FI66177B - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ANALYZER 4, -DIARYL-2- (SUBSTITUTE-TIO) IMIDAZOLER - Google Patents

Description

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Thomas Ray Sharpe, Wilmington, Delaware, USA (74) Oy Kolster Ab (54) Method for the preparation of therapeutically useful 4,5-diaryl-2- (substituted-thio) imidazoles - Förfarande för f ramstäilning av therapeutiskt användbara 4, 5 ~ diaryl-2- (substituted-thio) imidazoler

The invention relates to a process for the preparation of therapeutically useful 4,5-diaryl-2- (substituted thio) imidazoles of the formula: -γ (I <~ S <O) n -R11

B

wherein n is 0, 1 or 2, is C 1 -C 4 alkyl, allyl, vinyl, -Cl 2 COCH 6 or -C 1 -C 6 SiO 2 CH 2, where m is 0, 1 or 2, or mono- or polyhalo. C 1 -C 4 alkyl, and and R 1/2, which are the same or different, denote the group »tt.04.34 66177 Υ Υ * 1 2 wherein Y, j and Υ 2, which are the same or different, are hydrogen, C C 1-4 alkoxy, C 1 -C 4 alkyl, Cl, F, CF 3, NH 2, (CH 2 N, NO 2, CH 3 S-, CH 3 SO 2 -, or Y 1 and Y 2 together form a dioxymethylene bridge; provided that when n = 0, 1 or 2 and and Y 2 are both hydrogen, cannot be vinyl, and that when there is C 1 -C 4 haloalkyl in which halogen is a substituent in the 3- or 4-position, allyl or acetonyl, Y 1 and Y 2 cannot both be hydrogen, and further provided that when n is 0 and R 1 is CH 3 # R 2 and R 3 cannot both be p-chlorophenyl or p-methoxyphenyl, and to prepare pharmaceutically acceptable salts of these compounds.

U.S. Patent 3,707,475 describes anti-inflammatory 4,5-diaryl-2-substituted imidazoles, and U.S. Patent 3,505,350 describes anti-inflammatory 4-alkyl-5-aryl-1-substituted-2-mercaptoimidazoles. In Chem. Ber. 106, 1638 (1973) describe 4,5-bis (4-methoxyphenyl) -2-methylthioimidazoles and 4,5-bis (4-chlorophenyl) -2-methylthioimidazoles, but no use is mentioned.

From numerous references, such as the articles Current Sei. India 17, 184-85 (1948) and Acta Chem. Acad. Sci. Hung. 79 (2) 197-212 (1973) discloses 2- (substituted thio) -4,5-diphenylimidazoles having, for example, methyl, propyl, allyl and acetonyl as substituents.

There is a constant shortage of reliable and effective anti-inflammatory agents. Inflammation is a disease process characterized by redness, fever, swelling, and pain. The most common, chronic and severe inflammatory disease is arthritis in its various forms. Accidental injury and infection are also associated with inflammation, and are often treated with anti-inflammatory drugs. The usefulness of most commercially available contraceptives is limited due to toxicity and adverse side effects. Many cause stomach irritation and other difficulties such as changes in blood cells and the central nervous system. Adrenocorticosteroids cause stomach irritation and impaired normal adrenal function.

In the Journal of the American Medical Association,

Butter. 224, No. 5 (Supplement), 1973 "Primer on the Rheumatic Diseases" discloses that immunological reactions play a major role in the continuation of inflammation such as rheumatism. Widely used nonsteroidal anti-inflammatory drugs such as aspirin, indomethacin, phenylbutazone, and ibuprofen have no effect on these immunological reactions, but only alleviate the symptoms of the inflammatory reaction; these drugs do not stop the ongoing and eventually eradicating processes of rheumatoid arthritis. Immunosuppressive drugs such as cyclophosphamide are effective in the treatment of rheumatoid arthritis, but are too toxic for widespread use.

The compounds of this invention have been shown to have a unique anti-inflammatory and immune-regulating effect. The biological profiles of these compounds are different from those of non-steroidal anti-inflammatory and immunosuppressive drugs. Due to the unique properties of the new compounds, a new method for the treatment of rheumatoid arthritis has been provided, which method is also useful in the treatment of other diseases involving changes in immune status.

Two of the compounds of formula I are not new; those in which n is 0, R 2 is CH 2, and both R 2 and R 2 are either p-Cl-phenyl or p-OCH 2 -phenyl. A disclaimer is necessary to exclude compounds that are not active enough to be of practical significance.

Due to their activity, the preferred compounds are those in which R. | is -CF2CF2H.

Also preferred are compounds wherein R 2 and R y are independently -O- '' 4 66177 wherein Y 1 is H, Cl or F; also preferred are compounds wherein n is 1 or 2. More preferred are compounds wherein R 1 is -CF 2 CF 2 H, and R 2 and R 2, independently, are wherein Y 1 is H, Cl or F, and n is 0, 1 or 2.

Most preferred for ease of synthesis are compounds wherein R 1 is -CF 2 CF 2 H and R 2 and R 3 are independently "wherein Y 1 is H, Cl or F, and n is 0 or 2.

Of particular value are the following compounds: 4,5-bis- (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole, 4 (or 5) - (4-fluorophenyl) -5- (or 4) phenyl-2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole, 4,5-bis (4-chlorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole, 4 (or 5) - (4-chlorophenyl) -5- (or 4) phenyl-2- (1,1,2,2-tetrafluoroethylsulfonylimidazole, 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole, 4,5-Diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole.

In addition to their anti-inflammatory and immune-regulating properties, the compounds according to the invention also have analgesic activity. This property is also important in the treatment of arthritis and other related diseases. In addition, the compounds can be commonly used to relieve pain.

Particularly preferred for their analgesic activity are compounds of formula 5,6177 Ύ ^> ^ - S, O, n-R 1 Y 2 having C 1 -C 4 alkyl, monohalogen or polyhalo-C 1 -C 4 alkyl, and Y are the same or different and are hydrogen, 2-methoxy, 4-methoxy, 2-ethoxy, 4-ethoxy, 2-chloro or 4-chloro, n is 0, 1 or 2.

The most valuable of these are compounds having polyhalogen-C 1 -C 3 alkyl and are the same or different and are hydrogen, 2-methoxy, 4-methoxy, 2-ethoxy, 4-ethoxy, 2-chloro or 4-chloro, provided that at least one of Y 1 and 4 is methoxy or 4-ethoxy, n is 0, 1 or 2.

Particularly preferred for their analgesic activity are the following compounds: 4,5-bis (4-methoxyphenyl) -2- (1,1,2-trifluoroethylsulfonyl) imidazole, 4,5-bis (4-methoxyphenyl-2- (1,1,2,2 -tetrafluoroethylsulfonyl) imidazole, 4,5-bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethylthio) imidazole, 4,5-bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethylsulfonyl) imidazole, and 4,5-bis (4-methoxyphenyl) -2- (trifluoromethylsulfonyl) imidazole.

Tautomeerlt

When R 2 and R 2 are different, the next two structures are tautomeric forms

R, o H

Vv r2v * v I | J H 3 6 66177

Pharmaceutical salts

Pharmaceutically acceptable salts of compounds wherein n is 1 or 2 include salts with therapeutically acceptable metals such as sodium, potassium and calcium.

Synthesis

Compounds of formula I may be prepared as follows: benzoin or substituted benzoin prepared as described in Ide, W. S. and Buck, J. S., Organic Reactions, Vol. IV, p. 629, is condensed with thiourea in boiling dimethylformamide or other high boiling polar solvents to give 4,5-diaryl-2-mercaptoimidazole. A similar condensation method is described in Kochergin, P. M., Zhur, Obschei Khim., 31, 1093 (1961), cf. Chem. Abstr. 55, 23503f.

4,5-Diaryl-2-mercaptoimidazoles can also be prepared by heating 4,5-diarylimidazoles with sulfur at temperatures between 150 and 300 ° C with or without a solvent. One solvent suitable for use in this reaction is tetramethylene sulfone. This method is analogous to the reaction in which 1-methylbenzimidazole is converted to 2-mercapto-1-methylbenzimidazole as described in A. V. El'tsov and K. M. Krivozheiko, ZhOrKh, 2, 189 (1966).

The coupling of the group can be accomplished by alkylation of 4,5-diaryl-2-mercaptoimidazole with an alkylating agent such as ethyl iodide or 2,2,2-trifluoroethyl trichloromethanesulfonate. These methods and the use of other alkylating agents can be found in the examples.

4,5-Diaryl-2-mercaptoimidazole can also be reacted with tetrafluoroethylene to give 4,5-diaryl-2- (1,1,2,2-tetrafluoroethylthio) imidazole derivatives. Similar addition reactions of tetrafluoroethylene and other fluorinated olefins are described in England, D. C., et al., J. Am.

Chem. Soc. 82, 5116 (1960) and Rapp, K. E. et al., J. Am. Chem. Soc. 72, 3642 (1950).

7 66177

Compounds of formula I may also be prepared by reacting an N-protected diarylimidazole such as 4,5-diphenyl-1- (2-tetrahydropyranyl) imidazole or 1-benzyloxymethyl-4,5-diphenyl-4,5- diphenylimidazole, first to react with a strong base such as n-butyllithium, and then with a fluorinated alkylsulfenyl halide, disulfide or sulfonic anhydride. By appropriately selecting the protecting group and the preparation conditions, the desired 4,5-diaryl-2- (substituted thio or sulfonyl) imidazole can be isolated directly. Compounds with CF 2 can be conveniently prepared by this method.

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, RC et al., J. Med. Chem. 16, 1161 (1973)). ), sodium periodate (Leonard, NJ and Johnson, CR, J. Org. Chem. 27, 282 (1962)), hydrogen peroxide (Kochergin, PM and Shchukina, MN, J. Gen. Chem. USSR 25, 2289 (1955)) , or potassium permanganate (Rapp, KE et al., loc. cit.).

The general formula

R3 H

wherein R 1 and R 2 are phenyl or substituted phenyl, n is 0, 1 or 2, R 1 is a fluorinated alkyl group, especially CF 1, compounds can be prepared by contacting the N-protected diaryl imidazole with a strong base, then fluorinated alkylsulphenyl halo. with genide disulfide or sulfonic anhydride, followed by deprotection and then, if desired, oxidation of sulfur. The nature of the N-protecting group is such that it is resistant to strong bases but is readily removed by acid reagents or hydrogenolysis. Examples of useful protecting groups include 2-tetrahydropyranyl, benzyloxymethyl, methoxymethyl, methylthiomethyl, β-methoxyethoxymethyl and 2-tetrahydrofuranyl.

8 66177 N-protected diaryl imidazole is contacted with a strong base such as alkali metal alkyls (n-butyllithium and the like), alkali metal hydride (sodium hydride and the like), alkali metal alkoxides (sodium methoxide, potassium t-butoxide and the like), alkali metal amide isopropylamide and the like), in suitable non-hydroxyl solvents such as ether, tetrahydrofuran, ethylene glycol dimethyl ether, hexane, toluene, etc. The reaction temperature is preferably in the range of 0 to 78 ° C, although temperatures from 0 ° C to the boiling point of the solvent are The addition of a complexing agent such as tetramethylethylamine to the reaction medium often improves the yield of the product.

The imidazole anion thus produced is then contacted with a fluorinated alkylthio reagent of a sulfophenyl halide, disulfide or sulfonic anhydride. Examples of such reagents are trifluoromethanesulfenyl chloride, trifluoromethyl disulfide, trifluoromethanesulfonic anhydride, pentafluoroethanesulfenyl chloride, disulfide, etc. This part of the reaction is also carried out in the range of 0 to 78 ° C, although temperatures from 0 ° C to the boiling point of the solvent are.

The resulting N-protected 2-fluorinated alkylthio- (or sulfonyl) -4,5-diarylimidazole is treated by contacting it with an organic or inorganic acid such as acetic acid, hydrochloric acid, sulfuric acid or the like, or by contacting it with Lewis acids such as zinc bromide. , titanium tetrachloride, etc., or by hydrogenolysis by contacting it with hydrogen and a suitable catalyst to remove the protecting group. Hydrolysis of the protecting group can in some cases take place under normal aqueous working conditions.

The resulting 2-fluorinated alkylthio-4,5-diarylimidazole (in the case of a fluorinated alkylsulfenyl halide or disulfide) is oxidized to the corresponding sulfoxide and sulfone using oxidizing agents such as perazides (e.g. m-chloroperoxybenzoic acid), sodium metaperiodate, caliperperoxide, hydrogen peroxide, hydrogen peroxide similar.

66177

Pharmacological tests and their results

In order to find out and compare the anti-inflammatory and immune-regulating effects of the new compounds and normal drugs, a series of experiments were performed using a standard model which achieves a good correlation with the efficacy observed in humans. The model is adjuvant-induced arthritis in rats. In 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 - discloses that , has been widely used to screen for drugs that are effective in rheumatoid arthritis ".

Adjuvant-induced arthritis was observed in rats

An experiment used primarily to determine the anti-inflammatory effect.

0.1 ml of adjuvant (Difco heat-killed, lyophilized Mycobacterium butyricum suspension 5 mg / ml suspended in mineral oil) is injected subcutaneously into the plantar surface of the right hind paw of male Charles River Lewis rats (130-150 g). Twenty control animals are injected with mineral oil. Arthritis is allowed to develop in animals for 2 weeks. Paw volumes (uninjected, left hind paw) are measured and rats injected with adjuvant are sorted and divided into treatment groups of 10 equally severely infected animals. Control animals without arthritis are divided into two groups of 10 animals. Rats are orally administered by gavage using the compound or PVA-Acacia (polyvinyl alcohol 1%, acacia, USP. 5% and methyl paraben 0.5%; dose 10 ml / kg) on that day and 6 the following day. On the day after the last dose, paw volumes (uninjected, left hind paw) are measured using a Ugo Basile Volume Differential Meter Model 7101.

Arthritis Chancellery Treatment group Paw volume, mean (ml) _ Paw volume, mean (ml) ^

Arthritis Control - Arthritis Free Control Paw Volume, Mean (ml) Paw Volume, Mean (ml) 10 661 77

Decrease as a percentage of the mean paw volume of control animals.

The% decrease in dose-response regression lines are plotted on semi-logarithmic paper with visual fit, and the% decrease in ED paw volume in control animals has been determined by reviewing the results.

Undetected adjuvant-induced arthritis in rats

An experiment that has been used primarily to determine the effects of compounds on the immune reactions involved in the induction process and to prevent the development of arthritis.

0.1 ml of adjuvant (Difco heat-killed, lyophilized suspension of Mycobacterium butyricum suspended in 5 mg / ml mineral oil) is injected subcutaneously into the plantar surface of the right hind paw of male Charles River Lewis rats (130-150 g). Forty control animals without arthritis are injected with mineral oil. Groups of 20 rats are orally administered the compound in single daily doses (in PVA acacia medium, 10 ml / kg or medium using tube feeding, which is started immediately after paw injection, for a total of 14 doses. The volume of the uninjected hind paw is measured 24 hours after the last dose. after administration using a Ugp Basile Volume Differential-meter Model 7101. The decrease in ED 2 -q% compared to the control value is determined as described above.

To further evaluate the immunomodulatory properties of these compounds, the two additional experiments described below were used. The effect of the compounds on specific antibody-producing cells (B lymphocytes) was measured by the Jerne Hemolytic Plaque Assay. The relative amounts of B lymphocytes and T lymphocytes (involved in indirect cellular immunity) are determined using a fluorescent antibody staining method.

Modified Jerne Spleen Cell Blood Red Dissolution Spot Determination Methods A variation of the method described by N. K. Jerne and A. A. Nordin (Science 140, 450 (1963)) was used in these studies. Rats (Charles River Lewis) with adjuvant-induced arthritis and arthritis-free control animals were orally administered once daily PVA acacia medium (polyvinyl alcohol 1%, gum arabic 5%, methyl paraben 0.5% in water) or vehicle from day 14 (counting on adjuvant injection) to day 20. Animals were sensitized with sheep red blood cells (SRBC) (0.2 ml of 10% suspension = 2-3 x 10 ° cells) by intravenous administration on day 17. The SRBC (Microbiological Associates) aliquots were washed 3 times in 0.9% sodium chloride solution before injection, and on day 21 the rats were anesthetized with 1% sodium pentobarbital (intraperitoneal injection) and the spleens were removed, each spleen was placed on a stainless steel grid suspended on a plastic beaker in an ice bath and gently macerated using a glass piston pump. using a Pasteru pipette to add a batch of approximately 10 ml of Eagle's Minimal Essential Medium (MEM) during maceration until only fibrous material remained on the lattice. The large particles were allowed to settle for about 5 minutes and about 5 ml of the supernatant was transferred to a plastic tube. Dilutions of 1:10 and 1:20 were made by adding cold MEM liquid.

Plate test 2 ml of 0.7% agarose (1.4% diluted 1: 2 with 2X Eagle MEM) and 0.2 ml of 10% SRBC suspension were preheated at 45 ° C in a water bath. 20 lambda spleen cell dilutions were added, mixed gently and poured onto a medium containing 2 ml of 1.4% agarose in a plastic 60 x 15 mm Petri dish. The plates were germinated at 37 ° C for 1.5 hours in a humidified incubator. 1.5 ml of guinea pig complement (diluted 1:10 in MEM) was added and incubation was continued for another hour.

Magnification was calculated without using hemolysis areas (spots) per plate against a diffuse light source. Assuming that each spot was formed from hemolysin generated by one spleen cell, the number of spot-formed cells (PEC) per million spleen cells was calculated for each dilution. Statistical calculations (mean, standard error, and "f-test") included PFC / million for each dilution of each spleen.

66177 12

Immunofluorescent antibody dye of rat spleen B cells

Method

In the method of developing adjuvant arthritis, rats (Charles River Lewis) were used for B cell% assays. Rats were orally administered once daily PVA acacia (polyvinyl alcohol 1%, gum arabic 5%, methyl paraben 0.5% in water) medium or drug in the medium. Treatment was started 3 days before adjuvant administration. On day 0, 0.1 ml (5 mg / ml) of a mineral oil suspension of Mycobacterium butyricum (Dif-co-dried, heat-killed) was injected subcutaneously into the left hind paw of rats. Drug treatment was continued until the end of day 7. Spleens were harvested on day 8 after adjuvant administration.

The spleen cell suspension was prepared by macerating the spleens with a stainless steel sieve in RPMI 1640 medium. The large particles were allowed to settle and the supernatant was transferred to clean tubes and rotated for 10 minutes at 800 rpm. In an IEC-International Centrifuge Model K, Sige 2, centrifuge. The cell pellet was resuspended in 0.83% NH 4 Cl solution (pH adjusted to 7.0 with sodium urea hydroxide) to dissolve the erythrocytes (approximately 1 part cell concentrate in 3 parts NH Cl). These suspensions were kept on ice for 5-7 minutes and then stirred at 800 rpm. For 10 minutes. The cells were washed twice in Dulbecco's phosphate buffered saline (PBS) and finally suspended in Dulbecco's PBS. The final cell concentration was such that by dropping one drop of the cell suspension on a microscope slide coated with a coverslip, 10-15 cells were obtained in the field at high magnification. Evaluating the size of the cell button and experience, 8-10 ml of Dulbecco's PBS per spleen was added to this final cell suspension.

For immunofluorescent staining, 0.2 ml of the cell suspension was mixed with 0.2 ml of a 1: 4 dilution of Fluorescein Isothiocyanate conjugated Rabbit-Anti-Rat IngG (Miles-Yeda Laboratories). The cells were incubated at 2-4 ° C for 1 hour, mixed for 10 minutes at 800 rpm, washed twice in 2 ml of Dulbecco's PBS and resuspended in 0.2 ml of Dulbecco's PBS . A drop of the cell suspension was placed on a microscope slide, covered with a coverslip, and examined using illumination and 66177 fluorination microscopy. The spleen suspension was calculated to contain 200-300 cells. The number of fluorescent lymphocytes or B cells was expressed as a percentage.

The values associated with the effects of some of the compounds in this series observed in the experiments described above are summarized in Tables IV, V, and VI.

The compounds of this invention were equally effective in treating arthritis in rats (anti-inflammatory effect) and in preventing the development of arthritis in rats (non-binding arthritis), as shown in Table IV. Normal anti-inflammatory drugs, such as indomethacin and phenylbutazone, were less effective in preventing the development of arthritis in rats than in the treatment of inflammation in binding arthritis. An immunosuppressive drug, cyclophosphamide, was more effective in preventing the development of arthritis in rats than in the treatment of binding arthritis in rats. The compounds in this series proved to have unique properties in these experiments.

Rats with adjuvant-induced arthritis have highly modified immunological systems, as evidenced by an increase in the number of spot-forming (antibody-producing) cells (PFCs) in spleen cell suspensions (hemolytic spot assay, Table V). Treatment of arthritis rats with the compounds of this invention reduced PFC counts. Indomethacin treatment had no effect on PFC count while treatment with cyclophosphamide reduced PFC to much less than normal. The compounds in this series proved to be uniquely active in this experiment.

Spleen cell suspensions obtained from rats with adjuvant-induced arthritis have a higher proportion of B (antibody-producing) lymphocytes than T lymphocytes (mediators of cellular immunity) compared to cells obtained from normal rats (Table VI). Treatment of arthritis rats with the compounds of this invention reduced the proportion of B lymphocytes to normal. Indomethacin treatment had no effect on the lymphocyte population, whereas treatment with cyclophosphamide reduced the proportion of B lymphocytes to below normal.

14 661 77

Phenylquinone writhing test

The standard method used to determine the analgesic activity of the compounds, which correlates well with the effect obtained in humans, is that described by Siegmund et al., Proc. Soc. Exp. Biol. Med. 95, 729 (1957) modified phenylquinone torsion test. There, the test compound is suspended in 1% methylcellulose and administered orally to fasted (17-21 hours) white female mice, 5-20 animals per duplicate. 24 minutes later, an aqueous solution of phenylquinone (0.01% phenyl-p-quinone) is administered intraperitoneally as an injection of 0.20 ml per mouse. Thirty minutes after oral administration of the test compound, mice are observed for observations of their writhing, indicating phenylquinone-induced pain. The effective analgesic dose (ED 2 q) obtained in 50% of mice was calculated according to Thompson, Bact. Rev. 11, 115-145 (1947) by the moving average method. Observations were also made with several compounds regarding the time of maximal effect. These results are summarized in Table VII.

66177

Table ι 4,5-diaryl-2 -: (substituted thio) imidazoles and their rat adjutant-arthritis values. ^

V / ~ S_R

v-40j '

Adjuvant arthritis XYR M.p. (° C) (ED5q%) (2 4-F 4-CH3S CF3 105 - 155 (5 1,1 4-CH3O 4-CH3O3 CH2CH2CH2 152-153 9.0 4-F 4-F CH3 222 - 223.5 3.5 4-CH3O 4-CH3O CHF2 170.5 - 172 1.8 HH CHF2 227 228 21 4-Cl 4-Cl CHF2 222 - 223 0.35 4-F 4-F CHF2 192 .5 - 194 0.42 4-C14-F CH3 222 - 223 3.8 4-CF3 H CH3 176 - 177 20 4-F 4-CF3 CH3 196-197 17 4-C1 4-CF3 CH3 214 - 215 3.6 3,4-0CH2O 3.4-0CH2O CH3 201 - 202 20 4-CH.O 4-CH.O CF_CH 150 - 151 (3 20 3 3 3 2 4-Cl 4-Cl 212 “213 5, 0 (4 4-CH 3 O 4-CH 3 O 108 ~ 109 4.7 4-CH3 4-CH2-O CH2 = CHCH2 167 - 167.5 22 4-CH3O 4-CH3O3 CH3COCH2 115-117.5 9.4 4- CH30 4-CH30 CH3SOCH2 84.5 τ 86.5 52

(1 this biological system has been described previously (2 units mg / kg (3 polymorphs had a m.p. of 119-120 ° C (4 polymorphs had a m.p. of 146 ° C

(Δ mass spectrum: m / e = 384 16,661 77

Table 11 4,5-Diaryl-2- (polyhaloalkylthio) imidazoles and their rat adjuvant arthritis values ^ *

j -SCF2CFH

Adjuvant arthritis x Y z sP. (° c) (ed 50%) (2 4-CH 2 O 4 -CH 2 OF 134 - 136 4.2 4-Cl 4 -Cl F 222.5-223.5 0.3 4-F 4 -FF 220 - 221.5 0.075 HH Cl 187 - 188 3.9 4-Cl 4 -FF 206.5 - 207.5 0.18 4-CH 3 4-CH 3 F 204 - 205 18 4-CH 3 HF 175 - 175.5 20 4-C1 HF 205 - 206 0.3 3.4-0CH2O 3.4-0CH2O F 204 - 205.5 10 4-CF3 HF 202 - 204 4.5 4-F 4-CF3 F 182.5-183, 5 1.5 4-FHF 196 - 197.5 0.2 3-Cl 3-Cl F 208 - 209 1.2 4-CH 3 O 4-CH 3 Br 151 - 153 10 HH Br 184 - 186 11 4- (CH3) 2N HF 189 - 192.5 2.5 HHF 218 - 219.5 0.75 4-F 4-CH 3 S F 155.5 - 157 1.6 (1 this biological system has been described previously (2 units mg / kg 17 661 77

Table III

4,5-Diaryl-2- (alkylsulfinyl) imidazoles and 4,5-diaryl-2- (alkylsulfonyl) imidazoles and their rat adjuvant arthritis values *

Adjuvant arthritis (XYR n. M.p. (° C) (ED50%) HH CF CH 1 198 (dec.) 48 HH 2 226.5 (dec.) 12 4-CH3O 4-CH2 O CF3CH2 1 193.5 (dec.) 10 4-CH 3 O 4 -CH 3 O 3 ^ 2 2 173.5 - 174.5 3.8 4-Cl 4 -Cl ^ 3 ^ 2 1,214 (ha 3 · * 3.0 4-C 1-4 C1 CF3CH2 2 241 4 '5 4-CH3O 4-CH3O3 ^ 2 1 161' 162 10 4-CH3O 4-CH3O3 ^ 2 2 136-137 5.2 4-CH3O 4-CH3O CH2 = CHCH2 1 118 -119 (dec.) 11 4-CH O 4-CH.O CH = CHCH_2 162 - 163 11 3 3 2 2 4-CH30 4-CH30 CH3 1 167-168.5 6.2 4-CH30 4-CH30 CH3 2 142 - 143 6,4 4-Cl 4 -Cl 2 3 1,214 (ha 3 · * 3.0 4-C 4 -C 14 CH 1 202 (dec.) 2.3 3 HH HCF 2 CF 2 2,239 - 240 0 , 13 4-CH30 4-CH30 CH3CH2CH2 1 143 - 144.5 13 18 ✓ 1 7 7

Table III (continued) ®

Adjuvant-n o, (2 XYR n m.p. (c) (ED50%) 4-CH 3 O 4 -CH 3 O CH 3 (CH 2) 2 2 152 - 153 9 4-CH 3 O 4-CH 3 O (CH 2 CH 2 175 - 176 30 4-CH3O 4-CH3O HCF2CF2 2 156 - 157 1,1 4-CH3O 4-CH3O HCF2CF2 1 162.5-163.5 2.4 4-F 4-CH3SO2 CF2CF2H2 221-223 37% (15) 4- F 4 -CH 3 SO 2 CH 3 2 (3 1.8 HH HCF 2 CF 2 1181 - 182 0.18 4-Cl 4 -Cl CH 3 2 255 - 256 2.0 4-Cl 4 -Cl HCF 2 CF 2 1 198 (ha3 ·) 0.2 4-C1 4-Cl HCF2CF2 2 235-236.5 0.2 4-F 4-F CF3CH2 2 247 (ha3 ·) 3.5 4-F 4-F HCF2CF2 2 241.5-242 0.025 4-F 4 -F CH3 2,239 - 240 4.5 HH C1FCHCF2 2 213-214 0.25 4-CH, 0 4-CH O CHF 2 186 - 187 0.5 3 3 2 HH CHF2 2 265 0.35 HH HC12CF2 2223 -223.5 1.5 4-Cl 4-Cl CHF 2 2,244 - 245 0.35 4-F 4-F CHF 2 2,246.5 - 247 0.1 4-Cl 4 -F CH 3 2,226 - 227 2, 8 4-C14-F HCF2CF2 2 212 - 213 0.091 4-CH3 4-C®3 HCF2CF2 2 225 - 226 0.35 4-CH3 H HCF2CF2 2 169 - 170 1.1 2-Cl 4-CH JO HCF CF „2 176 - 177 7.2 3 2 2 1 9

Table III (continued) 661 77

Adjuvant arthritis X Y R n sp. (° C) (ED50%) (2 3-CH 3 O 3 -C 3 J 3 HCF 2 CF 2 2 155.5 - 156.5 4.0 4-Cl H CH 3 2 169 - 170 30 4-Cl H HCF 2 CF 2 2 206 - 207.5 0.065 4-F 4-CF 3 CH 3 2 189-190 3.7 4-Cl 4-CF CH 2 224 - 225 2.2 3 · * 4-CF 3 H HCF2CF2 2 188 - 189 2.4 4-C1 4-CF3 HCF2CF2 2,208 τ 209 1.8 2- Cl 2 -Cl HCF2CF2 2,183 - 184 0.8 4-FH HCF2CF2 2,228 - 229 0.027 3- C1 3 -Cl HCF CF 2 208 - 209 0.16 2 2 4- C1 4-Cl CHF2 1 203 - 206 0.19 4-CH3O 4-CH3O BrFCHCF2 2 187 - 188 2.4 4-CH3 H HCF2CF2 2 202 - 203 0.6 3.4-0CH2O 3.4-0CH2O HCF2CF2 2,212 - 214 1,0 4-CH30 4-CH30 CH3SCH2 1 142.5-143.5 28 4-CH30 4-CH30 CH3COCH2 1 138 - 140 56 4-CH30 4-CH30 CH3SO2CH2 2 202 - 203 54 4-CH30 4- CH 3 O 3 COCH 2 2 134 - 135 18 4-F 4 -NO 2 CF 2 CF 2 H 2 208 - 211 0.37 4-F 4 -NH 2 CF 2 CF 2 H 2 223 - 235 (18%) 3 4-NO 2 4 -NO 2 CF 2 CF 2 H 2 240-240.5 8.5 (1 this biological system has been described previously (2 units mg / kg (3 Analysis; calculated C 45.6, H 2.7, N 6.3 found C 45.7, H 2.8, N 6, 3

Mass spectrum: m / e = 448 20 6 6 1 7 7

Table IV Adjuvant-induced arthritis in rats ED50% mg / kg

Binding Detected Non-Binding Compound Arthritis Arthritis 4,5-Diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole 1,5 2,3 4,5-di (4-chlorophenyl) -2- (1,1, 2-Trifluoro-2-chloroethylthio) imidazole 0.2 0.06 4.5-di (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole 0.03 0.03 4- (4-Chloro-phenyl) -5-phenyl-2- (1,1,2,2-tetrafluoro-ethylsulfonyl) -imidazole 0.1

Phenylbutazone 10 35

Indomethacin 0.3 3

Cyclophosphamide 10 1/5 66177 21

Table V

Determination of hemolytic spot in spleen cell suspensions of arthritic, non-arthritic and drug-treated arthritic rats.

Spot forming

Oral average number of cells per day mill. spleen cell Compound dose per mg / kg (N = 20) - 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) -1,5 197 imidazole 15,320 4,5-di (4-chlorophenyl) -2- ( 1,1,2-Trifluoro-2-0.1,788 chloroethylthio) imidazole 1,0,488 4,5-di (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethyl-0,03,499 sulfonyl ) imidazole 0.3 439 i *

Arthritis control - 863 (*

Non-arthritis control - 323 / **

Indomethacin 1.0 720

Cyclophosphamide 5.0 25 (* Values calculated from 3 experiments (** Values calculated from 2 experiments 66177 22

Table VI

Proportion of B lymphocytes in spleen cell suspensions of non-arthritic and drug-treated arthritic rats as determined by fluorescent antibody staining.

Orally administered Avg.

Compound_daily dose mg / kg B cell% 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) -1,5 37 imidazole 15 33 4,5-di (4-chlorophenyl) -2- (1,1 , 2-Trifluoro-2-chloro-0.2 39 ethylthio) imidazole 2.0 38 4.5-di (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethyl-0.03 40 sulfonyl) imidazole 0 .34 4 4- (4-chlorophenyl) -5-phenyl-2- (1,1,2,2-tetrafluoroethylsulfonyl) -1,1 48 imidazole 1,0 42 (*

Arthritis Control - 57 (*

Non-arthritis control - 42

Phenylbutazone 20 53

Indomethacin 0.5 57

Cyclophosphamide 5 25 (* Values calculated from 7 experiments 66177 23

Table VII

Analgesic effect in phenylquinone torsion test lvv n "'XYR n ED50 mg / kg Time of maximum effect (min) 4-CH30 4-CH30 CHF2 2 1.5 4-CH30 4-CH30 CF3 2 0.045 240 4-CH30 4-CH30 1 0, 86 60 4-CH30 4-CH30 CH2CF3 0 1.2 240 4-CH30 4-CH30 CH2CF3 2 0.58 60 4-CH30 4-CH30 CE ^ Cl ^ F 2 0.25 160 4-CH30 4-CH30 CF2CHF2 1 0.8 4-CH 3 O 4-CH 3 O 2 ^ 2 2 0.11 120 4 ^ S30 4-CH 3 O CF 2fflBrF 2 2.8 4-CH 3 O 2 -Cl ce- £ sf2 2 0.56 60 4-CH 3 H CF 2 CHF 2 2 0.33 240 4-C2H50 H CE ^ CHE ^ 2 0.95 120 HH CF2CHF2 2 0.48 120 24 6 6 1 77

The following examples illustrate the invention.

Parts are by weight unless otherwise indicated. Temperature is given in degrees Celsius.

Example 1 4,5-Diphenyl-2- (2,2,2-trifluoroethylthio) imidazole

A mixture of 4,5-diphenyl-2-mercaptoimidazole (71.9 g, 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) were boiled under nitrogen for 4 hours. The mixture was allowed to cool to room temperature, and 13.4 g of unreacted 4,5-diphenyl-2-mercaptoimidazole was filtered off. The filtrate was washed twice with water, and as the organic phase cooled, the product crystallized. 46.2 g (49%) of 4,5-diphenyl-2- (2,2,2-trifluoroethylthio) imidazole were obtained as almost colorless crystals, m.p. 185.5 - 187 °.

Analysis:

Calculated for C 17 H 13 F N 5: C 61.06 H 3.92 N 8.33

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 g, 0.0416 mol) ) and chloroform (75 ml) cooled in an ice bath, 86.4% m-chloroperbenzoic acid (8.4 g, 0.042 mol) dissolved in chloroform (85 ml) was added dropwise. After stirring overnight, the mixture was washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, and the solvent was removed to give 12.3 g of a crude product. Recrystallization from toluene gave 10.1 g (69%) of 4,5-diphenyl-2- (2,2,2-trifluoroethylsulfinyl) imidazole as colorless prisms, m.p. 198 ° (decomposed).

Analysis:

Calculated for C 25 H 28 N 3 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-trifluoroethylthio) imidazole (15.7 g, 0.0470 mol) was obtained. ) and chloroform (100 ml) cooled in an ice bath, 86.4% m-chloro-6661 77 perbenzoic acid (19.0 g, 0.0952 mol) dissolved in chloroform (200 ml) was added dropwise. The mixture was stirred for 4 days at room temperature, tetrahydrofuran was added, and the mixture was washed with saturated sodium hydrogencarbonate, dried over magnesium sulfate, and the solvent was removed to give 18.9 g of a crude product. Recrystallization twice from acetonitrile gave 8.8 g (51%) of 4,5-diphenyl-2- (2,2,2-trifluoroethylsulfonyl) imidazole as colorless needles, m.p. 228 ° (decomposed).

Analysis:

Calculated for C 55.73 H 3.58 N 7.65 F 15.56 Found: C 56.18 H 3.95 N 7.52 F 15.44

Example 4 4,5-Bis- (4-methoxy-phenyl) -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) were boiled under nitrogen for 6 hours. The mixture was cooled, washed 3 times with water, dried over magnesium sulfate and concentrated to give 43.4 g of crude product which was chromatographed on a column of 450 g of silica gel eluting with chloroform. The residue of the main fraction was recrystallized from methylcyclohexane to give 21.5 g (55%) of 4,5-bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethylthio) imidazole as almost colorless crystals, m.p. 119-120 °. The m.p. is 150-151 °.

Analysis:

Calculated for gH, J ^ F ^ ^ C ^ S: C 57.86 H 4.34 N 7.10

Found: C 57.96 H 4.01 N 7.09

Example 5 4,5-Bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethylsulfinyl) imidazole

The procedure was as in Example 2, but using 4,5-bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethylthio) instead of 4,5-diphenyl-2- (2,2,2-trifluoroethylthio) imidazole. imidazole to give 4,5-bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethylsulfinyl) imid-66,6177 azole. Recrystallization of the crude product from aqueous ethanol gave the pure product in 83% yield, m.p. 193.5 ° (decomposed). Analysis:

Calculated for C 17 H 17 N 2 O 3 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-methoxyphenyl) -2- (2,2,2-trifluoroethylsulfonyl) imidazole

To a mixture of 4,5-bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethylthio) imidazole (6.0 g, 0.015 mol) and chloroform (75 ml) cooled in an ice bath was added dropwise 86 , 4% m-chloroperbenzoic acid (6.1 g, 0.031 mol) dissolved in chloroform (75 mL). After stirring overnight at room temperature, the mixture was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated to give 7.1 g of crude product. Recrystallization from 1-chlorobutane gave pure 4,5-bis (4-methoxyphenyl) -2- (2,2,2-trifluoroethylsulfonyl) imidazole as colorless needles, m.p. 173-174 °.

Analysis:

Calculated for C 18 H 19 F 3 N 2 O 2 S: C 53.51 H 4.02 N 6.57 Found: C 53.47 H 4.06 N 6.55 53.81 3.69 6.59

Example 7 4,5-Bis (4-chlorophenyl) -2- (2,2,2-trifluoroethylthio) imidazole

A mixture of 4,5-bis (4-chlorophenyl) -2- [nercaptoimidazole (32.1 g, 0.100 mol), 2,2,2-trifluoroethyl trichloromethanesulfonate (28.1 g, 0.100 mol), sodium methylate (5.9 g, 0.109 mol), and ethanol (300 mL) were boiled for 3 hours. The reaction mixture was poured into water, and the solid was collected by filtration, washed with water and dried. This solid (43.9 g) was then stirred overnight in ethyl acetate (400 mL). The mixture was filtered and the solution was removed from the filtrate to give 21.7 g of a residue. Recrystallization from toluene gave 15.1 g (37%) of pure 4,5-bis (4-chlorophenyl) -2- (2,2,2-trifluoroethylthio) imidazole as colorless crystals, m.p. 212-213 °.

Analysis:

Calculated for C 18 H 11 Cl 2 F 3 S: C 50.63 H 2.75 N 6.95 Found: C 50.87 H 3.05 N 6.69 27 66177

Example 8 4,5-Bis (4-chlorophenyl) -2- (2,2,2-trifluoroethylsulfinyl) imidazole

By proceeding as in Example 2, but using 4,5-bis (4-chlorophenyl) -2- (2,2,2-trifluoroethylthio) instead of 4,5-diphenyl-2- (2,2,2-trifluoroethylthio) imidazole imidazole, 4,5-bis- (4-chlorophenyl) -2- (2,2,2-trifluoroethylsulfinyl) imidazole was obtained. Recrystallization of the crude product from acetonitrile gave the pure product in 77% yield, m.p. 214 ° (decomposed).

Analysis:

Calculated for C 18 H 28 N 2 O 3 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-trifluoroethylthio) imidazole (5.3 g, 0.013 mol) and chloroform (50 ml) cooled in an ice bath was added dropwise 86, 4% m-chloroperbenzoic acid (5.3 g, 0.027 mol) dissolved in chloroform (60 mL). After stirring overnight at room temperature, the mixture was boiled for 15 minutes, cooled, and the solid was collected and washed with cold chloroform. The solid was then dissolved in a mixture of ether and tetrahydrofuran, and the resulting solution was washed with saturated sodium hydrogen carbonate solution. The organic phase was dried over magnesium sulfate and the solvent was washed to give 5.9 g of a colorless solid residue which was recrystallized from nitromethane (125 ml). 4.1 g (72%) of pure 4,5-bis (4-chlorophenyl) -2- (2,2,2-trifluoroethylsulphonyl) imidazole were obtained as colorless needles, m.p. 241 ° (decomposed).

Analysis:

Calculated for C 18 H 11 Cl 2 O 3 S: C 46.91 H 2.55 N 6.44 Found: C 47.13 H 2.67 N 6.56 47.29 2.58 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). ), sodium methylate (6.5 g, 0.12 mol) was added in one portion, and the mixture was stirred for 15 minutes. A solution of iodoethane (17.1 g, 0.11 mol) in methanol (50 ml) was added dropwise and the mixture was heated at reflux for 4.5 hours. After stirring overnight at room temperature, the mixture was poured into water, and the precipitated solid was collected, washed with water and dried to give 33.0 g of a crude product. Recrystallization from aqueous ethanol gave 28.8 g (85%) of pure 2-ethylthio-4,5-bis (4-methoxyphenyl) imidazole, m.p. 108-190 °.

Analysis:

Calculated for C 67.03 H 5.92 N 8.23

Found: C 66.96 H 6.20 N 7.85

Example 11 2-Allylthio-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 g, 0.108 mol), triethylamine (20.2 g, 0.200 mol) and chloroform (500 ml) were heated at reflux overnight. Allyl bromide (4.8 g, 0.040 mol) was then added and boiling was continued for 2 hours. An additional 2 portions (4.8 g) of allyl bromide were added, boiling for 2 hours after each addition. The clear solution was cooled, washed 3 times with water, dried over magnesium sulfate, and concentrated. The residue was triturated with ether and the solid collected to give 31.5 g of crude product. Recrystallization from aqueous ethanol gave 26.7 g (76%) of pure 2-allylthio-4,5-bis (4-methoxyphenyl) imidazole, m.p. 167-167.5 °. Analysis:

Calculated for C 20 H 20 N 2 O 2 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 Replacing the allyl bromide of Example 11 with chloromethylmethyl sulfide gave 4,5-bis (4-methoxyphenyl) -2- (methylthiomethylthio) imidazole, m.p. 171-172 °.

Analysis:

Calculated for C 61.26 H 5.41 N 7.52

Found: C 61.32 H 5.57 N 7.32 29 661 77

Example 13 2-Ethylsulfinyl-4,5-big (4-methoxyphenyl) imidazole To a solution of 2-ethylthio-4,5-bis (4-methoxyphenyl) imidazole (10.2 g, 0.030 mol) in dichloromethane (200 mL ) chilled in an ice bath. a solution of 86.4% m-chloroperbenzoic acid (6.0 g, 0.030 mol) in dichloromethane (100 ml) was added dropwise. After stirring overnight at room temperature, the reaction mixture was washed with 3 portions (75 mL) of saturated sodium hydrogen carbonate solution. The organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator. The residual oil was triturated with ether and the resulting solid was collected and recrystallized from 1-chlorobutane (500 mL) to give 7.5 g (70%) of pure 2-ethylsulfinyl-4,5-bis (4-methoxyphenyl) imidazole. , sp. 161-162 °.

Analysis:

Calculated for C 12 H 12 N 2 O 5: 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 Substituting 6.0 g of the 86.4% m-chloroperbenzoic acid of Example 13 with 12.0 g (0.060 moles) of 86.4% m- recrystallization from 1-chlorobutanoic acid (125 ml) gave 6.0 g (54%) of 2-ethylsulphonyl-4,5-bis (4-methoxyphenyl) imidazole, m.p. 136-137 °.

Analysis:

Calculated for C 19 H 20 N 2 O 4 S: C 61.27 H 5.41 N 7.52

Found: C 61.47 H 5.47 N 7.35

Example 15 2-Acetonylthio-4,5-bis (4-methoxyphenyl) imidazole To a stirred mixture of 2-mercapto-4,5-bis (4-methoxyphenyl) imidazole (31.2 g, 0.100 mol), triethylamine (11.0 g, 0.11 mol) and chloroform (500 ml) were added dropwise to chloroacetone (10.2 g, 0.11 mol) dissolved in chloroform (50 ml). After stirring overnight and boiling, the reaction mixture was washed 3 times with water, dried over magnesium sulfate and concentrated to give 32.0 g of crude product. Chromatography (silica gel column, eluting with chloroform) gave 30 661 77 27.0 g (73%) of pure 2-acetonylthio-4,5-bis (4-methoxyphenyl) imidazole, m.p. 115-117.5 °.

Analysis:

Calculated for C 20 H 20 N 2 O 3 S: C 65.20 H 5.47 N 7.60 Found: C 65.14 H 5.42 N 7.36

Example 16 4,5-Bis (4-methoxyphenyl) -2- (methylthiomethylsulfinyl) imidazole and 4,5-bis (4-methoxyphenyl) -2- (methylsulfinylmethylthio) imidazole

To a solution of 4,5-bis (4-methoxyphenyl) -2- (methylthiomethylthio) imidazole (7.4 g, 0.020 mol) in dichloromethane (100 mL) cooled in an ice bath was added a solution of 86.4% m-chloroperbenzoic acid (4.0 g, 0.020 mol) in dichloromethane (100 ml). After stirring overnight at room temperature, the reaction mixture was washed 3 times with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The residue (7.5 g) was chromatographed (silica gel column, eluting with a mixture of toluene and ethyl acetate).

The first compound eluting from the column was 4,5-bis (4-methoxyphenyl) -2- (methylthiomethylsulfinyl) imidazole, m.p. 142.5-143.5 °.

Analysis:

Calculated for C 18 H 20 N 2 O 3 S 2: c 58.74 H 5.19 N 7.21

Found: C 59.00 H 5.13 N 6.93

Continuation of the column elution gave pure 4,5-bis (4-methoxyphenyl) -2- (methylsulfinylmethylthio) imidazole, m.p.

84.5 - 86.5 °.

Analysis:

Calculated for 9H20N2 ° 3S2! C 56.74 H 5.19 N 7.21

Found: C 58.85 H 5.36 N 6.94

Example 17 4,5-Diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole To a stainless steel tube was added 4,5-diphenyl-2-mercaptoimidazole (5.0 g, 0.020 mol) and dimethylformamide (50 mL). ) containing 0.5 ml of a 40% methanol solution of benzyltrimethylammonium hydroxide. The tubes were purged several times with dry nitrogen and then introduced with tetrafluoroethylene (2.2 g, 0.022 mol). The tube was stirred for 7 hours. The reaction mixture was poured into water, and the solid was collected and washed with water to give 5.7 g of a crude product. Chromatography (silica gel column, eluting with chloroform) gave 3.5 g of pure 4,5-diphenyl-2- (1,1,2,2-tertafluoroethylthio) imidazole, m.p. 212-213 °.

Analysis:

Calculated for c ·] 7Η · | 2F4N4S: C 57.95 H 3.43 N 7.95 Found: C 57.71 H 3.70 N 7.89

Example 18 4,5-Bis (4-methoxyphenyl) -2-vinylthioimidazole To a stainless steel tube was added 4,5-bis (4-methoxyphenyl) -2-mercaptoimidazole (15.0 g, 0.05 mol), cuprous chloride (0.75 g). and 100 ml of dimethylformamide. The tubes were cooled, evacuated and then pressed with 1.3 g of acetylene. The tube was heated at 150 ° with shaking for 8 hours, cooled and degassed. The contents were diluted with 500 ml of water and 25 ml of concentrated ammonium hydroxide was added. The aqueous mixture was extracted with ether (4 x 300 mL). The combined ether extracts were washed with water (3 x 300 mL), then dried and concentrated on a rotary evaporator. The residue was chromatographed on a column of 600 g of silica gel (Silic AR® CC-7). The product was eluted with chloroform (fractions 6-811 each) to give 2.9 g of crystals after concentration. Recrystallization from 1-chlorobutane / hexane gave 2.8 g of pure product, m.p. 114-115 °.

Analysis:

Calculated for C 18 H 19 N 2 O 2 S: C 67.43 H 5.36 N 8.28 Found: C 67.17 H 5.40 N 8.42

Example 19 4,5-Bis (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 was added tri-n- butyltin hydride (9.0 g, 0.03 mol). The mixture was boiled for 4 hours. A second portion of 9.0 g of 32 6 6177 (0.03 moles) of tri-n-butyltin hydride was added and the mixture was boiled overnight. The mixture was then applied directly to a column of 900 g of silica gel (Silic AR® CC-7). Elution with toluene followed by toluene / ethyl acetate (95/5) gave 6.5 g of crystalline product. Recrystallization from methylhexane gave 5.6 g of pure product, m.p. 143.5 - 145 °.

Analysis:

Calculated for C 57.86 H 4.34 N 7.10

Found: C 57.95 H 4.71 N 7.04

Example 20 4,5-Diphenyl-1- (1,1,2-trifluoroethylthio) imidazole

Substituting 2- (2-bromo-1,1,2-trifluoroethylthio) -4,5-bis (4-methoxyphenyl) imidazole from Example 19 2- (2-bromo-1,1,2-trifluoroethylthio) - 4,5-Diphenylimidazole gave 4,5-diphenyl-2- (1,1,2-trifluoroethylthio) imidazole, m.p. 225-226.5 °.

Example 21 Sodium salt of 4,5-bis (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole

A mixture of 4,5-bis (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole (5.0 g, 0.0199 mol), sodium methylate (0.6 g, 0.0111 mol) and ether (300 ml) were stirred overnight at room temperature. The solid was collected and washed with ether to give 2.1 g of the sodium salt of 4,5-bis (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole, m.p. 290-292 °.

Analysis:

Calculated for C 18 H 18 F 3 N 2 SNa: C 46.16 H 2.05 N 6.33 Found: C 45.98 H 2.19 N 6.07

Example 22 Sodium salt of 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole Using the procedure described in Example 21 and starting from 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole, 4 , 5-diphenyl-2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole sodium salt, m.p. 296-302 ° (decomposed).

66177 33 Using the appropriate starting materials and the procedure described in Example 10, the compounds shown in Table I were prepared. Typical useful solvents are methanol, ethanol or toluene. Using the appropriate starting materials and the procedure described in Example 17, the compounds shown in Table II were prepared. Typical useful catalysts are diisopropylamine or benzyltrimethylammonium hydroxide.

Using the appropriate starting materials and the methods described in Examples 13 and 14, the compounds shown in Table III were prepared.

Example 23 A) 4,5-Diphenyl-1- (2-tetrahydropyranyl) imidazole

A mixture of 27 g (0.122 moles) of 4,5-diphenylimidazole, 21 g (0.25 moles) of dihydropyran, 250 ml of ethyl acetate and 4.0 g of BF 2 .E 2 Cl 2 was refluxed. days. The almost clear solution was diluted with ether and filtered to remove insoluble starting material (0.6 g). The ether filtrate was washed several times with 10% NaHCO 3, dried and evaporated. Thin layer chromatography indicated that the starting material was still present, so the crude product was chromatographed on 900 g of Silic AR®CC-7 and eluted with toluene containing 20-40% ethyl acetate. 30.3 g (81.7%) of pure product were obtained, m.p. 170-171 °. IR: 3.21 μm, = CH; 3.40, 3.49 pm, sat. CH; 6.25, 6.64, 6.73, arom. C = C and / or C = N; strong 9.10 μm, C-O-C; 12.98 and 14.38 μm, monosubstituted aromatic. N-NMR: raultplet (1.6-2.3.6 δ, 6H); multiplet (ci 3.4, 4.0, 4.8 δ, each Ci 1H); multiplet + singlet (7.0 - 7.6 + 7.4 S, 10H); S (7.8 S, 1 H).

Mass spectrum calculated for the formula: C20H20N2O: 304.1574 Found: 304.1559

Analysis:

Calculated for the formula c20H20N2O: c 78 * 92 H 6.62 N 9.20 Found: C 78.57 H 6.89 N 9.07 34 6 6 1 77 B) 4,5-Diphenyl-2-trifluoromethylthiol imidazole In a glass vessel dried in a hot air blower a solution of 0.9 g (3 mmol) of 4,5-diphenyl-1- (2-tetrahydropyranyl) imidazole in 15 ml of tetrahydrofuran and 15 ml of ether in a nitrogen blanket was cooled to -78 °. To the cold solution was added dropwise a solution of 2.5 mL (4 mmol) of a hexane solution of 1,6-m-n-butyllithium in 10 mL of ether. The solution was stirred at -78 °, then 0.55 g (4 mmol) of trifluoromethanesulfenyl chloride gas was added. The mixture was stirred for 2 hours at -78 °, then at room temperature overnight. The mixture was poured into water and extracted with ether (pH 14 of the aqueous phase). The aqueous phase was neutralized with sodium bicarbonate and then extracted with a new portion of ether. The combined ether extracts were dried and concentrated. The crude product obtained as a residue was chromatographed on 50 g of Silic AR 2 CC-7, eluting with toluene containing 2% ethyl acetate to give 0.45 g (47%) of the product. Recrystallization from toluene gave 0.3 g (31%) of a white solid, m.p. 254-256 °; IR: broad 3-4, NH; 3.28 μm, = CH; 6.24, 6.34, 6.42, 6.71, arom. C = C and / or C = N; strong 8.5-9 pm, C-F; 13.09, 14.34 μm, monosubstituted aroma. 1 H-NMR: multiplet (7.1-7.7 δ, 10H); broad (136, 1H).

F-NMR: δ (42.46 δ).

Mass spectrum: molecular ion c-j-F3N2S: found 320.0609

Analysis:

Calculated for the formula C., H-, F_N_S: C 59.99 H 3.46 N 8.75

Ib 11 j Z

Found: C 60.20 H 3.57 N 8.52

Example 24 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, with thin layer chromatography showing incomplete oxidation, at reflux temperature for another day. Thin layer chromatography further showed incomplete oxidation, so the methylene chloride was removed on a rotary evaporator and replaced with 30 mL of chloroform, and the mixture was refluxed for an additional 6 hours. The chloroform was evaporated and the residue was triturated with about 20 ml of ether. The ether-insoluble matter (about 3 g) was combined with about 0.1 g of a solid obtained from the ether extract by washing with 10% sodium sulfite, 10% sodium bicarbonate, drying and evaporation. Recrystallization from toluene gave 0.37 g (70%) of a white product, m.p. 292-293.5 ° (begins to sublime at 250 °).

IR: 3-4 pm, NH; 6.33, 6.44, 6.72, aromatic C = C and / or C = N; 7.23, 8.32 μm, 8.97 μm, C-F; 13.05, 14.30, monosubstituted aroma. 1 H-NMR: multiplet (7.1-7.7 δ, 10H). F-NMR: multi-pipet S (78.25 δ); small singlets were also observed at 42.43 δ (about 2%, sulfide) and 72.69 δ (about 3%, sulfoxide).

Analysis:

Calculated for C 11 H 19 F 3 N 2 O 2 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 adjuvant arthritis ED, .q of the compound of Example 24 in rats was 0.03 mg / kg.

Example 25 4- (or S) - (4-Fluorophenyl) -5- (or 4) - (4-methylthiophenyl) -2-Z (1,2,2-tetrafluoroethyl) thio] imidazole

4-FC6H4 \ / N

] ^> - scf2cf2h 4-MeSC6H4 ^ '“(Table II; X = 4-F, Y = 4-CH3S, Z = F, AA ED ^ = 1.6)

Solution of 4 (or 5) - (4-fluorophenyl) -5 (or 4) - (4-methylthiophenyl) -2-mercaptoimidazole (11.1 g, 0.035 mol) and diisopropylamine (3.5 g) In 100 ml of dimethylformamide, it was placed in a pressure vessel into which tetrafluoroethane (7.0 g) was introduced and then heated at 60 ° overnight. The reaction mixture was poured into 1 liter of ice water and extracted several times with ether. The ether extract was washed with water and concentrated to give a yellow oil which crystallized on standing. Recrystallization from methyl cyclohexane gave 9.2 g (63%) of the title product, m.p. 155.5-157 °.

66177 36

Example 26 4- (or 5) - (4-Fluorophenyl-5 (or 4) - (4-methylsulfonylphenyl-2 - [(1,1,2,2-tetrafluoroethyl) sulfonyl] imidazole 4-FC6H4

Jl so2cf2cf2h 4-MeSO_C, H.

2 6 4 H

(Table III; X = 4-F, Y = 4-CH 3 SC> 2f R = CF 2 CF 2 H, n = 2, AA ED 50 = (37%) 15)

A solution of 4 (or 5) - (4-fluorophenyl) -5 (or 4) - (4-methylthiophenyl) -2 - [(1,1,2,2-tetrafluoroethyl) thi] imidazole (4.2 g, 0 .01 mol) in ethyl acetate (150 ml), cooled to 0 ° and added dropwise to a solution of 10 g of 85% m-chloroperbenzoic acid in 75 ml of ethyl acetate. After two days, the mixture was extracted with 10% sodium sulfite solution, then saturated sodium bicarbonate solution and finally brine, dried over magnesium sulfate, and evaporated to give a glassy solid. Crystallization from a mixture of ethanol and water (1: 2, 150 ml) gave 1.6 g (33%) of the title product, m.p. 221-223 °.

Example 27 4- (or 5) - (4-Fluorophenyl) -5- (or 4) - (4-nitrophenyl) -2- (1,1,2,2-tetrafluoroethyl) sulfonyl] imidazole 4-FC, H. ^ .N.

] | so2cf2cf2h

4-NO 2 C 6 H 4 S

(Table III; X = 4-F, Y = 4-NC> 2, R = CF 2 CF 2 H, n = 2, AA ED 50 = 0.37) 37 6 6 1 77 4 (or 5) - (4-fluorophenyl) - A solution of 5 (or 4) -phenyl-2 - [(1,1,2,2-tetrafluoroethyl) sulfonyl] imidazole (4.02 g, 10 mmol) in trifluoroacetic acid (60 mL) was treated with 1.06 g of potassium nitric acid. after 22 hours an additional 100 mg of potassium nitrate was added, and after 7 hours the mixture was evaporated and the residue was dissolved in ethyl acetate. The organic solution was washed with water and brine, evaporated and the residue crystallized from chloroform to give 2.77 g (62%) of the title product, m.p. 208-211 °.

Example 28 4 (or 5) - (4-Aminophenyl) -5 (or 4) - (4-fluorophenyl) -2-C (1,1,2,2-tetrafluoroethyl) sulfonyl] imidazole 4-Ηε6Η4 \ ^ ΗΚ 11 V - so2cf2cf2h

4-NH 2 C 6 H 4 H

(Table III? X = 4-F, Y = 4-NH2 # R = CF2CF2H, n = 2, AA ED50 = 18%) 3)

To a solution of NaBH 4 (78 mg) in methanol (5 mL) was added 10% sodium hydroxide solution (0.5 mL), and the mixture was poured into an aqueous suspension of 10% Pd / C (20 mg) (5 mL). 4 (or 5) - (4-fluorophenyl) -5- (or 4) - (4-nitrophenyl) -2- (11,1,2,2-tetrafluoroethyl) sulfonyl] imidazole (447 mg, 1 mmol) in methanol (8 mL) and the mixture was stirred overnight. The mixture was acidified with hydrochloric acid by first adding dilute hydrochloric acid and finally concentrating, then filtering through Celite® diatomaceous earth and basifying the filtrate (pH 8) with ammonia solution. The resulting solution was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to give an oil which crystallized on standing. Treatment of the precipitate with ethereal hydrogen chloride gave the title compound as a solid hydrochloride, m.p. 238-241 ° (dec.).

38 661 77

In a second synthesis on a larger scale (4.47 g of starting material), in the first step, i.e. after basification with ammonia solution, 2.3 g of the title compound were obtained, m.p. 233-235 °; in addition, 1.4 g of the title product was obtained as the hydrochloride salt by further treatment as described above.

Example 29 4,5-Diphenyl-1- (2-tetrahydropyranyl) imidazole A mixture of 27 g (0.122 moles) of 4,5-diphenylimidazole, 21 g (0.25 moles) of dihydropyran, 250 ml of ethyl acetate and 4.0 g of BF 2 .Et ^ Ojta was boiled for 5 days. The almost clear solution was diluted with ether and filtered to remove residual insoluble starting material (6 g). The ether filtrate was washed several times with 10% sodium bicarbonate, then dried and evaporated. TLC showed that the starting material was still present, so the crude product was chromatographed on a column of 1 kg of silica gel Silic AR® CC-7. 30.3 g (81.7%) of pure product were obtained, m.p. 170-171 °. IR: 3.21 μm, = CH; 3.40, 3.49 pm, sat. CH; 6.25, 6.64, 6.73, aromatic C = C and / or C = N; strong 9-10 pm, C-O-C; 12.98 and 14.38 μm, monosubstituted aromatic. 1 H-NMR: multiplet (1.6 - 2.3.6, 6H); multiplet (^ 3.4, 4.0, 4.8 S, 1H each); multiplet + singlet (7.0 - 7.6 + 7.4 δ, 10H); S (7.8 S, 1 H). .

Mass spectrum, calculated for C20H20N2O: 304.1574 Found: 304.1559

Analysis:

Calculated for C 20 H 20 N 2 O: c 78.92 H 6.62 N 9.20

Found: C 78.57 H 6.89 N 9.07

In a similar manner, the 2-tetrahydropyranyl imidazoles listed in the following tables were prepared.

66177 39 χΎ V-

X

O

X Υ sp.

HH 170-171 ° pF pF 158-159 ° p-CH 3 O p-CH 3 O 123-125 ° pF or p-CH 3 O p-CH 3 O or pF 109-125 ° H or 3,4-diCl 3,4-diCl or H 113 - 120 °

Jl SR

"

Adjuvant articulated- XYR sd inflammation x YR p · ED50 (mg / kg) 3- Cl H CH3 202 - 203 ° 50 3,4-Cl2 H CH3 183/5 - 184.5 ° <25 4- F 4-F CH3 (CH 2) 3 175-175.5 ° <10 40 66177

Example 30 4,5-Diphenyl-2-trifluoromethyltoluimidazole (via trifluoromethanesulfenyl, without intermediate isolation)

Under nitrogen and dried in a glass vessel with a heat gun, a solution of 0.9 g (3 mmol) of 4,5-diphenyl-1- (2-tetrahydropyranyl) imidazole in 15 ml of tetrahydrofuran and 15 ml of ether was cooled to -78 °. To the cold solution was added dropwise a solution of 2.5 mL (4 mmol) of 1,6-m-n-butyllithium (in hexane) and 10 mL of ether. The solution was stirred at -78 ° and then 0.55 g (4 mmol) of trifluoromethanesulfenyl chloride was added as a gas. The mixture was stirred at -78 ° for 2 hours and then at room temperature overnight. The mixture was poured into water and extracted with ether (aqueous layer pH = 4). The aqueous layer was neutralized with sodium bicarbonate, then extracted once more with ether. The combined ether extracts were dried and concentrated. The crude residue was chromatographed on a column of 50 g of silica gel Silic AR'® 'CC-7 eluting with a mixture of toluene and ethyl acetate (98: 2) to give 0.45 g (47%) of product. Recrystallization from toluene gave 0.3 g (31%) of a white solid, m.p. 254-256 °. IR: broad 3-4 pm, NH; 3.28 μm, = CH; 6.24, 6.34, 6.42, 6.71, aromatic C = C and / or C = N; strong 8.5 -9 μm, C-F; 13.09, 14.34 μm, monosubstituted aromatic. 1 H-NMR: multiplet (7.1-7.7 δ, 10H); broad (13 6, 1H). F-NMR: δ (42.46S). Mass spectrum: molecular ion. Analysis:

Calculated for C 18 H 19 F 3 N 2 O 5 S: C 59.99 H 3.46 N 8.75 Found: C 60.20 H 3.57 N 8.52

Example 31 4,5-Diphenyl-1- (2-tetrahydropyranyl) -2-trifluoromethylthioimidazole (via trifluoromethyl disulfide)

In a glass vessel, dried with a heat gun and protected under nitrogen, a mixture of 1.5 g (5 mmol) of 4,5-diphenyl-1- (2-tetrahydropyranyl) imidazole in 20 ml of tetrahydrofuran and 20 ml of ether at -78 ° was added dropwise a solution of 3.75 mL (6 mmol) of 1,6-m n-butyllithium in hexane in 20 mL of ether. A solution of 1.2 g (6 mmol) of trifluoromethyl disulfide in 10 ml of ether was added dropwise to the pale yellow solution every 15 minutes at -78 °. The dark solution was stirred at -78 ° for 1 hour, then at room temperature for half an hour. The mixture was added to water and extracted 3 times with ether (pH of the aqueous layer -> 6). The ether extracts were dried and concentrated. The residue was chromatographed on a column of 150 g of silica gel Silic AR® CC-7 eluting with toluene to give, after crystallization from hexane, 0.55 g of product, m.p. 104-105 °. IR: 3.25 μm, = CH; 3.37, 3.48 pm, sat. CH; 6.23, 6.64, 6.74 μm, conjugated cyclic C = C and / or C = N; strong 9 μm region, -SCF 2 and C-O-C; 13.09, 14.36 μm, monosubstituted aromatic. 1 H-NMR: multiplet (1.1 - 2.0 S, 6H); multiplet (3.2 - 4.2 &, 2H); multiplet (5.3 5.6 δ, 1H); multiplet + singlet (7.0 - 7.5 + 7.4 δ, 10H). F-NMR: δ (42.20 δ).

Analysis:

Calculated for C 62.36 H 4.74 N 6.93

Found: C 62.70 H 4.83 N 6.91

The use of tetramethylethylenediamine to the same extent as the use of n-butyllithium resulted in improved product yields.

Example 32 4,5-Diphenyl-2-trifluoromethylthioimidazole (via hydrolysis of a tetrahydropyranyl derivative

A small sample of 4,5-diphenyl-1- (2-tetrahydropyranyl) -2-trifluoromethylthioimidazole was suspended in a ratio of 1: 1 ethanol: 0.1 hydrochloric acid. The mixture was heated on a steam bath (clear solution) for one hour. After cooling, crystals formed from the product and were collected, washed with water and dried. IR and TLC showed the solid to be 4,5-diphenyl-2-trifluoromethylthioimidazole, m.p. 255 °.

In a similar manner, the 4,5-diaryl-2-trifluoromethylthioimidazoles listed in the following tables were prepared.

66177 42 '-iol.

I S— scf3 * - {Θ] "

Adjuvant rheumatoid arthritis X Y sp. ED50 (m9 / kg) HH 254 - 256 ° <3 (26%) 3) pF pF 228 - 229 ° 0.02 p-CH30 p-CH3 181-182 ° 1.5 pF p-CH3 156-157.5 ° 2.7 H 3,4-diCl 241-242 ° 7.0

x ^ G1 N

I-SCF CFH

z

* 40] H

Adjuvant rheumatoid arthritis X Y Z sp. ED50 (m9 / k9) 3-Cl HF 212 - 213 ° 0.6 3-FHF 205.5 - 207 ° 2.5 3,4-Cl2 HF 209 - 211 ° 3.0 4-CH3O 4-FF 170- 171.5 ° 14 4-CH 3 O 4-CH 3 O 183-184 ° 40 66177 43

Example 33 4,5-Diphenyl-2-trifluoromethylsulfonylimidazole (via sulfide oxidation

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, as TLC indicated incomplete oxidation, boiled for another day. TLC still showed incomplete oxidation, so the methylene chloride was removed by rotary evaporation and replaced with 30 ml of chloroform and the mixture was boiled for another 6 hours. The chloroform was evaporated and the residue was triturated with 20 ml of ether. The ether-insoluble solid (rv 0.3 g) was combined with λ> 1.0 g of solid obtained from the ether filtrate; washed with 10% sodium sulfite and 10% sodium bicarbonate, and dried and evaporated. Recrystallization from toluene gave 0.37 g (70%) of a white product, m.p. 292-293.5 ° (sublimes above 250 °). IR: 3-4 / am, NH; 6.33, 6.44, 6.72 μm, aromatic C = C and / or C = N; 7.23, 8.32 μm, -SC 2 -; 8.97 μm, C-F; 13.05, 14.30, monosubstituted aromatic. 1 H-NMR: multiplet (7.1-7.7 & g, 10H). F-NMR: δ (78.25 δ); small singlets were also found at 42.43 δ (rv 2%, sulfide) and 72.69 (rv 3%, sulfoxide).

Analysis:

Calculated for C. | ν max λ max λ max λ max: 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

Example 34 4,5-Diphenyl-2-trifluoromethylsulfonylimidazole (via trifluoromethanesulfonic anhydride)

In a glass vessel, dried with a heat gun and protected under nitrogen, a solution of 1.5 g (5 mmol) of 4,5-diphenyl-1- (2-tetrahydropyranyl) imidazole in 20 ml of tetrahydrofuran and 20 ml of ether at -78 ° was added dropwise a solution of 3.75 mL (6 mmol) of 1,6-m n-butyllithium in hexane in 20 mL of ether. After stirring at -78 ° for 15 minutes, a solution of 1.7 g (6 mmol) of trifluoromethanesulfonic anhydride in 10 ml of ether was added. The reaction mixture was stirred at -78 ° for 2 hours and then at room temperature for 2 days.

The mixture was added to water, neutralized with sodium bicarbonate and extracted with ether. The ether extracts were dried and concentrated, and the residue was chromatographed on a column of 150 g of silica gel Silic AR® CC-7. Elution with toluene gave 0.25 g of a solid which was identified by mass spectrum as 4,5-diphenyl-1- (2-tetrahydropyranyl) -2-trifluoromethylsulfonylimidazole (IR: no NH, strong sulfone, C-O-C bonds). Elution with a mixture of toluene and ethyl acetate (9: 1) gave a solid product, recrystallization from toluene gave 80 mg (* v 5%) of 4,5-diphenyl-2-trifluoromethylsulfonylimidazole, m.p. 285 - 288. IR was similar to the product obtained by oxidation of 4,5-diphenyl-2-trifluoromethylthioimidate-Sol.

In an analogous manner, the 4,5-diaryl-2-trifluoromethylsulfonylimidazoles listed in the following tables were prepared.

x- {Ol v_ I> - so2cf3

* - {Oj H

Adjuvant rheumatoid arthritis X _Y_ sp. ED50 (m9 / kg) HH 292 - 293.5 ° 0.03 pF pF 264 - 265 ° 0.015 p-CH 3 O p-CH 3 O 201 - 202.5 ° 0.33 pF p-CH 3 O 187 - 188 ° 1.4 H 3,4-diCl 195.5 - 197 ° 0.35 45 6 6 1 77 * —ίο

jf ^ S (O) nR

γΟθΓ "

Adjuvant rheumatoid arthritis _X_Y_R _bp. ED50 (mg / kg) 3-C1H CH3 1150 - 151.5 ° <75 3-C1H CH3 2 171 - 172 ° <10 3-FH CH3 1 163.5 - 164.5 ° <100 3.4- Cl2 H CH3 1 188 - 189 ° 50 3.4- Cl2 H CH3 2 199 - 200 ° <50 3-C1 H HCF2CF2 2 193-194 ° 0.05 3- FH HCF2CF2 2 217-218 ° 0.06 4-C2H50 H HCF2CF2 2,162 - 163 ° 1.5 3.4- Cl2 H HCF2CF2 2 197-198 ° 0.2 4-F 4-F CH 3 1185 - 187 ° 4.0 4-F 4-F HCF 2 CF 2 1192.5 - 193 ° 0.055 4-CH3O 4-F HCF2CF2 2 189 - 190 ° 2.2 4-02N 4-02N hcf2CF2 2 240 - 240 »5 ° 8.5 4-CH3O 4-CH2O H2CFCF2 2 162 - 164 ° 5.0 HH HCBrFCF2 2,217-218 ° 0.85 HH H2CFCF2 2,239-240 ° 0.15 4-CH3O 4-CH3O HCFICF2 2190-192 ° 3.0 4-CH3O 4-CH3O CH3 (CH2) 3 2 99 - 101 ° < 50

Claims (2)

1 Y 2 is Y and Y 2, which may be the same or different, are hydrogen, C 1 -C 6 alkoxy, C 1 -C 12 alkyl, C 1, F, CF 2, NH 2, (CH 3 2, CH 3 S, O 2 SC 2 -j or Y and Y 2 taken together form a dioxiffletylene bridge; with the proviso that dl n = 0, 1 or 2 and Y1 and Y2 bidding are hydrogen, R 1 cannot be vinyl, and di R 2 is C 1 -C 4 alkyl, C 1 at the 3- or 4-position, allyl or acetonyl, both Y 2 and Y 2 cannot be hydrogen, and with the additional condition that when Ir 1 and R 2 are CH 3, both R2 and R 3 cannot be p p-methoxyphenyl, and the pharmaceutically acceptable salts of these compounds, characterized in that a) a compound of formula 3 H