CA1266474A - N-benzoyl urea compounds, antitumorous compositions containing them, and process for their preparation - Google Patents

Abstract

ABSTRACT
An N-benzoyl urea compound having the formula:
(I) wherein X is a hydrogen atom, a halogen atom or a nitro group, n is an integer of from 1 to 3, and Q is wherein Y1 is an unsubstituted or substituted alkyl group, or an alkoxy or alkoxycarbonyl group with its alkyl moiety unsubstituted or substituted, Y2 is a hydrogen atom, a halogen atom, a nitro group, an unsubstituted or substituted alkyl group, or an alkoxy or alkoxycarbonyl group with its alkyl moiety unsubstituted or substituted, Z is a hydrogen atom, a halogen atom, a trifluoromethyl group or a nitro group, and each of A and B is =CH- or a nitrogen atom, provided that one of A and B is =CH- and the other is a nitrogen atom, with the provisos (1) that when Q is wherein A is =CH-, is where when X is a hydrogen atom and Y1 is an alkyl group, Z is not a hydrogen atom, a halogen atom m or a trifluoromethyl group, and (2) that when Q is

Description

~266~4 Our Ref.: IH-64 . . .

- N-BENZOYL UREA COMPOUNDS, ANTITUMOROUS COMPOSITIONS
CONTAINING THE~, AND PROCESS FOR THEIR PREPARATION
The present invention relates to novel N-benzoyl urea compounds, antitumorous compositions containing them as active ingredients, a method for -treating a cancer by administering these compounds, and a process for preparing these compounds. More particularly, the present invention relates to the novel compounds including N-benzoyl-N'-[4-(2-pyrimidinyloxy or pyridyloxy~-phenyl]urea compounds, N-benzoyl-N'-~3-(2-pyrimidinyloxy)-phenyl]urea compounds and N-benzoyl-N'-[3-(3-pyridazinyloxy)-phenyl]urea compounds.
Compounds similar to the compounds of the present invention are disclosed in the following publications.
Namely, N-benzoyl-N'-[4-(2-pyrimidinyloxy or pyridyloxy)phenyl]urea compounds are disclosed in Japanese Unexamined Patent Publication No. 109721/1982.
However, they are different from the compounds of the present invention in the chemical structures with respect ~2~647~

to the substituents on the phenyl rings directly linked to the urea group. Further, the compounds of the present invention are superior in the antitumorous activities to the compounds disclosed in the publication. With respect to N-benzoyl-N'-~3-(2-pyrimidinyloxy)-phenyl]urea compounds and N-benzoyl-N'-[3-(3-pyr~dazinyloxy)-phenyl]-urea compounds, the applicants are aware o~ no prior art which discloses similar compounds. The closest prio. art references may be Japanese Unexamined Patent Publications No. 35174/1983 and No. 72566/1983, U.S. Patent 4,418,066 and U.K. Patent 2.062,634. However, disclosed in these references are N-benzoyl-N'-[3-(phenoxy)-phenyl]urea compounds and N-benzoyl-Nl-~3-(2-pyridyloxy)-phenyl urea compounds, which are substantially different in their chemical structures from the compounds of the present invention, and which are disclosed to be useful merely as pesticides, particularly as insecticides, and there has been no disclosure or suggestion for antitumour activities.
The present inventors have conducted extensive researche on N-benzoyl-N'-substituted phenyl urea compounds, particularly on the change of the substituents, and as a result, have found that novel N-benzoyl urea compounds having certain specific substituents have high antitumorous activities.
Further, the compounds of this type are generally hardly soluble in both water and organic solvents, and ~Z~S474 accordingly are poorly adsorbed 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. Whe~eas, it has been found that the compounds of the present inven-tion are practically useful for the treatment of tumour or cancer and exhibit excellent ~titumorous activities by a simple manner of administration and in a simple formulation for the administration without bringing about side effectsD
The present invention is based on these discoveries.
Namely, the present invention provides an N-benzoyl urea compound having the formula:

(X) -CONHCONH-Q (I) wherein X is a hydrogen atom, a halogen atom or a nitro group, n is an integer of from 1 to 3, and Q is O ~ ~ Z or ~ ~ ~

wherein Yl is an unsubstituted or substituted alkyl group, or an alkoxy or alkoxycarbonyl group with its alkyl moiety unsubstituted or substituted, Y2 is a hydrogen atom, a halogen atom, a nitro group, an i2664~74 unsubstituted or substituted aIkyl group, or an alkoxy or alkoxycarbonyl group with its alkyl moiety unsubstituted or substituted, Z is a hydrogen atom, a halogen atom, a`
trifluoromethyl group or a nitro group, and each of A and B is =CH- or a nitrogen atom, provided that one of A and B is =CH- and the other is a nitrogen atom, with the provisos (1) that when Q is O ~ O~ -Z wherein A :is =CH-, ~ CONHCONH- is X ~ -CONHCONH-where when X is a hydrogen atom and Yl is an alkyl group, Z is not a hydrogen atom, a halogen atom~or a trifluoromethyl group, and (2) that when Q is ~ Y 2_~A }
wherein A is a nitrogen atom and Yl is a trifluoromethyl group, Y2 is other than a hydrogen 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..
~0 Now, the present invention will be described in detail with reference to the preferred embodiments.
In the above-mentioned formula I, when Yl or Y2 is a ~ 4 substituted alkyl group, or an alkoxy or alkoxycarbonyl group with its alkyl moiety substituted, the alkyl group or the alkyl moiety may be substituted by one or more same or different substituents selected from the group consisting of halogen, alkoxy, alkylthio, cyano and thiocyanate. The alkyl group and the alkyl moiety may be of from l to ~ carbon atoms. SpeciEically, they may be methyl, ethyl, propyl, butyl r pentyl or hexyl.
The halogen atom in the formula I includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Preferred among the compounds represented by the formula I are as follows.
(l) (X)n is one or two halogen atoms or nitro groups.

(2) Yl is an alkyl or alkoxy group which may be substituted by halogen, alkoxy, alkylthio, cyano or thiocyanate, more preferably an alkyl group which may be substituted by halogen, alkoxy or alkylthio, especially an alkyl group which may be substituted by halogen.

(3) Y2 is a hydrogen atom or an alkyl or alkoxy group which may be substituted by halogen, alkoxy, alkylthio, cyano or thiocyanate, more preferably a hydrogen atom or an alkyl group.

(4) Q is ~ O ~ ~ -Z or 3L26~474 more preferably ~ ~ ~O~O}z wherein Z is preferably a ha:Logen atom.
The N-benzoyl urea compo~nd of the foxmula I, may be prepared, for instance, by a process which comprises reacting a compound having the formula:
(X) , n ~ C0Rl (II) wherein Rl is an isocyanate group, an amino group, -NHC0NH ~ -0H or -NHCONH ~ Y2 Y1 . OH
herein X, Yl, Y2 and n are as defined above, with à
compound having the formula:

R2 ~ ~ Z (III) or R2 ~ O ~ Z (IV) -- wherein R2 is R3 ~ 0- or R3 ~ Y2 Yl 0-(wherein Yl and Y2 are as defined above, and R3 is an amino group or an isocyanate group which is different from Rl) or a halogen atom, provided that when Rl is ~266474 y -- 7 ---NHCONH~OH or -NHCONH~ Y2 ~ 1 OH
R2 is a halogen atom, and when Rl is an isocyanate group or an amino group, R2 is R3 ~ 0- or R3 ~ , ~ ;
Yl 0- .
and A, B and Z are as defined above.

The above process will now be described in detail.
[A-l]

CONCO + ~2N ~ \ O} Z or ~2N

(II-l) (III-l) (IV-l) In the presence of a solvent 0-120C, 0.1-24 hrs.
As the solvent to be used in the above reaction, there may be mentioned octane, benzene, toluene, xylene, monochlorobenYene, pyridine, dioxane, tetrahydrofuran, dimethyl sulfoxide, dimethylacetamide, ethyl acetate, acetone or methyl ethyl ketone.

gL;2~;~47~

[A-2]

NH2 + OCN ~ O ~ ~ Z or OCN

(II-2) (III-2) (IV-2) In the presence_of a solvent ~ (I) 50 C-Reflux temperature 0.1-24 hrs.
The solven-t to be used in the above reaction, may be the same as used in the above reactio~ [A-l].
~A-3]

CONHCONH ~ OH + Hal ~ ~ -Z

n (II-3) (III-3) In the presence of an alkaline substance and a solvent ~ (I) 0 C-Reflux temperature 0.1-24 hrs.
wherein Hal is a halogen atom.
As the alkaline substance to be used, there may be mentioned sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, silver carbonate, sodium hydride, n-butyl lithium, etc. As the solvent, there may be mentioned an aprotic polar solvent such as dimethyl sulfoxide, dimethyIformamide, hexamethylphosphoramide or sulforlane, a ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or a halogenated hydrocarbon such as methylene chloride or chloroform, etc.

1266~74 [A-4]

-CONHCONH ~ + Hal ~ Z
OH
(II-4) (V)~?
In the presence of an alkaline "~
substance and a solv nt ~ (I) 0-150C, 0.1-24 hrs~
wherein Hal is a halogen atom.
The alkaline substance and the solvent may be the same as used in the above reaction tA-3].
The aniline compound of the formula III-l used in the above reaction [A-l] may be prepared, for instance, by the following process.
[B-l]

NH2 ~ OM + Hal ~ O} Z
Yl (III-3) In the presence of an alkaline substance and a solvent ~ 1 ~ (III- ) 0-200C, 0.1-10 hrs.-wherein Hal is a halogen atom, M is a hydrogen atom, potassium or sodium.
In the above reaction, when M is a hydrogen atom, the presence of the alkaline substance is required. The alkaline substance and the solvent used for the above reaction, may be the same as used for the above reaction ~647~

[A-3]. It is preferred to conduct the condensation reaction in the presence of a nitrogen atmosphere.
[B-2]

NO 2 ~ }lal + HO~O} Z , ~, In the presence of an alkaline 2 ~_~
substance and a solvent ~ NO2 ~ ~ ~ ~ Z
Room temperature-250 C
1 hour - 1 week Y

Reduced iron, qlacial acetic acid - - > ~III-1) 80 C-Reflux temperature 0.1-1 hour wherein Hal is a halogen atom.
The alkaline substance and the solvent used in the above reaction, may be the same as used in the.above reaction ~A-3].
tB-3]

~M + ( III-3) Same as in Step [B-l] ~ ~ O ~ O} Z

Concentrated sulfuric acid and 2 ~
nitric acid > NO2 ~ ~~ Z
-50C-100C, 0.1-1 hour ~ 1 Same as Step 2 of [B-2] > (III-l) ~3L266474 ~B-4]
~Y2 OM' ~ (III-3) Same as Step ts-l] ~ r~ O ~o} Z

N-Chlorosucci~imide ~ ~2 ,A~
BPO, CC14 ~ -O ~ O ~ Z
60C-Reflux temperature ~ N
2-12 hrs. G~I2C1 M'Yl', Ethanol > ~ ~ }
20C-Reflux temperature 1-12 hrs. CH2Y1 Same as Step 2 of [B-3] > NO2 ~ ~ O~-Z

Same a~s Step 2 of ~B-2] ~ NH2 ~ ~ } Z
CH2Yl' wherein M' is sodium or potassium, and Yl' is a halogen atom, an alkoxy group, an alkylthio group, a cyano group or a thiocyanate group.
[B-5]
2 HSCH2CH2SH, Y2 OH (C2H~2OBF3, acetic acid ~ OH
CHO 0-30C, 1-5 hrs.
OH + (III-3) ~2E;647~

Same as Step [B~ O } z HgC12, Acetonitrile /A

80C-Reflux temperature ~` ~ N }
3-10 hrs. C~O

(C2H5)2NSF3~ CH2C12 >. <~~}Z
0 C-Reflux temperature F
1-6 hrs. CH 2 Same as Step 2 of [B-3] > NO2 ~ ~N~

Same as Step 2 of [B-2] ~ NH2 ~ ~ } Z

10The isocyanate compound of the formula III-2 used for the above reaction [A-2], may be prepared, for instance, by -the following method:
[B-6]

(III-l) + COC12 In the presence of a solvent ~ (III 2) 50-150C, 0.1-24 hrs.
15The solvent used must be inert to phosgene and may be the same as used in in the above reaction [A-ll], with the process that dimethyl sulfoxide is not included.
The N-benzoyl-N'-phenylurea compound of the formula II-3 used in the above reaction [A-3], may be prepared, for instance, by the following method:

~L.Z~,EiD~7~

[B-7]

(II-l) + ~N ~ 3 Same as Step [~

[ C ] ,.: .
The aniline compound of the formula IV-l used for the

- 5 above reaction [A-l] may be prepared in the same manner . as in the above reactions ~B-l] to [B-5] from the - corresponding starting materials. The isocyanate compound of the formula IV-2 and the urea compound of the formula II-4 used in the above reactions ~A-2] and ~A-4], respectively, may be prepared in the same manner as in the above reactions ~B-6] and ~B-7]. Among the intermediates for the preparation of the N-benzoyl urea compounds of the formula I, as described above, most of the compounds represented by the following formulas VI
and VII are novel.

3 ~ ~O~-Z (VI) 3 1' Y2 and Z are as defined above Representative compounds of the formula VI will be listed in Table l.

~2~;~;47~

Table 1 _ .. . . _ Inter- Formula VI Physical . .
mediate properties No. _ ~ _ _ MeltingO
R3 Yl Y2 ~ Z point ( C

1 NH2 CH3 H N : Cl 58-64 2 .. ll ll ., Br 103-108 3 .. COOCH3 .. .. ll 139-140 4 .lC2H5 .l . l , 82-87 .
llCH2OCH3 . .. .. 89-95

6 ..CH2SCH3 .. ,. .,

7 "CH2CN " " " _

8 1,CH2SCN " " ,' _

9 ..CHF2 " " Cl _ nOCH3 1. n ., 91-96 11 ..C2H5 n .. .. 60-64 12 _ OCHF2 .. ,. _ 13 ll OCF2CHFCF3 ll ll ..
14 .. CH3 ............ ll H _ ll ,. ll - CF3 _ 16 _ .. ll NO2 _ -~26~7~

Table 1 (continued) .___ . . __ Inter- Formula VI Physical mediate _ . . properties , No. Melting R3 Yl Y2 A Z point ~C) _ .,~., _ 17 NH2 CH20CH3 Cl N :. Br 18 " CH3 CH3 , ll 182-185 19 ll ll C2~5 " ll 20 NCO ll H ll ll 21 NH2 CF3 Cl ll ll l Viscous oil 22 _ CH3CH20CH3 .. ..

23 _ COOCH3 24 ,. CF3 H =CH- Cl _ 25 ,. CH3 ~ N2 76-79 26 .. .. .. llBr 70-74 27 .- CF3 .. . . _ ...... ........ __ 28 .. .. ,. ..CF3 29 .. . .. ,.~ ~

~ CF2H .,Cl _ ~6~;47~

(VII) -wherein R3, Y2, A, B and Z are as defined above.
Representative compounds of the formula VII will-be shown in Table 2. `;`?
Table 2 Inter- ¦ Formula VII Physical mediate propertie No. Melting R3 Y2 A B Z ~ `point (C) . .
31 N~2 CH3 N C~ Cl 86-91 32 .. H., ll Br n 1'41.646 33 .l C2H5 .. .l .. n30.21 616 _ 34 n ~1 Cl n2D2'41.599 _._ .. ~ C~ N = 116-118 36 ll F N CH I _ 37 ll Cl ll ll Br _ .
. .._.. .
38 ll NO
39 ~. OCH3 ,l n .
ll CF3 ll ll ll 41 ..CH20CH3 .. .. NO2 ~647~

Table 2 (continued) .
Inter- Formula VII Physical~
mediate properties , No. _ Melting R3 Y2 A B Z point (C) ,.__ ,, .___ 42 NH2 CH20CH3 N CH':~, CF3 . ~__ 43 ,, CH3 _ H _ 44 ll .. ll ll Br Oily : _ substance NCO _ .. Cl 46 NH2 CH2CN ,l .- Br _ 47 ~ COOCH3 ,.

Note: -The physical properties of intermediates Nos. 32-34 are refractive indices.
The following compounds may be mentioned as compounds similar to those of Table 2.
Intermediate No. 48: 2-methyl-3-(5-chloro-2-pyrimidinyloxy)aniline Intermediate No. 49: 2-methyl-3-(5-bromo-2-pyrimidinyloxy)aniline Now, the present invention will be described in further detail with reference to Examples . However, it should be understood ~hat the present invention is by no means restricted by these specific Examples.

~2~;~474 Synthetic Example 1:
Synthesis oE Compound No. 1:
N-(2-nitrobenzoyl)-N'-~3-(5-chloro-2-pyrimidinyloxy)-4-methylphenyl]urea (1) A mixture of 19.8 g o~ 5-amino-2-methylphenol, 37 g of potassium carbonate, 20 g of 2,5-dlchloropyrimidine and 200 ml of dimethylsulfoxide, was reacted in a nitrogen atmosphere at 100C for 1.5 hours.
After the completion of the reaction, the product was poured into water, and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution, dried over anhydrous.sodium sulfate, and then purified by silica gel column chromatography, to obtain 30 g of 3-(5-chloro-2-pyrimidinyloxy)-4-methylaniline having a melting point of from 86 to 91C.
(2) A solution obtained by dissolving 20 g of 3-(5-chloro-2-pyrimidinyloxy)-4-methylaniline obtained in the above step (1) in 100 ml of dioxane was added to 19.6 g of 2-nitrobenzoylisocyanate, and the mixture was reacted at room temperature for 18 hours.
After the completion of the reaction, the product was poured into water, and washed with hot water at 50C and then with methyl alcohol, to obtain 33.6 g of the desired product having a melting point of from 214 to 219C.

~L26~74~

Synthetic Example 2:
Synthesis of Compound No. 8:
N-~2-nitrobenzoyl)-N'-~3-(6-chloro-3-pyridazinyloxy)-4-methylphenyl]urea (1) A mixture of 4.0 g of 3,6-dichloropyridazine, 3.3 g of 5-amino-2-methylphenol, 3.73 g of potassium carbonate and 40 ml of dimethylsulfoxide, was reacted in a nitrogen atmosphere at 120C for 1 hour.
After the completion of the reaction, the product was poured into water, and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and after distilling off the solvent, purified by silica gel column chromatography, to obtain 3.4 g of 3-(6-chloro-3-pyridazinyloxy)-4-methylaniline having a melting point of from 116 to 118C.
(2) A solution obtained by dissolving 2.0 g of 3-(6-chloro-3-pyridazinyloxy)-4-methylaniline obtained in the above step (1) in 20 ml of dioxane was added to 1.95 g of 2-nitrobenzoylisocyanate, and the mixture was reacted at room temperature for 17 hours.
After the completion of the reaction, the product was poured into water, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 3.43 g of the desired product having a melting point of from 231 to 236C.

Synthetic Example 3:
Synthesis of Compound No. 9:
N-(2-nitrobenzoyl)-N'-~4-fluoro-3-(5-iodo-2-pyrimidinyloxy)phenyl]urea (1) A mixture of 2.0 g of 2-chloro-5-iodopyrimidine, 1.03 g of 2-fluorophenol, 2.30g of potassium carbonate and 20 ml of dimethylsulfoxide, was reacted at 100C for 1 hour.
After the completion of the reaction, the product was poured into water, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 2.56 g of 2-(2-fluorophenoxy)-5-iodopyrimidine.
(2) 2.56 g of 2-(2-fluorophenoxy)-5-iodopyrimidine obtained in the above step (1), was dissolved in 10 ml of concentrated sulfuric acid, and an acid mixture of 0.68 ml of 60% nitric acid and 2 ml of concentrated sulfuric acid, was slowly dropwise added at room temperature for reaction.
After the completion of the reaction, the reaction product was poured into ice water, and extracted with ethyl acetateO The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. The ! residue was purified by silica gel column chromatography, to obtain 1.77 g of 2-(2-fluoro-5-nitrophenoxy)-5-iodopyrimidine.
(3) 1.60 g of 2-(2-fluoro-5-nitrophenoxy)-5-~ i6~74 iodopyrimidine obtained in the above step (2), was added to 10 ml of glacial acetic acid, and heated to 90C, and then 1.24 g of reduced iron was gradually added thereto.
The mixture was refluxed for 5 minutes, and then returned to room temperature. A solvent mixture of acetone and water, was added thereto, and the mixture was filtered.
The solvent in the filtrate was distilled off, and the residue thus obtained was poured into water, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 1.31 g of 3-(5-iodo-2-pyrimidinyloxy)-4-fluoroaniline.
(4) A solution obtained by dissolving 1.31 g of 3-(5-iodo-2-pyrimidinyloxy)-4-fluoroaniline obtained in the abo~e step (3) in 20 ml of dioxane, was added to 1.15 g of 2-nitrobenzoylisocyanate, and the mixture was reacted at room temperature for 15 hours.
After the completion of the reaction, the product was poured into warm water of 50C, subjected to filtration, washed with warm water of 50C, then suspended in ethyl acetate, and after an addition of n-hexane, subjected to filtration, to obtain 1.80 g of the desired product having a melting point of from 220 to 221C.

~ 47~

Synthetic Example 4:
Synthesis of Compound No. 23:
N-(2-nitrobenzoyl)-N'-~4-(S-chloro-2-pyrimidinyloxy)-3-methylphenyl]urea (1) A mixture of 2.0 g of 4-amino-2-methylphenol, 3.7 g of potassium carbonate, 2.0 g of 2,5-dichloropyrimidine and 20 ml of dimethylsulfoxide, was reacted in a nitrogen atmosphere at 100C for 2 hours.
After the completion of the reaction, the product was poured into water and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography, to obtain 2.0 g of 4-(5-chloro-2-pyrimidinyloxy)-3-methylaniline having a refractive index (n2D2 4) of 1.6105.
(2) Into a flask, 2.12 g of 2-nitrobenzoylisocyanate was introduced, and a solution obtained by dissolving 2.00 g of 4-(5-chloro-2-pyrimidinyloxy)-3-methylaniline obtained in the above step (1) in 30 ml of dioxane, was added thereto. The mixture was reacted at room temperature for 14 hours.
After the completion of the reaction, the product was ! poured into warm water of 50C, and subjected to filtration. Crystals thus obtained were washed with warm water of 50C, then suspended in ethyl acetate, and after an addition of n-hexane, subjected to filtration, to I

~;4~7~

obtain 2.82 g of the desired product having a melting point of from 204 to 206C.
Synthetic Example 5:
Synthesis of Compound No. 30:
N-(2-nitrobenzoyl)-N'-[4-(5-bromo-2-pyrimidinyloxy)-3-methoxymethylphenyl~urea ;
(1) A mixture of 2.2 g of 2-chloro-6-methoxymethyl-4-nitrophenol, 0.30g of 10% pal:Ladium carbon, 11.5 g of magnesium oxide, 20 ml of ethyl alcohol and 30 ml of waterj was reacted under a hydrogen pressure of 4 atm.
for 10 hours under shaking.
After the completion of the reaction, acetone was added to the product, and the mixture was filtered to obtain a filtrate, which was subjected to distillation under reduced pressure. To the residue thus obtained, acetone was added, and the mixture was filtered to obtain a filtrate, which was again subjected to distillation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.27 g of 4-amino-2-methoxymethylphenol having a melting point of from 121 to 126C.
(2) A mixture of 1.60 g of 5-bromo-2-chloropyrimidine, 1.27 g of 4-amino-2-methoxymethylphenol, 2.30 g of potassium carbonate and 30 ml of dimethylsulfoxide, was reacted in a nitrogen atmosphere at 100C for 1 hour.
After the completion of ~he reaction, the product was poured into water, and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain 1.38 g of 4-(5-bromo-2-pyrimidinyloxy)-3-methoxymethylaniline having a melting point of from 89 to 95C. ;
(3) A solution obtained by dissolving 1.38 g of 4-(5-bromo-2-pyrimidinyloxy)-3-methoxymethylaniline obtained in the above step (~) in 10 ml of dio~ane, was dropwise added to a solution of 1.04 g of 2-nitrobenzoyl-isocyanate in 10 ml of dioxane, and the mixture was reacted at room temperature for 17 hours.
After the completion of the reaction, the product was poured into water, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography, and - crystals thus obtained was washed with methanol, then-dissolved in dimethyl sulfoxide, and poured into water, followed by filtration to obtain 1.66 g of the desired product having a melting point of from 187 to 189C.
Synthetic Example 6:
Synthesis of Compound No. 34:
N-(2-nitrobenzoyl)-N'-[4-(5-chloro-2-pyrimidinyloxy)-3-difluoromethylphenylurea]
(1) 15 g of salicylaldehyde and 13.9 g of 1,2-ethanedithiol were dissolved in 100 ml of acetic acid, and 12 ml of ~26647~

boron trifluoride (an ether complex) was gradually dropwise added the;:eto under cooling with ice.
After the completion of the dropwise addition, the mixture was reacted at room temperature for 1 hour under stirring. ~?
After the completion of the reaction, acetic acid was distilled off under reduced pressure. To the residue, ethyl acetate and water were added for extraction. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and sodium chloride, and dried over anhydrous sodium sulfate. Thenl the solvent was distilled off to obtain 22.8 g of 2-(2-hydroxyphenyl)-1,3-dithiolan.
~2) 8.5 g of 2,5-dichloropyrimidine, 12.4 g of 2-(2-hydroxyphenyl) -1,3-dithiolan obtained in the above step (1) and 10 g of potassium carbonate were dissolved in 50 ml of dimethylformamide, and reacted at 100C under stirring.
After the completion of the reaction, the product was poured into ice water, and extracted with ethyl acetate.
The extract was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 14.6 g of 2-~2-(5-chloro-2-pyrimidinyloxy)-phenyl]-1,3-dithiolan.
(3) 28.7 g of mercuric chloride was dissolved in a ~2~i64~4 solvent mi~ture of 300 ml of acetonitrile and 60 ml of water, and then a solution obtained by dissolving 14.9 g of the dithiolan obtained in the above step (2) in 160 ml of acetonitrile and 12 ml of water, was gradually dropwise added under stirring. ,;~
After the completion of the dropwise addition, the mixture was stirred at room temperature until the starting materials disappeared. Then, the temperature was raised to the refluxing temperature, and the reaction was conducted for 4 hours.
After the completion of the reaction, insoluble materials were filtered off from the reaction producut, and the solvent was distilled off under reduced pressure.
The residue thus obtained was extracted by an addition of methylene chloride and water. The extract was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 5.5 g of 2-(5-chloro-2-pyrimidinyloxy)-ben aldehyde.
(4) A methylene chloride solution ~5 ml) of 2.5 g of the benzaldehyde obtained in the above step (3) was gradually dropwise added at room temperature to a solution obtained by dissolving 1.9 g of diethylamino sulfur trifluoride in 15 ml of methylene chloride. After the completion of the dropwise addition, the mixture was stirred at room ~6~47~

temperature for 1 hour under stirring.
After the completion of the reaction, the reaction product was poured into ice water and extracted with methylene chloride. The extract was washed with a saturated sodium chloride aqueous s~ution, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 1.1 g of 2-(5-chloro-2-pyrimidinyloxy)- benzalfluoride.

(5) A mixture of 0.85 ml of concentrated nitric acid and 0.85 ml of concentrated sulfuric acid, was dropwise added and reacted to a solution obtained by dissolving 2.2 g of the benzalfluoride obtained in the above step (4) in 15 ml of concentrated sulfuric acid under cooling with ice, while maintaining the temperature at a level of from 0 to 5C.
~ fter the completion of the reaction, the product was poured into ice water, and extracted with methylene chloride. The extrac-t was washed with a saturated aqueous solution of sodium hydrogen carbonate and sodium chloride, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 1.7 g of 2-(5-chloro-2-pyrimidinyloxy) 5-hitrobenzal-flurilde.(6) 1.7 g of the nitrobenzodifluoride obtained in the above step (5) was dissolved in 50 ml of acetic acid, and ~L26~i47D~

then the solution was heated to 90C. Then, 2.3 g of reduced iron was gradually added and reacted thereto under stirring.
After the completion of the reaction, insoluble matters were filtered off from the ~eaction product, and the filtrate was extracted by an addition of methylene chloride and water. The extract was washed with a saturated solution of sodium hydrogen carbonate and sodium chloride, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 0.96 g of 5-amino-2-(5-chloro-2-pyrimidinyloxy)- benzalfluoride.
- (7) A dioxane solution (10 ml) of 0.96 g of the amino benzalfluoride obtained in the above step (6) was gradually dropwise added at room temperature to a dioxane solution (5 ml) of 0.74 g of 2-nitrobenzoylisocyanate prepared from 2-nitrobenzamide. After the completion of the dropwise addition, the mixture was reacted at room temperature for 1 hour under stirring.
After the completion of the reaction, dioxane was distilled off under reduced pressure, and the residue was recrystallized from methylene chloride to obtain 0.9 g of N-(2-nitrobenzoyl)-N'-[4-(5-chloro-2-pyrimidinyloxy)-3-difluoromethylphenyl]urea having a melting point of from 185 to 186C.

~266474 Synthetic Example 7:
Synthesis of Compound Mo. 24:
N-(2-nitrobenzoyl)-N'-[4-(5-bromo-2-pyrimidinyloxy)-3-methylphenyl]urea (1) 4-(5-bromo-2-pyrimidinyloxy)-3-methylaniline was obtained in the same manner as in Synthetic Example 5(2) except that 1.27 g of 4-amino--2-methoxymethylphenol was changed to 1.02 g of 4-amino-2-methylphenol.
(2) A solution obtained by dissolving 1.7 g of the aniline obtained in the above step (1) in 5 ml of ethyl acetate, was dropwise added at room temperature to a solution of 0.01 mol of phosgene in 15 ml of ethyl acetate, and the mixture was reacted at room temperature for 3 hours under stirring and under reflux for further 1 hour.
After the completion of the reaction, ethyl acetate was distilled off under reduced pressure, and the residue was vacuum-dried to obtain 1.8 g of 4-(5-bromo-2-pyrimidinyloxy)-3-methylphenylisocyanate.
(3) To a solu~ion obtained by dissolving 1.8 g of the isocyanate obtained in the above step (2) in 20 ml of toluene, 0.98 g of 2-nitrobenzamide was added under stirring, and the mixture was reacted under reflux for 4 hours. ' After the completion of the reaction t 10 ml of methanol was added to the product, and the mixture was cooled. Precipitated crystals were collected by ~64 riltration to obtain 1.20 g of the desired product.
Synthetic Example 3:
Synthesis of Compound No. 37:
N-(2-nitrobenzoyl)-N'-[4-~5-chloro-2-pyrimidinyloxy)-3-ethylphenyl]urea ,;~
(1) A solution obtained by dissolving~5.78 g of 2-nitrobenzoylisocyanate in 10 ml of dioxane, is dropwise added at room temperature to a solution obtained by dissolving 4.12 g of 4-amino-2-ethylphenol in 100 ml of dioxane, and the mixture is reacted at room temperature for 12 hours under stirring.
After the completion of the reaction, the product is poured into water, and precipitated crystals are collected by filtration and washed with methanol to obtain N-~3-ethyl-4-hydroxyphenyl)-N'-(2-nitrobenzoyl)-urea.
(2) To a solution obtained by dissolving the urea obtained in the above step (1) in 100 ml of dimethylsulfoxide, 1.4 g of potassium hydroxide is added, and 4.9 g of 2,5-dichloropyrimidine is further added.
The mixture is reacted at 50C for 5 hours.
After the completion of the reaction, 200 ml of methanol is added to the reaction product, and precipitated crystals are collected by filtration. The crystals are washed with water and methanol to obtain the desired product.

~LZ664"~

Synthetic Example 9:
Synthesis of Compound No. 51:
N-(2-nitrobenzoyl)-N'-~4-(5-chloro-2-pyridyloxy)-3-trifluoromethylphenyl]urea (1) A mixture of 10 g of 5-chloro-2~pyridone, 14.3 g of 2-chloro-5-nitrobenzotrifluoride, 26.6 g of potassium carbonate and 60 ml of dimethylsulfoxide, was reacted at 100C for 2 hours.
After the completion of the reaction, the product was poured into 70 ml of ethyl ether, washed twice each sequentially with water, a 10% sodium hydroxide aqueous solution and a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate.
Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 6.4 g of 2-t5-chloro-2-pyridyloxy)-5-nitrobenzo-trifluoride.
(2) 6 g of 2-(5-chloro-2-pyridyloxy)-5-nitrobenzo-trifluoride obtained in the above step (1) was dissolved in 40 ml of glacial acetic acid, and 6.3 g of reduced iron was added thereto under vigorous stirring.~ The mixture was reacted for 30 minutes.
After the completion of the reaction, insoluble matters were filtered off from the reaction product, and the solvent was distilled off. The residue thus obtained was dissolved in 80 ml of methylene chloride, washed twice with an aqueous sodium hydrogen carbonate solution, 126~74 and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 4.2 g of 4-(5-chloro-2-pyridyloxy)-3-trifluoromethylaniline.
(3) A solution obtained by dissolving 1.6 g of 2-nitrobenzoylisocyanate in 5 ml of dioxane, was dropwise added to a solution obtained by dissoiving 2.0 g of 4-(5-chloro-2-pyridyloxy)-3-trifluoromethylaniline obtained in the above step (2) in 8 ml of dioxane, and the mixture was reacted at room temperature overnight.
After the completion of the reaction, the reaction product was poured into water, filtered, and washed with methanol. Crystals thus obtained were dissolved in ethyl acetate, and insoluble matters were filtered off. Then, n-hexane was added thereto for crystallization to obtain 3.1 g of the desired product having a melting point of from 196 to 198C.
Synthetic Example 10:
Synthesis of Compound No. 55:
N-(2,4-dinitrobenzoyl)-N'-[3-trifluoromethyl-4-(5-trifluoromethyl-2-pyridyloxy)phenyllurea (l) A mixture of 6 g of 2-trifluoromethylphenyl, 59 g of 2-chloro-5-trifluoromethylpyridine, 9.6 g of potassium carbonate and 40 ml of dimethylsulfoxide, was reacted at 100C for 4 hours.
After the completion of the reaction, the reaction product was poured into 70 ml of ethyl ether, washed twice each sequentially with water, a 10% sodium hydroxide aqueous solution, and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 8.2 g of 2-(5-trifluoromethyl-2-pyridyloxy)-benzotrifluoride. ,~
(2) 8 g of 2-(5-trifluoromethyl-2-pyridyloxy)-benzotrifluoride obtained in the above step (1), was dissolved in 45 ml oE concentrated sulfuric acid, and after cooling the solution to 0C, 3.3 g of 60~ nitric acid was dropwise added thereto at a temperature of from 0 to 5C. After the completion of the dropwise addition, the mixture was reacted at a temperature of from 0 to 5C
for 1 hour under stirring.
After the completion of the reaction, the reaction product was poured into water, and extracted twice with methylene chloride. The extract was washed twice with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 7.2 g of 2-(5-trifluoromethyl-2-pyridyloxy)-5-nitrobenzotrifluoride.
(3) 7 g of 2-(5-trifluoromethyl-2-pyridyloxy)-5-nitrobenzotrifluoride obtained in the above step (2) was dissolved in 50 ml of glacial acetic acid, and 6.7 g of ! reduced iron was added under vigorous stirring. The mixture was reacted for 30 minutes.
~ fter the completion of the reaction, insoluble matters were filtered off from the reaction product, and 1~;64~L
. - 34 -the solvent was distilled off. The residue thus obtained was dissolved in 80 ml of methylene chloride, then washed twice with an aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the resldue was purified by silica gel column chromatography to obtain 2.7 ~ of 4-(5-trifluoromethyl-2-pyridyloxy)-3-trifluoromethyl-aniline.
(4) A solution obtained by dissolving 1.~ g o~

2,4-dinitrobenzoylisocyanate in 5 ml of dioxane, was dropwise added to a solution obtained by dissolving 1.5 g of 4-(5-trifluoromethyl-2-pyridyloxy)-3-triflu`oromethylaniline obtained in the above step (3) in 8 ml of dioxane, and the mixture was reacted at room temperature overnight.
After the completion of the reaction, the reaction product was poured into water, and filtered. Crystals thus obtained were dissolved in ethyl acetate, and -- insoluble matters were filtered off. Then, n-hexane was added thereto for crystallization, to obtain 1.8 g of the desired product having a melting point of from 235 to Now, representative compounds of the present invention, are shown in Tables 3 and 4.

4'7~

Table 3 n -CONHCONH-Ql (Ql ~1"~

Compoun d ._ Q 1 Mel t i ng No. Y2 A B Z point (C) _ .
1 2--NO2 _CH3 N CH Cl 214--219 2 . H ..ll Br 207-210 .
3 ,. C2H5 .l .l 223-227 4 2-Cl .. . ll Cl 174-179 .
2--NO2 .l ...l .. 224--228 . _ 6 4-Cl,2-NO2 .. _ _ 199-205 72,4--(NO2) 2 ~ l .l .. 224--228 ._ 2--N02 CH3 CH N _ 231 - 236 9 . F N CH I 220 -221 _ .. Cl ll ,. Br _ 1 1 2--MO2 N2 ------ ~

12 . OCH 3 .. ll ....... _ _ 13 CF 3 .. _ _ Table 3 ~continued ?

Compound _ _ _ L = Meltlng No. Y2 A B Z point ~C) _ .

CH2SCH3 ,. _ CF3 _ 164-Cl,2-NO2 CH3 ll " Cl 188-190 _ _ 172,4-(NO2)2 ll ., i, ,. 199-202 184,6-C12,2 NO2 . _ _ _ 19 2-NO2 ll ll ll H _ . .
ll ll ll ll Br 230-232.5 _ 21 .. CH2CN" " .l _ _ 22 COOCH3 _ _ _ ~266474 Table 4 (X) y ONHcONH-Q2 ~Q2 ~_~y N

Compound ( X ) n Q 2 Melt ingO
No. Yl Y2 ~ ~ A Z point ( C ) _ .
23 2 - NO2 CH3 H N Cl 204 - 206 _ .
24 .. .. .. ll Br 214 -217 COOCH 3 .. _ .. 200 - 201 26 2 -Cl CH3 _ _ .. 204 -205 . .
27 4-Cl,2-NO2 " " " .. 229-235 28 2,4 - (NO2) 2 ~ ~ n ~ 232-235 29 2 - NO2 C2H5 " " " 211 - 212.5 .- CH2OCH3 " .. .. 187-189 31 .. CH2SCH3 ,.ll .. 200-201 _ .
32 .. CH 2CN _ _ ,. 231 - 233 33 CH 2 SCN " _ " 189 -190 ! 34 CHF 2 - - C 1 185 - 186 .. OCH 3 .. .. ~ 219 -221 36 2-Cl CH3 .. ll . 197-199 . ....... _ _ ~ZS~i47~L

Table 4 ( continued ) C ompound ( X ) n __ Q 2--= Mel ti ng No. Yl Y2 A Zpoint (C) .
3 7 _ C 2 E15 3 ~ N C 1181-18 4 38 ~- OCHF2 ll ..,. 217-219 .._ _ I _ 39 OCF2CEIE CF3 _ - _ 75-79 4 0 fi CH3 ll . " _ _ 41 2--NO2 .. _ H

4 2 . . 'l CF 3 ~
, 4 3 ll ll ll " NO2 ~
44 4, 6-C12, 2 NO2 .. Cl 2--NO2 CH2OCH3 Cl ll Br 236--238 46 CH3 CH3 __ 248-249. 5 47 .l .l C2H5 .. .l _ 4 8 CE 3 C l _ " 221- 22 4 49 _ CH3 CE 20CH3 .. _ 208- 210 5 0 I COOCH 3 n _ _ 47~

Table 4 ( continued ) Compounc tX)n _ _ Q2 MeltingO
No . _ Yl Y 2 A Z point ( C ) 512-N02 CF3 H =CH- Cl 196-198 52 - CH3 _ ~~ " N2 218 221 532,4-(N02)2 .. .. .- Br 193-200 _ 542-N02-4-Cl CF3 .. .. .. 213-216 552,4-(N02)2 ., _ CF3 235 - 238 562-N02 .. .. ." H _ 57 CF2H ~ _ Cl .

:L266~7~L

The Following compounds may be mentioned as compounds similar to those listed in Table 3-Compound No. 58:
N-(2-nitrobenzoyl)-N'-[2-methyl-3-(5-chloro-2-pyrimidinyloxy) phenyl]urea. Melting point 214-216C.
Compound No. 59: ;
N-(2-nitrobenzoyl)-N'-[2-methyl-3-(5-bromo-2-pyrLmidinyloxy) phenyl]urea. Melting point 202-206&.
The compounds of the present invention are effective against tumours such p-388 leukemia, L-1210 leukemia, B-16 melanoma, M-5076 sarcoma, colon 38, colon 26, Lewis lung carcinoma, etc. of test animals such as mice. On the other hand, certain in vivo testing systems and protocols have been developed by the National Cancer Institute for testing compounds to determine their suitability as antineoplastic agents. These have been reported in "Cancer Chemotherapy Reports", Part III, Vol.
3, No. 2 (1972), Deran, Greenberg, MacDonald, Schumacher and Abbott. These protocols have established standardized screening tests which are generally followed in the field of testing for antitumoral agents. Two of these systems are particularly significant to the present invention. They are lymphocyctic leukemia p388 and melanotic melanoma B16. These neoplasms are found in mice. Generally, good antitumor activity, shown in these protocols by a percentage increase of mean survival times of the treated tT) animals over the control (C) animals, ~6~7~

ls predictive of similar results in human leukemias. A
mean survival time ratio T/C x lO0 _ 125% is considered necessary to demonstrate antineoplastic activity by the substance being tested.
Now, the antitumour activities, acute toxicity, doses and administration routes of the N-benzoylurea compounds of the present invention will be described.
(l) Antitumour activities Test Example l (Intraperitoneal-intraperitoneal) To BDFl mice, p-388 leukemia cells were intraperitoneally inoculated in an amount of l x 106 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 increase life span ILS-(~) of each treated group was obtained with the number of survival days of mice of the control group to which a physiological saline was administered, being evaluated as 0. The results are shown in Table 5. The drugs were dispersions obtained by adding small a~mounts of 3~ c ~ t~r~le,r7~ ~
20~ surfactants (e.g. Tween-80)~ to the test compounds.

~4~7~
_ 42 _ Table 5 . . ~
Compound No. Dose (Active ingredient ILS
ma/kq/daY) t %) . . _ 1 12.5 - 867 2 100 ~/~? 99 3 50 ';` 126 12.5 , 74 12.5 75 9 200 ~42 17 6.25 91 12.5 6338 23 12.5 45 26 12.5 95 27 .. ~153 28 .. 84 29 ,. 132 36 12.5 89 37 .. >143 200 >118 12.5 41 ~ 47~
_ 43 _ Table 5 (continued) . _ _.
Compound No.Dose tActive ingredient ILS *
mg/kq/day) (%) _ _ 50 _ Note:
ILS(%)*: Increase Life Span, calculated in accordance with the following formula: ~
ILS(~ = MST-100, where MST is the ratio of median survival time of test and control animals.
Test Example 2 (intraperitoneal-oral) To BDFl mice, p-388 leukemia cells were intraperitoneally inoculated in an amount of 1 x 106 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 ILS (%) of each treated group was obtained with the number of survival days of mice of the control group to which a physiological saline was administered, being evaluated as 0. The results are shown in Tables 6-1, 6-2 and 6-3. The test drugs and comparative drugs were formulated in accordance with Formulation Example 4 given hereinaEter.

~L26~47~
~ 44 -Table 6-1 Compound No. Dose (Active ingredient ILS (%)*
mR/ka/daY ) . .
1 100 `67 3 400 '.`? 114 ~.00 ,;. 76 4 100 , 111 17 12.5 ,. 111 Table 6-2 Compound No.Dose (Active ingredient ILS (%)* .
ma/ka/dav) _ .
23 12.5 147 24 12.5 1484 . 50 51 ~36~i4~L
_ 45 -Table 6-2 ~continued?
Compound No.Dose (Active ingredient ILS (~)*
mq/kq/daY ? ~ .
Comparative 1600 86 Compound No. 1 800 . 43 Comparative 1600 " 24 .
Compound No. 2 800 11 Table 6-3 Compound No.Dose (Active ingredient ILS (~)*
mg/kq/day) 400 . 38 . 52 800 39 Comparative1600 11 Compound No. 3 800 2 .
Notes:
ILS(~)* is the same as mentioned above in Table 5.
Comparative Compound No. 1:
N-(2-nitrobenzoyl)-N'-[3-chloro-4-(5-iodo-2-pyrimidinyloxy)phenyl]urea, disclosed in Japanese Unex~mined Patent Publication Wo. 109721/1982.

~ 7~L

Comparative Compound No. 2:
N-(2-chlorobenzoyl)-N'-[3-chloro-4-(5-chloro-2-pyrimidinyloxy)phenyl]urea, disclosed in Japanese Unexamined Patent Publication No.
109721/1982.
Comparative Compound No. 3: ;
N-(2-nitrobenzoyl)-N'-[3 chloro-4-(5-trifluoro-methyl-2-pyridyloxy)phenyl]urea, disclosed in Japanese Unexamined Patent Publication Nos.
31664/1982 and 109721/1982.
Test Example 3 (intraperitoneal-oral) To BDFl mice, L-1210 leukemia cells were intraperitoneally inoculated in an amount of 1 x 105 cells/mouse. A test drug was orally administered twice i.e. one day and eight days after the inoculation. The mice were observed for 30 days for survival or death, and the ILS (%) of each treated group was obtained with the number of survival days of mice of the control group to which a physiological saline was administered, being evaluated as 0. The results are shown in Table 7. The test drugs and comparative drugs were formulated in accordance with Formulation Example 4 given hereinafter.

~ 7~
_ 47 _ Table 7 . . ~ ..... . _ .
Compound No. Dose (Active ingredient ILS (%)*
_ mq/kq/day) 12.5 ; 56 24 505 ' 177 400 ~ 137 Comparative Compound No. 1 800 30 Note: -ILS(%) is the same as mentioned in Table 5 and Comparative Compound No. 1 is the same as mentioned in Table 6-2.
Test Example 4 (intraperitoneal-oral) To BDFl mice, a suspension of B-16 melanoma cells were intraperitoneally inoculated in an amount of 0.5 ml/mouse. A test drug was orally administered three times i.e. one day, eight days and fifteen days after the inoculation. The mice were observed for 60 days for survival or death, and the ILS (%) of each treated group was obtained with the number of survival days of mice of the control group to which a physiological saline was 126~
- 48 ~
administered, being evaluated as 0. The results are shown in Table 8. The test drugs were formulated in accordance with Formulation Example 4 given hereinafter.
The suspension of B-16 melanoma cells was prepared by taking out under an aseptic conditio,~ the tumour cells successively subcutaneously transplanted in C57BL/6 mice, passing the tumour cells through a stainless steel mesh and suspending 1 g of the tumour cells in 9 ml o an isotonic solution such as a culture medium or a physiological saline.

Table 8 Compound No.Dose (Active ingredient ILS (~)*
mg/kg/day) 1 100 ' 49 ,, 23 12.5 744 37 22.5 5376 .

Note:
ILS(%) is the same as mentioned in Table 5.

Test Example 5 (intraperitoneal-oral) To BCFl mice, M-5076 sarcoma cells were intraperitoneally inoculated in an amount of 1 x 106 cells/mouse. A test drug was orally admini,stered three times i.e. one day, eight days and fifteen days after the inoculation. The mice were observed for 60 days for survival or death, and the ILS (%) o each treated group ~L266~

~'dS obtained with the number of survival days oE mice of the control group to which a physiological saline was administered, being evaluated as 0. The results are shown in Table 9. The test drugs and comparative drugs were formulated in accordance with Formulation Example 4 given hereinafter. ;
Table 9 Compound No. ` Dose (Active ingredient ILS (~)*
mg/kg/day ) 1 50 ~ 38 : 23 12.5 l82 Note: ~
ILS(~) is the same as mentioned in Table 5.
The compounds of the present invention exhibit high , 15 antitumour activities whether the deseased portions and the portions to which the drugs are administered, are the same or different. The reason is not clearly understood, but it is assumed that the excellent antitumour activities are attributable to that the compounds of the invention are superior in the absorption of the drugs by the gut, in the drug concentrations in blood and in the transfer property of the drugs to the target portions.
(2) Acute toxicity:
To ddY mice, a drug containing one of Compound Nos.
l, 5, 20, 23, 26-29, 36 and 37 of the present invention formulated in accordance with Formulation Example 4 was ~2~i~;~7~a -- so intraperitoneally administered, and the LD50 value was measured and found to be at least 25 mg/kg in each case.
The LD50 value of Compound No. 51 of the invention was found to be at least 50 mg/kg, that o each of Compound Nos. 3, 8, 30, 31, 39, 52, 53 and 54.. was found to be at least 100 mg/kg, and that of each of Compound Nos. 2, 9, 25, 32, 33, 35, 45 and 55 was found to be at least 400 mg/kg.
(3) Doses and administration :routes As to administration routes in the case of animals, the compounds of this invention are administered 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 administered 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 administered 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 ~12~ 7~
_ 51 _ d1sease. 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 cQnventional 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. For instance, the composition may contain at least 0.001% by weight.
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, if necessary, 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 ~2~

system until all particles have a particle size of not higher than 5 ~m, more preferably not higher than 2 ~m (80~ of particles), and a thickener is added thereto. As specific examples oE the surfactant, there may be mentioned an oxyethylated polyarylphenol phosphate, 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 - ~-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.

~26~

Formulation Example l 70 mg of a non-crystalline powder of the above Compound No. 9 or 23 was thoroughly mixed with 30 mg of lactose, and 100 mg of the mixture was filled into a capsule to obtain a capsule drug fo~ oral administration.
Formulation Example 2 85 parts by weight of a non-crystalline powder of the above Compound No. 3 or 24 was uniformly mixed with l part by weight of glucose, 10 parts by weight,of corn starch and l.S parts by weight of a 5% starch paste, and the mixture was granulated by a wet method. Then, l 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. 2 or 29 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-lOM (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 or 23 of the present invention was preliminarily pulverized by a centrifugal pulverizer. On the other hand, 5 parts by weight of polyoxyethylene (60) i~6~;4'7~

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 lO parts by weight of the above pulveriæed Compound No. l or 23 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 ~ 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 polyarylphenol 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. 5 or 25 of the present invention was addedr 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 ~m). Then, 5 parts by weight of xanthane gum (2~ solution) was added thereto to obtain an aqueous suspension.
Formulation Example 6 The Compound NoO l 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 ~'6 _ 55 _ obtained by stirring and dispersing 2 parts by weight of yolk phospholipid, 0.001 part by weight of a-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 ~m) to obtain an aqueous suspension.
Formulation Example 7 The Compound No. 37 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 were added to 60 parts by weight of a physiological saline to obtain an aqueous solution, to which 30 parts by weight of the above pulverized Compound No. 37 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 ~m). Then, 5 parts by weight of xanthane gum (2% solution) was added thereto to obtain an aqueous suspension.
Formulation Example ~
To an aqueous solution obtained by dissolving 1.5 parts by weight of oxyethylated polyarylphenol phosphate, 0.2 part by weight of silicone and 0.3 part by weight of a polyoxyethylene-polyoxypropylene block polymer in 81 parts by weight of a physiological saline, 10 parts by weight of the Compound No. 23 of the present invention _ 56 -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 ~m). Then, 7 parts by weight of xanthane gum (2% solution) was added thereto to obtain an aqueous suspens,ion.

Claims (15)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An N-benzoyl urea compound having the formula:
(I) wherein x is a hydrogen atom, a halogen atom or a nitro group, n is an integer of from 1 to 3, and Q is wherein Y1 is an alkyl group having 1 to 6 carbon atoms which may be substituted by halogen, alkoxy having 1 to 6 carbon atoms, alkyl thio having 1 to 6 carbon atoms, cyano or thiocyanate, or an alkoxy or alkoxycarbonyl group with its alkyl moiety having 1 to 6 carbon atoms which may be substituted by halogen, alkoxy having 1 to 6 carbon atoms, alkyl thio having 1 to 6 carbon atoms, cyano or thiocyanate, Y2 is a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms which may be substituted by halogen, alkoxy having 1 to 6 carbon atoms, alkyl thio having 1 to 6 carbon atoms, cyano or thio-cyanate, or an alkoxy or alkoxycarbonyl group with its alkyl moi-ety having 1 to 6 carbon atoms which may be substituted by halo-gen, alkoxy having 1 to 6 carbon atoms, alkyl thio having 1 to 6 carbon atoms, cyano or thiocyanate, z is a hydrogen atom, a halo-gen atom, a trifluoromethyl group or a nitro group, and each of A
and B is =CH- or a nitrogen atom, provided that one of A and B is =CH- and the other is a nitrogen atom, with the provisos (1) that when Q is wherein A is =CH-, is where when X is a hydrogen atom and Y1 is an alkyl group, z is not a hydrogen atom, a halogen atom or a trifluoromethyl group, and (2) that when Q is where in A is a nitrogen atom and Y1 is a trifluoromethyl group, Y2 is other than a hydrogen atom.

2. The N-benzoyl urea compound according to claim 1, where Q is wherein Y, Y2 and Z are as in claim 1.

3. The N-benzoyl urea compound according to claim 1, wherein Q is wherein Y2, Z, A and B are as in claim 1.

4. The N-benzoyl urea compound according to claim 4, wherein Y2 is an alkyl group having 1 to 6 carbon atoms which may be substituted by halogen, A is a nitrogen atom, B is =CH-, and Z
is a halogen atom.

5. N-(2-nitrobenzoyl)-N'-[4-(5-chloro-2-pyrimidinyl-oxy)-3-methylphenyl]urea.

6. N-(2-nitrobenzoyl)-N'-[4-(5-bromo-2-pyrimidinyl-oxy)-3-methylphenyl]urea.

7. N-(2-nitrobenzoyl)-N'-[3-(5-chloro-2-pyrimidinyl-oxy)-4-methylphenyl]urea.

8. A process for preparing an N-benzoyl urea compound having the formula:
(I) wherein X is a hydrogen atom, a halogen atom or a nitro group, n is an integer of from 1 to 3, and Q is or wherein Y1 is an alkyl group having 1 to 6 carbon atoms which may be substituted by halogen, alkoxy having 1 to 6 carbon atoms, alkyl thio having 1 to 6 carbon atoms, cyano or thiocyanate or an alkoxy or alkoxycarbonyl group with its alkyl moiety having 1 to 6 carbon atoms which may be substituted by halogen, alkoxy having 1 to 6 carbon atoms, alkyl thio having 1 to 6 carbon atoms, cyano or thiocyanate, Y2 is a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms which may be substituted by halogen, alkoxy having 1 to 6 carbon atoms, alkyl thio having 1 to 6 carbon atoms, cyano or thiocyanate or an alkoxy or alkoxycarbonyl group with its alkyl moiety having 1 to 6 carbon atoms which may be substituted by halogen, alkoxy having 1 to 6 carbon atoms, alkyl thio having 1 to 6 carbon atoms, cyano or thiocyanate, Z is a hydrogen atom, a halogen atom, a trifluo-romethyl group or a nitro group, and each of A and B is =CH- or a nitrogen atom, provided that one of A and B is =CH- and the other is a nitrogen atom, with the provisos (1) that when Q is wherein A is =CH-, is where when X is a hydrogen atom and Y1 is an alkyl group, Z is not a hydrogen atom, a halogen atom or a trifluoromethyl group, and (2) that when Q is wherein A is a nitrogen atom and Y1 is a trifluoromethyl group, Y2 is other than a hydrogen atom, which comprises reacting a com-pound having the formula:

(II) wherein R1 is an isocyanate group, an amino group, wherein X, Y1, Y2 and n are as defined above, with a compound having the formula:
(III) or (IV) wherein R2 is wherein Y1 and Y2 are as defined above, and R3 is an amino group or an isocyanate group which is different from R1 or a halogen atom, provided that when R1 is R2 is a halogen atom, and when R1 is an isocyanate group or an amino group, R2 is and A, B and Z are defined above.

9. The process according to claim 8, wherein is reacted with wherein x, n, R2, A and Z are as in claim 8.

10. The process according to claim 9, wherein R1 is an isocyanate group or an amino group, and R2 is wherein Y2, R3 and Y1 are as in claim 8.

11. The process according to claim 8, wherein is reacted with wherein X, n, R1, R2, A and % are as in claim 8.

12. The process according to claim 11, wherein R1 is an isocyanate group or an amino group, and R2 is wherein R3 and Y2 are as in claim 8.

13. An anti-tumorous composition comprising a therapeu-tically effective amount of an N-benzoyl urea compound as defined in claim 1, 2 or 3 and a pharmaceutically acceptable adjuvant.

14. An anti-tumorous composition comprising a therapeu-tically effective amount of an N-benzoyl urea compound as defined in claim 4, 5 or 6 and a pharmaceutically acceptable adjuvant.

15. An anti-tumorous composition comprising a therapeu-tically effective amount of an N-benzoyl urea compound as defined in claim 7 and a pharmaceutically acceptable adjuvant.