UREES TRISUBSTITUEES ANTI-ATHEROSCLEROTIQUES

ANTI-ATHEROSCLEROTIC TRISUBSTITUTED UREAS

Abrégé anglais

ABSTRACT
Substituted urea derivatives, and processes for their preparation
of the general formula
< IMG >
are described, in which A is a halo-substituted phenyl group; n is 1 to 5;
R1 and R2 are each hydrogen or lower alkyl; and Z is hydrogen, lower alkoxy,
halo, or the group (CH2)m-CR3R4-CH3, in which m is 0 to 5; and R3 and R4 are
hydrogen or lower alkyl, with the proviso that R1, R2, R3 and R4 cannot all be
hydrogen. These compounds find use in heating atherosclerosis, in reducing
the cholesterol content of arterial walls, in treating hyperlipidemia, and
in inhibiting atherosclerotic lesion development in mammals. The compounds
are generally administered combined with a suitable pharmaceutically acceptable
carrier, and passes the practical advantage that they may be administered
orally as well as by injection.

Revendications

- 23 -
THE EMBODIMENT OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS;
1. A process for the preparation of a compound
of the following formula (I):
< IMG >
(I)
wherein,
A is 4-(trifluormethyl)phenyl, 4-chloro 2-methylphenyl,
4-chloro-2,5-dimethylphenyl, 4-chloro-2,6-dimethylphenyl,
2,4-difluorophenyl, 2,4,6-trichlorophenyl, or 2,4,6-
-trifluorophenyl;
n is a positive integer from one to five;
R1 and R2 are independent of one another and are hydrogen
or (C1-C4)alkyl; and
Z is hydrogen, (C1-C5)alkoxy, halo or the group
< IMG >

- 24 -
in which m is an integer from 0 to 5 and
R3 and R4 are independent of one another and are hydrogen
or (C1-C4)alkyl; with the proviso that R1, R2, R3, and
R4 cannot all be hydrogen; characterized by reacting a
compound of the following formula A-Y
wherein A is as defined above and Y is -N=C=O or -NH-CO-B,
wherein B is halogen, (C1-C4)alkocy, (C1-C4)alkylthio,
phenoxy, 4-chlorophenoxy or 4-nitrophenoxy; with a
secondary amine of the formula;
< IMG >
wherein n, R1, R2, and Z are as defined above.
2. A compound of the following formula (I):
< IMG >
(I)
wherein A, R1, R2, and Z are as defined in Claim 1.

- 25 -
3. A process for the preparation of 3-(2,4-difluorophenyl)-
1-[[4 (2,2-dimethylpropyl)phenyl]methyl]-1-(n-heptyl)urea, which
comprises reacting 2,4-difluorophenylisocyanate with 4-(2,2-dime-
thylpropyl)-N-(n-heptyl)-benzenemethanamine.
4. The compound 3-(2,4-difluorophenyl)-1-[[4-(2,2-dimethyl-
propyl)phenyl]methyl]-1-(n-heptyl)urea.
5. A process for the preparation of 3-(4-chloro-2,6-dimethyl-
phenyl)-1-[[4-(2,2-dimethylpropyl)phenyl]methyl]-1-(n-heptyl)urea,
which comprises reacting 4-chloro-2,6-dimethylbenzeneamine with
phenyl chloroformate to yield phenyl(4-chloro-2,6-dimethylphenyl)
carbamate which is reacted with 4-(2,2-dimethylpropyl)-N-(n-heptyl)
benzenemethanamine.
6. The compound 3-(4-chloro-2,6-dimethylphenyl)-1-[[4-(2,2-
dimethylpropyl)phenyl]methyl]-1-(n-heptyl)urea.
7. A pharmaceutical composition comprising as active ingred-
ient, together with a pharmaceutically acceptable carrier therefor,
a compound of the Formula (I) as defined in claim 2.
8. A composition according to claim 7 wherein the active
ingredient is the compound of claim 4.
9. A composition according to claim 7 wherein the active
ingredient is the compound of claim 6.

Description

Ed
I
ANTI ATHEROSCLEROTIC UREAS AND THERESA
This invention relates to novel ureas containing
alkyd groups which are branched at the penultimate carbon
of the alkyd chain. The invention further relates to the
chemical syntheses of these ureas, pharmaceutical combo-
sessions containing these ureas, and the use of these urea sin the treatment of atherosclerosis.
The novel ureas of this invention are repro-
sensed by the following formula:
O R
If I .
A--NHCN--( SHEA ) nCCH3
SHEA R2
I
Z
wherein,
A is 4-(trifluoromethyl)phenyl, 4-chloro-2-methylphenyl,
4-chloro-2,5-dimethylphenyl, 4-chloro-2,6-dimethyl-
phenol, 2,4-difluorophenyl, 2,4,6-trichlorophenyl, or
2,4,6-trifluorophenyl;
n is a positive integer from one to five;
.
;,. I .

-- 2 --
Al and R2 are independent of one another and are
hydrogen or (Cl-C4)alkyl; and
Z is hydrogen, (Cl-Cs)alkoxy, halo or the group
- ( SHEA )m<CH3
R4
in which m is an integer from 0 to 5 and
R3 and R4 are independent of one another and are hydrogen
or (Cl-C4)alkyl; with the proviso that
Al, R2, R3, and R4 cannot all be hydrogen.
Preferred compounds of this invention are the
following ureas:
1-(3,3-Dimethylbutyl)-1-[[4-(n-butyl)phenyl]methyllo
(4-chloro-2,6-dimethylphenyl)urea,
1-(3,3-Dimethylbutyl)-1-[[4-(2,2-dimethylpropyl)phHoneywell]-
methyl]-3-(4-chloro-2,6-dimethylphenyl)urea,
1-(3,3-Dimethylbutyl)-1-[[4-(n-butyl)phenyl]methyllo
(2,4,6-trifluorophenyl)urea,
1-[[4-(2,2-Dimethylpropyl)phenyl]m~thyl]-l-(n-hepttwill)-
3-(2,4-difluorophenyl)urea,
1-[[4-(2,2-Dimethylpropyl~phenyl]methyl]-l-(n-hepttwill)-
3-(4-chloro-2,6-dimethylphenyl)urea,
1-[[4-(2,2-Dimethylpropyl)phenyl]methyl]-l-(n-hepttwill)-
3-(2,4,6-trifluorophenyl)urea,
30 1-[[4-(n-Butyl)phenyl]methyl]-1-(3,3-dimethylbutyllo
(4-chloro-2,6-dimethylphenyl)urea.
This invention also relates to a method of
treating atherosclerosis in mammals, reduction of the
cholesterol content of the arterial walls in mammals, the
treatment of hyperlipidemia in mammals and the inhibition
of atherosclerotic lesion development in mammals which
comprises administering to said mammals an effective amount
of a compound as defined above.
.

The compounds of this invention may be prepared
by reacting an arylisocyanate of the formula:
A-N=C=O
wherein A is as defined above, with a secondary amine of
the formula:
Al
10 Ho SHEA ) nCCH3
SHEA 12
wherein n, Al, R2, and Z are as defined above.
A second process for the preparation of compounds
of this invention involves reacting a compound of the
formula: -
A-NHC-B
wherein A is as defined above and B is selected from the
group consisting of halogen, (Cl-C4)alkoxy, (Cl-C4)alkyl-
trio, phonics, 4-chlorophenoxy, and 4-nitrophenoxy; with a
secondary amine of the formula:
... .

-- 4
Al
Ho SHEA ) n~CH3
SHEA R2
wherein n, Al, R2, and Z are as defined above.
Many of the novel ureas of this invention are
prepared by reacting arylisocyanates with secondary amine.
These reactions may be performed in aprotic solvents such
as hexane, deathly ether, Tulane, tetrahydrofuran, and
the like at temperatures from room temperature or below up
to the boiling point of the solvent used. The ureas are
isolated by filtration or by evaporating the solvent and
they may be purified by recrystallization, absorption
chromatography, or distillation under reduced pressure.
An example of this process is the reaction of deflower-
phenylisocyanate with 4-(2,2-dimethylpropyl)-N-(n-heptyl)-
benzenemethanamine to yield 3-t2,4-difluorophenyl)-1-[~4-
(2,2-dimethylpropyl)phenyl]methyl]-1-(n-heptyl)ureea.
Certain of the novel ureas of this invention are
prepared by reacting arylamines with activated derivatives
of carbonic acid such as phosgene or phenol chloroform ate
to yield an intermediate, for instance, an arylcarbamyl
chloride. This intermediate is then reacted with a second-
cry amine to yield the urea. The preparation of this
intermediate is conducted in an aprotic solvent such as
Tulane or zillion at temperatures from about room tempera-
lure up to the boiling point of the solvent in the presence
of a base, for example, N,N-dimethylaniline.
The intermediate is then reacted with a secondary
amine in an aprotic solvent such as Tulane at tempera
lures from room temperature or below up to the boiling
:,
- .
,
: . . : .
.

I P
-- 5 --
point of the solvent. An example of this process is the
reaction of 4-chloro-2,6-dimethylbenzeneamine with phenol
chloroform ate to yield phenol (4-chloro-2,6-dimethylphen-
yl)carbamate as an intermediate. This intermediate is
5 then reacted with a secondary amine such as Dow-
methylpropyl)-N-(n-heptyl)benzenemethanamine to yield a
urea, in this case 3-(4-chloro-2,6-dimethylphenyl)-1-
[[4-(2,2-dimethylpropyl)phenyl]methyl~-1-(n-heptylLowry.
The ureas of the present invention are obtained
as crystalline solids or distillable liquids. They are
characterized by distinct melting or boiling points and
unique spectra. They are appreciably soluble in organic
solvents but generally less soluble in water.
The properties and utility of the compounds of
this invention will be illustrated in conjunction with the
specific tables shown below.
The compounds of the present invention were
assayed for two types of biological activity related to
their potential use as anti atherosclerotic agents. Come
pounds were tested in vitro for their ability to inhibit
the enzyme fatty azalea CoA:cholesterol azalea transfers
(ACT) and in viva for hypolipidemic activity as measured
by their ability to inhibit lipid absorption in rats. The
compounds were tested for their ability to inhibit ACT
according to the following procedure:
Rat adrenals were homogenized in 0.2 M monobasic
potassium phosphate buffer, pi 7.4, and centrifuged at
Luke times gravity for 15 minutes at 5C. The super-
Nat ant, containing the microsomal fraction, served as the
source of the cholesterol-esterifying enzyme, fatty azalea
30 CoA:cholesterol azalea transfers (ACT). A mixture come
prosing 50 parts of adrenal supernatant, 10 parts of
albumin (BRA) (50 mg/ml), 3 parts of test compound, and
500 parts of buffer was preincubated at 37C for 10 mint
vies. After treatment with 20 parts of 14C-palmitoyl
35 CoA(final concentration 20 EM) the mixture was incubated
at 37C for 10 minutes. A control mixture, omitting the

I
--6--
test compound, was prepared and treated in the same manner.
The lipids from the incubation mixture were extracted into
an organic solvent and separated by thin-layer chromatog-
rough. The cholesterol ester fraction was counted in a
5 scintillation counter. This procedure is a modification
of that described by Hashimoto, et at , Life Science, 12
(Part II), 1-12 (1973). The results of this test at van-
out concentrations of each compound were then used to
obtain the Issue for that compound. The Issue is defined as
lo that concentration of a compound which produces 50~ inhibit
lion of the enzyme. Results of these tests are shown in
Table I.
TABLE I
_ I .
Compound ISSUE EM
_ _ _
3-(2,4-Difluorophenyl)-1-[[4-(2,2-dimethyl- 1.32
propyl)phenyl]methyl]-l-(n-heptyl)urea
3-(4-Chloro-2,6-dimethylphenyl)-1-[[4-(2,2- 0.31
dimethylpropyl)phenyl]methyl]-l-(n~heptyl)urea
1-[[4-(2,2-Dimethylpropyl)phenyl]methyl]-l-(n-0.122
heptyl)-3-(2,4,6-trifluorophenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 1.29
(4-chloro-2-methylphenyl)urea
25 1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-1.666
(4-chloro-2-methylphenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-0.554
(2,4,6-tirchlorophenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]-3-10..00
(2,4-difluorophenyl)urea
1-(3,3-Dimethylbutyl)-1-~4-(n-butyl)benzyl]-3- 1.50
(2,4-difluorophenyl)urea
.
.
.

I
TABLE I (continued)
Compound ISSUE EM
1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl~-3-0.633
(2,4,6-trichlorophenyl)urea
1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)benzyll-3-0.755
(4-chloro-2-methylphenyl)urea
.1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)benzyl]-3-1.200
(2,4-difluorophenyl)urea
1-(5,5-Dimethylhexyl)-1-~4-(n-butyl)benzyl]-3-0.066
(2,4,6-trichlorophenyl)urea
1-(3,3-Dimethylbutyl)-1-~4-chlorobenzyl)-3-(4-0.899
chloro-2-methylphenyl)urea
1-(3,3-Dimethylbutyl)-l-benzyl-3-(2,4-difluoro-3.114
phenyl)urea
1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 3.54
(2,4-aifluorophenyl)urea
1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 0.51
(2,4,6-trichlorophenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3-3.044
(4-trifluoromethylphenyl)urea
1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 2.61
(4-trifluoromethylphenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 1.00
propyl)benzyl]-3-(2,4-difluorophenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 0.95
propyl)benzyl]-3-(4-chloro-2-methylphenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 1.02
propyl)benzyl]-3-(2l4,6-trichlorophenyl)urea
3Q 1-(3,3-Dimethylbutyl)-1-[4-(n-butyl~benzyl]-3-0.700
(4-chloro-2,6-dimethylphenyl)urea
1-~3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3-(4-n . 65
chloro-2,6-dimethylphenyl)urea
.. . .

TABLE I continued)
I Compound ISSUE EM
5 1-(3,3-Dimethylbutyl)~ 4-(2,2-dimethyl- 0.84
propyl)benzyl]-3-(4-chloro-2,6-dimethylphenyl)-
urea
1-(3,3-Dimethylbutyl)-l-benzyl-3-(4-chloro-2- 1.16
methylphenyl)urea
l-t3,3-Dimethylbutyl)-l-(benzyl)-3-(4-chloro- 2.60
2,5-dimethylphenyl)urea
1-~(4-Butylphenyl)methyl]-1 [3,3-dimethyl- 0.11
butyl]-3-[2,4,6-trifluorophenyl~urea
l-Benzyl-l-[3,3-dimethylbutyl]-3-[2,4,6-tri- 0.91
fluorophenyl]urea
l-[3,3-Dimethylbutyl]-1-[4-(2,2-dimethyl- 0.05
propyl)phenyl]-3-[2,4,6-trifluorophenyl]urea
Inhibition of cholesterol absorption was deter-
mined by feeding male Sprague-Dawley rats, weighing 150-
170 g, a 1% cholesterol colic acid diet for 2 weeks.
The diet also contained compounds being tested at a dose
of 0.03% of the diet. Control rats were fed the same
diet without any compound. At the end of the test, the
rats were sacrificed by decapitation. Blood is collected,
centrifuged at 1.5 kg times gravity for 10 minutes at
4C; and the serum is then analyzed for cholesterol and
triglycerides enzymatic ally by the method of Tinder, P.,
3Q Analyst, 77, 321 (1952) on a Centrifichem 400 analyzer.
Livers are removed, a 0.4 g sample is taken from the eon-
ton of the large lobe, and the sample is subjected to
saponification using 25% saturated potassium hydroxide in
ethanol. The resulting neutral strolls are extracted
with petroleum ether and extract analyzed for cholesterol.
The effectiveness of the compound in inhibiting chores-
.. .
. . .
r

twirl absorption is measured by the lowering of either
serum cholesterol to liver cholesterol relative to the
values for control rats.
Compounds which produced statistically signify-
cant inhibition of cholesterol absorption are considered
to be active. Liver stroll LO and serum stroll (SO)
values are expressed as a percentage of control values.
The results of this test on typical compounds of this
invention appear in Table II.
TABLE II
Compound LO SO
._ .
3-(2,4-Difluorophenyl)-1-[[4-(2,2-dimethyl- 2424
propyl)phenyl]methyl]-l-(n-heptyl)urea
3-(4-Chloro-2,6-dimethylphenyl)-1-[[4-(2,2- 1731
dimethylpropyl)phenyl]methyl]-l-(n-heptyl)urea
1-[[4-(2,2-Dimethylpropyl)phenyl]methyl]-1- 1421
(n-heptyl)-3-(2,4,6-trifluorophenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 1346
(4-chloro-2-methylphenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]- 2261
3-(4-chloro-2-methylphenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]- 2052
3-(2,4,6-trichlorophenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(n-butoxy)benzyl]- 3242
3-(2,4-difluorophenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 3039
(2,4-difluorophenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 1337
(2,4,6-trichlorophenyl)urea
1-(5,5-Dime~hylhexyl)-1-[4-(n-butyl)benzyl]-3- 3442
(4-chloro-2-methylphenyl)urea
(5~5-Dimethylhexyl)-l-[4-(n-butyl)benzyl]-3- 5~59
(2,4-difluorophenyl)urea _
.

--10--
TALE II (continued)
Compound LO SO
1-(5,5-Dimethylhexyl)-1-[4-(n-butyl)benzyl~-3- 32 45
(2,4,6-trichlorophenyl)urea
1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 60 50
(4-chloro-2-methylphenyl)urea
1-(3,3-Dimethylbutyl)-l-benzyl-3-(2,4-di- 70 71
fluorophenyl)urea
I 1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 69 43
(2,4-difluorophenyl)urea
1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 70 85
(4-tri~luoromethylphenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 19 35
propyl)benzyl]-3-(2,4-difluorophenyl)urea
. 1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 20 51
propyl)benzyl]-3-(4-chloro-2-methylphenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 15 32
propyl)benzyl]-3-(2,4,6-trichlorophenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(n-butyl)benzyl]-3- 12 28
(4-chloro-2,6-dimethylphenyl)urea
1-(3,3-Dimethylbutyl)-1-(4-chlorobenzyl)-3- 25 46
(4-chloro-2,6-dimethylphenyl)urea
1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 11 31
propyl)benzyl]-3-(4-chloro-2,6-dimethyl.-
phenyl)urea
1-(3,3-Dimethylbutyl)-l-benzyl-3-(4-chloro-2- 51 64
methylphenyl)urea
1-(3,3-Dimethylbutyl)-l-(benzyl)-3-(4-chloro- ¦ 30 55
35 2,5-dimethylphenyl)urea
1-(3,3-Dimethylbutyl)~ 4-(n-butyl)benzyl]-3- 12 28
(4-chloro-2,5-dimethylphenyl)urea _

I
TABLE II (continued)
Compound LO
1-(3,3-Dimethylbutyl)-1-[4-(2,2-dimethyl- 15 29
propyl)benzyl]-3-(4-chloro-2,5-dimethyl-
phenyl)urea
1-[(4-Butylphenyl)methyl]-1-[3,3-dimethyl- 28 24
butyl]-3-[2,4,6-trifluorophenyl]urea
l-Benzyl-1-[3,3-dimethylbutyl~-3-[2,4,6-tri- 77 57
fluorophenyl]urea
1-[3,3-Dimethylbutyl]-1-[4-(2,2-dimethyl- 17 19
propyl)phenyl]-3-[2,4,6-trifluorophenyl]urea
1-[(4-Isopropylphenyl)methyl]-1-(3-methyl- 37
butyl)-3-(2,4-difluorophenyl)urea
1-[(4-Isopropylphenyl)methyl]-1-(3-methyl- 23
butyl)-3-(4-chloro-2,6-dimethyiphenyl)urea
1-[(4-Isopropylphenyl)methyl]-1-(3-methyl- 35
butyl)-3-(2,4,6-trifluorophenyl)urea
When the compounds are employed for the above
utility, they may be combined with one or more forum-
ceutically acceptable carriers, e.g., solvents, delineates,
and the like, and may be administered orally in such forms
as tablets, capsules, dispersible powders, granules, or
suspensions containing, for example, from about 0.5 to 5%
of suspending agent, syrups containing, for example, prom
about 10 to 50% of sugar, and elixirs containing, for
example, from about 20 to 50% ethanol, and the like, or
parenterally in the form of sterile injectable solutions
or suspensions containing from about 0.5 to 5% suspending
agent in an isotonic medium. These pharmaceutical prepay
rations ma contain, for example, from about 0.5 up to
about 90% or the active ingredient in combination with the
carrier, more usually between 5 and 60~ by weight.
The anti atherosclerotic effective dosage of
active ingredient employed may vary depending on the par-

titular compound employed, the mode of administration, and the severity of the condition being treated. However, in
general, satisfactory results are obtained when the come
pounds of the invention are administered at a daily dosage
of from about 2 my to about 500 mg/kg of animal body
weight, preferably given in divided doses two to four
times a day, or in sustained release form. For most large
mammals, the total daily dosage is from about 100 my to
about 5,000 my, preferably from about 100 my to 2,000 my.
Dosage forms suitable for internal use comprise from about
25 to 500 my of the active compound in intimate admixture
with a solid or liquid pharmaceutically acceptable car-
nor. This dosage regimen may be adjusted to provide the
optimal therapeutic response. For example, several divided
doses may be administered daily or the dose may be proper-
tonally reduced as indicated by the exigencies of the therapeutic situation. A decided practical advantage is
that these active compounds may be administered orally as
well as by intravenous, intramuscular, or subcutaneous
routes if necessary. Solid carriers include starch, fag-
lose, dicalcium phosphate, microcrystalline cellulose sucrose and kaolin, while liquid carriers include sterile
water, polyethylene glycols, non-ionic surfactants, and
edible oils such as corn, peanut, and sesame oils, as are
appropriate to the nature of the active ingredient and the
particular form of administration desired. Adjutants
customarily employed in the preparation of pharmaceutical
compositions may be advantageously included, such as flay
vowing agents, coloring agents, preserving agents, and
antioxidant, e.g., vitamin En, ascorbic acid, BUT, and
30 BRA.
The preferred pharmaceutical compositions from
the stand-point of ease of preparation and administration
are solid compositions, particularly tablets and hard-
filled or liquid-filled capsules. Oral administration of
the compounds is preferred.
,,

- 13 -
These active compounds may also be administered
parenterally or intraperitoneally. Solutions or suspend
sons of these active compounds as a free base or forum-
ecologically acceptable salt can be prepared in water suit-
5 ably mixed with a surfactant such as hydroxypropylcellu-
lose. Dispersions can also be prepared in glycerol, liquid
polyethylene glycols, and mixtures thereof in oils. Under
ordinary conditions of storage and use, these preparations
contain a preservative to prevent the growth of micro-
10 organisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and
sterile powders for the extemporaneous preparation of
sterile injectable solutions or dispersions. In all cases,
the form must be sterile and must be fluid to the extent
that easy syringability exists. It must be stable under
the conditions of manufacture and storage and must be
preserved against the contaminating action of micro-
organisms such as bacteria and fungi. The carrier can be
a solvent or dispersion medium containing, for example,
water, ethanol, polyol (e.g., glycerol, propylene glycol,
and liquid polyethylene glycol), suitable mixtures thereof,
and vegetable oils.
The preparation and properties of the compounds
of this invention will be described in greater detail in
conjunction with the specific examples shown below.
Example 1
3-(2,4-Difluorophenyl)-l-[[4-(2,2-dimethylpropYl)
phenyl]methyl]-l-(n-heptyl)urea
pa A solution of 6.73 g of 4-(neopentyl)benzoic
acid and 13.0 ml of thinly chloride in 40 ml of dichloro-
methane was heated at reflex for 4 hours. The reaction
mixture was cooled and the solvent was evaporated in
vacua. The residue was dissolved in dichloromethane and
evaporated again. This step was repeated a second time
and 4-(neopentyl)benzoyl chloride was obtained as a brown
O i 1 .
I.

I
14
The preceding product was dissolved in 40 ml of
dichloromethane and added with stirring to a cold solution
of 4.04 g of Natalie amine and 9.8 ml of triethylamine in
60 ml of dichloromethane. The resulting mixture was
stirred at room temperature for 16 hours. The mixture was
diluted with water and two layers were separated. The
organic layer was washed in succession with two 30 ml
portions of 3 N hydrochloric acid. The solution was dried
over an hydrous magnesium sulfate and filtered. The lit-
irate was evaporated in vacua to yield 13.0 g of a Griswold. The solid was purified by preparative high pressure
liquid chromatography on silica gel using ethyl acetate:-
hexane (1:9) as the fluent. Several fractions were come
brined and evaporated in vacua to yield 8.0 g of 4-(2,2-
dimethylpropyl)-N-(n-heptyl)benzamide as a beige solid,
my 58-60C.
A mixture of 7.5 g (0.026 moles) of the pro-
ceding aside and 20 ml (0.052 moles) of Nitride T [sodium
dihydrobis(2-methoxyethoxy)aluminate (70~ solution in
Tulane)] in 80 ml of Tulane was reflexed for 4 hours,
then cooled to room temperature. The complex was deco-
posed by adding drops, 40 ml of 2.5 N sodium hydroxide
with stirring during 30 minutes. The organic layer was
separated and washed with brine, dried over an hydrous
magnesium sulfate and filtered. The filtrate was vapor-
axed to dryness in vacua to yield a yellow oil. Kugelrohr
distillation (125C/0.15 mm of mercury) gave 5.45 g (90%)
of4-(2,2-dimethylpropyl)-N-(n-heptyl)benzenemethanammine
as a colorless liquid.
To a solution of 1.10 g (0.004 moles) of the
preceding amine in 15 ml of hexane was added with stirring
a solution of 0.62 g (0.004 moles) of 2,4-difluorophenyl-
isocyanate in 15 ml of hexane. The resulting mixture was
stirred at room temperature for 16 hours. The solvent was
35 evaporated in vacua to yield a colorless oil. Kugelrohr
distillation (140-155C/0.15 mm of mercury) gave 1.44 g
(84%) of the desired product as a colorless oil.

Example 2
3-(4-Chloro-2,6-dimethYlPhenyl)-1-~4-(2,2-dimethyll-
propvl)phenyl]methyl]-l-(n-heptyl)urea
To a mixture of 300 g t2.48 moles) of Dow-
methyl aniline, 2.4 liters of dichloromethane and 24 ml of ethanol cooled at 5C in an ice bath was added an hydrous
hydrogen chloride gas over a one hour period maintaining
the reaction mixture temperature at 4-11C. Chlorine gas
was passed through the mixture for approximately 2 hours
10 while the temperature was maintained at 5-10C during
which time approximately 217 g of chlorine was introduced.
The reaction mixture was examined several times by thin
layer chromatography using 10:1 ethyl acetate:hexane as a
solvent system. Upon completion of the reaction, the
15 mixture was purged with argon gas, then allowed to stand
at room temperature for 16 hours.
The mixture was cooled to 2C and filtered. The
precipitate was washed with 250 ml of dichloromethane,
followed by 1.5 liters of ether, and then air dried to
20 yield 371 g of 4-chloro-2,6-dimethylbenzeneamine mender-
chloride.
To a suspension of the preceding monohydrochlor-
ire 371 g (1.93 moles) in 1.5 liters of deathly ether
maintained at 12-17C in an ice bath was added one liter
25 of 2 M sodium acetate solution over a 2~3 minute period
with vigorous stirring. The mixture was stirred for 30
minutes then allowed to stand to separate 2 layers. The
organic layer was washed in succession with one liter
volumes of water, saturated sodium bicarbonate, then water
again. The organic solution was dried over an hydrous
sodium sulfate and filtered. Evaporation gave 288 g of
solid. This solid was recrystallized from 800 ml of petrol
Lomb ether and gave 229 g of 4~chloro-2l6-dimethylbenzene-
amine as colorless crystals, my 47-50C.
To a cold solution of 2.47 g (0.0163 moles) of
the above amine and 2.4 ml (0.0189 moles) of N,N-dimethyl-
aniline in 80 ml of Tulane was added drops a solution
. ,

- 16 -
of 2.56 g (0.0163 moles) of phenylchloroformate in 20 ml
of Tulane. The resulting mixture was stirred at room
temperature for 90 minutes then diluted with water. The
organic layer was separated and washed with two 40 ml
portions of 3 N hydrochloric acid, then with brine. The
organic solution was dried over an hydrous magnesium sulfate
and filtered. The filtrate was evaporated in vacua to
yield a white solid. The solid was recrystallized from
ethyl acetate:hexane to yield 3.8 g of phenyl(4-chloro-
10 2,6-dimethylphenyl)carbamate as a white solid, my 158-
160C.
A mixture of 1.11 g (0.004 moles) of the pro-
ceding carbamate, 1.10 g (0.004 moles) of 4-(2,2-dimethyl-
propyl)-N-(n-heptyl)benzenemethanamine (prepared in
15 Example 1) and 30 ml of Tulane was reflexed for 2 hours.
The solution was cooled, washed with two 30 ml portions of
1 _ sodium hydroxide, then with brine. The solution was
dried over an hydrous magnesium sulfate and filtered. The
filtrate was evaporated _ vacua to yield an oil. Cudgel-
I roar distillation (145-155C/0.1 mm of mercury) gave
1.47 g of colorless oil which solidified on standing to
yield the product of the Example as a white solid, my 111-
113C.
Example 3
1-~[4-(2,2-Dimethylpropyl)phenyl]methyl]-l-(n-hepttwill)-
3-(2,4,6-trifluorophenyl)urea
To a cold solution of 5.3 g (0~0359 moles) of
2,4,6-trifluoroaniline and 5.6 ml (5.4 g, 0.044 moles) of
N,N-dimethylaniline in 70 ml of Tulane was added drops
a solution of 5.63 g (0.0359 moles) of phenol chloroform ate
30 in 20 ml of Tulane. The resulting mixture was stirred at
room temperature for 16 hours and gave a precipitate. The
mixture was diluted with ethyl acetate and water. The
organic layer was separated and washed with two 50 ml
portions of 3 N hydrochloric acid, then with two 50 ml
35 portions of brine. The solution was dried over an hydrous
magnesium sulfate and filtered. The filtrate was vapor-
.

I Ed
axed in vacua to yield a solid. The solid was triturated
with hexane, collected by filtration, washed with hexane
and dried to yield 8.38 g ~96~) of phenyl(2,4,6-trifluoro-
phenyl)carbamate as a white solid, my 127-128C.
A mixture of 0.97 g ~0.004 moles) of the pro-
ceding carbamate, 1.10 g (0.004 moles) of 4-(2,2-dimethyl-
propyl)-N-(n-heptyl)ben~enemethanamine (prepared in
Example 1) and 40 ml of Tulane was reflexed or 2 hours.
The resulting solution was cooled, washed with two 30 ml
10 portions of 1 N sodium hydroxide, then with brine. The
solution was dried over an hydrous magnesium sulfate, lit-
toned and evaporated in vacua and gave a light yellow oil.
Kugelrohr distillation (140-150C/0.08 mm of mercury) gave
1.5 g of colorless oil. A 900 my portion of this oil was
lo redistilled (140-150C/0.160 mm of mercury) to yield 500 my
of the product of the Example as a colorless oil.
The ureas shown in Table III were prepared using
the methods described in Examples 1-3.
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