Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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NEW THERAPEUTIC COMBINATIONS OF (S)-2-(BENZYLAMINO-
METHYL)-2,3,8,9,-TETRAHYDRO-7H-1,4-DIOXINO [2,3-e]INDOL-8-ONE
AND NEUROLEPTICS FOR THE TREATMENT OR PREVENTION OF
PSYCHOTIC DISORDERS
Field of the Invention
The present invention relates to therapeutic combinations of (S)-2-
(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one, a
partial
agonist of the dopamine D2/D3 receptors, and antipsychotic agents, for the
treatment
or prophylaxis of psychotic disorders, to pharmaceutical compositions
containing
said combinations, and to their use in the treatment or prophylaxis of
psychotic
disorders.
Background of the Invention
Psychoses are serious mental illnesses characterized by defective or lost
contact with reality. These disorders are characterized by a variety of
symptoms
which are classified as positive symptoms (disordered thought, hallucinations,
and
delusions), negative symptoms (social withdrawal and unresponsiveness), and
cognitive deficits.
Neuroleptics or antipsychotics can be used to treat schizophrenia and other
related psychotic disorders by blocking the dopaminergic neurotransmission in
the
central nervous system. Neuroleptics are used widely to treat the "positive"
symptoms of schizophrenia. However, many of these drugs are not considered to
be
effective for the treatment of "negative" symptoms of schizophrenia and may in
fact
exacerbate these symptoms because of the dopaminergic blockade associated with
their mechanism of action. Cognitive deficits associated with schizophrenia,
such as
distractability, and executive skills such as a working memory and ability to
plan, are
also believed to be negatively effected by the blockade of dopamine receptors.
In addition, these neuroleptics have important side effects such as akathisia,
dystonia, Parkinsonism dyskinesia and late dyskinesia and the like, which are
caused
by blocking the dopaminergic neurotransmission.
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Anticholinergic agents such as Cogentin , have been used to reduce
Parkinson-like side effects, but also cause side effects such as mental and/or
physical
impairment, tachycardia, dysuria and gastrointestinal symptoms.
Some partial dopamine agonists with relatively high intrinsic activity have
been shown to have effectiveness against the negative symptoms of
schizophrenia. It
has been hypothesized that in this respect, some intrinsic activity is
desirable to
optimize the treatment of negative symptoms while minimizing side effects.
Lindenmayer, J.P., Acta Psychiatrica Scand. 1995:91 (supp. 388):15-19.
However, with increasing intrinsic activity, levels of dopamine transmission
are higher and thus, positive symptoms may be less effectively treated.
It has been found that partial dopamine agonists having moderate to high
intrinsic activity, such as preclamol, pramipexole and terguride have been
useful in
reversing the side effects of traditional neuroleptics. These reports indicate
that
higher intrinsic activity leads to greater effectiveness in alleviating motor
dysfunction-related side effects. Svensson, et al., Neuropharmacology,
32(10):1037-
1045 (1993).
New combination drug therapies may be useful for treatment of patients. It is
greatly desired to optimize the beneficial properties of both drugs, while
minimizing
the side effects associated with the drugs when given alone. Applicants have
found
useful therapeutic combination for the treatment of psychotic disorders.
Brief Description of the Drawings
Figure 1 is a schematic representation of the effect of (S)-2-(benzylamino-
methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (agent) on
haloperidol-
induced catalepsy in rats at 60 minutes after drug treatment, the time point
of greatest
reversal as measured by seconds spent in catelepsy over a dose range of 0.003
to 3
mg/kg s.c. of agent. The data are means SEM.
Figure 2 is a schematic representation of the ability of (S)-2-(benzylamino-
methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (agent) to induce
catalepsy in rats as measured by seconds spent in catelepsy over a dose range
of
0.003 to 3 mg/kg s.c. of agent. The data are means SEM.
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Figure 3 is a schematic representation of the effect of (S)-2-(benzylamino-
methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (agent) to reverse
d-
amphetamine induced hyperactivity in mice. The data are expressed as a
percentage of
the activity level (horizontal activity counts) observed in mice treated with
d-
amphetamine alone for eight doses ranging from 0.0001 to 1 mg/kg s.c. of
agent. The
data are presented as means SEM.
Detailed Description of the Invention
In accordance with the present invention is provided a composition
comprising (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]-
indol-8-one, or pharmaceutical salts thereof, and one or more antipsychotic
agents.
(S)-2-(Benzylamino-methyl)-2,3, 8,9-tetrahydro-7H-1,4-dioxino[2,3-e] indol-
8-one , a D2 partial agonist, is disclosed in U.S. Patent No. 5,756,532. (S)-2-
(Benzyl-
amino-methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one, as used
herein,
includes pharmaceutical salts thereof, unless otherwise indicated.
Pharmaceutically acceptable salts include acid addition salts such as
hydrochloric, fumaric, maleic, citric or succinic.
The term antipsychotic agent or neuroleptic agent includes those
antipsychotics which work as a full antagonist of the dopamine D2 receptor and
include both typical and atypical antipsychotics. Representative antipsychotic
agents
that are commercially available or known to those skilled in the art and
include, but
are not limited to:
Chlorpromazine, or 2-chloro-N,N-dimethyl- l OH-phenothiazine-10-propan-
amine, is described in U.S. Patent No. 2,645,640.
Mesoridazine, or 10-[2-(1-methyl-2-piperidinyl)ethyl]-2-(methylsulfinyl)-
lOH-phenothiazine is described in U.S. Patent No. 3,084,161.
Thioridazine, or 10-[2-(1-methyl-2-piperidinyl)ethyl]-2-(methylthio)-1 OH-
phenothiazine is described in Collect. Czech. Chem. Commun., 1990,55,1586-
1601.
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Fluphenazine, or 4-[3-[2-(trifluoromethyl)-l OH-phenothiazin-10-yl]propyl]-1-
piperazineethanol is described in GB 829,246.
Trifluoperazine, or 10- [3 -(4-methyl-l-piperazinyl) -prop yl] -2-(trifluoro-
methyl)-IOH-phenothiazine is described in GB 813,861.
Perphenazine, or 4-[3-(2-chloro-lOH-phenothiazin-1-yl)propyl]-1-piperazine-
ethanol, is described in U.S. Patent No. 2,766,235.
Clozapine, or 8-chloro-ll-(4-methyl-l-piperazinyl)-5H-dibenzo[b,e]-[ 1,4]-
diazepine is described in U.S. Patent No. 3,539,573.
Haloperidol, or 4-[4-(4-chlorophenyl)-4-hydroxy-l-piperidinyl]-1-(4-fluoro-
phenyl)-1-butanone is described in U.S. Patent No. 3,438,991.
Loxapine, or 2-chloro-ll-(4-methyl-l-piperazinyl)-dibenz[b,fJ [ 1,4]
oxazepine is described in U.S. Patent No. 3,546,226.
Molindone, or 3 -ethyl- 1,5,6,7-tetrahydro-2-methyl-5 -(4--morpholinylmethyl)-
4H-indol-4-one, is described in U.S. Patent No. 3,491,093.
Thiothixene, or N,N-dimethyl-9-[3-(4-methyl-l-piperazinyl)-propylidene-9H-
thioxanthene-2-sulfanamide is described in U.S. Patent No. 3,310,553.
Sulpiride, or 5-(aminosulfonyl)-N-[(1-ethyl-2-pyrolidinyl)methyl]-2-meth-
oxybenzamide, is described in U.S. Patent No. 3,342,826.
Amisulpiride, or 4-amino-N-[(1-ethyl-2-pyrrolidin-yl)methyl]-5-(ethyl-
sulfonyl)-2-methoxybezamide, is described in U.S. Patent No. 4,401,822.
Risperidone, or 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]-ethyl]-
imidazolidin-2-one, is described in U.S. Patent No. 4,804,663.
Seroquel, or 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f]-
[1,4]thiazepine, preparation is described in EP 240228.
Olanzapine, or 2-methyl-4-(4-methyl-l-piperazinyl)-IOH-thieno[2,3-b][1,5]-
benzodiazepine, is described in U.S. Patent No. 5,229,382.
Administration of (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-
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dioxino[2,3-e]indol-8-one in combination with one or more antipsychotic agents
is
useful for the treatment or prevention of psychotic disorders associated with
altered
neurotransmission activity of the dopaminergic system in the central nervous
system
such as schizophrenia, schizoaffective disorder, acute mania, and depression
with
psychotic features, while eliminating or minimizing certain side affects
associated
with said antipsychotics when taken alone such as akathisia, dystonia,
Parkinsonism
dyskinesia and late dyskinesia and the like.
This invention also provides a product comprising (S)-2-(benzylamino-
methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one and an
antipsychotic
agent as a combined preparation for simultaneous, separate or sequential
administration to treat a patient suffering from a psychotic disorder.
Combinations of (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-di-
oxino[2,3-e]indol-8-one and one or more antipsychotics, hereinafter referred
to as
"combinations" may be administered simultaneously, in the same or different
pharmaceutical formulation, or sequentially. Of course the tiining of the
sequential
administration should preserve the advantageous effects of the combination and
said
timing can be determined by a skilled practitioner.
A therapeutically acceptable amount of the combination will be understood to
be an amount which treats, inhibits, prevents or ameliorates one or more
symptoms of
the psychotic disorder in question, preferably with fewer side effects than
those
associated with the administration of the antipsychotic agent alone. The
dosages of
each of the drugs in the combination must be determined by a physician and
will
depend upon the specific psychotic disorder, as well as the size, age and
response
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pattern of the patient. Dosage guidelines are provided here. For the
combination, the
dosage guideline for each of the drugs of the combination would be considered.
In general, suitable doses of (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-
7H-1,4-dioxino[2,3-e]indol-8-one, range from about 0.5 mg per day to about 100
mg
per day, and more preferably from about 1 to about 50 mg per day.
A suitable dose of antipsychotic agent will be in the range recommended by
the manufacturer. The following guidelines are provided for some preferred
antipsychotics of the present invention:
Chlorpromazine: from about 300 to about 800 mg per day;
Mesoridazine: from about 100 to about 400 mg per day;
Thioridazine: from about 200 to about 600 mg per day;
Fluphenazine: from about 2 to about 5 mg per day;
Trifluoperazine: from about 6 to about 20 mg per day;
Perphenazine: from about 8 to about 40 mg per day;
Clozapine: from about 300 to about 600 mg per day:
Haloperidol: from about 1 to about 20 mg per day;
Loxapine: from about 60 to about 100 mg per day;
Molindone: from about 15 to about 225 mg per day;
Thiothixene: from about 20 to about 30 mg per day;
Risperidone: from about 4 to about 20 mg per day;
Seroquel: from about 15 to about 750 mg per day; and
Olanzapine: from about 10 to about 20 mg per day.
While it is possible for the active ingredients of the combination to be
administered as the raw chemical, it is preferable to present them as a
pharmaceutical
formulation. Pharmaceutical formulations according to the present invention
comprise a combination according to the invention together with one or more
pharmaceutically acceptable carriers or excipients and optionally other
therapeutic
agents. The carriers must be acceptable in the sense of being compatible with
the
other ingredients in the formula. When the individual components of the
combination
are administered separately, they are generally each presented as a
pharmaceutical
formulation.
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A combination of (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-
dioxino[2,3-e]indol-8-one and an antipsychotic agent may conveniently be
presented
as a pharmaceutical formulation in a unitary dosage form. A convenient unitary
dosage formulation contains the active ingredients in amounts from 0.1 mg to 1
g
each, for example 5 mg to 100 mg. Typical unit doses may, for example, contain
about 0.5 to about 100 mg (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-
dioxino[2,3-e]indol-8-one, and preferably about 1 mg to about 50 mg of (S)-2-
(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one .
Pharmaceutical formulations may be prepared as "patient packs" containing
the whole course of treatment in a single package, usually a blister pack.
Patient
packs have an advantage over traditional prescriptions, where a pharmacist
divides a
patient's supply of a pharmaceutical from a bulk supply, in that the patient
always has
access to the package insert contained in the patient pack, normally missing
in
traditional prescriptions. The inclusion of a package insert has been shown to
improve patient compliance with the physician's instructions.
It will be understood that the administration of the combination of the
invention by means of a single patient pack, or patient packs of each
formulation,
with a package insert directing the patient to the correct use of the
invention is a
desirable additional feature of this invention.
According to a further aspect of the invention, there is provided a patient
pack
comprising at least one active ingredient of the combination of the invention
and an
information insert containing directions on the use of the combination of the
invention.
Formulations include those suitable for oral, rectal, nasal, topical
(including
transdermal, buccal and sublingual), vaginal or parenteral (including
subcutaneous,
intramuscular, intravenous and intradermal) administration. The formulations
may be
prepared by any methods well known in the art of pharmacy, for example, using
methods such as those described in Gennaro et al., Remington's Pharmaceutical
Sciences (18th ed., Mack Publishing Company, 1990, see especially Part 8:
Pharmaceutical Preparations and their Manufacture). Such methods include the
step
of bringing into association the active ingredient with the carrier which
constitutes
one or more accessory ingredients. Such accessory ingredients include those
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conventional in the art, such as, fillers, binders, diluents, disintegrants,
lubricants,
colorants, flavouring agents and wetting agents.
Formulations suitable for oral administration may be presented as discrete
units such as pills, tablets or capsules each containing a predetermined
amount of
active ingredient; as a powder or granules; as a solution or suspension. The
active
ingredient may also be present as a bolus or paste, or may be contained within
liposomes.
Formulations for rectal administration may be presented as a suppository or
enema.
For parenteral administration, suitable formulations include aqueous and non-
aqueous sterile injection. The formulations may be presented in unit-dose or
multi-
dose containers, for example, sealed vials and ampoules, and may be stored in
a
freeze dried (lyophilized) condition requiring only the addition of the
sterile liquid
carrier, for example, water prior to use.
Formulations suitable for administration by nasal inhalation include fine
dusts
or mists which may be generated by means of metered dose pressurized aerosols,
nebulisers or insufflators.
The compounds of the combination of the present invention may be obtained
in a conventional manner by methods known in the art.
The following examples are intended for illustration only and are not intended
to limit the scope of the invention in any way.
As shown by the following examples, side effects caused by treatment with
haloperidol are influenced by concommitant treatment with (S)-2-(benzylamino-
methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one.
EXAMPLE 1
Tests for reversal of haloperidol-induced catalepsy in rats were conducted
according to a variation of the methods of Svensson et al., Neuropharmacology,
1993, 32:1037-1045. Rats (200 - 250g) were transported from the colony room to
the
experimental room and held there for the duration of the experiment.
Haloperidol,
dissolved in 0.25% Tween 80 , was administered to all animals at a dose of 3
mg/kg
i.p. Sixty minutes later, (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-
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dioxino[2,3-e]indol-8-one, also dissolved in 0.25% Tween 80 , was administered
s.c.
at 4 dose levels to 6 male Sprague-Dawley rats per dose level. A control
group,
assessed simultaneously with (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-
1,4-
dioxino[2,3-e]indol-8-one treated groups, received a vehicle (VEH) injection
of
0.25% Tween 80 at equal volumes (1 ml/kg). Animals were assessed for
catalepsy
at 30, 60, 90 and 120 minutes after drug administration by placing the
animal's
forepaws on a wooden cube (8x8x8cm). The time that the animal remained with at
least one of the forepaws on the cube was measured (maximum = 60 sec). The
righting reflex was then tested and used to discard sedated subjects. Data
were
analyzed using a two-factor analysis of variance with one repeated measure. A
subsequent least significant difference from control test (p < 0.05) was used
to
determine the minimal effective dose (MED) for reversing haloperidol-induced
catalepsy and to determine time of onset. A trend test was then used to
determine at
which time points (if any) there was a dose-related effect. From these time
points the
point showing the greatest degree of reversal (having the lowest catalepsy
scored)
was used to calculate EDso (dose producing 50% reduction in maximal response)
and
95% confidence intervals. This was done using nonlinear regression analysis
followed by inverse prediction.
Figure 1 is a schematic representation of the effect of (S)-2-(benzylamino-
methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (agent) on
haloperidol-
induced catalepsy in rats at 60 minutes after drug treatment, the time point
of greatest
reversal. The data are means SEM. As shown in the figure, a dose-dependent
decrease in time spent in catalepsy position was observed. A MED of 0.3 mg/kg
and
an ED50 of 0.08 mg/kg were calculated from these results.
EXAMPLE 2
Tests for cataleptogenic potential of (S)-2-(benzylamino-methyl)-2,3,8,9-
tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one in rats were conducted by a method
similar to that described in Example 1, except that haloperidol was not
administered.
Figure 2 is a schematic representation of the ability of (S)-2-(benzylamino-
methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (agent) to induce
catalepsy in rats. The data are means SEM. As shown in the figure, there is
a lack
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of ability of the agent to induce significant catalepsy in rats over a dose
range of
0.003 to 3 mg/kg s.c. at 60 min post dosing. Similar results were observed at
the
other time points tested.
EXAMPLE 3
The ability to antagonize amphetamine-induced hyperlocomotion was
tested according to a modified version of the methods of Riffee and Wilcox,
Psychopharmacology, 1985, 85:97-101. Mice (25 - 30g) were transported from the
colony room to the experimental room and held there for the duration of the
experiment. The animals were habituated in the locomotor test chambers (an
open
field 8 X 8 in.) for 60 min prior to testing. Following the habituation
period,
d-amphetamine (2.5 mg/kg i.p., dissolved in distilled water) was administered
to all
animals. Fifteen minutes later, test compounds dissolved in 0.25% Tween 80
were
administered s.c. at 8 dose levels to 8 mice per dose level. Control groups,
assessed
simultaneously with drug-treated groups, received vehicle at equal volumes
(10 ml/kg). Immediately after administration of the test compound, animals
were
placed individually into the locomotor activity chambers. Activity was
monitored for
30 minutes with lights on using Omnitech Digiscan (Columbus, Ohio) infrared
monitors. Each infrared beam break was counted by the automated system and
totaled at 10 minute intervals. Horizontal activity counts collected between
10 and
20 min after the onset of the test session were subjected to a one-way
analysis of
variance followed by Student-Newman-Keuls test (p < 0.05) to determine doses
which were effective at antagonizing d-amphetamine-induced hyperlocomotion
relative to the vehicle-treated control group. Mean horizontal activity counts
were
analyzed by nonlinear regression followed by inverse prediction to calculate
the ED50
(dose producing 50% reduction in activity) and 95% confidence intervals (CI)
as well
as slope and minimum activity level.
Figure 3 is a schematic representation of the effect of (S)-2-(benzylamino-
methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (agent) to reverse
d-amphetamine induced hyperactivity in mice. The data are expressed as a
percentage of the activity level observed in mice treated with d-amphetamine
alone
and are presented as means + SEM. As shown in the figure, a dose-dependent
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decreased in d-amphetamine-induced hyperactivity was observed. An EDso of
0.002
mg/kg was calculated from these results.
Thus, compositions of the present invention reduce side effects induced by
haloperidol as modeled by catelepsy, while not diminishing the ability of
haloperidol
to treat positive symptoms of schizophrenia as modeled by the amphetamine-
induced
hyperactivity.
