CH644108A5 - Anti-inflammatory imidazoles and processes for their preparation - Google Patents

Description

The invention relates to anti-inflammatory imide azoles and processes for their preparation.

U.S. Patent 3,707,475 describes anti-inflammatory 4,5-diaryl-2-substituted imidazoles.

U.S. Patents 3,505,350 and 3,651,080 disclose

toimidazoles and 4-tlkyl-2-alkylthio-5-ary 1-1-substituted imidazoles.

K. Zauer and co-workers describe 'in Chem. Bor. 106 (1973) 1638 4,5-bis (4-methoxyphenyl) -2-methylthiosimidazof and 4,5jBis (4-chlorophenyl) -2-methylthioimidazole' however no use.

A number of publications, e.g. Current Be. India 17 (1948) 184-185 and Acta. Chem. Acad. Be. Hugn. 79 (2) (1973) 197-212, describe 2- (Subst.-thio) -4,5-diphe-10 nylimidazoles and l-Methyl-2- (subst.-thio) -4,5-diphenylimide-azoles with substituents such as methyl, propyl, AUyl and acetonyl.

There is still a need for safe, harmless 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 common, chronic and severe of the inflammatory diseases. Traumatic injuries and infections are also accompanied by 20 inflammations. Anti-inflammatory drugs are often used for their treatment. The benefits of most commercially available anti-inflammatory agents are due to toxicity and adverse side effects, e.g. Changes in the blood cells and in the Zen-25 nervous system, limited. Adrenocortical steroids cause gastric irritation and suppression of normal adrenal function.

The invention is the result of efforts to develop new anti-arthritis compounds with good anti-inflammatory activity and minimal side effects that could be more effective in treating arthritis than the currently available drugs.

In addition to the anti-inflammatory effect, some compounds according to the invention also had analgesic effects in experiments. This additional property is desirable in the treatment of arthritis or related diseases, but these compounds can only be used for pain relief.

The invention relates to compounds with anti-inflammatory activity of the formula I.

S (0) n - Ri

(I)

Herein n = 0, 1 or 2;

R, = polyfluoro-CrC2-alkyl;

R2 and Rs, which are the same or different = 2-thienyl, 3-thienyl, 3-pyridyl, 3-pyridyl-N-> oxide, 2-furyl or

65 wherein Y] and Y2 are the same or different and stand for hydrogen, Cj-Cj-alkoxy, Cj-Cj-alkyl, CI, F or together form a dioxymethylene bridge with the mass

anti-ignition 4-alkyl-5-aryl-l-substituted 2-mercapa that only one of the radicals R2 and R3 for

644108

4th

can stand, and

R4 = hydrogen,

—Chorb I

r5

2-tetrahydropyranyI,

2-tetrahydrofurany I,

o o o

I! II II

-COR ,; -GR "-CAr or-S02Ar;

where R5 = H or methyl,

R "= C, -Cj-alkyl, benzyl, -CH2CH2OCH3 O

II

or —CR ,;

R, = C, -C4 alkyl or benzyl and

Ar = /, \ where Y "= H, F, Cl, Br, C, -C4 alkyl,

y— / C, -C4-alkoxy or nitro, with the

/ Stipulation that n must stand for 0,

Y _ if

3rd

O O O

II II II

R4 = jCOR7, -C-R7, -C-Ar or -S02Ar,

The invention also encompasses the pharmaceutically acceptable acid addition salts of compounds of the formula (I), in which n has the value 0 or in which at least one of the radicals R2 and R3 independently represents 3-pyridyl, and the pharmaceutically acceptable metal salt® of compounds of the formula (I ), where R4 is hydrogen and n is 1 or 2.

If R2 and R3 are different and R4 is hydrogen, the following two structures are tautomers:

Hi

Pharmaceutically acceptable acid addition salts of compounds in which n has the value 0 or in which at least one of the radicals R2 and R3 is independently a 3-pyridyl group are prepared with physiologically acceptable acids. These salts include the hydrochlorides, sulfates, phosphates and nitrates.

Suitable pharmaceutically suitable metal salts of compounds in which R4 is hydrogen and n has the value 1 or 2 are salts of certain metals such as sodium, potassium and calcium.

Compounds in which R is a group of the formula -CF2CF2H or -CF .. are preferred because of their action against arthritis. Compounds in which R2 and R3 independently represent 2-thienyl or 3-pyridyl are also preferred.

In addition, compounds are preferred in which R2 or R3 for

-Y

where Yx is hydrogen, CI, F or CH30.

Also preferred are compounds in which R4 is hydrogen, ätthoxycarbonyl, benzyloxymethyl, acetyl, benzoyl or 2-tetrahydrofuranyl '.

Be more preferred. Compounds in which R, = CF2CF2H or CF3,

R, and R3 independently represent 2-thienyl, 3-pyridyl or -, where Y] = H, CI, F or CH30, with the proviso that only one of the radicals R2 and R3 can stand for,

Yt = H, CI, F or CH30;

R4 = hydrogen, benzyloxymethyl, ethoxycarbonyl, acetyl, benzoyl or 2-tetrahydrofuranyl.

The following compounds are particularly preferred:

a) 4- (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) - 5- (2-thienyl) -1 H-imidazole,

b) 4- (4-Fiuorphen.yl) -5- (2-thienyl) -2-trifluoromethyl-sulfonyl-1 H-imidazole1,

c) 4- (4-methoxyphenyl) -5- (2-thienyl) -2-trifluoromethyl-sulfonyl-1 H-imidazole,

d) 4,5-bis- (2-thienyl) -2- (l, 1,2,2-tetrafluoroethylsulfonyl) -1 H-imidazole,

e) 4- (4-methoxyphenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) -5- (2-thienyl) -1 H-imidazole and f) 4- (3,4-dichlorophenyl) ) -2- (l, 1,2,2-tetrafluoroethylsulfonyl) -5- (2-thienyl) -l H-imidazole.

The compounds of the formula I are prepared according to the invention as follows: a 4,5-dicyclic imidazole of the formula

R

2nd

R

3rd

H

in which R2 and R3 have the meanings given above, and that according to that of H. Brederick and co-workers in Chem. Ber. 86 (1953) 88 has been prepared, is reacted with sulfur at a temperature in the range from 150 to 30 ° C. with or without solvent, a 2-mercaptoimidazole being formed. Tetramethylene sulfone, for example, is suitable as the solvent for this reaction This process is analogous to the conversion of 1-methylbenzimidazole to 2-mercapto-1-methylbenzimidazole, as described by AV El'tsov and KM Krivozheiko in Zh. Or. Kh. 2 (1966) 189.

4,5-disubstituted 2-mercaptoimidazoles can also be obtained by reacting compounds of the type

OH O OH O

I II I II

R2 — CH — C — R3 or R ..— CH — C — Ra

(wherein R2 and R :; have the meanings given above; various syntheses of compounds of this type are5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

those described by W. S. Ide and J. S. Buck in "Organic Reactions", Volume IV, page 269) with thourea in refluxed dimethylformamide or other high-boiling polar solvents. A similar condensation process is described by P. M. Kochergin in Zhur. Obshchei Khim. 31 (1961) 1093, Chem. Abstr. 55, 23503F.

Preferably, 4,5-disubstituted 2-mercapto-imidazoles can be obtained by reacting the above acyloins with ammonium thiocyanate at low temperatures in polar solvents, e.g. Ethanol or 1-Pro-panol.

The appropriate Rj can be substituted with a suitable alkylating agent, e.g. Tetrafluoroethylene, difluorocarbene or 2,2,2-trifluoroethyltrichloromethane sulfonate. Similar addition reactions are described by D.C. England and co-workers in J. Am. Chem. Soc. 82 (1960) 5116 and above K.E. Rapp and co-workers in J. Am.

Chem. Soc. 72 (1950) 3642. For the purposes of this description, tetrafluoroethylene and other fluorinated olefins are considered to be alkylating agents.

In certain cases, a polyhalogenoalkyl component can be further chemically modified in the formation of the Rj component of formula I. For example, imidazoles containing don 2- (2-bromo-l, l, 2-trifluoroethyIthio) substituents can be reduced by reduction with tri-n-butyltin hydride or other suitable reducing agents in 2- (1,1,2 --Trifluoriithylthio) imidazole. The imidazoles of the formulas

-S-R

1

Het.

(in which Het. = heterocyclic, as defined by R2 and R3 of the formula I) can be used using oxidizing agents such as m-chloroperoxybenzoic acid according to R.C. Med. Chem. 16 (1973) 1161, sodium metaperiodate according to N.V. Leonard and C.R. Johnson «J. Org. Chem. 27 (1962) 282, hydrogen peroxide according to P. M. Kochergin and M. N. Shchukina «Gen. Chem. U.S.S.R. » 25 (1955) 2289 or potassium permanganate according to K. E. Rapp and co-workers', loc. cit., are oxidized to the corresponding sulfoxide or sulfone.

If R2 or R-. in formula I is a pyridyl group, the pyridyl group can be converted into the N-oxide by the oxidation, while the -S- is converted into sulfoxide or sulfone. In such a process the 3-pyridyl-N-oxide group can be treated by treatment with a mild reducing agent, e.g. Trialkoxyphosphite or triphenylphosphine or tri-n-butyiphosphine, or

644108

another mild reducing agent can be converted back into the free 3-pyridyl group without reducing the sulfone function.

The appropriate substituent R4 can often be introduced by direct alkylation, acylation or sulfonylation of the compounds of formula I in which R4 is hydrogen. This reaction can take place in the absence or presence of a base, e.g. Potassium carbonate, pyridine, triethylamine, potassium t-butoxide or lithium methyl. The reaction can be carried out without solvent using the reagent as a solvent or in the presence of an inert solvent, e.g. Dimetylformamide, Gly-me, tetraydrofuran, pyridine or methyl chloride are carried out. The reaction temperature can range from -78 ° C to the boiling point of the solvent or of the reagent which may be used in excess as the solvent. Examples of suitable alkylating, acylating and sulfonylating agents are: alk-oxymethyl halides, e.g. Benzyloxymethyl chloride, acyl oxymethyl halides, e.g. Chloromethyl pivalate, dihydropyran, 2-chlorotetrahydrofuran, alkyl chloroformates, e.g. Ethyl chloroformate, alkanoic anhydrides and alkanoyl halides, e.g. Acetic anhydride, aroyl halides, e.g. Benzoyl chloride, and arylsulfonyl halides, e.g. Benzene sulfonyl chloride.

It is also possible to introduce an R4 substituent other than hydrogen in Formula I by firstly adding a 4,5-disubstituted imidazole with a suitable reagent, e.g. Benzylchloromethyl ether, e.g. 2-chlororte-trahydrofuran, dihydropyran or benzenesulfonyl chloride, is implemented. The 4,5-disubstituted 1-substituted imidazole obtained is then treated with a strong base, e.g. n-butyllithium, and then treated with a fluorinated alkylsulphenyl halide, disulfide or sulfonic acid anhydride. CF3SC1, CF..SSCF., And (CF3S02) 20 are typical of these reagents. Optionally, the choice of the protective group and the working-up conditions enables the direct isolation of the desired 4,5-cyclo-2- (subst.-thio— or sulfonyl) imidazoIs with R4 = H. Compounds in which Rj is a CF .. group, can be conveniently produced using this method.

Pharmaceutically acceptable salts of the formula I can be prepared by known methods of salt formation.

The preparation of these compounds is further illustrated by the following examples. In these examples, parts are by weight unless otherwise specified.

example 1

2-f (1,1,2,2-T etrafluoroethyl) thio J-4,5-bis (2-thienyl) -lH - imidazole

A) 4,5-bis (2-thienyl) -IH-imiclazole

A mixture of 31.6 g of a-thienoin and 175 ml of form amide was heated under reflux with an air cooler for 2 hours while stirring. The dark solution obtained was poured into 600 ml of cold water, stirred and filtered. The product was a semi-stole that slowly hardened. Yield 27.6 g. The product was dissolved in 35 ml of hot dimethylformamide. The product crystallized on cooling. The product was filtered off and washed with dimethylformamide and acetonitrile. The yield was 11.1 g. Melting point 218-221.5 "C. A further amount of product was isolated from the filtrates by chromatography on aluminum oxide.

5

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

644108

6

B) 4,5-bis (2-thienyl) -IH-2-imidazolthioI

A mixture of 12 g of 4,5-bis- (2-thienyl) -1 H-imidazole, 250 ml of tetramethylene sulfone (purified) and 2.5 g of sulfur was heated in a nitrogen atmosphere at 170 ° C. for 24 hours, followed by a further 2 g of sulfur were added and heating was continued for 19 hours. The mixture was cooled, poured into 2 liters of water, filtered, washed and dried. The dried product (9.8 g) was dissolved in dimethylformamide and poured onto an aluminum oxide column and eluted with dimethylformamide. The product came out with the first fractions. After evaporation and stirring with acetonitrile and filtration, 5.3 g of product with a melting point of 213 to 218 ° C. were obtained. Thin layer chromatography indicated that the product consisted of a mixture of the starting material with the desired thiol. A small portion of the crude compound chromatographed in the same manner gave

I, 02 g product of melting point 283-290 ° C.

In a further experiment, a mixture of 27.9 g (0.25 mol) of 2-thienoin and 13.3 g of ammonium thio-cyanate in 150 ml of 1-propanol was heated and cooled under reflux overnight, whereupon 22.7 g of 4. 5-bis (2-thîenyl) -lH-2-imidazolthiol with a melting point of 294-303 ° C. (dec.) (Recrystallized from 1-butanol) were filtered off. Elemental analysis: for CnH8N2S3:

Calculated: C 50.00 H 3.03 N 10.61 Found: C 50.15 H 3.15 N 10.73

C) 2 - [(1,1,2,2-TetrafIuoräthyl) thio] -4,5-bis- (2-thienyl) -lH - imidazole

6.0 g of the above products were dissolved in 50 ml of dimethylformamide and 2 ml of diisopropylamine. The solution was placed in a bomb tube and pressurized with 5 g tetrafluoride ethylene. The pressure was 15.5 kg / cm2 and was noticed in 23 minutes during pouring

II, 4 kg / cm2. The temperature ranged from 25 to 28 ° C. The bomb was shaken for another 4.5 hours while the pressure remained unchanged. The dimethylformamide solution was removed from the bomb tube and poured into water. The product was filtered off and washed with water. Yield 6.9 g. Melting point 131.5-142 ° C. The product was chromatographed on a silica gel column (Silicar CC-4) and eluted with chloroform, whereby 3.1 g of product with a melting point of 161.5-163.5 ° C. were obtained. A sample of melting point 166-177 ° C was obtained by recrystallization from toluene for analysis.

Elemental analysis: for C13H8F4N2S3

Calculated: C 42.86 H 2.20 N 7.69 Found: C 42.86 H 2.28 N 7.76

Example 2

4- (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5- (2-thienyl) - IH-imidazole

A) 2-Dimethylamino-2- (2-thienyl) acetonitrile

A solution of 131.5 g of dimethylamine hydrochloride in 200 ml of water was stirred and 59 g of sodium cyanide were added. A solution of 112 g of 2-thiophene carboxaldehyde in 100 ml of methanol was added from a dropping funnel while the temperature was kept below 30 ° C. The mixture was then held at 30 ° C for 4 hours and poured into 3 liters of water.

The water was extracted with ether. The ether extract was washed with water saturated with sodium bisulfite solution and finally with water. The ether extract was dried over anhydrous magnesium sulfate and concentrated to give 156.5 g of a yellow oil.

B) 2- (4-fluorophenyl) -1- (2-thienyl) cithanone

83.1 g of 2-dimethylamino-2- (2-thienyl) acetonitrile in 300 ml of dimethylformamide were added to a suspension of 15 g of sodium hydride in 250 ml of dimethylformamide. The mixture was stirred for 1 hour, during which hydrogen was evolved. 72.3 g of 4-fluorobenzyl chloride were added to the mixture in the course of one hour with stirring. The temperature rose to 50 ° C during the addition. The mixture was held at 40-45 ° C for an additional hour. It was partially concentrated under reduced pressure and poured into 500 ml of water. 500 ml of chloroform and 500 ml of concentrated hydrochloric acid were added to the mixture. The mixture was heated to reflux with stirring for 24 hours, cooled and separated. The water layer was extracted three times with chloroform. The chloroform extracts were combined and dried over anhydrous potassium carbonate. The dried extract was filtered and concentrated to give 103.9 g of a dark oil. The oil was distilled at 0.2 mm Hg to give 72.4 g of product with a melting point of 60-62 ° C.

In a further experiment, 111.0 g (0.65 mol) of trifluoroacetic anhydride were added dropwise to a mixture of 75.0 g (0.5 mol) of 4-fluorophenylacetic acid and 195.0 g of thiophene heated to 40 ° C. The mixture was heated to reflux for 3 hours, cooled and then poured into ice. The aqueous layer was made basic with sodium carbonate and the product extracted into ether. The combined ether extracts were washed with water and, after drying, evaporated over anhydrous potassium carbonate to give 112.0 g of an oil. Crystallization from methanol gave 70.0 g of 2- (4-fluorophenyl) -1- (2-thienyl) -ethanone with a melting point of 61-62.5 ° C.

Elemental analysis: for C] zHgFOS

Calculated: C 65.45 H 4.09

Found: C 65.45 H 4.06

C) 2-Bromo-2- (4-fluorophenyl) -l- (2-thienyl) cithanone

A solution of 71 g of 2- (4-fluorophenyl) -l- (2-thienyl) -ethanone in 300 ml of chloroform was added to a suspension of 160 g of copper (II) bromide in 500 ml of ethyl acetate, while the mixture was refluxed was heated. Reflux was continued for 2 hours after the addition, after which the mixture was cooled, filtered, and dried over anhydrous potassium carbonate. The mixture was filtered and concentrated to give 96.0 g of a residue which was used without further purification.

D) 4- (4-fluorophenyl) -5- (2-thienyl) -IH-imidazole

A mixture of 2-bromo-2- (4-fluorophenyl) -1- (2-thie-nyl) -ethanol and 400 ml formamide was heated under reflux under an air cooler for 2 hours. The mixture was poured into 1.5 liters of water and ice. The product was filtered off and dried. Yield 41.2 g. The product was chromatographed on 500 g of neutral aluminum oxide (Woelm, activity level I) using dimethylformamide as solvent and eluent. The first fractions were diluted with ethyl acetate and filtered to give 19.2 g of product. The product was recrystallized from acetonitrile, giving 14.8 g of product with a melting point of 163 to 164.5 ° C., which had a melting point of 198.5 to 200 ° C. overnight after drying in a vacuum oven. By s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

7

644108

Further work-up of filtrates gave a further 4.5 g of solid with a melting point of 197-198 ° C. The combined solids were crystallized from 350 ml of acetonitrile to give 16.4 g of product with a melting point of 199-200 ° C.

E) 2- (4-fluorophenyl) -2-hydroxy-l- (2-thienyl) cithanone

A solution of 56.0 g (0.35 mol) was added dropwise to a solution of 70.0 g (0.32 mol) of 2- (4-fluorophenyl-l- (2-thienyl) ethanolone in 600 ml of ether. Bromine was added to 120 ml of methylene chloride at room temperature and the reaction mixture was evaporated in vacuo to give 123.0 g of 2-bromo-2- (4-fluorophenyl) -l- (2-thien> yl) ethanol in the form of an oil.

A solution of the oil obtained as a residue in 275 ml of ethanol was added to a solution of 1 mole of sodium ethoxide in 1 liter of ethanol. The mixture was stirred at room temperature overnight. The reaction mixture was poured onto 3 l of 0.3 molar ice water, 63.4 g of the desired product of melting point 90-92 ° C. being obtained.

F) 4- (4-fluorophenyl) -5- (2-thienyl) -IH-2-imidazole kiol

A mixture of 16.0 g of 4- (4-fluorophenyl) -5- (2-thienyl) -1 H-imidazole and 4 g of sulfur in 100 ml of tetramethylene sulfone (redistilled) was heated at 200 ° C. for 8 hours, cooled, poured into water, filtered and dried. The mixture was chromatographed by dissolving it in 125 ml of Dr-methyformamide and passing it over neutral aluminum oxide (Woelm, activity level 1), which was arranged as a column of 60 mm in diameter and 200 mm in length. A light yellow band preceded the dark colored bands. The fractions obtained were combined and concentrated. Yield about 20 g. The product was stirred with ethyl acetate and filtered off. Yield 14.3 g. Melting point 228-237 ° C. In this way a dimethylformamide solvate of the product was obtained.

In a further experiment, by reacting 63.4 g (0.27 mol) of 2- (4-fluorophenyl) -2-hydroxy-l- (2-thienyl (ethanol) with 29.0 g (0.38 mol ) Ammonium thiocyanate in 1-propanol 71.6 g of 4- (4-fluorophenyl) -5- (2-thienyl) -1H-2-imidazolethiol with a melting point of 275-277 ° C. (recrystallized from 1-butanol).

Elemental analysis: for C] 3H9FN2S2

Calculated: C 56.52 'H 3.26 N 10.14 Found: C 56.55 H 3.42 N 10.18

G) 4- (4-fluorophenyl) -2- (l, 1,2,2-tetrafluoroethylthio) -5- (2-thienyl) -lH-imidazole

A solution of 14.0 g of 4- (4-fluorophenyl) -5- (2-thienyl) - 1H-2-imidazole ethiol in 40 ml of dimethylformamide and 1.5 g of diisopropylamine: was pressurized in a bomb with 4 g of tetrafluoroethylene brought. The pressure dropped from 12.25 kg / cm 2 to 0 in 1.5 hours. The solution was poured into water until most of the gummy product solidified, filtered and washed with water. The solid was dissolved in chloroform, dried over anhydrous sodium sulfate, concentrated and diluted with 1-chlorobutane. The crystalline product was separated. Yield 2.5 g. Melting point 164-168 ° C. The residue from the filtrate was chromatographed on silica gel (Silicar CC-4) using chloroform, whereby 4.1 g of product with a melting point of 167.5 to 170 ° C. were obtained. The combined product of 6.5 g was crystallized from 1-chlorobutane, 5.6 g of product having a melting point of 167-168.5 ° C. being obtained.

Elemental analysis: for C! 5H9F5N2S2

Calculated: C 47.87 H 2.39 N 7.45 Found: C 48.24 H 2.58 N 7.83

Example 3

4- (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) -5- (2-thienyl) -lH-imidazole A mixture of 6.5 g of 4- (4-fluorophenyl) - 2- (l, l, 2,2-tetrafluoroethylthio) -5- (2-thienyl) -l H-imidazole in 160 ml of chloroform was stirred and 9 g of 85% strength m-chloro-peroxybetazoic acid were added. Slight warming was observed. The mixture was left to stand for 2 days, whereupon 30 ml of dimethyl sulfide were added, with warming again being observed. The mixture was cooled and filtered. The filtrate was stirred with water and the water phase made basic with sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and concentrated. The solid was taken up in 40 ml of hot I-chlorobutane, treated with activated carbon (Darco), filtered and concentrated to a third of the volume. Here, crystals were deposited. Yield 2.1 g. Melting point 192-193 ° C. 20 Elemental analysis: for C15H9F5N202S2

Calculated: C 44.11 H 2.22 N 6.86

Found: C 44.55 H 2.46 N 7.04

Example 4

25th

4- (4-chlorophenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5- (2-thienyl) - IH-imidazole

A) 2- (4-chlorophenyl) -l- (2-thienyl) äthanon so A mixture of 85.3 g of p-chlorophenylacetic acid and 200 ml of thiophene was stirred at 40 ° C. 105 g of trifluoroacetic anhydride were added. The mixture was then heated to reflux for 4 hours. It was poured into ice water and basified with sodium carbonate. The mixture was extracted with dichloromethane, dried over potassium carbonate and concentrated. The yield of crude product was 126.4 g. This product was recrystallized from 300 ml of methanol, 103 g of the desired compound having a melting point of 98-99 ° C. 40 being obtained.

B) 2-bromo-2- (4-chlorophenyl) -l- (2-thienyl) ethanol

A solution of 100 g of 2- (4-chlorophenyl) -1- (2-thienyl) ethanol in 400 ml of chloroform was added to a suspension of 200 g of copper (II) bromide in 650 ml of ethyl acetate heated at the reflux. After the addition, the mixture was heated to reflux for 3 hours. The mixture was cooled in an ice bath and then filtered. The filtrate was stirred with ice and water. The solution was adjusted to a neutral pH by adding sodium bicarbonate. The organic layer was separated and the water extracted twice with chloroform. The combined extracts were dried over anhydrous potassium carbonate, filtered and concentrated to give 142 g of product. This product was used without further cleaning.

C) 4- (4-Chlorophenyl) -5- (2-thienyl) -IH-imidazole

A mixture of 35 g of 2-bromo-2- (4-chlorophenyl) -1- (2-60-thienyl) ethanol and 200 ml of formamide was heated under reflux under an air cooler for 2 hours. It was cooled, poured into water and adjusted to pH 8 to 9 by adding ammonium hydroxide. Chloroform was added to the solution. The solid which separated out was filtered off and washed with chloroform. Yield 19.3 g. The product was crystallized from dimethylformamide, filtered and washed with acetonitrile. Yield 14.7 g. Melting point 244-245 ° C.

644108

8th

D) 4- (4-chlorophenyl) -5- (2-thienyl) -1H-2-imidazolethiol A mixture of 9.4 g of 4- (4-chlorophenyl) -5- (2-thienyl) -

-1 H-imidazole, 2 g of sulfur and 50 ml of tetramethylene sulfone was stirred for 8 hours under nitrogen and heated to 200 ° C. The mixture was cooled, poured into water, filtered and washed thoroughly with water, giving 11.5 g of product. This product was dissolved in dimethylformamide and on an alumina column (Woelm, neutraf, activity level 1) of 6 cm in diameter and 125 cm in length using. Chromatographed dimethylformamide for elution. A yield of 5.6 g was obtained as a dimethylformamide adduct. A sample was dried by heating under high vacuum. Melting point 274.5 to 276 ° C.

E) 4- (4-chlorophenyl) -2- (l, 1,2,2-tetrafluoroethy! Thio) -5- (2-thienyl) -l H-imidazole

A solution of 6.9 g of 4- (4-chlorophenyl) -5- (2-thienyl) -IH-2-imidazolethiol in 40 ml of dimethylformamide and 1.5 ml of diisopropylamine was pressurized in a bomb with 3 g of tetrafluoroethylene and shaken until there was no further drop in pressure. The contents of the bomb were poured into water, the pH was adjusted to 8 and the solution was extracted with chloroform. The extract was dried and concentrated. It was chromatographed on silica gel (Silicar CC-4) to give 5.5 g of a fraction which was dissolved in hot 1-chlorobutane. After cooling, 4.5 g of product melting point 161.5-163 "C were obtained.

Elemental analysis: for C ^ H ,, C1F4N2S2

Calculated: C 45.86 H 2.31 N 7.13 S 16.33 Found: C 46.06 H 2.49 N 7.40 S 16.44

Example 5

2- (1,1,2,2-tetrafluoroethylsulfonyl) -4,5-bis- (2-thienyl) -lH - imidazole

A solution of 1.9 g of 2-r (1,1,2,2-tetrafluoroethyl) thio] - 4,5-bis (2-thienyl) -1 H-imidazole in 100 ml of chloroform was stirred, whereby 2.3 g of m-chloroperoxybenzoic acid were added. The solution turned dark green. The mixture was left at ambient temperature for one week, an additional 2 g of m-chloroperoxybenzoic acid was added and the mixture was left to stand overnight.

The excess of the oxidizing agent was then removed by stirring and adding 10 ml of methyl sulfide, stirring for one hour and concentration. The residue was stirred with ether and filtered to remove an insoluble solid which was not the desired product. The ether filtrate was concentrated and the residue was dissolved in chloroform, overlaid with aqueous potassium bicarbonate, stirred, separated and concentrated. Yield 1 g. The product was chromatographed on a silica gel column (Silicar CC-4, 3 cm in diameter, 27 cm in length) to give a product which was recrystallized from ethyl acetate and washed with 1-chlorobutane. Yield 0.282 g. Melting point 163-165 ° C. A second amount of product of 0.196 g was obtained from the filtrate: In a further experiment, 4.0 g (11 mmol) of 2- (1,1,2,2-T ctrafluoroethylthio) -4,5-bis- (2-thienyl ) -l H-imidazole at ice bath temperatures with 7.3 g (34.8 mmol) of 82.2% m-Chlorperbcnzocsiiurc oxidized in methyl chloride. m-Chlorobenzoic acid was filtered off and the filtrate was washed with 10% aqueous sodium bicarbonate solution. The methylene chloride solution was dried over anhydrous potassium carbonate and evaporated to give 3.2 g of an oil which was crystallized with 1-chlorobutane. By recrystallization from toluene ethyl acetate 1.5 g of the desired compound were obtained. Mass spectrum = 396.

A sample for the analysis was prepared by Chromatogra-5 phie on silica gel «Silicar CC-7» with chloroform. Melting point 167-168 ° C.

Elemental analysis: for C, 3H0F4N2O2S3

Calculated: C 39.39 H 2.02 N 7.07 Found: C 40.06 H 2.06 N 7.42

10th

Example 6

4- (3,4-dichlorophenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5- (2-thienyl) -! H-imidazole

15

A) 2- (3,4-dichlorophenyl) -l- (2-thienyl) ethanol

In the manner described in Example 4A, 100.7 g of 3,4-dichlorophenylacetic acid, 242.0 thiophene and 144.0 g of trifluoroacetic anhydride became 61.7 g of the desired compound of melting point 59.5-60.5 ° C. obtained from methanol.

Elemental analysis: for C12H8Cl2OS Calculated: C 53.14 H 2.95 Found: C 53.24 H 2.95

25th

B) 2- (3,4-dichlorophenyl) -2-hydroxy-l- (2-thienyl) ethanolone in the manner described in Example 2E

57.0 g (0.21 mol) of 2- (3,4-dichlorophenyl) -l- (2-thienyl) ethane in 49.8 g of the desired compound from melting point 30-109 ° C (from 1-chlorobutane recrystallized) obtained.

Elemental analysis: for CJ2H8CI202S Calculated: C 50.17 H 2.99 Found: C 50.34 H 2.86

35

C) 4- (3,4-dichlorophenyl) -5- (2-thienyl) -1H-2-imidazolethiol In the manner described in the second paragraph of Example 2F, 45.0 g (0.16 mol) of 2- (3rd , 4-dichlorophenyl) - 2-hydroxy-l- (2-thienyl) ethanol with ammonium thiocyanate

• w reacted in 1-propanoI1 with heating at the reflux, 32.6 g of the desired compound having a melting point of 263-265 ° C. (recrystallized from 1-butanol) were obtained. Elemental analysis: for C ,, H „CI2N2S2. 0.5H20 Calculated: C 46.42 H 2.69 N 8.33 Found: C 46.10 H 2.82 N 8.23

D) 4- (3,4-dichlorophenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5 - (2-thienyl) -l H-imidazole

4- (3,4-dichlorophenyl) -5- (2-thienyl) -IH-2-imidazolthiol so (30.0 g, 92 mmol) were reacted with 15.0 g of tetrafluoroethylene in the manner described in Example 4E, where After chromatography on silica gel “Silicar CC-7” with chloroform, 19.1 g of the desired compound of melting point 178-180 ° C. (recrystallized from toluene) were obtained.

Elementary analysis: for C15H „F4C12N2S2

Calculated: C 42.15 H 1.87 N 6.56 Found: C 42.88 H 2.03 N 6.57

60 Example 7

4- (3,4-dichlorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) - 5- (2-thienyl) -l H-imidazole

65 4- (3,4-dichlorophenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5 - (2-thienyl) -1 H-imidazole (5.0 g, 11.7 mmol) with 6.1 g (29 mmol) of 82.2% m-chloropcrbenzoic acid in the manner described in paragraph 2 of Example 5

9

644 108

puts. The crude product was purified by chromatography on silica gel “Silicar CC-7” with chloroform, giving 1.4 g of the desired compound of melting point 158 to 159.5 ° C. (recrystallized from toluene). Elemental analysis: for CriH..Cl., F, N, 0, S,

Calculated: C 39.2 H 1.74 N 6.1 Found: C 39.83 H 1.96 N 6.07

Example 8

4- (4-M ethoxyphenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5 - (2-thienyl) -l H-imielazole

In a series of reactions similar to those described in Example 6! the following compounds were obtained using 4-methoxy-phenylacetic acid:

A) 2- (4-methoxyphenyl) -l- (2-thienyl) äthanon melting point 75-77 ° C (recrystallized from methanol).

Elemental analysis: for C,;! H1202S

Calculated: C 67.24 H 5.17 Found: C 67.11 H 5.29

B) 2- (4-methoxyphenyl) -2-hydroxy-l- (2-thienyl) äthanon melting point 69-73 ° C (recrystallized from 1-chlorobutane).

Elemental analysis: for C] 3H] 20;! S

Calculated: C 62.90 H 4.84 Found: C 62.15 H 4.78

C) 4- (4-MethoxyphenyI) -5- (2-tliienyI) -IH-2-imidazolethiol. Melting point 266-268 ° C (recrystallized from ethanol).

Elemental analysis: for C14HJ2N2OS2

Calculated: C 58.33 H 4.17 N 9.72 Found: C 58.37 H 4.27 N 9.49

D) 4- (4-Methoxypì \ enyl) -2- (l, 1,2,2-tetrafluoroethylthio) -5 - (2-thienylj-l H-imidazole

Melting point 112-113.5 ° C (chromatographed on silica gel "Silicar CC-7" with chloroform and recrystallized from 1-chlorobutane).

Elemental analysis: for C] 6H12F4N2OS2

Calculated: C 49.48 H 3.09 N 7.22 Found: C 49.92 H 3.21 N 7.21

Example 9

4- (4-methoxyphenyl) -2- (1, 1,2,2-tetrafluoroethylsulfonyl) -5 - (2-thienyl) -IH-imidazole

4.0 g (10.3 mmol) of 4- (4-methoxyphenyl) -2- (1,1,2,2-tetra-fiiioräthyIthio) -5- (2-thienyl) -l H-imidazole were mixed with 6, 1 g (29 mmol) of 82.2% m-chloroperbenzoic acid oxidized. The crude product was purified by chromatography on silica gel "Silicar CC-7" with chloroform, 1.3 g of the desired compound having a melting point of 163 ° to 164.5 ° C. (recrystallized from chlorobutane) being obtained. Elemental analysis: for CI0H12F4N2O3S2

Calculated: C 45.71 H 2.86 N 6.67 Found: C 45.20 H 2.92 N 6.82

Example 10

4,5-bis- (2-juryl) -2- (1,1,2,2-tetrafluoroethylthio) -! H-imidazole

A) 4,5-bis (2-furyl) -1 H-2-imidazolethiol

19.2 g (0.1 mol) of a-furoin was reacted with 11.5 g (0.15 mol) of ammonium thiocyanate in ethanol heated to the reflux, whereby 11.4 g of the desired compound were obtained. A sample for analysis was prepared by chromatography on aluminum oxide with ethanol and recrystallization from nitromethane. Melting point 279-380 "C (dec.).

Elemental analysis: for CnH ^ N ^ 'S

Calculated: C 56.90 H 3.45 N 12.07 Found: C 57.20 H 3.86 N 11.72

B) 4,5-bis- (2-furyl) -2- (l, 1,2,2-tetrafluoroethylthio) -! H-imidazole

8.1 g (39.4 mmol) of 4,5-bis- (2-furyl) -1 H-2-imidazolethiol were reacted with 7.0 g of tetrafluoroethylene. The product was purified by chromatography on silica gel “Silicar CC-7” with chloroform, 3.0 g of the desired compound having a melting point of 166-167 ° C. (recrystallized from 1-chlorobutane) being obtained.

Elemental analysis: for Cr, HllF4N202S

Calculated: C 47.99 H 2.41 N 8.43 Found: C 47.13 H 2.81 N 8.45

Example 11

4-Plienyl-5- (3-pyridyl) -2- (1,1,2,2-tetrafluoroethylthio) -! H - imidaz.ol

A) 4-phenyl-5- (3-pyriclyl) -1 H-2-imidazolthioI

A solution of 30.0 g (0.15 mol) of 3-pyridylbenzyl-ketone (A. Burger and CR Walter, Jr., J. Am. Chem. Soc. 72 11950 | 1988) in 300 ml of acetic acid was added dropwise with a Solution of 25.0 g (0.16 mol) of bromine in 240 ml of acetic acid treated at room temperature. The mixture was stirred overnight, whereupon a precipitation of 26.8 g

3-pyridyl-a-bromocenzyl kctone hydrobromide was filtered off. A mixture of 5.0 g (14.0 mmol) of the above-mentioned salt with a solution of 0.1 mol of sodium ethoxide in 100 ml of ethanol was stirred at room temperature overnight and then poured onto 0.5 molar aqueous hydrochloric acid. The mixture was stirred for a few hours, after which the acidic aqueous solution was made basic with solid sodium carbonate and the product was extracted into the ether. The ether was dried over anhydrous potassium carbonate and removed under vacuum, with

4.5 g of 3-pyridyl-a-hydroxybenzyl ketone were obtained.

In another experiment, a mixture of 20.0 g (56.0 mmol) of 3-pyridyl-a-bromocenzyl ketone hydrobromide and 24.0 g (0.24 mol) of potassium acetate in 100 ml of acetic anhydride was stirred overnight at room temperature. The reaction mixture was poured into water and the product extracted into ether. The combined ether layers were washed with water and then with 10% aqueous sodium bicarbonate solution. The ether layer was dried over potassium carbonate and evaporated. A solution of the residue in 140 ml of aqueous 1N hydrochloric acid was heated to reflux for 30 minutes and, after cooling, made basic with solid sodium carbonate. The product was extracted into ether. The combined ether extracts were dried over anhydrous potassium carbonate and then evaporated to give 8.15 g of 3-pyridyl-a-hydroxybenzyl ketone.

8.15 g (38.3 mmol) of 3-pyridyl-a-hydroxybenzyl ketone were mixed with 7.5 g (0.1 mol) of ammonium thiocyanate in 1-propano! implemented, whereby 4.3 g

4-Phenyl-5- (3-pyridyI) -IH-2-imidazolthioI of melting point 3I7-323 ° C (after recrystallization from DMF: H20 f2: I I) were obtained.

Elemental analysis: for C14HnN., S

Calculated: C 66.40 H 4.35 N 16.60 Found: C 65.92 H 4.53 N 16.34

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

644108

10th

B) 4-phenyl-5- (3-pyridyl) -2- (l, l, 2,2-tetrafluoroethylthio) -lH - imidazole

2.0 g (7.9 mmol) of 4-phenyl-5- (3-pyridyl) -IH-2-imidazolethiol were reacted with 5.0 g (50 mmol) of tetrafluoroethylene. The crude product was purified by chromatography on silica gel "Silicar CC-7" with chloroform, 800 mg of the desired compound having a melting point of 153-154 ° C. (recrystallized from toluene).

Elemental analysis: for

Calculated: C 54.39 H 3.12 N 11.90 Found: C 54.69 H 3.37 N 11.69

Tables I and II below list further compounds which can be prepared using the corresponding starting materials in accordance with the processes described in Examples • and under the section “Synthesis”.

Example 12

2- (Trifluoromethylthio) -4- (4-fluorophenyl) -5- (3-pyridyl) -1H-imidazole was prepared from 4- (4-fluorophenyl) -5- (3-io-pyridyl) -1H-imidazole -2-thiol using CFSI as an alkylating agent. (Method according to V. N. Boiko, G. M. Schupak and L. M. Yagupol'skii, Zhur. Org. Kim. 13 [5], pp. 1057-61; pp. 972-5 of the English translation, May 1977). The yield was 13%, the melting point 15 of the compound obtained was 194-195 ° C.

The compound obtained in Example 12 is of the formula I with n = O, Rj = CF3, R2 = 4-fluorophenyl, R3 = 3-pyridyl and R4 = H.

TABLE I

s (0) nrj

Y,

R,

Ri

R.

n

H

CFS H

CF, CF, H

H

CF,

CF2CF2H

V

ci cl cf,

c02ch2-

/ w ch3o-

cf2h

H

11

TABLE I (continued)

644108

Yx Rs

Ri

Ri cf2cf2h ch3och2

Cl cf2cf2h so 2

IL

0

CF,

h cf, cf, h h ch, 0

r cf »

h cf,

O

II

—C — OCA

ch2cf3 h ch, 0-

cf2ch2f -CH2-OCH2

cf2chf2 CO- / v ch3o

CF,

H

644 108

12

TABLE I (continued)

Yj R3 Ri R4 n

cf2chf2

H

N

cf2chf2

coch,

R

TABLE II

2V -N

TABLE II (continued)

I ^ 2> 1 ^ 3

ri r4

^ vs (0) nri r-, «

! u r

hcf, h

I ^ 2> ^ 3

n '

Ri

R *

cf, cf, h SO

cf2of2h h

'li 1 [t cf,

co2ch3

cf2c f2h h cf2chf2

H

* n '

O

; n '

N '

cf3 h cf3 h cf2cf2h h ss The anti-arthritis agents and analgesics according to the invention can be administered for the treatment of arthritis and / or for pain relief in any way in which the active ingredient comes into contact with the place of action of the agent in the body of a warm-blooded animal. 60 is brought. The compounds of Formula I are effective against arthritis and some may also be used for pain relief. They can be administered by any of the usual means available for use in connection with medicines, either as a single medication or in a combination of medications. They can be administered alone, but are generally administered with a pharmaceutical carrier that is based on the

13

644108

selected, route of administration and selected pharmaceutical practice.

The dose administered is of course different depending on known factors such as the pharmacodynamic properties of the respective agent and on its type and its route of administration, on the age, state of health and weight of the recipient, on the type and intensity of the symptoms, the type of simultaneous treatment , the frequency of treatment and the desired effect. In general, a daily dose of the active ingredient can be about 0.01 to 40 mg per kg body weight. Usually the desired results are obtained with 0.05 to 20 mg, preferably with 0.01 to 10 mg per kg per day in two to four doses distributed over the day or in a form in which the release takes place over a longer period of time .

The dosage forms (agents) suitable for internal administration contain about 0.1 to 500 mg of active ingredient per unit. In these pharmaceutical preparations, the active ingredient is usually present in an amount of about 0.5 to 95% by weight, based on the total weight of the preparation.

The active ingredient can be taken orally in the form of solid drugs, e.g. Capsules, tablets and powder, or in liquid drugs, e.g. Elixirs, syrups and suspensions. It can also be administered parenterally in the form of sterile liquid drugs.

Gelatin capsules contain the active ingredient and powdered carrier, e.g. Lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate and stearic acid. Similar extenders can be used to make compressed tablets. Both tablets and capsules can be manufactured as products with the active ingredient released over a longer period of time, in which the active ingredient is continuously released over a period of hours. Pressed tablets can be wrapped with sugar or foil to mask any unpleasant taste and protect the tablet from the atmosphere, or they can be ducked with an enteric coating for selective disintegration in the gastrointestinal tract.

Liquid pharmaceutical forms for oral administration can contain colorants and flavorings in order to make the patient more comfortable to take.

In general, water, suitable oils, saline, aqueous dextrose (glucose) and related sugar solutions and glycols, e.g. Propylene glycol or poly-ethylene glycol, suitable as a carrier for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, buffer substances. Antioxidants, e.g. Sodium bisulfite, sodium sulfite or ascorbic acid either alone or in combination are suitable stabilizing agents. Citric acid and its salts and sodium EDTA are also used. In addition, parenteral solutions can contain preservatives, e.g. Benzalkonium chloride, methyl or propyl paraben and chlorobutanol.

Suitable pharmaceutical carriers are described in "Rem-engineering Pharmaceutical Sciences" by E.W. Martin, a standard reference in this field.

In order to determine and compare the anti-inflammatory effects of compounds of this series and of standard medications, an experiment was carried out on the basis of a standard model of arthritis, which is in good agreement with the effect on humans. The model is adjuvant-induced arthritis in rats. In Federation Proceedings,

Volume 32, No. 2 1973 “Models for the Study and Therapy of Rheumatoid Arthritis” - Symposium of the American Society for Pharmacolögy and Expérimental Therapeutics-— is closed: “The polyarthritis caused by intradermal injection of a suspension of Mycobacterium tuberculosis in mineral oil (adjuvants) in rats is widely used for the selection of drugs of possible suitability for rheumatoid arthritis ».

Male Charles River Lewis rats (130-150 g) received 0.1 ml of adjuvant (Difco, heat-soaked, freeze-dried, mineral oil-suspended Mycobacterium butyricum, 5 mg / ml) by subcutaneous injection into the plantar region of the right hind paw. The mineral oil is injected into 20 animals without arthritis. The animals are kept for two weeks so that the arthritis can develop. The volume of the paws (left hind paw that received no injection) is measured. The rats injected with the adjuvant are selected and the treatment groups of 10 animals each with the same severity of the disease are divided. The control animals without arthritis are formed into two groups of 10 animals each. The rats are given oral doses of the compound or polyvinyl alcohol gum arabic (1% polyvinyl alcohol, 5% gum arabic U.S.P., 0.5% methyl paraben) (10 ml / kg) with the drinking water that day and for the following six days. One day after the last dose, the paw volume (left hind paw, which was not injected) is measured with a volume differential meter "Ugo Basile", model 7101.

Average paw volume Average paw volume

(cm3) of the control animals - (cm3) the treated with arthritis group

-X 100

Average paw volume Average paw volume

(cm3) of control animals - control animals without arthritis with arthritis

= percentage decrease compared to the average paw volume of the control animals.

Dose-response regression lines of the percentage reduction are drawn on semi-logarithmic paper by eye measure, and the reduction in ED50% compared to the paw volume of the control animals is determined by eye measure. The values for some compounds according to the invention are summarized in Table III.

Compounds from this series have multiple effects of aspirin and ibuprofen in the treatment of adjuvant-induced: arthritis in rats. Four compounds were found to be more effective than phenylbutazone and one compound was found to be more effective than indomethacin in this test system.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

644 108

14

TABLE III

Adjuvant Established Rat Arthritis (A.A.)

Connection of example no.

1

2nd

3rd

4th

5

6

8th

9

10th

11

Indomethacin phenylbutazone ibuprofen aspirin

12

A.A. EDsite * mg / kg

32% at 50 mg / kg

1.3

0.1

12.0

2.2

50

30th

5

34% at 50 mg / kg

<25

0.3

10th

100

305

0.11

dard pain crunch test with phenylquinone by Siegmund and co-workers (Proc. Soc. Exp. Biol. Med. 95 [1957] 729). A test compound suspended in 1% methyl cellulose was orally administered to sober (17 to 21 hours) female white mice. 5 to 20 animals were used per double blind test. Aqueous (0.01% phenyl-p-benzoquinone) phenylquinone was injected intraperitoneally 25 hours later using 0.20 ml per mouse. Starting 30 minutes after i.o. oral administration of the test compound, the mice were observed for 10 minutes for a characteristic stretching or curving syndrome which is an indication of the pain caused by the phenylquinone. The effective analgesic effect for 50% of the mice (EDS0)> 5 was determined according to the moving average method by W. R. Thompson, Bact. Rev. 11 (1947) 115-145. The timing of the spike was also determined for many of the compounds. The results are summarized in Table IV below-20.

TABLE IV Phenylquinone pain curvature test

Connection of example no.

EDso *

* Determined as a percentage reduction in paw volume compared to the control animals.

A standard method for determining and comparing the analgesic effects of compounds from this series, which is in good agreement with the effectiveness in humans, is the modified standard.

3 5

8th

9

12

4.6

2.1

<130

45

1.67

0.33

40 * The units are expressed in mg / kg after 30 minutes.

Claims (12)

644108 2nd PATENT CLAIMS 1. Compounds with anti-inflammatory activity of formula (I) R2 Y ^ v 1> "S (0) n - R1 ' J I R ,, where n = 0, 1 or 2; Ri = polyfluoro-Cj-Cj-alkyl; R2 and R3, which are the same or different = 2-thie nyl, 3-thienyl, 3-pyridyl, 3-pyridyl-N-> oxide, 2-furyl or in which Y and Y2 are identical or different and stand for hydrogen, Cj-Q-alkoxy, CrC4-alkyl, Cl, F. or together form a dioxymethylene bridge with the proviso that only one of the radicals R2 and R3 for Y 1 can stand, and R4 = hydrogen, CHORUS r5 2-tetrahydropyranyI, 2-tetrahydrofuranyl, o o o II II II -COR ,; -GR7, -CAr or -SOzAr; where R5 = H or methyl, R6 = Cj-C3-alkyl, benzyl, -CH2CH2OCH3 O II or —CR?) R7 - Cj-Q-alkyl or benzyl and Ar = /. where Ys = H, F, Cl, Br, Cj-'Cj-alkyl, y_ / CrC4-alkoxy or nitro, with the proviso that n must stand for 0, v 'if 3rd o o o II II II R4 = -COR ,, -C-R „-C-Ar or -SOzAr, pharmaceutically acceptable acid addition salts of those compounds of the formula (I) in which n has the value 0 or in which at least one of the radicals R2 and R3 independently represents 3-pyridyl, and pharmaceutically acceptable metal salts of those compounds of the formula (I) in which R4 Is hydrogen and n is 1 or 2. 2. Compounds according to claim 1, characterized in that Rj stands for a group of the formula -CF2CFZH or -OF3. 3. Compounds according to claim 1, characterized in that R2 and R3 independently represent 2-thienyl or 3-pyridyl. 4. Compounds according to claim 1, characterized in that R2 or R3 is a group of the formula in which Yt is H, Cl, F or CH30. 5. Compounds according to claim 1, characterized in that R4 is ethoxycarbonyl, benzyloxymethyl, acetyl, benzoyl, 2-tetrahydrofuranyl or - preferably - hydrogen. 6. Compounds according to claim 1, characterized in that Rj represents -CF2CF2H or -CF3, R2 and R3 independently represent 2-thienyl or 3-pyridyl or where Y1 = H, Cl, F or CHsO, with the proviso that that only one of the residues R2 or R3 seta can and R4 stands for hydrogen, benzyloxymethyl, acetyl, benzoyl or 2-tetrahydrofuranyl. 7. The following compounds according to claim 1: 4- (4-fluorophenyl) -2- (l, 1,2,2-tetrafluoroethylsulfonyl) -5- (2- -thienyl) -1 H-imidazole, 4- (4-fluorophenyl) -5- (2-thienyl) -2-trifluoromethylsulfonyl-1H - imidazole, 4- (4-methoxyphenyl) -5- (2-thienyl) -2-trifluoromethylsulfonyl - 1 H -imidazole, 4,5-bis- (2-thienyl-2- (l, 1,2,2-tetrafluoroethylsulfonyl) -lH - imidazot, 4- (4-methoxyphenyl) -2- (l, l, 2,2-tetrafluoroethylsulfonyl) -5- - (2-thienyl) -11 H) -imidazole or 4- (3,4-dichlorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfoiryl) - 5- (2-thienyl) -IH-imidazole. 8. Pharmaceutical preparations containing a suitable pharmaceutical carrier and an anti-inflammatory effective amount of at least one compound according to claim 1. 9. A process for the preparation of compounds of the formula I, where n = 0, and in which R4 is hydrogen, characterized in that a compound of the formula SH H in which r2 and R3 have the meanings given above, with a suitable alkylating agent for introducing Rj with the meanings mentioned. 10. A process for the preparation of compounds of the formula I in which n = 1 or 2 and in which R4 is hydrogen, characterized in that a Ver5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 3rd 644108 Binding of formula I, wherein n = 0, prepared by the method according to claim 9 and reacting the compound obtained with an oxidizing agent. 11. A process for the preparation of compounds of the formula I with n = 0 or 2 and in which Rls R2 and R3 have the meanings given in Claim 1 and R4 is -CHORg, 2-tetrahydropyraayl, f Rs 2-tetrahydrofuranyl or S02Ar, in which R5, Re and Ar have the meanings given in claim 1, characterized in that a) a compound of the formula in which R2 and R3 have the meanings given above, with I) R'4X, where R'4 = RsOCH2-, 2-tetrahydrofuranyl- or ArS02- and X = chlorine, bromine or iodine, II) dihydropyran or III) RGOCH = CH2, in which R6 and Ar have the meanings given above, b) the product of step (a) is reacted with a base and c) the product of step (b) is reacted with a fluorinated Ct-C2-alkylsulfenyl halide, disulfide or sulfonic acid anhydride. 12. A process for the preparation of compounds of formula I, wherein R4 has the meaning given in claim 1 except hydrogen, characterized in that a compound of the formula R H in which n, Rj, R2 and R3 have the meanings given in claim 1, with a) a compound of the formula R4'X, where R4 'is -CH2OR6, 2-tetrahydrofuranyl, O O O CR7, -CAr or -S02Ar and -COR ,, X represents chlorine, bromine or iodine, or b) dihydropyran, c) (R7C) 2-0 or II ' O d) RgO-CH = CH2, wherein R6, R7 and Ar have the meanings given above.