JP2009091267A - Amide derivative, and selective agonist for sphingosine-1-phosphoric acid-1 (s1p1) receptor comprising the same as effective component - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an amide derivative having an excellent selective antagonistic action on the S1P<SB>1</SB>receptor. <P>SOLUTION: Disclosed are an amide derivative represented by formula (1) [wherein R<SP>1</SP>represents a benzyloxy group, an 1-6C alkyl group that may be substituted with a halogen atom, or the like; R<SP>2</SP>represents -(O)p-(CR<SP>a</SP>R<SP>b</SP>)q-COOH or -(CR<SP>c</SP>R<SP>d</SP>)q-PO<SB>3</SB>H<SB>2</SB>; R<SP>3</SP>represents a hydrogen atom, a halogen atom, a nitro group or the like; X represents a hydrogen atom or a halogen atom; Y represents O, S, SO or SO<SB>2</SB>; Z represents -CONH- or -NHCO-; and T represents -CH=CH- or -(CH<SB>2</SB>)m-], and a pharmacologically acceptable salt or hydrate thereof. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

The present invention relates to amide derivatives, salts and hydrates useful as S1P ₁ receptor selective agonists.

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 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 Gs present on the surface of a cell membrane. 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 .

From various studies on these S1P receptors, reports have been made that so-called S1P receptor modulators exhibiting agonist activity or antagonist activity on this receptor exert effectiveness against various diseases. For example, it is disclosed in Patent Document 1 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), It is disclosed in Patent Document 2 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. Has been. In addition, compounds with Edg-1 agonist activity 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 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, glomerulosclerosis (Patent Document 3). It is disclosed.

Furthermore, it has been reported that a compound having S1P receptor agonist activity regulates leukocyte migration (Non-patent Documents 4 and 5), and a series of derivatives introduced in these non-patent documents are various organs. Rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, Hashimoto's disease, multiple sclerosis, myasthenia gravis, autoimmune diseases such as type I and II diabetes, Crohn's disease, atopic dermatitis, It is disclosed in Patent Document 4 and Patent Document 5 that it is effective for allergic diseases such as allergic rhinitis, allergic conjunctivitis, allergic contact dermatitis, inflammatory bowel disease or ulcerative colitis. Has been. Moreover, the phosphoric acid derivative similar to the said (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, carboxylic acid derivatives (Patent Documents 7 to 62) have been used as S1P ₁ to S1P ₅ receptor modulators centered on S1P ₁ receptors or immunosuppression. It is disclosed as an agent.

There is a lot of interest in S1P receptor agonists with such a wide range of medical uses, but not all S1P receptor agonists necessarily provide the desired effects for the body. is not.
For example, S1P receptor agonists that have been shown to be useful in suppressing organ transplant rejection in clinical trials have bradycardia as a side effect after administration, and this effect is due to agonistic effects on S1P ₃ receptors. There are also reports that they may be present (Non-Patent Document 6, Non-Patent Document 7). There are also reports that agonists to the S1P ₃ receptor inhibit blood flow of the myocardium (Non-patent Document 8), cerebral artery spasm (Non-patent Document 9), and pulmonary edema (Non-patent Document 10). In addition, although the compound similar to this application compound is reported to patent document 3 as a S1P1 agonist, the selectivity with respect to a receptor is not reported. Further, Patent Document 3 does not include the claimed compound having a diaryl ether or diaryl sulfide structure, which is a feature of the compound of the present application.
WO0198301 pamphlet WO03020313 pamphlet WO02092068 pamphlet WO0218395 pamphlet WO02076995 pamphlet JP 2003-137894 A WO03040097 brochure WO02064616 pamphlet WO02062389 pamphlet JP 2002-316985 A JP 2003-267936 A WO 03051876 pamphlet WO03061567 pamphlet WO03062248 pamphlet WO03062252 pamphlet WO03073986 pamphlet WO03074008 pamphlet WO03105771 pamphlet WO04010949 pamphlet WO04024673 pamphlet WO04058149 brochure WO04071442 pamphlet WO04096752 pamphlet WO04096757 pamphlet WO04103279 pamphlet WO04103306 pamphlet WO04103309 pamphlet WO04110979 pamphlet WO04113330 pamphlet WO04074297 pamphlet WO05014603 pamphlet WO05020882 pamphlet WO04002531 pamphlet WO05032465 pamphlet WO05041899 pamphlet WO05058848 pamphlet WO05070886 pamphlet WO05082089 pamphlet WO05082841 pamphlet WO05021503 pamphlet WO0505040091 pamphlet WO05085179 pamphlet WO05118523 pamphlet WO05001425 pamphlet WO06020951 pamphlet WO06001463 pamphlet WO03029184 pamphlet WO03029205 pamphlet WO04026817 pamphlet WO04074297 pamphlet WO05021503 pamphlet JP 2004-307439 A JP 2004-307440 A JP 2004-307441 A JP 2004-307442 A WO06041015 pamphlet JP 2004-137208 A Japanese Patent Laid-Open No. 2005-41867 JP 2005-47899 A WO0505040091 pamphlet WO05063671 pamphlet WO05079788 pamphlet Y. Takuma et al., Mol. Cell. Endocrinol., 177, 3 (2001). Y. Igarashi, Ann, NY Acad. Sci., 845, 19 (1998). H. Okazaki et al., Biochem. Biophs. Res. Commun., 190, 1104 (1993). S. Mandala et al., Science, 296, 346 (2002). V. Brinkmann et al., J. Biol. Chem., 277, 21453 (2002). MGSanna et al., J. Biol. Chem., 279, 13839 (2004). M. Forrest et al., J. Pharmacol. Exp. Ther., 309, 758 (2004). B. Levkau et al., Circulation, 110, 3358 (2004). S. Salomone et al., Eur. J. Pharmacol. 469, 125 (2003). Y. Gon et al., PNAS 102,9270 (2005).

The problem to be solved by the present invention is to provide an amide derivative that has a weak agonistic action on the S1P ₃ receptor and has an excellent agonistic action on the S1P ₁ receptor and has few side effects.

The present inventors have agonize S1P ₁ receptor, SlP ₃ results so diligent research to create a compound having high weak safety of agonistic action for the receptor, novel amide derivative of the above-mentioned object We have found that this has been accomplished and completed the present invention.
That is, the present invention is 1)
General formula (1)

[Wherein, R ¹ represents a benzyloxy group, an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, an alkoxy group having 1 to 6 carbon atoms or a cycloalkylmethyloxy group having 4 to 8 carbon atoms. ,
R ² is-(O) p- (CR ^a R ^b ) q-COOH
(Wherein R ^a represents a hydrogen atom, a methyl group or a trifluoromethyl group, R ^b represents a hydrogen atom, a hydroxyl group or a carboxyl group, and p and q each represents 0 or 1), or
-(CR ^c R ^d ) q -PO ₃ H ₂
(Wherein R ^c represents a hydrogen atom or a halogen atom, R ^d represents a hydrogen atom, a halogen atom or a hydroxyl group, q represents 0 or 1),
R ³ represents a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a carboxyl group or a phosphate group,
X represents a hydrogen atom or a halogen atom,
Y is O, S, SO or SO _2,
Z represents -CONH- or -NHCO-
T represents —CH═CH— or — (CH ₂ ) m— (wherein m represents 2 or 3). ]
An amide derivative represented by the formula, a pharmacologically acceptable salt thereof or a hydrate thereof,

2) In the general formula (1), Z is —NHCO—.
1) The amide derivative according to 1), a pharmacologically acceptable salt thereof or a hydrate thereof,

3) The amide derivative according to 1) or 2), wherein R ¹ is a cycloalkylmethyloxy group having 4 to 8 carbon atoms in the general formula (1), a pharmacologically acceptable salt thereof or a hydrate thereof,

4) In the general formula (1), R ² is CO ₂ H, CH ₂ CO ₂ H, CH (CO ₂ H) ₂ , CH (OH) CO ₂ H, C (OH) CF ₃ CO ₂ H, OCH ( CO ₂ H) ₂ , OCMe (CO ₂ H) ₂ , PO ₃ H ₂ , CH ₂ PO ₃ H ₂ , CHFPO ₃ H ₂ , CF ₂ PO ₃ H ₂ or CH (OH) PO ₃ H ₂
The amide derivative according to any one of 1) to 3), a pharmacologically acceptable salt thereof or a hydrate thereof,

5) In the general formula (1), R ² is CO ₂ H, CH ₂ CO ₂ H, CH (CO ₂ H) ₂ , CH (OH) CO ₂ H, C (OH) CF ₃ CO ₂ H, OCH ( CO ₂ H) ₂ or OCMe (CO ₂ H) ₂
The amide derivative according to any one of 1) to 3), a pharmacologically acceptable salt thereof or a hydrate thereof,

6) In the general formula (1), R ² is PO ₃ H ₂ , CH ₂ PO ₃ H ₂ , CHFPO ₃ H ₂ , CF ₂ PO ₃ H ₂ or CH (OH) PO ₃ H ₂
The amide derivative according to any one of 1) to 3), a pharmacologically acceptable salt thereof or a hydrate thereof,

7) The compound represented by the general formula (1) is represented by the general formula (1a)

[Wherein R ⁴ represents CO ₂ H, PO ₃ H ₂ , CH ₂ PO ₃ H ₂ , CHFPO ₃ H ₂ , CF ₂ PO ₃ H ₂ or CH (OH) PO ₃ H ₂ , and R ⁵ represents a hydrogen atom. Represents a halogen atom, a hydroxyl group, a carboxyl group or a phosphate group, and R ¹ , X and Y are the same as defined above]
1) to 3) represented by amide derivatives, pharmaceutically acceptable salts or hydrates thereof,

8) The amide derivative according to 7), wherein R ⁴ and R ⁵ in the general formula (1a) are carboxyl groups, a pharmacologically acceptable salt thereof or a hydrate thereof,

9) The compound represented by the general formula (1) is
4- [3- (4- (3-benzyloxyphenylthio) -2-chlorophenyl) propanamide] phthalic acid,
4- [3- (2-chloro-4- (3-cyclohexylmethyloxyphenoxy) phenyl) propanamide] phthalic acid,
3- [3- (4- (3-benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenylphosphonic acid,
3- [3- (4- (3-benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenylmethylphosphonic acid,
[3- (3- (4- (3-benzyloxyphenylthio) -2-chlorophenyl) propanamido) phenyl] hydroxymethylphosphonic acid,
4- [4- (3-benzyloxyphenylthio) -2-chlorophenethylcarbamoyl] phthalic acid, the amide derivative according to 1), a pharmacologically acceptable salt thereof or a hydrate thereof,

10) Sphingosine-1-phosphate-1 (S1P ₁ ) receptor agonist comprising the amide derivative according to any one of 1) to 9), a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient ,

11) The present invention relates to a medicament containing the amide derivative according to any one of 1) to 9), a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient.

The present invention has been found that a novel amide derivative has an excellent S1P ₁ receptor agonistic action. Such S1P ₁ receptor agonistic compounds include arteriosclerosis, obstructive arteriosclerosis, obstructive thromboangiitis, renal fibrosis, liver fibrosis, chronic bronchial asthma, diffuse hamartoma pulmonary vascular Myomatosis, adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), interstitial pneumonia, idiopathic interstitial pneumonia, lung cancer, hypersensitivity pneumonitis, Buerger's disease, peripheral arterial disease of diabetic neuropathy, Sepsis, vasculitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edematous disease, varicose vein, dissecting aortic aneurysm, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure, failure, burn, ulcer Treatment and prevention of colitis, Crohn's disease, etc., and prevention or treatment of rejection such as heart transplantation, kidney transplantation, skin transplantation, liver transplantation, bone marrow transplantation, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, bridge Disease, multiple sclerosis, myasthenia gravis, diabetes, atopic dermatitis, is useful as allergic rhinitis, allergic conjunctivitis, prophylactic or therapeutic agent such as allergic contact dermatitis.

In the present invention, the halogen atom of R ¹ "alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom" is a fluorine atom or a chlorine atom.
A C1-C6 alkyl group is a linear or branched C1-C6 alkyl group. For example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group, hexyl group, etc. Can do.

A C1-C6 alkoxy group is a linear or branched C1-C6 alkoxy group. For example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, t-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, t-pentyloxy group And hexyloxy group.

Examples of the cycloalkylmethyloxy group having 4 to 8 carbon atoms include a cyclopropylmethyloxy group, a cyclobutylmethyloxy group, a cyclopentylmethyloxy group, and a cyclohexylmethyloxy group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Examples of the pharmacologically acceptable salt in the present invention include alkali metal salts such as sodium salt, potassium salt, magnesium salt, calcium salt and aluminum salt.

  Among the compounds represented by the general formula (1) according to the present invention, a compound in which Z is —CONH—, that is, the general formula (1b)

[Wherein R ¹ , R ² , R ³ , X, Y and T are as described above]
And a compound in which Z is —NHCO—, that is, the general formula (1c)

[Wherein R ¹ , R ² , R ³ , X, Y and T are as described above]
Can be produced, for example, by the synthesis route A as shown below.
<Synthesis route A>

The compound represented by the general formula (1b) in the synthesis route A is represented by the general formula (2).

[Wherein R ¹ , X, Y and T are as described above]
And a compound represented by the general formula (4)

[Wherein R ² and R ³ are as described above]
It can manufacture by condensing the compound represented by (process A-1).

  For the reaction, a commonly used condensation reaction of carboxylic acids and amines can be used. For example, it is used as a solvent such as methylene chloride or chloroform, and a compound represented by the general formula (2) is reacted with thionyl chloride or oxalyl chloride at 0 ° C. to heating under reflux to obtain an acid chloride, followed by a base such as triethylamine or pyridine. In the presence of 1,4-dioxane, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, ethyl acetate, methylene chloride, chloroform and the like as a reaction solvent. The compound represented by 4) can be reacted at 0 ° C to 100 ° C. In addition, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, acetonitrile, methylene chloride and the like are used as reaction solvents, and dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride. Salt (WSC), diphenylphosphoryl azide (DPPA), diethyl phosphate cyanide (DEPC) or 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride ( Using a condensing agent such as DMT-MM), 4-dimethylaminopyridine (DMAP) is optionally added, and the reaction can be carried out at 0 ° C. to room temperature. Furthermore, p-toluenesulfonyl chloride (TsCl) and N-methylimidazole are added, and 1,4-dioxane, DMSO, DMF, THF, acetonitrile, methylene chloride, etc. can be used as a reaction solvent at 0 ° C. to room temperature. .

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

[Wherein R ¹ , X, Y, and T are as described above]
The compound represented by General formula (2) can be manufactured by carrying out Curtius rearrangement (process A-2).

  In the reaction, DPPA was stirred in a benzene or toluene solvent in the presence of a base such as triethylamine, and then heated and stirred with acetic acid and water, or t-butanol was added and heated and stirred. The reaction can be carried out by adding trifluoroacetic acid at room temperature.

  The compound represented by the general formula (1c) in the synthesis route A includes the compound represented by the general formula (3) and the general formula (5).

[Wherein R ² and R ³ are as described above]
It can manufacture by condensing with the compound represented by (process A-3).
The reaction can be carried out in the same manner as in Step A-1.

In addition, R ² carboxylic acid or phosphonic acid of the compound represented by general formula (4) and general formula (5) in synthesis route A is protected with a corresponding alkyl group having 1 to 6 carbon atoms or benzyl group. Using an ester or phosphonic acid ester and a compound in which the carboxyl group or phosphoric acid group of R ³ is an ester protected with an alkyl group having 1 to 6 carbon atoms or a benzyl group, It can also be produced by deprotecting various ester groups.

  When the protecting group is a benzyl group, palladium carbon can be used as a catalyst, ethanol, methanol, and ethyl acetate can be used as a solvent, and the reaction can be performed at room temperature to 100 ° C. under hydrogen. In the case of a carboxylic acid ester protected with an alkyl group having 1 to 6 carbon atoms, an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution is added, and ethanol, methanol, 1,4-dioxane, DMSO, THF Etc. can be used as a solvent at 0 ° C. to 100 ° C. In the case of a phosphonic acid ester protected with an alkyl group having 1 to 6 carbon atoms, trimethylsilyl bromide or trimethylsilyl iodide is added in acetonitrile and the reaction can be carried out at 0 ° C. to room temperature.

(Example)
Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.
As the intermediate represented by the general formula (2), compounds in WO03029184, WO03029205, WO04026817, WO04074297, WO050444780, and WO06041019 pamphlets can be used. The newly synthesized intermediates are described below as reference examples.

<Reference Example 1>
Diethyl 5-amino-2-hydroxyphenylphosphonate

Diethyl 2-hydroxy-5-nitrophenylphosphonate (138 mg) was dissolved in ethyl acetate (2.5 mL), 10% Pd / C (27.5 mg) was added, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The catalyst was removed by filtration, and the solvent was concentrated under reduced pressure to obtain the desired product (129 mg) as a pale brown oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.33 (6H, t, J = 7.0
Hz), 3.44 (2H, br), 3.99-4.20 (4H, m), 6.67 (1H, dd, J = 15.3, 3.1 Hz),
6.79-6.87 (2H, m), 9.64 (1H, s).
EIMS (+): 245 [M]
⁺ .

<Reference Example 2>
Difluoro (3-nitrophenyl) methylphosphonate dimethyl

A 1 mol / L THF solution (2.93 mL) of hexamethyldisilazane sodium was added to THF (7.5 mL), and a THF solution (20 mL) of dimethyl 3-nitrobenzylphosphonate (328 mg) at −78 ° C. in an argon atmosphere at −78 ° C. ) Was added dropwise over 5 minutes and stirred at -78 ° C for 1 hour. A THF solution (6 mL) of N-fluorobenzenesulfonimide (1.05 g) was added to the reaction solution, and the mixture was stirred at -78 ° C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (127 mg) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 3.90 (6H, d, J = 10.4
Hz), 7.69 (1H, t, J = 7.9 Hz), 7.98 (1H, d, J = 7.9 Hz), 8.35-8.40 (1H, m),
8.47 (1H, s).
FABMS (+): 282 [M + H] ⁺ .

<Reference Example 3>
Dimethyl (3-aminophenyl) difluoromethylphosphonate

The target product was obtained as a colorless oil by reacting the compound of Reference Example 2 in the same manner as in Reference Example 1.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 3.84 (6H, d, J = 10.4
Hz), 6.79 (1H, d, J = 7.9 Hz), 6.94 (1H, s), 7.00 (1H, d, J = 7.9 Hz), 7.24 (1H,
t, J = 7.9 Hz).
FABMS (+): 252 [M + H] ⁺ .

<Reference Example 4>
(3-Aminophenyl) hydroxymethylphosphonate diethyl

Diethyl (3-nitrophenyl) hydroxymethylphosphonate was reacted in the same manner as in Reference Example 1 to obtain the desired product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.23 (3H, t, J = 7.3
Hz), 1.29 (3H, t, J = 7.3 Hz), 3.20 (1H, br s), 3.72 (2H, br s), 3.90-4.15 (4H,
m), 4.92 (1H, d, J = 11.0 Hz), 6.64 (1H, d, J = 7.9 Hz), 6.82-6.86 (2H, m),
7.14 (1H, t, J = 7.9 Hz).
FABMS (+): 260 [M + H] ⁺ .

<Reference Example 5>
Diethyl fluoro (3-nitrophenyl) methylphosphonate

Methylene chloride solution (5 mL) of diethyl (3-nitrophenyl) hydroxymethylphosphonate (600 mg) was added to diethylaminosulfatrifluoride (678 uL) in methylene chloride solution (2.5 mL) at -78 ° C under argon atmosphere. The solution was slowly added dropwise and stirred at −78 ° C. for 30 minutes and at room temperature for 6 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain the desired product (410 mg) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.29 (3H, t, J = 7.0
Hz), 1.34 (3H, t, J = 7.0 Hz), 4.08-4.24 (4H, m), 5.80 (1H, dd, J = 44.9, 11.0
Hz), 7.61 (1H, t, J = 7.9 Hz), 7.83 (1H, d, J = 7.9 Hz), 8.25 (1H, d, J = 7.9
Hz), 8.34 (1H, d, J = 1.8 Hz).
CIMS (+): 292 [M + H] ⁺ .

<Reference Example 6>
(3-Aminophenyl) fluoromethylphosphonic acid diethyl ester

The target product was obtained as a colorless oil by reacting in the same manner as in Reference Example 1 using the compound of Reference Example 5.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.28 (3H, t, J = 7.3
Hz), 1.29 (3H, t, J = 7.3 Hz), 3.99-4.16 (4H, m), 5.60 (1H, dd, J = 44.9,
7.9 Hz), 6.68 (1H, d, J = 7.9 Hz), 6.81-6.86 (2H, m), 7.17 (1H, t, J = 7.9 Hz).
FABMS (+): 262 [M + H] ⁺ .

<Reference Example 7>
(3-Nitrophenoxy) diethyl malonate

To a DMF solution (3.4 mL) of potassium fluoride (725 mg) was added diethyl bromomalonate (1.02 mL) at room temperature under an argon atmosphere, and the mixture was stirred at room temperature for 15 minutes. 3-Nitrophenol (696 mg) was added to the reaction solution and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (399 mg) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.33 (6H, t, J = 7.3
Hz), 4.35 (4H, q, J = 7.3 Hz), 5.27 (1H, s), 7.34 (1H, dd, J = 7.9, 1.8 Hz),
7.49 (1H, t, J = 7.9 Hz), 7.79 (1H, t, J = 1.8 Hz), 7.93 (1H, dd, J = 7.9, 1.8
Hz).
FABMS (+): 298 [M + H] ⁺ .

<Reference Example 8>
(3-Aminophenoxy) diethyl malonate

The target product was obtained as a colorless oil by reacting in the same manner as in Reference Example 1 using the compound of Reference Example 7.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.30 (6H, t, J = 7.3
Hz), 3.69 (2H, br s), 4.31 (4H, q, J = 7.3 Hz), 5.16 (1H, s), 6.29-6.38 (3H,
m), 7.05 (1H, t, J = 7.9 Hz).
FABMS (+): 267 [M] ⁺ .

<Reference Example 9>
2- (3-Aminophenyl) -3,3,3-trifluoro-2-hydroxypropionic acid methyl ester

Methyl trifluoropyruvate (200
1 mg / L THF solution (1.4 mL) of 3-bis (trimethylsilyl) aminophenyl magnesium chloride was added to a THF solution (13 mL) of mg) at −78 ° C. in an argon atmosphere, and then at 0 ° C. for 2 hours. Stir. Water was added to the reaction solution and stirred at room temperature for 30 minutes, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (200 mg) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 3.96 (3H, s), 6.71 (1H,
dt, J = 7.9, 1.8 Hz), 7.08 (1H, s), 7.11 (1H, d, J = 7.9 Hz), 7.18 (1H, t, J =
(7.9 Hz).
EI (+): 249 [M] ⁺ .

<Reference Example 10>
3- [4- (3-Benzyloxyphenylthio) -2-chlorophenyl] propionic acid

The compound of WO03029205 Pamphlet Reference Example 30 was subjected to alkaline hydrolysis to obtain the desired product as a colorless powder.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.67 (2H, t, J = 7.3
Hz), 3.02 (2H, t, J = 7.3 Hz), 5.01 (2H, s), 6.89 (1H, dd, J = 7.9, 1.8 Hz),
6.91-6.95 (2H, m), 7.10-7.18 (2H, m), 7.22 (1H, t, J = 7.9 Hz), 7.28-7.43 (6H,
m).
EIMS (+): 398 [M] ⁺ .

<Reference Example 11>
4- [4- (3-Benzyloxyphenylthio) -2-chlorophenyl] butyric acid

The compound of WO03029205 Pamphlet Reference Example 58-2 was subjected to alkaline hydrolysis to obtain the target product as a colorless powder.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.91-2.01 (2H, m), 2.41
(2H, t, J = 7.3 Hz), 2.77 (2H, t, J = 7.3 Hz), 5.02 (2H, s), 6.88 (1H, dd, J =
7.9, 1.8 Hz), 6.92-6.95 (2H, m), 7.14 (2H, s), 7.23 (1H, t, J = 7.9 Hz),
7.28-7.42 (6H, m).
EIMS (+): 412 [M] ⁺ .

<Reference Example 12>
3- [4- (3-Benzyloxyphenylthio) -2-chlorophenyl] acrylic acid

The compound of WO06041019 Pamphlet Example 1 was subjected to alkaline hydrolysis to obtain the desired product as a colorless powder.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 5.06 (2H, s), 6.40 (1H,
d, J = 15.9 Hz), 7.00 (1H, dd, J = 7.9, 1.8 Hz), 7.05-7.10 (3H, m), 7.23 (1H,
t, J = 7.9 Hz), 7.29-7.43 (6H, m), 7.51 (1H, d, J = 7.9 Hz), 8.13 (1H, d, J =
15.9 Hz).
EIMS (+): 396 [M] ⁺ .

<Reference Example 13>
3- [4- (3-Cyclohexylmethyloxyphenoxy) phenyl] methyl propionate

A phenol compound (3.00 g) obtained by reacting the compound of Reference Example 55 of WO03029184 Pamphlet in the same manner as in Reference Pamphlet 81 is dissolved in DMF (80 mL), cyclohexylmethyl bromide (1.84 mL), potassium carbonate (1.82 g) was added, and the mixture was stirred at 80 ° C. for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to obtain the desired product (3.38 g) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz,): δ 0.96-1.09 (2H, m),
1.12-1.35 (3H, m), 1.64-1.89 (6H, m), 2.63 (2H, t, J = 7.9 Hz), 2.93 (2H, t, J
= 7.9 Hz), 3.68 (3H, s), 3.71 (2H, d, J = 6.7 Hz), 6.51-6.64 (3H, m), 6.91-6.97
(2H, m), 7.13-7.22 (3H, m).

<Reference Example 14>
3- [4- (3-Cyclohexylmethyloxyphenoxy) phenyl] propionic acid

The compound of Reference Example 13 was alkali-hydrolyzed to obtain the target product as a colorless powder.
¹ H-NMR
(CDCl ₃ , 400 MHz,): δ 0.98-1.08 (2H, m),
1.13-1.34 (3H, m), 1.64-1.87 (6H, m), 2.68 (2H, t, J = 7.9 Hz), 2.95 (2H, t, J
= 7.9 Hz), 3.71 (2H, d, J = 6.7 Hz), 6.53-6.64 (3H, m), 6.93-6.97 (2H, m),
7.16-7.21 (3H, m).
EIMS (+): 354 [M] ⁺ .

<Reference Example 15>
Methyl 3- [2-chloro-4- (3-cyclohexylmethyloxyphenoxy) phenyl] propionate

The target product was obtained as a pale yellow oil by reacting in the same manner as in Reference Example 13 using the compound of Reference Example 39 of WO03029184.
¹ H-NMR
(CDCl ₃ , 400 MHz,): δ 0.96-1.10 (2H, m),
1.15-1.35 (3H, m), 1.65-1.90 (6H, m), 2.64 (2H, t, J = 7.9 Hz), 3.03 (2H, t, J
= 7.9 Hz), 3.69 (3H, s), 3.72 (2H, d, J = 6.1 Hz), 6.52-6.69 (3H, m), 6.85 (1H,
dd, J = 8.6, 2.4 Hz), 7.01 (1H, d, J = 2.4 Hz), 7.19 (1H, d, J = 8.6 Hz), 7.22
(1H, t, J = 8.6 Hz).

<Reference Example 16>
3- [2-Chloro-4- (3-cyclohexylmethyloxyphenoxy) phenyl] propionic acid

The compound of Reference Example 15 was alkali-hydrolyzed to obtain the target product as a colorless powder.
¹ H-NMR
(CDCl ₃ , 400 MHz,): δ 0.98-1.08 (2H, m),
1.13-1.34 (3H, m), 1.64-1.87 (6H, m), 2.70 (2H, t, J = 7.9 Hz), 3.04 (2H, t, J
= 7.9 Hz), 3.71 (2H, d, J = 6.7 Hz), 6.54-6.69 (3H, m), 6.85 (1H, dd, J = 8.6,
2.4 Hz), 7.02 (1H, d, J = 3.1 Hz), 7.19-7.24 (2H, m).
EIMS (+): 388 [M] ⁺ .

<Reference Example 17>
3- [2-Chloro-4- (3-trifluoromethylphenoxy) phenyl] propionic acid

The compound of WO03029184 Pamphlet Reference Example 87 was subjected to alkaline hydrolysis to obtain the desired product as a colorless powder.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.72 (2H, t, J = 7.3
Hz), 3.07 (2H, t, J = 7.3 Hz), 6.87 (1H, dd, J = 7.9, 1.8 Hz), 7.05 (1H, d, J =
1.8 Hz), 7.16 (1H, dd, J = 7.9, 1.8 Hz), 7.23-7.28 (2H, m), 7.38 (1H, d, J = 7.9
Hz), 7.46 (1H, t, J = 7.9 Hz).
EIMS (+): 344 [M] ⁺ .

<Reference Example 18>
2- [4- (3-Benzyloxyphenylthio) -2-chlorophenyl] ethylamine

The CN compound obtained by reacting the compound of WO03029205 Pamphlet Reference Example 59 in the same manner as in Reference Pamphlet 57-1 described in the pamphlet was reduced to obtain the desired product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz,): δ 1.85 (2H, br), 2.87
(2H, t, J = 7.9 Hz), 2.98 (2H, t, J = 7.9 Hz), 5.02 (2H, s), 6.87-6.97 (3H, m),
7.15-7.41 (9H, m).
EIMS (+): 369 [M] ⁺ .

<Example 1>
4- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] dimethyl phthalate

At room temperature, a solution of the compound of Reference Example 10 (450 mg), dimethyl 4-aminophthalate (314 mg), WSC (400 mg), triethylamine (0.5 mL), DMAP (50 mg) in methylene chloride (20 mL) for 8 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the desired product (600 mg) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.69 (2H, t, J = 7.3 Hz),
3.13 (2H, t, J = 7.3 Hz), 3.88 (3H, s), 3.90 (3H, s), 5.02 (2H, s), 6.88-7.00
(3H, m), 7.11-7.14 (1H, m), 7.18-7.39 (8H, m), 7.69-7.78 (3H, m).
FABMS (+): 590 [M + H] ⁺ .

Thereafter, the compound of Reference Example 10, 11 or 12 was reacted with various amines in the same manner as in Example 1 to synthesize the compounds of Examples 2 to 7.

<Example 2>
4- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) acrylamide] dimethyl phthalate

Pale yellow oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 3.88 (3H, s), 3.92 (3H,
s), 5.06 (2H, s), 6.50 (1H, d, J = 15.9 Hz), 6.98-7.11 (4H, m), 7.24-7.43 (8H,
m), 7.48 (1H, d, J = 8.5 Hz), 7.65 (1H, s), 7.80-7.90 (3H, m), 8.08 (1H, d, J =
15.9 Hz).
HREIMS (+): Calculated as 587.1163 (C ₃₂ H ₂₆ ClNO ₆ S) 587.1169.

<Example 3>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] ethyl benzoate

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.39 (3H, t, J = 7.3
Hz), 2.68 (2H, t, J = 7.3 Hz), 3.15 (2H, t, J = 7.3 Hz), 4.37 (2H, q, J = 7.3
Hz), 5.02 (2H, s), 6.87-6.96 (3H, m), 7.12-7.25 (4H, m), 7.32-7.41 (7H, m),
7.78 (1H, d, J = 7.8 Hz), 7.87 (1H, d, J = 7.8 Hz), 7.95 (1H, s).
HREIMS (+): Calculated as 545.1417 (C ₃₁ H ₂₈ ClNO ₄ S) 545.1428.

<Example 4>
4- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] ethyl benzoate

Colorless powder
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.38 (3H, t, J = 7.3
Hz), 2.69 (2H, t, J = 7.3 Hz), 3.14 (2H, t, J = 7.3 Hz), 4.35 (2H, q, J = 7.3
Hz), 5.02 (2H, s), 6.88-6.96 (3H, m), 7.11-7.25 (4H, m), 7.31-7.40 (6H, m), 7.54
(2H, d, J = 8.5 Hz), 7.98-8.00 (2H, m).
HRFABMS (+): Calculated as 546.1476 (C ₃₁ H ₂₉ ClNO ₄ S) 546.1506.

<Example 5>
Methyl 5- [3- (4- (3-benzyloxyphenylthio) -2-chlorophenyl) propanamide] -2-nitrobenzoate

Pale yellow oil
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.72 (2H, t, J = 7.3 Hz), 3.13 (2H, t, J =
7.3 Hz), 3.92 (3H, s), 5.02 (2H, s), 6.88-6.96 (3H, m), 7.11-7.24 (3H, m),
7.31-7.42 (7H, m), 7.75-7.78 (2H, m), 7.97-7.99 (1H, m).
HREIMS (+): Calculated as 576.1146 (C ₃₀ H ₂₅ ClN ₂ O ₆ S) 576.1122.

<Example 6>
4- [4- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) butanamide] dimethyl phthalate

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.05 (2H, quint, J = 7.3
Hz), 2.41 (2H, t, J = 7.3 Hz), 2.81 (2H, t, J = 7.3 Hz), 3.88 (3H, s), 3.90
(3H, s), 5.02 (2H, s), 6.88-6.96 (3H, m), 7.15-7.16 (2H, m), 7.22-7.25 (1H, m),
7.32-7.41 (7H, m), 7.72-7.79 (3H, m).
HRFABMS (+): Calculated as 604.1528 (C ₃₃ H ₃₁ ClN ₂ O ₆ S) 604.1561.

<Example 7>
4- [3- (2-Chloro-4- (3-trifluoromethylphenoxy) phenyl) propanamide] dimethyl phthalate

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.72 (2H, t, J = 7.3
Hz), 3.16 (2H, t, J = 7.3 Hz), 3.88 (3H, s), 3.90 (3H, s), 6.86 (1H, dd, J =
7.8, 2.5 Hz), 7.05 (1H, d, J = 2.5 Hz), 7.14-7.16 (1H, m), 7.24-7.30 (3H, m),
7.38 (1H, d, J = 7.8 Hz), 7.46 (1H, t, J = 7.8 Hz), 7.72-7.79 (3H, m).
HRFABMS (+): Calculated as 536.1063 (C ₂₆ H ₂₂ ClF ₃ NO ₆ ) 604.1561.

<Example 8>
Methyl 5- [3- (4- (3-benzyloxyphenylthio) -2-chlorophenyl) propanamide] -2-chlorobenzoate

To a solution of the compound of Reference Example 10 (120 mg) in acetonitrile (7 mL), paratoluenesulfonyl chloride (68.6 mg) and N-methylimidazole (71 μL) were added with ice cooling and stirred for 30 minutes. At the same temperature, a solution of methyl 2-chloro-5-aminobenzoate (45 mg) in acetonitrile (1 mL) was added and stirred for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (105 mg) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ2.66 (2H, t, J = 7.3 Hz),
3.13 (2H, t, J = 7.3 Hz), 3.91 (3H, s), 5.02 (2H, s), 6.88-6.96 (3H, m),
7.11-7.25 (4H, m), 7.31-7.40 (7H, m), 7.64 (1H, dd, J = 8.5, 2.4 Hz), 7.89 (1H,
d, J = 3.1 Hz).
HRFABMS (+): Calculated as 566.0957 (C ₃₀ H ₂₆ Cl ₂ NO ₄ S) 566.0960.

  Thereafter, in the same manner as in Example 8, the compounds of Reference Examples 10, 14 and 16 were reacted with Reference Examples 3, 6, 9 or various amines to synthesize Examples 9 to 23.

<Example 9>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenylacetic acid methyl ester

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.65 (2H, t, J = 7.3
Hz), 3.13 (2H, t, J = 7.3 Hz), 3.60 (2H, s), 3.68 (3H, s), 5.02 (2H, s),
6.87-6.96 (3H, m), 7.00-7.41 (14H, m).

<Example 10>
Methyl 5- [3- (4- (3-benzyloxyphenylthio) -2-chlorophenyl) propanamide] -2-fluorobenzoate

Colorless powder
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.67 (2H, t, J = 7.3
Hz), 3.14 (2H, t, J = 7.3 Hz), 3.92 (3H, s), 5.02 (2H, s), 6.89-6.96 (3H, m),
7.07-7.14 (3H, m), 7.20-7.25 (2H, m), 7.31-7.38 (6H, m), 7.78-7.86 (2H, m).
HRFABMS (+): Calculated as 550.1273 (C ₃₀ H ₂₆ ClFNO ₄ S) 550.1255.

<Example 11>
5- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] Dimethyl isophthalate

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.70 (2H, t, J = 7.3
Hz), 3.15 (2H, t, J = 7.3 Hz), 3.93 (6H, s), 5.02 (2H, s), 6.87-6.97 (3H, m),
7.12 (1H, dd, J = 8.0, 1.8 Hz), 7.21-7.25 (2H, m), 7.31-7.40 (7H, m), 8.34
(2H, s), 8.42 (1H, t, J = 1.8 Hz).
HRFABMS (+): Calculated as 590.1432 (C ₃₂ H ₂₉ ClNO ₆ S) 590.1404.

<Example 12>
2- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] methyl benzoate

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.76 (2H, t, J = 7.3
Hz), 3.16 (2H, t, J = 7.3 Hz), 3.91 (3H, s), 5.02 (2H, s), 6.87-6.96 (3H, m),
7.05-7.10 (1H, m), 7.13 (1H, dd, J = 8.0, 1.8 Hz), 7.22 (2H, t J = 8.0 Hz),
7.32-7.39 (6H, m), 7.52-7.56 (1H, m), 8.01 (1H, dd, J = 8.0, 1.2 Hz), 8.70
(1H, dd, J = 8.0, 1.2 Hz), 11.09 (1H, s).
Calculated as HREIMS (+): 531.1267 (C ₃₀ H ₂₆ ClNO ₄ S) 531.1271.

<Example 13>
4- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenylphosphonic acid diethyl ester

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.30 (6H, t, J = 7.3
Hz), 2.70 (2H, t, J = 7.3 Hz), 3.14 (2H, t, J = 7.3 Hz), 4.10-4.15 (4H, m),
5.02 (2H, s), 6.87-6.96 (3H, m), 7.12 (1H, dd, J = 8.0, 1.8 Hz), 7.20-7.25 (2H,
m), 7.32-7.38 (6H, m), 7.51 (1H, s), 7.58-7.61 (2H, m), 7.71-7.74 (2H, m).
HRFABMS (+): Calculated as 610.1584 (C ₃₂ H ₃₄ ClNO ₅ PS) 610.1584.

<Example 14>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenylphosphonic acid diethyl ester

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.26 (6H, t, J = 7.3
Hz), 2.72 (2H, t, J = 7.3 Hz), 3.15 (2H, t, J = 7.3 Hz), 3.97-4.08 (4H, m),
5.02 (2H, s), 6.87-6.96 (3H, m), 7.13 (1H, dd, J = 8.0, 1.8 Hz), 7.23 (2H, t, J
= 8.0 Hz), 7.32- 7.44 (8H, m), 7.77 (1H, d, J = 14.7 Hz), 8.19-8.21 (1H, m),
8.54 (1H, s).
Calculated as HRFABMS (+): 610.1626 (C ₃₂ H ₃₄ ClNO ₅ PS) 610.1584.

<Example 15>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] Dimethyl phthalate

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.71 (2H, t, J = 7.3
Hz), 3.13 (2H, t, J = 7.3 Hz), 3.86 (3H, s), 3.88 (3H, s), 5.02 (2H, s),
6.87-6.96 (3H, m), 7.12 (1H, dd, J = 8.0, 1.8 Hz), 7.20-7.25 (2H, m), 7.32-
7.43 (7H, m), 7.51 (1H, d, J = 8.0 Hz), 8.55 (1H, d, J = 8.7 Hz), 9.37 (1H, s).
HRFABMS (+): Calculated as 589.1365 (C ₃₂ H ₂₈ ClNO ₆ S) 589.1326.

<Example 16>
2- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenyl-3,3,3-trifluoro-2-hydroxypropionic acid methyl ester

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.67 (2H, t, J = 7.3
Hz), 3.14 (2H, t, J = 7.3 Hz), 3.97 (3H, s), 4.30 (1H, s), 5.02 (2H, s),
6.87-6.96 (3H, m), 7.13 (2H, dd, J = 8.0, 1.8 Hz), 7.20-7.25 (2H, m), 7.33-
7.39 (7H, m), 7.51 (1H, d, J = 7.3 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.74 (1H, s).
Calculated as HRFABMS (+): 630.1355 (C ₃₂ H ₂₈ ClF ₃ NO ₅ S) 630.1329.

<Example 17>
4- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] -3-methoxycarbonylphenylphosphonic acid diethyl ester

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.32 (6H, t, J = 7.3
Hz), 2.70 (2H, t, J = 7.3 Hz), 3.13 (2H, t, J = 7.3 Hz), 3.90 (3H, s),
4.08-4.17 (4H, m), 5.02 (2H, s), 6.89-6.97 (3H, m), 7.12 (1H, dd, J = 8.0, 1.8
Hz), 7.19-7.25 (2H, m), 7.31- 7.39 (6H, m), 7.55 (1H, s), 7.76-7.81 (2H, m),
7.89 (1H, dd, J = 13.5, 8.6 Hz).
FABMS (+): 668 [M + H] ⁺ .

<Example 18>
4- [3- (4- (3-Cyclohexylmethyloxyphenoxy) phenyl) propanamide] Dimethyl phthalate

Colorless powder
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 0.97- 1.07 (2H, m),
1.14-1.34 (3H, m), 1.67-1.85 (6H, m), 2.68 (2H, t, J = 7.3 Hz), 3.03 (2H, t, J
= 7.3 Hz), 3.71 (2H, d, J = 6.7 Hz), 3.70 (3H, s), 3.90 (3H, s), 6.51-6.64 (3H,
m), 6.93-6.97 (2H, m), 7.17-7.7.21 (3H, m), 7.29 (1H, s), 7.68-7.71 (2H, m),
7.77 (1H, d, J = 8.6 Hz).
EIMS (+): 545 [M] ⁺ .

<Example 19>
4- [3- (2-Chloro-4- (3-cyclohexylmethyloxyphenoxy) phenyl) propanamide] Dimethyl phthalate

Colorless powder
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 0.98- 1.08 (2H, m),
1.14-1.33 (3H, m), 1.67-1.86 (6H, m), 2.70 (2H, t, J = 7.3 Hz), 3.13 (2H, t, J
= 7.3 Hz), 3.72 (2H, d, J = 6.7 Hz), 3.88 (3H, s), 3.91 (3H, s), 6.53-6.55 (2H,
m), 6.66-6.69 (1H, m), 6.85 (1H, dd, J = 8.0, 2.5 Hz), 7.02 (1H, d, J = 2.5
Hz), 7.19-7.7.24 (2H, m), 7.27 (1H, s), 7.71-7.73 (2H, m), 7.77-7.79 (1H, m).
EIMS (+): 579 [M] ⁺ .

<Example 20>
5- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] -2-chlorophenylphosphonic acid diethyl ester

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.26 (6H, t, J = 7.3
Hz), 2.72 (2H, t, J = 7.3 Hz), 3.14 (2H, t, J = 7.3 Hz), 3.99-4.17 (4H, m),
5.02 (2H, s), 6.87-6.97 (3H, m), 7.13 (1H, dd, J = 8.0, 1.8 Hz), 7.21-7.25 (2H,
m), 7.31- 7.42 (7H, m), 7.89 (1H, dd, J = 15.3, 2.4 Hz), 8.32 (1H, dd, J = 8.6,
2.4 Hz), 8.95 (1H, s).
FABMS (+): 644 [M + H] ⁺ .

<Example 21>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenylmethylphosphonic acid dimethyl ester

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.66 (2H, t, J = 7.3
Hz), 3.10-3.17 (4H, m), 3.68 (6H, d, J = 10.4 Hz), 5.02 (2H, s), 6.84-6.97 (3H,
m), 7.03 (1H, d, J = 7.9 Hz), 7.10 (1H, s), 7.13 (1H, dd, J = 7.9, 1.8 Hz),
7.20-7.46 (11H, m).
FABMS (+): 596 [M + H] ⁺ .

<Example 22>
Dimethyl 3- [3- (4- (3-benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenyldifluoromethylphosphonate

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 2.67 (2H, t, J = 7.3
Hz), 3.14 (2H, t, J = 7.3 Hz), 3.83 (6H, d, J = 10.4 Hz), 5.02 (2H, s),
6.84-6.97 (3H, m), 7.13 (1H, dd, J = 7.9, 1.8 Hz), 7.21-7.42 (10H, m), 7.60
(1H, s), 8.32 (1H, dd, J = 8.6, 2.4 Hz), 7.80 (1H, d, J = 7.9 Hz).
FABMS (+): 632 [M + H] ⁺ .

<Example 23>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenyl fluoromethylphosphonic acid diethyl ester

Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.27 (6H, t, J = 7.3
Hz), 2.65 (2H, t, J = 7.3 Hz), 3.13 (2H, t, J = 7.3 Hz), 3.97-4.20 (4H, m),
5.02 (2H, s), 5.65 (1H, dd, J = 44.6, 7.9 Hz), 6.85-6.97 (3H, m), 7.18-7.42
(11H, m), 7.50 (1H, s), 7.66 (1H, d, J = 7.9 Hz).
FABMS (+): 642 [M + H] ⁺ .

<Example 24>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenyl malonate diethyl

To a methanol solution (10 mL) of diethyl (3-aminophenyl) malonate (327 mg) was added the compound of Reference Example 10 (471
mg) and 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM) (346 mg) were added and stirred at room temperature for 2 hours. And left overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (684 mg) as a colorless oil.
Colorless oil
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.26 (6H, t, J = 7.3
Hz), 2.65 (2H, t, J = 7.3 Hz), 3.13 (2H, t, J = 7.3 Hz), 4.15-4.25 (4H, m),
4.58 (1H, s), 5.02 (2H, s), 6.84-6.97 (3H, m), 7.14 (3H, dd, J = 7.9, 1.8 Hz),
7.22 (2H, d, J = 7.9 Hz), 7.26-7.42 (7H, m), 7.47 (1H, s), 7.57 (1H, d, J = 7.9
Hz).
FABMS (+): 632 [M + H] ⁺ .

<Example 25>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenoxymalonate diethyl

In the same manner as in Example 24, the compound of Reference Example 10 and the compound of Reference Example 8 were reacted to obtain the target product as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.30 (6H, t, J = 7.3
Hz), 2.65 (2H, t, J = 7.3 Hz), 3.13 (2H, t, J = 7.3 Hz), 4.31 (4H, q, J = 7.3
Hz), 5.02 (2H, s), 5.21 (1H, s), 6.70 (1H, dd, J = 7.9, 1.8 Hz), 6.87-6.97 (3H,
m), 7.03-7.09 (2H, m), 7.13 (1H, dd, J = 7.9, 1.8 Hz), 7.18-7.41 (10H, m).
FABMS (+): 648 [M + H] ⁺ .

<Example 26>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenyl-hydroxymethylphosphonic acid diethyl ester

In the same manner as in Example 24, the compound of Reference Example 10 and the compound of Reference Example 4 were reacted to obtain the target product as a colorless amorphous.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.21 (3H, t, J = 7.3
Hz), 1.28 (3H, t, J = 7.3 Hz), 2.65 (2H, t, J = 7.3 Hz), 3.00-3.09 (1H, m),
3.13 (2H, t, J = 7.3 Hz), 4.00-4.10 (4H, m), 4.98 (1H, dd, J = 11.0, 3.7 Hz),
5.02 (2H, s), 6.86-6.97 (3H, m), 7.12 (1H, dd, J = 7.9, 1.8 Hz), 7.18-7.41
(11H, m), 7.51 (1H, s), 7.62 (1H, d, J = 7.9 Hz),.
FABMS (+): 640 [M + H] ⁺ .

<Example 27>
2- [3- (3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamido) phenoxy] -2-methylmalonate diethyl

The compound of Example 25 (250 mg) was dissolved in DMF, potassium carbonate (108 mg) and methyl iodide (48 uL) 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 with water and then saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (250 mg) as a colorless oil.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.26 (6H, t, J = 7.3
Hz), 1.75 (3H, s), 2.63 (2H, t, J = 7.3 Hz), 3.13 (2H, t, J = 7.3 Hz), 4.28
(4H, q, J = 7.3 Hz), 5.02 (2H, s), 6.71 (1H, d, J = 7.9 Hz), 6.87-6.97 (3H, m),
7.03 (1H, s), 7.11-7.24 (6H, m), 7.31-7.40 (6H, m).
FABMS (+): 662 [M + H] ⁺ .

<Example 28>
2- [3- (3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamido) phenyl] -2-hydroxymalonate diethyl

The target product was obtained as a colorless oil by reacting in the same manner as in Example 27 using the compound of Example 24.
¹ H-NMR
(CDCl ₃ , 400 MHz): δ 1.30 (6H, t, J = 7.3
Hz), 2.65 (2H, t, J = 7.3 Hz), 3.14 (2H, t, J = 7.3 Hz), 4.23-4.35 (4H, m),
5.02 (2H, s), 6.86-6.97 (3H, m), 7.06 (1H, s), 7.13 (1H, dd, J = 7.9, 1.8 Hz),
7.22 (2H, d, J = 7.9 Hz), 7.29-7.42 (8H, m), 7.61 (1H, s), 7.67 (1H, d, J = 7.9
Hz).
FABMS (+): 648 [M + H] ⁺ .

<Example 29>
4- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phthalic acid

The compound of Example 1 (600 mg) was dissolved in ethanol (30 mL), 1 mol / L aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution to adjust the pH to 1 with dilute hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water and dried to obtain the desired product (550 mg) as a colorless powder.
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.68 (2H, t, J = 7.3
Hz), 3.00 (2H, t, J = 7.3 Hz), 5.08 (2H, s), 6.88-6.99 (3H, m), 7.20 (1H, dd, J
= 7.8, 1.8 Hz), 7.28-7.40 (8H, m), 7.67-7.72 (2H, m), 7.83 (1H, d, J = 1.8 Hz),
10.31 (1H, s), 12.98 (2H, br).
FABMS (+): 562 [M + H] ⁺ .

  Hereinafter, the compounds of Examples 30 to 47 were synthesized by reacting the compounds of Examples 2 to 4, 6 to 12, 15, 16, 18, 19, 24, 25, 27 and 28 in the same manner as the compound of Example 1. did.

<Example 30>
4- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) acrylamide] phthalic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 5.13 (2H, s), 6.84 (1H,
d, J = 15.9 Hz), 7.06-7.13 (3H, m), 7.22 (1H, dd, J = 8.6, 1.8 Hz), 7.30-7.43
(7H, m), 7.70-7.75 (2H, m), 7.82-7.86 (2H, m), 7.98 (1H, d, J = 2.1 Hz), 10.67
(1H, s), 13.08 (2H, br).
HRFABMS (+): Calculated as 560.0927 (C ₃₀ H ₂₃ ClNO ₆ S) 560.0935.

<Example 31>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] benzoic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ2.65 (2H, t, J = 7.6 Hz),
3.00 (2H, t, J = 7.6 Hz), 5.08 (2H, s), 6.88-6.99 (3H, m), 7.21 (1H, dd, J =
7.9, 1.8 Hz), 7.28-7.41 (9H, m), 7.58-7.61 (1H, m), 7.77-7.80 (1H, m), 8.20 (1H,
s), 10.12 (1H, s), 12.92 (1H, br).
HRFABMS (+): Calculated as 518.1210 (C ₂₉ H ₂₅ ClNO ₄ S) 518.1193.

<Example 32>
4- [4- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) butanamide] phthalic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 1.88 (2H, qui, J = 7.3
Hz), 2.38 (2H, t, J = 7.3 Hz), 2.73 (2H, t, J = 7.3 Hz), 5.09 (2H, s),
6.90-7.00 (3H, m), 7.21 (1H, dd, J = 7.8, 1.8 Hz), 7.29-7.41 (8H, m), 7.67-7.73
(2H, m), 7.85 (1H, d, J = 1.8 Hz), 10.25 (1H, s), 13.01 (2H, br).
HRFABMS (+): Calculated as 576.1213 (C ₃₁ H ₂₇ ClNO ₆ S) 576.1248.

<Example 33>
5- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] -2-chlorobenzoic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.64 (2H, t, J = 7.6 Hz),
2.99 (2H, t, J = 7.6 Hz), 5.08 (2H, s), 6.88-7.00 (3H, m), 7.20 (1H, dd, J = 7.9,
1.8 Hz), 7.28-7.45 (9H, m), 7.69 (1H, dd, J = 8.6, 2.4 Hz), 8.06 (1H, d, J = 2.4
Hz), 10.20 (1H, s), 13.38 (1H, br).
HRFABMS (+): Calculated as 552.0831 (C ₂₉ H ₂₄ Cl ₂ NO ₄ S) 552.0803.

<Example 34>
4- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] benzoic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.68
(2H, t, J = 7.6 Hz), 3.00 (2H, t, J = 7.6 Hz), 5.08 (2H, s), 6.88-7.00 (3H, m),
7.21 (1H, dd, J = 7.9, 1.8 Hz), 7.28-7.41 (8H, m), 7.67 (2H, d, J = 6.7 Hz),
7.86 (2H, d, J = 8.6 Hz), 10.24 (1H, s), 12.67 (1H, br).
HRFABMS (+): Calculated as 518.1154 (C ₂₉ H ₂₅ ClNO ₄ S) 518.1193.

<Example 35>
4- [3- (2-Chloro-4- (3-trifluoromethylphenoxy) phenyl) propanamide] phthalic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.68
(2H, t, J = 7.4 Hz), 3.01 (2H, t, J = 7.4 Hz), 7.01 (1H, dd, J = 8.6, 2.4 Hz),
7.21 (1H, d, J = 2.4 Hz), 7.29 (1H, dd, J = 8.6, 2.4 Hz), 7.35 (1H, brs), 7.41
(1H, d, J = 8.6 Hz), 7.51 (1H, d, J = 7.9 Hz), 7.62 (1H, t, J = 7.9 Hz),
7.66-7.72 (2H, m), 7.84 (1H, d, J = 1.2 Hz), 10.30 (1H, s), 13.00 (2H, br).
Calculated as HRFABMS (+): 508.0806 (C ₂₄ H ₁₈ ClF ₃ NO ₆ ) 508.0775.

<Example 36>
5- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] -2-fluorobenzoic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.63
(2H, t, J = 7.3 Hz), 2.99 (2H, t, J = 7.3 Hz), 5.08 (2H, s), 6.89 (1H, d, J =
8.6 Hz), 6.95-6.99 (2H, m), 7.18-7.38 (10H, m), 7.75-7.78 (1H, m), 8.10 (1H,
dd, J = 6.1, 2.4 Hz), 10.13 (1H, s), 13.23 (1H, br).
Calculated as HRFABMS (+): 536.1114 (C ₂₉ H ₂₄ ClFNO ₄ S) 536.1099.

<Example 37>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenylacetic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.62
(2H, t, J = 7.3 Hz), 2.98 (2H, t, J = 7.3 Hz), 3.50 (2H, s), 5.08 (2H, s),
6.88-6.99 (4H, m), 7.18-7.22 (2H, m), 7.28-7.41 (8H, m), 7.45-7.46 (2H, m),
9.92 (1H, s), 12.30 (1H, brs).
HRFABMS (+): Calculated as 532.1355 (C ₃₀ H ₂₇ ClNO ₄ S) 532.1349.

<Example 38>
5- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] isophthalic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.67
(2H, t, J = 7.4 Hz), 3.01 (2H, t, J = 7.4 Hz), 5.08 (2H, s), 6.88-6.99 (3H, m),
7.21 (1H, dd, J = 7.9, 1.8 Hz), 7.28-7.40 (8H, m), 8.13 (1H, t, J = 1.8 Hz),
8.40 (2H, d, J = 1.8 Hz), 10.30 (1H, s), 13.29 (2H, br).
HRFABMS (+): Calculated as 562.1063 (C ₃₀ H ₂₅ ClNO ₆ S) 562.1091.

<Example 39>
2- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] benzoic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.70
(2H, t, J = 7.3 Hz), 3.02 (2H, t, J = 7.3 Hz), 5.08 (2H, s), 6.87-6.99 (3H, m),
7.11-7.15 (1H, m), 7.19 (1H, dd, J = 7.9, 1.8 Hz), 7.27-7.40 (8H, m), 7.54-7.58
(1H, m), 7.95 (1H, dd, J = 7.9, 1.2 Hz), 8.43-8.45 (1H, m), 11.13 (1H, s),
13.58 (1H, br).
HRFABMS (+): Calculated as 518.1214 (C ₂₉ H ₂₅ ClNO ₄ S) 518.1193.

<Example 40>
2- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenyl-3,3,3-trifluoro-2-hydroxypropionic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.62
(2H, t, J = 7.3 Hz), 2.98 (2H, t, J = 7.3 Hz), 5.08 (2H, s), 6.89 (1H, dd, J =
6.7, 1.8 Hz), 6.96-6.99 (2H, m), 7.20-7.41 (11H, m), 7.72-7.74 (1H, m), 7.84 (1H,
brs), 10.03 (1H, s).
HRFABMS (+): Calculated as 616.1155 (C ₃₁ H ₂₆ ClF ₃ NO ₅ S) 616.1172.

<Example 41>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phthalic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.63
(2H, t, J = 7.3 Hz), 2.97 (2H, t, J = 7.3 Hz), 5.08 (2H, s), 6.89-7.00 (3H, m),
7.22 (1H, dd, J = 7.9, 1.8 Hz), 7.28-7.60 (10H, m), 7.74 (1H, d, J = 7.9 Hz),
9.69 (1H, brs), 13.22 (2H, br).
HRFABMS (+): Calculated as 560.0958 (C ₃₀ H ₂₃ ClNO ₆ S) 560.0935.

<Example 42>
4- [3- (4- (3-Cyclohexylmethyloxyphenoxy) phenyl) propanamide] phthalic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 0.94- 1.03 (2H, m),
1.12-1.27 (3H, m), 1.61-1.76 (6H, m), 2.66 (2H, t, J = 7.3 Hz), 2.90 (2H, t, J
= 7.3 Hz), 3.71 (2H, d, J = 6.7 Hz), 6.44-6.48 (2H, m), 6.65 (1H, dd, J = 8.6,
1.8 Hz), 6.93 (2H, d, J = 8.6 Hz), 7.21 (1H, t, J = 8.6 Hz), 7.25 (2H, d, J =
8.6 Hz), 7,67-7.72 (2H, m), 7.84 (1H, d, J = 1.2 Hz), 10.27 (1H, s), 13.00 (2H,
br).
Calculated as HRFABMS (+): 518.2197 (C ₃₀ H ₃₂ NO ₇ ) 518.2179.
Elemental analysis: Measured value C
Calculated as 69.41%, H 6.04%, N 2.70%, C ₃₀ H ₃₁ NO ₇ , C 69.62%, H 6.04%, N 2.71%.

<Example 43>
4- [3- (2-Chloro-4- (3-cyclohexylmethyloxyphenoxy) phenyl) propanamide] phthalic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 0.95- 1.05 (2H, m),
1.12-1.27 (3H, m), 1.61-1.77 (6H, m), 2.66 (2H, t, J = 7.3 Hz), 2.98 (2H, t, J
= 7.3 Hz), 3.74 (2H, d, J = 6.7 Hz), 6.53 (1H, dd, J = 8.0, 2.4 Hz), 6.57 (1H,
t, J = 2.4 Hz), 6.72 (1H, dd, J = 8.0, 2.4 Hz), 6.93 (1H, dd, J = 8.6, 2.4 Hz),
7.06 (1H, d, J = 2.4 Hz), 7.26 (1H, t, J = 8.0 Hz), 7.36 (1H, d, J = 8.6 Hz),
7.67-7.72 (2H, m), 7.84 (1H, d, J = 1.2 Hz), 10.30 (1H, s), 13.01 (2H, br).
HRFABMS (+): Calculated as 552.1818 (C ₃₀ H ₃₁ ClNO ₇ ) 552.1789.

<Example 44>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenylmalonic acid

Colorless amorphous
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.46
(2H, t, J = 7.4 Hz), 3.04 (2H, t, J = 7.4 Hz), 4.49 (1H, s), 5.06 (2H, s),
6.87-6.97 (3H, m), 7.03 (1H, d, J = 7.9 Hz), 7.15-7.42 (10H, m), 7.58 (1H, s),
7.64 (1H, d, J = 7.9 Hz), 8.07 (2H, s), 9.96 (1H, s).
HRFABMS (+): 576.1211 (C ₃₁ H ₂₇ ClNO ₆ S) Calculated value 576.1234.

<Example 45>
2- [3- (3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamido) phenyl] -2-hydroxyacetic acid

Pale yellow amorphous
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.62
(2H, t, J = 7.4 Hz), 2.98 (2H, t, J = 7.4 Hz), 4.96 (1H, s), 5.08 (2H, s),
6.87-6.99 (3H, m), 7.06 (1H, d, J = 7.9 Hz), 7.15-7.42 (11H, m), 7.54 (1H, d, J
= 7.9 Hz), 7.60 (1H, s), 9.98 (1H, s).
HRFABMS (+): Calculated as 548.1002 (C ₃₀ H ₂₇ ClNO ₅ S) 548.0986.

<Example 46>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenoxymalonic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.42
(2H, t, J = 7.4 Hz), 2.98 (2H, t, J = 7.4 Hz), 5.08 (2H, s), 5.19 (1H, s), 6.55
(1H, d, J = 7.9 Hz), 6.89 (1H, d, J = 7.9 Hz), 6.94-7.00 (2H, m), 7.11-7.42
(10H, m), 9.36 (1H, s).
FABMS (+): 592 [M + H] ⁺ .
Elemental analysis: Actual value C
Calculated as 62.26%, H 4.49%, N 2.34%, C ₃₁ H ₂₆ ClNO ₇ S / 1/3 H ₂ O C 62.33%, H 4.89%, N 2.49%.

<Example 47>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenoxy-methylmalonic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 1.67
(3H, s), 2.60 (2H, t, J = 7.4 Hz), 2.96 (2H, t, J = 7.4 Hz), 5.07 (2H, s), 6.46
(1H, br s), 6.87 (1H, d, J = 7.9 Hz), 6.92-6.99 (2H, m), 7.11 (2H, s),
7.16-7.42 (10H, m), 9.92 (1H, s).
HRFABMS (+): Calculated as 606.1374 (C ₃₂ H ₂₉ ClNO ₇ S) 606.1353.

<Example 48>
5- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] -2-nitrobenzoic acid

DMF (catalytic amount) and oxalyl chloride (80 μL) were added to a solution of the compound of Reference Example 10 (120 mg) in methylene chloride (0.75 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 1,4-dioxane (1 mL), 5-amino-2-nitrobenzoic acid (71 mg) and pyridine (0.29 mL) were added to the residue, and the mixture was stirred at 100 ° C. for 2 hr. After adding 1 mol / L hydrochloric acid and extracting with methylene chloride, the organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 9: 1 → 85: 15 → 6: 1) to obtain the desired product (175
mg) was obtained as a pale yellow powder.
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.69
(2H, t, J = 7.6 Hz), 3.00 (2H, t, J = 7.6 Hz), 5.08 (2H, s), 6.88-7.00 (3H, m),
7.20 (1H, dd, J = 7.9, 1.8 Hz), 7.28-7.40 (8H, m), 7.71 (1H, dd, J = 9.2, 2.4
Hz), 7.82 (1H, d, J = 9.2 Hz), 7.86 (1H, d, J = 2.4 Hz), 10.50 (1H, s), 13.99
(1H, br).
Calculated as HRFABMS (+): 563.1060 (C ₂₉ H ₂₄ ClN ₂ O ₆ S) 563.1044.

  Thereafter, in the same manner as in Example 48, the compound of Reference Example 10 and various aminobenzoic acid derivatives were reacted to synthesize compounds of Examples 49 and 50.

<Example 49>
5- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] -2-hydroxybenzoic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.59
(2H, t, J = 7.4 Hz), 2.98 (2H, t, J = 7.4 Hz), 5.08 (2H, s), 6.87-6.97 (3H, m),
7.22-7.38 (10H, m), 7.62 (1H, dd, J = 9.2, 3.1 Hz), 8.07 (1H, s), 9.90 (1H, s),
10.99 (1H, brs), 13.96 (1H, br).
Calculated as HRFABMS (+): 534.1103 (C ₂₉ H ₂₅ ClNO ₅ S) 534.1142.

<Example 50>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] -2-hydroxybenzoic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.74
(2H, t, J = 7.3 Hz), 2.98 (2H, t, J = 7.3 Hz), 5.08 (2H, s), 6.85-7.00 (4H, m),
7.21 (1H, dd, J = 7.9, 1.8 Hz), 7.28-7.41 (8H, m), 7.53 (1H, dd, J = 7.9,
1.8Hz), 8.10 (1H, d, J = 7.3 Hz), 9.37 (1H, s), 11.83 (1H, brs), 14.14 (1H,
br).
HRFABMS (+): Calculated as 534.1180 (C ₂₉ H ₂₅ ClNO ₅ S) 534.1142.

<Example 51>
2-Amino-5- [3- (4- (3-benzyloxyphenylthio) -2-chlorophenyl) propanamide] benzoic acid

The compound of Example 48 (752 mg) was dissolved in methanol (10 mL) and methylene chloride (5 mL), 10% -Pd / C (226 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4.5 hours. . The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained crystals were washed with methanol and dried to obtain the desired product (463 mg) as a pale yellow powder.
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.54 (2H,
t, J = 7.6Hz), 2.96 (2H, t, J = 7.3Hz), 5.08 (2H, s), 6.65 (1H, d, J = 9.2Hz),
6.87-6.99 (3H, m), 7.20 (1H, dd, J = 7.9,1.8Hz), 7.28-7.42 (9H, m), 7.88 (1H, d,
J = 2.4Hz), 8.43 (2H, brs), 9.63 (1H, s).
HRFABMS (+): Calculated as 533.1296 (C ₂₉ H ₂₆ ClN ₂ O ₄ S) 533.1302.
Elemental analysis: measured value C 64.57%,
Calculated as H 4.74%, N 5.26%, C ₂₉ H ₂₅ ClN ₂ O ₄ S ・ 1 / 3H ₂ O C 64.62%, H 4.80%,
N 5.20%.

<Example 52>
4- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenylphosphonic acid

To a solution of the compound of Example 13 (97.4 mg) in acetonitrile (1 mL) at 0 ° C. was added iodotrimethylsilane (65 μL) and stirred for 3 hours. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, dried, then washed with ethyl acetate and dried to obtain the desired product (36 mg) as a colorless powder.
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.74 2.65 (2H, t, J = 7.3 Hz), 2.99 (2H, t, J = 7.3 Hz), 5.08 (2H, s), 6.89
(1H, d, J = 7.9 Hz), 6.95-6.99 (2H, m), 7.20 (1H, dd, J = 7.9, 1.8 Hz), 7.28-7.41
(8H, m), 7.54-7.58 (4H, m), 10.10 (1H, s).
HRFABMS (+): Calculated as 554.0983 (C ₂₈ H ₂₆ ClNO ₅ PS) 554.0958.

  Hereinafter, in the same manner as in Example 52, the compounds of Examples 53 to 59 were synthesized using the compounds of Examples 14, 17, 20 to 23, and 26.

<Example 53>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenylphosphonic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.64 (2H, t, J = 7.3 Hz), 2.99 (2H, t, J = 7.3 Hz), 5.08 (2H, s), 6.88-6.99
(3H, m), 7.19-7.39 (11H, m), 7.71-7.73 (1H, m), 7.90 (1H, d, J = 14.7 Hz), 10.06
(1H, s).
HRFABMS (+): Calculated as 554.0981 (C ₂₈ H ₂₆ ClNO ₅ PS) 554.0958.

<Example 54>
4- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] -3-carboxyphenylphosphonic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.67 (2H, t, J = 7.6 Hz),
2.99 (2H, t, J = 7.6 Hz), 5.07 (2H, s), 6.88-6.98 (3H, m), 7.20 (1H, dd, J = 7.9,
1.8 Hz), 7.27-7.41 (8H, m), 7.70-7.84 (2H, m), 7.96 (1H, d, J = 3.1 Hz).
HRFABMS (+): Calculated as 596.0726 (C ₂₉ H ₂₄ ClNO ₇ PS) 596.0700.

<Example 55>
5- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] -2-chlorophenylphosphonic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.63 (2H, t, J = 7.6 Hz),
2.98 (2H, t, J = 7.6 Hz), 5.08 (2H, s), 6.89 (1H, dd, J = 8.6, 1.8 Hz),
6.95-7.00 (2H, m), 7.21 (1H, dd, J = 7.9, 2.4 Hz), 7.28-7.41 (9H, m), 7.82 (1H,
dd, J = 8.6, 2.4 Hz), 8.01 (1H, dd, J = 5.0, 2.8 Hz), 10.19 (1H, s).
HRESIMS (+): Calculated as 586.03983 (C ₂₈ H ₂₃ Cl ₂ N ₂ O ₅ PS) 586.04116.

<Example 56>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenylmethylphosphonic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.61 (2H, t, J = 7.6 Hz),
2.91 (2H, d, J = 21.4 Hz), 2.98 (2H, t, J = 7.6 Hz), 5.07 (2H, s), 6.87-6.92
(2H, m), 6.94-7.00 (2H, m), 7.16 (1H, t, J = 7.9 Hz), 7.20 (1H, dd, J = 7.9, 1.8
Hz), 7.26-7.41 (9H, m), 7.49 (1H, d, J = 7.9 Hz), 9.90 (1H, s).
Calculated as HRFABMS (+): 568.1118 (C ₂₉ H ₂₈ ClNO ₅ PS) 568.1114.

<Example 57>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenyldifluoromethylphosphonic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.64 (2H, t, J = 7.6 Hz),
2.99 (2H, t, J = 7.6 Hz), 5.08 (2H, s), 6.89 (1H, d, J = 7.9 Hz), 6.94-7.00 (2H,
m), 7.15- 7.23 (2H, m), 7.26-7.42 (9H, m), 7.75 (1H, s), 7.76 (1H, d, J = 7.9
Hz).
FABMS (-): 602 [MH] ⁺ .
Elemental analysis: measured value C 55.59%,
Calculated as H 4.11%, N 2.25%, C ₂₉ H ₂₅ ClF ₂ NO ₅ PS ・ 4 / 5H ₂ O C 55.59%, H 4.42%,
N 2.24%.

<Example 58>
3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenylfluoromethylphosphonic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.61 (2H, t, J = 7.6 Hz),
2.97 (2H, t, J = 7.6 Hz), 5.06 (2H, s), 5.61 (1H, dd, J = 44.3, 8.3 Hz), 6.87
(1H, d, J = 7.9 Hz), 6.92-6.98 (2H, m), 7.05 (1H, d, J = 7.3 Hz), 7.19 (1H, dd,
J = 8.6, 1.8 Hz), 7.24- 7.38 (9H, m), 7.57 (1H, s), 7.63 (1H, d, J = 7.9 Hz).
FABMS (+): 586 [M + H] ⁺ .
Elemental analysis: measured value C 57.76%,
Calculated as H 4.60%, N 2.31%, C ₂₉ H ₂₆ ClFNO ₅ PS ・ H ₂ O C 57.66%, H 4.67%,
N 2.32%.

<Example 59>
[3- (3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamido) phenyl] hydroxymethylphosphonic acid

Colorless powder
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.61 (2H, t, J = 7.6 Hz),
2.97 (2H, t, J = 7.6 Hz), 4.62 (1H, d, J = 14.1 Hz), 5.07 (2H, s), 6.89 (1H, d,
J = 7.9 Hz), 6.94-6.99 (2H, m), 7.04 (1H, d, J = 7.3 Hz), 7.18 (1H, dd, J =
8.6, 1.8 Hz), 7.26- 7.41 (8H, m), 7.50 (1H, s), 7.57 (1H, t, J = 7.9 Hz).
HRFABMS (+): Calculated as 584.1101 (C ₂₉ H ₂₈ ClNO ₆ PS) 5684.11064.

<Example 60>
5- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] -2-hydroxyphenylphosphonic acid

The compounds of Reference Example 1 and Reference Example 10 were condensed in the same manner as in Example 8, and then reacted in the same manner as in Example 52 to obtain the desired product as a colorless powder.
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.54 (2H, t, J = 7.6 Hz),
2.96 (2H, t, J = 7.6 Hz), 5.08 (2H, s), 6.47 (1H, dd, J = 8.6, 4.9 Hz),
6.89 (1H, d, J = 7.9 Hz), 6.93-7.05 (2H, m), 7.20 (1H, dd, J = 8.3, 1.5 Hz),
7.28-7.42 (10H, m), 9.62 (1H, s).
HRFABMS (+): Calculated as 568.0775 (C ₂₈ H ₂₄ ClNO ₆ PS) 568.0751.

<Example 61>
4- [4- (3-Benzyloxyphenylthio) -2-chlorophenethylcarbamoyl] phthalic acid

The compound of Reference Example 18 and 4-carboxyphthalic anhydride were condensed in the same manner as in Example 8, and then hydrolyzed in the same manner as in Example 29 to obtain the desired product as a colorless powder.
¹ H-NMR
(DMSOd ₆ , 400 MHz): δ 2.96 (2H, t, J = 6.7 Hz),
3.50 (2H, q, J = 6.7 Hz), 5.08 (2H, s), 6.89 (1H, dd, J = 6.7, 1.8 Hz),
6.96-6.99 (1H, m), 7.18 (1H, dd, J = 7.9, 1.8 Hz), 7.26-7.42 (8H, m), 7.93 (2H,
d, J = 6.7 Hz), 8.28 (1H, s), 8.82 (1H, t, J = 5.5 Hz).
HRFABMS (+): Calculated as 562.1128 (C ₃₀ H ₂₄ ClNO ₆ S) 562.1091.

Next, the results of supporting the usefulness of the compounds of the present invention are shown by experimental examples.
<Experimental Example 1> Induction of intracellular calcium mobilization of a test compound 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 and HS1P ₄ receptor expression CHO-K1 cells) was used. 96-well black clear bottom culture plate (BD Falcon) for hS1P ₁ and hS1P ₃ receptor-expressing CHO-K1 cells at 7 × 10 ⁴ cells / well and hS1P ₄ receptor-expressing CHO-K1 cells at 10 ⁴ cells / well And cultured overnight at 37 ° C. under 5% CO ₂ . Medium is aspirated in the well, as Ca ²⁺ binding fluorescent indicator was added Calcium Kit-Fluo3 reagent (Dojin Chemical Laboratories) in the attached reagent (Loading Loading buffer), 37 ° C., under 5% CO ₂ for Incubated for 80 minutes. After culturing, 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. 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 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 measured 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. In addition, 1000 nmol / L> EC ₅₀ value ≧ 100 nmol / L is indicated as +, 100 nmol / L> EC ₅₀ value ≧ 10 nmol / L is indicated as ++, and 10 nmol / L> EC ₅₀ value is indicated as +++, as shown in Table 1. It was.

From the above results, it was confirmed that the compound of the present invention has a weak action on the human S1P ₃ receptor and a strong action on the S1P ₁ receptor.

<Experimental Example 2> Effect on the total number of leukocytes in peripheral blood of mice The test compound was dissolved or suspended in DMSO, and then physiological saline was added to prepare an administration solution (final concentration of DMSO 1%). When the dosing solution was not dissolved or in a uniform suspension, Tween 80 was added to a final concentration of 0.01% to 0.1% and sonicated into a fine suspension. These test compound solutions were intraperitoneally administered to BALB / cCrSlc male mice (8 to 14 weeks of age, Japan SLC) at 0.1 mL or 0.2 mL per 10 g body weight. In the control group, only the solvent having the same composition as that used for the preparation of the test compound was similarly administered. Six hours after administration of the test compound solution, blood was collected from the posterior vena cava under ether anesthesia (10 μL of 10% EDTA was added as an anticoagulant). The total white blood cell count was measured using an automatic blood cell counter Sysmex F-820 (Sysmex).
The compounds of Examples 29, 43, 56, 59 and 61 showed an inhibition rate of 30% or more at a dose of 100 mg / kg.

The present invention has been found that a novel amide derivative has an excellent S1P ₁ receptor selective agonistic action. Such S1P ₁ receptor selective agonistic compounds include arteriosclerosis, obstructive arteriosclerosis, obstructive thromboangiitis, renal fibrosis, liver fibrosis, chronic bronchial asthma, diffuse hamartoma lung Vascular myomatosis, adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), interstitial pneumonia, idiopathic interstitial pneumonia, lung cancer, hypersensitivity pneumonitis, Buerger's disease, diabetic neuropathy peripheral artery Disease, sepsis, vasculitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edematous disease, varicose vein, dissecting aortic aneurysm, angina, DIC, pleurisy, congestive heart failure, multiple organ failure, illness, burn, As a therapeutic and prophylactic agent for ulcerative colitis, Crohn's disease, etc., and a prophylactic or therapeutic agent for rejection such as heart transplantation, renal transplantation, skin transplantation, liver transplantation, bone marrow transplantation, rheumatoid arthritis, lupus nephritis, systemic erythematode , Hashimoto's disease, multiple sclerosis, myasthenia gravis, diabetes, atopic dermatitis, is useful as allergic rhinitis, allergic conjunctivitis, prophylactic or therapeutic agent such as allergic contact dermatitis.

Claims (11)

General formula (1)

[Wherein, R ¹ represents a benzyloxy group, an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, an alkoxy group having 1 to 6 carbon atoms or a cycloalkylmethyloxy group having 4 to 8 carbon atoms. ,
R ² is-(O) p- (CR ^a R ^b ) q-COOH
(Wherein R ^a represents a hydrogen atom, a methyl group or a trifluoromethyl group, R ^b represents a hydrogen atom, a hydroxyl group or a carboxyl group, and p and q each represents 0 or 1), or
-(CR ^c R ^d ) q- PO ₃ H ₂
(Wherein R ^c represents a hydrogen atom or a halogen atom, R ^d represents a hydrogen atom, a halogen atom or a hydroxyl group, q represents 0 or 1),
R ³ represents a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a carboxyl group or a phosphate group,
X represents a hydrogen atom or a halogen atom,
Y is O, S, SO or SO _2,
Z represents -CONH- or -NHCO-
T represents —CH═CH— or — (CH ₂ ) m— (wherein m represents 2 or 3). ]
Or a pharmacologically acceptable salt or hydrate thereof. In the general formula (1), Z is —NHCO—.
The amide derivative according to claim 1, a pharmacologically acceptable salt thereof or a hydrate thereof. The amide derivative according to claim 1 or 2, a pharmacologically acceptable salt thereof, or a hydrate thereof, wherein in the general formula (1), R ¹ is a cycloalkylmethyloxy group having 4 to 8 carbon atoms. In the general formula (1), R ² is CO ₂ H, CH ₂ CO ₂ H, CH (CO ₂ H) ₂ , CH (OH) CO ₂ H, C (OH) CF ₃ CO ₂ H, OCH (CO ₂ H) ₂ , OCMe (CO ₂ H) ₂ , PO ₃ H ₂ , CH ₂ PO ₃ H ₂ , CHFPO ₃ H ₂ , CF ₂ PO ₃ H ₂ or CH (OH) PO ₃ H ₂
The amide derivative according to any one of claims 1 to 3, a pharmacologically acceptable salt thereof or a hydrate thereof. In the general formula (1), R ² is CO ₂ H, CH ₂ CO ₂ H, CH (CO ₂ H) ₂ , CH (OH) CO ₂ H, C (OH) CF ₃ CO ₂ H, OCH (CO ₂ H) ₂ or OCMe (CO ₂ H) ₂
The amide derivative according to any one of claims 1 to 3, a pharmacologically acceptable salt thereof or a hydrate thereof. In the general formula (1), R ² is PO ₃ H ₂ , CH ₂ PO ₃ H ₂ , CHFPO ₃ H ₂ , CF ₂ PO ₃ H ₂ or CH (OH) PO ₃ H _2.
The amide derivative according to any one of claims 1 to 3, a pharmacologically acceptable salt thereof or a hydrate thereof. The compound represented by the general formula (1) is represented by the general formula (1a).

[Wherein R ⁴ represents CO ₂ H, PO ₃ H ₂ , CH ₂ PO ₃ H ₂ , CHFPO ₃ H ₂ , CF ₂ PO ₃ H ₂ or CH (OH) PO ₃ H ₂ , and R ⁵ represents a hydrogen atom. Represents a halogen atom, a hydroxyl group, a carboxyl group or a phosphate group, and R ¹ , X and Y are the same as defined above]
The amide derivative in any one of Claims 1-3 represented by these, its salt accept | permitted pharmacologically, or its hydrate. The amide derivative according to claim 7, a pharmacologically acceptable salt thereof or a hydrate thereof, wherein R ⁴ and R ⁵ in the general formula (1a) are carboxyl groups. The compound represented by the general formula (1) is
1) 4- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phthalic acid,
2) 4- [3- (2-Chloro-4- (3-cyclohexylmethyloxyphenoxy) phenyl) propanamide] phthalic acid,
3) 3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenylphosphonic acid,
4) 3- [3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamide] phenylmethylphosphonic acid,
5) [3- (3- (4- (3-Benzyloxyphenylthio) -2-chlorophenyl) propanamido) phenyl] hydroxymethylphosphonic acid,
6) The amide derivative according to claim 1, which is 4- [4- (3-benzyloxyphenylthio) -2-chlorophenethylcarbamoyl] phthalic acid, a pharmacologically acceptable salt thereof or a hydrate thereof. Amide derivative according to any one of claims 1 to 9, pharmacologically acceptable salts thereof or sphingosine-1-phosphate -1 hydrate thereof as an active ingredient (SlP ₁₎ receptor agonists. A pharmaceutical comprising the amide derivative according to any one of claims 1 to 9, a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient.