WO2004077367A1 - Tetracyclic sulfenamide compound - Google Patents

Abstract

A compound represented by the following formula (I): [wherein R1 represents hydroxy, hydrogen, etc.; R2 and R4 each represents lower alkyl, lower alkoxy, hydrogen, etc.; R3 represents lower alkyl optionally substituted by, e.g., halogeno, etc.; A represents a benzene ring, etc.; B represents a single bond, amino, or a group represented by -NR- (R represents lower alkyl, lower alkenyl, etc.); and Z represents a counter anion]. The compound has excellent proton pump inhibitory activity and is hence useful as a therapeutic agent for digestive ulcers.

Description

 Tetracyclic sulfonamide compounds Technical Fields ''

 The present invention relates to a tetracyclic sulfenamide compound having a proton pump inhibitory activity and useful as a therapeutic agent for peptic ulcer. Background art

The most common cause of peptic ulcers is excessive secretion of gastric acid. Therefore, for the treatment of peptic ulcer, histamine receptor antagonists represented by cimetidine, ranitidine, famotidine, nizatidine, oral xazidine, and omebrazole, esomebazole, lansoprazole, labebrazole, and pantoprazole are representatives. Gastric acid secretion inhibitors such as proton pump (H ⁺ ZK and ATPase) inhibitors have been used. These have a strong gastric acid secretion inhibitory effect and are widely used clinically because of their high therapeutic effect. Disclosure of the invention

However, the histamine H ₂ receptor antagonists, there antiandrogenic, for central operation, etc. and the like inhibitory activity of metabolic enzymes in the liver problems.

 In addition, existing proton pump inhibitors have problems such as ulcer recurrence after treatment, and in recent years, development of proton pump inhibitors with improved undesired effects has been desired.

In recent years, in addition to compounds having a benzimidazole skeleton such as omebrazole, esomebrazole, lansoprazole, rabeprazole, and pantoprazole, compounds having a proton pump inhibitory action have been reported. No. 4 In the publication, a pentacyclic compound having a sulfenamide skeleton is described as a compound having a proton pump inhibitory action. However, the above publication does not describe data on the proton pump inhibitory effect, and further improvement in activity, stability, and therapeutic effect are expected.

 In view of the above circumstances, the present inventors have conducted intensive studies, and as a result, have found that a certain tetracyclic compound has an excellent proton pump inhibitory action and is excellent in stability, and thus completed the present invention. .

 That is, the present invention provides the following formula (I)

(In the formula, R ¹ is a lower alkyl group optionally substituted by a hydroxy group or a lower alkoxycarbonyl group, a lower acyl group optionally substituted by a halogen atom, a cyano group, a carbonyl group, a hydroxy group, R ² and R ⁴ are the same or different and represent a lower alkyl group, a lower alkoxy group or a hydrogen atom, and R ³ represents 1 to 8 halogen atoms, a hydroxy group, 1 Represents a lower alkyl group which may have a substituent selected from a lower alkoxy group, a furyl group and a morpholino group which may be substituted with from 8 to 8 halogen atoms, and A represents a benzene ring, a pyridine ring or Represents a thiophene ring, B is a single bond, an amino group or one NR-(R is a halogen atom, a hydroxy group, a phenyl group, a hydroxyphenyl group, an amino group, a lower Kokishi group, a lower alkoxy force Ruponiru group and a lower Arukirua It represents a lower alkyl group or a lower alkenyl group which may have a substituent selected from a mino group. ) Represents a group, and Z represents a counter anion. ) Is provided.

 The present invention also provides a medicine containing the compound represented by the above formula (I).

 Furthermore, the present invention provides a pharmaceutical composition comprising the compound represented by the above formula (I) and a pharmaceutically acceptable carrier.

 Furthermore, the present invention provides a use of the compound represented by the above formula (I) for the manufacture of a medicament.

 Furthermore, the present invention provides a method for treating peptic ulcer, which comprises administering an effective amount of the compound represented by the above formula (I).

 Since the compound (I) of the present invention has an excellent proton pump inhibitory action, it is useful as a therapeutic agent for peptic ulcer. BEST MODE FOR CARRYING OUT THE INVENTION

 In the present invention, “lower” means a straight, branched or cyclic carbon chain having 1 to 6 carbon atoms.

Accordingly, the term "lower alkyl group" includes linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl. , Sec-butyl, tert-butyl, cyclobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, tert-pentyl, 1,2-dimethylpropyl, neopentyl, 1- Ethylpropyl group, cyclopentyl group, hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, isohexyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1-dimethylbutyl Group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3 -Dimethylbutyl group, 3,3-dimethylbutyl group, 1-methyl-1-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, cyclo Hexyl group and the like. Among these, a more preferred lower alkyl group is a linear or branched alkyl group having 1 to 4 carbon atoms.

As the "lower alkoxy group", a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropoxy group, butoxy group, isobutoxy group , _{s ec} - butoxy, tert - butoxy group, cyclobutoxy group, Penchiruokishi group, 1 one methylbutoxy group, 2-methylbutoxy group, isopentyl Ruo alkoxy group, tert- Penchiruokishi group, 1, 2-dimethyl propoxy group , Neopentyloxy, 1-ethylpropoxy, cyclopentyloxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, iso- Xyloxy, 1-ethylbutoxy, 2_ethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutyl Xy group, 1,3-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutoxy group, 3,3-dimethylbutoxy group, 1-methyl-1-ethylpropoxy group, 1-ethyl-2 —Methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,2,2-trimethylpropoxy group, cyclohexyloxy group and the like. Among these, a more preferred lower alkoxy group is a linear or branched alkoxy group having 1 to 4 carbon atoms.

"Lower alkenyl group" means a straight-chain, branched or cyclic alkenyl group having 2 to 6 carbon atoms having 1 to 3 double bonds, for example, a pinyl group, a 1-propenyl group, Aryl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 11-pentenyl, 2-pentenyl, 3-pentenyl, 41-pentenyl, cyclo Pentenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-1-hexenyl group, 5-hexenyl group, cyclohexyl Examples include a senyl group and a 1,3-butaenyl group. Among these, a more preferred lower alkenyl group is an alkenyl group having 2 to 4 carbon atoms and having one double bond.

 The term "lower acetyl group" refers to an acetyl group having 2 to 6 carbon atoms, and examples thereof include an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, a valeryl group, an isovaleryl group, and a pivaloyl group. Of these, a more preferred lower acyl group is one having 2 to 5 carbon atoms.

The "lower alkoxycarbonyl group" is a group formed by bonding the above-mentioned "lower alkoxy group" to a lower alkoxy group, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and an isopropoxycarbonyl group. Group, cyclopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, cyclobutoxycarbonyl group, pentyloxycarbonyl group, 1-methylbutoxycarbonyl group, 2-methylbutoxycarbonyl group Methylbutoxycarbonyl group, isopentyloxycarbonyl group, tert-pentyloxycarbonyl group, 1,2-dimethylpropoxycarbonyl group, neopentyloxycarbonyl group, 1-ethylpropoxycarbonyl group, cyclopentyloxycarbonyl Group, Hexyloxycarbonyl group, 1-methylpentyloxycarbonyl group, 2-methylpentyloxycarbonyl group, 3-methylpentyloxycarbonyl group, isohexyloxycarbonyl group, 1-ethylbutoxycarbonyl group , 2_ethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 2,3- Dimethyl butoxy carbonyl, 3,3-dimethyl butoxy carbonyl, 1-methyl-1-ethyl propoxy carbonyl, 1-ethyl 2-methyl propoxy carbonyl, 1, 1, 2-trimethyl propoxy carbonyl, 1, 2, 2- Trimethylpropoxy carbonyl group, cyclohexyloxy carbonyl group And the like. this Among them, a more preferred lower alkoxy group is an alkoxy group having 2 to 5 carbon atoms.

基、 プロピルプチルァミノ基、 プロピルイソブチル アミノ基、 プロピルペンチルァミノ基、 プロピルへキシルァミノ基、 イソプロピ ルブチルァミノ基、 イソプロピルイソプチルァミノ基、 イソプロピルペンチルァ ミノ基、 イソプロピルへキシルァミノ基、 プチルイソブチルァミノ基、 プチルぺ ンチルァミノ基、 プチルへキシルァミノ基、 イソプチルペンチルァミノ基、 イソ プチルへキシルァミノ基、 ペンチルへキシルァミノ基等が挙げられる。 このう ち、 より好ましい低級アルキルァミノ基は炭素数 1〜 4のモノアルキルァミノ基 である。 The “lower alkylamino group” is a group in which one or two hydrogen atoms of an amino group are substituted with the above “lower alkyl group”, and examples thereof include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, and a cycloalkyl group. Propylamino group, butylamino group, isoptylamino group, pentylamino group, isopentylamino group, cyclopentylamino group, hexylamino group, cyclohexylamino group, dimethylamino group, getylamino group, dipropylamino group, diisopropylamino group, Dicyclopropylamino group, dibutylamino group, diisobutylamino group, dipentylamino group, diisopentylamino group, dicyclopentylamino group, dihexylamino group, dicyclohexylamino group, methylethylamino group, Methyl Mouth pillamino group, methylisopropylamino group, methylbutylamino group, methylisobutylamino group, methylpentylamino group, methylhexylamino group, ethylpropylamino group, ethylisopropylamino group, ethylbutylamino group, Ethylisobutylamino group, ethylpentylamino group, ethylhexylamino group,

Group, propylbutylamino, propylisobutylamino, propylpentylamino, propylhexylamino, isopropylbutylamino, isopropylisobutylamino, isopropylpentylamino, isopropylhexylamino, butylisobutylamino Groups, a butylpentylamino group, a butylhexylamino group, an isobutylpentylamino group, an isobutylhexylamino group, a pentylhexylamino group, and the like. Of these, a more preferred lower alkylamino group is a monoalkylamino group having 1 to 4 carbon atoms.

In the present invention, “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and a more preferred halogen atom is a fluorine atom. In the present invention, the “furyl group” includes both a 2-furyl group and a 3-furyl group, and a more preferred furyl group is a 2-furyl group.

 In the present invention, the term “hydroxyphenyl group” means a group obtained by substituting a phenyl group with one hydroxy group, for example, a 0-hydroxyphenyl group (2-hydroxyphenyl group, 6-hydroxyphenyl group). A hydroxyphenyl group), an m-hydroxyphenyl group (3-hydroxyphenyl group, 5-hydroxyphenyl group) and a p-hydroxyphenyl group (4-hydroxyphenyl group).

 The counteranion of the present invention is not particularly limited as long as it can form a pharmacologically acceptable compound. For example, halogen ions such as fluorine ion, chloride ion, bromide ion, iodine ion, sulfate ion, nitrate ion, phosphate ion, tetrafluoroborate ion, or acetate ion, oxalate ion, malonate ion, succinic acid ion Ion, maleate ion, fumarate ion, lactate ion, malate ion, citrate ion, tartrate ion, methanesulfonic acid ion, ethanesulfonic acid ion and the like.

As R ¹ in the compound (I) of the present invention, a hydrogen atom, a hydroxy group, a lower alkyl group and a lower alkoxycarbonylalkyl group are preferred, and among them, a hydrogen atom and a hydroxy group are particularly preferred. R ² is preferably a hydrogen atom, a lower alkyl group or a lower alkoxy group, and among them, a hydrogen atom is particularly preferable. R ³ is preferably a hydrogen atom, a lower alkyl group optionally substituted with 1 to 8 halogen atoms, or a lower alkoxyalkyl group optionally substituted with 1 to 8 halogen atoms, and more specifically. Specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2,2,2-trifluoroethyl, 4,4,4-trifluorobutyl, 2,2,3 , 3,4,4,4-heptafluorobutyl group, 2- (2,2,2-trifluoroethoxy) ethyl group, and 3- (2,2,2-trifluoroethoxy) propyl group . R ⁴ is preferably a hydrogen atom, a lower alkyl group or a lower alkoxy group, and more specifically, a hydrogen atom, a methyl group, Examples include an ethyl group, a methoxy group, and an ethoxy group. As A, a benzene ring is particularly preferred. B is preferably a single bond, an amino group or one NR— (R represents a lower alkyl group which may be substituted by a hydroxy group), and more specifically, a single bond, an amino group, a methylamino group, Examples include an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isopropylamino group or an N- (2-hydroxyethyl) amino group. As the counter anion, borofluoride ion and chloride ion are preferable.

 The compound (I) of the present invention may exist in stereoisomers, and the present invention includes any of its optically active, racemic, and diastereomers. The compounds of the present invention also include solvates represented by hydrates.

The compound (I) of the present invention can be produced, for example, by the following method.

Manufacturing method 1

 (IX) (lb)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , A and Z have the same meanings as described above, and X and X ^{1 each} represent a halogen atom.)

That is, 1H-benzimidazole-2-thiol (II) and 2-substituted methyl Reaction with pyridine (III) or condensation of 4-halogenopyridines (V) and alcohol (VI) in the presence of a base gives methylthiobenzimidazole (IV), Oxidation gives methylsulfinylpenzimidazoles (VI I).

 Examples of the base used for the reaction between 1 H-benzimidazole-2-thiol (II) and the 2-substituted methylpyridine derivative (III) include sodium hydroxide, lithium hydroxide, potassium hydroxide and the like. Examples of the solvent include alcohols such as methanol and ethanol or hydrous alcohols thereof, aprotic solvents such as dimethyl sulfoxide and N, N-dimethylformamide, and ethers such as tetrahydrofuran and dioxane. It is preferably carried out by stirring at a reflux temperature for 1 to 24 hours.

 4 Bases used for the condensation of 18-logenopyridines (V) with alcohols (VI) include metals such as sodium hydride, lithium hydride, hydrogen hydride and the like, and metals such as lithium, sodium and potassium. , Potassium tert-butoxide, n-butyllithium, etc., in a solvent such as dimethylsulfoxide, N, N-dimethylformamide, dimethyloxyethylene, tetrahydrofuran, dioxane or an alcohol (VI) as a solvent, from room temperature to reflux temperature. It is preferable to carry out by stirring for 1 to 24 hours.

 The oxidation reaction of the methylthiobenzimidazole (IV) is carried out using organic peracids such as Hi-chloroperbenzoic acid and peracetic acid, sodium metaperiodate, cumene hydroperoxide, tert-butoxyperoxide. It is preferable to use alcohol peroxide such as aqueous hydrogen peroxide, 0X0NE (manufactured by Dubon), or the like, in a solvent such as methylene chloride, chloroform, N, N-dimethylformamide, toluene, and ethyl acetate. It is preferable to carry out the stirring by stirring at 50 ° C. for 10 minutes to 24 hours.

By reacting the obtained methylsulfinylpenzimidazoles (VI I) with a counteranion and an acid comprising a hydrogen atom, the compound is one of the compounds of the present invention. (la) is obtained. As the solvent used in the reaction, alcohols such as methanol and ethanol are used, and as the acid comprising a counter anion and a hydrogen atom, borofluoric acid, hydrochloric acid and the like can be mentioned. The reaction is preferably carried out by stirring under cooling or at room temperature for 30 minutes to 2 hours. ·

On the other hand, the methylthiobenzimidazole derivative (IV) is reacted with N-tert-butoxycarboxyl 3- (4-cyanophenyl) oxaziridine and then subjected to conventional solvent decomposition to give 1-N-aminobenzide. To obtain imidazoles (VIII). The reaction is carried out according to a known method .0 ^ .0 ^ 111., 58,4791 (1993) or 16 ^ &] 16 0111 ^ "., 36,1439 (1995). The benzimidazoles (VIII) are converted to methylsulfinyl 11N-aminobenzimidazoles (IX) by the same operation as the above oxidation reaction, and furthermore, by the reaction of Kaun Yunani anion with an acid consisting of a hydrogen atom. (Lb) which is one of the compounds of the present invention can be obtained.

(式中、 R R ²、 R K R K A、 Zは前記と同意義を示し、 R ⁵はハロゲン原 子、 ヒドロキシ基、 フエニル基、 ヒドロキシフエニル基、 アミノ基、 低級アルコ キシ基、 低級アルコキシカルボニル基若しくは低級アルキルアミノ基から選ばれ る置換基を有していてもよい低級アルキル基若しくは低級アルケニル基あるいは 水素原子を示し、 R⁶はベンジルォキシカルポニル基又は ter卜ブトキシカルボ二 ル基を示し、 R⁷はハロゲン原子、 ヒドロキシ基、 フエニル基、 ヒドロキシフエ ニル基、 アミノ基、 低級アルコキシ基、 低級アルコキシカルボニル基若しくは低 級アルキルアミノ基から選ばれる置換基を有していてもよい低級アルキル基若し くは低級アルケニル基を示す。 )

(Wherein, RR ² , RKRKA, and Z have the same meanings as described above, and R ⁵ is a halogen atom, a hydroxy group, a phenyl group, a hydroxyphenyl group, an amino group, a lower alkoxy group, a lower alkoxycarbonyl group, or a lower alkoxycarbonyl group. have a substituent Ru is selected from alkylamino group show a lower alkyl group or a lower alkenyl group or a hydrogen atom, R ⁶ represents a benzyl O carboxymethyl Cal Poni group or ter Bok butoxycarbonyl two Le group, R ⁷ Represents a lower alkyl group which may have a substituent selected from a halogen atom, a hydroxy group, a phenyl group, a hydroxyphenyl group, an amino group, a lower alkoxy group, a lower alkoxycarbonyl group and a lower alkylamino group. Represents a lower alkenyl group.)

 That is, a benzyloxycarbonyl group or a tert-butoxycarbonyl group is added to the terminal amino group of hydrazines (X) to give (XI), the nitro group is reduced, and then in the presence of carbon disulfide and a base. Or mercaptoimidazoles (XII) can be obtained by reacting in the presence of a complex such as thiophene dimethyl xanthate. As the base used in the reaction, sodium hydroxide, potassium heptaoxide and the like are used, and as the solvent, alcohols such as methanol and ethanol are used. The reaction is preferably carried out by stirring at room temperature to reflux temperature for 1 to 24 hours.

 Subsequently, the compound (XIII) is obtained by reacting mercaptoimidazoles (XII) with 2-chloromethylpyridines in the presence of a base. As the base used in the reaction, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. are used. As the solvent, alcohols such as methanol, ethanol and the like, or hydrated alcohols thereof, dimethyl sulfoxide, N Protic solvents such as N, N-dimethylformamide and the like, and ethers such as tetrahydrofuran and dioxane are used. The reaction is preferably carried out by stirring at room temperature to reflux temperature for 1 to 24 hours.

Compound (XI II) is converted to (XV) via (XVI) by reductive alkylation. Can be The reaction is carried out by using an acid such as hydrochloric acid or trifluoroacetic acid or a base in a solvent such as ethers, alcohols or hydrous alcohols using the benzyloxycarponyl group or tert-butoxycarpoxyl group of (XI II). Or (XVI) after deprotection using a catalytic reduction reaction, and then (XVI) is converted to aldehydes such as formaldehyde and acetate aldehyde or ketones such as acetone and methyl ethyl ketone in the presence of an acid catalyst. It is carried out by reacting and further reducing with a reducing agent. Examples of the solvent used in the reaction include alcohols such as methanol and ethanol, ethers such as dimethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane, acetonitrile, and water-containing solvents thereof. Hydrochloric acid or the like is used, and sodium borohydride, sodium cyanoborohydride or the like is used as a reducing agent. The reaction can be carried out at 0 ° (: up to 60 ° C).

 Compound (XI II) is subjected to a substitution reaction with an amino group at the 11-N position, if necessary, followed by deprotection of a benzyloxycarbonyl group or a tert-butoxycarbonyl group, whereby the compound (XI II) is obtained. XV). Examples of the substitution reaction include known alkylation reactions, and the corresponding alkyl halides in a solvent such as dimethyl sulfoxide or N, N-dimethylformamide in the presence of a base such as sodium hydride or potassium hydride. The reaction is carried out. The reaction is usually performed at room temperature to 60 ° C.

 The compound (に), (XV) or (XVI) obtained above is subjected to an oxidation reaction to obtain a sulfoxide form (XVI I). The reaction is performed with organic peracids such as m-chloroperbenzoic acid and peracetic acid, sodium metaperiodate, cumene hydroperoxide, tert-butoxyperoxide, alcohol peroxides such as hydrogen peroxide, OX ON E ( 10 minutes at 0 to 50 ° C in a solvent such as methylene chloride, chloroform, N, N-dimethylformamide, toluene, ethyl acetate, or a mixture thereof. It is preferable to carry out by stirring for ~ 24 hours.

An acid consisting of a counteranion and a hydrogen atom is added to the obtained sulfoxide (XVI I). To give (Ic), one of the compounds of the present invention. As the solvent used in the reaction, alcohols such as methanol and ethanol are used, and as the acid comprising a counter anion and a hydrogen atom, borofluoric acid, hydrochloric acid and the like can be mentioned. The reaction is preferably performed by stirring under cooling or at room temperature for 30 minutes to 2 hours. ·

 The method for producing the compound (VE) in Production Method 1 is described in WO 03/024957. In addition, compounds (), (IX), and

The production method of compounds απι), (IN), (xv), (xvi) and aw) in

0 0 3 Z 0 8 2 8 5 4.

 The thus-obtained compound of the present invention has an excellent proton pump inhibitory action as described below, and thus is useful as a therapeutic agent for peptic ulcer.

 When the compound of the present invention is administered as a therapeutic agent for peptic ulcer, it may be administered orally as a powder, granules, capsules, oral tablets, suppositories, injections, or external use. It may be administered parenterally as an agent or infusion. The dosage varies depending on the degree of symptoms, age, type of ulcer, etc., but is usually about 0.01 to 200 mgZkg per day, preferably 0.05 to 50 mgZkg, more preferably 0.1 to 50 mgZkg. : Administer L OmgZkg once or several times a day.

 In formulating, it can be manufactured by a usual method using a usual drug carrier.

 That is, when preparing a solid preparation for oral use, an excipient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, etc., are added to the active substance, and then a conventional method is used. Tablets, coated tablets, granules, powders, capsules, etc.

Excipients include, for example, lactose, corn starch, sucrose, glucose, sorbite, crystalline cellulose, silicon dioxide, etc., and binders include, for example, polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, arabia gum, tragacanth, Gelatin, shellac, hydroxypropyl cellulose Disintegrants such as starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, hydrogen carbonate, thorium, calcium citrate, dextrin, pectin, etc. As a lubricant, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc. are permitted to be added to pharmaceuticals as coloring agents, and as a flavoring agent, cocoa powder, Heart muscle, aromatic acid, heart oil, dragon brain, cinnamon powder, etc. are used. These oral solid preparations can be prepared as enteric preparations using a covering base such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate and methacrylate copolymer. Of course, these tablets and granules may be sugar-coated, gelatin-coated, or appropriately coated as necessary.

 When preparing an injection, a pH adjuster, a buffer, a stabilizing agent, a solubilizing agent, and the like are added to the main drug, if necessary, and a subcutaneous, intramuscular, or intravenous injection is prepared by a conventional method. Example

 Next, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto. The starting compounds used in the following examples were produced by the method described in WO 03 / 0249.5.7 or WO03 / 0828854.

Example 1

4-methoxy-3_ (4,4,4-trifluorobutoxy) -15H-pyrido [1 ', 2,: 4,5] [1,2,4] thiadiazino [2,3-a] benzimidazole Synthesis of 13-ylium tetrafluoroporate

2-[[3-Methoxy-41 (4,4,4-trifluorobutoxy) pyridine-12-yl] methylsulfinyl] 500 mg sodium benzimidazole sodium is suspended in 1 mL of ethanol and cooled under ice-cooling. Then, 1.2 g of 42% borofluoric acid was added thereto, followed by stirring at the same temperature for 30 minutes. The precipitate was collected by filtration and washed with isopropyl ether to give 538 mg of the title compound as a powder.

'H-NMR (DMS0-d ₆ ) δ: 2.12-2.19 (2Η, m), 2.50-2.58 (2Η, m), 4.03 (3Η, s), 4.6 7 (2Η, t), 5.11 (2Η, s ), 7.42-7.53 (2Η, m), 7.69-7.88 (2Η, m), 7.97 (IH, d), 9 · 52 (IH, d) MS (FAB): 396M ⁺ (-BF ₄ )

Example 2

4-Methoxy-3- [2- (2,2,2-trifluoroethoxy) ethoxy] —5H-pyrido [Γ, 2,: 4,5] [1,2,4] thiadiazino [2,3-a ] Synthesis of Benzimidazole-13-iridium Tetrafluoroborate

In Example 1, 2-[[3-Methoxy_4- (4,4,4-trifluorobutoxy) pyridin-2-yl] methylsulfinyl] benzimidazol sodium was replaced with 2-[[3-methoxy_ 4_ [2- (2,2,2-Trifluoro mouth ethoxy) ethoxy] pyridine-12-yl] methylsulfinyl] benzimidazolnatridium was used to give the title compound. Ή-NMR (DMS0-d ₆ ) δ: 4.03 (3Η, s), 4.10-4.12 (2H, m), 4.22 (2Η, q), 4.80-4.81 (2Η, m), 5.11 (2Η, s) ), 7.44-7.51 (2H, m), 7.68-7.88 (2H, m), 7.98 (1H, d), 9.5 (1H, d)

MS (FAB): 412M ⁺ (-BF ₄ )

Example 3

3-(4,4,4_Trifluorobutoxy) — 5H—pyrido [1 ', 2': 4,5] [1,2,4] thiadiazino [2,3-a] benzimidazole— 13 Synthesis of iridium chloride

 In Example 1, 2-[[3-methoxy_4_ (4,4,4-trifluorobutoxy) pyridine-2-yl] methylsulfinyl] benzimidazo-l- sodium was replaced with 2 _ [[4-1-1 (4, 4,4-Trifluorobutoxy) pyridine-12-yl] methylsulfinyl] benzimidazol sodium, and the same operation as above using concentrated hydrochloric acid instead of borohydrofluoric acid to give the title compound Got.

^L H-NMR (DMS0-d ₆ ) δ: 1.90-2.05 (2Η, m), 2.22-2.50 (2Η, m), 4.25-4.35 (2Η, m), 4.60 (2Η, s), 7.30-7.45 ( 2Η, m), 7.60-7.70 (2Η, m), 7.80-7.95 (IH, m), 7.91 (IH, d), 9.10 (IH, d)

MS (FAB): 366M ⁺ (-Cl)

Example 4

3— [2— (2,2,2-trifluoroethoxy) ethoxy] —5H—pyrido [1 ', 2,: 4,5] [1,2,4] thiadiazino [2,3_a] benzimidazole — 13—Synthesis of iridium chloride

 In Example 1, 2-[[3-methoxy-4- (4,4,4-trifluorobutoxy) pyridine-2-yl] methylsulfinyl] benzimidazol sodium was replaced with 2-[[4- [2 — (2,2,2-Trifluoroethoxy) ethoxy] pyridine-12-yl] methylsulfinyl] benzimidazole sodium and the same procedure using concentrated hydrochloric acid instead of borofluoric acid. This gave the title compound.

[H-NMR (DMS0-d ₆ ) δ: 3.95-4.02 (2Η, m), 4.05-4.27 (4Η, m), 4.53 (2Η, s), 7.25-7.40 (2Η, m), 7.53- 7.60 (2H, m), 7.70-7.80 (IH, m), 7.87 (1H, d), 9.07 (IH, d) MS (FAB): 382M ⁺ (-Cl)

Example 5

4-Methyl-1- (2,2,2-trifluoroethoxy) -1,5,7-dihydropyrido [1 ', 2,: 5,6] [1,2,3,5] thiatriazepino [3,4 — A] Synthesis of benzimidazole-14-iridium tetrafluoroporate

 1-Amino-2-([3-Methyl-41- (2,2,2-trifluoroethoxy) pyridine-2-yl] metersulfinyl] benzimidazole 50 Omg was suspended in 1 Oml of methanol, Under ice cooling, 42 ml of 42% borofluoric acid was added, and the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration and recrystallized from acetonitrile to obtain 254 mg of the title compound.

Ή-NMR (DMS0-d ₆ ) δ: 2.45 (3Η, s), 4.58 (2Η, s), 5.49 (2H, q), 7.44-7.69 (3 H, m), 7.90-7.93 (IH, m) , 8.02 (IH, d), 9.06 (IH, s), 9.41 (1H, d)

MS (FAB): 367M ⁺ (-BF ₄ )

Melting point: 172-175 ° C (decomposition)

Example 6

10 (1 1) -Hydroxy-4-monomethyl-3- (2,2,2-trifluoroethoxy) -1,5,7-dihydropyrido [, 2,: 5,6] [1,2,3,5] thiatriazepino [3, 4—a] Synthesis of benzimidazole _ 14 _ iridium chloride

1-amino-1 5 (6) —hydroxy-1—— [[3-Methyl-1 -— (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole 8 Omg methanol The suspension was suspended in 2 ml, 0.1 ml of concentrated hydrochloric acid was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The precipitate was collected by filtration and dried under reduced pressure to obtain 65 mg of the title compound.

Ή-NMR (DMS0-d ₆ ) δ: 2.43 (3Η, s), 4.52 (2H, s), 5.47 (2Η, q), 7.05 (1Η, dd), 7.18 (1H, d), 7. (1H , d), 8.01 (1H, d), 9.31 (1H, s), 9.35 (1H, d), 9.68 (1H, s) MS (FAB): 383M ⁺ (-Cl)

Example 7

4,7-dimethyl-3_ (2,2,2-trifluoroethyl) 1,5,7-dihydropyrido [1 ', 2': 5,6] [1,2,3,5] thiatriazepino [3, 41-a] Synthesis of benzimidazole-14-iridium tetrafluoroborate

実施例 5において、 1—アミノー 2_ [ [3—メチルー 4 _ (2, 2, 2—ト リフルォロエトキシ） ピリジン— 2—ィル] メチルスルフィニル] ベンズイミダ ゾ一ルの代わりに 1一メチルアミノー 2— [ [3—メチルー 4一 (2, 2, 2— トリフルォロエトキシ） ピリジン一 2—ィル] メチルスルフィニル] ベンズイミ ダゾ一ルを用いて同様の操作を行うことにより、 標記化合物を得た。

In Example 5, 1-amino-2 _ [[3-methyl-4_ (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole was replaced by 1-methylamino-2 — [[3-Methyl-41- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole was used to give the title compound. .

'H-NMR (DMS0-d ₆ ) δ: 2.50 (3Η, s), 2.89 (3H, s), 4.7 (2Η, s), 5.35-5.45 (2 H, m), 7.46-7.69 (3Η, m ), 7.91-7.9 (1H, m), 8.06 (1H, d), 9.31 (1H, d)

MS (FAB): 387M +-BF ₄ )

Example 8

7-isobutyl-4-monomethyl-3- (2,2,2-trifluoroethoxy) -1,5,7-dihydropyrido [1,, 2 ': 5,6] [1,2,3,5] thiatriazepino Synthesis of [3,4_a] benzimidazole-14-iridium tetrafluoroborate

0 In Example 5, 1-amino-1 2-[[3-methyl-4- (2,2,2-trifluoroethoxy) pyridine-2-yl] methyl ^ / sulfinyl] instead of benzimidazole 1-isobutylamino-2-[[3-methyl_4_ (2,2,2-trifluoroethoxy) pyridine-2-yl] methylsulfinyl] benzimidazole The title compound was obtained.

Ή-NMR (DMS0-d ₆ ) δ: 0.78 (3Η, d), 0.83 (3Η, d), 1.9-1.55 (1H, m), 2.48 (3H, s), 2.66-2.88 (2H, m), 4.73 (2H, s), 5.43 (2H, q), 7.46-7.71 (3H, m), 7.92-7.95 (1H, m), 8.07 (lH, d), 9.37 (1H, d)

MS (FAB): 23M ⁺ (-BF ₄ )

Example 9

実施例 5において、 1—ァミノ— 2— [ [3—メチルー 4一 (2, 2, 2—ト リフルォロエトキシ） ピリジン一 2—ィル] メチルスルフィニル] ベンズイミダ ゾールの代わりに 1— (2—ヒドロキシェチルァミノ） _ 2— [ [3—メチル— 4一 (2, 2, 2—トリフルォロエトキシ） ピリジン— 2—ィル] メチルスルフ ィニル] ベンズィミダゾ一ルを用いて同様の操作を行うことにより、 標記化合物 を得た。 7- (2-Hydroxyethyl) 1-4-methyl-3- (2,2,2-trifluo ethoxy) 1,5,7-dihydropyrido [Γ, 2 ': 5, 6] [1, 2, 3, 5] ] Thiatriazepino [3, 4-a] Synthesis of Benzimidazolone 14-Iridium Te Trafluoroborate

In Example 5, 1-amino-2-[[3-methyl-4-1 (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole was replaced by 1- (2 —Hydroxyethylamino) _ 2— [[3-Methyl-41- (2,2,2-trifluoroethoxy) pyridine-2-yl] methylsulfinyl] Similar operation using benzimidazole This gave the title compound.

Ή-NMR (DMS0-d ₆ ) δ: 2.48 (3Η, s), 3.02-3.03 (2Η, m), 3.9-3.40 (3H, ra), 4.74 (2H, s), 5.37-5.45 (2H, m), 7.47-7.57 (2H, m), 7.72-7.92 (2H, m), 8.03 (1H, d), 9.27 (1H, d)

MS (FAB): 411M ⁺ (-BF ₄ )

Example 1 o

4-methyl-3- (2,2,2-trifluoroethoxy) 1,5,7-dihydropyrido [1,, 2 ': 5,6] [1,2,3,5] thiatriazepino [3,4- a] Synthesis of benzimidazo-1-ru-iridium chloride

実施例 6において、 1—ァミノ— 5 (6) —ヒドロキシー 2— [ [3—メチル 一 4— (2， 2, 2—トリフルォロエトキシ） ピリジン— 2—ィル] メチルスル フィニル] ベンズイミダゾールの代わりに 1一アミノー 2— [ [3—メチル—4 一 (2, 2， 2—トリフルォロエトキシ) ピリジン一 2—ィル] メチルスルフィ ニル] ベンズィミダゾールを用いて同様の操作を行うことにより、 標記化合物を 得た。

In Example 6, 1-amino-5 (6) -hydroxy-2-[[3-methyl-14- (2,2,2-trifluoroethoxy) pyridine-2-yl] methylsulfinyl] benzimidazole Perform the same operation using 1-amino-2-[[3-methyl-4-1 (2,2,2-trifluoroethoxy) pyridin-2-yl] methylsulfinyl] benzimidazole instead Afforded the title compound.

_{Ή-NMR (DMS0 - d 6} ) δ: 2.45 (3Η, s), 4.56 (2H, s), 5.50 (2Η, q), 7.45-7.69 (3 Η, m), 7.90-7.93 (1Η, m) , 8.03 (IH, d), 9.38 (IH, d), 9.53 (IH, s)

MS (FAB): 367M ⁺ (-Cl)

Example 11

4-Methoxy 3- (4,4,4-trifluorobutoxy) 1,5,7-dihydro Mouth pyrido [, 2,: 5,6] [1,2,3,5] thiatriazepino [3, 4 — a] Benzimidazole—Synthesis of 14-iridium tetrafluoroporate

 In Example 5, 1-amino-2-[[3-methyl-4-1 (2,2,2-trifluoroethoxy) pyridine-12-yl] methylsulfinyl] -benzimidazole was replaced with 1-amino-2- The same procedure was performed using [[3-methoxy-41 (4,4,4-trifluorobutoxy) pyridine_2-2-yl] methylsulfinyl] benzimidazole to give the title compound.

Ή-NMR (DMS0-d ₆ ) δ 2.14-2.20 (2Η, ηι), 2.49-2.59 (2Η, m), 4.05 (3H, s), 4.56 (2H, s), 4.66-4.70 (2H, m), 7.44-7.71 (3H, m), 7, 90-7.93 (IH, m), 8.05 (IH, d), 9.13 (1H, S), 9.20 (1H, d)

MS (FAB): 411M ⁺ (-BF4)

Test example (proton pump inhibitory action)

 (1) Preparation of H + ZK + — ATPase enzyme preparation

Separate the frozen stomach body of the stomach into the muscle layer and the mucosal layer, and store the mucosal layer in a 5-fold volume containing 0.25 mol l sucrose and 1 thigh olZL EGTA 2 On excitation 1 ZL Tris-HCl buffer After crushing using a mixer in pH 7.4 (hereinafter abbreviated as Tris-HCl buffer), the mixture was centrifuged at 9000 Xg for 30 minutes. The supernatant was gently overlaid on 8 mL of 20 ml of olZL Tris-HCl buffer, pH 7.4, containing 30% sucrose and ImmolZL EGTA, and ultracentrifuged at lOOOO Xg for 60 minutes. The interface fraction obtained by centrifugation was collected, and centrifugation was repeated twice at 113000 Xg for 60 minutes. After suspending the precipitate in Tris-HCl buffer, homogenize at low speed. The homogenized product was used as an enzyme sample and stored frozen at 180 ° C. The obtained sample was quantified for its protein content using the BCA protein atssay reagent using the method of Smith et al. (Anal. Biochem., 150, 76-85 (1985)). All of the above operations are performed under water cooling ft.

(2) Examination of H ⁺ / K ⁺ — ATPase inhibitory activity at pHl

'' The measurement of H + / K +-ATPase inhibitory activity is based on a method using ATP as a substrate and a method for quantifying the amount of inorganic phosphorus as a degradation product (Biochem. Biophys. Res. Coramun., 40, 880-886 (1970)). I went according to it. As a hydrochloric acid solution for pre-treating the test compound, a 1 × 1 O— ^ olZL (pH 1) hydrochloric acid solution containing 50% DMS0 was used in consideration of the solubility of the test compound. The test compound at each concentration was added to this hydrochloric acid solution so as to be diluted 1000 times, and left at room temperature for 15 minutes. After the above pretreatment, add 10 ^ iL of the solution to a buffer containing 40 mol / L Tris acetate buffer with or without 20 ol / L KC1, pH 7.5 (containing ₂ ol / L MgCl2; TE buffer ). Subsequently, 100 L of enzyme solution (5 g protein) diluted in TE buffer was added, and the mixture was heated at 37 ° C for 30 minutes. Then, 40 L ol / L ATP solution (dissolved in KC1-free TE buffer) 50 L Was added to start the enzyme reaction (total volume 1 mL, ATP final concentration 2 Fiber / L). After incubation at 37 ° C for 30 minutes, the enzyme reaction was stopped by adding 2 mL of ice-cooled 12% trichloroacetic acid. 1 mL of molybdenum reagent (3.75% ammonium molybdate / 1.5 mol / L sulfuric acid) and 5 mL of butyl acetate were added, mixed vigorously with shaking for 5 minutes, and the absorbance of the butyric acetate layer was measured at 31 Onm. The standard curve was dissolved K¾P0 ₄ to 8% TCA solution of each concentration were prepared from absorbance obtained by the same operation was carried out in terms of the inorganic phosphorus content. The measurement was performed in duplicate, and the residual activity was determined from the difference between the average value of the amount of inorganic phosphorus in the presence of KC1 and the amount of inorganic phosphorus in the absence of ΚC1, and the activity of the control value (DMS0) was taken as 100% to determine the inhibition rate of the compound. Calculated. IC ₅ as each test compound inhibition strength. The value was calculated and displayed. All test compounds were dissolved in dimethyl sulfoxide immediately before use. As a result, the compound of Example 1 had IC ₅ . The value is 1.28 28, The compound of Example 2 has an IC _5Q value of _1.51 M, and the compound of Example 3 has an IC _{5 of 5} . The value is 2.68 U, and the compound of Example 4 has IC ₅ . The value of 5.89 化合物 The compound of Example 10 has IC ₅ . The value is 5.09 μΜ.

Claims

The scope of the claims 1. The following equation (I)

(In the formula, R ¹ is a lower alkyl group optionally substituted by a hydroxy group or a lower alkoxycarbonyl group, a lower acyl group optionally substituted by a halogen atom, a cyano group, a carboxyl group, a hydroxy group, a lower group R ² and R ⁴ are the same or different and represent a lower alkyl group, a lower alkoxy group or a hydrogen atom; R ³ is 1 to 8 halogen atoms, a hydroxy group, 1 to 8 A represents a lower alkyl group which may have a substituent selected from a lower alkoxy group, a furyl group and a morpholino group which may be substituted by two halogen atoms, and A represents a benzene ring, a pyridine ring or a thiophene ring Wherein B is a single bond, an amino group or one NR-(R is a halogen atom, a hydroxy group, a phenyl group, a hydroxyphenyl group, an amino group, A lower alkyl group or a lower alkenyl group which may have a substituent selected from a oxy group, a lower alkoxyl propyl group and a lower alkylamino group.) Z represents a counteranion. The compound represented by). 2. R ¹ is a hydrogen atom or a hydroxy group; R ² is a hydrogen atom; R ³ is a lower alkyl group optionally substituted by 1 to 8 halogen atoms or a lower alkoxyalkyl group optionally substituted by 1 to 8 halogen atoms; R ⁴ is a hydrogen atom, a lower alkyl group or a lower alkoxy group;  A is a benzene ring;  B is a single bond, an amino group or one N R— (R represents a lower alkyl group which may be substituted by a hydroxy group);  2. The compound according to claim 1, wherein Z is a counteranion.  3. A medicament containing the compound according to claim 1 or 2.  4. The medicament according to claim 3, which is a therapeutic agent for peptic ulcer.  5. A pharmaceutical composition comprising the compound according to claim 1 or 2 and a pharmaceutically acceptable carrier.  6. Use of the compound according to claim 1 or 2 for the manufacture of a medicament.  7. The use according to claim 6, wherein the medicament is a therapeutic agent for peptic ulcer.  8. A method for treating peptic ulcer, which comprises administering an effective amount of the compound according to claim 1 or 2.