JP2008266236A - Cyclic amine derivative or salt thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a therapeutic, preventive or suppressing agent for a disease associated with abnormal production of IL-6 by discovering a novel compound having an IL-6 signaling inhibitory action. <P>SOLUTION: A compound represented by formula (1) (wherein X represents a single bond or the like; Y<SP>1</SP>-Y<SP>2</SP>represents -CH<SB>2</SB>NHC(O)CH<SB>2</SB>N= or the like; Z represents a single bond or the like; R<SP>1a</SP>, R<SP>1b</SP>, R<SP>1c</SP>, R<SP>2a</SP>, R<SP>2b</SP>and R<SP>2c</SP>each represents a hydrogen atom or the like; and R<SP>3</SP>and R<SP>4</SP>each represents a hydrogen atom or the like, provided that R<SP>1a</SP>and R<SP>2a</SP>are not both hydrogen atoms), and its derivative are disclosed. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a cyclic amine derivative or a salt thereof. More specifically, the present invention relates to a cyclic amine derivative or a salt thereof having an interleukin-6 (IL-6) signaling inhibitory action.

  Cytokines are proteinaceous factors responsible for information transmission between cells. Physiological activities such as cell proliferation and differentiation possessed by cytokines are exhibited by the binding of cytokine receptors and cytokines on the cell membrane. It has been reported that abnormal production of cytokines is deeply involved in cancer, inflammation, allergies, autoimmune diseases and the like (Non-patent Document 1). IL-6, which is one of cytokines, is a multifunctional cytokine, 1) induces antibody production of activated B cells, 2) induces proliferation of hybridomas, plasmacytoma, and myeloma, 3) induces T cells Acts to induce proliferation and differentiation into cytotoxic T cells, 4) stimulates hematopoietic stem cells to form pluripotent colonies, 5) acts on hepatocytes and in response to inflammation and tissue damage It is known to have functions such as inducing the synthesis of the resulting acute phase protein, 6) suppressing the growth of myeloid leukemia cell lines, inducing differentiation into macrophages, and 7) inducing neuronal differentiation. ing. Therefore, failure to control IL-6 activity causes various serious diseases. Examples of such diseases include rheumatoid arthritis, vasculitis syndrome, secondary amyloidosis, Castleman's disease, interstitial pneumonia (lymphocytic interstitial pneumonia; LIP), proliferative glomerulonephritis, inflammatory bowel disease (Crohn's disease), rejection associated with kidney transplantation, osteoporosis, AIDS, IL-6 producing tumors (multiple myeloma, renal cancer, cervical cancer, lung cancer, atrial myxoma) and cachexia.

  So far, it has been shown that inhibition of IL-6 function by humanized anti-human IL-6 receptor antibody (tocilizumab) is an effective treatment for diseases associated with abnormal production of IL-6. Yes. However, since tocilizumab contains a mouse-derived heterologous protein even though it is a humanized antibody, the appearance of an antibody against tocilizumab cannot be ruled out, and the risk of reduced action of tocilizumab and the appearance of anaphylaxis cannot be completely excluded. In addition, since tocilizumab is a high molecular weight (molecular weight 150 kD), it is forced to be administered intravenously, which significantly impairs patient convenience. Furthermore, because tocilizumab is expensive, it is economically costly. Therefore, development of a compound having excellent properties as a therapeutic, preventive or inhibitory agent for diseases associated with abnormal production of IL-6 is desired.

Currently, as a compound having an IL-6 signal transduction inhibiting action, a compound represented by the following formula (A) described in Patent Document 1 and a compound represented by the following formula (B) described in Patent Document 2 are known. ing.

JP 2003-183161 A JP 2002-265493 A Kishimoto, T .; Science 258, p. 593-597, 1992

  An object of the present invention is to find a novel compound having an inhibitory action on IL-6 signaling, and to provide a therapeutic, preventive or suppressive agent for diseases associated with abnormal production of IL-6.

  As a result of intensive studies, the present inventors have found that a novel cyclic amine represented by the following general formula (1) and a salt thereof have an IL-6 signal transduction inhibitory action, and completed the present invention.

（式中、
Ｘは、単結合又は−ＣＨ_２−を示し、
Ｙ^１−Ｙ^２は、式

で表される基を示し、
Ｚは、単結合、−ＣＨ_２−又は−Ｃ（Ｏ）−を示し、
Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^２ａ、Ｒ^２ｂ及びＲ^２ｃは、同一又は異なって、水素原子、ハロゲン原子又はハロゲン原子で置換されていてもよいＣ_１〜Ｃ_６アルキル基を示し、ただし、Ｒ^１ａ及びＲ^２ａが同時に水素原子を示すことはなく、
Ｒ^３及びＲ^４は、同一又は異なって、水素原子又はＣ_１〜Ｃ_６アルキル基を示す。）
［２］Ｚが−ＣＨ_２−である、上記［１］記載の化合物又はその塩。
［３］Ｚが−ＣＨ_２−であり、Ｒ^１ａがハロゲン原子であり、Ｒ^２ａが水素原子である、上記［１］記載の化合物又はその塩。
［４］Ｚが−ＣＨ_２−であり、Ｘが単結合であり、Ｒ^１ａがハロゲン原子であり、Ｒ^２ａが水素原子であり、
Ｙ^１−Ｙ^２が式

で表される基である、上記［１］記載の化合物又はその塩。
［５］Ｚが−ＣＨ_２−であり、Ｘが単結合であり、Ｒ^１ａがハロゲン原子であり、Ｒ^２ａが水素原子であり、
Ｙ^１−Ｙ^２が式

で表される基である、上記［１］記載の化合物又はその塩。 That is, the present invention provides the following [1] to [5].
[1] A compound represented by the following general formula (1) or a salt thereof.

(Where
X represents a single bond or —CH ₂ —;
Y ¹ -Y ² is a formula

Represents a group represented by
Z represents a single bond, —CH ₂ — or —C (O) —,
R ^1a , R ^1b , R ^1c , R ^2a , R ^2b and R ^2c are the same or different and each represents a hydrogen atom, a halogen atom or a C _{1 to} C ₆ alkyl group which may be substituted with a halogen atom, , R ^1a and R ^2a do not represent a hydrogen atom at the same time,
R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a C ₁ -C ₆ alkyl group. )
[2] The compound of the above-mentioned [1] or a salt thereof, wherein Z is —CH ₂ —.
[3] The compound according to the above [1] or a salt thereof, wherein Z is —CH ₂ —, R ^1a is a halogen atom, and R ^2a is a hydrogen atom.
[4] Z is —CH ₂ —, X is a single bond, R ^1a is a halogen atom, R ^2a is a hydrogen atom,
Y ¹ -Y ² is a formula

The compound or its salt of the said [1] description which is group represented by these.
[5] Z is —CH ₂ —, X is a single bond, R ^1a is a halogen atom, R ^2a is a hydrogen atom,
Y ¹ -Y ² is a formula

The compound or its salt of the said [1] description which is group represented by these.

  The cyclic amine derivative and the salt thereof of the present invention have an excellent IL-6 signal transduction inhibitory action. Therefore, the cyclic amine derivative and the salt thereof of the present invention are effective for treatment, prevention or suppression of diseases associated with abnormal production of IL-6.

  Hereinafter, the meanings of terms and symbols used in this specification will be described, and the contents of the present invention will be described in more detail.

  In the present specification, the structural formula of a compound may be expressed using a certain isomer, but there is no intention to limit the structural formula, and all isomers (geometric isomers, enantiomers) generated in the structure of the compound. Isomers, stereoisomers, tautomers and rotational isomers) and mixtures of isomers are also included in the compound. Moreover, when an enantiomer exists in the compound according to the present invention, both an optically active substance and a racemate are included.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The “C ₁ -C ₆ alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include a methyl group, an ethyl group, a 1-propyl group, 2 -Propyl group, 2-methyl-1-propyl group, 2-methyl-2-propyl group, 1-butyl group, 2-butyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group, 2-methyl -1-butyl group, 3-methyl-1-butyl group, 2-methyl-2-butyl group, 3-methyl-2-butyl group, 2,2-dimethyl-1-propyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2-methyl-1-pentyl group, 3-methyl-1-pentyl group, 4-methyl-1-pentyl group, 2-methyl-2-pentyl group, 3- Methyl-2-pentyl group, 4-methyl-2-pentyl group, 2-methyl-3-pentyl group 3-methyl-3-pentyl group, 2,3-dimethyl-1-butyl group, 3,3-dimethyl-1-butyl group, 2,2-dimethyl-1-butyl group, 2-ethyl-1-butyl group 3,3-dimethyl-2-butyl group and 2,3-dimethyl-2-butyl group.

A preferable “C ₁ -C ₆ alkyl group” is a linear or branched alkyl group having 1 to 3 carbon atoms (hereinafter referred to as “C ₁ -C ₃ alkyl group”). , Methyl group, ethyl group, 1-propyl group and 2-propyl group.

“C ₁ -C ₆ alkyl group optionally substituted with a halogen atom” means a part or all of hydrogen atoms in the above “C ₁ -C ₆ alkyl group” and the above “C ₁ -C ₆ alkyl group” Represents a group substituted by the above-mentioned “halogen atom”, and as specific examples, in addition to the above “C ₁ -C ₆ alkyl group”, a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a 1-fluoroethyl group 1-chloroethyl group, 2-chloroethyl group, difluoromethyl group, trifluoromethyl group, trichloromethyl group, and 2,2,2-trifluoroethyl group.

Preferred “C ₁ -C ₆ alkyl group optionally substituted with a halogen atom” is “C ₁ -C ₃ alkyl group optionally substituted by a halogen atom”.

  Hereinafter, preferred embodiments of each symbol of the compound of the present invention and the salt thereof will be described.

One of the R ^1a and R ^2a is preferably a hydrogen atom, and the other is preferably a fluorine atom, a chlorine atom, a methyl group or a trifluoromethyl group, one is a hydrogen atom, and the other is a fluorine atom or trifluoro More preferred is a methyl group.

で表される位置で置換されていることが好ましい。このような位置で置換されているＲ^１ａ及びＲ^２ａのうち、どちらか一方は水素原子であることがより好ましい。 R ^1b , R ^1c , R ^2b and R ^2c are preferably hydrogen atoms, and R ^1a and R ^2a are represented by the formula

It is preferably substituted at the position represented by It is more preferable that either one of R ^1a and R ^2a substituted at such a position is a hydrogen atom.

More preferable combinations of R ^1a and R ^2a include combinations represented by the following formulae.

R ³ and R ⁴ are preferably both hydrogen atoms or methyl groups, X is preferably a single bond, and Z is preferably —CH ₂ —.

で表される基は、Ｅ型であることが好ましい。 Among the ^Y 1 -Y ^2,

The group represented by is preferably E-type.

で表される基であることが好ましく、式

で表される基であることがより好ましい。 Y ¹ -Y ² is a formula

Is preferably a group represented by the formula:

It is more preferable that it is group represented by these.

  The salt of the compound of the present invention means a salt of the compound of the present invention with a pharmaceutically acceptable base (for example, an inorganic or organic base) or an acid (for example, an inorganic or organic acid), preferably a salt with an acid. is there.

  Examples of salts derived from pharmaceutically acceptable inorganic bases include, for example, inorganic bases such as aluminum, ammonium, calcium, copper, ferrous, ferric, lithium, magnesium, manganese, manganite, potassium and sodium. (Particularly preferably, ammonium, calcium, manganese, potassium and sodium salts).

  Examples of salts derived from pharmaceutically acceptable organic bases include organic bases such as primary, secondary, tertiary amines, substituted amines (eg, naturally occurring substituted amines), cyclic amines, and basic ion exchange resins. (For example, arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine , Glucosamine, Histidine, Hydrabamine, Isopropylamine, Lysine, Methylglucamine, Morpholine, Piperazine, Piperidine, Polyamine resin, Procaine, Purine, Theobromine, Triethylamine, Trimethylamine, Tripropylamine, Toro Salts with glutamic and the like).

  Examples of salts derived from pharmaceutically acceptable inorganic acids include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid.

  Examples of salts derived from pharmaceutically acceptable organic acids include acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearin. And salts with organic acids such as acids and palmitic acid.

  Furthermore, the compounds of the invention and their salts may exist as hydrates or solvates. Any hydrate and solvate formed by the cyclic amine derivative represented by the general formula (1) and the salt thereof, including the above-mentioned preferred compounds, are included in the scope of the present invention. Examples of the solvent that can form a solvate include methanol, ethanol, isopropanol, acetone, ethyl acetate, dichloromethane, diisopropyl ether, and the like.

  The compound of the present invention or a salt thereof can be produced by various synthetic methods. Hereinafter, typical production methods (Method A, Method B, Method C, Method D, Method E and Method G) will be described.

（上記スキーム中、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ及びＺは上記定義と同じであり、ｎは１〜３の整数を示す。） (Method A)

(In the above scheme, R ^1a , R ^1b , R ^1c , R ^2a , R ^2b , R ^2c and Z are the same as defined above, and n represents an integer of 1 to 3)

(First step)
This step is a step of producing compound (3) from compound (1) and compound (2). This step is carried out by using an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or potassium carbonate, sodium carbonate, cesium carbonate. N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, mesitylene, pyridine, quinoline, dichloromethane in the presence or absence of an inorganic base such as sodium acetate It can implement by processing for 30 minutes-48 hours at -20-150 degreeC in solvent, such as.

(Second step)
This step is a step of producing compound (4) by reducing the nitro group of compound (3). This step can be performed, for example, by treating 1 to 20 equivalents of iron with respect to compound (3) and treating in acetic acid at normal temperature to 100 ° C for 1 to 24 hours. Moreover, it can implement by processing at normal temperature-100 degreeC for 1 to 24 hours using palladium and Raney nickel.

(Third process)
This step is a step of producing compound (6) by acylating compound (4). This step is preferably performed in the presence of a suitable base. Examples of the base used in this step include triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, and other organic bases, or sodium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, and triphosphate. An inorganic base such as potassium can be exemplified. This step is preferably performed using an inert solvent that does not participate in the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, and toluene. it can. These solvents may be used alone or mixed in any ratio. This process can be implemented by processing at -20-100 degreeC for 30 minutes-48 hours.

(Fourth process)
This step is a step of producing compound (8) from compound (6) and compound (7). This step can be performed in the presence or absence of a base using 1 to 20 equivalents of compound (7) to compound (6). When a base is used, suitable bases include, for example, organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, or sodium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, carbonate Examples include inorganic bases such as cesium and tripotassium phosphate. When a solvent is used, an inert solvent that does not participate in the reaction, such as N, N-dimethylformamide, sulfolane, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, toluene, ethanol, water, or the like is used. This process can be implemented by processing at -20-150 degreeC for 30 minutes-48 hours.

（上記スキーム中、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ及びＺは上記定義と同じである。） (Method B)

(In the above scheme, R ^1a , R ^1b , R ^1c , R ^2a , R ^2b , R ^2c and Z are the same as defined above.)

(First step)
This step is a step of producing compound (10) from compound (9) and compound (2). This step is carried out in the presence or absence of an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, DBU or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium acetate, N, N -Treat in a solvent such as dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, mesitylene, pyridine, quinoline, dichloromethane at -20 to 150 ° C for 30 minutes to 48 hours. Can be implemented.

(Second step)
This step is a step of producing compound (12) from compound (10) and compound (11). This step can be performed, for example, by treatment in a solvent such as tetrahydrofuran or dioxane at −20 to 100 ° C. for 30 minutes to 48 hours in the presence of an inorganic base such as sodium hydride.

(Third process)
This step is a step of producing compound (13) by hydrolyzing the ester group of compound (12). This step is performed in the presence of a base in a solvent that does not affect the reaction according to a conventional method. Examples of the base include alkali metal salts such as potassium hydroxide and sodium hydroxide. Examples of the solvent that does not affect the reaction include tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, propanol, isopropanol, butanol, water, and the like. This step can be carried out usually by treating at 0 to 150 ° C. for 30 minutes to 48 hours.

(Fourth process)
This step is a step of producing compound (14) by a condensation reaction of compound (13) and compound (7). Examples of the condensing agent used in this step include dicyclohexylcarbodiimide (DCC), 3-ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), and dimethylimidazolinium chloride (DMC). Is added in solid form or as a solution in a suitable solvent. When a base is used in this condensation reaction, an alkali carbonate such as sodium hydrogencarbonate or potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicyclo [5.4.0] -7-undecene, pyridine, 4- Examples thereof include tertiary amines such as dimethylaminopyridine and 1,8-bis (dimethylamino) naphthalene. As the solvent used in this condensation reaction, an inert solvent not involved in the reaction, such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane, ethyl acetate, Dichloromethane or the like is used. This condensation reaction can be performed at -20-80 degreeC.
The condensation reaction in this step can also be carried out via a carboxylic acid halide, a carboxylic acid imidazolide, an active ester of a carboxylic acid, an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane, ethyl acetate in the presence or absence of an inorganic base such as sodium bicarbonate or potassium carbonate In a solvent such as toluene or dichloromethane, the treatment can be performed at -20 to 80 ° C for 30 minutes to 48 hours.

（上記スキーム中、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^２ａ、Ｒ^２ｂ及びＲ^２ｃは上記定義と同じであり、Ｒはアルキル基等の基を示し、Ｗは酸素原子又はＮＨを示し、Ｙ^２は窒素原子又はメチン基を示し、ＰＧは保護基を示し、ｎは１〜３の整数を示す。ＰＧで表される保護基としては、例えばアセチル基などのアシル基、ｔｅｒｔ−ブトキシカルボニル基などの低級アルコキシカルボニル基、及びベンジルオキシカルボニル基などの置換基を有してもよいアリールオキシカルボニル基などが挙げられる。） (Method C)

(In the above scheme, R ^1a , R ^1b , R ^1c , R ^2a , R ^2b and R ^2c are the same as defined above, R represents a group such as an alkyl group, W represents an oxygen atom or NH, Y ² represents a nitrogen atom or a methine group, PG represents a protecting group, and n represents an integer of 1 to 3. Examples of the protecting group represented by PG include an acyl group such as an acetyl group and a tert-butoxycarbonyl group. And a lower alkoxycarbonyl group such as benzyloxycarbonyl group and an aryloxycarbonyl group which may have a substituent such as a benzyloxycarbonyl group.

(First step)
This step is a step of producing compound (15) from compound (10). This step can be performed, for example, by treating with sodium cyanide and potassium permanganate in a methanol solvent at 0 to 100 ° C. for 30 minutes to 48 hours. In this case, R in the compound (15) is a methyl group.

(Second step)
This step is a step of producing compound (16) by hydrolyzing the ester group of compound (15). This process can be performed according to the said B method and 3rd process.

(Third process)
This step is a step of producing compound (18) from compound (16) and compound (17) by Curtius rearrangement reaction. This step can be performed, for example, by treating with diphenylphosphoryl azide at 0 to 100 ° C. for 30 minutes to 48 hours in the presence of an organic base such as triethylamine in a toluene solvent.

(Fourth process)
This step is a step of producing compound (19) by deprotecting compound (18). This step can be performed by deprotecting the protecting group PG in the compound (18) according to a known method such as “Protecting Groups in Organic Synthesis” (published by John Wily and Sons (1999)). Examples thereof include a method using acid, base, hydrazine, tetrabutylammonium fluoride, trimethylsilyl iodide and the like, and a reduction method.

(Fifth process)
This step is a step of producing compound (21) by dehydration condensation of compound (19) and compound (20). This step is usually carried out by treating with a reducing agent such as triacetoxyborohydride or cyanoborohydride in a solvent using a solvent such as dichloromethane or toluene at −20 to 100 ° C. for 30 minutes to 48 hours. be able to.

（上記スキーム中、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、Ｒ^３、Ｒ^４及びＺは上記定義と同じである。） (Method D)

(In the above scheme, R ^1a , R ^1b , R ^1c , R ^2a , R ^2b , R ^2c , R ³ , R ⁴ and Z are the same as defined above.)

(First step)
This step is a step of producing compound (22) by reducing the formyl group of compound (10). Examples of the reducing agent used in this step include sodium borohydride, diisobutylaluminum hydride (DIBAL), lithium aluminum hydride, lithium borohydride and the like. The solvent used in this step is an inert solvent not involved in the reaction, such as methanol, ethanol, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane, Ethyl acetate, dichloromethane or the like is used. This process can be implemented by processing at 0-100 degreeC for 30 minutes-48 hours.

(Second step)
This step is a step of producing compound (23) from compound (22). In this step, compound (22) and phthalimide are mixed with weak acid such as acetic acid and active methylene compound, azodicarboxylic acid esters such as ethyl azodicarboxylate and isopropyl azodicarboxylate, and phosphorus reagent such as triphenylphosphine and tributylphosphine. It can implement by making it react in presence of. As a solvent used in this step, an inert solvent not involved in the reaction, for example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane, benzene, toluene Etc. are used. This process can be implemented by processing at -80-100 degreeC for 30 minutes-48 hours.

(Third process)
This step is a step of producing compound (24) from compound (23) by Gabriel reaction. This step can be performed, for example, by treating with hydrazine monohydrate in an ethanol solvent at 0 to 100 ° C. for 30 minutes to 48 hours.

(Fourth process)
This step is a step of producing compound (26) from compound (24) and compound (25). This process can be performed according to said A method and 3rd process.

(Fifth process)
This step is a step of producing compound (27) from compound (26) and compound (7). This process can be performed according to said A method and 4th process.

（上記スキーム中、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、Ｗ、Ｙ^２、ＰＧ及びｎは上記Ｃ法における定義と同じである。） (E method)

(In the above scheme, R ^1a , R ^1b , R ^1c , R ^2a , R ^2b , R ^2c , W, Y ² , PG and n are the same as defined in the method C).

(First step)
This step is a step of producing compound (28) from compound (24) and compound (17). This step uses, for example, carbonyldiimidazole, an inert solvent that does not participate in the reaction, such as tetrahydrofuran, ethyl acetate, benzene, toluene, diethyl ether, dichloromethane, and the presence of a base such as pyridine or triethylamine as necessary. Can be done below. This process can be implemented by processing at 0-100 degreeC for 30 minutes-48 hours.

(Second step)
This step is a step of producing compound (29) by deprotecting compound (28). This process can be performed according to said C method and a 4th process.

(Third process)
This step is a step of producing compound (30) from compound (29) and compound (20). This process can be performed according to said C method and a 5th process.

（上記スキーム中、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ及びＺは上記定義と同じであり、ｎは１〜３の整数を示す。） (F method)

(In the above scheme, R ^1a , R ^1b , R ^1c , R ^2a , R ^2b , R ^2c and Z are the same as defined above, and n represents an integer of 1 to 3)

(First step)
This step is a step of producing compound (33) from compound (31) and compound (32). This process can be performed according to said A method and 1st process.

(Second step)
This step is a step of producing a compound (34) from the compound (33) and the compound (5). This process can be performed according to said A method and 3rd process.

(Third process)
This step is a step of producing the compound (35) from the compound (34) and the compound (7). This process can be performed according to said A method and 4th process.

（上記スキーム中、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ及びＺは上記定義と同じである。） (G method)

(In the above scheme, R ^1a , R ^1b , R ^1c , R ^2a , R ^2b , R ^2c and Z are the same as defined above.)

(First step)
This step is a step of producing compound (36) by reducing the carbonyl group of compound (8). Examples of the reducing agent used in this step include sodium borohydride, borane, borane-dimethyl sulfide complex, lithium aluminum hydride, lithium borohydride and the like. The solvent used in this step is an inert solvent not involved in the reaction, such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane, ethyl acetate, dichloromethane. Etc. are used. This process can be implemented by processing at -80-100 degreeC for 30 minutes-48 hours.

(Second step)
This step is a step of producing compound (38) by acylating compound (36). This step is preferably performed in the presence of a suitable base. Bases used in this step include organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, sodium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate or triphosphate. An inorganic base such as potassium can be exemplified. This step is preferably performed using an inert solvent that does not participate in the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, and toluene. it can. These solvents may be used alone or mixed in any ratio. This process can be implemented by processing at -20-100 degreeC for 30 minutes-48 hours.

  The compound of the present invention synthesized by the above-described method and the like can be isolated and purified by a usual separation means (for example, extraction, recrystallization, distillation, chromatography, etc.). When the obtained compound can form a salt, various salts can be produced by a usual method or a method equivalent thereto (for example, neutralization).

  The compound of the present invention or a salt thereof alone or appropriately mixed with a pharmacologically acceptable excipient, diluent or the like, for example, a preparation such as a tablet, capsule, granule, powder or syrup As a pharmaceutical composition orally or parenterally as a preparation such as injection or suppository.

  These preparations are produced by known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, and diluents.

  The excipient may be an organic excipient or an inorganic excipient. Organic excipients include, for example, sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; gum arabic Dextran; or pullulan and the like. Inorganic excipients include, for example, light inorganic silicates, synthetic aluminum silicates, calcium silicates, magnesium metasilicate magnesium silicate derivatives; phosphates such as calcium hydrogen phosphate; Carbonates; or sulfates such as calcium sulfate.

  Lubricants include, for example, stearic acid, calcium stearate, magnesium stearate such as magnesium stearate; talc; colloidal silica; waxes such as bee gum; adipic acid; sulfate such as sodium sulfate; glycol; It can be an acid; sodium benzoate; DL-leucine; fatty acid sodium; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicate hydrate; or the starch derivatives.

  The binder can be, for example, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, macrogol, or a compound similar to the excipients described above.

  Disintegrants are, for example, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally crosslinked sodium carboxymethylcellulose; or chemically modified such as carboxymethyl starch, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone. Starches and celluloses.

  Stabilizers include, for example, parahydroxybenzoates such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol and phenethyl alcohol; benzalkonium chloride; cresols such as phenol and cresol; thimerosal; Can be dehydroacetic acid; or sorbic acid.

  The flavoring agent can be, for example, commonly used sweeteners, acidulants, and fragrances.

  The diluent may be a commonly used one such as distilled water for injection, physiological saline, and glucose injection solution.

  The dose of the compound of the present invention or a salt thereof varies depending on the type, administration route, age of the patient, symptoms, etc., but for example, 0.001 to 0.001 as the compound of the present invention or a salt thereof for mammals including humans. 500 mg / kg / day. Administration is, for example, once a day or divided into several times.

  Hereinafter, the present invention will be described in more detail based on reference examples, examples, and test examples. Reference examples show production examples of raw material compounds used in the production of the compounds of the present invention. However, the following reference examples, examples and test examples are illustrative, and the present invention is not limited to the following specific examples in any case.

４−クロロチオフェノール（５．２０ｇ）をＮ−メチル−２−ピロリジノン（５０ｍＬ）に溶かし、０℃に冷却後、炭酸カリウム（１５ｇ）加えた。０℃で１５分撹拌した後、２−フルオロニトロベンゼン（５．００ｇ）を滴下した。反応液を常温に戻し、１時間撹拌した。反応液を水にあけ、酢酸エチルで抽出し、有機層を水と飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、反応液を濃縮し、残渣をヘキサンに懸濁した。沈殿をろ取し、乾燥し、黄色固体として２−（４−クロロフェニルチオ）ニトロベンゼン（８．８６ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 6.86 (1H, dd, J = 7.5, 1.2 Hz), 7.24 (1H, td, J = 7.5, 1.2 Hz), 7.37 (1H, td, J = 7.5, 1.2 Hz), 7.46 (2H, d, J = 8.6 Hz), 7.52 (2H, d, J = 8.6 Hz), 8.23 (1H, dd, J = 7.5, 1.2 Hz). (Reference Example 1)
2- (4-Chlorophenylthio) nitrobenzene

4-Chlorothiophenol (5.20 g) was dissolved in N-methyl-2-pyrrolidinone (50 mL), cooled to 0 ° C., and potassium carbonate (15 g) was added. After stirring at 0 ° C. for 15 minutes, 2-fluoronitrobenzene (5.00 g) was added dropwise. The reaction solution was returned to room temperature and stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the reaction mixture was concentrated and the residue was suspended in hexane. The precipitate was collected by filtration and dried to give 2- (4-chlorophenylthio) nitrobenzene (8.86 g) as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.86 (1H, dd, J = 7.5, 1.2 Hz), 7.24 (1H, td, J = 7.5, 1.2 Hz), 7.37 (1H, td, J = 7.5, 1.2 Hz), 7.46 (2H, d, J = 8.6 Hz), 7.52 (2H, d, J = 8.6 Hz), 8.23 (1H, dd, J = 7.5, 1.2 Hz).

２−（４−クロロフェニルチオ）ニトロベンゼン（参考例１の化合物：２００ｍｇ）を酢酸（１０ｍＬ）に溶かし、鉄粉（８４０ｍｇ）を加え、６０℃で１．５時間撹拌した。反応液を氷にあけ、炭酸水素ナトリウムで塩基性とした。酢酸エチルで抽出し、有機層を飽和重曹水と飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、反応液を濃縮し、無色油状物として２−（４−クロロフェニルチオ）アニリン（１８１ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 4.11 (2H, br s), 6.72-6.78 (2H, m), 6.98 (2H, d, J = 8.6 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.23 (1H, td, J = 7.6, 1.5 Hz), 7.42 (1H, dd, J = 7.6, 1.5 Hz). (Reference Example 2)
2- (4-Chlorophenylthio) aniline

2- (4-Chlorophenylthio) nitrobenzene (the compound of Reference Example 1: 200 mg) was dissolved in acetic acid (10 mL), iron powder (840 mg) was added, and the mixture was stirred at 60 ° C. for 1.5 hours. The reaction was poured into ice and basified with sodium bicarbonate. Extraction was performed with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the reaction mixture was concentrated to give 2- (4-chlorophenylthio) aniline (181 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.11 (2H, br s), 6.72-6.78 (2H, m), 6.98 (2H, d, J = 8.6 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.23 (1H, td, J = 7.6, 1.5 Hz), 7.42 (1H, dd, J = 7.6, 1.5 Hz).

２−（４−クロロフェニルチオ）アニリン（参考例２の化合物：１８０ｍｇ）をジクロロメタン（２ｍＬ）に溶かし、ピリジン（０．２ｍＬ）を加えた。０℃に冷却後、クロロアセチルクロリド（０．０６ｍＬ，０．７５ｍｍｏｌ）のジクロロメタン（０．５ｍＬ）溶液をゆっくりと滴下した。０℃で１時間撹拌した後、少量の水を加え反応を止めた。反応液を水にあけ酢酸エチルで抽出し、有機層を希塩酸と飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、反応液を濃縮し、褐色固体として２−クロロ−２’−（４−クロロフェニルチオ）−アセトアニリド（２５８ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 4.10 (2H, s), 7.03 (2H, d, J = 8.6 Hz), 7.17-7.23 (3H, m), 7.48 (1H, td, J = 7.9, 1.2 Hz), 7.62 (1H, dd, J = 7.9, 1.2 Hz), 8.45 (1H, dd, J = 7.9, 1.2 Hz), 9.42 (1H, s). (Reference Example 3)
2-Chloro-2 '-(4-chlorophenylthio) acetanilide

2- (4-Chlorophenylthio) aniline (the compound of Reference Example 2: 180 mg) was dissolved in dichloromethane (2 mL), and pyridine (0.2 mL) was added. After cooling to 0 ° C., a solution of chloroacetyl chloride (0.06 mL, 0.75 mmol) in dichloromethane (0.5 mL) was slowly added dropwise. After stirring at 0 ° C. for 1 hour, a small amount of water was added to stop the reaction. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with dilute hydrochloric acid and saturated brine. After drying over anhydrous sodium sulfate, the reaction mixture was concentrated to give 2-chloro-2 ′-(4-chlorophenylthio) -acetanilide (258 mg) as a brown solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.10 (2H, s), 7.03 (2H, d, J = 8.6 Hz), 7.17-7.23 (3H, m), 7.48 (1H, td, J = 7.9, 1.2 Hz), 7.62 (1H, dd, J = 7.9, 1.2 Hz), 8.45 (1H, dd, J = 7.9, 1.2 Hz), 9.42 (1H, s).

参考例３と同様の方法により、２−（４−クロロフェニルチオ）アニリン（参考例２の化合物：５０２ｍｇ）、及び３−クロロプロピオニルクロリド（０．２２ｍＬ）から無色粉末として３−クロロ−２’−（４−クロロフェニルチオ）−プロピオアニリド（５１３ｍｇ）を得た。
¹H -NMR (400 MHz, CDCl₃) δ 2.72(2H, t, J = 6.1 Hz), 3.77(2H, t, J = 6.1 Hz), 6.99(2H, d, J = 8.6 Hz), 7.15(1H, t, J = 7.3 Hz), 7.22(2H, d, J = 8.6 Hz), 7.47(1H, t, J = 7.3 Hz), 7.57(1H, d, J = 7.3 Hz), 8.27(1H, brs), 8.46(1H, d, J = 7.3 Hz). (Reference Example 4)
3-Chloro-2 '-(4-chlorophenylthio) propioanilide

According to the same method as in Reference Example 3, 2- (4-chlorophenylthio) aniline (Compound of Reference Example 2: 502 mg) and 3-chloropropionyl chloride (0.22 mL) as 3-chloro-2′- (4-Chlorophenylthio) -propioanilide (513 mg) was obtained.
¹ H -NMR (400 MHz, CDCl ₃ ) δ 2.72 (2H, t, J = 6.1 Hz), 3.77 (2H, t, J = 6.1 Hz), 6.99 (2H, d, J = 8.6 Hz), 7.15 ( 1H, t, J = 7.3 Hz), 7.22 (2H, d, J = 8.6 Hz), 7.47 (1H, t, J = 7.3 Hz), 7.57 (1H, d, J = 7.3 Hz), 8.27 (1H, brs), 8.46 (1H, d, J = 7.3 Hz).

２−（４−クロロフェニルチオ）アニリン（参考例２の化合物：２０２ｍｇ）をジクロロメタン（５ｍＬ）に溶解させ０℃に冷却し、トリエチルアミン（０．２４ｍＬ）、α―ブロモイソブチリルブロミド（０．１１５ｍＬ）を加え、４時間常温で撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥して溶媒を濃縮した。残渣をシリカゲルクロマトグラフィー（Ｃｈｒｏｍａｔｒｅｘ，ヘキサン：酢酸エチル＝１０：１）により精製し、黄色油状物として２−ブロモ−Ｎ−［２−（４−クロロフェニルチオ）フェニル］−２−メチルプロピルアミド（３１０ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.86(6H, s), 7.01(2H, d, J = 8.6 Hz), 7.14-7.24(3H, m), 7.49(1H, t, J = 7.3 Hz), 7.62(1H, dd, J = 7.3, 1.2 Hz), 9.49(1H, brs). (Reference Example 5)
2-Bromo-N- [2- (4-chlorophenylthio) phenyl] -2-methylpropylamide

2- (4-Chlorophenylthio) aniline (Compound of Reference Example 2: 202 mg) was dissolved in dichloromethane (5 mL), cooled to 0 ° C., triethylamine (0.24 mL), α-bromoisobutyryl bromide (0.115 mL). ) And stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated. The residue was purified by silica gel chromatography (Chromatrex, hexane: ethyl acetate = 10: 1) to give 2-bromo-N- [2- (4-chlorophenylthio) phenyl] -2-methylpropylamide (310 mg as a yellow oil). )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.86 (6H, s), 7.01 (2H, d, J = 8.6 Hz), 7.14-7.24 (3H, m), 7.49 (1H, t, J = 7.3 Hz ), 7.62 (1H, dd, J = 7.3, 1.2 Hz), 9.49 (1H, brs).

４−クロロベンゼンチオール（３．０１ｇ）をＮ−メチル−２−ピロリジノン（３０ｍＬ）に溶解し、氷冷下、炭酸カリウム（５．７５ｇ）、２−フルオロベンズアルデヒド（２．４４ｇ）を加え、８０℃で２時間撹拌した。反応液を水にあけ、酢酸エチルで抽出し、有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥して溶媒を濃縮した残渣をシリカゲルカラムクロマトグラフィー（シリカゲル６０，０．０４０〜０．０６３ｍｍ；ヘキサン：酢酸エチル＝２０：１）で精製し、黄色粉末として２−（４−クロロフェニルチオ）ベンズアルデヒド（４．６７ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 7.08(1H, d, J = 7.9 Hz), 7.30-7.47(6H, m), 7.89(1H, dd, J = 7.9, 1.2 Hz), 10.36(1H, s). (Reference Example 6)
2- (4-Chlorophenylthio) benzaldehyde

4-Chlorobenzenethiol (3.01 g) was dissolved in N-methyl-2-pyrrolidinone (30 mL), and potassium carbonate (5.75 g) and 2-fluorobenzaldehyde (2.44 g) were added under ice-cooling. For 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated. Purification by silica gel 60, 0.040 to 0.063 mm; hexane: ethyl acetate = 20: 1) gave 2- (4-chlorophenylthio) benzaldehyde (4.67 g) as a yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.08 (1H, d, J = 7.9 Hz), 7.30-7.47 (6H, m), 7.89 (1H, dd, J = 7.9, 1.2 Hz), 10.36 (1H , s).

トリエチルホスホノアセテート（４．５０ｇ）をテトラヒドロフラン（３０ｍＬ）に溶かし、０℃に冷却し、水素化ナトリウム（７５０ｍｇ）を加えた。０℃で１５分撹拌した後、２−（４−クロロフェニルチオ）ベンズアルデヒド（参考例６の化合物：３．２８ｇ）のテトラヒドロフラン溶液（１０ｍＬ）を滴下し、滴下後反応液を常温に戻し、２時間撹拌した。その後、少量の水を加えて反応を止めた。反応液を水にあけ、酢酸エチルで抽出し、有機層を水と飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、反応液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（シリカゲル６０，０．０４０〜０．０６３ｍｍ；ヘキサン：酢酸エチル＝１００：１）で精製し、無色固体として（Ｅ）−３−［２−（４−クロロフェニルチオ）フェニル］アクリル酸エチル（４．１９ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.32 (3H, t, J = 7.2 Hz), 4.25 (2H, q, J = 7.2 Hz), 6.36 (1H, d, J = 15.9 Hz), 7.16 (2H, d, J = 9.2 Hz), 7.24 (2H, d, J = 9.2 Hz), 7.31-7.38 (3H, m), 7.64 (1H, dd, J = 7.0, 2.1 Hz), 8.21 (1H, d, J = 15.9 Hz). (Reference Example 7)
(E) -3- [2- (4-Chlorophenylthio) phenyl] ethyl acrylate

Triethylphosphonoacetate (4.50 g) was dissolved in tetrahydrofuran (30 mL), cooled to 0 ° C., and sodium hydride (750 mg) was added. After stirring at 0 ° C. for 15 minutes, a tetrahydrofuran solution (10 mL) of 2- (4-chlorophenylthio) benzaldehyde (the compound of Reference Example 6: 3.28 g) was added dropwise, and after the dropwise addition, the reaction solution was returned to room temperature for 2 hours. Stir. Thereafter, a small amount of water was added to stop the reaction. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the reaction mixture is concentrated, and the residue is purified by silica gel column chromatography (silica gel 60, 0.040-0.063 mm; hexane: ethyl acetate = 100: 1) to give a colorless solid (E) Ethyl-3- [2- (4-chlorophenylthio) phenyl] acrylate (4.19 g) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.32 (3H, t, J = 7.2 Hz), 4.25 (2H, q, J = 7.2 Hz), 6.36 (1H, d, J = 15.9 Hz), 7.16 ( 2H, d, J = 9.2 Hz), 7.24 (2H, d, J = 9.2 Hz), 7.31-7.38 (3H, m), 7.64 (1H, dd, J = 7.0, 2.1 Hz), 8.21 (1H, d , J = 15.9 Hz).

（Ｅ）−３−［２−（４−クロロフェニルチオ）フェニル］アクリル酸エチル（参考例７の化合物：２．００ｇ）をエタノール（４０ｍＬ）に溶かし、水酸化ナトリウム水溶液（１ｍｏｌ／Ｌ、４０ｍＬ）を加え、８０℃で３時間撹拌した。反応液を氷にあけ、希塩酸で酸性にした。酢酸エチルで抽出し、有機層を水と飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、反応液を濃縮し、無色固体として（Ｅ）−３−［２−（４−クロロフェニルチオ）フェニル］アクリル酸（１．７０ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 6.38 (1H, d, J = 15.9 Hz), 7.17 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.6 Hz), 7.34-7.39 (3H, m), 7.67 (1H, dd, J = 7.0, 2.1 Hz), 8.32 (1H, d, J = 15.9 Hz). (Reference Example 8)
(E) -3- [2- (4-Chlorophenylthio) phenyl] acrylic acid

(E) Ethyl-3- [2- (4-chlorophenylthio) phenyl] acrylate (the compound of Reference Example 7: 2.00 g) was dissolved in ethanol (40 mL), and an aqueous sodium hydroxide solution (1 mol / L, 40 mL). And stirred at 80 ° C. for 3 hours. The reaction mixture was poured into ice and acidified with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the reaction mixture was concentrated to give (E) -3- [2- (4-chlorophenylthio) phenyl] acrylic acid (1.70 g) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.38 (1H, d, J = 15.9 Hz), 7.17 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.6 Hz), 7.34- 7.39 (3H, m), 7.67 (1H, dd, J = 7.0, 2.1 Hz), 8.32 (1H, d, J = 15.9 Hz).

２−（４−クロロフェニルチオ）ベンズアルデヒド（参考例６の化合物：２．６４ｇ）をメタノール（３０ｍＬ）に溶解させ、シアン化ナトリウム（２．５８ｇ）を加え常温で２時間撹拌後、二酸化マンガン（９．２０ｇ）を加え、２時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えセライトろ過した。濾液を酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥して溶媒を濃縮した。残渣をシリカゲルクロマトグラフィー（Ｃｈｒｏｍａｔｒｅｘ、ヘキサン：酢酸エチル＝１０：１）により精製し、無色粉末として２−（４−クロロフェニルチオ）安息香酸メチル（２．６１ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 3.95(3H, s), 6.81(1H, d, J = 7.9 Hz), 7.15(1H, t, J = 7.9 Hz), 7.23-7.31(1H, m), 7.40(2H, d, J = 8.6 Hz), 7.48(2H, d, J = 8.6 Hz), 7.98(1H, dd, J = 7.9, 1.2 Hz). (Reference Example 9)
Methyl 2- (4-chlorophenylthio) benzoate

2- (4-Chlorophenylthio) benzaldehyde (the compound of Reference Example 6: 2.64 g) was dissolved in methanol (30 mL), sodium cyanide (2.58 g) was added, and the mixture was stirred at room temperature for 2 hours. 20 g) was added and stirred for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated. The residue was purified by silica gel chromatography (Chromatrex, hexane: ethyl acetate = 10: 1) to obtain methyl 2- (4-chlorophenylthio) benzoate (2.61 g) as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.95 (3H, s), 6.81 (1H, d, J = 7.9 Hz), 7.15 (1H, t, J = 7.9 Hz), 7.23-7.31 (1H, m ), 7.40 (2H, d, J = 8.6 Hz), 7.48 (2H, d, J = 8.6 Hz), 7.98 (1H, dd, J = 7.9, 1.2 Hz).

２−（４−クロロフェニルチオ）安息香酸メチル（参考例９の化合物：１．５７ｇ）のメタノール（２０ｍＬ）溶液に水酸化カリウム水溶液（１ｍｏｌ／Ｌ、１７ｍＬ）を加え、２時間加熱還流した。反応液を濃縮し、塩酸（１ｍｏｌ／Ｌ）で酸性とした後、結晶をろ取し、水で洗浄後乾燥し無色粉末として２−（４−クロロフェニルチオ）安息香酸（１．４４ｇ）を得た。
¹H-NMR(400 MHz, DMSO) δ 6.43(1H, dd, J = 7.3, 1.2 Hz), 6.90(1H, td, J = 7.3, 1.2 Hz), 7.06(1H, td, J = 7.3, 1.2 Hz), 7.167.26(4H, m), 7.58(1H, dd, J = 7.3, 1.2 Hz), 12.94(1H, brs). (Reference Example 10)
2- (4-Chlorophenylthio) benzoic acid

An aqueous potassium hydroxide solution (1 mol / L, 17 mL) was added to a methanol (20 mL) solution of methyl 2- (4-chlorophenylthio) benzoate (the compound of Reference Example 9: 1.57 g), and the mixture was heated to reflux for 2 hours. The reaction mixture was concentrated and acidified with hydrochloric acid (1 mol / L), and the crystals were collected by filtration, washed with water and dried to give 2- (4-chlorophenylthio) benzoic acid (1.44 g) as a colorless powder. It was.
¹ H-NMR (400 MHz, DMSO) δ 6.43 (1H, dd, J = 7.3, 1.2 Hz), 6.90 (1H, td, J = 7.3, 1.2 Hz), 7.06 (1H, td, J = 7.3, 1.2 Hz), 7.167.26 (4H, m), 7.58 (1H, dd, J = 7.3, 1.2 Hz), 12.94 (1H, brs).

２−（４−クロロフェニルチオ）安息香酸（参考例１０の化合物：１５０ｍｇ）をトルエン（５ｍＬ）に溶解させ、ジフェニルホスホリルアジド（０．１４７ｍＬ）とトリエチルアミン（０．０８０ｍＬ）を加え３時間加熱還流した。放冷後、４−アミノ−１−ｔｅｒｔ−ブトキシカルボニルピペリジン（１１３ｍｇ）を加え、１時間撹拌した。反応液を酢酸エチルで希釈し、有機層を５％クエン酸水溶液、飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥して溶媒を濃縮した。残渣をシリカゲルクロマトグラフィー（Ｃｈｒｏｍａｔｒｅｘ、ヘキサン：酢酸エチル＝４：１）により精製し、無色アモルファスとして４−｛３−［２−（４−クロロフェニルチオ）フェニル］ウレイド｝ピペリジン−１−カルボン酸ｔｅｒｔ−ブチル（１８８ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.17-1.32(2H, m), 1.45(9H, s), 1.88(2H, d, J = 9.8 Hz), 2.82(2H, t, J = 12.2 Hz), 3.60-2.76(1H, m), 3.92-4.20(2H, m), 4.46(1H, d, J = 7.3 Hz), 6.81(1H, d, J = 7.9 Hz), 7.15(1H, t, J = 7.9 Hz), 7.23-7.31(1H, m), 7.40(2H, d, J = 8.6 Hz), 7.48(2H, d, J = 8.6 Hz), 7.98(1H, dd, J = 7.9, 1.2 Hz). (Reference Example 11)
4- {3- [2- (4-Chlorophenylthio) phenyl] ureido} piperidine-1-carboxylate tert-butyl

2- (4-Chlorophenylthio) benzoic acid (the compound of Reference Example 10: 150 mg) was dissolved in toluene (5 mL), diphenylphosphoryl azide (0.147 mL) and triethylamine (0.080 mL) were added, and the mixture was heated to reflux for 3 hours. . After allowing to cool, 4-amino-1-tert-butoxycarbonylpiperidine (113 mg) was added and stirred for 1 hour. The reaction solution was diluted with ethyl acetate, and the organic layer was washed successively with 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated. The residue was purified by silica gel chromatography (Chromatrex, hexane: ethyl acetate = 4: 1) to give 4- {3- [2- (4-chlorophenylthio) phenyl] ureido} piperidine-1-carboxylic acid tert- as a colorless amorphous substance. Butyl (188 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.17-1.32 (2H, m), 1.45 (9H, s), 1.88 (2H, d, J = 9.8 Hz), 2.82 (2H, t, J = 12.2 Hz ), 3.60-2.76 (1H, m), 3.92-4.20 (2H, m), 4.46 (1H, d, J = 7.3 Hz), 6.81 (1H, d, J = 7.9 Hz), 7.15 (1H, t, J = 7.9 Hz), 7.23-7.31 (1H, m), 7.40 (2H, d, J = 8.6 Hz), 7.48 (2H, d, J = 8.6 Hz), 7.98 (1H, dd, J = 7.9, 1.2 Hz).

参考例１１と同様の方法により、２−（４−クロロフェニルチオ）安息香酸（参考例１０の化合物：３００ｍｇ）、及び４−ヒドロキシメチル−１−ｔｅｒｔ−ブトキシカルボニルピペリジン（２９２ｍｇ）から無色粉末として４−｛［２―（４−クロロフェニルチオ）フェニルカルバモイルオキシ］メチル｝ピペリジン−１−カルボン酸ｔｅｒｔ−ブチル（４５０ｍｇ）を得た。
¹H- NMR (400 MHz, CDCl₃) δ 1.08-1.23(2H, m), 1.46(9H, s), 1.63(2H, d, J = 13.5 Hz), 1.73-1.85(1H, m), 2.62-2.73(2H, m), 3.97(2H, d, J = 6.7 Hz), 4.02-4.18(2H, m), 6.99(2H, d, J = 8.6 Hz), 7.08(1H, td, J = 7.3, 1.2 Hz), 7.20(2H, d, J = 8.6 Hz), 7.45(1H, td, J = 7.3, 1.2 Hz), 7.55(1H, dd, J = 7.3, 1.2 Hz), 7.63(1H, brs), 8.20(1H, d, J = 7.9 Hz). (Reference Example 12)
4-{[2- (4-Chlorophenylthio) phenylcarbamoyloxy] methyl} piperidine-1-carboxylate tert-butyl

In the same manner as in Reference Example 11, 4- (4-chlorophenylthio) benzoic acid (Compound of Reference Example 10: 300 mg) and 4-hydroxymethyl-1-tert-butoxycarbonylpiperidine (292 mg) were obtained as a colorless powder. -{[2- (4-Chlorophenylthio) phenylcarbamoyloxy] methyl} piperidine-1-carboxylate tert-butyl (450 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.08-1.23 (2H, m), 1.46 (9H, s), 1.63 (2H, d, J = 13.5 Hz), 1.73-1.85 (1H, m), 2.62 -2.73 (2H, m), 3.97 (2H, d, J = 6.7 Hz), 4.02-4.18 (2H, m), 6.99 (2H, d, J = 8.6 Hz), 7.08 (1H, td, J = 7.3 , 1.2 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.45 (1H, td, J = 7.3, 1.2 Hz), 7.55 (1H, dd, J = 7.3, 1.2 Hz), 7.63 (1H, brs ), 8.20 (1H, d, J = 7.9 Hz).

４−｛３−［２−（４−クロロフェニルチオ）フェニル］ウレイド｝ピペリジン−１−カルボン酸ｔｅｒｔ−ブチル（参考例１１の化合物：１８５ｍｇ）をジクロロメタン（４ｍＬ）に溶解させ、氷冷下トリフルオロ酢酸（０．３００ｍＬ）を加え、常温で一晩攪拌した。反応液を飽和炭酸水素ナトリウム水溶液によりアルカリ性とし酢酸エチルで抽出し、飽和食塩水で洗浄、硫酸ナトリウムで乾燥後濃縮し、無色アモルファスとして１−［２−（４−クロロフェニルチオ）フェニル］−３−（ピペリジン−４−イル）ウレア（１５０ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.50-1.68(2H, m), 2.00(2H, d, J = 11.0 Hz), 2.84(2H, t, J = 11.0 Hz), 3.26(2H, d, J = 11.0 Hz), 3.70-3.84(1H, m), 5.58(1H, brs), 6.97-7.07(3H, m), 7.17(2H, d, J = 8.6 Hz), 7.37(1H, t, J = 7.9 Hz), 7.42-7.50(2H, m), 8.09(1H, d, J = 7.9 Hz). (Reference Example 13)
1- [2- (4-Chlorophenylthio) phenyl] -3- (piperidin-4-yl) urea

4- {3- [2- (4-Chlorophenylthio) phenyl] ureido} piperidine-1-carboxylate tert-butyl (Compound of Reference Example 11: 185 mg) was dissolved in dichloromethane (4 mL) and trifluoro under ice-cooling. Acetic acid (0.300 mL) was added and stirred overnight at room temperature. The reaction mixture was made alkaline with saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate and concentrated to give 1- [2- (4-chlorophenylthio) phenyl] -3- (Piperidin-4-yl) urea (150 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.50-1.68 (2H, m), 2.00 (2H, d, J = 11.0 Hz), 2.84 (2H, t, J = 11.0 Hz), 3.26 (2H, d , J = 11.0 Hz), 3.70-3.84 (1H, m), 5.58 (1H, brs), 6.97-7.07 (3H, m), 7.17 (2H, d, J = 8.6 Hz), 7.37 (1H, t, J = 7.9 Hz), 7.42-7.50 (2H, m), 8.09 (1H, d, J = 7.9 Hz).

参考例１３と同様の方法により、４−｛［２―（４−クロロフェニルチオ）フェニルカルバモイルオキシ］メチル｝ピペリジン−１−カルボン酸ｔｅｒｔ−ブチル（参考例１２の化合物：２１０ｍｇ）から無色アモルファスとしてピペリジン−４−イルメチル２−（４−クロロフェニルチオ）フェニルカーバメイト（１６５ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.24-1.39(2H, m), 1.72(2H, d, J = 12.8Hz), 1.75-1.87(1H, m), 2.67(2H, td, J = 12.2, 2.4 Hz), 3.21(2H, d, J = 12.2 Hz), 3.98(2H, d, J = 6.7 Hz), 6.99(2H, d, J = 8.6 Hz), 7.03(1H, td, J = 7.3, 1.8 Hz), 7.20(2H, d, J = 8.6 Hz), 7.45(1H, td, J = 7.3, 1.8 Hz), 7.54(1H, dd, J = 7.3, 1.8 Hz), 7.64(1H, s), 8.20(1H, d, J = 8.6 Hz). (Reference Example 14)
Piperidin-4-ylmethyl 2- (4-chlorophenylthio) phenyl carbamate

By the same method as Reference Example 13, 4-{[2- (4-chlorophenylthio) phenylcarbamoyloxy] methyl} piperidine-1-carboxylate tert-butyl (compound of Reference Example 12: 210 mg) was converted into colorless amorphous piperidine. -4-ylmethyl 2- (4-chlorophenylthio) phenyl carbamate (165 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.24-1.39 (2H, m), 1.72 (2H, d, J = 12.8Hz), 1.75-1.87 (1H, m), 2.67 (2H, td, J = 12.2, 2.4 Hz), 3.21 (2H, d, J = 12.2 Hz), 3.98 (2H, d, J = 6.7 Hz), 6.99 (2H, d, J = 8.6 Hz), 7.03 (1H, td, J = 7.3, 1.8 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.45 (1H, td, J = 7.3, 1.8 Hz), 7.54 (1H, dd, J = 7.3, 1.8 Hz), 7.64 (1H, s), 8.20 (1H, d, J = 8.6 Hz).

２−（４−クロロフェニルチオ）ベンズアルデヒド（参考例６の化合物：１．５０ｇ）をメタノール（２０ｍＬ）に溶解させ、水素化ホウ素ナトリウム（２３２ｍｇ）を加え常温で４時間撹拌した。反応液を水にあけ、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して溶媒を濃縮した。残渣をシリカゲルクロマトグラフィー（Ｃｈｒｏｍａｔｒｅｘ、ヘキサン：酢酸エチル＝３：１）により精製し、無色油状物として［２−（４−クロロフェニルチオ）フェニル］メタノール（１．４９ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 4.77(2H, d, J = 6.7 Hz), 7.11(2H, d, J = 8.6 Hz), 7.20-7.31(3H, m), 7.34-7.41(2H, m), 7.53(1H, d, J = 7.3 Hz). (Reference Example 15)
[2- (4-Chlorophenylthio) phenyl] methanol

2- (4-Chlorophenylthio) benzaldehyde (the compound of Reference Example 6: 1.50 g) was dissolved in methanol (20 mL), sodium borohydride (232 mg) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated. The residue was purified by silica gel chromatography (Chromatrex, hexane: ethyl acetate = 3: 1) to give [2- (4-chlorophenylthio) phenyl] methanol (1.49 g) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.77 (2H, d, J = 6.7 Hz), 7.11 (2H, d, J = 8.6 Hz), 7.20-7.31 (3H, m), 7.34-7.41 (2H , m), 7.53 (1H, d, J = 7.3 Hz).

［２−（４−クロロフェニルチオ）フェニル］メタノール（参考例１５の化合物：７０５ｍｇ）を無水テトラヒドロフラン（２０ｍＬ）に溶解させ、フタルイミド（４９０ｍｇ）とトリフェニルホスフィン（８８０ｍｇ）、ジイソプロピルアゾジカルボキシラート（０．８３ｍＬ）を加え、常温で一晩攪拌した。反応液を濃縮し、残渣をシリカゲルクロマトグラフィー（Ｃｈｒｏｍａｔｒｅｘ、ヘキサン：酢酸エチル＝１０：１）により精製し、無色粉末として２−［２−（４−クロロフェニルチオ）ベンジル］イソインドリン−１，３−ジオン（１．０１ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 5.04(2H, s), 7.06(2H, d, J = 8.6 Hz), 7.15(2H, d, J = 8.6 Hz), 7.24-7.35(3H, m), 7.43(1H, d, J = 7.3 Hz), 7.67-7.75(2H, m), 7.78-7.84(2H, m). (Reference Example 16)
2- [2- (4-Chlorophenylthio) benzyl] isoindoline-1,3-dione

[2- (4-Chlorophenylthio) phenyl] methanol (Compound of Reference Example 15: 705 mg) was dissolved in anhydrous tetrahydrofuran (20 mL), phthalimide (490 mg), triphenylphosphine (880 mg), diisopropyl azodicarboxylate (0 .83 mL) was added and stirred overnight at ambient temperature. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (Chromatrex, hexane: ethyl acetate = 10: 1) to give 2- [2- (4-chlorophenylthio) benzyl] isoindoline-1,3- as a colorless powder. Dione (1.01 g) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.04 (2H, s), 7.06 (2H, d, J = 8.6 Hz), 7.15 (2H, d, J = 8.6 Hz), 7.24-7.35 (3H, m ), 7.43 (1H, d, J = 7.3 Hz), 7.67-7.75 (2H, m), 7.78-7.84 (2H, m).

２−［２−（４−クロロフェニルチオ）ベンジル］イソインドリン−１，３−ジオン（参考例１６の化合物：１．０１ｇ）をエタノール（１０ｍＬ）に溶解させ、ヒドラジン一水和物（０．３８ｍＬ）を加え、２時間加熱還流した。反応液をろ過、酢酸エチルで希釈後、飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥して溶媒を濃縮し無色油状物として［２−（４−クロロフェニルチオ）フェニル］メタナミン（６２０ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 3.94(2H, s), 7.12(2H, d, J = 8.6 Hz), 7.19-7.27(3H, m), 7.30-7.38(2H, m), 7.44(1H, dd, J = 7.3, 1.8 Hz). (Reference Example 17)
[2- (4-Chlorophenylthio) phenyl] methanamine

2- [2- (4-Chlorophenylthio) benzyl] isoindoline-1,3-dione (Compound of Reference Example 16: 1.01 g) was dissolved in ethanol (10 mL), and hydrazine monohydrate (0.38 mL) was dissolved. ) And heated to reflux for 2 hours. The reaction mixture was filtered, diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The extract was dried over anhydrous sodium sulfate and the solvent was concentrated to obtain [2- (4-chlorophenylthio) phenyl] methanamine (620 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.94 (2H, s), 7.12 (2H, d, J = 8.6 Hz), 7.19-7.27 (3H, m), 7.30-7.38 (2H, m), 7.44 (1H, dd, J = 7.3, 1.8 Hz).

参考例３と同様の方法により、［２−（４−クロロフェニルチオ）フェニル］メタナミン（ 参考例１７の化合物：３０２ｍｇ）から無色粉末として２−クロロ−Ｎ−［２−（４−クロロフェニルチオ）ベンジル］アセトアミド（２８３ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃ ) δ 4.01(2H, s), 4.60(2H, d, J = 5.5 Hz), 6.93(1H, brs), 7.10(2H, d, J = 8.6 Hz), 7.21-7.28(2H, m), 7.30(1H, td, J = 7.3, 1.2 Hz), 7.41(1H, dd, J = 7.3, 1.2 Hz), 7.45(1H, dd, J = 7.3 , 1.2 Hz). (Reference Example 18)
2-Chloro-N- [2- (4-chlorophenylthio) benzyl] acetamide

In the same manner as in Reference Example 3, 2-chloro-N- [2- (4-chlorophenylthio) benzyl as a colorless powder from [2- (4-chlorophenylthio) phenyl] methanamine (Compound of Reference Example 17: 302 mg) Acetamide (283 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.01 (2H, s), 4.60 (2H, d, J = 5.5 Hz), 6.93 (1H, brs), 7.10 (2H, d, J = 8.6 Hz), 7.21-7.28 (2H, m), 7.30 (1H, td, J = 7.3, 1.2 Hz), 7.41 (1H, dd, J = 7.3, 1.2 Hz), 7.45 (1H, dd, J = 7.3, 1.2 Hz) .

［２−（４−クロロフェニルチオ）フェニル］メタナミン（参考例１７の化合物：２５０ｍｇ）をテトラヒドロフラン（２ｍＬ）に溶解させ、Ｎ，Ｎ’−カルボニルジイミダゾール（１８５ｍｇ）を加え１時間撹拌した。反応液に、４−アミノ−１−ｔｅｒｔ−ブトキシカルボニルピペリジン（２２１ｍｇ）を加え、常温で時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して溶媒を濃縮した。残渣をシリカゲルカラムクロマトグラフィー（シリカゲル６０，０．０４０〜０．０６３ｍｍ；ヘキサン：酢酸エチル＝２：１）で精製し、淡黄色アモルファスとして１−ｔｅｒｔ−ブトキシカルボニル−４−｛３−［２−（４−クロロフェニルチオ）ベンジル］ウレイド｝ピペリジン（１１２ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.21-1.28(2H, m), 1.45(9H, s), 1.80-1.92(2H, m), 2.82(2H, t, J = 10.4 Hz), 3.60-3.72(1H, m), 3.90-4.06(3H, m), 4.44(2H, d, J = 6.1 Hz), 4.61(1H, d, J = 6.1 Hz), 7.08(2H, d, J = 8.6 Hz), 7.21-7.41(5H, m), 7.48(1H, d, J = 7.9 Hz). (Reference Example 19)
1-tert-butoxycarbonyl-4- {3- [2- (4-chlorophenylthio) benzyl] ureido} piperidine

[2- (4-Chlorophenylthio) phenyl] methanamine (the compound of Reference Example 17: 250 mg) was dissolved in tetrahydrofuran (2 mL), N, N′-carbonyldiimidazole (185 mg) was added, and the mixture was stirred for 1 hour. 4-Amino-1-tert-butoxycarbonylpiperidine (221 mg) was added to the reaction solution, and the mixture was stirred at room temperature for an hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated. The residue was purified by silica gel column chromatography (silica gel 60, 0.040 to 0.063 mm; hexane: ethyl acetate = 2: 1) to give 1-tert-butoxycarbonyl-4- {3- [2- (4-Chlorophenylthio) benzyl] ureido} piperidine (112 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.21-1.28 (2H, m), 1.45 (9H, s), 1.80-1.92 (2H, m), 2.82 (2H, t, J = 10.4 Hz), 3.60 -3.72 (1H, m), 3.90-4.06 (3H, m), 4.44 (2H, d, J = 6.1 Hz), 4.61 (1H, d, J = 6.1 Hz), 7.08 (2H, d, J = 8.6 Hz), 7.21-7.41 (5H, m), 7.48 (1H, d, J = 7.9 Hz).

参考例１３と同様の方法により、１−ｔｅｒｔ−ブトキシカルボニル−４−｛３−［２−（４−クロロフェニルチオ）ベンジル］ウレイド｝ピペリジン（参考例１９の化合物：１１０ｍｇ）から淡黄色粉末として１−［２−（４−クロロフェニルチオ）ベンジル］−３−（ピペリジン−４−イル）ウレア（６０．２ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.20-1.32(2H, m), 1.75-1.95(3H, m), 2.60-2.71(2H, m), 2.97-3.10(2H, m), 3.50-3.65(1H, m), 4.10(1H, d, J = 6.1 Hz), 4.44(1H, d, J = 6.1 Hz), 4.60-4.70(1H, m), 7.08(2H, d, J = 8.6 Hz), 7.15-7.40(5H, m), 7.49(1H, d, J = 7.3 Hz). (Reference Example 20)
1- [2- (4-Chlorophenylthio) benzyl] -3- (piperidin-4-yl) urea

In the same manner as in Reference Example 13, from 1-tert-butoxycarbonyl-4- {3- [2- (4-chlorophenylthio) benzyl] ureido} piperidine (the compound of Reference Example 19: 110 mg) as a pale yellow powder, 1 -[2- (4-Chlorophenylthio) benzyl] -3- (piperidin-4-yl) urea (60.2 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.20-1.32 (2H, m), 1.75-1.95 (3H, m), 2.60-2.71 (2H, m), 2.97-3.10 (2H, m), 3.50- 3.65 (1H, m), 4.10 (1H, d, J = 6.1 Hz), 4.44 (1H, d, J = 6.1 Hz), 4.60-4.70 (1H, m), 7.08 (2H, d, J = 8.6 Hz) ), 7.15-7.40 (5H, m), 7.49 (1H, d, J = 7.3 Hz).

炭酸カリウム（２．２ｇ）をＮ−メチル−２−ピロリジノン（５ｍＬ）に懸濁し、氷冷下、ベンジルメルカプタン（０．６２ｍＬ）を加え、その後２−フルオロ−５−（トリフルオロメチル）ベンズアルデヒド（１．００ｇ）を滴下した。常温で１日撹拌後、反応液を水にあけ、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（シリカゲル６０，０．０４０〜０．０６３ｍｍ；ヘキサン：酢酸エチル＝２０：１）で精製し、淡黄色固体として２−（ベンジルチオ）−５−（トリフルオロメチル）ベンズアルデヒド（１．７７ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 4.22 (2H, s), 7.27-7.36 (5H, m), 7.53 (1H, d, J = 8.0 Hz), 7.69 (1H, dd, J = 8.0, 2.0 Hz), 8.05 (1H, d, J = 2.0 Hz), 10.25 (1H, s). (Reference Example 21)
2- (Benzylthio) -5- (trifluoromethyl) benzaldehyde

Potassium carbonate (2.2 g) was suspended in N-methyl-2-pyrrolidinone (5 mL), benzyl mercaptan (0.62 mL) was added under ice cooling, and then 2-fluoro-5- (trifluoromethyl) benzaldehyde ( 1.00 g) was added dropwise. After stirring at room temperature for 1 day, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (silica gel 60, 0.040-0.063 mm; hexane: ethyl acetate = 20: 1), and 2- (benzylthio) -5- (trifluoromethyl) benzaldehyde ( 1.77 g) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.22 (2H, s), 7.27-7.36 (5H, m), 7.53 (1H, d, J = 8.0 Hz), 7.69 (1H, dd, J = 8.0, 2.0 Hz), 8.05 (1H, d, J = 2.0 Hz), 10.25 (1H, s).

参考例１５と同様の方法により、２−（ベンジルチオ）−５−（トリフルオロメチル）ベンズアルデヒド（参考例２１の化合物：７７０ｍｇ）から、淡黄色固体として［２−（ベンジルチオ）−５−（トリフルオロメチル）フェニル］メタノール（７２１ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.90 (1H, t, J = 6.3 Hz), 4.17 (2H, s), 4.71 (2H, d, J = 6.3 Hz), 7.25-7.33 (5H, m), 7.41 (1H, d, J = 7.9 Hz), 7.47 (1H, dd, J = 8.3, 1.5 Hz), 7.67 (1H, d, J = 1.5 Hz). (Reference Example 22)
[2- (Benzylthio) -5- (trifluoromethyl) phenyl] methanol

In the same manner as in Reference Example 15, from 2- (benzylthio) -5- (trifluoromethyl) benzaldehyde (the compound of Reference Example 21: 770 mg) as [2- (benzylthio) -5- (trifluoro Methyl) phenyl] methanol (721 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.90 (1H, t, J = 6.3 Hz), 4.17 (2H, s), 4.71 (2H, d, J = 6.3 Hz), 7.25-7.33 (5H, m ), 7.41 (1H, d, J = 7.9 Hz), 7.47 (1H, dd, J = 8.3, 1.5 Hz), 7.67 (1H, d, J = 1.5 Hz).

参考例１６と同様の方法により、［２−（ベンジルチオ）−５−（トリフルオロメチル）フェニル］メタノール（参考例２２の化合物：７２０ｍｇ）から、白色固体として２−［２−（ベンジルチオ）−５−（トリフルオロメチル）ベンジル］イソインドリン−１，３−ジオン（６１７ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 4.22 (2H, s), 4.97 (2H, s), 7.27-7.34 (6H, m), 7.38-7.41 (2H, m), 7.76 (2H, dd, J = 6.0, 3.0 Hz), 7.90 (2H, dd, J = 6.0, 3.0 Hz). (Reference Example 23)
2- [2- (Benzylthio) -5- (trifluoromethyl) benzyl] isoindoline-1,3-dione

In the same manner as in Reference Example 16, from [2- (benzylthio) -5- (trifluoromethyl) phenyl] methanol (the compound of Reference Example 22: 720 mg) as a white solid, 2- [2- (benzylthio) -5 -(Trifluoromethyl) benzyl] isoindoline-1,3-dione (617 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.22 (2H, s), 4.97 (2H, s), 7.27-7.34 (6H, m), 7.38-7.41 (2H, m), 7.76 (2H, dd, J = 6.0, 3.0 Hz), 7.90 (2H, dd, J = 6.0, 3.0 Hz).

参考例１７と同様の方法により、２−［２−（ベンジルチオ）−５−（トリフルオロメチル）ベンジル］イソインドリン−１，３−ジオン（参考例２３の化合物：３００ｍｇ）から、無色油状物として［２−（ベンジルチオ）−５−（トリフルオロメチル）フェニル］メタナミン（２２９ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 3.90 (2H, s), 4.18 (2H, s), 7.27-7.33 (5H, m), 7.38 (1H, d, J = 7.9 Hz), 7.43 (1H, dd, J = 7.9, 1.5 Hz), 7.59 (1H, d, J = 1.5 Hz). (Reference Example 24)
[2- (Benzylthio) -5- (trifluoromethyl) phenyl] methanamine

In the same manner as in Reference Example 17, 2- [2- (benzylthio) -5- (trifluoromethyl) benzyl] isoindoline-1,3-dione (the compound of Reference Example 23: 300 mg) was obtained as a colorless oil. [2- (Benzylthio) -5- (trifluoromethyl) phenyl] methanamine (229 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.90 (2H, s), 4.18 (2H, s), 7.27-7.33 (5H, m), 7.38 (1H, d, J = 7.9 Hz), 7.43 (1H , dd, J = 7.9, 1.5 Hz), 7.59 (1H, d, J = 1.5 Hz).

参考例３と同様の方法により、［２−（ベンジルチオ）−５−（トリフルオロメチル）フェニル］メタナミン（参考例２４の化合物：２２９ｍｇ）から無色固体としてＮ−［２−（ベンジルチオ）−５−（トリフルオロメチル）ベンジル］−２−クロロアセトアミド（２１９ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 4.07 (2H, s), 4.19 (2H, s), 4.52 (2H, d, J = 6.1 Hz), 6.96 (1H, br s), 7.28-7.34 (5H, m), 7.43 (1H, d, J = 8.3 Hz), 7.48 (1H, dd, J = 8.3, 1.8 Hz), 7.53 (1H, d, J = 1.8 Hz). (Reference Example 25)
N- [2- (benzylthio) -5- (trifluoromethyl) benzyl] -2-chloroacetamide

In the same manner as in Reference Example 3, [2- (benzylthio) -5- (trifluoromethyl) phenyl] methanamine (the compound of Reference Example 24: 229 mg) was converted to N- [2- (benzylthio) -5--5 as a colorless solid. (Trifluoromethyl) benzyl] -2-chloroacetamide (219 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.07 (2H, s), 4.19 (2H, s), 4.52 (2H, d, J = 6.1 Hz), 6.96 (1H, br s), 7.28-7.34 ( 5H, m), 7.43 (1H, d, J = 8.3 Hz), 7.48 (1H, dd, J = 8.3, 1.8 Hz), 7.53 (1H, d, J = 1.8 Hz).

２−アミノ−４−（トリフルオロメチル）チオフェノール（２．３０ｇ）をＮ−メチル−２−ピロリジノン（５０ｍＬ）に溶かし、カリウムエトキシド（８５０ｍｇ）を加えた。常温で３０分撹拌した後、反応液を０℃に冷却して、ベンジルブロミド（１．１９ｍＬ）を加えた。反応液を常温に戻し、３時間撹拌した。反応液を水にあけ、酢酸エチルで抽出した後、有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（シリカゲル６０，０．０４０〜０．０６３ｍｍ；ヘキサン：酢酸エチル＝２０：１）で精製し、淡黄色固体として２−（ベンジルチオ）−５−（トリフルオロメチル）アニリン（１．４１ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 3.94 (2H, s), 4.40 (2H, br s), 6.83 (1H, dd, J = 7.9, 1.2 Hz), 6.90 (1H, d, J = 1.2 Hz), 7.14-7.16 (2H, m), 7.22-7.28 (4H, m). (Reference Example 26)
2- (Benzylthio) -5- (trifluoromethyl) aniline

2-Amino-4- (trifluoromethyl) thiophenol (2.30 g) was dissolved in N-methyl-2-pyrrolidinone (50 mL) and potassium ethoxide (850 mg) was added. After stirring at room temperature for 30 minutes, the reaction solution was cooled to 0 ° C. and benzyl bromide (1.19 mL) was added. The reaction solution was returned to room temperature and stirred for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (silica gel 60, 0.040-0.063 mm; hexane: ethyl acetate = 20: 1), and 2- (benzylthio) -5- (trifluoromethyl) aniline ( 1.41 g) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.94 (2H, s), 4.40 (2H, br s), 6.83 (1H, dd, J = 7.9, 1.2 Hz), 6.90 (1H, d, J = 1.2 Hz), 7.14-7.16 (2H, m), 7.22-7.28 (4H, m).

塩化チオニル（８．０ｍＬ）にピペロニル酸（１．６７ｇ）を加えて２時間加熱還流した。反応液を減圧留去して黄色残渣が得られた。１−ベンジル−２，６−ジメチルピペラジン（ＷＯ２００５０５８３２７に記載の方法で調製した；２．０５ｇ）及びトリエチルアミン（７．０ｍＬ）をテトラヒドロフラン（２０ｍＬ）に溶かし、上記黄色残渣のテトラヒドロフラン（５ｍＬ）溶液を氷冷下で加えて、更に１時間撹拌後、常温で２時間撹拌した。反応液を酢酸エチルで希釈して、水及び飽和食塩水で順次洗浄後、無水硫酸ナトリウム上乾燥した。溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（シリカゲル６０，０．０４０〜０．０６３ｍｍ；ヘキサン：酢酸エチル＝２：１）で精製し、淡黄色油状物として１−ベンジル−４−（１，３−ベンゾジオキソール−５−イルカルボニル）−３，５−ジメチルピペラジンを得た（３．００ｇ）。
¹H-NMR (400 MHz, CDCl₃) δ 1.38 (6H, d, J = 7.3 Hz), 2.18 (2H, dd, J = 11.0 and 4.3 Hz), 2.65 (2H, d, J = 11.0 Hz), 4.20-4.40 (2H, br), 5.98 (2H, s), 6.78-6.86 (3H, m), 7.22-7.38 (5H, s). (Reference Example 27)
1 -Benzyl-4- (1,3-benzodioxol-5-ylcarbonyl) -3,5-dimethylpiperazine

Piperonyl acid (1.67 g) was added to thionyl chloride (8.0 mL), and the mixture was heated to reflux for 2 hours. The reaction solution was distilled off under reduced pressure to obtain a yellow residue. 1-Benzyl-2,6-dimethylpiperazine (prepared by the method described in WO2005058327; 2.05 g) and triethylamine (7.0 mL) were dissolved in tetrahydrofuran (20 mL), and a solution of the above yellow residue in tetrahydrofuran (5 mL) was dissolved in ice. The mixture was added under cooling and further stirred for 1 hour, and then stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (silica gel 60, 0.040 to 0.063 mm; hexane: ethyl acetate = 2: 1) to give 1-benzyl-4 as a pale yellow oil. -(1,3-Benzodioxol-5-ylcarbonyl) -3,5-dimethylpiperazine was obtained (3.00 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (6H, d, J = 7.3 Hz), 2.18 (2H, dd, J = 11.0 and 4.3 Hz), 2.65 (2H, d, J = 11.0 Hz), 4.20-4.40 (2H, br), 5.98 (2H, s), 6.78-6.86 (3H, m), 7.22-7.38 (5H, s).

１−ベンジル−４−（１，３−ベンゾジオキソール−５−イルカルボニル）−３，５−ジメチルピペラジン（参考例２７の化合物：２．９５ｇ）をＥｔＯＨ（２００ｍＬ）に溶かし、常温で１０％Ｐｄ−Ｃ（８００ｍｇ）を加えた。反応液を水素ガス雰囲気下、５ｋｇｆ／ｃｍ^２の圧力で常温で８時間撹拌した。反応液をろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（Ｃｈｒｏｍａｔｒｅｘ；ＥｔＯＡｃ）で精製し、無色固体として１−（１，３−ベンゾジオキソール−５−イルカルボニル）−２，６−ジメチルピペラジンを得た（１．８３ｇ）。
¹H-NMR (400 MHz, CDCl₃) δ 1.35 (6H, d, J = 6.7 Hz), 2.83 (2H, d, J = 12.2 Hz), 2.89 (2H, dd, J = 12.2 and 4.3 Hz), 4.15-4.35 (2H, br), 5.99 (2H, s), 6.80-6.86 (3H, m). (Reference Example 28)
1- (1,3-Benzodioxol-5-ylcarbonyl) -2,6-dimethylpiperazine

1-Benzyl-4- (1,3-benzodioxol-5-ylcarbonyl) -3,5-dimethylpiperazine (compound of Reference Example 27: 2.95 g) was dissolved in EtOH (200 mL), and 10 % Pd-C (800 mg) was added. The reaction solution was stirred at room temperature for 8 hours under a hydrogen gas atmosphere at a pressure of 5 kgf / cm ² . The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Chromatrex; EtOAc) to give 1- (1,3-benzodioxol-5-ylcarbonyl) -2,6-dimethylpiperazine as a colorless solid (1.83 g). .
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.35 (6H, d, J = 6.7 Hz), 2.83 (2H, d, J = 12.2 Hz), 2.89 (2H, dd, J = 12.2 and 4.3 Hz), 4.15-4.35 (2H, br), 5.99 (2H, s), 6.80-6.86 (3H, m).

１−（１，３−ベンゾジオキソール−５−イルカルボニル）−２，６−ジメチルピペラジン（参考例２８の化合物：１．００ｇ）をＴＨＦ（２０ｍＬ）とＥｔ_２Ｏ（１００ｍＬ）に溶かし、常温でリチウムアルミニウムハイドライド（３００ｍｇ）を加えた。反応液を常温で５時間撹拌した後、反応液を水にあけ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（Ｃｈｒｏｍａｔｒｅｘ；ＥｔＯＡｃ）で精製し、淡黄色油状物として２，６−ジメチル−１−ピペロニルピペラジンを得た（７２５ｍｇ）。
¹H-NMR (400 MHz, 400 MHz, CDCl₃) δ 1.00 (6H, d, J = 5.5 Hz), 2.42-2.58 (4H, m), 2.87 (2H, d, J = 8.6 Hz), 3.74 (2H, s), 5.93 (2H, s), 6.74 (1H, d, J = 7.9 Hz), 6.79 (1H, dd, J = 7.9 and 1.2 Hz), 6.92 (1H, d, J = 1.2 Hz). (Reference Example 29)
2,6-Dimethyl-1-piperonylpiperazine

1- (1,3-benzodioxol-5-ylcarbonyl) -2,6-dimethylpiperazine (the compound of Reference Example 28: 1.00 g) was dissolved in THF (20 mL) and Et ₂ O (100 mL), Lithium aluminum hydride (300 mg) was added at room temperature. After stirring the reaction solution at room temperature for 5 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Chromatrex; EtOAc) to give 2,6-dimethyl-1-piperonylpiperazine (725 mg) as a pale yellow oil.
¹ H-NMR (400 MHz, 400 MHz, CDCl ₃ ) δ 1.00 (6H, d, J = 5.5 Hz), 2.42-2.58 (4H, m), 2.87 (2H, d, J = 8.6 Hz), 3.74 ( 2H, s), 5.93 (2H, s), 6.74 (1H, d, J = 7.9 Hz), 6.79 (1H, dd, J = 7.9 and 1.2 Hz), 6.92 (1H, d, J = 1.2 Hz).

２−クロロ−２’−（４−クロロフェニルチオ）−アセトアニリド（参考例３の化合物：９０ｍｇ）と１−ピペロニルピペラジン（１２０ｍｇ）とトリエチルアミン（０．３ｍＬ）をジクロロメタン（３ｍＬ）に溶解し、１２時間加熱還流した。反応液を水にあけ、酢酸エチルで抽出し、有機層を水と飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、反応液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（シリカゲル６０，０．０４０〜０．０６３ｍｍ；ヘキサン：酢酸エチル＝２：１→１：１）で精製し、無色油状物として２−（４−ベンゾ［１，３］ジオキソール−５−イルメチル−ピペラジン−１−イル）−Ｎ−［２−（４−クロロフェニルチオ）フェニル］アセトアミド（９９ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 2.29 (4H, br s), 2.47 (4H, br s), 3.06 (2H, s), 3.35 (2H, s), 5.94 (2H, s), 6.70-6.77 (2H, m), 6.82 (1H, d, J = 1.4 Hz), 6.91 (2H, d, J = 8.6 Hz), 7.13 (1H, td, J = 7.6, 1.4 Hz), 7.19 (2H, d, J = 8.6 Hz), 7.47 (1H, td, J = 7.6, 1.4 Hz), 7.57 (1H, dd, J = 7.6, 1.4 Hz), 8.58 (1H, dd, J = 8.3, 1.4 Hz), 10.25 (1H, s).
MS(FAB⁺)m/z:469(M+H⁺)．
HRMS(FAB⁺) for C₂₅H₂₇ClN₃O₂S [M+H]⁺: calcd, 496.1462; found, 496.1488． Example 1
2- (4-Benzo [1,3] dioxol-5-ylmethyl-piperazin-1-yl) -N- [2- (4-chlorophenylthio) phenyl] acetamide

2-Chloro-2 ′-(4-chlorophenylthio) -acetanilide (Compound of Reference Example 3: 90 mg), 1-piperonylpiperazine (120 mg) and triethylamine (0.3 mL) were dissolved in dichloromethane (3 mL), Heated to reflux for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the reaction mixture is concentrated, and the residue is purified by silica gel column chromatography (silica gel 60, 0.040 to 0.063 mm; hexane: ethyl acetate = 2: 1 → 1: 1), and colorless oil As a product, 2- (4-benzo [1,3] dioxol-5-ylmethyl-piperazin-1-yl) -N- [2- (4-chlorophenylthio) phenyl] acetamide (99 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.29 (4H, br s), 2.47 (4H, br s), 3.06 (2H, s), 3.35 (2H, s), 5.94 (2H, s), 6.70 -6.77 (2H, m), 6.82 (1H, d, J = 1.4 Hz), 6.91 (2H, d, J = 8.6 Hz), 7.13 (1H, td, J = 7.6, 1.4 Hz), 7.19 (2H, d, J = 8.6 Hz), 7.47 (1H, td, J = 7.6, 1.4 Hz), 7.57 (1H, dd, J = 7.6, 1.4 Hz), 8.58 (1H, dd, J = 8.3, 1.4 Hz), 10.25 (1H, s).
MS (FAB ⁺ ) m / z: 469 (M + H ⁺ ).
HRMS (FAB ⁺ ) for C ₂₅ H ₂₇ ClN ₃ O ₂ S [M + H] ⁺ : calcd, 496.1462; found, 496.1488.

実施例１と同様の方法により、３−クロロ−２’−（４−クロロフェニルチオ）−プロピオアニリド（参考例４の化合物：７９．５ｍｇ）、及び１−ピペロニルピペラジン（１０９ｍｇ）から無色粉末として３−（４−ベンゾ［１，３］ジオキソール−５−イルメチル−ピペリジン−１−イル）−Ｎ−［２−（４−クロロフェニルチオ）フェニル］プロパンアミド（９０．８ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 2.25-2.65(12H, m), 3.30(2H, s), 5.94(2H, s), 6.69(1H, d, J = 7.9 Hz), 6.74(1H, d, J = 7.9 Hz), 6.81(1H, d, J = 1.8 Hz), 6.98(2H, d, J = 8.6 Hz), 7.11(1H, td, J = 7.9, 1.2 Hz), 7.22(2H, d, J = 8.6 Hz), 7.42(1H, t, J = 7.9 Hz), 7.46(1H, dd, J = 7.9, 1.2 Hz), 8.28 (1H, d, J = 7.9 Hz), 10.53(1H, brs).
FABMS (M+H): 510
HRMS(FAB⁺) for C₂₇H₂₉ClN₃O₂S [M+H]⁺: calcd, 510.1618; found, 510.1597． (Example 2)
3- (4-Benzo [1,3] dioxol-5-ylmethyl-piperidin-1-yl) -N- [2- (4-chlorophenylthio) phenyl] propanamide

In the same manner as in Example 1, from 3-chloro-2 ′-(4-chlorophenylthio) -propioanilide (the compound of Reference Example 4: 79.5 mg) and 1-piperonylpiperazine (109 mg) 3- (4-Benzo [1,3] dioxol-5-ylmethyl-piperidin-1-yl) -N- [2- (4-chlorophenylthio) phenyl] propanamide (90.8 mg) was obtained as a powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.25-2.65 (12H, m), 3.30 (2H, s), 5.94 (2H, s), 6.69 (1H, d, J = 7.9 Hz), 6.74 (1H , d, J = 7.9 Hz), 6.81 (1H, d, J = 1.8 Hz), 6.98 (2H, d, J = 8.6 Hz), 7.11 (1H, td, J = 7.9, 1.2 Hz), 7.22 (2H , d, J = 8.6 Hz), 7.42 (1H, t, J = 7.9 Hz), 7.46 (1H, dd, J = 7.9, 1.2 Hz), 8.28 (1H, d, J = 7.9 Hz), 10.53 (1H , brs).
FABMS (M + H): 510
HRMS (FAB ⁺ ) for C ₂₇ H ₂₉ ClN ₃ O ₂ S [M + H] ⁺ : calcd, 510.1618; found, 510.1597.

２−ブロモ−Ｎ−［２−（４−クロロフェニルチオ）フェニル］−２−メチルプロピルアミド（参考例５の化合物：１００ｍｇ）をＮ，Ｎ−ジメチルアセトアミド（５ｍＬ）に溶解させ、炭酸カリウム（７５ｍｇ）、１−ピペロニルピペラジン（１１５ｍｇ）を加え、８０℃で４時間加熱撹拌した。反応液を水にあけ、酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥して溶媒を濃縮した。残渣をシリカゲルカラムクロマトグラフィー（シリカゲル６０，０．０４０〜０．０６３ｍｍ；ヘキサン：酢酸エチル＝５：１→１：１）で精製し、無色アモルファスとして２−（４−ベンゾ［１，３］ジオキソール−５−イルメチル−ピペラジン−１−イル）−Ｎ−［２−（４−クロロフェニルチオ）フェニル］−２−メチルプロパンアミド（８８．０ｍｇ）得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.11(6H, s), 2.17-2.55(8H, m), 3.34(2H, s), 5.94(2H, s), 6.68-6.76(2H, m), 6.81(1H, s), 6.91(2H, d, J = 8.6 Hz), 7.11(1H, td, J = 7.3, 1.2 Hz), 7.20(2H, d, J = 8.6 Hz), 7.47(1H, t, td, J = 7.3 Hz), 7.57(1H, dd, J = 7.3, 1.2 Hz), 8.60(1H, dd, J = 7.3, 1.2 Hz), 10.37(1H, s).
ESIMS (M+H): 524
HRMS(ESI⁺) for C₂₈H₃₁ClN₃O₃S [M+H]⁺: calcd, 524.17746; found, 524.17527． (Example 3)
2- (4-Benzo [1,3] dioxol-5-ylmethyl-piperazin-1-yl) -N- [2- (4-chlorophenylthio) phenyl] -2-methylpropanamide

2-Bromo-N- [2- (4-chlorophenylthio) phenyl] -2-methylpropylamide (the compound of Reference Example 5: 100 mg) was dissolved in N, N-dimethylacetamide (5 mL), and potassium carbonate (75 mg) was dissolved. ), 1-piperonylpiperazine (115 mg) was added, and the mixture was heated and stirred at 80 ° C. for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated. The residue was purified by silica gel column chromatography (silica gel 60, 0.040 to 0.063 mm; hexane: ethyl acetate = 5: 1 → 1: 1) to give 2- (4-benzo [1,3] dioxole as a colorless amorphous substance. -5-ylmethyl-piperazin-1-yl) -N- [2- (4-chlorophenylthio) phenyl] -2-methylpropanamide (88.0 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.11 (6H, s), 2.17-2.55 (8H, m), 3.34 (2H, s), 5.94 (2H, s), 6.68-6.76 (2H, m) , 6.81 (1H, s), 6.91 (2H, d, J = 8.6 Hz), 7.11 (1H, td, J = 7.3, 1.2 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.47 (1H, t, td, J = 7.3 Hz), 7.57 (1H, dd, J = 7.3, 1.2 Hz), 8.60 (1H, dd, J = 7.3, 1.2 Hz), 10.37 (1H, s).
ESIMS (M + H): 524
HRMS (ESI ⁺ ) for C ₂₈ H ₃₁ ClN ₃ O ₃ S [M + H] ⁺ : calcd, 524.17746; found, 524.17527.

（Ｅ）−３−［２−（４−クロロフェニルチオ）フェニル］アクリル酸（参考例８の化合物：１００ｍｇ）、１−ピペロニルピペラジン（１２０ｍｇ）、１−ヒドロキシベンゾトリアゾール（６０ｍｇ）をジクロロメタン（４ｍＬ）に溶かし、Ｎ−エチル−Ｎ’−３−ジメチルアミノプロピルカルボジイミド塩酸塩（１２０ｍｇ）を加え、常温で一日撹拌した。反応液を水にあけ、酢酸エチルで抽出し、有機層を水と飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、反応液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（シリカゲル６０，０．０４０〜０．０６３ｍｍ；ヘキサン：酢酸エチル＝１：１）で精製し、無色アモルファスとして（１−［４−（ベンゾ［１，３］ジオキソール−５−イルメチル）ピペラジン−１−イル］−３−［２−（４−クロロフェニルチオ）フェニル］プロペン−１−オン（１５２ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 2.45 (4H, br s), 3.47 (2H, s), 3.56 (2H, br s), 3.72 (2H, br s), 5.94 (2H, s), 6.70-6.75 (3H, m), 6.85 (1H, s), 7.12 (2H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.26-7.37 (3H, m), 7.59 (1H, dd, J = 7.3, 1.8 Hz), 8.03 (1H, d, J = 15.3 Hz).
ESIMS (M+H): 493
HRMS(FAB⁺) for C₂₇H₂₅ClN₂O₃S [M+H]⁺: calcd, 493.1353; found, 493.1350. Example 4
(1- [4- (Benzo [1,3] dioxol-5-ylmethyl) piperazin-1-yl] -3- [2- (4-chlorophenylthio) phenyl] propen-1-one

(E) -3- [2- (4-Chlorophenylthio) phenyl] acrylic acid (the compound of Reference Example 8: 100 mg), 1-piperonylpiperazine (120 mg) and 1-hydroxybenzotriazole (60 mg) were added to dichloromethane ( 4 mL), N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride (120 mg) was added, and the mixture was stirred at room temperature for one day. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the reaction mixture is concentrated, and the residue is purified by silica gel column chromatography (silica gel 60, 0.040-0.063 mm; hexane: ethyl acetate = 1: 1) to give colorless amorphous (1- [4- (Benzo [1,3] dioxol-5-ylmethyl) piperazin-1-yl] -3- [2- (4-chlorophenylthio) phenyl] propen-1-one (152 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.45 (4H, br s), 3.47 (2H, s), 3.56 (2H, br s), 3.72 (2H, br s), 5.94 (2H, s), 6.70-6.75 (3H, m), 6.85 (1H, s), 7.12 (2H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.26-7.37 (3H, m), 7.59 (1H, dd, J = 7.3, 1.8 Hz), 8.03 (1H, d, J = 15.3 Hz).
ESIMS (M + H): 493
HRMS (FAB ⁺ ) for C ₂₇ H ₂₅ ClN ₂ O ₃ S [M + H] ⁺ : calcd, 493.1353; found, 493.1350.

１−［２−（４−クロロフェニルチオ）フェニル］−３−（ピペリジン−４−イル）ウレア（参考例１３の化合物：７０．０ｍｇ）をジクロロメタン（２ｍＬ）に溶解させ、ピペロナール（３０．０ｍｇ）、酢酸（０．０２５ｍＬ）、水素化トリアセトキシホウ素ナトリウム（６１．０ｍｇ）を加え、常温で８時間撹拌した。反応液に水を加え、飽和炭酸水素ナトリウム水溶液で塩基性とした後、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して溶媒を濃縮した。残渣をシリカゲルクロマトグラフィー（Ｃｈｒｏｍａｔｒｅｘ，ヘキサン：酢酸エチル＝２：１）により精製し、無色粉末として１−［１−（ベンゾ［１，３］ジオキソール−５−イルメチル）ピペリジン−４−イル］−３−［２−（４−クロロフェニルチオ）フェニル］ウレア（４９．２ｍｇ）得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.32-1.45(2H, m), 1.87(2H, d, J = 11.0 Hz), 2.04(2H, t, J = 11.0 Hz), 2.76(2H, d, J = 11.0 Hz), 3.28(2H, s), 3.46-3.60(1H, m), 4.35(1H, d, J = 7.3 Hz), 5.94(2H, s), 6.68-6.76(2H, m), 6.83(1H, s), 6.97(2H, d, J = 8.6 Hz), 7.04(1H, td, J = 7.3, 1.2 Hz), 7.15(1H, brs), 7.20(2H, d, J = 8.6 Hz), 7.42(1H, t, J = 7.3 Hz), 7.49(1H, dd, J = 7.3, 1.2 Hz), 8.20(1H, d, J = 7.3 Hz).
ESIMS (M+H): 496
HRMS(FAB⁺) for C₂₆H₂₇ClN₃O₃S [M+H]⁺: calcd, 496.14616; found, 496.14541． (Example 5)
1- [1- (Benzo [1,3] dioxol-5-ylmethyl) piperidin-4-yl] -3- [2- (4-chlorophenylthio) phenyl] urea

1- [2- (4-Chlorophenylthio) phenyl] -3- (piperidin-4-yl) urea (Compound of Reference Example 13: 70.0 mg) was dissolved in dichloromethane (2 mL) and piperonal (30.0 mg) was dissolved. , Acetic acid (0.025 mL) and sodium triacetoxyborohydride (61.0 mg) were added, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was basified with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated. The residue was purified by silica gel chromatography (Chromatrex, hexane: ethyl acetate = 2: 1) to give 1- [1- (benzo [1,3] dioxol-5-ylmethyl) piperidin-4-yl] -3 as a colorless powder. -[2- (4-Chlorophenylthio) phenyl] urea (49.2 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.32-1.45 (2H, m), 1.87 (2H, d, J = 11.0 Hz), 2.04 (2H, t, J = 11.0 Hz), 2.76 (2H, d , J = 11.0 Hz), 3.28 (2H, s), 3.46-3.60 (1H, m), 4.35 (1H, d, J = 7.3 Hz), 5.94 (2H, s), 6.68-6.76 (2H, m) , 6.83 (1H, s), 6.97 (2H, d, J = 8.6 Hz), 7.04 (1H, td, J = 7.3, 1.2 Hz), 7.15 (1H, brs), 7.20 (2H, d, J = 8.6 Hz), 7.42 (1H, t, J = 7.3 Hz), 7.49 (1H, dd, J = 7.3, 1.2 Hz), 8.20 (1H, d, J = 7.3 Hz).
ESIMS (M + H): 496
HRMS (FAB ⁺ ) for C ₂₆ H ₂₇ ClN ₃ O ₃ S [M + H] ⁺ : calcd, 496.14616; found, 496.14541.

実施例５と同様の方法により、ピペリジン−４−イルメチル２−（４−クロロフェニルチオ）フェニルカーバメイト（参考例１４の化合物：１６０ｍｇ）から無色油状物として［１−（ベンゾ［１，３］ジオキソール−５−イルメチル）ピペリジン−４−イル］メチル２−（４−クロロフェニルチオ）フェニルカーバメイト（１２３ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.23-1.35(3H, m), 1.55-1.67(2H, m), 1.91(2H, t, J = 11.6 Hz), 2.87(2H, d, J = 11.6 Hz), 3.39(2H, s), 3.97(2H, d, J = 5.5 Hz), 5.93(2H, s), 6.60-6.72(2H, m), 6.84(1H, s), 6.98(2H, d, J = 8.6 Hz), 7.07(1H, td, J = 7.3, 1.2 Hz), 7.19(2H, d, J = 8.6, Hz), 7.44(1H, td, J = 7.3, 1.2 Hz), 7.54(1H, dd, J = 7.3, 1.2 Hz), 7.62(1H, brs), 8.21(1H, d, J = 7.9 Hz).
ESIMS (M+H): 511
HRMS(FAB⁺) for C₂₇H₂₈ClN₂O₄S [M+H]⁺: calcd, 511.14683; found, 511.14564． (Example 6)
[1- (Benzo [1,3] dioxol-5-ylmethyl) piperidin-4-yl] methyl 2- (4-chlorophenylthio) phenylcarbamate

In the same manner as in Example 5, piperidin-4-ylmethyl 2- (4-chlorophenylthio) phenyl carbamate (the compound of Reference Example 14: 160 mg) was converted into [1- (benzo [1,3] dioxole- 5-ylmethyl) piperidin-4-yl] methyl 2- (4-chlorophenylthio) phenyl carbamate (123 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.23-1.35 (3H, m), 1.55-1.67 (2H, m), 1.91 (2H, t, J = 11.6 Hz), 2.87 (2H, d, J = 11.6 Hz), 3.39 (2H, s), 3.97 (2H, d, J = 5.5 Hz), 5.93 (2H, s), 6.60-6.72 (2H, m), 6.84 (1H, s), 6.98 (2H, d, J = 8.6 Hz), 7.07 (1H, td, J = 7.3, 1.2 Hz), 7.19 (2H, d, J = 8.6, Hz), 7.44 (1H, td, J = 7.3, 1.2 Hz), 7.54 (1H, dd, J = 7.3, 1.2 Hz), 7.62 (1H, brs), 8.21 (1H, d, J = 7.9 Hz).
ESIMS (M + H): 511
HRMS (FAB ⁺ ) for C ₂₇ H ₂₈ ClN ₂ O ₄ S [M + H] ⁺ : calcd, 511.14683; found, 511.14564.

実施例１と同様の方法により、２−クロロ−Ｎ−［２−（４−クロロフェニルチオ）ベンジル］アセトアミド（参考例１８の化合物：８０．５ｍｇ）から無色粉末として２−（４−ベンゾ［１，３］ジオキソール−５−イルメチル−ピペラジン−１−イル）−Ｎ−［２−（４−クロロフェニルチオ）ベンジル］−アセトアミド（１１６ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 2.30-2.54(8H, m), 2.98(2H, s), 3.39(2H, s), 4.56(2H, d, J = 6.1 Hz), 5.94(2H, s), 6.69-6.76(2H, m), 6.82(1H, s), 7.10(2H, d, J = 8.6 Hz), 7.22-7.39(5H, m), 7.43(1H, d, J = 7.3 Hz), 7.59(1H, brs).
ESIMS (M+H): 510
HRMS(FAB⁺) for C₂₇H₂₉ClN₃O₃S [M+H]⁺: calcd, 510.16181; found, 510.16131．
元素分析値 found: C, 63.54; H, 5.63; N, 8.02. calcd. for C₂₇H₂₈ClN₃O₃S: C, 63.58; H, 5.53; N, 8.24. (Example 7)
2- (4-Benzo [1,3] dioxol-5-ylmethyl-piperazin-1-yl) -N- [2- (4-chlorophenylthio) benzyl] acetamide

In the same manner as in Example 1, 2-chloro-N- [2- (4-chlorophenylthio) benzyl] acetamide (the compound of Reference Example 18: 80.5 mg) was converted into 2- (4-benzo [1 , 3] dioxol-5-ylmethyl-piperazin-1-yl) -N- [2- (4-chlorophenylthio) benzyl] -acetamide (116 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.30-2.54 (8H, m), 2.98 (2H, s), 3.39 (2H, s), 4.56 (2H, d, J = 6.1 Hz), 5.94 (2H , s), 6.69-6.76 (2H, m), 6.82 (1H, s), 7.10 (2H, d, J = 8.6 Hz), 7.22-7.39 (5H, m), 7.43 (1H, d, J = 7.3 Hz), 7.59 (1H, brs).
ESIMS (M + H): 510
HRMS (FAB ⁺ ) for C ₂₇ H ₂₉ ClN ₃ O ₃ S [M + H] ⁺ : calcd, 510.16181; found, 510.16131.
Elemental analysis found: C, 63.54; H, 5.63; N, 8.02.calcd.for C ₂₇ H ₂₈ ClN ₃ O ₃ S: C, 63.58; H, 5.53; N, 8.24.

２−クロロ−Ｎ−［２−（４−クロロフェニルチオ）ベンジル］アセトアミド（参考例１８の化合物：５０．０ｍｇ）をジクロロメタン（３ｍＬ）に溶かし、１−フェニルピペラジン（６０．０ｍｇ）とジイソプロピルエチルアミン（０．２ｍＬ）を加え、常温で１日撹拌した。反応液を水にあけ、酢酸エチルで抽出し、有機層を水と飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、反応液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（シリカゲル６０，０．０４０〜０．０６３ｍｍ；ヘキサン：酢酸エチル＝２：１）で精製し、無色油状物として２−［４−（１，３−ベンゾジオキソール−５−イル）ピペラジン−１−イル］−Ｎ−［２−（４−クロロフェニルチオ）ベンジル］アセトアミド（６０．０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 2.62 (4H, t, J = 4.9 Hz), 3.01 (4H, t, J = 4.9 Hz), 3.04 (2H, s), 4.57 (2H, d, J = 6.1 Hz), 5.90 (2H, s), 6.32 (1H, dd, J = 8.6, 2.4 Hz), 6.52 (1H, d, J = 2.4 Hz), 6.72 (1H, d, J = 8.6 Hz), 7.06-7.12 (2H, m), 7.20-7.38 (4H, m), 7.45 (1H, dd, J = 7.3, 1.2 Hz), 7.58 (1H, d, J = 5.5 Hz). (Example 8)
2- [4- (1,3-Benzodioxol-5-yl) piperazin-1-yl] -N- [2- (4-chlorophenylthio) benzyl] acetamide

2-Chloro-N- [2- (4-chlorophenylthio) benzyl] acetamide (the compound of Reference Example 18: 50.0 mg) was dissolved in dichloromethane (3 mL), and 1-phenylpiperazine (60.0 mg) and diisopropylethylamine ( 0.2 mL) was added and stirred at room temperature for 1 day. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the reaction mixture is concentrated, and the residue is purified by silica gel column chromatography (silica gel 60, 0.040-0.063 mm; hexane: ethyl acetate = 2: 1) to give 2- [4- (1,3-Benzodioxol-5-yl) piperazin-1-yl] -N- [2- (4-chlorophenylthio) benzyl] acetamide (60.0 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.62 (4H, t, J = 4.9 Hz), 3.01 (4H, t, J = 4.9 Hz), 3.04 (2H, s), 4.57 (2H, d, J = 6.1 Hz), 5.90 (2H, s), 6.32 (1H, dd, J = 8.6, 2.4 Hz), 6.52 (1H, d, J = 2.4 Hz), 6.72 (1H, d, J = 8.6 Hz), 7.06-7.12 (2H, m), 7.20-7.38 (4H, m), 7.45 (1H, dd, J = 7.3, 1.2 Hz), 7.58 (1H, d, J = 5.5 Hz).

実施例１と同様の方法により、２−クロロ−Ｎ−［２−（４−クロロフェニルチオ）ベンジル］アセトアミド（参考例１８の化合物：１３０ｍｇ）と、１−（１，３−ベンゾジオキソール−５−イルカルボニル）−２，６−ジメチルピペラジン（１１１ｍｇ）から、無色アモルファスとして２−［４−（１，３−ベンゾジオキソール−５−イルカルボニル）−３，５−ジメチルピペラジン−１−イル］−Ｎ−［２−（４−クロロフェニルチオ）ベンジル］アセトアミド（２２０ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.27 (6H, d, J = 7.3 Hz), 2.35 (2H, dd, J = 11.0 and 4.2 Hz), 2.60 (2H, d, J = 11.0 Hz), 3.01 (2H, s), 4.20-4.40 (2H, br), 4.59 (1H, d, J = 6.1 Hz), 5.99 (2H, s), 6.78-6.73 (3H, m), 7.07-7.12 (2H, m), 7.22-7.35 (4H, m), 7.38-7.46 (2H, m). Example 9
2- [4- (1,3-Benzodioxol-5-ylcarbonyl) -3,5-dimethylpiperazin-1-yl] -N- [2- (4-chlorophenylthio) benzyl] acetamide

In the same manner as in Example 1, 2-chloro-N- [2- (4-chlorophenylthio) benzyl] acetamide (the compound of Reference Example 18: 130 mg) and 1- (1,3-benzodioxole- From 5-ylcarbonyl) -2,6-dimethylpiperazine (111 mg) as colorless amorphous, 2- [4- (1,3-benzodioxol-5-ylcarbonyl) -3,5-dimethylpiperazine-1- Yl] -N- [2- (4-chlorophenylthio) benzyl] acetamide (220 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.27 (6H, d, J = 7.3 Hz), 2.35 (2H, dd, J = 11.0 and 4.2 Hz), 2.60 (2H, d, J = 11.0 Hz), 3.01 (2H, s), 4.20-4.40 (2H, br), 4.59 (1H, d, J = 6.1 Hz), 5.99 (2H, s), 6.78-6.73 (3H, m), 7.07-7.12 (2H, m), 7.22-7.35 (4H, m), 7.38-7.46 (2H, m).

実施例１と同様の方法により、２−クロロ−Ｎ−［２−（４−クロロフェニルチオ）ベンジル］アセトアミド（参考例１８の化合物：１３０ｍｇ）と、２，６−ジメチル−１−ピペロニルピペラジン（１０５ｍｇ）とジイソプロピルエチルアミン（０．２８ｍＬ）から、無色固体としてＮ−［２−（４−クロロフェニルチオ）ベンジル］−２−（３，５−ジメチル−４−ピペロニルピペラジン−１−イル）アセトアミド（２１５ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 0.98 (6H, d, J = 6.1 Hz), 2.00-2.09 (2H, m), 2.50-2.62 (4H, m), 2.91 (2H, s), 3.70 (2H, s), 4.54 (2H, d, J = 6.7 Hz), 5.93 (2H, s), 6.72-6.80 (2H, m), 6.88 (1H, d, J = 1.2 Hz), 7.03-7.09 (2H, m), 7.20-7.38 (5H, m), 7.43 (1H, dd, J = 7.3 and 1.2 Hz), 7.56 (1H, t, J = 6.1 Hz). (Example 10)
N- [2- (4-Chlorophenylthio) benzyl] -2- (3,5-dimethyl-4-piperonylpiperazin-1-yl) acetamide

In the same manner as in Example 1, 2-chloro-N- [2- (4-chlorophenylthio) benzyl] acetamide (the compound of Reference Example 18: 130 mg) and 2,6-dimethyl-1-piperonylpiperazine (105 mg) and diisopropylethylamine (0.28 mL) as a colorless solid N- [2- (4-chlorophenylthio) benzyl] -2- (3,5-dimethyl-4-piperonylpiperazin-1-yl) Acetamide (215 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.98 (6H, d, J = 6.1 Hz), 2.00-2.09 (2H, m), 2.50-2.62 (4H, m), 2.91 (2H, s), 3.70 (2H, s), 4.54 (2H, d, J = 6.7 Hz), 5.93 (2H, s), 6.72-6.80 (2H, m), 6.88 (1H, d, J = 1.2 Hz), 7.03-7.09 ( 2H, m), 7.20-7.38 (5H, m), 7.43 (1H, dd, J = 7.3 and 1.2 Hz), 7.56 (1H, t, J = 6.1 Hz).

実施例５と同様の方法により、１−［２−（４−クロロフェニルチオ）ベンジル］−３−（ピペリジン−４−イル）ウレア（参考例２０の化合物：６０．０ｍｇ）から無色粉末として１−［１−（ベンゾ［１，３］ジオキソール−５−イルメチル）ピペリジン−４−イル］−３−［２−（４−クロロフェニルチオ）ベンジル］ウレア（４１．５ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.29-1.43(2H, m), 1.86(2H, d, J = 11.0 Hz), 2.04(2H, t, J = 11.0 Hz), 2.74(2H, d, J = 11.0 Hz), 3.37(2H, s), 3.42-3.55(1H, m), 4.00(1H, d, J = 7.9 Hz), 4.44(2H, d, J = 6.1 Hz), 4.59(1H, brt, J = 6.1 Hz), 5.93(2H, s), 6.67-6.77(2H, m), 6.83(1H, s), 7.07(2H, d, J = 8.6 Hz), 7.20-7.29(3H, m), 7.30-7.40(2H, m), 7.49(1H, d, J = 9.2 Hz).
ESIMS (M+H): 510
HRMS(FAB⁺) for C₂₇H₂₉ClN₃O₃S [M+H]⁺: calcd, 510.16181; found, 510.16167．
元素分析値 found: C, 63.48; H, 5.55; N, 8.08. calcd. for C₂₇H₂₈ClN₃O₃S: C, 63.58; H, 5.53; N, 8.24. (Example 11)
1- [1- (Benzo [1,3] dioxol-5-ylmethyl) piperidin-4-yl] -3- [2- (4-chlorophenylthio) benzyl] urea

In the same manner as in Example 5, 1- [2- (4-chlorophenylthio) benzyl] -3- (piperidin-4-yl) urea (the compound of Reference Example 20: 60.0 mg) was obtained as a colorless powder. [1- (Benzo [1,3] dioxol-5-ylmethyl) piperidin-4-yl] -3- [2- (4-chlorophenylthio) benzyl] urea (41.5 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.29-1.43 (2H, m), 1.86 (2H, d, J = 11.0 Hz), 2.04 (2H, t, J = 11.0 Hz), 2.74 (2H, d , J = 11.0 Hz), 3.37 (2H, s), 3.42-3.55 (1H, m), 4.00 (1H, d, J = 7.9 Hz), 4.44 (2H, d, J = 6.1 Hz), 4.59 (1H , brt, J = 6.1 Hz), 5.93 (2H, s), 6.67-6.77 (2H, m), 6.83 (1H, s), 7.07 (2H, d, J = 8.6 Hz), 7.20-7.29 (3H, m), 7.30-7.40 (2H, m), 7.49 (1H, d, J = 9.2 Hz).
ESIMS (M + H): 510
HRMS (FAB ⁺ ) for C ₂₇ H ₂₉ ClN ₃ O ₃ S [M + H] ⁺ : calcd, 510.16181; found, 510.16167.
Elemental analysis found: C, 63.48; H, 5.55; N, 8.08.calcd.for C ₂₇ H ₂₈ ClN ₃ O ₃ S: C, 63.58; H, 5.53; N, 8.24.

３−（４−ベンゾ［１，３］ジオキソール−５−イルメチル−ピペリジン−１−イル）−Ｎ−［２−（４−クロロフェニルチオ）フェニル］プロパンアミド（実施例２の化合物：２０９ｍｇ）を無水テトラヒドロフラン（５ｍＬ）に溶解させ、ボラン−硫化ジメチル（０．０８ｍＬ）を加え、１時間加熱還流した。放冷後、反応液に水を滴下し、塩酸水溶液（２ｍＬ、２ｍｏｌ／Ｌ）を加え１時間加熱還流した。放冷後、水酸化ナトリウム水溶液（１ｍｏｌ／Ｌ）を加えアルカリ性とし、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥して溶媒を濃縮した。残渣をシリカゲルカラムクロマトグラフィー（シリカゲル６０，０．０４０〜０．０６３ｍｍ；ヘキサン：酢酸エチル＝３：１）で精製し、無色油状物としてＮ−｛３−［４−（ベンゾ［１，３］ジオキソール−５−イルメチル）ピペラジン−１−イル］プロピル｝−２−（４−クロロフェニルチオ）アニリン（１９０ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.71(2H, qui, J = 6.7 Hz), 2.24-2.54(10H, m), 3.17(2H, q, J = 6.7 Hz), 3.39(2H, s), 5.19(1H, brs), 6.63-6.70(2H, m), 6.84(1H, s), 6.96(2H, d, J = 8.6 Hz), 7.16(2H, d, J = 8.6 Hz), 7.31(1H, t, J = 7.3 Hz), 7.43(1H, dd, J = 7.3, 1.2 Hz).
ESIMS (M+H): 496
HRMS(ESI⁺) for C₂₇H₃₀ClN₃O₂S [M+H]⁺: calcd, 496.18255; found, 496.17824． (Example 12)
N- {3- [4- (Benzo [1,3] dioxol-5-ylmethyl) piperazin-1-yl] propyl} -2- (4-chlorophenylthio) aniline

3- (4-Benzo [1,3] dioxol-5-ylmethyl-piperidin-1-yl) -N- [2- (4-chlorophenylthio) phenyl] propanamide (the compound of Example 2: 209 mg) was anhydrous. Dissolve in tetrahydrofuran (5 mL), add borane-dimethyl sulfide (0.08 mL), and heat to reflux for 1 hour. After allowing to cool, water was added dropwise to the reaction solution, an aqueous hydrochloric acid solution (2 mL, 2 mol / L) was added, and the mixture was heated to reflux for 1 hour. After allowing to cool, an aqueous sodium hydroxide solution (1 mol / L) was added to make it alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated. The residue was purified by silica gel column chromatography (silica gel 60, 0.040-0.063 mm; hexane: ethyl acetate = 3: 1), and N- {3- [4- (benzo [1,3]] as a colorless oil. Dioxole-5-ylmethyl) piperazin-1-yl] propyl} -2- (4-chlorophenylthio) aniline (190 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.71 (2H, qui, J = 6.7 Hz), 2.24-2.54 (10H, m), 3.17 (2H, q, J = 6.7 Hz), 3.39 (2H, s ), 5.19 (1H, brs), 6.63-6.70 (2H, m), 6.84 (1H, s), 6.96 (2H, d, J = 8.6 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.31 (1H, t, J = 7.3 Hz), 7.43 (1H, dd, J = 7.3, 1.2 Hz).
ESIMS (M + H): 496
HRMS (ESI ⁺ ) for C ₂₇ H ₃₀ ClN ₃ O ₂ S [M + H] ⁺ : calcd, 496.18255; found, 496.17824.

Ｎ−｛３−［４−（ベンゾ［１，３］ジオキソール−５−イルメチル）ピペラジン−１−イル］プロピル｝−２−（４−クロロフェニルチオ）アニリン（実施例１２の化合物：７０．５ｍｇ）をジクロロメタン（２ｍＬ）に溶解させ０℃に冷却し、トリエチルアミン（０．０６ｍＬ）、アセチルクロリド（０．０２０ｍＬ）を加え、４時間常温で撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム溶液、水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥して溶媒を濃縮した。残渣をシリカゲルカラムクロマトグラフィー（シリカゲル６０，０．０４０〜０．０６３ｍｍ；ヘキサン：酢酸エチル＝２：１）で精製し、淡黄色油状物としてＮ−｛３−［４−（ベンゾ［１，３］ジオキソール−５−イルメチル）ピペラジン−１−イル］プロピル｝−Ｎ−［２−（４−クロロフェニルチオ）フェニル］アセトアミド（２５．０ｍｇ）得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.65-1.83(5H, m), 2.25-2.60(10H, m), 3.22-3.32(1H, m), 3.40(2H, s), 4.05-4.16(1H, m), 5.95(2H, s), 6.68-6.76(2H, m), 6.83(1H, s), 6.92-7.00(1H, m), 7.10-7.23(3H, m), 7.30-7.40(4H, m).
ESIMS (M+H): 538
HRMS(FAB⁺) for C₂₉H₃₀ClN₃O₃S [M+H]⁺: calcd, 538.19311; found, 538.19232． (Example 13)
N- {3- [4- (Benzo [1,3] dioxol-5-ylmethyl) piperazin-1-yl] propyl} -N- [2- (4-chlorophenylthio) phenyl] acetamide

N- {3- [4- (Benzo [1,3] dioxol-5-ylmethyl) piperazin-1-yl] propyl} -2- (4-chlorophenylthio) aniline (Compound of Example 12: 70.5 mg) Was dissolved in dichloromethane (2 mL), cooled to 0 ° C., triethylamine (0.06 mL) and acetyl chloride (0.020 mL) were added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated. The residue was purified by silica gel column chromatography (silica gel 60, 0.040-0.063 mm; hexane: ethyl acetate = 2: 1), and N- {3- [4- (benzo [1,3 ] Dioxol-5-ylmethyl) piperazin-1-yl] propyl} -N- [2- (4-chlorophenylthio) phenyl] acetamide (25.0 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.65-1.83 (5H, m), 2.25-2.60 (10H, m), 3.22-3.32 (1H, m), 3.40 (2H, s), 4.05-4.16 ( 1H, m), 5.95 (2H, s), 6.68-6.76 (2H, m), 6.83 (1H, s), 6.92-7.00 (1H, m), 7.10-7.23 (3H, m), 7.30-7.40 ( 4H, m).
ESIMS (M + H): 538
HRMS (FAB ⁺ ) for C ₂₉ H ₃₀ ClN ₃ O ₃ S [M + H] ⁺ : calcd, 538.19311; found, 538.19232.

２−（ベンジルチオ）−５−（トリフルオロメチル）アニリン（参考例２６の化合物：９０．０ｍｇ）、４−（１，３−ベンゾジオキソール−５−イルメチル）−１−ピペラジン酢酸 ２塩酸塩（１００ｍｇ）、をジクロロメタン（５ｍＬ）に溶かし、Ｎ−（３−ジメチルアミノプロピル）−Ｎ’−エチルカルボジイミド塩酸塩（ＷＳＣ−ＨＣｌ）（６５．５ｍｇ，０．３４２ｍｍｏｌ）を加え、常温で一日撹拌した。反応液を水にあけ、酢酸エチルで抽出し、有機層を水と飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、反応液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（シリカゲル６０，０．０４０〜０．０６３ｍｍ；酢酸エチル）で精製し、無色アモルファスとして２−［４−（１，３−ベンゾジオキソール−５−イルメチル）ピペラジン−１−イル］−Ｎ−［２−（ベンジルチオ）−５−（トリフルオロメチル）フェニル］アセトアミド（５９．７ｍｇ）を得た。
¹H -NMR (400 MHz, CDCl₃) δ 2.52 (4H, brs), 2.62 (4H, brs), 3.10 (2H, s), 3.40 (2H, s), 3.99 (2H, s), 5.94 (2H, s), 6.70-6.78 (2H, m), 6.84 (1H, s), 7.08-7.13 (2H, m), 7.00-7.28 (4H, m), 7.44 (1H, d, J = 7.9 Hz), 8.77 (1H, d, J = 1.8 Hz), 10.31 (1H, s). (Example 14)
2- [4- (1,3-Benzodioxol-5-ylmethyl) piperazin-1-yl] -N- [2- (benzylthio) -5- (trifluoromethyl) phenyl] acetamide

2- (Benzylthio) -5- (trifluoromethyl) aniline (Compound of Reference Example 26: 90.0 mg), 4- (1,3-benzodioxol-5-ylmethyl) -1-piperazineacetic acid dihydrochloride (100 mg) was dissolved in dichloromethane (5 mL), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (WSC-HCl) (65.5 mg, 0.342 mmol) was added, and one day at room temperature. Stir. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the reaction mixture is concentrated, and the residue is purified by silica gel column chromatography (silica gel 60, 0.040 to 0.063 mm; ethyl acetate) to give 2- [4- (1,3 -Benzodioxol-5-ylmethyl) piperazin-1-yl] -N- [2- (benzylthio) -5- (trifluoromethyl) phenyl] acetamide (59.7 mg) was obtained.
¹ H -NMR (400 MHz, CDCl ₃ ) δ 2.52 (4H, brs), 2.62 (4H, brs), 3.10 (2H, s), 3.40 (2H, s), 3.99 (2H, s), 5.94 (2H , s), 6.70-6.78 (2H, m), 6.84 (1H, s), 7.08-7.13 (2H, m), 7.00-7.28 (4H, m), 7.44 (1H, d, J = 7.9 Hz), 8.77 (1H, d, J = 1.8 Hz), 10.31 (1H, s).

(Test Example 1)
The IL-6 inhibitory action of the compound of the present invention was confirmed in the following test examples.
STAT3 phosphorylation test by IL-6 Simi T. Ahmed and Lionel B.M. Ivashkiv J.M. Immunol. , 165, 5227-5237 (2000), with some modifications. In medium supplemented with 1% fetal calf serum (RPMI-1640 added with 100 U / ml penicillin G, 100 μg / ml streptomycin sulfate, 10 mM HEPES (pH 7.4), 1 mM sodium pyruvate and 4.5 mg / ml glucose) U266 cells (obtained from ATCC) prepared at 4 × 10 ⁵ cells / ml were added to a 12-well plate at 1 ml / well and cultured at 37 ° C. under 5% CO ₂ for 22 hours. Next, the test compound was diluted with DMSO and added at 3 μl / well (final concentrations: 1, 3 and 10 μM) and incubated for 30 minutes. Thereafter, IL-6 (Roche) was diluted with a phosphate buffer (hereinafter referred to as PBS), added at 10 μl / well (final concentration: 1 ng / ml), and stimulated for 15 minutes. Thereafter, the cell culture solution was added to 3 ml of PBS, centrifuged at 4 ° C. and 1000 rpm for 5 minutes, and the supernatant was discarded. 1 ml of cell wash buffer (cell lysis kit, Bio-Rad) was added to the precipitated cells, suspended, and centrifuged at 4 ° C., 1000 rpm for 5 minutes, and the supernatant was discarded. 40 μl of cell lysis buffer (cell lysis kit, Bio-Rad) was added to the precipitated cells, suspended, and then centrifuged at 4 ° C., 15000 rpm for 15 minutes to collect the supernatant and used as a sample. The protein concentration of each sample was measured using BCA (registered trademark) Protein Assay Kit (PIERCE), and the protein concentration was adjusted to 900 μg / ml using cell lysis buffer, and then Bio-Plex (registered trademark) System (Bio -Rad) was used to measure the amount of STAT3 phosphorylation. The STAT3 phosphorylation inhibition rate of the test compound was calculated using the following calculation formula.
Inhibition rate (%) = (STAT3 phosphorylation value upon IL-6 stimulation−STAT3 phosphorylation value upon IL-6 stimulation in the presence of test compound) / (STAT3 phosphorylation value upon IL-6 stimulation−IL−) 6 STAT3 phosphorylation without stimulation) x 100
Table 1 shows the inhibition rates at the respective concentrations (1, 3 and 10 μg / ml) of the test compound thus calculated.

  As is clear from Table 1, the compounds of the present invention and salts thereof show an excellent IL-6 signal transduction inhibitory action.

  The compound of the present invention and a salt thereof have an excellent IL-6 signal transduction inhibitory action and low toxicity. Accordingly, the compounds of the present invention and salts thereof are diseases associated with abnormal production of IL-6 (rheumatoid arthritis, vasculitis syndrome, secondary amyloidosis, Castleman's disease, interstitial pneumonia, proliferative glomerulonephritis, inflammatory Intestinal diseases (Crohn's disease, etc.), rejection associated with kidney transplantation, osteoporosis, AIDS, IL-6-producing tumors (multiple myeloma, renal cancer, cervical cancer, lung cancer, atrial myxoma, etc.) and cachexia) It is a highly useful drug effective for treatment, prevention or suppression.

Claims (5)

A compound represented by the following general formula (1) or a salt thereof.

(Where
X represents a single bond or —CH ₂ —;
Y ¹ -Y ² is a formula

Represents a group represented by
Z represents a single bond, —CH ₂ — or —C (O) —,
R ^1a , R ^1b , R ^1c , R ^2a , R ^2b and R ^2c are the same or different and each represents a hydrogen atom, a halogen atom or a C _{1 to} C ₆ alkyl group which may be substituted with a halogen atom, , R ^1a and R ^2a do not represent a hydrogen atom at the same time,
R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a C ₁ -C ₆ alkyl group. ) Z is -CH ₂ - is a compound or its salt according to claim 1. The compound or a salt thereof according to claim 1, wherein Z is —CH ₂ —, R ^1a is a halogen atom, and R ^2a is a hydrogen atom. Z is —CH ₂ —, X is a single bond, R ^1a is a halogen atom, R ^2a is a hydrogen atom,
Y ¹ -Y ² is a formula

The compound or its salt of Claim 1 which is group represented by these. Z is —CH ₂ —, X is a single bond, R ^1a is a halogen atom, R ^2a is a hydrogen atom,
Y ¹ -Y ² is a formula

The compound or its salt of Claim 1 which is group represented by these.