JP2008208034A - Benzothiophene derivative and its addition salt and sphingosine-1-phosphoric acid (s1p4) receptor regulator - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a benzothiophene derivative which has an excellent regulating action on S1P4 receptors and is effective for articular rheumatism, chronic bronchial asthma, atopic dermatitis, and the like. <P>SOLUTION: The benzothiophene derivative represented by general formula (1) [R<SP>1</SP>is H, a halogen or a 1 to 6C alkyl; R<SP>2</SP>is H, a 1 to 6C alkyl or hydroxymethyl; R<SP>3</SP>is H or PO(OH)<SB>2</SB>; (m) is an integer of 2 to 4], its optical isomer, its pharmacologically acceptable salt or its hydrate have been found. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention relates to a benzothiophene derivative useful as a sphingosine-1-phosphate-4 (hereinafter abbreviated as S1P ₄ ) receptor modulator, a salt thereof and a hydrate thereof.

Sphingosine-1-phosphate (S1P) was considered to be only an intermediate metabolite in sphingosine metabolism, but has been reported to have a cell growth promoting action and a cell motility function controlling action, and has an apoptotic action. In addition, it has been clarified to be a new lipid mediator that exhibits various physiological actions such as cell shape regulation action and vasoconstriction (Non-patent Documents 1 and 2). This lipid mediator has both an action as an intracellular second messenger and two actions as an intercellular mediator. In particular, research on the action as an intercellular mediator has been actively conducted, and a plurality of G mediators existing on the surface of a cell membrane are being studied. protein-coupled receptors (E ndothelial D ifferentiation G ene,
It has been reported that information is transmitted through EDG) (Non-patent Documents 1 and 3). Currently, five subtypes of Edg-1, Edg-3, Edg-5, Edg-6 and Edg-8 are known for the S1P receptor, and S1P ₁ , S1P ₃ , S1P ₂ , S1P ₄ , S1P, respectively. Also called ₅ .

Various studies on these S1P receptors have led to reports that so-called S1P receptor modulators exhibiting agonistic or antagonistic activity on this receptor are effective against various diseases. For example, Patent Document 1 discloses that a compound that acts on Edg-5 (S1P ₂ ) is effective for arteriosclerosis, renal fibrosis, pulmonary fibrosis, and liver fibrosis. In addition, compounds acting on Edg-1 (S1P ₁ ), Edg-3 (S1P ₃ ) or Edg-5 may be chronic bronchial asthma, diffuse hamartoma pulmonary vascular myomatosis, adult respiratory distress syndrome (ARDS), Patent Document 2 discloses that it is effective as a therapeutic and preventive agent for respiratory diseases such as chronic obstructive pulmonary disease (COPD), interstitial pneumonia, idiopathic interstitial pneumonia, lung cancer, and hypersensitivity pneumonitis. Yes. Furthermore, compounds with Edg-1 agonistic action are obstructive arteriosclerosis, obstructive thromboangiitis, Buerger's disease, peripheral arterial disease of diabetic neuropathy, sepsis, vasculitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edema Varicoses, arteriosclerosis, hemorrhoids, anal fissures, fistulas, dissecting aortic aneurysms, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure, misalignment, burns, ulcerative colitis, Crohn's disease Patent Document 3 discloses that it is effective as a therapeutic and preventive agent for heart transplantation, kidney transplantation, skin transplantation, liver transplantation, bone marrow transplantation, osteoporosis, chronic hepatitis, cirrhosis, chronic renal failure, and glomerulosclerosis. ing.

Furthermore, it has been reported in Non-Patent Document 4 and Non-Patent Document 5 that a compound having S1P receptor agonist activity regulates leukocyte migration, and a series of derivatives of these S1P receptor agonists also against various organ transplants and GVHD. Besides efficacy, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, Hashimoto's disease, multiple sclerosis, myasthenia gravis, type I and II diabetes, autoimmune diseases such as Crohn's disease, atopic dermatitis, allergic rhinitis, Patent Document 4 and Patent Document 5 disclose that it is effective for allergic diseases such as allergic conjunctivitis and allergic contact dermatitis, inflammatory bowel diseases, and inflammatory diseases such as ulcerative colitis. Moreover, the phosphoric acid derivative of the structure similar to the said literature (patent document 4 and patent document 5) is also disclosed by patent document 6 as a S1P receptor antagonist. Recently, various compounds such as amino alcohol derivatives, phosphate ester derivatives and carboxylic acid derivatives have been disclosed as S1P ₁ to S1P ₅ receptor modulators centered on S1P ₁ receptors or as immunosuppressive agents ( For example, Patent Documents 7 to 12).

Furthermore, S1P ₄ receptors are extremely distributed in immune cells such as leukocytes and organs that are greatly involved in the immune system, suggesting a deep involvement in the immune system. In fact, autoimmunity such as SLE and rheumatism disease and asthma, a compound having a SlP ₄ agonistic activity for the purpose of allergic diseases and inflammatory diseases by such as atopic dermatitis is disclosed in Patent Document 9, Patent Document 10 and Patent Document 11. However, it is structurally different from the present compound. Although benzothiophene derivative present application compound structure is similar is disclosed in Patent Document 12 as a compound having an immunosuppressive effect, structurally different from the present compounds, reports the regulating action SlP ₄ receptor It has not been.

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An object of the present invention is to provide is to provide a benzothiophene derivative having a modulating effect which is excellent against SlP ₄ receptor.

As a result of intensive studies to create a compound having S1P ₄ receptor modulatory activity and high safety, the present invention has a structure different from that of previously known S1P receptor modulators. The present inventors have found that a novel benzothiophene derivative has a selective regulatory action on the S1P ₄ receptor, and completed the present invention.

That is, the present invention is 1)
General formula (1)

[Wherein R ¹ represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms,
R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a hydroxymethyl group,
R ³ represents a hydrogen atom or PO (OH) ₂ ,
m shows the integer of 2-4. ]
Benzothiophene derivatives represented by the following, optical isomers thereof, pharmaceutically acceptable salts or hydrates thereof,

2) General formula (1a)

[Wherein R ¹ , R ² and R ³ are as described above]
The benzothiophene derivative according to 1), an optically active form thereof, a pharmacologically acceptable salt thereof or a hydrate thereof,

3) The compound is
2-amino-2- [3- (6-trifluoromethylbenzo [b] thiophen-3-yl) propyl] -1,3-propanediol,
2-Amino-2-methyl-5- (2-methyl-6-trifluoromethylbenzo [b] thiophen-3-yl) pentan-1-ol 2-amino-5- (2-chloro-6-trifluoro Methylbenzo [b] thiophen-3-yl) -2-methylpentan-1-ol,
2-amino-2-methyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentan-1-ol,
The benzothiophene derivative according to 1), an optically active form thereof, a pharmacologically acceptable salt thereof or a hydrate thereof,

4) S1P ₄ receptor modulator comprising the benzothiophene derivative according to any one of 1) to 3), an optical isomer thereof, a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient,

5) A pharmaceutical comprising the benzothiophene derivative according to any one of 1) to 3), an optical isomer thereof, a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient,
It is about.

The present invention were found to have a SlP ₄ receptor regulating action excellent addition salts thereof and the novel benzothiophene derivatives. Compounds having such SlP ₄ receptor modulating action, rheumatoid arthritis, chronic bronchial asthma, is useful as a preventive or therapeutic agent such as atopic dermatitis.

In the present invention, the alkyl group having 1 to 6 carbon atoms of R ¹ and R ² is a linear or branched alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms. . Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a t-butyl group.

In the present invention, the halogen atom for R ¹ is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

  As the pharmacologically acceptable salt in the present invention, acid addition salts such as hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, citrate and tartrate, or Examples thereof include alkali metal salts such as sodium salt, potassium salt, magnesium salt, calcium salt, and aluminum salt.

According to the present invention, among the compounds represented by the general formula (1), R ² is a hydrogen atom or a hydroxymethyl group, and R ³ is a hydrogen atom, that is, the general formula (1b)

[Wherein R ⁴ represents a hydrogen atom or a hydroxymethyl group, and R ¹ and m are as described above]
The compound represented by can be produced by the following route, for example.

<Synthesis route A>

In the synthesis route A, the general formula (3)

[Wherein R ⁵ represents an alkyl group having 1 to 6 carbon atoms, Boc represents a t-butoxycarbonyl group, and R ¹ and m are as described above]
The compound represented by general formula (5)

[Wherein R ⁵ and Boc are as described above]
The compound represented by general formula (2) is treated with a base.

[Wherein Y represents a halogen atom, and R ¹ and m are as described above]
It can manufacture by making the compound represented by act (process A-1).

  The reaction uses sodium hydride, potassium hydride, sodium alkoxide or potassium alkoxide as a base, methanol, ethanol, 1,4-dioxane, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF). ) Or a mixed solvent of THF and DMF or the like as a solvent, and the reaction can be performed at 0 ° C. to heating under reflux, preferably under heating under reflux.

In the synthesis route A, the general formula (4)

[Wherein R ¹ , R ⁴ and Boc are as described above]
Can be produced by reducing the compound represented by the general formula (3) (step A-2).

The reaction is carried out using alkylborane derivatives such as borane (BH ₃ ) and 9-borabicyclo [3.3.1] nonane (9-BBN), diisopropylaluminum hydride (iBu ₂ AlH), lithium aluminum hydride (LiAlH ₄ ), A metal hydride complex compound such as sodium borohydride (NaBH ₄ ) or lithium borohydride (LiBH ₄ ), preferably LiBH ₄ is used, and the reaction is performed at −78 ° C. to reflux in a solvent such as THF, ethanol, and methanol. be able to.

The compound represented by the general formula (1b) in the synthesis route A can be produced by acid hydrolysis of the compound represented by the general formula (4) (step A-3).
The reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or mixed with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, ethyl acetate, etc. It can be carried out in a liquid at 0 ° C. to room temperature.

Among the compounds represented by the general formula (1), a compound in which R ² is a hydroxymethyl group and R ³ is PO (OH) _2, that is, the general formula (1c)

[Wherein R ¹ and m are as described above]
The compound represented by can be produced, for example, by the route shown below.

<Synthetic route B>

In the synthesis route B, the general formula (7)

Wherein, Pro represents a methoxymethyl group, t- butyl dimethyl silyl group, t- butyl diphenyl silyl group, a triisopropylsilyl group, a general protective group of alcohols such as tetrahydropyranyl group or an acetyl group, R ¹ , M and Boc are as described above]
Can be produced by subjecting the compound represented by the general formula (6) to various alcohol protecting group introduction reactions (step B-1).

  For example, when introducing a methoxymethyl group, methoxymethyl chloride or methoxymethyl bromide is added in a solvent such as THF, acetonitrile, or dichloromethane in the presence of a base such as sodium hydride, triethylamine, diisopropylethylamine, etc. It can be performed at room temperature. When a t-butyldimethylsilyl group, t-butyldiphenylsilyl group or triisopropylsilyl group is introduced, the reaction is carried out in the presence of a base such as triethylamine or imidazole, and the corresponding silyl chloride, silyl bromide, silyl trifluoromethanesulfonate. Can be carried out in a solvent such as THF, cyclopentyl methyl ether (CPME), DMF, acetonitrile, dichloromethane, etc. at 0 ° C. to room temperature. When a tetrahydropyranyl group is introduced, the reaction can be carried out by dihydropyran in the presence of an acid catalyst such as p-toluenesulfonic acid in a solvent such as dichloromethane at 0 ° C. to room temperature. When an acetyl group is introduced, the reaction is carried out in the presence of an organic base such as triethylamine, diisopropylethylamine, pyridine, etc. in a solvent such as THF, 1,4-dioxane, dichloromethane, etc. The reaction can be carried out at a temperature between room temperature and room temperature. In this case, pyridine or the like can also be used as a solvent that also serves as a base.

  In the synthesis route B, the general formula (8)

[Wherein R ⁶ represents an alkyl group having 1 to ⁶ carbon atoms, and R ¹ , m, Boc and Pro are as described above], the compound represented by the general formula (10)

[Wherein R ⁶ is as described above]
And the compound represented by the general formula (7) can be produced in the presence of carbon tetrabromide or tellurium tetrachloride (step B-2).

When carbon tetrabromide is used, the reaction can be carried out at 0 ° C. to room temperature using no solvent or a small amount of methylene chloride, chloroform, acetonitrile, ethyl acetate, THF, ether or the like as a solvent in the presence of pyridine. When tellurium tetrachloride is used, 2,6-lutidine, pyridine, 2,4,6-collidine, preferably 2,6-lutidine is used as a base, and the reaction is carried out in a solvent such as dichloromethane or chloroform at 0 ° C. to room temperature. be able to.

In the synthesis route B, the general formula (9)

[Wherein R ¹ , R ⁶ , m and Boc are as described above]
The compound represented by general formula (8) can be produced by subjecting the compound represented by general formula (8) to a deprotection reaction of a protective group for alcohols generally used (step B-3).

When the protecting group is a methoxymethyl group or a tetrahydropyranyl group, the reaction can be performed using hydrogen chloride-containing methanol, ethanol, ethyl acetate, diethyl ether, 1,4-dioxane, or the like at 0 ° C. to heating under reflux. . When the protecting group is a silyl group, use tetra-n-butylammonium fluoride or potassium fluoride, sodium fluoride, cesium fluoride, etc., in a solvent such as dichloromethane, DMF, THF, acetonitrile, and the like at 0 ° C. to room temperature. be able to. In the case of an acetyl group, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution, an aqueous sodium hydroxide solution, preferably an aqueous sodium hydroxide solution in a solvent such as methanol, ethanol, THF, CPME, DMSO, DMF or 1,4-dioxane. It can be carried out under normal temperature to heating under reflux.

The compound represented by general formula (1c) in the synthetic pathway B can be manufactured by making trimethylsilyl iodide act on the compound represented by general formula (9) (process B-4).
The reaction can be carried out in a solvent such as dichloromethane, acetonitrile, THF or DMF at −78 ° C. to room temperature.

Among the compounds represented by the general formula (1), a compound in which R ² is an alkyl group having 1 to 6 carbon atoms and R ³ is a hydrogen atom, that is, the general formula (1d)

[Wherein R ⁷ represents an alkyl group having 1 to 6 carbon atoms, and R ¹ and m are as described above]
And a compound in which R ² is an alkyl group having 1 to 6 carbon atoms and R ³ is PO (OH) _2, that is, the general formula (1e)

[Wherein R ¹ , R ⁷ and m are as described above]
The compound represented by can be produced, for example, by the route shown below.

<Synthetic route C>

In the synthesis route C, the general formula (12)

[Wherein R ⁸ represents an alkyl group having 1 to 6 carbon atoms, and R ⁷ and m are as described above]
The compound represented by general formula (17)

[Wherein R ⁷ and R ⁸ are as described above]
And a compound represented by the general formula (11)

[Wherein Y and m are as described above]
Can be produced by acting in the presence of a base (step C-1).

The reaction is carried out in a solvent such as THF, diethyl ether, 1,4-dioxane or dichloromethane using a base such as n-butyllithium, sec-butyllithium, lithium diisopropylamide, preferably n-butyllithium at −78 ° C. After the compound represented by the general formula (17) is treated, the compound represented by the general formula (11) is allowed to react at −78 ° C. and gradually raised to room temperature.

  In the synthesis route C, the general formula (13)

[Wherein R ¹ , R ⁷ , R ⁸ and m are as described above]
The compound represented by general formula (12) is treated with a base,
When R ¹ is an alkyl group having 1 to 6 carbon atoms, the general formula (18)

[Wherein R ⁹ represents an alkyl group having 1 to 6 carbon atoms, and X represents a halogen atom]
When R ¹ is a chlorine atom, by reacting a compound represented by the formula: When R ¹ is a bromine atom, by reacting carbon tetrabromide, R ¹ is In the case of an iodine atom, it can be produced by reacting diiodoethane (step C-2-1).

The reaction is carried out at −78 ° C. using a base such as n-butyllithium, sec-butyllithium or lithium diisopropylamide in a solvent such as diethyl ether, 1,4-dioxane, THF or dichloromethane, preferably n-butyllithium. after processing the compound represented by the general formula (12) Te, when R ¹ is an alkyl group having 1 to 6 carbon atoms, a compound represented by the general formula (18), when R ¹ is a chlorine atom hexa Chloroethane can be reacted with carbon tetrabromide when R ¹ is a bromine atom, and with diiodoethane when R ¹ is an iodine atom at −78 ° C., and gradually raised to room temperature.

In addition, the compound represented by the general formula (13) in the synthesis route C causes the compound represented by the general formula (17) and the compound represented by the general formula (2) to act in the presence of a base. (Step C-2-2).
The reaction is carried out in a solvent such as THF, diethyl ether, 1,4-dioxane or dichloromethane using a base such as n-butyllithium, sec-butyllithium, lithium diisopropylamide, preferably n-butyllithium at −78 ° C. After treating the compound represented by the general formula (17), the compound represented by the general formula (12) is allowed to react at −78 ° C. and gradually raised to room temperature.

In the synthesis route C, the general formula (14)

[Wherein R ¹ , R ⁷ , R ⁸ , m and Boc are as described above]
The compound represented by general formula (13) can be produced by acid hydrolysis of the compound represented by general formula (13) and then protecting the nitrogen atom with a t-butoxycarbonyl group (Boc group) (step C). -3).
The reaction was carried out at room temperature using methanol, ethanol, THF, 1,4-dioxane, ethyl acetate in which hydrochloric acid was dissolved, preferably 1,4-dioxane containing hydrochloric acid, and then neutralized with a base to give an amino ester. After the body is obtained, it is preferable to react with Boc ₂ O at 0 ° C. to room temperature in a solvent such as ethyl acetate, THF, DMF, 1,4-dioxane, methylene chloride, chloroform, methanol, ethanol, acetonitrile.

  In the synthesis route C, the general formula (15)

[Wherein R ¹ , R ⁷ , m and Boc are as described above]
Can be produced by reducing the compound represented by the general formula (14) (step C-4).
The reaction can be carried out in the same manner as in Step A-2.

In the synthesis route C, the general formula (1d)

[Wherein R ¹ , R ⁷ and m are as described above]
It can manufacture by deprotecting the compound represented by (process C-5).
The reaction can be carried out in a solvent such as methanol, ethanol, dichloromethane, etc. using hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like at normal temperature to heating under reflux.

In the synthesis route C, the general formula (16)

[Wherein R ¹ , R ⁶ , R ⁷ , m and Boc are as described above]
The compound represented by general formula (15) and the compound represented by general formula (10) can be produced by acting in the presence of carbon tetrabromide or tellurium tetrachloride. (Step C-6).
The reaction can be carried out in the same manner as in Step B-2.

In the synthesis route C, the general formula (1e)

[Wherein R ¹ , R ⁷ and m are as described above]
Can be produced by allowing iodotrimethylsilane to act on the compound represented by the general formula (16) (step C-7).
The reaction can be carried out in the same manner as in Step B-4.

Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

<Example 1>
Diethyl 2-tert-butoxycarbonylamino-2- [3- (6-trifluoromethylbenzo [b] thiophen-3-yl) propyl] malonate

Sodium hydride (82.9 mg) was added to a solution of 2- (N-Boc-amino) malonic acid diethyl ester (528 μL) in THF (10 mL) and DMF (1.0 mL) under an argon atmosphere at 80 ° C. for 30 minutes. Stir. To the reaction solution was added 3- (3-iodopropyl) -6-trifluoromethylbenzo [b] thiophene (500 mg) in THF (4
mL) and DMF (0.4 mL) were added dropwise, and the mixture was heated to reflux for 4 hours. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired product (747 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.20 (6H, t, J = 7.3 Hz),
1.40 (9H, s), 1.59−1.69 (2H, m), 2.34−2.47 (2H, m), 2.90 (2H, t, J = 7.3 Hz), 4.11−4.31 (4H, m), 5.94 (1H, s), 7.28 (1H, s), 7.58 (1H, dd, J =
8.6, 1.2 Hz), 7.78 (1H, d, J = 8.6 Hz), 8.12 (1H, brs).

<Example 2>
2-tert-Butoxycarbonylamino-2- [3- (6-trifluoromethylbenzo [b] thiophen-3-yl) propyl] propane-1,3-diol

To a THF solution (15 mL) of the compound of Example 1 (668 mg) was added lithium borohydride (280 mg) at 0 ° C., ethanol (1.5 mL) was added dropwise, and the mixture was stirred at 0 ° C. for 2 hr. Water and 10% aqueous citric acid solution were added, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (374 mg) as a white powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.42 (9H, s), 1.67−1.84 (4H, m), 2.88 (2H, t, J = 7.3 Hz), 3.22 (2H, brs), 3.60
(2H, d, J = 11.6 Hz), 3.82 (2H, d, J = 11.6 Hz), 4.94 (1H, s),
7.31 (1H, s), 7.60 (1H, dd, J = 8.6, 1.8 Hz), 7.81 (1H, d, J =
8.6 Hz), 8.14 (1H, brs).

<Example 3>
2-Amino-2- [3- (6-trifluoromethylbenzo [b] thiophen-3-yl) propyl] propane-1,3-diol hydrochloride

A 10% hydrochloric acid-methanol solution (5 mL) was added to the compound of Example 2 (96.2 mg) and stirred at room temperature for 12 hours. After evaporating the solvent of the reaction solution under reduced pressure, the residue was purified by recrystallization (methanol-diisopropyl ether) to obtain the desired product (66.5 mg) as a colorless powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ1.59-1.80 (4H,
m), 2.85 (2H, t, J = 7.3 Hz), 3.40−3.51 (4H, m),
5.32 (2H, t, J = 4.9 Hz), 7.65−7.77 (5H, m),
8.04 (1H, d, J = 8.6 Hz), 8.51 (1H, s).
FABMS (+): 334
[M + H] ⁺ .
HRFABMS (+):
334.1073 (calculated as C ₁₅ H ₁₈ F ₃ NO ₂ S 334.1089).
Elemental analysis: Measured value C 48.28%, H 5.05%, N 3.51%, C ₁₅ H ₁₈ F ₃ NO ₂ S, HCl, 1 / 8H ₂ O calculated value C 48.42%, H 5.21%, N 3.76%.

<Example 4>
2-tert-Butoxycarbonylamino-2-tert-butyldimethylsilyloxymethyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentan-1-ol

Triethylamine (137 mg) was added to a DMF (8 mL) solution of the compound of Example 2 (268 mg), tert-butyldimethylchlorosilane (107 mg) was added at 0 ° C., 30 minutes at 0 ° C., and 3 hours at room temperature. Stir. Water (20 mL) was added and extracted with ethyl acetate (50 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to obtain the desired product (193 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ0.05 (6H, d, J = 3.1 Hz),
0.87 (9H, s), 1.42 (9H, s), 1.52-1.74 (2H, m), 1.74-1.99 (2H, m), 2.82-2.91 (2H, m), 3.51 (1H,
d, J = 9.8 Hz), 3.56−3.71 (2H, m), 3.81 (1H, d, J
= 9.8 Hz), 4.06 (1H, s), 5.09 (1H, br s), 7.30 (1H, s), 7.58 (1H, d, J =
8.6 Hz), 7.81 (1H, d, J = 8.6 Hz), 8.13 (1H, s).

<Example 5>
2-tert-Butoxycarbonylamino-2-tert-butyldimethylsilyloxymethyl-1-dimethoxyphosphoryloxy-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentane

Carbon tetrabromide (303 mg, 0.913 mmol) and trimethyl phosphite (108 μL) were added to a pyridine (3 mL) solution of the compound of Example 4 (250 mg) at 0 ° C., and the mixture was stirred at 0 ° C. for 4 hours. . Water (50 mL) was added, and the mixture was extracted with ethyl acetate (150 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain the desired product (254 mg) as a pale brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ0.03 (6H, s), 0.86 (9H, s), 1.40
(9H, s), 1.68−1.87 (3H, m), 1.89−2.08 (1H, m), 2.87 (2H, t, J = 7.3 Hz), 3.59 (1H, d, J
= 9.2 Hz), 3.63 (1H, d, J = 9.2 Hz), 3.74 (3H, d, J = 1.2 Hz),
3.76 (3H, d, J = 1.2 Hz), 4.08−4.16 (2H, m),
4.67 (1H, br s), 7.29 (1H, s), 7.57 (1H, dd, J = 8.6, 1.8 Hz), 7.82 (1H,
d, J = 8.6 Hz), 8.13 (1H, s).

<Example 6>
2-tert-Butoxycarbonylamino-2-dimethoxyphosphoryloxymethyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentan-1-ol

To a THF (5 mL) solution of the compound of Example 5 (243 mg) was added 1 mol / L tetrabutylammonium fluoride-THF solution (445 μL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Water (30 mL) was added and extracted with ethyl acetate (50 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product (191 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.41 (9H, s), 1.61-1.88 (3H, m), 1.98-2.12 (1H, m), 2.88 (2H,
t, J = 7.3 Hz), 3.61 (1H, d, J = 12.2 Hz), 3.66 (1H, d, J
= 12.2 Hz), 3.76 (3H, d, J = 1.2 Hz), 3.78 (3H, d, J = 1.2 Hz),
4.11−4.24 (3H, m), 4.85 (1H, br s), 7.31 (1H, s), 7.58
(1H, dd, J = 8.6, 1.8 Hz), 7.82 (1H, d, J = 8.6 Hz), 8.13 (1H,
s).

<Example 7>
2-Amino-2-hydroxymethyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentylphosphonic acid monoester

A 10% hydrochloric acid-methanol solution (5 mL) was added to the compound of Example 6 (188 mg), and the mixture was stirred at room temperature for 16 hours. After evaporating the solvent of the reaction solution under reduced pressure, the residue was dissolved in ethyl acetate (10 mL), and the solution was neutralized with triethylamine. The precipitated crystals were removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure. The residue was dissolved in acetonitrile (3 mL), iodotrimethylsilane (148 μL) was added at 0 ° C. under an argon atmosphere, and the mixture was stirred at 0 ° C. for 1 hr. After distilling off the solvent under reduced pressure, the residue was subjected to reverse layer silica gel column chromatography (water: acetonitrile = 9: 1 →
Purification by 6: 1 → 3: 1 → 1: 1) gave the target product (25.7 mg) as a colorless powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ1.59-1.82 (4H,
m), 2.80−2.89 (2H, m), 3.15−3.52
(7H, m), 3.64−3.85 (2H, m), 7.70 (1H, dd, J =
8.6, 1.8 Hz), 7.74 (1H, s), 8.03 (1H, d, J = 8.6 Hz), 8.49 (1H, s).
FABMS (+): 414
[M + H] ⁺ .
HRFABMS (+):
414.0771 (calculated as C ₁₅ H ₁₉ F ₃ NO ₅ PS 414.0752).
Elemental analysis: Measured value C 42.53%, H 4.60%, N 3.24%, C ₁₅ H ₁₉ F ₃ NO ₅ PS, 1 / 2H ₂ O calculated value C 42.66%, H 4.77%, N 3.32%.

<Example 8>
(2R, 5S) -3,6-Diethoxy-2-methyl-5-isopropyl-2- [3- (6-trifluoromethylbenzo [b] thiophen-3-yl) propyl] -2,5-dihydropyrazine

(2S) -3,6-diethoxy-5-methyl-2-isopropyl-2,5-dihydropyrazine (0.962 mg) in a THF (20 mL) solution at −78 ° C. in an argon atmosphere at −67 ° C.
A mol / L n-butyllithium-hexane solution (1.59 mL) was added dropwise, and the mixture was stirred at -78 ° C for 30 minutes. 3- (3-iodopropyl) -6-trifluoromethylbenzo [b] thiophene (1.73 at −78 ° C.
A solution of g) in THF (7 mL) was added dropwise, stirred at −78 ° C. for 30 minutes, and then gradually warmed to room temperature. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1 v / v) to obtain the desired product (1.42 g) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ0.69 (3H, d, J = 6.7 Hz),
1.05 (3H, d, J = 7.3 Hz), 1.16−1.33 (10H, m),
1.38−1.65 (2H, m), 1.88−1.99
(1H, m), 2.19−2.33 (1H, m), 2.81 (2H, t, J = 7.3
Hz), 3.85−4.25 (5H, m), 7.24 (1H, s), 7.57 (1H, d, J
= 7.3 Hz), 7.77 (1H, d, J = 8.6 Hz), 8.12 (1H, s).

<Example 9>
(2S, 5R) -3,6-Diethoxy-2-methyl-5-isopropyl-2- [3- (6-trifluoromethylbenzo [b] thiophen-3-yl) propyl] -2,5-dihydropyrazine

(2R) -3,6-diethoxy-5-methyl-2-isopropyl-2,5-dihydropyrazine was used in the same manner as in Example 8 to obtain the desired product as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ0.70 (3H, d, J = 7.3 Hz),
1.05 (3H, d, J = 7.3 Hz), 1.15−1.29 (6H, m),
1.31 (3H, s), 1.38−1.49 (1H, m), 1.50−1.66 (2H, m), 1.89−1.99 (1H, m), 2.19−2.32 (1H, m), 2.81 (2H, t, J = 7.3 Hz), 3.90 (1H, br s), 3.94−4.21 (4H, m), 7.24 (1H, s), 7.57 (1H, dd, J = 8.6, 1.2 Hz),
7.77 (1H, d, J = 8.6 Hz), 8.12 (1H, br s).

<Example 10>
(2R, 5S) -2- [3- (2-Chloro-6-trifluoromethylbenzo [b] thiophen-3-yl) propyl] -3,6-diethoxy-2-methyl-5-isopropyl-2, 5-dihydropyrazine

Example 8 (1.15
To a THF (30 mL) solution of g), a 2.67 mol / L n-butyllithium-hexane solution (0.919 mL) was added dropwise at −78 ° C. under an argon atmosphere, and the mixture was stirred at −78 ° C. for 30 minutes. A solution of hexachloroethane (1.16 g) in THF (5 mL) was added dropwise at −78 ° C., stirred at −78 ° C. for 30 minutes, warmed to room temperature, and saturated aqueous ammonium chloride solution was added. The reaction mixture was extracted with ethyl acetate (150 mL), and the extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to obtain the desired product (1.12 g) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ0.68 (3H, d, J = 6.7 Hz),
1.03 (3H, d, J = 6.7 Hz), 1.14 (3H, t, J = 7.3 Hz), 1.21 (3H, t, J
= 7.3 Hz), 1.28−1.39 (1H, m), 1.29 (3H, s), 1.39−1.53 (1H, m), 1.53−1.64 (1H, m), 1.84−1.95 (1H, m), 2.16− 2.28 (1H, m), 2.82 (2H,
t, J = 7.3 Hz), 3.86 (1H, d, J = 3.1 Hz), 3.89−4.17 (4H, m), 7.55 (1H, dd, J = 8.6, 1.8 Hz), 7.66 (1H, d, J
= 8.6 Hz), 7.97 (1H, br s).

<Example 11>
(2S, 5R) -2- [3- (2-Chloro-6-trifluoromethylbenzo [b] thiophen-3-yl) propyl] -3,6-diethoxy-2-methyl-5-isopropyl-2, 5-dihydropyrazine

Using the compound of Example 9, the target product was obtained as a colorless oil in the same manner as in Example 10.
¹ H-NMR (400 MHz, CDCl ₃ ) δ0.68 (3H, d, J = 6.7 Hz),
1.03 (3H, d, J = 6.7 Hz), 1.14 (3H, t, J = 7.3 Hz), 1.21 (3H, t, J
= 7.3 Hz), 1.26−1.39 (1H, m), 1.29 (3H, s), 1.39−1.52 (1H, m), 1.52−1.62 (1H, m), 1.83−1.95 (1H, m), 2.15− 2.29 (1H, m), 2.82 (2H,
t, J = 7.3 Hz), 3.86 (1H, d, J = 3.1 Hz), 3.89−4.17 (4H, m), 7.56 (1H, dd, J = 8.6, 1.2 Hz), 7.66 (1H, d, J
= 8.6 Hz), 7.97 (1H, br s).

<Example 12>
(2R, 5S) -3,6-diethoxy-2-methyl-5-isopropyl-2- [3- (2-methyl-6-trifluoromethylbenzo [b] thiophen-3-yl) propyl] -2, 5-dihydropyrazine

To a solution of the compound of Example 8 (1.58 g) in THF (30 mL) was added dropwise 2.67 mol / L n-butyllithium-hexane solution (0.919 mL) at −78 ° C. in an argon atmosphere, and at −78 ° C. for 30 minutes. Stir. At -78 ° C, iodomethane (303
μL) in THF (5 mL) was added dropwise, stirred at −78 ° C. for 30 minutes, warmed to room temperature, and saturated aqueous ammonium chloride solution was added. The reaction mixture was extracted with ethyl acetate (150 mL), and the extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to obtain the desired product (1.60 g) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ0.67 (3H, d, J = 6.7 Hz),
1.03 (3H, d, J = 6.7 Hz), 1.14 (3H, t, J = 7.3 Hz), 1.21 (3H, t, J
= 7.3 Hz), 1.29 (3H, s), 1.33-1.45 (1H, m), 1.50-1.61 (1H, m), 1.82-1-1.94 (1H, m), 2.15-2.32 (1H, m), 2.49 ( 3H, s), 2.68−2.78 (2H,
m), 3.85 (1H, d, J = 3.1 Hz), 3.85 (1H, d, J = 3.1 Hz), 3.89−4.10 (4H, m), 7.51 (1H, dd, J = 8.6, 1.8 Hz), 7.61 (1H, d, J
= 8.6 Hz), 8.00 (1H, s).

<Example 13>
(2S, 5R) -3,6-diethoxy-2-methyl-5-isopropyl-2- [3- (2-methyl-6-trifluoromethylbenzo [b] thiophen-3-yl) propyl] -2, 5-dihydropyrazine

Using the compound of Example 9, the target product was obtained as a colorless oil in the same manner as in Example 12.
¹ H-NMR (400 MHz, CDCl ₃ ) δ0.58 (3H, d, J = 6.7 Hz),
1.03 (3H, d, J = 6.7 Hz), 1.09 (3H, t, J = 7.3 Hz), 1.19 (3H, t, J
= 7.3 Hz), 1.21 (3H, s), 1.30−1.65 (3H, m), 1.77−1.87 (1H, m), 2.24−2.36 (1H, m), 2.50 (3H,
s), 2.69−2.84 (2H, m), 3.81 (1H, d, J = 3.1 Hz),
3.90−4.10 (4H, m), 7.51 (1H, dd, J = 8.6, 1.2
Hz), 7.63 (1H, d, J = 8.6 Hz), 8.01 (1H, s).

<Example 14>
(R) -ethyl 2-tert-butoxycarbonylamino-2-methyl-5- (2-methyl-6-trifluoromethylbenzo [b] thiophen-3-yl) pentanate

To a solution of the compound of Example 12 (1.38 g) in 1,4-dioxane (30 mL) was added 0.5 mol / L hydrochloric acid (15 mL), and the mixture was stirred at room temperature for 24 hours. After concentration, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (150 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent of the extract under reduced pressure, the residue was dissolved in acetonitrile (25 mL), di-tert-butoxydicarbonate (637 mg) was added, and the mixture was stirred at room temperature for 24 hours. After evaporating the solvent of the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to obtain the desired product (1.02 g) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.14 (3H, t, J = 7.3 Hz),
1.38 (9H, s), 1.49 (3H, s), 1.52-1.68 (2H, m), 1.80-1.91 (1H, m), 2.25 (1H, br s), 2.51 (3H, s), 2.72-2.85 (2H, m), 4.05−4.16 (2H, m), 5.32 (1H,
br s), 7.52 (1H, dd, J = 8.6, 1.8 Hz), 7.63 (1H, d, J = 8.6 Hz),
8.01 (1H, s).

<Example 15>
(S) -ethyl 2-tert-butoxycarbonylamino-2-methyl-5- (2-methyl-6-trifluoromethylbenzo [b] thiophen-3-yl) pentanate

Using the compound of Example 13, the target product was obtained as a colorless oil in the same manner as in Example 14.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.14 (3H, t, J = 7.3 Hz),
1.38 (9H, s), 1.49 (3H, s), 1.52-1.67 (2H, m), 1.80-1.90 (1H, m), 2.15-2.36 (1H, m), 2.51 (3H,
s), 2.79 (2H, t, J = 7.3 Hz), 4.04−4.16 (2H, m),
5.31 (1H, br s), 7.51 (1H, d, J = 8.6 Hz), 7.63 (1H, d, J = 8.6
Hz), 8.01 (1H, s).

<Example 16>
(R) -ethyl 2-tert-butoxycarbonylamino-2-methyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentanate

Using the compound of Example 8, the target product was obtained as a colorless oil in the same manner as in Example 14.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.19 (3H, t, J = 7.3 Hz),
1.40 (9H, s), 1.52 (3H, s), 1.53-1.64 (1H, m), 1.67-1.83 (1H, m), 1.90 (1H, td, J = 13.4, 4.3 Hz), 2.19-2.36 ( 1H, m), 2.80−2.92 (2H, m), 4.08−4.22 (2H, m), 5.34 (1H, br s), 7.28 (1H, s), 7.58 (1H, dd, J
= 8.6, 1.8 Hz), 7.78 (1H, d, J = 8.6 Hz), 8.13 (1H, br s).

<Example 17>
(S) -ethyl 2-tert-butoxycarbonylamino-2-methyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentanate

Using the compound of Example 9, the target product was obtained as a colorless oil in the same manner as in Example 14.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.19 (3H, t, J = 7.3 Hz),
1.40 (9H, s), 1.52 (3H, s), 1.53-1.63 (1H, m), 1.67-1.83 (1H, m), 1.90 (1H, td, J = 12.2, 4.3 Hz), 2.17-2.38 ( 1H, m), 2.80−2.92 (2H, m), 4.08−4.19 (2H, m), 5.34 (1H, br s), 7.28 (1H, s), 7.58 (1H, dd, J
= 8.6, 1.8 Hz), 7.78 (1H, d, J = 8.6 Hz), 8.13 (1H, br s).

<Example 18>
(R) -2-tert-Butoxycarbonylamino-5- (2-chloro-6-trifluoromethylbenzo [b] thiophen-3-yl) -2-methyl-pentan-1-ol

To a solution of the compound of Example 10 (1.12 g) in 1,4-dioxane (30 mL) was added 0.5 mol / L hydrochloric acid (15 mL), and the mixture was stirred at room temperature for 24 hours. The solvent of the reaction solution was distilled off under reduced pressure, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (150 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent of the extract under reduced pressure, the residue was dissolved in acetonitrile (25 mL), and di-tert-butoxydicarbonate (637 mg) was added. Stir at ambient temperature for 24 hours. After distilling off the solvent of the reaction solution under reduced pressure, the residue was roughly purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1), and the resulting crude product was dissolved in THF (15 mL) and dissolved at 0 ° C. LiBH ₄ (243 mg) was added and ethanol (1.50 mL) was added dropwise. After stirring at 0 ° C. for 1 hour, the mixture was stirred at room temperature for 1 hour. 10% aqueous citric acid solution and water were added, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (730 mg) as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.11 (3H, s), 1.40 (9H, s),
1.52-1.79 (3H, m), 1.87−1.99 (1H, m), 2.90 (2H, t, J
= 7.3 Hz), 3.58 (1H, d, J = 11.6 Hz), 3.62 (1H, d, J = 11.6 Hz),
4.53 (1H, br s), 7.59 (1H, dd, J = 8.6, 1.2 Hz), 7.72 (1H, d, J =
8.6 Hz), 7.99 (1H, br s).

<Example 19>
(S) -2-tert-Butoxycarbonylamino-5- (2-chloro-6-trifluoromethylbenzo [b] thiophen-3-yl) -2-methyl-pentan-1-ol

Using the compound of Example 11, the target product was obtained as a colorless powder in the same manner as in Example 18.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.11 (3H, s), 1.40 (9H, s), 1.50−1.79 (3H, m), 1.87−2.00 (1H, m), 2.90 (2H,
t, J = 7.3 Hz), 3.58 (1H, d, J = 11.6 Hz), 3.62 (1H, d, J
= 11.6 Hz), 4.54 (1H, br s), 7.58 (1H, dd, J = 8.6, 1.2 Hz), 7.72 (1H,
d, J = 8.6 Hz), 7.99 (1H, br s).

<Example 20>
(R) -2-tert-Butoxycarbonylamino-2-methyl-5- (2-methyl-6-trifluoromethylbenzo [b] thiophen-3-yl) pentan-1-ol

LiBH ₄ (120 mg) and ethanol (1 mL) were added to a THF (10 mL) solution of the compound of Example 14 (1.02 g) at 0 ° C., and the mixture was stirred at 0 ° C. for 2 hours. Water and 10% aqueous citric acid solution were added, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (894 mg) as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.09 (3H, s), 1.39 (9H, s), 1.52-1.75 (3H, m), 1.86-1.98 (1H, m), 2.53 (3H,
s), 2.77−2.87 (2H, m), 3.60 (2H, s), 3.93 (1H, br s),
4.52 (1H, br s), 7.54 (1H, dd, J = 8.6, 1.8 Hz), 7.67 (1H, d, J =
8.6 Hz), 8.02 (1H, s).

<Example 21>
(S) -2-tert-butoxycarbonylamino-2-methyl-5- (2-methyl-6-trifluoromethylbenzo [b] thiophen-3-yl) pentan-1-ol

Using the compound of Example 15, the target product was obtained as a colorless powder in the same manner as in Example 20.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.09 (3H, s), 1.39 (9H, s), 1.55-1.74 (3H, m), 1.86-1.99 (1H, m), 2.53 (3H,
s), 2.76−2.87 (2H, m), 3.60 (2H, s), 3.93 (1H, br s),
4.52 (1H, br s), 7.54 (1H, dd, J = 8.6, 1.2 Hz), 7.67 (1H, d, J =
8.6 Hz), 8.02 (1H, s).

<Example 22>
(R) -2-tert-Butoxycarbonylamino-2-methyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentan-1-ol

Using the compound of Example 16, the target product was obtained as a colorless powder in the same manner as in Example 20.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.14 (3H, s), 1.41 (9H, s), 1.57
(1H, br s), 1.68−1.80 (2H, m), 1.80−1.97 (2H, m), 2.89 (2H, t, J = 7.3 Hz), 3.63 (2H, d, J
= 1.2 Hz), 4.57 (1H, br s), 7.31 (1H, s), 7.59 (1H, dd, J = 8.6, 1.2
Hz), 7.82 (1H, d, J = 8.6 Hz), 8.14 (1H, d, J = 1.2 Hz).

<Example 23>
(S) -2-tert-butoxycarbonylamino-2-methyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentan-1-ol

Using the compound of Example 17, the target product was obtained as a colorless powder in the same manner as in Example 20.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.14 (3H, s), 1.41 (9H, s), 1.65-1.99 (5H, m), 2.90 (2H, t, J = 7.3 Hz), 3.63 ( 2H, d, J
= 1.8 Hz), 4.57 (1H, br s), 7.31 (1H, s), 7.60 (1H, dd, J = 8.6, 1.2
Hz), 7.82 (1H, d, J = 8.6 Hz), 8.14 (1H, br s).

<Example 24>
(R) -2-Amino-5- (2-chloro-6-trifluoromethylbenzo [b] thiophen-3-yl) -2-methylpentan-1-ol hydrochloride

To the compound of Example 18 (350 mg) was added 10% hydrochloric acid-methanol solution (10 mL), and the mixture was stirred at room temperature for 24 hours. The solvent of the reaction solution was distilled off under reduced pressure and the desired product (285
mg) was obtained as a colorless powder.
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ1.09 (3H, s), 1.54-1.70 (4H, m), 2.85−2.95 (2H, m), 3.27−3.45 (2H, m), 5.46 (1H, t, J = 4.9 Hz), 7.72− 7.82 (4H, m), 8.04 (1H, d, J = 7.9 Hz), 8.52 (1H, br s).
FABMS (+):
352 [M + H] ⁺ .
Elemental analysis: Measured value C 46.11%, H 4.56%, N 3.59%, C ₁₅ H ₁₇ ClF ₃ NOS, calculated as C 46.40%, H 4.67%, N 3.61%.

<Example 25>
(S) -2-Amino-5- (2-chloro-6-trifluoromethylbenzo [b] thiophen-3-yl) -2-methylpentan-1-ol hydrochloride

Using the compound of Example 19, the target product was obtained as a colorless amorphous product in the same manner as in Example 24.
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ1.14 (3H, s), 1.53-1.82 (4H, m), 2.87 (2H, t, J = 7.3 Hz), 3.33−3.46 (2H, m), 5.47 (1H, t, J = 4.9 Hz) , 7.76 (1H, dd, J
= 8.6, 1.8 Hz), 7.76 (3H, br s), 8.04 (1H, d, J = 8.6 Hz), 8.51 (1H, br
s).
FABMS (+): 352
[M + H] ⁺ .
Elemental analysis: Measured value C 46.11%, H 4.51%, N 3.61%, C ₁₅ H ₁₇ ClF ₃ NOS, calculated as C 46.40%, H 4.67%, N 3.61%.

<Example 26>
(R) -2-Amino-2-methyl-5- (2-methyl-6-trifluoromethylbenzo [b] thiophen-3-yl) pentan-1-ol hydrochloride

Using the compound of Example 20, the target product was obtained as a colorless amorphous product in the same manner as in Example 24.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ1.08 (3H, s), 1.51-1.70 (4H, m), 2.55 (3H, s), 2.77-2.87 (2H,
m), 3.28−3.40 (2H, m), 5.45 (1H, t, J = 4.9 Hz),
7.66 (1H, dd, J = 8.6, 1.2 Hz), 7.76 (3H, br s), 7.90 (1H, d, J =
8.6 Hz), 8.38 (1H, s).
FABMS (+): 332
[M + H] ⁺ .
HRFABMS (+):
332.1262 (calculated as C ₁₆ H ₂₀ F ₃ NOS, HCl 332.1296).

<Example 27>
(S) -2-Amino-2-methyl-5- (2-methyl-6-trifluoromethylbenzo [b] thiophen-3-yl) pentan-1-ol hydrochloride

Using the compound of Example 21, the target product was obtained as a colorless amorphous product in the same manner as in Example 24.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ1.08 (3H, s), 1.50-1.70 (4H, m), 2.55 (3H, s), 2.77-2.87 (2H,
m), 3.27−3.40 (2H, m), 5.45 (1H, t, J = 5.5 Hz),
7.66 (1H, dd, J = 8.6, 1.2 Hz), 7.73 (3H, br s), 7.90 (1H, d, J =
8.6 Hz), 8.38 (1H, s).
FABMS (+): 332
[M + H] ⁺ .
HRFABMS (+):
332.1288 (calculated as C ₁₆ H ₂₀ F ₃ NOS, HCl 332.1296).

<Example 28>
(R) -2-Amino-2-methyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentan-1-ol hydrochloride

Using the compound of Example 22, the target product was obtained as a pale yellow amorphous product in the same manner as in Example 24.
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ1.14 (3H, s), 1.53-1.81 (4H, m), 2.83−2.91 (2H, m), 3.34−3.45 (2H, m), 5.47 (1H, t, J = 5.5 Hz), 7.71 ( 1H, dd, J
= 8.6, 1.8 Hz), 7.74 (1H, s), 7.83 (3H, br s), 8.04 (1H, d, J = 8.6 Hz), 8.51
(1H, br s).
FABMS (+):
318 [M + H] ⁺ .
Elemental analysis: Measured value calculated as C 50.63%, H 5.50%, N 3.88%, C ₁₅ H ₁₈ F ₃ NOS, HCl, 1 / 8H ₂ O
C 50.60%, H 5.45%, N 3.93%.

<Example 29>
(S) -2-Amino-2-methyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentan-1-ol hydrochloride

Using the compound of Example 23, the target product was obtained as a pale yellow amorphous product in the same manner as in Example 24.
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ1.14 (3H, s), 1.53-1.82 (4H, m), 2.87 (2H, t, J = 7.3 Hz), 3.33−3.46 (2H, m), 5.47 (1H, t, J = 4.9 Hz) , 7.71 (1H, dd, J
= 8.6, 1.8 Hz), 7.74 (1H, s), 7.83 (3H, br s), 8.04 (1H, d, J = 8.6 Hz),
8.51 (1H, br s).
FABMS (+):
318 [M + H] ⁺ .
Elemental analysis: Measured value C 50.61%, H 5.37%, N 3.94%, C ₁₅ H ₁₈ F ₃ NOS, HCl, 1 / 8H ₂ O calculated value C 50.60%, H 5.45%, N 3.93%.

<Example 30>
(R) -2-tert-butoxycarbonylamino-1-dimethoxyphosphoryloxy-2-methyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentane

Carbon tetrabromide (460 mg) and trimethyl phosphite (164 μL) were added to a solution of the compound of Example 22 (290 mg) in pyridine (5 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with 0.5 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1 →
The product was purified by 1: 1) to obtain the desired product (291 mg) as a pale brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.26 (3H, s), 1.40 (9H, s), 1.70-1.83 (2H, m), 1.90-2.06 (2H, m), 2.88 (2H,
t, J = 7.3 Hz), 3.74 (3H, d, J = 1.8 Hz), 3.77 (3H, d, J =
1.8 Hz), 3.98 (1H, dd, J = 9.8, 4.9 Hz), 4.16 (1H, dd, J = 9.8,
4.9 Hz), 4.53 (1H, br s), 7.30 (1H, s), 7.59 (1H, dd, J = 8.6, 1.2 Hz),
7.82 (1H, d, J = 8.6 Hz), 8.14 (1H, br s).

<Example 31>
(S) -2-tert-butoxycarbonylamino-1-dimethoxyphosphoryloxy-2-methyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentane

Using the compound of Example 23, the target product was obtained as a pale brown oil in the same manner as in Example 30.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.26 (3H, s), 1.40 (9H, s), 1.70-1.83 (2H, m), 1.90-2.07 (2H, m), 2.88 (2H,
t, J = 7.3 Hz), 3.74 (3H, d, J = 1.8 Hz), 3.77 (3H, d, J =
1.8 Hz), 3.98 (1H, dd, J = 9.8, 4.9 Hz), 4.16 (1H, dd, J = 9.8,
4.9 Hz), 4.53 (1H, br s), 7.30 (1H, s), 7.59 (1H, dd, J = 8.6, 1.2 Hz),
7.82 (1H, d, J = 8.6 Hz), 8.14 (1H, br s).

<Example 32>
(R) -2-tert-butoxycarbonylamino-1-dimethoxyphosphoryloxy-2-methyl-5- (2-methyl-6-trifluoromethylbenzo [b] thiophen-3-yl) pentane

Using the compound of Example 20, the target product was obtained as a pale brown oil in the same manner as in Example 30.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.21 (3H, s), 1.38 (9H, s), 1.55-1.65 (3H, m), 1.90−2.03 (1H, m), 2.52 (3H,
s), 2.80 (2H, t, J = 7.3 Hz), 3.73 (3H, d, J = 2.4 Hz), 3.75 (3H,
d, J = 2.4 Hz), 3.90−3.99 (1H, m), 4.08−4.15 (1H, m), 4.48 (1H, br s), 7.53 (1H, dd, J = 8.6, 1.2
Hz), 7.67 (1H, d, J = 8.6 Hz), 8.01 (1H, s).

<Example 33>
(S) -2-tert-butoxycarbonylamino-1-dimethoxyphosphoryloxy-2-methyl-5- (2-methyl-6-trifluoromethylbenzo [b] thiophen-3-yl) pentane

Using the compound of Example 21, the target product was obtained as a pale brown oil in the same manner as in Example 30.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.21 (3H, s), 1.39 (9H, s), 1.55-1.66 (2H, m), 1.90−2.07 (2H, m), 2.52 (3H,
s), 2.81 (2H, t, J = 7.3 Hz), 3.73 (3H, d, J = 2.4 Hz), 3.76 (3H,
d, J = 2.4 Hz), 3.95 (1H, dd, J = 9.8, 4.9 Hz), 4.08−4.17 (1H, m), 4.48 (1H, br s), 7.53 (1H, dd, J = 8.6, 1.8 Hz),
7.67 (1H, d, J = 8.6 Hz), 8.02 (1H, s).

<Example 34>
(R) -2-tert-butoxycarbonylamino-5- (2-chloro-6-trifluoromethylbenzo [b] thiophen-3-yl) -1-dimethoxyphosphoryloxy-2-methylpentane

Trimethyl phosphite (289 μL) and 2,6-lutidine (263 mg) were added to a solution of the compound of Example 18 (369 mg) in dichloromethane (10 mL) and stirred at 0 ° C. under an argon atmosphere. Tellurium chloride (440 mg) was added. After stirring at 0 ° C. for 2 hours, the solvent of the reaction solution was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (272 mg) as a light brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.22 (3H, s), 1.38 (9H, s), 1.58-1.76 (3H, m), 1.92−2.07 (1H, m), 2.85−2.93 (2H , m), 3.74 (3H, d, J = 2.4 Hz), 3.76 (3H, d, J
= 2.4 Hz), 3.95 (1H, dd, J = 9.8, 4.9 Hz), 4.12 (1H, dd, J = 9.8,
4.9 Hz), 4.49 (1H, br s), 7.58 (1H, dd, J = 8.6, 1.2 Hz), 7.72 (1H, d, J
= 8.6 Hz), 7.99 (1H, br s).

<Example 35>
(S) -2-tert-butoxycarbonylamino-5- (2-chloro-6-trifluoromethylbenzo [b] thiophen-3-yl) -1-dimethoxyphosphoryloxy-2-methylpentane

Using the compound of Example 19, the target product was obtained as a pale brown oil in the same manner as in Example 34.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.22 (3H, s), 1.38 (9H, s), 1.56-1.78 (3H, m), 1.92−2.05 (1H, m), 2.85−2.93 (2H , m), 3.74 (3H, d, J = 2.4 Hz), 3.76 (3H, d, J
= 2.4 Hz), 3.95 (1H, dd, J = 9.8, 5.5 Hz), 4.12 (1H, dd, J = 9.8,
5.5 Hz), 4.49 (1H, br s), 7.58 (1H, dd, J = 8.6, 1.2 Hz), 7.72 (1H, d, J
= 8.6 Hz), 7.99 (1H, br s).

<Example 36>
(R) -2-Amino-2-methyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentylphosphonic acid monoester

To a solution of the compound of Example 30 (291 mg) in acetonitrile (5 mL), iodotrimethylsilane (315 μL) was added dropwise at 0 ° C. in an argon atmosphere, and the mixture was stirred at 0 ° C. for 30 minutes. Water (30 mL) was added, and the precipitated crystals were collected by filtration. The crystals are washed with water and ethyl acetate, and the desired product (153
mg) was obtained as a colorless powder.
¹ H-NMR (400 MHz, DMSO-d ₆ + CF ₃ COOD)
δ1.20 (3H, s), 1.60−1.83 (4H, m), 2.85−2.93 (2H, m), 3.81 (1H,
dd, J = 11.0, 4.9 Hz), 3.87 (1H, dd, J = 11.0, 5.5 Hz), 7.71 (1H,
dd, J = 8.6, 1.2 Hz), 7.72 (1H, s), 8.05 (1H, d, J = 8.6 Hz),
8.50 (1H, br s).
FABMS (+):
398 [M + H] ⁺ .
Elemental analysis: Measured value C 45.10%, H 4.72%, N 3.51%, C ₁₅ H ₁₉ F ₃ NO ₄ PS calculated value C 45.34%, H 4.82%, N 3.53%.

<Example 37>
(S) -2-Amino-2-methyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentylphosphonic acid monoester

Using the compound of Example 31, the target product was obtained as a colorless powder in the same manner as in Example 36.
¹ H-NMR (400 MHz, DMSO-d ₆ + CF ₃ COOD)
δ1.20 (3H, s), 1.62-1.84 (4H, m), 2.85-2.93 (2H, m), 3.82 (1H,
dd, J = 11.0, 4.9 Hz), 3.87 (1H, dd, J = 11.0, 5.5 Hz), 7.71 (1H,
dd, J = 8.6, 1.2 Hz), 7.72 (1H, s), 8.05 (1H, d, J = 8.6 Hz),
8.50 (1H, br s).
FABMS (+):
398 [M + H] ⁺ .
Elemental analysis: Measured value C 45.23%, H 4.76%, N 3.49%, C ₁₅ H ₁₉ F ₃ NO ₄ PS calculated value C 45.34%, H 4.82%, N 3.53%.

<Example 38>
(R) -2-Amino-2-methyl-5- (2-methyl-6-trifluoromethylbenzo [b] thiophen-3-yl) pentylphosphonic acid monoester

Using the compound of Example 32, the target product was obtained as a colorless powder in the same manner as in Example 36.
¹ H-NMR (400 MHz, DMSO-d ₆ + CF ₃ COOD) δ1.15 (3H, s), 1.50−1.80 (4H, m), 2.55 (3H, s), 2.83 (2H, t, J = 7.9 Hz), 3.77
(1H, dd, J = 11.0, 5.5 Hz), 3.82 (1H, dd, J = 11.0, 5.5 Hz), 7.66
(1H, dd, J = 8.6, 1.8 Hz), 7.91 (1H, d, J = 8.6 Hz), 8.37 (1H,
s).
FABMS (+):
412 [M + H] ⁺ .
HRFABMS (+):
412.0934 (calculated as C ₁₆ H ₂₁ F ₃ NO ₄ PS 412.0959).

<Example 39>
(S) -2-Amino-2-methyl-5- (2-methyl-6-trifluoromethylbenzo [b] thiophen-3-yl) pentylphosphonic acid monoester

Using the compound of Example 33, the target product was obtained as a colorless powder in the same manner as in Example 36.
¹ H-NMR (400 MHz, DMSO-d ₆ + CF ₃ COOD) δ1.15 (3H, s), 1.51-1.64 (2H, m), 1.64-1.78 (2H, m), 2.55 (3H,
s), 2.78−2.88 (2H, m), 3.78 (1H, dd, J = 11.0,
4.9 Hz), 3.83 (1H, dd, J = 11.0, 5.5 Hz), 7.66 (1H, dd, J = 8.6,
1.2 Hz), 7.91 (1H, d, J = 8.6 Hz), 8.37 (1H, s).
FABMS (+):
412 [M + H] ⁺ .
HRFABMS (+):
412.0906 (calculated as C ₁₆ H ₂₁ F ₃ NO ₄ PS 412.0959).

<Example 40>
(R) -2-Amino-5- (2-chloro-6-trifluoromethylbenzo [b] thiophen-3-yl) 2-methylpentylphosphonic acid monoester

Using the compound of Example 34, the target product was obtained as a colorless powder in the same manner as in Example 36.
¹ H-NMR (400 MHz, DMSO-d ₆ + CF ₃ COOD)
δ1.15 (3H, s), 1.59−1.78 (4H, m), 2.87−2.96 (2H, m), 3.78 (1H,
dd, J = 11.0, 4.9 Hz), 3.83 (1H, dd, J = 11.0, 5.5 Hz), 7.75 (1H,
dd, J = 8.6, 1.2 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.51 (1H, br s).
FABMS (+): 432 [M + H] ⁺ .
Elemental analysis: Measured value C 40.84%, H 4.05%, N 3.15%, C ₁₅ H ₁₉ F ₃ NO ₄ PS, 2 / 5H ₂ O calculated value C 41.04%, H 4.32%, N 3.19%.

<Example 41>
(S) -2-Amino-5- (2-chloro-6-trifluoromethylbenzo [b] thiophen-3-yl) 2-methylpentylphosphonic acid monoester

Using the compound of Example 35, the target product was obtained as a colorless powder in the same manner as in Example 36.
¹ H-NMR (400 MHz, DMSO-d ₆ + CF ₃ COOD)
δ1.16 (3H, s), 1.59−1.78 (4H, m), 2.87−2.96 (2H, m), 3.79 (1H,
dd, J = 11.0, 5.5 Hz), 3.83 (1H, dd, J = 11.0, 5.5 Hz), 7.75 (1H,
dd, J = 8.6, 1.2 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.50 (1H, br s).
FABMS (+):
432 [M + H] ⁺ .
Elemental analysis: Measured value C 40.84%, H 4.39%, N 3.20%, C ₁₅ H ₁₉ F ₃ NO ₄ PS, 2 / 5H ₂ O calculated value C 41.04%, H 4.32%, N 3.19%.

  Next, the results of supporting the usefulness of the compounds of the present invention are shown by experimental examples.

<Experimental Example> Intracellular calcium mobilization induction test of test compounds against human S1P (sphingosine-1-phosphate) receptor-expressing cells
Human S1P receptor-expressing CHO-K1 cells (hS1P ₁ receptor-expressing CHO-K1 cells, hS1P ₃ receptor expression) subcultured in Ham's F-12 medium containing 10% fetal bovine serum and 400 μg / mL Geneticin CHO-K1 cells, hS1P ₄ receptor expression CHO-K1 cells) was used. hS1P ₁ and hS1P ₃ receptor-expressing CHO-K1 cells are 7 × 10 ⁴ cells / well, hS1P ₄ receptor-expressing CHO-K1 cells are 4 × 10 ⁴ cells / well, 96-well black clear bottom culture plate (BD Falcon ) And cultured overnight at 37 ° C. under 5% CO ₂ . As a Ca ²⁺ -binding fluorescent indicator, the attached reagent (Loading buffer) was added to Calcium Kit-Fluo3 reagent (Dojindo Laboratories), and incubated at 37 ° C. under 5% CO ₂ for 80 minutes. The wells were washed with PBS, and the attached reagent (Recording buffer) was added to the Calcium Kit-Fluo3 reagent, followed by incubation at 37 ° C. under 5% CO ₂ for 20 minutes. After incubation, the fluorescence intensity at an excitation wavelength of 485 nm and a detection wavelength of 525 nm was measured using a microplate fluorescence spectrophotometer (FLEX Station, molecular device). Add S1P prepared in the medium to a concentration 10 times the final concentration or test compound (final DMSO concentration 0.1%) 18 seconds after the start of fluorescence measurement, and continuously measure the fluorescence intensity every 1.5 seconds until 100 seconds after addition. did. Calculate the value obtained by subtracting the minimum fluorescence intensity from the maximum fluorescence intensity from the measurement data (fluorescence increase), and the difference between the fluorescence increase when the solvent is added and the fluorescence increase when S1P is applied at 10 ^-6 M Was 100%, and the fluorescence increase rate (%) of the test compound was calculated. The EC ₅₀ value was determined using PRISM software (GraphPad) as the intracellular calcium mobilization inducing action of the test compound. The EC ₅₀ value ≧ 1 μmol / L is represented as −, 1 μmol / L> EC ₅₀ value ≧ 0.01 μmol / L is represented as +, 0.01 μmol / L> EC ₅₀ value is represented as ++, and is shown in Table 1.

The compound of the present invention the above results were observed to act selectively against human SlP ₄ receptor.

The present invention were found to have a SlP ₄ receptor regulating action excellent addition salts thereof and the novel benzothiophene derivatives. Compounds having such SlP ₄ receptor modulating action, rheumatoid arthritis, chronic bronchial asthma, is useful as a preventive or therapeutic agent such as atopic dermatitis.

Claims (5)

General formula (1)

[Wherein R ¹ represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms,
R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a hydroxymethyl group,
R ³ represents a hydrogen atom or PO (OH) ₂ ,
m shows the integer of 2-4. ]
Or a pharmaceutically acceptable salt or hydrate thereof. General formula (1a)

[Wherein R ¹ , R ² and R ³ are as described above]
The benzothiophene derivative of Claim 1 represented by these, its optically active substance, its pharmacologically acceptable salt, or its hydrate. Compound is
1)
2-amino-2- [3- (6-trifluoromethylbenzo [b] thiophen-3-yl) propyl] -1,3-propanediol,
2)
2-amino-2-methyl-5- (2-methyl-6-trifluoromethylbenzo [b] thiophen-3-yl) pentan-1-ol,
3)
2-amino-5- (2-chloro-6-trifluoromethylbenzo [b] thiophen-3-yl) -2-methylpentan-1-ol,
4)
2-amino-2-methyl-5- (6-trifluoromethylbenzo [b] thiophen-3-yl) pentan-1-ol,
The benzothiophene derivative according to claim 1, a pharmacologically acceptable salt thereof or a hydrate thereof. Benzothiophene derivative, its optical isomers, SlP ₄ receptor modulators to pharmacologically acceptable salts or active ingredient hydrate thereof according to any one of claims 1 to 3. The pharmaceutical which contains the benzothiophene derivative of any one of Claims 1-3, its optical isomer, its pharmacologically acceptable salt, or its hydrate as an active ingredient.