CNS Stimulants

3-[Methyl(phenylmethyl)amino]-N-[(phenylamino)carbonyl]sydnone imine or a pharmaceutically acceptable salt thereof serve as central nervous system stimulants with much less sympathomimetic activity than is found in amphetamine like stimulants.

BACKGROUND OF THE INVENTION 
After the discovery of the central nervous system stimulatory properties of 
3-(1-methyl-2-phenylethyl)-N-(phenylcarbamoyl)sydnone imine (Sydnocarb; 
U.S.S.R. 329,890 and Offenlegungsschrift 2,028,880) various analogues have 
been reported. U.S.S.R. 222,370 and Offenlegungsschrift 2,738,022 disclose 
sydnone imines which contain phenyl, 1- or 2-phenylethyl and the 
phenylisopropyl groups in 3-position as well as N-meta- and 
para-chlorophenyl and N-phenyl carbamoyl groups. Variations of 3-benzyl 
sydnonimines are disclosed in U.S. Pat. No. 3,277,108. Other variously 
substituted 3-aralkyl sydnonimines are disclosed by Olovyanishinkiva et 
al. Khim. Geterotsikl Soedin, 2 170-175 (1978) and 9 1198-1203 (1975). 
Sydnocarb is conventionally produced by cyanomethylation of amphetamine 
followed by nitrosation and ring closure with a mineral acid to yield 
sydnophen as an acid halide salt which is reacted with phenylisocyanate 
under mildly basic conditions to introduce the N-phenylcarbamoyl group. As 
an asymmetric compound, amphetamine may be employed as the initial 
reactant as the racemic d,l-mixture or as the pure d- or l-isomer to yield 
racemic or optically active sydnophen and ultimately sydnocarb. 
Yashunskii et al., J. Med. Chem., 14 1013-1015 (1971) disclose the marked 
CNS-stimulatory effect of 3-(1-methyl-2-phenylethyl) sydnonimine 
(Sydnophen). The relative activities of a large number of alkyl, aryl and 
aralkylsydnonimines are presented in Table 1 on page 1014. Most of them, 
including compound XVIII (2-hydroxy-1-methyl-2-phenylethyl-sydnonimine), 
were essentially inactive central nervous system stimulants relative to 
compound XIII (Sydnophen), demonstrating the criticality of the structure 
of the 3-substituent in the Sydnocarb series of compounds as far as CNS 
stimulatory activity is concerned. Thus, although the activity profile of 
Sydnocarb is not identical to that of amphetamine, or for that matter 
Sydnophen, CNS stimulatory activity is a common property of the initial 
reactant amphetamine, the intermediate Sydnophen and the final product 
Sydnocarb. 
DESCRIPTION OF THE INVENTION 
In accordance with this invention there is provided new central nervous 
system (CNS) stimulants possessing comparable stimulatory activity to 
Sydnocarb while exhibiting much less sympathomimetic activity than 
norepinephrine, amphetamine, methamphetamine, l-Sydnocarb, 
l-3-[2-[(diethylaminoacetyl)oxy]-2-phenylethyl]N-[(phenylamino)carbonyl]sy 
dnone imine (Example 9, Ser. No. 193,042, filed Oct. 2, 1980) and 
dl-3-[2-(dimethylamino)-2-phenylethyl]-N-[(phenylamino)carbonyl]sydnone 
imine (Example 2, Ser. No. 193,043, filed Oct. 2, 1980, now U.S. Pat. No. 
4,289,885). 
The CNS stimulants of this invention are 
3-[methyl(phenylmethyl)amino]-N-[(phenylamino)carbonyl]sydnone imine or 
pharmaceutically acceptable salts thereof. These compounds differ from 
Sydnocarb in that they do not have an asymmetric center and there is no 
need for resolution of optical isomers at any stage of synthesis to 
determine in which optical antipode lies the most desirable activity. 
In addition, this invention provides a method for relief of anergia which 
comprises administering 
3-[methyl(phenylmethyl)amino]-N-[(phenylamino)carbonyl]sydnone imine or a 
pharmaceutically acceptable salt thereof, to a warm blooded animal in need 
thereof, orally or parenterally, in an amount sufficient to stimulate the 
central nervous system. 
The compounds of this invention are prepared by the following technique: 
##STR1## 
The starting material 1-benzyl-1-methylhydrazine is synthesized by the 
methods described by Butler et al., J. Med. Chem. 14 1052 (1971). The 
1-benzyl-1-methylhydrazine is reacted with the sodium bisulfite 
formaldehyde addition product followed by reaction with a cyanide salt. 
The resulting cyanomethyl derivative is converted to the nitroso nitrile 
derivative with acidic nitrous acid and the nitrosonitrile derivative is 
converted to the oxadiazolium salt by treatment with anhydrous HCl. 
Neutralization of the oxadiazolium salt with a very mild base, such as 
sodium acetate, in the presence of an arylisocyanate affords the desired 
product. The pharmaceutically acceptable salts are prepared by 
conventional techniques from such organic or inorganic acid as 
hydrochloric, sulfuric, phosphoric, nitric, formic, acetic, propionic, 
oxalic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, 
maleic, benzoic, salicylic, methane sulfonic, toluene sulfonic, and the 
like. The salts are employed in isolating the base in order to free it 
from reaction by-products. Due to the lability of the nitrosonitrile in 
the presence of base, direct conversion of the nitrosonitrile to the 
desired product in the presence of a base such as triethylamine is not as 
efficient as the stepwise conversion through the oxadiazolium salt (see 
Example 5, infra). 
The CNS stimulant activity of the compounds of this invention was 
determined via the following standard test procedure: 
Male mice weighing 17 to 25 gms. were injected orally with 
3-[methyl(phenylmethyl)amino]-N-[(phenylamino)carbonyl]sydnone imine, 
hydrochloride in 1% Tween.RTM. 80. Control animals were injected with 1% 
Tween.RTM. 80. 
Six Columbus Instrument Company activity chambers were employed. Three mice 
given identical treatment were placed in each chamber for all tests. 
During each run, control animals (1% Tween.RTM. only) occupy 3 chambers; 
the other 3 chambers measure activity of the drug treated animals. For 
each dose of drug the experiment was run two times in a counterbalanced 
design so that each specific activity chamber records the activity of 
control animals during one run, and the activity of drug animals on the 
other run. Thus at each dose level 18 mice were used in the drug group and 
18 mice in the control group. 
Activity counts were recorded every ten minutes for a period of 2 hours. 
The data was analyzed using Students "t" test comparing the means of the 
control and drug groups for each 10 minute period. The drug treated group 
was compared graphically with the control group in regard to duration of 
action and dose response at peak drug activity. 
The product of Example 4 demonstrated 318 activity counts (p&lt;0.05) at 10 
mg/kg p.o. while dl-Sydnocarb demonstrates 636 activity counts (p&lt;0.01) in 
the same test procedure. 
The sympathomimetic activity of the product of Example 4, which is 
representative of the free base and other salts of this invention, was 
compared to representative CNS stimulants by administering the drugs to 
anesthetized, atropinized (1 mg/kg i.p.) pithed rats. The Sprague-Dawley 
rats, at least four in a test group, were normotensive males. The drugs 
were administered intravenously via a cannulated jugular vein and the 
blood pressure was measured from the carotid artery with a Statham 
Pressure Transducer monitored continuously on a Beckmann Multichannel 
Recorder. The mean blood pressure plus or minus standard error was 
determined as a measure of sympathomimetic activity. The values determined 
are as follows: 
______________________________________ 
mg/kg iv 
mean B.P. 
______________________________________ 
Norepinephrine .0001 +33 .+-. 3 
.001 +82 .+-. 5 
.01 +114 .+-. 6 
Amphetamine .01 +9 .+-. 1 
.1 +33 .+-. 2 
1.0 +72 .+-. 1 
Methamphetamine .01 +10 .+-. 2 
.1 +34 .+-. 2 
1.0 +63 .+-. 4 
L-Sydnocarb .01 +5 .+-. 1 
.1 +6 .+-. 1 
1.0 +5 .+-. 2 
10.0 +32 .+-. 6 
Example 4 .01 +3 .+-. 1 
.1 +4 .+-. 2 
1.0 +3 .+-. 2 
10.0 +13 .+-. 5 
Example 2 .01 +10 .+-. 3 
S.N. 193,043 .1 +7 .+-. 2 
1.0 +8 .+-. 1 
10.0 +49 .+-. 3 
Example 9 .01 +6 .+-. 1 
S.N. 193,042 .1 +6 .+-. 2 
1.0 +10 .+-. 2 
10.0 + 45 .+-. 5 
______________________________________ 
Thus the compounds of this invention exemplified by the product of Example 
4 provide central nervous system stimulation with considerably less 
sympathomimetic activity than is found in known CNS stimulants such as 
amphetamine. The undesirable hypertensive side effect of amphetamines is 
not a problem with the compounds of this invention and they may be used to 
treat anergic patients suffering from hypertension without aggrevation of 
the latter problem. 
As central nervous system stimulants with a unique activity profile, the 
compounds of this invention are useful in the treatment of anergic 
disorders (such as sleepiness and fatigue) including related types of 
depression and narcolepsy. Based upon the potency of the compounds of this 
invention in use in mice, the dose contemplated for use in the 70 kilogram 
human would vary from about 0.5 to 2 grams administered orally once or 
twice per day under the guidance of a physician. Of course, the dosage 
regimen as well as the route of administration, oral or parenteral, will 
vary with the condition of the patient relative to age, severity of 
depression, etc. 
The following examples illustrate the preparation of the compounds of this 
invention employing 1-benzyl-1-methylhydrazine hydrochloride as the 
initial reactant (neutralized in situ with sodium bicarbonate) (Example 
1), employing 1-benzyl-1-methylhydrazine as the free base (Example 2) and 
conversion of the oxadiazolium halide to the desired product (Example 3) 
and its hydrohalide salt (Example 4) as well as the less preferred direct 
conversion of the nitroso-nitrile with triethylamine and phenylisocyanate 
to the desired product (Example 5).

EXAMPLE 1 
5-Amino-3-[methyl(phenylmethyl)amino]-1,2,3-oxadiazolium chloride 
Dissolve 1-benzyl-1-methylhydrazine hydrochloride (23.2 g) in water (150 
ml). If any neutral material remains out of solution remove it by 
extraction into diethyl ether. Stir the aqueous layer and add solid sodium 
bicarbonate (12.4 g) portionwise at a rate to prevent excessive foaming. 
After complete addition, stir, then add the sodium bisulfite addition 
product of formaldehyde (23.0 g) portionwise. Stir 15 minutes, then add 
potassium cyanide (13.0 g) and heat the reaction on the steam bath for 5 
hours. Let the reaction stand at room temperature overnight. Extract the 
reaction well with diethyl ether, then wash, dry and evaporate the ether 
in vacuo. Pump the oil to dryness, then treat the oil in diethyl ether 
with decolorizing charcoal, filter and evaporate the ether in vacuo to 
obtain 19.8 g of 1-benzyl-2-cyanomethyl-1-methylhydrazine as a yellow oil. 
Cover the oil (19.5 g) with water (200 ml), stir and cool with an ice 
bath, then drip in 5 N aqueous HCl (45 ml). Cool the solution further with 
an ice-salt bath, then with stirring drip in a solution of sodium nitrite 
(15.4 g) in water (100 ml). Quickly extract the reaction with methylene 
chloride, then wash the extract with brine and dry the extract over 
anhydrous sodium sulfate for one-half hour. Filter and treat the filtrate 
with 5 N isopropanolic-HCl (45 ml), then allow to stand overnight. 
Evaporate the solvents in vacuo, add acetone and let stand to crystallize. 
Cool and filter to obtain 6.40 g. of the crude title product; m.p. 
150.degree.-153.degree. C. (dec.). 
Obtain an analytical sample from acetone; m.p. 155.degree.-157.5.degree. C. 
(dec.). 
Analysis for: C.sub.10 H.sub.13 ClN.sub.4 O. Calculated: C, 49.90; H, 5.44; 
N, 23,28; Cl, 14.73%. Found: C, 49.40; H, 5.34; N, 22.51; Cl, 14.85%. 
EXAMPLE 2 
5-Amino-3-[methyl(phenylmethyl)amino]-1,2,3-oxadiazolium chloride 
Cover the oily free base, 1-benzyl-1-methylhydrazine (47.5 g) with water 
(400 ml) and with stirring add the sodium bisulfite addition product of 
formaldehyde (50.0 g) and warm the mixture on the steam bath for 1/2 hour. 
Cool and add potassium cyanide (25.0 g), stir, then heat the reaction on 
the steam bath for 5 hours. Let the reaction cool and stand at room 
temperature overnight. Extract well with diethyl ether, then wash the 
extract with brine and dry, evaporate the ether in vacuo and pump to 
dryness to obtain 54.5 g of 1-benzyl-2-cyanomethyl-1-methylhydrazine as a 
yellow oil. Cover the oil with water (300 ml), stir and cool with an ice 
bath, then drip in 5 N aqueous HCl (125 ml). Stir, then filter through a 
glasswool plug to remove a small amount of neutral material. Cool the 
aqueous filtrate with an ice bath and with stirring drip in a solution of 
sodium nitrite (42.9 g) in water (200 ml). Stir for 15 minutes, then 
extract the reaction with methylene chloride. Dry the extract with 
anhydrous sodium sulfate for 1/2 hour. Filter and treat the filtrate with 
5 N isopropanolic HCl (125 ml) and allow to stand overnight at room 
temperature. Evaporate the solvents in vacuo, add acetone, then cool and 
filter to obtain 15.4 g of the title product; m.p. 154.degree.-156.degree. 
C. (dec.). 
EXAMPLE 3 
3-[Methyl(phenylmethyl)amino]-N-[(phenylamino)carbonyl]sydnone imine 
Stir 5-amino-3-[methyl(phenylmethyl)amino]-1,2,3-oxadiazolium chloride 
(3.61 g) with isopropanol (30 ml), cool with an ice bath, then add 
anhydrous sodium acetate (1.48 g), stir, then add phenylisocyanate (1.95 
ml) and continue stirring at room temperature for 2 hours. Let stand 
overnight, then filter and air dry the resulting solid. Cover the solid 
with water (75 ml) and stir at room temperature for 2 hours. Filter and 
dry to obtain the free base form of the title product (3.95 g); m.p. 
127.5.degree.-129.0.degree. C. 
Obtain a pure sample of the above solid by recrystallization from 
isopropanol to get m.p. 124.0.degree.-125.5.degree. C. 
EXAMPLE 4 
3-[methyl(phenylmethyl)amino]-N-[(phenylamino)carbonyl]sydnone imine, 
hydrochloride 
Suspend the product of Example 3 (3.79 g) in ethyl acetate, add 5 
N-isopropanolic HCl (3 ml) and swirl until conversion to the hydrochloride 
is complete to obtain 4.22 g of the title product; m.p. 
168.5.degree.-169.0.degree. C. (dec.). 
EXAMPLE 5 
3-[Methyl(phenylmethyl)amino]-N-[(phenylamino)carbonyl]sydnone imine, 
hydrochloride 
Dissolve 1-benzyl-1-methylhydrazine hydrochloride (10.0 g) in water (40 
ml), stir and cool with an ice bath, then add 37% formaldehyde solution 
(8.1 g). Continue cooling and stirring for 40 minutes, then drip in a 
solution of potassium cyanide (3.0 g) in water (40 ml). Stir for 3 hours, 
then extract the reaction with methylene chloride. Wash, dry and evaporate 
the extract in vacuo to obtain 8.1 g of 1-benzyl-2-cyanomethyl-1-methyl 
hydrazine. Cover the product with water (40 ml), cool with an ice bath, 
then carefully add concentrated aqueous-HCl (7.8 ml) dropwise. Further 
cool the reaction with an ice-salt bath, then drip in a solution of sodium 
nitrite (6.3 g) in water (50 ml) with continued stirring. After completing 
the addition, stir cold for 11/2 hours. Extract the reaction with 
methylene chloride, then wash, dry and evaporate the solvent in vacuo to 
obtain the crude 1-benzyl-2-cyanomethyl-1-methyl-2-nitrosohydrazine (9.4 
g). Dissolve the oil in dry toluene (50 ml), add phenylisocyanate (7.04 
g), stir, then add triethylamine (4.7 g) and heat the reaction at 
50.degree.-60.degree. C. for 61/2 hours. Cool, filter and evaporate the 
solvents in vacuo, then pump dry to obtain 13.8 g of crude residue. 
Dissolve the product in ethyl acetate, add 5 N isopropanolic-HCl (17.2 
ml). Scratch and stir, then let stand to crystallize. Filter to obtain 
1.62 g of crude title product; m.p. 165.degree. C. (dec.). Dissolve the 
solid in methylene chloride-methanol, treat with decolorizing carbon, 
filter then evaporate to low volume in vacuo. Add 95% ethanol and let 
stand to crystallize. Filter and dry to obtain 974 mg of the pure title 
product; m.p. 169.degree. C. (dec.). 
Analysis for: C.sub.17 H.sub.17 N.sub.5 O.sub.2.HCl. Calculated: C, 56.74; 
H, 5.04; N, 19.46; Cl, 9.85%. Found: C, 56.45; H, 5.11; N, 19.90; Cl, 
9.78%.