NOVEL PHARMACEUTICAL COMPOSITION FOR TREATMENT OF SCHIZOPHRENIA
DESCRIPTION
Technical Field
The present invention relates to a novel pharmaceutical
use of BEC1 potassium channel inhibitor as an agent for treating
schizophrenia.
Background Art
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.
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).
Potassium channels are proteins which are present in the
plasma membrane of cells and selectively pass potassium 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
andperipheral 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.
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 andmuscle cells is induced,
concomitantly with the opening of the voltage-dependent channels
(Ionic Channels of Excited Membranes, Sinauer Associates,
Sunderland, 1992, herein incorporated by reference).
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).
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 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.
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-l,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 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
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.
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.
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.
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 BECl 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 BECl 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 preventing and/or treating
schizophrenia, comprising administering an effective amount of
a BEC1 potassium channel inhibitor or a pharmaceutically
acceptable salt thereof in a patient in need of such disease.
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.
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.
Detailed description of the present invention
Preferred embodiments of the present invention will be
presented in the following.
(1) A pharmaceutical composition for prevention and/or
treatment of schizophrenia, containing an effective amount of
a compound of formula (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) CN, (iii) NO2, (iv) halogen, (v) lower alkyl
which may be substituted with (1) CN, (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 R9-0-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-O- or OH, or (3) aryl;
and T1 represents 0 or S) , or (xi) R11--T2- (wherein R11 represents
(1) OH, (2) R7R8N-, (3) lower alkyl-O-, (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).
(3) The pharmaceutical composition according to (1) or (2),
wherein R1 and R2, whichmay 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-.
(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 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) .
(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 RIO 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) R^-T1- (wherein R10 represents lower alkyl; and T1
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 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).
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-tri
azine-2,4,6-triamine,

N-(4-fluorophenyl)-N'-(4-methoxyphenyl)-N"-(pyrimidin-2-ylme
thyl)-l,3,5-triazine-2,4,6-tiramine,
N,N'-bis(4-fluorophenyl)-N"-(pyrimidin-4-ylmethyl)-1,3,5-tri
azine-2,4,6-triamine, or
N-(4-fluorophenyl)-N'-[(2-fluoro-4-pyridyl) methyl]-N"-phenyl
-1,3,5-triazine-2,4,6-triamine.
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.
The term "lower alkyl" means linear or branched alkyl having
1 to 6 carbon atoms (hereinafter, abbreviated to Cl-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
Cl-4 alkyl, and in still another embodiment, the lower alkyl is
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
pentyl or hexyl.
The term "halogen" means F, CI, Br, or I.
The term "Ci_i0 alkylene" means linear or branched Ci-io
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.
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 cycloalkyl is C3-8 cycloalkyl, and in still
another embodiment, the cycloalkyl is C3_6 cycloalkyl.
The term "aryl" means a C6_i4 monocyclic to tricyclic aromatic
hydrocarbon cyclic group, and includes, for example, phenyl and
naphthyl. In. another embodiment, the aryl is phenyl.

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 andnitrogen, 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 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.
The "lower alkyl whichmay 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(Tower alkyl)2, -CN,
-COOH,N02, loweralkyl, -O-loweralkyl, 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, N02, loweralkyl, -O-loweralkyl, halogen, cycloalkyl, aryl
and a heterocyclic group).
The term "BEC1" or "BECl 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.
The term "BEC1 potassium channel inhibitor" means a
substance inhibiting the BECl potassium channel, and for example,
it means a substance having an IC50 value of 10 juM or less; in
another embodiment, 1 (xM or less; and in still another embodiment,
0. 5 J4.M or less, based on the evaluation method described in Example
1. The BECl 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.
The compound of the formula (I) may have tautomers or
geometric isomers, depending on the type of substituent. 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.
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 Prog. 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.
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 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, f umaric 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.
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.
A pharmaceutical composition containing the compound of
theformula (I) , or one or twoormore 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.
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.
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 magnesiumstearate,
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 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.
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.
Topical preparations include ointments, plasters, creams,
jellies, adhesive skin patches, sprays, lotions, 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.
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 preparation may also be in the form of an
appropriate ejector, for example, a pressurized aerosol spray
using a suitable gas such as chlorof luoroalkane, hydrof luoroalkane
or carbon dioxide.
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.
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.
Examples
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.
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: 8 (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.
Reference Example 1-1
75.0 g of chloroisocyanuric acid and 680 mL of THF 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 THF at -12.4°C or lower, and
75 mL of THF 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 carr-ied 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 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.
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 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).
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. 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
l-pyrimidin-2-ylmethylamine acetate as a colorless solid.
l-Pyrimidin-2-ylmethylamine acetate

NMR-DMSOd6:
1.88 (3H,s), 3.91 (2H,brs), 4.1-5.3 (3H,m), 7.38
(lH,t,J=4.9Hz), 8.78 (2H,d,J=4.9Hz)
EI: 109
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 MeCN, 2.507 g of l-pyrimidin-2-ylmethylamine acetate
and 5 . 2mLof 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 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-tri
azine-2,4,6-triamine as a colorless solid.
1.5 g of
N,N'-bis(4-fluorophenyl)-N"-(pyrimidin-2-ylmethyl)-1,3,5-tri
azine-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-tri
azine-2,4,6-triamine and hydrogen chloride at a ratio of 1:2"
as colorless crystals.
Reference Example 2-3
To a solution of 1.0 g of
N,N'-bis(4-fluorophenyl)-N"-(pyrimidin-2-ylmethyl)-1,3,5-tri

azine-2,4,6-triamine in 50 mL of ethanol was added a solution
of 285.6 mg of fumaric acid in 5 mL of ethanol. Soon, the
precipitation of a solid was initiated. This reaction solution
was heated under reflux to completely dissolve the solid, followed
by stirring while leaving it to be cooled. When the inner
temperature was lowered to 60°C, an extremely small amount of
the crystal of the salt having a ratio of
N,N'-bis(4-fluorophenyl)-N"-(pyrimidin-2-ylmethyl)-1,3,5-tri
azine-2,4,6-triamine to fumaric acid of 1:1 was added thereto,
followed by stirring at room temperature for 12 hours while leaving
it to be cooled. The precipitated crystals were collected by
filtration, washed with ethanol, and dried at 60°C for 2 days
under reduced pressure to obtain 970 mg of a "salt having a ratio
of
N,N'-bis(4-fluorophenyl)-NT-(pyrimidin-2-ylmethyl)-1,3,5-tri
azine-2,4,6-triamine to fumaric acid of 1:1" as colorless
crystals.
The compounds of Reference Example 3 ("salt of
N-(4-fluorophenyl)-N'-(4-methoxyphenyl)-N"-(pyrimidin-2-ylme
thyl)-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-tri
azine-2,4,6-triamine•1.7 hydrogen chloride-0.2 diethyl
ether-1.8 H20") as shown in the following Table 2 were synthesized
in the same manner as in Reference Examples 2-1, 2-2 and 2-3.
The structures and property values of the Reference Example
compounds are presented in the following Table 1 and 2.

(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 8 6Rb ions were st imula ted with 100 mMKCl, 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 (xCi/ml) , and the unincorporated 8 6Rb ions were removed by
washing the cells three times with HEPES buffered physiological

saline (pH 7.4, 2.5 mM KCl) . 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 KCl-containing HEPES buffer
solution (pH7.4) containing the same compound. The extracellular
fluid was recovered, and then the remaining cells were 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 8 6Rb 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 (as a free form which does not include salt) was
indicated as the IC50 value determined from the inhibition % (that
is, (control value - test value)x100/(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 3. The corresponding compounds were confirmed to have
BEC1 potassium channel inhibitory action.
Example 2
(Test Method)
Verification of the therapeutic effect on schizophrenia
was carried out using a methamphetamine induced hyperlocomotion
model. Methamphetamine is apsychostimulant, 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
(test compound (1)), 2-2(test compound (2a)), 3(test compound
(3)) and 4(test compound (4)), and
N-(4-fluorophenyl)-N'-[(2-fluoro-4-pyridyl)methyl]-N"-phenyl
-1,3,5-triazine-2,4,6-triamine hydrochloride(test compound
(5)), with a solvent at multiple concentrations(as a free form
which does not include salt), were orally administered to the
mice in each group. The 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.
(Results)
The results of the methamphetamine induced hyperlocomotion
suppressive action are presented in Table 3 . 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, especially the
positive symptoms of schizophrenia .
Example 3
(Test Method)

Verification of the therapeutic effect on schizophrenia
was carried out using a phencyclidine induced prolonged
immmobility model. Phencyclidine is a non-competitive
antagonist of the N-methyl-D-aspartate receptor, a type of
glutamate receptor, and abuse of this agent causes development
of psychotic symptoms indistinguishable from those of
schizophrenia. It was suggested that chronic treatment of
phencyclidine enhances immobility in forced swimming test (Noda
et al., 2000, Neuropsychopharmacol., 23:375-87, herein
incorporated by reference). Forced swimming test is used as a
screening assay for antidepressants, because immobility in this
test is thought to reflect some aspect of depression such as lowering
of motivation. Negative symptoms of schizophrenia also includes
similar aspects, we could evaluate the efficacy of drugs for
negative symptoms, such as apathy, using this test. Briefly, a
male ddY mouse was gently placed in a cylindrical pool, and activity
was measured for 3 min with SCANET (MV20-LAN, MELQUEST) . Afterward
immobility time was calculated with the SCANET file integrating
software. Two days later, Mice were anesthetized with sodium
pentobarbital. The Osmotic mini pumps (Alzet model 1002, DURECT
Corporation) were subcutaneously implanted to mice. The pump
infused saline or phencyclidine 1.2 mg/day/mouse with pumping
rate of 0.25 uL/hour. Fourteen days after implantation, a test
compound was administered to mice and an hour after administration,
each mouse was gently placed in a cylindrical pool, and activity
was measured for 3 min. Afterward immobility time was calculated.
A solvent (vehicle), or dilutions prepared by diluting the test
compounds (1) and (2b), with a solvent at multiple
concentrations (as a free form which does not include salt), were
orally administered to the mice in each group. The 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.
(Results)
The results of the phencyclidine induced prolonged
immobility improving action are presented in Table 3. The

numerical values in the table represent the respective minimum
effective doses for the compound administered groups (the smallest
dose inducing a significantly short immobility time with respect
to the immobility time of the solvent administered group) . The
test compounds (1) and (2b) suppressed phencyclidine induced
prolongation of immobility time. In other words, these two
compounds were shown to have an effect of improving the symptoms
of schizophrenia, especially the negative symptoms of
schizophrenia .
Example 4
(Test Method)
Verification of the therapeutic effect on schizophrenia
was carried out using a water finding task in mice after neonatal
treatment with phencyclidine. It was suggested that treatment
with phencyclidine at the neonatal stage produced schizophrenic
cognitive impairment (Depoortere et al., 2005,
Neuropsychopharmacology, 30:1963-85, herein incorporated by
reference). In addition, it has been reported that chronic
treatment of PCP prolonged finding latency in the water-finding
task (Mouri et al., 2007, Mol. Pharmacol., 180:152-60, herein
incorporated by reference) . Finding latency in the water-finding
. task provides a measure of latent learning in animals, which is
thought to reflect attention. Attention is one of the most
important domain of cognitive impairments in schizophrenia, we
could evaluate the efficacy of drugs for cognitive impairments
in schizophrenia using this task. Briefly, male ddY mice
subcutaneously received PCP at a dose of 15 mg/kg or saline on
postnatal day 7, 9 and 11. During the adult 7 weeks old, test
compounds were orally administered to animals and 60 minutes later,
the animals were placed in one corner of the open field and allowed
to freely explore the training apparatus for 3 min. Immediately
after the training trial, the animals were returned to their home
cage and deprived of water until the test trial the next day.
In the test trial, the mice were again placed individually in
the test apparatus. The time between entering the alcove and
drinking the water wasmeasured. Asolvent (vehicle) , or dilutions

prepared by diluting the test compounds (1) and (2b) , with a
solvent at multiple concentrations (as a free form which does not
include salt) , were orally administered to the mice in each group.
The 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.
(Results)
The results of the phencyclidine induced prolonged finding
latency improving action are presented in Table 3. The numerical
values in the table represent the respective minimum effective
doses for the compounds administered groups (the smallest dose
inducing a significantly short finding latency with respect to
the finding latency of the solvent administered group) . The test
compounds (1) and (2b) suppressed phencyclidine induced
prolongation of finding latency. In other words, these two
compounds were shown to have an effect of improving the symptoms
of schizophrenia, especially the cognitive impairment of
schizophrenia .
Test Compounds
Compound (1). means the compound of REx 1-2,
compound (2a) means the compound of REx 2-2,
compound (2b) means the compound of REx 2-3,
compound (3) means the compound of REx 3,
compound (4) means the compound of REx 4,
compound (5) means
N-(4-fluorophenyl)-N'-[(2-fluoro-4-pyridyl)methyl]-N"-phenyl
-1,3,5-triazine-2,4,6-triamine hydrochloride,
compound (6) means
N,N'-bis(4-fluorophenyl)-N"-[(2-fluoro-4-pyridyl)methyl]-1,3
,5-triazine-2,4,6-triamine dihydrochloride,
compound (7) means
N- (4-fluorophenyl)-N'-[(2-fluoro-4-pyridyl)methyl]-N"-(4-met
hylphenyl)-l,3,5-triazine-2,4,6-triamine hydrochloride,
compound (8) means
N- (4-fluorophenyl)-N'-[(2-fluoro-4-pyridyl)methyl]-N"-(4-met

hoxyphenyl)-1,3,5-triazine-2,4,6-triamine hydrochloride,
compound (9) means
N-(4-chlorophenyl)-N'-[(2-fluoro-4-pyridyl)methyl]-N"-(4-flu
orophenyl)-1,3,5-triazine-2,4,6-triamine hydrochloride,
compound (10) means
N-(4-fluorophenyl)-N'-[(2-fluoro-4-pyridyl)methyl]-N"-(3-met
hoxyphenyl)-1,3,5-triazine-2,4,6-triamine hydrochloride.
The compounds (5)-(10) are described in U. S . PatentNo. 7,375,222.

The data shows that BEC1 potassium channel inhibitors are
useful for the prevention and/or treatment of schizophrenia. The
pharmaceutical composition of the present invention is useful
for providing an excellent prophylactic 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.

Industrial Applicability
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.

we claim:
1. A pharmaceutical composition for prevention and/or
treatment of schizophrenia, comprising an effective amount of
a BEC1 potassium channel inhibitor or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
carrier.
2. The pharmaceutical composition according to claim 1,
wherein the BEC1 potassium channel inhibitor is a compound of
the following formula (I) or a pharmaceutically acceptable salt
thereof:

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) CN, (iii) NO2, (iv) halogen, (v) lower alkyl
which may be substituted with (1) CN, (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) lower alkyl which may
be substituted with aryl, or (3) 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-O- or OH, or (3)
aryl; and T1 represents 0 or S), or (xi) R11-T2- (wherein R11

represents (1) OH, (2) R7R8N-, (3) lower alkyl-O-, (4) lower alkyl,
(5) aryl, or (6) a heterocyclic group; and T2 represents CO or
SO2) .
3. The pharmaceutical composition according to claim 2,
wherein the formula (I) is a compound wherein
R and R2, which may be the same or different, each represents
H or lower alkyl 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) ,
or a pharmaceutically acceptable salt thereof.
4 . ABEC1 potassium channel inhibitor or a pharmaceutically
acceptable salt thereof for the prevention and/or treatment of
schizophrenia.
5. The BEC1 potassium channel inhibitor according to claim
4, wherein the BEC1 potassium channel inhibitor is a compound
of the following formula (I) or a pharmaceutically acceptable
salt thereof:

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) CN, (iii) NO2, (iv) halogen, (v) lower alkyl
which may be substituted with (1) CN, (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) lower alkyl which may
be substituted with aryl, or (3) R9-0-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-O- or OH, or (3)
aryl; and T1 represents 0 or S) , or (xi) R11-T2- (wherein R11
represents (1) OH, (2) R7R8N-, (3) lower alkyl-O-, (4) lower alkyl,
(5) aryl, or (6) a heterocyclic group; and T2 represents CO or
S02) .
6. The BEC1 potassium channel inhibitor according to claim
5, wherein the formula (I) is a compound wherein
R1 and R2, which may be the same or different, each represents
H or lower alkyl 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),
or a pharmaceutically acceptable salt thereof.
7. A method of preventing and/or treating schizophrenia,
comprising administering an effective amount of a BEC1 potassium
channel inhibitor or a pharmaceutically acceptable salt thereof
in a patient in need of such disease.
8. The method according to claim 7, wherein the BEC1 potassium
channel inhibitor is a compound of the following formula (I) or
a pharmaceutically acceptable salt thereof:


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) CN, (iii) NO2/ (iv) halogen, (v) lower alkyl
which may be substituted with (1) CN, (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) lower alkyl which may
be substituted with aryl, or (3) R9-0-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-O- or OH, or (3)
aryl; and T1 represents 0 or S) , or (xi) R11-T2- (wherein R11
represents (1) OH, (2) R7RBN-, (3) lower alkyl-O-, (4) lower alkyl,
(5) aryl, or (6) a heterocyclic group; and T2 represents CO or
S02) .
9. The method according to claim 8, wherein the formula
(I) is a compound wherein
R1 and R2, which may be the same or different, each represents
H or lower alkyl 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 O),
or a pharmaceutically acceptable salt thereof.

The present invention is useful for providing an excellent
pharmaceutical composition for prevention and/or treatment of
schizophrenia, containing a BEC1 potassium channel inhibitor or
a pharmaceutically acceptable salt thereof as an active
ingredient, and is particularly useful for providing a
pharmaceutical composition for prevention and/or treatment of
the positive symptoms, negative symptoms, cognitive impairments
and the like of schizophrenia.