Note: Descriptions are shown in the official language in which they were submitted.
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THERAPY FOR PSYCHOSES COMBININB AN ATYPICAL ANTIPSYCHOTIC AND AN MGLU2/3
RECEPTOR AGONIST
COMBINATION THERAPY FOR TREATMENT OF PSYCHOSES
Field of the Invention
The present invention provides for a pharmaceutical composition and methods
for
treating a psychiatric disorder comprising the combination of a first
component which is
an atypical antipsychotic with a second component which is a mGlu2/3 receptor
agonist.
The present invention also provides for a pharmaceutical composition and
method of
treating a psychiatric disorder comprising the combination of a first
component which is
an atypical antipsychotic with a second component which is a compound which
allosterically enhances receptor activity for mGlu2 and/or mGlu3.
Background of the Invention
Psychoses are serious mental illnesses characterized by defective or lost
contact
with reality. Psychotic patients may also suffer hallucinations and delusions
as part of
their disease. Psychoses exact a tremendous emotional and economic toll on
patients,
their families, and society as a whole. While the mechanisms underlying these
diverse
disease states are poorly understood, recently discovered therapies are
offering new hope
2 0 for the treatment of psychotic patients. Progress in the treatment of
psychotic conditions
has been achieved through the introduction of new, atypical antipsychotic
agents.
While the overall profile of atypical antipsychotics (e.g. clozapine,
olanzapine) is
superior to that of traditional agents (e.g. haloperidol), these agents still
produce
2 5 significant side-effects (e.g. CNS depression, weight gain, sexual
dysfunction)
which reduce the patients compliance and ultimately leads to relapses of
illness and thus
negatively impacts the life-long course of this disease. Also atypicals only
minimally
reverse many aspects of this illness such as negative symptoms (e.g. mood and
affect,
cognitive dysfunction). The discovery of new agents which could be used in
combination
3 o with atypical drugs to enhance their effectiveness at lower doses and/or
increase their
overall effectiveness against negative symptoms would be a considerable
advance in the
medical treatment of schizophrenia.
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One approach to this problem is to design novel agents that modulate the
glutamate systems of the brain, as opposed to atypicals which target monoamine
systems
(dopamine, serotonin) (so called glutamate hypothesis of schizophrenia). As
discussed
below, the most accepted test for novel glutamatergic agents involves finding
drugs
which can reverse the actions of psychotomimetic agents such as phencyclidine
(PCP) in
animals. Schoepp D.D. and Marek G.J., Current Drug Targets - CNS and
Neurological
Disorders, 1:215-225 (2002); Moghaddam, B.; Adams, B.W. Sciefzce, 281, 1349
(1998).
PCP and PCP-like drugs (e.g. ketamine, MK-801) are non-competitive NMDA
receptor antagonists. Anis, N.A.; Berry, S.C.; Burton, N.R., Lodge, D. British
JouJ°hal of
Pharmacology, 1983, 79, 565. The glutamate hypothesis of schizophrenia is
supported
by the clinical observation that these compounds produce schizophrenia-like
symptoms in
volunteers and can worsen symptoms in people with schizophrenia. Halberstadt,
A.L.
Clinical NeuT°opharmacology, 1995, 18, 237; Krystal, J.H.; Belger, A.;
D'Souza, C.;
Anand, A.; Charney, D.S.; Aghajanian, G.I~.; Moghaddam, B.
Neuropsychophaf°macology, 1999, 22, S 143. In particular, PCP appears
to better model
schizophrenia in humans than other agents (such as amphetamine), including
producing
both positive and negative symptoms. The recognition that other classes of
NMDA
receptor antagonists such as amino acid competitive antagonists also produced
2 0 schizophrenia-like effects in humans has further supported the glutamate,
or NMDA
receptor hypofunction hypothesis of schizophrenia. Rockstroh, S.; Emre, M.;
Tarral, A.;
Pokorny, R. Psychopharmacology, 1996, 124, 261; Olney, J.W.; Farber, N.B.
Areh.
Gen. Psychiatry, 1995, 52; 998; Olney, J.W.; Farber, N.B.
Neuf°opsychopharmacology,
1995, 13, 355. In an attempt to translate this information into a useful
animal model,
2 5 many years of preclinical research on the actions of PCP and PCP-like
drugs have been
performed. Atypical antipsychotics have been shown to be active in the PCP
animal
model of schizophrenia, but are not fully effective in this model unless
higher doses
which produce significant side effects such as CNS depression or motor
performance
impairment. Cartmell, J.; Monn, J.A.; Schoepp, D.D. Jouf°rr.al
ofPhar~Tacology ahd
3 0 Experimental Thes°apeutics, 1999, 291, 161. These new atypical
antipsychotic agents,
therefore, while holding the promise of improving the lives of psychotic
patients
immeasurably, may not be sufficient to treat every psychotic patient.
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Summary of the Invention
The present invention provides a pharmaceutical composition which comprises a
first component which is an atypical antipsychotic, and a second component
which is a
mGlu2/3 receptor agonist.
The invention also provides a method for treating a patient suffering from or
susceptible to a psychiatric disorder, comprising administering to said
patient an amount
of a first component which is an atypical antipsychotic, in combination with
an amount of
a second component which is a mGlu2/3 receptor agonist.
The present invention also provides a pharmaceutical composition which
comprises a first component which is an atypical antipsychotic, and a second
component
which is an mGlu2 potentiator.
The present invention further provides for a method for treating a patient
suffering
from or susceptible to a psychiatric disorder, comprising administering to
said patient an
amount of a first component which is an atypical antipsychotic, in combination
with an
amount of a second component which is an mGlu2 potentiator.
Brief Description of Drawing
Figure 1 depicts the examination of the combination of a representative
atypical
antipsychotic, clozapine, and representative second component (1R,4S,SS,6S)-4-
[(2'S)-
(2'-Amino)-propionyl]amino-(2-sulfonylbicyclo[3.1.0]hexane)-4,6-dicarboxylic
acid
(LY404039), a mGlu2/3 agonist, for their ability to influence phencyclidine
(PCP)-
induced motor activations in rats, by using an automated behavioral system.
Figure 2 depicts the examination of the combination of a representative
atypical
3 0 antipsychotic, clozapine, and a representative second component 1R, 4R,
SS, 6R-4-
amino-(2-oxabicyclo [3.1.0]hexane)-4, 6-dicarboxylic acid (LY379268), a
mGlu2/3
receptor agonist, for their ability to influence phencyclidine (PCP)-induced
motor
activations in rats, by using an automated behavioral system.
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Figure 3 depicts the examination of the combination of a representative
atypical
antipsychotic, clozapine, and a representative second component (1S, 2R, 4S,
SS, 6S)-2-
amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY459477), a mGlu2/3
receptor agonist, for their ability to influence PCP-induced motor activations
in rats, by
using an automated behavioral system.
Figure 4 depicts the examination of the combination of a representative
atypical
antipsychotic, clozapine, and a representative second component (+) -2-amino
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a mGlu2/3 receptor
agonist, for
their ability to influence PCP-induced motor activations in rats, by using an
automated
behavioral system.
Figure 5 depicts the examination of the combination of a representative
atypical
antipsychotic, olanzapine, and a representative second component, LY404039, a
mGlu2/3
receptor agonist, for their ability to influence PCP-induced motor activations
in rats, by
using an automated behavioral system.
Figure 6 depicts the examination of the combination of a representative
atypical
antipsychotic, olanzapine, and a representative second component, LY379268, a
mGlu2/3
2 0 receptor agonist, for their ability to influence PGP-induced motor
activations in rats, by
using an automated behavioral system.
Figure 7 depicts the examination of the combination of a representative
atypical
antipsychotic, olanzapine, and a representative second component, LY459477, a
mGlu2/3
2 5 receptor agonist, for their ability to influence PCP-induced motor
activations, by using an
automated behavioral system.
Figure 8 depicts the examination of the combination of a representative
atypical
antipsychotic, olanzapine, and a representative second component, LY354740, a
mGlu2/3
3 0 receptor agonist, for their ability to influence PCP-induced motor
activations in rats, by
using an automated behavioral system.
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Detailed Description of the Invention
The Compounds
In the general expressions of the present invention, the first component is a
compound which acts as an atypical antipsychotic. The essential feature of an
atypical
antipsychotic is less acute extra pyramidal symptoms, especially dystonias,
associated
with therapy as compared to a typical antipsychotic such as haloperidol.
Clozapine, the
prototypical atypical antipsychotic, differs from the typical antipsychotics
with the
following characteristics: (1) greater efficacy in the treatment of overall
psychopathology
in patients with schizophrenia nonresponsive to typical antipsychotics; (2)
greater
efficacy in the treatment of negative symptoms of schizophrenia; and (3) less
frequent and
quantitatively smaller increases in serum prolactin concentrations associated
with therapy
(Beasley, et al., Neuropsychopharnaacology, 14(2), 111-123 , (1996)).
Clozapine, 8-
chloro-1-(4-methyl-1-piperazinyl)-SH-dibenzo[1,4]diazepine, is described in
U.S. Patent
No. 3,539,573. Atypical antipsychotics include, but are not limited to:
Olanzapine, 2-methyl-4-(4-methyl-1-piperazinyl)-lOH-thieno[2,3
b][1,5]benzodiazepine, is a known compound and is described in U.S. Patent No.
5,229,382 as being useful for the treatment of schizophrenia, schizophreniform
disorder,
2 0 acute mania, mild anxiety states, and psychosis as described and claimed
in U.S. Patent
No. 5,229,382; a polymorph form is disclosed in U.S.'Patent No. 5,736,541;
Risperidone, 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-2-
methyl-
6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, and its use in the
treatment of
psychotic diseases are described in U.S. Patent No. 4,804,663;
Sertindole, 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol=3-yl]-1-
piperidinyl]ethyl]imidazolidin-2-one, is described in U.S. Patent No.
4,710,500. Its use
in the treatment of schizophrenia is described in U.S. Patent Nos. 5,112,838
and
5,238,945. U.S. PatentNos. 4,710,500; 5,112,838; and 5,238,945;
Quetiapine, 5-[2-(4-dibenzo[b,fJ[1,4]thiazepin-11-yl-1-
3 0 piperazinyl)ethoxy]ethanol, and its activity in assays which demonstrate
utility in the
treatment of schizophrenia are described in U.S. Patent No. 4,879,288,
Quetiapine is
typically administered as its (E)-2-butenedioate (2:1) salt; and
Ziprasidone, 5-[2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-
1,3-
dihydro-2H-indol-2-one, is typically administered as the hydrochloride
monohydrate.
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The compound is described in U.S. Patent Nos. 4,831,031 and 5,312,925. Its
activity in
assays which demonstrate utility in the treatment of schizophrenia are
described in U.S.
Patent No. 4,831,031. Additional atypical antipsychotic agents may be
discovered
beyond those specifically mentioned here. Antipsychotics which may be
disclosed in the
future may form the first component of the present invention.
Similarly, when the invention is regarded in its broadest sense, the second
component compound is a compound which functions as a mGlu2/3 receptor
agonist.
The measurement of a compound's activity in that utility may be identified for
example
by using the following experiment.
The affinity of a test compound for metabotropic glutamate receptors may be
demonstrated by the selective displacement of [3H]-2S-2-amino-2-(1S,2S-2-
carboxycyclopropan-1-yl)-3-(xanth-9-yl) propionic acid ([3H]-LY341495) (17.5
Ci/mmol). The binding of [3H]-LY341495 is conducted with crude membranes from
cell
lines expressing human mGlu2 and mGlu3 receptors which are derived as
described by
Johnson B.G., et al., Nem°opha~macology, 38: 1519-1529 (1999).
The ability of a test compound to act as an agonist at negatively coupled cAmp-
2 0 linked metabotropic glutamate receptors may be measured using the
following method.
Cell lines stably expressing mGlu2, mGlu3 may be derived as previously
described in
Schoepp D.D. et al., Neus°ophaf°nZacology, 36:1-11 (1997); Wu S.
et al., Mol. B~aih Res.,
53:88-97 (1998). Cells were then cultured in DMEM supplemented with 5%
dialysed
foetal calf serum, 1mM glutamine,lmM sodium pyruvate, lOmM HEPES, SOug/ml 6418
2 5 and 0.2mg/ml hygromycin B. Confluent cultures were passaged weekly. The
cells used
for transfection we have referred to previously as "RGT" cells (for Rat
Glutamate
Transporter). Structure, expression, and functional analysis of Na+-dependent
glutamate/aspartate transporter from rat brain. Proc. Natl. Acad. Sci. U.S.A.
89: 10955-
10959), as a means to keep glutamate in the media to a minimum, thus
preventing
3 0 receptor desensitization and minimize activation by endogenously formed
glutamate.
Phosphoinositide hydrolysis assays may then be performed with mGlul a and
mGluSa receptors Schoepp D.D. et al., Neu~opharmacology, 36:1-11 (1997).
Transfected
cells may be seeded into 24 well culture plates at 2.5 x 105 cells per well in
medium
3 5 containing no added glutamine, and cultured at 37°C in a humidified
atmosphere of 5%
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COZ in air. After 24 hours, the cells were labelled with [3H]-inositol (4
~.Ci/ml) for
another 20 hours. Cells were washed in assay medium containing HEPES (1 OmM),
inositol (lOmM) and lithium chloride (lOmM). Antagonists (when tested) were
added to
the cell cultures 20 min prior to the addition of the agonist and then further
incubated in
the presence of agonist for 60 min. The reaction was terminated by replacing
the medium
with acetone:methanol (1:1) and the cultures incubated on ice for 20 min.
Separation of
the [3H]-inositol phosphates was carried out by Sep-Pak Accell Plus QMA ion
exchange
chromatography (Waters, Millipore Ltd., UI~). The [3H]-inositol monophosphate
(1NS
P 1 ) fraction was eluted with 0.1 M triethyl ammonium bicarbonate buffer and
radioactivity was measured by liquid scintillation counting.
Cyclic-AMP (CAMP) assays may be carried out for cells expressing
mGlu2,mGlu3, mGlu4, mGlu7 and mGlu8 receptors as described by Wu S. et al.,
Mol.
Brai~r Research, 53:88-97 (1998). Cells may be washed with Dulbecco's
phosphate
buffered saline (PBS) plus 3mM glucose and 500 mM isobutylmethylxanthine
(IBMX)
and preincubated for 30 min at 37 °C. Each well was then washed
followed by mGlu
receptor agonists and/or forskolin (15 ~.M final concentration for mGlu2 and
mGlu3, 1
~.M final concentration for mGlu4, mGlu7, and mGluB; 0.5 ml final volume per
well).
Cells may be incubated for 20 minutes at 37 °C and then terminated by
adding 6mM
2 0 EDTA solution (0.75 ml) to each well and placing the plate in a boiling
water bath.
Concentrations of cAMP may be determined by an Amersham [3H]-cAMP SPA kit.
Protein content in each well may be determined using the modified Bradford-
Pierce assay
(Pierce Chemicals, USA).
2 5 Using the above test, (+)-2-aminobicyclo [3.1.0]hexane-2,6-dicarboxylic
acid
(LY354740), was found to give the result shown in Table I below. Data in Table
1 is
available in Schoepp D.D. et al., Neurophafnnacology, 36:1-11 (1997).
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Table 1 - Summary of effects of LY354740 monohydrate on human cloned
metabotropic
glutamate receptor second messenger responses.
EC50 (nM) IC50 (nM)
Second Messenger MGIu receptor (A~,onist Activityl (Anta~-onist Activityl
Decrease forskolin- Group II clones
stimulated cAMP human mGlu2 5.1 ~ 0:3 ----
human mGlu3 24.3 ~ 0.5
Group III clones
human mGlu4 >100,000 >100,000
human mGlu7 >100,000 >100,000
human mGlu8 36,000 ~ 5,400 ----
Increase PI Hydrolysis Group I clones
human mGlul >100,000 >100,000
human mGluS >100,000 >100,000
Data are mean + S.E.M.
Many compounds, including those discussed at length below, have such activity,
and no doubt many more will be identified in the future. mGlu2/3 agonists and
l0 potentiators include, but are not limited to:
LY354740 is in clinical development as an mGlu2/3 agonist and was first taught
by U.S. Patent No. 5,750,566. Its use as an anxiolytic and psychiatric agent
was disclosed
in U.S. Patent Nos. 5,882,671 and 5,661,184, respectively. Intermediates
useful in
preparation were first disclosed in U.S. Patent No. 5,925,782. A process
useful for
preparing a Bicyclohexane derivative and intermediates was first disclosed in
U.S. Patent
No. 5,726,320;
LY459477, (1S,2R,4S,5S,6S)-2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-
dicarboxylic acid is also disclosed in U.S. Patent No. 5,958,960;
LY379268 and LY404039 are disclosed in U.S. Patent No. 5,688,826. The
2 0 preferred enantiomer for (1R,4S,5S,6S)-4-[(2'S)-(2'-Amino)-propionyl]amino-
(2-
sulfonylbicyclo[3.1.0]hexane)-4,6-dicarboxylic acid is 1R,4S,5S,6S-4-amino-2,2-
dioxo-
s
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21R, 4S, 5S, 6S - 4 - Amino-2,2-dioxo-2~,6-thia-bicyclo[3.1.0]hexane-4,6-
dicarboxylic
acid-thia-bicyclo[3.1.0]hexane-4,6-dicarboxyic acid;
compounds which interact with mGlu2 and/or mGlu3 to allosterically
enhance receptor activity are mGlu 2 receptor potentiators which include, but
are not
limited to, those disclosed in International Application Number
PCT/LJSO1/00643,
published on August 9, 2001;
furthermore, the present invention contemplates fluorinated compounds as
disclosed in International Application Nos. PCT/JP99/03984, PCT/JP99/00324,
and
PCT/JPO1/05550. See International Publication Nos. WO/0012464, WO/9938839, and
WO/0200605, respectively. For example, the present invention contemplates
1S,2R,5S,6S-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid;
1S,2R,4S,5S,6S-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic
acid;
1S,2R,3R,5S,6S-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; and
1S,2R,3S,5S,6S-2-amino-6-fluoro-3-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic
acid
and prodrugs, including peptidyl prodrugs, thereof;
peptidyl prodrug forms of mGlu2/3 agonists which include but are not limited
to
(1 S,2S,5R,6S)-2-[(2's)-(2'-amino)-propionyl]amino-bicyclo[3.1.0]hexane-2,6-
dicarboxylic acid hydrochloride salt disclosed in PCT Application Serial No
PCT/USO1/45866, filed December 21, 2001 and those disclosed in PCT/US02/00488,
2 0 filed on January 9, 2002. All of the patents and patent applications which
have been
mentioned above are used in comlection with the present invention. L-alanyl
prodrugs
thereof are preferred;
peptidyl prodrugs forms of mGlu2/3 receptor agonists which could further
encompass aspects of the instant invention are disclosed in EP Application No.
2 5 02380120.2 (US Application No. 60/415936) and EP Application No.
02380121.0 (US
Application No. 60/415937).
It will also be understood that while the use of a single atypical
antipsychotic as a
first component compound is preferred, combinations of two or more atypical
antipsy-
3 0 chotics may be used as a first component if necessary or desired.
Similarly, while the use
of a single mGlu2/3 agonist or mGlu2 potentiator as a second component
compound is
preferred, combinations of two or more mGlu2/3 agonists may be used as a
second
component if necessary or desired.
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While all combinations of first and second component compounds are useful and
valuable, certain combinations and methods of administration are particularly
valued and
are preferred.
Preferred combinations which include clozapine as a first component are:
Clozapine / LY379268;
Clozapine / LY404039;
Clozapine / LY459477;
Clozapine / LY354740;
Clozapine / (1S,2S,SR,6S)-2-[(2'S)-(2'Amino)-propionyl]amino-
bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride salt (oral); and
Clozapine /(1S,2R,4S,SS,6S)-4-[(2'S)-(2'-Amino)-propionyl]amino-(2-
fluorobicyclo[3.1.0]hexane)-2,6-dicarboxylic acid hydrochloride.
Preferred combinations which include olanzapine as a first component are:
Olanzapine / LY379268;
Olanzapine / LY404039;
Olanzapine / LY459477;
2 0 Olanzapine / LY354740;
Olanzapine /(1S,2S,SR,6S)-2-[(2's)-(2'-Amino)-propionyl]amino-
bicyclo[3..1.0]hexane-2,6-dicarboxylic acid hydrochloride salt (oral); and
Olanzapine /(1S,2R,4S,SS,6S)-2-[(2'S)-(2'-Amino)-propionyl]amino-(4-
fluorobicyclo[3.1.0]hexane)-2,6-dicarboxylic acid hydrochloride (oral).
In general, combinations and methods of treatment using clozapine or
olanzapine
as the first component are preferred. Furthermore, combinations and methods of
treatment using LY404039 as the second component are preferred.
3 0 Furthermore, in general, it will be understood that alternative
formulations to
deliver components of the instant invention, particular mGlu2/3 agonists, may
be
accomplished via prodrugs, particularly peptidyl prodrugs.
to
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It will be understood by the skilled reader that most or all of the compounds
used
in the present invention are capable of forming salts, and that the salt forms
of
pharmaceuticals are commonly used, often because they are more readily
crystallized and
purified than are the free bases. In all cases, the use of the pharmaceuticals
described
above as salts is contemplated in the description herein, and often is
preferred, and the
pharmaceutically acceptable salts of all of the compounds are included in the
names of
them.
Many of the compounds used in this invention are amines, and accordingly react
with any of a number of inorganic and organic acids to form pharmaceutically
acceptable
acid addition salts. Since some of the free amines of the compounds of this
invention are
typically oils at room temperature, it is preferable to convert the free
amines to their
pharmaceutically acceptable acid addition salts for ease of handling and
administration,
since the latter are routinely solid at room temperature. Acids commonly
employed to
form such salts are inorganic acids such as hydrochloric acid, hydrobromic
acid,
hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic
acids, such as p-
toluenesulfonic acid, methanesulfonic acid, oxalic acid, g-bromophenylsulfonic
acid,
carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the
like. Examples
of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate,
bisulfate,
2 0 sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate,
metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate,
decanoate,
caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate,
oxalate,
malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,
hexyne-
1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,
hydroxybenzoate,
2 5 methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate,
phenylpropionate,
phenylbutyrate, citrate, lactate, hydroxybutyrate, glycollate, tartrate,
methanesulfonate,
propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate
and the
like. Preferred pharmaceutically acceptable salts are those formed with
hydrochloric acid,
oxalic acid or fumaric acid.
Administration
The dosages of the drugs used in the present invention must, in the final
analysis,
be set by the physician in charge of the case, using knowledge of the drugs,
the properties
11
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of the drugs in combination as determined in clinical trials, and the
characteristics of the
patient, including diseases other than that for which the physician is
treating the patient.
General outlines of the dosages, and some preferred dosages, can and will be
provided
here. Dosage guidelines for some of the drugs will first be given separately;
in order to
create a guideline for any desired combination, one would choose the
guidelines for each
of the component drugs.
Olanzapine: from about 0.25 to 50 mg, once/day; preferred, from 1 to 30 mg,
once/day; and most preferably 1 to 25 mg once/day;
Clozapine: from about 12.5 to 900 mg daily; preferred, from about 150 to 450
mg
daily;
Risperidone: from about 0.25 to 16 mg daily; preferred from about 2-8 mg
daily;
Sertindole: from about .0001 to 1.0 mg/kg daily;
Quetiapine: from about 1.0 to 40 mg/kg given once daily or in divided doses;
Ziprasidone: from about 5 to 500 mg daily; preferred from about 50 to 100 mg
daily.
In more general terms, one would create a combination of the present invention
by
choosing a dosage of first and second component compounds according to the
spirit of the
2 0 above guideline.
The adjunctive therapy of the present invention is carned out by administering
a
first component together with the second component in any manner which
provides
effective levels of the compounds in the body at the same time. All of the
compounds
2 5 concerned are orally available and are normally administered orally, and
so oral
administration of the adjunctive combination is preferred. They may be
administered
together, in a single dosage form, or may be administered separately.
However, oral administration is not the only route or even the only preferred
3 0 route. For example, transdermal administration may be very desirable for
patients who
are forgetful or petulant about taking oral medicine. One of the drugs may be
administered by one route, such as oral, and the others may be administered by
the
transdermal, percutaneous, intravenous, intramuscular, intranasal or
intrarectal route, in
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particular circumstances. The route of administration may be varied in any
way, limited
by the physical properties of the drugs and the convenience of the patient and
the
caregiver.
The adjunctive combination may be administered as a single pharmaceutical
composition, and so pharmaceutical compositions incorporating both compounds
are
important embodiments of the present invention. Such compositions may take any
physical form which is pharmaceutically acceptable, but orally usable
pharmaceutical
compositions are particularly preferred. Such adjunctive pharmaceutical
compositions
contain an effective amount of each of the compounds, which effective amount
is related
to the daily dose of the compounds to be administered. Each adjunctive dosage
unit may
contain the daily doses of all compounds, or may contain a fraction of the
daily doses,
such as one-third of the doses. Alternatively, each dosage unit may contain
the entire
dose of one of the compounds, and a fraction of the dose of the other
compounds. In such
case, the patient would daily take one of the combination dosage units, and
one or more
units containing only the other compounds. The amounts of each drug to be
contained in
each dosage unit depends on the identity of the drugs chosen for the therapy,
and other
factors such as the indication for which the adjunctive therapy is being
given.
2 0 The inert ingredients and manner of formulation of the adjunctive
pharmaceutical
compositions are conventional, except for the presence of the combination of
the present
invention. The usual methods of formulation used in pharmaceutical science may
be used
here. All of the usual types of compositions may be used, including tablets,
chewable
tablets, capsules, solutions, parenteral solutions, intranasal sprays or
powders, troches,
2 5 suppositories, transdermal patches and suspensions. In general,
compositions contain
from about 0.5% to about 50% of the compounds in total, depending on the
desired doses
and the type of composition to be used. The amount of the compounds, however,
is best
defined as the effective amount, that is, the amount of each compound which
provides the
desired dose to the patient in need of such treatment. The activity of the
adjunctive
3 0 combinations do not depend on the nature of the composition, so the
compositions are
chosen and formulated solely for convenience and economy. Any of the
combinations
may be formulated in any desired form of composition. Some discussion of
different
compositions will be provided, followed by some typical formulations.
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Capsules are prepared by mixing the compound with a suitable diluent and
filling
the proper amount of the mixture in capsules. The usual diluents include inert
powdered
substances such as starch of many different kinds, powdered cellulose,
especially
crystalline and microcrystalline cellulose, sugars such as fructose, mannitol
and sucrose,
grain flours and similar edible powders.
Tablets are prepared by direct compression, by wet granulation, or by dry
granulation. Their formulations usually incorporate diluents, binders,
lubricants and
disintegrators as well as the compound. Typical diluents include, for example,
various
types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate,
inorganic salts
such as sodium chloride and powdered sugar. Powdered cellulose derivatives are
also
useful. Typical tablet binders are substances such as starch, gelatin and
sugars such as
lactose, fructose, glucose and the like. Natural and synthetic gums are also
convenient,
including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the
like.
Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
A lubricant is necessary in a tablet formulation to prevent the tablet and
punches
from sticking in the die. The lubricant is chosen from such slippery solids as
talc,
2 0 magnesium and calcium stearate, stearic acid and hydrogenated vegetable
oils.
Tablet disintegrators are substances which swell when wetted to break up the
tablet and release the compound. They include starches, clays, celluloses,
algins and
gums. More particularly, corn and potato starches, methylcellulose, agar,
bentonite, wood
2 5 cellulose, powdered natural sponge, cation-exchange resins, alginic acid,
guar gum, citrus
pulp and carboxymethylcellulose, for example, may be used, as well as sodium
lauryl
sulfate.
Enteric formulations are often used to protect an active ingredient from the
3 0 strongly acid contents of the stomach. Such formulations are created by
coating a solid
dosage form with a film of a polymer which is insoluble in acid enviromnents,
and
soluble in basic environments. Exemplary films are cellulose acetate
phthalate, polyvinyl
acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl
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methylcellulose acetate succinate. It is preferred to formulate duloxetine and
duloxetine-
containing combinations as enteric compositions, and even more preferred to
formulate
them as enteric pellets.
Tablets are often coated with sugar as a flavor and sealant. The compounds may
also be formulated as chewable tablets, by using large amounts of pleasant-
tasting
substances such as mannitol in the formulation, as is nowwell-established
practice.
Instantly dissolving tablet-like formulations are also now frequently used to
assure that
the patient consumes the dosage form, and to avoid the difficulty in
swallowing solid
objects that bothers some patients.
When it is desired to administer the combination as a suppository, the usual
bases
may be used. Cocoa butter is a traditional suppository base, which may be
modified by
addition of waxes to raise its melting point slightly. Water-miscible
suppository bases
comprising, particularly, polyethylene glycols of various molecular weights
are in wide
use, also.
Transdermal patches have become popular recently. Typically they comprise a
resinous composition in which the drugs will dissolve, or partially dissolve,
which is held
2 0 in contact with the skin by a film which protects the composition. Many
patents have
appeared in the field recently. Other, more complicated patch compositions are
also in
use, particularly those having a membrane pierced with innumerable pores
through which
the drugs are pumped by osmotic action.
2 5 Benefit of the Invention
The present invention provides the advantage of treatment of psychotic
conditions
and mild anxiety with the atypical antipsychotics with decreased drug related
side-effects
typically observed with such treatment, conferring a marked and unexpected
benefit on
the patient. The present invention furthermore provides a potentiation of the
increase in
3 0 the efficacy of a first atypical antipsychotic component compound, by
administration of a
second component compound.
The present invention is particularly suited for use in the treatment of
bipolar
disorders, mania (mixed state), schizoaffective disorders characterized by the
occurance
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of a depressive episode during the period of illness, and depression with
psychotic
features. Such disorders may often be resistant to treatment with an
antipsychotic alone.
The present invention also is useful for the treatment of premenstrual
syndrome
(PMS) and anorexia nervosa. Furthermore, the present invention is useful for
the
treatment of the aggression/violence which may be associated with certain
disorders.
These disorders include, but are not limited to, mania, schizophrenia,
schizoaffective
disorders, substance abuse, head injury, and mental retardation.
The term "psychiatric disorder" refers to both acute and chronic psychiatric
conditions, including schizophrenia, anxiety and related disorders (e.g. panic
attach and
stress-related cardiovascular disorders), depression (or depression in
combination with
psychotic episodes), bipolar disorders, psychosis, and obsessive compulsive
disorders.
Psychotic conditions to be treated by the present method of adjunctive therapy
include schizophrenia, schizophreniform diseases, acute mania, schizoaffective
disorders,
and depression with psychotic features. The titles given these conditions
represent
multiple disease states. The following list illustrates a number of these
disease states,
many of which are classified in the Diagnostic and Statistical Manual of
Mental
2 0 Disorders, 4th Edition, published by the American Psychiatric Association
(DSM). The
DSM code numbers for these disease states are supplied below, when available,
for the
convenience of the reader.
Paranoid Type Schizophrenia 295.30
2 5 Disorganized Type Schizophrenia 295.10
Catatonic Type Schizophrenia 295.20
Undifferentiated Type Schizophrenia 295.90
Residual Type Schizophrenia 295.60
Schizophreniform Disorder 295.40
3 0 Schizoaffective Disorder 295.70
Schizoaffective Disorder of the Depressive Type
Major Depressive Disorder with Psychotic Features 296.24, 296.34
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Psychoses are often associated with other diseases and conditions, or caused
by
such other conditions. For example, they are associated with neurological
conditions,
endocrine conditions, metabolic conditions, fluid or electrolyte imbalances,
hepatic or
renal diseases, and autoimmune disorders with central nervous system
involvement.
Psychoses may also be associated with use or abuse of certain substances.
These
substances include, but are not limited to cocaine, methylphenidate,
dexmethasone,
amphetamine and related substances, cannabis, hallucinogens, inhalants,
opioids,
phencyclidine, sedatives, hypnotics and anxiolytics. Psychotic disorders may
also occur
in association with withdrawal from certain substances. These substances
include, but are
not limited to, sedatives, hypnotics and anxiolytics. The embodiments of the
present
invention are useful for treatment of psychotic conditions associated with any
of these
conditions.
As used herein, the term "effective amount" refers to the amount or dose of
the
compounds, upon single or multiple dose administration to the patient, which
provides
the desired effect in the patient under diagnosis or treatment.
An effective amount can be readily determined by the attending diagnostician,
as
one skilled in the art, by the use of known techniques and by observing
results obtained
2 0 under analogous circumstances. In determining the effective amount or dose
of
compounds administered, a number of factors are considered by the attending
diagnostician, including, but not limited to: the species of mammal; its size,
age, and
general health; the specific disease involved; the degree of or involvement or
the severity
of the disease; the response of the individual patient; the particular
compound
2 5 administered; the mode of administration; the bioavailability
characteristics of the
preparation administered; the dose regimen selected; the use of concomitant
medication;
and other relevant circumstances. For example, a typical daily dose may
contain from
about 25 mg to about 300 mg of the active ingredients. The compounds can be
administered by a variety of routes, including oral, rectal, transdermal,
subcutaneous,
3 0 intravenous, intramuscular, bucal or intranasal routes. Alternatively, the
compounds may
be administered by continuous infusion.
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As used herein the term "patient" refers to a mammal, such as a mouse, guinea
pig, rat, dog or human. It is understood that the preferred patient is a
human.
The term "treating" (or "treat") as used herein includes its generally
accepted
meaning which encompasses prohibiting, preventing, restraining, and slowing,
stopping,
or reversing progression of a resultant symptom. As such, the methods of this
invention
encompass both therapeutic and prophylactic administration.
In this document, all temperatures are described in degrees Celsius, and all
amounts, ratios of amounts and concentrations are described in weight units
unless
otherwise stated.
Examples
The following examples are submitted for illustrative purposes only and should
not be interpreted as limiting the invention in any way. A person of ordinary
skill, with
knowledge of this invention and of the prior art, will readily think of other
subjects, other
dysfunctions, and other glutamatergic substances that are readily substituted
in the
following examples. Also, the patents and publications cited in this
disclosure refect the
level of skill the art to which this invention pertains, and are herein
individually
2 0 incorporated by reference to the extent that they supplement, explain,
provide a
background for or teach methodology, techniques and/or compositions employed
herein.
Those of skill in the art will readily appreciate that the foregoing protocol
can be used,
with only minor modifications, to prepare the other compounds of the present
invention.
2 5 Example 1
Synergy between mGlu2/3 receptor agonist and atypical antipsychotic in an
animal model of schizophrenia.
PCP induction of motor ambulation is a well known and widely used animal
3 0 model of schizophrenia. The logic for this is based primarily on two
related sets of
findings:
1) PCP abuse in humans is known to provoke psychotic symptoms such as
increased motor behaviors, stereotypic and cognitive disruptions; and
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WO 03/084610 PCT/US03/07283
2) Antipsychotic drugs that are effective in the treatment of human
schizophrenia are also known to attenuate stereotypic behaviors
induced in rats by PCP.
Finding No. (2) indicates that PCP-induced behaviors in rates are a useful
model
for screening potential anti-schizophrenic drugs: Published authority for the
use and
reliability of this model is found in: Savitt et al., Recent Advances in the
Phencyclidine
Model of Schizophrenia, Am. J. Psychiatry, 148, 1301-1308 (1991); Halberstadt
Al, The
phencyclidine-glutamate Model of Schizophrenia, Clip. Nem°opharmacol.,
18, 237-249
(1995); Steinpries R.E., Behaviorial Brain Res., 74, 45-55 (1996).
In the present experiments, studies were performed in accordance with Eli
Lilly
and Company animal care and use policies. Male Sprague-Dawley rats (250-300 g)
were
group-housed (maximum of seven rats per cage) under standard laboratory
conditions
with ad libitum access to food and water (12 h light/dark cycle), for at least
1 day before
use.
Activity Assessment compounds were tested against PCP-induced motor
activation (ambulations) in rats. Behavioral parameters were monitored in
transparent,
2 0 shoe-box cages that measured 45 x 25 x 20 cm, with a 1 cm depth of wood
chips on the
cage floor and a metal grill on top of the cage. Rectangular photocell
monitors (Hamilton
Kinder, Poway, CA) with a bank of 12 photocell beams (8 x 4 formation)
surrounded
each test cage. A lower rack of photocell beams was positioned 5 cm above the
cage
floor to enable detection of the location of the animals body, while an upper
bank
2 5 positioned 10 cm above the first tabulated rearing activity. Ambulations
(locomotor
activity) and rearing were recorded by the computer and stored for each test
session as
discussed in Male Sprague-Dawley rats were generally food-fasted 12-18 hours
prior to
the experiment. In some experiments, rats were allowed food and water ad
libitum prior
to the experiment. On the~test day animals were placed in the test cage for a
30 min
3 0 habituation period before to testing to allow for acclimation to the test
cage environment.
Following this habituation period, animals were administered challenges of
phencyclidine
(PCP) (5 mg/kg s.c.) or 0.9% NaCI vehicle (1 ml/kg) and behavioral assessment
began
immediately following their administration. Animals were monitored over a 60
min
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WO 03/084610 PCT/US03/07283
period in all instances. Test drugs or vehicle were administered at various
pretreatment
times prior to the PCP challenge. Cartmell J., J. Pharmaeol. Exp. Tlz.er. 291:
161-170
(1999) and Cartmell J., Naunyn-Schmiedebefg's Af~chives Pha~°macology
361: 39-46
(2000).
Statistical analysis. Statistical Analysis were carried out using the GraphPad
PRISM statistical/graphing package (GraphPad, SanDiego, CA). Data were
analyzed
using a one-way analysis of variance (ANOVA) and post-hoc comparisons were
performed using Dmmett's multiple comparisons test.
Materials. PCP was obtained from Sigma (St. Louis, MO). Clozapine was
purchased from Research Biochemicals International (Natick, MA). MGlu2/3
receptor
agonists were synthesized as described U.S. Patent Nos. 5,958,960 (LY459477)
and
5,688,826 (LY404039).
The rats were tested 30 minutes post-injection of the test compound or
vehicle.
Behaviors were monitored over a 60 minute time period following S.C. injection
of PCP
or vehicle. Data (mean + S.E.) are presented as the total number of behaviors
expressed
during the timer period. P < 0.05, when compared to the corresponding vehicle.
,
As shown in Figure 1, there was a large induction of motor ambulations by
5 mg/kg PCP (S.C.) (II), compared to the vehicle (I). Clozapine (3 mg/kg) had
a
relatively small impact on PCP-induced ambulations (III), while the selected
mGlu2/3
receptor agonist, LY404039 at 1 mg/kg had statistically insignificant effect
on PCP-
2 5 induced ambulations (1V). However, together clozapine (3 mglkg) and
LY404039
(1 mg/kg) (V) produced a synergistic interaction, reducing PCP-induced
ambulations to a
level even less than that of clozapine alone at 10 mg/kg (VI).
Further, as shown in Figure 2, there was a large induction of motor
ambulations
3 0 by 5 mg/kg PCP (S.C.) (II), compared to the vehicle (I). Clozapine (3
mg/kg) had a
relatively small impact on PCP-induced ambulations (III), while the selected
mGlu2/3
receptor agonist LY379268 at 1 mg/kg had a smaller and statistically
insignificant effect
on PCP-indused ambulations (1V). However, together clozapine (3 mg/kg) and
CA 02478227 2004-09-03
WO 03/084610 PCT/US03/07283
LY379268 (1 mg/kg)(V) produced a synergistic interaction, reducing PCP-induced
ambulations to a level even less than that of clozapine alone at 10 mg/kg
(VI).
Figure 3 shows there was a large induction of motor ambulations by 5 mg/lcg
PCP
(S.C.) (II), compared to the vehicle (I). The selected mGlu2/3 receptor
agonist,
LY459477, at 1 mg/kg had a relatively small impact on PCP-induced ambulations
(III),
while clozapine (1 mg/kg) had a statistically insignificant effect on PCP-
induced
ambulations (IV). However, together clozapine (lmg/kg) and LY459477 (1
mg/kg)(V)
produced a synergistic interaction, reducing PCP-induced ambulations to a
level even less
than that of clozapine alone at 10 mg/kg (VI).
Figure 4 shows there was a large induction of motor ambulations by 5 mgllcg
PCP
(S.C.) (II), compared to the vehicle (I). Clozapine (3 mg/kg) had a
significant impact on
PCP-induced ambulations (III), while the selected mGlu2/3 receptor agonist,
LY354740,
at 10 mg/kg had a statistically insignificant effect on PCP-induced
ambulations (IV).
However, together clozapine (3 mg/kg) and LY354740 (10 mg/kg)(V) produced a
synergistic interaction, reducing PCP-induced ambulations to a level even less
than that
of clozapine alone at 10 mg/kg (VI).
2 0 As shown in Figure 5, there was a large induction of motor ambulations by
5
mg/kg PCP (S.C.) (II), compared to the vehicle (I). Olanzapine (1 mg/kg) had a
significant impact on PCP-induced ambulations (II), and the selected mGlu2/3
receptor
agonist, LY404039 at 1 mg/kg had statistically significant effect on PCP-
induced
ambulations (IV) as well. Together olanzapine (1 mg/kg) and LY 404039 (1
mg/kg) (V)
2 5 produced a s5mergistic interaction, reducing PCP-induced ambulations to a
level
comparable that of olanzapine alone at 3 mg/kg (II).
As shown in Figure 6, there was a large induction of motor ambulations by 5
mg/kg PCP (S.C.) (II), compared to the vehicle (I). Olanzapine (1 mg/kg) had a
3 0 significant impact on PCP-induced ambulations (III), and the selected
mGlu2/3 receptor
agonist, LY379268 at 1 mglkg had a tatistically insignificant effect on PCP-
induced
ambulations (IV) as well. Together olanzapine (1 mg/kg) and LY379268 (1 mglkg)
(V)
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WO 03/084610 PCT/US03/07283
produced a synergistic interaction, reducing PCP-induced ambulations to a
level.
comparable that of olanzapine alone at 3 mg/kg (VI).
As shown in Figure 7, shows a large induction of motor ambulations by 5 mg/kg
PCP (S.C.) (II), compared to the vehicle (I). Olanzapine (1 mg/kg) had a
significant
impact on PCP-induced ambulations (III), and the selected mGlu2/3 receptor
agonist,
LY459477 at 1 mglkg had a statistically insignificant effect on PCP-induced
ambulations
(IV) as well. Together olanzapine (1 mg/kg) and LY459477 mGlu2/3 receptor
agonist
(1 mglkg) (V) produced a synergistic interaction, reducing PCP-induced
ambulations to a
level comparable that of olanzapine alone at 3 mg/kg (VI).
As shown in Figure 8, there was a large induction of motor ambulations by
5 mg/kg PCP (S.C.) (II), compared to the vehicle (I). Olanzapine (1 mg/kg) had
minimal
impact on PCP-induced ambulations (III), and the selected mGlu2/3 receptor
agonist,
LY354740 at 10 mg/kg had a statistically insignificant effect on PCP-induced
ambulations (IV) as well. Together olanzapine (1 mg/kg) and LY354740 mGlu2/3
receptor agonist (10 mg/kg) (V) produced a synergistic interaction, reducing
PCP-induced
ambulations to a level comparable that of olanzapine alone at 3 mg/kg (VI).
2 0 The present invention therefore provides an improved method of treatment
of
psychosis via decreasing the side effects of an atypical antipsychotic at
efficacious doses.
Example 2
A first step in treating humans is generally determining that a particular
patient
2 5 exhibits the symptoms of a psychotic behaviour such as Schizophrenia or
Schizophreniform Disorder or Schizoaffective Disorder or Delusional Disorder
or Brief
Psychotic Disorder or Psychotic Disorder Due to a General Medical Condition or
Psychotic Disorder Not Otherwise Specified. This determination is made by a
person
skilled in the art using a number of readily available diagnostic procedures.
In general,
3 0 the presence of typical DSMIV psychotic dysfunctions in humans can be
ascertained via
observation, diagnosis, family history, questionnaires or interviews. The
success of
treatment is measured by monitoring and recording the abatement of the
symptoms of the
treated behavioral disorder.
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In addition, the present invention provides for kits with unit doses of
mGlu2/3
receptor agonists and an atypical antipsychotic either in oral or injectable
doses. In
addition to the containers containing the unit doses will be a informational
package insert
describing the use and attendant benefits of the cli-ugs in treating
psychiatric disorders.
Preferred combinations and unit doses include those described herein above.
23
