CA1074327A - Anti-inflammatory imidazoles - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Anti-inflammatory 4,5-diaryl-2-(substituted-thio)-imidazoles and their corresponding dulcoxides and sulfones, which are useful for treating arthritis and related diseases, are disclosed. The imidazoles are of the formula where n = 0-3; R1 is alkyl, allyl, vinyl, -CH2COCH3, CH2S(O)m-CH3 where m is 0-2, mono- or polyhaloalkyl; and R2 and R3, the same or different, are

Description

107~327 BACKGROUND
This lnvention relates to anti-inflammatorv lmidazoles.
Lombardlno, in U.S. Patent 3,707,475 dlscloses anti-inflammatory 4,5-diarvl-2-substituted imidazoles.
Doebel, in U.S. Patent 3,505,350 dlscloses anti-lnflammatory 4-alkyl-5-aryl-1-substituted-2-mercapto-imida-zoles.
Zauer, K., et al., in Chem. Ber. 106, 1638 (1973), dlsclose 4,5-bis(4-methoxyphenyl)-2-methylthioimidazole and 4,5-bis(4-chlorophenyl~2-methylthioimidazole but do not suggest any use.
A number of references, ~uch as Current Sci.
Indla 17, 184-85 (1948) and Acta. Chem. Acad. Sci. ~ung. 79

(2) 197-212 (1973) disclose 2-(substituted-thlo)-4,5-dlphenyl lmldazoles with substituents such as methyl, propyl, allyl, and acetonyl.
There is a continuin~ need for safe and efrective anti-inflammatory agents. Inflammation is a disease process characterized b~ redness, fever, swelling, and pain.
Arthritis, in its various forms, is the most prevalent, chronic, and severe of the inflammatory diseases. Traumatic in~ury and infection also involve lnflammation, and anti-inrlammatory drugs are often used in their treatment. The usefulness of most commercial anti-inflammatories is limited because of toxiclty and adverse side-effects. Many produce gastric irritation and other erfects, such as chan~es in blood cells and central nervous system. Adreno-cortical steroids produce gastric irritation and su~presslon Or normal adrenal function.

10743Z'7 The Journal of the American Medical Association, Vol. 224, No. 5 (Supplement), 1973 "Primer on the Rheumatic Dise~ases" states that "Immunologic reactions appear to play a major role in the perpetuation of rheumatoid inflammation."
Widely used non-steroidal anti-inflammatory drugs, such as aspirin, indomethacin, phenylbutazone and ibuprofen have no effect on these immunologic reactions, but merely relieve the symptoms of the inflammatory response; these drugs do not stop the progressive and ultimately destructive processes of rheumatoid arthritis. Immunosuppressive drugs, such as cyclophosphamide, are effective in the treatment of rheuma-toid arthritis, but are too toxic for wide-spread use.
The present invention results from efforts to develop new anti-arthritic compounds with good anti-inflammatory and immunoregulatory activity and minimal side effects that could be more effective in treating arthritis than presently avail-able drugs.
Compounds of this invention have demonstrated unique properties in several tests of anti-inflammatory and immuno-regulatory activity. The biological profiles of these com-pounds are different from non-steroidal anti-inflammatory drugs and immunosuppressive drugs. These unique properties provide for a novel approach to the treatment of rheumatoid arthritis, and in addition may also be useful in the treat-ment of other diseases involving altered immune states.

SUMMARY

According to this invention there is provided com-pounds of formula I and pharmaceutically suitable salts, processes for their manufacture, pharmaceutical compositions containing them,and methods of using them to treat arthritis in mammals.

107~3Z7 F~3~ >~S(O)n - Rl I

where n ~ O, 1, or 2;
Rl ~ Cl - C4 alk~l; all,vl; vinyl; -CH2COCH3;
-CH2S(O)m CH3, where m = O, 1, or 2;
mono- and polyhalo- Cl - C4 alkyl;
R2 and R3, the same or dirrerent -~Y
Yl 2 . Yl and Y2, the same or different =
hydrogen, hydroxy, Cl-C4 alkoxy, acetoxy, Cl-C4 alkyl, Cl, F, CF3, o NH2, -N(CH3)2, N02, -NHC-CH3, CH3S-~
CH3S02, or Yl and Y2 taken together forming a dioxymethylene bridge;
provided, when Rl = Cl-C4 alkyl, C3-C4 haloalkyl with halogen substituted at the 3 or 4 position, allyl, or acetonyl, both Yl and Y2 cannot be H.
Two compounds of formula I are not novel; th~se here n = O Rl ~ CH3, and both Yl and Y2 p-Cl or ~-OCH3-The proviso in formula I is necessary to exclude compounds that are not sufficiently active to have practical utility.
~E~
Compounds preferred for their activity are those where Rl = -CF2CF2H-Also preferred are those compounds where R2 and R3, independently, = ~ Yl where Yl = H, Cl, or F;

Also preferred are those compounds where n - 1 or 2.
More preferred are those compounds where:

Rl = -CF2CF2H;
R2 and R3, independently, = ~ Yl where Yl = H, Cl, or F; and n = O, 1, or 2.

Most preferred for ease of synthesis are those compounds where:
Rl = -CF2CF2H;
R2 and R3, independently, = ~ Yl where Yl = H, Cl, or F; and n = O or 2.

Specifically preferred are the following compounds:
4,5-bis(4-fluorophenyl)-2-(i,1,2,2-tetrafluoro-ethylsulfonyl)imidazole;
4(or 5)-(4-fluorophenyl)-5(or 4)-phenyl-2-tl,1,2,2-tetrafluoroethylsulfonyl)imidazole;
4,5-bis(4-chlorophenyl)-2-(1,1,2,2-tetrafluoro-ethylsulfonyl)imidazole;
4(or 5)-(4-chlorophenyl)-5(or 4)-phenyl-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole;
4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylsulfonyl)-imidazole;
4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imi-dazole.

1~7~
Tautomers When R2 and R3 are different, the following two structures are tautomers:

R ~ N ~ R2 ~ ~ S(0~n-R

Pharmaceutical ~alts .

Pharmaceutically suitable salts of compounds where n = 1 or 2 include those of certain metals, such as sodium, potassium, and calcium.

S.~nthesls The compounds of formula I can be prepared as ~ollow~: benzoln or an appropriately substituted benzoin prepared as described in Ide, W.S. and Buck, J.S., Organic Reactlons, ~ol. IV, P. 629, ls condensed with thiourea in refluxing dlmethylformamide or other hlgh boiling, polar solvents to give a 4,5-diaryl-2-mercaptolmldazole. A slmilar condensation procedure is described in Kochergln, P.M., Zhur. Obshchel Khim., 31, 1093 (1961); Chem. Abstr. 55, 23503f.
4,5-Diaryl-2-mercaptoimidazoles can also be prepared by heating 4,5-diarylimidazoles with sulfur at temperatures in the range of 150-300 either with or without solvent. One suitable solvent for this reaction is tetramethylene sulfone.
This procedure is analogous to the conversion of l-methylbenzi-~0743'~7 midazole to 2-mercapto-1-methylbenz~midazole as described in A.V. El'tsov and K.M. Krivozheiko. ZhOrKh, 2, 189 (1966).
The Qppropriate Rl group can be introduced by alkylating the 4,5-diaryl-2-mercaptoimidazole wlth a suitable alkylatlng agent such as ethyl iodide or 2~2,2-trifluoroethyl trichloromethanesulfonate. These procedures and the use of other alkylating agents can be found in the Examples.
Also, the 4,5-diaryl-2-mercaptoim~dazole can be reacted with tetrafluoroethylene to provide 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). For the purpose of this diæclosure tetra-fluoroethylene and other fluorinated olefins u~ed are considered alkylating agents.
S~nthe~is Compounds of formula I can also be made by reacting an N-protected diarylimldazole with a strong base, such as n-butyl lithium or the like, then with a fluorinated alkyl sul-fenyl halide, disul~ide or sulfonic anhydrlde. Proper cholce of the protecting group and the workup conditions allows iso-latlon of the desired 4,5-diaryl-2-(substituted thio or sul-fonyl)imidazole dlrectly.
The 4,5-diaryl-2-(substituted-thlo)imidazole can then be oxldlzed to the corresponding sul~oxide or sul~one by using oxidizing agents such as m-chloro-perbenzoic acid, Tweit, R.C., et al, J. Med. Chem 16, 1161 (1973) , sodium metaperiodate, Leonard, N.J. and Johnson, C.R., J. Org. Chem.
27, 282 (1962) ~ hydrogen peroxide, Kochergin, P.M. and ~hchukina, M.N., J. Gen. Chem. U.S.S.R. 25, 2289 (1955), or potassium permanganate, Rapp, K.E. et al loc. cit.

The preparation of these compounds i~ further illus-trated by the following Examples. Parts are by weight unless otherwise ~pecified.
,~LE 1 4,5-Diphenyl-2-(2,2,2-trifluoroethylthlo)imidazole A mixture of 4,5-diphenyl-2-mercaptolmidazole (71.9g, 0.285 mole), 2,2,2-trifluoroethyl trichloromethane~
sulfonate (80.3 g, 0.285 mole), triethyl~mine (28.8 g~ 0.285 mole), and toluene (700 ml) is refluxed under nltrogen for four hours. After cooling to room temperature there 18 re-covered (by flltration) 13.4 g of 4,5-diphenyl-2-mercaptoimi-dazole. m e filtrate is washed twice with water, and upon cooling the organic phase the product crystallizes. There is obtained 46.2 g (49~) of 4,5-diphenyl-2-(2,2,2-trifluoroethyl-thio)imidazole as nearly colorless crystals, m.p. 185.5-187.
Anal. Calc'd. for C17H13F3N2S: C, 61.06; H. 3.92;
N, 8.38. Found: C, 61.28; H, 3.97; N, 8.49.

4,5-DiPhenyl-2-(2J2J2-trifluoroethyl6ulflnyl)lmidazole To a mlxture of 4,5-dlphenyl-2-(2,2,2-trifluoro-ethylthlo)imidazole (13.9 g, 0.0416 mole) and chloro~orm (75 ml) cooled ln an ice bath 18 added dropwise 86.4% m-chloroperbenzoic acid (8.4 g, 0.042 mole) in chloroform (85 ml).
After stirring overnight the mixture is wa~hed with saturated sodium bicarbon~te, dried with magneslum sulfate and stripped of solvent to afford 12.3 g of crude product. Recrystalllza-tion from toluene glves 10.1 g (69~) of 4,5-dlphenyl-2-(2,2,2-trifluoroethyl~ulfinyl)imidazole as colorless prisms, m.p.
198 (dec.~.
Anal. Calc'd- ~or C17H13F3N20S C~ 5 N, 8.Qo. Found: C, 58.27; H, 3.76; N, 8.10.

1~17~Z ~

4,5-Diphenyl-2-(2,2,2-trifluoroethylsulfonyl)imidazole To a mixture of 4,5-diphenyl-2-(2,2,2-trlfluoro-ethylthio)lmidazole (15.7 g., 0.0470 mole) and chloroform (100 ml.) cooled in an ice bath is added dropwise 86.4g m-chloroperbenzoic acld (19.0 g., 0.0952 mole) in chloroform (200 ml.). After stirring for four days at room temperature, tetrahydrofuran is added, and the mixture is washed with saturated sodium bicarbonate, dried with magnesium sulfate, and stripped of solvent to give 16.9 g. of crude product.
After two recrystallizations from acetonitrile there is obtained 8.8 g. (51%) of 4,5-diphenyl-2-(2,2,2-trifluoroethyl-sulfonyl)imidazole as colorless needles, m.p. 228 (dec.).
A~al. Calc'd. for C17H13F3N202 N, 7.65; F, 15.56. Found: C, 56.18, 56.06; H, 3.94, 3.g5;
N, 7.45, 7.52; F, 15.44.

4,5-bis (4-Methoxyphenyl)-2-(2,2,2-trifluoroethyl'chio)imidazole A mixture of 2-mercapto-4,5-bis(4-methoxyphenyl)-imidazole (31.2 g., 0.100 mole), 2,2,2-trifluoroethyl trichlo-romethanesulfonate (31.0 g., 0.110 mole), triethylamine (11.1 g ~ 0.110 mole), and toluene (300 ml.) ls refluxed for six hours under nitrogen. The mixture is cooled, washed three times with water, dried with magnesium sulfate, and concentrated to g~ve 43O4 g. of crude product which is chroma-tographed on a column contain~ng one pound of silica gel eluting with chloroform. The residue from the major fraction is recrystallized from methylcyclohexane to g~ ve 21.5 g. (55%) of 4~5-bis(4-methoxyphenyl)-2-(2,2,2-trifluoroethylthlo)-lmldazole as nearly colorless crystals, m.p. 119-120~. A

1~7~3;~7 polymorphic form has m.p. 150-151.
Anal. Calc'd. for ClgH17F3N202S: C, 57.86; H, 4-34;
N, 7.10. Found: C, 57.96; H, 4.01; N, 7.09.

4,5-bis(4-Methoxyphenyl)-2-(2s2,2-trlfluoroethylsul~inyl)-imidazole .
By using 4,5-bis(4-methoxyphenyl)-2-(2,2,2-tri-fluoroethylthio)imidazole in place of the 4,5-dlphenyl-2-(2,2,2-trlfluoroethylthio)imidazole of Example 2 one obtains as product 4,5-bis(4-methoxyphenyl)-2-(2,2,2-trifluoroethy 1-sulfinyl)imidazole. Recrystallization of the crude product from aqueous ethanol gives an 83% yield of pure product, m.p.
193.5 (dec.).
Anal. Calc'd. for ClgH17F3N203S: C, 55.60; H, 4-18;
N, 6.83. Found: C, 55.52; H, 3.80; N, 6.77.

4,5-bis(4-Methoxyphenyl)-2-(2,2,2-trlfluoroethylsulfonyl)-im~ dazole To a mixture of 4,5-bis(4-methoxyphenyl)-2-(2,2,2-trifluoroethylthio)imidazole (6.0 g., 0.015 mole) and chloro-form (75ml.) cooled in an ice bath is added dropwise 86.4~ m-chloroperbenzoic acid (6.1 g., 0.031 mole) in chloroform (75 ml.). After st~ rring overnight at room temperature the mix-ture is washed wlth saturated sodium bicarbona~e, dried with magnesium sulfate, and concentrated to give 7.1 g. of crude product. Recrystallizatlon from l-chlorobutane gives pure 4,5-~is~4-methoxyphenyl)-2-(2,2,2-trifluoroethylsulfonyl)-lmidazole as colorless needles, m.p. 173-174.
Anal. Calc'd. for ClgH17F31Y204S: C, 53.51; H, 4.02;

N, 6.570 Found: C, 53.47, 53.81; H, 4.06, 3.69; N, 6.55, 6.59.

i~)743~7 4,5-bls(4-Chlorophenyl)-2-~2,2,2-trirluoroethylthio)il7lidazole . _ . _ . .
A mlxture of 4,5-bis(4-chlorophenyl)-2-mercapto-imldazole (32.1 g., 0.100 mole), 2,2,2-trifluoroethyl tri-chloromethanesulfonate (28.1 g., 0.100 mole), sodium meth-oxlde (5.9 g., 0.109 mole), and ethanol (300 ml.) is refluxed for three hours. The reaction mixture ls poured into water, and the solld is collected by filtration, washed with water, and drled. This solld (43.9 g.) i9 then stlrred overnight in ethyl acetate (400 ml.~. The mlxture is filtered, and the filtrate is strlpped of sol~ent to give 21.7 g. of a residue.
Thls resldue is recrystallized from toluene to give 15.1 g.
(37%) of pure 4,5-bis(4-chlorophenyl)-2-(2,2,2-trlfluoro-ethylthlo)imidazole as colorless crystals, m.p. 212-213.
Anal. Calc'd for C17HllC12F3N2S: C, 50.63; H3 2-7~;
N, 6.95. Found: C, 50.87; H, 3.05; N, 6.69.

4,5-bis(4~Chlorophenyl)-2-(2,2,2-trifluoroethylsulflnyl)lmidazole _ By using 4,5-bls(4-chlorophenyl)-2-(2,2,2-trlfluoro-? ethylth~ o)im1dazole in place of the 4,5-diphenyl-2-(2,2,2-trl fluoroethylthlo)imldazole of Example 2 one obtalns as product 4~5-bis(4-chlorophenyl)-2-t2~2~2-trifluoroethylsul-~inyl)irnldazole. Recrystallizatlon of the crude product from acetonitrile gives a 77% yleld of pure product, m.p. 214 (dec.).

Anal. Calc'd. for C17HllC12F3N20S: C, 48-70; H, 2.64; N, 6.68. Found: C, 48.97; H, 2.89; N, 6.47.

4,5-bis(4-Chlorophenyl)-2-(2,2,2-trifluoroethylsulfonyl)-_ imidazole To a mixture Or 4,5-bis(4-chlorophenyl)-2-(2,2,2-trifluoroethylthio)imidazole (5.3 g., 0.013 mole) and chloro-form (50 ml.) cooled ln an lce bath is added dropwi~e 86.4%
m-chloroperbenzoic acid (5.3 g., 0.027 mole) in chloroform (60 ml.). After stirring overnight at room temperature, the mixture is refluxed for fifteen minutes, cooled, and the solld ls collected and washed with cold chloroform. The solid is then dlssolved ln a mlxture Or ether and tetrahy-drofuran, and the resulting solution is washed with saturated sodium bicarbonate. The organic phase is dried with mag-nesium sulfate and stripped Or solvent to give 5.8 g. Or a colorless, solid residue which ~s recrystallized from nitro-methane (125 ml.). There ls obtained 4.1 g. (72%) of pure 4,5 bis(4-chlorophenyl)-2-(2,2,2-trifluoroethylsulfonyl)-lmidazole a~ colorless needles, m.p. 241 (dec.).
Anal- Calc'd rOr C17HllC12F3N22 2.55; N, 6.44. Found: C, 47.13, 47.29; H, 2.67, 2.58; N, 6.56, 6.58.

2-Ethylthio-4,5-bis(4-methoxyphenyl)imidazole _ To a suspension of 2-mercapto-4,5-bis(4-methoxy-phenyl)imidazole (31.2 g., 0.100 mole) in methanol (200 ml.) is added in one ~ortion sodium methoxide (6.5 g., 0.12 mole), and the mixture is stirred for 15 mln. A solution of iodo-ethane (17.1 g., 0.11 mole) in methanol (50 ml.) is added dropwise, and the mixture i8 heated at re~lux for 4.5 hours.

After stirring o~ernight at room temperature, the mixture ls poured into water, and the solid whlch precipltates is collected, washed with water, and dried to give 33.0 g. Or crude product. Recrystallization rrom aqueous ethanol gives 28.8 g. (85~) of pure 2-ethylthio-4,5-bis(4-methoxyphenyl)-lmi dazole, m.p. 108-109.
Anal. Calc'd. ror ClgH20N202S: C, 67.03; H, 5.92;
N, 8.23. Found: C, 66.96; H, 6.10; N, 7.85.

2-Allylthio-4,5-bis(4-methoxyphenyl)imidazole ~ .
A mixture Or 2-mercapto-4,5-bis(4-methoxyphenyl)-lmldazole (31.2 g., 0.100 mole), allyl bromide ~13.1 g., 0.108 mole), triethylamine (20.2 g., 0.200 mole), and chloro-form (500 ml.) is heated overnight at reflux. Allyl bromide (4. 8 g., 0.040 mole) is then added and reflux continued ror two hours. Two additional portions (4.8 g.) Or allyl bro-mide are added followed in each instance by a two-hour rerlux perlod. The clear solution i8 cooled, washed three tlmes with water, dried with magnesium sulfate, and concen-trated. The residue is triturated with ether, and the solld is collected to give 31.5 g. of crude product. Recrystalll-zatlon from aqueous ethanol gives 26.7 g. (76%) Or pure 2-allylthlo-4,5-bis(4-methoxyphenyl)imidaæole, m.p. 167-167.5.
al- Calc'd for C20H20N202S: C, 68.16; H, 5.72;
N, 7.95. Found: C, 67.22; H, 5.87; N, 7.81.

4,5-b~s(4-Methoxyphenyl)-2-(methylthiomethylthio)imidazole _ By substituting chloromethyl methyl sulflde for the allyl bromide o~ Example 11 one obtalns as product 4,5-bi~-10'74327 (4-methoxyphenyl)-2-(methylthiomethylthio)imidazole, m.p.
171-172.
Anal. Calc'd. for ClgH20N202S2: C, 61.26; H, 5.41;
N, 7.52. Found: C, 61.32; H, 5.57; N, 7.32.

2-Ethylsulfinyl-4,5-bis (4-methoxyphenyl)imldazole .
To a solution of 2-ethylthio-4,5-bis(4-methoxy-phenyl)imidazole (10.2 g., 0.0300 mole) in dlchloromethane (200 ml.) cooled in an ice bath is added dropwise a solution of` 86.4% m-chloroperbenozic acid (6.0 g., 0.030 mole) in dichloromethane (100 ml. ) . After stirring overnight at room temperature, the reaction mixture is wa~hed wlth three portlons (75 ml.) of saturated sodium blcarbonate. The organic phase is dried wlth magnesium sulfate and the solvent removed on a rotary evaporator. The resldual oil is trl-turated wlth ether, and the resulting solld ls collected and recrystalllzed from l-chlorobutane (500 ml.) to glve 7.5 g.
(70%) of pure 2-ethylsulflnyl-4,5-bls(4-methoxyphenyl)-imidazole, m.p. 161-162.
Anal. Calc'd. for ClgH20N203S: C, 64.02; H, 5.66;
N, 7.86. Found: C, 63.98; H, 5.59; N, 7.97.

2-Ethylsulfonyl-4,5-bis(4-methoxyphenyl)imldazole By substituting 12.0 g. (0.060 mole) of 86.4%
_-chloroperbenzoic acid ln place of the 6.0 g. of 86.4~ m-chloroperbenzoic acid of Example 13, one obta~ns after recrystalllzation from l-chlorobutane (125 ml.) 6.0 g. (54%) of 2-ethylsulfonyl-4,5-bis(4-methoxyphenyl)imidazole, m.p.
136-137.

Anal. Calc'd. for ClgH20N204S C, 61.27; H, 5.41;

1(~74327 N, 7.52. Found: C, 61.47; H, 5.47; Ng 7.35.

4,5-bls(4-Methoxyphenyl)-2-methylthiolmidazole By substitutlng iodomethane for the iodoethane o~
Example 10, one obtains as product 4,5-bis(4-methoxyphenyl)-2-methylthioimidazole, m.p. 157-158.5.
Anal. Calc'd. ror C18H18N202S: C, 66.23; H, 5.56;
N, 8.58. Found: C, 65.84; H, 5.53; N, 8.46.

2-Acetonylthio-4,5-bls(4-methoxyphenyl)imidazole To a stirred mixture of 2-mercapto-4,5-bis(4-methoxyphenyl)imidazole ~31.2 g., 0.100 mole), triethylamine (11.0 g., 0.11 mole), and chloroform (500 ml.) is added chloroacetone (10.2 g., 0.11 mole) dropwise in chloroform (50 ml.). After stirring overnight at reflux, the reactlon mixture is washed three times with water, dried wlth magne-slum sulfate, and concentrated to give 32.0 g. of crude product. Chromatography (silica gel, chloroform) a~fords 27.0 g. (73%) Or pure 2-acetonylthio-4,5-bis(4-methoxyphenyl)-lmldazole, m.p. 115-117.5.
Anal. Calc'd for C20H20N203S: C, 65.20; H, 5.47;
N, 7.60. Found: C, 65.14; H, 5.42i N, 7.36.
EXAMPL~ 17 4,5-bis(4-MethoxyphenylL2-(methylthiomethylsulfinyl)-imidazole and 4,5-bis(4-methoxyphenyl)-2-(methyl-_ sulfinylmethylthio)imidazole To a solution of 4,5-bis(4-methoxyphenyl)-2-(methylthiomethylthio)imidazole (7.4 g., 0.020 mole) in dichloromethane (100 ml.) cooled in an ice bath is added a solution of 86.4% m-chloroperbenzoic acid (4.0 g., 0.020 ~)743Z7 mole) ln dichloromethane (100 ml.). After stlrring overnight at room temperature, the reaction mixture is washed three times with saturated sodium bicarbonate solution, dried with magnesium sulfate, and concentrated. The residue (7.5 g.) is then chromatographed on a column of silica gel which ls eluted wlth a mixture of toluene and ethyl acetate.
The first pure compound to elute from the column is 4,5-bis(4-methoxyphenyl)-2-(methylthiomethylsulfinyl)-imldazole, m.p. 142.5-143.5.
Anal. Calc'd. for C19H20N203S2: C, 58.74; H, 5-19;
N, 7.21. Found: C, 59.00; H, 5.13; N, 6.93.
Further elution o~ the column provides pure 4,5-bis(4-methoxyphenyl)-2-(methylsulfinylmethylthio)imidazole, m.p. 84.5-86.5.
Anal. Calc'd. for ClgH20N203S2: C, 58.74; H, 5-19;
N, 7.21. Found: C, 58.85; H, 5.36; N, 6.94.

4,5-Diphenyl-2-(191,2,2-tetrafluoroethylthio)imidazole To a stainless steel tube is added 4,5-diphenyl-2-mercaptolmidazole (5.0 g., 0.020 mole) and dimethylform-amide (50 ml.) which contains 0.5 ml. of a 40~ methanol solution of benzyl trimethylammonium hydroxide. Subsequent to purging the tube several times wlth dry nitrogen, tetra-fluoroethylene (2.2 g., 0.022 mole) is introduced. The tube is agitated for seven hours. The reaction mixture is poured into water, and the solid is collected and washed with water affording 5.7 g. of crude product. Column chromatography (silica gel, chloroform) provides 3.5 g. of pure 4,5-d~phenyl-2-(1,1,2,2-tetrafluoroethyithio)imida~ole, m.p. 212-213.
Anal. Calc'd. for C17H12F4N2S: C, 57.95; H, 3-43;

3 N, 7.95. Found: C, 57.71; H, 3.70; N, 7.89.

1~37432~

4,5~ (4-Methoxyphenyl)-2-vinylthioimidazole To a stainless steel tube is added 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole (15.0 g. 0.05 mole), cuprous chloride (0.75 g.), and 100 ml. of dimethylformamide.
The tube is cooled, evacuated, and then pressured with 1.3 g.
of acetylene. The tube is heated at 150 with shaking for eight hours, cooled, and vented. The contents are diluted with 500 ml. of water, and 25 ml. of concentrated ammonium hydroxide is added. The aqueous mixture is extracted with ~ther (4x300 ml.). The combined ether extracts are back-washed with water (3x300 ml.) and then dried and concentrated on a rotary evaporator. The residue is chromatographed on a column containing 600 g. of silica gel (SilicAR~ CC-7).
The product is eluted with chloroform (cut 6-8, one liter each) to give after concentration 2.9 g. of crystals. A re-crystallization from l-chlorobutane/hexane gives 2.8 g. of pure product, m.p. 114-115.
Anal. Calc'd. for ClgH18N2O2S C, 67.43; H, 5.36;
N, 8.28~ Found: C, 67.17; H, 5.40; N, 8.42.

4,5-bis(4-Methoxyphenyl)-2-(1,1,2-trifluoroethylthio)-imidazole To a solution of 2-(2-bromo-1,1,2-trifluoroethyl-thio)-4,5-bis(4-methoxyphenyl)imidazole (14.2 g., 0.03 mole) in 150 ml. toluene is added tri-n-butyltin hydride (9.0 g., 0.03 mole). The mixture if refluxed for f~ur hours. Another 9.0 g. (0.03 mole) of tri-n-butyltin hydride is added and the mixture is refluxed overnight. The mixture is then added directly to a column of 2 lb. silica gel (SilicAR~ CC-7).
Elution with toluene followed by toluene/ethyl acetate t95/5) gives 6.5 g. of crystalline product. A recrys-tallization from methylcyclohexane gives 5.6 g. of pure product, m.p. 143.5-145.
-- 19 17F3N2O2S C, 57.86;
H, 4.34; N, 7.10. Found: C, 57.95; H, 4.71; N, 7.04.

_ 4,5-Diph ~ 1,2-trifluoroethylthio)imidazole By substituting 2-(2-bromo-1,1,2-trifluoroethyl-thio)-4,5-diphenylimidazole for the 2-(2-bromo-1,1,2-tri-fluoroethylethio)-4,5-bis(4-methoxyphenyl)imidazole of example 20, one obtains as product 4,5-diphenyl-2-(1,1,2-trifluoroethylthio)imidazole, m.p. 225-226.5.
EXA~IPLE 22 4,5-bis(4-Fluorophenyl)-2-(1,1,2,2-tetrafluoroethyl-sulfonyl)imidazole Sodium Salt -A mixtuxe of 4,5-bis(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole (5.0 g., 0.0119 mole), sodium methoxide (0.6 g., 0.0111 mole) and ether (300 ml.) is stirred overnight at room temperature. The solid is 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-tetrafluoroethyl-sulfonyl)imidazole, m.p. 290-292.
Anal. Calc'd. for Cl7H~F6N2o2sNa: C, 46.16;
H, 2.05; N, 6.33. Found: C, 45.98; H, 2.1~; N, 6.07.

10~ 32'~

4,5-Diphenyl-2-(1,1,2,2-tetrafluoroethylsulfonyl)-imidazole Sodium Salt By utilizing the procedure described in Example 22 and employing as starting material 4,5-diphenyl-2-~1,1,2,2-tetrafluoroethylsulfonyl)imidazole, one obtains as product 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylsulfonyl)-imidazole sodium salt, m.p. 296-302 (dec.~.

4,5-bis(4-Hydroxyphenyl)-2-(1,1,2,2-tetrafluoroethyl-sulfonyl)imidazole A mixture of 4,5-bis(4-t-butoxyphenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole and trifluoroacetic acid is stirred overnight at room temperature. The reaction mixture is poured into water, and work-up affords as product 4,5-bis(4-hydroxyphenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)-imidazole.

4,5-bis(4-Acetoxyphenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)-_ imidazole A mixture of 4,5-bis(4-hydroxyphenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole (0.1 mole), acetic anhydride ~0.2 mole), and pyridine (500 ml.) is heated for two hrs. on the steam bath. On pouring the mixture into water there is obtained as product 4,5-bis(4-acetoxyphenyl)-2-(1,1,2,2-tetra-fluoroethylsulfonyl)imidazole.

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

10743'~7 Using the appropriate starting materials and the pro-cedure described in Example 18, the compounds ln Table II can be prepared. Typical catalysts that can be used are diisopropyl-aminc or benzyl trimethylammonium hydroxide.
Uæing the appropriate starting materials and the pro-cedures described in Examples 13 and 14, the compounds in Table III can be prepared.
Table IV shows other compounds that can be prepared using the procedures described in the Examples.

A) 4,5-Diphenyl-1-(2-tetrahydropyranyl)imidazole A mixture of 27 g (0.122 mole) 4,5-diphenylimidazole, 21 g (0.25 mole) dihydropyran, 250 ml ethyl acetate and 4.0 g BF3-Et20 was refluxed for five days. m e nearly clear solution was diluted with ether and filtered to remove o.6 g insoluble starting material. m e ether filtrate was washed several times with 10~ NaHC03 then dried and evaporated. TLC showed starting material still present, so the crude product was chromatographed on 2 lb. Silic A ~ CC-7, eluting with toluene containing 20 to 40% ethyl acetate. The pure product thus obtained was 30.3 g (81.7%), m.p. 170-1. IR: 3.21 ~, =CH; 3.40, 3.49 ~ sat.
CH; 6.25, 6.64, 6.73~ aromatic C=C and/or C-N; strong 9-10 ~, C-O-C; 12.98 and 14.38 ~ monosubstltuted aromatic. H-NMR:
mult (1.6-2.3~, 6H); mult, (Y3.4, 4.0, 4.8~, each ~lH); mult +
singlet (7.o-7.6 + 7.46, 10 H); S (7.8~, lH). Mass spectrum, calcd for C20H2oN2o: 304.1574; found: 304.1559.
Anal. Calcd for: C20H20N20: C 78.92; H 6.62; N 9.20.
Found: C 78.57; H 6.89; N 9.07.
B~ 4,5-Dlphenyl-2-trifluoromethylthioimidazole Under nitrogen and in glassware dried wlth a heat gun, a solution of 0.9 g (3 mmol) of 4,5-diphenyl-1-(2-tetrahydro-pyranyl)imidazole in 15 ml THF and 15 ml ether was chilled to 10743;~7 -78 . To the cold solution was added dropwise a solution of 2.5 ml (4 mmol) of 1.6M n-butyl lithium in hexane in 10 ml ether. The solution was st~rred at -78, then 0.55 g (4 mmol) of trifluoromethanesulfenyl chloride (toxic) was addcd as a gas. The mixture was stirred at -78 for 2 hours, then at room temperature overnight. The mixture was poured into water and extracted with ether (pH of aqueous layer ~4). The aqueous layer was neutralized with bicarbonate then extracted with more ether. The combined ether extracts were dried and concentrated.
10 me crude residue was chromatographed on 50 g Sllic AR CC-7, eluting with 98% toluene/2% ethyl acetate, to glve 0.45 g (47%) of product. Recrystallization from toluene gave 0.3 g (31%) of whlte solld, m.p. 254-6; IR: broad 3-4 ,u, NEI; 3.28 11, = CH;
6.24, 6.34, 6.42, 6.71~, aromatlc C=C and/or C=N; strong 8.5-9~1, C-F; 13.09, 14.3411 monosubRtituted aromatic. H-NMR: mult (7.1-7.7~, 10 H); broad (13S, lH) F-NMR: S(42.46~). Mass spectrum: molecular ion C16~11F3N2S
Anal. Calc'd for: C16HllF3N2S: C 59.99; H 3.46; N 8.75 Found: C 60.20; H 3.57; N 8.52 EXA~PLE 102 4,5-Diphenyl-2-trifluoromethylsulfonylimidazole A mixturc of o.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 methylene chloride was stirred at room temperature overnight, then since thin layer chromato-graphy indicated incomplete oxidation, at reflux another day.
This layer chromatography ~till indicated incomplete oxidation, so the methylene chloride was removed by rotary evaporation and replaced by 30 ml chloroform and the mixture was refluxed 6 hours. me chloroform was evaporated and the residue triturated with ~20 ml ether. I~e ether insoluble æolid (~0.3 g~ was com-bined with~0.1 g of solid obtained from the ether filtrate by washing with 10% sodium sulfite, 10,~ sodium bicarbonate, dry~ng and evaporating. Recrystallizati-~n from toluene gave 0.~7 g (70%) of white product, m.p. 292-3.5 (sublimes above 250).

743Z ~
IR: 3-4u, NH; 6.33. 6.44, 6.72u, aromatic C=C and/or CsN; 7.23, 8.32u; -S02-; 8.97u, C-F; 13.05, 14.30u, monosubstituted aromatic.
H-NMR: mult (7.1-7.7~, 10 H). F-NMR: S (78.25~); small slng-letæ were also observed at 42.43~ (~2%, sulfide~ and at 72.69 (~3%, sulfoxide).
Anal. Calc'd for: C16HllF3N202S: CJ 54.54; H 3.15; N, 7.95 Found: C, 55.13; H, 2.94; N, 8.o6 54.98 2.95 8.o5 Compound of Example 102 had an ad~uvant arthritis EDso in the rat of 0.03 mg/kg.
Dosage Forms The anti-arthritic agents of this invention can be administered to treat thls condition by any means that produces contact of the active agent with the agent's slte of action in the body of a mammal. They can be administered by any conven-tional means avallable for use ln con~unction with pharmaceuti-cals; either as individual therapcutic agentæ or in a combina-tion of therapeutic agents. They can be administered alone, but are generally admlnistered wlth a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practic.
m e dosage admlni~tered wlll, or course, vary depend-ing upon known ~actors such as the pharmacodynamic character-istics of the partlcular agent, and its mode and route of administration; age, health, and welght of the recipient;
nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the cffect dcsired. Usually a daily dosage of active ingredient can be about .001 to 40 milli-gramæ per kilogram of body weight. Ordinarily .005 to 20, and preferably .01 to 4 milligrams per kllogram per day given in 10743Z f divided doses 2 to 4 times a day or in sustained release form is e~fective to obtain desired results.
Dosage forms (compositions) sultable for internal administration contain from about 0.1 milligrams to about 500 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 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 dosagc forms, such as elixirs, syrups, and suspensions; lt can al80 be administered parenterally, ln sterile liquid dosage forms.
Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid. and the like. Similar dlluents can be used to make compressed tablets. Both tablets and capsules can be manu-factured as sustained releaEe products to provide for con-tinuous release of medication over a period of hours. Com-pressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmo-sphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Llquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
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 107~32~

carriers for parenteral solutlons. Solutions for parenteral admlnistration contain preferably a water soluble salt of the active ingredient, suitable stabillzing agents, and if necessary, buffer substances. Antioxidizlng agents such a~
sodium bisulfite, sodium sulrlte~ or ascorblc acld either alone or comblned are sultable stabillzlng agents. Also used are citrlc acid and its salts and sodium EDTA. In addition parenteral solutlons can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, E. W. Martin, a stand~rd re~erence text in thls field.
Useful pharmaceutical dosage-forms for adminis-tration of the compounds of this inventlon can be illustrated as follows:

A large number of unit capsules are prepared by fllling standard two-plece hard gelatin capsules each with 50 milligrams of powdered active lngredlent, 110 milllgram~
of lactose, 32 milligrams of talc, and 8 milllgram~ magnesium ste~rateO
Capsules A m~xture of actlve ingredient ln soybean oil is prepared and in~ected by means of a posltive displacement pump into gelatin to form soft gelat~n capsules containlng 50 milligrams of the active ingredlent. The capsules are washed in petroleum ether and dried.
Tablets A large number of tablets are prepared by conven-tlonal procedures so that the dosage unlt ls 50 milligrame 10~3,'~ f o~ active ingredient, 7 milligrams of ethyl ce~lulose, 0.2 mllllgrams of colloidal ~ilicon dioxlde, 7 milligrams of magneslum stearate, 11 milligrams of microcrystalllne cellulose, 11 milllgrams of cornstarch and 98.8 milligrams of lactose. Appropriate coatings may be applied to lncrease palatabillty or delay absorption.
In,~ectable A parenteral composition ~ultable for admlnistra-tion by ln~ectlon 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.
Suspensicn An aqueou~ suspension is prepared for oral admln-l~tratlon so that each 5 milliliters contain 10 milligrams Or ~inely divided active lngredient, 500 milligrams Or acacia,

5 milligrams of sodlum benzoate, 1.0 grams of sorbitol solu-tion, U.S.P., 5 milligram~ of sodium saccharin, and 0.025 milllllters of vanilla tincture.
In,~ectable A parenteral composition suitable for admini~tra-tlon by ln,~ection is prepared by dissolving 1~ by weight Or actlve ingredient in sodium chloride in~ection U.S.P. XV
and ad~ustlng the pH of the solution to between 6 and 7.
The solut~on is sterilized by filtration.

Use To detect and compare the anti-inflammatory and immunoregulatory activities of compounds in this series and standard drugs, a series of tests was used based on a standard model for whicll there is good correlation with human efficacy. The model is adjuvant-induced arthritis in - 2~ -~07~3~7 rats. Federation P-oceedings, Vol. 32, No. ~, 1973 "Models Used for the Study and Therapy of Rheumatoid Arthritis" ~
Symposium of the American Society for Pharmacology and Experimental Therapeutics - states "The rat polyarthritis produced by intradermal injection of a suspension of Mycobacterium tuberculosis in mineral oil (adjuvant) has been used extensively for the screening of drugs of potential use in rheumatoid arthritis."
Established Adjuvant-Induced Arthritis in Rats A test used primarily to determine anti-inflammatory activity.
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 heat-killed, lycphilized Mycobacterium butyricum suspended in mineral oil 5 mg/ml). 20 ~on-arthritic controls are injected with mineral oil. The animals are held for 2 weeks to allow development of arthritis. Paw volumes (uninjected, left hind paw~ are measured and the adjuvant injected rats are ~0 culled and distributed to treatment groups of 10 of equal disease severity. Non-arthritic controls are distributed to ~ groups of 10. The rats are given oral doses of compound or PYA-Acacia* (10 ml/kg) by gavage on that day and on the 6 following days. One day after the last dose the paw volumes (uninjected, left hind paw)are measured using a Ugo Basile Volume Differential ~eter Model 7101.

*Polyvillyl A.cohol 1%, Gum Acacia, U.S.P. 5%, Methylparaben 0.570.

107432~7 Arthritic Control Treatment Group Mean Paw Volume (ml) - Mean Paw Vo].ume (ml) Arthritic Control - Non-Arthritic Control x 100 Mean Paw Volume (ml) Mean Paw Volume (ml) qO Decrease from Control Mean Paw Volume.
Dose-response regression lines of the % decrease are plotted on semi-log paper by visual fit and the ED50%
decrease from control paw volume is determined by inspection.
Non-Established Adjuvant-Induced Arthritis in Rats A test used primarily to determine the effects of compounds on the immunological reactions involved in the induction process and to prevent the development of arthritis.
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 heat-killed, lyophilized Mycobacterium butyricum suspended in mineral oil 5 mg/ml). 40 Non-arthritic controls are injected with mineral oil. Groups of 20 rats are given single, daily oral doses of compound (in PVA-Acacia vehicle,10 ml/kg) or vehicle by gavage beginning immediately following pa~v injection for a total of 14 doses. The paw volume of the uninjected (left) hind paw is measured 24 hours after the last dose using a U~o Basile Volume differential meter Model 7101. The ED50%
decrease from control is determined as described above.

To further evaluate the immunoregulatory properties of these comp~unds, two additional tests were used that are described below. The Jerne E~emolytic Plaqlle Assay measures the effect of compounds on specifi.c anti.body producing cells ~0 (B lymphocytes). The relative proportion of B lymphocytes 1~7~3Z7 and T lymphocytes (involved in cell mediated immunity) is determined by fluorescent antibody staining.

MODIFIED JERNE SPLEEN CELL HEMOLYTIC PLAQUE ASSAY
METHODS
~ modification of the technique 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 non-arthritic controls) were dosed orally once per day with PVA-Acacia vehicle* or compounds in vehicle from day 14 (following adjuvant injection) tO day 20. The animals were sensitized with sheep red blood cells (SRBC) (0.2 ml of a 10% suspension = 2 - 3 x 106 cells) I.V. on day 17. The SRBC (Microbiolo~ical Associates) were washed 3 times in 0.9% sodium chloride solution prior to injection. On day 21 the rats were anesthetized with 1%
sodium pentobarbital I.P. and the spleens were removed. Each spleen was placed on a stainless steel screen suspended over a plastic beaker in an ice bath and gently macerated with a glass syringe plunger. The cells were washed through the mesh into the beaker using a pasteur pipette to apply about 10 ml of Eagle's Minimal Essential Medium (MEM) during the maceration process until only fibrous material remained on the screen. Large particles were allowed to settle out for about 5 minutes and about 5 ml of supernatant was trans-~erred to a plastic tube. Dilutions of 1:10 and 1:20 were made in cold MEM.

__ ______,________________ *Polyvinyl Alcohol 1%, Gum Acacia 5%, Methylparaben Q.5% in water.

1(~7432 ~

Plating: 2 ml of 0.7% Agarose (1. 4qo diluted 1:2 . _ _ with 2X Eagles ,ME~) and 0.2 ml of a 10% SRBC suspension were pre-warmed in a 45C water bath. 20 Lambda of spleen cell dilution were added, mixed gently and poured into a supporting layer of 2 ml of 1.4% Agarose in a 60 x 15 mm plastic petri plate. Plates were incubated at 37~C for 1.5 hours in a humidified incubator. 1.5 ml of guinea pig complement (diluted 1:10 with MEM) was added and incubation was continued for 1 hour longer.

Zones of hemolysis tplaques) per plate were counted without magnification against a diffuse light source.
Assuming each plaque to have resulted from hemolysin pro-duced by a single spleen cell, the number of plaque forming cells (PFC) per million spleen cells was calculated for each dilution. The statistical calculations (mean, standard error and "t" test) included the PFC/million count for each dilu-tion of each spleen.

IMMUNOFLUORESCENT ANTIBODY STAINING OF
B-CELI.S IN RAT SPI,~EN
METHOD
For the % B-cell ratio determinations rats (Charles River Lewis strain) in the process of developing adjuvant arthritis were used. Rats were dosed orally once a day with PVA-Acacia* vehicle or drug in vehicle. Treatment was started on day -3 pre-adjuvant. On day O rats were injected ______________________ *Polyvinyl Alcohol 1%, Gum Acacia 5%, Methylparaben 0.5% in water.

_ ~g _ 1~)7~327 subcutaneously into the left hind paw with 0.1 ml (5 mg/ml) Mycobacterium butyricum (Difco-dried, heat-killed) in mineral oil. Drug treatment was continued through day 7. Spleens were harvested on day 8 post-adjuvant.
Spleen cell suspension were prepared by macerating spleens on stainless steel sieve into medium RPMI 1640.
Large particles were allowed to settle and the supernatant was transferred to clean tubes and spun at 800 rpm IEC
International Centrifuge Model K Size 2 for 10 minutes. The cell button was resuspended in 0.83% NH4Cl (pH adjusted to 7.0 with NaOH) for lysis of red cells (approximately 1 part packed cells to 3 parts NH4Cl). These suspensions were kept in ice for 5-7 minutes then spun at 800 rpm for 10 minutes.
Cells were washed twice in Dulbecco's Phosphate Buffered Saline (PBS) and finall~ suspended in nulbecco's PBS. The final cell concentration was such that one drop of cell sus-pension on a microscope slide covered with a coverslip gave 10-15 cells per high power field. Judging the si~e of the cell button and from experience 8-10 ml of Dulbecco's PBS
per spleen were added to this final cell suspension.
For immunofluorescent staining, 0.2 ml of cell suspension was mixed with 0.2 ml of a 1:4 dilution of Fluorescein Isothiocyanate conjugated ~abbit-Anti-Rat IgG
(Miles-Yeda Laboratories). Cells were incubated at 2-4C
for 1 hour, spun at ~00 rpm for 10 minutes, washed twice in 2 ml of Dulbecco's PBS and resuspended in 0.2 ml of Dulbecco's PBS. One drop of cell suspension was placed on a microscope slide, covered with a coverslide and examined by light and fluorescence microscopy. A total of 200-300 cells was counted per spleen suspension. The number of 1~)7432'7 fluorescing lymphocytes or B-cells was expressed as percent.
Data pertaining to the effects of some compounds from this series in the tests described above are summarized in Tables V, VI and VII.
Compounds of this invention were equipotent in the treatment of established arthritis in rats (anti-inflammatory effect) and in preventing the development of arthritis in rats (non-established arthritis) as shown in Table V.
Standard anti-inflammatory drugs such as indomethacin and phenylbutazone were less effective in preventing the develop-ment of arthritis in rats than in treating the inflammation in established arthritis. An immunosuppressive drug, cyclo-phosphamide, was more effective in preventing the development of arthritis in rats than in treating established arthritis in rats. Compounds of this series demonstrated unique properties in these tests.
Rats with adjuvant-induced arthritis have greatly modified immunological systems as indicated by the increased number of plaque forming (antibody producing) cells (PFC) in spleen cell suspensions (hemolytic plaque assay Table VI).
Treatment of arthritic rats with compounds of this invention reduced the number of PFC toward normal. Treatment with indomethacin had no effect on the number of PFC while treat-ment with cyclophosphamide reduced the PFC far below normal.
Compounds of this series produced unique activity in this test.
Spleen cell suspensions from rats with adjuvant-induced arthritis have a larger proportion of B (antibody producing) lymphocytes than T lymphocytes ~mediators of cellular immunity) when compared to cells from normal rats (Table VII). Treatment of arthritic rats ~ith compounds of this invention reduced the B lymphocyte proportion to normal.
Treatment tvith indomethacin had no effect on the lymphocyte population while treatment with cyclophosphamide reduced the B lymphocyte proportion to below normal.

Table I. 4,5-Diaryl-2-(substituted-thio)imidazoles and their Rat Adjuvant Arthriti~ Data X~
~N~
¦ ~ S-R
Y ~ H

Adjuvant Arthritis Example X Y R m.p. ( 50%) 4-CH30 4-~H30 CH3 156-157 4.4 26 4-C1 4-Cl CH3 241-242 3.0 27 4-CH30 4-CH30 CH3CH2CH2 152-153 9.0 28 4-F 4-F CH3 222-223.5 3.5 29 4-CH30 4-CH30 CHF2 170.5-172 1.8 H H CHF2 227-228~ 21 31 4-C1 4-Cl CHF2 222-223 0.35 32 ~-F 4-~ CHF2 192.5-194 0.42 33 4-C1 4-F CH3 222-223 3.8 36 4-C1 4-CF3 CH3 214-215 3.6 37 3,4-OCH20 3,4-OCH2o CH3 201-202 20 7 4-C1 4-C1 3 2 212-213 5.0 4-CH30 4-CH30 3 2 108-1094 4.7 11 4-CH3 4-CH30 CH2=CHCH2 167-167.5 22 16 4-CH30 4-CH30 CH3COCH2 115-117.5 9.4 17 4-CH30 4-CH30 CH3SOCH2 8~.5-86.5 52 I This biological system is described previously.
Units are in mcJ. /kg.
3 A polymorph had ~.p. 119-120 4 A polymorph had m.p. 146 ~ 33 ~

~7432~
Table II. 4,5-Diaryl-2-(polyhaloalkylthio)imidazoles and their Rat Adjuvant Arthritisl ~ata X~
~~ CF2 ~CFH
~ H
Y~ ~
Adjuvant Arthritis Exa~ple X Y Z m.p. (ED5o%)2 38 4-CH30 4-CH30 F 134-136 4.2 39 4-C1 4-Cl F 222.5-223.5 0.3 4-F 4-F F 220-221.5 0.075 41 H H Cl 187-188 3.9 42 4-C1 4-F F 206.5-207.5 0.18 44 4-CH30 H F 175-175.5 20 4-Cl H F 205-206 0.3 46 3,4-OCH2O 3,4-OCH2O F 204-205.5 10 47 4-CF3 H F 202-204 4.5 48 4-F 4-CF3 F 182.5-183.5 1.5 49 4-F H F 196-197.5~ 0.2 3-C1 3-Cl F 208-209 1.2 51 4-CH30 4-CH30 Br 151-153 10 5~ H H Br 184-186 11 53 ( 3)2 F 189-192.5 2.~
18 N H F 218-219.5 0-75 1 This biological system is described previously.
2 Units are in mg./kg.

~ 3~ ~

:lL0~74~

Table III. 4,5~D1aryl~2~(~lk3rl~ nyl) imidazoles and 4,5-Dia~l-2-~Alkyl~uli~nyl) i~ldazole~ and their R~t AdJu~r~nt Arthr~tisl Data X ~l \/ N
Il ~S(3 --N

Ad ~uvant Arthrît 18 Example X Y ~ n m. p. ( 50%?
2 H ~ CF3~2 1 198 ( ~ec . ) 48 3 H ~ CF3CR2 2 226 . 5 ( dec . ) 12 4-C~I30 4-C1~30 CF3C~2 1 193.~ (dec- ) 10

6 4-CH30 4-~H3~ C~3CH2 2 173 . 5-174 . 5 3 ~ 8 8 4-Cl 4-Cl CF3C~ 1 214~ (dec. ) 3.0 9 4~C1 4-C1 3 2 2 241 (dec. ) 4.5 13 4 CR30 4-C~30 C~C~2 1 16~ol62 10 14 4~CH30 4-C~30 C~}3C~2 2 136-137 5~ 2 54 4-C~3Q 4-CH30 CH2~CH2 1 118-119 (dec. ) 11 4~CH30 4-CH30 C~2~CH2 2 162-163 11 5~ 4_~30 4-CH30 ~13 1 167~ . 5 6. 2 57 4-C~3~ 4~CH30 ~3 2 142-143 6.4 5~3 4-C1 4-C~ 3C~2 1 214 ~decO ) 3~0 59 ~-Cl 4-Cl c~3 1 202 ~ de ) 2. 3 H ~ ~C~2CF~ 2 239-240 ~ o .13 61 ~ C~3~ ~4`~3~ ~3~2C~2 1 1430144,5~ 13 62 3 ~3 C~3~C~2~2 2 152_1~3 g 63 3 3 ~3)2~ 7~-176 3~
64 4-C~0 4~3 ~CF2cF~ 2 156-157 1.1 6~i 4 ~1~0 4 -C~30 EICF~2CF~ 1 }62.50163~5~ 2.4 - 3~ ~`

~0~74;~
Table III (Continu~d) Ad~uvant Arthrltis Ex~mple X Y R n la. p . ( ED50~ 2 66 H H ~CF2C~2 1 181-182 0,18 67 4-C1 4-Cl c~3 2 255-256 2 . O
68 4-C1 4-Cl H~F2CF2 1 198~ (dec. j 0.2 69 4-C1 4-Cl HC~2CF2 2 235-236. 5 ~ 0. 2

7 4-F 4-F CF3~2 2 247 (dec. ) 3.5 71 4-F 4-F HCF2CF2 2 241. 5-242 0. 025 72 4-F 4-F c~3 2 239-240 ~ 4 . 5 73 ~1 ll ClFCHCF~ 2 213-214 O.25 74 4-C~I30 4-C~30 C~F2 2 186-187 0. 5 ~I ~I CHF2 2 265 O . 35 76 H H HC12CF2 2 223-223 . 5 1. 5 77 4-C1 4-Cl C~F2 2 244-245 0. 35 78 4-F 4-F C~2 2 246. 5-247 0. 1 79 4-C1 4-F c~3 2 226-227 2 . 8 4-C1 4-F HCF2C~2 2 2l2-2l3~ 0.09 81 4-C~I3 4-CH3 HCF2~F2 2 225-226 O . 35 82 4-~30 H HCF2CF2 2 169-170 1.1 83 2-C1 4-C~30 E1~2CF2 2 176-177 7. 2 84 3-C~30 3-~3 H~F2CF2 2 155. 5-156. 5 4.0 4-C1 ~ ~H3 2 169-170~ 30 86 4-Cl ~I XCF2CF2 2 2û6-207 . 5 Q. 065 87 4-F 4-C~3 C~3 2 189-190 3.7 88 4~C1 4 CF3 C~3 2 224-225 2 . 2 89 4-CF3 H ~{CF2CF~ 2 188_189~ 2.4 4-C1 4-C~3 ~CF2C~2 2 208-209 1. 8 - 3~ -1~37~327 Table III (Continued) Adjuvant Arthritis Example X Y R n m.p. (ED50%) 2 _ 91 2-C-1 2-Cl C 2C 2 2 183-184 0.8 92 4-F C 2 2 2 228-229 0.027 93 3-C1 3-C1 2 2 2 208-209 0.16 94 4-C1 4-Cl CHF2 1 203-206 0.19 4-ca30 4-CH30 BrFCHCF2 2 187-188 2.4 9~ 4-CH 2 2 2 202-203 0.6 97 3 4-OCH20 3,4-OCH20 HCF2 2 2 212-214 1.0 1017 4-CH30 4-CH30 CH3SCH2 1 142.5-143.5 28 _ _ _ I This biological system is described previously.
2 Units are in mg./kg.

~ 3~ -1(~7~3~

Table IV

~_N
~ >~ () nR

X Y R n 2-C1 2-ClHCF2CF2 2 4-n-C H 4-n-C H2 2 2 4-NH2 4-NH~ 2 2 4-N(CH3) 4-N(CH3) 2 2 3,4-C1 H 2 2 2 4-t-C4H~0 4-t-C4H902 2 2 1~7~3~

TABLE V
ADJUVANT-INDUCED ARTHRITIS IN RATS

CHEMICAL ED5( 1~ m~
EXA~LE ESTABLISHRD NON-ESTABLI SHED
N UMBE R ARTH R I T I S _ ARTHR I T I S
18 1.5 2.3 39 0.2 0.06 71 0. 03 0. 03 86 0.1 Phenylbutazone 10 35 Indomethacin O. 3 3 Cyclophosphamide 10 1. 5 Test in progress.

_ 39 _ 1(~74327 TABLE VI
HEMOLYTIC PLAQUE ASSAY IN SPLEEN CELL SUSPENSIONS
FROM ART~IRITIC, NON-ARTIIRITIC AND
D~UG TREATED A~THRI~'IC RATS

_ _ MEAN PLAQUE FORMING
CHEMICALDAILY ORALCELLS PER .UILLION
EXAMPLE DOSE SPLEEN CELLS
NuMBER a mg/kg _(N = 20) 18 1.5 3290 39 0.1 788 1.0 488 71 0.~3 499 0.3 439 Arthritic Control* _ 863 Non-Arthritic _ 323 Indomethacin** 1.0 720 .
Cyclophosphamide5.0 25 . _ ~ .. . ._ * Data pooled from 3 experiments.
** Data pooled from 2 experiments.
a Chemical Example Number 86: test in progress.

~ 43 ~

TABI.~ VII
PROPORTION OF B LYMPHOCYTES IN SPLEEN CELL
SUSPENSIONS FROM ARTIIP.ITIC, NON-ARTHRITIC
AND DRUG TREATED ARTHnITIC RATS AS
DETERMINED BY FLUORESCENT ANTIBODY STAINING
CHEMICAL DAILY ORAL
EXAMPLE DQSE MEAN
NUMBER mg/kg % B CELLS

86 1 l 48 Arthritic Control* _ 57 Non-Arthritic 42 Control*
Phenylbutazone 20 53 Indomethacin 0.5 57 Cyclophosphamide 25 *Pooled data from 7 experiments.

- 41 ~

10~43;~7 SUPPLEMENTARY DISCIOSURE

As described hereinbefore the compounds of the present invention exhibit anti-inflammatory and immuno-regulating properties. It has now been found that compound~
of the inventlon exhlbit analgesic activity as measured by the phenylquinone writhing test described hercir~after.
With respect to analgesic activity the following compounds are prefcrred:

~s ( )n-R

where Rl = Cl-C4 alkyl, monohalo- and polyhalo-Cl-C4 ~lkyl;
Yl and Y2, the same or different, = H, 2-methoxy, 4-methoxy, 2-ethoxy, 4-ethoxy, 2-chloro, or 4-chloro; and n = 0, 1 or 2.
Particularly preferred are the compounds in which Rl i8 poly-halo-Cl-C2 alkyl and Yl and Y2, the same or different, are H, 2-methoxy, 4-methoxy, 2-ethoxy, 4-ethoxy, 2-chloro or 4-chloro, with the proviso that at least one of Yl and Y2 is ~-methoxy or 4-ethox~, and n is O, 1 or 2.
Specific compounds that are pre~erred ~or analgesic activity are:

4,5-bis(4-methoxyphenyl)-2-(1,1,2-trifluoro-ethylenesulfonyl)imidazole, 4,5-bis(4 methox~phenyl 3 -2-(1,1,2,2-tetra~luoroethyl-~ulfonyl)imidazole;

- 42 _ ~. ~

107~3'~7 4,5-bis(4-methoxyphenyl)-2-(2,2,2-trifluoroethyl-thio)imidazole;
4,5-biQ(4-methoxyphenyl)-2-(2,2,2-trifluoroethyl-sulfinyl)imldazole;
4,5-bis(4-methoxyphenyl)-2-(2,2,2-trifluoroethyl-sulfonyl)imidazolej 4,5-bis~4-methoxyphenyl)-2-(trifluoromethylsulfonyl)-imldazole.
The use of c~mpounds of the present invention as analgeQic agents i~ illustrated by the following example.

Example 103 A standard procedure for detecting and comparing the analgesic activity of compounds and for which there i8 good correlatlon with hllman e~ficacy i9 the standard phenyl-quinone wr1thing test modified ~rom Siegmund, et al., Proc.
Soc. Exp. Biol. Med. 95, 729 (1957). Accordlng to th~s procedure a test compound suspended in 1~ methylcellulose ~s given orally to fasted (17-21 hours) female white mice, 5-20 animal~ per double blind test. Aqueous (0.01~ phenyl-~-2~ benzoquinone) phenylquinone i~ in~ected intraperitoneally24 minute~ later uslng 0~20 ml per mouse. Commencing at 30 minute~ after the oral administration of the te~t compound, the mice are obser~ed for 10 minute~ for a characterist~c stretching or writhing syndrome which is indicative of pain induced by phenylquinone.
In this example, the ef~ective analgesic dose for 50~ of the mice (ED~o) was calculated by the mo~ing average method o~ Thompson, W. R., Bact. Rev. 11, 115-145 (1947).

In addition, the time of peak action was determ~ned for many o~ the compounds.

1~)74~ ~

I~e results for compound~ of the formula CH30~ ~S~o3n-R

CH30-/ ~ H

were as follows:
ED50* PEAK TIME
R n (~n) C~F2 2 1.5 CF3 2 0.045 240 CH2CF3 1 o.86 60 CH2CF3 0 1.2 240 CH2CF3 2 o.58 60 CF2CH2F 2 0.25 160 CF2CHF2 1 o.8 CF2CHF2 2 0.11 120 CF2CHBrF 2 2.8 * unit 8 are mg/kg The re~ult~ for compounds of the formula X~\~l ~~S()n~R

were a6 follow~:
X Y R n ED *PEAK TIME
5~(min) 4-CK30 2-ClCF2CHF2 2 0.5650 4-CH30 H 2 2 2 0.33240 4-c2H50 H ~F2CHF2 2 0.95120 E H CF2CHF2 2 o.48120 * un~ts are mg/kg lQ~

The preparation of compounds of the present invention may be :~urther illustra~ed ~y the ~ollowing examples:

Example 104 4,5-bis(4-Fluorophenyl)-2-trifluorometh,ylthioimidazole Using the procedures of Example 101, and substituting 4,5-bis~4-fluoropher-yl)imidazole for the 4,5-diphenylimidazole of Example 101, one obtains as final product 4,5-bis (4-fluorophenyl)-2-trifluoromethylthioirnidazole, mp 228-229C.
Anal. Ca~c'd. for C16H9F5N2S C, 53~93~ HJ 2~55; N~ 7-86-Found: C, 54.17, 54.12; H, 2.59, 2.58; N, 7.34, 7~97.

Example 105 Further to the data presented in Table IIl herein-before, it has now been found that the compcund of Table lII
in which X is 4-F, Y is 4-F, R is CF3 and n=2 has a melting point of 264-265~C and an ad~uvant arthritis ED5~ of 0. 015.

_ thod of Synthesi~
In an embodiment of the present invention compounds of the general formula R2 ~ N
~ ~ ~S~) where R2 and R3 are phenyl or substltuted phenyl, n = O, 1 or 2, R~ is a fluorinated alkyl group, espec~ally CF3;
may be prepared by contacting an N-prctected d~aryllmidazole wlth a strong base, then ~ith a fluorinated alkylsulfenyl - 4~ -1a743~

halide dlsulfide or sulfonic anhydride, followed by removal of the protecting group and by subsequent oxidation of the sulfur if desired.
The nature of the N-protecting group is such that it i8 stable to strong bases, but easily removed by acidic reagents or by hydrogenolysis. Examples o~ such protecting groups are 2-tetrahydropyranyl, benzyloxymethyl, methoxymethyl, methylthiomethyl, ~-methoxyethoxymethyl, and 2-tetrahydro-furanyl.
The N-protected diarylimidazole is contacted with a strong base, for example, alkali metal alkyls (n-butyl lithium and the like), alkali metal hydride (sodium hydr~de and the like), alkali metal alkoxides (sodium methoxide, potassium t-butoxide and the like), alkali metal amides (sodium amide, lithium diisopropylamide and the like), in a non-hydroxylic solvent, for example, ether, tetrahydrofuran, ethylene glycol dimethyl ether, hexane, toluene, etc. Preferably the reaction temperature i~ in the range 0C to -78C, temperatures from 0C
to the boiling point of the solvent may, however, be used. The addition of a complexation agent, for example tetramethyl-ethylenediamine, to the reaction medium may improve the yield of product.
The imidazole anion thus produced i8 then contacted with a fluorinated alkyl thio reagent of one of the following types: sulfenyl halide, disulfide or sulfonic anhydride.
Examples of such reagents are tri~uoromethanesulfenyl chloride, trifluoromethyl disulfide, tr~fluoromethanesulfonic anhydride, pentafluoroethanesulfenyl ch'oride, disulfide, etc. This portion o~ the reaction is also preferably carr~e~ out at a temperature in the range -78C to 0C, although temperatures from 0 to the bolling point of the solvent may be used.

- 4~ -1~)7~32 ~

~ le N-protected 2-fluor~nated alkylthio (or sulfonyl)-4,5-diarylimidazole thus obtained is treated to remove the protecting group, ~or example, by contactin~ with an or~anic or inor~anic acid, e.g, acetic acid, hydrochloric acid, sul-furic acid or the like, or b~ contacting with Lewis acids, e.g. zinc bromide, titanium tetrachloride, etc., or by hydro-~enolysis, e.g. by contactin~ with hydrogen and a suita~le catal~st. Hydr~lysis of the protecting group can in some cases take place under normal aqueous workup conditions.
The 2~fluorinated alkylthio-4,5-diarylimidazole thus obtained (in the case of ~luorinated alkyl sulfenyl halide or disulfide) is oxidized to the corresponding sulfoxide and sul~one by using an oxidizing agent, e.g. peracids (for example, m-chloroperoxybenzoic acid), sodium metaperiodate, hydrogen peroxide, potassium permanganate, or the like.
Specif~c examples of these general procedures are ~iven as Examples 106-111 and Tables VIII-X.
Example 106 4~5-Dlphenyl-1-(2-tetrahydropyranyl)imidazole A mixture of 27 g (0.122 mole) 4,5-diphenylimidazole, 21 g (0.25 mole~ dihydropyran, 250 ml ethyl acetate and 4.0 g BF3-Et20 was refluxed for five days. The nearly clear solution was dlluted with ether and ~iltered to remove o.6 g insoluble starting material. The ether filtrate was washed several times with 10% NaHC03 then dried and e~aporated. TLC showed starting material st~ll present, ~o the crude product was chromatographed on 2 lb SILIC AR CC-7, eluting with toluene conta~rlng 20 to 40 eth~l acet~te. The pure product thus obtalned was 30.3 ~ (81.7 mp 170-1. IR: 3.21 ~5 =CH; 3.40, 3.4g ~ sat. C~; 6.25, 6.64, 5.73 ~ aromatic C=C and/or C=N; strong 9^10 ~, C-0-C; 12.98 and 14.38 ~ monosubstituted aromatlc. H-N~: mult. ~1.6-2.3 ~, 6H);

- 1~7 -,, ~ 3 ~,'t mult. (~3.4, 4.0, 4.8 ~, each ~lH); mult. ~ singlet (7.Q-7.6 +
7.4 6J lOH); S (7.8 ~, lH). Mass spectrum, calcd for C20H2Q~20:
304.1547; Found: 304.1559.
Anal. Calcd for C20H2QN20: C, 78092; H, 6.62; N, 9.20 Found: CJ 7g.573 H, 6.~9; N, 9.07 2-Tetrahydropyranyl protected imidazoles obtained in a similar fashion are listed in Table VIII.
TA~LE VIII
1-(2-Tetrahydropyranyl)imidazoles .

X ~ N ~ -H

Y ~ I
~0 ~J
X Y m.p. Analysis H H 170-1 C,H,N
p-F p-F 158-9 C,H,N
pCH30 pCH30 123-5 C,H,N

pF or pCH30 pCH30 or pF 109-125~ C,H,N (mixture of both isomer~) or 3,4-DiC1 3,4-DiCl or ~ 113-120 C,H,N
Exa~ple 107 4,5-Diphenyl-2-trifluoromethylthioirnidazole Unde~ nitroa,en and in glassware dried with a heat c~un, a solution o~ C.9 g (3 mmole) o~ 4,5-diphenyl-1-(2-tetra~ydro-pyranyl~-midazole in 15 ml '~HF and 15 ml ether ~as chilled to -78~ To the cold solution was added dropwise a solution o.

2.5 ml ~4 mmole~ of 1.6 M n-butyl l.ithium in hexane in 10 ml ethPr. '~he solution was stirred at -78, then 0.55 .~3 (4 ~.ole) 10743,~,7 o~ trifluoromethanesulfenyl chloride (TOXIC) was added as a gas.
The mixture was stirred at -78 for 2 hours, then at RT over-night. The mixture was poured into water and extracted with ether (pH of aqueous layer ~ 4). The aqueous layer was neutra-lized with bicarbonate then extracted with more ether. The combined ether extracts were dried and concentrated. ~e crude res~due was chromatographed on a 50 g SILIC AR CC-7, eluting with 98% toluene/2~ ethyl acetate, to give 0.45 g (47,~') of productr ~ecrystallization from toluene gave 0.3 g (31%) of white solid, mp 254-6. IR: broad 3-4 ~, NHj 3.28 ~, =CH;
6.24, 6.34, 6.42, 6.71 ~, aromatic C=C and/or C=N; strong

8.5-9 ~, C~F; 13.09, 14.34 ~ monosubstituted aromatic. H-N~R:
mult. (7.1-7.7 ~, lOH); broad (13 6, IH). F-I~ S(42.45 ~).
Mas~ Spectrum: Molecular lon C16~11F3N2S
Anal. Calcd for C16HllF3N2S: C, 59.99; H, 3.46; N, 8.75 Found: C, 60.20; H, 3.57, N, 8.52 Example 108 4,5-Diphen~1-1-(2-tetrahydropyranyl)-2-trifluoro-methylthioimidazole (via trifluoromethyl d~sulfide~.
In glassware dried with a heat gun and under nitrogen, to a mixture of 1.5 g (5 mmole) of 4,5-diphenyl-1-(2-tetrahydro-pyranyl)imidazole in 20 ml THF and 20 ml ether at -78 was added dropwise a solution o~ 3.75 m~ (6 mmole) of 1.6 2~ n-butyl lithium in hexane in 20 ml ether. To the light yellow solution was added dropwise a~ter 15 mlnutes at -7~ a solution of 1.2 g (6 mmole) trifluoromethyldisul~ide (TOXIC~ in 1~ ml ether. The dark solution was stirred at -78 for 1 hr~ then RT one-half hour ~cvernlght is not detrimental). The m~xture was added to water and extracted three times with ether ~pH of aqueous layer ~ 6).
The ether extracts were dried and concentrated. ~ne residue was ch~omatographed on 150 g SILIC AR CC-7, ~luting with toluene _ L~g _ 10'~ 4;~7 to ~is~e, after recrystallization from hexane~ 0.55 ~ of product~
mp 104-5. IR: 3.25 u, =CH; 3.37, 3.48 ~, sat CH; 6.23, 6.64, 6.74, conju~ated cyclic C-C and/or C=N; strong 9 u region, -SCF3 and C-0-C; 13.09, 14.36 }1, monosubstituted aromatic. H-I\~:
mult (1.1-2.0 o, 6H); mult (3.2-4.2 o, 2~); mult (5.3-5.6 6, lH); mult + s (7.0-7.5 + 7.4 ~, lOH). F-NMR: S (42.20 ~).
Anal. Calcd for C21HlgF3N20S C, 6 3 ;
Found: C, 62.70; H, 4.~3; N, 6.91 The use of tetramethylethyldiamine in an amount equivalent to the n-butyl lithium used led to improved yields of product.
Example 109 4,5-Diphenyl-2-trifluoromethylthiolmidazole (via hydrolysis of tetrahydropyranyl derivative) A small sample of 4,5-diphenyl-1-(2-tetrahydro-pyranyl)-2-trifluoromethylthioimidazole was suspended in 1:1 ethanol:0.1 N hydrochloric acid. '~he mixture ~sas heated on a steam bath (clear solution) for one hour. Upon cooling, crystals of product fo~ned and were collected, washed with water and dried. 'rhe solid was shown to be 4,5-diphenyl~2-trifluoromethyl-thLoimidazole by IR, TLC and mp (255G).
4,5-Diaryl-2-trifluoromethylthioimidazoles prepared by methods sirnilar to those of Examples 106-lC9 are listed in ~able IX, along with their ED50 ~mg/kg) in the adJuvant arthri-tis screen.
TABLE IX
4,5-Diaryl-2-trifluoromethylthioimidazoles ~ . . _ X ~ ~ ~ N

Y

~o7 ~3'~-7 X Y m.p. A.A.ED50 H H 254-6 >3 ~26~ @ 3) pF pF 228-9 0.02 pCH30 pCH30 181-2 1.5 pF pCH30 156-157.5 2.7 H 3,4-DiC1 241-2 7.0 Example 110 4,5-Diphenyl-2-trifluorometh~lsulfonylimidazole fvia oxidat~on of sulfide) .
A mixture of o.48 g (1.5 mmole) of 4,5-diphenyl-2-trifluoromethylthioimidazole and 0.72 g (3.6 mmole~ of 85~o m-chloroperoxybenzoic acid in 30 ml methylene chlorlde was stirred at RT overni~ht, then slnce TLC indicated incomplet~
oxidation, at reflux another day~ T~C still indicated incomplete oxidation, so the methylene chloride was removed by rotary evaporatlon and replaced by 30 ml chloroform and the mixture was refluxed 6 hrs. The chloroform was evaporated and the re~idue triturated with ~ 20 ml ether. The ethe~ insoluble solid (~ 0.3 g) was combined with ~ 0.1 g of solid obtained from the ether filtrate by washing with 10~ sodium sulfite, 10~
sod~um bicarbonate, drying and evaporatlng. Recrystallization from toluene gave 0.37 g (70~) of white product, mp 2~2-3.5 (~ublime~s above 250). IR: 3-4 ~, M~; 6.33, 6.44, 6.72 ~, aromatic C=C and/or C=N; 7,23, 8.32 ~, -S02-; 8.97 ~; C-F;
13.05, 14.30 ~, monosubstituted aromat~c. H-~MR: mult (7.1-7.7 65 lOH). ~ S (78.25 ~; small singlets were also observed at 42.43 ~ (- 2G/o, sulf~de) and at 72.69 ~ (~3G~, sulfoxi~
Anal. Calcd for C15HllF3N202S C, 54O54; ~, 3 5;

Found: C, 55.13; H, 2.g4; N, 8.o6 54.98 2.9~ 8.05 '7 Example 111 4,5-Diphenyl-2-trifluoromethylsulfonylimidazcle (via trifluoromet~anesulfonic anhydride) In glassware dried with a heat gun and under nitrogen, to a solution of 1.5 g (5 mmole) 4,5-diphenyl-1-(2-tetrahydro-pyranyl)imidazole in 20 ml THF and 20 ml ether at -78 was added dropwise a solution of 3.75 ml (6 mmole) of 1.6 ~ n-butyl lithium in hexane in 20 ml ether. After stirring at -78 for 15 minutes, a solution of 1.7 g (6 mmole~ of trifluoromethanesulfonic anhydride in 10 ml ether was added. The reaction mixture was stirred at -78 for two hours, then RT 2 days. The mixture was added to water, neutralized with sodium bicarbonate and extracted with ether. me ether extracts were dried and concentrated and the residue was chromatographed on 150 g SILIC AR CC-7. Elution with toluene gave 0.25 g of solid whlch was identified by mass spectrum as 4,5-dlphenyl-1-(2-tetrahydropyranyl)-2-trifluoro-methylsulfonylimidazole (IR: no ~I, strong sulfone, C-0-C
bands). Elution with 90/10 toluene/ethyl acetate gave solid product, recrystallized from toluene to glve 80 mg (~ 5~) of 4,5-dlphenyl-2 trifluoromethylsulfonylimidazole, mp 285-288.
me IR was identical to the product obtained by oxidation of 4~5-diphenyl-2-trifluorornethylthloimidazole.
4,5-Diaryl-2-trifluoromethylsulfonylimidazoles pre-pared by methods similar to Examples 1lO and 111 are listed in Table X, with ad~uvant arthrit~s ED50's.
TAB~E X
4,5-Diaryl-2-trifluoromethylsulfonylimidazoles X f ~`~1 ~S02cF3 ~ / ~ N
Y ~ H

1~74327 X Y m.p. A.A.ED50 H H 292-293.5 0.03 pF pF 264-5 0.015 pCH30 pCH30 201-202.5 0.33 pF pCH30 187-8 1.4 H 3,4~DiC1 195.5-197 0.35 Using the procedure described hereinbefore in Example 10 and the appropriate starting materials, and further to the compounds of-Table I, the compounds of Table lA can be pre-pared.
TA~ IA

X ~ ~ -S-R
~ ~ N
Y ~ H

A.A.*
X Y R m.p. ED50 -3-Cl H CH3 202-203 50 3,4-C12 H CH3183.5-184.5 ~25 4-F 4-F CH3(CH2)3175-175.5 C10 *AA 1s ad~uvant arthritis. Units are in mg/kg.
Using the procedure described herein~efore in Example 18 and the approprlate starting materials, and further to the compounds of Table II, the compounds of Table IIA can be pre-pared.
TABLE IIA

/\XN Z
Y ~ H

~0743Z7 A.A.
X Y Z m.p. ~D50 3-Cl H F 212-213 0.5 3-F H F 205.5-207 2.5 3,4-C12 H . F 209-211 3.0 4-CH30 4-F F 170-171.5 14 Usin~ the procedure of Ex~mples 13 and 14 and the appropriate starting materials~ and further to the compounds of Table III, the compounds of Table IIIA can be prepared.
TABLE IIIA

X~

~ ~> ~S (O )nR
/~
Y _ ~ H

A.A.
X Y R n m.p. ED
3-Cl H CH3 1 150-151.5 ~75 3-Cl H CH3 2 171-172 < 10 3-F H CH3 1 163.5-164.5~ ~100 3,4-C12 H CH3 1 l88-l8go 50 3~4-C~2 H CH3 2 199-200 ~50 3-Cl HHGF2CF2 2 193-194 0.05 3-F H~CF2CF2 2 217-118 0. o6 4-c2H50 HHCF2CF2 2 162-163 1.5 3,4-Cl? H~ICF2CF2 2 197-198 0.2 4-F 4-F CH3 1 185-187 4.0 4-F 4-~HCF2CF2 1 192.5-193 0.055 4-CH30 4-FHCF2C~2 2 189-190 2.2 4-02N 4-02N HCF2CF2 2 240-240.5 8.5 17~327 TABLE IIIA (Contd) A.A.
X Y R n m.p. ED50 _ 4-CH30 4-CH30 H2CFCF2 2 162-164 5.0 H H HCBrFCF2 2 217-218 0.85 H H H2CFCF2 2 239-240 0.15 4-CH30 4-CH30 HCFICF2 2 190-192 3.0 4-CH30 4-CH30 CH3(C 2)3 99 101 ~50

Claims (44)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the formula where n = 0, 1, or 2;
R1 = C1 - C4 alkyl; allyl; vinyl; -CH2COCH3;
-CH2S(O)mCH3, where m = 0, 1, or 2;
mono- and polyhalo- C1 - C4 alkyl;
R2 and R3, the same or different =

Y1 and Y2, the same or different =
hydrogen, hydroxy, C1-C4 alkoxy, acetoxy, C1-C4 alkyl, Cl, F, CF3, NH2, -N(CH3)2, NO2, , CH3S-, CH3SO2-, or Y1 and Y2 taken together forming a dioxymethylene bridge;
provided, when R1 = C1-C4 alkyl, C3-C4 haloalkyl with halogen substituted at the 3 or 4 position, allyl, or acetonyl, both Y1 and Y2 cannot be H;
provided further, when n = 0 and R1 = CH3, both Y1 and Y2 cannot be p-C1 or p-OCH3, said process being selected from the group consisting of (A) contacting a compound of the formula with an alkylating agent;
(B) the process of (A) followed by contacting the resulting substituted-thioimidazole with a suitable oxidizing agent;
(C) contacting a compound of the formula where P is a protecting group, with a base and then with a fluorinated alkylsulfenyl halide, disulfide or sulfonic anhydride (RfSX or (RfSO2)2O
where X is halo or -SRf, Rf being a fluorinated alkyl group);
(D) the process of (C) followed by contacting the resulting product with a suitable oxidizing agent.

2. The process of Claim 1 when the process is (A).

3. The process of Claim 1 when the process is (B).

4. The process of Claim 1 when the process is (C).

5. The process of Claim 1 when the process is (D).

6. The process of Claim 1 where n = 0, 1, or 2, R1 = C1 - C4 alkyl; allyl; -CH2COCH3;
-CH2S(O)mCH3, where m - 0, 1, or 2;
mono- and polyhalo-C1 - C4 alkyl;
R2 and R3, the same or different =

Y1 and Y2, the same or different =
hydrogen, hydroxy, methoxy, ethoxy, acetoxy, C1-C4 alkyl, C1, F, CF3, NH2, -N(CH3)2, or Y1 and Y2 taken together forming a dioxymethylene bridge;
provided, when R1 = C1-C4 alkyl, C3-C4 fluoroalkyl with the fluorine substi-tuted at the 3 or 4 position, allyl, or acetonyl, both Y1 and Y2 cannot be H;
provided further, when n = 0 and R1 = CH3, both Y1 and Y2 cannot be p-Cl or p-OCH3.

7. The process of Claim 1 where R1 = -CF2CF2H.

8. The process of Claim 1 where R2 and R3 inde-pendently, = , where Y1 = H, C1, or F.

9. The process of Claim 1 where n = 1 or 2.

10. The process of Claim 1 where n = 0, 1 or 2;
R1 = -CF2CF2H;
R2 and R3, independently, = where Y1 = H, C1 or F.

11. The process of Claim 1 where n = 0 or 2;
R1 = -CF2CF2H;
R2 and R3, independently, = where Y1 = H, C1 or F.

12. The process of Claim 1 where n = 2, R1 = -CF2CF2H, and R2 and R3 are each 4-fluorophenyl.

13. The process of Claim 1 where n = 2, R1 =
-CF2CF2H, one of R2 and R3 is 4-fluorophenyl and the other is phenyl.

14. The process of Claim 1 where n = 2, R1 =
-CF2CF2H, and R2 and R3 are each 4-chlorophenyl.

15. The process of Claim 1 where n = 2, R1 =
-CF2CF2H, one of R2 and R3 is 4-chlorophenyl and the other is phenyl.

16. The process of Claim 1 where n = 2, R1 =
-CF2CF2H, and R2 and R3 are each phenyl.

17. The process of Claim 1 where n - 0, R1 =
-CF2CF2H, and R2 and R3 are each phenyl.

18. The process of Claim 1 where R1 = -CF3.

19. The process of Claim 1 where n = 2, R1 = -CF3 and R2 and R3 are each phenyl.

20. A compound of the formula where n - 0, 1, or 2;
R1 = C1 - C4 alkyl; allyl; vinyl; -CH2COCH3;
-CH2S(O)mCH3, where m = 0, 1, or 2;
mono- and polyhalo- C1 - C4 alkyl;
R2 and R3, the same or different =

Y1 and Y2, the same or different =
hydrogen, hydroxy, C1-C4 alkoxy, acetoxy, C1-C4 alkyl, Cl, F, CF3, NH2, -N(CH3)2, NO2, , CH3S-, CH3SO2-, or Y1 and Y2 taken together forming a dioxymethylene bridge;
provided, when R1 = C1-C4 alkyl, C3-C4 haloalkyl with halogen substituted at the 3 or 4 position, allyl, or acetonyl, both Y1 and Y2 cannot be H;
provided further, when n = O and R1 = CH3, both Y1 and Y2 cannot be p-Cl or p-OCH3, when made by the process of Claim 1.

21. A compound of the formula of Claim 20, when made by the process of Claim 2.

22. A compound of the formula of Claim 20, when made by the process of Claim 3.

23. A compound of the formula of Claim 20, when made by the process of Claim 4.

24. A compound of the formula of Claim 20, when made by the process of Claim 5.

25. A compound of the formula of Claim 20 where n = 0, 1, or 2;
R1 = C1 - C4 alkyl; allyl; -CH2COCH3;
-CH2S(O)mCH3, where m = 0, 1, or 2;
mono- and polyhalo- C1 - C4 alkyl;
R2 and R3, the same or different =

Y1 and Y2, the same or different =
hydrogen, hydroxy, methoxy, ethoxy, acetoxy, C1-C4 alkyl, Cl, F, CF3, NH2, -N(CH3)2, or Y1 and Y2 taken together forming a dioxymethylene bridge;
provided, when R1 = C1-C4 alkyl, C3-C4 fluoroalkyl with the fluorine substituted at the 3 or 4 position, allyl, or acetonyl, both Y1 and Y2 cannot be H;
provided further, when n = O and R1 = CH3, both Y1 and Y2 cannot be p-Cl or p-OCH3, when made by the process of Claim 6.

26. A compound of the formula of Claim 20 where R1 = -CF2CF2H, when made by the process of Claim 7.

27. A compound of the formula of Claim 20 where R2 and R3 independently, = , where Y1 = H, Cl, or F, when made by the process of Claim 8.

28. A compound of the formula of Claim 20 where n = 1 or 2, when made by the process of Claim 9.

29. A compound of the formula of Claim 20 where n = 0, 1 or 2;
R1 = -CF2CF2H;
R2 and R3, independently, = where Y1 = H, Cl or F, when made by the process of Claim 10.

30. A compound of the formula of Claim 20 where n = 0 or 2, R1 = -CF2CF2H;
R2 and R3, independently, = where Y1 = H, Cl or F, when made by the process of Claim 11.

31. 4,5-bis(4-fluorophenyl)-2-(1,1,2,2-tetra-fluoroethylsulfonyl)imidazole, a compound of the formula of Claim 20 where n = 2, R1 = -CF2CF2H, and R2 and R3 are each 4-fluorophenyl, when made by the process of Claim 12.

32. 4(or 5)-(4-fluorophenyl)-5(or 4)-phenyl-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole, a compound of the formula of Claim 20 where n = 2, R1 = -CF2CF2H, one of R2 and R3 is 4-fluorophenyl and the other is phenyl, when made by the process of Claim 13.

33. 4,5-bis(4-chlorophenyl)-2-(1,1,2,2-tetrafluoro-ethylsulfonyl)imidazole, a compound of the formula of Claim 20 where n = 2, R1 = -CF2CF2H, and R2 and R3 are each 4-chloro-phenyl, when made by the process of Claim 14.

34. 4(or 5)-(4-chlorophenyl)-5(or 4)-phenyl-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole, a compound of the formula of Claim 20 where n = 2, R1 = -CF2CF2H, one of R2 and R3 is 4-chlorophenyl and the other is phenyl, when made by the process of Claim 15.

35. 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylsulfonyl)-imidazole, a compound of the formula of Claim 20 where n = 2, R1 = -CF2CF2H, and R2 and R3 are each phenyl, when made by the process of Claim 16.

36. 4,5-phenyl-2-(1,1,2,2-tetrafluoroethylthio)-imidazole, a compound of the formula of Claim 20 where n = 0, R1 = -CF2CF2H, and R2 and R3 are each phenyl, when made by the process of Claim 17.

37. A compound of the formula of Claim 20 where R1 = -CF3, when made by the process of Claim 18.

38. 4,5-diphenyl-2-trifluoromethylsulfonylimidazole, a compound of the formula of Claim 20, where n = 2, R1 = -CF3 and R2 and R3 are each phenyl, when made by the process of Claim 19.

CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE

39. A process of Claim 1 where n = 0, 1 or 2;
R1 = C1-C4 alkyl, monohalo- or polyhalo-C1-C4 alkyl;
R2 and R3, the same or different =

Y1 and Y2, the same or different = H, 2-methoxy, 4-methoxy, 2-ethoxy, 4-ethoxy, 2-chloro or 4-chloro.

40. A compound of the formula of Claim 20 where n = 0, 1 or 2;
R1 = C1-C4 alkyl, monohalo- or polyhalo-C1-C4 alkyl;
R2 and R3, the same or different =

Y1 and Y2, the same or different = H, 2-methoxy, 4-methoxy, 2-ethoxy, 4-ethoxy, 2-chloro or 4-chloro, when made by the process of Claim 39.

41. The process of Claim 39 where R1 is polyhalo-C1-C2 alkyl.

42. The process of Claim 41 where R2 and R3, the same or different =
Y1 and Y2, the same or different = H, 2-methoxy, 4-methoxy, 2-ethoxy, 4-ethoxy, 2-chloro or 4-chloro, with the proviso that at least one of Y1 and Y2 is 4-methoxy or 4-ethoxy.

43. A compound of the formula of Claim 20 where n = 0, 1 or 2;
R1 = polyhalo-C1-C2 alkyl;
R2 and R3, the same or different =

Y1 and Y2, the same or different = H, 2-methoxy, 4-methoxy, 2-ethoxy, 4-ethoxy, 2-chloro or 4-chloro, when made by the process of Claim 41.

44. A compound of the formula of Claim 20 where n = 0, 1 or 2;
R1 = polyhalo-C1-C2 alkyl;
R2 and R3, the same or different = H, 2-methoxy, 4-methoxy, 2-ethoxy, 4-ethoxy, 2-chloro or 4-chloro, with the proviso that at least one of Y1 and Y2 is 4-methoxy or 4-ethoxy, when made by the process of Claim 42.