CS245758B2 - Production method of n-alkylsubstituted amides of cinnamic acid - Google Patents

Abstract

The compounds of the formula I are prepared by reacting a compound of the formula III R.NH.W, in which W denotes hydrogen or a group which can be eliminated, with an acid of the formula II <IMAGE> . Instead of the free acid, an active derivative of this acid can be used. The substituents in the formulae have the meanings given in Claim 1. The compounds of the formula I possess useful pharmacological properties. <IMAGE>

Description

where

X represents a fluorine, chlorine, bromine or iodine atom or a trifluoromethyl group;

R is a C 4 -C 8 alkyl group, a C 3 -C 8 cycloalkyl group, a cycloalkylalkyl group wherein the cycloalkyl moiety contains 3 to carbon atoms and the alkyl moiety is 1 to 3 carbon atoms, and when X is fluorine or trifluoromethyl R may also be a hydrogen atom or a C 1 -C 3 alkyl group, provided that when X is chlorine, R has a meaning other than a branched alkyl group having 4 carbon atoms and has antispasmodic properties in mammals. This finding has been proven by the action of these substances on mice as well as by evaluation of the effects established by known pharmacological tests:

1. The maximum electroshock test in mice, described by WoOdhury and Davenport in Arch. int. Pharmacodyn., Ther. 92, 97 (1952).

The metrazole assay in mice described by Swinyard, Brown and Goodman in J. Pharmacol. Exp. Therap. 106, 319 (1952).

Preferred compounds of formula I are those with a trans configuration.

Another preferred subgroup of compounds of formula (I) are those wherein X is fluorine or trifluoromethyl, and R is hydrogen or (C 1 -C 3) alkyl.

Another preferred subgroup of compounds of formula (I) are those wherein X is fluorine, chlorine, bromine or iodine or trifluoromethyl, and R is a branched alkyl group of 4 to 8 carbon atoms, the branched alkyl groups being isobutyl, sec-butyl and tert-butyl groups and similar groups derived from the homology groups of pentyl, hexyl, heptyl and octyl groups.

Another subgroup of compounds of formula (I) are those wherein X is fluorine, chlorine, bromine or iodine or trifluoromethyl and R is C 3 -C 8 cycloalkyl, preferably 3 to 6 carbon atoms. Particular mention may be made of compounds wherein R is cyclopropyl.

The compounds of formula I also include a subgroup of compounds wherein R is cycloalkyl as defined above.

Among the compounds of formula I, the following compounds are to be mentioned:

3-Fluoro-cinnamic acid amide,

3-Fluoro-cinnamic acid N-ethylamide,

Acid N-isopropylamide

3-fluorinated cinnamon,

3-Fluoro-cinnamic acid N-cyclopropylamide,

3-Fluoro-cinnamic acid N-cyclopentylamide,

3-Fluoro-cinnamic acid N-cyclohexylamide,

3-Fluoro-cinnamic acid N-cycloheptylamide,

3-Fluoro-cinnamic acid N-cyclooctylamide,

3-Fluoro-cinnamic acid N-cyclobutylamide,

Acid N-isobutylamide

3-chloro cinnamon,

N-cyclopropylamide acid

3-chlorinated cinnamon,

3-Chloro-cinnamic acid N-cyclopentylamide,

Acid N-cyclohexylamide

3-chlorinated cinnamon,

3-chloro-cinnamic acid N-cycloheptylamide,

3-chlorocinnamic acid N-cyclooctylamide,

3-Chloro-cinnamic acid N-cyclobutylamide,

3-Bromo-thioic acid N-isobutylamide,

3-Bromo-cinnamic acid N-cyclopropylamide,

3-Bromo-cinnamic acid N-tert-butylamide,

3-Bromocinnamic acid N-cyclobutylamide,

3-Bromocinnamic acid N-cyclopentylamide,

3-Bromocinnamic acid N-cyclohexylamide,

3-Bromocinnamic acid N-cycloheptylamide,

3-Bromocinnamic acid N-cyclooctylamide,

3-Bromocinnamic acid N-cyclohexylmethylamide,

3-Iodine cinnamic acid N-isobutylamide,

3-iodo-cinnamic acid N-tert-butylamide,

3-iodo-cinnamic acid N-cyclopropylamide,

3-iodo-cinnamic acid N-cyclopentylamide, 3-trifluoromethyl-cinnamic acid amide,

3-Trifluoromethylcinnamic acid N-methylamide,

3-Trifluoromethylcinnamic acid N-ethylamide,

3-Trifluoromethylcinnamic acid N-n-propylamide,

3-Trifluoromethylcinnamic acid N-isopropylamide,

3-Trifluoromethylcinnamic acid N-isobutylamide,

3-Trifluoromethylcinnamic acid N-cyclopropylamide,

3-Trifluoromethylcarboxylic acid N-cyclobutylamide,

N-cyclopentylamide acid

3-trifluoromethyl cinnamon,

Acid N-cyclohexylamide

3-trifluoromethyl cinnamon,

Acid N-cycloheptylamide

3-trifluoromethyl cinnamon,

3-Trifluoromethyl-cinnamic acid N-cyclooctylamide a

3-Trifluoromethylcinnamic acid N-cyclohexylamide.

The compounds of formula (I) may be prepared by any of the methods known for the synthesis of amine compounds ^. due to cinnamic acid of similar structures. According to the invention, the corresponding alcohol of the formula III or the aldehyde of the formula IV are used

CH = CH-CH3> OH (III)

where

X is as defined for Formula I.

These compounds are treated with an amine of formula V

RNHz (V) where

R is as hereinbefore defined, in the presence of nickel peroxide at a temperature between -85 and -10 ° C in an inert liquid medium such as ether, benzene, tetrahydrofuran or a mixture of hydrocarbons obtained by treatment with pores.

Alcohols of formula III and aldehydes of formula IV are prepared by conventional organic synthesis methods.

The compounds of the formula I can be used for the treatment or prophylaxis of convulsive conditions in mammals, such as mice, dogs and cats, and most importantly also in humans. In particular, they can be used in the treatment of large and small epileptic seizures, psychomotor epilepsy and focal inflammation. In view of its anticonvulsant properties, a particularly appreciated compound is 3-trifluoromethylcinnamic acid N-cyclopropylamide.

The compounds of formula (I), and in particular 3-fluoro-cinnamic acid N-cyclopropylamide, may also be used to reduce muscle; ton. For example, they can be used to induce skeletal muscle relaxation in the treatment or prophylaxis of spastic, hypertonic, or hyperktnetic conditions associated with agitation due to increased skeletal muscle tone. The compounds of the invention can be advantageously used in the treatment and symptomatic alleviation of conditions such as parkinsonism, chorea, arthritis, athetosis, epileptic condition and tetanus, in particular in relieving muscle cramps from conditions such as mysitis, spondylitis, cerebral paralysis and multiple sclerosis.

The compounds of formula I may be used in doses ranging from 2 to 200 mg per kilogram of body weight per day for the treatment of prophylaxis of convulsive processes or for the reduction of muscle tone. The optimum dose will, of course, vary depending on the nature of the compound, the condition of the patient and the route of administration, but the preferred dose is in the range of 20 to 60 mg, suitably 30 to 50 mg per kilogram of body weight per day. The daily dose is preferably administered in three divided doses. Suitable forms of administration are, for example, tablets each containing 100 to 500 mg of a compound of formula (I).

For use in medicine, the compounds of formula I may be administered as pure chemical compounds, but are usually combined with a suitable carrier to form a pharmaceutical composition. The carrier must be acceptable, i.e. compatible with the other ingredients, but must not be deleterious to the consumer of the composition. The carrier may be a solid or a liquid, or be a mixture of solids or liquids, and is preferably formulated to add a compound of formula I to the unit dosage form, such as tablets, capsules or sachets orally, or as suppositories. for rectal administration. Other pharmaceutically active compounds may also be included in the composition of the invention, and the composition may be shaped by any of the known pharmaceutical technology techniques based essentially on mixing the ingredients. Unit dosage formulations for oral, rectal or parenteral administration (see below) usually contain a compound of Formula I in an amount of 100 to 500 mg.

For oral administration, the fine powders or granules of the compounds may contain diluents and dispersing or surfactants and may be present in the infusion in water or syrup, or in the form of capsules or sachets in the dry state or in aqueous or non-aqueous suspension. it may also add a suspending agent. The compositions may also be in the form of a tablet, preferably made of granules of the active ingredient in the presence of a diluent by compression with binders and lubricants, or may be a suspension in water, syrup or oil or a water-in-oil emulsion, flavors, preservatives, suspensions. compositions, thickeners or emulsifiers. The granules or tablets may be coated, and the tablet may have incisions.

For parenteral administration [intramuscular or intraperitoneal injections], the compounds may be used in a single dose amount, or may be in multiple dose containers in aqueous or non-aqueous injection solutions, which may contain antiloxidizing agents, buffers, bacteriostats and solubilizers The pressure of the dissolved component on isotonic with blood. They may also be aqueous or non-aqueous suspensions containing suspending agents or thickeners. Sterile powders, granules or tablets may also be prepared as solutions or suspensions for injection, the solid compositions may also contain diluents, dispersing and surfactants, binders and lubricants.

Thus, pharmaceutical compositions comprising a compound of Formula I and a suitable pharmaceutical carrier are administered to mammals, including humans, in an anticonvulsant effective and non-toxic amount.

Further examples describe the process of the invention without limiting its scope. All temperatures are in degrees Celsius.

Example 1

The suppository is made from the following ingredients:

Trans-3-trifluoromethylcinnamic acid N-cyclohexylamide 300 mg cocoa butter 2 000 mg

Example 2

Soft gelatine capsules are filled with the following ingredients:

N-cyclopropylamide acid trans-3-trifluoromethyl cinnamon 300 mg lactose 75 mg cornstarch 20 May mg fused silica 2 mg magnesium stearic acid salt 3 mg

Example 3

A syrupy suspension is prepared from the following ingredients:

Trans-3-trifluoromethylcinnamic acid N-cyclopropylamide 300 mg carboxymethylcellulose sodium 20 mg microcrystalline cellulose 100 mg glycerol polysorbate 80 flavoring preservative sucrose syrup

Example 4

500 mg ml q. with.

0.1%

q. to 5 ml

The compressed tablet is made from the following ingredients:

N-cyclopropylamide acid trans-3-trifluoromethyl cinnamon 300 mg cornstarch 50 mg microcrystalline cellulose 50 mg stearic acid 4 mg magnesium stearic acid salt 1 mg fused silica 1 mg

Example 5

Soft gelatin capsules are filled with the following additional ingredients:

N-cyclopropylamide acid

trans-tri-fluorinated cinnamon 300 mg lactose 75 mg cornstarch 20 mg fused silica 2 mg magnesium salt of silicic acid 3 mg

Example 6

A syrupy suspension is prepared from the following ingredients:

N-cyclopropylamide acid

trans-3-brominated cinnamon 300 mg sodium carboxymethylcellulose 20 mg microcrystalline cellulose 100 mg glycerol 500 mg polysorbate 80 10 ml flavor q. with. preservative 0.1% sucrose syrup q. with. to 5 ml

Example 7

A syrupy suspension is prepared from the following ingredients:

N-cyclopropylamide acid

trans-3-fluorocin 300 mg sodium carboxymethylcellulose 20 mg microcrystalline cellulose 100 mg glycerol 500 mg polysorbate 80 10 ml flavor q. with. preservative 0.1% sucrose syrup q. with. to 5 ml

Example 8

The compressed tablet is made from the following ingredients:

Trans-3-cinnamic acid N-cyclopropylamide 300mg maize starch 50mg microcrystalline cellulose 50mg stearic acid 4mg magnesium stearate 1mg fused silica 1mg

Example 9

The compressed tablet is prepared from the following ingredients:

Trans-3-fluoro-cinnamic acid N-cyclopropylamide 300mg maize starch 50mg microcrystalline cellulose 50mg stearic acid 4mg magnesium stearate 1mg fused silica 1mg

Example 10

Anti-convulsive efficiency

In the maximum electroshock test, as discussed herein, the ED50 for each compound is evaluated for intraperitoneal administration to mice:

Compound ED 50 (mg / kg)

Trans-3-fluorocinnamic acid N-cyclopropylamide60

Trans-3-brominnamic acid N-cyclopropylamide77

Trans-3-fluorocinnamic acid N-cyclopropylamide56

Trans-3-fluoro-cinnamic acid N-isobutylamide46 Trans-3-fluoro-cinnamic acid amide58

Example 11

Muscle Relaxation Effectiveness:

The effect of trans-3-fluorocinnamic acid N-cyclopropylamide on central muscle relaxation was evaluated as described by F. M. Berger and W. Bradley, Brit. J. Pharmac. Ghemtherap. 1, 265 (1946) and D. P. Crankshawa, C. Tapper, Brit. J. Pharmac. 38, 148 (1970). At oral doses of 100 to 150 mg / kg, the compound suppresses polysynaptic reflex contraction in cats without affecting the monosynaptic knee reflex.

Example 12

Convulsive efficiency

When trans-3-trifluoromethylcinnamic acid N-cyclopropylamide is administered to rats in a maximum electroshock test, the ED50 is found to be 20 + 6 mg / kg by oral and 18+ + 3 mg / kg by imtiraperitoineal administration.

Example 13

Trans-3-trifluoromethylcinnamic acid N-cyclopropylamide

Air is purged from the suspension of 9.5 g of lithium aluminum hydride in 100 ml of dry ether by introducing dry nitrogen. A solution of 23.4 g of 3-trifluoromethylcinnamic acid chloride in 200 ml of dry ether is then added dropwise with stirring over 90 minutes while cooling to below 10 [deg.] C., and after the addition is completed, the reaction mixture is stirred for 3-4 hours at 10-15 minutes. Excess reducing agent is destroyed by the careful addition of 5 ml of ethanol and 50 ml of saturated aqueous sodium tartrate solution. The white solid which precipitated was filtered off and washed with ether, the ether washings were combined with an ether layer from the reaction mixture, the aqueous portion was shaken with ether, and the combined ethereal solutions were dried over anhydrous magnesium sulfate. Distilling off the solvent under reduced pressure gave γ- (3-trifluoromethylphenyl) -pmopeno-1 as an oil. To a solution of 5.1 g of the above compound and 25 g of cyclopropylamine in 400 ml of dry ether, freshly prepared nickel peroxide is added in small portions while cooling to -20 to -25 ° C. See Nakagawa et al., J. Org. Chem. 27, 1597 (1962) with stirring for about one hour. The reaction mixture is stirred for an additional 4 hours while cooling to -20 ° C to -25 ° C, the excess nickel peroxide is filtered off and washed with methanol, the methanol washes are combined with the ether solution, and the solution is concentrated in organic solvents under reduced pressure. The oily residue is isolated from the pressure and washed thoroughly with pentane and then dissolved in ethanol (20 ml). About 75 ml of pentane is added to the ethanol solution, which precipitates a solid which is recrystallized from ethanol / water to give 3-trifluoromethyl-cinnamic acid N-cyclopropylamide, m.p. 73 ° C.

2457S8

Examples 14 to 54

Using the appropriate starting materials and procedure of Example 1, the following compounds were prepared:

Example # X R Mp ° C 14 Br cyclopropyl 110 —111 15 Dec F cyclopropyl 90-91 16 Br isobutyl 104 —105 17 F hydrogen 121 —122 18 F cyclopentyl 138 —139 19 Dec F cyclohexyl 150 20 May F cycloheptyl 152 21 F cyclooctyl 149 —150 22nd Cl cyclopentyl 107 —108 23 Cl cyclohexyl 153 —154 24 Cl cycloheptyl 119 —120 25 Cl cyclooctyl 91 —92 26 Br cyclopentyl 109 —110 27 Mar: Br cyclohexyl 158 28 Br cycloheptyl 101 —102 29 Br cyclohexylmethyl 120 —121 30 AND cyclopentyl 126 —127 31 CF3 cyclopentyl 90 —92 32 CF3 cyclohexyl 125 33 CF3 cycloheptyl 98 —100 34 CF3 cyclooctyl 80 35 CF3 cyclohexylmethyl 96.5— 97.5 36 F C2H5 97 37 F isopnopyl 95 - 96 38 F cyclobutyl 105 39 Cl isobutyl 111.5—112.5 40 Cl cyclopropyl 112 —113 41 Cl cyclobutyl 99 42 Br tert-butyl 154 43 Br cyclobutyl 114 —115 44 Br cyclooctyl 101 45 AND Isobutyl 109 —110 46 AND tert-butyl 152 —153 47 AND cyclopropyl 123 48 CF3 hydrogen 102 49 CF3 methyl 125 50 CF3 ethyl 90 51 CF3 n-propyl 82-83 52 CF3 isopropyl 116 53 CF3 isobutyl 93 54 CF3 cyclobutyl 132

THE OBJECT OF THE INVENTION

Claims (6)

A process for the preparation of N-alkyl substituted cinnamic amides of the general formula I (I) wherein X represents a fluorine, chlorine, bromine or iodine atom or a trifluoromethyl group; and R is C 4 -C 8 alkyl, C 3 -C 8 cycloalkyl, cycloalkylalkyl wherein the cycloalkyl moiety contains 3 to 8 carbon atoms and the alkyl moiety is 1 to 3 carbon atoms, and when X is fluoro or trifluoromethyl R may also be a hydrogen atom or a C 1 -C 3 alkyl group, provided that when X is chlorine, R is other than a branched C 4 alkyl group, characterized in that the alcohol is or to the aldehyde IV. £ У ^С - ^- СС ~ -Н ° к, (d) ^ У ~ СН-СН-СНО <. (IV ⁾ where X is as defined above, with an amine of formula V R = NH2, (V) wherein R is as defined above, in the presence of nickel peroxide and at a temperature between -85 and -10 ° C in an inert liquid medium. 2. The process according to claim 1, wherein the starting material is an amine of the formula V as defined in Box 1, wherein R represents a cycloalkyl group having from 3 to 6 carbon atoms. 3. A process according to claim 1, wherein the starting material is an amine of the formula V as defined in item 1, wherein R is cyclopropyl. 4. A process according to any one of claims 1 to 3, wherein the starting material is an alcohol of formula III or an aldehyde of formula IV wherein X is fluorine or trifluoromethyl. 5. A process according to any one of claims 1 to 4, wherein the starting material is an alcohol of formula III or an aldehyde of formula IV wherein X is fluorine and an amine of formula V wherein R is cyclopropyl. 6. A process according to any one of claims 1 to 4, wherein starting materials are used, wherein in one case X is trifluoromethyl and in the other case R is cyclopropyl.