AMIDINOUREA PROCESS AND PHARMACEUTICAL COMPOSITION

PROCEDE DE PREPARATION DE L'AMIDINOUREE ET COMPOSE PHARMACEUTIQUE LE CONTENANT

English Abstract

Abstract
An improved process for the preparation of an amidinourea
of the formula
< IMG >
wherein the improvement comprises the use of a ketone as the
reaction medium and the resulting amidinourea is obtained in
higher yield and greater purity. The amidinoureas prepared
according to the present invention are known anti-diarrheal
agents.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. In a process for the preparation of a compound of
Formula I:
< IMG >
comprising the reaction of an isocyanate of Formula II:
< IMG > II
with a guanidine of Formula III:
< IMG > I I I
said guanidine being prepared m situ by the treatment of the
salt of Formula IV
28

< IMG >
IV U
with aqueous base, wherein:
X, Y and Z are hydrogen, lower alkyl, lower alkoxy, cyano,
lower acyloxy, lower alkenyl, lower alkynyl, halo, lower
haloalkyl, lower haloalkoxy, amino, lower acyl, lower
carbamoyl, nitro, hydroxy, lower arylalkoxy or lower
alkylsulfonyl;
R1, R2 and R3 are each independently hydrogen,
lower alkyl, cycloalkyl or lower aralkyl; or R2 and R3
together with the nitrogen atom to which they are attached
form a 5, 6 or 7 membered ring which may include 0-2
additional heteroatoms of N, O or S;
provided that at least one of R1, R2 or R3 is other than
hydrogen;
the improvement comprising the use of a ketone as the reaction
medium.
2. In a process according to Claim 1, the improvement
comprising the use of acetone as the reaction medium.
3. In a process according to Claim 2, the improvement
comprising removing the reaction product of Formula I from the
reaction mixture by filtration.
29

4. In a process according to Claim 3, wherein the
filtered reaction product is 1-(2,6-dimethylphenyl)-3-methyl
amidinourea.
5. A process for the preparation of a compound of
Formula V:
< IMG > V
wherein a compound of Formula VI:
< IMG > VI
is added to a reaction solution prepared by mixing a compound
of Formula VII:
< IMG > VII

and a neutralizing quantity of aqueous base in a ketone
solvent;
wherein X and Y are hydrogen, lower alkyl, halo, lower alkoxy,
lower haloalkyl or lower haloalkoxy; and R2 and R3 are
hydrogen, lower alkyl, cycloalkyl, lower aralkyl or lower
alkoxy; provided that at least one of R2 and R3 is other than
hydrogen.
6. The process according to Claim 5, wherein the
compound of Formula I is 1-(2,6-dimethylphenyl)-3-
methylamidino-urea.
31

Description

lZ30886
AMIDINOUREA PROCESS AND PHAR~CEl~TICAL COMPOSITION
Field of the Invention
This invention relates to amidinoureas, improved
processes for their preparation, and pharmaceutical
compositions.
Reported Developments
The amidinoureas prepared by the present invention
have been reported to be effective anti-diarrheal agents.
In US. Patent No. 4,060,635, amidinourea compounds and a
method for the treatment of diarrhea by administering
these compounds are described. Methods by which these
compounds have been prepared include the following
general syntheses.
Condensation of a substituted phenol isocyanate
prepared from an aniline and phosgene in the customary
manner) with guanidine results in a l-substituted phenol-
3-amidinourea as shown in Scheme I below. It it convent
tent to carry cut the reaction by preparing the issues-
:: :
1 . . .
....... . ...

-- Z30886
--2--
Nate in the reaction media and then forming guanidine in
situ by hydrolyzing guanidine carbonate with base. Con-
sensation of the isocyanate takes place when the guano-
dine forms and the amidinourea compound results.
R3 R2
R4 - NH2 COOK R4 _ NO
R6 R5 6
A
NH NH
~NH2 C NH2)2 H2CO3 + KOCH NH2-C-NH2
R3 R2
O NH
A B > R4 NH-C-NH-C-NH2
R5 R6
SCHEME I
The amidinoureas may also be prepared by
degradation of the corresponding biguanide as shown in
Scheme II below. When a l-substituted phenylbiguanide
compound is hydrolyzed in acid at raised temperature,
then the resultant product is l-substituted
phenyl-3-amidinourea.
I ,
:.. . , . . . . . . . ...

~Z3~886
--3--
4~N-C-N-C-N Lowe nil R4 N-C-N-C-~
R5 R6 R5 R6
SCHEME II
: When it is desired to have Run substitution, the
starting material of course will by an aniline having
N-al~yl substitution. Reaction with phosgene results in
the carbamoyl chloride which is then reacted with the
guanidine to prepare the amidinourea as shown in Scheme
III below.
R 3 R 2 Jo _/ O
/ _ NH + COOK R4 Run
R5 R6 R5 R6
.,, C
NO R ' NO R '
(NH2-C-N ) 2 }KIWI + KOCH > NH2_c_N
D
'
;
... . . . . . ...
,:.... ... ... . . .

lZ30886
--4--
R3 R2
C + D R 4 -C -NH -C -N
R5 R6
SCHEME III
The reported processes for the preparation of these
compounds are plagued by the presence of side products
which require tedious and expensive additional purification
steps.
It has been found surprisingly that a modification
of the reported process results in the formation of the
desired products as a crystalline precipitate which may be
easily and inexpensively separated from the reaction.
It has also been reported that the amidinourea
compounds may be formulated into anti-diarrheal
compositions. However, it has been found that liquid
compositions including the amidinourea compounds degrade
over prolonged periods of time, thereby limiting their use.
Summary of the Invention
This invention relates to an improved process for
the preparation of a compound ox Formula I
O Nil
N-c-NH-c-NR2R3 Formula I
/'--\ H
.
'
,

lZ30886
--5--
comprising the reaction of an isocyanate of Formula II
NO Formula II
<
Z Y
with a guanidine of Formula III
Nil
~-C-NR2R3 Formula III
said guanidine being prepared in situ by the treatment of
the salt of Formula IV
Nil
(H2N-C-NR2R3)2 H2S4 Formula IV
with aqueous base, wherein:
X, Y and Z are hydrogen, alkyd, alkoxy, cyan,
; acyloxy, alkenyl, alkynyl, halo, haloalkyl, haloalkoxy,
amino, azalea, carbamoyl, vitro, hydroxy, arylalkoxy or
alk~lsulfonyl;
Al, R2 and R3 are each independently hydrogen,
alkyd, cycloalkyl or aralkyl;
or R2 and R3 together with the nitrogen atom to
which they are attached form a S, 6, or 7 member Ed ring
which may include 0-2 additional heteroatoms of N, O or S;
provided that at least one of Al R2 or R3 is other
than hydrogen;
the improvement comprising the use of a kitten as
the reaction medium, with a lower alkyd kitten being
preferred.
Jo This invention also relates to a method for the
preparation of a liquid pharmaceutical composition
comprising a compound of Formula I.
.
.. . .. . . .
.. ,, .. . , , . , . . . .
.. .. ... . .

12:~08~36
Detailed Description of the Invention
The process according to this invention comprises
the use of a kitten as the reaction medium. It has been
found that the use of such reaction medium results in
formation of a crystalline precipitate of an amidinourea of
Formula I, which can be easily separated and purified for
use as a pharmaceutical product. The most desired kitten
is acetone, although other lower alkyd kittens such as
methyl ethyl kitten and ethyl ethyl kitten may be utilized in
the reaction process.
The nomenclature applied to the compounds of this
invention is as follows.
NO CON
\' (I
urea amidino
The term "lo reralkyl" refers to an alkyd hydrocar-
bun group of from 1 to 5 carbon atoms which may be
straight chained or branched, while "alkyd" refers to an
alkyd hydrocarbon group which may have as many as ten
carbon atoms.
The term "cycloalkyl" refers to a cycloalkyl group
- having 3-7 carbon atoms.
The "loweralkoxy" radical signifies an alkoxy
group containing from 1 to about 5 carbon atoms which may
be straight chained or branched.
The preferred "aureole" group is phenol.
The preferred "aralkyl" groups are bouncily and pen-
ethyl.
.. . - -
.

"' 1230886
The preferred "halo loweralkyl" group is trifler-
methyl.
The preferred "halo loweralkoxy" group is in-
fluoromethoxy.
The most preferred process is a process for the
preparation of a compound of Formula V
X
o NH
-N-c-NH-c-NR2R3
Y Formula V
wherein a compound of Formula VI
NO Formula VI
,.
is added to a reaction solution prepared by mixing a
compound of Formula VII
NH
(NH2-C-NR2R3)2 H2S4 Formula VII
and a neutralizing quantity of aqueous base in a kitten
solvent;
wherein X and Y are hydrogen, alkyd, halo, alkoxy,
haloalkyl or haloalkoxy;
and R2 and R3 are hydrogen, alkyd, cycloalkyl,
aralkyl or alkoxy;
provided that at least one of R2 and R3 is ether
than hydrogen.
. .

~Z~0886
--8
The following is a detailed example which shows
the process according to the present invention This is
to be construed as an illustration of this process and
not as a limitation thereof.
., "I
. .
... .. ,_. . .
7 7

~Z308~36
EXAMPLE
PREPARATION OF 1-(2,6-
DIMETHYLPHENYL)-3-METHYL~MIDINOUREA
736 g ox 50% w/w aqueous sodium hydroxide are
added to 1,123.6 g of methylguanidine sulfate suspended
in 5.2 1 of acetone (reagent grade). the mixture is
stirred for 3 his. To the rapidly stirred suspension
there is added drops over a period of 4 hours a
mixture of 1,176.0 g of 2,6-dimethylphenylisocyanate and
350 ml of acetone. During the addition a cold water bath
is used to maintain the temperature at approximately 25C.
After the addition is complete the reaction mixture is
stirred overnight.
The mixture is chilled to 10C in an ice bath and
the solid collected by filtration. The filter cake is
washed with 2 1 of cold acetone. The solid is suspended
in 4 1 of water and stirred for 30 minutes.
The suspension is filtered and the solid washed on
the filter with 4 1 of water. The solid is suspended in
2.5 1 of water at 60C. 670 ml of concentrated
hydrochloric acid are added to the suspension while
stirring. after dissolution is complete 360 g of sodium
chloride ~USP--crystal) is added in portions. Using a
water bath the mixture is cooled to 18C over a period of
1 hr. The suspension is filtered and the solid washed
with 1 1 of a cold I solution of sodium chloride in 0.36
molar hydrochloric acid. The material is partially dried
on the filter.
An Alcott ~100 9) of the filter cake is removed
to prepare a final wash solution. This Alcott is
dissolved in 800 ml of water, the solution is filtered
j and diluted to 1 1. The solution is stored at 5~C until
the bulk of the material is processed as follows:
i
,, . . . . .. . .. ...
. . .

10 1z30886
The remainder of the filter cake is dissolved in
2.5 1 of water (60C) and the solution is filtered. 250
ml of concentrated hydrochloric acid are added to the
stirred filtrate at 35C which induces crystallization.
218 g of sodium chloride (USP--crystal) are added to the
stirred suspension in portions. The mixture is stirred
for 1 hr. while a cold water bath is used to reduce the
temperature to 18C. The suspension is filtered and the
solid washed with 2 1 of a cold 4% solution of sodium
chloride in 0.36 molar hydrochloric acid and then with
the 1 1 of cold wash solution prepared above. The solid
is left on the filter until no additional filtrate can be
collected. The filter cake is spread on a tray and dried
at 50C in a mechanical convection oven for 24 his. This
yields 1480.3 g of 1-(2,6-dimethylphenyl)-3-methyl amid-
Norway hydrochloride, MOP. 200-203C.
The dried product is examined by TLC (1:1, SCHICK:
EtOCHO, Silica). The presence of mobile materials
~Rf>0.1) requires that the product be washed with methyl
tone chloride as follows:
1-~2,6-dimethylphenyl)-3-methylamidinourea hydra-
chloride ~1,267 g, greater than 0.1% N,N"-bis Dow-
methylphenylcarbamoyl)-N'-methylguanidine hydrochlclride)
is suspended in 2,534 ml of ethylene chloride at RUT and
stirred for 2 his. The suspension is filtered and the
filter cake is washed with 2 1 of ethylene chloride.
The solid is air dried to obtain 1,194 g ~94.2%) of
1-~2,6-dimethylphenyl)-3-methylamidinourea hydrochloride,
MOP. 200-203C. TLC ~1:1, CHC13:EtOCHO, Silica) shows no
mobile materials. The product obtained by this procedure
can be precipitated further from aqueous hydrochloric
acid - sodium chloride if desired.
: - - .
.,

~Z30886
--11--
When 2,6-dimethylphenyl isocyanate is replaced by
one of the isocyanates of Table I below, then the core-
sponging product of Table II is prepared when reacted
with methylguanidine.
TABLE I
2-methyl-6-chlorophenylisocyanate
2-methyl-6-fluorophenylisocyanate
2-methyl-6-bromophenylisocyanate
2-methyl-6-iodophenylisocyanate
2-methyl-6-methoxyphenylisocyanate
2-methyl-6-ethoxyphenylisocyanate
2-methyl-6-ethylphenylisocyanate
2-methyl-6-propylphenylisocyanate
2-methyl-6-i-propylphenylisocyanate
2-methyl-6-butylphenylisocyanate
2-methyl-6-cyanophenylisocyanate
2-methyl-6-trifluoromethylphenylisocyanate
2-methyl-6-nitrophenylisocyanate
2-methyl-6-methylsulfonylphenylisocyanate
2-ethyl-6-chlorophenylisocyanate
2-ethyl-6-fluorophenylisocyanate
2-ethyl-6-bromophenylisocyanate
2-ethyl-6-methoxyphenylisocyanate
2-ethyl-6-ethoxyphenylisocyanate
2,6-dlethylphenylisocyanate
2-ethyl-6 propylphenylisocyanate
2-ethyl-6-trifluoromethylphenylisocyanate
2-propyl-6-chlorophenylisocyanate
2-propyl-6-fluorophenylisocyanate
2-propyl-6-bromophenylisocyanate
... ...
- ` I, ' ` ` ' :

~Z3088~
--12-- -
2-propyl-6-methoxyphenylisocyanate
2-propyl-6-ethoxyphenylisocyanate
2,6-dipropylphenylisocyanate
2-i-propyl-6-chlorophenylisocyanate
2-i-propyl-6-fluorophenylisocyanate
2-i-propyl-6-methoxyphenylisocyanate
2-butyl-6-chlorophenylisocyanate
2,6-dichlorophenylisocyanate
2-chloro-6-fluorophenylisocyanate
2,6-di~luorophenylisocyanate
2,4,6-trimethylphenylisocyanate
2,4-dimethyl-6-ethylphenylisocyanate
2,4-dimethyl-6-chlorophenylisocyanate
2,4-dimethyl-6-bromophenylisocyanate
2,4-dimethyl-6-fluorophenylisocyanate
2,4-dimethyl-6-trifluorophenylisocyanate
2,4-dimethyl-6-nitrophenylisocyanate
2,4-dimethyl-6-methoxyphenylisocyanate
2,6-dimethyl-4-ethylphenylisocyanate
2,6-dimethyl-4-chlorophenylisocyanate
2,6-dimethyl-4-bromophenylisocyanate
2,6-dimethyl-4-fluorophenylisocyanate
2,6-dimethyl-4-methoxyphenylisocyanate
2-methyl-4,6-dichlorophenylisocyanate
2-methyl-4,6-difluorophenylisocyanate.
2-methyl-4-fluoro-6-bromophenylisocyanate
2-methyl-4-fluoro-6-chlorophenylisocyanate
2-methyl-4-bromo-6-chlorophenylisocyanate
2-methyl-4-chloro-6-fluorophenylisocyanate
2-methyl-4-chloro-6-bromophenylisocyanate
2-methyl-4-methoxy-6-chlorophenylisocyanate
2-methyl-4-ethyl-6-chlorophenylisocyanate
2-methyl-4-chloro-6-trifluoromethylphenylisocyanatlo
.

lZ30886
--13--
2-methyl-4-trifluormethyl-6-chlorophenylisocyanatee
2-ethyl-4,6-dichlorophenylisocyanate
2-ethyl-4,6-difluorophenylisocyanate
2-ethyl-4-fluoro-6-bromophenylisocyanate .
2-ethyl-4-fluoro-6-chlorophenylisocyanate
2-ethyl-4-bromo-6-chlorophenylisocyanate
2-ethyl-4-chlo~o-6-fluorophenylisocyanate
2-ethyl-4-chloro-6-bromophenylisocyanate
2,6-diethyl-4-chlorophenylisocyanate
2,6-diethyl-4-bromophenylisocyanate
2,6-diethyl-4-fluorophenylisocyanate
2,4-dimethyl-6-nitrophenylisocyanate
TABLE II
l-t2-methyl-6-chlorophenyl)-3-methylamidinourea
1-~2-methyl-6-fluorophenyl)-3-methylamidinourea
1-~2-methyl-6-bromophenyl)-3-methylamidinourea
1-~2-methyl-6-iodophenyl)-3-methylamidinourea
2-methyl-6-methoxyphenyl)-3-methylamidinourea
-methyl-6-ethoxyphenyl)-3-methylamidinourea
l-t2-methyl-6-ethylphenyl)-3-methylamidinourea
1-~2-methyl-6-propylphenyl)-3-methylamidinourea
1-~2-methyl-6-i-propylphenyl)-3-methylamidinourea
1-~2-methyl-6-butylphenyl)-3-methylamidin~urea
1-(2-methyl-6-cyanophenyl)-3-methylamidinourea
2-methyl-6-trifluoromethylphenyl)-3-methylamidin~uurea
1-~2-methyl-6-nitrophenyl)-3-methylamidinourea
2-methyl-6-methylsulfonylphenyl)-3-methylamidinourfee
1-~2-ethyl-6-chlorophenyl)-3-methylamidinourea
1-(2-ethyl-6-fluorophenyl)-3-methylamidinourea
, .
.... . .. .. .. . . - -
. ....... . .

~230886
-14-
1-(2-ethyl-6-bromophenyl~-3-methylamidinourea
1-(2-ethyl-6-methoxyphenyl)-3-methylamidinourea
1-(2-ethyl-6-ethoxyphenyl)-3-methylamidinourea
1-~2,6-diethylphenyl)-3-methylamidinourea
1-~2-ethyl-6-propylphenyl)-3-methylamidinourea
l-t2-ethyl-6-trifluoromethylphenyl)-3-methylamidinNorway
1-(2-propyl-6-chlorophenyl)-3-methylamidinourea
1-(2-propyl-6-fluorophenyl)-3-methylamidinourea
1-(2-propyl-6-bromophenyl)-3-methylamidinourea
1-~2-propyl-6-methoxyphenyl)-3-methylamidinourea
1-(2-propyl-6-ethoxyphenyl)-3-methylamidinourea
1-(2,6-dipropylphenyl)-3-methylamid.inourea
1-(2-i-propyl-6-chlorophenyl)-3-methylamidinourea
1-(2-i-propyl-6-fluorophenyl)-3-methylamidinourea
1-(2-i-propyl-6-methoxyphenyl)-3-methylamidinoureaa
1-(2-butyl-6-chlorophenyl)-3-methylamidinourea
1-(2,6-dichlorophenyl)-3-methylamidinourea
1-(2-chloro-6-fluorophenyl)-3-methylamidinourea
1-(2,6-difluorophenyl)-3-methylamidinourea
1-~2,4,6-trimethylphenyl)-3-methylamidinourea
1-(2,4-dimethyl-6-ethylphenyl)-3-methylamidinoureaa
1-(2,4-dimethyl-6-chlorophenyl~-3-methylamidinoureeta
1-(2,4-dimethyl-6-bromophenyl)-3-methylamidinoureaa
1-(2,4-dimethyl-6-fluorophenyl)-3-methylamidinoureeta
1-(2,4-dimethyl-6-trifluorophenyl)-3-methylamidinourea
1-(2,4-dimethyl-6-nitrophenyl)-3-methylamidinoureaa
1-(2,4-dimethyl-6-methoxyphenyl)-3-methylamidinourfee
1-(2,6-dimethyl-4-ethylphenyl)-3-methylamidinoureaa
1-(2,6-dimethyl-4-chlorophenyl)-3-methylamidinoureeta
1-(2,6-dimethyl-4-bromophenyl)-3-methylamidinoureaa
1-(2,6-dimethyl-4-fluorophenyl)-3~methylamidinoureeta
1-~2,6-dimethyl-4-methoxyphenyl)-3-methylamidinourfee
1-~2-methyl-4,6-dichlorophenyl)-3-methylamidinoureeta
.
.
.
.. . . .
Jo . ... ,
.... . . .

~230886
--15--
1-(2-methyl-4,6-difluorophenyl)-3-methylamidinoureeta
1-(2-methyl-4-fluoro-6-bromophenyl)-3-methylamidinNorway
1-(2-methyl-4-fluoro-6-chlorophenyl)-3-methylamidiinure
1-(2-methyl-4-bromo-6-chlorophenyl)-3-methylamidinNorway
1-(2-methyl-4-chloro-6-fluorophenyl)-3-methylamidiinure
l-(2-methyl-4-chloro-6-bromophenyl)-3-methylamidinNorway
l-(2-methyl-4-methoxy-6-chlorophenyl)-3-methylamiddowner
1-~2-methyl-4-ethyl-6-chlorophenyl)-3-methylamidinNorway
1-~2-methyl-4-chloro-6-trifluoromethylphenyl)-3-meethyl-
amidinourea
1-~2-methyl-4-trifluoromethyl-6-chlorophenyl)-3-meethyl-
amidinourea
1-~2-ethyl-4,6-dichlorophenyl)-3-methylamidinoureaa
1-(2-ethyl-4,6-difluorophenyl)-3-methylamidinoureaa
1-(2-ethyl-4-fluoro-6-bromophenyl)-3-methylamidinourea
l-(2-ethyl-4-fluoro-6-chlorophenyl)-3-methylamidinNorway
1-(2-ethyl-4-bromo-6-chlorophenyl)-3-methylamidinourea
1-~2-ethyl-4-chloro-6-fluorophenyl)-3-methylamidinNorway
1-(2-ethyl-4-chloro-6-bromophenyl)-3-methylamidinourea
l-~2,6-diethyl-4-chlorophenyl)-3-methylamidinoureaa
l-~2,6-diethyl-4-bromophenyl)-3-methylamidinourea
1-(2,6-diethyl-4-fluorophenyl)-3-methylamidinoureaa
l-t2,4-dimethyl-6-nitrophenyl)-3-methylamidinoureaa
The isocyanates of Table I may be prepared as
described above from the corresponding aniline which are
either known, or may be prepared by known techniques.
Thus, chlorination or bromination of an acetanilide or
aniline may be carried out in acetic acid, or in the
presence of a small amount of iodine dissolved in an
inert solvent such as carbon tetrachloride. A solution
of chlorine or bromide is then added while the
temperature it held near 0C. Iodination may also be
carried out by known methods using iodine monochloride
clue I).
O' I ' ' ' '
I.
. .
.. ..... Jo --
to

~Z30886
--16--
Alkylation may be carried out on an acetanilide
using an alkyd halide and aluminum chloride under
Friedel-Crafts conditions to obtain desired alkyd
substitution.
Nitration may be carried out using fuming nitric
acid at about 0C.
A vitro compound may be hydrogenated to the
corresponding amine which may then be diazotized and
heated in an alcohol medium to form the alkoxy compound.
n amino compound may also be diazotized to the
diazonium fluoroborate which is then thermally decomposed
to the flyer compound.
Diazotization followed by a Sand Meyer type
reaction may yield the broom, sheller or idea compound.
When an amino compound is diazotized followed by
reaction with potassium ethylxanthate and then
hydrolyzed, the Marquette compound results. This in turn
may be alkylated to the alkylthio group which is then
oxidized to the corresponding alkylsulfonyl substituent.
A sheller, broom or idea compound may also be
reacted with trifluoromethyliodide and copper powder at
about 150C in ~imethylformamide to obtain a
trifluoromethyl compound [Tetrahedron Letters: 47,4095
~1959)]. A halo compound may also be reacted with
cuprous methanesulfinate in quinoline at about 150C to
obtain a methylsulfonyl compound.
When it it desired that the final product contain
a hydroxy group, it is preferred that the starting
aniline contain the corresponding acyloxy or aralkyloxy
groups. These may be prepared in the usual fashion by
assaulting the starting hydroxy aniline compound with an
azalea halide or android in the presence of a tertiary
amine or aralkylating with an aralkyl halide or sulfate.
Of course the amine function would be protected in the
;:
, .
. .

lZ30886
-17-
customary manner. Hydrogenation to the desired hydroxy
compound may then take place after the formation of the
amidinourea. This may be accomplished with a metal
catalyst (Pd/C, Pi etc.) in a polar medium (ethanol, THY,
etc.), sodium in liquid ammonia, etc. Thus, for example,
the 3,4-dihydroxy amidinourea compound may be prepared
from the corresponding 3,4-dibenzyloxyaniline. The
hydroxy compounds may also be prepared by hydrolysis of
the azalea or alkoxy compounds with acid.
Reactions may also be carried out at other stages
of synthesis depending on the substituents present and
the substituents desired, and various combinations of the
foregoing reactions will be determined by one skilled in
the art in order that the desired product results. Thus,
a phenylamidinourea may be halogenated or nitrated as
above, etc.
The compounds of Formula I are useful
anti-diarrheal agents. Various tests can be carried out
in animal models to show the ability of the compounds of
Formula I to exhibit reactions that can be correlated
with anti-diarrheal activity in humans. The following
tests show the ability of the compounds of this invention
to inhibit diarrhea in animals and are known to correlate
well with anti-diarrheal activity in humans. These are
considered to be standard tests used to determine
anti-diarrhea properties. This correlation can be shown
by the activities of compounds known to be clinically
active. In view of the results of these tests, the
amidinoureas of this invention can be considered to be
anti-diarrheal agents.
1. Focal output in rat.
Rev: - Bass, P., Kennedy, JOY. and Witty, JON.:
Measurement of local output in rats. Am. J. Dig. Disk
10: 925-928, 1972.
:
. .
: ' .
... . . , .. . .
,. . . - - ,

1230886
-18-
2. Castor oil test in mice.
Rev: - Niemegeers, CUE Lenaerts, EM and
Janssen, PUDGY. Difenoxine, a potent, orally active and
safe anti-diarrheal agent in rats. Arzneim-Forscth (Drug
Ryes.) 22, 516-1518, 1972.
The compounds of Formula I may be administered
orally, parenterally or rectally. Administration by the
oral route is preferred. Orally, these compounds may be
administered in tablets, hard or soft capsules, aqueous
or oily suspensions, dispersible powders or granules,
emulsions, syrups or elixirs. The optimum dosage, of
course, will depend on the particular compound being used
and the type and severity of the condition being treated.
In any specific case the appropriate dosage selected will
further depend on factors of the patient which may
influence response to the drug; for example, general
health, age, weight, etc. of the subject being treated.
Although the optimum quantities of the compounds
of this invention to be used as anti-diarrheal agents
will depend on the compound employed and the particular
type of disease condition treated, oral dose levels of
preferred compounds when administered to a mammal in
dosages of 0.01 to 500 milligrams per kilogram of body
weight per day are particularly useful. The preferred
range is 0.05 to 200 mg/kg. Comparative dosages may be
used in parenteral or rectal administration.
The composition may contain such selected
excipients as inert delineates such as calcium carbonate,
lactose, etc.;granulating and disintegrating agents such
as maize starch, alginic acid, etc.; lubricating agents
such as magnesium Stewart, etc.; binding agents such as
starch gelatin, etc.; suspending agents such as methyl
cellulose, vegetable oil, etc.; dispersing agents such as
lecithin, etc.; thickening agents such as beeswax, hard
..... . Jo . . ........ .
, . .. ... . . . .
.. I_ Jo .... I.. _ .. _.. _ ._ . .... _._._ __ _ .. _ _ _ Jo .. _~__._.. ,____.__ _ _ _. __ _.. _ . . _ . ._ _, ~___~_ _ .. _ .. ...
_

lZ3088~
Jo
--19--
paraffin, etc.; emulsifying agents such as
naturally-occurring gums, etch; non-irritating excipients
such as cocoa butter, polyethylene glycols, etc.; and the
like. Further, in formulating these compounds for every
100 parts by weight of the composition, there may be
present between 5 and 95 parts by weight of the active
ingredient. The dosage unit form will generally contain
between 0.1 my and about 500 my of the active ingredients
of this invention. The preferred unit dose is between 1
my and about 50 my. The compositions may be taken 1-8
times daily depending on the dosage unit required.
Further the active amidinourea may be administered
alone or in admixture with other agents having the same
or different pharmacological properties.
The debilitating effects of diarrhea result
partially from electrolyte imbalance in the patient, so
that it is recommended that a solvent or delineate forming
the carrier of the liquid pharmaceutical compositions,
whether designed for injection or oral administration,
should incorporate electrolyte balance. The precise
composition of the electrolyte replenisher incorporated
in the liquid compositions will depend on the age and the
genera health and condition of the patient, but in many
cases it is appropriate to use a commercially available
electrolyte replenisher. These generally include sodium
chloride alone or in combination with potassium salts,
calcium salts, lactates or bicarbonates, and typical
examples are Ringer's Solution, Doris Solution for
injection), Ringer's Injection and Lactated Ringers
Injection. These and other examples of commercially
available electrolyte replenishers may be found in the
"Pharmacopoeia of the United States.
A particularly preferred liquid anti-diarrheal
composition is one in which the couriers a solvent or
... . .. I. . ,

~230886
--20--
delineate comprising a saline solution of substantially
isotonic concentration.
Liquid compositions for oral use are preferably
aqueous, so as to permit the inclusion of an electrolyte.
Ingredients suitable for incorporation in the carrier of
an aqueous liquid suspension are for example suspending
agents such as sodium carboxymethylcellulose,
methylcelluiose, hydroxypropylmethylcellulose, sodium
allegiant, polyv;nylpyrrolidine, gum tragacanth and gum
r Acadia; dispersing or wetting agents such as a naturally
occurring phosphatide, for example lecithin, condensation
products of an alkaline oxide with fatty acids, for
example polyoxyethylene Stewart, condensation products
of ethylene oxide with long-chain aliphatic alcohols, for
example heptadecaethyleneoxyethanol, condensation
products of ethylene oxide with partial esters derived
from fatty acids and a hexitol, for example
polyoxyethylene sorbitol moonlit or condensation
products of ethylene oxide with partial esters derived
from fatty acids and hexitol androids, for example
polyoxyethylene sorbitan moonlit. Aqueous
suspensions may also in particular contain one or more
preservatives, for example ethyl- or n-propyl-p-hydroxy-
bonniest, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents,
such as sucrose.
Oily suspensions may be formulated by suspending
the amidinourea in a vegetable oil, for example arachis
oil, olive oil, sesame oil or coconut oil, or in a
mineral oil such as liquid paraffin. The oily
suspensions may contain a thickening agent, for example
beeswax, hard paraffin or Seattle alcohol. Sweetening
agents, such as those set forth above, and flavourinq
agents may here also be added to provide a palatable oral
.
... . . . ... .

- 12:~0886
--21--
preparation. These compositions may also be preserved by
the addition of an anti-oxidant such as ascorbic acid.
Where the liquid compositions are in the form of
oil-in-water emulsions, the oily phase may be a vegetable
oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin, or mixtures of these.
The emulsions may also contain sweetening and flavoring
agents.
Syrups and elixirs in particular may be formulated
with sweetening agents, for example glycerol, sorbitol or
sucrose. Such formulations may also contain a demulcent,
a preservative, and flavoring and coloring agents.
The liquid compositions, as herei~before
described, may be formulated for injection. For example
they may take the form of a sterile injectable aqueous
suspension formulated according to the known art and
containing those suitable dispersing or wetting agents
and suspending agents which have been mentioned above.
An injectable composition is preferably a sterile
; injectable solution or suspension of the amidinourea in a
parenterally acceptable delineate or solvent, for example a
sterile aqueous solution buffered to a pi of 4.0 to 7.0
and made isotonic with sodium chloride.
It has been found that the liquid compositions
including an anti-diarrheal composition of Formula I
degrade over a period of time. Accordingly, the present
invention relates to a method of providing a stable
dosage form for preparation into a liquid form
:
::

~3088
--22--
immediately prior to its use. More particularly the
present invention is a method for the preparation of a
liquid pharmaceutical composition suitable for oral
administration or parenteral injection, said composition
comprising a pharmaceutically acceptable liquid vehicle
and from 1 to 25 my of a compound of the Formula I
.
X
Jo 0, I
N-C-NH-C-NR2R3 Formula I
H
z y
wherein X, Y and Z are hydrogen, alkyd, alkoxy,
cyan, acyloxy, alkenyl, alkynyl, halo, haloalkyl,
haloalkoxy, amino, azalea, carbamoyl, vitro, hydroxy,
arylalkoxy or alkylsulfonyl;
Al, R2 and R3 are each independently hydrogen,
alkyd, cycloalkyl or aralkyl;
or R2 and R3 together with the nitrogen atoms to
which they are attached form a 5, 6, or 7 member Ed ring
which may include 0-2 additional heteroatoms of N, O or
S;
provided that at least one of Al, R2 or R3 is
other than hydrogen;
which method comprises combining the compound of
Formula I with the vehicle by the steps of:
a) dissolving an effective anti-diarrheal dosage
amount of a salt of said compound in a liquid vehicle
comprising either sterile water or a sterile electrolyte
replenisher solution;
by sterilizing the solution by means of
micro filtration;
, .
,
.

` ~230886
-23-
(c) freeze-drying the sterilized solution to form
a dissected composition; and
(d) preparing the liquid composition for
administration by dissolving the dissected composition
in a dosage volume of liquid vehicle comprising either
sterile water or a sterile electrolyte replenisher
solution;
the said dosage amount and volume being for either
single or multiple doses, and in the latter case a
preservative being added in step (a) or step (d).
The following formulations are given in
illustration of the compositions prepared from the `
compounds of Formula I.
Formulation 1.
An aqueous solution for parenteral administration
is prepared as follows:
50 g of 1-(2,6-dimethylphenyl)-3-methylamidinourea
hydrochloride and 5 g of propel p-hydroxybenzoate are
dissolved and diluted to 5,000 cm3 with twice-distilled
water after the addition of modified Sorensen buffer soul-
lion in an amount sufficient to adjust the pi value to a
pi of 6Ø Sodium chloride is dissolved therein in an
amount sufficient to render the resulting solution is-
tonic. The resulting solution is passed through a beater-
illogical filter, the filtrate distributed to 1000 stern
tie ampules, the contents of each ampule is freeze-
dried and sealed for later use. Reconstitution with 5
cm3 of sterile water results in a parenterally applicable
solution which contains 50 my of 1-(2,6-dimethylphenyl)-
3-methylamidinourea hydrochloride in 5 cm3 of the
solution.
:

~L230886
--24--
Formulation 2.
A sterilized aqueous solution for oral administer-
lion containing l-(2,6-dimethylphenyl)-3-amidinourea
hydrochloride is made up from the following ingredients:
1-~2,6-dimethylphenyl)-3-
amidinourea hydrochloride my
Sodium chloride 86 my
Potassium chloride 3 my
Calcium chloride 2H20 3.3 my
Deionized water TV 100 cm3
Formulation 3.
A sterile solution suitable for inter peritoneal
injection, containing 10 my of 1-(2,6-dimethylphenyl)-3-
methylamidinourea hydrochloride in each 10 ml (1:1
wt/vol), is prepared from the following ingredients:
1-(2,6-dimethylphenyl)-3-
methylamidinourea hydrochloride 10 g
Bouncily bonniest 100 cm3
Methylparaben 1 g
Propylparaben 0.5 g
Cottonseed oil us SO cm3
.
Formulation 4.
500 ampules, each with 2 ml of solution containing
15 my of 1-~2,6-dimethylphenyl)-3-methylamidinourea hydra-
chloride, are prepared from the following types and amount
of materials.
,.. . .
.. , . .. ,... .

- i.;230886
-25-
1-(2,6-dimethylphenyl)-3-
methylamidinourea hydrochloride 7 5 g
Ascorbic acid 1 g
Sodium bisulphite 0.5 g
Sodium sulfite 1 g
Deionized water us 1000 cm3
Formulation 5.
Tablets of 850 my are prepared by maximum
compression of a mixture of the following ingredients:
l-t2,6-dimethylphenyl)-3-
methylamidinourea hydrochloride 500 my
Tricalcium phosphate 200 my
Talc . 50 my
Magnesium Stewart 10 my
Polyvinyl acetate 40 my
Protective excipients such as ethyl cellulose,
dibutylphthalate, propylene glycol, wax (white and/or
carnauba), spermaceti, ethylene chloride and rectified
.: deathly ether may optionally be included among the
ingredients.
Formulation 6.
. A lot of tablets, each containing 20 my of
1-~2,6-dlmethylphenyl)-3-methylamidinourea hydrochloride
are prepared from the following ingredients:
1-~2,6-dimethylphenyl)-3-
methylamidinourea hydrochloride 1 kg
Dicalcium phosphate 1 kg
Methyl cellulose US 75 kg
: Talc 150 g
Cornstarch 200 g
Magnesium Stewart 10 g
,::
I: '
:: :
._ . .
. . ,

~Z30886
--26--
The amidinourea and dicalcium phosphate are mixed
thoroughly and granulated with a 7.5~ solution of
methyl cellulose in water and Sassed through a #8 screen
and air-dried. The dried granules are passed through a
~12 screen and combined with the talc, starch and
magnesium Stewart with thorough mixing, after which the
composition is compressed into tablets.
Formulation 7:
A lot of two-piece hard gelatin capsules, each
containing 25 my of 1-(2,6-di~ethylphenyl)-3-methyl
amidinourea hydrochloride, are prepared from the
following types and amounts of ingredients:
1-(2,6-dimethylphenyl)-3-
methylamidinourea hydrochloride 500 g
Dicalcium phosphate 500 g
Talc 150 g
Magnesium Stewart 5 g
The ingredients are mixed thoroughly and filled
into capsules for oral administration to animals at the
rate of about one every four hours. If desired, slow
release or delay release forms can be provided, depending
on choice of capsules and formulating ingredients.
Formulation 8:
Tablets for oral administration, each containing
25 my of 1-~2,6-dimethylphenyl)-3-methylamidinourea
hydrochloride, are prepared prom a mixture of the
following ingredients:
1-~2,6-dimethylphenyl)-3-
methylamidinourea hydrochloride 500 g
Lactose US 350 g
Potato starch US 346 g
.
. . .

i2~0886
--27--
The mixture is moistened with an alcoholic
solution of 20 g of Starkey acid and granulated through a
sieve. After drying, the following ingredients are
added:
Potato starch US 320 g
Talc 400 g
Magnesium Stewart 500 g
Colloidal silicum dockside g
and the whole is thoroughly mixed and compressed into
tablets.
Formulation 9:
Capsules are prepared from the following mixture:
1-~2,6-dimethylphenyl)-3-
methylamidinourea hydrochloride 15 g
Magnesium Stewart 3 g
Finely divided silica sold under
the trademark CAB-O-SIL by Godfrey L.
Cabot, Inc., Boston, MA 2 g
: Lactose 369 g
The mixture is filled into gelatin capsules, each capsule
containing 500 my of the mixture and thus 15 my of
1-~2,6-dimethylphenyl)-3-methylamidinourea hydrochloride.
By analogous procedures, other amidinoureas of
general Formula I above can be formulated in a similar
manner for either oral or parenteral administration as
injectable or infusible solutions. The solid or liquid
formulations can also be dispersed in the food or
dissolved in the drinking water or the liquid diet of the
patient.