JPH10182685A - Production of n-acetylmannosamine - Google Patents
Production of n-acetylmannosamineInfo
- Publication number
- JPH10182685A JPH10182685A JP34792696A JP34792696A JPH10182685A JP H10182685 A JPH10182685 A JP H10182685A JP 34792696 A JP34792696 A JP 34792696A JP 34792696 A JP34792696 A JP 34792696A JP H10182685 A JPH10182685 A JP H10182685A
- Authority
- JP
- Japan
- Prior art keywords
- acetylmannosamine
- boric acid
- acetylglucosamine
- isomerization
- producing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- OVRNDRQMDRJTHS-OZRXBMAMSA-N N-acetyl-beta-D-mannosamine Chemical compound CC(=O)N[C@@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-OZRXBMAMSA-N 0.000 title claims abstract description 46
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 10
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 claims abstract description 22
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 claims abstract description 22
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000004327 boric acid Substances 0.000 claims abstract description 19
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 claims abstract description 18
- 238000006317 isomerization reaction Methods 0.000 claims abstract description 18
- 229950006780 n-acetylglucosamine Drugs 0.000 claims abstract description 18
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 238000004255 ion exchange chromatography Methods 0.000 description 3
- ZUQUTHURQVDNKF-WZPXOXCRSA-N 1-[(3S,4R,5S,6R)-3-amino-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]ethanone Chemical compound C(C)(=O)C1(O)[C@@H](N)[C@@H](O)[C@H](O)[C@H](O1)CO ZUQUTHURQVDNKF-WZPXOXCRSA-N 0.000 description 2
- 241000238557 Decapoda Species 0.000 description 2
- -1 N-acetylmannosamine-boric acid Chemical compound 0.000 description 2
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 2
- 238000005277 cation exchange chromatography Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- OVRNDRQMDRJTHS-ZTVVOAFPSA-N N-acetyl-D-mannosamine Chemical compound CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-ZTVVOAFPSA-N 0.000 description 1
- SQVRNKJHWKZAKO-PFQGKNLYSA-N N-acetyl-beta-neuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-PFQGKNLYSA-N 0.000 description 1
- DRUQKRWRXOUEGS-NGERZBJRSA-N Samin Chemical compound C1=C2OCOC2=CC([C@H]2OC[C@H]3[C@@H]2CO[C@@H]3O)=C1 DRUQKRWRXOUEGS-NGERZBJRSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、Ｎ−アセチルマン
ノサミンを高収率で生産することができるＮ−アセチル
マンノサミンの製造方法に関するものである。The present invention relates to a method for producing N-acetylmannosamine which can produce N-acetylmannosamine in high yield.
【０００２】[0002]
【従来の技術】Ｎ−アセチルマンノサミン(ManNAc)は、
例えば、医薬品や医薬品原料となるシアル酸（Ｎ−アセ
チルノイラムン酸）の酵素合成原料として用いられてい
るが、このＮ−アセチルマンノサミンは天然界からの供
給源はほとんどないため非常に高価なものであり、安価
な供給源が求められていた。2. Description of the Related Art N-acetylmannosamine (ManNAc)
For example, it is used as a raw material for synthesizing enzymes of sialic acid (N-acetylneuraminic acid), which is used as a drug or a raw material of a drug. Therefore, an inexpensive source was required.
【０００３】そこで、最近ではＮ−アセチルマンノサミ
ンの異性体であるＮ−アセチルグルコサミン(GlcNAc)を
異性化により変換して得る技術が提案されている。この
Ｎ−アセチルグルコサミンは、蟹や海老などの甲羅より
比較的多量かつ安価に得ることができるものである。と
ころが、このＮ−アセチルグルコサミンをアルカリ条件
下で異性化してＮ−アセチルマンノサミンとする製造方
法では、異性化によるＮ−アセチルマンノサミンの変換
収率が１７〜１８％が限度であるととともに、反応速度
も遅いため十分に安価な供給ができないという問題点が
あった。Therefore, a technique has recently been proposed in which N-acetylglucosamine (GlcNAc), which is an isomer of N-acetylmannosamine, is converted by isomerization. This N-acetylglucosamine can be obtained in a relatively large amount and at a lower cost than shells such as crab and shrimp. However, in the production method of isomerizing N-acetylglucosamine under alkaline conditions to obtain N-acetylmannosamine, the conversion yield of N-acetylmannosamine by isomerization is limited to 17 to 18%. At the same time, there was a problem that the supply was not sufficiently inexpensive due to the low reaction rate.
【０００４】[0004]
【発明が解決しようとする課題】本発明は上記のような
従来の問題点を解決して、異性化によるＮ−アセチルマ
ンノサミンの変換収率が高く、かつ反応速度も速くてＮ
−アセチルマンノサミンの供給を従来よりも安価に行う
ことができるＮ−アセチルマンノサミンの製造方法を提
供することを目的として完成されたものである。SUMMARY OF THE INVENTION The present invention solves the above-mentioned conventional problems and provides a high conversion yield of N-acetylmannosamine by isomerization, a high reaction rate, and a high reaction rate.
-Acetylmannosamine has been completed for the purpose of providing a method for producing N-acetylmannosamine which can supply acetylmannosamine at a lower cost than before.
【０００５】[0005]
【課題を解決するための手段】上記の課題を解決するた
めになされた本発明のＮ−アセチルマンノサミンの製造
方法は、Ｎ−アセチルグルコサミンをアルカリ条件下で
異性化してＮ−アセチルマンノサミンとするＮ−アセチ
ルマンノサミンの製造方法において、異性化する際にホ
ウ酸またはホウ酸塩を添加することにより、Ｎ−アセチ
ルマンノサミンへの異性化率を増大させることを特徴と
するものである。なお、添加する前記ホウ酸またはホウ
酸塩はホウ酸濃度を５０ｍＭ以上、１Ｍ以下の範囲で添
加することが好ましい。Means for Solving the Problems A method for producing N-acetylmannosamine according to the present invention, which has been made to solve the above-mentioned problems, comprises a process for isomerizing N-acetylglucosamine under alkaline conditions to produce N-acetylmannosamine. In the method for producing N-acetylmannosamine as a samin, the rate of isomerization to N-acetylmannosamine is increased by adding boric acid or a borate during isomerization. Things. The boric acid or borate to be added is preferably added at a boric acid concentration of 50 mM or more and 1 M or less.
【０００６】[0006]
【発明の実施の形態】 以下に、本発明の好ましい実施
の形態を示す。本発明における、Ｎ−アセチルグルコサ
ミン(GlcNAc)を異性化してＮ−アセチルマンノサミン(M
anNAc)とする処理技術は公知のものであり、前記Ｎ−ア
セチルグルコサミン(GlcNAc)としては蟹や海老などの甲
羅より採取されたものが採用される。そして、この異性
化処理はｐＨが９．５〜１３のアルカリ条件下で処理が
行われ、該アルカリの化学的作用によって化合物を構成
する原子または原子基の結合状態を換えることにより、
Ｎ−アセチルグルコサミンから他の異性体であるＮ−ア
セチルマンノサミンへ変換する。BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, preferred embodiments of the present invention will be described. In the present invention, N-acetylglucosamine (GlcNAc) is isomerized to give N-acetylmannosamine (M
The processing technique used for anNac) is known, and as the N-acetylglucosamine (GlcNAc), one collected from shells such as crab and shrimp is used. This isomerization treatment is carried out under alkaline conditions having a pH of 9.5 to 13, and by changing the bonding state of atoms or atomic groups constituting the compound by the chemical action of the alkali,
The conversion of N-acetylglucosamine to another isomer, N-acetylmannosamine.
【０００７】そして本発明においては、異性化する際に
ホウ酸またはホウ酸塩を添加することにより、Ｎ−アセ
チルマンノサミンへの異性化率を増大させる点に特徴を
有する。即ち、異性化の際にホウ酸またはホウ酸塩を添
加することにより異性化率が向上することを見出し本発
明に至ったものであり、その理由は以下のとおりであ
る。つまり、Ｎ−アセチルグルコサミンはホウ酸または
ホウ酸塩と容易、かつ速やかに反応して負の電荷をもつ
Ｎ−アセチルマンノサミン−ホウ酸錯体を形成すること
により、消化されることになり、この結果、見かけ上の
化学平衡がシフトするので反応液内においては更に次の
異性化が起こり、このように次々と異性化反応が進むこ
とでＮ−アセチルマンノサミンの変換率が大幅に向上す
ることになるのである。なお添加する前記ホウ酸または
ホウ酸塩はホウ酸濃度を５０ｍＭ以上、１Ｍ以下の範囲
で添加することが好ましい。これは、ホウ酸濃度が５０
ｍＭ未満であるとＮ−アセチルマンノサミンへの異性化
率向上の効果が小さく、一方、ホウ酸濃度が１Ｍより大
きくてもＮ−アセチルマンノサミンへの異性化率向上の
効果がそれ以上良くならないからである。The present invention is characterized in that the rate of isomerization to N-acetylmannosamine is increased by adding boric acid or a borate during isomerization. That is, it has been found that the isomerization ratio is improved by adding boric acid or a borate at the time of isomerization, and the present invention has been achieved, for the following reasons. That is, N-acetylglucosamine easily and quickly reacts with boric acid or a borate to form a negatively charged N-acetylmannosamine-boric acid complex, thereby being digested, As a result, the apparent chemical equilibrium shifts, so that the next isomerization occurs in the reaction solution, and the conversion of N-acetylmannosamine is greatly improved by such successive isomerization reactions. It will be. The boric acid or borate to be added is preferably added at a boric acid concentration of 50 mM or more and 1 M or less. This is because boric acid concentration is 50
When the concentration is less than mM, the effect of improving the isomerization rate to N-acetylmannosamine is small, while the effect of improving the isomerization rate to N-acetylmannosamine is higher even when the boric acid concentration is higher than 1M. Because it doesn't get better.
【０００８】このようにして得られた反応液はＮ−アセ
チルマンノサミン−ホウ酸錯体が負の電荷を有している
ことを利用して、例えばイオン交換クロマトグラフィー
や濾紙電気泳動などによって、Ｎ−アセチルグルコサミ
ンとＮ−アセチルマンノサミンとを分離しＮ−アセチル
マンノサミンのみを効率的、かつ高い収率で回収するこ
とができる。[0008] The reaction solution thus obtained is subjected to, for example, ion exchange chromatography or filter paper electrophoresis, utilizing the fact that the N-acetylmannosamine-borate complex has a negative charge. N-acetylglucosamine and N-acetylmannosamine can be separated, and only N-acetylmannosamine can be efficiently recovered at a high yield.
【０００９】[0009]
【実施例】以下、本発明の具体例を実施例として示す。 〔実施例１〕Ｎ−アセチルグルコサミン(GlcNAc)２００
ｇを１リットルの水に溶解し、これにホウ酸２５０ｍＭ
を加え、更に４Ｎ ＮａＯＨ水溶液を添加してｐＨ１
０．５に調整した。これを、３７℃の恒温水槽に入れて
反応させた。経時的にサンプリングして、５Ｎ塩酸水溶
液でｐＨ７．０に中和し、イオン交換クロマトにより変
換したＮ−アセチルマンノサミン量を定量分析したとこ
ろ、図１に示されるように、２０時間後のＮ−アセチル
グルコサミンのＮ−アセチルマンノサミンへの変換収率
は２２．６％であった。一方、ホウ酸を加えない点を除
けば上記と同じ方法によりＮ−アセチルマンノサミンを
製造した結果は、図２に示されるとおりであり、２０時
間後のＮ−アセチルグルコサミンのＮ−アセチルマンノ
サミンへの変換収率は１３．０％、５０時間後の変換収
率も１７．０％であり、本発明の優れた効果が確認でき
た。EXAMPLES Hereinafter, specific examples of the present invention will be shown as examples. [Example 1] N-acetylglucosamine (GlcNAc) 200
g in 1 liter of water,
And a 4N aqueous solution of NaOH is added to adjust the pH to 1.
Adjusted to 0.5. This was placed in a constant temperature water bath at 37 ° C. and reacted. Sampling was performed over time, neutralized to pH 7.0 with a 5N hydrochloric acid aqueous solution, and quantitatively analyzed for the amount of N-acetylmannosamine converted by ion exchange chromatography. As shown in FIG. The conversion yield of N-acetylglucosamine to N-acetylmannosamine was 22.6%. On the other hand, the result of producing N-acetylmannosamine by the same method as described above except that boric acid was not added is shown in FIG. 2, and the N-acetylmannosamine of N-acetylglucosamine after 20 hours was produced. The conversion yield to nosamine was 13.0%, and the conversion yield after 50 hours was 17.0%, confirming the excellent effects of the present invention.
【００１０】〔実施例２〕Ｎ−アセチルグルコサミン(G
lcNAc)２００ｇを１リットルの水に溶解し、これにホウ
酸１０００ｍＭを加え、更に４Ｎ ＮａＯＨ水溶液を添
加してｐＨ１０．５に調整した。これを、３７℃の恒温
水槽に入れて反応させた。経時的にサンプリングして、
５Ｎ塩酸水溶液でｐＨ７．０に中和し、イオン交換クロ
マトにより変換したＮ−アセチルマンノサミン量を定量
分析したところ、図３に示されるように、２０時間後の
Ｎ−アセチルグルコサミンのＮ−アセチルマンノサミン
への変換収率は３２．９％であった。なお、反応終了液
をホウ酸バッファーで平衡化した陽イオン交換クロマト
カラム（Dowex 社製 50Ｗ 100〜200mesh φ50mm×250m
m ）にチャージしたところ、６０．２ｇのＮ−アセチル
マンノサミンを回収することができ、この時のＮ−アセ
チルグルコサミンの混入量は３％以下であった。これ
は、図４に示されるように、ホウ酸と錯体を形成してい
るＮ−アセチルマンノサミンは負に荷電することから陽
イオン交換クロマトカラム内では排除効果を受けて、中
性糖であるＮ−アセチルグルコサミンよりも速く溶離す
るため、Ｎ−アセチルマンノサミンのみを的確に回収す
ることができるのである。Example 2 N-acetylglucosamine (G
200 g of (lcNAc) was dissolved in 1 liter of water, and thereto was added 1000 mM of boric acid, and the pH was adjusted to 10.5 by adding a 4N aqueous solution of NaOH. This was placed in a constant temperature water bath at 37 ° C. and reacted. Sampling over time,
Neutralized to pH 7.0 with a 5N hydrochloric acid aqueous solution and quantitatively analyzed for the amount of N-acetylmannosamine converted by ion-exchange chromatography, as shown in FIG. The conversion yield to acetylmannosamine was 32.9%. A cation exchange chromatography column (Dowex 50W 100-200mesh φ50mm × 250m
m), 60.2 g of N-acetylmannosamine could be recovered, and the amount of N-acetylglucosamine mixed in at this time was 3% or less. This is because N-acetylmannosamine, which forms a complex with boric acid, is negatively charged as shown in FIG. Since it elutes faster than certain N-acetylglucosamine, only N-acetylmannosamine can be accurately recovered.
【００１１】[0011]
【発明の効果】以上の説明からも明らかなように、本発
明は異性化によるＮ−アセチルマンノサミンの変換収率
が高く、かつ反応速度も速くてＮ−アセチルマンノサミ
ンの供給を従来よりも安価に行うことができるものであ
る。よって本発明は従来の問題点を一掃したＮ−アセチ
ルマンノサミンの製造方法として、産業の発展に寄与す
るところは極めて大である。As is clear from the above description, the present invention provides a high conversion yield of N-acetylmannosamine by isomerization, a high reaction rate, and a conventional supply of N-acetylmannosamine. It can be performed at lower cost. Therefore, the present invention greatly contributes to industrial development as a method for producing N-acetylmannosamine that has eliminated the conventional problems.
【図１】本発明の実施例１におけるＮ−アセチルマンノ
サミンの変換収率を示すグラフである。FIG. 1 is a graph showing the conversion yield of N-acetylmannosamine in Example 1 of the present invention.
【図２】比較例におけるＮ−アセチルマンノサミンの変
換収率を示すグラフである。FIG. 2 is a graph showing the conversion yield of N-acetylmannosamine in Comparative Example.
【図３】本発明の実施例２におけるＮ−アセチルマンノ
サミンの変換収率を示すグラフである。FIG. 3 is a graph showing the conversion yield of N-acetylmannosamine in Example 2 of the present invention.
【図４】本発明の実施例２における陽イオン交換クロマ
トカラム内でのＮ−アセチルマンノサミンの溶離状態を
示すグラフである。FIG. 4 is a graph showing an elution state of N-acetylmannosamine in a cation exchange chromatography column in Example 2 of the present invention.
Claims (2)
下で異性化してＮ−アセチルマンノサミンとするＮ−ア
セチルマンノサミンの製造方法において、異性化する際
にホウ酸またはホウ酸塩を添加することにより、Ｎ−ア
セチルマンノサミンへの異性化率を増大させることを特
徴とするＮ−アセチルマンノサミンの製造方法。1. A process for producing N-acetylmannosamine by isomerizing N-acetylglucosamine into N-acetylmannosamine under alkaline conditions, wherein boric acid or a borate is added during the isomerization. A process for producing N-acetylmannosamine, which comprises increasing the isomerization rate to N-acetylmannosamine.
ｍＭ以上、１Ｍ以下の範囲で添加する請求項１に記載の
Ｎ−アセチルマンノサミンの製造方法。2. A boric acid or borate having a boric acid concentration of 50.
The method for producing N-acetylmannosamine according to claim 1, wherein the N-acetylmannosamine is added in a range from mM to 1M.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34792696A JPH10182685A (en) | 1996-12-26 | 1996-12-26 | Production of n-acetylmannosamine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34792696A JPH10182685A (en) | 1996-12-26 | 1996-12-26 | Production of n-acetylmannosamine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH10182685A true JPH10182685A (en) | 1998-07-07 |
Family
ID=18393555
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP34792696A Withdrawn JPH10182685A (en) | 1996-12-26 | 1996-12-26 | Production of n-acetylmannosamine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH10182685A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013047773A1 (en) | 2011-09-29 | 2013-04-04 | 国立大学法人 東京大学 | Method for inducing orexin neuron |
| US8987232B2 (en) | 2008-09-04 | 2015-03-24 | The University Of Tokyo | Agent for ameliorating brain hypofunction |
| US9480695B2 (en) | 2011-09-29 | 2016-11-01 | The University Of Tokyo | Methods for inducing orexin neurons and agent for treating narcolepsy or eating disorder |
| US9968624B2 (en) | 2014-05-16 | 2018-05-15 | The University Of Tokyo | Depression treatment agent |
-
1996
- 1996-12-26 JP JP34792696A patent/JPH10182685A/en not_active Withdrawn
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8987232B2 (en) | 2008-09-04 | 2015-03-24 | The University Of Tokyo | Agent for ameliorating brain hypofunction |
| US9271995B2 (en) | 2008-09-04 | 2016-03-01 | The University Of Tokyo | Agent for ameliorating brain hypofunction |
| WO2013047773A1 (en) | 2011-09-29 | 2013-04-04 | 国立大学法人 東京大学 | Method for inducing orexin neuron |
| US9480695B2 (en) | 2011-09-29 | 2016-11-01 | The University Of Tokyo | Methods for inducing orexin neurons and agent for treating narcolepsy or eating disorder |
| US9968624B2 (en) | 2014-05-16 | 2018-05-15 | The University Of Tokyo | Depression treatment agent |
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