CS209866B2 - Method of making the substituted amids of the cinnamic acid - Google Patents

Description

The invention relates to a process for the manufacture of substituted cinnamic amides as biologically active amides, the invention further relates to pharmaceutical preparations containing said substances and their use in medicine.

It has been found that the substituted cinnamic amides of formula (I), as further defined herein, exhibit anticonvulsant activity in mammals; this is evidenced by evaluating the effects of the disclosed compounds on mice using known pharmacological tests.

These tests are:

1. Maximum electroshock test in mice; the procedure described by Woodbury and Davenport, Arch. int. Pharmacodyn. Ther. 92, 97 (1952).

2. Metrazole retention test in mice; the procedure is described by Swinyard, Brown and Goodman, J. Pharmacol. Exp. Therap. 106, 319 (1952).

In the general formula I, λ (I) X represents chlorine, bromine or iodine, R represents hydrogen or an alkyl group having 1 to 3 carbon atoms, provided that R has a meaning other than hydrogen when X represents chlorine, preferably trans- the configuration of the compounds of formula (I) and the compound wherein R is ethyl, X is bromo, is characterized by an extraordinary anticonvulsant activity in the two pharmacological tests mentioned above. Other examples of compounds within the scope of this invention and compounds of Formula I include:

3-Bromo-cinnamic acid N-methylamide, 3-bromo-cinnamic acid N-n-propylamide, 3-bromo-cinnamic acid N-1-propylamide, 3-chloro-cinnamic acid N-methylamide, 3-chloro-cinnamic acid N-ethylamide,

Compounds of formula I may be prepared by removing a water, hydrogen halide or halogen molecule from compounds of formula II

CW-CH-CONHR III

Λ

where A and B have the same meanings, and in each case are halogen, or one of A and B is halogen or a hydroxyl group and the other is hydrogen, wherein X and R have the meanings given in formula I. The .alpha .- or .beta.-hydroxy compounds of the formula II can be carried out by treatment with a dehydrating agent such as a base, for example an aqueous solution of sodium hydroxide, or with concentrated sulfuric acid or polyphosphoric acid. Mono-halogenated intermediates can be converted to compounds of formula (I) by treatment with a base such as potassium hydroxide or dimethylaniline, or the hydrogen halide can be cleaved by gentle heating. Intermediates of the dihalogenated nature can be reduced, for example by zinc and ethanol, or can be converted to the corresponding diiodo derivatives, for example by treatment with potassium iodide followed by molecular iodine cleavage.

The compounds of formula I may be used in the treatment or prophylaxis of seizures in animals such as mice, dogs and cats, and in particular in humans. They can be used in the treatment of grand mal seizures, petit mal seizures, psychometric epilepsy and local seizures at doses of 2 to 200 mg / kg body weight per day. The optimum dose will, of course, vary depending on the nature of the compound, the condition being treated and the mode of administration, but the preferred dose is in the range of 20 to 60 mg / kg, most preferably 30 to 50 mg / kg body weight per day. A suitable daily dose is preferably administered in three divided doses. For example, a suitable administration form is a tablet, each containing between 100 and 500 mg of a compound of formula I.

For use in medicine, the compounds of formula (I) may be administered as chemically pure substances, but are preferably formulated with a suitable carrier to form a pharmaceutical composition. Of course, the carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the packaging of the formulation. The carrier may be a solid or a liquid, or it may be a mixture of solids and liquids, and the carriers are preferably processed to add a compound of formula I to the unit dosage form, for example in the form of tablets, capsules or scents for oral administration, or in the form of suppositories for rectal administration. Other pharmaceutically active substances may be added to the compositions of the invention at the same time, and the compositions may be shaped by any of the conventional pharmaceutical techniques, which essentially depends on the mixing of the ingredients. Single dose formulations for oral, rectal or perenteral administration (see below) usually contain a compound of Formula I in an amount in the range of 100 to 500 mg.

For oral administration, the fine powders or granules of the compounds of formula (I) may contain diluents, dispersing agents and surfactants and may be powders for pouring into water or syrups; capsules or sachets in the dry state or in aqueous or non-aqueous suspension are also suitable, and 1 suspending agent may also be added; furthermore, tablets, preferably made of granules of the active ingredient and diluent, may be administered by compression using binders and glidants, or suspensions may be administered in water, syrup or oil, or in a water-in-oil emulsion, and flavors may also be added. , preservatives, suspending agents, thickeners and emulsifiers. The granules or tablets may be coated, and the tablets may have incisions to break the tablet.

For parenteral administration (intramuscularly or intraperitoneal injections), the compounds of the invention may be administered in unit doses or multi-dose containers in aqueous or non-aqueous solutions which may contain antioxidants, buffers, bacteriostates or soluble compounds that adjust solution pressure Alternatively, the active compounds may be administered in the form of aqueous or non-aqueous suspensions, and may also contain suspending agents and thickeners, from time to time injectable solutions and suspensions may be prepared from sterile powders, granules or tablets which may contain diluents, dispersing and surfactants, binders and glidants.

It will be apparent from the foregoing that, within the meaning of the invention, it is within the scope of the invention that the novel process described herein depends mainly, but not exclusively, on the preparation of a compound of formula I

CH = CH- _C1-4hr (I) wherein X is chlorine, bromine or iodine, and R is C1-C3alkyl, in particular compounds of the above formula having a trans configuration, in particular the preparation of N-ethylamide 3- the synthesis of said compounds can be carried out using any of the known methods, in particular using the procedures specifically described herein.

The invention also provides pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier, as well as a method of treating or prophylaxis of convulsions in mammals comprising administering anti-convulsive doses of a non-toxic amount of a compound of Formula I to mammals.

WITH

It is believed that all compounds corresponding to Formula I are novel except those wherein X is chlorine and R is hydrogen. This substance is described in the literature, see Chem. Abstr. 72, 21.696 (1970) as an intermediate for the synthesis of other derivatives, but is not attributed any pharmacological activity.

Further examples describe the process of the invention, but do not imply any limitation on the scope of the invention. All temperature data are in degrees Celsius.

Example

Preparation of 3-brominnamic acid N-ethylamide

A) 3-Hydroxy-3- (3-bromophenyl) -propionic acid ethyl ester

A solution of 83 g of ethyl bromoacetate, 100 ml of 3-bromobenzaldehyde in 40 ml of dry ether is prepared; from this mixture, with stirring, 15 ml is added to 45 g of zinc powder under external heating to about 60 ° C so as to initiate an exothermic reaction, and then the remainder of the solution is added at such a rate that the reaction mixture itself maintains a gentle reflux cooler (about 30 minutes). In addition, the reaction mixture was refluxed for an hour, cooled to 0 ° C and then hydrolyzed by the addition of 200 ml of a 15% sulfuric acid solution. The reaction mixture is extracted into 200 ml of benzene, and the benzene solution is washed with 50 ml of 5% sulfuric acid solution, 50 ml of 5% sodium carbonate solution and twice with 50 ml of water each time. Then, the reaction mixture is extracted three times into 75 ml of ether, the extracts in benzene and ether are combined, and the combined organic solution is dried by adding 10 g of anhydrous magnesium sulfate. Filtration and distillation of the solvents under reduced pressure gave a viscous, brown crude product in a yield of 135 g. Distillation under reduced pressure further afforded 3-hydroxy-3- (3-bromophenyl) propionic acid ethyl ester of boiling point (81 g, 59%). 112-114 ° C / 1.3 Pa. The results of elemental analysis, IR spectra, NMR spectra and thin layer chromatography are consistent with the indicated structure.

B) 3-Hydroxy-3- (3-bromophenyl) -N-ethylpropionic acid amide

A mixture of 13.7 g of 3-hydroxy-3- (3-bromophenyl) propionic acid ethyl ester and 9.0 g of anhydrous ethylamine in 250 ml of ethanol is heated to reflux for 8 hours; during this time a slow stream of ethylamine is introduced into the reaction mixture. Thereafter, excess ethylamine and solvent were distilled off at 24 g under reduced pressure, and crystallization of the residue from ethanol / water gave 7 g of a beige product, m.p.

Mp 109-122 ° C. After two recrystallizations from a mixture of 50 ml of ethanol and 200 ml of water, 4.1 g of 3-hydroxy-3- (3-bromophenyl) -propionic acid N-ethylamide, m.p.

128.5-129 ° C. The results of elemental analysis, infrared and NMR spectra, as well as the results of thin layer chromatography, are consistent with the above structure.

C) 3-Bromocinnamic acid N-ethyl amide

The finely stirred mixture of 5.5 g of 3-hydroxy-3- (3-bromophenyl) -propionic acid N-ethylamide and powdered fused potassium hydrogen sulphate is heated at 160-170 ° C for 25 minutes, then cooled, triturated with 100 ml. benzene, and after filtration, water is removed from the filtrate by azeotropic filtration. The residual solvent was distilled off under reduced pressure, and crystallization of the residue from a mixture of ethanol and water gave 3-bromo-cinnamic acid N-ethylamide, m.p. 89-90 ° C.

Example 2

The suppository is prepared from the following ingredients:

trans-3-brominnamic acid ethylamide 300 mg cocoa butter 2000 mg

Example 3

The soft gelatin capsule is filled with the following ingredients:

trans-3- ethylamide

-brominoceros 300 mg lactose 75 mg cornstarch 20 mg silicon dioxide 2 mg magnesium stearic acid salt 3 mg

Example 1 a d 4

A syrupy suspension is prepared from the following ingredients:

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

500 mg 10 ml q. 0.1% q. to 5 ml

Example 5

Compressed tablets are prepared from the following ingredients:

Trans-3-brominnamic acid N-ethylamide 300 mg

209886 maize starch 50 mg microcrystalline cellulose 50 mg stearic acid 4 mg magnesium stearic acid 1 mg fused silica 1 mg

Example 6

In the maximum electroshock test, as mentioned herein, trans-3-cinnamic acid N-ethylamide is characterized by an ED 50 value when administered orally to mice of 80 mg / kg, to rats of 26 mg / kg.

Example 7

The anticonvulsant activity of the compounds for mice was determined using the maximum electroshock test performed by the method described by Woodbury and Davenport (see above using corneal electrodes and the Wahlquist Electroshock Stimulator Model E) (manufactured by Wohlquist Instrument Co., Salt Lake City, Utah, USA). USA).

The trans-3-bromocinnamic acid ethylamide is suspended in a 0.5% aqueous methylcellulose solution by homogenization in a tissue homogenizer to produce particles of a size such that over 51% of the particles are up to 5 microns in size and over 87% of the particles are below 20 microns, and suspensions of 5, 7.5, 10, 15 and 20 mg of compound per ml of methylcellulose solution are prepared. Male mice (ICR Blue Spruce) of an average weight of 22 g were divided into 6 groups, each containing 10 mice. The trans-3-cinnamic acid N-ethylamide suspension is administered one hour prior to the actual test orally by direct injection into the stomach of the mouse. A control mouse receives an equivalent volume of an aqueous solution of 0.57% methylcellulose solution per os also an hour before the test. The 50 mA current is applied to the cornea of the mice for 0.2 seconds, the time elapsing between the time of the electroshock and the hind limb extensor spasm (cramp stretch of the hind limb) is recorded, and this is recorded as the hind limb stretch latency. Animals are expected to be protected when the hind limb extensor seizure component is blocked. An increase in the latency average compared to the control is also an indication of anticonvulsant efficacy.

The results are shown in the following table.

Hind Leg Stretch Latency (in seconds)

Dose, 0 50 75 100 ALIGN! 150 200 mg / kg (control) Mouse In the group 1. 2. 3. 4. 5. 6. 1 1,8 + / + / 1,2 ⁺ / ⁺ / 2 2,0 + / 2.8 4.8 + / ⁺ / 3 1.5 1,8 3.3 + / + / + / 4 1,8 1,8 2.1 2.2 + / ⁺ / 5 1,2 1,2 1,2 + / ⁺ / ⁺ / 6 1,2 1,2 + / + / + / + / 7 1,2 + / 1,8 1,8 + / ⁺ / 8 1,8 1,2 2.8 + / + / ⁺ / 9 1,8 1,2 ⁺ / + / + / ⁺ / 10 1,8 2.2 + / 1.5 + / ⁺ / % protected 0 30 · 40 50 100 ALIGN! 100 ALIGN! average latency 1.61 1.51 2.66 2.30 - - ‘7 = protected

From the above test results (% protection), it is clear that trans-3-bromocinnamic acid ethylamide is effective in preventing electro-shock hind limb stretch in the mouse.

Each group contained 10 mice, and different groups were used for each dosing. + / means protection against electroshock,

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of substituted cinnamic amides of the formula I CH = CHC 'NHR (I) wherein X is chlorine, bromine or iodine, and R is hydrogen or a (C 1 -C 3) alkyl group, provided that R has a meaning other than hydrogen, in that X and R have the meanings given in formula I, and A and B have the same meanings, in which case they are both halogen, or one of A and B is halogen and the other is hydrogen, or one of A and B is hydroxyl and the other is hydrogen, dehalogenates, dehydrohalogenates or dehydrates by heating at 160-170 ° C for 25 minutes and / or by treatment with a dehalogenating, dehydrohalogenating or dehydrating agent using a base, hydrogen sulphate as the dehydrating agent potassium, concentrated sulfuric acid or polyphosphoric acid as the dehydrohalogenating agent of the base and as the dehalogenating agent zinc in ethanol or potassium iodide.