Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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4- 1 8538/A
Substituted benzofuranylpiperidine as a nootropic agent
The invention relates to the use of 4-(7-bromo-5-methoxybenzofuran-2-yl)piperidine of
formula I
CH30~CNH (I)
Bt
or of a pharmaceutically acceptable salt thereof, as an active ingredient in nootropic
medicaments or for the preparation of a nootropic agent, to pharmaceutical compositions
comprising the above, and to a method of retarding the degeneration of nerve cells that
accompanies degenerative nerve disorders, such as Alzheimer's disease and Parkinson's
disease, and of treating disorders that are responsive to treatment with nootropic agents.
Pharmaceutically acceptable salts of 4-(7-bromo-5-methoxybenzofuran-2-yl)piperidine are
especially its pharmaceutically acceptable salts with suitable mineral acids, such as hydro-
halic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobrornides,
sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic
sulfonic acids or N-substituted sulfamic acids, for example methanesulfonates, benzene-
sulfonates, p-toluenesulfonates or N-cyclohexylsulfamates (cyclamates).
4-(7-Bromo-5-methoxybenzofuran-2-yl)piperidine and its pharmaceutically acceptable
salts are known. When administered subcutaneously to rats in a dose ranging fromapproximately 10 to approximately 50 mg/kg, they inhibit the uptake of noradrenaline into
the heart and they inhibit monoamine oxidase, and they have therefore been proposed as
active ingredients for antidepressant medicaments for the treatment of depression.
The invention is based on the surprising discovery that 4-(7-bromo-5-methoxybenzo-
furan-2-yl)piperidine and its pharrnaceutically acceptable salts have in addition pronoun-
ced nootropic activity and a pronounced retardant action on the degeneration of nerve
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cells, which occurs, for example, with Alzheimer's disease and Parkinson's disease. For
example, in mice they provide reliable protection against the amnesiogenic effect of a
cerebral electric shock and bring about a marked improvement in memory function. For
example, following peroral administration of a dose of from approximately 0.1 toapproximately 3 mg/kg p.o., a highly significant increase in the time which the mice spend
in the illuminated compartment of the test cage was observed, as compared with the
vehicle alone (vehicle: 10.4 s; 3.0 mg/kg of active ingredient in the form of the hydro-
chloride: 38.8 + 7.9 sec; p < 0.0002).
Furthermore, in the one-way active avoidance test, which was carried out on 27-month-old
rats, following peroral administration of doses of 0.3 and 3.0 mg/kg, they significandy
facilitate learning of the avoidance task, as compared with the vehicle, that is to say, they
reduced the number of learning attempts required to achieve five successive active avoi-
dance reactions (vehicle: 21.7 + 4.5; 3.0 mg/kg of active ingredient in the form of the
hydrochloride: 10.2 + 1.8; p < 0.05).
On account of these properties, 4-(7-bromo-5-methoxybenzofuran-2-yl)piperidine and its
pharmaceutically acceptable salts are excellently suitable for retarding the degeneration of
nerve cells that accompanies degenerative nerve disorders, such as Alzheimer's disease
and Parkinson's disease, and for treating disorders that are responsive to treatment with
nootropic agents, for example cerebral insufficiencies having very varied origins and
aedologies, especially memory disorders, such as senile dementia, multi-infarct dementia
or dementia of the Alzheimer type, and also the consequences of brain traumas orapoplexies.
The active ingredients for nootropic medicaments proposed according to the invention
may be administered enterally or parenterally, especially orally or intravenously. The
recommended daily dose is, for example, from approximately 0.6 to approximately
18 mg/kg or from approximately 40 to approximately 1250 mg/70 kg, preferably
approximately from 2 to 8 mg/kg or approximately from 150 to 600 mgn0 kg, for
example from approximately 2.5 to approximately 6 mg/kg or approximately from 175 to
420 mg/70 kg, which may, if necessary, be divided into 2 to 4 single doses of, for
example, from approximately 0.3 to approximately 6 mg/kg or from approximately 20 to
approximately 400 mg/70 kg, preferably approximately from 2 to 4 mg/kg or approxi-
mately from 150 to 300 mg/70 kg, for example from approximately 2.5 to approximately
3.2 mg/kg or approximately from 175 to 225 mgn0 kg.
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The nootropic pharmaceudcal composidons provided according to the invention are
preferably pharmaceudcal compositions in unit dose form for enteral, such as oral, also
rectal, and parenteral administradon to (a) warm-blooded animal(s), the composidons
comprising the pharmacological acdve ingredient on its own or together with a pharma-
ceutically acceptable carrier.
The nootropic pharmaceudcal compositions provided according to the invendon comprise,
for example, from approximately 10 % to approximately 80 %, preferably from approxi-
mately 20 % to approximately 60 %, acdve ingredient. Pharmaceutical compositionsaccording to the invendon for enteral or parenteral administradon are, for example,
composidons in unit dose form, such as dragées, tablets, capsules or suppositories, and
also ampoules. They are prepared in a manner known ~r se, for example by means of
convendonal mixing, granulating, confectioning, dissolving or lyophilising processes. For
example, pharmaceudcal composidons for oral administradon can be obtained by
combining the active ingredient with solid car iers, opdonally granulating a resuldng
mixture, and processing the mixture or granules, if desired or necessary after the addition
of suitable excipients, to form tablets or dragée cores.
Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose,
mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tri-
calcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes
using, for example, corn, wheat, rice or potato starch, gelatdn, tragacanth, methylcellulose
and/or polyvinylpyrrolidone, and, if desired, disintegrators, such as the above-mentioned
starches and also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic
acid or a salt thereof, such as sodium alginate. Excipients are especially flow condidoners
and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as
magnesium or calcium stearate, and/or polyethylene glycol. Dragée cores are provided
with suitable, opdonally enteric coatings, there being used inter alia concentrated sugar
soludons, which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene
glycol and/or tdtanium dioxide, coadng soludons in suitable organic solvents or solvent
mixtures or, for the preparation of enteric coatings, soludons of suitable cellulose prepara-
dons, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
Colourings or pigments may be added to the tablets or dragée coatings, for example for
idendficadon purposes or to indicate different doses of acdve ingredient.
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Pharmaceutical compositions for oral administration are also hard gelatin capsules, and
soft sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol.
The hard gelatin capsules may contain the active ingredient in the forrn of granules, for
exarnple in admixture with fillers, such as lactose, binders, such as starches, and/or
glidants, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules
the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty
oils, paraffin oil or liquid polyethylene glycols, it likewise being possihle to add
stabilisers.
Suitable rectally administrable pharmaceutical compositions are, for example,
suppositories that consist of a combination of the active ingredient with a suppository
base. Suitable suppository bases are, for example, natural or synthetic triglycerides,
paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use
gelatin rectal capsules, which contain a combinadon of the active ingredient with a base
material. Suitable base materials are, for example, liquid triglycerides, polyethylene
glycols or paraffin hydrocarbons.
For parenteral administration there are suitable, especially, aqueous solutions of an active
ingredient in water-soluble form, for example in the form of a water-soluble salt, and also
suspensions of the active ingredient, such as corresponding oily injection suspensions,
there being used suitable lipophilic solvents or vehicles, such as fatty oils, for example
sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or
aqueous injection suspensions that comprise viscosity-increasing substances, for example
sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilisers.
The following Examples serve to illustrate the invention; temperatures are given in
degrees Celsius, pressures in mbar.
Pharmacolo~ical ExamPle 1: Protection against the amnesiogenic effect of a cerebral
electric shock in mice
It is an empirical clinical fact that cerebral electric shock treatment leads to retrograde
amnesia; the ability to remember events immediately before the electric sho k is impaired.
Neither the biochemical mechanism nor the nature of the psychological process affected
by the treatment is known. However, there is virtually no doubt that the electric shock
affects the recollection process in some way. The fact that the retrograde arnnesia is
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time-dependent (the greater the period of time that has elapsed since the information was
absorbed, the less pronounced is the effect) suggests an influence on a time-limited
process, which most probably concerns fixing the memory pathway or consolidating the
contents of the memory. It is therefore to be assumed that medicaments that facilitate
fixing of the memory pathway have an advantageous effect on amnesia brought about by
the electric shock, for example they shorten the period of time during which fixing of the
memory pathway is impaired and thus reduce the extent of the amnesia. In the animal
experiment, amnesia induced by an electric shock can be observed when the cerebral
electric shock is applied within a few seconds following the learning process, which in the
present case is a passive avoidance task.
Experimental arrangement: A larger cage compartment (35 x 20 x 10 cm) communicates
with a smaller cage compartment (10 x 10 x 10 cm) by means of a sliding door. The
smaller cage compartment is illuminated from above by means of a 100 Watt light bulb;
the larger cage compartment is dark. The floor of both cage compartments consists of an
electrically conductive grid.
Method: The test animals are placed individually in the illuminated cage compartment.
Since mice have a natural preference for a dark environment, most of the test animals
move spontaneously into the dark cage compartment. As soon as all the test animals are
in that compartment, the sliding door is closed and an electric shock (1 mA, S sec) is
administered to their feet.
The test animals are removed immediately, and 24 hours later they are again placed in the
illuminated cage compartment. The period of time for which the test animals hesitate
before moving into the dark cage compartment is measured. In general, most of the test
animals remain in the illurninated cage compartment for the entire observation period
(150 sec)`, which means that virtually all the test animals have mastered the learning task.
If a cerebral electric shock (14 mA, 0.2 s, lS0 Hz) is administered immediately after the
foot-shock phase of the learning process, the test animals' ability to remember the foot
shock is impaired. 4-(7-Bromo-S-methoxybenzofuran-2-yl)piperidine in the form of the
hydrochloride has a pronounced anti-amnesiogenic protective effect in this model when
administered perorally 60 minutes prior to the cerebral electric shock.
Measurement results:
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Test compound Time in illuminated Significance
cage compartment
0.3 mg/kg p.o. active ing. 2~.9 s p<0.01
3.0 mg~g p.o. active ing. 38.9 s p<0.0002
30.0 mg/kg p.o. active ing. 14.5 s n. s.
.... ,
Vehicle on its own 10.4 s
Conclusion:
The active ingredient is effective at 0.3, 1.0 and 3.0 mg~cg p.o.. The most pronounced
activity is to be observed at 3.0 mg/kg p.o.; the average time spent in the illuminated cage
compartment in that case is 38.8 + 7.9 sec (p > 0.0002). At 30.0 mg/lcg p.o., no further
significant activity is observed. As compared with the time spent in the illurninated cage
compartment following administration of the vehicle on its own (10.4 s), this corresponds
to a statistically highly significant increase, by a factor of 3.7.
Pharmacological Example 2: Action in the case of chronic treatment on the learning
ability of elderly rats
A certain deterioration in higher intellectual functions, noticeable especially in the storage
and utilisation of information, is a feature and a consequence of the natural ageing process
in humans and animals. In animals, a decline in the ability to gather and utilise
information can be observed. Elderly test animals are therefore useful test subjects for
investigating age-related cognitive malfunctions, and especially for studying the effect of
active ingredients for medicaments on age-related memory dysfunctions.
Experimental arrangement: The experimental arrangement consists of two identical cage
compartments A and B (each measuring 20 x 20 x 30 cm) which communicate by meansof a door (12 x 16 cm) and are provided with electrically conductive floor grids. The
learning test consists in placing the test animal in cage compartment A and, after
10 seconds, subjecting it to an electric shock to its feet. The test animal can avoid this by
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moving into cage compartment B. Training in this active one-way avoidance task is
continued until the test animal is able to avoid the electric shock in this manner five times
in succession.
Method: Elderly rats (age at start of test: 27 months) are treated daily perorally with 0.3,
1.0, 3.0 and 30 mg,~g of the test compound. The vehicle is administered to a control
group. 60 minutes after the treatment, the test animals are subjected to the above training.
A further learning attempt takes place 4 hours later.
Measurement results:
Test compound Number of Significance
learning attempts
0.3 mg/kg p.o. active ing. 15.6 + 2.6 p<0.05
3.0 mg~g p.o. active ing.10.2 + 1.8 p<0.02
.
Vehicle on its own 21.7 + 4.5
Conclusion:
Doses of 0.3 and 3.0 mg~g p.o. of the active ingre~ient bring about a statistically
significant reduction, to 47 % of the control value, in the number of learning attempts
required to learn the active avoidance task.
Formulation Example 1: Tablets, each comprising 200 mg of 4-(7-bromo-5-methoxy-
benzofuran-2-yl)piperidine or of a salt, for example the hydrochloride, thereof, can be
prepared as follows:
Composition (10 000 tablets~
active ingredient 2000.0 g
lactose 500 0 g
potato starch 352.0 g
gelatin 8.0 g
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talc 60.0 g
magnesium stearate 10.0 g
silica (highly disperse) 20.0 g
ethanol q.s.
The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture
is moistened with an ethanolic solution of the gelatin and granulated through a sieve.
After drying, the remaining potato starch, the magnesium stearate, the talc and the silica
are mixed in and the mixture is compressed to form tablets which each weigh 295.0 mg
and comprise 50.0 mg of active ingredient, and which may, if desired, be provided with
dividing notches for finer adjustment of the dose.
Formulation Example 2: Film-coated tablets, each comprising 400 mg of 4-(7-bromo-5-
methoxybenzofuran-2-yl)piperidine or of a salt, for example the hydrochloride, thereof,
can be prepared as follows:
Composition (for 1000 film-coated tablets)
activeingredient 400.0 g
lactose 100.0 g
corn starch 70.0 g
talc 8.5 g
calciumstearate 1.5 g
hydroxypropylmethylcellulose 2.36 g
shellac 0.64 g
water q.s.
methylene chloride q.s.
The active ingredient, the lactose and 40 g of the corn starch are mixed, and the mixture is
moistened with a paste, prepared from 15 g of corn starch and water (with heating), and
granulated. The granules are dried, and the remaining corn starch, the talc and the calcium
stearate are added and mixed with the granules. The mixture is compressed to form
tablets (weight: 580 mg), which are coated with a solution of the
hydroxypropylmethylcellulose and the shellac in methylene chloride; final weight of each
film-coated tablet: 583 mg.
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g
Formulation Example 3: Hard gelatin capsules, each containing 500 mg of 4-(7-bromo-5-
methoxybenzofuran-2-yl)piperidine or of a salt, for example the hydrochloride, thereof,
can be prepared, for example, as follows:
Composition (for 1000 capsules)
active ingredient 500.0 g
lactose 250.0 g
microcrystalline cellulose 30.0 g
sodium lauryl sulfate 2.0 g
magnesium stearate 8.0 g
The sodium lauryl sulfate is added to the Iyophilised acdve ingredient through a sieve
having a mesh siæ of 0.2 mm. The two components are mixed intimately. Then, first the
lactose is added through a sieve having a mesh size of 0.6 mm and then the micro-
crystalline cellulose through a sieve having a mesh siæ of 0.9 mm. The mixture is mixed
intimately again for 10 minutes. Finally, the magnesium stearate is added through a sieve
having a mesh siæ of 0.8 mm. After further mixing for 3 minutes, hard gelatin capsules
of a suitable size are each filled with 790 mg of the resulting formulation.
Formulation Example 4: A 5 % injection or infusion solution of 4-(7-bromo-5-methoxy-
benzofuran-2-yl)piperidine or of a salt, for example the hydrochloride, thereof can be
prepared, for example, as follows:
Composition (for 1000 or 400 ampoules)
acdve ingredient 125.0 g
sodium chloride 22.5 g
phosphate buffer pH = 7.4 300.0 g
demineralised water ad 2500.0 ml
The active ingredient and the sodium chloride are dissolved in 1000 ml of water and
filtered through a microfilter. The buffer solution is added, and the mixture is made up to
2500 ml with water. To prepare unit dose forms, 1.0 or 2.5 ml are introduced into each
glass ampoule, which then contains 50 or 125 mg, respectively, of active ingredient.
