Note: Descriptions are shown in the official language in which they were submitted.
lV~ 36~
The present invention relates to a novel process for
preparing amidinourea derivatives of the general formula I or
its tautomeric form II when the R radical is hydrogen:
X X
y~ 1l NR' R~ y3~N-c-N-c/
Z Rn R R Z Rn \NR"R"'
II
where:
X, Y and Z may be the same or different and are:
hydrogen,
halo,
loweralkyl,
haloloweralkyl,
nitro,
loweralkoxy,
hydroxy,
arloweralkoxy,
acyloxy,
cyano,
haloloweralkoxy or
loweralkylsulfonyl;
R and R' are hydrogen or
loweralkyl,
R" and R"'are hydrogen,
alkyl,
loweralkyl,
loweralkenyl,
cycloalkyl,
cycloalkenyl up to 9 carbon atoms,
aralkyl,
~07Z~6~
cycloalkylloweralkyl,
loweralkynyl;
R" and R"' together may form a 5-7 atom ring which may
include 0-2 hetero atoms of N, 0 or S,
Rn is hydrogen or loweralkyl provided at least one of
R, R', R" and R"'is other than hydrogen; and
the non-toxic acid addition salts thereof.
Compounds of this invention which are preferred
include those where:
X, Y and Z are hydrogen,
halo,
loweralkyl,
haloloweralkyl,
nitro,
hydroxy or
loweralkoxy, provided not more than one of X, Y
and Z is hydrogeni and
R' and Rn are hydrogen or loweralkyl and
R" and R"'are hydrogen or alkyl, provided R, R', R" and
R"' are not all hydrogen at the same time.
The compounds of formula I or II of the present
invention exist as tautomeric forms when a proton is present
on the second nitrogen atom of the amidinourea chain. As with
tautomers certain compounds would naturally exist in one form
or the other depending on their character as discussed in
Journa~ of Organic C~emistry~ 33, 1968 p. 552.
The most preferred compounds of this invention are
those where:
X is methyl, ethyl, methoxy, chloro or bromo;
Y is methyl, ethyl, hydroxy, methoxy, chloro or bromo;
Z is hydrogen, methyl, ethyl, nitro, methoxy, ethoxy~
l~qZ9~
chloro, bromo or fluoroi
R, R' and Rn are hydrogen, methyl or ethyl; and
R" and R"'are hydrogen,
methyl,
ethyl,
propyl,
i-propyl,
butyl,
i-butyl,
sec-butyl,
t-butyl,
pentyl,
hexyl or
heptyl, provided R, R', R" and R"' are not all
hydrogen at the same time.
It is well known in the pharmacological arts that
non-toxic acid addition salts of pharmacologically active amine
compounds do not differ in activities from their free base.
The salts merely provide a convenient solubility factor.
The amines of this invention may be readily converted
to their non-toxic acid addition salts by customary methods in
the art. The non-toxic salts of this invention are those salts
the acid component of which is pharmacologically acceptable in
the intended dosages, such salts would include those prepared
from inorganic acids, organic acids, higher fatty acids, high
molecular weight acids, etc., and include such as:
hydrochloric acid, succinic acid,
hydrobromic acid, glycolic acid,
sulfuric acid, lactic acid,
nitric acid, salicylic acid,
phosphoric acid, benzoic acid,
~ 962
methane sulfonic acid, nicotinic acid,
benzene sulfonic acid, phthalic acid,
acetic acid, stearic acid,
propionic acid, oleic acid,
malic acid, abietic acid, etc.
The nomenclature applied to the compounds of this
invention is as follows:
~3
: - C - N C ~ N~
urea amidino
The term "loweralkyl" refers to an alkyl hydrocarbon
group from 1 to 5 carbon atoms which may be straight chained
or branched while "alkyl" refers to an alkyl 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 "aralkyl" groups are benzyl and
phenethyl.
The preferred "haloloweralkyl" group is trifluoro-
methyl.
The preferred "haloloweralkoxy" group is trifluoro-
methoxy.
In accordance with the present invention it has be2n
observed that the compounds having anti-diarrheal or spasmo-
lytic properties are preferably those compounds wherein X,Y,Z,
R,R',R",R"' and Rn represent a total number of carbon atoms
.
10~962 -
lower than seven. On the other hand, when the total number of
carbon atoms of those substituents is 3 or more the products
are found to possess both spasmolytic activity and surprisingly
high significant local anaesthetic and anti-arrhythmic activi-
ties.
The novel process of the present invention comprises
reacting a carbamoyl derivative of the formula:
X
~I e OR~
wherein X, Y, Z and Rn are as previously defined and R8 stands
for loweralkyl, phenyl or phenylloweralkyl, with a guanidine of
the formula:
NHR- 11- N/
R"'
wherein R, R', R" and R"'are as previously defined, thereby to
obtain an amidinourea of the formula:
X 1l NR' /R~ X I /NRR'
N-C-N-e-N ~ < _ _ > ~ I-l-N=C~
Rn R R"' Z Rn NR"R"'
wherein X, Y, Z, Rn~ R, R', R" and R"'are as defined previously.
The reaction is carried out in the presence of an
inert solvent such as a lower alcohol, for example ethanol or
isopropanol, toluene or phenol. The choice of the proper
solvent will depend on the substituents on the guanidine and
the selection is within the ability of one skilled in the art.
The reaction is also conveniently carried out at room tempera-
ture.
The compounds described in this application are
- 5 -
'
1~7~6~
useful anti-diarrheal agents. For these purposes they can 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 elixers. 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.
Compositions intended for oral use may be prepared
according to methods known to the art for the manufacture of
pharmaceutical compositions. Such compositions may contain one
or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents, preserving agents,
etc. in order to provide a pharmaceutically elegant and palata-
ble preparation.
Further the active amidinourea may be administered
alone or in admixture with other agents having the same or
different pharmacological properties.
The composition may contain selected excipients
such as inert diluents such as calcium carbonate, lactose,
. ., ~ . ~ . .
l~q296Z
ete.; granulating and disintegrating agents such as maize
starch, alginic acid, etc.; lubricating agents such as mag-
nesium stearate, etc.; binding agents such as starch gelatin,
ete.; suspending agents such as methylcell-lose, vegetable oil,
ete.; dispersing agents such as lecithin, etc.; thickening
agents such as beeswax, hard paraffin, etc.; emulsifying agents
such as naturally-occurring gums, etc.; non-irritating excipi-
ents 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 mg. and
about 500 mg. of the active ingredients of this invention. The
preferred unit dose is between 1 mg. and about 50 mg. The
compositions may be taken 1-8 times daily depending on the
dosage unit required.
Those products of the present invention which are
found to possess local anaesthetic or anti-arrhythmic activi-
ties are preferably administered in any of the well known forms
for subcutaneous administration while those products possessing
especially anti-arrhythmic activity may be administered orally,
parenterally or rectally.
Various tests can be carried out in animal models to
show the ability of the amidinoureas of this invention 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
.
~ 96'~
active. In view of the results of these tests, the amidino-
ureas of this invention can be considered to be anti-diarrheal
agents.
1. Fecal output in rat: - The oral ED50 (that dose
which would be expected to reduce fecal output by 50%) is de-
termined by a method described by Bass et aZ., 1972. Briefly,
the method involves dosing the rats and collecting the fecal
output over an 8 hour period (4 P.M. - 12 midnight) with the
room darkened starting at 4:30 P.M.
Ref: - Bass, P., Kennedy, J.A. and Willy, J.N.:
Measurement of fecal output in rats. Am. J. Dig. Dis. 10:
925-928, 1972.
2. Castor oil test in mice: - Groups of mice are
orally dosed with test compound and half an hour later all mice
are given 0.3 ml. of castor oil. Three hours after castor oil
administration, all mice are checked for diarrhea and the dose
of testing compound which protected 50% of mice from diarrhea
is the ED50 dose.
3. Castor oil test in rats: - The test is conducted
according to Niermegeers et aZ.~ 1972. The rat is orally dosed
with graded doses of test compound. One hour after dosing,
each animal is challenged with 1 ml. of castor oil orally.
Fecal output is examined 1, 2, 3, 4, 6 and 8 hours after castor
oil. Absence of diarrhea is criterion of drug effectiveness.
Ref: - Niemegeers C.J.E., Lenaerts, F.M. and Janssen,
P.A.J. Difenoxine, a potent, orally active and safe anti-
diarrheal agent in rats. Arzneim-Forssth (~rug Res.) 22,
516-1518, 1972.
The following are detailed examples which show the
properties of the compounds of this invention. They are to be
construed as illustrations of said compounds and not as limi-
tations thereof.
-- 8 --
i~'7Z96Z
The following are detailed examples which show the
preparation of the compounds in accordance with the process of
the present invention. They are to be construed as illus-
trations only and not as limitations.
EXAMPLE 1
1-(2',6'-dimethylphenyl~-3-methylamidinourea hydrochloride
With gentle warm;ng 300 ml of dry isopropanol was
treated with 4.6 9 of clean sodium metal (0.2 g-atms). When
the mixture was homogeneous there was added portionwise 24.4 9
(0.10 moles) of methylguanidine sulfate. The suspension was
stirred at room temperature for three hours.
To the above mixture at room temperature there was
added a solution of 48.3 9 (0.20 moles) of phenyl N-(2,6-
dimethylphenyl)carbamate in 100 ml of dry isopropanol. The
mixture was stirred at room temperature overnight and the
solvent removed in vao~o. The residue dissolved in ether and
the ether solution washed with 10% hydrochloric acid until the
wash was acidic. The acidic aqueous extracts combined and
washed once with ether. The aqueous solution made just basic
with 10% sodium hydroxide solution, cooled and filtered to give
the desired 1-(2,6-dimethylphenyl)-3-methylamidinourea free
base. The white solid dissolved in methanol and the solution
dried with anhydrous sodium sulfate. The filtered solution
made acidic with methanolic hydrogen chloride and evaporated to
a glass in vacuo. The glass was broken up and triturated with
a large volume of ether, the suspension filtered and the solid
dried to give 1-(2,6-dimethylphenyl)-3-methylamidinourea hydro-
chloride, m.p. 193-5C. Recrystallization from acetonitrile
containing some methanol gives analytically pure material m.p.
198-200C.
g
.:
~7~6Z
EXAMPLE 2
By proceeding in the same manner as in Example 1 and
using the appropriate carbonate and guanidine the compounds of
Table I are obtained.
- 10 -
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