CA1109076A

CA1109076A - Biologically active amides

Info

Publication number: CA1109076A
Application number: CA270,904A
Authority: CA
Inventors: Eugene Grivsky
Original assignee: Wellcome Foundation Ltd
Current assignee: Wellcome Foundation Ltd
Priority date: 1976-02-03
Filing date: 1977-02-02
Publication date: 1981-09-15
Also published as: FI770365A; FI69625B; DE2704365C2; IL51373A; IL51373A0; HU175435B; FR2340303B1; SE8300432L; PL119314B1; AR218865A1; JPS52116437A; SE436870B; GB1568401A; PL119716B1; DD130349A5; DE2704365A1; FI69625C; CS245756B2; JPS6056700B2; SE8300432D0

Abstract

ABSTRACT

Compounds of formula (I):
(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.

Description

~ .
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:-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;

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.

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.

, .

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 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.

C

' ~ , (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~'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.

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 .

' , 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

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.

A suppository was formulated from the following ingredients:-trans 3-trifluoromethyl-N-cyclopropylcinnamamide 300 mg cocoa butter 2000 mg 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 ` .J

39~76 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 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 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 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 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 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 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 .

, ~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.

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 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 37 F iso-propyl 95-96 _ 20 -' .

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 51 CF3 n-propyl 82-83 52 CF3 lso-propyl 116 53 CF3 iso-butyl 93 54 CF3 - eyelobutyl 132

Claims

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):

(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:

(III) (IV) 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):

(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).

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.

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.

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.