FI86178B - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA 4H-1,2,4-TRIAZOLDERIVAT. - Google Patents

Abstract

1. Process for the preparation of compounds of formula (IA ) : see diagramm : EP0176444,P12,F1 in which R1 , R2 , R3 and R4 identical or different, in whatever position on the benzene nuclei, represent a hydrogen atom, an hydroxyl radical, an alkyl radical containing from 1 to 4 carbon atoms, an Oalk1, radical, alk1 representing an alkyl radical containing from 1 to 4 carbon atoms, an NH2 , NHalk2 radical, alk2 representing an alkyl radical containing from 1 to 4 carbon atoms ; a radical see diagramm : EP0176444,P12,F2 alk3 and alk'3 , identical or different, representing an alkyl radical containing from 1 to 4 carbon atoms, a halogen atom, a CF3 radical or an NO2 radical, or R1 and R2 and/or R3 and R4 together form a methylenedioxy radical, RA represents a -CHOH-alk4 radical, or a see diagramm : EP0176444,P12,F3 radical, alk4 and alk5 , identical or different, representing an alkyl radical containing from 1 to 4 carbon atoms, in their racemic or optically active forms, as well as their addition salts with acids characterized in that a compound of formula (II) : see diagramm : EP0176444,P13,F3 in which R1 , R2 , R3 and R4 have the significances already indicated, is submitted to the action of a chlorination agent so as to obtain an imidyl chloride of formula (III) : see diagramm : EP0176444,P13,F4 which is submitted to the action of a hydrazide of formula (IV) see diagramm : EP0176444,P13,F5 in racemic or optically active form, in which Z is a see diagramm : EP0176444,P13,F6 group, alk4 being an alkyl radical containing from 1 to 4 carbon atoms, so as to obtain a compound of formula (V), in racemic or optically active form : see diagramm : EP0176444,P13,F7 which is cyclized by heating so as to obtain a compound of formula (I), in racemic or optionally active form, in which R is a see diagramm : EP0176444,P13,F8 group, which if desired is esterified so as to obtain a product of formula (I) in which RA is a see diagramm : EP0176444,P13,F9 group, which products of formula (I) are submitted, if desired, to the cation of an acid so as to form a salt.

Description

1 86178

A process for the preparation of therapeutically useful 4H-1,2,4-triazole derivatives

The invention relates to a process for the preparation of therapeutically useful compounds of formula (iA)

N - N

u li 10 ^ —CT ^ i *, ia) M,

Rf ΊΙ4 wherein R1, R2, R3 and R4, which may be the same or different at any position on the benzene rings, denote a hydrogen atom, a hydroxyl radical, an alkyl radical having 1 to 4 carbon atoms, an Oalk1 radical in which alkox 20 is an alkyl radical having 1 to 4 carbon atoms , the radical NH2 or NHalk2, in which alk2 is an alkyl radical having 1 to 4 carbon atoms, the radical 'I alk'3 25 to alk3 in which alk3 and alk'3, which may be the same or different, denote an alkyl radical having 1 to 4 carbon atoms, halogen atom, CF3 radical or NO2 radical, or Rx and R2 and / or R3 and R4 together form a methylene dioxide radical and RA is -CHOH-alk4, where alk4 is an alkyl radical having 1 to 4 carbon atoms or a radical -CH-alk4, in which alk4 and alk5, which may be the same or 35 0CO-alk5 2 86178

various, means an alkyl radical having 1 to 4 carbon atoms, the compounds being in racemic or optically active form, and for the preparation of their acid addition salts. Compounds of formula (IA) 5 are prepared so that a compound of formula II

m, 10 R 2 wherein R 1, R 2, R 3 and R 4 are as defined above, are chlorinated to give an imidoyl chloride of formula III - c = N - (. m) 2 O which is reacted with a hydrazide of formula IV in racemic or optically active form. with, h2n-nh-co-z dv) wherein Z is -CHOH-alk4, wherein alk4 is an alkyl radical having 1 to 4 carbon atoms, for the preparation of a compound of formula V in racemic or optically active form

N_NH-CO - Z

O ,, 'Γ30-ϊ - »» - Οζ-'3

R2 X

3,667,8 which is cyclized by heating to give a compound of formula (IA) in its racemic or optically active form, which is optionally esterified to give a compound of formula (IA) wherein R is a -CH-alk4 group, and that the resulting formula (IA ), if desired, is reacted with an acid to convert the compound to a salt.

When R 1, R 2, R 3 and R 4 denote an alkyl radical, it is preferably a methyl, ethyl, n-propyl, iso-propyl or n-butyl radical.

Alk3, alk2, alk3, alk3 ', alk4 and alk5 preferably denote a methyl, ethyl, n-propyl, isopropyl -15 or or n-butyl radical.

When R3, R2, R3 and R4 represent a halogen atom, it is a fluorine, chlorine, bromine or iodine atom, and preferably a chlorine or bromine atom.

It will be appreciated that the terms "racemic or optically active" may refer only to compounds having at least one asymmetric carbon.

Acid addition salts include inorganic ·. acids such as hydrochloric, hydrobromic, sulfuric or phosphoric acid or organic acids such as acetic acid. With pionic, maleic or hemimeric acid .1. ' tut salts.

The compounds of formula (IA) are novel.

A particular embodiment of the invention is the process described above for the preparation of compounds of formula IA, wherein one of the substituents, Rx or R2, represents a hydrogen atom and the other either a para-methoxy group or a para-dimethylamino group, and wherein the other substituents, R3 or R4, represent a hydrogen atom and the other represents either a para-methoxy group or a para-dimethylamino group, the compounds being in their racemic or optically active form, as well as their acid addition salts and in particular in their racemic or optically active form a process for the preparation of 5- [4- (dimethylamino) phenyl] -4- (4-methoxy-5-phenyl) -α-methyl-4H-1,2,4-triazole-3-methanol and its acid addition salts.

The closest prior art is represented by FI patent publication 72 971, FR application publication 2 244 462 and Chemical Abstracts, vol. 84 (1976), 17236p: Pol. J. Pharmacol.

10 Pharm., Vol. 27 (1975) no. 2, pp. 211-216.

The closest known compounds in structure otherwise correspond to formula (I), except that the symbol RA is replaced by an unsubstituted alkyl radical.

Compounds with a structure close to the compounds of formula (1A) are also described in Belgian patent BE-890035.

In this patent, the compounds are prepared in particular according to the following method: - hydrazine is allowed to act on the formula III ': 20

S

C-NH

to a compound of formula:: y: 30 N_nh2 -yy .....

5 to prepare a compound of formula 86178 to which an acid XCO 2 H or a functional derivative thereof is reacted, X preferably denoting an alkyl radical of one to four carbon atoms, to prepare a compound of formula V:

N — NH-C - X. B

R1-K |] C NH

1 (V) 10 "2 R4 which is cyclized by heating to produce the final products.

The intermediate amidrazone IV obtained in the process described above is unstable and impurities, in particular tetrazines, are formed during its synthesis. The formation of these degradation products complicates the purification of amidrazone and the subsequent acylamidrazone V. The process of the invention does not have an unstable intermediate, the acylamidrazone is easily obtained, it is stable and does not contain impurities, so it is easy to purify.

In a preferred embodiment of the process according to the invention: it is preferred to select thionyl chloride or phosgene as the chlorination reagent enabling the preparation of imidoyl chloride III. Phosphorus pentachloride or phosphorus oxychloride may also be used.

- 30 The reaction for the preparation of imidoyl chloride III can be carried out without solvent, simply by refluxing the chlorination reagent used.

If the reaction takes place in a solvent, it is, for example, toluene, benzene or dichloromethane.

'35 - When R1 R2> R3 or R4 represents a sensitive functional group such as group 6 86178 N \ alk3 '5 The chlorination reagent is preferably phosgene and the reaction is carried out at a low temperature, preferably between -30 ° C and -60 ° C . Moreover, in this special case, the reaction can be carried out in the presence of a tertiary amine, such as pyridine or triethylamine, which makes it possible to eliminate the hydrochloric acid formed.

- The condensation of imidoyl chloride III and hydrazide IV takes place in a solvent such as toluene, benzene and the reaction can be carried out under reflux.

The esterification reaction to prepare the product of formula (IA) in which R = -CH-alk4 takes place under conventional O-CO-alk5 conditions.

It will be appreciated that once the compound of formula (IA) has been prepared, the substituents R 3, R 2, R 3 and R 4 may be chemically modified in obvious ways. For example, the hydroxyl group can be etherified or esterified, the O-alkyl group can be cleaved to form a hydroxyl group, the NO 2 group is converted to an NH 2 group or an N (alkyl) 2 group, the fluorinated derivative is replaced with an amine.

The compounds of formula IA as defined above, as well as their acid addition salts, have interesting pharmacological properties. In particular, they have a very good analgesic effect. In addition, 5- [4- (dimethylamino) phenyl] -4- (4-methoxyphenyl) -α-methyl-4H-1,2,4-triazole-3-methanol has a certain anti-inflammatory effect in chronic inflammation.

Due to these properties, the compounds of formula (IA) as well as their addition salts with pharmaceutically acceptable acids can be used as medicaments.

7 86178

Among the compounds of the invention, mention may be made in particular of those compounds of formula (IA) in which one of Rx or R2 is a hydrogen atom and the other either a para-methoxy group or a para-dimethylamino group and in which one of R3 and R4 is a hydrogen atom and the other is either a para methoxy group in position or a dimethylamino group in para position, the compounds in racemic or optically active form, as well as their addition salts with pharmaceutically acceptable acids.

Of the compounds of the invention, mention may be made in particular of 5- [4- (dimethylamino) phenyl] -4- (4-methoxyphenyl) -α-methyl-4H-1,2,4-triazole-3-methanol and its pharmaceutically acceptable derivatives. addition salts with acids ήπιοί 5.

The compounds of the invention may be used in the treatment of muscle, joint or nerve pain, rheumatic diseases, dental pain, reflexes and migraines and also as adjunctive therapy in inflammatory or febrile conditions.

5- [4- (dimethylamino) phenyl] -4- (4-methoxyphenyl) -α-methyl-4H-1,2,4-triazole-3-methanol, in turn, may be recommended for degenerative inflammatory diseases such as osteoarthritis, for the treatment of various collagen diseases (tendonitis, etc.), rheumatic diseases, rheumatism, ankylosing spondylitis, as well as for the treatment of other diseases of an autoimmune nature such as collagen disease of the skin, glomerulonephritis, central nervous system colonic disease.

The compounds of formula (IA) can thus be used for the preparation of pharmaceutical products containing them as active ingredient.

These pharmaceutical products can be administered orally or anal, parenterally or topically to the skin and mucous membranes.

These pharmaceutical products may be solid or liquid substances and may be in the form of pharmaceuticals commonly used in medicine, such as single or granular tablets, medicated beads, granules, suppositories, injectables, ointments, ointments, gels and aerosols; they are prepared by conventional methods. The active ingredient may be admixed with excipients conventionally used in pharmaceutical products such as talc, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, vegetable or animal fats, glyphosides, paraffins various wetting, dispersing and emulsifying agents, preservatives. The dosage will vary, especially depending on the route of administration, the disease being treated and the individual.

For example, in adults, it may range from 20 mg to 2 g of active ingredient per day administered orally.

The compounds of the formula II used as starting materials for the process according to the invention are prepared as described in Belgian patent BE-890 035. (In these 20 patents, products of formula II are not isolated as they react directly with phosphorus pentasulfide to form products of formula III ').

The compounds of formula IV are prepared in a classical manner by reacting hydrazine hydrate with ca. . 25 van: CH 0 O-C-R or CoHCO 0 -R 3 il 2 5 il

O O

. . With a compound of formula 30 wherein R has the same meaning as in the products of formula I.

. . The examples below illustrate the invention.

Reference Example 1 3-Ethyl-4- (4-methoxyphenyl) -5- (4-nitrophenyl) -35,4H-1,2,4-triazole 9 86178

Example 1 3-Ethyl-4- (4-methoxyphenyl) -5- (4-nitrophenyl) -4H-1,2,4-triazole Step A: N- (4-Methoxyphenyl) -4-nitrobenzenecarboximidoyl chloride

Heat at reflux for 6 hours 1.36 g of N- (4-methoxyphenyl) -4-nitrobenzamide (preparation shown below) and 5 cm3 of thionyl chloride, then add 10 cm3 of benzene, remove the benzene and thionyl chloride under reduced pressure to give the desired product, melting 120 At -122 ° C.

Preparation of N- (4-methoxyphenyl) -4-nitrobenzamide 12.3 g of para-anisidine are added in small portions to a suspension of 18.6 g of 4-nitrobenzoic acid chloride in 100 cm3 of pyridine, heated under reflux for 2 hours. The solution is cooled to ambient temperature, poured into 500 cm3 of ice water, the precipitate formed is centrifuged, washed with water, dried under reduced pressure at 80 ° C and 20 g of the desired product are obtained, melting at 200 ° C.

Step B: N- (4-Methoxyphenyl) -4-nitrobenzenecarboxylic acid 2- (1-oxopropyl) hydrazide 2.8 cm3 of triethylamine are added to a solution which. 25 contains 1.76 g of propionic acid hydrazide (preparation shown below) in 80 cm3 of toluene. 2.87 g of the product obtained in step A are then added in one portion, stirred for 15 minutes, centrifuged, dried, the residue obtained is taken up in 100 cm3 of water, extracted with methylene chloride, dried,. Concentrate to dryness to give 2.2 g of the desired product, melting at 158 ° C.

-. Preparation of propionic acid hydrazide

38.83 cm3 of hydrazine hydrate and 52.42 g of ethyl propionate are kept under reflux for 10 hours. The desired product E / 6 mm Hg = 100 ° C is obtained.

ίο 86178

Step C: 3-Ethyl-4- (4-methoxyphenyl) -5- (4-nitrophenyl) -4H-1,2,4-triazole

After refluxing for 2 hours, 4.38 g of the product obtained in step B in 60 cm3 of toluene are evaporated off, the toluene is evaporated, the residue is taken up in isopropyl ether and the product obtained is recrystallized from a mixture of isopropyl ether and isopropanol (1-2). The desired product is obtained, melting at 174 ° C.

Reference Example 2 3-Ethyl-4- (4-methoxyphenyl) -5- (4-nitro-3-methylphenyl) -4H-1,2,4-triazole Step A: N- (4-methoxyphenyl) -4-nitro-3-methylbenzene-15 carboximidoyl chloride

Heat at reflux for 20 hours 14 g of N- (4-methoxyphenyl) -4-nitro-3-methylbenzamide slurried in 70 cm3 of thionyl chloride (preparation shown below). The solvent is removed by displacing it with benzene, dried under reduced pressure at ambient temperature to give 15 g of product, melting at about 80 ° C.

Preparation of N- (4-methoxyphenyl) -4-nitro-3-methylbenzene

Proceed as N- (4-methoxyphenyl) -4-nitrobenzamide (see Step A in Reference Example 1) using 15.5 g of 4-nitrometatoluyl chloride and 9.56 g of paranicidin in the presence of pyridine as starting materials. 16.7 g of the expected product are obtained.

:: Step B:: 3-Ethyl-4- (4-methoxyphenyl) -5- (4-nitro-3-methylphenyl) -4H-1,2,4-triazole: Add 1.4 cm3 of triethylamine and then 3 g of the product obtained in step A to a solution of 1.76 g of propionic acid hydrazide in 160 cm3 of toluene and refluxed and then cooled.

After refluxing for 1 hour, the toluene is removed under reduced pressure, the residue is taken up in 50 cm3 of chloroform and 50 cm3 of water. The aqueous phase is extracted with chloroform, dried, concentrated to give an oil which is purified by chromatography (solid phase: silica; eluent: ethyl acetate-cyclohexane (8-2)). 3 g of an oil with an Rf value of 0.6 are obtained by thin-layer chromatography (eluent: chloroform-methanol 9-1).

Reference Example 3 N, N-Dimethyl-4- [5-ethyl-4- (4-methoxyphenyl) -10 4H-1,2,4-triazol-3-yl] -2-methylbenzeneamine Cooled to + 5 ° To C 2.6 g of the product obtained in Reference Example 2, 13 cm 3 of formaldehyde and 5.2 g of zinc powder are then slowly added 13 cm 3 of pure acetic acid. Allow to warm to ambient temperature, stir for 20 hours, centrifuge and wash the zinc with 25 cm3 of acetic acid-water mixture, 100 cm3 of methylene chloride, 50 cm3 of water.

The filtrate is decanted, the aqueous phase is extracted with methylene chloride, the organic phase is washed with water, dried and concentrated.

3 g of oil are obtained, which is mixed with 20 cm3 of isopropyl ether and then cooled to -50 ° C. Warm to ambient temperature, centrifuge and dry under reduced pressure at 60 ° C.

1.85 g of product are obtained, which is recrystallized twice from a mixture of ethyl acetate and isopropyl ether (4-6).

1.2 g of the desired product are obtained, melting at 131-131 ° C.

Example 1 . : 5- [4-nitrophenyl] -4- (4-methoxyphenyl) methyl-4H-1,2,4-triazole-3-methanol (L-form)

3 cm3 of triethylamine are added at ambient temperature to a solution of 2 equivalents of β-lactic acid hydrazide (preparation shown below) in 60 cm3 of toluene. 4.3 g of N- (4-methoxyphenyl) -4-nitrobenzenecarboximidoyl chloride (Example 1, step A) are then added in two portions and stirred for 4 hours at ambient temperature. The compound is cyclized for 4 hours at reflux, the toluene is removed under reduced pressure, washed with water, centrifuged, dried to give 4.34 g of crude product which is purified by flash chromatography (eluent: chloroform-ethyl acetate-methanol: 47-50-3) to give 3 g of the desired product. melting at 140 ° C.

Preparation of 10 β-lactic acid hydrazide

At 50 [deg.] C., 9.7 cm <3> of ethyl lactate (L-form) are slowly added to 4.1 cm <3> of hydrazine hydrate, refluxed for 4 hours, evaporated under reduced pressure and a colorless oil is collected, which is used as such to prepare the product of Example 4.

Example 2 5- [4- (Dimethylamino) phenyl] -4- (4-methoxyphenyl) methyl-4H-1,2,4-triazole-3-methanol (L-form) 20 Proceed as in Reference Example 3 is shown starting from 3 g of the product of Example 1, 6 g of zinc powder, 15 cm3 of formaldehyde and 15 cm3 of acetic acid. 1.12 g of the desired product are obtained, melting at 145 ° C. Reference Example 4 3-Ethyl-4- (4-methoxyphenyl) -5- [4- (NN-dimethylamino) phenyl] -4H-1,2,4-triazole Is added under argon and with stirring 1 kg of 4- dimethylamino-4-methoxybenzanilide (preparation shown below) in 8 liters of dichloromethane and 1130 cm 3 of triethylamine, cooled to -40 + 1 ° C and added at this temperature 2.6 liters of toluene solution of phosgene, stirred, heated again to 20 ° C in 2 hours. The solution thus obtained is added to 40 liters of toluene previously heated under reflux and a second solution of 489 g of propionic acid hydrazide in 489 cm 3 of dichloromethane is added at the same time, keeping the temperature of the reaction mixture i3 861 78 at> 90 ° C. Distill continuously for the addition of two solutions. The volume of the distillate thus obtained is about 30 liters at the end of the addition and the heating is switched off when the temperature of the reaction mixture is> 100 ° C. Cool to 20 ° C and wash successively with water, sodium hydroxide solution (1-4) and water.

Extract with dichloromethane, dry, add 100 g of activated carbon, mix, centrifuge, wash with dichloromethane, concentrate by distillation at atmospheric pressure to a volume of 2 liters. Cool to 20 ° C and stir for 16 hours. Spin, wash with toluene, dry at 60 ° C to give 984 g of crude product.

61.5 g of crude product from toluene-containing crystallization broth solutions are also collected.

Purification Heat at reflux with stirring and under a nitrogen atmosphere 1045 g of crude product in 4182 cm3 of toluene, add 104.5 g of activated carbon in 15 minutes, stir at reflux for 15 minutes, centrifuge at 20 hot, wash with boiling toluene, then cool to 20 ° C: stirred overnight at 20 ° C, centrifuged, washed with toluene, dried at 60 ° C to give 862.6 g of the desired product, melting at 167 ° C.

. . Preparation of 4-dimethylamino-4-methoxybenzanilide 201 g of para-anisidine are added to a suspension of 300 g of 4-dimethylaminobenzoic acid chloride in 1200 cm3 of pyridine, stirred until dissolved, then heated to reflux for 3 hours. Cool to ambient temperature, pour the reaction mixture into 6 liters of ice water, centrifuge the precipitate, wash with water, dry under reduced pressure to give 423 g of the expected product. Mp = 173 ° C.

: Example 3 5- [4- (Dimethylamino) phenyl] -4- (4-methoxyphenyl) methyl 4H-1,2,4-triazole-3-methylacetate 35 0.47 g of sodium hydride are added to a suspension in which is 3.3 g of the product prepared in Example 2 in 33 cm3 of tetrahydrofuran. Stir for 30 minutes, add 0.962 g of acetyl chloride and stir for 16 hours under an inert atmosphere. Concentrate to dryness, mix the residue with 30 cm3 of water, stir for 30 minutes, centrifuge the precipitate, wash with water and dry. After purification by flash chromatography (eluent: ethyl acetate-chloroform 8-2), 8.2 g of the expected product are obtained, which is recrystallized from toluene. Mp = 208 ° C. [α] D = -16 ° ± 1 ° (c = 1% chloroform).

Analysis: C 21 H 24 N 4 O 3: 380.450 10 Calculated: C 66.30, H 6.36, N 14.73% Found: C 66.0, H 6.3, N 14.5%

Example 4 5- [4- (Dimethylamino) -phenyl] -4- (4-methoxy-phenyl) -α-methyl-4H-1,2,4-triazole-3-methanol (DL form)

2.36 g of triethylamine are added to a suspension of 5 g of de-4-dimethylamino-4-methoxybenzanilide (prepared as in Reference Example 4) in 50 cm3 of methylene chloride, cooled to -40 [deg.] C., added in 20 minutes at 20 minutes. in the atmosphere 5.75 cm 3 of a toluene solution of phosgene and reheated to 20 ° C in 1 hour and 30 minutes. The solution thus obtained is added to 200 cm3 of toluene, which is heated to reflux and added at the same time. 2.9 g of lactic acid (DL form) hydrazide in 6 cm3 of dimethylformamide. Remove some of the solvents by distillation, heat for 30 minutes to 107-110 ° C, cool the reaction mixture, wash with water and then with N sodium hydroxide solution and water. Extract with methylene chloride, concentrate to dryness to give 7.1 g of crude product, which is recrystallized from a mixture of ethyl acetyl acetate and isopropyl ether (3-6) and then in pure ethyl acetate. Mp = 170 ° C.

Analysis: C 18 H 22 N 4 O 2: 338,413 Calculated: C 67.43, H 6.55, N 16.55% V 35 Found: C 67.2, H 6.8, N 16.3% • · is 8 61 78

Preparation of lactic acid (DL form) hydrazide 50 g of DL-methyl lactate and 24.2 g of hydrazide hydrate are heated for 4 hours 30 minutes at 100/110 ° C. Water is removed by displacing it with xylene to give the desired product as an oil which is used as such to prepare the product of Example 4.

Example 5 5- [4- (Dimethylamino) phenyl] -4- (4-methoxyphenyl) -α-methyl-4H-1,2,4-triazole-3-methylacetate (DL form)

Proceed as in Example 3, starting from 2.4 g of the product prepared in Example 4, 0.336 g of sodium hydride and 0.660 g of acetyl chloride. 2.24 g of the expected product are obtained, which is recrystallized from ιοί 5. Mp = 190 ° C.

Analysis: C21H24N4O3: 380.450 Calculated: C 66.3, H 6.36, N 14.73% Found: C 66.4, H 6.5, N 14.8%

Pharmaceutical products 20 Tablets were prepared with the following composition:

The product of Example 2 is 50 mg of excipient as needed for a tablet of 350 mg ... total weight; 25 (Exact composition of the excipient: lactose, talc, starch, magnesium stearate).

Pharmacological study of the product of Example 2

Analgesic effect '30 The test used is based on the fact mentioned by R. Koster and colleagues (Fed.Proc. 1959, 1B412) that intraperitoneal injection of acetic acid causes repetitive stretching and torsional movements in mice that can last for more than six hours. Painkillers - 35 prevent or alleviate this syndrome, which! ... can be considered a manifestation of vague abdominal pain. A 1% aqueous solution of acetic acid is used. The dose that triggers the symptoms under these conditions is 0.01 cm 3 / g, i.e. 100 mg / kg of acetic acid.

The test product is administered orally half an hour 5 before the acetic acid injection with the mice fasting from the day before the experiment.

The stretching movements of each mouse are monitored and counted over a 15 minute observation period starting immediately after the acetic acid injection.

10 The results are expressed as the AD50 number, i.e. the dose that reduces the number of stretches by 50% of that in the control group.

The observed AD50 value was 4 mg / kg.

Anti-inflammatory effect: adjuvant chronic arthritis (prophylactic treatment)

Injection of a Freund-type excipient into the hind paw of a mouse causes a rapid onset of primary inflammatory injury in this paw and triggers a secondary arthritis affecting the other hind paw, especially after a latency period of 13-15 days. The test is performed on 42-50-day-old male rats receiving an intraplantar injection of 0.1 ml of a Freund's-type excipient (suspension containing 6 mg of killed Mycobacterium butyricum cell ... and / ml petrolatum. The animals receive the test product orally. from day 0 (the day of injection of the excipient) to the day before the day of their killing 17. Arthritis-treated and normal control animals receive vehicle only. .

Determine the AD50 value, i.e. the dose that reduces by 50% the increase in the volume of the hind paws of the treated animals compared to the control animals.

The result obtained showed that the product of Example 2 had a significant effect in this experiment.

Claims (2)

5 Rl —C0 ~ Nli — 3 αι) «2 _“ 4 of Rj, R2, R3 and R4 are selected from the group consisting of chlorine for 10 times with imidoyl chlorides of formula III 15 4 4 of the same composition with hydrazide of which of formula IV och är i en racemlsk ell optlskt Aktiv form, H2N-NH-C0-Z (IV) is Z--CHOH-alk4, is alk4 with alkyl radicals having 1-4 cholaters, for which the radicals are optically formed with a racemic or optically active form, 25 ('A N-NH-CO-Z i — K / 1 Ä JC-NH ._, Γ NgrJ .... k4 30 is a cyclic formation of a compound of formula (IA) and a racemic or optical active form , for which an esterifier is present, if a compound of the formula (IA) is used, for which the group is 22 861 78 -CH-alk4, and if a compound of the same formula is obtained from the group (IA) ) with regard to the conditions under which they are salted