Method for antagonizing aldosteronic action and inducing diuresis by administering a tetrasubstituted imidazolidine

Novel 1-(phenyl or p-chlorophenyl)-2,4-disubstituted-3-methylimidazolidines and a method for inducing diuresis and treating hyperaldosteronism by the administration thereof.

CROSS REFERENCE TO RELATED APPLICATION 
This application is a division of application Ser. No. 293,874, filed Oct. 
2, 1972 now U.S. Pat. No. 4,044,021 which is a continuation-in-part of our 
copending application Ser. No. 191,470, filed Oct. 21, 1971, now 
abandoned. 
BRIEF SUMMARY OF INVENTION 
This invention relates to new and useful 1-(phenyl or 
p-chlorophenyl)-2,4-disubstituted-3-methylimidazolidines and to a method 
for treating hyperaldosteronism and inducing diuresis by the 
administration thereof. It has been found that certain tetrasubstituted 
imidazolidines and pharmaceutically acceptable salts thereof cause 
diuresis without the loss of significant amounts of potassium and thus 
find considerably utility in the treatment of edema and hypertension. It 
has also been found that they demonstrate antialdosteronic activity in 
mammals. 
Aldosterone is a naturally occurring, potent mineralocorticoid which is 
involved in various physiologic processes involved in sodium, potassium 
and water homeostasis. An excess of this material results in a condition 
termed hyperaldosteronism which is present in a number of pathological 
conditions, such as cirrhosis with ascites, nephrosis, cardiac failure, 
idiopathic edema, adrenocortical tumor, adrenocortical hyperplasia, renal 
artery stenosis and malignant hypertension. Fluid and electrolyte 
imbalance often occurs in the preceding conditions due to the 
hyperaldosteronism. This imbalance can be corrected by agents which 
produce natriuresis without kaliuresis. The diuretic effect of the 
tetrasubstituted imidazolidines of this invention is primarily due to the 
antagonism of aldosterone but in part results from an additional direct 
renal tubular effect. 
The novel 1-(phenyl or 
p-chlorophenyl)-2,4-disubstituted-3-methyl-imidazolidines of this 
invention may be represented by the formula: 
##STR1## 
wherein X is selected from the group consisting of hydrogen and chlorine; 
Y and Z are each selected from the group consisting of NH, NCH.sub.3 and 
O, with the proviso that both Y and Z are not O in the same compound; and 
the pharmaceutically acceptable salts thereof. In addition, useful 
compositions of matter are disclosed utilizing the above said compounds, 
alone or in combination with other useful therapeutic agents. 
Representative groups of tetrasubstituted imidazolidines encompassed by 
this invention are 1-(phenyl or 
p-chlorophenyl)-2-imino-3-methyl-4-oxoimidazolidines, 1-(phenyl or 
p-chlorophenyl)-2-methylimino-3-methyl-4-oxoimidazolidines, 1-(phenyl or 
p-chlorophenyl)-2-imino-3-methyl-4-methyliminoimidazolidine, 1-(phenyl or 
p-chlorophenyl)-4-imino-3-methyl-2-oxoimidazolidines, 1-(phenyl or 
p-chlorophenyl)-3-methyl-4-methylimino-2-oxoimidazolidines and the like. 
The most preferred compounds of this invention are the tetrasubstituted 
imidazolidines, 1-phenyl-2-imino-3-methyl-4-oxoimidazolidine and 
1-p-chlorophenyl-2-imino-3-methyl-4-oxoimidazolidine, and their 
hydrochloride salts. These tetrasubstituted imidazolidines have exhibited 
the most outstanding diuretic and antialdosterone activity of the compound 
tested. 
BACKGROUND OF THE INVENTION 
Our application Ser. No. 191,470 was broadly concerned with including 
diuresis and treating hyperaldosteronism by the administration of certain 
substituted phenyl-2-imino-2-imidazolin-4-ones and substituted 
phenyl-2-imino-3-substituted-4-imidazolidinones. The latter compounds can 
also be named as imidazolidines. It has now been found that some of the 
imidazolidines disclosed in our previous application possess undesirable 
properties which render them unsuitable for the intended purpose of this 
invention and such compounds have been excluded herefrom. Such compounds 
has been excluded on the basis of toxicity, such as death of the animals, 
crystallization in the urine, lesions in the kidney, great variability in 
diuretic activity and in effect on Na/K ratio, and failure to obtain an 
increase in diuretic activity and in Na/K ratio with increased dosage. For 
example, it has been found that the compound 
1-(p-chlorophenyl)-2-amino-4-oxo-2-imidazoline, although active, is too 
toxic for use in that it causes crystalluria, as a result of its 
insolubility, and renal tissue damage in test animals. The compound 
1-(3,4-dichlorophenyl)-2-amino-4-oxo-2-imidazoline has also been shown to 
be too toxic for use, in that it is lethal to animals, is toxic to blood 
cells, and causes crystalluria as well as congestion in the medulla of the 
kidney. The compounds 1-phenyl-2-imino-3-ethyl-4-oxoimidazolidine, 
1-(p-chlorophenyl)-3-ethyl-2-imino-4-oxoimidazolidine and 
1-(3,4-dichlorophenyl)-3-ethyl-2-imino-4-oxoimidazolidine, all disclosed 
in our application Ser. No. 191,470, although active, exhibit one or more 
undesirable properties which render them unsuitable for the use intended 
herein. 
It has been shown that isomers of the compounds of the present invention, 
wherein the methyl group is merely moved from one nitrogen to another, are 
inactive for the purpose of this invention. Such inactive isomers are 
1-phenyl-2-methylamino-4-oxo-2-imidazoline and 
1-p-chlorophenyl-2-methylamino-4-oxo-2-imidazoline. It has also been shown 
that compounds are inactive or otherwise unsuitable for the purposes of 
this invention when the substituent on the 3-position of the imidazolidine 
ring is other than a methyl or ethyl group. For example, compounds such as 
1-p-chlorophenyl-2-imino-3-n-propyl-4-oxoimidazolidine, 
1-phenyl-2-imino-3-n-propyl-4-oxoimidazolidine, and 
1-p-chlorophenyl-2-imino-3-n-butyl-4-oxoimidazolidine have been shown to 
be inactive. 
It has now been found that only a limited number of tetrasubstituted 
imidazolidines and the pharmaceutically acceptable salts thereof 
demonstrate sufficient diuretic effect or antialdosteronic activity when 
administered to animals, and are sufficiently non-toxic and otherwise 
desirable to warrant consideration for the purpose of this invention. 
Certain 1-phenyl-2-imino-3-alkyl-4-oxoimidazolidines are disclosed, as 
glycocyamidines, in U.S. Pat. No. 2,557,911 and J. Am. Chem. Soc. 73: 2942 
(1951). U.S. Pat. No. 2,557,911, at column 4, lines 9-14 discloses that 
such imidazolidines are useful only as chemotherapeutic agents, 
bactericides and catalysts. There is no disclosure in this patent of their 
utility as diuretic agents or their use in the treatment of 
hyperaldosteronism. This type of diuretic action could not have been part 
of the utility in the patent above since the mineralocorticoid hormone, 
aldosterone, was not discovered until 1953 and the ability to antagonize 
its action and thereby produces a diuretic effect was not discovered until 
1955. Moreover, at the time of the patent, a chemotherapeutic agent meant 
that such agent had to do with the treatment of infectious disease. The 
closest specific compound to those of this invention disclosed in the 
above patent is the compound 1-phenyl-3-ethylglycocyamidine or, by our 
nomenclature, 1-phenyl-2-imino-3-ethyl-4-oxoimidazolidine. This 
imidazolidine is not encompassed within the present invention. Tests have 
shown that 1-phenyl-2-imino-3-ethyl-4-oxoimidazolidine as well as 
1-(p-chlorophenyl)-2-imino-3-ethyl-4-oxoimidazolidine, although active for 
the purpose of this invention, do not give a useful increase in diuretic 
activity and in Na/K ratio with increased dosage, are variable in their 
activity and are otherwise unsuitable for the purposes of this invention. 
Tests have also shown that the higher alkyl compounds disclosed in U.S. 
Pat. No. 2,557,911, such as the specifically disclosed 
1-phenyl-3-n-octyl-glycocyamidine (or 2-imino-4-oxoimidazolidine) and the 
broadly disclosed 1-phenyl-2-imino-3-n-propyl-4-oxoimidazolidine, 
1-(p-chlorophenyl)-2-imino-3-n-propyl-4-oxoimidazolidine, and 
1-(p-chlorophenyl)-2-imino-3-n-butyl-4-oxoimidazolidine, are inactive and 
therefore unsuitable for the purposes of this invention. A 
nitro-substituted compound is disclosed in the above references but such 
compounds, including also 
1-(p-nitrophenyl)-2-imino-3-methyl-4-oxoimidazolidine, are inactive for 
the purposes of this invention, as also are a variety of other 
substituted-phenyl compounds. The scope of U.S. Pat. No. 2,557,911 
comprises six categories of compounds: (1) 1-alkylglycocyamidines; (2) 
1-arylglycocyamidines; (3) 1,3-dialkylglycocyamidines; (4) 
1,3-diarylglycocyamidines; (5) 1-alkyl-3-arylglycocyamidines; and (6) 
1-aryl-3-alkylglycocyamidines. In addition to the categories shown above 
to be inactive, those of category 1 such as the specifically disclosed 
1-n-octylglycocyamidine and of category 4 such as the specifically 
disclosed 1,3-diphenylglycocyamidine and 
1-phenyl-3-(p-nitrophenyl)glycocyamidine are also inactive for the purpose 
of this invention. As mentioned above, two compounds of category 2 were 
active but too toxic for use; the rest of the compounds tested were 
inactive. Therefore, only compounds of category 6 are the subject of the 
present invention and, furthermore, only a very small part, namely two 
compounds, of those comprising category 6 are within the scope of the 
present invention. 
DETAILED DESCRIPTION OF THE INVENTION 
The 1-(phenyl or p-chlorophenyl)-2,4-disubstituted-3-methylimidazolidines 
of this invention may be prepared by the following reaction sequences: 
##STR2## 
wherein X is as hereinbefore designated, A is defined as a leaving group 
such as halogen, cyano and trimethylammonium. 
Generally, the aniline or 4-chloroaniline compound is reacted with an agent 
such as cyanogen bromide in a basic solution, e.g., using excess 
substituted aniline compound, or other organic bases such as 
diisopropylethylamine, or inorganic bases such as KHCO.sub.3, for 4-60 
hours at 30.degree.-80.degree. C. Depending upon the reaction time, a 
temperature of from 20.degree.-100.degree. C. is deemed suitable. The 
substituted phenylcyanamide formed is dissolved in a strong base, such as 
aqueous sodium hydroxide or alcoholic sodium alkoxide and reacted with a 
compound such as a haloacetamide for 48 hours at room temperature for 4 
hours at approximately 80.degree. C. to yield the desired 1-(phenyl or 
p-chlorophenyl)-2,4-disubstituted-3-methylimidazolidine. Suitable solvents 
which may be used in both steps include alcohols, ketones, ethers, esters, 
nitriles, amides, sulfoxides, sulfones, hydrocarbons and others. The 
acyclic intermediate above (I) can be replaced with an isomeric 
intermediate (III) synthesized as below. In both instances, the 
intermediate need not be isolated. An alternative ring closure to that of 
III producing II is the cyclization of IV to II. The reaction sequence is 
the same except that N-Z' has been added to the cyano group throughout and 
it is then lost in the last step leading to II. The sequence proceeds 
through the chloroacetyl derivatives of methylguanidine, 
N,O-dimethylisourea, or N,S-dimethylisothiourea which are then animated 
with aniline or p-chloroaniline, followed by cyclization. 
##STR3## 
The intermediates I and III can also be prepared from the N-(phenyl or 
p-chlorophenyl)glycine amides as their mono-anions and di-anions, 
respectively, as shown in the equations below. 
##STR4## 
These N-(phenyl or p-chlorophenyl)glycine amides in neutral media serve as 
starting materials for the 4-imino-2-oxoimidazolidines VII, which are then 
mono- or dimethylated, as required, to give VIII and IX. This sequence 
proceeds through diiminooxazolidines VI as in the equations above; VI also 
gives a small or large amount of II depending on the conditions and the 
substituents present. 
The 3-methyl compounds II are also synthesized by methylation of the 
imidazolidines X afer cyclization. For this purpose, methyl sulfate, 
methyl methanesulfate, methyl toluenesulfonate, methyl fluorosulfonate, 
trimethyloxonium fluoroborate and other methylating agents are suitable. 
The cyclized material X is prepared as indicated. 
##STR5## 
The dimethyl compounds below are prepared by carrying the N-methylation of 
the 3-methyl compound II further in situ or using the isolated 3-methyl 
compound prepared by the cyclization above of an .alpha.-substituted 
N-methyl acetamide. 
##STR6## 
These dimethyl compounds XI are also obtained by isomerizing the 3-methyl 
compounds II with a catalyst such as alkoxide to 
2-methylamino-2-imidazolines XII followed by methylation with a 
methylating agent as discussed above. 
##STR7## 
Another type of acyclic intermediate to the 2-imino-4-oxoimidazolidines II 
is the guanyl or isoureido structure XIII, analogous to structure IV. When 
XIII is a carboxylic acid, cyclization is usually accomplished in acidic 
solution, while when it is a lower alkyl ester, both acidic and basic 
media can be used. 
##STR8## 
The 2,4-diimino compounds are prepared by the same reactions except that 
the carboxylic amide or ester group is replaced by a nitrile or an amidine 
group depending on the degree of methylation desired in the direct 
cyclization product. 
Two standard test systems were used for the determination of 
antialdosterone diuretic activity for the tetrasubstituted imidazolidines. 
In the first model, compounds of this invention were initially tested in 
adrenalectomized, desoxycorticosterone-treated rats using the technique 
described by Kagawa [Proc. Soc. Exptl. Biol. Med. 99, 709 (1958).] Male 
Wistar rats weighing 150.degree.-200 g. were adrenalectomized under ether 
anesthesia. Following adrenalectomy, the animals were provided tap water 
and sugar tablets ad libitum until test time. Twenty-four hours 
postoperatively the animals were given 12.5 mcg. of desoxycorticosterone 
acetate subcutaneously in 0.1 ml. of corn oil. In addition, each animal 
received 2.5 ml. of 0.9% saline subcutaneously and the test compound 
suspended in 0.5 ml. of 2% starch suspension by gavage. Initially the test 
compounds were administered in a dose of 100 mg./kg. The rats were placed 
in metabolism cages, 2 animals per cage, and urine was collected for 4 
hours. Urine volume was measured and urinary sodium and potassium were 
determined. In all experiments the steroidal anti-aldosterone drug, 
spironolactone, was run simultaneously as a standard for comparison. The 
results using 400 rats are shown in Table I. The percent change is shown 
as (+) greater or (-) less urinary excretion of ions from the control rats 
which received DCA (desoxycorticosterone acetate), but no drug. 
TABLE I 
______________________________________ 
Effect of Tetrasubstituted Imidazolidines on Electrolyte Excre- 
tion in Adrenalectomized, Desoxycorticosterone-treated Rats 
Percent Change 
Dosage from Control 
Compound mg./kg. Na.sup.+ K.sup.+ 
______________________________________ 
1-(p-chlorophenyl)-2- 
10 82 -12 
imino-3-methyl-4-oxo- 
50 83 -32 
imidazolidine 100 97 -39 
1-phenyl-2-imino-3- 
1 +9 +4 
methyl-4-oxoimidazo- 
5 +45 -22 
lidine 10 +76 -4 
25 +129 -3 
50 +132 -9 
100 +290 +33 
1-phenyl-2-methylimino- 
1 +51 +14 
3-methyl-4-oxoimidazo- 
10 +67 +21 
lidine 100 +155 -12 
1-(p-chlorophenyl)-2- 
25 +41 -39 
methylimino-3-methyl-4- 
50 +74 -17 
oxoimidazolidine 
100 +48 -32 
1-phenyl-4-imino-3- 
10 +51 -6 
methyl-2-oxoimidazoli- 
50 +32 -41 
dine 100 +127 -19 
1-phenyl-3-methyl-4- 
25 +36 -66 
methylimino-2-oxoimida- 
zolidine 
Spironolactone 5 +9 -32 
10 +49 -38 
50 +90 -17 
100 +61 -38 
______________________________________ 
The second type of test was performed in concious dogs utilizing a method 
described by Kagawa et al. (Kagawa, C. M., Bouska, D. J., Anderson, M. T. 
and Krol, W. F., Arch. Internat. Pharmacodyn. 149: 8-24, 1964). The left 
jugular vein was cannulated for infusion of solutions and a retention 
catheter was placed in the bladder for collection of urine. Some animals 
were given 0.25 mg. of DCA intramuscularly and the test drug orally by 
capsule 2 hours before the beginning of urine collections. Others received 
the test drug and corn oil rather than DCA. Saline 0.45% and dextrose 2.5% 
was infused intravenously throughout the experiment at a rate of 0.3 
ml./kg./minute after a prime of 20 ml./kg. was given in approximately 20 
minutes. Urine was collected at 30-minute intervals and blood samples were 
drawn from the right jugular vein at the midpoint of each collection 
period. Collections were continued for five 30-minute periods and the 
urinary Na and K effects in Table II are the average of the values for the 
five periods. 
Table II records the results of the second type of test. Table II shows a 
favorable response also in dogs as indicated by substantial increase in 
sodium excretion without appreciable potassium loss. 
TABLE II 
______________________________________ 
The Effect of Tetrasubstituted Imidazolidines on Urinary Sodium 
and Potassium Excretion in Conscious Dogs in the Presence of 
Exogenous DCA 
Dosage Percent Change from Control 
Compound mg./kg. Na.sup.+ K.sup.+ 
______________________________________ 
1-phenyl-2-imino-3- 
5 125 20 
methyl-4-oxoimida- 
zoline 
1-phenyl-2-imino-3- 
10 162 19 
methyl-4-oxoimida- 
zoline 
1-phenyl-2-imino-3- 
25 194 9 
methyl-4-oxoimida- 
zoline 
1-p-chlorophenyl-2- 
25 69 9 
imino-3-methyl-4- 
oxoimidazoline 
______________________________________ 
The tetrasubstituted imidazolidines of this invention serve as useful 
anti-aldosterone diuretics in doses of 1 mg. per kg. to 50 mg. per kg. of 
body weight per day. A preferred dosage regimen would be from 4 mg. per 
kg. to 20 mg. per kg. of body weight per day. When such dosage units are 
employed, a total daily intake of a subject of about 70 kg. body weight is 
about 70 mg. to 3.5 g., preferably about 280 mg. to 1.4 g. 
The hydrochloride salts of 1-phenyl-2-imino-3-methyl-4-oxoimidazolidine and 
1-p-chlorophenyl-2-imino-3-methyl-4-oxoimidazolidine are as active as the 
free bases when administered orally. They have the advantage that they are 
soluble enough to administer by injection, under which conditions they are 
also highly active. 
Tetrasubstituted imidazolidines according to the present invention having 
the desired clarity, stability, and adaptability for parenteral use are 
obtained by dissolving the active compound in a vehicle consisting of a 
polyhydric aliphatic alcohol or mixtures thereof. Especially satisfactory 
are glycerin, propylene glycol, and the polyethylene glycols. The 
polyethylene glycols consist of a mixture of non-volatile, normally 
liquid, polyethylene glycols which are soluble in both water and organic 
liquids and which have molecular weights of from about 200 to about 1500. 
While concentrations can vary greatly, the amount of active compound 
dissolved in the above vehicle preferably should be from about 0.10% to 
about 10.0% by weight. Although various mixtures of the aforementioned 
non-volatile polyethylene glycols may be employed, it is preferred to use 
a mixture having an average molecular weight of from about 200 to about 
400. 
In addition to the active compounds, the parenteral solutions of the 
present invention may also contain various preservatives which may be used 
to prevent bacterial and fungal contamination. The preservatives which may 
be used for such purpose are, for example, benzyl alcohol, 
myristyl-gamma-picolinium chloride, phenyl mercuric nitrate, benzalkonium 
chloride, phenethyl alcohol, p-chlorophenyl-.alpha.-glycerol ether, methyl 
and propyl parabens, and thimerosal. As a practical matter it is also 
convenient to employ antioxidants. Suitable antioxidants include, for 
example, ascorbic acid, sodium bisulfite, sodium metabisulfite, and sodium 
formaldehyde sulfoxylate. Generally, from about 0.05% to about 0.2% 
concentrations of antioxidant are employed. 
The active compounds of the present invention may be orally administered, 
for example, with an inert diluent or with an assimilable edible carrier, 
or they may be enclosed in hard or soft gelatin capsules, or they may be 
compressed into tablets, or they may be incorporated directly with the 
food of the diet. For oral therapeutic administration, the active 
compounds of this invention may be incorporated with excipients and used 
in the form of tablets, troches, capsules, elixirs, suspensions, syrups, 
wafers, chewing gum, and the like. Such compositions and preparations 
should contain at least 0.1% of active compound. The percentage in the 
compositions and preparations may, of course, be varied and may 
conveniently be between about 5% to about 75% or more of the weight of the 
unit. The amount of active compound in such therapeutically useful 
compositions or preparations is such that a suitable dosage will be 
obtained. Preferred compositions or preparations according to the present 
invention are prepared so that an oral dosage unit form contains between 
about 100 and 500 milligrams of active compound. 
The tablets, troches, pills, capsules and the like may also contain the 
following: a binder such as gum tragacanth, acacia, corn strach or 
gelatin; an excipient such as dicalcium phosphate; a disintegrating agent 
such as corn starch, potato starch, alginic acid and the like; a lubricant 
such as magnesium stearate; and a sweetening agent such as sucrose, 
lactose or saccharin may be added or a flavoring agent such as peppermint, 
oil of wintergreen, or cherry flavoring. When the dosage unit form is a 
capsule, it may contain in addition to materials of the above type a 
liquid carrier such as a fatty oil. Various other materials may be present 
as coatings or to otherwise modify the physical form of the dosage unit, 
for instance, tablets, pills, or capsules may be coated with shellac, 
sugar, or both. A syrup or elixir may contain the active compounds, 
sucrose as a sweetening agent, methyl and propyl parabens as 
preservatives, a dye and a flavoring such as cherry or orange flavor. Of 
course, any material used in preparing any dosage unit form should be 
pharmaceutically pure and substantially non-toxic in the amounts employed. 
In addition, the tetrasubstituted imidazolidines of this invention may 
advantageously be administered in a single combination with other 
diuretics such as those listed below, especially bumetanide, furosemide 
and hydrochlorothiazide. These diuretics may be incorporated with the 
tetrasubstituted imidazolidines and in the dosage below: 
______________________________________ 
Recommended daily human 
Diuretic dosage range (mg./70 kg.) 
______________________________________ 
hydrochlorothiazide 
100-200 
ethacrynic acid 50-200 
furosemide 40-80 
quinethazone 50-100 
bumetanide 1-2 
______________________________________ 
In order to show the advantages of combining the compounds of this 
invention with known diuretic agents acting by other mechanisms, the 
following test was carried out. Rats were made sodium-deficient and 
hyperaldosteronic with low-sodium diet for a period of 2 weeks. The 
animals were deprived of food for approximately 18 hours prior to the test 
but had free access to water. At the beginning of the test, the animals 
were given the test compound orally by gavage in aqueous starch suspension 
along with 10 ml. of 0.9% saline. Two rats were placed in each metabolism 
cage for urine collections. Urine samples were collected at 6 hours after 
dosing, their volume was measured, and their sodium, potassium and 
chloride ion concentrations were determined. 
The effect of hydrochlorothiazide alone and in combination with two of the 
preferred tetrasubstituted imidazolidines of this invention is shown in 
Table III. 
TABLE III 
______________________________________ 
The Effect of Hydrochlorothiazide Alone and in Combination 
with Anti-aldosterone Diuretics in Sodium-Deficient Rats 
Urine 
Volume Na K Na/K 
Treatment (ml) (mEq) (mEq) ratio 
______________________________________ 
Hydrochlorothia- 
zide 
5 mg/kg 11.0 0.84 1.28 0.69 
Hydrochlorothia- 
zide 
5 mg/kg 
+ 12.2 1.41 1.20 1.53 
Spironolactone 
50 mg/kg 
Hydrochlorothia- 
zide 
5 mg/kg 
+ 17.4 1.71 1.45 1.18 
1-phenyl-2-imino- 
3-methyl-4-oxo- 
imidazolidine 
100 mg/kg 
Hydrochlorothia- 
zide 
5 mg/kg 
+ 15.7 1.63 1.33 1.26 
1-(p-chloro- 
phenyl-2-imino- 
3-methyl-4-oxo- 
imidazolidine 
100 mg/kg 
______________________________________ 
Rats were made sodium-deficient by diet. Collection period was 6 hours 
from time of dosing and excretion values are totals for 6 hours. 
The data in Table III shows that the combination of a thiazide diuretic 
(hydrochlorothiazide) with an aldosterone antagonist can lead to a greater 
sodium excretion without a significant increase in potassium excretion and 
hence a more favorable Na/K ratio. These data indicate that, with proper 
manipulation of dosage, sufficient sodium would be excreted without 
excessive potassium loss. 
The use of combination therapy with a saluretic-diuretic and an aldosterone 
antagonist is indicated in certain instances. Secondary hyperaldosteronism 
as the result of a pathologic condition such as cirrhosis or as a result 
of vigorous diuretic therapy leading to hyponatremia is an underlying 
factor in refractoriness to diuretic agents and is an indication for the 
use of combination therapy. In addition, the use of an aldosterone 
antagonist in combination with another diuretic agent may allow the 
physician to reduce the dose of the primary diuretic and still get 
sufficient sodium excretion without excessive potassium loss. 
Certain starting materials or intermediates used to prepare the 
tertrasubstituted imidazolidines of this invention can be prepared as 
follows: 
PREATION OF INTERMEDIATES 
I. 1-Phenyl-2-methylamino-4-oxo-2-imidazoline 
2.2 g. of 1-phenyl-2-imino-3-methyl-4-oxoimidazolidine, 0.26 g. of sodium 
methoxide and 65 ml. of absolute alcohol were heated to reflux for 20 
hours. The insoluble solid was filtered and ethanol was evaporated leaving 
a yellow solid. 
The crude precipitate as chromatographed twice over silica gel and the 
product then recrystallized from acetone to yield 990 mg. (45%) of 
material, m.p. 208.degree.-210.degree. C. This product is used in Example 
9. 
II. 2,5-Diimino-3-phenyloxazolidine 
To a mixture of 3.75 g. of anilinoacetamide, 2.5 g. of potassium 
bicarbonate and 50 ml. of ethanol was added rapidly 2.7 g. of cyanogen 
bromide in 20 ml. of ethanol. The reaction mixture was heated to reflux. 
After heating overnight and cooling, a small amount of precipitate was in 
the flask. This was filtered and the ethanolic filtrate shown to be 
slightly acidic. The ethanol filtrate was concentrated down to dryness 
leaving a solid which was washed with ethanol. The yield of product, m.p. 
117.degree.-9.degree. C., was 3.9 g. (88%). The mass spectrum of the 
product gives a parent ion at m/e 175. This product is used to prepare 
intermediate III. 
III. 1-Phenyl-4-amino-2-oxo-3-imidazoline 
To 2.0 g. of 2,5-diimino-3-phenyloxazolidine dissolved in 50 ml. of 
absolute alcohol was added 0.6 g. of sodium methoxide. A white precipitate 
immediately formed in the solution. This was filtered, washed with 
ethanol, and dried to give 2.0 g. (100%) of product, m.p. 
281.degree.-283.degree. C. The infrared spectrum matched the known 
1-phenyl-4-amino-2-oxo-3-imidazoline. This product is used in Examples 10 
and 11. 
IV. 1-Phenyl-4-amino-2-oxo-3-imidazoline 
To a mixture of 3.75 g. of anilinoacetamide, 2.5 g. of potassium 
bicarbonate and 40 ml. of ethanol was added dropwise 2.7 g. of cyanogen 
bromide in 20 ml. of ethanol. This mixture was heated to reflux overnight. 
On cooling, a light tan precipitate formed in the flask. The precipitate 
was filtered, washed with ethanol, water, and dried overnight. The yield 
of product, m.p. 277.degree.-9.degree. C. was 3.3 g. (75%). The mass 
spectrum of the compound gave a parent ion at m/e 175. An analytical 
sample was prepared by recrystallization from ethanol-methanol, m.p. 
280.degree.-2.degree. C. In this case the ethanol filtrate was basic at 
the conclusion of the reaction leading to formation of the imidazoline in 
situ. This product is used in Examples 10 and 11. 
V. 1-(p-Chlorophenyl)-2-methylamino-4-oxo-2-imidazoline 
A mixture of 150 ml. of ethanol, 2.0 g. of 
1-(p-chlorophenyl)-2-imino-3-methyl-4-oxoimidazolidine and 0.2 g. of 
sodium methoxide was heated to reflux for 20 hours. The solvent was 
removed on the rotating evaporator and the residue dissolved in acetone. 
The acetone solution was concentrated and the product obtained by 
crystallization from acetone-ether. The yield of product was 0.4 g. (20%), 
m.p. 204.degree.-6.degree. C. This product is used in Example 8.

The invention will now be described in greater detail in conjunction with 
the following specific examples of tetra-substituted imidazolidines within 
the scope of this invention. 
EXAMPLE 1 
1-(p-Chlorophenyl)-2-imino-3-methyl-4-oxoimidazolidine 
In 25 ml. of water containing 0.84 g. of sodium hydroxide was dissolved in 
3.2 g. of p-chlorophenylcyanamide. To the clear solution was added 2.25 g. 
of N-methylchloroacetamide. The reaction mixture was stirred for 48 hours 
at room temperature. The precipitate was filtered to yield 1.9 g. of 
product, m.p. 182.degree.-184.degree. C. After the initial product was 
filtered, the filtrate was left stirring another three days. An additional 
1.2 g. of product precipitated from solution. Total yield of product was 
3.1 g. (66%). 
EXAMPLE 2 
1-(p-Chlorophenyl)-2-imino-3-methyl-4-oxoimidazolidine 
58 g. of p-chlorophenylcyanamide was dissolved in 600 ml. of absolute 
alcohol. To the solution was added 20.5 g. of sodium methoxide and the 
mixture was stirred for 30 minutes. Then 40.8 g. of 
N-methylchloroacetamide was added and the mixture was refluxed for 4 and 
1/2 hours. The white solid was filtered, washed with ethanol and water. 
Its m.p. (183.degree.-185.degree. C.), infrared spectrum and thin-layer 
chromatography agreed with a previous sample. It weighed 63 grams (70.5% 
yield). 
EXAMPLE 3 
1-Phenyl-2-imino-3-methyl-4-oxoimidazolidine 
In 29 ml. of water containing 1.0 g. of sodium hydroxide was dissolved 3.55 
g. of phenylcyanamide. To the clear solution was added 2.7 g. of 
N-methylchloroacetamide. The reaction mixture was left to stir for 120 
hours at room temperature. At that time no precipitate had formed. The 
solvent was therefore stripped off on a rotary evaporator under vacuum. 
The solid residue was slurried in dilute alkali and filtered to yield 1.0 
g. (21%) of product, m.p. 163.degree.-165.degree. C. 
EXAMPLE 4 
1-Phenyl-2-imino-3-methyl-4-oxoimidazolidine 
133 g. of phenylcyanamide hemihydrate was dissolved in 1500 ml. of absolute 
alcohol. To this solution was added 55 g. of sodium methoxide. This 
mixture was stirred for 30 minutes and 113 g. of N-methylchloroacetamide 
then added. This mixture was heated to reflux for 4 hours and allowed to 
stand overnight. The white precipitate was filtered and washed with 
ethanol. This ethanol filtrate was concentrated on the rotating evaporator 
and cooled giving additional product. Both crops of product were combined, 
washed with water and dried to give 87 g. (47%) of 
1-phenyl-2-imino-3-methyl-4-oxoimidazolidine, m.p. 169.degree.-170.degree. 
C. The infrared spectrum and thin-layer chromatography of this product 
matched that of the previous sample. 
EXAMPLE 5 
1-Phenyl-2-imino-3-methyl-4-oxoimidazolidine 
A mixture of 1.2 g. of 1-phenyl-2-amino-4-oxo-2-imidazoline, 15 ml. 
methylene chloride and 3.6 ml. of methylfluorosulfonate was left to stir 
at room temperature for 20 hours. The reaction was stopped and filtered to 
give 1.9 g. (94%) of the acid salt of the product. The isolation of the 
free base (m.p. 164.degree.) is made by treating the salt with aqueous 
sodium hydroxide. 
EXAMPLE 6 
1-Phenyl-2-methylimino-3-methyl-4-oxoimidazolidine 
3.78 g. of 1-phenyl-2-imino-3-methyl-4-oxoimidazolidine, 40 ml. dry 
methylene chloride and 6 ml. of methylfluorosulfonate were mixed and 
stirred in a flash equipped with a drying tube at room temperature. After 
20 hours the solid was filtered and the filtrate was stripped to dryness. 
The residue was treated with 30 ml. of water and extracted once with 
ether. The aqueous layer was separated and added slowly to 12 ml. of 5N 
NaOH with cooling and stirring. The white precipitate was filtered, washed 
with water and dried. Thin-layer chromatography showed a single spot (Rf 
0.6, 5% EtOH.multidot.CH.sub.2 Cl.sub.2). The yield was 2.75 g. (68%), 
m.p. 116.degree.-118.degree. C. 
EXAMPLE 7 
1-(p-Chlorophenyl)-2-methylimino-3-methyl-4-oxoimidazolidine 
By the method of Example 6 using 4.47 g. of 
1-(p-chlorophenyl)-2-imino-3-methyl-4-oxoimidazolidine as starting 
material, 1-(p-chlorophenyl)-2-methylimino-3-methyl-4-oxoimidazolidine, 
m.p. 150.degree.-152.degree. C., was obtained. 
EXAMPLE 8 
1-(p-Chlorophenyl)-2-methylimino-3-methyl-4-oxoimidazolidine 
3 g. of 1-(p-chlorophenyl)-2-methylamino-4-oxo-2-imidazoline and 9 ml. 
dimethyl sulfate were heated slowly to 120.degree. C. with stirring. The 
reaction mixture, cooled to room temperature, was filtered. The clear 
filtrate diluted with 150 ml. H.sub.2 O was extracted once with 200 ml. 
ether. The aqueous layer was separated and made basic with 5N NaOH and 
cooling. The precipitate was filtered and recrystallized once with 
acetonitrile. Thin-layer chromatography gave a single spot. The yield of 
product, m.p. 150.degree.-152.degree. C., was 1.6 g. (50%). 
EXAMPLE 9 
1-Phenyl-2-methylimino-3-methyl-4-oxoimidazolidine 
By the method of Example 8 using 2.5 g. of 
1-phenyl-2-methylamino-4-oxo-2-imidazoline as starting material, 
1-phenyl-2-methylimino-3-methyl-4-oxoimidazolidine, m.p. 
116.degree.-118.degree. C., was obtained. 
EXAMPLE 10 
1-Phenyl-4-imino-3-methyl-2-oxoimidazolidine 
To 0.4 g. of 1-phenyl-4-amino-2-oxo-3-imidazoline was added 1 ml. of 
dimethyl sulfate. This mixture was slowly heated to 160.degree. C., over a 
45-minute period. The reaction mixture was put onto the vacuum pump and 
warmed to 90.degree. C. to remove excess dimethyl sulfate. To the reaction 
was added 10 ml. of absolute alcohol giving a white solid. This material, 
400 mg., was filtered and dried. This solid material was then added to 
water where it rapidly dissolved giving an acidic solution. This indicates 
the desired compound had precipitated from ethanol as the methyl sulfuric 
acid salt. Addition of 5N sodium hydroxide precipitated the desired 
product; after filtering and drying, 260 mg. (61%) of 
1-phenyl-4-imino-3-methyl-2-oxoimidazolidine was obtained. This material 
was then recrystallized from acetone to give pure product, m.p. 
156.degree.-158.degree. C. The mass spectrum of the compound gave a parent 
peak at m/e 189. 
EXAMPLE 11 
1-Phenyl-3-methyl-4-methylimino- 2-oxoimidazolidine 
To 0.5 g. of 1-phenyl-4-amino-2-oxo-3-imidazoline was added 1 ml. of 
dimethylsulfate. The reaction mixture was heated slowly to near reflux 
when all of the material went into solution. The solution was kept at this 
temperature for 10 minutes and allowed to cool. The reaction mixture was 
added to water and made basic with dilute sodium hydroxide. The reaction 
mixture was then stripped to a residue on the vacuum pump and the 
remaining material chromatographed. This gave the desired 
1-phenyl-3-methyl-4-methylimino-2-oxoimidazolidine which was washed with 
hexane to give 85 mg. (15%), m.p. 160.degree.-2.degree. C. The mass 
spectrum of the compound gave a parent ion at m/e 203. 
EXAMPLE 12 
1-(p-Chlorophenyl)-2-imino-3-methyl-4-oxoimidazolidine hydrochloride 
3.0 g. of 1-(p-chlorophenyl)-2-imino-3-methyl-4-oxoimidazolidine was 
dissolved in 25 ml. of ethanolic HCl. This solution was filtered and added 
to an excess of ether upon which the hydrochloride precipitated. This was 
filtered, dried, and recrystallized from ethanol to give 0.8 g. product, 
m.p. 276.degree.-8.degree. C. The ethanol filtrate was concentrated to 
give an additional 1.1 g. of material. The total yield of product was 1.9 
g. (55%). 
EXAMPLE 13 
1-Phenyl-2-imino-3-methyl-4-oxoimidazolidine 
1.0 g. of 1-phenyl-2-imino-3-methyl-4-oxoimidazolidine was dissolved in 20 
ml. of hot ethanol. This solution was added to 25 ml. of ethanolic HCl. No 
precipitate formed. This solution was then added to an excess of ether and 
the product precipitated. This was filtered and dried to give 1.0 g. (85%) 
of product, m.p. 279.degree.-281.degree. C. 
EXAMPLE 14 
The present compounds can be dispensed in dosage unit forms such as soft 
shell or hard shell capsules. A formulation useful in the preparation of 
such capsules is as follows: 
______________________________________ 
Ingredients Grams per 100 capsules 
______________________________________ 
1-phenyl-2-imino-3-methyl- 
4-oxoimidazolidine 45 
lactose, U.S.P. 300 
magnesium stearate (0.5%) 
3.1 
Total 348.1 
______________________________________ 
The above formulation is thoroughly mixed and placed in equal quantities in 
100 capsules. 
EXAMPLE 15 
The following example represents a formulation useful in preparing tablets. 
Larger tablets can be scored and divided in halves to be given once or 
twice a day. Smaller tablets can be used in multiple doses to obtain the 
daily amount of active material. The following formulation has been found 
useful: 
______________________________________ 
Ingredients mg. per tablet 
______________________________________ 
1-(p-chlorophenyl)-2-imino- 
3-methyl-4-oxoimidazolidine 
450 
corn starch 210 
methyl cellulose 400 350 
magnesium stearate; 1% 182 
Total 1192 
______________________________________ 
The active ingredient, corn starch and methyl cellulose are blended 
together. The mixture, after drying, is lubricated with 1% magnesium 
stearate and compressed into tablets in a suitable tableting machine. 
EXAMPLE 16 
The following example represents a formulation useful in preparing an oral 
syrup: 
______________________________________ 
1-phenyl-2-imino-3-methyl-4-oxo- 
imidazolidine 4500 mg. 
sorbitol solution (70% N.F.) 
40 ml. 
sodium benzoate 150 mg. 
saccharin 10 mg. 
red dye (F.D. and C. No. 2) 
10 mg. 
cherry flavor 50 mg. 
distilled water, q.s. ad 
100 ml. 
______________________________________ 
The sorbitol solution is added to 40 ml. of distilled water and the active 
ingredient is suspended therein. The saccharin, sodium benzoate, flavor 
and dye are added and dissolved in the above solution. The volume is 
adjusted to 100 ml. with distilled water. Each ml. of syrup contains 45 
mg. of drug. 
EXAMPLE 17 
For the preparation of a parenteral solution the following procedure is 
followed. In a solution of 700 ml. of propylene glycol and 200 ml. of 
water for injection is dissolved 20.0 g. of 
1-(p-chlorophenyl)-2-imino-3-methyl-4-oxoimidazolidine with stirring. 
After dissolution is complete, a solution of 2.5 g. of ascorbic acid in 20 
ml. of water is then added. The pH of this solution is adjusted to 5.5 
with hydrochloric acid and the volume is made up to 1.0 liter with 
distilled water. The formulation is filtered through a 0.22 micron 
sterilizing filter, filled into 5.0 ml. ampules each containing 2.0 ml. 
(representing 40 mg. of drug) and sealed under nitrogen.