AMIDES A ACTION BIOLOGIQUE

BIOLOGICALLY ACTIVE AMIDES

Abrégé anglais

ABSTRACT
Compounds of formula (I):
<IMG> (I)
X is fluoro, chloro, bromo, iodo or trifluoromethyl;
and
R is branched alkyl having 4 to 8 carbon atoms,
cycloalkyl having 3 to 8 carbon atoms, cycloalkylalkyl
wherein the cycloalkyl moiety has from 3 to 8 carbon atoms and
the alkyl moiety has 1 to 3 carbon atoms, and when X is fluoro
or trifluoromethyl then R may also be hydrogen or alkyl having
1 to 3 carbon atoms, have anticonvulsant properties.

Revendications

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:-
1. A method of preparing a compound of formula (I):
<IMG>
(I)
wherein X is fluoro, chloro, bromo, iodo or trifluoro-
methyl and R is branched alkyl having 4 to 8 carbon
atoms, cycloalkyl having 3 to 8 carbon atoms, cyclo-
alkylalkyl wherein the cycloalkyl moiety has 3 to 8
carbon atoms and the alkyl moiety has 1 to 3 carbon
atoms and when X is fluoro or trifluoromethyl R may
also be hydrogen or alkyl having 1 to 3 carbon
atoms provided that R is not branched alkyl when X is
chloro; characterised in that one (a) reacts an amine
of the formula R.NH2 with an acid of the formula (II):
_-X-Ph.CH=CH.C02H or a reactive derivative thereof,
where R and X have the meanings defined in formula
(I), or (b) reacts an amine of the formula R.NH2 with
an alcohol or aldehyde of formula (III) or (IV)
respectively:
<IMG>
<IMG>
(III) (IV)
22

where R and X have the meanings defined in formula
(I), at a temperature below 10°C in the presence of
nickel peroxide and an inert liquid medium, or
(c) reacts a compound of the formula (V):
R.NH.W with an acid of the formula (II):
m-X-PH.CH=CH.CO2H or a reactive derivative thereof,
where R and X have the meanings defined in formula
(I) and W is a leaving group, or
(d) eliminates the elements of water, a hydrogen
halide or molecular halogen, as appropriate, from a
compound of formula (VI):
<IMG> (VI)
wherein A and B are the same and each is halo, or
one of A and B is halo or hydroxy and the other is
hydrogen, and R and X have the meanings defined in
formula (I).
23

2. A method according to claim 1, wherein R is
cycloalkyl of 3 to 6 carbon atoms.
3. A method according to claim 2, wherein R is
cyclopropyl.
4. A method according to claim 1, wherein X is
fluoro or trifluoromethyl.
5. A method according to claim 1, wherein X is
fluoro and R is cyclopropyl.
6. A method according to claim 1, wherein X is
trifluoromethyl and R is cyclopropyl.
7. A method according to claim la), wherein the
reactive derivative of the acid of formula (II) is
selected from the group consisting of amide, and acid
halide, the acid anhydride, and an alkyl ester or alkyl
thioester wherein in each case the alkyl group has 1 to
4 carbon atoms.
8. A method according to claim 7, wherein the
reactive derivative of the acid of formula (II) is an
alkyl ester.
9. A method according to claim 7, wherein the
reactive derivative of the acid of formula (II) is the
acid chloride.
10. A method according to claim 9, wherein the
reaction is effected in the presence of a base selected
from the group consisting of triethylamine, pyridine, di-
methylaniline, potassium carbonate and sodium carbonate.
24

11. A method according to claim la), for the pre-
paration of trans 3-fluoro-N-cyclopropylcinnamamide,
which comprises reacting trans 3-fluoro-cinnamamide with
cyclopropylamine.
12. A method according to claim la), for the pre-
paration of trans 3-trifluoro-N-cyclopropylcinnamamide,
which comprises reacting trans 3-trifluorocinnamoyl
chloride with cyclopropylamine.
13. A method according to claim la, 7 or 10, where-
in the reaction is effected in an inert liquid medium.
14. A method according to claim lb), wherein the
inert liquid medium is selected from the group consist-
ing of ether, benzene, tetrahydrofuran and a petroleum
hydrocarbon.
15. A method according to claim lc), wherein the
leaving group W is selected from the group consisting
of -CO.H, -CONH2, CONHR wherein R has the same meaning
as formula (I) (substituted urea), -CO.alkyl and -COO.alkyl
wherein each case alkyl has 1 to 4 carbon atoms.
16. A method according to claim lc), wherein the
reactive derivative of the acid of formula (II) is
selected from the group consisting of acid halides and
acid anhydrides.
17. A method according to claim lc), wherein the
reactive derivatives of the acid of formula (II) is an
acid chloride.

18. A method according to claim lc), 15 or 16,
wherein the reactive derivative of the acid of formula
(II) is the acid anhydride and the reaction is
effected in the presence of a catalytic amount of
sulphuric acid.
19. A method according to claim ld), wherein one
of A and B is hydroxy and the other is hydrogen and the
compound of formula (VI) is reacted with a dehydrating
agent.
20. A method according to claim ld), wherein one
of A and B is halo and the other is hydrogen and the
compound of formula (VI) is treated with a base or is
heated.
21. A method according to claim ld), wherein A and
B are the same and each is halo and the compound of
formula (VI) is treated with a suitable reducing agent.
22. A method according to claim ld), wherein A and
B are the same and each is halo other than iodo, the
compound of formula (VI) is converted to the correspond-
ing diiodo compound with subsequent elimination of
molecular iodine to yield the cinnamamide of formula
(I).
23. A compound of formula (I), as defined in claim
1, whenever prepared by the method of claim 1, or by an
obvious chemical equivalent.
26

24. A compound of formula (I), as defined in
claim 1, wherein R is cycloalkyl of 3 to 6 carbon
atoms, whenever prepared by the method of claim 2, or
by an obvious chemical equivalent.
25. A compound of formula (I), as defined in
claim 1, wherein R is cyclopropyl, whenever prepared by
the method of claim 3, or by an obvious chemical equivalent.
26. A compound of formula (I), as defined in
claim 1, wherein X is fluoro or trifluoromethyl, whenever
prepared by the method of claim 4, or by an obvious
chemical equivalent.
27. A compound of formula (I), as defined in
claim 1, wherein X is fluoro and R is cyclopropyl,
whenever prepared by the method of claim 5, or by an
obvious chemical equivalent.
28. A compound of formula (I), as defined in
claim 1, wherein X is trifluoromethyl and R is cyclo-
propyl, whenever prepared by the method of claim 6, or
by an obvious chemical equivalent.
29. trans 3-Fluoro-N-cyclopropylcinnamamide, whenever
prepared by the method of claim 11, or by an obvious
chemical equivalent.
30. trans 3-Trifluoromethyl-N-cyclopropylcinnamide,
whenever prepared by the method of claim 12, or by an
obvious chemical equivalent.
27

Description

76
~ .
This invention is concerned with chemicals which
have valuable pharmacological properties. In particular,
the invention concerns cinnamamides, their synthesis,
pharmaceutical preparations containing them, and their
use in medicine.
It has been found that the cinnamamides of
formula (I), as defined below, have anti-convulsant
activity in mammals as is shown by their effects upon
mice when administered to them in established pharma-
cological tests. These tests are:-
1. Maximal Electroshock Test (MES) in mice, a
method described by~Woodbury and Davenport, Arch int.
Pharmacodyn, Ther. 92, P. 97-107 (1952).
2. Metrazol Seizure Test (MET) in mice, a method
described by Swinyard, Brown and Goodman, J. Pharmacol,
Exp. Therap. 106, 319-330 (1952).
In formula (I):
O
~ CH=CH-C D
~/ \
/ ~HR (I)
X
X is fluoro, chloro, bromo, iodo or tri-
fluoromethyl; and
R is branched alkyl having 4 to 8 carbon atoms,
cycloalkyl having 3 to 8 carbon atoms, cycloalkylalkyl
wherein the cycloalkyl moiety has from 3 to 8 carbon atoms
and the alkyl moiety has 1 to 3 carbon atoms, and when X
- 1 - q~
C

`76
is fluoro or -trifluoromethyl then R may also be hydrogen
or alkyl having 1 to 3 carbon atoms.
The present invention is concerned with the
novel compounds of formula (I) and their preparation.
The novel compounds of the invention are those of formula
(I) as defined above with the proviso that R is not
branched alkyl when X is chloro.
The compounds of formula (I) having the trans
configuration are preferred.
A subclass of compounds within formula (I) are
those compounds wherein X is fluoro or tri-fluoromethyl
and R is hydrogen or alkyi having 1 to 3 carbon atoms.
A furthér subclass of compounds within
formula (I) are those whèrein X is fluoro, chloro,
bromo, iodo or trifluoromethyl and R is branched alkyl
having 4 to 8 carbon atoms. Suitable branched alkyl
groups include iso butyl, sec butyl, t butyl and those
of the higher homologues pentyl, hexyl, heptyl and octyl.
A still further subclass of compounds of formula
(I) are those compounds wherein X is fluoro, chloro,
bromo, iodo or trifluoromethyl and R is cycloalkyl having
3 to 8 carbon atoms, and these wherein the cycloalkyl
moiety has 3 to 6 carbon atoms; in particular may be
mentioned those compounds wherein R is cyclopropyl.
Also included in formula (I) is the subclass
of compounds wherein R is cycloalkylalkyl.
Among the compounds within formula (I) may
specifically be mentioned:-

76
3-fluorocinnamamide,
3-fluoro-N-ethylcinnamamide,
3-fluoro-N-iso-propylcinnamamide;
3-fluoro-N-cyclopropylcinnamamide;
3-fluoro-N-cyclopentylcinnamamide;
3-fluoro-N-cyclohexylcinnamamide;
3-fluoro-N-cycloheptylcinnamamide;
3-fluoro-N-cyclooctylcinnamamide;
3-fluoro-N-cyclobutylcinnamamide;
3-chloro-N-iso-butylcinnamamide;
3-chloro-N-cyclopropylcinnamamide;
3-chloro-N-cyclopentylcinnamamide,
3-chloro-N-cyclohexylcinnamamide;
3-chloro-N-cycloheptylcinnamamide;
3-chloro-N-cyclooctylcinnamamide;
3-chloro-N-cyclobutylcinnamamide;
3-bromo-N-iso-butylcinnamamide;
3-bromo-N-cyclopropylcinnamamide;
3-bromo-N-t-butylcinnamamide;
3-bromo-N-cyclobutylcinnamamide;
3-bromo-N-cyclopentylcinnamamide:
3-bromo-N-cyclohexylcinnamamide;
3-bromo-N-cycloheptylcinnamamide;
3-bromo-N-cyclooctylcinnamamide;
3-bromo-N-cyclohexylmethylcinnamamide;
3-iodo-N-iso-butylcinnamamide;
3-iodo-N-t-butylcinnamamide;
3-iodo-N-cyclopropylcinnamamide;

76
3-iodo-N-cyclopentylcinnamamide;
3-trifluoromethylcinnamamide
3-trifluoromethyl-N-methylcinnamamide
3-trifluoromethyl-N-ethylcinnamamide;
3-trifluoromethyl-N-n-propylcinnamamide;
3-trifluoromethyl-N-iso-propylcinnamamide;
3-trifluoromethyl-N-iso-butylcinnamamide;
3-trifluoromethyl-N-cyclopropylcinnamamide;
3-trifluoromethyl-N-cyclobutylcinnamamide,
3-trifluoromethyl-N-cyclopentylcinnamamide;
3-trifluoromethyl-N-cyclohexylcinnamamide;
3-trifluoromethyl-N-cycloheptylcinnamamide;
3-trifluoromethyl-N-cyclooctylcinnamamide; and
3-trifluoromethyl-~-cyclohexylmethylcinnamamide.
The compounds of formula (I) may be made by any
method known for the synthesis of cinnamamides of analogous
structure. For example, they may be prepared by the
acylation of an amine RNH2 wherein R is the same as
in formula (I) by the corresponding acid of formula (II):
m-X-PhCH=CHC02H wherein X has the meaning given for
formula (I) or a reactive derivative thereof -such as a
thioester or an ester (e.g. an alkyl ester or thioester
where the alkyl has e.g. 1 to 4 carbon atoms), an amide,
an acid halide ~e.g. an acid chloride) or an acid
anhydride. A wide variety of reaction conditions may
be employed depending upon the nature of the acylating
agent, but in general the reactants may be refluxed
together, preferably in an inert liquid medium such as
ether, benzene, toluene or cyclohexane.

76
A most convenient method of synthesis is to
react the acid chloride with the appropriate amine.
Preferably one equivalent of the halide should be used
with two or more equivalents of the amine, but the molar
excess of the amine may be replaced by another base such
as triethylamine, pyridine, dimethylaniline, or potassium
or sodium carbonate. A wide variety of polar or non-
polar liquid media may be used including water, alkanols
such as methanol, ethanol, etc., ether, dioxane, benzene,
toluene, xylene, petroleum ether, cyclohexane, tetra-
hydrofuran, chloroform and carbon tetrachloride. A wide
range of temperature conditions may be employed, for
example, from -10C to the reflux temperature of the
reaction mixture.
The compounds of formula (I) may be further
prepared directly from the corresponding alcohol or
- aldehyde of formulae (III) and (IV) at a temperature
below 10C:
~C~i=CH--CHi!OH X C~=C~.C~O
(III ) (IV-)
wherein X has the meaning in formula (I), by reaction
with the appropriate amine RNH2 in the presénce of
nickel peroxide and an inert liquid medium such as
ether, benzene, tetrahydrofuran, or a petroleum hydrocarbon.
~6

~9q~76
The compounds of formula (I) may also be made
by the reaction of an amide of formula (V): R.NH.W
wherein W is a leaving group, f~r example, -CO.H (a
formamide), -CO.alkyl where the alkyl has e.g. 1 to 4
carbon atoms (an amide), -CONH2 (urea), -CONHR wherein R
has the same meaning as formula (I) (substituted urea),
-COO. alkyl (urethane having 1-4 carbon atoms in the
alkyl group), with an acid of formula (II) or a -
reactive derivative thereof, for example, the acid
anhydride or halide. When the anhydride is used, a
catalytic amount of sulphuric acid is preferably
included. The reactants are conveniently heated
together in a liquid medium.
In a further method for making a compound of
formula 5I), water, a hydrogen halide or molecular
halogen is eliminated from a compound of formula (VI):
~ CH - CH - CONHR (VI)
X
wherein A and B are the same and each is halo or one
of A and B is halo or hydroxy and the other is hydrogen,
2~ and X and R have the meaning given in formula (I) above.
For example, the elimination of water from the ~- or
~-hydroxy compounds of formula (VI) may be effected by
- reaction with a dehydrating agent such as a base (e.g.
-- 6 --
, .

9~76
aqueous sodium hydroxide) or concentrated sulphuric or
polyphosphoric acid. The monohalo intermediates may be
treated with a base (e.g. potassium hydroxide or
dimethylaniline) or merely heated to release the hydrogen
halide. 'rhe dihalo intermediates may be reduced, for
example, with zinc and ethanol or converted to the
diiodo compounds by treatment with potassium iodide ,
with subsequent release of molecular iodine. -
'rhe intermediate acids of formula (II) may be
made by classical organic synthetic methods such as the
Perkin synthesis, the Reformatsky reaction and the
Knoevenagel condensation.
'rhe compounds of formula (I) may be used for
the treatment of prophylaxis of convulsions of mammals
such as mice, dogs and cats, and more importantly of
man. In particular they may be used in the treatment
of grand mal, petit mal,,psychomotor epilepsy and focal
seizures. 'rhe compound 3-trifluoromethyl-~-cyclopropyl-
cinnamamide is particularly valuable for its anticonvul-
sant properties.
~rhe compounds of formula (I),,in particular
the compound 3-fluoro-~-cyclopropylcinnamamide, may also
be used to decrease skeletal muscle tone. For
example they may be used to induce relaxation of
skeletal muscle in the treatment or prophylaxis of
spastic, hypertonic-and hyperkinetic conditions
associated with disorders due to increased skeletal
muscle tone. In particular the compounds may be used

39~76
in the t~eatment and symptomatic relief of conditions
such as parkinsonism, chorea, arthritis, athetosis,
status epilepticus and tetanus and especially in the
relief of muscle spasm in conditions such as myositis,
spondylitis, cerebral palsy and multiple sclerosis.
For the treatment of prophylaxis of con-
vulsions, or for decreasing muscular tone, the com-
pounds of formula (I) may be used at a dose of from
2 to 200 mg~kg of bodyweight per day. The optimum dose
of course will vary with the nature of the compound,
the condition of the patient and the route of administration,
but the preferred dose is in the range of from 20 to 60
mg~kg, most conveniently from 30 to 50 mg/kg body weight,
per day. Administration of the desired daily dose i9
preferably in three divided doses. For example, con-
venient forms of administration include tablets each
containing from 100 to 500 mg of a compound of formula
(I).
For use in medicine the compounds of
formula (I) may be administered as a pure chemical
but are preferably presented with an acceptable carrier
therefor as a pharmaceutical composition. The carrier
- must of course be 'acceptable' in the sense of being
compatible with the other ingredients of the composition
and not deleterious to the recipient of the composition.
The carrier may be a solid or a liquid or a mixture of
solid and liquid substances, and is preferably
formulated with a compound of formula (I) as a unit-dose
composition, for example a tablet, capsule or cachet for

76
oral administration or a suppository for rectal
administration. Other pharmaceutically active substances
may also be present in compositions of the present
invention and the composition may be formulated by any
of the well-known techniques of pharmacy consisting
basically of admixture of its components. Unit-dose
compositions, for oral, rectal or parenteral
administration (vid. inf.), conveniently contain a
compound of formula (I) in an amount in the range 100
to 500 mg.
For oral administration, fine powders or -
granules of the compounds may contain diluents and
dispersing and surface active agents, and may be
presented in a draught in water or in a syrup, in
capsules or cachets in the dry state or in an aqueous
or non-aqueous suspension, when a suspending agent may
also be included; in tablets, preferably made from
granules of the active ingredient with a diluent, by
compression with binders and lubricants; or in a
suspension in water or a syrup or an oil or in a water/
oil emulsion, when flavouring, preserving, suspending,
thickening and emulsifying agents may also be included.
The granules or the tablets may be coated, and the
tablets may be scored.
For parenteral administration (by intramuscular
or intraperitoneal injection), the compounds may be
presented in unit dose or multi-dose containers in
aqueous or non-aqueous injection solutions which may
_ g _
, ~ .,

C~:76
contain antioxidants, buffers, bacteriostats and solutes
which render the compounds isotonic with the blood; or
in aqueous or non-aqueous suspensions when suspending
agents and thickening agents may also be included;
extemporaneous injection solutions and suspensions may
be made from sterile powders, granules or tablets
which may contain diluents, dispersing and surface
active agents, binders and lubricants.
It will be understood from the foregoing
description that what we will claim in accordance with
this invention comprises any novel feature described
herein, principally but not exclusively as follows:-
(a) Novel compounds of formula (I) hereinabove
defined.
(b) Novel compounds of formula (I) hereinabove
defined having the trans configuration.
(c) The synthesis of a novel compound of formula
(I) by any known method and in particular the methods
specifically described above and including the reaction
of an acid m-X-PhCH=CHC02H or a reactive derivative
thereof with a compound of the formula R.NH.W wherein
W is a leaving group and R and X have the meaning in
formula (I).
(d) A pharmaceutical composition comprising a
compound of formula (I) and a pharmaceutically accept-
able carrier therefor.
-- 10 --
C
' ~ ,

76
(e) A method for the treatment or prophylaxis of
convulsions of a mam~lal including man comprising the
administration to the mammal of an anti-convulsant
effective, non-toxic amount of a compound of formula
(I).
(f) A method of decreasing skeletal muscle tone
in a mammal including man which comprises administration
to said mammal of a non-toxic effective tone,decreasing
amount of a compound of formula (I).
m e following Examples illustrate the present
invention but should not be construed as in any,way con-
stituting a limitation thereof. All temperatures are
in degrees Celsius.
EXAMPLE 1 - Trans 3-sromo-N-cyclopropylcinnamamide
A mixture o~f trans 3-bromocinnamic acid
(m.p. 177-179; 11.4 g), thionyl chloride (11.9 g)
and dry benzene (150 ml)'was heated at reflux for 2 hrs.
Solvent and excess thionyl chloride were removed by
distillation under reduced pressure leaving trans 3-
bromocinnamoyl chloride (12.2 g), b.p. 100-100.5/
0.2 mm Hg.
A solution of trans 3-bromocinnamoyl chloride
(12.2 g) in dry toluene (150 ml) was added dropwise
(rapidly) with rapid stirring to a solution of cyclo-
propylamine (6.3 g) in dry'toluene (150 ml). me reaction
mixture was stirred at room temperature for 2 hrs., then
at 30-35 for an additional hour; and the solvent and
excess amine were removed under reduced pressure. The
residue was triturated with water to remove cyclopropyl-
- 11 -

11~'9~76
amine hydrochloride. The product was filtered, washed
with dilute hydrochloric acid and then with water. It
was then recrystallized from ethanol:water (1:10) to
give white crystalline trans 3-bromo-N-cyclopropyl-
cinnamamide m.p. 110-111. Elernental analysis, NMR
and IR data were all consistent with the assigned
structure. TLC gave one spot run on silica gel with
5:1 and with 3:1 hexane:ethanol.
EXAMPLE 2 - Trans 3-Fluoro-~-cyclopropYlcinnamamide
A mixture of 3-fluorobenzaldehyde (40 g),
malonic acid (47 g), and an ethanolic solution (l50 ml)
containing pyridin (10 g) and piperidine (5 g) was heated
at reflux with stirring for 8 hrs. The reaction
mixture was chilled and water (300 ml) was added,
giving crystalline trans 3-fluorocinnamic acid which
was removed by filtration, washed with water and
dried. The trans 3-fluorocinnamic acid, m.p. 162-163.
was obtained in 84% yield.
- 12 -
t~ ,

~0~3~!76
A mixture of trans 3-fluorocinnamic acid
(32.3 g), thionyl chloride (48 g) and dry benzene
(300 ml) was heated at reflux for 2 hrs. Solvent and
excess thionyl chloride were removed by distillation
under reduced pressure leaving trans 3-fluorocinnamoyl
chloride as an oil.
A solution of trans 3-fluorocinnamoyl chloride
(3.3 g) in dry toluene (100 ml) was added with stirring
to a solution of cyclopropylamine (2.5 g) in dry ether
(100 ml) at ambient temperature. me-reaction mixture 3was heated -at 30-34 for 2 hrs., and the solvent and
excess amine were removed under reduced pressure. The
residue was triturated with water, filtered and re- ¦-
crystallized from ethanol:water (1:10) to give trans
3-fluoro-N-cyclopropylcinnamamide, m.p. 90-91. Elemental
analysis, ~MR and IR confirmed the structure. ! TLC gave
one spot run on silica gel with 5:1 and with 3:1
hexane:eth~nol.
f .
' ,

76
EXAMPLE 3 - Trans 3-Trifluoromethyl-N-Cyclopropyl-
cinnamamide
Using a method analogous to that described
in Examples 2 and 3, 3-trifluoromethylcinnamoyl chloride
was reacted with cyclopropylamine to give trans 3-
trifluoromethyl-N-cyclopropylcinnama~ide, m.p. 73.
EXAMPLE 4 - Trans 3-Bromo-N-iso-butylcinnamamide
Using a method analogous to that described in
Examples 2 and 3, 3-bromocinnamoyl chloride was reacted
with isobutylamine to give trans 3-bromo-N-isobutyl-
cinnamamide, m.p. 104-105.
EXAMPLE 5 - Tr-ans 3-Fluoro-N-cinnamamide
A mixture of 3-fluorobenzaldehyde (40 g),
malonic acid (47 g), and an ethanolic solution (150 ml)
containing pyridine (10 g) and piperidine (5 g)- was
heated at reflux with stirring for 8 hrs. The reaction
mixture was chilled and water (300 ml) was added, giving
crystalline trans 3-fluorocinnamic acid which was removed
by filtration, washed with water and dried. The trans
3-fluorocinnamic acid, m.p. 162-163, was obtaïned.
A mixture of trans 3-fluorocinnamic acid
(32.3 g), thionyl chloride (48 g) and dry benzene (300
- ml) was heated at reflux for 2 hrs. Solvent and excess
thionyl chloride were removed by distillation under
reduced pressure leaving trans 3-fluorocinnamoyl chloride
as an oil.
_ 14 -
,,~ . .
~ . J

76
Dry ammonia was passed slowly into a solution
of trans 3-fluorocinnamoyl chloride (5.7 g) in dry
toluene (50 ml) with rapid stirring until ammonium
chloride was no longer formed. The reaction mixture
was stirred at ambient temperature for an additional 30
minutes. The solvent and excess ammonia were then
removed under reduced pressure and the residual product
triturated with water. Recrystallization from ethanol:
water (1:10) gave trans 3-fluorocinnamamide, m.p. 121-
122. Elemental analysis, NMR and IR data were consistent
with the assigned structure. TLC gave one spot run on
silica gel using 5:1 and using 3:1 hexane:ethanol.
EXAMPLE 6
A suppository was formulated from the following
ingredients:-
trans 3-trifluoromethyl-N-cyclopropylcinnamamide 300 mg
cocoa butter 2000 mg
EXAMPLE 7
A soft gelatin capsule was filled with the
following ingredients:-
trans 3-trifluoromethyl-N-cyclopropylcinnamamide 300 mg
lactose 75 mg
starch, corn 20 mg
fused silica 2 mg
magnesium stearate 3 mg
- 15 -
` .J

39~76
EXAMPLE 8
A syrup suspension was prepared from the
following ingredients:-
trans 3-trifluoromethyl-N-cyclopropylcinnamamide 300 mg
sodium carboxymethylcellulose 20 mg
microcrystalline cellulose 100 mg
glycerin 500 mg
Polysorbate 80 10 ml
flavouring agent q.s.
preserving agent 0.1%
sucrose syrup q.s. to 5 ml
EXAMPLE 9
A compressed tablet was prepared from the
following:
trans 3-trifluoromethyl-N-cyclopropylcinnamamide 300 mg
starch, corn 50 mg
microcrystalline cellulose 50 mg
stearic acid 4 mg
magnesium stearate 1 mg
fused silica 1 mg
EXAMPLE 10
A soft gelatin capsule was filled with the
following ingredients:-
trans 3-fluoro-~-cyclopropylcinnamamide300 mg
lactose 75 mg
starch, corn 20 mg
fused silica 2 mg
magnesium stearate 3 mg
- 16 _

i~D9~76
EXAMPLE 11
A syrup suspension was prepared from the
following ingredients:-
trans 3-bromo-N-cyclopropylcinnamamide 300 mg
sodium carboxymethylcellulose 20 mg
microcrystalline cellulose 100 mg
glycerin 500 mg
Polysorbate 80 10 ml
flavoring agent q.s.
preserving agent 0.1%
sucrose syrup q.s. to 5 ml
EXAMPLE 12
A syrup suspension was prepared from the
following ingredients:-
trans 3-fluoro-N-cyclopropylcinnamamide 300 mg
sodium carboxymethylcellulose 20 mg
microcrystalline cellulose 100 mg
glycerin 500 mg
Polysorbate 80 10 ml
flavoring agent q. 9 .
preserving agent 0.1%
sucrose syrup q.s. to 5 ml
EXAMPLE 13
A compressed tablet was prepared from the
following:

1~9¢176
trans 3-bromo-N-cyclopropylcinnamamide 300 mg
starch, corn . 50 mg
microcrystalline cellulose 50 mg
stearic acid 4 mg
magnesium stearate 1 mg
fused silica 1 mg
EXAMPLE 14
A compressed tablet was prepared from the
following ingredients:-
trans 3-fluoro-N-cyclopropylcinnamamide 300 mg
starch, corn 50 mg
microcrystalline cellulose 50 mg
stearic acid 4 mg
magnesium stearate 1 mg
fused silica 1 mg
EXAMPLE 15 - Antlconvulsant activitv
In the MES pharmacological test referred to
hereinbefore, the stated compounds had the given ED50
when administered i.p. to mice.
Compound ED50 (mg/kg)
trans 3-fluoro-N-cyclopropylcinnamamide 60
trans 3-bromo-N-cyclopropylcinnamamide 77
trans 3-trifluoromethyl-N-cyclopropyl-
cinnamamide 56
trans 3-bromo-N-isobutylcinnamamide 46
trans 3-fluorocinnamamide 58
.
- 18 -
,

~9~76
~XAMPLE 16 - Muscle Relaxant Activit~
~ he effect of 3-fluoro-N-cyclopropylcinnamamide
as a centrally acting muscle relaxant was determined using
a method based on that described in Berger, F.M. & Bradley,
W. (Br. J. Pharmac. Chemother., (1946), 1, 265-272)
and Crankshaw, D.P. & Raper, C. (Br. J. Pharmac. (1970),
38, 148-156). At an oral dose of from 100-150 mg/kg
the compound suppressed polysynaptic reflex contractions
in the cat without affecting the monosynaptic knee-jerk
reflex.
EXAMPLE 17 - Anticonvulsant Activity
When trans 3-trifluoromethyl-N-cyclopropyl-
cinnamamide was administered to rats according to the
MES test it was found tohave an ED50 to 20+6 mg~kg and
18+3 mg/kg when administered orally and intraperitoneally
respectively.
EXAMPLE 17A
A solution of trans 3-trifluoromethylcinnamoyl
chloride (8.5 g) in anhydrous toluene (150 ml) was added
to a solution of cyclopropylamine (5 g) in anhydrous
toluene (100 ml). The reaction mixture was allowed to
stand at room temperature for several hours. The solvent
and excess amine were removed under reduced pressure.
The residue thoroughly triturated with water and re-
crystallized from ethanol/water (1/15) to give trans
3-trifluoromethyl-N-cyclopropylcinnamamide, m.p. 98.
Elemental analysis as well as NMR and IR spectra confirmed
the structure.
,

116~9~76
EXAMPLES 18 - 54
Following the procedure of Example 1, the
following trans cinnamamide derivatives were prepared
(in all cases the NMR, IR and elemental analyses con-
firmed the structures), which derivatives are compounds
of formula (I) having the indicated values for X and
R:
Example X _ mp, C
18 F cyclopentyl 138-139
19 F cyclohexyl 150
F cycloheptyl 152
21 F cyclooctyl 149-150
22 C1 cyclopentyl 107-108
23 Cl cyclohexyl 153-154
24 Cl cycloheptyl 119-120
Cl cyclooctyl 91-92
26 Br cyclopentyl 109-110
27 Br cyclohexyl 158
28 Br cycloheptyl 101-102
29 Br cyclohexylmethyl 120-121
I cyclopentyl 126-127
31 CF3 cyclopentyl 90-92
32 CF3 cyclohexyl 125
33 CF3 cycloheptyl 98-100
34 CF3 cyclooctyl 80
CF3 cyclohexylmethyl 96.5-97.5
36 F C2H5 97
37 F iso-propyl 95-96
_ 20 -
'
.

76
Example X R mp, C
38 F cyclobutyl 105
39 Cl iso-butyl 111.5-112.5
Cl cyclopropyl 112-113
41 Cl cyclobutyl 99
42 Br tert-butyl 154
43 Br cyclobutyl 114-115
44 Br cyclooctyl 101
I iso-butyl 109-110
46 I tert-butyl 152-153
47 I eyelopropyl 123
48 CF3 H . 102
49 CF3 CH3 . 125
CF3 C2H5 90
51 CF3 n-propyl 82-83
52 CF3 lso-propyl 116
53 CF3 iso-butyl 93
54 CF3 - eyelobutyl 132