JPH0355470B2 - - Google Patents
Info
- Publication number
- JPH0355470B2 JPH0355470B2 JP10508482A JP10508482A JPH0355470B2 JP H0355470 B2 JPH0355470 B2 JP H0355470B2 JP 10508482 A JP10508482 A JP 10508482A JP 10508482 A JP10508482 A JP 10508482A JP H0355470 B2 JPH0355470 B2 JP H0355470B2
- Authority
- JP
- Japan
- Prior art keywords
- salt
- ascorbic acid
- solution
- acid group
- acid
- 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.)
- Expired
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- 150000001875 compounds Chemical class 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 11
- 229960005070 ascorbic acid Drugs 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000011668 ascorbic acid Substances 0.000 description 8
- 235000010323 ascorbic acid Nutrition 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 159000000009 barium salts Chemical class 0.000 description 5
- 210000000695 crystalline len Anatomy 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- -1 glutathione Chemical compound 0.000 description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- NASQLXHRHIUDEY-UHFFFAOYSA-N 4-dichlorophosphoryloxymorpholine Chemical compound ClP(Cl)(=O)ON1CCOCC1 NASQLXHRHIUDEY-UHFFFAOYSA-N 0.000 description 2
- 208000002177 Cataract Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002211 L-ascorbic acid Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical compound CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 230000001180 sulfating effect Effects 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- MHLMRBVCMNDOCW-UHFFFAOYSA-N acetic acid;butan-1-ol;hydrate Chemical compound O.CC(O)=O.CCCCO MHLMRBVCMNDOCW-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は下記式〔〕で表わされる化合物およ
びその塩類に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound represented by the following formula [] and salts thereof.
〔式中、R1およびR2は水素原子、リン酸基また
は硫酸基を示す。但し、R1およびR2は同時に水
素原子、リン酸基または硫酸基を示さない。R3
は低級アルキル基を示す。以下同じ。〕
アスコルビン酸は、水晶体や前房水に他の組織
より高濃度で存在している。（水晶体には20〜30
mg％含まれている。）
白内障水晶体では、アスコルビン酸のレベルが
低下する事が多くの研究者によつて報告されてい
る。一方、アスコルビン酸はグルタチオンと同様
に、水晶体の酸化還元系に関与しており、水晶体
の透明性保持に有用であるとされている。従つ
て、アスコルビン酸は白内障に有効であると考え
られる。しかし、アスコルビン酸はリボイドに対
する溶解度が極めて小さく、実際の治療剤として
の使用には制限がある。 [In the formula, R 1 and R 2 represent a hydrogen atom, a phosphoric acid group, or a sulfuric acid group. However, R 1 and R 2 do not represent a hydrogen atom, a phosphoric acid group, or a sulfuric acid group at the same time. R3
represents a lower alkyl group. same as below. ] Ascorbic acid exists in higher concentrations in the lens and anterior aqueous humor than in other tissues. (20-30 for the crystalline lens)
Contains mg%. ) Many researchers have reported that ascorbic acid levels are reduced in cataractous lenses. On the other hand, ascorbic acid, like glutathione, is involved in the redox system of the crystalline lens, and is said to be useful for maintaining the transparency of the crystalline lens. Therefore, ascorbic acid is considered to be effective against cataracts. However, ascorbic acid has extremely low solubility in riboids, which limits its use as an actual therapeutic agent.
また、アスコルビン酸は溶液にすると、３位の
水酸基の脱水素が原因となる酸化反応が起ること
により分解し、褐変する。 Furthermore, when ascorbic acid is made into a solution, it decomposes and turns brown due to an oxidation reaction caused by dehydrogenation of the hydroxyl group at the 3-position.
本発明者らは、アスコルビン酸の欠点を取り除
くべく鋭意研究した結果、アスコルビン酸の６−
Ｏ−アルカノイル誘導体をリン酸エステルまたは
硫酸エステルにすると、安定性が増し、リポイド
に対して適度な溶解性を有することがわかり、本
発明化合物〔〕は白内障治療剤として有用であ
る事を見い出し、本発明を完成した。 As a result of intensive research to eliminate the drawbacks of ascorbic acid, the present inventors discovered that the 6-
It was found that when the O-alkanoyl derivative is converted into a phosphate ester or a sulfate ester, the stability increases and it has an appropriate solubility in lipoids, and the compound of the present invention [] was found to be useful as a cataract treatment agent, The invention has been completed.
本発明化合物〔〕は、６−Ｏ−アルカノイル
アスコルビン酸をリン酸化または硫酸化すること
により合成される。 The compound of the present invention [] is synthesized by phosphorylating or sulfating 6-O-alkanoyl ascorbic acid.
リン酸化試薬としては、モルホリノ・ホスホ
ロ・ジクロリデート、オキシ塩化リン、テトラク
ロルピロリン酸などが挙げられる。リン酸化試薬
と反応後必要に応じて酸処理等を行う。 Examples of the phosphorylation reagent include morpholino phosphoro dichloridate, phosphorus oxychloride, and tetrachloropyrophosphoric acid. After the reaction with the phosphorylation reagent, acid treatment is performed as necessary.
硫酸化試薬としては、三酸化イオウトリメチル
アミン錯体、クロルスルホン酸、塩化スルフリル
などが挙げられる。反応後必要に応じてイオン交
換樹脂等で処理する。 Examples of the sulfating reagent include sulfur trioxide trimethylamine complex, chlorsulfonic acid, and sulfuryl chloride. After the reaction, it is treated with an ion exchange resin, etc., if necessary.
本発明化合物〔〕は必要に応じて、マグネシ
ウム塩、カルシウム塩、ナトリウム塩、カリウム
塩などの医薬として許容される塩とすることがで
きる。 The compound of the present invention [] can be converted into a pharmaceutically acceptable salt such as a magnesium salt, a calcium salt, a sodium salt, a potassium salt, etc., if necessary.
以下に実施例を示す。 Examples are shown below.
実施例 １
６−Ｏ−ピバロイル−Ｌ−アスコルビン酸−３
−リン酸エステル・マグネシウム塩の製造
６−Ｏ−ピバロイル−Ｌ−アスコルビン酸（30
ｇ）およびピリジン（18.2ｇ）のアセトン（75
ml）溶液にモルホリノ・ホスホロ・ジクロリデー
ト（30.6ｇ）のアセトン（25ml）溶液を氷冷撹拌
下滴下する。滴下終了後室温で４時間撹拌後一夜
放置する。沈殿物を別し液を減圧濃縮する。
残渣に0.5N塩酸（300ml）を加え80〜90℃で1.5時
間加熱する。冷却後水酸化バリウム水溶液を加
え、約PH９とし生成するバリウム塩を取する。
バリウム塩をアンバーライトCG120（H+）で常法
により処理した後ジシクロヘキシルアミンで約PH
８とする。この溶液を減圧濃縮後、分取用高速液
体クロマトで精製し、ジシクロヘキシルアミン塩
を得る。この塩をカチオン交換樹脂で処理し遊離
型とした後、酸化マグネシウムを加えPH7.4とす
る。この溶液を減圧濃縮し、得られる残渣にメタ
ノールおよびエーテルを加えて標記化合物27.9ｇ
（収率63％）を得る。Example 1 6-O-pivaloyl-L-ascorbic acid-3
-Production of phosphoric acid ester/magnesium salt 6-O-pivaloyl-L-ascorbic acid (30
g) and pyridine (18.2 g) in acetone (75
A solution of morpholino phosphoro dichloridate (30.6 g) in acetone (25 ml) was added dropwise to the solution under ice-cooling and stirring. After the addition was completed, the mixture was stirred at room temperature for 4 hours and left overnight. Separate the precipitate and concentrate the liquid under reduced pressure.
Add 0.5N hydrochloric acid (300ml) to the residue and heat at 80-90°C for 1.5 hours. After cooling, add barium hydroxide aqueous solution to bring the pH to about 9 and collect the barium salt produced.
After treating the barium salt with Amberlite CG120 (H + ) in a conventional manner, the pH of the barium salt is adjusted to approx.
8. After concentrating this solution under reduced pressure, it is purified by preparative high performance liquid chromatography to obtain a dicyclohexylamine salt. After this salt is treated with a cation exchange resin to form a free form, magnesium oxide is added to adjust the pH to 7.4. This solution was concentrated under reduced pressure, and methanol and ether were added to the resulting residue to obtain 27.9 g of the title compound.
(yield 63%).
融点250℃以上（メタノールーエーテル）
IR（KBr、cm-1）
3735〜3020、1722、1604、1402、1288、1152、
1120、1012
NMR（D2O、δ）
1.21（9H、ｓ、−Ｃ（ＣＨ 3）3）
4.29（3H、ｓ、C5−ＨおよびC6−H2）
UV λmax 260nｍ（H2O）
〔α〕28 D＋36.6゜（ｃ＝1.0、H2O）
TLC Rf値(a) 0.31
(a)：シリカゲル、ｎ−ブタノール−酢酸−水
（３：１：１）
実施例 ２
６−Ｏ−ピバロイル−Ｌ−アスコルビン酸−２
−硫酸エステル・カルシウム塩の製造
６−Ｏ−ピバロイル−Ｌ−アスコルビン酸（40
ｇ）の水（300ml）溶液に、10N水酸化ナトリウ
ム溶液を加えPH10とし、三酸化イオウトリメチル
アミン錯体（43ｇ）を加える。10N水酸化ナトリ
ウム溶液を反応後に追加することにより、反応液
をPH10付近に保ちつつ70℃で１時間撹拌する。冷
却後沈殿物を別し、液をアンバーライト
CG120（H+）で常法により処理する。溶出液およ
び洗浄液を合わせて、水酸化バリウムで中和し、
沈殿物を別する。液を減圧濃縮し、残渣にメ
タノールを加え得られる粉末を分取用高速液体ク
ロマトで精製し精製バリウム塩を得る。このバリ
ウム塩をカチオン交換樹脂で処理して遊離型とし
た後、水酸化カルシウムを加えPH7.5とする。こ
の溶液を減圧濃縮し、残渣にメタノールおよびテ
トラヒドロフランを加え得られる結晶を別し、
標記化合物39.2ｇ（収率69％）を得る。Melting point 250℃ or higher (methanol-ether) IR (KBr, cm -1 ) 3735-3020, 1722, 1604, 1402, 1288, 1152,
1120, 1012 NMR ( D2O , δ) 1.21 (9H, s, -C( CH3 ) 3 ) 4.29 (3H, s, C5 -H and C6 - H2 ) UV λmax 260nm ( H2O ) [α] 28 D +36.6° (c=1.0, H 2 O) TLC Rf value (a) 0.31 (a): Silica gel, n-butanol-acetic acid-water (3:1:1) Example 2 6 -O-pivaloyl-L-ascorbic acid-2
-Production of sulfate ester/calcium salt 6-O-pivaloyl-L-ascorbic acid (40
To a solution of g) in water (300 ml), add 10N sodium hydroxide solution to adjust the pH to 10, and add sulfur trioxide trimethylamine complex (43 g). By adding 10N sodium hydroxide solution after the reaction, the reaction solution is stirred at 70°C for 1 hour while keeping the pH around 10. After cooling, separate the precipitate and turn the liquid into Amberlite.
Treat with CG120 (H + ) in a conventional manner. Combine the eluate and wash solution, neutralize with barium hydroxide,
Separate the precipitate. The liquid is concentrated under reduced pressure, methanol is added to the residue, and the resulting powder is purified using preparative high performance liquid chromatography to obtain a purified barium salt. This barium salt is treated with a cation exchange resin to make it into a free form, and then calcium hydroxide is added to adjust the pH to 7.5. This solution was concentrated under reduced pressure, methanol and tetrahydrofuran were added to the residue, and the resulting crystals were separated.
39.2 g (69% yield) of the title compound are obtained.
融点250℃以上（メタノール−テトラビドロフラ
ン）
IR（KBr、cm-1）
3710〜3020、1722、1598、1400、1282、1228、
1054、
NMR（D2O、δ）
1.18（9H、ｓ、−Ｃ（ＣＨ 3）3）
4.24（3H、ｓ、C5−ＨおよびC6−H2）
4.54（1H、ｓ、C4−Ｈ）
UV λmax 254nｍ（H2O）
〔α〕27 D＋56.2゜（ｃ＝1.1、H2O）
TLC Rf値(a) 0.39
(a)：実施例１と同じ。Melting point 250℃ or higher (methanol-tetrahydrofuran) IR (KBr, cm -1 ) 3710-3020, 1722, 1598, 1400, 1282, 1228,
1054 , NMR (D2O, δ) 1.18 (9H, s, -C(CH3)3 ) 4.24 ( 3H, s, C5 -H and C6 - H2 ) 4.54 (1H, s, C4 −H) UV λmax 254 nm (H 2 O) [α] 27 D +56.2° (c=1.1, H 2 O) TLC Rf value (a) 0.39 (a): Same as Example 1.
Claims (1)
塩類。 〔式中、R1およびR2は水素原子、リン酸基また
は硫酸基を示す。但し、R1およびR2は同時に水
素原子、リン酸基または硫酸基を示さない。R3
は低級アルキル基を示す。〕[Claims] 1. A compound represented by the following formula [] and salts thereof. [In the formula, R 1 and R 2 represent a hydrogen atom, a phosphoric acid group, or a sulfuric acid group. However, R 1 and R 2 do not represent a hydrogen atom, a phosphoric acid group, or a sulfuric acid group at the same time. R3
represents a lower alkyl group. ]
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57105084A JPS58222078A (en) | 1982-06-17 | 1982-06-17 | Ascorbic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57105084A JPS58222078A (en) | 1982-06-17 | 1982-06-17 | Ascorbic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58222078A JPS58222078A (en) | 1983-12-23 |
| JPH0355470B2 true JPH0355470B2 (en) | 1991-08-23 |
Family
ID=14398053
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57105084A Granted JPS58222078A (en) | 1982-06-17 | 1982-06-17 | Ascorbic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58222078A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0182934B1 (en) * | 1984-11-29 | 1988-07-13 | Frisco-Findus Ag | Surfactants |
| JPS6263523A (en) * | 1985-09-17 | 1987-03-20 | Nikko Kemikaruzu Kk | Eye drop |
| JPH0813739B2 (en) * | 1986-12-03 | 1996-02-14 | 武田薬品工業株式会社 | Cataract remedy |
| IL91928A (en) * | 1989-10-08 | 1994-07-31 | Amrad Res & Dev | Pharmaceutical compositions containing prolactin |
| JPH10298174A (en) * | 1997-04-30 | 1998-11-10 | Showa Denko Kk | Ascorbic acid derivative and vitamin c agent containing the same |
| JP4111856B2 (en) | 2002-04-12 | 2008-07-02 | 昭和電工株式会社 | Stabilized ascorbic acid derivatives |
-
1982
- 1982-06-17 JP JP57105084A patent/JPS58222078A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58222078A (en) | 1983-12-23 |
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