JPH0153668B2 - - Google Patents
Info
- Publication number
- JPH0153668B2 JPH0153668B2 JP18145981A JP18145981A JPH0153668B2 JP H0153668 B2 JPH0153668 B2 JP H0153668B2 JP 18145981 A JP18145981 A JP 18145981A JP 18145981 A JP18145981 A JP 18145981A JP H0153668 B2 JPH0153668 B2 JP H0153668B2
- Authority
- JP
- Japan
- Prior art keywords
- guaya
- aluminum
- azulene
- sodium
- azulene sulfonate
- 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
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、新規グアヤアズレンスルホン酸アル
ミニウムと、その製法ならびに、その化合物の医
薬用途への応用に関するものである。
従来から、抗炎、抗潰瘍作用を有するグアヤア
ズレンは、油溶性であるため、これを水溶性にす
る目的でスルホン酸のナトリウム塩とし、胃潰
瘍、十二指腸潰瘍、急、慢性胃炎等の治療剤とし
て広く用いられてきたが、吸湿性、あるいは、室
温に放置すると、分解する等の欠点も認められて
いる。本願発明者は、このナトリウム塩の薬理作
用の改善を目的として種々検討してきたが、各種
糖類硫酸エステルのアルミニウム化合物が胃壁保
護作用並びに抗ペプシン作用を有し、一般にアル
ミニウム化合物は、胃壁保護作用が著明であるこ
と等に着目し、グアヤアズレンスルホン酸のアル
ミニウム塩として用いたところ、この化合物がナ
トリウム塩からは予測もされ得なかつた強力な潰
瘍抑制作用を有し、しかも著しく毒性が低下する
ことを見い出し、更に又、このアルミニウムイオ
ン塩を収率よく製造することにも成功したもので
ある。
本発明に係る新規グアヤアズレンスルホン酸ア
ルミニウム塩の製造は、グアヤアズレンスルホン
酸ナトリウムの水溶液にアルミニウムイオンを作
用させることにより達成することができる。この
際グアヤアズレンスルホン酸ナトリウムは、１〜
10％水溶液として用いることが望ましい。本反応
を速やかにかつ十分に完結せしめるためには、ア
ルミニウムイオンを10〜20％の濃度で反応させる
ことが必要である。反応は室温で行なえば十分で
あつて、グアヤアズレンスルホン酸ナトリウム水
溶液に、アルミニウムイオン水溶液を撹拌しなが
ら注加することにより、目的物を青紫色の沈澱と
して得ることができる。このようにして得られた
沈澱物は、過し十分水洗し未反応の原料物質を
除去する。
上記反応において、グアヤアズレンスルホン酸
ナトリウム水溶液の濃度及びアルミニウムイオン
濃度は、前記した範囲以外でも反応そのものは行
なわれるが、反応速度がきわめて遅く、かつ、目
的物の析出採取が困難なため実用性に乏しい。
又、反応後の液性は、PH3.5〜７の範囲で反応は
行なわれ得るが、PH4.5〜6.0の範囲に於て最も収
率が高い。尚この場合、予めグアヤアズレンスル
ホン酸ナトリウム塩水溶液をアルカリ性にしてお
いても、或は又、両液を混合後PHを調節してもど
ちらでもよい。又両液を反応せしめる場合、どち
らを先に他に注加しても差支えない。本製造方法
に使用されるアルミニウムイオンとしては、一般
に金属アルミニウム或は水酸化アルミニウム、塩
化アルミニウム等のアルミニウム塩に、酸又はア
ルカリを加えてPH3.5〜5.5にすることにより得ら
れるものの他アルミニウムイソプロポキサイドも
使用することができる。
本発明により得られるグアヤアズレンスルホン
酸アルミニウム塩は、水に不溶で、室温にその
まゝ放置しても吸湿その他外観上の変化を認めな
い。本反応の原料物質は、いづれも水溶性である
にもかゝわらず、生成物は水不溶性の青紫色沈澱
として得られることにより、生成物は、単なる混
合物ではなく新規化合物であることは明らかであ
つて、このことは、本願化合物の赤外吸収スペク
トルとグアヤアズレンスルホン酸ナトリウムのそ
れとを比較することにより確認され得る。
本観化合物を用いて、幽門結索ラツト
（Shayrat）に誘発される実験潰瘍の阻止率を調
べた所、原料物質たるグアヤアズレンスルホン酸
ナトリウム塩よりも、はるかに強力でしかも、本
願物質の特徴色たる青紫色を呈する物質が胃粘膜
に吸着しているのが、肉眼的にも観察され、アル
ミニウム化合物にすることにより、本願物質が、
胃粘膜に特異的に吸着されやすい特性を備えたも
のと考えられる。以下に薬理試験例及び製造実施
例を掲げる。
試験例 １
本願物質の急性毒性を、雄性マウスを用いて調
べたところ、５ｇ／Kg経口投与においても、投与
した５匹全例が生存しているためLD50は５ｇ／
Kg以上と考えられる。
試験例 ２
Shayの方法に従い、体重180〜200ｇの呑竜ラ
ツトを24時間絶食後幽門を結紮して16時間後に屠
殺開腹し、生じた潰瘍の面積を測定した結果を表
１に示す。尚本願物質は、１％メチルセルロース
に懸濁し、結紮直後に経口投与した。
The present invention relates to a novel aluminum guaya azulene sulfonate, a method for producing the same, and the application of the compound for pharmaceutical use. Since guaya azulene, which has anti-inflammatory and anti-ulcer effects, is oil-soluble, it has been made into a sodium salt of sulfonic acid to make it water-soluble, and has been widely used as a therapeutic agent for gastric ulcers, duodenal ulcers, acute and chronic gastritis, etc. However, it has been recognized that it has drawbacks such as hygroscopicity and decomposition when left at room temperature. The inventor of the present application has conducted various studies aimed at improving the pharmacological effects of sodium salts, and found that aluminum compounds of various sugar sulfate esters have gastric wall protective effects and anti-pepsin effects, and aluminum compounds generally have gastric wall protective effects. When we used guaya azulene sulfonic acid as an aluminum salt, we found that this compound had a strong anti-ulcer effect that could not have been expected from the sodium salt, and had significantly reduced toxicity. Furthermore, they have also succeeded in producing this aluminum ion salt in good yield. The novel aluminum salt of guaya azulene sulfonate according to the present invention can be produced by reacting an aqueous solution of sodium guaya azulene sulfonate with aluminum ions. At this time, sodium guaya azulene sulfonate is 1 to
It is preferable to use it as a 10% aqueous solution. In order to quickly and sufficiently complete this reaction, it is necessary to react aluminum ions at a concentration of 10 to 20%. It is sufficient to carry out the reaction at room temperature, and by adding an aqueous aluminum ion solution to an aqueous solution of sodium guaya azulene sulfonate with stirring, the desired product can be obtained as a blue-purple precipitate. The precipitate thus obtained is filtered and thoroughly washed with water to remove unreacted raw materials. In the above reaction, the concentration of the aqueous solution of sodium guaya azulene sulfonate and the concentration of aluminum ions can be set outside the above ranges, but the reaction rate is extremely slow and it is difficult to collect the target product as a precipitate, making it impractical. Poor.
The reaction can be carried out at a pH of 3.5 to 7, but the highest yield is achieved at a pH of 4.5 to 6.0. In this case, the guaya azulene sulfonic acid sodium salt aqueous solution may be made alkaline in advance, or the pH may be adjusted after mixing both solutions. In addition, when both solutions are reacted, it does not matter which one is added to the other first. The aluminum ions used in this production method are generally those obtained by adding acid or alkali to metal aluminum or aluminum salts such as aluminum hydroxide or aluminum chloride to adjust the pH to 3.5 to 5.5, as well as aluminum isopropyl ions. Poxides can also be used. The guaya azulene sulfonic acid aluminum salt obtained according to the present invention is insoluble in water, and does not absorb moisture or exhibit any other changes in appearance even if left as is at room temperature. Although all of the raw materials for this reaction are water-soluble, the product is obtained as a water-insoluble blue-purple precipitate, so it is clear that the product is not just a mixture but a new compound. This can be confirmed by comparing the infrared absorption spectrum of the compound of the present application with that of sodium guaya azulene sulfonate. When we investigated the inhibition rate of experimental ulcers induced in pylorus-linked rats using the present compound, we found that it was much more potent than the raw material, guaya azulene sulfonic acid sodium salt, and that the present compound was It was also observed with the naked eye that a substance exhibiting a characteristic bluish-purple color was adsorbed to the gastric mucosa, and by making it into an aluminum compound, the claimed substance
It is thought that it has the property of being easily adsorbed specifically to the gastric mucosa. Examples of pharmacological tests and manufacturing examples are listed below. Test Example 1 When the acute toxicity of the claimed substance was investigated using male mice, all five mice survived even after oral administration of 5 g/Kg, so the LD 50 was 5 g/Kg.
It is considered to be over Kg. Test Example 2 According to Shay's method, rats weighing 180 to 200 g were fasted for 24 hours, the pylorus was ligated, and 16 hours later, the rats were sacrificed and their abdomens opened, and the area of the resulting ulcer was measured. Table 1 shows the results. The substance of the present invention was suspended in 1% methylcellulose and orally administered immediately after ligation.
【表】
実施例 １
グアヤアズレンスルホン酸ナトリウム１ｇを約
50mlの水に溶かし（不溶物のある場合は過す
る）室温で撹拌中に、別にAlCl30.45ｇを20c.c.の
水に溶かしたものを加え、PHを4.0〜4.5になるよ
うに、NaOH溶液で調節し、１時間室温で放置
する。得られた沈澱を過し、数回水で洗い、乾
燥すると1.1ｇのグアヤアズレンスルホン酸のジ
ヒドロキシアルミニウム塩を得る。
IR：3250、2960、1545、1470cm-1
Al含量 7.1％（計算値7.9％）
実施例 ２
グアヤアズレンスルホン酸ナトリウム３ｇを水
30mlに溶かし、10％HCl12mlを加える。これに、
アルミニウムイソプロポキサイド2.2ｇを粉末の
まゝ加えて２時間室温で撹拌すると沈澱を生じ
る。これを過して数回水洗をくり返すと暗紫色
の結晶を得る。これは、実施例１で得られたもの
のIRスペクトルと同一である。
Al含量 7.4％（計算値7.9％）[Table] Example 1 1 g of sodium guaya azulene sulfonate is approx.
Dissolve in 50 ml of water (if there is any insoluble matter, filter it). While stirring at room temperature, add 0.45 g of AlCl 3 dissolved in 20 c.c. of water and adjust the pH to 4.0 to 4.5. Adjust with NaOH solution and leave at room temperature for 1 hour. The resulting precipitate is filtered, washed several times with water and dried to obtain 1.1 g of dihydroxy aluminum salt of guaya azulene sulfonic acid. IR: 3250, 2960, 1545, 1470 cm -1 Al content 7.1% (calculated value 7.9%) Example 2 Add 3 g of sodium guaya azulene sulfonate to water
Dissolve in 30ml and add 12ml of 10% HCl. to this,
Add 2.2 g of aluminum isopropoxide in powder form and stir at room temperature for 2 hours to form a precipitate. After this, repeat washing with water several times to obtain dark purple crystals. This is the same as the IR spectrum obtained in Example 1. Al content 7.4% (calculated value 7.9%)
第１図は、本願化合物の出発物質たるナトリウ
ム塩のIRスペクトルである。第２図は本願物質
のIRスペクトルである。
FIG. 1 is an IR spectrum of the sodium salt that is the starting material for the compound of the present application. FIG. 2 is an IR spectrum of the substance of the present application.
Claims (1)
ム塩。 ２ グアヤアズレンスルホン酸アルミニウムを有
効成分として含有する抗潰瘍剤。 ３ グアヤアズレンスルホン酸ナトリウムにPH３
〜７の範囲において、アルミニウムイオンを作用
させることを特徴とするグアヤアズレンスルホン
酸アルミニウムの製造方法。 ４ PH4.5〜６の範囲で行う請求の範囲第３項記
載の製造方法。 ５ グアヤアズレンスルホン酸ナトリウムを１〜
10％水溶液とし、アルミニウムイオンを10〜20％
水溶液として用いる請求の範囲第３項又は第４項
の製造方法。[Claims] 1 Formula: Guaya azulene sulfonic acid aluminum salt represented by 2. An anti-ulcer agent containing aluminum guaya azulene sulfonate as an active ingredient. 3 Sodium guaya azulene sulfonate with PH3
7. A method for producing aluminum guaya azulene sulfonate, which comprises reacting with aluminum ions. 4. The manufacturing method according to claim 3, which is carried out at a pH of 4.5 to 6. 5 Sodium guaya azulene sulfonate from 1 to
10% aqueous solution with 10-20% aluminum ion
The manufacturing method according to claim 3 or 4, which is used as an aqueous solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18145981A JPS5883667A (en) | 1981-11-12 | 1981-11-12 | Aluminum guaiazulenesulfonate, its preparation, and antiulcer comprising it as active ingredient |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18145981A JPS5883667A (en) | 1981-11-12 | 1981-11-12 | Aluminum guaiazulenesulfonate, its preparation, and antiulcer comprising it as active ingredient |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5883667A JPS5883667A (en) | 1983-05-19 |
| JPH0153668B2 true JPH0153668B2 (en) | 1989-11-15 |
Family
ID=16101120
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18145981A Granted JPS5883667A (en) | 1981-11-12 | 1981-11-12 | Aluminum guaiazulenesulfonate, its preparation, and antiulcer comprising it as active ingredient |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5883667A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60158160A (en) * | 1984-01-28 | 1985-08-19 | Kotobuki Seiyaku Kk | Azulene derivative sulfonate, antiulcer and anti-inflammatory agent and preparation thereof |
-
1981
- 1981-11-12 JP JP18145981A patent/JPS5883667A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5883667A (en) | 1983-05-19 |
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