N-Lower-alkyl 3-phenoxy-1-azetidinecarboxamides having the formula: ##STR1## wherein R is alkyl and R.sup.1 is hydrogen, aminocarbonyl and trifluoromethyl having central nervous system activity particularly anti-convulsant activity, are disclosed.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to certain novel heterocyclic compounds and 
more particularly to N-lower-alkyl 3-phenoxy-1-azetidinecarboxamides, 
compositions thereof and methods of making and using same. 
2. Description of the Prior Art 
N-Lower-alkyl 3-phenoxy-1-azatidinecarboxamides have not been described in 
the literature prior to the present invention. 
SUMMARY OF THE INVENTION 
The invention is especially concerned with novel N-lower alkyl 
3-phenoxy-1-azetidinecarboxamides having the formula: 
##STR2## 
wherein; 
R is lower alkyl, and 
R.sup.1 is hydrogen, aminocarbonyl and trifluoromethyl. 
The compounds of Formula I are useful because of their pharmacological 
action on the central nervous system. In particular, the novel compounds 
of Formula I possess anti-convulsant activity. 
Anticonvulsant properties were determined using groups of five adult female 
mice. The mice were given 50 and 150 mg/kg, i.p., of a test drug 30 
minutes prior to electrical or chemical challenge. 
Animals were challenged electrically by placing brass electrodes on the 
corneas and applying an electrical stimulus (60 Hz, 5 msec. pulse width, 
34 mA intensity) for 0.2 seconds by way of a Grass Stimulator and constant 
current unit and a Hunter Timer. The absence of tonic seizures upon 
cessation of the simuli was scored as protection in that animal. The 
number of animals protected from tonic seizures at each dose was 
determined. 
For chemical challenge, each animal received a convulsant dose of 
pentylenetetrazole (120 mg/kg, i.p.). Complete suppression of tonic 
seizures or prevention of death of the animal during the next hour was 
scored as protection in that animal. 
It is, therefore, an object of the present invention to provide certain 
novel N-lower-alkyl 3-phenoxy-1-azetidine-carboxamides, compositions 
thereof, and methods of making and using same. Another object is to 
provide novel N-lower-alkyl 3-phenoxy-1-azetidinecarboxamides having 
central nervous system activity. Other objects of the invention will be 
apparent to one skilled in the art and still other objects will become 
apparent hereinafter. 
In the foregoing Formula I and where they appear elsewhere throughout this 
specification, the terms have the following significance. 
The term "lower alkyl" as used herein includes alkyl radicals having one to 
six carbon atoms and includes such groups as methyl, ethyl, propyl, butyl, 
amyl and hexyl. Lower alkyl groups having one to four carbon atoms are 
preferred. 
The term "phenoxy" as used includes the unsubstituted phenoxy group and the 
monosubstituted phenoxy group wherein the substituent is an aminocarbonyl 
or a trifluoromethyl group. 
The compounds of the present invention may be conveniently prepared by 
contacting the appropriate 3-phenoxyazetidine of the formula: 
##STR3## 
wherein R.sup.1 is defined as hereinbefore with the appropriate isocyanate 
of the formula: 
EQU RNCO 
wherein R is defined as hereinabove. The reaction is carried out in the 
presence of a dry aprotic solvent such as benzene, toluene or xylene. 
Benzene is a preferred solvent. The temperature of the reaction can vary 
from about 5.degree. C. to about 20.degree. C. and time can vary from 
about 30 minutes to about 24 hours. 
The 3-phenoxyazetidines are novel compounds and are disclosed in copending 
application Ser. No. 886,487, filed Mar. 14, 1978.

The following examples describe in detail methods which have been devised 
for their preparation. It will be apparent to those skilled in the art 
that modifications may be practiced without departing from purpose and 
intent of the disclosure. 
EXAMPLE 1 
N-Methyl 3-phenoxy-1-azetidinecarboxamide 
The methanesulfonate of 3-phenoxyazetidine (10.5 g., 0.043 mole) was 
partitioned between 50 ml of benzene and 25 ml. of dilute sodium 
hydroxide. The benzene layer was dried over calcium sulfate and filtered. 
The filtrate was treated with 2.6 g. (0.043 mole) of methylisocyanate and 
the solution was stirred at room temperature for 18 hours. The resulting 
mixture was concentrated at reduced pressure and the residue was 
crystallized from a mixture of ethyl acetate-isopropyl ether to give 1.2 
g. (14%) of product (m.p. 139.degree.-141.degree. C.). 
Analysis: Calculated for C.sub.11 H.sub.14 N.sub.2 O.sub.2 : C, 64.06; H, 
6.84; N, 13.58. Found: C, 63.85; H, 6.81; N, 13.49. 
EXAMPLE 2 
N-Methyl 3-(2-aminocarbonylphenoxy)-1-azetidinecarboxamide 
To 8.0 g. (0.028 mole) of 2-(3-azetidinyloxy)benzamide stirring in 100 ml 
of dry benzene was added dropwise 1.6 g. (0.028 mole) of methylisocyanate 
with ice bath cooling. Stirring was continued at room temperature for 24 
hours. The solid material was filtered and was recrystallized from 95% 
ethanol. The product (4.0 g., 57%) melted at 236.degree.-240.degree. C. 
Analysis: Calculated for C.sub.12 H.sub.15 N.sub.3 O.sub.3 : C, 57.82; H, 
6.07; N, 16.86. Found: C, 57.74; H, 6.11; N, 16.48. 
EXAMPLE 3 
N-Methyl 3-(4-trifluoromethylphenoxy)-1-azetidinecarboxamide 
The oxalic acid salt of 3-(4-trifluoromethylphenoxy) azetidine (13.0 g., 
0.042 mole) was partitioned between 50 ml. of benzene and 50 ml. of 
potassium hydroxide solution. The benzene layer was dried over calcium 
sulfate and filtered, and to the stirring dried benzene solution was added 
2.6 g. (0.046 mole) of methyl-isocyanate. Stirring was continued 
overnight. The mixture was concentrated at reduced pressure and the solid 
residue was recrystallized from a mixture of isopropyl ether-ethyl 
acetate. The product weighed 7.5 g. (65%) and melted at 
154.degree.-157.degree. C. 
Analysis: Calculated for C.sub.12 H.sub.13 F.sub.3 N.sub.2 O.sub.2 : C, 
52.56; H, 4.78; N, 10.21. Found: C, 52.62; H, 4.75; N, 10.17. 
EXAMPLE 4 
N-Methyl 3-(3-trifluoromethylphenoxy)-1-azetidinecarboxamide 
To 6.0 g. (0.024 mole) of 3-(3-trifluoromethylphenoxy) azetidine in 50 ml. 
of dry benzene was added dropwise 1.37 g. (0.024 mole) of methylisocyanate 
with stirring, and stirring was continued for 30 minutes. The solid which 
crystallized in the flask was recrystallized using 95% ethanol to give 5.0 
g. (76%) of product (m.p. 145.degree.-147.degree. C.). 
Analysis: Calculated for C.sub.12 H.sub.13 F.sub.3 N.sub.2 O.sub.2 : C, 
52.56; H, 4.78; N, 10.22. Found: C, 52.67; H, 4.78; N, 10.16. 
EXAMPLE 5 
N-Methyl 3-(2-trifluoromethylphenoxy)-1-azetidinecarboxamide 
To a stirring solution of 3-(2-trifluoromethylphenoxy) azetidine (4.5 g., 
0.02 mole) in 50 ml. of dry benzene was added slowly at room temperature 
1.2 g. (0.02 mole) of methylisocyanate. After an additional 30 minutes a 
solid separated which was collected and recrystallized from benzene. The 
product (3.5 g., 68%) melted at 134.degree.-136.degree. C. 
Analysis: Calculated for C.sub.12 H.sub.13 F.sub.3 N.sub.2 O.sub.2 : C, 
52.56; H, 4.78; N, 10.22. Found: C, 52.28; H, 4.78; N, 10.07. 
EXAMPLE 6 
N-Methyl 3-(3-aminocarbonylphenoxy)-1-azetidinecarboxamide 
To a stirring solution of 7.0 g. (0.036 mole) of 
3-(3-azetidinyloxy)benzamide in 75 ml. of dry benzene was slowly added 2.0 
g. (0.036 mole) of methylisocyanate. Stirring was continued at room 
temperature for one hour. The solid which separated was filtered and 
recrystallized from 60% ethanol. The product weighed 6.0 g. (67%) and 
melted at 238.degree.-240.degree. C. 
Analysis: Calculated for C.sub.12 H.sub.15 N.sub.3 O.sub.3 : C, 57.82; H, 
6.07; N, 16.86. Found: C, 57.74; H, 6.13; N, 16.74. 
EXAMPLE 7 
N-Methyl 3-(4-aminocarbonylphenoxy)-1-azetidinecarboxamide 
To a stirring solution of 5.0 g. (0.026 mole) of 
4-(3-azetidinyloxy)benzamide in 75 ml. of dry benzene was added dropwise 
1.5 g. (0.026 mole) of methylisocyanate. Stirring was continued for 1.5 
hours. The white solid which separated was filtered and recrystallized 
using 95% ethanol. The solid was triturated with acetonitrile (due to 
solvation effects of the ethanol). The product weighed 4.0 g. (58%) and 
melted at 208.degree.-210.degree. C. 
Analysis: Calculated for C.sub.12 H.sub.15 N.sub.3 O.sub.3 : C, 57.82; H, 
6.07; N, 16.86. Found: C, 57.68; H, 6.10; N, 16.66. 
FORMULATION AND ADMINISTRATION 
The pharmacologically active 
N-lower-alkyl-3-phenoxy-1-azetidine-carboxamides of this invention are 
effective in the treatment of both petit mal epilepsy and grand mal 
epilepsy. Effective quantities of these compounds may be administered to a 
living animal body orally as in capsules, tablets or elixirs. It is only 
necessary that the active ingredient constitute an effective amount, i.e., 
such that a suitable effective dosage will be obtained consistent with the 
dosage form employed. The exact individual dosage as well as daily dosages 
will, of course, be determined according to standard medical principles 
under the direction of a physician or veterinarian. 
Based upon a comparison with known anticonvulsant compounds, daily dosages 
appear to preferably range from about 0.5 to 1.5 milligrams per kilogram 
of body weight in the treatment of petit mal epilepsy and about 25 to 35 
milligrams per kilogram of body weight in the treatment of grand mal 
epilepsy. Very small quantities of the active materials of the present 
invention, even as low as 0.1 milligram, are effective when minor therapy 
is involved. Unit dosages are usually 5 milligrams or above and preferably 
25, 50 or 100 milligrams per unit dose. The active ingredients of the 
invention may be combined with other pharmacologically active agents as 
previously indicated, or with buffers, antacids or the like, for 
administration and the proportion of the active agent in the composition 
may be varied widely. 
CAPSULES 
Capsules of 5 mg., 25 mg., and 50 mg. of active ingredient per capsule are 
prepared; with higher amounts of ingredient reduction may be made in the 
amount of lactose. 
______________________________________ 
Typical blend for encapsulation 
Per Capsule, mg. 
______________________________________ 
Active ingredient 5.0 
Lactose 296.7 
Starch 129.0 
Magnesium stearate 4.3 
Total 435.0 mg. 
______________________________________ 
Uniformly blend the selected active ingredient with lactose, starch and 
magnesium stearate and encapsulate the blend. 
Additional capsule formulations preferably contain a higher dose of active 
ingredient and are as follows: 
______________________________________ 
100 mg. per 
250 mg. per 
500 mg. per 
Ingredients Capsule Capsule Capsule 
______________________________________ 
Active ingredient 
100.0 250.0 500.0 
Lactose 231.5 126.5 31.1 
Starch 99.2 54.2 13.4 
Magnesium stearate 
4.3 4.3 5.5 
Total, mg. 435.0 435.0 550.0 
______________________________________ 
TABLETS 
A typical formulation for a tablet containing 5.0 mg. of active ingredient 
per tablet follows. The formulation may be used for other strengths of 
active ingredient by adjustment of weight of dicalcium phosphate. 
______________________________________ 
Ingredients Per Tablet, mg. 
______________________________________ 
(1) Active ingredient 
5.0 
(2) Corn Starch 13.6 
(3) Corn Starch (paste) 
3.4 
(4) Lactose 79.2 
(5) Dicalcium phosphate 
68.0 
(6) Calcium Stearate 
0.9 
Total 170.1 mg. 
______________________________________ 
Uniformly blend 1, 2, 4 and 5. Prepare 3 as a 10 percent paste in water. 
Granulate the blend with the starch paste and pass the wet mass through a 
number eight mesh screen. The wet granulation is dried and passed through 
a number twelve mesh screen. The dried granules are blended with calcium 
stearate and compressed. 
Additional tablet formulations preferably contain a higher dosage of the 
active ingredient and are as follows. 
______________________________________ 
50 mg. Tablet 
Ingredients Per Tablet, mg. 
______________________________________ 
Active ingredient 50.0 
Lactose 90.0 
Milo starch 20.0 
Corn starch 38.0 
Calcium stearate 2.0 
Total 200.0 
______________________________________ 
Uniformly blend the active ingredient, lactose, milo starch and corn 
starch. The blend is granulated, using water as a granulating medium. The 
wet granules are passed through an eight mesh screen and dried at 140 to 
160 degrees Fahrenheit overnight. The dried granules are passed through a 
number ten mesh screen and blended with the proper amount of calcium 
stearate and this blend is then converted into tablets on a suitable 
tablet press.