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GB2122602A - Novel 2,3-dihydro-indene derivatives - Google Patents
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GB2122602A - Novel 2,3-dihydro-indene derivatives - Google Patents

Novel 2,3-dihydro-indene derivatives Download PDF

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GB2122602A
GB2122602A GB08216496A GB8216496A GB2122602A GB 2122602 A GB2122602 A GB 2122602A GB 08216496 A GB08216496 A GB 08216496A GB 8216496 A GB8216496 A GB 8216496A GB 2122602 A GB2122602 A GB 2122602A
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dihydro
indene
oxo
acid
compd
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Kanji Noda
Akira Nakagawa
Kenji Yamagata
Yoichi Nakashima
Masayoshi Tsuji
Tetsuo Aoki
Hiroyuki Ide
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Hisamitsu Pharmaceutical Co Inc
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Hisamitsu Pharmaceutical Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/86—Unsaturated compounds containing keto groups containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/88—Unsaturated compounds containing keto groups containing halogen

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Novel 2,3-dihydro-indene derivatives having remarkable anti-inflammatory effects and represented by the following formula <IMAGE> wherein R<1> and R<2> are each a hydrogen atom, halogen atom, nitro group, lower alkyl group or lower alkoxy group with the proviso that R<1> and R<2> do not take a hydrogen atom at the same time, and n is an integer of 2-4.

Description

SPECIFICATION Novel 2,3-dihydro-indene derivatives This invention relates to a novel 2,3-dihydro-indene derivative having the following general formula
wherein n is an integer of 2-4, and R1 and R2 are each a hydrogen atom, nitro group, lower alkyl group or lower alkyloxy group with the proviso that R1 and R2 do not take a hydrogen atom at the same time.
More particularly, in the R1 and R2, the halogen atom is fluorine, chlorine, bromine or iodine, the lower alkyloxy group is methyloxy, ethyloxy, n-propyloxy or like group and the lower alkyl group is methyl, ethyl, n-butyl, isobutyl, n-propyl or isopropyl group.
Conventional compounds which are similar to the compounds of this invention include 4-methyl-oxo-2,3dihydro-2-indene acetic acid [Chemical Abstracts (hereinafter referred to as "C.A."), Vol. 57, 164301], 5,6-dimethoxy-1-oxo-2,3-dihydro-2-indene acetic acid (C.A. Vol. 73, 45192n), 5-methoxy-l -oxo-2,3-dihydro-2- indene acetic acid (C.A. Vol. 67, 1167391 < ), 4,7-dimethyl-l -oxo-2,3-dihydro-2-indene acetic acid (C.A. Vol.74, 88156s), 5-chloro-l -oxo-2,3-dihydro-2-indene acetic acid (C.A. Vol. 88, 104975e), 5-bromo-l -oxo-2,3-dihydro- 2-indene acetic acid (C.A. Vol. 90, 72131z) and 4-methoxy-1-oxo-2,3-dihydro-2-indene butyric acid (C.A. Vol.
88, 1 04979j). These similar compounds described in the above respective Chemical Abstracts are each disclosed as an intermediate for a certain end compound and, thus, the Chemical Abstracts neither teach nor even suggest anything about the medicinal utility of the similar compounds, not to speak of the pharmacological effects such as anti-inflammatory effect, analgesic effect, antipyretic effect, antiallergic effect, anticomplementary effect, anti-blood platelet aggregation effect and anti-hypercholesterol effect, although it is not known at all whether or not said similar compounds have such medicinal utility and pharmacological effects. It is only the process and chemical reactions for the production of the similar compounds that the Chemical Abstracts disclose.
The compounds of this invention are novel ones which have not yet described in any existing literature.
They have useful pharmacological effects such as remarkable anti-inflammatory effects, that is, anaphylaxis type, cytotoxicity type, Arthus type and cell-mediated immune type antiallergic effects, and particularly they exhibit high pharmacological activity in the case of the Arthus type effect. They are useful as a drug for prevention and treatment of allergic diseases such as nephritis, rheumatism, collagenosis and autoimmune diseases. They further have anti-blood platelet aggregation effect, anti-inflammatory effect, analgesic effect, antipyretic effect, anti-hypercholesterol effect and the like, and they are therefore useful as medicines.
Conventional non-steroid type medicines having an anti-inflammatory action are typified by indomethacin. Indomethacin is frequently taken by rheumatics and the like, but it is disadvantageous in that, for example, it must be taken continuously for a long period of time and administered in a great dose thereof with the result that it raises a problem as to gastrointestinal, liverish, renal and like diseases caused thereby as side effects.
In the treatment of nephritis, a hypotensive drug (such as cr-methyldopa or p-blocker) is used in the existence of high blood pressure, a diuretic drug (such as Furosemide) is used in the presence of remarkable swelling and anti-cholesterol drug or the like is used in the presence of nephrosis since hypercholesteremia is caused in this case. However, any of these treatments is no more than a general symptomatic one and is not a fundamental one.
Thus the present inventors made intensive studies in an attempt to obtain novel compounds which are of non-steroid type and are effective for inflammatory diseases associated with immunity and, as a result of their studies, they synthesized 2,3-dihydro-indene derivatives having the general formula (I) previously described and found after their various studies of pharmacological effects of the novel compounds that the novel compounds inhibit an Arthus type reaction which is not inhibited by the widely-used conventional anti-inflammatory drugs. As is seen from the above, the novel compounds have remarkable pharmacological effects and are very different from the conventional non-steroid type anti-inflammatory drugs in the respect that, for example, the former have such a medicinal effect on inflammations associated with immunity.
Even in the broad conception of antiallergy, the fact that the novel compounds exhibit remarkable inhibiting effects on Arthus type inflammatory reactions indicates the utility of the novel compounds as a drug for prevention of treatment of nepphritis, rheumatism, collagenosis, autoimmune diseases and the like.
The novel compounds which are those of this invention, exhibit excellent medicinal effects particularly on rheumatism, that is articular rheumatism and are quite different in functional mechanism from the conventional non-steroid type anti-inflammatory drug. They further have anti-platelet aggregation, anti-inflammatory, analgesic, antipyretic, anti-hypercholesterol and like effects, exhibit a low toxicity value even in acute toxicity tests and are industrially useful as a drug which is very high in safety.
The compounds of this invention are mixed with a pharmaceutically suitable carrier or excipient to form a mixture which is then treated to obtain the mixture in the capsulate, powdery, granular, pill, tablet, suspension, emulsion, syrupy, liquid, to-be-injected, suppository, external application or like form. The thus obtained preparations may be orally or non-orally administered.
A process for the preparation of the compounds of this invention will be mentioned hereinbelow.
The compounds of this invention may be prepared in a good yield by the following process, however, this process is no more than an exemplary one and other processes similar to said exemplary one may also be used for the purpose of this invention.
Preparation A
1 0 Ri 0 a CoR3 2 LJ ., X(CH2)nY C C X 2) hydrolysis R2 (11) (I) In the above formulae, R1 and R2 are each a hydrogen atom, halogen atom, nitro group, lower alkyl group or lower alkyloxy group with the proviso that R' and R2 do not take a hydrogen atom at the same time, R3 is a hydrogen atom, lower alkoxy group or lower alkoxycarbonyl group, Xis a halogen atom, Y is cyano group or lower alkoxycarbonyl group and n is an integer of 2-4.
Preparation B
R1 R4 R 4j :I 2) 1) CHZ=CH-Y hydro ly s ts 2) ydrolysis 2 (III) (1) In the above formulae, R1, R2 and Y are as defined in Preparation A and R4 is pyrrolidino, piperidino or morpholino.
Preparation C
R1 Ri COOn Ra CH2ss 2 n hydrolysis 3 hyd VCH2-CH- (CHz) ,-COOH R COOC2H5 royss R2 (IV) (v) a1 cyclization j, (CH ) n -COOH 2n R2 (I) In the above formulae, R1 and R2 are as defined in Preparation A and n' is an integer of 3-4.
The processes as indicated in Preparations A, B and C will be explained in more detail hereinbelow.
The process as indicated in Preparation A comprises reacting a compound (II) with an alkylating agent in a solvent in the presence of an alkali or an organic amine at room temperature or, if necessary, an elevated temperature for 3-48 hours and then hydrolyzing the resulting reaction product with a mineral acid such as hydrochloric or sulfuric acid to obtain a desired compound having the general formula (I). At the time of said hydrolysis, an organic solvent such as acetic acid may be used in order to keep the reaction uniform. The alkali used herein includes sodium methylate, sodium ethylate, potassium t.-butylate, sodium amide or sodium hydride. The organic amine used herein includestriethylamine, trimethylamine or N,Ndimethylaniline.The solvent used herein includes methanol, ethanol, tetrahydrofuran, benzene, toluene, xylene, dioxane, dimethylformamide, dimethylsulfoxide or hexamethylene-phosphotriamide.
The process as indicated in Preparation B comprises reacting a compound (III) with acrylonitrile or an acrylic acid lower alkyl ester in an organic solvent (such as methanol, ethanol, tetrahydrofuran, dioxane, benzene ordimethylformamide) at 30-120 C for 1-48 hours and, if necessary, under a nitrogen stream and then hydrolyzing the resulting reaction product with a mineral acid (such as hydrochloric or sulfuric acid) in an organic solvent such as acetic acid or with diluted hydrochloric, sulphuric acid or the like without the use of a solvent.
The process as indicated in Preparation C comprises hydrolyzing a compound having the formula (IV) with an alkali (such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) or with a mineral acid (such as hydrochloric or sulfuric acid) to produce a compound having the formula (V). At this time, the thus produced compound (V) may be isolated if necessary or subjected to the next reaction without the isolation thereof.The compound (V) may be cyclized in one step with a condensing agent (such as polyphosphoric acid, phosphoric acid, sulfuric acid, tin tetrachloride, phosphorus oxychloride or hydrobromic acid and acetic acid) or it may be firstly treated with a halogenating agent (such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride or phosphorus tribromide) and then reacting the resulting halogenated compound with a dehalogenating agent (such as aluminum chloride, stannic chloride or zinc chloride) in an inert solvent (such as carbon disulfide or nitrobenzene) to obtain a desired compound (I).
The compounds (if), (III) and (IV) which may be used as a starting compound in this invention, may be easily obtained in accordance with the process of, for example, E.S. Stratford, Journal of Pharmaceutical Sciences, 67,80(1978); E.D. Bergmann, Journal of Organic Chemistry, 26,3555 (1961); or C.K. Ingold, Journal of Chemical Society, 1954, 1204.
This invention will be better understood by the following examples.
Example 1 2.2 g of 6-fluoro-1 -oxo-2,3-dihydro-2-indene ethyl carboxylate were dissolved in 20 ml of dimethylformamide, incorporated with 0.53 g of 50% sodium hydride, agitated at room temperature for 2 hours, incorporated with 3.9 g of 3-bromo-ethyl butyrate, agitated at 90"C for 3 hours and heated to distil off the solvent under a reduced pressure thereby obtaining a residue. The thus obtained residue was incorporated with 20 ml of acetic acid and 15 ml of a 20% solution of sulfuric acid and then refluxed for3 hours. After the end of the reaction, the reaction mixture was incorporated with 100 ml of iced water to precipitate crystals.
The crystals so precipitated were filtered off, washed with water, dried and then recrystallized from isopropyl ether to obtain 1.45 g of 6-fluoro-1 -oxo-2,3-dihydro-2-indene butyric acid in the colorless needle form. The properties of the thus obtained end product are as shown below.
Melting point: 106-107OC Infrared absorption spectrum vc=0: 1705 cm-1 Molecular ion peak (Mass spectrum) M+ (m/e): 236 Example 2 2.4 g of 6-chloro-1 -oxo-2,3-dihydro-2-indene ethyl carboxylate, 1.82 g of triethylamine and 20 ml of benzene were mixed together to form a mixture which was incorporated with 2.93 g of 3-bromo-ethyl butyrate and refluxed for 10 hours. The resulting reaction mixture was then freed of the solvent by distilling it off under a reduced pressure to obtain a residue which was incorporated with 20 ml of acetic acid and 15 ml of 20% sulfuric acid and reacted together under reflux for 3 hours. After the end of the reaction, the reaction mixture was incorporated with 100 ml of iced water to precipitate crystals.The crystals so precipitated were filtered off, washed with water, dried and then recrystallized from ethyl acetate to obtain 1.0 g of 6-chlorn-1-oxo-2,3-dihydrn-2-indene butyric acid in the colorless needle form.
The thus obtained end product had the following properties.
Melting point: 141-142"C Infrared absorption spectrum: vc=O: 1706 cm-1 Molecular ion peak (Mass spectrum) M+ (m/e): 252 Example 3 Twenty-two (22) grams of 3-pyrrolidino-5-chloroindene and 18 g of methyl acrylate were dissolved in 70 ml of dioxane, refluxed for 5 hours and freed of the solvent by distilling it off, to obtain a residue. The thus obtained residue was incorporated with 100 ml of acetic acid and 100 ml of hydrochloric acid and heated for 3 hours. After the end of the reaction, the resulting reaction mixture was freed of the solvent by distilling it off under a reduced pressure and incorporated with iced water to precipitate crystals.The crystals so precipitated were filtered off, washed with water, dried and then recrystallized from ethyl acetateto obtain 16 g of 6-chloro-1-oxo-2,3-dihydro-2-indene propionic acid in the colorless needle form.
The thus obtained end product had the following properties.
Melting point: 171-173 C Infrared absorption spectrum vc=0: 1710 cm- Molecular ion peak (Mass spectrum) M+ (m/e): 238 Example 4 19.2 g of 2-oxocyclohexanecarboxylic acid ethyl ester, 21.4 g of p-fluorobenzyl bromide, 7.7 g of sodium ethoxide and 200 ml of ethanol were mixed together to form a mixture which was refluxed for 2 hours, incorporated with 500 ml of water and subjected to extraction with ethyl ether. The resulting ether layer was freed of the ether to obtain a residue.The thus obtained residue was dissolved in 500 ml of 70% ethanol, incorporated with 16.1 g of potassium hydroxide, refluxed for 3 hours and hydrolyzed to obtain 26.5 g of 1-(4-fluorobenzyl)-1,5-pentane dicarboxylic acid having a melting point of 80-81"C in the colorless needle form. 26 g of the thus obtained compound in the needle form and 300 g of polyphosphoric acid were mixed together to form a mixture which was agitated at 1 00'C for 3 hours. After the end of the reaction, the resulting reaction mixture was incorporated with iced water and subjected to extraction with ethyl acetate.
The organic layer was washed with water, dehydrated and freed of the solvent by distilling it off, thereby to obtain a residue. The thus obtained residue was recrystallized from isopropyl ether to obtain 18.2 g of 6-fluoro-1-oxo-2,3-dihydro-2-indene valeric acid in the colorless platyform.
The end product so obtained had the following properties.
Melting point: 122-123 C Infrared absorption spectrum vc=0: 1705, 1690 cm-l Molecular ion peak (Mass spectrum) M+ (m/e): 250 The end compounds indicated in the following Examples 5-20 are those which were obtained by the process as used in Examples 1-4.
Example5 4-fluoro-1-oxo-2,3-dihydro-2-indene propionic acid Melting point: 103-1050C Infrared absorption spectrum vc=0: 1710 cm-1 Molecular ion peak (Mass spectrum) M+ (m/e): 222 Example 6 6-fluoro-1-oxo-2,3-dihydro-2-indene propionic acid Melting point: 109-110.5"C Infrared absorption spectrum vc=0: 1712 cm- Molecular ion peak Me (m/e): 222 Example 7 4-chloro-1 -oxo-2,3-dihydro-2-indene propionic acid Melting point: 107-110"C Infrared absorption spectrum vc=0: 1705 cm- Molecular ion peak M+ (m/e): 238 Example 8 5-chloro-1 -oxo-2,3-dihydro-2-indene propionic acid Melting point: 184-186"C Infrared absorption spectrum vc=0: 1710 cm-l Molecular ion peak M+ (m/e): 238 Example 9 6-nitro-1-oxo-2,3-dihydro-2-indene propionic acid Melting point: 125-127"C Infrared absorption spectrum vc=0: 1716 cm- Molecular ion peak M+ (m/e): 249 Example 10 4,6-dichloro-1-oxo-2,3-dihydro-2-indene propionic acid Melting point: 142-145"C Infrared absorption spectrum vc=0: 1720, 1700 cm-l Molecular ion peak Me (m/e): 272 Example 11 4-chloro-1-oxo-2,3-dihydro-2-indene butyric acid Melting point: 102-103 C Infrared absorption spectrum vc=0: 1705 cm- Molecular ion peak M+ (m/e): 252 Example 12 6-bromo-1-oxo-2,3-dihydro-2-indene butyric acid Melting point: 155-157 C Infrared absorption spectrum vc=0: 1707 cm-l Molecular ion peak M+ (m/e): 296 Example 13 4,6-dichloro-1 -oxo-2,3-dihydro-2-indene butyric acid Melting point: 114-116 C Infrared absorption spectrum vc=0: 1710, 1700 cm- Molecular ion peak M+ (m/e): 286 Example 14 4-chloro-1-oxo-2,3-dihydro-2-indene valeric acid Melting point: 79-80"C Infrared absorption spectrum vc=0: 1710, 1690 cm- Molecular ion peak M+ (m/e): 266 Example 15 5-chloro-1-oxo-2,3-dihydro-2-indene valeric acid Melting point: 108-110 C Infrared absorption spectrum vc=0: 1705, 1690 cm-1 Molecular ion peak M+ (m/e): 266 Example 16 6-chloro-1-oxo-2,3-dihydro-2-indene valeric acid Melting point: 138-139 C Infrared absorption spectrum vc=0: 1708, 1692 cm- Molecular ion peak M+ (m/e): 266 Example 17 6-bromo-1-oxo-2,3-dihydro-2-indene valeric acid Melting point: 161-163 C Infrared absorption spectrum vc=0: 1710,1694cm- Molecular ion peak M+ (m/e): 310 Example 18 4,6-dichloro-1 -oxo-2,3-dihydro-2-indene valeric acid Melting point: 104-106 C Infrared absorption spectrum vc=0: 1710, 1695 cm-1 Molecular ion peak M+ (m/e): 300 Example 19 6-methyl-1-oxo-2,3-dihydro-2-indene butyric acid Melting point: 123-124 C The pharmacological effects of the compounds of this invention will be substantiated by the following experiments.
Experiment 1 Effect on passive Arthus reaction in rats Groups each consisting of 5-7 male rats of Wistar strain weighing 135-155 g each were tested in this experiment in accordance with the modified method of Denk et al. [Z. Immunitaetsforsch., 138, 169 (1969)].
The rats which had been fasted for 18 hours were sensitized by injecting 0.3 ml of a 10% solutionof an anti BSA rabbit serum (precipitation titer, 32 times) to them at the tail vein. Thirty minutes after their sensitization, they were each induced by hypodermically injecting 0.1 ml of an 0.025% solution of bovine serum albumin (BSA) to them at the plantar portion of their right hind paw. Three hours after having been induced, the volume of the hind paw was measured by the Fujihira et al's method [Pharmacometrics, 5, 169 (1971)] and the swelling inhibiting ratio for each test compound was calculated from the following equation.
The test compounds and indomethacin (as the control) were each suspended in an 0.5% aqueous solution of tragacanth gum and the solutions obtained were orally administered at doses of 100 mg/kg (test compound) and 5 mg/kg (control) to some of the test animals, respectively, one hour beofre they had been induced. On the other hand, only the vehicle was administered to the remainder of the test animals.
Foot volume Foot volume 3 hours after - beforeBSA Swelling ratio ~ BSAinduction induction x 100 (%) =' Foot volume before BSA induction Swelling ratio for Swelling ratio for control group - test compound Swelling administered group x 100 inhibiting = Swelling ratio ratio (%) for control group The results are as shown in Table 1.
TABLE 1 Effect on passive Arthus reaction in rats Amount of No. of Swelling Test Compound administered test inhibiting (mg/kg) animals ratio (%) Compd of Example 1 100 6 26.7 Compd of Example 2 100 6 37.7 Compd of Example 3 100 5 13.7 Compd of Example 5 100 5 41.7 Compd of Example 6 100 7 39.4 Compd of Example 8 100 6 17.5 Compd of Example 11 100 5 13.9 Compd of Example 13 100 6 ' 22.5 Compd of Example 14 100 5 18.6 Compd of Example 15 100 5 35.3 Compd of Example 16 100 6 16.2 Indomethacin 5 5 8.1 Note: The above swelling inhibiting ratios were determined with respect to that for the control group.
Experiment2 Test for acute toxicity on mice Groups each consisting of 6 male mice of ddY strain weighing between 22 and 26 g were used in this experiment.
Suspensions of the test compounds and indomethacin as the control in an 0.5% aqueous solution of tragacanth were orally administered respectively to the test animals, after which the test animals had been observed for a week to find the lethality thereof. The results are as indicated in Table 2.
TABLE 2 Amount of administered Test compound (mg/kg) Lethality 1) Compd. of Example 1 2,000 1/6 Compd. of Example 2 2,000 2/6 Compd. of Example 5 2,000 2/6 Compd. of Example 6 500 0/6 Compd. of Example 6 1,000 0/6 Compd. of Example 6 2,000 2/6 Compd. of Example 13 2,000 1/6 Compd. of Example 14 2,000 0/6 Compd. of Example 15 2,000 0/6 Indomethacin 50 6/6 1) Lethalities found one week after the administration.
It is apparent from the above pharmacological experimental results that the compounds of this invention are those associated with immunity, have remarkable pharmacological effects as compared with indomethacin which is typical of conventional non-steroid preparations, and exhibit low toxicity.

Claims (3)

1. 2,3-dihydro-indene derivatives having remarkable anti-inflammatory effects and represented by the following general formula (I)
wherein R1 and R2 are each a hydrogen atom, halogen atom, nitro group, lower alkyl group or lower alkyloxy group with the proviso that R1 and R2 do not take a hydrogen atom at the same time, and n is an integer of 2-4.
2. 2,3-dihydro-indene derivatives, substantially as described in any one of the foregoing Examples.
3. A pharmaceutical composition which comprises a 2,3-dihydro-indene derivative as claimed in claim 1 or 2 in association with a pharmacologically acceptable carrier.
GB08216496A 1982-06-07 1982-06-07 Novel 2 3-dihydro-indene derivatives Expired GB2122602B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115315298A (en) * 2020-07-13 2022-11-08 日本碍子株式会社 Refining method

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115315298A (en) * 2020-07-13 2022-11-08 日本碍子株式会社 Refining method
CN115315298B (en) * 2020-07-13 2023-09-15 日本碍子株式会社 Refining method

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