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KR0154281B1 - Benzimidazole derivatives containing fused pyridines - Google Patents

Benzimidazole derivatives containing fused pyridines

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Publication number
KR0154281B1
KR0154281B1 KR1019950016621A KR19950016621A KR0154281B1 KR 0154281 B1 KR0154281 B1 KR 0154281B1 KR 1019950016621 A KR1019950016621 A KR 1019950016621A KR 19950016621 A KR19950016621 A KR 19950016621A KR 0154281 B1 KR0154281 B1 KR 0154281B1
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South Korea
Prior art keywords
represented
pyridine
hydrogen
group
benzimidazole
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KR1019950016621A
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Korean (ko)
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KR970001357A (en
Inventor
염을균
최중권
조성윤
강승규
김성수
박경호
황기준
천혜경
김효정
양성일
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강박광
재단법인한국화학연구소
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Priority to KR1019950016621A priority Critical patent/KR0154281B1/en
Priority to PCT/KR1996/000091 priority patent/WO1997000875A1/en
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Publication of KR0154281B1 publication Critical patent/KR0154281B1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems
    • C07D491/044Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems
    • C07D491/044Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

본 발명은 포유동물의 위산분비 억제능력을 보유하고 있어 항궤양제의 유효성분으로서 매우 유용한 다음 구조식(I)로 표시되는 접합고리 피리딘을 함유한 벤즈이미다졸 유도체에 관한 것이다.The present invention relates to a benzimidazole derivative containing a conjugated ring pyridine represented by the following structural formula (I) which possesses the ability to inhibit gastric acid secretion in a mammal and is very useful as an active ingredient of an anti-ulcer agent.

상기식에서,In the above formula,

R은 수소원자, 할로겐원자, C1∼C3의 알콕시, C1∼C3의 할로알콕시 또는 C1∼C3의 할로알킬기이고;R is a hydrogen atom, a halogen atom, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy or C 1 -C 3 haloalkyl group;

R1, R2, R3, R4, R5및 R6은 서로 같거나 다른 것으로서 수소원자, 할로겐원자 또는 C1∼C3의 알킬기를 나타내되 다만, 모두 수소원자인 경우는 제외한다.ROne, R2, R3, R4, R5And R6Are the same as or different from each other and are hydrogen, halogen or COne-C3Alkyl group is represented except all hydrogen atoms.

Description

접합고리 피리딘을 함유한 벤즈이미다졸 유도체Benzimidazole derivatives containing conjugated pyridine

본 발명은 포유동물의 위산분비 억제능력을 보유하고 있어 항궤양제의 유효성분으로서 매우 유용한 다음 구조식(I)로 표시되는 접합고리 피리딘을 함유한 밴즈이미다졸 유도체에 관한 것이다.The present invention relates to a vanzimidazole derivative containing a conjugated ring pyridine represented by the following structural formula (I), which possesses the ability to inhibit gastric acid secretion of a mammal and is very useful as an active ingredient of an anti-ulcer agent.

상기식에서,In the above formula,

R은 수소원자, 할로겐원자, C1∼C3의 알콕시, C1∼C3의 할로알콕시 또는 C1∼ C3의 할로알킬기이고;R is a hydrogen atom, a halogen atom, C 1 ~C 3 alkoxy, C 1 ~C 3 haloalkoxy or a C 1 ~ C 3 of the haloalkyl group;

R1, R2, R3, R4, R5및 R6은 서로 같거나 다른 것으로서 수소원자, 할로겐원자 또는 C1∼C3의 알킬기를 나타내되 다만, 모두 수소원자인 경우는 제외한다.ROne, R2, R3, R4, R5And R6Are the same as or different from each other and are hydrogen, halogen or COne-C3Alkyl group is represented except all hydrogen atoms.

피리딘을 함유한 벤즈이미다졸 유도체들은 위산분비 억제능력이 탁월하여 위, 십이지장궤양의 치료약물로서 잘 알려져 있고, 또한 위산분비 억제제로서 개발되어 상품화되어 있는데, 예를들면 오메프라졸의 피리딘기에 새로운 치환체가 도입되어 우수한 위산분비 억제효과를 나타내는 란소프라졸, 펜토프라졸 등의 항궤양 치료제가 시판되고 있다. 그리고 이들 유도체 및 그의 제조방법에 대해서는 미합중국특허 제5,019,584호, 유럽특허 제130,729호, 유럽특허 제208,422호와 영국특허 제1,525,958호 등에 기재되어 있다. 그러나 오메프라졸(Omeprazole)로 대표되는 피리딘을 함유한 벤즈이미다졸 유도체는 위의 위산분비 억제에 탁월한 약효를 보이지만, 약효가 장시간 지속되어 체내에 약물의 축적과 반복 투여에 의한 가스트린(gastrin)의 농도상승을 초래하는 등의 부작용을 초래하고 있다.Benzimidazole derivatives containing pyridine are well known as therapeutic drugs for gastric and duodenal ulcers because of their excellent ability to inhibit gastric acid secretion, and have been developed and commercialized as gastric acid secretion inhibitors. For example, new substituents are introduced into the pyridine group of omeprazole. Anti-ulcer drugs such as lansoprazole and pentoprazole, which exhibit excellent gastric acid secretion inhibitory effects, are commercially available. These derivatives and their preparation are described in US Pat. No. 5,019,584, EP 130,729, EP 208,422, UK 1,525,958 and the like. However, benzimidazole derivatives containing pyridine, which is represented by omeprazole, have excellent efficacy in suppressing gastric acid secretion, but the drug lasts for a long time and increases the concentration of gastrin by accumulation of drugs in the body and repeated administration. It causes side effects such as causing.

이에 본 발명에서는 벤즈이미다졸 유도체 특히 오메프라졸(Omeprazole)의 산 불안정성 등의 문제를 극복하고자 연구 노력한 결과, 기존의 오메프라졸과 대등하거나 우수한 위산분비억제 효과를 갖는 신규 접합고리 피리딘을 함유한 벤즈이미다졸 유도체를 개발하므로써 본 발명을 완성하였다.Accordingly, in the present invention, as a result of research efforts to overcome problems such as acid instability of benzimidazole derivatives, in particular omeprazole, benzimidazole derivatives containing a novel conjugated pyridine having an equivalent or superior gastric acid secretion effect to existing omeprazole By completing the present invention, the present invention has been completed.

본 발명은 산소를 포함하는 다양한 고리와 접합된 피리딘 유도체에 2-머르캅토벤즈이미다졸 유도체가 결합된 구조를 나타내고, 오메프라졸의 약효와 유사하거나 우수한 위산분비 억제효과를 갖는 상기 구조식(I)로 표시되는 접합고리 피리딘을 함유하는 벤즈이미다졸 유도체를 제공하는데 그 목적이 있다.The present invention shows a structure in which a 2-mercaptobenzimidazole derivative is bonded to a pyridine derivative conjugated with various rings containing oxygen, and is represented by the above structural formula (I) having a gastric acid secretion inhibitory effect similar to or superior to that of omeprazole It is an object to provide a benzimidazole derivative containing a conjugated ring pyridine.

이하, 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.

본 발명은 위산분비 억제효능을 갖는 다음 구조식(I)로 표시되는 접합고리 피리딘을 함유한 벤즈이미다졸 유도체를 그 특징으로 한다.The present invention is characterized by a benzimidazole derivative containing a conjugated ring pyridine represented by the following structural formula (I) having an inhibitory effect on gastric acid secretion.

상기식에서,In the above formula,

R과 X는 상기에서 정의한 바와같다.R and X are as defined above.

이와같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.

본 발명은 위산분비 억제효능이 우수하여 위궤양 치료제의 유효성분으로서 유용한 상기 구조식(I)로 표시되는 피라졸을 함유한 벤즈이미다졸 유도체에 관한 것으로서, 이의 제조과정은 다음 반응식으로 나타낼 수 있다.The present invention relates to a benzimidazole derivative containing pyrazole represented by Structural Formula (I), which is useful as an active ingredient of gastric ulcer therapeutic agent because of excellent gastric acid secretion inhibitory effect, and its preparation process can be represented by the following scheme.

상기식에서,In the above formula,

R과 X는 상기에서 정의한 바와같다.R and X are as defined above.

먼저, 상기 구조식(II)로 표시되는 접합고리 피리딘 유도체를 통상적인 에스테르화, 환원반응 및 염소화 반응(Comprehensive Organic Transformations, 1989, VCH Publisher, Inc., R. C. Larock)을 연속적으로 시행하여 상기 구조식(III)으로 표시되는 화합물을 제조한다.First, the conjugated ring pyridine derivative represented by Structural Formula (II) is subjected to conventional esterification, reduction and chlorination (Comprehensive Organic Transformations, 1989, VCH Publisher, Inc., RC Larock) to continuously perform the structural formula (III). To prepare a compound represented by).

그리고, 상기 구조식(III)으로 표시되는 화합물을 유기용매 및 염기존재하에 상기 구조식(IV)로 표시되는 2-머르캅토벤즈이미다졸 1∼2당량과 반응시켜 상기 구조식(V)로 표시되는 화합물을 합성한다. 이때, 유기용매로는 테트라히드로퓨란, 디클로로메탄, 에탄올, 이소프로판올 등을 사용하며, 염기로는 수산화나트륨, 수산화칼륨, 수소화나트륨, 메톡시화 나트륨, 에톡시화 나트륨 등을 1∼3당량 사용한다.The compound represented by the above formula (V) is reacted with 1-2 equivalents of 2-mercaptobenzimidazole represented by the above formula (IV) in the presence of an organic solvent and a base. Synthesize At this time, tetrahydrofuran, dichloromethane, ethanol, isopropanol, etc. are used as an organic solvent, and 1-3 equivalents of sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, sodium ethoxylated, etc. are used as a base.

그리고 나서, 상기 구조식(V)로 표시되는 화합물은 일반적인 산화제 예를들면 메타클로로과벤조산, 과산화수소 또는 옥손(Oxone) 등으로 산화시켜 본 발명의 목적화합물인 상기 구조식(I)로 표시되는 접합고리 피리딘을 함유한 벤즈이미다졸 유도체를 제조한다.Then, the compound represented by the structural formula (V) is oxidized with a common oxidizing agent, for example, metachloroperbenzoic acid, hydrogen peroxide or oxone (Oxone), etc. A benzimidazole derivative containing is prepared.

또한, 본 발명에 있어서 출발물질로 사용된 상기 구조식(II)로 표시되는 접합고리 피리딘 유도체는 공지화합물로서 공지의 제조방법에 의해 쉽게 제조하여 사용할 수 있다. 예를들면, 5,6각-접합고리 피리딘 유도체(II)는 피리딘 유도체의 팔라듐(Pd) 촉매를 이용한 고리화 반응에 의해 쉽게 제조할 수 있고[Palladium Reagents in Organic Synthesis, Academic Press, 1985, R.F. Heck], 6각-접합고리 피리딘 유도체(II)는 4-히드록시피리딘을 출발물질로 하여 알킬화반응, 고리화반응 및 시아노기의 도입반응 등의 기존에 알려진 제조방법에 의해 쉽게 제조할 수 있다[Synthetic Communications, 1988, 18, 1111 ; Chem. Pharm. Bull., 1990, 38, 1775 ; J. Heterocyclic Chem., 1993, 30, 631].In addition, the conjugated ring pyridine derivative represented by the above formula (II) used as a starting material in the present invention can be easily prepared and used by a known production method as a known compound. For example, 5, hexagon-conjugated pyridine derivatives (II) can be readily prepared by cyclization reactions using palladium (Pd) catalysts of pyridine derivatives [Palladium Reagents in Organic Synthesis, Academic Press, 1985, R.F. Heck], hexagonal conjugated pyridine derivative (II) can be easily prepared by conventionally known production methods such as alkylation reaction, cyclization reaction and cyano group introduction reaction using 4-hydroxypyridine as a starting material. Synthetic Communications, 1988, 18, 1111; Chem. Pharm. Bull., 1990, 38, 1775; J. Heterocyclic Chem., 1993, 30, 631].

한편, 5 또는 6각-접합고리 피리딘 유도체(II)는 클로로피리딘을 출발물질로 하여 요드화반응, 알킬치환반응, 고리화반응 및 시아노기의 도입 등의 기존에 알려진 방법에 의하여 쉽게 합성할 수 있다[Heterocycles, 1993, 35, 151 ; J. Org. Chem., 1988, 53, 2740 ; Tetrahedron Lett., 1987, 44, 5291 ; Heterocycles, 1989, 29, 1013 ; J. Heterocyclic Chem., 1993, 30, 631].On the other hand, 5 or 6-membered conjugated pyridine derivative (II) can be easily synthesized by known methods such as iodide, alkyl substitution, cyclization and introduction of cyano groups using chloropyridine as a starting material. Heterocycles, 1993, 35, 151; J. Org. Chem., 1988, 53, 2740; Tetrahedron Lett., 1987, 44, 5291; Heterocycles, 1989, 29, 1013; J. Heterocyclic Chem., 1993, 30, 631].

본 발명에 따른 상기 구조식(I)로 표시되는 접합고리 피리딘을 함유한 벤즈이미다졸 유도체의 대표적인 예는 다음 표 1에 나타내었다.Representative examples of the benzimidazole derivatives containing the conjugated ring pyridine represented by the above formula (I) according to the present invention are shown in Table 1 below.

이와같은 본 발명을 실시예에 의거하여 상세히 설명하면 다음과 같은 바, 다음의 실시예와 유사한 제조방법에 본 발명에 따른 구조식(I)로 표시되는 화합물에 대한 대표적인 제조방법으로서 본 발명이 이에 한정되는 것은 아니다.When the present invention is described in detail based on the Examples as follows, the present invention is limited to the following as a typical preparation method for the compound represented by the formula (I) according to the present invention in the preparation method similar to the following examples It doesn't happen.

[실시예 1]Example 1

5-카르보에톡시-2,2-디메틸-2H-피라노[3,2-c]피리딘의 제조방법Method for preparing 5-carboethoxy-2,2-dimethyl-2H-pyrano [3,2-c] pyridine

5-시아노-2,2-디메틸-2H-피라노[3,2-c]피리딘(1.20g, 6.42mmol)을 에탄올(100㎖)에 녹이고 여기에 에톡시화 나트륨/에탄올(0.89mmol, 6.82mg-atom, 7.86㎖)을 가하여 상온에서 하룻밤동안 교반하였다. 6N HCl(7㎖)를 0℃에서 서서히 가하고 12시간 교반한 다음, 감압농축시켰다. 농축액에 디클로로메탄(30㎖)과 물(10㎖)을 가하고 물층은 포화 NaHCO용액으로 중화시킨 다음, 에틸아세테이트(30㎖)를 가하여 추출하였다. 유기층은 무수 황산마그네슘으로 건조하고 농축시킨 다음 에틸아세테이트-헥산을 용출용매로 하여 컬럼 크로마토그래피로 분리한 결과 목적화합물 0.80g(3.61mmol, 수율 56%)을 유상(oil)으로 얻었다.5-Cyano-2,2-dimethyl-2H-pyrano [3,2-c] pyridine (1.20 g, 6.42 mmol) was dissolved in ethanol (100 mL) and sodium ethoxylated / ethanol (0.89 mmol, 6.82 mg-atom, 7.86 ml) was added and stirred overnight at room temperature. 6N HCl (7 mL) was added slowly at 0 ° C., stirred for 12 h, and then concentrated under reduced pressure. Dichloromethane (30 mL) and water (10 mL) were added to the concentrate, and the water layer was neutralized with saturated NaHCO solution, and extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous magnesium sulfate, concentrated, and separated by column chromatography using ethyl acetate-hexane as an eluting solvent to obtain 0.80 g (3.61 mmol, 56% yield) of the target compound as an oil.

[실시예 2]Example 2

5-히드록시메틸-2,2-디메틸-2H-피라노[3,2-c]피리딘의 제조방법Method for preparing 5-hydroxymethyl-2,2-dimethyl-2H-pyrano [3,2-c] pyridine

상기 실시예 1에서 제조한 5-카르보에톡시-2,2-디메틸-2H-피라노[3,2-c]피리딘(1.49g, 6.59mmol)을 에틸에테르(10㎖)에 녹인다음, 이 용액은 LiAlH4(0.247g, 6.60mmol)가 디클로로메탄(20㎖)에 녹아있는 용액에 0℃에서 가하였다. 0℃에서 4시간 교반시킨 후, 반응이 종료되면 물(1㎖)을 가하고 10% NaOH(1㎖)를 가하여 과량의 LiAlH4를 제거하고 여과하였다.5-Carboethoxy-2,2-dimethyl-2H-pyrano [3,2-c] pyridine (1.49 g, 6.59 mmol) prepared in Example 1 was dissolved in ethyl ether (10 mL), This solution was added at 0 ° C. to a solution in which LiAlH 4 (0.247 g, 6.60 mmol) was dissolved in dichloromethane (20 mL). After stirring at 0 ° C. for 4 hours, when the reaction was completed, water (1 mL) was added and 10% NaOH (1 mL) was added to remove excess LiAlH 4 and filtered.

유기층은 물로 세척한 후, 무수 황산마그네슘으로 건조시키고 감압증발시킨 다음 디클로로메탄-메탄올(10 : 1)을 용출용매로 하여 컬럼 크로마토그래피로 분리한 결과 목적화합물 0.95g(5.33mmol, 수율 80.4%)을 유상(oil)으로 얻었다.The organic layer was washed with water, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and separated by column chromatography using dichloromethane-methanol (10: 1) as an eluting solvent. The target compound was 0.95 g (5.33 mmol, 80.4% yield). Was obtained in an oil phase.

[실시예 3]Example 3

5-클로로메틸-2,2-디메틸-2H-피라노[3,2-c]피리딘의 제조방법Method for preparing 5-chloromethyl-2,2-dimethyl-2H-pyrano [3,2-c] pyridine

상기 실시예 2에서 제조한 5-히드록시메틸-2,2-디메틸-2H-피라노[3,2-c]피리딘(0.95g, 5mmol)을 디클로로메탄(20㎖)에 녹인다음, 이 용액에 SOCl2(0.387㎖, 5.31mmol)을 0℃에서 가하였다. 0℃에서 30분 교반시킨 후, 상온에서 4시간 교반하였다. 반응이 종료되면 포화 NaHCO3용액으로 중화시키고, 에틸에테르로 추출하여 유기층을 취한다. 유기층은 무수 황산마그네슘으로 건조시키고, 감압증발시킨 다음 에틸아세테이트-헥산을 용출용매로 하여 컬럼 크로마토그래피로 분리한 결과 목적화합물 0.78g(3.33mmol, 수율 63%)을 얻었다.5-hydroxymethyl-2,2-dimethyl-2H-pyrano [3,2-c] pyridine (0.95 g, 5 mmol) prepared in Example 2 was dissolved in dichloromethane (20 mL). To SOCl 2 (0.387 mL, 5.31 mmol) was added at 0 ° C. After 30 minutes of stirring at 0 ° C., the mixture was stirred at room temperature for 4 hours. After the reaction was completed, neutralized with saturated NaHCO 3 solution, extracted with ethyl ether to take an organic layer. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and separated by column chromatography using ethyl acetate-hexane as an eluent to obtain 0.78 g (3.33 mmol, 63% yield) of the title compound.

[실시예 4]Example 4

5-(4-메톡시-1H-벤즈이미다졸-2-티오메틸)-2,2-디메틸-2H-피라노[3,2-c]피리딘의 제조Preparation of 5- (4-methoxy-1H-benzimidazole-2-thiomethyl) -2,2-dimethyl-2H-pyrano [3,2-c] pyridine

2-머르캅토-4-메톡시벤즈이미다졸(0.14g, 0.81mmol)을 이소프로판올(20㎖)에 녹인다음 10분간 교반시키고, 여기에 수산화나트륨(0.04g, 0.92mmol)을 가하고 30분동안 교반하였다. 그리고 여기에 상기 실시예 3에서 제조한 5-클로로메틸-2,2-디메틸-2H-피라노[3,2-c]피리딘(0.2g, 0.81mmol)을 이소프로판올(10㎖)에 녹인 용액을 상온에서 가한다음 12시간 교반하였다. 반응이 종료되면 반응용매를 감압하에서 제거하고 에틸아세테이트(30㎖)와 10% 수산화나트륨 용액(20㎖)을 가하여 유기층으로 추출시키고, 무수 황산마그네슘으로 건조시킨 다음 감압농축시킨 결과 목적화합물 0.255g(수율 75%)을 얻었다.2-mercapto-4-methoxybenzimidazole (0.14 g, 0.81 mmol) was dissolved in isopropanol (20 mL) and stirred for 10 minutes, and sodium hydroxide (0.04 g, 0.92 mmol) was added thereto and stirred for 30 minutes. It was. And a solution of 5-chloromethyl-2,2-dimethyl-2H-pyrano [3,2-c] pyridine (0.2 g, 0.81 mmol) prepared in Example 3 in isopropanol (10 mL) was prepared. It was added at room temperature and stirred for 12 hours. After the reaction was completed, the reaction solvent was removed under reduced pressure, ethyl acetate (30 ml) and 10% sodium hydroxide solution (20 ml) were added thereto, extracted with an organic layer, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Yield 75%).

[실시예 5]Example 5

5-(4-메톡시-1H-벤즈이미다졸-2-슬피닐메틸)-2,2-디메틸-2H-피라노[3,2-c]피리딘(화합물번호 1)의 제조Preparation of 5- (4-methoxy-1H-benzimidazole-2-sulfinylmethyl) -2,2-dimethyl-2H-pyrano [3,2-c] pyridine (Compound No. 1)

상기 실시예 4에서 제조한 5-(4-메톡시-1H-벤즈이미다졸-2-티오메틸)-2,2-디메틸-2H-피라노[3,2-c]피리딘(0.173g, 0.488mmol)을 디클로로메탄(20㎖)에 녹이고, -70℃에서 메타클로로과벤조산(0.093g, 0.553mmol)을 가한다음, 1시간동안 교반시킨 후 반응이 종혈되면 포화수산화나트륨(15㎖)을 가하고 서서히 상온으로 승온시켰다. 유기층은 과포화 중탄산나트륨(20㎖ ×2)로 씻어주고 유기층을 농축시켜 목적화합물 0.145g(0.392mmol, 수율 80.3%)을 얻었다.5- (4-methoxy-1H-benzimidazole-2-thiomethyl) -2,2-dimethyl-2H-pyrano [3,2-c] pyridine (0.173 g, 0.488) prepared in Example 4 mmol) was dissolved in dichloromethane (20 mL), and metachloroperbenzoic acid (0.093 g, 0.553 mmol) was added at -70 ° C. After stirring for 1 hour, when the reaction was completed, saturated sodium hydroxide (15 mL) was added slowly. The temperature was raised to room temperature. The organic layer was washed with supersaturated sodium bicarbonate (20 mL × 2), and the organic layer was concentrated to give 0.145 g (0.392 mmol, yield 80.3%) of the target compound.

상기 실시예에서는 본 발명의 접합고리 피리딘을 함유한 벤즈이미다졸 유도체중 화합물번호 1인 화합물의 제조방법만을 기재하였지만, 상기 표1에 제시되어 있는 나머지 화합물은 당업자에 의해 상기 실시예로부터 쉽게 제조될 수 있는 바, 본 발명에 따른 접합고리 피리딘을 함유한 벤즈이미다졸 유도체의 제조수율, 녹는점(mp) 및 NMR(200 ㎒) 결과는 다음 표 2에 나타내었다.In the above examples, only the method for preparing the compound of Compound No. 1 in the benzimidazole derivative containing the conjugated ring pyridine of the present invention is described, but the remaining compounds shown in Table 1 above can be easily prepared from the above examples by those skilled in the art. As can be seen, the production yield, melting point (mp) and NMR (200 MHz) of the benzimidazole derivative containing the conjugated ring pyridine according to the present invention are shown in Table 2 below.

또한, 본 발명에 따른 상기 구조식(I)로 표시되는 화합물 제조에 있어서 중간체화합물로서 제조되는 다음 구조식(V)로 표시되는 화합물 역시 신규 화합물인 바, 상기 실시예와 유사한 제조방법에 의해 제조된 구조식(V)로 표시되는 몇몇 화합물들의 제조수율, NMR(200 ㎒) 및 질량분석(MS) 결과는 다음 표 3에 나타내었다.In addition, in the preparation of the compound represented by the structural formula (I) according to the present invention, the compound represented by the following structural formula (V), which is prepared as an intermediate compound, is also a novel compound. The production yield, NMR (200 MHz) and mass spectrometry (MS) results of some compounds represented by (V) are shown in Table 3 below.

본 발명에 따른 상기 구조식(I)로 표시되는 접합고리 피리딘을 함유한 벤즈이미다졸 유도체 및 이의 약제학적 허용가능한 염(예를들면 산부가염 또는 나트륨염)은 위산분비 억제능력을 보유하고 있어 위궤양 치료제로서 매우 유용하다.Benzimidazole derivatives containing the conjugated ring pyridine represented by the above formula (I) and pharmaceutically acceptable salts thereof (for example, acid addition salts or sodium salts) according to the present invention have gastric acid secretion inhibitory ability to treat gastric ulcers Very useful as

따라서, 본 발명에서는 상기 신규 접합고리 피리딘을 함유한 벤즈이미다졸 유도체를 유효성분으로 하는 약제조성물을 포함하는 바, 이들 약제조성물은 상기 구조식(I)의 화합물에 통상의 약제학적 수용 가능한 담체, 보강제 및 부형제를 첨가하여 경구투여 또는 비경구투여 될 수 있다.Therefore, the present invention includes a pharmaceutical composition containing the novel conjugated ring pyridine-containing benzimidazole derivative as an active ingredient, and these pharmaceutical compositions are conventionally pharmaceutically acceptable carriers and adjuvant to the compound of formula (I). And oral or parenteral administration with the addition of excipients.

상기 구조식(I)로 표시되는 화합물을 유효성분으로 하는 약제조성물은 경구투여용 제형 예를들면 정제 트로케제(troches), 로젠지(lozenge), 수용성 또는 유성현탁액, 조제분말 또는 과립, 에멀젼, 하드 또는 소프트 캡슐, 시럽 또는 엘릭시르제(elixirs)로 제제된다. 정제 및 캡슐 등의 제형으로 제제하기 위해 락토오스, 사카로오스, 솔비톨, 만니톨, 전분, 아밀로펙틴, 셀룰로오스 또는 젤라틴과 같은 결합제 ; 디칼슘 포스페이트와 같은 부형제 ; 옥수수전분 또는 고구마전분과 같은 붕괴제 ; 스테아르산 마그네슘, 스테아르산 칼슘, 스테아릴푸마르산 나트륨 또는 폴리에틸렌글리콜왁스와 같은 윤활유가 함유된다. 캡슐제형의 경우는 상기에서 언급한 물질이외에도 지방유와 같은 액체담체를 함유한다.Pharmaceutical compositions comprising the compound represented by the above formula (I) as an active ingredient may be formulated for oral administration such as tablet troches, lozenges, water-soluble or oily suspensions, prepared powders or granules, emulsions, hard Or in soft capsules, syrups or elixirs. Binders such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin for preparation in formulations such as tablets and capsules; Excipients such as dicalcium phosphate; Disintegrants such as corn starch or sweet potato starch; Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate or polyethylene glycol wax. In the case of capsule formulation, in addition to the above-mentioned substances, it contains a liquid carrier such as fatty oil.

또한, 상기 구조식(I)로 표시되는 화합물을 유효성분으로 하여 비경구투여할 수 있으며, 비경구투여는 피하주사, 정맥주사, 근육내주사 또는 흉부내주사 주입방식에 의한다. 비경구투여용 제형으로 제제화하기 위해서는 상기 구조식(I)의 화합물을 안정제 또는 완충제와 함께 물에서 혼합하여 용액 또는 현탁액으로 제조하고 이를 앰플 또는 바이알의 단위투여형으로 제제한다.In addition, the compound represented by the formula (I) can be administered parenterally as an active ingredient, parenteral administration is by the injection method of subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. To formulate into a parenteral dosage form, the compound of formula (I) is mixed in water with a stabilizer or buffer to prepare a solution or suspension, which is formulated in unit dosage form of ampoules or vials.

구조식(I)로 표시되는 화합물의 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환정도 등에 따라서 달라질 수 있으며, 일반적으로 성인남자를 기준으로 했을때 1일 투여량은 15∼25mg이 바람직하다.The dosage of the compound represented by Structural Formula (I) may vary depending on the patient's age, weight, sex, dosage form, health condition and degree of disease. In general, the daily dosage of 15 to 15 adult males 25 mg is preferred.

[시럽제][Syrup]

유효성분 2%(중량/부피)를 함유하는 시럽을 다음과 같은 성분으로 제조하였다.A syrup containing 2% of active ingredient (weight / volume) was prepared by the following ingredients.

당, 사카린, 부가염들은 온수 80g에 용해시켰다. 이 용액을 냉각시킨 후, 여기에 글리세린, 사카린, 향미료, 에탄올, 소르브산 및 물로 이루어진 용액을 제조하여 병에 넣었다. 이 혼합물에 물을 첨가하여 100㎖가 되게 하였다. 상기 부가염은 또 다른 염으로 대치시킬 수 있다.Sugars, saccharin and addition salts were dissolved in 80 g of warm water. After cooling the solution, a solution consisting of glycerin, saccharin, spices, ethanol, sorbic acid and water was prepared and placed in a bottle. Water was added to this mixture to 100 ml. The addition salt can be replaced with another salt.

[정제][refine]

유효성분 15mg이 함유된 정제는 다음과 같은 방법으로 제조하였다.A tablet containing 15 mg of active ingredient was prepared by the following method.

5-(4-메톡시-1H-벤즈이미다졸-2-술피닐메틸)-2,2-디메틸-2H-피라노[3,2-c]피리딘·HCl 250g을 락토오스 175.9g, 감자전분 180g 및 콜로이드성 규산 32g과 혼합하였다. 이 혼합물에 10% 젤라틴 용액을 첨가시킨 후, 분쇄해서 14 메시체를 통과시켰다. 이것은 건조시키고, 여기에 감자전분 160g, 활석 50g 및 스테아린산 마그네슘 5g을 첨가해서 얻은 혼합물을 정제로 만들었다.250 g of 5- (4-methoxy-1H-benzimidazole-2-sulfinylmethyl) -2,2-dimethyl-2H-pyrano [3,2-c] pyridineHCl, 175.9 g of lactose, 180 g of potato starch And 32 g of colloidal silicic acid. 10% gelatin solution was added to the mixture, which was then ground to pass 14 meshes. It was dried, and the mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into a tablet.

[주사액제][Injection amount system]

5-(4-메톡시-1H-벤즈이미다졸-2-술피닐메틸)-2,2-디메틸-2H-피라노[3,2-c]피리딘·HCl 1g, 염화나트륨 0.6g 및 아스코르브산 0.1g을 증류수에 용해시켜서 100㎖를 얻었다. 이 용액은 유효성분 10mg을 함유하고 있으며, 이 용액을 병에 넣고, 20℃에서 30분간 가열하여서 멸균시켰다.5- (4-methoxy-1H-benzimidazole-2-sulfinylmethyl) -2,2-dimethyl-2H-pyrano [3,2-c] pyridineHCl 1g, sodium chloride 0.6g and ascorbic acid 0.1 g was dissolved in distilled water to give 100 ml. This solution contains 10 mg of the active ingredient, which is placed in a bottle and sterilized by heating at 20 ° C. for 30 minutes.

[약리활성 검색법][Pharmacological activity search method]

H+/K+-ATPase 효소원의 제조Preparation of H + / K + -ATPase Enzyme Source

뉴질랜드 화이트계 웅성토끼(2∼3kg)를 두부강타법으로 치사시킨뒤, 위를 척출하여 내용물을 제거하고 위내벽을 생리식염수로 씻었다. 슬라이드 글라스로 위내벽의 벽세포를 긁은 다음, 슈크로오스 완충액(슈크로오스 250mM, HEPES 2mM, MgCl22mM, 40mM 트리염산 완충액중의 EDTA 1mM pH 7.4) 상에서 테프론-유리균질기(teflon-glass homogenizer)로 세포를 균질화 하였다. 이 균질액을 10,000g로 4℃에서 30분간 원심분리하고 윗층을 취하여 다시 100,000g로 4℃에서 1시간동안 초고속원심분리 한 뒤 윗층은 버리고 침전된 펠렛(pellet)층을 40mM 트리스염산 완충액(pH 7.4)에 재현탁시켜 토끼 위벽세포 마이크로솜 펠렛(microsomal pellet)을 제조하였다. 이 마이크로솜 펠렛을 H+/K+-ATPase의 시험관내 효소반응실험을 수행하는 효소원으로 사용하였다.New Zealand white male rabbit (2 ~ 3kg) was killed by tofu smashing method, and then the contents were removed from the stomach and the stomach wall was washed with saline solution. After scraping the wall cells of the gastric lining with a slide glass, teflon-glass on sucrose buffer (250 mM sucrose, 2 mM HEPES, 2 mM MgCl 2 , EDTA 1 mM pH 7.4 in 40 mM trichloric acid buffer) cells were homogenized with a homogenizer. Centrifuge the homogenate at 10,000 g for 30 minutes at 4 ° C, take the upper layer, and then separate the supernatant at 100,000 g for 1 hour at 4 ° C, discard the upper layer and discard the precipitated pellet layer in 40 mM Tris hydrochloric acid buffer 7.4) was resuspended to prepare rabbit gastric wall microsomal pellets. This microsome pellet was used as an enzyme source for performing in vitro enzyme reaction experiment of H + / K + -ATPase.

H+/K+-ATPase 의 시험관내 효소반응 실험In vitro Enzyme Reaction of H + / K + -ATPase

H+/K+-ATPase의 시험관내 효소반응 실험은 Mg2+으로 자극된 H+/K+-ATPase 활성도를 음성대조군(negative control)으로 하고, Mg2+과 K+으로 자극된 H+/K+-ATPase 활성도를 양성대조군(positive control)으로 하였다. 즉, 음성·양성대조군 시험군과 시험물질군 시험관에 각각 20㎖를 넣고, 여기에 MgCl2(100㎕)와 마이크로솜 펠렛(50㎍)을 가한다. 그리고 대조군 시험관들에는 각각 디메틸술폭사이드(DMSO) 10㎕를 가하고, 시험물질군 시험관에는 시험관내 효소 반응조건에서 DMSO에 녹인 시험물질을 최대 용해도가 보이는 농도로부터 5개 농도로 시험물질의 농도를 희석해서 각각 10㎕를 가한다. 그리고 음성대조군 시험관에는 40mM 트리스염산 완충액(pH 7.4) 10㎕을 가하고 양성대조군과 시험물질군 시험관에는 300mM KCl + 100mM NH4Cl 혼합용액 100㎕를 가한뒤 전체반응 부피가 400㎕되도록 40mM 트리스염산 완충액(pH 7.4)을 가한다.In vitro enzymatic reaction of H + / K + -ATPase was performed with Mg 2+ -stimulated H + / K + -ATPase activity as negative control, and M + 2 + and K + -stimulated H + / K + -ATPase activity was taken as a positive control. That is, 20 ml of each of the negative and positive control group test tubes and the test substance group test tubes is added thereto, and MgCl 2 (100 µl) and microsomal pellet (50 µg) are added thereto. In addition, 10 μl of dimethyl sulfoxide (DMSO) was added to the control test tubes, and the test substance group was diluted to 5 concentrations of the test substance dissolved in DMSO under the in vitro enzyme reaction conditions to 5 concentrations. 10 μl each was added. 10 μl of 40 mM Tris hydrochloric acid buffer (pH 7.4) was added to the negative control tube, and 100 μl of 300 mM KCl + 100 mM NH 4 Cl mixed solution was added to the positive control group and the test substance group, and 40 mM Tris hydrochloric acid buffer was added so that the total reaction volume was 400 μl. (pH 7.4) is added.

이 반응 시험관들을 37℃에서 30분간 전반응(Pre-incubation)을 시켜 화합물(compound)과 H+/K+-ATPase 와의 결합조건(binding condition)을 준뒤, 33.3mM ATP-트리스염산 완충액 100㎕를 가하여 효소반응의 최종조건이 전체반응부피 500㎕내에 MgCl2(4mM), KCl(60mM), NH4Cl(20mM), DMSO-시험화합물2%(v/v), ATP(6.7mM), 마이크로솜 펠렛 50㎍(0.2㎍ ㎕) 그리고 트리스염산(pH 7.4) 완충액 40mM 되게 하여 37℃에서 30분간 효소반응을 시켰다. 이때의 효소반응 산물로 나오는 무기인을 혈액자동분석기(GILFORD SBA-300)로 정량하여 음성대조군과 양성대조군의 차이를 K+으로 자극된 H+/K+-ATPase 활성도로 정하였다. 그리고 시험물질의 IC50(H+/K+-ATPase 활성도 50% 억제하는 시험물질의 농도) 5개 농도로 가한 시험물질 시험관에서 효소활성도가 저해되는 각각의 % 값에서 리치필드-윌콕슨(Liitchfield-Wilcoxon)법으로 산출하였다. 시험결과(in vitro test)는 다음 표 4에 나타내었다.The reaction tubes were pre-incubated at 37 ° C. for 30 minutes to give a binding condition between the compound and H + / K + -ATPase, followed by 100 µl of 33.3 mM ATP-tris hydrochloride buffer. The final conditions of the enzyme reaction were MgCl 2 (4mM), KCl (60mM), NH 4 Cl (20mM), DMSO-Test Compound 2% (v / v), ATP (6.7mM) 50 µm (0.2 µl µm) of cotton pellets and 40 mM tris hydrochloric acid (pH 7.4) buffer were used to perform enzymatic reaction at 37 ° C for 30 minutes. At this time, it was determined by the weapon out of the enzyme reaction product by automatic blood analyzer (GILFORD SBA-300) quantified by stimulating the difference between the negative control and the positive control group by K + to H + / K + -ATPase activity. In addition, each of the 50% IC 50 (concentration of a test substance that inhibits 50% of H + / K + -ATPase activity) test substance added to each concentration of enzyme activity inhibited in the test tube of Lichfield (Liitchfield Calculated by the Wilcoxon method. In vitro tests are shown in Table 4 below.

[급성독성시험][Acute Toxicity Test]

본 발명에 따른 화합물에 대한 급성독성을 알아보기 위하여 ICR 수컷 마우스에 단회 경구투여하여 7일 간의 사망율, 일반증상, 체중변화 및 부검소견을 관찰하였다. 시험군은 5000, 3000, 1000, 500, 100 및 10 ㎎/㎏ 투여군의 6군으로 설정하였고, 각 군별 암수 각각 3마리씩 이었다.In order to examine the acute toxicity of the compound according to the present invention, a single oral dose was administered to ICR male mice to observe mortality, general symptoms, weight change, and autopsy findings for 7 days. The test group was set to 6 groups of 5000, 3000, 1000, 500, 100 and 10 mg / kg administration group, each was three male and female.

본 실험결과 모든 투여군에서 사망동물은 관찰되지 않았다. 일반증상의 경우 투여 1시간째에 2000㎎/㎏ 이상의 모든 동물에서 활동력저하 증상이 관찰되는데 3∼4시간까지 상기 증상이 지속된 5000㎎/㎏ 투여군을 제외하고 모두 빠르게 회복되었다. 체중변화 및 육안적인 부검소견에 있어서 시험물질에 의한 영향으로 사료되는 증상은 관찰되지 않았다. 이상의 결과로 보아 수컷 마우스에 있어서 본 발명에 따른 화합물의 LD값은 5000㎎/㎏ 이상으로 사료된다.As a result, no dead animals were observed in all treatment groups. In the general symptom, deactivation symptoms were observed in all animals at 2000 mg / kg or more at 1 hour after administration, and all recovered rapidly except the 5000 mg / kg administration group whose symptoms persisted for 3 to 4 hours. No change in body weight and gross autopsy findings were observed. In conclusion, the LD value of the compound according to the present invention in male mice is considered to be 5000 mg / kg or more.

Claims (7)

다음 구조식(I)로 표시되는 접합고리 피리딘을 함유하는 벤즈이미다졸 유도체.Benzimidazole derivatives containing the conjugated ring pyridine represented by the following formula (I). 상기식에서, R은 수소원자, 할로겐원자, C1∼C3의 알콕시, C1∼C3의 할로알콕시 또는 C1∼C3의 할로알킬기이고;Wherein R is a hydrogen atom, a halogen atom, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy or C 1 -C 3 haloalkyl group; R1, R2, R3, R4, R5및 R6은 서로 같거나 다른 것으로서 수소원자, 할로겐원자 또는 C1∼C3의 알킬기를 나타내되 다만, 모두 수소원자인 경우는 제외한다.ROne, R2, R3, R4, R5And R6Are the same as or different from each other and are hydrogen, halogen or COne-C3Alkyl group is represented except all hydrogen atoms. 제1항에 있어서, 상기 R이 수소원자, 염소원자, 브롬원자, 플루오르원자, 메톡시기, 에톡시기, 프로필옥시기, 트리플루오르메틸기, 또는 2,2-디플루오르에톡시기인 것을 특징으로 하는 접합고리 피리딘을 함유한 벤즈이미다졸 유도체.The method according to claim 1, wherein R is hydrogen, chlorine, bromine, fluorine, methoxy, ethoxy, propyloxy, trifluoromethyl or 2,2-difluoroethoxy. Benzimidazole derivatives containing conjugated pyridine. 제1항에 있어서, 상기 R1, R2, R3, R4, R5및 R6가 각각 같거나 다른 것으로서 수소원자, 메틸기, 에틸기 또는 프로필기(다만, 모두 수소원자인 경우는 제외)인 것을 특징으로 하는 접합고리 피리딘을 함유한 벤즈이미다졸 유도체.The method according to claim 1, wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different, respectively, hydrogen atom, methyl group, ethyl group or propyl group (except when all are hydrogen atoms) A benzimidazole derivative containing a conjugated ring pyridine. 다음 구조식(I)로 표시되는 벤즈이미다졸 유도체 및 이들의 약제학적 허용가능한 염을 유효성분으로 함유하고 있는 것을 특징으로 하는 위궤양 치료제 조성물.A benzimidazole derivative represented by the following formula (I) and a pharmaceutically acceptable salt thereof as an active ingredient. 상기식에서, R과 X는 상기 특허청구의 범위 제1항에서 정의한 바와같다.Wherein R and X are as defined in claim 1. 제4항에 있어서, 상기 약제학적으로 허용가능한 염은 산부가염 또는 나트륨염인 것을 특징으로 하는 위궤양 치료제 조성물.The gastric ulcer therapeutic composition according to claim 4, wherein the pharmaceutically acceptable salt is acid addition salt or sodium salt. 제4항에 있어서, 상기 R1, R2, R3, R4, R5및 R6가 각각 같거나 다른 것으로서 수소원자, 메틸기, 에틸기 또는 프로필기(다만, 모두 수소원자인 경우는 제외)인 것을 특징으로 하는 위궤양 치료제 조성물.The method according to claim 4, wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different, and each hydrogen atom, methyl group, ethyl group or propyl group (except when all are hydrogen atoms) Gastric ulcer therapeutic composition, characterized in that. 다음 구조식(I)로 표시되는 화합물 제조에 유용한 다음 구조식(V)로 표시되는 화합물.The compound represented by the following structural formula (V) useful for preparation of a compound represented by the following structural formula (I). 상기식에서, R과 X는 상기 특허청구의 범위 제1항에서 정의한 바와같다.Wherein R and X are as defined in claim 1.
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