HU195791B - Process for producing new, trisubstituted 1,2,4-triazol derivatives - Google Patents

Abstract

The present invention relates to a novel antirheumatic compound of formula (I), 1,3,5-trisubstituted-1,2,4-triazole derivatives and their acid addition salts, wherein R @ 1 * and R @ 1 are independently halogen; C1-4 alkylalkoxy, alkylthio or alkylsulfonyl, trifluoromethyl, nitro or amino, or one of them hydrogen, R3 and R4 are independently hydrogen, C1-C4 alkyl or alkylsulfonyl, or C2-C4 alkoxycarbonyl, optionally substituted with benzo, nitro, trifluoromethyl, C1-C4 alkoxy, alkylthio or alkylsulfonyl, wherein R3 and R4 are still 2 C4 -C4 alkanoyl, trifluoroacetyl, ρ-toluenesulfonyl, phenylcarbatnoyl, or phenylthiocarboxyl substituted with a halogen atom, if the other is hydrogen.

Description

The present invention relates to novel 1,3,5-trisubstituted 1,2,4-triazole aza derivatives of the general formula (I) and their corresponding addition salts, wherein

R * and R * are independently halogen, C 1-4 alkyl, alkoxy, alkylthio or alkylsulfonyl, and trifluoromethyl, nitro or amino, or one of them is hydrogen;

R ³ or R ⁴ are independently selected from hydrogen, C 1-4 alkyl or alkylsulfonyl or C 2-4 alkoxycarbonyl, and optionally with halogen, nitro, trifluoromethyl, C 1-4 alkoxy, alkyl benzoyl substituted with thio or alkylsulfonyl, and one of R ³ and R ^{4 may} also be C 2 -C 4 alkanoyl, trifluoroacetyl, ρ-lolenesulfonyl, phenylcarbamoyl or optionally halogen substituted phenylthiocarbamoyl, when the other is hydrogen.

Other compounds of formula (jl) are those described in the literature where R ¹ , R ² , R ³ and R ⁴ are hydrogen [J. Chem. Soc. (C), 1971, 3873], but no efficacy data are reported.

The compounds of formula (I) obtained by the process of the invention have valuable biological activities, namely antirheumatic activity.

A particularly preferred group of compounds of the present invention are those compounds of formula I wherein R ¹ and R ^J are chloro or fluoro, R ³ is hydrogen and R ⁴ is hydrogen, mesyl, trifluoroacetyl or acetyl.

The compounds of formula (I) according to the invention are prepared by:

(a) reacting a compound of general formula (II) wherein R ¹ and R ² , except amino, X is perchlorate or periodate, with cyanamide, or

b) reacting a compound of formula III wherein R ¹ and R ² , other than amino, with the same meaning as above, R ³ and R ⁴ independently of one another are hydrogen or C 1-4 alkyl; ) or a compound of formula I obtained by process b) wherein R * and R ¹ are as defined above and Π ³ and R ⁴ are hydrogen - acylated and / or alkylated and / or a compound of formula I where R ³ and R ⁴ are as defined in the introduction R * and / or R ¹ is nitro - and optionally an acid addition salt is formed.

In a preferred embodiment of the process (a) according to the invention, a solution of the compound of the formula II in an organic solvent, preferably methylcellulose, is dissolved at 0-30 ° C, preferably at room temperature, in 2-4 mol of an organic base such as triethyl. 1-3 moles of cyanamide in the presence of amine are preferably added in aqueous solution and the reaction mixture is kept at reflux for 1-10 hours. After completion of the reaction, the cooled reaction mixture is poured into water and the precipitated crystalline product is isolated by filtration and, if desired, purified by recrystallization.

In a preferred embodiment of process b) according to the invention, the compound of formula III is heated in a solution of an aprotic organic solvent, preferably dimethylformamide or benzene, for 1-10 hours, preferably 5-6 hours, at the boiling point of the solvent. An organic or inorganic base, preferably triethylamine or an alkali metal hydroxide, may be used as the condensing agent for the reaction. After completion of the reaction, the reaction mixture is evaporated, the residue is triturated with water and the precipitated product is isolated by filtration. The crude product may be purified by crystallization or, where appropriate, by column chromatography.

In a preferred embodiment of the process of the present invention, compounds of formula I wherein R ³ and R ⁴ are hydrogen are acylated. The acylation is carried out in a manner known per se in an organic solvent, preferably dioxane, benzene or pyridine. Acylating agents are preferably acid chlorides such as methanesulfochloride, p-toluenesulfochlorides benzoyl chloride, substituted benzoyl chlorides or trifluoroacetyl chloride;

acid anhydrides such as acetic anhydride or trifluoroacetic anhydride; chloric formic acid esters, such as ethyl chloroformate;

dialkylpyrocarbonates such as diethylpyrocarbonate or acylimidazoles.

In the case of acylation with acid chlorides, the organic or inorganic base, preferably triethylamine, pyridine, potassium carbonate or sodium bicarbonate, may be used as the acid scavenger.

Isothiocyanates such as phenyl isothiocyanate or substituted phenyl isothiocyanate can also be used to further react the compounds of formula (I).

In another preferred embodiment of the present invention, compounds of formula I wherein R ³ and R ⁴ are hydrogen are alkylated. Suitable alkylating agents are preferably an alkyl iodide such as methyl iodide or diazomethane.

The reaction can be carried out using an organic or inorganic base, preferably triethylamine, pyridine or potassium carbonate, as the binder. Reductive alkylation using formaldehyde in the presence of sodium borohydride and sulfuric acid proved to be very selective. Orloesters e.g. when triethyl orthoformane is used, the resulting methylene derivatives are reduced to the monoalkyl derivative with alkali borohydride. The alkylation is preferably carried out in a polar solvent or in an excess of the alkylating agent in a known manner.

In the Bzerinti process, the compounds of formula I wherein R ¹ and / or R 'is nitro are optionally reduced. The reduction may be carried out using charcoal palladium or hydrazine hydrate. Preferably, the compound of formula (I) is dissolved in alcohol, preferably methanol, and hydrogenated in the presence of palladium on charcoal. The final product is recovered from the reaction mixture in a known manner.

The compounds of formula (I) obtained by the process of the present invention are inorganic or organic acids, e.g. hydrochloric acid, maleic acid, fumaric acid, 4-toluenesulfonic acid, can be converted into the corresponding salt in a protic solvent such as isopropanol.

The compounds of formula (II) which are the starting materials for the process of the invention are, with one exception, new and can be prepared in analogy to the compounds known in the literature (wherein R ¹ and R * are hydrogen) [J. Chem. Soc. (C) 1970, 1397).

Compounds of formula (III) may be prepared by acylation of compounds disclosed in Hungarian Patent Application Publication No. T / 36,089.

As mentioned in the introduction, the compounds of formula (I) obtained by the process of the present invention have valuable therapeutic, namely antirheumatic, activity at low toxicity values.

Our studies were performed in the adjuvant arthritis test in rats using the modified Newbold test [Brit. J. Pharmacol. 21, 127 (1963)]. 0.25 mg of heat-killed Mycobacterium tuberculosis was injected intracutaneously in a volume of 0.15 mg of heat-killed Mycobacterium tuberculosis in male Long Evans rats (180-250 g). The test compounds were administered orally once daily for 3 weeks at the dose indicated in the table.

Foot volume was measured with a Lence mercury plethysmometer before administration of the irritant and on day 21. The left hind limb volume of control and test compound treated animals was determined and the percent inhibition was calculated based on changes in volume. The efficacy of the compounds was compared to the reference naproxen [D-2- (6-methoxy-2-naphthyl) propionic acid].

After completion of the treatment and measurement, the experimental animals were dissected and the gastrointestinal mucosa examined macroscopically for any mucosal application.

The inhibition data for antirheumatic activity are shown in Table 1.

From the data in the table it can be seen that most of the compounds are more effective than naproxen in therapy in inhibiting immune arthritis. Their advantage over the reference is that they have no side effect of causing gastric ulcer at the doses tested, even when sustained.

Table I

Efficacy of Compounds of Formula (I) in Adjuvant Arthritis Test in Rats

The number of the example % inhibition 6.25 mg / kg * p.o. 12.5 mg / kg * p.o. First 11 54 Second 46 - 4th 64 - 14th 14 44 15th 60 - 16th 90 - 18th 75 - 23rd 15 71 25th 39 - naproxen 44 52

* n = 6 animals / dose

The invention is illustrated in detail by the following non-limiting Examples.

Example I

3-Amino-1,5-bis (4-chlorophenyl) -1H-1,2,4-triazole

The method

II, 0 g (27.1 mmol) of 2,3-bis (4-chlorophenyl) -5-methyloxadiazolium perchlorate was dissolved in 50 ml of methylcellosolve, 11.5 ml (81.3 mmol) of trieltylamine. and 4.6 ml (54.2 mmol) of 50% aqueous chloramide solution were added and the reaction mixture was stirred at 120 ° C for 2.5 hours. After cooling, the reaction mixture is poured into 500 ml of water, the precipitated crystals are filtered off, washed with water and dried.

Yield: 6.9 g (84%), m.p. 172-173 ° C (from ethanol).

EXAMPLE 1 The compounds prepared according to Method A were prepared as described in Example II. Table.

II. spreadsheet

Compounds of formula (I) wherein R @ 4 and R @ 2 are hydrogen

Example- number Compound Yield* (% Op. 'C ** R ¹ R2 Second 4-fluoro 4-fluoro 75 142-143 Third 4-fluoro 4-chloro 81 136-137 4th 4-chloro 4-fluoro 77 130-132 5th 4-chloro 4-nitro 81 220-222 6th 4-chloro 4-methoxy 88 174-175 7th 4-chloro 4-methyl 87 133-135 8th 4-methyl 4-chloro 91 150-151 9th 4-chloro 2-methylthio 34 126-128 10th 4-nitro 4-chloro 71 218-221 11th 4-fluoro 4-H 80 145-146 12th 4-chloro 4-methylthio 79 183-188 13th 4-chloro 2methylsulfonyl 16 184-186

»Preparative yield recrystallized from 20 * ethanol

Method B.

1.15 g (5 mmol) of (4-chloro-phenylamino) -guanidine-acetic acid salt, 20 mL of abs. benzene and

A mixture of 1.5 ml of triethylemene (10.5 mmol) was reacted with 0.96 g (5.5 mmol) of 4-chlorobenzoyl chloride - stirred at 50 ° C for 4 hours and then at 80 ° C for 5 hours. . The reaction mixture was evaporated in vacuo, the residue was triturated with water (30 mL), the precipitate was filtered off, washed with water and dried.

Yield*. 1.05 g of crude product is purified by column chromatography to give 0.11 g (7.2%) of the product which is the same as 3-amino-1,5-bis (4-chlorophenyl) obtained by Method A. ) -lH-l, 2,4-triazole. mp 168-173 'C.

The starting material was prepared as follows:

A mixture of 4-chlorophenylhydrazine hydrochloride salt (7.4 g, 41 mmol) in ethanol (40 mL) and 26% aqueous cyanamide (14.4 mL) was heated to reflux for 9 hours and then concentrated in vacuo. The residue was recrystallized from hexane-ethanol (3: 2).

Sókészítés. ·

A) Preparation of hydrochloric acid salt:

A molar amount of base and alcoholic hydrochloric acid are reacted with ethanol and the crystals precipitated on cooling are filtered off and dried.

Yield: 96%, m.p. 171-173 ° C.

B) Preparation of salts with organic acids:

0.3 g (1 mmol) of the "amine" is dissolved in 10 volumes of isopropanol and hot added to the corresponding molar amount of eava dissolved in 10 volumes of isopropanol. The salt crystallizes upon cooling.

The following salts were prepared from 3-amino-1,5-bis (4-chlorophenyl) -1H-1,2,4-triazole (Example 1):

25 Salt Op. ('C) Yield (%) fumarate ' 185-187 75 * maleate 168-170 56 tosylate 171-173 61

- * sour salts

Example 14 35

1,5-bis (4-chlorophenyl) -3- (trifluoroacetamido) -1H-1,2,4-triazole

0.92 g (3 mmol) of the title compound of Example 1, 3-Amino-1,5-bis (4-chlorophenyl) -1H-1,2,4-triazole, obtained according to Method 40 in 10 ml of abs. To a solution of dioxane in trifluoroacetic anhydride (2.1 mL, 15 mmol) was added and the mixture was stirred at room temperature for 1 h. After cooling down, the reaction mixture was poured into water (50 mL), the precipitate was filtered off, washed with water and dried.

Yield: 1.12 g (93%), m.p. 179-181 ° C (from ethanol).

Example 15

5- (4-Fluoro-phenyl) -1- (4-chloro-phenyl) -355- (trifluoro-acetamido) -1H-1,2,4-triazole

Starting from 3-amino-5- (4-fluorophenyl) -1- (4-chlorophenyl) -1H-1,2,3-triazole (Example 4), proceed as in Example 12.

Yield: 82%, m.p. 166-169 ° C (from ethanol).

Example 16

3-acetamido-l, 5-bis (4-chlorophenyl) -1,2,4-triazole -lü

0.92 g (3 mmol) of 3-amino-1,5-bis (4-chlorophenyl) -1H-1,2,4-triazole obtained according to Method A of Example 1 in 10 ml of abs. Acetic anhydride (1.4 mL, 15 mmol) was added to a solution of dioxane and stirred at 60 ° C for 1 hour and at 90 ° C for 1 hour. The reaction mixture was poured into water (50 mL), the precipitate was filtered off, washed with water and dried. Yield: 0.94 g (90%), m.p. 175-178 ° C (from ethanol).

Example 17 1,5-bis-Bz (4-Chloro-phenyl) -3-melanesulfonamido-1,2-1,2,4-triazole

To a solution of 1.5 g (5 mmol) of 3-amino-1,5-bis (4-chlorophenyl) -1H-1,2,4-iriazole obtained in Example 1, Method A in 15 ml of pyridine. 1.15 ml (15 mmol) of methanesulfochloride are added dropwise over 10 minutes and the reaction mixture is stirred at room temperature for 5 hours and finally poured into 30 ml of water. The precipitate was refluxed with 6% sodium bicarbonate solution (40 mL) for 6 hours. The reaction mixture was acidified with 10% hydrochloric acid solution, the precipitate was filtered off, washed with water and dried.

Yield: 1.5 g (84%), m.p. 200-202 ° C (from ethanol).

The following compounds were prepared by the method of Example 17.

Example 21

1,5-bisBz (4-chlorophenyl) -3-bis (methanesulfonamido) -1H-1,2,4-triazole

1.5 g (5 mmol) of the 3-amino-1,5-bis (4-chlorophenyl) -1H-1,2,4-iriazole obtained according to Method 1A in 15 ml of abs. To a solution of pyridine in water at 0 to 5 ° C was added dropwise 1.15 ml (15 min) of melanesulfochloride over 10 minutes, the reaction mixture was stirred at room temperature for 5 hours and finally poured into 30 ml of water. The precipitate formed is filtered off, washed with water and dried and subjected to fractional crystallization.

Yield: 1.7 g (75%), m.p. 248-251 C (from ethanol).

Example 22 1,5-Bis (4-chlorophenyl) -3 - [(ethoxycarbonyl) amino] - 11-1,2,4-triazole

1.5 g (5 inmoles) of 3-amino-1,5-bis (4-chlorophenyl) -1H-1,2,4-triazole obtained according to Method 1 in 7.0 ml of diethyl pyrocarbonate were obtained. and the solvent was removed in vacuo. The residue was dissolved in ethanol (10 ml) and after the addition of concentrated hydrochloric acid (10 ml), it was refluxed for 4 hours and then poured into 50 ml of water under cooling. The precipitate was filtered off, washed with water and dried, and purified by layer chromatography.

Yield: 0.56 g (30%), m.p. 151-153 ° C (from methanol).

Example 18 1,5-bis-Bz (4-Fluorophenyl) -3-methenesulfonamido-1H-1,2,4-triazole

Yield: 78%, m.p. 210-211 ° C (from ethanol).

Example 19 1- (4-Fluorophenyl) -5- (4-chlorophenyl) -3-methanesulfonamido-1H-1,2,4-triazole

Yield: 91%, m.p. 205-210 ° C (from ethanol).

Example 20

5- (4-Fluorophenyl) -1- (4-chlorophenyl) -3-methenesulfonamido-1 H -1,2,4-Lriazole

Yield: 68%, m.p. 208-210 ° C (from ethanol).

Example 23

5- (4-fluorophenyl) -l- (4-chlorophenyl) -3 - [(ethoxycarbonyl) amino] -lH-l, 2,4-triazole

1.16 g (4 mmol) of the 3-amino-5- (4-fluorophenyl) -1- (4-chlorophenyl) -1H-1,2,4-triazole obtained according to the method of Example 1. 12 ml abs. 0.96 g (8.8 mmol) of ethyl chloroformate was added dropwise to the pyridine side at 5 'C and the mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, the mixture was poured into water (120 ml), the precipitate was filtered off, washed with water and dried. Yield: 1.07 g (74%), m.p. 110-112 ° C (from ethanol).

Example 24 1,5-Bis (4-chloro-phenyl) -3- [bis (ethoxycarbonyl) -amino] -1H-1,2,4-triazole

1.5 g (5 mmol) of 3-amino-1,5-bis (4-chlorophenyl) -1H-1,2,4-triazole obtained according to Method A of Example 1 in 7.0 ml of diethyl pyrocarbonate

The solution was heated to reflux for 1 hour, then the solvent was removed in vacuo and the residue was recrystallized from ethanol.

Yield: 1.4 g (61%), m.p. 114-115 ° C.

EXAMPLE 25 1,5-BIBB (4-k] H-Phenyl) -3- [2- (methyl] thio) -benzamido] -1H-1,2,4-triazole

3.0 g (10 mmol) of 3-amino-1,5-bis (4-chlorophenyl) -1H-1,2,4-triazole obtained according to method A in 30 ml of abs. to a solution of benzene in 1.8 ml (22 mmol) of abs. In the presence of pyridine, 4.1 g (22 mmol) of 2- (methylthio) benzoyl chloride was added dropwise over 30 minutes at 0 to 5 ° C. dissolved in benzene and refluxed for 7 hours. After completion of the reaction, the solvent was removed in vacuo and water (50 mL) was added to the residue.

The resulting oily product was extracted with dichloromethane and after drying subjected to column chromatography (95: 5 benzene / acetone as eluent).

Yield: 2.24 g (49%) M.p .: 147-149 ° C (from benzene _k) and l, 5-bis- (4-chloro-phenyl) -3- {bis [2- (methylthio) benzoyl] amino} -1H-1,2,4-triazole (Example 26)

Yield: 1.1 g (39%), m.p. 186-189 ° C (from ethanol15).

Example 25 was prepared using the method of Example III. Compounds of Table II.

III. Compounds of Formula I wherein R ¹ and R ^J are Chloro (at the 4-position)

example number compound yield % Op. ®C R ³ R ⁴ 27th H 4-methoxybenzoyl 83 210-212 28th H 4-chlorobenzoyl 75 209-211 29th H 4-nitrobenzoyl 68 124-126 30th H 3-trifluoromethyl benzoyl 85 191-193 31st H 2- (methylsulfonyl) - benzoyl 72 257-260 32nd 4-chlorobenzoyl 4-chlorobenzoyl 33 150-155 33rd H p-toluenesulfonyl 36 203-205

Example 34 1,5-Bis-4-chlorophenyl) -3- (methylamino) -1H-1,2,4-triazole "Method A

1.65 g (5.4 mmol) of 3-amino-1,5-bis (4-chlorophenyl) -1H-1,2,4-triazole obtained according to method A of Example 1 in 10 ml of abs. solution of benzene in 3 ml of abs. Methyl iodide (0.4 mL, 6 mmol) was added in the presence of dimethylformamide and refluxed for 1 hour. After cooling, the crystallized solid is filtered off, 100 ml of water are added to the filtrate and extracted with 3 x 20 ml of dichloromethane. The organic layer was dried over magnesium sulfate and evaporated. The evaporation residue was purified by preparative thin-layer chromatography.

Yield: 0.15 g (9%) of 1,5-bis (4-chlorophenyl) -3- (methylamino) -1H-1,2,4-triazole, m.p. 188190 ° C (from ethanol) and 0.5 g (27%) of 1,5-bis (4-chlorophenyl) -3- (dimethylamino) -1H-1,2,4-triazole (Example 35), m.p. 138 ° C (from ethanol).

“Method B

1.5 g (5 mmol) of 3-amino-1,5-bis (4-chlorophenyl) -1H-1,2,4-triazole obtained according to Method 1, in 7.5 ml of triethyl orthoformate The solution was stirred at reflux for 2 hours and the solvent removed in vacuo. The residue was taken up in 20 ml of abs. of alcohol, 1.1 g of sodium borohydride are added under ice-water cooling, followed by stirring at room temperature for 2 hours. After evaporation, the residue was dissolved in ethyl acetate (70 ml) and washed with water (70 ml). The ethyl acetate layer was dried over sodium sulfate and evaporated.

Yield: 1.13 g (71%) M.p .: 185-190 C ^J (milánóiból).

Example 35 1,5-Bis (4-chlorophenyl) -3- (dimethylamino) -111-1,2,4-lriazole

0.71 g (2 mmol) of Example 1, "Inode Se 6J. J

3-amino-1,5-bis (4-chlorophenyl) -1H-1,2,4-triazole, 0.55 g (1.5 mmol) of sodium borohydride and 14 ml of abs. A solution of tetrahydrofuran was added dropwise at -10 ° C to 20 ° C over 15 minutes to a mixture of 1.62 ml (5 mmol) of 3 M sulfuric acid and 1.05 ml of 35% aqueous formaldehyde and the reaction mixture was stirred at 10 to 20 ° C for 2 hours. stirring. During the work-up, the pH of the mixture was adjusted to 8 with 10% aqueous sodium hydroxide solution, the aqueous phase was decanted and the oily residue was taken up in dichloromethane. The solvent was evaporated in vacuo and the residue was triturated with ether. Yield: 0.64 g (96%), m.p. 127-128 ° C.

Example 36

3-Amino-5- (4-aminophenyl) -1- (4-chlorophenyl) -1H-1,2,4-triazole g (3.2 mmol), prepared as in Example 5, 1- (4-Chlorophenyl) -5- (4-nitrophenyl) -1H-1,2,4-triazole is dissolved in 100 ml of methanol and hydrogenated in the presence of palladium on charcoal. After uptake of the theoretically calculated hydrogen, the catalyst is filtered off and the residue is concentrated in vacuo.

Yield: 0.9 g (97%), m.p. 177-183 ° C (from ethanol).

Example 37

BÍBz 1.5- (4-chlorophenyl) -3- [N '- (4-chlorophenyl) thioureido] -lH-l, 2 4-triazole _t

1.5 g (5 mmol) of 3-amino-1,5-bis (4-chlorophenyl) -1H-1,2,4-triazole obtained according to method A in 15 ml of abs. To the dioxane side was added 4-chlorophenyl isothiocyanate (0.9 g, 5.3 mmol) and the solution was refluxed for 6 hours with 0.45 mL of abs. in the presence of pyridine. The reaction mixture was then poured into water under cooling. The precipitate was filtered off, washed with water and dried.

Yield: 1.6 g (67%), m.p. 226-231 ° C (from dimethylfortnamide).

Example 38

1.5-bis (4-chlorophenyl) -3- (N'-phenyl-ureido) -1H-1,2,4-triazole

1.5 g (5 mmol) of 3-amino-1,5-bis (4-chlorophenyl) -1H-1,2,4-triazole obtained according to method A in 15 ml of abs. To the pyridine solution was added 1.2 g (10 mmol) of phenyl isocyanate and stirred for 8 hours at room temperature. The mixture was poured into water (150 mL), the precipitate was filtered off, washed with water and dried after filtration.

Yield: 1.44 g (68%) m.p. 250-254 C (from dimethylformamide).

By following the procedure of Example 38, the following compound was prepared:

Example 39

1.5-Bis (4-Chlorophenyl) -3- (N'-phenyl) -lioureidoyl-1H-1,2,4-triazole

Yield: 90%, m.p. 224-231 ° C (from dimethylformamide).

Example 40

1.5-Bis (4-Fluorophenyl) -3 - [(N-methyl-14-methanesulfonyl) -amino] -1H-1,2,4-triazole

1.75 g (5 mmol) of the 1,5-bis (4-fluorophenyl) -3-methanesulfonamido-1H-1,2,4-triazole obtained in Example 16 in 10 mL of abs. To a side of diraethylformamide at 5 'C was added 0.35 g of sodium methylate in 5 ml of abs. dissolved in methanol and stirred at 5 ° C for 20 minutes. Methyl iodide (0.8 mL, 12.8 mmol) was added dropwise at 5 ° C, and the mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The reaction mixture was poured into water (20 ml), the precipitate was filtered off, washed with water and dried.

Yield: 1.33 g (73%), m.p. 146-147 ° C (from ethanol).

Example 41 1,5-Bis (4-chlorophenyl) -3 - [(N-methyl-N-methanesulfonyl) amino] -1H-1,2,4-triazole

Proceeding as in Example 40.

Yield: 93%, m.p. 152-154 ° C (from ethanol).

Claims (6)

PATENT CLAIMS A process for the preparation of novel 1,3,5-trisubstituted 1,2,4-triazole derivatives of the formula I and their acid addition salts, wherein R * and R ^J are each independently halogen, C 1-4 alkyl, alkoxy, alkylthio or alkylsulfonyl, and trifluoromethyl, nitro or amino, or one of them is hydrogen; R ³ and R 'are independently hydrogen, C 1-4 alkyl or alkylsulfonyl or C 2-4 alkoxycarbonyl, and optionally with halogen, nitro, trifluoromethyl, C 1-4 alkoxy, alkylthio or a benzoyl group substituted with an alkylsulfonyl group of 715, and one of R ³ and R ^{4 may} also be C 2 -C 4 alkanoyl, trifluoroacetyl, ρ-toluenesulfonyl, phenylcarbamoyl or phenyl optionally substituted with 5 halogens, when the other is hydrogen, characterized in that 10 (a) reacting a compound of formula (II) wherein R ¹ and R *, other than amino, are as defined above, with X being perchlorate or periodate with cyanamide; or. 15 b) reacting a compound of formula III wherein R ¹ and R 'are independently hydrogen or C 1 -C 4 alkyl, with the exception of R ¹ and R ⁴ , independently of one another; and if desired, a) or b) resulting compound of formula (I) process wherein R * and R ¹ are as defined above, R ^J, and R ⁴ stands for hydrogen - is acylated with 25 and / or alkylated and / or (I ), wherein R ³ and R ⁴ are as defined, R ¹ and / or R ³ is nitro, and then, if desired, an acid of any of the compounds of formula I obtained in any of the above forms. forming an acid addition salt. Process (a) according to claim 1, characterized in that the compound of formula (II) is reacted in methylcellosolve with an aqueous solution of cyanamide in the presence of an organic base. Process b) according to claim 1, characterized in that the ring closure is carried out in an aprotic organic solvent at the boiling point of the solvent in the presence of a condensing agent. A process according to claim 1, wherein the acylation is carried out with an acid anhydride or an acid chloride. A process according to claim I, wherein the alkylation is carried out with an alkyl iodide. 6. A process for the preparation of predominantly antirheumatic pharmaceutical compositions, characterized in that one or more compounds of the general formula (I) produced by the process of claim 1, wherein R ¹ , R ', R ³ and R ⁴ are as defined in claim 1, together with a compound of formula (I) which has no therapeutic synergism with the compound of formula (I) and the solvents, carriers, carriers and excipients used in the preparation of a medicament are conventionally prepared as a medicament.