IE46187B1 - Anti-inflammatory 4,5-dicyclic-2-(substituted thio)-imidazoles and their corresponding sulfoxides and sulfones - Google Patents

Abstract

The novel compounds having anti-inflammatory activity are of the formula R1 to R4 and n are defined in Patent Claim 1. The same activity is also exhibited by the pharmaceutically acceptable acid addition salts of the compounds mentioned, in which n has the value 0 or in which at least one of the radicals R2 and R3, independently, represents 3-pyridyl, and the pharmaceutically acceptable metal salts of the compounds mentioned, in which R4 is hydrogen and n has the value 1 or 2.

Description

This invention relates to anti-inflammatory imidazoles.

Lombardino, in U.S. Patent Specification 3,707,475 discloses anti-inflammatory 4,5-diary1-2-substituted imidazoles.

Doebel, in U.S. Patent Specifications 3,505,350 and 5 3,651,080, respectively, discloses anti-inflammatory 4alkyl-5-aryl-substituted-2-mercapto-imidazoles and 4-alkyl2-alkylthio-5-ary1-1-substituted imidazoles.

Zauer, K., et al., in Chem. Ber., 106, 1638 (1973) disclose 4,5-bis(4-methoxyphenyl)-2-methy1thioimidazole and 4,5-bis(410 chlorophenyl)-2-methylthioirnidazole but do not suggest any use.

A number of references, such as Current Sci. India, 17, 18485 (1948) and Acta. Chem. Acad. Sci. Hung., 79(2) 197/212. (1973) disclose 2-(substituted-thio)-4,5-diphenyl imidazoles with substituents such as methyl, propyl, allyl, and acetonyl.

There is a continuing need for safe and effective antiinflammatory agents.' Inflammation is a disease process characterised by redness, fever, swelling, and pain.

Arthritis, in its various forms, is the most prevalent, chronic,and severe of the inflammatory diseases. Traumatic injury and infection also involve inflammation, and anti-21618 7 inflammatory drugs are often used in their treatment. The usefulness of most commercial anti-inflammatories is limited because of toxicity and adverse side-effects. Many produce gastric irritation and other effects, such as changes in blood cells and central nervous system. Adrenocortical steroids produce gastric irritation and supression of normal adrenal function.

The present invention results from efforts to develop new anti-arthritic compounds with good anti-inflammatory activity and minimal side effects that could be more effective in treating arthritis than presently available drugs.

In addition to anti-inflammatory properties, some compounds of this invention have demonstrated analgesic activity in a test procedure. This additional property is desirable in treatment of inflammations such as arthritis or related diseases; however, such compounds can be employed solely to alleviate pain.

According to this invention there is provided compounds of formula I, pharmaceutical compositions containing them, and methods of using them to treat inflammation, especially arthritis in mammals. For legal reasons, we claim hereinafter the treatment of non-human mammals, but the compounds of formula I are believed to be of interest for human therapy also. -346187 -s(0)nwhere n is 0, 1 or 2; Rj is polyfluoro-Cj— C2 alkyl; R2 and Rg are the same Or different and are 2-thienyl, 3-thienyl, 3-pyridyl, l-oxido-3-pyridyl, 2-furyl or where Yj and Y2 are the same or different and are H, Cj - C4 alkoxy, Cj - alkyl, Cl, F, or Yj and Y2 taken together form a methylenedioxy bridge, provided that only one of R2 or Rg can be -446187 and is hydrogen; 2-tetrahydropyranyl; 2-tetrahydrofuranyl; — COR?; — CRy, -CAr, or - S02Ar; where Rg is H or methyl; Rg is Cj-Cg alkyl, benzyl, CHgCHgOCHg or - CR?; Ry is C1 - C4 alkyl or benzyl; and Ar is // where -546187 y3=h, f, ci provided when R4 is — COR·,, Br, C-j— C4 alkyl, ^-C^ alkoxy, or nitro; -C-R7, -C-Ar, or - SOgAr, then ! n must be 0; or a pharmaceutically suitable acid addition salt thereof where n is 0 or where at least one of Rg or Rg, independently, is 3-pyridyl; and a pharmaceutically acceptable metal salt thereof where R4 is hydrogen and n is 1 or 2.

Tautomers When Rg and R3 are different and R^ is hydrogen, the following two structures are tautomers: -646187 Pharmaceutical Salts Pharmaceutically suitable acid addition colt, of coni'ounds where n is 0 or where at least one of Rg and R3, independently, is 3-pyridinyl include those made with physiologically acceptable acids and such salts include the hydrochloride, sulfate, phosphate and nitrate.

Pharmaceutically suitable metal salts of compounds where R^ is hydrogen and n is 1 or 2 include those of certain metals, such as sodium, potassium and calcium.

Preferred Compounds Compounds preferred for their anti-arthritic activity are those where R^ is -CFgCFgH, or -CFg.

Also preferred are those compounds where Rg and R3, independently are 2-thienyl or 3-pyridyl.

Also preferred are these compounds where Rg or R3 is -74β1θ7 where Y1 is H, Cl, F or CHgO.

Also preferred are those compounds where is hydroge ethoxycarbonyl, benzyloxymethyl, acetyl, benzoyl, or 2 tetrahydrofuryl.

More preferred are these compounds where R-| is CFgCFgH or CF^; R2 and R3, independently are 2-thienyl, 3-pyridyl o .Y where Y^ is H, Cl, F or CHjO and provided that only one of Rg or R3 can be -846187 Yj is H, Cl, F or CHgO; and R4 is hydrogen, benzyloxymethyl, ethoxycarbonyl, acetyl, benzoyl, 2-tetrahydrofuranyT.

Specifically preferred are the following compounds: (a) 4 - (4 - fluorophenyl) - 2 - (1,1,2,2tetrafluoroethylsulfonyl) -5-(2- thienyl) - IHimidazole; (b) 4-(4- fluorophenyl) - 5 - (2-thienyl) -2trifluoromethyl-sulfonyl-IH-imidazole; (c) 4-(4- methoxyphenyl) -5-(2- thienyl) -2trifluoromethyl - sulfonyl - IH - imidazole; (d) 4,5-bis-(2-thienyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)-IH-imidazole; (e) 4-(4 -methoxyphenyl) - 2 - (1,1,2,2 - tetrafluoroethyl15 sulfonyl) -5-(2- thienyl) - IH - imidazole; (f) 4 -(3,4-dichlorophenyl) - 2 - (1,1,2,2-tetrafluoroethylsulfonyl) -5-(2- thienyl) - IH - imidazole. -946187 Synthesis Compounds of formula I can be prepared as follows: a 4,5dicyclic imidazole of the formula where R2 and R3 are defined above prepared as described in Brederick, H., et al., Chem. Ber., 86, 88(1953)is reacted with sulfur at temperatures in the range of 150300° either with or without solvent to form a 2mercaptoimidazole. One suitable solvent for this reaction is tetramethylene sulfone. This procedure is analogous to the conversion, of 1-methylbenzimidazole to 2-mercapto1-methylbenzimidazole as described in A.V.El'tsov and K.H. Krivozheiko, ZH.Or.Kh. 2, 189(1966). 4,5-Disubstituted-2-mercaptoimidazoles can also be prepared by reaction of compounds of the formula r2— CH—c— r3 -1046187 or oh q ι II r3- ch- c- r2 [r^ and Rg are described above; various synthesis of 5 compounds of this type are described in Ide, U.S. and Buck, J.S., Organic Reactions, Vol. IV, p. 269J with thiourea in refluxing dimethylformamide or other highboiling, polar solvents. A similar condensation procedure is described in Kochergin, P.M. Zhur, Obschei Khim., 31, 1093 (1961); Chem. Abstr. 55, 23503F.

Preferably, reaction of the acyloins above with ammonium thiocyanate at lower temperatures in polar solvents such as ethanol or 1-propanol can be used to prepare 4,5disubstituted, 2-mercaptoimidazoles.

The appropriate R1 group can be introduced with a suitable alkylating agent such as tetrafluoroethylene, difluorocarbene or 2,2,2,- trifluoroethyltrichloromethane sulfonate. Similar addition reactions 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). For the purpose of this disclosure tetrafluoroethylene and other fluorinated olefins used are considered alkylating agents. -1146187 In certain instances a polyhaloalkyl moiety can be further modified chemically in forming the R-j constituent of formula I. For example, imidazoles containing the 2-(2bromo-1,1,2-trifTuoropthylthio) substituent can be converted to 2-(1,1,2-trifluoroethylthioJimidazoles by reduction with tri-n-butyltin hydride or other suitable reducing agents.

The imidazoles of the formulae: (where Het. is heterocyclic defined by Rg and R3 of formula 10 I) can be oxidized to the corresponding sulfoxide or sulfone by using oxidizing agents such as m-chloroperoxybenzoic acid, Tweit, R. C. et al., J.Med. Chem., 16, 1161 (1973), sodium metaperiodate, Leonard, N.V. and Johnson, C.R., J.Org. Chem., 27,282 (1962), hydrogen peroxide, Kochergin, P.M. and -1246187 Shchukina, M.N., Gen. Chem. U.S.S.R. 25,2289 (1955) or potassium permanganate, Rapp, K.E. et al. loc, cit.

When R2 or R3 of formula I are pyridyl, the oxidation can convert the pyridyl group to the N-oxide as the -S — is converted to sulfoxide or sulfone. In such a case, the l-oxido-3-pyridyl group can be converted back to the free 3-pyridyl group by treating with a mild reducing agent such as a tri-alkoxy phosphite or triphenyl phosphine or tri-n-butyl phosphine or other mild reducing agent without reducing the sulfone function.

The appropriate R^ substituent can often be introduced by direct alkylation, acylation, or sulfonylation of the compounds of formula I where R^ is H. This reaction can be carried in the absense or presence of a base, such as potassium carbonate, pyridine, triethylamine, potassium t-butoxide or methyl lithium. The reaction can be run neat, using the reagent as solvent, or in the presence of an inert solvent, including but not limited to dimethylformamide, glyme, THF, pyridine and methylene chloride. The temperature of the reaction can be in the range -78°C to the boiling point of the solvent or reagent, if used in excess as the solvent. Examples of alkylating, acylating and sulfonylating agents that can be employed are aralkoxymethyl halides, such as benzyloxymethyl chloride; -1346ΐθ7 acyloxymethyl halides, such as chloromethyl pivalate; dihydropyran; 2-chlorotetrahydrofuran; alkyl chloroformates, such as ethyl chloroformate; alkanoic anhydrides and alkanoyl halides, such as acetic anhydride; aroyl halides, such as benzoyl chloride, and arylsulfonyl halides, such as benzene-sulfonyl chloride.

Alternatively, the R^-substituent other than hydrogen of formula I can be introduced by first reacting a 4,5disubstituted imidazole with an appropriate reagent such as benzyl chloromethyl ether, 2-chlorotetrahydrofuran, dihydropyran, or benzenesulfonyl chloride. The resulting, 4,5-disubsituted-l- (substituted)imidazole is then treated with a strong base, such as n-butyl lithium, followed by a fluorinated alkysulfenyl halide, disulfide, or sulfonic anhydride. Typical of these reagents are CFjSCl, CFgSSCFj and (CF3S02)20 . Optionally, the choice of the protecting group and the workup conditions allows isolation of the desired •4.5-dicyclic-2-(substituted thio or sulfonylJimidazole with R^ is H directly. Compounds where R^ is CFg can be conveniently prepared by this method.

Preparation of pharmaceutically suitable salts of formula I can be in accordance with well-known techniques of forming salts. -1446187 The preparation of these compounds is further illustrated by the following non-limiting examples. Parts are by weight and temperatures are in cendgi ade unite. _ otherwise specified.

A) 4,5-bis-(2-Thienyl)-lH-imidazole A mixture of 31.6 g of α-thienoin and 175 ml of formamide was refluxed while stirring beneath an air condenser for two hours. The resulting dark solution was poured into 600 ml of cold water, stirred and filtered. The product was a semi-solid which slowly hardened; yield 27.6 g. This was dissolved in 35 ml of hot dimethylformamide. The product crystallized on cooling, and was filtered and washed with dimethylformamide and acetonitrile. The yield was 11.1 g, m.p. 218 - 221.5°C. A further quantity of product was isolated from the filtrates by chromatography on alumina.

B) 4,5-bis(2-Thienyl)-1H 2-imidazolethiol A mixture of 12 g of 4,5-bis-(2-thienyl)-1H-imidazo1e, 250 ml of tetramethylene sulfone (purified), and 2.5 g of sulfur was heated at 170°C for 24 hours in a nitrogen atmosphere, then 2 g more sulfur was added and the heating continued 19 hrs. The mixture was cooled, poured into 2 1 water, filtered, washed and dried. The dried product (9.8 g) was dissolved in dimethylformamide and poured on a column of alumina and eluted with dimethylformamide.

The product came off with the first cuts, and after evaporating and stirring with acetonitrile and filtering 5.3 g of product was obtained, melting 213 - 218°. A thin layer chromatograph shows this to be a mixture of the starting material and the desired thiol. A small portion of the crude compound chromatographed in the same way gave 1.02 g, m.p'. 283 - 290°C.

Alternatively, a mixture of 27.9 g (0.25 mole) or 2thienoin and 13.3 g of ammonium thiocyanate in 150 ml of 1-propanol was heated at reflux overnight, cooled and then 22.7 g of 4,5-bis(2-thienyl)-lH£-imidazolethiol was collected by filtration, m.p. 294 - 303° (dec).

(Recrystailized from 1-butanol).

Anal.

Calc'd. for cnHgN2S3: C, 50.00; H, 3.03; N, 10.61.

Found: 50.15; H, 3.15; N, 10.73.

C) 2- [(1 ,1,2,2-Tetrafluoroethyl )thioJ -4,5-bis-(2-thieny1)- IH imidazole -1646187 A 6.0 g portion of the above products was dissolved in 50 ml of dimethylformamide and 2 ml of diisopropyl amine and placed in a bomb tube and pre-surea with g of tei.rafluoroethylene. The pressure was 220 psi and on shaking dropped to 162 psi in 23 minutes. The temperature was in the range 25 - 28°C. The bomb was shaken for 4.5 hrs longer and the pressure remained unchanged. The dimethylformamide solution was removed from the bomb tube, poured into water, the product filtered and washed with water - yield 6.9 g, m.p. 131.5 - 142°C. This was chromatographed on a silica gel column (Silicar CC-4) and eluted with chloroform to yield 3.1 g, m.p. 161.5 - 163.5°C. Recrystallization from toluene gave an analytical sample, m.p. 166-7°.

Anal. Calc’d for C13H8F4^2^3 ’ c, 42,86; H, 2.20; N. 7.69 Found: c, 42.86; H, 2.28; N, 7.76 EXAMPLE 2 4-(4-Fluorophenyl)-2-(1,1,2,2-tetrafluoroethy1thio)-5-(2-thieny1)-1H-imidazole A) 2-Dimethyl ami no-2-(2-thieny1) acetonitrile -1746187 A solution of 131.5 g of dimethylamine hydrochloride in 200 ml of water was stirred and 59 g of sodium cyanide added. A solution of 112 g of 2-thiophenecarboxaldehyde in 100 ml of methanol was added from a dropping funnel while the temperature was kept below 30°C. The mixture was then maintained at 30°C for 4 hours; it was then poured into 3 1 of water.

The water was extracted with ether, the ether extract was washed with water, saturated sodium bisulfate sClution and last by water. The ether was dried over anhydrous magnesium sulfate and concentrated to give 156.5 g of yellow oil.

B) 2-(4-Fluorophenylj-1-(2-thienyl)ethanone A suspension of 15 g sodium hydride in 250 ml of dimethylformamide was stirred as 83.1 g of 2idimethylamino-2-(2-thienyl)acetonitrile in 300 ml of dimethylformamide was added. The mixture was stirred 1 hr. and Hg was evolved. To this stirred mixture was added 72.3 g of 4-fluorobenzyl chloride over a period of 1 hr. The temperature rose to 50°C during-the addition and the mixture was kept at 40-45°C for an additional hour. The mixture was partially concentrated under reduced pressure, poured into 500 ml of water; to this was added 500 ml of chloroform and 500 ml of concentrated hydrochloric acid. -1846187 The mixture was stirred and refluxed 24 hrs., cooled and separated. The water layer was extracted three times with chloroform and the chloroform extracts L'lrjineu and dried over anhydrous potassium carbonate. The dried extract was filtered and concentrated to give 103.9 g of dark oil. This was distilled at 0,2 mm to give 72.4 g of product, m.p. 60 - 62°C, Alternatively, to a mixture of 75.0 g (0.5 mole) of 4r fluorophenylacetic acid and 195.0g^of'Fhiophene warmed to 40°C was added dropwise 111.0 g (0.65 mole) of trifluoroacetic anhydride. The reaction mixture was heated at reflux for 3 hours, cooled and then poured into ice. The aqueous layer was made basic with sodium carbonate and the product was extracted into ether. The combined ether extracts were washed with water and, after drying over anhydrous potassium carbonate, were evaporated to give 112.0 g of an oil. Crystallization from methanol afforded 70.0 g of 2-(4-fluorophenyl)l-(2-thienyl)ethanone, m.p. 61 - 2.5°.

Anal.

Calc'd. for C12HgF0S: C, 65.45; H, 4.09; Found: C, 65.45; H, 4.06. -1946187 C) 2-Bromo-2-(4-fluoropheny1)-l-(2-thienyl)ethanone.

A solution of 71 g of 2-(4-f1uorophenyl)-l-(2-thienylethanone in 300 ml of chloroform was added to 160 g of cupric bromide suspended in 500 ml of ethyl acetate while the mixture was refluxing. Refluxing was continued 2 hrs. after the addition, and the mixture was cooled, filtered and dried over anhydrous potassium carbonate. The mixture was filtered and concentrated to give 96.0 g of residue which was used without further purification.

D) 4-(4-Fluorophenyl)-5-(2-thienyl)-lH-imidazole.

A mixture of 2-bromo-2-(4-fluorophenyl)-l-(2-thienyl)ethanone and 400 ml of formamide was refluxed beneath an air condenser for 2 hours. It was poured into 1.5 1 of water and ice and the product filtered and dried - yield 41.2 g. This was chromatographed on 500 g of neutral alumina (Woelm activity grade I) using dimethylformamide as the solvent and eluant. The first cuts were diluted with ethyl acetate and filtered to give 19.2 g. This was recrystallized from acetonitrile to give 14.8 g m.p. 163 - 164.5°C, which after drying in vacuum oven overnight melted 198.5 - 200°C.

A further work-up of filtrates gave 4.5 g more solid, 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-l-(2-thienyl)ethanone To a solution of 70.0 g (0.32 mole) of 2-(4-fluorophenyl-l-2046187 {2-thieny1)ethanone in 600 ml of ethanol was added dropwise a solution of 56.0 g (0.35 mole) of bromine in 120 ml of methylene chloride at room temperature. The reaction mixture was concentrated under vacuum to give 123.0 g of 2-bromo-2-(4-fluorophenyl)-1 -(2-thieny1) ethanone as an oil.

A solution of the residual oil above in 275 ml of ethanol was added to a solution of 1 mole of sodium ethoxide in 1 1 of ethanol and the mixture stirred overnight at room temperature. The reaction mixture was poured onto 3 1 of 0.3 M ice-water to give 63.4 g of 2-(4-fluorophenyl)2-hydroxy-l-(2-thienyl)ethanone m.p. 90 - 2°.

F) 4-(4-F1uorophenyl)-5-(2-thienyl)-lH-2-imidazolethiol A mixture of 16.0 g of 4-(4-fluorophenyl)-5(2-thienyl)IH-imidazole and 4 g of sulfur in 100 ml of tetramethylene sulfone (redistilled) was heated to 200°C for 8 hrs., cooled, poured into water and filtered and dried. This was chromatographed by dissolving it in 125 ml of dimethylformamide and passing it over a neutral alumina (Woelm activity grade 1) column 60 mm in diameter and 200 mm long. A bright yellow band led the dark-colored bands giving cuts which were combined and concentrated yield about 20 g. This was stirred with ethyl acetate and filtered - yield 14.3 g, m.p. 228 - 237°C. This is a dimethylformamide solvate of the product. -2146187 Alternatively, reaction of 63.4 g (0.27 mole) of 2-(4fluorophenyl)-2-hydroxy-l-(2-thienyl)ethanone with 29.0 g (0.38 mole) of ammonium thiocyanate in 1-propanol gave ! 7.16 g of 4-(4-fluorophenyl)-5-(2-thienyl)-lH-2-imidazolethiol, m.p. 275 - 277° (Recrystallized from l - butanol).

Anal.

Calc'd. for CjgHgFNgSg: C, 56.52; H, 3.26; N, 10.14 Found: C, 56.55; H, 3.42; N, 10.18.

G) 4-(4-F1 uorophenyl )-2-(1,1,2,2-tetrafluoroethylthio)-5(2-thienyl)-IH-imidazole.

A solution of 14.0 g of 4-(4-fluorophenyl)-5-(2-thienyl)ΙΗ-2-imidazolethiol in 40 ml of dimethylformamide and 1.5 g of diisopropylamine was pressured in a bomb with 4 g of tetrafluoroethylene. The pressure dropped from 160 psi to 0 in 1.5 hrs. The solution was poured into water, stirred until most of gum solidifed, filtered and washed with water.

The solid was dissolved in chloroform, dried over anhydrous sodium sulfate, concentrated and diluted with 1-chlorobutane. The crystalline product was collected; yield 2.5 g, m.p. 164 - 168°C. The residue from the filtrate was chromatographed on silica gel (Silicar CC-4) using chloroform to give 4.1 g, m.p. 167.5 - 17O°C. The combined 6.5 g was crystallized from 1-chlorobutane to give 5.6 g m.p. 167-168.5°C. -2246187 Anal.

Calc'd. for C15HgF5N2S2: C, 47.87; H, 2.39; N, 7.45.

Found: C, 48.24; H, 2.58; N, 7.83.

EXAMPLE 3 4-(4-Fluorophenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)- 5-(2-thienyl)-1H-imidazole A mixture of 6.5 g of 4-(4-fluorophenyl)-2-(1,1,2,210 tetrafluoroethylthio)-5-(2-thienyl)-lH-imidazole in 160 ml of chloroform was stirred as 9 g of 85% m-chloroperoxybenzoic acid was added. Slight warming was noted. The mixture was allowed to stand two days, then 30 ml of dimethyl sulfide was added, and warming was again noted. The mixture was cooled and filtered, and the filtrate was stirred with water and the water phase made basic with sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and concentrated. The solid was taken up in 40 ml of hot 1-chlorobutane, treated with activated charcoal (Darco), filtered and concentrated to 1/3 volume. Crystals separated; yield 2.1 g, m.p. 192 - 193°C.

Anal.

Calc'd. for 5H9F5N2°2S2: C, 44.11; H, 2.22; N, 6.86 -2346187 Found: C 44.55;' H, 2.46; N, 7.04 .EXAMPLE 4 4-(4-Chlorophenyl )-2-(1,1,2,2 -tetrafluoro5 ethylthio)-5-(2-thienyl)-lH-imidazole A) 2-(4-Chlorophenyl)-1 -(2-thieny1)ethanone A mixture of 85.3 g of p-chlorophenylacetic acid and 200 ml of thiophene was stirred at 40°C as 105 g of trifluoroacetic anhydride was added. The mixture was then refluxed for 4 hrs. It was poured into ice and water and made basic with sodium carbonate. The mixture was extracted with dichloromethane, dried over potassium carbonate and concentrated. The crude yield was 126.4 g. This was recrystallized from 300 ml of methanol 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 refluxed three hours. The mixture was cooled in an ice bath, then filtered and the filtrate stirred with ice and water. The solution was brought to a neutral pH by adding sodium bicarbonate. The organic layer was separated and -244 618 7 the water extracted two times with chloroform. The combined extracts were dried over anhydrous potassium carbonate, filtered and concentrated; yield 142 g. This product was used without further purification.

C) 4-{4-Ch1orophenyl)-5-(2-thieny1)-lH-imidazole.

A mixture of 35 g of 2-bromo-2-(4-chlorophenyl)-1-(2thienyl)ethanone and 200 ml of formamide was refluxed under an air condenser for two hours. It was cooled, poured into water and the pH adjusted to 8 — 9 by adding ammonium hydroxide. Chloroform was added to the solution, and solid separated and was filtered and washed with chloroform; yield 19.3 g. This was recrystallized from dimethylformamide, filtered and washed with acetonitrile; yield 14.7 g, m.p. 244 - 245°C.

D) 4-(4-Chlorophenyl)-5-(2-thienyl)-1H-2-imidazolethiol A mixture of 9.4 g of 4-(4-chlorophenyl)-5-{2-1hieny1)ΙΗ-imidazole, 2 g of sulfur, and 50 ml of tetramethylene sulfone was stirred under nitrogen and heated to 200°C for 8 hrs. It was 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 diameter by 125 cm long of alumina (Woelm neutral activity grade 1) using dimethylformamide to elute. A yield of 5.6 g was obtained as the dimethylformamide adduct. A -2546187 sample was dried by heating under a high vacuum, m.p. 274.5 - 276°C.

E) 4-(4-Chlorophenyl)2-(1,1,2,2-tetrafluoroethylthio)-5(2-thienyl)-lH-imidazole A solution of 6.9 g of 4-(4-chlorophenyl)-5-(2-thienyl)-lH2-imidazolethiol in 40 ml of dimethylformamide and 1.5 ml of diisopropylamine was pressured in a bomb with 3 g of tetrafluoroethylene and shaken until there was no further pressure drop. The bomb contents were poured into water, the pH adjusted to 8 and the solution extracted with chloro form. The extract was dried and concentrated. It was chromatographed on silica gel (Silicar CC-4) to give 5.5 g of a cut which was dissolved in hot 1-chlorobutane. On cooling 4.5 g of product was obtained, m.p. 161.5 - 163°C.

Anal.

Calc'd. . for C]5H9C1F4N2S2: c, 45.86 ; H, 2.31; N, 7.13; s, 16 Found: c, 46.06; H, 2.49; N, 7.40; s, 16 EXAMPLE 5 2-(1,1,2,2-Tetrafluoroethy1 sulfonyl )-4,5bis-(2-thienyl)-1H-imidazole A solution of 1.9 g of 2βΐ ,1,2,2-tetrafluoroethyl )thioj -4 -2646187 -bis-(2-thieny1)-1H-imidazole in 100 ral of chloroform was stirred as 2.3 g of m-chloroperoxybenzoic acid was added. The solution turned dark green. The mixture was allowed to stand at ambient temperature one week at which time 2 g more m-chloroperoxybenzoic acid was added and the mixture allowed to stand overnight.

The excess oxidant was then removed by stirring and adding 10 ml of methyl sulfide, stirring 1 hour and concentrating. The residue was stirred with ether, filtered to remove an insoluble solid which was not the desired product. The ether filtrate was concentrated, the residue dissolved in chloroform, over-layered with aqueous potassium bicarbonate, and stirred, separated and concentrated - yield 1 g. This was chromatographed on a silica gel column (Silicar CC-4 3 cm diameter by 27 cm long) to give a product which was crystallized from ethyl acetate, washed with 1-chlorobutane; yield 0.282 g, m.p. 163 - 165°C. A second crop of 0.196 g was obtained from the filtrate.

In another experiment, 4.0 g (11 mmoles) of 2-(1,1,2,220 tetrafluoroethylthio)- 4,5-bis-(2-1hieny1)-1H-imidazo1e was oxidized at ice-bath temperatures with 7.3 g (34.8 mmoles) 82.2% m-chloroperbenzoic acid in methylene chloride, mChlorobenzoic acid was removed by filtration and the filtrate was washed with 10% aqueous sodium bicarbonate -2746187 solution. The methylene chloride solution was dried over anhydrous potassium carbonate and evaporated to yield 3.2 g of an oil, which was crystallized with 1-chlorobutane. Recrystallization from toluene: ethyl acetate gave 1.5 g of 2-(1,1,2,2-tetrafluoroethyl sulfonyl )-4, -bis(2-thienyl)-lH-imidazole; mass spectrum=396.

An analytical sample was prepared by chromatography on Silicar CC=/#7 with chloroform, m.p. 167-8.

Anal.

Calc'd. for c13H8F4N202S3: 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.

Using the procedure described in Example 4A, 100.0 g of 3,4-dichlorophenylacetic acid, 242.0 g of thiophene and 144.0gof trifluoroacetic anhydride gave from methanol 61.7 g of 2-(3,4-dichlorophenyl)-1-(2-thienylJethanone, m.p. 59.5 - 60.5. -2846187 Anal.

Calc’d. for C^HgClgOS: C, 53.14; H, 2.95.

Found C, 53.24; H, 2.95.

B) 2-(3,4-Di chloro phenyl)-2-hydroxy)-1-(2-thienyl )ethanone 2-(3,4-Dichlorophenyl)-1 -(2-thienyl)ethanone (57.0 g; 0.21 mole) was converted to 49.8 g of 2-(3,4-dichlorophenyl)10 2-hydroxy-l-(2-thienyl)ethanone, m.p. 108 - 9° (recrystailized from 1-chlorobutane) by the procedure described in Example 2E.

Anal. Calc'd, , for C 12H 8C12°2 c, 50.17; H, 2.99. Found: c, 50.34; H, 2.86.

C) 4-(3,4-Di chlorophenyl )-5-(2-thienyl)-lH-2-imidazolethiol By the procedure described in the second paragraph of Example 2F, 45.0 g (0.16 mole) of 2-(3,4-dichlorophenyl)2-hydroxy-1-(2-thienyl)ethanone was reacted with ammonium thiocyanate in 1-propanol at reflux to afford 32.6 g of 4-(3,4-dichioropheny1)-5-(2-thienyl)-1H-2-imidazolethiol m.p. 263 - 5°. (recrystailized from 1-butanol). -2946187 Anal.

Calc’d, , for C13H£;ci2n2: 52: 1/2H2 c, 46.42; H, 2.69; N, 8.33. Found: c, 46.10; H, 2.82; N, 8.23.

D) 4-(3,4-Dichiorophenyl)-2-(1,1,2,2-tetrafluoroethylthio )5-(2-thienyl)-1H-imidazole 4- (3,4-Dichlorophenyl)-5 - (2-thieny1)-1H-2-imidazolethiol (30.0 g; 92 mmoles) was reacted with 15.0 g of tetra10 fluoroethylene as described in Example 4E to give, after chromatography on Silicar CC // 7 with chloroform, 19.1 g of 4-(3,4-dichlorophenyl)-2-(1,1,2,2-tetrafluoroethylthio) - (2-thienyl)-lH-imidazole, m.p. 178 - 180° (recrystallized from toluene).

Anal.

Calc'd. for C]gHgF4ClgNgSg: C, 42.15; H, 1.87; N, 6.56 Found: C, 42.88; H, 2.03; N, 6.57.

EXAMPLE 7 4-(3,4-Dichlorophenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)-5-(2-thienyl)-1H-imidazole 4-(3,4-Dichlorophenyl)-2-(1,1,2,2-tetrafluoroethy1 thio )-5(2-thienyl)-lH- imidazole (5.0 g; 11.7 mmoles) was oxidized -3046187 with 6.1 g (29 mmoles) of 82.2% m-chloroperbenzoic acid according to the procedure described in the second paragraph of Example 5 and the crude product was purified by chromatography on Silicar CC j—f- 7 with chloroform to afford 1.4 g of 4-(3,4-dichlorophenyl)-2-(l,1,2,2tetrafluoroethylsulfonyl)5-(2-thienyl)-1H-imidazole, m.p. 158 - 159.5° (recrystallized from toluene).

Anal.

Calc'd for CqgHgCl2F4N202S2: 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-tetrafluoro15 ethyl thio)-5-(2-thienyl)-lH-imi dazole A series of reactions similar to those described in Example 6 using 4-methoxyphenyl acetic add gave the compounds below. A) 2-(4-Methoxyphenyl)-1-(2-thienyl)ethanone m.p. 75 - 7° (recrystallized from methanol).

Anal.

Calc'd. for Cq3Hq202S: C, 67.24, H, 5.17.

Found : C, 67.11; H, 5.29. -3146187 Β) 2-(4-Methoxyphenyl)-2-hydroxy-l-(2-thienyl)ethanone m.p. 69 - 73° (recrystallized from 1-chlorobutane) Anal.

Calc'd. for C^H^OgS: C, 62.90; H, 4.84.

Found: C, 62.15; H, 4.78.

C) 4-(4-Methoxyphenyl)-5-(2-thienyl)-1H-2-imidazolethiol m.p. 266 - 268: (recrystallized front ethanol) Anal.

Calc'd. for C]4^2^20S2 ! 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° (chromatographed on Silicar CC # 7 with chloroform and recrystallized from 1-chlorobutane).

Anal.

Calc'd for C]6H-]2F4N20S2: C, 49.48; H, 3.09; N, 7.22.

Found: C, 49.92; H, 3.21; N, 7.21. -3246187 EXAMPLE 9 4-(4-Methoxypheny1)-2-(1,1,2,2-tetrafluoroethylsulfonyl )-5-(2-thienyl)-1H-imidazole. 4-(4-Methoxyphenyl )-2-(1,1,2,2-tetrafluoroethylthio)-5-(2thienyl)-lH-imidazole (4.0 g; 10.3 mmoles) was oxidized with .1 g (29 mmoles) of 82.2% m-chloroperbenzoic acid and the crude product was purified by chromatography on Silicar CC # 7 with chloroform to give 1.3 g of 4-(4-methoxyphenyl)2-(1,1,2,2-tetrafluoroethyl sulfonyl )-5-(2-thienyl)-1 Himidazole.m.p. 163 - 4.5° (recrystallized from chlorobutane).

Anal.

Calc'd. for C]βΗ]2F4N203S2: 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-Fury1)-2-(1,1,2,2-tetrafluoroethylthio )-1H-imidazole A) 4,5-bis-(2-Furyl)-lH-2-imidazolethiol α-Furoin (19.2 g; 0.1 mole) was reacted with 11.5 g (0.15 mole) ammonium thiocyanate in ethanol heated at reflux to afford 11.4 g of 4,5-bis-(2-fury1)-1H~2-imidazolethiol. An analytical sample was prepared by chromatography on alumina with ethanol and recrystallization from nitromethane, m.p. 279 - 380° (dec).

Anal.

Calc'd. for C11HgN202S: 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)-lHimidazole. 4,5-bis-(2-Furyl)-lH-2-imidazolethiol) 8.1 g; 39.4 mmoles) was reacted with 7.0 g of tetrafluoroethylene and the product purified by chromatography on Silicar CC=#7 with chloroform to give 3.0 g of 4,5-bis-(2-furyl)-2-(1, 1,2,2-tetrafluoroethylthio)-lH-imidazole, m.p. 166 - 167°: (recrystallized from 1-chlorobutane).

Anal.

Calc'd. for C^HgF^OgS: C, 47.99; H, 2.41; N, 8.43. Found : c, 47.13; H, 2.81; N, 8.45.

EXAMPLE 11 4-Phenyl-5-(3-pyridy1)-2-(1,1,2,2-tetrafluoroethyl thio)-!H-imidazole -3446187 A) 4-Phenyl-5-(3-pyridyl)-ΙΗ-2-imidazolethiol A solution of 30.0 g (0.15 mole) of 1 -(3-pyridyl)-2phenylethanone (A. Burger and C.R.Walter, Jr., J. Am.

Chem. Soc., 72 1988 (1950), in 300 ml of acetic acid was treated dropwise with a solution of 25.0 g (0.16 mole) of bromine in 240 ml of acetic acid at room temperature. After stirring overnight, a precipitate of 26.8 g of 1(3-pyridyl)-2-bromo-2-phenylethanone hydrobromide was collected by filtration.

A mixture of 5.0 g (14.0 mmoles) of the salt above with a solution of 0.1 mole of sodium ethoxide in 100 ml of ethanol was stirred overnight at room temperature and then poured onto 0.5 M aqueous hydrochloric acid. After stirring for several hours and acidic aqueous solution was made basic with solid sodium carbonate and the product extracted into ether. The ether was dried over anhydrous potassium carbonate and removed under vacuum to give 4.5 g of 1-(3-pyridyl)-2-hydroxy-2-phenylethanone.

Alternatively, a mixture of 20.0 g (56.0 mmoles) of 1-(3pyridyl)-2-bromo-2-phenylethanone hydrobromide and 24.0 g (0.24 mole) of potassium acetate in 100 ml of acetic anhydride was stirred overnight at room temperature. The reaction mixture was poured into water and the product extracted into ether. The combined ether layers were washed with water and then 10% aqueous sodium bicarbonate -35solution. The ether layer was dried over potassium carbonate and evaporated. A solution of the residue in 140 ml of IN aqueous ’hydrochloric acid was heated at reflux for 30 minutes and after cooling made basic with solid sodium carbonate. The product was extracted into ether and the combined ether extracts evaporated, after drying over anhydrous potassium carbonate, to give 8.15 g of 1 -(3-pyridyl)-2-hydroxy-2-phenylethanone. l-(3-Pyridyl-2-hydroxy-2-phenylethanone (8.15 g: 38.3 10 mmoles) was reacted with 7.5 g (0.1 mole) of ammonium thiocyanate in 1-propanol heated at reflux to give 4.3 g of 4-phenyl-5-(3-pyridyl)-lH-2-imidazolethiol, m.p. 317323° recrystallized from DMF:H20(2:l).

Anal.

Calc'd. for C-,4HqqNgS: C, 66,40, H, 4.35; N, 16.60.

Found: C, 65.92; 4.53; N, 16.34 B) 4-Phenyl-5-(3-pyridyl)-2-(1,1,2,2-tetrafluoroethylthio)20 IH-imidazole 4-Phenyl-5-(3-pyridyl)-lH-2-imidazolethio1 (2.0 g; 7.9 mmoles) was reacted with 5.0 g (50 mmoles) of tetrafluoroethylene and the crude product purified by chromatography 3646187 on Silicar CC & 7 with chloroform to afford 800 mg of 4-phenyl-5-(3-pyridyl)-2-(1,1,2,2-tetrafluoroethylthio)IH-imidazole, m.p. 153-154° (recrystailized from toluene).

Anal.

Calc’d. for C^H^F^S: C, 54.39; H, 3.12; N, 11.90.

Found: C, 54.69; H, 3.37; N, 11.69.

Tables I and II illustrate other compounds that can be 10 prepared by using the appropriate starting materials and the procedures described in the examples and in the Synthesis section. -3746187 -3846187 TABLE I (contd). -3946187 TABLE I (contd). ch2cf3 ch30- -CH2-0CH2' cf2chf2 CO // \ ch30 cf2chf2 CF, -4046187 TABLE I (contd) R, R/i CFgCHFg COCH, TABLE II -4146187 TABLE II (contd) CF2CF2H hcf2 -4246187 TABLE II (contd) π ]TjL cf2c»f2 -4346187 Dosage Forms The anti-arthritic and analgesic agents of this invention can be administered to treat inflammations such as arthritis and/or pain by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. The compounds of formula I have anti-arthritic properties and in addition some can be used to alleviate pain. They can be administered by any conventional means available for use in conjunction with pharmaceuticals; either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recepient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually a daily dosage of active ingredient can be 0.01 to 40 milligrams per kilogram of body weight. Ordinarily 0.05 to 20, and preferably 0.1 to 10 milligrams per kilogram per day given in divided doses 2 to 4 times a day or in sustained release form is effective to obtain desired results. -4446187 Dosage forms (compositions) suitable for internal administration contain e.g. from 0.1 milligrams to 500 milligrams of active ingredient Der unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of e.g. 0.5 - 95% by weight based on the total weight of the composition.

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

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, and stearic acid. Similar diluents can be used to make compressed tablets.

Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavouring to increase patient acceptance. -4546187 In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration contain preferably a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remingtons' Pharmaceutical Sciences, E.W.Martin, a standard reference text in this field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 50 milligrams of powdered active ingredient, 110 milligrams of lactose, 32 milligrams of talc, and 8 milligrams magnesium -4646187 stearate.

Capsules A mixture of active ingredient in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 50 milligrams of the active ingredient. The capsules are washed in petroleum ether and dried.

Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 50 milligrams of active ingredient, 7 milligrams of ethyl cellulose, 0.2 milligrams of colloidal silicon dioxide, 7 milligrams of magnesium stearate, 11 milligrams of microcrystalline cellulose, 11 milligrams of cornstarch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Injectable A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by filtration. -4746187 Suspension An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 10 milligrams of finely divided active ingredient, 500 milligrams of acacia, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P. 5 milligrams of sodium saccharin, and 0.025 milliliters of vanilla tincture.

Injectable A parenteral composition suitable for administration by 10 injection is prepared by dissolving 1% by weight of active ingredient in sodium chloride injection U.S.P. XV and adjusting the pH of the solution to between 6 and 7. The solution is sterilized by filtration.

Use To detect and compare the anti-inflammatory activities of compounds in this series and standard drugs, a test was used based on a standard model of arthritis for which there is good correlation with human efficacy. The model is adjuvantinduced arthritis in rats. Federation Proceedings, Vol. 32, No. 2 1973 “Models Used for the Study and Therapy of Rheumatoid Arthritis - Symposium of the American Society for Pharmacology and Experimental Therapeutics - states The rat polyarthritis produced by intradermal injection of a suspension of Mycobacterium tuberculosis in mineral oil -4846187 (adjuvant) has been used extensively for the screening of drugs of potential use in rheumatoid arthritis.

Established Adjuvant-Induced Arthritis in Rats Charles River Lewis male rats (130 - 150 grams) are injected subcutaneously in the plantar area of the right hind paw with 0.1 ml of adjuvant [Difco ( Trade Mark) heatkilled, lyophilized Mycobacterium butyricum suspended in mineral oil 5 mg/ml]. 20 Nonarthritic controls are injected with mineral oil. The animals are held for two weeks to allow development of arthritis. Paw volumes (uninjected, left hind paw) are measured and the adjuvent injected rats are culled and distributed to treatment groups of 10 of equal disease severity. Nonarthritic controls are distributed to two groups of 10. The rats are given oral doses of compound or PVA-Acacia (Polyvinyl Alcohol 1%, Gum Acacia, U.S.P. 5% , Methylparaben 0.5%) (10 ml/kg) by gavage on that day and on the six following days. One day after the last dose the paw volumes (uninjected, left hind paw) are measured using a Ugo Basile Volume Differential Meter Model 7101.

Arthritic Control Treatment Group Mean Paw Volume (ml) - Mean Paw Volume (ml) ___x 10 0= Arthritic Control — Non-Arthritic Control Mean Paw Volume (ml) Mean Paw Volume (ml) 4946187 % Decrease from Control Mean Paw Volume.

Dose-response regression lines of the percent decrease are plotted on semi-log paper by visual fit and the EDSO% decrease from control paw volume is determined by inspection. Data for some of the compounds in this invention are summarized in Table III.

Compounds from this series are many times more potent than aspirin and ibuprofen in the treatment of adjuvant arthritis in rats. Four compounds have been shown to be more potent than phenylbutazone and one compound has been shown to be more potent than indomethacin in this test system.

TABLE III Established Adjuvant-Induced Arthritis in Rats (A.A.) Chemical Example Number A.A.ED5OX* mg/kg 32'/ @ 50 mg/kg 1.3 0.1 12.0 2.2 -5046187 TABLE III (contd) Established Adjuvant-Induced Arthritis in Rats (A.A.) A.A. ED50%* mg/kg 50 34% 0 50 mg/kg <25 0.3 100 305 Chemical 5 Example Number 11 Indomethacin Phenylbutazone Ibuprofen 15 Aspirin * Determined as % paw volume reduction from control.

Phenylquinone Writhing Test A standard procedure for detecting and comparing the analgesic activity of compounds in this series for which there is good correlation with human efficacy is the standard phenylquinone writhing test modified from Siegmund, et al., Proc. Soc. Exp. Biol. Med. 95, 729 (1957). A test compound suspended in 1% methylcellulose was given orally to fasted (17-21 hours) female white mice, 5-20 animals per double blind test. Aqueous (0.0H -5146187 phenyl-p-benzoquinone) phenylquinone was injected intraperitoneally at 24 minutes later using 0.20 ml per mouse. Commencing at 30 minutes after the oral administration of the test compound, the mice were observed for 10 minutes for a characteristic stretching or writhing syndrome which is indicative of pain induced by phenylquinone. The effective analgesic dose for 50% of the mice (EDj-θ) was calculated by the moving average method of Thompson, W.R., Bact. Rev.11, 115-145 (1947). This data is summarized in Table IV.

TABLE IV Phenylquinone Writhing Test Chemical Example Number ED * tu50 1 1.6 3 2.1 5 <130 8 45 9 1.67 * units are in mg/kg at J hour.

Claims (2)

1. A compound of the formula where 5 n is 0, 1, or 2; R^ is polyfluoro-C-|-Cg alkyl; Rg and Rg are the same or different and are 2-thienyl, 3thienyl, 3-pyridyl, l-oxido-3-pyridyl, 2-furyl or 10 where and Yg are the same or different and are H, C^-C^ alkoxy, C^-C 4 alkyl, Cl or F, or Y 1 and Yg taken together form a methylenedioxy bridge, provided that only one of Rg or R 3 can be -5346187 and R 4 is hydrogen; -CHOR,, I 6 S 5 5 2-tetrahydropyranyl, 2-tetrahydrofuranyl, θ Q 0. II 11 II - CORy, -CRy, —SOgA r; -CAr, or where R 5 is H or methyl; Rg is C^-C 3 alkyl, benzyl, -CHgCHgOCH or 0 II -CRy; Ry is C 1 -C 4 alkyl or benzyl; and -5446187 Ar is where Y 3 is H, F, Cl, Br, C-j-C 4 alkyl,C-j-C^ alkoxy or nitro; provided when then II iS- CORy, -SOgAr, il Q, II or n must be 0; or a pharmaceutically suitable addition salt thereof where 10 n is 0 or where at least one of Rg or R 3 independently, is 3-pyridyl or a pharmaceutically suitable metal salt thereof where R 4 is hydrogen and n is 1 or 2. 2. The compound of Claim 1 where R^ is -CFgCFgH or -CFg. 3. The compound of Claim 1 or 2 where Rg and R 3 15 independently are 2-thienyl or 3-pyridyl. 4. The compound of any of the preceding claims where Rg or R 3 is -5546187 where Y } is H, Cl, F, or CHgO. 5. The compound of any of the preceding claims where R^ 5 is hydrogen, ethoxycarbonyl, benzyloxymethyl, acetyl, benzoyl or 2-tetrahydrofuranyl. 6. The compound of Claim 4 wherein R^ is hydrogen. 7. The compound of Claim 1 where R-, is -CFgCFgH or -CF 3 Rg and R. 3 , independently, are 2-thienyl, or 3-pyridyl, or where Y^ is H, Cl, F or CHgO provided that only one of Rg or R 3 can be -5646187 and is hydrogen,benzyloxymethyl , acetyl, benzoyl, or 2-tetrahydrofuranyl. 8. 4- (4-Fluorophenyl) - 2 - (1,1,2,2 - tetrafluoroethyl sul fonyl ) -5-(2- thienyl) - IH - imidazole. 5 9. 4-(4-Fluorophenyl) - 5 - (2- thienyl) - 2 trifluoromethylsulfonyl - IH - imidazole. 10. 4- (4 - Methoxyphenyl) -4-(2- thienyl) - 2 trifluoromethyl - sulfonyl - IH - imidazole. 11. 4,5 - bis - (2 - Thienyl) - 2 - (1,1,2,2 10 tetrafluoroethylsulfonyl) - IH - imidazole. 12. 4- (4 - Methoxyphenyl) - 2 - (1,1,2,2 tetrafluoroethylsulfonyl) -5-(2- thienyl) - IH imidazole. 13. 4- (3,4 - Dichlorophenyl) - 2 - (1,1,2,2 tetrafluoroethylsulfonyl) -5-(2- thienyl) - IH imidazole. -5746187 14. Pharmaceutically acceptable metal salts of the compounds of Claims 8-13. 15. Compounds of Claim 1 as hereinbefore specifically disclosed and pharmaceutically acceptable salts thereof where 5 such can be formed excepting the compounds of Claims 8-14. 16. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of the compound of Claim 1. 0 17. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of the compound of any of Claims 2-6. 18. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic 6 amount of the compound of claim 7. 19. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of the compound of Claim 8. 20. A pharmaceutical composition comprising a suitable 3 pharmaceutical carrier and an effective anti-arthritic amount of the compound of Claim 9. -5846187 21. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of the compound of Claim 10. 22. A pharmaceutical composition comprising a suitable 5 pharmaceutical carrier and an effective anti-arthritic amount of the compound of Claim 11. 23. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of the compound of Claim 12. 10 24. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of the compound of Claim 13. 25. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic 15 amount of the compound of Claim 14 or 15. 26. The composition of Claim 16 substantially as hereinbefore described. 27. The composition of any of Claims 16-25 in unit dosage form. 20 28. A method of treating inflammation in a non-human mammal which comprises administering to the mammal -5946187 an effective amount of the compound of any of Claims 1-7 or 15. 29. A method of treating inflammation in a non-human mammal which comprises administering to the mammal an effective amount of the compound of any of Claims 8-14. 30. A process for preparing a compound of Claim 1 which comprises contacting a compound of the formula where R 2 and R 3 a.re as defined in Claim 1 with an TO alkylating agent, effective to introduce a desired group, R-| as defined in Claim 1, then optionally contacting the resulting substituted-thioimidazole with an oxidizing agent effective to convert it to a compound of Claim 1 wherein n is 1 or 2 and, if desired, converting the ]5 product into a salt thereof. 31. A process for preparing a compound of Claim 1 which comprises contacting a compound of the formula -6046187 and R 4 is hydrogen where n, Rp Rg and R 3 are as defined in claim 1/, with either (a) a compound of the formula R 4 ‘ X where R^ 1 is -CHgORg, 5 2-tetrahydrofuranyl, 9. 0 II II II -COR?, -CRp -CAr or -SOgAr; and X is chlorine, bromine or iodine; 10 (b) dihydropyran; (c) (R 7 C)g-0; or (d) RgO-CH=CHg, where R g , R? and Ar are as defined in Claim 1, and, if desired, converting the product into a salt thereof. 32. A process for preparing a compound of Claim 1, where N,RpRg and R 3 are as defined in Claim 1 and -6146187 R 4 is-CHORg,hydrogen R 5 2-tetrahydropyranyl, 2-tetrahydrofuranyl, or 5 SOgAr, where Rg,Rg and Ar are as defined in Claim 1 which compri ses (a) contacting a compound of the formula where Rg and R 3 are as defined in Claim 1 with 10 (i) R 1 4 X where R'^is RgOCy -, 2-tetrahydrofuryl-, or ArSOg-; and X is chloride, bromine or iodine; (ii) dihydropyran; or (iii) RgOCH=CHg 15 where R g andAr are as defined in Claim 1; (b) contacting product of (a) with a base; and (c) contacting product of (b) with a fluorinated C-j-Cg alkyl sulfenyl halide, disulfide or sulfonic anhydride (d) optionally removing the R^ 1 group; 20 (e) optionally oxidizing the product of (d); and (f), if desired, converting the product into a salt thereof: -6246187 33. The process of Claims 29-31 including the step of converting the product into a salt thereof. 34. A process for preparing a compound of Claim 1, substantially as hereinbefore described. 5 35. The compound of Claim 1 wherein R 2 or R^ is not

2. -furyl and R 4 is hydrogen, methoxymethyl, benzyloxy-methyl, methoxycarbonyl, ethoxycarbonyl or 2-tetrahydropyranyl.