JPH06256185A - Vitamin e derivative and antiulcer agent containing the same as active ingerdient - Google Patents
Vitamin e derivative and antiulcer agent containing the same as active ingerdientInfo
- Publication number
- JPH06256185A JPH06256185A JP5049303A JP4930393A JPH06256185A JP H06256185 A JPH06256185 A JP H06256185A JP 5049303 A JP5049303 A JP 5049303A JP 4930393 A JP4930393 A JP 4930393A JP H06256185 A JPH06256185 A JP H06256185A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- vitamin
- derivative
- formula
- group
- 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.)
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、抗潰瘍作用を有し、抗
潰瘍剤として有用な新規化合物およびこれを有効成分と
して含有してなる抗潰瘍剤に関する。FIELD OF THE INVENTION The present invention relates to a novel compound having an antiulcer action and useful as an antiulcer agent, and an antiulcer agent containing the same as an active ingredient.
【０００２】[0002]
【従来技術・発明が解決しようとする課題】消化性潰瘍
は種々の原因によって発生するが、一般には、過酸、ス
トレス、胃血流循環の阻害、薬物、その他の原因により
もたらされた酸、ペプシン、胃液等の攻撃因子と、消化
管粘膜の防禦力等の防禦因子との不均衡によって発生す
るとされている。BACKGROUND OF THE INVENTION Although peptic ulcers are caused by various causes, generally, acid caused by peracid, stress, inhibition of gastric blood flow circulation, drugs, and other causes. , Pepsin, gastric juice and other attack factors, and gastrointestinal mucosal defense factors such as defense factor is said to be caused by imbalance.
【０００３】抗消化性潰瘍剤としては、臨床的には、主
として攻撃因子を減弱させる薬剤が用いられているが、
攻撃因子を減弱させる薬剤には副作用を有するものが多
く、例えば、抗コリン剤は副交感神経遮断作用を有する
ので胃液分泌の抑制が過度になり、胃の活動を鈍化させ
て消化力を減退させることがあり、また、制酸剤は一時
的に胃酸を中和させるので、その反作用として胃酸分泌
を亢進させることがある。従って、優れた抗潰瘍作用を
有し、しかも毒性や副作用が少なくて長期の連用に付す
ことができる抗潰瘍剤が望まれているのが現状である。As an anti-peptic ulcer agent, clinically, agents that mainly attenuate attack factors are used.
Many drugs that reduce attack factors have side effects.For example, anticholinergic drugs have a parasympathetic nerve blocker action, which results in excessive suppression of gastric juice secretion, slowing gastric activity and diminishing digestive power. In addition, since the antacid temporarily neutralizes gastric acid, its reaction may increase gastric acid secretion. Therefore, under the present circumstances, there is a demand for an anti-ulcer agent which has an excellent anti-ulcer effect and has little toxicity and side effects and which can be applied for a long period of time.
【０００４】本発明の目的は、優れた抗潰瘍作用を有
し、しかも毒性や副作用が少なくて長期の連用に付すこ
とが可能な新規化合物を提供することにある。また、本
発明の他の目的は、優れた抗潰瘍作用を有し、かつ毒性
や副作用が少ない抗潰瘍剤を提供することにある。An object of the present invention is to provide a novel compound having an excellent anti-ulcer action, less toxicity and side effects and capable of being used for a long period of time. Another object of the present invention is to provide an anti-ulcer agent having an excellent anti-ulcer effect and having little toxicity and side effects.
【０００５】[0005]
【課題を解決するための手段】本発明者らが鋭意研究し
た結果、下記一般式（Ｉ）で表されるビタミンＥ誘導体
およびその塩により上記目的が達成されることを見出し
た。即ち、本発明は、一般式（Ｉ）Means for Solving the Problems As a result of intensive studies by the present inventors, they have found that the above-mentioned object can be achieved by the vitamin E derivative represented by the following general formula (I) and its salt. That is, the present invention has the general formula (I)
【０００６】[0006]
【化２】 [Chemical 2]
【０００７】（式中、Ｘは水素原子またはアシル基を示
す。）で表されるビタミンＥ誘導体（以下、ビタミンＥ
誘導体（Ｉ）と略称する）またはその塩に関する。ま
た、当該ビタミンＥ誘導体（Ｉ）またはその塩を有効成
分として含有してなる抗潰瘍剤に関する。(In the formula, X represents a hydrogen atom or an acyl group.) A vitamin E derivative (hereinafter referred to as vitamin E)
The derivative (I) is abbreviated) or a salt thereof. It also relates to an anti-ulcer agent containing the vitamin E derivative (I) or a salt thereof as an active ingredient.
【０００８】本明細書においてＸで表されるアシル基と
しては、置換基を有していてもよいアルカノイル基また
はアロイル基である。アルカノイル基は直鎖状または分
枝状のいずれでもよく、例えば、アセチル基、プロピオ
ニル基、ブチリル基、ピバロイル基、バレリル基、ステ
アロイル基等が挙げられ、また、これらは置換基として
フェニル基を有していてもよく、置換基を有するアルカ
ノイル基としては、例えば、フェニルアセチル基、フェ
ニルプロピオニル基等が挙げられる。また、アロイル基
としてはベンゾイル基等が挙げられる。The acyl group represented by X in the present specification is an alkanoyl group or an aroyl group which may have a substituent. The alkanoyl group may be linear or branched, and examples thereof include an acetyl group, a propionyl group, a butyryl group, a pivaloyl group, a valeryl group and a stearoyl group, and these have a phenyl group as a substituent. Examples of the alkanoyl group having a substituent include a phenylacetyl group and a phenylpropionyl group. Moreover, a benzoyl group etc. are mentioned as an aroyl group.
【０００９】本発明のビタミンＥ誘導体（Ｉ）は塩の形
態でも優れた特性を有するものとして存在し得る。その
ような塩としては、例えば、塩酸、硫酸、臭化水素酸、
リン酸等の無機酸、またはフマル酸、酒石酸、コハク
酸、クエン酸、メタンスルホン酸等の有機酸との酸付加
塩等が挙げられる。当該塩は、医薬上許容されうる塩で
あることが好ましい。The vitamin E derivative (I) of the present invention can be present in salt form as having excellent properties. Examples of such salts include hydrochloric acid, sulfuric acid, hydrobromic acid,
Examples thereof include inorganic acids such as phosphoric acid, and acid addition salts with fumaric acid, tartaric acid, succinic acid, citric acid, methanesulfonic acid, and other organic acids. The salt is preferably a pharmaceutically acceptable salt.
【００１０】本発明のビタミンＥ誘導体（Ｉ）には各種
の光学異性体が存在するが、本発明は光学異性体、ラセ
ミ体さらにはジアステレオ異性体、およびそれらの混合
物をも包含するものである。Although the vitamin E derivative (I) of the present invention has various optical isomers, the present invention includes optical isomers, racemates, diastereoisomers, and mixtures thereof. is there.
【００１１】本発明のビタミンＥ誘導体（Ｉ）は、例え
ば、下記反応工程Ａに従って合成することができる。The vitamin E derivative (I) of the present invention can be synthesized, for example, according to the following reaction step A.
【００１２】[0012]
【化３】 [Chemical 3]
【００１３】（上記反応工程中、Ｚはアミノ保護基を示
す。）(In the above reaction step, Z represents an amino protecting group.)
【００１４】工程１ カルノシンにアミノ保護基を付加する工程であり、通常
公知の方法により行うことができる。アミノ保護基とし
ては、通常用いられているものであれば特に制限はな
く、例えば、ベンジルオキシカルボニル基等が挙げられ
る。当該反応は、水酸化ナトリウム水溶液、炭酸ナトリ
ウム水溶液等のアルカリ性水溶液等の溶媒中、好ましく
はｐＨを８〜１０に調整し、反応温度−１０〜１０℃で
行われる。Step 1 is a step of adding an amino-protecting group to carnosine and can be carried out by a generally known method. The amino protecting group is not particularly limited as long as it is a commonly used group, and examples thereof include a benzyloxycarbonyl group. The reaction is carried out in a solvent such as an aqueous alkaline solution such as an aqueous sodium hydroxide solution or an aqueous sodium carbonate solution, preferably at a pH of 8 to 10, and at a reaction temperature of -10 to 10 ° C.
【００１５】工程２ アミノ基が保護されたカルノシン〔化合物（II）〕とト
コフェロールのエステル化反応である。即ち、塩化チオ
ニル等の脱水縮合剤の存在下に、トコフェロールとアミ
ノ基が保護されたカルノシンを反応させ、エステルを形
成させる。当該反応は、テトラヒドロフラン等の溶媒
中、反応温度−１０〜３０℃で行われる。Step 2 An esterification reaction of carnosine [compound (II)] with protected amino group and tocopherol. That is, tocopherol is reacted with carnosine whose amino group is protected in the presence of a dehydration condensing agent such as thionyl chloride to form an ester. The reaction is carried out in a solvent such as tetrahydrofuran at a reaction temperature of -10 to 30 ° C.
【００１６】工程３ アミノ基が保護されたビタミンＥ誘導体〔化合物(III)
〕を還元し、アミノ保護基を除去して、一般式（Ｉ）
においてＸが水素原子である化合物を得る工程である。
当該反応は、メタノール、エタノール、プロパノール、
テトラヒドロフラン、ジオキサン等の不活性溶媒中、反
応温度１５〜５０℃で、パラジウム−炭素、パラジウム
−黒等の触媒の存在下、水素を付加させることにより行
われる。Step 3 Amino group-protected vitamin E derivative [compound (III)
], The amino protecting group is removed to give a compound of the general formula (I)
In the step of obtaining a compound in which X is a hydrogen atom.
The reaction is methanol, ethanol, propanol,
It is carried out by adding hydrogen in an inert solvent such as tetrahydrofuran or dioxane at a reaction temperature of 15 to 50 ° C. in the presence of a catalyst such as palladium-carbon or palladium-black.
【００１７】また、Ｘがアシル基である化合物は、反応
工程Ａにおいて、アミノ基が保護されたカルノシン〔化
合物（II）〕の代わりにＮ−アシルカルノシン（イミダ
ゾール核上の窒素原子はアシル化されていない）を用
い、これとトコフェロールとのエステル化反応を行うこ
とにより得ることができる。In the reaction step A, the compound in which X is an acyl group is N-acylcarnosine (the nitrogen atom on the imidazole nucleus is acylated instead of the amino group-protected carnosine [compound (II)]. No.) is used to carry out an esterification reaction of this with tocopherol.
【００１８】例えばＮ−アシルカルノシンのうちＮ−ア
シル−Ｌ−カルノシンは、特開昭５８−１２４７５０号
公報によれば、アルカリ性水溶液中、ｐＨ９〜１３．
５、反応温度１５〜２０℃に保持しながら、Ｌ−カルノ
シンにアシル供与体を作用させることにより得られる。
アシル供与体としては、一般式（ＲＣＯ）2 Ｏ〔式中、
Ｒはアルキル基、アリール基またはアラルキル基を示
す〕で表されるカルボン酸無水物、または一般式ＲＣＯ
Ｃｌ〔式中、Ｒは前記と同義である〕で表されるカルボ
ン酸クロライドが好ましく用いられ、例えば、無水酢
酸、無水プロピオン酸、アセチルクロライド、プロピオ
ニルクロライド、ベンゾイルクロライド等が挙げられ
る。For example, N-acyl-L-carnosine among N-acyl carnosine has a pH of 9 to 13% in an alkaline aqueous solution according to JP-A-58-124750.
5. It is obtained by allowing an acyl donor to act on L-carnosine while maintaining the reaction temperature at 15 to 20 ° C.
As the acyl donor, a compound represented by the general formula (RCO) 2 O [in the formula,
R represents an alkyl group, an aryl group or an aralkyl group], or a general formula RCO
A carboxylic acid chloride represented by Cl [wherein R has the same meaning as defined above] is preferably used, and examples thereof include acetic anhydride, propionic anhydride, acetyl chloride, propionyl chloride and benzoyl chloride.
【００１９】このようにして得られるビタミンＥ誘導体
（Ｉ）は、シリカゲルクロマトグラフィーおよび分液法
等により精製することができる。また、ビタミンＥ誘導
体（Ｉ）の塩は自体既知の手段によって製造することが
できる。The vitamin E derivative (I) thus obtained can be purified by silica gel chromatography and a liquid separation method. The salt of the vitamin E derivative (I) can be produced by a means known per se.
【００２０】本発明のビタミンＥ誘導体（Ｉ）およびそ
の塩を医薬として用いる場合、通常、その有効成分量を
担体、賦形剤、希釈剤等と混合して、散剤、顆粒、錠
剤、糖衣剤、カプセル剤、シロップ剤、坐剤、外用剤、
注射剤、点滴用剤等の形態をとることができる。When the vitamin E derivative (I) and its salt of the present invention are used as a medicine, the active ingredient amount is usually mixed with a carrier, an excipient, a diluent and the like to prepare powders, granules, tablets and sugar-coated agents. , Capsules, syrups, suppositories, external preparations,
It can be in the form of injections, infusions and the like.
【００２１】投与量は投与経路、剤型等により変動し得
るが、一般に経口剤の場合、当該ビタミンＥ誘導体
（Ｉ）またはその塩として、１日当たり１０〜２０００
mg／kg、好ましくは２０〜２００mg／kgであり、注射剤
では１日１〜２００mg／kg、好ましくは１０〜５０mg／
kgである。投与回数は１日１〜３回の範囲で適宜選択し
得る。Although the dose may vary depending on the route of administration, dosage form, etc., in the case of an oral preparation, it is generally 10 to 2000 per day as the vitamin E derivative (I) or a salt thereof.
mg / kg, preferably 20 to 200 mg / kg, and 1 to 200 mg / kg, preferably 10 to 50 mg / day for injections
It is kg. The frequency of administration can be appropriately selected within the range of 1 to 3 times a day.
【００２２】[0022]
【実施例】以下の実施例により本発明をより詳細に説明
するが、本発明はこれらによって限定されるものではな
い。The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
【００２３】実施例１：化合物（IV）の合成 Ｌ−カルノシン５０．０ｇ（２２１mmol）を２Ｎ水酸
化ナトリウム水溶液１１０．５ml（２２１mmol）と２Ｎ
炭酸ナトリウム水溶液１６５mlに溶解し、５℃でベンジ
ルオキシカルボニルクロライド８３ｇ（４８７mmol）を
３０分間かけて滴下した。この間、反応液のｐＨを８〜
１０に保つように、適宜２Ｎ炭酸ナトリウム水溶液を加
えた。反応液を０〜５℃で１．５時間反応させた後、氷
水５００mlに投入した。希塩酸でこの反応液のｐＨを２
に調整し、酢酸エチル（６００ml×３回）で抽出した。
酢酸エチル層を飽和食塩水（１リットル×２回）で洗
い、無水硫酸マグネシウムで乾燥した。溶媒を留去して
得られた１１２ｇの粗生成物をシリカゲルカラムクロマ
トグラフィー（展開溶媒：クロロホルム／メタノール＝
１５／１〜９／１）に付し、６２．８ｇの化合物（II）
を得た。（収率６１％）Example 1 Synthesis of Compound (IV) 50.0 g (221 mmol) of L-carnosine was added to 110.5 ml (221 mmol) of 2N sodium hydroxide aqueous solution and 2N.
It was dissolved in 165 ml of an aqueous solution of sodium carbonate and 83 g (487 mmol) of benzyloxycarbonyl chloride was added dropwise at 5 ° C over 30 minutes. During this period, the pH of the reaction solution is 8 to
A 2N sodium carbonate aqueous solution was appropriately added so as to keep it at 10. The reaction solution was reacted at 0 to 5 ° C for 1.5 hours and then added to 500 ml of ice water. Adjust the pH of this reaction mixture to 2 with dilute hydrochloric acid.
The mixture was adjusted to pH 3, and extracted with ethyl acetate (600 ml x 3 times).
The ethyl acetate layer was washed with saturated saline (1 liter x 2 times) and dried over anhydrous magnesium sulfate. 112 g of a crude product obtained by distilling off the solvent was subjected to silica gel column chromatography (developing solvent: chloroform / methanol =
15/1 to 9/1) and 62.8 g of compound (II)
Got (Yield 61%)
【００２４】ＤＬ−α−トコフェロールを４７１．８
ｇ（１．１mol ）含有する乾燥テトラヒドロフラン溶液
に、塩化チオニル１３０．５ｇ（１．１mol ）を−１０
〜８℃で３０分間かけて滴下した。同温度で３０分間撹
拌した後、化合物（II）を１１３．５ｇ（２１９mmol）
含有する乾燥テトラヒドロフラン溶液１リットルを−１
０〜−７℃で２０分間かけて滴下した。滴下終了後、反
応液を室温に戻し、１８時間反応させた。この反応混合
物を氷水６リットルに投入し、２５％アンモニア水でｐ
Ｈを７に調整した。これに酢酸エチル５リットルを加
え、酢酸エチル層と水層に分配し、水層をさらに酢酸エ
チル（２リットル×２回）で抽出した。酢酸エチル層を
飽和食塩水（８リットル×２回）で洗った後、濃縮し５
８０ｇの粗生成物を得た。これをシリカゲルカラムクロ
マトグラフィー（展開溶媒：酢酸エチル／ｎ−ヘキサン
＝１／１〜３／１）に付し、４６ｇの粗生成物を得た。
これを再度シリカゲルカラムクロマトグラフィー（展開
溶媒：酢酸エチル／ｎ−ヘキサン＝１／１〜２／１）に
付し、３６ｇの化合物(III) を得た。（収率１９％）DL-α-tocopherol was added to 471.8.
In a dry tetrahydrofuran solution containing g (1.1 mol), thionyl chloride (130.5 g, 1.1 mol) was added to -10.
Dropwise at ~ 8 ° C over 30 minutes. After stirring at the same temperature for 30 minutes, 113.5 g (219 mmol) of compound (II)
1 liter of a dry tetrahydrofuran solution containing -1
It was added dropwise at 0 to -7 ° C over 20 minutes. After completion of dropping, the reaction solution was returned to room temperature and reacted for 18 hours. This reaction mixture was added to 6 liters of ice water, and the mixture was added with 25% aqueous ammonia to p
The H was adjusted to 7. To this, 5 liters of ethyl acetate was added, partitioned into an ethyl acetate layer and an aqueous layer, and the aqueous layer was further extracted with ethyl acetate (2 liters x 2 times). The ethyl acetate layer was washed with saturated saline (8 liters x 2 times) and then concentrated.
80 g of crude product was obtained. This was subjected to silica gel column chromatography (developing solvent: ethyl acetate / n-hexane = 1/1 to 3/1) to obtain 46 g of a crude product.
This was again subjected to silica gel column chromatography (developing solvent: ethyl acetate / n-hexane = 1/1 to 2/1) to obtain 36 g of compound (III). (Yield 19%)
【００２５】化合物(III) ３６ｇ（４１mmol）をメタ
ノール１．７リットルに溶解し、１０％パラジウム−炭
素３．６ｇを加え、水素雰囲気下、５０℃で３時間反応
させた。その後、失活したパラジウム−炭素を濾去し、
新たにパラジウム−炭素を３．６ｇ追加し、５０℃で３
時間反応させた。さらに３時間ごとに、失活した触媒を
除いて、新たにパラジウム−炭素３．６ｇを加える操作
を４回行った。化合物(III) および中間体が消失したこ
とを薄層クロマトグラフィーで確認した後、触媒を除
き、溶媒を留去した。得られた２０．６ｇの粗生成物を
シリカゲルカラムクロマトグラフィー（展開溶媒：クロ
ロホルム／１０％アンモニア含有メタノール＝８５／１
５）に付し、１４．９ｇの粗生成物を得た。これを再度
シリカゲルカラムクロマトグラフィー（展開溶媒：クロ
ロホルム／１０％アンモニア含有メタノール＝８５／１
５）に付し、１１．５ｇの化合物（IV）を得た。（収率
４３％）36 g (41 mmol) of compound (III) was dissolved in 1.7 liter of methanol, 3.6 g of 10% palladium-carbon was added, and the mixture was reacted at 50 ° C. for 3 hours in a hydrogen atmosphere. Then, the deactivated palladium-carbon was filtered off,
3.6 g of palladium-carbon was newly added, and 3 at 50 ° C.
Reacted for hours. Further, the operation of adding 3.6 g of new palladium-carbon was carried out four times every 3 hours except for the deactivated catalyst. After confirming the disappearance of compound (III) and the intermediate by thin layer chromatography, the catalyst was removed and the solvent was evaporated. The obtained 20.6 g of the crude product was subjected to silica gel column chromatography (developing solvent: chloroform / 10% ammonia-containing methanol = 85/1.
After 5), 14.9 g of crude product was obtained. This was again subjected to silica gel column chromatography (developing solvent: chloroform / 10% ammonia-containing methanol = 85/1.
After 5), 11.5 g of compound (IV) was obtained. (Yield 43%)
【００２６】ＩＲ（KBr)； 2930, 1750, 1640, 1570, 1
460, 1200, 1175 cm-1 ＮＭＲ（ＣＤＣｌ3 ）δ；0.86 (d, 12H), 1.00-1.80
(m, 26H), 1.90 (s, 6H), 2.05 (s, 3H),2.38 (t, 2H),
2.47 (t, 2H), 3.00 (t, 2H), 3.30 (d, 2H),4.50-5.0
0 (b, 3H), 5.10 (q, 1H), 6.82 (s, 1H), 7.46 (s, 1
H),8.30 (d, 2H)IR (KBr); 2930, 1750, 1640, 1570, 1
460, 1200, 1175 cm -1 NMR (CDCl 3 ) δ; 0.86 (d, 12H), 1.00-1.80
(m, 26H), 1.90 (s, 6H), 2.05 (s, 3H), 2.38 (t, 2H),
2.47 (t, 2H), 3.00 (t, 2H), 3.30 (d, 2H), 4.50-5.0
0 (b, 3H), 5.10 (q, 1H), 6.82 (s, 1H), 7.46 (s, 1
H), 8.30 (d, 2H)
【００２７】 試験例１：塩酸／エタノール潰瘍に対する作用 体重約２００ｇのウイスター（Wistar）系雄性ラットを
一群６〜７匹とし、２４時間絶食させた後、ラットに本
発明のビタミンＥ誘導体〔化合物（IV）〕１００mg／kg
を経口投与した。コントロール群には水を投与した。６
０分後に６０％エタノールの１５０ｍＭ塩酸溶液１．５
mlを経口投与し、塩酸／エタノール投与から１時間後に
ラットを屠殺した。胃を摘出して２％ホルマリンで固定
し、胃粘膜に見られる潰瘍の長さを求め、コントロール
群に対する抑制率を求めた。この結果を表１に示す。Test Example 1: Action on Hydrochloric Acid / Ethanol Ulcer A group of 6 to 7 male Wistar rats having a body weight of about 200 g was fasted for 24 hours, and then the vitamin E derivative of the present invention [compound ( IV)] 100 mg / kg
Was orally administered. Water was administered to the control group. 6
0 minutes later, 60% ethanol in 150 mM hydrochloric acid solution 1.5
ml was orally administered, and the rats were sacrificed 1 hour after the administration of hydrochloric acid / ethanol. The stomach was extracted and fixed with 2% formalin, the length of the ulcer found in the gastric mucosa was determined, and the inhibition rate relative to the control group was determined. The results are shown in Table 1.
【００２８】[0028]
【表１】 [Table 1]
【００２９】試験例２：酢酸潰瘍に対する作用 体重約２００ｇのウイスター（Wistar）系雄性ラットを
一群１６または１８匹とし、エーテル麻酔下に開腹し、
胃体部または十二指腸部に円形枠を当て、その中に１０
０％酢酸１００μｌを注入した。６０秒後に酢酸を除去
し、開腹部を縫合した。潰瘍モデル作成２日後から１５
日間、本発明のビタミンＥ誘導体〔化合物（IV）〕８０
mg／kgを１日１回経口投与した。コントロール群には水
を投与した。最終投与後１８時間絶食させ、ラットを屠
殺した。胃を摘出し、画像処理により潰瘍部位の面積を
求め、コントロール群に対する治癒率を求めた。この結
果を表２に示す。Test Example 2: Action against acetic acid ulcer A group of 16 or 18 male Wistar rats having a body weight of about 200 g was subjected to laparotomy under ether anesthesia,
Apply a circular frame to the stomach or duodenum and put 10
100 μl of 0% acetic acid was injected. After 60 seconds, acetic acid was removed, and the laparotomy was sutured. 15 days from 2 days after making ulcer model
For 80 days, the vitamin E derivative of the present invention [compound (IV)] 80
Orally administrated mg / kg once a day. Water was administered to the control group. The rats were sacrificed by fasting for 18 hours after the final administration. The stomach was removed, the area of the ulcer site was determined by image processing, and the cure rate for the control group was determined. The results are shown in Table 2.
【００３０】[0030]
【表２】 [Table 2]
【００３１】製剤例１ 実施例１で得られた化合物（IV）２５mg、コーンスター
チ２０mg、ヒドロキシプロピルセルロース３mg、ステア
リン酸マグネシウム３mgおよび乳糖１０２mgを用い、常
法に従って顆粒剤を調製した。Formulation Example 1 Using the compound (IV) 25 mg obtained in Example 1, corn starch 20 mg, hydroxypropyl cellulose 3 mg, magnesium stearate 3 mg and lactose 102 mg, a granule was prepared according to a conventional method.
【００３２】製剤例２ 実施例１で得られた化合物（IV）を１０mg／mlの割合で
溶解させた５％ブドウ糖溶液を、ポアサイズ０．２２μ
ｍのフィルターを通じて濾過滅菌した後、加熱滅菌した
バイアル瓶に５mlずつ無菌的に分注して注射剤とした。Formulation Example 2 A 5% glucose solution in which the compound (IV) obtained in Example 1 was dissolved at a ratio of 10 mg / ml was added to a pore size of 0.22 μm.
After sterilizing by filtration through a filter of m, 5 ml was aseptically dispensed into a vial sterilized by heat to prepare an injection.
【００３３】[0033]
【発明の効果】本発明のビタミンＥ誘導体およびその塩
は、優れた抗潰瘍作用を有し、毒性や副作用が少なく、
長期の連用が可能であり、抗潰瘍剤として有用である。INDUSTRIAL APPLICABILITY The vitamin E derivative and its salt of the present invention have excellent anti-ulcer activity, less toxicity and side effects,
It can be used for a long period of time and is useful as an anti-ulcer agent.
Claims (2)
れるビタミンＥ誘導体またはその塩。1. A compound represented by the general formula (I): (In the formula, X represents a hydrogen atom or an acyl group.) A vitamin E derivative or a salt thereof.
その塩を有効成分として含有してなる抗潰瘍剤。2. An anti-ulcer agent containing the vitamin E derivative according to claim 1 or a salt thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5049303A JPH06256185A (en) | 1993-03-10 | 1993-03-10 | Vitamin e derivative and antiulcer agent containing the same as active ingerdient |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5049303A JPH06256185A (en) | 1993-03-10 | 1993-03-10 | Vitamin e derivative and antiulcer agent containing the same as active ingerdient |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06256185A true JPH06256185A (en) | 1994-09-13 |
Family
ID=12827178
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5049303A Pending JPH06256185A (en) | 1993-03-10 | 1993-03-10 | Vitamin e derivative and antiulcer agent containing the same as active ingerdient |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06256185A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004026856A1 (en) * | 2002-09-17 | 2004-04-01 | Phenion Gmbh & Co. Kg | Tocopheryl ester |
-
1993
- 1993-03-10 JP JP5049303A patent/JPH06256185A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004026856A1 (en) * | 2002-09-17 | 2004-04-01 | Phenion Gmbh & Co. Kg | Tocopheryl ester |
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