JP2004300149A - Formulation for controlled release - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a prolonged-action preparation that releases an active ingredient in a digestive tract for a long period by controlling the release of the active ingredient at several levels. <P>SOLUTION: A formulation for controlled release where the speed of releasing the active ingredient (proton pump inhibitor) is controlled at 2 or more levels comprises (1) a release control section A that can control the speed of releasing the active ingredient at a specified level, (2) a release control section B that can control the speed of releasing the active ingredient at another specified lower level than the speed of releasing in the release control section A and (3) if necessary, a release control section C that can control the speed of releasing the active ingredient at another specified higher level than the speed of releasing in the release control section B. The formulation is characterized in that the active ingredient in the release control section B is released ahead of the active ingredient in the release control section A (if the release control section C is contained, the active ingredient in the release control section C is released ahead of the active ingredient in the release control section B). <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a controlled release composition that exhibits a multi-step release profile with different release rates by combining multiple release control portions with controlled release of the active ingredient.

  Oral administration preparations are the most frequently used dosage forms among pharmaceuticals, and in recent years, from the viewpoint of improving QOL, many oral administration preparations that maintain the efficacy by being administered 1-2 times a day have been developed. Attempts have been made to synthesize compounds that exhibit kinetics such that the drug effect is maintained by administration once or twice a day from the synthesis stage of the compounds themselves. There are many cases where corrections are made.

  Zero-order release has been reported as the dissolution of a sustained-release formulation which is desirable for sustaining the blood concentration of the drug. This means that if there is no difference in the absorption of the drug from the gastrointestinal tract depending on the absorption site, the drug is released at a constant rate over the entire gastrointestinal tract (small and large intestine) after taking the drug, thereby maintaining the drug concentration in plasma. It is based on the idea that it can be achieved. However, the inside of the digestive tract is not uniform, and the pH, the amount of digestive juice, the load applied to the preparation, the effective surface area, and the like differ depending on the site. For this reason, a preparation exhibiting zero-order dissolution in an in vitro dissolution test does not always show the same dissolution and absorption in the digestive tract. Therefore, depending on the type of drug used as the active ingredient, the blood concentration may not be able to be maintained for a long time in the effective therapeutic range, and a sustained-release preparation based on a different release control strategy according to the characteristics of the drug and the environment in the digestive tract. (See, for example, Patent Documents 1 to 3 and Non-Patent Document 1).

Controlled release preparations containing a compound having a proton pump inhibitory activity such as omeprazole as an active ingredient are generally described in several documents (Patent Documents 4 and 5). However, there is no report on what kind of controlled release strategy should be taken to obtain the desired duration of drug effect.
WO 99/51209 pamphlet Japanese Patent Publication No. 6-11699 JP-A-9-143073 US Patent Application Publication No. 2002-0051814 JP 2002-532425 A "European Journal of Pharmaceutical Sciences (Eur. J. Pharm. Sci.)", (Netherlands), Vol. 195-201, 1994

  It is an object of the present invention to provide a sustained release formulation in which the release of an active ingredient (eg, a proton pump inhibitor) is controlled in multiple stages and releases the active ingredient in the digestive tract over a long period of time.

  The present inventors have found that in the large intestine where the amount of digestive juice is small, the elution of the drug (proton pump inhibitor) from the preparation is significantly lower than predicted in vitro, so that a desirable sustained blood concentration can be obtained. In order to prevent a decrease in drug dissolution and absorption in the large intestine, drug dissolution should be enhanced in the latter half of the lower part of the small intestine, corresponding to dissolution in the vicinity of the large intestine (the release rate would be faster). An attempt was made to develop a formulation showing an elution pattern. As a result, by coating a core containing a drug and a sustained-release base at a composition ratio different from that of the nucleus with a quick release or a sustained release with relatively quick drug elution, the coating layer In the above, the sustained release in the first half by drug elution and the rapid release in the latter half by drug elution from the nucleus or the sustained release with increased release rate were successfully realized. Furthermore, by coating this controlled release composition with a drug-containing composition exhibiting immediate release, the rise of blood drug concentration in the initial stage after oral administration was successfully improved. The invention has been completed.

〔式中、環Ｃ’は置換基を有していてもよいベンゼン環または置換基を有していてもよい芳香族単環式複素環を、Ｒ^０は水素原子、置換基を有していてもよいアラルキル基、アシル基またはアシルオキシ基を、Ｒ^１、Ｒ^２およびＲ^３は、それぞれ同一または異なって、水素原子、置換基を有していもよいアルキル基、置換基を有していてもよいアルコキシ基または置換基を有していてもよいアミノ基を、およびＹは窒素原子またはＣＨを示す〕
で表される化合物もしくはその塩またはその光学活性体である、上記［１］〜［３］のいずれかに記載の放出制御組成物、
［７］ 各放出制御部に含有されるプロトンポンプインヒビターがランソプラゾールもしくはそのプロドラッグまたはその塩あるいはその光学活性体である上記［３］〜［５］のいずれかに記載の放出制御組成物、
［８］ 各放出制御部に含有される活性成分の重量割合が、Ａ：５−９５％、Ｂ：５−９５％およびＣ：０−４０％（但し、Ｃ：０％の場合、放出制御部Ｃは存在しない）である上記［２］記載の放出制御組成物、
［９］ 各放出制御部に含有される活性成分の重量割合が、Ａ：２０−７５％、Ｂ：２０−７５％およびＣ：５−３０％である上記［２］記載の放出制御組成物、
［１０］ 服用後２時間以内に放出制御部Ｃに含有される活性成分の放出が終了する経口投与用固形組成物である、上記［２］記載の放出制御組成物、
［１１］ 放出制御部Ｂが活性成分と親水性高分子を含む徐放性マトリックスである上記［１］または［２］記載の放出制御組成物、
［１２］ 放出制御部Ａが活性成分と親水性高分子を含む徐放性マトリックスである上記［１］または［２］記載の放出制御組成物、
［１３］ 放出制御部Ｂによる活性成分の放出が１−１８時間持続することを特徴とする上記［１］または［２］記載の放出制御組成物、
［１４］ 放出制御部Ａによる活性成分の放出が３０分−６時間持続することを特徴とする上記［１］または［２］記載の放出制御組成物、
［１５］ 放出制御部Ｃによる放出が速放性である上記［２］記載の放出制御組成物、
［１６］ 剤形が、錠剤、顆粒、ペレット錠およびカプセル剤からなる群より選択される上記［１］または［２］記載の放出制御組成物、などに関する。 That is, the present invention
[1] A controlled release composition in which the release of the active ingredient is controlled in two or more stages having different release rates,
1) a release control section A containing a proton pump inhibitor as an active ingredient and capable of controlling the release of the active ingredient at a predetermined rate;
2) A release control section B containing a proton pump inhibitor as an active ingredient and capable of controlling the release of the active ingredient to a predetermined rate lower than the release rate in the release control section A.
And wherein the release of the active ingredient in the release control section B precedes the release of the active ingredient in the release control section A.
[2] An active ingredient that is the same as or different from the active ingredient contained in the release control section A and / or the release control section B, and the release of the active ingredient is made a predetermined rate higher than the release rate in the release control section B The release control according to the above [1], further comprising a controllable release control section C, wherein the release of the active ingredient in the release control section C precedes the release of the active ingredient in the release control section B. Composition,
[3] The controlled release composition according to [1] or [2], wherein the controlled release part B covers the controlled release part A.
[4] The controlled release composition according to the above [3], wherein the controlled release part C covers the controlled release part B,
[5] The controlled release composition according to the above [2], wherein the active ingredient contained in the controlled release part C is a proton pump inhibitor.
[6] The proton pump inhibitors contained in each release control unit may be the same or different, and may have the following formula (I ′):

[In the formula, ring C ′ represents a benzene ring which may have a substituent or an aromatic monocyclic heterocyclic ring which may have a substituent, and R ⁰ has a hydrogen atom and a substituent. R ¹ , R ² and R ³ may be the same or different and each may have a hydrogen atom, an alkyl group which may have a substituent or a substituent, An alkoxy group or an amino group which may have a substituent, and Y represents a nitrogen atom or CH)
The controlled release composition according to any one of the above [1] to [3], which is a compound represented by the formula:
[7] The controlled release composition according to any of [3] to [5], wherein the proton pump inhibitor contained in each controlled release unit is lansoprazole, a prodrug thereof, a salt thereof, or an optically active substance thereof.
[8] The weight ratio of the active ingredient contained in each release control section is A: 5-95%, B: 5-95%, and C: 0-40% (however, when C: 0%, the release control is performed). Part C is not present), wherein the controlled release composition according to the above [2],
[9] The controlled release composition according to the above [2], wherein the weight ratio of the active ingredient contained in each controlled release part is A: 20-75%, B: 20-75%, and C: 5-30%. ,
[10] The controlled-release composition according to [2], which is a solid composition for oral administration in which the release of the active ingredient contained in the controlled-release part C is completed within 2 hours after taking the drug.
[11] The controlled release composition according to the above [1] or [2], wherein the controlled release part B is a sustained release matrix containing an active ingredient and a hydrophilic polymer.
[12] The controlled release composition according to the above [1] or [2], wherein the controlled release part A is a sustained release matrix containing an active ingredient and a hydrophilic polymer.
[13] The controlled release composition according to the above [1] or [2], wherein the release of the active ingredient by the controlled release unit B is maintained for 1 to 18 hours.
[14] The controlled-release composition according to [1] or [2], wherein the release of the active ingredient by the controlled-release unit A is continued for 30 minutes to 6 hours.
[15] The controlled release composition of the above-mentioned [2], wherein the release by the controlled release unit C is immediate release.
[16] The controlled release composition according to [1] or [2], wherein the dosage form is selected from the group consisting of tablets, granules, pellet tablets, and capsules.

  The controlled release composition of the present invention exhibits a drug release profile characterized by sustained drug release in the early / middle or middle phase and faster drug release in the late phase, and is used as a proton pump inhibitor formulation for oral administration. It has the effect of improving the drug dissolution in the lower intestine to the vicinity of the large intestine and maintaining the effective blood concentration of the drug for a long time.

The controlled release composition of the present invention is a composition in which the release of the active ingredient is controlled in two or more stages having different release rates, and comprises two release control sections containing the active ingredient (a release control section A and a release control section). Part B) (the active ingredients contained in the release control part A and the release control part B may be the same or different).
Here, the “release control unit” refers to a functional unit that contains the active ingredient itself and can control the release of the active ingredient at a predetermined rate. One release control, if it covers another release control, defines the start of release control by the inner release control coated by its collapse or dissolution, but otherwise Does not participate in controlling the release of the active ingredient contained in other release control sections. For example, when the release control section B covers the release control section A, the release of the active ingredient contained in the release control section A is performed after the release of the active ingredient in the release control section B or during the release (active component). The release control section B is started when the release control section A is exposed due to the disintegration, dissolution, etc. of the release control section B when the release control section A is released.

The release control section A controls the final release control step (corresponding to elution from the lower small intestine to the vicinity of the large intestine in the oral administration preparation) in the controlled release composition of the present invention in which the release of the active ingredient is controlled in two or more steps. It is a functional unit that acts as a quick release unit or a sustained release unit (second sustained release unit) that releases the active ingredient faster than the release control unit B described below. As used herein, the term "immediate release portion" refers to a release control portion in which the release characteristics of the active ingredient are immediate release, and "immediate release" refers to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method). Is performed under the conditions of a paddle rotation speed of 100 rpm using an appropriate test solution of 500 mL or 900 mL, the dissolution rate of the active ingredient 30 minutes after the start of the test is 85% or more. Here, as the test solution, for example, a test solution in which the concentration at which 100% of the active ingredient is eluted into the test solution is 1/3 or less of the saturation solubility of the active ingredient is used. As the test solution, those commonly used in the technical field of pharmaceutical preparations, for example, water, a buffer solution and the like are used. For the dissolution test of the active ingredient in the release control part A, the second test of the dissolution test of the Japanese Pharmacopoeia is preferably used. Liquid or water is used.
On the other hand, in the present specification, the “sustained release part” refers to a release control part having a sustained release characteristic of the active ingredient, and the “sustained release” means the Japanese Pharmacopoeia dissolution test method 2 (paddle). Method), the dissolution rate of the active ingredient 30 minutes after the start of the test is less than 85% when the appropriate test solution is used at 500 rpm or 900 mL at a paddle rotation speed of 100 rpm. Here, the same test liquid as described above is used. If the controlled release unit A is sustained unit, the release rate V _A of the active ingredient in said discharging control unit, meet the definition of the controlled release, and more release rate V _B of the active ingredient in the controlled release unit B There is no particular limitation as long as it is larger, but preferably, in the above-mentioned dissolution test, the dissolution rate of the active ingredient 30 to 30 minutes after the start of the test is 15 to 85%, more preferably 25 to 85%, and still more preferably 50 to 85%. It is.
Alternatively, the release characteristics of the active ingredient in the controlled release part A may be such that when the controlled release composition of the present invention is applied to the intended use (for example, in the case of an oral administration preparation, orally administered), the controlled release part A The release of the active ingredient in is preferably characterized by a duration of preferably from about 30 minutes to about 6 hours, more preferably from about 30 minutes to about 3 hours.

  When the release control part A is a quick release part, the release control part may be the active ingredient itself, but in addition to the active ingredient, a carrier acceptable in the field of use of the composition (for example, a pharmaceutical composition) In this case, it is preferable to contain a pharmacologically acceptable carrier).

The active ingredient contained in the release controlling portion A is not particularly limited, and substances effective for prevention and treatment of various diseases [eg, anti-inflammatory drugs such as indomethacin and acetaminophen, analgesics such as morphine, diazepam, diltiazem Cardiovascular agents such as chlorpheniramine maleate, antihistamines such as fluorouracil and aclarubicin, hypnotics such as midazolam, anticongestants such as ephedrine, diuretics such as hydrochlorothiazide, furosemide , Bronchodilators such as theophylline, antitussives such as codeine, antiarrhythmic drugs such as quinidine and dizoxine, antidiabetic drugs such as tolbutamide, pyroglitazone and troglitazone, vitamins such as ascorbic acid, anticonvulsants such as phenytoin, lidocaine Local anesthetics such as hydroco Corticosteroids such as thizone, drugs acting on the central nervous system such as donepezil (trade names: Aricept and Eisai), antihyperlipidemic drugs such as pravastatin, antibiotics such as amoxicillin and cephalexin, and the prevention or treatment of diabetes Useful dipeptidyl peptidase (DPP) -IV inhibitor, steroid C _17,20 lyase inhibitor useful for prevention or treatment of prostate and breast cancer, gastrointestinal motility enhancers such as mosapride, cisapride, gastritis, gastroesophageal reflux disease, famotidine is a therapeutic agent for gastric ulcer, ranitidine, H ₂ blockers and lansoprazole and prodrugs thereof and their optically active forms, such as cimetidine (R body and S body, preferably R-isomer), omeprazole and optically active substance thereof (S-form: esomeprazole), rabepura And its optically active substances, benzimidazole-based proton pump inhibitors (PPIs) such as pantoprazole and its optically active substances, and imidazopyridine-based PPIs such as tenatoprazole, etc.], detergent components, fragrances, fertilizers, deodorants, animals -Examples include pesticides, insecticides, herbicides, plant growth regulators, and the like.
Preferably, the active ingredient is a PPI, a steroid C _17,20 lyase inhibitor or a DPP-IV inhibitor, more preferably a PPI. Specific examples of these active ingredients are shown below.

式中、環Ｃ’は置換基を有していてもよいベンゼン環または置換基を有していてもよい芳香族単環式複素環を、Ｒ^０は水素原子、置換基を有していてもよいアラルキル基、アシル基またはアシルオキシ基を、Ｒ^１、Ｒ^２およびＲ^３は、それぞれ同一または異なって、水素原子、置換基を有していもよいアルキル基、置換基を有していてもよいアルコキシ基または置換基を有していてもよいアミノ基を、およびＹは窒素原子またはＣＨを示す。 A. Proton pump inhibitor (PPI)
As the PPI, particularly, an acid-labile imidazole compound represented by the following general formula (I ′), such as lansoprazole and its optically active substance, particularly an acid-labile benzimidazole compound represented by (I) Examples include compounds, imidazole-based compound derivatives (prodrug type PPI) which are relatively stable to acids represented by the following general formulas (II) and (III), salts thereof, and optically active forms thereof.

In the formula, ring C ′ represents a benzene ring which may have a substituent or an aromatic monocyclic heterocyclic ring which may have a substituent, and R ⁰ represents a hydrogen atom or a substituent. R ¹ , R ² and R ³ may be the same or different and each may be a hydrogen atom, an alkyl group which may have a substituent, or a substituent. A good alkoxy group or an amino group which may have a substituent, and Y represents a nitrogen atom or CH.

すなわち、式（Ｉ）中、環Ａは置換基を有していてもよいベンゼン環を示し、Ｒ^０、Ｒ^１、Ｒ^２、Ｒ^３およびＹは上記式（Ｉ’）におけると同意義である。
前記式（Ｉ）において、好ましい化合物は、環Ａが、ハロゲン原子、ハロゲン化されていてもよいＣ_1-4アルキル基、ハロゲン化されていてもよいＣ_1-4アルコキシ基および５または６員複素環基から選ばれた置換基を有していてもよいベンゼン環であり、Ｒ^０は水素原子、置換されていてもよいアラルキル基、アシル基またはアシルオキシ基であり、Ｒ^１がＣ_１−６アルキル基、Ｃ_１−６アルコキシ基、Ｃ_１−６アルコキシ−Ｃ_１−６アルコキシ基またはジ−Ｃ_１−６アルキルアミノ基であり、Ｒ^２が水素原子、Ｃ_１−６アルコキシ−Ｃ_１−６アルコキシ基またはハロゲン化されていてもよいＣ_１−６アルコキシ基であり、Ｒ^３が水素原子またはＣ_１−６アルキル基であり、Ｙが窒素原子である化合物である。 Among the compounds represented by the above formula (I '), particularly, a compound in which ring C' is a benzene ring which may have a substituent is represented by the following formula (I).

That is, in the formula (I), ring A represents a benzene ring which may have a substituent, and R ⁰ , R ¹ , R ² , R ³ and Y have the same meaning as in the above formula (I ′). is there.
In the above formula (I), preferred compounds are those wherein ring A is a halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4 alkoxy group and a 5- or 6-membered. A benzene ring which may have a substituent selected from a heterocyclic group, R ⁰ is a hydrogen atom, an aralkyl group which may be substituted, an acyl group or an acyloxy group, and R ¹ is C _{1- 6} alkyl group, C _1-6 alkoxy group, C _1-6 alkoxy-C _1-6 alkoxy group or di-C _1-6 alkylamino group, wherein R ² is a hydrogen atom, C _1-6 alkoxy-C _{1 A} compound in which _{-6 is an} alkoxy group or an optionally halogenated C _1-6 alkoxy group, R ³ is a hydrogen atom or a C _1-6 alkyl group, and Y is a nitrogen atom.

〔式中、Ｒ^１はＣ_１−３アルキル基またはＣ_１−３アルコキシ基、Ｒ^２はハロゲン化されているかまたはＣ_１−３アルコキシ基で置換されていてもよいＣ_１−３アルコキシ基、Ｒ^３は水素原子またはＣ_１−３アルキル基、Ｒ^４は、水素原子、ハロゲン化されていてもよいＣ_１−３アルコキシ基またはピロリル基（例えば、１−,２−または３−ピロリル基）を示す〕で表される化合物である。
式（Ｉａ）において、Ｒ^１がＣ_１−３アルキル基、Ｒ^２がハロゲン化されていてもよいＣ_１−３アルコキシ基、Ｒ^３が水素原子、Ｒ^４が水素原子またはハロゲン化されていてもよいＣ_１−３アルコキシ基である化合物が特に好ましい。 Particularly preferably, formula (Ia):

[Wherein, R ¹ is a C _1-3 alkyl group or a C _1-3 alkoxy group, R ² is a C _1-3 alkoxy group which may be halogenated or substituted with a C _1-3 alkoxy group, R ³ is a hydrogen atom or a C _1-3 alkyl group; R ⁴ is a hydrogen atom, an optionally halogenated C _1-3 alkoxy group or a pyrrolyl group (for example, a 1-, 2- or 3-pyrrolyl group) Is a compound represented by the following formula:
In the formula (Ia), R ¹ is a C _1-3 alkyl group, R ² is a C _1-3 alkoxy group which may be halogenated, R ³ is a hydrogen atom, R ⁴ is a hydrogen atom or halogenated. Particularly preferred are compounds that are C _1-3 alkoxy groups.

In the compound represented by the formula (I) [hereinafter, referred to as compound (I)], examples of the “substituent” of the “benzene ring which may have a substituent” represented by ring A include: Halogen atom, cyano group, nitro group, alkyl group which may have a substituent, hydroxy group, alkoxy group which may have a substituent, aryl group, aryloxy group, carboxy group, acyl group, acyloxy And a 5- to 10-membered heterocyclic group. These substituents may substitute about 1 to 3 benzene rings. When the number of substituents is two or more, each substituent may be the same or different. Among these substituents, a halogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent and the like are preferable.
Examples of the halogen atom include fluorine, chlorine, and bromine atoms. Of these, fluorine is preferred.
Examples of the “alkyl group” of the “alkyl group which may have a substituent” include, for example, a C _1-7 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- Butyl, pentyl, hexyl, heptyl and the like). Examples of the “substituent” of the “optionally substituted alkyl group” include a halogen atom, a hydroxy group, a C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, etc.), C ₁ Examples thereof include a _-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl group, etc.) and a carbamoyl group, and the number of these substituents may be about 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
Examples of the “alkoxy group” of the “optionally substituted alkoxy group” include, for example, a C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, etc.). No. As the “substituent” of the “optionally substituted alkoxy group”, those similar to the “substituent” of the above “optionally substituted alkyl group” can be exemplified. Is the same.

As the “aryl group”, for example, a C _6-14 aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenyl, 2-anthryl group and the like) and the like can be mentioned.
As the “aryloxy group”, for example, a C _6-14 aryloxy group (for example, phenyloxy, 1-naphthyloxy, 2-naphthyloxy group and the like) and the like can be mentioned.
Examples of the “acyl group” include formyl, alkylcarbonyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, alkylsulfinyl, and alkylsulfonyl groups.
As the “alkylcarbonyl group”, a C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl group, etc.) and the like can be mentioned.
As the "alkoxycarbonyl group", for example, a _C1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl group, etc.) and the like can be mentioned.
As the “alkylcarbamoyl group”, an N—C _1-6 alkyl-carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl group, etc.), an N, N-diC _1-6 alkyl-carbamoyl group (eg, N, N- Dimethylcarbamoyl, N, N-diethylcarbamoyl group and the like).
Examples of the “alkylsulfinyl group” include a C _1-7 alkylsulfinyl group (for example, a methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl group and the like).
As the “alkylsulfonyl group”, for example, a C _1-7 alkylsulfonyl group (for example, a methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl group and the like) can be mentioned.
Examples of the “acyloxy group” include an alkylcarbonyloxy group, an alkoxycarbonyloxy group, a carbamoyloxy group, an alkylcarbamoyloxy group, an alkylsulfinyloxy group, an alkylsulfonyloxy group, and the like.
Examples of the “alkylcarbonyloxy group” include a C _1-6 alkyl-carbonyloxy group (eg, acetyloxy, propionyloxy group, etc.).
Examples of the “alkoxycarbonyloxy group” include a C _1-6 alkoxy-carbonyloxy group (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy group, etc.).
Examples of the “alkylcarbamoyloxy group” include a C _1-6 alkyl-carbamoyloxy group (for example, a methylcarbamoyloxy group, an ethylcarbamoyloxy group, and the like).
Examples of the “alkylsulfinyloxy group” include, for example, a C _1-7 alkylsulfinyloxy group (for example, methylsulfinyloxy, ethylsulfinyloxy, propylsulfinyloxy, isopropylsulfinyloxy group, etc.).
As the “alkylsulfonyloxy group”, for example, a C _1-7 alkylsulfonyloxy group (for example, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy group and the like) can be mentioned.
As the "5- to 10-membered heterocyclic group", for example, a 5- to 10-membered heterocyclic group containing one or more (for example, 1 to 3) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom ( Preferred are 5- or 6-membered) heterocyclic groups, and specific examples are 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, 1-2, and 2-furyl. -Or 3-pyrrolyl group, 2-, 3-, 4-, 5- or 8-quinolyl group, 1-, 3-, 4- or 5-isoquinolyl group, 1-, 2- or 3-indolyl group and the like. No. Of these, a 5- or 6-membered heterocyclic group such as a 1-, 2- or 3-pyrrolyl group is preferred.
Preferably, ring A is a substituent selected from a halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4 alkoxy group and a 5- or 6-membered heterocyclic group. It is a benzene ring which may have one or two.

In the above formula (I ′), the “aromatic monocyclic heterocycle” of the “aromatic monocyclic heterocycle optionally having substituent (s)” represented by ring C ′ includes, for example, furan, Thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 5- or 6-membered aromatic monocyclic heterocycle such as triazine and the like. As the “aromatic monocyclic heterocyclic ring” represented by the ring C ′, the “optionally substituted benzene ring” represented by the aforementioned ring A and the “aromatic monocyclic heterocyclic ring” Pyridine ring "is preferred. The “pyridine ring optionally having substituent (s)” represented by the ring C ′ can be substituted with the same substituent as the “benzene ring optionally having substituent (s)” shown in the above ring A. You may have one to four at a position.
The position where the “aromatic monocyclic heterocycle” of the “aromatic monocyclic heterocycle optionally having substituent (s)” condenses with the imidazole moiety is not particularly limited.

In the above formula (I ′) or (I), the “aralkyl group” of the “aralkyl group optionally having substituent (s)” for R ⁰ is, for example, a C _7-16 aralkyl group (for example, benzyl And a C _6-10 aryl C _1-6 alkyl group such as phenethyl). Examples of the “substituent” of the “optionally substituted aralkyl group” include the same substituents as the “substituent” of the above “optionally substituted alkyl group”. The number of groups is about 1 to 4. When the number of substituents is two or more, each substituent may be the same or different.
As the “acyl group” for R ⁰ , for example, the “acyl group” described as a substituent for ring A above can be mentioned.
The “acyloxy group” represented by R ⁰ includes, for example, the “acyloxy group” described as a substituent for the ring A.
Desirable R ⁰ is a hydrogen atom.
In the above formula (I ′) or (I), the “alkyl group which may have a substituent” represented by R ¹ , R ² or R ³ is the “substituted group” described as the substituent of the ring A. Alkyl group which may have a group ".
Examples of the “optionally substituted alkoxy group” represented by R ¹ , R ² or R ³ include the “optionally substituted alkoxy group” described as the substituent of the ring A. No.
Examples of the “amino group which may have a substituent” represented by R ¹ , R ² or R ³ include, for example, an amino group, a mono-C _1-6 alkylamino group (eg, methylamino, ethylamino, etc.) A mono-C _6-14 arylamino group (eg, phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), a di-C _1-6 alkylamino group (eg, dimethylamino, diethylamino, etc.), di-C _{6 -14} arylamino group (for example, diphenylamino and the like).
Desirable R ¹ is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxy-C _1-6 alkoxy group, or a di-C _1-6 alkylamino group. More preferred R ² is a C _1-3 alkyl group or a C _1-3 alkoxy group.
Desirable R ² is a hydrogen atom, a C _1-6 alkoxy-C _1-6 alkoxy group, or an optionally halogenated C _1-6 alkoxy group. More preferred R ³ is a C _1-3 alkoxy group which may be halogenated or substituted with a C _1-3 alkoxy group.
Desirable R ³ is a hydrogen atom or a C _1-6 alkyl group. More preferred R ³ is a hydrogen atom or a C _1-3 alkyl group (particularly a hydrogen atom).
Preferred Y is a nitrogen atom.

Specific examples of the compound (I) include the following compounds.
2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-imidazole (lansoprazole), 2-[[(3,5-dimethyl-4 -Methoxy-2-pyridinyl) methyl] sulfinyl] -5-methoxy-1H-benzimidazole, 2-[[[4- (3-methoxypropoxy) -3-methyl-2-pyridinyl] methyl] sulfinyl] -1H- Benzimidazole sodium salt, 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole and the like.
Of these compounds, lansoprazole, particularly 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole, is preferred.
In addition to the above-mentioned PPI of a benzimidazole compound, the present invention is also suitably applied to a PPI of an imidazopyridine compound. As the PPI of such an imidazopyridine-based compound, for example, tenatoprazole can be mentioned.
The compound (I) or the compound (I ′) containing the imidazopyridine compound may be in a racemic form or an optically active form such as an R-form or an S-form. For example, optically active forms of lansoprazole, ie, (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole and Optically active forms such as (S) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole are particularly preferred in the present invention. It is suitable. The lansoprazole, lansoprazole R-form, lansoprazole S-form, and the like are usually preferably crystals. By providing such a compound, it is more stabilized, so that not only crystals but also amorphous materials can be used.

As the salt of compound (I ′) and compound (I), a pharmaceutically acceptable salt is preferable, and examples thereof include a salt with an inorganic base, a salt with an organic base, and a salt with a basic amino acid.
Preferable examples of the salt with an inorganic base include an alkali metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a calcium salt and a magnesium salt; an ammonium salt.
Preferred examples of the salt with an organic base include, for example, alkylamine (trimethylamine, triethylamine, etc.), heterocyclic amine (pyridine, picoline, etc.), alkanolamine (ethanolamine, diethanolamine, triethanolamine, etc.), dicyclohexylamine , N, N'-dibenzylethylenediamine and the like.
Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine and the like.
Of these salts, an alkali metal salt or an alkaline earth metal salt is preferred. Particularly, a sodium salt is preferable.

Compound (I ′) or (I) can be produced by a method known per se, for example, JP-A-61-50978, US Pat. No. 4,628,098, JP-A-10195068, WO 98/22101, It is manufactured by the method described in JP-A-52-62275, JP-A-54-141783, or the like, or a method analogous thereto. In addition, the optically active compound (I) can be obtained by a method such as an optical resolution method (a fractional recrystallization method, a chiral column method, a diastereomer method, a method using a microorganism or an enzyme), or asymmetric oxidation. The lansoprazole R-form can also be produced, for example, according to the production method described in WO 00-78745, WO 01/83473 and the like.
The benzimidazole compounds having an anti-ulcer effect used in the present invention include lansoprazole, omeprazole, rabeprazole, pantoprazole, reminoprazole, tenatoprazole (TU-199) and the like, or optically active substances thereof and pharmaceutically acceptable salts thereof. Is more preferable, and lansoprazole or an optically active form thereof, particularly R form, is more preferable. Lansoprazole or its optically active form, particularly R-form, is preferably in a crystalline form, but may be in an amorphous form. It is also advantageously applied to prodrugs of these PPIs.

上記式（ＩＩ）で表される化合物〔以下、化合物（ＩＩ）と称する〕としては、例えば、ＷＯ ０３／１０５８４５に記載の化合物が挙げられる。即ち、化合物（ＩＩ）において、Ｂ環は「置換基を有していてもよいピリジン環」を示す。
Ｂ環で示される「置換基を有していてもよいピリジン環」のピリジン環はその置換可能な位置に１ないし４個の置換基を有していてもよい。置換基としては、例えばハロゲン原子（例えば、フッ素、塩素、臭素、ヨウ素等）、置換基を有していてもよい炭化水素基（例えば、メチル基、エチル基、ｎ−プロピル基等の炭素数１ないし６のアルキル基等）、置換基を有していてもよいアミノ基（例えば、アミノ；メチルアミノ、ジメチルアミノ、エチルアミノ、ジエチルアミノ基等の炭素数１ないし６のアルキル基でモノ−置換ないしジ−置換されたアミノ基等）、アミド基（例えば、ホルムアミド、アセトアミド等のＣ_1-3アシルアミノ基等）、置換基を有していてもよい低級アルコキシ基（例えば、メトキシ、エトキシ、２，２，２−トリフルオロエトキシ、３−メトキシプロポキシ基等の炭素数１ないし６のアルコキシ基等）、低級アルキレンジオキシ基（例えば、メチレンジオキシ、エチレンジオキシ等のＣ_1-3アルキレンジオキシ基等）等が挙げられる。
Ｂ環で示される「置換基を有していてもよいピリジン環」の置換基が有し得る置換基としては、例えば、ハロゲン原子（例えば、フッ素、塩素、臭素、ヨウ素等）、低級アルキル基（例えば、メチル、エチル、プロピル基等の炭素数１ないし６のアルキル基等）、低級アルケニル基（例えば、ビニル、アリル基等の炭素数２ないし６のアルケニル基等）、低級アルキニル基（例えば、エチニル、プロパルギル基等の炭素数２ないし６のアルキニル基等）、シクロアルキル基（例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル基等の炭素数３ないし８のシクロアルキル基等）、低級アルコキシ基（例えば、メトキシ、エトキシ基等の炭素数１ないし６のアルコキシ基等）、ニトロ基、シアノ基、ヒドロキシ基、チオール基、カルボキシル基、低級アルカノイル基（例えば、ホルミル；アセチル、プロピオニル、ブチリル基等の炭素数１ないし６のアルキル−カルボニル基等）、低級アルカノイルオキシ基（例えば、ホルミルオキシ；アセチルオキシ、プロピオニルオキシ基等の炭素数１ないし６のアルキル−カルボニルオキシ基等）、低級アルコキシカルボニル基（例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル基等の炭素数１ないし６のアルコキシ−カルボニル基等）、アラルキルオキシカルボニル基（例えば、ベンジルオキシカルボニル基等の炭素数７ないし１１のアラルキルオキシ−カルボニル基等）、アリール基（例えば、フェニル、ナフチル基等の炭素数６ないし１４のアリール基等）、アリールオキシ基（例えば、フェニルオキシ、ナフチルオキシ基等の炭素数６ないし１４のアリールオキシ基等）、アリールカルボニル基（例えば、ベンゾイル、ナフトイル基等の炭素数６ないし１４のアリール−カルボニル基等）、アリールカルボニルオキシ基（例えば、ベンゾイルオキシ、ナフトイルオキシ基等の炭素数６ないし１４のアリール−カルボニルオキシ基等）、置換基を有していてもよいカルバモイル基（例えば、カルバモイル；メチルカルバモイル、ジメチルカルバモイル基等の炭素数１ないし６のアルキル基でモノ−置換ないしジ−置換されたカルバモイル基等）、置換基を有していてもよいアミノ基（例えば、アミノ；メチルアミノ、ジメチルアミノ、エチルアミノ、ジエチルアミノ基等の炭素数１ないし６のアルキル基でモノ−置換ないしジ−置換されたアミノ基等）等が挙げられ、置換基の数および置換位置に特に限定はない。
Ｂ環で示される「置換基を有していてもよいピリジン環」の置換基の数および置換位置に特に限定はないが、１ないし３個の上記置換基がピリジン環の３、４、および５位のいずれかに置換しているのが好ましい。
Ｂ環で示される「置換基を有していてもよいピリジン環」としては、３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジルが好ましい。
本発明において、Ｃ環はイミダゾール部分と縮合する「置換基を有していてもよいベンゼン環」または「置換基を有していてもよい芳香族単環式複素環」を示し、なかでも前者が好ましい。
Ｃ環で示される「置換基を有していてもよいベンゼン環」の該ベンゼン環はその置換可能な位置に１ないし４個の置換基を有していてもよく、置換基としては、例えば、ハロゲン原子（例えば、フッ素、塩素、臭素、ヨウ素等）、置換基を有していてもよい炭化水素基（例えば、メチル基、エチル基、ｎ−プロピル基等の炭素数１ないし６のアルキル基等）、置換基を有していてもよいアミノ基（例えば、アミノ；メチルアミノ、ジメチルアミノ、エチルアミノ、ジエチルアミノ基等の炭素数１ないし６のアルキル基でモノ−置換ないしジ−置換されたアミノ基等）、アミド基（例えば、ホルムアミド、アセトアミド等のＣ_1-3アシルアミノ基等）、置換基を有していてもよい低級アルコキシ基（例えば、メトキシ、エトキシ、ジフルオロメトキシ基等の炭素数１ないし６のアルコキシ基等）、低級アルキレンジオキシ基（例えば、メチレンジオキシ、エチレンジオキシ等のＣ_1-3アルキレンジオキシ基等）等が挙げられる。
Ｃ環で示される「置換基を有していてもよいベンゼン環」の置換基が有し得る置換基としては、例えば、ハロゲン原子（例えば、フッ素、塩素、臭素、ヨウ素等）、低級アルキル基（例えば、メチル、エチル、プロピル基等の炭素数１ないし６のアルキル基等）、低級アルケニル基（例えば、ビニル、アリル基等の炭素数２ないし６のアルケニル基等）、低級アルキニル基（例えば、エチニル、プロパルギル基等の炭素数２ないし６のアルキニル基等）、シクロアルキル基（例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル基等の炭素数３ないし８のシクロアルキル基等）、低級アルコキシ基（例えば、メトキシ、エトキシ基等の炭素数１ないし６のアルコキシ基等）、ニトロ基、シアノ基、ヒドロキシ基、チオール基、カルボキシル基、低級アルカノイル基（例えば、ホルミル；アセチル、プロピオニル、ブチリル基等の炭素数１ないし６のアルキル−カルボニル基等）、低級アルカノイルオキシ基（例えば、ホルミルオキシ；アセチルオキシ、プロピオニルオキシ基等の炭素数１ないし６のアルキル−カルボニルオキシ基等）、低級アルコキシカルボニル基（例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル基等の炭素数１ないし６のアルコキシ−カルボニル基等）、アラルキルオキシカルボニル基（例えば、ベンジルオキシカルボニル基等の炭素数７ないし１７のアラルキルオキシ−カルボニル基等）、アリール基（例えば、フェニル、ナフチル基等の炭素数６ないし１４のアリール基等）、アリールオキシ基（例えば、フェニルオキシ、ナフチルオキシ基等の炭素数６ないし１４のアリールオキシ基等）、アリールカルボニル基（例えば、ベンゾイル、ナフトイル基等の炭素数６ないし１４のアリール−カルボニル基等）、アリールカルボニルオキシ基（例えば、ベンゾイルオキシ、ナフトイルオキシ基等の炭素数６ないし１４のアリール−カルボニルオキシ基等）、置換基を有していてもよいカルバモイル基（例えば、カルバモイル；メチルカルバモイル、ジメチルカルバモイル基等の炭素数１ないし６のアルキル基でモノ−置換ないしジ−置換されたカルバモイル基等）、置換基を有していてもよいアミノ基（例えば、アミノ；メチルアミノ、ジメチルアミノ、エチルアミノ、ジエチルアミノ基等の炭素数１ないし６のアルキル基でモノ−置換ないしジ−置換されたアミノ基等）等が挙げられ、置換基の数および置換位置に特に限定はない。
Ｃ環で示される「置換基を有していてもよいベンゼン環」としては、ベンゼン環が好ましい。 Preferred examples of these prodrugs include compounds represented by the following general formulas (II) and (III) in addition to the prodrugs contained in the compound (I) or (I ′).

Examples of the compound represented by the above formula (II) [hereinafter, referred to as compound (II)] include compounds described in WO 03/105845. That is, in the compound (II), the ring B represents a “pyridine ring which may have a substituent”.
The pyridine ring of the “optionally substituted pyridine ring” represented by ring B may have 1 to 4 substituents at substitutable positions. Examples of the substituent include a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.) and a hydrocarbon group which may have a substituent (for example, carbon number such as methyl group, ethyl group, n-propyl group, etc.). Mono-substituted by an alkyl group having 1 to 6 carbon atoms such as 1 to 6 alkyl groups and an optionally substituted amino group (for example, amino; methylamino, dimethylamino, ethylamino and diethylamino groups); Or a di-substituted amino group), an amide group (eg, a C _1-3 acylamino group such as formamide and acetamido), and a lower alkoxy group which may have a substituent (eg, methoxy, ethoxy, A C1-C6 alkoxy group such as 2,2,2-trifluoroethoxy or 3-methoxypropoxy group), a lower alkylenedioxy group (for example, And C _1-3 alkylenedioxy groups such as xy and ethylenedioxy).
Examples of the substituent which the substituent of the “pyridine ring optionally having” represented by ring B may have include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a lower alkyl group (For example, an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl and the like), a lower alkenyl group (for example, an alkenyl group having 2 to 6 carbon atoms such as a vinyl and allyl group), and a lower alkynyl group (for example, Alkynyl group having 2 to 6 carbon atoms such as ethynyl, propargyl group, etc.), cycloalkyl group (eg, cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group), lower alkoxy group (For example, an alkoxy group having 1 to 6 carbon atoms such as methoxy and ethoxy), a nitro group, a cyano group, a hydroxy group, a thio group Group, carboxyl group, lower alkanoyl group (for example, formyl; C1-C6 alkyl-carbonyl group such as acetyl, propionyl and butyryl group), lower alkanoyloxy group (for example, formyloxy; acetyloxy, propionyloxy group) A lower alkoxycarbonyl group (e.g., a C1-C6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl group, etc.), aralkyloxycarbonyl Groups (for example, aralkyloxy-carbonyl groups having 7 to 11 carbon atoms such as benzyloxycarbonyl group), aryl groups (for example, aryl groups having 6 to 14 carbon atoms such as phenyl and naphthyl groups), and aryloxy groups (for example, For example, An aryloxy group having 6 to 14 carbon atoms such as enyloxy and naphthyloxy group, an arylcarbonyl group (eg, an aryl-carbonyl group having 6 to 14 carbon atoms such as benzoyl and naphthoyl group), and an arylcarbonyloxy group (eg. C6 to C14 aryl-carbonyloxy groups such as benzoyloxy and naphthoyloxy groups, etc., and carbamoyl groups which may have a substituent (for example, carbamoyl; carbon numbers such as methylcarbamoyl and dimethylcarbamoyl groups) A carbamoyl group mono-substituted or di-substituted with 1 to 6 alkyl groups, and an amino group optionally having a substituent (eg, amino; methylamino, dimethylamino, ethylamino, diethylamino, etc.) A mono-substituted or di-substituted alkyl group having 1 to 6 carbon atoms; And the number and position of substituents are not particularly limited.
The number and positions of the substituents of the “pyridine ring optionally having substituent (s)” represented by ring B are not particularly limited, but one to three of the above substituents are 3, 4 and Substitution at any of the 5-positions is preferred.
As the “pyridine ring optionally having substituent (s)” represented by ring B, 3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl is preferable.
In the present invention, the ring C represents a “benzene ring optionally having substituent (s)” condensed with the imidazole moiety or an “aromatic monocyclic heterocyclic ring optionally having substituent (s)”. Is preferred.
The benzene ring of the “optionally substituted benzene ring” represented by ring C may have 1 to 4 substituents at substitutable positions, and examples of the substituent include, for example, A halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.) and a hydrocarbon group which may have a substituent (for example, alkyl having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, etc.) Group), an amino group which may have a substituent (for example, amino; mono-substituted or di-substituted by an alkyl group having 1 to 6 carbon atoms such as methylamino, dimethylamino, ethylamino, diethylamino group, etc.) Amino group, etc.), amide group (for example, C _1-3 acylamino group such as formamide, acetamido, etc.), and lower alkoxy group which may have a substituent (for example, methoxy, ethoxy, difluoromethoate) Carboxymethyl 6 alkoxy group having 1 to carbon atoms such group), a lower alkylenedioxy group (e.g., methylenedioxy, C _1-3 alkylenedioxy group) such as ethylene dioxy, and the like.
Examples of the substituent which the substituent of the “optionally substituted benzene ring” represented by the ring C may have include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) and a lower alkyl group (E.g., an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl and propyl groups), a lower alkenyl group (e.g., an alkenyl group having 2 to 6 carbon atoms such as vinyl and allyl group), and a lower alkynyl group (e.g., Alkynyl group having 2 to 6 carbon atoms such as ethynyl, propargyl group, etc.), cycloalkyl group (eg, cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group), lower alkoxy group (For example, an alkoxy group having 1 to 6 carbon atoms such as methoxy and ethoxy), a nitro group, a cyano group, a hydroxy group, a thio group Group, carboxyl group, lower alkanoyl group (for example, formyl; C1-C6 alkyl-carbonyl group such as acetyl, propionyl and butyryl group), lower alkanoyloxy group (for example, formyloxy; acetyloxy, propionyloxy group) A lower alkoxycarbonyl group (e.g., a C1-C6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl group, etc.), aralkyloxycarbonyl Group (for example, an aralkyloxy-carbonyl group having 7 to 17 carbon atoms such as a benzyloxycarbonyl group), an aryl group (for example, an aryl group having 6 to 14 carbon atoms such as a phenyl or naphthyl group), an aryloxy group (for example, For example, An aryloxy group having 6 to 14 carbon atoms such as enyloxy and naphthyloxy group, an arylcarbonyl group (eg, an aryl-carbonyl group having 6 to 14 carbon atoms such as benzoyl and naphthoyl group), and an arylcarbonyloxy group (eg. C6 to C14 aryl-carbonyloxy groups such as benzoyloxy and naphthoyloxy groups, etc., and carbamoyl groups which may have a substituent (for example, carbamoyl; carbon numbers such as methylcarbamoyl and dimethylcarbamoyl groups) A carbamoyl group mono-substituted or di-substituted with 1 to 6 alkyl groups, and an amino group optionally having a substituent (eg, amino; methylamino, dimethylamino, ethylamino, diethylamino, etc.) A mono-substituted or di-substituted alkyl group having 1 to 6 carbon atoms; And the number and position of substituents are not particularly limited.
As the “benzene ring optionally having substituent (s)” represented by ring C, a benzene ring is preferable.

Examples of the “aromatic monocyclic heterocycle” of the “aromatic monocyclic heterocycle optionally having substituent (s)” represented by ring C include, for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole , Isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1, 5- or 6-membered aromatics such as 2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc. Monocyclic heterocycles and the like can be mentioned. As the “aromatic monocyclic heterocycle” represented by the ring C, a pyridine ring is particularly preferable. It may have 1 to 4 substituents at the substitutable position, which are the same as the “benzene ring optionally having substituent (s)” represented by ring C.
The position where the “aromatic monocyclic heterocycle” of the “aromatic monocyclic heterocycle optionally having substituent (s)” condenses with the imidazole moiety is not particularly limited.
In the present invention, X ₁ and X ₂ each represent an oxygen atom or a sulfur atom. It is preferred that X ₁ and X ₂ both represent an oxygen atom.

（式中、Ｗ₁、Ｗ₂はそれぞれ「二価の鎖状炭化水素基」または結合手を示し、Ｚは「置換基を有していてもよい二価の炭化水素環基」、「置換基を有していてもよい二価の複素環基」、酸素原子、ＳＯ_n（式中、ｎは０、1または２を示す）または＞Ｎ−Ｅ（式中、Ｅは水素原子、置換基を有していてもよい炭化水素基、置換基を有していてもよい複素環基、低級アルカノイル基、低級アルコキシカルボニル基、アラルキルオキシカルボニル基、チオカルバモイル基、低級アルキルスルフィニル基、低級アルキルスルホニル基、スルファモイル基、モノ−低級アルキルスルファモイル基、ジ−低級アルキルスルファモイル基、アリールスルファモイル基、アリールスルフィニル基、アリールスルホニル基、アリールカルボニル基、置換基を有していてもよいカルバモイル基を示す）を示し、Ｚが酸素原子、ＳＯ_nまたは＞Ｎ−Ｅである場合、Ｗ₁、Ｗ₂はそれぞれ「二価の鎖状炭化水素基」を示す）で表わされる二価の基を示す。なかでも、Ｗとしては「置換基を有していてもよい二価の鎖状炭化水素基」が好ましい。
Ｗで示される「置換基を有していてもよい二価の鎖状炭化水素基」の「二価の鎖状炭化水素基」および、Ｗ₁、Ｗ₂で示される「二価の鎖状炭化水素基」としては、例えば、Ｃ_1-6アルキレン基（例えば、メチレン、エチレン、トリメチレン等）、Ｃ_2-6アルケニレン基（例えば、エテニレン等）、Ｃ_2-6アルキニレン基（例えば、エチニレン等）等が挙げられる。Ｗの二価の鎖状炭化水素基は、Ｃ環で示される「置換基を有していてもよいベンゼン環」と同様の置換基をその置換可能な位置に１ないし６個有していてもよい。
Ｗで示される「置換基を有していてもよい二価の鎖状炭化水素基」の「二価の鎖状炭化水素基」および、Ｗ₁、Ｗ₂で示される「二価の鎖状炭化水素基」としては、メチレン基、エチレン基が好ましい。Ｗとしては、エチレン基が特に好ましい。Ｚが酸素原子、ＳＯ_nまたは＞Ｎ−Ｅ（ｎ及びＥは前義の通り）のとき、Ｗ₁で示される「二価の鎖状炭化水素基」としては、炭素数２以上の炭化水素基が好ましい。 In the present invention, W is “a divalent chain hydrocarbon group which may have a substituent”, or a formula:

(Wherein W ₁ and W ₂ each represent a “divalent chain hydrocarbon group” or a bond, and Z represents a “divalent hydrocarbon ring group which may have a substituent”, A divalent heterocyclic group which may have a group ", an oxygen atom, SO _n (where n represents 0, 1 or 2) or> NE (where E is a hydrogen atom, Hydrocarbon group which may have a group, heterocyclic group which may have a substituent, lower alkanoyl group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, thiocarbamoyl group, lower alkylsulfinyl group, lower alkyl Having a sulfonyl group, a sulfamoyl group, a mono-lower alkylsulfamoyl group, a di-lower alkylsulfamoyl group, an arylsulfamoyl group, an arylsulfinyl group, an arylsulfonyl group, an arylcarbonyl group, and a substituent. Indicates shown) a carbamoyl group optionally, Z is represented by an oxygen atom, a SO _{n or> N-E, W 1,} W 2 each represent a "divalent chain hydrocarbon group") Represents a divalent group. Among them, W is preferably a "divalent chain hydrocarbon group which may have a substituent".
The “divalent chain hydrocarbon group” of the “divalent chain hydrocarbon group which may have a substituent” represented by W and the “divalent chain hydrocarbon group” represented by W ₁ and W ₂ Examples of the “hydrocarbon group” include a C _1-6 alkylene group (eg, methylene, ethylene, trimethylene, etc.), a C _2-6 alkenylene group (eg, ethenylene, etc.), a C _2-6 alkynylene group (eg, ethinylene, etc.) ) And the like. The divalent chain hydrocarbon group represented by W has 1 to 6 substituents at the substitutable position same as those of the “optionally substituted benzene ring” represented by ring C. Is also good.
The “divalent chain hydrocarbon group” of the “divalent chain hydrocarbon group which may have a substituent” represented by W and the “divalent chain hydrocarbon group” represented by W ₁ and W ₂ As the "hydrocarbon group", a methylene group and an ethylene group are preferable. As W, an ethylene group is particularly preferred. Z is an oxygen atom, when the SO _n or> N-E (as n and E before defined), the "divalent chain hydrocarbon group" represented by W _1, 2 or more hydrocarbon atoms Groups are preferred.

Examples of the "hydrocarbon ring" of the "optionally substituted bivalent hydrocarbon ring group" represented by Z include, for example, an alicyclic hydrocarbon ring and an aromatic hydrocarbon ring, It preferably has 3 to 16 carbon atoms, and may have 1 to 4 substituents at the substitutable position similar to the “optionally substituted benzene ring” represented by ring C. . As the hydrocarbon ring, for example, cycloalkane, cycloalkene, arene and the like are used.
As the "cycloalkane" of the "divalent hydrocarbon ring group optionally having substituent (s)" for Z, for example, lower cycloalkane and the like are preferable, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane , Cycloheptane, cyclooctane, bicyclo [2.2.1] heptane, and C _3-10 cycloalkane such as adamantane are widely used.
As the "cycloalkene" of the "divalent hydrocarbon ring group optionally having substituent (s)" for Z, for example, lower cycloalkene is preferable, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclo C _4-9 cycloalkenes such as octene are widely used.
As the "arene" of the "divalent hydrocarbon ring group optionally having substituent (s)" represented by Z, for example, benzene, naphthalene, C _6-14 arene such as phenanthrene are preferable, and phenylene and the like are preferable. Commonly used.

The “heterocycle” of the “divalent heterocyclic group optionally having substituent (s)” represented by Z includes oxygen atom, sulfur atom, nitrogen atom and the like as an atom (ring atom) constituting a ring system. A 5- to 12-membered “aromatic heterocycle” containing at least one (preferably 1 to 4, more preferably 1 to 2) heteroatoms selected from the group consisting of 1 to 3 (preferably 1 to 2) heteroatoms Or a "saturated or unsaturated non-aromatic heterocyclic ring" or the like, and the same substituent as the "optionally substituted benzene ring" represented by the ring C may be substituted with 1 to You may have four.
Examples of the “aromatic heterocycle” of the “divalent heterocyclic group optionally having substituent (s)” for Z include an aromatic monocyclic heterocycle and an aromatic condensed heterocycle.
The "aromatic monocyclic heterocycle" includes, for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4 -Oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1 And 5- or 6-membered aromatic monocyclic heterocycles such as 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine.
Examples of the “aromatic fused heterocycle” include benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzoisoxazole, and benzothiazole 1,1,2-benzisothiazole, 1H-benzotriazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine, pteridine, carbazole, carbolin, acridine, phenoxazine, phenothiazine, phenazine, phenoxatiin, thianthrene , Phenanthridine, phenanthroline, indolizine, pyrrolo [1,2-b] pyridazine, pyrazolo [1,5-a] pyridine, imidazo [1,2-a] pyridine Imidazo [1,5-a] pyridine, imidazo [1,2-b] pyridazine, imidazo [1,2-a] pyrimidine, 1,2,4-triazolo [4,3-a] pyridine, 1,2, 8- to 12-membered fused aromatic heterocycles such as 4-triazolo [4,3-b] pyridazine and the like.

Examples of the “saturated or unsaturated non-aromatic heterocycle” of the “divalent heterocyclic group which may have a substituent” represented by Z include, for example, oxirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran , 3 to 8 members (preferably 5 to 5) 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocycle (aliphatic heterocycle). These may be oxo-substituted, for example, 2-oxoazetidine, 2-oxopyrrolidine, 2-oxopiperidine, 2-oxoazepane, 2-oxoazocan, 2-oxotetrahydrofuran, 2-oxotetrahydropyran, 2-oxotetrahydro Thiophene, 2-oxothian, 2-oxopiperazine, 2-oxooxepane, 2-oxooxazepane, 2-oxothiepane, 2-oxothiazepane, 2-oxooxocan, 2-oxothiocan, 2-oxooxazocan, 2-oxothiazocan And so on.
Z represents a “divalent hydrocarbon ring group which may have a substituent”, a “hydrocarbon ring group” or a “divalent heterocyclic group which may have a substituent”. The two bonds from the “ring group” may be at any possible position.

The “hydrocarbon group which may have a substituent” and the “heterocyclic group which may have a substituent” represented by E are as defined below.
As the “lower alkanoyl group” represented by E, for example, formyl; C _1-6 alkyl-carbonyl group such as acetyl, propionyl, butyryl, isobutyryl and the like are used.
As the “lower alkoxycarbonyl group” represented by E, for example, a C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like are used.
As the “aralkyloxycarbonyl” represented by E, for example, a C _7-11 aralkyloxy-carbonyl group such as benzyloxycarbonyl and the like are used.
As the “lower alkylsulfinyl group” represented by E, for example, a C _1-6 alkylsulfinyl group such as methylsulfinyl and ethylsulfinyl is used.
As the “lower alkylsulfonyl group” represented by E, for example, a C _1-6 alkylsulfonyl group such as methylsulfonyl and ethylsulfonyl is used.
As the “mono-lower alkylsulfamoyl group” represented by E, for example, a mono-C _1-6 alkylsulfamoyl group such as methylsulfamoyl and ethylsulfamoyl is used.
As the “di-lower alkylsulfamoyl group” represented by E, for example, di-C _1-6 alkylsulfamoyl groups such as dimethylsulfamoyl and diethylsulfamoyl are used.
As the “arylsulfamoyl group” represented by E, for example, a C _6-10 arylsulfamoyl group such as phenylsulfamoyl and naphthylsulfamoyl and the like are used.
As the “arylsulfinyl group” represented by E, for example, a C _6-10 arylsulfinyl group such as phenylsulfinyl and naphthylsulfinyl is used.
As the “arylsulfonyl group” represented by E, for example, a C _6-10 arylsulfonyl group such as phenylsulfonyl and naphthylsulfonyl is used.
As the “arylcarbonyl group” represented by E, for example, a C _6-10 aryl-carbonyl group such as benzoyl and naphthoyl is used.
Examples of the “carbamoyl group optionally having a substituent” represented by E include, for example, a group represented by the formula —CONR ₂ R ₃ (wherein, R ₂ and R ₃ may each have a hydrogen atom or a substituent. have a hydrocarbon group or a substituent shown also heterocyclic group. Further, in the equation -CONR ₂ R _3, R ₂ and R ₃ may form a ring together with the adjacent nitrogen atom.) in The groups represented are used.

In the present invention, R represents a "hydrocarbon group which may have a substituent" or a "heterocyclic group which may have a substituent", and R can be bonded to W; Among them, a C _1-6 hydrocarbon group which may have a substituent, particularly a lower (C _1-6 ) alkyl group, is preferred. The “hydrocarbon group which may have a substituent” and the “heterocyclic group which may have a substituent” represented by R are as defined below. The case where R is combined with W will be described later in detail.

In the present invention, D ₁ and D ₂ each represent a bond, an oxygen atom, a sulfur atom or> NR ₁ , wherein R ₁ represents a hydrogen atom or a hydrocarbon group which may have a substituent. Show. However, in the present invention, the case where both D ₁ and D ₂ are a bond is excluded. Of these, D ₁ and D ₂ are each preferably a bond or an oxygen atom, and particularly preferably D ₁ is an oxygen atom and D ₂ is an oxygen atom or a bond. The “optionally substituted hydrocarbon group” for R ₁ is as defined below.

In the present invention, G represents a “hydrocarbon group which may have a substituent” or a “heterocyclic group which may have a substituent”. _It may have a _1-6 hydrocarbon group or a substituent, and is preferably a saturated heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur as ring-constituting atoms. In particular, G is a C _1-6 hydrocarbon group which may have a substituent, or a hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom as a ring-constituting atom, which may have a substituent. A saturated oxygen-containing heterocyclic group which may further contain 1 to 3 atoms is preferred. The “optionally substituted hydrocarbon group” or the “optionally substituted heterocyclic group” represented by G is as defined below.

As the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by E, R, R ₁ and G, for example, a saturated or unsaturated aliphatic hydrocarbon group, a saturated or unsaturated Unsaturated alicyclic hydrocarbon group, saturated or unsaturated alicyclic-aliphatic hydrocarbon group, aromatic hydrocarbon group, aromatic-saturated or unsaturated alicyclic hydrocarbon group and the like, It preferably has 1 to 16 carbon atoms, more preferably 1 to 6 carbon atoms. Specifically, for example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkylalkyl group, a cycloalkenylalkyl group, an aryl group and an arylalkyl group are used.
The “alkyl group” is preferably, for example, a lower alkyl group (C _1-6 alkyl group) and the like, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-ethyl C _1-6 alkyl groups such as propyl and hexyl are widely used. R is preferably a lower alkyl group (C _1-6 alkyl group), and particularly preferably a methyl group.
The “alkenyl group” is preferably, for example, a lower alkenyl group or the like, for example, a C _2-7 alkenyl group such as vinyl, 1-propenyl, allyl, isopropenyl, butenyl, isobutenyl and 2,2-dimethyl-pent-4-enyl. Are commonly used.
The “alkynyl group” is preferably, for example, a lower alkynyl group, and for example, a C _2-6 alkynyl group such as ethynyl, propargyl and 1-propynyl is generally used.
The “cycloalkyl group” is preferably, for example, a lower cycloalkyl group and the like, for example, C _3- such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptanyl and adamantyl. ₁₀ cycloalkyl groups and the like are widely used.
The “cycloalkenyl group” is preferably, for example, a lower cycloalkenyl group or the like, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo [2.2.1] hept-5-en-2-. C _3-10 cycloalkenyl groups such as yl are widely used.
"Cycloalkyl group" is preferably, for example, such as lower cycloalkylalkyl group, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, C _4-9 cycloalkylalkyl such as cyclohexylmethyl and cyclohexylethyl Groups are widely used.
The “cycloalkenylalkyl group” is preferably, for example, a lower cycloalkenylalkyl group or the like, and is preferably cyclopentenylmethyl, cyclohexenylmethyl, cyclohexenylethyl, cyclohexenylpropyl, cycloheptenylmethyl, cycloheptenylethyl, and bicyclo [2.2 .1] C _4-9 cycloalkenylalkyl, etc., such as hept-5-en-2-ylmethyl and the like are generally used.
The “aryl group” is preferably, for example, a C _6-14 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl and 2-anthryl, and for example, a phenyl group is generally used.
An “arylalkyl group” has the above-defined “aryl group” as the aryl moiety and the above-defined “alkyl group” as the alkyl moiety. Among them, for example, a C _6-14 aryl-C _1-6 alkyl group is preferable, and for example, benzyl, phenethyl and the like are widely used.

Examples of the substituent which the “hydrocarbon group” of the “hydrocarbon group optionally having” represented by E, R, R ₁ and G may have include, for example, a halogen atom (eg, , Fluorine, chlorine, bromine, iodine, etc.), nitro group, cyano group, hydroxy group, thiol group, sulfo group, sulfino group, phosphono group, lower alkyl group which may be halogenated (for example, methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, C _1-6 alkyl, chloromethyl and 1-ethylpropyl and hexyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 4,4, - trifluorobutyl, 5,5,5-trifluoro pentyl, such as 6,6,6-trifluoro hexyl mono -, di- - or tri - halogeno -C _1-6 alkyl group, etc.), oxo group, amidino group An imino group, an alkylenedioxy group (eg, a C _1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.), a lower alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, A C _1-6 alkoxy group such as pentyloxy and hexyloxy, etc., and an optionally halogenated lower alkoxy group (eg, chloromethyloxy, dichloromethyloxy, trichloromethyloxy, fluoromethyloxy, difluoromethyloxy, Fluoromethyloxy, 2-bromoethyloxy, 2,2,2-trifluoroethyl Ruoxy, pentafluoroethyloxy, 3,3,3-trifluoropropyloxy, 4,4,4-trifluorobutyloxy, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy mono etc. -, di - or tri - halogeno -C _1-6 alkoxy group), a lower alkylthio group (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, such hexylthio C _1-6 Alkylthio group, etc.), carboxyl group, lower alkanoyl group (eg, formyl; C _1-6 alkyl-carbonyl group such as acetyl, propionyl, butyryl, isobutyryl, etc.), lower alkanoyloxy group (eg, formyloxy; acetyloxy, propionyl) Oxy, butyryloxy, isobutyryloxy C _1-6 alkyl etc. - carbonyloxy group, etc.), lower alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, C _1-6 alkoxy such as butoxycarbonyl - carbonyl group), an aralkyloxycarbonyl group ( For example, a C _7-11 aralkyloxy-carbonyl group such as benzyloxycarbonyl), a thiocarbamoyl group, a lower alkylsulfinyl group (eg, a C _1-6 alkylsulfinyl group such as methylsulfinyl and ethylsulfinyl), a lower alkylsulfonyl Groups (eg, C _1-6 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, etc.), sulfamoyl groups, mono-lower alkylsulfamoyl groups (eg, mono-C ₁ such as methylsulfamoyl, ethylsulfamoyl, etc.) _-6 alkyl Rufamoiru group), di - lower alkylsulfamoyl group (e.g., dimethylsulfamoyl, and di -C _1-6 alkylsulfamoyl group such as diethylsulfamoyl), an arylsulfamoyl group (e.g., phenyl A C _6-10 arylsulfamoyl group such as sulfamoyl and naphthylsulfamoyl, an aryl group (eg, a C _6-10 aryl group such as phenyl and naphthyl), an aryloxy group (eg, phenyloxy, A C _6-10 aryloxy group such as naphthyloxy and the like; an arylthio group (eg C _6-10 arylthio group such as phenylthio and naphthylthio); and an arylsulfinyl group (eg C _6-10 such as phenylsulfinyl and naphthylsulfinyl). Arylsulfinyl group, etc.), arylsulfonyl group (for example, phenylsulfonyl, naph Such C _6-10 arylsulfonyl group such Rusuruhoniru), an arylcarbonyl group (e.g., benzoyl, C _6-10 aryl such as naphthoyl - such carbonyl group), an arylcarbonyloxy group (e.g., benzoyloxy, naphthoyloxy, etc. C _6-10 aryl-carbonyloxy group, etc.) and optionally halogenated lower alkylcarbonylamino group (eg, optionally halogenated C _1-6 alkyl- such as acetylamino, trifluoroacetylamino, etc.) A carbamoyl group which may have a substituent (for example, a group represented by the formula -CONR ₂ R ₃ (wherein R ₂ and R ₃ are each a hydrogen atom, a carbon atom which may have a substituent) It represents a hydrogen group or a heterocyclic group which may have a substituent. In the formula —CONR ₂ R ₃ , R ₂ and R ₃ may form a ring together with an adjacent nitrogen atom. ) Group represented by), optionally substituted amino group (e.g., wherein -NR ₂ R ₃ (wherein, R ₂ and R ₃ are as defined above. In addition, the formula -NR ₂ In R ₃ , R ₂ and R ₃ may form a ring together with an adjacent nitrogen atom)), a ureido group which may have a substituent (for example, a formula —NHCONR ₂ R ₃₎ (Wherein, R ₂ and R ₃ have the same meanings as described above. In the formula —NHCONR ₂ R ₃ , R ₂ and R ₃ may form a ring together with an adjacent nitrogen atom.) Group), a carboxamide group which may have a substituent (for example, a group represented by the formula —NR ₂ COR ₃ (wherein, R ₂ and R ₃ have the same meanings as described above)), and a substituent and which may be a sulfonamide group (e.g., wherein -NR ₂ SO ₂ R ₃ (wherein, R ₂ and R ₃ are pre And a heterocyclic group which may have a substituent (equivalent to those represented by R ₂ and R ₃ ), and the like.
The “hydrocarbon group” of the “hydrocarbon group which may have a substituent” in R ₂ and R ₃ includes, for example, a lower alkyl group (for example, having 1 to 6 carbon atoms such as methyl, ethyl and propyl groups). A lower alkenyl group (eg, an alkenyl group having 2 to 6 carbon atoms such as vinyl or allyl group), a lower alkynyl group (eg, an alkynyl group having 2 to 6 carbon atoms such as ethynyl, propargyl group, etc.) ), Cycloalkyl groups (eg, cycloalkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups, etc.), and cycloalkenyl groups (eg, carbon atoms having 3 carbon atoms such as cyclobutenyl, cyclopentenyl, cyclohexenyl group, etc.) To 8 cycloalkenyl groups, etc.), cycloalkylalkyl groups (eg, cyclopropylmethyl, C3-C8 cycloalkyl-C1-C6 alkyl group such as cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl group, etc., cycloalkenylalkyl group (for example, cyclobutenylmethyl, cyclopentenylmethyl, cyclohexenyl) A C3-C8 cycloalkenyl-C1-6 alkyl group such as a methyl group, an aryl group (e.g., a C6-C14 aryl group such as a phenyl or naphthyl group), an arylalkyl group ( For example, an aryl group having 6 to 14 carbon atoms, such as a benzyl or naphthylmethyl group, or an alkyl group having 1 to 6 carbon atoms, etc.).
Examples of the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” represented by R ₂ and R ₃ include pyridyl, pyrrolidinyl, piperazinyl, piperidinyl, 2-oxoazepinyl, furyl, decahydroisoquinolyl A 5- to 12-membered monocyclic ring containing from 1 to 2 heteroatoms selected from nitrogen, sulfur and oxygen such as quinolinyl, indolyl, isoquinolyl, thienyl, imidazolyl and morpholinyl Or a fused heterocyclic group. Examples of the substituent of the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” in R ₂ and R ₃ include, for example, a halogen atom (for example, Fluorine, chlorine, bromine, iodine, etc.), lower alkyl groups (eg, alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl groups, etc.) and lower alkenyl groups (eg, 2 carbon atoms, such as vinyl, allyl group, etc.) To 6 alkenyl groups, etc.), lower alkynyl groups (eg, alkynyl groups having 2 to 6 carbon atoms, such as ethynyl and propargyl groups), and cycloalkyl groups (eg, carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group, etc.) 3 to 8 cycloalkyl groups, etc.), lower alkoxy groups (for example, C1 to C6 alkoxy groups such as methoxy, ethoxy, etc.) A nitro group, a cyano group, a hydroxy group, a thiol group, a carboxyl group, a lower alkanoyl group (for example, formyl; an alkyl-carbonyl group having 1 to 6 carbon atoms such as acetyl, propionyl and butyryl groups), a lower alkanoyloxy group ( For example, formyloxy; an alkyl-carbonyloxy group having 1 to 6 carbon atoms such as acetyloxy and propionyloxy group, and a lower alkoxycarbonyl group (for example, 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl group). An aralkyloxycarbonyl group (e.g., an aralkyloxy-carbonyl group having 7 to 17 carbon atoms such as a benzyloxycarbonyl group), and an aryl group (e.g., a aralkyloxy-carbonyl group such as phenyl or naphthyl group). 14 of An aryloxy group (for example, an aryloxy group having 6 to 14 carbon atoms such as phenyloxy and naphthyloxy group); an arylcarbonyl group (for example, an aryl group having 6 to 14 carbon atoms such as benzoyl and naphthoyl group) -Carbonyl group or the like), an arylcarbonyloxy group (for example, an aryl-carbonyloxy group having 6 to 14 carbon atoms such as a benzoyloxy or naphthoyloxy group), or a carbamoyl group which may have a substituent (for example, Carbamoyl; a carbamoyl group mono-substituted or di-substituted with an alkyl group having 1 to 6 carbon atoms such as a methylcarbamoyl group and a dimethylcarbamoyl group, and an amino group optionally having a substituent (for example, amino; methyl) 1 carbon atom such as amino, dimethylamino, ethylamino, diethylamino group Mono alkyl stone 6 - substituted or di - amino group is substituted), and the like. There is no particular limitation on the number and position of the substituents.
Examples of the ring formed by R ₂ and R ₃ together with the adjacent nitrogen atom include pyrrolidine, piperidine, homopiperidine, morpholine, piperazine, tetrahydroquinoline, and tetrahydroisoquinoline.
The “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by E, R, R ₁ and G is such that each of the above-mentioned substituents is located at a substitutable position of the hydrocarbon group. It may have 1 to 5, preferably 1 to 3, and when the number of substituents is 2 or more, each substituent may be the same or different.

  As the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” represented by E, R, and G, an oxygen atom, a sulfur atom, 5- to 12-membered aromatic containing at least 1 (preferably 1 to 4, more preferably 1 to 3) heteroatoms of 1 to 3 (preferably 1 to 2) selected from nitrogen atoms and the like Examples include a heterocyclic group or a saturated or unsaturated non-aromatic heterocyclic group. As described above, the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” represented by G includes, as described above, a heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like as a ring atom. A saturated oxygen-containing heterocyclic group containing 1 to 4, more preferably 1 to 3, and the like are preferable, and a 5 to 12-membered saturated oxygen-containing heterocyclic group and the like are particularly preferable.

Examples of the “aromatic heterocyclic group” include an aromatic monocyclic heterocyclic group and an aromatic condensed heterocyclic group.
Examples of the “aromatic monocyclic heterocyclic group” include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, , 3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl And a 5- or 6-membered aromatic monocyclic heterocyclic group such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
As the "aromatic condensed heterocyclic group", for example, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxyl Zolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ -Carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo [1,2-b] Ridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] 8- to 12-membered fused aromatic heterocyclic groups such as pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl (preferably, A heterocyclic ring wherein the 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring or two identical or different heterocyclic rings of the 5- or 6-membered aromatic monocyclic heterocyclic group are condensed; Heterocyclic ring) and the like.

  Examples of the `` saturated or unsaturated non-aromatic heterocyclic group '' include, for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, 3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic groups (such as fatty acids) such as oxepanyl, tiepanyl, oxazepanyl, thiazepanyl, azocanyl, oxocanyl, thiocanyl, oxazocanyl, and thiazocanyl. Group heterocyclic group). These may be oxo-substituted, for example, 2-oxoazetidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxoazepanyl, 2-oxoazocanyl, 2-oxotetrahydrofuryl, 2-oxotetrahydrofuryl, Oxotetrahydropyranyl, 2-oxothiolanyl, 2-oxothianyl, 2-oxopiperazinyl, 2-oxooxepanyl, 2-oxooxazepanyl, 2-oxothiepanyl, 2-oxothiazepanyl, 2-oxo Oxocanyl, 2-oxothiocanyl, 2-oxooxazocanyl, 2-oxothiazocanyl and the like. Preferred is a 5-membered non-aromatic heterocyclic group such as 2-oxopyrrolidinyl.

Examples of the substituent which the “heterocyclic group” of the “heterocyclic group optionally having” represented by E, R and G may have include, for example, the aforementioned E, R and R ₁ And G, the same as the “substituent” of the “hydrocarbon group which may have a substituent” and the like are used.
The “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” represented by E, R, and G is the same as described above, except that each of the above substituents is 1 to 5 at a substitutable position of the heterocyclic group. , Preferably 1 to 3, and when the number of substituents is 2 or more, each substituent may be the same or different.

The case where R binds to W in the compound of the present invention will be described. When R and W are bonded, the position at which R and W are bonded is not particularly limited as long as they can be bonded at R and W, respectively.
The bondable positions in R include the bondable positions in the “hydrocarbon group” and “substituent” of the “hydrocarbon group which may have a substituent” defined in the above R, and The bondable position in the "heterocyclic group" and the "substituent" of the "heterocyclic group which may have a substituent" as defined is mentioned.
The bondable position in W is a bondable position in the “divalent chain hydrocarbon group” of the “divalent chain hydrocarbon group optionally having substituent (s)” defined in the above W. The bondable position in the “divalent chain hydrocarbon group” defined by W ₁ and W ₂ , and the “optionally substituted hydrocarbon ring” defined by the Z ring. The bondable positions in the “hydrocarbon ring” and the bondable positions in the “heterocycle” of the “heterocycle optionally having substituent (s)” defined for the above-mentioned Z ring are exemplified.
R and W may be bonded to each other at a bondable position, and may form a ring together with an adjacent nitrogen atom. Examples of the ring include a saturated nitrogen-containing ring (eg, azetidine, pyrrolidine, piperidine, homopiperidine, etc.), an unsaturated nitrogen-containing ring (eg, tetrahydropyridine, etc.), an aromatic nitrogen-containing ring (eg, pyrrole, etc.), A heterocycle (eg, piperazine, morpholine, etc.) or a condensed ring (eg, indole, indoline) containing at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur in addition to the nitrogen atom to which R and W are adjacent , Isoindole, isoindoline, tetrahydroquinoline, tetrahydroisoquinoline, etc.). Among them, a 4- to 7-membered ring is preferable.
The ring formed by R and W bonded to each other at a bondable position and formed together with an adjacent nitrogen atom may have 1 to 4 substituents at the substitutable position. When the number of substituents is two or more, each substituent may be the same or different. As the substituent, the substituents of the “hydrocarbon group optionally having substituent (s)” and the “heterocyclic group optionally having substituent (s)” defined by R, and “ A substituent of a "divalent chain hydrocarbon group which may have a substituent". Specifically, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-ethylpropyl, hexyl and the like And a substituent such as a C _1-6 alkyl group.

等が形成されるがこれらに限定されない。これらは、上記で定義するように置換基を有していてもよく、また、異性体を含み得ることは当業者に理解されるべきである。 By combining R and W, for example,

Are formed, but not limited to these. It should be understood by those skilled in the art that these may have substituents as defined above and may include isomers.

  In the present invention, X represents a leaving group such as a halogen atom, a benzotriazolyl group or a (2,5-dioxypyrrolidin-1-yl) oxy group, among which fluorine, chlorine, bromine, iodine, etc. Is preferred, and chlorine is particularly preferred.

In the present invention, M represents a hydrogen atom, a metal cation or a quaternary ammonium ion.
As the “metal cation” in the present invention, an alkali metal ion (for example, Na ⁺ , K ⁺ , Li ⁺ , Cs ^+, etc.) can be mentioned, and Na ⁺ is particularly preferred.
Examples of the “quaternary ammonium ion” in the present invention include a tetramethylammonium ion, a tetraethylammonium ion, a tetrapropylammonium ion, a tetrabutylammonium ion and the like, and among them, a tetrabutylammonium ion is preferable.

In the compound (II), an acidic group in the molecule and an inorganic base or an organic base can form a pharmacologically acceptable base salt, and the basic group in the molecule and an inorganic or organic acid or the like can be formed. Can form a pharmacologically acceptable acid addition salt.
Examples of the inorganic base salts of compound (II) include salts with alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, etc.), ammonia, etc., and organic salts of compound (II). Examples of the base salt include salts with dimethylamine, triethylamine, piperazine, pyrrolidine, piperidine, 2-phenylethylamine, benzylamine, ethanolamine, diethanolamine, pyridine, collidine and the like.
Examples of the acid addition salt of compound (II) include inorganic acid salts (eg, hydrochloride, sulfate, hydrobromide, phosphate, etc.) and organic acid salts (eg, acetate, trifluoroacetate) Succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc.).

  The compound (II) of the present invention includes a hydrate. Examples of the “hydrate” include 0.5 hydrate to 5.0 hydrate. Of these, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate and 2.0 hydrate are preferred.

〔式中の記号は前記と同意義を示す〕で表わされる（Ｒ）体が好ましい。 The compound (II) of the present invention includes racemates and optically active compounds. As the optically active compound, those having one enantiomer having an enantiomeric excess (ee) of 90% or more are preferable, and those having an enantiomeric excess of 99% or more are more preferable. As the optically active substance, a general formula

The (R) form represented by the formula [wherein the symbols have the same meanings as described above] is preferable.

Preferred examples of the compound included in the compound (II) include, for example, the following compounds.
That is,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl acetate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl trimethyl acetate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl cyclohexanecarboxylate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl benzoate,
2- [methyl [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] amino ] Ethyl benzoate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 4-methoxybenzoate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 3-chlorobenzoate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 3,4-difluorobenzoate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 4-trifluoromethoxybenzoate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 4-fluorobenzoate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 3,4,5-trimethoxybenzoate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 2-pyridinecarboxylate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl methoxyacetate,
Ethyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Yl] carbonyl] amino] ethyl carbonate,
Isopropyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Yl] carbonyl] amino] ethyl carbonate,
Isopropyl 2- [methyl [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] Amino] ethyl carbonate,
Benzyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Yl] carbonyl] amino] ethyl carbonate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl tetrahydropyran-4-yl carbonate,
2-methoxyethyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole -1-yl] carbonyl] amino] ethyl carbonate,
2- [ethyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl acetate,
2- [isopropyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl acetate,
Ethyl 2- [isopropyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Yl] carbonyl] amino] ethyl carbonate,
2- [cyclohexyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl acetate,
2- [cyclohexyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl ethyl carbonate,
2-[[[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] Carbonyl] (phenyl) amino] ethyl acetate,
2-[[[2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (phenyl ) Amino] ethyl acetate,
tert-butyl [2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole -1-yl] carbonyl] amino] -3-pyridyl] methyl carbonate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] benzyl acetate,
2-[[2- (acetyloxy) ethyl] [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl]- 1H-benzimidazol-1-yl] carbonyl] amino] ethyl acetate,
[(2S) -1-[[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole- 1-yl] carbonyl] -2-pyrrolidinyl] methyl acetate;
Ethyl [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] Carbonyl] amino] acetate,
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (methyl) amino] ethyl Benzoate,
3- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] propyl benzoate,
2- [methyl [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] amino ] Ethyl tetrahydropyran-4-yl carbonate,
Ethyl 2- [methyl [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] Amino] ethyl carbonate,
Ethyl 2- [methyl [[(S) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Yl] carbonyl] amino] ethyl carbonate,
Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -3H-imidazo [4,5-b] pyridin-3-yl] Carbonyl] (methyl) amino] ethyl carbonate,
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -3H-imidazo [4,5-b] pyridin-3-yl] carbonyl ] (Methyl) amino] ethyl acetate,
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -3H-imidazo [4,5-b] pyridin-3-yl] carbonyl ] (Phenyl) amino] ethyl acetate,
4- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] butyl acetate;
Ethyl 4- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Yl] carbonyl] amino] butyl carbonate,
Ethyl 3- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Yl] carbonyl] amino] propyl carbonate,
3- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] propyl acetate,
3- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] propane-1,2-diyl diacetate,
Diethyl 3- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Yl] carbonyl] amino] propane-1,2-diyl biscarbonate,
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -3H-imidazo [4,5-b] pyridin-3-yl] carbonyl ] (Methyl) amino] ethyl 3-chlorobenzoate,
2- [methyl [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] amino ] Ethyl acetate,
2-ethoxyethyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole -1-yl] carbonyl] amino] ethyl carbonate,
3-methoxypropyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole -1-yl] carbonyl] amino] ethyl carbonate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl N, N-dimethylglycinate,
S- [2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole- 1-yl] carbonyl] amino] ethyl] thioacetate,
Ethyl 2- [2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole -1-yl] carbonyl] amino] ethoxy] ethyl carbonate,
Ethyl 2- [methyl [[2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H -Benzimidazol-1-yl] carbonyl] amino] ethoxy] carbonyl] amino] ethyl carbonate,
Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (methyl) amino] Ethyl carbonate,
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (phenyl) amino] ethyl acetate,
Ethyl 2-[[[(S) -5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] ( Methyl) amino] ethyl carbonate,
Ethyl 2-[[[[2-[[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (methyl) amino] ethyl Carbonate,
2-[[[2-[[[4- (3-Methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (phenyl) amino] ethyl acetate ,
2-[[[5- (Difluoromethoxy) -2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (methyl) amino] ethyl ethyl Carbonate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 1-methylpiperidine-4-carboxylate,
2-[[4- (aminocarbonyl) phenyl] [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl]- 1H-benzimidazol-1-yl] carbonyl] amino] ethyl acetate;
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 1-methyl-4-piperidinyl carbonate,
2-[[4- (aminocarbonyl) phenyl] [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole -1-yl] carbonyl] amino] ethyl acetate,
(-)-Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -3H-imidazo [4,5-b] pyridine- 3-yl] carbonyl] (methyl) amino] ethyl carbonate and (+)-ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl ] -3H-imidazo [4,5-b] pyridin-3-yl] carbonyl] (methyl) amino] ethyl carbonate and salts thereof.

Particularly, the following compounds and salts thereof are preferable.
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl acetate,
Ethyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Yl] carbonyl] amino] ethyl carbonate,
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl tetrahydropyran-4-yl carbonate,
2- [methyl [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] amino ] Ethyl tetrahydropyran-4-yl carbonate,
Ethyl 2- [methyl [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] Amino] ethyl carbonate,
Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -3H-imidazo [4,5-b] pyridin-3-yl] Carbonyl] (methyl) amino] ethyl carbonate,
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -3H-imidazo [4,5-b] pyridin-3-yl] carbonyl ] (Methyl) amino] ethyl acetate,
2- [methyl [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] amino ] Ethyl acetate,
Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (methyl) amino] Ethyl carbonate,
Ethyl 2-[[[(S) -5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] ( Methyl) amino] ethyl carbonate,
Ethyl 2-[[[[2-[[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (methyl) amino] ethyl Carbonate and 2-[[[5- (difluoromethoxy) -2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (methyl) amino ] Ethyl ethyl carbonate.

(式中の各記号は前記と同意義を示す。） Compound (II) can be produced, for example, by the method described in WO 03/105845. That is, it can be manufactured by the following method A or B.
(Method A)
Compound (II) or a salt thereof can be obtained by condensing compound (IV) or a salt thereof with compound (V) or a salt thereof in the presence or absence of a base. Examples of the salt of the compound (IV) and the salt of the compound (V) include the same salts as the salt of the compound (II). For example, inorganic acid salts (eg, hydrochloride, sulfate, hydrobromide, phosphate, etc.), organic acid salts (eg, acetate, trifluoroacetate, succinate, maleate, fumaric acid) Acid addition salts such as salts, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate and the like.

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

  The reaction in the method A is generally performed in a solvent, and a solvent that does not inhibit the reaction in the method A is appropriately selected. Examples of such a solvent include ethers (eg, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, etc.) and esters (eg, ethyl formate, ethyl acetate, butyl acetate, etc.). ), Halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, tricrene, 1,2-dichloroethane, etc.), hydrocarbons (eg, n-hexane, benzene, toluene, etc.), amides (eg, formamide) , N, N-dimethylformamide, N, N-dimethylacetamide, etc.), ketones (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), nitriles (eg, acetonitrile, propionitrile, etc.), and dimethyl sulfone. Oxide, sulfolane, hexamethylphosphoramide, water and the like can be mentioned, and these are used alone or as a mixed solvent. The amount of these solvents to be used is not particularly limited as long as the reaction mixture can be stirred, and is usually 2 to 100-fold weight, preferably 5 to 50-fold weight, per 1 mol of compound (IV) or a salt thereof. is there.

The amount of compound (V) or a salt thereof to be used is generally 1 mol to 10 mol, preferably 1 mol to 3 mol, per 1 mol of compound (IV) or a salt thereof.
The reaction of the method A is carried out usually at a temperature of 0 ° C to 100 ° C, preferably 20 ° C to 80 ° C.
The reaction time of Method A varies depending on the type of compound (IV), (V) or a salt thereof and the solvent, the reaction temperature and the like, but is usually 1 minute to 96 hours, preferably 1 minute to 72 hours, more preferably 15 minutes. ~ 24 hours.
Examples of the base in the method A include, for example, an inorganic base (eg, sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate, etc.) and a tertiary amine (eg, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, pyridine, Lutidine, γ-collidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 4-dimethylaminopyridine, etc., alkylene oxides (eg, propylene oxide, epichlorohydrin, etc.) and the like. No. The amount of the base to be used is generally 0.01 mol-10 mol, preferably 1 mol-3 mol, per 1 mol of compound (V) or a salt thereof.

（式中、各記号は前記と同義である）で表わされる化合物またはその塩にホスゲン、クロロギ酸トリクロロメチル、炭酸ビス（トリクロロメチル）、チオホスゲン等を作用させることにより得ることができる。あるいは、化合物（ＶＩＩ）またはその塩とクロロギ酸エチルを作用させることにより得られるエチルカルバメート体を、シンセティック コミュニケーションズ（ＳＧｎｔｈｅｔｉｃ Ｃｏｍｍｕｎｉｃａｔｉｏｎｓ） 第１７巻、１８８７頁（１９８７年）に記載の方法またはこれに準じた方法に従い、オキシ塩化リンで処理することによっても得ることができる。化合物（ＶＩＩ）の塩としては、例えば、無機酸塩（例えば、塩酸塩、硫酸塩、臭化水素酸塩、リン酸塩等）、有機酸塩（例えば、酢酸塩、トリフルオロ酢酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、プロピオン酸塩、クエン酸塩、酒石酸塩、乳酸塩、蓚酸塩、メタンスルホン酸塩、ｐ−トルエンスルホン酸塩等）等の酸付加塩等が挙げられる。 Compound (IV) or a salt thereof is produced by the method described in JP-A-61-50978, US Pat. No. 4,628,098, or the like, or a method analogous thereto.
Compound (V) or a salt thereof can be produced by a method known per se or a method analogous thereto. For example, when X is a chlorine atom, in a solvent (eg, tetrahydrofuran, acetonitrile, dichloromethane, etc.) in the presence of a deoxidizing agent, the compound represented by the formula (VII):

(Wherein each symbol is as defined above) or a salt thereof, which is obtained by reacting phosgene, trichloromethyl chloroformate, bis (trichloromethyl) carbonate, thiophosgene, or the like. Alternatively, an ethyl carbamate derivative obtained by reacting compound (VII) or a salt thereof with ethyl chloroformate was subjected to the method described in Synthetic Communications (SGnetic Communications) Vol. 17, p. 1887 (1987) or a method similar thereto. According to the method, it can also be obtained by treating with phosphorus oxychloride. Examples of the salt of compound (VII) include inorganic acid salts (eg, hydrochloride, sulfate, hydrobromide, phosphate, etc.) and organic acid salts (eg, acetate, trifluoroacetate, succinate, etc.) Acid addition salts such as acid, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate and the like. .

  Examples of the deoxidizing agent include, for example, inorganic bases (eg, sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate, etc.) and tertiary amines (eg, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, Pyridine, lutidine, γ-collidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 4-dimethylaminopyridine, and the like.

（式中、Ｒ₄は水素原子あるいは窒素原子の保護基、他の記号は前記と同義である）で表わされる化合物またはその塩と、式（ＩＸ）：

（式中、各記号は前記と同義である）で表わされるカルボン酸もしくはチオン酸またはそれらの反応性誘導体（例えば、無水物、ハロゲン化物等）、あるいはそれらの塩とを縮合させた後、必要に応じて脱保護することにより得ることができる。化合物（ＶＩＩＩ）の塩としては、例えば、無機酸塩（例えば、塩酸塩、硫酸塩、臭化水素酸塩、リン酸塩等）、有機酸塩（例えば、酢酸塩、トリフルオロ酢酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、プロピオン酸塩、クエン酸塩、酒石酸塩、乳酸塩、蓚酸塩、メタンスルホン酸塩、ｐ−トルエンスルホン酸塩等）等の酸付加塩等が挙げられる。
あるいは、Ｄ₁が結合手の場合は、適切な溶媒（例えば、酢酸エチル、テトラヒドロフラン、ジクロロメタン、Ｎ,Ｎ−ジメチルホルムアミド等）中、式（Ｘ）：

（式中、各記号は前記と同義である）で表わされるカルボン酸またはチオン酸もしくはそれらの反応性誘導体（例えば、無水物、ハロゲン化物等）、あるいはそれらの塩と、Ｇ−Ｄ₂−Ｈで表わされる化合物とを縮合させた後、必要に応じて脱保護することにより得ることができる。化合物（Ｘ）の塩としては、例えば、無機酸塩（例えば、塩酸塩、硫酸塩、臭化水素酸塩、リン酸塩等）、有機酸塩（例えば、酢酸塩、トリフルオロ酢酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、プロピオン酸塩、クエン酸塩、酒石酸塩、乳酸塩、蓚酸塩、メタンスルホン酸塩、ｐ−トルエンスルホン酸塩等）等の酸付加塩、例えば、アルカリ金属（例えば、ナトリウム、カリウム等）、アルカリ土類金属（例えば、カルシウム等）、アンモニア等との塩等、及び例えば、ジメチルアミン、トリエチルアミン、ピペラジン、ピロリジン、ピペリジン、２−フェニルエチルアミン、ベンジルアミン、エタノールアミン、ジエタノールアミン、ピリジン、コリジン等との有機塩基塩等が挙げられる。 Compound (VII) or a salt thereof can be produced by a method known per se or a method analogous thereto. For example, when D ₁ is other than a bond, in a suitable solvent (for example, ethyl acetate, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, etc.), the formula (VIII):

Wherein R ₄ is a protecting group for a hydrogen atom or a nitrogen atom, and other symbols are as defined above, or a salt thereof, and a compound of the formula (IX):

(Wherein each symbol is as defined above), after condensing with carboxylic acid or thioic acid or a reactive derivative thereof (eg, anhydride, halide, etc.), or a salt thereof, Can be obtained by deprotection according to Examples of the salt of compound (VIII) include inorganic acid salts (eg, hydrochloride, sulfate, hydrobromide, phosphate, etc.) and organic acid salts (eg, acetate, trifluoroacetate, succinate) Acid addition salts such as acid, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate and the like. .
Alternatively, when D ₁ is a bond, in a suitable solvent (eg, ethyl acetate, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, etc.), the formula (X):

(Wherein each symbol is as defined above), a carboxylic acid or a thioic acid or a reactive derivative thereof (eg, an anhydride, a halide or the like), or a salt thereof, and GD ₂ -H After condensing with the compound represented by the formula, and then deprotecting if necessary. Examples of the salt of compound (X) include inorganic acid salts (eg, hydrochloride, sulfate, hydrobromide, phosphate, etc.), organic acid salts (eg, acetate, trifluoroacetate, succinate, etc.) Acid addition salts such as acid, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc., for example, alkali Salts with metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, etc.), ammonia and the like, and, for example, dimethylamine, triethylamine, piperazine, pyrrolidine, piperidine, 2-phenylethylamine, benzylamine, Organic base salts with ethanolamine, diethanolamine, pyridine, collidine and the like can be mentioned.

In formulas (VIII) and (X), examples of the protecting group represented by R ₄ include a formyl group, a C _1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl, etc.), a benzyl group, and tert-butyl. An oxycarbonyl group, a benzyloxycarbonyl group, an allyloxycarbonyl group, a _C7-10 aralkyl-carbonyl group (for example, benzylcarbonyl and the like), a trityl group and the like are used. These groups may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, etc.), nitro groups and the like.
As a method for removing these protecting groups, a method known per se or a method analogous thereto is used, for example, a method using an acid, a base, reduction, ultraviolet light, palladium acetate or the like is used.

（式中、各記号は前記と同義である）
方法Ｂにおける反応は、例えば、硝酸、過酸化水素、過酸類、過エステル、オゾン、四酸化二窒素、ヨードソベンゼン、Ｎ−ハロスクシンイミド、１−クロロベンゾトリアゾール、次亜塩素酸tert−ブチル、ジアザビシクロ[２．２．２]オクタン臭素錯体、メタ過ヨウ素酸ナトリウム、二酸化セレン、二酸化マンガン、クロム酸、硝酸セリウムアンモニウム、臭素、塩素、スルフリルクロライド、モノパーオキシフタル酸マグネシウム塩等の酸化剤を用いて行うことができる。酸化剤の使用量は、化合物（ＶＩ）またはその塩１モルに対して、通常０．５モル〜２モル、好ましくは０．８モル〜１．２モルである。上記過酸化水素や過酸類の酸化剤を用い、さらにバナジウムアセテート、酸化バナジウムアセチルアセトナート、チタンテトライソプロポキシド等の触媒存在下に酸化を行うこともできる。 (Method B)
Compound (II) or a salt thereof can be obtained by subjecting compound (VI) or a salt thereof to an oxidation reaction.

(Wherein each symbol is as defined above)
The reaction in the method B includes, for example, nitric acid, hydrogen peroxide, peracids, perester, ozone, nitrous oxide, iodosobenzene, N-halosuccinimide, 1-chlorobenzotriazole, tert-butyl hypochlorite, Oxidizing agents such as diazabicyclo [2.2.2] octane bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cerium ammonium nitrate, bromine, chlorine, sulfuryl chloride, magnesium monoperoxyphthalate It can be performed using: The amount of the oxidizing agent to be used is generally 0.5 mol-2 mol, preferably 0.8 mol-1.2 mol, per 1 mol of compound (VI) or a salt thereof. Oxidation can also be carried out using the above-mentioned oxidizing agents of hydrogen peroxide and peracids, and further in the presence of a catalyst such as vanadium acetate, vanadium acetylacetonate, titanium tetraisopropoxide and the like.

The reaction of the method B is usually performed in a solvent inert to the above oxidation reaction. Examples of the “inert solvent” include water, alcohols (eg, methanol, ethanol, 1-propanol, 2-propanol, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile) , Propionitrile, etc.), amides (eg, formamide, N, N-dimethylformamide, etc.), ethers (eg, diethyl ether, tert-butylmethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, etc.), sulfoxides (eg, , Dimethylsulfoxide, etc.) and polar solvents (eg, sulfolane, hexamethylphosphoramide, etc.), and these are used alone or as a mixture of two or more. The "inert solvent" is generally used in a 1-fold weight to 100-fold weight relative to compound (VI) or a salt thereof.
The reaction temperature is generally -80C to 80C, preferably 0C to 30C.
The reaction time is generally 1 minute to 6 hours, preferably 15 minutes to 1 hour.

（式中、各記号は前記と同義である）で表される化合物を用い、方法Ａと同様の反応によって得ることができる。
化合物（ＸＩ）は、以下の文献に記載の方法またはそれに準じた方法に従って合成することができる：特開昭６１−５０９７８号、特開昭５４−１４１７８３号、特開昭６１−２２０７９号、特開平１−６２７０号、特開昭６３−１４６８８２号。 Compound (VI), which is the starting material of Method B, is obtained, for example, by replacing the compound (IV) with the following formula (XI):

(Wherein each symbol is as defined above), and can be obtained by the same reaction as in method A.
Compound (XI) can be synthesized according to the method described in the following literature or a method analogous thereto: JP-A-61-50978, JP-A-54-141783, JP-A-61-22079, Kaihei 1-6270 and JP-A-63-146882.

  Examples of the salt of compound (VI) include the same salts as the above-mentioned salts of compound (II), for example, inorganic acid salts (for example, hydrochloride, sulfate, hydrobromide, phosphate and the like), Organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p- Acid addition salts such as toluenesulfonic acid salt).

The compound (II) or a salt thereof obtained by the above method A or B can be reacted by a known separation means (for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc.). It can be isolated and purified from a mixture. The compound (II) or a salt thereof obtained by the above method A or B includes all isomers thereof, and thus the compound (II) or a salt thereof may be subjected to optical resolution, or the compound (VI) or a salt thereof. Can be obtained to obtain optically pure compound (II) or a salt thereof.
Examples of the method of optical resolution include a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method, and the like. The asymmetric oxidation may be performed by a method known per se, for example, the method described in WO 96/02535.
As the "fractionation recrystallization method", a racemic compound and an optically active compound [for example, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1 -Phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.), separated by a fractional recrystallization method or the like, optionally subjected to a neutralization step, A method for obtaining an optical isomer of

  The "chiral column method" includes a method of applying a racemate or a salt thereof to an optical isomer separation column (chiral column). For example, in the case of liquid chromatography, a racemate is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series manufactured by Daicel Corporation, and water, a buffer solution (for example, phosphate buffer solution), an organic solvent (for example, Hexane, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, triethylamine, etc.) or a mixed solvent thereof to separate optical isomers. For example, in the case of gas chromatography, a separation method using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences Inc.) may be mentioned.

  In the “diastereomeric method”, a racemic compound and an optically active reagent are reacted to obtain a mixture of diastereomers, and then one of the diastereomers is separated by ordinary separation means (for example, fractional recrystallization, chromatography, etc.). After obtaining the desired product, a chemical reaction (eg, an acid hydrolysis reaction, a basic hydrolysis reaction, a hydrogenolysis reaction, etc.) is performed to cut off the optically active reagent site to obtain a desired optical isomer. No. As the “optically active reagent”, for example, an optically active organic acid such as MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], (−)-menthoxyacetic acid; (1R-endo) -2 Optically active alkoxymethyl halides such as-(chloromethoxy) -1,3,3-trimethylbicyclo [2.2.1] heptane;

で表わされるベンズイミダゾール化合物またはその塩も上記プロドラッグの具体例として挙げられる。
上記式（ＩＩＩ）において、Ｄは酸素原子又は結合手を、Ｑは置換基を有していてもよい炭化水素基を示す。 In addition, the following general formula (III):

The benzimidazole compound represented by or a salt thereof is also a specific example of the prodrug.
In the above formula (III), D represents an oxygen atom or a bond, and Q represents a hydrocarbon group which may have a substituent.

The “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by Q includes an aliphatic or aromatic hydrocarbon group. A saturated or unsaturated, linear, branched or cyclic hydrocarbon group is meant. As the hydrocarbon group, a hydrocarbon group having 1 to 14 carbon atoms is preferable. For example, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group , A C _6-14 aryl group, and a C _1-6 alkyl group, a C _3-8 cycloalkyl group, and a C _6-14 aryl group are preferable. Among them, a C _1-6 alkyl group and a C _3-8 cycloalkyl group are preferred. Is more preferred.

The “alkyl group” is a linear or branched alkyl group, preferably an alkyl group having 1 to 6 carbon atoms (“C _1-6 alkyl group”), for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2- Examples thereof include dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, and 2-ethylbutyl, and an alkyl group having 1 to 4 carbon atoms is more preferable. In Q, methyl, ethyl, isopropyl and tert-butyl are preferred, and tert-butyl is particularly preferred.

The “C _2-6 alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, for example, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec- Butenyl, tert-butenyl, n-pentenyl, isopentenyl, neopentenyl, 1-methylpropenyl, n-hexenyl, isohexenyl, 1,1-dimethylbutenyl, 2,2-dimethylbutenyl, 3,3-dimethylbutenyl Examples thereof include enyl, 3,3-dimethylpropenyl, and 2-ethylbutenyl. An alkenyl group having 2 to 4 carbon atoms is preferable, and vinyl, n-propenyl and isopropenyl are particularly preferable.

The “C _2-6 alkynyl group” is a linear or branched alkynyl group having 2 to 6 carbon atoms, for example, ethynyl, n-propynyl (1-propynyl), isopropynyl (2-propynyl) ), N-butynyl, isobutynyl, sec-butynyl, tert-butynyl, n-pentynyl, isopentynyl, neopentynyl, 1-methylpropynyl, n-hexynyl, isohexynyl, 1,1-dimethylbutynyl, 2,2-dimethylbutynyl Examples thereof include 3,3-dimethylbutynyl, 3,3-dimethylpropynyl, and 2-ethylbutynyl, and an alkynyl group having 2 to 3 carbon atoms is preferable, and among them, ethynyl, 1-propynyl, and 2-propynyl are preferable.

The “C _3-8 cycloalkyl group” is a linear or branched cycloalkyl group having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl And the like. A cycloalkyl group having 5 to 7 carbon atoms is preferable, and among them, cyclopentyl, cyclohexyl, and cycloheptyl are preferable, and cyclohexyl is particularly preferable.

The “aryl group” is a monocyclic or condensed polycyclic aromatic hydrocarbon group, preferably an aromatic hydrocarbon group having 6 to 14 carbon atoms (“C _6-14 aryl group”). Examples thereof include phenyl, naphthyl, anthryl, phenanthryl, and acenaphthylenyl, and an aromatic hydrocarbon group having 6 to 10 carbon atoms is preferable. Among Q, phenyl is particularly preferable.

The above “hydrocarbon group” may be substituted, and examples of the substituent include, for example, a C _6-14 aryl group, a hydroxyl group, a halogen, a C _1-6 alkoxy group optionally substituted with a halogen, C _7-12 aralkyloxy groups, C _1-5 alkoxy - carbonyl group, halogen optionally substituted C _1-6 alkyl group, etc. are exemplified C _1-6 alkyl amino group which may be substituted with a group Can be

Examples of the substituent in the “alkyl group optionally having substituent (s)” include an aryl group, a hydroxyl group, a halogen, an alkoxy group optionally substituted with 1 to 5 halogens, and a C _7-12 aralkyloxy. And C _1-5 alkoxy-carbonyl groups. The number of the substituents is 1 to 5, preferably 1 to 3.

Examples of the substituent in the “aryl group optionally having substituent (s)” include, for example, halogen, an alkyl group optionally substituted with 1 to 5 halogens, an aryl group, a hydroxyl group, and 1 to 5 halogens. And an optionally substituted alkoxy group, a _C7-12 aralkyloxy group, a _C1-5 alkoxy-carbonyl group and the like. The number of the substituents is 1 to 5, preferably 1 to 3.

The “C _1-6 alkyl group”, “C _2-6 alkenyl group” and “C _2-6 alkynyl group” may be substituted, and examples of the substituent include (i) C _6-14 Aryl group, (ii) hydroxyl group, (iii) halogen, (iv) C _1-6 alkoxy group optionally substituted with halogen, (v) C _7-12 aralkyloxy group, (vi) C _1-5 alkoxy - carbonyl group, (vii) an acylamino group, (viii) C _1-6 such as an amino group which may be substituted with an alkyl group, and among them (i) ~ (vii) are preferred. The number of the substituents is 1 to 5, preferably 1 to 3.

The above “C _3-8 cycloalkyl group” and “C _6-14 aryl group” may be substituted, and examples of the substituent include (i) a C _6-14 aryl group, (ii) a hydroxyl group, (iii) halogen, (iv) C _1-6 alkoxy group optionally substituted with halogen, (v) C _7-12 aralkyloxy group, (vi) C _1-5 alkoxy-carbonyl group, (vii) halogen in an optionally substituted C _1-6 alkyl group, (viii) a C _1-6 alkyl amino group which may be substituted by group, and is preferably Among them, (i) ~ (vii). The number of the substituents is 1 to 5, preferably 1 to 3.

In the formula (III), Q represents (i) a C _6-14 aryl group, (ii) a hydroxyl group, (iii) halogen, (iv) a C _1-6 alkoxy group optionally substituted with halogen, (v) C _7-12 aralkyloxy group, (vi) C _1-5 alkoxy - may have a substituent group selected from the group consisting of a carbonyl group and (vii) an acylamino group, C _1-6 alkyl groups, C _{2- A 6} alkenyl group or a C _2-6 alkynyl group, or
(i) a C _6-14 aryl group, (ii) a hydroxyl group, (iii) a halogen, (iv) a C _1-6 alkoxy group optionally substituted with a halogen, (v) a C _7-12 aralkyloxy group, vi) C _3-8 cycloalkyl optionally having a substituent selected from the group consisting of a C _1-5 alkoxy-carbonyl group and (vii) a C _1-6 alkyl group optionally substituted with halogen. Group or a C _6-14 aryl group,

(1) (i) C _6-14 aryl group, (ii) hydroxyl group, (iii) halogen, (iv) C _1-6 alkoxy group optionally substituted with 1 to 5 halogens, (v) C _A C _1-6 alkyl group optionally having 1 to 5 substituents selected from the group consisting of a _7-12 aralkyloxy group and (vi) a C _1-5 alkoxy-carbonyl group, or (2) ( i) halogen, (ii) C _1-6 alkyl group _optionally substituted with 1 to 5 halogens, (iii) C _6-14 aryl group, (iv) hydroxyl group, (v) 1 to 5 1 to 5 substituents selected from the group consisting of a C _1-6 alkoxy group optionally substituted with halogen, (vi) a C _7-12 aralkyloxy group, and (vii) a C _1-5 alkoxy-carbonyl group. Is more preferably a C _6-14 aryl group which may have
(i) a C _6-14 aryl group, (ii) a hydroxyl group, (iii) halogen, (iv) a C _1-6 alkoxy group optionally substituted with halogen, (v) a C _7-12 aralkyloxy group, vi) a C _1-6 alkyl group optionally having a substituent selected from the group consisting of a C _1-5 alkoxy-carbonyl group and (vii) an acylamino group, or
(i) a C _6-14 aryl group, (ii) a hydroxyl group, (iii) halogen, (iv) a C _1-6 alkoxy group optionally substituted with halogen, (v) a C _7-12 aralkyloxy group, vi) C _3-8 cycloalkyl optionally having a substituent selected from the group consisting of a C _1-5 alkoxy-carbonyl group and (vii) a C _1-6 alkyl group optionally substituted with halogen. More preferably a group or a C _6-14 aryl group,

Among them, it is preferably Q is optionally substituted C _1-6 alkyl group or a C _6-14 aryl group a C _6-14 aryl group, or Q is a phenyl group or a methyl or tert- butyl, Particularly preferred is a group.

  The compound (III) can form a pharmacologically acceptable base salt with an acidic group in the molecule and an inorganic base or an organic base, and can form a basic salt in the molecule with an inorganic acid or an organic acid. Can form pharmacologically acceptable acid addition salts.

  In one preferred embodiment of the compound (III) of the present invention, D is a bond, and Q is an alkyl group which may have a substituent or an aryl group which may have a substituent. Certain compounds are mentioned.

  Examples of the inorganic base salt of the compound (III) include salts with an alkali metal (eg, sodium, potassium, etc.), an alkaline earth metal (eg, calcium, etc.), ammonia and the like. Examples of the base salt include salts with dimethylamine, triethylamine, piperazine, pyrrolidine, piperidine, 2-phenylethylamine, benzylamine, ethanolamine, diethanolamine, pyridine, collidine and the like.

  Examples of the acid addition salt of compound (III) include inorganic acid salts (eg, hydrochloride, sulfate, hydrobromide, phosphate, etc.) and organic acid salts (eg, acetate, trifluoroacetate) Succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc.).

  The compound (III) of the present invention includes a hydrate. Examples of the “hydrate” include 0.5 hydrate to 5.0 hydrate. Of these, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate and 2.0 hydrate are preferred.

〔式中の記号は前記と同意義を示す〕で表わされる（Ｒ）体が好ましい。 The compound (III) of the present invention includes racemates and optically active compounds. As the optically active compound, one having one enantiomer of 90% or more in enantiomeric excess (ee) is preferable, and one having 99% or more of enantiomeric excess is more preferable. As the optically active substance, a general formula

The (R) form represented by the formula [wherein the symbols have the same meanings as described above] is preferable.

  Compound (III) can be produced by a method known per se, for example, a method described in JP-A-2002-187890, WO 02/30920, or a method analogous thereto. In addition, the optically active compound (III) can be obtained by a method such as an optical resolution method (a fractional recrystallization method, a chiral column method, a diastereomer method, a method using a microorganism or an enzyme), or asymmetric oxidation. As the PPI of other benzimidazole-based compound derivatives, the compounds described in WO 03/27098 can also be applied to the present invention.

（式中、ｎは１ないし３の整数を示し、Ａｒは置換基を有していてもよい芳香環を示す。）で表される化合物もしくはその塩。
式（Ｉ）−Ａで表される化合物の好適な例としては、以下の化合物が挙げられる。
〔２〕Ａｒが置換基を有していてもよい単環もしくは二環性芳香族縮合環である上記〔１〕記載の化合物。
〔３〕Ａｒが置換されていてもよく、環構成原子として０ないし４個のヘテロ原子を含む５ないし１０個の原子から構成され炭素原子で結合する芳香環である上記〔１〕記載の化合物。
〔４〕Ａｒが式：

（式中、ｍ１は１ないし４の整数を、ｍ２は０ないし３の整数を示し、Ｒａ¹およびＲａ²は同一または異なってそれぞれ独立して水素原子、置換基を有していてもよい水酸基、置換基を有していてもよいチオール基、置換基を有していてもよいアミノ基、アシル基、ハロゲン原子または置換基を有していてもよい炭化水素基を示す）で表される基、式：

（式中、ｍ３は１ないし５の整数を、ｍ４は０ないし４の整数を示し、Ｒａ³およびＲａ⁴は同一または異なってそれぞれ独立して水素原子、置換基を有していてもよい水酸基、置換基を有していてもよいチオール基、置換基を有していてもよいアミノ基、アシル基、ハロゲン原子または置換基を有していてもよい炭化水素基を示す）で表される基または式：

（式中、ｍ５は１ないし４の整数を示し、Ｒａ⁵は水素原子、置換基を有していてもよい水酸基、置換基を有していてもよいチオール基、置換基を有していてもよいアミノ基、アシル基、ハロゲン原子または置換基を有していてもよい炭化水素基を示す）で表される基である上記〔１〕記載の化合物。
〔５〕Ａｒが式：

（式中、Ｒａ⁶およびＲａ⁷は同一または異なってそれぞれ独立して水素原子または低級アルキル基を示す）で表される基または、式：

（式中、ｍ４は０ないし４の整数を示し、Ｒａ³およびＲａ⁴は同一または異なってそれぞれ独立して水素原子、置換基を有していてもよい水酸基、置換基を有していてもよいチオール基、置換基を有していてもよいアミノ基、アシル基、ハロゲン原子または置換基を有していてもよい炭化水素基を示す）で表される基である上記〔１〕記載の化合物。
〔６〕Ａｒが式：

（式中、Ｒａ⁶およびＲａ⁷は同一または異なってそれぞれ独立して水素原子または低級アルキル基を示す）で表される基である上記〔１〕記載の化合物。
〔７〕立体配置がＳ配置のエナンチオマーである上記〔１〕記載の化合物。
〔８〕立体配置がＲ配置のエナンチオマーである上記〔１〕記載の化合物。 B. Steroid C _17,20 lyase inhibitor Specific examples of the steroid C _17,20 lyase inhibitor include the following compounds.
[1] The formula described in WO02 / 40484:

(Wherein, n represents an integer of 1 to 3, and Ar represents an aromatic ring which may have a substituent) or a salt thereof.
Preferred examples of the compound represented by the formula (I) -A include the following compounds.
[2] The compound of the above-mentioned [1], wherein Ar is a monocyclic or bicyclic aromatic condensed ring which may have a substituent.
[3] The compound of the above-mentioned [1], wherein Ar is an aromatic ring which may be substituted and is composed of 5 to 10 atoms including 0 to 4 heteroatoms as ring-constituting atoms and bonded by carbon atoms. .
[4] Ar is a formula:

(Wherein, m1 represents an integer of 1 to 4, m2 represents an integer of 0 to 3, and Ra ¹ and Ra ² are the same or different and are each independently a hydrogen atom or a hydroxyl group which may have a substituent. A thiol group which may have a substituent, an amino group which may have a substituent, an acyl group, a halogen atom or a hydrocarbon group which may have a substituent). Group, formula:

(Wherein, m3 is an integer of 1 5, m4 is an integer of 0 to 4, Ra ³ and Ra ⁴ are the same or different and each independently represent a hydrogen atom, hydroxyl group which may have a substituent A thiol group which may have a substituent, an amino group which may have a substituent, an acyl group, a halogen atom or a hydrocarbon group which may have a substituent). Group or formula:

(Wherein, m5 represents an integer of 1 4, Ra ⁵ is hydrogen atom, hydroxyl group which may have a substituent group, which may have a substituent thiol group, have a substituent [1] a compound represented by the following formula (1): an amino group, an acyl group, a halogen atom or a hydrocarbon group which may have a substituent.
[5] Ar is the formula:

Wherein Ra ⁶ and Ra ⁷ are the same or different and each independently represents a hydrogen atom or a lower alkyl group, or a group represented by the formula:

(Wherein, m4 represents an integer of 0 to 4, each independently represents a hydrogen atom Ra ³ and Ra ⁴ are the same or different, hydroxyl group which may have a substituent, it may have a substituent (1) a thiol group, an amino group which may have a substituent, an acyl group, a halogen atom or a hydrocarbon group which may have a substituent). Compound.
[6] Ar is a formula:

(Wherein, Ra ⁶ and Ra ⁷ are the same or different and each independently represents a hydrogen atom or a lower alkyl group).
[7] The compound of the above-mentioned [1], wherein the configuration is an enantiomer having an S configuration.
[8] The compound of the above-mentioned [1], wherein the configuration is an enantiomer having an R configuration.

The definition of each symbol in each formula is as follows.
n is an integer of 1 to 3, and is preferably 1.
m1 is an integer of 1 to 4, preferably 1 or 2, and particularly preferably 1.
m2 is an integer of 0 to 3, preferably 0 or 1, and particularly preferably 0.
m3 is an integer of 1 to 5, preferably 1 to 3, and particularly preferably 1.
m4 is an integer of 0 to 4, preferably 0 or 1, and particularly preferably 0.
m5 is an integer of 1 to 4, but is preferably 1 or 2, and particularly preferably 1.
m6 is an integer of 0 to 3, preferably 0 or 1, and particularly preferably 0.

Examples of the optionally substituted hydroxyl group represented by Ra ¹ , Ra ² , Ra ³ , Ra ⁴ and Ra ⁵ include, in addition to an unsubstituted hydroxyl group, a lower alkoxy group (for example, C 1 such as methoxy, ethoxy, propoxy, etc.). _1-4 alkoxy group), lower alkanoyloxy (eg, C _1-4 alkanoyloxy such as acetyloxy, propionyloxy), carbamoyloxy (eg, unsubstituted carbamoyloxy) which may have a substituent, for example, methyl Carbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy, ethylmethylcarbamoyloxy and the like, and carbamoyloxy substituted with one or two C _1-4 alkyl groups).
Examples of the optionally substituted thiol group represented by Ra ¹ , Ra ² , Ra ³ , Ra ⁴ and Ra ⁵ include unsubstituted thiol groups such as lower alkylthio (eg, methylthio, ethylthio, propylthio and the like) C _1-4 alkylthio group), lower alkanoylthio (eg, C _1-4 alkanoylthio such as acetylthio, propionylthio, etc.) and the like.
Examples of the optionally substituted amino group represented by Ra ¹ , Ra ² , Ra ³ , Ra ⁴ and Ra ⁵ include, in addition to unsubstituted amino groups, lower alkylamino (eg, methylamino, ethylamino _C1-4 alkylamino group such as propylamino, etc.), di-lower alkylamino (eg, _diC1-4 alkylamino such as dimethylamino, diethylamino), _C1-4 alkanoylamino (eg, acetylamino, propionylamino) Etc.).
Examples of the acyl group represented by Ra ¹ , Ra ² , Ra ³ , Ra ⁴ and Ra ⁵ include, for example, an alkanoyl group (eg, C _1-6 alkanoyl such as formyl, acetyl, propionyl) and an alkylsulfonyl group (eg, methylsulfonyl) , A C _1-4 alkylsulfonyl such as ethylsulfonyl), an aroyl group (eg, benzoyl, toluoyl, naphthoyl, etc.), a carbamoyl group which may have a substituent (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethyl) Mono- or di-C _1-10 alkylcarbamoyl groups such as carbamoyl, for example, mono- or di-C _6-14 arylcarbamoyl groups such as phenylcarbamoyl, diphenylcarbamoyl, etc. -C _7-16 Ararukiruka Bamoiru group), which may have a substituent sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, such as diethyl sulfamoyl mono- - or di -C _1-10 alkyl Sulfamoyl groups, such as mono- or di-C _6-14 arylsulfamoyl groups such as phenylsulfamoyl and diphenylsulfamoyl, such as mono- or di- such as benzylsulfamoyl and dibenzylsulfamoyl. C _7-16 aralkylsulfamoyl group) and the like.
Examples of the halogen represented by Ra ¹ , Ra ² , Ra ³ , Ra ⁴ and Ra ⁵ include fluorine, chlorine, bromine and iodine.
Examples of the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by Ra ¹ , Ra ² , Ra ³ , Ra ⁴ and Ra ⁵ include, for example, a chain hydrocarbon group or a cyclic hydrocarbon group. And a hydrogen group.

The chain hydrocarbon group includes, for example, a linear or branched chain hydrocarbon group having 1 to 10 carbon atoms, and specific examples include an alkyl group and an alkenyl group. Of these, an alkyl group is particularly preferred. Examples of the “alkyl group” include C _1-10 such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and isohexyl. Although the alkyl group and the like, C _1-6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, sec- butyl, tert- butyl, etc.) are preferable. Examples of the “alkenyl group” include C _2-10 alkenyl groups such as vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl and sec-butenyl. A _C2-6 alkenyl group (e.g., vinyl, 1-propenyl, allyl, etc.) is preferred. Examples of the “alkynyl group” include a C _2-10 alkynyl group such as ethynyl, 1-propynyl and propargyl, and a C _2-6 alkynyl group (eg, ethynyl) is preferable.
Examples of the cyclic hydrocarbon group include a cyclic hydrocarbon group having 3 to 18 carbon atoms, and specific examples include an alicyclic hydrocarbon group and an aromatic hydrocarbon group.
The “alicyclic hydrocarbon group” includes, for example, a monocyclic or fused polycyclic group composed of 3 to 10 carbon atoms, specifically, a cycloalkyl group, a cycloalkenyl group and And a bicyclic or tricyclic fused ring with a _6-14 aryl group (for example, benzene or the like). Examples of the “cycloalkyl group” include C _3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the “cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl. And C _3-6 cycloalkenyl groups.
Examples of the “aromatic hydrocarbon group” include a monocyclic aromatic hydrocarbon group composed of 6 to 18 carbon atoms, a condensed polycyclic aromatic hydrocarbon group, and the like. , phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, include C _6-14 aryl groups such as a 2-anthryl, C _6-10 aryl group (e.g., phenyl etc.) and the like are preferable.

  The substituent which the “chain hydrocarbon group” in the “hydrocarbon group optionally having” may have is not particularly limited, and is, for example, a halogen atom, a hydroxyl group, an alkoxy group, Examples include an acyloxy group, an alkylthio group, an acylamino group, a carboxyl group, an alkoxycarbonyl group, an oxo group, an alkylcarbonyl group, a cycloalkyl group, an aryl group, and an aromatic heterocyclic group. These substituents are substituted on the “chain hydrocarbon group” within the range chemically permitted, and the number of the substituents is 1 to 5, preferably 1 to 3. However, when the number of substituents is two or more, they may be the same or different.

  The substituent that the “cyclic hydrocarbon group” in the “hydrocarbon group optionally having” may have is not particularly limited, and is, for example, a halogen atom, a hydroxyl group, an alkoxy group, Acyloxy group, alkylthio group, alkylsulfonyl group, mono- or di-alkylamino group, acylamino group, carboxyl group, alkoxycarbonyl group, alkynylcarbonyl group, alkyl group, cycloalkyl group, aryl group, aromatic heterocyclic group, etc. No. These substituents are substituted on the “cyclic hydrocarbon group” within the range chemically permitted, and the number of the substituents is 1 to 5, preferably 1 to 3. However, when the number of substituents is two or more, they may be the same or different.

Examples of the “halogen atom” include fluorine, chlorine, bromine, iodine and the like. Examples of the “alkoxy group” include C _1-10 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy. Examples of the “acyloxy group” include formyloxy, C _1-10 alkyl-carbonyloxy (eg, acetoxy, propionyloxy, etc.). Examples of the “alkylthio group” include C _1-10 alkylthio groups such as methylthio, ethylthio, propylthio, and isopropylthio. Examples of the “alkylsulfonyl group” include C _1-10 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl and propylsulfonyl. Examples of the “acylamino group” include formylamino, diformylamino, mono- or di-C _1-10 alkyl-carbonylamino (eg, acetylamino, propionylamino, butyrylamino, diacetylamino, etc.). Examples of the “mono- or di-alkylamino group” include the same as the above-mentioned lower alkylamino and di-lower alkylamino. Examples of the “alkoxycarbonyl group” include C _1-10 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, and butoxycarbonyl. Examples of the “alkylcarbonyl group” include C _1-10 alkylcarbonyl groups such as acetyl, propionyl, butyryl and valeryl. Examples of the "alkynyl group" such as ethynyl, 1- propynyl carbonyl, etc. C _3-10 alkynyl group, such as 2-propynyl carbonyl and the like. Examples of the “cycloalkyl group” include C _3-10 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of the “aryl group” include a C _6-14 aryl group such as phenyl, 1-naphthyl and 2-naphthyl. The "aromatic heterocyclic group" is, for example, a mono- to tri-cyclic aromatic heterocyclic group containing one or two, preferably one to four, hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms. And the like. Specific examples include thienyl, pyridyl, furylpyrazinyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridazinyl, tetrazolyl, quinolyl, indolyl, isoindolyl and the like. Examples of the “alkyl group” include C _1-10 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and pentyl.

The substituent which the “hydrocarbon group” may have further has 1 to 5, preferably 1 to 3 substituents as shown below in a chemically acceptable range. Is also good. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, etc.), a hydroxyl group, and a C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.).

The lower alkyl group represented by Ra ⁶ and Ra ⁷ is, for example, a linear, branched or cyclic alkyl group having 1 to 4 carbon atoms, specifically, methyl, ethyl, n-propyl, isopropyl , Butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl and the like.

The optionally substituted aromatic ring represented by Ar is exemplified by a monocyclic or bicyclic aromatic condensed ring optionally having one or more substituents. In addition, an aromatic ring which may be substituted and is composed of 5 to 10 atoms including 0 to 4 heteroatoms as ring-constituting atoms (where the aromatic ring is not a heteroatom but a carbon atom and has the formula ( I) bonded to the condensed imidazole ring in -A) is also suitably exemplified as Ar.
As the substituent in the optionally substituted aromatic ring represented by Ar, a hydroxyl group which may have a substituent, a thiol group which may have a substituent, and a thiol group which may have a substituent Examples include a good amino group, an acyl group, a halogen atom or a hydrocarbon group which may have a substituent. The "optionally substituted hydroxyl group", the "optionally substituted amino group", the "acyl group", the "halogen atom" and the "optionally substituted as also may hydrocarbon group "include those respectively exemplified above ^{Ra 1, Ra 2, Ra 3} , Ra 4 and Ra ^5.

The compound represented by the formula (I) -A of the present invention may form a salt, and the salt may be an acid addition salt, for example, an inorganic acid salt (for example, hydrochloride, sulfate, hydrobromic acid) Salts, phosphates, etc.), organic acid salts (eg, acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalic acid) Salt, methanesulfonate, p-toluenesulfonate and the like).
In addition, the compound represented by the general formula (I) -A or a salt thereof may be a hydrate, and both are within the scope of the present invention. Hereinafter, the term "compound (I) -A" includes salts and hydrates.

The prodrug of compound (I) -A refers to a compound that is converted into compound (I) -A having steroid C _17,20 lyase inhibitory activity by a reaction with an enzyme, gastric acid, or the like in a living body.
Examples of the prodrug of compound (I) -A include compounds in which imidazole nitrogen of compound (I) -A is acylated or alkylated (eg, dimethylaminosulfonylation, acetoxymethylation, (5-methyl-2-oxo) -1,3-dioxolen-4-yl) methoxycarbonylmethylated, pivaloyloxymethylated, benzyloxymethylated compounds, etc.); the hydroxyl group of compound (I) -A is acylated, alkylated, phosphorylated , Sulfated, borated compounds (eg, compounds in which the hydroxyl group of compound (I) -A is acetylated, palmitoylated, propanoylated, pivaloyylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated) Etc.). These compounds can be produced by a method known per se.
The prodrug of compound (I) -A may be itself or a pharmacologically acceptable salt. As such a salt, when the prodrug of compound (I) -A has an acidic group such as a carboxyl group, an inorganic base (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, Transition metals such as zinc, iron and copper) and organic bases (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, and organic amines such as N, N'-dibenzylethylenediamine) , Arginine, lysine, basic amino acids such as ornithine, etc.).

When the prodrug of compound (I) -A has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonic acid, formic acid, acetic acid, propionic acid, Acidic amino acids such as trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid), aspartic acid and glutamic acid Salts.
The prodrug of compound (I) -A may be a hydrate or a non-hydrate.
Compound (I) -A has one or more asymmetric carbons in the molecule, and both R configuration and S configuration with respect to these asymmetric carbons are included in the present invention.
As compound (I) -A, a compound in which the absolute configuration of the carbon atom to which a hydroxyl group is bonded is S configuration is preferable.

Among the compounds represented by formula (I) -A, among others, (±) -7- (5-methoxybenzo [b] thiophen-2-yl) -6,7-dihydro-5H-pyrrolo [1,2 -C] imidazol-7-ol,
(±) -7- (5-fluorobenzo [b] thiophen-2-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol,
(±) -7- (4′-fluoro [1,1′-biphenyl] -3-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol,
(±) -7- (4′-fluoro [1,1′-biphenyl] -4-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol,
(±) -6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide;
(±) -N-cyclopropyl-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide;
(±) -N-ethyl-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide;
(±) -N-cyclobutyl-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide;
(±) -6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-isopropyl-2-naphthamide;
(±) -6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide;
(+)-7- (5-methoxybenzo [b] thiophen-2-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol,
(+)-7- (5-fluorobenzo [b] thiophen-2-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol,
(+)-7- (4′-fluoro [1,1′-biphenyl] -3-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol,
(+)-7- (4′-fluoro [1,1′-biphenyl] -4-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol,
(+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide;
(+)-N-cyclopropyl-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide;
(+)-N-ethyl-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide;
(+)-N-cyclobutyl-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide;
(+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-isopropyl-2-naphthamide;
(+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide;
(-)-7- (5-methoxybenzo [b] thiophen-2-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol,
(-)-7- (5-fluorobenzo [b] thiophen-2-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol,
(-)-7- (4'-fluoro [1,1'-biphenyl] -3-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol,
(-)-7- (4'-fluoro [1,1'-biphenyl] -4-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol,
(-)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide;
(-)-N-cyclopropyl-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide;
(-)-N-ethyl-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide;
(-)-N-cyclobutyl-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide;
(-)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-isopropyl-2-naphthamide;
(-)-6- (7-Hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide and the like are preferable.

Examples of other steroid C _17,20 lyase inhibitors include compounds described in WO92 / 15404, WO93 / 20097, EP-A288053, EP-A41270, and (1H-imidazole-1-) described in JP-A-64-85975. Yl) Methyl-substituted benzimidazole derivatives, carbazole derivatives described in WO 94/27989, WO 96/14090 and WO 97/00257, azole derivatives described in WO 95/09157, 1H-benzimidazole derivatives described in US 5,491,161, WO 99 / 18075 dihydronaphthalene derivatives.
The compounds having steroid C _17,20 lyase inhibitory activity described in each of the above publications can be produced by the methods disclosed in each of the publications.

［式中、Ａ^１環は置換されていてもよい５−１０員芳香環を、
Ｒｂ^１およびＲｂ^２は同一または異なって、置換されていてもよい炭化水素基または置換されていてもよい複素環基を、
Ｘｂは結合手、−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ_２−または−ＮＲｂ^３−（Ｒｂ^３は水素原子または置換されていてもよい炭化水素基を示す）を；
Ｌは２価の炭化水素基を示す］で表される化合物またはその塩。 C. DPP-IV Inhibitor As used herein, a DPP-IV inhibitor refers to a compound that inhibits the enzymatic activity of DPP-IV [classified by the United Nations Commission on Biochemistry (IUBMB): EC 3.4.14.5]. . The compounds may be either peptidic or non-peptidic.
The DPP-IV inhibitor may have a different form before and after administration to a living body, as long as the DPP-IV inhibitory activity is maintained. That is, the DPP-IV inhibitor may be an “active metabolite” having a DPP-IV inhibitory activity after being converted into a conformational form by undergoing metabolism in a living body. Furthermore, the DPP-IV inhibitor may be a “prodrug” that changes to an active form by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body.
Specific examples of the DPP-IV inhibitor include the following compounds [1] to [8].
[1] The formula described in WO02 / 062764:

[In the formula, the ring A ¹ is a 5- to 10-membered aromatic ring which may be substituted,
Rb ¹ and Rb ² are the same or different and each represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
Xb represents a bond, -O -, - S -, - SO -, - SO 2 - or -NRb ³ - a (Rb ³ represents a hydrogen atom or an optionally substituted hydrocarbon group);
L represents a divalent hydrocarbon group], or a salt thereof.

As the salt of the compound represented by the formula (I) -B, a pharmacologically acceptable salt is preferable. Examples of such a salt include a salt with an inorganic base, a salt with an organic base, and an inorganic acid. And salts with organic acids, salts with basic or acidic amino acids, and the like.
Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
Preferred examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine, and the like.
Preferred examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
Preferred examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- Salts with toluenesulfonic acid and the like can be mentioned.
Preferred examples of the salt with a basic amino acid include salts with arginine, lysine, ornithine and the like.
Preferred examples of the salt with an acidic amino acid include salts with aspartic acid, glutamic acid, and the like.
The compound represented by the formula (I) -B may be an anhydrate, a hydrate, or a prodrug.

Preferred examples of the compound represented by the formula (I) -B include the following compounds.
(Compound Ia)
A ¹ ring is
1) a cyano group;
2) a C _1-10 alkyl group (preferably ethyl) or a C _2-10 alkenyl group (preferably ethenyl) each of which may be substituted with a carbamoyl group or a carboxyl group;
3) an optionally substituted hydroxy group [preferably having one to three substituents selected from a carbamoyl group, a carboxyl group and an alkoxycarbonyl group having 2 to 5 carbon atoms (preferably methoxycarbonyl); An alkoxy group having 1 to 10 carbon atoms (preferably methoxy, isopropoxy); a hydroxy group; an aralkyloxy group having 7 to 13 carbon atoms (preferably benzyloxy)] [more preferably carbamoylmethoxy];
4) an acyl group [preferably having 1 to 3 substituents selected from C _1-6 alkyl-carbonyl (preferably acetyl), carbamoyl, mono- or di- (halogen atom and C _1-6 alkoxy-carbonyl); Optionally substituted C _1-6 alkyl) -carbamoyl (preferably methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl, trifluoroethylcarbamoyl, ethoxycarbonylmethylcarbamoyl and the like), C _3-10 cycloalkyl-carbamoyl (preferably Is cyclopropylcarbamoyl), C _7-13 aralkyl-carbamoyl (preferably benzylcarbamoyl), nitrogen-containing heterocycle-carbonyl optionally substituted with hydroxy (preferably pyrrolidinylcarbonyl, piperidinocarbonyl), C _{1 -6} alkyl Sulfonyl (preferably methylsulfonyl is), C _1-6 alkylsulfinyl (preferably methylsulfinyl), carboxyl, C _1-6 alkoxy - carbonyl (preferably methoxycarbonyl), thiocarbamoyl];
5) an optionally substituted amino group (preferably carbamoylamino);
6) a thiol group which may be substituted [preferably, an alkylthio group having 1 to 10 carbon atoms which is optionally substituted by a carbamoyl group (preferably methylthio);
7) an optionally substituted heterocyclic group [preferably a C _1-6 alkyl group (preferably methyl, trifluoromethyl) optionally substituted with 1 to 3 halogen atoms, a carboxyl group, 2 to 8 alkoxycarbonyl groups (preferably ethoxycarbonyl), cyano groups, carbamoyl groups, amino groups, mono- or di-C _2-10 alkanoylamino groups (eg, acetylamino, isopentanoylamino), C _{1- 10} alkoxy-carbonylamino group (eg, methoxycarbonylamino), carbamoylamino group, mono- or di-C _1-10 alkyl-carbamoylamino group (eg, methylcarbamoylamino, dimethylcarbamoylamino), C _6-14 aryl- carbonylamino group (e.g., benzoylamino), C _3-10 cycloalkyl - carbonyl amino group C _7-13 aralkyloxy - carbonylamino group, mono- - or di -C _1-10 alkylsulfonylamino group (e.g., methylsulfonyl, dimethylamino sulfonylamino), C _6-14 arylsulfonylamino group and a C _1-6 alkoxy -A carbamoylamino group (eg, methoxycarbamoylamino), an aromatic heterocyclic group (preferably furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, tetrazolyl, each of which may have one or two substituents selected from Pyridyl, pyrrolyl, triazolyl) or a non-aromatic heterocyclic group (preferably, dioxoisoindole, 5-oxooxadiazol-3-yl, 5-oxothiadiazol-3-yl)];
8) amidino group;
A benzene ring optionally having one or two substituents selected from:
It Rb ¹ is not 4 carbons 10 alkyl group (preferably isobutyl, neopentyl) or a cycloalkyl group (preferably cyclopropylmethyl) 4 to 10 carbon atoms;
Rb ² is an aryl group having 6 to 14 carbon atoms which may have one or two substituents selected from a halogen atom (preferably fluorine, chlorine) and C _1-6 alkyl (preferably methyl) (preferably Is phenyl);
Xb is a bond;
A compound wherein L is C _1-10 alkylene (preferably —CH ₂ —);

(Compound Ib)
A ¹ ring is
1) a C _1-10 alkyl group (preferably ethyl) or a C _2-10 alkenyl group (preferably ethenyl) each of which may be substituted with an alkoxycarbonyl group (preferably ethoxycarbonyl) or a carbamoyl group having 2 to 8 carbon atoms; );
2) an optionally substituted hydroxy group [preferably an alkoxy group having 1 to 10 carbon atoms (preferably methoxy) which may be substituted with a carbamoyl group; more preferably carbamoylmethoxy];
3) acyl groups (preferably carbamoyl, thiocarbamoyl, carboxyl);
4) an optionally substituted heterocyclic group [preferably a C _1-6 alkyl group (preferably methyl), a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms (preferably ethoxycarbonyl), a cyano group, carbamoyl Group, amino group, mono- or di-C _2-10 alkanoylamino group (eg, acetylamino, isopentanoylamino), C _1-10 alkoxy-carbonylamino group (eg, methoxycarbonylamino), carbamoylamino group, Mono- or di-C _1-10 alkyl-carbamoylamino group (eg, methylcarbamoylamino, dimethylcarbamoylamino), C _6-14 aryl-carbonylamino group (eg, benzoylamino), C _3-10 cycloalkyl-carbonyl amino group, C _7-13 aralkyloxy - carbonylamino group, mono- - or di -C _1-10 A Kill sulfonylamino group (e.g., methylsulfonyl, dimethylamino sulfonylamino), C _6-14 arylsulfonylamino group and a C _1-6 alkoxy - carbamoylamino group (e.g., methoxy carbamoylamino) substituted 1 to 2 atoms selected from An aromatic heterocyclic group (preferably furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, tetrazolyl, pyridyl, pyrrolyl, triazolyl) or a non-aromatic heterocyclic group (preferably 5-oxooxa) Diazol-3-yl)];
A benzene ring optionally having one or two substituents selected from:
It Rb ¹ is not 4 carbons 10 alkyl group (preferably isobutyl, neopentyl) or a cycloalkyl group (preferably cyclopropylmethyl) 4 to 10 carbon atoms;
Rb ² is an alkyl group having 1 to 10 carbon atoms which is optionally substituted by 1 to 3 halogen atoms (preferably butyl);
Xb is -O-;
A compound wherein L is C _1-10 alkylene (preferably —CH ₂ —);

で表される(2S)-1-{{{2-[(5-シアノピリジン-2-イル)アミノ]エチル}アミノ}アセチル}-2-シアノ-ピロリジン (DPP-728)（WO98／19998に記載）、
式

で表される(2S)-1-{[(3-ヒドロキシ-1-アダマンチル)アミノ]アセチル}-2-シアノ-ピロリジン (LAF237) （WO00／34241に記載）、
(2S)-1-{{{2-[(1-ピリミジン-2-イルピペリジン-4-イル}アミノ}アセチル}-2-シアノ-ピロリジン（WO02/30890に記載）、
(2S)-1-{{{2-[(ピラジン-2-イル)アミノ]エチル}アミノ}アセチル}-2-シアノ-ピロリジン（WO02/51836に記載）、
などのN-(N'-置換グリシル)-2-シアノ-ピロリジン誘導体。
〔３〕式

で表されるL-threo-イソロイシル チアゾリジン （P32/98）、L-allo-イソロイシル チアゾリジン、L-threo-イソロイシル ピロリジン、L-allo-イソロイシル ピロリジン、L-バリル ピロリジンなどのチアゾリジンあるいはピロリジン誘導体（WO01／72290などに記載）。 Among the compounds of the formula (I) -B, 2- [3- (aminomethyl) -4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl] -1 is particularly preferred. , 3-thiazole-4-carbonitrile;
2- [3- (aminomethyl) -4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl] -1,3-thiazole-4-carboxylic acid;
2- [3- (aminomethyl) -4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl] -1,3-thiazole-4-carboxamide;
Ethyl 2- [3- (aminomethyl) -4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl] -1,3-thiazole-4-carboxylate;
(E) -3- [3- (aminomethyl) -4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl] -2-propenamide;
(E) -3- [3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] -2-propenamide;
3- (aminomethyl) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide;
2-{[3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxy} acetamide and the like are preferable.
[2] Expression

(2S) -1-{{{2-[(5-cyanopyridin-2-yl) amino] ethyl} amino} acetyl} acetyl} -2-cyano-pyrrolidine (DPP-728) (see WO98 / 19998) Described),
formula

(2S) -1-{[(3-hydroxy-1-adamantyl) amino] acetyl} -2-cyano-pyrrolidine (LAF237) (described in WO00 / 34241),
(2S) -1-{{{2-[(1-pyrimidin-2-ylpiperidin-4-yl} amino} acetyl} -2-cyano-pyrrolidine (described in WO02 / 30890),
(2S) -1-{{{2-[(pyrazin-2-yl) amino] ethyl} amino} acetyl} -2-cyano-pyrrolidine (described in WO 02/51836),
And N- (N′-substituted glycyl) -2-cyano-pyrrolidine derivatives.
[3] Expression

Thiazolidine or pyrrolidine derivatives (WO01 / 72290).

[4] N-substituted 2-cyanopyrrole and 2-cyanopyrroline derivatives described in WO 01/55105. Preferably, (S, S) -1- (2-amino-3,3-dimethylbutyryl) -2,5-dihydro-1H-pyrrole-2-carbonitrile.
[5] The heterocyclic compound described in WO02 / 02560. Preferably, 7-benzyl-8- [6- (hydroxymethyl) -1,4-diazepan-1-yl] -1,3-dimethyl-3,7-dihydropurine-2,6-dione.
[6] A pyrrolidine derivative condensed with cyclopropane described in WO01 / 68603. Preferably, (1S, 3S, 5S) -2-[(2S) -2-amino-3,3-dimethylbutyryl] -3-cyano-2-azabicyclo [3.1.0] hexane.
[7] A proline derivative described in WO02 / 14271. Preferably, (2S) -1-[(2S, 4S) -4- (3-chloro-4-cyanophenyl) amino-2-pyrrolidinylcarbonyl] -2-cyanopyrrolidine.
[8] A cyanopyrrolidine derivative described in WO02 / 38541. Preferably, (2S, 4S) -1-[(2S, 3S) -2-amino-3-methyl-pentanoyl] -2-cyano-4-fluoropyrrolidine.

  The compounds having DPP-IV inhibitory activity described in each of the above publications can be produced by the methods disclosed in each of the publications.

  The active ingredient content in the whole of the release controlling part A is, for example, about 1 to 100% by weight, preferably about 10 to about 90% by weight, more preferably about 30 to about 80% by weight.

Examples of the pharmacologically acceptable carrier contained in the release controlling portion A include various organic or inorganic carrier materials commonly used as a preparation material, such as excipients, lubricants, binders, and disintegrants. If necessary, pharmaceutical additives such as preservatives, antioxidants, stabilizers, coloring agents, sweeteners and the like can also be used.
Preferred examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, dextrin, pullulan And light anhydrous silicic acid, synthetic aluminum silicate and magnesium aluminate metasilicate.
Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, acacia, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Propylmethylcellulose, polyvinylpyrrolidone and the like.
Preferred examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, low-substituted hydroxypropylcellulose (L-HPC (trade name) : Shin-Etsu Chemical Co., Ltd.)).
Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Suitable examples of the antioxidant include sulfite, ascorbate and the like.
In a preparation or the like in which the active ingredient is the above-mentioned PPI, it is preferable to add a basic inorganic salt as a stabilizer.
Examples of the basic inorganic salt used in the present invention include sodium, potassium, magnesium and calcium basic inorganic salts. Preferably, a basic inorganic salt of magnesium or calcium is used. More preferably, a basic inorganic salt of magnesium is used. These may be hydrates or solvates. In the following examples, hydrates and solvates are also meant, although not specifically described.
Examples of the basic inorganic salt of sodium include sodium carbonate, sodium hydrogen carbonate, and sodium hydroxide.
Examples of the basic inorganic salt of potassium include potassium carbonate, potassium hydrogen carbonate, potassium hydroxide and the like.
As a basic inorganic salt of magnesium, for example, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg ₆ Al ₂ (OH ₁₆ ) CO ₃ .4H ₂ O] and alumina / magnesium hydroxide [2.5 MgO.Al ₂ O ₃ .xH ₂ O], preferably heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, etc. Can be
Examples of the basic inorganic salt of calcium include precipitated calcium carbonate and calcium hydroxide.
More preferred basic inorganic salts include heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like.
The basic inorganic salt used in the present invention may be any one as long as the pH of a 1% aqueous solution or suspension thereof is basic (pH 7 or more).
The basic inorganic salt may be used alone or in combination of two or more kinds. The compounding amount is about 0.2 to about 0.6 part by weight, preferably 1 part by weight of PPI (such as a benzimidazole compound). About 0.2 to about 0.4 parts by weight may be blended. In particular, when the PPI is lansoprazole or its optically active substance, about 0.2 to about 0.4 parts by weight of a basic inorganic salt (preferably, a basic inorganic salt of magnesium or calcium, Preferably, magnesium carbonate) is blended.
Preferred examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows 4 and 5, edible blues 1 and 2), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye), and natural dyes (eg, β-carotene, chlorophyll, and red iron).
Preferred examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.

  When the release control unit A is a sustained release unit, the release mechanism of the active ingredient is not particularly limited, release by passive diffusion from the base, release by erosion of the base, release in response to environmental pH change, Either release using internal pressure generated by expansion of a base that has taken in environmental moisture may be used.

In the case of using release by passive diffusion, the release control unit A includes, in addition to the active ingredient (preferably further containing a pharmacologically acceptable carrier), a hydrophilic polymer, a lipophilic base, or another slow-release base. A release base is further contained.
As used herein, the term "hydrophilic polymer" refers to a hydrogel formed by absorbing water and diffusing an active ingredient contained in a preparation, or releasing an active substance by itself dissolving in water. Means a polymer that can control the
In the controlled release composition of the present invention, the release rate of the active ingredient from each controlled release unit can be arbitrarily adjusted by adjusting the viscosity and the amount of the hydrophilic polymer used as the base.
The viscosity of the hydrophilic polymer contained in the release control section A is, for example, preferably 1 mPa · s or more, more preferably 4 mPa · s or more as a viscosity (measurement temperature: 20 ° C.) of a 2% by weight aqueous solution.

Specific examples of the hydrophilic polymer include HPC-SSL (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: 2.0 to 2.9 mPa · s), HPC-SL ( Trade name, manufactured by Nippon Soda Co., Ltd. (viscosity of 2% by weight aqueous solution at 20 ° C .: 3.0 to 5.9 mPa · s), HPC-L (trade name, manufactured by Nippon Soda Co., Ltd.) (at 20 ° C.) Viscosity of 2% by weight aqueous solution: 6.0 to 10.0 mPa · s), HPC-M (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: 150 to 400 mPa · s), Hydroxypropylcellulose (HPC) such as HPC-H (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: 1000 to 4000 mPa · s);
TC-5S (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 15 mPa · s), TC-5R (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (20 ° C.) Of a 2% by weight aqueous solution at about: 6 mPa · s), TC-5E (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of a 2% by weight aqueous solution at 20 ° C .: about 3 mPa · s), TC-5MW ( (Trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 4 mPa · s), Metrose 60SH-50 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (2 weight at 20 ° C.) % Of aqueous solution: about 50 mPa · s), Metrolose 65SH-50 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 50 mPa · s), Metrolose 90SH-100 (product) Name, Shin-Etsu Chemical Co., Ltd.) Viscosity of 2% by weight aqueous solution: about 100 mPa · s), Metrolose 65SH-400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 400 mPa · s), Metrolose 90SH- 400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 400 mPa · s), METROLZ 65SH-1500 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (at 20 ° C.) Viscosity of 2% by weight aqueous solution: about 1500 mPa · s), Metrolose 60SH-4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 4000 mPa · s), Metrolose 65SH-4000 (Trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 4000 mPa · s), Metrolose 90SH-4000 (trade name) Shin-Etsu Chemical Co., Ltd. (viscosity of 2% by weight aqueous solution at 20 ° C .: about 4000 mPa · s), METROZE 90SH-30000 (trade name, Shin-Etsu Chemical Co., Ltd.) (2% by weight aqueous solution at 20 ° C.) Viscosity: hydroxypropyl methylcellulose such as about 30,000 mPa · s);
Metrolose SM15 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity: about 15 mPa · s, 2% by weight aqueous solution, 20 ° C.), Metrolose SM25 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (2 at 20 ° C.) Viscosity of aqueous solution by weight: about 25 mPa · s), Metrolose SM100 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 100 mPa · s), Metrolose SM400 (trade name, Shin-Etsu) (Manufactured by Chemical Industry Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 400 mPa · s), Metrolose SM1500 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: approx. 1500 mPa · s), Metrolose SM4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 4000 mPa · s), Metrolose SM800 (Trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of a 2 wt% aqueous solution at 20 ° C.: about 8000 mPa · s) methylcellulose and the like;
WSR N-12K (trade name, manufactured by Union Carbide Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: 400 to 800 mPa · s), WSR N-60K (trade name, manufactured by Union Carbide Co.) (2 weight at 20 ° C.) % Aqueous solution: 2000-4000 mPa · s), WSR 301 (trade name, manufactured by Union Carbide) (viscosity of 1% by weight aqueous solution at 25 ° C .: 1500-4500 mPa · s), WSR Coagulant (trade name, Union Carbide) WSR 303 (trade name, manufactured by Union Carbide Co., Ltd.) (viscosity of a 1% by weight aqueous solution at 25 ° C .: 7,500 to 10,000 mPa · s), WSR 308 (trade name, manufactured by Union Carbide Co.) (viscosity of 1% by weight aqueous solution at 25 ° C .: 10 00~15000mPa · s) poly (ethylene oxide) and the like;
Sunrose F-150MC (trade name, manufactured by Nippon Paper Industries) (viscosity of 1% by weight aqueous solution at 25 ° C .: 1200 to 1800 mPa · s), Sunrose F-300MC (trade name, manufactured by Nippon Paper Industries) (at 25 ° C.) Sodium carboxymethylcellulose such as 1% by weight aqueous solution viscosity: 2500 to 3000 mPa · s) and Sunrose F-1000MC (trade name, manufactured by Nippon Paper Industries) (viscosity of 1% by weight aqueous solution at 25 ° C .: 8000 to 12000 mPa · s) And the like. These hydrophilic polymers may be used as a mixture of two or more kinds at an appropriate ratio.
The content of the hydrophilic polymer in the entire release controlling portion A is, for example, about 5 to about 90% by weight, preferably about 10 to about 80% by weight.

Examples of the fat-soluble base include carnauba wax, hardened castor oil, hardened rapeseed oil, polyglycerin fatty acid ester, and the like.
Other sustained-release bases include, for example, cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer suspension (acrylic acid polymers such as Eudragit NE) ).

In the case of utilizing the release accompanying the erosion of the base, the release controlling part A includes, for example, a polyglycolized glyceride (eg, Gelucire 50/13) in addition to the active ingredient (preferably further containing a pharmacologically acceptable carrier). (Trade name, manufactured by GATTEFOSSE), and the like.
When releasing the active ingredient in response to a change in environmental pH, the release control unit A may include, for example, an enteric base [eg, Methacrylic acid copolymer L [Eudragit L (trade name, manufactured by Rohm Pharma)], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name, manufactured by Rohm Pharma)], methacrylic acid copolymer S [Eudragit S (product) Acryl-based polymer such as Rohm Pharma Co., Ltd.), hydroxypropylmethylcellulose-based polymer [hydroxypropylmethylcellulose phthalate (trade name: HPMCP, Shin-Etsu Chemical), hydroxypropyl methylcellulose acetate succinate (trade name: HPMCAS, Shin-Etsu) AQOAT, Shin-Etsu Chemical)], carboxymethylethyl cellulose (Trade name: CMEC, Freund Corporation), cellulose acetate phthalate (trade name: CAP, Wako Pure Chemical), etc.].
Examples of the composition which expands the interior of the composition by taking in environmental moisture and releases the active ingredient at the internal pressure include those using an OROS system (trade name, manufactured by Alza).

When the active ingredient is weakly acidic to weakly alkaline and has relatively low water solubility, and when used as an oral administration preparation, there is a possibility that the active ingredient may be insufficiently eluted and absorbed from the lower small intestine to the vicinity of the large intestine. For the purpose of adjusting the dissolution behavior from the part A, a pH adjuster and other solubilizing agents may be added to the release control part. By using a pH adjuster or the like, it is possible to reduce a change in drug dissolution due to environmental pH. Since individual patients may have different in vivo pHs, reducing the change in drug dissolution due to environmental pH is extremely significant in order to obtain uniform drug efficacy for various patients.
Examples of the pH adjuster include organic acids such as citric acid, tartaric acid, ascorbic acid, malic acid, fumaric acid, malonic acid, succinic acid, maleic acid, aspartic acid, glutamic acid, and edetic acid, and sodium edetate and dicitrate. Organic acid salts such as sodium and potassium hydrogen tartrate; inorganic acids such as phosphoric acid, hydrochloric acid and sulfuric acid; and inorganic acid salts such as potassium dihydrogen phosphate. Among them, citric acid, tartaric acid, ascorbic acid and the like are preferable. Examples of other solubilizers include Macrogol 4000, Macrogol 6000, and sodium lauryl sulfate.
The content of the pH adjusting agent and other solubilizing agents in the entire release control part A varies depending on the type and content of the active ingredient, the size of the preparation, etc., but is, for example, 0.5 to 50% by weight, preferably 2 to 50% by weight. ３０30% by weight.

The release control unit A can take the form of, but not limited to, tablets, granules, fine granules, pellets, capsules, crystals, pastes, liquids, and the like.
The preparation of the release controlling part A can be carried out according to a manufacturing method commonly used in the technical field of pharmaceutical preparations as long as it is a pharmaceutical composition. For example, when the release control part A is a quick release part, the active ingredient and a pharmacologically acceptable carrier are used. When the release control part A is a sustained release part, the active ingredient is pharmacologically acceptable. The carrier and the hydrophilic polymer are mixed and molded. The dispersion mode of the active ingredient in the molded product may be uniform dispersion or non-uniform dispersion, but uniform dispersion is desirable.

  In addition to the above-described production method, the release control unit A sprays a binder dissolved in a suitable solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.) on the surface of, for example, an inert carrier particle as a nucleus. In addition, the tumbling granulation method, the pan coating method, the fluidized bed coating method or the melt granulation method, in which the active ingredient or a mixture thereof with a hydrophilic polymer, an excipient, a lubricant, etc. is added little by little, is also used. Can be prepared. As the inert carrier particles, those produced from, for example, sucrose, lactose, starch, crystalline cellulose, and waxes can be used, and those having an average particle diameter of about 100 μm to about 1,500 μm are preferable.

  When the release control part A is a tablet, for example, the above-mentioned excipient, disintegrant, binder or lubricant is added to the active ingredient (and hydrophilic polymer) and mixed (if necessary, further kneading is performed). ), And can be prepared by compression molding.

In the controlled release composition of the present invention in which the release of the active ingredient is controlled in two or more steps, the release control part B is a (first) sustained release part (in the case of an oral administration preparation, dissolution in the vicinity of the upper small intestine to the lower part of the small intestine) ).
Release rate V _B of the active ingredient in the controlled release unit B satisfies the above definition of sustained release, and is not particularly limited so lower than the release rate V _A of the active ingredient in the controlled release unit A, preferably, When the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) was carried out at a paddle speed of 100 rpm using an appropriate test solution of 500 mL or 900 mL, the dissolution rate of the active ingredient 1 hour after the start of the test was About 5 to about 100%, more preferably about 10 to 50%. Here, the same test liquid as described above is used.
Alternatively, the release characteristics of the active ingredient in the controlled release portion B may be such that when the controlled release composition of the present invention is applied to the intended use (for example, in the case of an oral administration formulation, orally administered), the controlled release portion B The release of the active ingredient in is preferably characterized by a duration of preferably from about 1 to about 118 hours, more preferably from about 2 to about 10 hours.

The release control part B contains the same or different active ingredient as the active ingredient contained in the release control part A, the release rate of the active ingredient satisfies the above condition, and the release of the active ingredient is controlled by the release control part A. The release mechanism of the active ingredient is not particularly limited as long as it is prior to the release of the active ingredient contained therein, and may be any of those described above in the release control section A.
For example, the composition in which the active ingredient is released from the base by passive diffusion includes a matrix composition using the above-mentioned hydrophilic polymer (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, etc.), and a fat-soluble base. (Eg, carnauba wax, hardened castor oil, hardened rapeseed oil, polyglycerin fatty acid ester, etc.), sustained release base (eg, cellulosic polymer such as ethyl cellulose; aminoalkyl methacrylate copolymer RS, acrylic) A matrix composition using an ethyl acrylate-methyl methacrylate copolymer suspension (an acrylic acid polymer such as Eudragit NE) or the like can be used.

Examples of the composition that releases the active ingredient upon erosion of the base include a matrix composition using an amphiphilic base such as polyglycolized glyceride (eg, Gelucire 50/13 (trade name, manufactured by GATTEFOSSE)). No.
Examples of the composition which releases an active ingredient in response to a change in environmental pH include, for example, an enteric base [eg, methacrylic acid copolymer L [Eudragit L (trade name, manufactured by Rohm Pharma Co., Ltd.)], methacrylic acid copolymer LD Acrylic polymers such as [Eudragit L-30D55 (trade name, manufactured by Rohm Pharma Co., Ltd.)] and methacrylic acid copolymer S [Eudragit S (trade name, manufactured by Rohm Pharma Co., Ltd.)], hydroxypropylmethylcellulose-based polymer [hydroxy Propyl methyl cellulose phthalate (trade name: HPMCP, Shin-Etsu Chemical), hydroxypropyl methyl cellulose acetate succinate (trade name: HPMCAS, Shin-Etsu AQOAT, Shin-Etsu Chemical)], carboxymethyl ethyl cellulose (trade name: CMEC, Freund Sangyo), cellulose acetate phthalate (Product name: CAP, Japanese Such as matrix compositions using Pure Chemical), etc.] and the like.
Examples of the composition that expands the base by taking in environmental moisture and releases the active ingredient under the internal pressure include, for example, a composition using an OROS system (trade name, manufactured by Alza).

The active ingredient contained in the release control part B is preferably the same as that contained in the release control part A. If the active ingredient contained in the controlled release part B is the same as that contained in the controlled release part A, as described above, preferably a PPI, a steroid C _17,20 lyase inhibitor or a DPP-IV inhibitor, More preferably, PPI is exemplified. In this case, when the term “identical” is used, the active ingredients contained in both release control sections only need to be functionally identical. For example, in the case of PPI, the active ingredients contained in each release control section have PPI activity. As long as they are compounds, they may be the same compound or different compounds.
On the other hand, when the active ingredient contained in the release control part B is different from the active ingredient contained in the release control part A, it is preferable that the active ingredient be a mixture for the purpose of additive or synergistic effect of drug effect, reduction of side effects and the like. . For example, in the case of a DPP-IV inhibitor, drugs such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent, and an antithrombotic agent (hereinafter abbreviated as concomitant drug) Do) can be used in combination.
The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The mixing ratio of the DPP-IV inhibitor and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight based on 1 part by weight of the DPP-IV inhibitor.

Examples of the diabetes therapeutic agent include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli or yeast; insulin zinc; protamine zinc zinc; insulin) Or an insulin sensitizer (eg, pioglitazone hydrochloride, rosiglitazone (maleate), GI-262570, JTT-501, MCC-555, YM-440, KRP-) 297, CS-011, FK-614, NN-622, AZ-242, BMS-298585, EML-16336, compounds described in WO 99/58510 (for example, (E) -4- [4- (5-methyl-2) -Phenyl-4-oxazolylmethoxy) benzyloxyimino] 4-phenylbutyric acid)), PPARγ agonist, PPARγ antagonist, PPARγ / α dual agonist, α-glucosidase inhibitor (eg, voglibose, acarbose, miglitol, emiglitate), biguanide agent (eg, phenformin, metformin, buformin), insulin Secretagogues [sulfonylurea agents (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glibazole, etc.), repaglinide, senaglinide, nateglinide, mitiglinide or calcium salt hydrate thereof ], A GLP-1 receptor agonist [eg, GLP-1, NN-2211, AC-2993 (exendin-4), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH ₂ ], Amylin agonist ( , Pramlintide), a phosphotyrosine phosphatase inhibitor (eg, vanadate), a β3 agonist (eg, CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-1960085, AZ40140), gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, somatostatin receptor agonists), SGLT (sodium-glucose cotransporter) inhibitors (eg, T-1095), etc. Is mentioned.

As therapeutic agents for diabetic complications, aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SNK-860, CT-112), neurotrophic factors and drugs for increasing the same ( For example, a neurotrophin production / secretion enhancer described in NGF, NT-3, BDNF, WO 01/14372 (for example, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3 -(2-methylphenoxy) propyl] oxazole, etc.)), nerve regeneration promoter (eg, Y-128), PKC inhibitor (eg, LY-333531), AGE inhibitor (eg, ALT946, pimagedin, pyratoxatin, N -Phenacylthiazolium bromide (ALT766), EXO-226), Active oxygen scavengers (eg, thioctic acid) and cerebral vasodilators (eg, tiapride, mexiletine).
Examples of antihyperlipidemic agents include statin compounds which are cholesterol synthesis inhibitors (eg, cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or salts thereof (eg, sodium salt)), squalene synthesis Enzyme inhibitors (eg, compounds described in WO 97/10224, for example, N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3 -Dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid, etc., fibrate compounds (eg bezafibrate, Clofibrate, simfibrate, clinofibrate), ACAT inhibitors (eg, Avasimibe, Eflucimibe), anion exchange resins (eg, choles) Tyramine), probucol, nicotinic acid drugs (eg, nicomol (nicomol), niceritrol (niceritrol)), ethyl icosapentate, plant sterols (eg, soysterol, gamma oryzanol (γ-oryzanol)) and the like. Can be
Antihypertensives include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril), angiotensin II antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan, tasosartan), calcium antagonists (eg, Manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassium channel openers (eg, lebucromakalim, L-27152, AL 0671, NIP-121), clonidine and the like.
Examples of the antiobesity agent include central antiobesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex), pancreatic lipase inhibitor (Eg, orlistat), β3 agonist (eg, CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140), peptide appetite suppressant (eg, Leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonists (eg, lynch trypto, FPL-15849) and the like.

  Examples of the diuretic include xanthine derivatives (eg, sodium theobromine salicylate, calcium theobromine salicylate), thiazide-based preparations (eg, ethiazide, cyclopentiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, Methiclothiazide), anti-aldosterone preparations (eg, spironolactone, triamterene), carbonic anhydrase inhibitors (eg, acetazolamide), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide), azosemide, isosorbide, ethacrynic acid, piretanide , Bumetanide, furosemide and the like.

Examples of antithrombotic agents include heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drugs (eg, argatroban), thrombolytic drugs (eg, Examples, urokinase (urokinase), tisokinase (tisokinase), alteplase (alteplase), nateplase (nateplase), monteplase (monteplase), pamiteplase (pamiteplase)), platelet aggregation inhibitors (eg, ticlopidine hydrochloride), cilostazol ), Ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like.
The concomitant drug is preferably an insulin preparation, an insulin sensitizer, an α-glucosidase inhibitor, a biguanide, an insulin secretagogue (preferably a sulfonylurea) and the like.
One or both of the DPP-IV inhibitor and the concomitant drug are compounded in the controlled release part A of the controlled release composition of the present invention, and the other or both are compounded in the controlled release part B to obtain an additive or a medicinal effect. A combination drug may be used for the purpose of synergistic effect or reduction of side effects, or a concomitant drug may be separately administered as a single agent.

Among the controlled release compositions of the present invention, benzimidazole-based compounds such as lansoprazole and optically active substances thereof and PPIs of the above-mentioned imidazole-based compounds (especially the above-mentioned general formulas (I ′), (I) and (II)) And the compound represented by (III) or an optically active compound thereof) have excellent anti-ulcer action, gastric acid secretion inhibitory action, mucosal protective action, anti-Helicobacter pylori action, and the like. Since it is low, it is useful as a medicine. In this case, the controlled release composition of the present invention can be used in mammals (eg, humans, monkeys, sheep, horses, dogs, cats, rabbits, rats, mice, etc.) in peptic ulcers (eg, gastric ulcer, duodenal ulcer, anastomosis). Ulcers, etc.), Zollinger-Ellison syndrome, gastritis, reflux esophagitis, gastroesophageal reflux disease (Symptomatic GERD) without esophagitis, NUD (Non Ulcer Dyspepsia), gastric cancer (Including gastric cancer associated with promotion of interleukin-1β production by interleukin-1 gene polymorphism), treatment and prevention of gastric MALT lymphoma, eradication of Helicobacter pylori, peptic ulcer, acute stress ulcer, and hemorrhagic gastritis Suppression of upper gastrointestinal bleeding, invasive stress (cerebrovascular disorders requiring intensive management and intensive care after surgery, Suppression of upper gastrointestinal bleeding due to head trauma, multiple organ failure, stress caused by extensive burns), treatment and prevention of ulcers caused by nonsteroidal anti-inflammatory drugs; treatment and prevention of gastric hyperacidity and ulcers due to postoperative stress It can be administered orally for purposes. For eradication of Helicobacter pylori or the like, PPI may be used in combination with another active ingredient (for example, one to three kinds of active ingredients).
Examples of “other active ingredients” include antibacterial agents such as anti-Helicobacter pylori active substances, imidazole compounds, quinolone compounds, and bismuth salts. In particular, a medicine comprising a combination of a PPI and an antibacterial agent is preferred. Of these, combination use with antibacterial agents such as anti-Helicobacter pylori active substances and imidazole compounds is preferred.
Examples of the “anti-Helicobacter pylori active substance” include, for example, penicillin antibiotics (eg, amoxicillin, benzylpenicillin, piperacillin, mecillinam, etc.), cephem antibiotics (eg, cefixime, cefaclor, etc.), macrolide antibiotics ( Examples include erythromycin antibiotics such as erythromycin and clarithromycin), tetracycline antibiotics (eg, tetracycline, minocycline, streptomycin, etc.), aminoglycoside antibiotics (eg, gentamicin, amikacin, etc.), imipenem, and the like. Among them, penicillins and macrolides are preferred.
Examples of the “imidazole compound” include metronidazole, miconazole and the like.
Examples of the “bismuth salt” include bismuth acetate, bismuth citrate and the like.
Also preferred are "quinolone-based compounds" antibacterial agents, for example, ofloxacin, ciploxacin and the like.
In particular, for eradication of Helicobacter pylori, it is preferable to use PPI in combination with penicillin antibiotics (eg, amoxicillin) and / or erythromycin antibiotics (eg, clarithromycin).
The PPI and these concomitant drugs may be administered separately, or one or both of them may be compounded in the release control part A, and the other or both may be compounded in the release control part B, so that the additive or synergistic effect of the drug effect, Alternatively, it may be a mixture for the purpose of reducing side effects.

The content of the active ingredient in the whole release controlling part B is, for example, about 1 to 80% by weight, preferably about 5 to about 50% by weight, more preferably about 10 to about 30% by weight.
Further, the content of the active ingredient in each controlled release part in the whole controlled release composition of the present invention may be, for example, about 5 to about 95% by weight of the controlled release part A and about 5 to about 95% by weight of the controlled release part B. Preferably, the release control part A is about 20 to about 80% by weight and the release control part B is about 20 to about 80% by weight, more preferably the release control part A is about 30 to about 70% by weight and the release control part B is About 30 to about 70% by weight.

In one preferred embodiment, the release controlling part B contains a hydrophilic polymer as a sustained-release base in addition to the active ingredient. Specific examples of the hydrophilic base include those similar to those described above in the release control section A.
The viscosity of the hydrophilic polymer contained in the release control part B is preferably 1 mPa · s or more, more preferably 4 mPa · s or more, as the viscosity of a 2% by weight aqueous solution (measuring temperature: 20 ° C.).
The content of the hydrophilic polymer in the entire release controlling portion B is, for example, about 5 to about 90% by weight, preferably about 10 to about 80% by weight.

When both the release control unit A and the release control unit B are a sustained release matrix containing a hydrophilic polymer, the release rate in each release control unit is determined, for example, by adjusting the viscosity and blending amount of the contained hydrophilic polymer. The desired speed can be appropriately set by adjusting the speed. Those skilled in the art can easily make such a design change. For example, by using a relatively low-viscosity hydrophilic polymer for the release control section A and a relatively high-viscosity hydrophilic polymer for the release control section B, the release from the release control section A can be controlled by the release control section B. can be controlled fast release rate V _a than the release rate V _B from (e.g., see example 1-4). Alternatively, the release from the release control unit A is also released by blending a relatively low content of hydrophilic polymer into the release control unit A and blending a relatively high content of hydrophilic polymer into the release control unit B. it can be controlled fast release rate V _a than the release rate V _B from the control unit B.

In the controlled release composition of the present invention containing the controlled release part A and the controlled release part B, the release of the active ingredient contained in the controlled release part B precedes the release of the active ingredient contained in the controlled release part A. Any shape may be used as long as the shape is, for example, a tablet, a granule, a fine granule, a pellet, a capsule, a crystal, a paste, or the like, but is not limited thereto. Here, “advance” means that the release of the active ingredient contained in the release control part B is started earlier than the start of the release of the active ingredient contained in the release control part A, and the active ingredient in the release control part B is released. Means that the release of the active ingredient contained in the release control part A is started after or during the release of the active ingredient (the release of most of the active ingredient has been completed). Note that there is no particular limitation on the time relationship at which the release of the active ingredient from both release control sections ends. Usually, the release from the release control section B ends first, but the release of the active ingredient in the whole release control composition but so long as they exhibit the two-stage release pattern which changes slow release in immediate release or faster release rate from sustained release (V _a) at a given release rate (V _B), the active ingredient from the controlled release unit a May be terminated at the same time as or before the end of the release of the active ingredient from the release control section B.
Preferably, the controlled release composition of the present invention has a structure in which the controlled release portion B covers the controlled release portion A. Here, “cover” refers to a state in which the release control unit B covers substantially the entire surface of the release control unit A. “Substantially” means that the surface of release control A, even if not completely obscured, is such that release control B can itself define the start of release of active ingredient from release control A. Means hiding. On the other hand, if the release control unit B covers part of the release control unit A (for example, a spun-tab type tablet) or does not cover at all (for example, a mixed granule or a capsule containing the same). For the exposed surface portion of the release control portion A (that is, not in contact with the release control portion B), another means (for example, a pH-dependent soluble film such as a coating with the above-mentioned enteric base or a film dissolving film) is used. It is necessary to perform a treatment for delaying the start of release of the active ingredient by a known time-release system such as a mold, a membrane release type, a membrane disruption type or a membrane permeation type.

  If the controlled-release composition of the present invention is a pharmaceutical composition, the active ingredient and the sustained-release base, preferably the above-mentioned hydrophilic polymer, are mixed according to a method commonly used in the technical field of pharmaceutical preparations. By coating the controlled release portion A with the mixture. In the mixing and / or coating step, a pharmacologically acceptable carrier may be blended. As the pharmacologically acceptable carrier, the same carriers as described above in the release control section A can be used. The dispersion mode of the active ingredient in the release controlling portion B in the obtained composition may be uniform dispersion or non-uniform dispersion, but uniform dispersion is desirable.

  When the controlled-release composition of the present invention is a granule, the coating by the controlled-release part B is performed, for example, by using the controlled-release part A prepared by any of the above methods as a core, and water, a lower alcohol (eg, Spraying a binder dissolved in a suitable solvent such as methanol, ethanol, etc., while spraying a base such as an active ingredient and a hydrophilic polymer, or a pharmacologically acceptable base such as an excipient and a lubricant. Granulation, pan coating, fluidized bed coating or melt granulation, which is carried out by adding a small amount of a mixture with a carrier.

  Further, when the controlled release composition of the present invention is a tablet, the coating by the controlled release portion B is based on the controlled release portion A prepared by any of the above methods, and the active ingredient and the hydrophilic polymer are, for example, The mixture obtained by adding the above-mentioned excipients, disintegrants, binders, lubricants and the like and mixing (if necessary, further kneading) is used as an outer shell, and compression molding is carried out. it can.

  If the active ingredient in the release control part B is significantly deactivated under acidic conditions, the surface of the release control part is coated with an enteric base, for example, methacrylic acid copolymer L [Eudragit L (trade name, manufactured by Rohm Pharma Co.)] Acrylic polymer such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name, manufactured by Rohm Pharma Co.)], methacrylic acid copolymer S [Eudragit S (trade name, manufactured by Rohm Pharma Co.)], hydroxypropyl It may be coated with methyl cellulose phthalate [HP-50, HP-55, HP-55S (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.)).

In another preferred embodiment, the controlled release composition of the present invention contains an active ingredient that is the same as or different from the active ingredient contained in the controlled release part A and / or the controlled release part B, and releases the release of the active ingredient. It further includes a release control unit C that can control the discharge speed (V _B ) of the control unit B to a predetermined speed (V _c ) higher than the release speed (V _B ). In the controlled release composition, the release of the active ingredient in the controlled release section C precedes the release of the active ingredient in the controlled release section B. Here, “advance” has the same meaning as described above for the release of the active ingredient in the release control unit A and the release control unit B. That is, the release of the active ingredient contained in the release control section B is started after or during the release of the active ingredient in the release control section C (however, most of the active ingredient has been released). . In addition, regarding the time relationship at which the release of the active ingredient from both the release control sections ends, the release rate of the release control section B is usually higher because V _C is much faster than V _{B and the} release control section B usually has a higher active ingredient content. Release from the control unit C ends first.
Preferably, the controlled release composition of the present invention has a structure in which the controlled release portion B covers the controlled release portion A and the controlled release portion C covers the controlled release portion B. Here, “cover” has the same meaning as described above for the release control unit A and the release control unit B. On the other hand, if the release control unit C covers part of the release control unit B (for example, a spun-tab type tablet) or does not cover at all (for example, a mixed granule or a capsule containing the same). There is no particular problem if the release of the active ingredient from the release control section C is immediate release, but if the sustained release or delayed dissolution, the release control section B is exposed (that is, the release control section C For the surface portion that is not in contact, another means (for example, a pH-dependent soluble membrane such as the above-described coating with an enteric base, a known time-release system of a membrane-dissolving type, a membrane releasing type or a membrane-permeable type) ), It is necessary to carry out a treatment for delaying the start of release of the active ingredient.
The release control part C is responsible for the first release control step (corresponding to elution in the vicinity of the stomach and upper part of the small intestine in the preparation for oral administration) in the release control composition in which the release of the active ingredient is controlled in three steps. The release part or the sustained release part in which the release rate V _{C of the} active ingredient is faster than that (V _B ) in the release control part B (in the latter case, the release control part B is the second sustained release part and the release control part A is (If it is a sustained release part) it is a functional unit that acts as a third sustained release part).
Preferably, the release rate V _C of the active ingredient in the controlled release unit C is at the active ingredient release rate V _A equal to or more in the release control unit A, specifically, the Japanese Pharmacopoeia Dissolution Test Method 2 When the paddle method is carried out using a suitable test solution (500 mL or 900 mL) at a paddle rotation speed of 100 rpm, the dissolution rate of the active ingredient 30 minutes after the start of the test is 50% or more, more preferably 85% or more. % Or more.
Alternatively, the release characteristics of the active ingredient in the controlled release part C may be such that when the controlled release composition of the present invention is applied to an intended use (for example, in the case of an oral administration preparation, orally administered), the controlled release part C The release of the active ingredient contained in is completed within about 2 hours after application (eg, after administration), more preferably within about 30 minutes.

The active ingredient contained in the release control part C is preferably the same as that contained in the release control part A. When the active ingredient contained in the release control part C is the same as that contained in the release control part A, the above-mentioned ones are preferably exemplified.
On the other hand, when the active ingredient contained in the release control part C is different from that contained in the release control part A, it is preferable that the active ingredient is a combination for the purpose of additive or synergistic effect of drug effect, or reduction of side effects. For example, the same concomitant drug as described above in the release control section B can be used.

The content of the active ingredient in the whole of the controlled release part C is, for example, about 0.1 to 100% by weight, preferably about 1 to about 95% by weight, and more preferably about 5 to about 90% by weight.
Further, the content of the active ingredient in each controlled release part in the whole controlled release composition of the present invention is, for example, about 5 to 95% by weight for the controlled release part A, about 5 to about 95% by weight for the controlled release part B, and The release control part C is 0 to about 40% by weight (however, if it is 0%, the release control part C does not exist), preferably, the release control part A is about 20 to about 75% by weight, and the release control part B is about 20% by weight. And about 75% by weight and the release control part C is about 5 to about 30% by weight, more preferably the release control part A is about 30 to about 65% by weight, the release control part B is about 30 to about 65% by weight and the release control. Part C is about 5 to about 20% by weight.

  The release control section C is preferably a quick release section. In this case, the release control part may be the active ingredient itself, but in addition to the active ingredient, a carrier that is acceptable in the field related to the use of the composition (for example, if it is a pharmaceutical composition, it is pharmacologically acceptable). Carrier). Pharmacologically acceptable carriers include, for example, the excipients, lubricants, binders, disintegrants, preservatives, antioxidants, stabilizers, coloring agents, sweeteners and the like described above in the release control section A. Can be used.

The controlled release composition of the present invention containing the controlled release part A, the controlled release part B and the controlled release part C can take the form of tablets, granules, fine granules, pellets, capsules, crystals, pastes, etc. It is not limited to.
If the controlled-release composition of the present invention is a pharmaceutical composition, the active ingredient and a pharmacologically acceptable carrier are mixed according to a method commonly used in the technical field of pharmaceutical preparations. It can be prepared by further coating a composition obtained by coating part A with controlled release part B. The dispersion mode of the active ingredient in the release controlling portion C in the obtained composition may be uniform dispersion or non-uniform dispersion, but uniform dispersion is desirable.

  When the controlled release composition of the present invention is a granule, the coating by the controlled release portion C is, for example, a composition prepared by any one of the above-described methods, wherein the controlled release portion A is coated with the controlled release portion B. While spraying a binder dissolved in a suitable solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.) on the surface thereof, pharmacologically, such as an active ingredient or an excipient, a lubricant, etc. Granulation method, pan coating method, fluidized bed coating method and melt granulation method, which are carried out by adding a small amount of a mixture with a carrier acceptable to the above.

  Further, when the controlled release composition of the present invention is a tablet, the coating by the controlled release part C is a composition prepared by any of the methods described above, wherein the controlled release part A is coated with the controlled release part B. The mixture obtained by adding the above-mentioned excipients, disintegrants, binders or lubricants to the active ingredient and mixing (if necessary, further kneading) with the active ingredient is used as the outer shell, It can be prepared by molding. Further, the active ingredient has a release control part C by spraying an aqueous dispersion prepared by adding, for example, the above-mentioned excipient, disintegrant, binder or lubricant, using a fluidized bed coating method or the like. Controlled release compositions can be prepared.

  If the active ingredient in the release control part C is significantly deactivated under acidic conditions, the surface of the release control part is coated with an enteric base such as methacrylic acid copolymer L [Eudragit L (trade name, manufactured by Rohm Pharma Co.)] Acrylic polymer such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name, manufactured by Rohm Pharma Co.)], methacrylic acid copolymer S [Eudragit S (trade name, manufactured by Rohm Pharma Co.)], hydroxypropyl It may be coated with methyl cellulose phthalate [HP-50, HP-55, HP-55S (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.)).

The controlled release compositions of the present invention are particularly useful as oral dosage forms. After oral administration, the composition has a sustained drug dissolution (preferably about 1 to about 18 hours, more preferably about 2 to about 12 hours) from the stomach to the lower small intestine due to the release of the active ingredient from the controlled release part B. Time) followed by faster release of the drug from the lower small intestine to the vicinity of the large intestine (about 30 minutes to about 6 hours, preferably about 30 to about 3 hours) by the release of the active ingredient from the release controlling part A. Can be. Thereby, the drug dissolution and absorption in the lower part of the small intestine to the vicinity of the large intestine can be improved, and the blood concentration of the drug can be maintained in the effective therapeutic range for a longer period.
Furthermore, the controlled release composition in which the controlled release portion B is coated with the controlled release portion C is initially (within about 2 hours, preferably within about 30 minutes after oral administration) due to elution of the active ingredient contained in the controlled release portion C. ) Can realize rapid drug elution and absorption, and the drug blood concentration can rise more quickly.

The present invention will be described in more detail with reference to the following Reference Examples, Synthesis Examples, Comparative Examples, Examples and Experimental Examples, which do not limit the present invention and do not depart from the scope of the present invention. It may be changed.
In the following Reference Examples and Synthesis Examples, room temperature means about 15 to 30 ° C.
¹ H-NMR is measured using Varian Gemini-200 or Mercury-300, and using CDCl ₃ , DMSO-d ₆ , CD ₃ OD as a solvent, and chemical shift δ (ppm) from tetramethylsilane as an internal standard. showed that.
Other symbols have the following meanings.
s: singlet d: doublet t: triplet q: quartet m: multiplet
br: Broad
bs: Broad singlet
bm: Broad multiplet J: Coupling constant

Reference Example 1
Tert-butyl 2-hydroxyethyl (methyl) carbamate Di-tert-butyl dicarbonate (87.30 g) was added to a mixture of 2- (methylamino) ethanol (30.04 g) and ethyl acetate (90 mL) under ice cooling. A mixture of ethyl acetate (10 mL) was added dropwise. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), washed with water (100 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the title compound (66.19 g) was obtained as a colorless oil.
_{^{1 H-NMR (CDCl 3)}} : 1.47 (9H, s), 2.92 (3H, s), 3.40 (2H, t, J = 5.1Hz), 3.72-3.80 ( 2H, m).

Reference Example 2
2- (Methylamino) ethyl acetate hydrochloride Di-tert-butyl dicarbonate (4.37 g) was added to a mixture of 2- (methylamino) ethanol (1.50 g) and ethyl acetate (20 mL) under ice-cooling. . After stirring for 1.5 hours under ice cooling, acetic anhydride (2.08 mL), pyridine (1.78 mL), and 4-dimethylaminopyridine (0.12 g) were added. After stirring at room temperature for 2 hours, ethyl acetate (50 mL) was added to the reaction solution, and the mixture was washed with water (50 mL), 5% citric acid aqueous solution (50 mL), and saturated saline (50 mL). After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. A 4N hydrogen chloride-ethyl acetate solution (20 mL) was added to the residue, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (10 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (2.93 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.07 (3H, s), 2.53 (3H, s), 3.12-3.17 (2H, m), 4.24-4.30 ( 2H, m), 9.29 (2H, br).

Reference Example 3
2- (methylamino) ethyl trimethylacetate hydrochloride Triethylamine (1.67 mL) was added to a mixture of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (15 mL). Was added, and a mixture of trimethylacetyl chloride (1.35 mL) and ethyl acetate (5 mL) was added dropwise. After stirring at room temperature for 2 hours, pyridine (1.62 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (50 mL) was added to the reaction solution, washed with water (50 mL), 5% aqueous citric acid solution (50 mL), and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hours, diethyl ether (10 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (1.65 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.18 (9H, s), 2.56 (3H, s), 3.17 (2H, t, J = 10.5Hz), 4.22-4. 28 (2H, m), 9.19 (2H, br).

Reference example 4
2- (methylamino) ethyl cyclohexanecarboxylate hydrochloride Pyridine (0.97 mL) was added to a mixture of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (20 mL). ), 4-dimethylaminopyridine (catalytic amount), and then cyclohexanecarbonyl chloride (1.60 mL) was added dropwise. After stirring at room temperature for 2 hours, pyridine (0.65 mL) and cyclohexanecarbonyl chloride (0.58 mL) were added, and the mixture was stirred at room temperature overnight. Ethyl acetate (50 mL) was added to the reaction solution, washed with water (50 mL), 5% aqueous citric acid solution (50 mL), and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hours, diethyl ether (10 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (1.88 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.10-1.45 (5H, m), 1.54-1.73 (3H, m), 1.83-1.93 (2H, m), 2.29-2.42 (1H, m), 2.54 (3H, s), 3.12-3.18 (2H, m), 4.23-4.29 (2H, m), 9. 23 (2H, br).

Reference example 5
2- (methylamino) ethyl benzoate hydrochloride Di-tert-butyl dicarbonate (87.30 g) and ethyl acetate were added to a mixture of 2- (methylamino) ethanol (30.04 g) and ethyl acetate (90 mL) under ice-cooling. (10 mL) was added dropwise. After stirring at room temperature for 1 hour, benzoyl chloride (61.8 g) and pyridine (38.8 mL) were added under ice cooling. After stirring at room temperature for 1 hour, the solid was filtered off. The solid was washed with ethyl acetate (100 mL), the filtrate and the washing solution were combined, and washed with water (100 mL) and saturated saline (100 mL). After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), 4N hydrogen chloride-ethyl acetate solution (200 mL) was added, and the mixture was stirred at room temperature for 30 minutes. After addition of diethyl ether (100 mL), the solid was collected by filtration. After washing twice with ethyl acetate (100 mL), it was dried at 60 ° C. under reduced pressure to obtain the title compound (57.4 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.62 (3H, s), 3.32 (2H, m), 4.53 (2H, t, J = 9.9Hz), 7.51-7. 57 (2H, m), 7.68 (1H, m), 8.11 (2H, d, J = 7.8 Hz), 9.26 (2H, bs).

Reference Example 6
2- (methylamino) ethyl 4-methoxybenzoate hydrochloride 4-methoxybenzoyl was added to a mixture of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL). Chloride (1.88 g) and pyridine (0.97 mL) were added. After stirring at room temperature for 14 hours, 4-methoxybenzoyl chloride (0.70 g) and pyridine (0.97 mL) were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (80 mL) was added to the reaction solution, washed with water (20 mL), a saturated aqueous solution of sodium hydrogen carbonate (20 mL), and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in ethyl acetate (10 mL), and a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added. After stirring at room temperature for 1 hour, diethyl ether (20 mL) was added, and the precipitated solid was collected by filtration. After washing twice with ethyl acetate (15 mL), it was dried at 60 ° C. under reduced pressure to obtain the title compound (1.99 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.62 (3H, s), 3.32 (2H, m), 4.48 (2H, t, J = 5.0Hz), 7.07 (2H, d, J = 8.7 Hz), 8.06 (2H, d, J = 8.7 Hz), 9.04 (2H, bs).

Reference Example 7
2- (methylamino) ethyl 3-chlorobenzoate hydrochloride 3-chlorobenzoyl was added to a mixture of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL). Chloride (1.92 g) and pyridine (0.97 mL) were added. After stirring at room temperature for 1 hour, the mixture was stirred at 60 ° C. for 6 hours. Ethyl acetate (80 mL) was added to the reaction solution, washed with water (20 mL), a saturated aqueous solution of sodium hydrogen carbonate (20 mL), and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 22 hours, diethyl ether (15 mL) was added, and the precipitated solid was collected by filtration. After washing twice with ethyl acetate (15 mL), it was dried at 60 ° C. under reduced pressure to obtain the title compound (2.01 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.63 (3H, s), 3.32 (2H, m), 4.53 (2H, t, J = 4.9Hz), 7.60 (1H, t, J = 8.0 Hz), 7.78 (1H, d, J = 8.0 Hz), 8.05 (1H, d, J = 8.0 Hz), 8.15 (1H, s), 9. 07 (2H, bs).

Reference Example 8
2- (methylamino) ethyl 3,4-difluorobenzoate hydrochloride A mixture of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL) was added to the mixture. 4-Difluorobenzoyl chloride (1.77 g), pyridine (0.97 mL) were added. After stirring at room temperature for 3 days, ethyl acetate (80 mL) was added to the reaction solution, which was washed with water (20 mL), a saturated aqueous solution of sodium hydrogencarbonate (20 mL), and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 4 hours, the mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate (15 mL) and dried at 60 ° C. under reduced pressure to obtain the title compound (2.05 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.62 (3H, s), 3.32 (2H, m), 4.53 (2H, t, J = 5.0Hz), 7.64 (1H, m), 8.00 (1H, m), 8.25 (1H, m), 9.25 (2H, bs).

Reference Example 9
2- (methylamino) ethyl 4-trifluoromethoxybenzoate hydrochloride A mixture of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.30 g) obtained in Reference Example 1 and ethyl acetate (10 mL) was added to 4- (methylamino) ethyl 4-trifluoromethoxybenzoate hydrochloride. Trifluoromethoxybenzoyl chloride (1.83 g), pyridine (0.72 mL) were added. Stirred at 60 ° C. for 25 hours. Ethyl acetate (60 mL) was added to the reaction solution, washed with water (30 mL), a saturated aqueous solution of sodium hydrogen carbonate (20 mL), and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 14.5 hours, the mixture was concentrated under reduced pressure. The residue was washed twice with ethyl acetate (15 mL) and then dried at 60 ° C. under reduced pressure to obtain the title compound (1.83 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.63 (3H, s), 3.31 (2H, m), 4.54 (2H, t, J = 4.9Hz), 7.55 (2H, d, J = 8.5 Hz), 8.24 (2H, d, J = 8.5 Hz), 9.02 (2H, bs).

Reference example 10
2- (Methylamino) ethyl 4-fluorobenzoate hydrochloride 4-fluorobenzoyl was added to a mixture of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL). Chloride (1.74 g) and pyridine (0.97 mL) were added. Stirred at room temperature for 6.5 hours. Ethyl acetate (80 mL) was added to the reaction solution, and the mixture was washed with water (30 mL), a saturated aqueous solution of sodium hydrogencarbonate (30 mL), water (30 mL), and brine (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 1 hour, the precipitated solid was collected by filtration. After washing twice with ethyl acetate (15 mL), it was dried at 60 ° C. under reduced pressure to obtain the title compound (1.89 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.62 (3H, s), 3.32 (2H, m), 4.52 (2H, t, J = 4.9Hz), 7.34-7. 44 (2H, m), 8.16-8.24 (2H, m), 9.18 (2H, bs).

Reference Example 11
2- (methylamino) ethyl 3,4,5-trimethoxybenzoate hydrochloride A mixture of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL). 3,4,5-Trimethoxybenzoyl chloride (2.54 g) and pyridine (0.97 mL) were added. After stirring at 60 ° C for 14 hours, 3,4,5-trimethoxybenzoyl chloride (1.30 g), pyridine (0.97 mL) and ethyl acetate (10 mL) were added, and the mixture was stirred at 60 ° C for 24 hours. The reaction solution was filtered, and ethyl acetate (50 mL) and water (30 mL) were added to the filtrate. After liquid separation, the ethyl acetate layer was washed with 1N hydrochloric acid (30 mL), water (30 mL), aqueous copper (II) sulfate solution (30 mL), water (30 mL), and saturated saline (30 mL), and dried over anhydrous magnesium sulfate. . After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1). A 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the purified product. After stirring at room temperature for 4 hours, the mixture was concentrated under reduced pressure. Toluene (10 mL) was added, and the mixture was concentrated under reduced pressure. The residue was suspended in ethyl acetate and the solid was collected by filtration. After washing with ethyl acetate (15 mL), it was dried under reduced pressure to obtain the title compound (1.79 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.61 (3H, s), 3.28-3.35 (2H, m), 3.74 (3H, s), 3.87 (6H, s) , 4.48-4.54 (2H, m), 7.40 (2H, s), 9.43 (2H, br).

Reference Example 12
2- (methylamino) ethyl 2-pyridinecarboxylate dihydrochloride tert-butyl 2-hydroxyethyl (methyl) carbamate obtained in Reference Example 1 (1.75 g), 2-pyridinecarbonyl chloride hydrochloride (2. 67 g), pyridine (1.21 mL), and 4-dimethylaminopyridine (0.122 g) in tetrahydrofuran (100 mL) were added dropwise with triethylamine (2.09 mL) under ice-cooling, and the mixture was stirred at room temperature for 6 hours. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was sequentially washed with a 5% aqueous solution of copper (II) sulfate (100 mL), water (100 mL), and saturated saline (100 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and ethanol (100 mL), 4N hydrogen chloride-ethyl acetate solution (15 mL) was added, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed twice with ethyl acetate (100 mL), and dried at 60 ° C. under reduced pressure to obtain the title compound (1.08 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.62 (3H, t, J = 5.4Hz), 3.35 (2H, m), 4.63 (2H, t, J = 5.0Hz), 5.26 (1H, bs), 7.77-7.84 (1H, m), 8.14-8.18 (1H, m), 8.36-8.40 (1H, m), 8. 70-8.90 (1H, m), 9.48 (2H, br).

Reference Example 13
2- (methylamino) ethyl methoxyacetate To a mixture of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL), methoxyacetyl chloride (1.20 g) was added. , Pyridine (0.97 mL) was added. After stirring at room temperature for 3 hours, ethyl acetate (70 mL) was added to the reaction solution, which was washed with water (20 mL), a saturated aqueous solution of sodium hydrogen carbonate (20 mL), and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in ethyl acetate (5 mL), and a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. Water (60 mL) and diethyl ether (30 mL) were added to the residue, and after stirring, the aqueous layer was separated. The aqueous layer was made basic with sodium hydrogen carbonate, and then extracted twice with ethyl acetate (40 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (1.00 g) as a colorless oil.
_{^{1 H-NMR (CDCl 3)}} : 2.40 (1H, bs), 3.06 (3H, s), 3.44 (3H, s), 3.57 (2H, t, J = 5.1Hz) , 3.75-3.82 (2H, m), 4.13 (2H, s).

Reference Example 14
Ethyl 2- (methylamino) ethyl carbonate hydrochloride Pyridine (0.97 mL) was added to a mixture of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (20 mL). , 4-dimethylaminopyridine (catalytic amount) was added, and ethyl chlorocarbonate (1.25 mL) was added dropwise. After stirring at room temperature overnight, ethyl acetate (50 mL) was added, and the mixture was washed with water (50 mL), 5% citric acid aqueous solution (50 mL), and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hours, diethyl ether (10 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (1.66 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.23 (3H, t, J = 7.1Hz), 2.54 (3H, s), 3.16-3.22 (2H, m), 4. 15 (2H, q, J = 7.1 Hz), 4.32-4.37 (2H, m), 9.25 (2H, br).

Reference Example 15
Isopropyl 2- (methylamino) ethyl carbonate hydrochloride To a mixture of tert-butyl 2-hydroxyethyl (methyl) carbamate (3.50 g) obtained in Reference Example 1 and ethyl acetate (20 mL) was added chlorocarbonic acid under ice cooling. Isopropyl (1.35 g) and pyridine (1.94 mL) were added. After stirring under ice cooling for 3.5 hours, isopropyl chlorocarbonate (1.84 g) was added, and the mixture was stirred at room temperature for 2.5 hours. Ethyl acetate (120 mL) was added to the reaction solution, washed with water (50 mL) and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hours, the precipitated solid was collected by filtration. After washing with ethyl acetate (15 mL), it was dried at 60 ° C. under reduced pressure to obtain the title compound (1.38 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.25 (6H, d, J = 6.2Hz), 2.56 (3H, s), 3.20 (2H, t, J = 5.1Hz), 4.32 (2H, t, J = 5.1 Hz), 4.80 (1H, m), 8.95 (2H, bs).

Reference Example 16
Benzyl 2- (methylamino) ethyl carbonate hydrochloride Pyridine (0.97 mL) was added to a mixture of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (20 mL). , 4-dimethylaminopyridine (catalytic amount) was added, and then benzyl chlorocarbonate (1.57 mL) was added dropwise. After stirring at room temperature for 2 hours, pyridine (0.65 mL) and benzyl chlorocarbonate (1.28 mL) were added. After stirring at room temperature for 5 days, pyridine (0.81 mL) was added under ice-cooling, and a solution of benzyl chlorocarbonate (1.43 mL) in ethyl acetate (5 mL) was slowly added dropwise. After stirring at room temperature for 2 hours, ethyl acetate (50 mL) was added, and the mixture was washed with water (50 mL), a 5% aqueous citric acid solution (50 mL), and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hours, diethyl ether (10 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (1.99 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.55 (3H, s), 3.21 (2H, t, J = 5.1Hz), 4.37 (2H, t, J = 5.1Hz), 5.18 (2H, s), 7.30-7.50 (5H, m), 9.07 (2H, br).

Reference Example 17
2- (Methylamino) ethyl tetrahydropyran-4-yl carbonate hydrochloride Bis (trichloromethyl) carbonate (2.97 g) in tetrahydrofuran solution (40 mL) under ice cooling under ice cooling, pyridine (2.43 mL) in tetrahydrofuran solution (10 mL) Was dropped. After stirring for 10 minutes under ice cooling, a tetrahydrofuran solution (20 mL) of tetrahydropyran-4-ol (1.91 g) was slowly added dropwise. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure, and ethyl acetate (50 mL) and water (50 mL) were added to the residue. The ethyl acetate layer was separated, washed with 0.2N hydrochloric acid (20 mL) and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, tetrahydropyran-4-yl chlorocarbonate (1.53 g) was obtained. After adding pyridine (0.78 mL) to a mixture of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.40 g) obtained in Reference Example 1 and tetrahydrofuran (20 mL), the chlorocarbonate obtained above was added. A tetrahydrofuran solution (10 mL) of tetrahydropyran-4-yl (1.53 g) was added dropwise, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The extract was washed with a 5% aqueous citric acid solution (50 mL) and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 4: 1, then 3: 2). The obtained colorless oil (2.03 g) was dissolved in diethyl ether (2 mL), and a 4N hydrogen chloride-ethyl acetate solution (5 mL) was added. After stirring at room temperature for 30 minutes, diethyl ether (10 mL) was added, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.20 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.50-1.65 (2H, m), 1.87-1.98 (2H, m), 2.54 (3H, s), 3.20 ( 2H, m), 3.40-3.50 (2H, m), 3.74-3.83 (2H, m), 4.36 (2H, t, J = 5.1 Hz), 4.72- 4.83 (1H, m), 9.32 (2H, br).

Reference Example 18
2-methoxyethyl 2- (methylamino) ethyl carbonate hydrochloride A mixture of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (20 mL) was added to pyridine (1 After adding 0.62 mL), a solution of 2-methoxyethyl chlorocarbonate (2.77 g) in ethyl acetate (5 mL) was slowly added dropwise, followed by stirring at room temperature overnight. After the reaction solution was concentrated under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The extract was washed with a 5% aqueous citric acid solution (50 mL) and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in diethyl ether (2 mL), and a 4N hydrogen chloride-ethyl acetate solution (5 mL) was added. After stirring at room temperature for 30 minutes, diethyl ether (10 mL) was added, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.56 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.54 (3H, s), 3.19 (2H, m), 3.26 (3H, s), 3.52-3.57 (2H, m) , 4.20-4.25 (2H, m), 4.33-4.39 (2H, m), 9.26 (2H, br).

Reference Example 19
Tert-butyl ethyl (2-hydroxyethyl) carbamate Di-tert-butyl dicarbonate (21.8 g) was added to a mixture of 2- (ethylamino) ethanol (8.91 g) and ethyl acetate (100 mL) under ice-cooling. Was added. After stirring at room temperature for 3 days, the mixture was washed with saturated saline (100 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the title compound (19.0 g) was obtained as a colorless oil.
_{^{1 H-NMR (CDCl 3)}} : 1.11 (3H, t, J = 7.0Hz), 1.47 (9H, s), 3.27 (2H, q, J = 7.0Hz), 3. 37 (2H, t, J = 5.2 Hz), 3.73 (2H, q, J = 5.2 Hz).

Reference Example 20
2- (ethylamino) ethyl acetate hydrochloride A mixture of tert-butyl ethyl (2-hydroxyethyl) carbamate (1.89 g) obtained in Reference Example 19 and ethyl acetate (20 mL) was added to acetic anhydride (1.04 mL). , Pyridine (0.89 mL) and 4-dimethylaminopyridine (0.061 g) were added. After stirring at room temperature for 3 hours, ethyl acetate (50 mL) was added, and the mixture was washed with water (50 mL), a 5% aqueous citric acid solution (50 mL), and a saturated saline solution (50 mL). After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. A 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (10 mL) and diethyl ether (20 mL) were added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (1.54 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.22 (3H, t, J = 7.3Hz), 2.07 (3H, s), 2.95 (2H, q, J = 7.3Hz), 3.15 (2H, t, J = 5.3 Hz), 4.24-4.30 (2H, m), 9.17 (2H, br).

Reference Example 21
Tert-butyl 2-hydroxyethyl (isopropyl) carbamate To a solution of 2- (isopropylamino) ethanol (10.0 g) in tetrahydrofuran (30 mL) was added di-tert-butyl dicarbonate (22.2 g). Stirred for hours. After the reaction solution was concentrated under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (200 mL). The ethyl acetate layer was washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (21.21 g) as a colorless oil.
_{^{1 H-NMR (CDCl 3)}} : 1.12 (6H, d, J = 6.6Hz), 3.30 (2H, t, J = 5.0Hz), 3.71 (2H, t, J = 5 .0 Hz), 3.80-4.30 (1H, m).

Reference Example 22
2- (Isopropylamino) ethyl acetate hydrochloride Pyridine (6.0 mL) and acetic anhydride were added to a tetrahydrofuran solution (15 mL) of tert-butyl 2-hydroxyethyl (isopropyl) carbamate (5.0 g) obtained in Reference Example 21. (2.79 mL) was added and the mixture was stirred at room temperature for 18 hours. After the reaction solution was concentrated under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with a 5% aqueous citric acid solution (50 mL) and saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained colorless oil was dissolved in a 4N hydrogen chloride-ethyl acetate solution (10 mL) and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (3.14 g) as a colorless solid.
¹ H-NMR (DMSO-d ₆ ): 1.25 (6H, d, J = 6.6 Hz), 2.08 (3H, s), 3.10-3.40 (3H, m), 4. 29 (2H, t, J = 6.0 Hz), 9.11 (2H, br).

Reference Example 23
Ethyl 2- (isopropylamino) ethyl carbonate hydrochloride In a tetrahydrofuran solution (15 mL) of tert-butyl 2-hydroxyethyl (isopropyl) carbamate (5.0 g) obtained in Reference Example 21, pyridine (6.0 mL) and chloroform were added. Ethyl carbonate (2.81 mL) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction solution was concentrated under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with a 5% aqueous citric acid solution (50 mL) and saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained colorless oil was dissolved in a 4N hydrogen chloride-ethyl acetate solution (10 mL) and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (3.34 g) as a colorless solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.20-1.30 (9H, m), 3.10-3.40 (3H, m), 4.17 (2H, q, J = 7.4Hz ), 4.37 (2H, t, J = 5.6 Hz), 9.13 (2H, br).

Reference Example 24
Tert-butyl cyclohexyl (2-hydroxyethyl) carbamate Di-tert-butyl dicarbonate (21.8 g) was added dropwise to an ethanol solution (200 mL) of 2- (cyclohexylamino) ethanol (14.3 g). After stirring at room temperature for 2 days, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with water (100 mL) and saturated saline (100 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give the title compound (24.2 g) as a colorless oil.
_{^{1 H-NMR (CDCl 3)}} : 1.26-1.39 (4H, m), 1.47 (9H, s), 1.61-1.81 (6H, m), 3.30-3. 40 (2H, m), 3.69 (2H, t, J = 5.4 Hz), 3.66-3.90 (2H, br).

Reference Example 25
2- (Cyclohexylamino) ethyl acetate hydrochloride Pyridine (1.05 mL) was added to a tetrahydrofuran solution (50 mL) of tert-butyl cyclohexyl (2-hydroxyethyl) carbamate (2.43 g) obtained in Reference Example 24 under ice-cooling. ), Acetic anhydride (1.23 mL) and 4-dimethylaminopyridine (0.122 g) were added, and the mixture was stirred at room temperature for 12 hours. Ethyl acetate (100 mL) was added to the reaction solution, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (100 mL), a 5% aqueous solution of copper (II) sulfate (100 mL) and a saturated aqueous solution of sodium chloride (100 mL), and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), and a 4N hydrogen chloride-ethyl acetate solution (15 mL) was added. After stirring at room temperature for 3 hours, diisopropyl ether (20 mL) was added, and the precipitated solid was collected by filtration to give the title compound (1.78 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.05-2.03 (10H, m), 2.07 (3H, s), 2.90-3.10 (1H, m), 3.17 ( 2H, t, J = 5.2 Hz), 4.29 (2H, t, J = 5.2 Hz), 9.19 (2H, br).

Reference Example 26
2- (Cyclohexylamino) ethyl ethyl carbonate hydrochloride To a solution of tert-butyl cyclohexyl (2-hydroxyethyl) carbamate (2.43 g) obtained in Reference Example 24 in tetrahydrofuran (50 mL) was added pyridine (1. 45 mL), ethyl chlorocarbonate (1.71 mL) and 4-dimethylaminopyridine (0.122 g) were added, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (100 mL), a 5% aqueous solution of copper (II) sulfate (100 mL), water (100 mL) and saturated saline (100 mL), and then sulfuric anhydride Dried over sodium and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), and a 4N hydrogen chloride-ethyl acetate solution (15 mL) was added. After stirring at room temperature for 3 hours, diisopropyl ether (20 mL) was added, and the precipitated solid was collected by filtration to give the title compound (2.12 g) as a white solid.
¹ H-NMR (DMSO-d ₆ ): 1.01 to 2.08 (10H, m), 1.23 (3H, t, J = 7.0 Hz), 2.90-3.10 (1H, m ), 3.21 (2H, t, J = 5.2 Hz), 4.16 (2H, q, J = 7.0 Hz), 4.39 (2H, t, J = 5.2 Hz), 9.27 (2H, br).

Reference Example 27
2-anilinoethyl acetate hydrochloride In a tetrahydrofuran solution (700 mL) of 2-anilinoethanol (137 g) under ice cooling, pyridine (97.1 mL), acetic anhydride (113.2 mL), and 4-dimethylaminopyridine (12.22 g). Was added and stirred at room temperature for 20 hours. Ethyl acetate (1 L) was added to the reaction solution, and the mixture was washed successively with water (1 L), a saturated aqueous solution of sodium hydrogencarbonate (1 L), a 5% aqueous solution of copper (II) sulfate (1 L), and a saturated aqueous solution of sodium chloride (1 L). It was dried over sodium and evaporated under reduced pressure. A 4N hydrogen chloride-ethyl acetate solution (250 mL) was added to a solution of the obtained residue in ethyl acetate (700 mL) under ice-cooling, and the precipitated solid was collected by filtration to obtain the title compound (156 g) as a white solid. Was.
_{^{1 H-NMR (CD 3 OD}} ): 2.11 (3H, s), 3.71-3.76 (2H, m), 4.32-4.37 (2H, m), 7.49-7 .64 (5H, m).

Reference Example 28
tert-Butyl [2- (methylamino) -3-pyridyl] methyl carbonate [2- (methylamino) -3-pyridyl] methanol (2 g: synthesized by the method described in WO 01/32652) in tetrahydrofuran (50 mL) To the mixture were added di-tert-butyl dicarbonate (3.48 g) and 4-dimethylaminopyridine (0.18 g), and the mixture was refluxed for 1 hour. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The obtained organic layer was washed with saturated saline (50 mL) and then dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by flash silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 5) to give the title compound (1.51 g) as a white solid.
_{^{1 H-NMR (CDCl 3)}} : 1.49 (9H, s), 3.02 (3H, d, J = 4.8Hz), 4.99 (2H, s), 5.00 (1H, bs) , 6.55 (1H, dd, J = 7.0, 5.0 Hz), 7.37 (1H, dd, J = 7.0, 1.8 Hz), 8.16 (1H, dd, J = 5) 2.0, 1.8 Hz).

Reference Example 29
2- (Methylamino) benzyl acetate [2- (methylamino) phenyl] methanol (1.37 g: synthesized by the method described in WO 01/32652) in tetrahydrofuran solution (50 mL), pyridine (1.05 mL), and acetic anhydride (1.23 mL) and 4-dimethylaminopyridine (0.18 g) were added, and the mixture was stirred at room temperature for 8 hours. Water (100 mL) was added to the reaction solution, and extracted with ethyl acetate (100 mL). The organic layer was washed sequentially with a 5% aqueous solution of copper (II) sulfate (50 mL), a saturated aqueous solution of sodium hydrogen carbonate (50 mL), and a saturated aqueous solution of sodium chloride (50 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 5, then 1: 3) to give the title compound (0.38 g) as a white solid.
_{^{1 H-NMR (CDCl 3)}} : 2.08 (3H, s), 2.87 (3H, s), 4.40 (1H, br), 5.08 (2H, s), 6.64-6 .74 (2H, m), 7.17-7.32 (2H, m).

Reference Example 30
2-[(2-acetyloxyethyl) amino] ethyl acetate hydrochloride A mixture of 2,2′-iminodiethanol (2.10 g) and ethyl acetate (20 mL) was added to a mixture of di-tert-butyl dicarbonate (4 .37 g) was added. After stirring for 1.5 hours under ice cooling, acetic anhydride (2.08 mL), pyridine (1.78 mL), and 4-dimethylaminopyridine (0.12 g) were added. After stirring at room temperature for 2 hours, ethyl acetate (50 mL) was added to the reaction solution, and the mixture was washed with water (50 mL), 5% citric acid aqueous solution (50 mL), and saturated saline (50 mL). After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. A 4N hydrogen chloride-ethyl acetate solution (20 mL) was added to the residue, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (10 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (6.18 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.07 (6H, s), 3.23 (4H, t, J = 5.3Hz), 4.27-4.33 (4H, m), 9. 40 (2H, br).

Reference Example 31
(S) -2-Pyrrolidinylmethyl acetate hydrochloride A mixture of (S) -2-pyrrolidinylmethanol (1.01 g) and ethyl acetate (10 mL) was added to a mixture of di-tert-butyl dicarbonate (2 .18g) was added. After stirring for 1 hour under ice cooling, acetic anhydride (1.04 mL), pyridine (0.89 mL), and 4-dimethylaminopyridine (0.061 g) were added. After stirring at room temperature for 1 hour, ethyl acetate (50 mL) was added to the reaction solution, and the mixture was washed with water (50 mL), a 5% aqueous citric acid solution (50 mL), and a saturated saline solution (50 mL). After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. A 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hour. Diethyl ether (10 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (1.68 g) as a slightly brown solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.56-2.10 (4H, m), 2.06 (3H, s), 3.05-3.24 (2H, m), 3.63- 3.68 (1H, m), 4.15 (1H, dd, J = 11.8, 8.1 Hz), 4.26 (1H, dd, J = 11.8, 4.1 Hz), 9.21 (1H, br), 9.87 (1H, br).

Reference Example 32
3- (Methylamino) propyl benzoate hydrochloride To a mixture of 3-amino-1-propanol (0.75 g) and ethyl acetate (2.25 mL) was added di-tert-butyl dicarbonate (2.18 g) under ice-cooling. ) In ethyl acetate (0.25 mL) was added. After stirring at room temperature for 21.5 hours, benzoyl chloride (1.30 mL), pyridine (0.98 mL), and 4-dimethylaminopyridine (0.012 g) were added. After stirring at room temperature for 5 hours, ethyl acetate (32.5 mL) was added to the reaction solution, and the mixture was washed with water (12.5 mL) and saturated saline (12.5 mL). After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (20 mL) and methyl iodide (5 mL) was added. Under ice cooling, 60% sodium hydride (0.4 g) was added. After stirring at room temperature for 3 hours, the reaction solution was poured into an ice-cooled aqueous ammonium chloride solution (60 mL). The mixture was extracted with diethyl ether (80 mL) and washed with saturated saline (30 mL). After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1, then ethyl acetate, then acetone: ethyl acetate = 1: 9), and 3-[(tert-butoxycarbonyl) (methyl) amino ] Propyl benzoate (2.52 g) was obtained as a colorless oil. A 4N hydrogen chloride-ethyl acetate solution (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was added with ethyl acetate (10 mL), and the precipitated solid was collected by filtration. After washing with diethyl ether (10 mL), it was dried under reduced pressure to obtain the title compound (1.73 g) as a colorless solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.02-2.16 (2H, m), 2.56 (3H, s), 3.05 (2H, t, J = 7.3Hz), 4. 35 (2H, t, J = 6.1 Hz), 7.51 (2H, m), 7.65-7.73 (1H, m), 8.01 (2H, d, J = 7.2 Hz), 8.95 (2H, br).

Reference Example 33
2-[(Ethoxycarbonyl) (methyl) amino] ethyl ethyl carbonate To a solution of 2- (methylamino) ethanol (100 g) in ethyl acetate (1000 mL) was added pyridine (222 mL), and under ice-cooling, ethyl chlorocarbonate (240 mL). Was added dropwise over 2 hours. After the addition was completed, the reaction solution was stirred at room temperature for 18 hours. Water (300 mL) was added, and the ethyl acetate layer was separated, followed by washing with 1N hydrochloric acid (200 mL) and saturated saline (200 mL). After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was distilled under reduced pressure to give the title compound (180 g) as a colorless fraction having a boiling point of 95-100 ° C (pressure: 0.1-0.2 mmHg).
_{^{1 H-NMR (CDCl 3)}} : 1.20-1.40 (6H, m), 2.97 (3H, s), 3.50-3.60 (2H, m), 4.05-4. 35 (6H, m).

Reference Example 34
2-[(chlorocarbonyl) (methyl) amino] ethyl ethyl carbonate Acetonitrile solution (1500 mL) of 2-[(ethoxycarbonyl) (methyl) amino] ethyl ethyl carbonate (150 g) obtained in Reference Example 33 was mixed with phosphorus oxychloride ( (200 mL) and refluxed for 4 days. After the reaction solution was concentrated under reduced pressure, the residue was added little by little to a mixture of water (500 mL) -ice (700 g) -ethyl acetate (300 mL) with stirring. After stirring for 1 minute, saturated saline (500 mL) was added, and the mixture was extracted with ethyl acetate (500 mL). The ethyl acetate layer was washed successively with a saturated saline solution (300 mL), a saturated aqueous sodium hydrogen carbonate solution (300 mL), and a saturated saline solution (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was distilled under reduced pressure to give the title compound (77 g) as a colorless fraction having a boiling point of 100 to 105 ° C (pressure: 0.1 to 0.2 mmHg).
¹ H-NMR (CDCl ₃ ): 1.33 (3H, t, J = 7.2 Hz), 3.12 (3H × 0.4, s), 3.22 (3H × 0.6, s), 3.68 (2H × 0.6, t, J = 4.8 Hz), 3.78 (2H × 0.4, t, J = 4.8 Hz), 4.23 (2H, q, J = 7. 2Hz), 4.30-4.40 (2H, m).

Reference Example 35
Tert-butyl 4-hydroxybutylcarbamate A mixture of 4-aminobutanol (3.57 g) and ethyl acetate (9 mL) was added with di-tert-butyl dicarbonate (8.73 g) and ethyl acetate (1 mL) under ice-cooling. The mixture was added dropwise. After stirring at room temperature for 24 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with water (50 mL), 1N hydrochloric acid (40 mL), water (30 mL), and saturated saline (30 mL), and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure to give the title compound (7.54 g) as a colorless oil.
_{^{1 H-NMR (CDCl 3)}} : 1.44 (9H, s), 1.47-1.61 (4H, m), 3.07-3.22 (2H, m), 3.61-3. 76 (2H, m), 4.62 (1H, bs).

Reference Example 36
4-[(tert-butoxycarbonyl) amino] butyl acetate A mixture of tert-butyl 4-hydroxybutylcarbamate (3.83 g) obtained in Reference Example 35 and ethyl acetate (20 mL) was added with pyridine (1.80 mL). After adding acetic anhydride (2.27 g), the mixture was stirred at room temperature for 19 hours. Ethyl acetate (100 mL) was added to the reaction solution, washed with water (50 mL), aqueous copper sulfate solution (30 mL), water (30 mL), and saturated saline (30 mL), and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure to give the title compound (4.55 g) as a colorless oil.
_{^{1 H-NMR (CDCl 3)}} : 1.44 (9H, s), 1.51-1.69 (4H, m), 2.05 (3H, s), 3.15 (2H, m), 4 .07 (2H, t, J = 6.5 Hz), 4.55 (1H, bs).

Reference Example 37
4-((methylamino) butyl acetate hydrochloride N, N-dimethyl of 4-[(tert-butoxycarbonyl) amino] butyl acetate (4.50 g) obtained in Reference Example 36 and methyl iodide (4.85 mL) Sodium hydride (60% oily, 0.94 g) was added to the formamide solution (20 mL) under ice-cooling. After stirring at room temperature for 4 hours, the reaction solution was poured into ice-aqueous ammonium chloride solution, extracted with diethyl ether (120 mL), and the diethyl ether layer was washed with saturated saline (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 9). A 4N hydrogen chloride-ethyl acetate solution (20 mL) was added to the purified product, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (40 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (2.28 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.58-1.70 (4H, m), 2.01 (3H, s), 2.50 (3H, s), 2.82-2.90 ( 2H, m), 4.00 (2H, t, J = 6.0 Hz), 8.90 (2H, br).

Reference Example 38
4-[(tert-Butoxycarbonyl) amino] butyl ethyl carbonate To a mixture of tert-butyl 4-hydroxybutylcarbamate (3.71 g) obtained in Reference Example 35 and ethyl acetate (20 mL) under ice cooling was added pyridine ( After adding 1.71 mL) and ethyl chlorocarbonate (2.55 g), the mixture was stirred at room temperature for 24 hours. Ethyl acetate (100 mL) was added to the reaction solution, washed with water (50 mL), aqueous copper sulfate solution (30 mL), water (30 mL), and saturated saline (30 mL), and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure to give the title compound (4.92 g) as a colorless oil.
_{^{1 H-NMR (CDCl 3)}} : 1.31 (3H, t, J = 7.1Hz), 1.44 (9H, s), 1.46-1.80 (4H, m), 3.15 ( 2H, m), 4.11 to 4.25 (4H, m), 4.54 (1H, bs).

Reference Example 39
Ethyl 4- (methylamino) butyl carbonate hydrochloride N, N of 4-[(tert-butoxycarbonyl) amino] butyl ethyl carbonate (4.90 g) obtained in Reference Example 38 and methyl iodide (4.67 mL) To a dimethylformamide solution (20 mL) was added sodium hydride (60% oily, 0.90 g) under ice-cooling. After stirring at room temperature for 6 hours, the reaction solution was poured into ice-aqueous ammonium chloride solution, extracted with diethyl ether (120 mL), and the diethyl ether layer was washed with saturated saline (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 9). A 4N hydrogen chloride-ethyl acetate solution (20 mL) was added to the purified product, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (40 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (2.86 g) as a white solid.
¹ H-NMR (DMSO-d ₆ ): 1.21 (3H, t, J = 7.1 Hz), 1.51-1.73 (4H, m), 2.50 (3H, s), 2. 82-2.94 (2H, m), 4.05-4.15 (4H, m), 8.88 (2H, br).

Reference Example 40
Tert-butyl 3-hydroxypropylcarbamate A mixture of 3-aminopropanol (7.51 g) and ethyl acetate (30 mL) was added with di-tert-butyl dicarbonate (21.8 g) and ethyl acetate (3 mL) under ice-cooling. The mixture was added dropwise. After stirring at room temperature for 22 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with water (80 mL), 1N hydrochloric acid (60 mL), water (50 mL), and saturated saline (50 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the title compound (16.01 g) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): 1.45 (9H, s), 1.62-1.70 (2H, m), 3.24 (2H, q, J = 6.6 Hz), 3.66 ( 2H, q, J = 5.1 Hz), 4.73 (1H, bs).

Reference Example 41
3-[(tert-Butoxycarbonyl) amino] propyl acetate To a mixture of tert-butyl 3-hydroxypropylcarbamate (8.00 g) obtained in Reference Example 40 and ethyl acetate (50 mL), pyridine (4.06 mL) was added. After adding acetic anhydride (5.13 g), the mixture was stirred at room temperature for 21 hours. Ethyl acetate (200 mL) was added to the reaction solution, which was washed with water (100 mL), an aqueous solution of copper sulfate (40 mL), water (60 mL), and saturated saline (60 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give the title compound (8.34 g) as a colorless oil.
_{^{1 H-NMR (CDCl 3)}} : 1.44 (9H, s), 1.77-1.86 (2H, m), 2.06 (3H, s), 3.20 (2H, q, J = 6.3 Hz), 4.12 (2H, t, J = 6.3 Hz), 4.67 (1H, bs).

Reference Example 42
3- (Methylamino) propyl acetate hydrochloride N, N-dimethyl of 3-[(tert-butoxycarbonyl) amino] propyl acetate (17.28 g) obtained in Reference Example 41 and methyl iodide (19.8 mL) Sodium hydride (60% oily, 3.82 g) was added to the formamide solution (80 mL) under ice cooling. After stirring at room temperature for 15 hours, the reaction solution was poured into ice-aqueous ammonium chloride solution, extracted with diethyl ether (300 mL), and the diethyl ether layer was washed with saturated saline (100 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 8). A 4N hydrogen chloride-ethyl acetate solution (40 mL) was added to the purified product, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (100 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (2.93 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.85-1.97 (2H, m), 2.02 (3H, s), 2.50 (3H, s), 2.87-2.96 ( 2H, m), 4.06 (2H, t, J = 6.3 Hz), 8.87 (2H, br).

Reference Example 43
3-[(tert-Butoxycarbonyl) amino] propyl ethyl carbonate To a mixture of tert-butyl 3-hydroxypropylcarbamate (8.00 g) obtained in Reference Example 40 and ethyl acetate (50 mL) under ice cooling was added pyridine ( After adding 4.06 mL) and ethyl chlorocarbonate (5.95 g), the mixture was stirred at room temperature for 24 hours. Ethyl acetate (100 mL) was added to the reaction solution, washed with water (50 mL), aqueous copper sulfate solution (30 mL), water (30 mL), and saturated saline (30 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give the title compound (9.31 g) as a colorless oil.
_{^{1 H-NMR (CDCl 3)}} : 1.31 (3H, t, J = 7.1Hz), 1.44 (9H, s), 1.82-1.90 (2H, m), 3.22 ( 2H, t, J = 6.3 Hz), 4.15-4.23 (4H, m), 4.68 (1H, bs).

Reference Example 44
Ethyl 3- (methylamino) propyl carbonate hydrochloride N, N of 3-[(tert-butoxycarbonyl) amino] propyl ethyl carbonate (9.31 g) obtained in Reference Example 43 and methyl iodide (9.00 mL) To a dimethylformamide solution (40 mL) was added sodium hydride (60% oily, 1.82 g) under ice-cooling. After stirring at room temperature for 12 hours, the reaction solution was poured into ice-aqueous ammonium chloride solution, extracted with diethyl ether (200 mL), and the diethyl ether layer was washed with saturated saline (100 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 8). A 4N hydrogen chloride-ethyl acetate solution (40 mL) was added to the purified product, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (200 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (4.98 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.21 (3H, t, J = 7.1Hz), 1.91-2.00 (2H, m), 2.50 (3H, s), 2. 88-2.98 (2H, m), 4.08-4.16 (4H, m), 8.90 (2H, br).

Reference Example 45
Tert-butyl (2,3-dihydroxypropyl) methylcarbamate A mixture of 3- (methylamino) -1,2-propanediol (24.5 g) and ethyl acetate (50 mL) was added under ice-cooling to di-tert-dicarbonate. A mixture of butyl (51.4 g) and ethyl acetate (10 mL) was added dropwise. After stirring at room temperature for 15 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), washed with water (80 mL), 1N hydrochloric acid (60 mL), water (50 mL), and saturated saline (50 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give the title compound (26.9 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ): 1.47 (9H, s), 2.92 (3H, s), 3.20-3.36 (2H, m), 3.41 (2H, bs), 3 .50-3.62 (2H, m), 3.73-3.88 (1H, m).

Reference Example 46
3- (methylamino) propane-1,2-diyl diacetate hydrochloride A mixture of tert-butyl (2,3-dihydroxypropyl) methylcarbamate (10.26 g) obtained in Reference Example 45 and ethyl acetate (50 mL). After adding pyridine (10.11 mL) and acetic anhydride (12.76 g) to the mixture, the mixture was stirred at room temperature for 24 hours. Ethyl acetate (300 mL) was added to the reaction solution, washed with water (150 mL), aqueous copper sulfate solution (100 mL), water (100 mL), and saturated saline (100 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 8). A 4N hydrogen chloride-ethyl acetate solution (40 mL) was added to the purified product, and the mixture was stirred at room temperature for 3 hours. Diethyl ether (100 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (2.76 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.03 (3H, s), 2.07 (3H, s), 2.55 (3H, s), 3.18-3.22 (2H, m) , 4.09-4.28 (2H, m), 5.20-5.27 (1H, m), 9.01 (2H, br).

Reference Example 47
Diethyl 3- (methylamino) propane-1,2-diyl biscarbonate hydrochloride of tert-butyl (2,3-dihydroxypropyl) methylcarbamate (15.53 g) obtained in Reference Example 45 and ethyl acetate (100 mL) After adding pyridine (18.35 mL) and ethyl chlorocarbonate (24.62 g) to the mixture under ice cooling, the mixture was stirred at room temperature for 96 hours. Ethyl acetate (300 mL) was added to the reaction solution, washed with water (150 mL), aqueous copper sulfate solution (100 mL), water (100 mL), and saturated saline (100 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 6). A 4N hydrogen chloride-ethyl acetate solution (80 mL) was added to the purified product, and the mixture was stirred at room temperature for 3 hours. Diethyl ether (200 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (5.93 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.20-1.28 (6H, m), 2.57 (3H, s), 3.12-3.28 (2H, m), 4.10- 4.43 (6H, m), 5.13-5.22 (1H, m), 9.14 (2H, br).

Reference Example 48
2-ethoxyethyl 2- (methylamino) ethyl carbonate hydrochloride A solution of bis (trichloromethyl) carbonate (2.97 g) in tetrahydrofuran (20 mL) under ice-cooling was added to a solution of 2-ethoxyethanol (1.80 g) in tetrahydrofuran (10 mL). ) Was added dropwise. Subsequently, a solution of pyridine (2.43 mL) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2 N hydrochloric acid (20 mL) and saturated saline (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2-ethoxyethyl chlorocarbonate (1.29 g). . After adding pyridine (0.68 mL) to a tetrahydrofuran solution (15 mL) of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.23 g) obtained in Reference Example 1, the chlorocarbonate obtained above was added. A solution of -ethoxyethyl in tetrahydrofuran (5 mL) was added dropwise, and the mixture was stirred at room temperature for 3 days. After the reaction solution was concentrated under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with a 5% aqueous citric acid solution (50 mL) and saturated saline (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 5, then 2: 3). The purified product (1.60 g) was dissolved in diethyl ether (3 mL), and a 4N hydrogen chloride-ethyl acetate solution (3 mL) was added. After stirring at room temperature overnight, the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (0.94 g) as a white solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.10 (3H, t, J = 7.0Hz), 2.57 (3H, s), 3.18-3.25 (2H, m), 3. 44 (2H, q, J = 7.0 Hz), 3.56-3.60 (2H, m), 4.19-4.24 (2H, m), 4.30-4.37 (2H, m ), 8.79 (2H, br).

Reference Example 49
3-methoxypropyl 2- (methylamino) ethyl carbonate hydrochloride Tetrahydrofuran of methyl 3-methoxypropanoate (11.8 g) in a mixture of lithium aluminum hydride (2.85 g) and diethyl ether (100 mL) under ice-cooling The solution (50 mL) was slowly added dropwise. After stirring at room temperature for 1 hour, the mixture was ice-cooled again, and water (3 mL) and a 10% aqueous sodium hydroxide solution (3 mL) were added dropwise. After returning to room temperature, water (9 mL) was added dropwise, and the mixture was stirred for a while. The precipitate was separated by filtration, and the filtrate was concentrated under reduced pressure to give 3-methoxypropanol (7.64 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ): 1.83 (2H, quintet, J = 5.8 Hz), 2.43 (1H, t, J = 5.3 Hz), 3.36 (3H, s), 57 (2H, t, J = 6.0 Hz), 3.77 (2H, q, J = 5.5 Hz).
N-ethyldiisopropylamine (5.75 mL) was added dropwise to a solution of bis (trichloromethyl) carbonate (4.45 g) in tetrahydrofuran (50 mL) under ice-cooling. After stirring for a while, a solution of 3-methoxypropanol (2.70 g) obtained above in tetrahydrofuran (15 mL) was added dropwise. The mixture was stirred for 30 minutes under ice cooling and for 1 day at room temperature. After the reaction solution was concentrated under reduced pressure, dilute hydrochloric acid (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (30 mL) and saturated saline (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3-methoxypropyl chlorocarbonate (4.39 g). . After adding pyridine (0.97 mL) to a tetrahydrofuran solution (20 mL) of tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1, the chlorocarbonate 3 obtained above was added. A solution of -methoxypropyl (1.83 g) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After addition of pyridine (0.65 mL) and a solution of 3-methoxypropyl chlorocarbonate (1.22 g) in tetrahydrofuran (5 mL) and further stirring for 1 hour, the reaction solution was concentrated under reduced pressure. Water (50 mL) was added to the residue, and extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with a 5% aqueous citric acid solution (50 mL) and saturated saline (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 9, then 3: 7). The purified product (3.40 g) was dissolved in diethyl ether (5 mL), and a 4N hydrogen chloride-ethyl acetate solution (5 mL) was added. After stirring at room temperature overnight, the reaction solution was concentrated under reduced pressure. By crystallizing by adding diethyl ether, the title compound (2.06 g) was obtained as a colorless solid.
_{^{1 H-NMR (DMSO-d}} 6): 1.78-1.90 (2H, m), 2.54 (3H, s), 3.15-3.25 (2H, m), 3.23 ( 3H, s), 3.33-3.42 (2H, m), 4.16 (2H, t, J = 6.0 Hz), 4.36 (2H, t, J = 6.0 Hz), 9. 27 (2H, br).

Reference Example 50
2- (methylamino) ethyl N, N-dimethylglycinate dihydrochloride tert-butyl 2-hydroxyethyl (methyl) carbamate (3.50 g) obtained in Reference Example 1, N, N-dimethylglycine hydrochloride (5.29 g), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (7.67 g), triethylamine (5.58 mL), 4-dimethylaminopyridine (1.22 g) and N, A mixture of N-dimethylformamide (50 mL) was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated saline (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with methanol: ethyl acetate = 5: 95, followed by 20:80). 1N hydrochloric acid (24 mL) was added to the purified product (2.46 g), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to give the title compound (2.14 g) as a colorless solid.
_{^{1 H-NMR (DMSO-d}} 6): 2.52 (3H, s), 2.85 (6H, s), 3.20 (2H, m), 4.30 (2H, s), 4.43 -4.49 (2H, m), 9.60 (2H, br). 10.81 (1H, br).

Reference Example 51
S- [2- (Methylamino) ethyl] thioacetate hydrochloride tert-butyl 2-hydroxyethyl (methyl) carbamate obtained in Reference Example 1 (3.50 g), thioacetic acid (1.72 mL), triphenyl Under ice cooling, a tetrahydrofuran solution (10 mL) of diisopropyl azodicarboxylate (5.91 mL) was slowly added dropwise to a solution of phosphine (7.87 g) in tetrahydrofuran (50 mL). The mixture was stirred for 1 hour under ice cooling and for 2 hours at room temperature. The reaction solution was ice-cooled again, and a solution of triphenylphosphine (7.87 g) and diisopropyl azodicarboxylate (5.91 mL) in tetrahydrofuran (10 mL) was added, followed by stirring for 30 minutes under ice-cooling. Thioacetic acid (1.14 mL) was added, and the mixture was stirred under ice cooling for 30 minutes and at room temperature overnight. After the reaction solution was concentrated under reduced pressure, hexane and diisopropyl ether were added to the residue, the precipitate was separated by filtration, and the filtrate was concentrated under reduced pressure. After repeating this operation again, a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated saline (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 5: 95, followed by 15:85). A 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the purified product (4.47 g), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was crystallized by adding ethyl acetate and diethyl ether to give the title compound (1.79 g) as a pale-yellow solid.
¹ H-NMR (DMSO-d ₆ ): 2.38 (3H, s), 2.52 (3H, s), 2.96-3.08 (2H, m), 3.12-3.20 ( 2H, m), 9.35 (2H, br).

Reference Example 52
Ethyl 2- [2- (methylamino) ethoxy] ethyl carbonate hydrochloride Di-tert-butyl dicarbonate was added to a mixture of 2- (2-aminoethoxy) ethanol (99.52 g) and ethyl acetate (200 mL) under ice-cooling. (208.57 g) and a mixture of ethyl acetate (50 mL) was added dropwise. After stirring at room temperature for 60 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL), washed with water (200 mL), 1N hydrochloric acid (200 mL), water (300 mL), and saturated saline (300 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, tert-butyl [2- (2-hydroxyethoxy) ethyl] carbamate (169.2 g) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): 1.45 (9H, s), 3.33 (2H, q, J = 5.1 Hz), 3.54-3.59 (4H, m), 3.74 ( 2H, q, J = 5.1 Hz), 4.88 (2H, bs).
To a mixture of tert-butyl [2- (2-hydroxyethoxy) ethyl] carbamate (53.93 g) and ethyl acetate (350 mL) obtained above, under ice-cooling, pyridine (53.78 mL), ethyl chlorocarbonate ( After adding 70.57 g), the mixture was stirred at room temperature for 96 hours. Ethyl acetate (500 mL) was added to the reaction solution, which was washed with water (500 mL), an aqueous solution of copper sulfate (200 mL), water (300 mL), and saturated saline (300 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 2- [2-[(tert-butoxycarbonyl) amino] ethoxy] ethyl ethyl carbonate (93.19 g) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): 1.32 (3H, t, J = 7.2 Hz), 1.44 (9H, s), 3.32 (2H, t, J = 5.1 Hz), 54 (2H, t, J = 5.1 Hz), 3.67-3.74 (2H, m), 4.21 (2H, q, J = 7.2 Hz), 4.26-4.31 (2H , M), 4.91 (1H, bs).
To the N, N-dimethylformamide solution (350 mL) of 2- [2-[(tert-butoxycarbonyl) amino] ethoxy] ethyl ethyl carbonate (93.15 g) and methyl iodide (83.6 mL) obtained above. Under ice cooling, sodium hydride (60% oily, 16.12 g) was added. After stirring at room temperature for 24 hours, the reaction solution was poured into ice-aqueous ammonium chloride solution, extracted with diethyl ether (800 mL), and the diethyl ether layer was washed with saturated saline (300 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 8). A 4N hydrogen chloride-ethyl acetate solution (300 mL) was added to the purified product, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (300 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (33.21 g) as a white solid.
^{1 H-NMR (DMSO-d} 6): 1.21 (3H, t, J = 7.2Hz), 2.51 (3H, s), 3.02-3.09 (2H, m), 3. 65-3.72 (4H, m), 4.12 (2H, q, J = 7.2 Hz), 4.22 (2H, t, J = 4.5 Hz), 9.06 (2H, br).

Reference Example 53
Ethyl 2- [methyl [[2- (methylamino) ethoxy] carbonyl] amino] ethyl carbonate hydrochloride Pyridine (9.71 mL) was added to a tetrahydrofuran solution (100 mL) of bis (trichloromethyl) carbonate (11.87 g) under ice-cooling. ) In tetrahydrofuran (20 mL) was added dropwise. After stirring for 30 minutes under ice cooling, a solution of tert-butyl 2-hydroxyethyl (methyl) carbamate (17.52 g) obtained in Reference Example 1 in tetrahydrofuran (20 mL) was added dropwise, and the mixture was stirred at room temperature for 15 hours. After concentration under reduced pressure, water (500 mL) and anhydrous sodium sulfate were added to the residue. After filtration, the filtrate was concentrated under reduced pressure. To the obtained residue, a solution of 2- (methylamino) ethanol (5.00 g) in ethyl acetate (50 mL) and triethylamine (10.0 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate (300 mL) was added to the reaction solution, washed with water (150 mL) and saturated saline (200 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, pyridine (2.91 mL) and ethyl chlorocarbonate (3.44 g) were added to a mixture of the residue and ethyl acetate (100 mL) under ice-cooling, followed by stirring at room temperature for 48 hours. Ethyl acetate (200 mL) was added to the reaction solution, which was washed with water (100 mL), aqueous copper sulfate solution (50 mL), water (50 mL), and saturated saline (50 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 3). A 4N hydrogen chloride-ethyl acetate solution (30 mL) was added to the purified product, and the mixture was stirred at room temperature for 3 hours. Diethyl ether (100 mL) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave the title compound (2.90 g) as a white solid.
^{1 H-NMR (DMSO-d} 6): 1.21 (3H, t, J = 7.2Hz), 2.57 (3H, bs), 2.86 (1.5H, s), 2.93 ( 1.5H, s), 3.16 (2H, bs), 3.34 (1H, bs), 3.48 (1H, t, J = 5.1 Hz), 3.58 (1H, t, J = 5.1 Hz), 4.12 (2H, q, J = 7.2 Hz), 4.16-4.24 (4H, m), 8.94 (1H, br).

Reference Example 54
2- (methylamino) ethyl 1-methylpiperidine-4-carboxylate dihydrochloride ethyl piperidine-4-carboxylate (4.72 g), methyl iodide (2.24 mL), potassium carbonate (8.29 g) and acetonitrile (50 mL) was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, water (150 mL) was added, and the mixture was extracted with ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated saline (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A 1N aqueous sodium hydroxide solution (20 mL) was added to the residue (2.64 g), and the mixture was stirred at room temperature overnight. The reaction solution was neutralized by adding 1N hydrochloric acid (20 mL) and concentrated under reduced pressure. Ethanol was added to the residue, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. After repeating this operation again, ethanol and ethyl acetate were added to the residue for crystallization to obtain 1-methylpiperidine-4-carboxylic acid (1.79 g) as a colorless solid.
¹ H-NMR (CD ₃ OD): 1.80-1.98 (2H, m), 2.00-2.14 (2H, m), 2.28-2.42 (1H, m), 2 .78 (3H, s), 2.88-3.04 (2H.m), 3.32-3.44 (2H.m).
1-methylpiperidine-4-carboxylic acid (1.72 g) obtained above, tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1, 1-ethyl-3 A mixture of-[3- (dimethylamino) propyl] carbodiimide hydrochloride (2.30 g), 4-dimethylaminopyridine (0.24 g) and acetonitrile (50 mL) was stirred at room temperature for 16 hours. After the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated saline (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 50: 50, followed by 80:20). 1N hydrochloric acid (25 mL) was added to the purified product (2.73 g), and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, isopropanol was added, and the mixture was concentrated again under reduced pressure. The precipitated solid was collected by filtration to give the title compound (1.72 g) as a colorless solid.
^{1 H-NMR (DMSO-d} 6): 1.70-2.20 (4H, m), 2.40-3.50 (13H, m), 4.31 (2H, m), 9.25 ( 2H, br), 10.77 (1H, br).

Reference Example 55
2-[[4- (aminocarbonyl) phenyl] amino] ethyl acetate 4-fluorobenzonitrile (6.06 g), 2-aminoethanol (3.71 g), potassium carbonate (8.29 g) and dimethylsulfoxide (50 mL) Was stirred at 100 ° C. overnight. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 4). The ethyl acetate layer was washed with saturated saline (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 30: 70, then 50:50, then 80:20, then ethyl acetate) to give 4-[(2-hydroxyethyl ) Amino] benzonitrile (5.89 g) was obtained as a yellow solid.
_{^{1 H-NMR (CDCl 3)}} : 2.04 (1H, t, J = 4.8Hz), 3.33 (2H, m), 3.86 (2H, q, J = 4.8Hz), 4. 66 (1H, br), 6.58 (2H, d, J = 8.7 Hz), 7.39 (2H, d, J = 8.7 Hz).
A mixture of 4-[(2-hydroxyethyl) amino] benzonitrile (0.81 g), potassium hydroxide (1.12 g) and tert-butanol (20 mL) obtained above was stirred at 100 ° C. for 1 hour. Water (100 mL) was added to the reaction solution, and extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with brine (80 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a solution of the residue (0.83 g), pyridine (0.49 mL) and 4-dimethylaminopyridine (0.061 g) in tetrahydrofuran (10 mL), a solution of acetic anhydride (0.57 mL) in tetrahydrofuran (1 mL) was added dropwise. After stirring at room temperature for 1 hour, water (80 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated saline (80 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 30: 70, then 60:40) to give the title compound (0.68 g) as a colorless solid.
¹ H-NMR (CDCl ₃ ): 2.08 (3H, s), 3.44 (2H, q, J = 5.6 Hz), 4.29 (2H, t, J = 5.4 Hz), 4. 48 (1H, br), 6.59 (2H, d, J = 8.9 Hz), 7.43 (2H, d, J = 8.9 Hz).

Reference Example 56
2- (methylamino) ethyl 1-methyl-4-piperidinyl carbonate dihydrochloride In a tetrahydrofuran solution (40 mL) of N, N'-carbonyldiimidazole (3.36 g), 2-hydroxyethyl obtained in Reference Example 1 was added. A solution of tert-butyl (methyl) carbamate (3.30 g) in tetrahydrofuran (10 mL) was slowly added dropwise under ice cooling. After stirring under ice cooling for 40 minutes and at room temperature for 2 hours, N, N'-carbonyldiimidazole (0.31 g) was added, and the mixture was further stirred for 3 days. After the reaction solution was concentrated under reduced pressure, ethyl acetate (150 mL) was added to the residue, and the mixture was washed with saturated saline (100 mL x 2), water (50 mL x 3), and saturated saline (50 mL), and then dried over anhydrous magnesium sulfate. Drying and concentration under reduced pressure gave 2-[(tert-butoxycarbonyl) (methyl) amino] ethyl 1H-imidazole-1-carboxylate (5.24 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ): 1.39 (9H × 0.5, s), 1.42 (9H × 0.5, s), 2.94 (3H, m), 3.63 (2H, m), 4.51 (2H, t, J = 5.3 Hz), 7.06 (1H, m), 7.42 (1H, m), 8.13 (1H, s).
2-[(tert-butoxycarbonyl) (methyl) amino] ethyl 1H-imidazole-1-carboxylate (1.35 g) obtained above, 1-methyl-4-piperidinol (1.38 g) and acetonitrile ( 20 mL) was stirred at room temperature overnight. 1-Methyl-4-piperidinol (0.92 g) was added, and the mixture was further stirred overnight. After the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated saline (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 1N Hydrochloric acid (12 mL) was added to the residue (1.60 g), and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, water, isopropanol and ethyl acetate were added, and the precipitated solid was collected by filtration to give the title compound (1.09 g) as a colorless solid.
¹ H-NMR (DMSO-d ₆ ): 1.85-2.20 (4H, m), 2.55 (3H, s), 2.70 (3H × 0.5, s), 2.73 ( 3H × 0.5, s), 2.90-3.50 (6H, m), 4.38 (2H, m), 4.65-5.00 (1H, m), 9.21 (2H, m) br), 11.10 (1H, br).

Synthesis Example 1
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl acetate To a solution of bis (trichloromethyl) carbonate (0.50 g) in tetrahydrofuran (30 mL) was added dropwise a solution of pyridine (0.40 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice cooling, 2- (methylamino) ethyl acetate hydrochloride (0.77 g) obtained in Reference Example 2 was added. After a solution of triethylamine (0.70 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.11 g), triethylamine (0. 84 mL) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 1, then eluted with ethyl acetate), and further purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1, And eluted with ethyl acetate followed by acetone: ethyl acetate = 1: 4, then 1: 1) to give the title compound (1.13 g) as a yellow amorphous solid.
_{^{1 H-NMR (CDCl 3)}} : 2.10 (3H, s), 2.24 (3H, s), 3.09 (3H, bs), 3.60-4.00 (2H, br), 4 .25-4.50 (4H, m), 4.89 (1H, d, J = 13.3 Hz), 5.05 (1H, d, J = 13.3 Hz), 6.65 (1H, d, J = 5.5 Hz), 7.35-7.51 (3H, m), 7.80-7.90 (1H, m), 8.35 (1H, d, J = 5.5 Hz).

Synthesis Example 2
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl trimethylacetate To a solution of bis (trichloromethyl) carbonate (0.50 g) in tetrahydrofuran (30 mL) was added dropwise a solution of pyridine (0.40 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 1 hour under ice cooling, 2- (methylamino) ethyl trimethyl acetate hydrochloride (0.98 g) obtained in Reference Example 3 was added. A solution of triethylamine (0.70 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.11 g), triethylamine (0. 84 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by flash silica gel column chromatography (eluted with acetone: hexane = 1: 3, then 3: 2). Crystallization from acetone-diisopropyl ether and recrystallization from acetone-diisopropyl ether gave the title compound (1.01 g) as a colorless solid.
_{^{1 H-NMR (CDCl 3)}} : 1.23 (9H, s), 2.23 (3H, s), 3.08 (3H, bs), 3.40-4.30 (2H, br), 4 .30-4.50 (4H, m), 4.80-5.20 (2H, br), 6.64 (1H, d, J = 5.7 Hz), 7.35-7.50 (3H, m), 7.78-7.88 (1H, m), 8.35 (1H, d, J = 5.7 Hz).

Synthesis Example 3
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl cyclohexanecarboxylate To a solution of bis (trichloromethyl) carbonate (0.50 g) in tetrahydrofuran (30 mL) was added dropwise a solution of pyridine (0.40 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice cooling, 2- (methylamino) ethyl cyclohexanecarboxylate hydrochloride (1.11 g) obtained in Reference Example 4 was added. After a solution of triethylamine (0.70 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.11 g), triethylamine (0. 84 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by flash silica gel column chromatography (eluted with acetone: hexane = 1: 3, then 3: 2). Crystallization from acetone-diisopropyl ether and recrystallization from acetone-diisopropyl ether gave the title compound (1.11 g) as a colorless solid.
¹ H-NMR (CDCl ₃ ): 1.10-1.55 (5H, m), 1.55-1.82 (3H, m), 1.84-1.98 (2H, m), 2. 23 (3H, s), 2.27-1.40 (1H, m), 3.08 (3H, bs), 3.40-4.30 (2H, br), 4.30-4.50 ( 4H, m), 4.80-5.15 (2H, br), 6.64 (1H, d, J = 5.4 Hz), 7.35-7.48 (3H, m), 7.84 ( 1H, d, J = 6.9 Hz), 8.34 (1H, d, J = 5.4 Hz).

Synthesis Example 4
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl benzoate To a solution of bis (trichloromethyl) carbonate (0.50 g) in tetrahydrofuran (30 mL) was added dropwise a solution of pyridine (0.40 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 1 hour under ice cooling, 2- (methylamino) ethyl benzoate hydrochloride (1.08 g) obtained in Reference Example 5 was added. A solution of triethylamine (0.70 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.11 g), triethylamine (0. 84 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by flash silica gel column chromatography (eluted with acetone: hexane = 1: 3, then 3: 2). Crystallization from acetone-diethyl ether and recrystallization from acetone-diethyl ether gave the title compound (1.09 g) as a colorless solid.
_{^{1 H-NMR (CDCl 3)}} : 2.22 (3H, s), 3.12 (3H, bs), 3.50-4.30 (2H, br), 4.37 (2H, q, J = 7.8 Hz), 4.68 (2H, m), 4.80-5.20 (2H, br), 6.63 (1H, d, J = 5.7 Hz), 7.26-7.48 ( 5H, m), 7.53-7.61 (1H, m), 7.82 (1H, d, J = 8.1 Hz), 8.04 (2H, d, J = 7.2 Hz), 8. 33 (1H, d, J = 5.7 Hz).

Synthesis Example 5
2- [methyl [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] amino Ethyl benzoate To a solution of bis (trichloromethyl) carbonate (0.99 g) in tetrahydrofuran (30 mL) was added dropwise a solution of pyridine (0.81 mL) in tetrahydrofuran (2 mL) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2- (methylamino) ethyl benzoate hydrochloride (2.16 g) obtained in Reference Example 5 was added. After addition of a tetrahydrofuran solution (2 mL) of triethylamine (1.39 mL), the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, ethyl acetate (100 mL) and water (100 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, washed with saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (40 mL). 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (2.90 g), triethylamine (2.20 mL), 4 -Dimethylaminopyridine (0.096 g) was added, and the mixture was stirred at 60 ° C for 2 hours. After concentration under reduced pressure, ethyl acetate (150 mL) and water (80 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, washed with saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1, followed by ethyl acetate). Recrystallization from acetone gave the title compound (2.62 g) as a colorless solid.
¹ H-NMR (CDCl ₃ ): 2.22 (3H, s), 3.13 (3H, bs), 3.68-3.98 (2H, bm), 4.38 (2H, q, J = (7.8 Hz), 4.69 (2H, m), 4.80-5.10 (2H, bm), 6.64 (1H, d, J = 5.7 Hz), 7.27-7.48 ( 5H, m), 7.59 (1H, m), 7.83 (1H, m), 8.06 (2H, d, J = 6.0 Hz), 8.35 (1H, d, J = 5. 7 Hz).

Synthesis Example 6
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 4-methoxybenzoate To a tetrahydrofuran solution (18 mL) of bis (trichloromethyl) carbonate (0.584 g) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 40 minutes under ice cooling, 2- (methylamino) ethyl 4-methoxybenzoate hydrochloride (1.48 g) obtained in Reference Example 6 was added. After addition of a solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL), the mixture was stirred at room temperature for 80 minutes. After concentration under reduced pressure, ethyl acetate (80 mL) and water (50 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, washed with saturated saline (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (25 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.55 g), triethylamine (1. 17 mL) and 4-dimethylaminopyridine (0.051 g) were added, and the mixture was stirred at 60 ° C for 3 hours. After concentration under reduced pressure, ethyl acetate (150 mL) and water (50 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, washed with saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1, followed by ethyl acetate). The title compound (1.08 g) was obtained as a colorless solid by recrystallizing from ethyl acetate-hexane.
_{^{1 H-NMR (CDCl 3)}} : 2.22 (3H, s), 3.11 (3H, bs), 3.68-3.90 (2H, bm), 3.85 (3H, s), 4 .37 (2H, q, J = 7.9 Hz), 4.58-4.72 (2H, m), 4.82-5.14 (2H, bm), 6.63 (1H, d, J = 5.7 Hz), 6.91 (2H, d, J = 9.0 Hz), 7.27-7.40 (3H, m), 7.82 (1H, m), 7.99 (2H, d, J = 9.0 Hz), 8.33 (1H, d, J = 5.7 Hz).

Synthesis Example 7
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 3-chlorobenzoate To a tetrahydrofuran solution (20 mL) of bis (trichloromethyl) carbonate (0.582 g) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2- (methylamino) ethyl 3-chlorobenzoate hydrochloride (1.50 g) obtained in Reference Example 7 was added. After addition of a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, ethyl acetate (80 mL) and water (40 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, washed with saturated saline (25 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.44 g), triethylamine (1. 09 mL) and 4-dimethylaminopyridine (0.048 g) were added, and the mixture was stirred at 60 ° C for 3 hours. After concentration under reduced pressure, ethyl acetate (80 mL) and water (40 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, washed with saturated saline (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1) to give the title compound (0.84 g) as a colorless syrup.
_{^{1 H-NMR (CDCl 3)}} : 2.21 (3H, s), 3.12 (3H, bs), 3.78-4.08 (2H, bm), 4.38 (2H, q, J = 7.8 Hz), 4.64-5.08 (4H, bm), 6.64 (1H, d, J = 5.2 Hz), 7.34-7.42 (4H, m), 7.56 ( 1H, m), 7.82 (1H, m), 7.94 (1H, d, J = 7.6 Hz), 8.02 (1H, s), 8.34 (1H, d, J = 5. 2 Hz).

Synthesis Example 8
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 3,4-difluorobenzoate To a solution of bis (trichloromethyl) carbonate (0.582 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2- (methylamino) ethyl 3,4-difluorobenzoate hydrochloride (1.51 g) obtained in Reference Example 8 was added. After addition of a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, ethyl acetate (80 mL) and water (50 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, washed with saturated saline (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (25 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.71 g), triethylamine (1. 29 mL) and 4-dimethylaminopyridine (0.056 g) were added, and the mixture was stirred at 60 ° C for 17 hours. After concentration under reduced pressure, ethyl acetate (100 mL) and water (50 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate (20 mL). The ethyl acetate layers were combined, washed with saturated saline (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1, then 2: 1), and further basic silica gel column chromatography (ethyl acetate: hexane = 1: 1). (Elution). Crystallization from acetone-diisopropyl ether and recrystallization from ethyl acetate-hexane gave the title compound (1.37 g) as a colorless solid.
_{^{1 H-NMR (CDCl 3)}} : 2.21 (3H, s), 3.11 (3H, bs), 3.82-4.08 (2H, bm), 4.38 (2H, q, J = (7.8 Hz), 4.60-5.14 (4H, bm), 6.63 (1H, d, J = 5.7 Hz), 7.20 (1H, m), 7.33-7.41 ( 3H, m), 7.78-7.92 (3H, m), 8.33 (1H, d, J = 5.7 Hz).

Synthesis Example 9
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 4-trifluoromethoxybenzoate To a solution of bis (trichloromethyl) carbonate (0.582 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2- (methylamino) ethyl 4-trifluoromethoxybenzoate hydrochloride (1.79 g) obtained in Reference Example 9 was added. After addition of a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 1.5 hours. After concentration under reduced pressure, ethyl acetate (80 mL) and water (50 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, washed with saturated saline (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (25 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.57 g), triethylamine (1. 18 mL) and 4-dimethylaminopyridine (0.052 g) were added, and the mixture was stirred at 60 ° C for 4.5 hours. After concentration under reduced pressure, ethyl acetate (100 mL) and water (50 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate (30 mL). The ethyl acetate layers were combined, washed with saturated saline (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue is purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1), and further purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1). Gave the title compound (1.44 g) as a colorless syrup.
_{^{1 H-NMR (CDCl 3)}} : 2.22 (3H, s), 3.11 (3H, bs), 3.85-4.05 (2H, bm), 4.38 (2H, q, J = 7.8 Hz), 4.60-5.12 (4H, bm), 6.64 (1H, d, J = 5.7 Hz), 7.24 (2H, d, J = 8.7 Hz), 7. 25-7.40 (3H, m), 7.82 (1H, d, J = 7.2 Hz), 8.09 (2H, d, J = 8.7 Hz), 8.33 (1H, d, J) = 5.7 Hz).

Synthesis Example 10
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 4-fluorobenzoate To a solution of bis (trichloromethyl) carbonate (0.582 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice cooling, 2- (methylamino) ethyl 4-fluorobenzoate hydrochloride (1.40 g) obtained in Reference Example 10 was added. After addition of a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, ethyl acetate (80 mL) and water (40 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, washed with saturated saline (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.32 g), triethylamine (1. 00 mL) and 4-dimethylaminopyridine (0.049 g) were added, and the mixture was stirred at 60 ° C for 14.5 hours. After concentration under reduced pressure, ethyl acetate (150 mL) and water (50 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, washed with saturated saline (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was crystallized from ethyl acetate: hexane = 1: 1 and collected by filtration. Subsequently, by recrystallization from acetone, the title compound (1.39 g) was obtained as a colorless solid.
_{^{1 H-NMR (CDCl 3)}} : 2.22 (3H, s), 3.12 (3H, bs), 3.78-4.20 (2H, bm), 4.38 (2H, q, J = 7.8 Hz), 4.58-5.08 (4H, bm), 6.65 (1H, d, J = 5.6 Hz), 7.11 (2H, t, J = 8.4 Hz), 7. 28-7.44 (3H, m), 7.81-7.86 (1H, m), 8.03-8.11 (2H, m), 8.35 (1H, d, J = 5.6 Hz) ).

Synthesis Example 11
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 3,4,5-trimethoxybenzoate To a tetrahydrofuran solution (30 mL) of bis (trichloromethyl) carbonate (0.60 g) was added a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice cooling. It was dropped. After stirring for 10 minutes under ice-cooling, 2- (methylamino) ethyl 3,4,5-trimethoxybenzoate hydrochloride (1.22 g) obtained in Reference Example 11 was added. After dropwise adding a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with dilute hydrochloric acid (20 mL) and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.11 g), triethylamine (0. 84 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60 ° C for 3 hours and at room temperature for 2 days. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by flash silica gel column chromatography (eluted with acetone: hexane = 1: 3, then 3: 2) to give the title compound (1.56 g) as a yellow amorphous solid. .
_{^{1 H-NMR (CDCl 3)}} : 2.21 (3H, s), 3.12 (3H, bs), 3.50-4.30 (2H, br), 3.83 (6H, s), 3 .90 (3H, s), 4.38 (2H, q, J = 7.8 Hz), 4.67 (2H, m), 4.80-5.15 (2H, br), 6.64 (1H) , D, J = 5.7 Hz), 7.25-7.40 (5H, m), 7.78-7.86 (1H, m), 8.33 (1H, d, J = 5.7 Hz) .

Synthesis Example 12
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 2-pyridinecarboxylate To a solution of bis (trichloromethyl) carbonate (0.422 g) in tetrahydrofuran (30 mL) was added dropwise pyridine (0.345 mL) under ice-cooling. After stirring under ice-cooling for 30 minutes, 2- (methylamino) ethyl 2-pyridinecarboxylate dihydrochloride (1.08 g) obtained in Reference Example 12 was added, and triethylamine (1.19 mL) was added dropwise. Stirred at room temperature for 2 hours. The precipitated solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL) and (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benz Imidazole (1.31 g), triethylamine (0.99 mL) and 4-dimethylaminopyridine (0.043 g) were added, and the mixture was stirred at 60 ° C for 24 hours. Ethyl acetate (100 mL) was added to the reaction solution, washed with water (100 mL) and saturated saline (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 4: 1). Crystallization from acetone-diethyl ether gave the title compound (0.9 g) as a white solid.
_{^{1 H-NMR (CDCl 3)}} : 2.22 (3H, s), 3.16 (3H, s), 3.80-4.20 (2H, m), 4.38 (2H, q, J = 7.8 Hz), 4.60-5.10 (4H, m), 6.64 (1H, d, J = 5.8 Hz), 7.29-7.40 (2H, m), 7.47- 7.52 (2H, m), 7.81-7.89 (2H, m), 8.14 (1H, d, J = 7.8 Hz), 8.34 (1H, d, J = 5.8 Hz) ), 8.75-8.79 (1H, m).

Synthesis Example 13
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl methoxyacetate To a solution of bis (trichloromethyl) carbonate (0.652 g) in tetrahydrofuran (15 mL) was added dropwise a solution of pyridine (0.55 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2- (methylamino) ethyl methoxyacetate (0.99 g) obtained in Reference Example 13 was added. Stirred at room temperature for 3 hours. After concentration under reduced pressure, ethyl acetate (80 mL) and water (50 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, washed with saturated saline (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (15 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.13 g), triethylamine (0. 86 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60 ° C for 4 days. After concentration under reduced pressure, ethyl acetate (80 mL) and water (30 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (30 mL) and water (30 mL), and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate, followed by acetone: ethyl acetate = 1: 3), and further basic silica gel column chromatography (ethyl acetate: hexane = 1: 1, followed by ethyl acetate: hexane = 1: 1). And eluted 3: 1) to give the title compound (0.588 g) as a colorless syrup.
_{^{1 H-NMR (CDCl 3)}} : 2.32 (3H, s), 2.68 (3H, s), 3.48 (3H, s), 3.69-4.02 (4H, m), 4 .38 (2H, q, J = 7.8 Hz), 4.67 (2H, t, J = 6.6 Hz), 4.99 (1H, d, J = 13.9 Hz), 5.12 (1H, d, J = 13.9 Hz), 6.63 (1H, d, J = 5.7 Hz), 7.29-7.46 (2H, m), 7.62 (1H, m), 7.81 ( 1H, m), 8.25 (1H, d, J = 5.7 Hz).

Synthesis Example 14
Ethyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Il] carbonyl] amino] ethyl carbonate To a solution of bis (trichloromethyl) carbonate (1.31 g) in tetrahydrofuran (40 mL) was added dropwise a solution of pyridine (1.07 mL) in tetrahydrofuran (2 mL) under ice-cooling. After stirring for 10 minutes under ice cooling, the ethyl 2- (methylamino) ethyl carbonate hydrochloride (2.02 g) obtained in Reference Example 14 was added. After dropwise adding a tetrahydrofuran solution (2 mL) of triethylamine (1.84 mL), the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with 0.2 N hydrochloric acid (50 mL) and saturated saline (100 mL), and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (50 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (3.69 g), triethylamine (2. 09 mL) and 4-dimethylaminopyridine (0.12 g) were added, and the mixture was stirred at 60 ° C for 6 hours and at room temperature for 8 hours. After concentration under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated saline (100 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 3: 7, followed by elution with ethyl acetate). Crystallization from diethyl ether and recrystallization from diethyl ether gave the title compound (3.84 g) as a colorless solid.
_{^{1 H-NMR (CDCl 3)}} : 1.32 (3H, t, J = 7.2Hz), 2.23 (3H, s), 3.10 (3H, bs), 3.50-4.20 ( 2H, br), 4.22 (2H, q, J = 7.2 Hz), 4.39 (2H, q, J = 7.9 Hz), 4.45 (2H, m), 4.80-5. 15 (2H, br), 6.65 (1H, d, J = 5.6 Hz), 7.36-7.50 (3H, m), 7.84 (1H, d, J = 7.8 Hz), 8.35 (1H, d, J = 5.6 Hz).

Synthesis Example 15
Isopropyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Il] carbonyl] amino] ethyl carbonate To a solution of bis (trichloromethyl) carbonate (0.50 g) in tetrahydrofuran (30 mL) was added dropwise a solution of pyridine (0.40 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 1 hour under ice cooling, the isopropyl 2- (methylamino) ethyl carbonate hydrochloride (0.99 g) obtained in Reference Example 15 was added. After a solution of triethylamine (0.70 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 1 hour. Bis (trichloromethyl) carbonate (0.50 g), a solution of pyridine (0.40 mL) in tetrahydrofuran (1 mL), and a solution of triethylamine (0.70 mL) in tetrahydrofuran (1 mL) were sequentially added, followed by stirring at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.11 g), triethylamine (0. 84 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60 ° C for 12 hours and at room temperature for 3 days. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by flash silica gel column chromatography (eluted with acetone: hexane = 1: 3, then 3: 2) and further basic silica gel column chromatography (ethyl acetate: hexane = 3: 7, (Eluted with ethyl acetate). Crystallization from diethyl ether and recrystallization from acetone-diisopropyl ether gave the title compound (0.58 g) as a colorless solid.
_{^{1 H-NMR (CDCl 3)}} : 1.31 (6H, d, J = 6.3Hz), 2.23 (3H, s), 3.08 (3H, bs), 3.40-4.30 ( 2H, br), 4.37 (2H, q, J = 7.9 Hz), 4.32-4.53 (2H, m), 4.80-5.20 (3H, m), 6.63 ( 1H, d, J = 5.7 Hz), 7.35-7.50 (3H, m), 7.83 (1H, d, J = 7.2 Hz), 8.34 (1H, d, J = 5) 0.7 Hz).

Synthesis Example 16
Isopropyl 2- [methyl [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] Amino] ethyl carbonate To a solution of bis (trichloromethyl) carbonate (0.582 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring under ice-cooling for 30 minutes, isopropyl 2- (methylamino) ethyl carbonate hydrochloride (1.18 g) obtained in Reference Example 15 was added. After addition of a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, ethyl acetate (80 mL) and water (30 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, washed with saturated saline (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (25 mL). 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.73 g), triethylamine (1.31 mL), -Dimethylaminopyridine (0.057 g) was added, and the mixture was stirred at 60 ° C for 5 hours. After concentration under reduced pressure, ethyl acetate (100 mL) and water (50 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, washed with saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1), and further purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1, then 2: 1). (Elution). Crystallization from diisopropyl ether-hexane and recrystallization from diisopropyl ether gave the title compound (1.20 g) as a colorless solid.
_{^{1 H-NMR (CDCl 3)}} : 1.31 (6H, d, J = 6.6Hz), 2.23 (3H, s), 3.08 (3H, bs), 3.50-3.90 ( 2H, bm), 4.38 (2H, q, J = 7.8 Hz), 4.36-4.58 (2H, bm), 4.79-5.15 (3H, m), 6.64 ( 1H, d, J = 5.7 Hz), 7.35-7.48 (3H, m), 7.83 (1H, d, J = 7.5 Hz), 8.34 (1H, d, J = 5) 0.7 Hz).

Synthesis Example 17
Benzyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Il] carbonyl] amino] ethyl carbonate To a solution of bis (trichloromethyl) carbonate (0.50 g) in tetrahydrofuran (30 mL) was added dropwise a solution of pyridine (0.40 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 1 hour under ice cooling, the benzyl 2- (methylamino) ethyl carbonate hydrochloride (1.08 g) obtained in Reference Example 16 was added. A solution of triethylamine (0.70 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.11 g), triethylamine (0. 84 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by flash silica gel column chromatography (eluted with acetone: hexane = 1: 3, then 3: 2). Crystallization from acetone-diethyl ether and recrystallization from acetone-diethyl ether gave the title compound (1.17 g) as a colorless solid.
_{^{1 H-NMR (CDCl 3)}} : 2.22 (3H, s), 3.05 (3H, bs), 3.50-4.20 (2H, br), 4.37 (2H, q, J = 7.8 Hz), 4.46 (2H, m), 4.80-5.10 (2H, br), 5.17 (2H, s), 6.62 (1H, d, J = 5.6 Hz) , 7.26-7.48 (8H, m), 7.77-7.88 (1H, m), 8.33 (1H, d, J = 5.6 Hz).

Synthesis Example 18
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl tetrahydropyran-4-yl carbonate To a solution of bis (trichloromethyl) carbonate (0.48 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.39 mL) in tetrahydrofuran (1 mL) under ice-cooling. . After stirring for 20 minutes under ice cooling, 2- (methylamino) ethyl tetrahydropyran-4-yl carbonate hydrochloride (0.96 g) obtained in Reference Example 17 was added. After a solution of triethylamine (0.67 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.26 g), triethylamine (0. 71 mL) and 4-dimethylaminopyridine (0.042 g) were added, and the mixture was stirred at 60 ° C for 6 hours and at room temperature for 8 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 3: 7, followed by elution with ethyl acetate). Crystallization from diethyl ether and recrystallization from acetone-diisopropyl ether gave the title compound (1.45 g) as a colorless solid.
_{^{1 H-NMR (CDCl 3)}} : 1.64-1.81 (2H, m), 1.92-2.03 (2H, m), 2.23 (3H, s), 3.09 (3H, bs), 3.40-4.30 (2H, br), 3.45-3.57 (2H, m), 3.87-3.97 (2H, m), 4.38 (2H, q, J = 7.8 Hz), 4.45 (2H, m), 4.77-5.15 (3H, m), 6.64 (1H, d, J = 5.7 Hz), 7.35-7. 50 (3H, m), 7.83 (1H, d, J = 6.9 Hz), 8.35 (1H, d, J = 5.7 Hz).

Synthesis Example 19
2-methoxyethyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole -1-yl] carbonyl] amino] ethyl carbonate To a solution of bis (trichloromethyl) carbonate (0.59 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 10 minutes under ice cooling, the 2-methoxyethyl 2- (methylamino) ethyl carbonate hydrochloride (1.07 g) obtained in Reference Example 18 was added. After dropwise adding a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.85 g), triethylamine (1. 05 mL) and 4-dimethylaminopyridine (0.061 g) were added, and the mixture was stirred at 60 ° C for 6 hours and at room temperature for 8 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 3: 7, followed by elution with ethyl acetate). Crystallization from ethyl acetate-diethyl ether and recrystallization from ethyl acetate-diisopropyl ether gave the title compound (1.39 g) as a colorless solid.
¹ H-NMR (CDCl ₃ ): 2.23 (3H, s), 3.09 (3H, bs), 3.37 (3H, s), 3.50-4.20 (2H, br), 3 .59-3.65 (2H, m), 4.28-4.33 (2H, m), 4.38 (2H, q, J = 7.8 Hz), 4.46 (2H, m), 4 .80-5.15 (2H, br), 6.64 (1H, d, J = 5.7 Hz), 7.35-7.47 (3H, m), 7.83 (1H, d, J = 7.8 Hz), 8.34 (1 H, d, J = 5.7 Hz).

Synthesis Example 20
2- [ethyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl acetate To a solution of bis (trichloromethyl) carbonate (0.59 g) in tetrahydrofuran (30 mL) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 10 minutes under ice cooling, 2- (ethylamino) ethyl acetate hydrochloride (0.67 g) obtained in Reference Example 20 was added. After dropwise adding a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.11 g), triethylamine (0. 84 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 3: 7, followed by elution with ethyl acetate) to obtain the title compound (1.58 g) as a yellow amorphous solid. Was.
_{^{1 H-NMR (CDCl 3)}} : 1.25 (3H, m), 2.08 (3H, s), 2.23 (3H, s), 3.30-4.10 (4H, br), 4 .23-4.45 (2H, m), 4.38 (2H, q, J = 7.8 Hz), 4.75-5.20 (2H, br), 6.64 (1H, d, J = 5.7 Hz), 7.35-7.46 (3H, m), 7.84 (1H, d, J = 6.9 Hz), 8.36 (1H, d, J = 5.7 Hz).

Synthesis Example 21
2- [isopropyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl acetate To a solution of bis (trichloromethyl) carbonate carbonate (0.543 g) in tetrahydrofuran (10 mL) was added dropwise a solution of pyridine (0.445 mL) in tetrahydrofuran (5 mL) under ice-cooling, and the mixture was stirred at 0 ° C for 30 minutes. Stirred. To the reaction solution was added 2- (isopropylamino) ethyl acetate hydrochloride (1.0 g) obtained in Reference Example 22. After addition of a solution of triethylamine (0.805 mL) in tetrahydrofuran (5 mL), the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was dissolved in tetrahydrofuran (5 mL), and (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl]- The solution was added to a solution of 1H-benzimidazole (1.73 g), triethylamine (1.53 mL), and 4-dimethylaminopyridine (0.134 g) in tetrahydrofuran (20 mL), and the mixture was stirred at 40 ° C for 12 hours. After the reaction solution was concentrated under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 2: 1, followed by ethyl acetate) to give the title compound (1.50 g) as a pale-yellow amorphous solid.
¹ H-NMR (CDCl ₃ ): 1.20-1.40 (6H, m), 2.05 (3H × 0.4, s), 2.11 (3H × 0.6, s), 2. 18 (3H × 0.6, s), 2.27 (3H × 0.4, s), 3.40-3.60 (1H, m), 3.70-4.60 (6H, m), 4.70-5.25 (2H, m), 6.65 (1H, d, J = 5.8 Hz), 7.30-7.50 (3H, m), 7.75-7.90 (1H , M), 8.37 (1H, d, J = 5.8 Hz).

Synthesis Example 22
Ethyl 2- [isopropyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Yl] carbonyl] amino] ethyl carbonate To a solution of bis (trichloromethyl) carbonate (0.467 g) in tetrahydrofuran (10 mL) was added dropwise a solution of pyridine (0.381 mL) in tetrahydrofuran (5 mL) under ice-cooling. Stirred for minutes. The ethyl 2- (isopropylamino) ethyl carbonate hydrochloride (1.0 g) obtained in Reference Example 23 was added to the reaction solution. After addition of a solution of triethylamine (0.69 mL) in tetrahydrofuran (5 mL), the mixture was stirred at 0 ° C. for 15 minutes and at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was dissolved in tetrahydrofuran (5 mL), and (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl]- 1H-benzimidazole (1.48 g), triethylamine (1.32 mL), and a solution of 4-dimethylaminopyridine (0.115 g) in tetrahydrofuran (20 mL) were added, and the mixture was stirred at 40 ° C for 12 hours. After the reaction solution was concentrated under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 2: 1, followed by ethyl acetate) to give the title compound (1.20 g) as a pale-yellow amorphous solid.
¹ H-NMR (CDCl ₃ ): 1.20-1.40 (9H, m), 2.17 (3H × 0.6, s), 2.27 (3H × 0.4, s), 3. 40-3.70 (1H, m), 3.75-4.65 (8H, m), 4.70-5.30 (2H, m), 6.64 (1H, d, J = 5.8 Hz) ), 7.35-7.55 (3H, m), 7.75-7.90 (1H, m), 8.38 (1H, d, J = 5.8 Hz).

Synthesis Example 23
2- [cyclohexyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl [Carbonyl] amino] ethyl acetate Pyridine (0.485 mL) was added dropwise to a solution of bis (trichloromethyl) carbonate (0.593 g) in tetrahydrofuran (10 mL) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2- (cyclohexylamino) ethyl acetate hydrochloride (1.33 g) obtained in Reference Example 25 was added. After dropwise addition of triethylamine (0.84 mL), the mixture was stirred at room temperature for 2 hours. Ethyl acetate (50 mL) was added to the reaction solution, washed with water (50 mL) and saturated saline (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL) and (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benz Imidazole (1.61 g), triethylamine (1.21 mL) and 4-dimethylaminopyridine (0.053 g) were added, and the mixture was stirred at 60 ° C for 24 hours. Ethyl acetate (50 mL) was added to the reaction solution, washed with water (20 mL) and saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 4, followed by ethyl acetate) to give the title compound (2.12 g) as a pale-yellow amorphous solid.
_{^{1 H-NMR (CDCl 3)}} : 1.00-2.42 (16H, m), 3.30-3.70 (2H, m), 3.80-4.00 (1H, m), 4. 27-4.42 (2H, m), 4.40 (2H, q, J = 8.2 Hz), 4.78 (1H × 0.5, d, J = 13.2 Hz), 4.97 (2H, m) × 0.5, s), 5.20 (1H × 0.5, d, J = 13.2 Hz), 6.67 (1H, d, J = 5.8 Hz), 7.36-7.46 ( 3H, m), 7.81-7.91 (1H, m), 8.39 (1H, d, J = 5.8 Hz).

Synthesis Example 24
2- [cyclohexyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl Pyridine (0.20 mL) was added dropwise to a tetrahydrofuran solution (10 mL) of bis (trichloromethyl) carbonate (0.238 g) under ice-cooling. After stirring for 30 minutes under ice cooling, 2- (cyclohexylamino) ethyl ethyl carbonate hydrochloride (0.605 g) obtained in Reference Example 26 was added. After dropwise addition of triethylamine (0.335 mL), the mixture was stirred at room temperature for 2 hours. Ethyl acetate (50 mL) was added to the reaction solution, washed with water (50 mL) and saturated saline (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL) and (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benz Imidazole (0.60 g), triethylamine (0.45 mL) and 4-dimethylaminopyridine (0.02 g) were added, and the mixture was stirred at 60 ° C for 24 hours. Ethyl acetate (50 mL) was added to the reaction solution, washed with water (20 mL) and saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate: hexane = 1: 4, followed by elution with ethyl acetate) to give the title compound (0.92 g) as a pale yellow amorphous solid.
¹ H-NMR (CDCl ₃ ): 1.02-2.27 (16H, m), 3.40-4.60 (9H, m), 4.78 (1H × 0.5, d, J = 13) .2 Hz), 4.97 (2H × 0.5, s), 5.44 (1H × 0.5, d, J = 13.2 Hz), 6.69 (1H, d, J = 5.6 Hz) , 7.32-7.54 (3H, m), 7.80-7.91 (1H, m), 8.38 (1H, d, J = 5.6 Hz).

Synthesis Example 25
2-[[[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] Carbonyl] (phenyl) amino] ethyl acetate Pyridine (10.38 mL) was added dropwise to a solution of bis (trichloromethyl) carbonate (13.4 g) in tetrahydrofuran (350 mL) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-anilinoethyl acetate hydrochloride (25.9 g) obtained in Reference Example 27 was added. After dropwise addition of triethylamine (18.4 mL), the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, ethyl acetate (500 mL) and water (500 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated, washed with saturated saline (500 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2-[(chlorocarbonyl) (phenyl) amino] ethyl acetate. This was dissolved in tetrahydrofuran (300 mL) to give (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole. (41.2 g), triethylamine (15.6 mL) and 4-dimethylaminopyridine (1.363 g) were added, and the mixture was stirred at 60 ° C for 3 hours. Ethyl acetate (800 mL) was added to the reaction solution, and the mixture was washed twice with water (800 mL) and further with saturated brine (800 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 3: 7, then 1: 1). Crystallization from diethyl ether gave the title compound (54.1 g) as a white solid.
¹ H-NMR (CDCl ₃ ): 2.00 (3H, s), 2.25 (3H, s), 4.15-4.48 (6H, m), 4.83 (1H, d, J = 13.6 Hz), 5.05 (1H, d, J = 13.6 Hz), 6.67 (1H, d, J = 5.4 Hz), 7.03-7.45 (8H, m), 7.0. 64-7.69 (1H, m), 8.40 (1H, d, J = 5.4 Hz).

Synthesis Example 26
2-[[[2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (phenyl ) Amino] ethyl acetate In a tetrahydrofuran solution (10 mL) of 2-[(chlorocarbonyl) (phenyl) amino] ethyl acetate (0.58 g) prepared in the same manner as in Synthesis Example 25, 2-[[[3-methyl- 4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (0.739 g), triethylamine (0.558 mL) and 4-dimethylaminopyridine (0.024 g) Was added and stirred at 60 ° C. for 15 hours. Ethyl acetate (30 mL) was added to the reaction solution, washed with water (50 mL) and saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluted with acetone: hexane = 1: 4, then 3: 2). Crystallization from diethyl ether gave the title compound (0.779 g) as a white solid.
_{^{1 H-NMR (CDCl 3)}} : 1.99 (3H, s), 2.25 (3H, s), 4.20-4.48 (6H, m), 4.83 (1H, d, J = 13.6 Hz), 5.05 (1H, d, J = 13.6 Hz), 6.67 (1H, d, J = 5.8 Hz), 7.03-7.45 (8H, m), 7.0. 64-7.69 (1H, m), 8.40 (1H, d, J = 5.8 Hz).

Synthesis Example 27
tert-butyl [2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole -1-yl] carbonyl] amino] -3-pyridyl] methyl carbonate Pyridine (0.24 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis (trichloromethyl) carbonate (0.30 g) under ice-cooling. After stirring for 30 minutes under ice cooling, tert-butyl [2- (methylamino) -3-pyridyl] methyl carbonate (0.71 g) obtained in Reference Example 28 was added, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL) and (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benz Imidazole (0.92 g), triethylamine (0.70 mL) and 4-dimethylaminopyridine (0.031 g) were added, and the mixture was stirred at 60 ° C for 1 hour. Water (50 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluted with acetone: hexane = 1: 2), and further purified by basic silica gel column chromatography (eluted with ethyl acetate) to give the title compound (0.38 g). Obtained as a pale yellow amorphous solid.
_{^{1 H-NMR (CDCl 3)}} : 1.46 (9H, s), 2.25 (3H, s), 3.54 (3H, s), 4.37 (2H, q, J = 8.0Hz) , 4.95 (2H, s), 5.15 (1H, d, J = 14.0 Hz), 5.27 (1H, d, J = 14.0 Hz), 6.63 (1H, d, J = 5.4 Hz), 7.26-7.45 (3H, m), 7.69-7.87 (3H, m), 8.33 (1H, d, J = 5.4 Hz), 8.44- 8.46 (1H, m).

Synthesis Example 28
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl [Carbonyl] amino] benzyl acetate To a solution of bis (trichloromethyl) carbonate carbonate (1.46 g) in tetrahydrofuran (30 mL) was added dropwise pyridine (1.16 mL) under ice-cooling. After stirring for 30 minutes under ice cooling, 2- (methylamino) benzyl acetate (2.57 g) obtained in Reference Example 29 was added, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 mL) and (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benz Imidazole (4.41 g), triethylamine (3.33 mL) and 4-dimethylaminopyridine (0.15 g) were added, and the mixture was stirred at 60 ° C for 18 hours. Water (100 mL) was added to the reaction solution, and extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluted with acetone: hexane = 1: 4, then 1: 2). Crystallization from ethyl acetate-diethyl ether-hexane gave the title compound (2.76 g) as a white solid.
_{^{1 H-NMR (CDCl 3)}} : 2.10 (3H, s), 2.00-2.30 (3H, br), 3.20-3.50 (3H, br), 4.38 (2H, q, J = 7.6 Hz), 4.70-5.20 (2H, m), 5.20-5.50 (2H, m), 6.65 (1H, d, J = 5.4 Hz), 7.10-7.82 (8H, m), 8.38 (1H, d, J = 5.4 Hz).

Synthesis Example 29
2-[[2- (acetyloxy) ethyl] [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl]- 1H-benzimidazol-1-yl] carbonyl] amino] ethyl acetate A solution of pyridine (0.40 mL) in tetrahydrofuran (1 mL) was added to a solution of bis (trichloromethyl) carbonate (0.50 g) in tetrahydrofuran (30 mL) under ice-cooling. It was dropped. After stirring for 10 minutes under ice cooling, 2-[(2-acetyloxyethyl) amino] ethyl acetate hydrochloride (1.13 g) obtained in Reference Example 30 was added. After a solution of triethylamine (0.70 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 2 hours. The precipitated solid was separated by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (20 mL) was added to the residue, the precipitated solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.48 g), triethylamine (1. 12 mL) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1, then eluted with ethyl acetate), and further basic silica gel column chromatography (ethyl acetate: hexane = 1: 1, followed by ethyl acetate: hexane = 1: 1). And eluted with ethyl acetate). It was dissolved in ethyl acetate (20 mL), activated carbon was added, and the mixture was stirred overnight. The activated carbon was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.60 g) as a yellow amorphous solid.
_{^{1 H-NMR (CDCl 3)}} : 2.06 (3H, s), 2.08 (3H, s), 2.24 (3H, s), 3.40-4.45 (8H, m), 4 .39 (2H, q, J = 7.9 Hz), 4.88 (1H, d, J = 13.2 Hz), 5.05 (1H, d, J = 13.2 Hz), 6.66 (1H, d, J = 5.6 Hz), 7.38-7.50 (3H, m), 7.87 (1H, d, J = 6.9 Hz), 8.36 (1H, d, J = 5.6 Hz) ).

Synthesis Example 30
[(2S) -1-[[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole- 1-yl] carbonyl] -2-pyrrolidinyl] methyl acetate To a solution of bis (trichloromethyl) carbonate (0.50 g) in tetrahydrofuran (30 mL) was added dropwise a solution of pyridine (0.40 mL) in tetrahydrofuran (1 mL) under ice-cooling. . After stirring for 1 hour under ice cooling, (S) -2-pyrrolidinylmethyl acetate hydrochloride (0.90 g) obtained in Reference Example 31 was added. After a solution of triethylamine (0.70 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, extracted with ethyl acetate (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.11 g), triethylamine (0. 84 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60 ° C for 1 day and at room temperature for 2 days. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1, followed by ethyl acetate), and further purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1, followed by ethyl acetate: hexane = 3: 1). The residue was purified with ethyl acetate, followed by acetone: ethyl acetate = 1: 4, then 2: 3) to give the title compound (0.80 g) as a pale yellow amorphous solid.
¹ H-NMR (CDCl ₃ ): 1.80-2.30 (4H, m), 2.09 (3H, s), 2.30 (3H, s), 3.39 (1H, m), 3 .50-3.62 (1H, m), 4.20-4.45 (4H, m), 4.58 (1H, m), 4.89 (1H, d, J = 13.5 Hz), 4 .96 (1H, d, J = 13.5 Hz), 6.65 (1H, d, J = 5.9 Hz), 7.36-7.48 (3H, m), 7.89 (1H, d, J = 8.7 Hz), 8.38 (1H, d, J = 5.9 Hz).

Synthesis Example 31
Ethyl [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] Carbonyl] amino] acetate To a solution of bis (trichloromethyl) carbonate (0.50 g) in tetrahydrofuran (30 mL) was added dropwise a solution of pyridine (0.40 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice cooling, sarcosine ethyl ester hydrochloride (0.77 g) was added. After a solution of triethylamine (0.70 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 1 hour. The precipitated solid was separated by filtration, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue, and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (33 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole sodium salt (1.37 g), 4- Dimethylaminopyridine (catalytic amount) was added and stirred at 60 ° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1, followed by ethyl acetate) to obtain the title compound (0.40 g) as a yellow amorphous solid. Was.
¹ H-NMR (CDCl ₃ ): 1.33 (3H, t, J = 7.1 Hz), 2.24 (3H, s), 3.10 (3H, bs), 3.70-4.30 ( 5. 2H, br), 4.28 (2H, q, J = 7.1 Hz), 4.38 (2H, q, J = 7.8 Hz), 4.82-5.10 (2H, br), 6. 63 (1H, d, J = 5.5 Hz), 7.34-7.52 (2H, m), 7.70-7.90 (2H, m), 8.32 (1H, d, J = 5) .5 Hz).

Synthesis Example 32
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (methyl) amino] ethyl Benzoate A solution of pyridine (0.281 mL) in tetrahydrofuran (5 mL) was added dropwise to a solution of bis (trichloromethyl) carbonate (0.344 g) in tetrahydrofuran (10 mL) under ice cooling, followed by stirring at 0 ° C. for 30 minutes. To the reaction solution, 2- (methylamino) ethyl benzoate hydrochloride (0.750 g) obtained in Reference Example 5 was added. After adding a tetrahydrofuran solution (5 mL) of triethylamine (0.485 mL), the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was dissolved in tetrahydrofuran (5 mL), and 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (1.0 g) ), Triethylamine (0.808 mL) and a solution of 4-dimethylaminopyridine (0.071 g) in tetrahydrofuran (10 mL), and the mixture was stirred at 40 ° C for 18 hours. After the reaction solution was concentrated under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1, followed by ethyl acetate) to give the title compound and 2-[[[6-methoxy-2-[[(4-methoxy-3 , 5-Dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (methyl) amino] ethyl benzoate (1.50 g) as a pale yellow amorphous solid. Was.
_{^{1 H-NMR (CDCl 3)}} : 2.05-2.35 (6H, m), 3.00-3.30 (3H, br), 3.60-4.40 (8H, m), 4. 60-5.10 (4H, m), 6.80-7.00 (2H, m), 7.20-7.70 (4H, m), 7.95-8.25 (3H, m).

Synthesis Example 33
3- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] propyl benzoate To a solution of bis (trichloromethyl) carbonate (0.582 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.485 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 1 hour under ice cooling, 3- (methylamino) propyl benzoate hydrochloride (1.38 g) obtained in Reference Example 32 was added. After a solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, water (40 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with brine (25 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.63 g), triethylamine (1. 23 mL) and 4-dimethylaminopyridine (0.054 g) were added, and the mixture was stirred at 60 ° C for 4 hours. After concentration under reduced pressure, water (40 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1) to give the title compound (1.26 g) as a yellow amorphous solid. Obtained.
_{^{1 H-NMR (CDCl 3)}} : 2.21 (3H, s), 2.20-2.30 (2H, bm), 3.06 (3H, bs), 3.60-3.75 (2H, bm), 4.36 (2H, q, J = 7.8 Hz), 4.30-4.50 (2H, bm), 4.80-5.15 (2H, bm), 6.62 (1H, d, J = 5.7 Hz), 7.26-7.44 (5H, m), 7.54 (1H, m), 7.81 (1H, m), 7.93-8.03 (2H, bm), 8.35 (1H, d, J = 5.7 Hz).

Synthesis Example 34
2- [methyl [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] amino Ethyl tetrahydropyran-4-yl carbonate To a solution of bis (trichloromethyl) carbonate (0.582 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.485 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 20 minutes under ice cooling, 2- (methylamino) ethyl tetrahydropyran-4-yl carbonate hydrochloride (1.43 g) obtained in Reference Example 17 was added. A solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated saline (20 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.63 g), triethylamine (1.23 mL), 4 -Dimethylaminopyridine (0.027 g) was added, and the mixture was stirred at 60 ° C for 17.5 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (120 mL). The ethyl acetate layer was washed with brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1). Subsequently, purification was performed by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1, then 2: 1). The title compound (1.23 g) was obtained as a colorless solid by crystallization from diethyl ether.
_{^{1 H-NMR (CDCl 3)}} : 1.64-1.81 (2H, m), 1.92-2.03 (2H, m), 2.23 (3H, s), 3.10 (3H, bs), 3.40-4.30 (2H, br), 3.46-3.59 (2H, m), 3.87-3.99 (2H, m), 4.39 (2H, q, J = 7.9 Hz), 4.45 (2H, m), 4.77-5.15 (3H, m), 6.65 (1H, d, J = 5.4 Hz), 7.35-7. 50 (3H, m), 7.85 (1H, m), 8.36 (1H, d, J = 5.4 Hz).

Synthesis Example 35
Ethyl 2- [methyl [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] Amino] ethyl carbonate To a tetrahydrofuran solution (20 mL) of bis (trichloromethyl) carbonate (0.582 g) was added dropwise a solution of pyridine (0.485 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice cooling, the ethyl 2- (methylamino) ethyl carbonate hydrochloride (1.10 g) obtained in Reference Example 14 was added. A solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.63 g), triethylamine (1.23 mL), 4 -Dimethylaminopyridine (0.054 g) was added, and the mixture was stirred at 60 ° C for 14 hours. After concentration under reduced pressure, water (40 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1). Subsequently, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1, then 2: 1) to give the title compound (1.27 g) as a yellow amorphous solid.
_{^{1 H-NMR (CDCl 3)}} : 1.32 (3H, t, J = 7.1Hz), 2.23 (3H, s), 3.09 (3H, bs), 3.50-4.76 ( 4.H (4H, br), 4.21 (2H, q, J = 7.1 Hz), 4.38 (2H, q, J = 7.9 Hz), 4.84-5.14 (2H, m), 6. 64 (1H, d, J = 5.6 Hz), 7.36-7.46 (3H, m), 7.83 (1H, d, J = 7.2 Hz), 8.34 (1H, d, J) = 5.6 Hz).

Synthesis Example 36
Ethyl 2- [methyl [[(S) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Il] carbonyl] amino] ethyl carbonate To a solution of bis (trichloromethyl) carbonate (0.582 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.485 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 1 hour under ice cooling, the ethyl 2- (methylamino) ethyl carbonate hydrochloride (1.10 g) obtained in Reference Example 14 was added. After a solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (S) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.15 g), triethylamine (0. 87 mL) and 4-dimethylaminopyridine (0.035 g) were added, and the mixture was stirred at 60 ° C for 12 hours. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1). Crystallization from diethyl ether gave the title compound (0.40 g) as a colorless solid.
¹ H-NMR (CDCl ₃ ): 1.32 (3H, t, J = 7.2 Hz), 2.23 (3H, s), 3.10 (3H, bs), 3.50-4.56 ( 4.H (4H, br), 4.22 (2H, q, J = 7.2 Hz), 4.38 (2H, q, J = 7.9 Hz), 4.84-5.14 (2H, m), 6. 65 (1H, d, J = 5.6 Hz), 7.34-7.50 (3H, m), 7.85 (1H, m), 8.36 (1H, d, J = 5.6 Hz).

Synthesis Example 37
Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -3H-imidazo [4,5-b] pyridin-3-yl] Carbonyl] (methyl) amino] ethyl carbonate To a solution of bis (trichloromethyl) carbonate (0.582 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.485 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice cooling, the ethyl 2- (methylamino) ethyl carbonate hydrochloride (1.10 g) obtained in Reference Example 14 was added. A solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature for 2.5 hours. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-imidazo [4,5-b synthesized by the method described in JP-A-63-146882. Pyridine (1.44 g), triethylamine (1.16 mL) and 4-dimethylaminopyridine (0.049 g) were added, and the mixture was stirred at 60 ° C for 6 hours. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1). Crystallization from diethyl ether gave the title compound (0.721 g) as a colorless solid.
_{^{1 H-NMR (CDCl 3)}} : 1.25-1.34 (3H, m), 2.23 (6H, s), 3.15,3.32 ( total 3H, s), 3.72 (3H , S), 3.90-4.53 (9H, m), 4.86 (1H, d, J = 13.4 Hz), 4.95 (1H, d, J = 13.4 Hz), 6.79. (1H, d, J = 8.7 Hz), 7.95 (1H, d, J = 8.7 Hz), 8.22 (1H, s).

Synthesis Example 38
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -3H-imidazo [4,5-b] pyridin-3-yl] carbonyl ] (Methyl) amino] ethyl acetate To a tetrahydrofuran solution (20 mL) of bis (trichloromethyl) carbonate (0.582 g) was added dropwise a solution of pyridine (0.485 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2- (methylamino) ethyl acetate hydrochloride (0.922 g) obtained in Reference Example 2 was added. After a solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL). 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-imidazo [4,5-b synthesized by the method described in JP-A-63-146882. ] Pyridine (0.85 g), triethylamine (0.70 mL) and 4-dimethylaminopyridine (0.025 g) were added, and the mixture was stirred at 60 ° C for 5 hours. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (90 mL). The ethyl acetate layer was washed with brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1). Crystallization from diethyl ether gave the title compound (0.173 g) as a colorless solid.
¹ H-NMR (CDCl ₃ ): 2.04, 2.09 (3H, s in total), 2.24 (6H, s), 3.13, 3.30 (3H, s in total), 3.45− 3.97 (2H, m), 3.72 (3H, s), 3.97 (3H, s), 4.15-4.50 (2H, m), 4.85 (1H, d, J = 13.1 Hz), 4.96 (1H, d, J = 13.1 Hz), 6.80 (1H, d, J = 8.9 Hz), 7.96 (1H, d, J = 8.9 Hz), 8.22 (1H, s).

Synthesis Example 39
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -3H-imidazo [4,5-b] pyridin-3-yl] carbonyl ] (Phenyl) amino] ethyl acetate To a solution of bis (trichloromethyl) carbonate (0.291 g) in tetrahydrofuran (10 mL) was added dropwise a solution of pyridine (0.243 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-anilinoethyl acetate hydrochloride (0.647 g) obtained in Reference Example 27 was added. A solution of triethylamine (0.419 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL). 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-imidazo [4,5-b synthesized by the method described in JP-A-63-146882. ] Pyridine (0.867 g), triethylamine (0.697 mL) and 4-dimethylaminopyridine (0.020 g) were added, and the mixture was stirred at 60 ° C for 10 hours. After concentration under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1). The title compound (0.311 g) was obtained as a colorless solid by crystallization from diethyl ether.
¹ H-NMR (CDCl ₃ ): 1.96 (3H, s), 2.23 (3H, s), 2.25 (3H, s), 3.72 (3H, s), 4.01 (3H) , S), 4.12-4.52 (4H, m), 4.78-5.22 (2H, m), 6.62 (1H, d, J = 8.7 Hz), 7.02-7. .18 (3H, m), 7.32-7.48 (2H, m), 7.73 (1H, d, J = 8.7 Hz), 8.26 (1H, s).

Synthesis Example 40
4- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] butyl acetate To a solution of bis (trichloromethyl) carbonate (0.59 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice-cooling, 4- (methylamino) butyl acetate hydrochloride (1.08 g) obtained in Reference Example 37 was added. A solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.02 g), triethylamine (0. 77 mL) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1) to give the title compound (0.93 g) as a yellow amorphous solid. Obtained.
¹ H-NMR (CDCl ₃ ): 1.65-1.85 (4H, m), 2.03 (3H, s), 2.23 (3H, s), 3.02 (3H, bs), 3 .45-3.63 (2H, m), 4.03-4.13 (2H, m), 4.37 (2H, q, J = 7.8 Hz), 4.85-5.13 (2H, m) m), 6.64 (1H, d, J = 5.6 Hz), 7.36-7.46 (3H, m), 7.84 (1H, d, J = 8.4 Hz), 8.35 ( 1H, d, J = 5.6 Hz).

Synthesis Example 41
Ethyl 4- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Il] carbonyl] amino] butyl carbonate To a solution of bis (trichloromethyl) carbonate (0.59 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice cooling, the ethyl 4- (methylamino) butyl carbonate hydrochloride (1.27 g) obtained in Reference Example 39 was added. A solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.26 g), triethylamine (0. 95 mL) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1) to give the title compound (1.08 g) as a yellow amorphous solid. Obtained.
¹ H-NMR (CDCl ₃ ): 1.31 (3H, t, J = 7.2 Hz), 1.73-1.91 (4H, m), 2.23 (3H, s), 3.01 ( 3H, bs), 3.50-3.62 (2H, m), 4.15-4.22 (4H, m), 4.38 (2H, q, J = 7.8 Hz), 4.87- 5.13 (2H, m), 6.64 (1H, d, J = 5.4 Hz), 7.35-7.46 (3H, m), 7.83 (1H, d, J = 7.8 Hz) ), 8.35 (1H, d, J = 5.4 Hz).

Synthesis Example 42
Ethyl 3- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Il] carbonyl] amino] propyl carbonate To a solution of bis (trichloromethyl) carbonate (0.59 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice cooling, the ethyl 3- (methylamino) propyl carbonate hydrochloride (1.18 g) obtained in Reference Example 44 was added. A solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.10 g), triethylamine (0. 83 mL) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1) to give the title compound (0.88 g) as a yellow amorphous solid. Obtained.
¹ H-NMR (CDCl ₃ ): 1.29 (3H, t, J = 7.2 Hz), 2.10-2.20 (2H, m), 2.22 (3H, s), 3.02 ( 3H, bs), 3.55-3.77 (2H, m), 4.14-4.30 (4H, m), 4.37 (2H, q, J = 7.8 Hz), 4.83- 5.13 (2H, m), 6.64 (1H, d, J = 5.6 Hz), 7.35-7.46 (3H, m), 7.82 (1H, d, J = 8.1 Hz) ), 8.35 (1H, d, J = 5.6 Hz).

Synthesis Example 43
3- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] propyl acetate To a solution of bis (trichloromethyl) carbonate (1.19 g) in tetrahydrofuran (40 mL) was added dropwise a solution of pyridine (0.95 mL) in tetrahydrofuran (2 mL) under ice-cooling. After stirring for 30 minutes under ice-cooling, 3- (methylamino) propyl acetate hydrochloride (1.90 g) obtained in Reference Example 42 was added. After dropwise adding a tetrahydrofuran solution (2 mL) of triethylamine (1.68 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated saline (100 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (40 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.99 g), triethylamine (1. 50 mL) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated saline (100 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1) to give the title compound (1.22 g) as a yellow amorphous solid. Obtained.
¹ H-NMR (CDCl ₃ ): 1.97 (3H, s), 2.05-2.15 (2H, m), 2.22 (3H, s), 3.03 (3H, bs), 3 .42-3.72 (2H, m), 4.10-4.22 (2H, m), 4.37 (2H, q, J = 7.8 Hz), 4.85-5.13 (2H, m) m), 6.64 (1H, d, J = 5.6 Hz), 7.24-7.44 (3H, m), 7.83 (1H, d, J = 7.5 Hz), 8.35 ( 1H, d, J = 5.6 Hz).

Synthesis Example 44
3- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] propane-1,2-diyl diacetate To a solution of bis (trichloromethyl) carbonate (0.59 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. did. After stirring for 30 minutes under ice-cooling, 3- (methylamino) propane-1,2-diyl diacetate hydrochloride (1.35 g) obtained in Reference Example 46 was added. A solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.27 g), triethylamine (0. 96 mL) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60 ° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1) to give the title compound (0.64 g) as a yellow amorphous solid. Obtained.
_{^{1 H-NMR (CDCl 3)}} : 2.05 (3H, s), 2.13 (3H, s), 2.23 (3H, s), 3.07 (3H, bs), 3.42-3 .95 (2H, m), 4.06-4.43 (2H, m), 4.38 (2H, q, J = 7.8 Hz), 4.85-5.05 (2H, m), 5 .42-5.50 (1H, m), 6.63-6.66 (1H, m), 7.38-7.51 (3H, m), 7.78-7.85 (1H, m) , 8.33-8.36 (1H, m).

Synthesis Example 45
Diethyl 3- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Yl] carbonyl] amino] propane-1,2-diyl biscarbonate A solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) was added to a solution of bis (trichloromethyl) carbonate (0.59 g) in tetrahydrofuran (20 mL) under ice-cooling. It was dropped. After stirring under ice cooling for 30 minutes, diethyl 3- (methylamino) propane-1,2-diylbiscarbonate hydrochloride (1.71 g) obtained in Reference Example 47 was added. A solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.53 g), triethylamine (1. 16 mL) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1) to give the title compound (1.42 g) as a yellow amorphous solid. Obtained.
_{^{1 H-NMR (CDCl 3)}} : 1.28-1.34 (6H, m), 2.22 (3H, s), 3.07 (3H, bs), 3.42-4.60 (10H, m), 4.85-5.08 (2H, m), 5.30-5.42 (1H, m), 6.62-6.64 (1H, m), 7.37-7.42 ( 3H, m), 7.80-7.83 (1H, m), 8.32-8.35 (1H, m).

Synthesis Example 46
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -3H-imidazo [4,5-b] pyridin-3-yl] carbonyl ] (Methyl) amino] ethyl 3-chlorobenzoate To a solution of bis (trichloromethyl) carbonate (0.194 g) in tetrahydrofuran (7 mL) was added dropwise a solution of pyridine (0.162 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring under ice-cooling for 30 minutes, 2- (methylamino) ethyl 3-chlorobenzoate hydrochloride (0.50 g) obtained in Reference Example 7 was added. After a solution of triethylamine (0.279 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 2.5 hours. After concentration under reduced pressure, water (15 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL). 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-imidazo [4,5-b synthesized by the method described in JP-A-63-146882. ] Pyridine (0.445 g), triethylamine (0.357 mL) and 4-dimethylaminopyridine (0.012 g) were added, and the mixture was stirred at 60 ° C for 14 hours. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (70 mL). The ethyl acetate layer was washed with saturated saline (20 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 2, then eluted with 1: 1) to give the title compound (0.360 g) as a colorless amorphous solid. Obtained.
¹ H-NMR (CDCl ₃ ): 2.21 (3H, s), 2.23 (3H, s), 3.32, 3.38 (total 3H, s), 3.72 (3H, s), 3.81 (3H, s), 3.92-4.09 (2H, m), 4.50-4.73 (2H, m), 4.87 (1H, d, J = 13.4 Hz), 4.94 (1H, d, J = 13.4 Hz), 6.77 (1H, d, J = 8.8 Hz), 7.36 (1H, m), 7.52 (1H, m), 7. 80-8.03 (3H, m), 8.20 (1H, s).

Synthesis Example 47
2- [methyl [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] amino Ethyl acetate To a tetrahydrofuran solution (20 mL) of bis (trichloromethyl) carbonate (0.582 g) was added dropwise a solution of pyridine (0.485 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 1 hour under ice cooling, 2- (methylamino) ethyl acetate hydrochloride (0.922 g) obtained in Reference Example 2 was added. A solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature for 2.5 hours. After concentration under reduced pressure, water (40 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with brine (25 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (15 mL). 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.10 g), triethylamine (0.84 mL), 4 -Dimethylaminopyridine (0.036 g) was added, and the mixture was stirred at 60 ° C for 4.5 hours. After concentration under reduced pressure, water (40 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1, then 2: 1) to give the title compound (1.18 g) as a colorless solid.
_{^{1 H-NMR (CDCl 3)}} : 2.10 (3H, s), 2.24 (3H, s), 3.09 (3H, bs), 3.60-4.00 (2H, br), 4 .25-4.50 (2H, m), 4.38 (2H, q, J = 7.8 Hz), 4.84-5.18 (2H, m), 6.64 (1H, d, J = (5.6 Hz), 7.36-7.48 (3H, m), 7.85 (1H, d, J = 7.8 Hz), 8.35 (1H, d, J = 5.6 Hz).

Synthesis Example 48
Ethyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole-1- Yl] carbonyl] amino] ethyl carbonate (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (130 g) ), Triethylamine (63.8 mL), 4-dimethylaminopyridine (0.86 g), and 2-[(chlorocarbonyl) (methyl) amino] ethyl ethyl carbonate (84.8 g) obtained in Reference Example 34 in tetrahydrofuran (813 mL) )) The solution was stirred at 45-50 ° C for 18 hours. After the reaction solution was concentrated under reduced pressure, water (300 mL) was added to the residue, and the mixture was extracted with ethyl acetate (700 mL). After the ethyl acetate layer was washed three times with a saturated saline solution (300 mL), anhydrous magnesium sulfate (130 g) and activated carbon (13 g) were added. After stirring at room temperature for 30 minutes, the mixture was filtered. After the filtrate was concentrated under reduced pressure, the residue was dissolved in diethyl ether (600 mL) containing triethylamine (0.49 mL) and concentrated under reduced pressure. This operation was repeated twice more. The obtained oil was dissolved in ethanol (200 mL) containing triethylamine (2.45 mL), and water (120 mL) was added dropwise under ice cooling. The precipitated crystals were collected by filtration, washed three times with ice-cooled ethanol-water (volume ratio 1: 1, 150 mL), and dried to obtain the title compound (172.2 g) as a colorless solid. ¹ H-NMR (CDCl ₃ ) showed the same chart as the compound obtained in Synthesis Example 14.

Synthesis Example 49
2-ethoxyethyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole -1-yl] carbonyl] amino] ethyl carbonate To a solution of bis (trichloromethyl) carbonate (0.43 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.35 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 10 minutes under ice-cooling, 2-ethoxyethyl 2- (methylamino) ethyl carbonate hydrochloride (0.82 g) obtained in Reference Example 48 was added. After a solution of triethylamine (0.60 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 3 days. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.11 g), triethylamine (0. 63 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60 ° C for 6 hours and at room temperature for 11 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 3: 7, then ethyl acetate: hexane = 7: 3) to give the title compound (1.39 g). Obtained as a yellow amorphous solid.
¹ H-NMR (CDCl ₃ ): 1.19 (3H, t, J = 6.9 Hz), 2.23 (3H, s), 3.09 (3H, bs), 3.40-4.20 ( 2H, br), 3.53 (2H, q, J = 6.9 Hz), 3.63-3.36 (2H, m), 4.27-4.34 (2H, m), 4.39 ( 2H, q, J = 7.8 Hz), 4.47 (2H, m), 4.80-5.20 (2H, m), 6.65 (1H, d, J = 5.6 Hz), 7. 30-7.52 (3H, m), 7.84 (1H, d, J = 7.5 Hz), 8.35 (1H, d, J = 5.6 Hz).

Synthesis Example 50
3-methoxypropyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole -1-yl] carbonyl] amino] ethyl carbonate To a tetrahydrofuran solution (20 mL) of bis (trichloromethyl) carbonate (0.53 g) was added dropwise a solution of pyridine (0.44 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 5 minutes under ice-cooling, 3-methoxypropyl 2- (methylamino) ethyl carbonate hydrochloride (0.82 g) obtained in Reference Example 49 was added. A solution of triethylamine (0.75 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.11 g), triethylamine (0. 63 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60 ° C for 6 hours and at room temperature for 6 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 3: 7, followed by ethyl acetate: hexane = 7: 3). Crystallization from diethyl ether gave the title compound (0.70 g) as a colorless solid.
¹ H-NMR (CDCl ₃ ): 1.94 (2H, quintet, J = 6.2 Hz), 2.23 (3H, s), 3.09 (3H, bs), 3.31 (3H, s). , 3.40-4.20 (2H, br), 3.44 (2H, t, J = 6.2 Hz), 4.25 (2H, t, J = 6.5 Hz), 4.38 (2H, br). q, J = 7.8 Hz), 4.44 (2H, m), 4.80-5.20 (2H, m), 6.64 (1H, d, J = 5.6 Hz), 7.35- 7.48 (3H, m), 7.83 (1H, d, J = 7.8 Hz), 8.34 (1H, d, J = 5.6 Hz).

Synthesis Example 51
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl N, N-dimethylglycinate 2- (methylamino) ethyl N, N-dimethylglycinate dihydrochloride (1.06 g) obtained in Reference Example 50 was added to tetrahydrofuran (40 mL). After stirring for a while, bis (trichloromethyl) carbonate (0.77 g) was added. After cooling with ice, a solution of triethylamine (2.17 mL) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After the precipitated solid was separated by filtration, ethyl acetate (80 mL) was added, and the mixture was washed with an ice-cooled aqueous sodium hydrogen carbonate solution (50 mL) and a saturated saline solution (50 mL × 2), and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.11 g), triethylamine (0. 63 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60 ° C for 6 hours and at room temperature for 3 days. 4-Dimethylaminopyridine (0.037 g) was added, and the mixture was further stirred at 60 ° C for 6 hours. After concentration under reduced pressure, an aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1, then ethyl acetate, then methanol: ethyl acetate = 1: 19). Crystallization from diethyl ether gave the title compound (0.41 g) as a colorless solid.
_{^{1 H-NMR (CDCl 3)}} : 2.23 (3H, s), 2.35 (6H, s), 3.08 (3H, bs), 3.21 (2H, s), 3.50-4 .20 (2H, br), 4.38 (2H, q, J = 7.8 Hz), 4.44 (2H, m), 4.80-5.18 (2H, m), 6.64 (1H) , D, J = 5.6 Hz), 7.36-7.48 (3H, m), 7.84 (1H, d, J = 6.9 Hz), 8.35 (1H, d, J = 5. 6 Hz).

Synthesis Example 52
S- [2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole- 1-yl] carbonyl] amino] ethyl] thioacetate S- [2- (methylamino) ethyl] thioacetate hydrochloride (0.75 g) obtained in Reference Example 51 was added to tetrahydrofuran (30 mL) and stirred for a while. Thereafter, bis (trichloromethyl) carbonate (0.66 g) was added. After cooling with ice, a solution of triethylamine (1.85 mL) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 30 minutes. The precipitated solid was separated by filtration, ethyl acetate (50 mL) was added to the filtrate, and the mixture was washed with ice-cooled 0.2 N hydrochloric acid (20 mL) and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (0.96 g), triethylamine (0. 54 mL) and 4-dimethylaminopyridine (0.032 g) were added, and the mixture was stirred at 60 ° C for 6 hours and at room temperature for 8 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with acetone: hexane = 3: 7, then acetone: hexane = 7: 3) to give the title compound (1.19 g) as a yellow amorphous solid. As obtained.
_{^{1 H-NMR (CDCl 3)}} : 2.23 (3H, s), 2.34 (3H, s), 3.10 (3H, bs), 3.22 (2H, t, J = 6.6Hz) , 3.67 (2H, m), 4.38 (2H, q, J = 7.8 Hz), 4.80-5.20 (2H, m), 6.64 (1H, d, J = 5. 7 Hz), 7.35-7.50 (3H, m), 7.83 (1H, d, J = 6.9 Hz), 8.35 (1H, d, J = 5.7 Hz).

Synthesis Example 53
Ethyl 2- [2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole -1-yl] carbonyl] amino] ethoxy] ethyl carbonate To a solution of bis (trichloromethyl) carbonate (1.19 g) in tetrahydrofuran (40 mL) was added dropwise a solution of pyridine (0.95 mL) in tetrahydrofuran (2 mL) under ice-cooling. . After stirring for 30 minutes under ice-cooling, ethyl 2- [2- (methylamino) ethoxy] ethyl carbonate hydrochloride (2.73 g) obtained in Reference Example 52 was added. After dropwise adding a tetrahydrofuran solution (2 mL) of triethylamine (1.68 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated saline (100 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (40 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (2.80 g), triethylamine (2. 11 mL) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated saline (100 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1) to give the title compound (2.19 g) as a yellow amorphous solid. Obtained.
¹ H-NMR (CDCl ₃ ): 1.28 (3H, t, J = 7.2 Hz), 2.24 (3H, s), 3.10 (3H, bs), 3.38-3.80 ( 6H, m), 4.18 (2H, q, J = 7.2 Hz), 4.27-4.34 (2H, m), 4.38 (2H, q, J = 8.4 Hz), 4. 83-5.30 (2H, m), 6.65 (1H, d, J = 5.7 Hz), 7.35-7.50 (3H, m), 7.84 (1H, d, J = 7) .8 Hz), 8.36 (1H, d, J = 5.7 Hz).

Synthesis Example 54
Ethyl 2- [methyl [[2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H -Benzimidazol-1-yl] carbonyl] amino] ethoxy] carbonyl] amino] ethyl carbonate Tetrahydrofuran of pyridine (0.49 mL) in a solution of bis (trichloromethyl) carbonate (0.59 g) in tetrahydrofuran (20 mL) under ice-cooling The solution (1 mL) was added dropwise. After stirring for 30 minutes under ice-cooling, the ethyl 2- [methyl [[2- (methylamino) ethoxy] carbonyl] amino] ethyl carbonate hydrochloride (1.71 g) obtained in Reference Example 53 was added. A solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.59 g), triethylamine (1. 20 mL) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1) to give the title compound (1.62 g) as a yellow amorphous solid. Obtained.
_{^{1 H-NMR (CDCl 3)}} : 1.24-1.31 (3H, m), 2.24 (3H, bs), 2.97-2.99 (3H, m), 3.10 (3H, bs), 3.55-3.58 (2H, m), 4.09-4.50 (10H, m), 4.88-5.08 (2H, m), 6.65 (1H, t, J = 5.7 Hz), 7.36-7.48 (3H, m), 7.85 (1H, d, J = 6.9 Hz), 8.36 (1H, d, J = 5.7 Hz).

Synthesis Example 55
Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (methyl) amino] Ethyl carbonate To a tetrahydrofuran solution (10 mL) of bis (trichloromethyl) carbonate (0.291 g) was added dropwise a solution of pyridine (0.243 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 1 hour under ice cooling, the ethyl 2- (methylamino) ethyl carbonate hydrochloride (0.551 g) obtained in Reference Example 14 was added. After a solution of triethylamine (0.418 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, water (15 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL). 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (0.817 g), triethylamine (0.661 mL), 4-dimethylaminopyridine (0.012 g) was added, and the mixture was stirred at 60 ° C. for 12 hours. After concentration under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1) to give the title compound and ethyl 2-[[[6-methoxy- 2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (methyl) amino] ethyl carbonate 3: 2 mixture (0 .92 g) as a pale yellow amorphous solid.
_{^{1 H-NMR (CDCl 3)}} : 1.27-1.34 (3H, m), 2.10-2.30 (3H, m), 2.23 (3H, s), 2.99-3. 23 (3H, m), 3.40-3.85 (2H, m), 3.69 (6 / 5H, s), 3.71 (9 / 5H, s), 3.86 (6 / 5H, s), 3.88 (9 / 5H, s), 4.14-4.25 (2H, m), 4.38-4.60 (2H, m), 4.82-5.06 (2H, m), 6.92-7.08 (7 / 5H, m), 7.33 (3 / 5H, d, J = 9.0 Hz), 7.66 (1H, m), 8.21 (1H, s).

Synthesis Example 56
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (phenyl) amino] ethyl A solution of pyridine (0.243 mL) in tetrahydrofuran (1 mL) was added dropwise to a solution of bis (trichloromethyl) acetate carbonate (0.291 g) in tetrahydrofuran (10 mL) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-anilinoethyl acetate hydrochloride (0.647 g) obtained in Reference Example 27 was added. A solution of triethylamine (0.419 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL). 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (0.829 g), triethylamine (0.669 mL), 4-dimethylaminopyridine (0.012 g) was added and stirred at 60 ° C. for 14 hours. After concentration under reduced pressure, water (40 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2) to give the title compound and 2-[[[6-methoxy-2-[[(4- Methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (phenyl) amino] ethyl acetate in a 1: 1 mixture (1.10 g) as a colorless amorphous Obtained as a solid.
¹ H-NMR (CDCl ₃ ): 1.99 (3H, s), 2.19 (1.5 Hs), 2.21 (1.5 H, s), 2.25 (3H, s), 3 .70 (1.5H, s), 3.71 (3H, s), 3.78 (1.5H, s), 3.84 (1.5H, s), 4.15-4.56 (4H , M), 4.74-4.80 (1H, m), 4.91-4.98 (1H, m), 6.83-6.91 (1.5H, m), 7.04-7. .19 (3.5 H, m), 7.25-7.53 (2.5 H, m), 7.51 (0.5 H, d, J = 8.7 Hz), 8.25 (1 H, s) .

Synthesis Example 57
Ethyl 2-[[[(S) -5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] ( Methyl) amino] ethyl carbonate (S) -5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) synthesized by the method described in Synthesis Example 1 of Japanese Patent Application Laid-Open No. 10-504290. Methyl] sulfinyl] -1H-benzimidazole (1.34 g) in tetrahydrofuran solution (10 mL), 2-[(chlorocarbonyl) (methyl) amino] ethyl ethyl carbonate (0.9 mL) obtained in Reference Example 34, triethylamine (1.08 mL) and 4-dimethylaminopyridine (0.010 g) were added, and the mixture was stirred at 60 ° C for 6 hours. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1) to give the title compound and ethyl 2-[[[((S)- 6-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (methyl) amino] ethyl carbonate 3: 2 (0.92 g) was obtained as a pale yellow amorphous solid.
_{^{1 H-NMR (CDCl 3)}} : 1.25-1.34 (3H, m), 2.10-2.30 (3H, m), 2.23 (3H, s), 2.99-3. 23 (3H, m), 3.40-3.85 (2H, m), 3.69 (6 / 5H, s), 3.71 (9 / 5H, s), 3.86 (6 / 5H, s), 3.88 (9 / 5H, s), 4.14-4.25 (2H, m), 4.38-4.60 (2H, m), 4.79-5.05 (2H, m), 6.92-7.08 (7 / 5H, m), 7.33 (3 / 5H, d, J = 9.3 Hz), 7.65 (1H, m), 8.21 (1H, s).

Synthesis Example 58
Ethyl 2-[[[[2-[[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (methyl) amino] ethyl To a solution of bis (trichloromethyl) carbonate carbonate (0.291 g) in tetrahydrofuran (10 mL) was added dropwise a solution of pyridine (0.243 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice cooling, the ethyl 2- (methylamino) ethyl carbonate hydrochloride (0.551 g) obtained in Reference Example 14 was added. After a solution of triethylamine (0.418 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 2.5 hours. After concentration under reduced pressure, water (15 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL). 2-[[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (0.723 g), triethylamine (0.528 mL), 4-dimethylaminopyridine ( 0.012 g) and stirred at 60 ° C. for 17 hours. After concentration under reduced pressure, water (40 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2), followed by silica gel column chromatography (ethyl acetate: hexane = 1: 1 followed by ethyl acetate). The title compound (0.44 g) was obtained as a colorless amorphous solid.
_{^{1 H-NMR (CDCl 3)}} : 1.31 (3H, t, J = 7.1Hz), 2.05 (2H, m), 2.18 (3H, s), 3.08 (3H, bs) , 3.34 (3H, s), 3.54 (2H, t, J = 6.1 Hz), 3.61-4.01 (2H, m), 4.08 (2H, t, J = 6. 3Hz), 4.21 (2H, t, J = 7.1 Hz), 4.38-4.54 (2H, m), 4.81-5.12 (2H, m), 6.68 (1H, d, J = 5.6 Hz), 7.34-7.48 (3H, m), 7.83 (1H, d, J = 7.8 Hz), 8.27 (1H, d, J = 5.6 Hz) ).

Synthesis Example 59
2-[[[2-[[[4- (3-Methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (phenyl) amino] ethyl acetate To a solution of bis (trichloromethyl) carbonate (0.291 g) in tetrahydrofuran (10 mL) was added dropwise a solution of pyridine (0.243 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-anilinoethyl acetate hydrochloride (0.647 g) obtained in Reference Example 27 was added. A solution of triethylamine (0.419 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL). 2-[[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (0.877 g), triethylamine (0.641 mL), 4-dimethylaminopyridine ( 0.012 g) and stirred at 60 ° C. for 16 hours. After concentration under reduced pressure, water (40 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2), followed by silica gel column chromatography (eluted with ethyl acetate) to give the title compound (0.93 g). ) Was obtained as a colorless amorphous solid.
¹ H-NMR (CDCl ₃ ): 1.99 (3H, s), 2.07 (3H, s), 2.19 (3H, s), 3.35 (3H, s), 3.54 (2H) , T, J = 6.2 Hz), 4.09 (2H, t, J = 6.2 Hz), 4.14-4.40 (4H, m), 4.80 (1H, d, J = 13. 7 Hz), 5.00 (1H, d, J = 13.7 Hz), 6.71 (1H, d, J = 5.7 Hz), 7.03-7.34 (7H, m), 7.38 ( 1H, m), 7.65 (1H, m), 8.32 (1H, d, J = 5.7 Hz).

Synthesis Example 60
2-[[[5- (Difluoromethoxy) -2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] (methyl) amino] ethyl ethyl To a solution of bis (trichloromethyl) carbonate carbonate (0.174 g) in tetrahydrofuran (8 mL) was added dropwise a solution of pyridine (0.146 mL) in tetrahydrofuran (1 mL) under ice-cooling. After stirring for 1 hour under ice cooling, the ethyl 2- (methylamino) ethyl carbonate hydrochloride (0.330 g) obtained in Reference Example 14 was added. After a solution of triethylamine (0.250 mL) in tetrahydrofuran (1 mL) was added dropwise, the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (30 mL). The ethyl acetate layer was washed with saturated saline (10 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (8 mL). 5- (difluoromethoxy) -2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (0.432 g), triethylamine (0.279 mL), 4-dimethylaminopyridine ( 0.008 g) and stirred at 60 ° C. for 17.5 hours. After concentration under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated saline (10 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2, then 1: 1), followed by silica gel column chromatography (ethyl acetate: hexane = 2: 1, followed by ethyl acetate: hexane = 2: 1). Purification by elution with ethyl acetate) afforded the title compound and 2-[[[6- (difluoromethoxy) -2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole. A 1: 1 mixture of (-1-yl] carbonyl] methylamino] ethyl ethyl carbonate (0.09 g) was obtained as a pale yellow amorphous solid.
¹ H-NMR (CDCl ₃ ): 1.31 (3H, t, J = 7.2 Hz), 3.06 (3H, s), 3.42-3.98 (2H, m), 3.87 ( 3H, s), 3.90 (3H, s), 4.21 (2H, q, J = 7.2 Hz), 4.36-4.54 (2H, m), 4.90 (1H, d, J = 13.2 Hz), 4.98 (1 H, d, J = 13.2 Hz), 6.54 (0.5 H, t, J = 13.5 Hz), 6.61 (0.5 H, t, J) = 73.5 Hz), 6.78 (1H, d, J = 5.3 Hz), 7.15-7.25 (1.5H, m), 7.44 (0.5H, d, J = 9. 0 Hz), 7.59 (0.5 H, s), 7.80 (0.5 H, d, J = 9.0 Hz), 8.17 (1 H, d, J = 5.3 Hz).

Synthesis Example 61
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 1-methylpiperidine-4-carboxylate 2- (methylamino) ethyl 1-methylpiperidine-4-carboxylate dihydrochloride (0.98 g) obtained in Reference Example 54 was added to tetrahydrofuran (50 mL). ) And after stirring for a while, bis (trichloromethyl) carbonate (0.53 g) was added. After cooling on ice, a solution of triethylamine (2.01 mL) in tetrahydrofuran (50 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate (100 mL) was added, and the mixture was washed with an aqueous sodium hydrogen carbonate solution (100 mL) and saturated saline (80 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (0.74 g), triethylamine (0. 56 mL) and 4-dimethylaminopyridine (0.049 g) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, an aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 7: 3, then ethyl acetate, then methanol: ethyl acetate = 1: 19) to give the title compound ( 0.78 g) was obtained as a yellow-green amorphous solid.
¹ H-NMR (CDCl ₃ ): 1.65-2.05 (6H, m), 2.23 (3H, s), 2.25 (3H, s), 2.24-2.38 (1H, m), 2.75-2.85 (2H, m), 3.07 (3H, bs), 3.40-4.10 (2H, br), 4.38 (2H, q, J = 7. 8 Hz), 4.40 (2H, m), 4.80-5.10 (2H, br), 6.64 (1H, d, J = 5.6 Hz), 7.36-7.47 (3H, m), 7.84 (1H, d, J = 7.8 Hz), 8.35 (1H, d, J = 5.6 Hz).

Synthesis Example 62
2-[[4- (aminocarbonyl) phenyl] [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl]- 1H-benzimidazol-1-yl] carbonyl] amino] ethyl acetate 2-[[4- A solution of (aminocarbonyl) phenyl] amino] ethyl acetate (0.67 g) and triethylamine (0.63 mL) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (30 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.11 g), triethylamine (0. 63 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60 ° C for 30 minutes and at room temperature overnight. After concentration under reduced pressure, an aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 4: 6, then 6: 4, then 8: 2) to give the title compound (1.26 g). Was obtained as a yellow amorphous solid.
¹ H-NMR (CDCl ₃ ): 1.99 (3H, s), 2.26 (3H, s), 4.15-4.55 (4H, m), 4.41 (2H, q, J = 7.9 Hz), 4.80-5.20 (2H, br), 6.69 (1H, d, J = 5.7 Hz), 7.26-7.38 (3H, m), 7.48 ( 2H, d, J = 8.9 Hz), 7.54 (2H, d, J = 8.9 Hz), 7.66-7.73 (1H, m), 8.39 (1H, d, J = 5) 0.7 Hz).

Synthesis Example 63
2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl ] Carbonyl] amino] ethyl 1-methyl-4-piperidinyl carbonate 2- (methylamino) ethyl 1-methyl-4-piperidinyl carbonate dihydrochloride (1.01 g) obtained in Reference Example 56 was added to tetrahydrofuran (30 mL). After stirring for a while, the mixture was cooled with ice. After adding bis (trichloromethyl) carbonate (0.69 g), a solution of triethylamine (1.95 mL) in tetrahydrofuran (10 mL) was added dropwise. After stirring for 1 hour under ice cooling and 1 hour at room temperature, the precipitated solid was separated by filtration. After concentration under reduced pressure, ethyl acetate (50 mL) was added, and the mixture was washed with an ice-cooled aqueous sodium hydrogen carbonate solution (50 mL) and a saturated saline solution (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL). (R) -2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (1.11 g), triethylamine (0. 63 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60 ° C overnight. After concentration under reduced pressure, an aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1, then ethyl acetate, then methanol: ethyl acetate = 1: 19) to give the title compound ( 0.70 g) was obtained as a yellow amorphous solid.
_{^{1 H-NMR (CDCl 3)}} : 1.70-1.86 (2H, m), 1.90-2.04 (2H, m), 2.23 (3H, s), 2.28 (3H, s), 2.10-2.35 (2H, m), 2.60-2.72 (2H, m), 3.08 (3H, bs), 3.40-4.20 (2H, br) , 4.39 (2H, q, J = 7.9 Hz), 4.44 (2H, m), 4.60-4.74 (1H, m), 4.80-5.15 (2H, br) , 6.65 (1H, d, J = 5.9 Hz), 7.35-7.52 (3H, m), 7.84 (1H, d, J = 7.5 Hz), 8.35 (1H, d, J = 5.9 Hz).

Synthesis Example 64
2-[[4- (aminocarbonyl) phenyl] [[2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole -1-yl] carbonyl] amino] ethyl acetate 2-[[4- (aminocarbonyl)) obtained in Reference Example 55 in a tetrahydrofuran solution (5 mL) of bis (trichloromethyl) carbonate (0.12 g) under ice-cooling. A solution of phenyl] amino] ethyl acetate (0.22 g) and triethylamine (0.17 mL) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Water (20 mL) was added, and extracted with ethyl acetate (30 mL). The ethyl acetate layer was washed with saturated saline (20 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL). 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (0.37 g), triethylamine (0.28 mL), 4 -Dimethylaminopyridine (0.012 g) was added, and the mixture was stirred at 60 ° C for 1 hour. After concentration under reduced pressure, an aqueous sodium hydrogen carbonate solution (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (30 mL). The ethyl acetate layer was washed with saturated saline (20 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 3: 7, then 5: 5, then 8: 2) to give the title compound (0.34 g). Was obtained as a pale yellow amorphous solid.
¹ H-NMR (CDCl ₃ ): 1.99 (3H, s), 2.26 (3H, s), 4.15-4.55 (4H, m), 4.41 (2H, q, J = 7.9 Hz), 4.80-5.20 (2H, br), 6.69 (1H, d, J = 5.9 Hz), 7.26-7.40 (3H, m), 7.47 ( 2H, d, J = 8.8 Hz), 7.54 (2H, d, J = 8.8 Hz), 7.65-7.74 (1H, m), 8.38 (1H, d, J = 5) .9Hz).

Synthesis Example 65
(-)-Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -3H-imidazo [4,5-b] pyridine- 3-yl] carbonyl] (methyl) amino] ethyl carbonate 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl synthesized by the method described in JP-A-63-146882. ] Sulfinyl] -1H-imidazo [4,5-b] pyridine was obtained by optical resolution by preparative HPLC. 2-[(chlorocarbonyl) (methyl) amino] ethyl ethyl carbonate (0.081 g), triethylamine (0.080 mL), 4-dimethylaminopyridine ( .007G) was added and stirred for 18 hours at 50 ° C.. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (30 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 2: 1) to give the title compound (0.053 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ): 1.30 (3H, t, J = 7.1 Hz), 2.24 (6H, s), 3.15, 3.32 (total 3H, s), 3.73 (3H, s), 3.90-4.55 (9H, m), 4.85 (1H, d, J = 13.2 Hz), 4.97 (1H, d, J = 13.2 Hz), 6 .80 (1H, d, J = 8.8 Hz), 7.96 (1H, d, J = 8.8 Hz), 8.23 (1H, s).

Synthesis Example 66
(+)-Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -3H-imidazo [4,5-b] pyridine- 3-yl] carbonyl] (methyl) amino] ethyl carbonate 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl synthesized by the method described in JP-A-63-146882. ] Sulfinyl] -1H-imidazo [4,5-b] pyridine was obtained in Reference Example 34 in a tetrahydrofuran solution (5 mL) of the (+) enantiomer (0.10 g) obtained by optical resolution with preparative HPLC. 2-[(chlorocarbonyl) (methyl) amino] ethyl ethyl carbonate (0.081 g), triethylamine (0.080 mL), 4-dimethylaminopyridine ( .007G) was added and stirred for 18 hours at 50 ° C.. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine (30 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane = 2: 1) to give the title compound and (+)-ethyl 2-[[[5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-imidazo [4,5-b] pyridin-1-yl] carbonyl] (methyl) amino] ethyl carbonate 2: 1 (0.115 g) was obtained as a colorless oil.
_{^{1 H-NMR (CDCl 3)}} : 1.20-1.38 (3H, m), 2.24 (6H, s), 3.08,3.15,3.33 ( total 3H, s), 3 .73 (3H, s), 3.88-4.55 (9H, m), 4.78-5.05 (2H, m), 6.80, 6.86 (1H, d, J = 8. 8 Hz), 7.76, 7.96 (1H, d, J = 8.8 Hz), 8.21, 8.22 (1H, s in total).

  In the following Comparative Examples 1 and 2, Examples 1 to 3, and Experimental Examples 1 and 2, an optically active R-form of lansoprazole (hereinafter, referred to as compound A) was used as an active ingredient. In Comparative Examples and Examples, corn starch (corn starch), lactose, and hydroxypropyl methylcellulose used were products conforming to the Japanese Pharmacopoeia XIV.

Comparative Example 1
Compound A (450 mg) and HPMC (trade name: Metroose 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (1550 mg) were mixed in a mortar. 200 mg of the obtained mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain a tablet (comparative preparation 1) having a diameter of 8 mm.

Comparative Example 2
Compound A (450 mg), HPMC (trade name, Metroose 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (1085 mg), methacrylic acid copolymer L (trade name: Eudragit L100, manufactured by Rohm Pharma Co., Ltd.) (465 mg) in a mortar Mixed. 200 mg of the obtained mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain a tablet (comparative preparation 2) having a diameter of 8 mm.

Comparative Example 3
Compound obtained in Synthesis Example 14 Ethyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] amino] ethyl carbonate (compound 14) (900 mg) and HPMC (trade name: Metroose 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (2600 mg) were mixed in a mortar. . 350 mg of the obtained mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain a tablet (comparative preparation 3) having a diameter of 9 mm.

Example 1
Compound A (113 mg), lactose (303 mg), corn starch (50 mg), and low-substituted hydroxypropylcellulose (trade name: L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) (35 mg) were mixed in a mortar. 50 mg of the resulting mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets having a diameter of 5 mm. Compound A (450 mg) and HPMC (trade name: Metroze 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (1550 mg) were mixed in a mortar with the obtained tablet in the core, and 150 mg of the mixture obtained was hulled. Was obtained by compressing the dry coated tablet (formulation 1) having a diameter of 8 mm used in Example 1 with a hydraulic pump press (manufactured by Riken Seiki).

Example 2
Compound A (113 mg), lactose (303 mg), corn starch (50 mg), and low-substituted hydroxypropylcellulose (trade name: L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) (35 mg) were mixed in a mortar. 50 mg of the resulting mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets having a diameter of 5 mm. Using the obtained tablet as the core, compound A (450 mg), HPMC (trade name: Metroze 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (1085 mg), methacrylic acid copolymer L (trade name: Eudragit L100, Rohm Pharma Co., Ltd.) (465 mg) in a mortar and tableted with a press pad 8 mm in diameter (formulation 2) using 150 mg of the mixture obtained in the outer shell using a hydraulic pump press machine (manufactured by Riken Seiki). I got it.

Example 3
Compound A (225 mg), lactose (125 mg), corn starch (50 mg), and low-substituted hydroxypropylcellulose (trade name: L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) (10 mg) were mixed in a mortar. 50 mg of the resulting mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets having a diameter of 5 mm. Compound A (225 mg), HPMC (trade name: TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.) (350 mg), HPMC (trade name: TC-5S, Shin-Etsu Chemical Co., Ltd.) (225 mg) was mixed in a mortar, and a dry coated tablet having a diameter of 8 mm and using 150 mg of the mixture in a mortar was pressed using a hydraulic pump press (manufactured by Riken Seiki). . Further, using the obtained tablet as the core, compound A (100 mg), lactose (300 mg), corn starch (50 mg), low-substituted hydroxypropylcellulose (trade name: L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) (50 mg) Was mixed in a mortar, and a dry coated tablet (formulation 3) having a diameter of 10 mm using 100 mg of the mixture obtained in the mortar was pressed using a hydraulic pump press (manufactured by Riken Seiki).

Example 4
Compound 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl]-obtained in Synthesis Example 1 1H-benzimidazol-1-yl] carbonyl] amino] ethyl acetate (compound 1) (113 mg), lactose (303 mg), corn starch (50 mg), low-substituted hydroxypropylcellulose (trade name: L-HPC, Shin-Etsu Chemical Co., Ltd.) (Manufactured by K.K.) (35 mg) was mixed in a mortar. 50 mg of the resulting mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets having a diameter of 5 mm. Compound 1 (450 mg) and HPMC (trade name: Metroose 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (1550 mg) were mixed in a mortar with the obtained tablet as the core, and 150 mg of the mixture obtained was mixed with an outer shell. Was obtained by compressing the dry coated tablet (preparation 4) having a diameter of 8 mm used in Example 1 with a hydraulic pump press (manufactured by Riken Seiki).

Example 5
Compound 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl]-obtained in Synthesis Example 12 1H-benzimidazol-1-yl] carbonyl] amino] ethyl 2-pyridinecarboxylate (compound 12) (113 mg), lactose (303 mg), corn starch (50 mg), low-substituted hydroxypropylcellulose (trade name: L-HPC) And Shin-Etsu Chemical Co., Ltd.) (35 mg) were mixed in a mortar. 50 mg of the resulting mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets having a diameter of 5 mm. Compound 12 (450 mg) and HPMC (trade name: Metroose 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (1550 mg) were mixed in a mortar with the obtained tablet as the core, and 150 mg of the mixture obtained was mixed with an outer shell. Was obtained by compressing the dry coated tablet (preparation 5) having a diameter of 8 mm used in Example 1 with a hydraulic pump press (manufactured by Riken Seiki).

Example 6
Compound 14 (113 mg), lactose (303 mg), corn starch (50 mg), and low-substituted hydroxypropylcellulose (trade name: L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) (35 mg) were mixed in a mortar. 50 mg of the resulting mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets having a diameter of 5 mm. Compound 14 (450 mg) and HPMC (trade name: Metroose 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (1550 mg) were mixed in a mortar with the obtained tablet as the core, and 150 mg of the mixture obtained was mixed with an outer shell. Was obtained by compressing the dry coated tablet (preparation 6) having a diameter of 8 mm used in Example 1 with a hydraulic pump press (manufactured by Riken Seiki).

Example 7
Compound 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl]-obtained in Synthesis Example 18 1H-benzimidazol-1-yl] carbonyl] amino] ethyl tetrahydropyran-4-yl carbonate (compound 18) (113 mg), lactose (303 mg), corn starch (50 mg), low-substituted hydroxypropylcellulose (trade name: L -HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) (35 mg) was mixed in a mortar. 50 mg of the resulting mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets having a diameter of 5 mm. Compound 18 (450 mg) and HPMC (trade name: Metroose 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (1550 mg) were mixed in a mortar with the obtained tablet as the core, and 150 mg of the mixture obtained was mixed with an outer shell. Was obtained by compressing the dry coated tablet (preparation 7) having a diameter of 8 mm used in Example 1 with a hydraulic pump press (manufactured by Riken Seiki).

Example 8
Compound 2- [cyclohexyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl]-obtained in Synthesis Example 23 1H-benzimidazol-1-yl] carbonyl] amino] ethyl acetate (compound 23) (113 mg), lactose (303 mg), corn starch (50 mg), low-substituted hydroxypropylcellulose (trade name: L-HPC, Shin-Etsu Chemical Co., Ltd.) (Manufactured by K.K.) (35 mg) was mixed in a mortar. 50 mg of the resulting mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets having a diameter of 5 mm. Compound 23 (450 mg) and HPMC (trade name: Metroose 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (1550 mg) were mixed in a mortar with the obtained tablet as an inner core, and 150 mg of the mixture obtained was mixed with an outer shell. Was obtained by compressing the dry coated tablet (preparation 8) having a diameter of 8 mm used in Example 1 with a hydraulic pump press (manufactured by Riken Seiki).

Example 9
Compound 2-[[[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H obtained in Synthesis Example 25 -Benzimidazol-1-yl] carbonyl] (phenyl) amino] ethyl acetate (compound 25) (113 mg), lactose (303 mg), corn starch (50 mg), low-substituted hydroxypropylcellulose (trade names: L-HPC, Shin-Etsu) (Manufactured by Chemical Industry Co., Ltd.) (35 mg) was mixed in a mortar. 50 mg of the resulting mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets having a diameter of 5 mm. Compound 25 (450 mg) and HPMC (trade name: Metroze 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (1550 mg) were mixed in a mortar with the obtained tablet as the core, and 150 mg of the mixture obtained was mixed with an outer shell. Was obtained by compressing the dry coated tablet (preparation 9) having a diameter of 8 mm used in Example 1 with a hydraulic pump press (manufactured by Riken Seiki).

Example 10
Compound 2-[[2- (acetyloxy) ethyl] [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2] obtained in Synthesis Example 29 -Pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] amino] ethyl acetate (compound 29) (113 mg), lactose (303 mg), corn starch (50 mg), low-substituted hydroxypropylcellulose (trade name) : L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) (35 mg) was mixed in a mortar. 50 mg of the resulting mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets having a diameter of 5 mm. Compound 29 (450 mg) and HPMC (trade name: Metroose 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (1550 mg) were mixed in a mortar with the obtained tablet as the core, and 150 mg of the mixture obtained was mixed with an outer shell. Was obtained by compressing the dry coated tablet (preparation 10) having a diameter of 8 mm used in Example 1 with a hydraulic pump press (manufactured by Riken Seiki).

Example 11
Compound obtained in Synthesis Example 41 ethyl 4- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazol-1-yl] carbonyl] amino] butyl carbonate (compound 41) (113 mg), lactose (303 mg), corn starch (50 mg), low-substituted hydroxypropylcellulose (trade name: L-HPC, Shin-Etsu Chemical) (Manufactured by Kogyo Co., Ltd.) (35 mg) was mixed in a mortar. 50 mg of the resulting mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets having a diameter of 5 mm. Compound 41 (450 mg) and HPMC (trade name: Metroose 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (1550 mg) were mixed in a mortar with the obtained tablet as an inner core, and 150 mg of the mixture obtained was mixed with an outer shell. Was obtained by compressing the dry coated tablet (formulation 11) having a diameter of 8 mm used in Example 1 with a hydraulic pump press (manufactured by Riken Seiki).

Example 12
Compound 2-ethoxyethyl 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] obtained in Synthesis Example 49 ] Sulfinyl] -1H-benzimidazol-1-yl] carbonyl] amino] ethyl carbonate (Compound 49) (113 mg), lactose (303 mg), corn starch (50 mg), low-substituted hydroxypropylcellulose (trade name: L-HPC) And Shin-Etsu Chemical Co., Ltd.) (35 mg) were mixed in a mortar. 50 mg of the resulting mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets having a diameter of 5 mm. Compound 49 (450 mg) and HPMC (trade name: Metroose 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (1550 mg) were mixed in a mortar with the obtained tablet as an inner core, and 150 mg of the mixture obtained was mixed with an outer shell. Was obtained by compressing the dry coated tablet (preparation 12) having a diameter of 8 mm used in Example 1 with a hydraulic pump press (manufactured by Riken Seiki).

Example 13
Compound 2- [methyl [[(R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl]-obtained in Synthesis Example 51 1H-benzimidazol-1-yl] carbonyl] amino] ethyl N, N-dimethylglycinate (Compound 51) (113 mg), lactose (303 mg), corn starch (50 mg), low-substituted hydroxypropylcellulose (trade name: L -HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) (35 mg) was mixed in a mortar. 50 mg of the resulting mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets having a diameter of 5 mm. Compound 51 (450 mg) and HPMC (trade name: Metroose 65SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) (1550 mg) were mixed in a mortar with the obtained tablet as the core, and 150 mg of the mixture obtained was mixed with an outer shell. Was obtained by compressing the dry coated tablet (preparation 13) having a diameter of 8 mm used in Example 1 with a hydraulic pump press (manufactured by Riken Seiki).

Example 14
Compound 14 (400 mg), lactose (160 mg), corn starch (80 mg), and low-substituted hydroxypropylcellulose (trade name: L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) (160 mg) were mixed in a mortar. 80 mg of the obtained mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets having a diameter of 6 mm. Compound 14 (400 mg), HPMC (trade name: TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.) (700 mg), HPMC (trade name: Metro's 65SH-4000, Shin-Etsu Chemical Co., Ltd.) )) (700 mg) and granulated sugar (400 mg) were mixed in a mortar, and a nucleated tablet having a diameter of 9 mm using 220 mg of an outer shell was obtained using a hydraulic pump press machine (manufactured by Riken Seiki). Obtained by tableting. Further, using the obtained tablet as a core, compound 14 (100 mg), lactose (250 mg), corn starch (50 mg), low-substituted hydroxypropylcellulose (trade name: L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) (100 mg) Was mixed in a mortar, and a press coated tablet (preparation 14) having a diameter of 10 mm and using 50 mg of the mixture obtained in the mortar was pressed using a hydraulic pump press (manufactured by Riken Seiki).

Example 15
In the same manner as in Example 14, a dry coated tablet having a diameter of 9 mm and containing 40 mg of the compound 14 in the inner core having a diameter of 6 mm and 40 mg in the outer shell was obtained. The resulting dry coated tablet is coated with a compound 14-containing suspension having the following composition using a high coater HC-LABO (manufactured by Freund Corporation) to form an outermost layer containing 10 mg of compound 14 per dry coated tablet. A coated formulation 15 was obtained.
Coating liquid composition:
Hydroxypropyl cellulose: 2.5 g
(Product name: HPC-SL, manufactured by Nippon Soda Co., Ltd.)
Low-substituted hydroxypropylcellulose: 2.5 g
(Product name: L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.)
Compound 14: 10 g
Purified water: 105 g

Experimental example 1
The drug release properties of the controlled release composition of the present invention containing the controlled release portions A and B were evaluated by a dissolution test.
That is, with respect to the preparations 1 and 2 obtained in Examples 1 and 2, a dissolution test (paddle method, 500 mL of a phosphate buffer (pH 6.8) containing 0.1% sodium dodecyl sulfate, 500 rpm, use of a sinker) was performed. Was. As a control group, the same dissolution test was performed on Comparative Preparations 1 and 2 obtained in Comparative Examples 1 and 2. The results are shown in FIG.
Comparison with the comparative formulation showed that the controlled release composition of the present invention had multi-stage release properties. In addition, it was revealed that by changing the type (composition) of the polymer contained in the release control part B of the composition of the present invention, the release of the active ingredient from the release control part can be adjusted.

Experimental example 2
The drug dissolution of the controlled release composition of the present invention containing the controlled release portions A, B and C was evaluated by a dissolution test.
That is, the formulation 3 obtained in Example 3 was subjected to a dissolution test (paddle method, 500 mL of a 0.1% sodium dodecyl sulfate-containing phosphate buffer (pH 6.8), rotation speed of 100 rpm, use of a sinker). FIG. 2 shows the results.
Comparison with the comparative formulation (see FIG. 1) indicated that the controlled release composition of the present invention had multi-step release. In addition, by changing the type of the carrier contained in each release control section of the composition of the present invention and the ratio of the amount of the active ingredient in each release control section, it is possible to adjust the release of the active ingredient from each release control section. It became clear.

Experimental example 3
The formulations of the present invention were evaluated by dissolution.
That is, the dissolution test (paddle method, 500 mL of a phosphate buffer (pH 6.8) containing 0.1% sodium dodecyl sulfate, 500 mL, rotation speed of 100 rpm, use of a sinker) was performed on the preparation 14 obtained in Example 14. Further, as a control, the same dissolution test was performed on Comparative Preparation 3 obtained in Comparative Example 3. The results shown in FIG. 3 indicate that the controlled release composition of the present invention has a multi-stage release property that is fast in the early period, sustained in the middle period, and faster than the middle stage in the late period.

Experimental example 4
The formulations of the present invention were evaluated for absorbability.
That is, one tablet of the preparation 14 obtained in Example 14 was orally administered to a fasted beagle dog, and the change in blood drug concentration was evaluated. The same evaluation was performed using Comparative Preparation 3 obtained in Comparative Example 3 as a control. From the results shown in FIG. 4, it was considered that in Comparative Formulation 3 showing a constant sustained release, the blood concentration decreased 4 hours after administration, and the absorption in the lower intestine to the large intestine decreased. It has been clarified that Formulation 14 of the present invention maintains a high blood concentration even after 4 hours from administration and maintains a constant effective blood concentration for a long time.

  The controlled release composition of the present invention exhibits a drug release profile characterized by a sustained drug release in the early / middle or middle phase and a faster drug release in the late phase. The sustained-release preparation can maintain the effective blood concentration for a long period of time even for a drug whose absorbability is reduced due to a decrease in drug dissolution from the lower small intestine to the vicinity of the large intestine.

The controlled release composition of the present invention [formulation 1 (（) and formulation 2 (□)] comprising controlled release portions A and B and a sustained release formulation [Comparative formulation 1 (● 11) and Comparative Formulation 2 (■)]. The vertical axis shows the dissolution rate (%), and the horizontal axis shows the time (h) after the start of the test. It is a figure which shows the drug elution profile of the controlled release composition [Formulation 3] of the present invention containing controlled release units A, B and C. The vertical axis shows the dissolution rate (%), and the horizontal axis shows the time (h) after the start of the test. Drugs of the controlled release composition of the present invention [Formulation 14 (▲)] containing controlled release parts A, B and C and a sustained release preparation [Comparative preparation 3 (*)] composed of a single controlled release part It is a figure which shows an elution profile. The vertical axis shows the dissolution rate (%), and the horizontal axis shows the time (h) after the start of the test. FIG. 9 is a graph showing time-dependent changes in blood drug concentrations in beagle dogs to which [Formulation 14 (（)] or [Comparative Formulation 3 (*)] was orally administered. The vertical axis shows the drug concentration in blood (μg / mL), and the horizontal axis shows the time (h) after oral administration.

Claims (16)

A controlled release composition wherein the release of the active ingredient is controlled in two or more stages with different release rates,
1) a release control section A containing a proton pump inhibitor as an active ingredient and capable of controlling the release of the active ingredient at a predetermined rate;
2) A release control section B containing a proton pump inhibitor as an active ingredient and capable of controlling the release of the active ingredient to a predetermined rate lower than the release rate in the release control section A.
Wherein the release of the active ingredient in the controlled release section B precedes the release of the active ingredient in the controlled release section A.   The active ingredient contained in the release control part A and / or the release control part B is the same as or different from the active ingredient, and the release of the active ingredient can be controlled to a predetermined rate higher than the release rate in the release control part B. The controlled release composition according to claim 1, further comprising a controlled release part (C), wherein the release of the active ingredient in the controlled release part (C) precedes the release of the active ingredient in the controlled release part (B).   3. The controlled release composition according to claim 1, wherein the controlled release part B covers the controlled release part A.   The controlled release composition according to claim 3, wherein the controlled release part C covers the controlled release part B.   3. The controlled release composition according to claim 2, wherein the active ingredient contained in the controlled release part C is a proton pump inhibitor. The proton pump inhibitors contained in each release control unit may be the same or different, and may have the following formula (I ′):

[In the formula, ring C ′ represents a benzene ring which may have a substituent or an aromatic monocyclic heterocyclic ring which may have a substituent, and R ⁰ has a hydrogen atom and a substituent. R ¹ , R ² and R ³ may be the same or different and each may have a hydrogen atom, an alkyl group which may have a substituent or a substituent, An alkoxy group or an amino group which may have a substituent, and Y represents a nitrogen atom or CH)
The controlled release composition according to any one of claims 1 to 3, which is a compound represented by the formula: or a salt thereof, or an optically active form thereof.   The controlled release composition according to any one of claims 3 to 5, wherein the proton pump inhibitor contained in each controlled release unit is lansoprazole, a prodrug thereof, a salt thereof, or an optically active substance thereof.   The weight ratio of the active ingredient contained in each release control part is A: 5-95%, B: 5-95% and C: 0-40% (However, when C: 0%, the release control part C is 3. The controlled release composition of claim 2, wherein the composition is absent.   The controlled release composition according to claim 2, wherein the weight ratio of the active ingredient contained in each controlled release part is A: 20-75%, B: 20-75%, and C: 5-30%.   The controlled release composition according to claim 2, which is a solid composition for oral administration in which the release of the active ingredient contained in the controlled release portion C is completed within 2 hours after taking the drug.   3. The controlled release composition according to claim 1, wherein the controlled release part B is a sustained release matrix containing an active ingredient and a hydrophilic polymer.   The controlled release composition according to claim 1 or 2, wherein the controlled release part A is a sustained release matrix containing an active ingredient and a hydrophilic polymer.   3. The controlled release composition according to claim 1, wherein the release of the active ingredient by the controlled release part B lasts for 1-18 hours.   3. The controlled release composition according to claim 1, wherein the release of the active ingredient by the controlled release part A lasts for 30 minutes to 6 hours.   3. The controlled release composition according to claim 2, wherein the release by the controlled release part C is immediate release. 3. The controlled release composition according to claim 1, wherein the dosage form is selected from the group consisting of tablets, granules, pellet tablets and capsules.

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