Note: Descriptions are shown in the official language in which they were submitted.
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.
-- 2 --
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.
-- 3 --
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-
1074327
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.
1074327
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.
EXAMPLE 2
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.
-- 8 --
1~17~Z ~
EXAMPLE 3
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.
EXAMPLE 4
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.
EXAMPLE 5
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.
EXAMPLE 6
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.
-- 10 --
i~)743~7
EXAMPLE 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.
EXAMPLE 8
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.
-- 11 --
1074327
EXAMPLE 9
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.
EXAMPLE 10
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
- 12 -
10743Z7
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.
EXAMPLE 11
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.
EXAMPLE 12
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~-
-- 13 --
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.
EXAMPLE 13
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.
EXAMPLE 14
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;
-- 14 --
1(~74327
N, 7.52. Found: C, 61.47; H, 5.47; Ng 7.35.
EXAMPLE 15
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.
EXAMPLE 16
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
- 15 -
~)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.
EXAMPLE 18
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.
- 16 -
1~37432~
EXAMPLE 19
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.
EXAMPLE 20
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
10743Z7
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.
EXAMPLE 21
_
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.
- 18 -
10~ 32'~
EXAMPLE 23
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.~.
EXAMPLE 24
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.
EXAMPLE 25
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.
-- 19 --
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.
EXAMPLE 101
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
- 20 -
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
- 22 -
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
- 24 -
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.
- 26 -
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
- 27 -
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.
- 28 -
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
- 31 -
1074327
(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.
- 32 -
43Z7
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
34 4-CF3 H CH3 176-177 20
4-F 4-CF3 CH3 196-197 17
36 4-C1 4-CF3 CH3 214-215 3.6
37 3,4-OCH20 3,4-OCH2o CH3 201-202 20
4 4-CH30 4-CH30 3 2 150-1513 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
43 4-CH3 4-CH3 F 204-205 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
98 4-CH30 4-CH30 CH3COCH2 1 138-143 56
99 4-CH 0 4-CH30 CH3S02CH2 2 202-203 54
100 4-CH30 4-CH30 CH3COCH2 2 134-135 18
_ _ _
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
3-F 2C 2 2
3-C1 2 2
2-C1 2-ClHCF2CF2 2
4-n-C H 4-n-C H2 2 2
4 2 5 2 5 2C 2
4-NH2 4-NH~ 2 2
4-N(CH3) 4-N(CH3) 2 2
4-NHCOCH3 4-NHCOCH3 2 2 2
4-N02 2C 2 2
4-CH3S 4-CH3S 2C 2
3 2 3 2 2C 2 2
3,4-C1 H 2 2 2
4-CH30 4-CH30 2 2
4-t-C4H~0 4-t-C4H902 2 2
4-F 4-FH2CFCY2 2
- 38 -
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 ~
1074327
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
18 15-5 337
39 20 20 398
71 0 03 43
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.
- 43 -
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
- 44 -
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~)
3 H
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
- 5 -
~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
- 51 -
'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
-SCF2CFH
/\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
4-CH30 4-CH30 I 183-184 40
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
- 54 -
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
