CN1713897B

CN1713897B - Sustained release preparation

Info

Publication number: CN1713897B
Application number: CN200380103935.2A
Authority: CN
Inventors: 秋山洋子; 仓泽卓; 坂东博人; 永原直树
Original assignee: Takeda Chemical Industries Ltd
Current assignee: Takeda Pharmaceutical Co Ltd
Priority date: 2002-10-16
Filing date: 2003-10-15
Publication date: 2012-07-04
Anticipated expiration: 2023-10-15
Also published as: CN1713897A; AR103296A2; CR7761A; ZA200502318B

Abstract

A controlled release preparation wherein the release of active ingredient is controlled, which releases an active ingredient for an extended period of time by staying or slowly migrating in the gastrointestinal tract, is provided by means such as capsulating a tablet, granule or fine granule wherein the release of active ingredient is controlled and a gel-forming polymer. Said tablet, granule or fine granule has a release-controlled coating-layer formed on a core particle containing an active ingredient.

Description

Controlled release preparation

Technical field

The present invention relates to a kind of controlled release preparation, especially contain tablet, granule or fine grained agent that active component wherein disengaged by control and the capsule that forms the polymer of gel, this capsule has postponed the migration velocity in gastrointestinal tract.

Background technology

Oral formulations is to use the most general dosage form in the pharmaceutical preparation.In order to improve QOL, developed recent years a variety of through being administered once every day or keeping the oral Preparation of pharmaceutical efficacy for twice.Every day be administered once or twice after have the dynamic (dynamical) chemical compound of lasting pharmaceutical efficacy can be through by every means according to synthetic the obtaining of synthesizing mean of himself chemical compound; In order to go out controlled release preparation through the dosage form innovative design, people have done sizable trial to change its kinetics simultaneously.For the controlled release formulations for oral administration dosage form; Developed various controlled release system and drop into to have used, for example disengage through the control of controlled release coat layer or the diffusion through substrate control chemical compound, through corrode the disengaging of substrate (host material) control chemical compound, according to pH control chemical compound disengaging and according to disengage (wherein chemical compound disengages after definite lag time in process) of time control chemical compound.It is believed that through fully utilizing above-mentioned controlled release system and being controlled at the migration velocity in the gastrointestinal tract, can further prolong persistency.

Contain the medicine that has acid labile and need carry out enteric coating as formulations of active ingredients, the medicine that has acid labile for example is the benzimidazole compound with proton pump inhibitor (hereinafter being called PPI sometimes) effect.That is to say; Contain the compositions with the inhibiting benzimidazole compound of proton pump need be in small intestinal disintegrate fast; Therefore said composition is preferably processed wideer granule of surface area ratio tablet or fine grained agent, thereby carries out quick disintegrate or dissolving more easily.For the situation of tablet, it is desirable to reduce the size (for example referring to JP-A 62-277322) of tablet.

After the oral administration, tablet, granule or fine grained agent are moved through gastrointestinal tract, successively disengage active component to stomach, duodenum, jejunum, ileum and colon.During this period, active component is absorbed in each absorption position.The purpose of design controlled release preparation is to control this Absorption through postponing disengaging of active component with certain mode.According to thinking,, can further prolong persistency through the associating controlled release system and simultaneously by means of the means of migration velocity in the control gastrointestinal tract for example adhesive capacity, the ability of floating etc.These prior aries are disclosed in WO 01/89483, JP-A 2001-526213, USP 6,274,173, USP 6,093,734, USP 4; 045,563, USP 4,686, and 230, USP 4,873; 337, USP 4,965, and 269, in USP 5,021,433 documents such as grade.

Disclosure of the Invention

(goal of the invention)

The object of the invention is the controlled release preparation that provides a kind of wherein active component to be disengaged by control, and it is through delaying (staying) or slowing down migration in (slowly) gastrointestinal tract and delay time and disengage active component.

(summary of the invention)

That is to say, the invention provides:

(1) a kind of capsule, it contains tablet, granule or fine grained agent that active component wherein disengaged by control and the polymer that forms gel;

(2) according to the capsule of above-mentioned (1), wherein active component disengages through being formed on the controlled release coat layer control on the nuclear slug particle (core particle) that contains active component;

(3) according to the capsule of above-mentioned (2), wherein this controlled release coat layer contains the polymer (pH-dependently soluble polymer) by pH decision solubility;

(4) according to the capsule of above-mentioned (2), wherein this controlled release coat layer is the control diffusion layer;

(5) according to the capsule of above-mentioned (1), wherein disengaging through active component being scattered in the controlled release matrix that contains tablet, granule or fine grained agent of active component controlled;

(6) according to the capsule of above-mentioned (3) or (4); The tablet that wherein said wherein active component is disengaged by control, granule or fine grained agent have and are formed on the disintegrate layer that contains disintegrating agent on the nuclear slug particle that contains active component and are formed on the controlled release coat layer on the said disintegrate layer, and disengaging after certain lag time of active component begins;

(7) according to any one capsule in above-mentioned (3)-(6), the tablet that wherein said wherein active component is disengaged by control, granule or fine grained agent are with the polymer coating that forms gel;

(8) according to the capsule of above-mentioned (7), it further also contains the polymer that forms gel;

(9) according to any one capsule in above-mentioned (1)-(7), it contains two types have makes the active component difference disengage the tablet of characteristic, granule or fine grained agent;

(10) according to the capsule of above-mentioned (9), it contains, and to have at pH be that about to disengage tablet, granule or the fine grained agent of the enteric coating of active component at 5.5 o'clock and have at pH be about 6.0 or the tablet, granule or the fine grained agent that disengage the controlled release coat layer of active component when above;

(11) according to the capsule of above-mentioned (1), (7) or (8), wherein the polymer of this formation gel is about 3 for its 5% aqueous solution 25 ℃ viscosity, the polymer of 000MPas;

(12) according to the capsule of above-mentioned (1), (7) or (8), wherein the polymer of this formation gel is that molecular weight is 400,000-10,000,000 polymer;

(13) according to any one capsule in above-mentioned (2)-(4) or (6), wherein this controlled release coat layer is the layer that contains the following polymeric material of being selected from of one or more types: HPMCP, cellulose ethanoate phthalic acid ester, carboxymethylethylcellulose, methyl methacrylate-EUDRAGIT S100, EUDRAGIT L100-55, ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium ethyl ester chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, methacrylic acid-acrylic acid methyl ester .-methylmethacrylate copolymer, hydroxypropyl cellulose acetas succinate and polyvinyl acetate phthalic acid ester;

(14) according to the capsule of above-mentioned (13), wherein this controlled release coat layer is made up of the layer of two kinds or more kinds of types;

(15) according to the capsule of above-mentioned (1), wherein the particle size of this controlled release granule and fine grained agent is about 100-1,500 μ m;

(16) according to the capsule of above-mentioned (1), wherein this active component is proton pump inhibitor (PPI);

(17) according to the capsule of (16), wherein this PPI is imidazolium compounds or its salt or its optical isomer (optically active isomer) by formula (I ') representative:

Its medium ring C ' is optional substituted phenyl ring or the optional single heterocycle of substituted fragrance, R ⁰Be hydrogen atom, optional substituted aralkyl, acyl group or acyloxy, R ¹, R ²And R ³Identical or different and be hydrogen atom, optional substituted alkyl, optional substituted alkoxyl or optional substituted amino, Y represents nitrogen-atoms or CH;

(18) according to the capsule of above-mentioned (17), wherein this imidazolium compounds is lansoprazole (lansoprazole);

(19) according to the capsule of above-mentioned (17), wherein PPI is the R-optical isomer of lansoprazole;

(20) according to any one capsule in above-mentioned (1), (7) or (8); Wherein the polymer of this formation gel is the following material of being selected from of one or more types: PEO (PEO; Molecular weight: 400; 000-10,000,000), hydroxypropyl emthylcellulose (HPMC), carboxymethyl cellulose (CMC-Na), hydroxypropyl cellulose (HPC), hydroxyethyl-cellulose and carboxy vinyl polymer;

(21) according to any one capsule in above-mentioned (1), (7) or (8), wherein the polymer of this formation gel is PEO (molecular weight: 400,000-10,000,000);

(22) according to the capsule of above-mentioned (1) or (8), the polymer that wherein should form gel adds with powder, fine grained or particulate form;

(23) according to the capsule of above-mentioned (3), should be methyl methacrylate-EUDRAGIT S100 wherein by the polymer of pH decision solubility;

(24) tablet, granule or the fine grained agent that are disengaged by control of a kind of wherein active component, said tablet, granule or fine grained agent contain

Contain by the imidazolium compounds of formula (I ') representative or its salt or its optical isomer nuclear slug particle as active component:

Its medium ring C ' is optional substituted phenyl ring or the optional single heterocycle of substituted fragrance, R ⁰Be hydrogen atom, optional substituted aralkyl, acyl group or acyloxy, R ¹, R ²And R ³Identical or different and be hydrogen atom, optional substituted alkyl, optional substituted alkoxyl or optional substituted amino, Y represents nitrogen-atoms or CH; And

Controlled release coat layer by pH decision solubility; It contain one type polymeric material or two kinds or more kinds of types have a mixture that difference is disengaged the polymeric material of characteristic; This polymeric material is selected from HPMCP, cellulose ethanoate phthalic acid ester, carboxymethylethylcellulose, methyl methacrylate-EUDRAGIT S100, EUDRAGIT L100-55, methacrylic acid-acrylic acid methyl ester .-methylmethacrylate copolymer, hydroxypropyl cellulose acetas succinate, polyvinyl acetate phthalic acid ester and Lac, and said polymeric material is soluble in the pH of 6.0-7.5 scope;

(25) according to tablet, granule or the fine grained agent of above-mentioned (24), wherein on the intermediate layer that is formed on the nuclear slug particle, form this controlled release coat layer by pH decision solubility;

(26) capsule, it contains tablet, granule or the fine grained agent of with good grounds above-mentioned (24);

(27) capsule, it contains tablet, granule or the fine grained agent of with good grounds above-mentioned (24) and contains enteric coated tablet, granule or the fine grained agent by the chemical compound of formula (I ') representative;

(28) according to tablet, granule or the fine grained agent of above-mentioned (24), wherein this active component is a lansoprazole;

(29) according to tablet, granule or the fine grained agent of above-mentioned (24), wherein this active component is the R-optical isomer of lansoprazole;

(30) according to tablet, granule or the fine grained agent of above-mentioned (24), wherein this active component is the S-optical isomer of lansoprazole;

(31) according to tablet, granule or the fine grained agent of above-mentioned (24), wherein this active component is the derivant of lansoprazole;

(32) according to tablet, granule or the fine grained agent of above-mentioned (24), wherein this active component is the derivant of the R-optical isomer of lansoprazole;

(33) according to tablet, granule or fine grained agent any one in above-mentioned (24), (25) or (28)-(32), it contain contain the enteric coating layer that has on the nuclear slug particle of active component, at disintegrate layer that contains disintegrating agent on the said enteric coating layer and the controlled release coat layer on said disintegrate layer;

(34) according to tablet any in above-mentioned (28)-(33), granule or fine grained agent, it is with the polymer coating that forms gel;

(35) a kind of time-delay disengages capsule, and it contains tablet any in good grounds above-mentioned (28)-(33), granule or fine grained agent and forms the polymer of gel;

(36) according to tablet, granule or the fine grained agent of above-mentioned (24); Disengaging of the controlled release coat layer control active component through two kinds or more kinds of types wherein, and outmost controlled release coat layer is soluble under than the higher pH of the controlled release coat layer of its inside;

(37) according to tablet, granule or the fine grained agent of above-mentioned (36), wherein the controlled release coat layer of the inside is soluble in the pH of 6.0-7.0 scope, outmost controlled release coat layer 7.0 or above pH under be soluble;

(38) according to tablet, granule or the fine grained agent of above-mentioned (36), wherein the controlled release coat layer of the inside is soluble in the pH of 6.5-7.0 scope, outmost controlled release coat layer 7.0 or above pH under be soluble;

(39) according to tablet, granule or the fine grained agent of above-mentioned (36), the thickness of wherein outmost controlled release coat layer is 100 μ m or littler;

(40) according to the granule or the fine grained agent of above-mentioned (36), wherein the particle size of this controlled release granule or fine grained agent is about 100-1,500 μ m;

(41) a kind of capsule, it contains

(i) the wherein tablet, granule or the fine grained agent that are disengaged by control of active component; Said tablet, granule or fine grained agent contain by the imidazolium compounds of formula (I ') representative or its salt or its optical isomer nuclear slug particle as active component:

Its medium ring C ' is optional substituted phenyl ring or the optional single heterocycle of substituted fragrance, R ⁰Be hydrogen atom, optional substituted aralkyl, acyl group or acyloxy, R ¹, R ²And R ³Identical or different and be hydrogen atom, optional substituted alkyl, optional substituted alkoxyl or optional substituted amino, Y represent nitrogen-atoms or CH and

Controlled release coat layer by pH decision solubility; It contain one type polymeric material or two kinds or more kinds of types have a mixture that difference is disengaged the polymeric material of characteristic; This polymeric material is selected from HPMCP, cellulose ethanoate phthalic acid ester, carboxymethylethylcellulose, methyl methacrylate-EUDRAGIT S100, EUDRAGIT L100-55, methacrylic acid-acrylic acid methyl ester .-methylmethacrylate copolymer, hydroxypropyl cellulose acetas succinate, polyvinyl acetate phthalic acid ester and Lac, and said polymeric material is solvable (soluble) in the pH of 6.0-7.5 scope; And

(ii) contain the nuclear slug particle of active component and tablet, granule or the fine grained agent of having dissolved the enteric coating of (dissolved), active component is being not less than 5.0 or be not higher than under 6.0 the pH scope and disengage like this;

(42) according to the capsule of above-mentioned (41), wherein on the intermediate layer, form this controlled release coat layer by pH decision solubility, form the intermediate layer containing on the nuclear slug particle of active component;

(43) according to the capsule of above-mentioned (41), wherein this active component is a lansoprazole;

(44) according to the capsule of above-mentioned (41), wherein this active component is the R-optical isomer of lansoprazole;

(45) according to the capsule of above-mentioned (41), wherein this active component is the S-optical isomer of lansoprazole;

(46) according to the capsule of above-mentioned (41), wherein this nuclear slug particle that contains active component contains the stabilizing agent of basic inorganic salt;

(47) according to the capsule of above-mentioned (41), this wherein is being not less than 6.5 or be not higher than under 7.0 the pH scope and dissolve by the controlled release coat layer of pH decision solubility in the tablet, granule or the fine grained agent that are disengaged by control of active component;

(48), wherein contain the methyl methacrylate-EUDRAGIT S100 that difference is disengaged characteristic that has of two kinds or more kinds of types by the controlled release coat layer of pH decision solubility according to the capsule of above-mentioned (47); And

(49) according to the capsule of above-mentioned (41), it further also contains the polymer that forms gel.

(detailed Description Of The Invention)

The present invention relates to a kind of pharmaceutical composition that contains tablet, granule or fine grained agent that active component wherein disengaged by control, perhaps a kind of pharmaceutical composition of polymer that contains above-mentioned tablet, granule or fine grained agent and postpone the formation gel of digestive tract migration velocity.Pharmaceutical composition of the present invention can be exactly said tablet, granule or fine grained agent itself, or contains the mixture of polymers form of tablet, granule or fine grained agent and formation gel, perhaps is filled in the capsule in the capsule, preferred especially capsule.Clearly show at present, through the persistency of oral back blood content of having taken all factors into consideration these factor significant prolongations.

It is to carry out coating, or accomplish through active component is scattered in the controlled release matrix through the layer that the active component in tablet, granule or the fine grained agent is disengaged with the control active component that the control of the active component among the present invention " wherein active component disengaged by control tablet, granule or fine grained agent " disengages.In addition; The present invention " wherein active component disengaged by control tablet, granule or fine grained agent " also comprises tablet, granule or the fine grained agent that is used in dissolved common enteric coating coating under about 5.5 the pH, and the tablet that contains these granules or fine grained agent.

On the other hand; When mentioning " controlled release coat layer " in this manual; It is meant to have further delay or prolong the coatings that active component disengages function; (common enteric coating dissolves under about 5.5 pH) dissolved coatings and self undissolved control diffusion layer by pH decision solubility under the pH scope higher than common enteric coating for example, it disengages active component through the aperture that is formed in this layer.The coating that it does not comprise common enteric coating and under about 5.5 pH, dissolves, is dissolved in intestinal juice and disengages active component rapidly.In addition, mentioned here pH is meant the pH of Mcilvaine solution or Clark-Lubs solution.Hereinafter, determine the pH of the coatings of solubility to be meant the pH of said solution by pH.

Coatings in " controlled release coat layer " comprises that the coatings of form membrane has the coatings of big thickness with those.In addition; Said coatings not only comprises the coatings of kernel or internal layer being carried out complete coating; Comprise that also part kernel wherein or internal layer are not capped but most of kernel or internal layer are by the coatings of coating (having covered about at least 80% or the more coatings on kernel or internal layer surface, preferred covering surfaces fully).

Digestive tract passes through system's control of two types to the absorption of the active component in the pharmaceutical composition of the present invention; They utilize (1) to control disengaging of active component through controlled release tablet, granule or fine grained agent respectively and (2) make tablet, granule or fine grained agent keep being present in for a long time in the digestive tract through the polymer that forms gel, perhaps comprehensive this two aspects factor.In pharmaceutical composition of the present invention; Moisture during this contains the compositions of the polymer that forms gel its polymer through this formation gel is assimilated rapidly when by oral administration forms viscogel, and tablet, granule or fine grained agent are retained on the gel surface and slowly move through digestive tract then.When the control active component disengaged, active component disengaged through controlled release system from tablet, granule or fine grained agent continuously or with the form of pulsation, had so just reached the purpose of time-delay absorption and acquisition curative effect of medication.

Disengage to guarantee that the long-lasting said system of treatment effect level has these advantages through long-time control: it remains treatment effectively when the low dosage administration; Also reduce the side effect that causes because of risings such as initial haemoconcentrations simultaneously, and reduced administration time.

The polymer that forms gel can be a kind of like this polymer, thereby it has prolonged the retention time in digestive tract through contact the gel that forms high viscosity rapidly with water.It is about 3000MPas or bigger polymer that the polymer of this type formation gel is preferably 25 ℃ of its 5% viscosity in aqueous solution.In addition in general, the polymer of this formation gel is preferably the polymer that molecular weight is about 400000-10000000 usually.In order to prepare preparation, preferred powder powder, granular or granuliform polymer for the polymer that forms gel.7000000), Polyox WSR coagulating agent (molecular weight: 5000000), PolyoxWSR 301 (molecular weight: 4000000), Polyox WSR N-60K (molecular weight: 2000000) and Polyox WSR 205 (molecular weight: 600000) polymer that forms gel comprises PEO (PEO, for example PolyoxWSR 303 (molecular weight:; Dow Chemical Co., Ltd. makes), hydroxypropyl emthylcellulose (HPMC, Metlose 90SH10000, Metlose 90SH50000 and Metlose90SH30000; Shin-Etsu Chemical Co.; Ltd. manufacturing), carboxymethyl cellulose (CMC-Na; Sanlose F-1000MC), hydroxypropyl cellulose (HPC, HPC-H for example, Nippon Soda Co.; Ltd. manufacturing), hydroxyethyl-cellulose (HEC), carboxy vinyl polymer (HIVISWAKO (R) 103,104 and 105, Wako Pure Chemical Industries Ltd. manufacturing; CARBOPOL 943, and Goodrich Co., Ltd. makes), chitosan, sodium alginate, colloid (pectin) etc.They can use separately perhaps to contain two kinds or more kinds of form of mixtures use according to the blended powder of proper proportion at least.Especially, preferably use PEO, HPMC, HPC, CMC-Na, carboxy vinyl polymer etc. as the polymer that forms gel.

Wherein a kind of preferred dosage form of the tablet, granule or the fine grained agent that are disengaged by control of active component comprises that the nuclear slug particle that wherein contains at least a active component is with tablet, granule or the fine grained agent of controlled release coat layer coating and contain these granules or the tablet of fine grained agent.Have tablet, granule or the fine grained agent of examining core in order to prepare this type; The nuclear slug particle can use tablet, granule or fine grained agent; In this tablet, granule or fine grained agent, active component is coated on the nuclear core into inert carrier, said inert carrier is NONPAREIL (NONPAREIL-101 (particle diameter: 850-710,710-500 and 500-355), NONPAREIL-103 (particle diameter: 850-710,710-500 and 500-355), NONPAREIL-105 (particle diameter: 710-500,500-355 and 300-180) for example; Freund Industrial Co., Ltd. makes) and Celphere (CP-507 (particle diameter: 500-710) and CP-305 (particle diameter: 300-500); Asahi Kasei Corporation makes); The tablet that perhaps utilizes these granules or fine grained agent to prepare; Perhaps granule through utilizing active component and the excipient that is generally used for preparation to granulate and obtain.For example, they can prepare according to disclosed method in JP-A 63-301816.For example; When the nuclear slug particle is when preparing on through the nuclear core that active component is coated on inert carrier; This nuclear slug particle that contains active component can use for example centrifugal liquid bed granulator (CF-mini; CF-360, FreundIndustrial Co., Ltd. makes) or centrifugal fluidization coating granulator (POWREX MP-10) etc. obtain through wet granulation.In addition, simultaneously active component is carried out dusting at the solution that adding contains binding agent, so also can accomplish coating through on inert carrier, utilizing means such as spraying.Manufacturing installation is also unrestricted, and preference is as using centrifugal liquid bed granulator etc. in the coating steps of back.The coating of active component can be used above-mentioned two kinds of devices to be coated with to accomplish through uniting according to two-step method.If do not use inert carrier; The preparation of nuclear slug particle can be used granulation excipient for example lactose, white sugar, mannitol, corn starch and crystalline cellulose and active component; Use binding agent for example hydroxypropyl emthylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl alcohol, Macrogol, Pullronic F68, Radix Acaciae senegalis, gelatin and starch; If necessary; Add disintegrating agent for example sodium carboxymethyl cellulose, carboxymethylcellulose calcium, cross-linking sodium carboxymethyl cellulose (Ac-Di-Sol; FMC International Co., Ltd. makes), polyvinylpyrrolidone and low substituted hydroxypropyl cellulose, use mixer granulator, wet method extruding granulator, fluidised bed granulator etc. simultaneously.

Granule with satisfied size can obtain through resulting granules or fine grained are sieved.The nuclear slug particle can use compressors etc. to prepare through dry granulation.To use particle size be 50 μ m to 5mm, be preferably 100 μ m to 3mm, the granule of 100 μ m to 2mm more preferably.

The nuclear slug particle that contains active component that obtains through said method can be obtained middle coatings by further coating, and such granule can be used as the nuclear slug particle.When active component is to the unsettled medicine of acid for example during PPI etc., from improving the angle of medicine stability, preferably having this centre coatings is in order to cut off direct contact the between the nuclear slug particle that contains active component and the controlled release coat layer.The intermediate layer can be made up of multilamellar.

The coating material that is used for the intermediate layer comprises the coating material that obtains through suitable mixed polymerization material and saccharide; The wherein for example low substituted hydroxypropyl cellulose of polymeric material, hydroxypropyl cellulose, hydroxypropyl emthylcellulose (for example TC-5 etc.), polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose and hydroxyethylmethyl-cellulose, saccharide be for example corn starch, lactose, sugar alcohol (D-mannitol, erythritol etc.) of sucrose [sucrose of purification (grind to form powdery (Icing Sugar), do not grind to form powdery) etc.], starchy carbohydrate for example.In order to obtain hereinafter described preparation, can in this centre coatings, suitably add excipient (for example screening agent (titanium oxide etc.) and antistatic additive (titanium oxide, Talcum etc.) if necessary.

The granule that contains active component based on 1 weight portion calculates, and the coating consumption of middle coatings is typically about 0.02 weight portion to about 1.5 weight portions, is preferably about 0.05 weight portion to about 1 weight portion.Coating can carry out according to conventional method.For example, preferably each component of middle coatings is diluted with purified water, again with the liquid form spray coating.Preferably for example carry out coating in the hydroxypropyl cellulose spraying binding agent then.

For the controlled release tablet, granule or the fine grained agent that are included in the pharmaceutical composition of the present invention; Preferably above-mentioned nuclear slug particle is used by pH decision to dissolve/coating material that eluting control disengages carries out coating, preferred for preparation obtain having the controlled release coat layer tablet, granule or fine grained agent, or contain the tablet of these controlled release granules or fine grained agent.Here, " by pH decision " is meant that only dissolving/eluting comes out to disengage active component to coating material surpassing under the specific pH value environment.Thereby eluting comes out to cause disengaging of medicine to enteric coating commonly used under 5.5 the pH being approximately; Coating material of the present invention be preferably dissolving under the higher pH (preferred pH 6.0 or above and 7.5 or below, more preferably pH 6.5 or above and below 7.2) and more advantageously control medicine and disengage at stomach.

Control the coating material that active constituents of medicine disengages as being used for according to pH; Can use for example HPMCP (HP-55, HP-50 of polymer; Shin-Etsu Chemical Co.; Ltd. manufacturing), cellulose ethanoate phthalic acid ester, carboxymethylethylcellulose (CMEC; Freund Industrial Co., Ltd. makes), methyl methacrylate-EUDRAGIT S100 (EudragitL100 (EUDRAGIT S100 L) or Eudragit S100 (EUDRAGIT S100 S); Rohm Co. manufacturing), EUDRAGIT L100-55 (Eudragit L100-55 (exsiccant EUDRAGIT S100 LD) or Eudragit L30D-55 (EUDRAGIT S100 LD); Rohm Co. manufacturing), methacrylic acid-acrylic acid methyl ester .-methylmethacrylate copolymer (Eudragit FS30D; Rohm Co. manufacturing), hydroxypropyl cellulose acetas succinate (HPMCAS; Shin-Etsu Chemical Co., Ltd. makes), polyvinyl acetate phthalic acid ester and Lac.Tablet, granule or fine grained agent can contain two kinds or having of more kinds of types makes active component disengage the controlled release coat layer of characteristic to some extent.Polymer as above-mentioned coating material may be used solely to coating, and the polymer that also can unite at least two kinds or more kinds of types is used for coating, perhaps uses the polymer of at least two kinds or more kinds of types to carry out continuous coating and obtains multiple coatings.Ideal situation is, coating material use separately or unite if necessary use and guarantee this polymer preferably pH be 6.0 or above, more preferably pH be 6.5 or above, further be 6.75 or above dissolving more preferably at pH.Better in addition situation is; The associating use pH be 6.0 or more than soluble polymer and pH be 7.0 or more than soluble polymer; Better in addition situation is, according to 1: 0.5 to 1: 5 ratio unite use pH be 6.0 or more than soluble polymer and pH be 7.0 or more than soluble polymer.

In addition if necessary, can use plasticizer for example Polyethylene Glycol, dibutyl sebacate, diethyl phthalate, glyceryl triacetate (triacetin) and triethyl citrate, stabilizing agent etc. carry out coating.Calculate based on the nuclear slug particle, the consumption of coating material is 5% to 200%, is preferably 20% to 100%, more preferably 30% to 60%.Ideal situation is; Active component from making of obtaining the thus speed that eluting comes out tablet, granule or the fine grained agent that active component control disengages in the solution of pH 6.0, to continue after 5 hours be 10% or still less; In the solution of pH 6.8, to continue be 5% or still less after 1 hour, and to continue be 60% or more after 8 hours.

This controlled release tablet, granule or fine grained agent (being called for short controlled release granule below sometimes) can be wherein making in tablet, granule or the fine grained agent that active component control disengages of obtaining thus with a kind of and the tablet, granule or the fine grained agent that have the material coating of viscosity after water contacts; 7000000), Polyox WSR coagulating agent (molecular weight: 5000000), Polyox WSR 301 (molecular weight: 4000000), Polyox WSR N-60K (molecular weight: 2000000) and Polyox WSR 205 (molecular weight: 600000) wherein with the material that has viscosity after water contacts PEO (PEO, for example Polyox WSR 303 (molecular weight: for example; Dow Chemical Co., Ltd. makes), hydroxypropyl emthylcellulose (HPMC, Metlose 90SH10000, Metlose 90SH50000, Metlose 90SH30000; Shin-EtsuChemical Co.; Ltd. manufacturing), carboxymethyl cellulose (CMC-Na; Sanlose F-1000MC), hydroxypropyl cellulose (HPC; HPC-H for example, Nippon Soda Co., Ltd. makes), hydroxyethyl-cellulose (HEC), (HIVISWAKO (R) 103,104,105:Wako Pure ChemicalIndustries Ltd. make carboxy vinyl polymer; CARBOPOL 943, and Goodrich Co., Ltd. makes), chitosan, sodium alginate and pectin.

This controlled release granule can for the nuclear slug particle that wherein contains active component by the form of diffusion-controlled layer coating, this diffusion-controlled layer has through diffusion controls the effect that active component disengages.The material that is used for diffusion-controlled layer comprises ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium ethyl ester chloride (trimethylammoniumethyl methacrylate chloride) copolymer (Eudragit RS (EudragitRS PO EUDRAGIT RSPO eudragit RS-100 eudragit RS-PO) or Eudragit RL (amino alkyl methacrylate copolymer RL); Rohm Co. manufacturing), methyl methacrylate-ethyl acrylate copolymer (Eudragit NE30D, Rohm Co. makes), ethyl cellulose etc.In addition; The above-mentioned material that is used for diffusion-controlled layer can mix in accordance with the appropriate ratio; Also can mix use with hydrophilic pore-forming material according to the ratio of confirming, hydrophilic pore-forming material is HPMC, HPC, carboxy vinyl polymer, polyethylene glycol 6000, lactose, mannitol and organic acid for example.

In addition; Be controlled in tablet, granule or the fine grained agent that begins to disengage after definite lag time in order to prepare active component wherein, through before the above-mentioned diffusion-controlled layer of coating with swellability material disintegrating agent coating and containing between nuclear slug particle and the controlled release coat layer of active component and obtain a disintegrate layer for example.For example; Preferably at first examining on the slug particle with the for example crosslinked carmelose sodium of swellability material (Ac-Di-Sol; FMC International Co. manufacturing), (ECG 505 for carmelose calcium; GotokuChemicals Co. manufacturing), CROSSPOVIDON (ISP Inc.) and low substituted hydroxypropyl cellulose (L-HPC; Shin-Etsu Chemical Co.; Ltd. make) coating, then with resulting coated granule with diffusion-controlled layer coating for the second time, wherein diffusion-controlled layer through or more kinds of types a kind of according to the mixed of confirming be selected from following polymer and hydrophilic pore-forming material prepares: ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium ethyl ester chloride copolymer (Eudragit RS or Eudragit RL; Rohm Co. manufacturing), methyl methacrylate-ethyl acrylate copolymer (EudragitNE30D, Rohm Co. makes), ethyl cellulose etc.; Hydrophilic pore-forming material is HPMC, HPC, carboxy vinyl polymer, polyethylene glycol 6000, lactose, mannitol and organic acid for example.Coating material can be the enteric polymer of disengaging active component according to pH for the second time, for example HPMCP (HP-55, HP-50; Shin-Etsu Chemical Co., Ltd. makes), cellulose ethanoate phthalic acid ester, carboxymethylethylcellulose (CMEC; Freund Industrial Co., Ltd. makes), methyl methacrylate-EUDRAGIT S100 (Eudragit L100 (EUDRAGIT S100 L) or Eudragit S100 (EUDRAGIT S100 S); Rohm Co. manufacturing), EUDRAGIT L100-55 (Eudragit L100-55 (exsiccant EUDRAGIT S100 LD) or EudragitL30D-55 (EUDRAGIT S100 LD); Rohm Co. manufacturing), methacrylic acid-acrylic acid methyl ester .-methylmethacrylate copolymer (Eudragit FS30D; Rohm Co. manufacturing), hydroxypropyl cellulose acetas succinate (HPMCAS; Shin-Etsu Chemical Co., Ltd. makes), polyvinyl acetate and Lac.Calculate based on the nuclear slug particle, the consumption of coating material is 1% to 200%, is preferably 20% to 100%, more preferably 30% to 60%.

If necessary, can use plasticizer for example Polyethylene Glycol, dibutyl sebacate, diethyl phthalate, glyceryl triacetate and triethyl citrate, stabilizing agent etc. carry out coating.This controlled release tablet, granule or fine grained agent can be wherein making in tablet, granule or the fine grained agent that active component control disengages of obtaining thus with a kind of and the tablet, granule or the fine grained agent that have the material coating of viscosity after water contacts; 5000000), Polyox WSR 301 (molecular weight: 4000000), Polyox WSR N-60K (molecular weight: 2000000) and Polyox WSR 205 (molecular weight: 600000) 7000000), Polyox WSR coagulating agent (Coagulant) molecular weight wherein with the material that has viscosity after water contacts PEO (PEO, for example PolyoxWSR 303 (molecular weight:: for example; Dow Chemical Co., Ltd. makes), hydroxypropyl emthylcellulose (HPMC, Metlose 90SH10000, Metlose 90SH50000, Metlose 90SH30000; Shin-Etsu Chemical Co.; Ltd. manufacturing), carboxymethyl cellulose (CMC-Na; Sanlose F-1000MC), hydroxypropyl cellulose (HPC; HPC-H for example, NipponSoda Co., Ltd. makes), hydroxyethyl-cellulose (HEC), (HIVISWAKO (R) 103,104,105:Wako Pure Chemical Industries Ltd. make carboxy vinyl polymer; CARBOPOL 943, and Goodrich Co., Ltd. makes), chitosan, sodium alginate and pectin.

Active component is disengaged in tablet, granule or the fine grained agent of the controlled release coat layer of characteristic to some extent containing two kinds or having of more kinds of types, can between said controlled release coat layer, form one contain active component coatings.These comprise tablet, granule or the fine grained agent for preparing according to following method in the multiple structure form that contains active component between the controlled release coat layer: with coating, then reuse controlled release coat layer of the present invention coating in the active component tablet, granule or the fine grained agent that are disengaged by controlled release coat layer of the present invention control of active component therein.

Another form of the tablet that wherein at least a active component is disengaged by control, granule or fine grained agent can be that wherein active component is dispersed in tablet, granule or fine grained agent in the controlled release matrix.Preparing these controlled release tablets, granule or fine grained agent can for example prepare in wax class such as hardened castor oil, fixed oil Oleum Brassicae campestris, stearic acid and stearyl alcohol and the polyglyceryl fatty acid ester through active component being dispersed in hydrophobic carrier.Substrate is that wherein active component is dispersed in the composition forms in the carrier.If necessary, can for example lactose, mannitol, corn starch and crystalline cellulose disperse with active component with those excipient that are usually used in preparing medicine.In addition; Polyoxyethylene oxide, crosslinked acrylic acid polymer (HIVISWAKO (R) 103,104 and 105; CARBOPOL), the powder of HPMC, HPC, chitosan etc. is because of forming viscogel through contacting with water, so also can it be scattered in the substrate with active component and excipient.

For its preparation method, they can be through the method preparation of for example spray drying, spray cooling and melt granulation.

This controlled release tablet, granule or fine grained agent can be wherein making in tablet, granule or the fine grained agent that active component control disengages of obtaining thus with a kind of and the tablet, granule or the fine grained agent that have the material coating of viscosity after water contacts; 7000000), Polyox WSR coagulating agent (molecular weight: 5000000), Polyox WSR 301 (molecular weight: 4000000), Polyox WSR N-60K (molecular weight: 2000000) and Polyox WSR 205 (molecular weight: 600000) wherein with the material that has viscosity after water contacts PEO (PEO, for example Polyox WSR 303 (molecular weight: for example; Dow Chemical Co., Ltd. makes), hydroxypropyl emthylcellulose (HPMC, Metlose 90SH10000, Metlose 90SH50000, Metlose 90SH30000; Shin-Etsu Chemical Co.; Ltd. manufacturing), carboxymethyl cellulose (CMC-Na; Sanlose F-1000MC), hydroxypropyl cellulose (HPC; HPC-H for example, NipponSoda Co., Ltd. makes), hydroxyethyl-cellulose (HEC), (HIVISWAKO (R) 103,104,105:Wako Pure Chemical Industries Ltd. make carboxy vinyl polymer; CARBOPOL 943, and Goodrich Co., Ltd. makes), chitosan, sodium alginate and pectin.Above-mentionedly can coexist as in a kind of formulation example such as the capsule, also can be used for coating with the material that has viscosity after water contacts.

Wherein the tablet of the present invention, granule or the fine grained agent that are disengaged by control of active component can be for having the form of above-mentioned various types of controlled release coat layer, controlled release matrix etc. simultaneously.

The size of tablet, granule or the fine grained agent that is disengaged by control as for active component wherein, can to use particle size be 50 μ m to 5mm, be preferably 100 μ m to 3mm, the granule of 100 μ m to 2mm more preferably.Most preferably particle size is granule or the fine grained agent of about 100 μ m to 1500 μ m.

In addition; Can also use various additives for example to be used to prepare the excipient (for example glucose, fructose, lactose, sucrose, D-mannitol, erythritol, polyhydric alcohol (multitol), trehalose, Sorbitol, corn starch, potato starch, wheaten starch, rice starch, crystalline cellulose, silicic acid anhydride, inclined to one side calcium phosphide, deposition calcium carbonate, calcium silicates etc.) of preparation; Binding agent (for example hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, sodium carboxymethyl cellulose, part alphalise starch, alphalise starch, sodium alginate, Prussia blue (pullulan), gum arabic powder, gelatin etc.); Disintegrating agent (for example low substituted hydroxypropyl cellulose, carmelose, carmelose calcium, carboxymethyl starch sodium, crosslinked carmelose sodium, crospolyvinylpyrrolidone (crosspovidon), hydroxypropyl starch etc.); Flavoring agent (for example citric acid, ascorbic acid, tartaric acid, malic acid, aspartame sugar, acesulfame potassium, thaumatin, saccharin sodium, glycyrrhizin di-potassium (glycylrrhizin dipotassium), Kaglutam, 5 '-sodium inosinate, 5 '-sodium guanylate etc.); Surfactant (for example multi-solvent (multi-solvent 80 etc.), polyoxyethylene-polyoxypropylene copolymer, sodium lauryl sulphate etc.); Aromatic (for example Fructus Citri Limoniae oil, orange-seed oil, menthol, Herba Menthae wet goods); Lubricant (for example magnesium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, Talcum, Polyethylene Glycol etc.); Coloring agent (for example titanium oxide, yellow No. 5 of edible, blue No. 2 of edible, ferrum oxide (III), Huang Tie (III) oxide etc.); Antioxidant (for example sodium ascorbate, L-cysteine, sodium bisulfate etc.); Screening agent (for example titanium oxide etc.), and antistatic additive (for example Talcum, titanium oxide etc.).

Raw-material particle diameter for used does not have particular restriction, considers from processing and administration angle, and preferred diameter is about 500 μ m or littler particle.

The tablet that obtains thus, granule or fine grained agent can be mixed with the polymer thereby the administration of the formation gel that is retained in the gastrointestinal tract like this, perhaps process capsule in the capsule through it is inserted.For controlled release tablet, granule or fine grained agent, the polymer that is retained in the formation gel in the digestive tract is 0.1% to 100%, is preferably 2% to 50%, more preferably 10% to 40%, further more preferably 10% to 35%.

The pharmaceutical composition of the present invention that obtains thus has the pharmaceutically active of time-delay by means of controlled release system, its therapeutic effect kept 6 hours at least, and preferred 8 hours, more preferably 12 hours, further preferred 16 hours.

This pharmaceutically active field do not have particular restriction for active component, no matter all can be applied.Instance has anti-inflammatory agent for example indomethacin (indomethacin) and acetaminophen (acetaminophen); Analgesic is morphine for example; The cardiovascular antagonist is diazepam (diazepam) and diltiazepam for example; Antihistaminic is chlorphenamine maleate (chlorophenylamine meleate) for example; Antineoplastic agent is fluorouracil (fluorouracil) and aclarubicin (aclarubicin) for example, and anesthetics is midazolam (midazolam) for example, and anti-hemorrhage is ephedrine (ephedrine) for example; Diuretic is hydrochlorothiazide (hydrochlorothiazide) and FRS (furosemide) for example; Bronchodilator is bitter edible plant alkali (theophyline) for example, and cough medicine is codeine (codeine) for example, and anti-arrhythmic (antiarrythmic) is quinidine (quinidine) and dizoxin for example; Antidiabetic drug is tolbutamide (tolbutamide), pioglitazone (pioglitazone) and troglitazone (troglitazone) for example; Vitamins is vitamin C for example, and anticonvulsant is phenitoin for example, and local anesthetic is lignocaine (lidocaine) for example; Adrenocortical hormones is hydrocortisone for example; The nervus centralis active drug is eisai for example, and hypolipidemic is pravastatin for example, and antibiotics is amoxicillin and cefalexin for example; (exitomotory) medicine for example mosapride (mosapride) and cisapride (cisapride) are told by the digestive tract town; The S omeprazole), rabeprazole (rabeprazole) and optical isomer, pantoprazole (pantoprazole) and optical isomer thereof etc. are the benzimidazole proton pump inhibitor of representative (protonpump inhibitor the medicine H2 blocade of gastritis, symptomatic gastroesophageal reflux disease and gastric ulcer and duodenal ulcer is famotidine (famotidine), ranitidine (ranitidine) and Cimetidine (cimetidine) for example, and with (the S-isomer: of lansoprazole and optical isomer thereof (R-isomer and S-isomer, preferred R-isomer (being called compd A hereinafter sometimes)), omeprazole (rabeprazole) and optical isomer thereof; PPI), and with tenatoprazole etc. is the imidazopyridine PPI of representative.

According to the present invention; Said preparation has fabulous curative effect of medication persistency, it contain PPI for example by formula (I ') representative to the unsettled imidazolium compounds of acid such as lansoprazole and optical isomer thereof, especially by formula (I) representative to the unsettled benzimidazole compound of acid and corresponding by formula (II) or (III) sour relatively stable imdazole derivatives (preceding Types of Medicine PPI) or its salt or its optical isomer of representative as active component.Consequently the compliance of administration improves and has also improved therapeutic effect simultaneously.

Its medium ring C ' expression is chosen wantonly to have substituent phenyl ring or choose wantonly has the single heterocycle of substituent fragrance; R ⁰The expression hydrogen atom, optional have substituent aralkyl, acyl group or acyloxy, a R ¹, R ²And R ³Identical or different and represent hydrogen atom respectively, optional have substituent alkyl, optionally have substituent alkoxyl or optionally have substituent amino that Y representes nitrogen-atoms or CH.

In the chemical compound by above-mentioned formula (I ') representative, its medium ring C ' is that optional chemical compound with substituent phenyl ring is represented by formula (I) particularly.

That is to say that in formula (I), ring A representes optional have substituent phenyl ring, R ⁰, R ¹, R ², R ³With Y have with above-mentioned formula (I ') in identical implication.

In above-mentioned formula (I), preferred chemical compound is such chemical compound, and its medium ring A can have the halogen atom of being selected from, optional by halogenated C _1-4Alkyl, optional by halogenated C _1-4Substituent phenyl ring in alkoxyl and 5-or the 6-unit heterocyclic group; R ⁰Be hydrogen atom, optional substituted aralkyl, acyl group or acyloxy; R ¹Be C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Alkoxy-C _1-6Alkoxyl or two-C _1-6Alkyl amino; R ²Be hydrogen atom, C _1-6Alkoxy-C _1-6Alkoxyl or optional by halogenated C _1-6Alkoxyl; R ³Be hydrogen atom or C _1-6Alkyl, and Y is a nitrogen-atoms.

Especially, preferred chemical compound is the chemical compound by formula (Ia) representative;

R wherein ¹Expression C _1-3Alkyl or C _1-3Alkoxyl; R ²Expression can be by halo or can be by C _1-3The substituted C of alkoxyl _1-3Alkoxyl; R ³Expression hydrogen atom or C _1-3Alkyl, and R ⁴Expression hydrogen atom, optional by halogenated C _1-3Alkoxyl or pyrrole radicals (pyrrolyl) (for example 1-, 2-or 3-pyrrole radicals).

In formula (Ia), preferred especially such chemical compound, wherein R ¹Be C _1-3Alkyl; R ²Be optional by halogenated C _1-3Alkoxyl; R ³Be hydrogen atom and R ⁴It is hydrogen atom or optional by halogenated C _1-3Alkoxyl.

(in (back literary composition is called chemical compound (I)), is for example comprising halogen atom, nitro, optionally have substituent alkyl, hydroxyl, optionally having substituent alkoxyl, aryl, aryloxy group, carboxyl, acyl group, acyloxy, a first heterocyclic radical of 5-to 10-etc. by the chemical compound of above-mentioned formula (I) representative by " substituent group " on " optional have substituent phenyl ring " of ring A representative.Phenyl ring can be replaced by about 1-3 above-mentioned substituent group.When the substituent group number is 2 or more for a long time, each substituent group can be identical or different.In these substituent groups, preferred halogen atom, optionally have substituent alkyl, optionally have a substituent alkoxyl etc.

Halogen atom comprises fluorine, chlorine, bromine atoms etc.Wherein preferred fluorine.

For " alkyl " in " choose wantonly and have substituent alkyl ", C for example gives an example _1-7Alkyl (for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, hexyl, heptyl etc.).For " substituent group " on " choose wantonly and have substituent alkyl ", halogen atom, hydroxyl, C for example can give an example _1-6Alkoxyl (for example methoxyl group, ethyoxyl, propoxyl group, butoxy etc.), C _1-6Alkoxy carbonyl group (for example methoxycarbonyl group, carbethoxyl group, the third oxygen carbonyl etc.), carbamyl etc., substituent number can be about 1-3.When the substituent group number is 2 or more for a long time, each substituent group can be identical or different.

" alkoxyl " in " choosing wantonly and have substituent alkoxyl " comprises for example C _1-6Alkoxyl (for example methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, amoxy etc.) etc." substituent group " on that " substituent group " on " optional have substituent alkoxyl " can be given an example is above-mentioned " optional have substituent alkyl ", substituent number is identical.

" aryl " comprises for example C _6-14Aryl (for example phenyl, 1-naphthyl, 2-naphthyl, xenyl, 2-anthryl etc.) etc.

" aryloxy group " comprises for example C _6-14Aryloxy group (for example phenoxy group, 1-naphthoxy, 2-naphthoxy etc.) etc.

" acyl group " comprises for example formoxyl, alkyl-carbonyl, alkoxy carbonyl, carbamyl, alkylcarbamoyl group, alkyl sulphinyl, alkyl sulphonyl etc.

" alkyl-carbonyl " comprises C _1-6Alkyl-carbonyl (for example acetyl group, propiono etc.) etc.

" alkoxy carbonyl group " comprises for example C _1-6Alkoxy carbonyl group (for example methoxycarbonyl group, carbethoxyl group, the third oxygen carbonyl, butoxy carbonyl etc.) etc.

" alkylcarbamoyl group " comprises N-C _1-6Alkylcarbamoyl group (for example methyl carbamyl, ethyl carbamyl etc.), N, N-two C _1-6Alkylcarbamoyl group (for example N, N-dimethylamino formoxyl, N, N-diethyl amino formoxyl etc.) etc.

" alkyl sulphinyl " comprises for example C _1-7Alkyl sulphinyl (for example methylsulfinyl, ethyl sulfinyl, propyl group sulfinyl, isopropyl sulfinyl etc.) etc.

" alkyl sulphonyl " comprises for example C _1-7Alkyl sulphonyl (for example methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, isopropyl sulfonyl etc.) etc.

" acyloxy " comprises for example alkyl carbonyl oxy, alkoxyl carbonyl oxygen base, carbamoyloxy, alkyl carbamoyloxy base, alkyl sulfenyl oxygen base, alkylsulfonyloxy etc.

" alkyl carbonyl oxy " comprises C _1-6Alkyl carbonyl oxy (for example acetoxyl group, propionyloxy etc.) etc.

" alkoxyl carbonyl oxygen base " comprises for example C _1-6Alkoxyl carbonyl oxygen base (for example methoxyl group carbonyl oxygen base, ethyoxyl carbonyl oxygen base, propoxyl group carbonyl oxygen base, butoxy carbonyl oxy etc.) etc.

" alkyl carbamoyloxy base " comprises C _1-6Alkyl carbamoyloxy base (for example methylamino formyloxy, ethylamino formyloxy etc.) etc.

" alkyl sulfenyl oxygen base " comprises for example C _1-7Alkyl sulfenyl oxygen base (for example methyl sulfenyl oxygen base, ethyl sulfenyl oxygen base, propyl group sulfenyl oxygen base, isopropyl sulfenyl oxygen base etc.) etc.

" alkylsulfonyloxy " comprises for example C _1-7Alkylsulfonyloxy (for example sulfonyloxy methyl oxygen base, ethyl sulfonyloxy, sulfonyl propyl oxygen base, isopropyl sulfonyloxy etc.) etc.

5-to 10-unit heterocyclic radical comprises for example containing and except that carbon atom, also contains heteroatomic 5-to 10-unit (preferred 5-or the 6-unit) heterocyclic radical that one or more (for example 1-3) are selected from nitrogen-atoms, sulphur atom and oxygen atom.Instantiation comprises 2-or 3-thienyl, 2-, 3-or 4-pyridine radicals, 2-or 3-furyl, 1-, 2-or 3-pyrrole radicals, 2-, 3-, 4-, 5-or 8-quinolyl, 1-, 3-, 4-or 5-isoquinolyl, 1-, 2-or 3-indyl.Wherein, for example 1-, 2-or 3-pyrrole radicals of preferred 5-or 6-unit heterocyclic radical.

Ring A is preferably phenyl ring, and this phenyl ring can have 1 or 2 and be selected from halogen atom, optional by halogenated C _1-4Alkyl, optional by halogenated C _1-4The substituent group of alkoxyl and 5-or 6-unit heterocyclic radical.

In above-mentioned formula (I '), for example comprise the first fragrant single heterocycle of 5-to 6-for example furan, thiophene, pyrroles 、 oxazole 、 isoxazole, thiazole, isothiazole, imidazoles, pyrazoles, 1,2,3-oxadiazole, 1 by " fragrant single heterocycle " in " the optional single heterocycle of substituted fragrance (armaticity monocyclic heterocycles) " of ring C ' representative; 2,4-oxadiazole, 1,3,4-oxadiazole, furazan (furazane), 1; 2,3-thiadiazoles, 1,2,4-thiadiazoles, 1; 3,4-thiadiazoles, 1,2; 3-triazole, 1,2,4-triazole, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine and triazine.For " fragrant single heterocycle ", especially be preferably " can have substituent phenyl ring " and " choose wantonly and have substituent pyridine ring " by above-mentioned ring A representative by ring C ' representative." choose wantonly and have substituent pyridine ring " by ring C ' representative can have 1-4 identical substituent group of being given an example with " can have substituent phenyl ring " of being represented by above-mentioned ring A in the instead position.

" fragrant single heterocycle " in wherein " choosing wantonly and have the single heterocycle of substituent fragrance " do not have particular restriction with the condensed position of imidazole ring.

In above-mentioned formula (I ') or (I), by R ⁰" aralkyl " in representative " choose wantonly and have substituent aralkyl " comprises for example C _7-16Aralkyl (C for example _6-10Aryl C _1-6Alkyl is like benzyl and phenethyl etc.) etc." substituent group " instance on " optional have substituent aralkyl " comprise with above-mentioned " choose wantonly and have substituent alkyl " on those identical substituent groups of " substituent group ", substituent number is 1 to about 4.When the substituent group number is 2 or more for a long time, each substituent group can be identical or different.

By R ⁰" acyl group " of representative comprises substituent " acyl group " that for example is described on the above-mentioned ring A.

By R ⁰" acyloxy " of representative comprises substituent " acyloxy " that for example is described on the above-mentioned ring A.

Preferred R ⁰It is hydrogen atom.

In above-mentioned formula (I ') or (I), by R ¹, R ²Or R ³" choose wantonly and have substituent alkyl " of representative comprises substituent " choose wantonly and have substituent alkyl " that is described on the above-mentioned ring A.

By R ¹, R ²Or R ³" choose wantonly and have substituent alkoxyl " of representative comprises substituent " choose wantonly and have substituent alkoxyl " that is described on the above-mentioned ring A.

By R ¹, R ²Or R ³Representative " choose wantonly and have substituent amino " comprises for example amino, list-C _1-6Alkyl amino (for example methylamino, ethylamino etc.), list-C _6-14Arylamino (for example phenyl amino, 1-naphthyl amino, 2-naphthyl amino etc.), two-C _1-6Alkyl amino (for example dimethylamino, diethylamino etc.), two-C _6-14Arylamino (for example diphenyl amino etc.) etc.

Preferred R ¹Be C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Alkoxy-C _1-6Alkoxyl and two-C _1-6Alkyl amino.Further preferred R ²Be C _1-3Alkyl or C _1-3Alkoxyl.

Preferred R ²Be hydrogen atom, C _1-6Alkoxy-C _1-6Alkoxyl or optional by halogenated C _1-6Alkoxyl.Further preferred R ³Be C _1-3Alkoxyl, it can be chosen wantonly by halo and maybe can choose wantonly by C _1-3Alkoxyl replaces.

Preferred R ³Be hydrogen atom or C _1-6Alkyl.Further preferred R ³Be hydrogen atom or C _1-3Alkyl (especially hydrogen atom).

Preferred Y is a nitrogen-atoms.

Instantiation for chemical compound (I); Following chemical compound: 2-[[[3-methyl-4-(2 can give an example; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (lansoprazole), 2-[[(3; 5-dimethyl-4-methoxyl group-2-pyridine radicals) methyl] sulfinyl]-5-methoxyl group-1H-benzimidazole, 2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole sodium salt, 5-difluoro-methoxy-2-[[(3,4-dimethoxy-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole etc.

In these chemical compounds, especially preferred lansoprazole, 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole just.

The present invention also is preferably applied to the PPI of Imidazopyridine except the PPI that is applied to above-mentioned benzimidazole compound.For Imidazopyridine, tenatoprazole for example can give an example.

In addition, comprise that the above-claimed cpd (I) of Imidazopyridine and chemical compound (I ') can be raceme and for example R-isomer and S-isomer of optically-active compound.The optically-active compound of for example preferred especially optically-active compound such as lansoprazole; (R)-2-[[[3-methyl-4-(2 just; 2; The 2-trifluoro ethoxy)-the 2-pyridine radicals] methyl] sulfinyl]-the 1H-benzimidazole with (S)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole is used for the present invention.In addition; For lansoprazole; Usually preferred lansoprazole R-isomer and lansoprazole S-isomer, crystallization; But because they be through back civilian described method for preparing and basic inorganic salt be able to stable and and then obtain the intermediate layer, so its amorphous form is the same with its crystal form also can use.

The salt of chemical compound (I ') and chemical compound (I) is preferably officinal salt, the salt that for example can mention the salt that forms with inorganic base, form with organic base, the salt that forms with basic amino acid etc.

The preferred salt that forms with inorganic base for example comprises alkali metal salt for example sodium salt and potassium salt; Alkali salt is calcium salt and magnesium salt for example; Ammonium salt etc.

The preferred embodiment of the salt that forms with organic base for example comprises and alkylamine (trimethylamine, triethylamine etc.), heterocyclic amine (pyridine, picoline etc.), alkanolamine (ethanolamine, diethanolamine, triethanolamine etc.), dicyclohexylamine, N, the salt that N '-dibenzyl-ethylenediamin etc. form.

The preferred embodiment of the salt that forms with basic amino acid for example comprises the salt that forms with arginine, lysine, ornithine etc.

In these salt, preferred as alkali salt and alkali salt.Especially particular certain cancers.

Chemical compound (I ') or (I) can prepare according to known method is according to being disclosed in method in the documents such as JP-A 61-50978, USP 4628098, JP-A 10-195068, WO 98/21201, JP-A 52-62275, JP-A 54-141783 for example, or method similar with it preparation.In addition, optically-active compound (I) can be disassembled preparations such as method (fractional recrystallization method, chiral column method, diastereomer method, utilize the method for microorganism or enzyme etc.) and asymmetric oxidation method through optically-active.In addition, lansoprazole R-isomer can be according to the method for preparing preparation that is described in the document such as WO 00-78745, WO 01/83473 for example.

The preferred lansoprazole of the benzimidazole compound with anti-tumor activity, omeprazole, rabeprazole, pantoprazole, leminoprazole, tenatoprazole (TU-199) etc. or its optically-active compound and its officinal salt that are used for the present invention.Preferred lansoprazole or its optically-active compound, especially R-isomer.Lansoprazole or its optically-active compound, especially the R-isomer is preferably crystal form, but also can be amorphous form.In addition, they also are applicable to the prodrug of above-mentioned PPI.

The prodrug of the instance of these preferred prodrugs in being included in chemical compound (I) or (I '), also comprise by formula (II) and (III) representative chemical compound.

In the chemical compound (back literary composition is called chemical compound (II)) by following formula (II) representative, ring B representes " choose wantonly and have substituent pyridine ring ".

Pyridine ring by in ring B representative " choose wantonly and have substituent pyridine ring " can have 1-4 substituent group on its instead position.For substituent group; For example can mention halogen atom (for example fluorine, chlorine, bromine, iodine etc.), optionally have substituent alkyl (for example having the alkyl of 1-6 carbon atom etc.), optionally have substituent amino (amino for example like methyl, ethyl, n-pro-pyl etc.; Alkyl list with 1-6 carbon atom replaces or dibasic amino etc., for example methylamino, dimethylamino, ethylamino, diethylamino etc.), amide groups (C for example _1-3Acyl amino etc.; Like Methanamide, acetamide etc.), optional have substituent lower alkoxy (alkoxyl such as the methoxyl group, the ethyoxyl, 2 that for example have 1-6 carbon atom; 2,2-trifluoro ethoxy, 3-methoxy propoxy etc.), low-grade alkylidene dioxy base (C for example _1-3Alkylenedioxy groups etc. are like methylene-dioxy, ethylenedioxy etc.) etc.

For the substituent group that can have on " optional have substituent pyridine ring " by ring B representative, can mention halogen atom (for example fluorine, chlorine, bromine, iodine etc.) for example, low alkyl group (for example having alkyl such as methyl, ethyl, the propyl group of 1-6 carbon atom etc.), low-grade alkenyl (alkenyl such as vinyl, the pi-allyl etc. that for example have 2-6 carbon atom), alkynyl of low-grade chain (alkynyl group such as acetenyl, the propargyl etc. that for example have 2-6 carbon atom), cycloalkyl (for example having cycloalkyl such as cyclopropyl, cyclobutyl, cyclopenta, the cyclohexyl of 3-8 carbon atom etc.), lower alkoxy (alkoxyl such as methoxyl group, the ethyoxyl etc. that for example have 1-6 carbon atom), nitro, cyanic acid, hydroxyl, sulfydryl, carboxyl, low-grade alkane acidyl (formoxyl for example; C ₁-C ₆Alkyl-carbonyl such as acetyl group, propiono, bytyry etc.), lower alkanoyloxy (formyloxy for example; C ₁-C ₆Alkyl carbonyl oxy such as acetoxyl group, propionyloxy, butyryl acyloxy etc.), elementary alkoxy carbonyl (C for example ₁-C ₆Alkoxy carbonyl such as methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl etc.), aryl alkyl carbonyl oxygen (C for example ₇-C ₁₁Aryl alkyl carbonyl oxygen such as benzyloxycarbonyl group etc.), aryl (aryl such as phenyl, the naphthyl etc. that for example have 6-14 carbon atom), aryloxy group (aryloxy group such as phenoxy group, the naphthoxy etc. that for example have 6-14 carbon atom), aryl carbonyl (C for example ₆-C ₁₄Aryl carbonyl such as benzoyl, naphthoyl etc.), aryl-carbonyl oxygen (C for example ₆-C ₁₄Aryl-carbonyl oxygen such as benzoyloxy, naphthoyl oxygen base etc.), optional have a substituent carbamyl (carbamyl for example; Alkyl list with 1-6 carbon atom replaces or dibasic carbamyl etc., like methyl carbamyl, dimethylamino formoxyl etc.), it is optional that to have substituent amino (for example amino; Alkyl list with 1-6 carbon atom replaces or dibasic amino etc., like methylamino, dimethylamino, ethylamino, diethylamino etc.) etc., wherein there is not particular restriction for substituent number and substituent position.

Though for not having particular restriction by substituent group number and substituting group position on ring B representative " choose wantonly and have substituent pyridine ring ", preferred 1-3 above-mentioned substituent group replaces on 3-, 4-and the 5-position of pyridine ring.

" choose wantonly and have substituent pyridine ring " for by ring B representative is preferably 3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals.

In the present invention, " choose wantonly and have substituent phenyl ring " or " choose wantonly and have the single heterocycle of substituent fragrance " with the condensed ring of imidazoles part C representative.Wherein, preferably the former.

Phenyl ring by in ring C representative " choose wantonly and have substituent phenyl ring " can have 1-4 substituent group on the instead position.For substituent group, for example can mention halogen atom (for example fluorine, chlorine, bromine, iodine etc.), optionally have substituent alkyl (for example being selected from the alkyl with 1-6 carbon atom of methyl, ethyl, n-pro-pyl etc. etc.), optionally have substituent amino (amino for example; Alkyl list with 1-6 carbon atom replaces or dibasic amino etc., for example methylamino, dimethylamino, ethylamino, diethylamino etc.), amide groups (C for example _1-3Acyl aminos etc. are like Methanamide, acetamide etc.), optional have substituent lower alkoxy (for example having alkoxyl such as methoxyl group, ethyoxyl, the trifluoromethoxy of 1-6 carbon atom etc.), a rudimentary alkylenedioxy (C for example _1-3Alkylenedioxies etc. are like methylene dioxy base, ethylidene dioxy base etc.) etc.

For the substituent group that can have on " optional have substituent phenyl ring " by ring C representative, can mention halogen atom (for example fluorine, chlorine, bromine, iodine etc.) for example, low alkyl group (for example having alkyl such as methyl, ethyl, the propyl group of 1-6 carbon atom etc.), low-grade alkenyl (alkenyl such as vinyl, the pi-allyl etc. that for example have 2-6 carbon atom), alkynyl of low-grade chain (alkynyl group such as acetenyl, the propargyl etc. that for example have 2-6 carbon atom), cycloalkyl (for example having cycloalkyl such as cyclopropyl, cyclobutyl, cyclopenta, the cyclohexyl of 3-8 carbon atom etc.), lower alkoxy (alkoxyl such as methoxyl group, the ethyoxyl etc. that for example have 1-6 carbon atom), nitro, cyanic acid, hydroxyl, thiol (thiol group), carboxyl, low-grade alkane acidyl (formoxyl for example; C ₁-C ₆Alkyl-carbonyl such as acetyl group, propiono, bytyry etc.), lower alkanoyloxy (formyloxy for example; C ₁-C ₆Alkyl carbonyl oxy such as acetoxyl group, propionyloxy, butyryl acyloxy etc.), elementary alkoxy carbonyl (C for example ₁-C ₆Alkoxy carbonyl such as methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl etc.), aryl alkyl carbonyl oxygen (C for example ₇-C ₁₇Aryl alkyl carbonyl oxygen such as benzyloxycarbonyl group etc.), aryl (aryl such as phenyl, the naphthyl etc. that for example have 6-14 carbon atom), aryloxy group (aryloxy group such as phenoxy group, the naphthoxy etc. that for example have 6-14 carbon atom), aryl carbonyl (C for example ₆-C ₁₄Aryl carbonyl such as benzoyl, naphthoyl etc.), aryl-carbonyl oxygen (C for example ₆-C ₁₄Aryl-carbonyl oxygen such as benzoyloxy, naphthoyl oxygen base etc.), optional have a substituent carbamyl (carbamyl for example; Alkyl list with 1-6 carbon atom replaces or dibasic carbamyl etc., like methyl carbamyl, dimethylamino formoxyl etc.), it is optional that to have substituent amino (for example amino; Alkyl list with 1-6 carbon atom replaces or dibasic amino etc., like methylamino, dimethylamino, ethylamino, diethylamino etc.) etc., wherein there is not particular restriction for substituent number and substituent position.

" choose wantonly and have substituent phenyl ring " for by ring C representative is preferably phenyl ring.

For by " fragrant single heterocycle " in ring C representative " choose wantonly and have the single heterocycle of substituent fragrance ", can mention for example 5-or the first fragrant single heterocycle of 6-etc., for example furan, thiophene, pyrroles 、 oxazole 、 isoxazole, thiazole, isothiazole, imidazoles, pyrazoles, 1,2; 3-oxadiazole, 1,2,4-oxadiazole, 1,3; 4-oxadiazole, furazan, 1,2,3-thiadiazoles, 1,2; 4-thiadiazoles, 1,3,4-thiadiazoles, 1,2; 3-triazole, 1,2,4-triazole, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, triazine etc." fragrant single heterocycle " for by ring C representative especially is preferably pyridine ring.It can have on its instead position 1-4 with by the similar substituent group of substituent group on ring C representative " choose wantonly and have substituent phenyl ring ".

" fragrant single heterocycle " in " choose wantonly and have the single heterocycle of substituent fragrance " do not have particular restriction with the condensed position of imidazoles part.

In the present invention, X ₁And X ₂Difference represention oxygen atom and sulphur atom.Preferred X ₁And X ₂The while represention oxygen atom.

In the present invention, W representative " is chosen wantonly and is had substituent bivalence chain alkylene " or formula:

-W ₁-Z-W ₂-

W wherein ₁And W ₂Each bivalence chain alkylene or chemical bond naturally, Z are for example " optional have substituent bivalent cyclic alkyl ", " optional have substituent divalent heterocyclic group ", oxygen atom, SO of divalent group _nWherein n be 0,1 or 2, perhaps＞N-E wherein E be hydrogen atom, optionally have substituent alkyl, optionally have substituent heterocyclic group, low-grade alkane acidyl, elementary alkoxy carbonyl, rudimentary aromatic alkoxy carbonyl, thiocarbamoyl, low alkyl group sulfinyl, low alkyl group sulfonyl, sulfamoyl, list-low alkyl group sulfamoyl, two-low alkyl group sulfamoyl, ammonia aryl sulfonyl, aryl sulfonyl kia, aryl sulfonyl, aryl carbonyl, or choose wantonly and have substituent carbamyl, when Z is oxygen atom, SO _nOr＞during N-E, W ₁And W ₂Each is " bivalence chain alkylene " naturally.W especially is preferably " choose wantonly and have substituent bivalence chain alkylene ".

For " bivalence chain alkylene " in " choose wantonly and have substituent bivalence chain alkylene " of representing by W and by W ₁And W ₂" the bivalence chain alkylene " of representative can be mentioned for example C _1-6Alkylidene (for example methylene, ethylidene, propylidene etc.), C _2-6Alkylene group (for example ethenylidene etc.), C _2-6Inferior alkynyl group (for example ethynylene) etc.For W, this bivalence chain alkylene can have on its instead position 1-6 with by the similar substituent group of substituent group on ring C representative " choose wantonly and have substituent phenyl ring ".

For " bivalence chain alkylene " in " choose wantonly and have substituent bivalence chain alkylene " of representing by W and by W ₁And W ₂" the bivalence chain alkylene " of representative is preferably methylene and ethylidene.For W, especially be preferably ethylidene.When Z is oxygen atom, SO _nOr＞during N-E (n and E definition the same), by W ₁" the bivalence chain alkylene " of expression is preferably the alkyl with 2 or more a plurality of carbon atoms.

For " cyclic hydrocarbon group (the hydrocarbon ring) " in " choose wantonly and have substituent bivalent cyclic alkyl " of representing by Z; Can mention for example aliphatic cyclic hydrocarbon, aromatics cyclic hydrocarbon etc.; The aliphatic cyclic hydrocarbon, the aromatics cyclic hydrocarbon that preferably have 3-16 carbon atom, they can have on its instead position 1-4 with by the similar substituent group of substituent group on ring C representative " choose wantonly and have substituent phenyl ring ".About the hydrocarbon ring, can use for example cycloalkane, cycloolefin, aromatic hydrocarbon etc.

For the cycloalkane in " choose wantonly and have substituent bivalent cyclic alkyl " of being represented by Z, preference such as rudimentary cycloalkane etc. use for example C usually _3-10Cycloalkane etc. are like cyclopropane, Tetramethylene., Pentamethylene., cyclohexane extraction, cycloheptane, cyclooctane, dicyclo [2.2.1] heptane, diamantane (obsolete) etc.

For the cycloolefin in " choose wantonly and have substituent bivalent cyclic alkyl " of being represented by Z, preference such as rudimentary cycloolefin etc. use for example C usually _4-9Cycloolefins etc. are like cyclopropylene, cyclobutane, cyclopentenes, cyclohexene, cycloheptene, cyclo-octene etc.

For the aromatic hydrocarbon in " choose wantonly and have substituent bivalent cyclic alkyl " of representing by Z, preference such as C _6-14Aromatic hydrocarbon etc., for example benzene, naphthalene, phenanthrene etc. use for example phenylene usually.

For the heterocycle in " choose wantonly and have substituent divalent heterocyclic group " of representing by Z; Can mention that containing 1-3 kind (preferred 1 or 2 kind) is selected from least 1 (preferred 1-4 in oxygen atom, sulphur atom and the nitrogen-atoms etc.; More preferably 1 or 2) hetero atom is as 5-to the 12-unit " aromatic heterocycle " or " saturated or unsaturated nonaromatic heterocycles " that becomes annular atoms (annular atoms) etc., they can have on its instead position 1-4 with by the similar substituent group of substituent group on ring C representative " choose wantonly and have substituent phenyl ring ".

For by the aromatic heterocycle in Z representative " choose wantonly and have substituent divalent heterocyclic group ", can mention fragrant single heterocycle, fragrant condensed hetero ring etc.

For " fragrant single heterocycle ", for example can mention the fragrant single heterocycle of 5-or 6-unit etc., for example furan, thiophene, pyrroles 、 oxazole 、 isoxazole, thiazole, isothiazole, imidazoles, pyrazoles, 1,2,3-oxadiazole, 1; 2,4-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2; 3-thiadiazoles, 1,2,4-thiadiazoles, 1,3,4-thiadiazoles, 1; 2,3-triazole, 1,2,4-triazole, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, triazine etc.

For " fragrant condensed hetero ring ", for example can mention the fragrant condensed hetero ring of 8-to 12-unit etc., for example benzofuran, isobenzofuran, benzothiophene, different benzothiophene, indole, iso-indoles, 1H-indazole, benzimidazole, benzoxazole, 1; 2-benzoisoxazole, benzothiazole, 1,2-benzisothiazole, 1H-BTA, quinoline, isoquinolin, cinnolines, quinazoline, quinoxaline, 2, naphthyridines, purine, pteridine, carbazole, carboline, acridine 、 phenoxazine, phenothiazine, azophenlyene, phenoxthine, thianthrene, phenanthridines, 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-triazol [4,3-a] pyridine, 1,2; 4-triazol [4,3-b] pyridazine etc.

For the saturated or unsaturated nonaromatic heterocycles in " choose wantonly and have substituent divalent heterocyclic group " of representing by Z; For example can mention 3-to 8-unit (preferred 5-or 6-unit) saturated or unsaturated (preferred saturated) nonaromatic heterocycles (aliphatic heterocycle) etc., for example oxirane (oxylane), azetidine (azetidine), oxetanes (oxetane), Thietane (thietane), pyrrolidine (pyrrolidine), oxolane (tetrahydrofuran), Tetramethylene sulfide (tetrahydrothiophene), piperidines (piperidine), Pentamethylene oxide. (tetrahydropyran), tetrahydric thiapyran (tetrahydrothiopyran), morpholine (morpholine), thiomorpholine (thiomorpholine), piperazine (piperazine), azepan (azepane), oxepane (oxepane), thia cycloheptane (thiene), oxaza heptane (oxazepane), sulfur nitrogen heterocycle heptane (thiazepane), Azacyclooctane (azocane), oxocane (oxocane), thia cyclooctane (thiocane), oxaza octane (oxazocane), sulfur nitrogen heterocycle octane (thiazocane) etc.

These groups can oxo, promptly can be for example 2-aza-oxo-cyclobutane, 2-oxo-pyrrolidine, 2-oxo-piperidine, 2-oxo azepan, 2-oxo aza ring octane, 2-oxo-tetrahydrofuran, 2-oxo Pentamethylene oxide., 2-oxo Tetramethylene sulfide, 2-oxo thiophene alkane (2-oxothiane), 2-oxo piperazine, 2-oxo oxepane, 2-oxo oxaza heptane, 2-oxo thia cycloheptane, 2-oxo sulfur nitrogen heterocycle heptane, 2-oxo oxocane, 2-oxo thia cyclooctane, 2-oxo oxaza octane, 2-oxo sulfur nitrogen heterocycle octane etc.

By " cyclic hydrocarbon group " in " optional have substituent bivalent cyclic alkyl " of Z representative perhaps two chemical bonds in " heterocyclic group " in " optional have substituent divalent heterocyclic group " can appear at possible position arbitrarily.

" choose wantonly and have substituent alkyl " and " choose wantonly and have substituent heterocyclic group " by the E representative defines as follows.

" low-grade alkane acidyl " for by the E representative can use for example formoxyl, C _1-6Alkyl-carbonyls etc. are like acetyl group, propiono, bytyry, isobutyryl etc.

" elementary alkoxy carbonyl " for by the E representative uses for example C _1-6Alkoxy carbonyls etc. are like methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, butoxy carbonyl etc.

" aromatic alkoxy carbonyl " for by the E representative uses for example C _7-11Aromatic alkoxy carbonyls etc. are like benzyloxycarbonyl group etc.

" low alkyl group sulfinyl " for by the E representative uses for example C _1-6Alkyl sulphinyls etc. are like methylsulfinyl, ethyl sulfinyl etc.

" low alkyl group sulfonyl " for by the E representative uses for example C _1-6Alkyl sulphonyls etc. are like methyl sulphonyl, ethylsulfonyl etc.

For " list-low alkyl group sulfamoyl ", use and utilize list-C by the E representative _1-6Alkylsulfamoyl groups etc. are like methyl sulfamoyl, ethyl sulfamoyl etc.

For " two-low alkyl group sulfamoyl ", use for example two-C by the E representative _1-6Alkylsulfamoyl groups etc. are like dimethylamino sulfonyl, diethyl amino sulfonyl etc.

" ammonia aryl sulfonyl " for by the E representative uses for example C _6-10Ammonia aryl sulfonyls etc. are like phenyl sulfamoyl base, naphthyl sulfamoyl etc.

" aryl sulfonyl kia " for by the E representative uses for example C _6-10Aryl sulfonyl kias etc. are like phenyl sulfinyl, naphthyl sulfinyl etc.

" aryl sulfonyl " for by the E representative uses for example C _6-10Aryl sulfonyls etc. are like phenyl sulfonyl, naphthyl sulfonyl etc.

" aryl carbonyl " for by the E representative uses for example C _6-10Aryl carbonyls etc. are like benzoyl, naphthoyl etc.

" choose wantonly and have substituent carbamyl " for by the E representative is for example formula-CONR ₂R ₃Group etc., wherein R ₂And R ₃Each naturally hydrogen atom, optional have substituent alkyl or optionally have substituent heterocyclic group, at formula-CONR ₂R ₃Middle R ₂And R ₃Can with adjacent nitrogen-atoms ring formation.

In the present invention, R is " choose wantonly and have substituent alkyl " or " choose wantonly and have substituent heterocyclic group ", and R can link to each other with W.Wherein, be preferably the optional substituent C that has _1-6Alkyl especially is preferably rudimentary (C _1-6) alkyl." choose wantonly and have substituent alkyl " and " choose wantonly and have substituent heterocyclic group " by the R representative defines as follows.The situation that links to each other with W for R has wherein provided detailed description below.

In the present invention, D ₁And D ₂Each naturally chemical bond, oxygen atom, sulphur atom perhaps＞NR ₁, in formula, R ₁Be that hydrogen atom or optional has substituent alkyl.Yet the present invention has got rid of wherein D ₁And D ₂Be the situation of chemical bond.In all the other situations, preferred D ₁And D ₂Be chemical bond or oxygen atom, especially preferred D ₁Be oxygen atom, D ₂Be oxygen atom or chemical bond.By R ₁Definition as follows for " choose wantonly and have substituent alkyl " of representative.

In the present invention, G is " choose wantonly and have substituent alkyl " or " choose wantonly and have substituent heterocyclic group ".Wherein, be preferably the optional substituent C that has _1-6Alkyl or optional has substituent saturated heterocyclic group, and this heterocyclic group contains 1-4 and is selected from hetero atom in oxygen atom, sulphur atom and the nitrogen-atoms as becoming annular atoms.For G, in all the other situations, be preferably the optional substituent C that has _1-6Alkyl or optional has substituent saturated oxygen heterocycle group, and this heterocyclic group contains 1-3 and is selected from hetero atom in oxygen atom, sulphur atom and the nitrogen-atoms as becoming annular atoms." choose wantonly and have substituent alkyl " and " choose wantonly and have substituent heterocyclic group " by the G representative defines as follows.

For by above-mentioned E, R, R ₁With " alkyl " in " optional have substituent alkyl " of G representative can mention for example saturated or undersaturated aliphatic hydrocarbyl, saturated or undersaturated alicyclic hydrocarbon radical, saturated or undersaturated alicyclic-aliphatic hydrocarbyl, aryl radical, armaticity is saturated or undersaturated alicyclic hydrocarbon radical etc., preferably those have 1-16, the more preferably above-mentioned group of 1-6 carbon atom.Its instantiation comprises alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkenyl group, cycloalkyl-alkyl, cycloalkenyl alkyl, aryl and aralkyl etc.

" alkyl " is preferably for example low alkyl group (C _1-6Alkyl) etc., use for example C usually _1-6Alkyl etc. are like methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, 1-ethyl propyl, hexyl etc.For R, be preferably low alkyl group (C _1-6Alkyl), especially be preferably methyl.

" alkynyl group " is preferably for example alkynyl of low-grade chain etc., uses for example C usually _2-7Alkynyl group etc., like vinyl, 1-acrylic, pi-allyl, isopropenyl, cyclobutenyl, isobutenyl, 2,2-dimethyl-penta-4-thiazolinyl etc.

" alkynyl group " is preferably for example alkynyl of low-grade chain etc., uses for example C usually _2-6Alkynyl groups etc. are like acetenyl, propinyl, 1-propinyl etc.

" cycloalkyl " is preferably for example low-grade cycloalkyl etc., uses for example C usually _3-10Cycloalkyl etc. are like cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclopenta, ring octyl group, dicyclo [2.2.1] heptyl and adamantyl etc.

" cycloalkenyl group " is preferably for example lower alkenyl ring, uses for example C usually _3-10Cycloalkenyl group etc., as cyclopropanyl, cyclobutane base, cyclopentenyl, cyclohexenyl group, cycloheptenyl, cyclo-octene base, dicyclo [2.2.1] heptan-5-alkene-2-base etc.

" cycloalkyl-alkyl " is preferably for example low-grade cycloalkyl alkyl etc., uses for example C usually _4-9Cycloalkyl-alkyls etc. are like cyclopropyl methyl, cyclopropyl ethyl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl and cyclohexyl ethyl etc.

" cycloalkenyl alkyl " is preferably for example lower alkenyl ring alkyl etc., uses for example C usually _4-9Cycloalkenyl alkyl etc., as cyclopentenyl methyl, cyclohexenyl group methyl, cyclohexenyl group ethyl, cyclohexenyl group propyl group, cycloheptenyl methyl, cycloheptenyl ethyl and dicyclo [2.2.1] heptan-5-alkene-2-ylmethyl etc.

" aryl " is preferably for example C _6-14Aryl etc., for example phenyl, 1-naphthyl, 2-naphthyl, xenyl, 2-anthryl etc. use for example phenyl etc. usually.

" aralkyl " contains the same " aryl " of definition as aryl moiety and define the same " alkyl " as moieties.Wherein, be preferably for example C _6-14Aryl-C _1-6Alkyl uses for example benzyl, phenethyl etc. usually.

For by above-mentioned E, R, R ₁Go up the substituent group that can have with " alkyl " in " optional have substituent alkyl " of G representative, for example use halogen atom (for example fluorine, chlorine, bromine, iodine etc.), nitro, cyanic acid, hydroxyl, sulfydryl, sulfo group (sulfo), sulfonic group (sulphino), phosphate (phosphono), choose wantonly by halogenated low alkyl group (C for example _1-6Alkyl, like methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, 1-ethyl propyl, hexyl etc., single-, two-or three-halo-C _1-6Alkyl, like chloromethyl, dichloromethyl, trichloromethyl, methyl fluoride, difluoromethyl, trifluoromethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl group, 3; 3,3-trifluoro propyl, 4,4; 4-trifluoro butyl, 5,5,5-trifluoro amyl group, 6; 6,6-trifluoro hexyl etc., etc.), oxo base, amidino groups, imino group, alkylenedioxy group (C for example _1-3Alkylenedioxy groups etc. are like methylene-dioxy, ethylenedioxy etc.), lower alkoxy (C for example _1-6Alkoxyls etc. are like methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, amoxy, hexyloxy etc.), optional halogenated lower alkoxy (for example single-, two-or three-halo-C _1-6Alkoxyl etc., like chlorine methoxyl group, dichloro methoxyl group, trichlorine for methoxyl group, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, 2-bromine oxethyl, 2,2; 2-trifluoro ethoxy, five fluorine ethyoxyls, 3,3,3-trifluoro propoxyl group, 4; 4,4-trifluoro butoxy, 5,5; 5-trifluoro amoxy, 6,6,6-trifluoro hexyloxy etc.), low alkyl group sulfenyl (alkylthio) (C for example _1-6Alkyl sulfenyls etc. are like methyl sulfenyl, ethyl sulfenyl, propyl group sulfenyl, isopropyl sulfenyl, butyl sulfenyl, isobutyl group sulfenyl, amyl group sulfenyl, hexyl sulfenyl etc.), carboxyl, low-grade alkane acidyl (formoxyl for example; C _1-6Alkyl-carbonyls etc. are like acetyl group, propiono, bytyry, isobutyryl etc.), lower alkanoyloxy (formyloxy for example; C _1-6Alkyl carbonyl oxies etc. are like acetoxyl group, propionyloxy, butyryl acyloxy, isobutyl acyloxy etc.), elementary alkoxy carbonyl (C for example _1-6Alkoxy carbonyls etc. are like methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, butoxy carbonyl etc.), aromatic alkoxy carbonyl (C for example _7-11Aromatic alkoxy carbonyls etc. are like benzyloxycarbonyl group etc.), thiocarbamoyl, low alkyl group sulfinyl (C for example _1-6Alkyl sulphinyls etc. are like methylsulfinyl, ethyl sulfinyl etc.), low alkyl group sulfonyl (C for example _1-6Alkyl sulphonyls etc. are like methyl sulphonyl, ethylsulfonyl etc.), sulfamoyl, single low alkyl group sulfamoyl (list-C for example _1-6Alkylsulfamoyl groups etc. are like methyl sulfamoyl, ethyl sulfamoyl etc.), two-low alkyl group sulfamoyl (two-C for example _1-6Alkylsulfamoyl groups etc. are like dimethylamino sulfonyl, diethyl amino sulfonyl etc.), ammonia aryl sulfonyl (C for example _6-10Ammonia aryl sulfonyls etc. are like phenyl sulfamoyl base, naphthyl sulfamoyl etc.), aryl (C for example _6-10Aryl etc. are like phenyl, naphthyl etc.), aryloxy group (C for example _6-10Aryloxy group etc. are like phenoxy group, naphthoxy etc.), artyl sulfo (C for example _6-10Artyl sulfos etc. are like thiophenyl, naphthyl sulfenyl etc.), aryl sulfonyl kia (C for example _6-10Aryl sulfonyl kias etc. are like phenyl sulfinyl, naphthyl sulfinyl etc.), aryl sulfonyl (C for example _6-10Aryl sulfonyls etc. are like phenyl sulfonyl, naphthyl sulfonyl etc.), aryl carbonyl (C for example _6-10Aryl carbonyls etc. are like benzoyl, naphthoyl etc.), aryl-carbonyl oxygen (C for example _6-10Aryl-carbonyl oxygens etc. are like benzoyloxy, naphthoyl oxygen base etc.), optional amino (for example optional by halogenated C by halogenated lower alkylcarbonyl _1-6Alkyl-carbonyl-aminos etc. are like acetyl-amino, trifluoroacetyl group amino etc.), optional have substituent carbamyl (formula-CONR for example ₂R ₃Group, R wherein ₂And R ₃Each naturally hydrogen atom, optional have substituent alkyl or optionally have substituent heterocyclic group, at formula-CONR ₂R ₃Middle R ₂And R ₃Can with adjacent nitrogen-atoms ring formation), optional have substituent amino (formula-NR for example ₂R ₃Group, R wherein ₂And R ₃Define the same, at formula-NR ₂R ₃Middle R ₂And R ₃Can with adjacent nitrogen-atoms ring formation), optional have substituent urea groups (formula-NHCONR for example ₂R ₃Group, R wherein ₂And R ₃Define the same, at formula-CONR ₂R ₃Middle R ₂And R ₃Can with adjacent nitrogen-atoms ring formation), optional have substituent amide groups (carboxamide) (formula-NR for example ₂COR ₃Group, R wherein ₂And R ₃Define the same), optional have substituent sulfoamido (formula-NR for example ₂SO ₂R ₃Group, R wherein ₂And R ₃Define the same), optional have a substituent heterocyclic group (same R ₂And R ₃Definition) etc.

For R ₂And R ₃" alkyl " in representative " choose wantonly and have substituent alkyl " can be mentioned the low alkyl group (alkyl that for example has 1-6 carbon atom; Like methyl, ethyl, propyl group etc.), the low-grade alkenyl (alkenyl that for example has 2-6 carbon atom; Like vinyl, pi-allyl etc.), the alkynyl of low-grade chain (alkynyl group that for example has 2-6 carbon atom; Like acetenyl, propinyl etc.), the cycloalkyl (cycloalkyl that for example has 3-8 carbon atom; Like cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.), cycloalkenyl group (cycloalkenyl group that for example has 3-8 carbon atom is like cyclobutane base, cyclopentenyl, cyclohexenyl group etc.), cycloalkyl-alkyl (C for example ₃-C ₈Cycloalkyl-C ₁-C ₆Alkyl is like cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl etc.), cycloalkenyl alkyl (C for example ₃-C ₈Cycloalkenyl group-C ₁-C ₆Alkyl is like cyclobutane ylmethyl, cyclopentenyl methyl, cyclohexenyl group methyl etc.), aryl (aryl that for example has 6-14 carbon atom is like phenyl, naphthyl etc.), aralkyl (C for example ₆-C ₁₄Aryl-C ₁-C ₆Alkyl, as benzyl, naphthyl methyl, etc.) etc.

For by R ₂And R ₃" heterocyclic group " in representative " choose wantonly and have substituent heterocyclic group "; Can mention and contain 1 or 2 kind of 1-4 heteroatomic 5-to 12-unit's monocycle that is selected from nitrogen-atoms, sulphur atom and oxygen atom or annelated heterocycles group etc., like pyridine radicals, pyrrolidinyl, piperazinyl, piperidyl, 2-oxaza heptane base (2-oxazepinyl), furyl, Decahydroisoquinolinpreparation base, quinolyl, indyl, isoquinolyl, thienyl, imidazole radicals, morpholinyl etc.For R ₂And R ₃Substituent group on " optional have substituent alkyl " of representative and " choose wantonly and have substituent heterocyclic group " can be mentioned halogen atom (for example fluorine, chlorine, bromine, iodine etc.) for example, low alkyl group (for example having alkyl such as methyl, ethyl, the propyl group of 1-6 carbon atom etc.), low-grade alkenyl (alkenyl such as vinyl, the pi-allyl etc. that for example have 2-6 carbon atom), alkynyl of low-grade chain (alkynyl group such as acetenyl, the propargyl etc. that for example have 2-6 carbon atom), cycloalkyl (for example having cycloalkyl such as cyclopropyl, cyclobutyl, cyclopenta, the cyclohexyl of 3-8 carbon atom etc.), lower alkoxy (alkoxyl such as methoxyl group, the ethyoxyl etc. that for example have 1-6 carbon atom), nitro, cyanic acid, hydroxyl, sulfydryl, carboxyl, low-grade alkane acidyl (formoxyl for example; C ₁-C ₆Alkyl-carbonyl such as acetyl group, propiono, bytyry etc.), lower alkanoyloxy (formyloxy for example; C ₁-C ₆Alkyl carbonyl oxy such as acetoxyl group, propionyloxy, butyryl acyloxy etc.), elementary alkoxy carbonyl (C for example ₁-C ₆Alkoxy carbonyl such as methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl etc.), aryl alkyl carbonyl oxygen (C for example ₇-C ₁₇Aryl alkyl carbonyl oxygen such as benzyloxycarbonyl group etc.), aryl (aryl such as phenyl, the naphthyl etc. that for example have 6-14 carbon atom), aryloxy group (aryloxy group such as phenoxy group, the naphthoxy etc. that for example have 6-14 carbon atom), aryl carbonyl (C for example ₆-C ₁₄Aryl carbonyl such as benzoyl, naphthoyl etc.), aryl-carbonyl oxygen (C for example ₆-C ₁₄Aryl-carbonyl oxygen such as benzoyloxy, naphthoyl oxygen base etc.), optional have a substituent carbamyl (carbamyl for example; Alkyl list with 1-6 carbon atom replaces or dibasic carbamyl etc., like methyl carbamyl, dimethylamino formoxyl etc.), it is optional that to have substituent amino (for example amino; Alkyl list with 1-6 carbon atom replaces or dibasic amino etc., like methylamino, dimethylamino, ethylamino, diethylamino etc.) etc.There is not particular restriction for substituent number and position.

For by R ₂And R ₃With the ring that adjacent nitrogen-atoms forms, can mention for example pyrrolidine, piperidines, high piperidines (homopiperidino), morpholine, piperazine, tetrahydroquinoline, tetrahydroisoquinoline etc.

By above-mentioned E, R, R ₁Can on this alkyl instead position, have 1-5, preferred 1-3 aforementioned substituent group with " alkyl " in " optional have substituent alkyl " of G representative, wherein when the substituent group number was no less than 2, each substituent group was identical or different.

For " heterocyclic group " in " choose wantonly and have substituent heterocyclic group " of representing by above-mentioned E, R and G; Can mention and contain hetero atom that at least 1 of 1-3 kind (preferred 1 or 2 kind) (preferred 1-4, more preferably 1-3) is selected from oxygen atom, sulphur atom and nitrogen-atoms as 5-to the 12-membered aromatic heterocycle group that becomes annular atoms (annular atoms) and saturated or undersaturated heterocyclic group etc.As stated; For " heterocyclic group " in " choose wantonly and have substituent heterocyclic group " of representing by G; Be preferably contain 1-4, more preferably 1-3 be selected from the saturated oxygen heterocycle group of such as the hetero atom of oxygen atom, sulphur atom and nitrogen-atoms etc. as annular atoms, especially be preferably the saturated oxygen heterocycle group of 5-to 12-unit etc.

For " aromatic heterocycle group ", can mention fragrant monocyclic heterocyclic group, armaticity annelated heterocycles group.

For " fragrant monocyclic heterocyclic group ", can mention for example 5-or the first fragrant monocyclic heterocyclic group of 6-etc., like furyl, thienyl, pyrrole radicals 、 oxazolyl 、 isoxazolyl, thiazolyl, isothiazolyl, imidazole radicals, pyrazolyl, 1,2; 3-oxadiazole base, 1,2,4-oxadiazole base, 1,3; 4-oxadiazole base, furazan base, 1,2,3-thiadiazolyl group, 1,2; 4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2; 3-triazolyl, 1,2,4-triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl and triazine radical

For " fragrant annelated heterocycles group "; Can mention the fragrant annelated heterocycles group of the unit of 8-to 12-for example (the fragrant single heterocycle of preferred aforementioned 5-or 6-unit and phenyl ring mutually the condensed heterocycle group, or two kinds of identical or different aforementioned 5-or the first fragrant single heterocycle of 6-in heterocyclic group phase condensed heterocycle group) etc., like benzofuranyl, isobenzofuran-base, benzothienyl, isobenzo-thienyl, indyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazole base, benzothiazolyl, 1; 2-benzisothiazole base, 1H-BTA base, quinolyl, isoquinolyl, cinnolines base, quinazolyl, quinoxalinyl, 2; 3-phthalazinyl, naphthyridinyl, purine radicals, pteridyl, carbazyl, α-carbolinyl, B-carboline base, gamma-carbolines base, acridinyl 、 phenoxazine group, phenothiazinyl, phenazinyl, phenoxthine base (phenoxathiinyl), thianthrene group, phenanthridinyl, phenanthroline base, indolizine base, pyrrolo-[1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridine radicals, imidazo [1; 2-a] pyridine radicals, imidazo [1; 5-a] pyridine radicals, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidine radicals, 1; 2; 4-triazol [4,3-a] pyridine radicals, 1,2; 4-triazol [4,3-b] pyridazinyl etc.

For " saturated or undersaturated nonaromatic heterocycles group "; Can mention for example 3-to 8-unit (preferred 5-or 6-unit) saturated or undersaturated (preferred saturated) nonaromatic heterocycles group (aliphatic heterocyclic group), like oxirane base, azetidinyl, oxetanyl, Thietane base, pyrrolidinyl, tetrahydrofuran base, tetrahydro-thienyl (thiolanyl), piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base (thianyl), morpholinyl, thio-morpholinyl, piperazinyl, azepan base, oxepane alkyl, thia cycloheptane base (thiepanyl), oxaza heptane base, sulfur nitrogen heterocycle heptane base, Azacyclooctane base, oxocane base, thia cyclooctane base, oxaza octyl, sulfur nitrogen heterocycle octyl etc.These groups can be oxos, and the example comprises 2-aza-oxo-cyclobutane base, 2-oxo-pyrrolidine base, 2-oxo-piperidine base, 2-oxo azepan base, 2-oxo aza ring octyl, 2-oxo-tetrahydrofuran base, 2-oxo THP trtrahydropyranyl, 2-oxo tetrahydro-thienyl, 2-oxo tetrahydro thiapyran base, 2-oxo piperazinyl, 2-oxo oxepane alkyl, 2-oxo oxaza heptane base, 2-oxo thia cycloheptane base, 2-oxo sulfur nitrogen heterocycle heptane base, 2-oxo oxocane base, 2-oxo thia cyclooctane base, 2-oxo oxaza octyl, 2-oxo sulfur nitrogen heterocycle octyl etc.Preferred 5-unit's nonaromatic heterocycles group such as 2-oxo-pyrrolidine base.

For the substituent group that can have by " heterocyclic group " in " optional have substituent heterocyclic group " of above-mentioned E, R and G representative, for example use those with by above-mentioned E, R, R ₁With " substituent group " on " optional have substituent alkyl " of G representative similar substituent group etc.

Can have 1-5, preferred 1-3 substituent group in the instead position on heterocyclic group by " heterocyclic group " in above-mentioned E, R and G representative " choose wantonly and have substituent heterocyclic group "; When the substituent group number is 2 or more for a long time, these substituent groups are identical or different.

(bond) explains as follows to the connection between R in the The compounds of this invention and the W.When R links to each other with W, the link position between R and the W is not had particular restriction, as long as R links to each other with W.The connectable position of R is aforementioned to " alkyl " in " choosing wantonly and have substituent alkyl " in the R definition and the connectable position on " substituent group " and aforementioned to " heterocyclic group " and the connectable position on " substituent group " in " choosing wantonly and have substituent heterocyclic group " in the R definition.

For the connectable position of W, can mention aforementioned to the connectable position on " bivalence chain alkylene " in " choosing wantonly and have substituent bivalence chain alkylene " in the W definition, aforementioned to W ₁And W ₂Connectable position in the definition on " bivalence chain alkylene ", aforementioned to the connectable position on " cyclic hydrocarbon " in " optional have substituent cyclic hydrocarbon " in the ring Z definition and aforementioned to the connectable position on " heterocyclic group " in " optional have substituent heterocyclic group " in the ring Z definition.

R can link to each other at its each connectable position with W, thereby can form ring with adjacent nitrogen-atoms.For this type ring, can mention for example saturated containing azo-cycle (like azetidine, pyrrolidine, piperidines, high piperidines etc.), undersaturatedly contain azo-cycle (for example tetrahydropyridine etc.), aromatic nitrogen-contg ring (for example pyrroles etc.), containing and except the nitrogen-atoms adjacent with W, also contain at least one heteroatomic heterocycle that is selected from nitrogen, oxygen and sulfur (for example piperazine, morpholine etc.), fused rings (for example indole, indoine (indoline), iso-indoles, iso-indoles are because of, tetrahydroquinoline, tetrahydroisoquinoline etc.) etc. with R.Wherein, the first ring of preferred 4-to 7-.

Can on its instead position, have 1-4 substituent group by R and W at the ring that forms that links to each other with adjacent nitrogen-atoms on its each connectable position.When the substituent group number is 2 or more for a long time, these substituent groups are identical or different.For substituent group, can mention to the substituent group on " optional have substituent alkyl " in the R definition and " optional have substituent heterocyclic group " and to the substituent group on " choosing wantonly and have substituent bivalence chain alkylene " in the W definition.Specifically, can mention halogen atom (for example fluorine, chlorine, bromine, iodine etc.), C _1-6Alkyl etc. are like methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, 1-ethyl propyl, hexyl etc.

Connection between R and the W can for example form

Deng, but formed ring is not restricted to above-mentioned ring.They can have the as above substituent group of definition, and for those of ordinary skills, should be appreciated that they can also have isomer.

In the present invention, X represents leaving group, for example halogen atom, BTA base, (2,5-dioxy pyrrolidine-1-yl) oxygen base etc.Wherein, preferred halogen atom, for example fluorine, chlorine, bromine, iodine etc., especially preferably chlorine.

In the present invention, M represents hydrogen atom, metal cation or quaternary ammonium ion.

In the present invention, " metal cation " alkali metal ion (Na for example that can give an example ⁺, K ⁺, Li ⁺, Cs ⁺Deng), preferred Na ⁺

In the present invention, " quaternary ammonium ion " can give an example tetramethyl ammonium, tetraethyl ammonium ion, tetrapropyl ammonium ion, TBuA ion etc., preferred TBuA ion.

In chemical compound (II), can in molecule, form pharmaceutically acceptable basic salt between acidic-group and inorganic base or the organic base etc., and between molecule neutral and alkali group and mineral acid or organic acid etc., form the pharmaceutically acceptable acid addition salts.

The instance of the inorganic basic salt of chemical compound (II) comprises the salt that forms with alkali metal (for example sodium, potassium etc.), alkaline-earth metal (for example calcium etc.), ammonia etc. etc., and the instance of organic basic salt of chemical compound (II) comprises the salt that forms with DMA, triethylamine, piperazine, pyrrolidine, piperidines, 2-phenethylamine, benzylamine, ethanolamine, diethanolamine, pyridine, trimethylpyridine etc. etc.

The acid-addition salts of chemical compound (II) comprises inorganic acid salt (for example hydrochlorate, sulfate, bromate, phosphate etc.), acylate (for example acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalates, mesylate, tosilate etc.) etc.

Chemical compound of the present invention (II) comprises hydrate.The instance of " hydrate " comprises 0.5 hydrate to 5.0 hydrate.Wherein, preferred 0.5 hydrate, 1.0 hydrates, 1.5 hydrates and 2.0 hydrates.

The compounds of this invention (II) comprises racemic modification and optically-active compound.For optically-active compound, preferably wherein a kind of enantiomer is that enantiomeric excess (e.e.) is no less than 90% chemical compound, and more preferably wherein a kind of enantiomer is that enantiomeric excess is no less than 99% chemical compound.

For the optically-active form, (R)-form of preferably representing by following formula:

Wherein each symbol definition as above.For the preferred compound that is included in the chemical compound (II), can mention for example following particular compound.These chemical compounds can be mentioned

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl-trimethyl acetas,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl cyclohexane carboxylate,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethylamino benzonitrile acid esters,

2-[methyl [[2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylamino benzonitrile acid esters,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 4-methoxybenzoic acid ester,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 3-chlorobenzoic acid ester,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 3,4-difluoro-benzoic acid ester,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 4-trifluoro-methoxy-benzoic acid ester,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 4-fluobenzoic acid ester,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 3,4, the 5-TMB,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 2-Pyridinecarboxylic Acid ester,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 2-Methoxyacetic acid ester,

Ethyl 2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester,

Isopropyl 2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester,

Isopropyl 2-[methyl [[2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl carbonate ester,

Benzyl 2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl tetrahydropyran-4-base carbonic ester,

2-methoxyethyl 2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester,

2-[ethyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate,

2-[isopropyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate,

Ethyl 2-[isopropyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester,

2-[cyclohexyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate,

2-[cyclohexyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ethyl ester,

2-[[[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (phenyl) amino] ethylhexoate,

2-[[[2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (phenyl) amino] ethylhexoate,

The tert-butyl group [2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino]-the 3-pyridine radicals] methyl carbonic,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the benzylacetic acid ester,

2-[[2-(acetoxyl group) ethyl] [[(R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate,

[(2S)-1-[[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl]-the 2-pyrrolidinyl] the methyl acetic acid ester,

[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl acetate,

2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (methyl) amino] ethylamino benzonitrile acid esters,

3-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the propylbenzoic acid ester,

2-[methyl [[2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl tetrahydropyran-4-base carbonic ester,

Ethyl 2-[methyl [[2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl carbonate ester,

Ethyl 2-[methyl [[(S)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester,

Ethyl 2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-3H-imidazo [4,5-b] pyridin-3-yl] carbonyl] (methyl) amino] ethyl carbonate ester,

2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-3H-imidazo [4,5-b] pyridin-3-yl] carbonyl] (methyl) amino] ethylhexoate,

2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-3H-imidazo [4,5-b] pyridin-3-yl] carbonyl] (phenyl) amino] ethylhexoate,

4-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the butylacetic acid ester,

Ethyl 4-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the butyl carbonic ester,

Ethyl 3-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] propyl carbonate,

3-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] propyl carbonate,

3-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] propane-1,2-two basic two carbonic esters,

Diethyl 3-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] propane-1,2-two basic double manganese esters,

2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-3H-imidazo [4,5-b] pyridin-3-yl] carbonyl] (methyl) amino] ethyl 3-chlorobenzoic acid ester,

2-[methyl [[2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate,

2-ethoxyethyl 2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester,

3-methoxycarbonyl propyl 2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl n, N-dimethylglycine ester,

S-[2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl] thiacetate,

Ethyl 2-[2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyoxyl] the ethyl carbonate ester,

Ethyl 2-[methyl [[2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyoxyl] carbonyl] amino] the ethyl carbonate ester,

Ethyl 2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (methyl) amino] ethyl carbonate ester,

2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (phenyl) amino] ethylhexoate,

Ethyl 2-[[[(S)-and 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (methyl) amino] the ethyl carbonate ester,

Ethyl 2-[[[2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (methyl) amino] ethyl carbonate ester,

2-[[[2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (phenyl) amino] ethylhexoate,

2-[[[5-(difluoro-methoxy)-2-[[(3,4-dimethoxy-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (methyl) amino] ethyl ethyl acetate,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 1-methyl piperidine-4-carboxylate,

2-[[4-(amino carbonyl) phenyl] [[(R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate,

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 1-methyl-4-piperidyl carbonic ester,

2-[[4-(amino carbonyl) phenyl] [[2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate,

(-)-ethyl 2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-3H-imidazo [4,5-b] pyridin-3-yl] carbonyl] (methyl) amino] ethyl carbonate ester and

(+)-ethyl 2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-3H-imidazo [4,5-b] pyridin-3-yl] carbonyl] (methyl) amino] ethyl carbonate ester and salt thereof etc.

In these chemical compounds, preferred following chemical compound and salt thereof.

2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-2 methyl-2-pyridine radicals) methyl] sulfinyl]-3H-imidazo [4,5-b] pyridin-3-yl] carbonyl] (methyl) amino] ethylhexoate,

Ethyl 2-[[[2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (methyl) amino] ethyl carbonate ester and

2-[[[5-(difluoro-methoxy)-2-[[(3,4-dimethoxy-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (methyl) amino] ethyl ethyl acetate.

Chemical compound (II) is A or B preparation according to the methods below.

(method A)

Chemical compound (II) or its salt can through with chemical compound (IV) or its salt and chemical compound (V) or its salt alkali exist or not in the presence of carry out condensation and obtain.Can the give an example above-mentioned salt of chemical compound (II) of the salt of the salt of the chemical compound here (IV) and chemical compound (V).Can mention for example acid-addition salts such as inorganic acid salt (example hydrochloric acid salt, sulfate, hydrobromate, phosphate etc.), acylate (like acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalates, mesylate, tosilate etc.) etc.

Wherein each symbol definition as above.The reaction of method A is carried out in solvent usually, can suitably select those can not suppress the solvent of the reaction of method A.The instance of this solvent comprises ethers (for example diox, oxolane, diethyl ether, t-butyl methyl ether, diisopropyl ether, glycol dimethyl ether etc.), esters (for example Ethyl formate, ethyl acetate, butyl acetate etc.), halogenated hydrocarbon (for example dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1; 2-dichloroethanes etc.), hydro carbons (for example normal hexane, benzene, toluene etc.), amide-type (for example Methanamide, N; Dinethylformamide, N; N-dimethyl acetylamide etc.), ketone (for example acetone, butanone, methyl iso-butyl ketone (MIBK) etc.), nitrile (for example acetonitrile, propionitrile etc.) etc. and dimethyl sulfoxine, sulfolane, hexamethyl phosphoramide, water etc., they can use separately or use as mixed solvent.Consumption for solvent for use does not have particular restriction, as long as reactant mixture can stir, for 1 mole compound (IV) or its salt, the consumption of solvent for use is generally 2-to 100-times of weight, is preferably the consumption of 5-to 50-times of weight.

For 1 mole compound (IV) or its salt, the consumption of compound used therefor (IV) or its salt is generally the 1-10 mole, is preferably the 1-3 mole.Being reflected at of method A is approximately under 0 ℃ to 100 ℃, preferred 20 ℃ to 80 ℃ temperature range carries out.

The response time of method A changes with changes such as the type of chemical compound (IV), (V) or its salt and solvent, reaction temperatures, is generally 1 minute to 96 hours, is preferably 1 minute to 72 hours, more preferably 15 minutes to 24 hours.

Alkali among the method A is for example inorganic base (for example sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate etc.), tertiary amine (for example triethylamine, tripropylamine, TBuA, cyclohexyl dimethyl amine, pyridine, lutidines, γ-trimethylpyridine, N, accelerine, N-methyl piperidine, N-crassitude, N-methylmorpholine, 4-dimethylamino naphthyridine etc.); Alkylene oxide hydro carbons (for example expoxy propane, epoxychloropropane etc.) etc.For 1 mole compound (V) or its salt, the consumption of used alkali is generally 1 mole to 10 moles, is preferably 1 mole to 3 moles.

Chemical compound (IV) or its salt can be according to the method for in JP-A-61-50978, USP 4,628,098 grade, describing or method similar with it preparations.

Chemical compound (V) or its salt can be according to itself known method or method similar with it preparations.For example, when X is the chlorine atomic time, chemical compound (V) can be through will be by the compound or its salt of formula (VII) representative:

Wherein each symbol definition as above obtains reacting in the presence of the acid scavenger, in solvent (for example oxolane, acetonitrile, dichloromethane etc.) with phosgene, trichloromethyl chloroformate, two (trichloromethyl) carbonic ester, thiocarburyl chloride etc.Perhaps; Chemical compound (V) also can be according to being described in SyntheticCommunications; The 17th volume; Method in the 1887th page (1987) or method similar with it are handled urethanes and are obtained with phosphoryl chloride phosphorus oxychloride, wherein urethanes obtains through chemical compound (VII) or its salt and ethyl chloroformate are reacted.For the salt of chemical compound (VII), can mention for example acid-addition salts such as inorganic acid salt (example hydrochloric acid salt, sulfate, hydrobromate, phosphate etc.), acylate (like acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalates, mesylate, tosilate etc.) etc.

For acid scavenger used herein; For example can mention inorganic base (for example sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate etc.), tertiary amine (for example triethylamine, tripropylamine, TBuA, cyclohexyl dimethyl amine, pyridine, lutidines, γ-trimethylpyridine, N, accelerine, N-methyl piperidine, N-crassitude, N-methylmorpholine, 4-dimethylamino naphthyridine etc.).Chemical compound (VII) and salt thereof can be according to itself known method or method similar with it preparations.For example, work as D ₁When being not chemical bond, chemical compound (VII) can be through will be by the compound or its salt of formula (VIII) representative:

R wherein ₄Be hydrogen atom or nitrogen-protecting group, all the other symbol definitions as above, and carboxylic acid or thionic acid or its derivatives reactivity (for example anhydride, halogenide etc.) or its salt by formula (IX) representative:

Wherein each symbol definition is as above carried out condensation in suitable solvent (for example ethyl acetate, oxolane, dichloromethane, N, dinethylformamide etc.), and deprotection obtains subsequently if necessary.For the salt of chemical compound (VIII), for example acid-addition salts such as inorganic acid salt (example hydrochloric acid salt, sulfate, hydrobromate, phosphate etc.), acylate (like acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalates, mesylate, tosilate etc.) etc.

In addition, work as D ₁When being chemical bond, chemical compound (VII) can pass through carboxylic acid or thionic acid or its derivatives reactivity (for example anhydride, halogenide etc.) or its salt with formula (X) representative:

Wherein each symbol definition as above, and by G-D ₂The chemical compound of-H representative carries out condensation in suitable solvent (for example ethyl acetate, oxolane, dichloromethane, N, dinethylformamide etc.), deprotection obtains subsequently if necessary.Salt for chemical compound (X); Can mention for example acid-addition salts such as inorganic acid salt (example hydrochloric acid salt, sulfate, hydrobromate, phosphate etc.), acylate (like acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalates, mesylate, tosilate etc.) etc.; The salt that forms with alkali metal (for example sodium, potassium etc.), alkaline-earth metal (for example calcium etc.), ammonia etc. etc., and the salt that for example forms with organic base such as diethylamine, triethylamine, piperazine, pyrrolidine, piperidines, 2-phenethylamine, benzylamine, ethanolamine, diethanolamine, pyridine, trimethylpyridine etc.

For in formula (VIII) and the formula (X) by R ₄The protection base of representative uses for example formoxyl, C _1-6Alkyl-carbonyl (like acetyl group, ethyl carbonyl etc.), benzyl, tertbutyloxycarbonyl, benzyloxycarbonyl group, alkoxy carbonyl group, C _7-10Aromatic alkyl carbonyl (for example benzyloxycarbonyl group etc.), trimethylphenyl etc.These groups can be by replacements such as 1-3 halogen atom (for example fluorine, chlorine, bromine etc.), nitros.

For the method for removing the protection base, known method of use itself or method similar with it are for example used a kind of method of utilizing acid, alkali, reduction, UV light, palladium etc. etc.

(method B)

Chemical compound (II) and salt thereof can be through obtaining chemical compound (VI) or its salt through peroxidization.

Wherein each symbol definition as above.

The reaction of method B can use oxidant to accomplish, for example nitric acid, hydrogen peroxide, peroxy acid, peracid ester, ozone, dinitrogen tetroxide, iodosobenzene, N-chlorosuccinimide, 1-chlorinated benzotriazole, t-butyl hypochlorite. ester, diazabicylo [2.2.2] octane-bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, ammonium ceric nitrate, bromine, chlorine, sulfonic acid chloride, monoperphthalic acid magnesium etc.The consumption of used oxidant is generally 0.5 mole to 2 moles, preferred 0.8 mole to 1.2 moles every mole compound (VI) or its salt.Oxidation reaction can be used above-mentioned oxidant, and for example hydrogen peroxide and peroxy acid for example carry out in the presence of acetic acid vanadium, vanadium oxide acetylacetonate, the tetraisopropoxy titanium etc. at catalyst.

The reaction of method B is carried out in that above-mentioned oxidation reaction is in the inert solvent usually.The instance of this " atent solvent " comprises water, alcohols (for example methanol, ethanol, 1-propanol, 2-propanol etc.), ketone (for example acetone, butanone etc.), nitrile (for example acetonitrile, propionitrile etc.), amide-type (for example Methanamide, N; N-dimethyl formamide etc.), ethers (for example diethyl ether, t-butyl methyl ether, diisopropyl ether 、 diox, oxolane etc.), sulfoxide class (for example dimethyl sulfoxine etc.) and polar solvent (for example sulfolane, hexamethyl phosphoramide etc.), they can use separately or use as its mixed solvent." atent solvent " is usually according to the use of consumption that is 1-to 100 times of weight of chemical compound (VI) or its salt.

Reaction temperature is generally-80 ℃ to 80 ℃, is preferably 0 ℃ to 30 ℃.

Response time is generally 1 minute to 6 hours, is preferably 15 minutes to 1 hour.

As the initiation material among the method B, chemical compound (VI) can through with reaction like the method category-A, for example utilize chemical compound rather than chemical compound (IV) to prepare by following formula (XI) representative:

Wherein each symbol definition as above.

Chemical compound (XI) can be according to synthetic the obtaining of method or method similar with it that is described in the following list of references: JP-A-61-50978, JP-A-54-141783, JP-A-61-22079, JP-A-1-6270, JP-A-63-146882.

Can the give an example above-mentioned salt of chemical compound (II) of the salt of chemical compound (VI), they are acid-addition salts such as inorganic acid salt (example hydrochloric acid salt, sulfate, hydrobromate, phosphate etc.), acylate (like acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalates, mesylate, tosilate etc.) etc.

The chemical compound (II) or its salt that are prepared by said method A or B can separate and purification through own separation known method (for example concentration method, concentrating under reduced pressure method, solvent extraction, crystallization process, recrystallization method, phase transfer method, chromatography etc.) from reactant mixture.Because the chemical compound (II) and the salt thereof that obtain through said method A or B comprise its isomer arbitrarily, through for example with chemical compound (II) or its salt through optical resolution, or chemical compound (VI) or its salt are carried out asymmetric oxidation can obtain optically pure chemical compound (II) and salt thereof.

The method of optical resolution comprises itself known method, for example fractional recrystallization method, chiral column method, diastereomer method or the like.Asymmetric oxidation comprises known method itself, for example is described in method among the WO96/02535 etc.

" fractional recrystallization method " comprises a kind of like this method; Be formed on the salt between racemate and the optically-active compound [for example (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonine, brucine etc.] in the method; This salt separates through the fractional recrystallization method; If necessary, can pass through neutralization procedure and obtain free optical isomer.

" chiral column method " comprises a kind of like this method, in the method racemate or its salt is filled into and carries out optical isomer on the post and separate (chiral column).In liquid chromatography; For example through racemate being added to chiral column for example in ENANTIO-OVM (Tosoh Corporation production), the DAICELCHIRAL series (Daicel Corporation production) etc.; In water, buffer (for example phosphate buffer), organic solvent (for example hexane, ethanol, methanol, isopropyl alcohol, acetonitrile, trifluoroacetic acid, diethylamine, triethylamine etc.) or their solvent mixture, launch then, thereby isolate optical isomer.In gas chromatography, for example use chiral column such as CP-Chirasil-DeX CB (GL Science production) etc. to separate optical isomer.

" diastereomer method " comprises a kind of like this method; In the method racemate and optically-active reagent are reacted and obtain the diastereo-isomerism mixture; Then it is obtained any one diastereomer through conventional separation means (for example fractional recrystallization method, chromatography etc.); After chemical reaction again (for example acid hydrolysis, basic hydrolysis, hydrogenolysis etc.) cuts away optically-active reagent group, thereby obtains required optical isomer.Said " optically-active reagent " comprises that the alkoxy methyl halogenide of for example optically-active organic acid such as MTPA [α-methoxyl group-α-(trifluoromethyl) phenylacetic acid], (-)-Herba Menthae ethoxyacetic acid etc., optically-active is like (in the 1R-)-2-(chlorine methoxyl group)-1; 3,3-trimethyl bicyclo-[2.2.1] heptane or the like.

In addition, also mentioned instantiation by the benzimidazole compound of formula (III) or the representative of its salt as aforementioned prodrug.

In above-mentioned formula (III), D representes that oxygen atom or chemical bond, Q represent the optional substituent alkyl that has.

" alkyl " by in " optional have substituent alkyl " of Q representative comprises aliphatic series or aryl radical, and that aliphatic hydrocarbyl described here is meant is saturated or undersaturated, straight chain, side chain or cyclic hydrocarbon group.Alkyl is preferably the alkyl with 1-14 carbon atom, and for example C can give an example _1-6Alkyl, C _2-6Alkenyl, C _2-6Alkynyl group, C _3-8Cycloalkyl and C _6-14Aryl.Be preferably C _1-6Alkyl, C _3-8Cycloalkyl and C _6-14Aryl, C most preferably in above-mentioned all groups _1-6Alkyl and C _3-8Cycloalkyl.

Above-mentioned " alkyl " is the straight or branched alkyl, is preferably the alkyl (" C with 1-6 carbon atom _1～6Alkyl "); can give an example for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, 1-methyl-propyl, n-hexyl, isohesyl, 1; 1-dimethylbutyl, 2; 2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethyl propyl, 2-ethyl-butyl etc.The alkyl that preferably has 1-4 carbon atom.In these groups, be preferably methyl, ethyl, isopropyl and the tert-butyl group among the Q, especially be preferably the tert-butyl group.

Above-mentioned " C _2-6Alkenyl " for the alkenyl with 2-6 carbon atom of straight or branched.The example comprises vinyl, positive acrylic, isopropenyl, n-butene base, isobutenyl, secondary cyclobutenyl, uncle's cyclobutenyl, positive pentenyl, isopentene group, new pentenyl, 1-methylpropenyl, n-hexylene base, dissident's thiazolinyl, 1; 1-dimethyl butyrate thiazolinyl, 2; 2-dimethyl butyrate thiazolinyl, 3; 3-dimethyl butyrate thiazolinyl, 3,3-dimethyl propylene thiazolinyl, 2-ethyl cyclobutenyl etc.Be preferably alkenyl, especially be preferably vinyl, positive acrylic and isopropenyl with 2-4 carbon atom.

Above-mentioned " C _2-6Alkynyl group " for the alkynyl group with 2-6 carbon atom of straight or branched.The example comprises acetenyl, positive propinyl (1-propinyl), different propinyl (2-propynyl), positive butynyl, isobutyl alkynyl, secondary butynyl, uncle's butynyl, positive pentynyl, isoamyl alkynyl, new pentynyl, 1-methyl-prop alkynyl, positive hexyn, dissident's alkynyl, 1; 1-dimethyl butyrate alkynyl, 2; 2-dimethyl butyrate alkynyl, 3; 3-dimethyl butyrate alkynyl, 3,3-alkynyl dimethyl, 2-ethyl butynyl etc.Be preferably alkynyl group, especially be preferably acetenyl, 1-propinyl and 2-propynyl with 2-3 carbon atom.

Above-mentioned " C _3-8Cycloalkyl " for having the cycloalkyl of 3-8 carbon atom.The example comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclopenta, ring octyl group etc.Be preferably cycloalkyl, wherein be preferably cyclopenta, cyclohexyl and cyclopenta with 5-7 carbon atom.Especially be preferably cyclohexyl.

Above-mentioned " aryl " is monocycle or fused polycyclic aromatic hydrocarbon base, is preferably the aryl radical (" C with 6-14 carbon atom _6-14Aryl ").The example comprises phenyl, naphthyl, anthryl, phenanthryl and acenaphthenyl.Be preferably aryl radical, especially be preferably phenyl among the Q with 6-10 carbon atom.

Above-mentioned " alkyl " can be substituted, and substituent instance comprises for example aryl, hydroxyl, halogen, optional by halogenated C _1-6Alkoxyl, C _7-12Aralkoxy, C _1-5Alkoxy carbonyl group, optional by halogenated C _1-6Alkyl, can be by C _1-6The substituted amino of alkyl etc.

Substituent group instance on " choosing wantonly and have substituent alkyl " comprises for example C _6-14Aryl, hydroxyl, halogen, can be by 1-5 the substituted alkoxyl of halogen, C _7-12Aralkoxy, C _1-5Alkoxy carbonyl group etc.Said substituent number is 1-5, is preferably 1-3.

Substituent group instance on " optional have substituent aryl " comprise halogen, can by 1-5 the substituted alkyl of halogen, aryl, hydroxyl, can be by 1-5 the substituted alkoxyl of halogen, C _7-12Aralkoxy, C _1-5Alkoxy carbonyl group etc.Said substituent number is 1-5, is preferably 1-3.

Above-mentioned " C _1-6Alkyl ", " C _2-6Alkenyl " and " C _2-6Alkynyl group " can be substituted, substituent instance comprises (i) C _6-14Aryl, (ii) hydroxyl, (iii) halogen, (iv) optional by halogenated C _1-6Alkoxyl, (v) C _7-12Aralkoxy, (vi) C _1-5Alkoxy carbonyl group, (vii) acylamino-, (viii) can be by C _1-6The substituted amino of alkyl etc. wherein are preferably (i)-(vii).Said substituent number is 1-5, is preferably 1-3.

Above-mentioned " C _3-8Cycloalkyl " and " C _6-14Aryl " can be substituted, substituent instance comprises (i) C _6-14Aryl, (ii) hydroxyl, (iii) halogen, (iv) optional by halogenated C _1-6Alkoxyl, (v) C _7-12Aralkoxy, (vi) C _1-5Alkoxy carbonyl group, (vii) can be by the substituted C of halogen _1-6Alkyl, (viii) can be by C _1-6The substituted amino of alkyl etc. wherein especially are preferably (i)-(vii).Said substituent number is 1-5, is preferably 1-3.

In formula (III), Q is preferably the substituent C that can have in the following radicals of being selected from _1-6Alkyl, C _2-6Alkenyl and C _2-6Alkynyl group: (i) C _6-14Aryl, (ii) hydroxyl, (iii) halogen, (iv) optional by halogenated C _1-6Alkoxyl, (v) C _7-12Aralkoxy, (vi) C _1-6Alkoxy carbonyl group, (vii) acylamino-, perhaps Q is for can have the substituent C in the following radicals of being selected from _3-8Cycloalkyl or C _6-14Aryl: (i) C _6-14Aryl, (ii) hydroxyl, (iii) halogen, (iv) optional by halogenated C _1-6Alkoxyl, (v) C _7-12Aralkoxy, (vi) C _1-5Alkoxy carbonyl group and (vii) optional by halogenated C _1-6Alkyl.

Q more preferably (1) can have 1-5 and is selected from the substituent C in the following radicals _1-6Alkyl: (i) C _6-14Aryl, (ii) hydroxyl, (iii) halogen, (iv) can be by 1-5 the substituted C of halogen _1-6Alkoxyl, (v) C _7-12Aralkoxy and (vi) C _1-6Alkoxy carbonyl group, perhaps (2) can have 1-5 and are selected from the substituent C in the following radicals _6-14Aryl: (i) halogen, (ii) can be by 1-5 the substituted C of halogen _1-6Alkyl, (iii) C _6-14Aryl, (iv) hydroxyl, (v) can be by 1-5 the substituted C of halogen _1-6Alkoxyl, (vi) C _7-12Aralkoxy and (vii) C _1-5Alkoxy carbonyl group.

Q further more preferably can have the substituent C in the following radicals of being selected from _1-6Alkyl: (i) C _6-14Aryl, (ii) hydroxyl, (iii) halogen, (iv) optional by halogenated C _1-6Alkoxyl, (v) C _7-12Aralkoxy, (vi) C _1-5Alkoxy carbonyl group, (vii) acylamino-; Perhaps Q is for can have the substituent C in the following radicals of being selected from _3-8Cycloalkyl or C _6-14Aryl: (i) C _6-14Aryl, (ii) hydroxyl, (iii) halogen, (iv) optional by halogenated C _1-6Alkoxyl, (v) C _7-12Aralkoxy, (vi) C _1-5Alkoxy carbonyl group and (vii) optional by halogenated C _1-6Alkyl.

Wherein be preferably can be by C for Q _6-14The substituted C of aryl _1-6Alkyl or C _6-14Aryl, Q especially are preferably phenyl, methyl or the tert-butyl group.

In chemical compound (III), the acidic-group in the molecule can form pharmaceutically acceptable basic salt with inorganic salt or organic salt etc., and the basic group in the molecule can form the pharmaceutically acceptable acid addition salts with inorganic salt or organic salt etc.

A kind of preferred form of The compounds of this invention (III) comprises a kind of like this chemical compound, and D is that chemical bond, Q have substituent aryl for choosing wantonly to have substituent alkyl or choose wantonly in this chemical compound.

The instance of the inorganic basic salt of chemical compound (III) for example comprises the salt that forms with alkali metal (for example sodium, potassium etc.), alkaline-earth metal (for example calcium etc.), ammonia etc. etc., and the instance of organic basic salt of chemical compound (III) for example comprises the salt that forms with diethylamine, triethylamine, piperazine, pyrrolidine, piperidines, 2-phenethylamine, benzylamine, ethanolamine, diethanolamine, pyridine, trimethylpyridine etc.

The acid-addition salts of chemical compound (III) comprises for example inorganic acid salt (example hydrochloric acid salt, sulfate, hydrobromate, phosphate etc.), acylate (like acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalates, mesylate, tosilate etc.) etc.

Chemical compound of the present invention (III) comprises hydrate.Said " hydrate " comprises 0.5 hydrate-5.0 hydrate.Wherein, be preferably 0.5 hydrate, 1.0 hydrates, 1.5 hydrates and 2.0 hydrates.

The compounds of this invention (III) comprises racemic compound and optically-active compound.For optically-active compound, preferably wherein a kind of enantiomer is that enantiomeric excess (e.e.) is no less than 90% chemical compound, and more preferably wherein a kind of enantiomer is that enantiomeric excess is no less than 99% chemical compound.For the optically-active form, (R)-isomer of preferably representing by following formula:

Wherein each symbol definition as above.

Chemical compound (III) can be through known method preparation itself, perhaps through being disclosed in method or method similar with it preparation among for example JP-A2002-187890, the WO 02/30920 etc.In addition, optically-active compound (III) can obtain through encompasses processes for optical resolution (fractional recrystallization method, chiral column method, diastereomer method, utilize the method for microorganism or enzyme etc.) and asymmetric oxidation method etc.For other benzimidizole derivatives of PPI, the present invention can be applied to be disclosed in the chemical compound among the WO 03/27098.

Although be used for the present invention by general formula (I '), (I), (II) and (III) the mixing consumption of the active component of representative change with the type and the DM of active component; But for tablet of the present invention or granule total amount; Absorption of active ingredient for about 1 weight % for example to about 60 weight %; Be preferably about 1 weight % to about 50 weight %, further be preferably about 8 weight % to about 40 weight %.When active component was benzimidazole compound PPI, especially during lansoprazole, its consumption was that about 8 weight % are to about 40 weight %.

Contain imidazoles PPI, especially by the general formula (I ') or (I) the benzimidazole PPI of representative for example in lansoprazole or its optically-active compound (R-isomer etc.) and the capsule situation by formula (II) and the imdazole derivatives PPI that (III) represents; The difference that has of two kinds or more kinds of types is disengaged the tablet of characteristic, granule or fine grained agent (two types granule for example disengages granule relatively rapidly and the granule that disengages of active component time-delay wherein like active component wherein) and can be utilized and have the controlled release coat layer mixing filling that difference is disengaged characteristic and condition separately.In addition, two types said controlled release coat layer can be layered in corresponding granule and the fine grained agent with two-layer or more multiwalled form.A kind of like this preparation (being preferably capsule) below preparing: it has controlled release coat layer of the present invention and can be retained in tablet, granule or the fine grained agent of the polymer of the formation gel in the digestive tract except containing; Also contain and have the granule that is arranged in the intermediate layer on the nuclear slug particle that contains above-mentioned active component and is positioned at the unique one deck enteric coating on the said intermediate layer (just in above-mentioned controlled release granule of the present invention or fine grained agent, wherein active component disengages granule relatively rapidly); Perhaps contain tablet, granule or the fine grained agent with controlled release layer of the present invention and the polymer that can be retained in the formation gel in the digestive tract and a kind of preparation that contains granule with common enteric coating through taking simultaneously; Through above-mentioned two kinds of means a kind of like this preparation can be provided; Thereby this preparation more early time chien shih blood drug level after taking raises and demonstrates medicine usefulness, shows through the medicine usefulness that makes controlled release granule then and keeps this medicine usefulness.In addition, when this tablet that is filled (in situation, preferred undersized tablet), granule or fine grained agent have enough control when disengaging ability, capsule of the present invention can contain the polymer of this formation gel all the time.Controlled release tablet, granule or fine grained agent can be only used in the preparation of capsule, also can unite the quick-release granule that uses controlled release tablet, granule or fine grained agent and only have enteric coating.In above-mentioned combination formulations and administering drug combinations situation; Can prepare a kind of like this preparation; Through this preparation preferably at more early time rising blood drug level to obtain effect of drugs and to reach the first the highest blood drug level; Reach the second the highest blood drug level through disengaging active component the granule that is controlled from disengaging of its Chinese medicine then, that is to say to demonstrate two summits.In addition, the for example above-mentioned Extencap of the present invention of this controlled release preparation and wherein active component disengage relatively common rapidly capsule certain interval of can taking simultaneously or be separated by and take.Can in long-time, keep the high blood drug level of active component through this administering drug combinations method.

Common enteric coating capsule can be for example according to the method preparation that is described among the JP-A 63-301826.In addition, preferably prepare a kind of stable formulation according to the method that is described among the JP-A 62-277322.

In addition, this lansoprazole that contains higher concentration or its optically-active form etc. and sufficiently stable granule can prepare according to the methods below.That is to say; Use known method of granulating for example liquid bed granulation (like centrifugal liquid bed granulation), fluidized granulation method and stirring granulation (like liquid bed fluidized granulation method); Can prepare such granule; This granule has the active component layer, is formed on the intermediate layer on the said active component layer and is formed on the enteric coating layer on the said intermediate layer; Wherein based on this granule with as the total of the alkaline, inorganic salts of stabilizing agent, said active component layer contains about 10 weight % to the lansoprazole of about 40 weight % etc., and average particulate diameter is that about 600 μ m are to about 2500 μ m.

Specifically, the active component layer can be for example through on the nuclear slug particle, spraying adhesive solution for example in the hydroxypropyl cellulose etc., will examine the slug particle coating and prepare with the isolation powder that contains imidazoles PPI, alkali metal salt, excipient, disintegrating agent etc.For said nuclear slug particle, can give an example through Nonpareil that sucrose (75 weight portion) coating is prepared according to known method itself with corn starch (25 weight portion) and the globose nucleus slug particle that uses crystalline cellulose etc.In addition, nuclear slug particle itself also can be the active component of said medicine.The mean size of common said granule is the 14-80 order.

For " core " in the nuclear slug particle, the spherical granulation product of the spherical granulation product of can give an example sucrose and starch, spherical granulation product, crystalline cellulose and the lactose of crystalline cellulose etc.

Can coatings be confirmed within the specific limits with respect to the ratio of nuclear slug particle, so that can control the eluting characteristic of active component and the granular size of granule.For example, based on the nuclear slug particle calculating of 1 weight portion, coatings is typically about 0.2 weight portion to about 5 weight portions, is preferably about 0.1 weight portion to about 5 weight portions.

Then, on resulting active component layer, form the intermediate layer according to conventional method.For example with the component in intermediate layer with dilutions such as pure water, then mixture with liquid form with active component layer spray coating.At this moment, preferably spray binding agent for example in the hydroxy propyl cellulose with this active component layer coating.The instance in intermediate layer for example comprises wherein saccharide sucrose (purification white sugar (pulverize (Icing Sugar) and do not grind composition) etc.) for example; Starch sugar is corn starch for example; Lactose; Mel and sugar alcohol (D-mannitol; Erythritol etc.) and the for example low substituted hydroxypropyl cellulose of polymer matrix material; Hydroxypropyl cellulose; Hydroxypropyl emthylcellulose (like TC-5 etc.); Polyvinylpyrrolidone; Polyvinyl alcohol; Methylcellulose and hydroxyethylmethyl-cellulose suitably mix the layer that obtains.If necessary, can also suitably in middle coatings, add those and be used to prepare the excipient (for example screening agent (titanium oxide etc.)) and the antistatic additive (titanium oxide, Talcum etc.) of preparation.

The granule that contains benzimidazole PPI based on 1 weight portion calculates, and the coating consumption of middle coatings is generally for example about 0.02 weight portion to about 1.5 weight portions, is preferably about 0.05 weight portion to about 1 weight portion.

In addition, this lansoprazole that contains higher concentration or its optically-active form etc. and sufficiently stable granule can prepare through on middle coatings, forming enteric coating layer according to conventional method.For enteric coating layer, for example use sustained-release matrix material such as moisture enteric polymer host material such as cellulose ethanoate phthalic acid ester (CAP), HPMCP, hydroxy methocel acetas succinate, ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium ethyl ester chloride copolymer (Eudragit RS or RL; Rohm Co. manufacturing), methyl methacrylate-ethyl acrylate copolymer (Eudragit NE30D; Rohm Co. manufacturing), carboxymethylethylcellulose and Lac; Plasticizer such as water-soluble polymer, triethyl citrate, Polyethylene Glycol (polyethylene glycol 6000 (trade (brand) name: Macrogol 6000 etc.), acetylation mono glycerinate, glyceryl triacetate and Oleum Ricini.They can use or mix two kinds or more kinds of use separately.

Based on the granule total before the enteric coating, the coating consumption of enteric coating layer is extremely about 70 weight % of about 10 weight %, is preferably about 10 weight % to about 50 weight %, and more preferably about 15 weight % are to about 30 weight %.

In the situation of tablet, for example mixing such as benzimidazole compound, excipient, binding agent, disintegrating agent, lubricant are directly obtained tablet through pushing, the granule that perhaps will prepare according to the method identical with above-mentioned granule is squeezed into tablet.In addition, as alternative, can use the multilamellar tablet machine that is commercially available to utilize granular solid matter to prepare two-layer tablet.

In preparation of the present invention; Contain that for example the preparation of the PPI (especially by chemical compound and the optically-active compound thereof of above-mentioned general formula (II) with (III) representative) of the imidazolium compounds derivant of PPI, aforementioned all benzimidazole PPI chemical compounds and the prodrug type by general formula (I) representative of lansoprazole and optically-active form thereof has antiulcer effect in the fabulous body, gastric secretion suppresses effect, mucosa protection effect, anti-screw rod pyloric bacteria (Helicobacter pylori) effect etc. by the benzimidazole compound of general formula (I ') representative, and owing to having hypotoxicity thereby useful as drug.Especially; Because the imidazolium compounds by above-mentioned general formula (II) representative is stable to acid; Therefore need not prepare and supply oral enteric solubility preparation; Thereby reduced the cost of preparation enteric solubility preparation, and because the size decreases of preparation, especially old people and child can carry out administration at an easy rate to make the patient of dysphagia.In addition,, thereby demonstrate gastric secretion inhibition effect soon because its absorptance enteric solubility preparation is rapid, and because it slowly is converted into its precursor compound in vivo, so it has slow-release capability thereby can be used as antiulcer agent etc.The PPI chemical compound of The compounds of this invention (I ') or its salt has lower toxicity; Thereby can with independent compound form or according to known method itself through mix the oral safely or parenterai administration (for example part, rectum, intravenously administrable) of the form that obtains pharmaceutical composition with pharmaceutically suitable carrier; Pharmaceutical composition is preparation for example just, like tablet (comprising sugar coated tablet and film coated tablet), powder, granule, capsule (comprising soft capsule), interior with Orally disintegrating tablet, liquid agent, injection, suppository, slow releasing agent and liniment.

For treat or prevention of digestive tract ulcers (for example gastric ulcer, duodenal ulcer, marginal ulcer etc.), Zollinger-Ellison syndrome, gastritis, reflux esophagitis, no esophagitis symptom gastroesophageal reflux disease (Symptomatic GERD), NUD (non-ucler dyspepsia), gastric cancer (comprising that the gene pleiomorphism that is accompanied by because of il-1 causes the gastric cancer that il-1 β generates to be increased), gastric MALT lymphoma etc. are arranged; Eradicate the screw rod pyloric bacteria, suppress the upper gastrointestinal hemorrhage, acute stress ulcer and the hemorrhagic gastritis that cause by digestive tract ulcer; The upper gastrointestinal hemorrhage that inhibition stress be caused by invasion (by postoperative need that the major operation of scrupulous care causes stress; And by cerebrovascular accident, head injury, the imbalance of many organs and the various burns that require much care cause stress), and the ulcer that causes by NSAID of treatment and prevention; Gastrorrhoea of treating and preventing stress be caused by postoperative and ulcer etc. can be to the Orally administered tablet of the present invention of mammal (for example people, monkey, sheep, horse, Canis familiaris L., cat, rabbit, Mus etc.), granule or fine grained agent.In order to eradicate screw rod pyloric bacteria etc., granule of the present invention and capsule can be united use with other active component (for example 1-3 kind active component).

The instance of " other active component " comprises for example antimicrobial drug such as anti-screw rod pyloric bacteria active substance, imidazolium compounds and quinolone compounds and bismuth salt.Especially, preferably through uniting the medicine that granule of the present invention and capsule and antimicrobial drug obtain.Wherein, preferably unite with antimicrobial drug for example anti-screw rod pyloric bacteria active substance and imidazolium compounds.The instance of anti-screw rod pyloric bacteria active substance comprises that for example the penicillin antibiotic is (like amoxicillin (amoxicillin); Benzylpcnicillin (benzylpenicillin); Piperacillin (piperacillin); Mecillinam (mecillinam) etc.); Cephalosporins (cefixime (cefixime) for example; Cephachlor etc.); Macrolide antibiotic (for example erythromycin antibiotic such as erythromycin and clarithromycin); Fourth Ring antibiotic (tetracycline for example; Minocycline; Streptomycin etc.); Aminoglycoside antibiotics (gentamycin for example; Amikacin etc.); Imipenum (imipenem) etc.Especially preferred penicillin antibiotic, macrolide antibiotic etc.

The instance of " imidazolium compounds " comprises for example metronidazole, miconazole etc.The instance of " bismuth salt " comprises for example bismuth acetate, bismuth citrate etc.The antimicrobial drug of also preferred " quinolone compounds ", the ofloxacin (ofloxacin) of for example can giving an example, ciprofloxacin (ciproxacin) etc.Especially, in order to eradicate anti-screw rod pyloric bacteria, preferably unite and use granule of the present invention and capsule and penicillin antibiotic (for example amoxicillin etc.) and/or erythromycin antibiotic (for example clarithromycin etc.).

In addition, in the situation of lansoprazole, the capsule that contains 15mg crystallization lansoprazole is filled in the past in No. 3 capsules usually, and the capsule that contains 30mg is filled in No. 1 capsule in the past usually.Yet, do not reduce active component and stability of formulation through forming the intermediate layer, sneak into the basic inorganic salt stabilizing agent and further controlling the granular size of granule, unexpectedly find can to obtain like this to contain the granule of the active component of high concentration.So, owing to can reduce the consumption of other component of non-active ingredient, the capsule that therefore contains 15mg can be dwindled into capsule No. 4 to No. 5, and the capsule that contains 30mg can be dwindled into capsule No. 3 to No. 5.

In addition, No. 1 to No. 3 capsule also can be used for containing the capsule of 60mg.

In addition, in the situation of the optically-active compound of lansoprazole, No. 3 to No. 5 capsules, No. 2 to No. 4 capsules and No. 1 to No. 3 capsule can be respectively applied for the capsule that contains 30mg, 40mg and 60mg.

For example; Because the capsule that contains 60mg lansoprazole or lansoprazole R-isomer contains the active component of high concentration; Therefore with this capsule downsizing; In fact this is easy to accomplish, and this is suitable for treating the sour supersecretion symptom that especially comprises the Zollinger-Ellison syndrome.

Every day, dosage was different because of the type of age of the degree of symptom, administration object, sex, body weight, administration time, interval, active component, and it is not had particular restriction.For example, when this medicine as antiulcer agent to the adult during (60kg) oral administration, its dosage is that active component reaches about 0.5 to 1500mg/ day, is preferably about 5 to 150mg/ days.The preparation that contains above-mentioned benzimidazole or imidazolium compounds can once a day or separately be taken for one day 2-3 time.

In addition, in order to improve the stability of solid preparation of the present invention when storing or transport, can also make the form stabilisation of packing.For example; Packing (packing of place of gas rather than oxygen just) through utilizing the packing for example suppress oxygen and dampness and to infiltrate, place of gas, vacuum packaging and with the packaged form of deoxidant packages sealed can improve the stability of the capsule preparations that contains benzimidazole of the present invention or imidazolium compounds.Utilize above-mentioned packaged form, thereby its stability is improved through reducing the amount of oxygen that takes place directly to contact with this solid preparation.When being sealed into deoxidant, this medical solid preparation is received in oxygen and infiltrates material, and all the other packings just can be accomplished with this packing then.

Embodiment

Below through the present invention being elaborated with reference to various reference implementation examples, synthetic embodiment, embodiment and test example.The present invention is not limited by these embodiment.

The raw material of the 14th edition revised edition of the corn starch that uses in the FORMULATION EXAMPLE below, hydroxypropyl cellulose (HPC-L), polyethylene glycol 6000 and titanium oxide and Japanese Pharmacopoeia is consistent.

In below the reference implementation example and synthetic embodiment, room temperature is meant about 15-30 ℃.

¹The H-NMR spectrum is utilized CDCl ₃, DMSO-d ₆And CD ₃OD records as solvent, use VarianGemini-200 and Mercury-300; Data illustrate with chemical shift δ (ppm), are interior mark with tetramethylsilane.

All the other symbols in this description have following implication.

S: unimodal

D: bimodal

T: triplet

Q: quartet

M: multiplet

Br: broad peak

Bs: wide unimodal

Bm: wide multiplet

J: coupling constant

Reference implementation example 1

2-ethoxy (methyl) t-butyl carbamate

In frozen water cooling down, in the mixture of 2-(methylamino) ethanol (30.04g) and ethyl acetate (90mL) dropwise adding contain heavy carbonic di tert butyl carbonate (di-tert-butyl dicarbonate) (87.30g) and in the mixture of ethyl acetate (10mL).After the stirring at room 2 hours, the mixture concentrating under reduced pressure.Residue is dissolved in the ethyl acetate (150mL), with water washing (100mL), anhydrous magnesium sulfate drying.Concentrating under reduced pressure obtains the title compound (66.19g) into colorless oil.

¹H-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 implementation example 2

2-(methylamino) ethyl acetic acid ester hydrochloride

Under the frozen water cooling, in the mixture of 2-(methylamino) ethanol (1.50g) and ethyl acetate (20mL), add heavy carbonic di tert butyl carbonate (4.37g).The frozen water cooling is stirred after 1.5 hours down, adds acetic anhydride (2.08mL), pyridine (1.78mL) and 4-dimethylaminopyridine (0.12g).After the stirring at room 2 hours, in reactant mixture, add ethyl acetate (50mL), mixture water (50mL), 5% aqueous citric acid solution (50mL) and saturated brine (50mL) washing.Behind the anhydrous magnesium sulfate drying, the mixture concentrating under reduced pressure.In residue, add 4N hydrogen chloride-ethyl acetate solution (20mL), mixture stirring at room 2 hours.Add diethyl ether (10mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (2.93g) into white solid.

¹H-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 implementation example 3

2-(methylamino) ethyl-trimethyl acetic ester hydrochloride

In the mixture of 2-ethoxy (methyl) t-butyl carbamate (1.75g) that in reference implementation example 1, obtains and ethyl acetate (15mL), add the mixture of triethylamine (1.67mL) and trimethyl-aceyl chloride (1.35mL), dropwise add ethyl acetate (5mL) again.After the stirring at room 2 hours, add pyridine (1.62mL), mixture is stirred overnight at room temperature.In reactant mixture, add ethyl acetate (50mL), mixture water (50mL), 5% aqueous citric acid solution (50mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, in residue, add 4N hydrogen chloride-ethyl acetate solution (10mL).After the stirring at room 2 hours, add diethyl ether (10mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (1.65g) into white solid.

¹H-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 implementation example 4

2-(methylamino) ethyl cyclohexane formic acid esters hydrochlorate

In the mixture of 2-ethoxy (methyl) t-butyl carbamate (1.75g) that in reference implementation example 1, obtains and ethyl acetate (20mL), add pyridine (0.97mL) and 4-dimethylaminopyridine (catalytic amount), dropwise add cyclohexane extraction phosgene (1.60mL) again.After the stirring at room 2 hours, add pyridine (0.65mL) and cyclohexane extraction phosgene (0.58mL), mixture is stirred overnight at room temperature.In reactant mixture, add ethyl acetate (50mL), mixture water (50mL), 5% aqueous citric acid solution (50mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, in residue, add 4N hydrogen chloride-ethyl acetate solution (10mL).After the stirring at room 2 hours, add diethyl ether (10mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (1.88g) into white solid.

¹H-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 implementation example 5

2-(methylamino) ethyl benzoate ester hydrochloride

Under the frozen water cooling, in the mixture of 2-(methylamino) ethanol (30.04g) and ethyl acetate (90mL), dropwise add and contain in the mixture of heavy carbonic di tert butyl carbonate (87.30g) and ethyl acetate (10mL).After the stirring at room 1 hour, under the frozen water cooling, add Benzenecarbonyl chloride. (61.8g) and pyridine (38.8mL).After the stirring at room 1 hour, solids removed by filtration.Solid is with ethyl acetate washing (100mL), and merging filtrate and cleaning mixture are with its water (100mL) and saturated brine (100mL) washing.Behind the anhydrous magnesium sulfate drying, the mixture concentrating under reduced pressure.Residue is dissolved in the ethyl acetate (100mL), adds 4N hydrogen chloride-ethyl acetate solution (200mL), and mixture at room temperature stirred 30 minutes.Add diethyl ether (100mL), through solid collected by filtration.This solid obtains the title compound (57.4g) into white solid with ethyl acetate (100mL) washed twice at 60 ℃ of following drying under reduced pressure.

¹H-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＝7.8Hz)，9.26(2H，bs)。

Reference implementation example 6

2-(methylamino) ethyl 4-methoxybenzoic acid ester hydrochloride

In the mixture of 2-ethoxy (methyl) t-butyl carbamate (1.75g) that in reference implementation example 1, obtains and ethyl acetate (10mL), add 4-methoxy benzoyl chloride (1.88g) and pyridine (0.97mL).After the stirring at room 14 hours, add 4-methoxy benzoyl chloride (0.70g) and pyridine (0.97mL), mixture at room temperature stirred 1 hour.In reactant mixture, add ethyl acetate (80mL), mixture water (20mL), saturated sodium bicarbonate solution (20mL) and water (20mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the ethyl acetate (10mL), adds 4N hydrogen chloride-ethyl acetate solution (10mL).After the stirring at room 1 hour, add diethyl ether (20mL), collect the solid of separating out through filtering.This solid obtains the title compound (1.99g) into white solid with ethyl acetate (15mL) washed twice at 60 ℃ of following drying under reduced pressure.

¹H-NMR(DMSO-d ₆)：2.62(3H，s)，3.32(2H，m)，4.48(2H，t，J＝5.0Hz)，7.07(2H，d，J＝8.7Hz)，8.06(2H，d，J＝8.7Hz)，9.04(2H，bs)。

Reference implementation example 7

2-(methylamino) ethyl 3-chlorobenzoic acid ester hydrochloride

In the mixture of 2-ethoxy (methyl) t-butyl carbamate (1.75g) that in reference implementation example 1, obtains and ethyl acetate (10mL), add 3-chlorobenzoyl chloride (1.92g) and pyridine (0.97mL).After the stirring at room 1 hour, mixture stirred 6 hours down at 60 ℃.In reactant mixture, add ethyl acetate (80mL), mixture water (20mL), saturated sodium bicarbonate solution (20mL) and water (20mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, in residue, add 4N hydrogen chloride-ethyl acetate solution (10mL).After the stirring at room 22 hours, add diethyl ether (15mL), collect the solid of separating out through filtering.This solid obtains the title compound (2.01g) into white solid with ethyl acetate (15mL) washed twice at 60 ℃ of following drying under reduced pressure.

¹H-NMR(DMSO-d ₆)：2.63(3H，s)，3.32(2H，m)，4.53(2H，t，J＝4.9Hz)，7.60(1H，t，J＝8.0Hz)，7.78(1H，d，J＝8.OHz)，8.05(1H，d，J＝8.OHz)，8.15(1H，s)，9.07(2H，bs)。

Reference implementation example 8

2-(methylamino) ethyl 3,4-difluoro-benzoic acid ester hydrochloride

In the mixture of 2-ethoxy (methyl) t-butyl carbamate (1.75g) that in reference implementation example 1, obtains and ethyl acetate (10mL), add 3,4-difluoro benzoyl chloride (1.77g) and pyridine (0.97mL).After the stirring at room 3 days, in reactant mixture, add ethyl acetate (80mL).Mixture water (20mL), saturated sodium bicarbonate solution (20mL) and water (20mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, in residue, add 4N hydrogen chloride-ethyl acetate solution (10mL).After the stirring at room 4 hours, the mixture concentrating under reduced pressure.Residue obtains the title compound (2.05g) into white solid with ethyl acetate (15mL) washing at 60 ℃ of following drying under reduced pressure.

¹H-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 implementation example 9

2-(methylamino) ethyl 4-trifluoro-methoxy-benzoic acid ester hydrochloride

In the mixture of 2-ethoxy (methyl) t-butyl carbamate (1.30g) that in reference implementation example 1, obtains and ethyl acetate (10mL), add 4-trifluoromethoxy Benzenecarbonyl chloride. (1.83g) and pyridine (0.72mL).Mixture stirred 25 hours down at 60 ℃.In reactant mixture, add ethyl acetate (60mL), mixture water (30mL), saturated sodium bicarbonate solution (20mL) and water (20mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, in residue, add 4N hydrogen chloride-ethyl acetate solution (10mL).After at room temperature stirring 14.5 hours, the mixture concentrating under reduced pressure.Residue obtains the title compound (1.83g) into white solid with ethyl acetate (15mL) washed twice at 60 ℃ of following drying under reduced pressure.

¹H-NMR(DMSO-d ₆)：2.63(3H，s)，3.31(2H，m)，4.54(2H，t，J＝4.9Hz)，7.55(2H，d，J＝8.5Hz)，8.24(2H，d，J＝8.5Hz)，9.02(2H，bs)。

Reference implementation example 10

2-(methylamino) ethyl 4-fluobenzoic acid ester hydrochloride

In the mixture of 2-ethoxy (methyl) t-butyl carbamate (1.75g) that in reference implementation example 1, obtains and ethyl acetate (10mL), add 4-fluorobenzoyl chloride (1.74g) and pyridine (0.97mL).Mixture at room temperature stirred 6.5 hours.In reactant mixture, add ethyl acetate (80mL), mixture water (30mL), saturated sodium bicarbonate solution (30mL), water (30mL) and saturated brine (30mL) washing then, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, in residue, add 4N hydrogen chloride-ethyl acetate solution (10mL).After the stirring at room 1 hour, collect the solid of separating out through filtering.Solid obtains the title compound (1.89g) into white solid with ethyl acetate (15mL) washed twice at 60 ℃ of following drying under reduced pressure.

¹H-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 implementation example 11

2-(methylamino) ethyl 3,4,5-TMB hydrochlorate

In the mixture of 2-ethoxy (methyl) t-butyl carbamate (1.75g) that in reference implementation example 1, obtains and ethyl acetate (10mL), add 3,4,5-trimethoxy-benzoyl chloride (2.54g) and pyridine (0.97mL).After stirring 14 hours under 60 ℃, add 3,4,5-trimethoxy-benzoyl chloride (1.30g), pyridine (0.97mL) and ethyl acetate (10mL), mixture stirred 24 hours down at 60 ℃.Reactant mixture filters, and adds ethyl acetate (50mL) and water (30mL) in the filtrating.After the layering, ethyl acetate layer is with 1N hydrochloric acid (30mL), water (30mL), copper sulfate (II) aqueous solution (30mL), water (30mL) and saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=1: 1 eluting) through silica gel chromatography.In purified product, add 4N hydrogen chloride-ethyl acetate solution (10mL).After at room temperature stirring 4 hours, the mixture concentrating under reduced pressure.Add toluene (10mL), the mixture concentrating under reduced pressure.Residue is suspended in the ethyl acetate solids filtered.After ethyl acetate (15mL) washing, the solid drying under reduced pressure obtains the title compound (1.79g) into white solid.

¹H-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 implementation example 12

2-(methylamino) ethyl 2-Pyridinecarboxylic Acid ester dihydrochloride

Under the frozen water cooling, in 2-ethoxy (methyl) t-butyl carbamate (1.75g), 2-pyridine phosgene hydrochlorate (2.67g), pyridine (1.21mL) and 4-dimethylaminopyridine (0.122g) the solution (100mL) that in reference implementation example 1, obtains, dropwise add triethylamine (2.09mL) at oxolane.Mixture at room temperature stirred 6 hours.In reactant mixture, add (200mL), mixture extracts with ethyl acetate (150mL).Organic layer is continuously with 5% copper sulfate (II) aqueous solution (100mL), water (100mL) and saturated brine (100mL) washing, anhydrous sodium sulfate drying and reduction vaporization.Residue is dissolved in ethyl acetate (50mL) and the ethanol (100mL), adds 4N hydrogen chloride-ethyl acetate solution (15mL).Mixture at room temperature stirred 1 hour.Collect the solid of separating out through filtering,, obtain title compound (1.08g) into white solid at 60 ℃ of following drying under reduced pressure with ethyl acetate (100mL) washed twice.

¹H-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 implementation example 13

2-(methylamino) ethyl 2-Methoxyacetic acid ester

In the mixture of 2-ethoxy (methyl) t-butyl carbamate (1.75g) that in reference implementation example 1, obtains and ethyl acetate (10mL), add methoxyacetyl chloride (1.20g) and pyridine (0.97mL).After at room temperature stirring 3 hours, in reactant mixture, add ethyl acetate (70mL).Mixture water (20mL), saturated sodium bicarbonate solution (20mL) and water (20mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the ethyl acetate (5mL), adds 4N hydrogen chloride-ethyl acetate solution (10mL).After the stirring at room 1 hour, the mixture concentrating under reduced pressure.In residue, add entry (60mL) and diethyl ether (30mL).After the stirring, separate water layer and taking-up.Water layer alkalizes with sodium bicarbonate, and with ethyl acetate (40mL) extracted twice.Ethyl acetate layer is used anhydrous magnesium sulfate drying, and concentrating under reduced pressure obtains the title compound (1.00g) into colorless oil.

¹H-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 implementation example 14

Ethyl 2-(methylamino) ethyl carbonate ester hydrochloride

In the mixture of 2-ethoxy (methyl) t-butyl carbamate (1.75g) that in reference implementation example 1, obtains and ethyl acetate (20mL), add pyridine (0.97mL) and 4-dimethylaminopyridine (catalytic amount), and then dropwise add ethyl chloroformate (1.25mL).Mixture is stirred overnight at room temperature, adds ethyl acetate (50mL).Mixture water (50mL), 5% aqueous citric acid solution (50mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, in residue, add 4N hydrogen chloride-ethyl acetate solution (10mL).After the stirring at room 2 hours, add diethyl ether (10mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (1.66g) into white solid.

¹H-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＝7.1Hz)，4.32-4.37(2H，m)，9.25(2H，br)。

Reference implementation example 15

Isopropyl 2-(methylamino) ethyl carbonate ester hydrochloride

Under the frozen water cooling, in the mixture of 2-ethoxy (methyl) t-butyl carbamate (3.50g) that in reference implementation example 1, obtains and ethyl acetate (20mL), add isopropyl chlorocarbonate (1.35g) and pyridine (1.94mL).Under the frozen water cooling, stirred 3.5 hours, add isopropyl chlorocarbonate (1.84g), mixture at room temperature stirred 2.5 hours.In reactant mixture, add ethyl acetate (120mL), mixture water (50mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, in residue, add 4N hydrogen chloride-ethyl acetate solution (10mL).After the stirring at room 2 hours, collect the solid of separating out through filtering.Solid obtains the title compound (1.38g) into white solid with ethyl acetate (15mL) washing at 60 ℃ of following drying under reduced pressure.

¹H-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＝5.1Hz)，4.80(1H，m)，8.95(2H，bs)。

Reference implementation example 16

Benzyl 2-(methylamino) ethyl carbonate ester hydrochloride

In the mixture of 2-ethoxy (methyl) t-butyl carbamate (1.75g) that in reference implementation example 1, obtains and ethyl acetate (20mL), add pyridine (0.97mL) and 4-dimethylaminopyridine (catalytic amount), and then dropwise add benzyl chloroformate (1.57mL).After at room temperature stirring 2 hours, add pyridine (0.65mL) and benzyl chloroformate (1.28mL).After at room temperature stirring 5 days, under the frozen water cooling, add pyridine (0.81mL), and then slowly dropwise add the solution (5mL) of benzyl chloroformate (1.43mL) in ethyl acetate.After the stirring at room 2 hours, in mixture, add ethyl acetate (50mL), water (50mL), 5% aqueous citric acid solution (50mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, in residue, add 4N hydrogen chloride-ethyl acetate solution (10mL).After the stirring at room 2 hours, add diethyl ether (10mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (1.99g) into white solid.

¹H-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 implementation example 17

2-(methylamino) ethyl tetrahydropyran-4-base carbonate salt hydrochlorate

Under the frozen water cooling, in the tetrahydrofuran solution (40mL) of two (trichloromethyl) carbonic ester (2.97g), dropwise add the solution (10mL) of the oxolane of pyridine (2.43mL).After stirring 10 minutes under the frozen water cooling, slowly dropwise add the tetrahydrofuran solution (20mL) of Pentamethylene oxide .-4-alcohol (1.91g).After the stirring at room 2 hours, the mixture concentrating under reduced pressure adds ethyl acetate (50mL) and water (50mL) in residue.The separating ethyl acetate layer also takes out, with 0.2N hydrochloric acid (20mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Concentrating under reduced pressure obtains tetrahydropyran-4-base chloro-formate (1.53g).In the mixture of 2-ethoxy (methyl) t-butyl carbamate (1.40g) that in reference implementation example 1, obtains and oxolane (20mL), add pyridine (0.78mL); Dropwise add the tetrahydrofuran solution (10mL) of the resulting tetrahydropyran-4-base chloro-formate in front (1.53g) again, mixture is stirred overnight at room temperature.Behind the reactant mixture concentrating under reduced pressure, add entry (50mL), mixture extracts with ethyl acetate (50mL).Residue is with 5% aqueous citric acid solution (50mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through silica gel chromatography (use ethyl acetate: hexane=4: 1,3: 2 eluting) continuously.Resulting colorless oil (2.03g) is dissolved in the diethyl ether (2mL), adds 4N hydrogen chloride-ethyl acetate solution (5mL).At room temperature stirred 30 minutes, and added diethyl ether (10mL), the mixture stirred overnight.Collect the solid of separating out through filtering, drying under reduced pressure obtains the title compound (1.20g) into white solid.

¹H-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＝5.1Hz)，4.72-4.83(1H，m)，9.32(2H，br)。

Reference implementation example 18

2-methoxy ethyl 2-(methylamino) ethyl carbonate ester hydrochloride

In the mixture of 2-ethoxy (methyl) t-butyl carbamate (1.75g) that in reference implementation example 1, obtains and ethyl acetate (20mL), slowly dropwise add the ethyl acetate solution (5mL) of pyridine (1.62mL) and 2-methoxy ethyl chloro-formate (2.77g), mixture is stirred overnight at room temperature.Behind the reactant mixture concentrating under reduced pressure, add entry (50mL), mixture extracts with ethyl acetate (50mL).Mixture is with 5% aqueous citric acid solution (50mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the diethyl ether (2mL), adds 4N hydrogen chloride-ethyl acetate solution (5mL).At room temperature stirred 30 minutes, and added diethyl ether (10mL), the mixture stirred overnight.Collect the solid of separating out through filtering, drying under reduced pressure obtains the title compound (1.56g) into white solid.

¹H-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 implementation example 19

Ethyl (2-ethoxy) t-butyl carbamate

Under the frozen water cooling, in the mixture of 2-(ethylamino) ethanol (8.91g) and ethyl acetate (100mL), add two-tert-butyl group, two carbonic esters (21.8g).At room temperature stirred 3 days, mixture is with saturated brine (100mL) washing, anhydrous magnesium sulfate drying.Concentrating under reduced pressure obtains the title compound (19.0g) into colorless oil.

¹H-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＝5.2Hz)，3.73(2H，q，J＝5.2Hz)。

Reference implementation example 20

2-(ethylamino) ethyl acetic acid ester hydrochloride

In the mixture of ethyl (2-ethoxy) t-butyl carbamate (1.89g) that in reference implementation example 19, obtains and ethyl acetate (20mL), add acetic anhydride (1.04mL), pyridine (0.89mL) and 4-dimethylaminopyridine (0.061g).At room temperature stirred 3 hours, and added ethyl acetate (50mL), mixture water (50mL), 5% aqueous citric acid solution (50mL) and saturated brine (50mL) washing.Behind the anhydrous magnesium sulfate drying, the mixture concentrating under reduced pressure.In residue, add 4N hydrogen chloride-ethyl acetate solution (10mL), mixture at room temperature stirred 1 hour.Add ethyl acetate (10mL) and diethyl ether (20mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (1.54g) into white solid.

¹H-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＝5.3Hz)，4.24-4.30(2H，m)，9.17(2H，br)。

Reference implementation example 21

2-ethoxy (isopropyl) t-butyl carbamate

In the tetrahydrofuran solution (30mL) of 2-(isopropyl is amino) ethanol (10.0g), add two-tert-butyl group, two carbonic esters (22.2g), mixture at room temperature stirred 1 hour.The reactant mixture concentrating under reduced pressure adds entry (100mL) in residue.Mixture extracts with ethyl acetate (200mL).Ethyl acetate layer is with saturated brine (100mL) washing, and anhydrous sodium sulfate drying, concentrating under reduced pressure obtain the title compound (21.21g) into colorless oil.

¹H-NMR(CDCl ₃)：1.12(6H，d，J＝6.6Hz)，3.30(2H，t，J＝5.0Hz)，3.71(2H，t，J＝5.0Hz)，3.80-4.30(1H，m)。

Reference implementation example 22

2-(isopropyl is amino) ethyl acetic acid ester hydrochloride

In the tetrahydrofuran solution (15mL) of 2-ethoxy (isopropyl) t-butyl carbamate (5.0g) that in reference implementation example 21, obtains, add pyridine (6.0mL) and acetic anhydride (2.79mL), mixture at room temperature stirred 18 hours.The reactant mixture concentrating under reduced pressure adds entry (50mL) in residue, mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with 5% aqueous citric acid solution (50mL) and saturated brine (50mL) washing, anhydrous sodium sulfate drying and concentrating under reduced pressure.Resulting colorless oil is dissolved in 4N hydrogen chloride-ethyl acetate solution (10mL), and mixture at room temperature stirred 1 hour.Collect the solid of separating out through filtering, drying under reduced pressure obtains the title compound (3.14g) into colorless solid.

¹H-NMR(DMSO-d ₆)：1.25(6H，d，J＝6.6Hz)，2.08(3H，s)，3.10-3.40(3H，m)，4.29(2H，t，J＝6.0Hz)，9.11(2H，br)。

Reference implementation example 23

Ethyl 2-(isopropyl is amino) ethyl carbonate ester hydrochloride

In the tetrahydrofuran solution (15mL) of 2-ethoxy (isopropyl) t-butyl carbamate (5.0g) that in reference implementation example 21, obtains, add pyridine (6.0mL) and ethyl chloroformate (2.81mL), mixture at room temperature stirred 18 hours.The reactant mixture concentrating under reduced pressure adds in residue (50mL), and mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with 5% aqueous citric acid solution (50mL) and saturated brine (50mL) washing, anhydrous sodium sulfate drying, mixture concentrating under reduced pressure.Resulting colorless oil is dissolved in 4N hydrogen chloride-ethyl acetate solution (10mL), and mixture at room temperature stirred 1 hour.Collect the solid of separating out through filtering, drying under reduced pressure obtains the title compound (3.34g) into colorless solid.

¹H-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＝5.6Hz)，9.13(2H，br)。

Reference implementation example 24

Cyclohexyl (2-ethoxy) t-butyl carbamate

In the alcoholic solution (200mL) of 2-(cyclohexyl is amino) ethanol (14.3g), dropwise add two-tert-butyl group, two carbonic esters (21.8g).At room temperature stirred the mixture concentrating under reduced pressure 2 days.Residue is dissolved in the ethyl acetate (200mL) water (100mL) and saturated brine (100mL) washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure obtains the title compound (24.2g) into colorless oil.

¹H-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＝5.4Hz)，3.66-3.90(2H，br)。

Reference implementation example 25

2-(cyclohexyl is amino) ethyl acetic acid ester hydrochloride

Under the frozen water cooling; In the tetrahydrofuran solution (50mL) of cyclohexyl (2-ethoxy) t-butyl carbamate (2.43g) that in reference implementation example 24, obtains, add pyridine (1.05mL), acetic anhydride (1.23mL) and 4-dimethylaminopyridine (0.122g), mixture at room temperature stirred 12 hours.In reactant mixture, add ethyl acetate (100mL), mixture is used saturated sodium bicarbonate solution (100mL), 5% copper sulfate (II) solution (100mL) and saturated brine (100mL) washing, anhydrous sodium sulfate drying continuously.The mixture concentrating under reduced pressure.Residue is dissolved in the ethyl acetate (15mL), adds 4N hydrogen chloride-ethyl acetate solution (15mL).At room temperature stirred 3 hours, and added diisopropyl ether (20mL), collect the solid of separating out through filtration and obtain title compound (1.78g) into white solid.

¹H-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＝5.2Hz)，4.29(2H，t，J＝5.2Hz)，9.19(2H，br)。

Reference implementation example 26

Ethyl 2-(cyclohexyl is amino) ethyl carbonate ester hydrochloride

Under the frozen water cooling; In the tetrahydrofuran solution (50mL) of cyclohexyl (2-ethoxy) t-butyl carbamate (2.43g) that in reference implementation example 24, obtains, add pyridine (1.45mL), ethyl chloroformate (1.71mL) and 4-dimethylaminopyridine (0.122g), mixture at room temperature stirred 15 hours.In reactant mixture, add ethyl acetate (100mL), mixture is used saturated sodium bicarbonate solution (100mL), 5% copper sulfate (II) aqueous solution (100mL), water (100mL) and saturated brine (100mL) washing, anhydrous sodium sulfate drying continuously.Mixture concentrating under reduced pressure, residue are dissolved in the ethyl acetate (15mL).Add 4N hydrogen chloride-ethyl acetate solution (15mL).At room temperature stirred 3 hours, and added diisopropyl ether (20mL), collect the solid of separating out through filtration and obtain title compound (2.12g) into white solid.

¹H-NMR(DMSO-d ₆)：1.01-2.08(1OH，m)，1.23(3H，t，J＝7.0Hz)，2.90-3.10(1H，m)，3.21(2H，t，J＝5.2Hz)，4.16(2H，q，J＝7.0Hz)，4.39(2H，t，J＝5.2Hz)，9.27(2H，br)。

Reference implementation example 27

2-aniline ethyl acetic acid ester hydrochloride

Under the frozen water cooling, in the tetrahydrofuran solution (700mL) of 2-aniline ethanol (137g), add pyridine (97.1mL), acetic anhydride (113.2mL) and 4-dimethylaminopyridine (12.22g), mixture at room temperature stirred 20 hours.In reactant mixture, add ethyl acetate (1L), the continuous water of mixture (1L), saturated sodium bicarbonate solution (1L), 5% copper sulfate (II) aqueous solution (1L) and saturated brine (1L) washing, anhydrous sodium sulfate drying, reduction vaporization again.Under the frozen water cooling, in ethyl acetate (700mL) solution of resulting residue, add 4N hydrogen chloride-ethyl acetate solution (250mL), collect the solid of separating out through filtration and obtain title compound (156g) into white solid.

¹H-NMR(CD3OD)：2.11(3H，s)，3.71-3.76(2H，m)，4.32-4.37(2H，m)，7.49-7.64(5H，m)。

Reference implementation example 28

The tert-butyl group [2-(methylamino)-3-pyridine radicals] methyl carbonic

In the tetrahydrofuran solution (50mL) of [2-(methylamino)-3-pyridine radicals] methanol (2g: the method according to being described among the WO 01/32652 is synthetic), add heavy carbonic di tert butyl carbonate (3.48g) and 4-dimethylaminopyridine (0.18g), mixture refluxed 1 hour.In reactant mixture, add entry (30mL), extract with ethyl acetate (50mL).Resulting organic layer is with saturated brine (50mL) washing, anhydrous sodium sulfate drying.The residue that obtains through concentrating under reduced pressure (is used ethyl acetate: hexane=1: 5 eluting) obtain the title compound (1.51g) into white solid through silica gel chromatography fast.

¹H-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＝7.0，5.0Hz)，7.37(1H，dd，J＝7.0，1.8Hz)，8.16(1H，dd，J＝5.0，1.8Hz)。

Reference implementation example 29

2-(methylamino) benzylacetic acid ester

In the tetrahydrofuran solution (50mL) of [2-(methylamino) phenyl] methanol (1.37g: the method according to being described among the WO 01/32652 is synthetic), add pyridine (1.05mL), acetic anhydride (1.23mL) and 4-dimethylaminopyridine (0.18g), mixture at room temperature stirred 8 hours.In reactant mixture, add entry (100mL), mixture extracts with ethyl acetate (100mL).Organic layer is continuously with 5% copper sulfate (II) aqueous solution (50mL), saturated sodium bicarbonate solution (50mL) and saturated brine (50mL) washing, anhydrous sodium sulfate drying.Solvent removed by evaporation at reduced pressure, resulting residue obtains the title compound (0.38g) into white solid through quick silica gel chromatography (use continuously ethyl acetate: hexane=1: 5,1: 3 eluting).

¹H-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 implementation example 30

2-[(2-acetyl oxygen ethyl) amino] ethyl acetic acid ester hydrochloride

Under frozen water cooling, to 2,2 '-add di-tert-butyl dicarbonic acid ester (4.37g) in the mixture of imino-diacetic ethanol (2.10g) and ethyl acetate (20mL).Under the frozen water cooling, stir after 1.5 hours, add acetic anhydride (2.08mL), pyridine (1.78mL) and 4-dimethylaminopyridine (0.12g).After the stirring at room 2 hours, in reactant mixture, add ethyl acetate (50mL), mixture water (50mL), 5% aqueous citric acid solution (50mL) and saturated brine (50mL) washing.Behind the anhydrous magnesium sulfate drying, the mixture concentrating under reduced pressure.In residue, add 4N hydrogen chloride-ethyl acetate solution (20mL), mixture at room temperature stirred 2 hours.Add diethyl ether (10mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (6.18g) into white solid.

¹H-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 implementation example 31

(S)-2-pyrrolidinyl methyl acetic acid ester hydrochloride

Under the frozen water cooling, in the mixture of (S)-2-pyrrolidinyl methanol (1.01g) and ethyl acetate (10mL), add two-tert-butyl group, two carbonic esters (2.18g).After stirring 1 hour under the frozen water cooling, add acetic anhydride (1.04mL), pyridine (0.89mL) and 4-dimethylaminopyridine (0.061g).After at room temperature stirring 1 hour, in reactant mixture, add ethyl acetate (50mL), mixture water (50mL), 5% aqueous citric acid solution (50mL) and saturated brine (50mL) washing.Behind the anhydrous magnesium sulfate drying, the mixture concentrating under reduced pressure.In residue, add 4N hydrogen chloride-ethyl acetate solution (10mL), mixture at room temperature stirred 1 hour.Add diethyl ether (10mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains being light brown solid title compound (1.68g).

¹H-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＝11.8，8.1Hz)，4.26(1H，dd，J＝11.8，4.1Hz)，9.21(1H，br)，9.87(1H，br)。

Reference implementation example 32

3-(methylamino) propylbenzoic acid ester hydrochloride

Under the frozen water cooling, in the mixture of 3-amino-1-propanol (0.75g) and ethyl acetate (2.25mL), add the ethyl acetate solution (0.25mL) of heavy carbonic di tert butyl carbonate (2.18g).After at room temperature stirring 21.5 hours, add Benzenecarbonyl chloride. (1.30mL), pyridine (0.98mL) and 4-dimethylaminopyridine (0.012g).After at room temperature stirring 5 hours, in reactant mixture, add ethyl acetate (32.5mL), mixture water (12.5mL) and saturated brine (12.5mL) washing.Behind the anhydrous magnesium sulfate drying, the mixture concentrating under reduced pressure.Residue is dissolved in N, in the dinethylformamide (20mL), adds methyl iodide (5mL).Under the frozen water cooling, add 60% sodium hydride (0.4g).After at room temperature stirring 3 hours, in the cooled ammonium chloride solution of reactant mixture impouring cold water (60mL).Mixture is with diethyl ether (80mL) extraction, and saturated brine (30mL) washs.Behind the anhydrous magnesium sulfate drying, the mixture concentrating under reduced pressure.Residue is through silica gel chromatography (ethyl acetate: ethane=2: 1, ethyl acetate, acetone then then: ethyl acetate=1: 9) obtain 3-[(tertbutyloxycarbonyl) (methyl) amino] propylbenzoic acid ester (2.52g) into colorless oil.Add 4N hydrogen chloride-ethyl acetate solution (10mL), mixture at room temperature stirred 1 hour.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (10mL), collect the solid of separating out through filtering.After diethyl ether (10mL) washing, the solid drying under reduced pressure obtains the title compound (1.73g) into colorless solid.

¹H-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＝6.1Hz)，7.51(2H，m)，7.65-7.73(1H，m)，8.01(2H，d，J＝7.2Hz)，8.95(2H，br)。

Reference implementation example 33

Ethyl 2-[(carbethoxyl group) (methyl) amino] ethyl carbonate ester

In the ethyl acetate solution (1000mL) of 2-(methylamino) ethanol (100g), add pyridine (222mL), and then under the frozen water cooling, in 2 hours, dropwise add ethyl chloroformate (240mL).After dripping end, reactant mixture at room temperature stirred 18 hours.Add entry (300mL), the separating ethyl acetate layer is also with 1N hydrochloric acid (200mL) and saturated brine (200mL) washing.Behind the anhydrous sodium sulfate drying, mixture concentrating under reduced pressure, residue reduction vaporization obtain the title compound (180g) into colourless fraction, and its boiling point is a 95-100 ℃ of (pressure: 0.1-0.2mmHg).

¹H-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 implementation example 34

Ethyl 2-[(chloroformyl) (methyl) amino] ethyl carbonate ester

In the acetonitrile solution (1000mL) of ethyl 2-[(carbethoxyl group) (methyl) amino] the ethyl carbonate ester (150g) that in reference implementation example 33, obtains, add phosphoryl chloride phosphorus oxychloride (200mL), mixture refluxed 4 days.The reactant mixture concentrating under reduced pressure, stirring adds entry (500mL)-ice (700g)-ethyl acetate (300mL) mixture in batches in the residue.Stir after 1 minute, add saturated brine (500mL), mixture extracts with ethyl acetate (500mL).Ethyl acetate layer is used saturated brine (300mL), saturated sodium bicarbonate solution (300mL) and saturated brine (300mL) washing, anhydrous sodium sulfate drying and concentrating under reduced pressure continuously.The residue reduction vaporization obtains the title compound (77g) into colourless fraction, and its boiling point is a 100-105 ℃ of (pressure: 0.1-0.2mmHg).

¹H-NMR(CDCl ₃)：1.33(3H，t，J＝7.2Hz)，3.12(3H×0.4，s)，3.22(3H×0.6，s)，3.68(2H×0.6，t，J＝4.8Hz)，3.78(2H×0.4，t，J＝4.8Hz)，4.23(2H，q，J＝7.2Hz)，4.30-4.40(2H，m)。

Reference implementation example 35

4-hydroxyl butyl t-butyl carbamate

Under the frozen water cooling, in the mixture of 4-amino butanol (3.57g) and ethyl acetate (9mL), dropwise add the mixture of two-tert-butyl group, two carbonic esters (8.73g) and ethyl acetate (1mL).After at room temperature stirring 24 hours, the mixture concentrating under reduced pressure.Residue is dissolved in the ethyl acetate (200mL) mixture water (50mL), 1N hydrochloric acid (40mL), water (30mL) and saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Concentrating under reduced pressure obtains the title compound (7.54g) into colorless oil.

¹H-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 implementation example 36

4-[(tertbutyloxycarbonyl) amino] butylacetic acid ester

In the mixture of 4-hydroxyl butyl t-butyl carbamate (3.83g) that in reference implementation example 35, obtains and ethyl acetate (20mL), add pyridine (1.80mL) and acetic anhydride (2.27g), mixture at room temperature stirred 19 hours.In reactant mixture, add ethyl acetate (100mL), mixture water (50mL), copper sulfate solution (30mL), water (30mL) and saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Concentrating under reduced pressure obtains the title compound (4.55g) into colorless oil.

¹H-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＝6.5Hz)，4.55(1H，bs)。

Reference implementation example 37

4-(methylamino) butylacetic acid ester hydrochloride

Under the frozen water cooling, to 4-[(tertbutyloxycarbonyl) amino] the butylacetic acid ester (4.50g) that in reference implementation example 36, obtains and the N of methyl iodide (4.85mL), adding sodium hydride in the dinethylformamide solution (20mL) (60% oil solution, 0.94g).After at room temperature stirring 4 hours, in the reactant mixture impouring ammonium chloride frozen water solution.Mixture is with diethyl ether (120mL) extraction, and the diethyl ether layer is with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=1: 9 eluting) through silica gel chromatography.Add 4N hydrogen chloride-ethyl acetate solution (20mL) in the product behind purification, mixture at room temperature stirred 2 hours.Add diethyl ether (40mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (2.28g) into white solid.

¹H-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＝6.0Hz)，8.90(2H，br)。

Reference implementation example 38

Ethyl 4-[(tertbutyloxycarbonyl) amino] butyl carbonic ester

Under the frozen water cooling, in the mixture of 4-hydroxyl butyl t-butyl carbamate (3.71g) that in reference implementation example 35, obtains and ethyl acetate (20mL), add pyridine (1.71mL) and ethyl chloroformate (2.55g), mixture at room temperature stirred 24 hours.In reactant mixture, add ethyl acetate (100mL), mixture water (50mL), copper sulfate solution (30mL), water (30mL) and saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Concentrating under reduced pressure obtains the title compound (4.92g) into colorless oil.

¹H-NMR(CDCl ₃)：1.31(3H，t，J＝7.1Hz)，1.44(9H，s)，1.46-1.80(4H，m)，3.15(2H，m)，4.11-4.25(4H，m)，4.54(1H，bs)。

Reference implementation example 39

Ethyl 4-(methylamino) butyl carbonate salt hydrochlorate

Under the frozen water cooling, to ethyl 4-[(tertbutyloxycarbonyl) amino] the butyl carbonic ester (4.90g) that in reference implementation example 38, obtains and the N of methyl iodide (4.67mL), adding sodium hydride in the dinethylformamide solution (20mL) (60% oil solution, 0.90g).After at room temperature stirring 6 hours, in the reactant mixture impouring ammonium chloride frozen water solution, wash anhydrous magnesium sulfate drying with saturated brine (30mL) with diethyl ether (120mL) extraction, diethyl ether layer.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=1: 9 eluting) through silica gel chromatography.Add 4N hydrogen chloride-ethyl acetate solution (20mL) in the product behind purification, mixture at room temperature stirred 2 hours.Add diethyl ether (40mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (2.86g) into white solid.

¹H-NMR(DMSO-d ₆)：1.21(3H，t，J＝7.1Hz)，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 implementation example 40

3-hydroxypropyl t-butyl carbamate

Under the frozen water cooling, in the mixture of 3-aminopropanol (7.51g) and ethyl acetate (30mL), dropwise add the mixture of two-tert-butyl group, two carbonic esters (21.8g) and ethyl acetate (3mL).At room temperature stirred the mixture concentrating under reduced pressure 22 hours.Residue is dissolved in the ethyl acetate (200mL) water (80mL), 1N hydrochloric acid (60mL), water (50mL) and saturated brine (50mL) washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure obtains the title compound (16.01g) into colorless oil.

¹H-NMR(CDCl ₃)：1.45(9H，s)，1.62-1.70(2H，m)，3.24(2H，q，J＝6.6Hz)，3.66(2H，q，J＝5.1Hz)，4.73(1H，bs)。

Reference implementation example 41

3-[(tertbutyloxycarbonyl) amino] propyl-acetic acid ester

In the mixture of 3-hydroxypropyl t-butyl carbamate (8.00g) that in reference implementation example 40, obtains and ethyl acetate (50mL), add pyridine (4.06mL) and acetic anhydride (5.13g), mixture at room temperature stirred 21 hours.In reactant mixture, add ethyl acetate (200mL), mixture water (100mL), copper sulfate solution (40mL), water (60mL) and saturated brine (60mL) washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure obtains the title compound (8.34g) into colorless oil.

¹H-NMR(CDCl ₃)：1.44(9H，s)，1.77-1.86(2H，m)，2.06(3H，s)，3.20(2H，q，J＝6.3Hz)，4.12(2H，t，J＝6.3Hz)，4.67(1H，bs)。

Reference implementation example 42

3-(methylamino) propyl-acetic acid ester hydrochloride

In frozen water cooling down, to 34 (tertbutyloxycarbonyl) amino that in reference implementation example 41, obtains] N of propyl-acetic acid ester (17.28g) and methyl iodide (19.8mL), the middle adding of dinethylformamide solution (80mL) sodium hydride (60% oil solution, 3.82g).At room temperature stirred 15 hours, and in the reactant mixture impouring ammonium chloride frozen water solution, extracted with diethyl ether (300mL).The diethyl ether layer is with saturated brine (100mL) washing, anhydrous sodium sulfate drying.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=1: 8 eluting) through silica gel chromatography.Add 4N hydrogen chloride-ethyl acetate solution (40mL) in the product behind purification, mixture at room temperature stirred 2 hours.Add diethyl ether (100mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (2.93g) into white solid.

¹H-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＝6.3Hz)，8.87(2H，br)。

Reference implementation example 43

Ethyl 3-[(tertbutyloxycarbonyl) amino] propyl carbonate

Under the frozen water cooling, in the mixture of 3-hydroxypropyl t-butyl carbamate (8.00g) that in reference implementation example 40, obtains and ethyl acetate (50mL), add pyridine (4.06mL) and ethyl chloroformate (5.95g), mixture at room temperature stirred 24 hours.In reactant mixture, add ethyl acetate (100mL), mixture water (50mL), copper sulfate solution (30mL), water (30mL) and saturated brine (30mL) washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure obtains the title compound (9.31g) into colorless oil.

¹H-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＝6.3Hz)，4.15-4.23(4H，m)，4.68(1H，bs)。

Reference implementation example 44

Ethyl 3-(methylamino) propyl carbonate hydrochlorate

Under the frozen water cooling, to ethyl 3-[(tertbutyloxycarbonyl) amino] propyl carbonate (9.31g) that in reference implementation example 43, obtains and the N of methyl iodide (9.00mL), adding sodium hydride in the dinethylformamide solution (40mL) (60% oil solution, 1.82g).At room temperature stirred 12 hours, in the reactant mixture impouring ammonium chloride frozen water solution, mixture extracts with diethyl ether (200mL).The diethyl ether layer is with saturated brine (100mL) washing, anhydrous sodium sulfate drying.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=1: 8 eluting) through silica gel chromatography.Add 4N hydrogen chloride-ethyl acetate solution (40mL) in the product behind purification, mixture at room temperature stirred 2 hours.Add diethyl ether (200mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (4.98g) into white solid.

¹H-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 implementation example 45

(2, the 3-dihydroxypropyl) methyl carbamic acid tert-butyl ester

Under the frozen water cooling,, dropwise add the mixture of two-tert-butyl group, two carbonic esters (51.4g) and ethyl acetate (10mL) in the mixture of 2-propylene glycol (24.5g) and ethyl acetate (50mL) to 3-(methylamino)-1.At room temperature stirred the mixture concentrating under reduced pressure 15 hours.Residue is dissolved in the ethyl acetate (150mL) solution with water (80mL), 1N hydrochloric acid (60mL), water (50mL) and saturated brine (50mL) washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure obtains the title compound (26.9g) into colorless oil.

¹H-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 implementation example 46

3-(methylamino) propane-1,2-two basic diacetate esters hydrochlorates

In the mixture of (2, the 3-dihydroxypropyl) the methyl carbamic acid tert-butyl ester (10.26g) that in reference implementation example 45, obtains and ethyl acetate (50mL), add pyridine (10.11mL) and acetic anhydride (12.76g), mixture at room temperature stirred 24 hours.In reactant mixture, add ethyl acetate (300mL), mixture water (150mL), copper sulfate solution (100mL), water (100mL) and saturated brine (100mL) washing, anhydrous sodium sulfate drying.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=1: 8 eluting) through silica gel chromatography.Add 4N hydrogen chloride-ethyl acetate solution (40mL) in the product behind purification, mixture at room temperature stirred 3 hours.Add diethyl ether (100mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (2.76g) into white solid.

¹H-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 implementation example 47

Diethyl 3-(methylamino) propane-1,2-two basic two carbonate salt hydrochlorates

Under the frozen water cooling; To in reference implementation example 45, obtain (2; The 3-dihydroxypropyl) add pyridine (18.35mL) and ethyl chloroformate (24.62g) in the methyl carbamic acid tert-butyl ester (15.53g) and the ethyl acetate (100mL), mixture at room temperature stirred 96 hours.In reactant mixture, add ethyl acetate (300mL), mixture water (150mL), copper sulfate solution (100mL), water (100mL) and saturated brine (100mL) washing, anhydrous sodium sulfate drying.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=1: 6 eluting) through silica gel chromatography.Add 4N hydrogen chloride-ethyl acetate solution (80mL) in the product behind purification, mixture at room temperature stirred 3 hours.Add diethyl ether (200mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (5.93g) into white solid.

¹H-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 implementation example 48

2-ethoxyethyl group 2-(methylamino) ethyl carbonate ester hydrochloride

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (2.97g), add in the tetrahydrofuran solution (10mL) of cellosolvo (1.80g).Dropwise add the tetrahydrofuran solution (10mL) of pyridine (2.43mL) then, mixture at room temperature stirred 2 hours.The reactant mixture concentrating under reduced pressure adds entry (50mL) in residue.Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with 0.2N hydrochloric acid (20mL) and saturated brine (50mL) washing, and anhydrous magnesium sulfate drying, concentrating under reduced pressure obtain 2-ethoxyethyl group chloro-formate (1.29g).In the tetrahydrofuran solution (15mL) of 2-ethoxy (methyl) t-butyl carbamate (1.23g) that in reference implementation example 1, obtains, add pyridine (0.68mL); In this mixture, dropwise add the tetrahydrofuran solution (5mL) of the 2-ethoxy ethyl chloride carbonic ester that the front obtains, mixture at room temperature stirred 3 days.Behind the reactant mixture concentrating under reduced pressure, to wherein adding entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with 5% aqueous citric acid solution (50mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.The mixture concentrating under reduced pressure, residue is through silica gel chromatography (using ethyl acetate: hexane=1: 5,2: 3 eluting then).Product behind the purification (1.60g) is dissolved in the diethyl ether (3mL), adds 4N hydrogen chloride-ethyl acetate solution (3mL).Mixture is stirred overnight at room temperature, collects the solid of separating out through filtering, and drying under reduced pressure obtains the title compound (0.94g) into white solid.

¹H-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＝7.0Hz)，3.56-3.60(2H，m)，4.19-4.24(2H，m)，4.30-4.37(2H，m)，8.79(2H，br)。

Reference implementation example 49

3-methoxycarbonyl propyl 2-(methylamino) ethyl carbonate ester hydrochloride

Under the frozen water cooling, in the mixture of lithium aluminium hydride reduction (2.85g) and diethyl ether (100mL), slowly dropwise add the tetrahydrofuran solution (50mL) of methyl 3-methoxy propyl acid esters (11.8g).After the stirring at room 1 hour, mixture frozen water cooling once more dropwise adds entry (3mL) and 10% sodium hydrate aqueous solution (3mL).Mixture is placed to room temperature, dropwise adds entry (9mL).Mixture stirs a moment.Remove by filter deposition, filtrate decompression concentrates and obtains the 3-methoxypropanol (7.64g) into colorless oil.

¹H-NMR (CDCl ₃): 1.83 (2H, quintet, J=5.8Hz), 2.43 (1H, t, J=5.3Hz), 3.36 (3H, s), 3.57 (2H, t, J=6.0Hz), 3.77 (2H, q, J=5.5Hz).

Under the frozen water cooling, in the tetrahydrofuran solution (50mL) of two (trichloromethyl) carbonic ester (4.45g), dropwise add N-ethyl diisopropyl amine (5.75mL).Stir moments later, dropwise add the tetrahydrofuran solution (15mL) of the 3-methoxypropanol (2.70g) that the front obtains.Mixture frozen water cooling down, in stirring at room 30 minutes lasting 1 day.Behind the reactant mixture concentrating under reduced pressure, in residue, add dilute hydrochloric acid (50mL), mixture extracts with ethyl acetate (80mL).Ethyl acetate layer is with 0.2N hydrochloric acid (30mL) and saturated brine (30mL) washing, and anhydrous magnesium sulfate drying, concentrating under reduced pressure obtain 3-methoxycarbonyl propyl chloro-formate (4.39g).In the tetrahydrofuran solution (20mL) of 2-ethoxy (methyl) t-butyl carbamate (1.75g) that in reference implementation example 1, obtains, dropwise add in the tetrahydrofuran solution (5mL) of the 3-methoxycarbonyl propyl chloro-formate (1.83g) that pyridine (0.97mL) and front obtain, mixture at room temperature stirred 2 hours.The tetrahydrofuran solution (5mL) that adds pyridine (0.65mL) and 3-methoxycarbonyl propyl chloro-formate (1.22g), mixture continue to stir 1 hour.The reactant mixture concentrating under reduced pressure adds entry (50mL) in residue.Mixture is with ethyl acetate (80mL) extraction, and ethyl acetate layer is with 5% aqueous citric acid solution (50mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure.Residue is through silica gel chromatography (using ethyl acetate: hexane=1: 9,3: 7 eluting then).Product behind the purification (3.40g) is dissolved in the diethyl ether (5mL), adds 4N hydrogen chloride-ethyl acetate solution (5mL).Mixture is stirred overnight at room temperature, the reactant mixture concentrating under reduced pressure.Add the diethyl ether crystallization and obtain title compound (2.06g) into colorless solid.

¹H-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＝6.0Hz)，4.36(2H，t，J＝6.0Hz)，9.27(2H，br)。

Reference implementation example 50

N, N-dimethylglycine 2-(methylamino) ethyl ester dihydrochloride

2-ethoxy (methyl) t-butyl carbamate (3.50g), the N that will in reference implementation example 1, obtain; N-dimethyl glycine hydrochloride (5.29g), 1-ethyl-3-[3-(dimethylamino) propyl group] carbodiimide hydrochloride (7.67g), triethylamine (5.58mL); 4-dimethylaminopyridine (1.22g) and N, dinethylformamide (50mL) is stirred overnight at room temperature.The reactant mixture concentrating under reduced pressure adds saturated sodium bicarbonate solution (50mL) in residue.Mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure.Residue is through silica gel chromatography (using methanol: ethyl acetate=5: 95,20: 80 eluting then).Add 1N hydrochloric acid (24mL) in the product behind purification (2.46g), mixture is stirred overnight at room temperature.The reactant mixture concentrating under reduced pressure obtains the title compound (2.14g) into colorless solid.

¹H-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 implementation example 51

S-[2-(methylamino) ethyl] thiacetic acid. ester hydrochloride

Under the frozen water cooling, in the tetrahydrofuran solution (50mL) of 2-ethoxy (methyl) t-butyl carbamate (3.50g), thiacetic acid. (1.72mL) and the triphenylphosphine (7.87g) that in reference implementation example 1, obtain, slowly dropwise add the tetrahydrofuran solution (10mL) of diisopropyl azodicarboxylate (5.91mL).Mixture stirred 1 hour in the frozen water cooling, stirred 2 hours under the room temperature.Reactant mixture frozen water cooling once more, the diisopropyl azodicarboxylate's (5.91mL) of adding triphenylphosphine (7.87g) tetrahydrofuran solution (10mL).Mixture stirred 30 minutes under the frozen water cooling.Add thiacetic acid. (1.14mL), mixture at room temperature, stirring was spent the night in 30 minutes in the frozen water cooling.The reactant mixture concentrating under reduced pressure adds hexane and diisopropyl ether in residue.Remove by filter deposition, filtrate decompression concentrates.Repeat above-mentioned steps, add saturated sodium bicarbonate solution (50mL) then.Mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure.Residue is through silica gel chromatography (using ethyl acetate: hexane=5: 95,15: 85 eluting then).Add 4N hydrogen chloride-ethyl acetate solution (10mL) in the product behind purification (4.47g), mixture is stirred overnight at room temperature.The reactant mixture concentrating under reduced pressure adds ethyl acetate and diethyl ether crystallization in residue, obtain the title compound (1.79g) into light yellow solid.

¹H-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 implementation example 52

Ethyl 2-[2-(methylamino) ethyoxyl] ethyl carbonate ester hydrochloride

Under the frozen water cooling, in 2-(2-amino ethoxy) ethanol (99.52g) and ethyl acetate (200mL), dropwise add the mixture of heavy carbonic di tert butyl carbonate (208.57g) and ethyl acetate (50mL).At room temperature stirred the mixture concentrating under reduced pressure 60 hours.Residue is dissolved in ethyl acetate (500mL), water (200mL), 1N hydrochloric acid (200mL), water (300mL) and saturated brine (300mL) washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure obtains [2-(2-hydroxyl-oxethyl) ethyl] t-butyl carbamate (169.2g) into colorless oil.

¹H-NMR(CDCl ₃)：1.45(9H，s)，3.33(2H，q，J＝5.1Hz)，3.54-3.59(4H，m)，3.74(2H，q，J＝5.1Hz)，4.88(2H，bs)。

Under the frozen water cooling; Add pyridine (53.78mL) and ethyl chloroformate (70.57g) in [2-(2-hydroxyl-oxethyl) ethyl] t-butyl carbamate (53.93g) that obtains to the front and the mixture of ethyl acetate (350mL), mixture at room temperature stirred 96 hours.In reactant mixture, add ethyl acetate (500mL), mixture is with water washing (500mL), copper sulfate solution (200mL), water (300mL) and saturated brine (300mL) washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure obtains 2-[2-[(tertbutyloxycarbonyl) amino] ethyoxyl] the ethyl carbonate ethyl ester (93.19g) into colorless oil.

¹H-NMR(CDCl ₃)：1.32(3H，t，J＝7.2Hz)，1.44(9H，s)，3.32(2H，t，J＝5.1Hz)，3.54(2H，t，J＝5.1Hz)，3.67-3.74(2H，m)，4.21(2H，q，J＝7.2Hz)，4.26-4.31(2H，m)，4.91(1H，bs)。

In frozen water cooling down, 2-[2-[(tertbutyloxycarbonyl) amino] ethyoxyl] the ethyl carbonyl acetoacetic ester (93.15g) and the N of methyl iodide (83.6mL) that obtain to the front, the middle adding of dinethylformamide solution (350mL) sodium hydride (60% oil solution, 16.12g).At room temperature stirred 24 hours, and in the reactant mixture impouring ammonium chloride frozen water solution, extracted with diethyl ether (800mL).The diethyl ether layer is with saturated brine (300mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue (use ethyl acetate: hexane=wash at 1: 8) through silica gel chromatography.Add 4N hydrogen chloride-ethyl acetate solution (300mL) in the product behind purification, mixture at room temperature stirred 2 hours.Add diethyl ether (300mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (33.21g) into white solid.

¹H-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＝7.2Hz)，4.22(2H，t，J＝4.5Hz)，9.06(2H，br)。

Reference implementation example 53

Ethyl 2-[methyl [[2-(methylamino) ethyoxyl] carbonyl] amino] ethyl carbonate ester hydrochloride

Under the frozen water cooling, in the tetrahydrofuran solution (100mL) of two (trichloromethyl) carbonic ester (11.87g), dropwise add the tetrahydrofuran solution (20mL) of pyridine (9.71mL).Under frozen water, stir after 30 minutes, be added in the tetrahydrofuran solution (20mL) of 2-ethoxy (methyl) t-butyl carbamate (17.52g) that obtains in the reference implementation example 1, mixture at room temperature stirred 15 hours.Behind the concentrating under reduced pressure, in residue, add entry (500mL) and anhydrous sodium sulfate.After the filtration, filtrate decompression concentrates.Under the frozen water cooling, in resulting residue, add the solution (50mL) of 2-(methylamino) ethanol (5.00g) at ethyl acetate and triethylamine (10.0mL), mixture at room temperature stirred 15 hours.In reactant mixture, add ethyl acetate (300mL), water (150mL) and saturated brine (200mL) washing, anhydrous sodium sulfate drying.Behind the concentrating under reduced pressure, under the frozen water cooling, in the mixture of residue and ethyl acetate (100mL), add pyridine (2.91mL) and ethyl chloroformate (3.44g), mixture at room temperature stirred 48 hours.In reactant mixture, add ethyl acetate (200mL), water (100mL), copper sulfate solution (50mL), water (50mL) and saturated brine (50mL) washing, anhydrous sodium sulfate drying.The mixture concentrating under reduced pressure, residue (is used ethyl acetate: hexane=1: 3 eluting) through silica gel chromatography.Add 4N hydrogen chloride-ethyl acetate solution (30mL) in the product behind purification, mixture at room temperature stirred 3 hours.Add diethyl ether (100mL), collect the solid of separating out through filtering.The solid drying under reduced pressure obtains the title compound (2.90g) into white solid.

¹H-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＝5.1Hz)，3.58(1H，t，J＝5.1?Hz)，4.12(2H，q，J＝7.2Hz)，4.16-4.24(4H，m)，8.94(1H，br)。

Reference implementation example 54

1-methyl piperidine-4-carboxylic acid 2-(methylamino) ethyl ester dihydrochloride

The mixture of piperidines-4-carboxylic acid, ethyl ester (4.72g), methyl iodide (2.24mL), potassium carbonate (8.29g) and acetonitrile (50mL) was at room temperature stirred 2 hours.The reactant mixture concentrating under reduced pressure adds entry (150mL).Mixture extracts with ethyl acetate (150mL).Ethyl acetate layer is with saturated brine (100mL) washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure.In residue (2.64g), add 1N sodium hydrate aqueous solution (20mL), mixture is stirred overnight at room temperature.Reactant mixture is through adding 1N hydrochloric acid (20mL) neutralization, mixture concentrating under reduced pressure then.In residue, add ethanol, remove by filter deposition.Filtrate decompression concentrates.Repeat above-mentioned steps, in residue, add ethanol and ethyl acetate crystallization, obtain 1-methyl piperidine-4-carboxylic acid (1.79g) into colorless solid.

¹H-NMR(CD ₃OD)：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)。

The mixture of 1-methyl piperidine-4-carboxylic acid (1.72g) that the front is obtained, 2-ethoxy (methyl) t-butyl carbamate (1.75g), 1-ethyl-3-[3-(dimethylamino) propyl group] carbodiimide hydrochloride (2.30g), 4-dimethylaminopyridine (0.24g) and the acetonitrile (50mL) that in reference implementation example 1, obtain at room temperature stirred 16 hours.The reactant mixture concentrating under reduced pressure adds saturated sodium bicarbonate solution (50mL) in residue.Mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure.Residue is through alkaline silica gel purified (using ethyl acetate: hexane=50: 50,80: 20 eluting then).Add 1N hydrochloric acid (25mL) in the product behind purification (2.73g), mixture is stirred overnight at room temperature.The reactant mixture concentrating under reduced pressure adds isopropyl alcohol.Mixture is concentrating under reduced pressure once more, collects the solid of separating out through filtration and obtains the title compound (1.72g) into colorless solid.

¹H-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 implementation example 55

2-[[4-(amino carbonyl) phenyl] amino] ethylhexoate

With the mixture of 4-fluorobenzene cyanogen (6.06g), 2-ethylaminoethanol (3.71g), potassium carbonate (8.29g) and dimethyl sulfoxine (50mL) 100 ℃ of following stirred overnight.In reactant mixture, add entry (200mL), mixture extracts with ethyl acetate (200mL * 4).Ethyl acetate layer is with saturated brine (100mL) washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure.Residue obtains 4-[(2-ethoxy) amino] the benzene cyanogen (5.89g) into yellow solid through silica gel chromatography (using ethyl acetate: hexane=30: 70,50: 50 then, 80: 20 again, eluent ethyl acetate again).

¹H-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＝8.7Hz)，7.39(2H，d，J＝8.7Hz)。

The mixture of 4-[(2-ethoxy) amino] benzene cyanogen (0.81g), potassium hydroxide (1.12g) and the tert-butyl alcohol (20mL) that the front is obtained stirred 1 hour down at 100 ℃.In reactant mixture, add entry (100mL), extract with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (80mL) washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure.The tetrahydrofuran solution (1mL) that in the tetrahydrofuran solution (10mL) of residue (0.83g), pyridine (0.49mL) and 4-dimethylaminopyridine (0.061g), dropwise adds acetic anhydride (0.57mL).Mixture at room temperature stirred 1 hour, added entry (80mL), and mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (80mL) washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure.Residue obtains the title compound (0.68g) into colorless solid through silica gel chromatography (using ethyl acetate: hexane=30: 70,60: 40 eluting then).

¹H-NMR(CDCl ₃)：2.08(3H，s)，3.44(2H，q，J＝5.6Hz)，4.29(2H，t，J＝5.4Hz)，4.48(1H，br)，6.59(2H，d，J＝8.9Hz)，7.43(2H，d，J＝8.9Hz)。

Reference implementation example 56

2-(methylamino) ethyl 1-methyl-4-piperidyl carbonic ester dihydrochloride

Under the frozen water cooling,, slowly dropwise be added in the tetrahydrofuran solution (40mL) of N '-carbonyl dimidazoles (3.36g) in the tetrahydrofuran solution (10mL) of 2-ethoxy (methyl) t-butyl carbamate (3.30g) that obtains in the reference implementation example 1 to N.Mixture stirred 40 minutes under the frozen water cooling, at room temperature stirred 2 hours.Add N, N '-carbonyl dimidazoles (0.31g), mixture continue to stir 3 days.The reactant mixture concentrating under reduced pressure adds ethyl acetate (150mL) in residue.Mixture is with saturated brine (100mL * 2), water (50mL * 3) and saturated brine (50mL) washing, and anhydrous magnesium sulfate drying, concentrating under reduced pressure obtain 2-[(tertbutyloxycarbonyl) (methyl) amino] the ethyl 1H-imidazoles-1-carboxylate (5.24g) into colorless oil.

¹H-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＝5.3Hz)，7.06(1H，m)，7.42(1H，m)，8.13(1H，s)。

The mixture of 2-[(tertbutyloxycarbonyl) (methyl) amino] the ethyl 1H-imidazoles-1-carboxylate (1.35g) that the front is obtained, 1-methyl-4-piperidines alcohol (1.38g) and acetonitrile (20mL) is stirred overnight at room temperature.Add 1-methyl-4-piperidines alcohol (0.92g), the mixture stirred overnight.The reactant mixture concentrating under reduced pressure adds saturated sodium bicarbonate solution (50mL) in residue.Mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure.In residue (1.60g), add 1N hydrochloric acid (12mL), mixture is stirred overnight at room temperature.The reactant mixture concentrating under reduced pressure adds entry, isopropyl alcohol and ethyl acetate, collects the solid of separating out through filtration and obtains the title compound (1.09g) into colorless solid.

¹H-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，br)，11.10(1H，br)。

Synthetic embodiment 1

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate

Under the frozen water cooling, in the tetrahydrofuran solution (30mL) of two (trichloromethyl) carbonic ester (0.50g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.40mL).After stirring 30 minutes under the frozen water cooling, be added in 2-(methylamino) ethyl acetate hydrochloride (0.77g) that obtains in the reference implementation example 2.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.70mL), mixture at room temperature stirred 1 hour.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.The mixture concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.11g), triethylamine (0.84mL) and 4-dimethylaminopyridine (catalytic amount), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure; Residue is through alkaline silica gel purified (using ethyl acetate: hexane=1: 1, eluent ethyl acetate then), and silica gel chromatography (using ethyl acetate: hexane=2: 1, ethyl acetate, acetone more then: ethyl acetate=1: 4,1: 1 eluting then) obtains the title compound (1.13g) into yellow amorphous solid again.

¹H-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＝13.3Hz)，5.05(1H，d，J＝13.3Hz)，6.65(1H，d，J＝5.5Hz)，7.35-7.51(3H，m)，7.80-7.90(1H，m)，8.35(1H，d，J＝5.5Hz)。

Synthetic embodiment 2

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl-trimethyl acetas

Under the frozen water cooling, in the tetrahydrofuran solution (30mL) of two (trichloromethyl) carbonic ester (0.50g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.40mL).Under the frozen water cooling, stirred 1 hour, be added in 2-(methylamino) the ethyl-trimethyl acetic ester hydrochloride (0.98g) that obtains in the reference implementation example 3.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.70mL), mixture is stirred overnight at room temperature.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.11g), triethylamine (0.84mL) and 4-dimethylaminopyridine (0.037g), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through quick silica gel chromatography (using acetone: hexane=1: 3,3: 2 eluting then).With acetone-diisopropyl ether crystallization, acetone-diisopropyl ether recrystallization obtains the title compound (1.01g) into colorless solid.

¹H-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＝5.7Hz)，7.35-7.50(3H，m)，7.78-7.88(1H，m)，8.35(1H，d，J＝5.7Hz)。

Synthetic embodiment 3

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl cyclohexane carboxylate

Under the frozen water cooling, in the tetrahydrofuran solution (30mL) of two (trichloromethyl) carbonic ester (0.50g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.40mL).After stirring 30 minutes under the frozen water cooling, be added in 2-(methylamino) the ethyl cyclohexane carboxylate hydrochloride (1.11g) that obtains in the reference implementation example 4.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.70mL), mixture at room temperature stirred 1 hour.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.11g), triethylamine (0.84mL) and 4-dimethylaminopyridine (0.037g), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through quick silica gel chromatography (using acetone: hexane=1: 3,3: 2 eluting then).With acetone-diisopropyl ether crystallization, acetone-diisopropyl ether recrystallization obtains the title compound (1.11g) into colorless solid.

¹H-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)，2.27-2.40(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＝5.4Hz)，7.35-7.48(3H，m)，7.84(1H，d，J＝6.9Hz)，8.34(1H，d，J＝5.4Hz)。

Synthetic embodiment 4

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethylamino benzonitrile acid esters

Under the frozen water cooling, in the tetrahydrofuran solution (30mL) of two (trichloromethyl) carbonic ester (0.50g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.40mL).After stirring 1 hour under the frozen water cooling, be added in 2-(methylamino) the ethyl benzoate ester hydrochloride (1.08g) that obtains in the reference implementation example 5.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.70mL), mixture is stirred overnight at room temperature.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.11g), triethylamine (0.84mL) and 4-dimethylaminopyridine (0.037g), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through quick silica gel chromatography (using acetone: hexane=1: 3,3: 2 eluting then).With acetone-diethyl ether crystallization, acetone-diethyl ether recrystallization obtains the title compound (1.09g) into colorless solid.

¹H-NMR(CDCl ₃)：2.22(3H，s)，3.12(3H，bs)，3.50-4.30(2H，br)，4.37(2H，q，J＝7.8Hz)，4.68(2H，m)，4.80-5.20(2H，br)，6.63(1H，d，J＝5.7Hz)，7.26-7.48(5H，m)，7.53-7.61(1H，m)，7.82(1H，d，J＝8.1Hz)，8.04(2H，d，J＝7.2Hz)，8.33(1H，d，J＝5.7Hz)。

Synthetic embodiment 5

2-[methyl [[2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylamino benzonitrile acid esters

Under the frozen water cooling, in the tetrahydrofuran solution (30mL) of two (trichloromethyl) carbonic ester (0.99g), dropwise add the tetrahydrofuran solution (2mL) of pyridine (0.81mL).After stirring 30 minutes under the frozen water cooling, be added in 2-(methylamino) the ethyl benzoate ester hydrochloride (2.16g) that obtains in the reference implementation example 5.After adding the tetrahydrofuran solution (2mL) of triethylamine (1.39mL), mixture at room temperature stirred 1 hour.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (100mL) and water (100mL), mixture stirs.The separating ethyl acetate layer also takes out, with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (40mL).Add 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (2.90g), triethylamine (2.20mL) and 4-dimethylaminopyridine (0.096g), mixture stirred 2 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (150mL) and water (80mL), mixture stirs.The separating ethyl acetate layer also takes out, with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through silica gel chromatography (using ethyl acetate: hexane=1: 1, eluent ethyl acetate then).Use acetone recrystallization to obtain title compound (2.62g) as colorless solid.

¹H-NMR(CDCl ₃)：2.22(3H，s)，3.13(3H，bs)，3.68-3.98(2H，bm)，4.38(2H，q，J＝7.8Hz)，4.69(2H，m)，4.80-5.10(2H，bm)，6.64(1H，d，J＝5.7Hz)，7.27-7.48(5H，m)，7.59(1H，m)，7.83(1H，m)，8.06(2H，d，J＝6.0Hz)，8.35(1H，d，J＝5.7Hz)。

Synthetic embodiment 6

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 4-methoxybenzoic acid ester

Under the frozen water cooling, in the tetrahydrofuran solution (18mL) of two (trichloromethyl) carbonic ester (0.584g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.49mL).After stirring 40 minutes under the frozen water cooling, be added in 2-(methylamino) the ethyl 4-methoxybenzoic acid ester hydrochloride (1.48g) that obtains in the reference implementation example 6.Add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 80 minutes.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (80mL) and water (50mL), mixture stirs.The separating ethyl acetate layer also takes out, with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure; Residue is dissolved in the oxolane (25mL); Add (R)-2-[[[3-methyl-4-(2; 2,2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.55g), triethylamine (1.17mL) and 4-dimethylaminopyridine (0.051g), mixture stirred 3 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (150mL) and water (50mL), mixture stirs.The separating ethyl acetate layer also takes out, with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through silica gel chromatography (using ethyl acetate: hexane=1: 1, eluent ethyl acetate then).Use ethyl acetate-cyclohexane extraction recrystallization to obtain title compound (1.08g) as colorless solid.

¹H-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＝7.9Hz)，4.58-4.72(2H，m)，4.82-5.14(2H，bm)，6.63(1H，d，J＝5.7Hz)，6.91(2H，d，J＝9.0Hz)，7.27-7.40(3H，m)，7.82(1H，m)，7.99(2H，d，J＝9.0Hz)，8.33(1H，d，J＝5.7Hz)。

Synthetic embodiment 7

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 3-chlorobenzoic acid ester

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.582g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.49mL).After stirring 30 minutes under the frozen water cooling, be added in 2-(methylamino) the ethyl 3-chlorobenzoic acid ester hydrochloride (1.50g) that obtains in the reference implementation example 7.Add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 2 hours.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (80mL) and water (40mL), mixture stirs.The separating ethyl acetate layer also takes out, with saturated brine (25mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.44g), triethylamine (1.09mL) and 4-dimethylaminopyridine (0.048g), mixture stirred 3 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (80mL) and water (40mL), mixture stirs.The separating ethyl acetate layer also takes out, with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (0.84g) into colourless slurry through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then).

¹H-NMR(CDCl ₃)：2.21(3H，s)，3.12(3H，bs)，3.78-4.08(2H，bm)，4.38(2H，q，J＝7.8Hz)，4.64-5.08(4H，bm)，6.64(1H，d，J＝5.2Hz)，7.34-7.42(4H，m)，7.56(1H，m)，7.82(1H，m)，7.94(1H，d，J＝7.6Hz)，8.02(1H，s)，8.34(1H，d，J＝5.2Hz)。

Synthetic embodiment 8

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 3,4-difluoro-benzoic acid ester

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.582g), add the tetrahydrofuran solution (1mL) of pyridine (0.49mL).After stirring 30 minutes under the frozen water cooling, be added in 2-(methylamino) ethyl 3 that obtains in the reference implementation example 8,4-difluoro-benzoic acid ester hydrochloride (1.51g).Add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (80mL) and water (50mL), mixture stirs.The separating ethyl acetate layer also takes out, with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in oxolane (25mL) with residue.Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.71g), triethylamine (1.29mL) and 4-dimethylaminopyridine (0.056g), mixture stirred 17 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (100mL) and water (50mL), mixture stirs.The separating ethyl acetate layer also takes out, and water layer extracts with ethyl acetate (20mL).The combined ethyl acetate layer is with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through silica gel column chromatography (using ethyl acetate: hexane=1: 1,2: 1 eluting then), the alkaline silica gel column chromatography (is used ethyl acetate: purification hexane=1: 1 eluting) again.With acetone-diisopropyl ether crystallization, ethyl acetate-hexane recrystallization obtains the title compound (1.37g) into colorless solid.

¹H-NMR(CDCl ₃)：2.21(3H，s)，3.11(3H，bs)，3.82-4.08(2H，bm)，4.38(2H，q，J＝7.8Hz)，4.60-5.14(4H，bm)，6.63(1H，d，J＝5.7Hz)，7.20(1H，m)，7.33-7.41(3H，m)，7.78-7.92(3H，m)，8.33(1H，d，J＝5.7Hz)。

Synthetic embodiment 9

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 4-trifluoro-methoxy-benzoic acid ester

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.582g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.49mL).After stirring 30 minutes under the frozen water cooling, be added in 2-(methylamino) the ethyl 4-trifluoro-methoxy-benzoic acid ester hydrochloride (1.79g) that obtains in the reference implementation example 9.Add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 1.5 hours.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (80mL) and water (50mL), mixture stirs.The separating ethyl acetate layer also takes out, with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (25mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.57g), triethylamine (1.18mL) and 4-dimethylaminopyridine (0.052g), mixture stirred 4.5 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (100mL) and water (50mL), mixture stirs.The separating ethyl acetate layer also takes out, and water layer extracts with ethyl acetate (30mL).The combined ethyl acetate layer is with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, (use ethyl acetate: hexane=1: 1 eluting), the alkaline silica gel purified (is used ethyl acetate: hexane=1: 1 eluting) obtain the title compound (1.44g) into colourless slurry to residue again through silica gel chromatography.

¹H-NMR(CDCl ₃)：2.22(3H，s)，3.11(3H，bs)，3.85-4.05(2H，bm)，4.38(2H，q，J＝7.8Hz)，4.60-5.12(4H，bm)，6.64(1H，d，J＝5.7Hz)，7.24(2H，d，J＝8.7Hz)，7.25-7.40(3H，m)，7.82(1H，d，J＝7.2Hz)，8.09(2H，d，J＝8.7Hz)，8.33(1H，d，J＝5.7Hz)。

Synthetic embodiment 10

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 4-fluobenzoic acid ester

Under the frozen water cooling, in the tetrahydrofuran solution of two (trichloromethyl) carbonic ester (0.582g), dropwise add the tetrahydrofuran solution (20mL) of pyridine (0.49mL).After stirring 30 minutes under the frozen water cooling, be added in 2-(methylamino) the ethyl 4-fluobenzoic acid ester hydrochloride (1.40g) that obtains in the reference implementation example 10.Add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 2 hours.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (80mL) and water (40mL), mixture stirs.The separating ethyl acetate layer also takes out, with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.32g), triethylamine (1.00mL) and 4-methylamino pyridine (0.049g), mixture stirred 14.5 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (150mL) and water (50mL), mixture stirs.The separating ethyl acetate layer also takes out, with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is used ethyl acetate: hexane=crystallization in 1: 1, filter and collect.Use acetone recrystallization to obtain title compound (1.39g) as colorless solid.

¹H-NMR(CDCl ₃)：2.22(3H，s)，3.12(3H，bs)，3.78-4.20(2H，bm)，4.38(2H，q，J＝7.8Hz)，4.58-5.08(4H，bm)，6.65(1H，d，J＝5.6Hz)，7.11(2H，t，J＝8.4Hz)，7.28-7.44(3H，m)，7.81-7.86(1H，m)，8.03-8.11(2H，m)，8.35(1H，d，J＝5.6Hz)。

Synthetic embodiment 11

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 3,4, the 5-TMB

Under the frozen water cooling, in the tetrahydrofuran solution (30mL) of two (trichloromethyl) carbonic ester (0.60g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.49mL).After stirring 10 minutes under the frozen water cooling, be added in 2-(methylamino) ethyl 3,4 that obtains in the reference implementation example 11,5-TMB hydrochlorate (1.22g).Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 1 hour.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with dilute hydrochloric acid (20mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.11g), triethylamine (0.84mL) and 4-dimethylaminopyridine (0.037g), mixture stirred 3 hours down at 60 ℃, at room temperature stirred 2 days.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (1.56g) into yellow amorphous solid through quick silica gel chromatography (using acetone: hexane=1: 3,3: 2 eluting then).

¹H-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＝7.8Hz)，4.67(2H，m)，4.80-5.15(2H，br)，6.64(1H，d，J＝5.7Hz)，7.25-7.40(5H，m)，7.78-7.86(1H，m)，8.33(1H，d，J＝5.7Hz)。

Synthetic embodiment 12

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 2-Pyridinecarboxylic Acid ester

Under the frozen water cooling, in the tetrahydrofuran solution (30mL) of two (trichloromethyl) carbonic ester (0.422g), dropwise add pyridine (0.345mL).After stirring 30 minutes under the frozen water cooling, be added in 2-(methylamino) the ethyl 2-Pyridinecarboxylic Acid ester dihydrochloride (1.08g) that obtains in the reference implementation example 12.After dropwise adding triethylamine (1.19mL), mixture at room temperature stirred 2 hours.Remove by filter the solid of separating out, filtrate decompression concentrates.Residue is dissolved in the oxolane (10mL), adds (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.31g), triethylamine (0.99mL) and 4-dimethylaminopyridine (0.043g).Mixture stirred 24 hours at 60 ℃.In reactant mixture, add ethyl acetate (100mL), mixture water (100mL) and saturated brine (100mL) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue (is used ethyl acetate: hexane=4: 1 eluting) through the alkaline silica gel purified.Use acetone-diethyl ether crystallization to obtain title compound (0.9g) as white solid.

¹H-NMR(CDCl ₃)：2.22(3H，s)，3.16(3H，s)，3.80-4.20(2H，m)，4.38(2H，q，J＝7.8Hz)，4.60-5.10(4H，m)，6.64(1H，d，J＝5.8Hz)，7.29-7.40(2H，m)，7.47-7.52(2H，m)，7.81-7.89(2H，m)，8.14(1H，d，J＝7.8Hz)，8.34(1H，d，J＝5.8Hz)，8.75-8.79(1H，m)。

Synthetic embodiment 13

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 2-Methoxyacetic acid ester

Under the frozen water cooling, in the tetrahydrofuran solution (15mL) of two (trichloromethyl) carbonic ester (0.652g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.55mL).After stirring 30 minutes under the frozen water cooling, be added in 2-(methylamino) the ethyl 2-Methoxyacetic acid ester (0.99g) that obtains in the reference implementation example 13.Mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (80mL) and water (50mL), mixture stirs.The separating ethyl acetate layer also takes out, with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (15mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.13g), triethylamine (0.86mL) and 4-dimethylaminopyridine (0.037g), mixture stirred 4 days down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (80mL) and water (30mL), mixture stirs.The separating ethyl acetate layer also takes out, and ethyl acetate layer is with saturated sodium bicarbonate solution (30mL) and water (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure; (with ethyl acetate, acetone then: ethyl acetate=1: 3 eluting), alkaline silica gel purified (using ethyl acetate: hexane=1: 1,3: 1 eluting then) obtains the title compound (0.588g) into colourless slurry to residue again through silica gel chromatography.

¹H-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＝7.8Hz)，4.67(2H，t，J＝6.6Hz)，4.99(1H，d，J＝13.9Hz)，5.12(1H，d，J＝13.9Hz)，6.63(1H，d，J＝5.7Hz)，7.29-7.46(2H，m)，7.62(1H，m)，7.81(1H，m)，8.25(1H，d，J＝5.7Hz)。

Synthetic embodiment 14

Ethyl 2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution (40mL) of two (trichloromethyl) carbonic ester (1.31g), dropwise add the tetrahydrofuran solution (2mL) of pyridine (1.07mL).After stirring 10 minutes under the frozen water cooling, be added in ethyl 2-(methylamino) the ethyl carbonate ester hydrochloride (2.02g) that obtains in the reference implementation example 14.Dropwise add the tetrahydrofuran solution (2mL) of triethylamine (1.84mL), mixture at room temperature stirred 1 hour.Behind the concentrating under reduced pressure, in residue, add entry (100mL), mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with 0.2N hydrochloric acid (50mL) and saturated brine (100mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (50mL).Add (R)-2-[[[3-methyl-4-(2; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (3.69g), triethylamine (2.09mL) and 4-dimethylaminopyridine (0.12g), mixture stirred 6 hours down at 60 ℃, at room temperature stirred 8 hours.Behind the concentrating under reduced pressure, in residue, add entry (100mL), mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (100mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through alkaline silica gel purified (using ethyl acetate: hexane=3: 7, eluent ethyl acetate then).Use the diethyl ether crystallization, the diethyl ether recrystallization obtains the title compound (3.84g) into colorless solid.

¹H-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＝7.2Hz)，4.39(2H，q，J＝7.9Hz)，4.45(2H，m)，4.80-5.15(2H，br)，6.65(1H，d，J＝5.6Hz)，7.36-7.50(3H，m)，7.84(1H，d，J＝7.8Hz)，8.35(1H，d，J＝5.6Hz)。

Synthetic embodiment 15

Isopropyl 2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution (30mL) of two (trichloromethyl) carbonic ester (0.50g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.40mL).After stirring 1 hour under the frozen water cooling, be added in isopropyl 2-(methylamino) the ethyl carbonate ester hydrochloride (0.99g) that obtains in the reference implementation example 15.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.70mL), mixture at room temperature stirred 1 hour.Add two (trichloromethyl) carbonic esters (0.50g), the tetrahydrofuran solution (1mL) of pyridine (0-40mol) and the tetrahydrofuran solution (1mL) of triethylamine (0.70mL) continuously, mixture at room temperature stirred 1 hour.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.11g), triethylamine (0.84mL) and 4-dimethylaminopyridine (0.037g), mixture stirred 12 hours down at 60 ℃, at room temperature stirred 3 days.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through quick silica gel chromatography (using acetone: hexane=1: 3,3: 2 eluting then), again alkaline silica gel purified (using ethyl acetate: hexane=3: 7, ethyl acetate then).Use the diethyl ether crystallization, acetone-diisopropyl ether recrystallization obtains the title compound (0.58g) into colorless solid.

¹H-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＝7.9Hz)，4.32-4.53(2H，m)，4.80-5.20(3H，m)，6.63(1H，d，J＝5.7Hz)，7.35-7.50(3H，m)，7.83(1H，d，J＝7.2Hz)，8.34(1H，d，J＝5.7Hz)。

Synthetic embodiment 16

Isopropyl 2-[methyl [[2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.582g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.49mL).After stirring 30 minutes under the frozen water cooling, be added in isopropyl 2-(methylamino) the ethyl carbonate ester hydrochloride (1.18g) that obtains in the reference implementation example 15.Add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 2 hours.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (80mL) and water (30mL), mixture stirs.The separating ethyl acetate layer also takes out, with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (25mL).Add 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.73g), triethylamine (1.31mL) and 4-dimethylaminopyridine (0.057g), mixture stirred 5 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (100mL) and water (50mL), mixture stirs.The separating ethyl acetate layer also takes out, with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue through the alkaline silica gel purified (use ethyl acetate: hexane=1: 1 eluting), silica gel chromatography (use ethyl acetate: hexane=1: 1,2: 1 then) again.With diisopropyl ether-hexane crystallization, the diisopropyl ether recrystallization obtains the title compound (1.20g) into colorless solid.

¹H-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＝7.8Hz)，4.36-4.58(2H，bm)，4.79-5.15(3H，m)，6.64(1H，d，J＝5.7Hz)，7.35-7.48(3H，m)，7.83(1H，d，J＝7.5Hz)，8.34(1H，d，J＝5.7Hz)。

Synthetic embodiment 17

Benzyl 2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution (30mL) of two (trichloromethyl) carbonic ester (0.50g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.40mL).After stirring 1 hour under the frozen water cooling, be added in benzyl 2-(methylamino) the ethyl carbonate ester hydrochloride (1.08 g) that obtains in the reference implementation example 16.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.70mL), mixture is stirred overnight at room temperature.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.11g), triethylamine (0.84mL) and 4-dimethylaminopyridine (0.037g), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through quick silica gel chromatography (using acetone: hexane=1: 3,3: 2 eluting then).With acetone-diethyl ether crystallization, acetone-diethyl ether recrystallization obtains the title compound (1.17g) into colorless solid.

¹H-NMR(CDCl ₃)：2.22(3H，s)，3.05(3H，bs)，3.50-4.20(2H，br)，4.37(2H，q，J＝7.8Hz)，4.46(2H，m)，4.80-5.10(2H，br)，5.17(2H，s)，6.62(1H，d，J＝5.6Hz)，7.26-7.48(8H，m)，7.77-7.88(1H，m)，8.33(1H，d，J＝5.6Hz)。

Synthetic embodiment 18

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl tetrahydropyran-4-base carbonic ester

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.48g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.39mL).After stirring 20 minutes under the frozen water cooling, be added in 2-(methylamino) the ethyl tetrahydropyran-4-base carbonate salt hydrochlorate (0.96g) that obtains in the reference implementation example 17.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.67mL), mixture at room temperature stirred 2 hours.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with 0.2N hydrochloric acid (20mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.26g), triethylamine (0.71mL) and 4-dimethylaminopyridine (0.042g), mixture stirred 6 hours down at 60 ℃, at room temperature stirred 8 hours.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through alkaline silica gel purified (using ethyl acetate: hexane=3: 7, eluent ethyl acetate then).Use the diethyl ether crystallization, acetone-diisopropyl ether recrystallization obtains the title compound (1.45g) into colorless solid.

¹H-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＝7.8Hz)，4.45(2H，m)，4.77-5.15(3H，m)，6.64(1H，d，J＝5.7Hz)，7.35-7.50(3H，m)，7.83(1H，d，J＝6.9Hz)，8.35(1H，d，J＝5.7Hz)。

Synthetic embodiment 19

2-methoxy ethyl 2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.59g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.49mL).After stirring 10 minutes under the frozen water cooling, be added in 2-methoxy ethyl 2-(methylamino) the ethyl carbonate ester hydrochloride (1.07g) that obtains in the reference implementation example 18.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 1 hour.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with 0.2N hydrochloric acid (20mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in oxolane (20mL) with residue.Add (R)-2-[[[3-methyl-4-(2; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.85g), triethylamine (1.05mL) and 4-dimethylaminopyridine (0.061g), mixture stirred 6 hours down at 60 ℃, at room temperature stirred 8 hours.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through alkaline silica gel purified (using ethyl acetate: hexane=3: 7, eluent ethyl acetate then).With ethyl acetate-diethyl ether crystallization, ethyl acetate-diisopropyl ether recrystallization obtains the title compound (1.39g) into colorless solid.

¹H-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＝7.8Hz)，4.46(2H，m)，4.80-5.15(2H，br)，6.64(1H，d，J＝5.7Hz)，7.35-7.47(3H，m)，7.83(1H，d，J＝7.8Hz)，8.34(1H，d，J＝5.7Hz)。

Synthetic embodiment 20

2-[ethyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate

Under the frozen water cooling, in the tetrahydrofuran solution (30mL) of two (trichloromethyl) carbonic ester (0.59g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.49mL).After stirring 10 minutes under the frozen water cooling, be added in 2-(ethylamino) the ethyl acetic acid ester hydrochloride (0.67g) that obtains in the reference implementation example 20.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 1 hour.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.11g), triethylamine (0.84mL) and 4-dimethylaminopyridine (0.037g), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (1.58g) into yellow amorphous solid through alkaline silica gel purified (using ethyl acetate: hexane=3: 7, eluent ethyl acetate then).

¹H-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＝7.8Hz)，4.75-5.20(2H，br)，6.64(1H，d，J＝5.7Hz)，7.35-7.46(3H，m)，7.84(1H，d，J＝6.9Hz)，8.36(1H，d，J＝5.7Hz)。

Synthetic embodiment 21

2-[isopropyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate

Under the frozen water cooling, in the tetrahydrofuran solution (10mL) of two (trichloromethyl) carbonic ester (0.543g), dropwise add the tetrahydrofuran solution (5mL) of pyridine (0.445mL), mixture stirred 30 minutes down at 0 ℃.Be added in 2-(isopropyl is amino) the ethyl acetic acid ester hydrochloride (1.0g) that obtains in the reference implementation example 22.Dropwise add the tetrahydrofuran solution (5mL) of triethylamine (0.805mL), mixture at room temperature stirred 30 minutes.The reactant mixture concentrating under reduced pressure adds entry (30mL) in residue.Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous sodium sulfate drying, drying under reduced pressure.Resulting grease is dissolved in the oxolane (5mL); Be added to (R)-2-[[[3-methyl-4-(2 then; 2,2-trifluoro ethoxy)-the 2-pyridine radicals] methyl] sulfinyl]-tetrahydrofuran solution (20mL) of 1H-benzimidazole (1.73g), triethylamine (1.53mol) and 4-dimethylaminopyridine (0.134g) in.Mixture stirred 12 hours down at 40 ℃.The reactant mixture concentrating under reduced pressure adds entry (30mL) in residue.Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous sodium sulfate drying, drying under reduced pressure.Residue obtains the title compound (1.50g) into light yellow amorphous solid through silica gel chromatography (using ethyl acetate: hexane=2: 1, eluent ethyl acetate then).

¹H-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＝5.8Hz)，7.30-7.50(3H，m)，7.75-7.90(1H，m)，8.37(1H，d，J＝5.8Hz)。

Synthetic embodiment 22

Ethyl 2-[isopropyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution (10mL) of two (trichloromethyl) carbonic ester (0.467g), dropwise add the tetrahydrofuran solution (5mL) of pyridine (0.381mL), mixture stirred 30 minutes down at 0 ℃.In reactant mixture, be added in ethyl 2-(isopropyl is amino) the ethyl carbonate ester hydrochloride (1.0g) that obtains in the reference implementation example 23.The tetrahydrofuran solution (5mL) that dropwise adds triethylamine (0.69mL), mixture stirred 15 minutes down at 0 ℃, at room temperature stirred 30 minutes.The reactant mixture concentrating under reduced pressure adds entry (30mL) in residue.Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.Resulting grease is dissolved in the oxolane (5mL); Be added to (R)-2-[[[3-methyl-4-(2 then; 2; The 2-trifluoro ethoxy)-the 2-pyridine radicals] methyl] sulfinyl]-tetrahydrofuran solution (20mL) of 1H-benzimidazole (1.48g), triethylamine (1.32mL) and 4-dimethylaminopyridine (0.115g) in, mixture stirred 12 hours down at 40 ℃.The reactant mixture concentrating under reduced pressure adds entry (30mL) in residue.Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue obtains the title compound (1.20g) into light yellow amorphous solid through silica gel chromatography (using ethyl acetate: hexane=2: 1, eluent ethyl acetate then).

¹H-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＝5.8Hz)，7.35-7.55(3H，m)，7.75-7.90(1H，m)，8.38(1H，d，J＝5.8Hz)。

Synthetic embodiment 23

2-[cyclohexyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate

Under the frozen water cooling, in the tetrahydrofuran solution (10mL) of two (trichloromethyl) carbonic ester (0.593g), dropwise add pyridine (0.485mL).After stirring 30 minutes under the frozen water cooling, be added in 2-(cyclohexyl is amino) the ethyl acetic acid ester hydrochloride (1.33g) that obtains in the reference implementation example 25.Dropwise add triethylamine (0.84mL), mixture at room temperature stirred 2 hours.In reactant mixture, add ethyl acetate (50mL), mixture water (50mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure.Residue is dissolved in the oxolane (20mL), adds (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.61g), triethylamine (1.21mL) and 4-dimethylaminopyridine (0.053g).Mixture stirred 24 hours down at 60 ℃.In reactant mixture, add ethyl acetate (50mL), mixture water (20mL) and saturated brine (50mL) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue obtains the title compound (2.12g) into light yellow amorphous solid through quick silica gel chromatography (using ethyl acetate: hexane=1: 4, eluent ethyl acetate then).

¹H-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＝8.2Hz)，4.78(1H×0.5，d，J＝13.2Hz)，4.97(2H×0.5，s)，5.20(1H×0.5，d，J＝13.2Hz)，6.67(1H，d，J＝5.8Hz)，7.36-7.46(3H，m)，7.81-7.91(1H，m)，8.39(1H，d，J＝5.8Hz)。

Synthetic embodiment 24

2-[cyclohexyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl diethyldithiocarbamate carbonic ester

Under the frozen water cooling, in the tetrahydrofuran solution (10mL) of two (trichloromethyl) carbonic ester (0.238g), dropwise add pyridine (0.20mL).After stirring 30 minutes under the frozen water cooling, be added in ethyl 2-(cyclohexyl is amino) the ethyl carbonate ester hydrochloride (0.605g) that obtains in the reference implementation example 26.Dropwise add triethylamine (0.335mL), mixture at room temperature stirred 2 hours.In reactant mixture, add ethyl acetate (50mL), mixture water (50mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure.Residue is dissolved in the oxolane (10mL), adds (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (0.60g), triethylamine (0.45mL) and 4-dimethylaminopyridine (0.02g).Mixture stirred 24 hours down at 60 ℃.In reactant mixture, add ethyl acetate (50mL), mixture water (20mL) and saturated brine (50mL) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue obtains the title compound (0.92g) into light yellow amorphous solid through quick silica gel chromatography (using ethyl acetate: hexane=1: 4, eluent ethyl acetate then).

¹H-NMR(CDCl ₃)：1.02-2.27(16H，m)，3.40-4.60(9H，m)，4.78(1H×0.5，d，J＝13.2Hz)，4.97(2H×0.5，s)，5.44(1H×0.5，d，J＝13.2Hz)，6.69(1H，d，J＝5.6Hz)，7.32-7.54(3H，m)，7.80-7.91(1H，m)，8.38(1H，d，J＝5.6Hz)。

Synthetic embodiment 25

2-[[[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (phenyl) amino] ethylhexoate

Under the frozen water cooling, in the tetrahydrofuran solution (350mL) of two (trichloromethyl) carbonic ester (13.4g), dropwise add pyridine (10.38mL).After stirring 30 minutes under the frozen water cooling, be added in the 2-aniline ethyl acetic acid ester hydrochloride (25.9g) that obtains in the reference implementation example 27.Dropwise add triethylamine (18.4mL), mixture at room temperature stirred 2 hours.Behind the concentrating under reduced pressure, in residue, add ethyl acetate (500mL) and water (500mL), mixture stirs.The separating ethyl acetate layer also takes out, and with saturated brine (500mL) washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtain 2-[(chloroformyl) (phenyl) amino] ethylhexoate.It is dissolved in the oxolane (300mL); Add (R)-2-[[[3-methyl-4-(2; 2,2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (41.2g), triethylamine (15.6mL) and 4-dimethylaminopyridine (1.363g), mixture stirred 3 hours down at 60 ℃.In reactant mixture, add ethyl acetate (800mL), mixture water (800mL) and saturated brine (800mL) washed twice, anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue is through alkaline silica gel purified (using ethyl acetate: hexane=3: 7,1: 1 eluting then).Use the diethyl ether crystallization to obtain title compound (54.1g) as white solid.

¹H-NMR(CDCl ₃)：2.00(3H，s)，2.25(3H，s)，4.15-4.48(6H，m)，4.83(1H，d，J＝13.6Hz)，5.05(1H，d，J＝13.6Hz)，6.67(1H，d，J＝5.4Hz)，7.03-7.45(8H，m)，7.64-7.69(1H，m)，8.40(1H，d，J＝5.4Hz)。

Synthetic embodiment 26

2-[[[2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (phenyl) amino] ethylhexoate

In according to the tetrahydrofuran solution (10mL) of 2-[(chloroformyl) (phenyl) amino] ethyl acetate (0.58g) for preparing with synthetic embodiment 25 identical methods, add 2-[[[3-methyl-4-(2; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (0.739g), triethylamine (0.558mL) and 4-dimethylaminopyridine (0.024g), mixture stirred 15 hours down at 60 ℃.In reactant mixture, add ethyl acetate (30mL), mixture water (50mL) and saturated brine (50mL) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue is through quick silica gel chromatography (, use acetone: hexane=1: 4,3: 2 eluting then).Use the diethyl ether crystallization to obtain title compound (0.779g) as white solid.

¹H-NMR(CDCl ₃)：1.99(3H，s)，2.25(3H，s)，4.20-4.48(6H，m)，4.83(1H，d，J＝13.6Hz)，5.05(1H，d，J＝13.6Hz)，6.67(1H，d，J＝5.8Hz)，7.03-7.45(8H，m)，7.64-7.69(1H，m)，8.40(1H，d，J＝5.8Hz)。

Synthetic embodiment 27

The tert-butyl group [2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino]-the 3-pyridine radicals] methyl carbonic

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.30g), dropwise add pyridine (0.24mL).After stirring 30 minutes under the frozen water cooling, be added in the tert-butyl group [2-(the methylamino)-3-pyridine radicals] methyl carbonic (0.71g) that obtains in the reference implementation example 28, mixture at room temperature stirred 2 hours.Remove by filter the solid of separating out, filtrate decompression concentrates.Residue is dissolved in the oxolane (20mL); Add (R)-2-[[[3-methyl-4-(2; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (0.92g), triethylamine (0.70mL) and 4-dimethylaminopyridine (0.031g), mixture stirred 1 hour down at 60 ℃.In reactant mixture, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.(use acetone: hexane=1: 2 eluting), alkaline silica gel purified (using eluent ethyl acetate) obtains the title compound (0.38g) into light yellow amorphous solid to residue again through quick silica gel chromatography.

¹H-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＝14.0Hz)，5.27(1H，d，J＝14.0Hz)，6.63(1H，d，J＝5.4Hz)，7.26-7.45(3H，m)，7.69-7.87(3H，m)，8.33(1H，d，J＝5.4Hz)，8.44-8.46(1H，m)。

Synthetic embodiment 28

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the benzylacetic acid ester

Under the frozen water cooling, in the tetrahydrofuran solution (30mL) of two (trichloromethyl) carbonic ester (1.46g), add pyridine (1.16mL).After stirring 30 minutes under the frozen water cooling, be added in 2-(methylamino) the benzylacetic acid ester (2.57g) that obtains in the reference implementation example 29.Mixture at room temperature stirred 3 hours, removed by filter the solid of separating out, and filtrate decompression concentrates.Residue is dissolved in the oxolane (40mL); Add (R)-2-[[[3-methyl-4-(2; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (4.41g), triethylamine (3.33mL) and 4-dimethylaminopyridine (0.15g), mixture stirred 18 hours down at 60 ℃.In reactant mixture, add entry (100mL), mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (100mL) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue is through quick silica gel chromatography (use acetone: hexane=1: 4,1: 2 then).Use ethyl acetate-diethyl ether-hexane crystallization to obtain title compound (2.76g) as white solid.

¹H-NMR(CDCl ₃)：2.10(3H，s)，2.00-2.30(3H，br)，3.20-3.50(3H，br)，4.38(2H，q，J＝7.6Hz)，4.70-5.20(2H，m)，5.20-5.50(2H，m)，6.65(1H，d，J＝5.4Hz)，7.10-7.82(8H，m)，8.38(1H，d，J＝5.4Hz)。

Synthetic embodiment 29

2-[[2-(acetoxyl group) ethyl] [[(R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate

Under the frozen water cooling, in the tetrahydrofuran solution (30mL) of two (trichloromethyl) carbonic ester (0.50g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.40mL).After stirring 10 minutes under the frozen water cooling, be added in 2-[(the 2-acetoxyl group ethyl) amino] ethyl acetate hydrochloride (1.13g) that obtains in the reference implementation example 30.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.70mL), mixture at room temperature stirred 2 hours.Remove by filter the solid of separating out, filtrate decompression concentrates.In residue, add ethyl acetate (20mL), remove by filter the solid of separating out, filtrate decompression concentrates.Residue is dissolved in the oxolane (30mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.48g), triethylamine (1.12mL) and 4-dimethylaminopyridine (catalytic amount), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (50mL).Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through silica gel chromatography (using ethyl acetate: hexane=1: 1, eluent ethyl acetate then), again alkaline silica gel purified (using ethyl acetate: hexane=1: 1, eluent ethyl acetate then).Products therefrom is dissolved in the ethyl acetate (20mL), adds activated carbon, the mixture stirred overnight.Remove by filter activated carbon, filtrate decompression concentrates and obtains the title compound (1.60g) into yellow amorphous solid.

¹H-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＝7.9Hz)，4.88(1H，d，J＝13.2Hz)，5.05(1H，d，J＝13.2Hz)，6.66(1H，d，J＝5.6Hz)，7.38-7.50(3H，m)，7.87(1H，d，J＝6.9Hz)，8.36(1H，d，J＝5.6Hz)。

Synthetic embodiment 30

[(2S)-1-[[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl]-the 2-pyrrolidinyl] the methyl acetic acid ester

Under the frozen water cooling, in the tetrahydrofuran solution (30mL) of two (trichloromethyl) carbonic ester (0.50g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.40mL).Under the frozen water cooling, stirred 1 hour, be added in (the S)-2-pyrrolidinyl methyl acetic acid ester hydrochloride (0.90g) that obtains in the reference implementation example 31.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.70mL), mixture at room temperature stirred 2 hours.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture is with ethyl acetate (50mL) extraction, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.11g), triethylamine (0.84mL) and 4-dimethylaminopyridine (0.037g), mixture stirred 1 day down at 60 ℃, at room temperature stirred 2 days.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure; Residue is through alkaline silica gel purified (using ethyl acetate: hexane=1: 1, eluent ethyl acetate then), and silica gel chromatography (using ethyl acetate: hexane=3: 1, ethyl acetate, acetone more then: ethyl acetate=1: 4,2: 3 eluting again) obtains the title compound (0.80g) into light yellow amorphous solid again.

¹H-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＝13.5Hz)，4.96(1H，d，J＝13.5Hz)，6.65(1H，d，J＝5.9Hz)，7.36-7.48(3H，m)，7.89(1H，d，J＝8.7Hz)，8.38(1H，d，J＝5.9Hz)。

Synthetic embodiment 31

Ethyl [methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] acetas

Under the frozen water cooling, in the tetrahydrofuran solution (30mL) of two (trichloromethyl) carbonic ester (0.50g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.40mL).Under the frozen water cooling, stirred 30 minutes, add hydrochloride ethyl sarcosnate (0.77g).Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.70mL), mixture at room temperature stirred 1 hour.Remove by filter the solid of separating out, filtrate decompression concentrates.In residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (33mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole sodium (1.37g) and 4-dimethylaminopyridine (catalytic amount), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (0.40g) into yellow amorphous solid through alkaline silica gel purified (using ethyl acetate: hexane=1: 1, eluent ethyl acetate then).

¹H-NMR(CDCl ₃)：1.33(3H，t，J＝7.1Hz)，2.24(3H，s)，3.10(3H，bs)，3.70-4.30(2H，br)，4.28(2H，q，J＝7.1Hz)，4.38(2H，q，J＝7.8Hz)，4.82-5.10(2H，br)，6.63(1H，d，J＝5.5Hz)，7.34-7.52(2H，m)，7.70-7.90(2H，m)，8.32(1H，d，?J＝5.5Hz)。

Synthetic embodiment 32

2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (methyl) amino] ethylamino benzonitrile acid esters

Under the frozen water cooling, in the tetrahydrofuran solution (10mL) of two (trichloromethyl) carbonic ester (0.344g), dropwise add the tetrahydrofuran solution (5mL) of pyridine (0.281mL), mixture stirred 30 minutes down at 0 ℃.Be added in 2-(methylamino) the ethyl benzoate ester hydrochloride (0.750g) that obtains in the reference implementation example 5.The tetrahydrofuran solution (5mL) that adds triethylamine (0.485mL), mixture stirred 1 hour down at 0 ℃, at room temperature stirred 30 minutes.The reactant mixture concentrating under reduced pressure adds entry (30mL) in residue, mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.Resulting grease is dissolved in the oxolane (5mL); Be added to 5-methoxyl group-2-[[(4-methoxyl group-3 then; 5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-tetrahydrofuran solution (10mL) of 1H-benzimidazole (1.0g), triethylamine (0.808mL) and 4-dimethylaminopyridine (0.071g) in, mixture stirred 18 hours down at 40 ℃.The reactant mixture concentrating under reduced pressure adds entry (30mL) in residue.Mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue obtains being the title compound of light yellow amorphous solid and 1: 1 mixture (1.50g) of 2-[[[6-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (methyl) amino] ethylamino benzonitrile acid esters through silica gel chromatography (using ethyl acetate: hexane=1: 1, eluent ethyl acetate then).

¹H-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)。

Synthetic embodiment 33

3-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the propylbenzoic acid ester

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.582g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.485mL).Under the frozen water cooling, stirred 1 hour, be added in 3-(methylamino) the propylbenzoic acid ester hydrochloride (1.38g) that obtains in the reference implementation example 32.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 2 hours.Behind the concentrating under reduced pressure, in residue, add entry (40mL), mixture extracts with ethyl acetate (80mL).Ethyl acetate layer is with saturated brine (25mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.63g), triethylamine (1.23mL) and 4-dimethylaminopyridine (0.054g), mixture stirred 4 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add entry (40mL), mixture extracts with ethyl acetate (80mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (1.26g) into yellow amorphous solid through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then).

¹H-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＝7.8Hz)，4.30-4.50(2H，bm)，4.80-5.15(2H，bm)，6.62(1H，d，J＝5.7Hz)，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＝5.7Hz)。

Synthetic embodiment 34

2-[methyl [[2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl tetrahydropyran-4-base carbonic ester

Under the frozen water cooling, in the tetrahydrofuran solution of two (trichloromethyl) carbonic ester (0.582g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.485mL).After stirring 20 minutes under the frozen water cooling, be added in 2-(methylamino) the ethyl tetrahydropyran-4-base carbonate salt hydrochlorate (1.43g) that obtains in the reference implementation example 17.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 3 hours, behind the concentrating under reduced pressure, in residue, added entry (30mL), and mixture extracts with ethyl acetate (80mL).Ethyl acetate layer is with saturated brine (20mL) washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure.Residue is dissolved in the oxolane (20mL).Add 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.63g), triethylamine (1.23mL) and 4-dimethylaminopyridine (0.027g), mixture stirred 17.5 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (120mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then), again silica gel chromatography (using ethyl acetate: hexane=1: 1,2: 1 eluting then).Use the diethyl ether crystallization to obtain title compound (1.23g) as colorless solid.

¹H-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＝7.9Hz)，4.45(2H，m)，4.77-5.15(3H，m)，6.65(1H，d，J＝5.4Hz)，7.35-7.50(3H，?m)，7.85(1H，m)，8.36(1H，d，J＝5.4Hz)。

Synthetic embodiment 35

Ethyl 2-[methyl [[2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution of two (trichloromethyl) carbonic ester (0.582g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.485mL).After stirring 30 minutes under the frozen water cooling, be added in ethyl 2-(methylamino) the ethyl carbonate ester hydrochloride (1.10g) that obtains in the reference implementation example 14.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, in residue, add entry (30mL), mixture extracts with ethyl acetate (80mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.63g), triethylamine (1.23mL), 4-dimethylaminopyridine (0.054g), mixture stirred 14 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add entry (40mL), mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure; Residue is through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then), and silica gel chromatography (using ethyl acetate: hexane=1: 1,2: 1 eluting then) obtains the title compound (1.27g) into yellow amorphous solid again.

¹H-NMR(CDCl ₃)：1.32(3H，t，J＝7.1Hz)，2.23(3H，s)，3.09(3H，bs)，3.50-4.76(4H，br)，4.21(2H，q，J＝7.1Hz)，4.38(2H，q，J＝7.9Hz)，4.84-5.14(2H，m)，6.64(1H，d，J＝5.6Hz)，7.36-7.46(3H，m)，7.83(1H，d，J＝7.2Hz)，8.34(1H，d，J＝5.6Hz)。

Synthetic embodiment 36

Ethyl 2-[methyl [[(S)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.582g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.485mL).Under the frozen water cooling, stirred 1 hour, be added in ethyl 2-(methylamino) the ethyl carbonate ester hydrochloride (1.10g) that obtains in the reference implementation example 14.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 2 hours.Behind the concentrating under reduced pressure, in residue, add entry (30mL), mixture extracts with ethyl acetate (80mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (S)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.15g), triethylamine (0.87mL) and 4-dimethylaminopyridine (0.035g), mixture stirred 12 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add entry (30mL), mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=l: 2, l then: 1 eluting) through the alkaline silica gel purified.Use the diethyl ether crystallization to obtain title compound (0.40g) as colorless solid.

¹H-NMR(CDCl ₃)：1.32(3H，t，J＝7.2Hz)，2.23(3H，s)，3.10(3H，bs)，3.50-4.56(4H，br)，4.22(2H，q，J＝7.2Hz)，4.38(2H，q，J＝7.9Hz)，4.84-5.14(2H，m)，6.65(1H，d，J＝5.6Hz)，7.34-7.50(3H，m)，7.85(1H，m)，8.36(1H，d，J＝5.6Hz)。

Synthetic embodiment 37

Ethyl 2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-3H-imidazo [4,5-b] pyridin-3-yl] carbonyl] (methyl) amino] ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.582g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.485mL).After stirring 30 minutes under the frozen water cooling, be added in ethyl 2-(methylamino) the ethyl carbonate ester hydrochloride (1.10g) that obtains in the reference implementation example 14.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 2.5 hours.Behind the concentrating under reduced pressure, in residue, add entry (30mL), mixture extracts with ethyl acetate (80mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Synthetic 5-methoxyl group-2-[[(the 4-methoxyl group-3 that obtains of method that adding is described according to JP-A-63-146882; 5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-imidazo [4; 5-b] pyridine (1.44g), triethylamine (1.16mL) and 4-dimethylaminopyridine (0.049g), mixture stirred 6 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add entry (30mL), mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then).Use the diethyl ether crystallization to obtain title compound (0.721g) as colorless solid.

^lH-NMR (CDCl ₃): 1.25-1.34 (3H, m), 2.23 (6H, s), 3.15,3.32 (whole 3H, s), 3.72 (3H, s); 3.90-4.53 (9H, m), 4.86 (1H, d, J=13.4Hz), 4.95 (1H, d, J=13.4Hz); 6.79 (1H, d, J=8.7Hz), 7.95 (1H, d, J=8.7Hz), 8.22 (1H, s).

Synthetic embodiment 38

2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-3H-imidazo [4,5-b] pyridin-3-yl] carbonyl] (methyl) amino] ethylhexoate

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.582g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.485mL).After stirring 30 minutes under the frozen water cooling, be added in 2-(methylamino) ethyl acetate hydrochloride (0.922g) that obtains in the reference implementation example 2.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 2 hours.Behind the concentrating under reduced pressure, in residue, add entry (30mL), mixture extracts with ethyl acetate (80mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (10mL).Synthetic 5-methoxyl group-2-[[(the 4-methoxyl group-3 that obtains of method that adding is described according to JP-A-63-146882; 5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-imidazo [4; 5-b] pyridine (0.85g), triethylamine (0.70mL) and 4-dimethylaminopyridine (0.025g), mixture stirred 5 minutes down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add entry (30mL), mixture extracts with ethyl acetate (90mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then).Use the diethyl ether crystallization to obtain title compound (0.173g) as colorless solid.

¹H-NMR (CDCl ₃): 2.04,2.09 (whole 3H, s), 2.24 (6H, s), 3.13,3.30 (whole 3H, s); 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=13.1Hz), 4.96 (1H, d, J=13.1Hz), 6.80 (1H; D, J=8.9Hz), 7.96 (1H, d, J=8.9Hz), 8.22 (1H, s).

Synthetic embodiment 39

2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-3H-imidazo [4,5-b] pyridin-3-yl] carbonyl] (phenyl) amino] ethylhexoate

Under the frozen water cooling, in the tetrahydrofuran solution (10mL) of two (trichloromethyl) carbonic ester (0.291g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.243mL).After stirring 30 minutes under the frozen water cooling, be added in the 2-aniline ethyl acetic acid ester hydrochloride (0.647g) that obtains in the reference implementation example 27.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.419mL), mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, in residue, add entry (20mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (15mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (10mL).Synthetic 5-methoxyl group-2-[[(the 4-methoxyl group-3 that obtains of method that adding is described according to JP-A-63-146882; 5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-imidazo [4; 5-b] pyridine (0.867g), triethylamine (0.697mL) and 4-dimethylaminopyridine (0.020g), mixture stirred 10 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add entry (20mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (15mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=1: 1 eluting) through the alkaline silica gel purified.Use the diethyl ether crystallization to obtain title compound (0.311g) as colorless solid.

¹H-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＝8.7Hz)，7.02-7.18(3H，m)，7.32-7.48(2H，m)，7.73(1H，d，J＝8.7Hz)，8.26(1H，s)。

Synthetic embodiment 40

4-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the butylacetic acid ester

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.59g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.49mL).After stirring 30 minutes under the frozen water cooling, be added in 4-(methylamino) the butylacetic acid ester hydrochloride (1.08g) that obtains in the reference implementation example 37.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-lH-benzimidazole (1.02g), triethylamine (0.77mL) and 4-dimethylaminopyridine (catalytic amount), mixture is 60 ℃ of stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (0.93g) into yellow amorphous solid through alkaline silica gel purified (use ethyl acetate: hexane=l: 2,1: 1 eluting) then.

¹H-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＝7.8Hz)，4.85-5.13(2H，m)，6.64(1H，d，J＝5.6Hz)，7.36-7.46(3H，m)，7.84(1H，d，J＝8.4Hz)，8.35(1H，d，J＝5.6Hz)。

Synthetic embodiment 41

Ethyl 4-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the butyl carbonic ester

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.59g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.49mL).After stirring 30 minutes under the frozen water cooling, be added in ethyl 4-(methylamino) the butyl carbonate salt hydrochlorate (1.27g) that obtains in the reference implementation example 39.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.26g), triethylamine (0.95mL) and 4-dimethylaminopyridine (catalytic amount), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (1.08g) into yellow amorphous solid through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then).

¹H-NMR(CDCl ₃)：1.31(3H，t，J＝7.2Hz)，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＝7.8Hz)，4.87-5.13(2H，m)，6.64(1H，d，J＝5.4Hz)，7.35-7.46(3H，m)，7.83(1H，d，J＝7.8Hz)，8.35(1H，d，J＝5.4Hz)。

Synthetic embodiment 42

Ethyl 3-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] propyl carbonate

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.59g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.49mL).After stirring 30 minutes under the frozen water cooling, be added in ethyl 3-(methylamino) the propyl carbonate hydrochlorate (1.18g) that obtains in the reference implementation example 44.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.10g), triethylamine (0.83mL) and 4-dimethylaminopyridine (catalytic amount), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (0.88g) into yellow amorphous solid through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then).

¹H-NMR(CDCl ₃)：1.29(3H，t，J＝7.2Hz)，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＝7.8Hz)，4.83-5.13(2H，m)，6.64(1H，d，J＝5.6Hz)，7.35-7.46(3H，m)，7.82(1H，d，J＝8.1Hz)，8.35(1H，d，J＝5.6Hz)。

Synthetic embodiment 43

3-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the propyl-acetic acid ester

Under the frozen water cooling, in the tetrahydrofuran solution (40mL) of two (trichloromethyl) carbonic ester (1.19g), dropwise add the tetrahydrofuran solution (2mL) of pyridine (0.95mL).After stirring 30 minutes under the frozen water cooling, be added in 3-(methylamino) the propyl-acetic acid ester hydrochloride (1.90g) that obtains in the reference implementation example 42.Dropwise add the tetrahydrofuran solution (2mL) of triethylamine (1.68mL), mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, in residue, add entry (100mL), mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (100mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (40mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.99g), triethylamine (1.50mL) and 4-dimethylaminopyridine (catalytic amount), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (100mL), mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (100mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (1.22g) into yellow amorphous solid through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then).

¹H-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＝7.8Hz)，4.85-5.13(2H，m)，6.64(1H，d，J＝5.6Hz)，7.24-7.44(3H，m)，7.83(1H，d，J＝7.5Hz)，8.35(1H，d，J＝5.6Hz)。

Synthetic embodiment 44

3-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] propane-1,2-two basic diacetate esters

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.59g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.49mL).After stirring 30 minutes under the frozen water cooling, be added in 3-(methylamino) propane-1 that obtains in the reference implementation example 46,2-two basic diacetate esters hydrochlorates (1.35g).Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.27g), triethylamine (0.96mL) and 4-dimethylaminopyridine (catalytic amount), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (0.64g) into yellow amorphous solid through alkaline silica gel column chromatography (using ethyl acetate: hexane=1: 2,1: 1 eluting then).

¹H-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＝7.8Hz)，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)。

Synthetic embodiment 45

Diethyl 3-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] propane-1,2-two basic double manganese esters

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.59g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.49mL).After stirring 30 minutes under the frozen water cooling, be added in diethyl 3-(methylamino) propane-1 that obtains in the reference implementation example 47,2-two basic double manganese ester hydrochlorates (1.71g).Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.53g), triethylamine (1.16mL) and 4-dimethylaminopyridine (catalytic amount), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (1.42g) into yellow amorphous solid through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then).

¹H-NMR(CDCl ₃)：1.28-1.34(6H，m)，2.22(3H，s)，3.07(3H，bs)，3.42-4.60(1OH，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)。

Synthetic embodiment 46

2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-3H-imidazo [4,5-b] pyridin-3-yl] carbonyl] (methyl) amino] ethyl 3-chlorobenzoic acid ester

Under the frozen water cooling, in the tetrahydrofuran solution (7mL) of two (trichloromethyl) carbonic ester (0.194g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.162mL).After stirring 30 minutes under the frozen water cooling; Be added in 2-(methylamino) the ethyl 3-chlorobenzoic acid ester hydrochloride (0.50g) that obtains in the reference implementation example 7; Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.279mL), mixture at room temperature stirred 2.5 hours.Behind the concentrating under reduced pressure, in residue, add entry (15mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (15mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (10mL).Synthetic 5-methoxyl group-2-[[(the 4-methoxyl group-3 that obtains of method that adding is described according to JP-A-63-146882; 5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-imidazo [4; 5-b] pyridine (0.445g), triethylamine (0.357mL) and 4-dimethylaminopyridine (0.012g), mixture stirred 14 hours at 60 ℃.Behind the concentrating under reduced pressure, in residue, add entry (30mL), mixture extracts with ethyl acetate (70mL).Ethyl acetate layer is with saturated brine (20mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (0.360g) into colourless amorphous solid through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then).

¹H-NMR (CDCl ₃): 2.21 (3H, s), 2.23 (3H, s), 3.32,3.38 (whole 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=13.4Hz), 4.94 (1H, d, J=13.4Hz), 6.77 (1H, d, J=8.8Hz); 7.36 (1H, m), 7.52 (1H, m), 7.80-8.03 (3H, m), 8.20 (1H, s).

Synthetic embodiment 47

2-[methyl [[2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.582g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.485mL).After stirring 1 hour under the frozen water cooling, be added in 2-(methylamino) the ethyl acetic acid ester hydrochloride (0.922g) that obtains in the reference implementation example 2.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 2.5 hours.Behind the concentrating under reduced pressure, in residue, add entry (40mL), mixture extracts with ethyl acetate (80mL).Ethyl acetate layer is with saturated brine (25mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (15mL).Add 2-[[[3-methyl-4-(2,2, the 2-trifluoromethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.10g), triethylamine (0.84mL) and 4-dimethylaminopyridine (0.036g), mixture stirred 4.5 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add entry (40mL), mixture extracts with ethyl acetate (80mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (1.18g) into colorless solid through silica gel chromatography (using ethyl acetate: hexane=1: 1,2: 1 eluting then).

¹H-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＝7.8Hz)，4.84-5.18(2H，m)，6.64(1H，d，J＝5.6Hz)，7.36-7.48(3H，m)，7.85(1H，d，J＝7.8Hz)，8.35(1H，d，J＝5.6Hz)。

Synthetic embodiment 48

[[[3-methyl-4-(2 with (R)-2-; 2,2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-oxolane (813mL) solution of 1H-benzimidazole (130g), triethylamine (63.8mL), 4-dimethylaminopyridine (0.86g) and ethyl 2-[(chloroformyl) (methyl) amino] the ethyl carbonate ester (84.8g) that in reference implementation example 34, obtains stirred 18 hours down at 45-50 ℃.The reactant mixture concentrating under reduced pressure adds entry (300mL) in residue, mixture extracts with ethyl acetate (700mL).Ethyl acetate layer adds anhydrous magnesium sulfate (130g) and activated carbon (13g) with saturated brine (300mL) washing 3 times.Mixture at room temperature stirred 30 minutes and filtered.Filtrate decompression concentrates, and residue is dissolved in the diethyl ether (600mL) that contains triethylamine (0.49mL) the mixture concentrating under reduced pressure.Continue the repetition above-mentioned steps twice.Resulting grease is dissolved in the ethanol (200mL) that contains triethylamine (2.45mL), under the frozen water cooling, dropwise adds entry (120mL) then.Collect the crystallization of separating out through filtering, (volume ratio 1: 1 150mL) is washed three times, and drying obtains the title compound (172.2g) into colorless solid with the refrigerative alcohol-water of frozen water. ¹H-NMR (CDCl ₃) show and the identical wave spectrogram of chemical compound that in synthetic embodiment 14, obtains.

Synthetic embodiment 49

2-ethoxyethyl group 2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.43g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.35mL).After stirring 10 minutes under the frozen water cooling, be added in 2-ethoxyethyl group 2-(methylamino) the ethyl carbonate ester hydrochloride (0.82g) that obtains in the reference implementation example 48.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.60mL), mixture at room temperature stirred 3 days.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with 0.2N hydrochloric acid (20mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.11g), triethylamine (0.63mL) and 4-dimethylaminopyridine (0.037g), mixture stirred 6 hours down at 60 ℃, stirred 11 hours polite at present.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=3: 7, ethyl acetate then: hexane=7: 3 eluting) obtain the title compound (1.39g) into yellow amorphous solid through the alkaline silica gel purified.

¹H-NMR(CDCl ₃)：1.19(3H，t，J＝6.9Hz)，2.23(3H，s)，3.09(3H，bs)，3.40-4.20(2H，br)，3.53(2H，q，J＝6.9Hz)，3.63-3.69(2H，m)，4.27-4.34(2H，m)，4.39(2H，q，J＝7.8Hz)，4.47(2H，m)，4.80-5.20(2H，m)，6.65(1H，d，J＝5.6Hz)，7.30-7.52(3H，m)，7.84(1H，d，J＝7.5Hz)，8.35(1H，d，J＝5.6Hz)。

Synthetic embodiment 50

3-methoxycarbonyl propyl 2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] the ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.53g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.44mL).After stirring 5 minutes under the frozen water cooling, be added in 3-methoxy-propyl 2-(methylamino) the ethyl carbonate ester hydrochloride (0.82g) that obtains in the reference implementation example 49.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.75mL), mixture at room temperature stirred 1 hour.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture washs with ethyl acetate (50mL).Ethyl acetate layer is with 0.2N hydrochloric acid (20mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.11g), triethylamine (0.63mL) and 4-dimethylaminopyridine (0.037g), mixture stirred 6 hours down at 60 ℃, at room temperature stirred 6 hours.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=3: 7, ethyl acetate then: hexane=7: 3 eluting) through the alkaline silica gel purified.Use the diethyl ether crystallization to obtain title compound (0.70g) as colorless solid.

¹H-NMR (CDCl ₃): 1.94 (2H, quintet, J=6.2Hz), 2.23 (3H, s), 3.09 (3H, bs), 3.31 (3H, s); 3.40-4.20 (2H, br), 3.44 (2H, t, J=6.2Hz), 4.25 (2H, t, J=6.5Hz), 4.38 (2H; Q, J=7.8Hz), 4.44 (2H, m), 4.80-5.20 (2H, m), 6.64 (1H, d, J=5.6Hz); 7.35-7.48 (3H, m), 7.83 (1H, d, J=7.8Hz), 8.34 (1H, d, J=5.6Hz).

Synthetic embodiment 51

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl n, N-dimethylglycine ester

The N that will in reference implementation example 50, obtain, N-dimethylglycine 2-(methylamino) ethyl ester dihydrochloride (1.06g) is added in the oxolane (40mL), and mixture stirs a moment, to wherein adding two (trichloromethyl) carbonic esters (0.77g).In frozen water, after the cooling, dropwise add the tetrahydrofuran solution (5mL) of triethylamine (2.17mL), mixture at room temperature stirred 3 hours.Remove by filter the solid of separating out, add ethyl acetate (80mL).Mixture is with refrigerative sodium bicarbonate aqueous solution of cold water (50mL) and saturated brine (50mL * 2) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.11g), triethylamine (0.63mL) and 4-dimethylaminopyridine (0.037g), mixture stirred 6 hours down at 60 ℃, at room temperature stirred 3 days.Add 4-dimethylaminopyridine (0.037g), mixture continues to stir 6 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add sodium bicarbonate aqueous solution (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=1: 1, ethyl acetate, methanol more then: ethyl acetate=1: 19 eluting) through the alkaline silica gel purified.Use the diethyl ether recrystallization to obtain title compound (0.41g) as colorless solid.

¹H-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＝7.8Hz)，4.44(2H，m)，4.80-5.18(2H，m)，6.64(1H，d，J＝5.6Hz)，7.36-7.48(3H，m)，7.84(1H，d，J＝6.9Hz)，8.35(1H，d，J＝5.6Hz)。

Synthetic embodiment 52

S-[2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl] thiacetate

S-[2-(methylamino) ethyl] the thiacetic acid. ester hydrochloride (0.75g) that will in reference implementation example 51, obtain is added in the oxolane (30mL), and mixture stirs a moment, to wherein adding two (trichloromethyl) carbonic esters (0.66g).After the cold water cooling, dropwise add the tetrahydrofuran solution (10mL) of triethylamine (1.85mL), mixture stirred 30 minutes under the frozen water cooling.Remove by filter the solid of separating out, in filtrating, add ethyl acetate (50mL).Mixture is with refrigerative 0.2N hydrochloric acid of frozen water (20mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (0.96g), triethylamine (0.54mL) and 4-dimethylaminopyridine (0.032g), mixture stirred 6 hours down at 60 ℃, at room temperature stirred 8 hours.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue (is used acetone: hexane=3: 7, acetone then: hexane=7: 3 eluting) obtain the title compound (1.19g) into yellow amorphous solid through silica gel chromatography.

¹H-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＝7.8Hz)，4.80-5.20(2H，m)，6.64(1H，d，J＝5.7Hz)，7.35-7.50(3H，m)，7.83(1H，d，J＝6.9Hz)，8.35(1H，d，J＝5.7Hz)。

Synthetic embodiment 53

Ethyl 2-[2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyoxyl] the ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution (40mL) of two (trichloromethyl) carbonic ester (1.19g), dropwise add the tetrahydrofuran solution (2mL) of pyridine (0.95mL).After stirring 30 minutes under the frozen water cooling, be added in ethyl 2-[2-(methylamino) ethyoxyl] the ethyl carbonate ester hydrochloride (2.73g) that obtains in the reference implementation example 52.Dropwise add the tetrahydrofuran solution (2mL) of triethylamine (1.68mL), mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, minute add entry (100mL) to residue, mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (100mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (40mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (2.80g), triethylamine (2.11mL) and 4-dimethylaminopyridine (catalytic amount), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (100mL), mixture extracts with ethyl acetate (100mL).Ethyl acetate layer is with saturated brine (100mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (2.19g) into yellow amorphous solid through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then).

¹H-NMR(CDCl ₃)：1.28(3H，t，J＝7.2Hz)，2.24(3H，s)，3.10(3H，bs)，3.38-3.80(6H，m)，4.18(2H，q，J＝7.2Hz)，4.27-4.34(2H，m)，4.38(2H，q，J＝8.4Hz)，4.83-5.30(2H，m)，6.65(1H，d，J＝5.7Hz)，7.35-7.50(3H，m)，7.84(1H，d，J＝7.8Hz)，8.36(1H，d，J＝5.7Hz)。

Synthetic embodiment 54

Ethyl 2-[methyl [[2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyoxyl] carbonyl] amino] the ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.59g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.49mL).After stirring 30 minutes under the frozen water cooling, be added in ethyl 2-[methyl [[2-(methylamino) ethyoxyl] carbonyl] amino] the ethyl carbonate ester hydrochloride (1.71g) that obtains in the reference implementation example 53.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.84mL), mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.59g), triethylamine (1.20mL) and 4-dimethylaminopyridine (catalytic amount), mixture is 60 ℃ of stirred overnight.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (1.62g) into yellow amorphous solid through alkaline silica gel purified (using ethyl acetate: hexane=1: 2, washing in 1: 1 then).

¹H-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(1OH，m)，4.88-5.08(2H，m)，6.65(1H，t，J＝5.7Hz)，7.36-7.48(3H，m)，7.85(1H，d，J＝6.9Hz)，8.36(1H，d，J＝5.7?Hz)。

Synthetic embodiment 55

Ethyl 2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (methyl) amino] ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution (10mL) of two (trichloromethyl) carbonic ester (0.291g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.243mL).After stirring 1 hour under the frozen water cooling, be added in ethyl 2-(methylamino) the ethyl carbonate ester hydrochloride (0.551g) that obtains in the reference implementation example 14.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.418mL), mixture at room temperature stirred 2 hours.Behind the concentrating under reduced pressure, in residue, add entry (15mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (15mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (10mL).Add 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole (0.817g), triethylamine (0.661mL) and 4-dimethylaminopyridine (0.012g), mixture stirred 12 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add entry (20mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (15mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure; Residue obtains being the title compound of light yellow amorphous solid and 3: 2 mixture (0.92g) of ethyl 2-[[[6-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (methyl) amino] ethyl carbonate ester through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then).

¹H-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＝9.0Hz)，7.66(1H，m)，8.21(1H，s)。

Synthetic embodiment 56

2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (phenyl) amino] ethylhexoate

Under the frozen water cooling, in the tetrahydrofuran solution (10mL) of two (trichloromethyl) carbonic ester (0.291g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.243mL).After stirring 30 minutes under the frozen water cooling, be added in the 2-aniline ethyl acetic acid ester hydrochloride (0.647g) that obtains in the reference implementation example 27.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.419mL), mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, in residue, add entry (20mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (15mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (10mL).Add 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole (0.829g), triethylamine (0.669mL) and 4-dimethylaminopyridine (0.012g), mixture stirred 14 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add entry (40mL), mixture extracts with ethyl acetate (80mL).Ethyl acetate layer is with saturated brine (15mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure; Residue (is used ethyl acetate: hexane=1: 2 eluting) obtain being the title compound of colourless amorphous solid and 1: 1 mixture (1.10g) of 2-[[[6-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (phenyl) amino] ethyl acetate through the alkaline silica gel purified.

¹H-NMR(CDCl ₃)：1.99(3H，s)，2.19(1.5H.s)，2.21(1.5H，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(3.5H，m)，7.25-7.53(2.5H，m)，7.51(0.5H，d，J＝8.7Hz)，8.25(1H，s)。

Synthetic embodiment 57

Ethyl 2-[[[(S)-and 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (methyl) amino] the ethyl carbonate ester

To not examining synthetic (the S)-5-of method methoxyl group-2-[[(4-methoxyl group-3 of openly putting down among the synthetic embodiment 1 of 10-504290 through being described in Japanese patent application PCT; 5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-being added in ethyl 2-[(chloroformyl) (methyl) amino] ethyl carbonate ester (0.9mL), triethylamine (1.08mL) and the 4-dimethylaminopyridine (0.010g) that obtains in the reference implementation example 34 in the tetrahydrofuran solution (10mL) of 1H-benzimidazole (1.34g), mixture is 60 ℃ of stirrings 6 hours down.Behind the concentrating under reduced pressure, in residue, add entry (30mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (15mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure; Residue obtains the carbonyl into the title compound of light yellow amorphous solid and ethyl 2-[[[(S)-6-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then)] (methyl) amino] 3: 2 mixture (0.92g) of ethyl carbonate ester.

¹H-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＝9.3Hz)，7.65(1H，m)，8.21(1H，s)。

Synthetic embodiment 58

Ethyl 2-[[[2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (methyl) amino] ethyl carbonate ester

Under the frozen water cooling, in the tetrahydrofuran solution (10mL) of two (trichloromethyl) carbonic ester (0.291g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.243mL).After stirring 30 minutes under the frozen water cooling, be added in ethyl 2-(methylamino) the ethyl carbonate ester hydrochloride (0.551g) that obtains in the reference implementation example 14.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.418mL), mixture at room temperature stirred 2.5 hours.Behind the concentrating under reduced pressure, in residue, add entry (15mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (15mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (10mL).Add 2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (0.723g), triethylamine (0.528mL) and 4-dimethylaminopyridine (0.012g), mixture stirred 17 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add entry (40mL), mixture extracts with ethyl acetate (80mL).Ethyl acetate layer is with saturated brine (15mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure; (use ethyl acetate: hexane=1: 2 eluting), silica gel chromatography (using ethyl acetate: hexane=1: 1, eluent ethyl acetate then) obtains the title compound (0.44g) into colourless amorphous solid to residue again through the alkaline silica gel purified.

¹H-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＝6.1Hz)，3.61-4.01(2H，m)，4.08(2H，t，J＝6.3Hz)，4.21(2H，t，J＝7.1Hz)，4.38-4.54(2H，m)，4.81-5.12(2H，m)，6.68(1H，?d，J＝5.6Hz)，7.34-7.48(3H，m)，7.83(1H，d，J＝7.8Hz)，8.27(1H，d，J＝5.6Hz)。

Synthetic embodiment 59

2-[[[2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (phenyl) amino] ethylhexoate

Under the frozen water cooling, in the tetrahydrofuran solution (10mL) of two (trichloromethyl) carbonic ester (0.291g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.243mL).After stirring 30 minutes under the frozen water cooling, be added in the 2-aniline ethyl acetic acid ester hydrochloride (0.647g) that obtains in the reference implementation example 27.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.419mL), mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, in residue, add entry (20mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (15mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (10mL).Add 2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (0.877g), triethylamine (0.641mL) and 4-dimethylaminopyridine (0.012g), mixture stirred 16 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add entry (40mL), mixture extracts with ethyl acetate (80mL).Ethyl acetate layer is with saturated brine (15mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, (use ethyl acetate: hexane=1: 2 eluting), silica gel chromatography (using eluent ethyl acetate) obtains the title compound (0.93g) into colourless amorphous solid to residue again through the alkaline silica gel purified.

¹H-NMR(CDCl ₃)：1.99(3H，s)，2.07(3H.s)，2.19(3H，s)，3.35(3H，s)，3.54(2H，t，J＝6.2Hz)，4.09(2H，t，J＝6.2Hz)，4.14-4.40(4H，m)，4.80(1H，d，J＝13.7Hz)，5.00(1H，d，J＝13.7Hz)，6.71(1H，d，J＝5.7Hz)，7.03-7.34(7H，m)，7.38(1H，m)，7.65(1H，m)，8.32(1H，d，J＝5.7Hz)。

Synthetic embodiment 60

2-[[[5-(difluoro-methoxy)-2-[[(3,4-dimethoxy-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] (methyl) amino] ethyl diethyldithiocarbamate carbonic ester

Under the frozen water cooling, in the tetrahydrofuran solution (8mL) of two (trichloromethyl) carbonic ester (0.174g), dropwise add the tetrahydrofuran solution (1mL) of pyridine (0.146mL).Under the frozen water cooling, stirred 1 hour, be added in ethyl 2-(methylamino) the ethyl carbonate ester hydrochloride (0.330g) that obtains in the reference implementation example 14.Dropwise add the tetrahydrofuran solution (1mL) of triethylamine (0.250mL), mixture at room temperature stirred 3 hours.Behind the concentrating under reduced pressure, in residue, add entry (10mL), mixture extracts with ethyl acetate (30mL).Ethyl acetate layer is with saturated brine (10mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (8mL).Add 5-(difluoro-methoxy)-2-[[(3,4-dimethoxy-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole (0.432g), triethylamine (0.279mL) and 4-dimethylaminopyridine (0.008g), mixture stirred 17.5 hours down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add entry (20mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (10mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure; Residue is through alkaline silica gel purified (using ethyl acetate: hexane=1: 2,1: 1 eluting then); Silica gel chromatography (using ethyl acetate: hexane=2: 1, eluent ethyl acetate then) obtains being the title compound of light yellow amorphous solid and 1: 1 mixture (0.09g) of 2-[[[6-(difluoro-methoxy)-2-[[(3,4-dimethoxy-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] methylamino] ethyl carbonate ethyl ester again.

¹H-NMR(CDCl ₃)：1.31(3H，t，J＝7.2Hz)，3.06(3H，s)，3.42-3.98(2H，m)，3.87(3H，s)，3.90(3H，s)，4.21(2H，q，J＝7.2Hz)，4.36-4.54(2H，m)，4.90(1H，d，J＝13.2Hz)，4.98(1H，d，J＝13.2Hz)，6.54(0.5H，t，J＝73.5Hz)，6.61(0.5H，t，?J＝73.5Hz)，6.78(1H，d，J＝5.3Hz)，7.15-7.25(1.5H，m)，7.44(0.5H，d，J＝9.0Hz)，7.59(0.5H，s)，7.80(0.5H，d，J＝9.0Hz)，8.17(1H，d，J＝5.3Hz)。

Synthetic embodiment 61

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 1-methyl piperidine-4-carboxylate

1-methyl piperidine-4-carboxylic acid 2-(methylamino) the ethyl ester dihydrochloride (0.98g) that will in reference implementation example 54, obtain is added in the oxolane (50mL), and mixture stirs a moment, to wherein adding two (trichloromethyl) carbonic esters (0.53g).After the frozen water cooling, dropwise add the tetrahydrofuran solution (50mL) of triethylamine (2.01mL), mixture at room temperature stirred 3 hours.Add ethyl acetate (100mL), mixture is with sodium bicarbonate aqueous solution (100mL) and saturated brine (80mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (0.74g), triethylamine (0.56mL) and 4-dimethylaminopyridine (0.049g), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add sodium bicarbonate aqueous solution (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=7: 3, ethyl acetate, methanol more then: ethyl acetate=1: 19 eluting) obtain the title compound (0.78g) into the yellow green amorphous solid through the alkaline silica gel purified.

¹H-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＝5.6Hz)，7.36-7.47(3H，m)，7.84(1H，d，J＝7.8Hz)，8.35(1H，d，J＝5.6Hz)。

Synthetic embodiment 62

2-[[4-(amino carbonyl) phenyl] [[(R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate

Under the frozen water cooling; In the tetrahydrofuran solution (20mL) of two (trichloromethyl) carbonic ester (0.45g), dropwise be added in 2-[[4-(amino carbonyl) phenyl] amino] ethylhexoate (0.67g) that obtains in the reference implementation example 55 and the tetrahydrofuran solution (10mL) of triethylamine (0.63mL), mixture at room temperature stirred 1 hour.Behind the concentrating under reduced pressure, in residue, add entry (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with 0.2N hydrochloric acid (20mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (30mL).Add (R)-2-[[[3-methyl-4-(2; 2; The 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.11g), triethylamine (0.63mL) and 4-dimethylaminopyridine (0.037g), mixture stirred 30 minutes down at 60 ℃, at room temperature stirred overnight.Behind the concentrating under reduced pressure, in residue, add sodium bicarbonate aqueous solution (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (1.26g) into yellow amorphous solid through alkaline silica gel purified (using ethyl acetate: hexane=4: 6,6: 4 then, 8: 2 eluting again).

¹H-NMR(CDCl ₃)：1.99(3H，s)，2.26(3H，s)，4.15-4.55(4H，m)，4.41(2H，q，J＝7.9Hz)，4.80-5.20(2H，br)，6.69(1H，d，J＝5.7Hz)，7.26-7.38(3H，m)，7.48(2H，d，J＝8.9Hz)，7.54(2H，d，J＝8.9Hz)，7.66-7.73(1H，m)，8.39(1H，d，J＝5.7Hz)。

Synthetic embodiment 63

2-[methyl [[(R)-and 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethyl 1-methyl-4-piperidyl carbonic ester

2-(methylamino) the ethyl 1-methyl-4-piperidyl carbonic ester dihydrochloride (1.01g) that will in reference implementation example 56, obtain is added in the oxolane (30mL); Stir moments later; Add refrigerative two (trichloromethyl) carbonic esters (0.69g) of frozen water, dropwise add the tetrahydrofuran solution (10mL) of triethylamine (1.95mL) again.Under the frozen water cooling, stirred 1 hour, at room temperature stirred 1 hour, remove by filter the solid of separating out.Behind the concentrating under reduced pressure, add ethyl acetate (50mL), mixture is with refrigerative sodium bicarbonate aqueous solution of frozen water (50mL) and saturated brine (50mL) washing, anhydrous magnesium sulfate drying.This layer concentrating under reduced pressure is dissolved in residue in the oxolane (20mL).Add (R)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (1.11g), triethylamine (0.63mL) and 4-dimethylaminopyridine (0.037g), mixture is 60 ℃ of following stirred overnight.Behind the concentrating under reduced pressure, in residue, add sodium bicarbonate aqueous solution (50mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (50mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=1: 1, ethyl acetate, methanol more then: ethyl acetate=1: 19 eluting) obtain the title compound (0.70g) into yellow amorphous solid through the alkaline silica gel purified.

¹H-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＝7.9Hz)，4.44(2H，m)，4.60-4.74(1H，m)，4.80-5.15(2H，br)，6.65(1H，d，J＝5.9Hz)，7.35-7.52(3H，m)，7.84(1H，d，J＝7.5Hz)，8.35(1H，d，J＝5.9Hz)。

Synthetic embodiment 64

2-[[4-(amino carbonyl) phenyl] [[2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole-1-yl] carbonyl] amino] ethylhexoate

Under the frozen water cooling; In the tetrahydrofuran solution (5mL) of two (trichloromethyl) carbonic ester (0.12g), dropwise be added in the tetrahydrofuran solution (5mL) of 2-[[4-(amino carbonyl) phenyl] amino] ethylhexoate (0.22g) that obtains in the reference implementation example 55 and triethylamine (0.17mL), mixture at room temperature stirred 30 minutes.Add entry (20mL), mixture extracts with ethyl acetate (30mL).Ethyl acetate layer is with saturated brine (20mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue is dissolved in the oxolane (10mL).Add 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole (0.37g), triethylamine (0.28mL) and 4-dimethylaminopyridine (0.012g), mixture stirred 1 hour down at 60 ℃.Behind the concentrating under reduced pressure, in residue, add sodium bicarbonate aqueous solution (20mL), mixture extracts with ethyl acetate (30mL).Ethyl acetate layer is with saturated brine (20mL) washing, anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, residue obtains the title compound (0.34g) into light yellow amorphous solid through alkaline silica gel purified (using ethyl acetate: hexane=3: 7,5: 5 then, 8: 2 eluting again).

¹H-NMR(CDCl ₃)：1.99(3H，s)，2.26(3H，s)，4.15-4.55(4H，m)，4.41(2H，q，J＝7.9Hz)，4.80-5.20(2H，br)，6.69(1H，d，J＝5.9Hz)，7.26-7.40(3H，m)，7.47(2H，d，J＝8.8Hz)，7.54(2H，d，J＝8.8Hz)，7.65-7.74(1H，m)，8.38(1H，d，J＝5.9?Hz)。

Synthetic embodiment 65

(-)-ethyl 2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-3H-imidazo [4,5-b] pyridin-3-yl] carbonyl] (methyl) amino] ethyl carbonate ester

Will be according to synthetic 5-methoxyl group-2-[[(the 4-methoxyl group-3 that obtains of method that is described among the JP-A-63-146882; 5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-imidazo [4; 5-b] pyridine handles with preparation property HPLC and carries out optical resolution, obtains its (-) optical siomerism form (0.10g).In the tetrahydrofuran solution (5mL) of this form, be added in ethyl 2-[(chloroformyl) (methyl) amino] the ethyl carbonate ester (0.081g), triethylamine (0.080mL) and the 4-dimethylaminopyridine (0.007g) that obtain in the reference implementation example 34, mixture stirred 18 hours down at 50 ℃.Behind the concentrating under reduced pressure, in residue, add entry (30mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous sodium sulfate drying.Behind the concentrating under reduced pressure, residue (is used ethyl acetate: hexane=2: 1 eluting) obtain the title compound (0.053g) into colorless oil through the alkaline silica gel purified.

¹H-NMR (CDCl ₃): 1.30 (3H, t, J=7.1Hz), 2.24 (6H, s), 3.15,3.32 (whole 3H, s), 3.73 (3H; S), 3.90-4.55 (9H, m), 4.85 (1H, d, J=13.2Hz), 4.97 (1H, d, J=13.2Hz); 6.80 (1H, d, J=8.8Hz), 7.96 (1H, d, J=8.8Hz), 8.23 (1H, s).

Synthetic embodiment 66

(+)-ethyl 2-[[[5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-3H-imidazo [4,5-b] pyridin-3-yl] carbonyl] (methyl) amino] ethyl carbonate ester

Will be according to synthetic 5-methoxyl group-2-[[(the 4-methoxyl group-3 that obtains of method that is described among the JP-A-63-146882; 5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-imidazo [4; 5-b] pyridine handles with preparation property HPLC and carries out optical resolution, obtains its (+) optical siomerism form (0.10g).In the tetrahydrofuran solution (5mL) of this form, be added in ethyl 2-[(chloroformyl) (methyl) amino] the ethyl carbonate ester (0.081g), triethylamine (0.080mL) and the 4-dimethylaminopyridine (0.007g) that obtain in the reference implementation example 34, mixture stirred 18 hours down at 50 ℃.Behind the concentrating under reduced pressure, in residue, add entry (30mL), mixture extracts with ethyl acetate (50mL).Ethyl acetate layer is with saturated brine (30mL) washing, anhydrous sodium sulfate drying.Behind the concentrating under reduced pressure; Residue (is used ethyl acetate: hexane=2: 1 eluting) obtain title compound and (+)-ethyl 2-[[[5-methoxyl group-2-[[(4-methoxyl group-3 into colorless oil through the alkaline silica gel purified; 5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-imidazo [4,5-b] pyridine-1-yl] carbonyl] (methyl) amino] 2: 1 mixture (0.115g) of ethyl carbonate ester.

¹H-NMR (CDCl ₃): 1.20-1.38 (3H, m), 2.24 (6H, s), 3.08,3.15,3.33 (whole 3H, s), 3.73 (3H; S), and 3.88-4.55 (9H, m), 4.78-5.05 (2H, m), 6.80,6.86 (1H, d; J=8.8Hz), 7.76,7.96 (1H, d, J=8.8Hz), 8.21,8.22 (whole 1H, s).

Embodiment 1

With following component: 247.7g lansoprazole R-isomer (back literary composition is called ' compd A '), 184.6g magnesium carbonate, 492.2g purify that the low substituted hydroxypropyl cellulose of sucrose, 299.9g corn starch and 329.6g is evenly mixed to obtain dusting (dusting powder).With 880g sucrose spherex (trade name: Nonpareil-101; Freund Industrial Co., Ltd. makes) insert centrifugal liquid bed granulator (CF-360, Freund Industrial Co.; Ltd. make) in; In spraying hydroxypropyl cellulose solution (2w/w%), with the sucrose spherex with above-mentioned dusting coating, thereby prepare the microsphere particle agent.This microsphere particle agent obtains the granule of 710 μ m-1400 μ m then 40 ℃ of following vacuum dryings 16 hours through circular sieve.

300.0mg the composition of above-mentioned granule

Sucrose spherex 110.0mg

Compd A 30.0mg

Magnesium carbonate 22.4mg

Purify sucrose 59.8mg

Corn starch 36.4mg

Low substituted hydroxypropyl cellulose 40.0mg

Hydroxypropyl cellulose 1.4mg

Total amount 300.0mg

Embodiment 2

25g Macrogol 6000 and 10g polysorbate80 are dissolved in during 1206g purifies waste water, in resulting solution, disperse 78g Talcum, 25g titanium oxide and 866.7g EUDRAGIT S100 LD (solid concentration is 260g) to obtain enteric coating solution.The granule that will in embodiment 1, obtain is with above-mentioned enteric coating soln using forced fluidized bed granulator (SPIR-A-FLOW; Freund Industrial Co., Ltd. makes) coating under following condition: import temperature: 45 ℃, rotary speed of rotator: 200rpm, coating solution spray speed: 3.8g/ minute and spray pressure: 1.0kg/cm ², then when it is through circular sieve, carry out the enteric coating granule that drying obtains having 710 μ m-1400 μ m of following composition.Resulting microsphere particle agent was 40 ℃ of following vacuum dryings 16 hours.

369.2mg the composition of above-mentioned enteric coating granule

The granule 300.0mg of embodiment 1

The methyl acid copolymer LD 148.7mg that holds one's breath

(solid concentration is 44.6mg)

Talcum 13.8mg

Macrogol?6000 4.4mg

Titanium oxide 4.4mg

Polysorbate80 2.0mg

Total amount 369.2mg

Embodiment 3

With 36g EUDRAGIT S100 S, 12g EUDRAGIT S100 L and 4.8g triethyl citrate be dissolved in purify waste water (69.12g) and the mixed solution of dehydrated alcohol (622.08g) in, in resulting solution, disperse the 24g Talcum to obtain coating solution.The enteric coating granule that 100g is obtained in embodiment 2 is with above-mentioned enteric coating soln using forced fluidized bed granulator (SPIR-A-FLOW; FreundIndustrial Co., Ltd. makes) coating under following condition: import temperature: 30 ℃, rotary speed of rotator: 150rpm, coating solution spray speed: 3.3g/ minute and spray pressure: 1.0kg/cm ², obtain having the controlled release granule of following composition, it is used by the controlled release coat layer of pH decision solubility (disengaging active component surpassing under the environment of certain pH value) coating.Resulting microsphere particle agent obtains the controlled release granule of 710 μ m-1400 μ m through circular sieve.Then with resulting microsphere particle agent 40 ℃ of following vacuum dryings 16 hours.

605.5mg the composition of above-mentioned controlled release granule

The enteric coating granule 369.2mg of embodiment 2

EUDRAGIT S100 S 110.8mg

EUDRAGIT S100 L 36.9mg

Talcum 73.8mg

Triethyl citrate 14.8mg

Total amount 605.5mg

Embodiment 4

With 24g EUDRAGIT S100 S, 24g EUDRAGIT S100 L and 4.8g triethyl citrate be dissolved in purify waste water (69.12g) and the mixed solution of dehydrated alcohol (622.08g) in, in resulting solution, disperse the 24g Talcum to obtain coating solution.The enteric coating granule that 100g is obtained in embodiment 2 is with above-mentioned enteric coating soln using forced fluidized bed granulator (SPIR-A-FLOW; FreundIndustrial Co., Ltd. makes) coating under following condition: import temperature: 30 ℃, rotary speed of rotator: 150rpm, coating solution spray speed: 3.3g/ minute and spray pressure: 1.0kg/cm ², obtain having the controlled release granule of following composition, it is used by the controlled release coat layer of pH decision solubility (disengaging active component surpassing under the environment of certain pH value) coating.Resulting microsphere particle agent obtains the controlled release granule of 710 μ m-1400 μ m through circular sieve.Then with resulting microsphere particle agent 40 ℃ of following vacuum dryings 16 hours.

605.5mg the composition of above-mentioned controlled release granule

The enteric coating granule 369.2mg of embodiment 2

EUDRAGIT S100 S 73.85mg

EUDRAGIT S100 L 73.85mg

Talcum 73.8mg

Triethyl citrate 14.8mg

Total amount 605.5mg

Embodiment 5

The controlled release granule that enteric coating granule that 104mg is obtained in embodiment 2 and 500mg obtain in embodiment 3 is mixed; To wherein adding 205mg PEO (trade name: Polyox WSRCoagulant; Dow Chemical Co., Ltd. makes) obtain mixture.Resulting mixture is inserted among two pieces of capsule #0 and is obtained capsule.

Embodiment 6

The controlled release granule that enteric coating granule that 104mg is obtained in embodiment 2 and 500mg obtain in embodiment 4 is mixed; To wherein adding 205mg PEO (trade name: Polyox WSRCoagulant; Dow Chemical Co., Ltd. makes) obtain mixture.Resulting mixture is inserted among two pieces of capsule #0 and is obtained capsule.

Embodiment 7

300g compd A, 105g magnesium carbonate, 195g are purified sucrose and the evenly mixed dusting that obtains being used for the active component layer of the low substituted hydroxypropyl cellulose of 75g.75g is purified the evenly mixed dusting that obtains being used for the intermediate layer of the low substituted hydroxypropyl cellulose of sucrose, 48.8g titanium oxide and 18.8g.With 375g sucrose spherex (trade name: Nonpareil-101; Freund Industrial Co., Ltd. makes) insert centrifugal liquid bed granulator (CF-360, Freund Industrial Co.; Ltd. make) in; In spraying hydroxypropyl cellulose solution (2w/w%), the sucrose spherex with the above-mentioned dusting coating that is used for the active component layer, is prepared the microsphere particle agent like this.Then, in spraying hydroxypropyl cellulose solution (2 w/w%), resulting microsphere particle agent is obtained the microsphere particle agent with the above-mentioned dusting coating that is used for the intermediate layer.Resulting microsphere particle agent obtains the dusting of 710 μ m-1400 μ m 40 ℃ of following vacuum dryings 16 hours through circular sieve.

120.0mg the composition of above-mentioned granule

Sucrose spherex 37.5mg

Hydroxypropyl cellulose 0.75mg

Be used for the dusting of active component layer

Compd A 30.0mg

Magnesium carbonate 10.5mg

Purify sucrose 19.5mg

Low substituted hydroxypropyl cellulose 7.5mg

Be used for the dusting in intermediate layer

Purify sucrose 7.5mg

Low substituted hydroxypropyl cellulose 1.875mg

Titanium oxide 4.875mg

Total amount 120.0mg

Embodiment 8

25g Macrogol 6000 and 10g polysorbate80 are dissolved in during 1206g purifies waste water, in resulting solution, disperse 78g Talcum, 25g titanium oxide and 866.7g EUDRAGIT S100 LD (solid concentration is 260g) to obtain enteric coating solution.The granule that will in embodiment 7, obtain is with above-mentioned enteric coating soln using forced fluidized bed granulator (SPIR-A-FLOW; Freund Industrial Co., Ltd. makes) coating under following condition: import temperature: 45 ℃, rotary speed of rotator: 200rpm, coating solution spray speed: 3.8g/ minute and spray pressure: 1.0kg/cm ², when it is through circular sieve, carry out the 710 μ m-1400 μ m enteric coating granules that drying obtains having following composition then.Resulting microsphere particle agent was 40 ℃ of vacuum dryings 16 hours.

149.86mg the composition of above-mentioned enteric coating granule

The granule 120.00mg of embodiment 7

EUDRAGIT S100 LD 65mg

(solid concentration is 19.5mg)

Talcum 5.85mg

Macrogol?6000 1.88mg

Titanium oxide 1.88mg

Polysorbate80 0.75mg

Total amount 149.86mg

Embodiment 9

With 36g EUDRAGIT S100 S, 12g EUDRAGIT S100 L and 4.8g triethyl citrate be dissolved in purify waste water (69.12g) and the mixed solution of dehydrated alcohol (622.08g) in, in resulting solution, disperse the 24g Talcum to obtain coating solution.The enteric coating granule that 100g is obtained in embodiment 8 is with above-mentioned coating soln using forced fluidized bed granulator (SPIR-A-FLOW; FreundIndustrial Co., Ltd. makes) coating under following condition: import temperature: 30 ℃, rotary speed of rotator: 150rpm, coating solution spray speed: 3.3g/ minute and spray pressure: 1.0kg/cm ², obtain having the controlled release granule of following composition, it is used by the controlled release coat layer of pH decision solubility (disengaging active component surpassing under the environment of certain pH value) coating.Resulting microsphere particle agent obtains the controlled release granule of 710 μ m-1400 μ m through circular sieve.Then with resulting microsphere particle agent 40 ℃ of following vacuum dryings 16 hours.

245.86mg the composition of above-mentioned controlled release granule

The enteric coating granule 149.86mg of embodiment 8

EUDRAGIT S100 S 45.00mg

EUDRAGIT S100 L 15.00mg

Talcum 30.00mg

Triethyl citrate 6.00mg

Total amount 245.86mg

Embodiment 10

With 24g EUDRAGIT S100 S, 24g EUDRAGIT S100 L and 4.8g triethyl citrate be dissolved in purify waste water (69.12g) and the mixed solution of dehydrated alcohol (622.08g) in, in resulting solution, disperse the 24g Talcum to obtain coating solution.The enteric coating granule that 100g is obtained in embodiment 8 is with above-mentioned coating soln using forced fluidized bed granulator (SPIR-A-FLOW; FreundIndustrial Co., Ltd. makes) coating under following condition: import temperature: 30 ℃, rotary speed of rotator: 150rpm, coating solution spray speed: 3.3g/ minute and spray pressure: 1.0kg/cm ², obtain having the controlled release granule of following composition, it is used by the controlled release coat layer of pH decision solubility (disengaging active component surpassing under the environment of certain pH value) coating.Resulting microsphere particle agent obtains the controlled release granule of 710 μ m-1400 μ m through circular sieve.Then with resulting microsphere particle agent 40 ℃ of following vacuum dryings 16 hours.

245.86mg the composition of above-mentioned controlled release granule

The enteric coating granule 149.86mg of embodiment 8

EUDRAGIT S100 S 30.00mg

EUDRAGIT S100 L 30.00mg

Talcum 30.00mg

Triethyl citrate 6.00mg

Total amount 245.86mg

Embodiment 11

The controlled release granule that enteric coating granule that 35.5mg is obtained in embodiment 8 and 175mg obtain in embodiment 9 is mixed; To wherein adding 70.2mg PEO (trade name: PolyoxWSR Coagulant; Dow Chemical Co., Ltd. makes) obtain mixture.Resulting mixture is inserted and is obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #1.

Embodiment 12

The controlled release granule that enteric coating granule that 35.5mg is obtained in embodiment 8 and 175mg obtain in embodiment 10 is mixed; To wherein adding 70.2mg PEO (trade name: PolyoxWSR Coagulant; Dow Chemical Co., Ltd. makes) obtain mixture.Resulting mixture is inserted and is obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #1.

Test example 1

Use the 30ml mouth of a river to obey the capsule that administration obtains in embodiment 5 to the Bi Erge of fasting dog (beagle dog).When 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours, the PC of compd A is respectively 186ng/mL, 132ng/mL, 107ng/mL, 303ng/mL, 355ng/mL, 216ng/mL and 113ng/mL after administration.

Test example 2

Use the 30ml mouth of a river to obey the capsule that administration obtains in embodiment 6 to the Bi Erge of fasting dog.When 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours, the PC of compd A is respectively 192ng/mL, 137ng/mL, 473ng/mL, 478ng/mL, 364ng/mL, 257ng/mL and 28ng/mL after administration.

Test example 3

Use the 30ml mouth of a river to obey the capsule that administration obtains in embodiment 11 to the Bi Erge of fasting dog.When 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours, the PC of compd A is respectively 308ng/mL, 245ng/mL, 323ng/mL, 81ng/mL, 39ng/mL, 26ng/mL and 0ng/mL after administration.

Test example 24

Use the 30ml mouth of a river to obey the capsule that administration obtains in embodiment 12 to the Bi Erge of fasting dog.When 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours, the PC of compd A is respectively 160ng/mL, 319ng/mL, 631ng/mL, 371ng/mL, 230ng/mL, 144ng/mL and 25ng/mL after administration.

Embodiment 13

221.86mg the composition of above-mentioned controlled release granule

The enteric coating granule 149.86mg of embodiment 8

EUDRAGIT S100 S 33.75mg

EUDRAGIT S100 L 11.25mg

Talcum 22.5mg

Triethyl citrate 4.5mg

Total amount 221.86mg

Embodiment 14

221.86mg the composition of above-mentioned controlled release granule

The enteric coating granule 149.86mg of embodiment 8

EUDRAGIT S100 S 22.5mg

EUDRAGIT S100 L 22.5mg

Talcum 22.5mg

Triethyl citrate 4.5mg

Total amount 221.86mg

Embodiment 15

The controlled release granule that enteric coating granule that 35.5mg is obtained in embodiment 8 and 168mg obtain in embodiment 13 is mixed; To wherein adding 68.2mg PEO (trade name: PolyoxWSR Coagulant; Dow Chemical Co., Ltd. makes) obtain mixture.Resulting mixture is inserted and is obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #1.

Embodiment 16

The controlled release granule that enteric coating granule that 35.5mg is obtained in embodiment 8 and 168mg obtain in embodiment 14 is mixed; To wherein adding 68.2mg PEO (trade name: PolyoxWSR Coagulant; Dow Chemical Co., Ltd. makes) obtain mixture.Resulting mixture is inserted and is obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #1.

Embodiment 17

The controlled release granule that enteric coating granule that 35.5mg is obtained in embodiment 8 and 168mg obtain in embodiment 13 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #3.

Embodiment 18

The controlled release granule that enteric coating granule that 35.5mg is obtained in embodiment 8 and 168mg obtain in embodiment 14 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #3.

Test example 5

Use the 30ml mouth of a river to obey the capsule that administration obtains in embodiment 14 to the Bi Erge of fasting dog.When 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours, the PC of compd A is respectively 403ng/mL, 687ng/mL, 803ng/mL, 463ng/mL, 329ng/mL, 217ng/mL and 65ng/mL after administration.

Embodiment 19

The granule that 100g obtains in embodiment 1 is inserted centrifugal liquid bed granulator (CF-mini; Freund Industrial Co.; Ltd. make); When the spraying hydroxypropyl cellulose was dissolved in the solution in the isopropyl alcohol (8w/w%), the Ac-Di-Sol that on this granule, is used as disintegrating agent carried out coating with the ratio that accounts for granule 32 w/w%, thereby obtains microsphere particle agent (sphereical granule).This microsphere particle agent obtains 1400 μ m or littler granule 40 ℃ of following vacuum dryings 16 hours through circular sieve.

Embodiment 20

24g ylmethyl acrylic-amino alkyl ester copolymer RS is dissolved in acetone (120g) and the isopropyl alcohol (288g), in resulting solution, disperses the 48g Talcum to obtain coating solution.The granule that 100g is obtained in embodiment 19 is with above-mentioned coating soln using forced fluidized bed granulator (SPIR-A-FLOW; Freund Industrial Co., Ltd. makes) coating under following condition: import temperature: 30 ℃, rotary speed of rotator: 150rpm, coating solution spray speed: 3.1g/ minute and spray pressure: 1.0kg/cm ², obtain having the controlled release granule of following composition.Resulting microsphere particle agent obtains the controlled release granule of 710 μ m-1700 μ m through circular sieve.Then with resulting microsphere particle agent 40 ℃ of following vacuum dryings 16 hours.

130.0mg the composition of above-mentioned controlled release granule

The granule 100mg of embodiment 19

EudragitRS PO EUDRAGIT RSPO eudragit RS-100 eudragit RS-PO 10.0mg

Talcum 20.0mg

Total amount 130.0mg

Embodiment 21

The controlled release granule that enteric coating granule that 104mg is obtained in embodiment 2 and 420mg obtain in embodiment 20 is mixed; To wherein adding 175mg PEO (trade name: PolyoxWSR Coagulant; Dow Chemical Co., Ltd. makes) obtain mixture.Resulting mixture is inserted and is obtained capsule (being equivalent to the 30mg compd A) among two pieces of gel capsule #0.

Embodiment 22

The controlled release granule that enteric coating granule that 104mg is obtained in embodiment 2 and 420mg obtain in embodiment 20 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 30mg compd A) among two pieces of gel capsule #0.

Test example 6

Use the 30ml mouth of a river to obey the capsule that administration obtains in embodiment 21 to the Bi Erge of fasting dog.When 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours, the PC of compd A is respectively 657ng/mL, 406ng/mL, 223ng/mL, 504ng/mL, 399ng/mL, 228ng/mL and 50ng/mL after administration.

Embodiment 23

With 36g EUDRAGIT S100 S, 12g EUDRAGIT S100 L and 4.8g triethyl citrate be dissolved in purify waste water (69.12g) and the mixed solution of dehydrated alcohol (622.08g) in, in resulting solution, disperse the 24g Talcum to obtain coating solution.The granule that 100g is obtained in embodiment 19 is with above-mentioned coating soln using forced fluidized bed granulator (SPIR-A-FLOW; Freund Industrial Co., Ltd. makes) coating under following condition: import temperature: 30 ℃, rotary speed of rotator: 150rpm, coating solution spray speed: 3.3g/ minute and spray pressure: 1.0kg/cm ², obtain having the controlled release granule of following composition.Resulting microsphere particle agent obtains the controlled release granule of 710 μ m-1700 μ m through circular sieve.Then with resulting microsphere particle agent 40 ℃ of following vacuum dryings 16 hours.164.0mg the composition of above-mentioned controlled release granule

Embodiment 24

The controlled release granule that enteric coating granule that 104mg is obtained in embodiment 2 and 614mg obtain in embodiment 23 is mixed; To wherein adding 239mg PEO (trade name: Polyox WSR Coagulant; Dow Chemical Co., Ltd. makes) obtain mixture.Resulting mixture is inserted and is obtained capsule (being equivalent to the 30mg compd A) among two pieces of gel capsule #0.

Embodiment 25

Test example 7

Use the 30ml mouth of a river to obey the capsule that administration obtains in embodiment 24 to the Bi Erge of fasting dog.When 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours, the PC of compd A is respectively 106ng/mL, 135ng/mL, 639ng/mL, 129ng/mL, 49ng/mL, 16ng/mL and 0ng/mL after administration.

The comparative example 1

Obey one piece of gel #0 (it is filled with 414mg enteric coating granule) that administration obtains to the Bi Erge of the fasting dog use 30ml mouth of a river in embodiment 2.When 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours, the PC of compd A is respectively 2,068ng/mL, 689ng/mL, 70ng/mL, 0ng/mL, 0ng/mL, 0ng/mL and 0ng/mL after administration.

Embodiment 26

The low substituted hydroxypropyl cellulose of 150g compd A, 50g magnesium carbonate, 25g and 25g hydroxypropyl cellulose are suspended in 1420g obtain spray solution in purifying waste water.200g crystalline cellulose (microsphere) is inserted forced fluidized bed granulator (SPIR-A-FLOW; Freund Industrial Co.; Ltd. make) in, spray under following condition with above-mentioned spray solution: import temperature: 62 ℃, rotary speed of rotator: 300rpm, coating solution spray speed: 10g/ minute and spray pressure: 1.0kg/cm ²Obtain having the microsphere particle agent of following composition.Resulting microsphere particle agent obtains the controlled release granule of 500 μ m-1400 μ m then at 40 ℃ of vacuum dryings through circular sieve.

41.24mg the composition of above-mentioned granule

Crystalline cellulose (microsphere) 22.5mg

Compd A 11.25mg

Magnesium carbonate 3.75mg

Low substituted hydroxypropyl cellulose 10.0mg

Hydroxypropyl cellulose 1.87mg

Total amount 41.24mg

Embodiment 27

90g compd A, 31.5g magnesium carbonate, 58.5g are purified sucrose and the evenly mixed dusting that obtains being used for the active component layer of the low substituted hydroxypropyl cellulose of 22.5g.The granule that 110g obtains in embodiment 26 is inserted centrifugal liquid bed granulator (CF-mini; Freund Industrial Co.; Ltd. make) in; Then in spraying hydroxypropyl cellulose solution (2w/w%) with the dusting coating of above-mentioned active component layer, thereby obtain having the microsphere particle agent of following composition.Resulting microsphere particle agent obtains the granule of 710 μ m-1400 μ m then 40 ℃ of following vacuum dryings 16 hours through circular sieve.

118.03mg the composition of above-mentioned granule

The granule 41.25mg of embodiment 26

Compd A 33.75mg

Magnesium carbonate 11.81mg

Purify sucrose 21.94mg

Low substituted hydroxypropyl cellulose 8.44mg

Hydroxypropyl cellulose 0.84mg

Total amount 118.03mg

Embodiment 28

The granule that will in embodiment 27, obtain is used for coating soln using forced fluidized bed granulator (Ltd. makes for SPIR-A-FLOW, the Freund Industrial Co.) coating in intermediate layer, and complete then drying obtains having the granule of following composition.361.55g's this coating solution that is used for the intermediate layer purifies waste water and then in resulting solution, disperse 8.03g titanium oxide and 12.05g Talcum to obtain through the 20.09g METHOCEL E15LV is dissolved in.Coating operates under the following condition and carries out: import temperature: 62 ℃, rotary speed of rotator: 200rpm, coating solution spray speed: 3.0g/ minute and spray pressure: 1.0kg/cm ²Resulting microsphere particle agent obtains the granule of 710 μ m-1400 μ m then 40 ℃ of following vacuum dryings 16 hours through circular sieve.

133.03mg above-mentioned composition with intermediate layer coated granules agent

The granule 118.03mg of embodiment 27

METHOCEL E15LV 7.5mg

Talcum 4.5mg

Titanium oxide 3.0mg

Total amount 133.03mg

Embodiment 29

25g Macrogol 6000 and 10g polysorbate80 are dissolved in during 1206g purifies waste water, in resulting solution, disperse 78g Talcum, 25g titanium oxide and 866.7g EUDRAGIT S100 LD (solid concentration is 260g) to obtain enteric coating solution.The granule that will in embodiment 28, obtain is with above-mentioned enteric coating soln using forced fluidized bed granulator (SPIR-A-FLOW; Freund Industrial Co., Ltd. makes) coating under following condition: import temperature: 45 ℃, rotary speed of rotator: 200rpm, coating solution spray speed: 3.8g/ minute and spray pressure: 1.0kg/cm ², then when it is through circular sieve, carry out the enteric coating granule that drying obtains having 710 μ m-1400 μ m of following composition.Resulting microsphere particle agent was 40 ℃ of following vacuum dryings 16 hours.

165.18mg the composition of above-mentioned enteric coating granule

Embodiment 30

With 36g EUDRAGIT S100 S, 12g EUDRAGIT S100 L and 4.8g triethyl citrate be dissolved in purify waste water (69.12g) and the mixed solution of dehydrated alcohol (622.08g) in, in resulting solution, disperse the 24g Talcum to obtain coating solution.The granule that 100g is obtained in embodiment 28 is with above-mentioned coating soln using forced fluidized bed granulator (SPIR-A-FLOW; Freund Industrial Co., Ltd. makes) coating under following condition: import temperature: 30 ℃, rotary speed of rotator: 100rpm, coating solution spray speed: 3.0g/ minute and spray pressure: 1.0kg/cm ², obtaining having the controlled release granule of following composition, it is used by the controlled release coat layer of pH decision solubility (disengaging active component surpassing under the environment of certain pH value) and has carried out coating.Resulting microsphere particle agent obtains the controlled release granule of 1180 μ m-1700 μ m through circular sieve.Then with resulting microsphere particle agent 40 ℃ of following vacuum dryings 16 hours.

196.88mg the composition of above-mentioned controlled release granule

Embodiment 31

With 24g EUDRAGIT S100 S, 24g EUDRAGIT S100 L and 4.8g triethyl citrate be dissolved in purify waste water (69.12g) and the mixed solution of dehydrated alcohol (622.08g) in, in resulting solution, disperse the 24g Talcum to obtain coating solution.The granule that 100g is obtained in embodiment 28 is with above-mentioned coating soln using forced fluidized bed granulator (SPIR-A-FLOW; Freund Industrial Co., Ltd. makes) coating under following condition: import temperature: 30 ℃, rotary speed of rotator: 100rpm, coating solution spray speed: 3.0g/ minute and spray pressure: 1.0kg/cm ², obtaining having the controlled release granule of following composition, it is used by the controlled release coat layer of pH decision solubility (disengaging active component surpassing under the environment of certain pH value) and has carried out coating.Resulting microsphere particle agent obtains the controlled release granule of 1180 μ m-1700 μ m through circular sieve.Then with resulting microsphere particle agent 40 ℃ of following vacuum dryings 16 hours.

196.88mg the composition of above-mentioned controlled release granule

Embodiment 32

The controlled release granule that enteric coating granule that 28mg is obtained in embodiment 29 and 98.7mg obtain in embodiment 30 is mixed; To wherein adding 42.3mg PEO (trade name: PolyoxWSR Coagulant; Dow Chemical Co., Ltd. makes) obtain mixture.Resulting mixture is inserted and is obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #1.

Embodiment 33

The controlled release granule that enteric coating granule that 28mg is obtained in embodiment 29 and 98.7mg obtain in embodiment 31 is mixed; To wherein adding 42.3mg PEO (trade name: PolyoxWSR Coagulant; Dow Chemical Co., Ltd. makes) obtain mixture.Resulting mixture is inserted and is obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #1.

Embodiment 34

The controlled release granule that enteric coating granule that 56mg is obtained in embodiment 29 and 197.4mg obtain in embodiment 30 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 60mg compd A) among one piece of capsule #2.

Embodiment 35

The controlled release granule that enteric coating granule that 84mg is obtained in embodiment 29 and 296.1mg obtain in embodiment 30 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 90mg compd A) among one piece of capsule #1.

Embodiment 36

The controlled release granule that enteric coating granule that 42mg is obtained in embodiment 29 and 148.05mg obtain in embodiment 30 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 45mg compd A) among one piece of capsule #3.

Embodiment 37

With 48g EUDRAGIT S100 S and 4.8g triethyl citrate be dissolved in purify waste water (69.12g) and the mixed solution of dehydrated alcohol (622.08g) in, in resulting solution, disperse the 24g Talcum to obtain coating solution.The granule that 100g is obtained in embodiment 30 is with above-mentioned enteric coating soln using forced fluidized bed granulator (SPIR-A-FLOW; Freund Industrial Co., Ltd. makes) coating under following condition: import temperature: 30 ℃, rotary speed of rotator: 100rpm, coating solution spray speed: 3.0g/ minute and spray pressure: 1.0kg/cm ², obtain having the controlled release granule of following composition, it is used by the controlled release coat layer of pH decision solubility (disengaging active component surpassing under the environment of certain pH value) coating.Resulting microsphere particle agent obtains the controlled release granule of 1180 μ m-1700 μ m through circular sieve.Then with resulting microsphere particle agent 40 ℃ of following vacuum dryings 16 hours.

207.52mg the composition of above-mentioned controlled release granule

The granule 196.88mg of embodiment 30

EUDRAGIT S100 S 6.65mg

Talcum 3.32mg

Triethyl citrate 0.67mg

Total amount 207.52mg

Embodiment 38

With 48g EUDRAGIT S100 S and 4.8g triethyl citrate be dissolved in purify waste water (69.12g) and the mixed solution of dehydrated alcohol (622.08g) in, in resulting solution, disperse the 24g Talcum to obtain coating solution.The granule that 100g is obtained in embodiment 31 is with above-mentioned enteric coating soln using forced fluidized bed granulator (SPIR-A-FLOW; Freund Industrial Co., Ltd. makes) coating under following condition: import temperature: 30 ℃, rotary speed of rotator: 150rpm, coating solution spray speed: 3.3g/ minute and spray pressure: 1.0kg/cm ², obtain having the controlled release granule of following composition, it is used by the controlled release coat layer of pH decision solubility (disengaging active component surpassing under the environment of certain pH value) coating.Resulting microsphere particle agent obtains the controlled release granule of 1180 μ m-1700 μ m through circular sieve.Then with resulting microsphere particle agent 40 ℃ of following vacuum dryings 16 hours.

207.52mg the composition of above-mentioned controlled release granule

The granule 196.88mg of embodiment 31

EUDRAGIT S100 S 6.65mg

Talcum 3.32mg

Triethyl citrate 0.67mg

Total amount 207.52mg

Embodiment 39

The controlled release granule that enteric coating granule that 28mg is obtained in embodiment 29 and 103.8mg obtain in embodiment 37 is mixed; To wherein adding 43.9mg PEO (trade name: PolyoxWSR Coagulant; Dow Chemical Co., Ltd. makes) obtain mixture.Resulting mixture is inserted and is obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #1.

Embodiment 40

The controlled release granule that enteric coating granule that 28mg is obtained in embodiment 29 and 103.8mg obtain in embodiment 38 is mixed; To wherein adding 43.9mg PEO (trade name: PolyoxWSR Coagulant; Dow Chemicai Co., Ltd. makes) obtain mixture.Resulting mixture is inserted and is obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #1.

Embodiment 41

The controlled release granule that enteric coating granule that 56mg is obtained in embodiment 29 and 207.5mg obtain in embodiment 37 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 60mg compd A) among one piece of capsule #2.

Embodiment 42

The controlled release granule that enteric coating granule that 84mg is obtained in embodiment 29 and 311.3mg obtain in embodiment 37 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 90mg compd A) among one piece of capsule #1.

Embodiment 43

The controlled release granule that enteric coating granule that 42mg is obtained in embodiment 29 and 155.6mg obtain in embodiment 37 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 45mg compd A) among one piece of capsule #3.

Embodiment 44

300g compd A, 105g magnesium carbonate, 195g are purified sucrose and the evenly mixed dusting that obtains being used for the active component layer of the low substituted hydroxypropyl cellulose of 75g.75g is purified the evenly mixed dusting that obtains being used for the intermediate layer of the low substituted hydroxypropyl cellulose of sucrose, 48.8g titanium oxide and 18.8g.With 375g sucrose spherex (trade name: Nonpareil-101; Freund Industrial Co., Ltd. makes) insert centrifugal liquid bed granulator (CF-360, Freund Industrial Co.; Ltd. make) in; In spraying hydroxypropyl cellulose solution (2w/w%), the sucrose spherex with the above-mentioned dusting coating that is used for the active component layer, is prepared the microsphere particle agent like this.Resulting microsphere particle agent obtains the dusting of 710 μ m-1400 μ m 40 ℃ of following vacuum dryings 16 hours through circular sieve.

158.07mg the composition of above-mentioned granule

Sucrose spherex 56.25mg

Hydroxypropyl cellulose 0.57mg

Be used for the dusting of active component layer

Compd A 45.00mg

Magnesium carbonate 15.75mg

Purify sucrose 29.25mg

Low substituted hydroxypropyl cellulose 11.25mg

Total amount 158.07mg

Embodiment 45

The granule that will in embodiment 44, obtain is used for coating soln using forced fluidized bed granulator (Ltd. makes for SPIR-A-FLOW, the Freund Industrial Co.) coating in intermediate layer, and complete then drying obtains having the granule of following composition.361.55g's this coating solution that is used for the intermediate layer purifies waste water and then in resulting solution, disperse 8.03g titanium oxide and 12.05g Talcum to obtain through the 20.09g METHOCEL E15LV is dissolved in.Coating operates under the following condition and carries out: import temperature: 62 ℃, rotary speed of rotator: 200rpm, coating solution spray speed: 3.0g/ minute and spray pressure: 1.0kg/cm ²Resulting microsphere particle agent obtains the granule of 710 μ m-1400 μ m then 40 ℃ of following vacuum dryings 16 hours through circular sieve.

188.07mg above-mentioned composition with intermediate layer coated granules agent

The granule 158.07mg of embodiment 44

METHOCEL E15LV 15.00mg

Talcum 9.00mg

Titanium oxide 6.00mg

Total amount 188.07mg

Embodiment 46

With 36g EUDRAGIT S100 S, 12g EUDRAGIT S100 L and 4.8g triethyl citrate be dissolved in purify waste water (69.12g) and the mixed solution of dehydrated alcohol (622.08g) in, in resulting solution, disperse the 24g Talcum to obtain coating solution.The granule that 100g is obtained in embodiment 45 is with above-mentioned coating soln using forced fluidized bed granulator (SPIR-A-FLOW; Freund Industrial Co., Ltd. makes) coating under following condition: import temperature: 30 ℃, rotary speed of rotator: 100rpm, coating solution spray speed: 3.0g/ minute and spray pressure: 1.0kg/cm ², obtain having the controlled release granule of following composition, it is used by the controlled release coat layer of pH decision solubility (disengaging active component surpassing under the environment of certain pH value) coating.Resulting microsphere particle agent obtains the controlled release granule of 1180 μ m-1700 μ m through circular sieve.Then with resulting microsphere particle agent 40 ℃ of following vacuum dryings 16 hours.

278.35mg the composition of above-mentioned controlled release granule

Embodiment 47

The controlled release granule that enteric coating granule that 35.5mg is obtained in embodiment 8 and 139.2mg obtain in embodiment 46 is mixed; To wherein adding 58.2mg PEO (trade name: Polyox WSR Coagulant; Dow Chemical Co., Ltd. makes) obtain mixture.Resulting mixture is inserted and is obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #1.

Embodiment 48

The controlled release granule that enteric coating granule that 71mg is obtained in embodiment 8 and 278.35mg obtain in embodiment 46 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 60mg compd A) among one piece of capsule #1.

Embodiment 49

The controlled release granule that enteric coating granule that 106.5mg is obtained in embodiment 8 and 417.5mg obtain in embodiment 46 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 90mg compd A) among one piece of capsule #2.

Embodiment 50

The controlled release granule that enteric coating granule that 53.3mg is obtained in embodiment 8 and 208.8mg obtain in embodiment 46 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 45mg compd A) among one piece of capsule #2.

Embodiment 51

824.4g compd A, 303.2g magnesium carbonate, 1062g are purified sucrose and the evenly mixed dusting that obtains being used for the active component layer of the low substituted hydroxypropyl cellulose of 228.2g.With 722.4g sucrose spherex (trade name: Nonpareil-101; Freund Industrial Co., Ltd. makes) insert centrifugal liquid bed granulator (CF-360, Freund Industrial Co.; Ltd. make) in; In spraying hydroxypropyl cellulose solution (2w/w%), the sucrose spherex with the above-mentioned dusting coating that is used for the active component layer, is prepared the microsphere particle agent like this.Resulting microsphere particle agent obtains the dusting of 710 μ m-1400 μ m 40 ℃ of following vacuum dryings 16 hours through circular sieve.

86.67mg the composition of above-mentioned granule

Sucrose spherex 20.64mg

Hydroxypropyl cellulose 0.24mg

Be used for the dusting of active component layer

Compd A 22.50mg

Magnesium carbonate 8.25mg

Purify sucrose 28.83mg

Low substituted hydroxypropyl cellulose 6.21mg

Total amount 86.67mg

Embodiment 52

The granule that will in embodiment 51, obtain is used for coating soln using forced fluidized bed granulator (Ltd. makes for MP-10, the Powrex Co.) coating in intermediate layer, and complete then drying obtains having the granule of following composition.4874g's this coating solution that is used for the intermediate layer purifies waste water and then in resulting solution, disperse 163.5g titanium oxide and 108g Talcum to obtain through the 270.0g METHOCEL E15LV is dissolved in.Coating operates under the following condition and carries out: import temperature: 67 ℃, charge volume: 1.5m ³/ minute, coating solution spray speed: 12.0g/ minute, spray pressure: 0.28MPa and spray gas volume: 90Nl/ hour.Resulting microsphere particle agent obtains the granule of 710 μ m-1400 μ m then 40 ℃ of following vacuum dryings 16 hours through circular sieve.

97.50mg above-mentioned composition with intermediate layer coated granules agent

The granule 86.67mg of embodiment 51

METHOCEL E15LV 5.40mg

Talcum 2.16mg

Titanium oxide 3.27mg

Total amount 97.50mg

Embodiment 53

57.60g Macrogol 6000 and 26.40g polysorbate80 are dissolved in during 2724g purifies waste water, in resulting solution, disperse 174g Talcum, 57.6g titanium oxide and 19323g EUDRAGIT S100 LD (solid concentration is 579.6g) to obtain enteric coating solution.The granule that will in embodiment 52, obtain is with above-mentioned enteric coating soln using forced fluidized bed granulator (Ltd. makes for MP-10, Powrex Co.) coating under following condition: import temperature: 65 ℃, charge volume: 1.5m ³/ minute, coating solution spray speed: 15.0g/ minute, spray pressure: 0.30MPa and spray gas volume: 90Nl/ hour.Then when it is through circular sieve, carry out drying and obtain having the enteric coating granule of 710 μ m-1400 μ m of following composition.Resulting microsphere particle agent is 40 ℃ of following vacuum dryings 16 hours, in this granule of 1918g, adds the 0.96g Talcum then and 0.96g aerosil (aerosil) obtains the enteric coating granule.

120.0mg the composition of above-mentioned enteric coating granule

The granule 97.5mg of embodiment 52

EUDRAGIT S100 LD 48.3mg

(solid concentration is 14.49mg)

Talcum 4.35mg

Macrogol?6000 1.44mg

Titanium oxide 1.44mg

Polysorbate80 0.66mg

Talcum 0.06mg

Aerosil 0.06mg

Total amount 120.0mg

Embodiment 54

1131g compd A, 303.2g magnesium carbonate, 750.1g are purified sucrose and the evenly mixed dusting that obtains being used for the active component layer of the low substituted hydroxypropyl cellulose of 226.8g.With 720.0g sucrose spherex (trade name: Nonpareil-101; Freund Industrial Co., Ltd. makes) insert centrifugal liquid bed granulator (CF-360, Freund Industrial Co.; Ltd. make) in; In spraying hydroxypropyl cellulose solution (2w/w%), the sucrose spherex with the above-mentioned dusting coating that is used for the active component layer, is prepared the microsphere particle agent like this.Resulting microsphere particle agent obtains the dusting of 710 μ m-1400 μ m 40 ℃ of following vacuum dryings 16 hours through circular sieve.

189.0mg the composition of above-mentioned granule

Sucrose spherex 45.0mg

Hydroxypropyl cellulose 0.54mg

Be used for the dusting of active component layer

Compd A 67.5mg

Magnesium carbonate 18.0mg

Purify sucrose 44.46mg

Low substituted hydroxypropyl cellulose 13.5mg

Total amount 189.0mg

Embodiment 55

The granule that will in embodiment 54, obtain is used for coating soln using forced fluidized bed granulator (Ltd. makes for MP-10, the Powrex Co.) coating in intermediate layer, and complete then drying obtains having the granule of following composition.4255g's this coating solution that is used for the intermediate layer purifies waste water and then in resulting solution, disperse 141.6g titanium oxide and 94.8g Talcum to obtain through the 236.4g METHOCEL E15LV is dissolved in.Coating operates under the following condition and carries out: import temperature: 65 ℃, charge volume: 1.5m ³/ minute, coating solution spray speed: 12.0g/ minute, spray pressure: 0.26MPa and spray gas volume: 90Nl/ hour.Resulting microsphere particle agent obtains the granule of 710 μ m-1400 μ m then 40 ℃ of following vacuum dryings 16 hours through circular sieve.

212.64mg above-mentioned composition with intermediate layer coated granules agent

Embodiment 56

With 382.8g EUDRAGIT S100 S, 127.7g EUDRAGIT S100 L and 50.88g triethyl citrate be dissolved in purify waste water (734.8g) and the mixed solution of dehydrated alcohol (6614g) in, in resulting solution, disperse the 255.1g Talcum to obtain coating solution.The granule that will in embodiment 55, obtain is with above-mentioned coating soln using forced fluidized bed granulator (Ltd. makes for MP-10, Powrex Co.) coating under following condition: import temperature: 65 ℃, charge volume: 1.5m ³/ minute, coating solution spray speed: 15.0g/ minute, spray pressure: 0.30MPa and spray gas volume: 90Nl/ hour; Obtain having the controlled release granule of following composition, it is used by the controlled release coat layer of pH decision solubility (disengaging active component above under the environment of certain pH value) and has carried out coating.Resulting microsphere particle agent obtains the controlled release granule of 1180 μ m-1700 μ m through circular sieve.Then with resulting microsphere particle agent 40 ℃ of following vacuum dryings 16 hours, in this granule of 1101g, add the 0.525g Talcum then and the 0.525g aerosil obtains the enteric coating granule.

315.0mg the composition of above-mentioned controlled release granule

The granule 212.64mg of embodiment 55

EUDRAGIT S100 S 47.85mg

EUDRAGIT S100 L 15.96mg

Talcum 31.89mg

Triethyl citrate 6.36mg

Talcum 0.15mg

Aerosil 0.15mg

Total amount 315.0mg

Embodiment 57

The controlled release granule that enteric coating granule that 120mg is obtained in embodiment 53 and 315mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 90mg compd A) among one piece of capsule #1.

Embodiment 58

The controlled release granule that enteric coating granule that 80mg is obtained in embodiment 53 and 210mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 60mg compd A) among one piece of capsule #2.

Embodiment 59

The controlled release granule that enteric coating granule that 40mg is obtained in embodiment 53 and 105mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #3.

Embodiment 60

The controlled release granule that enteric coating granule that 240mg is obtained in embodiment 53 and 210mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 90mg compd A) among one piece of capsule #1.

Embodiment 61

The controlled release granule that enteric coating granule that 160mg is obtained in embodiment 53 and 280mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 90mg compd A) among one piece of capsule #1.

Embodiment 62

The controlled release granule that enteric coating granule that 192mg is obtained in embodiment 53 and 252mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 90mg compd A) among one piece of capsule #1.

Embodiment 63

The controlled release granule that enteric coating granule that 160mg is obtained in embodiment 53 and 210mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 75mg compd A) among one piece of capsule #1.

Embodiment 64

The controlled release granule that enteric coating granule that 100mg is obtained in embodiment 53 and 262.5mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 75mg compd A) among one piece of capsule #1.

Embodiment 65

The controlled release granule that enteric coating granule that 133.3mg is obtained in embodiment 53 and 233.3mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 75mg compd A) among one piece of capsule #1.

Embodiment 66

The controlled release granule that enteric coating granule that 200mg is obtained in embodiment 53 and 175mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 75mg compd A) among one piece of capsule #1.

Embodiment 67

The controlled release granule that enteric coating granule that 106.7mg is obtained in embodiment 53 and 186.7mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 60mg compd A) among one piece of capsule #2.

Embodiment 68

The controlled release granule that enteric coating granule that 128mg is obtained in embodiment 53 and 168mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 60mg compd A) among one piece of capsule #2.

Embodiment 69

The controlled release granule that enteric coating granule that 160mg is obtained in embodiment 53 and 140mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 60mg compd A) among one piece of capsule #2.

Embodiment 70

The controlled release granule that enteric coating granule that 60mg is obtained in embodiment 53 and 157.5mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 45mg compd A) among one piece of capsule #2.

Embodiment 71

The controlled release granule that enteric coating granule that 120mg is obtained in embodiment 53 and 105mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 45mg compd A) among one piece of capsule #2.

Embodiment 72

The controlled release granule that enteric coating granule that 80mg is obtained in embodiment 53 and 140mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 45mg compd A) among one piece of capsule #2.

Embodiment 73

The controlled release granule that enteric coating granule that 96mg is obtained in embodiment 53 and 126mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 45mg compd A) among one piece of capsule #2.

Embodiment 74

The controlled release granule that enteric coating granule that 53.3mg is obtained in embodiment 53 and 93.3mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #3.

Embodiment 75

The controlled release granule that enteric coating granule that 64mg is obtained in embodiment 53 and 84mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #3.

Embodiment 76

The controlled release granule that enteric coating granule that 80mg is obtained in embodiment 53 and 70mg obtain in embodiment 56 is mixed, and resulting mixture is inserted and obtained capsule (being equivalent to the 30mg compd A) among one piece of capsule #3.

Industrial usability

Because controlled release preparation of the present invention can disengage and the extended treatment effect in long-time through the control active component, so it can obtain to use the effectiveness that low dosage treats and reduces because of the raise side effect that causes and reduce administration time of blood drug level.

Claims

1. capsule contains the mixture of enteric coating granule and controlled release granule, wherein

(i) enteric coating granule: it contains lansoprazole or its salt or its optical isomer nuclear slug particle as active component through at first preparing; Then said granule is carried out enteric coating and make, thereby said enteric coating is being not less than 5.0, be not higher than that dissolving disengages active component under 6.0 the pH scope; And

(ii) controlled release granule: it makes through the controlled release coat layer coating by pH decision solubility; Should on the intermediate layer, form by the controlled release coat layer of pH decision solubility; This intermediate layer forms containing on the nuclear slug particle of active component, should use EUDRAGIT S100 S and EUDRAGIT S100 L by controlled release coat layer of pH decision solubility.

2. according to the capsule of claim 1, wherein this active component is the R-optical isomer of lansoprazole.

3. according to the capsule of claim 1, wherein this active component is the S-optical isomer of lansoprazole.

4. according to the capsule of claim 1, wherein this nuclear slug particle that contains active component contains the stabilizing agent of basic inorganic salt.

5. according to the capsule of claim 1, wherein should be to be not less than 6.5, not to be higher than soluble layer under 7.0 the pH scope by controlled release coat layer of pH decision solubility.

6. according to the capsule of claim 1, wherein said controlled release granule has the particle diameter of 100-1500 μ m.