Note: Descriptions are shown in the official language in which they were submitted.
i~856~
This invention relates to pharmaceutical compositions
comprising a benzoylurea of formula I
113~3_ CO-NH-CO-NH~ NH-CO )n I 15
R12 Rl 3 R14
Rll represents hydrogen, or 1 or 2 substituents chosen
from halogen, and alkyl and haloalkyl having 1-4 carbon atoms;
R12 represents hydrogen or halogen;
R13 representq hydrogen or 1 or 2 substituents which are
selected ~rom the group consisting of chlorine, methyl, and tri-
fluoromethyl;
R14 is a hydrogen atom, an alkyl group having 1-6 carbon
atoms, an alkenyl group having 2-6 carbon atoms; a cycloalkyl
group having 3-6 carbon atoms provided that (i) when X is O, R14
is absent; and (ii) when n is zero and R14 is hydrogen, R13 is
also hydrogen;
R15 represents either a phenyl group, a substituted
phenyl group having 1-3 substituents ~elected from halogen, and
alkyl, alkoxy, haloalkyl and haloalkoxy having 1-4 carbon atoms,
or R15 xepre~ents a bi-or polycyclic hydrocarbyl group having
8-14 carbon atoms, a cyclohexyl group, or a cyclohexyl group sub-
stituted with 1-3 alkyl or alkenyl groups each having 1-6 carbon
atoms;
- 1 -
12~3S6~
x represents N, CH, or o and
n represents O or 1,
provided that
~a) when X is N or CH, Rll is halogen in the 2-position,
R12 represents hydrogen or halogen in the 6-position and
R15 represents a phenyl group, or a substituted phenyl
group having 1-3 substituents chosen from halogen and alkyl,
alkoxy, haloalkyl, or haloalkoxy having 1-4 carbon atoms.
(b) when X is O, then n is zero, R12 is hydrogen, and
R15 represents a bi- or polycyclic hydrocarbyl group
having 8-14 carbon atoms, a cyclohexyl gxoup, or a cyclohexyl
group substituted with 1-3 alkyl or alkenyl groups each having
1-6 carbon atoms.
Cextain compounds in this broad class have been descri-
bed hitherto.
N-Benzoyl-N'-phenylurea compounds having insecticidal
activity are known from Applicants' Netherlands patent application
7105350. In Chem. Abstracts 91, 20141 (1979) benzoylurea com-
pounds are described having both an insecticidal and an acaricidal
activit~, for example N-(2,6-difluorobenzoyl)-N'-(4-benzyloxy-
phen~l)urea.
In European patent application 0016729 N-(p-aminophenyl)-
N'-benzoylurea are described, e.g. N-(2-chlorobenzoyl)-N'-[3,5-
dichloro-4 (N-m~thyl-N-allyl)aminophenyl]urea and N-(2,6-difluoro-
benzoyl)-N'-3,5-dichloro-4-N-methyl-N-alkyl)aminophenyl urea.
-- 2 --
lZ~8S~L
It has now been found that certain compounds of this
broad type ln addition to showing the above-mentioned agrochemical
activity as insecticides and acaricides, also have an unexpected
antitumor activity.
A preferred group of compounds from within those of
formula I are of the following formula II:
,,~ CO--NH--CO--NH~;~3. 0 ~ II
R2 1 R2 2 R2 3
wherein R21 is a hydrogen atom or represents 1 or 2 substituents
which are selected from the group consisting of halogen and alkyl
and haloalkyl havinc~
- 2a -
,~
.,, ,~
12~1~S6~L
1-4 carbon atoms,
R22 is a hydrogen atom or represents 1 or 2 substituents which
are selected from the group consisting of chlorine, methyl and trifluoromethyl,
and
R23 is a hydrogen atom or represents 1-3 alkyl or alkenyl groups
each having 1-6 carbon atoms, or wherein R23 together with the cyclohexyl ring
to which it is attached forms a bl- or polycyclic hydrocarbyl group having 8-14
carbon atoms.
A further preferred sub-group of compounds are those of formula
III
~ CO N11--CO --~ NH--CO ~n--X~ R34
wherein R31 .is a halogen atom,
R3~ is a hydrogen atom or a halogen atom,
R33 is a hydrogen atom or represents 1 or 2 substituents which are
selected from the group consisting of chlorine, methyl, and trifluoromethyl,
R34 is a hydrogen atom or represents 1-3 substituents which are
selected from the group consisting of halogen, and alkyl, alkoxy, haloalkyl
and haloalkoxy having 1-4 carbon atoms,
X is N or ~H,
n i.s 0 or 1, and
R35 is a hydrogen atom, an alkyl group having 1-6 carbon atoms,
an alkcnyl group having 2-6 carbon atoms, or a cycloalkyl group having 3-6
carbon atoms, with the proviso, that, if n is 0 and R35 is a hydrogen atom,
R33 is a hydrogen atom.
8561
In the compounds of formula I I, as defined above the cyclohexyl
ring can either be alkyl substituted or form part of a polycyclic ring system.
Of particular interest in this context are the menthylJ 2-bornyl and 2-ada-
mantyl groups
Thus a preferred group of compounds are those of the formula V
~ C0 - NH - C0 - Nll - ~ - 0 ~ V
in which: R6 is an alkyl or alkenyl group leaving 1-4 carbon atoms;
R7 is hydrogen or an alkyl or alkenyl group having 1-4 carbon atoms,
or
R6, R7 and the cyclohexyl ring form a 2-bornyl or 2-adamantyl group;
R8 is hydrogen, or 1 or 2 substituents selected from chlorine,
methyl and trifluoromethyl;
Rg is halogen or a methyl group; and
Rlo is hydrogen or a halogen.
In a preferred embodiment of formula V, R6, R7 and the cyclohexyl
ring comprise a menthyl group, and Rg, R9 and Rlo are as defined above.
Examples of compounds according to formula II are as fol]ows.
(1) N-(2,6-difluorobenzoyl)-N'-(4-dl-r,lenthyloxyphenyl)urea,
(2) N-(2,6-difluorobenzoyl)-N'-(4-d -mcnthyloxyphenyl~llrca,
(3) N-(2-chlorobenzoyl)-N'-(4-dl-menthyloxyphenyl)urea,
(4) N-(2-chlorobenzoyl)-N'-(4-d-menthyloxyphenyl~urea,
(5) N-(2,6-difluorobenzoyl~-N'-(4-1-menthyloxyphenyl)urea,
(6) N-(2-chlorobenzoyl)-N'-~4-1-menthyloxyphenyl)urea,
.~7) N-~2-methylbenzoyl)-N'-~4-dl-menthyloxyphenyl)urea,
~8) N-benzoyl-N'-~4-dl-menthyloxyphenyl)urea,
-- 4 --
12~85~
(9) N-benzoyl-N'-(3-chloro-4-dl-menthyloxyphenyl)urea,
(10) N-(2-chlorobenzoyl)-N'-(3-chloro-4-dl-menthyloxyphenyl)urea,
(11) N-(2,6-difluorobenzoyl)-N'-(3-chloro-4-dl-menthyloxyphenyl)urea,
(12) N-benzoyl-N'-(3-methyl-4-dl-menthyloxyphenyl)urea,
(13) N-(2-chlorobenzoyl)-N'-(3-methyl-4-dl-menthyloxyphenyl)urea,
(14) N-(2,6-difluorobenzoyl)-N'-(3-methyl-4-dl-menthyloxyphenyl)urea,
(15) N-(2-chlorobenzoyl)-N'-(4-cyclohexyloxyphenyl)urea~
(16) N-(2-methylbenzoyl)-N'-(4-cyclohexyloxyphenyl)urea,
(17) N-(2,6-difluorobenzoyl)-N'-(4-cyclohexyloxyphenyl)urea,
(18) N-(2-chlorobenzoyl)-N'-[4-(2-methylcyclohexyloxy)phenyl]urea,
(19) N-(2-methylbenzoyl)-N'-[4-(2-methylcyclohexyloxy)phenyl]urea,
(20) N-(2,6-difluorobenzoyl)-N'-[4-(2-methylcyclohexyloxy)phenyl]urea,
(21) N-benzoyl-N'-[4-(2-ethylcyclohexyloxy)phenyl]urea,
(22) N-(2-chlorobenzoyl)-N'-[4-(2-ethylcyclohexyloxy)phenyl]urea,
(23) N-(2,6-difluorobenzoyl)-N'-[4-(2-ethylcyclohexyloxy)phenyl]urea,
(24~ N-benzoyl-N'-[4-(2-tert.-butylcyclohexyloxy)phenyl]urea,
(25) N-(2-chlorobenzoyl)-N'-[4-(2-tert.-butylcyclohexyloxy)phenyl]urea,
(26) N-(2,6-difluorobenzoyl)-N'-[4-(2-tert.-butylcyclohexyloxy)phenyl]urea,
(27) N-benzoyl-N'-[4-(2,6-dimethylcyclohexyloxy)phenyl]urea,
(28) N-(2-chlorobenzoyl~-N'-[4-(2,6-dimethylcyclollexyloxy)phenyl]urea,
~2~) N-(2,6-difluorobenzoyl)-N'-[4-(2,6-dimethylcyclohexyloxy)phcnyl]urca,
(30) N-(2 chlorobenzoyl)-N'-[3-methyl-4-(2-ethylcyclohexyloxy)phenyl]urea,
(31~ N-(2,6-difluorobenzoyl)-N'-[3-methyl-4-(2-ethylcyclohexyloxy)phenyl~urea,
(32~ N-(2 chlorobenzoyl)--N'-[4-bornyl(-2)oxyp}lenyl]uroa,
(33) N-(2,6-difluorobenzoyl)-N'-[4-bornyl(-2)oxyphenyl]urea,
(34) N-benzoyl-N'-[3-methyl-4-bornyl(-2)oxyphenyl]urea,
(35) N-(2-chlorobenzoyl)-N'-[3-methyl-4-bornyl(-2)oxyphenyl]urea,
~'~U856~
~36) N-~2,6-difluorobenzoyl)-N'-[3-methyl-4-bornyl~-2)oxyphenyl]urea,
(37) N-benzoyl-N'-(3-trifluoromethyl-4-dl-menthyloxyphenyl)urea,
~38) N-~2-chlorobenzoyl)-N'-~3-trifluoromethyl-4-dl-menthyloxyphenyl]urea,
(39) N-(2,6-difluorobenzoyl)-N'-(3-trifluoromethyl-4-dl-menthyloxyphenyl)urea,
~40) N-benzoyl-N'-[4-~2-isopropenyl-5-methylcyclohexyloxy)phenyl]urea,
(41) N-(2-chlorobenzoyl)-N'-[4-(2-isopropenyl-5-methylcyclohexyloxy)phenyl]urea,
~42) N-~2,6-difluorobenzoyl)-N'-[4-~2-isopropenyl-5-methylcyclohexyloxy)phenyl]
urea,
(43) N-benzoyl-N'-[4-bornyl(-2)oxyphenyl]urea,
(44) N-benzoyl-N'-[3-chloro-4-bornyl(-2)oxyphenyl]urea,
(45) N-(2-chlorobenzoyl-N'-[3-chloro-4-bornyl(-2)oxyphenyl]urea,
(46) N-(2,6-difluorobenzoyl)-4'-[3-chloro-4-bornyl(-2)oxyphenyl]urea,
(47) N-benzoyl-N'-[4-adamantyl(-2)oxyphenyl]urea,
(48) N-(2-chlorobenzoyl)-N'-[4-adamantyl(-2)oxyphenyl]urea,
~49) N-(2,6-difluorobenzoyl)-N'-[4-adamantyl(-2~oxyphenyl]urea,
(50) N-(4-chlorobenzoyl)-N'-(4-dl-menthyloxyphenyl)urea,
(51) N-(4-trifluoromethylbenzoyl)-N'-(4-dl-menthyloxyphenyl)urea,
(52) N-(3,5-dichlorobenzoyl)-N'-(4-dl-menthyloxyphenyl)urea9
(53) N-(4-fluorobenzoyl)-N'-(4-dl-menthyloxyphenyl)urea,
(54) N-(3,4-dichlorobenzoyl)-N'-(4-dl-menthyloxyphenyl)urea,
(55) N-(4-bromobenzoyl)-N'-(4-dl-menthyloxyphenyl)llrea~
(56) N-(3-bromobenzoyl)-N'-(4-dl-menthyloxyphenyl)urca, and
(57) N-(2,4-difluorobenzoyl)-N'-(4-dl-menthyloxyphenyl)urea.
Similarly, in the compounds Oe formula III a prsfsrred group is
those having the formula IV
~Rl
C0 - NH - C0 - NH - ~ NH - C0 ~ N ~ IV
2 R3
-- 6 --
12~8561
wherein Rl and R2 are both fluorine atoms, or wherein Rl is a chlorine atom
and R2 is a hydrogen atom,
R3 and n have the above meanings for R33 and n
R4 represents 1 or 2 substituents which are selected from the group
consisting of halogen, and alkyl, haloalkyl and haloalkoxy having 1-4 carbon
atoms, and
R5 is a hydrogen atom or an alkyl group having 2-5 carbon atoms, with
the proviso, that, if n is 0 and R5 is a hydrogen atom, R3 is a hydrogen atom.
Examples of benzoylurea compounds according to formula III are
as follows:
(58) N-(2-chlorobenzoyl~-N'-[4-{N-(4-chlorophenyl)-N-ethylamino}phenyl]urea,
(59) N-(2,6-difluorobenzoyl)-N'-[4-{N-(4-chlorophenyl)-N-ethylamino}-phenyl]
urea,
(60) N-(2-chlorobenzoyl)-N'-[4-{N-(4-chlorophenyl)-N-propylamino}phenyl]urea,
(61) N-(2,6-difluorobenzoyl)-N'-[4-{N-(4-chlorophenyl)-N-propylamino}-phenyl]-
urea,
(62) N-(2,6-difluorobenzoyl)-N'-[3-chloro-4-{N-(4-chlorophenyl)-N-propylamino}-
phenyl]urea,
(63) N-(2~chlorobenzoyl)-N'-[4-{N'-(4-chlorophenyl)-N'--isopropylwreido}-
phenyl]urea,
(64) N-(2~chlorobenzoyl)-N'-~4-{N'-~4-chlorophenyl)-N'-propylllreido~phellyl]urea,
(65) N-~2,6-difluorobenzoyl)-N'-[4-{N'-(4-chlorophenyl)-N'-propylureidO}phenyl]- urea,
(66) N-(2-chlorobenzoyl)-N'-[4-t~-chloroallilino)phenyl]urea,
t67) N-t2-chlorobenzoyl)-N'-t4-anilinophenyl)urea,
t68) N-t2,6-difluorobenzoyl)-N'-[4-t2,4-dichloroanilino)phenyl]urea,
t69) N-t2-chlorobenzoyl)-N'-[3-chloro-4-{N-~4-chlorophenyl)-N-methylamino}phenyl]-
urea,
-- 7 --
i~)8561
(70) N-(2,6-difluorobenzoyl)-N'-[3-chloro-4-{N-(4-chlorophenyl)-N-methylamino}-
phenyl]urea,
(71) N-(2-chlorobenzoyl)-N'-[4-{N-(4-chlorophenyl)-N-butylamino}-phenyl]urea,
(72) N-(2,6-difluorobenzoyl)-N'-[4-{N-(4-chlorophenyl)-N-butylamino}phenyl]urea,
(73) N-(2-chlorobenzoyl)-N'-[4-{N-(4-trifluoromethylphenyl)-N-butylamino}-
phenyl]urea,
(74) N-(2,6-difluorobenzoyl)-N'-[4-{N-(4-trifluoromethylphenyl)-N-butylamino}-
phenyl]urea,
(75) N-(2,6-difluorobenzoyl)-N'-[4-(4-chloroanilino)phenyl]urea,
(76) N-(2-chlorobenzoyl)-N'-[3,5-dimethyl-4-{N-(4-chlorophenyl)-N-propylamino}-
phenyl]urea,
(77) N-2,6-difluorobenzoyl)-N'-[3,5-dimethyl-4-{N-(4-chlorophenyl)-N-propyl-
amino}phenyl]urea,
(78) N-(2-chlorobenzoyl)-N'-[4-{N-(4-1,1,2,2-tetrafluoroethoxyphcnyl)-N ethyl-
amino}phenyl~urea,
(79) N-(2,6-difluorobenzoyl)-N'-[4-{N-(4-1,1,2,2-tetrafluoroethoxyphenyl)-N-
propylamino}phenyl]urea,
(80) N-(2-chlorobenzoyl)-N'-[4-(4-1,1,2,2-tetrafluoroethoxyanilino)phenyl]urea,
(81) N-(2,6-difluorobenzoyl)-N'-[4-(4-1,1,2,2-~etrafluoroethoxyanilino)phenyl]-
urea,
(82) N-(2-chlorobenzoyl)-N'-[4-{N-(4-fluorophenyl)-N-ethylamino}phenyl~urea,
(83) N-(2,6-difluorobenzoyl)-N'-[4-{N-(4-fluorophenyl)-N-ethylamino}phenyl]urea,
.t84) N-(2-chlorobenzoyl)-N'-[4-(4-fluoroanilino)phenyl]urea,
(~5) N-(2,6-difluorobenzoyl~-N'-[4-(4-fluoroanilino)phenyl]urea,
~86) N-~2,6-difluorobenzoyl)-N'-[3-chloro-4-{N-~4-1,1,2,2-tetrafluoroethoxy-
phenyl)-N-ethylamino}phenyl]urea,
(87) N-(2-chlorobenzoyl)-N'-[4-{N-(4-chlorophenyl)-N-isopropylamino}phenyl]urea,
~ZC~8S61
(88) N-(2,6-difluorobenzoyl)-N'-[4-{N-(4-chlorophenyl)-N-isopropylamino}phenyl]-
urea,
(89) N-~2-chlorobenzoyl)-N'-[3-chloro-4-{N-(4-chlorophenyl)-N-ethylamino}phenyl]-
urea,
(90) N-(2,6-difluorobenzoyl)-N'-[3-chloro-4-{N-(4-chlorophenyl)-N-ethylamino}-
phenyl]urea,
(91) N-(2-chlorobenzoyl)-N'-[4-{N'-(4-chlorophenyl)-N'-ethylureido}phenyl]urea,
(92) N-(2,6 difluorobenzoyl)-N'-[4-{N'-(4-chlorophenyl)-N'-isopropylureido}-
phenyl]urea,
(93) N-(2-chlorobenzoyl)-N'-[4-{N'-(4-chlorophenyl)-N'-butylureido}phenyl]urea,
(94) N-(2,6-difluorobenzoyl)-N'-~4-{N'-(4-chlorophenyl)-N'-butylureido}phenyl]-
urea,
(95) N-(2-chlorobenzoyl)-N'-[3-chloro-4-{N'-(4-chlorophenyl)-N'-butylureido}-
phenyl]urea,
(96) N-~2,6-difluorobenzoyl)-N'-[3-chloro-4-{N'-(4-chlorophenyl)-N'-butyl-
ureido}phenyl]urea,
(97~ N-(2-chlorobenzoyl)-N'-[4-{N'-(4-trifluoromethylphenyl)-N'-butylureido}-
phenyl]urea,
(98) N-(2,6-difluorobenzoyl)-N'-[4-{N'-(4-trifluoromethylphenyl)-N'-butyl-
ureido}phenyl]urca,
(99) N-(2-chlorobenzoyl)-N'-~4-{N'-(4-methylphenyl)-N'-butylureido}phenyl]urea,
(lO0) N-(2,6-difluorobenzoyl)-N'-[4-{N'-(4-methylphenyl)-N'-butylureido}-
phenyl]urea,
(101) N-t2-chlorobcnzoyl)-N'-[3-chloro-4-{N'-(4-methylphenyl)-N'-butylureido}-
phcnyl]urea,
(102) N-(2,6-difluorobenzoyl)-N'-[3-chloro-4-{N'-(4-methylphenyl)-N'-butyl-
ureido}phenyl]urea,
12i~iS6i
(103) N-(2-chlorobenzoyl)-N'-~4-{N'-(4-1,1,2,2-tetrafluoroethoxyphenyl)-N'-
butylureido}phenyl]urea,
(104) N-(2,6-difluorobenzoyl)-N'-[4-{N'-(4-1,1,2,2-tetrafluoroethoxyphenyl)-N'-
butylureido}phenyl]urea,
(105) N-(2-chlorobenzoyl)-N'-[4-{N'-(4-1,1,2,2-tetrafluoroethoxyphenyl)-N'-
propylureido}phenyl]urea,
(106) N-(2,6-difluorobenzoyl)-N'-[4-{N'-(4-1,1,2,2-tetraf].uoroethoxyphenyl)-N'- propylureido}phenyl]urea,
(107) N-(2-chlorobenzoyl)-N'-[4-{N'-(4-chlorophenyl)-N'-isobutylureido}phenyl]-
urea,
(108) N-(2,6-difluorobenzoyl)-N'-[4-{N'-(4-chlorophenyl)-N'-isobutylureido}-
phenyl]ur~a,
(109) N-(2-chlorobenzoyl)-N'-[4-{N'-(4-chlorophenyl)-N'-hexylureido}phenyl]urea,(110) N-(2,6-di~luorobenzoyl)-N' [4-{N'-(4-chlorophenyl)-N'-hexylureido}phenyl]-' urea,
~111) N-(2-chlorobenzoyl)-N'-[4-{N'-(4-chlorophenyl~-N'-pentylureido}phenyl]-
urea,
(112) N-(2,6-difluorobenzoyl)-N'-[4-{N'-(4-chlorophenyl)-N'-pentylureido}phenyl]-
urea,
(113) N-(2-chloroben~oyl)-NI-~4-{N'-t2,6-dichlorophenyl)-N'-propylureido}phenyl]-
urea,
(114) N-(2,6-difluorobenzoyl)-N'-[4-{N'-(2,6-dichlorophenyl)-N'-propylurcido}-
phenyll,urca,
(115) N-(2-chlorobon~oyl)-N'-[4-{N'-(3,4-dimethylphenyl)-N'-propylurcido}phenyl]-
urea,
(116) N-(2,6-difluorobenzoyl)-N'-[4-{N'-(3,4-dimethylpropyl)-N'-propylureido}-
phenyl]urea,
- 10 -
12~35~1
(117) N-(2-chlorobenzoyl)-N'-[4-{N'-(4-fluorophenyl)-N'-propylureido}phenyl~urea,
(118) N-(2,6-difluorobenzoyl)-N'-~4-{N'-(4-fluorophenyl)-N'-propylureido}phenyl]-
urea,
(119) N-(2,6-difluorobenzoyl)-N'-[3-chloro-4-{N'-(4-chlorophenyl)-N'-propyl-
ureido}phenyl]urea,
(120) N-(2-chlorobenzoyl)-N'-[3-methyl-4-{N'-14-chlorophenyl)-N'-propylureido}-
phenyl]urea,
(121) N-(2,6-difluorobenzoyl)-N'-[3-methyl-4-{N'-(4-chlorophenyl)-N'-propyl-
ureido}phenyl]urea,
(122) N-(2-chlorobenzoyl)-N'-[4-{N'-(4-chlorophenyl)-N'-allylureido}phenyl]urea,
(123) N-(2,6-difluorobenzoyl)-N'-[4-{N'-(4-chlorophenyl)-N'-allylureido}phenyl]-
urea,
(124) N-(2-chlorobenzoyl)-N'-[4-{2-(4-chlorophenyl)-3-me~hylbutyrylamino}phenyl]-
urea,
tl25) N-(2,6-difluorobenzoyl)-N'-[4-{2-(4-chlorophenyl)-3-methylbutyrylamino}-
phenyl~urea,
(126) N-(2-chlorobenzoyl)-N?-[4-{2-~4-chlorophenyl)hexanoylamino}phenyl]urea,
(127) N-(2,6-difluorobenzoyl)-N'-[4-{2-(4-chlorophenyl)hexanoylamino}phenyl]urea,
(128) N-(2-chlorobenzoyl)-N'-~3,5-dimethyl-4-{N'-(4-chlorophenyl)-N' propyl-
ure:ido}phenyl~urea,
(129) N-(2,6-di~luorobenzoyl)-N'-[3,5-dimethyl-4-{N'-(4-chloroph~nyl)-N'-
propylureido}phenyl]urea,
(130) N-(2-chlorobenzoyl)-N'-~3-trifluoromethyl-4-{N'-(4-chloropllenyl)-N'-
propylureido}phenyl~urea, and
(131) N-(2,6-difluorobenzoyl)-N'-[3-trifluoromethyl-4-{N'-(4-chlorophenyl)-N'-
propylureido}phenyl]urea.
12~:)856~
The compounds used in the compositions of this invention are
prepared by procedures standard for compounds of this type. The following
examples are typical for compounds of formulae II and III respectively.
A. Preparation of N-(2,6-difluorobenzoyl)-N'-~4-dl-menthyloxyphenyl)urea. (1)
1.9 g of 2,6-difluorobenzoylisocyanate were added to a solution
of 2.47 g of 4-dl-menthyloxy-aniline in a mixture of 15 ml of diethyl ether and
15 ml of petroleum ether (60-80) while stirring at room temperature. After
adding 35 ml of petroleum ether (60-80), stirring was continued for another
hour, after which the formed precipitate was sucked off, washed with petroleum
ether and dried. The desired product was obtained in a yield of 4.1 g;
melting-point l~9-190C. The starting aniline was obtained from the corres-
ponding nitro compound by reduction with hydrogen under the influence of Raney
nickel as a catalyst, ethyl acetate being used as a solvent. l-Nitro-4-dl-
menthyloxybenzene was prepared by reaction of dl-menthol with l-fluoro-4-
nitrobenzene in tert.-butanol as a solvent in the presence of potassium tert.-
butoxide.
B. Preparation of N-(4 luorobenzoyl)-N'-(4-dl-menthyloxyphenyl)urea (53).
2.75 g of 4-dl-methyloxyphenylisocyanate were added to a solution
of 1,4 g of 4-fluorobenzamide in 30 ml of xylene. The mixture was refluxed
during 4 hours. After cooling down the formcd precipitate was sucked off,
washcd with diethylether, and dried. The desired product was obtained in a
yield of 2.~ g; molting point 203-204C. Thc starting isocyanate was obtained
from 4-dl-merlthyloxy-aniline tprepared as described in Example A) by a reaction
with phosgene in boiling toluene; purification by destillation.
C. Proparation o N ~2,6-dlfluorobenzoyl)-N'[~-{N-t4-chlorophenyl)-N-proPyl-
amino}phenyl~urea t61)
0.90 g of 2.6-difluorobenzoylisocyanate was added to a solution
lZ~8561
of 1.27 g of 4-[N-~4-chlorophenyl)-1~-propylamino]aniline in 15 ml of dry
diethylether while stirring at room temperature. After 1.5 hours at room tem-
perature the formed precipitate was sucked off, washed with acetonitrile and
diethylether, and dried. The desired product was obtained in a yield of
1.50 g; melting-point 169-169.5C.
The starting aniline was obtained from the corresponding nitro
compound by reduction with hydrogen under the influence of Raney nickel as a
catalyst; a mixture of equal parts by volume of ethanol and ethyl acetate was
used as a solvent. l-Nitro-4-[N-(4-chlorophenyl)-N-propylamino]benzene was
prepared by an alkylation of 1-nitro-4-(4-chloroanilino)benzene with propyl-
iodide in dimethylformamide as a solvent under the influence of KOH. l-Nitro-
4-(4-chloroanilino)benzene was formed by a coupling at high temperature of p-
chlorobenzeneisocyan~te and p-nitrophenol in nitrobenzene as a solvent.
_ Preparation of N-(2-chlorobenzoyl)-N'-[4-{N'-(4-chlorophenyl)-N'-propyl-
ureido}phenyl]urea (64)
1.09 g of 2-chlorobenzoylisocyanate was added to a solution of
2.00 g of N-(4~aminophenyl)-N'-(4-chlorophenyl)-N'-propylurea in 50 ml of aceto-
nitrile while stirring at room temperature. After stirring for 1.5 hours at
room temperature the formed precipitate was sucked off, washed with diethyl
ether, and dried. According to PMR the product had the dcsired structure; the
product melted at 170C. Tho starting anili.ne was obtained from tho corrcspond-
ing nitro compound by reduction with hydrogcn undcr the influene~ of Raney
nickel as a catalyst; in this reaction ethanol was used as a solvcllt. N-(4-
nitrophenyl3-N'-(4-cl-lorophellyl3-N'-propylurea was prepared by a coupling of
p-nitrophenyliso~yanate with N-propyl-4-chloroaniline in acetonitrile as a
solvent.
The pharmaceu1ical compositions of this invention are prepared
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56~l
from the active ingredient, or ingredients, in the usual way. Thus tablets,
solutions, syrups, capsules and the like can all be used as the pharmaceutical
vehicle whereby these compolmds are administered. If desired, the active
ingredient may also be mixed with another substance of pharmaceutical activity,
and may also be admixed with substances to make them more palatable such as
sugar syrups, sugar coatings, flavouring agents, and the like.
Examples
Inhibition of ~he growth of tumor cells
After pre-incubation at 37C during 3 hours the compounds to be
tested were added in amounts of 5000 ppm to Bl6 melanoma cells, growing as a
monolayer on a growing-medium. The experiments were carried out in triplicate.
The mixtures were then incubated at 37C during 20 hours. After removal of the
growing-medium and the test-compolmds the cells were washed and fresh growing-
mcdium was added. The amount of cells was determined 48 hours after the begin
ning of the incubation pcriod with a microcell Coulter Counter.
Using this procedure the following results were obtained; the
compound numbers correspond to those given above, and the percentage figures
to the inhibition of cell growth compared to a blank experiment without a test
compound.
Compound % Inhibition
3 54%
1 72%
59 93%
63 28%
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