JPH07215929A - Naphthyloxyacetic acid derivatives and drugs containing them as active ingredients - Google Patents

Abstract

(57) [Summary] [Structure] A naphthaleneoxyacetic acid derivative represented by the general formula (I) and a non-toxic salt thereof, a method for producing them and a drug containing them as an active ingredient (wherein R ¹ is -CO
Represents OR ⁴ , —CONR ⁵ R ⁶ or —CH ₂ OH;
B represents -NR ³ SO ₂ or -SO ^₂ NR ^3; R ₂
Is (i) an alkyl, alkenyl or alkynyl group, (ii)
An alkyl, alkenyl or alkynyl group substituted with 1 to 3 (substituted) phenyl or cycloalkyl groups, (ii
i) represents a naphthyl group. ) [Chemical 1] [Effect] Since the compound of the general formula (I) binds to the receptor of PGE _{2 and} exerts an antagonistic or agonistic action on the action,
It can be applied to a drug having uterine muscle contraction suppression, analgesia, gastrointestinal peristaltic motion suppression, and sleep-inducing action, or a drug having uterine contraction, gastrointestinal peristaltic motion promotion, gastric acid secretion suppression, and blood pressure lowering action.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to naphthyloxyacetic acid. More specifically, (1) general formula (I)

[0002]

[Chemical 9]

(In the formula, all symbols have the same meanings as described below.) (2) Method for producing them, and (3) Prostaglandin E ₂ containing them as an active ingredient (hereinafter abbreviated as PGE ₂ ). ) Regarding antagonists or agonists.

[0004]

BACKGROUND OF THE INVENTION of PGE ₂ agonist (work働剤), including the so-called PGE ₂ itself, have been known many, PG
A compound (antagonist) that antagonizes E ₂ and inhibits the action of PGE ₂ is not known. PGE ₂ is known as a metabolite in the arachidonic acid cascade, and its actions include uterine contraction, pain-reducing action, promotion of gastrointestinal peristalsis,
It is known to have a wakefulness action, a gastric acid secretion inhibitory action, a blood pressure lowering action and the like. It is expected to have the following actions by antagonizing these actions and acting.

Since antagonizing PGE ₂ suppresses these effects, they suppress uterine contraction, respectively.
It may lead to analgesia, gastrointestinal motility suppression, and sleep-inducing action. Therefore, the PGE ₂ antagonist is useful as a miscarriage preventive agent, an analgesic agent, an antidiarrheal agent, and a hypnotic agent. Also, PGE
That agonizing the _2, it becomes to promote these effects, respectively, uterine contraction, hyperactivity of the digestive tract, gastric acid secretion inhibiting action, leading to a blood pressure-lowering effect. Therefore, PGE
_{The two} agonists are useful as abortions, laxatives, anti-ulcer agents, anti-gastritis agents and antihypertensive agents.

[0006]

DISCLOSURE OF THE INVENTION The present invention is

(1) General formula

[Chemical 10]

(Wherein R ¹ is --COOR ⁴ (wherein R ⁴ represents a hydrogen atom or a C1-4 alkyl group),
CONR ⁵ R ⁶ (wherein R ⁵ and R ⁶ are each independently a hydrogen atom, a C1-4 alkyl group or a hydroxyl group is 1
It represents a C1-4 alkyl group which is individually substituted. ) Or —CH ₂ OH,

[0009]

[Chemical 11] Is

[Chemical 12]

(Wherein A represents a single bond or a C1-4 alkylene group) or

[0011]

[Chemical 13] (Wherein A is a formula

[0012]

[Chemical 14]

(Wherein m represents 0, 1, 2, 3, 4 and n represents 0, 1, 2, 3, 4 and m + n represents 2, 3, 4). Represents a group, and B is-
NR ³ SO ₂ — or —SO ₂ NR ³ — (wherein R ³ is a hydrogen atom, a C1-4 alkyl group or —CH ₂ COOR
⁷ (in the group, R ⁷ is a hydrogen atom or R ^4a (in the group, R ^4a is C 1
Represents an alkyl group of ~ 4. ) Is represented. ),
R ² is (i) a C 1-6 alkyl group, a C 2-6 alkenyl group or a C 2-6 alkynyl group, (ii) 1, 2 or 3 phenyl groups, a C 4-7 cycloalkyl group,
Alternatively, a C1-4 alkyl group, a C1-4 alkoxy group, or a C1-6 alkyl group substituted by a phenyl group substituted with 1, 2 or 3 substituents selected from halogen atoms, C2-6 Represents an alkenyl group or a C2-6 alkynyl group, or (iii) naphthyl group,

[0014]

[Chemical 15]

Represents a single bond or a double bond. ) Naphthyloxyacetic acid or a non-toxic salt thereof, (2) a method for producing them, and (3) a PGE ₂ antagonist or agonist containing them as an active ingredient.

In the general formula (I), R ³ , R ⁴ , R ^4a , R ⁵ and R
The C1-4 alkyl group represented by ⁶ means methyl, ethyl, propyl, butyl and isomers thereof. In the general formula (I), the C1-6 alkyl group represented by R ² is methyl, ethyl, propyl, butyl, pentyl,
Hexyl and isomers thereof are meant. In the general formula (I), examples of the C2-6 alkenyl group represented by R ² include vinyl, propenyl, butenyl, pentenyl and hexenyl. C2 represented by R ² in the general formula (I)
Examples of the alkynyl group of ~ 6 include ethynyl, propynyl,
Examples include butynyl, pentynyl and hexynyl. In the general formula (I), examples of the C4-7 cycloalkyl group as a substituent in R ² include cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.

In the general formula (I), the C1-4 alkyl group as a substituent of the phenyl group in R ² means methyl, ethyl, propyl, butyl and isomers thereof. In the general formula (I), the C1-4 alkoxy group as a substituent of the phenyl group in R ² is methoxy, ethoxy,
Propoxy, butoxy and their isomers are meant. In the general formula (I), the C1-4 halogen atom as a substituent of the phenyl group in R ² is fluorine, chlorine, bromine and iodine. In general formula (I), C1 represented by A1
Examples of the alkylene group of 4 include methylene, ethylene, trimethylene, tetramethylene and isomers thereof. In general formula (I),

[0018]

[Chemical 16]

Examples of the ring represented by:

[0020]

[Chemical 17] , For example,

[0021]

[Chemical 18] Is mentioned.

In the present invention, isomers include all isomers unless otherwise specified. For example, an alkyl group,
The alkylene group and the alkenylene group include straight-chain and branched-chain ones, and the double bond in the alkenylene group is
Including those which are E, Z and EZ mixtures. Also included are isomers formed by the presence of asymmetric carbon atoms, such as when a branched chain alkyl group is present.

In the compound of the present invention represented by the general formula (I),
Preferred compounds include the compounds described in the examples and the compounds shown below.

General formula (Ia)

[Chemical 19] A compound represented by

General formula (Ib)

[Chemical 20] A compound represented by

General formula (Id)

[Chemical 21] A compound represented by, and

General formula (Ic)

[Chemical formula 22]

A compound represented by: General formula (Ia), (I
All symbols in b), (Id) and (Ic) have the same meanings as described above. Particularly preferred compounds include the compounds described in the examples and the compounds shown below.

[0029]

[Table 1]

[0030]

[Table 2]

[0031]

[Table 3]

[0032]

[Table 4]

[0033]

[Table 5]

[0034]

[Table 6]

[0035]

[Table 7]

[0036]

[Table 8]

[0037]

[Table 9]

[0038]

[Table 10]

[0039]

[Table 11]

[0040]

[Table 12]

[0041]

[Table 13]

[0042]

[Table 14]

[0043]

[Table 15]

[0044]

[Table 16]

[0045]

[Salt] The compound of the present invention represented by the general formula (I) can be converted into the corresponding salt by a known method. The salt is preferably non-toxic and water-soluble. Suitable salts include alkali metal (potassium, sodium, etc.) salts, alkaline earth metal (calcium, magnesium, etc.) salts, ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, Salts of dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N-methyl-D-glucamine, etc.) can be mentioned.

The compound of the present invention represented by the general formula (I) can be converted into the corresponding acid addition salt by a known method. The acid addition salt is preferably non-toxic and water-soluble. Suitable acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, Oxalate, fumarate, maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate Organic acid salts such as salts may be mentioned.

[0047]

[Method for producing the compound of the present invention]

(1) Of the compounds of the present invention represented by the general formula (I),
General formula (Ia)

[0048]

[Chemical formula 23]

(Wherein all symbols have the same meanings as described above), the compound represented by the formula (I)
I):

[0050]

[Chemical formula 24]

(In the formula, R ^3c represents a hydrogen atom, a C1-4 alkyl group or —CH ₂ COOR ^4a , and R ^4a represents C1.
~ 4 alkyl, and other symbols have the same meanings as described above. ) And a compound represented by the general formula (III)

[0052]

Embedded image X ¹ SO ₂ —R ² (III)

(Wherein X ¹ represents a halogen atom, and other symbols have the same meanings as described above), the compound is subjected to an amidation reaction and, if necessary, a hydrolysis reaction under alkaline conditions or It can be produced by subjecting it to an amidation reaction or a reduction reaction.

Further, the compound represented by the general formula (Ia) is
(Ii) General formula (X):

[0055]

[Chemical formula 26]

(Wherein R ^2a and R ^2b are

[0057]

[Chemical 27]

(I) C1-5 alkyl group, C2
~ 5 alkenyl group, C3-5 alkynyl group, (ii)
1, 2 or 3 phenyl groups, or C4-7 cycloalkyl groups, or C1-4 alkyl groups, C
A C1-5 alkyl group, a C2-5 alkenyl group or a C3-5 alkyl group substituted by a phenyl group substituted by 1, 2 or 3 substituents selected from 1-4 alkoxy groups or halogen atoms. Represents an alkynyl group or (iii) naphthyl group, R ^3a represents a hydrogen atom or C
1 to 4 alkyl groups, and other symbols have the same meanings as described above. ) Or a compound represented by the general formula (XI)

[0059]

[Chemical 28]

( ^Wherein R ^2aa and R ^2bb are

[0061]

[Chemical 29]

(I) C1-5 alkyl group, (i
i) 1, 2 or 3 phenyl groups or C4-7 cycloalkyl groups, or C1-4 alkyl groups, C
A C1-5 alkyl group substituted by a phenyl group substituted by 1, 2 or 3 substituents selected from 1 to 4 alkoxy groups or halogen atoms, or (ii
i) represents a naphthyl group, and other symbols have the same meanings as described above. ) And a compound represented by the general formula (VI)

[0063]

[Chemical 30]

(Wherein X ³ represents a halogen atom and other symbols have the same meanings as described above), and, if necessary, hydrolysis reaction or amide reaction under alkaline conditions. It can be produced by subjecting to a chemical reaction or a reduction reaction. (2) Of the compounds of the present invention represented by the general formula (I), the general formula (Ib)

[0065]

[Chemical 31]

(Wherein all symbols have the same meanings as described above), a compound represented by the general formula (XVI)

[0067]

[Chemical 32]

(Wherein all symbols have the same meanings as described above), and a compound of the general formula (VI)

[0069]

[Chemical 33]

(Wherein all symbols have the same meanings as described above), and if necessary, subjected to hydrolysis, amidation or reduction under alkaline conditions. It can be manufactured. (3) Of the compounds of the present invention represented by the general formula (I), the general formula (Ic)

[0071]

[Chemical 34]

(Wherein all symbols have the same meanings as described above), the compound represented by the formula (XXII)
I)

[0073]

[Chemical 35]

(Wherein, X ² represents a halogen atom, and other symbols have the same meanings as described above) and a compound represented by the general formula (XXIV).

[0075]

[Chemical 36]

(Wherein all symbols have the same meanings as described above), the compound is subjected to an amidation reaction and, if necessary, a hydrolysis reaction, an amidation reaction, or a reduction under alkaline conditions. It can be produced by subjecting it to a reaction. Further, the compound represented by the general formula (Ic) has the formula (ii) the general formula (XXVIII)

[0077]

[Chemical 37]

(In the formula, A ⁶ represents a single bond or a C1,2 alkylene group, R ^8a represents a hydrogen atom or a C1,2 alkyl group, and other symbols have the same meanings as described above). Compounds shown and general formula (VI)

[0079]

[Chemical 38]

(Wherein all symbols have the same meanings as described above), the compound represented by the formula is reacted, and if necessary,
It can be produced by subjecting it to a hydrolysis reaction, an amidation reaction, or a reduction reaction under alkaline conditions. (4) Of the compounds of the present invention represented by the general formula (I), the general formula (Ie)

[0081]

[Chemical Formula 39]

(Wherein all symbols have the same meanings as described above), the compound represented by the general formula (XXXIII)

[0083]

[Chemical 40]

(Wherein all symbols have the same meanings as described above) and a compound of the general formula (VI)

[0085]

[Chemical 41]

(Wherein all symbols have the same meanings as described above), the compound represented by the formula is reacted, and if necessary,
It can be produced by subjecting it to a hydrolysis reaction, an amidation reaction, or a reduction reaction under alkaline conditions.

The amidation reaction is known and, for example, in an inert organic solvent (benzene, toluene, methylene chloride, etc.),
Alternatively, it is carried out in the presence of a tertiary amine (pyridine, triethylamine, etc.) at a temperature of 0 ° C. to 50 ° C. without using a solvent, or an inert organic solvent (methylene chloride, methylene chloride,
Tetramethylhydrofuran (THF) etc.) in the presence or absence of a suitable condensing agent (2-chloro-N-methylpyridinium iodide etc.) and a suitable base and 0-4.
It is carried out by reacting at a temperature of 0 ° C.

Hydrolysis under alkaline conditions is known and, for example, in an organic solvent miscible with water (methanol, ethanol, dimethoxyethane or a mixed solvent thereof), alkali (eg sodium hydroxide, hydroxide) is used. It is carried out at a temperature of 0 to 50 ° C. using an aqueous solution of potassium or the like).

The reduction reaction is known, and for example, in an inert organic solvent (methanol, ethanol, THF, methylene chloride, etc.), lithium aluminum hydride (LiAl
H ₄₎ or presence of hydrogen sodium borohydride (NaBH _4), at a temperature of 0 to 50 ° C..

Reactions (1)-(ii), (2), (3)-(i
i) and (4) are known, and for example, an inert organic solvent (dimethylformamide (DMF), acetone, etc.)
Medium, in the presence of potassium carbonate or sodium carbonate, 0
It is carried out at a temperature of ~ 160 ° C.

General formulas (II), (X), (XI), (XV
I), (XXIII), (XXVIII) and (XXXIII) are compounds represented by the following reaction process formulas (A), (B),
It can be manufactured according to (C), (D), (E) and (F). Reaction process formulas (A), (B), (C),
The symbols in (D), (E) and (F) have the following meanings or the same meanings as described above. Me: methyl, Et: ethyl, Ms: mesyl, Ts: tosyl, Boc: t-butoxycarbonyl, Cbz: benzyloxycarbonyl, TMEDA: N, N, N ', N'- tetramethylethylenediamine, X ^4: halogen atoms , R ^3b : C 1-4 alkyl, R ⁸ : C 1-3 alkyl, R ⁹ : methyl, ethyl, methoxymethyl, or tetrahydropyranyl A ^a

[0092]

[Chemical 42]

[0093]

[Chemical 43]

[0094]

[Chemical 44]

[0095]

[Chemical formula 45]

[0096]

[Chemical formula 46]

[0097]

[Chemical 47]

[0098]

[Chemical 48]

[0099]

[Chemical 49]

In each reaction in the present specification, the reaction product is a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography,
Alternatively, it can be purified by a method such as column chromatography, washing, recrystallization and the like. Purification may be carried out for each reaction or after completion of some reactions.

[0101]

[Starting materials and reagents] The starting materials and reagents used in the present invention are known per se or can be produced by known methods.

[0102]

[Pharmacological activity of the compound of the present invention] Since the compound of the present invention represented by the general formula (I) binds to the PGE ₂ receptor and antagonizes or acts on the action thereof, it is a PGE ₂ antagonist or PGE _{2. 2} Useful as an agonist. As described above, antagonizing PGE ₂ suppresses uterine contraction, analgesia,
It will lead to gastrointestinal motility suppression and sleep-inducing action.
Therefore, the PGE ₂ antagonist is useful as a miscarriage preventive agent, an analgesic agent, an antidiarrheal agent, and a hypnotic agent. In addition, the action on PGE ₂ leads to uterine contraction, gastrointestinal hyperactivity, gastric acid secretion inhibitory action, and blood pressure lowering action, as described above.
Therefore, the PGE ₂ agonist is useful as an abortion drug, a laxative, an antiulcer drug, an antigastritis drug, and an antihypertensive drug. For example, in laboratory experiments, these were confirmed by receptor experiments using cells expressing prostanoid receptor subtypes.

(I) Receptor Binding Experiment Using Prostanoid Receptor Subtype-Expressing Cells Method of Sugimoto et al. [J. Biol. Chem. 267 , 6
463-6466 (1992)], CHO cells expressing a prostanoid receptor subtype (mouse EP3a) were prepared and used as a membrane preparation. Prepared membrane fraction (0.5mg / m
l) The reaction solution (200 ml) containing 3H-PGE ₂ was incubated at room temperature for 1 hour. The reaction was stopped with ice-cold buffer (3 ml) and suction filtered under reduced pressure to bind ³ H.
-PGE ₂ was trapped in a glass filter (GF / B), and the bound radioactivity was measured with a liquid scintillator. K
The d value and Bmax value were obtained from Scatchard plots [An
n. NY Acad. Sci. 51 , 660 (1949)]. Non-specific binding was determined as binding in the presence of excess (2.5 nM) unlabeled PGE ₂ . The ³ H-PGE ₂ binding inhibitory action of the compound of the present invention was measured by adding 2.5 nM of ³ H-PGE ₂ and 1 mM of the compound of the present invention. The following buffer was used for all reactions. Buffer: 10 mM potassium phosphate (pH 6.0),
1 mM EDTA, 10 mM MgCl ₂ , 0.1 M NaC
l. The dissociation constant Ki (μM) of each compound was determined by the following formula. Ki = IC ₅₀ / (1 + ([C] / Kd)) The results are shown in Table 9.

[0104]

[Table 17]

[0105]

[Toxicity] The toxicity of the compound of the present invention is sufficiently low,
It was confirmed to be safe enough for use as a medicine.

[0106]

[Application to Pharmaceuticals] Since the compound of the present invention represented by the general formula (I) binds to the PGE ₂ receptor and antagonizes or acts on its action, it acts as a PGE ₂ antagonist or PGE ₂ receptor. It is useful as an agonist. Antagonism of PGE ₂ leads to the effects of uterine contraction suppression, analgesia, gastrointestinal motility suppression, and insomnia, as described above. Therefore, the PGE ₂ antagonist is useful as a miscarriage preventive agent, an analgesic agent, an antidiarrheal agent, and a hypnotic agent. In addition, the action on PGE ₂ leads to uterine contraction, gastrointestinal hyperactivity, gastric acid secretion inhibitory action, and blood pressure lowering action, as described above. Therefore, the PGE ₂ agonist is useful as an abortion drug, a laxative, an antiulcer drug, an antigastritis drug, and an antihypertensive drug. In order to use the compound of the present invention represented by the general formula (I), its non-toxic salt or its hydrate for the above-mentioned purpose, it is usually administered systemically or locally, orally or parenterally. .

The dose depends on age, body weight, symptoms, therapeutic effect,
Depending on the administration method, treatment time, etc., it is usually orally administered once per adult in the range of 1 μg to 100 mg once to several times a day, or 0.1 μg per adult per administration. To 10 mg once to several times a day by parenteral administration (preferably intravenous administration), or 1 hour to 24 hours a day by continuous intravenous administration. Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient in some cases, or a dose exceeding the range may be necessary in some cases. When the compound of the present invention is administered, it is used as solid compositions, liquid compositions and other compositions for oral administration, injections for parenteral administration, external preparations, suppositories and the like.

Solid compositions for oral administration include tablets,
Pills, capsules, powders, granules and the like are included. Capsules include hard capsules and soft capsules. In such solid compositions, the one or more active substances comprises at least one inert diluent such as lactose, mannitol, mannitol,
It is admixed with glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate. According to a conventional method, the composition contains an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin glycolate, a solubilizing agent such as glutamic acid or aspartic acid. May be included. If necessary, the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylcellulose phthalate, or may be coated with two or more layers. . Also included are capsules of absorbable material such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like. In such a liquid composition, one or more active substances are contained in a generally used inert diluent (eg, purified water, ethanol).
The composition may contain, in addition to an inert diluent, a wetting agent, an auxiliary agent such as a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent, and a preservative. Other compositions for oral administration include spray formulations which contain one or more active substances and are formulated in a manner known per se. This composition contains, in addition to an inert diluent, a stabilizer such as sodium bisulfite and a stabilizer that imparts isotonicity, an isotonic agent such as sodium chloride, sodium citrate or citric acid. May be. The manufacturing method of the spray agent is, for example, U.S. Patent Nos. 2,868,691 and 3,095,3.
No. 55 is described in detail.

Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (registered trademark). Such a composition may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers and solubilizing agents (eg glutamic acid, aspartic acid). These are sterilized by filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. They can also be used by preparing a sterile solid composition and dissolving it in sterilized or sterile distilled water for injection or other solvent before use. Other compositions for parenteral administration include external liquid preparations, ointments, liniments, suppositories for rectal administration and vaginal administration which include one or more active substances and are prescribed by a conventional method. Includes pessaries and the like.

[0111]

Reference Examples and Examples Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. The solvent in the parentheses shown at the place of separation by chromatography indicates the elution solvent or developing solvent used, and the ratio represents the volume ratio. NMR is measured in a deuterated chloroform solution unless otherwise specified.

Reference Example 1

[Chemical 50]

5-t-butoxycarbonylaminomethyl-1-naphthol (940 mg), potassium carbonate (70
A mixture of 9 mg), bromoacetic acid methyl ester (0.44 ml) and acetone (15 ml) was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, followed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.20
g) was obtained. mp: 109-110 ° C; NMR: δ 8.34 (1H, m), 7.
67 (1H, d), 7.50-7.36 (3H, m), 6.74 (1H, d), 4.90-4.63 (5
H, m), 3.82 (3H, s), 1.45 (9H, s).

Reference Example 2

[Chemical 51]

Compound synthesized in Reference Example 1 (200 mg)
4M hydrochloric acid / ethyl acetate (5 ml) was added to the methylene chloride solution (5 ml) of and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent of the reaction mixture was distilled off and concentrated under reduced pressure to obtain the title compound.

Example 1 5-[(2-phenylvinyl) sulfonylaminomethyl] naphthyloxyacetic acid methyl ester

[Chemical 52]

Compound synthesized in Reference Example 2 (150 mg)
Methylene chloride (10 ml), pyridine (0.24 ml),
Triethylamine (0.01 ml) and 2-phenylvinylsulfonyl chloride (192 mg) were added. The reaction mixture was stirred at room temperature for 4 hours and poured into water. The mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (87 mg) having the following physical data. Form: white solid; mp: 117-119 ° C .; NMR: δ 8.36 (1H, d), 7.68 (1H, d), 7.53-7.30 (9H,
m), 6.74 (1H, d), 6.61 (1H, d), 4.79 (2H, s), 4.67 (3H,
s), 3.83 (3H, s).

Reference Example 3

[Chemical 53]

6-keto-1-methoxy-5,6,7,8
-Molecular Sieves 4A (1) in a suspension of tetrahydrophenanthrene (1.00 g) in methanol (30 ml).
g), ammonium acetate (3.41 g) and sodium cyanoborohydride (292 mg) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate was concentrated. Aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over potassium carbonate and concentrated. The residue was dissolved in ethyl acetate and 4N hydrochloric acid / ethyl acetate was added. The precipitated crystals were collected by filtration, and 6-amine-1-
Methoxy-5,6,7,8-tetrahydrophenanthrene hydrochloride (1.0 g) was obtained. The amine hydrochloride (50
A solution of 0 mg) in methylene chloride (5 ml) was added to triethylamine (1 ml) and β-styrylsulfonamide (6
(06 mg) was added at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (331 mg) having the following physical data. TLC: Rf 0.55 (hexane: ethyl acetate = 1: 1
1).

Reference Example 4

[Chemical 54]

Compound produced in Reference Example 3 (300 mg)
Methylene chloride solution (4 ml) with tribromoboron (0.22 ml) in methylene chloride solution (2 ml) at -20 ° C.
And then stirred at -20 to 0 ° C for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give the title compound (282 mg) having the following physical data. TLC: Rf 0.39 (hexane: ethyl acetate = 1: 1
1).

Example 2 6-[(2-phenylvinyl) sulfonylamino]-
5,6,7,8-Tetrahydrophenanthren-1-yloxyacetic acid methyl ester

[Chemical 55]

The compound prepared in Reference Example 4 (150 m
g), bromoacetic acid methyl ester (0.056 ml) and sodium carbonate (85 mg) in DMF (3 ml) 10
The mixture was stirred at 0 ° C for 4.5 hours. The reaction mixture was cooled, poured into water, and extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: benzene = 1: 9) to give the title compound (142 mg) having the following physical data. TLC: Rf 0.35 (15% ethyl acetate / benzene);
NMR: δ 8.17 (1H, d), 7.58-7.16 (9H, m), 6.80 (1H,
d), 6.68 (1H, d), 4.79 (2H, s), 4.58 (1H, d), 4.00-3.75
(4H, m), 3.49 (1H, dd), 3.10-2.93 (3H, m), 2.25-2.08 (1
H, m), 2.03-1.80 (1H, m).

Reference Example 5

[Chemical 56]

A solution of 5- (2-aminoethyl) -1-tetrahydropyranyloxynaphthalene (3.0 g) in methylene chloride (15 ml) was added with triethylamine (2.81 ml).
And mesyl chloride (1.35 ml) were added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (2.20 g) having the following physical data. TLC: Rf 0.42 (hexane: ethyl acetate = 1: 1
1).

Reference Example 6

[Chemical 57]

Compound prepared in Reference Example 5 (300 mg)
Tetramethylethylenediamine (TMEDA; 0.26 ml) was added to the THF solution (5 ml) of, and cooled to -60 ° C under an argon atmosphere. N-Butyllithium (1.66M hexane solution; 1.6 ml) was added dropwise to the mixture, and the temperature was raised to -30 ° C over 1.5 hours. Again, the reaction mixture is -60
It was cooled to ℃, p-methoxybenzophenone (200m
A solution of g) in THF (3 ml) was added. Mixture -30
The temperature was raised with stirring until the temperature reached ℃. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 3: 1) gave the title compound (253 mg) having the following physical data. TLC: Rf 0.47 (hexane: ethyl acetate = 1: 1
1).

Reference Example 7

[Chemical 58]

Compound prepared in Reference Example 6 (243 mg)
Pyridinium p-toluenesulfonic acid (PPTS; 30 mg) was added to the methanol solution (3 ml) of and the mixture was stirred at room temperature overnight. Methanol was distilled off, the residue was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give the title compound (204 mg) having the following physical data.
Got TLC: Rf 0.16 (hexane: ethyl acetate = 2:
1).

Reference Example 8

[Chemical 59]

Compound produced in Reference Example 7 (194 mg)
In methylene chloride solution (2 ml), trifluoroacetic acid (TFA; 1 ml) and triethylsilane (0.20 m
1) was added, and the mixture was stirred overnight at room temperature. It was neutralized with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 2: 1) gave the title compound (162 mg) having the following physical data. TLC: Rf 0.29 (hexane: ethyl acetate = 1: 1
1).

Reference Example 9

[Chemical 60]

5- [2- [2-Hydroxy-2--2- (2-hydroxy-2-) was prepared in the same manner as in Reference Examples 5 and 6 using the corresponding compound.
To a solution of (4-methoxyphenyl) ethylsulfonylamino] ethyl] -1-tetrahydropyranyloxynaphthalene (318 mg) in methylene chloride (3 ml) was added triethylamine (0.20 ml) and mesyl chloride (83 μl) under ice cooling, and the mixture was cooled to room temperature. It was stirred for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The residue was dissolved in methanol, 2N aqueous hydrochloric acid solution was added under ice cooling, and the mixture was stirred at room temperature for 12 hours. Methanol was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (65 mg) having the following physical data. TLC: Rf 0.54 (hexane: ethyl acetate = 1: 1
1).

Example 3 5-[(2-phenylvinyl) sulfonylaminomethyl] naphthyloxyacetic acid

[Chemical formula 61]

The compound (84 mg) synthesized in Example 1 was dissolved in dimethoxyethane-methanol (2: 1, 3 ml), and the solution was 1N aqueous sodium hydroxide solution (0.5 ml) at 0 ° C.
After adding, the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid was added to the reaction solution to adjust the pH, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate,
It was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-hexane and purified by recrystallization to give the title compound (82 mg) having the following physical data. Shape: white powder; mp: 201-204 ° C; NMR (DM
SO-d ₆ ): δ 8.18 (1H, d), 7.88 (1H, t), 7.73 (1H, d),
7.68-7.30 (9H, m), 7.19 (1H, d), 6.92 (1H, d), 4.86 (2H,
s), 4.52 (2H, d).

Examples 3 (a) to 3 (ee) In the same manner as in Reference Examples 1 and 2 and Examples 1 and 3, or Reference Example 1 and Examples 1 and 3, compounds having the following physical properties were obtained. Obtained.

Example 3 (a) 5-[(2-phenylvinyl) sulfonylamino] naphthyloxyacetic acid

[Chemical formula 62]

Shape: milky white powder; mp: 218.5-219.5
° C; NMR (DMSO-d ₆ ): δ 13.03 (1H, brs), 9.95 (1H,
s), 8.13 (1H, dd), 7.84 (1H, d), 7.70-7.20 (10H, m), 6.8
7 (1H, d), 4.85 (2H, s).

Example 3 (b) 6-[(2-phenylvinyl) sulfonylamino] naphthyloxyacetic acid

[Chemical formula 63]

Shape: white powder; mp: 180-181
° C; NMR (DMSO-d ₆ ): δ 13.05 (1H, brs), 10.34 (1
H, s), 8.12 (1H, d), 7.76-7.25 (11H, m), 6.76 (1H, d), 4.
83 (2H, s).

Example 3 (c) 6-[(2-phenylvinyl) sulfonylaminomethyl] naphthyloxyacetic acid

[Chemical 64]

Shape: white powder; mp: 177-179
° C; NMR (DMSO-d ₆ ): δ 13.08 (1H, brs), 8.18 (1H,
d), 7.97 (1H, t), 7.80 (1H, s), 7.67-7.28 (9H, m), 7.13
(1H, d), 6.84 (1H, d), 4.84 (2H, s), 4.28 (2H, d).

Example 3 (d) 6-[(2,2-diphenylvinyl) sulfonylaminomethyl] naphthyloxyacetic acid

[Chemical 65]

Form: white powder; mp: 211.8-212.9 ° C .;
NMR (DMSO-d ₆ ): δ 8.22 (1H, d), 7.87 (1H, t), 7.8
1 (1H, s), 7.60-7.10 (11H, m), 7.00-6.80 (3H, m), 6.69 (1
H, s), 4.87 (2H, s), 4.28 (2H, d).

Example 3 (e) 6-[(2,2-diphenylvinyl) sulfonylamino] naphthyloxyacetic acid

[Chemical formula 66]

Form: white powder; TLC: Rf 0.24 (methanol: methylene chloride = 1: 5); NMR (DMSO-
d ₆ ): δ 10.12 (1H, s), 8.13 (1H, d), 7.50 (1H, s), 7.4
8-7.20 (9H, m), 7.10 (2H, d), 7.02 (2H, d), 6.97 (1H, s),
6.77 (1H, m), 4.84 (2H, s).

Example 3 (f) 5-[(2,2-diphenylvinyl) sulfonylaminomethyl] naphthyloxyacetic acid

[Chemical formula 67]

Shape: white powder; mp: 142-143
_{℃; NMR (DMSO-d 6} ): δ 8.22 (1H, d), 7.77 (1H, t),
7.72 (1H, d), 7.59-7.10 (12H, m), 7.02 (1H, d), 6.94 (1
H, d), 6.76 (1H, s), 4.88 (2H, s), 4.54 (2H, d).

Example 3 (g) 5- [2-[(2-phenylvinyl) sulfonylamino] ethyl] naphthyloxyacetic acid

[Chemical 68]

Form: white powder; mp: 182-184
° C; NMR (CDCl ₃ + CD ₃ OD): δ 8.26 (1H, m), 7.64 (1
H, d), 7.47-7.27 (9H, m), 6.74 (1H, d), 6.63 (1H, d), 4.7
7 (2H, s), 3.34-3.18 (4H, m).

Example 3 (h) 6- [2-[(2-phenylvinyl) sulfonylamino] ethyl] naphthyloxyacetic acid

[Chemical 69]

Shape: white powder; mp: 139-141
° C; NMR (CDCl ₃ + H ₂ O): δ 8.25 (1H, d), 7.62 (1H,
s), 7.42-7.24 (9H, m), 6.64 (1H, d), 6.61 (1H, d), 4.80
(2H, s), 3.38 (2H, t), 3.01 (2H, t).

Example 3 (i) 5-[(2,2-diphenylvinyl) sulfonylamino] naphthyloxyacetic acid

[Chemical 70]

Shape: pale yellow powder; mp: 200-202
° C; NMR (DMSO-d ₆ ): δ 13.08 (1H, brs), 9.93 (1H,
s), 8.19 (1H, dd), 7.86 (1H, d), 7.56-7.14 (15H, m), 7.1
2-7.00 (2H, m), 6.97-6.75 (4H, m), 4.89 (2H, s).

Example 3 (j) 5- [2-[(2,2-diphenylvinyl) sulfonylamino] ethyl] naphthyloxyacetic acid

[Chemical 71]

Shape: white powder; mp: 158-161
° C; NMR (DMSO-d ₆ + CDCl ₃ ): δ 8.17 (1H, m), 7.61
(1H, d), 7.46-7.08 (13H, m), 6.84 (1H, d), 6.76 (1H, s),
4.89 (2H, s), 3.22 (4H, s like).

Example 3 (k) 6- [2-[(2,2-diphenylvinyl) sulfonylamino] ethyl] naphthyloxyacetic acid

[Chemical 72]

Shape: pale yellow powder; mp: 149-151
° C; NMR (DMSO-d ₆ + CDCl ₃ ): δ 8.17 (1H, d), 7.66
(1H, s), 7.50-7.08 (13H, m), 6.84-6.73 (2H, m), 4.82 (2H,
s), 3.26 (2H, m), 2.92 (2H, t).

Example 3 (l) 6-[(2-phenylvinyl) sulfonylamino]-
5,6,7,8-Tetrahydronaphthyloxyacetic acid

[Chemical formula 73]

Form: white powder; mp: 180.5-181.5 ° C .;
NMR (CDCl ₃ + CD ₃ OD): δ 7.60-7.33 (6H, m), 7.05
(1H, t), 6.82 (1H, d), 6.69 (1H, d), 6.57 (1H, d), 4.61 (2
H, s), 3.75-3.60 (1H, m), 3.15-2.60 (4H, m), 2.20-2.00
(1H, m), 1.95-1.70 (1H, m).

Example 3 (m) 6- (naphth-2-yl-sulfonylamino) -5,
6,7,8-Tetrahydronaphthyloxyacetic acid

[Chemical 74]

Form: white powder; mp: 164.6-166.0 ° C;
NMR (CDCl ₃ + CD ₃ OD): δ 8.45 (1H, s), 8.03-7.80
(4H, m), 7.72-7.55 (2H, m), 7.00 (1H, t), 6.56 (1H, d),
6.53 (1H, d), 4.58 (2H, s), 3.75-3.53 (1H, m), 3.00-2.76
(2H, m), 2.75-2.50 (2H, m), 2.00-1.80 (1H, m), 1.80-1.5
5 (1H, m).

Example 3 (n) 6-[(2,2-diphenylvinyl) sulfonylamino] -5,6,7,8-tetrahydronaphthyloxyacetic acid

[Chemical 75]

Form: colorless amorphous; NMR: δ 7.50-7.2
0 (10H, m), 7.05 (1H, t), 6.87 (1H, s), 6.65 (1H, d), 6.55
(1H, d), 4.65 (2H, s), 4.20-3.20 (1H, br), 4.03 (1H, d),
3.59 (1H, m), 3.02-2.40 (4H, m), 2.13-1.74 (1H, m), 1.74
-1.50 (1H, m).

Example 3 (o) 5-[(2-phenylvinyl) sulfonylamino]-
5,6,7,8-Tetrahydronaphthyloxyacetic acid

[Chemical 76]

Form: white powder; mp: 210.7-211.5 ° C .;
NMR (CDCl ₃ + CD ₃ OD): δ 7.60-7.40 (6H, m), 7.17-
7.00 (2H, m), 6.90 (1H, d), 6.62 (1H, dd), 4.62 (2H, s),
4.50 (1H, t), 2.90-2.55 (2H, m), 2.10-1.70 (4H, m).

Example 3 (p) 5-[(2,2-diphenylvinyl) sulfonylamino] -5,6,7,8-tetrahydronaphthyloxyacetic acid

[Chemical 77]

Form: white powder; mp: 184.5-185.3 ° C .;
NMR (CDCl ₃ + CD ₃ OD): δ 7.53-7.20 (10H, m), 7.20
-7.00 (2H, m), 6.90 (1H, s), 6.62 (1H, d), 4.62 (3H, m),
2.88-2.48 (2H, m), 2.10-1.50 (4H, m).

Example 3 (q) 5- (naphth-2-yl-sulfonylamino) -5,
6,7,8-Tetrahydronaphthyloxyacetic acid

[Chemical 78]

Form: white powder; mp: 230.8-231.2 ° C;
NMR (CDCl ₃ + CD ₃ OD): δ 8.50 (1H, s), 8.05-7.85
(4H, m), 7.74-7.58 (2H, m), 6.95 (1H, t), 6.61 (1H, d),
6.56 (1H, d), 4.57 (2H, s), 4.47 (1H, m), 2.88-2.67 (1H,
m), 2.67-2.40 (1H, m), 2.00-1.60 (4H, m).

Example 3 (r) 6-[(2-phenylvinyl) sulfonylaminomethyl] -5,6,7,8-tetrahydronaphthyloxyacetic acid

[Chemical 79]

Shape: white powder; mp: 159-160
° C; NMR: δ 7.45 (6H, m), 7.05 (1H, t), 6.75 (1H,
d), 6.73 (1H, d), 6.55 (1H, d), 4.67 (1H, s).

Example 3 (s) 5- [2-[(2-phenylvinyl) sulfonylamino] ethyl] -5,6,7,8-tetrahydronaphthyloxyacetic acid

[Chemical 80]

Form: white powder; mp: 101.0-103.0 ° C;
NMR: δ 7.55-7.32 (6H, m), 6.99 (1H, d), 6.81-6.68
(2H, m), 6.52 (1H, d), 5.00 (1H, brs), 4.63 (2H, s), 3.15
(2H, m), 2.95-2.51 (4H, m), 2.06-1.53 (6H, m).

Example 3 (t) 5- [3-[(2-phenylvinyl) sulfonylamino] propyl] naphthyloxyacetic acid

[Chemical 81]

TLC: Rf 0.30 (methanol: methylene chloride = 1: 5); NMR (CDCl ₃ + CD ₃ OD): δ 8.12
(1H, dd), 7.47 (1H, d), 7.40-7.10 (9H, m), 6.63 (1H, d),
6.60 (1H, d), 4.65 (2H, s), 2.97 (4H, m), 1.87 (2H, m).

Example 3 (u) 5- [3-[(2,2-diphenylvinyl) sulfonylamino] propyl] naphthyloxyacetic acid

[Chemical formula 82]

TLC: Rf 0.30 (methanol: methylene chloride = 1: 4); NMR (CDCl ₃ + CD ₃ OD): δ 8.25
(1H, d), 7.60-7.15 (14H, m), 6.78 (1H, s), 6.75 (1H, d),
4.78 (2H, s), 3.05-2.82 (4H, m), 1.73 (2H, m).

Example 3 (v) 5-[(2-phenylethyl) sulfonylamino] naphthyloxyacetic acid

[Chemical 83]

TLC: Rf 0.26 (30% methanol /
Chloroform); NMR (CD ₃ OD: CDCl ₃ = 2: 1): δ
8.33 (1H, d), 7.88 (1H, d), 7.64 (1H, d), 7.54-7.42 (2
H, m), 7.30-7.03 (5H, m), 6.87 (1H, d), 4.83 (2H, s), 3.4
0-3.27 (2H, m), 3.18-3.05 (2H, m).

Example 3 (w) 5- [2-[(2-phenylethyl) sulfonylamino] ethyl] naphthyloxyacetic acid

[Chemical 84]

TLC: Rf 0.29 (30% methanol /
Chloroform); NMR (CDCl ₃ : CD ₃ OD = 1: 2): δ
8.31 (1H, m), 7.71 (1H, d), 7.52-7.06 (8H, m), 6.81 (1
H, d), 4.80 (2H, s), 3.48-3.22 (4H, m), 3.17-2.89 (4H,
m).

Example 3 (x) 5- (pentylsulfonylamino) naphthyloxyacetic acid

[Chemical 85]

TLC: Rf 0.26 (30% methanol /
Chloroform); NMR (CD ₃ OD: CDCl ₃ = 2: 1): δ
8.33 (1H, d), 7.84 (1H, d), 7.62 (1H, d), 7.53-7.40 (2
H, m), 6.87 (1H, d), 4.84 (2H, s), 3.14-3.02 (2H, m), 1.9
3-1.74 (2H, m), 1.42-1.16 (4H, m), 0.85 (3H, t).

Example 3 (y) 6-[(2-phenylvinyl) sulfonylaminomethyl] naphth-3-yloxyacetic acid

[Chemical 86]

TLC: Rf 0.19 (25% methanol /
Chloroform); NMR (DMSO-d ₆ ): δ 13.02 (1H, br
s), 7.93 (1H, t), 7.83-7.68 (3H, m), 7.63-7.51 (2H, m),
7.43-7.04 (8H, m), 4.77 (2H, s), 4.26 (2H, d).

Example 3 (z) 5- [2-[(2-phenylethyl) sulfonylamino] ethyl] -7,8-dihydronaphthyloxyacetic acid

[Chemical 87]

TLC: Rf 0.32 (30% methanol /
Chloroform); NMR: δ 7.33-7.07 (6H, m), 6.88
(1H, d,), 6.68 (1H, d), 5.94 (1H, 7), 5.00-4.00 (1H, br
s), 4.65 (2H, s), 4.32 (1H, t), 3.28-2.95 (4H, m), 2.80
(2H, t), 2.65 (2H, t), 2.22 (2H, m).

Example 3 (aa) 5- [2-[(2-phenylvinyl) sulfonylamino] ethyl] -7,8-dihydronaphthyloxyacetic acid

[Chemical 88]

TLC: Rf 0.29 (30% methanol /
Chloroform); NMR (CDCl ₃ : CD ₃ OD = 1: 2): δ
7.54-7.30 (6H, m), 7.04 (1H, t), 6.91 (1H, d), 6.80 (1
H, d), 6.67 (1H, d), 5.95 (1H, t), 4.60 (2H, s), 3.15 (2H,
t), 2.84-2.63 (4H, m), 2.19 (2H, m).

Example 3 (bb) 6-[(2-phenylvinyl) sulfonylaminomethyl] -5,6,7,8-tetrahydronaphth-3-yloxyacetic acid

[Chemical 89]

TLC: Rf 0.24 (30% methanol /
Chloroform); NMR (DMSO-d ₆ ): δ 12.90 (1H, br
s), 7.87-7.64 (2H, m), 7.49-7.26 (5H, m), 7.19 (1H, d),
6.94 (1H, d), 6.67-6.55 (2H, m), 4.55 (2H, s), 2.95-2.27
(6H, m), 2.00-1.74 (2H, m), 1.44-1.20 (1H, m).

Example 3 (cc) 5- [2-[(2,2-diphenylethyl) sulfonylamino] ethyl] naphthyloxyacetic acid

[Chemical 90]

TLC: Rf 0.29 (chloroform: methanol = 5: 1); NMR (CDCl ₃ + CD ₃ OD): δ 8.09
4 (1H, d), 7.28-7.03 (14H, m), 6.58 (1H, d), 4.50 (1H, t),
4.45 (2H, s), 3.64 (2H, d), 2.89-2.85 (2H, m), 2.79-2.7
5 (2H, m).

Example 3 (dd) 5- [2-[(2-phenylvinyl) sulfonyl-N-
Ethylamino] ethyl] naphthyloxyacetic acid

[Chemical Formula 91]

TLC: Rf 0.50 (chloroform: methanol: acetic acid = 19: 1: 0.1); NMR (DMSO-d ₆ ):
δ 8.16 (1H, dd), 7.75-7.66 (3H, m), 7.50-7.35 (7H, m),
7.25 (1H, d), 6.89 (1H, d), 4.87 (2H, s), 3.60-3.30 (4H,
m), 3.28 (2H, q), 1.14 (3H, t).

Example 3 (ee) 5- [2-[(2-phenylvinyl) sulfonyl-N-
Carboxymethylamino] ethyl] naphthyloxyacetic acid

[Chemical Formula 92]

TLC: Rf 0.08 (chloroform: methanol = 5: 1); NMR (CD ₃ OD): δ 8.28-8.22 (1
H, m), 7.22 (1H, d), 7.50-7.32 (9H, m), 6.84 (1H, d), 6.7
9 (1H, d), 4.80 (2H, s), 4.07 (2H, s), 3.60-3.51 (2H, m),
3.44-3.35 (2H, m).

Example 3 (ff) 6-[(2-phenylvinyl) sulfonylamino]-
5,6,7,8-Tetrahydrophenanthren-1-yloxyacetic acid

[Chemical formula 93] Using the compound produced in Example 2, the same operation as in Example 3 was carried out to obtain the title compound having the following physical properties.

TLC: Rf 0.21 (30% methanol /
Chloroform); NMR (DMSO-d ₆ ): δ 12.96 (1H, br
s), 8.04 (1H, d), 7.75-7.55 (3H, m), 7.50-7.15 (8H, m),
6.81 (1H, d), 4.81 (2H, s), 3.78-3.30 (2H, m), 3.07-2.81
(3H, m), 2.21-2.03 (1H, m), 1.94-1.68 (1H, m).

Examples 3 (gg) to 3 (11) Using the compounds prepared in Reference Example 8 or Reference Example 9,
Example 2 → Reference Example 5 → Reference Example 6 → Reference Example 7 is carried out in the same manner as in Example 3 or using the corresponding compound.
→ Reference Example 8 → Example 2 → Example 3 or Reference Example 5 →
The same operations as in Reference Example 6 → Reference Example 9 → Example 2 → Example 3 were performed to obtain a compound having the following physical properties.

Example 3 (gg) 5- [2-[[2- (4-methoxyphenyl) -2-phenylethyl] sulfonylamino] ethyl] naphthyloxyacetic acid

[Chemical 94]

TLC: Rf 0.30 (25% methanol /
Chloroform); NMR (DMSO-d ₆ ): δ 8.17 (1H, d),
7.59-7.05 (11H, m), 6.91-6.72 (3H, m), 4.72 (2H, s), 4.
37 (1H, t), 4.20-3.20 (7H, m), 3.15-3.00 (4H, m).

Example 3 (hh) 5- [2-[(2-phenylpropyl) sulfonylamino] ethyl] naphthyloxyacetic acid

[Chemical 95]

TLC: Rf 0.26 (25% methanol /
Chloroform); NMR (DMSO-d ₆ ): δ 8.16 (1H, m),
7.70-7.11 (9H, m), 6.89 (1H, d), 4.86 (2H, s), 3.80-2.9
0 (9H, m), 1.50 (3H, d).

Example 3 (ii) 5- [2-[(2-cyclohexyl-2-phenylethyl) sulfonylamino] ethyl] naphthyloxyacetic acid

[Chemical 96]

TLC: Rf 0.32 (25% methanol /
Chloroform); NMR (DMSO-d6): δ 8.18 (1H, d),
7.60-6.80 (11H, m), 4.88 (2H, s), 3.60-2.80 (8H, m), 2.0
0-0.50 (11H, m).

Example 3 (jj) 5- [2-[[2- (4-methoxyphenyl) vinyl]]
Sulfonylamino] ethyl] naphthyloxyacetic acid

[Chemical 97]

TLC: Rf 0.38 (chloroform: methanol: acetic acid = 19: 1: 0.1); NMR (DMSO-d ₆ ):
δ 8.20-8.10 (1H, m), 7.68-7.57 (3H, m), 7.48-7.25 (5
H, m), 7.00-6.83 (4H, m), 4.85 (2H, s), 3.79 (3H, s), 3.5
0-3.10 (4H, m).

Example 3 (kk) 5- [2-[[2- (4-chlorophenyl) -2-phenylvinyl] sulfonylamino] ethyl] naphthyloxyacetic acid

[Chemical 98]

TLC: Rf 0.49 (chloroform: methanol: acetic acid = 19: 1: 0.1); NMR (DMSO-d ₆ ):
δ 8.20-8.10 (1H, m), 7.62-7.52 (1H, m), 7.50-7.08 (13
H, m), 6.90-6.78 (2H, m), 4.70 (2H, s), 3.30-3.10 (4H,
m).

Example 3 (ll) 5- [2-[[2- (4-chlorophenyl) vinyl] sulfonylamino] ethyl] naphthyloxyacetic acid

[Chemical 99]

TLC: Rf 0.25 (chloroform: methanol = 3: 1); NMR: δ 8.33-8.26 (1H, m), 7.5
7 (1H, d), 7.45-7.20 (8H, m), 6.69 (1H, d), 6.37 (1H, d),
4.77 (2H, s), 4.60-4.50 (1H, br.), 3.52-3.28 (4H, m).

Reference Example 10

[Chemical 100]

5-Hydroxynaphthalenesulfonic acid sodium salt (10 g) in dimethylformamide (50 m)
l) Sodium carbonate (6.46 g) and methyl bromoacetate (9.32 g) were added to the solution. 100 reaction mixture
The mixture was stirred at 0 ° C for 10 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue is dimethylformamide (50 m
1), thionyl chloride (9.67 g) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. After the reaction, water (100
ml) was added and filtered. Wash the residue with hexane,
After drying, the title compound having the following physical properties was obtained. TL
C: Rf 0.17 (ethyl acetate: hexane = 1: 5); N
MR: δ 8.83 (1H, d), 8.46-8.35 (2H, m), 7.68 (1H, t),
7.62 (1H, t), 6.92 (1H, d), 4.87 (2H, s), 3.84 (3H, s).

Example 4 Methyl 5- [N- (2-phenylethyl) sulfamoyl] naphthyloxyacetate

[Chemical 101]

Compound synthesized in Reference Example 10 (0.315 g)
Was added dropwise to a solution of 2-phenylethylamine (0.158 g) in methylene chloride (10 ml) and triethylamine (0.395 g). The reaction solution was stirred at room temperature for 4 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and water,
It was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization (ethyl acetate-hexane) to give the title compound (0.279 g) having the following physical data. Shape: pale yellow powder; mp: 97.5-98.5 ° C; NMR: δ
8.67 (1H, d), 8.27 (1H, d), 8.12 (1H, d), 7.56 (1H, t), 7.
47 (1H, t), 7.20-7.10 (3H, m), 6.96-6.87 (2H, m), 6.81 (1
H, d), 4.87 (2H, s), 4.55 (1H, t), 3.84 (3H, s), 3.17 (2H,
dt), 2.65 (2H, t).

Reference Example 11

[Chemical 102]

To a solution of N- (2,2-diphenylethyl) methanesulfonamide (5.51 g) in THF (60 ml) and TMEDA (12.1 ml) was added -78 n-butyllithium (1.66M hexane solution; 24.1 ml). Dropwise at ° C. Stir the mixture until it reaches -20 ° C, then again at -70 ° C.
Cooled to. A solution of 5-aldehyde-1-methoxynaphthalene (3.72 g) in THF (20 ml) was added to the above mixture-
Slowly added at 50 ° C and the mixture was stirred until it was -15 ° C. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated to give the title compound (6.64 g) having the following physical data. TLC: Rf 0.37 (hexane: ethyl acetate = 2: 1); NMR: δ 8.29 (1H, d,), 7.70 (1H, d), 7.54-7.38 (3H,
m), 7.38-7.13 (10H, m), 6.84 (1H, d), 5.95 (1H, m), 4.45
(1H, t), 4.19 (1H, t), 4.00 (3H, s), 3.74 (2H, t), 3.42-
3.23 (2H, m).

Reference Example 12

[Chemical 103]

Compound (130 g) prepared in Reference Example 11
To a methylene chloride (870 ml) and trifluoroacetic acid (271 ml) solution of was added triethylsilane (81.9 g) at room temperature. After stirring the mixture at room temperature for 15 hours, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 6 → 1 :).
Purified in 3) and having the following physical properties, the title compound (95.1
g) was obtained. TLC: Rf 0.43 (ethyl acetate: hexane = 1: 1
2); NMR: δ 8.23 (1H, d), 7.55-7.10 (15H, m), 6.8
5 (1H, d), 4.08-3.93 (4H, m), 3.58 (2H, dd), 3.53-3.37 (2
H, m), 3.37-3.22 (2H, m).

Reference Example 13

[Chemical 104]

To a solution of the compound (94.0 g) prepared in Reference Example 12 in methylene chloride (700 ml) was added a solution of tribromoboron (158.6 g) in methylene chloride (300 ml) at -3.
Added at 0 ° C. The mixture was stirred for 2 hours until it reached 0 ° C. The reaction mixture was poured into ice water. The suspension was filtered, and the obtained white crude crystals were washed with water and ether and dried to obtain the title compound (76.9 g). The combined filtrate was extracted with methylene chloride. The organic layer was washed with water, dried over sodium sulfate, and then concentrated to obtain the title compound (9.0 g; total 85.9 g) having the following physical properties. TLC: Rf 0.26 (ethyl acetate: hexane = 1: 1
2); NMR: δ 8.20 (1H, d), 7.50-7.10 (14H, m), 6.8
7 (1H, d), 4.05 (1H, t), 3.59 (2H, d), 3.50-3.37 (2H, m),
3.37-3.20 (2H, m).

Example 5 Methyl 5- [2- [N- (2,2-diphenylethyl) sulfamoyl] ethyl] naphthyloxyacetate

[Chemical 105]

A solution of the compound (2.99 g) produced in Reference Example 13 in DMF (70 ml) was added with sodium carbonate (1.10 g).
And bromoacetic acid methyl ester (1.59 g) were added.
The mixture was stirred at 100 ° C. overnight. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: benzene = 1: 10) to obtain the title compound (2.33 g) having the following physical properties. TLC: Rf 0.23 (ethyl acetate: hexane = 1: 1
2); NMR: δ 8.32 (1H, d), 7.57 (1H, d), 7.50-7.07
(13H, m), 6.74 (1H, d), 4.83 (2H, s), 4.15-3.93 (2H, m),
3.82 (3H, s), 3.61 (2H, t), 3.53-3.35 (2H, m), 3.35-3.20
(2H, m).

Example 6 5- [N- (2-phenylethyl) sulfamoyl] naphthyloxyacetic acid

[Chemical formula 106]

2N aqueous sodium hydroxide solution (1.5 ml) was added to a solution of the compound (0.256 g) synthesized in Example 4 in methanol-dimethoxyethane (2 ml to 5 ml). The reaction solution was stirred at room temperature for 3 hours. 2N in reaction solution
The mixture was neutralized by adding hydrochloric acid. The resulting white precipitate was collected by filtration, washed with water and ether, and dried under reduced pressure to give the title compound (0.125 g) having the following physical data. Shape: White powder; mp: 174.4-176.2 ° C; NMR (CDCl
₃ + CD ₃ OD): δ 8.68 (1H, d), 8.23 (1H, d), 8.13 (1H,
d), 7.53 (1H, t), 7.50 (1H, t), 7.23-7.07 (3H, m), 7.00-
6.80 (3H, m), 4.83 (2H, s), 3.13 (2H, t), 2.63 (2H, t).

Examples 6 (a) to (d) By the same operations as in Reference Example 10, Examples 4 and 6, compounds having the following physical properties were obtained.

Example 6 (a) 5- (N-phenylmethylsulfamoyl) naphthyloxyacetic acid

[Chemical formula 107]

Form: white powder; mp: 200.2-201.7 ° C;
NMR (CDCl ₃ + CD ₃ OD): δ 8.67 (1H, d), 8.25 (2H,
d), 7.54 (1H, t), 7.50 (1H, t), 7.20-7.00 (5H, m), 6.89
(1H, d), 4.83 (2H, s), 4.03 (2H, s).

Example 6 (b) 5- [N- (2,2-diphenylethyl) sulfamoyl] naphthyloxyacetic acid

[Chemical 108]

Form: white powder; mp: 198.7-199.0 ° C;
NMR (CDCl ₃ + CD ₃ OD): δ 8.73 (1H, d), 8.28 (1H,
d), 8.00 (1H, d), 7.57 (1H, t), 7.42 (1H, t), 7.25-7.07
(6H, m), 7.00-6.83 (5H, m), 4.87 (2H, s), 4.00-3.68 (1H,
m), 3.48 (2H, d).

Example 6 (c) 5- [N- (4-phenylbutyl) sulfamoyl] naphthyloxyacetic acid

[Chemical 109]

Form: white powder; mp: 162.1-164.5 ° C;
NMR (CDCl ₃ + CD ₃ OD): δ 8.67 (1H, d), 8.23 (2H,
d), 7.53 (2H, t), 7.28-7.07 (3H, m), 7.00 (2H, d), 6.88
(1H, d), 4.83 (2H, s), 2.87 (2H, t), 2.43 (2H, t), 1.60-
1.27 (4H, m).

Example 6 (d) 6-[(2,2-diphenylethyl) sulfamoyl]
-5,6,7,8-Tetrahydrophenanthrene-1-
Iloxyacetic acid

[Chemical 110]

Examples (e) to (f) Using the compounds prepared in Example 5, the same operation as in Example 6 was carried out, or the corresponding compounds were used in Reference Example 11 → Reference Example 12 → The following compounds were obtained by the same procedure as in Reference Example 13 → Example 5 → Example 6.

Example 6 (e) 5- [2- [N- (2-phenylethyl) sulfamoyl] ethyl] naphthyloxyacetic acid

[Chemical 111] TLC: Rf 0.15 (methanol: methylene chloride = 1: 1
5); NMR (CDCl ₃ -CD ₃ OD): δ 8.32 (1H, d), 7.57
(1H, d), 7.47-7.10 (8H, m), 6.78 (1H, d), 4.80 (2H, s),
3.53-3.35 (2H, m), 3.35-3.20 (4H, m), 2.78 (2H, t).

Example 6 (f) 5- [2- [N- (2,2-diphenylethyl) sulfamoyl] ethyl] naphthyloxyacetic acid

[Chemical 112] TLC: Rf 0.21 (methanol: methylene chloride = 1: 1
5); NMR (DMSO-d ₆ ): δ 8.17 (1H, d), 7.57-7.10
(14H, m), 6.91 (1H, d), 4.89 (2H, s), 4.18 (1H, t), 3.67
(2H, m), 3.60-3.00 (4H, m).

Example 7 5- [2-[(2-phenylvinyl) sulfonylamino] ethyl] -1-dimethylaminocarbonylmethyloxynaphthalene

[Chemical 113]

THF of the compound of Example 2 (g) (0.061 g) produced in the same manner as in Reference Examples 1 and 2 and Example 1
To the solution (0.5 ml), 50% dimethylamine aqueous solution (0.1
ml) was added and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) and recrystallized from chloroform-diethyl ether to obtain the title compound (0.051 g) having the following physical properties. TLC: Rf 0.60 (chloroform: methanol = 9:
1); NMR: δ 8.24 (1H, dd), 7.58 (1H, d), 7.45-7.
26 (9H, m), 6.84 (1H, d), 6.54 (1H, d), 4.85 (2H, s), 4.47
(1H, t), 3.43 (2H, t), 3.32 (2H, t), 3.13 (3H, s), 3.00 (3
H, s).

Example 7 (a)-(b) The following compounds were obtained in the same manner as in Example 7.

Example 7 (a) 5- [2-[(2-phenylvinyl) sulfonylamino] ethyl] naphthaleneoxyacetamide

[Chemical 114] TLC: Rf 0.59 (chloroform: methanol = 9:
1); NMR: δ 8.14 (1H, dd), 7.66 (1H, d), 7.48-7.
32 (9H, m), 6.78 (1H, d), 6.55 (1H, d), 4.63 (2H, s), 3.42
-3.30 (4H, m).

Example 7 (b) 5- [2-[(2-phenylvinyl) sulfonylamino] ethyl] -1- (2-hydroxyethyl) aminocarbonylmethyloxynaphthalene

[Chemical 115] TLC: Rf 0.50 (chloroform: methanol = 9:
1); NMR (CDCl ₃ + CD ₃ OD): δ 8.16 (1H, dd), 7.65
(1H, d), 7.48-7.28 (9H, m), 6.76 (1H, d), 6.55 (1H, d),
5.40 (1H, t), 4.64 (2H, s), 3.73 (2H, t), 3.53 (2H, t), 3.
44-3.29 (4H, m).

Example 8 5- [2-[(2-phenylvinyl) sulfonylamino] ethyl] -1- (2-hydroxyethyl) oxynaphthalene

[Chemical formula 116] Methanol-THF of the compound of Example 2 (g) (0.118 g) produced in the same manner as in Reference Examples 1 and 2 and Example 1.
Sodium borohydride (0.057 g) was added to the solution (2 ml-1 ml) under ice cooling, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (0.106 g) having the following physical data. TLC: Rf 0.15 (hexane: ethyl acetate = 2:
1); NMR (DMSO-d ₆ ): δ 8.204 (1H, dd), 7.72-7.
57 (4H, m), 7.49-7.34 (6H, m), 7.16 (1H, d), 6.97 (1H, d),
5.01 (1H, t), 4.17 (2H, t), 3.90 (2H, t), 3.38-3.35 (1H,
m), 3.28-3.26 (4H, m).

Formulation Example 1 The following components were admixed in a conventional method and punched out to give 100 tablets each containing 5 mg of active ingredient.・ 5-[(2-Phenylvinyl) sulfonylaminomethyl] naphthyloxyacetic acid …………………… 500mg ・ Carboxymethylcellulose calcium …………
………… 200 mg ・ Magnesium stearate ………………………………
………… 100mg ・ Microcrystalline cellulose …………………………………………
………… 9.2g

[Chemical 98]

[Chemical 98]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/215 ACJ 9454-4C C07C 303/38 7419-4H 311/07 7419-4H 311/13 7419 -4H 311/28 7419-4H

Claims (10)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ is —COOR ⁴ (in the group, R ⁴ represents a hydrogen atom or a C1-4 alkyl group), —CONR ⁵ R ⁶
(In the group, R ⁵ and R ⁶ are each independently a hydrogen atom,
It represents a C1-4 alkyl group or a C1-4 alkyl group in which one hydroxyl group is substituted. ) Or —CH ₂ OH
Is represented by Is (In the group, A represents a single bond or a C1-4 alkylene group.) Or (In the group, A is of the formula: (In the group, m represents 0, 1, 2, 3, 4, n is 0,
1, 2, 3, and 4, and m + n represents 2, 3, and 4. Represents a group represented by), B is -NR ³ SO ₂ - or -SO ₂ NR ³ - (in group, R ³ is a hydrogen atom, C1 -4
Or -CH ₂ COOR ⁷ (in the group, R ⁷ represents a hydrogen atom or R ^4a (in the group, R ^4a represents a C1-4 alkyl group)) and R ² represents (i. ) C1
~ 6 alkyl group, C2-6 alkenyl group or C2
~ 6 alkynyl group, (ii) 1, 2 or 3 phenyl groups, C4-7 cycloalkyl group, or C1-4
Alkyl group, a C1-4 alkoxy group, or a C1-6 alkyl group substituted by a phenyl group substituted with 1, 2 or 3 substituents selected from halogen atoms, a C2-6 alkenyl group, or A C2-6 alkynyl group or (iii) a naphthyl group, Represents a single bond or a double bond. ) Or a non-toxic salt thereof. 2. The formula: The compound according to claim 1, wherein A has the same meaning as in claim 1. 3. The formula: The compound according to claim 1, wherein A has the same meaning as in claim 1. 4. The compound according to claim 1, wherein B is —NR ³ SO ₂ (wherein R ³ has the same meaning as in claim 1). 5. The compound according to claim 1, wherein B is —SO ₂ NR ³ (wherein R ³ has the same meaning as in claim 1). 6. The compound is (1) 5-[(2-phenylvinyl) sulfonylaminomethyl] naphthyloxyacetic acid,
(2) 5-[(2-phenylvinyl) sulfonylaminomethyl] naphthyloxyacetate methyl, (3) 5-[(2-phenylvinyl) sulfonylamino] naphthyloxyacetic acid, (4) 6-[(2-phenyl Vinyl) sulfonylamino] naphthyloxyacetic acid, (5) 6-[(2-phenylvinyl) sulfonylaminomethyl] naphthyloxyacetic acid,
(6) 6-[(2,2-diphenylvinyl) sulfonylaminomethyl] naphthyloxyacetic acid, (7) 6-[(2,2
-Diphenylvinyl) sulfonylamino] naphthyloxyacetic acid, (8) 5-[(2,2-diphenylvinyl) sulfonylaminomethyl] naphthyloxyacetic acid, (9) 5-
[2-[(2-phenylvinyl) sulfonylamino] ethyl] naphthyloxyacetic acid, (10) 6- [2-[(2-
Phenylvinyl) sulfonylamino] ethyl] naphthyloxyacetic acid, (11) 5-[(2,2-diphenylvinyl) sulfonylamino] naphthyloxyacetic acid, (12) 5
-[2-[(2,2-Diphenylvinyl) sulfonylamino] ethyl] naphthyloxyacetic acid, (13) 6- [2-
[(2,2-Diphenylvinyl) sulfonylamino] ethyl] naphthyloxyacetic acid, (14) 6-[(2-phenylvinyl) sulfonylamino] -5,6,7,8-tetrahydronaphthyloxyacetic acid, (15) 6- (Naft-2
-Yl-sulfonylamino) -5,6,7,8-tetrahydronaphthyloxyacetic acid, (16) 6-[(2,2-diphenylvinyl) sulfonylamino] -5,6,7,8
-Tetrahydronaphthyloxyacetic acid, (17) 5-[(2
-Phenylvinyl) sulfonylamino] -5,6,7,
8-tetrahydronaphthyloxyacetic acid, (18) 5-
[(2,2-Diphenylvinyl) sulfonylamino]-
5,6,7,8-tetrahydronaphthyloxyacetic acid, (1
9) 5- (naphth-2-yl-sulfonylamino)-
5,6,7,8-Tetrahydronaphthyloxyacetic acid, (2
0) 6-[(2-phenylvinyl) sulfonylaminomethyl] -5,6,7,8-tetrahydronaphthyloxyacetic acid, (21) 5- [2-[(2-phenylvinyl) sulfonylamino] ethyl]- 5,6,7,8-Tetrahydronaphthyloxyacetic acid, (22) 5- [3-[(2-phenylvinyl) sulfonylamino] propyl] naphthyloxyacetic acid, (23) 5- [3-[(2,2 -Diphenylvinyl) sulfonylamino] propyl] naphthyloxyacetic acid, (24) 5-[(2-phenylethyl) sulfonylamino] naphthyloxyacetic acid, (25) 5- [2-[(2-
Phenylethyl) sulfonylamino] ethyl] naphthyloxyacetic acid, (26) 5- (pentylsulfonylamino)
Naphthyloxyacetic acid, (27) 6-[(2-phenylvinyl) sulfonylaminomethyl] naphth-3-yloxyacetic acid, (28) 5- [2-[(2-phenylethyl) sulfonylamino] ethyl] -7, 8-dihydronaphthyloxyacetic acid, (29) 5- [2-[(2-phenylvinyl))
Sulfonylamino] ethyl] -7,8-dihydronaphthyloxyacetic acid, (30) 6-[(2-phenylvinyl) sulfonylaminomethyl] -5,6,7,8-tetrahydronaphth-3-yloxyacetic acid, (31 ) 5- [2-
[(2,2-Diphenylethyl) sulfonylamino] ethyl] naphthyloxyacetic acid, (32) 5- [2-[(2-
(Phenylvinyl) sulfonyl-N-ethylamino] ethyl] naphthyloxyacetic acid, (33) 5- [2-[(2-phenylvinyl) sulfonyl-N-carboxymethylamino] ethyl] naphthyloxyacetic acid, (34) 5- [2-
[[2- (4-methoxyphenyl) -2-phenylethyl] sulfonylamino] ethyl] naphthyloxyacetic acid,
(35) 5- [2-[(2-phenylpropyl) sulfonylamino] ethyl] naphthyloxyacetic acid, (36) 5-
[2-[(2-cyclohexyl-2-phenylethyl)
Sulfonylamino] ethyl] naphthyloxyacetic acid, (37)
5- [2-[[2- (4-methoxyphenyl) vinyl] sulfonylamino] ethyl] naphthyloxyacetic acid,
(38) 5- [2-[[2- (4-chlorophenyl) -2
-Phenylvinyl] sulfonylamino] ethyl] naphthyloxyacetic acid, (39) 5- [2-[[2- (4-chlorophenyl) vinyl] sulfonylamino] ethyl] naphthyloxyacetic acid, (40) 5- [2- [ (2-Phenylvinyl) sulfonylamino] ethyl] -1-dimethylaminocarbonylmethyloxynaphthalene, (41) 5- [2-
[(2-Phenylvinyl) sulfonylamino] ethyl]
Naphthaleneoxyacetamide, (42) 5- [2-
[(2-Phenylvinyl) sulfonylamino] ethyl]
-1- (2-hydroxyethyl) aminocarbonylmethyloxynaphthalene, or (43) 5- [2-[(2-
Phenylvinyl) sulfonylamino] ethyl] -1-
The compound according to claim 1, which is (2-hydroxyethyl) oxynaphthalene. 7. The compound is (1) 6-[(2-phenylvinyl) sulfonylamino] -5,6,7,8-tetrahydrophenanthren-1-yloxyacetic acid, or (2).
6-[(2-phenylvinyl) sulfonylamino]-
The compound of claim 1 which is methyl 5,6,7,8-tetrahydrophenanthren-1-yloxyacetate. 8. The compound is (1) 5- [N- (2-phenylethyl) sulfamoyl] naphthyloxyacetic acid, (2)
Methyl 5- [N- (2-phenylethyl) sulfamoyl] naphthyloxyacetate, (3) 5- (N-phenylmethylsulfamoyl) naphthyloxyacetic acid, (4) 5- [N
-(2,2-Diphenylethyl) sulfamoyl] naphthyloxyacetic acid, (5) 5- [N- (4-phenylbutyl) sulfamoyl] naphthyloxyacetic acid, (6) 5-
[2- [N- (2,2-diphenylethyl) sulfamoyl] ethyl] naphthyloxyacetic acid, (7) 5- [2-
[N- (2,2-diphenylethyl) sulfamoyl]
Ethyl] naphthyloxymethyl acetate, or (8) 5-
[2- [N- (2-phenylethyl) sulfamoyl]
The compound according to claim 1, which is ethyl] naphthyloxyacetic acid. 9. The compound according to claim 1, wherein the compound is 6-[(2,2-diphenylethyl) sulfamoyl] -5,6,7,8-tetrahydrophenanthren-1-yloxyacetic acid. 10. A prostaglandin E ₂ antagonist or agonist containing the naphthyloxyacetic acid compound represented by the general formula (I) according to claim 1 or a non-toxic salt thereof as an active ingredient.