JPH07145147A - Benzoic acid derivative or its salt - Google Patents

Abstract

PURPOSE:To obtain a new benzoic acid derivative useful as a testosterone alpha-reductase inhibitor for treating prostatic hypertrophy, prostatic carcinoma, etc. CONSTITUTION:A compound of formula I[R<1a> to R<1g> each is H, an alkyl, an alkenyl, an alkynyl, a halogen, a trihalogenomethyl, OH, an alkoxy, CN, NO2, NH2, a mono- or di-alkylamino; X is O or S; X<2> is O, S, NR<2> (R<2> is an alkyl, an aryl, an N-containing heterocyclic group or an aralkyl which may be substituted ring A is group of formula II to formula XI (R<3> is H, an aryl- substituted alkyl, an alkenyl, an alkynyl, a halogen, a trihalogenomethyl, OH, an alkoxy, CN, NO<2>, NH2, a mono- or dialkylamino, an acyl, a replaceable aryl, a replaceable arylcarbonyl, etc.)] or its salt such as 4-[[1-(4- biphenylmethyl)-1H-indol-5-yl]oxy]-3-chlorobenzonic acid.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel benzoic acid derivative having a testosterone 5α-reductase inhibitory activity and a pharmaceutically acceptable salt thereof, which is useful as a medicine.

[0002]

Testosterone (TS) secreted from testis and adrenal gland is taken up by androgen target cells and then reduced to dihydrotestosterone (DHT) by the action of intracellular 5α-reductase. . The DHT thus produced is believed to be closely associated with the development of benign prostatic hyperplasia and prostate cancer. Furthermore, androgenetic alopecia, occurrence of acne, acne and seborrhea,
It is believed that the enhancement is also due to the excess of DHT and TS.

Therefore, it is considered that suppressing the action of TS reduced to DHT, which has a higher androgenic activity, is extremely effective for diseases such as prostatic hypertrophy, and has conventionally been a testosterone 5α-reductase inhibitory action. Various attempts have been made to study the synthesis of compounds having
Conventionally, steroid type compounds and non-steroid type compounds are known as substances having testosterone 5α-reductase inhibitory activity. Examples of steroid-type compounds include compounds described in JP-B-63-65080, and examples of non-steroid-type compounds include EP-A-511,477 and EP-A-458,207. Each of the compounds represented by the formulas below is described. European Published Patent No. 511,477

[0004]

[Chemical 6]

European Patent Publication No. 458,207

[0006]

[Chemical 7]

[0007] However, although the publication describes that these compounds have a good inhibitory activity against rat-derived testosterone 5α-reductase, they have a sufficient inhibitory effect on human-derived testosterone 5α-reductase. It wasn't.

[0008]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
The benzoic acid derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof which is a non-steroidal type compound having a completely different structure from the above-mentioned conventionally known compound has been conventionally known. The present invention has been completed by recognizing that it has a superior testosterone 5α-reductase inhibitory action as compared with the known non-steroid type compounds.
That is, the compound of the present invention is different from conventionally known non-steroid type compounds in that human-derived testosterone 5
It is a compound having an excellent inhibitory action on α-reductase.

That is, an object of the present invention is to provide a benzoic acid derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[0010]

[Chemical 8]

[The groups in the formula have the following meanings. R ^{1a to} R ^1g : the same or different, hydrogen atom, lower alkyl group, lower alkenyl group, lower alkynyl group, halogen atom, trihalogenomethyl group, hydroxyl group, lower alkoxy group, cyano group, nitro group, amino group or mono- Or di-lower alkylamino group X ¹ : oxygen atom or sulfur atom X ² : oxygen atom, sulfur atom or group represented by the following formula

[0012]

[Chemical 9]

R ^{2 is a} hydrogen atom; a lower alkyl group which may be substituted with a cycloalkyl group or an aryloxy group, wherein the cycloalkyl group or the aryloxy group is
Substituted with a lower alkyl group, lower alkenyl group, lower alkynyl group, halogen atom, trihalogenomethyl group, hydroxyl group, lower alkoxy group, cyano group, nitro group, amino group, mono- or di-lower alkylamino group, aryl group An optionally substituted group; an aryl group or a heterocyclic group containing a nitrogen atom, wherein the aryl group or the heterocyclic group containing a nitrogen atom is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a halogen atom, a trihalogeno group. A group which may be substituted with a methyl group, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group, an amino group or a mono- or di-lower alkylamino group; an aralkyl group which is a lower alkyl group, Lower alkenyl group, lower alkynyl group optionally substituted with aryl group, halogen atom, trihalogeno It may be substituted with a tyl group, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-lower alkylamino group, a cycloalkyl group, an aryl group, an aryloxy group and a biscycloalkyl group. Basis. Ring A: a group represented by the following formula

[0014]

[Chemical 10]

R ^{3 is the} same or different and is a lower alkyl group which may be substituted with a hydrogen atom or an aryl group, a lower alkenyl group, a lower alkynyl group, a halogen atom, a trihalogenomethyl group, a hydroxyl group, a lower alkoxy group, a cyano group. ,
A nitro group, an amino group or a mono- or di-lower alkylamino group, an acyl group, an aryl group, an arylcarbonyl group, wherein the aryl group and the arylcarbonyl group are a lower alkyl group, a lower alkenyl group, a lower alkynyl group, Halogen atom, trihalogenomethyl group, hydroxyl group,
A lower alkoxy group, a cyano group, a nitro group, an amino group or a mono- or di-lower alkylamino group may be substituted, and the aralkyl group is an aralkyl group,
It may be substituted with a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a halogen atom, a trihalogenomethyl group, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group, an amino group or a mono- or di-lower alkylamino group. Good. Alternatively, when R ³ is a group represented by the following formula, which is bonded to the same carbon atom.

[0016]

[Chemical 11]

R ³ together represents an oxo group or a thioxo group. The same applies to the following] In the compound of the present invention, a benzene ring which is condensed with a heterocycle at the p-position or m-position of benzoic acid to form a bicyclic or tricyclic group is bonded via an oxygen atom or a sulfur atom It is a novel compound having chemical structural characteristics.

The compound of the present invention will be described in more detail below. In the definition of the group of the general formula in the present specification, “lower” means a linear or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.

Therefore, the "lower alkyl group" is specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group. Group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, and the like,
Of these, a C ₁ -C ₄ alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group, and particularly a methyl group and an ethyl group are preferable.

The "lower alkenyl group" has 2 to 6 carbon atoms.
Are straight-chain or branched alkenyl groups, specifically vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl group. -1-propenyl group, 2-methylallyl group, 1-methyl-1-propenyl group, 1-methylallyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 3-methyl-1 -Butenyl group, 3-methyl-2-butenyl group, 3-methyl-3-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-
Examples thereof include a hexenyl group, a 3-methyl-1-butenyl group, a 4-hexenyl group, a 5-hexenyl group and the like. Among them, a vinyl group, an allyl group, a C ₂ -C ₄ alkenyl group such as each butenyl group, especially a vinyl group and C ₂ -C ₃ alkenyl groups such as allyl groups are preferred.

The "lower alkynyl group" is a linear or branched alkynyl group having 2 to 6 carbon atoms, and is ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2- Butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 3-methyl-1-butynyl group, 2-methyl- 3-butynyl group, 1
-Methyl-2-butynyl group, 1-methyl-3-butynyl group, 1,1-dimethyl-2-propynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5- hexynyl and the like, preferably ethynyl, 1-propynyl, 2-propynyl group, C ₂ -C ₄ alkynyl groups, such as the butynyl group, ethynyl group and the like are optimally.

The "lower alkoxy group" includes methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy (amyloxy) group, Examples include a pentyloxy group, a tert-pentyloxy group, a neopentyloxy group, a 2-methylbutoxy group, a 1,2-dimethylpropoxy group, a 1-ethylpropoxy group, a hexyloxy group, and a methoxy group, an ethoxy group, C ₁ -C ₃ alkoxy groups such as propoxy group are preferable.

The "halogen atom" is not particularly limited and includes all halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom. Examples of the “trihalogenomethyl group” include a trifluoromethyl group and a trichloromethyl group, with the trifluoromethyl group being particularly preferred. "Mono- or di-lower alkylamino group"
Means a group in which one or two hydrogen atoms of an amino group are substituted with the lower alkyl group. Specifically, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group,
Pentylamino group, isopentylamino group, hexylamino group, isohexylamino group, etc. monoalkylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, dipentylamino group, dihexylamino group And the like, such as di-substituted symmetric dialkylamino group, ethylmethylamino group, methylpropylamino group, ethylpropylamino group, butylmethylamino group, butylethylamino group, butylpropylamino group, and other asymmetric dialkylamino groups. Among them, methylamino group, ethylamino group,
A propylamino group, a dimethylamino group, a diethylamino group, a dipropylamino group and the like are preferable.

Examples of the "aryl group" include monocyclic, bicyclic and tricyclic aryl groups such as phenyl group, naphthyl group, biphenyl group, anthracenyl group and phenanthrenyl group, and among them, phenyl group and naphthyl group. Is preferred. The "aralkyl group" is a group in which any one to three hydrogen atoms of the above lower alkyl group are substituted with the above aryl group, and when exemplified by a phenyl group, a benzyl group, a phenethyl group, a 1-phenylethyl group , 3-phenylpropyl group, 2-phenylpropyl group, 1-phenylpropyl group, 1-methyl-2-phenylethyl group, 4-phenylbutyl group, 2-methyl-3-phenylpropyl group, 5-
Examples thereof include a phenylpentyl group, a 6-phenylpentyl group, a benzhydryl group, and a trityl group. Among them, a benzyl group, a phenethyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group, a 2- (1-naphthyl) ethyl group, 2 −
A (2-naphthyl) ethyl group, a diphenylmethyl group and the like are preferable.

Specific examples of the "cycloalkyl group" include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group, among which a cyclopentyl group, a cyclohexyl group and a cycloheptyl group. Is preferred. The "aryloxy group" means a monocyclic, bicyclic or tricyclic aryl group such as a phenyloxy group, a naphthyloxy group, a biphenyloxy group, an anthracenyloxy group or a phenanthrenyloxy group, and oxygen. Examples include groups in which atoms are bonded,
Of these, a phenyloxy group and a naphthyloxy group are preferable. Examples of the “biscycloalkyl group” include an adamantyl group, a decalin group, a norbornyl group and the like. Examples of the “acyl group” include a formyl group, an acetyl group,
A lower alkanoyl group such as a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, and a pivaloyl group, an acyl group such as a benzoyl group, and the like are more preferable, and an acetyl group and a benzoyl group are more preferable.

The compound (I) of the present invention forms a salt with a base. Further, depending on the kind of the substituent, it may form an intramolecular salt, and may further form a salt with an acid.
The present invention also includes pharmaceutically acceptable salts of these compounds, and specific examples of such salts include inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, methylamine, ethylamine and ethanolamine. , Organic bases such as cyclohexylamine, salts with bases such as basic amino acids such as lysine and ornithine, mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, formic acid, acetic acid, Propionic acid, oxalic acid,
Malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid,
Examples thereof include an acid addition salt with an organic acid such as malic acid, tartaric acid, citric acid, carbonic acid, methanesulfonic acid and ethanesulfonic acid, and an acid such as acidic amino acid such as aspartic acid and glutamic acid, and an ammonium salt.

Compound (I) and pharmaceutically acceptable salts thereof, depending on the kind of the substituent, are optical isomers based on the presence of an asymmetric carbon atom and geometric isomerism based on the presence of a double bond. Body and various isomers such as keto-enol tautomers. The present invention also includes isolated isomers and mixtures thereof. In addition, the compound of the present invention may be isolated as a hydrate, a solvate such as ethanol, or a crystalline polymorph, and the present invention also includes a substance of such a hydrate, a solvate or a crystalline polymorph. Be done. In the compound of the present invention, the ring A is preferably a group represented by the following formula.

[0028]

[Chemical 12]

Further, a compound in which R ^1a is a halogen atom and R ^{1b to} R ^1g are hydrogen atoms is more preferable.

(Production Method of Compound) Compound (I) of the Present Invention
The compounds (a) to (IV) can be produced by applying various synthesizing methods by utilizing the characteristics based on the basic skeleton or the kind of the substituent. The typical manufacturing method is shown below. First manufacturing method

[0031]

[Chemical 13]

The pharmaceutical compound (I) of the present invention can be produced by hydrolyzing the corresponding nitrile compound (II). The reaction can be carried out by a conventional method, and heating, preferably heating and refluxing, in a concentrated alkali such as sodium hydroxide or potassium hydroxide or in a strong acid such as hydrochloric acid, sulfuric acid or phosphoric acid is preferred. As the solvent, an organic solvent that can be mixed with water, such as alcohol such as ethanol, methanol and isopropanol, is usually used. Second manufacturing method

[0033]

[Chemical 14]

(Wherein R ⁴ represents a lower alkyl group or an aralkyl group; the same applies hereinafter) Compound (I) of the present invention
Can also be produced by subjecting the corresponding ester compound (III) to ester hydrolysis or hydrogenolysis. As the lower alkyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group,
Examples of the sec-butyl group, tert-butyl group and the like, and the aralkyl group include groups which are usually used for an ester of a raw material for producing a carboxylic acid such as a benzyl group. In this hydrolysis reaction, a conventional method of hydrolyzing in the presence of a base such as sodium carbonate or sodium hydroxide or an acid such as trifluoroacetic acid or hydrochloric acid, in the case of hydrogenolysis, palladium-carbon, Conventional methods such as catalytic reduction in the presence of a catalyst such as Raney nickel can be applied. Third method

[0035]

[Chemical 15]

The compound (I) of the present invention can also be produced by reacting the corresponding aldehyde compound (IV) with an oxidizing agent. Suitable oxidizing agents used are silver nitrate, silver oxide, potassium permanganate, chromic acid, hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid, and organic peracids such as peracetic acid. The reaction varies depending on the type of oxide, but when silver nitrate is used, for example, it can be carried out by heating, preferably by heating under reflux, in an alkaline aqueous solution of sodium hydroxide, potassium hydroxide or the like. In this case, an organic solvent that can be mixed with water, such as ethanol, methanol and isopropanol, is usually used as the solvent. When an organic peracid is used, it is usually carried out at room temperature in an organic solvent such as chloroform, toluene, alcohols such as methanol and ethanol, and ether.
When hydrogen peroxide is used, it is carried out by reacting hydrogen peroxide or a mixture thereof with an alcohol such as methanol or ethanol, or an ether, and heating if necessary. When hydrogen peroxide is used, it may be effective to use a metal catalyst such as vanadium or molybdenum.

(Other Production Method) The compound of the present invention can also be produced by a conversion reaction thereof in consideration of the characteristics of the substituents R ^{1 to} R ³ and the divalent group such as X ¹ and X ² . For example, the target product (I) can be produced according to the methods described in Examples and Reference Examples or according to these methods. Specifically, for example, (1) reduction (a) synthesis of an alkyl or alkylene compound in which the corresponding alkenyl, alkenylene, alkynyl, or alkynylene compound is catalytically hydrogenated using palladium carbon or the like as a catalyst. (B) Synthesis of an aromatic ring amino compound in which a corresponding aromatic ring nitro compound is catalytically hydrolyzed using palladium carbon or the like as a catalyst. (2) Etherification, thioetherification Synthesis of an ether or thioether compound in which the corresponding alcohol or phenol or thiol or thiophenol is reacted with the corresponding halide in the presence of a base. (3) Hydrolysis Synthesis of carboxylic acid which undergoes alkaline saponification, acidic hydrolysis or hydrogenolysis of the corresponding ester compound. (4) Synthesis of alkenes Synthesis of alkenyl and alkenylene compounds by reacting corresponding aromatic aldehyde compounds with corresponding diethylphosphonates and triphenylphosphine.

(5) N-alkylation Synthesis of secondary or tertiary amino compounds by reacting corresponding halides, sulfonates, aldehydes, ketones with corresponding primary or secondary amino compounds. (6) Oxidation Synthesis of phenol by treating the corresponding aromatic aldehyde compound with organic peracid or hydrogen peroxide. (7) Nitration Synthesis of nitro compounds in which a corresponding aromatic ring compound is reacted with a nitrating agent such as nitronium tetrafluoroborate. A conventional method can be applied to obtain the compound of the present invention. The reaction product obtained by each of the above production methods is isolated and purified as a free compound, its salt or various solvates. The salt can be produced by subjecting it to a usual salt-forming reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization and various chromatographies.

[0039]

The compounds of the present invention are testosterone 5
It has an α-reductase inhibitory activity, particularly a good inhibitory activity against human-derived testosterone 5α-reductase, and is associated with various diseases caused by the effects of prostatic hypertrophy and other male hormones such as prostate cancer and seborrhea. It is useful for treating acne and male pattern baldness. The testosterone 5α-reductase inhibitory action of the compound of the present invention is clear by the test of 5α-reductase inhibitory activity (in vitro) using human prostate as shown below. The test methods are listed below.

(1) Preparation of testosterone 5α-reductase 0.3 was added to human prostate tissue obtained from a benign prostatic hypertrophy patient.
3M sucrose, 1 mM dithiothreitol, 50 μM
10 mM Tris-hydrochloric acid buffer containing NADPH (pH
7.0) was added and the mixture was homogenized with a polytron and a sonicator, and then centrifuged at 140,000 × g. The precipitate thus obtained was mixed with 10 mM Tris-HCl buffer (pH 7.
What was suspended in 0) was used as the enzyme solution.

(2) Measurement of inhibitory activity of testosterone 5α-reductase To 100 μl of the above enzyme solution, 50 mM Tris-HCl buffer (pH 5.0) and dithiothreitol (final concentration) were added.
1 mM), NADPH (final concentration 5 mM), [4- ¹⁴
C] -Testosterone (final concentration 1 μM, 0.04 μ
Ci) and several concentrations of the compound of the present invention were added to make a total volume of 500 μl. This mixture was incubated at 37 ° C. for 60 minutes, 2.0 ml of ethyl acetate was added to stop the enzyme reaction, and testosterone, dihydrotestosterone, 4-androstane-3,17 was used as a carrier.
-Dione, 5α-androstane-3α, 17β-diol was added. Then, centrifugation was performed, and 1.0 ml of the obtained supernatant was concentrated and then separated using silica gel thin layer chromatography (developed with a mixed solution of ethyl acetate and cyclohexane (1: 1)), 4-androstane- 3,1
The spots of 7-dione, dihydrotestosterone and 5α-androstane-3α, 17β-diol were isolated, the radioactivity of each was measured with a liquid scintillation counter, and the inhibition rate was calculated by the following formula. The 50% inhibitory concentration was determined from the results.

[0042]

[Equation 1]

A: Total amount of radioactivity spotted on TLC (when the compound of the present invention is not added) B: Sum of radioactivity amounts of dihydrotestosterone and 5α-androstane-3α, 17β-diol (without addition of the compound of the present invention) A): Total radioactivity amount spotted on TLC (when the compound of the present invention is added) B ′: Sum of radioactivity amounts of dihydrotestosterone and 5α-androstane-3α, 17β-diol (when the compound of the present invention is added) When the compound of the present invention is used for testosterone 5α in human prostate,
-It shows extremely high activity in a test for reductase inhibitory activity, and can be expected to have high clinical utility.

A pharmaceutical composition containing, as an active ingredient, one or more kinds of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a carrier or excipient usually used for formulation. It is prepared using excipients and other additives. Carriers and excipients for formulation include solid or liquid non-toxic pharmaceutical substances. Examples of these are lactose, magnesium stearate, starch, talc, gelatin, agar, pentin, gum arabic, olive oil,
Examples include sesame oil, cocoa butter, ethylene glycol, and other commonly used ones. The administration may be in any form of oral administration such as tablets, pills, capsules, granules and liquids, or parenteral administration such as injections such as intravenous injection and intramuscular injection, suppositories and transdermal agents. . The dose is appropriately determined depending on the individual case in consideration of symptoms, age of the subject, sex and the like. In the case of oral administration, it is usually 0.00
It is 1 mg to 500 mg, preferably 0.01 to 200 mg, and is administered once to several times a day. In addition, depending on the symptoms, when administered transdermally, it is usually 0.0001-50 at a time.
The range of 0 mg is administered once to several times a day. However, the dose is not limited to these ranges, as a smaller dose may be sufficient depending on symptoms and the like.

(Prescription Example) Next, a prescription example of the compound of the present invention as a medicine will be described. Prescription example 1 20 g of the compound (I) of the present invention, 57 g of lactose, and 38 g of corn starch are uniformly mixed. Next, 40 g of a 10% hydroxypropyl cellulose solution is added and wet granulation is performed. After sieving, it is dried. 1 g of magnesium stearate is added to the obtained granulated product and mixed. Tablet using a 7 m / m 5.6 R pestle.

Prescription example 2 15 g of the compound (I) of the present invention, 40 g of crystalline cellulose, 144 g of crystalline lactose, and 1 g of magnesium stearate are uniformly mixed and filled into No. 3 capsule with a capsule filling machine to give a capsule.

[0047]

EXAMPLES Next, the compounds of the present invention and the method for producing the same will be specifically described by way of Examples. As a reference example, a method for producing the raw material compounds used in the examples will be described.

Reference Example 1 5-Benzyloxy-1H-indole (13.4 g,
60.0 mmol) and dimethyl sulfoxide (100 m
1) potassium hydroxide (15.8) at room temperature with stirring.
g, 240 mmol) was added all at once. 1 reaction mixture
After stirring for an hour, benzyl bromide (10.8
g, 63.0 mmol) of dimethyl sulfoxide (50
(ml) solution was added dropwise and stirred for 3 hours. Water was added, the reaction product was extracted with ethyl acetate, the extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. By recrystallizing the obtained crystalline residue with ethanol, 1-benzyl-5-benzyloxy-
1H-indole (16.0 g, 51.0 mmol, 8
5%) as off-white crystals.

Melting point 108-109 ° C. NMR (CDCl ₃ ) δ: 5.08 (s, 2H), 5.26 (s, 2H),
5.45 (d, 1H, J = 3.1 Hz), 6.90 (d
d, 1H, J = 8.5, 2.4 Hz), 7.08-7.
09 (m, 3H), 7.14 (d, 1H, J = 9.2H
z), 7.17 (d, 1H, J = 2.4 Hz), 7.2
3-7.31 (m, 4H), 7.37 (t, 2H, J =
7.3 Hz), 7.45 (d, 2H, J = 7.3 Hz) MS: m / z 313 (M ⁺ ).

Reference Example 2-8 In the same manner as in Reference Example 1, the compound of Reference Example 2-8 shown in Table 1 below was obtained. The physicochemical properties of these compounds are shown in Table 1 below.
Shown in.

Reference Example 9 5-Benzyloxy-1H-indole (4.47 g,
20.0 mmol) and acetic acid (50 ml) at room temperature sodium cyanoborohydride (3.77 g, 60 m)
mol) was added and stirred for 30 minutes. The reaction mixture was poured into ice water and the reaction product was extracted with dichloromethane. The extract was washed successively with 5N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-benzyloxyindoline (4.19 g, 1
8.6 mmol, 93%) was obtained as a yellow oil. NMR (CDCl ₃ ) δ: 2.99 (t, 2H, J = 8.3 Hz), 3.53
(T, 2H, J = 8.3 Hz), 4.98 (s, 2
H), 6.57 (d, 1H, J = 8.3 Hz), 6.6
6 (dd, 1H, J = 8.3, 2.4 Hz), 7.3
7.5 (5H, m) MS: m / z 225 (M ⁺ ).

Reference Example 10 5-Benzyloxyindoline (4.17 g, 18.5)
benzoyl chloride (3.94 g, 28 mmol) was added to a mixture of (mmol) and pyridine (20 ml) at 0 ° C., and 1
Stir for hours. Water was added to the reaction mixture, and the reaction product was extracted with ethyl acetate. The extract was washed successively with 3N hydrochloric acid, water, 1N aqueous sodium hydroxide solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystalline residue was recrystallized from ethyl acetate to give 1-benzoyl-5-benzyloxyindoline (5.26).
g, 16.0 mmol, 86%) was obtained as colorless crystals. Mp _{137-138 ℃ NMR (CDCl 3) δ} : 3.08 (t, 2H, J = 8.0Hz), 4.03
(Br, 2H), 5.04 (br, 2H), 6.85
(S, 1H), 7.3-7.6 (m, 12H) MS: m / z 329 (M ⁺ ).

Reference Example 11 A mixture of 4-methoxyaniline (8.00 g, 65 mmol) and N, N-dimethylaniline (12 ml) was added to 17 parts.
2-Bromoacetophenone (3.98 g, 20.
A mixture of 0 mmol) and N, N-dimethylaniline (7 ml) was added, and the mixture was stirred for 1 hour and allowed to cool. The reaction product was extracted with ethyl acetate, the extract was washed successively with 2N hydrochloric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 9: 1, then 4: 1), and recrystallized from ethyl acetate to give 5-methoxy-2-phenyl-1H-indole. (1.62 g, 7.26 mmol, 36%) was obtained as yellow crystals. Mp _{170-172 ℃ NMR (CDCl 3) δ} : 3.86 (s, 3H), 6.75 (s, 1H),
6.85 (dd, 1H, J = 8.8, 2.4Hz),
7.09 (s, 1H), 7.2-7.3 (m, 2H),
7.42 (dd, 2H, J = 7.8, 7.3 Hz),
7.63 (d, 2H, J = 7.8 Hz), 8.22 (b
r, 1H) MS: m / z 223 (M ⁺ ).

Reference Example 12 N-benzoylpyrrolidine (1.05 g, 6.00 mm)
ol) and 1,2-dichloroethane (6 ml) under heating under reflux with phosphorus oxychloride (2.76 g, 18 mmo).
l) was added and stirred for 40 minutes, then 5-benzyloxy-
1-Methyl-1H-indole (1.42 g, 6.00
(mmol) and 1,2-dichloroethane (4 ml) were added and the mixture was stirred with heating under reflux for 6 hours and allowed to cool. Water was added to the reaction mixture and neutralized with a 1N aqueous sodium hydroxide solution, and the reaction product was extracted with ethyl acetate. Extract the water,
The extract was washed successively with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 1: 4, then 2: 3) to give 3-benzoyl-5-benzyloxy-1-methyl-1H-indole (1. 33 g, 3.90 mmol, 65%) was obtained as colorless crystals.

Melting point 91-92 ° C NMR (CDCl ₃ ) δ: 3.81 (s, 3H), 5.18 (s, 2H),
7.07 (dd, 1H, J = 8.8, 2.4 Hz),
7.26 (s, 1H), 7.32 (t, 1H, J = 7.
3 Hz), 7.40 (dd, 2H, J = 7.8, 6.9)
Hz), 7.5-7.6 (m, 5H), 7.80 (d,
2H, J = 7.5 Hz), 8.08 (d, 1H, J =
2.4 Hz) MS: m / z 341 (M ⁺ ).

Reference Example 13 1-Benzoyl-5-benzyloxyindoline (2.
36 g, 7.16 mmol), methanol (20 m
10% Palladium-carbon (100 mg) was added to a mixture of l) and ethyl acetate (100 ml), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 days. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give 1-
Benzoyl-5-hydroxyindoline (1.58 g,
6.60 mmol, 92%) was obtained as colorless crystals. Mp _{215-217 ℃ NMR (DMSO-d 6} ) δ: 2.99 (t, 3H, J = 8.3Hz), 3.94
(Br, 2H), 6.59 (br, 1H), 6.68
(S, 1H), 7.4-7.5 (m, 4H), 7.5
4,7.90 (each br, 2H in total) MS: m / z 239 (M ⁺ ).

Reference Example 14 1-benzyl-5-hydroxyindoline (359 mg, 1.50 mmol), THF under an argon atmosphere
After adding the boron trifluoride ether complex (426 mg, 3.00 mmol) to the mixture (0.30 ml), 30
Heated to reflux for minutes. Borane dimethyl sulfide complex (0.30 ml, 2.0 mmol) was added to the reaction mixture, the oil bath temperature was raised to 100 ° C., and the solvent was distilled off for 1 hour.
Hydrochloric acid (1 ml) was added, and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was ice-cooled, neutralized with 5N aqueous sodium hydroxide solution, ethyl acetate was added, and the reaction product was extracted. The insoluble material was filtered off, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 9: 1, then 4: 1) to give 1-benzyl-5-hydroxyindoline (221 m).
g, 0.981 mmol, 65%) was obtained as colorless crystals.

Melting point 118-119 ° C. NMR (CDCl ₃ ) δ: 2.90 (br, 2H), 3.23 (br, 2)
H), 4.15, 4.34 (each br, 2H in total),
6.3-6.7 (m, 2H), 7.2-7.4 (m, 6
H) MS: m / z 225 (M ⁺ ).

Reference Example 15 1-benzyl-5-benzyloxy-1H-indole (16.0 g, 51.0 mmo) under an argon atmosphere.
l) A mixture of 10% palladium-carbon (1.6 g) and ethanol (300 ml) was added with ammonium formate (2
5.7 g, 408 mmol) was added all at once. The reaction mixture was stirred at room temperature for 3 hours, the insoluble material was filtered off, and the mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-benzyl-5-hydroxy-1H-indole (10.9 g, 48.9 mmol, 96%). ) Was obtained as off-white crystals.

Melting point 90-92 ° C. NMR (CDCl ₃ ) δ: 4.61 (s, 1H), 5.25 (s, 2H),
6.41 (d, 1H, J = 2.4 Hz), 6.72 (d
d, 1H, J = 8.8, 2.4 Hz), 7.03 (d,
1H, J = 2.4 Hz), 7.07-7.10 (m, 4
H), 7.22-7.30 (m, 3H) MS: m / z 223 (M ⁺ ).

Reference Example 16-18 Reference Example 16-1 shown in Table 1 below in the same manner as Reference Example 15
8 compounds were obtained. The physicochemical properties of these compounds are shown in Table 1 below.

Reference Example 19 5-Methoxy-2-phenyl-1H under an argon atmosphere
-A mixture of indole (670 mg, 3.00 mmol), dichloromethane (5 ml) at -78 ° C in a 1.0 M solution of boron tribromide in dichloromethane (9.0 ml, 9.0).
(mmol) and stirred for 10 minutes, and then stirred at room temperature for 13 hours. The reaction mixture was poured into ice water and the reaction product was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to give 5-hydroxy-2-phenyl-1H-indole (459m).
g, 2.19 mmol, 73%) was obtained as colorless crystals.

Melting point 236-239 ° C NMR (CDCl ₃ ) δ: 5.33 (s, 2H), 6.53 (d, 1H, J =
2.9 Hz), 6.76 (d, 1H, J = 8.3H)
z), 6.88 (dd, 1H, J = 8.8, 2.4H
z), 7.12-7.14 (m, 2H), 7.21.
(D, 1H, J = 2.9 Hz), 7.25-7.37
(M, 6H), 7.71 (d, 1H, J = 2.0Hz) MS: m / z 209 (M ⁺ )

Reference Example 20 In the same manner as in Reference Example 19, 5-hydroxy-2-phenylbenzofuran was obtained. NMR (CDCl ₃ ) δ: 4.67 (br, 1H), 6.79 (dd, 1H,
J = 8.8, 2.4 Hz), 6.93 (d, 1H, J =
1.0 Hz), 6.99 (d, 1H, J = 2.4H
z), 7.33-7.38 (m, 2H), 7.42-
7.46 (m, 2H), 7.83-7.85 (m, 2
H) MS: m / z 210 (M ⁺ )

Reference Example 21 1-Benzyl-5-hydroxy-1H-indole (3.35 g, 15.0 mmol), 3-chloro-4-
Fluorobenzonitrile (2.45g, 15.8mmo
1) and N, N-dimethylformamide (50 ml) were added to potassium carbonate (3.11 g, 2
2.5 mmol) was added all at once. Reaction mixture at 80 ° C
After stirring for 7 hours, the mixture was allowed to cool. Water was added, the reaction product was extracted with ethyl acetate, the extract was washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4- [ (1
-Benzyl-1H-indol-5-yl) oxy]-
3-chlorobenzonitrile (5.67g, 15.0mm
ol, 100%) as a brown oil.

NMR (CDCl ₃ ) δ: 5.33 (s, 2H), 6.53 (d, 1H, J =
2.9 Hz), 6.76 (d, 1H, J = 8.3H)
z), 6.88 (dd, 1H, J = 8.8, 2.4H
z), 7.12-7.14 (m, 2H), 7.21.
(D, 1H, J = 2.9 Hz), 7.25-7.37
(M, 6H), 7.71 (d, 1H, J = 2.0Hz) MS: m / z 358 (M ⁺ )

Reference Example 22-31 Reference Example 22-3 shown in Table 1 below in the same manner as in Reference Example 21.
1 compound was obtained. The physicochemical properties of these compounds are shown in Table 1 below.

Reference Example 32 6-Hydroxyflavone (1.19 g, 5.00 mmo)
l), 3,4-dichlorobenzaldehyde (880 m
g, 5.00 mmol), dimethyl sulfoxide (10
ml) at room temperature under stirring with potassium carbonate (1.04
g, 7.50 mmol) were added all at once. The reaction mixture was stirred at 100 ° C. for 17 hours and then left to cool. Add water,
The reaction product was extracted with ethyl acetate, the extract was washed successively with water, a 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crystalline residue was washed with acetone to give 3-chloro-4-[(4-oxo-2-phenyl-4H-chromen-6-yl) oxy] benzaldehyde (540 mg,
1.43 mmol, 29%) was obtained as brown crystals.

Melting point 188-189 ° C NMR (DMSO-d ₆ ) δ: 7.09 (s, 1H), 7.29 (d, 1H, J =
8.3 Hz), 7.51 (d, 1H, J = 3.0H
z), 7.58-7.66 (m, 3H), 7.71 (d
d, 1H, J = 9.3, 3.0 Hz), 7.91 (d
d, 1H, J = 8.3, 2.0 Hz), 7.95 (d,
1H, J = 9.3 Hz), 8.13-8.18 (m, 3
H), 9.97 (s, 1H) MS: m / z 376 (M ⁺ ).

Reference Example 33 In the same manner as in Reference Example 32, 4- (2-dibenzofuranyloxy) benzaldehyde was obtained. NMR (TMS internal standard in CDCl ₃ ) δ: 7.08 (2H, m), 7.21 (1H, m),
7.34 (1H, m), 7.49 (2H, m), 7.5
9 (2H, m), 7.67 (1H, d), 7.8-7.
9 (3H, m), 9.92 (1H, m) MS: m / z 288 (M ⁺ ).

Reference Example 34 3-Benzoyl-5-benzyloxy-1-methyl-1
A mixture of H-indole (478 mg, 1.40 mmol), ethanol (3 ml), ethyl acetate (10 ml), acetic acid (3 ml) was added with 10% palladium-carbon (50 ml).
mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 days.
The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1) to give 3-benzyl-
5-hydroxy-1-methyl-1H-indole (15
5 mg, 0.653 mmol, 47%) was obtained as a yellow oil. NMR (CDCl ₃ ) δ: 3.69 (s, 3H), 4.03 (s, 2H),
6.74 (s, 1H), 6.78 (dd, 1H, J =
8.3, 2.4 Hz, 6.88 (d, 1H, J = 2.
4 Hz), 7.1-7.3 (m, 6H) MS: m / z 237 (M ⁺ ).

Reference Example 35 Under an argon atmosphere, 2-hydroxy-5-methoxybenzaldehyde (760 mg, 5.00 mmol), α-
Bromophenylacetic acid (1.80 g, 5.00 mmo
1), a mixture of N, N-dimethylformamide (10 ml) at room temperature under stirring with 60% sodium hydride (460 m
g, 11.5 mmol) was added portionwise over 5 minutes. After the reaction mixture was stirred at room temperature for 23 hours, the reaction product was extracted with water, the extract was washed with chloroform, and the mixture was washed with 1N.
The pH was adjusted to <3 with hydrochloric acid. Toluene was added, and the obtained organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol: acetic acid = 95: 4.5: 0.5) to obtain α-[(2-formyl-4-methoxy) phenoxy] phenylacetic acid. (560 mg, 1.96 mmol, 3
9%) as a brown oil.

NMR (CDCl ₃ ) δ: 3.80 (s, 3H), 5.64 (s, 1H),
6.86 (d, 1H, J = 9.3 Hz), 7.04−
7.07 (m, 1H), 7.32 (d, 1H, J = 3.
4 Hz), 7.38-7.45 (m, 3H), 7.56
-7.57 (m, 2H), 10.45 (s, 1H) MS: m / z 286 (M ⁺ ).

Reference Example 36 Triethylamine (710 mg, 7.00 mmol),
p-toluenesulfonyl chloride (670 mg, 3.5
To a mixture of 0 mmol) and toluene (12 ml), a solution of α-[(2-formyl-4-methoxy) phenoxy] phenylacetic acid (500 mg, 1.75 mmol) in toluene (15 ml) was added dropwise with heating under reflux. The reaction mixture was stirred with heating under reflux for 4 hr, allowed to cool, and concentrated under reduced pressure.
Toluene (5 ml) and 1N aqueous sodium hydroxide solution (20 ml) were added to the obtained residue, and the mixture was stirred at room temperature for 15 hr. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. By recrystallizing the obtained crystalline residue with ethanol, 5-methoxy-2-phenylbenzofuran (100 mg, 0.45 m
mol, 26%) was obtained as brown crystals.

Melting point 130-131 ° C NMR (CDCl ₃ ) δ: 3.85 (s, 3H), 6.88 (dd, 1H, J
= 8.8, 2.4 Hz), 6.96 (s, 1H), 7.
04 (d, 1H, J = 2.4 Hz), 7.34 (t, 1
H, J = 7.3 Hz), 7.39-7.46 (m, 3
H), 7.83-7.85 (m, 2H) MS: m / z 224 (M ⁺ ).

Reference Example 37 5-Benzyloxy-1H-indole (6.03 g, 27.0 mmol), THF (50
solution of n-butyllithium in hexane (18.8 ml, 1.6 M, 30 mmo) at -78 ° C with stirring.
l) was added and after stirring at room temperature for 15 minutes the reaction mixture was recooled to -78 ° C. Benzenesulfonyl chloride (3.8 ml, 30 mmol) was added, and the mixture was stirred at -78 ° C for 1 hr and then at room temperature for 3.5 hr. Water was added to the reaction mixture, and the reaction product was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; dichloromethane: hexane = 1: 3) to give 1-benzenesulfonyl-5-benzyloxy-1H-indole (4.
73 g, 13.0 mmol, 48%) was obtained as a yellow oil. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 38 A solution of lithium diisopropylamide in THF (4 ml) prepared from n-butyllithium (4.4 mmol) and diisopropylamine (4.4 mmol) was added to 1-benzenesulfonyl under an argon atmosphere at -78 ° C. -5
Benzyloxy-1H-indole (1.45 g, 4.
00 mmol) in THF (4 ml) was added,
The mixture was stirred at 20 ° C for 0.5 hours. After recooling the reaction mixture to -78 ° C, benzaldehyde (0.45 ml, 4.
4 mmol) was added, and the mixture was stirred at −78 ° C. for 10 minutes and then at 0 ° C. for 1.5 hours. 1N hydrochloric acid was added to the reaction mixture, and the reaction product was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; hexane: ethyl acetate =
4: 1), 5-benzyloxy-1-benzenesulfonyl-2- (α-hydroxybenzyl) -1H
-Indole (1.44 g, 2.90 mmol, 77
%) As a yellow oil. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 39 1-Benzenesulfonyl-5-benzyloxy-1H-indole (1.35 g, 3.7 m) under an argon atmosphere.
mol) and a solution of THF (7 ml) under stirring at -78 ° C in a hexane solution of n-butyllithium (2.8 ml, 1.
6M, 4.4 mmol) was added. After stirring under ice cooling for 10 minutes, the reaction mixture was recooled to -78 ° C. Benzoyl chloride (1.4 ml, 11.0 mmol) was added,
The mixture was stirred at 78 ° C. for 10 minutes, and then under ice cooling for 20 minutes.
The reaction mixture was poured into ice water and the reaction product was extracted with ethyl acetate. The extract is a 1N aqueous sodium hydroxide solution, water,
The extract was washed successively with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethanol (20 ml) and 5N aqueous sodium hydroxide solution (6 m
1) was added, the mixture was heated with stirring at 60 ° C. for 3 days, and then allowed to cool to room temperature. Water was added to the reaction mixture, and the reaction product was extracted with ethyl acetate. The extract was washed with a 1N aqueous sodium hydroxide solution, water and saturated brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate / ethanol to give 2-benzoyl-5-benzyloxy-1H-indole (719 mg, 2.2.
0 mmol, 59%) was obtained as yellow crystals. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 40 1-Benzenesulfonyl-5-benzyloxy-2-
(Α-Hydroxybenzyl) -1H-indole (54
A 5N aqueous sodium hydroxide solution (1 ml) was added to a mixture of 0 mg, 1.15 mmol) and ethanol (5 ml), and the mixture was stirred at room temperature for 7 hours. After neutralizing the reaction mixture by adding 1N hydrochloric acid, the reaction product was extracted with ethyl acetate.
The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate (20 ml), methanol (10 ml) and 10% to the obtained residue.
Palladium-carbon (200 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 days. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 2-benzyl-5-hydroxy-1H-indole (224 mg, 1.00 mmol, 87%) as a yellow oil. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 41 4-isopropylphenyl methyl ketone (1.62
g, 9.99 mmol), dichloromethane (12 m
phenyltrimethylammonium tribromide (4.l) and methanol (4.8 ml) at room temperature with stirring.
14 g, 11.0 mmol) were added all at once. The reaction mixture was stirred at room temperature for 10 hours, water was added, the reaction product was extracted with chloroform, the extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ether = 98: 2) to give bromomethyl 4-isopropylphenyl ketone (1.65 g, 6.84 mmo).
1, 68%) as a pale yellow oil. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 42 Bromomethyl was added to a mixture of 4-methoxyaniline (2.02 g, 16.4 mmol) and N, N-dimethylaniline (3 ml) heated under reflux in an argon atmosphere while stirring.
4-Isopropylphenyl ketone (1.32 g, 5.
47 mmol) and N, N-dimethylaniline (3 ml)
The mixture was added dropwise, and the oil bath temperature was maintained at 170 ° C., followed by stirring for 3 hours. The reaction mixture was allowed to cool, diluted with ethyl acetate, 1N hydrochloric acid was added, and the reaction product was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ether = 9: 1) and then recrystallized from ethanol to give 2- (4-isopropylphenyl) -5-methoxy-1H-indole. (0.528
g, 1.99 mmol, 36%) was obtained as pale yellow crystals. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 43 5-Benzyloxindole (2.23 g, 10.0
mmol), di-tert-butyl dicarbonate (2.62 g, 12.0 mmol), and acetonitrile (20 ml) were added 4-dimethylaminopyridine (120 mg, 1.00 mmol) all at once at room temperature with stirring. The reaction mixture was stirred at room temperature for 3 hours, water was added, and the reaction product was extracted with ethyl acetate. Extract the water,
The extract was washed successively with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 97: 3) to give 5-benzyloxy-1-t.
ert-butoxycarbonyl-1H-indole (2.
86 g, 8.85 mmol, 89%) was obtained as a colorless oil. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 44 4-[(2-benzyl-1H-indol-5-yl)
Oxy] -3-chlorobenzonitrile (115 mg,
0.320 mmol), methyl iodide (228 mg,
Potassium hydroxide (90 mg, 1.6 mmol) was added to a mixture of 1.00 mmol) and DMSO (1.5 ml), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the reaction product was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-[(2-benzyl-1-methyl-1H-indol-5-yl) oxy] -3-. Chlorobenzonitrile (116 mg, 0.311 mmol, 97%) was obtained as colorless crystals. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 45-78 In the same manner as Reference Example 44, Reference Example 45-7 shown in Table 1 below.
8 compounds were obtained. The physicochemical properties of these compounds are shown in Table 1 below.

Reference Example 79 Ground potassium hydroxide (502 mg, 8.96 mmo)
l), DMSO (8 ml) in a mixture with stirring at room temperature
Chloro-4-[(1H-indol-5-yl) oxy] benzonitrile (600 mg, 2.24 mmol)
Was added all at once. The reaction mixture was stirred at room temperature for 40 minutes, then cyclopentylmethyl p-toluenesulfonate (285 mg, 1.12 mmol), DMSO (1.5
(ml) mixture was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour and at 50 ° C. for 5 hours, allowed to cool, water was added, and the reaction product was extracted with ethyl acetate. Extract the water,
The extract was washed successively with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform) and then recrystallized from ethanol to give 3-chloro-4-[(1-cyclopentylmethyl-1H-indol-5-yl). Oxy] benzamide (104 mg,
0.282 mmol, 25%) was obtained as colorless crystals.
The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 80 5-Benzyloxy-1-ethoxycarbonyl-1H-
A solution of indole (5.38 g, 18.2 mmol) in ethanol (80 ml) was added with 10% palladium-carbon (5
40 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hours. The catalyst was filtered off, and the obtained filtrate was concentrated under reduced pressure to give 1-ethoxycarbonyl-5-hydroxyindoline (3.72 g, 18.0 mmol, 98%) as colorless crystals. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 81 The compound of Reference Example 81 shown in Table 1 below was obtained in the same manner as in Reference Example 80. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 82 5-Benzyloxy-1- (4-isobutylbenzyl)
-1H-indole (19.8g, 53.6mmo
l) 10% palladium-carbon (1.98 g) in ethanol (300 ml) in ammonium formate (27.
0 g, 429 mmol) was added all at once at room temperature, and
Stir for 0 hours. The catalyst was filtered off, the filtrate was concentrated under reduced pressure,
The obtained residue was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate,
By concentrating under reduced pressure, 5-hydroxy-1- (4
-Isobutylbenzyl) -1H-indole (14.7
g, 52.8 mmol, 98%) was obtained as off-white crystals. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 83-92 Reference Example 83-9 shown in Table 1 below in the same manner as in Reference Example 82.
Two compounds were obtained. The physicochemical properties of these compounds are shown in Table 1 below.

Reference Example 93 1- (4-biphenylylmethyl) -5-methoxy-2-
Methyl-1H-indole (980mg, 3.00mm
48% hydrobromic acid (10 ml) was added to ol) and the mixture was stirred with heating under reflux for 4 hours. After allowing to cool, the reaction mixture was poured into ice water, neutralized with potassium carbonate, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1) and recrystallized from ethanol to give 1- (4-biphenylylmethyl) -5.
-Hydroxy-2-methyl-1H-indole (290
mg, 0.93 mmol, 31%) was obtained as colorless crystals. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 94 2-Benzoyl-5-benzyloxy-1H-indole (668 mg, 2.04 mmo) under an argon atmosphere.
l) and a mixture of dichloromethane (6 ml) at 0 ° C. in a 1.0 M solution of boron tribromide in dichloromethane (6.1 ml,
(6.1 mmol) was added and stirred for 30 minutes. The reaction mixture was poured into ice water and the reaction product was extracted with ethyl acetate.
The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; hexane:
After purification with ethyl acetate = 4: 1, then 3: 2), it was recrystallized from chloroform to give 2-benzoyl-5-hydroxy-1H-indole (380 mg, 1.06 mm).
ol, 79%) as colorless crystals. The physicochemical properties of this compound are shown in Table 1 below.

Reference Examples 95-96 Reference Example 95-9 shown in Table 1 below in the same manner as in Reference Example 94.
6 compound was obtained. The physicochemical properties of these compounds are shown in Table 1 below.

Reference Example 97 2-benzyl-5-hydroxy-1H-indole (2
15 mg, 0.963 mmol), 3-chloro-4-fluorobenzonitrile (155 mg, 1.00 mmo
l), potassium carbonate (207 mg, 1.5 mmol),
A mixture of N, N-dimethylformamide (1.5 ml) was stirred at 60 ° C for 8 hours. After allowing to cool, water was added to the reaction mixture, and the reaction product was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 9: 1, then 6: 1) to give 4-[(2
-Benzyl-1H-indol-5-yl) oxy]-
3-chlorobenzonitrile (202mg, 0.563m
mol, 58%) as a colorless oil.

Reference Example 98-116 Reference Example 98-1 shown in Table 1 below in the same manner as in Reference Example 97.
16 compounds are obtained. The physicochemical properties of these compounds are shown in Table 1 below.

Reference Example 117 N-benzoylpyrrolidine (210 mg, 1.20 mm
ol) and 1,2-dichloroethane (1.5 ml) under heating under reflux with phosphorus oxychloride (0.335 ml,
3.60 mmol) was added and the mixture was stirred for 40 minutes, and then 3-chloro-4-[(1-methyl-1H-indol-5-yl) oxy] benzonitrile (339 mg, 1.20 m).
(mol) and 1,2-dichloroethane (1 ml) were added, and the mixture was stirred under heating under reflux for 14 hours and allowed to cool. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution, and the reaction product was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1,
Then, it is purified by 3: 2) to give 4-[(3-benzoyl-1-
Methyl-1H-indol-5-yl) oxy] -3-
Chlorobenzonitrile (91mg, 0.235mmo
1, 20%) as a colorless oil. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 118 3-Chloro-4-[(5-indolinyl) oxy] benzoic acid (870 mg, 300 mmol) in ethanol (2
Concentrated sulfuric acid (2 ml) was added to the solution (0 ml) and heated under reflux to
Stir for 2 hours. The reaction mixture was allowed to cool and then poured into ice water, 5N
It was neutralized with an aqueous sodium hydroxide solution. The reaction product was extracted with ethyl acetate, the extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) to give ethyl 3-chloro-4-[(5-indolinyl) oxy] benzoate (940 mg, 2.95 mmol, 9
9%) as a colorless oil. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 119 3-chloro-4-[(1-tert-butoxycarbonyl-5-indolinyl) oxy] benzonitrile (9.
19 g, 23.5 mmol) to trifluoroacetic acid (10
0 ml) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. By recrystallizing the obtained crystalline residue from ethanol, 3-chloro-4-[(5-indolinyl) oxy] benzonitrile (6.07 g, 22.
4 mmol, 81%) was obtained as tan crystals. The physicochemical properties of this compound are shown in Table 1 below.

Reference Example 120 Ethyl 3-chloro-4-[(5-indolinyl) oxy] benzoate (320 mg, 1.01 mmol),
Benzhydryl bromide (300mg, 1.21mmo
l), potassium iodide (30.0 mg, 0.18 mmo
1) and N, N-dimethylformamide (5 ml) at room temperature under stirring with potassium carbonate (210 mg, 1.51).
mmol) was added all at once. The reaction mixture was stirred at room temperature for 4 hours, water was added, and the reaction product was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 95: 5) to give ethyl 4-.
[(1-Benzhydryl-5-indolinyl) oxy]
-3-Chlorobenzoate (370 mg, 0.76 mm
ol, 76%) as a colorless oil. The physicochemical properties of this compound are shown in Table 1 below.

Reference Examples 121-129 Reference Example 121 shown in Table 1 below in the same manner as Reference Example 120.
The compound of -129 was obtained. The physicochemical properties of these compounds are shown in Table 1 below.

Reference Example 130 3-chloro-4-[(5-indolinyl) oxy] benzonitrile (540 mg, 2.00 mmol), cyclohexanecarboxaldehyde (240 mg, 2.10)
mmol), acetic acid (1.20 g, 20.0 mmol),
A mixture of methylene chloride (20 ml) was stirred at room temperature under sodium triacetoxyborohydride (640 mg, 3.
00 mmol) was added all at once. Reaction mixture at room temperature 1
After stirring for an hour, the mixture was concentrated under reduced pressure. The obtained residue was neutralized with potassium carbonate and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystalline residue was washed with ethanol to give 3-chloro-4-[(1-cyclohexylmethyl-5-indolinyl) oxy] benzonitrile (650 mg, 1.77 mmol, 89%).
Was obtained as colorless crystals. The physicochemical properties of this compound are shown in Table 1 below.

Reference Examples 131-137 Reference Example 131 shown in Table 1 below in the same manner as Reference Example 130.
The compound of -137 was obtained. The physicochemical properties of these compounds are shown in Table 1 below.

Reference Example 138 Reference Example 138 shown in Table 1 below in the same manner as Reference Example 120.
Was obtained. The physicochemical properties of these compounds are shown in Table 1 below.

Example 1 4-[(1-benzyl-1H-indol-5-yl)
Oxy] -3-chlorobenzonitrile (5.66 g, 1
5.8 mmol) in ethanol (50 ml),
N potassium hydroxide aqueous solution (50 ml) was added all at once at room temperature, and the mixture was stirred with heating under reflux for 3 hours. After allowing to cool, concentrate under reduced pressure,
The pH was adjusted to <3 with 10% hydrochloric acid. The reaction product was extracted with ethyl acetate, the extract was washed successively with water and saturated brine,
It was dried over anhydrous sodium sulfate and concentrated under reduced pressure. By recrystallizing the obtained crystalline residue with a mixed solvent of ethanol: hexane = 1: 1, 4-[(1-benzyl-1
H-indol-5-yl) oxy] -3-chlorobenzoic acid (3.53 g, 9.34 mmol, 59%) was obtained as brown crystals. The physicochemical properties of this compound are shown in Table 2 below.
Shown in.

Example 2-14 In the same manner as in Example 1, the compounds of Example 2-14 shown in Table 2 below were obtained. The physicochemical properties of these compounds are shown in Table 2 below.

Example 15 3-Chloro-4-[(4-oxo-2-phenyl-4H
-Chromen-6-yl) oxy] benzaldehyde (5
10 mg, 1.35 mmol), silver nitrate (480 mg,
2.84 mmol), water (10 ml), ethanol (1
0 ml), N, N-dimethylformamide (10 ml)
To a mixture of sodium hydroxide (220 m) at room temperature with stirring.
g, 5.40 mmol) were added all at once. The reaction mixture was stirred with heating under reflux for 6 hours, and then with 1N hydrochloric acid under ice cooling to pH <.
The insoluble matter was filtered off. The reaction product was extracted with ethyl acetate, the extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crystalline residue obtained was washed with ethanol to give 3-chloro-4-[(4-oxo-2-phenyl-4H-chromen-6-yl) oxy] benzoic acid (190 mg, 0.
48 mmol, 36%) was obtained as off-white crystals. The physicochemical properties of this compound are shown in Table 2 below.

Example 16 The compound of Example 16 was obtained in the same manner as in Example 15. The physicochemical properties of this compound are shown in Table 2 below.

Example 17 3-Chloro-4-[(1-methyl-1H-indole-
5-yl) oxy] benzonitrile (198 mg, 0.
8N to a mixture of 70 mmol) and ethanol (3 ml)
Aqueous sodium hydroxide solution (1 ml) was added, and the mixture was heated under reflux 1
Stir for 4 hours. The reaction mixture was allowed to cool, concentrated under reduced pressure, neutralized with 1N hydrochloric acid, and the reaction product was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystalline residue was recrystallized from ethanol to give 3-chloro-4-
[(1-Methyl-1H-indol-5-yl) oxy] benzoic acid (157 mg, 0.520 mmol, 74
%) As brown crystals. The physicochemical properties of this compound are shown in Table 2 below.

Example 18-55 Example 18-5 shown in Table 2 below in the same manner as in Example 17.
5 compound was obtained. The physicochemical properties of these compounds are shown in Table 2 below.

Example 56 Ground potassium hydroxide (156 m) under an argon atmosphere.
g, 2.78 mmol) and dimethyl sulfoxide (4 m
3-chloro-4-[(1H
-Indol-5-yl) oxy] benzoic acid (200 m
g, 0.695 mmol) was added all at once. The reaction mixture was stirred at room temperature for 40 minutes, and then a mixture of 4-phenoxybenzyl bromide (274 mg, 1.04 mmol) and dimethyl sulfoxide (1.5 ml) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 hours, 1N hydrochloric acid was added, and the reaction product was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. By recrystallizing the obtained crystalline residue from ethanol, 3-chloro-4-[[1
-(4-phenoxybenzyl) -1H-indole-5
-Yl] oxy] benzoic acid (240 mg, 0.511 m
(73 mmol, 73%) was obtained as colorless crystals. The physicochemical properties of this compound are shown in Table 2 below.

Example 57 The compound of Example 57 shown in Table 2 below was obtained in the same manner as in Example 56. The physicochemical properties of this compound are shown in Table 2 below.

Example 58-61 Example 58-6 shown in Table 2 below in the same manner as in Example 17.
1 compound was obtained. The physicochemical properties of these compounds are shown in Table 2 below.

Example 62 Ethyl 4-[(1-benzhydryl-5-indolinyl)]-3-chlorobenzoate (350 mg, 0.7
To the mixture of 2mmmol), dioxane (1.5 ml) and ethanol (4 ml), 5N aqueous sodium hydroxide solution (5 ml) was added all at once at room temperature with stirring. The reaction mixture was stirred at room temperature for 2 hours and then neutralized with 10% hydrochloric acid. The reaction product was extracted with ethyl acetate, the extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crystalline residue obtained was reprecipitated from ether-hexane to give 4-[(1-benzhydryl-5).
-Indolinyl) oxy] -3-chlorobenzoic acid (15
0 mg, 0.32 mmol, 46%) was obtained as off-white crystals. The physicochemical properties of this compound are shown in Table 2 below.

Examples 63 and 64 Examples 63 and 6 shown in Table 2 below are carried out in the same manner as in Example 62.
4 compound was obtained. The physicochemical properties of these compounds are shown in Table 2 below.

Example 65 3-Chloro-4- (5-indolinyloxy) benzoic acid (580 mg, 2.00 mmol), 4-isopropylbenzaldehyde (330 mg, 2.20 mmol),
A mixture of acetic acid (120 mg, 2.00 mmol) and dichloroethane (20 ml) was stirred at room temperature under sodium triacetoxyborohydride (640 mg, 3.00 mmo).
l) was added all at once. The reaction mixture was stirred at room temperature for 3 hours, water was added, the mixture was neutralized with a 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; chloroform: methanol = 95: 5).
By purification with 3-chloro-4-[[1- (4
-Isopropylbenzyl) -5-indolinyl] oxy] benzoic acid (760 mg, 1.80 mmol, 90
%) As colorless crystals. The physicochemical properties of this compound are shown in Table 2 below.

Examples 66-68 The same as Example 65, Examples 66-6 shown in Table 2 below.
8 compounds were obtained. The physicochemical properties of these compounds are shown in Table 2 below.

Example 69-84 Example 69-8 shown in Table 2 below in the same manner as in Example 17.
4 compound was obtained. The physicochemical properties of these compounds are shown in Table 2 below.

Preferred compounds among the compounds of the present invention are shown in Table 3. These compounds can be manufactured by the same method as the above-mentioned manufacturing method and the method shown as an example.

[0118]

[Table 1]

[0119]

[Table 2]

[0120]

[Table 3]

[0121]

[Table 4]

[0122]

[Table 5]

[0123]

[Table 6]

[0124]

[Table 7]

[0125]

[Table 8]

[0126]

[Table 9]

[0127]

[Table 10]

[0128]

[Table 11]

[0129]

[Table 12]

[0130]

[Table 13]

[0131]

[Table 14]

[0132]

[Table 15]

[0133]

[Table 16]

[0134]

[Table 17]

[0135]

[Table 18]

[0136]

[Table 19]

[0137]

[Table 20]

[0138]

[Table 21]

[0139]

[Table 22]

[0140]

[Table 23]

[0141]

[Table 24]

[0142]

[Table 25]

[0143]

[Table 26]

[0144]

[Table 27]

[0145]

[Table 28]

[0146]

[Table 29]

[0147]

[Table 30]

[0148]

[Table 31]

[0149]

[Table 32]

[0150]

[Table 33]

[0151]

[Table 34]

[0152]

[Table 35]

[0153]

[Table 36]

[0154]

[Table 37]

[0155]

[Table 38]

[0156]

[Table 39]

[0157]

[Table 40]

[0158]

[Table 41]

[0159]

[Table 42]

[0160]

[Table 43]

[0161]

[Table 44]

[0162]

[Table 45]

[0163]

[Table 46]

[0164]

[Table 47]

[0165]

[Table 48]

[0166]

[Table 49]

[0167]

[Table 50]

[0168]

[Table 51]

[0169]

[Table 52]

[0170]

[Table 53]

[0171]

[Table 54]

[0172]

[Table 55]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 311/30 335/16 401/04 209 401/06 209 // A61K 31/34 9454-4C 31 / 35 9454-4C 31/38 ADU 9454-4C 31/40 ACV 9454-4C AED 9454-4C 31/44 9454-4C 31/47 9454-4C C12N 9/99 (72) Inventor Hiroshi Hara Abiko, Chiba Prefecture Tennodai 5-5-2-902 (72) Inventor Hiroshi Shintoku 3-25-4-203 Matsushiro Tsukuba, Ibaraki

Claims (7)

[Claims] 1. A benzoic acid derivative represented by the following general formula (I) or a salt thereof. [Chemical 1] [The groups in the formula have the following meanings. R ^{1a to} R ^1g : the same or different, hydrogen atom, lower alkyl group, lower alkenyl group, lower alkynyl group, halogen atom, trihalogenomethyl group, hydroxyl group, lower alkoxy group, cyano group, nitro group, amino group or mono- Alternatively, a di-lower alkylamino group X ¹ : an oxygen atom or a sulfur atom X ² : an oxygen atom, a sulfur atom or a group represented by the following formula: R ² : hydrogen atom; a lower alkyl group which may be substituted with a cycloalkyl group or an aryloxy group, wherein the cycloalkyl group or the aryloxy group is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a halogen atom. , A trihalogenomethyl group, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-lower alkylamino group, a group which may be substituted with an aryl group; a hetero group containing an aryl group or a nitrogen atom A cyclic group, wherein the aryl group or a heterocyclic group containing a nitrogen atom is a lower alkyl group, a lower alkenyl group, a lower alkynyl group,
Halogen atom, trihalogenomethyl group, hydroxyl group, lower alkoxy group, cyano group, nitro group, amino group or mono-
Or a group which may be substituted with a di-lower alkylamino group; an aralkyl group which is a lower alkyl group, a lower alkenyl group, a lower alkynyl group optionally substituted with an aryl group, a halogen atom, Substituted with a trihalogenomethyl group, hydroxyl group, lower alkoxy group, cyano group, nitro group, amino group, mono- or di-lower alkylamino group, cycloalkyl group, aryl group, aryloxy group, biscycloalkyl group Good group. Ring A: a group represented by the following formula: R ^3: the same or different and represent a hydrogen atom, a lower alkyl group which may be substituted with an aryl group, a lower alkenyl group, a lower alkynyl group, a halogen atom, trihalogenomethyl group, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group ,
Amino group or mono- or di-lower alkylamino group, acyl group, aryl group, arylcarbonyl group, wherein the aryl group and the arylcarbonyl group are a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a halogen atom, It may be substituted with a trihalogenomethyl group, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group, an amino group or a mono- or di-lower alkylamino group, and the aralkyl group is a lower alkyl group. , A lower alkenyl group, a lower alkynyl group, a halogen atom, a trihalogenomethyl group, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group, an amino group or a mono- or di-lower alkylamino group.
Or, when R ³ is a group represented by the following formula, which is bonded to the same carbon atom: R ³ together represents an oxo group or a thioxo group. ] 2. The compound or a salt thereof according to claim 1, wherein ring A is a group represented by the following formula. [Chemical 5] 3. R ^1a is a halogen atom, and R ^{1b to} R ^1b
The compound or salt thereof according to claim 2, wherein ^{1 g} is a hydrogen atom. 4. 4-[[1- (4-Biphenylylmethyl) -1H-indol-5-yl] oxy] -3-chlorobenzoic acid or a salt thereof. 5. 3-chloro-4-[(1-isoamyl-
1H-indol-5-yl) oxy] benzoic acid or a salt thereof. 6. 3-Chloro-4-[[1- (4-phenoxybenzyl) -1H-indol-5-yl] oxy] benzoic acid or a salt thereof. 7. 3-Chloro-4-[[1- (4-phenoxybenzyl) -5-indolinyl] oxy] benzoic acid or a salt thereof.