Note: Descriptions are shown in the official language in which they were submitted.
WO 03/013539 , r P CT/E P02/08614
CA 02455628 2004-O1-26
78503pct.209
Neuroprotective Drug
The present invention relates to the use of 1-[2-(4-(3-trifluoromethyl-
phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one, optionally in
the
form of the pharmaceutically acceptable acid addition salts and optionally in
the form
of the hydrates or solvates, for preparing a pharmaceutical composition with a
neuroprotective activity.
Background to the invention
The compound 1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-
dihydro-1 H-
benzimidazol-2-one (flibanserin) is known in the form of its hydrochloride
from
European Patent Application EP-A-526434 and has the following chemical
structure:
O
HN' \ CF3
N~N
U
1 x HCI
Flibanserin shows an affinity for the 5-HT,A and 5-HT2 receptor. For this
reason it can
be used therapeutically to treat a number of diseases. These include, for
example,
depression, schizophrenia, Parkinson's disease, anxiety states as well as
sleep
disorders, for example.
Description of the invention
Surprisingly it has been found that the compound 1-[2-(4-(3-trifluoromethyl-
phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one, optionally in
the
form of the pharmaceutically acceptable acid addition salts as well as
optionally in
the form of the hydrates or solvates, may also be used to prepare a
pharmaceutical
composition with a neuroprotective activity.
Accordingly, the present invention relates to the use of 1-[2-(4-(3-
trifluoromethyl-
phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1 H-benzim idazol-2-one, optionally
in the
form of the pharmaceutically acceptable acid addition salts as well as
optionally in
WO 03/013539 , , P CT/E P02/08614
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the form of the hydrates or solvates, for preparing a pharmaceutical
composition with
a neuroprotective activity.
Preferably, the present invention relates to the use of 1-[2-(4-(3-
trifluoromethyl-
phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one, optionally in
the
form of the pharmaceutically acceptable acid addition salts as well as
optionally in
the form of the hydrates or solvates for preparing a pharmaceutical
composition for
the treatment and/or prevention of neurodegenerative diseases as well as
cerebral
ischaemia of various origins, selected from among epilepsy, hypoglycaemia,
hypoxia, anoxia, brain trauma, brain oedema, amyotropic lateral sclerosis,
Huntington's disease, Alzheimer's disease, hypotension, cardiac infarct, brain
pressure (elevated intracranial pressure), ischaemic and haemorrhagic stroke
(stroke), global cerebral ischaemia during stoppage of the heart, diabetic
polyneuropathy, tinnitus, perinatal asphyxia, cardiac hypertrophia (thickening
of the
heart muscle), cardiac insufficiency (weakness of the heart muscle) and
Parkinson's
disease.
The present invention relates, more preferably, to the use of 1-[2-(4-(3-
trifluoromethyl-phenyl)piperazin-1-yl)ethylJ-2,3-dihydro-1 H-benzimidazol-2-
one,
optionally in the form of the pharmaceutically acceptable acid addition salts
as well
as optionally in the form of the hydrates or solvates, for preparing a
pharmaceutical
composition for the treatment and/or prevention of diseases selected from
among
brain pressure (elevated intracranial pressure), ischaemic and haemorrhagic
stroke
(stroke), cardiac hypertrophia (thickening of the heart muscle) and cardiac
insufficiency (weakness of the heart muscle), while particular importance is
attached
to the use thereof according to the invention for the treatment and/or
prevention of
stroke.
By pharmaceutically acceptable acid addition salts are meant, according to the
invention, salts selected from the salts of hydrochloric acid, hydrobromic
acid,
sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric
acid,
succinic acid, lactic acid, citric acid, tartaric acid and malefic acid, while
the salts of
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and
acetic acid
are particularly preferred. The salts of hydrochloric acid are of particular
importance.
As an alternative to being used in the form of the abovementioned
pharmaceutically
acceptable acid addition salts thereof the compound 1-[2-(4-(3-trifluoromethyl-
phenyl)piperazin-1-yl)ethylJ-2,3-dihydro-1 H-benzimidazol-2-one may also be
used in
the form of its free base for the purpose according to the invention.
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3
The free base of 1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-
dihydro-
1 H-benzimidazol-2-one is not yet known in the art. It has been found that the
free
base of 1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1
H-
benzimidazol-2-one may be obtained in two different crystal modifications,
polymorphs A and B.
The formation of the different polymorphs A and B is crucially dependent on
the
choice of the reaction conditions used during preparation. Within the scope of
the
present invention, the use of polymorph A of the free base of 1-[2-(4-(3-
trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1 H-benzimidazol-2-
one is
particularly important for preparing a pharmaceutical composition with a
neuroprotective activity.
Polymorph A of 1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-
dihydro-1 H-
benzimidazol-2-one is characterised by a melting point of 161 °C
(measured by DSC;
heating rate 10 K/min). Polymorph B has a melting point of 120°C
(measured by
DSC; heating rate 10 IVmin). DSC stands for Differential Scanning Calorimetry.
One possible method of synthesis for preparing the free base of 1-[2-(4-(3-
trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1 H-benzimidazol-2-
one,
particularly for preparing polymorph A, can be inferred from the following
experimental procedure described by way of example.
Example:
375 kg of 1-[(3-trifluoromethyl)phenyl]-4-(2-chloroethyl)piperazine are taken
up in
2500 kg of water in a suitable reactor and combined with 200 kg of aqueous
NaOH
solution (45% strength). 169.2 kg of 1-(2-propenyl)-1,3-dihydro-benzimidazol-
2H-
one, 780 kg of isopropanol, 2000 kg of water and 220 kg of aqueous NaOH
solution
(45% strength) are added with stirring. The reaction mixture is heated to 75-
85°C
and combined first with 160 kg of concentrated hydrochloric acid then with 200
kg of
water. The resulting mixture is stirred for about 45 minutes at constant
temperature.
After a mixture of water and isopropanol (roughly 3000 kg) has been distilled
off, the
residue remaining is cooled to about 65-75°C and the pH is adjusted to
about 6.5 -
7.5 using 125 kg of aqueous NaOH solution (45% strength). After cooling to 45-
50°C
the pH is adjusted to about 8-9 by the addition of 4 kg of aqueous NaOH
solution
(45% strength). Then the mixture obtained is cooled to 30-35°C and
centrifuged. The
residue thus obtained is washed with 340 I of water and 126 I of isopropanol.
The
product obtained is dried in vacuo at about 45-55°C. Yield: 358 kg of
crude product;
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The crude product is taken up in 1750 kg of acetone in a suitable reactor and
the
resulting mixture is heated to reflux temperature with stirring. The solution
obtained
is filtered, the filtrate is then concentrated by distillation. It is then
cooled to 0-5°C for
about 1 hour, the solid that crystallises out is filtered off and finally
dried at about
55°C for about 12 hours. Yield: 280 kg of polymorph A.
Suitable pharmaceutical preparations of 1-[2-(4-(3-trifluoromethyl-
phenyl)piperazin-
1-yl)ethyl]-2,3-dihydro-1 H-benzimidazol-2-one for use according to the
invention
include, for example, tablets, capsules, suppositories, solutions -
particularly
solutions for injection (s.c., i.v., i.m.) and infusion, - syrups, emulsions
or dispersible
powders. The proportion of the pharmaceutically active compound in each case
should be in the range from 0.1 to 90 wt.%, preferably 0.5 to 50 wt.% of the
total
composition, i.e. in amounts which are sufficient to achieve the dosage range
specified below.
The dosage of flibanserin for use according to the invention may for example
be in a
range from about 0.1 to 500 mg of flibanserin per day. Preferably, the dosage
is in a
range from about 1 - 300 mg/day, more preferably in a range from about 2-200
mg/day based on flibanserin in the form of its free base. Anyone skilled in
the art will
see that it may possibly be necessary to depart from the quantities specified,
depending on body weight or the route of administration, the individual
response to
the drug, the type of formulation and the time or interval at which it is
administered.
Thus, in some cases it may be enough to use less than the minimum amount
specified, while in other cases the upper limit will have to be exceeded. When
larger
amounts are being administered, it may be advisable to spread them over a
number
of individual doses throughout the day.
Tablets containing the active substance may be obtained, for example, by
mixing the
active substances) with known excipients, for example inert diluents such as
calcium carbonate, calcium phosphate or lactose, disintegrants such as corn
starch
or alginic acid, binders such as starch or gelatine, lubricants such as
magnesium
stearate or talc and/or agents for delaying release, such as carboxymethyl
cellulose,
cellulose acetate phthalate, or polyvinyl acetate. The tablets may also
comprise
several layers.
Coated tablets may be prepared accordingly by coating cores produced
analogously
to the tablets with substances normally used for tablet coatings, for example
collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve
delayed
WO 03/013539 ~ CA 02455628 2004-O1-26 PCT/EP02/08614
release or prevent incompatibilities the core may also consist of a number of
layers.
Similarly the tablet coating may consist of a number or layers to achieve
delayed
release, possibly using the excipients mentioned above for the tablets.
Syrups or elixirs containing the active substances or combinations thereof
according
to the invention may additionally contain a sweetener such as saccharine,
cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as
vanillin or orange extract. They may also contain suspension adjuvants or
thickeners
such as sodium carboxymethyl cellulose, wetting agents such as, for example,
condensation products of fatty alcohols with ethylene oxide, or preservatives
such as
p-hydroxybenzoates.
Solutions for injection and infusion are prepared in the usual way, e.g. with
the
addition of isotonic agents, preservatives such as p-hydroxybenzoates, or
stabilisers
such as alkali metal salts of ethylenediamine tetraacetic acid, optionally
using
emulsifiers and/or dispersants, while if water is used as the diluent, for
example,
organic solvents may optionally be used as solubilisers or cosolvents, and the
solutions are transferred into injection vials or ampoules or infusion
bottles.
Capsules containing one or more active substances or combinations of active
substances may for example be prepared by mixing the active substances with
inert
carriers such as lactose or sorbitol and packing them into gelatine capsules.
Suitable suppositories may be made for example by mixing with carriers
provided for
this purpose, such as neutral fats or polyethyleneglycol or the derivatives
thereof.
Examples of suitable excipients include for example water, pharmaceutically
harmless organic solvents, such as paraffins (e.g. petroleum fractions), oils
of
vegetable origin (e.g. groundnut or sesame oil), mono- or polyfunctional
alcohols
(e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders
(e.g. kaolins,
clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silica
and
silicates), sugars (e.g. glucose, lactose and dextrose), emulsifiers (e.g.
lignin, spent
sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and
lubricants (e.g.
magnesium stearate, talc, stearic acid and sodium laurylsulphate).
The preparations are administered in the usual way, preferably parenterally,
by
intravenous route, particularly by infusion. For oral use the tablets may, of
course,
contain, in addition to the abovementioned carriers, additives such as sodium
citrate,
calcium carbonate and dicalcium phosphate, together with various additives
such as
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starch, preferably potato starch, gelatine and the like. Lubricants such as
magnesium stearate, sodium laurylsulphate and talc may also be used in the
tablet
production. In the case of aqueous suspensions the active substances may be
combined with various flavour enhancers or colourings in addition to the
abovementioned excipients. For parenteral use, solutions of the active
substances
may be used, with suitable liquid carriers. One type of parenteral
administration is
by infusion, for example, which may in certain circumstances be administered
over
longer periods (hours or days) depending on the nature of the illness.
The following examples of formulations which can be prepared by current
methods
illustrate the present invention without restricting its scope:
Examples of pharmaceutical formulations
A) Tablets per tablet
flibanserin x HCI 10 mg
lactose 187 mg
maize starch 50 mg
magnesium stearate 3 mg
250 mg
B) Tablets per tablet
flibanserin (free base) 80 mg
lactose 88 mg
maize starch 190 mg
microcrystalline cellulose 40 mg
magnesium stearate 2 mg
400 mg
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C) Capsules per tablet
flibanserin (free base) 10 mg
lactose 188 mg
magnesium stearate 2 mg
200 mg
The above mixture can be packed into suitable hard gelatine capsules.
D) Ampoule solution
flibanserin x HCI 2 mg
sodium chloride 9 mg
water for inj. 5 ml
