Note: Descriptions are shown in the official language in which they were submitted.
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NOVEL PHARMACEUTICAL COMPOSITION FOR TREATMENT OF
SCHIZOPHRENIA
FIELD OF THE INVENTION
[0001]
The present invention relates to a novel
pharmaceutical use of BEC1 potassium channel inhibitor as
an agent for treating schizophrenia.
BACKGROUND OF THE INVENTION
[0002]
Schizophrenia is one of major mental disorders, is a
disease with poor prognosis, and has a relatively high
lifetime prevalence, as high as 0.7 to 2.0% (PLoS Med.
2:413-433, 2005, herein incorporated by reference). The
symptoms of schizophrenia are classified into positive
symptoms, negative symptoms, cognitive impairments and mood
disorder. The treatment of schizophrenia utilizes
psychotherapy, occupational therapy and pharmacotherapy.
Among these, pharmacotherapy achieves an important role.
However, schizophrenic patients still suffer from the
problems of the disease becoming recurrent, chronic and
incurable, or of tardive dyskinesia or extrapyramidal
adverse side effects of antipsychotics.
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[0003]
In the pharmacotherapy for schizophrenia,
antipsychotics are primarily used. The antipsychotics may
be classified into first generation antipsychotics and
second generation antipsychotics. The first generation
antipsychotics are central dopamine receptor antagonists,
and particularly dopamine D2 receptor antagonists.
Specifically, chlorpromazine, haloperidol, bromperidol,
perphenazine and the like may be mentioned. On the other
hand, the second generation antipsychotics include those
having additional blocking action against serotonin
receptors in addition to that against dopamine D2 receptors
(risperidone, perospirone, ziprasidone, and the like), or
those having additional blocking action against many other
receptors (clozapine, olanzapine, and the like), those
acting as partial agonists for dopamine D2 receptors
(aripiprazole and the like), and the like. For any of
those antipsychotics, the improving effects are considered
to be still insufficient, and emergence of adverse side
effects based on the dopamine receptor blocking action has
become a problem (Japanese Journal of Clinical
Psychopharmacology, 11:1089-1011, 2008, herein incorporated
by reference).
[0004]
Potassium channels are proteins which are present in
the plasma membrane of cells and selectively pass potassium
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ions, and are conceived to be in charge of an important
role for the control of membrane potential in cells. In
particular, the potassium channels contribute to the
neurotransmission of central and peripheral nerves, heart
pace-making, contraction of muscles, and the like, by
regulating the frequency, durability and the like of the
action potential in neurons and muscle cells.
[0005]
When the channels are classified based on the
opening-closing mechanism, voltage-dependent potassium
channels, inwardly rectifying potassium channels, calcium-
dependent potassium channels, receptor coupled potassium
channels, and the like have been identified hitherto.
Among these, the voltage-dependent potassium channels have
a characteristic of being opened when the membrane
potential is depolarized. Typically, potassium ions exist
in a non-equilibrium state of about 5 mM in the
extracellular moiety and about 150 mM in the intracellular
moiety. For this reason, when the voltage-dependent
potassium channels open due to depolarization, potassium
ions are discharged from the intracellular part to the
extracellular part, and consequently induce recovery
(repolarization) of the membrane potential. Therefore, a
decrease in the excitability of neurons and muscle cells is
induced, concomitantly with the opening of the voltage-
dependent channels (Ionic Channels of Excited Membranes,
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Sinauer Associates, Sunderland, 1992, herein incorporated
by reference).
[0006]
A compound modifying the opening of the voltage-
dependent channels regulates various physiological
phenomena by regulating the excitability of neurons, muscle
cells and the like, and also has a possibility of serving
as a therapeutic drug for various diseases. For example,
4-aminopyridine which is an inhibitor of A-type voltage-
dependent potassium channels found in nerve cells, is known
to induce epilepsy by increasing the nerve excitability
(Epilepsy Res. 11:9-16, 2002, herein incorporated by
reference). Furthermore, dofetilide which is an inhibitor
of hERG potassium channels expressed in the heart among the
voltage-dependent potassium channels, is used as a drug for
treatment arrhythmia based on the controlling of the
excitability of myocardial cells (J. Pharmacol. Exp. Ther.
256:318-324, 1991, herein incorporated by reference).
[0007]
The potassium channel as set forth in SEQ ID NO:2 in
Example 1 of U.S. Patent No. 6,326,168 (hereinafter,
indicated as BEC1 or BEC1 potassium channel) is a voltage-
dependent potassium channel showing a distribution of
expression localized in the brain (U.S. Patent No.
6,326,168 is herein incorporated by reference). Expression
of this channel is conspicuous in the hippocampus or the
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cerebral cortex. The hippocampus and cerebral cortex are
regions suggested to be strongly associated with learning
and memory (The Neuron: Cell and Molecular Biology, Oxford
University Press, New York, NY, 1991, herein incorporated
by reference).
From this, there is conceived a possibility that the
BEC1 potassium channel is associated with learning and
memory. In fact, it was revealed with regard to a
transgenic mouse having the BEC1 channel described in U.S.
Patent No. 7,375,222 highly expressed in the hippocampus
and the cerebral cortex, that the mouse has a decreased
learning ability in the Morris water maze learning test and
the passive avoidance learning test (U.S. Patent No.
7,375,222 is herein incorporated by reference). From this
fact, it is conceived that an inhibitor of BEC1 potassium
channel enhances learning and memory, and thus is
considered to be highly promising as a therapeutic drug for
dementia.
[0008]
A number of potassium channel inhibitors have been
reported hitherto, but the compounds reported to inhibit
BEC1 potassium channel are only the 2,4,6-triamino-1,3,5-
triazine derivatives described in U.S. Patent No.
7,375,222, herein incorporated by reference. Furthermore,
it is disclosed in WO 2002/050066 that certain types of
1,3,5-triazine-2,4,6-triamine derivatives have protein
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kinase inhibitory activity and are useful as agents for
treating Alzheimer's disease or Parkinson's disease (WO
2002/050066 is herein incorporated by reference) . However,
there is no report to date on a finding suggesting that the
BEC1 channel inhibitors show usefulness for diseases other
than dementia, for example, schizophrenia.
SUMMARY OF THE INVENTION
[0009]
An object of the present invention is to provide a
therapeutic agent for schizophrenia having a novel
mechanism of action which is different from conventional
antipsychotics.
[0010]
In order to achieve the above-mentioned object, the
inventors of the present invention conducted research based
on a unique idea, and found that BEC1 potassium channel
inhibitors exhibit a remarkable therapeutic effect on
schizophrenia, thus completing the present invention.
[0011]
According to an aspect of the present invention,
there is provided a pharmaceutical composition for
prevention and/or treatment of schizophrenia, containing an
effective amount of a BEC1 potassium channel inhibitor or a
pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
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According to another aspect of the present invention,
there is provided a prophylactic agent and/or therapeutic
agent for schizophrenia, containing a BEC1 potassium
channel inhibitor or a pharmaceutically acceptable salt
thereof as an active ingredient.
According to another aspect of the present invention,
there is provided a BEC1 potassium channel inhibitor or a
pharmaceutically acceptable salt thereof for the prevention
and/or treatment of schizophrenia.
According to still another aspect of the present
invention, there is provided a use of a BEC1 potassium
channel inhibitor or a pharmaceutically acceptable salt
thereof for the manufacture of a medicament for treating
schizophrenia.
According to still another aspect of the present
invention, there is provided a method of treating
schizophrenia, comprising administering an effective amount
of a BEC1 potassium channel inhibitor or a pharmaceutically
acceptable salt thereof.
According to still another aspect of the present
invention, there is provided a method for preparing a
pharmaceutical composition for treating schizophrenia, the
method comprising mixing a BEC1 potassium channel inhibitor
or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient.
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According to still another aspect of the present
invention, there is provided a commercial package
comprising a pharmaceutical composition comprising a BEC1
potassium channel inhibitor or a pharmaceutically
acceptable salt thereof as an active ingredient, and an
instruction describing that the BEC1 potassium channel
inhibitor or a pharmaceutically acceptable salt thereof can
be used or should be used to treat schizophrenia.
[0012]
The present invention is useful in providing an
excellent prophylactic agent and/or therapeutic agent for
schizophrenia. The present invention is also particularly
useful in providing a prophylactic agent and/or therapeutic
agent for positive symptoms (hallucinations, delusions,
xenopathic experiences, disorganized speech, highly
disorganized or catatonic behavior, and the like), negative
symptoms (affective flattening, poverty of thinking,
apathy, autism, anhedonia, and the like), cognitive
impairments, mood disorder (depression, anxiety, and the
like) or the like associated with schizophrenia.
DETAILED DESCRIPTION OF THE INVENTION
[0013]
Preferred embodiments of the present invention will
be presented in the following.
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(1) A pharmaceutical composition for prevention
and/or treatment of schizophrenia, containing an effective
amount of a compound of formula (I):
R 1 2
R 3 ~N~R
Rs
R4 NI \ N R6
NN~N
H H (I)
wherein the symbols are as follows.
R1 and R2, which may be the same or different, each
represents H, OH, lower alkyl-O-, aryl-CO-, NH2, lower
alkyl-NH which may be substituted with OH, (lower alkyl)2N,
a lower alkyl which may be substituted, or a heterocyclic
group which may be substituted; and
R3, R4, R5 and R6, which may be the same or different,
each represents (i) H, (ii) ON, (iii) NO2, (iv) halogen,
(v) lower alkyl which may be substituted with'(1) ON, (2)
halogen, or (3) OH, (vi) cycloalkyl, (vii) aryl which may
be substituted with lower alkyl, (viii) a heterocyclic
group which may be substituted with lower alkyl, (ix)
R7R8N- (wherein R7 and R8 may be the same or different, and
each represents (1) H, (2) aryl, or (3) lower alkyl which
may be substituted with R9-O-CO- (wherein R9 represents (1)
H, or (2) lower alkyl which may be substituted with aryl)),
(x) R10-T1- (wherein R10 represents (1) H, (2) lower alkyl
which may be substituted with aryl, HO-C1-10 alkylene-0- or
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OH, or (3) aryl; and T' represents 0 or S) , or (xi) R11-T2-
(wherein R11 represents (1) OH, (2) R7R8N-, (3) lower alkyl-
0-, (4) lower alkyl, (5) aryl, or (6) a heterocyclic group;
and T2 represents CO or SO2),
or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
(2) The pharmaceutical composition according to (1),
wherein R1 and R2, which may be the same or different, each
represents H, or lower alkyl which may be substituted with
a heterocyclic group which may be substituted; and R3, R4,
R5 and R6, which may be the same or different, each
represents (i) H, (ii) halogen, or (iii) R10-T1- (wherein
R10 represents lower alkyl, and T1 represents 0).
[0014]
(3) The pharmaceutical composition according to (1)
or (2), wherein R1 and R2, which may be the same or
different, each represents H, or lower alkyl which may be
substituted with a heterocyclic group selected from
pyrimidine and pyridine, which may be substituted with a
substituent selected from the group consisting of halogen,
lower alkyl and lower alkyl-O-.
[0015]
(4) The pharmaceutical composition according to (1)
to (3), wherein R1 represents H; and R2 represents lower
alkyl substituted with a heterocyclic group selected from
pyrimidine and pyridine, which may be substituted with a
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substituent selected from the group consisting of halogen,
lower alkyl and lower alkyl-O-; R3 and R6 each represents
H; and R4 and R5, which may be the same or different, each
represents (i) H, (ii) halogen, or (iii) R10-T1- (wherein
R10 represents lower alkyl; and T' represents 0).
(5) The pharmaceutical composition according to (1)
to (4), wherein R1 represents H; R2 represents lower alkyl
substituted with pyrimidine which may be substituted with a
substituent selected from the group consisting of halogen,
lower alkyl and lower alkyl-O-; R3 and R6 each represents
H; and R4 and R5, which may be the same or different, each
represents (i) H, (ii) halogen, or (iii) R10-T1- (wherein
R10 represents lower alkyl; and T1 represents 0).
(6) The pharmaceutical composition according to (1)
to (4), wherein R1 represents H; R2 represents lower alkyl
substituted with pyridine which may be substituted with a
substituent selected from the group consisting of halogen,
lower alkyl and lower alkyl-O-; R3 and R6 each represents
H; and R4 and R5, which may be the same or different, each
represents (i) H, (ii) halogen, or (iii) R10-T1- (wherein
R10 represents lower alkyl; and T' represents 0).
(7) The pharmaceutical composition according to (1)
to (6), wherein the schizophrenia is selected from the
group consisting of positive symptoms associated with
schizophrenia (hallucinations, delusions, xenopathic
experiences, disorganized speech, highly disorganized or
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catatonic behavior, and the like), negative symptoms
associated with schizophrenia (affective flattening,
poverty of thinking, apathy, autism, anhedonia, and the
like), cognitive impairments associated with schizophrenia,
and mood disorder associated with schizophrenia
(depression, anxiety, and the like).
[0016]
As for specific compounds of the formula (I) included
in the present invention, the following compounds may be
mentioned.
N-(4-fluorophenyl)-N'-phenyl-N"-(pyrimidin-2-
ylmethyl)-1,3,5-triazine-2,4,6-triamine, N,N'-bis(4-
fluorophenyl)-N"-(pyrimidin-2-ylmethyl)-1,3,5-triazine-
2,4,6-triamine, N-(4-fluorophenyl)-N'-(4-methoxyphenyl)-N"-
(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-tiramine, N,N'-
bis(4-fluorophenyl)-N"-(pyrimidin-4-ylmethyl)-1,3,5-
triazine-2,4,6-triamine, or N-(4-fluorophenyl)-N'-[(2-
fluoro-4-pyridyl)methyl]-N"-phenyl-1,3,5-triazine-2,4,6-
triamine.
[0017]
In regard to the above or following descriptions of
the present specification, appropriate examples of various
definitions included in the scope of the present invention
will be described in detail as follows.
[0018]
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The term "lower alkyl" means linear or branched alkyl
having 1 to 6 carbon atoms (hereinafter, abbreviated to C1-
6), and includes, for example, methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-
pentyl, n-hexyl groups and the like. In another
embodiment, the lower alkyl is C1-4 alkyl, and in still
another embodiment, the lower alkyl is methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or
hexyl.
[0019]
The term "halogen" means F, Cl, Br, or I.
[0020]
The term "co 1-1alkylene" means linear or branched C1-
to alkylene, and includes, for example, methylene,
ethylene, trimethylene, tetramethylene, pentamethylene,
hexamethylene, heptamethylene, octamethylene,
nonamethylene, decamethylene, propylene, methylmethylene,
ethylethylene, 1,2-dimethylethylene, 1,1,2,2-
tetramethylethylene group, and the like.
[0021]
The term "cycloalkyl" means a C3-10 saturated
hydrocarbon cyclic group, and may be bridged. The
cycloalkyl includes, for example, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl
groups, and the like. In another embodiment, the
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cycloalkyl is C3_B cycloalkyl, and in still another
embodiment, the cycloalkyl is C3-6 cycloalkyl.
[0022]
The term "aryl" means a C6-14 monocyclic to tricyclic
aromatic hydrocarbon cyclic group, and includes, for
example, phenyl and naphthyl. In another embodiment, the
aryl is phenyl.
[0023]
The term "heterocyclic" group means a 3- to 15-
membered, in another embodiment, 5- to 10-membered,
monocyclic to tricyclic heterocyclic group containing 1 to
4 heteroatoms selected from oxygen, sulfur and nitrogen,
and includes a saturated cyclic group, an aromatic cyclic
group, and a partially hydrogenated cyclic group. The
sulfur or nitrogen atom, both of which are ring atoms, may
be oxidized to form oxide or dioxide. Specific examples
include monocyclic heteroaryl such as pyridyl, pyrrolyl,
pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl,
triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl,
oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl,
or furyl; bicyclic heteroaryl such as indolyl, isoindolyl,
benzimidazolyl, indazolyl, quinolyl, isoquinolyl,
quinazolinyl, quinoxalinyl, phthalazinyl, benzothiazolyl,
benzisothiazolyl, benzothiadiazolyl, benzoxazolyl,
benzisoxazolyl, benzofuranyl or benzothienyl; tricyclic
heteroaryl such as carbazolyl, dibenzo[b,d]furanyl, or
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dibenzo[b,d]thienyl; non-aromatic monocyclic heterocyclic
ring such as azetidinyl, pyrrolidinyl, piperidyl,
piperazinyl, azepanyl, diazepanyl, morpholinyl,
thiomorpholinyl, tetrahydropyridinyl, oxetanyl,
tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, dioxanyl,
or tetrahydrothiopyranyl; non-aromatic bicyclic
heterocyclic ring such as indolinyl, tetrahydroquinolyl,
tetrahydroisoquinolyl, dihydrobenzimidazolyl,
tetrahydrobenzimidazolyl, tetrahydroquinoxalinyl,
dihydroquinoxalinyl, dihydrobenzoxazolyl,
dihydrobenzoxazinyl, dihydrobenzofuryl, chromanyl,
chromenyl, methylenedioxyphenyl, or ethylenedioxyphenyl;
bridged heterocyclic rings such as quinuclidinyl; and the
like. In another embodiment, the heterocyclic group is a
5- to 10-membered monocyclic or bicyclic heterocyclic
group, and in still another embodiment, the heterocyclic
group is a 5- to 6-membered monocyclic heterocyclic group,
and in still another embodiment, the heterocyclic group is
5- to 6-membered monocyclic heteroaryl.
[0024]
The "lower alkyl which may be substituted" and
"heterocyclic group which may be substituted" mean that the
"lower alkyl" and "heterocyclic group" may be respectively
substituted with substituents including one or two or more
groups shown below.
-OH, -NH2, -NH(lower alkyl), -N(lower alkyl) 2, -CN,
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-COOH, NO2, lower alkyl, -0-lower alkyl, halogen,
cycloalkyl, aryl, and a heterocyclic group (wherein the
aforementioned cycloalkyl, aryl and heterocyclic group may
be substituted with one or two or more substituents
selected from the following groups.
-OH, -NH2, -NH(lower alkyl), -N(lower alkyl)2, -CN,
-COOH, NO2, lower alkyl, -0-lower alkyl, halogen,
cycloalkyl, aryl and a heterocyclic group).
[0025]
The term "BEC1" or "BEC1 potassium channel" means a
protein as set forth in SEQ ID NO.2, which has been known
in U.S. Patent No. 6,326,168 or U.S. Patent No. 7,375,222.
[0026]
The term "BEC1 potassium channel inhibitor" means a
substance inhibiting the BEC1 potassium channel, and for
example, it means a substance having an IC50 value of 10 M
or less; in another embodiment, 1 M or less; and in still
another embodiment, 0.5 M or less, based on the evaluation
method described in Example 1. The BEC1 potassium channel
inhibitor is obtained by subjecting a test compound to a
representative screening method, for example, the method
described in U.S. Patent No. 6,326,168 or U.S. Patent No.
7,375,222, herein incorporated by reference.
[0027]
The compound of the formula (I) may have tautomers or
geometric isomers, depending on the type of substituent.
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In the present specification, the compound of the formula
(I) may be described only as one form of isomers in some
cases, but the present invention also includes the other
isomers, as well as separated isomers or mixtures thereof.
The compound of the formula (I) may also have
asymmetric carbon atoms or axial asymmetry, and optical
isomers based thereon may also exist. The present
invention includes separated optical isomers of the
compound of the formula (I), or mixtures thereof.
[0028]
Furthermore, the present invention also includes
pharmaceutically acceptable prodrugs of the compound
represented by the formula (I). A pharmaceutically
acceptable prodrug is a compound having a group which can
be converted to the amino group, hydroxyl group, carboxyl
group or the like (of the present invention) by solvolysis
or under physiological conditions. Examples of the group
forming a prodrug include the groups described in Frog.
Med., 5, 2157-2161 (1985) or "Development of Pharmaceutical
Products" (Hirokawa-Shoten, Ltd., 1990), Vol. 7 Molecular
Design, 163-198, both are herein incorporated by reference.
[0029]
The compound of the formula (I) may also form a salt
with an acid addition salt depending on the type of
substituent, and such salt is included in the present
invention so long as it is a pharmaceutically acceptable
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salt. Specific examples include acid addition salts with
an inorganic acid such as hydrochloric acid, hydrobromic
acid, hydroiodic acid, sulfuric acid, nitric acid, or
phosphoric acid; or an organic acid such as formic acid,
acetic acid, propionic acid, oxalic acid, malonic acid,
succinic acid, fumaric acid, maleic acid, lactic acid,
malic acid, mandelic acid, tartaric acid, dibenzoyltartaric
acid, ditoluoyltartaric acid, citric acid, methanesulfonic
acid, ethanesulfonic acid, benzenesulfonic acid, p-
toluenesulfonic acid, aspartic acid, or glutamic acid; and
the like.
[0030]
The compound of the formula (I) and/or
pharmaceutically acceptable salts thereof can be obtained
by the production method described in U.S. Patent No.
7,375,222, herein incorporated by reference, or by a
production method equivalent thereto.
[0031]
A pharmaceutical composition containing the compound
of the formula (I), or one or two or more of
pharmaceutically acceptable salts thereof, as an active
ingredient can be prepared by using pharmaceutical
excipients, pharmaceutical carriers and the like that are
conventionally used in the pertinent art, according to a
conventionally used method.
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Administration may be carried out by any of the oral
administration mode by means of tablets, pills, capsules,
granules, powders, liquids or the like, and the parenteral
administration mode by means of injectable preparations via
intraarticular, intravenous, intramuscular routes,
suppositories, eye drops, eye ointments, transdermal
liquids, ointments, transdermal adhesive patches,
transmucosal liquids, transmucosal adhesive patches,
inhalants or the like.
[0032]
As solid compositions for oral administration,
tablets, powders, granules and the like are used. In these
solid compositions, one or two or more active ingredients
are mixed with at least one inert excipient, for example,
lactose, mannitol, glucose, hydroxypropylcellulose,
microcrystalline cellulose, starch, polyvinylpyrrolidone,
and/or magnesium metasilicate aluminate, and the like. The
composition may also contain inert additives, for example,
a gliding agent such as magnesium stearate, a disintegrant
such as carboxymethyl starch sodium, a stabilizer, and a
dissolution aid, according to standard methods. Tablets or
pills may be coated, if necessary, with sugar coating or a
film of a gastrosoluble or enterosoluble material.
Liquid compositions for oral administration include
pharmaceutically acceptable emulsions, solutions,
suspensions, syrups or elixirs, and the like, and include a
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generally used inert diluent, for example, purified water
or ethanol. The liquid compositions may also contain, in
addition to the inert diluent, an auxiliary agent such as a
solubilizer, a wetting agent or a suspending agent, a
sweetener, a flavor, an aromatic, or an antiseptic.
[0033]
An injectable preparation for parenteral
administration contains a sterile, aqueous or non-aqueous
solution, suspension or emulsion. Examples of aqueous
solvents include distilled water for injection and
physiological saline. Examples of non-aqueous solvents
include propylene glycol, polyethylene glycol, plant oils
such as olive oil, alcohols such as ethanol, Polysorbate 80
(name in the Japanese Pharmacopoeia), and the like. These
compositions may further include an isotonic agent, an
antiseptic, a wetting agent, an emulsifier, a dispersant, a
stabilizer, or a dissolution aid. These are sterilized by,
for example, filtration through a bacteria-retaining
filter, incorporation of a bactericide, or irradiation.
Furthermore, these can be used such that a sterile solid
composition is prepared, and then dissolved or suspended in
sterilized water or in a sterile solvent for injection
before use.
[0034]
Topical preparations include ointments, plasters,
creams, jellies, adhesive skin patches, sprays, lotions,
CA 02660962 2009-03-31
eye drops, eye ointments and the like. The topical
preparations contain generally used ointment bases, lotion
bases, aqueous or non-aqueous liquids, suspensions,
emulsions and the like. For example, as the ointment or
lotion base, polyethylene glycol, propylene glycol, white
petrolatum, bleached beeswax, polyoxyethylene hydrogenated
castor oil, glycerin monostearate, stearyl alcohol, cetyl
alcohol, lauromacrogol, sorbitan sesquioleate, and the like
may be mentioned.
[0035]
The transmucous preparations such as inhalants or
transnasal preparations are used in a solid, liquid or
semi-solid form, and can be produced according to
conventionally known methods. For example, known
excipients, and furthermore, a pH adjusting agent, an
antiseptic, a surfactant, a gliding agent, a stabilizer or
thickening agent, and the like may be appropriately added.
Administration can be carried out by using appropriate
devices for inhalation or insufflation. For example, the
compound can be administered alone or as a powder of a
prescribed mixture, or as a solution or suspension in
combination with a pharmaceutically acceptable carrier,
using a known device such as a metered dose inhaler, or a
sprayer. A dry powder inhaler or the like may be for a
single dose or multiple doses, and dry powders or powder-
containing capsules can be used. Alternatively, the
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preparation may also be in the form of an appropriate
ejector, for example, a pressurized aerosol spray using a
suitable gas such as chlorofluoroalkane, hydrofluoroalkane
or carbon dioxide.
[0036]
Typically, in the case of oral administration, the
daily dosage is appropriately about 0.001 to 100 mg/kg,
preferably 0.1 to 30 mg/kg, and more preferably 0.1 to 10
mg/kg, of body weight, and this is administered once, or in
two to four divided portions. In the case of carrying out
intravenous administration, the daily dosage is
appropriately about 0.0001 to 10 mg/kg of body weight, and
this is administered once or in many divided portions per
day. As for the transmucous preparations, about 0.001 to
100 mg/kg of body weight is administered once or in many
divided portions per day. The dosage is appropriately
determined in accordance with the individuals, while taking
symptoms, age, gender and the like into consideration.
[0037]
The compound of the formula (I) can be used in
combination with an agent for treating or preventing
schizophrenia. This combination may be administered
simultaneously or separately and sequentially, or even may
be administered at a desired time interval. The
preparation for simultaneous administration may be a blend
preparation, or may be separately formulated.
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EXAMPLES
[0038]
The following Reference Examples and Examples are
intended to describe the present invention in more detail,
and the present invention is not to be limited to the
following Examples. Although the present invention is
sufficiently described by the Reference Examples and
Examples, those ordinarily skilled in the art will
understand that various alterations or modifications are
definitely possible. Therefore, as long as such
alterations or modifications does not depart from the scope
of the present invention, they are included in the present
invention.
[0039]
In the Reference Examples, Examples and tables
described below, the following abbreviations will be used.
Ex: Example number, REx: Reference example number,
No: Compound number, mp: Melting point, Data:
Physicochemical data (FAB+: FAB-MS(M+H)+, EI: EI-MS(M)+,
NMR-DMSOd6: 5 (ppm) of peaks from 1H NMR in DMSO-d6), DMF:
N,N-dimethylformamide, DMSO: dimethylsulfoxide, THF:
tetrahydrofuran, 4 M hydrogen chloride/dioxane solution: 4
mol/1 hydrogen chloride dioxane solution, MeCN:
acetonitrile, MeOH: methanol, EtOH: ethanol.
23
CA 02660962 2009-03-31
[0040]
Reference Example 1-1
75.0 g of chloroisocyanuric acid and 680 mL of THE
were added to a 2-L flask, followed by addition of 51.10 g
of potassium carbonate at -19 C under stirring. 41.08 g of
p-fluoroaniline that has been diluted with 75 mL of THE at
-12.4 C or lower, and 75 mL of THE were added thereto. The
reaction was carried out at -12.8 to -14.4 C for 1 hour,
and 450 mL of water was added. Liquid separation was
carried out at room temperature to separate the aqueous
layer, 300 mL of water was added thereto, and liquid
separation was carried out again to separate the aqueous
layer. To the organic layer were added an aqueous solution
obtained by adding 1) 600 mL of THF, and 2) 1.1 g of
potassium carbonate in 308 mL of water, and liquid
separation was carried out to separate the aqueous layer.
To the organic layer was added 150 mL of water, liquid
separation was carried out to separate the aqueous layer,
and the organic layer was concentrated under reduced
pressure until the remaining amount of the solution became
280 mL. To the concentrated solution was added 750 mL of
MeCN, and the concentration operation was carried out three
times under reduced pressure until the remaining amount of
the solution became 280 mL. Subsequently, 600 mL of MeCN
was added thereto under cooling, followed by addition of
34.43 g of aniline and 75 mL of MeCN at -5.9 C or less, and
24
CA 02660962 2009-03-31
addition of 47.79 g of N,N-diisopropylethylamine and 38 mL
of MeCN at -9.2 C. Thereafter, the temperature was
elevated to room temperature, and after stirring for 12
hours, 48.42 g of 2-aminomethylpyrimidine and 75 mL of MeCN
were added thereto at room temperature, followed by
addition of 57.35 g of N,N-diisopropylethylamine and 38 mL
of MeCN at room temperature. The inner temperature was
elevated to 82.4 C, followed by stirring for 4.5 hours, and
560 mL of water was added thereto at an inner temperature
of 70 C or higher, followed by cooling. The crystal
precipitation at an inner temperature of 65.8 C was
confirmed, followed by stirring at room temperature
overnight, and filtration. The obtained crystal was washed
with a mixed solution of MeCN:water = 2:1, and subsequently
washed with 300 mL of water. The obtained crystal was
dried at 50 C for 1 day under reduced pressure to obtain
108.54 g of N-(4-fluorophenyl)-N'-phenyl-N"-(pyrimidin-2-
ylmethyl)-1,3,5-triazine-2,4,6-triamine.
[0041]
Reference Example 1-2
414 L of methyl ethyl ketone and 23.00 kg of the N-
(4-fluorophenyl)-N'-phenyl-N"-(pyrimidin-2-ylmethyl)-1,3,5-
triazine-2,4,6-triamine were added to a reaction vessel 1,
and dissolved at an inner temperature of 65.0 C. After
filtration, the mixture was transferred to a reaction
vessel 2, followed by heating again. 6.90 kg of fumaric
CA 02660962 2009-03-31
acid and 115 L of EtOH were added to the reaction vessel 1,
dissolved at an inner temperature of 58.3 C, transferred to
the reaction vessel 2. After cooling, the crystallization
was initiated at an inner temperature of 54.2 C, followed
by stirring at 0 C overnight. After filtration, the
crystal was washed with 46 L of EtOH, and 30.34 kg of the
obtained "crystal of the salt having a ratio of the N-(4-
fluorophenyl)-N'-phenyl-N"-(pyrimidin-2-ylmethyl)-1,3,5-
triazine-2,4,6-triamine to fumaric acid of 1:1" (type III
crystal: wet) and 460 L of EtOH were added to the reaction
vessel 2. They were stirred at an inner temperature of
52.4 to 69.2 C in a suspension state for 42 hours, cooled,
and stirred at room temperature overnight. After
filtration, the obtained crystal was washed with 46 L of
EtOH, and then dried at 60 C for 4 days under reduced
pressure to obtain 20.97 kg of a "crystal of an anhydrous
salt having a ratio of the N-(4-fluorophenyl)-N'-phenyl-N"-
(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine to
fumaric acid of 2:1" (type I).
[0042]
Reference Example 2-1
To a mixed solution of 25 g of 2-
pyrimidinecarbonitrile in 100 mL of acetic acid and 100 mL
of ethyl acetate, 1 g of 10% palladium/carbon was added,
and the mixture was stirred for 14 hours at room
temperature in a hydrogen atmosphere at ambient pressure.
26.
CA 02660962 2009-03-31
The palladium/carbon was removed from the reaction mixture
by filtration through Celite, and an operation of adding
toluene to a residue obtained by distilling off the
solvent, and concentrating the mixture, was repeated four
times. MeCN was added to the obtained residue to solidify
the residue, and the solids were collected by filtration,
to obtain 15.7 g of 1-pyrimidin-2-ylmethylamine acetate as
a colorless solid.
1-Pyrimidin-2-ylmethylamine acetate
NMR-DMSOd6:
1.88 (3H,s), 3.91 (2H,brs), 4.1-5.3 (3H,m), 7.38
(1H,t,J=4.9Hz), 8.78 (2H,d,J=4.9Hz)
EI: 109
[0043]
Reference Example 2-2
To a solution of 4.71 g of 6-chloro-N,N'-bis(4-
fluorophenyl)-1,3,5-triazine-2,4-diamine in 50 mL of NeON,
2.507 g of 1-pyrimidin-2-ylmethylamine acetate and 5.2 mL
of N,N-diisopropylethylamine were added, and the mixture
was stirred for 17 hours at 75 C. The reaction mixture was
cooled to room temperature, and then to the residue
obtained by distilling off the solvent, ethyl acetate was
added. The organic layer was washed with 5% aqueous citric
acid solution and saturated brine, and dried over anhydrous
magnesium sulfate, and then the solvent was distilled off.
The obtained residue was purified by silica gel column
27
CA 02660962 2009-03-31
chromatography (chloroform:MeOH = 100:0 to 95:5), to obtain
6.0 g of a pale yellow amorphous material. This was
dissolved in 180 mL of EtOH, 2 g of activated carbon was
added, and the mixture was stirred for one hour. The
activated carbon was removed by filtration through Celite,
and the residue obtained by distilling off the solvent was
solidified from 150 mL of aqueous EtOH (EtOH 80%), to obtain
4.84 g of N,N'-bis(4-fluorophenyl)-N"-(pyrimidin-2-
ylmethyl)-1,3,5-triazine-2,4,6-triamine as a colorless
solid.
1.5 g of N,N'-bis(4-fluorophenyl)-N"-(pyrimidin-2-
ylmethyl)-1,3,5-triazine-2,4,6-triamine was dissolved in
300 mL of MeOH, and 2 mL of a 4 M hydrogen chloride/dioxane
solution was added. Then, the solvent was distilled off,
and the obtained residue was crystallized from ethanol, to
obtain 1.66 g of a "salt of N,N'-bis(4-fluorophenyl)-N"-
(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine and
hydrogen chloride at a ratio of 1:2" as colorless crystals.
[0044]
The compounds of Reference Example 3 ("salt of N-(4-
fluorophenyl)-N'-(4-methoxyphenyl)-N"-(pyrimidin-2-
ylmethyl)-1,3,5-triazine-2,4,6-triamine and hydrogen
chloride at a ratio of 1:2") and Reference Example 4
("composition of N,N'-bis(4-fluorophenyl)-N"-(pyrimidin-4-
ylmethyl)-1,3,5-triazine-2,4,6-triamine= 1.7 hydrogen
chloride-0.2 diethyl ether-1.8 H2O") as shown in the
28
CA 02660962 2009-03-31
following Table 1 were synthesized in the same manner as in
Reference Example 2.
[0045]
The structures and property values of the Reference
Example compounds are presented in the following Table 1.
29
CA 02660962 2009-03-31
Table 1
R~N-~R2
a s
R \ I N \N
R
N N\ I
H H
REx R - N - R 2 Ra R5 Salt/Attach DATA
ed solvent
NMR-DMSOd6
4.71-4.73 (2H,m), 6.91-7.26 (5H,m), 7.37
(1H,dd, J=5.2Hz, 4.8Hz), 7.44-7.80
(5H,m), 8.78 (2H,d, J=4.8Hz), 9.01-9.05
N (2H,m)
1-1 Hj F H - FAB+ : 389
N Elemental Analysis. Calcd for C20H17FN8
: C, 61.85; H, 4,41; N, 28.85; F, 4.89; Cl,
0.00. Found: C, 61.78; H, 4.43; N, 28.81; F,
4.95; Cl, 0.00
NMR-DMSOd6
4.71-4.73 (2H,m), 6.64 (1H,s), 6.91-7.23
(5H,m), 7.37ppm (1H,dd, J=5.2Hz, 4.8Hz),
N 7.44-7.80 (5H,m), 8.78 (2H,d, J=4.8Hz),
1-2 H i F H 0.5 Fumaric 9.01-9.06 (2H,m),13.06 (1H,br)
acid FAB+ : 389
Elemental Analysis. Calcd for
C20Hl7FN8 - 0.5C4H404: C, 59.19; H,
4,29; N, 25.10; F, 4.26; 0, 7.17. Found: C,
59.09; H, 4.3 6; N, 25.19; F, 4.3 1.
NMR-DMSOd6
4.78 (2H, m), 7.10 (2H, brs), 7.25 (2H, t,
J=8.7Hz), 7.3-7.8 (6H, m), 8.85 (2H, d,
J=4.9Hz), 8.9-9.4 (1H, m), 10.39 (1H, s),
N
Hj 10.74 (1H, brs)
2-2 F F 2HCl Elemental Analysis. Calcd for
C20H16F2N8 - 2HCI: C, 50.12; H, 3.79;
N, 23.33; F, 7.93; Cl, 14.79. Found: C,
50.06; H, 3.85; N, 23.38; F, 8.05; Cl, 14.91.
mp: 183-186 C
NMR-DMSOd6
N 3.70-3.82 (3H, m), 4.6-5.0 (2H, m), 6.7-7.8
3 Hj F OMe 2HC1 (I OH, m), 8.85 (2H, d, J=4.9Hz), 9.0-9.7
(1H, m), 10.1-11.3 (2H, m)
FAB+ : 419
NMR-DMSOd6
HN N 1.7HC1/ 4,65 (2H, brs), 6.8-7.3 (4H, m), 7.3-7.9
~
4 F F 0.2C4H10O/ (6H, m), 8.6-9.0 (1H, m), 9.17 (1H, d,
1.8H20 J=1.2Hz), 9.8-10.7 (2H, m)
FAB+ : 407
CA 02660962 2009-03-31
[0046]
Example 1
(Test Method)
Method for measuring BEC1 inhibitory activity of
compound utilizing 86Rb ion release amount as index
The channel activity of BEC1 was measured according
to the method described in U.S. Patent No. 6,326,168 or
U.S. Patent No. 7,375,222, herein incorporated by
reference, utilizing the release of the ions of radioactive
isotope 86Rb from BEC1 expressing cells as an index.
Specifically, when BEC1 expressing cells which had taken in
86Rb ions were stimulated with 100 mM KC1, the
radioactivity released from the same cells was designated
as the channel activity of BEC1. 86Rb ions were
incorporated into cells by culturing (3 hours, 37 C) BEC1
stably expressing cells in the presence of 86RbCl (0.5
Ci/ml), and the unincorporated 86Rb ions were removed by
washing the cells three times with HEPES buffered
physiological saline (pH 7.4, 2.5 mM KC1). The same cells
were incubated for 15 minutes at room temperature in the
presence of a DMSO solution containing the test compound
and HEPES buffered physiological saline, and then were
further incubated for 5 minutes at room temperature in the
presence of a 100 mM KC1-containing HEPES buffer solution
(pH 7.4) containing the same compound. The extracellular
fluid was recovered, and then the remaining cells were
31
CA 02660962 2009-03-31
lysed in 0.1 N NaOH and recovered. The Cherenkov
radioactivities of the extracellular fluid and the cell
lysate were respectively measured, and the sum was
designated as the total radioactivity. The release amount
of 86Rb ions was expressed as the percentage of the
radioactivity of the extracellular fluid with respect to
the total radiation activity. The value obtained in the
presence of the compound was designated as a test value,
the value obtained in the absence of the compound was
designated as a control value, and the value obtained when
the cells were not stimulated with 100 mM KC1 was
designated as a blank value. The inhibitory action of the
compound was indicated as the IC50 value determined from
the inhibition % (that is, (control value - test
value)xlOO/(control value - blank value)). In addition, as
for the BEC1 expressing cells, BEC1 stably expressing cells
produced according to the method described in U.S. Patent
No. 6,326,168 or U.S. Patent No. 7,375,222, herein
incorporated by reference, using a dihydrofolate reductase
(dhfr)-deficient strain of Chinese Hamster ovary cells,
were used.
(Results)
The test results of representative compounds are
presented in Table 2. The corresponding compounds were
confirmed to have BEC1 potassium channel inhibitory action.
32
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[0047]
Example 2
(Test Method)
Verification of the therapeutic effect on
schizophrenia was carried out using a methamphetamine
induced hyperlocomotion model. Methamphetamine is a
psychostimulant, and is known to cause symptoms that are
similar to schizophrenia by increasing the transmission in
the dopaminergic neurons. The abnormal behavior produced
when methamphetamine is administered to an animal is
generally used as a screening method for a therapeutic drug
for schizophrenia (Oka et al., 1993, J. Pharmacol. Exp.
Ther., 264:158-165, herein incorporated by reference).
That is, a male ddY mouse was placed in an activity
monitoring apparatus, and after 30 minutes, methamphetamine
was administered. After administering methamphetamine, the
mouse was immediately returned to the monitoring apparatus,
and the activity for one hour from immediately after the
return was measured. For the measurement of the activity,
a Supermex sensor manufactured by Muromachi Kikai Co., Ltd.
was used. A solvent (vehicle), or dilutions prepared by
diluting the compounds described in Reference Examples 1-2,
2-2, 3 and 4, and N-(4-fluorophenyl)-N'-[(2-fluoro-4-
pyridyl)methyl]-N"-phenyl-1,3,5-triazine-2,4,6-triamine
hydrochloride, with a solvent at multiple concentrations,
were orally administered to the mice in each group. The
33
CA 02660962 2009-03-31
solvent used was a 0.5% aqueous solution of
methylcellulose. The statistical analysis was carried out
between the solvent administered group and the drug
administered groups, using Dunnett's test.
[0048]
(Results)
The results of the methamphetamine induced
hyperlocomotion suppressive action are presented in Table
2. The numerical values in the table represent the
respective minimum effective doses for the compound
administered groups (the smallest dose inducing a
significantly small activity with respect to the activity
of the solvent administered group). The test compounds (1)
to (5) all suppressed methamphetamine induced
hyperlocomotion. In other words, these five compounds were
shown to have an effect of improving the symptoms of
schizophrenia.
[0049]
Test Compounds
Compound (1): (REx 1-2), compound (2): (REx 2-2),
compound (3): (REx 3), compound (4): (REx 4), compound (5)
(N-(4-fluorophenyl)-N'-[(2-fluoro-4-pyridyl)methyl]-N"-
phenyl-1,3,5-triazine-2,4,6-triamine hydrochloride),
compound (6) : (N,N'-bis(4-fluorophenyl)-N"-[(2-fluoro-4-
pyridyl)methyl]-1,3,5-triazine-2,4,6-triamine
dihydrochloride), compound (7) : (N-(4-fluorophenyl)-N'-
34
CA 02660962 2009-03-31
[(2-fluoro-4-pyridyl)methyl]-N"-(4-methylphenyl)-1,3,5-
triazine-2,4,6-triamine hydrochloride), compound (8) : (N-
(4-fluorophenyl)-N'-[(2-fluoro-4-pyridyl)methyl]-N"-(4-
methoxyphenyl)-1,3,5-triazine-2,4,6-triamine
hydrochloride), compound (9) : (N-(4-chlorophenyl)-N'-[(2-
fluoro-4-pyridyl)methyl]-N"-(4-fluorophenyl)-1,3,5-
triazine-2,4,6-triamine hydrochloride), compound (10) : (N-
(4-fluorophenyl)-N'-[(2-fluoro-4-pyridyl)methyl]-N"-(3-
methoxyphenyl)-1,3,5-triazine-2,4,6-triamine
hydrochloride).
The compounds (5)-(10) are described in U.S. Patent No.
7,375,222.
Table 2
Minimum effective dose
Test 1C50 (pM) (mg/kg p. o. )
Compound (Example 1)
(Example 2)
1 0.077 0.1
2 0.065 0.03
3 0.092 0.03
4 0.058 0.01
5 0.085 1.0
6 0.10 -
7 0.24 -
8 0.17 -
9 0.65 -
10 0.25 -
[0050]
The pharmaceutical composition of the present
invention is useful for providing an excellent prophylactic
CA 02660962 2009-03-31
agent and/or therapeutic agent for schizophrenia, and is
particularly useful for providing a prophylactic agent
and/or therapeutic agent for the positive symptoms,
negative symptoms and cognitive impairments and the like of
schizophrenia.
While the invention has been described in detail
and with reference to specific embodiments thereof, it will
be apparent to one skilled in the art that various changes
and modifications can be made therein without departing
from the scope thereof.
36
