NO850476L - PROCEDURE FOR THE PREPARATION OF NEW 1,2,4-TRIAZOLD DERIVATIVES - Google Patents

Description

The present invention relates to new 1,2,4-triazole derivatives and pharmaceutical preparations containing these, as well as a method for their production.

The new 1,2,4-triazole derivatives according to the invention correspond to general formula (I)

in which

denotes an unsubstituted phenyl group or a phenyl group which is substituted with one or more of fluorine, chlorine or bromine, C^_^-alkyl, C^_^-alkyl-, nitro-, trifluoromethyl-, C^_^ -alkylthio-, C-L-4-alkylsulfinyl- or C1-4-alkylsulfonyl groups, and further a naphthyl group,

1*2 denotes an unsubstituted phenyl group or a phenyl group which is substituted by one or more fluorine, chlorine or bromine atoms, C^_4-alkyl-, C^_4~ alkoxy-, nitro-, trifluoromethyl-, C-L_4-alkylthio -, C-^^-alkylsulfonyl or C1-4~alkylsulfonyl groups, and furthermore a thienyl group, ;1*2 denotes an unsubstituted C^_4-alkyl group or a C^_4-alkyl group substituted by one or more fluoro- or chlorine atoms, hydroxy, C2_4~ alkoxycarbonyl, cyano or pyridyl groups, and further C2_4 alkoxycarbonyl, C2_5~ oxoalkyl groups or a phenyl-C^_4~ alkyl group substituted with one or more fluorine or chlorine atoms in the phenyl ring , and

n denotes 0, 1 or 2,

provided that when n represents 0 and R 3 represents a methyl group, only one of R 1 and R 2 can be an unsubstituted phenyl group.

From the compounds of general formula (I), the compound in which R^ and R2 denote a phenyl group, R^ denotes a methyl group, and n denotes 0, is described in the literature (Augustin et al.: J. f. prakt. Chemie 322, 55-68 (1980)), but no "pharmacological data are provided.

The compounds of general formula (I) are produced by the method according to the invention in that a compound of general formula (II) or (V)

wherein and R 2 are as defined above, dissolved in an inert solvent and in the presence of an organic or inorganic base, reacted in an alkaline pH range with a compound of general formula (III) wherein R 2 is as defined above and X denotes a halogen -atom or a tosyloxy group, after which, if desired, the resulting compound of general formula (I) in which R 1 , R 2 and R 2 are as defined above and n denotes 0, is oxidized to form a compound of general formula (I) in which R 1 '^2°^R3 is as defined above, and n is 1 or 2. The compounds of general formula (I) in which R^ and R2 are as defined above, R^ denotes an ethyl group substituted by one or more fluorine or chlorine atoms and n denotes 0, can also be prepared by the method according to the invention by addition of an ethylene derivative of general formula (IV)

wherein Y can independently represent fluorine or chlorine atoms, to a

compound of general formula (II) or (V), in which R, and R2 are as defined above, dissolved in an inert solvent in the presence of an inorganic or organic base and at an alkaline pH range.

The compounds of general formula (I) in which R 1 and R 2 are as defined above, R 2 denotes a C 4 alkyl group and n denotes 0, can also be prepared by alkylation of a compound of general formula (II) or (V) in which R. and R.sub.2 are as defined above, dissolved in an inert solvent and in the presence of an inorganic or organic base, with diazomethane or with a C.sub.2-4-dialkyl sulfate in an alkaline pH range.

According to a preferred method according to the invention, a solution of 1 mol of a compound of general formula (II) in 1.2 to 2.2 M aqueous sodium hydroxide is reacted with 1.0 to 3.0 mol of a compound of general formula (III) in the presence of a lower alcohol, preferably methanol or ethanol, in a temperature range of from -50 to 100°C, preferably at -10 to 80°C, after which the product of general formula (I) is isolated after completion of the reaction.

According to another preferred method according to the invention, a solution of 1 mol of a compound of general formula (V) in 1.5 to 2.5 mol of aqueous sodium hydroxide is reacted with 1.0 to 1.1 mol of the compound of general formula (III) at a pH above 7.5, in the presence of a lower alcohol, preferably methanol or ethanol, in the temperature range from -10 to 80°C, after which the product of general formula (I) is isolated after completion of the reaction.

According to a further preferred method according to the invention, a compound of general formula (II) is dissolved

in an organic, aprotic solvent, preferably anhydrous dimethylformamide, and tetrafluoroethylene or trifluorochloroethylene is introduced into this solution in the presence of triethylamine

(s)

or benzyl trimethylammonium hydroxide (Tritorr-'B) at a temperature of -20 to 60°C, preferably at 0 to 20°C, after which the reaction mixture is stirred for 1 hour at 40°C to 50°C. After completion of the reaction, the product of general formula (I) is isolated in which R^ denotes a tetrafluoroethyl- or tri-

fluorochloroethyl group in a manner known in the art.

According to a further preferred method according to the invention, 1 to 1.5 mol of dimethyl sulfate or diethyl sulfate is added dropwise to a solution of 1 mol of a compound of general formula (II) or (V) in 2.0 to 3.5 mol of aqueous sodium hydroxide solution . After completion of the reaction, the product of general formula (I) is isolated in which R3 denotes a methyl or ethyl group in a manner known in the art.

According to a further variant of the method, a compound of general formula (II) suspended in an inert solvent, preferably in ether, is reacted with diazomethane, dissolved in ether at 0 to 30°C. After completion of the reaction, the product of general formula (I) is isolated in which R_ denotes a methyl group in a known manner.

The 1,5-diaryl-1,2,4-triazoles obtained by the above methods are preferably oxidized with m-chloro-perbenzoic acid or peracetic acid. The reaction carried out with 1.0 to 1.1 mol m-chloro-perbenzoic acid or peracetic acid forms the monoxide (sulfoxide) (n = 1), while the reaction carried out with 2.0 to 2.2 mol m-chloro-perbenzoic acid or peracetic acid gives the dioxide (sulfone) (n = 2). The oxidation with the peracids is preferably carried out at 0°C in anhydrous chloroform. The sulfoxides (n = 1) can also be prepared using preferably bromine as an oxidizing agent in an alkaline medium at room temperature. It is advantageous to carry out the oxidation with bromine in a two-phase system in a mixture of a halogenated solvent, preferably dichloromethane, and aqueous potassium bicarbonate. The oxidation of the sulfoxide can be inhibited by adding 5 to 10% dimethyl sulfoxide to the mixture.

The process for the preparation of the compounds of general formula (II) which serve as starting materials in the preparation of the compounds of general formula (I) is known from the literature (J. Chem. Soc., Perkin Trans. I.,

1979, 724).

The compounds of general formulas (III) and (IV) are commercially available products.

The compounds of general formula (V) are partly known and partly unknown compounds and can preferably be prepared by the following method: a 1-(substituted)-phenylthiosemicarbazide of general formula (VI) in which R^ is as defined above (these compounds are mostly known from the literature, e.g. Chem. Ber., 28, 2081 (1895); Gazette, 28, II. 560 or J. Indian Chem. Soc, 5, 653; C. Z. 19 29, I. 1110) is reacted with a equimolar amount of an acyl halide of general formula (VII)

wherein R 2 and X are as defined above except for the tosyloxy group, either without any solvent, or in a solvent, preferably benzene, at a temperature of 0 to 150°C, preferably at 30 to 90°C. The reaction can also be carried out in the presence of an acid-binding agent, and this is particularly advantageous in the case of compounds having an acid-sensitive group in their molecule (e.g. the methoxy group).

In pharmacological tests, the compounds of general formula (I) have been shown to have low toxicity and exhibit valuable therapeutic, namely antirheumatic - anti-inflammatory properties.

The compounds were tested by the modified Newbould test (Brit, J. Pharmacol. 21, 127 (1963)). Intraplantar injections of 0.25 mg of killed Mycobacterium tuberculosis were administered in volumes of 0.1 ml each to the right hind paw of male Long Evans rats weighing 180 to 250 g. The rats were treated with single daily oral doses of the compounds (indicated in table 1) for 3 weeks a total of 16 times. The change induced in the paw swelling was measured daily for 21 days with a Lence-type mercury plethysmometer. From the 10th day, the volume of the swelling of the left hind paw was also determined. The percentage inhibition was calculated by relating the changes in the volume of the swelling to this value. The inhibition data characteristic of the antirheumatic effect are given in Table 1. The data measured after treatment with phenylbutazone-(4-butyl-1,2-diphenyl-3,5-pyrazolidinedione) and naproxen-[D-2-( 6-methoxy-2-naphthyl)-propionic acid used as reference compounds are also listed in Table 1 to facilitate comparison.

The EDb,, o values for certain compounds are also indicated. The oral ED^Q values for the compounds prepared according to Examples 27, 44 and 55 are 7.4, 2.1 and 6.8 mg/kg, while the oral ED^ value for naproxen is 12.5 mg/kg . The compounds also have relatively low acute toxicity values, as the LD,-.0 value for the products prepared according to examples 27, 44 and 55 are 480, 170 and 380 mg/kg, while the LD50~

the value for naproxen is 543 mg/kg p.o. All data were measured

- on rats.

The ulcerogenic side effect is the most critical feature of all anti-inflammatory drugs. The compounds produced according to the invention are also superior in this respect compared to other commercial products: a single 15 mg/kg dose of indomethacin-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-indol-3-yl- acetic acid] induces ulcers in 100% of the rats, while a single 1000 mg/kg dose of the compound prepared according to Example 27 induces ulcers in only 10% of the animals. Even chronic treatment with 16 x 20 mg/kg oral doses induces suffusion in only some of the animals.

These observations show that several compounds are more powerful than phenylbutazone and naproxen, which are currently used with great success in therapy. The compounds produced according to the invention also have the great advantage over the reference substance that they do not cause stomach ulcers as a side effect with the doses used both during acute and chronic treatment. This is particularly beneficial as anti-rheumatic treatment generally lasts a long time.

According to observations, the compounds of general formula (I) represent such a type of antirheumatic agents where the immunomodulating property of the compounds plays a role in their mode of action.

The invention also relates to pharmaceutical preparations containing as active ingredient at least one compound of general formula (I) together with one or more conventional pharmaceutical carriers, diluents and/or additives. The pharmaceutical preparations may also contain other biologically active substances, in particular other antirheumatic agents.

The pharmaceutical preparations can be prepared according to

well-known methods in the field.

The new compounds according to the invention can generally be administered in daily doses of 2 to 6 mg/kg body weight, the exact dose being dependent on body weight, age and general state of health of the patient.

The following examples illustrate the invention.

Example 1

1/ 5- bis-(4- chlorophenyl)- 3-( propylthio)- 1 , 2 , 4- triazole

A mixture of 3.0 g (9.3 mmol) 1,5-bis-(4-chloro-phenyl)-1,2,4-triazolin-3(2H)-thione, 10 ml aqueous sodium hydroxide (0.48 g = 12 mmol sodium hydroxide), 20 ml ethanol and 1.59 g (9.3 mmol) propyl iodide were boiled under reflux for 1 hour with stirring. The solvent was then evaporated, the residue was dissolved in chloroform, and the organic layer was extracted several times with water and then dried over magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from ethanol.

Yield: 2.65 g (78%), m.p. 67 to 68°C.

The compounds of general formula (I) prepared as described in this example are listed in Table 2.

Example 21

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

8 g (63.4 mmol) of dimethyl sulfate was added dropwise over 10 minutes with constant stirring to a solution of 20.0 g (62.07 mmol) of 1,5-bis-(4-chlorophenyl)-1,2, 4-triazoline-3(2H)-thione in 70 mL aqueous sodium hydroxide (5.0 g, 125 mmol sodium hydroxide) and 150 mL methanol. The mixture was stirred at 60°C for 1 hour and then allowed to stand overnight. The solvent was evaporated, the residue was extracted with chloroform, the extract was dried, the solvent was evaporated and the residue recrystallized from ethanol.

Yield: 15.0 g (72%), m.p. 122 to 123°C.

The compounds of general formula (I) prepared according to Example 27 are listed in Table 3.

The compound according to example 27 can also be prepared by adding 25 ml of a 12% solution of diazomethane in ether dropwise over 10 minutes under constant stirring and at room temperature to a suspension of 2 g (6.2 mmol) 1.5-- tol-(4-chlorophenyl)-1,2,4-triazolin-3(2H)-thione in 30 ml of ether. This procedure is repeated after 8 hours, after which the mixture is stirred at room temperature overnight. 10 ml of 10% alcoholic hydrochloric acid is then added dropwise, the solvents are evaporated, and the residue is recrystallized from ethanol. Yield: 1.5 g (72%), m.p. 121 to 123°C.

Example 38

1-( 4- chlorophenyl)- 5-( 3- trifluoromethylphenyl)- 3-( methylthio)-1, 2, 4- triazole

1.58 g (12.5 mmol) of dimethyl sulfate was added dropwise with constant stirring to a mixture of 3.62 g (10 mmol) of 1-(4-chlorophenyl)-1-(3-trifluoromethylbenzoyl)-thio-semicarbazide, 1 .2 g (30 mmol) of sodium hydroxide in 24 ml of water and 48 ml of methanol, and the mixture was stirred at 60°C for 2 hours. After evaporation of the methanol, the residue was extracted with chloroform, the extract was dried over magnesium sulfate, and after evaporation of the chloroform, the residue was recrystallized from ethanol.

Yield: 3.3 g (88%), m.p. 108 to 110°C.

The compounds of general formula (I) prepared as described in this example are listed in Table 4.

Example 56

1,5-bis-(phenyl)-3-(2-chloro-1,1,2-trifluoroethylthio)-1,2,4-triazole

1,1,2-trifluoro-2-chloroethylene was introduced into a mixture of 2.0 g (7.9 mmol) 1,5-bis-(phenyl)-1,2,4-triazolin-3(2H)- thione, 50 ml of anhydrous dimethylformamide and 0.18 ml

10.1 mmol) Triton<®->B with constant stirring and at room temperature until saturation is achieved, after which stirring was continued for a further 1 hour at 40-50°C. The reaction mixture was poured into 200 ml of water, cooled, filtered, washed with water and recrystallized from ethanol. Yield: 2.68 g (87%), m.p. 64 to 66°C.

The procedure described in this example was used to prepare the following compounds of general formula (I) according to examples 57 to 59.

Example 57

1, 5- bis-(phenyl)- 3-( 1, 1, 2, 2- tetrafluoroethylthio)- 1, 2, 4- triazole Yield: 61%, m.p. 48 to 49°C.

Example 58

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

Yield: 59%, m.p. 91 to 92°C.

Example 59

1, 5- bis-(4- fluorophenyl)- 3-( 1, 1, 2, 2- tetrafluoroethylthio)-1, 2, 4- triazole

Yield: 53%, m.p. 83 to 86°C.

Example 60

1, 5- bis-(4- fluorophenyl)- 3-( 2, 2, 3, 3- tetrafluoropropylthio)-1, 2, 4- triazole

To a solution of 3.07 g (10 mmol) 1-(4-fluoro-phenyl)-1-(4-fluorobenzoyl)-thiosemicarbazide and 0.64 g (16 mmol) sodium hydroxide in 6.4 ml water was added 12 .8 mL of methanol and then 3.43 g (12 mmol) of 1-(4-p-tosyloxy)-(2,2,3,3-tetrafluoro)-propane, and the reaction mixture was stirred at 50 to 70°C for 90 minutes. After evaporation, the residue was dissolved in dichloromethane, extracted with water, and the extract was dried over sodium sulfate. The evaporation residue (1.0 g, 24%) was a non-crystallizing oil.

Example 61

1, 5- bis-(phenyl)- 3-( methylsulfinyl)- 1, 2, 4- triazole

To a solution of 0.58 g (2.17 mmol) 1,5-bis-(phenyl)-3-(methylthio)-1,2,4-triazole in 10 ml of anhydrous chloroform was added dropwise a solution of 0, 42 g (2.2 mmol) of m-chloro-perbenzoic acid in 5 ml of chloroform, and the mixture was stirred at room temperature overnight. The mixture was then extracted with 6% sodium bicarbonate solution, then with water, and finally dried over sodium sulfate. Yield: 0.4 g (64%), m.p. 121 to 123°C (recrystallized from ethanol).

The procedure described in this example was used to prepare the following compounds of general formula (I) according to examples 62 and 63.

Example 62

1-( 4- chlorophenyl)- 5-( 4- fluorophenyl)- 3-( methylsulfinyl)- 1, 2, 4-triazole

Yield: 39.5%, oil.

Example 63

1, 5- bis-(4- chlorophenyl)- 3-( methylsulfinyl)- 1, 2, 4- triazole Yield: 35%, m.p. 95 to 96°C.

Example 64

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

A solution of 2.3 g (12 mmol) of 90% m-chloro-perbenzoic acid in 25 ml of chloroform at 0°C and during 30 minutes with constant stirring. After 2 hours, the mixture was extracted with a 6% aqueous sodium bicarbonate solution, then with water, and the organic layer was dried over magnesium sulfate. Yield: 1.8 g (98%), m.p. 183 to 185°C (recrystallized from ethanol).

The compounds of general formula (I) prepared according to this example are listed in Table 5.

Example 7 3

Production of tablets

^Microcrystalline cellulose produced from Degussa, BRD.

Claims (2)

1. Process for the preparation of new 1,2,4-triazole derivatives of general formula (I) in which R-^ denotes an unsubstituted phenyl group or a phenyl group substituted by one or more fluorine, chlorine or bromine atoms, C 1 -4 -alkyl-, C 1 -4 -alkyl-, nitro-, trifluoromethyl-, C 1 -4 -alkylthio-, C1 -4~ alkylsulfinyl or C-^^ -alkylsulfonyl groups, and further a naphthyl group, R 2 denotes an unsubstituted phenyl group or a phenyl group substituted with one or more fluorine, chlorine or bromine atoms, C 2 -alkyl-, C 1 _4~ alkoxy-, nitro-, trifluoromethyl-, C 1 _4~ alkylthio-, C-^- alkylsulfinyl or C1_4~ alkylsulfonyl groups, and further a thienyl group, R^ denotes an unsubstituted C1 _4~ alkyl group or a C1 _4~ alkyl group substituted by one or more fluorine or chlorine atoms, hydroxy-, C2 _4 - alkoxycarbonyl-, cyano- or pyridyl groups, and further C2 _4 - alkoxycarbonyl-, C2_ ,--oxo-alkyl groups or a phenyl-C1 _4 -alkyl group substituted with one or more fluorine or chlorine atoms on the phenyl ring, and n denotes 0, 1 or 2, provided that when n denotes 0 and R^ denotes a methyl group, only one of R^ and R 2 may denote an unsubstituted phenyl group, characterized in that a compound of general formula (II) or (V) wherein and R2 are as defined above, dissolved in an inert solvent and in the presence of an organic or inorganic base, reacted in an alkaline pH range with a compound of general formula (III) R3 - X (III) wherein R^ is as defined above, and X denotes a halogen atom or a tosyloxy group, after which, if desired, the resulting compound of general formula (I) wherein R^, R2 and R^ are as defined above, and n denotes 0, are oxidized to form the compounds of general formula (I) in which R^ , R 2 and R^ are as defined above, and n is 1 or 2. 2. Process according to claim 1 for the production of 1,5-bis-(4-chlorophenyl)-3-(methylthio)-1,2,4-triazole, 1-(4-chlorophenyl)-5-(4-fluorophenyl) -3-(methylthio)-1,2,4-triazole, 1-(4-fluorophenyl)-5-(4-chlorophenyl)-3-(methylthio)-1,2,4-triazole, 1-(4- chlorophenyl)-5-(4-fluorophenyl)-3-(methylsulfonyl)-1,2,4-triazole, 1,5-bis-(4-fluorophenyl)-3-(methylsulfonyl)-1,2,4-triazole .