Note: Descriptions are shown in the official language in which they were submitted.
CA 02513077 2005-07-11
Use of L-dopa, derivatives thereof and medicaments comprising said compounds
for the prophylaxis of psychotic disorders
The invention concerns the use of 3,4-dihydroxy-L-phenylalanine (L-dopa) and
its
derivatives for the production of pharmaceuticals as well as their use for the
prophylaxis
of psychotic disorders as well as for the treatment of diseases which are
caused by
disrupted tyrosine transport or disrupted tyrosine decarboxylase.
The symptoms of schizophrenic disorders are usually treated at the present
time by
neuroleptics such as chlorpromazine, haloperidol, sulphide and their chemical
relatives.
Since treatment with neuroleptics does not cure the underlying disorder, a
lapse in the
treatment usually Ieads to a relapse for the patient.
Various psychic disorders axe associated with a disturbance in the metabolism
of
I S noradrenaline, dopamine and serotonin.
L-dopa and its derivatives, particularly esters, have been utilized up to now,
among other
things, for the therapy of Parkinson's disease and of restless leg syndrome. L-
dopa acts
on the dopamine concentration in neurons of the brain. Unlike dopamine itself,
it can
pass through the blood-brain barrier and is converted to dopamine in the
brain.
L-dopa is administered usually in pharmaceuticals with active additives.
Combinations
of L- dopa with peripheral decarboxylase inhibitors, with catechol-O-
methyltransferase
(COMT) inhibitors, with monoamine oxidase (MAO) inhibitors and with dopamine-
(3-
hydroxylase inhibitors particularly find use.
CA 02513077 2005-07-11
2
In this connection, the decarboxylase inhibitors used are, for example: D,L-
serine 2-
(2,3,4-trihydroxybenzyl) hydrazide (benserazide), (-)-L-a-hydrazino-3,4-
dihydroxy-a-
methylhydrocinnamic acid (carbidopa), L- serine 2-(2,3,4-trihydroxybenzyl)
hydrazide,
glycine 2-(2,3,4-trihydroxybenzyl) hydrazide and L-tyrosine 2-(2,3,4-
trihydroxybenzyl)
hydrazide. Examples of combination preparations of L-dopa and decarboxylase
inhibitors include, among others: Madopar° (L-dopa and benserazide
hydrochloride) as
well as NacomG (L-dopa and carbidopa).
Examples of COMT inhibitors are entacapone (Comtan~) and cabergoline and
frequently used MAO inhibitors are selegiline hydrochloride, moclobemide and
tranylcypromine.
Calcium 5-butyl picolinate and calcium 5-pentyl picolinate are described as
dopamine-
~3-hydroxylase inhibitors (DE-A-2,049,115).
According to the invention, use of L-dopa is preferred for relapse prophylaxis
in
psychotic disorders, particularly in schizophrenic disorders.
It was surprisingly found that L-dopa can be used for the prophylaxis of
psychotic
disorders. This is even more surprising since psychotic disorders are known to
occur as
side effects with high dosage of L-dopa.
The use of L-dopa, its derivatives and its physiologically compatible salts is
preferred in
combination with one enzyme inhibitor or several enzyme inhibitors for the
prophylaxis
of psychotic disorders as well as for the treatment of diseases which are
caused by
disrupted tyrosine transport or disrupted tyrosine decarboxylase.
CA 02513077 2005-07-11
3
It is advantageous if the enzyme inhibitor or the enzyme inhibitors involve
decarboxylase inhibitors and/or catechol-O-methyltransferase inhibitors and/or
monoamine oxidase inhibitors and/or (3-hydroxylase inhibitors.
It is particularly advantageous if the decarboxylase inhibitor is selected
from the group
consisting of the following: D,L-serine 2-(2,3,4-trihydroxybenzyl) hydrazide
(benserazide),
(-)-L-a-hydrazino-3,4-dihydroxy-a-methylhydrocinnamic acid (carbidopa), L-
serine 2-
(2,3,4-trihydroxybenzyl) hydrazide, glycine 2-(2,3,4-trihydroxybenzyl)
hydrazide and L-
tyrosine 2-(2,3,4-trihydroxybenzyl) hydrazide as well as their physiologically
compatible salts.
In particular, it is also advantageous if the catechol-O-methyltransferase
inhibitor is
I S selected from entacapone and cabergoline as well as physiologically
compatible salts
thereof.
It is also preferred if the monoamine oxidase inhibitor is selected from the
group
consisting of selegiline, moclobemide and tranylcypromine as well as
physiologically
compatible salts thereof.
1n addition, it is particularly preferred if the ~i-hydroxylase inhibitor is
selected from
calcium 5-butyl picolinate and calcium 5-pentyl picolinate as well as their
physiologically compatible salts.
Another subject of the invention is the use of L-dopa, its derivatives and
physiologically
CA 02513077 2005-07-11
4
compatible salts thereof for the production of pharmaceuticals for the
prophylaxis of
psychotic disorders as well as for the treatment of diseases which are caused
by
disrupted tyrosine transport or disrupted tyrosine decarboxylase.
Another subject of the present invention is a pharmaceutical composition,
which
contains L-dopa, its derivatives as well as physiologically compatible salts
thereof for
the prophylaxis of psychotic disorders as well as for the treatment of
disorders which
are caused by disrupted tyrosine transport or disrupted tyrosine
decarboxylase, in
addition to pharmaceutically compatible adjuvants and additives.
Particularly advantageous is a pharmaceutical composition which contains L-
dopa, its
derivatives as well as physiologically compatible salts thereof for the
prophylaxis of
psychotic disorders as well as for the treatment of diseases which are caused
by
disrupted tyrosine transport or disrupted tyrosine decarboxylase and one or
more
enzyme inhibitors, in addition to pharmaceutically compatible adjuvants and
additives.
A pharmaceutical composition is particularly preferred in which the enzyme
inhibitor or
the enzyme inhibitors involve decarboxylase inhibitors and/or catechol-O-
methyltransferase inhibitors and/or monoamine oxidase inhibitors and/or j3-
hydroxylase
inhibitors.
Additionally preferred is a pharmaceutical composition in which the
decarboxylase
inhibitor is selected from the group consisting of D,L-serine 2-(2,3,4-
trihydroxybenzyl)
hydrazide (benserazide), (-)-L-a-hydrazino-3,4-dihydroxy-oc-
methylhydrocinnamic acid
(carbidopa),
L-serine 2-(2,3,4-trihydroxybenzyl) hydrazide, glycine 2-(2,3,4-
trihydroxybenzyl)
hydrazide and L-tyrosine 2-(2,3,4-trihydroxybenzyl) hydrazide as well as their
CA 02513077 2005-07-11
physiologically compatible salts.
Particularly advantageous is a pharmaceutical composition in which the
catechol-O-
methyltransferase inhibitor is selected from entacapone and cabergoline as
well as
5 physiologically compatible salts thereof.
Additionally advantageous is a pharmaceutical composition in which the
monoamine
oxidase inhibitor is selected from the group consisting of selegiline,
moclobemide and
tranylcypromine as well as physiologically compatible salts thereof.
In addition, a pharmaceutical composition is preferred in which the (3-
hydroxylase
inhibitor is selected from calcium 5-butyl picolinate and calcium S-pentyl
picolinate as
well as physiologically compatible salts thereof.
The production of L-dopa and its derivatives such as, for example, the alkyl
ester is
known in and of itself.
For the production of physiologically compatible salts of L-dopa and its
derivatives, the
usual physiologically compatible inorganic and organic acids such as
hydrochloric acid,
hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, malefic acid,
fumaric acid,
lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic
acid and benzoic
acid can be used. Additional acids that can be used are described, for
example, in
Fortschritte der Arzneimittelforschung, Vol. 10, pp. 224-225, Birkhauser
Publishers,
Basel and Stuttgart (1966) and Journal of Pharmaceutical Sciences, Vol. 66,
pp. 1-5
( 1977).
The acid addition salts of L-dopa and its derivatives are usually obtained in
a way
CA 02513077 2005-07-11
known in and of itself by mixing the free base or solutions thereof with the
corresponding acids or solutions thereof in an organic solvent, for example, a
lower
alcohol, such as methanol, ethanol, n-propanol or isopropanol or a lower
ketone such as
acetone, methyl ethyl ketone or methyl isobutyl ketone or an ether such as
diethyl ether,
tetrahydrofuran or dioxane. For better crystal precipitation, mixtures of the
named
solvents also can be used. In addition, physiologically compatible aqueous
solutions of
acid addition salts of the compounds used according to the invention can be
produced
therefrom in an aqueous acid solution.
The acid addition salts of L-dopa and its derivatives can be converted to the
free base in
a way known in and of itself, e.g., with alkalis or ion exchangers. Other
salts can be
obtained from the free base by reaction with inorganic or organic acids,
particularly
those which are suitable for the formation of therapeutically usable salts.
These or also
other salts of the new compound, such as, e.g., the picrate, may also serve
for
purification of the free base by converting the free base into a salt,
separating this salt,
and again releasing the base from the salt.
The subject of the present invention is also pharmaceuticals for oral, buccal,
sublingual,
nasal, rectal, subcutaneous, intravenous or intramuscular application as well
as for
inhalation,
which, in addition to the usual vehicle and dilution agents, also contain L-
dopa, a
derivative, or the acid addition salt thereof as the active ingredient.
The pharmaceuticals of the invention are produced, in the known way and with
suitable
dosage, with the usual solid or liquid vehicle substances or dilution agents
and the
usually used pharmaceutical-technical adjuvants corresponding to the desired
type of
application. The preferred preparations consist of a form of administration
which is
suitable for oral application. Such forms of administration are, for example,
tablets,
CA 02513077 2005-07-11
7
sucking tablets, film tablets, dragees, capsules, pills, powders, solutions,
aerosols or
suspensions or slow-release forms.
Of course, parenteral preparations such as injection solutions are also
considered. In
addition, suppositories, for example, have also been named as preparations.
Corresponding tablets can be obtained, for example, by mixing the active
substance with
known adjuvants, for example, inert dilution agents such as dextrose, sugar,
sorbitol,
mannitol, polyvinylpyrrolidone, bursting agents such as corn starch or alginic
acid,
binders such as starches or gelantins, lubricants such as magnesium stearate
or talc
and/or agents for achieving a slow-release effect such as
carboxypolymethylene,
carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The
tablets may
also consist of several layers.
I 5 In a corresponding manner, for the preparation of controlled or slow-
release forms,
dragees can also be produced by the coating of cores that have been produced
analogously to tablets, by using agents commonly used in dragee coatings, for
example,
polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar.
The dragee
envelope may also consist of several layers, wherein the adjuvants mentioned
above in
the case of tablets can be used.
Solutions or suspensions containing the active substance used according to the
invention
may additionally contain agents that improve taste, such as saccharin,
cyclamate or
sugar, as well as, e.g., taste enhancers such as vanilla or orange extract.
They may also
contain suspension adjuvants such as sodium carboxymethylcellulose or
preservatives
such as p-hydroxybenzoate. Capsules containing active substances can be
produced, for
example, by mixing the active substance with an inert vehicle such as lactose
or sorbitot
CA 02513077 2005-07-11
8
and encapsulating this mixture in gelatin capsules.
Suitable suppositories can be produced, for example, by mixing with vehicle
agents
provided therefor, such as neutral fats or polyethylene glycol or derivatives
thereof.
The production of the pharmaceutical preparations according to the invention
is known
in and of itself, and is described in handbooks known to the person skilled in
the art, for
example, Hager's Handbuch (5'" ed.) 2, 622-1045; List et al.,
Arzneiformenlehre
[Instructions for Drug Forms], Stuttgart: Wiss. Verlagsges. 1985; Sucker et
al.,
Pharmazeutische Technologie [Pharmaceutical Technology], Stuttgart; Thieme
1991;
Ullmann's Enzyklopadie [Encyclopedia] (5th ed.) A 19, 241-271; Voigt,
Pharmazeutische Technologie [Pharmaceutical Technology], Berlin: Ullstein
Mosby
1995.
The following example explains the invention:
Example
Ten patients with acute schizophrenia, who had accordingly received
maintenance
therapy with fluphenazine for more than one year and were clinically stable,
were
successively taken off this drug. According to clinical experience (see Gitlin
M.,
Nuechterlein K., Subotnik K. L. et al., Am. J. Psychiatry (2001 ) 158( 11),
pp. 1835-42),
about 8 of the 10 patients would be expected to suffer a relapse within the
following 12
months. Our patients were treated with L-dopa or a combination preparation
containing
L-dopa for 2 months prior to withdrawal and during the entire withdrawal
phase. In
these patients, a relapse occurred in only 2 of 10 cases.
