NO146571B - ANALOGY PROCEDURE FOR THE PREPARATION OF ANTI-INFLAMMATORALLY ACTIVE IMIDAZOLS - Google Patents

Description

The present invention relates to the production of anti-inflammatory active iroidazoles.

US patent 3-707,475 relates to anti-inflammatory 4,5-diaryl-2-substituted-imidazoles.

US patent 3-505-350 relates to anti-inflammatory 4-alkyl-5~

aryl-1-substituted-2-mercapto-imidazoles.

K. Sauer et al. reviews in Chem. Pray. 106, 1638 (1973) 4,5-bis-(4-methoxyphenyl)-2-methylthioimidazole and 4,5-bis-(4-chlorophenyl)-2-methylthioimidazole, but states no use.

A number of publications such as Current Sei. India 17, 184~85

(1948) and Acta. Chem. Acad. Pollock. Hung. 79 (2), 197-212 (1973)

relates to 2-(substituted-thio)-4,5-diphenylimidazoles with substituents such as methyl, propyl, allyl and acetonyl.

There is a continuing need for safe and effective anti-inflammatory agents. Inflammation is a disease process characterized by redness, fever, swelling and pain. Arthritis,

in its various forms, is the most prevalent, chronic and severe of the inflammatory disorders. Traumatic injury and infection also involve inflammation, and anti-inflammatory drugs are often used in their treatment. The usefulness of most commercial anti-inflammatory agents is limited by their toxicity and adverse side effects. Many cause gastric irritation and other effects, such as changes in blood cells and the central nervous system. Adrenocortical steroids cause gastric irritation and suppression of normal adrenal function.

Journal of the American Medical Association, Vol. 224>

No. 5 (Supplement), 1973 "Primer on the Rheumatic Diseases"

states that "Immunological reactions seem to play an essential

role in the duration of rheumatoid inflammation." Widely used non-steroidal anti-inflammatory drugs, such as "Aspirin", "Indomethacin", phenylbutazone and ibuprofen have no effect on these immunological reactions, but only relieve the symptoms of

the inflammatory response. These drugs do not halt the progressive and ultimately destructive processes of rheumatoid arthritis. Immunosuppressive drugs, such as cyclophosphamide, are effective in treating rheumatoid arthritis, but are too toxic for widespread use.

The present invention originates from attempts to develop

new anti-arthritic compounds with good anti-inflammatory and immunoregulatory activity and minimal side effects that could be more effective in the treatment of arthritis than the currently available drugs.

The compounds produced according to the invention have shown outstanding properties in several tests on anti-inflammatory and immunoregulatory activity. The biological profiles of these compounds are different from non-steroidal anti-inflammatory drugs and immunosuppressive drugs. These unique properties provide a new way to treat rheumatoid arthritis, and may also be useful in treating other disorders involving altered immune states.

The present invention relates to analogue methods for the production of therapeutically active compounds with the general formula:

and pharmaceutically acceptable salts thereof as stated in claim 1.

Compounds preferred for their anti-inflammatory and immunoregulatory activity are those wherein R 1 is -CF 2 CF 2 H.

Particularly preferred are the following compounds: 4,5-bis-(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)-imidazole and

4-(or 5)-(4-chlorophenyl)-5-(or 4)-phenyl-2-(1,1,2,2-tetrafluoroethylsulfonyl)-imidazole.

Particularly preferred because of their analgesic activity are the following compounds: 4,5-bis-(4-methoxyphenyl)-2-(1,1,2,2-tetrafluoroethyl-sulfonyl)-imidazole and

4,5-bis-(4-methoxyphenyl)-2-(2,2,2-trifluoroethylsulfonyl)-imidazole.

When R^ and R^ are different, the following two structures are tautomers:

Pharmaceutically acceptable salts of compounds where n is

1 or 2, include salts of certain metals, such as sodium, potassium or calcium.

The compounds of formula I may be prepared as follows: benzoin or a suitably substituted benzoin prepared as described by Ide, W.S. and Buck, J.S. in Organic Reactions, Vol. IV, page 629, is condensed, with thiourea in refluxing dimethylformamide or other high-boiling polar solvent to give 4,5-diaryl-2-mercaptoimidazole. A similar condensation method is described by Kochergin, P.M., in Zhur. Obshchei Khim., 31, 1093 (1961); Chem. Abstract 55, 23503f.

4>5-diaryl-2-mercaptoimidazoles can also be prepared by

to heat 4>5-diarylimidazoles with sulfur at temperatures in the range 150 - 300°C with or without solvent. A suitable solvent for this reaction is tetramethylene sulfone. This procedure is analogous to the transfer of 1-methylbenzimidazole to 2-mercapto-1-methylbenzimidazole as described by A. V. El'tsov and K. M. Krivozheiko, in ZhOrKh, 2,

189 (1966).

The appropriate R 1 group can be introduced by alkylating the 4>5~ diaryl-2-mercaptoimidazole with a suitable alkylating agent such as ethyl iodide or 2,2,2-trifluoroethyl-trichloromethanesulfonate. These methods and the use of other alkylating agents appear

of the examples.

Also, the 4,5-diaryl-2-mercaptoimidazole can be reacted with tetrafluoroethylene to form 4,5-diaryl-2-(1,1,2,2-tetrafluoroethylthio)-imidazole derivatives. Similar addition reactions of tetrafluoroethylene and other fluorinated olefins are described by England, D.C., et al. in J. Am. Chem. Soc. 82, 5ll6 (I96O) and

Rapp, K.E., et al. in J. Ara. Chem. Soc. 72, 3642 (1950). In the present description, tetrafluoroethylene and other fluorinated olefins used are regarded as alkylating agents.

Compounds of formula I can also be prepared by reacting an N-protected diarylimidazole (such as, for example, 4,5-diphenyl-1-(2-tetrahydropyranyl)-imidazole or 1-benzyloxymethyl-4,5-diphenylimidazole) with a strong base such as n-butyllithium or similar,

and then with a fluorinated alkyl sulfenyl halide, disulfide or sulfonic anhydride. An appropriate choice of the protecting group and work-up conditions allows isolation of the desired 4,5-diaryl-2-(substituted thio or sulfonyl)-imidazole directly. Compounds where R 1 is trifluoromethyl can be conveniently prepared

by this procedure.

The 4,5-diaryl-2-(substituted thio)-imidazole can then be oxidized to the corresponding sulfoxide or sulfone using oxidizing agents such as m-chloroperbenzoic acid, Tweit, R.C., et al., J. Med.

Chem. 16, 116l (1973); sodium metaperiodate, Leonard N.J. and Johnson, C.R., J. Org. Chem. 27, 282 (1962); hydrogen peroxide, Kochergin, P.M. and Shchukina, M.N., J. Gen. Chem. U.S.S.R. 25, 2289 (1955); or potassium permanganate, Rapp, K.E. et al. lol. one.

Phenylquinone "Writhing" test

A standard method for detecting and comparing the analgesic activity of compounds in this series for which there is good correlation with efficacy in humans is the standard phenylquinone "writhing" test modified from Siegmund, et al.,

Pro. Soc. Exp. Biol. With. 95, 729 (1957). A test compound suspended in 1% methylcellulose was given orally to fasting subjects

(17-21 hours) white female mice, 5-20 animals per double blind test. Aqueous (0.01% phenyl-p-benzoquinone)-phenylquinone was injected intraperitoneally 24 minutes later using 0.20 ral per mouse. Beginning

30 minutes after the oral administration of the test compound

the mouse was observed for 10 minutes to determine a characteristic stretching or writhing syndrome indicative of pain caused by phenylquinone. The effective analgesic dose for 50%

of the mice (ED^q) was calculated by the moving average method according to Thompson, W.R., Bact, Rev. 11<_>, 115-145 (1947). and likewise the time of peak action was determined for many of the compounds. These data can be summarized as follows:

The following examples illustrate the invention. Parts are given by weight where not expressly stated otherwise.

Example 1

4, 5- diphenyl- 2-( 2, 2, 2- trifluoroethylthio)- imidazole

A mixture of 4,5-diphenyl-2-arecaptoimidazole (71>99 0.285 mol) 2,2,2-trifluoroethyl trichloromethanesulfonate (80.3 g 0.285 mol), triethylamine (28.8 9, 0.285 mol) and toluene ( 700 ml) is refluxed under nitrogen for 4 hours. After cooling to room temperature, 13.4 9 4>5-

Phenylquinone "Writhing" test

A standard method for detecting and comparing the analgesic activity of compounds in this series for which there is good correlation with efficacy in humans is the standard phenylquinone "writhing" test modified from Siegmund, et al.,

Pro. Soc. Exp. Biol. With. 95, 729 (1957). A test compound suspended in 1% methylcellulose was given orally to fasting subjects

(17-21 hours) white female mice, 5-20 animals per double blind test. Aqueous (0.01% phenyl-p-benzoquinone)-phenylquinone was injected intraperitoneally 24 minutes later using 0.20 ml per mouse. Beginning

30 minutes after the oral administration of the test compound

the mouse was observed for 10 minutes to determine a characteristic stretching or writhing syndrome indicative of pain caused by phenylquinone. The effective analgesic dose for 50%

of the mice (ED^-q) was calculated by the moving average method according to Thompson, W.R., Bact, Rev. 11, 115-145 (1947). and likewise the time of peak action was determined for many of the compounds. These data can be summarized as follows:

The following examples illustrate the invention. Parts are given by weight where not expressly stated otherwise.

Example 1

4, 5- diphenyl- 2-( 2, 2, 2- trifluoroethylthio)- imidazole

A mixture of 4,5-diphenyl-2-mercaptoimidazole (71 >9 9 0.285 mol) 2,2,2-trifluoroethyl trichloromethanesulfonate (80.3 g 0.285 mol), triethylamine (28.8 g, 0.285 mol) and toluene (700 mL) is refluxed under nitrogen for 4 hours. After cooling to room temperature, 13.4 9 4>5~ diphenyl-2-ercaptoimidazole is recovered by filtration. The filtrate is washed twice with water, and upon cooling the organic phase the product crystallizes. 46.2 g (49%) of 4,5-diphenyl-2-(2,2,2-trifluoroethylthio)-imidazole are obtained as almost colorless crystals with m.p. 185j5 - 187C.

Anal. Calculate, for C^-^F^S: C 61.06; H 3.92; N 8.38

Found: C 61.28; H 3.97; N 8.49-

Example 2

4 , 5- diphenyl- 2-( 2, 2, 2- trifluoroethylsulfinyl)- imidazole

To a mixture of 4,5-diphenyl-2-(2,2,2-trifluoroethylthio)-imidazole (13.9 9, 0.04l6 mol) and chloroform (75 ml) cooled in an ice bath is added dropwise 86.4% -mg of m-chloroperbenzoic acid (8.4 g, 0.042 mol) in chloroform (85 ml). After stirring overnight, the mixture is washed with saturated sodium bicarbonate, dried over magnesium sulfate, and the solvent is evaporated, whereby 12.3 g of crude product is obtained. Recrystallization from toluene gives 10.1 g (69%) of 4,5-diphenyl-2-(2,2,2-trifluoroethylsulfinyl)-imidazole as colorless prisms with m.p. 198°C (dec.).

Anal. Calculate, for C-^-^F^OS: C 58.28; H 3.74; N 8.00.

Found: C 58.27} H 3.76; N 8,10.

Example 3

4, 5- diphenyl- 2-( 2, 2, 2- trifluoroethylsulfonyl)- imidazole

To a mixture of 4,5-diphenyl-2-(2,2,2-trifluoroethyl-thio)-imidazole (15.7 g, 0.0470 mol) and chloroform (100 ml) cooled in an ice bath is added dropwise 86, 4% m-chloroperbenzoic acid (19.0 g, 0.0952 mol) in chloroform (200 mL). After stirring for 4 days at room temperature, tetrahyrofuran is added, and the mixture is washed with saturated sodium bicarbonate, dried with magnesium sulfate, and the solvent is distilled off, whereby 16.9 g of crude product is obtained. After two recrystallizations from acetonitrile, 8.8 g (51%) of 4,5-diphenyl-2-(2,2,2-trifluoroethylsulfonyl)-imidazole are obtained as colorless needles with m.p. 228°C (dec.).

Anal. Calculate, for cl7H13p3^ 2°2Sz C 55.73; H 3.58; N 7.65; F 15.56

Found: c 56.18, 56.o6; h 3.94, 3.95;

N 7.45, 7.52; F 15.44.

Example 4

4, 5- bis-(4- methoxyphenyl)- 2-( 2, 2, 2- trifluoroethylthio)- imidazole

A mixture of 2-mercapto-4,5-bis-(4-methoxyphenyl)-imidazole (31.2 g, 0.100 mol), 2,2,2-trifluoroethyl trichloromethanesulfonate (31.0 g, 0.110 mol), triethylamine (11.1 g,

0.110 mol) and toluene (300 mL) are refluxed for 6 hours under nitrogen. The mixture is cooled, washed three times with water, dried over magnesium sulfate and evaporated, thereby obtaining 43.4 g of crude product which is chromatographed on a column containing 450 g of silica gel, eluting with chloroform. The residue from the main fraction is recrystallized from methylcyclohexane whereby 21.5 9 (55%) of 4,5-bis-(4-methoxyphenyl)-2-(2,2,2-trifluoro-ethylthio)-imidazole is obtained as almost colorless crystals with m.p. .

119 - 120°C. A polymorphic form has m.p. 150 - 151°C.

Anal. Calculate, for c19H1yF ^ 2°2S: C 5?'865 H 4.34; N 7,10.

Found: C 57.96; H 4,Ol; N 7,09-Example 5 4,15-bis-(4-methoxyphenyl)-2-(2,2,2-trifluoroethylsulfinyl)-imidazole By using 4»5~bis-(4-methoxyphenyl)-2- (2,2,2-trifluoro-ethylthio)-imidazole instead of 4,5-diphenyl-2-(2,2,2-trifluoro-ethylthio)-imidazole in example 2 is obtained as product 4,5-bis-(4- methoxyphenyl)-2-(2,2,2-trifluoroethylsulfinyl)-imidazole. Recrystallization of the crude product from aqueous ethanol gives 83% yield of pure product with m.p. 193.5°C (dec.).

Anal. Calculate, for C^H^F^^S: C 55.60; H 4.18; N 6.83-Found: C 55, 52; H 3.80; N 6.77.

Example 6 4,5-bis-(4-1°ethoxyphenyl)-2-(2,2,2-trifluorinated hylsulfonyl)-imidazole For a mixture of 4 > 5-bis-(4-methoxyphenyl)-2 -(2,2,2-tri-fluoroethylthio)-imidazole (6.0 g, 0.015 mol) and chloroform (75 ml) cooled in an ice bath are added dropwise to 86.4% m-chloroperbenzoic acid (6.1 g, 0.031 mol) in chloroform (75 mL). After stirring overnight at room temperature, the mixture is washed with saturated sodium bicarbonate, dried with magnesium sulfate and evaporated, whereby 7.1 g of crude product is obtained. Recrystallization from 1-chlorobutane gives pure 4,5-bis-(4-methoxyphenyl)-2-(2,2,2-trifluoroethylsulfonyl)-imidazole as colorless needles with m.p. 173 - 174°C.

Anal. Calculate, for C^<H>^<F>^<O>^<S:> C 53.51; H 4.02; N 6.57-Found: c 53.47, 53.81; h 4.o6, 3.69;

n 6.55, 6.59-

Example 7

4, 5- bis-(4- chlorophenyl)- 2-( 2, 2, 2- trifluoroethylthio)- imidazole

A mixture of 4>5-bis-(4-chlorophenyl)-2-mercaptoimidazole (32.1 g, 0.100 mol), 2,2,2-trifluoroethyl trichloromethanesulfonate (28.1 g, 0.100 mol) sodium ethoxide (5, 9 9, 0.109 mol) and ethanol (300 ml) are refluxed for 3 hours. The reaction mixture is poured into water, and the solid is collected by filtration, washed with water and dried. This solid (43.9 g) is then stirred overnight in ethyl acetate (400 ml). The mixture is filtered, and the solvent is driven off from the filtrate, whereby 21.7 g of a residue is obtained. This residue is recrystallized from toluene, whereby 15.1 g (37%) of pure 4'5-bis-(4-chlorophenyl)-2-(2,2,2-trifluoroethylthio)-imidazole is obtained as colorless crystals

with m.p. 212 - 213°C.

Anal. Calculate, for C^^H^Cl^ NgS: C 50.63; H 2.75; N 6.95.

Found: C 50.87; H 3.05; N 6.69.

Example 8 4,5-bis-(4-chlorophenyl)-2-(2,2,2-trifluoroethylsulfinyl)-imidazole Using 4,5-bis-(4-chlorophenyl)-2-(2,2,2 -trifluoroethylthio)-imidazole instead of 4,5-diphenyl-2-(2,2,2-trifluoroethylthio)-imidazole in example 2 is obtained as product 4,5~bis-(4-chlorophenyl)-2-( 2,2,2-trifluoroethylsulfinyl)-imidazole. Recrystallization of the crude product from acetonitrile gives a 77% yield of pure product with m.p. 2l4°C (splint.).

Anal. Calculate, for C^^Cl^^OS: C 48.70; H 2.64; N 6.68-

Found: C 48.97; H 2.89; N 6.47-Example 9

4, 5- bis-(4- chlorophenyl)- 2-( 2, 2, 2- trifluoroethylsulfonyl)- imidazole

To a mixture of .4,5-bis-(4-chlorophenyl)-2-(2,2,2-trifluoro-ethylthio)-imidazole (5.3 9 0.013 mol) and chloroform (50 ml) cooled in 86.4% m-chloroperbenzoic acid (5.3 g, 0.027 mol) in chloroform (60 ml) is added dropwise to an ice bath. After stirring overnight at room temperature, the mixture is refluxed for 15 minutes, cooled, and the solid is collected and washed with cold chloroform. The solid is then dissolved in a mixture of ether and tetrahydrofuran, and the resulting solution is washed with saturated sodium bicarbonate. The organic phase is dried with magnesium sulphate and the solvent is evaporated, whereby 5.8 g of a colourless, solid residue is obtained which is recrystallized from nitromethane (125 ml). 4,1 9 (72%) pure 4,5~bis-(4-chloro-phenyl)-2-(2,2,2-trifluoroethylsulfonyl)-imidazole is obtained as colorless needles with m.p. 24l°C (split.).

Anal. Calculate, for c1- fi11cl2F$ N2°2SC 46'915 H 2' 55; N 6.44-Found: C 47.13, 47.29; H 2.67, 2.58;

N 6.56, 6.58-

Example 10

2-ethylthio-4,5-bis-(4-methoxyphenyl)-imidazole

To a suspension of 2-mercapto-4,5-bis-(4-methoxyphenyl)-imidazole (31.2 g, 0.100 mol) in methanol (200 ml) is added in one portion sodium methoxide (6.5 g, 0.12 mol) ), and the mixture is stirred for 15 minutes. A solution of iodoethane (17.1 g, 0.11 mol) in methanol (50 ml) is added dropwise, and the mixture is heated under reflux for 4.5 hours. After stirring overnight at room temperature, the mixture is poured into water, and the solid material that separates is collected, washed with water and dried, whereby 33.0 g of crude product is obtained. Recrystallization from aqueous ethanol gives 28.8 g (85%) of pure 2-ethylthio-4,5-bis-(4-methoxyphenyl)-imidazole with m.p. 108 - 109°C.

Anal. Calculate, for c19H2oN2°2<S:> C 67>°3' H 5.92; N 8.23-

Found: C 66.96; H 6.10; N 7.85-Example 11

2-Alylthio-4,5-bis-(4-Methoxyphenyl)-imidazole

A mixture of 2-mercapto-4,5-bis-(4-methoxyphenyl)-imidazole (31.2 g, 0.100 mol), allyl bromide (13.1 9, 0.108 mol), triethylamine (20.2 g, 0.200 mol ) and chloroform (500 mL) are heated overnight under reflux. Allyl bromide (4.8 g, 0.040 mol) is then added and reflux is continued for 2 hours. Two more portions (4.8 g) of allyl bromide are added, in each case followed by 2 hours of reflux. The clear solution is cooled, washed three times with water, dried over magnesium sulphate and evaporated. The residue is triturated with ether, and the solid is collected, whereby 31.5 g of crude product is obtained. Recrystallization from aqueous ethanol yields 26.7 g (76%) of pure 2-allylthio-4,5-bis-(4-methoxyphenyl)-imidazole with mp 167 -

167.5°C.

Anal. Calculate, for C^H^N^S: C 68.16;.H 5.72; N 7.95-

Found: C 67.22; H 5.87; N 7.81-

Example 12

4, 5- bis-(4- methoxyphenyl)- 2-( methylthiomethylthio)- imidazole

By using chloromethyl-methylsulfide instead of allyl-

bromide in example 11 is obtained as product 4,5~bis-(4-methoxyphenyl)-2-(methylthiomethylthio)-imidazole with m.p. 171 - 172°C.

Anal. Calculate, for ^ 1^ i2(^ 202S2: C 6l.26; H 5.4l; N 7.52.

Found: C 61.32; H 5.57; N 7.32.

Example 13

2-ethylsulfinyl-4,5-bis-(4-methoxyphenyl)-imidazole

A solution of 86.4 % m-chloroperbenzoic acid (6.0 g, 0.030 mol) in dichloromethane (100 mL). After stirring overnight at room temperature, the reaction mixture is washed with three portions (75 ml) of saturated sodium bicarbonate. The organic phase is dried with magnesium sulfate, and the solvent is removed on a rotary evaporator. The remaining oil is triturated with ether, and the solid formed is collected and recrystallized from 1-chlorobutane (500 ml), whereby 7.5 g is obtained

(70%) pure 2-ethylsulfinyl-4,5-bis-(4-methoxyphenyl)-imidazole with

m.p. l6l - l62°C.

Anal. Calculate, for C^H^<I>^<O>^S: C 64.02; H 5.66; N 7.86.

Found: C 63.98; H 5.59; N 7.97.

Example 14

2-ethylsulfonyl-4,5-bis-(4-methoxyphenyl)-imidazole

By using 12.0 g (0.060 mol) of 86.4% m-chloroperbenzoic acid instead of the 6.0 g of 86.4% m-chloroperbenzoic acid in example 13, after recrystallization from 1-chlorobutane

(125 mL) 6.0 g (54%) of 2-ethylsulfonyl-4,5-bis-(4-methoxyphenyl)-imidazole with m.p. I36 - 137°C.

Anal. Calculate, for C^H^N^S: C 61.27; H 5.4l; N 7.52.

Found: C 61.47; H 5.47; N 7.35-

Example 15

4 , 5- bis - ( 4- methoxyphenyl) - 2 - methy lt hioimidazole

By using iodomethane instead of iodoethane in example 10, 4,5-bis-(4-methoxyphenyl)-2-methylthioimidazole with m.p. 157 - 158.5°C.

Anal. Calculate, for C18H18<N>2<0>2<S:> C d6>23» h 5.56; N 8.58-

Found: C 65.84; H 5.53; N 8.46.

Example 16

2-acetonylthio-4,5-bis-(4-methoxyphenyl)-imidazole

To a stirred mixture of 2-mercapto-4,5-bis-(4-methoxy-phenyl)-imidazole (31.2 g, 0.100 mol), triethylamine (11.0 g,

0.11 mol) and chloroform (500 ml) is added dropwise to chloroacetone (10.2 g, 0.11 mol) in chloroform (50 ml). After stirring overnight under reflux, the reaction mixture is washed 3 times with water, dried with magnesium sulfate and evaporated, whereby 32.0 g of crude product is obtained. Chromatography (silica gel, chloroform) gives 27.0 g (73%) of pure 2-acetonylthio-4,5-bis-(4-methoxyphenyl)-imidazole with m.p. 115 - 117.5°C.

Anal. Calculate, for <c>2oH20<N>2°3<S:> C 65' 20> ' H 5.47; N 7.60.

Found: C 65.14; H 5.42; N 7.36.

Example 17

4,5-bis-(4-methoxyphenyl)-2-(methylthiomethylsulfinyl)-imidazole and 4,5-bis-(4-methoxyphenyl)-2-(methylsulfinylmethylthio)-imidazole

A solution of 86, 86 4% m-chloroperbenzoic acid (4.0 g, 0.020 mol) in dichloromethane (100 ml). After stirring overnight at room temperature, the reaction mixture is washed three times with saturated sodium bicarbonate solution, dried with magnesium sulfate and evaporated. The residue (7.5 g) is then chromatographed on a column of silica gel which is eluted with a

mixture of toluene and ethyl acetate.

The first pure compound eluted from the column is 4,5-bis-(4-methoxyphenyl)-2-(methylthiomethylsulfinyl)-imidazole with m.p. 142.5 - 143.5°C.

Anal. Calculate, for C-^H^r^O^: C 58.74; H 5.19; N 7.21.

Found: C 59.OO; H 5.13; N 6.93-

Further elution of the column gives pure 4,5-bis-(4-methoxy-phenyl)-2-(methylsulfinylmethylthio)-imidazole with m.p. 84.5 - 86.5°C

Anal. Calculate, for <c>19H2oN2O3S2: c 58.74; H 5.19; N 7.21.

Found: C 58.85; H 5.36; N 6.94-Example 18

4, 5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)-imidazole.

To a stainless steel tube are added 4,5-diphenyl-2-mercapto-imidazole (5.0 g, 0.020 mol) and dimethylformamide (50 ml) containing 0.5 ml of a 40% methanol solution of benzyl trimethylammonium hydroxide. After flushing the tube several times with dry nitrogen, tetrafluoroethylene (2.2 g, 0.022 mol) is introduced. The tube is shaken for 7 hours. The reaction mixture is poured into water, and the solid is collected and washed with water, giving 5.7 g of crude product. Column chromatography (silica gel, chloroform) gives 3.5 g of pure 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)-imidazole with m.p. 212 - 213°C.

Anal. Calculate, for C^^F^S: C 57.95; H 3.43; N 7.95-

Found: C 57.71; H 3.70; N 7.89-Example 19

4, 5-bis-(4-methoxyphenyl)-2-vinylthioimidazole

To a stainless steel tube is added 4,5-bis-(4-methoxy-phenyl)-2-mercaptoiraidazole (15.0 g, 0.05 mol), cuprochloride

(0.75 g) and 100 ml of dimethylformamide. The tube is cooled, evacuated and then pressurized with 1.3 9 acetylene. The tube is heated at 150°C with shaking for 8 hours, cooled and vented. The contents are diluted with 500 ml of water, and 25 ml of concentrated ammonium hydroxide is added. The aqueous mixture is extracted with ether (4 x 300 ml). The combined ether extract is backwashed with

water (3 x 300 ml) and then dried and evaporated on a rotary evaporator. The residue is chromatographed on a column containing 600 g of silica gel ("SilicAR CC-7"). The product is eluted with chloroform (fraction 6-8.1 liters each) which after evaporation gives 2.9 g of crystals. A recrystallization from 1-chlorobutane/hexane yields 2.8 g of pure product with m.p. 114 - 115°C.

Anal. Calculate, for C19H18<N>2<0>2<S:> C 67.43; H 5.36; N 8.28-

Found: C 67.17; H 5.40; N 8.42.

Example 2Q

4 , 5- his -( 4- methoxyphenyl)- 2-( 1, 1, 2-trifluoroethylthio)- imidazole To a solution of 2-(2-bromo-1,1,2-trifluoroethylthio)-4,5 -bis-(4-methoxyphenyl)-imidazole (14.2 g, 0.03 mol) in 150 ml of toluene is added tri-n-butyltin hydride (9.0 g, 0.03 mol). The mixture is boiled under reflux for 4 hours. An additional 9.0 g (0.03 mol) of tri-n-butyltin hydride is added, and the mixture

boil under reflux overnight. The mixture is then added directly to a column of 900 g of silica gel ("SilicAR CC-7"). Elution with toluene followed by toluene/ethyl acetate (95/5) gives 6.5 g of crystalline product. Recrystallization from methylcyclohexane gives 5.6 g of pure product with m.p. 143.5 - 145°C.

Anal. Calculate, for c19ul7Fj<q>2°2S1 C 57'°65 H ^>34; N 7,10.

Found: C 57.95; H 4.71; N 7,o4-Example 21

4, 5- diphenyl- 2-(1, 1, 2- trifluoroethylthio)- imidazole

By using 2-(2-bromo-1,1,2-trifluoroethylthio)-4,5-diphenylimidazole instead of 2-(2-bromo-1,1,2-trifluoroethylthio)-4,5-bis-(4 -methoxyphenyl)-imidazole in example 20, is obtained as product 4,5-diphenyl-2-(1,1,2-trifluoroethylthio)-imidazole with m.p. 225 - 226.5°C

Example 22

4,5-bis-(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)-imidazole sodium salt

A mixture of 4,5-bis-(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)-imidazole (5.0 g, 0.0119 mol) sodium methoxide (0, 6 g, 0.0111 mol) and ether (300 ml) are stirred overnight at room temperature. The solid is collected and washed with ether, whereby 2.1 g of the sodium salt of 4>5-bis-(4-fluorophenyl)-2-(1,1,2,2-t rafluoroethylsulfonyl)-imidazole is obtained with m.p. 290 - 292°C.

Anal. Calculate, for C^y-I FgN^O^Na: C 46.16; H 2.05; N 6.33-Found: C 45.98; H 2.19; N 6.07-Example 23

4,5-Diphenyl-2-(1,1,2,2-trifluoroethylsulfonyl)-imidazole sodium salt

By using the method described in example 22 and using 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethyl-sulfonyl)-imidazole as starting material, the product 4,5-diphenyl-2-( 1,1,2,2-tetrafluoroethylsulfonyl)-imidazole sodium salt with m.p. 296 - 302°C (dec.).

A. ) 4>5-diphenyl-1-(2-tetrahydropyranyl)-imidazole

A mixture of 27 g (0.122 mol) of 4,5-diphenylimidazole, 21 g (0.25 mol) of dihydropyran, 250 ml of ethyl acetate and 4.0 g of BF 2 -E 2 O was refluxed for 5 days. The almost clear solution was diluted with ether and filtered to remove 0.6 g of insoluble starting material. The ether filter was washed several times with 10% sodium bicarbonate and then dried and evaporated. Thin-layer chromatography showed that the starting material was still present, and the crude product was therefore chromatographed on 900 g.

"Silic AR CC-7" eluting with toluene containing 20 to 40% ethyl acetate. The pure product thus obtained was 30.3 g (81.7%), m.p. 170-171°C. IR: 3.21u, =CH; 3.40, 3.49M- saturated CH; 6.25, 6.64, 6.73|in aromatic C=C and/or C=N; strong 9-10u, C-O-C; 12.98 and 14>38U monosubstituted aromatic. H-NMR: mult (1.6-2.35, 6H); mult, (^3.4, 4.0, 4.8$, each^lH);

mult + singlet (7.0-7.6+ 7.4*, lOH) ; S (7.8S, 1H). Mass spectrum, calculated for c2oH20<N>2°: 3°4'1574; found: 304.1559-Anal. Calculate, for: <C>20H20N2<0:> C 78.92; H 6.62; N 9.20.

Found: C 78.57; H 6.89; N 9.07.

B. ) 4, 5- diphenyl- 2- trifluoromethylthioimidazole

Under nitrogen and in heat-dried glassware, a solution of 0.9 g (3 mmol) of 4,5-diphenyl-1-(2-tetrahydro-pyranyl)-imidazole in 15 ml of THF and 15 ml of ether was cooled to -78 °C. To the cold solution was added dropwise a solution of 2.5 ml (4 mmol) of 1.6 M n-butyllithium in hexane in 10 ml of ether. The solution was stirred at -78°C, and then 0.55 g (4 mmol) of trifluoromethanesulfenyl chloride (toxic) was added as gas. The mixture was stirred at -78°C for 2 hours, and then at room temperature overnight. The mixture was poured into water and extracted with ether (pH of the aqueous layer was approx. 4) - The aqueous layer was neutralized with bicarbonate and then extracted with more ether. The combined ether extracts were dried and evaporated. The crude residue was chromatographed on 50 g of "Silic AR CC-7" eluting with 98% toluene/2% ethyl acetate, whereby 0.45 g (47%) of product was obtained. Recrystallization from toluene gave 0.3 g (31%) of a white solid, m.p. 254-256°C; IR: broad 3~4(i, NH;

3.28u, = CH; 6.24, 6.34, 6.42, 6.7lH, aromatic C=C and/or C=N; strong 8.5-9^, C-F; 13.09, 14.34|in monosubstituted aromatic. H-NMR: mult (7.1-7.74, 10H); broad (135, 1H) F-NMR: S(42.46fi). Mass spectrum: molecular ion C^H^F N2S: found 320.0609-

Anal. Calculate, for: C^H^F^S: C 59.99; H 3.46; N 8.75

Found: C 60.20; H 3.57; N 8.52

Example 100

4, 5- diphenyl- 2- trifluoromethylsulfonylimidazole

A mixture of 0.48 g (1.5 mmol) of 4,5-diphenyl-2-trifluoromethylthioimidazole and 0.72 g (3.6 mmol) of 85% m-chloroperoxybenzoic acid in 30 ml of methylene chloride was stirred at room temperature overnight, and then, when thin-layer chromatography indicated incomplete oxidation, under reflux for an additional day. Thin layer chromatography still indicated incomplete oxidation so the methylene chloride was removed by rotary evaporation and replaced with 30 ml of chloroform and the mixture was refluxed for 6 hours. The chloroform was evaporated and the residue triturated with approx. 20 ml of ether. The ether-insoluble solid (ca. 0.3 g) was combined with ca. 0.1 g solid obtained from the ether filtrate by washing with 10% sodium sulphite,

10% sodium bicarbonate, drying and evaporation. Recrystallization from toluene gave 0.37 g (70%) of white product with m.p. 292 - 293.5°C (sublimes above 250°C). IR: 3"4H, NH; 6.33, 6.44, 6.72a, aromatic C=C and/or C=N; 7.23, 8.32u; -SO2~; 8.97ji, C-F; 13 .05, 14.30u, monosubstituted aromatic. H-NMR: mult (7.1-7.7$, 1OH). F-NMR: S (78.255); small singlets were also observed at 42.435 (=*2%, sulfide) and at 72.695 (a£3%, sulfoxide) .

Anal. Calculate, for: C^H^F^^S: C 54.54; H 3.15; N 7.95

Found: C 55.13; H 2.94; N 8.06

54.98 2.95 8.05

The compound of Example 100 had an adjuvant-induced arthritis ED₂Q in rats of 0.03 mg/kg.

Example 10J.

4, 5-bis-(4-fluorophenyl)-2-trifluoromethylthioimidazole

By applying the methods in example 99, and using 4,5-bis-(4-fluorophenyl)-imidazole instead of 4,5-diphenylimidazole in example 99, the final product is 4,5-bis-(4-fluorophenyl)-2- trifluoromethylthioimidazole, with m.p. 228-229°C.

Anal. Calculate, for Cl6H F^S: C 53.93; H 2.55; N 7.86.

Found: C 54.17, 54.12; H 2.59, 2.58,

N 7.34, 7.97-

Example 103

By proceeding as described in the previous examples, the following compounds were prepared:

4-(3,4-dichlorophenyl)-5-phenyl-2-(1',1',2•,2'-tetrafluoroethylsulfonyl)-1H-imidazole; sm.p. 192 - 194°C.

Provoked arthritis test ED5Q =0.2 mg/kg.

i Using the appropriate starting materials and the procedure described in Example 10, the compounds of Table I can be prepared. Typical solvents that can be used are methanol, ethanol or toluene.

Using the appropriate starting materials and the procedure described in Example 18, the compounds in Table II can be prepared. Typical catalysts that can be used are diisopropylamine or benzyltrimethylammonium hydroxide.

Using the appropriate starting materials and procedures described in Examples 13 and 14, the compounds of Table III can be prepared.

The compounds produced according to the invention can be administered in the treatment of arthritis by any means which provides contact between the active agent and the area of action of the agent in the body of a mammal. They may be administered by any conventional means available for use with pharmaceuticals, either as individual therapeutic agents or in combination with therapeutic agents. They can be administered alone, but are usually administered with a pharmaceutical carrier selected on the basis of the chosen mode of administration and common pharmaceutical practice.

The administered dose will of course vary depending on known factors such as the pharmacodynamic properties of the particular agent, its method and route of administration, the patient's age, health and weight, the nature and degree of symptoms, the type of concomitant treatment, frequency of treatment and the desired effect. Generally, a daily dose of active ingredient can be 0.001 to 40 mg per kg body weight. Usually gives 0.005 to 20, and preferably 0.01 to 4 mg/kg per day in divided doses 2 to 4 times a day or in prolonged release form the desired results.

Dosage forms (preparations) suitable for internal administration contain from 0.1 mg to 500 mg of active ingredient per unit. In these pharmaceutical preparations, the active ingredient will usually be present in an amount of 0.5 -

95% by weight, calculated on the weight of the preparation.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be produced as delayed release products to provide continuous release of the drug over a period of hours. Pressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective breakdown in the intestinal tract.

Liquid dosage forms for oral administration may contain coloring and flavoring substances to increase patient acceptance.

In general, water, a suitable oil, brine,

aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, buffering materials. Antioxidants such as sodium bisulphite, sodium sulphite or ascorbic acid, either alone or in combination, are suitable stabilizers. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propyl paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, E.W. Martin, a standard reference work in this field.

In order to demonstrate and compare the anti-inflammatory and immunoregulatory activities of the compounds produced according to the invention and standard drugs, a series of tests based on a standard model for which there is a good correlation with the activity in humans was used. The model is excipient-induced arthritis in rats. Federation Proceedings, Vol. 32, No. 2, 1973 "Models Used for the Study and Therapy of Rheumatoid Arthritis" - Symposium of the American Society for Pharmacology and Experimental Therapeutics - states "The rat polyarthritis produced by intradermal injection of a suspension of Mycobacterium tuberculosis in mineral oil (adjuvant) has been used extensively for the screening of drugs of potential use in rheumatoid arthritis."

Established adjuvant-induced arthritis in rats

A sample was used to determine anti-inflammatory activity.

Male Charles River Lewis rats (130 - 150 g) were injected subcutaneously in the sole of the right hind paw with 0.1 ml of adjuvant ("Difco<11> heat-killed, lyophilized Mycobacterium butyricum suspended in mineral oil 5 mg/ml). 20 non-arthritic control animals was injected with mineral oil. Animals were kept for 2 weeks to allow development of arthritis. Paw volumes (uninjected, left hind paw) were measured, and the vehicle-injected rats were sorted and divided into treatment groups on IO of equal disease grade. Non-arthritic control animals were divided into 2 groups of 10 each. The rats were given oral doses of the compound or PVA-Acacia (polyvinyl alcohol 1%, gum acacia, USP 5%, methylparaben 0.5%) (10 ml/kg) by gavage on that day and on the following 6 days.One day after the last dose, paw volume (uninjected, left hind paw) was measured using an "Ugo Basile Volume Differential Meter Model 7101".

Dose-response regression lines of the % reduction were plotted on semi-log paper by visual fitting, and the ED,-^ reduction from control paw volume was determined by inspection.

Non-established adjuvant-induced arthritis in rats

A test used mainly to determine the effects of compounds on the immunological reactions involved in the induction process and to prevent the development of arthritis.

Male Charles River Lewis rats (130 - 150 g) are injected subcutaneously in the sole of the right hind paw with 0.1 ml of adjuvant ("Difco" heat-killed, lyophilized Mycobacterium butyricum suspended in mineral oil 5 mg/ml). 4o non-arthritic control animals were injected with mineral oil. Groups of 20 rats are given single, daily oral doses of compound (in PVA-acacia medium, 10 ml/kg) or medium by gavage starting immediately after the paw injection with a total of 14 doses. The paw volume of the uninjected (left) hind paw is measured 24 hours after the last dose using an "Ugo Basile Volume differential meter Model 7101". ED^^ o reduction from the control is determined as described above.

For further assessment of the immunoregulatory properties of these compounds, two further samples were used, which are described below. "The Jerne Hemolytic Plaque Assay" measures the effect of compounds on specific antibody-producing cells (B lymphocytes). The relative amounts of B lymphocytes and T lymphocytes (involved in cell-mediated immunity) are determined by fluorescent antibody staining.

Modified "Iron Spleen Cell Hemolytic Plaque Assay" methods

A modification of the method described by N. K. Jerne and

A. A. Nordin (Science, 140, 450, 1963) was used in these investigations. Rats (Charles River Lewis) with adjuvant-induced arthritis (and non-arthritic controls) were dosed orally once per day with PVA-acacia medium (polyvinyl alcohol 1%, gum acacia 5%, methylparaben 0.5% in water) or compounds in medium from day 14 (after adjuvant injection) to day 20. The animals were sensitized with sheep red blood cells (SRBC) (0.2 ml of a 10% suspension = 2 - 3 x 10<6> cells) I.V. on day 17. SRBC (Microbiological Associates) were washed 3 times in 0.9% sodium chloride solution before injection. On day 21, the rats were anesthetized with 1% sodium pentobarbital I.P., and the spleens were removed. Each spleen was placed on a stainless steel mesh placed over a plastic beaker in an ice bath and gently macerated with a glass syringe plunger. The cells were washed through the mesh into the beaker using a pasteur pipette to add approx. 10 ml "Eagle's Minimal Essential Medium" (MEM) during the maceration process until only fibrous material remained on the web. Large particles were allowed to settle for approx. 5 minutes, and approx. 5 ml of the supernatant was transferred to a plastic tube. Dilutions of 1:10 and 1:20 were made in cold MEM.

Preparation of plates: 2 ml of 0.7% "Agarose" (1.4% diluted 1:2 with 2X Eagles MEM) and 0.2 ml of a 10% SRBC suspension were pre-warmed in a 45°C water bath. 20 lambda spleen cell dilution was added, mixed gently and poured onto a support layer of 2 ml 1.4% "Agarose" in a 60 x 15 mm plastic Petri dish. The dishes were incubated at 37°C for 1.5 hours in a humidified incubator. 1.5 ml of guinea pig complement (diluted 1:10 with MEM) was. was added, and the incubation was continued for a further 1 hour.

Hemolysis zones (spots) per bowls were counted without magnification against a diffuse light source. Assuming that each stain originated from hemolysin produced by a single spleen cell, the number of stain-forming cells (PFC) per million spleen cells calculated for each dilution. The statistical calculations (mean, standard deviation and "t" test) included the PFC/million count for each dilution of each spleen.

Immunofluorescent antibody staining of B cells in rat spleen Method

For % B cell ratio determinations, rats (Charles River Lewis strain) were used in the process of developing adjuvant arthritis. Rats were dosed orally once per day with PVA-acacia medium (polyvinyl alcohol, 1%, rubber acacia 5%, methylparaben 0.5% in water) or drug in the medium. Treatment was started on day -3 before administration of aids. On day O, the rats were injected subcutaneously in the left hind paw with 0.1 ml

(5 mg/ml) Mycobacterium butyricum ("Difco" dried, heat killed)

in mineral oil. Drug treatment was continued up to and including day 7. Spleens were harvested on day 8 after adjuvant administration.

Spleen cell suspension was prepared by macerating spleens on stainless steel mesh into medium RPMI l640. Large particles were allowed to settle and the supernatant was transferred to clean tubes and spun at 800 rpm "IEC International Centrifuge Model K Size 2" for 10 minutes. The cell pellet was resuspended in 0.83% ammonium chloride (pH adjusted to 7.0 with sodium hydroxide) for red cell lysis (approximately 1 part packed cells in 3 parts ammonium chloride). These suspensions were kept on ice for 5-7 minutes and then spun at 800 rpm for 10 minutes. Cells were washed 2 times in Dulbecco's Phosphate Buffered Saline (PBS) and finally suspended in Dulbecco's PBS. The final cell concentration was such that a drop of cell suspension on a preparation glass covered with a cover glass gave 10 - 15 cells at a highly magnified field. Judging the size of the cell button and from experience, 8 - 10 ml of "Dulbecco's" PBS per spleen added to this final cell suspension.

For immunofluorescent staining, 0.2 ml of cell suspension was mixed with 0.2 ml of a 1:4 dilution of "Fluorescein Isothiocyanate conjugated Rabbit-Anti-Rag IgG" (Miles-Yeda Laboratories). The cells were incubated at 2 - 4°C for 1 hour, spun at 800 rpm for 10 minutes, washed twice with 2 ml "Dulbecco's" PBS and resuspended in 0.2 ml "Dulbecco"<*>'s PBS .

A drop of cell suspension was placed on a slide, covered with a coverslip and examined by light and fluorescence microscopy. A total of 200 - 300 cells were counted per mild suspension. The number of fluorescent lymphocytes or B cells was expressed as a percentage.

Data concerning the effects of some compounds of this series in the experiments described above are set forth in Tables IV, V and

VI.

Compounds produced according to the invention were equally strong in the treatment of established arthritis in rats (anti-inflammatory effect) and tfl. to prevent the development of arthritis in rats (non-established arthritis) as shown in Table TV. Standard anti-inflammatory drugs such as "Indomethacin" and phenylbutazone were less effective in preventing the development of arthritis in rats than in treating the inflammation in established arthritis. An immunosuppressive drug, cyclophosphamide, was more effective in preventing the development of arthritis in rats than in treating established arthritis in rats. Compounds of this series exhibit outstanding properties in these experiments.

Rats with adjuvant-induced arthritis have highly modified immunological systems as evidenced by the increased number of stain-forming (antibody-producing) cells (PFC) in , spleen cell suspensions (hemolytic stain determination table V ). Treatment of arthritic rats with the method compounds decreased the number of PFCs towards normal. Treatment with "Indomethacin" had no effect on the number of PFCs, while treatment with cyclophosphamide reduced PFCs far below normal. The compounds prepared according to the invention showed an outstanding activity in this experiment.

• Spleen cell suspensions from rats with adjuvant-induced arthritis have a greater proportion of B (antibody-producing) lymphocytes than T lymphocytes (mediators of cellular immunity) compared with cells from normal rats (Table VI ). Treatment of arthritic rats with method compounds reduced the B lymphocyte ratio to normal. Treatment with "Indomethacin" had no effect on the lymphocyte ratio, while treatment with cyclophosphamide reduced the B lymphocyte ratio to below normal.

Claims (5)

1. Analogy method for the preparation of therapeutically active compounds with the general formula: and pharmaceutically acceptable salts thereof, where n is 0, 1 or 2; Rx is C± - alkyl; allyl; vinyl; - CH^ CHy -CH2S(0)mCH3, where m is 0, 1 or 2; mono- or polyhalo-C 1 -C 4 alkyl; R 2 and R 3 , which are the same or different, are where and , which are the same or different, are hydrogen, C1_C4 alkoxv' ci~c4 alkv1/ c1' F' CF3 or -N(CH3)2, or Y.^ and Y2 together form a dioxymethylene bridge; with the proviso that when n is 0, 1 or 2, and Y. and Y.sub.2 are hydrogen, cannot be vinyl, and that when R^ is C.sub.-C.sub.4 alkyl, C.sub.-C.sub.3 haloalkyl with the halogen substituent in the 3- or 4-position, allyl or acetonyl, both Y 1 and Y 2 cannot be hydrogen; and with the further proviso that when n is 0 and R^ is methyl, both Y-j^ and Y2 cannot be p-Cl or p-CH30, characterized in that a) a compound with the formula: where 1*2 and R are as indicated above, is subjected to an alkylation or acetonylation, or b) a compound of the general formula: wherein R 1 and R 2 are as defined above, and Q is a suitable protecting group, is contacted with a strong base and then treated with a fluorinated alkylsulfenyl halide, or c) a compound of formula I wherein R 2 is 2-bromo-1 ,1,2-trifluoroethyl and R2, R.J and n are as indicated above, treated with tri-n-butyltin hydride, and that optionally a formed substituted thioimidazole or sulfinyl-imidazole is brought into contact with a suitable oxidizing agent, and that the compound thus obtained is optionally transferred to a salt thereof. 2. Method according to claim 1, in the preparation of 4,5-bis-(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)-imidazole, characterized in that starting materials are used where 1,1, 2,2-tetrafluoroethyl, R 2 and R 1 are 4-fluorophenyl, and n is 2. 3. Process according to claim 1, in the preparation of 4-(4-chlorophenyl)-5-phenyl-2-(1,1,2,2-tetrafluoroethylsulfonyl)-imidazole, characterized in that starting materials are used where R^ is 1, 1,2,2-tetrafluoroethyl, n is 2, R2 is 4-chlorophenyl, and R1 is phenyl. 4. Method according to claim 1, in the preparation of 4,5-bis-(4-methoxyphenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)-imidazole, characterized in that starting materials are used where R1 is 1,1 ,2,2-tetrafluoroethyl, R2 and R3 are 4-methoxyphenyl, and n is 2. 5. Process according to claim 1, in the preparation of 4,5-bis-(4-methoxyphenyl)-2-(2,2,2-trifluoroethylsulfonyl)-imidazole, characterized in that starting materials are used where 2,2,2- trifluoroethyl, R^ and R^ are 4-methoxyphenyl, and n is 2.