Note: Descriptions are shown in the official language in which they were submitted.
This invention relates to new azatetracyclic compounds, par-
ticularly ~o 5-hydroxy 2,3-dihydro-lH-dibenzo [2J3:6~7~(thiepino and oxe-
pino)[4,5-c]pyrrole compounds, substituted in the l-position, of the ~;
formula
Rl ~ :
/N\
H2 \ / H2 :'
~ ~ -OH
wherein X represents oxygen or sulphur and Rl stands for lower alkyl or
lower alkenyl, and to pharmaceutically acceptable salts of such compounds,
as well as to processes for the production thereof.
A lower alkyl group Rl has up to 7, preferably up to ~, carbon
atoms and is, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl
or tert.-butyl, also straight-chain or oranched-chain pentyl, hexyl or -
heptyl bound in any position. ~;
A lower alkenyl group Rl has up to 7, pre~erably up to 4, car-
bon atoms and is, e.g., 2-lower-alkenyl such as allyl or methallyl.
5alts o~ compounds of formula I are, in particular, acid
addition salts, especially pharmaceutically applicable nontoxic acid addi-
tion salts, e.g. with inorganic acids such as hydrochloric acid, hydro-
bromic acid, sulphuric acid or phosphoric acid, or with organic acids, such
as organic carboxylic and sulphonic acids such as methanesulphonic acid,
ethanesulphonic acid, 2-hydroxyethanesulphonic acid, acetic acid, malic
. : i . .
acid, tartaric acid, citric acid, lactic acidJ oxalic acid, succinic acid,
fumaric acid, maleic acidl benzoic acid, salicylic acid, phenylacetic
acidJ mandelic acid or embonic acid.
The new compounds have valuable pharmacological properties, e.g.
properties affecting the central nervous system. They are characterised
above all by their central-depressant action and agitation-inhibiting action
(amphetamine-antagonistic), which can be demonstrated by pharmacological
A `~ :
2 ~
.. . .
10~i5871
tests~ They thus exhibit in the amphetamine-antagonism test ~Niemegeers
and Janssen, Arzneimittelforsch., Vol. 24, p. 45 (1974) on the rat an agi-
tation-inhibiting action in a dosage range of 3 to 10 mg/kg subcutaneously,
or 10 to 40 mg/kg orally. At the same time, in the catalepsy test on the
rat (Wirth et al., Arch.Int.Pharmacodyn., Vol. 115, p. 1 (1958)), it is
only with oral administration of doses as high as about 20 to 100 mg/kg that
the new compounds show cataleptic efects; the relationship between cata-
leptic (extrapyramidal) action and amphetamine-antagonistic action is there-
fore favourable with respect to the agitation-inhibiting action. The new
compounds can thus be used as tranquillising, antipsychotic and agitation-
inhibiting compounds for the treatment of conditions of tension and agita-
tion.
The invention relates Eore st to compounds of formula I wherein
X stands for sulphur, as well as for oxygen, and Rl for lower alkyl having ~
up to 4 carbon atoms~ e.g. methyl or ethyl, as well as allyl; it relates : ;
especially to the compounds given in the examples, or salts thereof, par-
ticularly acid addition salts, such as pharmaceutically applicable nontoxic
acid addition salts thereof.
The new compounds can be produced in a manner known per se. They
are obtained, for example, by a process in which a compound of the formula
Xl X2
H2 l l H2
~ (II),
wherein Xl and X2 represent reactive esterified hydroxy groups, is reacted
witll an amine of the formula
Rl-N~2 (III)
and,optionally, in a resulting compound of formula I, and/or, optionally, a
resulting salt is converted into the free compound or into another salt,
or a free compound obtained
)~
~ ~ - 3 -
8 7
is converted into a salt.
A reac~ive esterified hydroxy group Xl or X2 is
a hydroxy group esterified with a strong acid of inorganic
or organic character, such as a hydroxy group esterified
with a mineral acid, e.g. a hydrohalic acid such as
hydrochloric acid, hydrobromic acid or sulphuric acid,
or with a strong organic sulphonic acid, e.g. an aliphatic
or aromatic sulphonic acid such as methanesulphonic acid,
p-toluenesulphonic acid, 4-bromobenzenesulphonic acid
or 4-nitrobenzenesulphonic acid. Xl or X2 stands, in
particular~ for halogen, especially ~or bromine; it can
however also represent organic sulphonyloxy, e~g. p-
toluenesulphonyloxy.
The reaction of the star~ing material of formula II
with the amine of formula III is usually performed in
the presence of a basic agent, preferably an excess -
of the amlne of formula III, but also in the presence
of an additional inorganic or organic base, and preferably
in the presence of a solvent or diluent, particularly
one that is inert to the reactants under the reaction
conditions, e.g. an aliphatic, cycloaliphatic or aromatic
hydrocarbon such as benzene or toluene, a halogenated
aliphatic, cycloaliphatic or aromatic hydrJcarbon such
A
` Y
~ ~ ~ 5 ~7 ~
as chloroform, a lower alkanol such as methanol or
ethanol, an ether such as diethyl ether or dioxane,
a lower alkanone such as acetone, methyl ethyl ketone
or diethyl ketone, or a nitrile such as acetonitrile,
or a mixture of such solvents, especially a mixture
of a lower alkanol and a hydrocarbon, e.g. ben~ene.
The reaction is perfor~ed if necessary with cooling
or heating, e.g. in a temperature range of about -10C
to about ~50C, in a closed vessel and/or in an inert
gas atmosphere, e.g. in a nitrogen atmosphere.
The starting materials of formula II can be produced
in a manner known per se, e.g~ by a process in which
a 2-(4-RA-phenyl-X-)-phenylacetic acid, wherein RA
denotes a suitably protected hydroxy group, e.g. a
suitably esterified hydroxy group, such as one esterified
by the acyl radical of a carbonic acid semi-ester, or
an etherified hydroxy group, such as one e~herified by
a lower alkyl radical or 2-oxocycloalkyl radical, is
converted into an ester such as a lower alkyl ester, e.g.
methyl or ethyl es~er; and this is condensed, in the
presence of an alkali metal such as sodium, with a di-
lower alkyl carbonate, e.g. diethyl carbonate, to the
di-ester of the corresponding 2-(4 RA-phenyl-X-)-phenyl-
~,
.. . . .. . .. . ... .
.
.
. .
':
;5137~
malonic acid This is methylated in the a-position in
the usual manner, e.g. by treatment with a metallising
reagent such as an alkali metal lower alkanolate,
alkali metal amide or alkali metal hydride, and reaction
with a reactive ester of methanol, such as with a
methyl halide, e.g. methyl iodide. The malonic es~er
compound is then converted, with simultaneous decarboxylation,
into the corresponding 2-~4-RA-phenyl-X-)-hydratropic
acid. This yields, with the action oI a suitable acid
reagent such as hydrofluoric acid, an ll-methyl-10-oxo-
10,11-dihydro-dibenzo[b,flthiepin or an ll-methyl-10-oxo-
10,11-dihydro-dibenzo[b,f]oxeping which contains in the
8-position, depending on the meaning of the group RA
present in the starting material, the group RA or a
hydroxy group liberated under the reaction conditions;
the last-mentioned is converted back, in a manner known
per se, into a suitably protected hydroxy group RA. The
keto compound obtained in this manner is subsequently
treated with a suitable methyl Grignard's reagent such
as methyl magnesium iodide; water is then split off from
the resulting 8-RA-10,11-dimethyl-10-hydroxy-10,11-dihydro-
dibenzolb,f]thiepin or -dibenzo[b,f]oxepin, e.g. by heating
in the presence of aqueous mineral acid such as hydro-
chloric or sulphuric acid; and the 8-RA-ll-methyl-10-
_ ~ _ . .
._, , .
.
:
8t~
methylene-10,11-dihydro-dibenzo~b,f]thiepin compound
or -dibenzo[b,f]oxepin compound obtainable as the main
product is converted, e.g. by treatment with a suitable
base such as an alkali metal hydroxide, e.g. potassium
hydroxide, in the presence ~f a lower alkanol, e.g.
ethanol, to the corresponding 8-RA-10,11-dimethyl-
dibenzo[b,f]thiepin or -dibenzo[b,~]oxepin. The methyl
groups in this are converted into the reactive esterified
hydroxymethyl groups of the formula Xl-CH2- or X2-CHz-,
e.g. by treatment with a positive halogen-releasing agent
such as an N-halogen-imide, e.g. bromosuccinimide. In
an 8-RA-lO,ll-bis-halomethyl-dibenzoIb,f]~hiepin or
-dibenzo[b,f]oxepin ob~ainable in this manner, halogen,
especially bromine, can be converted in a manner known
per se, e.g. with formation and subsequent esterifying
of hydroxyl groups, into another reactive esterified
hydroxy; furthermore, the protected hydroxy group RA can
be converted in a manner known per se, e.g. as described
below, at this preliminary stage or at some other suitable
one, into the group R.
- The new compounds can be obtained also by substituting
in a compound of the formula
i87:1L
H
2 ~ 2 (I~) -
the secondary amino group by the group Rl, and, optionally,
carrying out the additional stages of ~he process.
.. . .
The substitution o~ the N-unswbstituted star~ing
material of formula IV is performed in a manner Icnown
per se, e.g. by treatment with a reactive ester of a
lower alkanol or lower alkenol, wherein the esterified
hydroxy group has, e.g., the above given meaning, and
stands, in particular~ for halogen, e.g. chlorine, bromine
or iodine, or organic sulphonyloxy, e.g. p-toluene-
sulphonyloxy. The reaction is performed preferably in
the presence of a suitable base such as a tertiary amine,
e.g. in the presence of a preferably sterically hindered
tri-lower-alkylamine, such as ethyl-diisopropylamine
~Hunig base). A methyl group Rl can be introduced also
by reaction with formaldeIlyde in the presence of formic acid.
The above reaction is performed, depending on the
employed reagent, in the presence of a solvent or diluent
and, if necessary, with cooling or heating, in a closed
vessel and/or under an inert gas, e.g. in a nitrogen
.
-, , . , . ,......... , . . .: . . .
- .. . . .... ~
- - , ' - ' ~ '',:. " ' ' . ,
~ 06 ~'7
atmosphere.
The starting material of formula IV can be produced
in a manner known per se, e.g. by reaction of a compound
of formula II with an excess of ammonia. Furthermore,
in a 2-(2-lower alkenyl)-, especially 2-allyl-5-R-2,3-
dihydro-lH-dibenzoE2,3:6,7]thiepino[4,5-c]pyrrole or
-dibenæol2,3:6,7]oxepino[4,5-c]pyrrole, the N-2-lower-
alkenyl substituent, particularly the N-allyl substituent,
can be replaced by an acyl group that can be split off,
especially by a lower alkoxycarbonyl group, e.g. ethoxy-
carbonyl group, e.g. by treatment with a suitable acid
halide, such as with a haloformic acid lower alkyl ester,
e.g. chloroformic acid ethyl ester. In the thus obtainable
2-acyl-, such as 2-lower-alkoxy-carbonyl-, e g. 2-ethoxy-
carbonyl-5-R-2,3-dihydro-lH-dibenzo[2,3:6,7~thiepino
14,5-clpyrrole compound or -dibenzo[2,3:6,7]oxepino[4,5-c]
pyrrole compound, the acyl group, such as the lower alkoxy
carbonyl group, e.g. ethoxycarbonyl group, is split off
hydrolytically, e.g. by treatment with a suitable aqueous
acid or basic agent such as aqueous hydrobromic acid or
aqueous-ethanolic potassium hydroxide; or alcoholytically,
e.g. by treat~ent with a lower alkanol such as ethanol,
in the presence of an alkali metal hydroxide, e.gO potassium
hydroxide, and thus replaced by hydrogen.
q
- . ~ .
'
-
. . ~ . , , ~ .
- ,~
~i5~
The new compounds of formula I can be produced also by a process
in which, in a compound of the formula
, 1 . ~ .
/N~
H C CH
2\ 1 2 (V)
~ ~ R
wherein Ro represents alkoxy or alkanoyloxy, the group Ro is converted into
the free hydroxy group, and, optionally, the additional steps are carried
out.
Such a group Ro can be converted into the free hydroxy group, in
a manner known per se, such as by means of solvolysis, e.g. hydrolysis, al- ;
coholysis or acidolysis, or by means of reduction, e.g. hydrogenolytically,
or by treatment with a chemical reagent, and also photolytically.
Such etherified alkoxy is especially methoxy, as well as ethoxy,
n-propyloxy, isopropyloxy or n-butyloxy, also tert.-lower alkoxy such as
tert.-butyloxy or tert.-pentyloxy.
R as alkanoyloxy is especially lower-alkanoyloxy such as acetyl-
oxy, propionyloxy or pivaloyloxy.
The splitting off of a group Ro can be performed in a manner
known per se3 usually by hydrolysis, if necessary in the presence of acid or
basic agents, such as mineral acids, e.g. hydrochloric acid or hydrobromic
acid ~whereby the last-mentioned arè suitable in particular for the splitting
off of a lower-alkoxy group Ro, such as methoxy), or alkali metal hydroxides
or alkali metal carbonates, e.g. sodium hydroxide or potassium hydroxide.
Certain suitable etherified or esterified hydroxy groups can be split off
also by means of other methods; thus, e.g., tert.-lower-alkoxy- or tert.-
lower-alkoxycarbonyloxy, or diphenyl-methoxycarbonyloxy optionally containing
lower alkoxy, by acidolysis (e.g. by treatment of the corresponding
-- 1 0
5137~
starting material with a suitable protonic, at most
slightly nucleophilic, strong organic carboxylic or
sulphonic acid, e.g. formic acid or trifluoroacetic
acid), optionally substituted a-phenyl-lower-alkoxy or
a-phenyl-lower-alkoxycarbonyloxy by hydrogenolysis
~e.g. by treatment of the corresponding starting material
with hydrogen in the presence o a metal catalyst suitable
for hydrogenation purposes, such as palladium), 2-nitro-
4,5-dimethoxy-benzyloxycarbonyloxy photolytically (e.g~
by irradiation of the corresponding starting material
with ultraviolet light, e.g. of a wave-length of above 290 mm),
or benzoylmethoxycarbonyloxy optionally containing halogen
or 2-halo-lower-alkoxycarbonyloxy by treatment with a
chemical reducing agent (i.e. by means of nascent hydrogen,
e.g. by treatment of the corresponding starting material
with a suitable metal, e.g. zinc, or with a suitable
metal salt, e.g. chromium-II-chloride, in the presence of
of a hydrogen donor, eOgO aqueous acetic acid, whereby,
e.g., a 2-bromoethoxycarbonyloxy is converted, before the
treatment with the chemical reducing agent, advantageously,
e.g., by treatment with a suitable iodine salt, such as
sodium iodide, into the 2-iodoethoxycarbonyloxy group).
The above splitting-off reaction is usually performed
"~ .
:'' - ' -, ' , ,' ''' ' ~-' "' ' :'' .':
,. . , ~ : : . .; .
. . -- ~ , .
~36S~37~
in ~he presence o a solvent or diluent or of a mixture thereof; the - -
splitting-off reagent used in excess can simultaneously also serve as
so~vent or diluent. Furthermore, the reaction is performad, if necessary
or if desired, with cooling or heatingJ e.g. in a temperature range of about
-10C to about 120C, in a closed vessel u~der pressure and/or in an inert
gas atmosphere, e.g. in a nitrogen atmosphere.
.' " ,,','' '
:: :
'`, ~'''~,
!o ,`~ I ~ 12 -
87~
The starting materials of formula V are kno~n or
can be produced in a manner known per se, e.g. by a process
in whlch a compound of the formula
Il 12
2 ~ CH2
~ ~ X ~ ~ RB (VI)
wherein Xl and X2 have the above-given meanings, and
RB represents the radical Ro or a radical convertible
into this~ is reacted with an amine of the formula
~l-NH2 (III), and, if necessary or required, in a compound
thus obtained, the group RB is converted into ~he
radical Ro.
The groups Xl and X2 stand in particular for halogen
and especially for bromine, while RB preferably stands
for Ro and particularly for lower alkoxy, e.g. methoxy~
but also, e.g., for a protected amino group such as an
acylated amino group, wherein the acyl radical represents,
e.g., one of the corresponding radicals which occur in
an acyloxy radical Ro.
The reaction of a compound of formula ~rI wi~h an
- - - . . . . . . . . . .. .
~ ~6 S~ 7 ~
amine of ~ormula III can be carried out, e.g., in the
manner described above for the reaction of a compound
of formula II with a compound of formula III. If
necessary, a group ~ is converted in a resulting
5 compound, e.g. an acylated amino group RB such as a lower-
alkanoylamino group, in a mamler Icnown per se, e.g. by
hydrolysis in an acid or alkali medium, into a group Ro,
e.g. into ~he free amino group.
In a compound of formula I obtainable according to
the process, an alkanoyloxy group R can be converted
in a ma-nner known per se, e.g. by solvolysis such as
hydrolysis or alcoholysis, optionally in the presence o~
a basic or acid agent such as an aqueous alkali metal
hydroxide, e.g. sodium or potassium hydroxide, into the
free hydroxy group R. Alternatively, it is possible to
convert in a compound obtainable by the process the free
hydroxy group R into an alkanoyloxy group R by acylation,
e.g. by treatment with a symmetrical or mixed anhydride
of an alkanecarboxylic acid, such as with an alkane-
carboxylic acid halide, e.g. chloride, usually in thepresence of a basic agent such as an inorganic base, e.g.
an agent forming phenolate, such as an alkali metal, e.g.
sodium or potassium, or a suitable alkali metal compound,
t e.g. a sodium or potassium compound, such as 2 suitable
/~ - - '
'. ' ''' . , - ' ' '~ :~'., ' - .', :' ', ' .:':. :~
.. ~.. ~ ~ , - , .. ..
10~587~
hydride, ~mide or hydroxide, or a suitable organic
nitrogen base such as diisopropylethylamine or pyridine3
including a quaternary ammonium base.
' Depending on the conditions of the process and on
the starting materials, there are obtained optionally
salt-forming final materials in the free form or in the
fonm of their salts which can be converted in the usual
manner into each other or into other salts. Thus, free
compounds of formula I are formed from resulting acid
addition salts~ e.g. by treatment with bases or with
basic ion exchangers, whereas free bases of formula I
are converted into acid addition salts, e.g. by reaction with
organic or inorganic acids, especially with those that
are suitable for the formation of pharmaceutically
applicable saltsg such as the aforementioned.
Salts of the new compounds can also be used for
purification purposes, e.g. by a process wherein the free
compounds are converted into their salts, these are
isolated and optionally purified, and again converted
into the free compounds. In consequence of the close
relationship between the new compounds in the free form
and in the form of their salts, it is to be taken, in the
foregoing and in the following, that by thc term 'free
: - -
~L06587~ -
compounds' is meant, where the case applies and with the appropriate
modifications, also the corresponding salts. -
The invention relates also to those modifications of the
process whereby a compound occurring as an intermediate at some
stage is used as the starting material, and the uncompleted steps
are performed, or whereby the process is interrupted at some stage,
or whereby a starting material is formed under the reaction condi-
tions, or whereby a reaction constituent is optionally present in
the form of its salts. ~-
For the carrying out of the process according to the
invention, there are advantageously used such starting materials
which yield the initially specially mentioned groups of final pro-
ducts, and particularly the specifically described or emphasised
final materials.
The new compounds can be used, e.g., in the form of phar-
maceutical preparations which contain an effective amount of the ~-
active substance, optionally together with inorganic or organlc,
solid or liquid, pharmaceutically usable carrier substances suitable
for enteral, e.g. oral, or parenteral administration. There are thus
used tablets or gelatine capsules containing the active substance
together with extenders, e.g. lactose, dextrose,
,:
- 15a -
6SE~
sucrose~ mannitol, sorbltol, cellulose and/or glycin,
and lubricants, e.g. diatomaceous earth, talcum,
stearic acid or salts thereof, such as magnesium or
calcium stearate, and/or polyethylene glycol; tablets
contain also binding agents, e.g. magnesium aluminium
silicate, starches such as maize, wheat, rice or
arrowroot starch, gelatine, tragacanth, methylcellulose,
sodium carboxymethylcellulose and/or polyvinylpyrrolidone,
and, optionally, effervecent agents, e.g. s~arches, agar,
alginic acid or a salt thereof, such as sodlum alginate,
and/or effervescent mixtures, or adsorption agents,
colouring agents, flavouring agents and sweetening agents.
Furthermore, the new pharmacologically effective compounds
can be used in the form of injectable preparations, e.g.
intravenously administered preparations, or in the form
of infusion solutions. Such solutions are preferably
isotonic a~ueous solutions or suspensions; these can be
prepared before use, e.g. as lyophilised preparations
containing the active substance alone or together with a
carrier material, e.g. mannitol. The pharmaceutical
preparations can be sterilised and/or contain auxiliaries~
e.g. preservatives, stabilising agents, wetting and/or
emulsifying agents, solubility-promoting agents, salts for
~6
: : . - ... :. . . .. .
- . . . . . . . . . .
- - i . , .
~L06~;871
regulation of the osmotic pressure, and/or buffers.
The present pharmaceutical preparations, which can
optionally contain further pharmacologically valuable
substances~ are produced in a manner known per se,
S e.g. by means of conventional mixing, granulating,
coating, solution or lyophilising processes, and they contain
from about 0.1% to 100%, especially from about 1% to 50%, o
lyophilisates ~o up to 100% of active substance. The
dosage amounts depend on the mode of application, on
the species, on the age and on the individual condition.
The daily doses of the free base or of pharmaceutically
acceptable salts thereof vary between about 0.05 g and
0.3 g for warm-blooded animals having a weight of about
70 kg.
The following examples serve to illustrate the - ;
invention; temperatures are given in degrees Centigrade.
.' ~'~~ '
. , ~
: ILC3t; i~i~7:~
Example 1
A mixture of 23.0 g of 2-methyl-5-methoxy-2,3-dihydro-
lH-dibenzol2,3:6,7]thiepino[4,5-c]pyrrole and 115 ml
of 48% aqueous hydrobromic acid is refluxed for 3 hours
with stirring, and then cooled to 20. The precipi~ated
hydrobromide of 2-methyl-5-hydroxy-2,3-dihydro-lH-
dibenzo[2,3:6,7jthiepino[4,5-c]pyrrole is filtered off
and dissolved in 250 ml of 60% aqueous methanol. The
solution is rendered alkaline by addition of concentrated
aqueous ammonia solution (phenolphthalein), whereupon free
2-methyl-5-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7]thiepino
14,5-c]pyrrole crystallises out. The product melts at
242-245 after recrystallisation from methanol.
Example 2
A suspension of 14.5 g of 2-methyl-5-hydroxy-2~3-
dihydro-lH-dibenzol2,3:6,7]thiepino[4,5-c]pyrrole in a
mixture of 50 ml of absolute ethanol and 100 ml of acetone
is made neutral with 4.95 g of methanesulphonic acid,
whereupon the base goes into solution, and after some
time the methanesulphonic acid salt of 2-methyl-5-hydroxy-
2,3-dihydro-1~-dibenzol2,3:6,7jthiepinol4,5-c]pyrrole
crystallises out. The salt melts at 194 - 195 after
recrystallisation from absolute ethanol.
- : . :: . .
-
,.
. . - .. ~ - , .~ . . -
~ID65~7~
Example 3
By boiling 11 g of 2-ethyl-5~methoxy-2a3-dihydro-lH-
dibenzo~2,3:6,7]thiepinol4,5-c]pyrrole in 55 ml of 48%
aqueous hydrobromic acid there is obtained, by a process
analogous to that described in Example 1, 2-ethyl-5-
hydroxy-2,3-dihydro-lH-dibenzo[2,3:6~7]thiepino[4,5-c]
pyrrole, which melts at 22~-227 after recrystallisation
from ethanol. ~he methanesulphonic acid salt of 2-ethyl-5-
hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7]thiepinoL4,5-c]
pyrrole is obtained by a procedure analogous to that
of Example 2; it melts at 252-255 after recrystallisation
from 80% ethanol.
Example 4
By boiling 14 g of 2-methyl-5-methoxy-2,3-dihydro~
dibenzol2,3:6,7]oxepinol4,5-c]pyrrole in 70 ml of 48%
aqueous hydrobromic acid there is obtained, by a process
analogous to that described in Example 1, 2-methyl-S-
hydroxy-2,3-dihydro-lH-dibenæo[2,3:6,7]oxepino[4,5-c]
pyrrole, which melts at 244-250 after recrystallisation
from methanol. The methanesulphonic acid salt of 2-methyl
5-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7]oxepinol4,5-c]pyrrole
is obtained by a procedure analogous to tha~ of Example 2;
it melts at 235-238 after recrystallisation from methanol.
19
. .
~3lO6~87~L
Example 5
By boiling 14.7 ~ of 2-ethyl-5-methoxy-2,3-dihydro-
lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole in 73.5 ml of
48% aqueous hydrobromic acid there is obtained, ~y a
method analogous to that described in Example 1, 2-ethyl-
S-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7]oxepinol4,5-c]
pyrrole, which melts at 172-174 af~er recrystallisation
from methanol. The methanesulphonic acicl salt o 2-e~hyl-
5-hydroxy-2,3-dihydro-lH-dibenzoE2,3:6,7]oxepino E 4 s 5 - c ]
pyrrole is obtained by a process analogous to that of
Example 2: it melts a~ 219-222 after recrystallisation
from ethanol.
Example 6
A solution of 4.7 g of acetyl chloride in 20 ml of
absolute benzene is added dropwise within one hour, with
stirring, to a solution of 8.4 g of 2-methyl-5-hydroxy-
2,3-dihydro~ dibenzo[2,3:697~thiepino[4,5-c]pyrrole in
150 ml of absolute pyridine, with the temperature being
maintained at between 0 and 5. Stirring is subsequently
continued for 2 hours at room temperature, the reaction
mixture is then poured on ice water and extracted with
ether. The ether solution is separated, washed with water
~0
!~,.. ~ .
' . . ' .' ., . . ' '' ., ' ' ~ . , ' . ~,.
', ,' ' ' ' '. ' ' ''.. '. '. ', ~'. ' '''1 . ., :
. ' . . , ' .,
. . ..
iS!37~
and, after drying over sodium sulphate, concentrated
by evapora~ion, whereupon 2-methyl-5-acetoxy-2,3-dihydro-
lH-dibenzo¦2,3:6,7lthiepino[4,5-c]pyrrole is obtained
as oil.
9.5 g of the oily crude base is dissolved in 50 m]
of acetone, and neutralised with a solution of 2.7 g
of anhydrous oxalic acid in 10 ml of absolute ethanol,
whereupon the oxalate crystallises out; this melts at
117-120 after recrystallisation from abs. ethanol/abs.ether.
Example 7
The following final produc~s are produced analogously
to Example 6:
a) from 5.6 g of 2-methyl-5-hydroxy-2,3-dihydro-lH
dibenzo[2,3:6,7}thiepino~4,5-c]pyrrole in 120 ml of
absolute pyridine and 5.9 g of heptanoyl chloride in
10 ml of abs. benzene:- 2-methyl-5-heptanoyloxy-2,3
dihydro-lH-dibenzo[2,3:6,7]thiepinol4,5-c~pyrrole, the
oxalate of which melts at 195-197 after recrystallisation
from abs. ethanol.
b) from 5.6 g of 2-ethyl-5-hydroxy-2,3-dihydro-lH-dibenzo
12,3:6,7]oxepino[4,5-c]pyrrole in 120 ml of absolute
pyrridi~e and 3.1 g of acetyl chloride in 10 ml of abs.
~1 :
,
:
.
~()6587~
benzene:- 2-ethyl-5-acetoxy-2,3-dihydro-lH-dibenzo
l2,3:6,7]oxepinol4 3 5-c]pyrrole, the oxalate of which
melts at 152-155 after recrystallisation from abs.
ethanol/acetone.
Example 8
Tablets containing 0.02 g of the methanesulphonic acid
salt of 2-methyl-5-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7]
thiepinol4,5-c]pyrrole are produced as ollows:
Composition (for 10000 tablets)
methanesulphonic acid salt of 2-methyl-S-hydroxy-
2,3-dihydro-lH-dibenzo[2,3:6,7]thiepino[4,5-c]
pyrrole 200.00 g
lactose 200.80 g
potato starch 354.70 g
stearic acid 10.00 g
lS talcum 200.00 g
magnesi~ stearate 2.50 g
colloidal silicon dioxide 32.00 g
ethanol q.s.
A mixture of the methanesulphonic acid salt of 2-methyl-
5-hydroxy-2,3-dihydro-lH-dibenzo¦2,3:6,7]thiepino[4,5-c3
pyrrole, the lactose and 194.70 g of potato starch is
-- ~B -- .. ......
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.
~Q6587~1
moistened with an ethanolic solution of stearic acid
and then granulated through a sieve. The granulate is
dried and the remaining potato s~arch, the talcum, the
magnesium stearate and the colloidal silicon dioxide -
are mixed in, and the mixture is pressed to form
tablets each weighing 0.1 g, which can optionally be
provided with grooves for a finer adjustment of the
dosage amount.
Example 9
Dragees containing 0.02 g of the methanesulphonic
10 acid salt of 2-methyl-5-hydroxy-2,3-dihydro-lH-dibenzo
12,3:6,7]thiepino[4,5-c]pyrrole are produced as follows:
Composition (for 10,000 dragées)
methanesulphonic acid salt of 2-methyl-5-hydroxy-
2,3-dihydro-lH-dibenzo[2,3:6,7]thiepinoL4~5-c3
pyrrole 100.00 g
lactose 1i5.90 g
stearic acid 10.00 g
colloidal silicon dioxide 56.60 g
talcum 165.00 g
potato starch 20.00 g
magnesium stearate 2.50 g
saccharose (cryst.) 502~28 g
_ ~ _
~ -
.. . . . .
-
1~6587~
shellac 6.00 g ~.
gum arabic 10.00 g
dyestuff 0.22 g
titanium dioxide 1.50 g
ethanol q.s.
A granulate is produced from 2-methyl-S-hydroxy-
2,3-dihydro-lH-dibenzol2,3:6,7~thiepino[4,5-c]pyrrole,
lactose and an ethanolic solution of stearic acid; and,
after drying, the granulate is mixed with colloidal
silican dioxide, talcum, potato starch and magnesium
stearate, and the mixture is pressed to form dragée
cores. These are subsequently coated with a concentrated
syrup made from saccharose, shellac, gum arabic, dyestuff
and titanium dioxide to thus obtain dragées each
weighing O.lOS g.
1065873L : ~
Ex~nple_lO
Capsules containing 0.02 g of the methanesulphonic
acid salt of 2-methyl-5-hydroxy-2,3-dihydro-lH-diber1zo
12,3:6,7]thiepinol4~5-cJpyrrole are produced as follows:
Composition for lO00 capsules: -
S Methanesulphonic acid salt of 2-methyl-5-hydroxy-
2,3-dihydro-lH-dibenzo[2,3:6,7~thiepinol4,5~cl ~,
pyrrole 20.00 g
lactose 253.00 g
gelatine 2.00 g
maize stareh lO.00 g
talcum 15.00 g
water q.s.
The methanesulphonic acid salt of 2-methyl-5-hydroxy-
2,3-dihydro-lH-dibenzo[2,3:6,73thiepinol4,5-clpyrrole
is mixed with lactose, the mixture is uniformly moistened
with an aqueous solution o~ gelatine, and is then
granulated through a suitable sieve (eOg. Sieve III
according to Ph.Helv. V). The granulate is mixed with
the dried maize starch and talcum, and the mixture is
evenly filled into hard gelatine capsules (size 1).
0~S
. : :
~5~7~
Example 11
An aqueous injection solution containing 0.01 g/ml
of the methanesulphonic acid salt of 2-methyl-5-hydroxy-
2~3-dihydro-lH-dibenzo[2~3:6~7Jthiepino[4~5-c~pyrrole
is produced as follows:
Composition (for 1000 ampoules)-
methanesulphonic acid salt of 2-methyl-5-11ydroxy-
2,3-dihydro-lH-clibenzo[2,3:6~7]thiepino[4~5-c]
pyrrole 10.00 g
water q.s.
A solution of the methanesulphonic acid salt of
2-methyl-5-hydroxy 2,3-dihydro-lH-dibenzo[2~3:G,7]
thiepino[4,5-clpyrrole in 1000 ml of water is illed
into ampoules and sterilised. An ampoule con~ains a
1% solution of the active substance.
~6
~j, ,,,~ \ '
587~
Example 12
Also the following compounds can be used as active
substance for tablets, dragées, capsules, suppositories,
ampoules, etc.:
2-ethyl-5-hydroxy-2 ? 3-dihydro-lH-dibenzo[2,3:6~7]thiepino
[4,5-~]pyrrole or a salt, e.g. the methanesulphonic
acid salt thereof;
2-methyl-S-acetoxy-2,3-dihydro-lH-dibenzo[2~3:6~7]thiepino
14,5-clpyrrole or a salt thereof; and
2-methyl-5-heptanoyloxy-2,3-dihydro-lH-dibenzo[2,3:6~7]
thiepinol4,5-c]pyrrole o-r a salt thereof.
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