WO1997030988A1 - Cycloalkanopyridine derivatives, process for producing the same, and peptic ulcer remedy comprising the same - Google Patents

Abstract

A peptic ulcer remedy which comprises as the active ingredient(s) a compound (a) which is any of cycloalkanopyridine compounds represented by general formula (I) and pharmacologically acceptable salts thereof and/or a composite comprising the compound (a) and a metal salt selected among aluminum salts, bismuth salts, and zinc salts. In said formula (I), R1 represents hydrogen, hydroxy, optionally substituted lower alkoxy, lower alkylthio, amino, mono- or disubstituted amino, or cyclic amino; R2 represents hydrogen or lower alkyl; R3 represents à monocyclic or fused, aromatic heterocycle containing two or more nitrogen atoms; m is 1, 2, or 3; n is 2 or 3; and X represents sulfur or oxygen. The remedy has a selective antimicrobial action on Helicobacter pylori.

Description

 Specification

 TECHNICAL FIELD The present invention relates to a cycloarkinopyridine derivative, a method for producing the same and a peptic ulcer agent containing the same.

 The present invention relates to cycloalkanopyridine derivatives. This compound has an antipeptic ulcer effect based on a selective antibacterial effect against Helicobacter pylori and an effect of preventing relapse of peptic ulcer from recurring, and is useful as a peptic ulcer agent. Background art

Pharmaceutical treatments for peptic ulcers such as gastric ulcer and duodenal ulcer are antagonists of histamine-2 receptor and are distributed in gastric tissue lining cells and are thought to regulate gastric acid secretion (IT-K ⁺ ) ATPase ( Drugs such as inhibitors for proton pumps, that is, drugs based on the action of inhibiting gastric acid secretion, are widely used in clinical settings. For example, 5-Methoxy-2 — (((4-Methoxy-3,5-dimethyl-1-pyridyl) methyl) sulfinyl) 1-1H— disclosed in Japanese Patent Publication No. 60-34956. Benzimizole (generic name: omebrazole) is useful as a peptic ulcer with potent proton pump inhibitory activity and is widely used in clinical practice. The gastric acid secretion inhibitory action of proton pump inhibitors is extremely powerful, and shows an extremely high cure rate for peptic ulcers such as gastric ulcer and duodenal ulcer. Research has been done. For example, Japanese Unexamined Patent Application Publication Nos. Sho 59-181,277, Hei 1-6270, 1-79177, and International Publication WO 89/0566 The gazette discloses a compound showing a gastric acid secretion inhibitory action based on a proton pump inhibitory action and useful as a peptic ulcer agent.

On the other hand, recent research has shown that Helicobacter pylori inhabits the human gastric mucosa, and the infection of Helicobacter pylori is closely related to the development of peptic ulcers and the exacerbation of the disease state. It was obvious that it was. Since the above-mentioned omeprazole and its related compounds have antibacterial activity against Helicobacter pylori, research on compounds intended for the elimination of Helicobacter pylori has also been developed. For example, International Publication W09 3/2 480, JP-A-6-100 Nos. 449 and 7-257767 disclose a group of compounds related to 2-pyridylmethylthio-1H-benzimidazole derivatives, which are related compounds of omeprazole. . Research on compounds having antibacterial activity against Helicobacter pylori has been extended to compounds other than 2-pyridylmethylthio-11H-benzimidazole derivatives. No. 4-3 6 4 16 0, No. 6 2 9 8 6 1 No. 1, No. 6 3 0 6 0 3 No. 2, No. 6 3 no. It is disclosed in each of the publications of No. 9353.

 As described above, gastric acid secretion inhibitors such as histamine-2 receptor antagonists and proton pump inhibitors have been developed and clinically applied, and the treatment of peptic gallbladder has progressed dramatically. On the other hand, peptic ulcers treated with these gastric acid secretion inhibitors often recur once after they have been cured. The high frequency of such relapses in drug therapy for peptic ulcers is currently a major clinical problem. On the other hand, as a helical gram-negative bacterium found in the gastric mucosa of patients with gastric ulcer, Helicobacter pylori gastritis, a factor that causes peptic ulcer onset and exacerbation of pathological condition, and a factor that causes peptic ulcer relapse With attention, ulcer treatment by eradication is being studied clinically.

As eradication therapy, gastric acid secretion inhibitors such as proton pump inhibitors, antibiotics such as tetracycline, ampicillin, amoxinline, and clarithromycin, antiprotozoal agents such as methidanidazole, bismuth quenate, etc. Combination therapy with bismuth compounds has been attempted, but high doses of antimicrobial agents are required for complete eradication of Helicobacter pylori. Administration of high-dose antibacterial agents not only can cause the production of drug-resistant strains of Helicobacter pylori itself, but also can cause bacterial replacement in the body, as well as causing high rates of side effects such as diarrhea and nausea. Treatment with long-term antibiotics is not preferred. In addition, antibiotics used here are often unstable, and have been pointed out to be problematic in that they are easily decomposed, especially under acidic conditions in the stomach. Therefore, in order to establish more effective eradication therapy, the development of a new drug that is selective for Helicobacter pylori, has a strong antibacterial action, and is more stable has been desired. Disclosure of the invention

 TECHNICAL FIELD The present invention relates to a novel compound and a method for producing the same, and also relates to a novel therapeutic agent for an ulcer ulcer. The compounds according to the invention have the general formula (I)

Or a pharmacologically acceptable salt thereof, or a metal salt selected from an aluminum salt, a bismuth salt or a zinc salt, and the above-mentioned novel cycloalkanopyridine derivative or a pharmacology thereof. A complex formed from the above and an acceptable salt.

(Wherein, R ¹ represents a hydrogen atom, a hydroxyl group, an optionally substituted lower alkoxy group, a lower alkylthio group, an amino group, a mono- or di-substituted amino group or a cyclic amino group, and R ² represents a hydrogen atom or a lower amino group. An alkyl group; R ³ represents a monocyclic or condensed-ring aromatic heterocyclic group containing two or more nitrogen atoms; m represents an integer of 1, 2 or 3; n represents an integer of 2 or 3 And X represents a sulfur atom or an oxygen atom.) The cycloalkanopyridine compound represented by the general formula (I) of the present invention has a strong antibacterial activity against Helicobacter-pylori, It is an extremely useful compound that has an extremely high selectivity that has no effect on intestinal bacteria, and has excellent physicochemical stability that is not decomposed even under strongly acidic conditions.

Examples of the optionally substituted lower alkoxy group for R ¹ include an alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy, or methoxymethoxy. , Ethoxymethoxy, proboxymethoxy, butoxymethoxy, benzyloxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-propoxyethoxy, 2-butoxyethoxy, 2-phenoxyethoxy, 2-benzyloxy Xietoquin, 2-methoxypropoxy, 3-methoxypropoxy, 2-ethoxyquinoxy, 3-ethoxy Examples thereof include an alkoxy group having 1 to 4 carbon atoms substituted with a lower alkoxy group such as roboxy, 4-methoxybutoxy, and 4-benzyloxybutoxy.

Examples of the lower alkylthio group for R ¹ include an alkylthio group having 1 to 4 carbon atoms such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, and t-butylthio.

Examples of the substituent of the mono- or di-substituted amino group for R ¹ include a lower alkyl group such as methyl, ethyl, hydroxethyl and methoxethyl.

Examples of the cyclic amino group for R ¹ include pyrrolidinyl, piberidinyl, azepinyl, oxazolinyl, thiazolinyl, morpholino, piperazinyl, N-methylbiperazinyl, 2,6-dimethylmorpholino, thiomorpholino, 2-oxybenzo morpholino, and 2-oxy. Monocyclic or condensable such as benzothiomorpholino, 2-oxy-1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, benzopiperazinyl And an amino group.

The lower alkyl group for R ² may be linear or branched and includes a lower alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, and butyl.

As the aromatic heterocyclic group for R ³ , for example, optionally substituted benzimidazole-2-yl, 4,5-diphenylimidazole-2-yl, thienoimidazole-1-yl, 1 H—Pyrazo mouth [3,4-d] pyrimidine 4-yl, purine 6-yl, 1-phenyl-1H-tetrazole 5-yl, 5-methyl-1-1,3,4-thiadiazol Groups such as 2-yl, 4-methyl-14H-triazole-3-yl and the like can be mentioned.

Examples of the substituent of the benzimidazole-2-yl group which may have a substituent include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-substituents at the 5-position or the 5- and 6-positions. —Butoxy, t-butoxy and other lower alkoxy groups having 1 to 4 carbon atoms, nitro group, fluorine atom, chlorine atom, bromine atom and other halogen atoms, methyl, ethyl, n-propyl, isopropyl, n-butyl, Examples thereof include lower alkyl groups having 1 to 4 carbon atoms such as t-butyl, and carbonyl groups such as hydroxycarbonyl, methoxycarbonyl, and ethoxycarbonyl. In addition, the substitution group at position 1 is methoxycarbonyl, ethoxycarbonyl, n-propoxycarbo. N-, isopropoxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl, lower alkoxycarbonyl group having 1 to 4 carbon atoms or benzyloxycarbonyl group, or methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t Lower alkoxy having 1 to 4 carbon atoms such as butoxy; and optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc. Examples include 1 to 4 lower alkyl groups.

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

 [Method 1] General formula (II)

(Wherein, Y represents a halogen atom, a lower alkylsulfonyloxy group or an arylsulfonyloxy group, and the other R ″, R m, n and X have the same meanings as described above). , The general formula (III)

R ³ -SH (III)

(Wherein, R ³ has the same meaning as described above.), Whereby a compound represented by the general formula (I) is obtained.

 Examples of the halogen atom of the substituent Y in the compound of the formula (II) include a chlorine atom, a bromine atom and an iodine atom. Examples of the lower alkylsulfonyloxy group include methanesulfonyloxy, ethanesulfonyloxy, Examples of n-propanesulfonyloxy and isopropylsulfonyloxy include arylsulfonyloxy groups such as benzenesulfonyloxy, p-chlorobenzenebenzenesulfonyloxy, and p-toluenesulfonyloxy.

The reaction between compound (II) and compound (III) is preferably performed in an inert solvent in the presence of a base. Inert solvents include, for example, water, methanol, ethanol, Propanol, dioxane, tetrahydrofuran, acetone, methylethylketone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphamide, sulfolane, or the like, or a mixed solvent thereof can be used. Is water, methanol, ethanol or a mixed solvent thereof. As the base, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium amide, lithium amide, sodium hydride, sodium methoxide, sodium ethkind, sodium carbonate, potassium carbonate, potassium t-butkind, carbonate Sodium hydrogen, potassium hydrogen carbonate, triethylamine and the like are used. The reaction temperature is from 110 ° C to the boiling point of the solvent used, preferably 40 to 100 ° C, and the reaction time is about 10 minutes to 15 hours, preferably 30 minutes to 8 hours. is there.

 Compound (11) has the general formula (V)

(In the formula, Z represents a nitro group or a halogen atom, and other symbols are as defined above.) And a compound represented by the general formula (VI)

_{HX - (CH 2) m -} R '(VI)

 (Wherein the symbols have the same meanings as described above.) A compound represented by the general formula (VI I) obtained by reacting a compound represented by the following formula:

(Each symbol in the formula has the same meaning as described above.).

Examples of the halogen atom of the substituent Z in the compound of the formula (V) include a chlorine atom and a bromine atom. The reaction between compound (V) and compound (VI) can be carried out in an inert solvent in the presence of a base. The _c inert solvent may be used the compound (VI) as a solvent, for example dimethylformamide § Mi de, dimethyl § Seth Ami de, di Okisan, as tetrahydrofuran, acetone, methyl E chill ketone, dimethylsulfoxide Kisamechiru to, Phosphoamide, sulfolane, isopropanol, t-butanol and the like, or a mixed solvent thereof can be used, and dimethylformamide, inopropanol or a mixed solvent thereof can be preferably used. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium amide, lithium amide, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, and potassium t. — Butoxide, sodium bicarbonate, potassium hydrogen carbonate, triethylamine, etc. can be used. The reaction temperature is from 11 ° C to the boiling point of the solvent used, preferably from room temperature to 80 ° C, and the reaction time is from about 5 minutes to 15 hours, preferably from 10 minutes to 6 hours. .

 Production of compound (II) from compound (VI I) can be performed as follows. The compound (VI I) is heated at 60 ° C. to 100 ° C. in the presence of acetic anhydride for about 10 minutes to 12 hours, preferably 30 minutes to 2 hours, to obtain a compound of the general formula (VI [I])

(Wherein each symbol has the same meaning as described above). The obtained compound (ΥΠ 1) is subjected to a hydrolysis reaction under basic conditions to give a compound of the general formula (IX)

(Each symbol in the formula has the same meaning as described above.)

 The hydroxyl group of compound (IX) is converted to a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a lower alkylsulfonyloxy such as methanesulfonyloxy, ethanesulfonyloxy, n-propanesulfonyloxy, or isopropylsulfonyloquine. The compound (II) can be produced by converting the compound to an aryl group or an arylsulfonyloquine group such as benzenesulfonyloxy, benzenesulfonyloxy, and p-toluenesulfonyloxy. .

 [Method 2]

 General formula (I-1)

(Wherein each symbol has the same meaning as described above.) The hydroxyl group of the compound represented by the formula (1) is reacted with an active atom or group, for example, a halogen atom such as a chlorine atom or a bromine atom, methanesulfonyloxy, ethanesulfonyloxy, n — To lower alkylsulfonyloquine groups such as propanesulfonyloquine and isopropylsulfonyloxy, or arylsulfonylooxy groups such as benzenesulfonyloquine, p-chlorobenzenebenzenesulfonyloxy and p-toluenesulfonylooxy After conversion, the general formula (

IV)

R ⁴ — B (IV) (In the formula, R ⁴ represents an amino group, a nitrogen substituent which can be converted into an amino group by a conventional method, a mono- or di-substituted amino group or a cyclic amino group, and B represents a hydrogen atom or an alkali metal. ) By reacting with the compound represented by the general formula (1-2)

(The symbols in the formula have the same meanings as described above.)

 Nitrogen substituents that can be converted to an amino group of R <in a conventional manner include lower alkoxy groups such as an azido group, a nitro group, a methoxycarbonylamino group, an ethoxycarbonylamino group, and a t-butoxycarbonylamino group. And a carbonylamino group. Examples of the alkali metal atom of B include lithium, sodium, and potassium. )

 Compound (I-I) is a compound of the formula (VI-1)

_{HX - (CH 2) m -} OR 5 (VI - 1)

(In the formula, R ⁵ represents a hydrogen atom, or a hydrogen atom substituted by a general protecting group for a hydroxyl group by a conventional method, for example, a trialkylnyl group or a triphenylmethyl group, and other symbols are as defined above. General formula (X) obtained by reacting with a compound represented by the following formula:

(Wherein the symbols have the same meanings as described above). The compound can be produced by performing a reaction according to the above method 1 from the compound represented by General protecting groups for the marine group of R ⁵ include trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, dimethylisopropylsilyl group, dimethyl isopropylsilyl group, dimethylethylsilyl group, t-butyldimethylsilyl group, t Examples include tri-substituted silyl groups such as monobutyldiphenylsilyl group, diphenylmethylsilyl group, and tribenzylsilyl group, benzyl group, and triphenylmethyl group.

 The compound (I) thus produced can be isolated and purified by a conventional means such as recrystallization or column chromatography. The optical isomer of the compound (I) can be obtained by reacting the reaction product with an optically active organic acid such as citric acid, lactic acid or tartaric acid, or an optically active organic acid such as dibenzoyltartaric acid or di (4-chlorobenzoyl) tartaric acid. A diastereomer salt can be formed by using the derivative of the above and subjected to fractional crystallization or the like, or can be produced under the above-mentioned reaction conditions using an optically active starting compound that has been previously optically resolved.

 The compound of the general formula (I) of the present invention includes inorganic acids such as hydrogen chloride, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, and acetic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, An acid-added salt can be obtained by treating with an organic acid such as mesylic acid or tosylic acid by a conventional method. In addition, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, lithium hydride, sodium methoxide, sodium methoxide, potassium t-butoxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, etc. By reacting with a base, alkali metal salts and alkaline earth metal salts can be obtained.

The compound of the general formula (I) of the present invention and a pharmacologically acceptable salt thereof can form a complex with an aluminum, bismuth or zinc salt, and the obtained complex is It does not impair the antibacterial activity against Helicobacter and H. pylori, but rather improves the affinity for gastric mucosa and mucus tissue, and can add a feature that the drug can be distributed in tissues at high concentrations over a long period of time. That is, as a result of selectively retaining the drug at the site where Helicobacter pylori inhabits, the eradication effect on Helicobacter pylori can be significantly improved. The aluminum, bismuth or zinc salts used here include aluminum hydroxide, aluminum sulfate Aluminum, aluminum nitrate, aluminum phosphate, aluminum bromide, aluminum chloride, aluminum fluoride, bismuth carbonate, bismuth nitrate, bismuth sulfate, bismuth chloride, zinc hydroxide, zinc sulfate, zinc phosphate, zinc carbonate, Zinc iodide, zinc bromide, zinc chloride, zinc fluoride, and the like can be used.

Organic acid salts of the compounds of the formula I) or of the compounds of the general formula (I), such as acetate, propionate, citrate, malate, lactate, succinate, succinate, maleate, fumarate Organic solvents such as methanol, ethanol, acetone, acetonitrile, ethylene daricol, dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethylsulfoxide, etc. The reaction can be carried out by dissolving in water, and the resulting solid can be obtained by filtration, or the organic solvent can be distilled off to obtain a complex-formed product. In addition, the above-mentioned salt of aluminum, bismuth or zinc and the compound of the general formula (I) are combined with an inorganic acid such as sulfuric acid, sulfurous acid, hydrochloric acid, hydrobromic acid, nitric acid, hypochlorous acid, perchloric acid and phosphoric acid. After dissolving in an aqueous solution or dissolving an inorganic acid salt of the compound of the formula (I) in water, adding an aluminum, bismuth or zinc salt and dissolving, then reacting 11 with 3 to 9, preferably 4 The complex can be precipitated by adjusting the value to 77, and can be easily obtained by filtration.

 The compounds of the present invention not only have excellent antibacterial activity against Helicobacter pylori, but also surprisingly, antibiotics and antiprotozoal drugs clinically used for the purpose of eradication of Helicobacter pylori Further, it was found that when used in combination with an antibacterial agent such as a bismuth compound, this antibacterial activity was extremely strongly enhanced, and had a property of synergistically improving the activity by several tens to several times. That is, the compound of the present invention can be used alone as a peptic ulcer agent, and also shows that a more excellent clinical effect can be obtained by combining it with an antibacterial agent. It shows that it provides important drugs.

As mentioned above, the current clinical eradication of Helicobacter pylori includes gastric acid secretion inhibitors such as proton pump inhibitors and antibiotics such as tetracycline, ampicillin, amoxicillin, and clarithromycin. Combination therapy with antiprotozoal drugs such as metronidazole and bismuth compounds such as bismuth citrate has been tried. High doses of antimicrobial agents are required to eradicate Helicobacter pylori. Administration of high-dose antibacterial drugs is not only therapeutically favorable because it can not only produce drug-resistant strains of Helicobacter pylori itself but also cause bacterial replacement in the body, and also induces high rates of side effects such as diarrhea and nausea. Not good.

 By using the compound of the present invention in combination, the amount of the antibacterial agent used can be significantly reduced, and it is possible to suppress the occurrence of side effects that are of concern for clinical use. It is positioned as an important drug.

 Antibacterial agents that can provide antibacterial activity against Helicobacter pylori when used in combination with the compounds of the present invention include penicillin antibiotics such as amoxicillin and ampicillin, cephachlor, cefteram, ceftizoxime, ratamoxef, cephalodim such as ceftazidime and cefuroxime. Sporin antibiotics, nemine antibiotics such as imidenem, macrolide antibiotics such as erythromycin and clarithromycin, lincomycin antibiotics such as clidamycin, minocycline, oxycycline, chlortetracycline, etc. Tetracycline antibiotics, quinolone synthetic antibacterial agents such as ofloxacin, norfloxacin, ciprofloxacin, and enoxacin; metronidal antiprotozoal agents; Pharmaceutically acceptable bismuth compounds such as sma, bismuth salicylate, and bismuth nitrate.

 Means for obtaining a synergistic effect by the combined use of the compound of the present invention and the above-mentioned antibacterial agent is not particularly limited, but it is preferable to simultaneously use the respective agents or use them as a combination containing the respective agents. . In the former case, it is often offered in the form of a kit.

A compound of the formula (I) and a pharmacologically acceptable salt thereof or a metal salt selected from aluminum salts, bismuth salts or zinc salts and a compound of the above formula (I) or a pharmacologically acceptable salt thereof. The complex formed from the resulting salt is useful as a peptic ulcer. Pharmacologically acceptable salts include the above-mentioned acid addition salts. When the compound of the present invention and a combination of the compound of the present invention and an antibacterial agent are used as a peptic ulcer, the ability to be orally or parenterally administered is generally preferred. Examples of dosage forms for oral administration include tablets (sugar-coated tablets, Pills, granules, powders, capsules (including soft capsules), syrups, emulsions and suspensions. Examples of dosage forms for parenteral administration include injections, infusions, drops, and suppositories.

As a method for producing the compound of the present invention and a combination of the compound of the present invention and an antibacterial agent into the above-mentioned dosage form, a known production method generally used in the art can be applied. In the case of producing the above-mentioned dosage form, excipients, binders, disintegrants, lubricants, sweeteners, surfactants, and the like, which are usually used in the pharmaceutical field when producing the dosage form, Suspending agents, emulsifiers and the like can be included as necessary. For example, when a tablet of the compound of the present invention or a combination of the compound of the present invention and an antibacterial agent is prepared, the tablet can be prepared by including an excipient, a binder, a disintegrant, a lubricant and the like. . In the case of preparing pills and granules, they can be prepared by incorporating a pill, a binder, a disintegrant and the like. In the case of preparing powders and capsules, it can be manufactured by incorporating excipients and the like, and in the case of manufacturing syrups, it can be manufactured by adding sweeteners and the like. In the case of preparing emulsions and suspensions, the emulsions and suspensions can be prepared by incorporating an emulsifier, a suspending agent, a surfactant and the like. Excipients include, for example, lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, candy powder, mannitol, sodium hydrogencarbonate, calcium phosphate, calcium sulfate and the like. Examples of the binder include 5 to 10% by weight of starch paste solution, 10 to 20% by weight of arabia gum solution or gelatin solution, 1 to 5% by weight of tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, glycerin and the like. No. Disintegrators include, for example, starch, calcium carbonate and the like. Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, and purified talc. Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like. Examples of the surfactant include sodium paralinoleate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl stearate 40, and the like. Examples of the suspending agent include gum arabic, sodium alginate, sodium carboquine methylcellulose, methylcellulose, bentonite and the like. Emulsification Examples of the agent include arabia gum, tragacanth, gelatin, polysorbate 80 and the like.

 Further, when the compound of the present invention and the combination of the compound of the present invention and an antibacterial agent are produced in the above-mentioned dosage form, a coloring agent, a preservative, a fragrance, a flavor, and a flavor, which are ordinarily used in the field of pharmaceutical preparation, are sometimes used. Agents, stabilizers, thickeners and the like can be added.

 The daily dose of the compound of the present invention for an adult can vary depending on the patient's condition, body weight, age, type of compound, administration route, and the like.In the case of oral administration, the dose is about 1 to 1, 00 Omg is suitable, with about 10 to 30 Omg being preferred. In the case of a combination of the compound of the present invention and an antibacterial agent, one to three kinds selected from antibacterial agents can be mixed, and the antibacterial agent and the compound of the present invention or a pharmacologically acceptable salt thereof are used. The mixing ratio varies depending on the type of antibacterial agent, for example, antibiotics, metal compounds, etc., but is usually in the range of 1: 1 to 1:10, preferably 1: 2 to 1: 5. The dose of the combination drug is suitably about 0.2 to 50 Omg, preferably about 2 to 15 Omg per adult per day as the compound of the present invention. When the antibacterial agent and the compound of the present invention are used in combination, the dose of the compound of the present invention is the same as that of the above-mentioned combination drug. BEST MODE FOR CARRYING OUT THE INVENTION

 Example

 The compounds of the present invention exhibit selective antibacterial activity against Helicobacter pylori. In the following test examples, the compounds of the present invention were tested for antibacterial activity against Helicobacter pylori and various bacteria, synergistic effects with antibacterial agents, safety, and physicochemical stability.

 Test Example 1 The antibacterial activity of the compound of the present invention on Helicobacter pylori in vitro (invitro) was determined by the following agar plate dilution method.

Using a Brain Heart Infusion agar plate supplemented with 5% horse defibrinated blood, suspend Helicobacter pylori cultured at 37 ° C for 3 days under microaerobic conditions in Brain Heart Infusion liquid medium. about it was diluted to prepare inoculum in 1 0 ⁶ CFUZm 1 to become so the culture ground. Using a microplanter (manufactured by Sakuma Seisakusho), use this microbial solution as a medium for measuring the minimum inhibitory concentration (MIC) at each spot 51. Inoculated above. The same medium as the pre-culture medium was used for the MIC measurement medium. A solution prepared by dissolving the compound of the present invention in dimethyl sulfoxide or ethanol, and then diluting it with sterile ultrapure water in a two-fold dilution series and a medium at a ratio of 1:49, and solidifying the mixture on a petri dish is used as a MIC measurement medium And After culturing Helicobacter pylori under microaerobic conditions for 3 days at 37 ° C in the same manner as in the preculture, the bacterial growth was observed with the naked eye, and the minimum concentration of the compound of the present invention where no growth was observed was observed The MIC was the mean MIC, and the mean value of tests performed on 10 to 30 helicobacter pylori clinical isolates was taken as the mean MIC.

 The results are shown in Table 1. As is evident, some of the compounds of general formula (I) showed a stronger antibacterial activity than tetracycline or metronidazole used in Helicobacter pylori eradication therapy.

 Table 1 Compounds of Examples Average MI C in g / m 1)

1 1. 2 9

 1 6 2. 2 4

 2 4 1. 9 8

 2 6 0.8

 3 1 0.9.7

 3 4 0.2 9

 6 3 0.5 3 Tetracycline 1.0.0

 Metronidazole 3.0 9

[Test Example 2] The in vitro (invitro) antibacterial activity of the compound of the present invention against Gram-positive bacteria and Gram-negative bacteria was determined by the following agar plate dilution method.

The test bacteria were precultured in heart infusion broth, about in the same medium 1 0 ⁶ C The inoculum was diluted to FU / ml. This bacterial solution was inoculated on a culture medium for MIC measurement by using a microplanter (manufactured by Sakuma Seisakusho) with 5 β1 of each spot. The same medium as the pre-culture medium was used for the MIC measurement medium. After dissolving the compound of the present invention in dimethyl sulfoxide or ethanol, a solution of 2-fold dilution series with sterilized ultrapure water and a medium were mixed at a ratio of 1:49, and the mixture was solidified on a petri dish and subjected to MIC measurement. It was used as a culture medium. After culturing at 37 ° C for one day, the growth of the bacteria was visually observed, and the minimum concentration of the compound of the present invention where no growth was observed was defined as MIC. The results are shown in Table 2. The compounds of the present invention were ineffective against Gram-positive and Gram-negative bacteria. In Table 2, E is E. coli (col i), S is S. aureus (aureus), K is Κ. Pneumoni ae, Ps is Ps. Aluginosa (aerugi nosa), Et Means Et. Faecal is.

 Table 2 Example M I C (/ m 1)

 Compound

 Ps Bt

1> 5 1 2> 5 1 2> 5 1 2> 5 1 2> 5 1 2

2 4> 5 1 2> 5 1 2> 5 1 2> 5 1 2> 5 1 2

2 6> 5 1 2> 5 1 2> 5 1 2> 5 1 2> 5 1 2 3 1> 5 1 2> 5 1 2> 5 1 2> 5 1 2> 5 1 2

3 4> 5 1 2> 5 1 2> 5 1 2> 5 1 2> 5 1 2

[Test Example 3] In order to examine the combined effect of the compound of the present invention and an antibacterial agent, the antibacterial activity against Helicobacter pylori at in Vitro was determined by the following agar plate dilution method.

In the same manner as in Test Example 1, a Helicobacter pylori cultured at 37 ° C for 3 days under microaerobic conditions on a Brain Heart Infusion Agar plate supplemented with 5% of horse defibrinated blood was used. It suspended one John liquid medium, from about 1 0 ⁶ CFU / The inoculum was prepared by diluting with the same medium so as to obtain m1. Using a microbrunter (manufactured by Sakuma Seisakusho), the bacterial solution was inoculated onto a medium for measuring the minimum inhibitory concentration (MIC) of 5 spots of each spot. The same medium as used for the preculture was used for the MIC measurement medium. According to the checkerboard method, a solution of the compound of the present invention (the compound of Example 34) dissolved in dimethyl sulfoxide or ethanol, and then serially diluted with sterile ultrapure water in a two-fold dilution series. A solution and medium, which had been dissolved in ethanol and made into a two-fold dilution series with sterile ultrapure water, were mixed at a ratio of 1: 1: 48, and the mixture solidified on a petri dish was used as a medium for MIC measurement. . After culturing Helicobacter pylori at 37 ° C for 3 days under microaerobic conditions in the same manner as in the preculture, the growth of the bacteria was observed with the naked eye, and the minimum concentration of the compound of the present invention where no growth was observed was determined. The MIC was used as the average MIC, and the average value of tests performed on 27 clinical isolates of Helicobacter pylori was used as the average MIC. The effect of omebrazole and clarithromycin was also tested and used as a control.

The results are shown in Tables 3 and 4. When compared in the presence of 0.0125 / g / m1, which is about 4 to 5 times the average MIC of each of amoxicillin and clarithromycin, the compound of the present invention (the compound of Example 34) The antimicrobial activity of) was markedly enhanced, with about 20-fold higher activity for amoxicillin and about 7-fold for clarithromycin. On the other hand, the combined effect of omebrazole and clarithromycin at the same concentration was about three-fold and slight.

Table 3 Antibiotics Example 3 Average MIC (g / m1) ing / 1 of compounds of 4)

(None) 0.2 9

 AMP C 0 0 2 5 0. 0 1 1

 AMPC 0 0 1 2 5 0. 0 1 5

 AMPC 0 0 0 6 3 0. 0 2 3

CAM 0.0 2 5 0. 0 2 5

 CAM 0.0 1 2 5 0 .0 4 4

AMP C: Amoxinline CAM: Clarithromycin Table 4

 CAM: Clarithromycin

 [Test Example 4] To examine the safety of the compound of the present invention, a toxicity test was conducted by single oral administration and repeated oral administration for one week.

Using the compound of Example 34 as a test compound, 100, 500, 1, 000, and 2,000 Omg / kg were individually administered to three SD rats of each group under fasting conditions. It was orally administered and observed for 3 days. As a result, in the 2000 mg Okg There was only one death, LD ₅ . The value is 2,000 mg / kg or more.c Also, using the compound of Example 34 as a test compound, 20, 100 and 5001118 Zkg were applied to 5 SD rats in each group. Oral administration was repeated for one week. As a result, a decrease in food consumption and suppression of weight gain were observed in the 50 OmgZkg group, but no changes were observed in general symptoms in any of the administration groups.

 [Test Example 5] The compound of Example 34 was used as the compound of the present invention, and subjected to the following acid, basic, and heat stability tests.

 In the stability test for liquid properties, the test compound was dissolved in a buffer solution of PHI.2 to 11 and the residual ratio was measured over time by high performance liquid chromatography. The stability test against heat was performed by heating the solution of the test compound to 50 ° C. and measuring the residual ratio over time by the method described above. As a result, in the respective buffer solutions of pH 1.2, pH 7.4 and pH 11, all showed a residual rate of 98% or more after 6 hours. In addition, even after heating at 50 ° C, the residual ratio was 97% after 3 hours, and the compounds of the present invention showed excellent stability in any of the tests.

 As a result of these tests, it was confirmed that the compound of the present invention has a strong antibacterial activity against Helicobacter pylori and has a highly selective antibacterial action that does not affect other bacteria. In addition, the compound of the present invention synergistically increases the mutual antibacterial activity when used in combination with an antibacterial agent having an antibacterial activity against Helicobacter pylori. This avoids various side effects caused by large doses of antimicrobial agents, which are clinically problematic. Furthermore, the compound of the present invention is highly safe, has sufficient physicochemical stability under gastric pH conditions and normal conditions, and is easily manufactured on an industrial scale. It is a very useful compound.

 Next, the present invention will be described more specifically with reference to Reference Examples and Examples, but the present invention is not limited thereto.

 [Reference Example 1] 4- (2-Hydroxyshetylthio) 1 5H—6,7,8,9-te J ^ he j ^ cyclohepta ^] pyridine dioxide

4 12-trough 5Η—6,7,8,9-tetrahydrocycloheptane [b] pyridin N—aged oxide 4.35 g dissolved in 5 ml of 2-mercaptoethanol, room temperature Add 67 g to sodium hydroxide with 50. The mixture was stirred at C for 4 hours, and further stirred at room temperature for one hour. After the solvent was distilled off, distilled water was added, and the mixture was extracted with a mixed solvent of chloroform and methanol. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated. The residue was washed with ethyl acetate to obtain 4.13 g of 4- (2-hydroxyethylthio) -15H-6,7,8,9-tetrahydrocyclohep [b] pyridine N-oxide.

 'H-NMRCCDCh): δ 1.50-2.04 (6H, m), 2.77-3.92 (9H, m), 7.09 (1H, d), 8.00 (1H, d).

_{IR-les-ma x (KBr): 3399,} 3183, 3093, 2925, 2850, 1444, 1422, 1275, 1247, 122 6, 1195, 1178, 1165, 1130, 1054, 1036 cm-

 [Reference Example 2] 4-(2-morpholinoethylthio)-1H_6,7,8,9-tetrahydrodronchlorhepta [b] pyridine N-oxide

 4- (2-Hydroxyshetylthio) -15H—6,7,8,9—Tetrahydrocyclohepta [b] Dissolve 1.0 g of pyridine N-oxide in 10 ml of chloroform. At 18.degree. C., thionyl chloride 1.Om1 was added and the mixture was stirred overnight. After distilling off the solvent, distilled water was added and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crystals were washed with ethyl acetate to obtain crude 4- (2-chloroethylthio) -15H- 6,7,8,9-tetrahydrocyclohepta [b] pyridine N-oxide as brown crystals. .

 The resulting 4- (2-chloroethylthio) -1.5H- 6,7,8,9-tetrahydrochlorophene [b] pyridine N-oxide mixed with N, N-dimethylformamide-toluene (2: 3) The solution was dissolved in 15 ml of a solvent, 629 mg of sodium iodide and 993 m 2 of potassium carbonate were added thereto, and morpholine 5501 was added thereto, followed by stirring at 90 ° C. under reduced pressure. After distilling off the solvent, distilled water was added, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification using a silica gel column yielded 908 mg of 4- (2-morpholinoethylthio) -15H-6,7,8,9-tetrahydrocycloheptan [b] pyridine N monooxide as a colorless amorphous.

'H-NMRCCDCh): δ 1.05-2.16 (6H, m), 2.49 (211, dd), 2.64 (2H, dd), 2.80-3.19 (6H, m), 3.23-3.50 (2H, m), 3.60-3.86 (4H, m), 6.92 (1H, d), 8.01 (1H, d). 1R _max (neat): 3361, 3098, 2925 , 2852, 1601, 1424, 1333, 1304, 1246, 1 207, 1117, 1069, 1037, 1001 cm- ¹ .

 [Reference Example 3] 9-acetoxy-1- (2-morpholinoethylthio) -5H-6,7,8,9-tetrahydrocyclohep [b] pyridine

 4- (2-morpholinoethylthio) -15H- 6,7,8,9-tetrahydrone chlorohepta [b] Dissolve 893 mg of pyridine N-oxide in 20 ml of acetic anhydride and add 1 0 Stir at 0 ° C for 2 hours, evaporate the solvent, and 9-acetoxy 4- (2-morpholinoethylthio) -5H—6,7,8,9-tetrahydrocyclohepta [b] pyridine with 8 10 mg Obtained.

_{'H-NMR (CDC1 3)} : δ 1.40- 3.83 (24H, m), 5.95 (1H, m), 6.95 (1H, d), 8.20 (1H, d).

IRy _max (neat): 2930, 2855, 2808, 1736, 1564, 1454, 1370, 1303, 1237, 1 145, 1116 cm- ¹ .

 [Reference Example 4] 9-Hydroquine-1 41- (2-morpholinoethylthio) 1-5H—6,7, _8,9-Tetrahydronclohephep [b] Pyridine

 9-acetoxy 4- (2-morpholinoethylthio) -15H-6,7,8,9-tetrahydrocyclohepta [b] pyridine 810 mg was dissolved in ethanol 16 ml, and the mixture was dissolved at 0 ° C. A 10% aqueous sodium hydroxide solution was added, and the mixture was stirred for 1 hour. After the solvent was distilled off, distilled water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification was carried out using a silica gel column, and 9-hydroxy-41- (2-morpholinoethylthio) -15H—6,7,8,9-tetrahydronchlorhepta [b] pyridine was converted to pale yellow crystals. 12 mg were obtained.

 'H-NMR (CDC): δ 0.93-3.44C16H, m), 3.72 (4H, dd), 4.77 (1H, brd), 5.83 (1H, brs), 6.98 (1H, d), 8.17 (1H, d).

_{IR ^ max (neat): 3349} , 2925, 2852, 2800, 1573, 1454, 1392, 1304, 1267, 1 117, 1065, 1004 cm '1.

[Reference Example 5] 9-bromo-41 (2-morpholinoethylthio) — 5 H— 6, 7 , 8, 9—Tetrahydric mouth

 Under an argon atmosphere, 9-hydroxy-4- (2-morpholinoethylthio) -5H-6,7,8,9-tetrahydrocycloheptan [b] pyridine 866.3 mg of tetrahydrofuran 4 O m 1 At 0 ° C, add 1.38 g of triphenylphosphine, further add 1.09 g of carbon tetrabromide, stir for 10 minutes, return to room temperature and stir for 2 hours did. Distilled water was added, the mixture was extracted with chloroform, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification was performed using a silica gel column to give 691 mg of 9-bromo-4- (2-morpholinoethylthio) -15H-6,7,8,9-tetrahydrocyclohep [b] pyridine as a colorless oil. .

 'H-NMRCCDC): 6 1.22-3.79C20H, m), 5.59 (1H, m), 6.93 (1H, d), 8.12 (1H, d).

_{lRv ma x (Br): 3395} , 3071, 2938, 2866, 1740, 1531, 1452, 1429, 1388, 136 8, 1290, 1066 cm '.

 [Reference Example 6] 4- (3-methylthiopropoxy) -1,5,6,7,8-tetrahydrocyclohexa [b] pyridine N-sulfoxide

 Under an argon atmosphere, 4-chloro-5,6,7,8-tetrahydrocyclohexa [b] pyridine N-oxide (602 mg) and 3-methylthio-11-propanol (0.68 ml) were added to anhydrous dimethylformamide. Dissolved in 30 ml, added sodium hydride (266 mg) at 0 ° C, stirred at 0 ° C for 10 minutes, and further stirred at 60 ° C for 1.5 hours. After distilling off the solvent, distilled water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated. Purification with a silica gel column gave 705 mg of 4_ (3-methylthiopropoquine) -5,6,7,8-tetrahydrocyclohexa [b] pyridine N-methoxide as a brown oil.

 ■ H-NMRCCDC): δ 1.60-2.25 (6H, m), 2.12 (3H, s), 2.50-3.03 (6H, m), 4.09 (2H, t), 6.58 (1H, d), 8.09 (1H, d).

_{IRv ma x (neat): 3349} , 2939, 1614, 1566, 1448, 1335, 1293, 1254, 1192, 1 089, 1070, 754 cm- 1. [Reference Example 7] (2- (22-1,4 -benzothiazine-1 3 (4Η) one-one _ 4-yl) ethylthio) — 5,6,7,8-tetrahydrocyclohexane [b] Pyridine N-oxide

 Under an argon atmosphere, 4 12-trough 5, 6, 7, 8-tetrahydrocyclohexa

[b] Pyridine N-year-old oxide 6 17.9 mg and 4- (2-mercaptoethyl) -2H-1,4-benzothiazine-1 3 (4H) -one In addition to 30 ml of nonol, 3 ml of DMF was further added. 129.9 mg of sodium hydroxide was added at 0 ° C, and the mixture was stirred at 0 ° C for 5 minutes, stirred at room temperature for 10 minutes, and further stirred at 60 ° C for 3 hours. The reaction solution was filtered through celite, the solvent was distilled off, then distilled water was added, and the mixture was extracted with a mixed solvent of chloroform-methanol (4: 1) .The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. Dried. After concentrating this, it was purified using a silica gel column to obtain a light brown amorphous substance, 41- (2- (2H-1, 4-benzothiazine-13 (4H) -one-4-yl) ethylthio) -1,5, There was obtained 0.55.7 mg of 6,7,8-tetrahydrocyclohexa [b] pyridine N-oxide.

_{'H-NMR (CDC1 3)} : δ 1, 65- 1.92 (4H, m), 2.58 (2H, brm), 2.92 (2H, brm), 3.21 (2 H, dd), 3.38 (2H, s), 4.20 (2H, dd), 6.94-7.25 (5H, m), 8.09 (1H, d).

\ Uu _mi AK r: 3405, 3079, 2937, 2856, 1664, 1581, 1479, 1431, 1377, 133 0, 1256, 1181, 1144, 1041cm— '.

 [Reference Example 8] 8-chloro-41- (2-morpholino) etokine-5,6,7,8 Nitetrahydrocyclohexa [b] pyridine

8-Hydroxy-1- (2-morpholino) ethoxy-5,6,7,8-tetrahydronchlorohexa [b] 1 g of pyridine was dissolved in 15 ml of dehydrated clonal form, and thionyl chloride was added at 18 ° C. Then, the mixture was stirred at 18 ° C. to room temperature for 22 hours. After evaporating the solvent under reduced pressure, 40 ml of water was added, sodium hydrogencarbonate was added to neutralize the mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 8-chloro-41- (2-morpholino) ethoxyquin-5,6,7,8-tetrahydrone chloride as a brown oil. Hexa [b] pyridine (1.03 g) was obtained. _{'H-NMR (CDC1 3)} : δ 1.66- 2.45 (6H, m), 2.59 (4H, t), 2.83 (2H, d), 3.73 (4H, t), 4.16 (2H, d), 5.19-5.32 (1H, br), 6.65C1H, d), 8.37 (1H, d).

IR _max (neat): 3402, 2948, 2854, 1580, 1455, 1327, 1295, 1116, 1058, 6 93 cm "'.

 [Example 1] 91- (benzimidazol-2-yl) thio 4- (2-morpholinoethylthio) -5H- 6,7,8,9-tetrahydrocyclohepta [b] pyridine

 Under argon atmosphere, 9-bromo-1- (2-morpholinoethylthio) — 5H—6,7,8,9-tetrahydrocyclohepta [b] 108 mg of pyridine was dissolved in 5.0 ml of ethanol. Then, 79 mg of 2-mercaptobenzimidazole and 5 Omg of sodium ethoxide were added, and the mixture was stirred with heating under reflux for 3 hours. After the solvent was distilled off, distilled water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification using a silica gel column yields 9- (benzimidazol-2-yl) thio 4- (2-morpholinoethylthio) -5H—6,7,8,9-tetrahydrocyclohexane as a colorless amorphous [b] pyridine 149 mg was obtained.

 'HN RCCDCh): δ 1.19-3.20 (16Η, π, 3.74 (4H, dd), 5.14 (1Η, brt), 7.01 (1Η, d), 7.07-7.66 (4Η, m), 8.22 (1Η, d ).

IR _max (neat): 3414, 3135, 3048, 2925, 2854, 2810, 1618, 1563, 1499, 1438, 1406, 1347, 1304, 1267, 1115 cm— '.

 [Example 2] 4- (3-methylthiopropoxy) -18- (1H-pyrazo [3,4-1d] pyrimidine-14-yl) thio-1,5, _, 7,8-tehirahidronclo Hexa [b] pyridine

Under an argon atmosphere, 8 mg of 8-bromo-1- (3-methylthiopropoxy) -5,6,7,8-tetrahydrodronchlorohexa [b] pyridine was dissolved in 3.0 ml of anhydrous dimethylformamide. Then, 37 mg of 4-mercapto-11H-pyrazo [3,4-d] pyrimidine and 43 mg of lithium carbonate were added, and the mixture was stirred at 100 ° C for 2 hours. After the solvent was distilled off, distilled water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. silica gel Purification using a column yields a colorless amorphous, 4- (3-methylthiopropoxy) -18- (1H-pyrazo [3,4-d] pyrimidine-14-yl) thio 5,6,7,8 — 16 mg of tetrahydrocyclohexa [b] pyridine was obtained.

_{'H-NMR (CDC1 3)} : δ 1.55-2.92 (7H, m), 2.15 (3H, s), 2.70 (2H, t), 4.16 (2H, t), 5.77 (1H, t), 6.65 (1H , d), 7.94 (1H, s), 8.36 (1H, d), 8.68 (1H, s).

IR _max (neat): 3410, 2921, 2865, 1558, 1451, 1386, 1293, 1116, 1046, 930 cm " ¹ .

 [Example 3] 4- (2-Azidoethylthio) -1-91 (benzimidazol-2-yl) thio 5 H—6,7,8,9-tetrahydrocycloheptan “b” pyridine Under an argon atmosphere, 91-1 ( Benzimidazol-2-yl) Chi-41- (2-Methanesulfonyloxyshethylthio)-1 5H-6, 7, 8, 9-Tetrahydrosik Mouth hepta [b] pyridine 4 24 4 mg And 126 mg of sodium azide were dissolved in 15 ml of anhydrous dimethylformamide and stirred overnight at room temperature.The solvent was distilled off, distilled water was added, and the mixture was extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated, and purified by a silica gel column to give a colorless amorphous amorphous 4- (2-azidoethylthio) -1-9- (benzimidazol-2-yl) thio-1 5 H—6, 7, 8, 9—Tetrahydrosk There were obtained 23.1 mg of rohepta [b] pyridine.

_{'H - NMR (CDC1 3)} : δ 1.40-2.25 (8H, m), 3.13 (2H, t), 3.56 (2H, t), 5.17 (1H, t), 7.0K1H, d), 7.08-7.60 ( 4H, m), 8.25 (1H, d).

1R v _max (neat): 3051, 2926, 2856, 2103, 1717, 1560, 1437, 1348, 1267 cm— [Example 4] 4- (2-aminoethylthio) -191- (benzimidazol-2-yl) ) Thio 5 H—6,7,8,9-tetrahydr _ ^ mouth mouth [b] pyridine hydrochloride

4-1 (2-azidoethylthio) 9-1 (benzimidazol-2-yl) thio 5H-6,7,8,9-tetrahydrocyclohepta [b] pyridine 213.1 mg and trifinylphosphine 175 mg Was dissolved in 20 ml of a mixed solvent of tetrahydrofuran / aqueous (50: 1) and stirred at room temperature overnight. The solvent was distilled off, the residue was dissolved in methanol, a solution of hydrogen chloride in getyl ether was added dropwise, and the formed crystals were collected by filtration. this Is dried over diphosphorus pentoxide under reduced pressure to give colorless crystals (melting point 117-122 ° C) as 4- (2-aminoethylthio) -191- (benzimidazol-12-yl) thio 5 H— 6,7,8,9-tetrahydrocyclohepta [b] pyridine hydrochloride (122 mg) was obtained.

 'H-NMRCCDCh + CDaOD): 6 1.30-3.80 (12H, m), 5.93 (1H, br), 7.42-8.08 (6H, m).

IR _maK (KBr): 3395, 2929, 2846, 2856, 1608, 1507, 1450, 1377, 1265, 119 0, 1153 cm-

[Example 5] 9- (1-Methylbenzimidazol-2-yl) thio-4- (2-morpholinoethylthio) -5H-6,7,8,9-tetrahydrocyclone [b] Pyridine

Under an argon atmosphere, 9- (benzimidazol-2-yl) thio 4- (2-morpholinoethylthio)-1H- 6,7,8,9-tetrahydronchlorohepta [b] pyridine 1 46 mg was dissolved in 6.0 ml of anhydrous tetrahydrofuran, and methyl chloride 30 // 1 and 19 mg of sodium hydride were sequentially added at 0 ° C., followed by stirring for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification was carried out using silica gel column, and as a colorless amorphous 91- (1-methylbenzimidazol-2-yl) thio-14- (2-morpholinoethylthio) -15H- 6,7,8,9-tetrahydrocyclo Hep evening [b] 13 Omg of pyridine was obtained. _{'H-NMR (CDC1 3)} : δ 1.20- 2.13 (8H, m), 2.51 (4H, m), 2.72 (2H, m), 3.05 (2H, m), 3.73 (4H, m), 3.74 (3H , s), 5.68 (1H, brd), 6.98 (1H, d), 7.22 (2H, m), 7.65 (2H, m), 8.20 (1H, d).

IR ^ _max (KBr): 3042, 2924, 2846, 2800, 1562, 1460, 1416, 1358, 1278, 1116, 1005, 744 cm "'.

 [Example 6] 8- (2-imidazo [4,51-c] pyridyl) thio-4-1 (2-morpholinoethylthio) -1,5,6,7,8-tetrahydrocyclohexa [b] pi Lysine

Under an argon atmosphere, 8-chloro-1,4- (2-morpholinoethylthio) -1,5,6 1,6.8 mg of 1,7,8-tetrahydrocyclohexa [b] pyridine was dissolved in 10 ml of ethanol, and 67.5 mg of 2-mercaptoimidazo [4,5-c] pyridine was dissolved in 10 ml of ethanol. 36.4 m of sodium ethoxide was added, and the mixture was heated under reflux for 1 hour. After the solvent was distilled off, distilled water was added thereto, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with ethyl acetate and converted into a colorless amorphous 8- (2-imidazo [4,5-c] pyridyl) thio-4-1 (2-morpholinoethylthio) -1,5,6,7,8-tetrahydrone chloride 14.8. 8 mg of oxa [b] pyridine was obtained.

_{, H-NMR (CDC1 3)} :. <5 1.87-2.64 (10H, m), 2.74 (2H, dd), 3.14 (2H, dd), 3.65-3 76 (4H, m), 4.82 (1H, brt ), 7.08 (1H, d), 7.44 (1H, d), 8.33 (2H, d), 8.88 (1H, s).

 neat): 3116, 3014, 2946, 2856, 2809, 1615, 1567, 1404, 1310, 1 274, 1192, 1117, 1031 cm '.

 [Example 7] 8— (benzimidazol-2-yl) thio 4 (2-(4-fu 322 rubiperazine-1 1-1-inyl) ethyl) 1-5, 6, 7, 8- Tetrahydrocyclohexa [b] pyridine

 Under an argon atmosphere, 8-methanesulfonyloxy-1- (2- (4-phenylpyrazine-111-yl) ethylthio) -1,5,6,7,8-tetrahydrocyclohexa [b] pyridine 10 7 8 mg was dissolved in 5 ml of ethanol, 43.3 mg of 2-mercaptobenzimidazole and 23.l mg of sodium ethoxide were added, and the mixture was heated under reflux for 2 hours. After the solvent was distilled off, distilled water was added and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel to give a colorless amorphous 8- (benzimidazol-2-yl) thio_4-1 (2- (4-phenylbiperazine-111) ethylthio) -1,5,6, 6,6.7 mg of 7,8-tetrahydrocyclohexa [b] pyridine was obtained.

 'H-NMR (CDCh): δ 1.70-3.32 (19H, m), 4.77 (1H, brt), 6.70-7.72 (10H, m), .33 (1H, d).

_{IR-les-ma x (KBr): 3386,} 3059, 2942, 2813, 1735, 1599, 1561, 1504, 1498, 143 8, 1406, 1351, 1309, 1267, 1233, 1142 cm

 [Example 8] 4- (2- (2- (2-Methoxyethoxyquin) ethokine) ethylthio) -1- (1-H-pyrazo [3,4-d] pyrimidine-1-4-yl) thio_ 5,6,7,8-tetrahydrocyclohexa [b] pyridine

 Under an argon atmosphere, 4- (2- (2- (2-methoxyethoxyquin) ethoxy) ethylthio) -18-methanesulfonyloxy-5,6,7,8-tetrahydrocyclohexa [b] pyridine 10 9.4 mg was dissolved in anhydrous dimethylformamide (5.0 ml), and 4-mercapto-1H-pyrazo [3,4-d] pyrimidine 62.1 mg and potassium carbonate 58 mg were added. The mixture was stirred at 00 ° C for 3 hours. After distilling off the solvent, distilled water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification was performed using a silica gel column to give 4- (2- (2- (2-methoxyethoxyquin) ethokine) ethylthio) -18- (1H-pyrazo [3,4-d] pyrimidine-1 as a brown oil. 1-yl) 5,6,7,8-Tetrahydroncyclohexa [b] pyridine (57.4 mg) was obtained.

_{'H - NMR (CDC1 3)} : δ 1.60-2.92 (6H, m), 3.22 (2H, t), 3.38 (3H, s), 3.47-3.87 (10H, m), 5.77 (1H, br), 7.04 (1H, d), 7.88 (1H, s), 8.35 (1H, d), 8.65 (1H, s).

 IRv maxCneat): 3395, 3181, 3107, 2921, 2880, 1557, 1455, 1404, 1330, 1 254, 1191, 1103 cm— '.

 [Example 9] 8-(benzimidazol-2-yl) thio-4- (2-morpholinoethylthio) -5,6,7,8-tetrahydrocyclohexane [bl pyridine aluminum complex

91.4 mg of aluminum hydroxide was dissolved in 6 ml of concentrated sulfuric acid, diluted with distilled water, diluted with 500 mg of the compound of Example 34, and dissolved by adding 10% aqueous sodium hydroxide solution. The precipitated crystals are collected by filtration and dried to give 8- (benzimidazol-2-yl) thio-4- (2-morpholinoethylthio) -1,5,6,7,8-tetrahydrocyclohexa [b ] 13.8 mg of pyridine aluminum complex was obtained. Colorless crystal (mp 172-174 ° C).

'H- thigh _{(DMS0-d 6): δ} 1.62-2.35 (4H, m), 2.42-2.74 (2H, m), 3.00- 3.58 (8H, m), 3.66-3.92 (4H, m), 5.17- 5.38 (1H, br), 7.09-7.23 (2H, m), 7.32 (1H, d), 7.40-7.55 (2H, m), 8.35 (1H, d).

IR _max (KBr): 3448, 3070, 2949, 2865, 2679, 2599, 2438, 1608, 1437, 126 7, 1113, 749, 619 cm— ¹ .

 [Example 10] 81- (benzimidazol-2-yl) thio 4- (2,1-morpholinoethylthio) -5,6,7,8-tetrahydrocyclohexa [bl pyridine aluminum complex

 47.2 mg of aluminum sulfate was dissolved in 10 ml of diluted sulfuric acid by heating and stirred for 1 hour. 100 mg of the compound of Example 34 was added and dissolved.After stirring for 30 minutes, 10% sodium hydroxide was added. An aqueous solution was added, and the precipitated crystals were collected by filtration and dried, and the same compound as in Example 9 8- (benzimidazol-2-yl) thio-4 (2-morpholinoethylthio) -1,5,6 There was obtained 76.4 mg of 7,7,8-tetrahydrocyclohexa [b] pyridine aluminum complex.

 [Example 1 1] 8— (benzimidazol-2-yl) thio 4— (2-morpho linetino ^ _thio) -1,5,6,7,8-tetrahydrocyclohexa [b] pyridine bismuth complex

 10 Omg of the compound of Example 34 was dissolved in 10 ml of chloroform, 10 ml of a solution of 73.9 mg of bismuth chloride in ethyl acetate was added, and the deposited precipitate was collected by filtration and dried. — (Benzimidazol-1-yl) thio-4-1- (2-morpholinoethylthio) -1,5,6,7,8-tetrahydrocyclohexa [b] pyridine bismuth complex 10.9 mg was obtained. .

Colorless powder (discoloration point: 173 ° C).

IR ^ (KBr): 3448, 3050, 2947, 2862, 2700, 1608, 1438, 1266, 1171, 112 0, 1072, 751 cm 1.

[Example 1 2] 81- (benzimidazol-2-yl) thio-4- (21-morpholinoethylthio) -1,5,6,7,8-tetrahydrocyclohexa “b” pyridine zinc complex 100 mg of the compound of Example 34 was dissolved in 10 ml of dilute hydrochloric acid, and a solution of 23.8 mg of zinc hydroxide in hydrochloric acid (10 m) was added.After stirring for 5 minutes, a 10% aqueous solution of sodium hydroxide was added. , And the precipitated precipitate was collected and dried, and 8- (benzimidazol-2-yl) thio-4- (2-morpholinoethylthio) -1,5,6,7,8-tetrahydrosik [b] 107.2 mg of pyridine zinc complex was obtained.

Colorless powder (discoloration point: 20.7 ° C).

IR _max (KBr): 3449, 3067, 2953, 2865, 1584, 1439, 1275, 1122, 813, 749, 653 cm '.

 [Example 13] 8-(benzimidazol-2-yl) thio-41- (2-morpholinoethylthio) -1,5,6,7,8-tetrahydro P_ / chlorohexa “b bpyridine succinic Acid salt

 Example 3 200 mg of the compound of 4 was dissolved in 10 ml of a mixed solvent of 1: 1 formaldehyde-methanol (1: 1), and 55.4 mg of succinic acid was added to 50.1 mg of formaldehyde-methanol (1: 1). 10 ml of a mixed solvent was added, and the mixture was stirred at room temperature for 5 minutes. The solvent was distilled off under reduced pressure. Ethyl acetate and ether were added to the residue, and the precipitate was collected by filtration. 8- (benzimidazol-2-yl) thio-14-1 (2-morpholinoethylthio) -1,5,6 2,7,8-Tetrahydrocyclohexa [b] pyridine succinate 21.4 mg was obtained.

Colorless powder (melting point 144-145 ° C).

_{'H- NMR (CDC1 3):} δ 2.53-2.83 (10H, m), 3.27-3.35 (8H, m), 3.73 (4H, t), 5.02 - 5.18 (1H, br), 7.15-7.27 (3H, m), 7.46-7.85 (2H, m), 8.26 (1H, d).

IR ^ _max (KBr): 3422, 3046, 2946, 2867, 2481, 1924, 1717, 1569, 1431, 1114, 740 cm- ¹ .

 The following compounds were synthesized according to the method of Example 1.

 [Example 14] 4- (2-Morpholi ^> ^^^^^^^^^^^^^^^^^^^^^^^^^^, 7,8,9-tetrahydronchlorhepta [ b] pyridine

Yellow crystals (mp 98-104 ° C).

_{'H-NMR (CDC1 3)} : δ 1.25-3.50 (20H, m), 5.07 (1H, br), 7.06 (1H, d), 7.50 (1H, br), 8.10 (1H, dd), 8.24 (1H , D), 8.38 (1H, br).

3 o IR _X (KBr): 3088, 2926, 2846, 2818, 1735, 1563, 1525, 1432, 1332, 127

4, 1237, 1116, 1069, 819, 735 cm " ¹ .

 [Example 15] 9 -_ (5-fluorobenzimidazol-1-yl) thio-41- (2-morpholinoethylthio) -15H-6,7,8,9-tetrahydrocyclohepta [b] pyridine

Colorless amorphous.

_{'H-NMR (CDC1 3)} : <5 1.25-2.77 (14H, m), 3.07 (2H, m), 3.72 (4H, m), 5.10 (1H, t), 6.75-7.50 (311, m), 7.01 (1H, d), 8.18 (1H, d).

 IR max (neat): 3423, 3153, 3070, 2925, 2854, 2809, 1627, 1561, 1439, 1

408, 1346, 1305, 1262, 1133, 1115, 837, 768 cm one ^1.

 [Example 16] To 9- (5-Methoxybenzimidazol-2-yl) thio 4- (2-ruholinoethylthio) -5H- 6,7, -8,9-tetrahydrocyclo Putta [b] pyridine

Colorless amorphous.

_{'H-NMR (CDC1 3)} : δ 1.08- 3.10 (16H, m), 3.72 (4H, t), 3.84 (3H, s), 5.11 (1H, br), 6.70-7.51 (3H, m), 7.02 (1H, d), 8.22 (1H, d).

1R les _{ma x (neat): 3423,} 3163, 3079, 2926, 2856, 2809, 1626, 1562, 1450, 1 414, 1349, 1304, 1269, 1200, 1153, 1116 cm-

 [Example 17] 91- (5,6-dimethoxybenzimidazol-2-yl) -41- (2-morpholinoethylthio) -1-5H-6,7,8-, 1-tetrahydron ^ _Mouth mouth-ta [b] pyridine

Yellow amorphous.

 Ή-NMR (CDC "): δ 1.48-2.28 (6H, m), 2.44- 2.64 (4H, m), 2.73 (2H, d), 2.96 -3.23 (4H, m), 3.64-3.84 (4H, m ), 3.9K6H, s), 5.01-5.21 (1H, m), 7.03 (1H, s), 7.32 (2H, s), 8.14 (1H, d).

IRy _max (KBr): 3414, 3264, 3060, 2931, 2857, 1560, 1490, 1439, 1323, 119 8, 1136 cm

[Example 18] 4- (2-morpholinoethylthio) -9-1 (5-trifluoromethylbenzimidazol-2-yl) thio 5H-6,7,8,9-tetrahydrid Mouth cyclohepta [b] pyridine

Colorless crystals (mp 90-91 ° C).

 Ή-NMR (CDC): 6 1.44-2.36 (6H, m), 2.50 (4H, t), 2.67-2.75 (2H, m), 2.99 -3.14 (4H, m), 3.73 (4H, t), 5.20 (1H, t), 7.00 (1H, d), 7.28-7.73 (3H, m), 8.23 (1H, d).

IR _mix (KBr): 3470, 3042, 2936, 2856, 2809, 1567, 1426, 1329, 1246, 1163, 1119, 1049, 930, 812, 771, 661 cm ¹ .

 [Example l9] 9-1 (3H-imidazo [4,5-b] pyridino-12-yl) thio41- (2-morpholinoethylthio) -15H-6,7,8,9 —Tetrahydric cyclohepta [b] pyridine

Colorless amorphous.

 Ή-NMR (CDCU): 6 1.49-2.84 (1211, m), 2.92-3.22 (3H, m), 3.63-3.83 (4H, m), 5.22-5.46 (1H, m), 6.92-7.33 (2H, m), 7.70- 7.94 (1H, m), 8.06-8.32 (2H, m)

IR v _max (KBr): 3423, 3070, 3303, 2926, 2857, 2816, 2660, 1736, 1562, 1447, 1407, 1278, 1259, 1228, 1113, 770 cm '.

 [Example 20] 4- (2-morpholinoethylthio) -19- (thieno [3,4-dl imidazol-12-yl) thio-5H-6,7,8,9-tetrahydrocyclohepta [ b] pyridine

Light brown amorphous.

 Ή-NMR (CDC "): δ 1.58-2.40 (6H, m), 2.55 (4H, t), 2.65-2.82 (2H, m), 3.00 -3.22C4H, m), 3.76 (4H, t), 5.18 -5.36 (1H, m), 6.67 (1H, s), 7.05 (1H, d), 8.16 (1H, d).

 IR max (KBr): 3442, 3237, 3116, 3070, 2934, 2846, 2809, 1560, 1449, 135 6, 1118 cnT '.

 [Example 21] 4- (21-morpholinoethylthio) 191 (imidazole-2-yl) thio 5H—6,7,8,9-tetrahydrocyclohepta “b pyridine colorless amorphous.

'H-NMRCCDC): δ 1.40-2.25 (6H, m), 2.5K4H, m), 2.67-3.16 (6H, m), 3.72 ( 4H, m), 4.84 (1H, m), 6.97 (1H, d), 7.00 (2H, s), 8.15 (1H, d).

IR _max (KBr): 3433, 3126, 3023, 2928, 2856, 2809, 1646, 1561, 1441, 140

5, 1321, 1265, 1116, 867, 763 cm- ¹ .

 [Example 22] 9- (4,5-diphenyl-1H-imidazole-1-yl) thio-41 (2-morpholinoethylthio) -5H-6,7,8,9-1 f Traheidrocyclohepta [b] pyridine

Colorless crystal (melting point 83-85 ° C).

 Ή-NMR (CDC1: δ 1.40-2.34 (6H, m), 2.52 (4H, t), 2.68-2.76 (2H, m), 3.00 -3.15 (4H, m), 3.79 (4H, t), 4.86- 5.06 (1H, br), 7.03 (1H, d), 7.12-7.62 (10H, m), 8.17 (1H, d).

IRv _ma , (Br): 3423, 3153, 3051, 2922, 2846, 2809, 1561, 1490, 1447, 132

9, 1246, 1117, 765, 696 cm—

 [Example 23] 91- (4-methyl-4H-triazol-3-yl) thio-41- (2-morpholinoethylthio) -15H-6,7,8,9-tetrahydrocyclohepta [b ] Pyridine

Colorless crystal (mp 156-157 ° C).

 Ή-NMR (CDCI3 + CD3OD): δ 1.51-2.16 (6H, m), 2.53-2.77 (6H, m), 2.93-3.40 (4 H, m), 3.63 (3H, s), 3.74 (4H, t) ), 5.27-5.62 (1H, br), 7.01 (1H, d), 8.12 (1H, s), 8.20 (1H, d).

IRv _max (KBr): 3423, 3070, 2925, 2853, 2800, 1565, 1512, 1451, 1413, 130 5, 1113, 1068, 1005 cm

 [Example 24] 91- (5-Methyl-1,3,4-thiadiazol-2-yl) thio-41 (2-morpholinoethylthio) -5H- 6,7,8,9-tetrahydrocyclohep Evening [b pyridine

Colorless crystal (mp 10.9 ° C).

 Ή-NMR (CDCI3): δ 1.64-2.21 (6Η, m), 2.51 (4H, t), 2.68-2.76 (2H, m), 2.72 (3H, s), 2.82-3.25 (4H, m), 3.73 (4H, t), 5.37-5.61 (1H, br), 7.00 (1H, d), 8.19 (1H, d).

IR (neat): 3461, 2924, 2852, 2808, 1563, 1453, 1380, 1303, 1269, 1 189, 1117, 1067, 1004, 867, 768, 735 cm—

 [Example 25] 41- (2-morpholinoethylthio) -19- (1-phenyl-2-H-tetrazol-1-5-yl) thio-5H-6,7,8,9-tetrahydrocyclohepta [b] pyridine

Colorless crystal (mp 174-175 ° C).

_{Ή-NR (CDC1 3):} δ 1.54-2.24 (6H, m), 2.52 (4H, t), 2.69-2.77 (2H, m), 3.02 - 3.18 (4H, m), 3.74 (4H, t), 5.67 (1H, d), 7.01 (1H, d), 7.49-7.61 (5H, m), 8.17 (1H, d).

IR _max (KBr): 3414, 2933, 2846, 2809, 1561, 1502, 1453, 1407, 1386, 1306, 1270, 1234, 1114, 838, 765, 695 cm '.

[Example 26] 4- (2-morpholinoethylthio) -9- (purin-6-yl) thio-5H—6,7,8,9-tetrahydronchlorohepta b) pyridine colorless crystal (melting point 109-1 13 ^D C).

 'H-R (CDCh): δ 1.44- 2, 38 (6H, m), 2.52 (4H, t), 2.68-2.76 (2H, m), 2.88 -3.24 (4H, m), 3.73 (4H, t), 5.82-6.16 (1H, br), 6.95 (1H, d), 8.27 (1H, d), 8.46 (1H, s), 8.72C1H, s).

_{IR-les-max (KBr): 3423, 3088} , 2921, 2856, 2808, 1561, 1459, 1330, 1247, 112 5, 1005, 939, 847, 781, 725, 641 cm 1.

 [Example 27] 91- (benzimidazol-2-yl) thio-41- (2-thiomoleholinoethylthio) -5H-6,7,8,9-tetrahydrocyclohepta [top] ^ [Gin

Colorless amorphous.

 'H-NMRCCDC): δ 1.30-2.36 (10H, m), 2.58-3.20 (10H, m), 5.17 (1H, br), 6.92-7.79 (5H, m), 8.20 (1H, d).

IR _max (KBr): 3395, 3135, 3051, 2923, 2800, 1655, 1561, 1497, 1437, 140 7, 1339 cm— ¹ .

[Example 28] 9- (benzimidazol-2-yl) thio 4- (2- (1,2,3,4-tetrahydroisoquinolyl) ethylthio) -15H-6,7 , 8, 9 —tetrahydrocycloheptan [b] pyridine Yellow amorphous.

_{'H-NMR (CDC1 3)} : δ 1.22- 2.33 (8H, m), 2.73- 3.29 (8Η, m), 3.72 (2Η, s), 5.13 (1H, m), 7.00-7.25 (5H, m) , 8.23 (1H, d).

IRv _ro ax (KBr): 3425, 3022, 2922, 2852, 2802, 1654, 1561, 1437, 1407, 1342, 1308, 1266, 1132, 1095 cm- ¹ .

 [Example 2 9] 9_- (benzimiguzol-2-yl) thio 4 _ (2-piperidinoethylthio) 1 5 H——6, 7, 8, 9-tetrahydrocycloheppu [b] pyridine

Colorless amorphous.

 'H-NMR (CDCh): δ 1.20-2.72 (18H, m), 2.95-3.19 (4H, m), 5.12 (1H, br), 6,9 9-7.65 (5H, m), 8.20 (1H, d).

_{IR-les-ma x (KBr): 3386,} 3135, 3051, 2930, 2846, 2790, 1562, 1497, 1439, 134 8, 1307, 1267, 1227, 1116 cm- '.

 [Example 30] 9— (benzimidazol-2-yl) thio—4— (2-piperazinoethylthio) —5H——6,7,8,9-tetrahydrocycloheptane [b] pyridine

Colorless amorphous.

 'H-NMR (CDCh): δ 1.20-3.20 (21H, m), 4.88 (2H, m), 5.12 (2H, m), 5.72 (1H, br), 6.87-7.70 (5H, m), 8.16 ( 1H, d).

_{IRy ma x (KBr): 3377} , 3153, 3033, 2924, 2809, 1561, 1438, 1339, 1274, 115 3, 1125, 1005, 819, 741 cm-

 [Example 3 1] 41- (2-piperidinoethylthio) 191 (-purine-6-yl) thio-5H-7,9-tetrahedral Drosik mouth hepta [b] Pyridine colorless Crystal (melting point 83-85 ° C).

_{'H - NMR (CDC1 3)} : δ 1.30-2.75 (18H, m), 2.93-3.24 (4H, m), 5, 85 (1H, br), 6.9 8 (1H, d), 8.17 (2H, m ), 8.72 (1H, br).

_{IRy ma x (KBr): 3423} , 3088, 3042, 2930, 2837, 2800, 1562, 1439, 1377, 132 2, 1240, 1116, 847 cm '1.

[Example 3 2] 9— (benzimidazol-2-yl) thio 4— (3-morpho Linopropylthio) 1 5H—6,7,8,9— ■ ^ trahydrocyclohepta “bl pyridine

Colorless amorphous.

_{'H-NMR (CDC1 3)} : δ 1.20-2.35 (10H, m), 2 · 45 (4Η, m), 2.85-3.20 (4Η, m), 3.69 (4Η, m), 5.17 (1H, br) , 6.91-7.57 (5H, m), 8.18 (1H, d).

IR _max (KBr): 3135, 3063, 2926, 2846, 2800, 1566, 1504, 1435, 1347, 126 7, 1229, 1117, 912 cm— '.

 [Example 3 3] 41- (2-morpholinoethylthio) -18- (purin-6-yl) thio 5,6,7,8-tetrahydrocyclohexa [b] pyridine

Colorless crystal (melting point: 23-22 ° C).

 Ή-NMR (CDC "): δ 1.88-2.86 (12H, m), 3.17 (2H, m), 3.76 (4H, t), 5.58-5.85 (1H, br), 7.05 (1H, d), 8.03 (1H, s), 8.37 (1H, d), 8.6K1H, s).

IR _max (KBr): 3414, 3088, 3046, 2938, 2856, 2807, 1563, 1434, 1322, 124 0, 1163, 1117, 1002, 920, 847, 645 cm '.

 [Example 3 4] 81- (benzi midazol-2-yl) thio 4- (2,1-morpho linolethiol) 1,5,6.7,8-tetrahydrocyclohexa bl bl pyridine colorless crystal (melting point: 74 to 76) ° C).

 Ή-NMR (CDC "): 6 1.76-2.42 (6H, m), 2.52 (4H, t), 2.64-2.79 (2H, ra), 3.05-3.2K2H, m), 3.74 (4H, t), 4.78 (1H, t), 7.06 (1H, d), 7.13-7.26 (2H, m), 7.51-7.61 (2H, m), 8.34 (1H, d).

lR (neat): 3134, 3050, 2955, 2856, 2809, 1732, 1617, 1567, 1436, 1 267, 1117, 911, 734 cm— ¹ .

 [Example 35] 82 (5-Methyl-1,3,4-thiadiazol-2-yl) thio4-1 (2-morpholinoethylthio) -1.5,6,7,8-tetrahydrocyclohexa [b ] Pyridine

Colorless crystals (melting point 86-87 ° C).

Ή-NR (CDC): δ 1.68-2.40 (6H, m), 2.52 (4H, t), 2.69-2.78 (2H, m), 2.73 (3H, s), 3.04- 3.20 (2H, m), 3.75 (4H, t), 5.12- 5.34 (1H, br), 6.98 (1H, d), 8.32 (1H, d). IR _max (KBr): 2934, 2852, 2809, 1559, 1542, 1489, 1398, 1375, 1116, 106 7, 1038, 866 cm— ¹ .

 [Example 36] 4-((2-morpholinoethylthio) -18- (pyrimidine-12-yl) thio-5,6,7,8-tetrahydrocyclohexa [b] pyridine yellow powder (melting point 48) (~ 50 ° C).

 'H-NMRCCDCh): δ 1.82-2.41 (6Η, m), 2.53 (4H, t), 2.71-2.79 (2H, m), 3.05- 3.19 (2H, m), 3.74 (4H, t), 5.28- 5.52 (1H, br), 6.93-7.02 (2H, m), 8.34 (1H, d), 8.54 (2H, d).

IR _max (KBr): 2934, 2846, 2809, 1562, 1547, 1442, 1380, 1183, 1116 cm— '. [Example 3 7] 8— (4-Hydroxypyrimidine-1-yl) Chioni 4 -(2 ^^ Notylthio) 1 ^, 6,7,-^^ Drocyclohexa [b] pyridine

Colorless amorphous.

 'H-NMRCCDC): δ 1.79-2.38 (6H, m), 2.53 (4H, t), 2.72 (2H, t), 3.07-3.22 (2H, m), 3.74 (4H, t), 4.86 (1H, t), 6.20 (1H, d), 7.07 (1H, d), 7.77 (1H, d), 8.36 (1H, d).

IR _max (KBr): 2937, 2856, 2812, 1682, 1566, 1530, 1454, 1271, 1116, 730 cm—

 [Example 38] 8- (4,6-dimethylpyrimidin-2-yl) thio 4- (2-morpholinoletylthio) -1,5,6,7,8-tetrahydrocyclohexa [b] pyridine

Colorless oil.

 Ή-NMRCCDCla): δ 1.82- 2.30 (6H, m), 2.39 (6H, s), 2.54 (4H, 0, 2.62-2.77 (2H, m), 2.96-3.19 (2H, m), 3.75 (4H, t), 5.35-5.51 (1H, br), 6.69 (1H, s), 6.94 (1H, d), 8.33 (1H, d).

IR _max (neat): 3445, 2935, 2854, 2810, 1579, 1561, 1533, 1440, 1262, 1 117, 731 cm

[Example 3 9] 8- (5-amino-1,3,4-thiadiazole-2-yl) thio-14-1 (2-morpholinoethylthio) -1,5,6,7,8-tetrahydrosic Mouthhexa [b] pyridine

Colorless crystals (mp 180-181 ° C).

H-NMRCCDCh): 5 1.82-2.37 (6H, m), 2.53 (4H, t), 2.70-2.79 (2H, m), 3.01-3.20 (2H, m), 3.74 (4H, t), 4.83-5.09 (1H, br), 6.98 (1H, d), 8.33 1H, d), IR (KBr): 3280, 3097, 2932, 2844, 2812, 1633, 1560, 1510, 1439, 111 9, 1039, 649 cm— ¹ .

 [Example 40] _4-Methoxy 9- (5-ditrobenzimidazol-l- 2-yl :) thio 5H2 6,7,8, -9-teto_ ^ hydroncrota [b] pyridine Yellow crystals (mp 198-200 ° C).

_{'H-NMR (CDC1 3)} : 6 1.42- 2.43 (6H, m), 2.8K1H, dd), 3.26 (1H, dd), 3.89 (3H, s), 5.17 (1H, t), 6.77 (1H, d), 7.52 (1H, d), 8.09 (1H, dd), 8.3K1H, d), 8.39 (1H, d).

_{IRv max (KBr): 3097,} 2926, 2854, 2716, 1735, 1621, 1581, 1516, 1475, 142 7, 1333, 1243, 1191, 1092, 1052 cm 1.

 [Example 41] 9- (imidazole-2-yl) thio 4-methoxy-5H-6,7,8,9-tetrahydrocyclohep [b] pyridine

Colorless crystal (mp 159-161 ° C).

_{'HN R (CDC1 3):} δ 1.08-2.20 (8H, m), 2.88-3.15 (2H, m), 3.87 (3H, s), 4.79 (1H, t), 6.7K1H, d), 7.00 (2H , S), 8.11 (1H, d).

IR _rema KBr): 3405, 3098, 3005, 2924, 2846, 2763, 2679, 2642, 1579, 154 4, 1473, 1330, 1289, 1137, 1093, 1054 cm " ¹ .

 [Example 4 2] 8- (benzimidazol-2-yl) thio 4 _ (2- (2-methoxyethoxyquin) ethoxy) 1,5,6,7,8-tetra_ ^ docyclohexa [b] Pyridine

Colorless amorphous.

_{'H-NMR (CDC1 3)} : δ 1.70-2.12 (2H, m), 2.18- 2.45 (2H, m), 2.60-2.88 (2H, m), 3.38 (3H, s), 3.50-3.97 (6H, m), 4.19 (211, brm), 4.72 (1H, br), 6.72 (1H, d), 7.09-7.66 (4H, m), 8.36 (1H, d).

IR _max (neat): 3051, 2933, 2874, 1673, 1581, 1441, 1351, 1295, 1267, 1 111, 926 cm— '.

Example 4 3 ⁽² i ⁽² Ichime Tokishietokin) ethoxy) Single 8- (pre Hmm 6 I le) Chio one 5, 6, 7, hexa [b] to the 8-Te Bok Rahi Doroshikuro pyridine down

Colorless amorphous.

 'H-NMR (CDCh): δ 1.80-2.14 (2H, m), 2.20-2.45 (2H, m), 2.50-2.92 (2H, m), 3.40 (3H, s), 3.49-3.97 (6H, m ), 4.22 (2H, brm), 5.50 (1H, br), 6.70 (1H, d), 8.05 (1H, br), 8.36 (1H, d), 8.63 (1H, br).

_{IRi ma x (neat): 3088} , 3042, 2935, 2679, 1556, 1455, 1384, 1316, 1237, 1 107, 1065 cm- '.

 [Example 44] 4- (3-Methylthiopropoxy) -18- (purine-6-yl) thio-5,6,7,8-tetrahydronclohexa [b] pyridine

Colorless crystal (melting point (decomposition) 220-250 ° C).

■ H-NMRCCDCh): δ 1.60-3.10 (7H, m), 2.14 (3H, s), 2.7K2H, t), 4.22 (2H, t), 5.40 (1H, br), 6.8K1H, d), 8.20 . (1H, br), 8.49 (1H, d), 8.71C1H, br) IRv ma x (Br): 3435, 3126, 1592, 1445, 1405, 1247, 1177, 1110, 1019 cm 1.

 [Example 4 5] 8-1- (benzimidol-2-yl) thio-4- (3-methoxypropoxy) -1,5,6,8-tetrahydrocyclohexa [b] pyridine Colorless amorphus.

_{'H-NMR (CDC1 3 +} CD 3 0D): δ 1.70-2.85 (8H, m), 3.37 (3H, s), 3.58 (2H, t), 4.15 (2H, t), 4. T4 (1H, br), 6.73C1H, d), 7.10-7.77 (4H, m), 8.34 (1 H, d).

IR _max (KBr): 3414, 3051, 2932, 2865, 1582, 1507, 1438, 1339, 1293, 118 8, 1118 cm " ¹ .

 [Example 46] 4- (3-Methoxy) propoxy-1- (5-methyl-1-, 1,3,4-thiadiazol-2-yl) thio-5,6,7,8-tetrahydrocyclohexa [b] pyridine

Colorless oil.

'H-NMRCCDCh): δ 2.70-3.05 (8H, m), 2.73 (3H, s), 3.35 (3H, s), 3.54 (2H, t), .09 (2H, t), 5.22 (1H, br ), 6.63 (1H, d), 8.31 (1H, d). IR V max (neat): 3377, 2921, 2865, 1577, 1460, 1377, 1291, 1191, 1109, 1061, 1041 cm

 [Example 47] 4- (3-Methoxypropoquine) -18- (purine-6-yl) thio 5,6,7,8-tetrahydrocyclohexa [b] pyridine

Colorless crystal (melting point 186-18 ° C).

_{'H-NMR (CDC1 3)} : 6 1.85-2.89 (7H, m), 3.37 (3H, s), 3.58 (2H, t), 4.16 (2H, t), 5.53 (1H, br), 6.73 (1H , d), 8.03 (1H, brs), 8.38 (1H, d), 8.59 (1H, s). IR _max (KBr): 3414, 3088, 3042, 2939, 2874, 2521, 1563, 1459, 1385, 132 0, 1293, 1240, 1113, 839 cm

 [Example 4 8] 9- (Benzymidazol-1-yl) Thio-41 (2-hydroquinethyl) 1 5H—6,7,8,9-tetrahydrocyclohepta [b] pyridine

Colorless amorphous.

'H-NMR (CDCl3 + CD 3 0D): δ 1.50- 2.25 (8H, m), 3.13 (2H, m), 3.82 (2H, m), 5.27 (1H, br), 7.03- 7.67 (6H, br ), 7.0K1H, d), 8.12 (1H, d).

IR _max (KBr): 3376, 3153, 3079, 2925, 2846, 1562, 1507, 1437, 1405, 1349, 1269, 1228, 1046, 967, 819, 744, 661 cnT ¹ .

 [Example 49] 8-(benzimidazol-2-yl) thio-41- (2-pyridino) ethylthio-5,6,7,8-tetrahydronchlorohexa [bl pyridine pale yellow crystal ( (Melting point: 134-137 ° C).

 'H-NMRCCDCh): δ 1.23-3.28 (20Η, m), 4.79 (1H, brt), 7.02- 7.29 (3H, m), 7.44-7.65 (2H, m), 8.32 (1H, d).

1R Les _{max (neat): 3126, 3047} , 2934, 2846, 2800, 2210, 1559, 1542, 1507, 1 437, 1349, 1308, 1267, 1228, 1188, 1107 cm 1.

Example 5 0] 4- (2-Piberijino -) Echiruchio - 8- (purine one 6-I le 1_ Chio: ^{5-one 6, 7, 8} Niteto - to La t Doroshikuro hexa [b] pyridine

Light yellow crystals (melting point 205-209 ° C).

_{'H-NMR (CDC1 3)} : δ 1.20-3.30 (20H, m), 5.64 (1H, br), 7.06 (1H, d), 8.03 (1H, s), 8.3K1H, d), 8.66 (1H, s). IR (KBr): 3414, 3247, 3181, 3088, 3042, 2934, 2846, 2790, 1561, 143

8, 1322, 1240, 1191, 1107 cm— '.

 [Example 5 1] 4- (2-Piperidyl) ethylthio-1- (5-methyl-1,3,4-thiadiazol-2-yl) thio-1,5,6,7,8-tetrahydrocyclohexa [ b] pyridine

Yellow oil.

 'H-NMR (CDCh): δ 1.30-3.22 (20H, m), 2.74 (3H, s), 5.23 (1H, br), 6.97 (1H, d), 8.28C1H, d).

_{IR-les-ma x (neat): 3446,} 2932, 2851, 2801, 2754, 1557, 1435, 1375, 1308, 1 261, 1188, 1158, 1104, 1038 cm-

 [Example 5 2] 8- (benzimidazol-2-yl) thio-4 (2- (4-benzyl) piperidino) ethylthio-1,5,6,7,8-tetrahydrocyclohexa [b] pyridine

Light yellow crystal (melting point: 201-203 ° C).

 'H-NMRCCDC + CDaOD): δ 1.13-3.46 (21H, m), 4.75 (1H, br), 7.03-7.65 (10H, m), 8.29 (1H, d).

_{IR-les-ma x (KBr): 3395,} 3060, 3023, 2927, 2846, 2800, 1560, 1497, 1438, 134 9, 1266, 1237, 1191, 1107 cm 1.

 [Example 5 3] 4-(2-(4 べ: ピ)-pi ^ ^ dino) ethylthio 1-8-(purine 6-yl) thio 5, 6, 7, 1- Kisa [bl pyridine

Light yellow crystal (melting point: 183-187 ° C).

 'H-NMRCCDC): δ 1.12- 3.28 (21H, m), 5.67 (1H, br), 7.01-7.33 (6H, m), 7.99 (1H, brs), 8.32 (1H, d), 8.59 (1H , brs).

IR ^ _max (KBr): 3414, 3079, 3033, 2921, 2846, 2790, 1562, 1442, 1337, 132 1, 1237, 1125 cm '.

[Example 5 4] 4- (2- (4-benzyl) piperidino) ethylthio-1- (5-methyl-1,3,4-thiadiazol-2-yl) thio 5,6,7,8-tetra Trahydrocyclohexa [b] pyridine Colorless oil.

_{'H-NMR (CDC1 3)} : δ 1.12-3.2K21H, m), 2.73 (3H, s), 5.23 (1H, brt), 6.95 (1H, d), 7.00-7.31 (5H, m), 8.27 ( 1H, d).

IR _max (neat): 3026, 2927, 2846, 2805, 2224, 1558, 1455, 1374, 1339, 1188, 1039 cm- ¹ .

 [Example 55] 8— (benzimidazol-2-yl) thio — 41- (3-morpholino) propylthoni 5,6,7,8-tetrahydrocyclohexa [b] pyridin

Light yellow crystal (melting point: 114-120 ° C).

 ■ H-NMRCCDC + CDsOD): δ 1.67-3.98 (20H, m), 4.78 (1H, br), 7.03-7.61 (5H, m), 8.29 (1H, d).

_{IRi ma x (KBr): 3399} , 3237, 2949, 2856, 1656, 1572, 1497, 1442, 1349, 126 5, 1115 cm- people

 [Example 5 6] 8-(benzimidazol-2-yl) thio-1 4-1 (2-thiomolholino) ethylthio 5.6.7,8-tetrahydrocyclohexa [b] pyridine

Colorless amorphous.

 'H-NMRCCDCh): δ 1.80-3.23 (18H, m), 4.77 (1H, brt), 7.04 (1H, d), 7.10-7.81 (4H, m), 8.33 (1H, d).

IR _max (KBr): 3421, 3058, 2929, 2856, 2811, 1561, 1508, 1499, 1467, 143 8, 1406, 1344, 1267, 1179, 1119, 1006 cm.

 [Example 5 7] 81- (benzimidazol-2-yl) thio-4 (2- (2H—1,4_benzothiazine-3 (4H) -one-4-yl) ethylthio-5 , 6,7,8-tetrahydrocyclohexane [b] pyridine

Colorless crystal (mp 174-175 ° C).

 'H-NMRCCDCh): δ 1.86-2.77 (7H, m), 3.39 (2H, dd), 3.4K2H, s), 4.25 (2H, dd), 4.78 (1H, br), 6.92-7.63 (9H, m ), 8.37 (1H, d).

IR _max (KBr): 3414, 3060, 2949, 2856, 2790, 1676, 1655, 1560, 1508, 145 8, 1440, 1395, 1268, 1230, 1184, 1143 cm " ¹ . [Example 5 8] 8-(benzimidazol-2-yl) thio 4 _ (2- (3-ethoxybonyl) piperidinoethylthio) 1,5,6,7,8-tetrahydrocyclohexa [b ] Pyridine

Colorless amorphous.

 'H-NMRCCDCh): δ 1.26 (3Η, t), 1.40-3.25 (19H, m), 4.14 (2H, q), 4.79 (1H, brt), 7.01-7.21 (3H, m), 7.37-7.63 ( 2H, m), 8.3K1H, d).

lRy _ma KBr): 3135, 3060, 2943, 2856, 2800, 1730, 1618, 1563, 1497, 143 9, 1358, 1265, 1181, 1107, 1033 cm— ¹ .

 [Example 5 9] 8- (benzimidazol-2-yl) thio-4- (2- (3-hydroxycarbonyl) piberidinoethylthio) 1,5,6,7,8-tetrahydrido Cyclohexa [b] pyridine

Light brown amorphous.

 'H-N RCCDC): δ 1.58-3.29 (19H, brm), 4.78 (1H, bt), 6.98-7.22 (3H, m), 7.49-7.63 (2H, m), 8.33 (1H, d).

IR maxCKBr): 3405, 3247, 2949, 2856, 2809, 1561, 1414, 1349, 1274, 1200, 1097 cm " ¹ .

 [Example 60] 8— (benzimidazol-2-yl) thio 41- (2-pyrrolinoe-norethio) 1,5,6,7,8-tetrahydrocyclohexa “b”! Pyridine Colorless amorphous.

'H- Tsuyoshi _{R (CDC1 3): 6 1.48-2.74} (14H, m), 2.82 (2H, d), 3.17 (2H, d), 4.74 (1H, brs), 7.07 (1H, d), 7.05- 7.27 (2H, m), 7.38-7.68 (2H, m), 8.3K1H, d).

_{IR ^ m ax (Br):} 3395, 3135, 3049, 2957, 2874, 2796, 1561, 1438, 1406, 135 0, 1267, 1227, 1191 cm - 1.

 [Example 6 1] 8- (Benzimidazol-2-yl) thio-41- (2-thiazo-zin-1-3-ylethylthio) -1,5,6,7,8-tetrahydrocyclohexa [b] pyridine

Colorless amorphous.

_{'H-NMR (CDC1 3)} : δ 1.80-2.17 (2H, m), 2.22-2.48 (2H, m), 2.56- 3.25 (12H, m), 4.1K2H, s), 4.78C1H, brt), 7.01 -7.22 (3H, m), 7.42-7.60 (2H, m), 8.33 (1H , d).

IR _max (Br): 3386, 3135, 3057, 2943, 2868, 1566, 1544, 1508, 1499, 146 7, 1438, 1406, 1348, 1309, 1267, 1226, 1188 cm- ¹ .

 [Example 6 2] 8- (benzimidazol-2-yl) thio-4-1 (2- (3-ethoxycarbonyl) piberidinoethylthio) -1,5,6,7,8-tetrahydro Cyclohexa [b] pyridine

Colorless amorphous.

_{'H-NMR (CDC1 3)} : δ 1.26 (3H, t), 1.40-2.24 (19H, m), 4.14 (2H, q), 4.76 (1H, brt), 7.03-7.27 (3H, m), 7.44 -7.63 (2H, m), 8.34 (1H, d).

IR v _max (KBr): 3135, 3051, 2944, 2800, 1727, 1566, 1497, 1438, 1311, 126 5, 1183, 1046 cm—

 The following compounds were synthesized according to the method of Example 2.

 [Example 6 3] 4- (2-morpholinoethylthio) -1-91 (1H-pyrazo-mouth [3,4-d] pyrimidine-14-yl) Chi-5H- 6,7,8 , 9-Tetrahydrid p-blot

Yellow crystals (melting point 83-85 ° C).

 Ή-NMR (CDC "): 6 1.68-2.29 (6H, m), 2.53 (4H, t), 2.69-3.17 (6H, m), 3.74 (4H, t), 5.80-6.12 (1H, br), 7.00 (1H, d), 8.19 (1H, s), 8.25 (1H, d), 8.79 (1H, s).

_{IRv ma x (KBr): 3181} , 3107, 2923, 2852, 2809, 1561, 1450, 1403, 1259, 111 6, 1002, 936, 840, 787 cm-

[Example 6 4] 4- (2- (2-Methoxyxetoxy) ethoxy) 18- (1H-Hinirazolo [ ³ , -d] pyrimidine-41-yl) thio-5,6,8-tetra y rocyclohexa [b] pyridi

Colorless amorphous.

_{'H-NMR (CDC1 3)} : δ 1.80-2.14 (2H, m), 2.20-2.44 (2H, m), 2.52-2.88 (2H, m), 3.4K3H, s), 3.49-3.98 (6H, m ), 4.20 (2H, brm), 5.76 (1H, br), 6.65 (1H, d), 7.92 (1H, s), 8.37 (1H, d), 8.66 (1H, s).

_{IRz ma x (neat): 3088} , 2921, 2865, 1558, 1455, 1384, 1302, 1247, 1109, 1 061, 933, 837 cm- ¹ .

 [Example 6 5] 4-(2 1 morpho-noethylthio) 1 8-(1 H-pyrazo opening [3, 4-d] pyrimidine 1-4 -yl) 1, 6, 6, 7, 8- Tetrahydrodic mouth hexa [b] pyridi

Light yellow amorphous.

_{'H-NMR (CDC1 3)} : δ 1.91-2.40 (6H, m), 2.56 (4H, t), 2.77-2.83 (2H, m), 3.06- 3.25 (2H, m), 3.77 (4H, t) , 5.70-5.85 (1H, br), 7.05 (1H, d), 7.82 (1H, s), 8.43 (1H, d), 8.62 (1H, s).

_{IR raax (Br): 3082,} 2933, 2856, 2812, 1561, 1447, 1402, 1268, 1116, 935, 840, 730 cm 1.

 [Example 6 6] 4- (3-Methoxy) propoxy-8- (1H-pyrazo-mouth [3,4-d] pyrimidine-14-yl) Chi-5,6,7,8- Tetrahydronchlorohexa [b] pyridine

Yellow crystals (mp 177-179 ° C).

_{'H-NMR (CDC1 3)} : δ 2.60- 3.08 (8H, m), 3.36 (3H, s), 3.55 (2H, t), 4.13 (2H, t), 5.70 (1H, br), 6.68 (1H , d), 7.72 (1H, s), 8.43 (1H, d), 8.56 (1H, s).

IR (KBr): 3414, 3181, 3079, 2935, 2880, 1579, 1561, 1459, 1405, 131 5, 1295, 1254, 1217, 1191, 1115, 1059 cm—

 [Example 6 7] 4- (2-morpholinoethylthio) -8- (4 (3H) -quinazolinone-1-yl) thio 5,6,7,8-tetrahydronchlorohexa [b] pyridine

Colorless crystal (melting point: 144-146 ° C).

'Eta - Tsuyoshi _{R (CDC1 3): δ 1.51-2.41} (6Η, m), 2.54 (4H, t), 2.67-2.81 (2H, m), 3.08- 3.25 (2H, m), 3.75 (4H, t ), 4.81-4.95 (1H, m), 7.08 (1H, d), 7.38-7.80 (3H, m), 8.24 (1H, d), 8.40 (1H, d).

IR v _max (KBr): 3449, 2949, 2850, 1687, 1560, 1467, 1260, 1160, 1117, 762, 614 cm- ¹ .

[Example 6 8] 41- (2-piperidino) ethylthio-1- (birazolo [3,4-d] pyrimidin-1-yl) thio 5,6,7,8-tetrahydroclone [B] pyridine

Light yellow crystal (melting point: 185-187 ° C).

 'H-NMRCCDCh + CDaOD): <5 1.22-3.50 (20H, m), 5.78 (1H, br), 7.19 (1H, d), 7.99 (1H, s), 8.33 (1H, d), 8.68 (1H, s).

IRi _max (KBr): 3375, 2945, 1637, 1560, 1448, 1405, 1269, 1142 cm ¹ .

 [Example 6 9] 4- (2- (4-benzyl) piperidino-) ethylthio-81- (pyrazo-mouth [3,4-d] pyrimidine-1-4-yl) chi-5,6,7 8-tetrahydronchlorohexa [b] pyridine

Light yellow crystal (melting point: 160-162 ° C).

_{'H-NMR (CDC1 3)} : δ 1.12-3.38 (21H, m), 5.74 (1H, br), 6.90-7.35 (6H, m), 7.8 6 (1H, s), 8.36 (1H, d), 8.63 (1H, s).

_{IR m ax (KBr): 3423} , 3172, 3086, 2925, 2805, 2754, 1560, 1447, 1401, 132 8, 1267, 1217, 1140, 1107 cnT 1.

 [Example 70] 41- (3-morpholino) propylthio-1- (birazolo ラ 3,4-dlpyrimidine-14-yl) thio 5,6,7,8-tetrahydrocyclohexa [b] Pyridine

Light yellow crystals (melting point 109-112 ° C).

 'H-NMRCCDC + CDsOD): δ 1.71-3.94 (20H, m), 5.78 (1H, br), 7.00 (1H, d), 7.99 (1H, s), 8,30 (1H, d), 869 (1H, s).

1R _max (KBr): 3423, 3181, 3105, 2938, 2856, 2809, 1561, 1449, 1401, 133 0, 1257, 1216, 1139, 1117 cm— ¹ .

 [Example 7 1] 4- (2-thiomorpholino) ethylthio-1- (birazo p [3, _4-d] pyrimidine-1-41) thio: 5,6 ^ 78 ditetrahydrodronic chloride [ b] pyridine

Light yellow crystal (melting point 144-148 ° C).

 'H-NMRCCDCh): δ 1.70-3.42 (18H, m), 5.78 (1H, br), 6.93 (1H, d), 8.00 (111, s), 8.29 (1H, d), 8.70 (1H, s) .

_{IR ma x (KBr): 3420} , 3200, 3107, 3060, 2933, 2809, 2772, 1560, 1458, 143 9, 1400, 1270 cm 1. [Example 7 2] 8— (1 H-pyrazo mouth [3,4-d] pyrimidine-1-41yl) thio-4— (2-pyrrolidinoethylthio) -1 5.—6,7,8— Tetrahydrodic mouth hexa [b] pyridi

Yellow morphus.

_{'H-NMR (CDC1 3)} : δ 1.74-2.82 (14H, m), 2.87 (2H, dd), 3.2K2H, dd), 5.86 (1H, brs), 7.06C1H, d), 7.79 (1H, s ), 8.38 (1H, d), 8.56C1H, s).

 IR max (Br): 3405, 3181, 3088, 2940, 2865, 2800, 1560, 1442, 1405, 1330, 1265, 1191, 1144 cm—

 The following compounds were synthesized according to the method of Example 5.

Example 7 _3] 9 Γ (1 Etokishika Boniru - 5 two Torobe Nzuimidazoru one 2- Inore) Chio one 4-menu butoxy one 5 Η- 6, 7, 8, 9 Tetorahi Doroshikuro heptene evening [b] Lysine

Colorless crystals (mp: 188-190 ° C).

'H-顧_{(CDC1 3): δ 1.09-3.42 (} 11H, m), 3.86 (3H, s), 4.65 (2H, brq), 5.66 (1H, r), 6.70 (1H, d), 7.62 (1H , D), 7.89-8.75 (3H, m).

 IR (KBr): 3448, 3096, 2925, 2851, 1755, 1578, 1523, 1435, 1376, 132 8, 1277, 1240, 1200, 1137, 1082, 1054, 1011 cm—

 [Example 7 4] 8- (1-Methylbenzimidazol-2-yl) thio_4-1- (2-morpholinoethylthio) -5,6,7,8-tetrahydrocyclohexa "b

] Pyridines

Colorless amorphous (viscous).

_{'H-NMR (CDC1 3)} : δ 1.90-2.80 (12H, m), 3.00-3.17 (2H, m), 3.67-3.79 (4H, in), 5.38 1H, br), 6.95 (1H, d), 7.24 (2H, br), 7.55- 7.76 (2H, brm), 8.27 (1H, d),

IR ^ _max (neat): 3421, 3060, 3023, 2938, 2854, 2811, 1562, 1444, 1417, 1359, 1280, 1237, 1116, 1043, 1005 cm

 The following compounds were synthesized according to the method of Example 6.

[Example 75] 8- (benzimidazol-2-yl) thio 4- (2-morpholino) ethoxy-5,6,7,8-tetrahydrocyclohexapyridine Colorless amorphous.

 ■ HN RCCDC): δ 1.65-2.08 (2H, br), 2.08-2.41 (2Η, br), 2.41-2.95 (2H, br), 2.55 (4H, t), 2.79 (2H, d), 3.70 (4H , t), 4.11 (2H, d), 4.62- 4, 88 (1H, br), 6.63 (1H, d), 7.09-7.20 (2H, m), 7.48-7.59 (2H, m), 8.32 (1H , d).

_{IRv ma x (KBr): 3367} , 3135, 3051, 2940, 2856, 2800, 1580, 1439, 1293, 111 5, 742 cm one '.

 The following compounds were synthesized according to the method of Example 7.

 [Example 7 6] 8— (benzimidazol-2-yl) thio 4— (21- (2- (2-methoxetoxy) ethoxy) ethylthio) 1,5,6,7,8-tetrahide ^^ G g hexane [b] pyridine

Colorless oil.

'.Eta. Tsuyoshi _{R (CDC1 3): δ 1.60-2.94C6H} , m), 3.21 (2H, t), 3.37 (3H, s), 3.45-3.88 (10H, m), 4.75 (1H, brt), 7.09 -7.28 (3H, m), 7.40-7.65 (2H, brm), 8.31 (1H, d).

_{IRi ^ ma x (neat):} 3135, 3051, 2930, 2878, 1566, 1497, 1442, 1405, 1351, 1 267, 1196, 1104 cm- 1.

 [Example 7 7] 4- (2- (2- (2-Methoxyethoxy) ethoxy) ethylthio) -1- (5-methyl-1,3,4-thiadiasol-2-yl) thio5,6 7, 8-tetrahydrocyclohexa [b] pyridine

Yellow oil.

 'H-NMRCCDCh): δ 1.70-2.90 (6H, m), 2.73 (3H, s), 3.19 (2H, t), 3.37 (3H, s), 3.48-3.95 (10H, m), 5.25 (1H, brs), 7.00 (1H, d), 8.29 (1H, d).

1R _ma neat): 3406, 2921, 2874, 1637, 1563, 1447, 1403, 1293, 1247, 1196, 1103, 1041 cm— '.

 [Formulation Example 1]

 150 g of the compound of Example 9

 Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g

 30g corn starch

Magnesium stearate 2g Hydroxypropylmethylcellulose 10g Polyethylene glycol 6003g Castor oil 40g Methanol 40g After mixing and polishing the compound of the present invention, Avicel, corn starch and magnesium stearate, the mixture is tableted with sugar coating R10 # kine. The obtained tablets are coated with a film coating agent comprising hydroxypropyl methylcellulose, polyethylene glycol-600, castor oil and methanol, and a film-coated tablet containing 15 Omg of the compound of the present invention is obtained. 0 tablets are manufactured.

 [Formulation Example 2]

 Compound of Example 9 150 g l.Og lactate 33.5 g Dicalcium phosphate 70.0 g Pluronic F-6 83.0 g sodium lauryl sulfate 0.0 g polyvinylpyrrolidone 15.0 g polyethylene glycol 500 g) Polyethylene glycol (600 000 rubourax) 45.0 g corn starch 30.0 g dried sodium lauryl sulfate 3.0 g dried magnesium stearate 3.0 g ethanol

The compound of the present invention, citrate, lactose, dicalcium phosphate, pull nick F168 and sodium laurin sulfate are mixed. The above mixture is sieved with a No. 60 screen and wet granulated with an alcoholic solution containing polyvinylpyrrolidone, potassium wax 150 and 600. If necessary, alcohol is added to make the powder into a paste-like mass. Add corn starch and continue mixing until uniform particles are formed. No. 10 Pass through the screen, put it in the tray, and press — Dry in a bun for 12-14 hours. The dried particles are sieved through a No. 16 screen, dry sodium lauryl sulfate and dry magnesium stearate are added, mixed and compressed into the desired shape with a tablet press. Treat the above core with varnish, spray talc to prevent moisture absorption. An undercoat layer is coated around the core. Apply enough varnish for internal use. Further subbing layers and smooth coatings are applied to make the tablets completely round and smooth. Color coating is carried out until the desired hue is obtained. After drying, the coated tablets are polished to give tablets of uniform gloss, and 100,000 tablets containing 15 O mg of the compound of the present invention are produced.

 [Formulation Example 3]

 50 g of the compound of Example 34

 Amoxicillin 50g

 Lactose 55g

 Crystalline cellulose 20g

 20g corn starch

 3% aqueous solution of hydroxypropylcellulose 100ml Magnesium stearate 2g

 The compound of the present invention, amoxicillin, lactose, crystalline cellulose and corn starch were mixed, put into a kneading machine with a No. 60 screen, and kneaded by pouring an aqueous solution of 3% hydroxypropyl pill cellulose. . The mixture was sieved with a No. 16 screen, granulated, and dried by blowing at 50 ° C. After drying, sieving is performed, dried magnesium stearate is added and mixed, and the mixture is tabletted with a tableting machine. If necessary, sugar coating or film coating is applied to obtain 5 Omg of the compound of the present invention and 5 mg of amoxicillin. 100 mg of sugar-coated tablets or film-coated tablets containing O mg are prepared.

 [Formulation Example 4]

 50 g of the compound of Example 9

 Amoxicillin 50g

 Lactose 200g

 97g corn starch

Magnesium stearate 3g The compound of the present invention, amoxicillin, lactose, corn starch and magnesium stearate are finely powdered and mixed well so as to be uniform.Then, 20 mg of the compound of the present invention is filled into gelatin capsules, and 25 mg of the compound of the present invention and 2000 capsules containing 25 mg of amoxicillin are prepared.

 [Formulation Example 5]

 Compound of Example 9 50 g Clarithromycin 50 g Lactose 150 g Crystalline cellulose 50 g Corn starch 54 g CarboxymethylcelluloseCa 40 g Magnesium stearate 6 g Compound of the present invention, clarithromycin, lactose, crystalline cellulose, cone starch and carboxymethylcellulose The Ca was mixed, and the mixture was kneaded by a No. 60 screen into a sieve kneader. The mixture was sieved with a No. 16 screen, granulated, and dried by blowing at 50 ° C. After drying, sizing is performed, dried magnesium stearate is added and mixed, and the mixture is tabletted with a tableting machine. If necessary, sugar coating or film coating is applied to obtain 5 mg of the compound of the present invention 5 mg Manufacture 100 tablets of sugar-coated tablets or film-coated tablets containing Omg.

 [Formulation Example 6]

 Example 3 Compound of 4 80 g Amoxicillin 20 g Lactose 55 g Microcrystalline cellulose 20 g Corn starch 20 g

3% Hydroxypropylcellulose aqueous solution 100ml Magnesium stearate 2g The compound of the present invention, amoxicillin, lactose, crystalline cellulose and corn starch are mixed, and the mixture is placed in a screen kneading machine with a No. 60 screen, and the mixture is mixed with 3% hydroxypropyl. An aqueous pill cellulose aqueous solution was poured and kneaded. The mixture was sieved with a No. 16 screen, granulated, and dried by blowing at 50 ° C. After drying, the mixture is sized, dried magnesium stearate is added and mixed. The mixture is tabletted with a tableting machine, and if necessary, sugar-coated or film-coated to give 8 Omg of the compound of the present invention and 2 Omg of amoxicillin. Sugar-coated tablets or film-coated tablets were prepared into 100 tablets.

 [Formulation Example 7]

 Compound of Example 9 75 g Amoxin phosphorus 25 g Lactose 200 g Corn starch 97 g Magnesium stearate 3 g The compound of the present invention, amoxicillin, lactose, corn starch and magnesium stearate are finely powdered and thoroughly mixed so as to be uniform. This was filled into gelatin capsules at a concentration of 200 mg, to produce 2000 capsules containing 37.5 mg of the compound of the present invention and 12.5 mg of amoxicillin.

 [Formulation Example 8]

Compound of Example 9 66.7 g Clarithromycin 33.3 g Lactose 150 g Crystalline cellulose 50 g Corn starch 54 g CarboxymethylcelluloseCa 40 g Magnesium stearate 6 g The quinmethylcellulose / Ca was mixed and put into a sieve kneading machine with a No. 60 screen and kneaded. The mixture was sieved with a No. 16 screen, granulated, and dried by blowing at 50 ° C. After drying, sieving is performed, dried magnesium stearate is added and mixed, and the mixture is tabletted with a tableting machine. If necessary, sugar coating or film coating is applied to obtain 66.7 mg of the compound of the present invention and clarithro Mycin 33.3 mg A sugar-coated tablet or a film-coated tablet containing 100 mg was prepared. Industrial applicability

 The cycloalkanopyridine derivative of the present invention has a selective antibacterial action against Helicobacter pylori and is useful as a peptic ulcer agent.

Claims

-General formula (I)

 Contract

(In the formula, R ¹ represents a hydrogen atom, a hydroxyl group, an optionally substituted lower alkoxy group, a lower alkylthio group, an amino group, a mono- or di-substituted amino group or a cyclic amino group, and R ² represents a hydrogen atom. Or a lower alkyl group; R ³ is a monocyclic or condensed-ring aromatic heterocyclic group containing two or more nitrogen atoms; m is an integer of 1, 2 or 3; n is 2 or 3 And X is a sulfur atom or an oxygen atom.) And a pharmacologically acceptable salt thereof.

 2. A complex formed from a metal salt selected from aluminum salts, bismuth salts or zinc salts and the compound according to claim 1.

 3. The compound or complex formed product according to claim 1, wherein R ′ is an amino group, a mono- or di-substituted amino group or a cyclic amino group.

 4. The compound or complex-formed product according to claim 1, wherein R ′ is a lower alkoxy group which may be substituted.

 5. The compound or complex of claim 1, 2, or 3, wherein X is a sulfur atom.

 6. General formula (II)

(11:

(Wherein, R ¹ represents a hydrogen atom, a hydroxyl group, an optionally substituted lower alkoxy group, a lower alkylthio group, an amino group, a mono- or di-substituted amino group or a cyclic amino group, and R ² represents a hydrogen atom or a lower amino group. M represents an integer of 2 or 3, m represents an integer of 2 or 3, X represents a sulfur atom or an oxygen atom, γ represents a halogen atom, a lower alkylsulfonyloxy group or And a compound represented by the formula (II):

R ³ — SH (III)

(Wherein, R ³ represents a monocyclic or condensed-ring aromatic heterocyclic group containing two or more nitrogen atoms.) A compound represented by the formula: Manufacturing method of compound.

 7. The complex-forming product according to claim 2, wherein a metal salt selected from aluminum salts, bismuth salts, or zinc salts and the compound according to claim 1 are dissolved in a solvent and reacted. Manufacturing method.

 8. —General formula (I-1)

(Wherein, R ² represents a hydrogen atom or a lower alkyl group, R ³ represents a monocyclic or condensed-ring aromatic heterocyclic group containing two or more nitrogen atoms, and m represents an integer of 1, 2, or 3. And n represents an integer of 2 or 3, X represents a sulfur atom or an oxygen atom.) And a compound represented by the general formula (IV)

R ⁴ ~ B (IV)

(Wherein, IT represents an amino group, a nitrogen substituent convertible to an amino group, a mono- or di-substituted amino group or a cyclic amino group, and B represents a hydrogen atom or an alkali metal.) 4. The method for producing a compound according to claim 3, wherein the compound is reacted.

9. At least one kind of the compound or the complex formed product according to any one of claims 1 to 5, and one to three kinds of drugs selected from antibacterial agents having antibacterial activity against Helicobacter pylori. A peptic ulcer which is used in combination.

 10. A peptic ulcer agent comprising at least one compound or complex formed product according to any one of claims 1 to 5 as an active ingredient.

 11. The peptic ulcer agent according to claim 10, comprising 1 to 3 drugs selected from antibacterial agents having antibacterial activity against Helicobacter pylori.