JPH0459788A - New flavone-c-glycoside and aldose-reductase inhibitor containing the flavone-c-glycoside as active component - Google Patents
New flavone-c-glycoside and aldose-reductase inhibitor containing the flavone-c-glycoside as active componentInfo
- Publication number
- JPH0459788A JPH0459788A JP2165697A JP16569790A JPH0459788A JP H0459788 A JPH0459788 A JP H0459788A JP 2165697 A JP2165697 A JP 2165697A JP 16569790 A JP16569790 A JP 16569790A JP H0459788 A JPH0459788 A JP H0459788A
- Authority
- JP
- Japan
- Prior art keywords
- flavone
- glycoside
- water
- extracted
- residue
- 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.)
- Pending
Links
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- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- RBTVSNLYYIMMKS-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)N1CC(N)C1 RBTVSNLYYIMMKS-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野Ｉ
本発明はアルドースリダクターゼ阻害活性を有し、医薬
品として有用なフラボン−Ｃ−配糖体に関するものであ
る。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application I] The present invention relates to flavone-C-glycosides that have aldose reductase inhibitory activity and are useful as pharmaceuticals.
［従来の技術および課題］
近年、白内障、網膜症、腎障害等の糖尿病における各種
合併症の成因として、グルコースの代謝経路であるポリ
オール経路を介した細胞内ソルビトールの蓄積が注目さ
りている。ポリオール経路よ、グルコース、ガラクトー
ス等のアルドースがソルビトール、ガラクチトール等の
ポリオールを介してフルクトース等のケトースに変換さ
れる代謝経路であり、免疫組織化学的手法により全身請
臓器に広く存在することが明らかになってきた。[Prior Art and Problems] In recent years, the accumulation of intracellular sorbitol via the polyol pathway, which is a glucose metabolic pathway, has attracted attention as a cause of various complications in diabetes such as cataracts, retinopathy, and renal damage. The polyol pathway is a metabolic pathway in which aldoses such as glucose and galactose are converted to ketoses such as fructose via polyols such as sorbitol and galactitol, and immunohistochemical techniques have revealed that it exists widely in the organs of the whole body. It has become.
この経路の第一段階であるアルドース−ポリオール間の
変換を触媒する酵素をアルドースリダクターゼといい、
この酵素がポリオール経路の律速酵素と考えられている
。このアルドースリダクターゼを阻害し、ソルビトール
の生産や蓄積を低下させることが、糖尿病患者における
合併症の治療に有効であるという報告がなされている。The first step in this pathway, the enzyme that catalyzes the conversion between aldose and polyol, is called aldose reductase.
This enzyme is considered to be the rate-limiting enzyme in the polyol pathway. It has been reported that inhibiting this aldose reductase and reducing the production and accumulation of sorbitol is effective in treating complications in diabetic patients.
そこで、アルドースリダクターゼ阻害作用を有する薬剤
の開発か望まれてい１こ。Therefore, it is desired to develop a drug that has an aldose reductase inhibitory effect.
「課題を解決するための手段−
本発明者等は、上記の課題を解決すべく鋭意研究を重ね
た結果、臨床的にも広く用いられている生薬半夏＝カラ
スヒノヤク、Ｐｉｎｅｌｌｉａ ｔｅｒｎａｔａＢｒｅ
ｉｔｅｎｂａｃｈ（Ａｒａｃｅａｅ）のコルク層を除い
た塊茎］から新規フラボン配糖体２種を見いだし、さら
にその薬理活性について検討したところ、優れたアルド
ースリダクターゼ阻害作用を有することを見いたし、本
発明を完成させるに至った。"Means for Solving the Problems" As a result of extensive research in order to solve the above problems, the inventors of the present invention have developed the crude drug Hanka, which is widely used clinically.
discovered two new flavone glycosides from the cork-layered tubers of C. itenbach (Araceae), and further investigated their pharmacological activities, and found that they had an excellent aldose reductase inhibitory effect, thus completing the present invention. reached.
すなわち本発明は、
■
（にだし式中、Ｒ１およびＲ９は、Ｃ−β−Ｄ−ガラク
トピラノンル基またはＣ−β−Ｄ−キノロピラノンル基
を示す。）
て表されるフラボン−〇−配糖体および該ワラホンＣ−
配糖体（以下、本発明の化合物という、、）を有効成分
とするアルドースリダクターゼ阻害剤である。That is, the present invention provides a flavone-〇-configuration represented by (1) (In the formula, R1 and R9 represent a C-β-D-galactopyranone group or a C-β-D-quinolopyranone group.) Glycoside and the wallahon C-
This is an aldose reductase inhibitor containing a glycoside (hereinafter referred to as the compound of the present invention) as an active ingredient.
本発明の化合物を得るには例えば、次のような方法が挙
げられる。For example, the following methods can be used to obtain the compound of the present invention.
カラスヒンヤクあるいはその他辺縁植物を水、アルコー
ル類、水とアルコール類の混合溶媒まｆこは水とアセ）
・ンの混合溶媒で抽出し、該抽出液から溶媒を除去した
残渣をそのまま、または必要に応じて水に溶解し、石油
エーテル、エーテル、クロロホルム、ｎ−ヘキサンなど
の有機溶媒で抽出し、有機溶媒に移行する脂溶性成分を
除去した後、ｎ−ブタノールで抽出し、抽出液から溶媒
を除去して得た残渣を水、メタノール、エタノール、酢
酸、クロロホルム、酢酸エチル、ｎ−ヘキサン、アセト
ン、アセトニトリル、ベンゼンから選ばれる少なくとも
一つを溶出溶媒としてダイヤイオンＨＰ２０、ＭＣＩゲ
ルＣＨＰ２０Ｐ等のポーラスポリマー セファデックス
ＬＨ−２０等のセファデックス、逆相系シリカゲル、シ
リカゲル、ポリアミド、活性炭またはセルロース等を担
体に用いたカラムクロマトクラフィーまたはＴＳＫゲル
０ＤＳＩ２０Ｔ等を用いた分取用高速液体クロマトク
ラフィーに１回まには数回付し、薄層クロマトグラフィ
ーで目的成分を確認しながら分画することにより得るこ
とができる。Add water, alcohol, or a mixture of water and alcohol to water and other peripheral plants.
- Extract with a mixed solvent of After removing fat-soluble components that migrate to the solvent, extraction is performed with n-butanol, and the residue obtained by removing the solvent from the extract is mixed with water, methanol, ethanol, acetic acid, chloroform, ethyl acetate, n-hexane, acetone, Using at least one selected from acetonitrile and benzene as an elution solvent, use porous polymers such as Diaion HP20 and MCI Gel CHP20P, Sephadex such as Sephadex LH-20, reverse phase silica gel, silica gel, polyamide, activated carbon, cellulose, etc. as a carrier. It is obtained by subjecting it to column chromatography or preparative high performance liquid chromatography using TSK gel 0DSI20T once or several times, and fractionating while confirming the target component using thin layer chromatography. be able to.
また、場合に゛よりメタノール、エタノール等の適当な
溶媒を用いて再結晶することにより精製してもよい。In addition, if necessary, it may be purified by recrystallization using an appropriate solvent such as methanol or ethanol.
次に、本発明の化合物がアルドースリダクターゼ阻害作
用を有することを実験例を挙げて説明する。Next, the fact that the compound of the present invention has an aldose reductase inhibitory effect will be explained with reference to experimental examples.
実験例
〈アルドースリダクターゼ活性の測定〉６週齢のウィス
ター（Ｗｉｓｔａｒ）系雄性ラットをエーテル麻酔下に
致死させ、直ちに水晶体を摘出し、２０°Ｃにて保存し
た。Experimental Example <Measurement of aldose reductase activity> Six-week-old male Wistar rats were sacrificed under ether anesthesia, and the crystalline lenses were immediately removed and stored at 20°C.
水晶体は０．５１フエニルメチルスルホニルフロリドを
含む１３５州ナトリウム−カリウム−リン酸緩衝液（ｐ
Ｈ７，０）にてホモジナイズして、３０．０００ｒｐｍ
で３０分間遠心した。その上清をアルドースリダクター
ゼ粗酵素液とし１こ。The crystalline lens was prepared using a 135-state sodium-potassium-phosphate buffer (p
Homogenize at 30,000 rpm
Centrifuged for 30 minutes. Use the supernatant as an aldose reductase crude enzyme solution.
また、以上の操作はすべて４°Ｃて行い、粗酵素液は一
２０°Ｃて保存した。All of the above operations were performed at 4°C, and the crude enzyme solution was stored at -20°C.
アルドースリダクターゼ活性の測定はデュフラン（Ｄｕ
ｆｒａｎｅ）らの方法［Ｂｉｏｃｈｅｍｉｃａｌ Ｍｅ
ｄｉｃｉｎｅ、３２゜９９−１０５（１９８４）］によ
り行った。すなわち、１００關硫酸リチウム、０．０３
州ＮＡＤＰＨ（還元型ｎｉｃｏｔｉｎａｍｉｄｅ ａｄ
ｅｎｉｎｅ ｄｉｎｕｃｌｅｏｔｉｄｅ ｐｈｏｓｐｈ
ａｔｅ）、および基質として２０朋グルコースを含むよ
うに調製した１ ３５ 、Ｍナトリウム−カリウム−リ
ン酸緩衝液（ｐＨ７，０）８００Ｊに、上記の粗酵素液
１００７Ｊおよび本発明の化合物をそれぞれジメチルス
ルフオキシド（ＤＭＳＯ）に１．０ｘｌＯ−５〜４、Ｏ
ｘｌ０−７Ｍの終濃度となるように溶解させた本発明の
化合物の溶解液１００ｄをそれぞれ加え、３０℃にて３
０分間反応させた。次に、０．５Ｎ塩酸０．３−を加え
て反応を停止させ、１０朋イミダゾールを含む６Ｎ水酸
化ナトリウムｌ−を添加することにより、前記の反応に
よって生じたＮＡＤＰ（酸化型ｎｉｃｏｔｉｎａｍｉｄ
ｅ ａｄｅｎｉｎｅｄｉｎｕｃｌｅｏｔｉｄｅ ｐｈｏ
ｓｐｈａｔｅ）を蛍光物質に変換して、３０分後にその
蛍光強度を測定した。蛍光強度は、室温で分光光度計Ｆ
−４０００（日立製作新製）を用いて励起波長３６０鷹
、蛍光波長４６０ ｎｍの条件で測定した。また、本発
明の化合物の溶解液を加えるかわりにＤ Ｍ Ｓ Ｏを
加える以外は上記と同様にして反応させて測定した蛍光
強度をコントロール値とした。Aldose reductase activity was measured using Dufuran (Dufuran).
frane) et al. [Biochemical Me.
dicine, 32°99-105 (1984)]. That is, 100% lithium sulfate, 0.03
State NADPH (reduced nicotinamide ad
enine dinucleotide phosph
1007 J of the above crude enzyme solution and the compound of the present invention were added to 800 J of a 135 M sodium-potassium-phosphate buffer (pH 7.0) prepared to contain 20 glucose as a substrate in dimethyl sulfate. 1.0xlO-5~4,0 in fluoride (DMSO)
100 d of a solution of the compound of the present invention dissolved to a final concentration of 0-7 M was added to each, and the mixture was incubated at 30°C for 3
The reaction was allowed to proceed for 0 minutes. Next, 0.5N hydrochloric acid (0.3-) was added to stop the reaction, and by adding 6N sodium hydroxide (1-) containing 10-imidazole, NADP (oxidized nicotinamide) produced by the above reaction was removed.
e adenine nucleotide pho
sphate) was converted into a fluorescent substance, and the fluorescence intensity was measured 30 minutes later. Fluorescence intensity was measured using a spectrophotometer F at room temperature.
-4000 (manufactured by Hitachi Seisakusho) under the conditions of an excitation wavelength of 360 nm and a fluorescence wavelength of 460 nm. Further, the fluorescence intensity measured by reacting in the same manner as above except that DMSO was added instead of adding the solution of the compound of the present invention was used as a control value.
アルドースリダクターゼはＮＡＤＰＨを補酵素として、
ＤＬ−グリセルアルデヒドあるいはグルコースをポリオ
ールに変換する酵素であり、この反応に伴ってＮＡＤＰ
ＨはＮＡＤＰに変化する。Aldose reductase uses NADPH as a coenzyme,
DL-An enzyme that converts glyceraldehyde or glucose into polyol, and along with this reaction, NADP
H changes to NADP.
従ってＮＡＤＰが少なければ、アルドースリダクターゼ
が阻害されていることになる。Therefore, if NADP is low, aldose reductase is inhibited.
その結果、例えば実施例２の化合物は１００／−ｆＭの
濃度てアルドースリダクターゼの活性を６４．７％阻害
することが認められ、ま１こ実施例１で得た化合物につ
いても同様の効果か期待されることから、本発明の化合
物が白内障、網膜症、腎障害等の糖尿病における各種合
併症の治療に有効であることか期待される。As a result, for example, the compound of Example 2 was found to inhibit aldose reductase activity by 64.7% at a concentration of 100/-fM, and we expected that the compound obtained in Example 1 would have a similar effect. Therefore, it is expected that the compounds of the present invention will be effective in treating various complications of diabetes such as cataracts, retinopathy, and renal disorders.
さらに、実施例１および２て得た化合物をＩＣＲ系雄性
マウスにＩｆｆ／ｋｇ経口投与しｆ二ところ、いずれも
死亡例は認められなかった。Furthermore, when the compounds obtained in Examples 1 and 2 were orally administered to ICR male mice at a dose of If/kg, no deaths were observed in any of them.
このように、本発明の化合物は毒性が低く、安全性の高
いものである。Thus, the compounds of the present invention have low toxicity and high safety.
次に、本発明の化合物の投与量および製剤化について説
明する。Next, the dosage and formulation of the compound of the present invention will be explained.
本発明の化合物はそのまま、あるいは慣用の製剤担体と
共に動物および人に投与することができる。投与形態と
しては、特に限定がなく、必要に応じ適宜選択して使用
され、錠剤、カプセル剤、顆粒剤、細粒剤、散剤等の経
口剤、注射剤、全開等の非経口剤が挙げられる。The compounds of the present invention can be administered to animals and humans either neat or with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be selected and used as necessary, and may include oral dosage forms such as tablets, capsules, granules, fine granules, and powders, parenteral dosage forms such as injections, and full dosage forms. .
経口剤として所期の効果を発揮するためには、患者の年
令、体重、疾患の程度により異なるが、通常成人で本発
明の化合物の重量として］ ＯＯ１ｈｇ〜６９を、１日
数回に分けての服用が適当と思われる。In order to exert the desired effect as an oral agent, although it varies depending on the age, weight, and severity of the disease of the patient, the weight of the compound of the present invention for an adult is usually 1 hg to 69 OO, divided into several doses per day. It seems appropriate to take .
本発明において錠剤、カプセル剤、顆粒剤等の経口剤は
、例えばデンプン、乳糖、白糖、マンニット、カルボキ
シメチルセルロース、コーンスターチ等を用いて常法に
従って製造される。In the present invention, oral preparations such as tablets, capsules, and granules are manufactured according to conventional methods using, for example, starch, lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch, and the like.
この種の製剤には、適宜前記賦形剤の他に、結合剤、崩
壊剤、界面活性剤、滑沢剤、流動性促進剤、矯味剤、着
色剤、香料等を使用することができる。それぞれの具体
例は以下に示すごとくである。In addition to the excipients mentioned above, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used in this type of preparation as appropriate. Specific examples of each are shown below.
［結合剤］
デンプン、デキストリン、アラビアゴム末、ゼラチン、
ヒドロキシプロピルスターチ、メチルセルロース、ヒド
ロキンプロピルセルロース、結晶セルロース、エチルセ
ルロース、ポリビニルピロリドン、マクロゴール。[Binder] Starch, dextrin, gum arabic powder, gelatin,
Hydroxypropyl starch, methylcellulose, hydroquinepropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol.
Ｕ崩壊剤コ
デンプン、ヒドロキシプロピルスターチ、カルボキシメ
チルセルロースカルノウム、カルホキツメチルセルロー
ス、低置換ヒドロキノプロピルセルロース。U-disintegrant co-starch, hydroxypropyl starch, carboxymethyl cellulose carnoum, calhokit methyl cellulose, low substituted hydroquinopropyl cellulose.
［界面活性剤］
大豆レシチン、ンヨ糖脂肪酸エステル、ポリソルベート
８０゜
二滑沢剤］
タルク、ロウ類、水素添加植物油、ショ糖脂肪酸エステ
ル、ステアリン酸マグネソウム、ステアリン酸カルシウ
ム、ステアリン酸アルミニウム、ポリエチレングリコー
ル。[Surfactant] Soybean lecithin, sugar fatty acid ester, polysorbate 80° di-lubricating agent] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.
［流動性促進剤］
軽質無水ケイ酸、乾燥水酸化アルミニウムゲル、合成ケ
イ酸アルミニウム、ケイ酸マグネシウム。[Fluidity promoter] Light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.
また、本発明の化合物は、懸濁液、エマルジョン剤、７
０ツブ剤、エリキシル剤としても投与することができ、
これらの各種剤形には、矯味矯臭剤、着色剤を含有して
もよい。The compound of the present invention can also be used in suspensions, emulsions, 7
It can also be administered as a pill or elixir.
These various dosage forms may contain flavoring agents and coloring agents.
非経口剤として所期の効果を発揮するためには、患者の
年令、体重、疾患の程度により異なるが、通常成人で本
発明の化合物の重量として１日１〜＋００ｆｆ＠までの
静注、点滴静注、皮下注射、筋肉注射か適当と思われる
。In order to exert the desired effect as a parenteral agent, although it varies depending on the patient's age, weight, and degree of disease, the compound of the present invention is usually administered intravenously to an adult at a dose of 1 to +00 ff per day. Intravenous drip, subcutaneous injection, or intramuscular injection are considered appropriate.
この非経口剤は常法に従って製造され、希釈剤として一
般に注射用蒸留水、生理食塩水、ブドウ糖水溶液、注射
用植物油、ゴマ油、ラッカセイ油、ダイズ油、トウモロ
コン油、プロピレングリコール、ポリエチレングリコー
ル等を用いることかできる。さらに必要に応じて、殺菌
剤、防腐剤、安定剤を加えてもよい。また、この非経口
剤は安定性の点から、バイアル等に充填後冷凍し、通常
の凍結乾燥技術により水分を除去し、使用直前に凍結乾
燥物から液剤を再調製することもてきる。さらに、必要
に応じて適宜、等張化剤、安定剤、防腐剤、無痛化剤等
を加えても良い。This parenteral preparation is manufactured according to a conventional method, and generally uses distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. as a diluent. I can do it. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation may be filled into a vial or the like, then frozen, water removed by ordinary freeze-drying techniques, and a liquid preparation prepared from the freeze-dried product immediately before use. Furthermore, isotonizing agents, stabilizers, preservatives, soothing agents, etc. may be added as appropriate.
その他の非経口剤としては、外用液剤、軟膏等の塗布剤
、直腸内投与のｆこめの末剤等が挙げられ、常法に従っ
て製造される。Other parenteral preparations include liquid preparations for external use, liniments such as ointments, powder preparations for intrarectal administration, and the like, which are manufactured according to conventional methods.
次に実施例を挙げて本発明をさらに詳細に説明するが、
本発明はこれにより同等制限されるものではない。Next, the present invention will be explained in more detail with reference to Examples.
The invention is not intended to be equally limited thereby.
実施例１
生薬半夏１００ ＆＠をメタノール＋００（て加熱抽出
し、得られた抽出液から溶媒を減圧下留去し、メタノー
ルエキスを得た。このメタノールエキスを１０％水性メ
タノールに溶解し、ｎ−ヘキサンで脱脂後、減圧下メタ
ノールを留去し、ダイヤイオンＨＰ−２０（三菱化成製
）カラムクロマトグラフィーに付した。これを水２０Ｑ
１次いて５０％水性メタノール２０ρ、メタノール２０
Ｑで溶出した。５０％水性メタノール溶出部は溶媒を減
圧下留去した後、セファデックスＬＨ−２０（ファルマ
ノア製）カラムクロマトグラフィーに付し、最初は水、
逐次メタノール濃度を増やして溶出し、５０〜８０％メ
タノール−水で溶出される画分を得た。この両分をポー
ラスポリマーであるＭＣＩゲルＣＨＰ２０Ｐ（三菱化成
製）を用いたカラムクロマトグラフィーに付して、水か
ら順次メタノール含量を増やして溶出し、３５〜４５％
メタノール−水で溶出される画分を、さらにμ Ｂｏｎ
ｄａｐａｋ Ｃ＋ｓ（ウォーターズ製）カラムクロマト
クラフィーに付し、最初は水、逐次メタノール含量を増
加して溶出し、画分ＡおよびＢを得た。Example 1 The crude drug Hanka 100&@ was heated and extracted with methanol + 00 (methanol + 00), and the solvent was distilled off from the obtained extract under reduced pressure to obtain a methanol extract. This methanol extract was dissolved in 10% aqueous methanol, After defatting with n-hexane, methanol was distilled off under reduced pressure and subjected to Diaion HP-20 (manufactured by Mitsubishi Kasei) column chromatography.
First, 50% aqueous methanol 20ρ, methanol 20
It eluted with Q. After distilling off the solvent under reduced pressure, the 50% aqueous methanol eluate was subjected to Sephadex LH-20 (manufactured by Pharmanoa) column chromatography.
Elution was performed by successively increasing the methanol concentration to obtain a fraction eluted with 50-80% methanol-water. Both fractions were subjected to column chromatography using MCI Gel CHP20P (manufactured by Mitsubishi Kasei), a porous polymer, and eluted with increasing methanol content sequentially starting from water.
The fraction eluted with methanol-water was further subjected to μ Bon
The mixture was subjected to dapak C+s (manufactured by Waters) column chromatography, and fractions A and B were obtained by eluting with water first and successively increasing methanol content.
この画分Ｂを分取用高速液体クロマトグラフィーである
ＴＳＫ ｇｅｌ ０ＤＳ−１２０Ｔ（２，１ｃＭ ｉ、
ｄ。This fraction B was collected using TSK gel 0DS-120T (2,1 cM i,
d.
Ｘ３０（ｇ、トーソー製）に付し、アセトニトリルメタ
ノール−水−酢酸−２５：２５：１５０：２で溶出し、
目的成分を得た。目的成分は水−メタノールの混液から
結晶化し、Ｒｆ値０．２７［薄層プレｉト・キーゼルゲ
ル６０ Ｆ ２５４．展開溶媒：ｎ−ブタノール−酢酸
−水（４・１：５）、発色試薬：塩化第二鉄試薬；緑黄
色〕の黄色粒状晶３５ｍ９を得た。X30 (g, manufactured by Toso) and eluted with acetonitrile methanol-water-acetic acid-25:25:150:2.
The target component was obtained. The target component was crystallized from a water-methanol mixture and had an Rf value of 0.27 [thin layer plate Kieselgel 60 F 254. Developing solvent: n-butanol-acetic acid-water (4.1:5), coloring reagent: ferric chloride reagent; green-yellow] 35 m9 of yellow granular crystals were obtained.
この黄色粒状晶の理化学的性質は、以下のごとくであり
、これらのデータよう、式Ｉ中Ｒ１かＣ〜β−Ｄ−ガラ
クトピラノシル基であり、Ｒ７がＣ−β−Ｄ−キシロピ
ラノシル基である化合物と構造を決定した。The physicochemical properties of this yellow granular crystal are as follows, and as shown in these data, R1 in formula I is a C~β-D-galactopyranosyl group, and R7 is a C-β-D-xylopyranosyl group. The compound and structure were determined.
融 点＝２１８〜２２２°Ｃ
比旋光度ゴαＪ’ｉ；＋２０．８゜
ＰＡＢ−ＭＳ ｍ／ｚ：５６５ＣＭ±Ｈｒ’赤外線吸
収スペクトル ν Ｗａｘ Ｉ’２’１３３０４、Ｉ
６５２．１６２８．１５７８紫外線吸収スペクトル λ
： ａ２Ｈｎｍ（ＩＯｇε）：２１６．８（４，６６
）、２７３．０（４，４１）。Melting point = 218-222°C Specific optical rotation αJ'i; +20.8° PAB-MS m/z: 565CM±Hr' Infrared absorption spectrum ν Wax I'2'13304, I
652.1628.1578 Ultraviolet absorption spectrum λ
: a2Hnm (IOgε): 216.8 (4,66
), 273.0 (4,41).
３３２．０（４，４３）
プロトン核磁気共鳴スペクトル
（δ ｐｐｍ ｉｎ ＤＭＳＯ−ｄｓ＋ ＤｔＯ；５０
０ＭＨｚ）：３．２４（ＩＨ，ｔ、Ｊ＝ｌ １．０Ｈｚ
）。332.0 (4,43) Proton nuclear magnetic resonance spectrum (δ ppm in DMSO-ds+DtO; 50
0MHz): 3.24 (IH, t, J=l 1.0Hz
).
３．３２（ＩＨ，ｔ、Ｊ＝８．７Ｈｚ）３．５０（ＩＨ
，ｄｄ、Ｊ＝９．２ａｎｄ２．８Ｈｚ）３．３６〜３．
６５（４Ｈ，ｍ）。3.32 (IH, t, J = 8.7Hz) 3.50 (IH
, dd, J=9.2and2.8Hz) 3.36-3.
65 (4H, m).
３．８８（ＩＨ，ｄ、Ｊ＝２．８Ｈｚ）。3.88 (IH, d, J=2.8Hz).
３．８８ （Ｉ Ｈ，ｄｄ、Ｊ ＝ ９．６ａｎｄ９．
２ Ｈｚ）。3.88 (I H, dd, J = 9.6 and 9.
2 Hz).
３．９４（Ｉ Ｈ，ｄｄ、Ｊ ＝ １１．０ａｎｄ５．
５Ｈｚ）。3.94 (I H, dd, J = 11.0 and 5.
5Hz).
３．９８ （Ｉ Ｈ、ｄｄ、Ｊ ＝ ９．８ ａｎｄ８
．７Ｈｚ）。3.98 (I H, dd, J = 9.8 and8
．． 7Hz).
４．７６（Ｉ Ｈ，ｄ、Ｊ＝９．８Ｈｚ）。4.76 (IH, d, J=9.8Hz).
４．８０（Ｉ Ｈ９ｄ、Ｊ＝９．６Ｈｚ）。4.80 (IH9d, J=9.6Hz).
６．７２（Ｉ Ｈ，ｓ）。6.72 (IH,s).
６．９８（２Ｈ，ｄ、Ｊ＝８．９Ｈｚ）７．９１（２Ｈ
，ｃｌ、Ｊ＝８．９Ｈｚ）”ｃ−核磁気共鳴スペクトル
（δ ｐｐｍ ｉｎ ＤＭＳＯ−ｄｅ＋ Ｄ２０；６０
°Ｃ、５０ＭＨｚ） ：６０．９（ｔ）、６８．５（ｄ
）、６９．６（ｄ）７０．１（ｄ）、７０．５（ｔ）、
７０．９（ｄ）。6.98 (2H, d, J = 8.9Hz) 7.91 (2H
, cl, J=8.9Hz)" c-nuclear magnetic resonance spectrum (δ ppm in DMSO-de+ D20; 60
°C, 50MHz): 60.9 (t), 68.5 (d
), 69.6(d) 70.1(d), 70.5(t),
70.9(d).
７４．０（ｄ）、７４．４（２Ｃ，ｅａｃｈ ｃｌ）７
ｇ、８（ｄ）、７ ９．２（ｄ）、１ ０２．９（
ｄ）。74.0 (d), 74.4 (2C, each cl) 7
g, 8(d), 7 9.2(d), 1 02.9(
d).
１ ０３．６（ｓ）、１ ０４．７（ｓ）１０８．１（
ｓ）、１ １６．０（２Ｃ，ｅａｃｈ ｄ）１ ２
１．７（ｓ）、１ ２ ８．５（２Ｃ，ｅａｃｈ ｄ
）。1 03.6 (s), 1 04.7 (s) 108.1 (
s), 1 16.0 (2C, each d) 1 2
1.7 (s), 1 2 8.5 (2C, each d
).
１ ５ ５ 、１ （ｓ ）、 １ ５ ８ 、 Ｉ
（ｓ ）。1 5 5, 1 (s), 1 5 8, I
(s).
１ ６ １．０（ｓ）、１ ６ １．３（ｓ）。1 6 1.0 (s), 1 6 1.3 (s).
１ ６４．０（ｓ）、１ ８ ２．２（ｓ）実施例２
実施例１で得られた画分Ａを分取用高速液体クロマトグ
ラフィーであるＴＳＫ ｇｅｌ ０ＤＳ１２０Ｔ（２，
１（ｇ ｉ、ｄ、ｘ３０ａ’）に付し、アセトニトリル
−メタノール−水−酢酸−２５：２５：１５０：２で溶
出し目的成分を得た。目的成分は水−メタノールの混液
から結晶化し、Ｒｆ値０３３ｃ薄層プレート：キーゼル
ゲル６０ Ｆ ２５４．展開溶媒・ｎブタノール−酢酸
−水（４：１ ：５）、発色試薬・塩化第二鉄試薬：緑
黄色ｊの黄色粒状晶１７０πｇを得１こ。1 64.0 (s), 1 8 2.2 (s) Example 2 Fraction A obtained in Example 1 was subjected to preparative high performance liquid chromatography, TSK gel 0DS120T (2,
1 (g i, d, x30a') and eluted with acetonitrile-methanol-water-acetic acid-25:25:150:2 to obtain the target component. The target component was crystallized from a water-methanol mixture and had an Rf value of 033c. Thin layer plate: Kieselgel 60 F 254. Developing solvent: n-butanol-acetic acid-water (4:1:5), coloring reagent: ferric chloride reagent: 170 πg of greenish-yellow yellow granular crystals were obtained.
この黄色粒状晶の理化学的性質は、以下のごとくであり
、これらのデータより、式Ｉ中Ｒ３がＣβ−Ｄ−キノロ
ピラノンル基であり、Ｒ７かＣ−βＤ−ガラクトピラノ
シル基である化合物と構造を決定した。The physical and chemical properties of this yellow granular crystal are as follows, and from these data, it can be said that R3 in formula I is a Cβ-D-quinolopyranone group, and R7 is a C-βD-galactopyranosyl group. The structure has been decided.
融 点＝２１５〜２１９°Ｃ
比旋光度＝［α］”ｎ＝ ＋５２．４゜ＦＡＢ−ＭＳ
ｍ／ｚ：５６５ ［Ｍ十Ｈド赤外線吸収スペクトル
ν ”ｎ２’ｘ（’ＩＮ−’：３３９２．１６５０．１
６２Ｂ、１５７４゜１３５８．１２１６，１０８２．１
０５２紫外線吸収スペクトル λ ：：？Ｈｙｉ（ｌｏ
ｇε）＝２１６．６（４，５３）、２７３．０（４，２
７）３３３．８（４，２９）
プロトン核磁気共鳴スペクトル
（δ ｐｐｍ ｉｎ ＤＭＳＯ−ｄｓ＋Ｄｚｏ；９０℃
、 ２００ＭＨｚ） ：３．１〜４．２（Ｉ ＩＨ，ｍ
）。Melting point = 215-219°C Specific optical rotation = [α]”n = +52.4°FAB-MS
m/z: 565 [M10H infrared absorption spectrum
ν ”n2'x('IN-':3392.1650.1
62B, 1574° 1358.1216, 1082.1
052 Ultraviolet absorption spectrum λ ::? Hyi (lo
gε)=216.6(4,53), 273.0(4,2
7) 333.8 (4,29) Proton nuclear magnetic resonance spectrum (δ ppm in DMSO-ds+Dzo; 90°C
, 200MHz): 3.1 to 4.2 (IIH, m
).
４．６４ （Ｉ Ｈ，ｄ 、Ｊ ＝ ９．８ Ｈｚ）。4.64 (IH, d, J = 9.8 Hz).
４．９４ （Ｉ Ｈ，ｄ 、Ｊ ＝ ８．８ Ｈｚ）。4.94 (IH, d, J = 8.8 Hz).
６．６７（Ｉ Ｈ，ｓ）。6.67 (IH,s).
６．９３（２Ｈ，ｄ、Ｊ＝８．８Ｈｚ）。6.93 (2H, d, J=8.8Hz).
７９７（２Ｈ，ｄ、Ｊ＝８．８Ｈｚ）
１３ｃ−核磁気共鳴スペクトル
（δ ｐｐｍ ｉｎ ＤＭＳＯ−ｄｅ＋ Ｄ２０：５０
ＭＨ２）：６１．２（ｔ）、６８．７（ｄ）。797 (2H, d, J = 8.8Hz) 13c-nuclear magnetic resonance spectrum (δ ppm in DMSO-de+ D20:50
MH2): 61.2(t), 68.7(d).
７０．３（３Ｃ，ｅａｃｈ ｄ） ７０．６（ｔ）、７４．０（ｄ）、７４．６（ｄ）。70.3 (3C, each d) 70.6(t), 74.0(d), 74.6(d).
７５．３（ｄ）、７９．７（２Ｃ，ｅａｃｈ ｄ）１０
２．８（ｃｌ）、Ｉ ０３．４（ｓ）１０３．９（ｓ）
、１０９．５（ｓ）。75.3 (d), 79.7 (2C, each d) 10
2.8 (cl), I 03.4 (s) 103.9 (s)
, 109.5(s).
１１６．３（２Ｃ，ｅａｃｈ ｄ）、１２１．６（ｓ）
。116.3 (2C, each d), 121.6 (s)
.
１２９．０（２Ｃ，ｅａｃｈ ｄ）、１５３．７（ｓ）
。129.0 (2C, each d), 153.7 (s)
.
１６０．４．（ｓ）、１６１．４（ｓ）１６１．９（ｓ
）、Ｉ ６３．９（ｓ）１８２．６（ｓ）
実施例３
■コーンスターチ ４４９
■結晶セルロース ４０９
■カルボキシメチル
セルロースカルシウム ５９
■軽質無水ケイ酸 ０．５９■ステアリン酸
マグネシウム ０．５９■実施例！で得た化合物
１０ｇ
計 １００９
上記の処方に従って■〜■を均一に混合し、打錠機にて
圧縮成型して一部２００７’＋９の錠剤を得た。160.4. (s), 161.4 (s) 161.9 (s)
), I 63.9 (s) 182.6 (s) Example 3 ■Corn starch 449 ■Crystalline cellulose 409 ■Carboxymethylcellulose calcium 59 ■Light silicic anhydride 0.59■Magnesium stearate 0.59■Example! Compound obtained with
10g total 1009 According to the above recipe, ① to ③ were uniformly mixed and compressed using a tablet machine to obtain a portion of 2007'+9 tablets.
この錠剤−錠には、実施例で得た化合物２０Ｒ９が含有
されており、成人１日−５〜７錠を数回にわけて服用す
る。These tablets contain the compound 20R9 obtained in Example, and are taken by adults in 5 to 7 tablets per day in several doses.
実施例４
■結晶セルロース ８４．５ｇ■ステアリン酸
マグネシウム Ｏ，Ｓ！？■カルボキンメチル
セルロースカルシウム ５９
■実施例２で得た化合物 ＋０９
計 １００９
上記の処方に従って■、■および■の一部を均一に混合
し、圧縮成型した後、粉砕し、■および■の残量を加え
て混合し、打錠機にて圧縮成型して一部２００〜の錠剤
を得た。Example 4 ■Crystalline cellulose 84.5g■Magnesium stearate O,S! ? ■Carboquine Methylcellulose Calcium 59 ■Compound obtained in Example 2 +09 Total 1009 According to the above recipe, ■, ■, and part of ■ were uniformly mixed, compression molded, and then crushed, and the remaining amounts of ■ and ■ were mixed uniformly. The mixture was added, mixed, and compressed using a tablet machine to obtain 200 to 200 tablets.
この錠剤−錠には、実施例２で得た化合物２０ｍ９が含
有されており、成人１日５〜７錠を数回にわけて服用す
る。This tablet contains 20m9 of the compound obtained in Example 2, and is taken by adults in 5 to 7 tablets a day in several doses.
実施例５
■結晶セルロース ３４．５＠■１０％ヒドロ
キシプロピル
セルロースエタノール溶液 ５０ｙ
■カルボキンメチル
セルロースカルシウム ５９
■ステアリン酸マグネシウム ０．５ｇ■実施例１で得
た化合物 １０ｆ／計 １００９
上記の処方に従って■、■および■を均一に混合し、常
法によりねっ和し、押し出し造粒機により造粒し、乾燥
・解砕した後、■および■を混合し、打錠機にて圧縮成
型して一部２００卯の錠剤を得た。Example 5 ■Crystalline cellulose 34.5@■10% hydroxypropyl cellulose ethanol solution 50y ■Carboquine methylcellulose calcium 59 ■Magnesium stearate 0.5g■Compound obtained in Example 1 10f/total 1009 According to the above recipe■, ■ and ■ are mixed uniformly, and the mixture is wetted using a conventional method, and then granulated using an extrusion granulator, dried and crushed. 200 mu tablets were obtained.
この錠剤−錠には、実施例１で得た化合物２０ｍ９か含
有されており、成人１日５〜７錠を数回にわけて服用す
る。This tablet contains 20m9 of the compound obtained in Example 1, and adults should take 5 to 7 tablets a day in several doses.
実施例６
■コーンスターチ ８４９
■ステアリン酸マグネシウム ０．５ｇ■カルボキシメ
チル
セルロースカルシウム ５７
■軽質無水ケイ酸 ０．５９■実施例２で得
た化合物 ＋０９
計 １００９
上記の処方に従って■〜■を均一に混合し、圧縮成型機
にて圧縮成型後、破砕機により粉砕し、篩別して顆粒剤
を得た。Example 6 ■Corn starch 849 ■Magnesium stearate 0.5g ■Carboxymethylcellulose calcium 57 ■Light silicic anhydride 0.59■Compound obtained in Example 2 +09 Total 1009 Mix ■~■ uniformly according to the above recipe, After compression molding using a compression molding machine, the mixture was crushed using a crusher and sieved to obtain granules.
この顆粒剤１１？には、実施例２で得た化合物１００
ｍ９が含有されており、成人１日１〜２５９を数回にわ
けて服用する。This granule 11? is the compound 100 obtained in Example 2.
Contains m9, and adults should take 1 to 259 doses a day in several doses.
実施例７
■結晶セルロース ４０９
■ｌＯ％ヒドロキシプロピル
セルロースエタノール溶液 ５０ｇ
■実施例１で得た化合物 １０９
計 １００９
上記の処方に従って■〜■を均一に混合し、ねつ和した
。押し出し造粒機により造粒後、乾燥し、篩別して顆粒
剤を得た。Example 7 ■ Crystalline cellulose 409 ■ 1O% hydroxypropyl cellulose ethanol solution 50 g ■ Compound obtained in Example 1 109 Total 1009 ■ ~ ■ were uniformly mixed and slurried according to the above recipe. After granulation using an extrusion granulator, the mixture was dried and sieved to obtain granules.
この顆粒剤１９には、実施例１で得た化合物１００ Ｒ
９が含有されており、成人１日１〜２．５ｇを数回にわ
けて服用する。This granule 19 contains the compound 100 R obtained in Example 1.
9, and adults should take 1 to 2.5 g per day in several doses.
実施例８
■コーンスターチ ８９５ｇ
■軽質無水ケイ酸 ０．５ｇ■実施例２で得
た化合物 １０ｇ
計 １００９
上記の処方に従って■〜■を均一に混合し、２００ ！
７＠を２号カプセルに充填しに。Example 8 ■Corn starch 895g ■Light silicic anhydride 0.5g■Compound obtained in Example 2 10g Total 1009 According to the above recipe, ■~■ were mixed uniformly, and 200!
To fill 7@ into No. 2 capsule.
このカプセル剤１カプセルには、実施例２で得た化合物
２（１＠か含有されており、成人１日５〜７カプセルを
数回にわけて服用する。One capsule of this preparation contains Compound 2 (1@) obtained in Example 2, and adults should take 5 to 7 capsules a day in several doses.
実施例９
■注射用蒸留水 通量
■ブドウ糖 ２００ ｍ９■実施例１
で得た化合物 ｌＯ〜
全量 １５７
注射用蒸留水に■および■を溶解させた後、５−のアン
プルに注入し、１２１℃で１５分間加圧滅菌を行って注
射剤を得た。Example 9 ■ Distilled water for injection Amount ■ Glucose 200 m9 ■ Example 1
Compound obtained in IO ~ Total amount 157 After dissolving ① and ② in distilled water for injection, it was poured into an ampoule of 5- and autoclaved at 121°C for 15 minutes to obtain an injection.
Claims (2)
ラクトピラノシル基またはＣ−β−Ｄ−キシロピラノシ
ル基を示す。） で表されるフラボン−Ｃ−配糖体。(1) The following formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (However, in the formula, R_1 and R_2 represent a C-β-D-galactopyranosyl group or a C-β-D-xylopyranosyl group. ) Flavone-C-glycoside represented by.
トピラノシル基またはＣ−β−Ｄ−キシロピラノシル基
を示す。） で表されるフラボン−Ｃ−配糖体を有効成分とするアル
ドースリダクターゼ阻害剤。(2) The following formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (However, in the formula, R and R represent a C-β-D-galactopyranosyl group or a C-β-D-xylopyranosyl group. An aldose reductase inhibitor containing a flavone-C-glycoside represented by the following formula as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2165697A JPH0459788A (en) | 1990-06-26 | 1990-06-26 | New flavone-c-glycoside and aldose-reductase inhibitor containing the flavone-c-glycoside as active component |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2165697A JPH0459788A (en) | 1990-06-26 | 1990-06-26 | New flavone-c-glycoside and aldose-reductase inhibitor containing the flavone-c-glycoside as active component |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0459788A true JPH0459788A (en) | 1992-02-26 |
Family
ID=15817334
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2165697A Pending JPH0459788A (en) | 1990-06-26 | 1990-06-26 | New flavone-c-glycoside and aldose-reductase inhibitor containing the flavone-c-glycoside as active component |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0459788A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2008261185A1 (en) * | 2008-12-23 | 2010-07-08 | National Yang-Ming University | Biologically active extract from dendrobium plant, use thereof and process for preparing the same |
| US8426371B2 (en) | 2007-06-29 | 2013-04-23 | National Yang-Ming University | Biologically active extract from Dendrobium plant, use thereof and process for preparing the same |
-
1990
- 1990-06-26 JP JP2165697A patent/JPH0459788A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8426371B2 (en) | 2007-06-29 | 2013-04-23 | National Yang-Ming University | Biologically active extract from Dendrobium plant, use thereof and process for preparing the same |
| AU2008261185A1 (en) * | 2008-12-23 | 2010-07-08 | National Yang-Ming University | Biologically active extract from dendrobium plant, use thereof and process for preparing the same |
| AU2008261185B2 (en) * | 2008-12-23 | 2011-09-22 | National Yang-Ming University | Biologically active extract from dendrobium plant, use thereof and process for preparing the same |
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