Compounds of the formula ##STR1## wherein n is a integer of 0 to 2; R.sub.1 ' and R.sub.2 ' are, independently, hydrogen, halogen, trifluoromethyl, lower alkoxy or lower alkyl; and X is pyrimidinyl, thiazolyl or ##STR2## wherein R is hydrogen, lower alkyl, aryl or ar-lower alkyl; provided that at least one or R.sub.1 ' and R.sub.2 ' is other than hydrogen, PA0 and their pharmaceutically acceptable acid addition salts, and an anti-inflammatory method utilizing a compound of the formula ##STR3## wherein n is an integer of 0 to 2; R.sub.1 and R.sub.2 are, independently, hydrogen, halogen, trifluoromethyl, nitro, amino, lower alkylamino, di-lower-alkylamino, lower alkoxy or lower alkyl; and X is pyrimidinyl, thiazolyl or ##STR4## wherein R is hydrogen, lower alkyl, aryl or ar-lower alkyl; and their pharmaceutically acceptable acid addition salts, are described.

BRIEF SUMMARY OF THE INVENTION 
The invention relates to compounds of the formula 
##STR5## 
wherein n is an integer of 0 to 2; R.sub.1 ' and R.sub.2 ' are, 
independently hydrogen, halogen, trifluoromethyl, lower alkoxy or lower 
alkyl; and X is pyrimidinyl, thiazolyl or 
##STR6## 
wherein R is hydrogen, lower alkyl, aryl or ar-lower alkyl; provided that 
at least one of R.sub.1 ' and R.sub.2 ' is other than hydrogen, 
and their pharmaceutically acceptable acid addition salts. 
In another aspect, the invention relates to an anti-inflammatory method 
utilizing compounds of the formula 
##STR7## 
wherein n is an integer of 0 to 2; R.sub.1 and R.sub.2 are, independently, 
hydrogen, halogen, trifluoromethyl, nitro, amino, lower alkylamino, 
di-lower-alkylamino, lower alkoxy or lower alkyl; and X is pyrimidinyl, 
thiazolyl or 
##STR8## 
wherein R is hydrogen, lower alkyl, aryl or ar-lower alkyl: and their 
pharmaceutically acceptable acid addition salts. 
The compounds of formula I are useful as agents for the treatment of 
inflammatory diseases such as arthritis, inflammatory bowel diseases such 
as colitis, skin diseases such as psoriasis, and bronchopulmonary diseases 
such as asthma.

DETAILED DESCRIPTION OF THE INVENTION 
As used herein, the term "lower alkyl" denotes a straight or branched chain 
saturated hydrocarbon radical containing 1 to 8 carbon atoms, for example, 
methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, 
heptyl, octyl and the like. The term "lower alkoxy" denotes an ether 
derivative of a straight or branched chain saturated hydrocarbon 
containing 1 to 8 carbon atoms, for example, methoxy, ethoxy, propoxy, 
isopropoxy, butoxy, t-butoxy, neopentoxy, heptoxy, octoxy and the like. 
The term "halogen" denotes all the halogens, that is, bromine, chlorine, 
fluorine, and iodine. The term "aryl" or "ar" denotes phenyl or phenyl 
bearing one or two substituents independently selected from the group 
consisting of halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, 
amino, lower alkylamino and di-lower alkylamino. The term "ar-lower alkyl" 
denotes a straight or branched chain lower alkyl group in which one or 
more of the hydrogen atoms have been replaced by an aryl group, for 
example, benzyl, phenethyl and the like. 
Examplary of pyrimidinyl are 2-pyrimidinyl, 4-pyrimidinyl and 
5-pyrimidinyl. Examplary of thiazolyl are 2-thiazolyl, 4-thiazolyl and 
5-thiazolyl. Examples of lower alkylamino groups are methylamino, 
ethylamino, propylamino, butylamino and the like. Examples of 
di-loweralkylamino groups are dimethylamino, diethylamino, dipentylamino, 
dihexylamino dioctylamino and the like. 
The invention relates to compounds of the formula 
##STR9## 
wherein R.sub.1 ' and R.sub.2 ' are, independently, hydrogen, halogen, 
trifluoromethyl, lower alkoxy or lower alkyl; and X is pyrimidinyl, 
thiazolyl or 
##STR10## 
wherein R is hydrogen, lower alkyl, aryl or ar-lower alkyl; provided that 
at least one of R.sub.1 ' and R.sub.2 ' is other than hydrogen, 
and their pharmaceutically acceptable acid addition salts. 
In another aspect, the invention relates to an anti-inflammatory method 
utilizing compounds of the formula 
##STR11## 
wherein R.sub.1 and R.sub.2 are, independently, hydrogen, halogen, 
trifluoromethyl, nitro, amino, lower alkylamino, di-lower-alkylamino, 
lower alkoxy or lower alkyl; and X is pyrimidinyl, thiazolyl or 
##STR12## 
wherein R is hydrogen, lower alkyl, aryl or ar-lower alkyl; and their 
pharmaceutically acceptable acid addition salts. 
A preferred group of compounds of formula I are those wherein one or both 
of R.sub.1 and R.sub.2 are independently, lower alkoxy, halogen or 
trifluoromethyl and X is pyrimidinyl and 
##STR13## 
wherein R is as previously described. 
A more preferred group of compounds of formula I are those wherein one or 
both of R.sub.1 and R.sub.2 are, independently halogen or trifluoromethyl 
and X is 
##STR14## 
wherein R is lower alkyl. 
Preferred compounds of formula I of the invention: 
2-[(2-chlorophenyl)thio]-1H-imidazole; 
2-[(4-chlorophenyl)thio]-1H-imidazole; and 
2-[(4-chlorophenyl)thio]-pyrimidine. 
Examplary of compounds of formula I of the invention are: 
2[(4-Methyl-2-nitrophenyl)thio]-1-methyl-1H-imidazole; 
1-n-Butyl-2-[(2-chloro-4-methylphenyl)thio]-1H-imidazole; 
2-[(2-Chloro-4-methylphenyl)thio]-1-phenyl-1H-imidazole; 
2-[(4-Chloro-3-methylphenyl)thio]-1-methyl-1H-imidazole; 
2-[[2-Chloro-(4-methylamino)phenyl]thio]-1-methyl-1H-imidazole; 
2-[[4-Chloro-(2-methylamino)phenyl]thio]-l-methyl-1H-imidazole; 
2-[[2-Chloro-(4-n-propylamino)phenyl]thio-1-methyl-1H-imidazole: 
2-[[(2-Trifluoromethyl)-(4-methylamino)phenyl]thio]-1-methyl-1H-imidazole; 
2-[[2-Chloro-(4-dimethylamino)phenyl]thio]-1-methyl-1H-imidazole; 
2-[[(2-Dimethylamino)-4-methoxyphenyl]thio]-1-methyl-1H-imidazole; 
2-[[2-Chloro-(4-diethylamino)phenyl]thio]-1-methyl 1H-imidazole; 
2-[[(4-Trifluoromethyl)phenyl]thio]pyrimidine; 
2-[[(2-Dimethylamino)phenyl]thio]pyrimidine; 
2-[[(4-Methylamino)phenyl]thio]pyrimidine; 
2-[[4-Chloro-(2-trifluoromethyl)phenyl]thio]pyrimidine; 
2-[[(4-Dimethylamino)phenyl]thio]thiazole; and 
2-[[4-Methyl-2-(trifluoromethyl)phenyl]thio]thiazole. 
The compounds of formula II, which include the compounds of formula I, can 
be prepared as hereinafter described in Reaction Schemes I-III. 
Reaction Scheme I 
##STR15## 
wherein X is as previously described and R.sub.1 " and R.sub.2 " are 
independently, hydrogen, halogen, trifluoromethyl nitro, lower alkylamino, 
di-loweralkylamino, lower alkoxy or lower alkyl. 
In Reaction Scheme I, a compound of formula III, which are known compounds 
or can be prepared according to known procedures, can be diazotized using 
sodium nitrite in acidic medium, a standard Sandmeyer type reaction. The 
diazonium solution is then added to a compound of formula IV which are 
known compounds or can be prepared according to known procedures, in an 
acidic solution. The reactions can be carried out at temperatures in the 
range of -20.degree. C. to 50.degree. C. with -5.degree. C. to 25.degree. 
C. being preferred. The acid is neutralized by the addition of an 
inorganic base such as, ammonium hydroxide, and the reaction product is 
extracted with an organic solvent such as diethyl ether ethyl acetate or 
dichloromethane to yield the corresponding compound of formula IIa. The 
resulting compound of formula IIa can be recovered utilizing standard 
procedures, for example, crystallization, precipitation, chromatography 
and the like. 
REACTION SCHEME II 
##STR16## 
wherein X, R.sub.1 " and R.sub.2 " are as previously described, and n' is 
1 or 2. 
In Reaction Scheme II, a compound of formula IIa is treated with one molar 
equivalent of an organic peracid such as metachloro perbenzoic acid if a 
compound of formula Ilb, wherein n' is one (1), is to be prepared, and two 
molar equivalents, if a compound of formula IIb, wherein n' is two (2), is 
to be prepared, in an inert organic solvent such as dichloromethane at 
temperatures in the range of -20.degree. C. to 100.degree. C. The 
resulting product of formula IIb is isolated from the reaction mixture by 
the addition of an inorganic base, such as sodium hydroxide followed by 
extraction with an organic solvent such as diethyl ether, ethyl acetate or 
dichloromethane and recovery by standard procedures, for example, 
crystallization, precipitation, chromatography and the like. 
REACTION SCHEME III 
##STR17## 
wherein n, X.sub.1, R.sub.1 " and R.sub.2 " are as previously described, 
provided that one or both of R.sub.1 " and R.sub.2 " are nitro, and 
wherein X, R.sub.1 "' and R.sub.2 '" are independently, hydrogen, halogen, 
trifluoromethyl, amino, lower alkylamino, di-lower alkylamino, lower 
alkoxy or lower alkyl, provided that at least one of R.sub.1 "' or R.sub.2 
"' is amino. 
In Reaction Scheme III, a compound of formula IIc, which can be prepared as 
described in Reaction Scheme I, is reacted whereby the nitro group is 
transformed into an amino group to yield the corresponding compound of 
formula IId. The conversion to the amino group can be carried out by 
standard reduction methods such as use of stannous chloride or catalytic 
hydrogenation. A stannous chloride reduction can be carried out in acidic 
medium at temperatures in the range of 0.degree. C. to 50.degree. C. to 
yield the corresponding compound of formula IId. The resulting compound of 
formula IId is isolated by neutralizing the acid with an inorganic base 
followed by extraction with an organic solvent such as diethyl ether, 
ethyl acetate or dichloromethane and can be recovered utilizing standard 
procedures for example, crystallization precipitation, chromatography and 
the like. If desired, an amino group can be replaced by a halogen group 
utilizing standard procedures for the diazotization of an amine, i.e. 
sodium nitrite, acidic medium, temperatures of from -10.degree. C. to 
50.degree. C. followed by treatment with the appropriate halide such as 
cuprous chloride cuprous bromide or potassium iodide. 
REACTION SCHEME IV 
##STR18## 
wherein X, R.sub.1 and R.sub.2 are as previously described, provided that 
one of R.sub.1 or R.sub.2, or both, are nitro. 
In Reaction Scheme IV, a compound of formula V, which are known compounds 
or can be prepared according to known procedures, is treated with a 
mercaptoheterocyclic compound of Formula IV in the presence of a base such 
as sodium hydride sodium methoxide, or sodium hydroxide. The reaction can 
be carried out in an organic solvent such as N,N-dimethylformamide, lower 
alkanol such as methanol or ethanol, or dimethyl sulfoxide at temperatures 
ranging from room temperature to 150.degree. C. to yield the corresponding 
compound of formula IIe. A compound of formula IIe can be isolated by 
quenching the reaction mixture with water or sodium chloride solution 
followed by extraction with an organic solvent such as diethyl ether, 
ethyl acetate or dichloromethane, and can be recovered utilizing standard 
procedures for example, crystallization precipitation chromatography and 
the like. 
The compounds of formula I and formula II form acid addition salts and such 
salts are also within the scope of this invention. Thus the compounds of 
formula I and formula II form pharmaceutically acceptable addition salts 
with, for example, both pharmaceutically acceptable organic and inorganic 
acids, such as acetic acid, succinic acid, formic acid, methanesulfonic 
acid, p-toluene-sulfonic acid, hydrochloric acid, nitric acid, phosphoric 
acid, sulfuric a id and the like. 
The compounds of formula I are useful as agents for the treatment of 
inflammatory diseases such as arthritis; inflammatory bowel disease such 
as colitis, skin diseases such as psoriasis; and bronchopulmonary diseases 
such as asthma. 
Carrageenan Pleurisy Test (In Vivo) 
The animals utilized in these studies were male Lewis rats (Charles River 
Breeding Laboratories) weighing between 230-250 g. Carrageenan (CG) 
pleurisy was induced by injecting 0.2 ml of 1% lambda carrageenan (Sigma 
Lot #60F-0652) dissolved in sterile, pyrogen free, saline into the right 
pleural cavity of the rat using a 26 gauge (3/8") intradermal needle. 
Compounds suspended in aqueous suspending vehicle (ASV, 0.5% 
carboxymethylcellulose containing 0.9% NaCl, 0.37% Tween 80 and 0.85% 
benzyl alcohol) were administered by intubation 1 hour before CG injection 
for the 5 hour treatment period and 1 hour before and 5 hours after CG 
injection for the 24 hour treatment period. Drugs were administered at 
doses which, on the basis of preliminary experiments, would significantly 
suppress the development of CG-induced pleurisy under our experimental 
conditions. 
At 5 or 24 hours after CG injection, the rats were killed by decapitation, 
exsanguinated, and the pleural cavity exposed by cutting the ribs on both 
sides of the sternum. The exudate fluid was removed from the pleural 
cavity with disposable plastic pipettes and its volume quantitated. The 
pleural cavity was then washed once with phosphate buffered saline 
containing fetal bovine serum (1:1) and the washings combined with the 
exudate. The total number of cells in the pleural cavity was quantitated 
using a Coulter Counter (Model ZM) adjusted to exclude any contaminating 
RBC. (Published in "Plant Flavonoids in Biology & Medicine: Biochemical, 
Pharmacological and Structure-Activity Relationships" p. 231-242 (1986) 
Alan R. Liss, Inc.) 
Data for the compounds of this invention in this test are reported in Table 
I. 
TABLE I 
______________________________________ 
Exudate 
Com- Dose, Volume 
pound R.sub.1 R.sub.2 
X mg/kg % Reduction 
______________________________________ 
1 2-NO.sub.2 
H 
##STR19## 30 59 
2 2-Cl H 
##STR20## 30 58 
3 4-Cl H 
##STR21## 30 60 
4 4-NO.sub.2 
H 
##STR22## 100 83 
5 4-Cl 
##STR23## 100 58 
6 2-Cl 6-Cl 
##STR24## 30 54 
7 2-NO.sub.2 
4-Cl 
##STR25## 30 50 
8 4-NO.sub.2 
H 
##STR26## 30 59 
9 4-NO.sub.2 
H 
##STR27## 30 35 
10 2-Cl H 
##STR28## 30 32 
11 4-Cl H 
##STR29## 30 59 
12 4-CF.sub.3 
H 
##STR30## 30 50 
13 2-Cl H 
##STR31## 30 63 
14 2-Cl 4-I 
##STR32## 47 39 
15 2-CF.sub.3 
4-Cl 
##STR33## 30 36 
16 2-Cl H 
##STR34## 40 50 
______________________________________ 
A compound of formula I or formula II or a salt thereof or a composition 
containing a therapeutically effective amount of a compound of formula I 
or formula II or a salt thereof can be administered by methods well known 
in the art. Thus, a compound of formula I or formula II or a salt thereof 
can be administered either singly or with other pharmaceutical agents, 
orally, parenterally, rectally or by inhalation, for example, in the form 
of an aerosol, micropulverized powder or nebulized solution. For oral 
administration the described compounds can be administered in the form of 
tablets, capsules, for example, in admixture with talc, starch, milk sugar 
or other inert ingredients, that is, pharmaceutically acceptable carriers, 
in the form of aqueous solutions, suspensions, elixirs or aqueous 
alcoholic solutions, for example, in admixture with sugar or other 
sweetening agents, flavoring agents, colorants, thickeners and other 
conventional pharmaceutical excipients, or beadlets for oral 
administration. For parenteral administration, the desired compound can be 
administered in solutions or suspension, for example as an aqueous or 
peanut oil solution or suspension using excipients and carriers 
conventional for this mode of administration. For administration as 
aerosols, they can be dissolved in a suitable pharmaceutically acceptable 
solvent, for example, ethyl alcohol or combinations of miscible solvents, 
and mixed with a pharmaceutically acceptable propellant. Such aerosol 
compositions are packaged for use in a pressurized container fitted with 
an aerosol valve suitable for release of the pressurized composition. 
Preferably, the aerosol valve is a metered valve, that is one which on 
activation releases a predetermined effective dose of the aerosol 
composition. For rectal administration the desired compound can be 
administered in the form of suppositories utilizing an inert carrier 
material cocoa butter and the like. For topical administration, the 
described compounds can be incorporated into ointments, creams, lotions, 
gels, and the like. In general, the solutions, ointments and creams which 
are useful in accordance with this invention include formulations having 
absorbable, water soluble or emulsion-type bases, such as petrolatum, 
lanolin, polyethylene glycols, or the like. 
Suitable solutions will contain the compounds of formula I or formula II or 
their salts dissolved in a pharmaceutically acceptable solvent, such as 
polyethylene glycol, or the like. 
Suitable lotions include, true solutions to aqueous or hydroalcoholic 
formulations containing finely divided particles. Lotions can contain 
suspending or dispersing agents such as cellulose derivatives, for 
example, methyl cellulose, ethyl cellulose, or the like. Gels will 
typically be semi-solid preparations made by gelling a solution or 
suspension of a compound of formula I or formula II in a suitable hydrous 
or anhydrous vehicle, using a gelling agent such as a carboxy 
polymethylene, or the like, and thereafter neutralizing it to proper 
consistency with an alkali metal hydroxide, for example, sodium hydroxide, 
and an amine, for example, polyethylenecocoamine. Topical pharmaceutical 
compositions containing a compound of formula I or formula II or a salt 
thereof can also be formulated to include conventional ingredients such as 
preservatives, stabilizers, wetting agents, emulsifying agents, buffers, 
and the like, in conventional amounts adjusted for particular requirements 
and which are readily determinable by those skilled in the art. 
In the practice of the invention, the dose of a compound of formula I or 
formula II or a salt thereof to be administered and the frequency of 
administration will be dependent on the potency and duration of activity 
of the particular compound of formula I or formula II or salt to be 
administered and on the route of administration, as well as the severity 
of the condition, age of the mammal to be treated and the like. Oral doses 
of a compound of formula I or formula II or a salt thereof contemplated 
for use in practicing the invention are in the range of from about 5 to 
about 100 mg/kg per day. 
The Examples which follow further illustrate the invention. All 
temperatures are given in degrees Centrigrade, unless otherwise stated. 
EXAMPLE I 
1-Methyl-2-[(2-nitrophenyl)thio]-1H-imidazole 
To a slurry of 0.8 g (20 mmoles) of sodium hydride (60% dispersion in 
mineral oil) in 10 ml of N,N-dimethylformamide, stirred in an ice bath, 
and under a nitrogen atmosphere, was added dropwise a solution of 2.28 g 
(20 mmoles) of 2-mercapto-1-methylimidazole in 5 ml of 
N,N-dimethylformamide. After the evolution of hydrogen gas had ceased, the 
ice bath was removed and the reaction mixture stirred at room temperature 
for 0.5 hours. To the reaction was added, dropwise, a solution of 2.82 g 
(20 mmoles) of 1-fluoro-2-nitrobenzene in 10 ml of N,N-dimethylformamide. 
After stirring at room temperature for 16 hours, the mixture was poured 
into a saturated sodium chloride solution (100 ml) and extracted with 
dichloromethane. The organics were dried and the solvents were removed in 
vacuo. The resulting yellow solid was triturated with ether and collected 
by filtration to give 3.5 g (74%) of product as yellow prisms, mp 
117.degree.-119.degree. C. 
EXAMPLE 2 
1-Methyl-2-[(2-nitrophenyl)thio]-1H-imidazole hydrochloride dihydrate 
The product obtained in Example 1 was converted to the hydrochloride salt 
by treatment in a mixture of ether and dichloromethane with gaseous 
hydrogen chloride. The product was obtained as yellow prisms, mp 
160.degree.-165.degree. C. 
EXAMPLE 3 
1-Methyl-2-[(4-nitrophenyl)thio]-1H-imidazole 
The same procedure described in Example 1 was used except that 
1-fluoro-4-nitrobenzene was used instead of 1-fluoro-2-nitrobenzene. The 
product was obtained as yellow prisms, mp 120.degree.-121.degree. C. 
EXAMPLE 4 
4-(1-Methyl-1H-imidazole-2-yl)thio]]benzenamine 
To a solution of 1.4 g (6 mmols) of the product from Example 3 in 15 ml of 
glacial acetic acid was added a solution of 6.8 g (30 mmoles) of stannous 
chloride dihydrate in 20 ml of 6N hydrochloric acid and 30 ml of glacial 
acetic acid. After stirring at room temperature for 16 hours, the reaction 
mixture was cooled in an ice bath and partially neutralized with a 
solution of 6 g of sodium hydroxide in 30 ml of water. The mixture was 
concentrated in vacuo to remove most of the acetic acid and the residues 
was treated with concentrated ammonium hydroxide until basic. The mixture 
was filtered and the solid was washed with water. The filtrates were 
extracted with dichloromethane and combined with the collected solid. The 
organic solution was dried and concentrated. The residue was 
chromatographed on silica gel using dichloromethane/methanol (9:1 by 
volume) to elute the product. The fractions containing the product were 
combined and concentrated to give a solid which was triturated with ether 
and collected by filtration to give the product (0.6 g. 50%) as off-white 
prisms mp 115.degree.-117.degree. C. 
EXAMPLE 5 
2-[(1-Methyl-1H-imidazole-2-yl)thio]]benzenamine 
Utilizing the procedure given in Example 4, and using the product obtained 
in Example 1 as starting material, the product was obtained as off-white 
prisms in 75% yield mp 118.degree.-120.degree. C. 
EXAMPLE 6 
2-[(2-Chlorophenyl)thio]-1H-imidazole 
Method A. To a solution of 24.6 g (0.12 mole) of the product from Example 5 
in 180 ml of 3N hydrochloric acid and 180 ml of glacial acetic acid 
(stirred in an ice bath) was added dropwise over 20 minutes, a solution of 
8.4 g (0.12 mole) of sodium nitrite in 24 ml of water. This mixture was 
then added in portions over 20 minutes to a solution (at -5.degree. C.) of 
35 g (0.35 mole) of cuprous chloride in 325 ml of 6N hydrochloric acid. 
The reaction mixture was then stirred at room temperature for 1 hour and 
then cooled in an ice bath. The solid was collected by filtration and 
combined with the solid obtained from an identical, duplicate run. The 
solid was partitioned with ethyl acetate and ammonium hydroxide and the 
organics were combined, dried and concentrated to give 31.4 g (58%) of the 
product as a yellow oil. The oil was chromatographed on silica gel and 
eluted with ethyl acetate. The fractions containing the product were 
combined and concentrated to give 24.6 g of product as an oil which 
crystallized upon standing at -10.degree. C. The product was obtained as 
off-white prisms, mp 37.degree.-39.degree. C. 
Method B. A mixture of 0.6 g of zinc powder was stirred for 20 minutes at 
60.degree. C. with 25 ml of 1N sulfuric acid and then filtered. To the 
filtrate was added 0.35 g of cuprous oxide followed by 0.9 g (7.8 mmoles) 
of 2-mercapto-1-methylimidazole. 2-Chloroaniline (1 g, 7.8 mmoles) in 36 
ml of 1N sulfuric acid was diazotized by cooling in an icebath followed by 
the dropwise addition of a solution of 0.57 g (8.2 mmoles) of sodium 
nitrite in 5 ml of water. The diazonium solution was then added over 30 
minutes, and at 0.degree. C. to the above solution of 
2-mercapto-1-methylimidazole. The mixture was stirred at 0.degree. for 2 
hours and then at room temperature for 2 hours. The mixture was decanted 
and made basic by treatment with ammonium hydroxide and extracted with 
ether. The organics were washed with saturated sodium chloride solution, 
dried and concentrated. The residue was dissolved in a small amount of 
dichloromethane and filtered through silica gel using ether as the eluent. 
The fractions containing the product were combined and concentrated to 
give 1.1 g (63%) of the product, identical to the product obtained in 
Method A. 
EXAMPLE 7 
2-[(2-Chlorophenyl)thio]-1H-imidazole hydrochloride 
The product from Example 6 was dissolved in ether and treated with gaseous 
hydrogen chloride. The product was obtained as off-White prisms, mp 
165.degree.-170.degree. C. 
EXAMPLE 8 
2-[(4-Chlorophenyl)thio]-1H-imidazole 
Using the procedure given in Example 6 and starting with the product from 
Example 4. there was obtained a 65% yield of the product as off-white 
prisms, mp 86.degree.-88.degree. C. 
EXAMPLE 9 
2-[(4-Chlorophenyl)thio]-1H-imidazole hydrochloride 
The product from Example B was dissolved in ether and treated with gaseous 
hydrogen chloride. The product was collected by filtration, washed with 
ether and air-dried and was obtained as off-white prisms, mp 
180.degree.-185.degree. C. 
EXAMPLE 10 
2-[(4-Chlorophenyl)sulfinyl-1-methyl-1H-imidazole 
A solution of 450 mg (2 mmoles) of the product from Example 8 in 50 ml of 
dichloromethane was treated with 360 mg (2.1 mmoles of 
meta-chloroperbenzoic acid. After stirring at room temperature for 40 
minutes, the mixture was poured into ammonium hydroxide and extracted with 
dichloromethane. The organics were combined, dried and concentrated. The 
residue was chromatographed on silica gel using ethyl acetate as the 
eluent. The fractions containing the product were combined and 
concentrated. The residue was crystallized from petroleum ether (bp 
30.degree.-60.degree. C.) to give 300 mg (63%) of the product as light tan 
prisms, mp 96.degree.-97.degree. C. 
EXAMPLE 11 
2-[(4-Chlorophenyl)sulfonyl-1-methyl-1H-imidazole 
To a solution of 0.9 g (4 mmoles) of the product from Example 8 in 100 ml 
of dichloromethane, was added 1.7 g (10 mmoles) of meta-chloroperbenzoic 
acid. After stirring at room temperature for 16 hours the product was 
isolated following the procedure given in Example 10 and gave, after 
column chromatography, 0.7 g (68%) of the product as off-White prisms, mp 
164.degree.-166.degree. C. 
EXAMPLE 12 
1-n-Butyl-2-[(4-nitrophenyl)thio]-1H-imidazol hydrochloride 
To a solution of 0.98 g (25 mmoles) of sodium hydride (60% dispersion in 
mineral oil) in 13 ml of N,N-dimethylformamide was added 3.2 g (20.4 
mmoles) of 2-mercapto-1-n-butylimidazole and the mixture stirred at room 
temperature for a few minutes until the evolution of hydrogen had stopped. 
The reaction mixture was cooled in an icebath and 3.76 g (26.7 mmoles) of 
1-fluoro-4-nitrobenzene was added. The mixture was stirred at 0.degree. C. 
for 20 minutes and then at room temperature for 3 hours. The reaction was 
quenched with ice and water to give a total volume of 175 ml. The product 
was extracted with 3.times.75ml of dichloromethane. The organics were 
combined, dried and concentrated. The residual oil was triturated with 50 
ml of petroleum ether (bp 30.degree.-60.degree. C.) which was removed by 
decanting. This process was repeated three times. The remaining oil was 
dissolved in 200 ml of ether and washed with 100 ml of water. The organic 
phase was dried and concentrated. The residue was treated with excess 10N 
hydrogen chloride in ethanol to form the hydrochloride salt. Ether was 
added and the precipitate collection by filtration and washed with ether. 
Recrystallization from methanol/ether gave 3.8 (59%) of the product as 
colorless needles, mp 182.degree.-184.degree. C. 
EXAMPLE 13 
4-[(1-n-Butyl-1H-imidazol-2-yl)thio]]benzenamine 
To a solution of 7.2 g (32 mmoles) of stannous chloride dihydrate in 8.6 ml 
of concentrated hydrochloric acid, stirred in an ice bath, was added 1.0 g 
(3.2 mmoles) of the product from Example 12 dissolved in 15 ml of 
concentrated hydrochloric acid. After stirring at room temperature for 0.5 
hours, ice and water were added to the reaction mixture and 3N sodium 
hydroxide added until the mixture was alkaline. The product was extracted 
with dichloromethane and the organics were combined dried and 
concentrated. The residue was crystallized from ether and petroleum ether 
(bp 30.degree.-60.degree. C.) to give 0.58 g (73%) of the product as 
off-white prisms, mp 70.degree.-72.degree. C. 
EXAMPLE 14 
1-Butyl-2-[(4-chlorophenyl)thio]-1H-imidazole hydrochloride 
To a solution of 3.0 g (12.1 mmoles) of the product from Example 13 in 30 
ml of 3N hydrochloric acid, cooled in an ice bath at -5.degree. C. was 
added, dropwise, a solution of 0.89 g (12.9 mmoles) of sodium nitrite in 
45 ml of water. After stirring for 5 minutes, the reaction mixture was 
poured into a solution of 2.4 g (24.2 mmoles) of cuprous chloride in 24 ml 
of concentrated hydrochloride acid. After stirring for 10 minutes, the 
mixture was heated on a steam bath for 2 hours. After cooling in an 
icebath, the mixture was made alkaline by the addition of 10N sodium 
hydroxide. The product was extracted with dichloromethane and the organics 
combined dried and concentrated. To the residue was added 10N hydrogen 
chloride in ethanol to form the hydrochloride salt. Ether was added and 
the precipitate collected by filtration. The product (1.0 g, 30%) was 
obtained as light tan prisms, mp 143.degree. -148.degree. C. following 
recrystallization from a mixture of tetrahydrofuran, methanol and ether. 
EXAMPLE 15 
2-[(2-Chloro-6-nitrophenyl)thio]-1-methyl-1H-imidazole 
Starting with 1.92 g (10 mmoles) of 2,3-dichloronitrobenzene and 1.14 g (10 
mmoles) of 2-mercapto-1-methylimidazole and following the procedure 
described in Example 1 there was obtained 2 g (74%) of the product as 
yellow prisms, mp 102.degree.-104.degree. C. 
EXAMPLE 16 
3-Chloro-2[-(1-methyl-1H-imidazol-2yl)thio]benzenamine 
Starting with 11 g (40 mmoles) of the product from Example 15 and following 
the procedure described in Example 4, there was obtained 7.6 g (79%) of 
the product as off-white prisms, mp 123.degree.-124.degree. C. 
EXAMPLE 17 
2-[(2,6-Dichlorophenyl)thio]-1-methyl-1H-imidazole 
Starting with 2.4 g (10 moles) of the product from Example 16 and using the 
procedure described in Example 14, there was obtained 0.9 g (35%) of the 
product as off-white prisms mp 113.degree.-115.degree. C. 
EXAMPLE 18 
2-[(2,6-Dichlorophenyl)thio]-1-methyl-1H-imidazole hydrochloride 
The product from Example 17 was treated with hydrogen chloride in ether and 
dichloromethane to give a 77% yield of the product as colorless prisms, mp 
211.degree.-222.degree. C. 
EXAMPLE 19 
2-[(4-Chloro-2-nitrophenyl)thio]-1-methyl-1H-imidazole 
Starting with 1.92g (10 moles) 2,5-dichloronitrobenzene and 1.14 g (10 
mmoles) of 2-mercapto-1-methylimidazole and following the procedure 
described in Example 1 there was obtained 1.0 g (37%) of the product as 
yellow prisms, mp 143.degree.-145.degree. C. 
EXAMPLE 20 
2-[(4-Chloro-2-nitrophenyl)thio]-1-methyl-1H-imidazole hydrochloride 
The product from Example 19 was treated with hydrogen chloride in 
dichloromethane and ether to give the product as yellow prisms mp 
155.degree.-160.degree. C. 
EXAMPLE 21 
5-Chloro-2-[(1-methyl-1H-imidazol-2-yl)thio]benzenamine 
Starting with 4.1 g (15 mmoles) of the product from Example 19 and using 
the procedure described in Example 4, there was obtained 2 g (57%) of the 
product as off-white prisms, mp 127.degree.-129.degree. C. 
EXAMPLE 22 
2-(2.6-Dichlorophenyl)thio]-1-methyl-1H-imidazole 
Starting with 2.4 g (10 mmoles) of the product from Example 21 and using 
the procedure described in Example 14, there was obtained 1.2 g (46%) of 
the product as light yellow prisms, mp 79.degree.-80.degree. C. 
EXAMPLE 23 
2-[(2,4-Dichlorophenyl)thio]-1-methyl-1H-imidazole hydrochloride 
Treatment of 0.8g (3.1 mmoles) of the product from Example 22 with hydrogen 
chloride in ether and dichloromethane gave the product (0.75 g. 76%) which 
was obtained as off-white prisms, mp 165.degree.-175.degree. C. 
EXAMPLE 24 
2-[(4-Nitrophenyl)thio]-1-phenyl-1H-imidazole 
To a mixture of 0.6 g (13.6 mmoles) of 50% sodium hydride in mineral oil 
and 8 ml of N,N-dimethylformamide was added 2.0 g (11.4 mmoles) of 
2-mercapto-1-phenylimidazole. After stirring for 10 minutes the mixture 
was cooled in an icebath and 2.1 g (14.8 mmoles) of 
1-fluoro-4-nitrobenzene was added. After stirring for 20 minutes, the 
mixture was warmed to room temperature and stirred for 3 hours. Ice was 
added and the mixture partitioned between dichloromethane and water. The 
aqueous phase was separated and extracted with dichloromethane. The 
organics were dried and concentrated. The residue was recrystallized from 
dichloromethane/petroleum ether (bp 30.degree.-60.degree. C.) to give 0.9 
g (27%) of the product as off-white prisms, mp 123.degree.-125.degree. C. 
EXAMPLE 25 
2-[(4-Nitrophenyl)thio]-1-phenyl-1H-imidazole hydrochloride 
The product from Example 24 was converted to the hydrochloride salt by 
treatment with ethanolic hydrogen chloride. After recrystallization from 
methanol/isopropanol/ether the product was obtained off-white prisms, mp 
215.degree.-218.degree. C. 
EXAMPLE 26 
2-[(4-Nitrophenyl)thio]-1H-imidazole 
To a mixture of 6.2 g (0.12 mmoles) of sodium methoxide and 90 ml of ethyl 
alcohol was added 5.8 g (0 058 mmoles) of 2-mercaptoimidazole. After 
stirring for 0.5 hour, 8.2 g (0.058 mole) of 1-fluoro-4-nitrobenzene was 
added and the mixture refluxed for 4 hours. The mixture was allowed to 
cool and filtered to give 5.0 g (39%) of the product. An additional 2.0 g 
(16%) of product was recovered from the filtrates. Recrystallization from 
dichloromethane/methanol gave the product as yellow rods. mp 
207.degree.-209.degree. C. 
EXAMPLE 27 
2-[(4-Nitrophenyl)thio]-1H-imidazole hydrochloride 
The product from Example 26 was dissolved in methanol and treated with an 
excess of hydrogen chloride in ethyl alcohol. The mixture was concentrated 
and the residue triturated with ether and filtered. The solid was 
recrystallized from methanol to give the product as colorless prisms, mp 
235.degree.-240.degree. C. (sealed tube). 
EXAMPLE 28 
2-[(4-Nitrophenyl)thio]-1-(phenylmethyl)-1H-imidazole 
A mixture of 0.85 g (15.8 mmoles) of sodium methoxide and 15 ml of ethanol 
was refluxed for 5 minutes and then cooled to room temperature. To this 
solution was added 1.5 g (7.9 mmoles) of 
2-mercapto-1-phenylmethylimidazole. After stirring for 10 minutes, 1.1 g 
(7.9 mmoles) of 1-fluoro-4-nitrobenzene was added and the mixture refluxed 
for 4 hours. An additional 0.85 g of sodium methoxide was added and the 
mixture refluxed for 9 hours. The mixture was filtered and the filtrate 
cooled and the resulting precipitate collected by filtration. The solid 
was recrystallized from dichloromethane/methanol to give the product as 
beige prisms, mp 122.degree.-123.degree. C. 
EXAMPLE 29 
2-[(4-Nitrophenyl)thio]-1-(phenylmethyl)-1H-imidazole hydrochloride 
The product from Example 28 was dissolved in mixture of dichloromethane and 
ethyl alcohol and treated with excess hydrogen chloride in ethyl alcohol. 
The solvents were removed in vacuo and the residue triturated with ether 
and filtered. The solid was recrystallized from methanol/ether to give the 
product as colorless prisms, mp 240.degree.-245.degree. C. (sealed tube). 
EXAMPLE 30 
1-(4-Nitrophenyl)-2-[(4-nitrophenyl)thio]-1H-imidazole 
This product was isolated by a byproduct from the reaction described in 
Example 26. The compound was obtained as yellow rods after 
recrystallization from dichloromethane/methanol, mp 
173.degree.-175.degree. C. 
EXAMPLE 31 
2-[(2-Nitrophenyl)thio]-1H-imidazole 
A mixture of 5.0 g (0.05 mole) of 2-mercaptoimidazole. 7.9 g (0.05 mole) of 
2-chloronitrobenzene, 6.5 g (0.12 mole) of sodium methoxide and 150 ml of 
ethanol was stirred and refluxed for 5 hours. An additional 0.8 g of 
2-chloronitrobenzene, was added and refluxing continued for 5 more hours. 
The mixture was filtered hot and the filtrates concentrated. The residue 
was partitioned with water and dichloromethane. The undissolved solid was 
collected by filtration to give 8.3 g of product. The dichloromethane was 
dried and concentrated. The residue was recrystallized from 
dichloromethane to give an additional 1.2 g of product. The total yield 
was 87% and the product was obtained as yellow rods, mp 
178.degree.-181.degree. C. 
EXAMPLE 32 
2-[(2-Aminophenyl)thio]-1H-imidazole 
To a solution of 8.0 g (37.6 mmoles) of the product from Example 31 in 80 
ml of glacial acetic acid was added to a solution of 25.5 g (113 mmoles) 
of stannous chloride dihydrate in 40 ml of 6N hydrochloric acid. The 
mixture was allowed to stir at room temperature overnight and then 
concentrated to a small volume. Ice was added and the solution made basic 
by the addition of 10N sodium hydroxide. The mixture was filtered and the 
solid washed with water. The filtrates were extracted with 
dichloromethane, washed with water, dried and concentrated. The residue 
was treated with ether, cooled and the solid collected by filtration to 
give 2.5 g of the product. The aqueous solution was adjusted to pH 9 with 
hydrochloric acid and filtered. The solid was stirred with methanol and 
then with methanol/dichloromethane. After filtration the filtrates were 
used to extract all of the aqueous layers. The organics were dried and 
concentrated to give an additional 3.5 of product. The product (83%) was 
obtained as colorless prisms, mp 135.degree.-137.degree. C. 
EXAMPLE 33 
2-[(2-Chlorophenyl)thio]-1H-imidazole 
To a solution of 5.6 g (29.3 mmoles) of the product from Example 32 in 50 
ml of 3N hydrochloric acid and 50 ml of glacial acetic acid (cooled in an 
ice bath), was added dropwise over 20 minutes, a solution of 2.0 g (29.3 
mmoles) of sodium nitrite in 8 ml of water. After stirring for 10 minutes, 
the mixture was added to a cold solution of 8.7 g (80 mmoles) cuprous 
chloride in 80 ml of 6N hydrochloric acid. After stirring at room 
temperature for 5 hours, the mixture was concentrated and the residue made 
alkaline with ammonium hydroxide. The product was extracted with 
dichloromethane which was washed with saturated sodium chloride, dried and 
concentrated. The residue was dissolved in hot dichloromethane and 
filtered through silica gel using dichloromethane/ethyl acetate (1:1 by 
volume) as the eluent. The fractions containing the product were 
concentrated to give 4.9 g (79%) of the product which was crystallized 
from dichloromethane to give colorless rods, mp 138.degree.-141.degree. C. 
EXAMPLE 34 
2-[(2-Chlorophenyl)thio]-1H-imidazole hydrochloride 
A solution of the product from Example 33 in methanol was treated with an 
excess of hydrogen chloride in ethyl alcohol. The mixture was concentrated 
in vacuo and the residue triturated with ether and filtered. The solid was 
recrystallized from methanol/ether to give the product as colorless 
prisms, mp 189.degree.-192.degree. C. (sealed tube). 
EXAMPLE 35 
2-[(4-Methoxy-2-nitrophenyl)thio]-1-methyl-1H-imidazole 
To a mixture of 2-mercapto-1-methylimidazole (1.14 g, 10 mmoles), 0.6 of 
60% sodium hydride in mineral oil and 20 ml of N,N-dimethylformamide was 
added 1.88 g (10 mmoles) of 4-chloro-3-nitroanisole. The mixture was 
stirred at room temperature for 0.5 hours and then heated at 
90.degree.-100.degree. C. for 4 hours. After cooling in an icebath, 0.5 ml 
of acetic acid was added and the mixture was partitioned between 
dichloromethane and dilute sodium bicarbonate. The organics were 
concentrated on a steam bath to a small volume and the residue was 
chromatographed on silica gel using ethyl acetate as the eluent. The 
fractions containing the product were combined and concentrated to give 
1.0 g (38%) of the product, mp 117.degree.-120.degree. C.). 
EXAMPLE 36 
2-[(4-Nitrophenyl)thio]pyrimidine 
A mixture of 1.12 g (10 mmoles) of 2-mercaptopyrimidine, 1.4 (10 mmoles) of 
1-fluoro-4-nitrobenzene, 0.5 of potassium hydroxide and 10 ml of 
dimethylsulfoxide were heated at 120.degree.-130.degree. C. for 6 hours 
and then cooled. After pouring into a mixture of ice, water and sodium 
chloride the mixture was allowed to stand for 30 minutes and then 
filtered. The solid was washed with water, air dried and chromatographed 
on silica gel using ethyl acetate/hexane (1:1 by volume) as the eluent. 
The fractions containing the product were combined and concentrated to 
give 1 g (43%) of the product as yellow rods, mp 103.degree.-104.degree. 
C. 
EXAMPLE 37 
4-[(2-pyrimidinyl)thio]benzenamine 
Using the procedure described in Example 4 and starting with 2.4 g (10 
mmoles) of the product from Example 36, there was obtained 0.8 g (40%) of 
the product as yellow prisms, mp 124.degree.-126.degree. C. 
EXAMPLE 38 
2-[(4-Chlorophenyl)thio]pyrimidine 
Using the procedure described in Example 6 and starting with 3.05 g (15 
mmoles) of the product from Example 37, there was obtained 1.5 g (45%) of 
the product as yellow prisms, mp 68.degree.-70.degree. C. 
EXAMPLE 39 
2-[(2-Chloro-4-methoxyphenyl)thio]-1-methyl-1H-imidazole hydrochloride 
The product from Example 35 was converted to the corresponding amino 
compound by reduction of the nitro group with stannous chloride following 
the procedure described in Example 4. The amino compound was obtained in 
16% yield as colorless rods, mp 139.degree.-140.degree. C. The amino group 
was converted to a chloro group by diazotization following the procedure 
given in Example 6, Method A. The product was converted to the 
hydrochloride salt by treatment with gaseous hydrogen chloride in ether 
and obtained as light yellow prisms, mp 178.degree.-183.degree. C. The 
yield from the amino compound was 61%. 
EXAMPLE 40 
2-[(3,4-Dimethoxyphenyl)thio]-1-methyl-1H-imidazole hydrochloride 
A solution of 1 g (14.4 mmoles) of sodium nitrite in 7 ml of water was 
added dropwise to a solution of 2.0 g (13.1 mmoles) of 4-aminoveratrole in 
65 ml of 1N sulfuric acid. The reaction was carried out under nitrogen in 
an icebath. The resulting solution was added dropwise to a mixture of 1.4 
g (13.1 mmoles) of 2-mercapto-1-methylimidazole and 0.7 g of cupric oxide 
in 45 ml of 1N sulfonic acid, cooled in an icebath. After stirring for 1 
hour, the icebath was removed and the mixture stirred overnight at room 
temperature. Ether and ammonium hydroxide were added and the mixture 
filtered. The filtrates were separated and the aqueous fraction extracted 
with ether. The organics were combined, dried and concentrated in vacuo. 
Ethanolic hydrogen chloride was added to the residue and the mixture 
concentrated. The product was recrystallized from 2-propanol and then from 
methanol/ether and obtained as colorless rods (21% yield), mp 
194.degree.-196.degree. C. (sealed tube). 
EXAMPLE 41 
2[(2-Chlorophenyl)sulfinyl]-1H-imidazole 
To a solution of 2.0 g (9.5 mmoles) of the product from Example 33 in 250 
ml of dichloromethane, cooled in an icebath, was added over 15 minutes, 
2.3 g (11.4 moles) of 85% meta-chloroperbenzoic acid. The mixture was 
allowed to stand for 3 days and then quenched by the addition of dilute 
ammonium hydroxide. Filtration yielded 0.2 g of the product. The filtrates 
were separated and the aqueous extracted with dichloromethane. The 
filtrates were dried and concentrated to give an additional 1.0 of 
product. The aqueous extracts were acidified with acetic acid and then 
made basic with sodium bicarbonate. After extracting with dichloromethane 
the organics were combined and concentrated to give 0.9 g of product. All 
of the solids were combined and recrystallized from 
dichloromethane/methanol to give 1.5 g (70%) of the product as colorless 
rods, mp 188.degree.-190.degree. C. 
EXAMPLE 42 
2-[(2-Chlorophenyl)sulfonyl]-1H-imidazole 
To a suspension of 3.5 g (15.4 mmoles) of the product from Example 41 in 
500 ml of dichloromethane was added 3.8 g (18.5 moles) of 85% 
meta-chloroperbenzoic acid. After stirring for 5 hours at room 
temperature, the reaction was quenched with sodium bicarbonate solution. 
The layers were separated and the aqueous extracted with dichloromethane. 
The organics were combined, dried and concentrated in vacuo. Petroleum 
ether (bp 30.degree.-60.degree. C.) was added and the mixture filtered. 
The solid was recrystallized from dichloromethane/ methanol/ether to give 
3.5 (93%) of the product as colorless needles, mp 204.degree.-207.degree. 
C. 
EXAMPLE 43 
2-[(2-Chlorophenyl)sulfinyl]-1-methyl-1H-imidazole 
To a solution of 0.9 g (4 mmoles) of the product from Example 6 in 80 ml of 
dichloromethane was added 0.8 g (4.7 mmoles) of 85% meta-chloroperbenzoic 
acid over a period of 5 minutes. After stirring for 2 hours the reaction 
was quenched by the addition of dilute ammonium hydroxide with vigorous 
stirring. The layers were separated and the organics dried and 
concentrated. The residue was triturated with 10 ml of ether and filtered 
to give 0.6 g (62%) of the product as off-white prisms, mp 
132.degree.-134.degree. C. 
EXAMPLE 44 
2-[(2-Chlorophenyl)sulfonyl]-1-methyl-1H-imidazole 
To a stirred solution of 0.9 g (4 mmoles) of the product from Example 6 in 
80 ml of dichloromethane was added 1.6 g (9 mmoles) of 
meta-chloroperbenzoic acid. After stirring overnight, an additional 1.6 g 
of the per acid was added followed by an additional 1.6 g after stirring 
for 1 hour. After stirring for 15 minutes the layers were separated and 
the organics dried and concentrated to give 1.1 g (100%) of the product as 
off-white prisms, mp 156.degree.-159.degree. C. 
EXAMPLE 45 
2[[4-(Trifluoromethyl)phenyl]thio]-1-methyl-1H-imidazole hydrochloride 
A mixture of 11 g (50 mmoles) of 4-trifluoromethyl-1-bromobenzene, 5.7 g 
(50 mmoles) of 1-methyl-2-mercaptoimidazole, 4 g of potassium hydroxide 
and 100 ml of dimethylsulfoxide was heated at 130.degree.-140.degree. C. 
for 16 hours and then cooled. The mixture was poured over a mixture of ice 
and sodium chloride and extracted with dichloromethane. The organics were 
dried, concentrated and the residue chromatographed on silica gel using 
ethyl acetate as the eluent. The residue was treated with an excess of 
hydrogen chloride in ether to form the hydrochloride salt. The salt which 
precipitated was collected by filtration, washed with ether and dried to 
give 3.2 g (22%) of the product as off-white prisms, mp 
180.degree.-188.degree. C. 
EXAMPLE 46 
2-[(2-Chlorophenyl)thiol-1-(1,1-dimethylethyl)-1H-imidazole 
The procedure given in Example 6, Method B, was used to prepare this 
product starting with 0.3 g (1.9 mmoles) of 
1-(1,1-dimethylethyl)-2-mercaptoimidazole and 0.24 g (1.9 mmoles) of 
2-chloroaniline. In this case the reaction time was extended to 18 hours. 
The crude product was chromatographed through silica gel using 
dichloromethane and then a mixture of dichloromethane/ether (8:1 by 
volume) as the eluent. The fractions containing the product were combined 
and concentrated. The residue was recrystallized from ether/petroleum 
ether (bp 30.degree.-60.degree. .C) to give 0.2g (39%) of the product as 
off-white prisms, mp 97.degree.-99.degree. C. 
EXAMPLE 47 
2-[(2-Chlorophenyl)thio]-1-(1,1-dimethylethyl)-1H-imidazole hydrochloride 
The product obtained in Example 46 was converted to the hydrochloride salt 
using hydrogen chloride in ethanol. The crude product was recrystallized 
from 2-propanol/ether to give the salt (20%) as off-white prisms, mp 
173.degree.-175.degree. C. (sealed tube). 
EXAMPLE 48 
2-[(2-Chlorophenyl)thio-1-octyl-1H-imidazole hydrochloride 
To a solution of 0.3 g (1.42 mmoles) of the product from Example 33 in 2 ml 
of dry N,N-dimethylformamide was added 0.18 g (1.56 mmoles) of potassium 
t-butoxide with stirring and under nitrogen. After stirring for 20 minutes 
the reaction was cooled in an icebath and 0.33 g (1.70 mmoles) of 
1-bromooctane was added. The mixture was stirred for 15 minutes and then 
warmed to room temperature and stirred for 18 hours. The mixture was 
partitioned between ether and water. The organics were combined, washed 
with sodium chloride solution, dried and concentrated. The crude product 
was converted to the hydrochloride salt by the addition of ethanolic 
hydrogen chloride. The solution was concentrated to dryness and the 
residue recrystallized from 2-propanol/ether to give the salt as colorless 
needles (0.25 g, 49%), mp 114.degree.-116.degree. C. 
EXAMPLE 49 
2-[(3-Chloro-6-nitrophenyl)thio]-1-methyl-1H-imidazole 
To a solution of 10 g (87.7 mmoles) of 2-mercapto-1-methylimidazole in 300 
ml of ethanol was added 10.4 g (193 mmoles) of sodium methoxide followed 
by 20.8 g (92.1 mmoles) of 1-chloro-3,4-dinitrobenzene. The mixture was 
stirred and refluxed for 8 hours. An additional 3 g of sodium methoxide 
was added and refluxing was continued for 5 more hours. The mixture was 
filtered hot and the filtrates concentrated in vacuo. The residue was 
partitioned between dichloromethane and water. The organics were dried and 
concentrated. The residue was recrystallized from dichloromethane and 
methanol to give 12.5 g (53%) of the product as yellow prisms, mp 
130.degree.-131.degree. C. 
EXAMPLE 50 
4-Chloro-2-[(1-methyl-1H-imidazol-2-yl)thio]benzenamine 
A mixture of 3.0 g (10.7 mmoles) of the product from Example 49, 1.5 
spatulas of Raney nickel and 200 ml of ethanol was hydrogenated at 1 
atmosphere and room temperature for 18 hours. An additional spatula of 
Raney nickel was added and hydrogenation continued for 90 minutes. The 
mixture was filtered to remove the catalyst and the filtrates 
concentrated. The residue was recrystallized from 
dichloromethane/petroleum ether (bp 30.degree.-60.degree. C.) to give the 
product as colorless plates (1.7 g, 66%), mp 116.degree.-120.degree. C. 
EXAMPLE 51 
2-[(2,5-Dichlorophenyl)thio]-1-methyl-1H-imidazole 
From a large scale preparation of the product described in Example 6, 
Method A, there was isolated the current product as a minor component 
(yield 1%) by column chromatography. The product was obtained as yellow 
prisms, mp 66.degree.-67.degree. C. 
EXAMPLE 52 
2-[(2-Chloro-4-nitrophenyI)thio)-1-methyl-1H-imidazole 
To 18 ml of concentrated sulfuric acid stirred in an icebath, was added in 
portions, 1.5 g (6.7 mmoles) of the product obtained in Example 6. After 
the addition was complete, potassium nitrate (0.63 g, 6.3 mmoles) was 
added in portions keeping the temperature between 0.degree. and 5.degree. 
C. After stirring in an icebath for 2 hours, the reaction mixture was 
poured over ice and made basic with concentrated ammonium hydroxide. The 
mixture was extracted with dichloromethane. The organics were combined, 
washed with water, dried and concentrated. The residue was dissolved in 
200 ml of refluxing ether, treated with charcoal and filtered. The 
filtrate was concentrated to 50 ml and then cooled. The resulting solid 
was collected by filtration to give 0.64 g of product. The filtrate was 
diluted with petroleum ether (bp 30.degree.-60.degree. C.) and filtered to 
give an additional 0.28 g of the product. The total yield was 51% and the 
product was obtained as yellow-green needles, mp 127.degree.-129.degree. 
C. 
EXAMPLE 53 
3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]benzenamine 
The product from Example 52 was reduced with stannous chloride following 
the procedure described in Example 4. The product was recrystallized from 
dichloromethane/hexane and obtained as off-white prisms (yield 81%), mp 
122.degree.-123.degree. C. 
EXAMPLE 54 
2-[(2-Chloro-4-iodophenyl)thio]-1-methyl-1H-imidazole 
To a solution of 0.49 g (2 mmoles) of the product from Example 53 in 4.8 ml 
of 3N hydrochloric acid and 4.8 ml of glacial acetic acid, stirred in an 
icebath, was added dropwise a solution of 0.16 g (2.3 mmoles) of sodium 
nitrite in 1.5 ml of water keeping the temperature at 0.degree.-5.degree. 
C. After stirring for 10 minutes, a solution of 0.69 g (4.2 mmoles) of 
potassium iodide in 2.1 ml of water was added with vigorous stirring, 
again keeping the temperature below 5.degree. C. The mixture was stirred 
in the cold for 1 hour and then at room temperature for 3 hours. After 
pouring over ice the mixture was made basic with 40% sodium hydroxide, 
keeping the temperature below 10.degree. C. The mixture was extracted with 
ethyl acetate which was dried and concentrated. The residue was triturated 
with hot ether and filtered to remove some insoluble material. The ether 
was concentrated in vacuo and the residue chromatographed on silica gel 
using dichloromethane/ethyl acetate (9:1 by volume) as the eluent. The 
fractions containing the product were concentrated and the product 
purified by recrystallization from ether/petroleum ether (bp 
30.degree.-60.degree. C.). The yield was 0.32 g (46%) and the product was 
obtained as colorless prisms, mp 99.degree.-101.degree. C. 
EXAMPLE 55 
2-[(4-Fluoro-2-nitrophenyl)thio]-1-methyl-1H-imidazole 
To a mixture of 0.6 g of 60% sodium hydride in mineral oil in 25 ml of 
N,N-dimethylformamide was added 1.1 g (10 mmoles) of 
2-mercapto-1-methylimidazole. After stirring for 30 minutes, 1.6 g (10 
mmoles) of 2,5-difluoronitrobenzene was added and the mixture stirred at 
room temperature for 16 hours. After adding 0.5 ml of acetic acid, the 
mixture was poured into a mixture of ice, water and sodium chloride. After 
standing for 1 hour the solid was collected by filtration, washed with 
water and dried. The crude product was purified by chromatography on 
silica gel using ethyl acetate as the eluent. The fractions containing the 
product were combined and concentrated to give 0.7 g (28%) of the product 
as yellow prisms, mp 123.degree.-126.degree. C. 
EXAMPLE 56 
2-[(2-Fluoro-4-nitrophenyl)thio]-1-methyl-1H-imidazole 
This product was prepared starting with 3,4-difluoronitrobenzene and using 
the procedure described in Example 5. The product was obtained in 24% 
yield after column chromatography and obtained as yellow prisms, mp 
97.degree.-99.degree. C. 
EXAMPLE 57 
2-[(4-Trifluoromethyl)-2-nitrophenyl]thio-1-methyl-1Himidazole 
To a suspension of 0.6 g of sodium hydride (60% dispersion in mineral oil) 
in 25 ml of N,N-dimethylformamide was added 1.15 g (10 mmoles) of 
2-mercapto-1-methylimidazole. The mixture was stirred at room temperature 
for 30 minutes and then 2.3 g of 4-chloro-3-nitrobenzotrifluoride was 
added. After stirring at room temperature for 18 hours, the mixture was 
poured into a mixture of ice, water, sodium chloride, and acetic acid. The 
resulting precipitate was collected by filtration, washed with water and 
air dried. The crude product was purified by column chromatography on 
silica gel using ethyl acetate as the eluent. The fractions containing the 
product were combined and concentrated to give 2.3 g (76%) of the product 
as yellow prisms, mp 123.degree.-125.degree. C. 
EXAMPLE 58 
5-(Trifluoromethyl)-2-[(1-methyl-1H-imidazol-2-yl)thio]benzenamine 
The compound obtained from Example 57 was converted to the product of this 
example using the procedure described in Example 53. The product was 
obtained in 73% yield and obtained as off-white prisms, mp 
112.degree.-114.degree. C. 
EXAMPLE 59 
2-[[2-Chloro-4-(trifluoromethyl)phenyl]thio]-1-methyl-1Himidazole 
hydrochloride 
The amino compound from Example 58 was converted to the corresponding 
chloro compound in 38% yield employing the procedure described in Example 
6, Method A, and converted to the hydrochloride salt using the procedure 
of Example 7. The product was obtained as off-white prisms, mp 
175.degree.-185.degree. C. 
EXAMPLE 60 
2-[[2-(Trifluoromethyl)-4-nitroohenyl]thio]-1-methyl-1Himidazole 
This product was prepared starting with 2-chloro-5nitrobenzotrifluoride 
using the procedure described in Example 57 and obtained in 73% yield. The 
product, after purification, was obtained as light yellow prisms, mp 
98.degree.-100.degree. C. 
EXAMPLE 61 
3-(Trifluoromethyl)-4-[(1-methyl-1H-imidazol-2-yl)thio]benzenamine 
This product was prepared using the procedure described in Example 53 
starting with the product from Example 60. The product was obtained as 
light yellow prisms (62% yield), mp 91.degree.-93.degree. C. 
EXAMPLE 62 
2-[[4-Chloro-2-(trifluoromethyl)phenyl)thio]-1-methyl-1Himidazole 
hydrochloride 
This product was prepared starting with the compound obtained in Example 61 
and using the procedure described in Example 6, Method A, and converted to 
the hydrochloride salt using the procedure of Example 7. The product was 
obtained as off-white prisms, mp 163.degree.-166.degree. C. 
EXAMPLE 63 
2[[2-(Trifluoromethyl)phenyl]thio]thiazole hydrochloride 
To a solution of 3.22g (20 mmoles) of 1-amino-2-trifluoromethylbenzene in 
90 ml of 1N sulfuric acid, was added dropwise a solution of 1.45 g (21 
mmoles) of sodium nitrite in 10 ml of water. The reaction was stirred in 
an ice bath and the temperature was kept below 5.degree. C. during the 
addition. This mixture was then added dropwise to a mixture of 2.34 g (20 
mmoles) of 2-mercaptothiazole and 1 g of cuprous oxide in 70 ml of 1N 
sulfuric acid, stirred in an icebath. The reaction was allowed to slowly 
warm to room temperature and stirred overnight. The mixture was 
partitioned with ammonium hydroxide and ether, the organics were combined, 
washed with brine, dried and concentrated. The residue was chromatographed 
on silica gel using hexane/ether (2:1 by volume) as the eluent. The 
residue was converted to the hydrochloride salt by treatment with dry 
hydrogen chloride in ether. The solid was collected by filtration and 
recrystallized from ethyl acetate to give 1.3 g (22%) of the product as 
off-white needles, mp 149.degree.-152.degree. C. 
EXAMPLE 64 
______________________________________ 
TABLET FORMULATION (Wet Gramulation) 
mg/tablet 
Item Ingredient 100 mg 500 mg 
1000 mg 
______________________________________ 
1 2-[(4-chlorophenyl)thio]- 
100 500 1000 
1-methyl-IH-imidazole 
2. Lactose 132 -- -- 
3. Pregelantinized Starch 
16 30 50 
4. Modified Starch 30 40 50 
5. Magnesium Stearate 
2 6 8 
Total 280 576 1108 
______________________________________ 
Manufacturing Procedure 
1. Mix items 1, 2. 3 and 4 and granulate with water. 
2. Dry the granulation at 50.degree. C. 
3. Pass the granulation through suitable milling equipment. 
4. Add Item 5 and mix for three minutes; compress on a suitable press. 
EXAMPLE 65 
______________________________________ 
CAPSULE FORMULATION 
Item Ingredient mg/tablet 
______________________________________ 
1. 2-[(4-chlorophenyl)thio]- 
25 50 100 500 
1-methyl-IH-imidazole 
2. Lactose Hydrous 143 168 148 -- 
3. Corn Starch 20 20 40 70 
4. Talc 10 10 10 25 
5. Magnesium Stearate 
2 2 2 5 
Total 200 250 300 600 
______________________________________ 
Manufacturing Procedure 
1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes. 
2. Add items 4 and 5 and mix for 3 minutes. 
3. Fill into suitable capsules. 
EXAMPLE 66 
______________________________________ 
WET GRANULATION FORMULATION 
Item Ingredient mg/tablet 
______________________________________ 
1. 2-[(4-chlorophenyl)thio]- 
25 50 
1-methyl-IH-imidazole 
2. Polyvinyl Pyrrolidone 
5 10 
3. Lactose Anhydrous DTG 
133 142 
4. Avicel PH 102 25 30 
5. Modified Starch 10 15 
6. Magnesium Stearate 
2 3 
Total 200 250 
______________________________________ 
Manufacturing Procedure 
1. Dissolve item 2 in water. 
2. Mix items 1, 3, 4 and 5 in a suitable mixer and granulate with solutio 
in Step 1. 
3. Dry overnight at 45.degree. C., screen through #20 mesh and add Item 6 
and mix. Compress on a suitable press. 
EXAMPLE 67 
Cream 5% 
The following is the quantitative composition of drug: 
______________________________________ 
Reasonable 
Ingredient g/kg Variations 
______________________________________ 
2-[(4-chlorophenyl(thio]- 
51.50* -- 
1-methyl-IH-imidazole 
Glyceryl Monostearate S.E..sup.1 
100.00 80-120 
Polysorbate 60.sup.2 
20.00 15-25 
Cetyl Alcohol 50.00 40-60 
Petrolatum 70.00 50-90 
Methylparaben 1.50 1.25-1.75 
Propylparaben 0.50 0.4-0.6 
Propylene Glycol 200.00 150-250 
Purified Water 521.70 475-575 
Total 1015.20 
______________________________________ 
1. The items are placed in a suitable mixer according to known procedures 
and a homogenous cream is prepared. 
*3% excess 
.sup.1 Arlacel 165 
.sup.2 Tween 60 
EXAMPLE 68 
______________________________________ 
SOFT GELATIN FORMULATION 
Item Ingredient mg capsule 
______________________________________ 
1. 2-[(4-chlorophenyl)thio]- 
50 250 
1-methyl-IH-imidazole 
2. PEG 400 325 550 
3. MCM 90 100 150 
4. Tween 80 25 50 
Total 500 1000 
______________________________________ 
Manufacturing Procedure: 
1. Dissolve item 1 in item 2. 
2. Add item 3 and mix well. 
3. Add item 4 and mix well until dissolved. 
4. Fill in soft gelatin capsules.