JP3081359B2 - 2-amino-1-phenyl-1-ethanol derivative - Google Patents
2-amino-1-phenyl-1-ethanol derivativeInfo
- Publication number
- JP3081359B2 JP3081359B2 JP04109081A JP10908192A JP3081359B2 JP 3081359 B2 JP3081359 B2 JP 3081359B2 JP 04109081 A JP04109081 A JP 04109081A JP 10908192 A JP10908192 A JP 10908192A JP 3081359 B2 JP3081359 B2 JP 3081359B2
- Authority
- JP
- Japan
- Prior art keywords
- ethanol
- ethyl
- reaction
- chlorophenyl
- hydroxy
- 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 - Fee Related
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【０００１】[0001]
【産業上の利用分野】本発明は、化２（式中、Ｒ1 は水
素原子またはアセチル基、Ｒ2 は水素原子または低級ア
ルキル基、Ｘは塩素原子または臭素原子、ＹはＮＲ3 基
（Ｒ3 は低級アルキル基、またはシアノ基を表す。）ま
たはＣＨ−ＮＯ2 基を表す。）で表される文献未記載の
２−アミノ−１−フェニル−１−エタノール誘導体に関
する。The present invention relates to a compound represented by the formula (2) wherein R 1 is a hydrogen atom or an acetyl group, R 2 is a hydrogen atom or a lower alkyl group, X is a chlorine atom or a bromine atom, and Y is an NR 3 group ( R 3 relates to a lower alkyl group or a cyano group.) or 2-amino-1-phenyl-1-ethanol derivatives not disclosed in any literature represented by representative.) the CH-NO 2 group.
【化２】 これら化合物は抗潰瘍作用を有し、消化管における潰瘍
の予防、治療に有用である。Embedded image These compounds have an anti-ulcer effect and are useful for the prevention and treatment of ulcers in the gastrointestinal tract.
【０００２】[0002]
【従来の技術】従来、抗消化性潰瘍剤としては攻撃因子
抑制型又は防御因子増強型に大別され各種誘導体が知ら
れている。一般に攻撃因子抑制型の誘導体は著効をしめ
すが、種々の副作用を有し、リバウンドにより潰瘍の再
発をまねくという欠点があり、一方防御因子増強型の誘
導体は遅効性であり、かつ効果も満足いくものでなかっ
た。2. Description of the Related Art Hitherto, various derivatives have been known as anti-peptic ulcers which are roughly classified into aggressive factor suppressing type and protective factor enhancing type. In general, aggressive factor-suppressing derivatives are very effective, but have various side effects and have the disadvantage of causing relapse of ulcers due to rebound.On the other hand, protective factor-enhancing derivatives are slow-acting and have satisfactory effects. It didn't work.
【０００３】[0003]
【発明が解決しようとする課題】安全性が高く、すみや
かにかつ優れた効果を発揮する抗消化性潰瘍剤の開発が
望まれている。There is a demand for the development of an anti-peptic ulcer agent which is highly safe, promptly and exhibits excellent effects.
【０００４】[0004]
【課題を解決するための手段】本発明者等は、かかる課
題を解決するため鋭意研究の結果、化２（式中、Ｒ1は
水素原子またはアセチル基、Ｒ2 は水素原子または低級
アルキル基、Ｘは塩素原子または臭素原子、ＹはＮＲ3
基（Ｒ3 は低級アルキル基、またはシアノ基を表す。）
またはＣＨ−ＮＯ2 基を表す。）で表される文献未記載
の２−アミノ−１−フェニル−１−エタノール誘導体
が、優れた抗消化性潰瘍作用を有していることを見いだ
し、本発明を完成するに至った。本明細書中、低級アル
キル基はメチル基、エチル基又はプロピル基を意味す
る。The present inventors have SUMMARY OF THE INVENTION As a result of intensive studies for solving the above problems, of 2 (wherein, R 1 represents a hydrogen atom or an acetyl group, R 2 is a hydrogen atom or a lower alkyl group , X is a chlorine atom or a bromine atom, Y is NR 3
Group (R 3 represents a lower alkyl group or a cyano group)
Or a CH-NO 2 group. The present inventors have found that a 2-amino-1-phenyl-1-ethanol derivative described in the literature, which has not been described in the literature, has an excellent antipeptic ulcer effect, and completed the present invention. In the present specification, a lower alkyl group means a methyl group, an ethyl group or a propyl group.
【０００５】上記化２で表される化合物は種々の方法で
合成可能である。例えば、化３（式中、Ｘは塩素原子ま
たは臭素原子を表す。）で表されるアミノアルコール誘
導体と、式ＣＨ3Ｓ−Ｃ（＝Ｙ）−ＳＣＨ3（式中、Ｙは
ＮＲ3 基（Ｒ3 は低級アルキル基、またはシアノ基を表
す。）またはＣＨ−ＮＯ2 基を表す。）で表される化合
物とを反応させることにより化４（式中、Ｘ、Ｙは前記
と同じ。）の化合物に変換し、ついでこれを式ＮＨ2Ｒ2
（式中、Ｒ2 は、水素原子または低級アルキル基を表
す。）で表されるアミンまたはアンモニア水と反応させ
ることにより化５（式中、Ｘ、Ｙ、Ｒ2 は前記と同
じ。）の誘導体を合成することができる。The compound represented by the above formula (2) can be synthesized by various methods. For example, an amino alcohol derivative represented by the formula 3 (wherein X represents a chlorine atom or a bromine atom) and a formula CH 3 SC (= Y) -SCH 3 (where Y is an NR 3 group (Wherein R 3 represents a lower alkyl group or a cyano group) or a CH—NO 2 group) by reacting with a compound represented by the formula (wherein X and Y are the same as described above). ), Which is then converted to a compound of the formula NH 2 R 2
(Wherein R 2 represents a hydrogen atom or a lower alkyl group) by reacting with an amine represented by the following formula (5) (wherein X, Y and R 2 are the same as above). Derivatives can be synthesized.
【化３】 Embedded image
【化４】 Embedded image
【化５】 Embedded image
【０００６】化３で表されるアミノアルコールより化４
で表される化合物への変換は溶媒の存在下実施される。
使用される溶媒としては反応を阻害しないもので適当で
あるが、アルコール、アセトニトリル、水、あるいはこ
れらの混合溶媒が好ましく、反応温度は０℃から溶媒の
沸点の範囲、反応時間は、反応条件にもよるが１時間か
ら２４時間程度である。反応生成物は、反応終了後析出
した結晶を濾取することにより、あるいは溶媒を留去
後、適当な溶媒、例えばエタノール、エタノール−石油
エーテル等より結晶化する事により単離される。The amino alcohol represented by Chemical Formula 3 is converted to Chemical Formula 4
Is carried out in the presence of a solvent.
As the solvent used, any solvent that does not inhibit the reaction is suitable, but alcohol, acetonitrile, water, or a mixed solvent thereof is preferable.The reaction temperature ranges from 0 ° C. to the boiling point of the solvent, and the reaction time depends on the reaction conditions. Depending on the case, it is about 1 hour to 24 hours. The reaction product is isolated by filtering the precipitated crystals after completion of the reaction, or by distilling off the solvent and then crystallization from an appropriate solvent such as ethanol, ethanol-petroleum ether or the like.
【０００７】ついで化５で表される化合物への変換は、
溶媒中アミンと反応させることにより実施される。使用
される溶媒としては反応を阻害しないもので適当である
が、アルコール、水、あるいはこれらの混合溶媒が好ま
しく、過剰のアミンを溶媒として用いてもよい。反応温
度は室温から溶媒の沸点の範囲、反応時間は１〜１０時
間程度である。反応生成物は、反応終了後溶媒を留去
し、残渣を適当な溶媒、例えばエタノール、エタノール
−水等より結晶化する事により単離される。Next, the conversion into the compound represented by the formula (5)
It is carried out by reacting with an amine in a solvent. As the solvent to be used, any solvent that does not inhibit the reaction is suitable, but alcohol, water, or a mixed solvent thereof is preferable, and an excess of amine may be used as the solvent. The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time is about 1 to 10 hours. The reaction product is isolated by distilling off the solvent after completion of the reaction and crystallizing the residue from an appropriate solvent, for example, ethanol, ethanol-water or the like.
【０００８】化５で表される化合物は、化３で表される
アミノアルコールと、式ＣＨ3 Ｓ−Ｃ（＝Ｙ）−ＮＨＲ
2 （式中、Ｙ、Ｒ2 は前記と同じ。）で表される化合物
とを反応させることにより合成することもできる。反応
は溶媒の存在下実施され、例えば好適な溶媒としてアル
コール、アセトン、水等が挙げられ、反応系中にアルカ
リを存在させてもよい。反応温度は室温から溶媒の沸点
の範囲、反応時間は１〜１０時間程度である。反応生成
物は、反応終了後溶媒を留去し、残渣を適当な溶媒、例
えばエタノール、エタノール−水等より結晶化する事に
より単離される。The compound represented by the formula (5) is obtained by combining the amino alcohol represented by the formula ( 3 ) with a compound of the formula CH 3 SC (= Y) -NHR
2 (wherein, Y and R 2 are the same as described above). The reaction is carried out in the presence of a solvent, for example, suitable solvents include alcohol, acetone, water and the like, and an alkali may be present in the reaction system. The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time is about 1 to 10 hours. The reaction product is isolated by distilling off the solvent after completion of the reaction and crystallizing the residue from an appropriate solvent, for example, ethanol, ethanol-water or the like.
【０００９】化５で表される化合物はまた、例えば特開
昭６４−５２７４９号に開示されている下記化６（式
中、Ｘ、Ｒ2 は前記と同じ。）で表される化合物をヨウ
化メチルと反応しイソチオウレア誘導体とし、ついで式
ＮＨ2Ｒ3 （式中、Ｒ3は前記と同じ。）で表されるアミ
ンと反応することによっても合成することができる。The compound represented by the formula (5) may be a compound represented by the following formula (6) wherein X and R 2 are the same as those disclosed in JP-A-64-52749. By reacting with methyl chloride to form an isothiourea derivative, and then reacting with an amine represented by the formula NH 2 R 3 (wherein R 3 is the same as described above).
【化６】 Embedded image
【００１０】化５で表される化合物から化７（式中、Ｒ
1 はアセチル基を表し、Ｘ、Ｙ、Ｒ2 は前記と同じ。）
で表される化合物への変換は、無水酢酸と反応させるこ
とにより合成される。From the compound represented by the formula (5), the compound represented by the formula (7)
1 represents an acetyl group, X, Y, R 2 are as defined above. )
Is synthesized by reacting with acetic anhydride.
【化７】 反応は直接無水酢酸と反応させてもよく、またピリジン
等の塩基存在下反応を実施してもよい。反応温度は０℃
〜溶媒の沸点の範囲、反応時間は１〜３時間程度で十分
である。反応生成物は、反応終了後析出した結晶を濾取
することにより、あるいは溶媒を留去後、適当な溶媒、
例えばエタノール、エタノール−水等より結晶化する事
により単離される。Embedded image The reaction may be carried out directly with acetic anhydride or may be carried out in the presence of a base such as pyridine. Reaction temperature is 0 ° C
The range of the boiling point of the solvent and the reaction time of about 1 to 3 hours are sufficient. The reaction product is obtained by filtering the precipitated crystals after completion of the reaction, or after distilling off the solvent, an appropriate solvent,
For example, it is isolated by crystallization from ethanol, ethanol-water, or the like.
【００１１】[0011]
【実施例】以下、実施例を挙げて本発明を詳細に説明す
る。 実施例 １ 本発明化合物の評価例（水浸拘束ストレス潰瘍） Wistar系のラット（オス：体重１５０〜２００ｇ）を２
４時間絶食後、被験薬（１０ｍｇ／５ｍｌ／ｋｇ）及び
対照溶媒を経口投与し、直ちにストレスゲージに入れ不
動化し、２２℃の水槽内に剣状突起の深さまで浸し、ス
トレスを負荷した。７時間後にラットを殺し全胃を摘出
して２％ホルマリン液を１２．５ｍｌ胃内に注入し、２
％ホルマリン液中に１０分間浸した。胃は大彎に沿って
切開し腺胃部に発生した潰瘍の長さをノギスにより測定
し潰瘍係数とし、対照溶媒の潰瘍係数と比較し抑制率を
求めた。（１群６〜１０匹）結果を表１に示す。The present invention will be described below in detail with reference to examples. Example 1 Evaluation Example of Compound of the Present Invention (Water Immersion Stress Ulcer) Two Wistar rats (male: body weight 150 to 200 g) were used.
After a 4-hour fast, the test drug (10 mg / 5 ml / kg) and a control solvent were orally administered, immobilized immediately in a stress gauge, and immersed in a water bath at 22 ° C. to the depth of the xiphoid process to apply stress. Seven hours later, the rat was killed, the whole stomach was removed, and 12.5 ml of 2% formalin solution was injected into the stomach.
% Formalin solution for 10 minutes. The stomach was incised along the greater curvature and the length of the ulcer generated in the glandular stomach was measured with a caliper to determine the ulcer index, which was compared with the ulcer index of the control solvent to determine the inhibition rate. (6 to 10 animals per group) The results are shown in Table 1.
【表１】 [Table 1]
【００１２】実施例 ２ エタノール２５ｍｌにα−アミノメチル−ｐ−クロロベ
ンジルアルコール３．８ｇとＳ，Ｓ’−ジメチル−Ｎ−
シアノジチオイミノカーボネイト２．９ｇを溶解し、室
温で３時間攪拌した。反応終了後冷蔵庫に一晩放置し、
析出した結晶を濾取することにより、中間体、Ｎ−シア
ノ−Ｎ’−［２−ヒドロキシ−２−（ｐ−クロロフェニ
ル）エチル］−Ｓ−メチルイソチオウレア４．１ｇを得
た。 実施例 ３ Ｎ−シアノ−Ｎ’−［２−ヒドロキシ−２−（ｐ−クロ
ロフェニル）エチル］−Ｓ−メチルイソチオウレア３ｇ
をエタノール２０ｍｌに懸濁し、攪拌下メチルアミン４
０％メタノール溶液２０ｍｌを加え室温３時間攪拌し
た。反応終了後減圧下溶媒を留去し、残渣をエタノール
−石油エーテルより結晶化することによりＮ−シアノ−
Ｎ’−メチル−Ｎ”−［２−ヒドロキシ−２−（ｐ−ク
ロロフェニル）エチル］グアニジン２．６ｇを得た。
融点 １３９〜４２℃ ＴＬＣ Ｒｆ＝０．４５ (CHCl3ーMeOH=9:1) 元素分析値 （Ｃ11Ｈ13ＣｌＮ4Ｏとして） 計算値 (%) C: 52.28% H: 5.18% N: 22.17% 測定値 (%) C: 52.44% H: 5.25% N: 22.03% 赤外線吸収スペクトル 2160cm-1 (CN) 実施例 ４ 実施例３においてメチルアミン４０％メタノール溶液２
０ｍｌに代えてエチルアミン７０％溶液１０ｍｌを用い
同様に処理することによりＮ−シアノ−Ｎ’−エチル−
Ｎ”−［２−ヒドロキシ−２−（ｐ−クロロフェニル）
エチル］グアニジン２．４ｇを得た。 ＴＬＣ Ｒｆ＝０．５７ (CHCl3ーMeOH=9:1) 実施例 ５ 実施例３においてメチルアミン４０％メタノール溶液２
０ｍｌに代えて濃アンモニア水２０ｍｌを用い同様に処
理し、エタノール−水より結晶化することによりＮ−シ
アノ−Ｎ’−［２−ヒドロキシ−２−（ｐ−クロロフェ
ニル）エチル］グアニジン１．３ｇを得た。 ＴＬＣ Ｒｆ＝０．２８ (CHCl3ーMeOH=9:1)Example 2 3.8 g of α-aminomethyl-p-chlorobenzyl alcohol and 25% of S, S′-dimethyl-N-ethanol were added to 25 ml of ethanol.
2.9 g of cyanodithioiminocarbonate was dissolved and stirred at room temperature for 3 hours. After the reaction, leave it in the refrigerator overnight,
The precipitated crystals were collected by filtration to obtain 4.1 g of an intermediate, N-cyano-N '-[2-hydroxy-2- (p-chlorophenyl) ethyl] -S-methylisothiourea. Example 3 3 g of N-cyano-N '-[2-hydroxy-2- (p-chlorophenyl) ethyl] -S-methylisothiourea
Is suspended in 20 ml of ethanol, and methylamine 4 is stirred under stirring.
20 ml of a 0% methanol solution was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was crystallized from ethanol-petroleum ether to give N-cyano-
2.6 g of N′-methyl-N ″-[2-hydroxy-2- (p-chlorophenyl) ethyl] guanidine were obtained.
139-42 ° C TLC Rf = 0.45 (CHCl 3 -MeOH = 9: 1) Elemental analysis (as C 11 H 13 ClN 4 O) Calculated (%) C: 52.28% H: 5.18% N: 22.17 % Measured value (%) C: 52.44% H: 5.25% N: 22.03% Infrared absorption spectrum 2160 cm -1 (CN) Example 4 Methylamine 40% methanol solution 2 in Example 3
The same treatment was carried out using 10 ml of a 70% solution of ethylamine instead of 0 ml to obtain N-cyano-N′-ethyl-.
N "-[2-hydroxy-2- (p-chlorophenyl)
2.4 g of [ethyl] guanidine were obtained. TLC Rf = 0.57 (CHCl 3 -MeOH = 9: 1) Example 5 Methylamine 40% methanol solution 2 in Example 3
The same treatment was carried out using 20 ml of concentrated ammonia water instead of 0 ml, and crystallization from ethanol-water gave 1.3 g of N-cyano-N ′-[2-hydroxy-2- (p-chlorophenyl) ethyl] guanidine. Obtained. TLC Rf = 0.28 (CHCl 3 -MeOH = 9: 1)
【００１３】実施例 ６ Ｎ−メチル−Ｎ’−［２−ヒドロキシ−２−（ｐ−クロ
ロフェニル）エチル］−チオウレア２．５ｇをメタノー
ル３０ｍｌに溶解し、ヨウ化メチル１．４２ｇを加え２
時間攪拌下還流した。反応後、減圧下濃縮し、残渣をエ
タノール２０ｍｌに溶解し、攪拌下メチルアミン４０％
メタノール溶液２０ｍｌを加え、室温３時間、５０℃５
時間攪拌した。反応終了後、減圧下濃縮し残渣をエタノ
ールから結晶化することにより、Ｎ，Ｎ’−ジメチル−
Ｎ”−［２−ヒドロキシ−２−（ｐ−クロロフェニル）
エチル］グアニジン１．５ｇを得た。 融点 １９９〜２０１℃ ＴＬＣ Ｒｆ＝０．２４ (CHCl3ーMeOH=9:1) 元素分析値 （Ｃ11Ｈ16ＣｌＮ3Ｏとして） 計算値 (%) C: 54.66% H: 6.67% N: 17.38% 測定値 (%) C: 54.81% H: 6.83% N: 17.11% 実施例 ７ 実施例６においてＮ−メチル−Ｎ’−［２−ヒドロキシ
−２−（ｐ−クロロフェニル）エチル］−チオウレアに
代えてＮ−エチル−Ｎ’−［２−ヒドロキシ−２−（ｐ
−クロロフェニル）エチル］−チオウレア２．６ｇを用
い同様に処理し、エタノール−エーテルより結晶化する
ことによりＮ−エチル−Ｎ’−メチル−Ｎ”−［２−ヒ
ドロキシ−２−（ｐ−クロロフェニル）エチル］グアニ
ジン１．３ｇを得た。 融点 １３７〜８℃ ＴＬＣ Ｒｆ＝０．３０ (CHCl3ーMeOH=9:1)Example 6 2.5 g of N-methyl-N '-[2-hydroxy-2- (p-chlorophenyl) ethyl] -thiourea was dissolved in 30 ml of methanol, and 1.42 g of methyl iodide was added.
The mixture was refluxed under stirring for an hour. After the reaction, the mixture was concentrated under reduced pressure, and the residue was dissolved in 20 ml of ethanol.
Add methanol solution (20 ml), room temperature for 3 hours,
Stirred for hours. After completion of the reaction, the mixture is concentrated under reduced pressure, and the residue is crystallized from ethanol to give N, N'-dimethyl-.
N "-[2-hydroxy-2- (p-chlorophenyl)
1.5 g of [ethyl] guanidine were obtained. Melting point 199-201 ° C TLC Rf = 0.24 (CHCl 3 -MeOH = 9: 1) Elemental analysis (as C 11 H 16 ClN 3 O) Calculated (%) C: 54.66% H: 6.67% N: 17.38 % Measured value (%) C: 54.81% H: 6.83% N: 17.11% Example 7 In Example 6, N-methyl-N ′-[2-hydroxy-2- (p-chlorophenyl) ethyl] -thiourea was used instead. N-ethyl-N ′-[2-hydroxy-2- (p
-Chlorophenyl) ethyl] -thiourea and 2.6 g of N-ethyl-N′-methyl-N ″-[2-hydroxy-2- (p-chlorophenyl) by crystallization from ethanol-ether 1.3 g of ethyl] guanidine Melting point 137-8 ° C. TLC Rf = 0.30 (CHCl 3 -MeOH = 9: 1)
【００１４】実施例 ８ エタノール５０ｍｌにα−アミノメチル−ｐ−クロロベ
ンジルアルコール６．９ｇと１，１−ビス（メチルチ
オ）−２−ニトロエチレン６．６ｇを加え、６０〜７０
℃で５時間攪拌した。反応終了後、減圧下濃縮し残渣を
エタノール−石油エーテルから結晶化することにより、
中間体、Ｎ−［２−ヒドロキシ−２−（ｐ−クロロフェ
ニル）エチル］−１−メチルチオ−２−ニトロエテンア
ミン８．３ｇを得た。 実施例 ９ Ｎ−［２−ヒドロキシ−２−（ｐ−クロロフェニル）エ
チル］−１−メチルチオ−２−ニトロエテンアミン２ｇ
をエタノール２０ｍｌに懸濁し、攪拌下メチルアミン４
０％メタノール溶液１５ｍｌを加え、７０℃終夜攪拌し
た。反応終了後減圧下濃縮し、残渣をエタノールから結
晶化することにより、Ｎ−［２−ヒドロキシ−２−（ｐ
−クロロフェニル）エチル］−Ｎ’−メチル−２−ニト
ロ−１，１−エテンジアミン０．９２ｇを得た。 融点
１７５〜６℃ ＴＬＣ Ｒｆ＝０．２９ (CHCl3ーMeOH=9:1) 元素分析値 （Ｃ11Ｈ14ＣｌＮ3Ｏ3として） 計算値 (%) C: 48.63% H: 5.19% N: 15.47% 測定値 (%) C: 48.79% H: 5.32% N: 15.36% 実施例１０ 実施例９においてメチルアミン４０％メタノール溶液１
５ｍｌに代えてエチルアミン７０％溶液１０ｍｌを用い
同様に処理し、エタノール−石油エーテルより結晶化す
ることにより、Ｎ−［２−ヒドロキシ−２−（ｐ−クロ
ロフェニル）エチル］−Ｎ’−エチル−２−ニトロ−
１，１−エテンジアミン１．５ｇを得た。 融点 １３６〜９℃ ＴＬＣ Ｒｆ＝０．４０ (CHCl3ーMeOH=9:1) 実施例１１ Ｎ−［２−ヒドロキシ−２−（ｐ−クロロフェニル）エ
チル］−１−メチルチオ−２−ニトロエテンアミン２ｇ
をエタノール２０ｍｌに懸濁し、攪拌下濃アンモニア水
を加え、室温３時間、７０℃５時間攪拌した。反応終了
後減圧下濃縮し、残渣に１Ｎ塩酸を加え抽出、アルカリ
で中和後冷蔵庫に一晩放置し、析出した結晶を濾取する
ことにより、Ｎ−［２−ヒドロキシ−２−（ｐ−クロロ
フェニル）エチル］−２−ニトロ−１，１−エテンジア
ミン０．８３ｇを得た。 融点 １８８〜９℃ ＴＬＣ Ｒｆ＝０．１４ (CHCl3ーMeOH=9:1)Example 8 To 50 ml of ethanol, 6.9 g of α-aminomethyl-p-chlorobenzyl alcohol and 6.6 g of 1,1-bis (methylthio) -2-nitroethylene were added,
Stirred at C for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol-petroleum ether.
8.3 g of the intermediate, N- [2-hydroxy-2- (p-chlorophenyl) ethyl] -1-methylthio-2-nitroethenamine, were obtained. Example 9 2 g of N- [2-hydroxy-2- (p-chlorophenyl) ethyl] -1-methylthio-2-nitroethenamine
Is suspended in 20 ml of ethanol, and methylamine 4 is stirred under stirring.
15 ml of a 0% methanol solution was added, and the mixture was stirred at 70 ° C. overnight. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol to give N- [2-hydroxy-2- (p
-Chlorophenyl) ethyl] -N'-methyl-2-nitro-1,1-ethenediamine 0.92 g was obtained. Melting point 175-6 ° C TLC Rf = 0.29 (CHCl 3 -MeOH = 9: 1) Elemental analysis (as C 11 H 14 ClN 3 O 3 ) Calculated (%) C: 48.63% H: 5.19% N: 15.47% measured value (%) C: 48.79% H: 5.32% N: 15.36% Example 10 In Example 9, methylamine 40% methanol solution 1
The same treatment was carried out using 10 ml of a 70% ethylamine solution instead of 5 ml, and crystallization from ethanol-petroleum ether gave N- [2-hydroxy-2- (p-chlorophenyl) ethyl] -N′-ethyl-2. -Nitro-
1.5 g of 1,1-ethenediamine was obtained. Mp 136~9 ℃ TLC Rf = 0.40 (CHCl 3 over MeOH = 9: 1) Example 11 N-[2-hydroxy-2- (p-chlorophenyl) ethyl] -1-methylthio-2-nitro ethene amine 2g
Was suspended in 20 ml of ethanol, concentrated aqueous ammonia was added with stirring, and the mixture was stirred at room temperature for 3 hours and at 70 ° C. for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, extracted, neutralized with alkali, left standing in a refrigerator overnight, and the precipitated crystals were collected by filtration to give N- [2-hydroxy-2- (p- 0.83 g of [chlorophenyl) ethyl] -2-nitro-1,1-ethenediamine were obtained. Melting point 188-9 ° C TLC Rf = 0.14 (CHCl 3 -MeOH = 9: 1)
【００１５】実施例１２ エタノール２５ｍｌにα−アミノメチル−ｐ−ブロモベ
ンジルアルコール４．３ｇとＳ，Ｓ’−ジメチル−Ｎ−
シアノジチオイミノカーボネイト２．９ｇを溶解し、室
温で３時間攪拌した。反応終了後冷蔵庫に一晩放置し、
析出した結晶を濾取することにより、中間体、Ｎ−シア
ノ−Ｎ’−［２−ヒドロキシ−２−（ｐ−ブロモフェニ
ル）エチル］−Ｓ−メチルイソチオウレア４．８ｇを得
た。中間体（イソチオウレア誘導体）２ｇをエタノール
２０ｍｌに懸濁し、攪拌下メチルアミン４０％メタノー
ル溶液１０ｍｌを加え、室温３時間攪拌した。反応終了
後、減圧下濃縮し、残渣をエタノール−水より結晶化す
ることにより、Ｎ−シアノ−Ｎ’−メチル−Ｎ”−［２
−ヒドロキシ−２−（ｐ−ブロモフェニル）エチル］グ
アニジン２．６ｇを得た。 融点 １５９〜６０℃ ＴＬＣ Ｒｆ＝０．４５ (CHCl3ーMeOH=9:1) 実施例１３ エタノール４０ｍｌにα−アミノメチル−ｏ−クロロベ
ンジルアルコール３．８ｇとＳ，Ｓ’−ジメチル−Ｎ−
シアノジチオイミノカーボネイト２．９ｇを溶解し、室
温で３時間攪拌した。反応終了後冷蔵庫に一晩放置し、
析出した結晶を濾取することにより、中間体、Ｎ−シア
ノ−Ｎ’−［２−ヒドロキシ−２−（ｏ−クロロフェニ
ル）エチル］−Ｓ−メチルイソチオウレア４．１ｇを得
た。中間体（イソチオウレア誘導体）２ｇをエタノール
２０ｍｌに懸濁し、攪拌下エチルアミン７０％溶液１０
ｍｌを加え、室温３時間攪拌した。反応終了後、減圧下
濃縮し、残渣をエタノール−水より結晶化することによ
り、Ｎ−シアノ−Ｎ’−エチル−Ｎ”−［２−ヒドロキ
シ−２−（ｏ−クロロフェニル）エチル］グアニジン
２．６ｇを得た。 ＴＬＣ Ｒｆ＝０．５４ (CHCl3ーMeOH=9:1) 実施例１４ エタノール５０ｍｌにα−アミノメチル−ｏ−クロロベ
ンジルアルコール６．９ｇと１，１−ビス（メチルチ
オ）−２−ニトロエチレン６．６ｇを加え、６０〜７０
℃で５時間攪拌した。反応終了後、減圧下濃縮し残渣を
エタノール−石油エーテルから結晶化することにより、
中間体、Ｎ−［２−ヒドロキシ−２−（ｏ−クロロフェ
ニル）エチル］−１−メチルチオ−２−ニトロエテンア
ミン８．３ｇを得た。該中間体２ｇをエタノール２０ｍ
ｌに懸濁し、攪拌下エチルアミン７０％溶液１０ｍｌを
加え、７０℃終夜攪拌した。反応終了後減圧下濃縮し、
残渣をエタノール−水から結晶化することにより、Ｎ−
［２−ヒドロキシ−２−（ｏ−クロロフェニル）エチ
ル］−Ｎ’−エチル−２−ニトロ−１，１−エテンジア
ミン０．９２ｇを得た。 融点 １３３〜８℃ ＴＬＣ Ｒｆ＝０．５２ (CHCl3ーMeOH=9:1)Example 12 4.3 g of α-aminomethyl-p-bromobenzyl alcohol and 25% of S, S′-dimethyl-N-ethanol were added to 25 ml of ethanol.
2.9 g of cyanodithioiminocarbonate was dissolved and stirred at room temperature for 3 hours. After the reaction, leave it in the refrigerator overnight,
The precipitated crystals were collected by filtration to obtain 4.8 g of an intermediate, N-cyano-N '-[2-hydroxy-2- (p-bromophenyl) ethyl] -S-methylisothiourea. 2 g of the intermediate (isothiourea derivative) was suspended in 20 ml of ethanol, 10 ml of a 40% methanol solution of methylamine was added with stirring, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture is concentrated under reduced pressure, and the residue is crystallized from ethanol-water to give N-cyano-N′-methyl-N ″-[2
-Hydroxy-2- (p-bromophenyl) ethyl] guanidine 2.6 g was obtained. Melting point 159-60 ° C TLC Rf = 0.45 (CHCl 3 -MeOH = 9: 1) Example 13 3.8 g of α-aminomethyl-o-chlorobenzyl alcohol and S, S′-dimethyl-N- in 40 ml of ethanol
2.9 g of cyanodithioiminocarbonate was dissolved and stirred at room temperature for 3 hours. After the reaction, leave it in the refrigerator overnight,
The precipitated crystals were collected by filtration to obtain 4.1 g of an intermediate, N-cyano-N '-[2-hydroxy-2- (o-chlorophenyl) ethyl] -S-methylisothiourea. An intermediate (isothiourea derivative) (2 g) was suspended in ethanol (20 ml), and stirred with ethylamine (70% solution 10).
Then, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol-water to give N-cyano-N'-ethyl-N "-[2-hydroxy-2- (o-chlorophenyl) ethyl] guanidine. TLC Rf = 0.54 (CHCl 3 -MeOH = 9: 1) Example 14 6.9 g of α-aminomethyl-o-chlorobenzyl alcohol and 1,1-bis (methylthio)-were added to 50 ml of ethanol. 6.6 g of 2-nitroethylene was added, and 60 to 70
Stirred at C for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol-petroleum ether.
8.3 g of the intermediate, N- [2-hydroxy-2- (o-chlorophenyl) ethyl] -1-methylthio-2-nitroethenamine, were obtained. 2 g of the intermediate is ethanol 20 m
and added 10 ml of a 70% solution of ethylamine with stirring, followed by stirring at 70 ° C. overnight. After completion of the reaction, the mixture is concentrated under reduced pressure.
By crystallizing the residue from ethanol-water, N-
[2-hydroxy-2- (o-chlorophenyl) ethyl] -N'-ethyl-2-nitro-1,1-ethenediamine 0.92 g was obtained. 133-8 ° C TLC Rf = 0.52 (CHCl 3 -MeOH = 9: 1)
【００１６】実施例１５ Ｎ−シアノ−Ｎ’−メチル−Ｎ”−［２−ヒドロキシ−
２−（ｐ−クロロフェニル）エチル］グアニジン２ｇを
無水酢酸２０ｍｌに懸濁し、攪拌下ピリジン２ｍｌを加
え室温で攪拌した．いったん溶液となったが引き続き攪
拌すると結晶が析出し、一晩冷蔵庫に放置後、析出した
結晶を濾取することにより、Ｎ−シアノ−Ｎ’−メチル
−Ｎ”−［２−アセトキシ−２−（ｐ−クロロフェニ
ル）エチル］グアニジン１．７ｇを得た。 融点 １５
３〜４℃ ＴＬＣ Ｒｆ＝０．５２ (CHCl3ーMeOH=9:1) 元素分析値 （Ｃ13Ｈ15ＣｌＮ4Ｏ2として） 計算値 (%) C: 52.98% H: 5.13% N: 19.01% 測定値 (%) C: 53.08% H: 5.17% N: 18.76% 赤外線吸収スペクトル 1735cm-1 (C=O) 実施例１６ Ｎ−シアノ−Ｎ’−エチル−Ｎ”−［２−ヒドロキシ−
２−（ｏ−クロロフェニル）エチル］グアニジン２ｇを
無水酢酸２０ｍｌに懸濁し、攪拌下ピリジン２ｍｌを加
え室温で３時間攪拌した。反応終了後減圧下溶媒を留去
し、残渣をエタノール−水から結晶化することにより、
Ｎ−シアノ−Ｎ’−エチル−Ｎ”−［２−アセトキシ−
２−（ｏ−クロロフェニル）エチル］グアニジン１．７
ｇを得た。 融点 １２０〜１℃ ＴＬＣ Ｒｆ＝０．９２ (CHCl3ーMeOH=9:1)Example 15 N-cyano-N'-methyl-N "-[2-hydroxy-
2- (p-Chlorophenyl) ethyl] guanidine (2 g) was suspended in acetic anhydride (20 ml), pyridine (2 ml) was added with stirring, and the mixture was stirred at room temperature. Once a solution was obtained, crystals were precipitated with continued stirring. After standing in a refrigerator overnight, the precipitated crystals were collected by filtration to give N-cyano-N'-methyl-N "-[2-acetoxy-2-. 1.7 g of (p-chlorophenyl) ethyl] guanidine were obtained, mp 15
3-4 ° C. TLC Rf = 0.52 (CHCl 3 -MeOH = 9: 1) Elemental analysis (as C 13 H 15 ClN 4 O 2 ) Calculated (%) C: 52.98% H: 5.13% N: 19.01 % Measured value (%) C: 53.08% H: 5.17% N: 18.76% Infrared absorption spectrum 1735cm -1 (C = O) Example 16 N-cyano-N'-ethyl-N "-[2-hydroxy-
2- (o-chlorophenyl) ethyl] guanidine (2 g) was suspended in acetic anhydride (20 ml), pyridine (2 ml) was added with stirring, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was crystallized from ethanol-water.
N-cyano-N'-ethyl-N "-[2-acetoxy-
2- (o-chlorophenyl) ethyl] guanidine 1.7
g was obtained. Melting point 120-1 ° C TLC Rf = 0.92 (CHCl 3 -MeOH = 9: 1)
【００１７】[0017]
【発明の効果】以上の説明から明かな様に、文献未記載
の２−アミノ−１−フェニル−１−エタノール誘導体
は、優れた抗潰瘍作用を有する事が見いだされ、本発明
化合物は消化管における潰瘍の予防、治療に有用であ
る。As apparent from the above description, it has been found that a 2-amino-1-phenyl-1-ethanol derivative, which has not been described in the literature, has an excellent antiulcer action, and the compound of the present invention has a gastrointestinal tract. It is useful for the prevention and treatment of ulcers in children.
Claims (1)
チル基、Ｒ2 は水素原子または低級アルキル基、Ｘは塩
素原子または臭素原子、ＹはＮＲ3 基（Ｒ3は低級アル
キル基、またはシアノ基を表す。）またはＣＨ−ＮＯ2
基を表す。）で表される２−アミノ−１−フェニル−１
−エタノール誘導体。 【化１】 (1) wherein R 1 is a hydrogen atom or an acetyl group, R 2 is a hydrogen atom or a lower alkyl group, X is a chlorine atom or a bromine atom, Y is an NR 3 group (R 3 is a lower alkyl group) , Or a cyano group.) Or CH-NO 2
Represents a group. 2-amino-1-phenyl-1 represented by the formula:
-Ethanol derivatives. Embedded image
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP04109081A JP3081359B2 (en) | 1992-04-03 | 1992-04-03 | 2-amino-1-phenyl-1-ethanol derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP04109081A JP3081359B2 (en) | 1992-04-03 | 1992-04-03 | 2-amino-1-phenyl-1-ethanol derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH05286908A JPH05286908A (en) | 1993-11-02 |
| JP3081359B2 true JP3081359B2 (en) | 2000-08-28 |
Family
ID=14501121
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP04109081A Expired - Fee Related JP3081359B2 (en) | 1992-04-03 | 1992-04-03 | 2-amino-1-phenyl-1-ethanol derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3081359B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101915974B1 (en) * | 2017-02-16 | 2018-11-12 | 주식회사 디유이엔지 | Emergency ladder for electric trains |
| KR102655806B1 (en) * | 2021-08-11 | 2024-04-09 | 주식회사 세기엔지니어링 | Ladder |
-
1992
- 1992-04-03 JP JP04109081A patent/JP3081359B2/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101915974B1 (en) * | 2017-02-16 | 2018-11-12 | 주식회사 디유이엔지 | Emergency ladder for electric trains |
| KR102655806B1 (en) * | 2021-08-11 | 2024-04-09 | 주식회사 세기엔지니어링 | Ladder |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH05286908A (en) | 1993-11-02 |
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