Method for controlling hypertension and compositions

A method for controlling hypertension by administering to hypertensive subjects a N-aryl-N'-(2-imidazolidinylidene)urea compound and compositions suitable therefor are described.

FIELD OF INVENTION 
This invention relates to method for controlling hypertension employing 
N-aryl-N'-(2-imidazolidinylidene)urea compositions. 
PRIOR ART 
Certain imidazolidine ureas are known in the art. Thus, in U.S. Pat. No. 
3,168,520 imidazolidine ureas and hexahydropyrimidine ureas are taught. 
These compounds are taught to be useful as dye stabilizers. The patent 
specifically teaches 2-phenylcarbiliminoimidazolidine which is 
N-(2-imidazolidinylidene)-N'-phenylurea. There is no teaching or 
suggestion in the patent however for the use of imidazolidineureas and 
hexahydropyrimidineureas as active ingredients in pharmaceutical 
compositions. 
Some urea compounds have been disclosed to have certain pharmacological 
properties. Thus, U.S. Pat. No. 4,060,635 discloses amidinoureas. These 
compounds have an aryl group on one urea nitrogen and a substituted 
amidino group on the other urea nitrogen. U.S. Pat. Nos. 3,539,616 and 
3,784,582 teach amidinoureas in which one urea nitrogen is substituted 
with an aryl group and the other urea nitrogen is substituted with an 
unsubstituted amidino group. U.S. Pat. No. 4,058,557, also directed to 
amidinoureas but more remote, teaches compounds in which one of the 
amidino nitrogens necessarily is attached to an oxygen. None of the 
patents teach or suggest the substitution of an imidazolidino group on a 
urea nitrogen. None of these patents teach or suggest anti-hypertensive 
activity. 
A recent publication, G. H. Douglas et al., Arz. Forsch/Drug Res. 28(II), 
1480 (1978) discloses the results of many aryl substituted amidinoureas 
screened for antimotility and antisecretory activity. 
N-(2,6-Dimethylphenyl)-N'-(2-imidazolidinylidene)urea and 
N-(2,6-dimethylphenyl)-N'-(1-methyl-2-imidazolidinylidene)urea are among 
the compounds tested. No other pharmacological test is reported or use 
suggested for these compounds. 
DESCRIPTION OF THE INVENTION 
This invention is concerned with a method for treating hypertension by 
administering to a subject requiring therapy, a composition comprising a 
N-aryl-N'-(2-imidazolidinylidene)urea compound of the formula 
##STR1## 
or a pharmaceutically acceptable acid addition salt thereof. It also 
embraces compositions suitable for such application wherein the foregoing 
urea compound is in admixture with a pharmaceutically acceptable carrier. 
In the foregoing and subsequent formulas, Ar is phenyl substituted with 
from 0 to 3 substituents independently selected from groups characterized 
by the presence of halogen or of a carbon-containing group of from 1 to 2 
carbon atoms which is optionally attached to the phenyl through a 
non-basic hetero atom. Representative substituents are halo, such as 
fluoro, chloro and bromo; lower alkyl such as methyl and ethyl; lower 
alkoxy, such as methoxy and ethoxy; trifluoromethyl; methylthio; 
methylsulfonyl; methylsulfinyl; and cyano. In the most preferred 
compounds, Ar may be represented by 
##STR2## 
wherein R is methyl, ethyl, chloro, bromo, or methoxy and n is an integer 
of from 0 to 3. 
The activities of the above compounds reside in the urea base so that 
useful acid addition salts may be from various acids provided only that 
the acids be pharmaceutically acceptable. Representative acid salts 
include hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, 
p-toluenesulfonate, benzenesulfonate, malate, tartrate, fumarate, citrate, 
pamoate, maleate, malonate, succinate, oxalate, methosulfate, 
methanesulfonate, 2-napsylate and the like. 
The pharmacologically useful N-aryl-N'-(2-imidazolidinylidene)urea 
compounds are prepared by substantially two methods. The most generally 
useful method is by the reaction of an appropriate 2-imino-imidazoline 
(II) with an aryl isocyante (III) according to the following equation: 
##STR3## 
The 2-iminoimidazoline starting materials conveniently may be prepared 
(according to art methods and as subsequently described) and stored as an 
acid addition salt 
##STR4## 
Thus, the initial step is usually the conversion of the acid addition salt 
to the free base. This may be carried out by thoroughly stirring a 
solution or suspension in tetrahydrofuran of the acid addition salt with 
two molar equivalents of 50 percent aqueous sodium hydroxide, followed by 
the addition of anhydrous sodium sulfate to remove excess water. The thus 
obtained biphasic mixture is contacted with an appropriate aryl isocyanate 
to produce the desired N-aryl-N'-imidazolidinylideneurea compound. 
In a preferred method for carrying out the reaction between the aryl 
isocyanate and the 2-imidazolidine, a solution of aryl isocyanate in 
tetrahydrofuran is added portionwise with stirring to the biphasic mixture 
at temperatures in the range of about 20.degree. to 30.degree. C. and the 
mixture stirred for from a few hours to overnight. The 
N-aryl-N-'-imidazolidinylideneurea compound thus obtained is recovered, 
converted to an acid addition salt form, if desired, and purified 
employing conventional procedures. 
The free base may be generated by another procedure in which a solution of 
2-iminoimidazolidine acid addition salt is brought into contact with a 
suspension of lithium hydride, preferably, in the same solvent, in an 
inert atmosphere. Suitable solvents include dry dimethylformamide, 
dimethylsulfoxide, tetrahydrofuran, and the like. The temperature for 
addition is generally in the range of 0.degree. to 30.degree. C. An inert 
atmosphere is conveniently provided by use of nitrogen or argon. 
In a preferred method for carrying out the reaction, a solution of 
2-iminoimidazolidine acid addition salt is added dropwise with stirring to 
a cooled suspension of lithium hydride in a dry solvent under nitrogen 
atmosphere while maintaining temperatures in the 0.degree.-5.degree. C. 
range. Stirring is continued after the completion of the addition while 
the mixture is gradually allowed to warm to room temperature to obtain the 
free base. 
The reaction between 2-iminoimidazolidine and aryl isocyanate may be 
carried out by adding a solution of an aryl isocyanate, dropwise with 
stirring and cooling, to the reaction mixture containing the free base in 
an inert atmosphere, stirring the resulting mixture while gradually 
warming to ambient temperature and thereafter in the temperature range of 
from about 30.degree. to 110.degree. C., preferably in the range of 
65.degree. to 110.degree. C. for optimizing yields, to obtain the desired 
N-aryl-N'-(2-imidazolidinylidene)urea product. When the reaction is 
carried out at ambient temperatures, stirring is usually continued for 
several hours or overnight; when it is carried out at the elevated 
temperatures, about two hours is satisfactory. 
A second general but less preferred method for the preparation of 
N-aryl-N'-(2-imidazolidinylidene)urea compounds proceeds through the 
following sequence of reactions. 
##STR5## 
It is seen that the initial step is a reaction between an appropriate aryl 
isocyanate (III) and thiourea to produce a 
N-arylthioimidodicarbonicdiamide (IV) which is then reacted with methyl 
iodide to produce a methyl N'-[(arylamino)carbonyl]carbamimdothioate (V). 
The latter when reacted with an appropriately substituted ethylenediamine 
(VI) produces the N-aryl-N'-(2-imidazolidinylidene)urea (I) as a 
hydroiodide addition salt and which may be converted to the free base by 
conventional means. The foregoing reaction sequence however is not 
applicable for the preparation of urea compounds in which the aryl group 
is a 2,6-disubstituted phenyl group. 
The first step may be carried out employing a modification of a procedure 
reported by Lakra et al., (J. Am. Chem. Soc. 51, 2220 (1929)) in which an 
appropriate aryl isocyanate (III) and thiourea are reacted to produce a 
N-arylthioimidodicarbonic diamide compound (IV), hereinafter referred to 
for convenience as a "thiobiuret compound". For the reaction, 
substantially equimolar amounts of the reactants, preferably a slight 
excess of the thiourea, are employed. The temperature for the reaction may 
be in the range of from about 80.degree. to 120.degree. C. The reaction is 
preferably carried out in a solvent. Suitable solvents include 
dimethylformamide, dimethyl sulfoxide, and the like. 
The reaction is preferably carried out by heating the isocyanate and 
thiourea at steam bath temperature for from about two to twelve hours 
whereupon the thiobiuret compound (IV) is formed in the reaction mixture. 
The mixture is then diluted with water and cooled to induce 
crystallization of the thiobiuret compound which is then separated from 
the reaction mixture and purified employing conventional procedures. 
In the second step of the reaction, the N-aryl thiobiuret compound and an 
S-methylating agent are reacted to produce a methyl 
N'[(arylamino)carbonyl]carbamimidothioate compound (V), hereinafter 
referred to for convenience as the "thioate compound". Substantially 
equimolar amounts of the reactants, preferably a slight excess of 
methylating agent, are employed. Although other methylating agents such as 
dimethyl sulfate and the like also may be used, methyl iodide is 
preferred. A solvent is preferably employed. Suitable solvents include 
acetone, methanol, ethanol, isopropanol, and the like. The temperature of 
the reaction may range from ambient to reflux temperatures, ambient 
temperatures being preferred. 
The reaction is conveniently carried out by mixing together the thiobiuret 
compound and methyl iodide in methanol at ambient temperature for several 
hours. The product which forms in the reaction mixture as its hydroiodide 
addition salt is recovered and purified, if desired, employing 
conventional procedures. 
In the third step, the thioate compound (V) as the hydroiodide salt and an 
appropriate ethylenediamine compound (VI) are reacted to produce the 
desired N-aryl-N'-imidazolidinylideneurea product as a hydroiodide salt. 
Substantially equimolar amounts of the reactants are employed. The 
reaction is preferably carried out in methanol and other lower alkanols, 
methanol being preferred. 
The reaction is conveniently carried out by refluxing together the 
hydroiodide salt of (V) and the ethylenediamine compound in methanol for 
from about one to several hours and thereafter vaporizing the solvent to 
obtain as residue the desired N-aryl-N'-imidazolidinylideneurea product as 
a hydroiodide salt. The product may then be recovered and purified 
employing conventional procedures. 
The salt may be converted to the free-base. If another salt is desired, the 
free base is caused to react with another acid to form a desired acid 
addition salt. Conventional procedures may be employed for these 
conversions. Thus, for example, a representative convenient procedure for 
obtaining the free base from the salt is dissolving the acid addition salt 
in a minimal amount of lower alkanol solvent such as methanol or ethanol, 
warming with an organic base such as triethylamine and the like, and 
cooling to obtain the free-base product as a crystalline solid. Similarly, 
a representative convenient procedure for converting the free base to an 
acid addition salt is mixing the base with an alcoholic solution of an 
acid corresponding to the addition salt desired and cooling to obtain the 
acid addition salt. 
The N-aryl-N'-(2-imidazolidinylidene)urea compounds have been found to 
alleviate hypertension and further, to generally accomplish this without 
an accompanying increase in heart rate. An agent which has an 
antihypertensive effect without increasing but rather maintaining or 
decreasing heart rate, is the one considered most useful for beneficially 
treating a hypertensive subject. The extent to which a compound possesses 
these properties may be determined in the antihypertensive test on rodents 
and in the hemodynamic evaluation in dog hereinafter described. 
Rodent Antihypertensive Screen 
This test evaluates compounds for effects on arterial pressure and heart 
rate. In this test, the arterial pressure of spontaneously hypertensive 
rats or rats made hypertensive with injections of desoxycorticosterone 
acetate and 2 percent sodium chloride for drinking water, is monitored 
directly via an aortic cannula. Rats are anesthetized with an inhalation 
anesthetic (methoxyflurane or ether). The left carotid artery is isolated 
and cannulated. The tip of the cannula is advanced to the aorta and the 
cannula is exteriorized behind the neck at the level of the scapula. 
Animals are placed in individual cases and allowed to recover from the 
anesthetic and are kept unrestrained. The arterial cannula is connected to 
the presssure transducer which is attached to the recorder. Heart rate is 
determined from the arterial pressure recording. Animals with pressures 
greater than 149 millimeters of mercury are considered sufficiently 
hypertensive to be employed in the test for antihypertensive effects. The 
test compounds are administered either orally (p.o) by gavage or by 
intraperitoneal (i.p.) injection. The arterial pressure and heart rate are 
monitored for a minimum of 4 hours. A test compound is considered to be 
active as an antihypertensive agent if the mean arterial pressure (MAP) 
indicates a fall of &gt; 19 mm of Hg. Each animal serves as his own control. 
The results of this test employing two rats for each compound and performed 
with N-aryl-N'-(2-imidazolidinylidene)urea compounds are shown in Table I. 
Hemodynamic Evaluation in Dog 
This test is used to evaluate the effects of a given compound on both the 
cardiovascular and autonomic nervous systems in normal 
anesthetizedanimals. 
In this test, mongrel dogs are anesthetized with 20 mg/kg (milligrams per 
kilogram of body weight) of thiopental sodium and 60 mg/kg of 
alpha-chlorolose. Supplemental alpha-chlorolose (60 mg/kg) is used for 
maintenance of anesthesia, if necessary. A cuffed endotracheal tube is 
inserted to maintain an unobstructed airway, and the animal is respired 
with a ventilation pump. A femoral artery and vein are catheritized for 
recording of arterial pressure and for intravenous injections, 
respectively. Both common carotid arteries are isolated for performance of 
bilateral carotid occlusion. The vagus nerve is stimulated electrically at 
the peripheral end for ten seconds with five volts at 20 pulses per second 
each with a two milli-second duration to obtain cardiac arrest. The 
electrocardiogram is monitored through Limb Lead II. 
Control cardiovascular responses are obtained to the following 
pharmacological procedures: 1.0 mcg/kg I.V. (microgram per kilogram of 
body weight, intravenous) of l-epinephrine, carotid occlusion, 10 mcg/kg 
I.V. of dimethylphenylpiperazinium iodide (DMPP), peripheral vagal 
stimulation, 10 mcg/kg I.V. of acetylcholine and 2 mcg/kg I.V. of 
angiotensin. These control responses are produced twice, then the test 
compound is injected at 5 mg/kg (milligram per kilogram) I.V. employing 
bolus injections over approximately a one minute period. If no change in 
arterial pressure, heart rate, or ECG (Limb Lead II) occurs, an additional 
5 mg/kg I.V. of the test compound is administered. The effects of the test 
compound are noted on the electrocardiogram, arterial pressure, and heart 
rate. Ten minutes after administration of the test compound, another 
series of hemodynamic responses is obtained. 
Employing a dog for each test compound, heart rate data are obtained for 
N-aryl-N'-(2-imidazolidinylidene)urea compounds. The results from this 
test are also shown in Table I. 
The results seen in Table I shown that 
N-aryl-N'-(2-imidazolidinylidene)urea compounds and their salts possess 
not only the beneficial antihypertensive property but also the desirable 
property of maintaining or lowering normal heart rate. The properties are 
utilized in the methods and compositions of the present invention. 
The process of the present invention, namely, a method for treating 
hypertension or alleviating high blood pressure, comprises administering 
to subjects in need of treatment, a therapeutically effective hypertension 
or arterial pressure reducing amount of a N-aryl-N'(2 imidazolinylidene) 
urea compound of Formula I or its pharmaceutically acceptable salt as 
active agent. The active agents may be administered with or without 
carrier in the amounts hereinafter set forth. A preferred method of 
administration is by the use of pharmaceutical compositions in unit dosage 
form as described below. 
The operable ranges for carrying out the process is the administration, 
orally or parenterally, of from about 5 milligrams to about 500 milligrams 
of a N-aryl-N'-(2-imidazolidinylidene)urea compound in dosage unit form. 
While the therapeutic method is most useful for human subjects, it may 
also be employed for other mammals. Operable amounts are generally within 
the range of from about 0.5 to 50 mg/kg of body weight. 
The outstanding properties are most effectively utilized with the 
pharmaceutical compositions of the present invention. The pharmaceutical 
compositions comprising a N-aryl-N'(2-imadozolidinylidene)urea compound or 
acid addition salt thereof, as the active ingredient, may be prepared by 
intimately mixing the urea compound with a pharmaceutical carrier 
according to conventional pharmaceutical compounding techniques, which 
carrier may take a wide variety of forms depending on the form of 
preparation desired for administration, e.g., oral or parenteral. In 
preparing the compositions in oral dosage form, any of the usual 
pharmaceutical media may be employed, including liquid carriers such as 
water, glycols, oils, alcohols and the like for oral liquid preparations 
such as suspensions, elixers and solutions; and solid carriers such as 
starches, sugars, kaolin, calcium stearate, ethyl cellulose, etc., 
including materials which function as lubricants, binders, disintegrating 
agents and the like for powders, capsules and tablets. Because of their 
ease in administration, tablets and capsules represent the most 
advantageous oral dosage form. These compositions employ solid 
pharmaceutical carriers such as the aforementioned starches, sugars, 
kaolin and the like, generally with a lubricant such as calcium stearate. 
It is especially advantageous to formulate the aforementioned 
pharmaceutical compositions in dosage unit form for ease of administration 
and uniformity of dosage. The term "dosage unit form" as used in the 
specification and claims herein refers to physically discrete units 
suitable as unitary dosages, each unit containing a predetermined quantity 
of active ingredient calculated to produce the desired therapeutic effect 
in association with the required pharmaceutical carrier. Examples of such 
dosage unit forms are tablets, capsules, pills, powder packets, wafers, 
teaspoonful, tablespoonful and the like, and segregated multiples thereof. 
A dosage unit generally will contain from about 5 to about 500 mg of the 
N-aryl-N'-(2-imidazolidinylidene)urea compound. 
TABLE I 
__________________________________________________________________________ 
ANTIHYPERTENSIVE AND CARDIAC RATE 
DETERMINATIONS 
Compound 
##STR6## DoseDecreaseMaximumEffect on Heart RateSpontaneously 
Hypertensive (SH) Rat at Dosage 10 mg/kg I.V.in Heart 
BeatMaximum DecreaseHemodynamic 
Dog 
Ar HX (mg/kg i.p.) 
in MAP (mmHg) 
(beats/minute) 
(beats/min) 
__________________________________________________________________________ 
.phi. -- 30 72 +78 No change (NC) 
.phi. -- 10 p.o. 
39 -108 -- 
.phi. -- 100 p.o. 
30 +30 -- 
3-Cl .phi. 
HI 30 63 -42 -30 
2,6-Cl.sub.2 .phi. 
HCl 20-200 (p.o.) 
39-96 -39 to -108 
-54 
2,6-(CH.sub.3).sub.2 .phi. 
HCl . 1/2 H.sub.2 O 
30 &gt;19 .dwnarw.* 
-60 
2-Cl,6-CH.sub.3 .phi. 
HCl 30 &gt;19 .dwnarw. 
-42 
2,6-Br.sub.2 .phi. 
HCl 30 &gt;19 .dwnarw. 
-54 
2-C.sub.2 H.sub.5,6-CH.sub.3 .phi. 
2/3 fumarate 
30 &gt;19 .dwnarw. 
-42 
4-CH.sub.3 .phi. 
HCl 30 &gt;19** NC NC (5 mg/kg I.V.) 
2-OCH.sub.3 .phi. 
HCl 30 95 -108*** 
+30*** 
2-OCH.sub.3 .phi. 
HCl 10 p.o. 
23 -84 -- 
2-OCH.sub.3 .phi. 
HCl 100 p.o. 
90 -84 -- 
2-Cl .phi. 
HCl 30 &gt;19 -108 No change 
__________________________________________________________________________ 
*Decrease 
**One-half the number of rats 
***Large slowing effect on spontaneously hypertensive rat regarded to be 
more meaningful

The following examples illustrate the preparation of the 
N-aryl-N'-(2-imidazolidinylidene)urea compounds and the novel 
pharmaceutical compositions suitable in the practice of the invention but 
are not to be construed as limiting: 
Starting Material 
The 2-imidazolidine starting material of Formula II may be prepared by 
literature described methods or by the following representative 
preparation of the hydroiodide addition salt: 
213 grams (1.5 moles) of methyl iodide is added with stirring over one hour 
to a suspension of 153.24 grams (1.5 moles) of ethylenethiourea in 300 
milliliters of methanol. Stirring is continued for about an additional 
hour to complete the formation of S-methyl-ethylenethiourea. Anhydrous 
ammonia then is added thereto whereupon a reaction takes place with the 
formation of 2-iminoimidazolidine hydroiodide and methylmercaptan 
by-product. The stirring and intermittent addition of ammonia is continued 
for a total of about 26 hours. The mixture is concentrated with 
concomitant addition of isopropanol to replace the vaporized methanol, and 
then cooled and ether added thereto to produce 2-iminoimidazoline 
hydroiodide as a crystalline solid which after recrystallization from 
methanol/tert.-butanol has a melting point of 152.degree.-154.degree. C. 
Anal. Calcd. for C.sub.3 H.sub.7 N.sub.3.HI: C, 16.92; H, 3.79. Found: C, 
16.85; H, 3.82. 
EXAMPLE I 
N-(2,6-Dichlorophenyl)-N'-(2-imidazolidinylidene)urea Hydrochloride 
##STR7## 
To a stirred suspension of 2.13 grams (0.01 mole) of 2-iminoimidazolidine 
hydroiodide in 50 milliliters of dry tetrahydrofuran under an atmosphere 
of nitrogen is added 0.8 gram (0.01 mole) of aqueous 50 percent sodium 
hydroxide to produce free 2-iminoimidazolidine base and sodium iodide. 
Thereafter, 1 gram of anhydrous sodium sulfate is added and the stirring 
continued for another one-half hour. To the mixture then is added dropwise 
over a 2.5 hour period, a solution of 0.94 gram (0.005 mole) of 
2,6-dichlorophenyl isocyanate in 20 milliliters of tetrahydrofuran and the 
mixture allowed to stir overnight at room temperature to obtain a 
N-(2,6-dichlorophenyl)-N'-(2-imidazolidinylidene)urea product. The sodium 
salts are removed by filtration and the filtrate concentrated on a water 
bath under reduced pressure to obtain a pale yellow oil. The latter is 
dissolved in methylene chloride, and the methylene chloride solution first 
washed with saturated brine, dried over anhydrous potassium carbonate and 
treated with hydrogen chloride until pH &lt; 3 is reached. The solvent and 
excess hydrogen chloride are removed in vacuo and the residue 
recrystallized from methanol/ether to obtain purified 
N-(2,6-dichlorophenyl)-N'-(2-imidazolidinylidene)urea hydrochloride, m.p. 
210.degree.-212.degree. C., which decomposes to a new solid which melts at 
239.degree. C. 
EXAMPLE II 
N-(2-Chloro-6-methylphenyl)-N'-(2-imidazolidinylidene)urea and 
Hydrochloride 
A solution of 10.65 grams (0.05 mole) of 2-iminoimidazolidine hydroiodide 
in dimethylformamide is added dropwise with stirring over a 15 minute 
period to a cooled to 5.degree. C. suspension of 397.5 milligrams (0.05 
mole) of lithium hydride in 50 milliliters of dry dimethylformamide under 
nitrogen whereupon hydrogen evolution is observed. While stirring is 
continued, the mixture is allowed to gradually warm to room temperature. 
Thereafter, the reaction mixture is cooled to 0.degree.-5.degree. C. and a 
solution of 5.0 grams (0.03 mole) of 2-chloro-6-methylphenyl isocyanate in 
25 milliliters of dry dimethylformamide is added dropwise over a two hour 
period. After completion of the addition, the mixture is allowed to warm 
gradually to room temperature while the stirring under nitrogen atmosphere 
is continued overnight to obtain the desired 
N-(2-chloro-6-methylphenyl)-N'-(2-imidazolidinylidene)urea product which 
remains in solution. The product is recovered from the reaction mixture by 
(a) adding the mixture to 300 milliliters of ice water with stirring, (b) 
lowering the pH below 2 with aqueous 10 percent hydrochloric acid to 
precipitate acid insoluble material (c) filtering, (d) basifying the 
filtrate to pH 8-9 with solid potassium carbonate, and (e) saturating the 
solution with solid sodium chloride to precipitate the desired 
N-(2-chloro-6-methylphenyl)-N'-(2-imidazolidinylidene)urea free base as a 
white solid. The product after washing thoroughly with water has a melting 
point of 169.degree.-171.degree. C. 
The product urea base is dissolved in 30 milliliters of methanol, and 
methanolic hydrogen chloride added thereto to a pH below 3. Ether is then 
added whereupon a 
N-(2-chloro-6-methylphenyl)-N'-(2-imidazolidinylidene)urea hydrochloride 
product precipitates. The latter is recovered and recrystallized 
successively from 2-propanol and methanol-ether to obtain a purified 
product, m.p. 209.degree.-211.degree., which decomposes to a solid melting 
at 270.degree. C. (dec.). 
Anal. Calcd. for C.sub.11 H.sub.13 ClN.sub.4 O.HCl: C, 45.69; H, 4.88; N, 
19.37. Found: C, 45.59; H, 4.93; N, 19.35. 
EXAMPLE III 
N-(2,6-Dibromophenyl)-N'-(2-imidazolidinylidene)urea Hydrochloride 
In a manner similar to that described in Example II, a solution of 12.0 
grams (0.0563 mole) of 2-iminoimidazolidine hydroiodide in 50 milliliters 
of dry dimethylformamide is added dropwise with cooling and under an 
atmosphere of nitrogen to a suspension of 447 milligrams (0.0563 mole) of 
lithium hydride in 50 milliliters of dry dimethylformamide. After 
completion of the addition the mixture is allowed to warm to room 
temperature over a period of about half an hour, then cooled to 
0.degree.-5.degree. C., and a solution of 7.8 grams (0.0282 mole) of 
2,6-dibromophenyl isocyanate in 25 milliliters of dry dimethylformamide is 
added dropwise over a two hour period while maintaining the cooled 
temperature range. The mixture is then allowed to warm to room temperature 
and stirred overnight under nitrogen to obtain the desired 
N-(2,6-dibromophenyl)-N'-(2-imidazolidinylidene)urea product in the 
reaction mixture. The product is recovered from the reaction mixture by 
pouring the mixture into 400 milliliters of ice water, acidifying with 10 
percent hydrochloric acid to pH below 3, filtering to remove impurities, 
saturating the filtrate with solid sodium chloride and basifying with 
potassium carbonate to a pH of 8-9 to precipate the 
N-(2,6-dibromophenyl)-N'-(2-imidazolidinylidene)urea product as a white 
solid, m.p. 185.degree.-190.degree. C. (dec.). 
The thus obtained base urea product is suspended in 40 milliliters of 
methanol and methanolic hydrogen chloride added thereto to a pH below 2. 
Ether is then added to precipitate the 
N-(2,6-dibromophenyl)-N'-(2-imidazolidinylidene)urea hydrochloride as a 
white solid, m.p. 200.degree.-202.degree. C. (dec.). After two 
recrystallizations from methanol/2-propanol/ether, there is obtained a 
purified product, m.p. 215.degree.-217.degree. C. decomposing to a solid, 
m.p. 255.degree. C. (dec.). 
Anal. Calcd. for C.sub.10 H.sub.10 N.sub.4 Br.sub.2 O.HCl: C, 30.14; H, 
2.78; N, 14.06. Found: C, 30.12; H, 2.81; N, 14.04. 
EXAMPLE IV 
In a similar manner the following compound is prepared: 
N-(2-Imidazolidinylidene)-N'-(2-methoxyphenyl)urea.hydrochloride, m.p. 
197.degree.-199.5.degree. C., by reacting 2-iminoimidazolidine (prepared 
from 2-iminoimidazolidine hydroiodide and lithium hydride) and 
2-methoxyphenyl isocyanate at about 5.degree. to 10.degree. C. to obtain a 
N-(2-imidazolidinylidene)-N'-(2-methoxyphenyl)urea product, followed by 
reacting the urea base with methanolic hydrogen chloride and 
recrystallizing first from methanol/2-propanol, then twice from methanol 
ether. 
Anal. Calcd. for C.sub.11 H.sub.14 N.sub.4 O.sub.2. HCl: C, 48.80; H, 5.58; 
N, 20.70. Found: C, 48.75; H, 5.61; N, 20.71. 
EXAMPLE V 
N-(2-Ethyl-6-methylphenyl)-N'-(2-imidazolidinylidene)urea. Fumarate (3:2) 
In a manner similar to that previously described, 15.55 grams (0.073 mole) 
of 2-iminoimidazoline hydroiodide is added dropwise to a dry cooled 
suspension of 596 milligrams (0.075 mole) of lithium hydride in 30 
milliliters of dimethylformamide under an atmosphere of nitrogen. After 
completion of the addition, the mixture is allowed to warm to room 
temperature to complete the reaction. Thereafter the mixture is again 
cooled, a solution of 8.1 grams (0.05 mole) of 2-ethyl-6-methylphenyl 
isocyanate in 25 milliliters of dry dimethylformamide is added dropwise 
over a two hour period and then after the resulting mixture is stirred 
overnight while the temperature is allowed to rise to ambient temperatures 
to obtain a N-(2-ethyl-6-methylphenyl)-N'-(2-imidazolidinylidene)urea 
product. The base product is recovered by procedures similar to that 
previously described and after recrystallization from methanol-water, a 
purified base product, m.p. 185.degree.-187.degree. C. is obtained. 
A solution of 4.32 grams (0.0175 mole) of the base product thus obtained in 
35 milliliters of hot isopropanol is mixed with a solution of 2.04 grams 
(0.0175 mole) of fumaric acid in 35 milliliters of hot isopropanol and the 
resulting solution is allowed to cool whereupon a 
N-(2-ethyl-6-methylphenyl)-N'-(2-imidazolidinylidene)urea fumarate 
addition salt product crystallizes. The salt product after washing first 
with isopropanol and thereafter with ether melts at 180.degree. C. (dec.). 
Successive recrystallizations from methanol isopropanol, methanol/ether, 
and methanol does not produce a salt of reproducibly sharp melting point. 
Elemental analysis indicates the salt to be formed from three moles of 
base and two moles of fumaric acid. 
Anal. Calcd. for (C.sub.13 H.sub.18 N.sub.4 O).sub.3.(C.sub.4 H.sub.4 
O.sub.4).sub.2 : C, 58.13; H, 6.44; N, 17 .31. Found: C, 58.03; H, 6.57; 
N, 17.59. 
EXAMPLE VI 
In a similar operation there is prepared 
N-(2-Chlorophenyl)-N'-(2-imidazolidinylidene(urea.hydrochloride, 
m.p.187.degree.-189.degree. C. by reacting 2-iminoimidazoline (prepared 
from 2-iminoimidazoline hydroiodide and lithium hydride in 
dimethylformamide at about 20.degree. C.) and 2-chlorophenyl isocyanate at 
about 20.degree.-30.degree. C. overnight, then heating for 15 minutes to 
100.degree. C. on a steam bath to obtain a 
N-(2-chlorophenyl)-N'-(2-imidazolidinylidene(urea product as a crystalline 
solid, and thereafter reacting the urea base with methanolic hydrogen 
chloride. 
Anal. Calcd. for C.sub.10 H.sub.11 N.sub.4 OCl.HCl: C, 43.66; H, 4.40; N, 
20.36. Found: C, 43.69; H, 4.43; N, 20.36. 
EXAMPLE VII 
In operations carried out in a manner similar to that described in Examples 
II-VI, the following compounds may be prepared: 
N2-Imidazolidinylidene-N'-(4-methoxyphenyl)urea and its hydrobromide. 
N-(2-Chloro-5-trifluoromethylphenyl)-N'-(2-imidazolidinylidene)urea and its 
tartrate. 
N-(4-Fluoro-2,6-dimethylphenyl)-N'-(2-imidazolidinylidene)urea and its 
malonate. 
N-(2-Imidazolidinylidene)-N'-(4-methylphenyl)urea and its hydrochloride, 
m.p.210.degree.-212.degree. C. 
N-(2,4-Dichlorophenyl)-N'-(2-imidazolidinylidene)urea and its 
hydrochloride, m.p. 217.degree.-219.degree. C. 
N-(2,3-Dichlorophenyl)-N'-(2-imidazolidinylidene)urea and its 
hydrochloride, m.p. 218.degree.-220.degree. C. 
N-(3,5-Dichlorophenyl)-N'-(2-imidazolidinylidene)urea and its 
hydrochloride, m.p. 200.degree.-202.degree. C. 
N-(3,4-Dichlorophenyl)-N'-(2-imidazolidinylidene)urea and its 
hydrochloride, m.p. 217.degree.-219.degree. C. 
N-(2,5-Dichlorophenyl)-N'-(2-imidazolidinylidene)urea and its 
hydrochloride, m.p. 213.degree.-215.degree. C. 
N-(2-Imidazolidinylidene)-N'-(2,4,6-trichlorophenyl)urea and its 
hydrochloride, m.p. 232.degree. C. decomposes to solid, m.p. 260.degree. 
C. (dec.). 
N-(2-Fluoro-6-methylphenyl)-N'-(2-imidazolidinylidene)urea and its 
hydrochloride. 
N-(2-Imidazolidinylidene)-N'-(2-methyl-6-trifluoromethylphenyl)urea and its 
hydrochloride. 
N-(2-Imidazolidinylidene)-N'-(2-methyl-6-methylsulfonylphenyl)urea and its 
hydrochloride. 
N-(2-Cyano-6-methylphenyl)-N'-(2-imidazolidinylidene)urea and its 
hydrochloride. 
EXAMPLE VIII 
N-(2-imidazolidinylidene)-N'-phenyl urea and its Hydroiodide 
##STR8## 
As the first step in the reaction, phenyl isocyanate, 119 grams (1 mole) is 
added in one portion with swirling to a warm solution of 83.73 grams (1.1 
mole) of thiourea in 120 milliliters of dry dimethylformamide and the 
resulting solution heated for three hours. Thereafter, the solution is 
cooled, a mixture of ice and ice water cautiously added and the vessel 
scratched to induce crystallization of the desired intermediate 
N-phenylthioimidodicarbonic diamide. After crystallization starts, 
additional ice water (to about 1 liter) is added. The crystals which form 
are then recovered, washed with water and recrystallized from methanol to 
obtain 127 grams of a N-phenylthioimidodicarbonic diamide intermediate 
product, m.p. 176.degree.-180.degree. C. 
As a second step, 45.5 grams (0.32 mole) of methyl iodide is added to a 
solution of 59.5 grams (0.305 mole) of N-phenylthioimidodicarbonic diamide 
in 300 milliliters of acetone and stirring the resulting mixture for about 
two hours at room temperature. As a result of these operations crystals 
form in the reaction mixture which then are filtered and dried to obtain a 
methyl N'-[(phenylamino)carbonyl]carbamimidothioate hydroiodide product, 
m.p. 195.degree.-200.degree. C. An analytical sample, m.p. (190.degree.) 
200.degree.-202.degree. C. (Hoover) is obtained by recrystallization from 
methanol. 
Anal. Calcd. for C.sub.4 H.sub.11 N.sub.3 OS.HI: C, 32.06; H, 3.59; N, 
12.46. Found: C, 32.11; H, 3.62; N, 12.48. 
Next, a methanol solution of 33.72 grams (0.1 mole) of the thus prepared 
methyl N'-[(phenylamino)-carbonyl]carbamimidothioate hydroiodide and a 
methanol solution of 6.01 grams (0.1 mole) of ethylenediamine (about 50 
milliliters total of methanol) are mixed together and heated under reflux 
for about 1.5 hours. The mixture is then cooled to -20.degree. C. to 
crystallize N-(2-imidazolidinylidene)-N'-phenylurea product as its 
hydroiodide. Several crops are recovered, combined and the combined crops 
purified by dissolving in methanol, filtering, and evaporating the 
filtrate to isolate the hydroiodide product as residue. 
The hydroiodide product residue is converted to the urea base product and 
purified by a series of steps including dissolving the residue in a 
minimal amount of methanol, mixing and warming with 8.0 grams (0.079 mole) 
of triethylamine, replacing the methanol with ethanol, and then cooling to 
obtain crystals of N-(2-imidazolidinylidene)-N'-phenylurea base m.p. 
(181.degree.) 182.degree.-183.degree. C. after recrystallization from 
methanol. 
Anal. Calcd. for C.sub.10 H.sub.12 N.sub.4 O: C, 58.81; H, 5.92; N, 27.43. 
Found: C, 58.79; H, 5.92; N, 27.48. 
The hydroiodide addition salt after recrystallization from acetone had a 
melting point of 223.degree.-225.degree. C. (dec.). when immersed at 
225.degree. C., m.p. 230.degree. C. (dec.). 
Anal. Calcd. for C.sub.10 H.sub.12 N.sub.4 O.HI: C, 36.16; G, 3.94; N, 
16.87; I, 38.21. Found: C, 36.22; H, 3.96; N, 16.88; I, 38.21. 
EXAMPLE IX 
N-(3-Chlorophenyl)-N'-(2-imidazolidinylidene)urea 
In operations carried out in a manner similar to that described in Example 
VIII, 153.57 grams (1.0 mole) of m-chlorophenyl isocyanate is added to a 
warm solution of 95.15 grams (1.25 mole) of thiourea in 100 milliliters of 
dimethylformamide and the resultant mixture warmed overnight on the steam 
bath to obtain a N-(3-chlorophenyl)thioimidodicarbonicdiamide intermediate 
product in the reaction mixture. The mixture is then cooled to completely 
precipitate the desired intermediate product which after recovery by 
filtration and washing with ether has a melting point of 
187.degree.-189.degree. C. (dec.). Additional crops are obtained, combined 
and recrystallized twice from methanol-water and twice from acetonitrile 
to obtain a purified product, m.p. 205.degree.-207.degree. C. (dec.) 
To a clear solution of 80.3 grams (0.35 mole) of 
N-(3-chlorophenyl)thioimidodicarbonic diamide (prepared as 
above-described) is added 75.0 grams (0.525 mole) of methyl iodide and the 
reaction mixture stirred overnight to obtain the desired methyl 
N'-{[(3-chlorophenyl)amino]carbonyl}-carbamimidothioate hydroiodide 
product as a crystalline solid, m.p.182.degree.-183.degree. C. (dec.). 
To 37.1 grams (0.1 mole) of methyl 
N'-{[(3-chlorophenyl)amino]carbonyl}-carbamimidothioate hydroiodide thus 
prepared is added 6.0 grams (0.1 mole) of ethylenediamine in 100 
milliliters of methanol and the resulting mixture allowed to heat under 
reflux for five hours. The resulting reaction mixture is evaporated to 
dryness in vacuo and diluted with tertiary-butyl alcohol to obtain 
crystals of N-(3-chlorophenyl)-N'-(2-imidazolidinylidene) urea hydroiodide 
product as a crystalline solid. The crystals are recrystallized from 
tertiary butyl alcohol several times to obtain a purified product, m.p. 
192.degree.-194.degree. C. (dec.). 
Anal. Calcd. for C.sub.10 H.sub.11 ClN.sub.4 O.HI: C, 32.76, H, 3.29. 
Found: C, 32.82, H, 3.33. 
The following examples illustrate the novel pharmaceutical compositions but 
are not to be construed as limiting: 
EXAMPLE X 
1,000 hard gelatin capsules, each containing 200 milligrams of 
N-(2,6-dichlorophenyl)-N'-(2-imidazolidinylidene)urea are prepared from 
the following formulation: 
______________________________________ 
Grams 
______________________________________ 
N-(2,6-Dichlorophenyl) 
N'-(2-imidazolidinylidene) urea 
200 
Starch 250 
Lactose 750 
Talc 250 
Calcium stearate 10 
______________________________________ 
A uniform mixture of the ingredients is prepared by blending and employed 
to fill two-piece hard gelatin capsules. The capsules are suitable to be 
orally administered to hypertensive subjects to reduce blood pressure. 
EXAMPLE XI 
Gelatin capsules are prepared as described in Example X except that in the 
formulation, 325 grams of 
N-(2,6-dimethylphenyl)-N'-(2-imidazolidinylidene) urea is employed as 
active agent providing capsules containing 325 milligrams of 
N-(2,6-dimethylphenyl)-N'-(2-imidazolidinylidene) urea. 
EXAMPLE XII 
1,000 compressed tablets, each containing 500 milligrams of 
N-(2-imidazolidinylidene)-N'-(2-methoxyphenyl) urea are prepared from the 
following formulation. 
______________________________________ 
Grams 
______________________________________ 
N-(2-imidazolidinylidene)- 
N'-(2-methoxyphenyl)urea 
500 
Starch 750 
Dibasic calcium phosphate hydrous 
5,000 
Calcium stearate 2.5 
______________________________________ 
The finely powdered ingredients are mixed well and granulated with 10 
percent starch paste. The granulation is dried and compressed into tablets 
using starch as a disintegrant and calcium stearate as a lubricant. 
EXAMPLE XIII 
Tablets are prepared as described in Example XII except that 
N-(2,6-dibromophenyl)-N'-(2-imidazolidinylidene)urea is employed as active 
agent. 
EXAMPLE XIV 
Gelatin capsules are prepared as described in Example X except that 
N-(3-chlorophenyl)-N'-(2-imidazolidinylidene)urea is employed as active 
agent.