Note: Descriptions are shown in the official language in which they were submitted.
t~
The present invention relates to certain novel heterocyclic
compounds and more particularly to 3-phenoxy-1-azetidines, and methods of
making and using same.
Accordingly, the invention provides a 3-phenoxyazetidine oE
the formula:
H-N ~ ~ ~ R~
wherein Rl is hydrogen, aminocarbonyl or trifluoromethyl, or a salt
thereof.
The invention also provides a process for preparing a
3-phenoxyazetidine of formula
3 ~ (Il)
or salt thereof, wherein Rl is hydrogen, aminocarbonyl or trifluoromethyl,
which comprises hydrogenating a compound of formula
R ~ O ~
wherein R is an ~-me-thylbenzyl or diphenylmethyl group, in the presence of
a palladium on charcoal catalysk and, if required converting the product
to a salt.
t.,~ ,~
s3~37~
The novel compounds ~II) of the in~ention are use~ul as
intermediates in the preparation of N-lower alkyl 3-phenoxy-1-azetidine-
carboxamides having the formula:
; R-NHCO- ~ ~ 0 - ~ Rl ~I)
wherein;
R is lower alkyl, and
Rl is hydrogen, aminocarbonyl and trifluoromethyl, which
form the subject matter of our Canadian Patent Application No.361,59
filed October 6, 19~0.
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 anticonvulsant 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 chemtcal 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 stimuli 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 pentylenet~trazole(l20 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,
~.~t~
In the foregoing formula (I) or (II) and where they appearelsewhere throughout this specification, 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 herein includes the unsubstituted
phenoxy group and the monosubstituted phenoxy group wherein the substituent
is an aminocarbonyl or a trifluoromethyl group.
The compounds (I) may be conveniently prepared by contacting
the appropriate 3-phenoxyazetidine of the invention of the formula:
H-~ ~ 0 ~ Rl (II)
wherein Rl is defined as hereinbefore with an isocyanate of the formula:
RNC0
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 ~emperature o the reaction can vary
from about 5C to about 20C and time can vary from about 30 minutes to
about 24 llours.
Tlle following examples illustrate the invention and the
utility thereof.
62-CIP
~ S3 ~
Example 1
N-Methyl ~-phenoxy~-l-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. (14O of product
(m.p. 139-141C.).
Analysis: calculated for CllHl4N2O2: c,64.o6; H,6.84;
N,13-58
Found : C,63.85; H,6.81;
N,13.49
Example 2
N=Methyl ~-(2-aminocarbonylphenoxy)-1-azetidine-
carboxamide.
To 8.o g. (o.o28 mole) of 2-(~-azetidinyloxy)benzamide
stirring in 100 ml of dry benzene was added dropwise 1.6 g.
(o.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. ~he product (4.0 g., 57O melted at 236-240 C.
Analysis: calculated for ClzHl5N303: C,57.& ; H,6-o7;
N,16.86
Found : C,57.74; H,6.11;
N,16.48
Example 3
~0 N-Methyl 3-(4-trifluoromethylphenoxy)-1-azetidine=
carboxamide.
The oxalic acid salt of 3-(4-trifluoromethylphenoxy)
azetidine (13.0 g., o.o42 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.
~ 62-CIP
~ 3~7~3 i ~
(o.o46 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 et~er-ethyl acetate. The product weighed 7.5 g.
(65 0 and meIked at 154-157 C.
Analysis: calculated for Cl2Hl3F3N2O2~ C,52.56; H,4.78;
N,10.21
Found : C,52.62; H,4.75;
N,10.17
Example 4
N-Methvl 3-(~-trifluoromethylphenoxy~ azetidine-
carboxamide.
To 6.o g. (o.024 mole) of 3-(3-txifluoromethylphenoxy)
azetidine in 50 ml. of dry benzene was added dropwise 1.37 g.
(o.o'24 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. 145-147 C.).
Analysis: calculated for Cl2H13F3N202: CJ52-56: H,4-78;
N,10.22
Found : C,52.67; H,4.78;
N,10.16
Example ~
~-Methyl 3-(2-trifluoromethylphenoxy)-1-azetidine-
carboxamide.
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 ~0 minutes a solid
separated which was collected and recrystallized from
benzene. The product (3.5 g., 68O melted at 1~4-136 C.
Analysis: Calculated for Cl2Hl3F3NzO2: C,52.56; H,~.78,
N,10.22
Found : C,52.28, H,4.78,
N,10.07
~62 ~CIP
Example 6
~-Methyl ~-(;3-aminocarbonylphenoxy)-l-azetidine-
carboxamide.
To a stirring solution of 7.0 g. (o.o~6 mole) of
~i-( 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.o g. (670 and
melted at 238-240C.
10 Analysis: Calculated for Cl~HlsN303: C.,57.82; 1~,6.07;
N,16.86
Found : C,57.74; H,6.13;
~,16.7
Example 7
N-Methyl 3-(4-aminocarbonylphenoxy)-1-azetidine-
carboxamide.
To a stirring solution of 5.0 g. (o.026 mole) of
4-( ~-azetidinyloxy)benzamide in 75 ml. of dry benzene was
added dropwise 1.5 g. (o.026 mole) of methylisocyanate.
20 Stirring was continued for 1.5 hours. The white solid
which separated was filtered and recrystallized using 95%
ethanol. I~le solid was triturated with acetonitrile (due
to solvation effects of the ethanol). The product weighed
4.0 g. (58%) and melted at 208-210C.
25 AnalysiS: Calculated for Cl2Hl5N303: C,57-82; H,6.o7;
N,16.86
Found : C,57.68; H,6.10;
~J 16.66
l ~.t;~3 7~
Example 8
3-(phenoxy)-azetidine methanesulfonate
! A 200 ml solution of 7.8 g. (0.025 mole) of 1-diphenylmethyl-3-
phenoxyazetidine in ethanol was treated with 20% Pd(OH)2 on carbon and
hydrogenated or 23 hours at about 45 psi and 80C. The mixture was
filtered and the filtrate concentrated. The residue was diluted to 30 ml
with ethanol and 2.5 g. of methanesulfonic acid added. The isolatfid
methanesulfonate salt was recrystallized from ethanol. The salt weighed
2.3 g. (37.5%) and melted at 128D - 130C.
Analysis Calculated for CloH15N04S
C 48.97 H 6.16 N 5.71
Found
C 48.4 H 6.19 N 5.63
The compound was also prepared by hydrogenolysis of 1-(~ -methyl-
benzyl)-3-~3-chlorophenoxy) azetidine in isopropyl alcohol using the same
type catalyst and conditions.
Formulation and Administration
The pharmacologically active N-lower-alkyl-3-phenoxy-1-
azetidine-carboxamides of formula (I) 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
-
3B7~
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 formula ~I), 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 formula ~I) 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
compos~tion may be varied widely.
-7a -
'~ , 352-CIF
~J ~ 7~ ' 3
Capsules
capsu1es 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.
Tvpical blend for encapsulation Per Capsule, mq.
Active ingredient 5.0
Lactose 2 96 . 7
Starch 129.0
Magnesium stearate 4.~
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 ingxedient and are as follows:
_ _ -
100 mg. per 250 mg.per 500 mg. per
Inqredien~s CaPsule Capsule caPsule
Active ingredient 100.0 2 50 . o 500 . 0
Lactose 231.5 126.5 31.1
Starch 99 .2 54 ~2 13 . 4
Magnesium stearate 4.~ 4.3 5.5
.
Total, mg. 435.0 435-0 550 o
Tablets
A typical formulation for a tablet c:ontaining 5.o mg.
25 of active ingredient per tablet follows. The Eormulation
may be used for other strengths of active ingredient by
adjustment of weight of dicalcium phosphate.
InqredientsPer Tablet, mg.
1 Active ingredient5.o
2 Corn Starch 13.6
~50 3 Corn Starch (paste)3.4
4 Lactose 79.2
5 Dicalcium phosphate68.o
6 Calcium Stearate o.g
Total170.1 mg.
~ 3~7~ 62-CIE
Uniformly blend 1, 2, 4 and 5. Prepare ~ 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
Inqredients Per Tablet,~
Active ingredient 5Q.0
Lactose go.o
Milo starch 20.0
Corn starch ~8.o
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 t~n mesh screen and blended with the proper amount
of calcium stearate and this blend is then converted into
tablets on a suitable tablet press.
