10-Substituted 5-cyanomethylene-10,11-dihydro-dibenzo-[a,d]-cycloheptenes, their preparation, and therapeutic agents containing these compounds

10-Substituted 5-cyanomethylene-10,11-dihydro-dibenzo[a,d]-cycloheptenes, their pharmaceutically tolerated addition salts with acids, processes for their preparation, and their use as drugs, especially as sedatives, hypnotics or tranquilizers.

The present invention relates to 10-substituted 
5-cyanomethylene-10,11-dihydro-dibenzo[a,d]-cycloheptenes and their 
pharmaceutically tolerated addition salts with acids, processes for their 
preparation, and the use of the compounds as drugs, especially as 
sedatives, hypnotics or tranquilizers. 
It is known that tricyclic ring systems with a dibenzo structure and a 
central heterocyclic 7-membered ring, which may or may not possess a basic 
branch, for example an N-methylpiperazine radical, can exhibit neuroleptic 
effects. Examples of such tricyclic compounds are N-methylpiperazine 
derivatives of dibenzo[b,e][1,4]-diazepines (clozapine), 
dibenzo[b,f][1,4]-thiazepines (clotiapine), dibenzo[b,f][1,4]-oxazepines 
(loxapine) or morphantridines (perlapine), as described, for example, in 
the review by J. Schmutz in Arzneimittelforschung 25 (1975), 712-720. 
German Patent Application No. P 2,918,778.8 proposes 6-substituted 
11-alkylene-morphantridines having valuable pharmacological properties. 
The application in question concerns derivatives having a modified ring 
system and exhibiting a different pattern of pharmacological effects. 
We have found that 10-substituted 
5-cyanomethylene-10,11-dihydro-dibenzo[a,d]-cycloheptenes of the general 
formula I 
##STR1## 
where R.sup.1 and R.sup.2 are hydrogen, halogen, especially fluorine, 
chlorine or bromine, alkyl of 1 to 3 carbon atoms or trifluoromethyl, and 
A is an amino radical -NR.sup.3 R.sup.4, where R.sup.3 and R.sup.4 
together with the nitrogen atom by which they are linked are a 5-, 6- or 
7-membered saturated ring, which may or may not contain a nitrogen or an 
oxygen atom as a further hetero-atom, an additional nitrogen atom being 
unsubstituted or substituted by alkyl of 1 to 3 carbon atoms, hydroxyalkyl 
of 2 or 3 carbon atoms, alkoxyalkyl, the alkoxy and alkyl radical each 
being of 1 to 3 carbon atoms, cycloalkyl or cycloalkylmethyl, of 3 to 7 
carbon atoms in the cycloalkyl ring, or alkynyl of 2 to 5 carbon atoms and 
being additionally, where appropriate, substituted by oxygen in the form 
of an N-oxide, and their physiologically tolerated addition salts with 
acids, exhibit valuable pharmacological properties. 
Important meanings of R.sup.1 and R.sup.2 include hydrogen, fluorine, 
chlorine, methyl and trifluoromethyl, amongst which hydrogen and chlorine 
are particularly preferred. 
Examples of amine radicals A, ie. -NR.sup.3 R.sup.4, are piperazinyl, 
homopiperazinyl, piperidinyl and morpholinyl. 
Particularly preferred radicals -NR.sup.3 R.sup.4 are 4-methyl-piperazinyl, 
4-methyl-4-oxy-piperazinyl, 4-cyclopropyl-piperazinyl, 
4-cyclopropylmethyl-piperazinyl, 4-prop-2-ynyl-piperazinyl, 
4-(2-hydroxy)-ethyl-piperazinyl, 4-ethyl-piperazinyl and 
N-methyl-homopiperazinyl. 
It is to be noted that the novel compounds of the formula I exist as 
cis-trans isomers Ia and Ib. 
##STR2## 
If desired, the cis-trans isomers (which are as a rule present in the form 
of 1:1 mixtures) can be separated, for example by fractional 
crystallization or by column chromatography. 
In accordance with the above meanings, the following compounds may be 
mentioned as being particularly preferred and active: 
cis,trans-5-cyanomethylene-10-(4-methyl-piperazin-1-yl)-10,11-dihydro-dibe 
nzo[a,d]-cycloheptene, 
cis,trans-5-cyanomethylene-10-(4-methyl-4-oxy-piperazin-1-yl)-10,11-dihydr 
o-dibenzo[a,d]-cycloheptene, 
cis,trans-5-cyanomethylene-2-chloro-10-(4-methyl-piperazin-1-yl)-10,11-dih 
ydro-dibenzo[a,d]-cycloheptene, 
cis,trans-5-cyanomethylene-10-(4-.beta.-hydroxyethylpiperazin-1-yl)-10,11- 
dihydro-dibenzo[a,d]-cycloheptene, 
cis,trans-5-cyanomethylene-10-(4-ethyl-piperazin-1-yl)-10,11-dihydro-diben 
zo[a,d]-cycloheptene and 
cis,trans-5-cyanomethylene-10-(N'-methyl-homopiperazin-1-yl)-10,11-dihydro 
-dibenzo[a,d]-cycloheptene. 
The novel compounds of the formula I are prepared by reacting a compound of 
the formula II 
##STR3## 
where R.sup.1 and R.sup.2 have the meanings given for formula I, or the 
preferred meanings, and Z is a nucleofugic leaving group, with a 
nucleophilic agent AH, where A has the meanings given for formula I, and, 
if desired, converting the resulting compound to the N-oxide and/or to an 
addition salt with a physiologically tolerated acid. 
Suitable nucleofugic leaving groups Z are halogen, especially bromine and 
chlorine, preferably bromine. 
The reaction is advantageously carried out in the presence of an excess of 
the amine AH, in a dipolar aprotic solvent, preferably dimethylformamide, 
in the presence of about 7/8 mole equivalent of a monovalent silver or 
copper salt, preferably of silver nitrate, at from room temperature to 
80.degree. C., and is in general complete within from 0.5 to 4 hours. In 
some cases, it may be advantageous to exclude atmospheric oxygen and carry 
out the reaction under an inert gas, for example under nitrogen. 
In the reactions, the nucleophilic agent AH is advantageously used in not 
less than 2-molar, and up to 20-molar, excess. 
Advantageously, the 5-cyanomethylene-dibenzo[a,d]-cycloheptene formed as a 
by-product in the reaction, through elimination of hydrogen halide, is 
separated off by column chromatography. 
The conversion of a compound of the formula I to its N-oxide is carried out 
in a conventional manner, advantageously with aqueous (30% strength by 
weight) hydrogen peroxide in ethanol solution. The conversion of a 
compound to its addition salt with a physiologically tolerated acid is 
also carried out in a conventional manner. 
The starting compounds of the formula II are prepared by reacting a 
5-cyanomethylene-10,11-dihydro-dibenzo[a,d]-cycloheptene of the formula 
III 
##STR4## 
where R.sup.1 and R.sup.2 have the meanings given for formula I, with 1 
mole of N-bromosuccinimide or N-chlorosuccinimide in a halohydrocarbon, at 
from 50.degree. to 100.degree. C., to give the 
10-bromo-(chloro)-5-cyanomethylene-10,11-dihydro-dibenzo[a,d]-cycloheptene 
of the formula II. 
The 5-cyanomethylene-10,11-dihydro-dibenzo[a,d]-cycloheptenes of the 
formula III are prepared by a carbonyl olefination, wherein a 
dibenzosuberone (known from the literature) of the formula IV (cf. E. L. 
Engelhardt et al., J. Med. Chem. 8 (1965) 829) 
##STR5## 
wherein R.sup.1 and R.sup.2 have the meanings given for formula I, is 
reacted with a phosphonate of the formula IVa 
##STR6## 
where R is alkyl of 1 to 3 carbon atoms, under the conditions of a 
Wittig-Horner reaction, in an inert solvent-dimethylformamide being 
particularly preferred--in the presence of one mole equivalent of a base, 
preferably a sodium alcoholate, sodium hydride or sodium amide, at from 
20.degree. to 80.degree. C., or is reacted with a phosphonium salt of the 
formula IVb 
##STR7## 
where Ph is a phenyl radical, under the conditions of a classical Wittig 
reaction, in an aprotic organic solvent, especially a saturated aliphatic 
or saturated cyclic ether, eg. diethyl ether, tetrahydrofuran or dioxane, 
or, preferably, in dimethylformamide, in the presence of one mole 
equivalent of a base, especially of an alkali metal alcoholate, preferably 
sodium methylate or sodium ethylate, or sodium hydride or sodium amide, or 
of an organometallic compound, such as butyl-lithium, at from 20.degree. 
to 100.degree. C. 
In addition to the compounds referred to in the Examples, the following 
compounds may be mentioned by way of illustration: 
cis,-trans-8-chloro-5-cyanomethylene-10-(4-methyl-piperazin-1-yl)-10,11-di 
hydro-dibenzo-[a,d]-cycloheptene, 
cis,trans-5-cyanomethylene-10-(4-cyclopropyl-piperazin-1-yl)-10,11-dihydro 
-dibenzo[a,d]-cycloheptene, 
cis,trans-5-cyanomethylene-10-(4-cyclopropylmethyl-piperazin-1-yl)-10,11-d 
ihydro-dibenzo[a,d]-cycloheptene and 
cis,trans-5-cyanomethylene-10-(4-prop-2-ynyl-piperazin-1-yl)-10,11-dihydro 
-dibenzo[a,d]-cycloheptene. 
The compounds according to the invention, of the formula I, are as a rule 
obtained in the form of yellowish or yellow crystals, and can be 
recrystallized from the conventional organic solvents, preferably from a 
lower alcohol, such as ethanol, or be purified by column chromatography. 
The free 10-substituted 
5-cyanomethylene-10,11-dihydro-dibenzo[a,d]-cycloheptenes of the formula I 
can be converted to an addition salt with a pharmacologically tolerated 
acid in a conventional manner, preferably by adding one equivalent of the 
corresponding acid to the solution. Examples of suitable conventional 
physiologically tolerated acids are, amongst inorganic acids, hydrochloric 
acid, hydrobromic acid, phosphoric acid and sulfuric acid, and, amongst 
organic acids, oxalic acid, maleic acid, fumaric acid, lactic acid, 
tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and 
benzoic acid; other acids are listed in Fortschritte der 
Arzneimittelforschung, published by Birkhauser, Basel and Stuttgart, 10 
(1966), 224-225. 
The compounds according to the invention possess valuable pharmacological 
properties. They may be used as sedatives, tranquilizers, hypnotics, 
neuroleptics or antidepressants. Any one compound according to the 
invention may exhibit one or more of the above types of effect. 
According to the results of the pharmacological experiments we have carried 
out, the compounds according to the invention are, by virtue of their 
sedative-tranquilizing, muscle-relaxing and anti-monaminergic effect, 
particularly suitable for use as sedatives, hypnotics and minor or major 
tranquilizers. 
The following methods were used to analyze the action of the compounds: 
1. Sedative action 
4-8 groups of 3 female NMRI mice are given the compound orally. The 
orientation hypermotility induced by a new environment is determined 
photoelectrically, 30 minutes after administration of the compound, for a 
period of 30 minutes. 
The ED.sub.50 is the dose which produces a decrease in orientation 
hypermotility by 50%, compared to control animals treated with placebo. 
2. Muscle-relaxing action 
The measurement is based on quantifying the tonic extensor reflex on the 
rabbit gastrocnemius (Teschendorf et al., Arch. Pharmacol. exp. Path. 266 
(1970), 462). The rabbit is fixed in a special apparatus which permits 
bending the paw at the talocalcanean joint in a defined and reproducible 
manner. As a result of this bending, a tonic extensor reflex is triggered 
in the thigh muscle. The electrical activity of the muscle during 
contraction is registered and the individual pulses are counted. The 
extension (duration 5 s) is repeated at intervals of one minute. After a 
constant number of pulses has been reached (constituting the control 
value), the test compound is administered intravenously. The number of 
pulses after administration is related to the previous value. For each 
dose investigated, 4-6 animals are used. The ED 50% is the dose which 
reduces the muscle activity to half, based on the initial value. 
3. Antimethamphetamine action 
Methamphetamine (2.5 mg/kg administered intravenously) regularly causes the 
following symptoms in rats: motor restlessness, searching and sniffing 
movements, bristling fur and tremor (Janssen et al., Arzneim.-Forsch./Drug 
Res. 13 (1963), 205; Randrug et al., Psychopharmacologia 11 (1967), 300). 
The test substances are administered intraperitoneally, 30 minutes before 
the methamphetamine. The criterion of whether a compound has an effect is 
whether the sniffing movements remain absent over 5 minutes' observation 
after the injection of methamphetamine. That dose is determined as the 
mean inhibitory dose (ED 50%) by means of Probit analysis which prevents 
the symptom in half the number of animals. Number of animals examined per 
dose: 10. 
4. Antiapomorphine action 
Mandibular movements are triggered in groups of 4-6 female Sprague-Dawley 
rats by subcutaneous administration of 1.5 mg/kg of apomorphine and are 
registered by implanted electrodes (mandibulogram as described by Kubacki, 
Psychopharmacology 59 (1978), 209). The test substances are administered 
orally 90 minutes before the apomorphine. 
The ED 50% is determined as the dose which reduces the number of mandibular 
movements by 50% compared to those in placebo-treated control animals. 
5. Anticholinergic action 
Groups of 10 female NMRI mice are given physostigmine subcutaneously, at a 
lethal dose (0.825 mg/kg). The test substances are administered orally 30 
minutes before the administration of physostigmine. 
The ED 50% is determined as the dose of compound which protects 50% of the 
animals against death from physostigmine. 
6. Acute toxicity 
Groups of 5-10 female NMRI mice are given the compounds intraperitoneally. 
The LD 50 is determined as the dose after which 50% of the treated animals 
die. 
In these experiments (cf. Table 1) conspicuously sedative-hypnotic effects 
of the compounds according to the invention were demonstrated, these 
effects being about as pronounced as in the case of the reference 
compounds clozapine and perlapine. There is also a muscle-relaxing action, 
which in some cases markedly surpasses those of the comparative 
substances; this is the case with the compounds of Example 4. 
The antimonaminergic action, measured in the present case in terms of the 
methamphetamine-antagonism or apomorphine-antagonism, may be regarded as a 
parameter of the neuroleptic quality. The strength of the effect is as 
great as or even markedly (up to 7 times) greater than in the case of the 
comparative compounds clozapine and perlapine. In contrast to clozapine, 
the novel compounds show no anticholinergic properties, as demonstrated by 
the antiphysostiamine test on mice, from which it may be concluded that 
the peripheral side-effects on therapeutic use are less. 
On the basis of the pharmacological findings, the novel compounds can be 
used, in appropriate pharmaceutical formulations, as sedatives, hypnotics, 
minor tranquilizers or major tranquilizers. 
TABLE 1 
__________________________________________________________________________ 
Anti- Antiapo- 
Muscle methamphet- 
morphine 
Anticholin- 
Example 
Sedation relaxation 
amine action 
action ergic action 
Toxicity 
No. ED 50% 
R.A..sup.1 
ED 50% 
R.A. 
ED 50% 
R.A. 
ED 50% 
R.A. 
LD 50 LD 50 
__________________________________________________________________________ 
1 5.6 0.85 
0.1 0.46 
5.4 6.85 &gt;46.4 &gt;100 
7 10.0 0.47 30 1.23 &gt;100 &gt;100 
5 6.7 0.71 
0.1 0.46 
13 2.85 &gt;46.4 &gt;100 
8 15.2 0.31 39 0.95 
7 1.14 
&gt;100 &gt;100 
4 5.5 0.86 
0.02 2.30 
4.6 8.04 
Cloza- 
4.74 1.0 0.046 
1.0 
37 1.00 
8 1.00 
14.1 215 
pine 
Perla- 
2.01 2.36 
0.1 0.46 
31 1.19 
21.5 0.37 
&gt;21.5 215 
pine 
__________________________________________________________________________ 
.sup.1 R.A. = relative activity 
Accordingly, the present invention also relates to a therapeutic agent 
which in addition to conventional carriers and diluents contains a 
compound of the formula I, or a physiologically tolerated addition salt 
thereof with an acid, as the active compound. 
Therapeutic agents containing conventional carriers or diluents and the 
conventionally used technical auxiliaries can be prepared in a 
conventional manner, in accordance with the desired route of 
administration and employing a unit dosage suitable for the particular 
application. A suitable individual dose in man is from 10 to 100 mg. 
The novel compounds may be employed in the conventional solid or liquid 
pharmaceutical forms, such as tablets, capsules, powders, granules, 
dragees or solutions. These are prepared in a conventional manner, and to 
do so the active compounds can be mixed with the conventional 
pharmaceutical auxiliaries, such as talc, gum arabic, sucrose, lactose, 
cereal starch or corn starch, potato flour, magnesium stearate, alginates, 
gum tragacanth, carraghenates, polyvinyl alcohol, polyvinylpyrrolidone, 
aqueous or non-aqueous carriers, wetting agents, dispersants, emulsifiers 
and/or preservatives (cf. L. G. Goodman and A. Gilman, The Pharmacological 
Basis of Therapeutics). The formulations thus obtained normally contain 
from 0.001 to 99% by weight of the active compound. 
The preferred formulations are those suitable for oral administration. 
Examples of these are tablets, film tablets, dragees, capsules, pills, 
powders, solutions, suspensions and depot forms. Parenteral formulations, 
such as injection solutions, may also be used. Suppositories are a further 
example of suitable formulations. 
Appropriate tablets may be obtained, for example, by mixing the active 
compound with conventional auxiliaries, for example inert diluents, such 
as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, calcium 
carbonate, calcium phosphate or lactose, disintegrating agents, such as 
corn starch or alginic acid, binders, such as starch or gelatin, 
lubricants, such as magnesium stearate or talc, and/or agents for 
achieving a depot effect, such as carboxypolymethylene, 
carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. 
The tablets can also consist of a plurality of layers. 
Accordingly, dragees can be prepared by coating cores, prepared similarly 
to the tablets, with agents conventionally used in dragee coatings, for 
example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. 
The dragee coating can also consist of a plurality of layers, and the 
auxiliaries mentioned above in connection with tablets may be used 
therein. 
Solutions or suspensions containing the novel active compounds may 
additionally contain flavor improvers, such as vanillin or orange extract. 
They may also contain suspending agents, such as sodium 
carboxymethylcellulose, or preservatives, such as p-hydroxybenzoates. 
Capsules containing the active compounds may be prepared, for example, by 
mixing the active compound with an inert carrier, such as lactose or 
sorbitol, and encapsulating the mixture in gelatin capsules. Suitable 
suppositories can be prepared, for example, by mixing the active compounds 
with appropriate carriers, such as neutral fats or polyethylene glycol or 
their derivatives. 
The Examples which follow illustrate the invention.

EXAMPLE 1 
cis,trans-5-Cyanomethylene-10-(4-methyl-piperazin-1-yl)-10,11-dihydro-diben 
zo[a,d]-cycloheptene. 1/2 H.sub.2 O 
1.0 g (5.9 millimoles) of silver nitrate are dissolved in 10 ml of stirred 
absolute dimethylformamide, and a large excess (5-50 ml) of 
N-methylpiperazine is added. A solution of 7.0 g (22.6 millimoles) of 
10-bromo-5-cyanomethylene-10,11-dihydro-dibenzo[a,d]-cycloheptene 
(cis,trans-isomer mixture) in 35 ml of dimethylformamide is then 
immediately added dropwise (a slight rise in temperature of the reaction 
mixture, to 28.degree.-30.degree. C., indicates the exothermic reaction is 
taking place, and the color changes from yellow to gray as a result of 
precipitated silver), and the reaction mixture is stirred for 1-3 hours at 
room temperature, under nitrogen. It is then poured onto 2 liters of ice 
water (thorough stirring being necessary), and after a further hour's 
stirring the gray solids which have precipitated are filtered off. The 
crude product, which is colored gray due to finely divided silver, is 
dispersed in a small amount of methylene chloride and is purified direct 
by column chromatography on silica gel, using a 95/5 methylene 
chloride/methanol mixture; this removes the 
5-cyanomethylene-dibenzo[a,d]-cycloheptene formed as a by-product. 1.5 g 
(20%) of product are isolated as a cis,trans-isomer mixture, which can 
subsequently be recrystallized from ethanol. Colorless crystals of melting 
point 141.degree.-143.degree. C. 
EXAMPLE 2 
cis,trans-10-Bromo-5-cyanomethylene-10,11-dihydro-dibenzo[a,d]-cycloheptene 
To prepare the intermediate 
10-bromo-5-cyanomethylene-10,11-dihydro-dibenzo[a,d]-cycloheptene, 13.0 g 
(56 millimoles) of 
5-cyanomethylene-10,11-dihydro-dibenzo[a,d]-cycloheptene are dissolved in 
200 ml of carbon tetrachloride and 10.0 g (56 millimoles) of 
N-bromosuccinimide and 100 mg of benzoyl peroxide are added. The reaction 
mixture is refluxed for 3 hours and when it has cooled the succinimide 
formed is filtered off. After concentrating the mother liquor, the crude 
product is obtained as a crystal/oil mixture, which is recrystallized from 
ethanol. 16.0 g (92%) of product of melting point 148.degree.-150.degree. 
C. are isolated. 
EXAMPLE 3 
cis,trans-5-Cyanomethylene-10,11-dihydro-dibenzo[a,d]-cycloheptene 
To prepare the intermediate 
5-cyanomethylene-10,11-dihydro-dibenzo[a,d]-cycloheptene, a carbonyl 
olefination is carried out by means of a Wittig-Horner reaction or by a 
classical Wittig synthesis: 20.0 g (96 millimoles) of dibenzosuberone are 
dissolved in 200 ml of warm dimethylformamide and the solution is stirred 
under nitrogen. 20.3 g (115 millimoles) of diethylcyanomethyl-phosphonate 
and 20.1 g (115 millimoles) of 30% strength sodium methylate dissolved in 
100 ml of dimethylformamide are then slowly and simultaneously added 
dropwise (an intensification of color, and rise in temperature, indicate 
the start of the Wittig reaction). After stirring for a further 12 hours 
at room temperature, the reaction product is poured onto ice water and 
stirred thoroughly for 3 hours to complete the crystallization, and the 
solid which has precipitated is filtered off. After thorough washing with 
water, the crude product is dried and recrystallized from ethanol. Yield: 
14.0 g (63%) of colorless crystals of melting point 
105.degree.-107.degree. C. 
Classical Wittig process: Triphenyl-cyanomethylphosphonium chloride is 
introduced into dimethylformamide, 1 mole equivalent of a 30% strength 
sodium methylate solution is then added dropwise, or 1 mole equivalent of 
sodium hydride is added, and finally 1 mole equivalent of a solution of 
dibenzosuberone in dimethylformamide is introduced. The reaction mixture 
is stirred for 5-8 hours at 50.degree.-80.degree. C. and is then poured 
onto ice water and extracted repeatedly with methylene chloride. The 
organic phase is dried and concentrated, and the crude product obtained is 
recrystallized from ethanol. Yield: 45%; colorless crystals of melting 
point 104.degree.-107.degree. C. 
EXAMPLE 4 
cis,trans-2-Chloro-5-cyanomethylene-10-(4-methylpiperazin-1-yl)-10,11-dihyd 
ro-dibenzo[a,d]-cycloheptene 
(a) 
cis,trans-2-Chloro-5-cyanomethylene-10,11-dihydro-dibenzo[a,d]-cyclohepten 
The synthesis is carried out analogously to Example 3, with different 
working up by extracting the crude product from ice water with methylene 
chloride, followed by washing the organic phase three times with water and 
drying and concentrating it. 
The cis,trans-isomer mixture obtained as a crystal/oil mixture is subjected 
to fractional crystallization from ethanol, the most sparingly soluble 
fraction is isolated, and this operation is repeated two or three times, 
in each case with the most sparingly soluble fraction, to give the pure 
trans-isomer, of melting point 142.degree.-143.degree. C. (analysis by 270 
MHz .sup.1 H-NMR spectroscopy in CDCl.sub.3 : the doublet of H.sub.6 which 
appears in the lowest field, of .delta.=7.45 ppm, exhibits m-coupling, 
which naturally does not occur with the cis-isomer). 
(b) 
cis,trans-10-Bromo-2-chloro-5-cyanomethylene-10,11-dihydro-dibenzo[a,d]-cy 
cloheptene: Synthesis similar to Example 2. Colorless crystals of melting 
point 142.degree.-145.degree. C. (after recrystallization from ethanol). 
(c) 
cis,trans-2-Chloro-5-cyanomethylene-10-(4-methylpiperazin-1-yl)-10,11-dihy 
dro-dibenzo[a,d]-cycloheptene: Synthesis similar to Example 1. After column 
chromatography (silica gel, 95/5 methylene chloride/methanol), colorless 
crystals of melting point 77.degree.-80.degree. C. are obtained. 
EXAMPLE 5 
cis,trans-5-Cyanomethylene-10-(4-ethyl-piperazin-1-yl)-10,11-dihydro-dibenz 
o[a,d]-cycloheptene. 1/2 H.sub.2 O 
Synthesis similar to Example 1, using N-ethylpiperazine. After purification 
by column chromatography (silica gel, 95/5 methylene chloride/methanol), 
colorless crystals of melting point 68.degree.-71.degree. C. are obtained. 
EXAMPLE 6 
cis,trans-5-Cyanomethylene-10-(N'-methyl-homopiperazin-1-yl)-10,11-dihydro- 
dibenzo[a,d]-cycloheptene. 1/2 H.sub.2 O 
Synthesis similar to Example 1, using N-methylhomopiperazine. After 
purification by column chromatography (silica gel, 95/5 methylene 
chloride/methanol), colorless crystals of melting point 
85.degree.-88.degree. C. are obtained. 
EXAMPLE 7 
cis,trans-5-Cyanomethylene-10-(N-.beta.-hydroxyethyl-piperazin-1-yl)-10,11- 
dihydro-dibenzo[a,d]-cycloheptene. 1/2 H.sub.2 O 
Synthesis similar to Example 1, using N-.beta.-hydroxyethyl-piperazine. 
After purification by column chromatography (silica gel, 95/5 methylene 
chloride/methanol), colorless crystals of melting point 
75.degree.-78.degree. C. are obtained. 
EXAMPLE 8 
cis, 
trans-5-Cyanomethylene-10-(4-methyl-4-oxy-piperazin-1-yl)-10,11-dihydro-di 
benzo[a,d]-cycloheptene. 1/2 H.sub.2 O 
2.4 g (7.3 milimoles) of 
cis,trans-5-cyanomethylene-10-(4-methyl-piperazin-1-yl)-10,11-dihydro-dibe 
nzo[a,d]-cycloheptene (Example 1) are dissolved in 100 ml of hot ethanol 
and 5 ml of 30% strength hydrogen peroxide are added. After refluxing the 
mixture for 5 hours, the excess hydrogen peroxide is destroyed by dropping 
a small platinum sheet into the reaction mixture and then refluxing for 2 
hours. After filtration, the reaction mixture is concentrated and the 
N-oxide obtained is purified by column chromatography (silica gel, mobile 
phase 95/5 methylene chloride/methanol). 1.5 g (60%) of colorless crystals 
of melting point 78.degree.-80.degree. C. are isolated. 
Pharmaceutical formulations prepared in a conventional manner: 
______________________________________ 
Examples of tablets 
______________________________________ 
1. An active compound of the formula I 
5 mg 
Lactose 200 mg 
Methylcellulose 15 mg 
Corn starch 50 mg 
Talc 11 mg 
Magnesium stearate 4 mg 
2. An active compound of the formula I 
20 mg 
Lactose 178 mg 
Avicel 80 mg 
Polywachs 6000 20 mg 
Magnesium stearate 2 mg 
3. An active compound of the formula I 
50 mg 
Polyvinylpyrrolidone (mean molecular 
170 mg 
weight 25,000) 
Polyethylene glycol (mean molecular 
14 mg 
weight 4,000 
Hydroxypropylmethylcellulose 
40 mg 
Talc 4 mg 
Magnesium stearate 2 mg 
______________________________________ 
The active compound is moistened with a 10% strength aqueous solution of 
the polyvinylpyrrolidone and the mixture is forced through a sieve of 1.0 
mm mesh width and is dried at 50.degree. C. The granules thus obtained are 
mixed with polyethylene glycol (mean molecular weight 4,000), 
hydroxypropylmethylcellulose, talc and magnesium stearate and the mixture 
is pressed to give tablets each weighing 280 mg. 
______________________________________ 
4. Example of dragees 
______________________________________ 
An active compound of the formula I 
60 mg 
Lactose 90 mg 
Corn starch 60 mg 
Polyvinylpyrrolidone 6 mg 
Magnesium stearate 1 mg 
______________________________________ 
The mixture of the active compound with lactose and corn starch is 
moistened with an 8% strength aqueous solution of the polyvinylpyrrolidone 
and granulated by passing through a 1.5 mm sieve; the granules are dried 
at 50.degree. C. and forced through a 1.0 sieve. The granules obtained 
after this operation are mixed with magnesium stearate and the mixture is 
pressed to form dragee cores. These are coated in a conventional manner 
with a shell which essentially consists of sugar and talc. 
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5. Capsule formulation 
An active compound of the formula I 
5 mg 
Magnesium stearate 2.0 mg 
Lactose 19.3 mg 
6. Injection solution 
An active compound of the formula I 
10 mg 
Sodium chloride 9 mg 
Distilled water, q.s. to make 1.0 ml 
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