Description
Technical Field
This invention relates to medicaments, particularly an
anti-dementia agent which comprises a substance having BEC 1
potassium channel inhibitory action as the active ingredient,
preferably an anti-dementia agent wherein the substance
having BEC 1 potassium channel inhibitory action is a 2,4,6-
triamino-1,3,5-triazine derivative or a pharmaceutically
acceptable salt thereof, and a novel 2 , 4,6-triamino-1,3,5-
triazine derivative or a pharmaceutically acceptable salt
thereof.
Background of the Invention
Potassium channel is a protein which distributes in the
plasma membrane of cells and lets potassium ions selectively
pass trough it and is considered to be taking an important
role in controlling membrane potential of cells.
Particularly, this is contributing to the neurotransmission
of central and peripheral nerves, pace-making of the heart,
contraction of muscles and the like by regulating frequency,
persistency and the like of action potential in nerve and
muscle cells.

As the classification based on the opening and closing
mechanism of the channel, a voltage-dependent potassium
channel, an inwardly rectifying potassium channel, a calcium-
dependent potassium channel, a receptor coupling type
potassium channel and the like have so far been identified.
Among them, the voltage-dependent potassium channel has a
property to open it when the membrane potential is
depolarized. In general, potassium ions are present in a
non-equilibrium state of about 5 mM in the extracellular
moiety and about 150 mM in the intracellular moiety.
Accordingly, when the voltage-dependent potassium channel is
opened due to depolarization, potassium ions flow out from
the intracellular part into the extracellular part and cause
restoration (re-polarization) of membrane potential as a
result. Thus, reduction of excitability of nerve and muscle
calls is induced accompanied by the opening of the voltage-
dependent channel [Non-patent reference 1] .
Compounds capable of modifying opening of the voltage-
dependent channel have a possibility to regulate various
physiological phenomena by regulating excitability of nerve
and muscle cells and therefore to become therapeutic drugs of
various diseases.
For example, it is known that 4-aminopyridine which is
an inhibitor of the A type voltage-dependent potassium
channel found in nerve cells causes epilepsy by increasing

excitability of nerves [Non-patent reference 3]. In
addition, dofetilide which is an inhibitor of HERG potassium
channel expressing in the heart, among voltage-dependent
potassium channels, is used as an agent for treating
arrhythmia based on its property to control excitability of
cardiac muscle cells [Non-patent reference 4] .
The potassium channel described as SEQ ID NO: 2 in
Example 1 of U.S. Patent 6,32 6,168 (corresponding
international patent publication pamphlet WO 99/37677)
[Patent reference 1] (to be referred to as BEC 1 or BEC 1
potassium channel hereinafter) is a voltage-dependent
potassium channel which shows an expression distribution
localized to the brain. Its expression is significant
particularly in the hippocampus and cerebral cortex. The
hippocampus is a region whose relation to memory and learning
are strongly suggested [Non-patent reference 5].
Particularly, granule cells of dentate gyrus and CA 1
and CA 3 pyramidal cells wherein BEC 1 pottasium channel
expresses form a neural circuit, and input of various
memories is transmitted from the granule cells of dentate
gyrus to the CA 3 pyramidal cell through the CA 1 pyramidal
cell, via an excitatory synapse which uses glutamic acid as
the neurotransmitter. It is considered that long-term
changes in the long-term potentiation, long-term depression
and the like synaptic transmission efficiencies found in

respective synapses are deeply concerned in the memory and
learning. These long-term changes are regulated by the
excitation frequency and excitation strength of nerve cells.
In addition, the voltage-dependent potassium channel
generally has a possibility of being able to control
excitability of nerve cells.
Accordingly, it is considered that BEC 1 is concerned
in the formation of memory and learning via the excitability
control of nerve cells, but this has not been illustratively
proved.
A large number of 2,4,6-triamino-1,3,5-triazine
derivatives are currently known, and their uses are disclosed
as an anti-HIV agent [Non-patent reference 6], an adenosine A
3 antagonist [Patent reference 2] , and antimicrobial agents
[Non-patent reference 7] , [Non-patent reference 8] , [Non-
patent reference 9] and [Patent reference 3]. Though many
potassium channel inhibitors and 2,4,6-triamino-1,3,5-
triazine derivatives have so far been reported [Patent
reference 3] and [Non-patent reference 10] , there are no
reports or suggestions stating that they have BEC 1 potassium
channel inhibitory action.
The object of the invention is to provide an anti-
dementia agent which uses a substance having BEC 1 potassium
channel inhibitory action (to be referred to as BEC 1
potassium channel inhibitor hereinafter) as the active

ingredient, preferably an anti-dementia agent wherein the BEC
1 potassium channel inhibitor is a 2 , 4,6-triamino-1,3,5-
triazine derivative or a pharmaceutically acceptable salt
thereof, a novel 2 , 4,6-triamino-1,3,5-triazine derivative
having BEC 1 potassium channel inhibitory action or a
pharmaceutically acceptable salt thereof, and a medicament
comprising said novel derivative or a pharmaceutically
acceptable salt thereof.
The present inventors have conducted studies with the
aim of achieving the above object and found as a result that
a BEC 1 potassium channel inhibitor can become an anti-
dementia agent. In addition, it was found unexpectedly that
a compound having the 2,4,6-triamino-1,3,5-triazine structure
has a BEC 1 potassium channel inhibitory action, thus
resulting in the accomplishment of the invention.
[Non-patent reference 1]
• Hille, B. (ed), Ionic Channels of Excitable Membranes
(Sinauer Associates, Sunderland, 1992)
[Non-patent reference 2]
• Catterall, W.A., Chandy, K.G. & Gutman G.A. (eds), The
IUPHAR Compendium of Voltage-gated Ion Channels (IUPHAR
Media, Leeds, UK, 2002)
[Non-patent reference 3]
• Yamaguchi, S. and Rogawski, M.A., Epilepsy Res., .11: 9 — 16
(1992)

[Non-patent reference 4]
• Gwilt, M., Arrowsmith, J.E., Blackburn, K.J., Burges, R.A.,
Cross, P.E., Dalrymple, H.W. and Higgins, A.J., J. Pharmacol.
Exp. Ther., 256: 318 - 324 (1991)
[Non-patent reference 5]
• Levitan, I.B. and Kaczmarek L.K. (1991), The Neuron: Cell
and Molecular Biology, Oxford University Press, New York, NY.
[Non-patent reference 6]
• Bioorg. Med. Chem. Lett., (2001) 11, 2229 - 2234
[Non-patent reference 7]
• Acta Cienc. Indica. Chem., (1992) 18(4), 405 - 406
[Non-patent reference 8]
• Acta Cienc. Indica. Chem., (1985) 11(1), 66 - 70
[Non-patent reference 9]
• J. Indian Chemical Society, (1987) 64(12), 770 - 771
[Non-patent reference 10]
• J. Inst. Chem. (India), (1987) 59(4), 183 - 185
[Patent reference 1]
• U.S. Patent 6,326,168
[Patent reference 2]
• JP-A-11-158073
[Patent reference 3]
• International Publication Pamphlet WO 99/1442

Disclosure of the Invention
The invention relates to an anti-dementia agent which
comprises a substance having BEC 1 potassium channel
inhibitory action as the active ingredient.
It is preferably an anti-dementia agent wherein the
substance having BEC 1 potassium channel inhibitory action is
a 2 , 4,6-triamino-1,3,5-triazine derivative represented by a
formula (I) or a pharmaceutically acceptable salt thereof

(symbols in the formula are as follows
R1 and R2: the same or different from each other, and
each represents H, OH, an alkyl-O-, an aryl-CO-, H2N, an
alkyl-NH which may be substituted with OH, an (alkyl)2N, a
hydrocarbon radical which may be substituted or a hetero ring
which may be substituted, or R1, R2 and the adjacent N may
together form a nitrogen-containing hetero ring and said ring
may be substituted,
R3, R4, R5 and R6: the same or different from one
another, and each represents (i) H, (ii) CN, (iii) NO2, (iv)
a halogen, (v) a lower alkyl which may be substituted with
(1) CN, (2) a halogen or (3) OH, (vi) a cycloalkyl, (vii) an
aryl which may be substituted with a lower alkyl, (ix) a
hetero ring which may be substituted with a lower alkyl, (x)

R7R8N- (R7 and R8: the same or different from each other, and
each represents (1) H or (2) a lower alkyl which may be
substituted with an aryl or R9-O-CO- (R9: (1) H or a lower
alkyl which may be substituted with an aryl) , (xi) R10-T1-
(R10: (1) H, (2) a lower alkyl which may be substituted with
an aryl, an HO-C1-10 alkylene-O- or HO or (3) an aryl, T1: O or
S) , or (xii) R11-T2- (R11: (1) OH, (2) R7R8N-, (3) a lower
alkyl-O-, (4) a lower alkyl, (5) an aryl or (6) a hetero
ring, (T2 : CO or SO2)) ,
further, R3, R4 and the adjacent C, or R5, R6 and the
adjacent C, may together form a hetero ring or cyclic
hydrocarbon ring, and the ring may be condensed with a
benzene ring).
Another embodiment of the invention is BEC 1 pottasium
channel described as SEQ ID NO:2 inhibitor having a 2,4,6-
triamino-1,3,5-triazine derivative represented by a formula
(I) or a pharmaceutically acceptable salt thereof as an
ingredient.
Also, another embodiment of the invention is a 2,4,6-
triamino-1,3,5-triazine derivative represented by a formula
(II) or a pharmaceutically acceptable salt thereof

(symbols in the formula are as follows

R1 and R2: the same or different from each other, and
each represents H, OH, an alkyl-O-, an aryl-CO-, H2N, an
alkyl-NH which may be substituted with OH, an (alkyl)2N, a
hydrocarbon radical which may be substituted or a hetero ring
which may be substituted, or R1, R2 and the adjacent N may
together form a nitrogen-containing hetero ring and said ring
may be substituted,
R3, R4, R5 and R6: the same or different from one
another, and each represents (i) H, (ii) CN, (iii) NO2, (iv)
a halogen, (v) a lower alkyl which may be substituted with
(1) CN, (2) a halogen or (3) OH, (vi) a cycloalkyl, (vii) an
aryl which may be substituted with a lower alkyl, (ix) a
hetero ring which may be substituted with a lower alkyl, (x)
R7R8N- (R7 and R8: the same or different from each other, and
each represents (1) H or (2) a lower alkyl which may be
substituted with an aryl or R9-O-CO- (R9: (1) H or a lower
alkyl which may be substituted with an aryl) , (xi) R10-T1-
(R10: (1) H, (2) a lower alkyl which may be substituted with
an aryl, an HO-C1-10 alkylene-O- or HO or (3) an aryl, T1: O or
S) , or (xii) R11-T2- (R11: (1) OH, (2) R7R8N-, (3) a lower
alkyl-O-, (4) a lower alkyl, (5) an aryl or (6) a hetero
ring, (T2: CO or SO2) ) ,
further, R3, R4 and the adjacent C, or R5, R6 and the
adjacent C, may together form a hetero ring or cyclic

hydrocarbon ring, and the ring may be condensed with a
benzene ring),
excluding a case in which R1 and R2 in the aforementioned
formula (II) are the same or different from each other, and
each represents (i) H, NH2, a cyclohexyl, phenyl which may be
substituted, Ra- (CH2)2- (Ra: HS, HO, R7R8N, COOH, an ethoxy,
CN, morpholino or chloro), an alkyl which may be substituted
with a substituent group of the following (a) to (e) ((a),
HOOC, (b) an alkyl-O-CO-, (c) phenyl which may be
substituted, (d) R7R8NCONHCO or (e) R7R8NCONHCO-) , an alkenyl,
phenyl-S-, phenyl-SO2-, phenyl-NHCS- which may be
substituted, phenyl-NHCO- which may be substituted, an alkyl-
O-CO-, H2NCS, chloro-COCH2- or 1,3,4-oxadiazol-2-ylmethyl
which may be substituted, or R1, R2 and the adjacent C
together form pyrazol-1-yl, indol-1-yl, indazol-2-yl,
piperidin-1-yl or morpholin-4-yl and R3, R4, R5 and R6 are the
same or different from one another and each represents H, a
halogen, NO2, acetyl, HO, a 1 ower alkyl—O-, HOOC—, a lower
alkyl-O-CO-, H2NSO2- or a lower alkyl; the same shall apply
thereinafter).
Still another embodiment of the invention is a
medicament which comprises the 2,4,6-triamino-1,3,5-triazine
derivative described by the aforementioned formula (II) or a
pharmaceutically acceptable salt thereof.

Preferred embodiment of the invention is a 2,4,6-
triamino-1,3,5-triazine derivative or a pharmaceutically
acceptable salt thereof having the following substituent
groups in the formula (I) or formula (II);
(1) R1 and R2 are different from each other and are H
and a hydrocarbon radical which may be substituted, and the
hydrocarbon radical is more preferably an alkyl, further
preferably a hetero ring-substituted alkyl which may be
substituted,
(2) R1 and R2 are different from each other and are H
and a hetero ring which may be substituted, and said hetero
ring is more preferably a four- to six-membered single ring
containing 1 or 2 hetero atoms selected from S and O,
(3) R3, R4, R5 and R6 are H,
(4) R3, R4, R5 and R6 are the same or different from one
another and are H and a halogen,
(5) R3, R4, R5 and R6 are the same or different from one
another and are H and a lower alkyl which may be substituted
with [(1) a halogen or (2) OH],
(6) R , R4, R5 and R are the same or different from one
another and are H, a halogen and a lower alkyl which may be
substituted with [(1) a halogen or (2) OH],
(7) R3, R4, R5 and R6 are the same or different from one
another and are H and R10-T1-, or

(8) R3, R4, R5 and R6 are the same or different from one
another and are H, a halogen and R10-T1-.
Particularly preferred is a 2,4,6-triamino-1,3,5-
triazine derivative or a pharmaceutically acceptable salt
thereof, having a combination of the aforementioned (1) or
(2) with any one of (3) to (8) .
Preferred compound is any one of the 2,4,6-triamino-
1,3,5-triazine derivatives shown in the following table or a
pharmaceutically acceptable salt thereof.


A further embodiment of the invention is a method for
treating dementia, which comprises administering the
aforementioned BEC 1 inhibitor to a patient.
. A still further embodiment is a method for preparing a
medicament, particularly a pharmaceutical composition for

dementia treatment use, which comprises a compound obtained
by a screening method in which a compound to be tested is
allowed to contact with BEC 1 potassium channel-expressed
cells to identify if it inhibits said channel activity.
The symbols used hereinafter have the same meanings.
The following further describes the compound
represented by the general formula (I) or (II) . Unless
otherwise noted, the term "lower" as used in the definition
of the general formula of this specification means a straight
or branched carbon chain having from 1 to 6 carbon atoms.
As the "halogen", fluorine, chlorine, bromine or iodine
atom can be cited.
The "hydrocarbon radical" is a straight or branched
chain hydrocarbon radical having from 1 to 15 carbon atoms,
preferably from 1 to 10 carbon atoms, or a cyclic hydrocarbon
radical having from 3 to 15 carbon atoms. The straight or
branched chain hydrocarbon radical is an "alkyl", an
"alkenyl" or an "alkynyl". Illustrative example of the
"alkyl" is methyl, ethyl, isopropyl, hexyl, decyl,
tetradecyl, pentadecyl or the like. The "alkenyl" is a
hydrocarbon radical having at least one or more double bonds,
such as vinyl, propenyl, allyl, isopropenyl, hexenyl or the
like. The "alkynyl" is a hydrocarbon radical having at least
one or more triple bonds, such as ethynyl, propynyl, butynyl
or the like. The cyclic hydrocarbon radical is a

"cycloalkyl", a "cycloalkenyl" or an "aryl". Illustrative
example of the "cycloalkyl" is a monocyclic saturated ring
such as cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl,
cyclodecyl or the like. Said cycloalkyl may be bridged or
condensed with benzene. For example, a C3-10 cycloalkyl shown
below is desirable. The "cycloalkenyl" is a hydrocarbon ring
having one or more double bonds, and said cycloalkenyl may be
condensed with a hetero ring, an aryl or a C3-10 cycloalkyl.
For example, a C3-8 cycloalkenyl shown below is desirable.
The "aryl" means an aromatic hydrocarbon radical including a
C6-14 aryl such as phenyl, naphthyl, anthryl or the like.
Said aryl may be condensed with a hetero ring, a C3-10
cycloalkenyl, a C3-10 cycloalkyl or a benzene-condensed
cycloalkyl. For example, a di or tricyclic shown below is
desirable.
Particularly, a di or tricyclic aryl condensed with
benzene ring together with R3, R4 and the adjacent C, or R5,
R6 and the adjacent C, may be substituted.
As said substituent group, oxo (=O), an aryl, an OH-
aryl and a lower alkyl-O-aryl can be exemplified.



The "hetero ring" is a four- to seven-membered
monocyclic, bicyclic or tricyclic aliphatic ring or aromatic
ring containing from 1 to 4 hetero atoms selected from N, S
and O. Said ring may be bridged or condensed with a C3-10
cycloalkyl or a aryl. For example, the hetero rings shown in
the following are preferred illustrative examples.



Regarding an aromatic nitrogen-containing hetero ring
among the aforementioned hetero rings, a nitrogen atom on
said ring may be quaternarized or form N-oxide.
The "nitrogen-containing hetero ring" is the
aforementioned hetero ring having at least one nitrogen atom.
As the substituent group of the "hydrocarbon, radical
which may be substituted", substituent groups of the group a
described in the following can preferably be exemplified.
As the substituent group of the "hetero ring which may
be substituted" and "nitrogen-containing hetero ring which
can be formed by R1 and R2 together with the adjacent N",
substituent groups of the group a described in the following
can preferably be exemplified.

Group a: (i) CN, (ii) NO2, (iii) a halogen, (iv) R7R8N-
(R7 and R8: the same or different from each other, and each
represents (1) H, (2) a lower alkyl which may be substituted
with an aryl or R9-O-CO- (R9: (1) H or a lower alkyl which may
be substituted with an aryl) , (3) an aryl which may be
substituted with CN or a lower alkyl, (4) a hetero ring, (5)
a lower alkyl-CO-, (6) a lower alkyl-O-CO-. (7) a cycloalkyl
which may be substituted with HS- or a lower alkyl-S-, (8) an
aryl-SO2- which may be substituted with NO2 or (9) a hetero
ring-SO2-) , (v) R10-T1- (R10: (1) H, (2) a lower alkyl which
may be substituted with an aryl, an HO-C1-10 alkylene-O- or HO
or (3) an aryl, T1: O or S) , (vi) R11-T2- (R11: (1) OH, (2)
R7R8N-, (3) a lower alkyl-O-, (4) a lower alkyl, (5) an aryl
or (6) a hetero ring (T2: CO or SO2) ) , (vii) a lower alkyl
which may be substituted with a substituent group among the
following (1) to (6) ((1) a halogen, (2) CN, (3) OH, (4)
R10CO-, (5) R7R8N- or (6) an aryl), (viii) a cycloalkyl which
may be substituted with a lower alkyl, (ix) a cycloalkenyl,
(x) a cycloalkynyl, (xi) an aryl which may be substituted
with a substituent group among the following (1) to (5) ( (1)
a halogen, (2) NO2, (3) R12-T1- (R12: R10 or a lower alkyl-aryl
which may be substituted with OH, (4) H2NO2S- or (5) a lower
alkyl which may be substituted with a halogen or OH) , or
(xii) a hetero ring which may be substituted with a
substituent group among the following (1) to (9) ( (1) a

halogen, (2) oxo (=0) , (3) NO2, (4) a lower alkyl which may
be substituted with [R7R8N-, R10-T1-, an aryl which may be
substituted with (OH, a halogen or a lower alkyl-O-), (5) an
aryl which may be substituted with a halogen, (6) OH, (7) a
lower alkyl-O-, (8) R7R8N-, or (9) a hetero ring,
The "BEC 1" and "BEC 1 potassium channel" mean the
complete length protein represented by SEQ ID NO:2, or a
fragment of said protein having the same function of said
protein, or a fragment or complete length protein of said
protein in which one or more amino acids may be substituted,
deleted or inserted.
The "substance having BEC 1 potassium channel
inhibitory action" can be obtained by subjecting compounds to
be tested to a typical screening method such as the method
described in U.S. Patent 6,326,168.
a) Screening method which uses voltage-clump method
It is possible to measure channel activity of the BEC 1
potassium channel protein by the whole-cell voltage-clamp
method. Cells expressing this channel protein are voltage-
clamped and whole-cell current is recorded by the whole-cell
voltage-clamp method. For example, a solution containing 145
mM NaCl, 5.4 mM KC1, 2 mM CaCl2 and 0.8 mM MgCl2 is used as
the extracellular solution, and a solution containing 155 mM
KC1 is used as the intracellular solution (patch electrode
solution). A compound and a peptide capable of modifying

activity of the BEC 1 potassium channel protein can be
screened by comparing outward currents generated by a
depolarization stimulus, namely shifting a membrane potential
from a holding potential (e.g., -70 mV) to a depolarization
side (e.g., -80 mV) , in the presence and absence of each drug
to be tested,
b) Screening method which uses release of Rb+ ion
In general, the potassium channel can pass Rb+ ion
similar to K+ ion, so that the channel activity can be
measured using release of a radioisotope 86Rb+ as a marker.
By incubating cells expressing the novel potassium channel
protein together with 86RbCl (e.g., 18 hr, 37°C) , 86Rb+ can be
incorporated into the cells. The cells are washed with a low
K+ concentration physiological saline (e.g., 4.5 mM K+) and
then suspended in the same solution. When a high K+
concentration solution (e.g., 100 mM in final concentration)
is added to the cell suspension, membrane potential of the
cell is depolarized and the potassium channel therefore is
activated. As a result, the intracellular 6Rb+ is released
into the extracellular part, thus radioactivity of the
extracellular solution can be used as a marker of the channel
activity. It is possible to screen a compound and a peptide
capable of modifying activity of the BEC 1 potassium channel
protein, by comparing the radioactivity released into the

extracellular part when the high K+ concentration solution is
added in the presence and absence of each drug to be tested.
c) Screening method which uses a voltage-sensitive dye or a
intracellular K+-detecting dye
It is possible that a voltage-sensitive dye or a
intracellular K+-detecting dye can optically detect a change
in the potential or intracellular K+ concentration
accompanied by the opening of potassium channel. As the
voltage-sensitive dye, RH 155, WW 781, Di-4-ANEPPS,
derivatives thereof and the like can be used. In addition, a
chimeric protein in which the amino acid sequence of green
fluorescent protein is inserted into the C-terminal
intracellular region of a Shaker type membrane voltage-
dependent potassium channel can also be used in the detection
of membrane potential (Siegel, M.S. and Isacoff, E.Y. (1997),
Neuron, 19, 735 - 741) . As the intracellular K+~detecting
dye, K+-binding benzofuran isophthalate and the like can be
used. By the use of these dyes, channel activity of the BEC
1 potassium channel can be measured and it is possible to
screen a compound and a peptide capable of modifying activity
of the BEC 1 potassium channel protein by comparing their
changing amounts in the presence and absence of a drug to be
tested.

Preferred screening method is a method for measuring
BEC 1 inhibitory activity of a compound using 86Rb ion
releasing amount as the index, which is described later.
In addition, by allowing the Example 13 as a typical
compound of the invention and a compound to be tested to
undergo competitive BEC 1 potassium channel inhibition, a
substance having said action can be obtained.
The compound to be tested may be illustratively any
substance which has said inhibitory activity, and its
examples include known compounds commercially available or
registered in chemical file, a group of compounds obtained by
combinatorial chemistry techniques, culture supernatants of
microorganisms, natural components derived from plants and
marine organisms, animal tissue extracts, antibodies and
dominant negative proteins and the like. Also included are
those in which said substances are modified with a
substituent group or the like by a chemical conversion as a
conventional method for those skilled in the art.
Depending on the type of groups, optical isomers
(optically active substances, diastereomers and the like) are
present in the compounds of the invention. Since compounds
having amide bond and double bond are present in the
compounds of the invention, tautomers based on the amide bond
and geometrical isomers are also present. Separated or mixed
forms of these isomers are included in the invention.

The compound of the invention forms a salt with an acid
or a base. Examples of the salt with an acid include acid
addition salts with inorganic acid such as hydrochloric acid,
hydrobromic acid, hydroiodic acid, sulfuric acid, nitric
acid, phosphoric acid and the like mineral acids, and with
organic acids such as formic acid, acetic acid, propionic
acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
maleic acid, lactic acid, malic acid, citric acid, tartaric
acid, carbonic acid, picric acid, methanesulfonic acid,
ethanesulfonic acid, glutamic acid and the like.
Examples of the salt with a base include salts with
sodium, potassium, magnesium, calcium, aluminum and the like
inorganic bases, methylamine, ethylamine, meglumine,
ethanolamine and the like organic bases, or lysine, arginine,
ornithine and the like basic amino acids, as well as an
ammonium salt. Also, the compound of the invention can form
a hydrate, solvates with ethanol and the like and
polymorphism.
In addition, all of the compounds which are metabolized
and converted in the living body, so-called prodrugs, are
also included in the active ingredient of the invention or
compound of the invention. Examples of the group which forms
the prodrug of the invention include the groups described in
Prog. Med., 5, 2157 - 2161 (1985) and "Iyakuhin-no Kaihatsu

(Development of Medicaments", Vol. 7 (Hirokawa Shoten, 1990),
Bunshi Sekkei (Molecular Design), pp. 163 - 198.
(Production methods)
The compound of the invention and a pharmaceutically
acceptable salt thereof can be produced applying various
conventionally known synthesis methods, making use of the
characteristics based on its basic nucleus and kinds of
substituent groups. For example, oxidation, reduction,
amination, alkylation, amidation, sulfonamidation,
esterification, urea formation and the like reactions can be
carried out by referring to the conditions described in
references such as "Jikken Kagaku Koza (Experimental
Chemistry Series)" 4th edition, edited by The Chemical
Society of Japan (1991) (published by Maruzen). In that
case, depending on the kinds of functional groups, it is
sometimes effective in view of production techniques to
replace said functional groups by appropriate protecting
groups (groups which can be easily converted into said
functional groups) at the stage of the material or an
intermediate. Examples of such functional groups include
amino group, OH (hydroxyl group), COOH (carboxy) and the
like, and examples of their protecting groups include the
protecting groups described in "Protective Groups in Organic
Synthesis (3rd edition)" edited by Greene and Wuts, which may
be optionally selected in response to the reaction

conditions. In such a method, the compound of interest can
be obtained by eliminating the protecting group as occasion
demands after carrying out the reaction by introducing said
protecting group.
Materials of the compounds of the invention and
production methods of the compounds of the invention are
described in detail in the following. Though the compounds
of the invention can be produced by conventionally known
methods, such as the methods described in Bull. Soc. Chim.
Fr. , 6, 2112 (1973) and the like, or modified methods
thereof, typical production methods are shown in the
following.



As the leaving group, (i) a halogen, (ii)
methylsulfanyl, (iii) methylsulfinyl, (iv) a C1-6
alkanesulfonyloxy group which may be substituted with 1 to 3
halogen (e.g., methanesulfonyloxy,
trifluoromethanesulfonyloxy or the like) , or (v) a C6-10
allenesulfonyloxy group which may be substituted with 1 to 4
C1-6 alkyl or halogen (e.g., p-toluenesulfonyloxy, p-
bromobenzenesufonyloxy or the like) can be exemplified.
Process A
The material compound (IV) or (VII) of the compound of
the invention can be synthesized by conventionally known
methods described in Agric. Biol. Chem., 51, 9, 2563 (1989)
and J. Am. Chem. Soc., 116, 4326 (1994) or modified methods
thereof.

Process B
The material compound (V) , (VI) or (VIII) of the
compound of the invention can be synthesized by
conventionally known methods described in J. Am. Chem. Soc.,
116, 2382 (1994), U.S. Patent 2,476,548, J. Chem. Soc, 561
(1948) and Yuki Gosel Kagaku Kyoka-shi (Journal of the
Society of Synthetic Organic Chemistry), vol. 18, p. 332
(1960) or modified methods thereof.
Process C
This Process is a method in which the compound (1-a) or
(1-b) of the invention is obtained by allowing a compound
(IV) , (V) , (VI) or (VIII) to react with an amine compound
(IX) or an aniline compound (X) or (XI). The reaction is
carried out under cooling to heating reflux using the
compound (IV) , (V) , (VI) or (VIII) and the compound (IX) , (X)
or (XI) at an equivalent molar ratio, or one of them in an
excess amount, without a solvent or in a solvent inert to the
reaction such as benzene, toluene, xylene or the like
aromatic hydrocarbon, diethyl ether, tetrahydrofuran (THF),
dioxane or the like ether, dichloromethane, 1,2-
dichloroethane, chloroform or the like halogenated
hydrocarbon, N,N-dimethylformamide (DMF), N,N-
dimethylacetamide (DMA), N-methylpyrrolidone, ethyl acetate
or acetonitrile. The reaction temperature can be optionally
set in response to the compounds. Depending on the

compounds, it is desirable in some cases to carry out the
reaction in the presence of an organic base (preferably
diisopropylethylamine, N-methylmorpholine, pyridine or 4-
(N,N-dimethylamino)pyridine) or a metal salt base (preferably
sodium hydride, potassium carbonate, sodium carbonate, sodium
bicarbonate, sodium hydroxide or potassium hydroxide). In
addition, depending on the compounds, it is advantageous in
some cases to carry out the reaction in the absence of a
base, for effecting smooth reaction.
The compound (I) of the invention can be isolated and
purified by conventionally known techniques such as solvent
extraction, liquid conversion, solvent partition,
crystallization, recrystallization, chromatography and the
like. In addition, material compound of the compound (III),
(IV) , (V) , (VI) , (VII) or (VIII) or a pharmaceutical^
acceptable salt thereof can be isolated and purified by the
same conventionally known techniques as described in the
above, but it may be directly used as the material of the
subsequent step as a reaction mixture without isolation.
In this connection, the aforementioned Processes are
not limited to the substituent groups in the formulae and can
be broadly applied to cases in which the compounds of the
invention have similar substituent groups.

The compound of the invention produced in such a manner
is isolated and purified in its free form or as a
pharmaceutically acceptable salt thereof.
The isolation and purification are carried out by
employing usual chemical operations such as extraction,
concentration, evaporation, crystallization, filtration,
recrystallization, various types of chromatography and the
like.
Various isomers can be separated by selecting an
appropriate material compound or making use of the difference
in physical property between isomers. For example, optical
isomers can be made into a stereochemically pure isomer by
selecting an appropriate material or by subjecting to optical
resolution of racemic compound (e.g., a method in which
optical resolution is carried out after converting into
diastereomer salts with a general optically active base).
Industrial Applicability
The invention relates to an anti-dementia agent which
uses a BEC 1 potassium channel inhibitor as the active
ingredient.
When a transgenic mouse in which the BEC 1 potassium
channel is frequently expressed in the hippocampus and
cerebral cortex was prepared and its behavior was analyzed,
it was revealed that learning performance of said mouse was

reduced in a Morris water maze learning test, a passive
avoidance task and a fear conditioning, which are described
later. In addition, immunohistochemical detection of the BEC
1 potassium channel using the brain of Alzheimer patients
suggested that its expression is increased in nerve cells of
the hippocampus and cerebral cortex. The above results
suggest a possibility that increase in the expression of the
BEC 1 potassium channel in the hippocampus and cerebral
cortex of the Alzheimer patient is inhibiting a memory and
learning-related neural transmission by reducing excitability
of nerve cells.
As a result of further conducting intensive studies, it
was confirmed that a BEC 1 potassium channel inhibitor, or a
compound shown in Invention Example 744 as a typical
compound, has an action to improve an amnesia induced by
electroconvulsive shock (ECS) in a mouse passive avoidance
task .
Based on the above, it was verified that the BEC 1
potassium channel inhibitor has an action to improve learning
disorder and is useful as a preventive or therapeutic agent
for a disease in which the BEC 1 potassium channel is
considered to be concerned, preferably dementia.
The pharmaceutical composition which contains one or
two. or more of the BEC 1 potassium channel inhibitors or
phannaceutically acceptable salts thereof as the active

ingredient is prepared using generally used pharmaceutical
carriers, fillers and other additives.
The pharmaceutical carriers and fillers may be either
in solid or liquid forms, and their examples include lactose,
magnesium stearate, starch, talc, gelatin, agar, pectin, gum
arabic, olive oil, sesame oil, cacao butter, ethylene glycol
and the like and other generally used substances.
The administration may be effected in the form of
either oral administration by tablets, pills, capsules,
granules, powders, solutions or the like or parenteral
administration by injections for intravenous injection,
intramuscular injection or the like, suppositories,
percutaneous preparations and the like.
The dose is optionally decided in response to each case
by taking into consideration symptoms and age, sex and the
like of each patient to be treated, but is usually within the
range of from 1 to 1,000 mg, preferably from 50 to 200 mg,
per adult per day by oral administration, or dividing the
daily dose into several doses per day, or from 1 to 500 mg by
parenteral administration, per day per adult, by dividing the
daily dose into 1 to several doses per day, or within the
range of from 1 hour to 2 4 hours per day by intravenous
continued administration. Since the dose varies under
various conditions as described in the foregoing, a smaller

dose than the aforementioned range may be sufficient enough
in some cases.
The solid composition for use in the oral
administration according to the present invention is used in
the form cf tablets, powders, granules and the like. In such
a solid composition, one or more active substances are mixed
with at least one inert diluent such as lactose, mannitol,
glucose, hydroxypropylcellulose, microcrystalline cellulose,
starch, polyvinyl pyrrolidone or aluminum magnesium silicate.
In the usual way, the composition may contain other additives
than the inert diluent, such as magnesium stearate or the
like lubricant, calcium cellulose glycolate or the like
disintegrating agent, lactose or the like stabilizing agent
and glutamic acid, aspartic acid or the like solubilization
assisting agent.
If necessary, tablets or pills may be coated with a
sugar coat or a film of a gastric or enteric substance such
as sucrose, gelatin, hydroxypropylcellulose,
hydroxypropylmethylcellulose phthalate or the like.
The liquid composition for oral administration includes
pharmaceutically acceptable emulsions, solutions,
suspensions, syrups, elixirs and the like and contains a
generally used inert diluent such as purified water or ethyl
alcohol. In addition to the inert diluent., this composition
may also contain a moistening agent, a suspending agent and

the like auxiliary agents, as well as sweeteners, flavors,
aromatics and antiseptics.
The injections for parenteral administration includes
aseptic aqueous or non-aqueous solutions, suspensions and
emulsions. Examples of the diluent for use in the aqueous
solutions and suspensions include distilled water for
injection and physiological saline. Examples of the diluent
for use in the non-aqueous solutions and suspensions include
propylene glycol, polyethylene glycol, olive oil or the like
plant oil, ethanol or the like alcohol, polysorbate 80 and
the like. Such a composition may further contain additive
agents such as an antiseptic, a moistening agent, an
emulsifying agent, a dispersing agent, a stabilizing agent
(e.g., lactose) and a solubilization assisting agent (e.g.,
glutamic acid or aspartic acid). These compositions are
sterilized by filtration through a bacteria retaining filter,
blending of a germicide or irradiation. Alternatively, they
may be used by firstly making.into sterile solid compositions
and dissolving them in sterile water or a sterile solvent for
injection use prior to their use.
Best Mode for Carrying Out the Invention
(Examples)
Next, the invention is described further in detail
based on examples, but the invention is not limited to these

examples. In this connection, production methods for the
starting compounds to be used in the Invention Examples are
described as Reference Examples.
Unless otherwise noted, the term % as used in the
following means percent by weight. Other abbreviations as
used herein means as follows.
Symbols in the tables are as follows.
Ex: Invention Example Number
Ref: Reference Example Number
F: fluoro, Cl: chloro, NO2: nitro, OH: hydroxy, CN: cyano,
Me: methyl, Et: ethyl, Ph: phenyl, Py: pyridine, Py-2-
ylCH2NH: pyridin-2-ylmethylamino, Py-3-ylCH2NH: pyridin-3-
ylmethylamino, Py-4-ylCH2NH: pyridin-4-ylinethylamino, CF3:
trifluoromethyl, iPr: isopropyl, Pen: pentyl, cPr:
cyclopropyl, cHex: cyclohexyl, Bzl: benzyl, Bz: benzoyl,
diMePhNH: dimethylphenylamino, diMeOPhNH:
dimethoxyphenylamino, diClPhNH: dichlorophenylamino,
diCF3PhNH: ditrifluoromethylphenylamino, Ac: acetyl, AcOEt:
ethyl acetate, free: free form,
NMR: nuclear magnetic resonance spectrum (measured with
tetramesylsilane (TMS) internal standard (indicated by ppm) )
The 1H-NMR spectrum is expressed by chemical shift
value when TMS is used as the internal standard, and the
signals are indicated by the following abbreviations. s:
singlet, d: doublet, t: triplet, q: quartet, br: broad, m:

multiplet, m.p.: melting point [°C] (Melting point was
measured using a melting point measuring apparatus Yanako MP-
S3 manufactured by Yanagimoto and shown by uncorrected
value.)
MS: FAB-MS, MASS: ESI-MS, HPLC rt: HPLC retention time
Measuring apparatus: HPLC: 2790 separation module
manufactured by WATERS; MS: ZMD manufactured by Micromass
PDA detector: A 996 photodiode array detector
manufactured by WATERS
Measuring conditions: Column, WAKOSIL-2 5C18AR, 2.0 mm
I.D. x 30 mm
Column temperature: 35°C
Mobile phase solution A = 5 mM trifluoroacetic acid
aqueous solution, solution B = methanol
Detection wavelength: 254 nm or 210 nm
Sample input: 5 µl
Flow rate: 1.2 ml/min
In this connection, regarding mixing ratio of the
mobile phase, the initial stage solvent condition was used as
a 10% mobile phase B and increased thereafter to a 100%
mobile phase B with linear gradient spending 4 minutes, and
the subsequent 0.5 minute was used as a 100% mobile phase B.
Material compounds are shown in Reference Examples.

Reference Example 1
A 2.41 g portion of 2,4-dichloro-6-anilino-1,3,5-
triazine was dissolved in 20 ml of acetonitrile, and 2.09 ml
of diisopropylethylamine and 1.23 g of p-fluoroaniline were
added thereto and stirred overnight at room temperature. The
reaction solution was mixed with water and extracted with
ethyl acetate, and the organic layer was washed with 1 M
hydrochloric acid and saturated brine and then dried using
anhydrous magnesium sulfate.
The solvent was evaporated under a reduced pressure,
the thus obtained residue was applied to a silica gel column
chromatography and eluted with ethyl acetate:n-hexane (1:9),
and then the thus obtained crude product was crystallized
from benzene, thereby obtaining 2.25 g of 6-chloro-N-(4-
fluorophenyl)-N'-phenyl-1,3,5-triazine-2,4-
diamine as a white solid.
The compounds of Reference Examples 2 to 5 shown in the
following Table 4 were synthesized in the same manner as in
Reference Example 1.
Reference Example 6
A 2.59 g portion of 4,6-dichloro-N-(4-fluorophenyl)-
1,3,5-triazine was dissolved in 20 ml of acetonitrile, and
2.09 ml of diisopropylethylamine and 1.18 g of p-toluidine
were added thereto and stirred overnight at room temperature.

The reaction solution was mixed with water and extracted with
ethyl acetate, and the organic layer was washed with 1 M
hydrochloric acid and saturated brine and then dried using
anhydrous magnesium sulfate. The solvent was evaporated
under a reduced pressure, the thus obtained residue was
applied to a silica gel column chromatography and eluted with
ethyl acetate:n-hexane (1:9), and then the thus obtained
crude product was crystallized from benzene, thereby
obtaining 2.74 g of 6-chloro-N-(4-fluorophenyl)-N'-(4-
methylphenyl)-1,3,5-triazine-2,4-diamine as a white solid.
The compounds of Reference Examples 7 to 12 shown in
the following Table 4 were synthesized in the same manner as
in Reference Example 6.
Invention Example 1
A 200 mg portion of 6-chloro-N,N'-diphenyl-1,3,5-
triazine-2,4-diamine was dissolved in 10.0 ml of
acetonitrile, and 145 mg of 4-(aminomethyl)pyridine and 0.585
ml of diisopropylethylamine were added thereto and stirred
overnight at 80°C. The reaction solution was cooled down to
room temperature, and then mixed with water and extracted
with chloroform. The organic layer was washed with 5% citric
acid and saturated brine and then dried using anhydrous
magnesium sulfate. The solvent was evaporated under a
reduced pressure, the thus obtained residue was applied to a

silica gel column chromatograp********hy and eluted with ethyl
acetate:n-hexane (2:1), and then the thus obtained crude
product was crystallized from ethyl acetate/n-hexane, thereby
obtaining 107 mg of N,N'-diphenyl-N"-(4-pyridylmethyl)-1,3, 5-
triazine-2,4,6-triamine as light red crystals.
The compounds of Invention Examples 2 to 38 and
compounds of Invention Examples 740 to 815 shown in the
following Tables 5 to 7 and the following Tables 28 to 35
were synthesized in the same manner as in Invention Example
1.
Invention Example 39
A 207 mg portion of (4,6-dichloro-1,3,5-triazin-2-yl)
isopropylamine was dissolved in 10.0 ml of acetonitrile, and
369 mg of 4-methoxyaniline was added thereto and stirred at
80°C for 3 days. The reaction solution was cooled down to
room temperature, and then mixed with water and extracted
with ethyl acetate. The organic layer was washed with 1 M
hydrochloric acid aqueous solution and saturated brine and
then dried using anhydrous magnesium sulfate. The solvent
was evaporated under a reduced pressure, and the thus
obtained residue was applied to a silica gel column
chromatography and eluted with ethyl acetate:n-hexane (2:1)
to obtain a clued product. This crude product was dissolved
in ethyl acetate and mixed with 4 M hydrochloric acid ethyl

acetate solution, the solvent was evaporated under a reduced
pressure, and the thus obtained residue was crystallized from
ethyl acetate, thereby obtaining 332 mg of N-isopropyl-N' ,N"-
bis(4-methoxyphenyl)-1,3,5-triazine-1,3,5-triamine
hydrochloride as colorless crystals.
The compounds of Invention Examples 40 to 44 shown in
the following Table 7 were synthesized in the same manner as
in Invention Example 39.
Invention Example 45
A 316 mg portion of the 6-chloro-N-(4-fluorophenyl)-N'-
phenyl-1,3,5-triazine-2,4-diamine was dissolved in 10.0 ml of
acetonitrile, and 0.523 ml of diisopropylethylamine and 0.170
ml of isopropylamine were added thereto and stirred overnight
at 80°C. The reaction solution was cooled down to room
temperature, and then mixed with water and extracted with
ethyl acetate. The organic layer was washed with 5% citric
acid aqueous solution and saturated brine and then dried
using anhydrous magnesium sulfate. The solvent was
evaporated under a reduced pressure, and the thus obtained
residue was applied to a silica gel column chromatography and
eluted with ethyl acetate:n-hexane (2:1) to obtain a crude
product. This crude product was dissolved in ethyl acetate
and mixed with 4 M hydrochloric acid ethyl acetate solution,
the solvent was evaporated under a reduced pressure, and the

thus obtained residue was crystallized from ethyl acetate,
thereby obtaining 327 mg of N-(4-fluorophenyl)-N'-isopropyl-
N"-phenyl-1,3,5-triazine-2,4,6-triamine hydrochloride as
colorless crystals.
The compounds of Invention Examples 4 6 to 50 shown in
the following Table 8 were synthesized in the same manner as
in Invention Example 45.
Invention Example 51 (A synthesis example by combinatorial
chemistry)
A 7.5 mg (60 umol) portion of p-fluorobenzylamine and
52 µl of diisopropylethylamine were added to a mixed solution
of 400 µl of acetonitrile and 120 µl of N-methylpyrrolidone
containing 8.9 mg (30 µmol) of 6-chloro-N,N'-diphenyl-1,3,5-
triazine-2,4-diamine and stirred at 80°C for 3 hours. The
reaction solution was filtered and then injected into a
fractional LC-MS apparatus to collect a fraction containing
the desired molecular weight. By evaporating the solvent,
6.1 mg (yield 45%) of N,N'-diphenyl-N"-(4-fluorobenzyl)-
1,3,5-triazine-2,4,6-triamine was obtained. A retention time
of 2.77 minutes and a purity of 93% were determined by an
analytical LC-MS.
The compounds of Invention Examples 52 to 418 shown in
the following Tables 9 to 18 were synthesized in the same
manner as in Invention Example 51.

Invention Example 419
A 6.7 mg (60 µmol) portion of 2-fluoroaniline was added
to a mixed solution of 400 µl of acetonitrile and 120 µl of
N-methylpyrrolidone containing 8.9 mg (30 µmol) of 6-chloro-
N,N'-diphenyl-1,3,5-triazine-2,4-diamine and stirred at 80°C
for 3 hours. The reaction solution was filtered and then
injected into a fractional LC-MS apparatus to collect a
fraction containing the desired molecular weight.
By evaporating the solvent, 6.0 mg (yield 54%) of N,N'-
diphenyl-N"-(2-fluorophenyl)-1,3,5-triazine-2,4,6-triamine
was obtained. A retention time of 3.01 minutes and a purity
of 94% were determined by an analytical LC-MS.
The compounds of Invention Examples 420 to 583 shown in
the following Tables 19 to 22 were synthesized in the same
manner as in Invention Example 419.
Invention Example 584
A 10 mg portion of 2,6-dichloro-N-isopropyl-1,3,5-
triazine-4-amine was dissolved in 600 ul 'of N-methyl-2-
pyrrolidone, and 400 µl of 0.5 mM 2-fluoroaniline N,N-
dimethylformamide solution and 2 6 µl of diisopropylethylamine
were added thereto and stirred at 120°C for 3 days. The
reaction solution was mixed with 50 mg (4.27 mmol/g) of PS-
trisamine manufactured by Algonote and further stirred at

120°C for 7 hours. After cooling down to 50°C, the reaction
solution was mixed with 50 mg (1.53 mmol/g) of PS-
benzaldehyde manufactured by Algonote and further stirred at
50°C for 16 hours. The reaction solution was cooled down to
room temperature and then mixed with saturated sodium
bicarbonate aqueous solution and chloroform and stirred.
After filtration of the solution, the organic layer was dried
using anhydrous sodium sulfate, and then the solvent was
evaporated under a reduced pressure to obtain 7 mg of N,N'-
di- (2-fluorophenyl)-N"-isopropyl-1,3,5-triazine-2,4,6-
triamine as a brown resinous substance.
The compounds of Invention Examples 585 to 636 shown in
the following Tables 23 and 24 were synthesized in the same
manner as in Invention Example 584.
Invention Example 637
A 14 mg portion of 6-chloro-N-isopropyl-N'-phenyl-
1,3,5-triazine-2,4-diamine was dissolved in 800 µl of N-
methyl-2-pyrrolidone, and 200 µl of 0.5 mM 2-fluoroaniline
N,N-dimethylformamide solution and 50 µl of 4 M hydrochloric
acid/dioxane were added thereto and stirred at 80°C for 7
hours. After cooling down the reaction solution to 60oC, SO
mg (4.27 mmol/g) of PS-trisamine and 50 mg (1.53 mmol/g) of
PS-benzaldehyde both manufactured by Algonote were added to
the reaction solution and further stirred at 60°C for 16

hours. The reaction solution was cooled down to room
temperature and then mixed with saturated sodium bicarbonate
aqueous solution and chloroform and stirred. After
filtration of the solution, the organic layer was dried using
anhydrous sodium sulfate, and then the solvent was evaporated
under a reduced pressure to obtain 13 mg of N-(2-
fluorophenyl)-N'-isopropyl-N"-phenyl-1,3,5-triazine-2,4,6-
triamine as a brown resinous substance.
The compounds of Invention Examples 638 to 739 shown in
the following Tables 2 4 to 27 were synthesized in the same
manner as in Invention Example 637.
Invention Example 816
A 565 mg portion of the N-(4-fluorophenyl)-N'-[(6-
methoxypyridin-3-yl)methyl]-N"-phenyl-1,3,5-triazine-2,4,6-
triamine hydrochloride synthesized in Invention Example 753
was mixed with 5 ml of 25% hydrobromic acid acetic acid
solution and 1 ml of 48% hydrobromic acid aqueous solution
and stirred at 80°C for 6 hours. After evaporation of the
reaction solution under a reduced pressure, the residue was
mixed with ethyl acetate and sodium bicarbonate aqueous
solution in that order and extracted with ethyl acetate. The
organic layer was washed with saturated brine and dried using
anhydrous magnesium sulfate. The solvent was evaporated
under a reduced pressure, and the thus obtained residue was

applied to a silica gel column chromatography and eluted with
chloroform:methanol (99:1) to obtain a crude product. This
crude product was dissolved in ethyl acetate and mixed with 4
M hydrochloric acid ethyl acetate solution, and the thus
formed crystals were collected by filtration and dried to
obtain 195 mg of 5-[ ({4-anilino-6-[(4-fluorophenyl)amino]-
1,3,5-triazin-2-yl)amino)methyl]pyridine-2(1H) -one
hydrochloride as colorless crystals.
The compounds of Invention Examples 817 and 818 shown
in the following Table 35 were synthesized in the same manner
as in Invention Example 816.
Invention Example 819
A 250 mg portion of the tert-butyl {6-[({4-anilino-6-
[(4-fluorophenyl)amino]-1,3,5-triazin-2-yl}-
) amino]methyl}pyridin-2-yl)carbamate hydrochloride
synthesized in Invention Example 758 was dissolved in 10.0 ml
of ethyl acetate, and 10.0 ml of 4 M hydrochloric acid ethyl
acetate solution was added thereto and stirred at room
temperature for 4 hours. The thus formed pale yellow
crystals were collected by filtration and dried to obtain 190
mg of N-[(6-aminopyridin-2-yl)methyl]-N'-(4-fluorophenyl)-N"-
phenyl-1, 3,5-triazine-2,4,6-triamine hydrochloride as pale
yellow crystals.

Invention Example 820
A 360 mg portion of the N-(4-fluorophenyl)-N'-{[1-(4-
methoxybenzyl)-1H-1,2,4-triazol-5-yl]methyl}-N"-phenyl-1,3,5-
triazine-2,4,6-triamine hydrochloride synthesized in
Invention Example 7 67 was dissolved in 5 ml of
trifluoroacetic acid and stirred at 70°C overnight. After
evaporation of the reaction solution under a reduced
pressure, the residue was mixed with ethyl acetate and sodium
bicarbonate aqueous solution in that order and extracted with
ethyl acetate. The organic layer was washed with saturated
brine and dried using anhydrous magnesium sulfate. The
solvent was evaporated under a reduced pressure, and the thus
obtained residue was applied to a silica gel column
chromatography and eluted with chloroform:methanol (92.8) to
obtain a crude product. This crude product was dissolved in
ethyl acetate and mixed with 4 M hydrochloric acid ethyl
acetate solution, and the thus formed crystals were collected
by filtration and dried to obtain 268 mg of N-(4-
fluorophenyl)-N'-phenyl-N"-(1H-1,2,4-triazol-3-yl) -
1, 3,5-triazine-2,4,6-triamine hydrochloride as colorless
crystals.
Invention Example 821
A 678 mg portion of [(1-trityl-1H-imidazol-4-
yl)methyl]amine was dissolved in 10.0 ml of acetonitrile, and

0.52 ml of diisopropylethylamine and 316 mg of the 6-chloro-
N-(4-fluorophenyl)-N'-phenyl-1,3,5-triazine-2,4-diamine
synthesized in Reference Example 1 were added thereto and
stirred at 80°C for 3 days. After cooling down to room
temperature, the reaction solution was mixed with water and
extracted with ethyl acetate. The organic layer was washed
with citric acid aqueous solution and saturated brine and
dried using anhydrous magnesium sulfate. The solvent was
evaporated under a reduced pressure, and the thus obtained
residue was applied to a silica gel column chromatography and
eluted with chloroform:methanol (99:1) to obtain a crude
product. This crude product was dissolved in 9 ml of acetic
acid and 1 ml of water and stirred at 70°C for 2 hours.
After evaporation of the reaction solution under a reduced
pressure, the residue was mixed with ethyl acetate and sodium
bicarbonate aqueous solution in that order and extracted with
ethyl acetate. The organic layer was washed with saturated
brine and dried using anhydrous magnesium sulfate. The
solvent was evaporated under a reduced pressure, and the thus
obtained residue was applied to a silica gel column
chromatography and eluted with chloroform:methanol (90:10) to
obtain a crude product. This crued product was dissolved in
ethyl acetate and mixed with 4 M hydrochloric acid ethyl
acetate solution, and the thus formed crystals were collected
by filtration and dried to obtain 306 mg of N-(4-

fluorophenyl)-N'-(1H-imidazol-4-ylmethyl)-N"-phenyl-1,3,5-
triazine-2,4,6-triamine hydrochloride as colorless crystals.
In the following, structures and physical property
values of the compounds of Reference Examples and Invention
Examples are shown in Tables 4 to 35.
In addition, the compounds shown in the following
Tables 36 to 39 can also be synthesized in the same manner as
in the aforementioned Invention Examples. The sign "No" in
the tables indicates compound number.
Invention Example 822
(Test method)
Method for measuring BEC 1 inhibitory activity of
compounds using released amount of 86Rb ions as the index
The channel activity of BEC 1 was measured in
accordance with the method described in WO 99/37677, using
amount of a radioisotope 86Rb ion released from a BEC 1-
expressing cell as the index. That is, when an 86Rb ion-
incorporated BEC 1-expressing cell was stimulated with 100 mM
KCl, the radioactivity released from the cell was used as the
channel activity of BEC 1. The 86Rb ions were incorporated
into a BEC 1-stably expressing cell by culturing the cell (3
hours, 37°C) in the presence of 86RbCl (0.5 µCi/ml) , and the
un-incorporated 86Rb ions were removed by washing three times
with HEPES-buffered saline (pH 7.4, 2.5 mM KCl) . The cells

were incubated with HEPES-buffered saline containing a
compound to be tested at room temperature for 15 minutes and
then further incubated with 100 mM KCl-containing HEPES-
buffered saline (pH 7.4) containing the compound to be tested
at room temperature for 5 minutes . The extracellular medium
was recovered, and then the remaining cells were lysed with
0.1 N NaOH and recovered.
The Cerenkov radioactivity of the extracellular medium
and cell lysate was respectively measured, and their total
was used as the total radioactivity. The released amount of
86Rb ions was expressed by the percentage of extracellular
medium radioactivity based on the total radioactivity. The
value obtained in the presence of the compound was used as a
test value, and the value obtained in the absence of the
compound as a control value and the value obtained when not
stimulated with 100 mM KCl as a blank value. Inhibitory
action of each compound was expressed by % inhibition, namely
(control value - test value) x 100/(control value - blank
value) , or by an IC50 value calculated from the % inhibition.
As the test results of typical compounds are shown in the
following Tables 2 and 3, it was confirmed that said
compounds have the BEC 1 potassium channel inhibitory action.
In this connection, as the BEC 1-expressing cell, a BEC
1-stably expressing cell prepared in accordance with the
method described in WO 99/37677 using a dihydrofolate

reductase (dhfr)-deficient strain of a Chinese hamster ovary-
cell was used.


Invention Example 823
Evaluation of BEC 1 current inhibitory activity by a
compound using an electrophysiological technique
BEC 1-expressing cells were voltage-clamped and whole-
cell current was recorded by the whole-cell voltage-clamp
method. A solution containing 140 mM NaCl, 5.4 mM KCl, 2 mM
CaCl2, 0.8 mM MgCl2, 15 mM glucose and 10 mM HEPES (pH = 7.4
by adding NaOH) was used as the extracellular solution, and a
solution containing 125 mM KC1, 1 mM CaCl2, 2 mM MgCl2, 11 mM
EGTA and 10 mM HEPES (pH = 7.2 by adding KOH) was used as the
intracellular solution (patch electrode solution).
A continuous outward current is induced by depolarizing
the membrane potential from -90 mV to 0 mV. By comparing
amplitude of this outward current in the absence of an agent
(control value) with the current amplitude at the time of the
administration of a compound to be tested (test value), %
inhibition [(test value/control value) x 100] was calculated.
Test results
As a result, in the case of the compound of Invention
Example 13, it showed 50% or more of inhibition at a
concentration of 1 µM.

Invention Example 824
Preparation of transgenic mouse

The transgene for production of a transgenic mouse
overexpressing BEC1 having the amino acid sequence described
in SEQ ID NO:2 comprises a gene in which a BEC 1 cDNA (SEQ ID
NO:l) with a 5' intron and poly(A) addition signal is linked
to a downstream of the promoter region of α-calcium-
calmodulin-dependent kinase II gene. The promoter region of
α-calcium-calmodulin-dependent kinase II was obtained as two
fragments having a mutually overlapping region, by PCR using
a C57BL/6 mouse genomic DNA as the template. The C57BL/6
mouse genomic DNA was purified from a blood sample of the
same mouse using a genomic DNA extraction kit (QIAamp DNA
Blood Midi Kit, mf d. by QIAGEN) . Primers were designed based
on the sequence registered in a gene data base GenBank
(Accession No. AJ222796) . A gene fragment of 4.6 kb was
obtained using an oligonucleotide comprising the nucleotide
sequence represented by SEQ ID NO:3 as the forward primer and
using an oligonucleotide comprising the nucleotide sequence
represented by SEQ ID NO:4 as the reverse primer. An Aatll
recognition sequence is added to the 5' terminal side of the
aforementioned forward primer. In addition, a gene fragment
of 3.7 kb was obtained using an oligonucleotide comprising

the nucleotide sequence represented by SEQ ID NO:5 as the
forward primer and using an oligonucleotide comprising the
nucleotide sequence represented by SEQ ID NO:6 as the reverse
primer. A Sail recognition sequence is added to the 5'
terminal side of the aforementioned reverse primer. Each PCR
was carried out using a DNA polymerase (Pfu Turbo, mfd. by
Stratagene) by employing a thermal denaturation at 99°C (1
minute) and subsequent repetition of 45 cycles each
comprising 99°C (15 seconds) , 58°C (15 seconds) and 75°C (10
minutes) , or a thermal denaturation at 95°C (1 minute) and
subsequent repetition of 40 cycles each comprising 95°C (15
seconds) , 62°C (15 seconds) and 75°C (8 minutes) , and the thus
obtained gene fragment was cloned into a cloning vector (pCR-
XL-TOPO plasmid, mfd. by Invitrogen). An endogenous Xmal
recognizing sequence is present in the overlapping region of
the 4.6 kb fragment and 3.7 kb fragment. The 4.6 kb fragment
was digested with restriction enzymes AatcII and XmaI, and the
3.7 kb fragment was digested with restriction enzymes XmaI
and SaiI. The thus obtained respective fragments were
ligated and cloned into a plasmid pUC18 (mfd. by Toyobo)
making use of the AatII and SaiI recognition sequences. The
α-calcium-calmodulin-dependent kinase II promoter region of
interest was obtained by the above operation.
On the other hand, the BEC 1 cDNA (SEQ ID NO:1) was
obtained as a fragment containing a 5' intron and poly(A)

addition signal by PCR using a potassium channel expression
vector pME-E1 (described in WO 99/37677) as the template. An
oligonucleotide comprising the nucleotide sequence
represented by SEQ ID NO:7 was designed as the forward
primer, and an oligonucleotide comprising the nucleotide
sequence represented by SEQ ID NO:8 as the reverse primer,
respectively from the upstream sequence of 5' intron and
downstream sequence of poly(A) addition signal.
A SaiI recognition sequence was added to the
aforementioned forward primer, and KpnI and NotcI recognizing
sequences to the reverse primer. PCR was carried out using a
DNA polymerase (Pfu Turbo, mfd. by Stratagene) by employing a
thermal denaturation at 96°C (1 minute) and subsequent
repetition of 30 cycles each comprising 96°C (15 seconds),
60°C (15 seconds) and 75°C (8 minutes) . The thus obtained 3.7
kb fragment was cloned into a cloning vector (pCR-XL-TOEO
plasmid, mfd. by Invitrogen) . This fragment was subcloned
into a plasmid pUCl8 (mfd. by Toyobo) making use of the SpeI
recognition sequence and KpnI recognition sequence, and the
aforementioned α-calcium-calmodulin-dependent kinase II
promoter region was further subcloned into its upstream
making use of the AatII recognition sequence and SalI
recognition sequence. A plasmid (named pCM-El plasmid)
having a transgene (12 kb) for use in the preparation of a

BEC 1-overexpressing transgenic mouse was finally obtained by
the above operation.

The transgene (12 kb) for production of a BEC-
overexpressing transgenic mouse was cut out from pCM-E1 using
restriction enzymes AatII and NotcI and then isolated and
purified. The thus obtained gene was micro-injected into 283
fertilized eggs of F1 hybrid mice of C57BL/6 and DBA2 mice,
and then the resulting fertilized eggs were transplanted into
oviducts of ICR foster mother mice (Hogan, B. et al. (1986),
Manipulating the mouse embryo: a laboratory manual,
Plainview, New York; Cold Harbor Press) . The pregnant mice
were allowed to undergo spontaneous delivery, and the thus
obtained 81 offspring mice were subjected to the
identification of transgenic mice.
In order to identify transgenic mice, PCR was carried
out using genomic DNA isolated from the tail of each
offspring mouse as the template. The genomic DNA was
purified from the tail of each mouse using a genomic DNA
extraction kit (MagExtractor —Genome-, mfd. by Toyobo). When
an oligonucleotide comprising the nucleotide sequence
represented by SEQ ID NO:9 is designed as the forward primer,
and an oligonucleotide comprising the nucleotide sequence
represented by SEQ ID NO:10 as the reverse primer, from the

BEC 1 cDNA (SEQ ID NO:1), and PCR is carried out using them,
a 245 bp fragment is amplified from the transgene, and a 338
bp fragment containing 93 bp intron of mouse BEC 1 from the
mouse genomic DNA. PCR was carried out on the thus obtained
baby mouse genomic DNA preparations using these priers.
PCR was carried out using a DNA polymerase (AmpliTaq,
mfd. by Roche) by employing a thermal denaturation at 94°C (1
minute) and subsequent repetition of 35 cycles each
comprising 94°C (15 seconds), 60°C (15 seconds) and 72°C (30
seconds). As a result, it was identified that 16 of the 81
baby mice are transgenic mice.

In order to confirm that the introduced gene is
actually functioning and BEC 1 mRNA is over-expressing,
expression of BEC 1 mRNA in the brain of transgenic mouse was
analyzed. In order to obtain F1 mice for brain extraction
use, 11 animals among the 16 transgenic mice were crossed
with C57BL/6 mice. As a result, transfer of the transgene to
Fl mice was confirmed in 5 transgenic mice. The fore-brain
and cerebellum were sampled from each of the thus obtained Fl
transgenic mice (4-week-old) to isolate respective RNA.
Each RNA was digested with a DNase (mfd. by Promega)
for the purpose of preventing contamination of genomic DNA.
The number of copies of BEC 1 mRNA in the thus obtained RNA
was determined by a real time PCR using PRISM 7700 (mfd. by

ABI) and a fluorescence reagent SYBR Green (mfd. by Molecular
Probe). A single-stranded cDNA synthesized from each RNA
using a reverse transcriptase-polymerase chain reaction kit
(Advantage RT-for-PCR Kit, mfd. by Clontech) was used as the
template of the real time PCR. An oligonucleotide comprising
the nucleotide sequence represented by SEQ ID NO:11 was
designed as the forward primer, and an oligonucleotide
comprising the nucleotide sequence represented by SEQ ID
NO:12 as the reverse primer, from a sequence common to the
transgene, human BEC 1, and rat and mouse BEC 1.
As a result of the real time PCR, over-expression of
fore-brain-selective BEC 1 mRNA about 10 times larger than
that of wild type was found in 3 lines (# 6-5, # 7-7 and # 9-
5) among the 5 lines of transgenic mice. By selecting the
line # 9-5, expressed amounts of BEC 1 mRNA in respective
regions of the brain (cerebral cortex, hippocampus, corpus
striatum, hypothalamus, thalamus, mid-brain, brain stem,
cerebellum) of wild type mouse were compared with those of
the transgenic mouse. As a result, it was confirmed that the
BEC 1 mRNA over-expression in the transgenic mouse is
significant in cerebral cortex, hippocampus and corpus
striatum in which the expression was also found in the wild
type.

Invention Example 825

In order to analyze action of BEC 1 over-expression
upon cognition, learning and memory of # 9-5 line transgenic
mice and that of wild type mice in a Morris water maze were
compared.
Male 10-week-old transgenic mice (12 animals) and wild
type mice (15 animals) were used. A circular pool of 100 cm
in diameter was filled with water which had been clouded
using paints, and a circular platform of 10 cm in diameter
was arranged at a position of 5 mm below the water. Room
temperature and water temperature at the time of the test was
23°C. Swimming pattern of each mouse put into the pool was
recorded and analyzed by a water maze image analyzer (NIH
image, mfd. by O'Hara & CO.), and the escape latency to the
platform and the time spent in each quadrant of the pool were
measured. Maximum trial duration was 70 seconds, and the
training was carried out 3 trials per day for 5 days. The
escape latency to the platform on the first day of the
training was almost the same value in both groups, but the
escape latency was prolonged in the transgenic mice than the
wild type mice on and after the 3rd day of the start of the
training. On the final day of the training, the escape
latency to the platform (average value ± standard deviation)

became 6.9 ± 1.0 seconds in the wild type and 18.1 ± 6.4
seconds in the transgenic mice, thus showing a statistically
significant difference (p < 0.05: two-way layout analysis of
variance) .
After completion of the training, each mouse received a
single 40 seconds test with the platform had been removed,
and the time of the mouse spend in the platform-existed
quadrant was measured. As a result, the time spend in the
platform-existed quadrant of transgenic mice was
significantly shorter than that of the wild type (p < 0.01:
Student's t test).
The above results show that learning and memory on the
platform position are reduced in the transgenic mice.
Invention Example 82 6

Female # 9-5 line transgenic mice (6 animals) and wild
type mice (8 animals) , 8-week-old, were used. Each mouse was
put into the light compartment of a light and dark test
apparatus for mice (mfd. by O'Hara & CO.), and a 60 V shock
for 2 seconds was applied to the mouse when it entered the
dark compartment. The mouse was again put into the light
compartment 24 hours thereafter, and the entry latency into
the dark compartment at this time was measured.

As a result, the entry latency of the transgenic mice
was 167 seconds (median value) which was significantly short
compared to the 600 seconds (median value) of the wild type
mice (p < 0.05: Wilecoxon rank sum test).
It was shown that the ability to learn the dark
compartment-related electric shock is reduced in the
transgenic mice.
Invention Example 827
Electricity chorea shock (ECS)-induced learning disorder
(mouse passive evasion reaction test)
The evaluation was carried out in the following manner
with reference to a report (Eur. J. Pharmacology, 321; 273 -
278, 1997).
Animals; Male ddy mice (SLC, five weeks of age at the time of
the training) were used. Arranged into 31 or 32 animals per
group.

Drug preparation
A compound to be evaluated was suspended in a solution
prepared by dissolving methyl cellulose in physiological
saline to a concentration of 0.5% (hereinafter, 0.5% methyl
cellulose solution) . The administration volume was set to 10
ml per 1 kg body weight. As a placebo of the compound to be

evaluated, 10 ml of the 0.5% methyl cellulose solution per 1
kg body weight, (hereinafter, vehicle) was administered.
Training
(1) Mice were allowed to stand in a laboratory for 1
hour or more on the first day of the test.
(2) Each mouse was put into the light compartment of a
passive avoidance task apparatus and allowed to stand for 30
seconds. Thereafter, the Guillotine door was opened. When
the mouse received an electric shock (intensity 60 V, delay 1
sec, duration 3 sec) by entering into the dark compartment
and then returned into the light compartment, the Guillotine
door was closed to let the mouse to stand for 30 seconds in
the light compartment.
(3) The mouse was removed and attached with a cornea
electrode quickly (within 1 minute), and then an
electroconvulsive shock (ECS, 50 Hz, interval 20 ms, duration
10 ms, amplitude 20 mA, gate 1 sec) was applied.
(4) The compound was administered intraperitoneally.
(5) Returned to the home cage.
(6) After completion of the training, allowed to stand
in the laboratory for 60 minutes or more and then returned to
the rearing room.
Test (24 hours after the training)
(1) Animals were allowed to stand in a laboratory for 1
hour or more. ' <

(2) Each mouse was put into the light compartment and
allowed to stand for 30 seconds, and then the Guillotine door
was opened.
(3) A period of time until the mouse crossed a sensor
in the dark compartment after opening the Guillotine door
(step-through latency) was recorded. The maximum measuring
time was set to 600 seconds.
(4) The step-through latency was employed as the index
of the formation of learning. Effect of the compound on ECS-
induced amnesia was evaluated by comparison between a step-
through latency of (ECS + vehicle administration) group and a
that of (ECS + evaluation compound administration) group.
Data were analyzed using two-tailed steel test. P<0.05 was
considered significant. When the compound described in
Invention Example 744 was intraperitoneally administered, its
minimum effective dose was 3 mg/kg.
As a result of the above, it was confirmed that the
compound described in Invention Example 744 as a typical
compound has the BEC 1 potassium channel inhibitory activity
and shows the improving effect on electroconvulsive shock
(ECS)-induced amnesia in the mouse passive avoidance task.

WE CLAIM:
1. A 2,4,6-triamino-1,3,5-triazine selected from the group consisting of the following
compounds or a pharmaceutically acceptable salt thereof:
N,N'-diphenyl-N"-(4-pyridylmethyl)-1,3,5-triazine-2,4,6-triamine,
N,N'-diphenyl-N"-(pyridin-3-ylmethyl)-1,3,5-triazine-2,4,6-triamine,
N,N'-diphenyl-N"-(pyridin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine,
N-[(2-fluoropyridin-4-yl)methyl]-N',N"-diphenyl-1,3,5-triazine-2,4,6-triamine,
N-[(2-chloropyridin-4-yl)methyl]-N',N"-diphenyl-1,3,5-triazine-2,4,6-triamine,
N-[(2-isopropylpyridin-4-yl)methyl-N',N"-diphenyl-1,3,5-triazine-2,4,6-triamine,
N,N'-diphenyl-N"-(2-pyridin-4-ylethyl)-1,3,5-triazine-2,4,6-triamine,
N-(3,4-difluorophenyl)-N'-[(2-fluoropyridin-4-yl)methyl]-N"-phenyl-1,3,5-triazine-2,4,6-
triamine,
N-[(2-fluoropyridin-4-yl)methyl]N'-(4-methoxyphenyl)-N"-phenyl-1,3,5-triazine-2,4,6-
triamine,
N-(4-fluorophenyl)-N'-[(2-fluoropyridin-4-yl)methyl]-N"-(4-methylphenyl)-1,3,5-
triazine-2,4,6-triamine,
N-[(5-methyl-2-furyl)methyl]-N',N"-diphenyl-1,3,5-triazine-2,4,6-triamine,
N,N'-diphenyl-N"-(2-thienylmethyl]-1,3,5-triazine-2,4,6-triamine,
N-(2-furylmethyl)-N',N"-diphenyl-1,3,5-triazine-2,4,6-triamine,
N-(4-fluorophenyl)-N'-phenyl-N"-(pyrimidin-4-ylmethyl)-1,3,5-triazine-2,4,6-
triamine,
N'-bis(4-fluorophenyl)-N"-(pyrimidin-4-ylmethyl)-1,3,5-triazine-2,4,6-triamine,
N-(4-fluorophenyl)-N'-[(2-fluoropyridin-4-yl)methyl]-N"-(4-methoxyphenyl)-1,3,5-
triazine-2,4,6-triamine,
N-(4-chlorophenyl)-N'-(4-fluorophenyl)-N''-[(2-fluoropyridin-4-yl)methyl]-1,3,5-triazine-
2,4,6-triamine,
N-(4-chlorophenyl)-N'-[(2-fluoropyridin-4-yl)methyl)-N"-phenyl-1,3,5-triazine-2,4,6-triamine,

3-{[(4,6-dianilino-1,3,5-triazin-2-yl)amino]methyl}dihydrofuran-2(3H)-one,
N,N'-bis(4-fluorophenyl)-N'-(2-furylmethyl)-1,3,5-triazine-2,4,6-triamine,
N-(4-fluorophenyl)-N'-(phenyl)-N"-(1,3-thiazol-2-ylm-ethyl)-1,3,5-triazine-2,4,6-
triamine,
N-(4-fluorophenyl)-N'-(4-methoxyphenyl)-N"-(pyrimidin-4-ylmethyl]-1,3,5-triazine-
2,4,6-triamine,
N-(4-fluorophenyl)-N'-phenyl-N"-(pyridazin-4-ylm-ethyl)-1,3,5-triazine,2,4,6-
triamine,
N,N'-bis(4-fluorophenyl)-N"-(pyridazin-4-ylmethyl)-1,3,5-triazine-2,4,6-triamine,
N-(4-fluorophenyl)-N'-(4-methoxyphenyl)-N"-(pyridazin-4-ylmethyl)-1,3, 5-triazine, and
N-(2-furylmethyl)-N'-(4-methylphenyl)-N"-phenyl-1,3,5-triazine-2,4,6-triamine,
N,N'-diphenyl-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'-phenyl-N"-(pyrimidin-2-ylm-ethyl)-1,3,5-triazine-2,4,6-triamine,
N-(4-fluorophenyl)-N'-(4-methoxyphenyl)-N"-(pyrimi-din-2-ylmethyl)-1,3,5-triazine-
2,4,6-triamine,
N,N'-bis(4-fluorophenyl)-N"-(pryidin-4-ylmethyl)-1,3,5-triazine-2,4,6-triamine,
N,N'-bis(4-fluorophenyl)-N"-(pyridin-3-ylmethyl)-1,3,5-triazine-2,4,6-triamine,
N,N'-bis(4-fluorophenyl)-N"-(pyridin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine,
N,N'-bis(4-fluorophenyl)-N"-(2-fluoropyridin-4-yl)methyl]-1,3,5-phenyl-1,3,5-triazine-
2,4,6-triamine,
N-(4-fluorophenyl)-N'-(2-methylpyridin-4-yl)methyl]-N"-phenyl-1,3,5-triazine-2,4,6-
triamine,
N-[(2-fluoropyridin-4-yl)methyl]-N'-(4-methylphenyl)-N"-phenyl-1,3,5-triazine-
2,4,6-triamine,
{4-[({4-anilino-6-[(4-fluorophenyl)amino]-1,3,5-triazin-2-yl}amino)methyl]pyridin-2-
yl}methanol,
N-(4-fluorophenyl]-N'-(2-furylmethyl)-N"-phenyl-1,3,5-triazine-2,4,6-triamine,

N-(4-fluorophenyl)-N'-phenyl-N"-(1,3-thiazol-4-ylmethyl)-1,3,5-triazine-2,4,6-triamine,
N—(4-fluorophenyl)-N'-phenyl-N"-(pyridazin-3-ylm-ethyl)-1,3,5-triazine-2,4,6-triamine.
2. A 2,4,6-triamino-1,3,5-triazine selected from the group consisting of the
following compounds or a pharmaceutically acceptable salt thereof:
N,N'-diphenyl-N"-(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine,
N,N'-bis(4-fluorophenyl)-N"-(pyridin-2-ylmethyl)-l ,3,5-triazine-2,4,6-triamine,
N-(4-fluorophenyl)-N'-phenyl-N"-(pyrimidin-2-ylm-ethyl)-1,3,5-triazine-2,4,6-triamine,
and
N-(4-fluorophenyl)-N'-(4-methoxyplxenyl)-N"-(pyrimidin-2-ylmethyl)-1,3,5-triazine-
2,4,6-triamine.
3. A 2,4,6-triamino-1,3,5-triazine selected from the group consisting of the
following compounds or a pharmaceutically acceptable salt thereof:
N-(4-fiuorophenyl)-N'-phenyl-N"-(pyrimidin-4-ylm-ethyl-1,3,5-triazine-2,4,6-
triamine,
N,N'-bis(4-fluorophenyl)-N"-(pyrimidin-4-ylmethyl)-l ,3,5-triazine-2,4,6-triamine, and
N-(4-fluorophenyl)-N'-(4-methoxyphenyl)-N"-(pyrimidin-4-ylmethyl)-1,3,5-triazine-2,4,6-triamine,

A 2,4,6-triamine-1,3,5-triazine represented by formula (II) or a
pharmaceutically acceptable salt thereof

(symbols in the formula are as follows
R1:H
R2: a hydrocarbon radical which is lower alkyl, and which may be
substituted with substituents from a hetero ring which is a group
selected from a group of pyrrolidine, piperazine, azepin, thiophen,
1,2,4-triazole, tetrazole, 1,3-dioxane, thiazole, imidazole,
imidazo[2,1-b][1,3] thiazole, isoindoline, pyridine, tetrahydro-2H-
pyran, pyrimidine, pyridazine, indole, 1,2,3,4-
tetrahydroisoquinoline, benzimidazole and benzothiazole and said

hetero ring may be substituted with a substituent group among
the following (1) to (9)
((1) a halogen,
(2) oxo (=O),
(3) NO2,
(4) a lower alkyl which may be substituted with R7R8N-(R7 and R8:
the same or different from each other, and each represents (1) H,
(2) a lower alkyl which may be substituted with an aryl or R9a-O-
CO-(R9a:H or a lower alkyl which may be substituted with an aryl),
R10-T1-(R10: (1) H, (2) a lower alkyl which may be substituted with
an aryl, an HO-C1-10 alkylene-O- or HO or (3) an aryl, (T1:O or S),
aryl which may be substituted with OH, a halogen
or a lower alkyl-O-,
(5) an aryl which may be substituted with a halogen,
(6) OH,
(7) a lower alkyl-O-,
(8) R7R8N-, or
(9) a hetero ring),
R3,R4,R5 and R6: the same or different from one another, and each
represents
(i)H,
(ii) NO2,

(iii) a halogen
(iv) a lower alkyl which may be substituted with (1) CN, (2) a
halogen or (3) OH,
(v) a cycloalkyl,
(vi) an aryl which may be substituted with a lower alkyl,
(vii) R7R8N-(R7 and R8: the same or different from each other, and
each represents (1) H or (2) a lower alkyl which may be
substituted with an aryl or R9b-O-CO-(R9b: (1) H or a lower alkyl
which may be substituted with an aryl), or
(viii) R10-T1-(R10 : (1) H,(2) a lower alkyl which may be substituted
with an aryl, an HO-C1-10 alkylene-O-or HO or (3) an aryl,(T1:O or
S).