CA1105024A - Anti-inflammatory-4,5-dicyclic-2-(substituted thio) imidazoles and their corresponding sulfoxides and sulfones - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Antiinflammatory 4,5-dicyclic-2-(substituted thio)-imidazoles and their corresponding sulfoxides and sulfones, such as, 4-(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethyl-sulfonyl)-5-(2-thienyl)-1H-imidazole, useful for treating arthritis and related diseases.

Description

;2~
BACKGROUND OF THE INVENTION

This invention relates to antiin~lammatory imidazoles.
Lombardirlo, in U.S. Patent 3,707,475 discloses anti-inflammatory 4,5-diaryl-2-substituted imidazoles~
Doebel, in U.S. Patents 3,505,350 and 3~651,080, respectively, discloses antiinflammatory 4-alkyl-5-aryl-l-substituted-2-mercapto~imidazoles and 4-alkyl-2-alkylthio-5-aryl-1-substituted imidazoles.
Zauer, K., et al., in Chem. Ber., 106~ 1638 (1973) disclose ~l,5-bis(4-methoxyphenyl)-2-methylthioimidazole and 4,5-bis(4-chlorophenyl)-2-methylthioimidazole but do not suggest any use.
A number of reerences, such as Current Sci.
India, 17, 184-85 (1948) and Acta. Chem. Acad. Scl. 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 anti-inflammatory agents. Inflar~mation is a disease process characterized by redness, fever, swelling, and pain.
Arthritis, in its various forms, is the most prevalent, chronic, and severe o the inflammatory diseases. Traumatic injury and infection also involve inflammation, and anti-in1a~natory drugs are often used in their treatment. The usefulness oE most commercial anti-inElammatories 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 sys-tem. Adreno-cortical steroids produce yastric irritation and suppression 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 ef-Eective 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 arthritis or related diseases;
however, such compounds can be employed solely to alleviate paln .

SUMMARY OF THE INVENTION

According to this invention there is pro~ided com-pounds of formula I, pharmaceutical compositions containing them, and methods of using them to treat arthritis in mammals~

~ ~ 5(0)n ~ Rl I

R~

where n = 0, 1, or 2;
Rl = polyfluorO-cl-c2 alkyl; :
R2 and R3, the same or different -2-thienyl, 3-thienyl, 3-pyridyl,

3-pyridyl-N~oxide, 2~furyl or , Y~y : . ~

. ~ ~ ,}

, - . . . : `' where Yl and Y2, the ~ame or different =
H, Cl-C4 alkoxy, Cl-C4 alkyl, C], F, or Yl and Y2 taken together forming a dioxymethylene bridge, provided that only one of R2 or R3 can =

; and R4 = hydrogen;

-CHOR6;

2-tetrahydropyranyl;
2-tetrahydrofuranyl;

O O O
" ., 1.
7 7, r; or -S02Ar;
~: where R5 = H or methyl;

R6 Cl C3 alkyl r benzyl, CH2CH2 3;
O , 7 : .
R7 = Cl--C4 alkyl or benzyl; and 20 Ar y.3 ~ where Y = H F Cl, Br, Cl-C4 alkyl, -Cl-C4 lkoxy, or nitro~

"- ' .: ' , .. .
~ ' ' -provided when O o O
R4 = -COR7, -C-R7, C Ar or 2 then n must be 0; or its pharmaceutically suitable acid addition salts where n = 0 or where at least one of R2 or R3, independently, = 3-pyridyl; and its pharmaceutically acceptable metal salts where R~ = hydrogen and n = 1 or 2.

Tautomers When R~ and R3 are different and R~ = hydrogen, the following two structures are tautomers:

El R3 X ~ ~ ( )nRl = ~ ~ S(0) -R

Pharmaceutlcal Salts Pharmaceutically suitable acid addition salts of com-pounds where n = 0 or where at least one of R2 and R3, inde~
pendently, = 3-pyridyl include those made with physiologically acceptable acids and such salts include hydrochloride, sulfate, phosphate and nitrate.
Pharmaceutically suitable metal salts of compounds where R4 = hydrogen and n = 1 or 2 include those of certain metals, such as sodium, potassium, and calcium.
`~' ' ' _ 5 _ `.: ~,~

. .

DETAILED DESCRIPTION OF THE INVENTION

Preferred Compounds Compounds preferred for their antiarthritic activity are those where Rl = -CF2CF2H, or -CF3.
Also preferred are those compounds where R2 and R3, independently = 2-thienyl or 3-pyridyl.
Also preferred are these compounds where R2 or R3 =

r ~ ~ ~ Yl~ where Yl = H, Cl, F or CH30.

Also preferred are those compounds where R~ =

l.O hydrogen, ethoxycarbonyl, benzyloxymethyl, acetyl, benzoyl, or 2-tetrahydrofuranyl.

More preferred are these compounds where:

Rl = CF2CF2H or CF3;

R~ and R3, independently = 2-thienyl, 3-pyridyl or - ~ -Yl, where Yl = H, Cl/ F or CH30, and A

provided that only one of R2 or R3 can = - ~ 1;
Yl H, Cl, F or CH30;
R4 = hydrogen, benzyloxymethyl, ethoxycarbonyl, acetyl, henzoyl, 2-tetrahydrofuranyl.
Specifically preferred are the following compounds:
(a) 4-(4-fluorophenyl) 2-(1~1,2,2-tetrafluoroethylsulfonyl)-5-(2-thienyl)-lH-imidazole;
(b) 4-(4-fluorophenyl)-5-(2-thienyl)-2-trifluoromethyl-sulfonyl-lH-imidazole;
(c) 4-(4-mehoxyphenyl) 5-(2-thienyl)-2-tri1uoromethyl-sulfonyl-lH-imidazole;

', 5~ ~ 4 (d) 4,5-bis-(2-thienyl)-2-(1,1,2,2-tetrafluoroethyl-sulfonyl)-lH-imldazole;
(e) 4-4(4-methoxyphenyl)-2-(1,1,2,2-tetrafluoroethyl-sulfonyl)-5-(2-thienyl)-lH-imidazole;
(f) 4-(3,4-dichlorophenyl) 2-(1,1,2,2 tetrafluoro-ethylsulfonyl)-5-(2-thienyl)-lH-imidazole.

Synthesis Compounds of formula I can be prepared as -follows:
a 4,5-dicyclic imidazole of the formula R N

3 ~ N /
H

where R2 and R3 are defined above prepared as descri~ed in Brederick, H., et al., Chem. Ber., 86, 88 (1953) is reacted with sulfur at temperatures in the range of 150-300 either with or without solvent to form a 2-mercaptoimidazole. One suitable solvent for this reaction is tetramethylene sulfone. This procedure is analogous to the conversion of l-methylbenzimidazole to 2-mercapto-1-methylbenzimidazole as described in A. V. El'tsov and K. M. Krivozheiko, Zh.Or.Kh. 2, 189 (1966).

4,5-Disubstituted-2-mercaptoimidazoles can also be ; prepared by reaction of compounds of the type ~l~?

.

OH O O~I O
R2-C~I-C-R3 or R3-CH-C-R~

[R2 and R3 are clescribed above; various syntheses of compounds of this type are described in Ide, W. S. and Buck, J. S., Organic Reactions, Vol. IV, p. 269~ with thiourea in reflux-ing dimethylformamide or other hi~h-boiling, polar solvents.
A similar condensation procedure is described in Kochergin, P. M., Zhur. Obshchei Khim., 31, 1093 (1961); Chem. Abstr. 55, 23503F.
Preferably, reaction of the acyloins above wi~h ammonium thiocyanate at lower temperatures in polar solvents such as ethanol or l-propanol can be used to prepare 4,5-disubstituted-2-mercaptoimidazoles.
The appropriate Rl 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 (19~0)~
E'or the purpose o this disclosure tetraf]uoroethylene and other fluorlnated olefi.ns used are considered alkylating agents.
In certain instances a polyhaloalkyl moiety can be further modified chemically in forming the Rl constituent of formula I. For example, imidazoles containing the 2-(2-bromo-1,1,2-trifluoroethylthio) substituent can be con-verted to 2-(1,1,2-trifluoroethylthio) imidazoles by reduction with tri-n-butyltin hydride or other suitable reducing agents.

,: .
.... :

g~

The imidazoles of the types:

N ~let. N

Het. ~l Het. H

, ~where Het. = heterocyclic defined by R2 and R3 of the formula 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 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 3-pyridyl-N-oxide group can be converted back to the free 3-pyridyl group by treating with a mild reducin~ agent such as tri-alkoxy phosphite or triphenyl phosphine or tri-n-butyl phosphine or other mild reducing agent without reducing the sul~one function.
The appropriate R4 substituent can often he introduced by dlrect alkylatlon, acylatlon, or sulfonyla-tion of the compounds of formula I where R~ = H. This reaction can be carried in the absence or presence of a base, such as potassium carbonate, pyridine, triethylamine, potassium t-butoxide, methyl lithium or the like. The reaction , ~

' g ':' ~

can be run neat, using the reagent as solvent, or ln the presence of an inert solvent, including but not limited to dimethylformamide, glyme, THF, pyridine, methylene chloride.
The temperature of the reaction can be in the range -78C
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 alkoxymethyl halides, such as benzyloxymethyl chloride, acyloxyme-thyl halides, such as chloromethylpivalate; dihydro-pyran; 2 chlorotetrahydrofuran; alkyl chloroformates, such asethyl chloroformate; alkanoic anhydrides and alkanoyl halides, such as acetic anhydride; aroyl halides, such as benzoyl chloride; arylsulfonyl halides, such as benzenesulfonyl chloride.
Alternati~ely, the R4-substituent other than hydrogen of formula I can be introduced by first reacting a 4,5-disub-stituted imidazole with an appropriate reagent such as benzyl chloromethyl ether, 2-chlorotetrahydrofuran, dihydropyran, or benzenesulfonyl chloride. The resulting 4,5-disubstituted-1-(substituted)imidazole is then treated with a strong base, suchas n-butyl lithium, followed by a fluorinated alkylsulfenyl halide, disulfide, or sulfonic anhydride. I'ypical of these reagents are CF3SCl, CF3SSCF3, and (CF3SO2)2O. Optionally, the choice of the protectiny group and the workup conditions allows isolation of the desired 4,5-cyclic 2-(substituted thio or sulfonyl)imidazole with R4-EI directly. Compounds where Rl =
CF3 can be conveniently prepared by this method.
Preparation o~ pharmaceutically suitable salts of formula I can be in accordance with well-known techniques 3~ of forming salts.
'~'~.,',', - 10 - ' ,,. :

The preparatlon of these compounds is further illustrated by the following examples. Parts are by weight and temperatures are in centigrade unless otherwise specified.

2-[(1,1,2,2-Tetrafluoroethyl)thio]-4,5-b -(2-thienyl)~
imida~ole A) 4,5-bis-(2-Thienyl)-lH-imidazole A mixture of 31.6 g of ~-thienoin and 175 ml of flormamide was refluxed whi~e s-tirring 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.
218-221.5C. A further quantity of product was isolated from the filtrates by chromatography on alumina.
B) _,5-bis(2-~hienyl)-lH-2-imidazolethiol A mixture of 12 g of 4,5-bis-(2~thienyl)-1~-imidazole, 250 ml of tetramethylene sulfone (purified), and 2.5 g of sulfur was heated at 170C for 2~ 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 alumi.na 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. 283-290C.

~,~.., Alternatively, a mixture of 27.9 g (0~25 mole) of 2-thienoin and 13.3 g of ammonium thiocyanate in 150 ml of l-propanol was heated at reflux overnight, cooled and then 22.7 g of 4,5-bls(2-thienyl)-lH-2-imidazolethiolwas collected by filtration, m.p. 294-303 (dec.~ (Recrystallized from l-butanol).

Anal. Calc'd. for C lH N2S3: C, 50.00; H, 3.03;

N, 10.61. Found: 50.15; H, 3.15; N, 10.73.

C) 2-[(1,1,2l2-Tetrafluoroethyl)thio]-4,5-bls-(2-thienyl)-lH-imidazole _ _ 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 pressured with 5 g of tetrafluoro-ethylene. The pressure was 220 psi and on shaking dropped to 162 psi in 23 minutes. The temperature was in the range 25-28C. 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. 131.5-142C.
This was chromatographed on a silica gel column (Silicar CC-4) and eluted with chloroorm to yield 3.1 y, m.p. 161.5-163.5C.
Recrystallization from toluene gave an analytical sample, m.p. 166-7. Anal. Calc'd. for C13EI8F4N2S3: C, 42.86; ET, 2.20;
N, 7.69. Found~ C, 42.86; H, 2.28; Nr 7.76.

4-(4-Fluorophenyl)~2 (1/1,2,2-tetraEluoroethylthio)-5-(2-thienyl)-lH-lmidazole .
A) 2 imethylamino-2-(2-thienyl)acetonitrile A solution o 131.5 g of dimethylamine hydrochloride in 200 ml of water was stirred and 59 g of sodium cyanide ~ -; added. A solution of lI2 g of 2-thiophenecarboxaldehyde : :

~: :

in 100 ml of meth~nol was added from a dropping funnel while the temperature was kept below 30C. The mixture was then maintained at 30C. for ~ hours; it was then poured lnto 31. of water.
The water was extracted with ether, the ether ex-tract was washed with water, saturated sodium bisulfite solution and last by water. The ether was dried o~er anhydrous magnesium sulfate and concentrated to give 156.5 g of yellow oil.
B) 2-(4 Fluorophenyl)-1-(2-thienyl)ethanone ~ suspension of 15 g sodium hydride in 250 ml of di-methylformamide was stirred as 83.1 g of 2-dimethylamino-2-(2-thienyl)acetonitrile in 300 ml of dimethylformamide was added. The mixture was stirred 1 hr. and H2 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 50C during the addition and the mixture was kept at 40-45C 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.
The mixture was stirred and refluxed 24 hrs., cooled and separated. The water layer wa~ extracted three time with chloroform and the chloroform extracts comblned 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. 60-62C.
Alternatively, to a mixture of 75.0 g (0.5 mole) of 4-fluorophenylacetic acid and 195O0 g of thiophene warmed to 40C 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 : ;' ~ 13 -"~ ~

- . ' ~ . .. ' water and, after drying over anhydrous potassium carbonate, were evapora-ted to give 112.0 g of an oil. Crystallization Erom methanol afforded 70.0 g of 2-(4-fluorophenyl)-1-(2~thienyl)ethanone, m.p. 61-2.5.
Anal. Calc'd. for C12HgFOS: C, 65.45; H, 4.09;
Found: C, 65.45; H, 4.06.
C) 2-sromo-2-(4-fluorophenyl)-l-(2-thienyl)ethanone A solution of 71 g of 2-(4-fluorophenyl)-1-(2-thienyl)-ethanone 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)-1-(2-thienyl)-ethanon~ and 400 ml of formamide was refluxed beneath an air condenser for 2 hrs. It was poured into 1.5 1. of water and ice and the product filtered and dried - yield 41.2 g. Thls 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 aceto~
nitrile to give L4.8 g, m.p. 163-164.5~C, which after drying in vacuum oven overnight melted 198.5-200C. A further work-up of filtrates gave 4.5 g more solid, m.p. 197-198C~ The combined solids were crystallized from 350 ml of acetonitrile to give 16.4 g, m.p. 199-200C.

~ .
.

:

r ~
~' 1 ~ " .

E) 2-(4-Fluorophenyl)-2-hydroxy-1-(2-thienyl)ethanone.
To a solution of 70.0 g (0.32 mole) of 2-(4-fluoro-phenyl~l-(2-thienyl)ethanone in 600 ml of ether was added ~lropwise 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)~ 2-thienyl)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 tem-perature. The reaction mixture was poured onto 3 1 of 0.3 M
ice-water to give 63.4 g of 2-t4-fluorophenyl)-2-hydroxy-1-(2-thienyl)ethanone m.p. 90-2.
F) 4-(4-Fluorophenyl)-5-(2-thienyl)-lH-2-imidazolethiol A mixture o 16.0 g of 4-(4-fluorophenyl)-5-(2-thienyl)-lH-imidazole and 4 g o sulfur in 100 ml of tetra-methylene sulfone (redistilled) was heated to 200C for 8 hrs., cooled, poured into water and filtered and dried. This was chromatographed by dissolving it in 125 ml of dimethylform-amide and passing it over a neutral alumina (Woelm ~ctivity grade 1) column 60 mm in diameter and 200 mm long. A bright yellow band led the dar]c-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. 228-237C.
This is a dimethylformamide solvate of the product.
AlternAtively, reaction of 63.4 g t0.27 mole) of 2-(4~-Eluorophenyl)-2-hydroxy-1-(2-thienyl)ethanone with 29.0 g (O.38 mole) of ammonium thiocyanate in l-propanol gave 71.6 g of 4 t4-fluorophenyl)-5-t2-thienyl)-lH-2-imidazolethiol~ m.p.
275-277 (Recrystallized from l-butanol).
:

~ - 15 -Anal- Calc'd- for C13HgFN2S2 C, 56-52; H, 3-26; N~ 10-14-Found: C, 56.55; M, 3.42; N, 10018~

G) 4-(4-Fluorophenyl)-2-(1,1,2,2-tetrafluoroethyl-thio)-5-(2 thienyl~-lH-imidazole.
A solution of 14.0 g of 4-(4-fluorophenyl)-5-(2-thienyl)-lH-2-imida~olethiol 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 solutlon was poured into water, stirred un~il most of gum solidified, Eiltered and washed with water.
The solid was dissolved in chloroform, dried over anhydrous sodium sulfate, concentrated and diluted with l-chlorobutane.
The crystalline product was collected; yield 2.5 g, m.p. 164-168C. The residue from the filtrate was chromatographed on silica gel (Silicar CC-4) using chloroform to give 4.1 g, m.p. 167.5-170C. The combined 6.5 g was crystallized from l-chlorobutane to give 5.6 g, m.p. 167-168.5C. ;

Anal. Calc'd. for C HgF5N2S2 C,47.87 H, 2.39; N, 7.45. `- -Found: C, 48.24 ~, 2.58 N, 7.83, :

:' ''' ~.
,.......

4-(4-Fluorophenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)-

5-(2-thienyl)-H-imidazole A mixture of 6.5 g of 4-(4 fluorophenyl)-2-(1,1,2,2-tetrafluoroethylthio)-5-(2-thlenyl)-lH-imidazole in 160 ml of chloro~orm 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 dime-thyl 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 concen-trated. The solid was taken up in 40 ml of hot l-chloro-butane, treated with activated charcoal (Darco), filtered and concentrated to 1/3 volume. Crystals separated; yield 2.1 g, m.p~ 192-193C.
Anal- Calc'd- for C15~I9F5N22S2 C, 44-11; H~ 2-22; N, 6-86-Found: C, 44.55; H, 2.46; N, 7.04.

20 4-(4-Chlorophenyl)-2-tl,1,2,2-tetrafluoroethylthio)-5-(2-thienyl)-lH-lmidazole A) 2 -Chlorophenyl)-l-(2-thienyl)ethanone A mixture of 85.3 g of p-chlorophenylacetic acid and 200 ml ofthiophene was stirred at 40C as 105 g o~ tri-fluoroacetic anhydride was added. The mixture was then re-fluxed for 4 hrs. It was poured illtO 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 30 recrystallized from 300 ml of methanol to give 103 g, m.p.
98-99 qc .

~:

..,,~.

`

B) 2-Bromo-2~(~l-chlorophenyl)-1-(2-thienyl)ethanon_ A solution of ].00 g of 2-(4-chlorophenyl)-1-(2--thienyl)-ethanone in 400 ml of chloroEorm was added to a re1uxing sus-pension 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 the water extracted two times with chloroform. The combined extracts w~re dried over anhydrous potassium carbonate, filtered and concentrated;
yield 142 g. This product was used without further purification. .
C) 4-(~-Chlorophenyl)-5-(2-thienyl)-lH-imidazole A mixture of 35 g of 2-bromo-2-(4-chlorophenyl)-1- ;.
(2-thienyl)ethanone and 200 ml of formamide was refluxed under an air condenser for two hours. It was coo~ed, 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.
20 This was recrystallized from dimethylformamide, filtered and :
washed with acetonitrile; yield 14.7 g, m.p. 244-2~5C.
D) 4-(4-Chloro~henyl)-5~(2-thienyl)~lH-2-imidazolethiol __ A mixture o~ 9.~ g of ~-(4-chlorophenyl) 5-(2--thienyl)-lH-imidazole, 2 g of sulfur, and 50 ml of tetramethylene sulfone was stirred under nitrogen and heated to 200C 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 acti~ity grade 1) using dlmethyl-formamide to elute. A yield of 5.6 g was obtained as the di-' .

,~
., . .

s~r~

methylformamide adduct. A sample was dried by heating under a high vacuum, m.p. 274.5-276C.

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)-lH-2-imidazolethiol in 40 ml of dimethylformamide and 1.5 ml of diisopropylamine was pressured in a bomb with 3 g of tetra-fluoroethylene and shaken until there was no further pressure drop. The bomb contents were poured into water, the pII ad-justed to 8 and the solution extracted with chloroform. The extract was dried and concentrated. It was chromatographed on silica gel (Silicar CC-4) to give 5.5 g of a cut which was dissolved in hot l-chlorobutane. On cooling 4.5 g of product was obtained, m.p. 161.5-163C.
Anal. Calc'd. for C15H9ClF4N2S2: C, 45.36; II, 2.31; N, 7.13;
S, 16.33. Found: C, 46.06; H, 2.49; N, 7.40; S, 16.44.

2-(1,1,2,2-Tetrafluoroethylsulfonyl)-4,5-bis-(2-thienyl)-lH imidazole A solution of 1.9 g of 2-[(1,1,2,2-tetrafluoroethyl)-thio]-4,5-bis-(2-thienyl)~lH-imidazole in 100 ml of chloro-form 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 s-tand overnight.
The excess oxidant was then removed by stirring and adding 10 ml of methyl sulfide, stirring 1 hr. and concentrating.
The residue was stirred with ether, filtered to remove an in-soluble solid which was not the desired product. The ether :

.

.c~
' flltrate 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 l-chlorobutane; yield 0.282 g, m.p. 163-165C. A
second crop of 0.196 g was obtained from the filtrate.
In another experiment, ~.0 g (11 mmoles) of 2-(1,1,2,2-tetrafluoroethylthio)-4,5~bis-(2-thienyl)-lH-imidazole was oxidized at ice~bath temperatures with 7.3 g (34.8 mmoles) 82.2% m-chloroperbenzoic acid in methylene chloride. m-Chloro-benzoic acid was removed by filtration and the filtrate was washed with 10~ aqueous sodium bicarbonate solution. The methylene chloride solution was driecl over anhydrous potassium carbonate and evaporated to yield 3.2 g of an oil, which was crystallized with l-chlorobutane. Recrys-tallization from toluene: ethyl acetate gave 1.5 g o~ 2-(1,1,2,2-tetra-fluoroethyl sulfonyl)-~,5-bls-(2-thienyl)-1~1~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 C13H8F4N2O2S3: C, 39.39; H, 2.02;

N, 7.07. Found: C, 40.06; H, 2.06; N, 7.42.
EXAMPLE _ ~-(3,~-Dichlorophenyl)-~2-(1,1,2,2-tetrafluoroethylthio)-5-(2-thienyl)-lI-I-imidazole.
A) 2-(3,~-Dichlor phen~l)-1-(2-thienyl)ethanone.

.

.
: . : . - . . .

s~

Using the procedure described in Example 4A, 100.0 g of 3,4-dichlorophenylacetic acid, 242.0 g of thiophene and 144.0 g of trifluoroacetic anhydride gave from methanol 61.7 g o 2-(3,4-dichlorophenyl)-~(2-thienyl)ethanone, m.p. 59.5-60.5.
Anal. Calc'~. for C12~C120S C, 53.14; H, 2.95.
Found: C, 53.24; H, 2.95.

B) ~ ~ Yl~
e.~hanone 2-(3,4-Dichlorophenyl)-1-(2-thienyl)ethanone t57.0 g;
0.21 mole) was conv~rted to 49.8 g of 2-(3,4-dichlorophenyl)-2-hydroxy-1-(2 thienyl)ethanone, m.p. 108-3 (recxystallized from l-chlorobutane) by the procedure described in Example 2E.
Anal. Calc'd. for C12E~C12O2S: C, 50.17; H, 2.99. Found:
C, 50.34; H, 2.86.
C) 4-(3~4-Dichlorophenyl)-5-(2-thienyl)-lH-2~imldazole thicl.
~y the procedure described in the second paragraph of Ex~mple 2F, 45.0 g (0.16 mole) of 2-(3,4-dichlorophenyl)-2-hydroxy-1-(2-~h.ienyl)ethanone was reacted with ammanium ~hio-cyanate in l-propanol at reflux to a~ford 32.6 g o~ 4-(3,4-di-chlorophenyl)-5-(2-thienyl)-lH-2-imidazolethiol m~p. 263-5.
(xec~ystallized ~rom l-butanol)-Anal. CalC'd. or Cl3H8cl2~2s2~ 1/2H20; C, H, 2.~9; N, 8.33. Found: C,46.10; H, 2.82; N, 8.23.
D) 4~(3,_4-_ chLoro~enyl)-2-(1,1,2,2-_etrafluoroethyl thio)-5~2_thlenyl)-lH-imidazole 4-(3,4-Dichlorophenyl)-$-(2-thienyl)-1~-2-imidazole-- thiol ~30.0 g; g~ mmoles) was reacted with 15.0 g of tetra :~

~luoroethylene as described in Example 4E ~o give, after chromatography on silicar CCX7 with chloro~orm, 19.1 g of ~ ~ ~ 21 --, -:
.

~5~

4-(3,4-dichlorophenyl)-2-(1,1,2,2-tetrafluoro~thylthio)-5-(2-thienyl)-lH-imidazole, m.p. 178-180 (recrys~allized from toluenQ ) O
Anal~ Calc'd. for Cl5H8F4Cl2N2S2: C, 42.15; H, 1~7;
N, 6.56. Found: C, 42.88; H, 2.03; I~, 6.57.

EX~MPLE 7 ~2-thi~n~ e 4-(3,4~ hlorophenyl)-2-(1,1,2,2-tetrafluQroethylthio)-5-(2-tnienyl)-lH-imidazole (5.0 g; 11.7mmoles) was oxidized with

6.~ g (29mmoles) of ~32~2~ m-chloxoperbenzoic acid according to the proc dure described in the second paragraph of Example 5 and the crude product was puriiecl by chro~a~ography on Silicar CC~7 with chLorofo.rm to afford 1.4 g o~ 4-(3,4~dichlorophenyl)- ~:
2-(1,1,2,2-tetrafluoroe~hy}sulfonyl)-5-(2-thienyl)-l~imidazole, m.p. 158-159.5 (recrystallized from toluene).
A~al. Calc'd. or C15H8Cl2F~N 0 S : C, 39.2; H, 1.74;

N, 6.1. Found: C, 39.83; H, 1.96; N, 6.07.
EXAMPLE a .... . .

thien~l) lH-imida201e A ~eries of reactiQns similar to those desc~ibed in ~xample 6 u~ing 4 me~hoxyphenylacetic acid ~av~ ~he compounds below.

!d~ m.p. 75-7~ (xecrystallized `from me~hanol).
nal- calc~dO or~C13~12~2s: C,67.24, H,5~17. Found:
C, 67.11; H, 5.29.~ -: , B~ 2-(4-MethoxY~henYl)-2-hvdroxy l-(2~thienYl) ethanone. m.p.:69-73 ~recrystallized from l-chlorobutana) - 22 - ~
- :

.

~5~4 .~nal. C lc'd. for C13Hl~o3s: C~ 62-50; ~ 4-34-Found; C, 62.15; H, 4.78.
Cl 4 (4-Metho:~ypne~yl)-5-(2-thlen~ H-2-imidazoleth m.p. 266 268: (recrystallized from ethanol) ~nal. Calc d. for C14H12N2os2: C, 58.33; ~, 4.17;
~, 9.72. Found: C, 58.37; H, 4.27; N, 9.49.
D~
~ . m.p. 112-113.5 (chroma~ographed on Silicar CC~7 with chlorofonm and recrysta~lized from l-chloro-butane).
~nal. Calc'd- for C16~12F4N252 N, 7.22. Found: C, 4g.92; H, 3.21; N~ 7.21.
EXaMPLE 9 4-(4 Methoxy~henyl)-2~ 2,2-tetrafluoroethy~ul~onyl)-5--lH-imidazole ~ .
4~(4-~ethoxyphenyl)-2-(1,1,2, 2-tetrafluoroethylthio)-5 (2-thienyl)-lH--imidazole (4.0 g; 10.3mmolesj was oxidized with 6.1 g (29 moles) o~ 82.2~ m-chLorop~rbenzoic acid and the crude product was puri~ied by chromatography on Silicar CC~7 with chloroform to give 1.3 g of 4-(4-methQxyphenyl)-2-(1~1,2,2-tqtra-fluoroethyl~ul~onyl)-5-(2-thienyl)~ midazole, m.p. 163-4.S~
(recrystallized~rom chlorobu~ane).~
al. Calc',d~ ~r CL6Hl~F4N203S2 N, 6.67. Found: C, 45.20; ~, 2.32; N, 6.82.
:
EX~UPLE 10 4 r 5-~is-~2-Fur~l) A) ~ 2- ryl:) lH-2-1m dazolethiol Furoin (19.2 g, 0.1 mole) was reacted with ll.S g :
(0.15 mole) ammonium thiocyanate in ethanol heated at reflux ~ :
to afford Ll.4~g of 4,5-bis-(2-furyL)-1~-2-imida2O1ethiol.
: ~ , : ' "
- ~3 -- : ~

;

. - . . . .
. - . - . . . .:

An analytlcal sample was prepared by chromatography on alumina with ethanol and recrystallization from nitromethane, m.p. 279-380 (dec.).
Anal. Calc d. ~or C~lH8N202S: C, 56-90, H, 3-45;
N, 12.07. Found: C, 57.20; ~, 3.86; N, 11.72.
B) 4,5-bls-(2-F ~ ) l~-imidazole.
4,5-bLs-(2 Furyl)-lH-2-imidazolethiol (8.1 g; 39.4 mmoles) was reacted with 7.0 ~ o~ tetrafluoroethylene and the product purified by chxomatogxaphy on Silicar CC~7 with chloroform to give 3.0 g of 4,5-bis~(2-furyl)-2-(1,1,~,2-tetrafluoroethylthio)-lH-imidazole, m.p. 166-167: (re-crystallized from 1 chlorobu~ane).
Anal. Calc'd- for C13H8F~N202S C, 47-N, 8.43. Found: C, 47013; H, 2.81; N, 8.45.

4-Phen 1-5-(3~ ridYl)-2~ 2~2~tetrafluor-oe-th-ylthlo~lH
imidazole.
A) 4-PhenYl-5-~3-pyridyl)~lH 2-imida201ethiol A SOlUtiOIl of 30.0 g (0.15 mole) of 3-pyridyl benæyl ketone (A. Burger and C. R. Walter, Jr., ~ Am. Chem. Soc., 72 1988 (1950), in 300 ml o~ acetic acid was traa~ed dropwise with a solu~ion of 2S.0 g (0.16-m~le) of bromine in 240 ml of acetic acid at room tempera~ure. ~fter s~irring overnight, a precipa-tate of 26. 8 g of 3-pyridyl a-bromobenzyl ketor~e hydrobromide was collected by filtration.
A mixture of 5.0 g (14.0mmoles) of the salt above with a solution o~ 0.1 moLe of sodium ethoxide in 100 ml o ethanol was stirred overnigh~ at room temperature and then poured on~o 0.5M aqueous hydrochloric acid. After stirring for sevexal - 2 4 - .

t~

hours the 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 re-moved under vacuum to give 4.5 g of 3-pyridyl ~-hydroxybenzyl ketone.
Altsrnatively, ~ mixture o~ 20.0 ~ (56.0 mmoles) of 3-pyridyl ~-bromobenzyl ketone hydrobromide and 24.0 g (0.24 mole) of potassiu~ acetate in 100 ml of acetic anhydride was stirred overnigh~ at room tempexature. The reaction mixture was poured into water and the product extracted into ether.
The combined ether layers were washe~ with water and then 10% aqueQus sodium bicarbona~e solution~ ~he ether layer was dried oYer potassium carbonate and evaporated. A
solution of the residue in 140 ml of lN aqueous hydrochloric acid was h~ated at reflux for 30 minutes and after cooling made basic with solid sodium carbonate. The produc~ was extracted into ether and the combi~ed ether extract3 evaporated, a~ter drying over anhydrous potassium carbonate, to give 8.15 g of 3-pyridyl a-hydroxybe~2yl ketons.

3-Pyridyl ~-hydroxybenzyl ke~one (8.15 g; 38.3 mmoles) was reacted with 7.5 g (0.1 mole) of am~lonium thiocyanate in l-propanol heated at reflux to give 4.3 g o 4-phenyl-5-(3-pyridyl)-lH-2 imidazolethiol, m.p. 317-323 recrystallized ~rom DMF:H~O (2:1).
Analv Calc'd. for C14HllN3S: C, 66.40, H, 4.35;
N, 16.60. Found: C, 65.92; 4.53; N, 16.34.
~ o-et~lthi~lH-imidazole 4-Phe~l 5-(3-pyridyl)-1H~2-imidaæolPthiol (2.0 g7

7.9 mmoles) was reacted with 5.0 g t50 mmoles) of tetra~luoro-.
.
' .

ethylene and the crude product purified by chromatography on Silicar CC~7 with chloroform to afford 800 mg of 4-phenyl 5-(3-pyridyl)-2-(1,1,2,2-tetrafluoroethylthio)-lH-imidazole, m.p. 153-154 (recrystallized from toluene).

Anal. Calc'd. for C HllF4N3S: 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 prepared by using the appropriate starting materials and the procedures described in the examples and in the Synthesis section.

!,~, ', ~. ` '& ~

, ~ , ~ . ' ~B

Y~ S (O) nR~

~ ~4 ..
Y ~ R3 Rl R4 n <O~- - CF~ ~ ~ 2 F 2CF 2~ 1 ~
S ..

F ~ CF:3 CQ~'- 2 F ~ - rF2CF2R [~ 2 Cl ~3, CF9 CO ~CH 2 ~ 0 CX30~ CF2EI H 2 : F ~ t::F2CF2H C~I30CH~- 2 :

: Cl ~ C~2CF2tsI so2 ~3 o , ~ ` :

)} CF3 O

27 ~
. .

.

2~L

'rABI~ I
( con t ;nued ) R3__ ~ ~1~ n F <~ CF2CF2H H 2 ~3~3 [~ 3~ CF3 E~ 2 S , ` ., , '.

__ ,. . .
F ~s~L CF3 -C-C2H5 ~ ~`

.
~3_ CH2CF3 . H
S , ..

:~ G~30~ CF2CH2F -CEI2-0CH2~ 2 ~ ~
,: :
~ C~

.:
C~:30 ~ ~_ CF3 ~ 2 F ~ 5 ~ CF2C~IF2 ~I 2 .: : : : -- ~ 0 u ` - ~

2~

TABLE I
(Continued ) Yl R3 Rl R4 n F ~ CF3 H 2 ~S.

[~ 2 2 3 N

:

~s~

T~BIE

S () n~
R.4 R4 n ~3_ CF2C~if2~ SO~

CF~3 H 2 N

(~ C:F3 H 2 ~.

CF~2CP
_ , : HC~2 ,S

~ .CF~ ~02CH3 a S ' ,.

2 2 ~: H

~ 30 ~

Dosa~e Forms The anti~arthritic and an~lgesic agents o~ this invention can be a~minis~ered to trea~ arthritis and/or pain by any means that produces contact of the acti~e agent with the agent's site of action in the body of a ma~mal.
The com~ounds o formula I have anti-ar~hri~ic proper~ies and in addil:ion soMe carl be used to alleviate pain. They call be administered by any conventional means available for use in conjunction with pharmaceuticals; either as individual therapeutlc a~ents or ln a combination o~ ther2peutic agents.
They can be administered alone, but are generally administered wi~h a pharmaceutical carrier selected on the basis o~ the chosen rou~e of administration and st~ndard pharmaceutlcal pract~ ce .
The dos2ge administered will, o~ cours~ vary depending upon known ~actors such as the pharmacodynamic characteristics of the particular agent, and its node and ; route of~ dministratlon; age, health, and ~teigh~ of the re-cipient; na~ure and exten~ af ~ymptoms, kind of concurrent treatment, ~requency of treatment, and the e~ect desired.
Usually a dally dosa~e o~ active in~redien~ can be 2bout 0;01 to 40 mllli~rams per kilogram of body weight. Ordin-arily 0.05 to 20, and prererably O.l to~-io milligrams per k.llogram per day given in divided doses 2 ~o 4 times a day or in~sustained release~orm is e~fective to obtain desired resul~s.
; Dosage forms ~compositlons) suitable for internal administration contaln rrom about 0.1 milligrams to about 500 milli~rams o~ act1ve ingredlent per unit. In these :: 30~ pharmac utical compos1tions the ac~ive in~redient will :
~ 31 ~
.,: ,~
.. . . - ,,. : .. .. . :

-5'~
ordinarily be present in an amount of about 0.5 ~ 95~ by weight based on the total weight of the composition.
The active ingredlent 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, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manu-factured as sustained release products to provide for con- ~ `
tinuous 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 flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, ac~ueous destrose (glucose), and related sugar solutions and glyeols sueh as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration eontain preferably a water soluble salt of the active inyredient, s~litable stabilizing agents, and if necessary, buffer substances. Antio~idizing agents such as sodium bisulfite, sodium sulfite, or aseorbie aeid either alone or combined are suitable stabiliæing agents. Also ~
30 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 a~e ~escri~ed in Remington's Pharmaceutical Sciences, E. W. Martin,~a standard reference text in this field.
Useful pharmaceutical dosage-forms for adminis-tration of the compounds of this invention can be illustrated as follows-~ Capsules A large number of unit capsules are prepared byfilling 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 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 conven-tional 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 mil].igrams 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.

. . . .. - . . . . . . .-5~

A parenteral composition sui~able for adrninistra-tion by inj ection is i?repared by sti~ g 1~ 5~ ~y weight o~
actl~re ingre~licnt ln lOg by ~olume propylcne glycol and water. The solution is s'cerill~ed by filtra'clon.

An aqueou~ susperlslon i~ prcpared for oral admin-~stration ~o that each 5 milliliters contain 70 mlllirams o:~ ~inely divlded act~e in~,redient,, 500 milligrams of' acacia, 5 milli.gram~ o~ sodium ben~oate, 1.0 graTns o~ sorbitol solu-tiOng U.S .P. 2 5 milliE;ralTIs Or sodium saccharin, and O . 025 milliliters of ~ranllla tlncture.
_~ e ct ab le A parenteral composit:on suitable ~or adm:~nls~ra tion by injection is pre~ared by disso:Lving ld~ by wei 3ht of active ingredient~ in sodium chlorlde inJection U.S.P. XV
an~ ~ usting the pH Or the solution to bet~ieen 6 and 7.
he solu~ion is steri\l~zed by îiltration.
Use .
q'o detect and compare the arlti-in~}ammatory actlvltles of compounds irl this series and standard drugs, a ~est was us~d based on a standard model o~ arthritis for which ther~ is good correlation with human efficacy. The model is ad~uvant-induced arthritis in rats. Federation Proceedings, Vol. 32, No. 2 1973 "Models Used ~or the Study and Therapy of Rheumatoid Arthritis" - Symposium of the American Society for Pharmacology and Experimental Therapeutics - states "The rat polyarthritis produced by in~radermal injection o~ a suspension of Mycobacterium tuberculosis in mineral oil (adjuvant) has been used . ~ 34 ~

' :

-~:a.@~5~2~L

extensively for the screenlng of drugs of potential use in rheumatoid arthritis.
Established Adju ~
Charles River Lewis male rats ( 130 150 grams) are in~ected subcutaneously in the plantar area o~ the right hind paw with O.l ml of ad~uvant (Difco heat-killed, lyophilized Mycobacterium but~ricum suspended in mineral oil 5 mg~ml). 20 Nonarthritic controls are injected ~lth mineral oil. The animals are held ~or two weeks to allow development of arthritis. Paw volumes (unin~ected, left hind paw) are measured and the ad~uvant injected rats are culled and dlstributed to treatment groups of lO of equal disease severity. Nonarthritic controls are dls tributed to two groups of lO. The rats are ~iven oral doses of compound or PVA-Acacia (Polyvinyl Alcohol 1%, Gum Acacia~
U.S.P. 5%, Methylparaben 0.5~) (lO ml/kg) by ga~age on that day and on the six followlng day~. One day after the last dose the paw ~olumes (uninjec~ed, left hind paw) are measured using a Ugo Basile Volume Dif~erential Meter Model 710l.
Arthritic Control Treatment Group ;:
Mean Paw Volume ~ml) - Mean Paw Volume (ml) Arthritic control Non-Arthritic Control`~ lOO
Mean Paw Volume (ml) - Mean P2w Volume (ml) % Decrease from Control Mean Paw ~olume.
Dose-response regression lines of the percent decrease are plotted on semi-log paper b~ visual fit and the ED50% decrease from control paw volume is determined by ~nspection. Data ~or some of the compounds in this inventlon are summari~ed in Table III.

~ 35 ~

; ~
: - - . . . ..................... . .. . . . .
. . . : : .: : , . . . . , : .

Compounds from this ser~es are many times more potent than aspirin and ibuprofen in the treatment of adjuvant induced arthrit~s in rats. Four compounds have been shown to be more potent than phenylbutazone and one com-pound 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 A. A. ED50~*
Number m~/k~

32% @ S0 mg/kg 2 1.3 3 0.1 12.0 ~ 2.~ .:
6 . 50

8: 30 : g 5 ~ 20 : lO 34% ~ S0 mg/kg : ll C25 Indomethacin 0.3 Phenylbutazone lO
Ibupro~en 100 Aspirin ~ 305 .

~Determlned as % paw volume reduc~ion from çontr~l.
~: : `
:
~ 36 ~
.
:

, ';

`s~
Phen 1 uinone ~lrit~lin~ Tcst Y q~
A s~ndard procedure for detecting and comparln~
the analgesic activity of compounds in ~hi~ serles for which t~re is good correlakion with human erricacy is the standard phenylquinone writhing test modi~ied from Siegmund, et al., Proc~ Soc. EY~P. Biol. Med. 95, 729 (1957).
A test compound suspended in 1% methylcellulose was given orally to ~asted (11-21 hours) female white mice, 5-20 animals per double blind te~. Aqueous (0.01% phenyl~-benzoquinone~ phenylquinone was injected lntraperitoneallyat 24 minutes later using 0.20 ml per.mouse. Commencing at 30 mlnutes after the oral administration Or the test compound, the mice were observed for 10 minutes for a characteristic stretching or writhin~ syndrome which is ~ndicati~e of pain induced by phenylquinone. The effecti~e analgesic dose ~or 50% of the mice (ED50) was cal~ulated by the moving average method of Thompson) W. R., act. Rev. 11, 115-145 (1947); also time o~ peak actlon was determined for many of the compounds. Th~s data is summariæed in Table . . .
2Q IV.

. ':

' .

:

~ ~ 37 ~

, TP.BLE I v Chemical Example Number ED5 0*
= _. ~ .
4.6 3 . 2.1 ~30: ~
8 45 ~:

9 1 . 67 *units are in mg/kg at a~ hour.

. ' ': ' :

,:
: :
, ~ ~ : : :

.: ~ :
~ : ~ 3 8 -:
, ~ , : ~ -:

,, :

:,:

Claims (66)

The embodiments of the invention in which an exclusive 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 = polyfluoro-C1-C2 alkyl;
R2 and R3, the same or different =
2-thienyl, 3-thienyl, 3-pyridyl, 3-pyridyl-N?oxide, 2-furyl or where Y1 and Y2, the same or different =
H, C1-C4 alkoxy, C1-C4 alkyl, Cl, F, or Y1 and Y2 taken together forming a dioxymethylene bridge, provided that only one of R2 or R3 can =

; and R4 = hydrogen;

, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, -?OR7, -?R7, -?Ar, or -SO2Ar;
where R5 = H or methyl;
R6 = C1-C3 alkyl, benzyl, -CH2CH2OCH3 or -?R7;
R7 = C1-C4 alkyl or benzyl; and Ar = where Y3 = H, F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy or nitro;

provided when R4 = -?OR7, -?R7, -?Ar, or -SO2Ar, then n must be 0; or its pharmaceutically suitable acid addition salt where n = 0 or where at least one of R2 and R3, independently, = 3-pyridyl or its pharmaceutically suitable metal salt where R4 = hydrogen and n = 1 or 2, said process being selected from the group consisting of (A) a process comprising contacting a compound of the for-mula with a suitable alkylating agent;
(B) a process comprising contacting the product of (A) with a suitable oxidizing agent;
(C) a process comprising contacting the product of (B) with an agent selected from the group consisting of (a) a compound of the formula R4'X
where R4' = -CH2OR6, 2-tetrahydrofuranyl, -?OR7, -?R7, -?Ar or -SO2Ar; and X = chlorine, bromine or iodine;
(b) dihydropyran;
(c) (R7?)2-0; or (d) R6O-CH=CH2;
(D) when R4 = , H, 2-tetrahydropyranyl-, 2-tetrahydro-furanyl-, or -SO2Ar, a process comprising (i) contacting a compound of the formula with an agent selected from the group consisting of (a) a compound of the formula R4'X
where R4' = R6OCH2-, 2-tetrahydrofuranyl-, or ArSO2-, and X = chlorine, bromine or iodine;
(b) dihydropyran; or (c) R6OCH = CH2;
(ii) contacting the resulting product with a base, and (iii) contacting the product so obtained with a fluorinated C1-C2 alkyl sulfenyl halide, di-sulfide or sulfonic anhydride;
(E) a process comprising treating the product of (D) so as to remove the R4' group; and (F) a process comprising oxidizing the product of (E).

2. The process of Claim 1 in which R1 is selected from the group consisting of -CF2CF2H and -CF3.

3. The process of Claim 1 in which R2 and R3 are each selected from the group consisting of 2 thienyl and 3-pyridyl.

4. The process of Claim 1 in which one of R2 and R3 is where Y1 - H, Cl, F or -OCH3.

5. The process of Claim 1 in which R4 is selected from the group consisting of H, ethoxycarbonyl, benzyloxymethyl, acetyl, benzoyl and 2-tetrahydrofuranyl.

6. The process of Claim 1 in which R4 is hydrogen.

7. The process of Claim 1 in which R1 is -CF2CF2H or -CF3, R2 and R3 are each selected from the group consisting o 2-thienyl, 3-pyridyl and , where Y1 is H, Cl, F or -OCH3, provided that only one of R2 and R3 can be , and R4 is selected from the group consisting of hydrogen, benzyloxymethyl, acetyl, benzoyl and 2-tetrahydro-furanyl.

8. A process for preparing a compound of the formula where R1 = polyfluoro -C1-C2 alkyl;
R2 and R3, the same or different =
2-thienyl, 3-thienyl, 3-pyridyl, 3-pyridyl-N?oxide, 2-furyl or where Y1 and Y2, the same or different =
H, C1-C4 alkoxy, C1-C4 alkyl, Cl, F, or Y1 and Y2 taken together forming a dioxymethylene bridge, provided that only one of R2 or R3 can =

; or its pharmaceutically suitable acid addition salt, said process comprising contacting a compound of the formula with a suitable alkylating agent.

9. The process of Claim 8 in which R1 is selected from the group consisting of -CF2CF2H and -CF3.

10. The process of Claim 8 in which R2 and R3 are each selected from the group consisting of 2-thienyl and 3-pyridyl.

11. The process of Claim 8 in which one of R2 and R3 is where Y1 = H, Cl, F or -OCH3.

12. The process of Claim 8 in which R1 is -CF2CF2H
or -CF3, and R2 and R3 are each selected from the group con-sisting of 2-thienyl, 3-pyridyl and , where Y1 is H, Cl, F or -OCH3, provided that only one of R2 and R3 can be .

13. A process for preparing a compound of the formula where n = 1 or 2 R1 = polyfluoro -C1-C2 alkyl;
R2 and R3, the same or different =
2-thienyl, 3-thienyl, 3-pyridyl, 3-pyridyl-N?oxide, 2-furyl or where Y1 and Y2, the same or diferent =
H, C1-C4 alkoxy, C1-C4 alkyl, Cl, F, or Y1 and Y2 taken together forming a dioxymethylene bridge, provided that only one of R2 or R3 can =

; or its pharmaceutically suitable acid addition salt where at least one of R2 and R3, independently, is 3-pyridyl, or its pharmaceutically suitable metal salt, said process comprising contacting a compound of the formula with a suitable oxidizing agent.

14. The process of Claim 13 in which R1 is selected from the group consisting of -CF2CF2H and -CF3.

15. The process of Claim 13 in which R2 and R3 are each selected from the group consisting of 2-thienyl and 3-pyridyl.

16. The process of Claim 13 in which one of R2 and R3 is where Y1 = H, Cl, F or -OCH3.

17. The process of Claim 13 in which R1 is -CF2CF2H
or -CF3, and R2 and R3 are each selected from the group con-sisting of 2-thienyl, 3-pyridyl and , where Y1 is H, Cl, F or -OCH3, provided that only one of R2 and R3 can be .

18. The process of Claim 1 which is process (C).

19. The process of Claim 1 which is process (D).

20. The process of Claim 1 which is process (E).

21. The process of Claim 1 which is process (F).

22. The process of Claim 1 in which R1 is -CF2CF2H, R2 is 4-fluorophenyl, R3 is 2-thienyl, R4 is hydrogen and n = 2.

23. The process of Claim 1 in which R1 is -CF3, R2 is 4-fluorophenyl, R3 is 2-thienyl, R4 is hydrogen and n is 2.

24. The process of Claim 1 in which R1 is -CF3, R2 is 4-methoxyphenyl, R3 is 2-thienyl, R4 is hydrogen and n is 2.

25. The process of Claim 1 in which R1 is -CF2CF2H, R2 and R3 are each 2-thienyl, R4 is hydrogen and n is 2.

26. The process of Claim 1 in which R1 is -CF2CF2H, R2 is 4-methoxyphenyl, R3 is 2-thienyl, R1 is hydrogen and n is 2.

27. The process of Claim 1 in which R1 is -CF2CF2H, R2 is 3,4-dichlorophenyl, R3 is 2-thienyl, R4 is hydrogen and n is 2.

28. The process of Claim 13 in which R1 is -CF2CF2H, R2 is 4-fluorophenyl, R3 is 2-thienyl, R4 is hydrogen and n = 2.

29. The process of Claim 13 in which R1 is -CF3, R2 is 4-fluorophenyl, R3 is 2-thienyl, R4 is hydrogen and n is 2.

30. The process of Claim 13 in which R1 is -CF3, R2 is 4-methoxyphenyl, R3 is 2-thienyl, R4 is hydrogen and n is 2.

31. The process of Claim 13 in which R1 is -CF2CF2H, R2 and R3 are each 2-thienyl, R4 is hydrogen and n is 2.

32. The process of Claim 13 in which R1 is -CF2CF2H, R2 is 4-methoxyphenyl, R3 is 2 thienyl, R4 is hydrogen and n is 2.

33. The process of Claim 13 in which R1 is -CF2CF2H, R2 is 3,4-dichlorophenyl, R3 is 2-thienyl, R4 is hydrogen and n is 2.

34. A compound of the formula where n = 0, 1 or 2;
R1 = polyfluoro -C1-C2 alkyl;
R2 and R3, the same or different =
2-thienyl, 3-thienyl, 3-pyridyl, 3-pyridyl-N?oxide, 2-furyl or where Y1 and Y2,the same or different =
H, C1-C4 alkoxy, C1-C4 alkyl, Cl, F, or Y1 and Y2 taken together forming a dioxymethylene bridge, provided that only one of R2 or R3 can =

; and R4 = hydrogen;
, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, -?OR7, -?R7, -?Ar, or -SO2Ar;
where R5 = H or methyl;
R6 =C1-C3 alkyl, benzyl, -CH2CH2OCH3 or -?R7 ;
R7 = C1-C4 alkyl or benzyl; and Ar =

where Y3 = H, F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy or nitro;
provided when R4 = -?OR7, -?R7, -?Ar, or -SO2Ar, then n must be 0; or its pharmaceutically suitahle acid addition salt where n = 0 or where at least one of R2 and R3, indepen-dently, = 3-pyridyl or its pharmaceutically suitable metal salt where R4 = hydrogen and n = 1 or 2, when prepared by the process of Claim 1.

35. The compound of Claim 34 in which R1 is selected from the group consisting of -CF2CF2H and -CF3, when prepared by the process of Claim 2.

36. The compound of Claim 34 in which R2 and R3 are each selected from the group consisting of 2-thienyl and 3-pyridyl, when prepared by the process of Claim 3.

37. The compound of Claim 34 in which one of R2 and R3 is where Y1 = H, Cl, F or -OCH3, when prepared by the process of Claim 4.

38. The compound of Claim 34 in which R4 is selected from the group consisting of H, ethoxycarbonyl, benzy oxymethyl, acetyl, benzoyl and 2-tetrahydrofuranyl, when prepared by the process of Claim 5.

39. The compound of Claim 34 in which R4 is hydro-gen, when prepared by the process of Claim 6.

40. The compound of Claim 34 in which R1 is -CF2CF2H or -CF3, R2 and R3 are each selected from the group consisting of 2-thienyl, 3-pyridyl and , where Y1 is H, Cl, F or -OCH3, provided that only one of R2 and R3 can be , and R4 is selected from the group consisting of hydrogen, benzyloxymethyl, acetyl, benzoyl and 2-tetrahydro-furanyl, when prepared by the process of Claim 7.

41. A compound of the formula where R1 = polyfluoro -C1-C2 alkyl;
R2 and R3, the same or different =
2-thienyl, 3-thienyl, 3-pyridyl, 3-pyridyl-N?oxide, 2-furyl or where Y1 and Y2, the same or different =
H, C1-C4 alkoxy, C1-C4 alkyl, Cl, F or Y1 and Y2 taken together forming a dioxymethylene bridge, provided that only one of R2 or R3 can =

; or its pharmaceutically suitable acid addition salt, said process when prepared by the process of Claim 8.

42. The compound of Claim 41 in which R1 is selected from the group consisting of -CF2CF2H and -CF3, when prepared by the process of Claim 9.

43. The compound of Claim 41 in which R2 and R3 are each selected from the group consisting of 2-thienyl and 3-pyridyl, when prepared by the process of Claim 10.

44. The compound of Claim 41 in which one of R2 and R3 is where Y1 = H, Cl, F or -OCH3, when prepared by the process of Claim 11.

45. The compound of Claim 41 in which R1 is -CF2CF2H or -CF3, and R2 and R3 are each selected from the group consisting of 2-thienyl, 3-pyridyl and , where Y1 is H, Cl, F or -OCH3, provided that only one of R2 and R3 can be , when prepared by the process of Claim 12.

46. A compound of the formula where n = 1 or 2 R1 = polyfluoro -C1-C2 alkyl;
R2 and R3, the same or different =
2-thienyl, 3-thienyl, 3-pyridyl, 3-pyridyl-N?oxide, 2-furyl or where Y1 and Y2, the same or different =
H, C1-C4 alkoxy, C1-C4 alkyl, Cl, F or Y1 and Y2 taken together forming a dioxymethylene bridge, provided that only one of R2 or R3 can =
; or its pharmaceutically suitable acid addition salt where at least one of R2 and R3, independently, is 3-pyridyl, or its pharmaceutically suitable metal salt, said process when prepared by the process of Claim 13.

47. The compound of Claim 46 in which R1 is selected from the group consisting of -CF2CF2H and -CF3 when prepared by the process of Claim 14.

48. The compound of Claim 46 in which R2 and R3 are each selected from the group consisting of 2-thienyl and 3-pyridyl when prepared by the process of Claim 15.

49. The compound of Claim 46 in which one of R2 and R3 is where Y1 = H, Cl, F or -OCH3,when prepared by the process of Claim 16.

50. The compound of Claim 46 in which R1 is -CF2CF2H
or -CF3, and R2 and R3 are each selected from the group con-sisting of 2-thienyl, 3-pyridyl and , where Y1 is H, Cl, F or -OCH3, provided that only one of R2 and R3 can be , when prepared by the process of Claim 17.

51. The compound of Claim 34, when prepared by the process of Claim 18.

52. The compound of Claim 34, when prepared by the process of Claim 19.

53. The compound of Claim 34, when prepared by the process of Claim 20.

54. The compound of Claim 34, when prepared by the process of Claim 21.

55. 4-(4-fluorophenyl)-2-(1,1,2,2-tetrafluoro-ethylsulfonyl)-5-(2-thienyl)-1H-imidazole, the compound of Claim 34 in which R1 is -CF2CF2H, R2 is 4-fluorophenyl, R3 is 2-thienyl, R4 is hydrogen and n = 2, when prepared by the process of Claim 22.

56. 4-(4-fluorophenyl)-5-(2-thienyl)-2-trifluoro-methylsulfonyl-1H-imidazole, the compound of Claim 34 in which R1 is -CF3, R2 is 4-fluorophenyl, R3 is 2-thienyl, R4 is hy-drogen and n is 2, when prepared by the process of Claim 23.

57. 4-(4-methoxyphenyl)-4-(2-thienyl)-2-tri-fluoromethylsulfonyl-1H-imidazole, the compound of Claim 34 in which R1 is -CF3, R2 is 4-methoxyphenyl, R3 is 2-thienyl, R4 is hydrogen and n is 2, when prepared by the process of Claim 24.

58. 4,5-bis-(2-thienyl)-2-(1,1,2,2-tetrafluoro-ethylsulfonyl)-1H-imidazole, the compound of Claim 34 in which R1 is -CF2CF2H, R2 and R3 are each 2-thienyl, R4 is hydrogen and n is 2, when prepared by the process of Claim 25.

59. 4-(4-methoxyphenyl)-2-(1,1,2,2-tetrafluoro-ethylsulfonyl)-5-(2-thienyl)-1H-imidazole, the compound of Claim 34 in which R1 is -CF2CF2H, R2 is 4-methoxyphenyl, R3 is 2-thienyl, R4 is hydrogen and n is 2, when prepared by the process of Claim 26.

60. 4-(3,4-dichlorophenyl)-2-(1,1,2,2-tetrafluoro-ethylsulfonyl)-5-(2-thienyl)-1H-imidazole, the compound of Claim 34 in which R1 is -CF2CF2H, R2 is 3,4-dichlorophenyl, R3 is 2-thienyl, R4 is hydrogen and n is 2, when prepared by the process of Claim 27.

61. 4-(4-fluorophenyl)-2-(1,1,2,2-tetrafluoro-ethylsulfonyl)-5-(2-thienyl)-1H-imidazole, the compound of Claim 34 in which R1 is -CF2CF2H, R2 is 4-fluorophenyl, R3 is 2-thienyl, R4 is hydrogen and n = 2, when prepared by the process of Claim 28.

62. 4-(4-fluorophenyl)-5-(2-thienyl)-2-trifluoro-methylsulfonyl-1H-imidazole, the compound of Claim 34 in which R1 is -CF3, R2 is 4-fluorophenyl, R3 is 2-thienyl, R4 is hy-drogen and n is 2, when prepared by the process of Claim 29.

63. 4-(4-methoxyphenyl)-4-(2-thienyl)-2-tri-fluoromethylsulfonyl-1H-imidazole, the compound of Claim 34 in which R1 is -CF3, R2 is 4-methoxyphenyl, R3 is 2-thienyl, R4 is hydrogen and n is 2, when prepared by the process of Claim 30.

64. 4,5-bis-(2-thienyl)-2-(1,1,2,2-tetrafluoro-ethylsulfonyl)-1H-imidazole, the compound of Claim 34 in which R1 is -CF2CF2H, R2 and R3 are each 2-thienyl, R4 is hydrogen and n is 2, when prepared by the process of Claim 31.

65. 4-(4-methoxyphenyl)-2-(1,1,2,2-tetrafluoro-ethylsulfonyl)-5-(2-thienyl)-1H-imidazole, the compound of Claim 34 in which R1 is -CF2CF2H, R2 is 4-methoxyphenyl, R3 is 2-thienyl, R4 is hydrogen and n is 2, when prepared by the process of Claim 32.

66. 4-(3,4-dichlorophenyl)-2-(1,1,2,2-tetrafluoro-ethylsulfonyl)-5-(2-thienyl)-1H imidazole, the compound of Claim 34 in which R1 is -CF2CF2H, R2 is 3,4-dichlorophenyl, R3 is 2-thienyl, R4 is hydrogen and n is 2, when prepared by the process of Claim 33.