Fluoroalkoxy substituted benzimidazoles useful as gastric acid secretion inhibitors

Fluoroalkoxy compounds of the general formula I ##STR1## wherein R1 represents a 1-3C-alkyl radical which is completely or predominantly substituted by fluorine, or a chlorodifluoromethyl radical, R1' represents hydrogen, halogen, trifluoromethyl, a 1-3C-alkyl radical, or a 1-3C-alkoxy radical which is optionally completely or predominantly substituted by fluorine, R2 represents hydrogen or a 1-3C-alkyl radical, R3 represents hydrogen or a 1-3C-alkyl or 1-3C-alkoxy radical, R4 represents hydrogen or a 1-3C-alkyl radical and n represents the number 0 or 1, and their salts are new compounds with a marked protective effect on the stomach.

FIELD OF THE INVENTION 
The invention relates to new fluoroalkoxy compounds, processes for their 
preparation, their use and medicaments containing them. 
The compounds according to the invention are used in the pharmaceutical 
industry as intermediates and for the preparation of medicaments. 
PRIOR ART 
The European Patent Application No. 0 005 129 (=U.S. Pat. No. 4,255,531) 
describes substituted pyridylsulfinylbenzimidazoles which are said to be 
potent gastric acid secretion inhibitors. In European Patent Application 0 
074 341 the use of a group of benzimidazole derivatives for inhibiting 
gastric acid secretion is described. 
It has now been found, surprisingly, that the fluoroalkoxy compounds which 
are described below in more detail have interesting and unexpected 
properties which advantageously distinguish them from the known compounds. 
DESCRIPTION OF THE INVENTION 
The invention relates to new fluoroalkoxy compounds of formula I 
##STR2## 
wherein R1 represents a 1-3C-alkyl radical which is completely or 
predominantly substituted by fluorine, or a chlorodifluoromethyl radical, 
R1' represents hydrogen, halogen, trifluoromethyl, a 1-3C-alkyl radical or 
a 1-3C-alkoxy radical which is optionally completely or predominantly 
substituted by fluorine, 
R2 represents hydrogen or a 1-3C-alkyl radical, 
R3 represents hydrogen or a 1-3C-alkyl or 1-3C-alkoxy radical, 
R4 represents hydrogen or a 1-3C-alkyl radical and 
n represents the number 0 or 1, 
and the salts of these compounds. 
Examples of 1-3C-alkyl radicals which are completely or predominantly 
substituted by fluorine are the 1,1,2-trifluoroethyl radical, the 
perfluoropropyl radical, the perfluoroethyl radical and, in particular, 
the 1,1,2,2-tetrafluoroethyl, the trifluoromethyl, the 
2,2,2-trifluoroethyl and the difluoromethyl radical. 
Halogen in the context of the present invention is bromine, chlorine and, 
in particular, fluorine. 
1-3C-Alkyl radicals are the propyl, isopropyl, ethyl and, in particular, 
methyl radical. 
Besides the oxygen atom, 1-3C-alkoxy radicals contain the noted 1-3C-alkyl 
radicals. The methoxy radical is preferred. 
Besides the oxygen atom, a 1-3C-alkoxy radical which is completely or 
predominantly substituted by fluorine contains the previously-mentioned 
1-3C-alkyl radicals which are completely or predominantly substituted by 
fluorine. The 1,1,2,2-tetrafluoroethoxy radical, the trifluoromethoxy 
radical, the 2,2,2-trifluoroethoxy radical and, in particular, the 
difluoromethoxy radical may be mentioned. 
Illustrative salts of compounds of formula I in which n denotes the number 
0 (sulfides) are, above all, the acid-addition salts. The 
pharmacologically-acceptable salts of the inorganic and organic acids 
customarily used in galenics are particularly noteworthy. 
Pharmacologically-unacceptable salts, which may initially be obtained, for 
example, as process products in the preparation of compounds according to 
the invention on an industrial scale, are converted into 
pharmacologically-acceptable salts by processes which are known to the 
expert. Examples of suitable salts are water-soluble and water-insoluble 
acid-addition salts, such as the hydrochloride, hydrobromide, hydroiodide, 
phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, 
hibenzate, fendizoate, butyrate, sulfosalicylate, maleate, laurate, 
malate, fumarate, succinate, oxalate, tartrate, amsonate, embonate, 
metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 
3-hydroxy-2-naphthoate and mesilate. 
Illustrative salts of compounds of formula I in which n denotes the number 
1 (sulfoxides) are above all the basic salts, in particular 
pharmacologically-acceptable salts with inorganic and organic bases 
customarily used in galenics. Examples of basic salts are the sodium, 
potassium, calcium or aluminum salts. 
Compounds of formula I, wherein R1 represents a 1-3C-alkyl radical which is 
completely or predominantly substituted by fluorine, R1' represents 
hydrogen, halogen, trifluoromethyl or a 1-3C-alkoxy radical which is 
completely or predominantly substituted by fluorine, R2, R3, R4 and n have 
the meaning given above, and their salts, form an embodiment (embodiment 
a) of the invention. 
Compounds of formula I, wherein R1 represents a 1-3C-alkyl radical which is 
completely or predominantly substituted by fluorine, and R1', R2, R3, R4 
and n have the meaning given above, and their salts, form another 
embodiment (embodiment b) of the invention. 
Compounds of formula I, wherein R1' represents hydrogen, halogen, 
trifluoromethyl, or a 1-3C-alkoxy radial which is completely or 
predominantly substituted by fluorine, and R1, R2, R3, R4 and n have the 
meaning given above, and their salts, form another embodiment (embodiment 
c) of the invention. 
Compounds according to the invention which are noteworthy are those of 
formula I, wherein R1 represents a trifluoromethyl, 
1,1,2,2-tetrafluoroethyl, 2,2,2-trifluoroethyl, difluoro methyl or 
chlorodifluoromethyl radical, R1' represents hydrogen, fluorine, methoxy 
or difluoromethoxy, R2 represents hydrogen or methyl, R3 represents 
hydrogen or methoxy, R4 represents hydrogen or methyl and n represents the 
number 0 or 1, and wherein R2, R3 and R4 are not simultaneously hydrogen 
atoms, and the salts of these compounds. 
Compounds of embodiment a which are noteworthy are those of formula I, 
wherein R1 represents a trifluoromethyl, 1,1,2,2-tetrafluoroethyl, 
2,2,2-trifluoroethyl, or difluoromethyl radical, R1' represents hydrogen, 
fluorine, or difluoromethoxy, R2 represents hydrogen or methyl, R3 
represents hydrogen or methoxy, R4 represents hydrogen or methyl and n 
represents the number 0 or 1, and wherein R2, R3 and R4 are not 
simultaneously hydrogen atoms, and the salts of these compounds. 
Compounds of embodiment b which are noteworthy are those of formula I, 
wherein R1 represents a trifluoromethyl, 1,1,2,2-tetrafluoroethyl, 
2,2,2-trifluoroethyl, or difluoromethyl radical, R1' represents hydrogen, 
fluorine, methoxy or difluoromethoxy, R2 represents hydrogen or methyl, R3 
represents hydrogen or methoxy, R4 represents hydrogen or methyl and n 
represents the number 0 or 1, and wherein R2, R3 and R4 are not 
simultaneously hydrogen atoms, and the salts of these compounds. 
Compounds of embodiment c which are noteworthy are those of formula I, 
wherein R1 represents a trifluoromethyl, 1,1,2,2-tetrafluoroethyl, 
2,2,2-trifluoroethyl, difluoromethyl, or chlorodifluoromethyl radical, R1' 
represents hydrogen, fluorine, or difluoromethoxy, R2 represents hydrogen 
or methyl, R3 represents hydrogen or methoxy, R4 represents hydrogen or 
methyl and n represents the number 0 or 1, and wherein R2, R3 and R.sub.4 
are not simultaneously hydrogen atoms, and the salts of these compounds. 
Preferred compounds according to the invention are those of formula I, 
wherein R1 represents a trifluoromethyl, 1,1,2,2-tetrafluoroethyl, 
2,2,2-trifluoroethyl, difluoromethyl or chlorodifluoromethyl radical, R1' 
represents hydrogen, R2 represents hydrogen or methyl, R3 represents 
methoxy, R4 represents hydrogen or methyl and n represents the number 0 or 
1, and the pharmacologically acceptable salts of these compounds. 
Preferred compounds according to the invention are furthermore those of 
formula I, wherein R1 represents a difluoromethyl radical, R1' represents 
fluorine, methoxy or difluoromethoxy, R2 represents hydrogen or methyl, R3 
represents methoxy, R4 represents hydrogen or methyl and n represents the 
number 0 or 1, and the pharmacologically acceptable salts of these 
compounds. 
Preferred compounds of embodiment a are those of formula I, wherein R1 
represents a trifluoromethyl, 1,1,2,2-tetrafluoroethyl, 
2,2,2-trifluoroethyl or difluoromethyl radical, R2 represents hydrogen or 
methyl, R3 represents methoxy, R4 represents hydrogen or methyl and n 
represents the number 0 or 1, and the pharmacologically acceptable salts 
of these compounds. 
Preferred compounds of embodiment b are those of formula I, wherein R1 
represents a trifluoromethyl, 1,1,2,2-tetrafluoroethyl, 
2,2,2-trifluoroethyl or difluoromethyl radical, R1' represents fluorine, 
methoxy or difluoromethoxy, R2 represents hydrogen or methyl, R3 
represents methoxy, R4 represents hydrogen or methyl and n represents the 
number 0 or 1, and the pharmacologically acceptable salts of these 
compounds. 
Preferred compounds of embodiment c are those of formula I, wherein R1 
represents a trifluoromethyl, 1,1,2,2-tetrafluoroethyl, 
2,2,2-trifluoroethyl, difluoromethyl or chlorodifluoromethyl radical, R1' 
represents hydrogen, R2 represents hydrogen or methyl, R3 represents 
methoxy, R4 represents hydrogen or methyl and n represents the number 0 or 
1, and the pharmacologically acceptable salts of these compounds. 
Examples of compounds according to the invention are: 
2-[(4-ethoxy-3-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimida 
zole, 
2-[(4-ethoxy-3-methyl-2-pyridyl)methylsulfinyl)-5-trifluoromethoxy-1H-benzi 
midazole, 
2-[(3-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole, 
2-[(3-methyl-2-pyridyl)methylsulfinyl]-5-trifluoromethoxy-1H-benzimidazole, 
2-[(5-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole, 
2-[(5-methyl-2-pyridyl)methylsulfinyl)-5-trifluoromethoxy-1H-benzidazol, 
2-[(3,5-dimethyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole, 
2-[(3,5-dimethyl-2-pyridyl)methylsulfinyl]-5-trifluoromethoxy-1H-benzimidaz 
ole, 
2-[(4-ethoxy-3-methyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1 
H-benzimidazole, 
2-[(4-ethoxy-3-methyl-2-pyridyl)methylsulfinyl]-5-(1,1,2,2-tetrafluoroethox 
y)-1H-benzimidazole, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-pentafluoroethoxy-1H-benzimi 
dazole, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-5-pentafluoroethoxy-1H-ben 
zimidazole, 
2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-5-pentafluoroethoxy-1H-benzimi 
dazole, 
2-[(4-methoxy-5-methyl-2-pyridyl)methylsulfinyl]-5-pentafluoroethoxy-1H-ben 
zimidazole, 
5-heptafluoropropoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-1H-benzim 
idazole, 
5-heptafluoropropoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-1H-be 
nzimidazole, 
5-heptafluoropropoxy-2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-1H-benzim 
idazole, 
5-heptafluoropropoxy-2-[(4-methoxy-5-methyl-2-pyridyl)methylsulfinyl]-1H-be 
nzimidazole, 
2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-5-(2,2,2-trifluoroethoxy)-1H-b 
enzimidazole, 
2-[(4-methoxy-5-methyl-2-pyridyl)methylsulfinyl]-5-(2,2,2-trifluoroethoxy)- 
1H-benzimidazole, 
2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-5-(2,2,2-trifluoroethoxy)- 
1H-benzimidazole, 
2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-5-(2,2,2-trifluoro-eth 
oxy)-1H-benzimidazole, 
2-[(4-ethoxy-3-methyl-2-pyridyl)methylthio]-5-(2,2,2-trifluoroethoxy)-1H-be 
nzimidazole, 
2-[(4-ethoxy-3-methyl-2-pyridyl)methylsulfinyl]-5-(2,2,2-trifluoroethoxy)-1 
H-benzimidazole, 
2-[(3-methyl-2-pyridyl)methylthio]-5-(2,2,2-trifluoroethoxy)-1H-benzimidazo 
le, 
2-[(3-methyl-2-pyridyl)methylsulfinyl]-5-(2,2,2-trifluoroethoxy)-1H-benzimi 
dazole, 
2-[(4-methoxy-2-pyridyl)methylthio]-5-(1,1,2-trifluoroethoxy)-1H-benzimidaz 
ole, 
2-[(4-methoxy-2-pyridyl)methylsulfinyl)-5-(1,1,2-trifluoroethoxy)-1H-benzim 
idazole, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-(1,1,2-trifluoroethoxy)-1H-b 
enzimidazole, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-5-(1,1,2-trifluoroethoxy)- 
1H-benzimidazole, 
2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-5-(1,1,2-trifluoroethoxy)-1H-b 
enzimidazole, 
2-[(4-methoxy-5-methyl-2-pyridyl)methylsulfinyl]-5-(1,1,2-trifluoroethoxy)- 
1H-benzimidazole, 
2-[(4-methoxy-3,5-methyl-2-pyridyl)methylthio]-5-(1,1,2-trifluoroethoxy)-1H 
-benzimidazole, 
2-[(4-methoxy-3,5-methyl-2-pyridyl)methylsulfinyl]-5-(1,1,2-trifluoroethoxy 
)-1H-benzimidazole, 
2-[(4-ethoxy-3-methyl-2-pyridyl)methylthio]-5-(1,1,2-trifluoroethoxy)-1H-be 
nzimidazole, 
2-[(4-ethoxy-3-methyl-2-pyridyl)methylsulfinyl]-5-(1,1,2-trifluoroethoxy)-1 
H-benzimidazole, 
2-[(3-methyl-2-pyridyl)methylthio]-5-(1,1,2-trifluoroethoxy)-1H-benzimidazo 
le, 
2-[(3-methyl-2-pyridyl)methylsulfinyl]-5-(1,1,2-trifluoroethoxy)-1H-benzimi 
dazole, 
6-fluoro-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy)-1 
H-benzimidazole, 
6-fluoro-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-5-trifluoromethox 
y-1H-benzimidazole, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-6-trifluoro 
methyl-1H-benzimidazole, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-5-trifluoromethoxy-6-trifl 
uoromethyl-1H-benzimidazole, 
5,6-bis(trifluoromethoxy)-2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-1H-b 
enzimidazole, 
5,6-bis(trifluoromethoxy)-2-[(4-methoxy-5-methyl-2-pyridyl)methylsulfinyl]- 
1H-benzimidazole, 
2-[(3-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-6-trifluoromethyl-1H- 
benzimidazole, 
2-[(3-methyl-2-pyridyl)methylsulfinyl]-5-trifluoromethoxy-6-trifluoromethyl 
-1H-benzimidazole, 
6-fluoro-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluor 
oethoxy)-1H-benzimidazole, 
6-fluoro-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-5-(1,1,2,2-tetraf 
luoroethoxy)-1H-benzimidazole, 
2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)- 
6-trifluoromethyl-1H-benzimidazole, 
2-[(4-methoxy-5-methyl-2-pyridyl)methylsulfinyl]-5-(1,1,2,2-tetrafluoroetho 
xy)-6-trifluoromethyl-1H-benzimidazole, 
5,6-bis(1,1,2,2-tetrafluoroethoxy)-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)met 
hylthio]-1H-benzimidazole, 
5,6-bis(1,1,2,2-tetrafluoroethoxy)-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)met 
hylsulfinyl]-1H-benzimidazole, 
2-[(3-methyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-6-trifluor 
omethoxy-1H-benzimidazole, 
2-[(3-methyl-2-pyridyl)methylsulfinyl]-5-(1,1,2,2-tetrafluoroethoxy)-6-trif 
luoromethoxy-1H-benzimidazole, 
2-[(4-methoxy-2-pyridyl)methylthio]-5-pentafluoroethoxy-1H-benzimidazole, 
2-[(4-methoxy-2-pyridyl)methylsulfinyl]-5-pentafluoroethoxy-1H-benzimidazol 
e, 
2-[(5-methyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimi 
dazole, 
2-[(5-methyl-2-pyridyl)methylsulfinyl]-5-(1,1,2,2-tetrafluoroethoxy)-1H-ben 
zimidazole, 
2-[(3,5-dimethyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-ben 
zimidazole, 
2-[(3,5-dimethyl-2-pyridyl)methylsulfinyl]-5-(1,1,2,2-tetrafluoroethoxy)-1H 
-benzimidazole, 
2-[(4-methoxy-2-pyridyl)methylthio]-5,6-bis(trifluoromethoxy)-1H-benzimidaz 
ole, 
2-[(4-methoxy-2-pyridyl)methylsulfinyl]-5,6bis(trifluoromethoxy)-1H-benzimi 
dazole, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5,6-bis(trifluoromethoxy)-1H-b 
enzimidazole, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-5,6-bis(trifluoromethoxy)- 
1H-benzimidazole, 
2-[(4-methoxy-2-pyridyl)methylthio]-5,6-bis(1,1,2,2-tetrafluoroethoxy)-1H-b 
enzimidazole, 
2-[(4-methoxy-2-pyridyl)methylsulfinyl]-5,6-bis(1,1,2,2-tetrafluoroethoxy)- 
1H-benzimidazole, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5,6-bis(1,1,2,2-tetrafluoroeth 
oxy)-1H-benzimidazole, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-5,6-bis(1,1,2,2-tetrafluor 
oethoxy)-1H-benzimidazole, 
5-difluoromethoxy-2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-1H-benzimida 
zole, 
5-difluoromethoxy-2-[(4-methoxy-5-methyl-2-pyridyl)methylsulfinyl]-1H-benzi 
midazole, 
5-difluoromethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-1H-benzi 
midazole, 
5-difluoromethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-b 
enzimidazole, 
5-difluoromethoxy-2-[(3-methyl-2-pyridyl)methylthio]-1H-benzimidazole, 
5-difluoromethoxy-2-[(3-methyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 
5-difluoromethoxy-2-[(5-methyl-2-pyridyl)methylthio]-1H-benzimidazole, 
5-difluoromethoxy-2-[(5-methyl-2-pyridyl)methylsulfinyl]-1H-benzimidazol, 
5-difluoromethoxy-2-[(3,5-dimethyl-2-pyridyl)methylthio]-1H-benzimidazole, 
5-difluoromethoxy-2-[(3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazo 
le, 
5-chlorodifluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-1H-ben 
zimidazole, 
5-chlorodifluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-1H 
-benzimidazole, 
5-chlorodifluoromethoxy-2-[(3-methyl-2-pyridyl)methylthio]-1H-benzimidazole 
5-chlorodifluoromethoxy-2-[(3-methyl-2-pyridyl)methylsulfinyl]-1H-benzimida 
zole, 
5,6-bis(difluoromethoxy)-2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-1H-be 
nzimidazole, 
5,6-bis(difluoromethoxy)-2-[(4-methoxy-5-methyl-2-pyridyl)methylsulfinyl]-1 
H-benzimidazole, 
5,6-bis(difluoromethoxy)-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-1 
H-benzimidazole, 
5,6-bis(difluoromethoxy)-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfiny 
l]-1H-benzimidazole, 
5,6-bis(difluoromethoxy)-2-[(3-methyl-2-pyridyl)methylthio]-1H-benzimidazol 
e, 
5,6-bis(difluoromethoxy)-2-[(3-methyl-2-pyridyl)methylsulfinyl]-1H-benzimid 
azole, 
5-difluoromethoxy-6-fluoro-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-1H- 
benzimidazole, 
5-difluoromethoxy-6-fluoro-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulsfinyl 
)-1H-benzimidazole, 
5-difluoromethoxy-6-methoxy-2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-1H 
-benzimidazole, 
5-difluoromethoxy-6-methoxy-2-[(4-methoxy-5-methyl-2-pyridyl)methylsulfinyl 
]-1H-benzimidazole, 
5-difluoromethoxy-6-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio 
]-1H-benzimidazole, 
5-difluoromethoxy-6-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulf 
inyl]-1H-benzimidazole, 
5-difluoromethoxy-6-methoxy-2-[(3-methyl-2-pyridyl)methylthio]-1H-benzimida 
zole, 
5-difluoromethoxy-6-methoxy-2-[(3-methyl-2-pyridyl)methylsulfinyl]-1H-benzi 
midazole, 
5-difluoromethoxy-6-methoxy-2-[(5-methyl-2-pyridyl)methylthio]-1H-benzimida 
zole, 
5-difluoromethoxy-6-methoxy-2-[(5-methyl-2-pyridyl)methylsulfinyl]-1H-benzi 
midazole, 
5-difluoromethoxy-6-methoxy-2-[(3,5-dimethyl-2-pyridyl)methylthio]-1H-benzi 
midazole, 
5-difluoromethoxy-6-methoxy-2-[(3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-b 
enzimidazole, 
5-methoxy-2-[(4-methoxy-2-pyridyl)methylthio]-6-trifluoromethoxy-1H-benzimi 
dazole, 
5-methoxy-2-[(4-methoxy-2-pyridyl)methylsulfinyl]-6-trifluoromethoxy-1H-ben 
zimidazole, 
5-methoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-6-trifluoromethoxy-1 
H-benzimidazole, 
5-methoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-6-trifluorometho 
xy-1H-benzimidazole, 
5-methoxy-2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-6-trifluoromethoxy-1 
H-benzimidazole, 
5-methoxy-2-[(4-methoxy-5-methyl-2-pyridyl)methylsulfinyl]-6-trifluorometho 
xy-1H-benzimidazole, 
5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-6-trifluorometho 
xy-1H-benzimidazole, 
5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-6-trifluorom 
ethoxy-1H-benzimidazole, 
5-methoxy-2-[(3-methyl-2-pyridyl)methylthio]-6-trifluoromethoxy-1H-benzimid 
azole, 
5-methoxy-2-[(3-methyl-2-pyridyl)methylsulfinyl]-6-trifluoromethoxy-1H-benz 
imidazole, 
b 
5-methoxy-2-[(5-methyl-2-pyridyl)methylthio]-6-trifluoromethoxy-1H-benzimi 
dazole, 
5-methoxy-2-[(5-methyl-2-pyridyl)methylsulfinyl]-6-trifluoromethoxy-1H-benz 
imidazole, 
5-methoxy-2-[(4-methoxy-2-pyridyl)methylthio]-6-(1,1,2,2-tetrafluoroethoxy 
)-1H-bnzimidazole, 
5-methoxy-2-[(4-methoxy-2-pyridyl)methylsulfinyl]-6-(1,1,2,2-tetrafluoroeth 
oxy)-1H-benzimidazole, 
5-methoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-6-(1,1,2,2-tetrafluo 
roethoxy)-1H-benzimidazole, 
5-methoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-6-(1,1,2,2-tetra 
fluoroethoxy)-1H-benzimidazole, 
5-methoxy-2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-6-(1,1,2,2-tetrafluo 
roethoxy)-1H-benzimidazole, 
5-methoxy-2-[(4-methoxy-5-methyl-2-pyridyl)methylsulfinyl]-6-(1,1,2,2-tetra 
fluoroethoxy)-1H-benzimidazole, 
5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-6-(1,1,2,2-tetra 
fluoroethoxy)-1H-benzimidazole, 
5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-6-(1,1,2,2-t 
etrafluoroethoxy)-1H-benzimidazole, 
5-difluoromethoxy-2-[(4-methoxy-2-pyridyl)methylthio]-6-methyl-1H-benzimida 
zol, 
5-difluoromethoxy-2-[(4-methoxy-2-pyridyl)methylsulfinyl]-6-methyl-1H-benzi 
midazole, 
5-difluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-6-methyl-1H- 
benzimidazole, 
5-difluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-6-methyl 
-1H-benzimidazole, 
5-difluoromethoxy-1-[(4-methoxy-2-pyridyl)methylthio]-6-(1,1,2,2-tetrafluor 
oethoxy)-1H-benzimidazole, 
5-difluoromethoxy-1-[(4-methoxy-2-pyridyl)methylsulfinyl]-6-(1,1,2,2-tetraf 
luoroethoxy)-1H-benzimidazole, 
5-difluoromethoxy-1-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-6-(1,1,2,2-t 
etrafluoroethoxy)-1H-benzimidazole, 
5-difluoromethoxy-1-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-6-(1,1,2 
,2-tetrafluoroethoxy)-1H-benzimidazole 
and their salts. 
Because of tautomerism in the imidazole ring, 5-substitution in the 
benzimidazole is identical to 6-substitution. 
The invention furthermore relates to a process for the preparation of the 
fluoroalkoxy compounds of formula I, wherein R1, R1', R2, R3, R4 and n 
have the previously-ascribed meanings, and their salts. 
The process is characterized in that 
(a) mercaptobenzimidazoles of formula II are reacted with picoline 
derivatives III 
##STR3## 
or 
(b) benzimidazoles of formula IV are reacted with mercaptopicolines V 
##STR4## 
or 
(c) o-phenylenediamines of formula VI are reacted with formic acid 
derivatives VII 
##STR5## 
and, when appropriate, the 2-benzimidazolyl 2-pyridyl sulfides obtained 
according to (a), (b) or (c), of formula VIII 
##STR6## 
are then oxidized and/or converted into the salts, or in that 
(d) benzimidazoles of formula IX are reacted with pyridine derivatives X 
##STR7## 
or 
(e) sulfinyl derivatives of formula XI are reacted with 2-picoline 
derivatives XII 
##STR8## 
and, when appropriate, the products are then converted into salts, Y, Z, 
Z' and Z" representing suitable leaving groups, H representing an alkali 
metal atom (Li, Na or K). M' representing the equivalent of a metal atom 
and R1, R1', R2, R3, R4 and n having the afore-mentioned meanings. 
In the described reactions, compounds II-XII are used as such or, when 
appropriate, in the form of their salts. 
Preparation processes (a), (b) and (c) lead to sulfides according to the 
invention, and the oxidation of compounds VIII and processes (d) and (e) 
yield sulfoxides according to the invention. 
The expert is familiar with which leaving groups Y, Z, Z' and Z" are 
suitable, on the basis of his expert knowledge. A suitable leaving group Y 
is, for example, a group which forms a reactive sulfinic acid derivative 
together with the sulfinyl group to which it is bonded. Examples of 
suitable leaving groups Y are alkoxy, dialkylamino and alkylmercapto 
groups. Examples of suitable leaving groups Z, Z' and Z" are halogen 
atoms, in particular chlorine atoms, or hydroxyl groups activated by 
esterification (for example with p-toluenesulfonic acid). The equivalent 
of a metal atom M' is, for example, an alkali metal atom (Li, Na or K) or 
an alkaline earth metal atom (for example Mg), which is substituted by a 
halogen atom (for example Br, Grignard reagent), or any other optionally 
substituted metal atom which is known to react like the mentioned metals 
in substitution reactions of organometallic compounds. 
The reaction of II with III is carried out in a manner which is known per 
se in suitable solvents, preferably polar protic or aprotic solvents (such 
as methanol, isopropanol, dimethylsulfoxide, acetone, dimethylformamide or 
acetonitrile), with addition or in the absence of water. It is carried 
out, for example, in the presence of a proton acceptor. Suitable proton 
acceptors are alkali-metal hydroxides, such as sodium hydroxide; alkali 
metal carbonates, such as potassium carbonate; or tertiary amines, such as 
pyridine, triethylamine or ethyldiisopropylamine. Alternatively, the 
reaction is carried out without proton acceptors, in which case--depending 
on the nature of the starting compounds--the acid-addition salts are 
initially optionally separated off in a particularly pure form. The 
reaction temperature is ordinarily between 0.degree. and 150.degree. C., 
preferred temperatures being between 20.degree. C. and 80.degree. C. in 
the presence of proton acceptors, between 60.degree. and 120.degree. C. 
without proton acceptors--and, in particular, at the boiling point of the 
solvents used. The reaction times are between 0.5 and 12 hours. 
Similar reaction conditions to those for the reaction of II with III are 
used in the reaction of IV with V, which is carried out in a manner which 
is known per se. 
The reaction of VI with VII is preferably carried out in polar (optionally 
water-containing) solvents in the presence of a strong acid, for example 
hydrochloric acid, in particular at the boiling point of the solvent used. 
The sulfides VIII are oxidized in a manner which is known per se under 
conditions with which the expert is familiar for the oxidation of sulfides 
to sulfoxides [in this context, see, for example, J. Drabowicz and M. 
Mikolajczyk, Organic preparations and procedures int. 14(1-2), 45-89 
(1982) or E. Block in S.Patai, The Chemistry of Functional Groups, 
Supplement E, Part 1, pages 539 to 608, John Wiley and Sons (Interscience 
Publication), 1980]. Possible oxidizing agents are all the reagents 
usually employed for the oxidation of sulfides, in particular peroxyacids, 
such as peroxyacetic acid, trifluoroperoxyacetic acid, 
3,5-dinitroperoxybenzoic acid, peroxymaleic acid or, preferably, 
m-chloroperoxybenzoic acid. 
The reaction temperature is between -70.degree. C. and the boiling point of 
the solvent used (depending on the reactivity of the oxidizing agent and 
the degree of dilution), but is preferably between -30.degree. C. and 
+20.degree. C. Oxidation with halogens or with hypohalites (for example 
with aqueous sodium hypochlorite solution) has also proved advantageous, 
and is appropriately carried out at temperatures between 0.degree. C. and 
30.degree. C. The reaction is advantageously carried out in inert solvent, 
for example aromatic or chlorinated hydrocarbons, such as benzene, 
toluene, methylene chlorid or chloroform, preferably in esters, such as 
ethyl acetate or isopropyl acetate, or ethers, such as dioxane. 
The reaction of IX with X is preferably carried out in inert solvent, such 
as those which are also usually employed for the reaction of enolate ions 
with alkylating agents. Examples which may be mentioned are aromatic 
solvents, such as benzene or toluene. The reaction temperature is, as a 
rule, between 0.degree. and 120.degree. C. (depending on the nature of the 
alkali metal atom M and the leaving group Z), the boiling point of the 
solvent used being preferred. For example [when M represents Li (lithium) 
and Z represents Cl (chlorine) and the reaction is carried out in benzene] 
the boiling point of benzene (80.degree. C.) is preferred. 
Compounds XI are reacted with compounds XII in a manner which is known per 
se, such as that with which the expert is familiar for the reaction of 
organometallic compounds. 
The compounds according to the invention are first obtained either as such 
or in the form of their salts, depending on the nature of the starting 
compounds, which are optionally employed, when appropriate, in the form of 
their salts, and depending on the reaction conditions. 
The salts are otherwise obtained by dissolving the free compounds in a 
suitable solvent, for example in a chlorinated hydrocarbon, such as 
methylene chloride or chloroform, a low-molecular aliphatic alcohol 
(ethanol or isopropanol), an ether (diisopropyl ether), a ketone 
(acetone), or water, which contains the desired acid or base or to which 
the desired acid or base--when appropriate in the exactly calculated 
stoichiometric amount--is then added. 
The salts are isolated by filtration, reprecipitation or precipitation or 
by evaporation of solvent. 
Salts obtained are converted into the corresponding free compounds by 
alkalization or acidification, for example with aqueous sodium bicarbonate 
or with dilute hydrochloric acid, and the free compounds are in turn 
converted into the salts. In this manner, the compounds are purified or 
pharmacologically-unacceptable salts are converted into 
pharmacologically-acceptable salts. 
The sulfoxides according to the invention are optically-active compounds. 
The invention thus relates both to the enantiomers and to their mixtures 
and racemates. The enantiomers are separated in a manner which is known 
per se (for example by preparation and separation of corresponding 
diastereomeric compounds). However, the enantiomers are alternatively 
prepared by asymmetric synthesis, for example by reacting optically-active 
pure compounds XI or diastereomeric pure compounds XI with compounds XII 
[in this context, see K. K. Andersen, Tetrahedron Lett., 93 (1962)]. 
The compounds according to the invention are preferably synthesized by 
reaction of II with III and, when appropriate, subsequent oxidation of the 
sulfide VIII formed. 
Compounds of formula II are new and are likewise the subject of the 
invention. Compounds III-VII and IX-XII are either known or they are 
readily prepared analogously to known compounds from available starting 
materials. Compounds II are obtained, for example, by reacting compounds 
VI with carbon disulfides in a reaction mixture containing alkali-metal 
hydroxide or alkali-metal O-ethyldithiocarbonate. Compounds III are 
prepared in accordance with the method of O. E. Schulz and S. Fedders, 
Arc. Pharm. (Weinheim) 310, 128-136 (1977). 
Compounds VI are synthesized by preparation method shown in the following 
equation A: 
##STR9## 
The starting compounds A1-A3 are prepared by known or analogous methods 
[for example J.Org.Chem. 44, 2907-2910 (1979); J.Org.Chem. 29, 1-11 
(1964); German Offenlegungsschrift 2,029,556; J. Fluorine Chem. 18, 281-91 
(1981); and Synthesis 1980, 727-8], it also being possible for isomer 
mixtures to be formed when substituents R1' and R1-O are not identical. 
Compounds IX are obtained, for example, from compounds II by methylation, 
oxidation and subsequent deprotonation--for example with alkali metal 
hydrides or alcoholates or customary organometallic compounds. Compounds X 
are prepared in accordance with the method of Z. Talik, Roczniki Chem. 35, 
475 (1961). 
The following examples illustrate the invention in more detail without 
limiting it. "m.p." denotes melting point; the abbreviation "h" is used 
for hour(s); the abbreviation "min." is used for minutes. "Ether" is 
understood as meaning diethyl ether.

EXAMPLES 
1. 
2-[(4-Methoxy-2-pyridyl)methylsulfinyl]-5-trifluoromethoxy-1H-benzimidazol 
e 
A solution of 1.45 g of 85% pure m-chloroperoxybenzoic acid in 20 ml of 
methylene chloride is added dropwise to a solution of 2.4 g of 
2-[4-methoxy-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole in 
30 ml of methylene chloride at -30.degree. C. in the course of 20 min., 
with thorough stirring. Stirring is continued at -30.degree. C. for a 
further h, the temperature is allowed to rise gradually to -10.degree. C., 
1 ml of triethylamine is added and the solution is washed at 
0.degree.-10.degree. C. with 1M potassium bicarbonate solution and then 
with water and dried with magnesium sulfate. The solvent is distilled off 
in vacuo at a maximum temperature of 30.degree. C. and the residue is 
crystallized from ether. 2.2 g (86%) of the title compound are obtained. 
M.p. 150.degree.-152.degree. C. (decomposition). 
The following compounds are obtained analogously: 
2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-5-trifluoromethoxy-1H-benz 
imidazole of m.p. 165.degree.-166.degree. C. (decomposition) from methanol, 
in 65% yield, 
2-[(4-methoxy-5-methyl-2-pyridyl)methylsulfinyl]-5-trifluoromethoxy-1H-benz 
imidazole of m.p. 170.degree.-172.degree. C. (decomposition) from ethyl 
acetate, in 91% yield, 
2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-5-trifluoromethoxy-1H- 
benzimidazole of m.p. 160.degree.-162.degree. C. (decomposition) from ethyl 
acetate, in 75% yield, 
2-[(4-methoxy-2-pyridyl)methylsulfiny]-5-(1,1,2,2-tetrafluoroethoxy)-1H-ben 
zimidazole of m.p. 131.degree.-132.degree. C. (decomposition) from 
diisopropyl ether, in 93% yield, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfiny]-5-(1,1,2,2-tetrafluoroethox 
y)-1H-benzimidazole of m.p. 135.degree.-136.degree. C. (decomposition) from 
ethyl acetate/petroleum ether (50.degree. C./70.degree. C.), in 77% yield, 
2-[(4-methoxy-5-methyl-2-pyridyl)methylsulfiny]-5-(1,1,2,2-tetrafluoroethox 
y)-1H-benzimidazole of m.p. 163.degree.-164.degree. C. (decomposition) from 
diisopropyl ether, in 93% yield, 
2-[(3-methyl-2-pyridyl)methylsulfiny]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benz 
imidazole of m.p. 110.degree.-111.degree. C. (decomposition) from 
diisopropyl ether, in 61% yield. 
2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfiny]-5-(1,1,2,2-tetrafluoroe 
thoxy)-1H-benzimidazole of m.p. 132.degree.-133.degree. C. (decomposition) 
from ether, in 59% yield, 
2-[(4-methoxy-2-pyridyl)methylsulfinyl]-5-(2,2,2-trifluoroethoxy)-1H-benzim 
idazole of m.p. 95.degree.-97.degree. C. from ether, in 69% yield, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-5-(2,2,2-trifluoroethoxy)- 
1H-benzimidazole of m.p. 172.degree.-173.degree. C. (decomposition) from 
acetonitrile, in 81% yield, 
5-chlorodifluoromethoxy-2-[(4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimid 
azole of m.p. 154.degree.-156.degree. C. (decomposition) from ethyl acetate 
in 65% yield. 
5-difluoromethoxy-2-[(4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole 
of m.p. 159.degree.-161.degree. C. (decomposition) from ethyl acetate in 
74% yield, 
5-difluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-1H-benzi 
midazole of m.p. 166.degree.-168.degree. C. (decomposition) from ethyl 
acetate in 77% yield, 
5,6-bis(difluoromethoxy)-2-[(4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimi 
dazole of m.p. 173.degree.-175.degree. C. (decomposition) from ethyl 
acetate in 60% yield, 
5,6-bis(difluoromethoxy)-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-1 
H-benzimidazole of m.p. 184.degree.-185.degree. C. (decomposition) from 
ethyl acetate in 50% yield, 
5-difluoromethoxy-6-fluoro-2-[(4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzi 
midazole of m.p. 160.degree.-162.degree. C. (decomposition) from ethyl 
acetate in 54% yield, 
5-difluoromethoxy-6-methoxy-2-[(4-methoxy-2-pyridyl)methylsulfinyl]-1H-benz 
imidazole of m.p. 180.degree.-181.degree. C. (decomposition) from ethyl 
acetate in 88% yield, 
5-difluoromethoxy-6-methoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl 
]-1H-benzimidazole of m.p. 94.degree.-96.degree. C. (decomposition) from 
ethyl acetate in 89% yield, 
by reacting 
2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimid 
azole, 
2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimid 
azole, 
2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benz 
imidazole, 
2-[(4-methoxy-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzim 
idazole, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)- 
1H-benzimidazole, 
2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)- 
1H-benzimidazole, 
2-[(3-methyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimi 
dazole, 
2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroetho 
xy)-1H-benzimidazole, 
2-[(4-methoxy-2-pyridyl)methylthio]-5-(2,2,2-trifluoroethoxy)-1H-benzimidaz 
ole, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-(2,2,2-trifluoroethoxy)-1H-b 
enzimidazole, 
5-chlorodifluoromethoxy-2-[(4-methoxy-2-pyridyl)methylthio]-1H-benzimidazol 
e, 
5-difluoromethoxy-2-[(4-methoxy-2-pyridyl)methylthio]-1H-benzimidazole, 
5-difluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-1H-benzimida 
zole, 
5,6-bis(difluoromethoxy)-2-[(4-methoxy-2-pyridyl)methylthio]-1H-benzimidazo 
le, 
5,6-bis(difluoromethoxy)-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-1H-be 
nzimidazole, 
5-difluoromethoxy-6-fluoro-2-[(4-methoxy-2-pyridyl)methylthio]-1H-benzimida 
zole, 
5-difluoromethoxy-6-methoxy-2-[(4-methoxy-2-pyridyl)methylthio]-1H-benzimid 
azole and 
5-difluoromethoxy-6-methoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-1H 
-benzimidazole, 
with m-chloroperoxybenzoic acid. 
2. 
2-[(4-Methoxy-2-pyridyl)methylsulfinyl]-5-(1,1,2,2-tetrafluoroethoxy)-1H-b 
enzimidazole 
A mixture of 8.5 ml of commercially available sodium hypochlorite solution 
(about 15% of active chlorine) and 6 ml of 10% strength sodium hydroxide 
solution is added dropwise to a solution of 1.5 g 
2-[(4-methoxy-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzi 
midazole in 30 ml of ethyl acetate at 0.degree. C. in the course of 20 
min., stirring is continued at this temperature for 20 min. and 0.6 ml of 
10% strength sodium thiosulfate solution is then added. 1.5 g of ammonium 
sulfate are added and the organic phase is separated off, washed with 
saturated sodium chloride solution, dried with magnesium sulfate and 
concentrated to a small volume. 1.3 g (85%) of the title compound of 
melting point 131.degree.-132.degree. C. (decomposition) are obtained by 
precipitation with diisopropyl ether. 
3. 2-[(4-Methoxy-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole 
4.0 g of 2-mercapto-5-trifluoromethoxy-1H-benzimidazole and 3.5 g of 
2-chloromethyl-4-methoxypyridine hydrochloride are heated at the boiling 
point in 100 ml of isopropanol for 4.5 h, under nitrogen. The mixture is 
cooled in an ice-bath and 7.0 g (96%) of the dihydrochloride of the title 
compound of m.p. 164.degree.-165.degree. C. (decomposition) are obtained. 
The salt is dissolved in water, the solution is clarified with active 
charcoal and the base is liberated with potassium bicarbonate solution. 
The mixture is extracted with methylene chloride and the organic solution 
is dried with magnesium sulfate and concentrated in vacuo. The residue is 
crystallized from cyclohexane. 5.2 g (86%) of the title compound of m.p. 
134.degree.-135.degree. C. are obtained. 
The following compounds are obtained analogously: 
2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimid 
azole of m.p. 180.degree.-181.degree. C. (from cyclohexane) and 
2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimid 
azole of m.p. 148.degree.-149.degree. C. (from water) 
by reacting 
2-mercapto-5-trifluoromethoxy-1H-benzimidazole with 
2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride and 
2-chloromethyl-4-methoxy-5-methylpyridine hydrochloride. 
The following compounds are obtained analogously: 
2-[(4-methoxy-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzim 
idazole of m.p. 130.degree.-131.degree. C. (from isopropanol). 
2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)- 
1H-benzimidazole of m.p. 110.degree.-111.degree. C. (from isopropanol), 
2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)- 
1H-benzimidazole of m.p. 135.degree.-136.degree. C. (from isopropanol) and 
2-[(3-methyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimi 
dazole of m.p. 129.degree.-130.degree. C. (from isopropanol) 
by reacting 
2-mercapto-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole with the 
hydrochlorides of 2-chloromethyl-4-methoxypyridine, 
2-chloromethyl-4-methoxy-3-methylpyridine, 
2-chloromethyl-4-methoxy-5-methylpyridine and 
2-chloromethyl-3-methylpyridine in isopropanol. 
The following compounds are obtained analogously: 
2-[(4-methoxy-2-pyridyl)methylthio]-5-(2,2,2-trifluoroethoxy)-1H-benzimidaz 
ole of m.p. 134.degree.-135.degree. C. (from toluene), 
2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-(2,2,2-trifluoroethoxy)-1H-b 
enzimidazole of m.p. 178.degree.-179.degree. C. (from toluene), 
5-chlorodifluoromethoxy-2-[(4-methoxy-2-pyridyl)methylthio]-1H-benzimidazol 
e of m.p. 135.degree.-137.degree. C. (from toluene), 
5-chlorodifluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-1H-ben 
zimidazole of m.p. 171.degree.-173.degree. C. (from toluene), 
5-difluoromethoxy-2-[(4-methoxy-2-pyridyl)methylthio]-1H-benzimidazole of 
m.p. 115.degree.-117.degree. C. (from toluene), 
5-difluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-1H-benzimida 
zole of m.p. 167.degree.-169.degree. C. (from toluene), 
5,6-bis(difluoromethoxy)-2-[(4-methoxy-2-pyridyl)methylthio]-1H-benzimidazo 
l of m.p. 132.degree.-134.degree. C. (from toluene), 
5,6-bis(difluoromethoxy)-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-1H-be 
nzimidazole of m.p. 163.degree.-165.degree. C. (from toluene), 
5-difluoromethoxy-6-fluoro-2-[(4-methoxy-2-pyridyl)methylthio]-1H-benzimida 
zole of m.p. 140.degree.-142.degree. C. (from toluene), 
5-difluoromethoxy-6-methoxy-2-[(4-methoxy-2-pyridyl)methylthio]-1H-benzimid 
azole of m.p. 124.degree.-125.degree. C. (from toluene), 
5-difluoromethoxy-6-methoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-1H 
-benzimidazole of m.p. 198.degree.-191.degree. C. (from toluene) 
by reacting 
2-mercapto-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole, 
5-chlorodifluoromethoxy-2-mercapto-1H-benzimidazole, 
5-difluoromethoxy-2-mercapto-1H-benzimidazole, 
5,6-bis(difluoromethoxy)-2-mercapto-1H-benzimidazole, 
5-difluoromethoxy-6-fluoro-2-mercapto-1H-benzimidazole and 
5-difluoromethoxy-2-mercapto-6-methoxy-1H-benzimidazole with 
2-chloromethyl-4-methoxypyridine and 
2-chloromethyl-4-methoxy-3-methylpyridine. 
4. 
2-[(4-Methoxy-3,5-dimethyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-ben 
zimidazole 
5 ml of 4M sodium hydroxide solution are added dropwise to a mixture of 
2.34 g of 2-mercapto-5-trifluromethoxy-1H-benzimidazole and 2.2 g of 
2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride in 50 ml of 
ethanol at room temperature and the mixture is stirred overnight at room 
temperature. The solvent is distilled off in vacuo, water is added, the 
mixture is extracted with ethyl acetate, the solution is dried and 4.3 g 
(95%) of the dihydrochloride of the title compound are precipitated with 
4M hydrogen chloride in ether. The salt is dissolved in water and the base 
is precipitated with dilute sodium carbonate solution at pH 8 and 
recrystallized from diisopropyl ether. 3.0 g (78%) of the title compound 
of m.p. 152.degree.-154.degree. C. are obtained. 
The following compound is obtained analogously: 
2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroetho 
xy)-1H-benzimidazole (m.p. 120.degree.-122.degree. C.) 
by reacting 
2-mercapto-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole with 
2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride. 
5. 2-Mercapto-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole 
(a) 55 g of 1-nitro-4-(1,1,2,2-tetrafluoroethoxy)benzene are hydrogenated 
in 300 ml of ethanol on 0.5 g of 10% strength palladium-on-charcoal in a 
circulatory hydrogenation apparatus under atmospheric pressure at 
20.degree.-45.degree. C. for 1 h, the catalyst is filtered off and the 
solution is concentrated at 40.degree. C. in vacuo. The 
4-(1,1,2,2-tetrafluoroethoxy)aniline is diluted with 100 ml of glacial 
acetic acid, 23 ml of acetic anhydride are added dropwise at room 
temperature, 2 ml of water are added after 30 min., the solution is 
concentrated in vacuo at 50.degree. C. after a short time and 500 ml of 
ice-water are added. 56 g (97%) of 
N-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-acetamide of m.p. 
121.degree.-122.degree. C. are obtained. 
(b) 55 g of the last-noted compound are dissolved in 380 ml of methylene 
chloride, 55 ml of 100% strength nitric acid are added dropwise at room 
temperature in the course of 10 min. and stirring is continued for 6 h. 
The organic solution is then washed with aqueous sodium carbonate solution 
and water, dried with magnesium sulfate and concentrated. 65 g (100%) of 
N-[2-nitro-4-(1,1,2,2-tetrafluoroethoxy)phenol]-acetamide of m.p. 
80.degree.-81.degree. C. (from cyclohexane) are obtained. 
(c) 63 g of the last-noted compound are dissolved in 450 ml of methanol. 
106 ml of 6M sodium hydroxide solution are added dropwise at room 
temperature, the mixture is cooled in an ice-bath and 53 g (98%) of 
2-nitro-4-(1,1,2,2-tetrafluoroethoxy)-aniline (m.p. 85.degree.-86.degree. 
C.) are precipitated by dropwise addition of 900 ml of water. 
(d) 33 g of the last-noted compound are hydrogenated in about 600 ml of 
isopropanol on 1 g of 10% strength palladium-on-charcoal in a circulatory 
hydrogenation apparatus under atmospheric pressure and at room 
temperature. The catalyst is filtered off with suction and 34 g (89%) of 
4-(1,1,2,2-tetrafluoroethoxy)-1,2-phenylenediamine dihydrochloride of m.p. 
275.degree.-276.degree. C. (decomposition) are precipitated with 4M 
hydrogen chloride in ether. 
(e) 330 ml of ethanol, 60 ml of water, 8.9 g of sodium hydroxide and 23 g 
of potassium 0-ethyldithiocarbonate (recrystallized from isopropanol) are 
added to 33 g of the compound obtained from step (d) and the mixture is 
heated at the boiling point under reflux for 15 h. 1.2 liters of icewater 
are added, the pH is brought to 13-14 with sodium hydroxide solution, the 
mixture is clarified with active charcoal and the product is precipitated 
with dilute hydrochloric acid up to pH 3.5. 27 g (91%) of the title 
compound of m.p. 316.degree.-319.degree. C. (from isopropanol) are 
obtained. 
6. 2-Mercapto-5-trifluoromethoxy-1H-benzimidazole 
The title compound of m.p. 305.degree.-307.degree. C. (decomposition, from 
toluene) is obtained in 75% yield analogously to Example 5e) by reacting 
4-trifluoromethoxy-1,2-phenylenediamine dihydrochloride (compare C.A. 55, 
23408d, 1961) with potassium 0-ethyldithiocarbonate and sodium hydroxide 
solution in ethanol. 
7. 2-Mercapto-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole 
(a) 50 g of 1-(2,2,2-trifluoroethoxy)-4-nitrobenzene (Synthesis 1980, page 
727) are hydrogenated and acetylated analogously to Example 5a. 50 g (95%) 
of N-[4-(2,2,2-trifluoroethoxy)-phenyl]-acetamide of m.p. 
140.degree.-141.degree. C. are obtained. 
(b) 42 g of the above compound are stirred with 9.7 ml of 100% strength 
nitric acid in 290 ml of glacial acetic acid at room temperature for 18 h, 
and the product is precipitated with water. 47 g (94%) of 
N-[2-nitro-4-(2,2,2-trifluoroethoxy)-phenyl]-acetamide of m.p. 
117.degree.-118.degree. C. are obtained. 
(c) 47 g of the above compound are hydrolysed analogously to Example 5c, 
and 38.7 g (97%) of 2-nitro-4-(2,2,2-trifluoroethoxy)-aniline (m.p. 
84.degree.-85.degree. C.) are obtained. 
(d) 37 g of the above compound are hydrogenated analogously to Example 5d, 
and 41 g (94%) of 4-(2,2,2-trifluoroethoxy)-1,2-phenylenediamine 
dihydrochloride of m.p. 230.degree.-233.degree. C. (decomposition) are 
obtained. 
(e) 36 g of the above compound are reacted analogously to Example 5e to 
give 30 g (94%) of the title compound of m.p. 288.degree.-290.degree. C. 
8. 5-Chlorodifluoromethoxy-2-mercapto-1H-benzimidazole 
(a) 10.0 g of N-[4-(chlorodifluoromethoxy)phenyl]-acetamide (m.p. 
101.degree.-103.degree. C., obtained from 4-chlorodifluoromethoxyaniline 
and acetic anhydride) and 12.3 ml of 100% strength nitric acid are stirred 
at 20.degree. C. for 4 h in 80 ml of methylene chloride. The solution is 
neutralized with aqueous potassium bicarbonate solution, the organic phase 
is concentrated and 11.4 g (96%) of 
N-(4-chlorodifluoromethoxy-2-nitrophenyl)-acetamide of m.p. 
89.degree.-91.degree. C. are obtained. 
(b) 8.6 ml of a 30% strength solution of sodium methylate in methanol are 
added dropwise at 5.degree. C. to a solution of 10.5 g of the above 
compound in 200 ml of methanol, stirring is continued for 2 h without 
cooling, ice-water is added, the pH is brought to 8 and 8.7 g (97%) of 
4-chlorodifluoromethoxy-2-nitroaniline of m.p. 40.degree.-42.degree. C. 
are obtained. 
(c) 8.5 g of the above compound are hydrogenated in 200 ml of methanol on 
0.8 g of 10% strength palladium-on-charcoal under atmospheric pressure, 
and concentrated hydrochloric acid is added. The solution is filtered, 
concentrated and stirred with diisopropyl ether. 8.5 g (97%) of 
4-chlorodifluoromethoxy-1,2-phenylenediamine dihydrochloride are obtained. 
(d) 6.3 g (72%) of the title compound of m.p. 268.degree.-270.degree. C. 
(decomposition) are obtained from 8.5 g of the above compound ananlogously 
to Example 5e). 
9. 5-Difluoromethoxy-2-mercapto-1H-benzimidazole 
(a) 11.8 g of N-(4-difluoromethoxyphenyl)-acetamide [L. M. Jagupol'skii et 
al., J. General Chemistry (USSR) 39, 190 (1969)] dissolved in 200 ml of 
methylene chloride are stirred with 12.1 ml of 100% strength hydrochloric 
acid for 1.5 h at room temperature. Analogously to Example 5b 13.3 g (92%) 
of N-[(4-difluoroethoxy-2-nitro)phenyl]-acetamide of m.p. 
71.degree.-73.degree. C. are obtained. 
(b) Analogously to Example 8b, 4-difluoromethoxy-2-nitroaniline of m.p. 
68.degree.-70.degree. C. is obtained in 96% yield. 
(c) Analogously to Example 8c, 4-difluoromethoxy-1,2-phenylenediamine 
dihydrochloride is obtained in 94% yield. 
(d) Analogously to Example 5e, the title compound of m.p. 
250.degree.-252.degree. C. (from isopropanol) is obtained in 78% yield. 
10. 5,6-Bis(difluoromethoxy)-2-mercapto-1H-benzimidazole 
(a) Analogously to L. N. Sedova et al., Zh. Org. Khim. 6, 568 (1970), 275 g 
of chlorodifluoromethane are passed into a solution of 100 g of 
o-dihydroxy-benzene, 220 g of sodium hydroxide and 60 g of sodium 
dithionite in 500 ml of water and 400 ml of dioxane at 
50.degree.-55.degree. C. After distillation at 61.degree.-62.degree. 
C./1.0-1.1 kPa a mixture of 1,2-bis(difluoromethoxy)benzene and 
2-difluoroethoxyphenol is obtained, which is separated by chromatography 
on silica gel with cyclohexane/ethyl acetate (4:1). 
(b) A solution of 15 g of 1,2-bis(difluoromethoxy)benzene and 15 ml of 100% 
strength nitric acid in 150 ml of methylene chloride is stirred for 7 h at 
room temperature. The solution is neutralized with potassium bicarbonate 
solution and the organic phase is separated off. After chromatography on 
silica gel with cyclohexane/ethyl acetate (4:1), 
1,2-bis(difluoromethoxy)-4-nitrobenzene is obtained, which is hydrogenated 
and acetylated analogously to Example 5a to yield 
N-[3,4-bis(difluoromethoxy)phenyl]-acetamide of m.p. 81.degree.-83.degree. 
C. Further reaction analogously to Example 5 gives 
N-[4,5-bis(difluoromethoxy)-2-nitrophenyl]-acetamide of m.p. 
65.degree.-67.degree. C., N-[4,5-bis(difluoromethoxy)-2-nitro]-aniline of 
m.p. 107.degree.-109.degree. C., 
4,5-bis(difluoromethoxy)-1,2-phenylenediamine dihydrochloride and the 
title compound of m.p. 285.degree.-287.degree. C. (decomposition; from 
isopropanol). 
11. 5-Difluoromethoxy-2-mercapto-6-methoxy-1H-benzimidazole 
(a) 58 g of chlorodifluoromethane are passed into a solution of 55.5 g of 
guaiacol and 130 g of sodium hydroxide in 300 ml of water and 300 ml of 
dioxane at 60.degree. C. The mixture is filtered at 10.degree. C. and the 
organic phase is separated off, dried with anhydrous potassium carbonate 
and distilled. 56 g (73%) of 1-difluoromethoxy-2-methoxybenzene of boiling 
point 75.degree.-79.degree. C./0.9 kPa are obtained. 
(b) A solution of 33.8 ml of 100% strength nitric acid in 90 ml of 
methylene chloride is added dropwise at 0.degree.-5.degree. C. to a 
solution of 47 g of the above compound in 230 ml of methylene chloride. 
After 30 min., 250 ml of ice-water are added, and the mixture is 
neutralized with potassium bicarbonate. The dried organic phase is 
concentrated in vacuo, and the residue is recrystallized from cyclohexane. 
53 g (90%) of 1-difluoromethoxy-2-methoxy-5-nitrobenzene (m.p. 
48.degree.-49.degree. C.) are obtained, which are hydrogenated and 
acetylated analogously to Example 5a. 
N-(3-difluoromethoxy-4-methoxyphenyl)-acetamide of m.p. 
129.degree.-130.degree. C. are obtained in 90% yield. 
(c) 46 g of the above compound are nitrated with 33 ml of 100% strength 
nitric acid in methylene chloride analogously to the above procedure. 
N-(5-difluoromethoxy-4-methoxy)-2-nitrophenyl)-acetamide of m.p. 
116.degree.-117.degree. C. are obtained in 99% yield. 
(d) 54 g of the above compound in 810 ml of methanol are stirred for 1 h at 
room temperature with 44.8 ml of a 30% strength solution of sodium 
methylate in methanol. The mixture is concentrated in vacuo, ice-water and 
glacial acetic acid are added up to pH 8, and 
5-difluoromethoxy-4-methoxy-2-nitroaniline of m.p. 144.degree.-145.degree. 
C. is obtained in 99% yield. 
(e) 25 g of the above compound in 300 ml of methanol are hydrogenated on 
1.25 g of 10% strength palladium-on-charcoal analogously to Example 5d. 26 
g (88%) of 3-difluoromethoxy-4-methoxy-1,2-phenylenediamine 
dihydrochloride of m.p. 218.degree.-220.degree. C. (decomposition) are 
obtained. 
(f) 25 g of the above compound are reacted with 19 g of 
potassium-0-ethyldithiocarbonate analogously to Example 5e. 20 g of (89%) 
of the title compound of m.p. 280.degree.-282.degree. C. (decomposition; 
from isopropanol) are obtained. 
12. 5-Difluoromethoxy-6-fluoro-2-mercapto-1H-benzimidazole 
(a) Analogously to Example 11a, 1-difluoromethoxy-2-fluorobenzene (boiling 
point 86.degree. C./10 kPa; n.sub.D.sup.20 =1.4340) is obtained from 
2-fluorophenol and chlorodifluoromethane. 
(b) 38.4 ml of 100% strength nitric acid are added dropwise with stirring 
at -10.degree. C. to 30 g of the above compound in 300 ml of methylene 
chloride, and stirring is continued for 1 h at -10.degree. C. and 2.5 h at 
0.degree. C. After addition of ice-water, neutralization and 
chromatography on silica gel with ethyl acetate/cyclohexane (4:1), 34 g of 
an oil are obtained, consisting of 90% of 
1-difluoromethoxy-2-fluoro-4-nitrobenzene and 10% of 
1-difluoromethoxy-2-fluoro-5-nitrobenzene (NMR-spectrum). 
(c) 30 g of the above mixture are hydrogenated and acetylated analogously 
to Example 5a. After recrystallization from toluene, 21 g (65%) of 
N-(4-difluoromethoxy-3-fluorophenyl)-acetamide of m.p. 
112.degree.-113.degree. C. are obtained. 
(d) 22.5 ml of 100% strength nitric acid are added dropwise to 20 g of the 
above compound in 200 ml of methylene chloride at 20.degree. C. in the 
course of 30 min., and stirring is continued for 15 h at room temperature. 
Analogously to Examples 11c, 
N-(4-difluoroethoxy-5-fluoro-2-nitrophenyl)-acetamide of m.p. 
72.degree.-74.degree. C. (89% yield, from cyclohexane), is obtained. 
Stirring this compound for several hours with 1M hydrogen chloride in 
methanol at 60.degree. C. yields 4-difluoromethoxy-5-fluoro-2-nitroaniline 
of m.p. 95.degree.-97,5.degree. C. (95% yield), and further reaction 
analogously to Example 11e gives 
4-difluoromethoxy-5-fluoro-1,2-phenylenediamine dihydrochloride (85% 
yield, decomposition at 210.degree. C.) 
(e) 15 g of the above compound are reacted analogously to Example 5e with 
11.8 g of potassium 0-ethyldithiocarbonate. 11.1 g (84%) of the title 
compound of m.p. 275.degree.-276.degree. C. (from isopropanol) are 
obtained. 
13. 
2-[(4-Methoxy-2-pyridyl)methylsulfinyl]-5-(1,1,2,2-tetrafluoroethoxy)-1H-b 
enzimidazole sodium salt 
50 ml of 0.1M sodium hydroxide solution and 50 ml of aceton are added to 
2.017 g of 
2-[(4-methoxy-2-pyridyl)methylsulfinyl]-5-(1,1,2,2-tetrafluoroethoxy)-1H-b 
enzimidazole. The resulting solution is concentrated on a rotatory 
evaporator at 60.degree. C., and the residue is crystallized from ether. 
After drying at 60.degree. C. in vacuo over calcium chloride the title 
compound is obtained as hydrate. 
The following compounds are obtained analogously: 
2-[(4-methoxy-2-pyridyl)methylsulfinyl]-5-trifluoromethoxy-1H-benzimidazole 
sodium salt, 
2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-5-trifluoromethoxy-1H-benz 
imidazole sodium salt and 
5-difluoromethoxy-6-methoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl 
]-1H-benzimidazole sodium salt. 
14. 2-Chloromethyl-4-methoxypyridine hydrochloride 15 ml of thionyl 
chloride are added dropwise to a solution, cooled to -10.degree. C., of 10 
g (0.072 mole) of 2-hydroxymethyl-4-methoxypyridine in 30 ml of dry 
chloroform in the course of 15 min.. The solution is allowed to come to 
room temperature and stirring is continued for 1.5 h. After the solvent 
and the eccess thionyl chloride have been stripped off, colorless crystals 
are obtained, and these are recrystallized from isopropanol [12.1 g (87%), 
m.p. 149.degree.-150.degree. C., decomposition]. 
Analogously, reaction of 
2-hydroxymethyl-4-methoxy-3-methylpyridine, 
2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine, 
2-hydroxymethyl-4methoxy-5-methylpyridine and 
2-hydroxymethyl-3-methylpyridine with thionyl chloride 
gives 
2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride (m.p. 
157.degree.-158.degree. C., decomposition, from isopropanol/ether), 
2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride [m.p. 
135.degree.-136.degree. C. (decomposition) from isopropanol ether]. 
2-chloromethyl-4-methoxy-5-methylpyridine hydrochloride (m.p. 147.degree. 
C., decomposition) and 
2-chloromethyl-3-methylpyridine hydrochloride (m.p. 163.degree.-165.degree. 
C.). 
The hydroxy-pyridines (see also Example 15) are obtained in accordance with 
the method of or the instructions of O. E. Schulz and S. Fedders. Arch. 
Pharm. (Weinheim) 310, 128 (1977). The appropriately required 
intermediates are prepared in accordance with the method of H. C. Brown, 
S. Johnson and H. Podall, J.Am.Chem.Soc. 76, 5556 (1954). 
15. 2-Hydroxymethyl-4-methoxy-3,5-dimethylpyridine hydrochloride 
18 g of 2,3,5-trimethylpyridine [F. Bohlmann, A. Englisch, J. Politt, H. 
Sander and W. Weise, Chem. Ber. 88 (1955)] and 17 ml of 30% strength 
hydrogen peroxide are warmed at 100.degree. C. in 80 ml of glacial acetic 
acid for 2.5 h. A further 10 ml of 30% strength hydrogen peroxide are then 
added and the temperature is maintained for a further 8 h. The mixture is 
subsequently concentrated to half the volume under a waterpump vacuum and 
is subjected to a peroxide test. When free from peroxide, all the solvent 
is stripped off in vacuo and the residue is distilled under a high vacuum. 
19.2 g (95%) of 2,3,5-trimethylpyridine N-oxide pass over at 
95.degree.-98.degree. C. under 0.01 mm Hg (1.33 Pa). 
5.0 g of this product are dissolved in a mixture of 7 ml of fuming nitric 
acid and 7 ml of concentrated sulfuric acid at room temperature and the 
solution is warmed at a bath temperature of 40.degree. C. for 18 h. 
Thereafter, it is poured onto ice-water and rendered alkaline with 
concentrated sodium hydroxide solution, with cooling. Extraction of the 
mixture with ethyl acetate and removal of the solvent in vacuo gives crude 
2,3,5-trimethyl-4-nitropyridine N-oxide, which is dissolved in 20 ml of 
dry methanol without further purification. 4.7 ml of commercially 
available 30% strength sodium methoxide in methanol are added to this 
solution and the mixture is warmed at 50.degree. C. for 12 h. Thereafter, 
the solvent is stripped off; the residue is taken up in a little water and 
the mixture is extracted with ethyl acetate. After the solvent has been 
stripped off, the crude 4-methoxy-2,3,4-trimethylpyridine N-oxide which 
remains as an oil, is poured, without further purification, into 20 ml of 
hot acetic anhydride at 100.degree. C. and is warmed at this temperature 
for 1 h. Thereafter, the mixture is concentrated in vacuo, the residue is 
taken up, without further purification, in 20 ml of 10% strength aqueous 
hydrochloric acid and the mixture is stirred at 50.degree. C. for 2.5 h. 
It is concentrated to half the volume is vacuo, rendered alkaline with 
potassium carbonate and extracted with ethyl acetate. The combined 
extracts are dried over sodium sulfate; the solvent is stripped off in 
vacuo. The oily residue is dissolved in 50 ml of ethyl methyl ketone, and 
ethereal hydrochloric acid is added until precipitation is quantitative. 
The precipitate is recrystallized from dioxane with a little isopropanol. 
3.1 g of the title compound of m.p. 126.degree. C. are obtained. After 
chromatography of the free base on a silica gel column, an m.p. of 
49.degree.-51.degree. C. is found for the free base and, after 
reprecipitation in hydrogen chloride/ether, an m.p. of 133.5.degree. C. 
(decomposition) is found for the hydrochloride. 
2-Hydroxymethyl-4-methoxy-5-methylpyridine (m.p. 102.degree.-104.degree. 
C.) is obtained in a similar manner. 
COMMERCIAL USEFULNESS 
The fluoroalkoxy compounds of formula I and their salts have useful 
pharmacological properties which render them commercially useful. They 
significantly inhibit the secretion of gastric acid in warm-blooded 
animals and moreover have an excellent protective effect on the stomach 
and intestines in warm-blooded animals. This protective effect on the 
stomach and intestine is already observed when doses below the acid 
secretion-inhibiting doses are administered. Furthermore the compounds 
according to the invention are characterized by an absence of significant 
side-effects and an advantageous therapeutic range. 
In this context, "protection of the stomach and intestines" means the 
prevention and treatment of gastrointestinal diseases, in particular 
gastrointestinal inflammatory diseases and lesions (such as, gastric 
ulcer, duodenal ulcer, gastritis, hyperacid stomach irritation or stomach 
irritation caused by medicaments), which can be caused, for example, by 
microorganisms, bacterial toxins, medicaments (for example certain 
antiphlogistics and antirheumatics), chemicals (for example ethanol), 
gastric acid or stress situations. 
A further advantage of the compounds according to the invention is their 
comparatively high chemical stability. 
Surprisingly, the excellent properties of the compounds according to the 
invention prove to be significantly superior to those of the compounds 
known for the prior art. On the basis of these properties, the 
fluoroalkoxy compounds and their pharmacologically-acceptable salts are 
outstandingly suitable for use in human and veterinary medicine, and they 
are particularly used for the treatment and prophylaxis of diseases of the 
stomach and intestines and those diseases based on excessive secretion of 
gastric acid. 
The invention thus furthermore relates to the compounds according to the 
invention for use in the treatment and prophylaxis of the mentioned 
diseases. 
The invention also relates to the use of the compounds according to the 
invention in the preparation of medicaments which are used for the 
treatment and prophylaxis of the mentioned diseases. 
The invention furthermore relates to medicaments which contain one or more 
fluoroalkoxy compounds of formula I and/or their 
pharmacologically-acceptable salts. 
The medicaments are prepared by processes which are known per se and with 
which the expert is familiar. As medicaments, the pharmacologically-active 
compounds (=active substances) according to the invention are used either 
as such or, preferably, in combination with suitable pharmaceutical 
auxiliaries, in the form of tablets, coated tablets, capsules, 
suppositories, emulsions, suspensions or solutions, the content of active 
substance advantageously being between 0.1 and 95%. 
The expert is familiar with the auxiliaries which are suitable for the 
desired medicament formulations, on the basis of his expert knowledge. 
Besides solvents, gel-forming agents, suppository bases, tablet 
auxiliaries and other active-substance carriers, optional components 
include for example, antioxidants, dispersing agents, emulsifiers, 
anti-foaming agents, flavor-correcting agents, preservatives, solubilizing 
agents, colorants and, in particular, percutaneaous absorption promotors 
and complexing agents (e.g. cyclodextrins). 
The active substances can be administered orally, parenterally or 
percutaneously. 
In general, it has proved advantageous in human medicine to administer the 
active compound or compounds, in the case of oral administration, in a 
daily dose of from about 0.01 to about 20, preferably from 0.05 to 5 and 
in particular from 0.1 to 1.5 mg/kg of body weight, if necessary in the 
form of several, preferably 1 to 4, individual doses, in order to achieve 
the desired result. Similar or (especially in the case of intravenous 
administration of the active substances) as a rule lower dosages can be 
used for parenteral treatment. The particular optimum dosage required and 
the mode of administration of the active substances is easily determined 
by any expert on the basis of his expert knowledge. 
When the compounds according to the invention and/or their salts are used 
for the treatment of the mentioned diseases, the pharmaceutical 
formulations contain one or more pharmacologically active constituents 
from other groups of medicaments, such as antacids, for example aluminum 
hydroxide and magnesium aluminate; tranquilizers, such as benzodiazepines, 
for example diazepam; spasmolytic agents, such as bietamiverine and 
camylofin; anticholinergic agents, such as oxyphencyclimine and 
phencarbamide; local anesthetics, such as tetracaine and procaine; and, 
when appropriate, also enzymes, vitamines or aminoacids. 
The active substances are formulated, for example, in the following manner: 
(a) Tablets containing 40 mg of active substance 
20 kg of 
2-[(4-methoxy-3-methyl-2-pyridyl)-methylthio]-5-trifluoromethoxy-1H-benzim 
idazole, 40 kg of lactose, 26 kg of maize starch and 3 kg of 
polyvinylpyrrolidone are moistened with about 210 liters of water and the 
mixture is granulated through a sieve of 1.25 mm mesh width. The granules 
are dried in a fluidized bed drier to a relative moisture of 50-60%, and 8 
kg of sodium carboxymethylcellulose, 2 kg of talc and 1 kg of magnesium 
stearate are then added. The finished granules are pressed to tablets 
weighing 200 mg and having 8 mm in diameter. 
(b) Capsules containing 30 mg of active substance 
300 g of 
2-[(4-methoxy-3-methyl-2-pyridyl)-methylsulfinyl]-5-trifluoromethoxy-1H-be 
nzimidazole, 695 g of microcrystalline cellulose and 5 g of amorphous 
silicic acid are finely powdered and mixed thoroughly and size 4 hard 
gelatin capsules are filled with the mixture. 
(c) Capsules containing 10 mg of active substance 
100 g of 
2-[(4-methoxy-3-methyl-2-pyridyl)-methylsulfinyl]-5-(1,1,2,2-tetrafluoroet 
hoxy-1H-benzimidazole, 895 g of microcrystalline cellulose and 5 g of 
amorphous silicic acid are finely powdered and mixed thoroughly and size 4 
hard gelatin capsules are filled with the mixture. 
(d) Ampoules containing 10 mg of active substance 
3,16 g of 
2-[(4-methoxy-2-pyridyl)methylsulfinyl]-5-trifluoromethoxy-1H-benzimidazol 
e sodium salt is dissolved in a solution of 0.5 g of sodium carbonate and 
165,5 g of mannit in 1300 ml of distilled water, with stirring. The 
resulting solution is made up to 1500 ml with distilled water and 
sterile-filtered. In each case 5 ml of this solution are metered into a 15 
ml vial and lyophilized. The lyophilizate can be reconstituted with 10 ml 
of water. 
PHARMACOLOGY 
The excellent protective effect on the stomach and the gastric 
secretion-inhibiting action of the fluoroalkoxy compounds according to the 
invention is demonstrated in animal experiments using the Shay rat model. 
In these experiments, the compounds according to the invention were 
compared with prior art compounds (A-D) of European Patent Applications 
Nos. 0 005 129 and 0 074 341. The compounds investigated are numbered as 
follows: 
______________________________________ 
Serial No. 
Name of compound 
______________________________________ 
A 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl- 
methyl)thio]-1H--benzimidazole (EP 0 074 341) 
B 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl- 
methyl)sulfinyl]-1H--benzimidazole (EP 0 005 129) 
(INN: Omeprazole) 
C 5-methoxy-2-[(4-methoxy-5-methyl-2-pyridylmethyl)- 
thio]-1H--benzimidazole (EP 0 074 341) 
D 5-methoxy-2-[(4-methoxy-5-methyl-2-pyridylmethyl)- 
sulfinyl]-1H--benzimidazole (EP 0 005 129) 
1 2-[(4-methoxy-2-pyridyl)methylsulfinyl]-5-trifluoro- 
methoxy-1H--benzimidazole 
2 2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-tri- 
fluoromethoxy-1H--benzimidazole 
3 2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-5- 
trifluoromethoxy-1H--benzimidazole 
4 2-[(4-methoxy-5-methyl-2-pyridyl)methylsulfinyl]-5- 
trifluoromethoxy-1H--benzimidazole 
5 2-[(4-methoxy-2-pyridyl)methylsulfinyl]-5-(1,1,2,2- 
tetrafluoroethoxy)-1H--benzimidazole 
6 2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-5- 
(1,1,2,2-tetrafluoroethoxy)-1H--benzimidazole 
7 2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5- 
(1,1,2,2-tetrafluoroethoxy)-1H--benzimidazole 
8 2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]- 
5-trifluoromethoxy-1H--benzimidazole 
9 2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-5- 
trifluoromethoxy-1H--benzimidazole 
10 2-[(4-methoxy-3-methyl-2-pyridyl)methylsulfinyl]- 
5-(2,2,2-trifluoroethoxy)-1H--benzimidazole 
11 2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]- 
5-(2,2,2-trifluoroethoxy)-1H--benzimidazole 
12 5-difluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)- 
methylsulfinyl]-1H--benzimidazole 
13 5,6-bis(difluoromethoxy)-2-[(4-methoxy-2-pyridyl)me- 
thylsulfinyl]-1H--benzimidazole 
14 5,6-bis(difluoromethoxy)-2-[(4-methoxy-3-methyl-2- 
pyridyl)methylsulfinyl]-1H--benzimidazole 
15 5,6-bis(difluoromethoxy)-2-[ (4-methoxy-3-methyl-2- 
pyridyl)methylthio]-1H--benzimidazole 
16 5-difluoromethoxy-6-methoxy-2-[(4-methoxy-3- 
methyl-2-pyridyl)methylsulfinyl]-1H--benzimidazole 
17 5-difluoromethoxy-6-methoxy-2-[(4-methoxy-3- 
methyl-2-pyridyl)methylthio]-1H--benzimidazole 
18 5-chlorodifluoromethoxy-2-[(4-methoxy-2-pyridyl)- 
methylsulfinyl]-1H--benzimidazole 
______________________________________ 
The influence of the compounds of the prior art and the compounds according 
to the invention on gastric lesion formation induced by pyloric ligature 
(4 h; so-called Shay rat) and oral administration of 100 mg/kg of 
acetylsalicyclic acid, and the gastric secretion (HCl) in the course of 4 
h in rats is shown in the following table. 
______________________________________ 
Protective effect on the stomach and inhibition of gastric secretion 
Protective 
effect on the 
stomach (rats) 
Gastric secretion 
Inhibition of 
(rats) 
n the lesion % inhibi- 
Seri- 
[Number index, ED50* 
tion of ED25* ED50* 
al of [mg/kg, HCl secre- 
[mg/kg, 
No. animals] perorally] tion** perorally] 
______________________________________ 
A 88 9.0 20 12.0 25.0 
B 112 2.2 29 1.9 4.6 
C 24 .about.30.0 &gt;60.6 
D 40 .about.5.0 10 8.0 18.0 
1 79 0.6 32 0.5 1.1 
2 16 0.3 20 0.35 0.5 
3 55 0.3 32 &lt;0.3 0.4 
4 74 0.9 32 0.6 1.6 
5 70 0.7 33 0.5 1.2 
6 55 0.5 35 0.3 0.7 
7 24 0.5 40 0.35 0.7 
8 24 0.4 20 1.0 1.5 
9 24 1.0 10 1.4 2.0 
10 24 0.5 25 0.5 0.7 
11 24 0.5 25 0.5 0.7 
12 16 .about.0.3 .about.20 
.about.0.3 
.about.0.6 
13 16 .about.1.2 .about.30 
.about.1.1 
.about.1.7 
14 32 0.2 20 .about.0.3 
0.6 
15 32 0.6 30 0.5 1.0 
16 32 0.2 .about.0.8 
17 32 .about.0.3 .about.25 
.about.0.3 
.about.0.8 
18 16 1.3 35 &lt;1.0 1.8 
______________________________________ 
*ED25 and ED50 = dose which reduces the lesion index or the HCL 
secretion(4h) in the rat stomach by 25 and, respectively, 50% in the 
treated group in comparison with the control group. 
**after administration of the antiulcerous ED50. 
The antiulcerogenic action was tested by the so-called Shay rat method: 
Ulcers are caused in rats which have been fasted for 24 hours (female, 
180-200 g, 4 animals per cage on a high grid) by pyloric ligature (under 
diethyl ether anesthesia) and oral administration of 100 mg/10 ml/kg of 
acetylsalicylic acid. The substances to be tested are administered orally 
(10 ml/kg) one hour before the pyloric ligature. The wound is closed by 
means of Michel clamps. 4 hours thereafter, the animals are sacrificed 
under ether anesthesia by Atlas dislocation and resection of the stomach. 
The stomach is opened longitudinally and attached to a cork plate, after 
the amount of gastric juice secreted (volume) and later its HCl content 
(titration with sodium hydroxide solution) have first been determined; the 
number and size (=diameter) of the ulcers present are determined under a 
stereomicroscope at 10-fold magnification. The product of the degree of 
severity (according to the following points scale) and number of ulcers 
serves as the individual lesion index. 
______________________________________ 
Points scale: 
______________________________________ 
no ulcers 0 
Ulcer diameter 0.1-1.4 mm 
1 
1.5-2.4 mm 2 
2.5-3.4 mm 3 
3.5-4.4 mm 4 
4.5-5.4 mm 5 
&gt;5.5 mm 6 
______________________________________ 
The reduction in the average lesion index of each treated group compared 
with the control group (=100%) serves as a measure of the antiulcerogenic 
effect. The ED25 and ED50 designate those doses which reduce the average 
lesion index or the HCl secretion by 25% or, respectively, 50% in 
comparison with the control. 
Toxicity 
The LD50 of all the compounds tested is above 1,000 mg/kg [perorally] in 
mice.