Derivatives of pyrimidine for treating acute cerebrovascular disorders

A pharmaceutical composition comprising a compound of the following general formula I! or its salt. ##STR1## wherein R.sup.1 represents aryl or a heteroaromatic group. R.sup.2 represents hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, haloalkyl, alkoxy, alkylthio, amino, monoalkylamino, dialkylamino, or phenyl. R.sup.3 and R.sup.4 independently represent hydrogen or alkyl or R.sup.3 and R.sup.4 taken together with the adjacent N atom represent a 5- through 7-membered cyclic amino group. A represents C.sub.2-10 alkylene. W represents O, S, or (CH).sub.n (where CH may be substituted by alkyl; n is an integer of 1 or 2). X, Y, and Z may be the same or different and each represents CH (which may be substituted by alkyl), or N. Provided, however, that the case in which X, Y, and Z concurrently represent CH is excluded. The compound of the invention has excellent neuronal death inhibitory activity and is useful as a therapeutic drug for cerebrovascular diseases.

TECHNICAL FIELD 
The present invention relates to a heterocyclic derivative which is useful 
as a medicine. 
BACKGROUND ART 
Cerebrovascular disease is a condition in which the blood vessels 
circulating the brain are impaired by, for example, cerebral infarction, 
cerebral hemorrhage, head trauma, or subarachnoid hemorrage. As the flow 
of blood to the brain is interrupted or decreased by a cerebrovascular 
disease and the brain becomes ischemic, the nerve cells are damaged. Even 
if the patient narrowly escapes death, he or she suffers from sequelae of 
neuronal death caused by this impairment. Therapeutic agents for 
cerebrovascular disease may be classified into the agents which act 
against brain infarction, hemorrhage, etc. and those which inhibit said 
neuronal death. 
It has recently become clear that once the brain tissue is brought into an 
ischemic state, even if the ischemia is transiently and the complete 
recovery of regional blood flow reinstates the normal energy metabolism 
and neural activity once, the final outcome is death of nerve cells. Such 
pathological changes of nerve cells, which characteristically occur 
predominantly in the hippocampus, manifest themselves in 3-4 days after 
ischemia and, therefore, are called delayed neuronal death. Moreover, even 
in the cerebral region not exposed to reperfusion, there are domains in 
which the blood flow is not completely interrupted but decreased. It is 
said that the nerve cells in such domains also succumb to death on 
prolongation of ischemia. This death of nerve cells could be blocked, the 
sequelae of a cerebrovascular disease following ischemia could be 
prevented. 
It is known that the cerebral metabolism enhancer, propentofylline is 
effective against delayed neuronal death but, partly because of its side 
effects, is not a fully satisfactory medicine. 
With therapeutic drugs in this field being the target, much research has 
been undertaken into inhibitors of excitatory amino acids. This is 
predicated on the concept of preventing ischemic death of neurons by 
inhibiting the excessive excitation of neurons following brain ischemia. 
It is well known that glutamic acid or glutamate is such an excitatory 
amino acid. As inhibitors of the excitatory amino acid, many glutamate 
antagonists which would specifically block the receptors of this amino 
acid and compounds which inhibit the release of glutamate are already 
known. The glutamate receptors are classified into the 
N-methyl-D-aspartate (hereinafter referred to as NMDA) receptors and 
receptors other than said NMDA receptors (hereinafter referred to as 
non-NMDA receptors). As an NMDA antagonist, MK-801, for instance, is 
known, while YM-90K, for instance, is known to be a non-NMDA antagonist. 
As glutamate release inhibitors, 
2,4-diamino-5-(2,3,5-trichlorophenyl)pyrimidine and 
2,4-diamino-5-(2-chlorophenyl)pyrimidine are known EP-A 459830; 6th 
SCI-RSC Medical Chemistry Symposium, Sep. 8-11, 1991!. 
Meanwhile, it is described in WO 92/04333 that a phenylpyrimidine 
derivative has learning-and-memory disorder improving activity and finds 
application in dementia. While various nerve systems have been impaired in 
dementia, it is known that the impairment of the cholinergic nervous 
system playing an important role in learning-and-memory is particularly 
serious. The phenylpyrimidine derivative disclosed in WO 92/04333 acts on 
the cholinergic nervous system and activates the residual nerve cells to 
ameliorate the learning-and-memory defects. This learning-and-memory 
improving action is quite different from the action to inhibit the onset 
of sequelae of a cerebrovascular disease through inhibition of neuronal 
death. 
In addition to the above-mentioned compounds, a variety of pyrimidine 
derivatives have so far been reported. For example, Japanese Examined 
Publication S48-21949 discloses that 
4-methyl-2-phenyl-6-2-(4-phenylpiperazin-1-yl)ethyloxy!pyrimidine, among 
others, has .alpha.-sympatholytic activity (sedation, hypotension, and 
vasodilation). Moreover, it is reported in CA 100: 209733u and CA 106: 
18488r that 4-2-(N,N-dimthylamino)ethyloxy!-6-methyl(or 
phenyl)-2-phenylpyrimidine and 
4-2-(N,N-dimethylamino)ethylthio!-6-methyl(or phenyl)-2-phenylpyrimidine 
respectively have the property to amplify the action of phleomycin. 
Furthermore, it is reported in J. Med. Chem. 31(6), 1231-40 (1988) that 
2-(2-dimethylamino)ethylthio-4-methyl(or unsubstituted)-6-phenyl(or 
aromatic heterocyclyl)pyrimidine derivatives and 
2-2-(N,N-dimethylamino)ethoxy!-4-thienylpyrimidine derivatives amplify 
the action of bleomycin. 
DISCLOSURE OF INVENTION 
The present invention has for its object to provide a pharmaceutical 
composition having a neuronal death inhibitory action and a novel 
heterocyclic compound which is an active ingredient of said composition. 
To accomplish the above-mentioned object, the inventors of the present 
invention have synthesized and screened a variety of compounds. In the 
course, they have discovered that a compound of the following general 
formula I! has a protetive activity aginst neuronal death, which is quite 
different from said learning-and-memory disorder improving action, with 
low toxicity, and have perfected the present invention. The compound of 
the present invention exhibits an excellent protective activity against 
neuronal death particularly in the acute phase of a cerebrovascular 
disorder and is, therefore, useful for the therapy of a cerebrovasuclar 
disorder and the inhibition of the onset of its sequelae. 
The present invention, in one aspect, relates to a pharmaceutical 
composition comprising a compound of the following general formula or a 
salt thereof, or a solvate thereof, as an active ingredient. 
##STR2## 
wherein R.sup.1 represents an aryl group that may be substituted or a 5- 
through 10-membered heteroaromatic group that may be substituted. The 
heteroaromatic group mentioned above is a monocyclic or fused ring system 
containing at least one hetero-atom selected from the group consisting of 
nitrogen, oxygen, and sulfur as a ring member. Each of said aryl group and 
heteroaromatic group may be substituted by 1-3 substitutes, whether the 
same or different, as selected from the group consisting of hydroxy, 
halogen, alkyl, haloalkyl, hydroxyalkyl, aralkyl, alkenyl, alkoxy, 
haloalkyloxy, alkylthio, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, 
alkylsulfonyl, sulfamoyl, alkanoyl, amino, monoalkylamino, dialkylamino, 
carboxy, alkoxycarbonyl, cyano, and nitro. 
R.sup.2 represents hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, 
hydroxyalkyl, haloalkyl, alkoxy, alkylthio, amino, monoalkylamino, 
dialkylamino, or phenyl that may be substituted. The phenyl mentioned just 
above may be substituted by 1-3 same or different substitutes selected 
from the group consisting of halogen, alkyl, and alkoxy. 
R.sup.3 and R.sup.4 may be the same or different and each represents 
hydrogen or alkyl that may be substituted (this alkyl may be substituted 
by 1 or 2 same or different substitutes selected from the group consisting 
of hydroxy, alkoxy, amino, monoalkylamino, and dialkylamino), or R.sup.3 
and R.sup.4 taken together with the adjacent N atom represent a 4- through 
8-membered cyclic amino group of the formula NR.sup.3 R.sup.4. This cyclic 
amino group may contain N, O, or S in addition to said N atom as a ring 
member and may be substituted by 1-3 substitutes, whether the same or 
different, as selected from the group consisting of alkyl, alkoxy, 
hydroxy, oxo, amino, monoalkylamino, dialkylamino, aryl that may be 
substituted, and pyridyl. 
The N atom to which R.sup.3 and R.sup.4 are bound may form an oxide. 
The symbol A represents alkylene of 2-10 carbon atoms. The alkylene may be 
substituted by one or more substitutes selected from the group consisting 
of alkoxy, hydroxy, and oxo in optional substitutable positions. 
E represents O or S. 
W represents a single bond, O, S, or (CH.sub.2).sub.n (where CH.sub.2 may 
be substituted by alkyl; n is an integer of 1 or 2). 
X, Y, and Z may be the same or different and each represents CH, CR (where 
R represents alkyl), or N. Excluded, however, is the case in which X, Y, 
and Z concurrently represent carbon, i.e. CH or CR. 
Ring G represents pyridine, pyrimidine, or 1,3,5-triazine. 
When any one through all the three of X, Y, and Z represent N, one of them 
may form an oxide. 
The present invention, in another aspect, relates to a compound of the 
following general formula Ia! and a salt thereof, inclusive of a solvate 
thereof. 
##STR3## 
wherein R.sup.11, R.sup.12, R.sup.13, R.sup.14, A.sup.1, E.sup.1, W.sup.1, 
X.sup.1, Y.sup.1, and Z.sup.1 correspond to R.sup.1, R.sup.2, R.sup.3, 
R.sup.4, A, E, W, X, Y, and Z, respectively, in formula I!; 
Provided, however, that the following compounds are excluded. 
(a) The compound in which A.sup.1 is an alkylene group of 2-3 carbon atoms, 
X.sup.1 =Y.sup.1 =N with Z.sup.1 =CH or X.sup.1 =Z.sup.1 =N with Y.sup.1 
=CH, W.sup.1 is a single bond, E.sup.1 is O, R.sup.11 is phenyl that may 
be substituted by hydroxy, alkoxy, trifluoromethyl, or halogen, R.sup.12 
is methyl, trifluoromethyl, or tert-butyl. 
(b) The compound in which A.sup.1 is an alkylene group of 2 carbon atoms, 
X.sup.1 =Y.sup.1 =N with Z.sup.1 =CH, W.sup.1 is --(CH.sub.2).sub.2 --, 
E.sup.1 is O, R.sup.11 is phenyl, and R.sup.22 is methyl. 
(c) The compound in which A.sup.1 is an alkylene group of 2 carbon atoms, 
ring G is pyrimidine, W.sup.1 is a single bond, E.sup.1 is S, and R.sup.12 
is hydrogen, methyl, or phenyl. 
One of the features of the present invention is that the compound of 
formula I! has brain neuronal death (death of nerve cells) protective 
activity which is quite different from the learning-and-memory disturbance 
ameliorating activity of the known phenylpyrimidine derivative (WO 
92/04333) which is structurally analogous to the compound of the invention 
or from the .alpha.-sympatholytic activity of the piperazine derivative 
described in JP Examined Publication S48-21949. 
The structural characteristics of the compound Ia! of the present 
invention are as follows: (1) the compound is structurally remote from the 
known therapeutic agents for cerebrovascular disease which are predicated 
either on glutamate antagonist-like activity or on glutamate release 
inhibitory activity and (2) the compound is different from the 
phenylpyrimidine derivative disclosed in WO 92/04333 in the number of 
carbon atoms constituting the alkylene chain. 
Among species of the compound of general formula I!, the above compound 
categories (a)-(c) include known species. However, the present inventors 
should be credited with the first discovery of excellent neuronal death 
inhibitory activity in these compounds. 
As examples of the compound of general formula I!, species of the 
following compound categories (A)-(D) can be mentioned. 
(A) The compound in which NR.sup.3 R.sup.4 is a 4- through 8-membered 
cyclic amino group and A is an alkylene group of 4-10 carbon atoms. The 
cyclic amino group may have oxygen or sulfur as a ring member and may have 
alkyl, alkoxy, hydroxy, oxo, amino, monoalkylamino, dialkylamino, pyridyl, 
or aryl as a substituent. The aryl mentioned just above may be substituted 
by 1-3 same or different substitutes selected from the group consisting of 
hydroxy, halogen, alkyl, haloalkyl, hydroxyalkyl, aralkyl, alkenyl, 
alkoxy, haloalkyloxy, alkylthio, cycloalkyl, cycloalkylalkyl, 
cycloalkyloxy, alkylsulfonyl, sulfamoyl, alkanoyl, amino, monoalkylamino, 
dialkylamino, carboxy, alkoxycarbonyl, cyano, and nitro. 
(B) The compound in which, referring to general formula I!, R.sup.1 is a 
5- through 10-membered heteroaromatic group, R.sup.2 is hydrogen, A is an 
alkylene group of 2-3 carbon atoms, which may be substituted by alkoxy, 
hydroxy, or oxo in an optional substitutable position, and E is O. The 
heteroaromatic group mentioned above is a monocyclic or fused ring system 
containing at least one hetero-atom selected from the group consisting of 
nitrogen, oxygen, and sulfur as a ring constituent atom and may be 
substituted by 1-3 same or different substitutes selected from the group 
consisting of hydroxy, halogen, alkyl, haloalkyl, hydroxyalkyl, aralkyl, 
alkenyl, alkoxy, haloalkyloxy, alkylthio, cycloalkyl, cycloalkylalkyl, 
cycloalkyloxy, alkylsulfonyl, sulfamoyl, alkanoyl, amino, monoalkylamino, 
dialkylamino, carboxy, alkoxycarbonyl, cyano, and nitro. 
(C) The compound in which R.sup.1 is a 5- through 10-membered membered 
heteroaromatic group which may be a monocyclic or fused ring system 
containing at least one hetero-atom selected from the group consisting of 
nitrogen, oxygen, and sulfur as a ring constituent atom, said 
heteroaromatic group being optionally substituted by 1-3 same or different 
substitutes selected from the group consisting of hydroxy, halogen, alkyl, 
haloalkyl, hydroxyalkyl, aralkyl, alkenyl, alkoxy, haloalkyloxy, 
alkylthio, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkylsulfonyl, 
sulfamoyl, alkanoyl, amino, monoalkylamino, dialkylamino, carboxy, 
alkoxycarbonyl, cyano, and nitro; R.sup.2 is alkyl, alkenyl, cycloalkyl, 
cycloalkylalkyl, hydroxyalkyl, haloalkyl, alkoxy, alkylthio, amino, 
monoalkylamino, dialkylamino, or phenyl; said phenyl may be substituted by 
1-3 same or different substitutes selected from the group consisting of 
halogen, alkyl, and alkoxy; and A is an alkylene group of 2-3 carbon 
atoms, which may be substituted by alkoxy, hydroxy, or oxo in an optional 
substitutable position. 
(D) The compound in which R.sup.1 is a 5- through 10-membered 
heteroaromatic group which may be a monocyclic or fused ring system which 
may contain at least one hetero-atom the group consisting of nitrogen, 
oxygen and sulfur as a ring constituent atom and be optionally substituted 
by 1-3 same or different substitutes selected from the group consisting of 
hydroxy, halogen, alkyl, haloalkyl, hydroxyalkyl, aralkyl, alkenyl, 
alkoxy, haloalkyloxy, alkylthio, cycloalkyl, cycloalkylalkyl, 
cycloalkyloxy, alkylsulfonyl, sulfamoyl, alkanoyl, amino, monoalkylamino, 
dialkylamino, carboxy, alkoxycarbonyl, cyano, and nitro; NR.sup.3 R.sup.4 
is piperazino which may be unsubstituted or substituted by alkyl, alkoxy, 
hydroxy, oxo, amino, monoalkylamino, dialkylamino, pyridyl, or aryl, said 
aryl being optionally substituted by 1-3 same or different substitutes 
selected from the group consisting of hydroxy, halogen, alkyl, haloalkyl, 
hydroxyalkyl, aralkyl, alkenyl, alkoxy, haloalkyloxy, alkylthio, 
cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkylsulfonyl, sulfamoyl, 
alkanoyl, amino, monoalkyl-amino, dialkylamino, carboxy, alkoxycarbonyl, 
cyano, and nitro. 
As used throughout this specification, the term "alkyl" means a 
straight-chain or branched alkyl group of 1-6 carbon atoms, such as 
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 
tert-butyl, n-pentyl, isopentyl, n-hexyl, or isohexyl. Particularly 
preferred is an alkyl group of 1-4 carbon atoms. 
The alkenyl means a group of 2-6 carbon atoms, such as vinyl, allyl, 
3-butenyl, 2-pentenyl, or 4-hexenyl. 
The cycloalkyl is preferably a group of 3-10 carbon atoms, such as 
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 
1-adamantyl, or 2-adamantyl. 
The aryl means a group of 6-13 carbon atoms, such as phenyl, 1-naphthyl, 
2-naphthyl, or biphenyl. Particularly preferred is phenyl. 
The aralkyl means a group of 7-13 carbon atoms, whose alkyl moiety is 
either straight-chain or branched, thus including benzyl, phenethyl, 
phenylpropyl, phenylbutyl, diphenylmethyl, and naphthylmethyl, among 
others. 
The halogen includes chlorine, fluorine, bromine, and iodine. 
The alkoxy is preferably a straight-chain or branched group of 1-6 carbon 
atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 
isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, 
or isohexyloxy. 
The alkanoyl means a straight-chain or branched group of 1-6 carbon atoms, 
such as acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, hexanoyl, or 
2-methylpentanoyl. 
The alkylthio is preferably a group having a straight-chain or branched 
alkyl moiety of 1-6 carbon atoms, such as methylthio, ethylthio, 
n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, 
tert-butylthio, n-pentylthio, isopentylthio, n-hexylthio, or isohexylthio. 
The alkylsulfonyl is preferably a group having a straight-chain or branched 
alkyl moiety of 1-6 carbon atoms, such as methylsulfonyl, ethylsulfonyl, 
n-propylpentylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutyl- 
sulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, 
isopentylsulfonyl, n-hexylsulfonyl, or isohexylsulfonyl. 
The hydroxyalkyl is a group having a straight-chain or branched alkyl 
moiety of 1-6 carbon atoms, such as 2-hydroxyethyl, 3-hydroxypropyl, 
2-hydroxy-propyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl, or 
6-hydroxyhexyl. 
The haloalkyl is a group having a straight-chain or branched alkyl moiety 
of 1-6 carbon atoms, such as trifluoromethyl, fluoromethyl, 2-bromoethyl, 
or 3-chloroethyl. 
The monoalkylamino is a group having a straight-chain or branched alkyl 
moiety of 1-6 carbon atoms, such as methylamino, ethylamino, propylamino, 
butylamino, heptylamino, or hexylamino. 
The dialkylamino is a group having straight-chain or branched alkyl 
moieties of 1-6 carbon atoms, such as dimethylamino, diethylamino, 
dipropylamino, dibutylamino, diheptylamino, or dihexylamino. 
The alkoxycarbonyl is preferably a straight-chain or branched group of 2-7 
carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 
iso-propoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, 
sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, 
isopentyloxycarbonyl, n-hexyloxycarbonyl, or isohexyloxycarbonyl. 
The cycloalkyloxy is preferably a group of 3-10 carbon atoms, such as 
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, 
cycloheptyloxy, cyclooctyloxy, or 2-adamantyloxy. 
The cycloalkylalkyl is preferably a group of 4-11 carbon atoms, such as 
cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, 
cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, 
cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, or 
2-adamantylmethyl. 
The 4- through 8-membered cyclic amino group includes azetidin-1-yl, 
pyrrolidin-1-yl, piperidino, hexamethylenimino, tetrahydropyridino, 
octahydroazocin-1-yl, piperazin-1-yl, homopiperazin-1-yl, morpholino, and 
thiomorpholino. 
The substituent that may be present on said cyclic amino group includes 
alkyl, alkoxy, hydroxy, oxo, amino, monoalkylamino, dialkylamino, aryl 
that may be substituted, and pyridyl that may be substituted. The 
substituent that may be present on the aryl or pyridyl includes the groups 
mentioned for the substituent on R.sup.1. 
The 5- through 10-membered heteroaromatic group is a monocyclic or fused 
ring system, which contains not less than 1 hetero-atom selected from the 
group consisting of oxygen, sulfur and nitrogen. Thus, for example, 
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 2-furyl, 2-pyrimidinyl, 
4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1-isoquinolyl, 
4-isoquinolyl, 2-quinazolinyl and 1-methyl-2-indolyl can be mentioned. 
The alkylene represented by A may be straight-chain or branched. For use of 
the compound as a therapeutic drug for cerebrovascular disease, A is 
preferably an alkylene group of 3-6 carbon atoms and more preferably a 
group of 4-6 carbon atoms. As far as the chemical compound is concerned, 
A.sup.1 is preferably an alkylene group of 4-6 carbon atoms. 
E preferably represents O. 
W preferably represents a single bond. 
X, Y, and Z are preferably such that X=Z=N with Y=CH or Z=N with X=Y=CH. 
The former combination is particularly preferred. 
R.sup.1 preferably represents halogen-substituted phenyl, particularly 
fluorophenyl. 
R.sup.2 is preferably alkyl or haloalkyl and more preferably alkyl. 
Particularly preferred is methyl. 
Preferably, R.sup.3 and R.sup.4 taken together with the adjacent N atom 
represent a cyclic amino group of the formula --NR.sup.3 R.sup.4. In 
particular, a cyclic amino group containing only one nitrogen atom as a 
ring-constituent hetero-atom is preferred. Especially preferred is 
piperidino. 
The compound which is particularly preferred in the sense that the delayed 
neuronal death can be inhibited regardless of whether it is administered 
before the onset of brain ischemia or after the onset is the compound of 
formula Ib!. 
##STR4## 
In the formula, A.sup.21 represents an alkylene group of 4-6 carbon atoms. 
E.sup.21 represents O. 
X.sup.21 .dbd.Z.sup.21 .dbd.N with Y.sup.21 .dbd.CH, or X.sup.21 
.dbd.Y.sup.21 .dbd.CH with Z.sup.21 .dbd.N. 
R.sup.21 represents halogen-substituted phenyl. 
R.sup.22 represents alkyl or haloalkyl. 
R.sup.23 and R.sup.24 taken together with the adjacent N atom represent a 4 
through 8 membered cyclic amino group of the formula --NR.sup.23 R.sup.24, 
said cyclic amino group containing only one nitrogen atom as a ring 
constituent hetero-atom. 
As particularly preferred species of the above compoud, there can be 
mentioned 4-(4-fluorophenyl)-2-methyl-6-(4-piperidinobutoxy)pyrimidine, 
4-(4-fluorophenyl)-2-methyl-6-(1-methyl-4-piperidinobutoxy)pyrimidine, 
4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine, 
4-(4-fluorophenyl)-2-methyl-6-(6-piperidinohexyloxy)pyrimidine, 
2-(4-fluorophenyl)-4-methyl-6-(4-piperidinobutoxy)pyrimidine, 
4-(4-fluorophenyl)-2-methyl-6-(3-piperidinopropoxy)pyridine, and 
4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyridine, inclusive 
of their salts. 
The solvate of compound I! falling within the scope of the present 
invention includes the hydrate and solvate with ethanol. 
The salt of compound I! falling within the scope of the invention includes 
salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric 
acid, phosphoric acid, hydrofluoric acid and hydrobromic acid, and salts 
with organic acids such as acetic acid, tartaric acid, lactic acid, citric 
acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, 
ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 
naphthalenesulfonic acid and camphorsulfonic acid. 
The compound of formula I! according to the present invention can be 
produced by, for example, the following processes. 
Process A 
##STR5## 
In the above reaction schema, R.sup.1 -R.sup.4, A, E, X, Y, Z, and W are as 
defined hereinbefore. Q represents halogen, preferably chlorine. 
The compound Ia! of the invention can be synthesized by reacting halide 
II! with compound III! in the presence of a base in a solvent inert to 
the reaction. The reaction solvent that can be used includes aprotic polar 
solvents such as N,N-dimethylformamide (DMF), aromatic hydrocarbons such 
as benzene, toluene and xylene, hydrocarbons such as n-hexane, n-heptane 
and cyclohexane, and ethers such as tetrahydrofuran, dimethoxyethane, 
diethyl ether, dioxane and diethylene glycol dimethyl ether, inclusive of 
mixtures of such solvents. The base that can be used includes sodium 
hydride, sodium amide, potassium tert-butoxide, butyllithium, and so on. 
This reaction is conducted generally at 0-140.degree. C. and preferably at 
10-110.degree. C. Dependent on the species of reactants, solvent, and 
base, a reaction time of 2-24 hours is generally appropriate. The 
preferred proportions of compound III! and said base are generally 1-1.2 
moles per mole of compound II!. 
Process B 
##STR6## 
In the above reaction schema, R.sup.1 -R.sup.4, A, E, X, Y, Z, W, and Q are 
as defined hereinbefore. 
The compound of formula Ia! can be synthesized by reacting compound IV! 
with halide V! in the presence of a base in a solvent inert to the 
reaction at 0-80.degree. C. The reaction solvent that can be used includes 
aprotic polar solvents such as acetonitrile, dimethyl sulfoxide, and 
N,N-dimethylformamide (DMF), alcohols such as methanol, ethanol and 
isopropyl alcohol, ethers such as tetrahydrofuran, dimethoxyethane, 
diethyl ether and dioxane, glymes such as methylcellosolve and ethylene 
glycol dimethyl ether, halogenated hydrocarbons such as methylene chloride 
and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, 
and mixtures of such solvents. The base that can be used includes sodium 
hydride, potassium carbonate, sodium hydroxide, potassium hydroxide, 
silver carbonate and the like. Dependent on the species of reactants, 
base, and solvent, the reaction time may generally range from 2 to 10 
hours. The preferred proportions of halide V! and said base are generally 
1-1.2 moles per mole of compound IV!. 
Process C 
##STR7## 
In the above reaction schema, R.sup.1 -R.sup.4, A, E, X, Y, Z. W, and Q are 
as defined hereinbefore. 
Compound Ia! can be synthesized by reacting halide VI! with amine VII! 
in the presence of a base in a solvent inert to the reaction. The reaction 
solvent that can be used includes aprotic polar solvents such as 
acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide (DMF) and acetone, 
ethers such as tetrahydrofuran, dimethoxyethane, diethyl ether and 
dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, etc., and 
mixtures of such solvents. The base that can be used includes alkali metal 
salts such as potassium carbonate, sodium carbonate, sodium hydrogen 
carbonate, sodium hydroxide, and potassium hydroxide. In lieu of such a 
base, the amine VII! may be used in excess. This reaction is conducted at 
10-100.degree. C. Depending on the species of reactants, base, and solvent 
used, the reaction time may generally range from 2 to 20 hours. The 
preferred proportion of compound VII! is generally 1-3 moles per mole of 
compound VI!. The preferred proportion of the base is generally 1-1.2 
moles per mole of compound VI!. 
Process D (Compound in which A represents an alkylene group of 3-10 carbon 
atoms and which have hydroxy, oxo, or alkoxy in the .beta.-position of 
NR.sup.3 R.sup.4) 
##STR8## 
In the above reaction schema, R.sup.1 -R.sup.4, E, W, X, Y, Z, and Q are as 
defined hereinbefore. A.sup.0 represents an alkylene group of 1-8 carbon 
atoms which may be substituted. 
Compound Id! having hydroxy in the .beta.-position of NR.sup.3 R.sup.4 
according to the invention can be synthesized by conducting the reaction 
according to Process C using epoxy compound VI.sup.a ! in lieu of halide 
VI!. This reaction proceeds in the absence of a base. The proportion of 
the amine varies with its species but is generally equimolar or excess 
relative to compound VI.sup.a !. 
By oxidizing the above compound Id! in a solvent inert to the reaction 
(e.g. DMSO/acetic anhydride) using an oxidizing agent such as chromic 
acid, manganese dioxide, or potassium permanganate in the per se known 
manner, the compound having oxo in the above-mentioned position can be 
obtained. 
Moreover, by reacting compound Id! with an alkyl halide in the presence of 
a base such as sodium hydride, or butyllithium in a solvent inert to the 
reaction, the compound having alkoxy in the same position can be obtained. 
Process E (the compound of formula I! in which W represents O or S! 
##STR9## 
In the above reaction schema, R.sup.1 -R.sup.4, A, E, X, Y, Z, and Q are as 
defined hereinbefore. Wa represents O or S. 
Compound Ic! in which W is 0 or S, which belongs to the compound of the 
present invention, can be synthesized by reacting compound VIII! with 
compound III! in the presence of a base in a solvent inert to the 
reaction. The reaction solvent that can be used includes aprotic polar 
solvents such as N,N-dimethylformamide (DMF), ethers such as 
tetrahydrofuran, dimethoxyethane, diethyl ether and dioxane, and mixtures 
of such solvents. The base that can be used includes sodium hydride, 
sodium amide, potassium tert-butoxide, butyllithium and the like. 
The reaction is carried out at 0-80.degree. C., preferably 10-30.degree. C. 
Depending on the species of reactants, base, and solvent, the reaction 
goes to completion generally in 2-24 hours. The proportions of compound 
VIII! and compound III! used are preferably equimolar. The preferred 
proportion of the base is generally 1-1.2 moles per mole of compound 
VIII!. 
In case the objective compound is a compound I! having an amino group or a 
hydroxyl group, it can be obtained by protecting the starting compound 
with a leaving group beforehand as necessary, carrying out the reaction 
according to any of the above processes A through E, and removing the 
protective group in the per se known manner. The amino-protecting group 
that can be used includes but is not limited to benzyl, benzyloxycarbonyl, 
trifluoroacetyl, and t-butoxycarbonyl. The hydroxy-protecting group that 
can be used includes but is not limited to methoxymethyl, 
2-methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl, t-butyl, 
benzyl, trimethylsilyl, and t-butyldimethylsilyl. By way of illustration, 
the compound having a phenolic hydroxyl group according to the invention 
can be obtained by using a starting compound protected with benzyl 
beforehand and, after the reaction, removing the protective group by 
catalytic reduction. Such catalytic reduction is generally carried out 
under atmospheric to under pressure in a solvent at 0-80.degree. C. The 
solvent that can be used includes alcohols, e.g. methanol, ethanol, etc., 
water, carboxylic acids such as acetic acid etc., esters such as ethyl 
acetate, and ethers such as dioxane and tetrahydrofuran. The catalyst that 
can be used includes palladium-on-carbon, palladium black, platinum oxide, 
and the like. Depending on the species of the starting compound, catalyst, 
and solvent used, the preferred reaction time is generally 30 minutes to 
48 hours. 
The starting compounds II! and IV! can be produced by the known method 
WO 92/04333! as will be described hereinafter as reference examples. 
The starting compound VI! can be produced according to the following 
reaction schema. 
##STR10## 
In the above schema, R.sup.1 -R.sup.2, A, E, X, Y, Z, W, and Q are as 
defined hereinbefore. 
Compound VI! can be synthesized by reacting compound IX! with halide X! 
in the presence of a base in a solvent inert to the reaction. The reaction 
solvent that can be used includes aprotic polar solvents such as 
acetonitrile, dimethyl sulfoxide, and N,N-dimethylformamide (DMF), ethers 
such as tetrahydrofuran, dimethoxyethane, diethyl ether and dioxane, 
aromatic hydrocarbons such as benzene, toluene, and xylene, and mixtures 
of such solvents. The base that can be used includes silver carbonate, 
potassium carbonate, sodium carbonate, sodium hydride, sodium hydroxide, 
and potassium hydroxide. The reaction is conducted at 20-160.degree. C., 
preferably 70-120.degree. C. Depending on the kinds of reactants, base, 
and solvent used, the reaction time may appropriately be 5-60 hours. The 
preferred proportion of halide X! is generally 1-4 moles per mole of 
compound IX!. The preferred proportion of the base is 0.5-1.2 moles per 
mole of compound IX!. 
The starting epoxy compound VI.sup.a ! can be produced according to the 
following reaction schema. 
##STR11## 
In the above reaction schema, R.sup.1 -R.sup.2, A.sup.0, E, X, Y, Z, W, and 
Q are as defined hereinbefore. 
(Step 1) 
Compound XII! can be synthesized by reacting compound IV! with halide 
XI! in the presence of a base in a solvent inert to the reaction. This 
reaction can be conducted under the same conditions as the above-mentioned 
process for producing VI!. The preferred proportion of halide XI! is 
generally 1-3 moles per mole of compound IV!. 
(Step 2) 
Epoxy compound VI.sup.a ! can be synthesized by oxidizing compound XII! 
with a suitable oxidizing agent in a solvent inert to the reaction. The 
reaction solvent that can be used includes halogenated hydrocarbons such 
as dichloromethane, dichloroethane and chloroform, ethers such as 
tetrahydrofuran, dimethoxyethane, diethyl ether and dioxane, aromatic 
hydrocarbons such as benzene, toluene and xylene, and mixtures of such 
solvents. The oxidizing agent that can be used includes but is not limited 
to organic peracids such as perbenzoic acid, m-chloroperbenzoic acid, 
peracetic acid and monoperoxyphthalic acid; hydrogen peroxide; and t-butyl 
hydroperoxide. The amount of the oxidizing agent varies with its species 
but is preferably 1-2 moles per mole of compound XII!. This reaction is 
conducted at 0-50.degree. C., preferably 10-30.degree. C. Depending on the 
species of the starting compound, oxidizing agent, and solvent used, the 
reaction time may generally range from 2 to 24 hours. 
The starting compound VIII! can be produced in accordance with the 
following reaction schema. 
##STR12## 
In the reaction schema, R.sup.1, R.sup.2, X, Y, Z, Wa, and Q are as defined 
hereinbefore. 
Compound VIII! can be synthesized by reacting halide XIII! with compound 
XIV! in the presence of a base in a solvent inert to the reaction. This 
reaction can be carried out under the same conditions as the 
above-mentioned reaction for producing Ia!. 
The preferred proportion of compound XIV! is 2-2.5 moles per mole of 
halide XIII!. 
The compound I! of the present invention can be treated with a peracid in 
the per se known manner to provide the oxide. 
While some species of the compound of the invention contain asymmetric 
carbon, the respective optical isomers as well as the racemic mixtures 
also fall within the scope of the invention. Thus, the racemic compound 
synthesized by any of the above-mentioned processes can be fractionated 
into the optical isomers by the conventional optical resolution technique 
utilizing its basicity, i.e. with a chiral acid (e.g. tartaric acid, 
dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid), or such 
optical isomers can be respectively synthesized by using an optically 
active compound prepared beforehand (e.g. 1,2-epoxypropane) as a starting 
material. 
The compound I! of the present invention can be converted to the salts 
mentioned hereinbefore in a well known manner. For example, the 
hydrochloride of compound I! can be obtained by dissolving compound I! 
in an alcoholic solution of hydrogen chloride. 
Among species of compound I! according to the present invention, any 
compound containing a carboxyl group can be converted to the corresponding 
salt by the known process. The salt here includes alkali metal salts such 
as sodium salt and potassium salt, and alkaline earth metal salts such as 
calcium salt. For instance, an alkali metal salt of compound I! of the 
invention can be produced by adding one equivalent of sodium hydroxide, 
potassium hydroxide, or the like to a carboxy-containing compound I! of 
the invention, preferably in an alcoholic solvent. An alkaline earth metal 
salt of compound I! of the invention can be produced by dissolving the 
above alkali metal salt in water, methanol, or ethanol, or a mixture 
thereof, for instance, and adding one equivalent of, for example, calcium 
chloride. 
The solvate (inclusive of the hydrate) of the compound I! or salt of the 
invention is also included in the scope of the present invention. The 
solvate can be generally produced by recrystallizing the compound from the 
corresponding solvent or a suitable mixed solvent containing example, 
corresponding solvent. For example, the hydrate of compound I! of the 
present invention can be obtained by recrystallizing compound I! from an 
aqueous alcohol. 
Compound I! of the present invention may show crystal polymorphism. The 
polymorphs in such cases are also included in the scope of the invention. 
The object compound I! thus obtained can be isolated and purified in the 
form of the free base or an acid addition salt by per se known procedures 
such as concentration, pH adjustment, phase transfer, solvent extraction, 
crystallization, fractional distillation, and chromatography. 
The compound of the present invention is useful as a therapeutic drug for 
cerebrovascular disease or as a drug for inhibiting onset of sequelae of 
cerebrovascular disease. 
For use as a medicine, the compound of the present invention can be 
administered to an animal including human being either as it is or in the 
form of a pharmaceutical composition containing, for example, 0.01-99.5%, 
preferably 0.5-90%, of the compound in a pharmaceutically acceptable 
nontoxic, inert carrier. 
As the carrier, one or more of solid, semisolid, or liquid diluent, filler, 
and other formulation auxiliaries can be employed. The pharmaceutical 
composition is preferably administered in unit dosage forms. The 
pharmaceutical composition of the present invention can be administered 
orally, parenterally (e.g. intravenously), locally (e.g. transdermally), 
or rectally. Of course, dosage forms suited for respective routes of 
administration should be selected. Particularly preferred is intravenous 
or oral administration. 
The dosage as a therapeutic drug for cerebrovascular disease is preferably 
established with reference to the patient's age, body weight and other 
factors, route of administration, nature and severity of illness, etc. 
Usually, however, the daily oral dosage for human adults may range 
generally from 0.1 mg to 1 g/patient and preferably from 1 to 300 
mg/patient. In the case of intravenous administration, the usual daily 
dose is 0.01 mg-100 mg/patient and preferably 0.1-30 mg/patient. Lower 
dose levels may be sufficient in some cases, while higher doses may be 
necessary in other cases. The above-mentioned dosage can be preferably 
administered in 2-4 divided doses. 
Oral administration can be carried out using solid or liquid unit dosage 
forms such as bulc powders, powders, tablets, dragees, capsules, granules, 
suspensions, solutions, syrups, drops, sublingual tablets, etc. 
Bulc powders can be manufactured by comminuting the active substance into a 
finely divided form. Powders can be manufactured by comminuting the active 
substance into a finely-divided form and blending it with a similarly 
comminuted pharmaceutical carrier, e.g. an edible carbohydrate such as 
starch or mannitol. Where necessary, a corrigent, a preservative, a 
dispersant, a coloring agent, a perfume, etc. can also be added. 
Capsules can be manufactured by filling said finely-divided bulc powders or 
powders, or granules described below for tablets, in capsule shells such 
as gelatin capsule shells. Preceding the filling operation, a lubricant or 
a fluidizing agent, such as colloidal silica, talc, magnesium stearate, 
calcium stearate or solid polyethylene glycol, can be blended with the 
powders. Improvement in the efficacy of the drug after ingestion can be 
expected when a disintegrator or a solubilizer, such as 
carboxymethylcellulose, carboxymethylcellulose calcium, 
low-substitution-degree hydroxypropylcellulose, croscarmellose sodium, 
carboxymethylstarch sodium, calcium carbonate or sodium carbonate, is 
added. 
Soft capsules can be provided by suspending said finely divided powders in 
vegetable oil, polyethylene glycol, glycerin, or a surfactant and wrapping 
the suspension in gelatin sheets. Tablets can be manufactured by adding an 
excipient to said powders, granulating or slugging the mixture, adding a 
disintegrator and/or a lubricant, and compressing the whole composition. A 
powdery mixture can be prepared by mixing said finely divided powders with 
said diluent or a base. Where necessary, a binder (e.g. 
carboxymethylcellulose sodium, methylcellulose, 
hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl 
alcohol, etc.), a dissolution retardant (e.g. paraffin), a reabsorption 
agent (e.g. quaternary salts), and an adsorbent (e.g. bentonite, kaolin, 
dicalcium phosphate, etc.) can be added. The powdery mixture can be 
processed into granules by wetting it with a binder, e.g. a syrup, a 
starch paste, gum arabic, a solution of cellulose, or a solution of a high 
polymer, stirring to mix, drying it, and pulverizing the same. Instead of 
granulating such powders, it is possible to compress the powders with a 
tablet machine and crush the resulting slugs of crude form to prepare 
granules. The resulting granules can be protected against interadhesion by 
the addition of a lubricant such as stearic acid, a salt of stearic acid, 
talc or mineral oil. The mixture thus lubricated is then compressed. The 
resulting uncoated tablets can be coated with a film coating composition 
or a sugar coating composition. 
The compound of the invention can be mixed with a free-flowing inert 
carrier and the mixture be directly compressed without resort to the 
above-mentioned granulation or slugging process. A transparent or 
translucent protective coat consisted of, for example, a hermetic shellac 
coat, a sugar or polymer coat, or a polishing wax coat can also be 
applied. Other oral compositions such as a solution, a syrup, and an 
elixir can also be provided in unit dosage forms each containing a 
predetermined amount of the drug substance. Syrups can be manufactured by 
dissolving the compound in suitable flavored aqueous media, while elixirs 
can be manufactured using nontoxic alcoholic vehicles. Suspensions can be 
formulated by dispersing the compound in nontoxic vehicles. Where 
necessary, solubilizers and emulsifiers (e.g. ethoxylated isostearyl 
alcohol, polyoxyethylene sorbitol ester, etc.), preservatives, and 
flavorants (e.g. peppermint oil, saccharin, etc.) can also be added. 
Where necessary, the unit dosage formulation for oral administration can be 
microencapsulated. This formulation can be coated or embedded in a 
polymer, wax or other matrix to provide a prolonged action or sustained 
release dosage form. 
Parenteral administration can be carried out using liquid unit dosage forms 
for subcutaneous, intramuscular, or intravenous injection, e.g. solutions 
and suspensions. Such unit dosage forms can be manufactured by suspending 
or dissolving a predetermined amount of the compound of the invention in 
an injectable nontoxic liquid vehicle, for example an aqueous vehicle or 
an oily vehicle, and sterilizing the resulting suspension or solution. For 
isotonizing an injection, a nontoxic salt or salt solution can be added. 
Moreover, stabilizers, preservatives, emulsifiers, etc. may also be added. 
Rectal administration can be carried out by using suppositories 
manufactured by dissolving or suspending the compound in a low-melting 
water-soluble or water-insoluble solid carrier such as polyethylene 
glycol, caccao butter, semisynthetic oil (e.g. Witepsol.RTM.), a higher 
ester (e.g. myristyl palmitate) or a mixture thereof. 
The toxicity of the compound of the invention is extremely low as will be 
described hereinafter.

BEST MODE FOR CARRYING OUT THE INVENTION 
The following reference examples and examples of production of the compound 
of the invention and test examples using some representative species of 
the compound of the invention are intended to illustrate the present 
invention in further detail. 
Reference Example 1 
4-(4-Fluorophenyl)-6-hydroxy-2-methylpyrimidine 
(Step 1) 
To 1.3 L (liters) of dry tetrahydrofuran (THF) was added 162 g of 60% 
sodium hydride (NaH) and 342 g of diethyl carbonate. To this mixture was 
added a solution of 200 g p-fluoroacetophenone in 440 ml dry THF dropwise 
over about 1 hour while refluxing, followed by 6 hours of refluxing. This 
reaction mixture was cooled, poured into iced water, neutralized with 
concentrated hydrochloric acid, and extracted with ethyl acetate. The 
organic layer was washed with water, dried over anhydrous magnesium 
sulfate (MgSO.sub.4), and concentrated. The residue was distilled under 
reduced pressure to provide 291 g of ethyl 
3-(4-fluorophenyl)-3-oxopropionate as pale yellow oil. 
b.p. 145-150.degree. C. (5 mmHg) 
(Step 2) 
A mixture of 145 g of ethyl 3-(4-fluorophenyl)-3-oxopropionate, 97.8 g of 
acetamidine hydrochloride, 191 g of powdered potassium carbonate, and 1.16 
L of ethanol was stirred at 60-70.degree. C. for 16 hours. This reaction 
mixture was filtered to remove insolubles and the filtrate was 
concentrated. To the residue was added water and the resultant was 
neutralized with acetic acid. The crystals that separated out were 
collected by filtration, washed with water, and dried to provide 88.7 g of 
the title compound as white crystals. m.p. 290-292.degree. C. (decomp.) 
In the same manner as above, the following compounds were synthesized. 
4-(2-Chlorophenyl)-6-hydroxy-2-methylpyrimidine 
4-(2 4-Dichlorophenyl)-6-hydroxy-2-methylpyrimidine 
m.p. 271-274.degree. C. 
2.5-Dimethyl-4-(4-fluorophenyl)-6-hydroxypyrimidine 
m.p. 242-243.degree. C. 
4-(4-Fluorophenyl)-6-hydroxy-5-methylpyrimidine 
m.p. 228-229.degree. C. 
Reference Example 2 
4-Chloro-6-(4-fluorophenyl)-2-methylpyrimidine 
To 21 g of 4-(4-fluorophenyl)-6-hydroxy-2-methylpyrimidine was added 63 ml 
of phosphorus oxychloride and the mixture was refluxed for 1 hour. This 
reaction mixture was cooled, poured into iced water, and neutralized with 
28% aqueous ammonia and the crystals that separated out were collected by 
filtration. The crystals were washed with water and dried to provide 21 g 
of the title compound. 
m.p. 95-98.degree. C. 
In the same manner as above, the following compounds were synthesized. 
4-Chloro-6-(2-chlorophenyl)-2-methylpyrimidine 
m.p. 88-90.degree. C. 
4-Chloro-6-(2,4-dichlorophenyl)-2-methylpyrimidine 
m.p. 104-105.degree. C. 
4-Chloro-2,5-dimethyl-6-(4-fluorophenyl)pyrimidine 
m.p. 110-113.degree. C. 
4-Chloro-6-(2-fluorophenyl)-5-methylpyrimidine 
m.p. 88-90.degree. C. 
Reference Example 3 
4-(4-Chlorobutoxy)-2-(4-fluorophenyl)-6-methylpyridine hydrochloride 
A mixture of 2.5 g of 2-(4-fluorophenyl)-4-hydroxy-6-methylpyridine, 3.16 g 
of 1-bromo-4-chlorobutane, 1.7 g of silver carbonate, and 100 ml of 
toluene was refluxed for 40 hours. This reaction mixture was filtered to 
remove insolubles and the filtrate was concentrated. The residue was 
purified with silica gel column chromatography to provide 1.45 g of the 
title compound as white crystals. 
m.p. 59-61.degree. C. 
Reference Example 4 
4-(4-Fluorophenyl)-2-hydroxy-6-methylpyrimidine 
A mixture of 5 g of 4-fluorobenzoylacetone, 1.66 g of urea, 25 ml of 
ethanol, and 3.8 ml of concentrated hydrochloric acid was refluxed for 20 
hours. This reaction mixture was cooled, poured into iced water, made 
basic with aqueous solution of potassium carbonate, and neutralized with 
acetic acid. The crystals that separated out were collected by filtration, 
washed with isopropyl ether, and dried to provide 2.65 g of pale yellow 
crystals. 
m.p. 265-268.degree. C. 
Reference Example 5 
4,6-Bis(4-fluorophenoxy)-2-methylpyrimidine 
In a solvent mixture of 13 ml THF and 2.7 ml DMF was dissolved 448 mg of 
4-fluorophenol and while the solution was stirred at room temperature, 160 
mg of 60% NaH was added in small portions. The mixture was further stirred 
at the same temperature for 30 minutes. Then, 326 mg of 
4,6-dichloro-2-methylpyrimidine was added and the mixture was further 
stirred at room temperature for 12 hours. This reaction mixture was poured 
into iced water and extracted with ethyl acetate. The organic layer was 
washed with water, dried over MgSO.sub.4, and concentrated under reduced 
pressure. The residue, 700 mg, was purified with silica gel column 
chromatography (Wakogel.TM. C-200, n-hexane-ethyl acetate=9:1) and 
recrystallized from n-hexane to provide 461 mg of white crystals. 
m.p. 93-97.degree. C. 
In the same manner as above, the following compound was synthesized. 
4,6-Bis(4-fluorophenylthio)-2-methylpyrimidine 
m.p. 134-136.degree. C. 
Reference Example 6 
4-(4,5-Epoxypentyloxy)-6-(4-fluorophenyl)-2-methylpyrimidine 
(Step 1) 
A mixture of 2 g of 4-(4-fluorophenyl)-6-hydroxy-2-methylpyrimidine 
obtained in Reference Example 1, 2.8 g of 5-bromo-1-pentene, 1.5 g of 
silver carbonate, and 80 ml of toluene was refluxed for 22 hours. This 
reaction mixture was filtered to remove insolubles and the filtrate was 
concentrated. The residue was purified with silica gel column 
chromatography to provide 370 mg of 
4-(4-fluorophenyl)-2-methyl-6-(4-pentenyl)pyrimidine as white crystals. 
m.p. 44.5-45.5.degree. C. 
(Step 2) 
In 5 ml of methylene chloride was dissolved 350 mg of 
4-(4-fluorophenyl)-2-methyl-6-(4-pentenyl)pyrimidine. To this solution on 
an ice-water bath was added 217 mg of 70% m-chloroperbenzoic acid with 
stirring. This mixture was then stirred at room temperature for 18 hours. 
The reaction mixture thus obtained was concentrated and n-hexane and ethyl 
acetate were added to the residue. The mixture was washed with aqueous 
solution of sodium hydrogen carbonate four times and further with water, 
dried over MgSO.sub.4, and concentrated. The residue was purified with 
silica gel column chromatography to provide 160 mg of the title compound 
as white crystals. 
m.p. 63.0-64.0.degree. C. 
Reference Example 7 
2-Chloro-4-methyl-6-phenyl-1,3,5-triazine 
(Step 1) 
To 50 g of 2,4,6-trichloro-1,3,5-triazine was added 300 ml of dry 
tetrahydrofuran and while the mixture was stirred at room temperature, 150 
ml of 2M phenylmagnesium bromide-tetrahydrofuran was added dropwise over 
about 30 minutes. After completion of dropwise addition, the mixture was 
stirred at room temperature for 1 hour, and then concentrated. To the 
residue was added iced water and the resultant was extracted with ether. 
The extract was washed with water, dried over MgSO.sub.4, and 
concentrated. The resulting crystal crop was recrystallized from isopropyl 
alcohol to provide 21.1 g of 2,4-dichloro-6-phenyl-1,3,5-triazine as pale 
yellow crystals. 
(Step 2) 
In 85 ml of dry tetrahydrofuran was dissolved 17 g of 
2,4-dichloro-6-phenyl-1,3,5-triazine. To this solution on an ice-water 
bath was added 135 ml of 1M methylmagnesium bromide-tetrahydrofuran 
dropwise over about 30 minutes. After completion of dropwise addition, the 
mixture was stirred at room temperature for 2 hours. This reaction mixture 
was poured into iced water and extracted with ethyl acetate. The extract 
was washed with water, dried over MgSO.sub.4, and concentrated. The 
residue was purified with silica gel column chromatography to provide 3.6 
g of the title compound as white crystals. 
Reference Example 8 
2-Benzyloxyphenyl-4-hydroxy-6-methylpyrimidine 
(Step 1) 
In 200 ml of methanol was suspended 23 g of 4-benzyloxybenzonitrile and 
hydrogen chloride gas was bubbled through the suspension on an ice-water 
bath for about 1 hour. Thereafter, the mixture was stirred at the same 
temperature for 2 hours and, then, at room temperature for 1.5 hours. To 
this reaction mixture was added ether and the crystals that separated out 
were collected by filtration to provide 28 g of white crystals. These 
crystals were suspended in 200 ml of methanol and, on an ice-water bath, 
ammonia gas was bubbled through the suspension for about 1 hour. The 
mixture was then stirred at room temperature for 15 hours. This reaction 
mixture was concentrated and ethyl acetate was added to the residue. The 
crystals that separated out were collected by filtration and dried to 
provide 21.6 g of 4-benzyloxybenzamidine hydrochloride as white crystals. 
(Step 2) 
A mixture of 12 g of 4-benzyloxybenzamidine hydrochloride, 6.3 g of ethyl 
acetoacetate, 13.9 g of potassium carbonate, and 144 ml of ethanol was 
refluxed for 24 hours. This reaction mixture was filtered to remove 
insolubles and the filtrate was concentrated. To the residue was added 
water and the resultant was neutralized with acetic acid. The crystals 
that separated out were collected by filtration, rinsed with water, and 
dried to provide 12.0 g of the title compound as white crystals. 
EXAMPLE 1 
4-(4-Fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine 
hydrochloride 
To a solvent mixture of 155 ml dry THF and 33 ml dry DMF was added 3.59 g 
of 60% sodium hydride (NaH) and while the mixture was stirred at room 
temperature, 7.06 g of 5-piperidino-1-pentanol was added. The mixture was 
further stirred for 10 minutes. Then, 10 g of 
4-chloro-6-(4-fluorophenyl)-2-methylpyrimidine was added and the mixture 
was stirred at room temperature for 20 hours. This reaction mixture was 
poured into iced water and extracted with ethyl acetate. The organic layer 
was washed with water, dried over MgSO.sub.4, and concentrated. The 
residue was purified with silica gel column chromatography (Wakogel.TM. 
C-200, chloroform containing 1% of methanol) to give a pale yellow oil. 
This oil was dissolved in methanol and the solution was adjusted to pH 5 
with 1N-HCl, and concentrated. To the residue was added ether and the 
crystals that separated out were collected by filtration. This crystal 
crop was recrystallized from acetonitrile to provide white crystals of 
type I or II. 
Crystals of type I 
m.p. 184-186.degree. C. 
Elemental analysis for C.sub.21 H.sub.28 FN.sub.3 O.HCl Calcd. (%): C, 
64.03; H, 7.42; N, .10.67 Found (%): C, 63.82; H, 7.39; N, 10.70. 
Crystals of type II 
m.p. 182-184.degree. C. 
Elemental analysis for C.sub.21 H.sub.28 FN.sub.3 O.HCl Calcd. (%): C, 
64.03; H, 7.42; N, 10.67 Found (%): C., 63.80; H, 7.38; N, 10.74. 
In the same manner as Example 1, the following compounds were synthesized. 
EXAMPLE 2 
4-(4-Fluorophenyl)-2-methyl-6-(4-piperidinobutoxy)pyrimidine hydrochloride 
m.p. 174-176.degree. C. 
Elemental analysis for C.sub.20 H.sub.26 FN.sub.3 O.HCl Calcd. (%): C, 
63.23; H, 7.16; N, 11.06 Found (%): C, 62.83; H, 7.23; N, 11.01. 
EXAMPLE 3 
4-(4-Fluorophenyl)-2-methyl-6-(6-piperidinohexyloxy)primidine hydrochloride 
m.p. 190.5-192.degree. C. 
Elemental analysis for C.sub.22 H.sub.30 FN.sub.3 O.HCl Calcd. (%): C, 
64.77; H, 7.66; N, 10.30 Found (%): C, 64.49; H, 7.66; N, 10.48. 
EXAMPLE 4 
2-(4-Fluorophenyl)-4-methyl-6-(4-piperidinobutoxy)pyrimidine hydrochloride 
m.p. 168-172.degree. C. 
Elemental analysis for C.sub.20 H.sub.26 FN.sub.3 O.HCl Calcd. (%): C, 
63.23; H, 6.90; N, 11.06 Found (%): C, 63.10; H, 7.11; N, 10.80. 
EXAMPLE 5 
2-(4-Fluorophenyl)-4-methyl-6-(5-piperidinopentyloxy)pyrimidine 
hydrochloride 
m.p. 184-185.degree. C. 
Elemental analysis for C.sub.21 H.sub.28 FN.sub.3 O.HCl Calcd. (%): C, 
64.03; H, 7.42; N, 10.67 Found (%): C, 63.80; H, 7.52; N, 10.60. 
EXAMPLE 6 
4-(2-Chlorophenyl)-2-methyl-6-(4-piperidinobutoxy)pyrimidine hydrochloride 
m.p. 147-149.degree. C. 
Elemental analysis for C.sub.20 H.sub.26 ClN.sub.3 O.HCl Calcd. (%): C, 
60.01; H, 6.87; N, 10.60 Found (%): C, 60.43; H, 7.05; N, 10.80. 
EXAMPLE 7 
S 4-(2,4-Dichlorophenyl)-2-methyl-6-(4-piperidinobutoxy)pyrimidine 
hydrochloride 
m.p. 144-146.degree. C. 
Elemental analysis for C.sub.20 H.sub.25 Cl.sub.2 N.sub.3 O.HCl Calcd. (%): 
C, 55.76; H, 6.08; N, 9.75 Found (%): C, 55.40; H, 6.21; N, 9.74. 
EXAMPLE 8 
4-(4-Fluorophenyl)-2-methyl-6-4-(4-phenylpiperidino)butoxy!pyrimidine 
hydrochloride 
m.p. 169-171.degree. C. 
Elemental analysis for C.sub.26 H.sub.30 FN.sub.3 O.HCl Calcd. (%): C, 
68.48; H, 6.85; N, 9.21 Found (%): C, 68.20; H, 7.01; N, 9.27. 
EXAMPLE 9 
2-(4-Fluorophenyl)-4-methyl-6-4-(4-phenylpiperidino)butoxy!pyrimidine 
hydrochloride 
m.p. 148-153.degree. C. 
Elemental analysis for C.sub.26 H.sub.30 FN.sub.3 O.HCl Calcd. (%): C, 
68.48; H, 6.85; N, 9.21 Found (%): C, 68.20; H, 6.89; N, 9.03. 
EXAMPLE 10 
2-(4-Fluorophenyl)-4-methyl-6-4-(4-phenylpiperazino)butoxy!pyrimidine 
maleate 
After the same reaction procedure as described in Example 1, the title 
compound was obtained by using a solution of maleic acid in ethanol. 
m.p. 218.degree. C. (decomp.) 
Elemental analysis for C.sub.25 H.sub.29 FN.sub.4 O.C.sub.4 H.sub.4 O.sub.4 
Calcd. (%): C, 64.91; H, 6.20; N, 10.44 Found (%): C, 64.93; H, 6.24; N, 
10.32. 
In the same manner as Example 1 or Example 11, the following compounds were 
synthesized. 
EXAMPLE 11 
2-(4-Fluorophenyl)-4-methyl-6-4-(4-phenylpiperazino)butoxy!pyrimidine 
maleate 
m.p. 155-156.degree. C. 
Elemental analysis for C.sub.25 H.sub.29 FN.sub.4 O.C.sub.4 H.sub.4 O.sub.4 
Calcd. (%): C, 64.91; H, 6.20; N, 10.44 Found (%): C, 64.81; H, 6.29; N, 
10.48. 
EXAMPLE 12 
2.4-Bis(4-fluorophenyl)-6-(4-piperidinobutoxy)pyrimidine hydrochloride 
m.p. 207-208.5.degree. C. 
Elemental analysis for C.sub.25 H.sub.27 F.sub.2 N.sub.3 O.HCl Calcd. (%): 
C, 65.28; H, 6.14; N, 9.14 Found (%): C, 65.05; H, 6.26; N, 9.08. 
EXAMPLE 13 
2,4-Bis(4-fluorophenyl)-6-(5-piperidinopentyloxy)pyrimidine hydrochloride 
m.p. 196-198.50.degree. C. 
Elemental analysis for C.sub.26 H.sub.29 F.sub.2 N.sub.3 O.HCl Calcd. (%): 
C, 65.88; H, 6.38; N, 8.87 Found (%): C, 65.50; H, 6.44; N, 8.64. 
EXAMPLE 14 
4-(4-Hydroxyphenyl)-2-methyl-6-4-(4-phenylpiperidino)butoxy!pyrimidine 
hydrochloride 
Using 4-(4-phenylpiperidino)-1-butanol and 
6-(4-benzyloxyphenyl)-4-chloro-2-methylpyrimidine, the procedure of 
Reference Example 25, which appears hereinafter, was otherwise followed to 
provide the title compound. 
m.p. 182-183.degree. C. 
Elemental analysis for C.sub.26 H.sub.31 N.sub.3 O.sub.2.HCl Calcd. (%): C, 
68.78; H, 7.10; N, 9.26 Found (%): C, 68.58; H, 6.96; N, 8.99. 
EXAMPLE 15 
2-(4-Fluorophenyl)-4-(4-piperidinobutoxy)-6-methylpyridine hydrochloride 
A mixture of 1.45 g of the 
4-(4-chlorobutoxy)-2-(4-fluorophenyl)-6-methylpyridine obtained in 
Reference Example 3, 1.26 g of piperidine, and 12 ml of DMF was stirred at 
100.degree. C. for 1.5 hours. This reaction mixture was cooled, poured 
into iced water, and extracted with ethyl acetate. The organic layer was 
washed with an aqueous solution of sodium chloride several times, dried 
over MgSO.sub.4, and then concentrated. The residue was purified with 
silica gel column chromatography to provide 1.2 g of the objective 
compound as oil. This oil was dissolved in methanol and the solution was 
adjusted to pH 5 with 3.5 ml of 1N-HCl and concentrated. To the residue 
was added ether and the resulting crystal crop was collected by filtration 
and recrystallized from the mixture of acetonitrile and ether to provide 
1.02 g of the title compound as white crystals. 
m.p. 164-166.degree. C. 
Elemental analysis for C.sub.21 H.sub.27 FN.sub.2 O.HCl Calcd. (%): C, 
66.57; H, 7.45; N, 7.39 Found (%): C, 66.21; H, 7.45; N, 7.09. 
In the same manner as Example 15, the following compounds were synthesized. 
EXAMPLE 16 
4-(4-Fluorophenyl)-2-methyl-6-(3-piperidinopropoxy)pyridine hydrochloride 
m.p. 135.degree. C. 
Elemental analysis for C.sub.20 H.sub.25 FN.sub.2 O.HCl Calcd. (%): C, 
65.83; H, 7.18; N, 7.68 Found (%): C, 65.40; H, 7.24; N, 7.44. 
EXAMPLE 17 
4-(4-Fluorophenyl)-2-methyl-6-(4-piperidinobutoxy)pyridine hydrochloride 
m.p. 148.5-150.5.degree. C. 
Elemental analysis for C.sub.21 H.sub.27 FN.sub.2 O.HCl Calcd. (%): C, 
66.57; H. 7.45; N, 7.39 Found (%): C, 66.54; H, 7.57; N, 7.41. 
EXAMPLE 18 
4-(4-Fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyridine hydrochloride 
m.p. 138-140.degree. C. 
Elemental analysis for C.sub.22 H.sub.29 FN.sub.2 O.HCl Calcd. (%): C, 
67.25; H, 7.70; N, 7.13 Found (%): C, 67.00; H, 7.68; N, 6.95. 
EXAMPLE 19 
2,4-Bis(4-fluorophenyl)-6-(4-piperidinobutoxy)pyridine hydrochloride 
m.p. 219-220.5.degree. C. 
Elemental analysis for C.sub.26 H.sub.28 F.sub.2 N.sub.2 O.HCl Calcd. (%): 
C, 68.04; H, 6.37; N, 6.10 Found (%): C, 68.40; H, 6.37; N, 6.20. 
EXAMPLE 20 
2.4-Bis(4-fluorophenyl)-6-(5-piperidinopentyloxy)pyridine hydrochloride 
m.p. 165-166.5.degree. C. 
Elemental analysis for C.sub.27 H.sub.30 F.sub.2 N.sub.2 O.HCl Calcd. (%): 
C, 68.56; H, 6.61; N, 5.92 Found (%): C, 68.57; H. 6.74; N, 5.99. 
In the same manner as Example 1, the following compound was synthesized. 
EXAMPLE 21 
4-(4-Fluorophenyl)-2-methyl-6-(1-methyl-4-piperidinobutoxy)pyrimidine 
hydrochloride 
m.p. 146.degree. C. 
Elemental analysis for C.sub.21 H.sub.28 FN.sub.3 O.HCl Calcd. (%): C, 
64.03; H, 7.42; N, 10.67 Found (%): C, 63.90; H, 7.44; N, 10.42. 
EXAMPLE 22 
4-(4-Fluorophenyl)-6- 5-(4-hydroxypiperidino)pentyloxy!-2-methylpyrimidine 
hydrochloride 
A mixture of 4 g of the 4-(4-fluorophenyl)-6-hydroxy-2-methylpyrimidine 
obtained in Reference Example 1, 13.5 g of 1,5-dibromopentane, 2.97 g of 
silver carbonate, and 160 ml of toluene was refluxed for 50 hours. This 
reaction mixture was filtered to remove insolubles and the filtrate was 
concentrated. The residue was purified with silica gel column 
chromatography to provide 2.6 g of colorless oil. To 800 mg of this oil 
was added 275 mg of 4-hydroxypiperidine as well as 468 mg of potassium 
carbonate and 8 ml of acetonitrile and the mixture was stirred at room 
temperature for 19 hours. This reaction mixture was poured into iced water 
and extracted with ethyl acetate. The extract was washed with aqueous 
solution of sodium chloride, dried over MgSO.sub.4, and concentrated. The 
residue was purified with silica gel column chromatography to provide 600 
mg of oil. This oil was dissolved in methanol and the solution was 
adjusted to pH 5 with 1.61 ml of 1N-HCl, and concentrated. To the residue 
was added isopropyl ether and the crystals that separated out were 
collected by filtration and recrystallized from acetonitrile-isopropyl 
ether to provide 559 mg of the title compound as white crystals. 
m.p. 167.0-169.5.degree. C. 
Elemental analysis for C.sub.21 H.sub.28 FN.sub.3 O.sub.2.HCl Calcd. (%): 
C, 61.53; H, 7.13; N, 10.25 Found (%): C, 61.42; H, 7.09; N, 10.47. 
EXAMPLE 23 
4-(4-Fluorophenyl)-6-(4-hydroxy-5-piperidinopentyloxy)-2-methylpyrimidine 
hydrochloride 
A mixture of 160 mg of the 
4-(4,5-epoxypentyloxy)-6-(4-fluorophenyl)-2-methylpyrimidine obtained in 
Reference Example 6, 140 mg of piperidine, and 3 ml of acetonitrile was 
stirred at 80.degree. C. for 20 hours. This reaction mixture was cooled 
and then poured into iced water and extracted with ethyl acetate. The 
extract was washed with aqueous solution of sodium chloride, dried over 
MgSO.sub.4, and concentrated. The residue was purified with silica gel 
column chromatography to provide 158 mg of oil. This oil was dissolved in 
methanol and the solution was adjusted to pH 5 with 0.42 ml of 1N-HCl and 
concentrated. To the residue was added isopropyl ether and the resulting 
crystal crop was collected by filtration and recrystallized from 
acetonitrile to provide 121 mg of the title compound as white crystals. 
m.p. 149.0-150.5.degree. C. 
Elemental analysis for C.sub.21 H.sub.28 FN.sub.3 O.sub.2.HCl Calcd. (%): 
C, 61.53; H, 7.13; N, 10.25 Found (%): C, 61.36; H, 7.06; N, 10.25. 
In the same manner as Example 1, the following compounds were synthesized. 
EXAMPLE 24 
4-5-(N,N-diethylamino)pentyloxy!-6-(4-fluorophenyl)-2-methylpyrimidine 
hydrochloride 
m.p. 134.5-136.5.degree. C. 
Elemental analysis for C.sub.20 H.sub.28 FN.sub.3 O.HCl.1/4H.sub.2 O Calcd. 
(%): C, 62.17; H, 7.69; N, 10.87 Found (%): C, 62.15; H, 7.68; N, 10.84. 
EXAMPLE 25 
2-Methyl-4-(5-piperidinopentyloxy)-6-(2-thienyl)pyrimidine hydrochloride 
m.p. 192.5-194.0.degree. C. 
Elemental analysis for C.sub.19 H.sub.27 N.sub.3 OS.HCl Calcd. (%): C, 
59.75; H, 7.39; N, 11.00 Found (%): C, 59.35; H, 7.32; N, 10.98. 
EXAMPLE 26 
2-Methyl-4-(5-piperidinopentyloxy)-6-(pyridin-4-yl)pyrimidine hydrochloride 
m.p. 178.5-179.5.degree. C. 
Elemental analysis for C.sub.20 H.sub.28 N.sub.4 O.HCl Calcd. (%): C, 
63.73; H, 7.75; N, 14.86 Found (%): C, 63.38; H, 7.70; N, 14.86. 
EXAMPLE 27 
4-(4-Fluorophenyl)-6-methyl-2-(5-piperidinopentyloxy)pyrimidine 
hydrochloride 
Using 4-(4-fluorophenyl)-2-hydroxy-6-methylpyrimidine obtained in Reference 
Example 4, the procedure of Example 22 was otherwise carried out to 
provide the title compound. 
m.p. 173.5-175.0.degree. C. 
Elemental analysis for C.sub.21 H.sub.28 FN.sub.3 O.HCl Calcd. (%): C, 
64.03; H, 7.42; N, 10.67 Found (%): C, 63.85; H, 7.48; N, 10.82. 
In the same manner as Example 27, the following compounds were synthesized. 
EXAMPLE 28 
4-(4-Fluorophenyl)-6-methyl-2-(5-piperidinopentylthio)pyrimidine 
hydrochloride 
m.p. 156-158.degree. C. 
Elemental analysis for C.sub.21 H.sub.28 FN.sub.3 S.HCl.1/4H.sub.2 O Calcd. 
(%): C, 60.85; H, 7.17; N, 10.14 Found (%): C, 60.80; H, 7.05; N, 10.02. 
In the same manner as Example 1, the following compound was synthesized. 
EXAMPLE 29 
4-(4-Fluorophenyl)-2-methyl-6-(3-piperidinopropylthio)pyrimidine 
hydrochloride 
m.p. 192-194.degree. C. 
Elemental analysis for C.sub.19 H.sub.24 FN.sub.3 S.HCl.1/4H.sub.2 O Calcd. 
(%): C, 59.05; H, 6.59; N, 10.87 Found (%): C, 58.96; H, 6.54; N, 10.79. 
EXAMPLE 30 
4-(4-Fluorophenoxy)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine 
hydrochloride 
In a solvent mixture of 4.3 ml THF and 0.9 ml DMF was suspended 51 mg of 
60% NaH. While this suspension was stirred at room temperature, 218 mg of 
5-piperidino-1-pentanol was added and the mixture was stirred at room 
temperature for 30 minutes. Then, 400 mg of the 
2,4-bis(4-fluorophenoxy)-6-methylpyrimidine obtained in Reference Example 
5 was added thereto and the mixture was stirred at room temperature for 18 
hours. This reaction mixture was poured into iced water and extracted with 
ethyl acetate. The organic layer was washed with water, dried over 
MgSO.sub.4, and concentrated under reduced pressure. As a result, 600 mg 
of an oily residue was obtained. This oil was purified with silica gel 
column chromatography Wakogel.TM. C-200, 
chloroform.fwdarw.chloroform-methanol (25:1)! to provide 200 mg of 
light-yellow oil. A 190 mg of this oil was dissolved in methanol and the 
solution was adjusted to pH 5 with 0.5 ml of 1N-HCl and concentrated under 
reduced pressure. To the residue was added ether and the resulting 
crystals were collected by filtration. This crystal crop was washed with 
ether and recrystallized from acetone to provide 137 mg of the title 
compound as white crystals. 
m.p. 164-165.degree. C. 
Elemental analysis for C.sub.21 H.sub.28 FN.sub.3 O.sub.2.HCl Calcd. (%): 
C, 61.53; H, 7.13; N, 10.25 Found (%): C, 61.40; H, 7.08; N, 10.26. 
EXAMPLE 31 
4-(4-Fluorophenylthio)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine 
hydrochloride 
Using the 4,6-bis(4-fluorophenylthio)-2-methyl-pyrimidine obtained in the 
same manner as in Reference Example 5, the procedure was otherwise carried 
out in the same manner as Exampel 30 to provide the title compound as 
light-yellow crystals. 
m.p. 127-131.degree. C. (as recrystallized from acetone/ether) 
Elemental analysis for C.sub.21 H.sub.28 FN.sub.3 OS.HCl.1/2H.sub.2 O 
Calcd. (%): C, 57.98; H, 6.72; N, 9.66 Found (%): C, 58.03; H, 6.86; N, 
9.62. 
In the same manner as Example 1, the following compounds were synthesized. 
EXAMPLE 32 
4-(4-Fluorobenzyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine 
hydrochloride 
m.p. 109-115.degree. C. 
Elemental analysis for C.sub.22 H.sub.30 FN.sub.3 O.HCl.H.sub.2 O Calcd. 
(%): C, 62.03; H, 7.81; N, 9.86 Found (%): C, 62.30; H, 8.10; N, 9.94. 
EXAMPLE 33 
2-Methyl-4-phenethyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride 
m.p. 128-130.degree. C. 
Elemental analysis for C.sub.23 H.sub.33 N.sub.3 O.HCl.1/2H.sub.2 O Calcd. 
(%): C, 66.89; H, 8.54; N, 10.17 Found (%): C, 66.83; H, 8.35; N, 10.17. 
EXAMPLE 34 
2,5-Dimethyl-4-(4-fluorophenyl)-6-(4-piperidinobutoxy)pyrimidine 
hydrochloride 
m.p. 154-157.degree. C. 
Elemental analysis for C.sub.21 H.sub.28 FN.sub.3 O.HCl Calcd. (%): C, 
64.03; H, 7.42; N, 10.67 Found (%): C, 63.86; H, 7.30; N, 10.61. 
EXAMPLE 35 
4-(4-Fluorophenyl)-5-methyl-6-(4-piperidinobutoxy)pyrimidine hydrochloride 
m.p. 146-149.degree. C. 
Elemental analysis for C.sub.20 H.sub.26 FN.sub.3 O.HCl Calcd. (%): C, 
63.23; H, 7.16; N, 11.06 Found (%): C, 63.01; H, 7.10; N, 11.08. 
EXAMPLE 36 
2-Methyl-4-phenyl-6-(4-piperidinobutoxy)-1,3,5-triazine hydrochloride 
m.p. 177-178.degree. C. 
Elemental analysis for C.sub.19 H.sub.26 N.sub.4 O.HCl Calcd. (%): C, 
62.88; H, 7.50; N, 15.44 Found (%): C, 62.55; H, 7.68; N, 15.28. 
EXAMPLE 37 
2-Methyl-4-phenyl-6-(3-piperidinopropoxy)-1.3,5-triazine hydrochloride 
m.p. 175-178.degree. C. 
Elemental analysis for C.sub.18 H.sub.24 N.sub.4 O.HCl Calcd. (%): C, 
61.97; H, 7.22; N, 16.06 Found (%): C, 61.87; H, 7.41; N, 16.14. 
EXAMPLE 38 
2-(4-Chlorophenyl)-4-methyl-6-(3-piperidinopropoxy)-1,3,5-triazine maleate 
m.p. 125-128.degree. C. 
Elemental analysis for C.sub.18 H.sub.23 ClN.sub.4 O.C.sub.4 H.sub.4 
O.sub.4.1/4H.sub.2 O Calcd. (%): C, 56.53; H, 5.93; N, 11.99 Found (%): C, 
56.22; H, 6.07; N, 12.01. 
EXAMPLE 39 
2-Methyl-4-phenyl-6-3-(4-phenylpiperidino)propoxy!-1,3,5-triazine 
hydrochloride 
m.p. 159-163.degree. C. 
Elemental analysis for C.sub.24 H.sub.28 N.sub.4 O.HCl.1/2H.sub.2 O Calcd. 
(%): C, 66.58; H, 6.75; N, 12.94 Found (%): C, 66.56; H, 7.15; N, 13.30. 
EXAMPLE 40 
2-Methyl-4-(2-naphthyl)-6-(4-piperidinobutoxy)pyrimidine hydrochloride 
m.p. 174-175.degree. C. 
Elemental analysis for C.sub.24 H.sub.29 N.sub.3 O.HCl Calcd. (%): C, 
69.97; H, 7.34; N, 10.20 Found (%): C, 69.80; H, 7.20; N, 10.21. 
Production examples for the compound of formula I! are presented below. 
Where the procedures are not particularly described, the procedure of 
Example 1 was followed. 
Reference Example 9 
4-(4-Fluorophenyl)-2-methyl-6-(2-piperidinoethoxy)pyrimidine hydrochloride 
m.p. 198-199.degree. C. 
Elemental analysis for C.sub.18 H.sub.22 FN.sub.3 O.HCl Calcd. (%): C, 
61.45; H, 6.59; N, 11.94 Found (%): C, 61.23; H, 6.78; N, 11.74. 
Reference Example 10 
4-(4-Fluorophenyl)-2-methyl-6-(3-piperidinopropoxy)pyrimidine hydrochloride 
m.p. 195.5-197.degree. C. 
Elemental analysis for C.sub.19 H.sub.24 FN.sub.3 O.HCl Calcd. (%): C, 
62.37; H, 6.89; N, 11.48 Found (%): C, 62.00; H, 7.03; N, 11.13. 
Reference Example 11 
2-(4-Fluorophenyl)-4-methyl-6-(2-piperidinoethoxy)pyrimidine hydrochloride 
m.p. 216-218.degree. C. 
Elemental analysis for C.sub.18 H.sub.22 FN.sub.3 O.HCl Calcd. (%): C, 
61.45; H, 6.56; N, 11.94 Found (%): C, 61.10; H, 6.78; N, 11.63. 
Reference Example 12 
2-(4-Fluorophenyl)-4-methyl-6-(3-piperidinopropoxy)pyrimidine hydrochloride 
m.p. 205-206.5.degree. C. 
Elemental analysis for C.sub.19 H.sub.24 FN.sub.3 O.HCl Calcd. (%): C, 
62.37; H, 6.89; N, 11.48 Found (%): C, 62.01; H, 6.99; N, 11.47. 
Reference Example 13 
2-(4-Chlorophenyl)-4-methyl-6-(3-piperidinopropoxy)pyrimidine hydrochloride 
m.p. 212-214.degree. C. 
Elemental analysis for C.sub.19 H.sub.24 ClN.sub.3 O.HCl Calcd. (%): C, 
59.69; H, 6.59; N, 10.99 Found (%): C, 59.23; H, 6.53; N, 10.80. 
Reference Example 14 
4-(4-Fluorophenyl)-2-methyl-6-2-(4-phenylpiperidino)ethoxy!pyrimidine 
hydrochloride 
m.p. 184-186.degree. C. 
Elemental analysis for C.sub.24 H.sub.26 FN.sub.3 O.HCl Calcd. (%): C, 
67.36; H, 6.36; N, 9.82 Found (%): C, 67.10; H, 6.73; N, 9.78. 
Reference Example 15 
4-(4-Fluorophenyl)-2-methyl-6-3-(4-phenylpiperidino)propoxy!pyrimidine 
hydrochloride 
m.p. 169-171.degree. C. 
Elemental analysis for C.sub.25 H.sub.28 FN.sub.3 O.HCl Calcd. (%): C, 
68.09; H, 6.40; N, 9.53 Found (%): C, 67.80; H, 6.60; N, 9.31. 
Reference Example 16 
2-(4-Fluorophenyl)-4-methyl-6-2-(4-phenylpiperidino)-ethoxy!pyrimidine 
hydrochloride 
m.p. 211-212.degree. C. 
Elemental analysis for C.sub.24 H.sub.26 FN.sub.3 O.HCl Calcd. (%): C, 
67.36; H, 6.36; N, 9.82 Found (%): C, 67.01; H, 6.49; N, 9.61. 
Reference Example 17 
2-(4-Fluorophenyl)-4-methyl-6-3-(4-phenylpiperidino)propoxy!pyrimidine 
hydrochloride 
m.p. 195-198.degree. C. 
Elemental analysis for C.sub.25 H.sub.28 FN.sub.3 O.HCl Calcd. (%): C, 
67.94; H, 6.61; N, 9.51 Found (%): C, 67.82; H, 6.50; N, 9.49. 
Reference Example 18 
2-(4-Chlorophenyl)-4-methyl-6-2-(4-phenylpiperidino)ethoxy)pyrimidine 
hydrochloride 
m.p. 208.5-210.degree. C. 
Elemental analysis for C.sub.24 H.sub.26 ClN.sub.3 O.HCl Calcd. (%): C, 
64.86; H, 6.12; N, 9.46 Found (%): C, 64.62; H, 6.10; N, 9.42 
Reference Example 19 
2-(4-Fluorophenyl)-4-3-4-(4-fluorophenyl)-1,2.3,6-tetrahydropyridin-1-yl! 
propoxy!-6-methylpyrimidine. hydrochloride 
m.p. 197.5-199.5.degree. C. 
Elemental analysis for C.sub.25 H.sub.25 F.sub.2 N.sub.3 O.HCl Calcd. (%): 
C, 65.57; H, 5.72; N, 9.18 Found (%): C, 65.30; H, 5.68; N, 9.12. 
Reference Example 20 
2-(4-Fluorophenyl)-4-methyl-6-3-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)p 
ropoxy!pyrimidine hydrochloride 
m.p. 197-199.degree. C. 
Elemental analysis for C.sub.25 H.sub.26 FN.sub.3 O.HCl Calcd. (%): C, 
68.25; H, 6.19; N, 9.55 Found (%): C, 68.08; H, 6.24; N, 9.31. 
Reference Example 21 
2-(4-Fluorophenyl)-4-3-4-(4-fluorophenyl)piperidino!propoxy!-6-methylpyri 
midine hydrochloride 
m.p. 186-187.degree. C. 
Elemental analysis for C.sub.25 H.sub.27 F.sub.2 N.sub.3 O.HCl Calcd. (%): 
C, 65.28; H, 6.14; N, 9.14 Found (%): C, 64.90; H, 6.23; N, 8.90. 
Reference Example 22 
2-(4-Fluorophenyl)-4-methyl-6-3-4-(pyridin-4-yl)piperidino!propoxy!pyrimi 
dine hydrochloride 
m.p. 186-187.degree. C. 
Elemental analysis for C.sub.24 H.sub.27 FN.sub.4 O.HCl Calcd. (%): C, 
65.08; H, 6.37; N, 12.65 Found (%): C, 64.80; H, 6.46; N, 12.35. 
Reference Example 23 
4-(4-Fluorophenyl)-2-methyl-6-3-(4-phenylpiperazino)propoxy!pyrimidine 
maleate 
m.p. 158-159.degree. C. 
Elemental analysis for C.sub.24 H.sub.27 FN.sub.4 O.C.sub.4 H.sub.4 O.sub.4 
Calcd. (%): C, 64.36; H, 5.98; N, 10.72 Found (%): C, 64.02; H, 5.93; N, 
10.60. 
Reference Example 24 
2-(4-Fluorophenyl)-4-methyl-6-3-(4-phenylpiperazino)propoxy!pyrimidine 
maleate 
m.p. 174-175.degree. C. 
Elemental analysis for C.sub.24 H.sub.27 FN.sub.4 O.C.sub.4 H.sub.4 O.sub.4 
Calcd. (%): C, 64.36; H. 5.98; N, 10.72 Found (%): C, 64.62; H, 6.01; N, 
10.79. 
Reference Example 25 
2-(4-Hydroxyphenyl)-4-methyl-6-(3-piperidinopropoxy)pyrimidine 
hydrochloride 
To a solvent mixture of 13 ml dry THF and 1.5 ml dry DMF was added 258 mg 
of 60% sodium hydride (NaH). While this mixture was stirred at room 
temperature, 461 mg of 3-piperidino-1-propanol was added thereto, followed 
by 10 minutes' stirring. To this reaction mixture was added 1 g of the 
2-(4-benzyloxyphenyl)-4-chloro-6-methylpyrimidine obtained in Reference 
Example 8 and the mixture was stirred at room temperature for 48 hours. 
This reaction mixture was poured into iced water and extracted with ethyl 
acetate. The organic layer was washed with water, dried over MgSO.sub.4, 
and concentrated. The residue was purified with silica gel column 
chromatography (Wakogel.TM. C-200; chloroform) to provide 1.08 g of pale 
yellow oil. This oil was dissolved in methanol and subjected to catalytic 
reduction in the presence of 5% palladium-on-carbon (Pd/C) at atmospheric 
temperature and pressure. The resulting reaction mixture was filtered and 
the filtrate was concentrated. The residue was dissolved in methanol and 
the solution was adjusted to pH 5 with 1N-HCl and concentrated. To the 
residue was added ether and the crystals that formed were collected. This 
crystal crop was recrystallized from methanol to provide 572 mg of the 
title compound as white crystals. 
m.p. 248-249.degree. C. 
Elemental analysis for C.sub.19 H.sub.25 N.sub.3 O.sub.2.HCl Calcd. (%): C, 
62.71; H, 7.20; N, 11.55 Found (%): C, 62.36; H, 7.22; N, 11.76. 
The following compounds were synthesized in the same manner. 
Reference Example 26 
4-(4-Hydroxyphenyl)-2-methyl-6-(2-piperidinoethoxy)pyrimidine hydrochloride 
m.p. 301.degree. C. 
Elemental analysis for C.sub.18 H.sub.23 N.sub.3 O.sub.2.HCl Calcd. (%): C, 
61.80; H, 6.91; N, 12.01 Found (%): C, 61.50; H, 6.83; N, 11.87. 
Reference Example 27 
4-(4-Hydroxyphenyl)-2-methyl-6-(3-piperidinopropoxy)pyrimidine 
hydrochloride 
m.p. 234-235.degree. C. 
Elemental analysis for C.sub.19 H.sub.25 N.sub.3 O.sub.2.HCl Calcd. (%): C, 
62.71; H, 7.20; N, 11.55 Found (%): C, 62.45; H, 7.24; N, 11.51. 
Reference Example 28 
4-(4-Hydroxyphenyl)-2-methyl-6-2-(4-phenylpiperidino)ethoxy!pyrimidine 
hydrochloride 
m.p. 185.degree. C. (decomp.) 
Elemental analysis for C.sub.24 H.sub.27 N.sub.3 O.sub.2.HCl Calcd. (%): C, 
67.67; H, 6.63; N, 9.86 Found (%): C, 67.30; H, 6.58; N, 9.72. 
Reference Example 29 
2-(4-Hydroxyphenyl)-4-methyl-6-3-(4-phenylpiperidino)propoxyl!pyrimidine 
hydrochloride 
m.p. 229-230.5.degree. C. 
Elemental analysis for C.sub.25 H.sub.29 N.sub.3 O.sub.2.HCl Calcd. (%): C, 
68.25; H, 6.87; N, 9.55 Found (%): C, 67.91; H, 7.01; N, 9.64. 
Reference Example 30 
4-(4-Hydroxyphenyl)-2-methyl-6-3-(4-phenylpiperazino)propoxy!pyrimidine 
maleate 
m.p. 210.degree. C. 
Elemental analysis for C.sub.24 H.sub.28 N.sub.4 O.sub.2.C.sub.4 H.sub.4 
O.sub.4 Calcd. (%): C, 64.60; H, 6.20; N, 10.76 Found (%): C, 64.20; H, 
6.47; N, 10.36. 
Reference Example 31 
2-(4-Hydroxyphenyl)-4-methyl-6-3-4-phenylpiperazino)propoxy!pyrimidine 
hydrochloride 
m.p. 253-254.degree. C. 
Elemental analysis for C.sub.24 H.sub.28 N.sub.4 O.sub.2.HCl Calcd. (%): C, 
65.37; H, 6.63; N, 12.71 Found (%): C, 64.98; HI 6.73; N, 12.33. 
Reference Example 32 
4-(4-Fluorophenyl)-2-methyl-6-2-4-(2-methoxyphenyl)piperazino!ethoxy!pyri 
midine hydrochloride 
m.p. 193.0-194.5.degree. C. 
Elemental analysis for C.sub.24 H.sub.27 FN.sub.4 O.sub.2.HCl Calcd. (%): 
C, 62.81; H, 6.15; N, 12.21 Found (%): C, 62.68; H, 6.18; N, 12.34. 
Reference Example 33 
4-(4-Fluorophenyl)-2-methyl-6-2-(4-phenylpiperazino)ethoxy!pyrimidine 
hydrochloride 
m.p. 201-204.degree. C. 
Elemental analysis for C.sub.23 H.sub.25 FN.sub.4 O.HCl Calcd. (%): C, 
64.40; H, 6.11; N, 13.06 Found (%): C, 64.21; H, 6.10; N, 13.26. 
Formulation Example 1 
According to the following recipe, an injection, 1 ml, can be prepared in 
the routine manner. 
______________________________________ 
Recipe 
______________________________________ 
Compound of the invention (Example 1) 
1 mg 
Sodium chloride 9 mg 
Water for injection q.s. 
______________________________________ 
Formulation Example 2 
According to the following recipe, an injection, 1 ml, can be prepared in 
the routine manner. 
______________________________________ 
Recipe 
______________________________________ 
Compound of the invention (Example 2) 
1 mg 
Glucose 48 mg 
Sodium dihydrogen phosphate 
1.25 mg 
Sodium monohydrogen phosphate 
0.18 mg 
Water for injection q.s. 
______________________________________ 
Formulation Example 3 
According to the following recipe, an injection, 1 ml, can be prepared in 
the routine manner. 
______________________________________ 
Recipe 
______________________________________ 
Compound of the invention (Example 4) 
1 mg 
Sorbitol 48 mg 
Benzyl alcohol 20 mg 
Sodium dihydrogen phosphate 
2.5 mg 
Sodium monohydrogen phosphate 
0.36 mg 
Water for injection q.s. 
______________________________________ 
Formulation Example 4 
According to the following recipe, a tablet, 120 mg, can be prepared in the 
routine manner. 
______________________________________ 
Recipe 
______________________________________ 
Compound of the invention (Example 3) 
3 mg 
Lactose 58 mg 
Corn starch 30 mg 
Crystalline cellulose 20 mg 
Hydroxypropylcellulose 
7 mg 
Magnesium stearate 2 mg 
______________________________________ 
Test Example 1 
Delayed Neuronal Death (DND) Inhibitory Activity in Gerbils 
The delayed neuronal death protective effect of the compound of the 
invention was confirmed by an experiment using gerbils. This test is the 
most widely used for all relevant in vivo evaluation protocols and it is 
reported that any drug showing DND inhibitory activity in this test system 
can be expected to be clinically effective in humans GENDAI-IRYO, 24, 
129-133 (1992), Neurology 1987, 37, 1281-1287). 
Experimental 
Male gerbils weighing 60-80 g were anesthetized with pentobarbital sodium 
35 mg/kg i.p. and placed in supine position. After the skin in the 
cervical region was incised, the bilateral common carotid arteries were 
exposed and sutures were placed around each artery. Both ends of each 
suture was introduced into a polyethylene tube and in suturing the incised 
wound, the tube was secured to the cervical skin with the suture emerged 
from the other end of the tube. On the following day, with the animal 
under no anesthesia, both ends of the suture were gently pulled out and 
the carotid artery snared by the suture was urged in a bent position into 
the tube to thereby occlude the carotid artery. After a transient ischemic 
loading of 5 minutes' duration by occlusion of the bilateral common 
carotid arteries, the arteries were reperfused. After 7 days, the brain 
was excised and fixed. A section centered around the hippocampus was 
prepared and Nissle-stained with 0.05% cresyl violet and the pyramidal 
cells in the hippocampal CA-1 subfield were microscopically examined for 
degeneration and death. The degree of neuronal death was scored according 
to the following criteria. 
Criteria for evaluation of neuronal death in the hippocampal CA-1 subfield 
______________________________________ 
Degeneration and death of 
Score pyramidal cells 
______________________________________ 
0 0-10% death (nearly normal) 
1 10-25% death 
2 25-50% death 
3 50-75% death 
4 75-100% death 
______________________________________ 
The test drug was dissolved in saline and administered intraperitoneally at 
the same time as reperfusion following the 5-minute ischemic loading. The 
results are presented in Table 1. 
TABLE 1 
______________________________________ 
Delayed neuronal death protectivre 
activity in gerbils 
DND inhibition 
50 mg/kg i.p. 
______________________________________ 
Control 4.00 (5) 
Compound of Example 1 0.60 (5)** 
Compound of Example 2 0.80 (5)** 
Compound of Example 3.sup.*1 
0.60 (5)** 
Compound of Example 4 0.60 (5)** 
Compound of Example 16 0.60 (5)** 
Compound of Example 18 0.80 (5)** 
Compound of Example 21 0.60 (5)** 
Compound of Reference Example 10 
0.60 (5)** 
______________________________________ 
**: p &lt; 0.01 (Wilcoxon's U test) 
.sup.*1 : 30 mg/kg, i.p. 
The figure in parentheses denotes the number of animals. 
It will be apparent from the above results that the compound of the 
invention markedly inhibited neuronal death in the gerbil model of 
transient ischemia. Moreover, when administered orally, the compound of 
the invention inhibited delayed neuronal death. Furthermore, even when the 
compound of Example 1 was administered in a single dose after a lapse of 
1-2 hours after ischemia, it exhibited a protection activity against the 
delayed neuronal death. 
These results indicate that the compound of the invention is not only 
useful for preventing the onset of sequelae of a cerebrovascular disease 
but also useful as a therapeutic drug for cerebrovascular disease. 
Test Example 2 
Protection of Cerebral Infarction in Rats With Middle Cerebral Artery 
Occlusion 
The cerebral infarction protective effect of the compound of the invention 
was confirmed in a rat middle cerebral artery occlusion model. This is an 
animal model of brain regional ischemia which is similar to human cerebral 
infarction and it is known that the model is useful as a therapeutic model 
as well (Cerebral Apoplexy Experiment Handbook, 91-97, 1990, published by 
ICP). Any drug showing cerebral infarction protective activity in this 
test system can be expected to be clinically effective in humans. 
Experimental 
Male SD rats aged 7-8 weeks were anesthetized with ketamin hydrochloride 
120-150 mg/kg, i.p. and the head was placed in lateral recumbent position 
on an operation table. The skin was linearly incised midway between the 
external auditory foramen and the outer canthus along the anterior margin 
of the temporal muscle to the zygoma. Using an electric dental drill, a 
small hole was drilled midway between the oval foramen and the orbital 
fissure and the dura mater was incised. The middle cerebral arterial trunk 
traversing the transverse olfactory nerves (olfactory cord) was 
electrically coagulated and cut within the olfactory cord using a bipolar 
electrode and the incision wound was sutured. Two days after the 
operation, the animal was decapitated and the brain was excised. Then, 
frontal sections of the brain were prepared at 2 mm intervals from the 
rostal part of the olfactory bulb. Using a saline solution (2%) of 
2,3,5-triphenyltetrazolium chloride (TTC), a compound which is colorless 
by itself but is enzymatically converted to a red dye in living tissues, 
the sections were stained at 37.degree. C. for 30 minutes. Then, the 
frontal sections were photographed and using an image processor, the areas 
of infarction were measured. The percentage of the infarct area in the 
frontal section 6 mm caudal to frontal rostrum, that is at the striatal 
level, relative to the total area of the tissue section and the total 
infarct area of the 5 frontal sections prepared at 2 mm intervals from the 
frontal rostrum was calculated and the percentage of the total infarct 
area relative to the total area of all the sections was calculated. As the 
test drug, the compound of Example 1 was administered intravenously after 
middle cerebral artery occlusion. As a result, the compound of the 
invention at the dose of 0.125 mg/kg markedly inhibited neuronal death in 
the rat model of persistent brain ischemia. 
Test Example 3 
NMDA-Induced Convulsion Inhibitory Activity 
Mice were intraperitoneally dosed with 200 mg/kg of N-methyl-D-aspartate 
(NMDA) and observed for the consequent convulsion and death over a period 
of 30 minutes after administration. As test drugs, the compound of Example 
1, compound of Example 2, compound of Reference Example 10, and compound 
of Reference Example 12 were used and each was administered 
intraperitoneally 30 minutes before administration of NMDA. As a result, 
the compound of the invention at 20 mg/kg did not inhibit the NMDA-induced 
convulsion. These results suggest that the compound of the present 
invention does not act on the NMDA receptor. 
Test Example 4 
Acute Toxicity Study 
Male SD rats (Slc:SD, Japan SLC) were used. The rats were purchased at 7 
weeks of age and the animals which went through a week-long quarantine and 
acclimation were used in groups of 6. The dose volume was 5 ml/kg for 
intraperitoneal administration and 10 ml/kg for intravenous 
administration. Based on the result of a preliminary experiment, the dose 
range was established to include the mortality rats of 0% and 100%. The 
drug solutions were prepared using physiological saline and filtered 
through a 0.22 .mu.m bacterial filter. As test drugs, the compounds of 
Example 1, Example 2, Example 3, Example 4, Example 16, Example 18, 
Example 21, and Reference Example 10 were respectively administered 
intraperitoneally and the animals were observed daily for death and 
general condition for 7 days from the administration day. As a result, no 
remarkable change was found in the general condition of animals. 
Incidentally, the intraperitoneal and intravenous LD.sub.50 values of the 
compound of Example 1 were 65.8 mg/kg and 22.8 mg/kg, respectively. 
INDUSTRIAL APPLICABILITY 
As established by the above test results, the compound of the present 
invention shows an excellent protective activity against neuronal death 
regardless of whether it is administered simultaneously with the onset of 
brain ischemia or infarction or administered a few hours following the 
episode. Moreover, the toxicity of the compound is low. Therefore, the 
compound of the invention is of great use as a neuronal death inhibitor in 
the acute phase of a cerebrovascular disease. In addition, the compound is 
useful as a therapeutic drug for cerebrovascular diseases such as cerebral 
infarction, cerebral hemorrhage, head trauma and subarachnoid hemorrhage, 
and further as a medicine which inhibits the onset of sequelae of 
cerebrovascular diseases (e.g. nervous symptoms such as dyskinesia and 
convulsion and mental symptoms such as emotional and intellectual 
disturbances), thus protecting the brain.