diekhyl ether~ The reaction
mi~ure is subsequently re1uxed for 16 hours~ then cooled
to 0~ and d:ilutecl wlth 130 ml of water (dro~wise addit-.ion~.
The or~anic phase is separated, washed with wclter, dried over
sodium sulphate~ and concent~ated to a small vo:Lun~e~ ~.7hereupon
dibenzo~bgf]thi.epine-10,11 diethanol with a melting point
ol 131-133C crystallises outO
15 g (O.OS mole) of dibenæo[b,~thiepillP 10,11-
diethanol are dissolved at room temperature in 60 ml o
pyridine and ~he solution ls ~reated dropwise in an i.ce-
~odlum chloride bath, at a reacl.ion temperature of 5C, wi~l
8.4 ml (~2.6 g, 0.11 mo:l.e) of m~thanesulphonyl chloride.
The reaction mix~ture is subsequently stirred for 30 minutes
at 0C and then Ior 1 hour at 15 25C. Together with 500 ml
of methyl~ne ch}.oride the reaction mi~ture is then extracted
in a separating funnel in succession with 400 ml of 2N hydro-
chloric acid and 400 ml of water~ The methylene chloride
solution is separated, dried over magnesium sulphat~, and
concenkraked in a water jet vacuum to give as r~sidue lO,~
bis-[2--(methylsulphonyloxy)-etllyl]-diberlzo[b~fJthiepine with
a melti.ng point of 107-108C.




31.--



~xample 6
,: :In accor~anc~ with the procedure described i.n
Example S, the ~ollowlng compounds oa~ be p~epared using the
correspondlng starting materials:
A) 3-(2-pheny1ethyl~-2,3,4~5~te~rahydro--lH~dibenæo[2~3:6~7]
t'L-Liepino~4~5--d~azep:ine ~7ith a melting point of 96-99C (from
acetonitri.le)~ ~elting point o the methanesulphonate 161-
164C (~rom abs~ ethano]); starting from 22u7 g (0.05 mole)
of lO~:Ll-bis--[2-(methyls.llphonyloxy)-ethyl-dibenzo[b,f]thiepine~
7.3 g (0,06 mol.e) of 2--phenylethylamine and 16.25 g (0 125 moLe?
of dlisopropyl ethylamine in abs. ethanol;
B) 7 methoxy-3-methyl-2,3,4,5-tetrahydro-lH-dibenxo[~.,3:6,7~
thiepino[4,5-d]azepine, melting point 108-112C (F~om acetorle);
melting point of the hydrochloride 220-224C (from ~bs.
ethanol); starting frorn 24~.2 g ~0.05 mole) o~ ]0~ bis-~2-

(methylsulphonyloxy)-ethyl]-2~methoxy-dibenzo~b,L]thie~)ine~ ;
1~85 g of methylartlin2 (0.06 mole) and 16025 g ~0~125 mole)
of dii.sopropyl ethylamine in abs. ethanol 5 ;
C) 7 met:hyl~.hio-3~(cyclopentylm~thyl)-2,3,4~5-tetrahydro-lH
dibenzo[2,3:6~7]thiepino~,5-d]aæepine, crude produe~;
melting point of the metharLesttlphonate 206-209C (from abs
ethanol); sta-rti.ng from 25 g (O.OS moi~-) of 10,11-bis-[2
(methylsulphonylo~y)~eth~1]-2-methylthio-di.beIlzo~b~f]~thi2pine~
6 g (0.06 mole~ of (ami1lolnethyI) cyclopentane an~ 16025 g
~0.125 mole) of di~sopropyl ethylamine in abs~ ethanolj
: . :
- 32 _




:..
. . . ~ . -
- . : . . :

Dj ~i,7~ di.me.tllyl-2,3,4,5-t:etrahydro~ l-dibenzo~2,3:6,7]thiepino
L~S~c~]azepine, crude product; melting pc)int of the hydro-
ch:Lo~ide 255-268"C ~frorn abs~ etllanol)~ sta.rting from 23.,4 g
(O.OS mole) of 10, ll-bis- [2 ~methylsulphonyloxy)-ethyl~--2
me~hyl--d:Lbe.nz,o[b,:F~t:hiepine, 1.85 g (O.Q6 rool~) of meth~lamine
and 16025 g ~0. :L25 mole.) of diisopropyl ethy~ mine in abs~ :
ethano l;
13) 7-bromo- 3 ~methyl~2, 3, 4, 5~- te~rahydro- lH- dibenæo [ 2, ~: 6, 7 3
thiepino~,5-d~azepine~ crucie product; melting point of the
hydrochloride ~80C, witll clecormpositioll (from abs, ethanol) j
starting from 26.7 g (ûoO5 mole) of 10,11-bis [2-(rnethylsul-
phonyloxy)-ethyl]~2- brorno-clibenæo[b,f3thiepine~ 1c85 g (0.6 mole)
~ rl~et~hyl.a~lin~. ancl 16.25 g (00125 moi!e) of cliisoprcJpyl et:llyl.
clmine i.n abs, ethanol j
~; 3~methy:l 2,3,~,5~tetrahydro-lH phenanthro[9,10~d]a.zepine,
mOpO 142-145C ~rom acetone3, mOp. o~ the methanesulfona~e
242 "~244~C (f~:om ethanol); startlng rorn 21.1 g (oOns mole) of
9,1~ bis~2 ~methylsulphonyl.oxy)~ethyl] phenanthrene, 1085 g
06 mole) o~ rnethylarnine and 16.25 g (0,125 mole) o
~ii.fiopropv:l.ethylatnille iII abs. ethanol;

C}~3
.~ ' '



\

- 3 ~


. . ~ . -
. .
. .

.- ' . ,.::', ' '

4~i~;6
~ ;
G) 3 met~lyl-2~3~4~5-~etrahydro~lH~thieno[2~3~ 2Jnaphtilo
E4, 5-d]azepine, c--.tde of produc~;m.p~ of the hydrochloride
273-28~C with decom-po~ition ~:Erom met~lanol~ starting rorr.
21 4 g (0.()5 mole) of 4~5~bis ~2-(methyl.sulphonylogy)-ett.~yl]~-
naphthol~l,2-b]thiophene, 1~85 g (0.06 mole) o~ methyl3in;ne
and 16.25 g (0.125 n,ole) of diisopropylethylam~ne;

C~3 . :.
. ' I ' '


>/
~ \~ S

H) 3-metllyl~ 3,4,5--te~rahydro-l~l-dihenz[2,3:6,7~oxepinoL4~$~
azepine, m~-p. 147-149C (~rom acetonitrile); m~p. o the.
hydrochlorida 282~-28$C (from absO ethanol); sta.rting Irom
21.9 g (0.05 mole) of lV,ll-bls-~2-(methylsulpho~yloxy)~ethyl~
dibenz~b,~o~epine, 1,85 g (0.06 mole) of methyla~ine and
16~25 g (0.12.5 mole) of di.i.sopropyl ethylamine;




( ~
~`'o ~

- 34 ~ ~

~ .


- ` - . . . ,. - . ~ .

. `~
.. ~,
`

I) 3 isopropyl-2,3,4,5-t~trahydro-lH-dibenz[2,3:6~7]oxepino
[4,5-d]azepine, m.p. 125-128C (from acetonitrile); m.p. of '
the maleate 175-177C (from acetone); starting ~rom 21.9 g
(O.OS mole) of 10,11 bis-~2-(methylsulphonyloxy)-ethyl~- -
dibenæ~b,f]oxepine, 3.5 g (0.06 mole) oE isopropylamine and
16~25 g (0.125 molP) of diisopropyl ethylamine;
K) 3-mPthyl-10-ethyl-1,293,4,5,10-hexahydro-dibenz[b,f~azepino
[4,5-d~azepine, m.p. 99 - 100C (from toluene); m.p~ of t~e
oxalate 180 - 183~C (from abs. ethanol); starting from
23 3 g (0.05 mole) of 10,11-bis-~2-~methylsulphonyloxy)-ethyl]-
5-ethyl-5H-dibenz[b,]aæepine, 1.85 g (0,006 mole) oE methyl-
amine and 16.2S g (0.125 mole) of dlisopropyl ethylamine;

CH3 ~
N~




N
C2H5




L) 3-allyl-10-ethyl-1,2,3,4,5,10-hexahydro-dibenz~b,f]azepino
14,5~d]azepine, m.p. 100 - 101C (from hexane); m.p. of the
hydrochloride 245 - 248C (from abs. ethanoljacetone);
starting from 23.3 g (0.05 mole) of 10911-bis-E2-(methy1
sulphonyloxy)-ethyl]-5-ethyl 5H-dibenz[b,f~azepine, 3.4 g
(0.06 mole) of allylamine and 16.25 g (0.125 mole) of
diisopropyl ethylamine9


- 35 -
:'


.
. ' ' ~ ' ' :

! ~

., . .. . - . .

M) 3-methyl-1~2,3,4,5,10-hexahydro-dibenz[b,f]azepino[4,5-d]
azep~le, m.p. 121 - 124C (from methanol~; m.p. of the methane-
sulphonate 263 - 266C (from abs. ethanol/acetone); and
starting from 21.9 g (0.05 mole) of 10,11-bis-[2-(methyI-
sulphonyloxy)-ethyl]-5H-dibenz~b,f]azepine, 1.85 g (0.06 mole)
of methylamine and 16.25 g (0.125 mole) of diisopropyl ethyl-
amine;
N) 3-~cyclopentylmethyl)-1,2,3,4,5,10-hexahydro-dibenz[b,f~
azepino~4,5-d]azepine, m.p. 72 - 75C (from pentane);
mOp. of the methanesulphonate 271 - 274C (rom methanol);
s~arting from 21.9 g (0.05 mole) o 10,11-bis-~2-(methylsul-
phonyloxy)-e~hyl]-5H-dibenz~b,f]aæepine, 6.0 g (0~06 mole)of
(aminomethyl)-cyclopentane and 16,25 g (0.125 mole) of
diisopropyl ethylamine.



The starting materials can bé prepared as follows~
for B) 2-methoxy-dibenzolb,f]thiepine-10,11-diacetonitrile, m.p.
198 - 200C (from acetonitrile); starting from 42.3 g (0
mole) of 2-methoxy-10,11-bis(bromomethyl)-dibenzo[b,f]
thiepine and 11.8 g (0.24 mole) of sodium cyanide in 500 ml
of a acetonitrile;
dimethyl 2-methoxy-dibenzoEb,f]thiepine-10,11-diacetate, m.p.
96 - 98C (from toluenej, starting~from 31.8 g (O~.l mole)
of 2-methoxy-dibenzo[b,f]thiepine-10,11-diacetonitriIe,
400 ml of methanol, 3.8 ml of water and dry hydrogén chloride;

i
, . .
~ - 36 ~



, : ~

2-methoxy-dibenzo[b,f]thiepine-10~ dieth2nol, m.p. 116 -
119C (from ethyl acetate/hexane), starting from 38.5 g ~0~1
mole) of dimethyl 2-metho~y-dibenzo~b,f]thiepine-10,11-
diacetate and 7.6 g (0.2 mole) of lithium aluminium hydride
in 1 litre of abs. diethyl ether;
10,11-bis-[2-(methylsulphonyloxy)-ethyl]-2-methoxy-dibenzo[b,f]
thiepine, crude product, starting from 32.8 g ~0.1 mole) of
2-methoxy-dibenzo[b,f]thiepine-10,11-die~thanol, 25.2 g (0.22
mole) of methanesulphonyl chloride in 120 ml pyridine);
for C) 2~methylthio-dibenzo[b,f3thiepine-10,11-d~acetonitrile,
m.p. 204 - 206C (from ethyl acetate); starting frorn 44,2 g
(0~1 mole) of 2-methylthio-10,11-bis-(bromomethyl~-dibenzo~b,f~
thiepine and 11,8 g (0.24 mole) of sodium cyanide in 500 ml
of acetonitrile;
dimethyl 2-methylthiodibenzo~b,f]thiepine-10,11-diacetate,
m.p~ 85 - 86C (from pentane), starting from 33~4 g (Q.l mole)
of Z-methylthio-dibenzo~b,f3thiepine-L0,11-diacetonitrile,
400 ml of methanol, 3.8 ml of water and dry hydrogen chloride;
2-methylthio-dibenzo[b,f]thiepine-10,11-diethanol, m.p.
58 - 60C (frorn diethylether), starting from 40.0 g (0.1 mole)
of dimethyl 2-methylthio-dibenzo[b,f3thiepine-10,11-diacetate
and 7.6 g (0.2 mole) of lithium aluminium hydride in 1 litre
of absO diethyl ether;
10,11-bis-~2-(methyl-sulphonyloxy3~ethyl]-2-methylthio-
dibenzo~b,f]thiepineJ crude product starting from 34.5 g




- 37 ~

.
7 ' : ~ ~ ~


:-

~: , '
:, ~ ' ';,'

(0.1 mole) of 2-methylthio-dibenzo[b,f]thiepine-10,11-diethyl,
25 2 g (0.22 mole) of methanesulphonyl chloride in 120 ml
of pyridine;
for D) 2-methyl-dibenzo~b,f]thiepine-10,11-diacetonitrile,
m.p. 198 - 200C (from acetonitrile), ~;tarting ~rom 41.0 g
~0.1 mole) of 2-methyl-10,11-bis-(bromomethyl)-dibenzo~b,f]
thiepine and 11.8 g ~0.24 mole) of sodium cyanide in 500 ml
acetonitrile;
dimethyl 2-methyl-dibenzo[b,f] thiepine-10,11-diaceta;te, m.p,
76 - 77~C (from methanQl), starting from 30.2 g (0,1 mole) of
2-methyl-dibenzo[b,f]thiepine-lO,ll-diace~onitrile, 400 ml
of me~hanol, 3.8 ml of water and dry hydrogen chloride;
2-methyl~dibenzo[b~f]thiepine-10,11-diethanol, m.p. 126 ~
129C (from acetoni~rile), starting from 36.9 g (0.1 mole) of
dimethyl 2-ethyl-dibenzo[b,f]thiepine-10,11-diacetate and
7.6 g ~0.2 mole3 of lithium aluminium hydride in 1 litre o~
abs. diethyl ether;
10,11-bis-[2-(methylsulphonyloxy)-ethyl]-2-methyl-dibenzo[b,f~
thiepine, crude product, starting from 31~2 g (0.01 mole) of
2-meth~l-dibenzo[b,f]thiepine-10,11-diethanol, 25.2 g (0,22
mole) of methanesulphonyl chloride in 120 ml pyridine;
for E) 2-bromo-dibenzo[b,f]thiepine-10,11-diacetonitrile~
m.p. 200 - 204C (from acetonitrile), starting rom 47.5 g
(0.1 mole) of 2-bromo-10,11-bis-(bromoethyl)-dibenzo[b,f}
thiepine and 11.8 g (0.24 mole) of sodium cyanide in 500 ml ;




- 38 -


: ,

'~

5~ -

o E a acetonitrile,
dimethyl 2 -bromo-clibenzo~b,f]thiepine-10,11- diac etate, m.p.
90 - 93C (from abs. ethanol), starting from 36.7 g (0.01 mole)
of 2-bromo~dibenzo[b,]thiepine-10,11-diacetonitrile~ 400 ml
of methanol9 3.8 ml of wat~r and dry hydrogen chloride,
2-bromo-dibenzo~b,f]thiepine-10,11 diethanol, m.p. 166 - 169C
(from diethylether), starting ~rom 4303 g (0.1 mole) of
dimethyl 2-bromo-dibenzo[b,f]thiepine 10,11-diacetate and
7.6 g (0.2 mole) of lithium aluminium hydride in 1 litre o
abs. diethyl ether;
10,11-bis-[2-~methylsulphonyloxy)-ethyl~-2-bromo-dibenæo[b,f]
thiepine, m.p. 94 - 96C (from benzene ether), starting from
37.7 g (O,1 mole) o E 2-bromo-dibenzo[b, f]thiepine-10,11-
diethanol and 25.2 g (0.22 mole) oE methanesulphonyl chloride
in 120 ml of pyridine;
for F) dimethyl phenanthrene-9,10-diacetate, m.p, 143-145C `~
(from methanol~, starting from 25.6 g (0.1 mole) of phenan-
threne-9,10-diacetoni~rile [cf. S. Hauptmann, Chem. Ber, 93,
2604 (1960)], 400 ml of methanol, 3.8 ml of water and dry
hydrogen chloride;
phenanthryl-9,10-diethanol, m.p. 175-177C (from methanol)"
starting from 32.2 g (0.1 mole) of dimethyl phenanthrene-9,10-
diacetate and 7.6 g (0.2 mole~ of lithium aluminium hydride
in 1 litre of abs. diethyl ether;
9,10-bis-[2-(methylsulphonyloxy)-ethyl]-phenanthrene, m,p,




- 39 -

,. , . - . :. : : .




',,
, .~

~ 5 ~ 6



157-159C (from acetonitrile), starting from 26,6 g ~0.1 mole)
of phenanthrene-9,10-diethanol and 25.2 g (0.22 mole3 of
methanesulphonyl chloride in 120 mol of pyridine;
for G) A mixture of 122 g (0.5 mole) of 4,5-dimethyl~benzo[f}
thieno~2,3-b]thieplne (Case 4-3230), 980 ml of ethylene glycol
and lOO g of potassium hydroxide is refluxed for 2 hours with
stirxing in a nitrogen atmosphere. The mixture is then cooled
to 20C, diluted with 800 ml of water and extracted with ;
petroleum ether. The organic phase is separated, washed with
water, dried over sodium sulphate and concentrated. The
residue, 4,5~dimethyl-naphtho~1,2-b~thiophene, melts after
recrystallisation rom methanol at 88-90C;
106 g (0.5 ~nole) of 4.5-dimethyl-naphtho~1,2-b~thiophene are
dissolved in 2.5 litres of carbon tetrachloride and the
solution is treated with 178 g (l mole) of N-bromosuccinimide.
With s~irring and in an at sphere of nitrogen, ~he mixture
is heated to the boil while irradiating with a UV lamp. The -
~ixture is kept at the boil until all the N-bromosuccinimide
which lies at the bottom of the reaction vessel has become~
transformed into succinimide floating on the surface of the
solution (time taken: approx. 20 minutes). The mixture is
thereafter diluted with 400 ml of water and the crystallised
4,5-bis-~bromomethyl)-naphtho~1,2-b]thiophene ~mel~ing point:
202-204C) is filtered off;
naphto~l,2-b]thiophene-4,5-diacetonitrile, m.p. 250-251C

,
- 40 -
; :

:
,
' ' ~ :: ' ~ ~'
' ~ ' ' ~` ' ' ' '

. , ~ , . ' ~.

' :. ' ' ~ ` '
"

>


(from acetone), starting from 37 g (0.1 mole) of 4~5~bis-
bromomethyl-naphtho~1,2-b]thiophene and 11.8 g (0 24 mole)
of sodium cyanide in 500 ml of acetonitrile;
dimethyl naphtho~l,2-b]thiophene-~,5-diacetate, m.p. 136-138C
(from methanol), starting from 26.2 g (0.1 mole) of naphtho
~1,2-b]thiophene-4,5-diacetonitrile, 400 ml of methanol, 3.8
ml of water and dry hydrogen chloride;
naphtho~l,2~b]thiophene-4,5-diethanol, m.p. 163-166C (from
aceton~), starting from 32.8 g (0,1 mole) of dimethyl naphtho
~1,2-b]thiophene-~,5-diacetate and 7.6 g (0.2 moLe) of lithium
aluminium hydride in 1 litre Q~ abs. diethyl ether;
4,5-[2-(methylsulphonyloxy)-ethyl]-naphtho~1,2 b]thiophene,
m.p. 132-135C (from methylene chloride~, starting from
27.2 g (Ool mole) of naphtho~l,2-b]thiophene-4,5-diethanol
and 25.2 g (0.22 mole) in 120 ml of pyridine;~
for H~ and I) dibenz~b,f~oxepine-lO,ll-diacetonitrile, m.p.
176-178C (from methanol)~ starting from 38 g (0.1 mole)
of lO,ll~bis-(bromomethyl)-dibenz~b,f]oxepine and 11.8 g
(0.2b~ mole) of sodium cyanide in 500 ml of acetonitrile; ; `~
dimethyl dibenz~b,f]oxepine-lQ,ll-diacetate, m.p. 65-67C
(from pentane), starting from 27.2 g (0.1 mole) of diben~b,f~
oxepine-10,11-diacetonitrile, 400 ml of methanol, 3.8 ml of
water and dry hydrogen chloride;
dibenz[bgf]oxepine-10,11-diethanol, m.p. 138-140C (from
acetone), starting from 33.8 g (0,1 mole) of dime~hyl

.

dibenz[b,f]oxepine-lO,ll-diacetate and 7.6 g (0.2 mole) of
lithium aluminium hydride in 1 litre of abs. diethyl ether;
10,11-bis-~2-(methylsulphonyloxy)-ethyl]-dibenzEb,]oxepine,
m,p. 112-114C (from methylene chloride), starting from 28.2 g
of dibenz[b,f}oxepine-10,11-diethanol and 2592 g (0.22 mole)
of methanesulphonyl chloride in 120 ml of pyridine;
for K)~L) 5-acetyl~5H-dibenz[b,~]azepine-10,11-diacetonltrile
m,p. 183-185C (from benzene~, starting from 42.1 g (0.1 mole~
of S-acetyl-10,11-bis-(bromomethyl~-SH-dibenz[b,~]azepine
and 11.8 g (0.24 mole) of sodium cyanide in 500 ml of
acetonitrile;
dimethyl S-acetyl-5H~dibenz~b,f]azepine-10,11-diaceta~e, m.p.
123-124C (from toluene~, starting ~rom 31.3 g (0.1 mole)
of 5-acetyl-SH-dibenz~b,f]azepine-10,11-diacetonitrile;
5-ethyl5H-dibenz[b,f~azepine-10,11-diethanol, m.p. 102-
105C (from ether), starting from 37.9 g (0.1 mole) of
dimethyl 5-aeetyl~5H-dibenz~b,f]azepine-10,11-diacetate and
~6 g of lithium aluminium hydride in 150 ml o abs,
tetrahydrofuran;
10,11-bis-~2-(methylsulphonyloxy)-ethyl] 5-ethyl-SH-dibenz
[b,]azepine, m.p. 140-143C (~rom toluene), starting from
30.9 g (0.1 mole) of 5-ethyl-5H-dibenz[b,f]azepine-10,11- -
diethanol and 25.2 g (0.22 mole) of methanesulphonyl chloride
in 120 ml of pyrLdine;
for M) ~ N) 5H-dibenzEb~]azepine-10,11-diethanol~ m.p~
180~182C (from acetone), starting from 37.9 g (0.1 mole)


- 42 -

;. , . ~ , ~

: .. ' ' ' ' '~ ' : :

: - .. :,;, :: ~ ~: .. , ,.. ,.: .-, , ;, ;

~ 6




of dimethyl 5-acetyl-5H-diben2[b,f]azepine-10,11w-diacetate,
10,11-bis-[2-(methylsulphonyloxy)-ethyl3-SH-dibenz[b,f~
azepine, m.p. 140-142C (from toluene), starting from
28,1 g (0.1 mole) of SH-dibenz[b,f~azepine-10,11-diethanol :
and 25~2 g ~0.22 mole) of methanesulpho:nyl chloride.




Example 7 ~ :~

A mixture of 16.2 g (0.05 mole) of 7-methoxy-3-methyl-
2~3,4,5-tetrahydro-lH dibenzo~2,3:6,7]thiepino~4,5-d}azepine
(prepared in accordance wi~h Example 6) and 140 ml of 48 % ~-
aqueous hydrobromic acid is re:Eluxed for 2 hours with stirring
and then cooled to 20C. The precipitated hydrobromide of the
7-hydroxy-3-methyl-2,3,4,5-tetrahydro-lH-dibenzo[2,3:6,7]
thiepino[4,5-d]azepine is filtered off and dissolved in 160 ml
of 60 % aqueous methanol, The solution is made alkaline to
phenolphthalein by adding a concentrated ammonia solution,
~hereupon the free 7-hydroxy-3-methyl-2,3,4,5-tetrahydro-lH-
dibenzo[2,3:6,7]thiepino[~,5-d]azepine crystallises out.
After recrystallisation from acetonitrile, the product melts
at 216-218C,
For conversion into the methanesulphonate, 9.3 g
(0.3 mole) of the base is dissolv~ed in 380 ml of acetone and
the resultant solution is treated, with stirring, with 2~88 g

(0.03 mole~ of methanesulphonic acid, whereupon the 7-hydroxy-




~ .
- ~3 - ~




' . . ' : , "'

3-methyl-2,3~!~,5-tetrahydro-lH-dibenæo~2,3:6,7]thiepino[4,5 d]
azepine methanesulphonate with a melti.ng point of 282-286C
crystallises out




~ .
A mixture of 18~6 g (O.OS mole) of 7-bromo-3-methyl-
2,3,4,5-tetrahydro-lH-dibenzo~2,3:6~7]thiepino[4,5-d]azepine ~-
(prepared in accordance with Example 6), 10.7 g ~0~12 mole) of
copper(I) cyanide in 20 ml of dimethyl formamide is heated,
with stirring, in a nitrogen atmosphere to 180C, The miæture
is thereafter cooled to 30C, dlluted with 100 ml o~ methy~ene
chloride and extracted with 50 ml of a 50 Vb aqueous solutlon
of ethylenediamine. The organic phase is subsequently separated,
washed with water, dried over sodium sulphate, and concentrated.
The crystalline residue, 7-cyano-3-methyl-2,3,4,5.tetrahydro-lH-
dibenzo~2,3:6,7]thiepino~4,5-d]azepine, melts at 154-157C
after recrystallisati.on from hexane/ethyl acetate.
For conversion into the methanesulphonate, 9.6 g
(0.03 mole) of the base is dissolved in acetone and the
solution is treated with 2.88 g (0.03 molé) of methanesulphonic
acid, whereupon the 7-cyano-3-methyl-2,3,4,5-tetrahydro-lH

dibenzo~2,3:6~7]thiepino~4,5-d]azepine-methanesulphonate
with a melting point of 247-250C crystallises out.
- ~ .




, . . .
.: : ~: ::

Example 9

With st;rring, 12.2 g (0.075 mole) of octanoyl
chloride are added dropwise in the course of 15 minutes to a
solution of 16.9 g ~0.05 mole~ of 2,3,4,5-tetrahydro-lH-
dibenæo~2,3:6,7~thiepino[4,5-d]azepine-3-propanol in 50 ml
of abs. pyridine, the temperature being kept between 0 and
5C. The reaction mixture is subsequently stirred for ~0
hours at room temperature and then poured onto ice-water and
e~tracted with ether. The organic phase is separated~ washed
with water, dried over sodium sulphate and completely
evaporated to dryness, leaving 3-octanoyloxypropyl-2,3,4,5-
~etrahydro-lH-dibenzo[2,3:6,7]~hiepino[4,5-d]azepine as oily
residue.
The crude base (21.5 g) is dissolved in 150 ml of
acetone and to the solution are added 4.2 g (0.047 mole) of
anhydrous oxalic acid in 22 ml of abs. al~ohol, whereupon
3-octanoyloxypropyl-2,3,4,5-tetrahydro-lH-dibenzo[2,3:6,7]
thiepinoE4,5-d]azepine oxalate crystallises out, Melting
point after recrystallisation from abs. ethanol: 157-162C.
The following compound can be prepared in analogous
manner:
3-acetoxypropyl-2,3,4,5-tetrahydro-lH-dibenzo[2,3:6,7]thiepino
~4,5-d]azepine, starting from 16.9 g (0.05 mole) of 2,3,4,5-
tetrahydro-lH-dibenzo~2,3:6,7~thiepino~4,5-d]azepine-2
propanol in S0 ml o abs~ pyridine and 509 g (0~75 mole) of
acetyl chloride.

~ .




,, . ,; '' ;
~ , .

Example 10

To 75 ml of a 7.4 % solution of ethylamine in abs. '
ethanol (corresponding to 0 012 mole) are added 3 25 g
(0.025 mole) of diisopropyl ethylarnine, 50 ml o abs, ethanol
and 4.5 g (0.01 mole) of lO~ bis-~2-~methylsulphonyloxy)-
ethyl]-dibenzo~b,f~thiepine (prepared in accordance with
Example 5) and the mixture is heated in a closed tube for .:
20 hours to 80-90C. After it has cooled, the reaction
mixture is rinsed in a separating funnel together with
250 ml of me~hylene chloride and extracted in succession with
50 ml of 2N sodium hydroxide solution ancl 50 ml of water. The
methylene chloride solution is concentrated .in a water jet
vacuum and the crude 3-ethyl-2,3,4,5-tetrahydro-lH-dibenzo
~2,3:6,7]thiepino[4,5-d]azepine is converted in the following
manner into the hydrochloride: 3.1 g oi the residual:viscous ~:;
brown oil is dissolved in 25 ml of methylene chloride and the :~
solution is treated with 3 ml of a 4N ethereal hydrogen
chloride solutionO The 3-ethyl-2,3,4,5-tetrahydro-lH-dibenzo
E2,3:6,7~thiepino[4,5-d]azepine hydrochloride is precipitated
with ether, collectedwith suction, and recrystallised once
from ethanol/ether; melting point of the me~hanesulphonate: ~:
212-214C.
'



~; .


..
. ~ - . . .



'. ~ ~ '. ' :


With stirrin~, a suspension of 32.1 g (0.1 mole) of
3-methyl-1,5-dihydro-2H-dibenzoE2,3:657~thiepino[4,5-d]azepine-
2,4(3~)-dione in 500 ml of abs. diethyl ether are added, in a
nitrogen atmosphere, to a suspension of 14,6 g (0.38 mole)
of lithium aluminium hydrid~ in 1 litre of abs O diethyl ether. ;~
During the addition the temperature is kept at 20-30C.
Thereafter the reaction mixture is refluxed for 15 hours and ;
then cooled to 0-5C. Excess lithium aluminium hydride is
decomposed by the cautious dropwise addition of 75 ml of
ethyl acetate and subsequently oE 150 ml o~ water. The organic
phase is separated and extrac~cd repeatedly with 5 % methane-
sulphonic acid. The acid extracts are made alkaline to
phenolphthalein with CODCo ammonia and crude 3-methyl-2,~3,4,~5-
~tetrahydro-lH-dibenzo[2,3:6,7]thiepino~4,5-d]azepine precipita-~ -
tes as an oil. The crude base is extracted with ~ebher and the
organic phase is separated, washed with water, dried over ;~
sodium sulphate and then evaporated completely to dryness,
The xesidue is dissolved in 50 ml of petroleum ether and
cooled to 0C, whereupon the pure base with a melting point of
, .
83-86C crystallises out, Melting point of the methanesulpho-

nate: 256-258C.
:: ~
The starting material, 3-methyl-1,~5-dihydro-2H-- ~ ~ ;
dibenzo~2,3:6,7]thiepino~4,5-d]azepine-2,4(3H)-dione can be
prepared as follows: ~
: ::
:
- .
~ ~ ~7 - ~

With stirring, a solution of 28,5 g (0.11 mole) of tetra- ;
butylammonium hydroxide in 45 ml of water is added dropwise
in a nitrogen atomosphere and in -the course of 30 minutes
to a solution of 30.7 g ~0.1 mole~ of 1,5-dihydro-2H-dibenzo
~2,3:6,7~thiepino~4,5-d]aæepine-2,4(3H)-dione (prepared in
accordance with the particulars of Example 6) and 16,6 g
~0.12 mole) of methyl iodide in 1 litre of methylene chloride,
and the temperature rises from 20 to 25C. Thereafter the
reaction mixture is further stirred for 5 hours at room
temperature and then diluted with 250 ml of water. The organic
phase is then separated, washed with water, dried over sodium
sulphate, and completely evaporated ~o dryness. The
crystalline residue is stirred with 50 ml of abs, ethanol,
then collected with suction, and washed with abs. ethanoL.
The product, 3-methyl-1,5-dihydro-2H-dibenzol2,3:6,7]thiepino
[4,5-d]azepine-2,4(3H)-dione, melts at 216-222C after
drying.




Example 12

With stirring and excluding moisture, a suspension
of 1.14 g (0.03 mole) of lithium aluminium hydride ln 75 ml
of abs. diethyl ether is introd~ced slowly in a nitrogen
atmosphere to an ice-cooled solution of 4 g (0.03 mole) of

aluminium chloride in 100 ml of abs. diethyl ether in such
~-. :

- 4~ -


~: , ~ . . . . - ,,

' ~ '. . ' . . ~

.
. ~ , . . : . .
: '

~ 4~66

a manner that the reaction temperature does not exceed 5C.
Thereafter a suspension of 2.93 g (0.01 mole) of 1,3,4,5-

tetrahydro-2H-dibenzo~2,3:6,7]thiepino[4,5-d]azepine-2-one ~ ;
in 50 ml of abs. diethyl ether is added and the mLxture is
refluxed for 24 hoursO After cooling to 0-5~C, excess alumini-
um hydride is decomposed cautiously by the dropwise addition
of 10 ml of water. The organic phase is then separated,
washed with two 30 ml portions of water, dried over sodium
sulphate and concentrated, to give 2,3,4,5-tetrahydro-lH~
dibenzo[2,3 6,73thiepino~4,5-d]azepine as residue, which melts
at 142 143C after recrystallisation from methanol. Melting
polnt of the methanesulphonate: 305-307C.
The starting material, 1,3,4,5-tetrahydro~2H-
dibenzo[2,3:6,7]azepin-2-one,can be prepared as follows;
With stirring, 198 g (0O5 mole) of 10,11-bis-~bromomethyl)-
dibenzo[b,f]thiepine are dissolved in a nitrogen atmo~sphere
at 50C in 2.5 litres o~ acetonitrile~ To this solution is
added in the course of 10 minutes a solution of 59 g ~of
sodium cyanide in 180 ml of distilled water, the internal
~emperature being kept at 50C by weak cooling. The reaction
mixture is further stirred for 30 minutes at this temperature
and then 1.5 litres of ice-water are introd~ced, whereupon
dibenzo[b,f]thiepine-10,11-diacetonitrile crystallises out.
The grey crystals are collected with suction, washed wlth
water, then with acetonitrile, and subsequently dried in



.
'

: : ~ ~'',




. . . ~ . , ~

vacuo at 60C. Melting point: 205-207C.
With stirring, 145 g (C.5 mole) of dibenzo~b,f]thiepine-10,11-
diace~onitrile are dissolved in 2.75 litres o methylene
chloride. While cooling with ice, dry hydroge~ bromide is
introduced into this solution at 5-7C in the course o~
30 minutes and after a time yellow crystals fall out of the
reaction mixture. The flow of hydrogen bromide is subsequently
stopped and the batch is stirred for a further 30 minutes at
5-7C. Approximately hal~ of the solvent is then distilled
off from the reaction mixture in vacuo. The residual crystal
slurry is collected with suction, well washed with methylene
chloride, and the yellow crystals are dried under reduced
pressure at 60C. The resultant 2-amino-4-bromo-1~-I-dibengo
[2,3:6,7]~hiepino~4,5-d]azepine hydrobromide i9 further
processed as crude product.
With stirring, 90 g (002 mole) of the above hydrobromide,
l.S litres of dimethyl formamide and 1.3 litres of water are
refluxed for 2 hours in a nitrogen atmosphere. The reaction
mixture is then diluted with 800 ml of water at 90-100C
and then cooled with ice cooling to 5C, when 1,5-dibenzo-2H-
dibenæo~2,3:6,7]thiepino[4,5-d~aæepine-2,4~3H)--dione crystal-
lises out. The crystals are collected with suction and well
washed with water and acetone. After drying at lOO~C under
reduced pressure, the crude product melts at 253-256C.
With stirring and while keeping the temperature at 20-30C9


.
- 50 -


.. . . . . ~
- ~ , : .. . . .
-' ' '': : ,

. . .
. ~
- .
- . ,

a suspension of 61~4 g (0 2 mole) of 1,S-dihydro-2H-dibenæo
[2,3:6,7]thiepino~4~5-d]azepine-2,4(3H~dione in 200 ml of abs.
diethyl ~ther is added in a nitrogen atmosphere and in the
course of 30 minutes to a suspension of 22.8 g (0.6 mole) of
lithium aluminium hydride in 3.5 litres of abs. diethyl ether
and 350 ml of abs. tetrahydrofuran. The reaction mixture is
subsequently refluxed for 24 hours and then cooled to 0-5C.
Excess lithium aluminium hydride is cautiously dec~omposed by
the dropwise addition of 150 ml of ethyl acetate and then
of 300 ml of water. The organic phase is separated, washed
firstly with 2N hydrochloric acid and then repeatedly with
water, dried over sodium sulphate and hen completely
evaporated to dryness, leaving as residue 1,3,4,5-t~trahydro-
2H-dibenzo[2,3:6,7]thiepino~4,5-d]aæepin-2-one with a melting
point of 195-198C.




Example 13

With stirring, 8.38 g (0.03 mole) of 2,354l5-tetra-
hydro-lH-dibenzo~2,3:657]thiepino~4,5-d]azepine are dissolved
in 6 ml of 85 % formic acicl at 40-50C. To this solution
are then added 2.4 ml of 35 % formaldehyde solution and the
mixture is then stirred for a further 12 hours at an internal
temperature of 95-100C. The reaction mixture is then
cooled to 20C~ diluted with 100 ml of water, and this

: ,
- 51 -




' - , . ' ' '

solution is made alkaline to phenolphthalein with conc.
ammonia, whereupon crude 3-methyl-2,3,~,5-tetrah~dro-lH-
dibenzo~2,3:6,7]thiepino[4,5-d]azepine precipitates as an
oil. The crude base is extracted with ether, the organic phase
separated, washed twice with water, dried over sodium sulphate
and evapora~ed completely to dryness. The base is then converted
as follows into the methanesulphonate:
The crude base (8.4 g) is dissolved in acetone and the solution
is treated cautiously with 2.6 g of methanesulphonic acid,
whereupon the 3-methyl-2f3,4,5-tetrahydro-lH-dibenzo~2,3:6,7]
thiepino~4,5-d]azepine methanesulphonate crystallises out,
Melting point: 256-258C ater recrystallisation rom
abs, ethanol.




Example 14

With stirring, 8.38 g (0.03 mole) of 2,3,4,5-tetra- ~ /;
hydro-lH-dibenzo[2,3:6,7]thiepinoL4,$~d]azepine are dissolved
in 80 ml of 50 % acetic acid. To this solution a~e then added
all at once 8.16 g (0.08 mole~ Q acetic anhydride and the
reaction mi~ture is allowed to stand for 12 hours at room
temperature. The reaction mixture is subsequently compLetely ~ -
evaporated to dryness by rotary evaporation. The residue is
dissolved in ether and the ethereal solution washed once with
2N~sodium hydroxide solution and twice with water. After it




- 52 -



'
. .

,,, ~
., . . ~ . .. ..


has been dried over sodium sulphate, the ~thereal solution
is completely evaporated to dryness. The residue~ 3-acetyl-
2,3,4,5-tetrahydro-lH-dibenzo[2~3:6,7~thiepino[4,5-d3azepine,
is a yellow oil The crude acetyl compolmd (9~4 ~) is
dissolved in 150 ml of abs. diethyl ether and this solution
is added dropwise in the course of hal~ an hour to a suspension
vf 1.6 g (0.042 mole) of lithium alumin:ium hydride in 50 ml
of absO diethyl ether, whereupon the reaction mixture comes to
the boil. The reaction mixture is then refluxed for a further
6 hours 5 cooled to 0-5C, and diluted by the dropwise addition
fo 40 ml of water. The organic pllase is separated, washed with
water, dried over sodium sulphate, and completely evaporated
to dryness. The oily residue is dissolved in 10 ml of acetone
and the solution is cooled to -10C, whereupon 3-ethyl-2,3,4,5-
tetrahydro-lH-dibenzo[2,3:6,7]thiepino[4,5-d]azepine with a
melting point of 106-107C crystallises out. The methane-
sulphonate is prepared by the process described in Example 7;
melting point 212-214C (from abs, ethanol).




Example 15

The following end product is prepared by proceeding
according to Example 12: 2,3,4,5-tetrahydro-lH-thienoL2',3':2,3
~l~benzo-thiepino~4,5-d~azepine, m.p. 119-120C (from diethyl `
ether), starting from 30 g ~0.1 mole) of a mixture of 1,39495




- 53 -

. , . ~ .
- .'' ': , . . . : , . : ~

. . , ; . '.~

.. ~ .

5~6
.

tetrahydro-2H-thieno[2',3':2,3][1]benzothiepinol4,5-d3azepin-2-
one and 1,2,3,5 tetrahydro-4H-thieno[2',3':2,3]~1]benzo~
thiepino[4,5-d]azepin-4-one~ .;

H



: ~ :
,
The starting material, the mixture of 1,3~4,5-tetrahydro-2H-
thieno[2',3':2,3~[1]benzothiepino[4,5-d]azepin-2-one and ~ :
1,2,3,5-tetrahydro-4H-thieno~2',3':2,3][1]thiepino~4,5~d]
azepin-2-one, can be prepared in a manner analogous to that
dèscribed in Examplè 12:
thieno~2,3-b][l]benzothiepine-4,5-diacetonitrile, m.p.
170-172 C (from acetonitrile), starting from 201 g (0.5~mole)
of 4,5-bis-(bromomethyl)-thieno[2,3-b~l]benzothiepine;
a mixture of 2-amino-4-bromo-lH-thieno[2',3'::2,3]~1]benzo- :
thiepino~4,5-:d]azepine-hydrobromide and 4-amino-2-bromo-5H-
~hieno[2',3':2,3~[1]benzothiepino[4,5-d]azepine hydrochloride
as crude product, starting from 147 g (0.5 mole) of thienol
~2,3-b~l]benzothiepine-4,5-diacetoni~rile; `
: : .
l~5~dihydro-2H-thieno~2',3':2,3]~1]benzothiepino[4,5-:d]azepine- :

2,4(3H)-dione, m.p. 215-218C (from methanol), and starting

; ~
~,
54


,

from a mixture of 92 g (0.2 mole) of 2-amino~4-bromo-lH-thieno
[2',3':2,3]~1]benzothiepino[4,5-d]azepine-hydrobromide and
4~amino~2-bromo-SH-thieno~2',3':2,3][1]benzothiepino~4,5-d]
azepine-hydrobromide;
a mixture of 1,3,4,5-tetrahydro-2H-thieno~2'~3':2,3]~1]benæo-
thiepino[4,5-d]azepin-2-one and 1,2,3,5-tetrahydro-4H-thieno
~2',3':2,3][1]benzothiepino[4,5-d]azepin-4-one, crude product,
~arting from 62.6 g (0.2 mole) of 1,5-dihydro-2H-thieno[2',3':
2,3]~1]benzothiepinoE4,5-d]azepine 2,4(3H)-dione ~;


Example 16
The following end product i~ prepared in accordance
with the procedure of Example 13:
3-methyl-2,3,4,5-tetrahydro-lH-thieno[2',3':Z,3][1]benzothie-
pino[4,5-d]azepine as crude product; melting point of the ~;
methanesulphonate 208-209C (from abs. ethanol), starting ~;
from 14,3 g ~0.05 mole) 2,3,4,5-tetrahydro-lH~thieno[2',3':2,3}
[l~benzothiepinol4,5 d]azepine.

:;'
. :
Example 17
The following end product is prepared in accordance
with the procedure of Example 14:
3-ethyl-2,3,~,5-tetrahydro-lH-thieno~2',3':2,3]~1~benzo

- 55 -

.. ,.................... . .. , . .... .. . .. ........ .... j ., .. .. .. .. ...... . . ... , .. , .. .... ..... . ~. . . ......
, .. ., .. . ~, .. ~


.~ . . -. :
, , . .. , . : . - . :

,' ~:

5~

thiepino~4,5-d]azepine, m.p. 127-L29C (from acetone),
melting point of the methanesulphonate 209 211C ~from abs.
ethanol), starting :Erom 14.3 g ~0.05 mole) of 2,3,4,5-tetra-
hydro-lH-thieno[2',3':2,3][1~benzothiepino[4,5-d~azepine.




~ ~ :
The following compounds can be prepared in accordance
with the procedure of Example 11, using the appropriate
starting materials:
3-[3-(dimethylamino~-propyl~-2,3,4,5-l:etrahydro-lltI-cliberlzo
C2,3:6,7]thiepino[4,5-d~azepine as crude product; tnelting point
of the dihydrochloride 285-289C with decompos, starting
from 39.3 g (0.1 mole) of 3-[3-(dimethylamino)-propyl}-
1,5-dihydro-2H-dibenzo~2,3:6,7]thiepino[4,5-d]azepine-2,4(3H)-
dione and 14.6 g (0.38 mole) of lithium aluminlum hydride in
absolute diethyl ether;
3-[3-(dimethylamino)-propyl]-2,3,4,5-tetrahydro-lH-thieno
[2'j3':2,3][1]benzothiepino[4,5-d]azepine as crude product;
melting point of the dihydrochloride 265-27~SC with decompos.;
starting from 39.9 g (0.1 mole) of 3-[3~ (dimethylamino~-
propyl~-1,5-dihydro-2E-thieno[2',3':2,3][1]benzothiepino[4,5-d]
azepine-2,4(3H)-dione and 14.6 g (0.38 mole) of lithium alumi- ~`
nium hydride in absolute diethyl ether;
3-E3-(dimethylamino)-propyl]-1,2,3,4,s~lo-hexanhydro-dibenzo
:
- 56 -
'.~'.

, . ..
. . ~ .

S6i~

[3,4:6,7]cyclohepta~1,2-d~azepine, m.p. 80-82C (from pentane~; ?
melting point of the dihydrochloride approx. 315C (with
decompos.); starting from 37.4 g (0.1 mole~ of 3-[3-(dimethyl-
amino)-propy]]-5,10-dihydro-dibenzo~3,4 6,7]cyclohepta~1,2-d]
azepine-2,4~(1H,3H)-dione and 14.6 g (0038 mole) o lithium
aluminium hydride in absolute diethyl ether~
The starting material can be prepared as follows:
aa) With stirring, a suspension of 2.3 g ~Ool mole) of lithium
amidein 6.9 ml o~ abs, toluene is added dropwise in a nitrogen
atmosphere and in the course of 2 hours to a suspension Qf
30,7 g (0,1 mole) of 1,5-dihydro-2H-dibenzo~2,3:6,7]thiepino
[4,5-d]azepine-2~4(3H)-dione in 14.6 g (0.12 mole) o~ freshly
distilled 3-(dimethylamino)-propyl chloride and 600 ml of abs.
toluene. The reaction mixture is then refluxed for a further
20 hours and thereafter cooled to room temperature. After
addition of 100 ml of water, the organic phase is separated
and extracted with three 50 ml portions of 10 % methanesulphonic
acid. The acid extracts are made alkaline to phenolphthalein ~ -
with conc. ammonia, whereupon the 3-~3-(dimethylamino)-propyl]-
1,5-dihydro-2H-dibenzo[2,3:6,7]thiepino~4,5-d]azepine-2,4(31
dione precipita-tes in crystalline formO Melting point
102-103C after recrystallisation from ether/pentane.
The methanesulp~onate is prepared as follows:
The base (30 g) is dissolved in 75 ml of acetone and treated
cautiously with 7.3 g (0.076 mole) of methanesulphonic acid,


- 57 -

6 ~




whereupon the 3~[3-(dimethylamino)propyl]-1.,5-dihydro-2H-
dibenzo~2,3:6,7~thiepino~4,5-d]azepine-2,4(3H)-dione
methanesulphonate erystallises out. Melt:ing point 270-275C
after recrystallisation from ~ethanol.
The followlng compounds can be prepared in analogous manner:
bb) 3-[3-(dimethylamino)-propyl]-1,5~dihydro~2H-thieno[2',3':
2,3][1]benzothiepino[4,5-d3azepine-2,4(3H)-dione, m.p.
117-119C (from acetone); melting poin~ of the hydrochloride
224~227C (from abs. ethanol), starting from 31.2 g (0 1 mole)
o~ 1,5-dihydro-2H-thieno[2',3':2,3][1]benzothiepino[4,5-d]
azepine-2,4(3H)-dione, 14.6 g (0,12 mole) of 3-(dimethylamino)
propylchloride and 2.3 g (0 1 mole) of lithium amide;
and
cc) 3-[3-(dimethylamino)~propyl]-5,10-dihydro--dibenzo[3,4:6,7]
cyclohepta~l,2-d]azepine~2,4(1H,3H)-dione, m~p. 113-115C
(from hexane~; melting point of the hydrochloride 265-268G
(from ethanol), starting from 28.9 g (0.1 mole) of 5,10-
dihydro-dibenæo[3,4:6,7]cyclohepta~1,2-d]azepine-2,4(1H,3H)-

dione, 14,6 g (0.12 mole) of 3-(dimethylamino)-propylchloride ~:
and 2.3 g (0.1 mole) of lithium amide; .
5,10-Dihydro-dibenzo~3,4:6,7]cyclohepta[1,2-d3azepine-2,4
(lH,3H)-dione is prepared in the same manner as the starting ~.
materials o~ Example 14:
5H-dibenzo~a,d3cycloheptene-10,11-diacetonitrile, m.p.
217-220C ~from acetonitrile), starting from 189 g ~095 mole)




- 58 -




'

~ 6 ~



of 10,11-bis-(bromomethyl)-5H-dibenzo~a,d~cycloheptene
(DOS 2,125,654) in 2.5 litres of acetonltrile and 59 g
(1.2 mole) of sodium cyanide;

2-amino-4-bromo~l,lO~diyhdro-dibenzo[3,4:6,7]cyclohepta~152-d]
azepine hydrobromide3 crude product, starting from 135 g
(0.5 mole) of 5H-dibenzo[a~bJcycloheptene-lo~ diacetonitrile
in 2.75 litres of methylene chloride with dry hydrogen
bromide;
SalO-dihydro-dibenzo~3,4:6,7]cyclohepta[1,2-d]azepine-2,4
~lH,3H) dione, m.p. 265C (from acetone), starting from
86.5 g (0.2 mole) of 2-amino-4-bromo-1,10-dihydro-dibenzo
~3,4:6,7]cyclohepta[1,2-d]azepine hydrobromide, L,5 litres of
dimethyl formamide and 1.3 litres of water,


ExamPl e 19 :
Using the appropriate starting material, the
following compounds can be prepared in accordance with the
particulars of Example 5:
3-butyl-2,3~4,5-te~rahydro-lH-dibenzo[2,3:6,7]thiepino[4,5-d~
azepine, m.pO 107-108~C (from acetone); m~pA 0~ the methane-
sulphonate 21~-220C (from abs~ ethanol), starting from
22~7 g (0.05 mole) of lOall-bis~ ~2-~methylsulphonyloxy)-e~hyl3-~ ;;
dibenzo[b,f]thiepine, 4.4 g (0.06 mole) of n-butylamine and
16.25 g (0.125 mole) of diisopropyl ethyIamine in absolute
e~hanol;


- 59 -



. .



3-allyl-2,3,4,5-tetrahydro-lH-dibenzo[2,3:6,7]thiepino~,5-d]
aæepine as crude product; m.p. of the methanesulphonate
225-227~C (from abs. ethanol~, starting from 22 7 g (0 05 mole)
of 10,11-bis-~2-(methylsulphonyloxy)-ethyl]-dibellzo[b,f~thie-
pine, 3.4 g (0.06 mole) of allylamîne and 16.25 g (0.125 mole)
of diisopropyl ethylamine in absolute ethanol;
3-propinyl-2,3,4,5-tetrahydro-lH-dibenzo[2,3:6,7]thiepino~4,5-d3
azepine as crude product; m,p. of the methanesulphonate
218-221C (from abs. ethanol), starting from 22.7 g (0.35 mole)
of 10~11-bis-~2-(methylsulphonyloxy)~ethylJ-dibenzo[b,f~
thiepine, 3.3 g (0.06 mole) o propargylamine and 16.25 g
(0,125 mole) o~ diisopropyl ethylamine in absolute ethanol;
3-(cyclopentylmethyl)-Z,3,4,5-tetrahydro-lH-d:Lbenæo[2,3;6,7]
thiepino~4,5-d]azepine, m.p. 113 115C (from abs. ethanol);
m.p. of the methansulphonate 2~8-252C (from abs. ethanol),
starting from 22.7 g (O.OS mole) of 10,11-bis-~2-(methyl~
sulphonyloxyj-ethyl]~dibenzo[b,f]thiepine, 6.0 g (0.06 mole)
of(aminomethyl)-cyclopentane and 16.25 g (0.125 mole) of
diisopropyl ethylamine in absolute ethanol;
3 (cyclohexylmethyl)-2,3,4,5-tetrahydro-lH-dibenzo[2,3:6,7]
thiepino~4,5-d~azepine, m.p. 113-115C (from acetone);
m. p. of the methanesulphonate 256-258C (from abs. ethanol?, ;
starting from 22.7 g (0.05 mole) of 10,11-bis-[2-methylsul-
phonyloxy)-ethyl]-dibenæo[b,f]thiepine, 607 g (0.06 mole)
of(aminomethyl)-cyclohexaneand 16~5 g (0~125 mole) of

. :
60 -




- . ... :, . . .

~ ~ 4


diisopropyl ethylamine in absolute ethanol;
1,2,4,5-tetrahydro-3H~dibenzo~2,3:6,7]thiepino~4,5-d}azepin-3-
ethanol, m.p. 157-159C (from acetone); m.p. of the methane-
sulphonate 194-198C (from abs ethanol), starting from
22 7 g (0.05 mole) of 10,11-bis-~2-(methylsulphonyloxy)-ethyl~
dibenzo~b,f]thiepine, 307 g (0~06 mole) of ethanolamine and
16.25 g (0.125 mole) of diisopropyl ethylamine in absolute
ethanol;
1,2,4~5-tetrahydro-3H-dibenæo~2,3:6,7]thiepino[4,5-d3azepin-3-
propanol, m~p. 120-132C (from acetone); m.p. of the methane-
sulphonate 181-183C (from abs. ethanol), starting rom
22.7 g (0.05 mole) of 10,11-bis-[2-(methylsulphonyloxy)-ethyl]-
dibenzo~b,f]thiepine, 4.5 g (0 06 mole) of 3-aminopropanol and
16.25 g (0.125 mole) of diisopropyl ethylamine in absolute

.
ethanol; -
3-(3-methoxypropyl)-2,3,4,5-tetrahydro-lH-dibenzo~2,3:6,7] ~ -
thiepino[4,5-d]azepine as crude product, mp.p of the methane-
sulphonate 213-216C (from abs. ethanol), starting from
22.7 g (0,05 mole) of 10,11-bis~~2-(methylsulphonyloxy)-ethyl]-
dibenzo~b,f]thiepine, 504 g (0.06 mole) of 3-methoxypropylamine
and 16.25 g (0.125 mole) of diisopropyl ethylamine in absolute
ethanol;
3-[3-(methylthio) propyl]-2,3,4,5-tetrahydro-lH-dibenzo~2,3:
6,7]thiepino[4,5-d]azepine as crude product, m.p. of the
methanesulphonate 212-214C (from absD ethanol), s~arting
~-~ from 22.7 g (0.05 mole) of 10,11-bis-[2-(methylsulphonyloxy)- -
.
~ 61 -


.


:- ,: . ,

~ Q~




ethyl~-dibenzo[b,f]thiepine, 6.3 g (0.06 mole~ of 3-(methylthio)-
propylamine and 16.25 g {0.125 mole~ of diisopropyl ethylamine
in absolute ethanol;
3-~2-(methylthio)-ethyl~-2,3~4,5-tetrahydro~lH dibenzo[2,3:6~7]
thiepino[4,5-d]azepine, m.p. 9lo-92oc (from pentane); m.p. of
the met:hanesulphonate 218-220C (from abs. ethanol), starting
from 22.7 g (0.05 mole) of 10,11-bis-[2-(methylsulphonyloxy)~
ethyl]-dibenzo[b,f]thiepine, 5.5 g (0.06 mole) of 2-(methyl-
thio)-ethylamine and 16.25 g (0.125 mole~ of diisopropyl
ethylamine in absolute ethanol;
7-chloro-3-methyl-2,3,4,5-tetrahydro~ dibenzo[2,3:6,7]
thiepine[b~,S-d]EIzepine as crude product; m.p. of the hydro-
chloride 266-268C (from abs~ ethanol), starting from 2~.5 g
(0.05 mole~ of 10,11-bis-[2~methylsulphonyloxy)-ethyl]-2-
chloro-dib enzo[b,f]thiepine, 1.85 g of methylamine (0.06 mole)
and 16.25 g (0.125 mole) of diisopropyl ethylamine in methanol;
7-chloro-~(cyclopentylmethyl)-2,3,4,5-tetrahydro-lH-dibenzo
[2,3:6,7~thiepin[4,5-d~azepine, m.p.l23-126C (from acetone);
m,p. of the methanesulphonate 195-198C (from abs. ethanol),
starting from 24.5 g (0.05 mole) of 10,11-bis-~2-methylsul-
phonyloxy)-ethyl~-2-chloro-dibenzo[b,f]thiep-lne, 6~7 g (0.06
mole) of (aminomethyl)-cyclopentane and 16,25 g (0.125 mole~
o~ diisopropyl ethylamine in absO ethanol.
The starting material for the two last mentioned end products
can be prepared according to Examples 5 and 12 respectively:




- 62 -

.. . ..



- - ~


2-chloro-dibenzo~b~f]thiepine-10,11-diacetonitrile, m.p.
207V-210C (from chloroform), starting from 43.1 g (0.1 mole)
of 2-chloro-10,11-bis-(bromomethyl~-dibenzo[b,f]thiepine and
11.8 g of sodium cyanide in 500 ml of acetoni~rile;
dimethyl 2-chloro-dibenzo[b,f]thiepine-10,11-diacetate, m.p. i- ~
111-113C (from methanol), starting from 32~3 g ~0.1 mole) of ~ -
2-chloro-dibenzo~b,f]thiepine-10,11-diacetonitrile, 400 ml o
methanol, 3.8 ml of water and dry hydrogen chloride;
2-chloro-dibenzo[b,f]thiepine-10,11-diethanol, m.p. 152-154C
(from diethyl acetate), starting from 38.9 g (0.1 mole) of
dimethyl 2-chloro-dibenzo~b~f]thiepine-10,11-diaceta~e and
7.6 g (0.2 mole) of lithium aluminium hydride in :L litre of
abs, die~hyl ether; and
10,11-bis-[2-(methylsulphonyloxy)-ethyl~ 2-chloro-dibenzo[b,f] ~ ~;
thiepine, m.p. 118-120C (from diethyl ether), starting from
33.3 g (0.1 mole) of 2-chloro-dibenzo[b,f~thiepine-10,11-
diethanol, 25.2 g (0.22 mole) of methanesulphonyl chloride
in 120 ml of pyridine.




xample 20

Tablets containing 0.02 g of the methanesulphonate
of 3-methyl-2,3?4,5-tetrahydro-lH-dibenzo[2,3:6,7]thiepino
[4,5~d]azepine are manufactured as follows
Composition (for 10,000 tablets~:


`:

- 63 -

- .. ~
:' :

~ 6 ~



methanesulphonate of 3-methyl-2,3,4,5-tetrahydro-
lH-dibenzo[2,3:6,73thiepino~4,5-d]azepine 200~00 g
lactose 20Q 80 g
potato starch 354.70 g
stearic acid 10.00 g
talc 200.00 g
magnesium stearate 2 50 g
colloidal silica 32.00 g
ethanol q.s.



A mixture of the methanesulphonate of 3~methyl-2,3,4,5-tetra-
hydro-lH-dibenzo[2,3:6,7]thiepino~4,5-d]azepine, the lactose
and 194.70 of the potato starch is moistened with an ethanolic
solution of the stearic acid and granulated through a sieve.
After drying, the remainder of the potato starch, the talcg
the magnesium stearate and the colloidal silica is admixed ;~
and the mixture is pressed to tablets weighing 0.1 g each,
which can be provided, if desired, with breaklng notches for
a finer adjustement of the dose.




Coated tablets containing 0.005 g of the methane-

sulphonate oE 3-methyl-7-cyano-2,3,4,5-tetrahydro-lH-dibenzo
~2,3:6,73thiepino[4,5-d]azepine are manufactured as follows:
,~


~ 6


.
.
~'~

6~ ~


C position (for 10~000 coated tablets)
methanesulphonate of 3-methyl-7-cyano-2,3,4,5-
tetrahydro-lH-dibenzo~2,3:6,7]thiepino~4,5-d~
azepine 50.00 g
lactose 175.90 g ;; -
stearic acid 10.00 g
.
colloidal silica 56.60 g
talc 165.00 g
potato starch ~20.00 g
magnesium stearate ~ ~ 2.50 g
saccharose (crystals~ 502.28 g
shellack 6.00 g
gum arabic 10.00 g
colourant 0.22 g
titanium dioxide 1.50 g
ethanol q 5
~:
,
Granules are prepared from the methanesulphonate of 3-methyl-
; ~ 7-cyano-2,3,4-5-tetrahydro-lH-dlbenzo~2,3:6,7]thiepino[~4,5-d]
azepine, the lactose and an ethanolic solution of the stearic
.~
acid. After drying, these granules are mixed wlth the colloidal
silica, the talc, the potato starch and the magnesium stearate
and pressed to coated tabIet cores. These cores are~then
coated with a concentrated syrup of the saccharose, the -~
: ~:
shellack, the gum arabic, the colourant and the titanium~
dioxide, and dried, giving coated tablets weighing 0.100 g~each.
:.
.
- 65 -
:
:
,- - - , . . . ,~ : ..
. . : :

.

.

Examp].e 22

Capsules containing 0.02 g o~ the hydrochloride of
3-methyl-2,3,~,5-tetrahydro-lH-dibenzo~2,3:6,7]oxepino~,5-d~
azepine are manufactured as follows:
Composition (for 1000 .capsules) ~: ~

hydrochloride of 3-methyl-2,3,4,5-tetrah~dro-lH- :
dibenzo[2,3:6,7]oxepino[4,5-d]azepine 20,00 g
lactose 253.00 g
gelatin 2.00 g
corn starch 10.00 g
talc 15000 g
water q. 9 .

:. `
The hydrochloride of 3-methyl-2,3,4,5 tetrahydro-lH-dibenzo
. ~
[2,3:6,7]oxepino~4,5-d]azepine~is mixed with the lactose~and :~
the mixture is~ uniformly moistened with an aqueous solution~
of the gelatin and granulated through:an appropriate sieve ~ :
(~or example a sieve having a maximum mesh size of 1.5 mm)0:~
The granules are mixed with the dried corn starch and the talc
and packed into hard gelatin capsules (size 1).


:
Eæample 23

An aqueous injection solution containing 0.01 g/ml

- of the methanesulphonate of 3-meLhyl-Z,3,4,5-tetrahydro-lH~



:~ ~ - 66 -

:: : : ~ : :




. . ~ .

dibenzo~2,3:6,7]thiepino[~,5-d]azepine i~ prepared as follows:
ComEosition (for 1000 capsules)
,
methanesulphonate of 3-methyl-2,3,4,5-tetrahydro-lH~
dibenzo~2,3:6~7~thiepino~4,5-d]azepine 10,00 g
wate~ q. 5 .

Ampoules are filled with a solution of the methanesulphonate
of 3-methyl-2,3,4,5-tetrahydro-lH-dibenzo[2,3:6,7~thiepino
~4~5-d]azepine in 1000 ml of water and steril;sed. An ampoule
contains a 1 % solution of the active substance.

.




~ :.... , '




.
.. . .

~ . ~ , ,,