N-benzoyl-N'-pyrimidinyloxyphenyl urea compounds, and antitumorous compositions containing them

N-benzoyl-N'-pyrimidinyloxyphenyl urea compounds having the formula: ##STR1## wherein X represents a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group and Z represents a hydrogen atom or a halogen atom, are useful as active ingredients of antitumorous compositions.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to novel N-benzoyl-N'-pyrimidinyloxyphenyl 
urea compounds, antitumorous compositions containing them as active 
ingredients, a method for therapy of cancer by using these compounds, and 
a process for producing these compounds. 
2. Discussion of the Background 
N-benzoyl-N'-pyridinyloxyphenyl urea compounds are disclosed in U.S. Pat. 
No. 4,321,388. It is disclosed that these compounds are useful as 
agricultural chemicals and pharmaceuticals (antitumour drugs). Further, in 
Japanese Unexamined Patent Publication No. 109721/1982, it is disclosed 
that N-benzoyl-N'-pyridinyl(pyrimidinyl)oxyphenyl urea compounds are 
useful as antitumour drugs. 
However, it is not known that novel N-benzoyl-N'-pyrimidinyloxyphenyl urea 
compounds wherein the benzoyl group has a hydrogen atom, a halogen atom, a 
nitro group or a trifluoromethyl group at the 2-position, the phenyl group 
has a trifluoromethyl group at the 3-position, and the pyrimidinyl group 
has a hydrogen atom or a halogen atom at the 5-position, have high 
antitumour activities. 
SUMMARY OF THE PRESENT INVENTION 
The present inventors have conducted extensive researches on the changes of 
the substituents for N-benzoyl-N'-pyrimidinyloxyphenyl urea compounds, and 
have finally found that novel N-benzoyl-N'-pyrimidinyloxyphenyl urea 
compounds wherein the benzoyl group has a hydrogen atom, a halogen atom, a 
nitro group or a trifluoromethyl group at the 2-position, the phenyl group 
has a trifluoromethyl group at the 3-position, and the pyrimidinyl group 
has a hydrogen atom or a halogen atom at the 5-position, have high 
antitumour activities. 
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The compounds of this type are generally hardly soluble in both water and 
organic solvents, and accordingly poorly absorbable by the gut. Therefore, 
depending upon the manner of administration, they sometimes hardly exhibit 
antitumour activities, and there is a limitation for the intraperitoneal 
administration of such drugs for curing purposes. Whereas, it has been 
found that the compounds of the present invention are practically useful 
for the treatment of tumour or cancer and exhibit excellent antitumour 
activities by a simple manner of administration and in a simple 
formulation for the administration without bringing about side effects. 
The present invention is based on these discoveries. 
Namely, the present invention provides an N-benzoyl-N'-pyrimidinyloxyphenyl 
urea compound having the formula: 
##STR2## 
wherein X is a hydrogen atom, a halogen atom, a nitro group or a 
trifluoromethyl group, and Z is a hydrogen atom or a halogen atom. 
The present invention also provides an antitumorous composition containing 
such a compound as the active ingredient, a method for therapy of cancer 
by using such a compound, and a process for producing such a compound. 
Now, the present invention will be described in detail with reference to 
the preferred embodiments. 
In the above-mentioned formula I, X is preferably a halogen atom or a nitro 
group. More preferably, X is a nitro group. Likewise, Z is preferably a 
halogen atom. As the halogen atom for X and Z in the formula I, there may 
be mentioned a chlorine atom, a bromine atom, an iodine atom, etc. 
The N-benzoyl-N'-pyrimidinyloxyphenyl urea compound of the above-mentioned 
formula I, may be prepared, for instance, as follows: 
##STR3## 
In the above formula, X and Z are as defined above. 
As the solvent to be used in the above reaction, there may be mentioned 
benzene, toluene, xylene, pyridine, dioxane, dimethylsulfoxide, etc. 
##STR4## 
In the formula, X and Z are as defined above. 
As the solvent to be used for the above reaction, there may be mentioned 
toluene, xylene, monochlorobenzene, ethyl acetate, dioxane, etc. 
The aniline compound and the phenyl isocyanate compound used as the 
starting materials in the above reactions may be prepared, for instance as 
follows: 
##STR5## 
wherein Hal is a halogen atom, and Z is as defined above. 
As the alkaline substance to be used, there may be mentioned sodium 
hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, 
etc. As the solvent, there may be mentioned an aprotic polar solvent such 
as dimethylsulfoxide, dimethylformamide or hexamethylphosphoramide, a 
ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, 
etc. 
##STR6## 
wherein Z is as defined above. 
##STR7## 
wherein Z is a defined above. 
As the solvent to be used, there may be mentioned a solvent inert to 
phosgene, such as toluene, xylene, monochlorobenzene, ethyl acetate, 
dioxane, etc. 
Now, specific examples for the synthesis of the compounds of the present 
invention will be described.

SYNTHETIC EXAMPLE 1 
Synthesis of 
N-(N2-nitrobenzoyl)-N'-[4-(5-bromo-2-pyrimidinyloxy)-3-trifluoromethylphen 
yl]urea (Compound No. 1) 
(1) Into a flask, 50 ml of a dimethylsulfoxide solution containing 4.18 g 
of 5-bromo-2-chloropyrimidine, 3.5 g of 2-trifluoromethylphenol and 5.96 g 
of potassium carbonate was introduced and stirred at 120.degree. C. for 2 
hours. Then, the reaction mixture was poured into water, and extracted 
with ethyl acetate. The extract was washed with water and dried over 
anhydrous sodium sulfate. Then, ethyl acetate was distilled off, and the 
residue was purified by silica gel column chromatography, whereupon 5.03 g 
of 5-bromo-2-(2-trifluoromethylphenoxy)pyrimidine having a refractive 
index (n.sub.D.sup.30.2) of 1.5417 was obtained. 
(2) Into a flask, 5.0 g of the substituted pyrimidine obtained in the above 
step (1), was introduced, and dissolved in 25 ml of concentrated sulfuric 
acid. Then, a solution mixture comprising 1.2 ml of 60% nitric acid and 3 
ml of concentrated sulfuric acid, was gradually dropwise added at room 
temperature over a period of 30 minutes, and the mixture was reacted at 
room temperature for 20 minutes. After completion of the reaction, the 
reaction mixture was poured into ice water, and extracted with ethyl 
acetate. The extract was washed with water, and dried over anhydrous 
sodium sulfate. Then, ethyl acetate was distilled off to obtain 4.8 g of 
5-bromo-2-(2-trifluoromethyl-4-nitrophenoxy)pyrimidine having a refractive 
index (n.sub.D.sup.32.2) of 1.5719. 
(3) Into a flask, a solution obtained by dissolving 4.8 g of the 
substituted pyrimidine obtained in the above step (2) in 40 ml of glacial 
acetic acid, was introduced, and heated to 100.degree. C. Then, 3.69 g of 
reduced iron was gradually added, and the mixture was refluxed for 5 
minutes, and then cooled to room temperature. To the reaction mixture, 
acetone was added, and the mixture was filtered. Acetone was distilled off 
under reduced pressure from the filtrate, and ethyl acetate was added to 
the residue. The mixture was washed with water, then with a sodium 
hydrogen carbonate solution and further with water, and then dried over 
anhydrous sodium sulfate. Then, ethyl acetate was distilled off, and the 
residue was purified by silica gel column chromatography, whereupon 3.42 g 
of 4-(5-bromo-2-pyrimidinyloxy)-3-trifluoromethylaniline having a melting 
point of from 140.degree. to 145.degree. C. was obtained. 
(4) Into a flask, a solution obtained by dissolving 1.0 g of the 
substituted aniline obtained in the above step (3) in 10 ml of dioxane, 
was introduced, and a solution obtained by dissolving 0.89 g of 
2-nitrobenzoyl isocyanate in 10 ml of dioxane, was added thereto. The 
mixture was reacted at room temperature for 5 hours. After completion of 
the reaction, the product was poured into hot water, and the precipitates 
were filtered. The crystals thereby obtained were suspended in ethyl 
acetate, and, after an addition of n-hexane, was filtered, washed with 
methanol and dried, to obtain 0.82 g of the desired compound having a 
melting point of from 196.degree. to 197.degree. C. 
SYNTHETIC EXAMPLE 2 
Synthesis of 
N-(2-nitrobenzoyl)-N'-[4-(5-chloro2-pyrimidinyloxy)-3-trifluoromethylpheny 
l]urea (Compound No. 2) 
(1) Into a flask, 50 ml of a dimethylsulfoxide solution containing 5.0 g of 
2,5-dichloropyrimidine, 6.6 g of 2-trifluoromethylphenol and 9.4 g of 
potassium carbonate, was introduced, and stirred at 100.degree. C. for 2 
hours. Then, the reaction mixture was poured into ice water, and extracted 
with ethyl acetate. The extract was washed with water, and dried over 
anhydrous sodium sulfate. Then, ethyl acetate was distilled off, and the 
residue was purified by silica gel column chromatography, whereupon 7.7 g 
of 5-chloro-2-(2-trifluoromethylphenoxy)pyrimidine was obtained. 
(2) Into a flask, 7.7 g of the substituted pyrimidine obtained in the above 
step (1) was introduced, and dissolved in 45 ml of concentrated sulfuric 
acid. Then, a solution mixture comprising 2.1 ml of 60% nitric acid and 10 
ml of concentrated sulfuric acid, was gradually dropwise added at room 
temperature over a period of 30 minutes, and the mixture was stirred at 
room temperature for 20 minutes. After completion of the reaction, the 
reaction mixture was poured into ice water, and extracted with ethyl 
acetate. The extract was washed with water, and dried over anhydrous 
sodium sulfate. Then, ethyl acetate was distilled off, and the residue was 
purified by silica gel column chromatography, whereupon 8.4 g of 
5-chloro-2-(2-trifluoromethyl-4-nitrophenoxy)pyrimidine was obtained. 
(3) Into a flask, a solution obtained by dissolving 8.4 g of the 
substituted pyrimidine obtained in the above step (2) in 70 ml of glacial 
acetic acid, was introduced, and heated to 100.degree. C. Then, 7.4 g of 
reduced iron was gradually added, and refluxed for 10 minutes. Then, the 
reaction mixture was cooled to room temperature, then poured into water 
and extracted with methylene chloride. The extract solution was washed 
with water, and dried over anhydrous sodium sulfate. Then, methylene 
chloride was distilled off, and the residue was purified by silica gel 
column chromatography, whereupon 6.0 g of 
4-(5-chloro-2-pyrimidinyloxy)-3-trifluoromethylaniline having a melting 
point of from 154.degree. to 155.5.degree. C. was obtained. 
(4) Into a flask, a solution obtained by dissolving 2.0 g of the 
substituted aniline obtained in the above step (3) in 15 ml of dioxane, 
was introduced, and a solution obtained by dissolving 1.62 g of 
2-nitrobenzoyl isocyanate in 10 ml of dioxane, was added thereto. The 
mixture was then reacted at room temperature for 16 hours. After 
completion of the reaction, the product was poured into hot water, and 
precipitates were filtered. The crystals thereby obtained were suspended 
in ethyl acetate, and after the addition of n-hexane, subjected to 
filtration and drying, to obtain 0.8 g of the desired product having a 
melting point of from 201.degree. to 205.degree. C. 
Other compounds of the present invention will be listed as follows: 
Compound No. 3: 
N-(2-nitrobenzoyl)-N'-[4-(5-iodo-2-pyrimidinyloxy)-3-trifluoromethylphenyl] 
urea 
Melting point: 211.degree.-214.degree. C. 
Intermediate of Compound No. 3: 
4-(5-iodo-2-pyrimidinyloxy)-3-trifluoromethylaniline 
Melting point: 115.degree.-117.degree. C. 
Compound No. 4: 
N-(2-chlorobenzoyl)-N'-[4-(5-chloro-2-pyrimidinyloxy)-3-trifluoromethylphen 
yl]urea 
Compound No. 5: 
N-(2-trifluoromethylbenzoyl)-N'-[4-(5-chloro-2-pyrimidinyloxy)-3-trifluorom 
ethylphenyl]urea 
Compound No. 6: 
N-(2-bromobenzoyl)-N'-[4-(5-chloro-2-pyrimidinyloxy)-3-trifluoromethylpheny 
l]urea 
Compound No. 7: 
N-(2-nitrobenzoyl)-N'-[4-(2-pyrimidinyloxy)-3-trifluoromethylphenyl]urea 
Compound No. 8: 
N-benzoyl-N'-[4-(5-chloro-2-pyrimidinyloxy)-3-trifluoromethylphenyl]urea 
Now, the antitumour activities, acute toxicity, doses and administration 
routes of the N-benzoyl-N'-pyrimidinyloxyphenyl urea compounds of the 
present invention will be described. 
(1) Antitumour activities 
TEST EXAMPLE 1 
(Intraperitoneal-intraperitoneal) 
To BDF.sub.1 mice, p-388 leukemia cells were intraperitoneally inoculated 
in an amount of 1.times.10.sup.6 cells/mouse. A test drug was 
intraperitoneally administered twice, i.e. one day and four days after the 
inoculation. The mice were observed for 30 days for survival or death. The 
ratio (%) of median survival time of test and control animals was obtained 
with the number of survival days of mice of the control group to which a 
physiological saline was administered, being evaluated as 100. The results 
are shown in Table 1. The comparative drugs were dispersions obtained by 
adding small amounts of surfactants (e.g. Tween-80) to the comparative 
compounds. The drugs of the present invention were those prepared in 
accordance with Formulation Example 4 given hereinafter. 
TABLE 1 
______________________________________ 
Dose (Active ingredient 
T/C (%) 
Compound No. mg/kg/day) of MST.sup.1 
______________________________________ 
1 3.125 153 
2 3.125 160 
Comparative 25 230 
Compound No. 1 
12.5 171 
Comparative 200 183.9 
Compound No. 2 
Comparative 100 236.8 
Compound No. 3 
Comparative 100 165 
Compound No. 4 
______________________________________ 
Note: MST.sup.1 Ratio of median survival time of test and control animals 
Comparative Compounds Nos. 1 to 4 are disclosed in Japanese Unexamined 
Patent Publication No. 109721/1982, and their chemical names are as 
follows: 
Comparative Compound No. 1: 
N-(2 nitrobenzoyl)-N'-[3-chloro-4-(5-iodo-2-pyrimidinyloxy)phenyl]urea 
Comparative Compound No. 2: 
N-(2-chlorobenzoyl)-N'-[3-chloro-4-(5-chloro-2-pyrimidinyloxy)phenyl]urea 
Comparative Compound No. 3: 
N-(2-chlorobenzoyl)-N'-[3-chloro-4-(5-iodo-2-pyrimidinyloxy)phenyl]urea 
Comparative Compound No. 4: 
N-(2-bromobenzoyl)-N'-[3-chloro-4-(5-iodo-2-pyrimidinyloxy)phenyl]urea 
TEST EXAMPLE 2 
(intraperitoneal-oral) 
To BDF.sub.1 mice, p-388 leukemia cells were intraperitoneally inoculated 
in an amount of 1.times.10.sup.6 cells/mouse. A test drug was orally 
administered twice i.e. one day and four days after the inoculation. The 
mice were observed for 30 days for survival or death, and the ratio of 
median survival time of test and control animals was obtained with the 
number of survival days of mice of the control group to which a 
physiolocal saline was administered, being evaluated as 100. The results 
are shown in Table 2. The test drugs and comparative drugs were formulated 
in accordance with Formulation Example 4 given hereinafter. 
TABLE 2 
______________________________________ 
Dose (Active ingredient 
T/C (%) 
Compound No. mg/kg/day) of MST.sup.1 
______________________________________ 
1 6.25 186 
2 6.25 167 
Comparative 1600 186 
Compound No. 1 
800 143 
400 116 
______________________________________ 
Notes: MST.sup.1 is as defined above. 
Comparative Compound No. 1 is the same as mentioned above. 
As is evident from the comparative data in Test Example 2, the compounds of 
the present invention have remarkably high antitumour activities as 
compared with the comparative compound. The reason is not clearly 
understood, but it is assumed that due to the differences in the 
absorption of the drugs by the gut, the drug concentrations in blood and 
the transfer property of the drugs to the target portions, there may be 
substantial difference in the arrival of the drugs to the diseased 
portions, whereby a substantial difference in the antitumour activities is 
brought about. 
(2) Actute toxicity: 
To ddY mice (10 animals), a drug containing the Compound No. 1 or No. 2 of 
the present invention formulated in accordance with Formulation Example 4 
was orally administered in an amount of the compound of 12.5 mg/kg, 
whereupon no mice died. Thus, the acute toxicity values (LD.sub.50) of the 
Compounds No. 1 and No. 2 were found to be at least 12.5 mg/kg. 
On the other hand, a similar test was conducted by intraperitoneally 
administering a suspension obtained by adding a small amount of a 
surfactant (Tween-80) to the Compound No. 3 of the present invention, to 
the same mice, whereby the LD.sub.50 values were from 50 to 100 mg/kg. 
(3) Doses and administration routes 
As to administration routes in the case of animals, the compounds of this 
invention are administrated as injections such as intraperitoneal 
injection, intravenous injection, local injection and the like, or as oral 
drugs. In the case of human beings, said compounds are administrated as 
injections such as intravascular (intravenous or intraarterial) injection, 
local injection and the like, or oral drugs, suppositories or the like. As 
to the dose, said compounds are administrated continuously or 
intermittently in a range in which the total dose does not exceed a 
certain level, in consideration of the results of animal experiments and 
various conditions. However, the dose may, of course, be properly varied 
depending on the administration route and on the conditions of a patient 
or an animal to be treated (for example, age, body weight, sex, 
sensitivity, food and the like), interval of administration, drugs used in 
combination with said compounds and the degree of disease. An optimum dose 
and the number of administrations under certain conditions should be 
determined by medical specialists. The antitumorous composition of this 
invention are prepared in the same manner as for conventional drugs. For 
example, they are prepared from an active ingredient and various 
pharmacologically acceptable adjuvants such as inactive diluent and the 
like. Oral and intravenous administration of these antitumorous 
compositions is most suitable. The content of the active ingredient in the 
antitumorous compositions of this invention may vary depending on various 
conditions and cannot be determined uniquely. It is sufficient that the 
active ingredient is contained similarly to the case of conventional 
antitumorous compositions. 
The compounds of the present invention are hardly soluble in both water and 
organic solvents. Therefore, they are preferably formulated into an 
aqueous suspension which may further contain phospholipids. As a method 
for producing an aqueous suspension containing no phospholipids, there may 
be mentioned a method wherein the active compound is preliminarily 
pulverized into fine powder, then the fine powder of the active compound 
is added to an aqueous solution containing a surfactant and, if necessary, 
a defoaming agent, the mixture is pulverized in a wet system until 80% of 
particles have a particle size of not higher than 5 .mu.m, more preferably 
not higher than 2 .mu.m, and a thickener is added thereto. As specific 
examples of the surfactant, there may be mentioned a non-ionic phosphoric 
acid ester, a polyoxyethylene hardened castor oil, a polyoxyethylene 
sorbitan fatty acid ester, a sugar ester, a polyoxyethylene 
polyoxypropylene block polymer, etc. As specific examples of the defoaming 
agent, there may be mentioned dimethylpolysiloxane, methylphenylsiloxane, 
a sorbitan fatty acid ester, a polyoxyethylene-polyoxypropylene cetyl 
ether, silicone, etc. As specific examples of the thickener, there may be 
mentioned guar gum, alginic acid, gum arabic, pectin, starch, xanthane 
gum, gelatin, etc. On the other hand, as a method for preparing an aqueous 
suspension containing a phospholipid, there may be mentioned a method 
wherein a phospholipid such as soybean phospholipid or yolk phospholipid 
is used instead of the surfactant in the above-mentioned method, and an 
antioxidant such as .alpha.-tocopherol is used instead of the thickener. 
Further, these compounds may be formulated into tablets, capsules, enteric 
agents, granules, powders, injection solutions or suppositories by common 
methods for formulations. 
Now, Formulation Examples of the antitumour drugs of the present invention 
will be described. 
FORMULATION EXAMPLE 1 
70 mg of a non-crystalline powder of the above Compound No. 1 was 
thoroughly mixed with 30 mg of lactose, and 100 mg of the mixture was 
filled into a capsule to obtain a capsule drug for oral administration. 
FORMULATION EXAMPLE 2 
85 parts by weight of a non-crystalline powder of the above Compound No. 3 
was uniformly mixed with 1 part by weight of glucose, 10 parts by weight 
of corn starch and 1.5 parts by weight of a 5% starch paste, and the 
mixture was granulated by a wet method. Then, 1 part by weight of 
magnesium stearate was added thereto. The mixture was tableted to obtain 
tablets for oral administration. 
FORMULATION EXAMPLE 3 
5 g of the above Compound No. 1 was dissolved in 5 ml of dimethylacetamide, 
and 25 ml of coconut oil, 7 g of Pegnol HC-17 (manufactured by Toho Kagaku 
K.K.) and 6 g of HO-10M (manufactured by Toho Kagaku K.K.) were added to 
obtain an emulsion. To this emulsion, the same amount of sterilized 
distilled water was added, and the mixture was subjected to ultrasonic 
treatment for from 20 to 30 seconds to obtain an oily suspension. 
FORMULATION EXAMPLE 4 
The Compound No. 1 of the present invention was preliminarily pulverized by 
a centrifugal pulverizer. On the other hand, 5 parts by weight of 
polyoxyethylene (60) hardened castor oil, 0.2 part by weight of silicone 
and 0.3 part by weight of a polyoxyethylene-polyoxypropylene block polymer 
were added to 79.5 parts by weight of a physiological saline to obtain an 
aqueous solution, to which 10 parts by weight of the above pulverized 
Compound No. 1 of the present invention was added. The mixture was 
pulverized in a wet system by a sand mill using glass beads (80% of 
particles having a particle size of not larger than 2 .mu.m). Then, 5 
parts by weight of xanthane gum (2% solution) was added thereto to obtain 
an aqueous suspension. 
FORMULATION EXAMPLE 5 
To an aqueous solution obtained by dissolving 1.5 parts by weight of 
oxyethylated polyallylphenol phosphate and 0.2 part by weight of silicone 
in 53.3 parts by weight of a physiological saline, 40 parts by weight of 
the Compound No. 2 of the present invention puverlized by a centrifugal 
pulverizer, was added, and the mixture was pulverized in a wet system in 
the sand mill by using glass beads (90% of particles having a particle 
size of not larger than 2 .mu.m). Then, 5 parts by weight of xanthane gum 
(2% solution) was added thereto to obtain an aqueous suspension. 
FORMULATION EXAMPLE 6 
The Compound No. 1 of the present invention was preliminarily pulverized by 
a centrifugal pulverizer. 5 parts by weight of the pulverized Compound No. 
1 of the present invention was added to an aqueous solution obtained by 
stirring and dispersing 2 parts by weight of yolk phospholipid, 0.001 part 
by weight of .alpha.-tocopherol and 92.999 parts by weight of a 
physiological saline. Then, the mixture was pulverized in a wet system in 
a sand mill by using glass beads (80% of particles having particle size of 
not larger than 2 .mu.m) to obtain an aqueous suspension.