JPH068283B2 - Benzimidazole derivative, method for producing the same, and antiulcer agent containing the same - Google Patents
Benzimidazole derivative, method for producing the same, and antiulcer agent containing the sameInfo
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- JPH068283B2 JPH068283B2 JP60061194A JP6119485A JPH068283B2 JP H068283 B2 JPH068283 B2 JP H068283B2 JP 60061194 A JP60061194 A JP 60061194A JP 6119485 A JP6119485 A JP 6119485A JP H068283 B2 JPH068283 B2 JP H068283B2
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Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は新規なベンズイミダゾール誘導体、更に詳細に
は次の一般式(I) （式中、Ｒ1及びＲ2は水素原子又は低級アルキル基を示
し、Ｒ3及びＲ4は少なくとも一方がハロゲン原子、トリ
フルオロメチル基、低級アルキル基、低級アルコキシ
基、低級アルコキシカルボニル基又はアミノ基を示し、
残余は水素原子を示す。但し、Ｒ3が低級アルコキシ基
で、Ｒ4が水素原子の場合を除く） で表わされるベンズイミダゾール誘導体及びその製造法
並びにこれを含有する抗潰瘍剤に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel benzimidazole derivative, more specifically, the following general formula (I): (In the formula, R 1 and R 2 represent a hydrogen atom or a lower alkyl group, and at least one of R 3 and R 4 is a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group or an amino group. Shows the group
The rest represents hydrogen atoms. Provided that R 3 is a lower alkoxy group and R 4 is a hydrogen atom.), A process for producing the same, and an antiulcer agent containing the same.
従来、Ｈ++K+ＡＴＰアーゼは胃細胞における最終的な胃
酸分泌機構であることは当該分野において周知であり
〔スカンジナビアン・ジャーナル・オブ・ガストロエン
テロロジイ（Scand.J.Gastroenterol.)14,131〜135(197
9)〕、H++K+ＡＴＰアーゼ阻害作用を有する物質として
ノリニウムブロマイドが知られている〔プロシーディン
グ・オブ・ザ・ソサエティ・フォー・エキスペリメンタ
ル・バイオロジイ・アンド・メデシン（Proceeding of
the Society for Experimental Biology and Medicin
e),172,308〜315(1983)〕。Conventionally, H + + K + ATP-ase it is the final gastric acid secretion mechanism in the stomach cells are well known in the art [Scandinavian Journal of Gastroenterology enteritidis Rollo diisopropyl (Scand.J.Gastroenterol.) 14 , 131〜135 (197
9)], Norinium bromide is known as a substance having an H + + K + ATPase inhibitory action [Proceeding of the Society for Experimental Biology and Medesin (Proceeding of
the Society for Experimental Biology and Medicin
e), 172 , 308-315 (1983)].
一方、２−〔２−（３，５−ジメチル−４−メトキシ）
−ピリジルメチルスルフィニル〕−（５−メトキシ）−
ベンズイミダゾール〔オメプラゾール〕はH++K+ＡＴＰ
アーゼ阻害作用を有する抗潰瘍剤として開発されている
〔アメリカン・ジャーナル・オブ・フィジオロジイ（A
m.J.of Physiol.)245,G64-G71(1983)〕。On the other hand, 2- [2- (3,5-dimethyl-4-methoxy)
-Pyridylmethylsulfinyl]-(5-methoxy)-
Benzimidazole [omeprazole] is H + + K + ATP
It has been developed as an anti-ulcer drug with an ase inhibitory effect [American Journal of Physiology (A
mJof Physiol.) 245 , G64-G71 (1983)].
〔発明が解決しようとする問題点〕 従って、優れたH++K+ＡＴＰアーゼ阻害作用を有する新
規な化合物の提供が望まれている。[Problems to be Solved by the Invention] Therefore, it is desired to provide a novel compound having an excellent H + + K + ATPase inhibitory action.
斯かる実情において、本発明者らは鋭意研究を行った結
果、(I)式で表わされる新規なベンズイミダゾール誘導
体が特異的なH++K+ＡＴＰアーゼ阻害作用に基く優れた
胃酸分泌抑制作用を有することを見出し、本発明を完成
した。Under such circumstances, the present inventors have conducted diligent research, and as a result, the novel benzimidazole derivative represented by the formula (I) has an excellent inhibitory action on gastric acid secretion based on the specific inhibitory action on H + + K + ATPase. The present invention has been completed by finding out that
従って、本発明は抗潰瘍剤として有用なベンズイミダゾ
ール誘導体(I)を提供するものである。Therefore, the present invention provides a benzimidazole derivative (I) useful as an anti-ulcer agent.
また、本発明のベンズイミダゾール誘導体(I)を製造す
るための新規な方法を提供するものである。It also provides a novel method for producing the benzimidazole derivative (I) of the present invention.
更にまた、本発明はベンズイミダゾール誘導体(I)を有
効成分として含有する抗潰瘍剤を提供するものである。Furthermore, the present invention provides an anti-ulcer agent containing a benzimidazole derivative (I) as an active ingredient.
本発明のベンズイミダゾール誘導体(I)は、例えば、次
の反応式に従って、２−メルカプトベンズイミダゾール
類(II)に２−アミノベンジル化合物(III)を反応せしめ
て化合物(IV)となし、次いでこれを酸化することにより
製造される。The benzimidazole derivative (I) of the present invention is prepared, for example, by reacting a 2-mercaptobenzimidazole (II) with a 2-aminobenzyl compound (III) according to the following reaction formula to form a compound (IV). It is manufactured by oxidizing.
（式中、Ｘは反応性基を示し、R1〜R4は前記と同じ） 本発明方法の原料(II)はすでに公知の化合物であり、例
えばオーガニック・シンセシス（Org.Synth.）第３０
巻、第５６頁に記載の方法によって製造される。また原
料(III)のＸで表わされる反応性基としては、塩素、臭
素等のハロゲン原子、メチルスルホニルオキシ、トルエ
ンスルホニルオキシ基等のスルホニルオキシ基を挙げる
ことができ、例えば、Ｘが塩素原子の化合物はジャーナ
ル・オブ・ザ・ケミカル・ソサエテイ（J.Chem.Soc.)98
〜102(1942)に記載の方法によって製造される。これら
は塩の形で反応に供することもできる。 (In the formula, X represents a reactive group and R 1 to R 4 are the same as above.) The starting material (II) of the method of the present invention is a known compound, for example, Organic Synthesis (Org.Synth.) No. 30
Vol., Page 56. Examples of the reactive group represented by X in the raw material (III) include halogen atoms such as chlorine and bromine, and sulfonyloxy groups such as methylsulfonyloxy and toluenesulfonyloxy groups. For example, X is a chlorine atom. Compounds are Journal of the Chemical Society (J.Chem.Soc.) 98
~ 102 (1942). These may be subjected to the reaction in the form of salt.
化合物(II)と化合物(III)又はその塩との反応は、トル
エン、ベンゼン、エタノール、アセトン等の不活性溶媒
中、室温ないし還流下の温度で、３０分ないし２４時間
攪拌することによって行われる。この際、NaOH、KOH、K2C
O3、NaHCO3等のアルカリ剤を存在せしめて、生成する酸
を受容するのが好ましい。The reaction of compound (II) with compound (III) or a salt thereof is carried out by stirring in an inert solvent such as toluene, benzene, ethanol, acetone or the like at a temperature from room temperature to reflux for 30 minutes to 24 hours. . At this time, NaOH, KOH, K 2 C
It is preferable to allow an alkaline agent such as O 3 or NaHCO 3 to be present to receive the acid produced.
化合物(IV)のオキソ化は常法によって行うことができ、
例えば過酸化水素、ｍ−クロル過安息香酸等の有機過
酸、メタ過ヨウ素酸ソーダ等の酸化剤を使用して、化合
物(IV)を酸化すればよい。反応は、クロロホルム、ジク
ロルメタン、メタノール、酢酸エチル等の不活性溶媒
中、−３０℃〜５０℃、好ましくは−１５℃〜５℃の温
度で行われる。Oxidation of compound (IV) can be carried out by a conventional method,
For example, the compound (IV) may be oxidized using hydrogen peroxide, an organic peracid such as m-chloroperbenzoic acid, or an oxidizing agent such as sodium metaperiodate. The reaction is carried out in an inert solvent such as chloroform, dichloromethane, methanol and ethyl acetate at a temperature of -30 ° C to 50 ° C, preferably -15 ° C to 5 ° C.
斯くして得られる本発明化合物(I)の代表的化合物につ
いて薬理効果を試験した結果は次のとおりである。The results of testing the pharmacological effects of the thus obtained representative compounds of the compound (I) of the present invention are as follows.
(1) H++K+ＡＴＰアーゼ阻害作用 フォルト（Forte）らの方法〔ジャーナル・オブ・アプ
ライド・フィジオロジイ(J.Applied Physiol.)32,714〜
717(1972)〕に従い、ウサギ胃粘膜の胃酸分泌細胞を分
離し、H++K+ＡＴＰアーゼを含ベシクルはフイコールの
不連続密度勾配中で遠心分離することにより調製した。
５ｍＭイミダゾール緩衝液（pH 6.0）、試験物質２×１
０-4Ｍを含む溶液0.5ｍ中で酵素を室温で２５分間イ
ンキュベートしたのち、３７℃に移しさらに５分間放置
した。４ｍＭ塩化マグネシウム、８０ｍＭイミダゾール
緩衝液（pH7.4）、２ｍＭ塩化カリウム及び４ｍＭＡＴ
Ｐを含む溶液0.5ｍを加えて、３７℃で１５分間反応
させたのち、２４％トリクロル酢酸１ｍを加えて反応
を止め、遊離した無機リンをトスキー（Taussky）およ
びショール（Shorr）の方法〔ジャーナル・オブ・バイ
オロジカル・ケミストリー（J.Biol.Chem.)202,675-685
(1953)〕に従って定量した。K+依存性ＡＴＰアーゼ活性
は、塩化カリウムを含まない時の活性を差し引いて求め
た。その結果を第１表に示す。(1) H + + K + ATPase inhibitory action Method of Forte et al. [J. Applied Physiol. 32,714-
717 (1972)], gastric acid-secreting cells of rabbit gastric mucosa were isolated, and vesicles containing H + + K + ATPase were prepared by centrifugation in a discontinuous density gradient of Ficoll.
5 mM imidazole buffer (pH 6.0), test substance 2 x 1
The enzyme was incubated at room temperature for 25 minutes in 0.5 m of a solution containing 0 −4 M, then transferred to 37 ° C. and left for another 5 minutes. 4 mM magnesium chloride, 80 mM imidazole buffer (pH 7.4), 2 mM potassium chloride and 4 mM AT
After adding 0.5 m of a solution containing P and reacting at 37 ° C. for 15 minutes, the reaction was stopped by adding 1 m of 24% trichloroacetic acid, and the released inorganic phosphorus was separated by the method of Taussky and Shorr [Journal.・ Biological Chemistry (J.Biol.Chem.) 202,675-685
(1953)]. The K + -dependent ATPase activity was calculated by subtracting the activity in the absence of potassium chloride. The results are shown in Table 1.
(2) 胃酸分泌抑制作用 常法〔シェイ・エツチら，ガストロエンテロロジイ（Sh
ay,H.et al.,Gastroenterology),5,43-61(1945)〕に従
い体重２００〜２５０ｇのドンリュウ（Donryu）系雄性
ラットを２４時間絶食後（水の摂取は自由）、エーテル
麻酔下で開腹し、幽門部を結紮し、被検化合物を十二指
腸内に投与した。４時間後に動物を殺し、胃を取り出し
胃液を採取した。酸度（Acid out-put）は、自動滴定装
置を用い、0.1ＮNaOHでpH7.0まで滴定し得られた値を、
同様に処置したが但し被検化合物を与えていない対照動
物の値と比較した。その結果を第２表に示す。 (2) Suppressive action of gastric acid secretion [Shei Ettsu et al., Gastroenterology (Sh
ay, H. et al., Gastroenterology), 5 , 43-61 (1945)], and fasted Donryu male rats weighing 200 to 250 g for 24 hours (water intake freely) under ether anesthesia. A laparotomy was performed, the pylorus was ligated, and the test compound was administered intraduodenally. After 4 hours, the animals were killed, the stomach was removed and the gastric juice was collected. Acidity (Acid out-put) is the value obtained by titrating to pH 7.0 with 0.1N NaOH using an automatic titrator,
Comparisons were made with the values of control animals treated in the same way but without the test compound. The results are shown in Table 2.
(3) 急性毒性試験 体重８０ｇから９０ｇのウィスター(Wistar)系雄ラット
に、本発明化合物を0.2％ＣＭＣ生理食塩水に懸濁した
ものを、腹腔内投与し、７日間観察した。 (3) Acute toxicity test The compound of the present invention suspended in 0.2% CMC physiological saline was intraperitoneally administered to Wistar male rats weighing 80 to 90 g and observed for 7 days.
結果を第３表に示す。The results are shown in Table 3.
（４） 熱安定性試験 本発明に従う下記化合物（Ａ）と（Ｂ）： （Ａ） （Ｂ） 比較用の下記化合物（Ｃ）： （Ｃ） について、大気中６０℃に加熱してそれぞれの熱安定性
を評価した。 (4) Thermal stability test The following compounds (A) and (B) according to the present invention: (A) (B) The following compound (C) for comparison: (C) Was heated to 60 ° C. in the atmosphere and the thermal stability of each was evaluated.
それぞれの評価結果を第４表に示す。なお、表中の数値
は、被加熱化合物の残存率を表わす。The respective evaluation results are shown in Table 4. The numerical values in the table represent the residual rate of the compound to be heated.
以上の結果から、本発明のアミノ基以外の置換基を有ル
キルを有するベンズイミダゾール化合物は、置換基がア
ミノ基のみであるベンズイミダゾール化合物に比べて、
熱安定性が優れていることがわかる。 From the above results, the benzimidazole compound having a substituent having a substituent other than the amino group of the present invention has a substituent as compared with a benzimidazole compound having only an amino group,
It can be seen that the thermal stability is excellent.
（５） 膀胱障害作用試験 上記の本発明化合物Ａ、Ｂと、比較用の化合物Ｃとをそ
れぞれビーグル犬に１３５mg/kg（体重）の投与量にて
１４日間連続的に経口投与し、膀胱障害の発生の可能性
を試験した。その結果、本発明化合物Ａ、Ｂの連続投与
では何ら膀胱障害の発生は見られなかったが、比較用の
化合物Ｃの連続投与では膀胱障害の発生（びらんの発
生）が観察された。(5) Bladder disorder effect test The above-mentioned compounds A and B of the present invention and the compound C for comparison were orally administered to beagle dogs at a dose of 135 mg / kg (body weight) continuously for 14 days to obtain bladder disorders. The possibility of occurrence of As a result, no occurrence of bladder damage was observed in the continuous administration of Compounds A and B of the present invention, whereas occurrence of bladder damage (occurrence of erosion) was observed in the continuous administration of Compound C for comparison.
本発明化合物(I)は経口、非経口のいずれにおいても投
与できる。経口投与剤の剤型としては、例えば錠剤、カ
プセル剤、散剤、顆粒剤およびシロップ剤等があげら
れ、非経口投与剤の剤型としては、注射剤等があげられ
る。これらの調製には、通常の賦形剤、崩壊剤、結合
剤、滑沢剤、色素、希釈剤などが用いられる。賦形剤と
しては、ブドウ糖、乳糖などが、崩壊剤としてはデンプ
ン、カルボキシメチルセルロースカルシウムなどが、滑
沢剤としてはステアリン酸マグネシウム、タルクなど
が、結合剤としてはヒドロキシプロピルセルロース、ゼ
ラチン、ポリビニルピロリドンなどが用いられる。The compound (I) of the present invention can be administered orally or parenterally. Examples of the dosage form of the orally-administered agent include tablets, capsules, powders, granules, syrups and the like, and examples of the dosage form of the parenteral administration agent include injections and the like. Conventional excipients, disintegrants, binders, lubricants, pigments, diluents and the like are used for the preparation of these. As excipients, glucose, lactose, etc., as disintegrants, starch, carboxymethylcellulose calcium, etc., as lubricants, magnesium stearate, talc, etc., as binders, hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, etc. Is used.
投与量は、通常成人において、注射剤で１日約１mg〜５
０mg、経口投与で１日約１０mg〜５００mgであるが、年
令、症状等により増減することができる。The dosage is usually about 1 mg to 5 mg daily by injection in adults.
The dose is 0 mg orally and is about 10 mg to 500 mg per day, but it can be increased or decreased depending on the age, symptoms and the like.
次に参考例及び実施例を挙げて本発明を説明する。 Next, the present invention will be described with reference to Reference Examples and Examples.
参考例１ (i)２−ベンジルチオベンズイミダゾール： ２−メルカプトベンズイミダゾール５ｇ、ベンジルクロ
ライド4.2ｇをNaOH1.47ｇの水５ｍ−エタノール５０
ｍ溶液中に加え、１時間加熱還流した。反応混合物を
氷水中に注ぎ、析出した結晶を取し、7.7ｇ（９６
％）の粗結晶を得た。エタノールより再結晶し、5.9ｇ
の無色針状晶を得た。m.p.１８４℃。Reference Example 1 (i) 2-Benzylthiobenzimidazole: 2-mercaptobenzimidazole 5 g, benzyl chloride 4.2 g, NaOH 1.47 g water 5 m-ethanol 50.
m solution and heated to reflux for 1 hour. The reaction mixture was poured into ice water, and the precipitated crystals were taken out to obtain 7.7 g (96
%) Crude crystals were obtained. Recrystallized from ethanol, 5.9g
Colorless needle crystals were obtained. mp 184 ° C.
(ii)２−ベンジルスルフィニルベンズイミダゾール： ２−ベンジルチオベンズイミダゾール4.5ｇをクロロホ
ルム３０ｍに溶解し、ｍ−クロロ過安息香酸（純度７
０％）4.6ｇを０℃以下で少しずつ加えた。さらに２０
分攪拌後、析出した結晶を別し、液を飽和NaHCO3溶
液、チオ硫酸ナトリウム溶液及び飽和食塩水で洗浄し、
芒硝で乾燥した。溶媒を減圧留去し、4.3ｇの粗結晶を
得た。エタノールより再結晶し、2.0ｇの２−ベンジル
スルフィニルベンズイミダゾールを無色結晶として得
た。m.p.169-170℃ 実施例１ （ｉ）２−（２−ジメチルアミノベンジルチオ）−４−
メチルベンズイミダゾール： ２−メルカプト−４−メチルベンズイミダゾール1.0ｇ
のエタノール１０ｍ懸濁液に２−ジメチルアミノベン
ジルクロライド塩酸塩1.26ｇを加え、２時間室温で攪拌
した。析出した結晶を取し、エタノール、エーテルで
洗浄後、クロロホルムに溶解し、飽和NaHCO3溶液で中和
した。クロロホルム溶液を飽和食塩水で洗浄し、芒硝で
乾燥後溶媒を減圧留去し、残渣にエーテルを加え、析出
した結晶を取し、２−（２−ジメチルアミノベンジル
チオ）−４−メチルベンズイミダゾールを白色結晶性粉
末として1.38ｇを得た。1 HNMR(CDC3)δ：2.52(s,3H),2.84(s,6H),4.36(s,2H),
6.8-7.6(m,7H) (ii)２−（２−ジメチルアミノベンジルスルフィニル）
−４−メチルベンズイミダゾール： ２−（２−ジメチルアミノベンジルチオ）−４−メチル
ベンズイミダゾール1.1gをクロロホルム15mに溶解し、氷冷下
m-CPBA0.8ｇ（純度８０％）を少量ずつ加えた。同温度
で１０分間攪拌後、飽和NaHCO3溶液及び飽和食塩水で洗
浄後、芒硝で乾燥した。溶媒を減圧留去し、残渣をアセ
トニトリルより再結晶して0.81ｇの２−（２−ジメチル
アミノベンジルスルフィニル）−４−メチルベンズイミ
ダゾールを黄色結晶として得た。(ii) 2-Benzylsulfinylbenzimidazole: 4.5 g of 2-benzylthiobenzimidazole was dissolved in 30 m of chloroform, and m-chloroperbenzoic acid (purity 7
4.6% (0%) was added little by little at 0 ° C or lower. 20 more
After stirring for minutes, the precipitated crystals were separated, and the solution was washed with saturated NaHCO 3 solution, sodium thiosulfate solution and saturated saline,
Dried with mirabilite. The solvent was distilled off under reduced pressure to obtain 4.3 g of crude crystals. Recrystallization from ethanol gave 2.0 g of 2-benzylsulfinylbenzimidazole as colorless crystals. mp169-170 ° C Example 1 (i) 2- (2-dimethylaminobenzylthio) -4-
Methylbenzimidazole: 2-mercapto-4-methylbenzimidazole 1.0 g
1.26 g of 2-dimethylaminobenzyl chloride hydrochloride was added to a suspension of 10 m of ethanol in, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected, washed with ethanol and ether, dissolved in chloroform, and neutralized with a saturated NaHCO 3 solution. The chloroform solution was washed with saturated brine, dried over sodium sulfate, the solvent was distilled off under reduced pressure, ether was added to the residue, and the precipitated crystals were collected, and 2- (2-dimethylaminobenzylthio) -4-methylbenzimidazole was collected. Was obtained as a white crystalline powder to give 1.38 g. 1 HNMR (CDC 3 ) δ: 2.52 (s, 3H), 2.84 (s, 6H), 4.36 (s, 2H),
6.8-7.6 (m, 7H) (ii) 2- (2-dimethylaminobenzylsulfinyl)
-4-Methylbenzimidazole: 2- (2-Dimethylaminobenzylthio) -4-methylbenzimidazole (1.1 g) was dissolved in chloroform (15 m) and cooled with ice.
0.8 g of m-CPBA (purity 80%) was added little by little. The mixture was stirred at the same temperature for 10 minutes, washed with a saturated NaHCO 3 solution and saturated saline, and then dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from acetonitrile to obtain 0.81 g of 2- (2-dimethylaminobenzylsulfinyl) -4-methylbenzimidazole as yellow crystals.
mp 112-114℃（分解）1 HNMR(CDC3)δ：2.2-2.8(br,3H),2.60(s,6H),4.52 an
d 4.84(each d,J＝13Hz,2H),6.7-7.6(m,7H) ＩＲ：3200,1480,1440,1420,1290,1040,750 実施例２ （ｉ）２−（２−ジメチルアミノ−６−メチルベンジル
チオ）ベンズイミダゾール： ２−ジメチルアミノ−６−メチルベンジルクロライド塩
酸塩4.41ｇをアセトン４０ｍに溶解し、２−メルカプ
トベンズイミダゾール3.64ｇ、K2CO3１０ｇ及び水４ｍ
を加えて１時間室温で攪拌した。クロロホルム及び水
を加え、クロロホルム層を分取し、飽和食塩水で洗浄
し、芒硝で乾燥後、溶媒を減圧留去した。残渣をエタノ
ール、ヘキサンより結晶化させ、結晶を取し、２−
（２−ジメチルアミノ−６−メチルベンジルチオ）ベン
ズイミダゾールを淡褐色粉末として4.68ｇを得た。1 HNMR(CDC3)δ：2.42(s,3H),2.84(s,6H),4.42(s,2H),
6.8-7.6(m,7H) (ii)２−（２−ジメチルアミノ−６−メチルベンジルス
ルフィニル）ベンズイミダゾール： ２−（２−ジメチルアミノ−６−メチルベンジルチオ）
ベンズイミダゾール2.97ｇをクロロホルム３０ｍ及び
メタノール３ｍの混合溶媒に溶解し、氷冷下ｍ−CPBA
2.18ｇ（純度８０％）を少量ずつ加えた。同温度で１０
分間攪拌後、飽和NaHCO3溶液及び飽和食塩水で洗浄後、
芒硝で乾燥した。溶媒を減圧留去し、残渣をクロロホル
ム−エタノールより再結晶して0.75ｇの２−（２−ジメ
チルアミノ−６−メチルベンジルスルフィニル）ベンズ
イミダゾールを白色結晶粉末として得た。mp 112-114 ° C (decomposition) 1 HNMR (CDC 3 ) δ: 2.2-2.8 (br, 3H), 2.60 (s, 6H), 4.52 an
d 4.84 (each d, J = 13Hz, 2H), 6.7-7.6 (m, 7H) IR: 3200,1480,1440,1420,1290,1040,750 Example 2 (i) 2- (2-dimethylamino- 6-Methylbenzylthio) benzimidazole: 4.41 g of 2-dimethylamino-6-methylbenzyl chloride hydrochloride is dissolved in 40 m of acetone, 3.64 g of 2-mercaptobenzimidazole, 10 g of K 2 CO 3 and 4 m of water.
Was added and stirred for 1 hour at room temperature. Chloroform and water were added, the chloroform layer was separated, washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is crystallized from ethanol and hexane, and the crystals are collected.
(2-Dimethylamino-6-methylbenzylthio) benzimidazole was obtained as a light brown powder to give 4.68 g. 1 HNMR (CDC 3 ) δ: 2.42 (s, 3H), 2.84 (s, 6H), 4.42 (s, 2H),
6.8-7.6 (m, 7H) (ii) 2- (2-dimethylamino-6-methylbenzylsulfinyl) benzimidazole: 2- (2-dimethylamino-6-methylbenzylthio)
Dissolve 2.97 g of benzimidazole in a mixed solvent of 30 m of chloroform and 3 m of methanol, and under ice cooling, m-CPBA.
2.18 g (80% purity) was added in small portions. 10 at the same temperature
After stirring for 1 minute, wash with saturated NaHCO 3 solution and saturated saline,
Dried with mirabilite. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-ethanol to obtain 0.75 g of 2- (2-dimethylamino-6-methylbenzylsulfinyl) benzimidazole as a white crystalline powder.
mp 141-142℃（分解）1 HNMR(CDC3)δ：2.31(s,3H),2.61(s,6H),4.68 and 4.
92(each d,J＝13Hz,2H),6.8-7.8(m,7H) ＩＲ ν▲KBr max▼cm-1：3230,1435,1400,1270,1040,7
40 実施例３〜１４ 実施例１又は２と同様にして次の化合物を製造した。mp 141-142 ° C (decomposition) 1 HNMR (CDC 3 ) δ: 2.31 (s, 3H), 2.61 (s, 6H), 4.68 and 4.
92 (each d, J = 13Hz, 2H), 6.8-7.8 (m, 7H) IR ν ▲ KBr max ▼ cm -1 : 3230,1435,1400,1270,1040,7
40 Examples 3 to 14 The following compounds were produced in the same manner as in Example 1 or 2.
フロントページの続き (72)発明者 林 正敏 東京都新宿区市谷台町６Continuation of the front page (72) Inventor Masatoshi Hayashi 6 Tanidaimachi, Shinjuku-ku, Tokyo
Claims (3)
し、Ｒ3及びＲ4は少なくとも一方がハロゲン原子、トリ
フルオロメチル基、低級アルキル基、低級アルコキシ
基、低級アルコキシカルボニル基又はアミノ基を示し、
残余は水素原子を示す。但し、Ｒ3が低級アルコキシ基
で、Ｒ4が水素原子の場合を除く）で表わされるベンズ
イミダゾール誘導体。1. The following general formula (I): (In the formula, R 1 and R 2 represent a hydrogen atom or a lower alkyl group, and at least one of R 3 and R 4 is a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group or an amino group. Shows the group
The rest represents hydrogen atoms. Provided that R 3 is a lower alkoxy group and R 4 is a hydrogen atom).
般式(III)、 （式中、Ｘは反応性基を示す） で表わされる２−アミノベンジル化合物を反応せしめて
一般式(IV)、 で表わされる化合物となし、次いでこれを酸化すること
を特徴とする一般式(I) （式中、Ｒ1及びＲ2は水素原子又は低級アルキル基を示
し、Ｒ3及びＲ4は少なくとも一方がハロゲン原子、トリ
フルオロメチル基、低級アルキル基、低級アルコキシ
基、低級アルコキシカルボニル基又はアミノ基を示し、
残余は水素原子を示す。但し、Ｒ3が低級アルコキシ基
で、Ｒ4が水素原子の場合を除く） で表わされるベンズイミダゾール誘導体の製造法。2. General formula (II), 2-mercaptobenzimidazoles represented by the general formula (III), (In the formula, X represents a reactive group), a 2-aminobenzyl compound represented by the formula is reacted to give a compound represented by the general formula (IV): A compound represented by the general formula (I) (In the formula, R 1 and R 2 represent a hydrogen atom or a lower alkyl group, and at least one of R 3 and R 4 is a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group or an amino group. Shows the group
The rest represents hydrogen atoms. Provided that R 3 is a lower alkoxy group and R 4 is a hydrogen atom).
し、Ｒ3及びＲ4は少なくとも一方がハロゲン原子、トリ
フルオロメチル基、低級アルキル基、低級アルコキシ
基、低級アルコキシカルボニル基又はアミノ基を示し、
残余は水素原子を示す。但し、Ｒ3が低級アルコキシ基
で、Ｒ4が水素原子の場合を除く） で表わされるベンズイミダゾール誘導体を有効成分とし
て含有する抗潰瘍剤。3. The following general formula (I), (In the formula, R 1 and R 2 represent a hydrogen atom or a lower alkyl group, and at least one of R 3 and R 4 is a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group or an amino group. Shows the group
The rest represents hydrogen atoms. However, an anti-ulcer agent containing a benzimidazole derivative represented by the formula ( 3) wherein R 3 is a lower alkoxy group and R 4 is a hydrogen atom).
Priority Applications (17)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60061194A JPH068283B2 (en) | 1985-03-26 | 1985-03-26 | Benzimidazole derivative, method for producing the same, and antiulcer agent containing the same |
| AU46409/85A AU4640985A (en) | 1984-08-31 | 1985-08-19 | Benzimidazole derivatives |
| ES546445A ES8703142A1 (en) | 1984-08-31 | 1985-08-27 | Benzimidazole derivatives |
| BE0/215506A BE903128A (en) | 1984-08-31 | 1985-08-27 | BENZIMIDAZOLE DERIVATIVES PROCESS FOR THEIR PREPARATION AND ANTI-ULCER AGENTS CONTAINING THEM |
| CH3709/85A CH665417A5 (en) | 1984-08-31 | 1985-08-29 | BENZIMIDAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND ANTI-ULCER AGENTS CONTAINING THESE DERIVATIVES. |
| GB08521493A GB2163747B (en) | 1984-08-31 | 1985-08-29 | Benzimidazole derivatives, and antiulcer agents containing the same |
| SE8504048A SE500669C2 (en) | 1984-08-31 | 1985-08-30 | Benzimidazoles |
| IT67743/85A IT1189601B (en) | 1984-08-31 | 1985-08-30 | Benzyl sulphinyl benzimidazole |
| DE3531487A DE3531487C2 (en) | 1984-08-31 | 1985-08-30 | benzimidazole derivatives |
| AR85301474A AR242195A1 (en) | 1984-08-31 | 1985-08-30 | A procedure for the preparation of benzimidazole derivatives and their salts. |
| FR858512961A FR2569691B1 (en) | 1984-08-31 | 1985-08-30 | BENZIMIDAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND ANTI-ULCER AGENTS CONTAINING THEM |
| NL8502384A NL8502384A (en) | 1984-08-31 | 1985-08-30 | BENZIMIDAZOLE DERIVATIVES, PHARMACEUTICAL PREPARATIONS WITH AN ACTION AGAINST SILES CONTAINING THEM AND METHODS FOR PREPARING THESE DERIVATIVES |
| MX206462A MX159807A (en) | 1984-08-31 | 1985-08-30 | PROCEDURE FOR PREPARING BENZMIDAZOLE DERIVATIVES |
| BR8504252A BR8504252A (en) | 1984-08-31 | 1985-08-30 | BENZIMIDAZOL DERIVATIVE, PROCESS FOR THE PREPARATION OF A BENZIMIDAZOL DERIVATIVE AND AN ANTI ULCEROSAL AGENT |
| KR1019850006307A KR920004936B1 (en) | 1984-08-31 | 1985-08-30 | Method for producing of benzimidazole derivatives |
| AU41271/89A AU4127189A (en) | 1984-08-31 | 1989-09-11 | Benzimidazole derivatives, process for preparing the same and antiulcer agents containing the same |
| AU29750/92A AU647978B2 (en) | 1984-08-31 | 1992-11-27 | Benzimidazole derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60061194A JPH068283B2 (en) | 1985-03-26 | 1985-03-26 | Benzimidazole derivative, method for producing the same, and antiulcer agent containing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61221175A JPS61221175A (en) | 1986-10-01 |
| JPH068283B2 true JPH068283B2 (en) | 1994-02-02 |
Family
ID=13164114
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60061194A Expired - Lifetime JPH068283B2 (en) | 1984-08-31 | 1985-03-26 | Benzimidazole derivative, method for producing the same, and antiulcer agent containing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH068283B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8417271D0 (en) * | 1984-07-06 | 1984-08-08 | Fisons Plc | Biologically active nitrogen heterocycles |
| JPS63230633A (en) * | 1987-03-19 | 1988-09-27 | Nippon Chemiphar Co Ltd | Protecting agent for gastroenteric cell |
| JPH01121273A (en) * | 1987-11-05 | 1989-05-12 | Nippon Chemiphar Co Ltd | Polymorphic substance of benzimidazole derivative |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6156168A (en) * | 1984-07-06 | 1986-03-20 | フアイソンズ・ピ−エルシ− | Novel compounds and manufacture |
-
1985
- 1985-03-26 JP JP60061194A patent/JPH068283B2/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6156168A (en) * | 1984-07-06 | 1986-03-20 | フアイソンズ・ピ−エルシ− | Novel compounds and manufacture |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61221175A (en) | 1986-10-01 |
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