JP2779206B2 - Sulfenamide derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a sulfenamide derivative having an anti-ulcer action.

[Background of the Invention]

As a cause of peptic ulcer such as gastric and duodenal ulcer,
It has been described that when an aggressive factor such as acid and pepsin and a protective factor such as mucosal resistance, mucus, blood flow, and duodenal depression are out of balance, autolysis occurs and an ulcer is formed.

Treatment of peptic ulcer is medical treatment in principle, and various drug treatments have been attempted. Currently, the anti-ulcer agents which are most used, cimetidine based on histamine H ₂ receptor antagonism (cimetidine), ranitidine (Ranitidin
e) and the like. However, these drugs have been reported as side effects such as anti-androgenic action, hepatic metabolic enzyme activity inhibitory action and the like.

Under such circumstances, it has recently been suggested that an inhibitor of an enzyme called H ⁺ -K ⁺ ATPase, which is specifically present in different cells, may be an excellent acid secretion inhibitor.

From this aspect, various compounds have been proposed, but these compounds are structurally benzimidazole derivatives.

The present inventors have searched for a compound having an excellent anti-ulcer action over a long period of time over the conventional benzimidazole derivatives, and as a result, have found a benzimidazole compound having an excellent anti-ulcer action, and have already filed a patent application. No. 62-286668).

After that, the inventors of the present invention have conducted further studies from the metabolic point of view, and found that the sulfenamide derivative, which is considered to be a conversion product thereof, is an excellent anti-ulcer which is not inferior to the above-mentioned patent application. It has been found to have an effect.

[Structure and effect of the invention]

 The present invention has been completed based on the above findings.

The target compound of the present invention is a sulfenamide derivative represented by the following general formula (I).

[In the formula, R ¹ and R ² represent the same or different hydrogen atoms, lower alkyl groups, lower alkoxy groups, halogenated lower alkyl groups, lower alkoxycarbonyl groups, carboxyl groups, and halogen atoms.

R ³ and R ⁴ each represent a hydrogen atom or a lower alkyl group.

 m means an integer of 2 to 10.

Z is a group represented by the formula —OR ⁵ (wherein R ⁵ represents a hydrogen atom, a lower alkyl group, an aryl group or an arylalkyl group), or a formula —O— (CH ₂ ) _n —O—R ⁶ (Where
n means the integer of 1-3. R ⁶ represents a hydrogen atom, a lower alkyl group, an aryl group or an arylalkyl group).

X ^- is meant a pharmaceutically acceptable anion] Accordingly, an object of the present invention is useful novel sulfenamide derivatives as peptic ulcer agent, a method of manufacturing the same, and novel peptic ulcer containing the same To provide an agent.

In the above definition of the compound (I) of the present invention,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , the lower alkyl group found in the definition of R ⁶ is a linear or branched alkyl group having 1 to 6 carbon atoms,
For example, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-
Examples include groups such as butyl, n-pentyl, 1-ethylpropyl, isoamyl, and n-hexyl, and the most preferred examples are a methyl group and an ethyl group.

"Lower alkoxy group" in the definition of R ¹ and R ²
“Halogenated lower alkyl group” and “lower alkoxycarbonyl group” mean a group derived from the above lower alkyl group, and the most preferred group is a group derived from a methyl group, an ethyl group, or a propyl group. is there. In particular,
For example, the "lower alkoxy group" includes a methoxy group, an ethoxy group and a propoxy group, and the "lower alkoxycarbonyl group" includes a methoxycarbonyl group and an ethoxycarbonyl group. As the “halogenated lower alkyl group”, for example, a trifluoromethyl group is preferable.

The halogen atom in the definitions of R ¹ and R ² means chlorine, bromine, iodine, and fluorine.

In particular, R ¹ and R ² are preferably a hydrogen atom, a lower alkyl group such as a methyl group, a lower alkoxy group such as a methoxy group, and a trifluoromethyl group.
One is preferably a lower alkyl group or a lower alkoxy group, and one is preferably a hydrogen atom, and both are preferably a hydrogen atom.

In the definitions of R ⁵ and R ⁶ , an aryl group is a phenyl group,
It refers to a tolyl group, a xylyl group, a naphthyl group or the like, and may be substituted with a lower alkoxy group such as a methoxy group or an ethoxy group, a hydroxyl group, a halogen or the like.

In the definitions of R ⁵ and R ⁶ , the arylalkyl group means, for example, a benzyl group, a phenethyl group and the like.

m represents an integer of 2 to 10, and most preferably m = 3.

X ^- While not limited an anion Pharmaceutically acceptable, specifically, for example ^{Cl -, Br -, I -} , BF 4 -, PF 6 -, HSO 4 -, S
_{^{O 4 2-, CH 3 SO 3}} -, PO ₄ ^3-, ClO ₄ ^- or AuCl ₄ ^- and the like.

Next, among the methods for producing the compound of the present invention, representative methods are shown below.

That is, the target compound (I) can be obtained by subjecting a pyridine derivative represented by the general formula (II) to a heat reaction in the presence of an acid by a conventional method. As the acid used at this time, for example, tetrafluoroboric acid, hexafluorophosphoric acid,
Examples thereof include sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, methanesulfonic acid, and toluenesulfonic acid. The use of 1 equivalent to 3 equivalents of acid gives the preferred results.

Usually, as a solvent used in the reaction, ethers, ethers such as tetrahydrofuran, methyl alcohol, alcohols such as ethyl alcohol, water, chloroform, dichloromethane, acetone, acetonitrile,
Examples include dimethylformamide, dimethylsulfoxide and mixtures thereof. The reaction temperature is from -40C to about 100C, preferably from about 30 to 50C. The reaction time is a few minutes to a few hours.

The pyridine derivative used as a starting material in this reaction can be produced, for example, by the method described in Japanese Patent Application No. 62-286668.

That is, it can be manufactured by the following methods A and B.

That is, the compound represented by the general formula (III) and the compound represented by the general formula (I
Compound (V) can be obtained by reacting with a halogen compound or a sulfonate compound represented by V).

In the definition of Y, halogen means, for example, chlorine, bromine, iodine, etc., and various sulfonyloxy groups include, for example, alkylsulfonyloxy groups such as methylsulfonyloxy group, ethylsulfonyloxy group, benzenesulfonyloxy group, and tosyloxy group. And an aromatic sulfonyloxy group such as a group.

It is preferable to carry out this reaction in the presence of a deoxidizing agent. Examples of the deoxidizing agent include carbonates or bicarbonates of alkali metals such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, alkali hydroxides such as sodium hydroxide and potassium hydroxide, and organic compounds such as pyridine and triethylamine. Amines and the like. Examples of the solvent used for the reaction include alcohols such as methyl alcohol and ethyl alcohol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, and a mixture of these with water.

The reaction temperature is from -40 ° C to the boiling point of the solvent, preferably from about 0 to 60 ° C.

By subjecting the obtained compound (V) to an oxidation reaction, the pyridine derivative (II) as a starting material of the present invention can be easily obtained.

The oxidation reaction can be performed by an ordinary method using an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite, and sodium bromite. As a solvent used in the reaction, a solvent selected from dichloromethane, chloroform, benzene, toluene, methanol, ethanol and the like is usually used.

Reaction temperatures range from about -70 ° C to the boiling point of the solvent,
Preferably it is −60 to 25 ° C.

(Wherein R ¹ , R ² , R ³ , R ⁴ , m, and Z have the above-mentioned meaning, and Hal means a halogen atom) That is, a halogen compound represented by the general formula (VI) Reacting with an alcohol, thiol or amine represented by the general formula ZH (VII) to obtain a compound represented by the general formula (V), and oxidizing the same as above to obtain a compound (II) Can be. This reaction is also preferably performed in the presence of a deoxidizing agent. Examples of the deoxidizing agent include carbonates or bicarbonates of alkali metals such as potassium carbonate and sodium carbonate, alkali hydroxides such as sodium hydroxide and potassium hydroxide, and triethylamine. As a reaction solvent, for example, tetrahydrofuran,
Ethers such as dioxane, ketones such as acetone and methyl ethyl ketone, benzene solvents such as benzene, toluene, and xylene, acetonitrile, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide are used. The reaction is carried out at a temperature from ice-cooling to the boiling point of the solvent.

Next, in order to specifically detail the effects of the present invention, pharmacological experimental examples of typical compounds of the present invention will be described.

Pharmacological experiments H ⁺ -K ⁺ -ATPase activity inhibitory activity (1) Regulation of H ⁺ -K ⁺ ATPase Saccomani (Saccomi) was obtained from the fundic gland of the gastric mucosa of fresh pigs.
ani) et al. [Biochem. and Biophys. Acta, 464 , 313 (1
977)].

(2) Measurement of H ⁺ -K ⁺ ATPase activity Various concentrations of the compound of the present invention, H ⁺ -K ⁺ ATPase, 10 μm
Incubated with g protein / ml in 40 mM Tris.HCl buffer pH 7.40 at 37 ° C. for 30 minutes. 10 minutes after the addition of 15 mM CKl, the ATPase reaction was started with 3 mM MgCl ₂ and ATP. After 10 minutes, the released inorganic phosphate was analyzed by the method of Yoda and Hokin (Biochem. Bi
ophys. Res., com., 40, 880 , 1970).

3- (3-methoxy) propoxy- as a test compound
4-methyl-5H-pyrido [1'.2 ': 4.5] [1.2.4] thiadiano [2.3-a] benzimidazole-13-ium tetrafluroborate (the compound of Example 1) was selected and It was dissolved in methanol and used.

For the inhibitory effect, the difference between the measured values in the test compound was determined from the measured values in the control group to which only the solvent was added, and this was calculated as a percentage of the measured value in the control group.

The test compound had an IC ₅₀ (M) of 4.4 × 10 ⁻⁷ .
Omeprazole (Omeprazol) was used as a control compound.
e) was selected, but the IC _{50 of} this compound was 1.1 × 10 ⁻⁵ .

As is clear from the above pharmacological experimental examples, the compound of the present invention has a strong H ⁺ -K ⁺ ATPase activity inhibitory action.

Therefore, the compound of the present invention has an excellent gastric acid secretion inhibitory action based on a strong H ⁺ -K ⁺ ATPase activity inhibitory action, and is useful as a therapeutic or preventive agent for peptic ulcer in humans or animals.

When the compound of the present invention is administered as a therapeutic / prophylactic agent for peptic ulcer, it may be orally administered as an acid, granule, capesel, syrup, or the like, or a suppository, injection,
It may be administered parenterally as an external preparation or a drip. The dose varies significantly depending on the degree of symptoms, age, type of ulcer, etc., but is usually about 0.01 to 2000 mg / kg per day, preferably 0.05 to 50 mg / kg, more preferably 0.1 to 20 mg / kg per day. Administer several divided doses.

At the time of production, it is produced by a conventional method using a usual pharmaceutical carrier.

That is, when preparing a solid preparation for oral use, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, etc. are added to the main drug, if necessary, and then the tablet, Coated tablets, granules, powders, capsules, etc.

As excipients, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, etc., as binders, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, Hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc., as disintegrants, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, etc., as lubricants For example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oils and the like are those that are permitted to be added to pharmaceuticals as coloring agents, but as flavoring agents Include cocoa powder, menthol, aromatic acid, peppermint oil, borneol, cinnamon powder and the like are used. Of course, these tablets and granules may be sugar-coated, gelatin-coated and optionally coated as needed.

When preparing an injection, a pH adjuster, a buffer, a stabilizer, a solubilizing agent, and the like are added to the main drug, if necessary, to give a subcutaneous, intramuscular, or intravenous injection according to a conventional method.

〔Example〕

Next, examples of the present invention will be described. However, it goes without saying that the present invention is not limited to these examples.

Example 1 3- (3-methoxy) propoxy-4-methyl-5H-pyrido [1'.2 ': 4.5] [1.2.4] thiadiazino [2.3-
a) Benzimidol-13-ium tetrafluoroborate Method a) A mixture of 0.36 g of 2- [4- (3-methoxy) -propoxy-3-methylpyridin-2-yl] methylsulfinyl-1H-benzimidazole, 5 ml of methanol and 0.19 g of 85% tetrafluoroborate ether complex was prepared. 40 ℃
After stirring for 10 minutes under ice cooling, the mixture was stirred for 30 minutes under ice cooling, and the precipitated crystals were collected by filtration to obtain 0.32 g of the desired product as yellow crystals.

Method b) 0.38 g of 2- [4- (3-methoxy) peropoxy-3-methylpyridin-2-yl] methylsulfinyl-1H-benzimidazole sodium salt, methanol 5 ml, 85
A mixture of 0.38 g of a tetrafluoroborate ether complex (0.38 g) was stirred at 40 ° C. for 10 minutes, then stirred under ice cooling for 30 minutes, and the precipitated crystals were collected by filtration to obtain 0.32 g of the target product.
Was obtained as yellow crystals.

Melting point (° C); 141 to 143 (decomposition) ¹ H-NMR (90 MHz, CDCl ₃ -CD ₃ OD) δ; 2.22 (2H, m), 2.51 (3H, s), 3.36 (3H, s), 3.59 ( 2H, t,
J = 6.3Hz), 4.58 (2H, t, J = 6.3Hz), 4.85 (2H, s), 7.23
~ 7.77 (4H, m), 7.64 (1H, d, J = 7.2Hz), 9.37 (1H, d, J
= 7.2 Hz) Example 2 3- (3-methoxy) propoxy-4-methyl-5H-pyrido [1'.2 ': 4.5] [1.2.4] thiadiazino [2.3-
a) Benzimidol-13-ium hexafluorophosphate 0.38 g of 2- [4- (3-methoxy) -propoxy-3-methylpyridin-2-yl] methylsulfinyl-1H-benzimidazole sodium salt, 5 ml of methanol,
After stirring a mixture of 0.48 g of 60% hexafluorophosphoric acid at 40 ° C. for 10 minutes, the mixture was stirred under ice cooling for 30 minutes, and the precipitated crystals were collected by filtration to obtain 0.30 g of the desired product as pale yellow crystals.

Melting point (° C.); 143-145 (decomposition) ¹ H-NMR (90 MHz, CDCl ₃ -DMSO d ₆ ) δ; 2.25 (2H, m), 2.53 (3H, s), 3.38 (3H, s), 3.62 ( 2H, t,
J = 6.3Hz), 4.65 (2H, t, J = 6.3Hz), 4.99 (2H, s), 7.37
-7.93 (4H, m), 7.81 (1H, d, J = 7.2Hz), 9.57 (1H, d, J
= 7.2 Hz) Example 3A + 3B 9-methoxy-3- (3-methoxy) propoxy-4-
Methyl-5H-pyrido [1'.2 ': 4.5] [1.2.4] thiadiazino [2.3-a] benzimidazole-13-ium
Tetrafluoroborate (3A) and 10-methoxy-3- (3-methoxy) propoxy-4-
Methyl-5H-pyrido [1'.2 ': 4.5] [1.2.4] thiadiazino [2.3-a] benzimidazole-13-ium
Tetrafluoroborate (3B) (mixture of isomers) The desired product was obtained in the same manner as in Example 1b.

Melting point (° C); 149 to 151 (decomposition) ¹ H-NMR (90 MHz, CDCl ₃ -DMSO d ₆ ) δ; 2.23 (2H, m), 2.52 (3H, s), 3.19 (2H, t, J = 6.3) Hz), 3.
36 (3H, s), 4.10 (3H, s), 4.58 (2H, t, J = 6.3Hz), 4.88
(2H, s), 6.76 to 7.80 (4H, m), 9.40 (1H, d, J = 7.2 Hz) Example 4 3- (3-methoxy) propoxy-2-methyl-5H-pyrido [1'.2 ': 4.5] [1.2.4] thiadiazino [2.3-
a) Benzimidol-13-ium tetrafluoroborate The desired product was obtained in the same manner as in Example 1b.

127-130 (decomposition) ¹ H-NMR (90 MHz, CDCl ₃ -DMSO d ₆ ) δ; 2.24 (2H, m), 2.47 (3H, s), 3.38 (3H, s), 3.62 ( 2H, t,
J = 6.3Hz), 4.68 (2H, t, J = 6.3Hz), 5.06 (2H, s), 7.33
7.97.93 (4H, m), 8.03 (1H, s), 9.40 (1H, s) Example 5 3- (3-methoxy) propoxy-5H-pyrido [1 ′.
2 ': 4.5] [1.2.4] thiadiazino [2.3-a] benzimidazole-13-ium tetrafluoroborate The desired product was obtained in the same manner as in Example 1b.

Melting point (° C.); 90-95 (decomposition) ¹ H-NMR (90 MHz, CDCl ₃ −CD ₃ OD) δ; 1.96 to 2.36 (2H, m), 3.36 (3H, s), 3.62 (2H, t, J = 6.3H
z), 4.61 (2H, t, J = 6.3Hz), 4.96 (2H, s), 7.46-8.12
(6H, m), 9.39 (1H, d, J = 8.1 Hz) Example 6 3- (4-methoxy) butyloxy-4-methyl-5H-
Pyrido [1'.2 ': 4.5] [1.2.4] thiadiazino [2.3-
a) Benzimidazole-13-ium tetrafluoroborate The desired product was obtained in the same manner as in Example 1b.

Melting point (° C.); 161-164 (decomposition) ¹ H-NMR (90 MHz, CDCl ₃ −CD ₃ OD) δ; 1.58 to 2.16 (4H, m), 2.52 (3H, s), 3.36 (3H, s), 3.48
(2H, t, J = 6.3Hz), 4.53 (2H, t, J = 6.3Hz), 4.88 (2H, t, J = 6.3Hz)
s), 7.22 to 7.82 (4H, m), 7.73 (1H, d, J = 7.2Hz), 9.45
(1H, d, J = 7.2 Hz) Example 7 2,4-dimethyl-3- (3-methoxy) propoxy-5H
-Pyrido [1'.2 ': 4.5] [1.2.4] thiadiazino [2.3
-A] Benzimidazole-13-ium tetrafluoroborate The desired product was obtained in the same manner as in Example 1b.

Melting point (° C.); 103-108 (decomposition) ¹ H-NMR (90 MHz, CDCl ₃ -CD ₃ OD) δ; 1.90-2.30 (2H, m), 2.62 (6H, s), 3.38 (3H, s), 3.60
(2H, m), 4.60 (2H, m), 4.89 (2H, br), 7.20-7.82 (4
H, m), 9.52 (1H, s) Example 8 9,10-Dimethyl-3- [2- (2-methoxy) ethoxy] ethoxy-4-methyl-5H-pyrido [1'.2 ': 4.
5] [1.2.4] thiadiazino [2.3-a] benzimidazole-13-ium tetrafluoroborate The desired product was obtained in the same manner as in Example 1b.

Melting point (° C); 154-155 (decomposition) ¹ H-NMR (90 MHz, CDCl ₃ -CD ₃ OD) δ; 2.36 (3H, s), 2.40 (3H, s), 2.53 (3H, s), 3.38 ( 3H,
s), 3.65 (4H, m), 3.90 to 4.10 (2H, m), 4.56 to 3.78 (2
H, m), 4.86 (2H, s), 7.20 (1H, s) 7.49 (1H, s), 7.80
(1H, d, J = 7.2 Hz), 9.42 (1H, d, J = 7.2 Hz) Example 9A + 9B 9-chloro-3- [2- (2-methoxy) ethoxy] ethoxy-4-methyl-5H-pyrido [1'.2 ': 4.5] [1.
2.4) thiadiazino [2.3-a] benzimidazole-13
-Ium tetrafluoroborate (9A) and 10-chloro-3- [2- (2-methoxy) ethoxy] ethoxy-4-methyl-5H-pyrido [1'.2 ': 4.5] [1.
2.4) thiadiazino [2.3-a] benzimidazole-13
-Ium tetrafluoroborate (9B) (mixture of isomers) The desired product was obtained in the same manner as in Example 1b.

Melting point (° C); 147 to 149 (decomposition) ¹ H-NMR (90 MHz, CDCl ₃ -DMSO d ₆ ) δ; 2.54 (3H, s), 3.36 (3H, s), 3.66 (4H, m), 3.88 to 4.10
(2H, m), 4.56-4.81 (2H, m), 5.03 (2H, s), 7.24-7.9
8 (4H, m), 9.52 (1H, d, J = 5.4Hz) Example 10 3- (3-benzyloxy) propoxy-4-methyl-
5H-pyrido [1'.2 ': 4.5] [1.2.4] thiadiazino [2.3-a] benzimisol-13-ium tetrafluoroborate The desired product was obtained in the same manner as in Example 1b.

Melting point (° C); 147 to 149 (decomposition) ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 2.22 (2H, m), 2.40 (3H, s), 3.68 (2H, t, J = 6.3 Hz), 4 .
51 (2H, s), 4.61 (2H, t, J = 6.3Hz), 4.84 (2H, s), 7.20
7.87.88 (10H, m), 9.40 (1H, d, J = 7.2 Hz) Example 11 3- (3-hydroxy) propoxy-4-methyl-5H-
Pyrido [1'.2 ': 4.5] [1.2.4] thiadiazino [2.3-
a) Benzimidol-13-ium tetrafluoroborate The target product (amorphous) was obtained in the same manner as in Example 1b. ¹ H-NMR (90 MHz, CDCl ₃ -DMSO d ₆ ) δ; 2.18 (2H, m), 2.53 (3H, s), 3.80 (2H, t, J = 6.3 Hz), 4.
70 (2H, t, J = 6.3Hz), 5.01 (2H, s), 7.33 ~ 7.99 (4H,
m), 7.87 (1H, d, J = 7.2Hz), 9.57 (1H, d, J = 7.2Hz)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 285: 00) (72) Inventor Seiichiro Nomoto 1-14-2-2 Kariyacho, Ushiku-shi, Ibaraki Prefecture (72) Inventor Makoto Okita Ibaraki Prefecture 4-9-14 Matsushiro, Tsukuba City Garden House Teshirogi 201 (72) Inventor Naoyuki Shimomura 2-23-5 Mekugan Gakuen 207-5-23, Akubo, Tsukuba City, Ibaraki Prefecture (72) Inventor Toshihiko Kaneko 4-18 Kasuga, Tsukuba City, Ibaraki Prefecture -4 Market Rate 203 (72) Inventor Masatoshi Fujimoto 2-5-4 Tokodai, Tsukuba City, Ibaraki Prefecture (72) Inventor Manabu Murakami 1-6-8 Tokodaidai, Tsukuba City, Ibaraki Prefecture (72) Inventor Kiyoshi Oketani Ibaraki 1-9-16 Tokodai, Tsukuba Pref., Japan (72) Inventor Hideaki Fujisaki 2-24-2 Umezono, Tsukuba, Ibaraki Pref. (72) Inventor Hisashi Shibata 110-8 Off Arakawa, Tsuchiura, Ibaraki Pref. 205 Yubara Mansion 205 (72) Invention Yasuo Wakabayashi 368 Motoyoshida-cho, Mito-shi, Ibaraki (56) Reference JP-A-61-7281 (JP, A) JP-A-62-277392 (JP, A) JP-A-62-205077 (JP, A) Hei 1-6270 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 513/14 A61K 31/54 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) General formula [In the formula, R ¹ and R ² represent the same or different hydrogen atoms, lower alkyl groups, lower alkoxy groups, halogenated lower alkyl groups, lower alkoxycarbonyl groups, carboxyl groups, and halogen atoms. R ³ and R ⁴ each represent a hydrogen atom or a lower alkyl group. m means an integer of 2 to 10. Z is a group represented by the formula —OR ⁵ (wherein R ⁵ is a hydrogen atom, a lower alkyl group,
Groups represented by means an aryl group or an arylalkyl group), or the formula -O- (CH ₂₎ in _n -O-R ⁶ (wherein, n is an integer of 1 to 3 .R ⁶ is hydrogen , Lower alkyl group, aryl group or arylalkyl group). X ^- is sulfenamide derivative represented by means a pharmaceutically acceptable anion].