JPH01149766A - Indole derivative - Google Patents

Abstract

NEW MATERIAL:An indole derivative expressed by the formula (A is CH=CH or CH2CH2). USE:A treating agent for nephritis. A preventing and treating agent for disease participated by superoxide radical, e.g. self-immune disease such as rheumatics, arteriosclerosis, ischemic cardiopathy, ischemic cerebral disorder, hepatic insufficiency, renal insufficiency, etc. PREPARATION:Aspergillus terreus OFR-1562 strain (FERM P-9611) separated from a soil on the Ishigaki island, Okinawa prefecture or bacterium belonging to the genus Aspergillus and having an ability for producing a compound expressed by the formula (A is CH=CH) such as valiant thereof is cultivated in a proper culture medium to afford a compound expressed by the formula (A is CH=CH), which is then as necessary catalytically reduced to provide the compound expressed by the formula (A is CH2CH2).

Description

[Detailed description of the invention] Rikayo L ■Ridan I The present invention relates to novel compounds.

Conventional technology The compound of the present invention is a novel compound that has not been described in any literature.

Problem 11 to be Solved by the Invention The purpose of the present invention is to provide a compound useful as a pharmaceutical, as described later.

Means for Solving the Problems The above object is achieved by an indole derivative represented by the following formula (1).

(In the formula, A represents -CH=CH- or -CH20H2-.) As a result of intensive research, the present inventors found that a certain type of microorganism newly isolated from the soil of Ishigaki Island, Okinawa Prefecture, It was discovered that a new substance having activity was produced, and the substance was isolated and expressed by the above formula (1) (where A is -CH=CH-
We succeeded in obtaining an indole derivative represented by "Compound IAJ" from this compound, and by subjecting this derivative to catalytic reduction treatment, we obtained a derivative (A10H20H2- Formula (1) is
We succeeded in producing a compound, hereinafter referred to as Compound 1BJ, and hereby completed the present invention.

Hereinafter, the production of the compound of the present invention will be explained in detail.

Compound 1A of the present invention can be produced by culturing microorganisms.

A specific example of the strain used in the above is Aspergillus terreus 0FR-1562 (Asl) ergill, which the present inventors newly isolated from the soil of Ishigaki Island, Okinawa Prefecture.
An example of the strain is a strain belonging to the genus Aspergillus, named "U.S. terreuso FR-1562". The strain was given accession number “FERM P-9” to the Institute of Microbial Technology, Agency of Industrial Science and Technology, Ministry of International Trade and Industry.
611>. Its mycological properties are as follows.

(a) Morphology According to microscopic observation, the conidial head is long cylindrical, and the size is 40 to 60 x 10 to 20 μm. Conidiophores are 80~150X4.0~. It has a size of 6.5 μm, is colorless, smooth, and slightly bent. The apex has a diameter of 1
It has a hemispherical shape with a diameter of 1 to 15 μm, and a measurement occurs from the upper half.

Metric is 5.0-7. OX2. It has a size of 0 to 2.5 μm and is colorless. Also, Aialide is 6.0-8. O
X is 1.5 to 2.0 μm.

Conidia have a diameter of 2.0-0.5 μm, are spherical to spheroidal, and have a smooth surface.

No sexual spores are observed.

(b) Growth status on various media This strain was inoculated onto various agar media shown below, and grown at 25°C.
The macroscopic observation results when culturing for 10 days to form huge colonies are as follows.

<Malt extract agar medium> Growth is good, the surface is relatively flat, and the edges spread out radially. The center area is rich in spore formation and has a slightly brownish-yellow color. The surrounding area is covered with white mycelia. The back side is ocher.

〈Zapek agar medium〉 It grows well and is white, cottony and slightly raised.

The margins are localized. The center has a slightly pale yellow color. The back side is light ocher.

<Vallejo glucose agar medium> Good growth. The white hyphae grow densely, the center is light yellow, and spore formation is abundant. The underside is dark brown.

<Sabouraud agar medium> Good growth. White mycelium spreads like cotton.

There is a faint yellow tinge near the center. The back side is orange.

<Oatmeal agar medium> Growth is good, but mycelium on the surface is sparse. Spore formation is abundant and light brown in color. The back side is ocher.

<YpSS agar medium> Good growth. It is flat and densely grown. The mycelium is white with a bright yellow center and a slightly light brown color in the center. The back side is yellow.

(C) Physiological properties Growth temperature range = 17-45°C Growth pH range = 3-10 Optimal growth temperature range = 25-38°C Optimum growth pH range: 5-8 Based on the above mycological properties , Kenneth Bee Raper (
ENNETHB, RAPER) and DOROTHY 1.FENNELL,
The Genus A
spergillus).

As a result of a search conducted in accordance with 1977, this strain forms metoli, the conidial head is long cylindrical and yellow, the conidiophore is colorless, and the apical capsule is hemispherical. Aspergillus terreus (Aspergillus terreus)
It was identified as a strain belonging to P. terreus. Therefore, this strain was used as Aspergillus tereus OF R-
1562 (Asperoillus sterreus OF
It was named R-1562>.

Compound 1A of the present invention can be produced by culturing a bacterium belonging to the genus Aspergillus, such as the above-mentioned Aspergillus terreus strain 0FR-1562 and its mutant strains, and having the ability to produce the above-mentioned compound 1A, in an appropriate medium. The method for culturing the above-mentioned microorganisms is in principle based on the culture method for general microorganisms, but it is usually preferable to carry out the culture under aerobic conditions such as a shaking culture method using liquid culture or an aerated agitation culture method.

The medium used for culturing may be any medium containing a nutrient source that can be used by microorganisms belonging to the genus Aspergillus, and any of various synthetic media, semi-synthetic media, natural media, etc. can be used.

As for the medium composition, carbon sources such as glucose, sucrose, fructose, glycerin, dextrin, starch, molasses, corn staple liquor, and organic acids may be used alone or in combination. As the nitrogen source, organic nitrogen sources such as pharmamedia, peptone, meat extract, yeast extract, soy flour, casein, amino acids, and urea, and inorganic nitrogen sources such as sodium nitrate and ammonium sulfate can be used alone or in combination. Sodium salts, potassium salts, magnesium salts, phosphates, other heavy metal salts, etc. may also be added and used as necessary. If foaming is significant during culture, various known antifoaming agents may be appropriately added to the culture medium, but it is necessary that the addition and use thereof do not adversely affect the production of the target compound.

The pH of the medium is preferably within the optimum pH range of the microorganism, usually around neutrality. The culture temperature is preferably kept at a temperature at which microorganisms can grow well, usually from 17 to 45°C, particularly preferably around 30°C. In the case of liquid culture, the culture time is generally about 1 to 5 days. The desired compound is produced and accumulated through the above culture. Of course, the various culture conditions described above can be changed as appropriate depending on the type and characteristics of the microorganism used, external conditions, etc., and optimal conditions are selected and adjusted from the above ranges accordingly.

Isolation of the substance produced by the above-mentioned culture is carried out by a salting-out method such as ammonium sulfate precipitation method, for example, according to a general method for collecting fermentation products, when the accumulation of the substance reaches its maximum.
It can be carried out by using various means such as dialysis, extraction, various gel chromatography, ion exchange chromatography, adsorption chromatography, etc. alone or in combination in any order.

More specifically, since the target compound produced by the above culture is mainly present in the culture liquid (furnace liquid), filtration,
After first separating the culture furnace fluid from the bacterial solids by means such as centrifugation, the resulting furnace fluid is extracted with ethyl acetate, etc.
The extract layer containing the target substance may be concentrated, and then the concentrated solution may be further purified, for example, by silica gel column chromatography, chromatography using a Sephadex LH20 column (manufactured by Pharmacia), or the like.

The details will be shown in Examples below.

The compound 1A of the present invention thus obtained has the formula (1) (
However, in the formula, A represents 10H=CH-), and it has various physical and chemical properties shown in the examples below. Furthermore, as will be described later, Compound 1A has pharmacological effects such as anti-proteinuric action against Masugi nephritis, and is useful in the pharmacological and clinical fields as a therapeutic agent for nephritis.

Moreover, the compound 1B of the present invention can be produced by 'aJ' by using the above compound 1A as a starting material and subjecting it to catalytic reduction treatment. This catalytic reduction can be carried out according to various conventional methods, typically using a catalytic reduction catalyst in a suitable solvent. Catalytic reduction catalysts used include, for example, platinum catalysts such as platinum oxide, platinum black, and colloidal platinum, palladium black, palladium chloride, palladium oxide, palladium-carbon, palladium-barium sulfate, and palladium-carbon.
Palladium catalysts such as barium carbonate and spongy palladium, nickel catalysts such as reduced nickel, nickel oxide, and Raney nickel, cobalt catalysts such as reduced cobalt and Raney cobalt, reduced iron, iron catalysts such as Raney iron, reduced copper, and Raney copper. It is possible to demonstrate copper catalysts such as In addition, as a solvent,
For example, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, and anisole, nitro compounds such as nitromethane and nitrobenzene, alcohols such as methanol and ethanol, and acetic acid. Acetate esters such as ethyl and methyl acetate; aliphatic hydrocarbons such as hexane, heptane and octane; aromatic hydrocarbons such as benzene, toluene and xylene; amines such as pyridine and piperidine; dimethylformamide and hexamethylphosphorus. Examples include aprotic polar solvents such as acid triamide and dimethyl sulfoxide, carbon disulfide, water or a mixed solvent of water and various organic solvents such as 2nd etc. The amount of the catalytic reduction catalyst to be used is about 0.1 to 10 times the molar amount, preferably about 0.1 to 1 times the molar amount of the compound 1A used as the starting material. This is usually carried out at a temperature of about 0 to 200°C, preferably about 0 to 100'C, and is generally completed in about 30 minutes to 48 hours.

After the completion of the above reaction, by conventional separation and purification methods such as solvent extraction, column chromatography, recrystallization, etc.
Target compound of the present invention 1B@: Can be easily isolated. More specifically, as this separation means, for example, after extraction with ethyl acetate, column chromatography using a Sephadex LH-20 column is performed, and both the obtained fractions are crystallized in methanol.

The compound 1B of the present invention thus obtained is the same as the compound 1A
In addition to having similar pharmacological effects such as anti-protein action against Masugi nephritis, it also has an inhibitory effect on superoxide (02-), which is released by stimulation from rabbit neutrophils, and is effective against nephritis. It is useful as a therapeutic agent, and also as a prophylactic and therapeutic agent for autoimmune diseases such as rheumatism, arteriosclerosis, ischemic heart disease, ischemic brain damage, liver failure, renal failure, etc. in which the superoxide radicals are involved, It is useful in various clinical fields.

When the compounds of the present invention are used as pharmaceuticals containing them as active ingredients, they are usually prepared in the form of pharmaceutical preparations. The formulation contains commonly used fillers,
It is adjusted using diluents or excipients such as enhancers, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, liquids, suspensions, emulsions, granules, capsules, small portions, and injections (liquids). , suspensions, etc.), ointments, etc. When forming into a tablet, carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propatool, simple syrup, etc. , glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate,
Binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate,
Disintegrants such as stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc., absorption enhancers such as quaternary ammonium bases, sodium lauryl sulfate, etc., humectants such as glycerin, starch, etc. Adsorbents such as , starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol can be used. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets.

When forming into a pill form, carriers include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and laminaran. , agar, etc. can be used. When molding into small pieces, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. can be used as carriers. Capsules are usually prepared by mixing the active ingredient with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules, etc. according to conventional methods.

When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and when molded into these forms, diluents such as water, water, etc.
Ethyl alcohol, macrogol, propylene glycol, ethoxylated instearyl alcohol, polyoxylated instearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used. In this case, a sufficient amount of salt, glucose, or glycerin may be included in the pharmaceutical preparation to adjust the isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. You can. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary. When forming into a paste, cream or gel form, white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as diluents.

The amount of the active ingredient to be contained in the above pharmaceutical preparation is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 70% by weight in the pharmaceutical preparation.

The method of administering the above pharmaceutical preparation is not particularly limited and is determined depending on various preparation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and furthermore, if necessary, are administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. Small portions are administered rectally.

The dosage of the above pharmaceutical preparation is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the amount of the active ingredient is usually about 0.5 to 30 per kg of body weight per day.
The dosage is preferably on the order of mg, and the preparation can be administered in 1 to 4 divided doses per day.

Examples Hereinafter, production examples of the compounds of the present invention and pharmacological test examples of the obtained compounds will be given as examples.

Example 1 Production of compound 1A of the present invention 1 Cultured microorganism starch 30CJ/Q, glucose 5CJ/Q, soybean flour 5Q/Q, yeast extract 1Q/Q, polypeptone 1Q/Q, CaCO33Q/Q and Mg5Oa 0.5
Pour 100 mQ of a medium consisting of CJ/Q into a 500 mQ Erlenmeyer flask, and add Aspergillus terreus 0F.
One platinum loopful of preserved slant-cultured bacterial cells of R-1562 strain (Keiken Bacteria No. 9611) was inoculated and incubated at 28°C.
The culture was performed by shaking or rotating for 20 hours.

The 0FR-1562 strain was incubated at 30°C in a slant medium (pH 6.5) containing 4% maltose, 1% polypeptone, and 2% agar.
The image below was cultured for one week.

2 Purification of Target Substance After culturing in 1 above, the culture was filtered to obtain 100 mQ of culture solution.

The above culture solution was extracted with ethyl acetate, the ethyl acetate layer was concentrated, the concentrate was purified by silica gel column chromatography (eluent; chloroform:ethyl acetate = 2:1), and the active fraction was purified with Sephadex LH-20 column. (manufactured by Pharmacia), and both fractions eluted with chloroform:methanol=1=1 were collected and concentrated to obtain the target compound 1A. The maximum amount of target material collected per 1Q of culture solution is approximately 10m! ;It was I.

3. Identification of target substance Compound 1A thus obtained had the following physical and chemical properties.

Infrared absorption spectrum (IR): The IR analysis diagram for the KBr tablet is as shown in Figure 1, and the following main absorptions are observed.

3300.3050.2960.1650.1630.
1540,1490,740.695Cm-' Nuclear Magnetic Resonance Spectrum (PMR): PMR measured at 400 MHz in CD CQ 3
The analysis results are shown in FIG. The main peaks are shown below.

9.59 (d, J=9.3), 8.09 (br>7
．． 81 (d, J=7.5> 7.77 (d, J=7.5> 7.46 (dd, J=14.7, 9.3) 7.1-7
．． 35 (m> 6.52 (d, J=14.7) 6.27 (d, J=14.7> 6.18 (d, J=8.02> 6.00 (d, J=8. 02>5.25 (t, J=7.2>4.89 (t, J=7.2) 4.72 (dd, J=6.7,8.02>4.50
(t, J=8.02>3.52 (dd, J=7.2,14..2>3.44
(dd, J=7.2, 14.2) 3-11 (s
> 3.07 (dd, J=7.2. 14.2>3, 0
0 (s> , 2.96 (rrr) 2.10 (S
), 2.00 (m) 1.98 (s>, 1.32 (m> 0.93 (d, J=6.7> 0.85 (d, J=6.7) 0.66 (d , J=6.7> Example 2 Production of the present compound 1B
1 was dissolved in 5 ml of ethanol, 5 mg of palladium-carbon (Pd-C) was added as a catalyst to this solution, and the mixture was stirred overnight at room temperature to perform a catalytic reduction reaction. After the reaction was completed, the reaction solution was filtered, ethanol was distilled off, and the target compound was purified by silica gel column chromatography (developing solvent: benzene: ethyl acetate - 2:1) to obtain 40 m (l@
Obtained.

Compound 1B thus obtained has the following physical and chemical properties, and has the general formula (1) (where A is CH2CH2
- group) was confirmed to have the structure.

Infrared absorption spectrum (IR): The IR analysis diagram for the KBr tablet is as shown in Figure 3, and the following main absorptions are observed.

3380.3050, 3000゜1680 (sh), 1650, 1550.1470
, '1100,750.710Cm-' Mass spectrum (MS): M = 462.303.179.143 Nuclear magnetic resonance spectrum (PMR): PMR analysis results measured at 400 MHz in CDCQ3 are As shown in the figure. The main peaks are shown below.

8.28 (br), 8°24 (br) 7.59 (
d, J=7.6>7.53 (d, J=7.6>7.50 (br), 7.15-7.37 (m>7.
10 (t, J=7.6> 6.88 (d, J=2.0> 6.86 (d, J=2.0> 6.25 (d, J=8.0> 5.99 ( t, J=6.0>5.95 (d, J=8.8>5.17 (t, J=7.6>4.77 (t, J=6.0>4.62 (dd, J=8.8.6.8)4.37 (
t, J=8.0>3.62 (m>, 3.54 (m>3.47 (m
> 3.40 (dd, J=14.1, 6.0>3.32
(dd, J=14.1, 7.6>2.97 (S), 2
．． 91 (s>2.85-2.90 (m>, 1.
95 (br) 1.90 (s>, 1.75 (s> 1.77 (rn>, 1.31 (m>0.77
(d, J=6.8>0.76 (d, J=6.8) 0.75 (d, J=6.8>0.56 (d, J=6.8) <Pharmacology Test Example 1 〉 Rabbit neutrophils (PMNs) convert blood into Ficoll (Ficoll).
COl + ) liquid (specific gravity '1.077) and 25
It was obtained by centrifugation at 1500 ppm for 1 minute and prepared by washing with Hank's Solution.

02- was measured using the cytochrome C reduction method (T.

Matsumoto, Ni, Ta, Keshige an
dS,) linakami.

Biochemical and Biophysics
al Research Communications
, 88 (3), 974-979 (1979))
The following procedure was carried out according to the following. That is, PMN was added to a final concentration of 2×10 6 to a 50 μM cytochrome C solution 'I mQ, the compound of the present invention or water (control group) was added, and the mixture was incubated for 1 minute at 37°C. Next, cytochalasin B was added at 5μcJ/mQ, concanavalin (concanavalin)
+r n)A was added to give 100 μC1/+nQ, and the reaction was allowed to proceed for 1 minute. The difference in absorbance at OD 550 during this period was measured, and the IC5° value was calculated as a ratio to the control group.

As a result, both the compounds 1A and 1B of the present invention have an IC5o
The value was 80 μq/mQ.

<Pharmacological Test Example 2> A rice bowl toxin (abbreviated as rNTJ) 70 toxin (abbreviated as rNTJ) was prepared as follows. That is, the rat kidney cortex (k
idney cortex> with an equal volume of physiological saline, and the resulting homogenate was treated with Freund's Complete Adjuvant (Freurid's Co., Ltd.).
complete adjuvant (manufactured by ifco)
The resulting mixture 2ynQ was injected intramuscularly into rabbits (body weight >3.1 kg) to induce immunization. Part 1
．． After 5 months, blood was collected from the rabbit's heart to obtain serum. After inactivating the obtained serum at 56°C for 30 minutes,
It was fractionated by salting out using 0% saturated ammonium sulfate. The immunoglobulin-gamma-globulin (IgG) fraction was collected to obtain the desired NT.

For this test, Wistar strain (W) weighing 150-160g was used.
i5ter) Male rats were used, and one dose of NT was intravenously injected into the tail vein of the rats. Further, the compound of the present invention was similarly injected intravenously into the tail vein of rats at 30 ml/ko at the same time as the above-mentioned NT administration. A physiological saline administration group was established as a control group.

Urine protein amount (υrinarvProtein) (
The total amount excreted in urine for 24 hours after administration of antiserum) is
Turbidity method using bovine serum albumin (BSA) with sulfosalicylic acid as a control (J, Iab, CI ir, Med
, , 1 yu.

981-989 (1926), in ngsbury
, F, B.

Chark, C.P. et al.), and the urinary protein suppression rate (%) in the group administered with the compound of the present invention was determined based on the measured value in the control group.

The results are shown in Table 1 below with Mean±S, [, 6 animals in each group.

From the test results shown in Table 1 and above, the compound of the present invention has an inhibitory effect on superoxide radicals and also has an anti-proteinuric effect on nephritis, and is useful not only as a therapeutic agent for nephritis but also as a 02- It is expected to be widely used as a medicine for various diseases that are assumed to be involved, such as autoimmune diseases such as rheumatoid arthritis, arteriosclerosis, ischemic heart disease, ischemic brain damage, liver failure, and renal failure.

Examples of formulations using the compounds of the present invention are listed below.

Formulation Example 1 Compound 1A of the present invention 150.0 CI citric acid 1.0 CI lactose 33.5 C] dicalcium phosphate 70.0 g Prone F-68 (PI
uronicF-68) 30, 0 g sodium lauryl sulfate 15. OQ polyvinylpyrrolidone 15. OC] polyethylene glycol
4.5g (Carbowax 1500) Polyethylene glycol 45. OQ (Carbowax 6000) Cornstarch 30.0CI Dry Sodium Lauryl Sulfate 3.0g Etate Dry Magnesium Stearate 3.0CI Ethanol Appropriate amount Water Invention Compound 1A
, citric acid, lactose, dicalcium phosphate, Purone F-68 and sodium lauryl sulfate.

The above mixture is sieved through a NO.60 screen and wet granulated with an alcoholic solution consisting of polyvinylpyrrolidone, Carbowax 1500 and Carbowax 6000. Add alcohol if necessary to make the powder into a pasty mass. Add cornstarch and continue mixing until uniform particles are formed. No. 10 Pass through a screen, put in a tray, and heat in a 100℃ oven for 12~
Dry for 14 hours. The dry particles are sieved through a NO. 16 screen, dry sodium lauryl sulfate and dry magnesium stearate are added, mixed and compressed into the desired shape in a tablet machine.

The core is treated with varnish and sprinkled with talc to prevent moisture absorption. A subbing layer is applied around the core.

Apply varnish a sufficient number of times for internal use. In order to make the tablet completely round and smooth, further subbing layers and smoothing coats are applied.

Pigmented coatings are applied until the desired shade is achieved. After drying, the coated tablets are polished to obtain uniformly glossy tablets.

[Brief explanation of the drawing]

FIG. 1 is an IR analysis diagram of the compound 1A of the present invention as a 8r tablet, and FIG. 2 is a diagram showing the PMR analysis results of the same substance. Moreover, FIG. 3 shows the IR of the compound 1B of the present invention as a KBr tablet.
This is an analysis diagram, and FIG. 4 is a diagram showing the PMR analysis results of the same substance. (that's all)

Claims (1)

[Claims] (1) Indole derivative represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, A represents -CH=CH- or -CH_2CH_2-.)