Pyrimidine and pyridine derivatives, their production and use

The present invention relates to a compound represented by the general formula (I): ##STR1## [wherein R.sup.1 is a lower alkyl group or the like, R.sup.2 is a lower alkyl group or the like, R.sup.3 and R.sup.4, which may be the same or different, are halogen atoms or the like, R.sup.5, R.sup.6 and R.sup.7, which may be the same or different, are halogen atoms or the like, and X is .dbd.N-- or .dbd.CH--] or a pharmacologically acceptable salt thereof, which has inhibitory effect on acyl-CoA:cholesterol O-acyltransferase (ACAT), a process for producing said compound, and uses of said compound.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to pyrimidine and pyridine derivatives or 
pharmacologically acceptable salts thereof, which have an excellent 
inhibitory effect on acyl-CoA:cholesterol O-acyltransferase (ACAT). 
The compounds of the present invention have the effect of reducing serum 
cholesterol by inhibiting the absorption of cholesterol from intestinal 
tract and suppress the accumulation of cholesterol esters in the arterial 
wall. Therefore, they are useful as a prophylactic and therapeutic agent 
for hypercholesterolemia, atherosclerosis and various diseases caused by 
them (for example, ischemic heart diseases such as myocardial infarction, 
and cerebrovascular diseases such as cerebral infarction and cerebral 
apoplexy). 
2. Related Art 
Japanese Patent Unexamined Publication Nos. 61-40272 and 1-207234 disclose 
compounds (e.g. 
5-[3-(2-dimethylaminoethyl)ureido]-6-methyl-4-(3-nitrophenyl)-2-phenylpyri 
midine) and 
3-[3-(2-dimethylaminoethyl)ureido]-4-(3-nitrophenyl)-2-methyl-6-phenylpyri 
dine, respectively, as pharmaceutical compositions for curing 
cerebrovascular diseases. Japanese Patent Unexamined Publication No. 
5-320028 discloses compounds such as 4-(phenylureido)pyridine and 
4-(phenylureido)pyrimidine as hair tonics. But, these references do not 
describe the above compounds as having ACAT-inhibitory activity or 
serum-cholesterol-lowering activity, at all. Japanese Patent Unexamined 
Publication Nos. 62-258366, 63-253060, 2-258756 and 5-92950 disclose 
pyrimidine and pyridine derivatives having ACAT-inhibitory effect, but the 
effect of all the pyrimidine and pyridine derivatives are not sufficient. 
SUMMARY OF THE INVENTION 
The present invention provides novel pyrimidine and pyridine derivatives or 
pharmacologically acceptable salts thereof, a process for production of 
the derivatives, and ACAT inhibitors containing the derivative or the salt 
as an active ingredient.

DETAILED DESCRIPTION OF THE INVENTION 
The present inventors found that novel compounds not known in any 
literature, N-phenyl-N'-(4-phenylpyrimidin-5-yl)urea and 
N-phenyl-N'-(4-phenyl-pyridin-5-yl)urea derivatives represented by the 
general formula (I): 
##STR2## 
[wherein R.sup.1 is a lower alkyl group, a lower cycloalkyl group, a lower 
alkoxy group, an aliphatic cyclic amino group which may be substituted by 
one or more lower alkyl groups, or a phenyl group which may be substituted 
by one or more halogen atoms, R.sup.2 is a hydrogen atom or a lower alkyl 
group, R.sup.3 and R.sup.4, which may be the same or different, are 
hydrogen atoms, halogen atoms, lower alkyl groups, lower haloalkyl groups, 
lower alkoxy groups or lower alkylthio groups, R.sup.5, R.sup.6 and 
R.sup.7, which may be the same or different, are hydrogen atoms, halogen 
atoms, lower alkyl groups, lower haloalkyl groups, lower alkoxy groups, 
lower alkylthio groups or lower dialkylamino groups, and X is .dbd.N-- or 
.dbd.CH--] have ACAT-inhibitory activity much higher than that of 
well-known pyrimidine and pyridine derivatives and are useful as a serum 
cholesterol lowering agent or an agent for curing arteriosclerosis, 
whereby the present invention has been accomplished. 
In the above general formula (I), the halogen atoms include fluorine atom, 
chlorine atom, bromine atom and iodine atom. The lower alkyl groups 
include linear or branched alkyl groups having 1 to 8 carbon atoms, such 
as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 
tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, 
1,2-dimethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 
3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 
1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 
2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 
1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and the like. The lower 
cycloalkyl group includes cyclopropyl group, cyclobutyl group, cyclopentyl 
group, cyclohexyl group, cycloheptyl group, etc. The lower haloalkyl 
groups include trichloromethyl group, trifluoromethyl group, 
1,1,1-trifluoroethyl group, etc. The lower alkoxy groups include methoxy 
group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, 
isobutoxy group, sec-butoxy group, tertbutoxy group, etc. The lower 
alkylthio groups include methylthio group, ethylthio group, n-propylthio 
group, isopropylthio group, n-butylthio group, isobutylthio group, 
sec-butylthio group, tert-butylthio group, etc. The aliphatic cyclic amino 
group which may be substituted by one or more lower alkyl groups includes 
pyrrolidino group, piperidino group, morpholino group, 2-methylmorpholino 
group, 2,6-dimethylmorpholino group, thiomorpholino group, piperazino 
group, N-methylpiperazino group, etc. The lower dialkylamino groups 
include dimethylamino group, diethylamino group, di-n-propylamino group, 
diisopropylamino group, di-nbutylamino group, etc. 
Preferable examples of the compounds of the present invention are 
N-[4-(2-chlorophenyl)-6-methyl-2-phenylpyrimidin-5-yl]-N'-(2,6-diisopropyl 
phenyl)urea, 
N-(2,6-diisopropylphenyl)-N'-[4-(2-fluorophenyl)-2-phenylpyrimidin-5-yl]ur 
ea, 
N-(2,6-diisopropylphenyl)-N'-[4-(2-methoxyphenyl)-2-phenylpyrimidin-5-yl]u 
rea, 
N-[4-(2-chlorophenyl)-2-isopropylpyrimidin-5-yl]-N'-(2,6-diethylphenyl)ure 
a, 
N-[2-t-butyl-4-(2-chlorophenyl)pyrimidin-5-yl]-N'-(2,6-diisopropylphenyl)u 
rea, 
N-[4-(2-chlorophenyl)-2-ethoxypyrimidin-5-yl]-N'-(2,6-diisopropylphenyl)ur 
ea, 
N-[4-(2-chlorophenyl)-2-(N-pyrrolidino)pyrimidin-5-yl]-N'-(2,6-diethylphen 
yl)urea, 
N-[4-(2-chlorophenyl)-2-(N-piperidino)pyrimidin-5-yl]-N'-(2,6-diisopropylp 
henyl)urea, 
N-[2-(2-chlorophenyl-6-phenylpyridin-3-yl]-N'-(2,6-diethylphenyl)urea, and 
N-[2-(2-chlorophenyl)-6-cyclohexylpyridin-3-yl]-N'-(2,6-diethylphenyl)urea 
. 
Particularly preferable examples of the compounds of the present invention 
are 
N-[4-(2-chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2,6-diethylphenyl)urea, 
N-[4-(2-chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2,6-diisopropylphenyl)ur 
ea, N-(2,6-diisopropylphenyl)-N'-[2,4-diphenylpyrimidin-5-yl]urea, 
N-(2,6-diisopropylphenyl)-N'-[4-(2-methylphenyl)-2-phenylpyrimidin-5-yl]ur 
ea, 
N-(2,6-diethylphenyl)-N'-[2-phenyl-4-(2-trifluoromethylphenyl)pyrimidin-5- 
yl]urea, 
N-(2,6-diethylphenyl)-N'-[4-(2-methylthiophenyl)-2-phenylpyrimidin-5-yl]ur 
ea, 
N-[4-(2-chlorophenyl)-2-(N-piperidino)pyrimidin-5-yl]-N'-(2,6-diethylpheny 
l)urea, 
N-[4-(2-chlorophenyl)-2-(N-morpholino)pyrimidin-5-yl]-N'-(2,6-diethylpheny 
l)urea, 
N-[2-(2-chlorophenyl)-6-methylpyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea 
, and 
N-[2-(2-chlorophenyl)-6-cyclohexylpyridin-3-yl]-N'-(2,6-diisopropylphenyl) 
urea. 
The compound of the general formula (I) can be synthesized by a process 
represented by the following formulas: 
##STR3## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and 
X are as defined above. 
In detail, the compound of the general formula (I) can be produced by 
reacting a compound of the general formula (II) with diphenylphosphoryl 
azide in the presence of an organic amine such as triethylamine in an 
inert solvent such as benzene, toluene, xylene, fluorobenzene or dioxane 
in a temperature range of room temperature to about 150.degree. C. to 
obtain an isocyanate (III), and then reacting the isocyanate with a 
compound of the general formula (IV) in a temperature range of room 
temperature to about 150.degree. C. without isolating the isocyanate. 
Since the reactions are equimolar reactions, it is sufficient that the 
reactants for carrying out each reaction are used in equimolar amounts, 
though either of them may be used in excess. 
The compound of the general formula (II) used in the reaction can be 
synthesized by any of the following processes. 
Process A 
A compound of the general formula (II) in which X is .dbd.N-- and R.sup.2 
is a hydrogen atom can be synthesized from a compound of the general 
formula (V) by the process described in Journal of Heterocyclic Chemistry 
p. 183 (1981) or a process based thereon. 
##STR4## 
wherein R.sup.1, R.sup.3 and R.sup.4 are as defined above, R.sup.8 is 
COOR.sup.9 (wherein R.sup.9 is a C.sub.1 -C.sub.4 alkyl group) or a 
nitrile group, and Me is a methyl group. 
In detail, a compound (V) can be converted into a compound (VI) by its 
reaction with a dimethylformamide dialkylacetal in an inert solvent (e.g. 
benzene, toluene or xylene) or without a solvent in a temperature range of 
room temperature to about 150.degree. C. Then, the compound (VI) can be 
converted into a pyrimidine (VIII) by its reaction with an amidine (VII) 
in an ordinary solvent (e.g. methanol, ethanol, isopropanol or dioxane) in 
a temperature range of room temperature to about 100.degree. C. 
Subsequently, the pyrimidine (VIII) is hydrolyzed with an aqueous alkali 
solution (e.g. sodium hydroxide or potassium hydroxide) or a mineral acid 
(e.g. hydrochloric acid, sulfuric acid or hydrobromic acid), whereby a 
carboxylic acid (IIa) can be produced. As a solvent used in this reaction, 
methanol, ethanol, isopropanol, dioxane, etc. are suitable. The reaction 
may be carried out without a solvent. The reaction temperature is 
preferably in a range of room temperature to about 120.degree. C. 
Process B 
A compound of the general formula (II) in which X is .dbd.N-- and R.sup.2 
is a lower alkyl group can be synthesized from a compound of the general 
formula (IX) by the process described in Chem. Phar. Bul. 40, 2423 (1992) 
or a process based thereon. 
##STR5## 
wherein R.sup.1, R.sup.3, R.sup.4 and R.sup.9 are as defined above, and 
R.sup.2 ' is a lower alkyl group. 
In detail, a benzaldehyde (IX) can be converted into a compound (XI) by its 
reaction with a .beta.-keto-ester (X) in the presence of an organic base 
(e.g. triethylamine, pyridine, piperazine or piperidine) and an organic 
acid (e.g. acetic acid). This reaction is carried out preferably in an 
inert solvent (e.g. benzene, toluene or xylene) in a temperature range of 
room temperature to about 150.degree. C. Then, the compound (XI) can be 
converted into a dihydropyrimidine (XII) by its reaction with an amidine 
(VII) in an ordinary solvent (e.g. methanol, ethanol, isopropanol, 
n-butanol or dioxane) in a temperature range of room temperature to about 
100.degree. C. Subsequently, the oxidation of the dihydropyridine (XII) 
into a pyrimidine (XIII) can be carried out with an oxidizing agent such 
as manganese dioxide, nickel peroxide, sulfur, 
2,3-dichloro-5,6-dicyano-1,4-benzoquinone, potassium permanganate, or 
palladium-carbon. Thereafter, the pyrimidine (XIII) can be converted into 
a carboxylic acid (IIb) in the same manner as in process A. 
Process C 
A compound of the general formula (II) in which X is .dbd.C-- and R.sup.2 
is a hydrogen atom can be synthesized from a compound of the general 
formula (XIV) by a process represented by the following formulas. 
##STR6## 
wherein R.sup.1, R.sup.3, R.sup.4, and R.sup.9 and Me are as defined 
above. 
In detail, a .beta.-keto-ester (XIV) can be converted into a compound 
(XVII) by its reaction with a Mannich base (XV) or a vinylketone (XVI) in 
the presence of a metal alkoxide (e.g. sodium methoxide, sodium ethoxide 
or potassium t-butoxide) or a metal hydride (e.g. sodium hydride or 
potassium hydride). This reaction is carried out preferably in an ordinary 
solvent (e.g. methanol, ethanol, isopropanol, t-butanol, tetrahydrofuran, 
ether or dioxane) in a temperature range of room temperature to about 
100.degree. C. Then, the compound (XVII) can be converted into a nicotinic 
ester (XVIII) by its reaction with a fatty acid ammonium (e.g. ammonium 
formate or ammonium acetate) in the presence of ferric chloride. This 
reaction is carried out preferably in a solvent such as formic acid or 
acetic acid in a temperature range of room temperature to about 
120.degree. C. Thereafter, the nicotinic ester (XVIII) can be converted 
into a carboxylic acid (IIC) in the same manner as in process A. 
Typical examples of compounds of the general formula (I) obtained by the 
above production processes are given in Table 1, but they are not intended 
in any way to limit the scope of the present invention. 
In the Table, the following abbreviations are used to stand for the 
substituent groups as specified below: 
Ph; phenyl, 
Me; methyl, 
Et; ethyl, 
iPr; isopropyl, 
tBu; tert-butyl, and 
nHep; n-heptyl. 
TABLE 1 
__________________________________________________________________________ 
##STR7## 
Compound No. 
X R.sup.1 R.sup.2 
R.sup.3 
R.sup.4 
R.sup.5 
R.sup.6 
R.sup.7 
__________________________________________________________________________ 
1 N Ph Me 2-Cl 
H 2-iPr 
6-Me 
H 
2 N Ph Me 2-Cl 
H 2-iPr 
6-iPr 
H 
3 N Ph Me 2-Cl 
H 2-Me 4-Me 
6-Me 
4 N Ph Me 2-Cl 
H 2-F 4-F 
H 
5 N Ph Me 2-Cl 
H 2-F 4-F 
6-F 
6 N Ph Me 2-Cl 
H 4-NMe.sub.2 
H H 
7 N Ph H 2-Cl 
H H H H 
8 N Ph H 2-Cl 
H 2-CF.sub.3 
H H 
9 N Ph H 2-Cl 
H 2-OMe 
H H 
10 N Ph H 2-Cl 
H 2-SMe 
H H 
11 N Ph H 2-Cl 
H 2-Me 4-Me 
H 
12 N Ph H 2-Cl 
H 3-Me 4-Me 
H 
13 N Ph H 2-Cl 
H 2-Me 6-Me 
H 
14 N Ph H 2-Cl 
H 2-Et 6-Et 
H 
15 N Ph H 2-Cl 
H 2-iPr 
6-iPr 
H 
16 N Ph H 2-Cl 
H 2-iPr 
6-Me 
H 
17 N Ph H 2-Cl 
H 2-tBu 
6-Me 
H 
18 N Ph H 2-Cl 
H 2-Me 4-Me 
6-Me 
19 N Ph H 2-Cl 
H 2-NMe.sub.2 
6-Me 
H 
20 N Ph H 2-Cl 
H 2-F 4-Me 
H 
21 N Ph H 2-Cl 
H 2-F 4-F 
H 
22 N Ph Me 2-Cl 
H 2-F 6-F 
H 
23 N Ph Me 2-Cl 
H 2-F 4-F 
6-F 
24 N Ph Me 2-Cl 
H 2-Br 6-Br 
H 
25 N Ph Me 3-Cl 
H 2-Et 6-Et 
H 
26 N Ph Me 3-Cl 
H 2-iPr 
6-iPr 
H 
27 N Ph Me 4-Cl 
H 2-Et 6-Et 
H 
28 N Ph H 4-Cl 
H 2-iPr 
6-iPr 
H 
29 N Ph H 2-Cl 
4-Cl 
2-Et 6-Et 
H 
30 N Ph H 2-Cl 
4-Cl 
2-iPr 
6-iPr 
H 
31 N Ph H H H 2-Et 6-Et 
H 
32 N Ph H H H 2-iPr 
6-iPr 
H 
33 N Ph H 2-F H 2-Et 6-Et 
H 
34 N Ph H 2-F H 2-iPr 
6-iPr 
H 
35 N Ph H 2-Me 
H 2-Et 6-Et 
H 
36 N Ph H 2-Me 
H 2-iPr 
6-iPr 
H 
37 N Ph H 2-CF.sub.3 
H 2-Et 6-Et 
H 
38 N Ph H 2-CF.sub.3 
H 2-iPr 
6-iPr 
H 
39 N Ph H 2-OMe 
H 2-Et 6-Et 
H 
40 N Ph H 2-OMe 
H 2-iPr 
6-iPr 
H 
41 N Ph H 2-SMe 
H 2-Et 6-Et 
H 
42 N Ph H 2-SMe 
H 2-iPr 
6-iPr 
H 
43 N 
##STR8## 
H 2-Cl 
H 2-Et 6-Et 
H 
44 N 
##STR9## 
H 2-Cl 
H 2-iPr 
6-iPr 
H 
45 N Me H 2-Cl 
H 2-Et 6-Et 
H 
46 N Me H 2-Cl 
H 2-iPr 
6-iPr 
H 
47 N iPr H 2-Cl 
H 2-Et 6-Et 
H 
48 N iPr H 2-Cl 
H 2-iPr 
6-iPr 
H 
49 N tBu H 2-Cl 
H 2-Et 6-Et 
H 
50 N tBu H 2-Cl 
H 2-iPr 
6-iPr 
H 
51 N OEt H 2-Cl 
H 2-Et 6-Et 
H 
52 N OEt H 2-Cl 
H 2-iPr 
6-iPr 
H 
53 N 
##STR10## 
H 2-Cl 
H 2-Et 6-Et 
H 
54 N 
##STR11## 
H 2-Cl 
H 2-iPr 
6-iPr 
H 
55 N 
##STR12## 
H 2-Cl 
H 2-Et 6-Et 
H 
56 N 
##STR13## 
H 2-Cl 
H 2-iPr 
6-iPr 
H 
57 N 
##STR14## 
H 2-Cl 
H 2-Et 6-Et 
H 
58 N 
##STR15## 
H 2-Cl 
H 2-iPr 
6-iPr 
H 
59 N 
##STR16## 
H 2-Cl 
H 2-Et 6-Et 
H 
60 N 
##STR17## 
H 2-Cl 
H 2-iPr 
6-iPr 
H 
61 CH Ph H H H 2-iPr 
6-iPr 
H 
62 CH Ph H 2-Cl 
H 2-Et 6-Et 
H 
63 CH Ph H 2-Cl 
H 2-iPr 
6-iPr 
H 
64 CH Me H 2-Cl 
H 2-iPr 
6-iPr 
H 
65 CH nHep H 2-Cl 
H 2-iPr 
6-iPr 
H 
66 CH 
##STR18## 
H 2-Cl 
H 2-Et 6-Et 
H 
67 CH 
##STR19## 
H 2-Cl 
H 2-iPr 
6-iPr 
H 
__________________________________________________________________________ 
The compounds of the present invention are administered as a prophylactic 
and therapeutic agent for hypercholesterolemia and atherosclerosis orally 
or parenterally (intramuscularly, subcutaneously or intravenously). They 
are administered to human beings preferably orally. Since the compounds of 
the present invention are applicable in themselves as ACAT inhibitors, 
they are contained in compositions as active ingredients usually in an 
amount of 0.01 to 100% by weight. Although the dose of the compounds is 
varied depending on the condition of a disease, age, sex, body weight, 
administration route, etc., the dose for an adult is usually 0.1 to 1000 
mg per day. 
When the compound of the present invention is formulated into a 
pharmaceutical form, it is prepared into powder, granules, tablets, 
dragees, capsules, pills, a suspension, solution, emulsion, ampule, 
injection, isotonic solution or the like by a conventional preparation 
method. When an oral solid pharmaceutical is prepared, an excipient and 
optionally a binder, wetting agent, disintegrator, surfactant, lubricant, 
dispersant, taste-improver, odor-improver, etc. are added to the active 
ingredient, and the resulting mixture is made into tablets, coated 
tablets, granules, capsules or the like by a conventional method. The 
excipient includes, for example, lactose, glucose, sorbitol, corn starch 
and mannitol. The binder includes, for example, poly(vinyl alcohol)s, 
poly(vinyl ether)s, ethyl cellulose, gum arabic, gelatin, hydroxypropyl 
cellulose and poly(vinylpyrrolidone)s. The disintegrator includes, for 
example, calcium carbonate, calcium citrate, dextrin, starch and gelatin 
powder. The lubricant includes, for example, magnesium stearate, talc and 
poly(ethylene glycol)s. The odor-improver includes, for example, cocoa 
powder, menthol, and peppermint oil. The tablets and the granules may be 
properly coated with a frosting, gelatin or the like if necessary. When an 
injection is prepared, a pH adjustor, buffer, surfactant, solubilizer, 
solvent, stabilizer, preservative, etc. are added to the active ingredient 
if necessary, and the resulting mixture is made into a subcutaneous, 
intramuscular or intravenous injection by a conventional method. 
Examples, reference examples, formulation examples and test examples of the 
present invention are described below but should not be construed as 
limiting the scope of the invention. 
EXAMPLE 1 
N-[4-(2-Chlorophenyl)-6-methyl-2-phenylpyrimidin-5-yl]-N'-(2-isopropyl-6-me 
thylphenyl)urea (compound 1) 
To a stirred mixture of 325 mg of 
4-(2-chlorophenyl)-6-methyl-2-phenyl-5-pyrimidinecarboxylic acid and 0.26 
cc of diphenylphosphoryl azide in 5 cc of benzene was added dropwise 0.14 
cc of triethylamine at room temperature. The resulting mixture was stirred 
at room temperature for 20 minutes and then heated under reflux for 20 
minutes. After cooling, 0.18 cc of 2-isopropyl-6-methylaniline was added, 
followed by refluxing for 2 hours. After cooling, water was added to the 
reaction mixture and extracted with chloroform. The extract was dried over 
magnesium sulfate, and distilled to remove the solvent. The crude product 
thus obtained was purified by a silica gel column chromatography (eluent: 
ethyl acetate-hexane) to obtain 350 mg of compound 1. 
Yield 74.3%, m.p. 266.degree.-267.degree. C. NMR (.delta., ppm; 
DMSO-d.sub.6) 1.07 (d, 2H), 2.03 (s, 3H), 2.60 (s, 3H), 2.99 (m, 1H), 
6.98-7.13 (m, 3H), 7.42-7.66 (m, 7H), 7.71 (s, 1H), 8.02 (s, 1H), 
8.29-8.40 (m, 2H). 
The compounds described in Examples 2 to 6 were obtained in the same manner 
as in Example 1. 
EXAMPLE 2 
N-[4-(2-Chlorophenyl)-6-methyl-2-phenylpyrimidin-5-yl]-N'-(2,6-diisopropylp 
henyl)urea (compound 2) 
Yield 69.1%, m.p. 233.degree.-234.degree. C. 
EXAMPLE 3 
N-[4-(2-Chlorophenyl)-6-methyl-2-phenylpyrimidin-5-yl]-N'-(2,4,6-trimethylp 
henyl)urea (compound 3) 
Yield 75.3%, m.p. 250.degree.-251.degree. C. 
EXAMPLE 4 
N-[4-(2-Chlorophenyl)-6-methyl-2-phenylpyrimidin-5-yl]-N'-(2,4-difluorophen 
yl)urea (compound 4) 
Yield 66.5%, m.p. 249.degree.-250.degree. C. 
EXAMPLE 5 
N-[4-(2-Chlorophenyl)-6-methyl-2-phenylpyrimidin-5-yl]-N'-(2,4,6-trifluorop 
henyl)urea (compound 5) 
Yield 68.4%, m.p. 248.degree.-249.degree. C. 
EXAMPLE 6 
N-[4-(2-Chlorophenyl)-6-methyl-2-phenylpyrimidin-5-yl]-N'-(4-dimethylaminop 
henyl)urea (compound 6) 
Yield 74.2%, m.p. 285.degree.-285.5.degree. C. 
EXAMPLE 7 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-phenylurea (compound 7) 
To a stirred mixture of 311 mg of 
4-(2-chlorophenyl)-2-phenyl-5-pyrimidinecarboxylic acid and 0.26 cc of 
diphenylphosphoryl azide in 5 cc of fluorobenzene was added dropwise 0.15 
cc of triethylamine at room temperature. The resulting mixture was stirred 
at room temperature for 30 minutes and then heated at a temperature of 
65.degree.-70.degree. C. for 10 minutes. After cooling, 0.11 cc of aniline 
was added and the resulting mixture was stirred heated at a temperature of 
70.degree. C. for 2 hours. After cooling, water was added to the reaction 
mixture and extracted with chloroform. The extract was dried over 
magnesium sulfate, and distilled to remove the solvent. The crude product 
thus obtained was purified by a silica gel column chromatography (eluent: 
chloroform) to obtain 200 mg of compound 7. 
Yield 49.9%, m.p. 195.degree.-198.degree. C. NMR (.delta., ppm; 
DMSO-d.sub.6) 7.00 (t, 1H), 7.29 (t, 2H), 7.41-7.43 (d, 2H), 7.50-7.51 (m, 
3H), 7.60-7.64 (m, 3H), 7.71 (d, 1H), 7.93 (s, 1H), 8.31-8.34 (m, 2H), 
9.16 (s, 1H), 9.56 (s, 1H). 
The compounds described in Examples 8 to 44 were obtained in the same 
manner as in Example 7. 
EXAMPLE 8 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2-trifluoromethylphenyl)u 
rea (compound 8) 
Yield 58.3%, m.p. 224.degree.-225.degree. C. 
EXAMPLE 9 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2-methoxyphenyl)urea 
(compound 9) 
Yield 79.1%, m.p. 241.degree.-242.degree. C. 
EXAMPLE 10 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2-methylthiophenyl)urea 
(compound 10) 
Yield 64.5%, m.p. 196.degree.-197.degree. C. 
EXAMPLE 11 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2,4-dimethylphenyl)urea 
(compound 11) 
Yield 82.3%, m.p. 212.degree.-213.degree. C. 
EXAMPLE 12 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(3,4-dimethylphenyl)urea 
(compound 12) 
Yield 81.6%, m.p. 216.degree.-217.degree. C. 
EXAMPLE 13 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2,6-dimethylphenyl)urea 
(compound 13) 
Yield 66.0%, m.p. 241.degree.-242.degree. C. 
EXAMPLE 14 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2,6-diethylphenyl)urea 
(compound 14) 
Yield 70.0%, m.p. 198.degree.-199.degree. C. 
EXAMPLE 15 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2,6-diisopropylphenyl)ure 
a (compound 15) 
Yield 76.5%, m.p. 200.degree.-201.degree. C. 
EXAMPLE 16 
N-[4-(2-chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2-isopropyl-6-methylpheny 
l)urea (compound 16) 
Yield 70.9%, m.p. 193.degree.-194.degree. C. 
EXAMPLE 17 
N-(2-t-Butyl-6-methylphenyl)-N'-[4-(2-chlorophenyl)-2-phenylpyrimidin-5-yl] 
urea (compound 17) 
Yield 45.3%, m.p. 213.degree.-216.degree. C. 
EXAMPLE 18 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]N'-(2,4,6-trimethylphenyl) 
urea (compound 18) 
Yield 35.0%, m.p. 225.degree.-226.degree. C. 
EXAMPLE 19 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2-dimethylamino-6-methylp 
henyl)urea (compound 19) 
Yield 66.2%, m.p. 210.degree.-211.degree. C. 
EXAMPLE 20 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2-fluoro-4-methylphenyl)u 
rea (compound 20) 
Yield 35.2%, m.p. 206.degree.-208.degree. C. 
EXAMPLE 21 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2,4-difluorophenyl) urea 
(compound 21) 
Yield 69.0%, m.p. 210.degree.-211.degree. C. 
EXAMPLE 22 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2,6-difluorophenyl)urea 
(compound 22) 
Yield 45.6%, m.p. 202.degree.-203.degree. C. 
EXAMPLE 23 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2,4,6-trifluorophenyl)ure 
a (compound 23) 
Yield 73.7%, m.p. 230.degree.-231.degree. C. 
EXAMPLE 24 
N-[4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2,6-dibromophenyl)urea 
(compound 24) 
Yield 42.4%, m.p. 200.degree.-202.degree. C. 
EXAMPLE 25 
N-[4-(3-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2,6-diethylphenyl)urea 
(compound 25) 
Yield 64.9%, m.p. 275.degree.-277.degree. C. 
EXAMPLE 26 
N-[4-(3-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2,6-diisopropylphenyl)ure 
a (compound 26) 
Yield 45.4%, m.p. 275.degree.-276.degree. C. 
EXAMPLE 27 
N-[4-(4-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2,6-diethylphenyl)urea 
(compound 27) 
Yield 69.0%, m.p. 285.degree.-287.degree. C. 
EXAMPLE 28 
N-[4-(4-Chlorophenyl)-2-phenylpyrimidin-5-yl]-N'-(2,6-diisopropylphenyl)ure 
a (compound 28) 
Yield 56.7%, m.p. &gt;300.degree. C. 
EXAMPLE 29 
N-[4-(2-(2,4-Dichlorophenyl)-2-phenylpyrimidin-5-yl 
]-N'-(2,6-diethylphenyl)urea (compound 29) 
Yield 40.2%, m.p. 230.degree.-232.degree. C. 
EXAMPLE 30 
N-[4-(2,4-Dichlorophenyl)-2-phenylpyrimidin-5-yl]-N'-[2,6-diisopropylphenyl 
)urea (compound 30) 
Yield 67.4%, m.p. 200.degree.-201.degree. C. 
EXAMPLE 31 
N-(2,6-Diethylphenyl)-N'-(2,4-diphenylpyrimidin-5-yl)urea (compound 31) 
Yield 82.4%, m.p. 279.degree.-280.degree. C. 
EXAMPLE 32 
N-(2,6-Diisopropylphenyl)-N'-(2,4-diphenylpyrimidin-5-yl)urea (compound 32) 
Yield 82.9%, m.p. 237.degree.-238.degree. C. 
EXAMPLE 33 
N-(2,6-Diethylphenyl)-N'-[4-(2-fluorophenyl)-2-phenylpyrimidin-5-yl]urea 
(compound 33) 
Yield 60.1%, m.p. 219.degree.-221.degree. C. 
EXAMPLE 34 
N-(2,6-Diisopropylphenyl)-N'-[4-(2-fluorophenyl)-2-phenylpyrimidin-5-yl]ure 
a (compound 34) 
Yield 70.9%, m.p. 213.degree.-214.degree. C. 
EXAMPLE 35 
N-(2,6-Diethylphenyl)-N'-[4-(2-methylphenyl)-2-phenylpyrimidin-5-yl]urea 
(compound 35) 
Yield 76.5%, m.p. 181.degree.-182.degree. C. 
EXAMPLE 36 
N-(2,6-Diisopropylphenyl)-N'-[4-(2-methylphenyl)-2-phenylpyrimidin-5-yl]ure 
a (compound 36) 
Yield 78.1%, m.p. 220.degree.-222.degree. C. 
EXAMPLE 37 
N-(2,6-Diethylphenyl)-N'-[2-phenyl-4-(2-trifluoromethylphenyl)pyrimidin-5-y 
l]urea (compound 37) 
Yield 57.6%, m.p. 191.degree.-192.degree. C. 
EXAMPLE 38 
N-(2,6-Diisopropylphenyl)-N'-[2-phenyl-4-(2-trifluoromethylphenyl)pyrimidin 
-5-yl]urea (compound 38) 
Yield 74.3%, m.p. 177.degree.-179.degree. C. 
EXAMPLE 39 
N-(2,6-Diethylphenyl)-N'-[4-(2-methoxyphenyl)-2-phenylpyrimidin-5-yl]urea 
(compound 39) 
Yield 77.8%, m.p. 225.degree.-226.degree. C. 
EXAMPLE 40 
N-(2,6-Diisopropylphenyl)-N'-[4-(2-methoxyphenyl)-2-phenylpyrimidin-5-yl]ur 
ea (compound 40) 
Yield 82.5%, m.p. 200.degree.-201.degree. C. 
EXAMPLE 41 
N-(2,6-Diethylphenyl)-N'-[4-(2-methylthiophenyl)-2-phenylpyrimidin-5-yl]ure 
a (compound 41) 
Yield 78.8%, m.p. 185.degree.-187.degree. C. 
EXAMPLE 42 
N-(2,6-Diisopropylphenyl)-N'-[4-(2-methylthiophenyl)-2-phenylpyrimidin-5-yl 
]urea (compound 42) 
Yield 55.9%, m.p. 209.degree.-210.degree. C. 
EXAMPLE 43 
N-[4-(2-Chlorophenyl)-2-(3,5-dichlorophenyl)pyrimidin-5-yl]-N'-(2,6-diethyl 
phenyl)urea (compound 43) 
Yield 43.1%, m.p. 230.degree.-231.degree. C. 
EXAMPLE 44 
N-[4-(2-Chlorophenyl)-2-(3,5-dichlorophenyl)pyrimidin-5-yl]-N'-(2,6-diisopr 
opylphenyl)urea (compound 44) 
Yield 56.6%, m.p. 240.degree.-241.degree. C. 
EXAMPLE 45 
N-[4-(2-Chlorophenyl)-2-methylpyrimidin-5-yl]-N'-(2,6-diethylphenyl)urea 
(compound 45) 
To a stirred mixture of 373 mg of 
4-(2-chlorophenyl)-2-methyl-5-pyrimidinecarboxylic acid and 0.39 cc of 
diphenylphosphoryl azide in 5 cc of benzene was added dropwise 0.22 cc of 
triethylamine at room temperature. The resulting mixture was stirred at 
room temperature for 30 minutes and then heated under reflux for 30 
minutes. After cooling, 0.3 cc of 2,6-diethylaniline was added, followed 
by refluxing for 3 hours. After cooling, water was added to the reaction 
mixture and extracted with chloroform. The extract was dried over 
magnesium sulfate, and distilled to remove the solvent. The crude product 
thus obtained was purified by a silica gel column chromatography (eluent: 
ethyl acetate/hexane=3/2) to obtain 510 mg of compound 45. 
Yield 86.1%, m.p. 186.degree.-187.degree. C. NMR (.delta., ppm; 
DMSO-d.sub.6) 1.08 (t, 6H), 2.47 (q, 4H), 2.59 (s, 3H), 7.11-7.23 (m, 3H), 
7.50-7.60 (m, 3H), 7.66 (m, 1H), 7.85 (s, 1H), 8.01 (s, 1H), 9.11 (s, 1H). 
The compounds described in Examples 46 to 50 were obtained in the same 
manner as in Example 45. 
EXAMPLE 46 
N-[4-(2-Chlorophenyl)-2-methylpyrimidin-5-yl]-N'-(2,6-diisopropylphenyl)ure 
a (compound 46) 
Yield 85.7%, m.p. 181.degree.-182.degree. C. 
EXAMPLE 47 
N-[4-(2-Chlorophenyl)-2-isopropylpyrimidin-5-yl]-N'-(2,6-diethylphenyl)urea 
(compound 47) 
Yield 85.1%, m.p. 161.degree.-162.degree. C. 
EXAMPLE 48 
N-[4-(2-Chlorophenyl)-2-isopropylpyrimidin-5-yl]-N'-(2,6-diisopropylphenyl) 
urea (compound 48) 
Yield 81.3%, m.p. 172.degree.-174.degree. C. 
EXAMPLE 49 
N-[2-t-Butyl-4-(2-chlorophenyl)pyrimidin-5-yl]-N'-(2,6-diethylphenyl)urea 
(compound 49) 
Yield 88.5%, m.p. 209.degree.-210.degree. C. 
EXAMPLE 50 
N-[2-t-Butyl-4-(2-chlorophenyl)pyrimidin-5-yl]-N'-(2,6-diisopropylphenyl)ur 
ea (compound 50) 
Yield 87.4%, m.p. 194.degree. C. 
EXAMPLE 51 
N-[4-(2-Chlorophenyl)-2-ethoxypyrimidin-5-yl]-N'-(2,6-diethylphenyl)urea 
(compound 51) 
To a stirred mixture of 418 mg of 
4-(2-chlorophenyl)-2-ethoxy-5-pyrimidinecarboxylic acid and 0.39 cc of 
diphenylphosphoryl azide in 5 cc of benzene was added dropwise 0.22 cc of 
triethylamine at room temperature. The resulting mixture was stirred at 
room temperature for 30 minutes and then heated under reflux for 30 
minutes. After cooling, 0.3 cc of 2,6-diethylaniline was added, followed 
by refluxing for 3 hours. After cooling, water was added to the reaction 
mixture and extracted with chloroform. The extract was dried over 
magnesium sulfate, and distilled to remove the solvent. The crude product 
thus obtained was purified by a silica gel column chromatography (eluent: 
chloroform/methanol =100/1) to obtain 439 mg of compound 51. 
Yield 68.9%, m.p. 190.degree.-191.degree. C. NMR (.delta., ppm; 
DMSO-d.sub.6) 1.05 (t, 6H), 1.32 (t, 3H), 2.44 (q, 4H), 4.32 (q, 2H), 
7.00-7.10 (m, 3H), 7.11-7.18 (m, 1H), 7.41-7.60 (m, 2H), 7.60-7.69 (m, 
1H), 7.80 (s, 1H), 7.85 (s, 1H), 8.84 (s, 1H). 
The compound described in Example 52 was obtained in the same manner as in 
Example 51. 
EXAMPLE 52 
N-[4-(2-Chlorophenyl)-2-ethoxypyrimidin-5-yl]-N'-(2,6-diisopropylphenyl)ure 
a (compound 52) 
Yield 67.7%, m.p. 141.degree.-142.degree. C. 
EXAMPLE 53 
N-[4-(2-Chlorophenyl)-2-(N-pyrrolidino)pyrimidin-5-yl]-N'-(2,6-diethylpheny 
l)urea (compound 53) 
To a stirred mixture of 456 mg of 
4-(2-chlorophenyl)-2-(N-pyrrolidino)-5-pyrimidinecarboxylic acid and 0.39 
cc of diphenylphosphoryl azide in 6 cc of benzene was added dropwise 0.22 
cc of triethylamine at room temperature. The resulting mixture was stirred 
at room temperature for 30 minutes and then heated under reflux for 20 
minutes. After cooling, 0.3 cc of 2,6-diethylaniline was added, followed 
by refluxing for 3 hours. After cooling, water was added to the reaction 
mixture and extracted with chloroform. The extract was dried over 
magnesium sulfate, and distilled to remove the solvent. The crude product 
thus obtained was purified by a silica gel column chromatography (eluent: 
chloroform/methanol=100/1) to obtain 588 mg of compound 53. 
Yield 87.1%, m.p. 241.degree.-242.degree. C. NMR (.delta., ppm; 
DMSO-d.sub.6) 1.03 (t, 6H), 1.92 (t, 4H), 2.38 (q, 4H), 3.46 (t, 4H), 
7.00-7.08 (m, 2H), 7.08-7.10 (m, 1H), 7.40-7.62 (m, 6H), 8.43 (s, 1H). 
The compounds described in Examples 54 to 60 were obtained in the same 
manner as in Example 53. 
EXAMPLE 54 
N-[4-(2-Chlorophenyl)-2-(N-pyrrolidino)pyrimidin-5-yl]-N'-(2,6-diisopropylp 
henyl)urea (compound 54) 
Yield 88.6%, m.p. 224.degree.-225.degree. C. 
EXAMPLE 55 
N-[4-(2-Chlorophenyl)-2-(N-piperidino)pyrimidin-5-yl]-N'-(2,6-diethylphenyl 
)urea (compound 55) 
Yield 79.3%, m.p. 235.degree.-238.degree. C. 
EXAMPLE 56 
N-[4-(2-Chlorophenyl)-2-(N-piperidino)pyrimidin-5-yl]-N'-(2,6-diisopropylph 
enyl)urea (compound 56) 
Yield 84.0%, m.p. 222.degree.-224.degree. C. 
EXAMPLE 57 
N-[4-(2-Chlorophenyl)-2-(N-morpholino)pyrimidin-5-yl]-N'-(2,6-diethylphenyl 
)urea (compound 57) 
Yield 88.3%, m.p. 255.degree.-256.degree. C. 
EXAMPLE 58 
N-[4-(2-Chlorophenyl)-2-(N-morpholino)pyrimidin-5-yl]-N'-(2,6-diisopropylph 
enyl)urea (compound 58) 
Yield 85.6%, m.p. 224.degree.-225.degree. C. 
EXAMPLE 59 
N-[4-(2-Chlorophenyl)-2-(4-methyl-1-piperazino)pyrimidin-5-yl]-N'-(2,6-diet 
hylphenyl)urea (compound 59) 
Yield 65.1%, m.p. 210.degree.-212.degree. C. 
EXAMPLE 60 
N-[4-(2-Chlorophenyl)-2-(4-methyl-1-piperazino)pyrimidin-5-yl]-N'-(2,6-diis 
opropylphenyl)urea (compound 60) 
Yield 70.5%, m.p. 212.degree.-214.degree. C. 
EXAMPLE 61 
N-(2,6-Diisopropylphenyl)-N'-(2,6-diphenylpyridin-3-yl)urea (compound 61) 
To a stirred mixture of 551 mg of 2,6-diphenyl-3-pyridinecarboxylic acid 
and 0.52 cc of diphenylphosphoryl azide in 6 cc of fluorobenzene was added 
dropwise 0.29 cc of triethylamine at room temperature. The resulting 
mixture was stirred at room temperature for 30 minutes and then heated at 
a temperature of 65.degree.-70.degree. C. for 10 minutes. After cooling, 
0.45 cc of 2,6-diisopropylaniline was added and the resulting mixture was 
heated at a temperature of 70.degree. C. for 1.5 hours. After cooling, 
water was added to the reaction mixture and extracted with chloroform. The 
extract was dried over magnesium sulfate, and distilled to remove the 
solvent. The crude product thus obtained was purified by a silica gel 
column chromatography (eluent: chloroform) to obtain 817 mg of compound 
61. 
Yield 90.9%, m.p. 206.degree.-208.degree. C. NMR (.delta., ppm; 
DMSO-d.sub.6) 1.16 (d, 12H), 3.16 (m, 2H), 7.05-7.19 (m, 3H), 7.20-7.26 
(m, 1H), 7.35-7.60 (m, 5H), 7.76-7.78 (m, 2H), 7.92-7.94 (m, 1H), 8.05 
8.13 (m, 3H), 8.15 (s, 1H), 8.20-8.23 (m, 1H). 
The compounds described in Examples 62 to 67 were obtained in the same 
manner as in Example 61. 
EXAMPLE 62 
N-[2-(2-Chlorophenyl)-6-phenylpyridin-3-yl]-N'-(2,6-diethylphenyl)urea 
(compound 62) 
Yield 69.7%, m.p. 190.degree.-191.degree. C. 
EXAMPLE 63 
N-[2-(2-Chlorophenyl)-6-phenylpyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea 
(compound 63) 
Yield 79.9%, m.p. 241.degree.-242.degree. C. 
EXAMPLE 64 
N-[2-(2-Chlorophenyl)-6-methylpyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea 
(compound 64) 
Yield 92.0%, amorphous. NMR (.delta., ppm; DMSO-d.sub.6) 1.12 (d, 12H), 
2.42 (s, 3H), 3.08 (m, 2H), 7.10-7.12 (m, 2H), 7.19-7.24 (m, 2H), 
7.43-7.61 (m, 5H), 7.94 (s, 1H), 8.10-8.12 (m, 1H). 
EXAMPLE 65 
N-[2-(2-Chlorophenyl)-6-(n-heptyl)pyridin-3-yl]-N'-(2,6-diisopropylphenyl)u 
rea (compound 65) 
Yield 92.2%, m.p. 74.degree.-75.degree. C. 
EXAMPLE 66 
N-[2-(2-Chlorophenyl)-6-cyclohexylpyridin-3-yl]-N'-(2,6-diethylphenyl)urea 
(compound 66) 
Yield 74.7%, m.p. 122.degree.-124.degree. C. 
EXAMPLE 67 
N-[2-(2-Chlorophenyl)-6-cyclohexylpyridin-3-yl]-N'-(2,6-diisopropylphenyl)u 
rea (compound 67) 
Yield 83.8%, m.p. 202.degree.-203.degree. C. 
REFERENCE EXAMPLE 1 
4-(2-Chlorophenyl)-6-methyl-2-phenyl-5-pyrimidinecarboxylic acid 
1) Ethyl 2-(2-chlorobenzylidene)acetoacetate (compound A) 
A mixture of 25.0 g of 2-chlorobenzaldehyde, 23.1 g of ethyl acetoacetate, 
2.1 g of acetic acid and 0.6 g of piperidine in 100 cc of benzene was 
heated under reflux for 8 hours and removed water by a Dean-Stark trap. 
After cooling, to the reaction mixture was added ethylacetate and water. 
The organic layer was further washed with a saturated aqueous sodium 
chloride solution and dried over magnesium sulfate. The solvent was 
distilled off and the crude product thus obtained was purified by a silica 
gel column chromatography (eluent: ethyl acetate/hexane=1/9) to obtain 
44.0 g of compound A. Yield: 97.9%. 
2) Ethyl 1,6-dihydro-6-(2-chlorophenyl)-4-methyl-2-phenyl-5-carboxylate 
(compound B) 
A mixture of 2.53 g of compound A, 1.88 g of benzamidine hydrochloride and 
2.73 g of triethylamine in 20 cc of n-butanol was heated under reflux for 
90 minutes. After cooling, to the reaction mixture was added ethyl acetate 
and water. The organic layer was further washed two times with water and 
dried over magnesium sulfate. The solvent was distilled off and the crude 
product thus obtained was purified by a silica gel column chromatography 
(eluent: ethyl acetate/hexane =1/3) to obtain 2.71 g of compound B. Yield: 
76.4%. 
3) Ethyl 4-(2-chlorophenyl)-2-phenyl-6-methyl-5-pyrimidinecarboxylate 
(compound C) 
To a stirred solution of 2.71 g of compound B in 50 cc of toluene was added 
2.08 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone at room temperature 
and the resulting mixture was heated at a temperature of 
40.degree.-50.degree. C. for 1 hour. After cooling, the toluene was 
distilled off and a cyclohexane-AcOEt (4/1) solution was added to the 
residue. The insoluble material was filtered off and further washed with a 
cyclohexane-AcOEt (4/1) solution. The combined filtrate was distilled to 
remove the solvent. The crude product thus obtained was purified by a 
silica gel column chromatography (eluent: ethyl acetate/hexane=1/8) to 
obtain 2.0 g of compound C. Yield: 74.2%. 
4) 4-(2-Chlorophenyl)-2-phenyl-6-methyl-5-pyrimidine-carboxylic acid 
A mixture of 3.0 g of compound C and 1.43 g of powdered KOH in 20 cc 
ethanol was heated under reflux for 2 hours. After cooling, the reaction 
mixture was acidified with 1N HCl, and extracted with chloroform. The 
extract was dried over magnesium sulfate, and distilled to remove the 
solvent. Thus, 2.75 g of 
4-(2-chlorophenyl)-2-phenyl-6-methyl-5-pyrimidinecarboxylic acid was 
obtained. Yield: 99.6%. 
REFERENCE EXAMPLE 2 
4-(2-Chlorophenyl)-2-phenyl-5-pyrimidinecarboxylic acid 
1) Ethyl 2-(2-chlorobenzoyl)-3-dimethylaminopropenoate (compound D) 
To a stirred solution of 5.0 g of ethyl 2-chlorobenzoylacetate in 50 cc of 
benzene was added dropwise 5 cc of dimethylformamide dimethylacetal in 15 
cc of benzene at room temperature. The resulting mixture was heated under 
reflux for 6 hours. After cooling, the solvent was distilled off to obtain 
6.2 g of compound D. Yield: 97.3%. 
2) Ethyl 4-(2-chlorophenyl)-2-phenyl-5-pyrimidinecarboxylate (compound E) 
To a stirred solution of 3.45 g of benzamidine hydrochloride in 50 cc of 
ethanol was added 1.50 g of sodium ethoxide at room temperature and the 
mixture was stirred for 10 minutes. The resulting suspension was added to 
6.2 g of compound D in 50 cc of ethanol and the resulting mixture was 
heated under reflux for 6 hours. After cooling, the solvent was distilled 
off, and AcOEt and water were added to the residue. The organic layer was 
further washed with a saturated aqueous sodium bicarbonate solution and 
dried over magnesium sulfate. The solvent was distilled off and the crude 
product thus obtained was purified by a silica gel column chromatography 
(eluent: ethyl acetate/hexane=1/8) to obtain 5.80 g of compound E. Yield: 
77.6%. 
3) 4-(2-Chlorophenyl)-2-phenyl-5-pyrimidinecarboxylic acid 
A mixture of 5.70 g of compound E and 2.83 g of potassium hydroxide in 40 
cc of ethanol and 0.5 cc of water was heated under reflux for 3 hours. 
After cooling, the reaction mixture was acidified with 1N HCl, and 
extracted with chloroform. The extract was dried over magnesium sulfate, 
and distilled to remove the solvent. Thus, 5.20 g of 
4-(2-chlorophenyl)-2-phenyl-5-pyrimidinecarboxylic acid was obtained. 
Yield: 99.6%. 
The following compounds were obtained in the same manner as in Reference 
Example 2: 
(1) 4-(3-chlorophenyl)-2-phenyl-5-pyrimidinecarboxylic acid, 
(2) 4-(4-chlorophenyl)-2-phenyl-5-pyrimidinecarboxylic acid, 
(3) 4-(2,4-dichlorophenyl)-2-phenyl-5-(pyrimidinecarboxylic acid, 
(4) 2,4-diphenyl-5-pyrimidinecarboxylic acid, 
(5) 4-(2-fluorophenyl)-2-phenyl-5-pyrimidinecarboxylic acid, 
(6) 4-(2-methylphenyl)-2-phenyl-5-pyrimidinecarboxylic acid, 
(7) 2-phenyl-4-(2-trifluoromethylphenyl)-5-pyrimidinecarboxylic acid, 
(8) 4-(2-methoxylphenyl)-2-phenyl-5-pyrimidinecarboxylic acid, 
(9) 4-(2-methylthiophenyl)-2-phenyl-5-pyrimidinecarboxylic acid, 
(10) 4-(2-chlorophenyl)-2-(3,5-dichlorophenyl)-5-pyrimidinecarboxylic acid. 
REFERENCE EXAMPLE 3 
4-(2-Chlorophenyl)-2-methyl-5-pyrimidinecarboxylic acid 
1) Ethyl 4-(2-chlorophenyl)-2-methyl-5-pyrimidinecarboxylate (compound F) 
To a stirred solution of 2.09 g of acetoamidine hydrochloride in 50 cc of 
ethanol was added 1.50 g of sodium ethoxide at room temperature and the 
mixture was stirred for 10 minutes. The resulting suspension was added to 
6.1 g of compound D in 50 cc of ethanol and the resulting mixture was 
heated under reflux for 6 hours. Thereafter, 4.5 g of compound F was 
obtained in the same manner as for compound E. Yield: 73.7%. 
2) 4-(2-Chlorophenyl)-2-methyl-5-pyrimidinecarboxylic acid 
In the same manner as in the production of 
4-(2-chlorophenyl)-2-phenyl-5-pyrimidinecarboxylic acid from compound E, 
3.7 g of 4-(2-chlorophenyl)-2-methyl-5-pyrimidinecarboxylic acid was 
obtained from 4.5 g of compound F. Yield: 91.3%. 
The following compounds were obtained in the same manner as in Reference 
Example 3: 
(1) 4-(2-chlorophenyl)-2-isopropyl-5-pyrimidinecarboxylic acid, 
(2) 2-t-butyl-4-(2-chlorophenyl)-5-pyrimidinecarboxylic acid, 
(3) 4-(2-chlorophenyl)-2-ethoxy-5-pyrimidinecarboxylic acid, 
(4) 4-(2-chlorophenyl)-2-(N-pyrrolidino)-5-pyrimidinecarboxylic acid, 
(5) 4-(2-chlorophenyl)-2-(N-piperidino)-5-pyrimidinecarboxylic acid, 
(6) 4-(2-chlorophenyl)-2-(N-morpholino)-5-pyrimidinecarboxylic acid, 
(7) 4-(2-chlorophenyl)-2-(4-methyl-1-piperazino)-5-pyrimidinecarboxylic 
acid. 
REFERENCE EXAMPLE 4 
2,6-Diphenyl-3-pyridinecarboxylic acid 
1) Ethyl 2-benzoyl-5-oxo-5-phenylvalerate (compound G) 
To a stirred mixture of 2.14 g of .beta.-dimethylaminopropiophenone 
hydrochloride and 1.92 g of ethyl benzoylacetate in 30 cc of ethanol was 
added in small portions 1.36 g of sodium ethoxide at room temperature. The 
resulting mixture was stirred at room temperature for 30 minutes and then 
heated under reflux for 1 hour. After cooling, the solvent was distilled 
off and water was added to the residue. The aqueous layer was acidified 
with 1N HCl, and extracted twice with chloroform. The combined organic 
layer was washed with a saturated aqueous sodium chloride solution and 
dried over magnesium sulfate. The solvent was distilled off and the crude 
product thus obtained was purified by a silica gel column chromatography 
(eluent: ethyl acetate/hexane=1/5) to obtain 2.45 g of compound G. Yield: 
75.5%. 
2) Ethyl 2,6-diphenyl-3-pyridinecarboxylate (compound H) 
A mixture of 2.30 g of compound G, 8.20 g of ammonium acetate and 8.43 g of 
ferric chloride hexahydrate in 50 cc of acetic acid was heated under 
reflux for 7 hours. After cooling, the insoluble materials were removed by 
filtration through Celite and the filtrate was distilled to remove the 
solvent. The residue was adjusted to pH 8 with an aqueous sodium 
bicarbonate solution, and extracted three times with ethyl acetate. The 
combined organic layer was washed with a saturated aqueous sodium chloride 
solution and dried over magnesium sulfate. The solvent was distilled off 
and the crude product thus obtained was purified by a silica gel column 
chromatography (eluent: ethyl acetate/hexane=1/5) to obtain 1.98 g of 
compound H. Yield: 92.1%. 
3) 2,6-Diphenyl-3-pyridinecarboxylic acid 
In the same manner as in the production of 
4-(2-chlorophenyl)-2-phenyl-5-pyrimidinecarboxylic acid from compound E, 
1.62 g of 2,6-diphenyl-3-pyridinecarboxylic acid was obtained from 1.90 g 
of compound H. Yield: 95.0%. 
The following compound was obtained in the same manner as in Reference 
Example 4: 
2-(2-chlorophenyl)-6-phenyl-3-pyridinecarboxylic acid. 
REFERENCE EXAMPLE 5 
2-(2-Chlorophenyl)-6-n-heptyl-3-pyridinecarboxylic acid 
1) Ethyl 5-oxo-2-(2-chlorobenzoyl)laurate (compound I) 
To a stirred solution of 0.91 g of ethyl 2-chlorobenzoylacetate in 10 cc of 
ethanol was added 0.27 g of sodium ethoxide at room temperature, and the 
mixture was stirred at room temperature for 10 minutes. Then, 0.62 g of 
3-oxo-1-decene in 10 cc of ethanol was added and the resulting mixture was 
stirred overnight at room temperature. Water was added to the reaction 
mixture, and the aqueous layer was acidified with 1N HCl and extracted 
three times with ethyl acetate. The combined organic layer was washed with 
a saturated aqueous sodium chloride solution and dried over magnesium 
sulfate. The solvent was distilled off and the crude product thus obtained 
was purified by a silica gel column chromatography (eluent: ethyl 
acetate/hexane =1/9) to obtain 0.90 g of compound I. Yield: 59.1%. 
2) 2-(2-Chlorophenyl)-6-n-heptyl-3-pyridinecarboxylic acid (compound J) 
A mixture of 0.90 g of compound I, 2.73 g of ammonium acetate and 2.80 g of 
ferric chloride hexahydrate in 20 cc of acetic acid was heated under 
reflux for 8 hours. Thereafter, 0.60 g of compound J was obtained in the 
same manner as in the production of compound H from compound G, Yield: 
70.6%. 
3) 2-(2-Chlorophenyl)-6-n-heptyl-3-pyridinecarboxylic acid 
In the same manner as in the production of 
4-(2-chlorophenyl)-2-phenyl-5-pyrimidinecarboxylic acid from compound E, 
0.47 g of 2-(2-chlorophenyl)-6-n-heptyl-3-pyridinecarboxylic acid was 
obtained from 0.60 g of compound J. Yield: 85.0%. 
The following compounds were obtained in the same manner as in Reference 
Example 5: 
(1) 2-(2-chlorophenyl)-6-methyl-3-pyridinecarboxylic acid, 
(2) 2-(2-chlorophenyl)-6-cyclohexyl-3-pyridinecarboxylic acid. 
In the following formulation examples, parts are all by weight. 
FORMULATION EXAMPLE 1 
A powder was prepared by mixing uniformly and pulverizing or granulating 
finely the following ingredients: 
______________________________________ 
Each compound of the invention 
10 parts 
Magnesium stearate 10 parts 
Lactose 80 parts 
______________________________________ 
FORMULATION EXAMPLE 2 
Granules were prepared by kneading together uniformly, grinding, and 
granulating the following ingredients, followed by sieving: 
______________________________________ 
Each compound of the invention 
50 parts 
Starch 10 parts 
Lactose 15 parts 
Ethyl cellulose 20 parts 
Poly(vinyl alcohol) 5 parts 
Water 30 parts 
______________________________________ 
FORMULATION EXAMPLE 3 
Tablets with a diameter of 10 mm were prepared by mixing 99 parts of the 
granules obtained in Formulation Example 2 with 1 part of calcium 
stearate, and compression-molding the resulting mixture. 
FORMULATION EXAMPLE 4 
Granules were prepared in the same manner as in Formulation Example 2 
except for using the following ingredients: 
______________________________________ 
Each compound of the invention 
95 parts 
Poly(vinyl alcohol) 5 parts 
Water 30 parts 
______________________________________ 
To 90 parts of the granules obtained was added 10 parts of crystalline 
cellulose, and the resulting mixture was compression-molded into tablets 
with a diameter of 8 mm. Then, the tablets were made into dragee by the 
use of suitable amounts of a mixed suspension of syrup, gelatin and 
precipitated calcium carbonate and a coloring agent. 
FORMULATION EXAMPLE 5 
An injection was prepared by mixing by heating, and then sterilizing the 
following ingredients: 
______________________________________ 
Each compound of the invention 
0.5 parts 
Nonionic surfactant 2.5 parts 
Physiological saline 97 parts 
______________________________________ 
FORMULATION EXAMPLE 6 
Capsules were prepared by packing the powder obtained in Formulation 
Example 1 into commercially available capsular containers. 
Next, test examples are described below for proving the effectiveness of 
the present invention. 
TEST EXAMPLE 1 
Inhibitory activity on acyl-CoA:cholesterol acyltransferase (ACAT) 
The enzyme used in the test was prepared according to the method of Heider 
et al. [J. Lipid, Res. 24, 1127 (1983)]. The intestinal mucosa of a white 
rabbit was homogenized and microsomal fraction was obtained by stepwise 
centrifugation. The microsomal fraction was suspended in 0.154M phosphate 
buffer (pH 7.4) and stored at -80.degree. C. until use. 
ACAT activity was determined by a modification of the method of Helgerud et 
al. [J. Lipid Res. 22, 271 (1981)] by measuring radioactivity incorporated 
into cholesterol esters from [1-.sup.14 C]oleyl-CoA, as an indication. As 
to the ACAT-inhibitory activity of each compound to be tested, the 
inhibition rate was calculated by the following equation. The results 
obtained are shown in Table 2. 
##EQU1## 
TABLE 2 
______________________________________ 
Com- Com- 
pound [Inhibition rate %] 
pound [Inhibition rate %] 
No. 1 0.01 .mu.M 
No. 1 0.01 .mu.M 
______________________________________ 
1 98.0 16.7 37 72.3 
2 99.2 58.5 40 47.5 
3 88.3 41 56.3 
6 23.0 44 46.8 
13 97.5 40.2 46 32.0 
14 99.0 58.8 50 48.4 
15 99.5 67.6 52 64.7 
18 79.7 53 70.0 
19 35.9 55 75.7 
23 87.0 56 69.5 
26 58.9 57 63.2 
28 40.7 60 40.1 
30 37.1 63 53.1 
32 73.5 64 43.6 
34 65.8 65 29.8 
36 72.9 67 58.0 
______________________________________ 
TEST EXAMPLE 2 
Serum cholesterol lowering activity in hamsters fed on a high-cholesterol 
diet 
Male Syrian hamsters of 10-week-old were divided into three groups. The 
first group (normal group) was fed an ordinary diet for 4 days. The second 
group (control group) was fed a high cholesterol diet (containing 0.5% 
cholesterol and 8.0% coconut oil) for 4 days. The third group (treated 
group) was fed a high cholesterol diet and was treated with a compound for 
4 days. Simultaneously with the beginning of the above feeding, the 
compound was suspended in a 0.5% carboxymethyl cellulose solution and 
administered to the treated group, in a dose of 30 mg (in terms of the 
compound) per kg of body weight per day for 4 days. A 0.5% carboxymethyl 
cellulose solution was also administered to the normal group and the 
control group in the same manner as above. 
After 24 hours of the last administration, blood was collected and the 
cholesterol concentration in serum was measured by an enzymatic method. 
The reduction rate of the total serum cholesterol concentration was 
calculated from values obtained for the three groups by the following 
equation. The results obtained are shown in Table 3. 
##EQU2## 
wherein A: the serum cholesterol concentration of the control group. 
B: the serum cholesterol concentration of the treated group. 
C: the serum cholesterol concentration of the normal group. 
TABLE 3 
______________________________________ 
Compound No. Reduction rate (%) 
______________________________________ 
2 42.7 
14 59.4 
15 57.6 
32 63.7 
34 74.0 
36 63.4 
37 63.3 
55 77.5 
57 59.5 
______________________________________ 
TEST EXAMPLE 3 
Inhibitory effect on cholesterol esterification in macrophages 
The test was carried out by a modification of the method of Goldstein et 
al. [Pro. Nat. Acad. Sci. U.S.A. 71, 4288 (1974)]. J774 A.I cells, the 
mouse macrophage-like cell line, were suspended in Dulbecco's modified 
Eagle's medium (DMEM) containing 10% fetal calf serum (FCS), in a 
proportion of 3.times.10.sup.5 cells per 2 ml and were seeded into 6-well 
plates. The cells were cultured under a humidified atmosphere of 95% 
air/5% CO.sub.2 at 37.degree. C. for 24 hours. The medium was replaced by 
1 ml of DMEM containing 10% of FCS and 50 .mu.g/ml of acetylated human low 
density lipoprotein (AcLDL), followed by culturing for 16 hours. Five 
microliters of each compound dissolved in dimethyl sulfoxide was added to 
the medium, and the cells were cultured for another 2 hours. Then, 
[.sup.14 C]oleate (2.times.10.sup.6 dpm/well) bovine serum albumin complex 
was added in the medium. After 2 hours of culture, cells were collected 
and the cholesterol-esterifying activity was determined by measuring 
radioactivity incorporated into cholesterol esters in the cells. The 
recovery of the cholesterol esters was determined by the addition of 
[.sup.3 H]cholesteryl oleate, and the esterifying activity was corrected 
using the recovery. As to the inhibitory activity on cholesterol 
esterification of the compound to be tested, the inhibition rate was 
calculated by the following equation. The results obtained are shown in 
Table 4. 
##EQU3## 
wherein A: the cholesterol-esterifying activity of AcLDL-loaded cells to 
which the compound to be tested was added. 
B: the cholesterol-esterifying activity of AcLDL-loaded cells to which 
dimethyl sulfoxide was added. 
TABLE 4 
______________________________________ 
(Inhibition rate %) 
Compound No. 1 0.3 .mu.M 
______________________________________ 
15 73.3 29.5 
32 74.3 58.0 
36 51.6 
37 87.2 67.1 
55 34.9 
______________________________________ 
The compounds of the present invention have ACAT-inhibitory activity and 
are useful as a prophylactic and therapeutic agent for 
hypercholesterolemia, atherosclerosis and various diseases caused by them.