Anxiety alleviating compositions containing loweralkyl-N-[amino(arylaminocarbonyl)-iminomethyl]-N-methylglycinates

Compounds of the class of loweralkyl N-[amino(arylaminocarbonyl)iminomethyl]-N-methylglycinate acid addition salts are useful as antianxiety agents.

This invention relates to loweralkyl 
N-[amino(arylaminocarbonyl)iminomethyl]-N-methylglycinate acid addition 
salts (I) which are useful as antianxiety agents. 
DESCRIPTION OF PREFERRED EMBODIMENTS 
The novel loweralkyl 
N-[amino(arylaminocarbonyl)iminomethyl]-N-methylglycinates in the form of 
their acid addition salts may be structurally represented by the following 
formula: 
##STR1## 
wherein Ar is phenyl substituted in the 3-position by a radical selected 
from the group consisting of halo, methoxy, methyl, ethyl, or 
trifluoromethyl; R is lower alkyl; and HX is a pharmaceutically acceptable 
strong acid. Typical examples of suitable acid addition salts include: 
HCl, H.sub.2 SO.sub.4, CH.sub.3 SO.sub.3 H, p-tolyl--SO.sub.3 H, H.sub.3 
PO.sub.4 and the like. 
As used herein, "loweralkyl" may be straight or branched chain and have 
from 1 to about 8 carbon atoms, such as, for example, methyl, ethyl, 
propyl, isopropyl, butyl, pentyl, octyl and the like alkyls. The term 
"halo" is generic to fluoro, bromo, chloro, and iodo. 
The compounds of Formula I are prepared by the following two step process 
[which is depicted in Reaction Scheme A, below]: 
(1) Reaction of arylisocyanate of Formula II with a soluble salt, for 
example, a tetralkylammonium salt or trialkylaralkylammonium (Z.sup.+) 
salt such as, for example, tetrabutylammonium salt or 
benzyltrimethylammonium salt of creatine III to give an 
N-[amino(arylaminocarbonyl)iminomethyl]-N-methylglycine of Formula IV 
following acidification. This reaction is preferably conducted in an 
anhydrous, polar, inert, aprotic solvent such as, for example, DMF, DMSO, 
HMPA, tetramethylurea, THF, dioxane, DME, ethyl acetate and the like. 
(2) Fischer esterification of the compound of Formula IV in an anhydrous 
lower alkanol such as, for example, methanol, ethanol, 2-propanol, 
1-butanol and the like in the presence of excess strong acid such as, for 
example, HCl, H.sub.2 SO.sub.4, CH.sub.3 SO.sub.3 H, p-tolyl-SO.sub.3 H, 
H.sub.3 PO.sub.4 and the like. 
##STR2## 
The compounds of Formula I have been found to possess useful CNS depressant 
properties, particularly antianxiety effects, by the following test 
indicative of such activities on laboratory animals, with the results 
shown in Table I, below. 
The antianxiety assay was conducted by the procedure reported by I. Geller 
in Psychosomatic Medicine, J. H. Wodine and J. H. Moyer, Eds., Lea and 
Febiger, Philadelphia, 1962, p. 267. The antianxiety activity of the 
compound to be tested is studied in rats after intraperitoneal injection 
of the compound at doses generaly ranging from 10-25 mg/kg body weight and 
the effect of the compound on nonpunished and punished responses 
determined. Hungry rats are trained to press a bar for a food 
reinforcement: a dipper full of milk is delivered to the rat on the 
average of one every two minutes (variable interval schedule-V.I. II). 
Following 12 minutes on this schedule, a tone is presented for three 
minutes which signals the rewarding and simultaneous punishment of each 
bar press (a dipper full of milk is presented and accompanied by a shock, 
delivered through the grid floor, with each bar press). The shock 
delivered is 0.2 seconds in duration and ranges in intensity from 0.5-3.5 
milliamperes. Each rat is presented with six alternating pairs of 
nonpunished periods when milk alone is given and punished periods when 
milk and shock are administered. Control responses are obtained for each 
rat after a saline intraperitoneal injection on the two days immediately 
preceding the compound treatment day. Each rat is evaluated at the same 
time of day and in the same test chamber. Responses are recorded and 
reinforcements (milk) and punishment (shock) were delivered by means of 
suitable automated equipment. 
Each rat served as its own control in assessing the statistical 
significance of the effects of the test compound on nonpunished and 
punished responses respectively. The average of the total nonpunished and 
punished responses, respectively, observed on the two saline treatment 
days immediately preceding the test compound treatment day was compared to 
the total unpunished and the total punished responses, respectively, 
observed on the test compound treatment day. The statistical significance 
of the difference observed between the nonpunished responses and the 
punished responses, respectively, observed on the saline treatment day and 
the test compound treatment day was the t-test for paired observations. 
TABLE I 
______________________________________ 
Mean Responses 
Dose Nonpunished Punished 
Compound mg/kg ip N* C** TC*** C TC 
______________________________________ 
I, R.dbd.C.sub.2 H.sub.5 
15 7 1795 1290 2.3 25.1s 
I, R.dbd.CH.sub.3 
25 6 3604 .sup. 2137s 
2.1 21.8s 
I, R.dbd.CH(CH.sub.3).sub.2 
25 8 1785 1325 2.4 12.0s 
______________________________________ 
N* Number of rats 
C** Control 
TC*** Test Compound 
S Significantly different from control P &lt; 0.05 
In view of the foregoing, an effective CNS depressant amount of a compound 
of Formula I intimately admixed with a pharmaceutically acceptable carrier 
may be systemically administered to warm-blooded animals, including 
humans, to elicit a CNS depressant (anxiety alleviating) response. When 
administering the hereinabove described dosage unit forms for such 
purpose, amounts of active ingredient ranging about 15-500 mg, and 
preferably about 15-250 mg, per dosage unit may be utilized which may be 
administered orally or parenterally three or four times a day. 
The preferred compounds of the present invention are those of Formula I 
wherein Ar is 3-chlorophenyl and R is C.sub.1-3 lower alkyl. 
The following examples are intended to illustrate and not limit the scope 
of the present invention. Example 1 illustrates the preparation of the 
intermediate of Formula IV, while the other examples illustrate preparing 
the final products of Formula I.

EXAMPLE 1 
N-{Amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycine 
A solution of 9.58 g (0.073 mole) of anhydrous creatine in 96 ml (0.073 
mole) of 0.76M tetrabutylammonium hydroxide in methanol was evaporated to 
an oil in vacuo. The residue was dissolved in 100 ml of DMF. An 11.2 g 
(0.073 mole) sample of m-chlorophenylisocyanate was added dropwise and the 
reaction was stirred for two hours. The mixture was poured into 200 ml of 
water and 73 ml of 1N HCl. The gummy precipitate was induced to 
crystallize by scratching. The solid was collected and triturated with 
tetrahydrofuran to give 6.6 g (30% yield) of light yellow solid 
N-{amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycine. A 
hydrochloride salt was prepared from conc. HCl to yield a pink solid, m.p. 
228.degree.-234.degree. C. 
Anal. Calcd. for C.sub.11 H.sub.12 N.sub.4 O.sub.3.HCl: C, 41.13; H, 4.39; 
N, 17.44. Found: C, 41.11; H, 4.47; N, 17.46. NMR (DMSO d.sub.6 +TFA) 
.delta.11.4 (1H, s); 9.1 (2H, s); 7.65-7.08 (4H, m), 4.5 (2H, s), 3.2 (3H, 
s). 
EXAMPLE II 
Methyl 
N-{Amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycinate hydr 
ochloride 
A solution of 5.0 g of 
N-{amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycine in 50 
ml of 5% methanolic hydrogen chloride was allowed to stand at room 
temperature for four hours. The white crystalline methyl 
N-{amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycinate 
hydrochloride was collected by filtration; 3.2 g (57% yield), m.p. 
177.degree. C. (d). 
Anal. Calcd. for C.sub.12 H.sub.14 N.sub.4 O.sub.3.HCl: C, 43.00; H, 4.81; 
N, 16.71. Found: C, 43.01; H, 4.84; N, 16.80. NMR (DMSO d.sub.6 +TFA) 
.delta.11.71 (1H, s), 7.4 (4H, m); 4.6 (2H, s), 3.75 (3H, s); 3.2 (3H, s). 
EXAMPLE III 
Ethyl N-{amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycinate 
hydrochloride 
A 6.6 g sample of 
N-{amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycine was 
dissolved in 350 ml of 2% ethanolic hydrogen chloride and allowed to stand 
at room temperature for 16 hours. The solution was cooled and the 
precipitated solid collected. A second crop of crystals was taken by 
concentration of the filtrate. The combined solids were washed with THF 
and recrystallized from 2% ethanolic hydrogen chloride to give 3.8 g (48% 
yield) of white crystalline ethyl 
N-{amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycinate, 
m.p. 171.degree.-172.degree. C. 
EXAMPLE IV 
2-Propyl 
N-{Amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycinate 
hydrochloride 
A 5.0 g sample of 
N-{amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycine was 
stirred in 200 ml of 4% hydrogen chloride in 2-propanol for 30 minutes. 
The undissolved solid was removed by filtration. The filtrate was stirred 
for 24 hours at 25.degree.. The solution was cooled and the precipitated 
white crystalline 2-propyl 
N-{amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycinate, 3.5 
g (55% yield), was collected and dried, m.p. 185.degree. C. (d). 
EXAMPLES V-XIV 
By following the procedure of Example I, but substituting an equivalent 
amount of an appropriate arylisocyanate for the m-chlorophenylisocyanate 
used therein, and then by following the procedure of the appropriate one 
of Examples II-IV (as indicated), the following respective products may be 
prepared: 
______________________________________ 
Ex- Example 
ample Compound followed 
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V Methyl N--{amino[(3-bromophenyl)aminocar- 
2 
bonyl]iminomethyl}-N--methylglycinate 
hydrochloride 
VI Methyl N--{amino[(3-iodophenyl)aminocar- 
2 
bonyl]iminomethyl}-N--methylglycinate 
hydrochloride 
VII Methyl N--{amino[(3-methoxyphenyl)amino- 
2 
carbonyl]iminomethyl}-N--methylglycinate 
hydrochloride 
VIII Methyl N--{amino[(3-methylphenyl)aminocar- 
2 
bonyl]iminomethyl}-N--methylglycinate 
hydrochloride 
IX Methyl N--{amino[(3-ethylphenyl)amino- 
2 
carbonyl]iminomethyl}-N--methyl- 
glycinate hydrochloride 
X Methyl N--{amino[(3-trifluoromethylphenyl)- 
2 
aminocarbonyl]iminomethyl}-N-- 
methylglycinate hydrochloride 
XI Ethyl N--{amino[(3-fluorophenyl)amino- 
3 
carbonyl]iminomethyl}-N-- 
methylglycinate hydrochloride 
XII Ethyl N--{amino[(3-methylphenyl)amino- 
3 
carbonyl]iminomethyl}-N-- 
methylglycinate hydrochloride 
XIII Propyl N--{amino[(3-methoxyphenyl) 
4 
aminocarbonyl]iminomethyl}-N-- 
methylglycinate hydrochloride 
XIV Propyl N--{amino[(3-ethylphenyl)amino- 
4 
carbonyl]iminomethyl}-N-- 
methylglycinate hydrochloride 
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