WO1997040039A1 - Pyridine compounds and medicinal uses thereof - Google Patents

Abstract

Pyridine compounds represented by general formula (I) or pharmaceutically acceptable salts thereof, wherein each symbol is as defined above; medicinal compositions containing these compounds and pharmaceutically acceptable carriers; medicinal compositions containing the above compounds and antiulcer drugs optionally together with antibiotics or antiprotozoan drugs; a method of preventing or treating digestive diseases which comprises administering the above compounds; and a method of preventing or treating digestive diseases which comprises administering the above compounds and antiulcer drugs optionally together with antibiotics or antiprotozoan drugs. The above compounds are usable for mammals including human beings in preventing and treating various diseases caused by helicobacters, preventing the reoccurrence of ulcer, controlling vomiting and preventing and treating non-ulcer dyspepsia and tumors such as gastric cancer. Moreover, these compounds have inhibitory effects on gastric hydrochloric acid secretion, antiulcer effects, protective effects on gastrointestinal cells, antidiarrheal effects, etc. and, therefore, are useful as preventives and remedies for digestive diseases such as gastric ulcer, duodenal ulcer, gastritis, diarrhea and colon inflammation.

Description

 Specification

 Pyridine compounds and their pharmaceutical uses

 Technical field

 The present invention relates to a novel pyridine compound or a pharmaceutically acceptable salt thereof having an antibacterial action against Helicobacter pylori, a gastric acid secretion inhibitory action, an anti-ulcer action, a gastrointestinal cell protective action, an ulcer relapse prevention action, and the like.

 Further, the present invention provides a pharmaceutical composition comprising the pyridine compound and a pharmaceutically acceptable carrier, a pharmaceutical composition comprising the pyridine compound or a pharmaceutically acceptable salt thereof and an anti-ulcer drug, The present invention relates to a pharmaceutical composition comprising the pyridine compound or a pharmaceutically acceptable salt thereof, an anti-ulcer drug, and an antibiotic or antiprotozoal. Furthermore, a method for preventing or treating a gastrointestinal disease by administering the pyridine compound or a pharmaceutically acceptable salt thereof, and a gastrointestinal disease by administering the pyridine compound or a pharmaceutically acceptable salt thereof and an anti-ulcer drug. And a method for preventing and treating digestive diseases by administering the pyridine compound or a pharmaceutically acceptable salt thereof, an antitumor drug, an antibiotic or an antiprotozoal drug.

 Helicobacter pylori (H. pylori) is a gram-negative bacterium isolated from the gastric mucosa of patients with active chronic gastritis (Warren, JR & Marshall, BJ Lanceti: 1273). -1275, 1983). The bacterium is isolated at a higher rate than gastroduodenal ulcer patients and shows evidence of active gastritis apparently from infection experiments with human volunteers (Morris, A. & Nicholoson, G. Am. J. Gastroenterology, 82 : 192-199, 1987), and experimental animals infected with H. Pylori also show symptoms of gastritis similar to humans. Thus, the association with upper gastrointestinal diseases has become quite clear. Recently, it has been noted as one of the important risk factors for gastric cancer (Parsonnet, J. et al. N. Eng. J. Med. 325: 1127-1131, 1991).

Although the pathogenesis of gastric 'duodenal ulcer by H. Pylori has not been elucidated, it is thought that cytotoxicity of the background gastric mucosa caused by infection with this bacterium contributes to this. It has been studied in terms of bacterial pathogenesis and host-side immune response. Factors on the bacterial side include the cytotoxicity of ammonia caused by urease produced by the bacteria (Hazell SL, Lee A. Lancet ii: 15-17, 1986), as well as the aggressive factors due to degradation of the mucus layer of proteases and lipases J. Slomiany A. & Slomiany BL Scand. J. Gastroenterol. 23: 585-590, 1988), direct cytotoxicity due to vacuolated cytotoxin (Vac A, Cag A) (Figura N., Guglielmetti 0., Rossolini A. et al. J. Clin Microbiol. 27: 225, 1989, Cover TL, Dooley CPk Blaser MJ Infection and Immunity, 58: 603, 1990, Cover TL & Blaser. JJ Biol. Chem. 267: 10570, 1992). On the other hand, the fact that H. Pylori infection stimulates the host immune system means that serum induces specific antibodies against H. Pylori pathogens, and that polynuclear leukocytes, macrophages, This is apparent from the infiltration of inflammatory cells such as spheres. Recently, remarkable enhancement of interleukin-8 production was observed in gastric mucosa infected with H. Pylori, and it has been reported that polynuclear leukocytes migrate and activate (Crabtree JE, Wyatt JI, Trejdosiewics LK et al. Clin. Pathol. 47:61, 1994). As described above, it is considered that the pathogenesis of gastric mucosal damage due to H. Pylori infection is correlated with the harmful factor of bacteria and the immune response induced by persistent infection.

 In recent years, the treatment of gastric and duodenal ulcers has made remarkable progress. However, problems such as recurrence due to drug reduction or discontinuation and drug-resistant intractable ulcer disease are problems. As the involvement of H. Pylori in stomach 'duodenal disease has been pointed out, attempts to eradicate H. Pylori by administration of drugs having antibacterial activity have been considered (Chiba N. et al. Am. J. Gastroenterology 87: 1716-1727, 1992).

The fact that the elimination of H. Pylori significantly suppresses the relapse and recurrence of peptic ulcers supports the relationship between the two. NIH should be eradicated in combination with antibacterial agents in combination with gastric acid secretion inhibitors, regardless of the initial or recurrence of the disease. " Recently, this bacterium has been identified as one of the causes of the pathogenesis leading to the development of gastric cancer. Substance), and the relationship between the two is being widely recognized. In addition, it has been reported that gastric cancer has prevented recurrence of gastric cancer in patients who underwent gastrectomy.

Antibacterial activity against H. Pylori is particularly good among the antibacterial drugs, amoxicillin and clarithromycin. The weak while also antibacterial activity in Purotonbo pump inhibitors such as Omeburazoru is seen, cimetidine, not found in H ₂ receptor antagonists such as famotidine. However, drugs with such antibacterial activity have only a weak clinical effect when administered alone.

 Against this background, vigorous eradication therapy is currently being studied, but many problems still remain before complete eradication therapy can be established. For example, classical triple therapy using bismuth in combination with two antibacterial agents has been studied mainly in Europe and the United States because of its high eradication effect.However, side effects such as diarrhea and central toxicity occur frequently. Bismuth has problems such as not being approved as an anti-ulcer drug in Japan. Therapies with fewer side effects than this eradication method have been studied. Dual therapy using one antibacterial agent (such as amoxicillin or clarithromycin) in combination with a gastric acid secretion inhibitor, and two agents (amoxicillin, clarithromycin, or nitroimidazole) One of two antibacterial agents) New triple therapy in combination has been attempted. Although the incidence of side effects is low with dual therapy, the eradication rate is lower than that of classical triple therapy, amoxicillin cannot be used for patients with penicillin allergies, and eradication fails with Clarice Mouthmycin This raises the problem that the emergence rate of resistant bacteria will be high, and new triple therapy will have a high eradication effect, but the incidence of side effects will be high. All of these eradication methods use large amounts of antibacterial agents that have antibacterial activity on bacteria other than H. Pylori, and thus affect the intestinal bacteria and increase the incidence of diarrhea. Furthermore, it is known that in some patients, oral candidiasis and the like occur due to the effect on bacteria in the oral cavity, and a safe and reliable eradication method has not yet been established.

However, there have been many reports describing the usefulness of eradication of H. Pylor i, and there is a consensus that the eradication healed intractable ulcers and prevented the recurrence of ulcers. In view of the above points, there is a demand for the development of an anti-ulcer agent that has selective antibacterial activity against H. Pylori and has few side effects. From the viewpoint of ulcer healing, it is needless to say that a drug having both an antibacterial activity against H. Pylor i and a gastric acid inhibitory activity is more desirable.

 As compounds having an antibacterial activity against H. Pylori, Japanese Patent Application Laid-Open Nos. 2-20909, 3-385223, 3-48860, Japanese Patent Application Laid-open No. Hei 3-528887, Japanese Patent Laid-open No. Heisei 3-52812, Japanese Patent Laid-open No. Hei 6-110449, International Publication WO92 / 12976 International Publication No.WO 9 3 Z 2 480 0 Publication, International Publication WO 95/118 9 7 Publication, International Publication WO 95 3 545 5 Publication However, compounds having better activity than these compounds are desired.

 In order to solve the above-mentioned problems, the present inventors have conducted various studies. As a result, they have not only selectively excellent antibacterial activity against H. Pylori, but also have an inhibitory effect on gastric acid secretion and anti-inflammatory activity. A compound that also has an ulcer action, a gastrointestinal cell protective action, and an action to prevent relapse of ulcers has been found.Furthermore, the compound of the present invention reflects the antibacterial action in vitro against H. Pylor i. The present inventors have found that Pyl ori has an excellent bactericidal effect, and have completed the present invention.

 Further, the present invention, as seen in two-agent and new three-agent combination therapy, by using a compound represented by the general formula (I) of the present invention in combination with an anti-ulcer drug, preferably a proton pump inhibitor, Alternatively, by using the compound represented by the general formula (I) in combination with an anti-ulcer drug and an antibiotic or an antiprotozoal drug, a clearly superior eradication effect, The present inventors have found that an ulcer effect, an ulcer relapse, and a recurrence prevention effect can be obtained, and the present invention has been completed.

 Disclosure of the invention

That is, the present invention provides a compound represented by the general formula (I):

[Wherein, R is one (CH ₂ -CH ₂ -0) k -D,

(In the formula, represents a haloalkyl, and k represents an integer of 1 to 10.) or one (A-0) m one (B-0) n one D ₂

(In the formula, D ₂ represents haloalkyl, m represents an integer of 1 to 10, n represents an integer of 0 to 10 and A and B may be the same or different and each have a substituent. Good alkylene having 2 to 10 carbon atoms, provided that when n represents 0, A represents alkylene having 3 to 10 carbon atoms, and when n represents an integer of 1 to 10, A and B At least one of them represents an alkylene having 3 to 10 carbon atoms.

R ¹ represents hydrogen, amino, logen, alkyl, alkoxy, hydroxy, alkoxycarbonyl, carboxyl or haloalkyl.

R ² and R ³ are the same or different and each represents hydrogen, halogen, alkyl or alkoxy.

R ⁴ is hydrogen or one CO OR ⁵

(Wherein, R ⁵ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, carboxyalkyl, carbamoylalkyl, monoalkyl-rubumoylalkyl, dialkyl-rubumoylalkyl, alkoxycarbonylalkyl, A phenyl which may have a substituent and an aralkyl which may have a substituent.

Represents a group represented by

 Z and Y are the same or different and represent CH or N, respectively.

P and q are the same or different and each represents 0, 1 or 2. ] Or a pharmaceutically acceptable salt thereof.

 Specific examples of each group in the general formula (I) are as follows.

In R ^1, the halogen denotes chlorine, fluorine, bromine, iodine. Alkyl refers to alkyl having 1 to 20 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, octyl, decyl, dodecyl, octadecyl, and icosyl, and is preferable. Is an alkyl having 1 to 5 carbon atoms, particularly preferably an alkyl having 1 to 3 carbon atoms. Alcoquin is defined as having 1 to 20 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, octyloxy, decyloxy, dodecyloxy, octadecyloxy and eicosiloxy. Represents alkoxy, preferably alkoxy having 1 to 5 carbon atoms, particularly preferably alkoxy having 1 to 3 carbon atoms. Alkoxycarbonyl refers to methoxycarbonyl, ethoxyquincarbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxycarbonyl, isobutynecarbonyl, tertiary butkincarbonyl, pentyloxycarbonyl, hexoxycarbonyl, octyloxycarbonyl. And alkoxycarbonyl having 2 to 20 carbon atoms, such as deoxycarbonyl, dodecyloxycarbonyl, octadecyloxycarbonyl and eicosyloxycarbonyl. Haloalkyl is trifluoromethyl, 2-fluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,3,3-trifluorotrifluoropropyl, 1,2,2 —Tetrafluoroethyl, pentafluoroethyl, 3,3,3—Trifluoropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3 —Pentafluoropropyl, hepta Fluoropropyl, hexafluoroisopropyl, 2,2,3,3,4,4,4-heptafluorobutyl, 2-chloroethyl, 3-chloropropyl pill, 2-bromoethyl, 3-bromopropyl And haloalkyl having 1 to 10 carbon atoms, preferably haloalkyl having 1 to 5 carbon atoms, particularly haloalkyl having 1 to 3 carbon atoms. R ¹ is preferably hydrogen. In R ² and R ³ , examples of the halogen, alkyl and alkoxy are the same as those described for R ′. R ² is preferably alkyl having 1 to 4 carbon atoms, and particularly preferably methyl. R ³ is preferably hydrogen.

Examples of the alkyl and haloalkyl in R ⁵ of COOR ⁵ of R ⁴ are the same as those in R ¹ . Hydroxyalkyl means hydroxymethyl, 1-hydroxyl, 2-hydroxyl, 3-hydroxypropyl, 2,3-dihydroquinpropyl, 4-hydroxylbutyl, etc. Indicates droxyalkyl. Acyloxyalkyl means acetyloxymethyl, propionyloxymethyl, 2-acetyloxyshethyl, 3-acetyloxypropyl, 4-acetyloxybutyl, benzoyloxymethyl, 2-benzo Select from halogen, alkyl, alkoxy, haloalkyl, hydroquine, nitro, and amino for iloxhetyl and phenyl! And benzoyloxymethyl having 2 to 3 substituents, 21-benzoyloxyshethyl and the like. The acrylalkyl is selected from acetylmethyl, propylionylmethyl, 2-acetylethyl, 3-acetylpropyl, 4-acetylbutyl, benzoylmethyl, 2-benzoylethyl, halogen, alkenyl, alkoxy, haloalkyl, hydroxy, nitro, and amino for the phenyl group. _C- carboxyalkyl representing benzoylmethyl having 1 to 3 substituents, 2-benzoylethyl and the like is carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl and the like having 2 to 5 carbon atoms. Represents carboxyalkyl. Alkoxycarbonylalkyl means methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylethyl, isopropoxycarbonylethyl, butoxycarbonylmethyl, isobutoxycarbonylethyl, tertiary butoxycarbonylmethyl, pentyloxycarbonylmethyl, Xyloxy force Rubonylmethyl, octyloxycarbonylmethyl, decyloxycarbonylmethyl, etc. It shows that an alkoxycarbonyl of 0 is bonded to an alkyl having 1 to 4 carbon atoms. Alkoxyalkyl is defined as methoxymethyl, 2-methoxyl, 3-methoxypropyl, 4-methoxybutyl, 2-ethoxyquinethyl, In particular, 3-ethoxyquinbutyl, etc., in which alkoxy having 1 to 10 carbon atoms is bonded to alkyl having 1 to 10 carbon atoms. Lumbamoylalkyl refers to those in which lumbamoyl is bonded to an alkyl having 1 to 10 carbon atoms, such as lumbamoylmethyl, 2-lbumbylethyl, 3-lbumbylpropyl, and 4-lbumbylbutyl. Mono-dialkyl rubamoylalkyl What is N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, 2- (N-methylcarbamoyl) ethyl, 2- (N, N-dimethylcarbamoyl) ethyl, 3- (N —Methylcarbamoyl) propyl, 3— (N, N-dimethylcarbamoyl) propyl, N-ethylcarbamoylmethyl, N, N-getylcarbamoylmethyl, etc., especially those with 1 to 10 carbon atoms. Shown are those bonded to の 10 alkyl. Examples of the substituent of phenyl which may have a substituent and aralkyl which may have a substituent include 1 to 3 groups selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, nitro and amino. can give. Aralkyl of aralkyl which may have a substituent means aralkyl of benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 8-phenyloctyl, etc. Represents an alkyl of 8.

As R ⁵ , alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, dirubamoylalkyl, monoalkylcarbamoylalkyl, dialkyldirubamoylalkyl are preferable, and particularly alkyl, non-alkyl, alkoxy. Alkyl, rubamoylalkyl, monoalkyl rubamoylalkyl, dialkyl rubamoylalkyl are preferred.

Examples of the haloalkyl for D 1, and D ₂ are the same as those described for R ¹ .

Preferably, Z and Y are both CH.

The alkylene having 2 to 10 carbon atoms in A and B means ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, etc., and has an appropriate branched chain. It may be. Examples of the substituent of the alkylene having 2 to 10 carbon atoms which may have a substituent include substituents such as alkyl, haloalkyl, alkoxy, alkoxyalkyl, hydroxy, and hydroxyalkyl. Further, alkylene having 3 to 10 carbon atoms means propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, etc., and may have a branched chain as appropriate. Good. As A and B, alkylenes having 2 to 4 carbon atoms such as ethylene, trimethylene and tetramethylene are preferable.

 p is preferably 0 or 1.

 q is preferably 0.

 k is preferably 2 to 4.

 m is preferably from 3 to 3.

 n is preferably from 0 to 3.

 As the compound of the general formula (I), the compounds of the following two embodiments (1) and (2) are preferable.

 ① General formula (II)

[In the formula, R ′ represents hydrogen, halogen, alkyl, alkoxy, hydroxy, alkoxycarbonyl, carboxyl or haloalkyl.

R ² and R ³ are the same or different and each represents hydrogen, halogen, alkyl or alkoxy.

R ⁴ is hydrogen or one CO OR ⁵

(Wherein, R ⁵ is alkyl, haloalkyl, hydroxyalkyl, alkoxyal Kill, acyloxyalkyl, acylalkyl, carboxyalkyl, carbamoylalkyl, monoalkyllrubamoylalkyl, dialkyllrubamoylalkyl, alkoxycarbonylalkyl, fuynyl which may have a substituent, may have a substituent Indicates an aral kill. )

Represents a group represented by

 D, represents haloalkyl.

 Z and Y are the same or different and represent CH or N, respectively.

 P and Q are the same or different and each represents 0, 1 or 2.

 k represents an integer of 1 to 10; ]

Or a pharmaceutically acceptable salt thereof.

 Also, among the compounds of the general formula (II),

 R ′ is hydrogen, halogen, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, hydroquine or haloalkyl having 1 to 5 carbons,

R ² and R ³ are the same or different and are each hydrogen or an alkyl having 1 to 5 carbon atoms, and the others are the same as described above, and a pyridine compound or a pharmaceutically acceptable salt thereof is more preferable.

 Further, among the compounds of the general formula (II), the compounds of the general formula (IIa)

R ⁴

[In the formula, R represents hydrogen, halogen, alkyl having 1 to 3 carbons, alkoxy, hydroxy, or haloalkyl having 1 to 3 carbons.

R ⁴ is hydrogen or COOR ⁵

(Wherein R ⁵ is alkyl, haloalkyl, hydroquinine alkyl, alkoxyal Kill, acyloxyalkyl, acylalkyl, carboxyalkyl, carbamoylalkyl, monoalkyllrubamoylalkyl, dialkyllrubamoylalkyl, alkoxycarbonylalkyl, phenyl which may have a substituent, may have a substituent Indicates an aral kill. )

Represents a group represented by

 D, represents haloalkyl.

 P represents 0, 1 or 2.

 k represents an integer of 1 to 10; ]

And a pharmaceutically acceptable salt thereof are particularly preferred. Here, in R ^la of the general formula (IIa), the same halogen as R ¹ is exemplified. Examples of the alkyl having 1 to 3 carbon atoms, the alkoxy having 1 to 3 carbon atoms and the haloalkyl having 1 to 3 carbon atoms include those having 1 to 3 carbon atoms among those exemplified for R ¹ .

② General formula (I I I)

 Four

[In the formula, R ′ represents hydrogen, halogen, alkyl, alkyne, hydroxy, alkoxycarbonyl, carboxyl or haloalkyl.

R ² and R ³ are the same or different and each represents hydrogen, halogen, alkyl or alkoxy.

R ⁴ is hydrogen or COOR ⁵

(Wherein, R ⁵ is alkyl, haloalkyl, hydroquinine alkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, carboquinalkyl carbamo Examples thereof include ylalkyl, monoalkyl rubamoylalkyl, dialkyl rubamoylalkyl, alkoxycarbonylalkyl, phenyl which may have a substituent, and aralkyl which may have a substituent. )

Represents a group represented by

D ₂ represents haloalkyl.

 Z and Y are the same or different and represent CH or N, respectively.

 P and q are the same or different and each represents 0, 1 or 2. ]

 m represents an integer of 1 to 10.

 n represents an integer of 0 to 10.

 A and B are the same or different and each may have a substituent. It represents alkylene of 0.

 However, when n represents 0, A represents alkylene having 3 to 10 carbon atoms, and when n represents an integer of 10 to M, at least one of A and B is an alkylene having 3 to 10 carbon atoms. To indicate ]

Or a pharmaceutically acceptable salt thereof.

 Further, among the compounds of the general formula (I I I),

R ¹ is hydrogen, halogen, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, hydroxy or haloalkyl having 1 to 5 carbons,

R ² and R ³ are the same or different, each is hydrogen or alkyl having 1 to 5 carbon atoms, and the other is the same as described above, more preferably a pyridine compound or a pharmaceutically acceptable salt thereof.

Further, among the compounds of the general formula (III),

[In the formula, R ^la represents hydrogen, halogen, alkyl having 1 to 3 carbons, alkoxy, hydroxy or haloalkyl having 1 to 3 carbons.

R ⁴ is hydrogen or — COOR ⁵

(Wherein, R ⁵ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, carboxyalkyl, carbamoylalkyl, monoalkyl rubamoylalkyl, dialkyl rubamoylalkyl, alkoxycarbonylalkyl, A phenyl which may have a substituent and an aralkyl which may have a substituent.

Represents a group represented by

D ₂ represents haloalkyl.

 P represents 0, 1 or 2.

 m represents an integer of 1 to 10.

 n represents an integer of 0 to 10.

 However, when n represents 0, A represents an alkylene having 3 to 10 carbon atoms, and when n represents 1 and an integer of 10 or more, at least one of A and B has 3 to 0 carbon atoms. Indicates alkylene. And a pharmaceutically acceptable salt thereof are particularly preferred.

Here, the general formula (I lia) of R ^'a halogen, alkyl of 1 to 3 carbon atoms, a haloalkyl having a carbon number of 1 to 3 alkoxy and the number of carbon atoms from 1 to 3, respectively, the general formula (II a) It includes the R 'those exemplified ^a.

Among the general formula (I), the following compounds are most preferred. 2-((3-Methyl-1-41) (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) -1-pyridyl) methylsulfanyl) 1 1H Midazo,

 2 — ((3-Methyl-4— (2— (2— (2_ (2,2,2-trifluoroethoxy) ethokine) ethokine) ethylsulfanyl) 1-2_pyridyl) methylsulfanyl) — 1 H— Benzomidazole,

 2 — ((3-Methyl-4— (4_ (2,2,2-tritrifluoroethoxy) butylsulfanyl) -12-pyridyl) methylsulfanyl) —1H-benzoimidazole,

 2-((4- (2- (2-chloroethyne) ethylsulfanyl) -1-3-methyl-2-pyridyl) methylsulfanyl)-1H-benzimidazole,

 1-ethoxycarbonyl-1-((3-methyl-4-1 (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) -1-pyridyl) methylsulfanyl) 1 H—Benzoi midazole,

 1—Methoxycarboxy 2 — ((3-Methyl-4-1 (2- (2— (2,2,2-tritrifluoroethoxy) ethoxy) ethylsulfanyl) -1-2-Pyridyl) methylsulfanyl) 1 H—Benzo Midazo,

 1—Tertiary butoxycarbonyl 2 -— ((3-Methyl-4-1 (2- (2- (2,2,2-Tritrifluoroethoxy) ethoxy) Ethylsulfanyl) 1-2-Pyridyl) Methylsulfanyl) 1 H-benzimidazole,

 1 1 (2-Methoxyxetoxycarbonyl) 1 2— ((3-Methyl-4— (2— (2— (2,2,2—Trifluoroethoxy) Ethkin) Ethylsulfanyl) — 2-Pyridyl ) Methylsulfanyl) _ 1 H-benzimidazole,

1 1 (2,2,2-Trifluoroethoxycarbonyl) 1 2 — ((3-Methyl 1-4-1 (2— (2— (2,2,2—Trifluoroethoxy) ethkin) Ethils ruphanyl) 1 2-pyridyl) methylsulfanyl) 1 1H-benzoid midazole, 1- (N, N-dimethylcarbamoylmethoxycarbonyl) 1-2-((3-methyl-14- (2- (2- (2,2,2-trifluorotrifluoroethoxy) ethoxyquin) ethylsulfanyl) — 2-pyridyl) methylsulfanyl) 1 H-benzoimidazole,

 2— ((3-Methyl-4— (2— (2- (2,2-Difluoroethoxy) ethoxy) Ethylsulfanyl) -1-2-Pyridyl) Methylsulfanyl) — 1H—Benzomidazole,

 2-((3-Methyl-1-41- (2- (2- (2-Fluoroethoxy) ethoxy) Ethylsulfanyl) -1-2-Pyridyl) methylsulfanyl) 1-1H-Benzimidazole, and

 2-((3-Methyl-1-41) (2- (2- (2,2,2-Trifluoroethoxy) ethoxy) ethylsulfanyl) -1-2-Pyridyl) methylsulfinyl) 1H-Henzomidazole.

 When the compound of the general formula (I) has an asymmetric atom, at least two types of optical isomers exist. These optical isomers and their racemates are included in the present invention. In addition, cis isomers, trans isomers, and mixtures thereof are also included. Pharmaceutically acceptable salts of the compounds of general formula (I) include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, phosphate, citrate, maleate Acid addition salts such as acid salts, fumarate, malonate, malate, tartrate, succinate, methanesulfonate, benzenesulfonate, alkali metal salts such as sodium salt, potassium salt, calcium And alkaline earth metal salts such as magnesium salts. The compounds of the present invention also exist as hydrates (hemihydrate, monohydrate, sesquihydrate and the like) and solvates, and these are also included in the present invention.

 —The compound of the general formula (I) can be produced as follows.

Method 1

General formula (IV)

(In the formula, each symbol is as defined above.)

And a compound represented by the general formula (V)

[In the formula, W represents a reactive atom or group (sulfonyloxy group such as halogen or methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.), and other symbols are as defined above. is there. ]

Or a compound of the general formula (I) wherein p is 0 by reacting the compound represented by

 (0) q

(1 -1)

(In the formula, each symbol is as defined above.)

 The compound represented by is obtained.

The reaction between the compound of the general formula (IV) and the compound of the general formula (V) is usually inert. In a solvent (water or methanol, ethanol, dimethylformamide, or a mixed solvent thereof, preferably aqueous ethanol), a base (sodium hydroxide, hydroxide hydroxide, sodium hydride, hydrogenation catalyst) Temperature from about 0 ° C to the boiling point of the solvent used, preferably 20 ° C to 80 ° C, in the presence of lium, sodium methoxide, sodium carbonate, potassium carbonate, metallic sodium, triethylamine, pyridine and the like. in ° C, about 1 0 minutes to 2 4 hours, preferably _c also proceeds at 3 0 minutes to 7 hours, the acid addition salts of the compounds of general formula (V), hydrochloride salt, hydrobromic acid salt mentioned Can be

 Next, the compound of the general formula (I) in which is 1 or 2 is produced by subjecting the compound of the general formula (I-1) in which p is 0 to an oxidation reaction.

 Examples of the oxidizing agent used in the oxidation reaction include metabenzo-perbenzoic acid, peracetic acid, trifluoroperacetic acid, permalic acid, potassium superoxide, sodium hypobromite, sodium hypobromite, and hydrogen peroxide. Can be The reaction is usually carried out in a solvent inert to the reaction (water or dichloromethane, chloroform, tetrahydrofuran, dioxane, dimethylformamide or a mixture thereof) in an organic acid (formic acid, acetic acid, propionic acid, butyric acid, Temperature from 170 ° C to the boiling point of the solvent used in the presence of maleic acid, fumaric acid, malonic acid, succinic acid, benzoic acid, metachlorobenzoic acid, P-nitrobenzoic acid, phthalic acid, etc. Preferably at a temperature of 50 ° C to room temperature, more preferably at a temperature of 20 ° C to 0 ° C for about 5 minutes to 24 hours, preferably about 5 minutes to 20 hours, or water or ethanol, In an alcoholic solvent such as methanol or propanol, in the presence of a base (alkali hydroxide such as sodium hydroxide, potassium hydroxide or calcium hydroxide), the temperature is reduced to 170 ° C. Temperature up to the boiling point of the solvent used, usually from 150 ° C to room temperature, preferably from 120 ° C to 10 ° C, for about 5 minutes to 24 hours, preferably from 1 hour to 10 hours. Do.

Method 2

General formula (I-I-2) (1-2)

(In the formula, each symbol is as defined above.)

And a compound represented by the general formula (V I)

R ⁵ 0- C 0-H a 1 (VI)

(In the formula, Ha represents a halogen, and R ⁵ has the same meaning as described above.)

Or a compound represented by the general formula (V I I)

_{^{(R 5 0 - CO) 2}} 0 (VII) ( wherein, R ⁵ is as defined above.)

Reacting the compound represented by the general formula (I-I) with the compound represented by the general formula (I-I)

 R for OH (V I I I)

(Wherein, R ⁵ has the same meaning as described above.)

Is reacted in the presence of phosgene to give R ⁴

-COOR ⁵ (wherein R ⁵ is as defined above), of the general formula (I)

(p = 0) is manufactured.

 Examples of the deoxidizing agent include sodium hydride, sodium hydroxide, potassium hydroxide, sodium methylate, potassium carbonate, and metallic sodium.

 The reaction is usually carried out in an inert solvent (N, N-dimethylformamide, ethanol, methanol, methanol, dichloromethane, water, etc.) at a temperature of less than 20 ° C.

140 ° C., preferably at 0 ° C. to 80 ° C., for about 10 minutes to 24 hours, preferably

It takes 30 minutes to 6 hours.

Method 3 Substituents R ', by hydrolyzing a compound of general formula (I one 1) with an acid or base having an ester group in R ^4, the compounds of general formula (I one 1) having a corresponding carboxylic acid group is prepared Is done.

 The compound of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method and a column chromatography method. When the resulting product is a racemic form, it is separated into the desired optically active form, for example, by fractional recrystallization of a salt with an optically active acid or by passing through a column filled with an optically active carrier. Can be. Individual diastereomers can be separated by such means as fractional crystallization, chromatography and the like. These can also be obtained by using optically active starting compounds and the like. Stereoisomers can be isolated by a recrystallization method, a column chromatography method, or the like.

 The compound of the general formula (I) of the present invention includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, maleic acid, fumaric acid, malonic acid, malic acid, tartaric acid, The above-mentioned acid addition salt can be obtained by treating with succinic acid, methanesulfonic acid, benzenesulfonic acid or the like in a conventional manner. The corresponding metal salt can be obtained by reacting with sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and the like. Further, when the obtained crystals of the compound of the present invention are anhydrous, a hydrate or a solvate can be obtained by treating the compound of the present invention with water, an aqueous solvent or another solvent.

 The compound of the general formula (V) can be produced, for example, according to the following reaction route.

Hydrolysis

CH;

0 (IX) (X) (0) q (0) q

 Small

R ² S-RS -R

 Halogenation

 Or

HOCH: A sulfonylation W-CH ₂ eight N

 (XI) (V)

(In the above reaction pathway, Ac represents acetyl, and other symbols are as defined above.)

 That is, the compound of the general formula (IX) is heated with acetic anhydride, and the obtained compound of the general formula (X) is hydrolyzed using sodium hydroxide or the like to obtain a compound of the general formula (XI). Then, by treating this with a halogenating agent such as thionyl chloride or a sulfonylating agent such as methanesulfonyl chloride, a compound of the general formula (V) is obtained.

 Further, the compound in which Q is 0 in the general formula (IX) can be produced, for example, according to the following reaction scheme.

SH S -R

W'-R (XIII) click CH ₃ eight

 (XII) 0 (IX-1)

(In the above reaction, represents a leaving group such as chlorine, bromine, iodine, methanesulfonyloxyquin, p-toluenesulfonyloxy, and other symbols are as defined above.)

Or, W

w ² R ² S -R

 HS-R (XV)

CH _; CH ₂

 (XIV) (IX-1)

(In the above reaction, w ² represents chlorine, bromine, iodine or nitro, and other symbols are as defined above.)

 In any of the above reactions, the reaction is usually carried out in a solvent that is inert to the reaction (water or alcohols such as methanol or ethanol, chloroform, dichloromethane, benzene, toluene, dimethylformamide, or a mixture thereof). Used from about o ° c in the presence of a base (sodium hydroxide, hydroxide hydroxide, sodium hydride, sodium methoxide, sodium methoxide, sodium carbonate, potassium carbonate, metal sodium, triethylamine, pyridine, etc.) It proceeds at a temperature up to the boiling point of the solvent, preferably 20 to 80, for about 10 minutes to 24 hours, preferably 30 minutes to 7 hours.

 The compound of the general formula (IX) in which q is 1 or 2 can be produced by subjecting the compound of the general formula (IX) in which Q is 0 to an oxidation reaction. Oxidizing agents used in the oxidation reaction include metabenzo-perbenzoic acid, peracetic acid, trifluoroperacetic acid, permalic acid, superoxide, sodium hypobromite, sodium hypobromite, hydrogen peroxide, etc. Is raised. The reaction is usually carried out in a solvent inert to the reaction (water or dichloromethane, chloroform, tetrahydrofuran, dioxane, dimethylformamide or a mixture thereof) and an organic acid (formic acid, acetic acid, propionic acid, maleic acid). Acid, fumaric acid, malonic acid, succinic acid, benzoic acid, metachlorobenzoic acid, p-nitrobenzoic acid, phthalic acid, etc.) in a temperature range from 170 ° C to the boiling point of the solvent used, preferably — Performed at 50 ° C. to room temperature, more preferably at 20 ° C. to 0 ° C., for about 5 minutes to 24 hours, preferably for about 5 minutes to 20 hours.

The compounds of W'—R (XIII) and HS—R (XV) Can be produced according to the reaction route shown in

D-0H

H0-EW ³ H0-R

 (XVI) (XVII) Halogenated

 W-R HS-R

 Or

 Sulfonylation (XV)

[In the above reaction, W ³ represents a reactive atom or group (sulfonyloxy group such as halogen or methanesulfonyloxy, benzenesulfonyloxy, ρ-toluenesulfonyloquine, etc.), and E represents one (CH ₂ CH ₂ 0) k—or—

(A—O) m— (B—O) n—, D represents D or D ₂ , and other symbols are as defined above. ]

 That is, the compound of the general formula (XVI) is reacted with an alcohol corresponding to the haloalkyl in D in the presence of a deoxidizing agent such as sodium hydride and sodium metal, and the obtained compound of the general formula (XVII) is treated with thionyl chloride. By treating with a halogenating agent such as chloride or treating with a sulfonylating agent such as methanesulfonyl chloride, a compound of the general formula (XIII) can be obtained. The compound of the general formula (XV) can be obtained by reacting with thiourea and then thiolating by hydrolysis using sodium hydroxide or the like.

 Alternatively, a compound having a removable alcohol protecting group may be used instead of the compound of the general formula (XVI), and the compound may be reacted with an alcohol to remove the protecting group. ) Can be produced.

 The eliminable alcohol protecting group is a general protecting group, for example, acetyl, tetrahydroviranyl, etc., and the elimination method includes acid or alcohol hydrolysis.

The compound (I) of the present invention and a pharmaceutically acceptable salt thereof are represented by Pylori. Selective antibacterial activity against Helicobacter bacteria, and also shows good eradication activity in H. Pylori-infected animal models, indicating that various infectious diseases such as gastritis and gastric ulcer caused by Helicobacter bacteria. It is effective for prevention and treatment of Namely, the compound of the present invention represented by the general formula (I) and a pharmaceutically acceptable salt thereof are useful for preventing and treating various diseases caused by Helicobacter genus and preventing recurrence of ulcers in mammals including humans. It is used to prevent vomiting, prevent and treat non-ulcer dyspepsia, and prevent and treat tumors (such as gastric cancer). In addition, the compound (I) of the present invention and a pharmaceutically acceptable salt thereof have a gastric acid secretion inhibitory action, an anti-hampering action, a gastrointestinal cell protecting action, an anti-diarrheal action, and the like. It is useful for the prevention and treatment of duodenal ulcer, gastritis, diarrhea, colitis, etc.). Furthermore, it has low toxicity, is stable against acids, etc., and has characteristics such as a small increase in blood gastrin level.

 Furthermore, the present invention relates to the use of a compound represented by the general formula (I) of the present invention in combination with an anti-ulcer drug, preferably a proton pump inhibitor, as seen in two-drug and new-drug combination therapy. In addition, by using the compound represented by the general formula (I) of the present invention together with an anti-ulcer drug and an antibiotic or antiprotozoal, a clearly superior eradication effect can be obtained with each drug alone. , Anti-hamlet effect, ulcer relapse and recurrence prevention effect.

The antiulcer drugs to be used in the present invention together with the above compound (I), pro Tonbon flop inhibitors, histamine H ₂ antagonists, and the like protective factor enhancer. Specific examples of the proton pump inhibitor include omebrazole, lansoprazole, pantoprazole, parabrazole and the like. Is a specific example of Hisutami emissions H ₂ antagonists, cimetidine, ranitidine, famotidine, Ru is like mouth Kisachijin. Specific examples of the protective factor enhancer include cetraxate hydrochloride, sucralfate, ecabapide, prostaglandin derivatives (misoprostol, ornoprosteel, etc.).

The medicament of the present invention includes an antibiotic or an antibiotic together with the compound (I) and the anti-ulcer drug. Is an antiprotozoal drug. Specific examples of antibiotics include, in particular, antibacterial antibiotics such as amoxicillin, clarithromycin, ampicillin or its prodrug. Specific examples of antiprotozoal drugs include metronidazole, tinidazole and the like. These drugs can preferably use a commercially available preparation.

The dose of Compound (I) is appropriately selected depending on the type and symptoms of gastritis and peptic ulcer. Compound (I) having an anti-H. Pylori action is 0.1 to 50 mg / kg ZB, preferably 0.3 to 0.3. 11 OmgZkg days can be administered. On the other hand, in the case of a proton pump inhibitor, the antiulcer drug to be used in combination is administered at 0.01 to 1 OmgZkg / day, preferably at 0.1 to 1.0 mgZkg day. For Hisuta Mi emissions H ₂ antagonists 0. 1~1 0 Omg / k gZ day, preferably administered 1~1 OmgZk gZ date. In the case of a protective factor enhancer, the dose is 1.0 to 10 OmgZkgZ days, preferably 10 to 50 mg / kg / day. In addition, antibiotics to be used in combination are 0.1 to 10 Omg / kg day, preferably 5 to 3 OmgZkg days, and antiprotozoal drugs are 0.1 to 1 OmgZk gZ days, preferably 1 to 10 OmgZk gZ days. Is administered.

 Compound (I) is mixed with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, solubilizing agent, etc.) to form a pharmaceutical composition, Tablets, pills, powders, granules, capsules, troches, syrups, solutions, emulsions, suspensions, injections (solutions, suspensions, etc.), suppositories, inhalants, transdermal absorbers, eye drops Or parenteral formulation as a preparation such as an ointment or an ointment.

In the case of a solid preparation, carriers include, for example, sucrose, lactose, cellulose sugar, D-mannitol, maltitol, dextran, starches, agar, alginate, chitins, chitosans, pectins, Tran gum, gum arabic, gelatin, collagen, casein, albumin, calcium phosphate, sonorebitol, glycine, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxyquinpropylmethylcellulose, Glycerin, polyethylene glycol, sodium bicarbonate, magnesium stearate, Luk or the like is used. Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets or multilayer tablets.

 In the case of semi-solid preparations, animal and vegetable oils (oil, corn oil, castor oil, etc.), mineral oils (vaseline, white petrolatum, solid paraffin, etc.), waxes (jojoba) Oils, carnauba wax, beeswax, etc.), partially or totally synthesized glycerin fatty acid esters (lauric acid, myristic acid, palmitic acid, etc.) are used. Examples of these commercially available products include Witepsol (manufactured by Dynamid Nobel), Pharmasol (manufactured by NOF Corporation), and the like. In the case of a liquid preparation, examples of the carrier include sodium chloride, glucose, sorbitol, glycerin, olive oil, propylene glycol, and ethyl alcohol. In particular, in the case of an injection, a sterile aqueous solution such as physiological saline, isotonic solution, or oily solution such as sesame oil or soybean oil is used. If necessary, a suitable suspending agent such as sodium carboxymethyl cellulose, a nonionic surfactant, a solubilizing agent such as benzyl benzoate or benzyl alcohol may be used in combination.

 Further, the above pharmaceutical composition may further contain an anti-ulcer drug, or may contain an anti-ulcer drug and an antibacterial substance or an antiprotozoal drug.

 Hereinafter, the present invention will be specifically described with reference to raw material preparation examples, examples, formulation examples, and experimental examples, but the present invention is not limited thereto.

Raw material preparation example 1

C 1-(CH ₂ CH ₂ 0) ₂ -CH ₂ CF ₃

(1) 2, 2, 2 — Trifluoroethanol 35 g 1 at room temperature with stirring, slowly add 2.2 g of sodium metal, and heat to 70 ° C to completely dissolve. 2— (2— (2-ethylenquin) ethoxy) Add 20 g of tetrahydropyran and return for 2 days Shed. After completion of the reaction, excess 2,2,2-trifluoroethanol was distilled off, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and hexane: ethyl acetate = 5: 1 was distilled out to give a colorless oily 2- (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethoxy) ethoxy ) 10.5 g of tetrahydropyran was obtained.

 'H-NMRCCDCI: δ (ppm) = l.50-1.90 (m, 6H), 3.46-3.90 (m, 10H), 3.93 (q, 2H), 4.63 (dd, 1H)

 (2) 2- (2- (2- (2,2,2-trifluoroethyl) ethoxy) ethoxy) tetrahydropyran obtained in (1) was obtained by adding 0.5 g of methanol: dichloromethane = 1: 1. Was dissolved in 200 ml of a mixed solvent of the above, 2.3 ml of concentrated hydrochloric acid was added dropwise with stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized by adding 11 g of sodium hydrogen carbonate, and the solvent was distilled off. Then, ethyl ether was added to remove the insoluble matter, and the solvent was distilled off to remove 2 -— (2 -— (2 7.3 g of 2,2,2-trifluoroquinone) etokine) ethanol was obtained.

 'H-NMRCCDCla): 5 (ppm) = 2.31 (s, 1H), 3.60-3.82 (m, 8H), 3.91 (q, 2H)

 (3) Dissolve 7.3 g of 2- (2- (2,2,2-trifluoroethyl) ethoxy) ethanol obtained in (2) in 3.4 ml of pyridine and chloride under ice-cooling. 3. lml of thionyl was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water, extracted with getyl ether, and washed with water. The getyl ether layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 6.9 g of 2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethyl chloride as a yellow oil. .

 'H-NMRCCDC): δ (ppm) = 3.60-3.85 (m, 8H), 3.92 (q, 2H)

 The following compounds can be obtained in the same manner as in the above-mentioned raw material preparation example 1.

 • 2-(2— (2-(2, 2, 2—Trifluoroetkin) Etkin) Ethoxy)

• 4— (2,2,2—Trifluoroetkin) butyl chloride • 2-(2-black ethoxy) ethyl lip

 • 2— (2— (2—Trifluorometoxetoxy) Etkin)

 • 2— (2— trifluoromethyl ethoxylate)

 • 2— (2— (2,2-difluoroethoxy) ethoxy)

• 2-(2— (2-fluoroethoxy) Etkin)

 • 2— (2— (3, 3, 3—Trifluoropropoxy) Etkin) Ethyl chloride

 • 2-(2— (2-black ethoxy) ethoxy)

 • 2— (2— (2-bromoethoxy) ethoxy) ethyl lip

 • 3— (3— (2, 2, 2—Trifluoroethoxy) Provoquine) Propyl chloride

 • 4— (4— (2, 2, 2—Trifluoroethoxy) Butoxy) Butyl Chlorai F

 • 3— (2— (2, 2, 2—Trifluoroethoxy) Etkin) Provir chloride

 • 2 _ (3— (2, 2, 2—Trifluoroetkin) Proboxy) Ethyl chloride

 • 4— (2— (2, 2, 2—Trifluoroetkin) Etkin) Butyl Chlorai F

 • 2- (4- (2,2,2-trifluoroethoxy) butoxy) ethyl chloride Raw material preparation example A

2， 3 —ジメチルー 4—メルカプトピリジン一 N—ォキシド 5. 2 gをェタノ ール 8 0 m 1 に溶解し、 原料調製例 1で得られた 2— （2 — ( 2 , 2 , 2 — トリ フルォロエトキン） ェトキシ） ェチルク口ライ ド 6. 9 gおよび水 5 m 1に溶解 した水酸化ナトリウム 2. O gを加え、 8. 5時間攪拌還流した。 冷却後、 エタ ノールを留去し、 水を加えて酢酸ェチルで抽出した。 酢酸ェチル層を無水硫酸マ グネシゥムで乾燥し、 溶媒を留去することによって黄褐色油状の 2， 3 —ジメチ ル一 4一 （2 — （2 — (2， 2 , 2 _ トリフルォロエトキン） エトキシ） ェチル スルファニル） ピリジン一 N—ォキシド 6. 4 gを得た。

5.2 g of 2,3-dimethyl-4-mercaptopyridine-N-oxide was dissolved in 80 ml of ethanol, and 2- (2— (2,2,2—tri) obtained in Raw Material Preparation Example 1 was obtained. Fluoroquine) ethoxy) ethyl chloride mouth light (6.9 g) and sodium hydroxide (2.0 g) dissolved in water (5 ml) were added, and the mixture was stirred and refluxed for 8.5 hours. After cooling, ethanol was distilled off, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation to give a yellow-brown oily 2,3-dimethyl-2-41 (2 — (2 — (2,2,2_trifluoroetkin)) 6.4 g of ethoxy) ethylsulfanyl) pyridine-N-oxide were obtained.

_{'H-NMR (CDC1 3)} : δ (ppm) = 2.34 (s, 3H), 2.55 (s, 3H), 3.15 (t, 2H), 3.60 - 3.82 (m, 6H), 3.90 (q, 2H) , 7.03 (d, 1H), 8.10 (d, 1H)

Raw material preparation example B

 0 In Raw Material Preparation Example A, instead of 2 — (2— (2,2,2-trifluoroethoxy) ethoxy) ethyl chloride, 2— (2— (2— (2,2,2-tritrifluoroethoxykin) ) Ethkin) Ethoxy) Ethyl chloride and 2,3-dimethyl 4- — (2- (2--(2-(2, 2, 2 — trifluoroethoxy) ethoxy) in the same manner as in Raw Material Preparation Example A ) Ethoxy) ethylsulfanyl) pyridine

N-oxide was obtained.

_{'HN R (CDC1 3):} δ (ppm) = 2.34 (s, 3H), 2.55 (s, 3H), 3.15 (t, 2H), 3.65-3.80 (m, 10H), 3.91 (q, 2H), 7.03 (d, 1H), 8.10 (d, 1H) Raw material preparation example c

_{S - CH 2 CH 2 CH 2} CH 2 - 0- CH 2 CF 3

 0 In Raw Material Preparation Example A, instead of 2-((2- (2,2,2-trifluoroethoxy) ethoxy) ethyl chloride, 4- (2,2,2-trifluoroethoxy) butyl chloride 2,3-Dimethyl-4-1 (4-1 (2,2,2-trifluoroethyl) butylsulfanyl) pyridine-1-N-oxide was obtained in the same manner as in Raw Material Preparation Example A using Was.

_{'H-NMR (CDC1 3)} :. Δ (ppm) = l.48-1.90 (m, 4H), 2.32 (s, 3H), 2.55 (s, 3H), 2.90-3 04 (m, 2H), 3.58 (t, 2H), 3.80 (q, 2H), 6.94 (d, 1H), 8.10 (d, 1H)

Raw material preparation example D

 0 In Raw Material Preparation Example A, instead of using 2- (2- (2,2,2-trifluoroethyl) ethoxy) ethyl chloride, use 2- (2-cycloethylethoxy) ethyl chloride instead of In the same manner as in Raw Material Preparation Example A, 4- (2- (2-chloroethoxy) ethylsulfanyl) -1,2,3-dimethylviridine-1-N-oxide was obtained.

'H-NMR (CDCh): δ (ppm) = 2.53 (s, 3H), 2.56 (s, 3H), 3.10-3.20 (m, 2H), 3.60-3.75 (m, 6H), 7.06 (d, lH ), 8.10 (d, 1H) Raw material preparation example E

 In Raw Material Preparation Example A, instead of 2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethyl chloride, replace 2- (2- (2-trifluorotrifluoroethoxy) ethoxy) ethyl chloride Is used to obtain 2,3-dimethyl-1- (2- (2- (2-trifluoromethoxetoxy) ethoxy) ethylsulfanyl) pyridine-1-N-oxide in the same manner as in Raw Material Preparation Example A.

Raw material preparation example F

 In the raw material preparation example A, the raw material preparation was carried out by using 2- (2-trifluoromethyloxy) ethyl chloride instead of 2- (2- (2,2,2-trifluoroethoxy) ethoxy chloride) ethyl chloride. In the same manner as in Example A, 2,3-dimethyl-1-4- (2- (2-trifluoromethyloxetoxy) ethylsulfanyl) pyridine-1-N-oxide is obtained.

Raw material preparation example G

 In Raw Material Preparation Example A, instead of 2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethyl chloride, replace 2- (2- (2,2-difluoroethoxy) ethoxy) ethylchlory 2,3-Dimethyl-4- (2- (2- (2,2-difluoroethoxy) ethoxy) ethylsulfanyl) pyridine-N-oxide in the same manner as in Raw Material Preparation Example A obtain.

 Raw material preparation example H

 In Preparation Example A, use 2- (2- (2,2,2-trifluoroethoxy) ethoxy chloride) ethyl chloride instead of 2- (2- (2,2,2-trifluoroethyl) ethoxy chloride) ethyl chloride. In the same manner as in Raw Material Preparation Example A, 2,3-dimethyl-4- (2- (2- (2-fluoroethoxy) ethoxyquin) ethylsulfanyl) pyridine-N-methyl oxide is obtained.

 Raw material preparation example I

In Raw Material Preparation Example A, 2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethyl chloride is replaced with 2- (2- (3,3,3-trifluorofluoride). 2,3-Dimethyl-14- (2- (2— (3,3,3—trifluoropropoxy) ethkin) in the same manner as in Raw Material Preparation Example A using propoxy) ethoxy) ethyl chloride Tylsulfanyl) Pyridine-1 N-year-old oxide is obtained.

Raw material preparation example J

 In Raw Material Preparation Example A, instead of 2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethyl chloride, 2- (2— (2-chloro-2-ethoxyquin) ethoxy) ethyl chloride In the same manner as in Raw Material Preparation Example A, 2,3-dimethyl-2- (2- (2- (2-chloroethoxy) ethoxy) ethoxy) ethylsulfanyl) pyridine-N-oxide is obtained.

Raw material preparation example K

 In Raw Material Preparation Example A, use 2- (2- (2- (2-bromoethoxy) ethoxy) ethyl chloride instead of 2— (2- (2,2,2-trifluoroethyl) ethoxy) ethyl chloride. In the same manner as in Raw Material Preparation Example A, 2,3-dimethyl-2- (2- (2- (2-bromoethoxy) ethoxy) ethylsulfanyl) pyridine-1-N-oxide is obtained.

Raw material preparation example L

 In Raw Material Preparation Example A, instead of 2-((2- (2,2,2-trifluoroethoxy) ethoxy) ethyl chloride, 3— (3— (2,2,2-trifluorotrifluoro) propoxy) propyl 2,3-Dimethyl-4-((3- (3- (2,2,2-trifluoroethoxy) propoxy) propylsulfanyl) pyridine in the same manner as in Preparation A of raw material using chloride Get one N-oxide.

Raw material preparation example M

In Raw Material Preparation Example A, instead of 2- (2- (2,2,2-trifluoroethyl) ethoxy) ethyl chloride, 4- (2- (2,2,2-trifluoroethyl) butoxy) butyl chloride 2,3-Dimethyl-4 — (4 — (4 — (2,2,2 — trifluoroethoxy) butoxy) butylsulfanyl) pyridine-N— Get oxide. Raw material preparation example N

 In Raw Material Preparation Example A, instead of 2- (2- (2,2,2-trifluoroethyl) ethoxy) ethyl chloride, 3- (2- (2,2,2, -trifluoroethyl) ethoxy) propyl 2,3-Dimethyl-1-4- (3- (2- (2,2,2-trifluoroethoxy) ethoxyquin) propylsulfanyl) pyridine Obtain N-oxide.

Raw material preparation example 0

 In raw material preparation example A, instead of 2- (2- (2,2,2-trifluoroethyl) ethoxy chloride) ethyl chloride, 2- (3- (2,2,2-trifluorotrifluoroethoxy) propoxy) ethyl chloride 2,3-Dimethyl-1- (2- (3- (2,2,2-trifluoroethoxy) propoxy) ethylsulfanyl) pyridine-N in the same manner as in Raw Material Preparation Example A —Get the oxide.

Raw material preparation example P

 In raw material preparation example A, instead of 2-((2- (2,2,2-trifluoroethyl) ethoxy) ethyl chloride, 4- (2- (2,2,2-trifluoroethyl) ethoxyquin) butyl chloride 2,3-Dimethyl-4- (4-1 (2- (2,2,2-trifluoroethoxy) ethoxy) butylsulfanyl) pyridine-N in the same manner as in Raw Material Preparation Example A Get oxide.

 Raw material preparation example Q

 In Raw Material Preparation Example A, 2- (4- (2,2,2-trifluoroethyl) ethoxy chloride) was replaced with 2- (4- (2,2,2-trifluoroethyl) butoxy) ethyl chloride. 2,3-dimethyl-1- (2- (4- (2,2,2-trifluoroethoxy) butoxy) ethylsulfanyl) pyridine Obtain N-oxide.

 Raw material preparation example R

In Raw Material Preparation Example A, instead of 2,3-dimethyl-4-mercaptopyridine-N-oxide, 2,5-dimethyl-14-mercaptopyridine-N-oxide 2,5-Dimethyl-4- (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) pyridin-1 N- Get oxide.

Raw material preparation example S

 In the same manner as in Raw Material Preparation Example A, except that 2,6-dimethyl-4-mercaptopyridine-1N-oxide is replaced with 2,6-dimethyl-14-mercaptopyridine-1N-oxide in Raw Material Preparation Example A This gives 2,6-dimethyl-4- (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) pyridin-1-N-oxide.

Raw material preparation example T

 In Preparation A of Raw Material, Preparation of Raw Material A was prepared by using 4-mercapto-1,2,3,5—trimethylpyridine-1-N-oxide instead of 2,3-dimethyl-4-mercaptopyridine-N-oxide. In the same manner as described above, 4- (2- (2- (2,2,2-trifluorotrifluoroethoxy) ethoxy) ethylsulfanyl) -1,2,3,5-trimethylpyridine-1-N-oxide is obtained.

Raw material preparation example U

 In the same manner as in the preparation of the raw material A, but in place of the 2,3-dimethyl-4-mercaptopyridine-1N-oxide in the preparation of the raw material A, using 4-mercapto-12-methylpyridine-1-N-oxide. 2-Methyl- 4- (2- (2-(2,2,2-1-trifluoroethoxy) ethoxyquin) ethylsulfanyl) pyridine-1-N-oxide is obtained.

Raw material preparation example V

In Preparation Example A, using Preparation Example A instead of 2,3-Dimethyl-4-mercaptopyridine-1-N-oxide instead of 4-Mercapto-13-methoxy-12-methylpyridine-1-N-oxide. In a similar manner, 3-methoxy-2-methyl-4- (2- (2- (2,2,2-trifluoroethyl) ethyn) ethylsulfanyl) pyridine-N-oxide is obtained. Raw material preparation example w

 In Preparation A of Raw Material, Preparation of Raw Material A using 3-ethyl-14-mercapto-12-methylpyridine-1-N-oxide instead of 2,3-dimethyl-4-mercaptopyridine-N-oxide In the same manner as described above, 3-ethyl-2-methyl-4- (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) pyridine-N-oxide is obtained.

Raw material preparation example X

 In the same manner as in the preparation of the raw material A, except that the preparation of the raw material A is performed using 3-fluoro-4-mercapto-12-methylpyridine-1N-oxide instead of 2,3-dimethyl-4-mercaptopyridine-N-oxide. 3-fluoro-2-methyl-4-1- (2- (2- (2,2,2-trifluoroethyl) ethoxy) ethylsulfanyl) pyridine-N-methyl oxide.

Raw material preparation example Y

 Raw material preparation example In Example A, instead of 2,3-dimethyl-4-mercaptopyridine-1-N-oxide, 3-chloro-1--4-mercapto-12-methylpyridine-1-N-oxide was used to prepare the raw material. In the same manner as in A, 3-cyclomethyl-2-methyl-4- (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfmanyl) pyridine-N-oxide is obtained.

Raw material preparation example A A

原料調製例 Aで得られた 2， 3—ジメチルー 4— (2— (2— (2, 2, 2— トリフルォロエトキシ） エトキシ） ェチルスルファニル） ピリジン一 N—ォキシ ド 6. 4 gを無水酢酸 7 Om 1 に溶解し、 8 0°Cで 2時間攪拌した。 冷却後、 溶 媒を留去して得た残渣をエタノール 7 0 m 1に溶解し、 水 1 5 m lに溶解した水 酸化ナトリウム 1. 5 gを加え、 5 0°Cで 3時間攪拌した。 反応終了後、 ェタノ —ルを留去し、 水を加えてクロ口ホルムで抽出した。 クロ口ホルム層を無水硫酸 マグネシウムで乾燥し、 溶媒を留去することによって黄褐色油状の 3—メチルー 4 - (2 - (2 - (2, 2， 2— トリフルォロエトキシ） エトキシ） ェチルスル ファニル） ピリジン一 2—メタノール 4. 9 gを得た。 S- (CH ₂ CH ₂ 0) ₂ -CH _z CF _;

6.4 g of 2,3-dimethyl-4- (2- (2- (2,2,2-trifluoroethyl) ethoxy) ethylsulfanyl) pyridine-N-oxide obtained in Raw Material Preparation Example A The residue was dissolved in acetic anhydride (7 Om 1) and stirred at 80 ° C. for 2 hours. After cooling, The residue obtained by distilling off the medium was dissolved in 70 ml of ethanol, 1.5 g of sodium hydroxide dissolved in 15 ml of water was added, and the mixture was stirred at 50 ° C for 3 hours. After completion of the reaction, ethanol was distilled off, water was added, and the mixture was extracted with chloroform. The form layer at the mouth is dried over anhydrous magnesium sulfate, and the solvent is distilled off to give a yellow-brown oily 3-methyl-4- (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethyl) sulfanyl 4.9 g of pyridine-1-methanol were obtained.

_{'HN R (CDC1 3):} <5 (ppm) = 2.14 (s, 3H), 3.21 (t, 2H), 3.60-3.81 (m, 6H), 3.89 (q, 2H), 4.67 (s, 2H) , 7.07 (d, 1H), 8.27 (d, 1H)

Raw material preparation example B B

原料調製例 Bで得られた 2， 3—ジメチル— 4一 (2 - (2 - (2 - (2, 2， 2— トリフルォロェトキシ） エトキン） ェトキシ） ェチルスルファニル） ピリジ ン— N—才キシドを用いて、 原料調製例 A Aと同様の方法で、 3—メチルー 4一 (2— (2— （2— （2， 2， 2 _ トリフルォロエトキシ） エトキシ） エトキン） ェチルスルファニル） ピリジン一 2—メタノールを得た。 S— (CH ₂ CH ₂ 0) ₃ — CH ₂ CF ₃

2,3-Dimethyl-4-1,2- (2- (2- (2- (2,2,2-trifluoroethoxy) ethoxyquin) ethoxy) ethylsulfanyl) pyridin obtained in raw material preparation example B 3-Methyl-4-1 (2- (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethoxyquin) ethylsulfanyl) Pyridine-12-methanol was obtained.

_{'H-NMR (CDC1 3)} : <5 (ppm) = 2.14 (s, 3H), 3.21 (t, 2H), 3.63-3.80 (m, 10H), 3.89 (q, 2H), 4.67 (s, 2H ), 7.07 (d, lH), 8.27 (d, 1H)

Raw material preparation example C C

S— CH ₂ CH ₂ CH ₂ CH ₂ — 0— CH ₂ CF ₃

原料調製例 Cで得られた 2， 3—ジメチル— 4一 （4一 （2， 2， 2— トリフ ルォロエトキシ） プチルスルファニル） ピリジン一 N—才キシドを用いて、 原料 調製例 A Aと同様の方法で、 3—メチル— 4— (4一 （2, 2， 2—トリフルォ 口エトキシ） ブチルスルファニル） ピリジン一 2—メタノールを得た。 HO

Raw Material Preparation Example 2,3-Dimethyl-4-1 (4-1 (2,2,2-trifluoroethoxy) butylsulfanyl) Pyridine-1 N-year-old oxide Using the same method as Raw Material Preparation Example AA Thus, 3-methyl-4- (4- (2,2,2-trifluoroethoxy) butylsulfanyl) pyridine-12-methanol was obtained.

 'H-NMRCCDCh): δ (ppm) = l.46-2.00 (m, 4H), 2.14 (s, 3H), 3.02 (t, 2H), 3.60-3.75 (m, 2H), 3.82 (q, 2H ), 4.68 (s, 2H), 7.02 (d, 1H), 8.28 (d, 1H)

Raw material preparation example DD

Using 4- (2- (2_ (2_ethyl) ethyn) ethylsulfanyl) -1,2,3-dimethylviridine-1N-year-old oxide obtained in Raw Material Preparation Example D, in a similar manner to Raw Material Preparation Example AA , 4- (2- (2-chloroethyne) ethylsulfanyl) -13-methylpyridine-12-methanol was obtained.

_{'H - NMR (CDC1 3)} : 5 (ppm) = 2.15 (s, 3H), 3.10-3.20 (m, 2H), 3.60-3.82 (m, 6H), 4, 60 (s, 2H), 7.04 ( d, 1H), 8.28 (d, 1H)

 Raw material preparation example EE

 2,3-Dimethyl-4-1 (2- (2- (2-trifluoromethoxyethoxyquin) ethoxyquin) ethylsulfanyl) obtained in raw material preparation example E Same as raw material preparation example A using pyridine monooxide 3-Methyl-41- (2- (2- (2-trifluoromethylshethoxy) ethoxy) ethylsulfanyl) pyridine-12-methanol.

 Raw material preparation example FF

Raw material preparation example Using 2,3-dimethyl-4- (2- (2-trifluoromethoxyethoxyquin) ethylsulfanyl) pyridine-N-oxide obtained in F In the same manner as in Preparation Example AA, 3-methyl-4- (2- (2-trifluoromethoxyethoxy) ethylsulfanyl) pyridine-12-methanol is obtained.

Raw material preparation example GG

 Raw material preparation example 2,3-dimethyl-4-1 (2- (2- (2,2-difluoroethoxy) ethoxy) ethylsulfanyl) obtained in G. Same as raw material preparation example AA using pyridine-1N-oxide. By the method, 3-methyl-4- (2- (2- (2,2 difluoroethoxy) ethoxyquin) ethylsulfanyl) pyridine-1- 2-methano

—Get a le.

Raw material preparation example HH

 Raw material preparation example 2,3-Dimethyl-4 _ (2- (2- (2-fluoroethoxy) ethkin) ethylsulfanyl) pyridine-N-year-old oxide obtained by H Method similar to raw material preparation example AA This gives 3-methyl-4-1 (2- (2- (2-fluoroethoxy) ethoxy) ethylsulfanyl) pyridine-12-methanol. Raw material preparation example I I

 Using 2,3-dimethyl-4- (2- (2- (3,3,3-trifluoropropoxy) ethoxyquin) ethylsulfanyl) pyridine-N-oxoside obtained in Raw Material Preparation Example I Raw Material Preparation Example 3-Methyl-4-1 (2- (2- (3,3,3-trifluoropropoxy) ethoxy) ethylsulfanyl) pyridin-12-methanol is obtained in the same manner as in AA.

Raw material preparation example J J

 Raw material preparation example 2,3-Dimethyl-4-1 (2- (2- (2-chloroethoxy) ethoxy) ethylsulfanyl) pyridine-N-oxide A method similar to that of raw material preparation example AA. This gives 3-methyl-4- (2- (2- (2-chloroethoxy) ethoxyquin) ethylsulfanyl) pyridine-12-methanol.

Raw material preparation example KK

Raw material preparation example 2,3-Dimethyl-4-1 (2- (2- (2-promoethoxy) ethoxy) ethylsulfanyl) pyridine-1 In the same manner as in Preparation Example AA, 3-methyl-4-1 (2- (2- (2-bromoethoxy) ethoxy) ethylsulfanyl) pyridine-12-methanol is obtained.

Raw material preparation example L L

 Example of raw material preparation Example of raw material preparation using 2,3-dimethyl-4-1 (3- (3- (2,2,2-trifluoroethoxy) propoxy) propylsulfanyl) pyridine-N-oxide obtained in L In the same manner as in AA, 3_methyl-41- (3- (3- (2,2,2-trifluoroethoxy) propoxy) propylsulfanyl) pyridine-12-methanol is obtained.

Raw material preparation example MM

 Raw material preparation example Raw material preparation using 2,3-dimethyl-4-1 (4-1 (4- (2,2,2-trifluoroethoxy) butoxy) butylsulfanyl) pyridine-1-N-oxide obtained in M Example In the same manner as in AA, 3-methyl-4-1 (4-1 (4,2,2,2-trifluoroethoxy) butyne) butylsulfanyl) pyridine-12-methanol is obtained.

Raw material preparation example NN

 Raw material preparation example Raw material preparation using 2,3-dimethyl-4_ (3- (2- (2,2,2-trifluoroethyl) ethoxyquin) propylsulfanyl) pyridine-N-oxo obtained in N Example In the same manner as in AA, 3-methyl-4-1 (3- (2- (2,2,2-trifluoroethoxy) ethoxy) propylsulfanyl) pyridin-1-2-methanol is obtained.

 Raw material preparation example 00

 Raw Material Preparation Example 2,3-Dimethyl-4-1 (2- (3- (2,2,2-trifluoroethyl) propoxy) ethylsulfanyl) Pyridine-1-N-oxo In a manner similar to that of Preparation Example AA, 3-methyl-4- (2- (3- (2,2,2-trifluoroethyl) propoxy) ethylsulfanyl) pyridin-12-methanol is obtained.

Raw material preparation example PP Example of raw material preparation Example of raw material preparation using 2,3-dimethyl-4-1 (4- (2- (2,2,2-trifluoroethoxy) ethoxy) butylsulfanyl) pyridine-1N-oxide obtained in P In the same manner as for AA, 3-methyl_4- (4- (2- (2,2,2-trifluoroethoxy) ethoxy) butylsulfanyl) pyridine-12-methanol is obtained.

Raw material preparation example QQ

 Raw material preparation Example 2,3-dimethyl-4-1 (2- (4-1 (2,2,2-trifluoroethyl) butoxy) ethylsulfanyl) obtained in Q Preparation of raw material using pyridine-1N-oxide Example In the same manner as in AA, 3-methyl-4- (2- (4- (2,2,2-trifluoroethoxy) butoxy) ethylsulfanyl) pyridine-2-2-methanol is obtained.

Raw material preparation example RR

 Raw material preparation example 2,5-dimethyl-4-1 (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) obtained in R Using pyridine-N-oxide In the same manner as in Preparation Example AA, 5-methyl-41- (2- (2- (2,2,2-trifluoroetokine) ethokine) ethylsulfanyl) pyridine--2-methanol is obtained.

Raw material preparation example S S

 Raw material preparation example Using 2,6-dimethyl-1,4- (2- (2- (2,2,2-trifluorotrifluoroethoxy) ethoxy) ethylsulfanyl) pyridine-N-oxide obtained in S In the same manner as in Preparation Example AA, 6-methyl-41- (2- (2- (2,2,2-trifluoroethyl) ethoxy) ethylsulfanyl) pyridine-2-methanol is obtained.

Raw material preparation example TT

Raw material preparation example Using 4- (2- (2- (2,2,2-trifluoroethyl) ethoxy) ethylsulfanyl) -1,2,3,5-trimethylpyridine-N-oxide obtained in T , Raw material preparation example 3,5-Dimethyl-4-1 2— (2— (2,2,2-Trifluoroethoxy) ethoxy) ethylsulfanyl) Pyridine-12-methanol is obtained.

Raw material preparation example UU

 Raw material preparation example 2 —Methyl—4— (2— (2— (2,2,2—trifluoroethoxy) ethoxy) ethylsulfanyl) pyridine obtained from U Same as raw material preparation example Ν using Ν-oxide To obtain 4- (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) pyridine-12-methanol.

Raw material preparation example VV

 Raw material preparation example 3-Methoxy-2-methyl-4-1 obtained in V (2- (2- (2,2,2-trifluoroethyl) ethoxy) ethylsulfanyl) pyridin In the same manner as in Raw Material Preparation Example AΑ, 3-Methoxy-4-1 (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) pyridine-12-methanol Get.

Raw material preparation example WW

 Raw material preparation example 3-Ethyl_2-methyl-4 obtained in W— (2— (2— (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) pyridine N-oxide Raw material preparation example In a similar manner to AA, 3-ethyl-4_ (2-((2- (2,2,2-trifluoroethyl) ethoxyquin) ethylsulfanyl) pyridin-12-methanol is obtained.

Raw material preparation example XX

 Raw material preparation example 3 -Fluoro-2-methyl-4-1 (2 — (2 — (2,2,2-trifluoroethyl) ethynine) ethylsulfanyl) pyridine-N Raw Material Preparation Example In the same manner as in AA, 3-fluoro-4-1 (2-1 (2- (2,2,2-trifluorotrifluoroethoxy) ethoxy) ethylsulfanyl) pyridine-12-methanol is obtained.

Raw material preparation example YY Raw material preparation example 3-Methyl mouth 2-methyl-4-1 (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) pyridine monooxide obtained from Y In the same manner as in Raw Material Preparation Example ΑΑ, 3-chloro-41- (2- (21- (2,2,2-trifluoroethoxy) ethoxyquin) ethylsulfanyl) pyridin-12-methanol is obtained.

原料調製例 AAで得られた 3—メチル— 4 _ (2— (2— （2， 2， 2— トリ フルォロエトキシ） エトキシ） ェチルスルファニル） ピリジン一 2—メタノール 4. 9 gをクロ口ホルム 8 O m l に溶解させ、 氷冷下、 塩化チォニル 2. 2 m 1 を滴下し、 4 0〜5 (TCで 3. 5時間攪拌した。 反応液を氷水中にあけ、 炭酸力 リゥムでアル力リ過飽和したのちクロ口ホルムにて抽出した。 クロ口ホルム層を 無水硫酸マグネシウムにて乾燥したのち溶媒を留去して 2—クロロメチルー 3— メチル一 4一 （ 2— （ 2— （ 2， 2， 2— トリフルォロエトキン） エトキシ） ェ チルスルファニル） ピリジンの油状物 4. 5 gを得た。 これを 2—メルカプトべ ンズイ ミダゾール 2. 0 gおよび水酸化ナトリウム 1. 0 gを水 3 m l に溶解し たものを含有するエタノール 9 0 m 1中に加え、 室温で 2時間攪拌した。 不溶物 を濾去し、 エタノールを留去し、 残渣に水を加えてクロ口ホルムで抽出した。 ク ロロホルム層を無水硫酸マグネシウムにて乾燥し、 溶媒を留去した。 残渣にエタ ノール性塩酸を加え、 塩酸塩としたのち、 エタノールより再結晶を行い、 2— ( (3—メチルー 4— (2— （2— （2， 2 , 2— トリフルォロエトキシ） ェ卜キ シ） ェチルスルファニル） 一 2—ピリジル） メチルスルファニル） 一 1 H—ベン ゾィミダゾール · 2塩酸塩の白色結晶 2. 2 gを得た。 融点 1 8 5〜 1 8 8 °C ( 分解；対応する free base体の融点 9 2〜 9 3 °C) 。 Example 1 H ₂ CF _;

Raw material preparation example 3-Methyl-4_ (2- (2- (2,2,2-trifluoroethyl) ethoxy) ethylsulfanyl) obtained from AA O2 ml, and under ice-cooling, 2.2 ml of thionyl chloride was added dropwise, and the mixture was stirred at 40 to 5 (TC for 3.5 hours. The reaction solution was poured into ice water, and carbonic acid was added thereto. After being supersaturated, the extract was extracted with chloroform.The foam layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to remove 2-chloromethyl-3-methyl-1-41 (2- (2- (2, 2, 4.5 g of 2-trifluoroethoxyquin) ethoxy) ethylsulfanyl) pyridine oil was obtained, and 2.0 g of 2-mercaptobenzimidazole and 1.0 g of sodium hydroxide were added to 3 ml of water. Ethanol containing the dissolved substance is added to 90 ml, and is added at room temperature. The mixture was stirred for 2 hours, the insolubles were removed by filtration, the ethanol was distilled off, water was added to the residue, and the mixture was extracted with chloroform.The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. After adding ethanolic hydrochloric acid to the hydrochloride, the solution was recrystallized from ethanol to give 2- ((3-methyl-4- (2- (2- (2,2,2-trifluorotrifluoroethoxy) ethoxylate). Xy) ethylsulfanyl) -l-pyridyl) methylsulfanyl) -lH-Benzoimidazole dihydrochloride 2.2 g of white crystals was obtained, mp 185-18.8 ° C ( Decomposition; melting point of the corresponding free base body 92-93 ° C).

Example 2

原料調製例 B Bで得られた 3—メチルー 4 一 (2 - ( 2 - (2 - ( 2, 2 , 2 — ト リフルォロェトキシ） エトキシ） ェ トキシ） ェチルスルファニル） ピリ ジン 一 2—メタノ一ル 0. 9 gをクロ口ホルム 1 0 m lに溶解させ、 氷冷下、 塩化チ ォニル 0. 5 3 m lを滴下し、 4 0〜5 0 °Cで 2. 5時間攪拌した。 反応液を氷 水中にあけ、 炭酸力リゥムでアル力リ過飽和したのちクロロホルムにて抽出した。 クロ口ホルム層を無水硫酸マグネシウムにて乾燥したのち溶媒を留去して 2—ク 口ロメチル一 3—メチル一 4 一 （ 2 _ ( 2 — (2— ( 2， 2 , 2 — ト リフルォロ エトキン） エトキシ） エトキシ） ェチルスルファニル） ピリ ジンの油状物 0. 5 gを得た。 これを、 2—メルカプトべンズイ ミダゾ一ル 0. 2 gおよび水酸化ナ トリウム 0. 0 6 gを水 1 m 1に溶解したものを含有するェタノ一ル 7 m 1中に 加え、 3 0分間攪拌した。 反応終了後、 不溶物を濾去し、 エタノールを留去し、 残渣に水を加えてクロ口ホルムで抽出した。 クロ口ホルム層を無水硫酸マグネシ ゥムにて乾燥し、 溶媒を留去した。 残渣をシリカゲルカラムクロマトグラフィ一 に付し、 酢酸ェチルで留出して得た油状物にエタノール性塩酸を加え、 塩酸塩と したのち、 エタノールより再結晶を行い、 2 — ( ( 3—メチルー 4 一 ( 2 - ( 2 一 （ 2 — （2， 2 , 2 — ト リフルォロエトキシ） エトキシ） エトキン） ェチルス ルファニル） — 2 —ピリ ジル） メチルスルファニル） 一 1 H—べンゾイ ミダゾー ル · 2塩酸塩 · 1ノ 2水和物の淡黄色不定形結晶 0. 1 3 gを得た。

Raw material preparation example 3-Methyl-4-1 (2- (2- (2- (2,2,2—trifluoroethoxy) ethoxy) ethoxy) ethylsulfanyl) pyridin-1 2-methano obtained from BB 0.9 g of ethyl acetate was dissolved in 10 ml of chloroform, and 0.53 ml of thionyl chloride was added dropwise under ice cooling, followed by stirring at 40 to 50 ° C for 2.5 hours. The reaction solution was poured into ice water, supersaturated with carbon dioxide, and extracted with chloroform. After drying the form layer at the mouth with anhydrous magnesium sulfate, the solvent is distilled off to remove 2-methyl-1,3-methyl-1,4- (2 _ (2— (2— (2,2,2—trifluoroethoxy). 0.5 g of an oily product of)) ethoxy) ethoxy) ethylsulfanyl) pyridin was obtained. This was added to 7 ml of ethanol containing 0.2 g of 2-mercaptobenzimidazole and 0.06 g of sodium hydroxide dissolved in 1 ml of water, and the mixture was added for 30 minutes. Stirred. After the reaction was completed, insoluble materials were removed by filtration, ethanol was distilled off, water was added to the residue, and the mixture was extracted with chloroform. The black mouth form layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the oily substance obtained by distilling with ethyl acetate was added with ethanolic hydrochloric acid to form a hydrochloride, and then recrystallized from ethanol to give 2 — ((3-methyl-4-1 ( 2-(2-1 (2-(2,2,2-trifluorofluoroethoxy) ethoxy) ethoxyquin) ethyls ruphanyl)-2-pyridyl) methylsulfanyl 1-1H-benzoisomidazole dihydrochloride 0.13 g of pale yellow amorphous crystals of monohydrate dihydrate were obtained.

_{lH-NMR (CD 3 0D)} : δ (ppm) = 2.43 (s, 3H), 3.50-3.60 (m, 4H), 3.63-3.78 (m, 6H), 3.88-3.99 (m, 4H), 5.04 ( s, 2H), 7.59-7.64 (m, 2H), 7.75-7.79 (m, 2H), 7.94 (d, 1H), 8.37 (d, 1H)

原料調製例 C Cで得られた 3—メチルー 4— (4一 （2, 2, 2— トリフルォ 口エトキシ） ブチルスルファニル） ピリジン一 2—メタノール 2. 5 gをクロ口 ホルム 6 0 m 1に溶解させ、 氷冷下、 塩化チォニル 1. 5 m lを滴下し、 4 0〜 5 0°Cで 2. 5時間攪拌した。 反応液を氷水中にあけ、 炭酸カリウムで過飽和し たのちクロロホルムにて抽出した。 クロロホルム層を無水硫酸マグネシゥ厶にて 乾燥したのち溶媒を留去することによって油状の 2—ク口ロメチル— 3—メチル — 4一 （4— (2， 2, 2— トリフルォロエトキン） ブチルスルファニル） ピリ ジン 2. 1 gを得た。 これを 2—メルカプトべンゾイミダゾ一ル 1. 0 gおよび 水酸化ナトリウム 0. 5 gを水 5 m 1に溶解したものを含有するェタノール 3 0 m l中に加え、 室温で 4. 5時間攪拌した。 不溶物を濾去し、 エタノールを留去 し、 残渣に水を加えてクロ口ホルムで抽出した。 クロ口ホルム層を無水硫酸マグ ネシゥムにて乾燥し、 溶媒を留去した。 残渣をシリカゲルカラムクロマ卜グラフ ィ一に付し、 クロロホルム： メタノ一ル = 2 0 : 1で留出して得た油状物にエタ ノール性塩酸を加えて塩酸塩としたのち、 エタノールより再結晶を行い、 2— ( (3—メチルー 4— (4一 （2， 2， 2— トリフルォロエトキシ） ブチルスルフ ァニル） 一 2—ピリジル） メチルスルファニル） 一 1 H—ベンゾイミダゾ一ル . 2塩酸塩の淡黄色結晶 1. 1 gを得た。 融点 1 8 8〜 1 9 1 °C (分解） 実施例 4 Example _{3 H 2 - 0- CH 2 CF} 3

Example of raw material preparation 2.5 g of 3-methyl-4- (4- (2,2,2-trifluoroethoxy) butylsulfanyl) pyridine-2-methanol obtained by CC is dissolved in 60 ml of chloroform. Under ice-cooling, 1.5 ml of thionyl chloride was added dropwise, and the mixture was stirred at 40 to 50 ° C for 2.5 hours. The reaction solution was poured into ice water, supersaturated with potassium carbonate, and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to give an oily 2-clomethyl-3-methyl-4-1- (4- (2,2,2-trifluoroethyl) butylsulfanyl. ) 2.1 g of pyridine were obtained. This was added to 30 ml of ethanol containing 1.0 g of 2-mercaptobenzoimidazole and 0.5 g of sodium hydroxide dissolved in 5 ml of water, followed by stirring at room temperature for 4.5 hours. The insoluble material was removed by filtration, the ethanol was distilled off, water was added to the residue, and the mixture was extracted with chloroform. The black-mouthed form layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the oily substance obtained by distilling with chloroform: methanol = 20: 1 was added with ethanolic hydrochloric acid to form a hydrochloride, which was then recrystallized from ethanol. 2 − ((3-Methyl-4- (4-I- (2,2,2-trifluoroethoxy) butylsulfanyl) -l-Pyridyl) methylsulfanyl) -lH-benzimidazole. 1.1 g of pale yellow crystals were obtained. Melting point 18 88 ~ 19 1 ° C (decomposition) Example 4

原料調製例 DDで得られた 4一 （2— (2—クロ口エトキン） ェチルスルファ ニル） 一 3—メチルピリ ジン一 2—メタノ一ル 9. 1 gをクロ口ホルム 2 0 0 m 1に溶解させ、 氷冷下、 塩化チォニル 4 m 1を滴下し、 室温で 1時間攪拌した。 反応液を氷水中にあけ、 炭酸力リゥムで過飽和したのちクロ口ホルムにて抽出し た。 クロロホルム層を無水硫酸マグネシゥムにて乾燥したのち溶媒を留去するこ とによって 4一 （2— (2—クロ口エトキシ） ェチルスルファニル） 一 2—クロ ロメチル _ 3—メチルピリジン 9. 0 gを得た。 これを 2—メルカプトべンゾィ ミダゾール 3. 9 3 gおよび水酸化ナトリウム 2. 0 8 gを水 2 5 m 1に溶解し たものを含有するエタノール 2 0 0 m 1中に加え、 室温で 2時間攪拌した。 エタ ノールを留去し、 残渣に水を加えてクロ口ホルムで抽出した。 クロ口ホルム層を 無水硫酸マグネシウムにて乾燥し、 溶媒を留去した。 残渣をシリカゲルカラムク ロマトグラフィ一に付し、 クロロホルム ： メタノールニ 1 0 : 1で留出して得ら れた残渣にェタノ一ル性塩酸を加えて塩酸塩としたのち、 ェタノールより再結晶 を行い、 2— ( ( 4 - (2— (2—クロ口エトキシ） ェチルスルファニル） 一 3 —メチル一 2—ピリ ジル） メチルスルファニル） 一 1 H—ベンゾイ ミダゾ一ル ' 2塩酸塩の白色結晶 6. 7 gを得た。 融点 1 9 8〜2 0 1 °C (分解）

Raw material preparation example Dissolve 9.1 g of 4- (2- (2-chloroethyne) ethylsulfanyl) -13-methylpyridine-12-methanol obtained in DD in 200 ml of chloroform. Under ice cooling, 4 ml of thionyl chloride was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, supersaturated with carbonated lime, and extracted with black-mouthed form. The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 9.0 g of 4- (2- (2-chloroethoxy) ethylsulfanyl) -12-chloromethyl_3-methylpyridine. Obtained. This was added to ethanol (200 ml) containing 3.93 g of 2-mercaptobenzoimidazole and 2.08 g of sodium hydroxide dissolved in 25 ml of water, and was added at room temperature for 2 hours. Stirred. Ethanol was distilled off, water was added to the residue, and the mixture was extracted with chloroform. The black-mouthed form layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the residue obtained by distilling with chloroform: methanol (10: 1) was added with ethanolic hydrochloric acid to form a hydrochloride, which was then recrystallized from ethanol. , 2-((4- (2- (2-chloroethoxy) ethylsulfanyl) 1-3-methyl-12-pyridyl) methylsulfanyl) 1H-Benzimidazol '2 hydrochloride white crystals 6 7 g were obtained. Melting point 198-210 ° C (decomposition)

The following compounds can be obtained in the same manner as in any of Examples 1 to 4. • 2— ((3-Methyl-1-41 (2 -— (2- (2-Trifluoromethoxetoxy) ethoxyquin) Ethylsulfanyl) 1-2-Pyridyl) Methylsulfanyl) 1 1 H—Benzimidazole • 2 — ((3—Methyl-4-1 (2— (2-Trifluoromethoxetoxy) ethylsulfanyl) -12-Pyridyl) methylsulfanyl) 1-1H—Benzimidazole

 • 2 — ((3-Methyl-14- (2— (2- (2,2-difluoroethoxy) ethoxy) ethylsulfanyl) -1-2-Pyridyl) methylsulfanyl) 1H-Benzimidazole

 • 2 — ((3—Methyl-1-4) (2— (2- (2-Fluoroethoxy) ethoxy) ethylsulfanyl) 1-2—Pyridyl) methylsulfanyl) -1 1H—Benzimidazole

 • 2 — ((3—Methyl_4— (2— (2— (3,3,3-Trifluoropropoxy) Etkin) Ethylsulfanyl) 1—2—Pyridyl) Methylsulfanyl) 1

1 H—Benzi Midazo

 • 2-((3-Methyl 1-4-(2--2- (2-Cloth ethoxy) ethoxyquin) ethylsulfanyl) 1-2-pyridyl) methylsulfanyl)-1 H-Benzimidazole

 • 2 — ((3—Methyl-1-4 (2— (2— (2—Bromoethoxy) ethoxy) ethylsulfanyl) _2-Pyridyl) methylsulfanyl) -1H—Benzimidazole

 • 2-((3-Methyl-4-1 (3— (3- (2,2,2-trifluoroethoxy) propoxy) propylsulfanyl) -1-2-pyridyl) methylsulfanyl)-

1 H—Benzi midazole

 • 2 — ((3-Methyl-1 4 -— (4-1 (4,2,2,2-Trifluoroethoxy) butoxy) Butylsulfanyl) 1-2—Pyridyl) Methylsulfanyl) 1 1H Midazole

• 2 — ((3—Methyl-4— (3— (2— (2,2,2-tritrifluoroethyl) ethkin) propylsulfanyl) -1-2-pyridyl) methylsulfanyl) 1 1H—benzimidazole • 2 — ((3-Methyl-1-41 (2— (3- (2,2,2-trifluoroethoxy) propoxy) ethylsulfanyl) -12-pyridyl) methylsulfanyl) Nzi midazole

 • 2 _ ((3-Methyl-4-(4-(2-(2, 2, 2-Trifluoroetkin) Etkin) Butylsulfanyl)-2-Pyridyl) Methylsulfanyl)-1 H-Benzimidazole

 • 2 — ((3-Methyl-1-4— (2— (4— (2,2,2-trifluoroethoxy) butoxy) ethylsulfanyl) -1-2-pyridyl) methylsulfanyl) 1 1H Nzi Midazoru

 • 2 — ((5-Methyl-4— (2— (2— (2,2,2-trifluoroethoxy) ethokine) ethylsulfanyl) -1-2-pyridyl) methylsulfanyl) 1 H—benzimidazole

 • 2-((6-methyl-4-1 (2- (2_ (2,2,2-trifluoroethoxy) ethoxyquin) ethylsulfanyl) -1-2-pyridyl) methylsulfanyl) 1H-benzimidazole

 • 2 — ((3,5-dimethyl-4— (2— (2— (2,2,2-trifluoroethoxy) ethoxyquin) ethylsulfanyl) -12-pyridyl) methylsulfanyl) 1 1H—benzimidazo One liter

 • 2 — ((4_ (2— (2— (2,2,2-tritrifluoroethoxy) ethoxy) ethylsulfanyl) -1-2-pyridyl) methylsulfanyl) 1H—Benzimidazole

 • 2— ((3—Methoxy-1 4— (2— (2— (2,2,2-Trifluoroethoxy) Ethkin) Ethylsulfanyl) 1-2-Pyridyl) Methylsulfanyl) 1 1 H— Benzi midazole

• 2 — ((3-Ethyl-1-41) (2— (2— (2,2,2-trifluoroetkin) Etkin) ethylsulfanyl) _2-pyridyl) methylsulfanyl) — 1 H Nzi Midazoru • 2 — ((3-Fluoro-4-1 (2— (2— (2,2,2-trifluoroethyl) ethoxy) ethylsulfanyl) —2-pyridyl) methylsulfanyl) 1 1H—Benzy Midazole

 • 2— ((3-—Mouth-one-4-1) (2 -— (2 -— (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) —2-pyridyl) methylsulfanyl) 1 1H One Benzi Midazole

 • 5-Fluoro-2-((3-Methyl-1- (2- (2- (2,2,2-trifuroloethoxyquin) ethoxy) ethylsulfanyl) -12-pyridyl) methylsulfanyl) _ 1 H-benzi Midazols

 • 5-Methyl-2 — ((3-Methyl-4— (2— (2- (2,2,2-trifluoroethoxyquin) ethokine) ethylsulfanyl) 1-2-pyridyl) methylsulfanyl) 1 1H— Nsui Midazoru

 • 2-((3-Methyl-1-41) (2- (2- (2,2,2-Trifluoroethoxy) ethoxy) ethylsulfanyl) -1-2-Pyridyl) methylsulfanyl) -5-Trifluo 1-H-benzimidazole

 • 5-Methoxy-1 2— ((3-Methyl-4-1) (2— (2— (2,2,2-trifuroloetokine) Ethkin) ethylsulfanyl) -12-Pyridyl) methylsulfanyl) 1 1H —Benzi Midazoru

Example 5

2— ((3-Methyl-1 4— (2— (2— (2,2,2-Trifluoroethoxy) ethoxy) ethylsulfanyl) -1-2-Pyridyl) methylsulfanyl) 1 1H 1.0 g of benzimidazole was dissolved in 10 ml of dimethylformamide, 0.15 g of 60% sodium hydride was added, and the mixture was stirred at room temperature for 0.5 hours. Then, under ice cooling, 0.285 g of ethyl ethyl carbonate was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was poured into water, and the precipitated solid was collected by filtration. The solid was recrystallized from ethanol to give colorless crystals of 1-ethoxyquincarbonyl 2-((3-methyl-1-4- (2-(2- There were obtained 1.075 g of 2,2,2-trifluoroquinine) ethokine) ethylsulfanyl) -12-pyridyl) methylsulfanyl) -1H-benzimidazole. Melting point 8 51

6 ° C

Example 6

2-((3-Methyl-4-1) (2- (2- (2,2,2-Trifluoroethoxy) ethoxyquin) ethylsulfanyl) -1-2-pyridyl) methylsulfanyl) 1H-Henbenzoimidazole 2. 0 g was dissolved in 20 ml of dimethylformamide, 0.19 g of 60% sodium hydride was added, and the mixture was stirred at room temperature and stirred for 5 hours. Next, 0.45 g of methyl chlorocarbonate was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was poured into water, and the precipitated solid was collected. The residue was recrystallized from ethanol to give 1-methoxycarbonyl-2-yl ((3-methyl-1-4-1 (2- (2- (2,2,2 There were obtained 1.9 g of white crystals of, 2-trifluorethoxy) ethokine) ethylsulfanyl) _2-pyridyl) methylsulfanyl) -1H-benzoimidazole. Melting point 109-1 1 1 ° C Example 7

C00C (CH ₃ ) ₃

2— ((3-Methyl-1-4-—2- (2- (2,2,2-Trifluoroethoxy) ethoxy) ethylsulfanyl) —2-Pyridyl) methylsulfanyl) — 1 H-benzoimidazole 2.0 g was dissolved in 20 ml of dimethylformamide, 0.19 g of 60% sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Next, 1.1 ml of di-tert-butyl dicarbonate was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into water, and the precipitated solid was collected by filtration. The solid was recrystallized from ethanol to give 1-tert-butoxycarbonyl-1-(-(3-methyl-1-4- (2- (2- (2- 1.4 g of white crystals of (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) -12-pyridyl) methylsulfanyl) 11H-benzimidazole were obtained. Melting point 92-94 ° C

Example 8

C00CH ₂ CH ₂ OCH ₃

2— ((3—Methyl-1 4— (2— (2— (2,2,2-Trifluoroethoxy) ethoxy) ethylsulfanyl) 2-pyridyl) methylsulfanyl) 1 1 H Dissolve 2.0 g of benzimidazole in 20 ml of dichloromethane, add 0.69 ml of 2-methoxyethanol, add 0.886 g of triphosgene under ice cooling, and add 8.5 g at room temperature. Stirred for hours. The reaction solution was poured into water, neutralized with potassium carbonate, and extracted with chloroform. The black-mouthed form layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Ethanol was added to the residue, and the precipitated solid was collected by filtration and recrystallized from ethanol to give 1- (2-methoxetoxycarbonyl) —2-((3-methyl 4- (2- (2 — 0.44 g of white crystals of — (2,2,2-trifluoroethyl) ethoxy) ethylsulfanyl) -12-pyridyl) methylsulfanyl) 1H-benzimidazole was obtained. Melting point 80 ~ 82 ° C

Example 9

C00CH ₂ CF-

2— ((3-Methyl-4-1) (2- (2- (2,2,2-Trifluoroethoxy) ethoxy) ethylsulfanyl) -1-2-Pyridyl) methylsulfanyl) — 1 H—Benzimidazole 2 Dissolve 0.0 g in 20 ml of dichloromethane, add 0.62 ml of 2,2,2-trifluoroethanol and then add 0.886 g of triphosgene under ice-cooling for 4 hours at room temperature. Stirred. The reaction solution was poured into water, neutralized with potassium carbonate, and extracted with black form. The foam layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Ethanol was added to the residue, and the precipitated solid was collected by filtration and recrystallized from ethanol to obtain 1,2- (2,2,2-trifluoroethoxyquincarbonyl) 1-2-((3-methyl-14- ( 1.7 g of white crystals of 2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) -1-2-pyridyl) methylsulfanyl) -1H-benzimidazole were obtained. Melting point 87-89 ° C The following compounds can be obtained in the same manner as in any of Examples 5 to 9 above. • 1-isobutoxycarbonyl 1-2-((3-methyl-4-1- (2- (2- (2,2,2—trifluoroethoxy) ethoxy) ethylsulfanyl) 1-2-pyridyl) methylsulfanyl ) _ 1 H—Benzomidazole

 1-benzyloxycarbonyl-1-((3-methyl-1-41- (2- (2-(2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) -1-pyridyl) methyl Sulfanyl) 1 1 H—Benzoi midazo

 • 1-phenoxycarbonyl- 1-((3-methyl-1-4-(2-(2-(2, 2, 2-trifluoroethoxy) ethoxy) ethysulfanyl) 1-2-pyridyl) methylsulfanyl ) ― 1 H-Benzomidazole

 • 1 — (2-Hydroxychetoxycarbonyl) _ 2— ((3-Methyl-4— (2-1 (2- (2,2,2-trifluoroethoxy) ethoxy) ethyl) sulfanyl) — 2-Pyri Jil) Methylsulfanyl) 1 H-benzoimidazole

 • 1- (2-acetoxetoxycarbonyl) -1-2-((3-methyl-4-1 (2- (2- (2,2,2-tritrifluoroethoxy) ethoxy) ethylsulfanyl) —2-pyri Jil) Methylsulfanyl) 1 1 H-Benzomidazole

 • 1-Carboxymethoxycarbonyl 2-((3-methyl-4-1 (2- (2- (2,2,2-trifluoroethoxy) ethoxyquin) ethylsulfanyl) 1-2-Pyridyl) methylsulfanyl ) One 1 H—Benzoi Midazo

 • 1— (Ethoxycarbonyl) methoxycarbonyl 2 -— ((3-Methyl-1- (2- (2- (2,2,2-trifluoroethoxy) ethoxyquin) ethylsulfanyl) — 2-pyri (Zyl) methylsulfanyl) — 1 H-benzimidazole • 1 — carbamoylmethoxycarbonyl-1-(— (3-methyl-4-1 (2- (2-(2,2,2—trifluoroethoxy) ethoxyquin)) 1-H-Benzoimidazole

• 1-Benzylmethoxycarbonyl 2 _ ((3-Methyl-4-1 (2- (2- (2,2,2_trifluoroethoxy) ethoxy) ethyl) ethylsulfanyl) 1 2— Pyridyl) methylsulfanyl) 1H-benzoimidazole

Example 10

 2-((3-Methyl-4- (2- (2- (2,2,2-trifluoroethoxy)) ethyn) ethylsulfanyl) 1-2-pyridyl) methylsulfanyl obtained in Example 1 —1H-Benzomidazole was dissolved in chloroform at room temperature, 80% metabenzoic perbenzoic acid was added under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. After the completion of the reaction, the solvent was distilled off, and the residue was subjected to alumina column chromatography. The solvent was distilled off with chloroform: methanol (99: 1) to give an oily 2-((3-methyl-1--4- (2- (2- (2,2,2-trifluorotrifluoroquine) ethoxy) ethylsulfanyl) -12-pyridyl) methylsulfinyl) 1-1H-benzimidazole was obtained.

 The following compounds can be obtained by a method similar to that of Example 10 above.

 2 — ((3-Methyl-1-41) (2- (2- (2,2,2-Trifluoroethoxy) ethoxy) ethylsulfanyl) -1-2-Pyridyl) methylsulfonyl) 1 1H-Menazo Midazo One liter

 The medicament of the present invention can be formulated according to the following formulation examples.

 As the compound (I) in the formulation example, 2-((3-methyl-4-1 (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethysulfanyl) -12-pyridyl) methylsulfanyl) One example is 1H-benzimidazole 'dihydrochloride (the compound of Example 1).

 Formulation example 1

 A tablet containing compound (I) 2 Omg is prepared according to the following composition.

 Compound of Example 1 20 mg

 Corn starch 1 5 mg

 Lactose 5 7 mg

 Microcrystalline cellulose 25 mg

 Magnesium stearate 3 mg

Total 120 mg 20 parts of the compound of Example 1, 57 parts of lactose, 19 parts of microcrystalline cellulose and 4 parts of corn starch were thoroughly mixed, and then kneaded well with a binder made with 3 parts of corn starch. The kneaded mixture is sieved with 16 mesh, dried in an oven at 50 ° C, and sieved with 24 mesh. The kneaded powder obtained here is mixed well with 8 parts of corn starch, 6 parts of microcrystalline cellulose and 3 parts of magnesium stearate, and then pressed and compressed to obtain tablets containing 20 mg of active ingredient per tablet. .

Formulation example 2

 The compound of Example 1 (1.0 mg) and sodium chloride (9.0 mg) were dissolved in water for injection, filtered to remove pyrogens, and the filtrate was aseptically transferred to an ampoule, sterilized, and then sealed by melting. The active ingredient is obtained as an injection containing O mg.

 The medicament of the present invention can also be used in a combination therapy of two drugs and a new triple drug, in which case compound (I) and an anti-ulcer drug, or compound (I) and an anti-ulcer drug and an antibiotic or an antibiotic or It is sufficient that the antiprotozoal drug coexist in the living body, and it may be combined with one drug or may be separately formulated and administered to a patient simultaneously or separately.

 The pyridine combination drug of the present invention is formulated, for example, as follows.

Formulation example 3

 (1) Omebrazole enteric coated tablets (Omebrazone tablets (trade name, available from Yoshitomi Pharmaceutical Co., Ltd.))

 (2) Compound (1) Capsules of the following formulation containing 2 Omg

 Compound of Example 1 20 mg

 Cornstarch 30 mg

 Lactose 6 3 mg

 Hydroquinpropyl cellulose 6mg

 Magnesium stearate 1 mg

 Total 120 mg

The preparations (1) and (2) can be administered to a patient simultaneously or separately. Formulation example 4 T

(1) Omebrazole enteric coated tablets (Omebrazone tablets (trade name, available from Yoshitomi Pharmaceutical Co., Ltd.))

 (2) Amoxicillin capsules (available as amolin capsules (trade name, manufactured by Takeda Pharmaceutical Company Limited))

 (3) Capsules containing the compound (1) 20 mg and having the following formulation

 Compound of Example 1 20 mg

 Cornstarch 30 mg

 Lactose 6 3 mg

 Hydroquinpropyl cellulose 6mg

 Magnesium stearate 1 mg

 Total 120 mg

 The preparations (1), (2) and (3) can be administered to a patient simultaneously or separately.

Manufacturing formula example 5

 (1) Omebrazole enteric coated tablets (Omebrazone tablets (trade name, available from Yoshitomi Pharmaceutical Co., Ltd.))

 (2) Oral tablets of metronidazole (available as Oral tablets of Frasil (trade name, manufactured by Shionogi & Co., Ltd.))

 (3) Capsules containing the compound (1) 20 mg and having the following formulation

 Compound of Example 1 20 mg

 Cornstarch 30 mg

 Lactose 6 3 mg

 Hydroxypropyl cellulose 6mg

 Magnesium stearate 1 mg

 Total 120 mg

The preparations (1), (2) and (3) can be administered to a patient simultaneously or separately. The pharmacological action of the compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be confirmed by the following method.

Experimental Example 1: In vitro antibacterial activity against H. Pylori

A clinical isolate (18 strains) cultured for 72 hours at 37 ° C in microaerobic conditions using 5% horse serum was diluted with Brucella broth to obtain a bacterial population of about 10 ⁶ cells / m1. A liquid was prepared.

The diluted bacterial solution was spot-inoculated on agar plates containing test compounds in 2-fold dilution series using a microplanter, and cultured at 37 ° C under 8% carbon dioxide for 3 to 4 days. The minimum inhibitory concentration (MIC) was determined. MIC ₅ based on that value. Values (minimum concentration that inhibits growth by 50%) and MIC ₉ . Values (minimum concentration that inhibits 90% growth) were calculated.

As a result, MIC _{5 of the} compound of the present invention. Value is 0. 0 1 2 5~0. TS z gZm to MIC _9. The value was 0.025-1.56 gZml.

Experimental example 2: Effect of gastric perfusion rat on gastric acid secretion

 According to the method of Ghosh et al. [British 'Journal ♦ Pharmaceutical Sciences (Br. J. Pharmacol.), Vol. 13, p. 54 (1958)]. After fasting the Wistar rat for 20 hours, anesthetize it with urethane (1.5 g / kg, subcutaneous), and attach polyethylene tubes for inflow and outflow of gastric perfusion. 3 7. The physiological saline of C is perfused in the stomach at a rate of 7 mlZ, and the perfusate is collected at 10-minute intervals. Histamine hydrochloride lmlkg is administered intravenously at hourly intervals to induce gastric acid secretion. The test solution containing the test compound is administered intravenously 5 minutes before the administration of histamine hydrochloride. The acidity of the stomach is titrated to pH 7.0 using an automatic infusion device, and the rate of inhibition of gastric acid secretion by the test compound is measured.

Experiment 3

Seven-week-old male gerbils, fasted for about 20 hours, are forcibly orally administered a culture of a standard strain of H. Pylori (ATCC 43504) for about 24 hours. After administration of the culture solution, fasting for about 4 hours and maintaining the water deprivation are performed, and a normal gerbil model infected with H. Pylori is prepared by feeding normal solid food and drinking water. 6 weeks after infection, drug 1 Oral administration twice a day for 2 weeks. Six weeks after drug administration, gerbils are sacrificed and the stomach is removed. After the stomach is cut along the greater curvature and the contents are removed, the stomach is crushed with a homogenizer in 10 ml of phosphate buffered saline. Dilute the lysate with the same buffer and inoculate 0.1 ml of it into the selective medium for H. Pylori. This is cultured in the presence of carbon dioxide to check for the presence of H. Pylori. The following shows the H. pylori eradication effect in a H. pylori-infected gerbil model in which no bacteria were detected. Compound dose Eradication rate (%) MI Cso Compound of Example 1 10ml / kg, bid 14 days 1 0 0 0.1

 Comparative compound 1 10 ml / kg, b.i.d. 14 days 5 0 0.0 1 2 Comparative compound 2 10 ml / kg, b.i.d. 14 days 5 0 0.0 2 5

Comparative compound 1: 2-((3-methyl-4-1) (2- (2- (2-methoxetoxy) ethoxy) ethylthio) -1 2-pyridyl) methylthio) one

1 H—benzimidazole hydrochloride

 Comparative compound 2: 2-((3-Methyl-1- (2- (2-Methoxyethoxyquin) ethylthio) -12-pyridyl) methylthio) -1H-benzimidazole hydrochloride

 The eradication rate of Comparative Compound 1 and Comparative Compound 2 was 50%, while the eradication rate of the compound of Example 1 was 100%, and the compound of Example 1 was clearly in vivo. Excellent eradication effect.

 Experiment 4

A 7-week-old male gerbil, which has been fasted for about 20 hours, is gavaged with a culture of a standard strain of H. Pylori (ATC C4354) for about 24 hours. After administration of the culture solution, the animals are fasted for about 4 hours and maintained in a water-free state, and then fed with normal solid food and drinking water to create a gerbil model infected with H. Pylori. The drug is orally administered twice a day for 2 weeks from 6 weeks after infection. The compound of Example 1 and a proton pump inhibitor In a combination experiment with the compound of Example 1 or a combination of the compound of Example 1 with a proton pump inhibitor and an antibiotic or an antiprotozoal drug, administration of the proton pump inhibitor first

The compound of Example 1, or the compound of Example 1, and an antibiotic or antiprotozoal are orally administered. Six weeks after drug administration, gerbils are sacrificed and the stomach is removed. After incising the stomach along the greater curvature and removing the contents, the stomach is crushed with a homogenizer in 1 Om1 of phosphate buffered saline. Dilute the disrupted solution appropriately with the same buffer, and inoculate 1 ml of the solution into the selective medium for H. Pyl or i bacteria. This is cultured in the presence of carbon dioxide to check for the presence of H. Pyl or i.

 Although the compound of Example 1 shows an excellent eradication effect even when administered alone, the compound of Example 1 is administered in combination with a proton pump inhibitor, or the compound of Example 1 is administered with a proton pump inhibitor and an antibiotic or an antibiotic. Coadministration with the antiprotozoal drug clearly enhanced the eradication effect, and promoted gross and histopathological repair of inflammatory symptoms. No inflammatory symptoms recurred in the complete eradication group by the combined administration. Example 5

 1) Acute oral toxicity test in mice

 A single oral dose of the compound of Example 1 was administered to a 5-week-old male ICR mouse (Charles River Japan, Japan) that had been fasted for about 24 hours, and the subsequent death was observed.

 2) Intravenous acute toxicity test in mice

 A single intravenous administration of the compound of Example 1 was performed to a 5-week-old ICR male mouse (Charles River Japan), and the survival and death 3 days later were observed.

 Mouse acute toxicity test Dose (mgZkg) Number of deaths Intravenous administration

 5 0 0/5 Oral administration

1 0 0 0 0/5 n = 5 From the above results, the compound (I) of the present invention and a pharmaceutically acceptable salt thereof selectively show antibacterial activity against bacteria of Helicopter 厲 represented by H. Pylori. It shows good eradication activity in infected animal models, and is effective in preventing and treating various diseases such as gastritis and gastric ulcer caused by Helicobacter bacteria. That is, the compound of the present invention represented by the general formula (I) and a pharmaceutically acceptable salt thereof are useful for preventing and treating various diseases caused by Helicobacter genus and preventing recurrence of ulcers in mammals including humans. It is used to control vomiting, prevent and treat non-ulcer dyspepsia, and prevent and treat tumors (such as gastric cancer). In addition, the compound (I) of the present invention and a pharmaceutically acceptable salt thereof have a gastric acid secretion inhibitory action, an anti-ulcer action, a gastrointestinal cell protective action, an anti-diarrheal action, and the like. , Diarrhea, colitis, etc.). Furthermore, it has low toxicity, is stable against acids, etc., and has characteristics such as a small increase in blood gastrin level.

 Further, according to the present invention, the eradication effect is enhanced by the combined administration of compound (I) and an anti-ulcer agent or the combined administration of compound (I) and an anti-ulcer agent with an antibiotic or antiprotozoal. The effect of promoting ulcer healing is obtained. In addition, since the dose can be reduced as compared with single administration, side effects and improvement in patient compliance can be expected.

Claims

The scope of the claims  1. General formula (I)

[Wherein, R is-(CH ₂ -CH ₂ -0) k -Di (In the formula, represents a haloalkyl, and k represents an integer of 1 to 10.) or one (A-0) m-(B-0) n one D ₂ (In the formula, D ₂ represents haloalkyl, m represents an integer of 1 to 10, n represents 0 force, represents an integer of 10 or more, and A and B are the same or different and each have a substituent. Represents an alkylene having 2 to 10 carbon atoms, provided that when n represents 0, A represents an alkylene having 3 to 10 carbon atoms, and n represents an integer of 1 to 10; And at least one of A and B represents an alkylene having 3 to 10 carbon atoms. R ¹ represents hydrogen, halogen, alkyl, alkoxy, hydroxy, alkoxycarbonyl, carbonyl, or halalkyl. R ² and R ³ are the same or different and each represents hydrogen, halogen, alkyl or alkoxy. R ⁴ is hydrogen or — C00R ⁵ (Wherein, R ⁵ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, carboxyalkyl, carbamoylalkyl, monoalkyl rubamoylalkyl, dialkyl rubamoylalkyl, alkoxycarbonylalkyl, A phenyl which may have a substituent and an aralkyl which may have a substituent. Represents a group represented by Z and Y are the same or different and represent CH or N, respectively.  P and q are the same or different and each represents 0, 1 or 2. ] Or a pharmaceutically acceptable salt thereof.  2 · General formula (II)

[In the formula, represents hydrogen, halogen, alkyl, alkoxy, hydroxy, alkoxycarbonyl, carboxyl or haloalkyl. R ² and R ³ are the same or different and each represents hydrogen, halogen, alkyl or alkoxy. R ⁴ is hydrogen or COOR ⁵ (Wherein, R ⁵ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, carboxyalkyl, carbamoylalkyl, monoalkyl rubamoylalkyl, dialkyl rubamoylalkyl, alkoxycarbonylalkyl, A phenyl which may have a substituent and an aralkyl which may have a substituent. Represents a group represented by  Di represents haloalkyl.  Z and Y are the same or different and represent CH or N, respectively.  P and q are the same or different and each represents 0, 1 or 2.  k represents an integer of 1 to 10; ] Or a pharmaceutically acceptable salt thereof. 3. In general formula (II), R ¹ is hydrogen, halogen, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, hydroxy or haloalkyl having 1 to 5 carbons, The pyridine compound or the pharmaceutically acceptable salt thereof according to claim ² , wherein R ² and R ³ are the same or different and are each hydrogen or alkyl having 1 to 5 carbons. C 4. Compound power represented by general formula (II) General formula (IIa)

R ⁴ [In the formula, R ^la represents hydrogen, halogen, alkyl having 1 to 3 carbons, alcohol having 1 to 3 carbons, hydroxy or haloalkyl having 1 to 3 carbons. R ⁴ is hydrogen or COOR ⁵ (Wherein, R ⁵ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, carboxyalkyl, carbamoylalkyl, monoalkyl rubamoylalkyl, dialkyl rubamoylalkyl, alkoxycarbonylalkyl, A phenyl which may have a substituent and an aralkyl which may have a substituent. Represents a group represented by  Όι represents haloalkyl.  P represents 0, 1 or 2.  k represents an integer of 1 to 10; ] 4. The pyridine compound according to claim 3, which is a compound represented by the formula: or a pharmaceutically acceptable salt thereof. 5. —General formula (III)

[In the formula, R ¹ represents hydrogen, halogen, alkyl, alkoxy, hydroxy, alkoxycarbonyl, carboxyl or haloalkyl. R ² and R ³ are the same or different and each represents hydrogen, halogen, alkyl or alkoxy. R is hydrogen or — COOR ⁵ (Wherein, R ⁵ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, carboxyalkyl, carbamoylalkyl, monoalkyl rubamoylalkyl, dialkyl rubamoylalkyl, alkoxycarbonylalkyl, A phenyl which may have a substituent and an aralkyl which may have a substituent. Represents a group represented by  D 2 represents haloalkyl.  Z and Y are the same or different and represent CH or N, respectively.  P and q are the same or different and each represents 0, 1 or 2. ]  m represents an integer of 1 to 10.  n represents an integer of 0 to 10.  A and B are the same or different and each represents an alkylene having 2 to 10 carbon atoms which may have a substituent. However, when n represents 0, A represents alkylene having 3 to 10 carbon atoms, and when n represents an integer of 1 to 10, at least one of A and B has 3 to 10 carbon atoms. Indicates alkylene. ] Or a pharmaceutically acceptable salt thereof.  6. — In the general formula (I I I), R ¹ is hydrogen, halogen, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, hydroxy or haloalkyl having 1 to 5 carbons, The pyridine compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein R ² and R ³ are the same or different and are each hydrogen or alkyl having 1 to 5 carbons. 7. The compound represented by the general formula (III) has the general formula (Ilia)

[In the formula, R ^la represents hydrogen, halogen, alkyl having 1 to 3 carbons, alkoxy, hydroxy having 1 to 3 carbons or haloalkyl having 1 to 3 carbons. R is hydrogen or — COOR ⁵ (Wherein, R ⁵ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, carboxyalkyl, carbamoylalkyl, monoalkyl rubamoylalkyl, dialkyl rubamoylalkyl, alkoxycarbonylalkyl, A phenyl which may have a substituent and an aralkyl which may have a substituent. Represents a group represented by  D2 represents haloalkyl.  p represents 0, 1 or 2.  m represents an integer of 1 to 10.  n represents an integer of 0 to 10. However, when n represents 0, A represents alkylene having 3 to 10 carbon atoms, and n represents 1 When an integer of 10 is shown, at least one of A and B represents alkylene having 3 to 10 carbon atoms. ] 7. The pyridine compound according to claim 6, which is a compound represented by the formula: or a pharmaceutically acceptable salt thereof.  8. The pyridine compound or a pharmaceutically acceptable salt thereof according to claim 1 selected from the following compound group.  2— ((3-Methyl-4— (2— (2— (2,2,2-tritrifluoroethoxy) ethoxy) ethylsulfanyl) 1-2-pyridyl) methylsulfanyl) 1 1H ,  2 — ((3-Methyl-1 4— (2— (2— (2— (2,2,2-trifluoroethoxy) ethoxy) ethoxy) ethylsulfanyl) -12-pyridyl) methylsulfanyl) 1 1H —Benzomidazole,  2 _ ((3-Methyl-1-4— (4-1 (2,2,2-Tritrifluoroethoxy) butylsulfanyl) -12-Pyridyl) methylsulfanyl) 1H-Benzoimidazole,  2-((4- (2- (2-chloroethoxy) ethylsulfanyl) -1-3-methyl-2-pyridyl) methylsulfanyl)-1H-benzoimidazole,  1-ethoxycarbonyl-2 — ((3-methyl-4 -— (2— (2— (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) _2-pyridyl) methylsulfanyl) 1 1 H—Benzomidazole,  1-Methoxycarbonyl-1 2-((3-Methyl-4-1 (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) -1-2-Pyridyl) methylsulfanyl) 1 H—Benzomidazole,  1—Tertiary butoxycarbonyl—2 — ((3-Methyl-4-1 (2- (2- (2,2,2-Tritrifluoroethoxy) ethoxy) ethynsulfanyl) 1-2-Pyridyl) methyl Sulfanyl) _ 1 H—Benzoi midazo, 1-(2—Methoxyxoxycarbonyl) 1 2— ((3—Methyl 1 4— (2— (2 -— (2,2,2-trifluoroethyl) ethoxy) ethylsulfanyl) —2-pyridyl) methylsulfanyl) 1H-benzimidazole,  1 — (2, 2, 2 — trifluoroethoxycarbonyl) 1 2 — ((3-methyl-4--(2-(2-(2, 2, 2 — trifluoroethoxy) ethoxyquin) Ethins Ruphanyl) 1-2-pyridyl) methylsulfanyl) 1H-benzimidazole,  1 1 (N, N-Dimethylcarbamoylmethoxycarbonyl) 1 2 — ((3-Methyl-41- (2— (2- (2,2,2_trifluoroetkin) Etkin) Ethylsulfanyl) 1-2-pyridyl) methylsulfanyl) 1H-benzoimidazole,  2-((3-Methyl-1-41) (2- (2- (2,2-Difluoroethoxy) ethoxy) ethylsulfanyl) -1-Pyridyl) methylsulfanyl) 1H-Benzoimidazole,  2-((3-Methyl-1-4-) 2- (2- (2-Fluoroethoxy) ethoxy) ethylsulfanyl) -2-pyridyl) methylsulfanyl) 1-1H-benzomidazol, and  2-((3-Methyl-1-41) (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethylsulfanyl) -1-2-Pyridyl) methylsulfinyl) 1 1 H Nzomidazole.  9. A pharmaceutical composition comprising the pyridine compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  10. A pharmaceutical composition comprising the pyridine compound or a pharmaceutically acceptable salt thereof according to any one of claims to 8, and an anti-ulcer drug.  1 1. A pharmaceutical composition comprising the pyridine compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, an anti-ulcer drug, and an antibiotic or antiprotozoal. 1 2. A method for preventing or treating a gastrointestinal disease, which comprises administering the pyridine compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof. 13. A method for preventing or treating a gastrointestinal disease, which comprises administering a pyridine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 and an anti-ulcer drug. .  14. A digestive system characterized by administering the pyridine compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, an antitumor agent, and an antibiotic or antiprotozoal. Disease prevention and treatment methods.  15. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is used in combination with an anti-ulcer drug.  16. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is used in combination with an anti-ulcer drug and an antibiotic or an antiprotozoal drug.