KR100651651B1 - Beta-methylcarbapenem derivatives, preparation thereof and antibiotic composition comprising the same - Google Patents

Beta-methylcarbapenem derivatives, preparation thereof and antibiotic composition comprising the same Download PDF

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KR100651651B1
KR100651651B1 KR1020050073660A KR20050073660A KR100651651B1 KR 100651651 B1 KR100651651 B1 KR 100651651B1 KR 1020050073660 A KR1020050073660 A KR 1020050073660A KR 20050073660 A KR20050073660 A KR 20050073660A KR 100651651 B1 KR100651651 B1 KR 100651651B1
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김봉진
허정희
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한국화학연구원
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D477/00Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/18Oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D477/00Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20Sulfur atoms
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    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

Provided is a beta-methylcarbapenem derivative showing excellent antibacterial effect on resistant bacteria such as methicillin resistant Staphylococcus Aureus(MRSA) and having strong antibacterial effect on Gram positive bacillus so as to be usefully used as antibiotics for incurable resistant bacteria inflammations. The beta-methylcarbapenem derivative is represented by the formula(1) and is prepared by reacting a 2-diphenylphosphoryloxy carbapenem derivative represented by the formula(2) with a cyclopentano pyridineazetidine-3-yl-thiol derivative represented by the formula(3) to prepare a carbapenem ester derivative represented by the formula(4) and then removing a protecting group(R1) from the compound represented by the formula(4). In the formulae, R1 is a carboxy protecting group, and M is H or zwitterion forming a physiologically acceptable salt.

Description

베타-메틸카바페넴 유도체, 이의 제조방법 및 이를 포함하는 항생제 조성물 {BETA-METHYLCARBAPENEM DERIVATIVES, PREPARATION THEREOF AND ANTIBIOTIC COMPOSITION COMPRISING THE SAME}Beta-methylcarbapenem derivative, preparation method thereof, and antibiotic composition comprising same {BETA-METHYLCARBAPENEM DERIVATIVES, PREPARATION THEREOF AND ANTIBIOTIC COMPOSITION COMPRISING THE SAME}

본 발명은 그람양성균에 우수한 항균효과를 나타내며, 메티실린 내성 스타필로코쿠스 아우레우스(Methicillin Resistant Staphylococcus Aureus, MRSA)를 비롯한 내성균에도 특히 우수한 항균효과를 갖는 베타-메틸카바페넴 유도체, 이의 제조 방법 및 이를 함유하는 항생제 조성물에 관한 것이다.The present invention shows an excellent antimicrobial effect on Gram-positive bacteria, beta-methylcarbapenem derivative having a particularly excellent antimicrobial effect against resistant bacteria, including Methicillin Resistant Staphylococcus Aureus (MRSA), a preparation method thereof And to antibiotic compositions containing the same.

1940년대 현대적인 개념의 항생제로서 처음으로 임상에서 사용된 페니실린은 감염질환을 가진 수많은 환자의 생명을 구함으로써 기적의 약으로 알려져 왔다. 그러나 페니실린이 사용된지 얼마 되지 않아, 이에 대해 내성을 가지는 포도상 구균이 등장하였다. 1960년대에 들어서는 반합성 페니실린인 메티실린이 개발되어 페니실린 내성 포도상 구균 감염증 치료에 사용되기 시작하였으며, 1973년에는 세팔로스포린계인 세파졸린이 개발되었다. 그러나 이후 메티실린이나 세파졸린에 내성을 가지는 메티실린 내성 포도상 구균(MRSA)이 발생하기 시작하여 또 다른 문제를 야기하게 되었다. 이어 1980년대에는 각종 세팔로스포린 제제와 퀴놀론, 카바페넴, 모노박탐, 글리코사이드 등 수많은 항생제가 개발되어 실제 임상에서 사용되었다. 그러나 이 시기에는 페니실린 내성 폐렴구균, MRSA 등이 세계 각지에서 문제가 되기 시작하였고, 1990년대에는 반코마이신 내성 장구균(VRE)이 출현하면서 항생제 내성균 문제가 세계 의약계의 관심사로 대두되었다. 따라서, 그람양성균과 그람음성균에 광범위하게 항균력을 가지면서 또한 내성균의 치료에 효과가 있는 새로운 항생제의 개발이 요구되고 있다.First used in clinic as a modern concept antibiotic in the 1940s, penicillin has been known as a miracle medicine by saving the lives of many patients with infectious diseases. But soon after penicillin was used, staphylococci appeared to be resistant to it. In the 1960s, methicillin, a semisynthetic penicillin, was developed and used to treat penicillin-resistant staphylococcal infections. In 1973, cephazoline, a cephalosporin family, was developed. However, methicillin-resistant staphylococcus aureus (MRSA), which is resistant to methicillin or cefazoline, began to develop, causing another problem. Subsequently, in the 1980s, numerous cephalosporin preparations and numerous antibiotics such as quinolone, carbapenem, monobactam, and glycoside were developed and used in actual clinical practice. At this time, however, penicillin-resistant pneumococci and MRSA began to be a problem all over the world. In the 1990s, vancomycin-resistant enterococci (VRE) emerged and antibiotic-resistant bacteria became a global concern. Therefore, there is a demand for the development of new antibiotics having a broad antimicrobial activity against Gram-positive bacteria and Gram-negative bacteria and effective in the treatment of resistant bacteria.

최근에는 카바페넴계 항생제인 머크(MERCK)사의 2-아릴카바페넴 화합물(L-695256 과 L-742728)들이 MRSA와 VRSA에 좋은 활성을 나타내는 것으로 보고되었으며(Hugh rosen et al., Sciences, 703(1999)), 국제공개번호 제 WO 99 62906 호에는 2-벤조티아졸에테닐 카바페넴이 MRSA에 좋은 효과를 나타낸다고 보고된 바 있다. 본 발명자들이 최근에 제시한 아제티딘 유도체가 치환된 카바페넴유도체들이 광범위한 항균 효과를 가지면서 내성균에도 우수한 항균력을 보이는 물질들을 보고 한 바 있다(한국특허공개 제 2003-14858호, 한국특허공개 제 2003-23968호, 한국특허공개 제 2004-74181호 및 한국특허공개 2004-85384호). 이 외에도 MRSA에 좋은 효과를 보이는 카바페넴계 항생제가 다수 보고되어 있으며, 시판되는 것으로는 이미페넴(imipenem)과 메로페넴(meropenem)이 약한 내성을 갖는 MRSA의 치료제로에 이용되고 있다.Recently, two-arylcarbapenem compounds (MER-6), a carbapenem antibiotic, have been reported to exhibit good activity against MRSA and VRSA (Hugh rosen et al., Sciences , 703 ( 1999), International Publication No. WO 99 62906 has reported that 2-benzothiazoleethenyl carbapenem has a good effect on MRSA. The inventors of the present invention have recently reported substances having a wide range of antimicrobial effects and excellent antimicrobial activity against resistant bacteria, while substituted azetidine derivatives have been suggested (Korean Patent Publication No. 2003-14858, Korean Patent Publication No. 2003). -23968, Korean Patent Publication No. 2004-74181 and Korean Patent Publication No. 2004-85384. In addition, a number of carbapenem antibiotics that have a good effect on MRSA has been reported, and commercially available imipenem (meropenem) and meropenem (meropenem) has been used as a therapeutic agent for MRSA with weak resistance.

이러한 항생제 내성의 문제는 필연적으로 환자 치료의 실패라는 결과를 초래하게 되어, 이를 극복하는 새로운 항생제의 개발이 강력히 요구되고 있는 실정이다.The problem of antibiotic resistance inevitably results in failure of patient treatment, and the development of new antibiotics to overcome this situation is strongly required.

이에 본 발명자들은 그람양성균에 강한 항균활성을 나타내며, MRSA 감염을 비롯한 내성균 감염에 대한 치료효과를 갖는 항생제를 개발하기 위해 계속 연구를 진행한 결과, 새로운 카바페넴 유도체를 개발함으로써 본 발명을 완성하게 되었다. The present inventors have shown strong antimicrobial activity against Gram-positive bacteria, and as a result of continuing research to develop an antibiotic having a therapeutic effect against resistant bacterial infections including MRSA infection, the present invention was completed by developing a new carbapenem derivative. .

따라서, 본 발명의 목적은, 광범위한 약효를 가지면서 MRSA, QRSA등의 내성균 감염에 대한 항생효과를 갖는, 베타-메틸카바페넴 유도체 및 이의 제조 방법을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a beta-methylcarbapenem derivative having a wide range of medicinal effects and having an antibiotic effect against infection with resistant bacteria such as MRSA and QRSA.

본 발명의 다른 목적은 상기 카바페넴 유도체를 유효성분으로 함유하는 항생제 조성물을 제공하는 것이다.Another object of the present invention is to provide an antibiotic composition containing the carbapenem derivative as an active ingredient.

상기 목적을 달성하기 위하여, 본 발명에서는 하기 화학식 1의 베타-메틸카바페넴 유도체 또는 이의 약리학적으로 허용가능한 염을 제공한다:In order to achieve the above object, the present invention provides a beta-methylcarbapenem derivative of Formula 1 or a pharmacologically acceptable salt thereof:

화학식 1Formula 1

Figure 112005044286249-pat00002
Figure 112005044286249-pat00002

상기 식에서, M은 수소 또는 약리학적으로 허용가능한 염을 형성하는 짝이온이다.Wherein M is hydrogen or a counterion to form a pharmacologically acceptable salt.

또한, 본 발명에서는 In the present invention,

1) 하기 화학식 2의 2-디페닐포스포릴옥시 카바페넴 카복실레이트 유도체를 화학식 3의 사이클로펜타노피리딘아제티딘-3-일싸이올 유도체와 반응시켜 화학식 4의 카바페넴 에스테르 유도체를 제조하는 단계, 및 1) preparing a carbapenem ester derivative of formula 4 by reacting a 2-diphenylphosphoryloxy carbapenem carboxylate derivative of Formula 2 with a cyclopentanopyridinazetidin-3-ylthiol derivative of Formula 3, And

2) 하기 화학식 4의 화합물의 보호기(R1)를 제거하는 단계를 포함하는, 2) removing the protecting group (R 1 ) of the compound of formula (4),

화학식 1의 카바페넴 유도체의 제조방법을 제공한다.Provided is a method for preparing a carbapenem derivative of Formula 1.

Figure 112005044286249-pat00003
Figure 112005044286249-pat00003

Figure 112005044286249-pat00004
Figure 112005044286249-pat00004

Figure 112005044286249-pat00005
Figure 112005044286249-pat00005

상기 식에서,Where

R1은 카르복시 보호기로서, 예를 들면, p-니트로벤질 또는 알릴기를 나타낸다.R 1 is a carboxy protecting group, for example, p-nitrobenzyl or allyl group.

상기 다른 목적을 달성하기 위하여, 본 발명에서는 화학식 1의 카바페넴 유 도체 또는 이의 약리학적으로 허용되는 염을 유효 성분으로 포함하는 항생제 조성물을 제공한다.In order to achieve the above another object, the present invention provides an antibiotic composition comprising the carbapenem derivative of Formula 1 or a pharmacologically acceptable salt thereof as an active ingredient.

이하 본 발명을 좀더 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.

본 발명에서 화학식 1의 베타-메틸카바페넴 유도체는 화학식 2의 화합물과 화학식 3의 화합물을 축합 반응시켜 화학식 4의 화합물을 제조한 다음, 화학식 4의 화합물에서 카르복시보호기(R1)를 제거함으로써 제조할 수 있다.In the present invention, the beta-methylcarbapenem derivative of Formula 1 is prepared by condensation reaction of a compound of Formula 2 with a compound of Formula 3 to prepare a compound of Formula 4, and then removing the carboxy protecting group (R 1 ) from the compound of Formula 4. can do.

우선, 화학식 2의 2-디페닐포스포릴옥시 카바페넴 카복실레이트 유도체를 화학식 3의 사이클로펜타노피리딘아제티딘-3-일싸이올 유도체와 반응시켜 화학식 4의 카바페넴 에스테르 유도체를 제조하는 것은 당분야에서 공지된 방법에 따라 수행될 수 있다. 예를 들어, 화학식 2의 화합물을 건조된 유기용매, 예를 들어 아세토나이트릴, 메틸렌클로라이드 또는 아세톤, 바람직하게는 아세토나이트릴에 용해시키고, -30℃∼ -20℃로 냉각시킨 다음, N,N-디아이소프로필에틸아민을 천천히 가한다. 여기에 화학식 3의 화합물을 가하고 동 온도에서 2시간 내지 4시간 동안 교반하여 반응이 종결되는 것을 확인한 후 통상적인 방법에 따라 생성물을 분리시켜 화학식 4의 화합물을 수득할 수 있다.First, the reaction of 2-diphenylphosphoryloxy carbapenem carboxylate derivative of Formula 2 with a cyclopentanopyridinazetidin-3-ylthiol derivative of Formula 3 to prepare a carbapenem ester derivative of Formula 4 It can be carried out according to a method known in the art. For example, the compound of formula 2 is dissolved in a dried organic solvent such as acetonitrile, methylene chloride or acetone, preferably acetonitrile, cooled to -30 ° C to -20 ° C, and then N, N-diaisopropylethylamine is added slowly. After adding the compound of Formula 3 and stirring at the same temperature for 2 to 4 hours to confirm that the reaction is terminated, the product may be separated by a conventional method to obtain the compound of Formula 4.

이렇게 얻어진 화학식 4의 화합물의 카르복시 보호기, R1이 p-니트로벤질기인 경우는 통상의 방법인 수소화 촉매반응으로 환원하여 제거할 수 있으며, R1이 알 릴기인 경우는 유기산 또는 그의 염(예를 들어, 아세트산, 2-에틸헥사논산, 또는 이들의 나트륨 및 칼륨염) 존재하에서 트리페닐포스핀, 테트라키스(트리페닐포스핀)팔라듐과 반응시킴으로써 제거할 수 있다.When the carboxy protecting group and R 1 of the compound of the formula (4) thus obtained are p-nitrobenzyl groups, they may be reduced and removed by a conventional hydrogenation catalysis. When R 1 is an allyl group, an organic acid or a salt thereof may be used. For example, it can be removed by reacting with triphenylphosphine and tetrakis (triphenylphosphine) palladium in the presence of acetic acid, 2-ethylhexanoic acid, or sodium and potassium salts thereof.

상기 보호기의 제거반응 후 수득된 반응물을 역상 실리카겔 칼럼크로마토그래피방법으로 정제한 다음 동결건조하여 비결정성 고체 상태의 최종 생성물인 화학식 1의 화합물을 수득할 수 있다.The reactant obtained after the removal of the protecting group may be purified by reverse phase silica gel column chromatography and then lyophilized to obtain a compound of formula 1 which is a final product in an amorphous solid state.

화학식 2의 화합물은 카바페넴 화합물을 합성하기 위한 일반적인 중간체로서 당분야에서 공지된 방법(일본특허 특개평 4-330085호(1992) 참조)에 따라 제조할 수 있다. Compounds of formula (2) can be prepared according to methods known in the art (see Japanese Patent Laid-Open No. 4-330085 (1992)) as general intermediates for synthesizing carbapenem compounds.

한편, 본 발명에서 사용된 화학식 3의 화합물은 하기 반응식 1에 제시된 방법에 따라 제조할 수 있다. Meanwhile, seen The compound of formula 3 used in the invention can be prepared according to the method shown in Scheme 1 below.

Figure 112005044286249-pat00006
Figure 112005044286249-pat00006

구체적으로, 화학식 5의 에틸 시아노아세테이트와 브로모아세트알데하이드 디에틸아세탈을 예를 들면, 디메틸아세트아미드 용매에 용해시킨 후, 포타슘 tert-부톡사이드와 같은 염기를 가하여 2시간 동안 가열 환류 반응시켜 화학식 6의 화합물을 수득한 후, 이를 예를 들면, 테트라하이드로퓨란 용매에 용해시키고 포타슘 tert-부톡사이드와 같은 염기를 가하여 상온에서 3 내지 4시간 동안 교반한 후, 여기에 2-클로로사이클로펜타논을 가하여 2 내지 3시간 동안 교반 반응하여 화학식 7의 화합물을 얻을 수 있다.Specifically, ethyl cyanoacetate of Formula 5 and bromoacetaldehyde diethylacetal are dissolved in, for example, a dimethylacetamide solvent, and then heated to reflux for 2 hours by addition of a base such as potassium tert -butoxide. After obtaining the compound of 6, it was dissolved in, for example, a tetrahydrofuran solvent, and a base such as potassium tert -butoxide was added thereto, stirred at room temperature for 3 to 4 hours, and then 2-chlorocyclopentanone was added thereto. Addition and stirring for 2-3 hours may yield a compound of Formula 7.

이어서, 화학식 7의 화합물을 예를 들면, 테트라하이드로퓨란 용매에 용해시키고 황산과 같은 산을 가하여 상온에서 4 내지 5시간 동안 교반하여 알데하이드 화합물을 생성시키고, 이를 무수 에탄올과 같은 용매에 용해시켜 하이드록실아민 염산염과 함께 2 내지 3시간 동안 가열 환류하여 고리화 반응으로 진행된 화학식 8의 화합물을 얻을 수 있다. 이어서, 화학식 8의 화합물의 N-옥사이드를 환원하기 위하여 삼염화인을 클로로포름과 같은 용매하에서 화학식 8의 화합물과 혼합하여 2 내지 3시간 동안 가열 환류하여 화학식 9의 화합물을 수득할 수 있다.Subsequently, the compound of formula 7 is dissolved in, for example, a tetrahydrofuran solvent, and an acid such as sulfuric acid is added, followed by stirring at room temperature for 4 to 5 hours to form an aldehyde compound, which is dissolved in a solvent such as anhydrous ethanol to hydroxyl. It is possible to obtain a compound of formula 8 which has undergone a cyclization reaction by heating under reflux with an amine hydrochloride for 2-3 hours. Subsequently, to reduce the N-oxide of the compound of formula 8, phosphorus trichloride may be mixed with the compound of formula 8 in a solvent such as chloroform and heated to reflux for 2 to 3 hours to obtain a compound of formula 9.

이 화학식 9의 화합물과 3-tert-부틸디메틸실릴아제티딘을 무수 테트라하이드로퓨란과 같은 용매중에서 tert-부틸마그네슘클로라이드를 가하여 상온에서 2 내지 4시간 동안 반응시켜 아제티딘아마이드 화합물인 화학식 10의 화합물을 얻을 수 있다. 화학식 10의 화합물을 염산과 같은 산 존재하에서 보호기를 제거하고 얻은 아제티딘알콜 화합물에 미쥬노브(mitsunobu)반응을 시켜 아세틸싸이오아제티딘 화 합물인 화학식 11의 화합물을 얻은 후, 이를 메탄올과 같은 용매하에서 묽은 수산화나트륨과 같은 알칼리를 가하여 가수분해 반응을 하여 원하는 화학식 3의 사이클로 펜타노피리딘일 싸이올 화합물을 수득할 수 있다. 이 화합물은 서서히 디설파이드 화합물로 변환될 수 있으므로 곧바로 다음 반응에 사용하여야 한다. The compound of by reacting for 2 to 4 hours at room temperature, was added butyl magnesium chloride azetidin-amide of formula (10) compounds are compounds of formula (9) and 3- tert-butyldimethylsilyl azetidin-tetracarboxylic anhydride in a solvent such as tetrahydrofuran tert You can get it. After a protecting group was removed in the presence of an acid such as hydrochloric acid to give a compound of formula 11, which is an acetylthioazetidine compound, by reacting with an azetidine alcohol, a mizunobu reaction was carried out. Hydrolysis reaction may be performed by addition of an alkali such as dilute sodium hydroxide to give a desired cyclopentanopyridinyl thiol compound of the general formula (3). This compound may be slowly converted to a disulfide compound and should be used immediately for the next reaction.

본 발명의 화학식 1의 화합물은 그람양성균에 우수한 항균활성을 나타내며, 메티실린 내성균(MRSA), 엔테로코쿠스(enterococcus) 페니실린 내성균 및 뉴모코쿠스(pneumococcus)와 같은 그람양성 미생물에 대해 우수한 항 박테리아 활성을 갖는다.The compound of formula 1 of the present invention exhibits excellent antibacterial activity against Gram-positive bacteria, and has excellent antibacterial activity against Gram-positive microorganisms such as methicillin resistant bacteria (MRSA), enterrococcus penicillin resistant bacteria and pneumococcus. Has

따라서, 본 발명에서는 유효량의 화학식 1의 화합물 또는 이의 약리학적으로 허용되는 염, 및 약제학적으로 허용되는 담체를 포함하는 항생용 조성물을 제공한다.Accordingly, the present invention provides an antibiotic composition comprising an effective amount of a compound of Formula 1 or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable carrier.

본 발명의 약학 조성물은 활성 성분인 화학식 1의 화합물이 조성물의 총중량을 기준으로 하여 0.1 내지 75 중량%, 바람직하게는 1 내지 50 중량%의 양으로 함유될 수 있다. The pharmaceutical composition of the present invention may contain the compound of formula 1 as an active ingredient in an amount of 0.1 to 75% by weight, preferably 1 to 50% by weight, based on the total weight of the composition.

본 발명의 약학 조성물은 다양한 경구 또는 비경구 투여 형태로 제형화 할 수 있다. 경구 투여용 제형으로는 예를 들면 정제, 환제, 경.연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및 또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/ 또는 폴리에틸렌 글리콜)를 함유할 수 있다. 정제는 또한 마그네슘 알루미늄 실리케이 트, 전분 페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카르복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다. 상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있다. 또한 비경구 투여용 제형의 대표적인 것은 주사용 제형으로 등장성 수용액 또는 현탁액이 바람직하다.The pharmaceutical compositions of the invention can be formulated in a variety of oral or parenteral dosage forms. Formulations for oral administration include, for example, tablets, pills, hard and soft capsules, solutions, suspensions, emulsifiers, syrups, and granules. These formulations may contain diluents (e.g., lactose, dextrose, water, etc.) in addition to the active ingredients. Cross, mannitol, sorbitol, cellulose and or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, optionally starch, agar, alginic acid Or disintegrants or boiling mixtures such as sodium salts thereof and / or absorbents, colorants, flavors, and sweeteners. The formulations may be prepared by conventional mixing, granulating or coating methods. Also representative of parenteral formulations are injectable formulations, preferably aqueous isotonic solutions or suspensions.

상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.The composition may contain sterile and / or auxiliaries such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, which are conventional methods of mixing, granulating Or according to a coating method.

유효 성분으로서 화학식 1의 화합물은 사람을 포함하는 포유동물에 대해 하루에 2.5 내지 100 ㎎/㎏(체중), 바람직하게는 5 내지 60 ㎎/㎏(체중)의 양으로 1일 1회 또는 분할하여 경구 또는 비경구적 경로를 통해 투여할 수 있다. As an active ingredient, the compound of formula 1 may be divided or divided once a day in an amount of 2.5 to 100 mg / kg body weight, preferably 5 to 60 mg / kg body weight, per day for mammals including humans. Administration can be via oral or parenteral routes.

이하 하기 제조예 및 실시예에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 단, 하기 제조예 및 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Preparation Examples and Examples. However, the following Preparation Examples and Examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

제조예 1 내지 6 : 4-(3-머르캅토아제티딘-1-일)카보닐-사이클로펜타노피리딘(화학식 3의 화합물)의 제조Preparation Examples 1 to 6: Preparation of 4- (3-mercaptoazetidin-1-yl) carbonyl-cyclopentanopyridine (compound of formula 3)

제조예 1 : 에틸 4,4-다이메톡시-2-시아노부틸레이트(화학식 6의 화합물)의 제조Preparation Example 1 Preparation of Ethyl 4,4-Dimethoxy-2-cyanobutylate (Compound 6)

질소분위기 하에서 화학식 5의 에틸 시아노아세테이트(6 ml, 56,4 밀리몰)을 디메틸포름아마이드(40ml)에 용해시키고, 포타슘 tert-부톡사이드(6.6 g, 56.4 밀리몰)을 가한 후 상온에서 4시간 동안 교반하였다. 동 온도에서 브로모아세트알데하이드(8.75 ml, 56.4 밀리몰)를 천천히 가하여 상온에서 20분간 교반한 후 2시간 동안 가열 환류시켰다. 반응액을 상온으로 냉각시킨 후 물과 클로로포름을 가하여 추출하고, 유기층을 무수 마그네슘설페이트로 건조하여, 여과, 감압농축한 후 잔여물을 진공증류(bp 111-115℃/1.3 밀리바)로 정제하여 순수한 목적화합믈 6.689 g(55% 수율)을 얻었다.Ethyl cyanoacetate of formula 5 (6 ml, 56,4 mmol) was dissolved in dimethylformamide (40 ml) under nitrogen atmosphere, and potassium tert -butoxide (6.6 g, 56.4 mmol) was added thereto for 4 hours at room temperature. Stirred. Bromoacetaldehyde (8.75 ml, 56.4 mmol) was slowly added at the same temperature, stirred at room temperature for 20 minutes, and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, extracted with water and chloroform, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by vacuum distillation (bp 111-115 ° C / 1.3 ml) to obtain pure water. 6.689 g (55% yield) of the title compound was obtained.

1H-NMR(CDCl3, 200MHz) δ 1.15-1.37(3개의 triplet, 9H), 2.28-2.33(m, 2H), 3.44-3.77(m, 5H), 4.24(q, 2H), 4.72(t, 1H). 1 H-NMR (CDCl 3 , 200 MHz) δ 1.15-1.37 (3 triplet, 9H), 2.28-2.33 (m, 2H), 3.44-3.77 (m, 5H), 4.24 (q, 2H), 4.72 (t , 1H).

제조예 2 : 에틸 4,4,-다이에톡시-2-시아노-2-(사이클로펜타논-2-일)부틸레이트(화학식 7의 화합물)의 제조Preparation Example 2 Preparation of Ethyl 4,4, -Diethoxy-2-cyano-2- (cyclopentanone-2-yl) butylate (Compound 7)

제조예 1에서 수득한 화학식 6의 에틸 4,4-다이메톡시-2-시아노부틸레이트(6.698 g, 29.21 밀리몰)을 테트라하이드로퓨란(40 ml)에 용해시키고, 포타슘 tert-부톡사이드(3.68 g, 32.73 밀리몰)을 천천히 가한 후 상온에서 3시간 교반하였다. 동 온도에서 2-클로로사이클로펜타논(4.16 g, 3 밀리몰)을 적가한 후 2시간 더 교반하였다. 반응물에 물과 초산에틸을 가하고 추출하여 얻은 유기층을 무수 마그네슘설페이트로 건조시켜, 여과, 감압농축하여 실리카겔 칼럼크로마토그래피(용리제: 헥산/초산에틸=1/9)로 정제하여 순수한 목적 화합물 5.485 g(60% 수율)을 노란색 액체 상태로 얻었다.Ethyl 4,4-dimethoxy-2-cyanobutylate of formula 6 obtained in Preparation Example 1 (6.698 g, 29.21 mmol) was dissolved in tetrahydrofuran (40 ml), and potassium tert -butoxide (3.68) g, 32.73 mmol) was slowly added and stirred at room temperature for 3 hours. 2-Chlorocyclopentanone (4.16 g, 3 mmol) was added dropwise at the same temperature, followed by further stirring for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the extracted organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/9) to give a pure compound of 5.485 g. (60% yield) was obtained as a yellow liquid.

1H-NMR(CDCl3, 200MHz) δ 1.15-1.37(3개의 triplet, 9H), 1.85-2.43(m, 6H), 3.44-3.77(m, 5H), 4.04-4.32(m, 4H), 4.72(t, 1H). 1 H-NMR (CDCl 3 , 200 MHz) δ 1.15-1.37 (3 triplet, 9H), 1.85-2.43 (m, 6H), 3.44-3.77 (m, 5H), 4.04-4.32 (m, 4H), 4.72 (t, 1 H).

제조예 3: N-옥소-4-에톡시카보닐-사이클로펜타노피리딘(화학식 8의 화합물)의 제조Preparation Example 3 Preparation of N-oxo-4-ethoxycarbonyl-cyclopentanopyridine (Compound 8)

Figure 112005044286249-pat00007
Figure 112005044286249-pat00007

제조예 2에서 얻은 화학식 7의 화합물(2.0 g, 6.42 밀리몰)을 테트라하이드로퓨란(17 ml)에 용해시키고, 황산(1.8 ml, 32.12 밀리몰)과 물(1.8 ml)의 혼합액을 천천히 가한 후 상온에서 4시간 동안 교반하였다. 반응이 완결된 후 물(20 ml)로 희석한 후 초산에틸로 추출하여 무수 마그네슘설페이트로 건조시켜, 여과, 감압농축하여 알데하이드화합물 1.353 g(85% 수율)를 얻었다. 이 알데하이드 화합물(2.240 g, 9.44 밀리몰)을 무수 에탄올(45 ml)에 용해시키고, 하이드록실아민 염산염(1.64 g, 23.6 밀리몰)를 가한 후 2시간 동안 가열 환류시켰다. 반응액을 상온으 로 냉각하여 용매를 감압하에서 농축시키고, 잔여물에 수산화나트륨(1 g)과 얼음물(20 ml)의 혼합액을 가하고, 클로로포름으로 추출하였다. 유기층을 무수 마그네슘설페이트로 건조시켜, 여과, 감압농축하여 목적 화합물 1.873 g(96% 수율)를 얻었다.The compound of formula 7 obtained in Preparation Example 2 (2.0 g, 6.42 mmol) was dissolved in tetrahydrofuran (17 ml), and a mixed solution of sulfuric acid (1.8 ml, 32.12 mmol) and water (1.8 ml) was slowly added thereto at room temperature. Stir for 4 hours. After completion of the reaction, the mixture was diluted with water (20 ml), extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 1.353 g (85% yield) of an aldehyde compound. This aldehyde compound (2.240 g, 9.44 mmol) was dissolved in anhydrous ethanol (45 ml), and hydroxylamine hydrochloride (1.64 g, 23.6 mmol) was added and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure, and a mixed solution of sodium hydroxide (1 g) and ice water (20 ml) was added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 1.873 g (96% yield) of the target compound.

1H-NMR(CDCl3, 200MHz) δ 1.37(t, J= 8.8Hz, 3H), 2.11(quintet, J= 7.7Hz, 2H), 3.05(t, J= 7.74Hz, 2H), 3.30(t, J= 7.74Hz, 2H), 4.32(q, J= 7.1Hz, 2H), 7.63(d, J= 6.8Hz, 1H), 7.98(d, J= 6.8Hz, 1H); MS(EI, 70eV) m/z 191(M+), 162, 146, 117. 1 H-NMR (CDCl 3 , 200 MHz) δ 1.37 (t, J = 8.8 Hz, 3H), 2.11 (quintet, J = 7.7 Hz, 2H), 3.05 (t, J = 7.74 Hz, 2H), 3.30 (t , J = 7.74 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 7.63 (d, J = 6.8 Hz, 1H), 7.98 (d, J = 6.8 Hz, 1H); MS (EI, 70 eV) m / z 191 (M + ), 162, 146, 117.

제조예 4 : 4-에톡시카보닐-사이클로펜타노피리딘(화학식 9의 화합물)의 제조Preparation Example 4 Preparation of 4-Ethoxycarbonyl-Cyclopentanopyridine (Compound 9)

제조예 3에서 얻은 화학식 8의 N-옥소-4-에톡시카보닐-사이클로펜타노피리딘(1.873g)을 클로로포름(30 ml)에 용해시키고, 포스포러스 트리클로라이드(2.13 ml, 24.4 밀리몰)을 가한 후 2시간 동안 가열 환류 시켰다. 반응 종료 후 상온으로 냉각하여 물을 가하여 반응을 정지시키고 10% 수산화 칼륨 수용액을 가한 후 클로로포름으로 추출하여 얻은 유기층을 무수 마그네슘설페이트로 건조시켜, 여과, 감압농축하여 실리카겔 칼럼크로마토그래피(용리제: 초산에틸/n-헥산=3/2)로 정제하여 순수한 목적 화합물 319 mg(19%)를 얻었다.N-oxo-4-ethoxycarbonyl-cyclopentanopyridine (1.873 g) obtained in Preparation Example 3 was dissolved in chloroform (30 ml), and phosphorus trichloride (2.13 ml, 24.4 mmol) was added thereto. After heated to reflux for 2 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, water was added to stop the reaction, and an aqueous 10% potassium hydroxide solution was added thereto. The organic layer was extracted with chloroform, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, followed by silica gel column chromatography (eluent: acetic acid). Purification with ethyl / n-hexane = 3/2) gave 319 mg (19%) of pure target compound.

1H-NMR(CDCl3, 200MHz) δ 1.37(t, J= 8.8Hz, 3H), 2.10(quintet, J= 7.7Hz, 2H), 3.05(t, J= 7.74Hz, 2H), 3.30(t, J= 7.74Hz, 2H), 4.23(q, J= 7.1Hz, 2H), 7.63(d, J= 6.8Hz, 1H), 7.98(d, J=6.8Hz, 1H); MS(EI, 70eV) m/z 175(M+), 82, 69. 1 H-NMR (CDCl 3 , 200 MHz) δ 1.37 (t, J = 8.8 Hz, 3H), 2.10 (quintet, J = 7.7 Hz, 2H), 3.05 (t, J = 7.74 Hz, 2H), 3.30 (t , J = 7.74 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 7.63 (d, J = 6.8 Hz, 1H), 7.98 (d, J = 6.8 Hz, 1H); MS (EI, 70 eV) m / z 175 (M + ), 82, 69.

제조예 5 : 4-(4-tert-부틸다이메틸실릴옥시아제티딘-1-일)카보닐-사이클로펜타노피리딘(화학식 10의 화합물)의 제조Preparation Example 5 Preparation of 4- (4- tert -butyldimethylsilyloxyazetidin-1-yl) carbonyl-cyclopentanopyridine (Compound 10)

질소 분위기에서 3-(tert-부틸디이메틸실릴옥시)아제티딘(339 mg, 1.844 밀리몰)을 건조된 테트라하이드로퓨란(7 ml)에 용해시키고, tert-부틸마그네슘클로라이드(2.0M 테트라하이드로퓨란 용액)(1.26 ml, 2.515 밀리몰)을 천천히 가하여 5분간 교반하였다. 이 반응물에 제조예 4에 따라 제조한 화학식 9의 4-에톡시카보닐-사이클로펜타노피리딘(319 mg, 1.677 밀리몰)을 적가한 후 2시간 동안 교반하였다. 반응물에 물과 초산에틸을 가하여 추출하고 얻은 유기층을 무수 마그네슘설페이트로 건조하여, 여과, 감압농축하여 실리카겔 칼럼크로마토그래피(용리제: 초산에틸)로 정제하여 순수한 목적 화합물 207 mg(37% 수율)을 얻었다.3- ( tert -butyldimethylsilyloxy) azetidine (339 mg, 1.844 mmol) in a nitrogen atmosphere was dissolved in dried tetrahydrofuran (7 ml) and tert -butylmagnesium chloride (2.0M tetrahydrofuran solution) (1.26 ml, 2.515 mmol) was added slowly and stirred for 5 minutes. To this reaction was added dropwise 4-ethoxycarbonyl-cyclopentanopyridine (319 mg, 1.677 mmol) prepared according to Preparation Example 4, followed by stirring for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, purified by silica gel column chromatography (eluent: ethyl acetate) to give 207 mg (37% yield) of the pure target compound. Got it.

1H-NMR(CDCl3, 200MHz) δ 0.05(s, 6H), 0.85(s, 9H), 2.10(quintet, J= 7.7Hz, 2H), 3.05(t, J= 7.74Hz, 4H), 4.00(m, 2H), 4.18(m, 1H), 4.38(m, 1H), 4.64(m, 1H), 6.98(d, J= 6.8Hz, 1H), 8.38(d, J= 6.8Hz, 1H); MS(EI, 70eV) m/z 332(M+), 262, 246, 195. 1 H-NMR (CDCl 3 , 200 MHz) δ 0.05 (s, 6H), 0.85 (s, 9H), 2.10 (quintet, J = 7.7 Hz, 2H), 3.05 (t, J = 7.74 Hz, 4H), 4.00 (m, 2H), 4.18 (m, 1H), 4.38 (m, 1H), 4.64 (m, 1H), 6.98 (d, J = 6.8 Hz, 1H), 8.38 (d, J = 6.8 Hz, 1H) ; MS (EI, 70 eV) m / z 332 (M + ), 262, 246, 195.

제조예 6 : 4-[(3-아세틸싸이오)아제티딘-1-일]카보닐-사이클로펜타노피리딘(화학식 11의 화합물)의 제조Preparation Example 6 Preparation of 4-[(3-acetylthio) azetidin-1-yl] carbonyl-cyclopentanopyridine (Compound 11)

Figure 112005044286249-pat00008
Figure 112005044286249-pat00008

제조예 5에서 제조한 화학식 10의 4-(4-tert-부틸다이메틸실릴옥시아제티딘-1-일)카보닐-사이클로펜타노피리딘(207 mg, 0.623 밀리몰)을 메탄올(4 ml)에 용해시키고, 0℃로 냉각시킨 후, 4노르말-염산(0.6 ml, 2.49 밀리몰)을 천천히 가하여 주었다. 상온에서 2시간 동안 교반한 다음 반응물에 포화 중조 수용액으로 pH를 7.0으로 조절하여 주고 용매를 감압하에서 날려 보냈다. 잔여물에 물과 초산에틸을 가하여 추출하고 얻은 유기층을 무수 마그네슘설페이트로 건조시켜, 여과, 감압농축하여 알콜화합물 120 mg(88% 수율)을 수득하였다. 다른 플라스크에 트리페닐포스핀(163 mg, 0.623 밀리몰)을 건조된 테트라하이드로퓨란(2 ml)에 용해시키고 0℃로 냉각시킨 후, 다이아이소프로필아조다이카르복실레이트(0.12 ml, 0.623 밀리몰)을 적가하여 1시간 동안 교반하였다. 동 온도에서 싸이오아세트산(0.045 ml, 0.623 밀리몰)과 앞에서 제조한 알콜화합물을 차례로 가한 후 상온으로 온도를 올려 2시간 동안 교반하였다. 반응 완결후 용매를 감압하에서 농축하여 실리카겔 칼럼크로마토그래피(용리제: n-헥산/초산에틸=1/2)로 정제하여 순수한 목적 화합물 64 mg(75%)을 노란색 액체상으로 얻었다.4- (4- tert -butyldimethylsilyloxyazetidin-1-yl) carbonyl-cyclopentanopyridine (207 mg, 0.623 mmol) of Formula 10 prepared in Preparation Example 5 was dissolved in methanol (4 ml). After cooling to 0 ° C., 4-normal-hydrochloric acid (0.6 ml, 2.49 mmol) was added slowly. After stirring for 2 hours at room temperature, the reaction was adjusted to pH 7.0 with a saturated aqueous sodium bicarbonate solution and the solvent was sent off under reduced pressure. Water and ethyl acetate were added to the residue, followed by extraction. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 120 mg (88% yield) of the alcohol compound. In another flask, triphenylphosphine (163 mg, 0.623 mmol) was dissolved in dried tetrahydrofuran (2 ml) and cooled to 0 ° C., followed by diisopropylazodicarboxylate (0.12 ml, 0.623 mmol). It was added dropwise and stirred for 1 hour. At the same temperature, thioacetic acid (0.045 ml, 0.623 mmol) and the previously prepared alcoholic compound were sequentially added, and the temperature was raised to room temperature, followed by stirring for 2 hours. After completion of the reaction, the solvent was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/2) to give 64 mg (75%) of the pure target compound as a yellow liquid.

1H-NMR(CDCl3, 200MHz) δ 2.10(quintet, J= 7.7Hz, 2H), 2.34(s, 3H), 3.05(t, J= 7.74Hz, 4H), 3.90-4.18(m, 2H), 4.20-4.38(m, 1H), 4.50-4.63(m, 2H), 4.64(m, 1H), 6.98(d, J= 6.8Hz, 1H), 8.38(d, J= 6.8Hz, 1H); MS(EI, 70eV) m/z 2762(M+), 233, 218, 175, 146. 1 H-NMR (CDCl 3 , 200 MHz) δ 2.10 (quintet, J = 7.7 Hz, 2H), 2.34 (s, 3H), 3.05 (t, J = 7.74 Hz, 4H), 3.90-4.18 (m, 2H) , 4.20-4.38 (m, 1H), 4.50-4.63 (m, 2H), 4.64 (m, 1H), 6.98 (d, J = 6.8 Hz, 1H), 8.38 (d, J = 6.8 Hz, 1H); MS (EI, 70 eV) m / z 2762 (M + ), 233, 218, 175, 146.

제조예 6 : 4-(3-머르캅토아제티딘-1-일)카보닐-사이클로펜타노피리딘(화학식 3의 화합물)의 제조Preparation Example 6 Preparation of 4- (3-mercaptoazetidin-1-yl) carbonyl-cyclopentanopyridine (compound of Formula 3)

제조예 5에서 얻은 화학식 11의 4-[(3-아세틸싸이오)아제티딘-1-일]카보닐-사이클로펜타노피리딘((64 mg, 0.4 밀리몰)을 메탄올(1.5 ml)에 용해 시키고, 0℃로 냉각시킨 후 2N-수산화나트륨(0.25 ml, 0.4 밀리몰)을 천천히 적가하여 2시간 동안 교반하여 주었다. 반응이 완결된 후 반응물에 2N-염산으로 pH를 4-5로 조절하여 준 후 용매를 감압하에서 농축하고, 잔여물에 물과 초산에틸을 가하여 용해 추출하여 준 후 유기층을 무수 마그네슘설페이트로 건조하고, 여과, 감압농축하여 조생성물을 얻었으며 이는 공기중에서 쉽게 변화되므로 곧바로 다음 반응에 사용하였다.4-[(3-acetylthio) azetidin-1-yl] carbonyl-cyclopentanopyridine ((64 mg, 0.4 mmol) of Formula 11 obtained in Preparation Example 5 was dissolved in methanol (1.5 ml), After cooling to 0 ° C., 2N-sodium hydroxide (0.25 ml, 0.4 mmol) was slowly added dropwise and stirred for 2 hours.After completion of the reaction, the reaction product was adjusted to pH 4-5 with 2N hydrochloric acid, followed by solvent. Was concentrated under reduced pressure, and the residue was dissolved in water and ethyl acetate, and extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. It was.

실시예 1 : 소디윰 (1R,5S,6S)-2-{[1-(사이클로펜타노피리딘-4-일)카보닐]아제티딘-3-싸이오}-6-[(1R)-하이드록시]-1-메틸카바펜-2-엠-3-카르복실레이트(화학식 1의 화합물)의 제조Example 1 Sodium (1R, 5S, 6S) -2-{[1- (cyclopentanopyridin-4-yl) carbonyl] azetidine-3-thio} -6-[(1R) -hydr Roxy] -1-methylcarbafen-2-m-3-carboxylate (compound of formula 1)

Figure 112005044286249-pat00009
Figure 112005044286249-pat00009

공지된 방법에 따라 제조한 화학식 2의 화합물에 해당하는 4-니트로벤질 (1R,5R,6S)-2-(디페닐포스포릴옥시)-6-[(1R)-1-하이드록시에틸]-1-메틸카바펜-2-엠-3-카르복실레이트(138 mg, 0.232 밀리몰)을 아세토니트릴(2 ml)에 녹이고 -20℃에서 다이아이소프로필에틸아민(0.1 ml, 0.464 밀리몰)을 가한 후 이어서 제조예 6에서 제조한 화학식 3의 4-(3-머르캅토아제티딘-1-일)카보닐-사이클로펜타노피리딘을 적가한 다음 동 온도에서 2시간 동안 교반하여 반응을 완결시켰다. 반응액에 물과 초산에틸을 가하여 추출하여 유기층을 취한 후 무수 마그네슘 설페이트로 건조시켜, 여과, 감압하에서 농축하였다. 잔사를 실리카겔 칼럼크로마토그래피(용리제: 초산에틸/메탄올=9/1)정제하여 순수한 카바페넴 에스테르 화합물 79 mg(57% 수율)얻었다. 4-nitrobenzyl (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl]-corresponding to the compound of formula 2 prepared according to a known method Dissolve 1-methylcarbafen-2-m-3-carboxylate (138 mg, 0.232 mmol) in acetonitrile (2 ml) and add diisopropylethylamine (0.1 ml, 0.464 mmol) at -20 ° C. Subsequently, 4- (3-mercaptoazetidin-1-yl) carbonyl-cyclopentanopyridine of Chemical Formula 3 prepared in Preparation Example 6 was added dropwise, followed by stirring at the same temperature for 2 hours to complete the reaction. Water and ethyl acetate were added to the reaction mixture, followed by extraction. The organic layer was taken, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 9/1) to obtain 79 mg (57% yield) of pure carbapenem ester compound.

얻어진 카바페넴 에스테르 화합물의 보호기를 제거하기 위하여 카바페넴 에 스테르 화합물(79 mg, 0.17 밀리몰)을 테트라하이드로퓨란(0.5 ml)과 에탄올(0.3 ml)에 용해시키고, 나트륨 2-에틸헥사노에이트(30 mg, 0.17 밀리몰)와 10% 팔라듐카본(8 mg)을 가한 후 수소분위기 하에서 8시간 동안 상온에서 교반하였다. 여과하여 팔라듐 촉매를 제거하고 용매를 감압하에서 농축시켰다. 잔여물에 소량의 물을 가한 후 초산에틸로 불순물을 세척하여 주고, 물층을 C18 역상 MPLC(용리제: 10% 아세토니트릴 수용액)을 통과시켜 얻어진 목적물이 포함된 부분을 분취하고 동결건조하여 흰색 고체의 목적 화합물 27 mg(25%)을 수득하였다. In order to remove the protecting group of the obtained carbapenem ester compound, the carbapenem ester compound (79 mg, 0.17 mmol) was dissolved in tetrahydrofuran (0.5 ml) and ethanol (0.3 ml), and sodium 2-ethylhexanoate ( 30 mg, 0.17 mmol) and 10% palladium carbon (8 mg) were added thereto, followed by stirring at room temperature for 8 hours under a hydrogen atmosphere. Filtration removed the palladium catalyst and the solvent was concentrated under reduced pressure. A small amount of water was added to the residue, and the impurities were washed with ethyl acetate. The water layer was passed through a C18 reversed-phase MPLC (eluant: 10% acetonitrile solution), and the fraction containing the desired product was separated and lyophilized to obtain a white solid. 27 mg (25%) of the desired compound were obtained.

1H-NMR(D2O, 200MHz) δ1.15(d, J=7 .2Hz, 3H), 1.38(d, J= 6.2Hz, 3H), 2.06-2.24(m, 2H),2.95-3.10(m, 5H), 3.21(m, 1H), 4.00(m, 1H), 4.20-4.35(m, 5H), 4.40-4.65(m, 2H), 6.98(s, 1H), 7.25(m, 2H); MS(FAB, m/e) 442(M+-Na). 1 H-NMR (D 2 O, 200 MHz) δ 1.15 (d, J = 7.2 Hz, 3H), 1.38 (d, J = 6.2 Hz, 3H), 2.06-2.24 (m, 2H), 2.95-3.10 (m, 5H), 3.21 (m, 1H), 4.00 (m, 1H), 4.20-4.35 (m, 5H), 4.40-4.65 (m, 2H), 6.98 (s, 1H), 7.25 (m, 2H ); MS (FAB, m / e) 442 (M + -Na).

실시예 2 : 소디윰 (1R,5S,6S)-2-{[1-(사이클로펜타노피리딘-4-일)카보닐]아제티딘-3-싸이오}-6-[(1R)-하이드록시]-1-메틸카바펜-2-엠-3-카르복실레이트Example 2 Sodium (1R, 5S, 6S) -2-{[1- (cyclopentanopyridin-4-yl) carbonyl] azetidine-3-thio} -6-[(1R) -hydr Roxy] -1-methylcarbaphen-2-m-3-carboxylate

Figure 112005044286249-pat00010
Figure 112005044286249-pat00010

화학식 2의 화합물로서 4-알릴 (1R,5R,6S)-2-(디페닐포스포릴옥시)-6-[(1R)-1-하이드록시에틸]-1-메틸카바펜-2-엠-3-카로복실레이트(138 mg, 0.276 밀리몰)를 사용하는 것을 제외하고는 상기 실시예 1과 동일하게 실시하여 순수한 카바페넴 에스테르 화합물 83 mg(61% 수율)얻었다. 4-Allyl (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methylcarbafen-2-m- as a compound of formula (2) 83 mg (61% yield) of pure carbapenem ester compound was obtained in the same manner as in Example 1 except that 3-carocarboxylate (138 mg, 0.276 mmol) was used.

얻어진 카바페넴 에스테르 화합물(83 mg, 0.17 밀리몰)을 건조된 메틸렌클로라이드(2 ml)에 용해시키고, 트리페닐포스핀(6 mg, 0.021 밀리몰)과 소디윰 2-에틸헥사노에이트(57 mg, 0.17 밀리몰) 및 테트라키스(트리페닐포스핀)팔라듐(0.5 mg)을 각각 가하였다. 반응액을 상온에서 5시간 동안 교반하여 반응을 완결시킨 후 물(5 ml)를 가하였다. 30분간 더 교반하여 주고 메틸렌클로라이드(5 ml)을 가하여 유기층을 분리하여 버리고, 남은 물층을 C18 역상 MPLC(용리제: 10% 아세토니트릴 수용액)을 통과시켜 얻어진 목적물이 포함된 부분을 분취하고 동결건조하여 흰색 고체의 목적 화합물 22 mg(23%)을 수득하였다. 1H-NMR로 분석한 결과는 실시예 1과 동일하였다. The obtained carbapenem ester compound (83 mg, 0.17 mmol) was dissolved in dried methylene chloride (2 ml), triphenylphosphine (6 mg, 0.021 mmol) and Sodium -2-ethylhexanoate (57 mg, 0.17) Mmol) and tetrakis (triphenylphosphine) palladium (0.5 mg) were added respectively. The reaction solution was stirred at room temperature for 5 hours to complete the reaction, followed by addition of water (5 ml). After further stirring for 30 minutes, methylene chloride (5 ml) was added to separate the organic layer, and the remaining water layer was passed through a C18 reversed phase MPLC (eluent: 10% acetonitrile solution). To give 22 mg (23%) of the title compound as a white solid. 1 H-NMR analysis was the same as in Example 1.

시험예 1 Test Example 1

상기 실시예 1 또는 2에서 제조한 본원 발명에 따른 화합물의 그람 양성균 및 그람음성균과 메티실린 내성균주(MRSA) 및 오플록사신 내성균주(QRSA)에 대한 항균작용을 다음과 같이 시험하였다. 뮬러-힌톤(Muller-Hinton) 한천을 사용하여 2배수 아가(agar)희석법에 의한 한천배지 희석법에 따라 최소성장 억제농도(Minimum Inhibitory Concentration, MIC)를 측정함으로써, 실시예 1, 2에서 제조된 본 발명의 카바페넴 유도체의 항균작용을 평가하여 그 결과를 표 1에 나타내었다. 대조군으로는 시판되고 있는 카바페넴 항생제인 메로페넴을 사용하였다.The antimicrobial activity of Gram-positive and Gram-negative bacteria and methicillin-resistant strains (MRSA) and oploxacin-resistant strains (QRSA) of the compounds according to the present invention prepared in Example 1 or 2 was tested as follows. The present invention prepared in Examples 1 and 2 by measuring the Minimum Inhibitory Concentration (MIC) using a Muller-Hinton agar according to the agar medium dilution method by the double-fold agar dilution method. The antimicrobial activity of the carbapenem derivatives of the invention was evaluated and the results are shown in Table 1. As a control, meropenem, a commercial carbapenem antibiotic, was used.

Figure 112005044286249-pat00011
Figure 112005044286249-pat00011

상기 표 1로부터 알 수 있는 바와 같이, 본 발명의 화학식 1의 카바페넴 유도체는 대조물질에 비하여 그람양성균에 우수한 항균력을 보이며, MRSA균 및 QRSA균과 같은 내성균에 대해서도 강한 항균력을 나타내었다. As can be seen from Table 1, the carbapenem derivative of the formula (1) of the present invention showed excellent antimicrobial activity against Gram-positive bacteria, and also showed strong antimicrobial activity against resistant bacteria such as MRSA and QRSA bacteria compared to the control material.

본 발명의 카바페넴 유도체는 그람양성균에 대하여 우수한 항균력을 보이며, 메티실린 내성 스타필로코쿠스 아우레우스(MRSA) 및 오플록사신 내성 스타필로코쿠스 아우레우스(QRSA)에 대한 항균효과가 매우 우수하여 MRSA 및 QRSA 감염증을 비롯한 난치성 내성균 감염에 대한 항생제로서 유용하게 사용될 수 있다.The carbapenem derivative of the present invention shows excellent antimicrobial activity against Gram-positive bacteria, and has very high antibacterial effect against methicillin-resistant Staphylococcus aureus (MRSA) and oploxacin-resistant Staphylococcus aureus (QRSA). It is excellent and can be usefully used as an antibiotic against intractable resistant bacterial infections, including MRSA and QRSA infections.

Claims (5)

하기 화학식 1의 베타-메틸카바페넴 유도체 또는 이의 약리학적 허용가능한 염:A beta-methylcarbapenem derivative of formula 1 or a pharmacologically acceptable salt thereof: 화학식 1Formula 1
Figure 112005044286249-pat00012
Figure 112005044286249-pat00012
상기 식에서, M은 수소 또는 약리학적으로 허용가능한 염을 형성하는 짝이온을 나타낸다.Wherein M represents hydrogen or a counterion that forms a pharmacologically acceptable salt.
(1) 하기 화학식 2의 2-디페닐포스포릴옥시 카바페넴 카복실레이트 유도체를 화학식 3의 사이클로펜타노피리딘아제티딘-3-일싸이올 유도체와 반응시켜 화학식 4의 카바페넴 에스테르 유도체를 제조하는 단계, 및 (1) reacting a 2-diphenylphosphoryloxy carbapenem carboxylate derivative of Formula 2 with a cyclopentanopyridinazetidin-3-ylthiol derivative of Formula 3 to prepare a carbapenem ester derivative of Formula 4 , And (2) 하기 화학식 4의 화합물의 보호기(R1)를 제거하는 단계를 포함하는, (2) removing the protecting group (R 1 ) of the compound of formula (4), 하기 화학식 1의 베타-메틸카바페넴 유도체 또는 이의 약리학적으로 허용가능한 염의 제조 방법:Method for preparing a beta-methylcarbapenem derivative of Formula 1 or a pharmacologically acceptable salt thereof: 화학식 1Formula 1
Figure 112005044286249-pat00013
Figure 112005044286249-pat00013
화학식 2 Formula 2
Figure 112005044286249-pat00014
Figure 112005044286249-pat00014
화학식 3Formula 3
Figure 112005044286249-pat00015
Figure 112005044286249-pat00015
화학식 4Formula 4
Figure 112005044286249-pat00016
Figure 112005044286249-pat00016
상기 식에서,Where R1은 카르복시보호기이고,R 1 is a carboxyprotecting group, M은 수소 또는 약리학적으로 허용가능한 염을 형성하는 짝이온을 나타낸다.M represents hydrogen or a counterion forming a pharmacologically acceptable salt.
제2항에 있어서, The method of claim 2, 상기 단계 1을, 화학식 2의 화합물과 화학식 3의 화합물을 유기용매 중에서 N,N-디아이소프로필에틸아민의 존재하에 -30℃ 내지 -20℃에서 2시간 내지 4시간 동안 반응시킴으로써 수행하는 것을 특징으로 하는 방법.Step 1 is carried out by reacting the compound of Formula 2 and the compound of Formula 3 in the organic solvent in the presence of N, N-diaisopropylethylamine for 2 to 4 hours at -30 ℃ to -20 ℃ How to. 제2항에 있어서, The method of claim 2, 화학식 3의 화합물이 하기 단계를 포함하는 방법에 의해 제조되는 것임을 특징으로 하는 방법: Wherein the compound of formula 3 is prepared by a process comprising the following steps: 1) 하기 화학식 5의 에틸 시아노아세테이트와 브로모아세트알데하이드를 가열 환류 반응시켜 하기 화학식 6의 화합물을 제조하는 단계,1) preparing a compound of Chemical Formula 6 by heating under reflux reaction with ethyl cyanoacetate of Chemical Formula 5 and bromoacetaldehyde, 2) 하기 화학식 6의 화합물을 2-클로로사이클로펜타논과 반응시켜 하기 화학식 7의 화합물을 제조하는 단계,2) preparing a compound of formula 7 by reacting a compound of formula 6 with 2-chlorocyclopentanone; 3) 하기 화학식 7의 화합물을 산과 반응시켜 알데하이드 화합물을 얻은 후, 이를 고리화 반응시켜 하기 화학식 8의 화합물을 제조하는 단계,3) reacting a compound of Formula 7 with an acid to obtain an aldehyde compound, and then cyclizing the compound to prepare a compound of Formula 8; 4) 하기 화학식 8의 화합물의 N-옥사이드를 환원하여 하기 화학식 9의 화합물을 제조하는 단계, 4) reducing the N-oxide of the compound of Formula 8 to produce a compound of Formula 9, 5) 하기 화학식 9의 화합물과 3-tert-부틸디메틸실릴아제티딘을 반응시켜 하기 화학식 10의 아제티딘아마이드 화합물을 제조하는 단계,5) Compounds of formula (9) and 3- tert-butyldimethylsilyl is reacted with azetidine preparing an azetidin-amide compound of formula (10), 6) 하기 화학식 10의 화합물의 tert-부틸디메틸실릴기를 제거하고 미쥬노브 반응시켜 하기 화학식 11의 아세틸싸이오아제티딘 화합물을 제조하는 단계, 및6) of tert compound of formula (10) - to prepare a Compound of acetyl Im Iowa jetties to by removing the butyldimethylsilyl and mijyu knob reaction formula (11), and 7) 하기 화학식 11의 화합물을 가수분해 반응시켜 화학식 3의 사이클로펜타노피리딘 아제티딘일 싸이올 화합물을 제조하는 단계.7) preparing a cyclopentanopyridine azetidinyl thiol compound of Chemical Formula 3 by hydrolyzing the compound of Chemical Formula 11; 화학식 5Formula 5
Figure 112005044286249-pat00017
Figure 112005044286249-pat00017
화학식 6Formula 6
Figure 112005044286249-pat00018
Figure 112005044286249-pat00018
화학식 7Formula 7
Figure 112005044286249-pat00019
Figure 112005044286249-pat00019
화학식 8Formula 8
Figure 112005044286249-pat00020
Figure 112005044286249-pat00020
화학식 9Formula 9
Figure 112005044286249-pat00021
Figure 112005044286249-pat00021
화학식 10Formula 10
Figure 112005044286249-pat00022
Figure 112005044286249-pat00022
화학식 11Formula 11
Figure 112005044286249-pat00023
Figure 112005044286249-pat00023
유효성분으로서의 제1항의 화학식 1의 베타-메틸카바페넴 유도체 또는 이의 약리학적 허용가능한 염, 및 약제학적으로 허용되는 담체를 포함하는 항생제 조성물.An antibiotic composition comprising the beta-methylcarbapenem derivative of claim 1 or an pharmacologically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.
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