FI69462B - FOERFARANDE FOER FRAMSTAELLNING AV INFLAMMATIONSMOTVERKANDE 4, -DIARYL-2- (SUBSTITUTE TIO SULFINYL ELLER SULFONYL) IMIDA ZODERIVAT - Google Patents

Description

nr ^ FTl ΓΒ1 (11i ADVERTISEMENT 69469 figHjA LBJ m) UTLÄGGNINGSSKRIFT 0:74 0 /

c (45) P- .exent granted / ¾¾) P- tent re P '-'-. t 1C CP 10CC

(51) Kv.ik.4 / lnt.CI. * C 07 D * 409/0 * 4, 401/04, ** 05/01 SUOMI FINLAND (21) Patent application - PatentansBkning 780 * 428 (22) Application date - Ansöknlngsdag 09.02 78 (EN) (23) Start date —Giltighetsdag 09.02.78 (41) Has become public - Blivit offentlig 1 0.08 78

Patent * and National Board of Registration (44) Date of publication and date of publication. -

Patent-oeh registerstyrelsen '' Ansökan utlagd och utl.skriften publicerad 31.10.85 (32) (33) (31) Privilege claimed — Begärd priority 09.02 77 05.01.78 USA (US) 767220, 865832 (71) ElduPont de Nemours and Company, 1007 Market Street, Wilmington, Delaware 19898, USA (72) Saul Carl Cherkofsky, Wilmington, Delaware, Thomas Ray Sharpe, Wilmington, Delaware, USA (7 **) Oy Kolster Ab (5 * 4 ) Process for the preparation of imidazole derivatives of its * 4,5-diaryl-2- (substituent, sulfinyl or sulfonyl) imitazole derivatives - For the preparation of framsta 11 Ning av inflammationmotverkande * 4,5 - Diary 1-2 The present invention relates to a process for the preparation of an anti-inflammatory 4,5-diaryl-2- (substituted thio, sulfinyl or sulfonyl) imidazole derivative of the formula: - (Substituent, sulfinyl or sulfonyl) imidazole derivatives

Rv \ A> - S (0, n-Rl 1 R '

3 I

B

wherein n is an integer from 0 to 2, R 1 is polyfluoro-C 1 -C 2 alkyl, R 2 is 2-thienyl, 2-furyl, phenyl or 4-fluoro, 4-chloro, 3,4-dichloro or 4 -methoxyphenyl and R 3 is 2-thienyl, 2-furyl or 3-pyridyl, or for the preparation of their pharmaceutically acceptable acid addition salts when n is O or is 3-26462 pyridyl, or for the preparation of their pharmaceutically acceptable metal salts when n is 1 or 2.

In U.S. Patent 3,707,745, Lombardino discloses anti-inflammatory 4,5-diaryl-2-substituted imidazoles.

In U.S. Patents 3,505,350 and 3,651,080, Doebel discloses anti-inflammatory 4-alkyl-5-aryl-1-substituted-2-mercaptoimidazoles and 4-alkyl-2-alkylthio-5-aryl-1-substituted imidazoles.

K. Zauer et. ai, Chem. Ber., 106, 1638 (1973) have disclosed 4,5-bis - (4-methoxyphenyl) -2-methylthioimidazoles and 4,5-bis- (4-chlorophenyl) -2-methylthioimidazoles, but do not suggest any use for them.

In several references, e.g., Current Sci. India, 17, 184-185 (1948) and Acta. Chem Acad, Sci. Hung., 79, (2), 197-212 (1973) disclose 2- (substituted thio) -4,5-diphenylimidazoles having, for example, methyl, propyl, allyl and acetonyl as substituents.

There is a constant need for new safe and effective anti-inflammatory drugs. Inflammation is a disease process characterized by redness, fever, swelling, and pain. Of the inflammatory diseases, arthritis is the most common, chronic, and most severe. Accidents and infections also cause inflammation, and are often treated with anti-inflammatory drugs. The usefulness of most commercial anti-inflammatory agents is limited due to toxicity and adverse side effects. Many have a stomach irritating effect and other side effects, such as causing blood cell and central nervous system changes. Adrenal choroid steroids irritate the stomach and lower the normal function of adrenaline.

The present invention has been based on the aim of developing new anti-arthritic compounds which have good anti-inflammatory activity and minimal side effects and which are more effective than currently available drugs in the treatment of arthritis.

3 69462

In addition to their anti-inflammatory properties, some of the compounds of this invention have an analgesic effect according to an experimental method. This additional feature is desirable in the treatment of arthritis or similar diseases, but such compounds can also be used solely for pain relief.

In the process of the invention, a compound of formula

R2 \ / N

[I - SH II

R3 ^ 'f

B

wherein R 2 and are as defined above, is reacted with a suitable alkylating agent, and the resulting substituted thioimidazole is optionally oxidized with a suitable oxidant, and the resulting compound is converted, if desired, to a pharmaceutically acceptable salt.

When R_ and R are different, the compound of formula I * S

may occur as tautomers:

R Ro H

2 \ XN \ - S (0) nRl ^ S (0) n_Rl J H 3

Compounds in which n is 0 or R 1 is 3-pyridyl form pharmaceutically acceptable acid addition salts with physiologically acceptable acids; such salts include, for example, hydrochloride, sulfate, phosphate and nitrate.

Compounds in which n is 1 or 2 form pharmaceutically acceptable metal salts with certain metals, e.g. sodium, potassium or calcium.

Due to their anti-arthritic activity, compounds in which R 1 is -CH 2 CF 2 or -CF 2 are preferred.

Also preferred are compounds wherein R 2 is 2-thienyl and R 2 is 2-thienyl or 3-pyridyl.

4 69462

Also preferred are compounds having phenyl or 4-chloro, 4-fluoro or 4-methoxyphenyl.

More preferred are compounds wherein R 1 is CF 2 CF 2 H or CF 2, R 2 is 2-thienyl, phenyl or 4-chloro, 4-fluoro or 4-methoxyphenyl and R 1 is 2-thienyl or 3-pyridyl.

Particularly preferred are the following compounds: a) 4- (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) -5- (2-thienyl) -1H-imidazole, b) 4- (4 (fluorophenyl) -5- (2-thienyl) -2-trifluoromethylsulfonyl-1H-imidazole, c) 4- (4-methoxyphenyl) -5- (2-thienyl) -2-trifluoromethylsulfonyl-1H-imidazole, d) 4,5-bis- (2-thienyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) -1H-imidazole, e) 4- (4-methoxyphenyl) -2- (1,1 , 2,2-tetrafluoroethylsulfonyl) -5- (2-thienyl) -1H-imidazole, f) 4- (3,4-dichlorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) - 5- (2-thienyl) -lH-imidazole.

The starting material of formula II can be prepared by reacting a 4,5-disubstituted imidazole of formula R2.

Tl ^

I / III

R, ^ N

3 I

B

wherein R 2 and R 2 are as defined above (prepared according to H. Brederick et al., Chem. Ber., 86, 88 (1953)) to react with sulfur at 150-300 ° C in a solvent or without a solvent to give 2-mercaptoimidazole. A suitable solvent for use in this reaction is tetramethylenesulfone. This method corresponds to the conversion of 1-methylbenzimidazole to 2, - mercapto-1-methylbenzimidazole as described by A.V. Eltsov and K.M. Krivozheiko, Zh. Or. Kh., 2, 189 (1966).

4,5-Disubstituted-2-mercaptoimidazole can also be prepared by reacting OH 0 OH 0 13 1 ί

R is -CH-C-Rj or R-CH-C-R

5 69462 (I 1 and R 2 are as defined above) (various syntheses of this type of compound have been described by W.

S. Ide and J.S. Buck, Organic Reactions, Vol. IV, p. 269) to react with thiourea at reflux temperature in dimethylformamide or other high boiling polar solvent. A similar condensation method has been described by P.M. Kochergin, Zhur. Obshschei. Khim., 31, 1093 (1961); Chem. Abstr. 55, 23503F.

4,5-Disubstituted-2-mercaptoimidazole can be more preferably prepared by reacting the above-mentioned acyline with ammonium cyanate at lower temperatures in polar solvents such as ethanol or propanol.

A suitable group may be attached by means of a suitable alkylating agent such as tetrafluoroethylene, difluorocarbene or 2,2,2-trifluoroethyl trichloromethanesulfonate. Corresponding addition reactions have been described by D.C. England et. ai., J. Am. Chem. Soc., 82, 5116 (1960) and K. E. Rapp et al., J. Am. Chem. Soc., 72, 3642 (1950). Alkylating agents in this publication include tetrafluoroethylene and other fluorinated olefins.

In certain cases, when forming a group R 1, the polyhaloalkyl group may be chemically modified. For example, imidazoles containing a 2- (2-bromo-1,1,2-trifluoroethylthio) substituent can be converted to 2- (1,1,2-trifluoroethylthio) imidazoles with reducing agents.

The compounds of formulas

Ph Het. .Nv.

γ Νγ_ · "if S-R

1 Y S-Ri 3a Jl / 1

Het. 1 i

B

imidazoles (wherein Het is a heterocycle as defined by R 3 3a of R 3 of formula I and the pH is an optionally substituted phenyl as defined by R 2) can be oxidized to the corresponding sulfoxides or sulfones with oxidants, e.g. m-chloroperoxybenzoic acid, R.C.

_ Γ 6 69462

Tweit et. ai., J. Med. Chem., 16, 1161 (1973), with sodium metaperiodate N.V. Leonard and C.R. Johnson, J. Org. Chem., 27, 282 (1962), with hydrogen peroxide, P.M. Kochergin and M.N. Shucukina, Gen.Chem. USSR., 25, 2289 (1955) or with potassium permanganate, K.E. Rapp. et al., loc. cit.

When R 1 in formula I is pyridyl, the oxidation converts the pyridyl group to the N-oxide while -S- is converted to the sulfoxide or sulfone. In such a case, the 3-pyridyl-N-oxide group can be converted back to the free 3-pyridyl group by treatment with a weak reducing agent such as trialkoxy phosphite, triphenylphosphine or tri-n-butylphosphine or other weak reducing agent without reducing the sulfone function.

Pharmaceutically acceptable salts of the compounds of formula I are prepared by conventional methods used in the preparation of salts.

To determine the anti-arthritic efficacy of the compounds of the invention and the standard reference drugs, an experiment based on a standard model of arthritis, which correlates well with efficacy in humans, was used.

The experiments were performed by inducing arthritis in rats (so-called adjuvant-induced arthritis; Federation Proceedings,

Butter. 32, no. 2 1973, "Models Used for the Study and Therapy of Rheumatoid Arthritis", Symposium of the American Society for Pharmalogy and Experimental Therapeutics) by subcutaneous injection of a suspension of Mycobacterium tuberculosis in mineral oil (excipient).

Charles River Lewis male rats (130-150 g) were injected subcutaneously in the plantar region of the right hind paw with 0.1 ml of adjuvant (Difco heat-sterilized, lyophilized Mycobacterium butyricum suspended in mineral oil 5 mg / ml). Twenty non-arthritic control animals were injected with mineral oil. Animals were maintained for two weeks for the development of arthritis. The paw volumes of the animals were measured (uninjected left hind paw and 7 69462 groups of 10 animals were selected according to the severity of the disease. Non-arthritic controls were divided into two groups of 10 animals. Rats were orally administered test compound or PVC acacia 5% methyl paraben) 10 ml / kg on the same day and for the following six days The next day after the last dose, paw volumes were measured (non-injected left hind paw) using an Ugo Basile Volume Differential Meter, model 7101.

The percentage reduction from the mean paw volume of the control group was calculated as follows:

Control group Treatment group mean paw volume mean paw volume (ml) - value (ml) _x 100

Control group Arthritis unpaired paw volume value (ml) mean paw volume mean (ml)

Regression curves corresponding to the percent reduction doses were visualized on semi-logarithmic paper and the paw volume of the ED 50% control was determined from the curves. The results are shown in Table I.

The compounds of formula I are many times more effective than aspirin and ibuprofen in treating adjuvant-induced arthritis in rats. Four compounds have been found to be more potent than phenylbutazone in this experiment and one compound has been found to be more potent than indomethacin.

8 69462

Table I

Adjuvant-induced arthritis in the rat (AN)

Compound from Example no_ED 50% mg / kg * ^ _ 1 32% / 50 mg / kg 2 1.3 3 0.1 4 12.0 5 2.2 6 50 8 30 9 5 10 34% / 50 mg / kg 11 less than 25 12 0.11 13 0.17 indomethacin 0.3 phenylbutazone 10 ibuprefene 100 aspirin 305 +) determined as percentage reduction in paw volume from control

Fenyylikinonivärähtelykoe

To determine and compare the analgesic efficacy, a phenylquinone vibration assay was used that has a good correlation with efficacy in humans. The experimental method, i.e. a modification of the method proposed by Siegmund et. et al., Proc. Soc. Exp. Biol.

Med., 95, 729 (1957). The test compound suspended in 1% methylcellulose was orally administered to fasted (17-21 h) white female mice, 5-20 animals / double-blind experiment. 24 minutes later, the animals are injected intraperitoneally with an aqueous solution of phenylquinone (0.01% phenyl-p-benzoquinone) at 0.20 ml / mouse. Observation of the mice was started 30 minutes after administration of the test compound, during which time 10,646,462 symptoms of stretching or vibration were observed, which are indicative of phenylquinone-induced pain. The effective analgesic dose for 50% of mice (ED 2 g) was calculated according to the moving average method, W.R. Thompson, Bact.Rev., 11, 115-145 (1947).

The peak effect of several compounds was also determined. These values are shown in Table II.

Table II

Fenyylikinonivärähtelykoe Compound Example No. ED ^ g +) 1 4.6 3 2.1 5 less than 130 8 4-5 9 1.67 12 0.33 +) units are in mg / kg in half-hour

The following examples illustrate the preparation of these compounds. It should be noted that in the preparation of compounds of general formula I in which n is 2 by oxidation of compounds in which n is 1, the compounds in which n is 1 are always also determined by chromatography, on the basis of the data given for compounds of formula I in which n is 1 or 2. the preparation and biological activity of compounds where n is 1 are evident.

The parts given in the examples are parts by weight and temperatures in degrees Celsius, unless otherwise indicated.

Example 1 2- (11,1,2,2-Tetrafluoroethyl) -thio] -4,5-bis- (2-thienyl) -1H-imidazole A) 4,5-Bis- (2-thienyl) -1H-imidazole

A mixture of 31.6 g of>> thienoine and 175 ml of formamide was heated under reflux and stirred for two hours with an air condenser. The resulting dark solution was poured into 600 mL of cold water, stirred and filtered. The product was semi-solid, slowly curing, yield 27.6 g. This was dissolved in 35 ml of hot dimethylformamide. On cooling, the product crystallized, the crystals were isolated by filtration and washed with dimethylformamide and acetonitrile. The yield was 11.1 g and m.p. 218 to 221.5 ° C. Additional product was obtained from the filtrates by chromatography on alumina.

10 69462 B) 4,5-Bis- (2-thienyl) -ΙΗ-2-imidazolethiol

A mixture of 12 g of 4,5-bis- (2-thienyl) -1H-imidazole, 250 ml of tetramethylene sulfone (purified) and 2.5 g of sulfur was heated for 1 day at 170 ° C under nitrogen, 2 g of sulfur and heating were added. continued for 19 hours. The mixture was cooled, poured into two liters of water, filtered, washed and dried. The dried product (9.8 g) was dissolved in dimethylformamide, poured onto an alumina column and eluted with dimethylformamide. The product was obtained in the first fractions. Evaporated, stirred with acetonitrile and filtered to give 5.3 g of product, m.p. 213-218 ° C. Thin layer chromatography showed the product to be a mixture of the starting material and the desired thiol. Chromatography in a similar manner of a small portion of the crude product gave 1.02 g, m.p. 283-290 ° C.

Alternatively, a mixture of 27.9 g (0.25 moles) of 2-thienoine and 13.3 g of ammonium thiocyanate in 150 ml of 1-propanol was heated under reflux overnight, cooled and isolated by filtration from 22.7 g of 4.5- bis- (2-thienyl) -1H-2-imidazolithiol, m.p. 294-303 ° C (decomposes), recrystallization occurred from 1-butanol.

Analysis for cnH3N2S3

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-tetrafluoroethyl) thio] -4,5-bis- (2-thienyl) -1H- imidazole

A 6.0 g portion of the above product was dissolved in 50 ml of dimethylformamide and 2 ml of diisopropylamine, the solution was added to a bomb tube and a pressure of 5 g of tetrafluoroethylene was obtained.

2

The pressure was 15.4 kp / cm, which dropped to 11.3 kp / cm 2 in 23 minutes when shaken. The temperature was 25-28 ° C. The bomb was shaken for an additional 4.5 hours and the pressure remained unchanged. The dimethylformamide solution was removed from the bomb tube, poured into water, the product isolated by filtration and washed with water to give 6.9 g, m.p. 131.5 to 142 ° C. The product was chromatographed on a silica gel column (Silicar CC-4), eluted with chloroform to give 3.1 g, m.p. 161.5 to 163.5 ° C. Recrystallization from toluene gave an analytical sample, m.p. 166-167 ° C.

Analysis ^ ρ3 ^ 8 ^ 4Ν2 ^ 3

Calculated: C 42.86, H 2.20, N 7.69

Found: C 42.86, H 2.28, N 7.76.

11 69462

Example 2 4- (4-Fluorophenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5- (2-thienyl) -1H-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 dropping funnel containing 112 g of 2-thiophenecarboxaldehyde in 100 ml of methanol was added keeping the temperature below 30 ° C. The mixture was then allowed to stand for four hours at 30 ° C and poured into three liters of water.

The water was extracted with ether, the ether extract was washed with water, saturated sodium bisulfite solution and finally with water.

The ether was dried over anhydrous magnesium sulfate and evaporated to give 156.5 g of a yellow oil.

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

A suspension of 15 g of sodium hydride in 250 ml of dimethylformamide was stirred while 83.1 g of 2-dimethylamino-2- (2-thienyl) acetonitrile in 300 ml of dimethylformamide were added. The mixture was stirred for one hour and hydrogen evolved. To this stirred mixture was added 72.3 g of 4-fluorobenzyl chloride over 1 hour. During the addition, the temperature rose to 50 ° C and the mixture was maintained at 40-45 ° C for an additional hour. The mixture was partially evaporated in vacuo, poured into 500 ml of water, and to this were added 500 ml of chloroform and 500 ml of concentrated hydrochloric acid. The mixture was stirred and heated under reflux for 1 day. cooled and isolated. The aqueous layer was extracted three times with chloroform, and the chloroform extracts were combined and dried over anhydrous potassium carbonate. The dried extract was filtered, evaporated to give 103.9 g of a dark oil. This was distilled at 0.2 mm Hg to give 72.4 g of product, m.p. 60-62 ° C.

Alternatively, a mixture of 75.0 g (0.5 moles) of 4-fluorophenylacetic acid and 195.0 g of thiophene heated to 40 ° C was added dropwise 111.0 g (0.65 moles) of trifluoroacetic anhydride. The reaction mixture was heated under reflux for three hours, cooled and poured onto ice. The aqueous layer was basified with sodium carbonate and the product was extracted into ether. The combined ether extracts were washed with water, dried over anhydrous potassium carbonate and evaporated to give 112.0 g of an oil. Recrystallization from 12,646,462 of methanol gave 70.0 g of 2- (4-fluorophenyl) -1- (2-thienyl) ethanone, m.p. 61 to 62.5 ° C.

Analysis for C12HgFOS

Calculated: C 65.45, H 4.09

Found: C 65.45, H 4.06 C) 2-Bromo-2- (4-fluorophenyl) -1- (2-thienyl) ethanone

A solution of 71 g of 2- (4-fluorophenyl) -1- (2-thienyl) ethanone in 300 ml of chloroform was added to a suspension of 160 g of copper bromide in 500 ml of ethyl acetate with heating under vertical cooling. After the addition, under reflux, heating was continued for two hours, the mixture was cooled, filtered and dried over anhydrous potassium carbonate. The mixture was filtered and evaporated to give 96.0 g of a residue which was used without further purification.

D) 4- (4-fluorophenyl) -5- (2-thienyl) -1H-imidazole

A mixture of 2-bromo-2- (4-fluorophenyl) -1- (2-thienyl) ethanone and 400 ml of formamide was heated under reflux for 2 hours with an air condenser. The mixture was poured into 1.5 liters of water and ice, the product was filtered off, dried to give 41.2 g. This was chromatographed on 500 g of neutral alumina (Woelm, activity grade I) using dimethylformamide as solvent and eluent. The first fractions were diluted with ethyl acetate, filtered to give 19.2 g. This was recrystallized from acetonitrile to give 14.8 g, m.p. 163-164.5 ° C, dried in vacuo overnight, m.p. 198.5 to 200 ° C. Treatment of the filtrates gave an additional 4.5 solids, m.p. 197-198 ° C. The combined solids were crystallized from 350 ml of acetonitrile to give 16.4 g, m.p. 199-200 ° C.

E) 2- (4-fluorophenyl) -2-hydroxy-1- (2-thienyl) ethanone

To a solution of 70.0 g (0.32 mol) of 2- (4-fluorophenyl) -1- (2-thienyl) ethanone in 600 ml of ether was added dropwise at room temperature a solution of 56.0 g (0, 35 moles) of bromine in 120 ml of methylene chloride. The reaction mixture was evaporated in vacuo to give 123.0 g of 2-bromo-2- (4-fluorophenyl) -1- (2-thienyl) ethanol as an oil.

A solution of the above oily residue in 275 ml of ethanol was added to a solution of 1 mol of sodium ethoxide in ethanol, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into 3 liters of 0.3 M ice water to give 63.4 g of 2- (4-fluorophenyl) -2-hydroxy-1- (2-thienyl) ethanone, m.p. 90-92 ° C.

F) 4- (4-fluorophenyl) -5- (2-thienyl) -1H-2-imidazolithiol A mixture of 16.0 g of 4- (4-fluorophenyl) -5- (2-thienyl) -1H-imidazole and 4 g of sulfur in 100 ml of tetramethylenesulfone (freshly distilled) was heated for eight hours at 200 ° C, cooled, poured into water, filtered and dried. The residue was chromatographed by dissolving in 125 ml of dimethylformamide and draining through neutral alumina (Woelm, activity grade I), column diameter 60 mm and length 200 mm. The bright yellow zone was preceded by dark colored zones from which the resulting fractions were combined and evaporated. The yield was about 20 g. This and ethyl acetate were mixed and filtered, yield 14.3, m.p. 228-237 ° C. This is the dimethylformamide solvate of the product.

Alternatively, 63.4 g (0.27 moles) of 2- (4-fluorophenyl) -2-hydroxy-1- (2-thienyl) ethanone and 29.0 g (0.38 moles) of ammonium thiocyanate in 1-propanol were reacted. 71.6 g of 4- (4-fluorophenyl) -5- (2-thienyl) -1H-2-imidazolethiol, m.p. 275-277 ° C (recrystallized from 1-butanol).

Analysis for ci3H9FN2S2

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- (1,1,2,2-tetrafluoroethylthio) -5- (2-thienyl) -1H- imidazole

A solution of 14.0 g of 4- (4-fluorophenyl) -5- (2-thienyl) -1H-2-imidazoleethiol in 40 ml of dimethylformamide and 1.5 g of diisopropylamine was pressurized in a 4 g bomb. - 2 rafluoroethylene. The pressure decreased from 11.2 kp / cm in 1.5 hours to zero. The solution was poured into water, stirred until most of the gummy material had hardened, filtered and washed with water. The solid was dissolved in chloroform, dried over anhydrous sodium sulfate, evaporated and diluted with 1-chlorobutane. The crystalline product was isolated, yield 2.5 g, m.p. 164-168 ° C. The residue obtained from the filtrate was chromatographed on silica gel (Silicar CC-4) as chloroform as eluent to give 4.1 g, m.p. 167.5 to 170 ° C. The combined 6.5 g was crystallized from 1-chlorobutane to give 5.6 g, m.p. 167 to 168.5 ° C.

Analysis for ci5HgF5N2S2

Calculated: C 47.87, H 2.39, N 7.45

Found: C 48.24, H 2.58, N 7.83 69462

Example 3 4- (4-Fluorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) -5- (2-thienyl) -1H-imidazole

A mixture of 6.5 g of 4- (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5- (2-thienyl) -1H-imidazole in 160 ml of chloroform was stirred and 9 g were added. 85% m-chloroperoxybenzoic acid. Mild warming was observed. The mixture was allowed to stand for two days, 30 ml of dimethyl sulfide were added and warming was again observed. The mixture was cooled, filtered, the filtrate and water were mixed and the aqueous phase was basified with sodium bicarbonate. The organic layer was isolated, dried over sodium sulfate and evaporated. The solid was dissolved in 40 ml of hot 1-chlorobutane, treated with activated carbon (Darco), filtered and evaporated to one third volume. The yield of separable crystals was 2.1 g, m.p. 192-193 ° C.

Analysis for C 15 H 9 F 5 N 2 O 2 S 2

Calculated: C 44.11, H 2.22, N 6.68

Found: C 44.55, H 2.46, N 7.04

Example 4 4- (4-chlorophenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5- (2-thienyl) -1H-imidazole A) 2- (4-chlorophenyl) -1- (2- thienyl) ethanone

A mixture of 85.3 g of p-chlorophenylacetic acid and 200 ml of thiophene was stirred at 40 ° C and 105 g of trifluoroacetic anhydride were added. The mixture was heated under reflux for four hours. It was poured into ice water and basified with sodium carbonate. The mixture was extracted with dichloromethane, dried over potassium carbonate and evaporated. The yield of crude product was 126.4 g. The product was recrystallized from 300 ml to give 103 g, m.p. 98-99 ° C.

B) 2-Bromo-2- (4-chlorophenyl) -1- (2-thienyl) ethanone

A solution of 100 g of 2- (4-chlorophenyl) -1- (2-thienyl) ethanone in 400 ml of chloroform was added to a refluxing suspension of 200 g of cupric bromide in 650 ml of ethyl acetate. At the end of the addition, the mixture was heated under reflux for three hours. The mixture was cooled in an ice bath, filtered and the filtrate was stirred with ice and water. The solution was neutralized with sodium bicarbonate. The organic layer was isolated and the aqueous layer was extracted twice with chloroform. The combined extracts were dried over anhydrous potassium carbonate, filtered and evaporated, yield 142 g. The product was used without further purification.

C) 4- (4-chlorophenyl) -5- (2-thienyl) -1H-imidazole A mixture of 35 g of 2-bromo-2- (4-chlorophenyl) -1- (2-thienyl) ethanone and 200 g of ml of formamide was heated under reflux for two hours with an air condenser. It was cooled, poured into water and the pH was adjusted to 8-9 with ammonium hydroxide. Chloroform was added to the solution, and a precipitate formed, which was isolated by filtration and washed with chloroform, yield 19.3 g. Recrystallized from dimethylformamide, filtered and washed with acetonitrile, yield 14.7 g, m.p. 244-245 ° C.

D) 4- (4-chlorophenyl) -5- (2-thienyl) -ΙΗ-2-imidazoleethiol A mixture of 9.4 g of 4- (4-chlorophenyl) -5- (2-thienyl) -1H-imidazole , 2 g of sulfur and 50 ml of tetramethylenesulfone were stirred under a nitrogen blanket and heated at 200 ° C for eight hours. Cooled, poured into water, filtered and washed well with water to give 11.5 g. This was dissolved in dimethylformamide and chromatographed on a column, 6 cm in diameter and 125 cm long, with alumina (Woelm neutral, activity grade I) dimethylformamide as eluent. Yield 3.6 g as dimethylformamide coupling product. The sample was dried by heating under high vacuum, m.p. 274.5 to 276 ° C.

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

A solution of 6.9 g of 4- (4-chlorophenyl) -5- (2-thienyl) -1H-2-imidazoleethiol in 40 ml of dimethylformamide and 1.5 nl of diisopropylamine was pressurized in a bomb with 3 g of tetrafluoroethylene. and shaken until the pressure no longer dropped. 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 evaporated. The residue 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 were obtained, m.p. 161.5 to 163 ° C.

Analysis for C15HgClF4N2S2

Calculated: C 45.86, H 2.31, N 7.13

Found: C 46.06, H 7.40, N 16.44 16 69462

Example 5 2- (1,1,2,2-Tetrafluoroethylsulfonyl) -4,5-bis- (2-thienyl) -1H-imidazole

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

Excess oxidant was removed by stirring and adding 10 ml of methyl sulfide, stirring for one hour and evaporating. The residue and ether were mixed and filtered to remove insoluble solids which were not the desired product. The ether filtrate was evaporated, the residue was dissolved in chloroform, aqueous potassium bicarbonate solution was poured on, stirred, isolated and evaporated, yield 1 g. This was chromatographed on a silica gel column (Silicar CC-4, diameter 3 cm and length 27 cm) to a product which was crystallized from ethyl acetate, washed with 1-chloroburan to give 0.282 g, m.p. 163-165 ° C. An additional 0.196 g of filtrate was obtained.

In another experiment, 4.0 g (11 mmol) of 2- (1,1,2,2-tetrafluoroethylthio) -4,5-bis- (2-thienyl) pH-imidazole were oxidized at 7.3 ° C in an ice bath. .8 mmol) of 82.2% m-chloroperoxybenzoic acid in methylene chloride. The m-chlorobenzoic acid was removed by filtration and the filtrate was washed with 10% aqueous sodium bicarbonate solution. The methylene chloride solution was dried over anhydrous potassium carbonate, evaporated to give 3.2 g of an oil which was crystallized from 1-chlorobutane. Recrystallization from toluene-ethyl acetate gave 1.5 g of 2- (1,1,2,2-tetrafluoroethylsulfonyl) -4,5-bis- (2-thienyl) -1H-imidazole, mass spectrum = 396.

An analytical sample was prepared by chromatography on Silicar No. 7 with chloroform as eluent, m.p. 167-168 ° C.

Analysis for C

Calculated: C 39.39, H 2.02, N 7.07

Found: C 40.06, H 2.06, N 7.42

Example 6 4- (3,4-Dichlorophenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5- (2-thienyl) -1H-imidazole A) 2- (3,4-dichlorophenyl) -1 - (2-thienyl) ethanone 69462 Using the procedure of Example 4A, 100.0 g of 3,4-dichlorophenylacetic acid, 242.0 g of thiophene and 144.0 g of trifluoroacetic anhydride gave 61.7 g of 2- (3,4-dichlorophenyl) from methanol. ) -1- (2-thienyl) -ethanone, m.p. 59.5 to 60.5 ° C.

Analysis for C 23 H 19 Cl 2 O Calcd: C 53.14, H 2.95

Found: C 53.24, H 2.95 B) 2- (3,4-dichlorophenyl) -2-hydroxy-1- (2-thienyl) ethanone 57.0 g (0.21 mol) of 2- ( 3,4-dichlorophenyl) -1- (2-thienyl) -ethanone, m.p. 108-109 ° C (recrystallized from 1-chlorobutane) by the method described in Example 3E.

Analysis for C 8 H 8 Cl 2 2 2 2 2

Calculated: C 50.17, H 2.99

Found: C 50.34, H 2.86 C) 4- (3,4-dichlorophenyl) -5- (2-thienyl) -1H-2-imidazole thiol

According to the procedure described in the second paragraph of Example 3F, 45.0 g (0.16 mol) of 2- (3,4-dichlorophenyl) -2-hydroxy-1- (2-thienyl) ethanone and ammonium thiocyanate were reacted in 1-propanol at reflux temperature. to give 32.6 g of 4- (3,4-dichlorophenyl) -5- (2-thienyl) -ΙΗ-2-imidazoleethiol, m.p. 263-265 ° C (recrystallized from 1-butanol).

Analysis for ci3Hgcl2N2S2. 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) - H-imidazole

30.0 g (92 mmol) of 4- (3,4-dichlorophenyl) -5- (2-thienyl) -1H-2-imidazolithiol and 15.0 g of tetrafluoroethylene were reacted as described in Example 4E, chromatographed on Silicar: o 7 in chloroform as eluent to give 19.1 g of 4- (3,4-dichlorophenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5- (2-thienyl) -1H-imidazole, mp. 178-180 ° C (recrystallized from toluene).

Analysis for C 15 H 8 F 4 Cl 2 N 2 S 2 Calculated: C 42.15, H 1.87, N 6.56

Found: C 42.88, H 2.03, N 6.57

Example J7 4- (3,4-Dichlorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) -5- (2-thienyl) -1H-imidazole __ - τρ ie 69462

Oxidation of 5.0 g (11.7 mmol) of 4- (3,4-dichlorophenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5- (2-thienyl) -1H-imidazole 6.1 g (29 mmol) of 82.2% m-chloroperbenzoic acid according to the method described in the second paragraph of Example 5. The crude product was purified by chromatography on Silicar CC-7 as chloroform as eluent to give 1.4 g of 4- (3,4-dichlorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) -5- (2-thienyl) - 1H-imidazole, m.p. 158-159.5 ° C (recrystallized from toluene).

Analysis for C 15 H 8 Cl 2 F 4 N 2 O 2 S 2 Calculated: C 39.2, H 1.74, N 6.1 Found: C 39.83, H 1.96, N 6.07

Example 8 4- (4-Methoxyphenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5- (2-thienyl) -1H-imidazole

Using a series of reactions similar to Example 6, 4-methoxyphenylacetic acid gave the following compounds.

A) 2- (4-methoxyphenyl) -1- (2-thienyl) ethanone, m.p. 75-77 ° C (recrystallized from methanol).

Analysis for C 23 H 22 O 2 S Calculated: C 67.24, H 5.17

Found: C 67.11, H 5.29 B) 2- (4-methoxyphenyl) -2-hydroxy-1- (2-thienyl) ethanone, m.p. 69-73 ° C (recrystallized from 1-chlorobutane).

Analysis for C 13 H 12 O 3 S Calculated: C 62.90, H 4.84

Found: C 62.15, H 4.78 C) 4- (4-methoxyphenyl) -5- (2-thienyl) -ΙΗ-2-imidazolithiol, m.p. 266-268 ° C (recrystallized from ethanol).

Analysis of ci4Hi2N2OS2

Calculated: C 58.33, H 4.17, N 9.72

Found: C 58.37, H 4.27, N 9.49 D) 4- (4-methoxyphenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5- (2-thienyl) -1H- imidazole, m.p. 112-113.5 ° C (chromatographed on Silicar CC-7 as chloroform as eluent and recrystallized from 1-chlorobutane).

Analysis cxgH ^ 2F4N2OS2

Calculated: C 49.48, H 3.09, N 7.22

Found: C 49.92, H 3.21, N 721 and 69462

Example 9 4- (4-Methoxy (phenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) -5- (2-thienyl) -1H-imidazole 4.0 η (10-3 nunols) were oxidized ) 4- (4-methoxyphenyl) -2- (1,1,2,2-tetrafluoroethylthio) -5- (2-thienyl) -1H-imidazole from 6.1 g (29 nols) of 82.2% m-Chloroperbenzoic acid and crude product from 82.2% m-Chloroperbenzoic acid and crude product were purified by chromatography on Silicar CC-7 as chloroform as eluent to give 1.3 g of 4- (4-methoxyphenyl) -2- (1.1.2 , (2-tetrafluoroethylsulfonyl) -5- (2-thienyl) -1H-imidazole, mp 163-164.5 ° C (recrystallized from chlorobutane).

Analysis for C 16 H 12 F 4 N 2 O 3 S 2 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-furyl) -2- (1,1,2,2-tetrafluoroethylthio) -1H-imidazole A) 4,5-Bis- (2-furyl) -1H-2-imidazolithiol

19.2 g (0.1 mol) of β-furoine and 11.5 g (0.15 mol) of ammonium thiocyanate in refluxing ethanol were reacted to give 11.4 g of 4,5-bis- (2-furyl) -1H- imidazole-2-thiol.

An analytical sample was prepared by chromatography on alumina with ethanol as eluent and recrystallized from nitromethane, m.p. 279-380 ° C (decomposes).

Analysis cnHgN2 ° 2S

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- (1,1,2,2-tetrafluoroethylthio) -1H-imidazole

8.1 g (39.4 mmol) of 4,5-bis- (2-furyl) -1H-2-imidazolethiol and 7.0 g of tetrafluoroethylene were reacted and the product was purified by chromatography on Silicar CC-7 as chloroform as eluent to give 3 0.0 g of 4,5-bis- (2-furyl) -2- (1,1,2,2-tetrafluoroethylthio) -1H-imidazole, m.p. 166-167 ° C (recrystallized from 1-chlorobutane).

Analysis for C 13 H 8 F 4 N 2 O 2 S

Calculated: C 47.99, H 2.41, N 8.43

Found: C 47.13, H 2.81, N 8.45 20 69462

Example 11 4-Phenyl-5- (3-pyridyl) -2- (1,1,2,2-tetrafluoroethylthio) -1H-imidazole A) 4-Phenyl-5- (3-pyridyl) -1H-2-imidazolethiol

A solution of 30.0 g (0.15 mol) of 3-pyridylbenzyl ketone (A. Burger and CR Walter Jr., J. Am. Chem. Soc., 72, 1988 (1950)) in 300 ml of acetic acid was treated dropwise at room temperature with a solution of 25.0 g (0.16 mol) of bromine in 240 ml of acetic acid. After stirring overnight, 26.8 g of 3-pyridyl-Oc-bromobenzyl ketone hydrobromide were obtained as a precipitate, which was isolated by filtration.

A mixture of 5.0 g (14.0 mmol) of the salt obtained above and 0.1 mol of sodium ethoxide in 100 ml of a solution containing ethanol was stirred overnight at room temperature and poured into 0.5 M aqueous hydrochloric acid. After stirring for several hours, the acidic aqueous solution was basified with solid sodium carbonate and the product was extracted into ether. The ether was dried over anhydrous potassium carbonate and removed in vacuo to give 4.5 g of 3-pyridyl-β-hydroxybenzyl ketone.

Alternatively, a mixture of 20.0 g (56.0 mmol) of 3-pyridyl-α-bromobenzyl 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 was 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. The residue was dissolved in 140 ml of 1N aqueous hydrochloric acid solution and heated under reflux for 30 minutes and, after cooling, basified with solid sodium carbonate. The product was extracted into ether, the combined ether extracts dried over anhydrous potassium carbonate and evaporated to give 8.15 g of 3-pyridyl -, - X-hydroxybenzyl ketones.

8.15 g (38.3 mmol) of 3-pyridyl-N, hydroxybenzyl ketone and 7.5 g (0.1 mol) of ammonium thiocyanate in refluxing 1-propanol were reacted to give 4.3 g of 4-phenyl 5- (3-pyridyl) -1H-2-imidazolithiol, m.p. 317-323 ° C recrystallized from DMF (2: 1).

69462 21

Analysis of ci4HnN3S

Calculated: C 66.40, H 4.35, N 16.60

Found: C 65.92, H 4.53, N 16.34 B) 4-Phenyl-5- (3-pyridyl) -2- (1,1,2,2-tetrafluoroethylthio) -1H-imidazole

2.0 g (7.9 mmol) of 4-phenyl-5- (3-pyridyl) -1H-2-imidazolithiol and 5.0 g (50 mmol) of tetrafluoroethylene were reacted and the crude product was purified by chromatography on Sili-car CC -7 in chloroform as eluent to give 800 mg of 4-phenyl-5- (3-pyridyl) -2- (1,1,2,2-tetrafluoroethylthio) -1H-imidazole, m.p. 153-154 ° C (recrystallized from toluene).

Analysis for c16HnF4N3S

Calculated: C 54.39, H 3.12, N 11.90

Found: C 54.69, H 3.37, N 11.69

Example 12 2- (Trifluoromethylthio) -4- (4-fluorophenyl) -5- (3-pyridyl) -1H-imidazole

The title compound was prepared from 4- (4-fluorophenyl) -5- (3-pyridyl) -1H-imidazole-2-thiol using CF 2 I as the alkylating agent / method: V.N. Boiko, G.M.Shchubak and L.M. Yagupol'skii,

Zhur. Org. Khim. 3 ^ 3 (5), 1057-1061 (May 1977) y. Yield 13%, m.p. 194-195 °.

Example 13 2- (1,1,2,2-Tetrafluoroethylthio) -4- (4-fluorophenyl) -5- (3-pyridyl) -1H-imidazole was prepared in a similar manner, m.p. 150-152 °.

Claims (3)

A process for the preparation of anti-inflammatory 4,5-diaryl-2- (substituted thio, sulfinyl or sulfonyl) imidazole derivatives of the formula * 2 (1) -S (O) n -R 1 IR R 3 1H where n is an integer from 0 to 2 is polyfluoro-C 1 -C 4 -alkyl, R 2 is 2-thienyl, 2-furyl, phenyl or 4- fluoro, 4-chloro, 3,4-dichloro or 4-methoxyphenyl and R 1 is 2-thienyl, 2-furyl or 3-pyridyl, or a pharmaceutically acceptable acid addition salt thereof, when n is 0 or R 1 is 3 -pyridyl, or for the preparation of their pharmaceutically acceptable metal salts when n is 1 or 2, characterized in that the compound of formula R / N 2 "" 3 H where R 2 and R 2 are as defined above is reacted with a polyfluorinated olefin and the substituted thioimidazole formed is optionally oxidized with a suitable oxidant and the resulting compound is converted to a pharmaceutically acceptable salt if desired.