KR970001477B1 - N-substituted benzimidazole derivatives with amide groups - Google Patents
N-substituted benzimidazole derivatives with amide groups Download PDFInfo
- Publication number
- KR970001477B1 KR970001477B1 KR1019930020833A KR930020833A KR970001477B1 KR 970001477 B1 KR970001477 B1 KR 970001477B1 KR 1019930020833 A KR1019930020833 A KR 1019930020833A KR 930020833 A KR930020833 A KR 930020833A KR 970001477 B1 KR970001477 B1 KR 970001477B1
- Authority
- KR
- South Korea
- Prior art keywords
- compound
- structural formula
- alkyl
- substitution
- hydroxyalkyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/28—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
본 발명은 다음 일반식(Ⅰ)로 표시되는 신규한 벤즈이미다졸 유도체와 그의 약제학적으로 허용가능한 염의 제조 방법에 관한 것이다.The present invention relates to a novel benzimidazole derivative represented by the following general formula (I) and a method for preparing a pharmaceutically acceptable salt thereof.
상기 식에서, R1은 치환반을이나 측합반응으로 도입가능한 치환체로서, 탄소수 1∼6개의 저급알킬, 히드록시알킬, 알코시카보닐 및 알콕시카보닐알킬등을 포함한다. R2는 수소, 메칠기를 포함하여 알킬, 알콕시등이다. R3, R4, R5는 수소, C1∼C3알킬, C1∼C3알콕시, 트리할로메틸 또는 C1, F등이다. n은 0 또는 1이다.In formula, R <1> is a substituent which can introduce | transduce a substitution board or by side reaction, and contains C1-C6 lower alkyl, hydroxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, etc. R 2 is hydrogen, alkyl including a methyl group, alkoxy and the like. R 3, R 4, R 5 is hydrogen, C 1 ~C 3 alkyl, C 1 ~C 3 alkyl, trihaloalkyl or C1 methyl, F or the like. n is 0 or 1;
위궤양은 발생원인이 확실하지는 않으나 위산의 과다 분비가 중요한 요인으로 알려져 있으며, 위산분비 마지막 단계에 작용하는 H+/K+-ATRase의 작용을 효과적으로 차단함으로써 궤양치료작용을 가지는 물질들이 최근들어 관심의 촛점이 되고 있다.The cause of gastric ulcer is not clear, but the excessive secretion of gastric acid is known as an important factor, and substances that have an ulcer treatment effect by effectively blocking the action of H + / K + -ATRase acting at the last stage of gastric acid secretion are of interest. The focus is on.
그중 1-[2-(3,5-디메틸-4-메톡시)-피리딘메칠술피닐]-(5-메톡시)벤즈이미다졸[오메프라졸]은 위와 같은 작용을 가지는 물질로[Am. J. of Physiol., 245, G64-71(1983)]개발되어 왔다. 오메프라졸의 개발에 따라서 여러가지 헤테로고리 화합물을 가지는 술피닐 벤즈이미다졸[JMC, 1989, 32, 1970, Chem. Pharm. Bull, 1990, 38, 534, GB2, 069, 492, DE3, 240, 248, DE3, 415, 971, EP167, 943, JP60, 233, 070, EP178, 438, EP187, 977, EP174, 726, EP201, 094, DE3, 530, 342, GB2, 172, 285, EP234, 485]이 보고되고 있다.Among them, 1- [2- (3,5-dimethyl-4-methoxy) -pyridinemethylsulfinyl]-(5-methoxy) benzimidazole [omeprazole] is a substance having the same action as above [Am. J. of Physiol., 245, G64-71 (1983). According to the development of omeprazole, sulfinyl benzimidazoles having various heterocyclic compounds [JMC, 1989, 32, 1970, Chem. Pharm. Bull, 1990, 38, 534, GB2, 069, 492, DE3, 240, 248, DE3, 415, 971, EP167, 943, JP60, 233, 070, EP178, 438, EP187, 977, EP174, 726, EP201, 094, DE3, 530, 342, GB2, 172, 285, EP234, 485 are reported.
그러나 이러한 종래의 물질들은 궤양체료기간이 짧은 장점이 있는 반면 너무 긴 작용시간에 기인하는 부작용의 우려를 내포하는 결점이 있었다.However, these conventional materials have the advantage of short duration of ulceration and have the drawback of concern of side effects due to too long action time.
항궤양 조성물로서 위산분비 억제와 위점막보호에 모두 효과적인 제제가 요구되어 왔는데, 위산분비를 억제하는 제제로서 시메티딘으로 대표되는 H2수용체에 대한 길항제가 사용되나, 이들은 위점막보호에는 효과적이지 못하였다. 그 이유는 중추신경제에 대한 부작용으로 인해 궤양을 치료하거나 예방하는데 있어서, 이들의 작용이 저하되었기 때문이다. 또다른 위산분비 억제제로서 오메프라졸(Omeprazole)로 대표되는 H+/K+-ATPase 저해제는 위산분비를 억제시키는데는 매우 효과적이지만 위산결핍증을 유발하는 것으로 알려져 있을 뿐 아니라 이들이 산에 불안정하기 때문에 위산에 의해 쉽게 분해된다는 단점도 있다. 따라서 위산분비 억제와 위점막보호에 모두 균형있게 효과를 나타내는 항궤양제의 개발이 중요하게 되었다. 특히 오메프라졸(Omeprazole)과 같은 H+/K+-ATPase 억제의 작용을 가지면서 화학적으로 산에도 안정한 물질의 개발이 요구되어 왔다. 본 발명자들은 항궤양 작용를 가진 신규한 벤즈이미다졸 화합물을 개발하기 위해 노력한 결과 아미드기를 가지는 벤즈이미다졸이 탁월한 효소 저해 효과를 가지는 것을 발견하였고 상기 구조(Ⅰ)의 벤즈이미다졸 유동체도 H+/K+-ATPase를 기존의 오메프라졸과 비견될 수 있는 강력한 효소저해 효과가 있음을 알게되어 본 발명을 완성하였다.As anti-ulcer compositions, agents that have been effective for suppressing gastric acid secretion and gastric mucosal protection have been required. As agents for inhibiting gastric acid secretion, antagonists for H 2 receptors represented by cimetidine have been used, but they have not been effective for gastric mucosal protection. . The reason is that side effects on the central economy have lowered their actions in treating or preventing ulcers. Another inhibitor of gastric acid secretion, H + / K + -ATPase inhibitors, represented by omeprazole, is very effective in inhibiting gastric acid secretion but is known to cause gastric acid deficiency, and because of their acid instability, It also has the disadvantage of being easily broken down. Therefore, the development of anti-ulcer drugs that have a balanced effect on both gastric acid secretion and gastric mucosal protection has become important. In particular, it has been required to develop a chemically stable substance that has an effect of H + / K + -ATPase inhibition such as omeprazole. The present inventors have tried to develop a novel benzimidazole compound having an anti-ulcer effect and found that benzimidazole having an amide group has an excellent enzyme inhibitory effect. The benzimidazole fluid of the structure (I) is also H + / K. + -ATPase was found to have a potent enzyme inhibitory effect that can be compared to the existing omeprazole to complete the present invention.
이하 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
본 발명은 다음 구조식(Ⅰ)로 표시되는 벤즈이미다졸 유도체에 관한 것이다.The present invention relates to a benzimidazole derivative represented by the following structural formula (I).
상기 식에서, R1은 치환반응이나 축합반응으로 도입가능한 치환체로서, 탄소수 1∼6개의 저급알킬, 히드록시알킬, 알콕시카보닐 및 알콕시카보닐알킬등을 포함한다. R2는 수소, 메칠기를 포함하여 알킬, 알콕시등이다. R3,R4,R5는 수소, C1∼C3알킬, C1∼C3알콕시, 트리할로메틸 또는 C1, F등이다. n은 0 또는 1이다.In formula, R <1> is a substituent which can be introduce | transduced by substitution reaction or condensation reaction, and includes C1-C6 lower alkyl, hydroxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, etc. R 2 is hydrogen, alkyl including a methyl group, alkoxy and the like. R 3, R 4, R 5 is hydrogen, C 1 ~C 3 alkyl, C 1 ~C 3 alkyl, trihaloalkyl or C1 methyl, F or the like. n is 0 or 1;
또한 본 발명은 다음 구조식(Ⅱ)를 출발물질로하여 황원자를 산화시킨 후 생성된 중간체(Ⅲ)을 이용하여 최종 물질(Ⅰ)을 제조하는 방법과 먼저 (Ⅱ)를 치환체로서, 탄소수 1∼6개의 저급알킬, 히드록시알킬, 알콕시카보닐 및 알콕시카보닐알킬등을 치환시킨 후 형성된 중간체(Ⅳ)를 산화하여 최종 물질(Ⅰ)을 제조하는 방법을 포함한다.In addition, the present invention is a method for preparing the final substance (I) by using the intermediate (III) produced by oxidizing the sulfur atom after the following structural formula (II) as a starting material and (II) as a substituent, 1 to 6 carbon atoms To lower alkyl, hydroxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl and the like to oxidize the intermediate (IV) formed to prepare the final material (I).
상기 식에서 R1, R2, R3, R4, R5는 앞에서 정의한 바 있다. 상기 화합물(Ⅲ)과 (Ⅰ)을 제조하는데 사용되는 산화반응은 이 기술분야에서 잘 알려져 있으며, m-클로로퍼벤조산, 과산화수소수, 차아염소산나트륨, 메타퍼요드산나트륨 같은 산화제가 주로 사용되며, m-클로로퍼벤조산을 사용할 경우 용매로는 클로로포롬, 메칠렌클로라이드를 주로 사용하지만 용해도가 문제가 될때에는 위의 용매에 아세톤이나 메탄올로 비율을 조절하여 사용한다. 반응온도는 상온에서 -50℃까지 가능하며 0℃에서 -20℃ 정도가 바람직하다.In the above formula, R 1 , R 2 , R 3 , R 4 , R 5 have been defined above. Oxidation reactions used to prepare the compounds (III) and (I) are well known in the art, and oxidizing agents such as m-chloroperbenzoic acid, hydrogen peroxide, sodium hypochlorite, sodium metaperiodate are mainly used, When m-chloroperbenzoic acid is used as a solvent, chloroform and methylene chloride are mainly used, but when solubility is a problem, the ratio is adjusted to acetone or methanol in the above solvent. The reaction temperature may be up to -50 ° C at room temperature and preferably about 0 ° C to -20 ° C.
상기 화합물(Ⅳ)와 (Ⅰ)을 얻는 치환반을 단계에서는 사용물질의 성질에 따라 반응조건이 달라지지만 대개 염기 존재하에서 반응이 잘 진행되며 사용되는 염기는 Et3N, DBU등의 유기염기와 NaOH, K2CO3등의 무기염기가 가능하다.In the step of substitution of the compounds (IV) and (I), the reaction conditions vary depending on the nature of the substance used, but the reaction proceeds well in the presence of a base, and the base used is an organic base such as Et 3 N or DBU. Inorganic bases such as NaOH and K 2 CO 3 are possible.
위와 같이 합성된 본 발명의 신규한 벤즈이미다졸 유도체는 H+/K+-ATPase를 저해하는 효과가 우수하여 항궤양 약제의 성분으로 유용하게 사용될 수 있다. 이하 본 발명의 실시예에 의거 상세히 설명하면 다음과 같은 바 본 발명이 실시예에 의해 한정 되는 것은 아니다.The novel benzimidazole derivatives of the present invention synthesized as described above are excellent in inhibiting H + / K + -ATPase and thus may be usefully used as components of anti-ulcer drugs. Hereinafter, the present invention will be described in detail with reference to the following examples, which are not intended to limit the scope of the present invention.
실시예 1Example 1
(발명화합물 11)(Invention Compound 11)
2-[N-(2-프로오로-4-클로로)페닐아세트아미드]티오벤즈이미다졸 1g과 Et3N 5㎖를 메칠렌클로라이드 20㎖에 녹인다음 온도를 -20℃로 냉각한다. 에칠클로로포메이트 0.32㎖를 5㎖의 메칠렌클로라이드 용매에 녹인 후 위의 용액에 천천히 적가한다. 적가가 끝난 후 -20℃에서 30분, 0℃에서 30분 반응 후 용매를 감압증류하고, 잔유물에 물을 가하여 생긴 흰색고체 발명화합물 11 1. 15g을 94%수율로 얻는다. (MP : 170∼171℃)1H-NMR(200MHz, ppm, CDC13)δ1.53(t,3H), 4.05(s,2H), 4.60(q, 2H), 8.0∼7.20(m,7H), 10.65(s,1H)1 g of 2- [N- (2-prooro-4-chloro) phenylacetamide] thiobenzimidazole and 5 ml of Et 3 N are dissolved in 20 ml of methylene chloride and the temperature is cooled to -20 ° C. 0.32 ml of ethylchloroformate is dissolved in 5 ml of methylene chloride solvent and slowly added dropwise to the above solution. After completion of the dropwise addition, the solvent was distilled under reduced pressure after 30 minutes at -20 ° C. and 30 minutes at 0 ° C., and water was added to the residue to obtain 15 g of a white solid compound 11 having a yield of 94%. (MP: 170-171 ° C) 1 H-NMR (200 MHz, ppm, CDC1 3 ) δ 1.53 (t, 3H), 4.05 (s, 2H), 4.60 (q, 2H), 8.0 to 7.20 (m, 7H) , 10.65 (s, 1H)
실시예 2Example 2
(발명화합물 12)(Invention Compound 12)
위의 실시예 1에서 합성한 술파이드 0.82g을 메칠렌클로라이드와 아세톤에 녹인 후 m-클로로퍼벤조산 0.5g을 메칠렌클로라이드에 녹인 용액을 10℃에서 10분에 걸쳐 적가한 후 10℃에서 12시간 반응 후 생긴 흰색고체를 여과하고 희색고체를 5% NaHCO3용액과 메칠렌클로라이드 용매로 세척하여 발명화합물 12 0.2gdmf 23% 수율로 얻는다. (MP : 148∼150℃)After dissolving 0.82 g of sulfide synthesized in Example 1 in methylene chloride and acetone, a solution of 0.5 g of m-chloroperbenzoic acid in methylene chloride was added dropwise at 10 ° C. over 10 minutes, and then 12 ° C. at 10 ° C. The white solid produced after the reaction was filtered, and the white solid was washed with 5% NaHCO 3 solution and methylene chloride solvent to obtain 0.2 gdmf 23% yield of Inventive Compound 12. (MP: 148-150 ° C)
1H-NMR(200MHz, ppm, CDC13)δ1.50(t,3H), 4.09(s, 2H), 4.57(q. 2H), 8.50∼7.00(m, 7H), 10.75(s,1H) 1 H-NMR (200 MHz, ppm, CDC1 3 ) δ 1.50 (t, 3H), 4.09 (s, 2H), 4.57 (q. 2H), 8.50 to 7.00 (m, 7H), 10.75 (s, 1H)
실시예 3Example 3
(발명화합물 9)(Invention Compound 9)
2-[N-(3-트리프로오로메칠)페닐아세트아미딜]티오-5-메칠벤즈이미다졸 2g을 50㎖의 디옥산에 녹인 후, 38%의 포름알데히드 용액 2㎖를 가하고 70℃에서 48시간 반응시킨 다음 용매를 감압증류하고, 물과 아세톤(1:2)비율로 용매를 가하여 강하게 교반하여 결정화시켜 발명화합물 9 1.5g을 70% 수율로 얻었다.After dissolving 2 g of 2- [N- (3-trifluoromethyl) phenylacetamidyl] thio-5-methylbenzimidazole in 50 ml of dioxane, 2 ml of a 38% formaldehyde solution was added and the mixture was dried at 70 캜. After reacting for 48 hours, the solvent was distilled under reduced pressure, and solvent was added at a ratio of water and acetone (1: 2), followed by strong stirring to crystallize to obtain 1.5 g of Inventive Compound 9 in 70% yield.
실시예 4Example 4
(발명화합물 10)(Invention Compound 10)
위의 실시예 3에서 합성한 발명화합물 9 1.5g과 DMAP 20㎖을 피리딘 5㎖에 녹인 다음 초산 무수물 1.5㎖을 0℃에서 적가한다. 상온에서 1시간 10분 반응후 물을 가하고 에칠아세테이트로 추출한 후 얻어진 잔유물을 실리카겔 관 크로마토 그래피로(메탄올 : 메칠렌크로라이드=1 : 10)분리정제후 1.2g의 발명화합물 10을 75% 수율로 얻었다. 얻어진 화합물을 아세토니트릴에서 재결정하여 0.2g의 순수한 발명화합물 10을 얻었다.1.5 g of the inventive compound 9 synthesized in Example 3 and 20 ml of DMAP were dissolved in 5 ml of pyridine, and 1.5 ml of acetic anhydride was added dropwise at 0 ° C. After the reaction at room temperature for 1 hour 10 minutes, water was added, extraction was performed with ethyl acetate, and the obtained residue was separated and purified by silica gel column chromatography (methanol: methylene chloride = 1: 10), and 1.2 g of Inventive Compound 10 was obtained in 75% yield. Got it. The obtained compound was recrystallized from acetonitrile to obtain 0.2 g of pure Inventive Compound 10.
실시예 5Example 5
(발명화합물 8)(Invention Compound 8)
위의 실시예 4에서 합성한 발명화합물 10 0.2g을 메칠렌클로라이드에 녹이고 -78℃로 냉각한다. 0.13g의 m-클로로퍼벤조산 메칠렌클로라이드 용액을 -78℃에서 적가 후 1시간 교반한 다음, 상온에서 2시간 더 교반한다. 5% NaHCO3용액으로 처리 후 유기층을 메칠렌클로라이드로 추출해 농축하여 얻어진 잔유물에 벤젠과 n-헥산용액으로 결정화하여 0.12g의 발명화합물 8을 57% 수율로 얻었다.0.2 g of the inventive compound 10 synthesized in Example 4 above was dissolved in methylene chloride and cooled to −78 ° C. 0.13 g of m-chloroperbenzoic acid methylene chloride solution is added dropwise at -78 ° C, and then stirred for 1 hour, followed by further stirring at room temperature for 2 hours. After treating with 5% NaHCO 3 solution, the organic layer was extracted with methylene chloride, concentrated, and the residue was crystallized with benzene and n-hexane solution to obtain 0.12 g of Inventive Compound 8 in 57% yield.
1H-NMR(200MHz, ppm, CDC13) :δ2.05(s, 3H), 4.55(d, 2H), 6.3(d, 1H), 6.5(d, 1H), 7.2∼7.8(m, 7H), 9.7(s, 1H) 1 H-NMR (200 MHz, ppm, CDC1 3 ): δ 2.05 (s, 3H), 4.55 (d, 2H), 6.3 (d, 1H), 6.5 (d, 1H), 7.2-7.8 (m, 7H) , 9.7 (s, 1H)
실시예 6Example 6
(발명화합물 6)(Invention Compound 6)
2-[N-(3-트리플로오로메칠)페닐아세트아미딜]티오벤즈이미다졸 0.74g과 K2CO30.3g을 15㎖ 아세톤에 녹인 후 에필브로모아세테이트 0.36g을 위용액에 가하여 상온에서 4시간 30분 반응 후 물 30㎖를 가해 생성된 고체 화합물 0.84g을 96%의 수율로 여과하여 얻는다.Dissolve 0.74 g of 2- [N- (3-trifluoromethyl) phenylacetamidyl] thiobenzimidazole and 0.3 g of K 2 CO 3 in 15 ml of acetone, and then add 0.36 g of epilbromoacetate to the gastric solution. After 4 hours and 30 minutes of reaction, 30 ml of water was added, and 0.84 g of the produced solid compound was obtained by filtration in a yield of 96%.
1H-NMR(200MHz, ppm, CDC13)δ1.2(t, 3H), 4.0(s, 2H), 4.3(q, 2H), 4.8(s, 2H), 7.2∼7.4(m, 5H), 7.8(d, 1H), 7.9(s, 1H), 11.6(s,NH) 1 H-NMR (200 MHz, ppm, CDC1 3 ) δ 1.2 (t, 3H), 4.0 (s, 2H), 4.3 (q, 2H), 4.8 (s, 2H), 7.2 to 7.4 (m, 5H), 7.8 (d, 1H), 7.9 (s, 1H), 11.6 (s, NH)
합성된 물질 1-에톡시카르보닐메칠-2-[N-(3-트리플로오로메칠)페닐아세트아미딜]티오벤즈이미다졸 0.84g을 메칠렌클로라이드 15㎖에 녹인 후 -35℃로 냉각한다. m-클로로퍼벤조산 0.48g을 메칠렌클로라이드 5㎖에 녹인 후 위 용액에 천천히 적가한다. 상온에서 12시간 반응 후 5% NaHCO3용액을 하하고 교반하여 메칠렌클로라이드로 추출하여 농축하고 잔유물에 에칠에테르를 가하여 결정화하여 0.4g의 발명화합물 6을 44%의 수율로 얻는다. (mp : 123∼124℃)Synthesized 0.84 g of 1-ethoxycarbonylmethyl-2- [N- (3-trifluoromethyl) phenylacetamidyl] thiobenzimidazole in 15 ml of methylene chloride was cooled to -35 ° C. . 0.48 g of m-chloroperbenzoic acid is dissolved in 5 ml of methylene chloride and slowly added dropwise to the stomach solution. After 12 hours of reaction at room temperature, 5% NaHCO 3 solution was added, stirred, extracted with methylene chloride, concentrated, and ethyl acetate was added to the residue to crystallize to obtain 0.4 g of Inventive Compound 6 in 44% yield. (mp: 123 ~ 124 ℃)
위의 실시예들을 이용하여 합성한 발명화합물을 표 1에 정리하였고, 얻어진 1H-NMR결과는 표 2에 정리하였다.Inventive compounds synthesized using the above examples are summarized in Table 1, and the obtained 1H-NMR results are summarized in Table 2.
실시예 7Example 7
H /K -ATP 효소저해효과H / K -ATP enzyme inhibitory effect
포르테(Forte)등의 방법(J. Applied Physiol., 32, 714-717(1972)]에 따라, 토끼 위점막의 위산분비 세포를 분리하고, 이 세포를 불연속 밀도구배의 피콜(Ficoll)내에서 원심분리하여 H /K -ATP 효소를 포함하는 소포를 제조한다. 이 효소를 각 시험화합물 2×10 M및 이미다졸 완층물(pH 6)5mM을 포함하는 용액 0.5㎖내에서 실온에서 25분간 배양한 후, 이 혼합물을 37℃까지 가열하고 이 온도에서 5분간 정치시킨다. 염화마그네슘 4mM, 이미다졸 완충물 (pH 7.4) 80mM, 염화칼륨 20mM 및 ATP 4mM을 함유하는 용액 0.5㎖를 혼합물에 첨가한다. 결과 생성된 혼합물 37℃에서 15분간 가열하고 24% 삼염화초산 용액 1㎖를 첨가하여 반응을 종결시킨다. 분리된 무기인은 Fiske Subbarow법 [J.Bolo, Chem, 66, 375-440(1925)]에 따라 측정하여 효소활성도를 계산하였다. 발명화합물에 대한 in vitro 효소활성결과를 표 3.에 정리하였다.According to the method of Forte et al. (J. Applied Physiol., 32, 714-717 (1972)), gastric secretion cells of rabbit gastric mucosa are isolated, and the cells are separated in Ficoll of discrete density gradients. Centrifuge H / K Prepare vesicles containing the ATP enzyme. This enzyme was added to each test compound 2 × 10 After incubating for 25 minutes at room temperature in 0.5 ml of a solution containing M and imidazole complete (pH 6) 5 mM, the mixture is heated to 37 ° C. and left at this temperature for 5 minutes. 0.5 ml of a solution containing 4 mM magnesium chloride, 80 mM imidazole buffer (pH 7.4), 20 mM potassium chloride and 4 mM ATP is added to the mixture. The resulting mixture was heated at 37 ° C. for 15 minutes and 1 ml of 24% trichloroacetic acid solution was added to terminate the reaction. The isolated inorganic phosphorus was measured according to Fiske Subbarow method [J.Bolo, Chem, 66, 375-440 (1925)] to calculate the enzyme activity. In vitro enzyme activity results for the compounds of the present invention are summarized in Table 3.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019930020833A KR970001477B1 (en) | 1993-10-08 | 1993-10-08 | N-substituted benzimidazole derivatives with amide groups |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019930020833A KR970001477B1 (en) | 1993-10-08 | 1993-10-08 | N-substituted benzimidazole derivatives with amide groups |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR950011417A KR950011417A (en) | 1995-05-15 |
| KR970001477B1 true KR970001477B1 (en) | 1997-02-06 |
Family
ID=19365477
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019930020833A KR970001477B1 (en) | 1993-10-08 | 1993-10-08 | N-substituted benzimidazole derivatives with amide groups |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR970001477B1 (en) |
-
1993
- 1993-10-08 KR KR1019930020833A patent/KR970001477B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR950011417A (en) | 1995-05-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5021433A (en) | Novel pharmacological compounds | |
| CA2289409C (en) | Sulfoxide compounds and acetone complexes, and a process for producing the same | |
| HU195210B (en) | Process for producing pyridine derivatives and pharmaceutical preparations comprising these compounds as active substance | |
| EP1560826B1 (en) | Pyridopyrimidinone compounds, method for production thereof and medicaments comprising the same | |
| SU1757464A3 (en) | Method for preparation of amino derivatives of benzoxazolone | |
| FR2705095A1 (en) | Novel substituted indoles, process for their preparation and pharmaceutical compositions containing them | |
| KR0142815B1 (en) | Novel 5-pyrrolyl-o-halogeno-2-pyridyl methylsulfinylbenzimidazole derivatlves | |
| EP0541807A1 (en) | Novel benzopyran derivative | |
| US4806534A (en) | Therapeutically active flavonyl-1,4-dihydrophyridines | |
| AU2002358535B2 (en) | Use of pyridine-2,4-dicarboxylic acid diamides and of pyrimidine-4,6-dicarboxylic acid diamides for selective collagenase inhibition | |
| HRP980115A2 (en) | Process for the preparation of 2-// (2-pyridinyl)-methyl/-sulfynyl/-1h-benzimidazoles and novel compounds of use for such purpose | |
| FI81339C (en) | FOERFARANDE FOER FRAMSTAELLNING AV PYRROLIDINODERIVAT, MELLANPRODUKT OCH DESS FRAMSTAELLNINGSFOERFARANDE. | |
| KR970001477B1 (en) | N-substituted benzimidazole derivatives with amide groups | |
| US5294629A (en) | Benzothiazole and benzimidazole derivatives and antiulcer agent containing the same | |
| EP0115979A1 (en) | Derivatives of 1H,3H-pyrrolo(1,2-c)thiazole, their preparation and pharmaceuticals containing them | |
| FI64149B (en) | REFERENCE TO ANYHYPERTENSIVE PYRIDAZINYLHYDRAZONER | |
| EP2022789A1 (en) | Process for the preparation of a gastric acid secretion inhibitor | |
| KR970001476B1 (en) | New benzimidazole derivatives with amide groups | |
| EP0124384A1 (en) | Derivatives of orthocondensed pyrrole useful for the preparation of medicines and their preparation | |
| JPH02169572A (en) | Dihydropyridineamide and its physiologically | |
| US5091403A (en) | Sulfinyl imidazole derivatives and antiulcer agents containing the same | |
| JPH0140033B2 (en) | ||
| KR950014792B1 (en) | Benzimidazole derivatives and process for their preparations | |
| IE903385A1 (en) | New process for the synthesis of oxazolopyridine derivatives | |
| KR970011576B1 (en) | Benzimidazole derivatives having hetero aromatic amids |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| G160 | Decision to publish patent application | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| LAPS | Lapse due to unpaid annual fee |