Note: Descriptions are shown in the official language in which they were submitted.
CA 02461248 2004-03-18
USE OF D4 AND 5-HT2A ANTAGONISTS, INVERSE AGONISTS OR PARTIAL
AGONISTS
Field of the invention
The invention relates to the field of neuro-degenerative diseases and related
cognitive
diseases or disorders. More specifically, the invention relates to the use of
compounds
which have D4 and/or 5-HT2A antagonist, inverse agonist or partial agonist
activity for the
preparation of medicaments.
Background to the invention
Data demonstrate that dopamine D4 receptors play an important role in the
induction of
behavioral sensitization to amphetamine and accompanying adaptations in pre-
and
postsynaptic neural systems associated with the meso-limbo-cortical dopamine
projections
(D. L. Feldpausch et al; The journal of pharmacology and experimental
therapeutics Vol.
286, Issue 1, 497-508, July 1998). Further, results show that dopamine D4
receptor
antagonism in the brain does not result in the same neuro-chemical
consequences
(increased dopamine metabolism or hyperprolactinemia) observed with typical
neuroleptics
(Smita Patel et al; The journal of pharmacology and experimental therapeutics
Vol. 283,
Issue 2, 636-647, 1997). The selective D4 dopamine receptor antagonist L-
745,870 was
ineffective as an antipsychotic for the treatment of neuroleptic responsive
inpatients with
acute schizophrenia (Kramer MS et al; Arch Gen Psychiatry 1997 Dec;
54(12):1080).
It has been shown that dopamine D4 receptors play an important role in novelty-
seeking
and exploratory behaviors mediated by dopamine in the basal ganglia.
Furthermore,
electron microscopy studies showed the exclusive presynaptic localization of
D4 receptors
in the two main striatal output fields, the globus pallidus and the substantia
nigra pars
reticulata. In contrast, double labeling experiments using immunofluorescent
secondary
antibodies showed that choline acetyltransferase-, somatostatin- and
parvalbumin-
containing interneurons did not express D4 receptors (Cuellar, B., Rivera, A.,
Martin, A.B.,'
De Ia Calle, A. and Moratalla, R. - Facultad de Biologia. Dpto. Biologia
Celular.
Universidad de Malaga).
Direct-acting dopamine agonists - important in the treatment of Parkinson
Disease because
they relieve the excessive burden of remaining neurons without being subject
to
metabolism into toxic free radicals inside dopamine neurons as has been
hypothesized for
levodopa - have significant drawbacks and side effects. Their potency is lower
than that of
levodopa and they can rarely be used as mono-therapy, except in the initial
stages of the
CA 02461248 2009-05-13
2
disease. As ergoline derivatives, they are not very specific and interact with
several
subtypes of dopamine receptors as well as with 5-HT receptors. Dl stimulation
may
contribute to the occurrence of dyskinesias, while 5-HT and D4 stimulation may
result in
confusion, hallucinations and other psychiatric manifestations. Dopamine
agonisis act also
at the periphery, and this may contribute to significant side effects such as
orthostafic
hypotension and nausea.
Moreover, in the nigrostriatal dopaminergic neuron serotonin inhibils dopamine
release via
its 5-HT2A receptor, both at the level of dopamine cell bodies in the
brainstem substantia
nigra and at the level of the axon terminals in the basal ganglia-neostriatum.
In both cases,
the release of serotonin acts as a "brake" on dopamine release (Essential
Psychopharmacology, S.M. Stahl, 2000, Neuroscientific Basis And Practical
Applications;
Cambridge University Press; 2nd Revised edition).
Post mortem and in vivo studies have revealed a loss of dopamine D2 receptors
in the
temporal lobes in Alzheimer Disease (AD). Moreover, the role of hippo-campal
D2
receptors on memory performance has been suggested in experimental studies.
Multiple
linear regression analysis showed that the D2 receptor binding potentials in
the right
hippocampus had a significant positive association with verbal memory
performance
(Wechsler Memory Scale - Revised) (P = 0.001) and picture naming (the Boston
Naming
Test) (P = 0.002). The findings suggest a role for temporal lobe D2 receptors
in the
memory and naming performance in AD. (Kemppainen N, Laine M, Laakso MP,
Kaasinen
V, Nigren K, Vahlberg T, Kurki T, Rinne JO.; Eur J Neurosci 2003;18:149-154).
Atypical
antipsychotic drugs (SDA's) may improve cognitive functions in both
schizophrenic and
Alzheimer pafients. They may boost the actions of cholinesterase inhibitors in
Alzheimer's
disease throughout a blockade of the 5HT2A receptors in the mesocortical
dopamine
pathways leading to dopamine release, which could compensate for the dopamine
deficiency caused by the neurotoxic process of the plaques, which are produced
from R-
amyloid protein (11A4). Otherwise, SDA's are blocking the postsynaptic
dopamine 2
receptors by their high dopamine receptor D2 affinity merely in the mesolimbic
pathway -
and this will in fact at least partially counteract the mentioned boosting.
In addition, since Alzheimer disease obviously is accompanied with many
behavioral
disturbances - merely aggression and confusion - there is also very often a
need for the
synergistic actions between a cholinesterase inhibibDr and a behavior
regulating agent.
CA 02461248 2008-03-13
2a
It is therefore an aim of the present invention to provide for new and
effective therapies for
treating neurodegenerative diseases such as Parkinson Disease and related
cognitive
diseases or disorders.
CA 02461248 2004-03-18
3
Summary of the invention
The present invention relates to the use of compounds and pharmaceutical
compositions
having D4 and/or 5-HT2A antagonistic, partial agonistic or inverse agonistic
activity for the
preparation of medicaments and to methods entailing administering to a patient
in need
thereof a pharmaceutical composition containing (i) compounds having D4
antagonistic,
partial agonistic or inverse agonistic activity and/or (ii) compounds having 5-
HT2A
antagonistic, partial agonistic or inverse agonistic, and/or (iii) any known
medicinal
compound or composition of compounds. The combined D4 and 5-HT2A antagonistic,
partial agonistic or inverse agonistic effects may reside within a single
compound or in two
different compounds. In one embodiment, the term "first compound" relates to a
compound
having both D4 and 5-HT2A antagonistic, partial agonistic or inverse agonistic
activity. In
another embodiment, it is contemplated that the term "first composition" is
used to indicate
a composition comprising a compound having D4 antagonistic, partial agonistic
or inverse
agonistic activity and a compound having 5-HT2A antagonistic, partial
agonistic or inverse
agonistic activity.
5-HT2A antagonists, partial agonists or inverse agonists according to the
invention are, for
instance, pipamperone, fananserin, L-745,870, PNU-101387G and U-101387.
Preferably, the compounds of the invention which have a selective affinity for
the 5-HT2A
receptor, are compounds which have a pKi value equal to or higher than 8
towards the 5-
HT2A receptor and less than 8 towards other 5HT receptors.
D4 antagonists, partial agonists or inverse agonists according to the
invention are, for
instance, pipamperone, fananserin, ORG 5222, zotepine, olanzepine, clozapine,
S16924,
S18327, amperozide, serindole, MDL 100.907, tiospirone, fluspirilene,
ocaperidone,
paliperidone, risperidone and ziprasidone.
Preferably, the compounds of the invention have a selective affinity for the
D4 receptor ,
are compounds which have a pKi value equal to or higher than 8 towards the D4
receptor
and less than 8 towards other Dopamine receptors.
One example of a compound which has both a selective affinity for the 5-HT2A
receptor
with a pKi value equal to or higher than 8 towards the 5-HT2A receptor and
less than 8
towards other 5HT receptors, and a selective affinity for the D4 receptor with
a pKi value
equal to or higher than 8 towards the D4 receptor and less than 8 towards
other Dopamine
receptors and which is therefore useful in a combination therapy is
pipamperone.
CA 02461248 2004-03-18
4
Further, the invention relates to the use of first compounds or compositions
as defined
above for treating a disease whereby a further, i.e. a second or third,
compound is
administered simultaneously with, separate from or sequential to said first
compound or
composition to augment the therapeutic effect of said further compound on said
disease, or
to provide a faster onset of the therapeutic effect of said further compound
on said disease.
According to a first embodiment, the present invention relates to the use of a
first
compound for the preparation of a medicament for treating neurodegenerative
diseases or
disorders and/or (related) cognitive diseases or disorders, characterized in
that said
compound is administered simultaneously with, separate from or prior to the
administration
of a second compound to augment the therapeutic effect or to provide a faster
onset of the
therapeutic effect of said second compound, further characterized in that said
first
compound has (i) a selective affinity for the Dopamine-4 (D4) receptor with a
pKi value
equal to or higher than 8 towards the D4 receptor and less than 8 towards
other Dopamine
receptors, and (ii) a selective affinity for the 5-HT2A receptor with a pKi
value equal to or
higher than 8 towards the 5-HT2A receptor and less than 8 towards other 5HT
receptors.
Preferably, said first compound is pipamperone, preferably to said first
compound is to be
administered to a patient in a dose ranging between 5 and 15 mg of the active
ingredient.
More particularly, the invention relates to any of the uses described above,
wherein said
neurodegenerative disease or disorder is Parkinson Disease.
The present invention further relates to any of the uses described above,
wherein said first
compound is to be administered daily at least one day before administering
said second
compound.
According to a preferred embodiment, the present invention relates to any of
the uses
described above, wherein said second compound is a dopamine receptor agonist.
Preferably, said dopamine receptor agonist is chosen from the group consisting
of
amantadine, bromocriptine, cabergoline lisuride, pergolide, ropinirole and
pramipexole, or a
pro-drug or an active metabolite thereof, or a pharmaceutically acceptable
salt thereof.
More preferably, said dopamine receptor agonist is pergolide and is to be
administered in a
dose ranging between 0.5 and 10 mg of the active ingredient.
In particular, the invention also relates to a pharmaceutical composition
comprising
(a) a compound having (i) a selective affinity for the Dopamine-4 (D4)
receptor with
a pKi value equal to or higher than 8 towards the D4 receptor and less than 8
towards
other Dopamine receptors, and (ii) a selective affinity for the 5-HT2A
receptor with a pKi
CA 02461248 2004-03-18
value equal to or higher than 8 towards the 5-HT2A receptor and less than 8
towards other
5HT receptors and
(b) a dopamine receptor agonist,
as a combined preparation for simultaneous, separate or sequential use for
treating a
5 neurodegenerative disease or disorder such as Parkinson Disease.
According to another preferred embodiment, the present invention relates to
any of the
uses described above, wherein said second compound is levodopa associated with
a
decarboxylase inhibitor. Preferably, said levodopa/decarboxylase-inhibitor is
chosen from
the group consisting of levodopa/carbidopa and levodopa/benserazide, or a pro-
drug or an
active metabolite thereof, or a pharmaceutically acceptable salt thereof. More
preferably,
said levodopa/decarboxylase-inhibitor is levodopa/carbidopa and is to be
administered in a
dose ranging between 2000 mg/ 200 mg and 100 mg/ 10 mg of the active
ingredients.
In particular, the invention also relates to a pharmaceutical composition
comprising
(a) a compound having (i) a selective affinity for the Dopamine-4 (D4)
receptor with
a pKi value equal to or higher than 8 towards the D4 receptor and less than 8
towards
other Dopamine receptors, and (ii) a selective affinity for the 5-HT2A
receptor with a pKi
value equal to or higher than 8 towards the 5-HT2A receptor and less than 8
towards other
5HT receptors, and
(b) a levodopa associated with a decarboxylase inhibitor,
as a combined preparation for simultaneous, separate or sequential use for
treating a
neurodegenerative disease or disorder such as Parkinson Disease.
According to a further preferred embodiment, the present invention relates to
any of the
uses described above, wherein said second compound is a mono-amine oxidase B
(MAO-
B) inhibitor. Preferably, said second compound is selegilinehydrochloride or a
pro-drug or
an active metabolite thereof, or a pharmaceutically acceptable salt thereof.
More
preferably, said selegilinehydrochloride is to be administered in a dose
ranging between 2
and 25 mg of the active ingredient.
In particular, the invention also relates to a pharmaceutical composition
comprising
(a) a compound having (i) a selective affinity for the Dopamine-4 (D4)
receptor with
a pKi value equal to or higher than 8 towards the D4 receptor and less than 8
towards
other Dopamine receptors, and (ii) a selective affinity for the 5-HT2A
receptor with a pKi
value equal to or higher than 8 towards the 5-HT2A receptor and less than 8
towards other
5HT receptors and
(b) a mono-amine oxidase B (MAO-B) inhibitor,
CA 02461248 2004-03-18
6
as a combined preparation for simultaneous, separate or sequential use for
treating a
neurodegenerative disease or disorder such as Parkinson Disease.
The present invention further relates to the use of a composition for the
preparation of a
medicament for treating a neurodegenerative disease or disorder and/or a
(related)
cognitive disease or disorder, characterized in that said composition is
administered
simultaneously with, separate from or prior to the administration of a third
compound to
augment the therapeutic effect or to provide a faster onset of the therapeutic
effect of said
third compound, further characterized in that said composition comprises a
first compound
having (i) a selective affinity for the D4 receptor with a pKi value equal to
or higher than 8
towards the D4 receptor and less than 8 towards other Dopamine receptors, and
a second
compound having (ii) a selective affinity for the 5-HT2A receptor with a pKi
value equal to
or higher than 8 towards the 5-HT2A receptor and less than 8 towards other 5HT
receptors. According to a preferred embodiment, said neurodegenerative disease
or
disorder is Parkinson Disease.
In particular, the invention relates to the use described above, wherein said
first compound
is chosen from the group consisting of, pipamperone, fananserin, L-745,870,
PNU-
101387G and U-101387 or a pro-drug or a pharmaceutically acceptable salt
thereof and
wherein said second compound is chosen from the group comprising pipamperone,
fananserin, ORG 5222, zotepine, olanzepine, clozapine, S16924, S18327,
amperozide,
serindole, MDL 100.907, tiospirone, fluspirilene, ocaperidone, risperidone,
paliperidone and
ziprasidone or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable
salt thereof. Preferably, the composition referred to in the above uses is to
be administered
to a patient in a dose ranging between 0,5 pg and 2000 mg for each of the
active
ingredients.
According to a preferred embodiment, the invention relates to any of the uses
described
above, wherein said third compound is a dopamine receptor agonist. Preferably
said
dopamine receptor agonist is chosen from the group consisting of amantadine,
bromocriptine, cabergoline lisuride, pergolide, ropinirole and pramipexole, or
a pro-drug or
an active metabolite thereof, or a pharmaceutically acceptable salt thereof.
More
preferably, said dopamine receptor agonist is pergolide and is to be
administered in a dose
ranging between 0.5 and 10 mg of the active ingredient.
In particular, the present invention relates to a pharmaceutical composition
comprising
CA 02461248 2004-03-18
7
(a) a compound having a selective affinity for the Dopamine-4 (D4) receptor
with a
pKi value equal to or higher than 8 towards the D4 receptor and less than 8
towards other
Dopamine receptors,
(b) a compound having a selective affinity for the 5-HT2A receptor with a pKi
value
equal to or higher than 8 towards the 5-HT2A receptor and less than 8 towards
other 5HT
receptors, and
(c) a dopamine receptor agonist,
as a combined preparation for simultaneous, separate or sequential use for
treating a
neurodegenerative disease or disorder such as Parkinson Disease.
According to another preferred embodiment, the invention relates to any of the
uses
described above, wherein said third compound is levodopa associated with a
decarboxylase inhibitor. Preferably, said levodopa/decarboxylase-inhibitor is
chosen from
the group comprising levodopa/carbidopa, levodopa/benserazide, or a pro-drug
or an
active metabolite thereof, or a pharmaceutically acceptable salt thereof. More
preferably,
said levodopa/decarboxylase-inhibitor is levodopa/carbidopa and is to be
administered in a
dose ranging between 2000 mg/ 200 mg and 100 mg/ 10 mg of the active
ingredients.
In particular, the present invention relates to a pharmaceutical composition
comprising
(a) a compound having a selective affinity for the Dopamine-4 (D4) receptor
with a
pKi value equal to or higher than 8 towards the D4 receptor and less than 8
towards other
Dopamine receptors, and
(b) a compound having a selective affinity for the 5-HT2A receptor with a pKi
value
equal to or higher than 8 towards the 5-HT2A receptor and less than 8 towards
other 5HT
receptors, and
(c) levodopa associated with a decarboxylase inhibitor,
as a combined preparation for simultaneous, separate or sequential use for
treating a
neurodegenerative disease or disorder such as Parkinson Disease.
According to a further preferred embodiment, the invention relates to any of
the uses
described above, wherein said third compound is a mono-amine oxidase B (MAO-B)
inhibitor. Preferably, said mono-amine oxidase B (MAO-B) inhibitor is
selegelinehydrochloride or a pro-drug or an active metabolite thereof, or a
pharmaceutically
acceptable salt thereof. More preferably, said selegilinehydrochloride is to
be administered
in a dose ranging between 2 and 25 mg of the active ingredient.
In particular, the present invention relates to a pharmaceutical composition
comprising
CA 02461248 2004-03-18
8
(a) a compound having a selective affinity for the Dopamine-4 (D4) receptor
with a
pKi value equal to or higher than 8 towards the D4 receptor and less than 8
towards other
Dopamine receptors, and
(b) a compound having selective affinity for the 5-HT2A receptor with a pKi
value
equal to or higher than 8 towards the 5-HT2A receptor and less than 8 towards
other 5HT
receptors. and
(c) a mono-amine oxidase B (MAO-B) inhibitor,
as a combined preparation for simultaneous, separate or sequential use for
treating a
neurodegenerative disease or disorder such as Parkinson Disease.
According to a further embodiment, the present invention relates to the use of
a first
compound or a composition for the preparation of a medicament for treating a
cognitive
disease or disorder, characterized in that said compound or composition is
administered
simultaneously with, separate from or prior to the administration of a further
compound to
augment the therapeutic effect or to provide a faster onset of the therapeutic
effect of said
further compound, further characterized in that said first compound has (i) a
selective
affinity for the Dopamine-4 (D4) receptor with a pKi value equal to or higher
than 8 towards
the D4 receptor and less than 8 towards other Dopamine receptors, and (ii) a
selective
affinity for the 5-HT2A receptor with a pKi value equal to or higher than 8
towards the 5-
HT2A receptor and less than 8 towards other 5HT receptors; or characterized in
that said
composition comprises a first compound having (i) a selective affinity for the
D4 receptor
with a pKi value equal to or higher than 8 towards the D4 receptor and less
than 8 towards
other Dopamine receptors, and a second compound having (ii) a selective
affinity for the 5-
HT2A receptor with a pKi value equal to or higher than 8 towards the 5-HT2A
receptor and
less than 8 towards other 5HT receptors.
The invention also relates to the use of a compound as defined above, or of a
composition
as defined above, for the preparation of a medicament for treating a cognitive
disease or
disorder, characterized in that said compound or composition is administered
simultaneously with, separate from or sequential to a cholinesterase inhibitor
to augment
the therapeutic effect or to provide a faster onset of the therapeutic effect
of said
cholinesterase inhibitor. Preferably, said disease or disorder is selected
from the group
consisting of delirium; dementia, such as Alzheimer Disease, substance-induced
persisting dementia, vascular dementia, dementia due to a general medical
condition
chosen from the group comprising HIV disease, head trauma, Parkinson Disease,
Huntington Disease, Pick Disease and Creutzfeldt-Jacob Disease; amnestic
disorders
CA 02461248 2004-03-18
9
due to a general medical condition or a substance-induced persisting amnestic
disorder;
mild cognitive impairment disorder; and other cognitive disorders.
The invention further relates to the any of the uses described above, wherein
said
cholinesterase inhibitor is chosen from the group consisting of donepezil, ENA-
713,
galantamine, memantine and tacrine, or a pro-drug or an active metabolite
thereof, or a
pharmaceutically acceptable salt thereof. Preferably said cholinesterase
inhibitor is
galantamine and is to be administered in a dose ranging between 5 and 50 mg of
the
active ingredient.
In particular, the present invention relates to a pharmaceutical composition
comprising
(a) a compound having (i) a selective affinity for the Dopamine-4 (D4)
receptor with
a pKi value equal to or higher than 8 towards the D4 receptor and less than 8
towards
other Dopamine receptors, and (ii) a selective affinity for the 5-HT2A
receptor with a pKi
value equal to or higher than 8 towards the 5-HT2A receptor and less than 8
towards other
5HT receptors, and
(b) a cholinesterase inhibitor
as a combined preparation for simultaneous, separate or sequential use for
treating a
cognitive disease or disorder.
The invention also particularly relates to a pharmaceutical composition
comprising
(a) a compound having a selective affinity for the Dopamine-4 (D4) receptor
with a
pKi value equal to or higher than 8 towards the D4 receptor and less than 8
towards other
Dopamine receptors, and
(b) a compound having a selective affinity for the 5-HT2A receptor with a pKi
value
equal to or higher than 8 towards the 5-HT2A receptor and less than 8 towards
other 5HT
receptors, and
(c) a cholinesterase inhibitor ,
as a combined preparation for simultaneous, separate or sequential use for
treating a
cognitive disease or disorder.
The invention further relates to any of the pharmaceutical composition herein
described
wherein said compound having (i) a selective affinity for the Dopamine-4 (D4)
receptor with
a pKi value equal to or higher than 8 towards the D4 receptor and less than 8
towards
other Dopamine receptors, and (ii) a selective affinity for the 5-HT2A
receptor with a pKi
value equal to or higher than 8 towards the 5-HT2A receptor and less than 8
towards other
5HT receptors, is pipamperone and is present in the composition in a dose
ranging
CA 02461248 2004-03-18
between 5 and 15 mg of active ingredient, expressed as the daily dose to be
administered
to a patient in need thereof.
Detailed description of the invention
The present inventors surprisingly found that compounds which have a high
selective
5 affinity towards the 5-HT2A receptor and which, at the same time have a high
selective
affinity towards the Dopamine-4 (D4) receptor show an improved effect in
combination with
other compounds when treating certain diseases or disorders.
The combined D4 and 5-HT2A antagonistic, partial agonistic or inverse
agonistic effects
may reside within the same chemical or biological compound or in two different
chemical or
10 two different biological compounds or in a combination of a chemical &
biological
compound.
In one embodiment of the invention, the 5-HT2A receptor and/or Dopamine-4
receptor
antagonist, inverse agonist or partial agonist is used in treatment of
patients having neuro-
degenerative diseases or disorders, or related cognitive diseases or
disorders. The
diseases or disorders of the present invention are characterized by an
underlying
degeneration of the Central Nervous System (CNS), preferably selected from the
group
consisting of, but not limited to, neurodegenerative diseases such as
Parkinson Disease,
and related cognitive diseases or disorders such as Alzheimer Disease.
Parkinson Disease, which is a chronic progressive nervous disease chiefly of
later life, is
linked to decreased dopamine production in the substantia nigra and is marked
by tremor
and weakness of resting muscles and by a shuffling gait. Because of the need
of specific
D4 and 5-HT2A antagonism in the treatment of Parkinson Disease with Dopamine
agonists
and even levodopa, it seems reasonable to combine with a compound with a high
selective
D4 and 5-HT2A antagonism i.e. merely no activity towards the other receptors
especially
the D2 receptor because of the primary need of the relieve of the excessive
burden of
remaining Dopaminergic neurons. Therefore, the use of the so called atypical
anti-
psychotics or serotonin-dopamine antagonists (SDA's) are absolutely contra-
indicated
since their high affinity for the D2 receptor. Even the use of serotonin
releasing compounds
such as SSRI's in the absence of an effective 5-HT2A antagonism are contra-
productive
towards the Parkinson symptoms although many Parkinson patients are in need
for an
antidepressant since major depression is a very common and disabling condition
in this
kind of patients.
CA 02461248 2004-03-18
11
The expression "(related) cognitive diseases or disorders" according to the
invention
comprises, the following group of diseases or disorders: delirium (F05),
dementia (such as
Alzheimer Disease (F00), vascular dementia (F01), dementia due to other
general medical
conditions (HIV disease (F02.4), head trauma (F06.8), Parkinson Disease
(F02.3),
Huntington Disease (F02.2), Pick Disease (F02.0), Creutzfeldt-Jacob Disease
(F02.1) and
other (F02.8)), substance-induced persisting dementia (Flx.6)), amnestic
disorders due to
a general medical condition (F06.8) or a substance-induced persisting amnestic
disorder
(Flx.6), mild cognitive impairment disorder (F06.7) and other cognitive
disorders (F04).
The above list of diseases is provided by way of example and is not intended
to limit the
invention.
Alzheimer Disease is a degenerative brain disease of unknown cause that is the
most
common form of dementia. Alzheimer Disease usually starts in late middle age
or in old
age as a memory loss for recent events spreading to memories for more distant
events and
progresses over the course of five to ten years to a profound intellectual
decline
characterized by dementia and personal helplessness. The disease is marked
histologically by the degeneration of brain neurons especially in the cerebral
cortex and by
the presence of neurofibrillary tangles and plaques containing beta-amyloid.
Because
dopamine receptor D4 (DRD4) antagonism can inhibit the behavioral disturbances
-
merely aggression and confusion - accompanied with Alzheimer disease and 5HT2A
antagonism has an important boosting effect towards the effect of
cholinesterase inhibitors
like used in the treatment, a high selective D4/5HT2A-antagonist would be a
more
preferable compound to combine with a cholinesterase inhibitor since this
avoids the
counteracting effect of SDA's on the cognitive functioning by its dopamine
receptor D2-
antagonism.
These diseases and their diagnosis are very clearly defined in the
"International Statistical
Classification of Diseases and Related Health Problems, 1989 Revision, Geneva,
World
Health Organization, 1992 (lCD-10). This manual sets forth diagnostic
criteria, descriptions
and other information to guide the classification and diagnosis of
neurodegenerative
disorders and is commonly used in the field of neurology. According to the ICD-
10
classification, the cognitive disorders are classified under several classes
of disorders, i.e.
dispersed under categories F00 to F19 (see above: respective classification
between
parentheses). Following the DSM classification, however, they are grouped in
one class of
diseases or disorders. The "Diagnostic and Statistical Manual of Mental
Disorders (DSM)"
is published by the American Psychiatric Association. This manual sets forth
diagnostic
criteria, descriptions and other information to guide the classification and
diagnosis of
CA 02461248 2004-03-18
12
mental disorders and is commonly used in the field of neuropsychiatry. It is
for instance
available on the internet under: http://www.behavenet.com/ capsules/disorders/
dsm4tr.htm.
A problem to be solved by the present invention is thus the provision of a
more efficient
therapy and efficient, highly selective and efficacious medicaments for
treating
neurodegenerative disorders and/or related cognitive disorders.
The inventors found that the non-response to dopamine receptor agonists (DA's)
in
Parkinson Disease may be declared by (partial) inhibition of the dopamine
release since in
the nigrostriatal dopaminergic neuron serotonin inhibits dopamine release via
its 5-HT2A
receptor stimulation. Des-inhibition thereof via 5-HT2A antagonism seems to be
an answer
to this problem.
The present inventors found that a simultaneous or foregoing treatment of the
patient with a
compound having a high selective 5-HT2A antagonist, inverse agonist or partial
agonist
activity, could lead to a greater response towards dopamine receptor agonists.
However, not
all compounds exhibiting 5-HT2A antagonism are useful: competition between 5-
HT2A
stimulation via serotonin and 5-HT2A antagonism via the compound could be
responsible for
the lack of more efficacy of compounds which have both a selective serotonin
re-uptake
inhibitory and 5-HT2A antagonist profile, such as trazodone and nefazodone.
The present inventors further surprisingly found that a simultaneous or
foregoing treatment
with a compound having a high selective D4 antagonist, inverse agonist or
partial agonist
activity in combination with a compound having a high selective 5-HT2A
antagonist,
inverse agonist or partial agonist activity could lead to a greater response
not only towards
dopamine receptor agonists but also towards other compounds such as, but not
limited to,
levodopa/decarboxylase-inhibitors, mono-amine-oxidase B inhibitors and
cholinesterase
inhibitors.
The present inventors found that a compound which binds to the 5-HT2A receptor
with a
pKi of at least 8 but for which the binding affinity, ie pKi, towards other
5HT receptors is
less than 8 in combination with a compound which has a high selective affinity
for the D4
receptor, i.e. which bind to the D4 receptor with a pKi of at least 8 but for
which the binding
affinity, ie pKi, towards other dopamine receptors is less than 8 also show
such an
improved effect in treatment. These effects, ie D4 antagonism, inverse agonism
or partial
agonism and 5-HT2A antagonism, inverse agonism or partial agonism, preferably
reside in
the same compound. In other embodiments of the invention, these effects reside
in
separate compounds.
CA 02461248 2004-03-18
13
'Other 5HT receptors' as used herein are for instance 5-HT1 receptors (i.e. 5-
HT1A, 5-
HT1 B, 5-HT1 D, 5-HT1 E, 5-HT1 F), 5-HT2B, 5-HT2C, 5-HT6 (rat) and 5-HT7
(rat).
5-HT2A responsive compounds according to the invention are, for instance
pipamperone,
fananserin, L-745,870, PNU-101387G and U-101387. All these compounds are known
in
the art and may be used in doses according to the supplier's or physician's
prescription.
By the expression 'selective affinity for the 5-HT2A receptor' is meant that
the receptor has
a higher affinity for the 5-HT2A receptor than for other known 5-HT receptors,
preferably
having a pKi value equal to or higher than 8 towards the 5-HT2A receptor and
less than 8
towards other known 5-HT receptors.
Table 1 illustrates the selective affinities of some compounds for several
receptors,
including 5-HT receptors. It should be noted that this table comprises a non-
exhaustive list
of exemplified compounds of the invention. The man skilled in the art will
appreciate that
this table can be easily completed with the pKi values for the other compounds
mentioned
in the present application, by using conventional methods for measuring pKi
values, such
as the methods described further.
Preferably, the compounds of the invention which have a selective affinity for
the 5-HT2A
receptor, are compounds which have a pKi value equal to or higher than 8
towards the 5-
HT2A receptor and less than 8 towards other 5HT receptors, as can be measured,
for
instance by methods known in the art. For instance, the "NIMH Psychoactive
Drug
Screening Program (PDSP)" K; database (http://kidb.cwru.edu/nimh/5htp.php), is
a unique
resource in the public domain which provides information on the abilities of
drugs to
interact with an expanding number of molecular targets. The PDSP K; database
serves as
a data warehouse for published and internally-derived pKi, or affinity, values
for a large
number of drugs and drug candidates at an expanding number of G-protein
coupled
receptors, ion channels, transporters and enzymes. The PDSP internet site also
provides
for commonly used protocols and assays for measuring pKi values of 5HT
receptors.
Preferred compounds which have a selective affinity for the 5-HT2A receptor
according to
the invention are, for instance amperozide and pipamperone.
The expression 'selective affinity for the D4 receptor' means that the
receptor has a higher
affinity for the Dopamine D4 receptor than for other known Dopamine receptors.
D4 responsive compounds according to the invention are, for instance,
pipamperone,
fananserin, ORG 5222, zotepine, olanzepine, clozapine, S16924, S18327,
amperozide,
serindole, MDL 100.907, tiospirone, fluspirilene, ocaperidone, risperidone,
paliperidone and
CA 02461248 2009-05-13
14
ziprasidone. All these compounds are known in the art and are to be used in
doses
according to the supplier's or physician's prescription.
'Other Dopamine receptors' are, for instance, Dl, D2 and D3.
pKi values of test compounds for Dopamine receptors can be measured using
commonly
known assays (see above).
Compounds which have a selective affinity for the D4 receptor preferably have
a pKi value
equal to or higher than 8 towards the D4 receptor and less than 8 towards
other known
Dopamine receptors.
One example of a compound which has both a selective affinity for the 5-HT2A
receptor
with a pKi value equal to or higher than 8 towards the 5-HT2A receptor and
less than 8
towards other 5HT receptors, and a selective affinity for the D4 receptor with
a pKi value
equal to or higher than 8 towards the D4 receptor and less than 8 towards
other Dopamine
receptors and which is therefore useful in a combina6on therapy is
pipamperone.
Pipamperone is the conventional name given for the compound of the formula 1'-
[3-(p-
Fluorobenzoyl)propyl]-[1,4'-bipiperidine}4'-carboxamide. Pipamperone is also
the active
ingredient of dipiperonTM (DipiperonTM tabletten 40mg, Janssen Cilag B.V.,
2000, Product
Monograph).
Table 1 illustrates the selective affinity of for instance pipamperone for the
5-HT2A and for
the D4 receptor. Table 1 further illustrates the low or absence of affinity of
pipamperone for
other receptors such as the adrenergic receptors Alpha 1A, Alpha 2A, Alpha 2B,
Alpha 2C,
Betal, Beta2, and the histamine receptor H1. As such, treating patients with
pipamperone
will provide for less side effects which otherwise result from simultaneous
stimulation of
other receptors. Therefore, and according to preferred embodiments, useful
compounds
according to the invention not only have a selective 5-HT2A and/or D4 affinity
but also a
low affinity for other receptors such as the adrenergic and h'stamine
receptors.
Further, the present inventors surprisingly found that the dosage of active
ingredient for
pipamperone in treatment could be very low compared to conventionally used
dosages for
treating mental disorders. Preferred dosages which, according to the
invention, have been
shown to be effective in combination therapy with other compounds, range
between 5 and
15 mg per day or between 5 and 10 mg per day. More preferably, dosages of 5,
6, 7, 8, 9,
10, 11, 12, 13, 14 or 15 mg per day are used in treatrnent of the diseases of
the invention.
The present dosages are represented as unitary daily doses applicable for a
person having
an average (ie normal) body weight. It is appreciated that the man skilled in
the art can
knows howto adapt the unitary daily doses herein described when dealirg with
smaller or
CA 02461248 2004-03-18
taller persons, or when dealing with children. Therefore, unitary daily doses
can easily be
converted, for instance to doses per kg of bodyweight. In conventional
pipamperone
treatment, the active ingredient is available in tablets of 40 mg per tablet
or in solutions of 2
mg per drop. Conventional usage of high doses ranging from 40 to 360 mg is
prescribed.
5 For instance for children up to the age of 14, a doses corresponding with 2
to 6 mg per kg
body weight is conventionally prescribed. The high selective affinity of
pipamperone
towards the 5-HT2A receptor and the D4 receptor is reflected in the low dosage
which is
needed for the treatment of the diseases or disorders listed herein and also
contributes to
the high selective affinity of the compound towards the 5-HT2A receptor and
the D4
10 receptor and therefore also to the efficacy of the treatment.
In the following embodiments of the invention relating to treatment of
neurodegenerative
diseases or disorders or related cognitive diseases or disorders, treatment is
preferably
done in a combination therapy consisting of a simultaneous or foregoing
treatment with
pipamperone, said pipamperone preferably administered in a dose ranging from 5
to 15 mg
15 of active ingredient per day.
According to a general aspect of the invention, it thus has been found by the
present
inventors that the compounds having a selective 5-HT2A and D4 antagonist,
inverse
agonist or partial agonist activity as described above are useful for
augmenting the
therapeutic effect of another, i.e. second compound on a disease.
According to another embodiment of the invention it has also been found that
the
compounds having a selective 5-HT2A and D4 antagonist, inverse agonist or
partial
agonist activity as described above are useful for providing a faster onset of
the therapeutic
effect of another, i.e. second compound on a disease.
One example of a neurodegenerative disorder which is treated using compounds
having a
high selective affinity for the 5-HT2A and D4 receptor, for instance
pipamperone, in a
combination therapy with a dopamine receptor agonist is for instance Parkinson
Disease. It
should however be clear that the term "neurodegenerative diseases" is not
limited to the
one disease exemplified herein.
The present inventors not only found that the selective 5-HT2A and D4
antagonists,
inverse agonists or partial agonists have an effect in augmenting the
therapeutic effect or in
providing a faster onset of the therapeutic effect of dopamine receptors
agonists, but that
this effect is also obtained when treating neurodegenerative diseases or
disorders, such as
Parkinson Disease, with selective 5-HT2A and D4 antagonists, inverse agonists
or partial
agonists in combination with other pharmaceutical compounds. Some examples of
other
CA 02461248 2004-03-18
16
pharmaceutical compounds whose effects are augmented or where the onset of the
effect
is fastened upon simultaneous or fore-going treatment with a selective 5-HT2A
and D4
antagonist, inverse agonist or partial agonist, are levodopa/decarboxylase
inhibitors and
mono-amine oxidase B (MAO-B) inhibitors.
The present inventors also found that the 5-HT2A and D4 antagonists, inverse
agonists or
partial agonists have similar effects on treatment or alleviating related
cognitive diseases or
disorders, such as Alzheimer Disease, with certain compounds, such as, but not
limited to
cholinesterase inhibitors.
The terms "treatment", "treating", and the like, as used herein include
amelioration or
elimination of a developed mental disease or condition once it has been
established or
alleviation of the characteristic symptoms of such disease or condition. As
used herein
these terms also encompass, depending on the condition of the patient,
preventing the
onset of a disease or condition or of symptoms associated with a disease or
condition,
including reducing the severity of a disease or condition or symptoms
associated therewith
prior to affliction with said disease or condition. Such prevention or
reduction prior to
affliction refers to administration of the compound or composition of the
invention to a
patient that is not at the time of administration afflicted with the disease
or condition.
"Preventing" also encompasses preventing the recurrence or relapse-prevention
of a
disease or condition or of symptoms associated therewith, for instance after a
period of
improvement. It should be clear that neurodegenerative conditions may be
responsible for
mental complaints. In this respect, the term "treating" also includes
prevention of a mental
disease or condition or amelioration or elimination of the developed mental
disease or
condition once it has been established or alleviation of the characteristic
symptoms of such
conditions.
As used herein, the term "medicament" also encompasses the terms "drug",
"therapeutic",
"potion" or other terms which are used in the field of medicine to indicate a
preparation with
therapeutic or prophylactic effect.
According to one embodiment, the invention thus relates to the use of a
compound having
a high selective affinity for the 5-HT2A and D4 receptor in combination with a
dopamine
receptor agonist, for instance chosen from the group consisting of, but not
limited to
amantadine, bromocriptine, cabergoline lisuride, pergolide, ropinirole and
pramipexole, or a
pro-drug or an active metabolite thereof, or a pharmaceutically acceptable
salt thereof.
According to a preferred embodiment of the invention, the above described
compounds
having a 5-HT2A and D4 antagonist, inverse agonist or partial agonist activity
are useful for
CA 02461248 2008-03-13
17
augmenting the therapeutic effect of pergolide, or for providing a faster
onset of the
therapeutic effect of pergolide. Pergolide is a dopamine receptor agonist.
Pergolide is
administered in a dose ranging between 0.5 and 10 mg of the active ingredient
per day.
Preferably, daily doses of active ingredient ranging between 2 and 5 mg per
day are
administered. More preferably a daily dose of 3 mg of the active ingredient is
administered.
According to a further embodiment, the invention relates to the use of
pipamperone,
preferably in a dose ranging from 5 to 15 mg of the active ingredient per day,
in
combination with pergolide, in a dose ranging from 0.5 to 10 mg of active
ingredient per
day, for treating Parkinson Disease.
The compound having a selective 5-HT2A and D4 antagonist, inverse agonist or
partial
agonist activity is thus also used in a combination therapy with other, i.e.
second
compounds in treatment of the same disease or disorder, i.e. neurodegenerative
diseases
such as Parkinson Disease.
In certain embodiments of the invention said second compound is levodopa
associated
with a decarboxylase-inhibitor. Preferred levodopa/decarboxylase-inhibitors to
be
administered to patients with an underlying degeneration of the CNS in
combination with
the selective 5-HT2A and D4 antagonist, inverse agonist or partial agonist of
the invention
are chosen from the group comprising, but not limited to levodopa/carbidopa,
levodopa/benserazide, pharmaceutically acceptable salts, pro-drugs and
mixtures thereof.
These compounds are known in the art and may be used in doses according to the
supplier's or physician's prescription.
According to a preferred embodiment of the invention, the above described
compounds
having a 5-HT2A and D4 antagonist, inverse agonist or partial agonist activity
are useful for
augmenting the therapeutic effect of levodopa/carbidopa, or for providing a
faster onset of
the therapeutic effect of levodopa/carbidopa.
Chemically, levodopa is known as (-)-3-(3,4-dihydroxy-phenyl)-L-alanine. It is
commercially
available for instance under the names doparTM or IarodopaT''". Levodopa is
required by the
brain to produce the neurotransmitter dopamine.
Levodopa/carbidopa is a combination drug comprising the active compound
levodopa and
the decarboxylase-inhibitor carbidopa: both compounds are administered in a
combined
preparation, i.e. the decarboxylase inhibitor prevents that levodopa is
peripherally
converted in dopamine, as such avoiding undesired peripheral dopamine
activity; on the
other hand, the decarboxylase does not pass the blood-brain barrier so that
the inactive
CA 02461248 2004-03-18
18
levodopa is converted in the CNS to the active dopa. Levodopa/carbidopa is
commercially
available for instance under the name sinemet (Merck & Co). Levodopa/carbidopa
is
administered in a dose ranging between 2000 mg and 100 mg (levodopa) and
between
200 mg and 10 mg (carbidopa) per day, respectively for the active ingredients
levodopa
and carbidopa. As used herein, the doses of the combined
levodopa/decarboxylase-
inhibitor are noted: "between 2000 mg/ 200 mg and 100 mg/ 10 mg of the active
ingredients". Preferably, daily doses of active ingredients ranging between
1500 mg/ 150
mg and 250 mg/ 25 mg per day are administered. More preferably a daily dose of
500 mg/
50 mg of the active ingredients are administered.
According to a further embodiment, the invention relates to the use of
pipamperone,
preferably in a dose ranging from 5 to 15 mg of the active ingredient per day,
in
combination with levodopa/carbidopa, in a dose ranging from 2000 mg/ 200 mg to
100 mg/
10 mg of active ingredients per day, for treating Parkinson Disease.
In other preferred embodiments, said second compound is a mono-amine oxidase B
(MAO-B) inhibitor. Preferred MAO-B inhibitor to be administered to patients
with an
underlying degeneration of the CNS in combination with the selective 5-HT2A
and D4
antagonist, inverse agonist or partial agonist of the invention are chosen
from the group
consisting of, but not limited to, selegelinehydrochloride, pharmaceutically
acceptable salts,
pro-drugs or active metabolites thereof, or mixtures thereof.
According to a preferred embodiment of the invention, the above described
compounds
having a 5-HT2A and D4 antagonist, inverse agonist or partial agonist activity
are useful for
augmenting the therapeutic effect of selegelinehydrochloride, or for providing
a faster onset
of the therapeutic effect of selegelinehydrochloride. Selegelinehydrochloride
is a mono-
amine oxidase B (MAO-B) inhibitor. Selegelinehydrochloride is administered in
a dose
ranging between 2 and 25 mg of the active ingredient per day. Preferably,
daily doses of
active ingredient ranging between 5 and 15 mg per day are administered. More
preferably
a daily dose of 7.5 mg of the active ingredient is administered.
According to a further embodiment, the invention relates to the use of
pipamperone,
preferably in a dose ranging from 5 to 15 mg of the active ingredient per day,
in
combination with selegelinehydrochloride, in a dose ranging from 0.5 to 10 mg
of active
ingredient per day, for treating Parkinson Disease.
In other embodiments of the invention, the second compound is used to treat
another
disease or group of diseases or disorders. In one such embodiment, said second
compound is a cholinesterase inhibitor and is used for treating cognitive
diseases, and the
CA 02461248 2004-03-18
19
first compound, i.e. the selective 5-HT2A and D4 antagonist, inverse agonist
or partial
agonist of the invention, augments the therapeutic effect or provides for a
faster onset of
the therapeutic effect of said second compound on said cognitive disease or
disorder.
The cognitive disease or disorder to be treated according to the combination
therapy with a
selective 5-HT2A and D4 antagonist, inverse agonist or partial agonist
described above is
selected from the group consisting of, but not limited to delirium, dementia
(such as
Alzheimer Disease, vascular dementia, dementia due to other general medical
conditions
(HIV disease, head trauma, Parkinson Disease, Huntington Disease, Pick
Disease,
Creutzfeldt-Jacob Disease and other), substance-induced persisting dementia),
amnestic
disorders due to a general medical condition or a substance-induced persisting
amnestic
disorder, mild cognitive impairment disorder and other cognitive disorders.
Preferred cholinesterase inhibitors to be administered in combination with the
selective 5-
HT2A and D4 antagonist, inverse agonist or partial agonist of the invention
are chosen
from the group consisting of, but not limited to, donepezil, ENA-713,
galantamine,
memantine and tacrine, or pharmaceutically acceptable salts thereof, or pro-
drugs or active
metabolites thereof, or mixtures thereof.
According to a preferred embodiment of the invention, the above described
compounds
having a 5-HT2A and D4 antagonist, inverse agonist or partial agonist activity
are useful for
augmenting the therapeutic effect of galantamine, or for providing a faster
onset of the
therapeutic effect of galantamine. Galantamine is a cholinesterase inhibitor.
Galantamine is
administered in a dose ranging between 5 and 50 mg of the active ingredient
per day.
Preferably, daily doses of active ingredient ranging between 10 and 30 mg per
day are
administered. More preferably a daily dose of 16 mg of the active ingredient
is
administered.
According to a further embodiment, the invention relates to the use of
pipamperone,
preferably in a dose ranging from 5 to 15 mg of the active ingredient per day,
in
combination with galantamine, in a dose ranging from 0.5 to 10 mg of active
ingredient per
day, for treating cognitive diseases or disorders, such as the ones described
earlier.
From the above it should be clear that the selective 5-HT2A and D4 antagonist,
inverse
agonist or partial agonist is also named 'the first compound' in the
embodiments of the
invention.
According to the invention, when the 5-HT2A and D4 antagonist, inverse agonist
or partial
agonist activity reside in separate compounds, the term "composition" may be
used.
CA 02461248 2004-03-18
Compositions of the invention comprise a first compound having (i) a selective
affinity for
the D4 receptor with a pKi value equal to or higher than 8 towards the D4
receptor and less
than 8 towards other Dopamine receptors, and a second compound having (ii) a
selective
affinity for the 5-HT2A receptor with a pKi value equal to or higher than 8
towards the 5-
5 HT2A receptor and less than 8 towards other 5HT receptors.
The expression "the 5-HT2A and D4 antagonist, inverse agonist or partial
agonist" is used
herein to indicate a single compound having both activities or to indicate the
composition
comprising the activity in separate compounds.
It should be clear that when, in the present invention, a composition of
separate
10 compounds is used instead of a single compound, they may be used in
combination with
another, i.e. a third, compound to augment the therapeutic effect of the
other, i.e. the third,
compound on a disease.
When the 5-HT2A and D4 antagonist, inverse agonist or partial agonist and the
second
compound or third compound, are administered simultaneously, the compounds or
active
15 ingredients may be present in a single pharmaceutical composition or
formulation.
Alternatively the compounds or active ingredients are administered in separate
pharmaceutical compositions or formulations for simultaneous or separate use.
When the 5-HT2A and D4 antagonist, inverse agonist or partial agonist of the
invention is
administered prior to the second or third compound, as defined, the 5-HT2A and
D4
20 antagonist, inverse agonist or partial agonist is administered at least
during 1 day prior to
said second or third compound. Preferably the 5-HT2A and D4 antagonist,
inverse agonist
or partial agonist is administered for at least 1, 2 3, 4, 5, 6, 7, 8, 9 or 10
days, prior to the
administration of the second or third compound. Preferably the 5-HT2A and D4
antagonist,
inverse agonist or partial agonist is administered for at least 2, 3, 4, 5
weeks prior to the
administration of the second or third compound, or for at least 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11
or 12 months prior to the administration of the second or third compound.
Also encompassed by the invention are pro-drugs to these second or third
compounds or
active metabolites of these compounds.
The term "active metabolite" as used herein relates to a therapeutically
active compound
produced by the metabolism of a parent drug. Drugs administered to treat
diseases are
usually transformed (metabolized) within the body into a variety of related
chemical forms
(metabolites), some of which may have therapeutic activity (an active
metabolite).
CA 02461248 2004-03-18
21
The present invention also encompasses the use of these second or third
compounds,
administered in the form of a pharmaceutically acceptable salt in admixture
with a suitable
pharmaceutically acceptable excipient.
The present invention in particular also relates to pharmaceutical
compositions comprising the
first and second and/or third compounds.
To prepare the pharmaceutical compositions of the invention, comprising the
compounds
or the combination of the first and second and/or third compounds described
herein, an
effective amount of the active ingredients, in acid or base addition salt form
or base form, is
combined in admixture with a pharmaceutically acceptable carrier, which can
take a wide
variety of forms depending on the form of preparation desired for
administration. These
pharmaceutical compositions are desirably in unitary dosage form suitable, for
administration orally, nasal, rectally, percutaneously or by parenteral
injection. Other
preferred routes of administration according to the present invention are
topical
administration, for instance involving the use of transdermal administration
such as
transdermal patches or iontophoresis devices.
For example, in preparing the compositions in oral dosage form, any of the
usual
pharmaceutical inert media or diluents may be employed, such as, for example,
water,
glycols, oils, alcohols and the like in the case of oral liquid preparations
such as
suspensions, syrups, elixirs and solutions; or solid carriers such as
starches, sugars,
kaolin, lubricants, binders, disintegrating agents and the like in the case of
powders, pills,
capsules and tablets. Because of their ease in administration, solid dosage
forms represent
the most advantageous oral dosage unit form, in which case solid
pharmaceutical carriers
are obviously employed. Solid dosage forms for oral administration can include
capsules,
sustained-release capsules, tablets, sustained release tablets, chewable
tablets, sublingual
tablets, effervescent tablets, pills, powders, granules and gels. Such dosage
forms can
also comprise, as is normal practice, additional substances other than inert
diluents, e.g.,
lubricating agents, such as magnesium stearate. In the case of capsules,
tablets,
effervescent tablets, and pills, the dosage forms can also comprise buffering
agents. Soft
gelatin capsules can be prepared to contain a mixture of the active compound
or
composition and vegetable oil. Hard gelatin capsules can contain granules of
the active
compound in combination with a solid, pulveruient carrier, such as lactose,
saccharose,
sorbitol, mannitol, potato starch, corn starch, amylopectin, or cellulose
derivatives of
gelatin. Tablets and pills can be prepared with enteric coatings.
CA 02461248 2008-03-13
22
"Sustained release" refers to the release of a therapeutically active compound
and/or
composition such that the blood levels of the therapeutically active compound
are
maintained within a desirable therapeutic range over an extended period of
time. The
sustained release formulation can be prepared using any conventional method
known to
one skilled in the art to obtain the desired release characteristics.
The compounds and compositions can also be applied topically using a
transdermal
system, such as one of an acrylic-based polymer adhesive with a resinous
crosslinking
agent impregnated with the composition and laminated to an impermeable
backing. In a
particular embodiment, the compositions of the present invention are
administered as a
transdermal patch, more particularly as a sustained-release transdermal patch.
The
transdermal patches of the present invention can include any conventional form
such as,
for example, adhesive matrix, polymeric matrix, reservoir patch, matrix or
monolithic-type
laminated structure, and are generally comprised of one or more backing
layers,
adhesives, penetration enhancers, an optional rate controlling membrane and a
release
liner which is removed to expose the adhesives prior to application. Polymeric
matrix
patches also comprise a polymeric-matrix forming material. Suitable
transdermal patches
are described in more detail in, for' example, U.S. Pat. Nos. 5,262,165,
5,948,433,
6,010,715 and 6,071,531.
Another aspect of the present invention thus provides transdermal patches
comprising a
therapeutically effective amount of at least one of the compounds or
compositions
described herein to treat the diseases herein described, for instance one of
the
neurodegenerative diseases or disorders or related cognitive diseases or
disorders herein
specifically described. Preferably, in the combination therapies herein
described, the
5HT2A and/or D4 antagonist, inverse agonist or partial agonist as defined
above, and
which preferably is pipamperone, and the second or third compounds, as herein
described,
are comprised within the same or distinct transdermal patch, said transdermal
patches are
for simultaneous, separate or sequential application.on a patient's body.
Dosage forms for topical administration of the compounds and compositions can
include
creams, sprays, lotions, gels, ointments, and the like. In such dosage forms,
the
compositions of the invention can be mixed to form white, smooth, homogeneous,
opaque
cream or lotion with, for example, benzyl alcohol 1% or 2% (wt/wt) as a
preservative,
emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water
and sorbitol
solution. In addition, the compositions can contain polyethylene glycol 400.
They can be
CA 02461248 2004-03-18
23
mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt) as
preservative, white
petrolatum, emulsifying wax, and tenox II (butylated hydroxyanisole, propyl
gallate, citric
acid, propylene glycol). Woven pads or rolls of bandaging material, e.g.,
gauze, can be
impregnated with the compositions in solution, lotion, cream, ointment or
other such form
can also be used for topical application.
Liquid dosage forms for oral administration can include pharmaceutically
acceptable
emulsions, solutions, suspensions, syrups, and elixirs containing inert
diluents commonly
used in the art, such as water. Such compositions can also comprise adjuvants,
such as
wetting agents, emulsifying and suspending agents, and sweetening, flavoring,
and
perfuming agents.
Various delivery systems are known and can be used to administer the compounds
or
compositions of the present invention, including, for example, encapsulation
in liposomes,
microbubbles, emulsions, microparticles, microcapsules, nanoparticles, and the
like. The
required dosage can be administered as a single unit or in a sustained release
form.
The term parenteral includes subcutaneous injections, intravenous,
intramuscular,
intrasternal injection, or infusion techniques. Injectable preparations, for
example, sterile
injectable aqueous or oleaginous suspensions can be formulated according to
the known
art using suitable dispersing agents, wetting agents and/or suspending agents.
The sterile
injectable preparation can also be a sterile injectable solution or suspension
in a nontoxic
parenterally acceptable diluent or solvent, for example, as a solution in 1,3-
butanediol.
Among the acceptable vehicles and solvents that can be used are water,
Ringer's solution,
and isotonic sodium chloride solution. Sterile fixed oils are also
conventionally used as a
solvent or suspending medium.
Examples of other pharmaceutical compounds whose effects are augmented or
where the
onset of the effect is fastened upon simultaneous or fore-going treatment with
a selective
5-HT2A and D4 antagonist, inverse agonist or partial agonist as defined above,
and which
preferably is pipamperone according to a preferred embodiment of the
invention, are:
selective serotonin re-uptake inhibitors, nor-epinephrine re-uptake
inhibitors, neuroleptic
agents, and NK1 antagonists which all are used for treating diseases or
disorders with an
underlying dysregulation of the emotional functionality, for instance the
mental disorders
chosen from mood disorders, anxiety disorders, schizophrenia and other
psychotic
disorders, eating disorders, premenstrual syndrome, somatoform disorders,
factitious
disorders, dissociative disorders, sexual and gender identity disorders, sleep
disorders,
adjustment disorders, impulse control disorders, pervasive development,
attention-deficit
CA 02461248 2004-03-18
24
and disruptive behaviour disorders, substance-related disorders, personality
disorders,
psychological factors affecting medical conditions, malingering, antisocial
behaviour,
bereavement, occupational, identity, phase of life, academic problem, problems
related to
abuse or neglect.
Preferred selective serotonin re-uptake inhibitor are chosen from the group
cconsisting of,
but not limited to citalopram, fluoxetine, venlafaxine, fluvoxamine,
paroxetine, sertraline,
milnacipran and duloxetine, or a pro-drug or an active metabolite thereof, or
a
pharmaceutically acceptable salt thereof. An even more preferred selective
serotonin re-
uptake inhibitor is citalopram and is administered in a dose ranging between
10 and 40 mg
of the active ingredient.
According to a further preferred embodiment, the invention relates to the use
of
pipamperone, preferably in a dose ranging from 5 to 15 mg of the active
ingredient per day,
in combination with citalopram, in a dose ranging from 10 to 40 mg of active
ingredient per
day, for treating diseases or disorders with an underlying dysregulation of
the emotional
functionality.
Preferred nor-epinephrine re-uptake inhibitors are chosen from the group
consisting of, but
not limited to tandamine, pirandamine, ciclazindol, fluparoxan, lortalamine,
talsupram,
talopram, prindamine, nomifensine, viloxazine, tomoxetine, duloxetine,
venlafaxine,
milnacipran and reboxetine, or a pro-drug or an active metabolite thereof, or
a
pharmaceutically acceptable salt thereof.
Preferred neuroleptic agents are chosen from the group consisting of, but not
limited to
chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine,
trifluoperazine,
fluphenazine, clozapine, olanzapine, risperidone, paliperidone, ziprasidone,
quetiapine,
sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone,
perospirone, raclopride,
zotepine, DU-127090, ORG-5222, SM-13496, amisulpride, CP-361428, Lu 35-138,
balaperidone, S-18327, WAY-135452, eplivanserin, E-5842, SR-31742, NE-100,
osanetant, SR-141716, SR-48692, BSF-201640, BSF-190555, LAX-101 a, sarizotan,
CX-
691 and SB-271046, or a pro-drug or an active metabolite thereof, or a
pharmaceutically
acceptable salt thereof.
Preferred NK1 antagonists are chosen from the group consisting of, but not
limited to, MK-
0869, GW597599, GW679769, GW823296, Compound A, NKP608, CP-96,345 (cis-3-(2-
methoxybenzyl-amino-2-benzhydrylquinuclidine), CP-122721, CP-99994, GR-82334
(D-
Pro9-[Spiro-y-lactam]-Leu10,Trp11)-Physalaemin(1-11)), R673, TAK-637,
RPR100893
(perhydroisoindolol), RP-67580, LY303870, SR-140333 and trans-4-hydroxy-1-(1 H-
indol-3-
CA 02461248 2004-03-18
ylcarbonyl)-L-prolyl-N-methyl-N-(phenylmethyl)-L-tyrosineamide (a derivative
of FK888), or
a pro-drug or an active metabolite thereof, or a pharmaceutically acceptable
salt thereof. A
more preferred NK1 antagonist is MK-0869 and is administered in a dose ranging
between
10 and 160 mg of the active ingredient; even more preferred in a dose of 80 mg
of the
5 active ingredient.
According to a further preferred embodiment, the invention relates to the use
of
pipamperone, preferably in a dose ranging from 5 to 15 mg of the active
ingredient per day,
in combination with MK-0869, in a dose ranging from 10 to 160 mg of active
ingredient per
day, for treating diseases or disorders with an underlying dysregulation of
the emotional
10 functionality.
A still other group of pharmaceutical compounds whose effects are augmented or
where
the onset of the effect is fastened upon simultaneous or fore-going treatment
with a
selective 5-HT2A and D4 antagonist, inverse agonist or partial agonist, for
instance
pipamperone, are COX-2 inhibitors, used for treating or alleviating
musculoskeletal
15 diseases or disorders, such as rheumatoid arthritis, osteoarthritis or
ankylosing spondylitis;
or for the management of acute pain or for primary treatment of dysmenorrhea.
Preferred
COX-2 inhibitors are chosen from the group consisting of, but not limited to,
celecoxib,
rofecoxib, meloxicam, piroxicam, deracoxib, parecoxib, valdecoxib, etoricoxib,
a chromene
derivative, a chroman derivative, N-(2-cyclohexyloxynitrophenyl)-methane
sulfonamide,
20 COX189, ABT963 and JTE-522, or a pro-drug or an active metabolite thereof,
or a
pharmaceutically acceptable salt thereof.
COX-2 inhibition works through a direct neuronal mechanism; COX-2 enzyme does
not kill
the neurons through inflammation, but by oxidizing other molecules in the
dopamine-
producing cells. The oxidized molecules then react with and damage other
components of
25 the cell. Excessive damage can kill the cell. They are more familiar in
arthritis, but the
enzymes produce inflammation in all damaged tissues, including the brain. The
present
inventors found that inflammation might be a critical process in
neurodegenerative
diseases, and that oxidative damage might be responsible for killing of
neurons in
Parkinson's disease. Therefore, treatment of neurodegenerative diseases with
COX-2
inhibitors may reduce aberrant and lethal oxidation in brain cells, thereby at
least alleviating
or ameliorating the disease.
It should be clear, given the general applicable character of the invention,
that the herein
presented list of other pharmaceutical compounds which effect is modulated,
for instance
augmented, by the selective 5-HT2A and D4 antagonists, inverse agonists or
partial
CA 02461248 2008-03-13
26
agonists of the present invention, and, accordingly the diseases or disorders
which can be
treated, is very brief and is should be clear that the invention should not be
restricted to the
ones exemplified herein.
It should be clear that the compounds and compositions described herein are
useful for
treating any patient in need thereof. As used herein the term "patient" is not
restricted to
humans but also to other mammals, for instance domestic animals which may also
suffer
from any form of a mental disease or disorder described herein.
The invention, now being generally described, will be more readily understood
by reference
to the following tables and examples, which are included merely for purposes
of illustration
of certain aspects and embodiments of the present invention and are not
intended to limit
the invention.
CA 02461248 2004-03-18
27
Examples
Example 1: Measuring pKi values of test compounds
In Table 1, the pKi values of test compounds are given for each of the
dopamine receptors,
5HT receptors, adrenergic receptors and the histaminel receptor. The affinity
of test
compounds for the respective receptors has been performed according to
conventional
procedures known in the art.
An indication "0" means that no affinity has been measured between the test
compound
and the receptor.
The columns displaying the pKi values for the D4 and the 5-HT2A receptor are
filled with
dark grey. pKi values between 8 and 9 and higher than 9 are represented by
light grey
shaded boxes.
Example 2: Foregoing pipamperon-citalopram treatment in mayor depressive
disorder: a placebo and active controlled period finding clinical trial
Table 2 represents the set-up of a clinical trial comprising for treatment
groups:
Group Plc - Active / Day 0 represents the group receiving 10 mg citalopram,
twice a day,
starting the first day (Day 0) of active treatment in the clinical trial. This
administration
regime is also indicated as the mono therapy.
Group Pip - Active / Day 0 represents the group receiving a combination of 4
mg
pipamperon and 10 mg citalopram, twice a day, starting the first day (Day 0)
of active
treatment in the clinical trial. This administration regime is also indicated
as the non-
foregoing combo therapy.
Group Pip - Active / Day 4 represents the group receiving 4 mg pipamperon,
twice a day,
starting the first day (Day 0) of active treatment in the clinical trial,
followed by a
combination of 4 mg pipamperon and 10 mg citalopram, twice a day, starting the
fifth (Day
4) day of active treatment in the clinical trial. This administration regime
is also indicated as
the foregoing therapy with combination therapy starting after 4 days of active
treatment.
Group Pip - Active / Day 7 represents the group receiving 4 mg pipamperon,
twice a day,
starting the first day (Day 0) of active treatment in the clinical trial,
followed by a
combination of 4 mg pipamperon and 10 mg citalopram, twice a day, starting the
eight (Day
7) day of active treatment in the clinical trial. This administration regime
is also indicated
as the foregoing therapy with combination therapy starting after 7 days of
active treatment.
All subjects also undergo a placebo (PLC) run-in therapy, administered during
a period of
about 7 days before the active treatment starts.
CA 02461248 2004-03-18
28
During daily (D), weekly (W) or monthly (M) visits, several parameters are
measured.
Under NECT is to be understood: Neuronal E-clinical Trial = Vesalius Expert
development
for this trial which includes the bottom-up measurement of:
- In- and exclusion-criteria
- Functional status evaluation
- Medical history
- (Pre-)treatment signs & symptoms
- DSM-IV rules for diagnosis & efficacy
- HDRS-28 (Hamilton Depression Rating Scale - 28 items)
- Medical resource utilisation
- Pre-trial & Concomittant medication
- Drug administration
- (Serious) Adverse events
- Admission to the acute and extension phase of treatment
- Right flow of the trial
Example 3: Foregoing pipamperon-pergolide treatment in Parkinson Disease: a
placebo and active controlled period finding clinical trial
Table 3 represents the set-up of a clinical trial comprising for treatment
groups:
Group Plc - Active / Day 0 represents the group receiving 1.5 mg pergolide,
twice a day,
starting the first day (Day 0) of active treatment in the clinical trial. This
administration
regime is also indicated as the mono therapy.
Group Pip - Active / Day 0 represents the group receiving a combination of 4
mg
pipamperon and 1.5 mg pergolide, twice a day, starting the first day (Day 0)
of active
treatment in the clinical trial. This administration regime is also indicated
as the non-
foregoing combo therapy.
Group Pip - Active / Day 4 represents the group receiving 4 mg pipamperon,
twice a day,
starting the first day (Day 0) of active treatment in the clinical trial,
followed by a
combination of 4 mg pipamperon and 1.5 mg pergolide, twice a day, starting the
fifth (Day
4) day of active treatment in the clinical trial. This administration regime
is also indicated as
the foregoing therapy with combination therapy starting after 4 days of active
treatment.
Group Pip - Active / Day 7 represents the group receiving 4 mg pipamperon,
twice a day,
starting the first day (Day 0) of active treatment in the clinical trial,
followed by a
combination of 4 mg pipamperon and 1.5 mg pergoiide, twice a day, starting the
eight (Day
CA 02461248 2004-03-18
29
7) day of active treatment in the clinical trial. This administration regime
is also indicated as
the foregoing therapy with combination therapy starting after 7 days of active
treatment.
All subjects also undergo a placebo (PLC) run-in therapy, administered during
a period of
about 7 days before the active treatment starts.
During daily (D), weekly (W) or monthly (M) visits, several parameters are
measured.
Under NECT is to be understood: Neuronal E-clinical Trial = Vesalius Expert
development
for this trial which includes the bottom-up measurement of:
- In- and exclusion-criteria
- Functional status evaluation
- Medical history
- (Pre-)treatment signs & symptoms
- ICD-10 rules for diagnosis & efficacy
- UPDRS measurement in Parkinson's disease
- Medical resource utilization
- Pre-trial & Concomitant medication
- Drug administration
- (Serious) Adverse events
- Admission to the acute and extension phase of treatment
- Right flow of the trial
_---
CA 02461248 2004-03-18
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CA 02461248 2004-03-18
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