Note: Descriptions are shown in the official language in which they were submitted.
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Use of Rotigotine for the Treatment or Prevention of
Dopaminergic Neuron Loss
Introduction
Parkinson's disease occurs as a result of a chronic, progressive degeneration
of neurons,
the cause of which has not yet been completely clarified. It is clinically
manifested in the
form of the cardinal symptoms of resting tremors, rigidity, bradykinesia and
postural
instability.
Primarily used as medicaments for alleviating the motor symptoms are levodopa,
dopamine agonists such as, for example, rotigotine, pramipexole,
bromocriptine,
ropinirole, cabergoline, pergolide, apomorphine and lisuride, anticholinergic
agents,
NMDA antagonists, 0-blockers as well as the MAO-B inhibitor selegeline and the
COMT
inhibitor entacapone. Most of these active substances intervene in the
dopaminergic
and/or cholinergic signal cascade and symptomatically influence in this manner
the motor
disturbances that are typical of Parkinson's disease.
The therapy of Parkinson's disease has, to date, been initiated with the onset
of the
cardinal symptoms. Morbus Parkinson is generally deemed to be clinically
confirmed if at
least two of the four cardinal symptoms (bradykinesia, resting tremors,
rigidity and
postural instability) can be determined and L-Dopa has an effect (Hughes, J
Neurol
Neurosurg Psychiatry 55, 1992, 181). Unfortunately, however, patients with
Parkinson's
disease only develop the motor disturbances once approximately 70 to 80% of
the
dopaminergic neurons in the substantia nigra (SN) have been irreversibly
damaged
(Becker et al, J Neurol 249, 2002, Suppl 3: III, 40; Hornykiewicz,
Encyclopaedia of Life
Science 2001, 1). The chances of a therapy with lasting effects are minimal at
this time. It
is thus desirable to commence therapy as early as possible.
Current clinical observations as well as anatomical and genetic research now
show that it
is possible to both diagnose patients with Parkinson's disease at an early
stage and to also
identify high-risk patients.
The following, for example, can thereby be used as diagnostic markers:
-
Biochemical markers, such as neuromelanin (Gerlach, Neurotox Res 5, 2003, 35;
WO
02/31499), S-100 beta (Muramatsu, Glia 42, 2003, 307), alpha synuclein (WO
03/069332; WO 00/02053) or parkin protein (Sharma, Neurol Clin N Am 20, 2002,
759) and semaphorin (WO 03/007803).
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- Genetic markers, such as the park genes 1-8 (Guttnian, CMAJ 4, 2003, 168;
WO
03/76658); CYP2D6-B (WO 03/012137), chromosome 2q 36-37 (Pankratz, Am J
Hum Gen 72, 2003, e-pub), a-synuclein (Polymeropoulos, Science. 276, 1997,
2045)
or mutations in CYP2D6-B and GSTM1 deletion (WO 03/012137).
- Imaging methods, such as ultrasound examination of the SN size, possibly in
combination with other methods (Becker et al, J Neurol 249, 2002, Suppl 3:
III, 40) or
MRI (Hutchinson M, Raff U., J Neurol Neurosurg Psychiatry. 1999 Dec; 67(6):
815-
8).
- Imaging methods such as PET or SPECT (Prunier C, Bezard E et al,
Neuroimage.
2003 July; 19(3): 810-6).
- Sensory disorders or behavioural abnormalities, such as sleep and
olfactory disorders,
in particular, sleep disorders of the type "REM sleep behaviour disorder",
(Henderson, J Neurol Neurosurg Psychiatry 74, 2003, 956) or cognitive
abnormalities
(Rammsayer, Int J Neurosci. 91, 1997, 45).
- Organic problems such as constipation (Krygowska-Wajs, Funct Neurol 15,
2000,
41).
- Depression (Camicioli R. Drugs Today (Barc). 2002 Oct; 38(10): 677-86).
- Short-term movement anomalies, such as chorea or orthostatic
abnormalities.
- Combinations of the aforementioned markers (Stem, Annals of Neurol 56,
2004, 169).
This thus creates the opportunity to influence the process of the disease at a
point when
more neurons are still present than is the case at the time of onset of
several cardinal
motor symptoms of Morbus Parkinson, and to thus protect a quantitatively
greater number
of neurons. It can be expected that the administration of an effective
neuroprotective
agent at an early stage will significantly delay the disease process: The
earlier a therapy
can be initiated, the greater the chances of a long-lasting prevention of the
onset of
symptoms that lower the quality of life.
There is thus a need for medicaments that are not only able to influence
dopaminergic
transmission and alleviate the symptoms of Morbus Parkinson in advanced
stages, but that
are also able to reverse, prevent or at least significantly slow down the
progressive
destruction of dopaminergic neurons in the early, largely motor-asymptomatic
stages of
Parkinson's disease (Dawson, Nature Neuroscience Supplement 5, 2002, 1058).
Rotigotine [(-)-5,6,7,8-tetrahydro-6- [propyl [2-(2-thienypethyl]amino]-1-
naphthol] is
known from the prior art as a dopamine agonist and as a therapeutic agent
purely for the
symptoms of Parkinson's disease. WO 02/089777 describes, for example, the
transdermal
administration of rotigotine to patients with Parkinson's disease and the
associated
improvement in the UPDRS (Unified Parkinson's Disease Rating Scale) score. The
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UPDRS score is an important instrument for diagnosing and monitoring the
progression
and/or therapy of patients with Parkinson's disease (Fahn S, Elton RL, Members
of the
UPDRS Development Committee (1987) Unified Parkinson's Disease Rating Scale.
In:
Fahn, S, CD Marsden, DB Caine, M Goldstein (eds) Recent Developments in
Parkinson's
Disease. Vol. II. Macmillan Healthcare Infoiniation, Florham Park (NJ), pages
153-163,
293-304). However, the UPDRS score only records the effect of an active
substance on
the symptoms of Parkinson's disease. It does not allow any statements to be
made with
regard to whether or not an active substance has an influence on the
destruction of
dopaminergic cells, which is the underlying cause of the symptoms.
Metman et al (Clin Neuropharmacol 24, 2001, 163) also describe the effect of
rotigotine
on motor disturbances associated with Parkinson's disease. The treated
patients already
had pronounced dyskinesias, which were improved by administering rotigotine.
Thus, rotigotine is known from the prior art as a dopamine agonist for the
symptomatic
treatment of Parkinson's disease. However, Parkinson medicaments that only
have an
effect on the symptoms do not promise any advantage with regard to the
prophylactic
treatment of Parkinson's disease since they do not have any influence on the
destruction
of dopaminergic cells or on the progression and/or intensity of the disease.
Experimental tests have, however, now surprisingly shown that rotigotine,
which had
hitherto only been used for the symptomatic therapy of Parkinson's disease,
has
neuroprotective properties and/or promotes the regenerative capacity of
neuronal elements
such that rotigotine can thus be used as a medicament and/or prophylactic
agent for the
prevention of dopaminergic cell loss also and in particular in very early
stages of
Parkinson's disease or in high-risk patients.
Figures
Fig. 1 shows representative examples of the neuroprotective effect of
rotigotine measured
on the basis of the density of the dopamine transporters as an indication of
the density of
the remaining nerve endings in the striatum.
Groups 1 to 7 were treated as follows: Group 1: untreated control group; Group
2: control
group treated with a vehicle solution for rotigotine and MPTP; Group 3: MPTP
treatment;
Group 4: MPTP treatment plus rotigotine 0.3 mg/kg; Group 5: MPTP treatment
plus
rotigotine 1.0 mg/kg; Group 6: MPTP treatment plus rotigotine 3.0 mg/kg; Group
7:
treatment solely with rotigotine (3.0 mg/kg).
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Fig. 2 shows dopamine transporter (DAT) binding in the dorsal and ventral part
of the
striatum in different groups by quantifying the DAT density according to an
experiment as
shown in Fig. 1. Bar graphs 1 to 7 correspond to groups 1 to 7 as shown in
Fig. 1. The
groups marked with * displayed a significant decline in DAT binding as
compared to the
control group 2. The groups marked with # displayed a significant gain in DAT
binding as
compared to the MPTP-treated Group 3.
Description of the Invention
Apoptotic processes are supposed to play an important role in the destruction
of
dopaminergic neurons in the pathogenesis of Parkinson's disease (Barzilai,
Cell Mol
Neurobiol 21, 2001, 215). Neuroprotective substances that can stop or even
reverse
dopaminergic cell destruction are thus desired. The MPTP model is thereby
deemed to be
predictive of the required neuroprotective characteristics (Dawson, Nature
Neuroscience
Supplement 5, 2002, 1058).
Rotigotine surprisingly shows the desired pharmacological profile in both an
acute and a
sub-acute MPTP model. The test results suggest that apoptotic processes are
prevented by
rotigotine.
Rotigotine displays, for example, a neuroprotective effect in a mouse model of
Parkinson's disease: Following the acute administration of MPTP, which causes
Parkinson's syndrome in both humans and monkeys, the number of the
degenerating
neurones in the acute phase was measured on the one hand (Table 1) and the
functional
integrity of the striatum in the sub-acute phase was ascertained on the other
by
determining the density of the dopamine transporter in the terminal nerve
endings (Figs. 1
and 2). It could be demonstrated in both cases that rotigotine had a
neuroprotective effect:
On the one hand, the number of degenerating neurones in the mesencephalon was
reduced
following the administration of rotigotine and on the other hand, the
dopaminergic
innervation of the striatum was almost completely maintained or restored.
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Table 1: Number of degenerating neurons in the mouse, shown by FluoroiadeTM
staining
Group
No. of degenerating Standard deviation
neurones
5: MPTP ¨vehicle + rotigotine 3.0 mg/kg 3.8 4.3
In a pilot study, the neuroprotective effect of rotigotine on monkeys was also
examined.
In the model used, which reflects the progressive course of Morbus Parkinson
in primates,
monkeys (macaques) were injected with subliminal toxic doses of MPTP for
several days.
Parkinson's symptoms developed in the model over a period of approximately 2
weeks.
As soon as a certain level of damage had been reached, rotigotine was injected
daily in a
formulation that produced a continuous plasma level over 24 hours. The MPTP
injections
were stopped as soon as the motor activity had been reduced to a certain
extent
(approximately 5 days later). The behaviour of the animals was assessed on a
daily basis.
Six weeks after the start of MPTP administration, the rotigotine injections
were stopped
and the animals were observed for a further two weeks without treatment. It
was observed
that the motor activity of the animals clearly improved during treatment and
also in the
following clearance phase.
A group of animals was killed at the end of both the rotigotine administration
and the
clearance phase, and the condition of the basal ganglia was histologically and
biochemically examined. The density of the nerve endings in the striatum had
significantly increased as compared to the untreated animals. The content of
pre-pro-
enkephalin, which is an indicator of the intact network in the "indirect
pathway" of the
basal ganglia, showed a tendency towards normalisation following treatment and
the
clearance phase.
The results show that the neuroprotective potential of rotigotine can also be
proven in a
primate model of Morbus Parkinson. A neuroprotective effect can therefore also
be
expected in humans.
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6
Thus, with rotigotine an active substance was provided for therapy, which is
ideally
suitable for producing a medicament and/or prophylactic agent for the
prevention of
= dopaminergic neurone loss in neurodegenerative diseases.
A subject matter of the present application is therefore the use of rotigotine
for the
production of a medicament for the treatment or prevention of dopaminergic
neuron loss
in patients suffering from a neurodegenerative disease that is associated with
increased
dopaminergic cell destruction or in patients having an increased risk of
augmented
dopaminergic cell destruction.
Increased dopaminergic neurone loss regularly occurs in patients with
Parkinson's
disease, however, it is also frequently observed in other neurodegenerative
diseases, for
example, in alpha-synucleopathies or in Huntington's disease as well as in REM
sleep
disturbances and olfactory disorders.
As compared to the hitherto use of rotigotine, which was limited solely to the
symptomatic treatment of Parkinson's patients with motor disturbances, in
particular the
prophylactic treatment of individuals in an early stage of Parkinson's disease
and/or who
are predisposed to developing Parkinson's disease owing to genetic or other
risks has been
developed as a new area of use. As already described above, such individuals
profit in
particular from the neuroprotective effect of rotigotine since owing to the
administration
of rotigotine, dopaminergic cell loss is stopped or slowed down at a time when
a higher
number of dopaminergic neurons are still present than is the case in patients
already
displaying motor symptoms.
A subject matter of the invention is therefore the use of rotigotine or its
salts and prodrugs
as a medicament for the prophylactic treatment of dopaminergic cell loss in
individuals in
whom, before commencement of the prophylactic treatment, at least three of the
four
cardinal symptoms of Parkinson's disease from the group bradykinesia,
rigidity, resting
tremors and postural instability are not yet present or are only rudimentary
or partially
present.
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In one particular embodiment there is provided use of rotigotine, its salts or
prodrugs
thereof for producing a medicament for the treatment or prophylaxis of
diseases
associated with increased dopaminergic cell destruction in an individual,
wherein the
disease associated with increased dopaminergic cell destruction is selected
from alpha-
synucleopathies excluding Parkinson's disease and Huntington's disease, and
wherein the
prodrugs of rotigotine are selected from the group of esters, carbamates,
acetals, ketals,
phosphates, phosphonates, sulphates, sulphonates, silyl ethers, carbonates,
acyloxyalkyl
ethers, thiocarbonyl esters, oxythiocarbonyl esters, thiocarbamates and
ethers.
The individuals can also be apparently healthy individuals whose genetic or
epidemic
predisposition may not indicate an increased risk of developing Parkinson's
disease.
However, in particular individuals having an increased risk of developing
Parkinson's
disease or patients in whom early clinical, clinical/chemical or
clinical/physical symptoms
of Parkinson's disease can be detected, but who do not yet display two or more
of the
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cardinal symptoms of Parkinson's disease, come into consideration for
treatment with
rotigotine.
Finally, rotigotine can also be used as a neuroprotective agent if the
diagnosis is not clear,
but development of the symptoms towards Parkinson-like neurodegeneration can
be
expected.
Prevention of neuronal dopaminergic cell loss is required in particular by
(a) individuals with an increased risk of Parkinson's disease or
(b) individuals with early symptoms of Parkinson's disease.
The terms "Morbus Parkinson" and "Parkinson's disease" are used as synonyms in
this
patent application and include idiopathic and genetic Parkinson's disease. The
so-called
Parkinson-Plus syndrome as well as secondary Parkinsonism are to be
differentiated
therefrom.
The term "cardinal symptoms" of Parkinson's disease is to be understood in
this patent
application as one or more of the symptoms of bradykinesia, rigidity, resting
tremors and
postural instability.
"Individuals with an increased risk of Parkinson's disease" are to be
understood in this
patent application in particular as individuals who do not yet display any
detectable
symptoms of Parkinson's disease, but who have certain risk factors.
Such risk factors can be genetic mutations (Nussbaum NEJM 348, 2003, 25). For
example, the parkin gene on chromosome 6q25.2-27 (PARK2) is associated with
juvenile
Parkinsonism and occurs more frequently in families with autosomal recessive
Parkinson
inheritance (Matsumine, Am. J. Hum. Genet., 60, 1997, 588; Kitada, Nature 392,
1998,
605; Abbas, Hum. Mol. Genet. 8, 1999, 567; Tassin, Am. J. Hum. Genet., 63,
1998, 88
und Lucking, N. Engl. J. Med. 342, 2000, 1560-7). Other gene loci, for
example, PARK6
and PARK7, were also found with increased frequency in families with juvenile,
recessively-inherited Parkinson's disease (Valente, Am. J. Hum. Genet. 68,
2001, 895;
van Dujin, Am. J. Hum. Genet. 69, 2001, 629). The PARKS gene is, on the other
hand,
associated with the late onset of Parkinson's disease (WO 03/076658).
Mutations in the
alpha-synuclein gene (PARK1) were detected in families with juvenile,
autosomal
dominantly-inherited Parkinson's disease (Polymeropoulos, Science 276, 1997,
2045).
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In addition to genetic predisposition, environmental influences, such as high
exposure to,
for example, insecticides (Vanacore, Neurol Sci., Sep; 23 Suppl 2, 2002, page
119) can
also represent risk factors.
In this patent application, "individuals with early symptoms of Parkinson's
disease" are to
be understood in particular as individuals in whom at least three of the four
cardinal
symptoms (rigidity, resting tremors, bradykinesia and postural instability)
are not yet
present, or are only rudimentarily or partially present, but who manifest
diagnostically
useable early clinical, clinical/biochemical and/or clinical/physical
symptoms.
Clinical/biochemical markers can be modifications in the alpha synuclein or
neuromelanin
pattern (WO 02/31499). Such modifications can be due, for instance, to the
expression of
genetic variants, for example of alpha synuclein, the development of
aggregates or
filaments, for example of alpha synuclein, or the increased release from
cellular stores, for
example, from the cytoplasms of cells that are being destroyed, as is the case
with
neuromelanin.
Early clinical/physical symptoms can be structural or functional changes to
the brain,
which can be physically detected, for example, by means of PET and SPECT
studies or by
means of transcranial sonography (Becker, J Neurol 249, Suppl 3, 2002, 111/40;
Prunier C,
et al., Neuroimage. 2003 Jul; 19(3): 810-6).
Early clinical symptoms can be olfactory disorders, depression, constipation,
impairments
of visual and cognitive functions or specific forms of sleep disorders, in
particular of the
type "REM sleep behaviour disorders", whereby a combination of different tests
can also
be used for early diagnosis (Becker, J Neurol 249, Suppl 3, 2002, 111/40;
Stem, Annals of
Neurol 56, 2004, 169).
As already discussed above, approximately 70 to 80% of the dopaminergic
neurones of
the substantia nigra have already been destroyed by the time at least two of
the four
cardinal symptoms have manifested themselves for the first time. In order to
effectively
use the surprising neuroprotective potential of rotigotine, the prophylactic
treatment of the
patients is therefore preferably initiated at a stage when the patients have a
lower loss of
dopaminergic cells of the substantia nigra (SN). Individuals displaying just
one or none of
the cardinal symptoms of Parkinson's disease in a clearly pronounced foul' are
therefore
preferably treated with rotigotine.
Individuals displaying a dopaminergic cell loss in the SN of less than 70%,
60%, 50% and
particular preferred of less than 40%, 30%, 20% or 10% are preferably treated.
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Two scores can be used as aids for diagnosing and controlling the therapy of
patients
already displaying noticeable motor disturbances, i.e. the UPDRS score and the
Hoehn
and Yahr score.
In a preferred aspect of the invention, the group of patients prophylactically
treated with
rotigotine has a modified Hoehn and Yahr score of 0 to 2, particularly
preferred of 0 to 1
and especially preferred of 0.
Table 2: Modified stage determination according to Hoehn, The natural history
of
Parkinson's disease in the pre-levodopa and post-levodopa eras. Neurologic
Clinics 10,
1992, 331
Stage 0 = No sign of disease.
Stage 1 = Unilateral disease.
Stage 1.5 = Unilateral plus axial involvement.
Stage 2 = Bilateral disease without impairment of balance.
Stage 2.5 = Mild bilateral disease with recovery on pull test.
Stage 3 = Mild to moderate bilateral disease: slight postural instability;
physically
independent.
Stage 4 = Severe disability; still able to walk or stand unaided.
Stage 5 = Wheelchair-bound or bedridden unless aided
Patients with a UPDRS score, part III (see embodiment 5), of at least 10 are
normally
classified as patients who can be considered for dopaminergic therapy.
However, the
group of patients suitable for benefiting from the neuroprotective effect of
rotigotine
preferably has a very low or undetectable motor UPDRS score (part III). Within
the
meaning of the present invention, the prophylactic treatment with rotigotine
should
therefore preferably be carried out on patients having a UPDRS motor score of
less than
10, 9, 8, 7, 6, 5, 4, 3, 2 or 1. It is particularly preferred for the patients
to still not display
any motor disturbances at all.
The terms "prevention", "prophylaxis" and "prophylactic treatment" are used as
synonyms in this patent application. They include the administration of a
medicament to
individuals in whom dopaminergic cell loss is to be expected or has already
occurred.
These are, in particular, patients in whom at least three of the four cardinal
symptoms of
Parkinson's disease (rigidity, resting tremors, bradykinesia, postural
instability), are not
yet present, or are only rudimentarily or partially present, in order to
prevent or delay the
appearance or significant development of the motor symptoms of Parkinson's
disease
and/or further dopaminergic neuron loss, particularly in the substantia nigra.
The
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individuals to be prophylactically treated preferably do not yet display any
of the cardinal
symptoms in a clearly pronounced form. The individuals to be prophylactically
treated
preferably have a UPDRS score of less than 10, less than 9, 8, 7 or 6 and
particularly
preferred of less than 5, 4, 3, 2 or 1.
In this patent application, "prodrugs" of rotigotine are to be understood in
particular as
compounds that are cleaved, converted or metabolised into rotigotine in the
human body
in a therapeutically effective amount, in particular in the plasma or during
the passage
through the skin or mucous membrane.
Rotigotine has the formula
OO
OH
In particular derivatives of the phenolic hydroxy group thus come into
consideration as
prodrugs, for example, esters, e.g. arylcarbonyl esters, alkylcarbonyl esters
or
cycloalkylcarbonyl esters, in particular alkylcarbonyl esters and
cycloalkylcarbonyl esters
with up to 6 carbon atoms; carbonates; carbamates; acetals; ketals;
acyloxyalkyl ethers;
phosphates; phosphonates; sulphates; sulphonates; thiocarbonyl esters;
oxythiocarbonyl
esters; thiocarbamates; ethers and silyl ethers.
The term "alkylcarbonyl esters" includes compounds in which the oxygen atom of
the
rotigotine is bound in each case to the group ¨C(0)-alkyl.
The tei ___________________________________________________________________ in
"cycloalkylcarbonyl esters" includes compounds in which the oxygen atom of
the rotigotine is bound in each case to the group ¨C(0)-cycloalkyl.
The term "arylcarbonyl esters" includes compounds in which the oxygen atom of
the
rotigotine is bound in each case to the group ¨C(0)-aryl.
The telln "carbonates" includes compounds in which the oxygen atom of the
rotigotine is
bound in each case to the group ¨C(0)-0-R.
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The term "carbamate" includes compounds in which the oxygen atom of the
rotigotine is
bound in each case to the group ¨C(0)-NRR1, ¨C(0)-NH-R1, or ¨C(0)-NH2.
The term "acetals" includes compounds in which the oxygen atom of the
rotigotine is
bound in each case to the group ¨CH(OR)R1.
The term "ketals" includes compounds in which the oxygen atom of the
rotigotine is
bound in each case to the group ¨C(OR)R1R2.
The term "acyloxyalkyl ethers" includes compounds in which the oxygen atom of
the
rotigotine is bound in each case to the group ¨CHR-O-C(0)-R1 or CH2-0-C(0)-R1.
The term "phosphate" includes compounds in which the oxygen atom of the
rotigotine is
bound in each case to the group ¨P(02H)OR.
The term "phosphonate" includes compounds in which the oxygen atom of the
rotigotine
is bound in each case to the group ¨P(02H)R.
The tei __________________________________________________________________ -11
"sulphate" includes compounds in which the oxygen atom of the rotigotine is
bound in each case to the group ¨S(0)20R.
The term "sulphonate" includes compounds in which the oxygen atom of the
rotigotine is
bound in each case to the group ¨S(0)2R.
The teini "thiocarbonyl esters" includes compounds in which the oxygen atom of
the
rotigotine is bound in each case to the group ¨C(=S)-R.
The term "oxythiocarbonyl esters" includes compounds in which the oxygen atom
of the
rotigotine is bound in each case to the group ¨C(=S)-0-R.
The tei __________________________________________________________________ m
"thiocarbamate" includes compounds in which the oxygen atom of the rotigotine
is bound in each case to the group ¨C(=S)-N-RR1, ¨C(=S)-NH-R1 or ¨C(=S)-NH2.
The term "ethers" includes compounds in which the oxygen atom of the
rotigotine is
bound in each case to the group ¨R.
In the above definitions of the prodrugs, R, R1 and R2 are each independently
selected
from hydrogen, alkyl, cycloalkyl or aryl, and preferably from the group C1-6
alkyl, C3-10
cycloalkyl and phenyl.
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R3 is alkyl, in particular C1-6 alkyl.
"Alkyl" can be a branched or non-branched alkyl group, which preferably has 1
to 10 C-
atoms, particularly preferred 1 to 6 C-atoms. Alkyl groups can also be
substituted with
one or more substituents, for example with halogen.
"Cycloalkyl" is an alkyl group that can consist of only pure ring-forming C-
atoms or can
optionally have other branching C-atoms. Preferred chain lengths are 3 to 10,
particularly
preferred 4 to 8 or 4 to 6 C-atoms.
"Aryl" is preferably phenyl. Phenyl can possibly also be substituted at one or
more
positions, for example, with alkoxy, alkyl, halogen or nitro.
The production of prodrugs by reacting rotigotine with corresponding reactive
precursors
such as acid chlorides, acid anhydrides, carbamyl chlorides, sulphonyl
chlorides etc. is
known to the person skilled in the field of clinical chemistry and can be seen
in pertinent
technical literature. Examples of literature are Bundgaard: Design of
prodrugs, Elsevier,
Amsterdam, 1985; Higuchi and Stella: Pro-drugs as novel drug delivery systems
in
American Chemical Society, Washington DC, 1975; Sloan: Prodrugs ¨ Topical and
Ocular Drug Delivery, Ed: M. Dekker, 1992; Roche: Design of biophaiinaceutical
properties through prodrugs and analogs, Washington, DC, 1977.
Various prodrugs of the racemate of Rotigotine (N-0437) are described, for
example, in
Den Haas et al , Naunyn-Schmiedeberg's Arch Pharmacol 342, 1990, 655; Den Haas
et
al, Naunyn-Schmiedeberg's Arch Pharmacol. 341, 1990, 186 and Den Haas et al, J
Pharm
Pharmacol 43, 1991, 11.
The basic suitability of a rotigotine derivative as a prodrug can be
determined by
incubating the respective compound under defined conditions with an enzyme
cocktail, a
cell homogenate or an enzyme-containing cell fraction and measuring the
resulting
rotigotine. A suitable enzyme mixture is contained, for example, in the S 9
liver
preparation of the firm Gentest, Woburn, Ma., USA.
Incubation can alternatively take place with fresh blood or plasma or even
with a
homogenate of the hypodermis in order to demonstrate a liver-independent
metabolisation
of the prodrugs into active components. For transdermal application, an in
vitro
examination of the pei ___________________________________________________
nieation on excised skin is necessary. The final proof of suitability
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and potential effectiveness in the disease models is obtained by determining
in the plasma
the 2-N-propylamino-5-hydroxytetralins formed from the prodrug.
In vivo, a prodrug should release so much rotigotine that a therapeutically/
prophylactically effective steady state concentration of rotigotine is
achieved in the
plasma. Rotigotine concentrations of between 0.01 and 50 ng/mL, preferably
between
0.05 ng and 20 ng/mL and particularly preferred between 0.1 and 10 ng/mL
plasma, are
thereby considered to be effective concentrations.
Rotigotine is the S(-)-enantiomer of 5,6,7,8-tetrahydro-6-[propyl[2-(2-
thienyl)ethyl]-
amino]-1-naphthol. This means that according to the invention, the proportion
of (R)-
enantiomer, which inactive in Parkinson's models, in the medicament is low.
The (R)-
enantiomer is preferably present in the medicament in a proportion of < 10
mol%,
particularly preferred in a proportion of < 2 mol% and especially preferred in
a mole
proportion of < 1 %, based on the total amount of rotigotine.
Rotigotine and its prodrugs can be present in the medicament as free bases or
in the form
of physiologically acceptable salts, for example, in the form of the
hydrochloride.
"Physiologically acceptable salts" include non-toxic addition salts of
rotigotine with
organic or inorganic acids. A preferred example of a suitable salt is the HC1
salt.
There are many methods of application available for administering rotigotine
and its
prodrugs, which the person skilled in the art can select and adapt depending
on the need,
condition and age of the patient, the required dosage and the desired
application interval.
A preferred mode of administering rotigotine is transdermal administration.
The form of
administration may, in principle, be selected from, for example, an ointment,
a paste, a
spray, a film, a plaster or an iontophoretic device.
Rotigotine is preferably applied to the skin of the patient in plaster form,
with the active
substance preferably being present in a matrix of adhesive polymer, for
instance a self-
adhesive polysiloxane. Examples of suitable transdermal formulations can be
found in
WO 99/49852, WO 02/89777, WO 02/89778, WO 2004/058247 and WO 2004/012721 as
well as in embodiment 1. Such a form of administration enables a substantially
constant
plasma level to be established and therefore a constant dopaminergic
stimulation over the
entire application interval (WO 02/89778; Metman, Clinical Neuropharmacol. 24,
2001,
163).
CA 02547645 2011-10-28
14
If, on the other hand, a medicament for parenteral administration, i.e. in the
form of a
subcutaneous or intramuscular depot form, is desired, rotigotine may be
suspended, for
example as a salt crystal, for instance as crystalline hydrochloride, in a
hydrophobic
anhydrous medium and injected, such as described in WO 02/15903 and in
embodiment 2.
Rotigotine can basically also be administered in the form of microcapsules,
microparticles
or implants based on biodegradable polymers, such as described, for example,
in WO 02/
38646.
Other conceivable forms of administering rotigotine and its prodrugs are
transmucosal
formulations, for example sublingual sprays, rectal formulations or aerosols
for
pulmonary administration.
Suitable dosages of rotigotine are between 0.05 and approximately 50 mg/day,
with daily
doses of preferably between 0.1 and 40 mg and in particular of between 0.2 and
20 mg/day being administered. Dosage can thereby take place in a gradually
increasing
manner, i.e. the treatment may optionally start with low doses which are then
increased
until the maintenance dose is reached.
It is clear to the person skilled in the art that the dosage interval may vary
depending on
the applied quantity, the mode of application and the daily requirement of the
patient.
Thus, a transdermal form of application may be designed, for example, for
administration
once a day, once every three days or once every seven days, whilst a
subcutaneous or
intramuscular depot can make it possible to administer injections, for
example, in one-
weekly, two-weekly or four-weekly cycles.
Other active substances which prevent the progression of dopaminergic cell
loss can also
be present in the neuroprotective medicament in addition to rotigotine.
Examples hereof are substances with an anti-apoptotic effect (minocycline, FK-
506,
cyclosporine A, zVAD) as well as neurotrophins such as, for example, Glial-
cell-derived
neurotrophic factor (GDNF).
In a combination preparation, a sequential administration can be achieved, for
example, in
that an administration form, for example an oral tablet, has two different
layers with
differing release profiles for the different pharmaceutically active
ingredients. It is clear to
the person skilled in the art that various forms of administration and
application patterns
are conceivable within the context of the present invention, which all form
subject matter
of the invention.
CA 02547645 2011-10-28
A further subject matter of the application is a kit for the early diagnosis
and treatment of
Morbus Parkinson. Such a kit contains (a) a diagnostic agent that enables the
diagnosis of
Parkinson's disease and/or the predisposition to develop Parkinson's disease
at an early or
asymptomatic stage as well as (b) a pharmaceutical formulation containing
rotigotine, its
salts or prodrugs for the treatment or prophylaxis of dopaminergic cell loss.
Such a kit may comprise, for example:
(a) an agent or a diagnosis kit for detecting neuromelanin,
(b) a pharmaceutical formulation containing rotigotine, its salts and
prodrugs.
In another embodiment of the invention, the kit may contain:
(a) an agent or a diagnosis kit for detecting semaphorin 3,
(b) a pharmaceutical formulation containing rotigotine, its salts and
prodrugs.
In another embodiment of the invention, the kit may contain:
(c) an agent or a diagnosis kit for detecting alpha-synuclein and/or its
aggregates,
(d) a pharmaceutical formulation containing rotigotine, its salts and
prodrugs.
In a further embodiment of the invention, the kit may contain:
(a) an agent or a diagnosis kit for genetically detecting a mutation
associated with the
appearance of Parkinson's disease and/or an allele associated with the more
frequent
appearance of Parkinson's disease, in particular, from the group of PARK genes
1, 2,
3, 4, 5, 6, 7 or 8 as well as the gene loci CYP2D6-B and GSTM1,
(b) a pharmaceutical formulation containing rotigotine, its salts and
prodrugs.
Embodiments:
Embodiment 1: Rotigotine Plaster
1.8 g of rotigotine (free base) were dissolved in 2.4 g of ethanol and added
to 0.4 g of
KollidoTMn 9OF (dissolved in 1 g of ethanol). This mixture was added to a 74%
solution of
TM
silicone polymers (8.9 g of BioPSA 7-4201 + 8.9 g of BIO-PSA 7-4301 [Dow
Corning])
in heptane. Following the addition of 2.65 g of petrol ether, the mixture was
stirred for 1
CA 02547645 2011-10-28
16
hour at 700 rpm in order to obtain a homogeneous dispersion. Following
lamination on
polyester, it was dried at 50 C. The final weight of the plaster was 50 g/cm2.
Embodiment 2: Rotigotine Depot Suspensions
TM TM
(a) 1411.2 g of Miglyol 812 were weighed into a Duran flask. 14.4 g of
Imwitor 312
were added to the Miglyol and then heated for 30 minutes to 80 C whilst being
stirred.
The clear solution was cooled to room temperature and filtered.
(b) 1188 g of the solution produced in (a) were transferred into a glass
laboratory
reactor, 12 g of rotigotine were added and homogenised for 10 minutes under
nitrogen
with an UltraturraTMx at 10,000 rpm. The suspension was decanted into brown
glass bottles
whilst the Ultraturrax was running (2,000 rpm).
Embodiment 3: Sub-Acute MPTP Model
For the purpose of intoxication, 80 mg/kg of the neurotoxin 1-methy1-4-pheny1-
1,2,3,6-
tetrahydro-pyridine (MPTP) were administered to mice (in doses of 20 mg/kg at
two-hour
intervals, groups 3 to 6 in Figs. 1 and 2), which led to the degeneration of
approximately
50 to 60% of the neurons of the substantia nigra (maximum degeneration in
group 3 in
Figs. 1 and 2). Rotigotine was administered daily for 7 days in doses of 0.3,
1 or 3 mg/kg
respectively as the so-called "slow-release formulation" (see embodiment 2)
(groups 4 to
6 in Figs. 1 and 2). A group of MPTP-treated animals (group 3) was given a
rotigotine
vehicle solution (see embodiment 2 without rotigotine HC1) and served as a
reference.
Groups 1, 2 and 7 served as controls, whereby group 1 did not receive any
treatment at all,
group 2 was treated with the vehicle solutions for MPTP and rotigotine and
group 7
received exclusively rotigotine. The animals were killed on day 8 and their
brains were
removed and frozen. The frozen sections were incubated with 100 pm [1251] PE2I
([125n-
(E)-N(3-iodoprop-2-eny1)-213-carboxymethy1-3(1-(4'-methylpheny1)-nortropane)
in phos-
phate buffer, pH 7.4, in order to mark the amount of dopamine transporters
still present in
the striatum, which indicates the number of functioning nerve endings.
Rotigotine
improved the survival of the neurons and their nerve endings depending on the
dosage.
This is a clear indication of the neuroprotective properties of the substance
(Figs. 1 and 2).
Embodiment 4: Acute MPTP Model (Including Apoptosis)
For the purpose of intoxication, 80 mg/kg of the neurotoxin 1-methy1-4-pheny1-
1,2,3,6-
tetrahydro-pyridine (MPTP) were administered to mice (in doses of 20 mg/kg at
two-hour
intervals), which led to the degeneration of approximately 50 to 60% of the
neurons of
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PCT/EP2004/014655
the substantia nigra. Approximately 16 hours beforehand, rotigotine was
administered in
doses of 0.3, 1 or 3 mg/kg respectively, as the so-called "slow-release
formulation".
Diffusion and absorption latencies led to rotigotine then being optimally
available when
MPTP was administered. The animals were killed after 24 hours and their brains
fixed.
The brain sections were stained with FluoroJade to identify degenerating
cells. The
immunohistochemical marking of tyrosine-hydroxylase helped to identify
dopaminergic
neurones. The staining of tyrosine hydroxylase did not display any differences
between
the treated and untreated animals; staining with FluoroJade showed a large
number of
degenerating neurones; the neurones had, however, not yet been completely
removed; this
suggests that the cell destruction occurs apoptotically. The number of
degenerating
neurones was approximately 50% less following application of rotigotine, which
further
demonstrates the neuroprotective property of the substance (Table 1).
Embodiment 5: Determination of the Motor UPDRS Score
The motor UPDRS score (part III of the UPDRS score) is determined by examining
the
patient using criteria 18 to 31 as given below in Table 2, with the point
scores resulting for
each of the criterion being respectively added together.
III. MOTOR EXAMINATION
18. Speech:
O 0 - Normal.
O 1 - Slight loss of expression, diction and/or volume.
O 2 - Monotone, slurred but understandable; moderately impaired.
O 3 - Marked impairment, difficult to understand.
O 4 - Unintelligible.
19. Facial Expression:
_ 0 0 - Noimal.
E 1 - Minimal hypomimia, could be a normal "poker face".
_ ri 2 - Slight but definitely abnormal diminution of facial expression.
O 3 - Moderate hypomimia; lips parted some of the time.
LI 4 - Masked or fixed face with severe or complete loss of expression; lips
parted by
7 mm.
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20. Tremor at rest: (F = face, RH = right hand, LH = left hand, RF = right
foot,
LF = left foot)
F RH LH RF LF
O 0 D 0 II 0 - Absent.
O 0 D 0 0 1 - Slight and infrequently present.
0 II 0 0 0 2 - Mild in amplitude and persistent; or moderate in amplitude
but only intermittently present.
O D E 0 0 3 - Moderate in amplitude and present most of the time.
O D 0 El 0 4 - Marked in amplitude and present most of the time.
21. Action or Postural Tremor of the Hands: (R= right, L = left)
R L
O E 0 - Absent.
ID 0 1 - Slight; present with action.
O 0 2 - Moderate in amplitude, present with action.
0 0 3 - Moderate in amplitude, present with posture holding as well as
action.
O 0 4 - Marked in amplitude; interferes with eating.
22. Rigidity: (Judged on passive movement of major joints on a patient in the
sitting position. Cogwheeling can be ignored). (N = neck, RUE = right upper
extremity, LUE = left upper extremity, RLE = right lower extremity, LLE = left
lower extremity).
O RUE LUE RLE LLE
O D D 0 LI 0 - Absent.
0 0 0 0 0 1 - Slight or detectable only when activated by
mirror-
image or other movements.
O 0 0 0 0 2 - Mild to moderate.
El 0 0 E 0 3 - Marked, but full range of motion still
achievable.
0 0 0 0 0 4 - Severe, difficulty in carrying out all movements.
23. Finger Taps: (Patient taps thumb against index finger in rapid succession
with maximum possible amplitude and separately with each hand). (R = right, L
= left).
R L
O 0 0 - Normal.
O 0 1 - Slight slowing and/or reduction in amplitude.
0 0 2 - Moderately restricted. Distinct and premature fatiguing. Movement may
occasionally be interrupted.
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O 0 3 - Severely restricted. Delayed start of the movements or interruption
of
continuous movements.
0 0 4 - Can barely perform the task.
24. Hand Movements: (Patient opens and closes the hands in rapid succession
with greatest possible amplitude and separately with each hand). (R = right, L
=
left).
R L
O 0 0 - N o rm a 1 .
O 0 1 - Slight slowing and/or reduction in amplitude.
El 171 2 - Moderately restricted. Distinct and premature fatiguing. Movement
may
occasionally be interrupted.
El 0 3 - Severely restricted. Delayed start of the movements or interruption
of
continuous movements.
0 0 4 - Can barely perform the task.
25. Rapid Alternating Movements of the Hands: (pronation/supination
movements of the hands, vertically or horizontally, with largest possible
amplitude, both hands simultaneously).
R L
O 0 0 - Normal.
O 0 1 - Slight slowing and/or reduction in amplitude.
2 - Moderately restricted. Distinct and premature fatiguing. Movement may
occasionally be interrupted.
O 0 3 - Severely restricted. Delayed start of the movements or interruption
of
continuous movements.
O 0 4 - Can barely perform the task.
26. Leg Agility: (Patient taps heel on the ground in rapid succession thereby
lifting the _entire leg. Amplitude should be at least 7.5 cm).
R L
El 0 0 - N o rm a 1 .
O 0 1 - Slight slowing and/or reduction in amplitude.
O 0 2 - Moderately restricted. Distinct and premature fatiguing. Movement
may
occasionally be interrupted.
O 0 3 - Severely restricted. Delayed start of the movements or interruption
of
continuous movements.
El 111 4 - Can barely perform the task.
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27. Rising from Chair: (Patient attempts to rise from a straight-back wooden
or
metal chair with arms folded across chest).
O 0- Normal.
O 1 - Slow; may need more than one attempt.
O 2 - Pushes self up using aims of seat.
LI 3 - Tends to fall back and may possibly have to make several attempts, but
can
rise without assistance.
O 4 - Unable to rise without assistance.
28. Posture:
LI 0 - Noi __ mai erect.
O 1 - Not quite erect, slightly stooped posture; could be normal for an
older person.
E 2 - Moderately stooped posture, definitely abnoiinal; can be leaning
slightly to
one side.
E 3 - Severely stooped posture with kyphosis; can be leaning moderately to
one side.
O 4 - Marked flexion with extremely abnormal posture.
29. Gait:
0 0 - Normal.
E 1 - Walks slowly, may shuffle a few short steps, but no festination or
propulsion.
E 2 - Walks with difficulty, but requires little or no assistance; possibly
slight
festination, short steps or propulsion.
E 3 - Severe disturbance of gait, requires assistance.
E 4 - Cannot walk at all, even with assistance.
30. Postural Stability: (Response to sudden rearwards displacement caused by
pulling on the patient's shoulders whilst patient is erect and has their eyes
open
and feet slightly apart. Patient is prepared.)
O 0 - Normal.
0 1 - Retropulsion, but recovers unaided.
O 2 - No postural response; would fall if not caught by examiner.
O 3 - Very unstable, tends to lose balance spontaneously.
O 4 - Unable to stand without assistance.
31. Body Bradykinesia and Hypokinesia: (Combination of slowness, hesitancy,
decreased arm-swing, small movement amplitude and poverty of movement in
general)
El 0 - None.
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El 1 - Minimal slowing, movement is intentional; could be normal for some
persons.
Possibly reduced amplitude.
0 2 - Slight slowing and poverty of movement, which is clearly abnormal.
Alternatively also reduced amplitude.
LI 3 - Moderate slowing and poverty of movement or reduction in amplitude.
E 4 - Marked slowing, poverty of movement or reduction in amplitude.
Embodiment 6: In Vitro Conversion of a Prodrug into the Active Substance
The microsome fraction that contains the essential metabolising enzymes is
obtained from
the liver cell homogenates of a human, monkey, dog, rat or mouse by means of
differential centrifugation; the cytoplasmatic fraction can alternatively also
be obtained.
The subcellular fraction is suspended with a buffer such that a solution
having a defined
protein content is obtained. Following the addition of I JAM of the prodrug to
be tested,
incubation takes place at 37 C for 60 min. Rotigotine is then quantified by
means of
HPLC/UV or also by means of HPLC/MS and is related to the used amount. The
concentration or time series are examined for detailed analyses.
