WO2001012626A1

WO2001012626A1 - Indole compounds, process for the preparation of the same and uses thereof

Info

Publication number: WO2001012626A1
Application number: PCT/JP1999/004390
Authority: WO
Inventors: Masako Nakagawa; Atsushi Nishida; Mihoko Fuwa; Haruo Saito
Original assignee: Lead Chemical Co., Ltd
Priority date: 1999-08-13
Filing date: 1999-08-13
Publication date: 2001-02-22
Also published as: AU5197899A; JP4452969B2

Abstract

Novel indole compounds represented by general formula (I): [wherein X is oxygen or sulfur; R1 is hydrogen, optionally halogenated C1-C4 alkyl or optionally halogenated C1-C4 alkoxy; and R2 is C1-C20 alkyl]. These compounds can be prepared by a process which comprises condensing optionally substituted tryptamine with a carboxylic acid halide to form an amide, and subjecting the amide to oxidation and cyclization successively to form an oxazole or thiazole ring. The compounds exhibit a lipoperoxidation-inhibiting activity and other physiological activities and are therefore utilizable in the form of lipoperoxidation inhibitors containing them as the active ingredient.

Description

TECHNICAL FIELD The present invention relates to a novel indole compound, a method for producing the compound, and a use of the compound. Conventional technology

An indole compound (malteflazine A) represented by the following formula and isolated from the extract of the seaweed Aranishiki (Martensiafragilis Harvey) belonging to the family Sphingidae is known [Abstract of The 16th Annual Meeting of the Pharmaceutical Society of Japan Vol. 2, 2 15 pages (1996)].

And it is known that the above-mentioned indole compound has an antioxidant effect and has a use as a medicine and the like. WO 99/12932 discloses the following compound (1) or a salt thereof, a method for producing the same and use.

{Where γ is a group * ノ X

/ No ι ,,,

R1 ^R 122

[In the formula, X ′ is an alkyl group having 1 to 5 carbon atoms (the alkyl group is a hydroxyl group, a carboxyl group, an amino group, a methylthio group, a mercapto group, a dawanidyl group, an imidazolyl group or It represents base Njiru may be substituted by a group.), Rn. 'and R _2' each independently represents a hydrogen atom, an alkyl group, Aruaruki group, a cycloalkyl group or Ariru group. ]

*

Or one (CH ₂ ) ₂ — C (CH ₃ ) H—CH ₂ represents CH ₃ ;

R 'represents a hydrogen atom, an alkyl group, an aralkyl group, a cycloalkyl group, an aryl group, a monovalent metal atom, an amine or an ammonium; * indicates the position of an asymmetric carbon atom. }.

After intensive studies, the present inventors have found a novel indole compound having a lipid peroxidation inhibitory action superior to the above compounds. Disclosure of the invention

The present invention relates to an indole compound represented by the following formula I:

Wherein X represents an oxygen atom or a sulfur atom; Ri is a hydrogen atom, an unsubstituted or halogen-substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or halogen atom. Represents an alkoxy group having 1 to 4 carbon atoms. R ₂ represents an alkyl group having 1 to 20 carbon atoms. ]

The group Ri which is an alkyl group having 1 to 4 carbon atoms represents, for example, a methyl group, an ethyl group, a propyl group, an n-butyl group, an isobutyl group and a tert-butyl group.

Further, a group which is an alkoxy group having 1 to 4 carbon atoms is, for example, a methoxy group, Represents ethoxyquin, propoxy, n-butoxy, isobutoxy, and tert-butoxy.

When R x is a halogen-substituted alkyl or alkoxy group, the halogen atom of the substituent is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

R ₂ may be a linear or branched alkyl group having 1 to 20 carbon atoms, for example, an alkyl group having 5 to 15 carbon atoms. Pentyl groups are preferred.

Among the formula compounds represented by I, X represents an oxygen atom or a sulfur atom, but a hydrogen atom or a compound of from 1 -C compound is a 4 alkoxy group is preferably _c further preferred invention the formula I In the formula, X represents an oxygen atom or a sulfur atom, preferably represents a hydrogen atom or a methoxy group, and R ₂ is preferably a pentyl group.

The following compounds represented by MF-15, MF-17, MF-20 and MF-21 are preferred compounds represented by formula I of the present invention.

MF-21 The present invention also provides the following formula W

Oxidizes the compound represented by the following formula V

A compound represented by the formula I:

And a method for producing an indole compound represented by the formula:

[In the formula, X represents an oxygen atom or a sulfur atom, and R i is a hydrogen atom, an unsubstituted or halogen-substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or halogen atom. Represents an alkoxy group having 1 to 4 carbon atoms substituted by. R ₂ represents an alkyl group having 1 to 20 carbon atoms. ]

The compound represented by the above formula W can be obtained by condensation of tributamine or substituted trimin and carboxylic acid halide.

Accordingly, the present invention also relates to a method for producing a compound represented by the formula I using a tryptamine or a substituted triptamin and a carboxylic acid halide as starting materials as described below. That is,

The compound represented by the following formula ID

Condensed with a carboxylic acid halide represented by the following formula IV

And oxidizing the compound of formula IV to obtain the compound of formula V

And further cyclized to form a compound represented by the following formula I

To produce an indole compound represented by the above formula I.

Wherein X represents an oxygen atom or a sulfur atom, is a hydrogen atom, an unsubstituted or halogen-substituted alkyl group having 1 to 4 carbon atoms or an unsubstituted alkyl group. Alternatively, it represents an alkoxy group having 1 to 4 carbon atoms substituted with a halogen atom, R ₂ represents an alkyl group having 1 to 20 carbon atoms, and Ha 1 represents a halogen substituent. ]

The halogen substituent of the carboxylic acid halide may be any of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. However, chlorine atoms are most preferred.

The C 1 -C 20 alkyl moiety of the carboxylic acid halide is preferably C 5 -C 15 alkyl, most preferably a pentyl group. The oxidation of the compound of the formula IV is particularly preferably carried out in the presence of 2,3-dichloro-5,6-disocyanobenzoquinone (DDQ).

Among the compounds represented by the formula I of the present invention, those in which X represents an oxygen atom can be obtained by amylation of the carboxylic acid halide with the tryptamine or substituted tryptamine represented by (1). Then, the amide form is oxidized in the presence of, for example, DDQ to form a keto form, and finally ③ the ketone form is heated to reflux with, for example, oxychlorine. By cyclizing the compound, an oxazole ring can be constructed and produced.

Among the compounds represented by the formula I of the present invention, the compounds in which X represents a sulfur atom are as follows: (1) Amylation by acylation of the tryptamine or substituted tryptamine represented by the formula (2) with a carboxylic acid halide; Then, (2) the amide is oxidized in the presence of, for example, DDQ to form a ketone, and finally (3) the keto is dissolved in, for example, phosphorus pentasulfide in the presence of chloroform. The thiazole ring can be produced by heating and refluxing to form a thiazole ring.

The novel indole compound of the present invention is an aldoloid having an indole ring and an oxazole ring or a thiazole ring, has lipid peroxidation inhibitory activity, and has cardiovascular disorders such as arterial stiffening, hypertension, and thrombosis. Used as a prophylactic and therapeutic agent for inflammation such as nephritis, liver damage such as alcoholic hepatitis, gastrointestinal disorders such as gastric ulcer, diabetes, carcinogenesis and aging, and other ultraviolet damage, and as a preventive agent for ultraviolet damage in cosmetic materials. You can do it.

Therefore, the present invention further relates to a lipid peroxidation inhibitor containing the indole compound represented by the formula I as an active ingredient. BEST MODE FOR CARRYING OUT THE INVENTION

The production examples and the biological examples of the indole compound of the present invention are shown below. This example is not intended to limit the present invention.

I. Production Examples of Indole Compounds

Example 1 Synthesis of Compound of Formula I When R is H

It is prepared according to the following synthesis scheme 1.

Scheme 1 Synthesis of MF-15, 17

MF-17

1. Acylation of tryptamine

Two

Three

Tryptamine (1) lg (6.24 mmo 1) and 75 mL of methylene chloride were added to a 30-OmL three-necked flask, and cooled to 0 ° C. Subsequently, 1.05 mL (8.11 mmo1, 1.3 eq) of hexane acid chloride dissolved in 5 mL of methylene chloride and 6 mL of 5% aqueous sodium hydroxide solution (8.11 mmo 1, 1.3 eq) were simultaneously added via a dropping funnel. After stirring at 0 for 30 minutes and at room temperature for 1 hour, the mixture was extracted with methylene chloride, washed with saturated aqueous sodium hydrogen carbonate, 5% aqueous hydrochloric acid, and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. . The residue Karamukuroma preparative chromatography _{(S i 0 2 4 5 g} , hexane n-: acetate Echiru 1: 1) to give amino-de-body shall be the object (3) 1. 2 4 g ( 7 7%) Obtained. This was recrystallized with ethyl acetate and n-hexane to obtain a colorless powder.

itp. 93-94 ° C (AcOEt / n-Hex).

IR (KBr): v 3398, 3256, 3084, 2933, 2850, 1631, 1560, 1458, 741cm ""] ^-MRi 400MHz, CDCl ₃ ): δ 8.05 (1H, broad, Nl-H), 7.62 (1H , td, J = 7. Hz, C7-H), 7.38 (1H, td, J = 7.1, l.OHz, C4-H), 7.22 (1H, td, J = 7.1, 1.2Hz, C5-H), 7.13 (1H, td, J = 7.1, l.OHz, C6-H), 7.04 (1H, d, J = 2.5Hz, C2-H), 5.48 (1H, broad, 3'NH), 3.6K2H, q, J = 6.4Hz, C2'-H), 2.98 (2H, t, J = 6.lHz ₍ Cl'-H), 2.09 (2H, t, J = 7.6Hz, C2 "-H), 1.64-1.50 (2H, rn, C3 "-H), 1-36-1.28 (2H, m, C4" -H), 1.28- 1.20 (2H, m, C5 "-H), 0.87 (3H, t, J = 7.5Hz, C6" -H ^{.) 13 C- NMR (100 Hz} , CDC1 3): 5173.12 (C1 "), 136.41 (C7a), 127.36 (C3),

122.19 (C5), 121.99 (C2), 119.47 (C6), 118.72 (C7), 113.08 (C3a), 111.23 (C4), 39.63 (C2 '), 36.85 (C2 "), 31.43 (C5"), 25.40 ( C1 '), 25.36 (C3 "), 22.36 (C4"), 13.9KC6 ").

LRFAB S m / z (%): 259 (M ⁺ + H, 80), 143 (100). 2. DDQ oxidation of acyltryptamine

After adding and dissolving 1 g (3.87 mmol) of the amide form (3) and 100 mL of water-THF (10:90) in a 3 OO mL eggplant-shaped flask, add DDQ 1.76 g (7.74 mm 01, 2 eq) and stir at room temperature for 2 hours. After terminating the reaction by adding a saturated aqueous solution of sodium thiosulfate, tetrahydrofuran is removed under reduced pressure. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol to obtain colorless crystals (yield 1.03 g, 96%).

3. Synthesis of MF-15

To a 25 mL eggplant-shaped flask equipped with a reflux condenser and a salt tube, add 0.84 mg (2.95 mmo 1) of keto-form (4) and 8 mL of phosphorus oxychloride, and heat to reflux for 1.5 hours. did. The reaction solution was cooled to room temperature, the reaction solution was poured into a beaker containing water, and aqueous ammonia was added until the aqueous layer became basic. Then, out extraction with acetic acid Echiru, the organic layer was washed with water, dried over anhydrous sulfate Na Application Benefits um, the solvent was distilled off under reduced pressure <column chromatography of the residual _{(S i 0 2 2 0 g} , n - to Purification with xan: ethyl acetate 1: 1) gave 63.8.9 mg (85.2%) of the desired cyclized product MF-15. Then, recrystallization was performed with ethyl acetate n-hexane to obtain colorless crystals.

rtp.130.5-131.5 ° C (AcOEt / n-Hex).

IR (KBr): 3134, 2935, 2856, 1637, 1570, 1456, 1348, 1248, 1182, 1122, 1012, 916, 768, 737cm- ¹ . UV (MeOH): λ max 298.6, 281.0, 266.8, 225. Onm.

"-HN Ri 400MHz, CDCl ₃ ): δ 8.38 (1H, broad, Nl-H), 7.84 (1H, dd, J = 7.7, 0.98Hz, C7-H), 7.5K1H, d, J = 2.7Hz, C2-H), 7.43 (1H, dd, J = 7.3, 1.2Hz, C4-H), 7.28 (1H, td, J = 7.7, 1.2Hz, C5-H), 7.24 (1H, td, J = 7.7 , 1.2Hz, C6-H), 7.15 (1H, s, C4'-H), 2.84 (2H, t, J = 7.7Hz, Cl "-H), 1.85 (2H, f, J = 7.6Hz, C2 "-H), 1.47-1.40 (2H, m, C3" -H), 1.40-1.38 (2H, m, C4 "-H), 0.92 (3H, t, J = 7.0Hz, C5" -H).

3C-丽_{(100MHz, CDC1 3): δ} 162.97 (C2 '), 147.07 (C5'), 136.24 (C7a),

124.14 (C3), 122.97 (C5), 121.46 (C2), 120.8KC6), 120.00 (C7), 119.88 (C4 '), 111.47 (C4), 106.12 (C3a), 31.35 (C3 "), 28.18 (C1") ), 26.86 (C2 "), 22.32 (C4"), 13.93 (C5 ").

Anal.Calcd for C1.eH1.8N2O: C 75.76; H 7.13; N 11.01,

Found: C 75.46; H 7.15 N 10.97.

4. Synthesis of MF-17

MF-17 In a 25 mL eggplant-shaped flask equipped with a reflux condenser and a salt tube, keto body (4) 150 mg (0.55 mmo 1), 7 mL of porcine form and 7 mL of pentasulfide 122 mg (0.55 mmo1, 1 eQ) was added and the mixture was heated under reflux for 20 hours. After cooling the reaction solution to 0 ° C., a 10% aqueous solution of potassium hydroxide was added thereto, and the mixture was extracted with chloroform.

Example 2 prepared according to synthesis scheme 2 the synthesis following compounds of the formula I when R Gar OCH _3.

1

Five

Me

m

0

Thus, 0.93 g (62%) of the desired condensate (6) was obtained.

s, -OCH ₃ ), 3.59 (2H, q, J = 6.6Hz, C2'-H), 2.93 (2H, t, J = 6.6Hz, Cl'-H), 2.10 (2H, t, J = 7.7 Hz, C2 "-H), 1.58 (2H, ddd, J = 29.8, 14.9, 7.3Hz, C3" -H), 1.34- 1.26 (2H, m, C4 "-H), 1.26-1.20 (2H, m , C5 "-H), 0.86 (3H, t, J = 6.8Hz, C6" -H).

^{_{13 C- MR (100MHz, CDC1 3}} ): δ 173.22 (C1 "), 153.98 (C5), 131.58 (C7a),

127.70 (C3), 122.82 (C2 ), 112.56 (C3a), 112.29 (C6), 112.00 (C7), 100.47 (C4) 55.90 (-OCH 3), 39.54 (C2 '), 36.82 (C2 "), 31.39 ( C5 "), 25.40 (C1 '),

25.32 (C3 "), 22.32 (C4"), 13.86 (C6 ").

LRFABMS m / z (%): 289 (+ H, 80), 173 (100).

_{_{HRFABMS Calcd for Ci_ H 24 N 2}} 0 2 + H: 289.1916; Found 289.1916.

2. DDQ oxidation of acyltryptamine

6

To a 20 O mL eggplant-shaped flask were added 500 mg (1.73 mmo 1) of the acyl compound (6) and 50 mL of a water-THF (90: 10) solution, and the mixture was stirred. 7 mg (3.47 mmo1, 2 eq) was added, and the mixture was stirred at room temperature for 0.9 hours. After adding sodium thiosulfate aqueous solution to terminate the reaction, tetrahydrofuran was removed by distillation under reduced pressure. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product was recrystallized from ethyl acetate to obtain 482.6 mg (92%) of colorless crystals. o

3. M

Reflux

0 mg

Heat reflux

And aqueous ammonia was added until the aqueous layer became basic. Thereafter, the solution was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue Karamukuroma preparative chromatography (S i 0 ₂ 5 g, the n one hexane: acetic acid Echiru 1: 1) cyclized MF-2 0 to 1 3 5 mg of interest was purified by (95%) of Compound . After that, recrystallization was performed with ethyl acetate- _n- hexane to obtain colorless crystals.

"-H-NMR (400 MHz, CDCl ₃ ): δ 8.60 (1H, broad, Nl-H), 7.47 (1H, d, J = 2.4 Hz, C2-H), 7.30 (1H, d, J = 8.8 Hz , C7-H), 7.26 (1H, d, J = 2.7Hz, C4-H), 7.1K1H, s, C4'-H), 6.93 (1H, dd, J = 8.8, 2.2Hz, C6-H) , 3.90 (3H, s, -OCH ₃ ), 2.84 (2H, t, J = 7.6HZ, Cl "-H), 1.84 (2H, dt, J = 14.7, 7.6, 7.1Hz, C2" -H), 1.47- 1.33 (2H, m, C3 "-H), 1.32- 1.23 (2H, m, C4" -H), 0.9K3H, t, J = 6.8Hz, C5 "-H).

¹³ C-note (100MHz, CDCI3): 6162.90 (C2 '), 154.92 (C5), 147.19 (C5'),

131.34 (C7a), 124.67 (C3), 122.25 (C2), 119.5KC4 '), 113.04 (C6),

112.23 (C7), 105.75 (C3a ), 101.87 (C4), 55.89 (-OCH 3), 31.32 (C3 "), 28.17 (C1"), 26.87 (C2 "), 22.31 (04"), 13.9KC5 ") .

ERFAB S m / z (%): 284 (M *, 100).

HRFAB S: Calcd for C HsoK C + H 285.1603 '' Found 285.1611.

P ₂ S _S , CHCI

£ _:

reflux, 92%

MF-21

In a 25 mL eggplant-shaped flask equipped with a reflux condenser and a salt tube, the ketone (7) 150 mg (0.50 mmol), chloroform 6 mL and diphosphorus pentasulfide 11 mg ( 0.5 mmO 1, 1 eq) was added and the mixture was refluxed for 14 hours. After the reaction solution was cooled to 0 ° C., a 10% aqueous solution of potassium hydroxide was added, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. this Column chromatography (S i 0 ₂ 5 g, hexane n-: acetate Echiru 1: 1) the cyclized compound MF-2 1 of interest was purified by 1 3 8. 6 mg (9 2. 4% ) Obtained. Thereafter, recrystallization was performed with ethyl n-hexane, and colorless crystals were obtained.

mp93-94 ° C (AcOEt / n-Hex).

IR (KBr): v 3153, 3049, 2954, 2918, 2858, 163 full 1566, 1475, 1350, 1309, 1254, 1209, 1128, 1036, 928, 901, 837, 787cm _1.

UV (MeOH): λ max 309.4, 284.0, 218.6 nm.

- negation _{(400MHz, CDC1 3): δ} 8.86 (1H, broad, Nl-H), 7.79 (1H, s, C4 H), 7.35 (1H, d, J = 2.6Hz, C2-H), 7.30 (1H , d, J = 2.5Hz, C4-H), 7.28 (1H, d, J = 9.0Hz, C7-H), 6.92 (1H, dd, J = 8.8, 2.2Hz, C6-H), 3.88 (3H , s, -0CH ₃ ), 3,03 (2H, t, J = 7.7Hz, Cl "-H), 1.85 (2H, dt, J = 14.8, 7,7, 7.3Hz, C2" -H), 1.48-1.42 (2Η, m, C3 "-H), 1.42-1.33 (2H, m, C4" -H), 0.92 (3H, t, J = 7.1Hz, C5 "-H).

^13C -NMR (100MHZ, CDCI3): 6169.69 (C2 '), 155.57 (C5), 137.15 (C2),

132.4KC5 '), 132.17 (C7a), 126.57 (C3), 123.99 (C4'), 113.68 (C6),

112.88 (C7), 108.46 (C3a ), 101.79 (C4), 56.16 (-OCH 3), 33.56 (C3 "), 31.4KC1"), 29.87 (C2 "), 22.46 (C4"), 13.97 (C5 ") .

ERFAB S m / z (%): 301 H, 100).

_{_{HRFABMSrCalcd for Ci 2O N 2 S0 +}} H 301.1375;. Found 301.1371 biological effects of Π indole compounds.

[Example 3] Indole compound against lipid peroxidation of rat liver microsomes Effect

(1) Measurement of lipid peroxide

0.1 M Tris-HCl buffer (pH 7.5) containing 14 mM MgCl ₂ (0.5 ml) −50 mg / m 1) 10/1 and a solution of the test compound in the following table in ethanol were added, mixed, and pre-incubated at 37 ° C. for 5 minutes. Then, 0. 2 M adenosine diphosphate 1 0 zl, 1 2 mM F e S 0 4 1 0 ^ 1, the addition of NA DPH reproducing system 4 0 mu 1 and distilled water and 1 m 1, after mixing, The reaction was carried out at 37 ° C for 10 minutes. After the reaction, 0.

3 Add 75 ml of 15% thiobarbituric acid (TBA) and 15 ml of 15% trichloroacetic acid solution containing 0.25N hydrochloric acid, and react in a boiling water bath for 15 minutes. The amount of thiobarbituric acid-reactive substances such as malondialdehyde was determined by measuring the absorbance at a wavelength of 535 nm. Based on this value, lipid peroxidation

The value (IC _5. value) to suppress 0% was determined.

(2) Test results

Maltefurazine derivatives MF-15, MF-17, MF-20 and MF-21 produced in the above production examples, and synthetic (1 "S, 3" S) maltefurazine A having the same structure as the natural type The lipid peroxidation inhibitory activity of each indole compound of the (1〃S, 3〃S) form of the compound of the formula (1A) was compared. As a result, Marutefurajin derivative MF-1 5 as shown in the table below, MF - 1 7, MF - 2 0 and MF-2 1 of IC _5. Each value 0.5 9, 0.2 9, 0.3 8 and 0.5 are 4 8 g / m 1 and synthetic (1〃 S, 3〃 S) IC ₅ of Marutefurajin A. The value was 1.35 / g / m1, and each derivative according to the present invention exhibited stronger activity.

The invention's effect

According to the present invention, a novel amide compound is formed by condensing an unsubstituted or substituted tryptamine with a carboxylic acid halide, and then oxidizing and cyclizing to form an oxazole ring or a thiazole ring. It has become possible to obtain novel inner compounds by a synthetic method. The alkyloid having an indole ring and an oxazolyl ring or a thiazolyl ring of the present invention has physiological activity such as lipid peroxidation inhibitory activity and can be used for pharmaceuticals and cosmetic materials. is there.

Claims

The scope of the claims

1. Indole compound represented by the following formula I <

ゥ

(In the formula, X represents an oxygen atom or a sulfur atom, is a hydrogen atom, an unsubstituted or halogen-substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted with a halogen atom. R ₂ represents an alkoxy group having 1 to 20 carbon atoms. R ₂ represents an alkyl group having 1 to 20 carbon atoms. ]

2. The indole compound according to claim 1, wherein in the formula I, X represents an oxygen atom, and represents a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms.

3. The indole compound according to claim ₂ , wherein in the above formula I, X represents an oxygen atom, represents a hydrogen atom or a methoxy group, and R ₂ represents a pentyl group.

4. The indole compound according to claim 1, wherein in the formula I, X represents a sulfur atom, and represents a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms.

5. The indole compound according to claim 4, wherein in the above formula I, X represents a sulfur atom, represents a hydrogen atom or a methoxy group, and R ₂ represents a pentyl group.

6. Next Formula IV

Oxidizes the compound represented by the following formula V

A compound represented by the formula I:

A method for producing an indole compound represented by the formula:

Wherein X represents an oxygen atom or a sulfur atom, is a hydrogen atom, an unsubstituted or halogen-substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted halogen atom. Represents an alkoxy group having 1 to 4 carbon atoms. R ₂ represents an alkyl group having 1 to 20 carbon atoms. ]

7.

The compound represented by the following formula m π

Condensed with a carboxylic acid halide represented by the following formula IV

And oxidizing the compound of formula W to obtain the compound of formula V

V

And further cyclized to form a compound represented by the following formula I

^{R 1}

A method for producing an indole compound represented by the formula:

Wherein X represents an oxygen atom or a sulfur atom, and R _t is a hydrogen atom, an unsubstituted or halogen-substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or halogen atom. Represents an alkoxy group having 1 to 4 carbon atoms, R ₂ represents an alkyl group having 1 to 20 carbon atoms, and H a 1 represents a halogen atom. ].

8. The method according to claim 6 or 7, wherein the oxidation of the compound represented by the formula IV is performed in the presence of 2,3-dichloro-5,6-disocyanobenzoquinone (DDQ).

9. The cyclization of a compound represented by the formula V in the presence of phosphorus oxychloride to obtain a compound represented by the formula I wherein X is an oxygen atom. The described method.

10. Cyclization of compounds of formula V in the presence of phosphorus pentasulfide and chloroform The method according to claim 6 or 7, wherein the method is carried out to obtain a compound represented by the formula I wherein X is a sulfur atom.

11. A lipid peroxidation inhibitor comprising the indole compound according to any one of claims 1 to 5 as an active ingredient.