Sulfenamide derivatives and their production

The compound of the formula ##STR1## wherein R.sup.1 is hydrogen, methoxy or trifluormethyl, R.sup.2 and R.sup.3 are the same or different and are each hydrogen or methyl, R.sup.4 is a fluorinated lower alkyl having 2 to 5 carbon atoms and 1 to 11 fluorine atoms and X.sup.- is a pharmaceutically acceptable anion, respectively, possesses both strong antisecretory activity and gastric mucosal protective activity, which is produced by reacting a pyridine derivative of the formula ##STR2## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same meaning as defined above, with an acid.

The present invention relates to sulfenamide derivatives, which work well 
as antiulcer drugs etc., and the method of their production. 
Pyridine derivatives possessing antiulcer activity include the compound 
described in U.S. Pat. No. 4,255,431 (corresponding to Japanese Unexamined 
Patent Laid-open No. 141783/1979), which is known to suppress the 
secretion of gastric acid by inhibiting H.sup.+, K.sup.+ -ATPase in the 
stomach. It has been pointed out that the inhibition of H.sup.+, K.sup.+ 
ATPase by such pyridine derivatives are not due to the compounds 
themselves, but due to the products of their conversion in European Patent 
Publication No. 171,372A (Japanese Unexamined Patent Laid-open No. 
7281/1986). 
The compounds described in the European Patent Publication No. 171,372A 
require improvements in relation to stability, absorbability, antiulcer 
effect, antisecretory activity, etc. 
The present inventors made further studies, focusing on their attention on 
the problems mentioned above, and completed the present invention. 
The present invention relates to: 
(1) Sulfenamide derivatives expressed by the formula 
##STR3## 
wherein R.sub.1 is hydrogen, methoxy or trifluoromethyl R.sup.2, and 
R.sup.3 are the same or different and are each hydrogen or methyl, R.sup.4 
is a fluorinated lower alkyl group having 2 to 5 carbon atoms and 1 to 11 
fluorine atoms and X.sup.- is an anion, respectively, and 
(2) A method for producing, sulfenamide derivatives of the formula (I), 
which comprises reacting pyridine derivatives of the formula 
##STR4## 
wherein R.sup.1 is hydrogen, methoxy or trifluoromethyl, R.sup.2 and 
R.sup.3 are the same or different and are each hydrogen or methyl, and 
R.sup.4 is a fluorinated lower alkyl group having 2 to 5 carbon atoms with 
an acid. 
Fluorinated lower alkyls having 2 to 5 carbon atoms and 1 to 11 fluorine 
atoms, preferably 3 to 8 fluorine atoms, which are represented by R.sup.4 
in the formulas shown above, include 2,2,2-trifluoroethyl 
2,2,3,3,3-pentafluoropropyl, 2,2,3,3-tetrafluoropropyl, 
1-trifluoromethyl-2,2,2-trifluoroethyl, 2,2,3,3,4,4,4-heptafluorobutyl and 
2,2,3,3,4,4,5,5-octafluoropentyl etc. 
Anions represented by X.sup.- include Cl.sup.-, Br.sup.-, 
I.sup.-,SO.sub.4.sup.2- CH.sub.3 SO.sub.3.sup.-, 
##STR5## 
PO.sub.4.sup.3-, ClO.sub.4.sup.-, BF.sub.4.sup.-, PF.sub.6.sup.- and 
AuCl.sub.4.sup.- etc, which are derived from a pharmaceutically acceptable 
acid. 
Sulfenamide derivative (I), the desired compound of the present invention, 
can be produced by heating (from about 40.degree. to 100.degree. C.) 
pyridine derivative (II), which can be obtained by the method described 
later; however, it is preferable that the desired compound be produced by 
reacting the pyridine derivative with an acid. Acids which can be used 
include hydrochloric acid, hydrobromic acid, hydriodic acid, phosphoric 
acid, sulfuric acid, perchloric acid, methanesulfonic acid, 
p-toluenesulfonic acid, fluoboric acid, hexafluorophosphoric acid and 
hydrogen tetrachloroaurate; they are used usually in an equivalent of 1 to 
2.about.5. Solvents to be used include alcohols such as methanol, ethanol 
and propanol; water, acetone, acetonitrile, chloroform and dichloromethane 
etc. Reaction temperature should be chosen in the range of ice-cooling 
temperature to 60.degree. C.; reaction time should be between several 
minutes and 24 hours. 
The desired compound (I), produced via the reaction described above, can be 
separated and purified using a conventional method such as 
recrystallization or chromatography etc. 
The production method for the starting material (II) is hereinafter 
explained. 
The compound (II) can be produced by subjecting the compound of the formula 
##STR6## 
wherein R.sup.l, R.sup.2, R.sup.3 and R.sup.4 have the same meaning as 
defined above, to oxidation. 
Oxdizing agents to be used for this purpose include peracids such as 
m-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid and 
permaleic acid; sodium bromite; and sodium hypochlorite etc. Solvents to 
be used for the reaction include halogenated hydrocarbons such as 
chloroform and dichloromethane; ethers such as tetrahydrofuran and 
dioxane; amides such as dimethylformamide; and water etc. These solvents 
can be used either singly or in combination. It is recommended that said 
oxidizing agents are used in an amount of about 1 equivalent to slightly 
excess relative to the compound (III), i.e., about 1 to 3 equivalent, 
preferably about 1 to 1.5 equivalent. Reaction temperature can be chosen 
in a range of ice-cooling temperature to the boiling point of the used 
solvent, generally ice-cooling temperature to room temperature, preferably 
about 0.degree. C. to 10.degree. C. Reaction time should be about 0.1 to 
24 hours, preferably about 0.1 to 4 hours. 
The compound (III) can be produced by reacting the compound of the formula 
##STR7## 
wherein R.sup.l has the same meaning as defined above with the compound of 
the formula 
##STR8## 
wherein R.sup.2, R.sup.3 and R.sup.4 have the same meaning as defined 
above, and Y is a halogen atom. 
Halogen atoms represented by Y include, for example, chlorine, bromine and 
iodine. 
It is preferable that the reaction is carried out in the presence of a 
base. Bases to be used include alkali metal hydrides such as sodium 
hydride and potassium hydride etc., alkali metal such as metallic sodium 
etc., sodium alcoholates such as sodium methoxide and sodium ethoxide 
etc., alkali metal carbonates such as potassium carbonate and sodium 
carbonate etc., and organic amines such as triethylamine and so on. 
Solvents to be used for the reaction include alcohols such as methanol and 
ethanol, and dimethylformamide and so on. Said bases are usually used in 
an amount of 1 equivalent to slightly excess, but can be used in an 
equivalent of much more than 1. It is recommended that they are used in an 
equivalent of about 2 to 10, preferably about 2 to 4. Reaction temperature 
should be between about 0.degree. C. and around the boiling point of the 
used solvent, preferably betweem about 20.degree. C. and 80.degree. C. 
Reaction time should be 0.2 to 24 hours, preferably about 0.5 to 2 hours. 
The compound (V) can be produced as follows: 
##STR9## 
The alkoxy derivative of the formula (VIII) wherein R.sup.2, R.sup.3 and 
R.sup.4 have the same meaning as defined above can be produced by reacting 
the nitro compound of the formula (VI) wherein R.sup.2 and R.sup.3 have 
the same meaning as defined above with the alcohol derivative R.sup.4 OH 
(VII) wherein R.sup.4 has the same meaning as defined above in the 
presence of a base. Bases to be used for this reaction include alkali 
metals such as lithium, sodium and potassium, alkali metal hydrides such 
as sodium hyride and potassium hydride, alcohlates such as potassium 
t-butoxide and sodium propoxide, alkali metal carbonates or hydrogen 
carbonates such as potassium carbonate, lithium carbonate, potassium 
hydrogen carbonate and sodium hydrogen carbonate, and alkali hydroxides 
such as sodium hydroxide and potassium hydroxide and so on. Solvents to be 
used for the reaction include R.sup.4 OH itself, ethers such as 
tetrahydrofuran and dioxane etc., ketones such as acetone and methyl ethyl 
ketone etc., acetonitrile, dimethylformamide, and hexamethylphosphoric 
triamide and so on. Reaction temperature can be chosen in a range of 
ice-cooling temperature to around the boiling point of the solvent. 
Reaction time should be about 1 to 120 hours. 
The compound (VIII), obtained as described above, is then heated (from 
about 80.degree. to 120.degree. C.) in the presence of either acetic 
anhydride alone or both acetic anhydride and a mineral acid such as 
sulfuric acid and perchloric acid to yield the 2-acetoxymethylpyridine 
derivative of the general formula (IX) wherein R.sup.2, R.sup.3 and 
R.sup.4 have the same meaning as defined above. Reaction time should be 
generally about 0.1 to 10 hours. 
The compound (IX) is then subjected to alkali hydrolysis to produce the 
2-hydroxymethylpyridine derivative of the formula (X) wherein R.sup.2 
R.sup.3 and R.sup.4 have the same meaning as defined above. The alkalis to 
be used for the hydrolysis include, for example, sodium hydroxide, 
potassium hydroxide, potassium carbonate and sodium carbonate etc. 
Solvents to be used include, for example, methanol, ethanol and water etc. 
The reaction should be generally carried out at about 20.degree. to 
60.degree. C. for about 0.1 to 2 hours. 
The compound (X) is then halogenated with a halogenating agent such as 
thionyl chloride to produce the 2-halogeno-methylpyridine derivative of 
the formula (V) wherein R.sup.2, R.sup.3 and R.sup.4 have the same meaning 
as defined above; and .gamma. is chlorine, bromine, or iodine. Solvents to 
be used for this reaction include chloroform, dichloromethane and 
tetrachloroethane etc. The reaction should be generally carried out at 
about 20.degree. to 80.degree. C. for about 0.1 to 2 hours. 
The compound (V), produced as described above, is a salt of hydrohalogenic 
acid corresponding to the used halogenating agent; it is preferable that 
it is used immediately for the reaction with the compound (IV). 
##STR10## 
Using the same reaction as that in Method (l), the compound of the formula 
(XI) wherein R.sup.2 and R.sup.3 have the same meaning as defined above is 
derivatized to the compound of the formula (XII) wherein R.sup.2, R.sup.3 
and R.sup.4 have the same meaning as defined above. 
The compound (XII) is then methylated with dimethyl sulfate to the compound 
of the formula (XIII) wherein R.sup.2, R.sup.3 and R.sup.4 have the same 
meaning as defined above. This reaction usually requires no solvent, 
reaction temperature should be about 100.degree. to 120.degree. C. and 
reaction time should be about 0.1 to 4 hours. 
The compound (X) can be produced by reacting the compound (XIII) with a 
radical source such as ammonium persulfate or another persulfate in 
methanol. Reaction temperature should be about 20.degree. to 80.degree. C. 
and reaction time should be between about 0.5 and 4 hours. 
The compound (I), the desired compound produced by the method described 
above, possessing antiulcer activity, antisecretory activity, mucosal 
protective activity, etc., can be used as a therapeutic drug for digestive 
ulcers. 
When the compound (I) of the present invention is used to treat a mammal 
for peptic ulcers, it can be orally administered in the dose form of a 
capsule, tablet, granule, or others, in combination with a 
pharmacologically acceptable carrier, excipient, diluent, etc. Its dose 
should be about 0.01 .about.30 mg/kg/day, preferably about 0.1.about.3 
mg/kg/day