JPH075593B2 - Novel sulfoxide compound and method for producing the same - Google Patents
Novel sulfoxide compound and method for producing the sameInfo
- Publication number
- JPH075593B2 JPH075593B2 JP1616986A JP1616986A JPH075593B2 JP H075593 B2 JPH075593 B2 JP H075593B2 JP 1616986 A JP1616986 A JP 1616986A JP 1616986 A JP1616986 A JP 1616986A JP H075593 B2 JPH075593 B2 JP H075593B2
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- compound
- same
- hydrogen atom
- general formula
- alkyl group
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Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は新規なスルホキシド体、更に詳細には次の一般
式（Ｉ） 〔式中、R1およびR2は、それぞれ水素原子又は低級アル
キル基を示し、R3及びR4はそれぞれ水素原子、低級アル
コキシ基又は低級アルキル基を示す〕で表わされるスル
ホキシド体及びその製造法に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel sulfoxide compound, more specifically, the following general formula (I): [In the formula, R 1 and R 2 each represent a hydrogen atom or a lower alkyl group, and R 3 and R 4 represent a hydrogen atom, a lower alkoxy group or a lower alkyl group] and a method for producing the same. Regarding
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（1
979）、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〔ピロシーディ
ング・オブ・ザ・ソサエティ・フォー・エキスプリメン
タル・バイオロジイ・アンド・メデシン（Proceeding o
f 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 (1
979), norinium bromide is known as a substance having an H + + K + ATPase inhibitory action [Piroceeding of the Society for Supplementary Biology & Medellin (Proceeding o
f 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イニル〕−（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] has been developed as an anti-ulcer drug having an H + + K + ATPase inhibitory action [American Journal of Physiology (A
mJof Physiol.) 245 , G64-G71 (1983)].
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。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
果一般式（Ｉ）で表わされる新規なスルホキシド体が特
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 sulfoxide compound represented by the general formula (I) has an excellent gastric acid secretion inhibitory action based on the specific H + + K + ATPase inhibitory action. It was found that the present invention has been completed.
従って、本発明は抗潰瘍剤として有用なスルホキシド体
（Ｉ）を提供するものである。Therefore, the present invention provides a sulfoxide derivative (I) useful as an antiulcer agent.
また、本発明はスルホキシド体（Ｉ）を製造するための
新規な方法を提供するものである。The present invention also provides a novel method for producing the sulfoxide derivative (I).
本発明のスルホキシド体（Ｉ）は、例えば次の反応式に
従ってメルカプト体（II）に化合物（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 sulfoxide compound (I) of the present invention is produced, for example, by reacting the mercapto compound (II) with the compound (III) to form the compound (IV) according to the following reaction formula, and then oxidizing this.
［式中、Ｘは反応性基をし、R1，R2，R3及びR4は前記と
同じ］ 本発明方法の原料（II）は、例えば、ジアミノピリジン
化合物にキサントゲン酸カリウムをアルコール溶媒中で
作用させることにより製造される。また原料（III）の
Ｘで表わされ反応性基としては塩素、臭素等のトロゲン
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又はアセトキシ基等を挙
げることができる。 [Wherein, X is a reactive group, and R 1 , R 2 , R 3 and R 4 are the same as above] The raw material (II) of the method of the present invention is, for example, a diaminopyridine compound containing potassium xanthate and an alcohol solvent. Manufactured by working in. Examples of the reactive group represented by X in the raw material (III) include trogen atoms such as chlorine and bromine, sulfonyloxy groups such as methylsulfonyloxy and toluenesulfonyloxy groups, and acetoxy groups.
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
撹拌することによって行なわれる。その際、NaOH、KO
H、K2CO3、NaHCO3等のアルカリ剤を存在せしめて、生成
する酸を受容することもできる。The reaction between compound (II) and compound (III) or a salt thereof is
It is carried out by stirring in an inert solvent such as toluene, benzene, ethanol or acetone at room temperature or under reflux for 30 minutes to 24 hours. At that time, NaOH, KO
An alkaline agent such as H, K 2 CO 3 , NaHCO 3 can be present to accept the acid produced.
化合物（IV）のオキソ化は常法によって行なうことがで
き例えば過酸化水素、ｍ−クロル過安息香酸などの有機
過酸、次亜塩素酸ナトリウム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
クロロメタン、メタノール、酢酸エチル等の不活性溶媒
入、−30℃〜50℃、好ましくは−15℃〜５℃の温度で行
なわれる。Oxidation of compound (IV) can be carried out by a conventional method, for example, using hydrogen peroxide, an organic peracid such as m-chloroperbenzoic acid, an oxidizing agent such as sodium hypochlorite, and the like. Should be oxidized. The reaction is carried out in an inert solvent such as chloroform, dichloromethane, methanol or ethyl acetate at a temperature of -30 ° C to 50 ° C, preferably -15 ° C to 5 ° C.
次に、本発明化合物（Ｉ）の薬理効果を試験した結果を
示す。Next, the result of having tested the pharmacological effect of this invention compound (I) is shown.
（Ｉ）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アーゼを含むベシクルはフイ
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（pH6.0）、試験物質２
×10-4を含む溶液0.5ml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25分間放置した。
4mM塩化マグネシウム、90mMイミダゾール緩衝液（pH7.
4）、20mM塩化カリウム及び4mM ATPを含む溶液0.5mlを
加えて、37℃で15分間反応させたのち、24％トリクロル
酢酸1ml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.Bio
l.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 （本発明化合物１は、実施例１で得られた化合物を表わ
す） （２）胃酸分泌抑制作用 常法〔シェイ・エッチら、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 output）は自動滴定装置を用
い、0.1N NaOHでpH7.0まで滴定し得られた値を、同様に
処置した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。(I) H + + K + ATPase inhibitory action 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
After incubating the enzyme for 25 minutes at room temperature in 0.5 ml of a solution containing × 10 −4 , the enzyme was transferred to 37 ° C. and left for another 25 minutes.
4 mM magnesium chloride, 90 mM imidazole buffer (pH 7.
4), 0.5 ml of a solution containing 20 mM potassium chloride and 4 mM ATP was added and reacted at 37 ° C. for 15 minutes, then 1 ml of 24% trichloroacetic acid was added to stop the reaction, and the released inorganic phosphorus was removed by Tosky (Taussky) and The method of Shorr [Journal of Biological Chemistry (J.Bio
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. (Compound 1 of the present invention represents the compound obtained in Example 1) (2) Suppressive action on gastric acid secretion [Shay Et et al., Gastroenterology (Sh
a.H. et al., Gastroenterology), 5 , 43-61 (1945)]
According to the above, male Donryu rats weighing 200 to 250 g were fasted for 24 hours (water intake freely), the abdomen was opened under ether anesthesia, the pylorus was ligated, and the test compound was intraduodenally administered. After 4 hours, the animals were killed, the stomach was removed and the gastric juice was collected. The acidity (Acid output) was titrated to pH 7.0 with 0.1 N NaOH using an automatic titrator, and the obtained value was compared with that of a control animal which was not treated with the test compound. The results are shown in Table 2.
〔実施例〕 次に参考例・実施例を挙げて本発明を説明する。 EXAMPLES Next, the present invention will be described with reference to reference examples and examples.
実施例１ （ｉ）２−（２−ジメチルアミノベンジルチオ）イミダ
ゾ〔4,5,−ｂ〕ピリジン： ２−メルカプトイミダゾ〔4,5−ｂ〕ピリジン3.0gを水
酸化ナトリウム1.71gのエタノール100ml及び水5ml溶液
に加えた後、２−ジメチルアミノベンジルクロリド塩酸
塩4.09gを加え室温で17.5時間撹拌した。溶媒を減圧留
去し残渣を酢酸エチルで抽出した。Example 1 (i) 2- (2-Dimethylaminobenzylthio) imidazo [4,5, -b] pyridine: 3.0 g of 2-mercaptoimidazo [4,5-b] pyridine, 1.71 g of sodium hydroxide and 100 ml of ethanol. And water (5 ml), 2-dimethylaminobenzyl chloride hydrochloride (4.09 g) was added, and the mixture was stirred at room temperature for 17.5 hours. The solvent was distilled off under reduced pressure and the residue was extracted with ethyl acetate.
有機層を５％水酸化ナトリウム溶液、水及び飽和食塩水
で洗浄後芒硝乾燥した。芒硝を別後溶媒を減圧留去し
て得られる残渣カーテルを加えて加温し、不溶物を別
した。The organic layer was washed with a 5% sodium hydroxide solution, water and saturated saline and then dried over sodium sulfate. After removing Glauber's salt, the solvent was distilled off under reduced pressure and a residual cartel obtained was added and heated to separate insoluble matter.
液を濃縮して2.95gの２−（２−ジメチルアミノベン
ジルチオ）イミダゾ〔4,5−ｂ〕ピリジンを白色粉末と
して得た。1 H NMR(CDCl3)δ:2.96（S,6H）、4.44（S,2H） 7.0−8.2（m,7H） （ii）２−（２−ジメチルアミノベンジルスルフィニ
ル）イミダゾ〔4,5,−ｂ〕ピリジン（本発明化合物
１）： ２−（２−ジメチルアミノベンジルチオ）イミダゾ〔4,
5−ｂ〕ピリジン1.5gをクロロホルム50mlに溶かし−10
℃に冷却下、ｍ−クロル過安息香酸（純度80％）1.36g
を少量ずつ加えた。The liquid was concentrated to obtain 2.95 g of 2- (2-dimethylaminobenzylthio) imidazo [4,5-b] pyridine as a white powder. 1 H NMR (CDCl 3 ) δ: 2.96 (S, 6H), 4.44 (S, 2H) 7.0-8.2 (m, 7H) (ii) 2- (2-dimethylaminobenzylsulfinyl) imidazo [4,5,- b] Pyridine (inventive compound 1): 2- (2-dimethylaminobenzylthio) imidazo [4,
5-b] Dissolve 1.5 g of pyridine in 50 ml of chloroform-10
1.36 g of m-chloroperbenzoic acid (80% purity) under cooling to ℃
Was added in small portions.
反応終了後飽和NaHCO3溶液、水、飽和食塩水で洗浄し芒
硝乾燥した。芒硝を別後溶媒を減圧留去して得られる
固形物を、エタノールより再結晶して1.15gの２−（２
−ジメチルアミノベンジルスルフィニル）イミダゾ〔4,
5−ｂ〕ピリジンを白色結晶粉末として得た。mp:135−1
36℃ 1H NMR(CDCl3)δ:2.60（S,6H）、4.48 and 4.84 （each d,2H,J＝14Hz）、6.8−8.7（m,7H） 参考例１ ２−メルカプトイミダゾ［4,5−ｂ］ピリジン； 2,3−ジアミノピリジン5g、キサントゲン酸カリウム14.
3g、エタノール50ml及び水10mlの混合物を８時間加熱還
流後、溶媒を減圧留去して得られる固形物をアセトンで
洗浄した。得られた固形物を水に溶解し酢酸酸性として
析出する結晶を取し水及びエーテルで洗浄して5gの２
−メルカプトイミダゾ［4,5−ｂ］ピリジンを得た。mp;
250℃以上After completion of the reaction, the mixture was washed with saturated NaHCO 3 solution, water and saturated saline, and dried over sodium sulfate. The solid obtained by separating the sodium sulfate and distilling off the solvent under reduced pressure was recrystallized from ethanol to give 1.15 g of 2- (2
-Dimethylaminobenzylsulfinyl) imidazo [4,
5-b] Pyridine was obtained as a white crystalline powder. mp: 135-1
36 ° C 1 H NMR (CDCl 3 ) δ: 2.60 (S, 6H), 4.48 and 4.84 (each d, 2H, J = 14Hz), 6.8-8.7 (m, 7H) Reference Example 1 2-Mercaptoimidazo [4,5- b] Pyridine; 2,3-diaminopyridine 5 g, potassium xanthate 14.
A mixture of 3 g, 50 ml of ethanol and 10 ml of water was heated under reflux for 8 hours, the solvent was distilled off under reduced pressure, and the obtained solid was washed with acetone. The obtained solid was dissolved in water and acidified with acetic acid to precipitate crystals, which were washed with water and ether to give 5 g of 2
-Mercaptoimidazo [4,5-b] pyridine was obtained. mp;
250 ° C or higher
Claims (2)
キル基を示し、R3及びR4はそれぞれ水素原子、低級アル
コキシ基又は低級アルキル基を示す〕で表わされるスル
ホキシド体。1. The following general formula (I): [In the formula, R 1 and R 2 each represent a hydrogen atom or a lower alkyl group, and R 3 and R 4 each represent a hydrogen atom, a lower alkoxy group or a lower alkyl group].
キル基を示す〕で表わされるメルカプト誘導体に、一般
式（III） 〔式中、R1およびR2は、それぞれ水素原子又は低級アル
キル基をR4は水素原子、低級アルコキシ基及び低級アル
キル基を示し、Ｘは反応性基を示す〕で表わされる化合
物又はその塩を反応せしめて、一般式（IV） 〔式中、R1，R2，R3及びR4は前記と同じ〕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，R2，R3及びR4は前記と同じ〕で表わされる
スルホキシド体の製造法。2. General formula (II) [In the formula, R 3 represents a hydrogen atom, a lower alkoxy group or a lower alkyl group], and a mercapto derivative represented by the general formula (III) [Wherein, R 1 and R 2 are each a hydrogen atom or a lower alkyl group, R 4 is a hydrogen atom, a lower alkoxy group and a lower alkyl group, and X is a reactive group], or a salt thereof. To react with the general formula (IV) [Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above], and the compound is then oxidized to give a compound of the general formula (I) [Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above].
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1616986A JPH075593B2 (en) | 1986-01-28 | 1986-01-28 | Novel sulfoxide compound and method for producing the same |
| KR1019870000149A KR950001015B1 (en) | 1986-01-10 | 1987-01-10 | Process for preparing sulfoxide derivatives |
| DE8787300228T DE3770020D1 (en) | 1986-01-10 | 1987-01-12 | SULFOXIDE DERIVATIVES AND THEIR PRODUCTION. |
| ES198787300228T ES2032436T3 (en) | 1986-01-10 | 1987-01-12 | A PROCEDURE FOR THE PREPARATION OF A SULFOXIDE DERIVATIVE. |
| EP87300228A EP0234690B1 (en) | 1986-01-10 | 1987-01-12 | Sulfoxide derivatives and their preparation |
| CA000527149A CA1304087C (en) | 1986-01-10 | 1987-01-12 | Sulfoxide derivatives and their preparation |
| AU67492/87A AU604668B2 (en) | 1986-01-10 | 1987-01-12 | Imidazo-(4,5-b) pyridine, pyrido-(2,3-b)-pyrazine and quinoxaline sulfoxide derivatives |
| AR87306447A AR246263A1 (en) | 1986-01-10 | 1987-01-22 | Procedure for preparing new sulphoxide derivatives. |
| US07/198,086 US4933458A (en) | 1986-01-10 | 1988-05-24 | Certain gastric acid secretion inhibiting sulfoxides |
| US07/506,171 US5106976A (en) | 1986-01-10 | 1990-04-09 | Fused pyrazine sulfoxide derivatives for use as antiulcer agents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1616986A JPH075593B2 (en) | 1986-01-28 | 1986-01-28 | Novel sulfoxide compound and method for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62175481A JPS62175481A (en) | 1987-08-01 |
| JPH075593B2 true JPH075593B2 (en) | 1995-01-25 |
Family
ID=11909007
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1616986A Expired - Lifetime JPH075593B2 (en) | 1986-01-10 | 1986-01-28 | Novel sulfoxide compound and method for producing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH075593B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2546841B2 (en) * | 1986-07-25 | 1996-10-23 | 東京田辺製薬株式会社 | Novel imidazo [4,5-b] pyridine derivative, production method thereof and antiulcer agent containing the same |
| JP2582406B2 (en) * | 1988-04-11 | 1997-02-19 | 日清製粉株式会社 | Novel quinoxaline derivative and anti-ulcer agent containing the same |
-
1986
- 1986-01-28 JP JP1616986A patent/JPH075593B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS62175481A (en) | 1987-08-01 |
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