KR0183542B1 - Beta-methylcarbapenem derivatives and process for preparation thereof - Google Patents
Beta-methylcarbapenem derivatives and process for preparation thereof Download PDFInfo
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- KR0183542B1 KR0183542B1 KR1019950039974A KR19950039974A KR0183542B1 KR 0183542 B1 KR0183542 B1 KR 0183542B1 KR 1019950039974 A KR1019950039974 A KR 1019950039974A KR 19950039974 A KR19950039974 A KR 19950039974A KR 0183542 B1 KR0183542 B1 KR 0183542B1
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- C07D477/00—Heterocyclic 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
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic 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
- C07D477/10—Heterocyclic 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
- C07D477/12—Heterocyclic 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
- C07D477/14—Heterocyclic 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 hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
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Abstract
본 발명은 하기 일반식(1)의 베타메틸 카르바페넴 유도체, 이의 제조방법 및 이를 포함하는 약제학적 조성물에 관한 것으로, 하기 일반식(2)의 포밀 카르바페넴 화합물을 R2M과 반응시켜 일반식(3)의 2차 알코올을 얻고, 이 화합물로부터 히드록시 보호기 및 카르복실 보호기를 제거하는 단계를 포함하는 방법에 의해 제조되는 일반식(1)의 화합물은 녹농균을 제외한 그람양성균 및 그람음성균에 대하여 우수한 항균활성을 나타내며 경구 투여시 높은 흡수율을 나타낸다.The present invention relates to a betamethyl carbapenem derivative of the general formula (1), a preparation method thereof and a pharmaceutical composition comprising the same, wherein the formyl carbapenem compound of the general formula (2) is reacted with R 2 M Compounds of formula (1) prepared by a method comprising obtaining a secondary alcohol of formula (3) and removing a hydroxy protecting group and a carboxyl protecting group from the compound are Gram-positive and Gram-negative bacteria except Pseudomonas aeruginosa. Excellent antimicrobial activity against and high absorption rate upon oral administration.
Description
본 발명은 녹농균을 제외한 그람 음성균 및 그람 양성균에 대하여 우수한 항균력을 가지며 높은 경구 흡수율을 나타내는 새로운 베타메틸 카르바페넴 유도체, 이의 제조방법 및 이를 포함하는 약제학적 조성물에 관한 것이다.The present invention relates to a new betamethyl carbapenem derivative, a preparation method thereof, and a pharmaceutical composition comprising the same, having excellent antimicrobial activity and high oral absorption rate against Gram-negative bacteria and Gram-positive bacteria except Pseudomonas aeruginosa.
티에나마이신(미국특허 3,950,357)이 광범위 항균 스펙트럼을 가지고 있음이 발표된 이래, 보다 뛰어난 항균력을 가지며 데히드로펩티다제-1 효소에 안정한 카르바페넴계 항생제의 개발에 많은 연구가 진행되어 메로페넴(유럽특허 126587), 바이어페넴(일본특허 425779) 등과 같은 주사용 화합물들이 발표되었으며, 최근에는 경구용 카르바페넴계 항생제로서 트라이박탐(유럽특허 416953)계 화합물이 개발되었다. 그러나 12단계 이상이 요구되는 다단계 생산 공정에서 이성체의 분리가 용이하지 않으며 연쇄상구균(Streptococcus facium)과 엔테로박터 클로아크(Enterobacter cloacae)에 항균 활성이 낮고 특히 녹농균에는 항균 효과가 없는 단점이 나타났다.Since the publication of thienamycin (US Pat. No. 3,950,357) has a broad antimicrobial spectrum, much research has been conducted on the development of carbapenem antibiotics having superior antibacterial activity and stable to dehydropeptidase-1 enzyme. Injectable compounds such as European Patent 126587), Bayerpenem (Japanese Patent 425779) and the like have been published. Recently, tribactam (European patent 416953) compounds have been developed as oral carbapenem antibiotics. However, in the multi-stage production process requiring more than 12 steps, the separation of isomers is not easy, and the antimicrobial activity is low on Streptococcus facium and Enterobacter cloacae, and especially on Pseudomonas aeruginosa.
본 발명자는 그람 양성균과 그람 음성균 모두에 대하여 뛰어난 항균 작용을 가지고 체네 흡수도가 향상된 항균제를 개발하기 위하여 연구를 행한 결과, 우수한 경구 흡수도를 갖는 새로운 카르베페넴 유도체를 개발하게 되어 본 발명을 완성하게 되었다.The present inventors have conducted research to develop an antimicrobial agent having excellent antimicrobial activity against both Gram-positive bacteria and Gram-negative bacteria and having improved absorption in the body. As a result, a new carbepenem derivative having excellent oral absorption is completed to complete the present invention. Was done.
즉, 본 발명의 목적은 그람 양성균은 물론 녹농균을 제외한 그람 음성균에 대하여 우수한 항균 작용을 가지며 높은 경구 흡수율을 나타내는 새로운 카르바페넴 유도체, 이의 제조 방법 및 이를 포함하는 약제학적 조성물을 제공하는 것이다.That is, an object of the present invention is to provide a new carbapenem derivative, a preparation method thereof, and a pharmaceutical composition comprising the same, having an excellent antimicrobial activity against Gram-negative bacteria except Gram-positive bacteria and Pseudomonas aeruginosa and showing high oral absorption.
상기 목적을 달성하기 위하여 본 발명에서는 하기 일반식(1)의 베타메틸 카르바페넴 유도체를 제공한다 :In order to achieve the above object, the present invention provides a betamethyl carbapenem derivative of the following general formula (1):
상기 식에서In the above formula
R는 C1-C6의 저급 알킬, 시클로알킬 또는 헤테로 아릴기를 나타내며, R1은 수소원자이거나 칼륨 또는 나트륨이다.R represents a lower alkyl, cycloalkyl or heteroaryl group of C 1 -C 6 , wherein R 1 is a hydrogen atom or is potassium or sodium.
또한 본 발명에서는 하기 일반식(2)의 포밀 카르바페넴을 RM과 반응시켜 하기 일반식(3)의 2차 알코올 화합물을 얻고, 이 화합물로부터 히드록시 보호기 및 카르복실 보호기를 제거하는 단계를 포함하는 일반식(1)의 화합물의 제조 방법을 제공한다 :In addition, the present invention includes the step of reacting formyl carbapenem of formula (2) with RM to obtain a secondary alcohol compound of formula (3), and removing hydroxy protecting group and carboxyl protecting group from the compound. It provides a process for the preparation of a compound of formula (1):
여기에서 R2은 히드록시 보호기를 나타내며, R3는 카르복실 보호기를 나타내고, M은 금속 원자를 나타내고, R는 일반식(1)에서 정의한 것과 같다.Here, R 2 represents a hydroxy protecting group, R 3 represents a carboxyl protecting group, M represents a metal atom, and R is as defined in the general formula (1).
더 나아가 본 발명에서는 일반식(1)의 화합물과 생리학적으로 허용되는 담체 또는 부형제를 포함하는 약제학적 조성물을 제공한다.Furthermore, the present invention provides a pharmaceutical composition comprising the compound of formula (1) and a physiologically acceptable carrier or excipient.
이하 본 발명에 대하여 상세히 설명한다.Hereinafter, the present invention will be described in detail.
일반식(1)의 화합물은 하기 일반식(1a)와 (1b)의 2개 이상의 입체 이성질체 및 그 혼합물을 포함할 수 있다 :Compounds of formula (1) may comprise two or more stereoisomers of the following formulas (1a) and (1b) and mixtures thereof:
상기 식에서 쐐기 모양 결합은 결합이 종이 평면위에 있는 것을 나타내고, 파선형 결합은 결합이 종이 평면 아래에 있는 것을 나타낸다. 일반식(1a)에서 1'-위치의 탄소원자에 대하여 나타낸 배위는 이하에 β-배위(R이성질체)로 표시되고 일반식(1b)에서 1'-위치의 탄소 원자 배위는 α-배위(S이성질체)로 표시된다.Wedge-shaped bond in the above formula Indicates that the bond is on the paper plane, and the dashed bond Indicates that the bond is below the paper plane. Coordination shown for carbon atoms in the 1'-position in general formula (1a) is represented by β-coordination (R isomer) below and carbon atom coordination in the 1'-position in general formula (1b) is α-coordination (S). Isomers).
일반식(1)에서 R는 C1-C6의 저급 알킬, 알케닐, 시클로알킬, 페닐, 헤테로아릴기로서, 이소프로필, 시클로프로필 또는 시클로펜틸이 바람직하다. R1은 수소원자이거나 무기 또는 유기 염료로부터 유도된 양이온으로서, 약제학적으로 허용되는 양이온으로는 나트륨, 칼륨, 칼슘, 라이신, 에탄올아민 또는 N,N'-디벤질에틸렌디아민을 들 수 있으며, 이에 제한되는 것은 아니다. 일반식(1)의 양이온염으로는 나트륨 또는 칼륨염이 바람직하다.In the general formula (1) R is lower alkyl, alkenyl of C 1 -C 6, cycloalkyl as alkyl, phenyl, a heteroaryl group, an isopropyl, cyclopropyl or cyclopentyl are preferred. R 1 is a hydrogen atom or a cation derived from an inorganic or organic dye, and pharmaceutically acceptable cations include sodium, potassium, calcium, lysine, ethanolamine or N, N'-dibenzylethylenediamine. It is not limited. As a cation salt of General formula (1), sodium or potassium salt is preferable.
본 발명에 따른 일반식(1a) 또는 (1b)의 구조를 가지는 대표적인 화합물은 다음과 같다 :Representative compounds having the structure of formula (1a) or (1b) according to the present invention are as follows:
본 발명에 따른 일반식(1)의 화합물은 녹농균을 제외한 대부분의 박테리아에 대하여 우수한 항균 활성을 나타내고 신장 데히드로펩티다제-I 에 대하여 매우 안정하며 모든 베타락타마제에 대하여 높은 내성을 가지고 있다.The compound of formula (1) according to the present invention exhibits excellent antibacterial activity against most bacteria except Pseudomonas aeruginosa, is very stable against renal dehydropeptidase-I and has high resistance to all beta lactamases.
일반식(1)의 화합물은 하기 반응도식에 따라 제조할 수 있다.The compound of formula (1) can be prepared according to the following scheme.
상기 반응도에서 R2은 히드록시 보호기로서 트리메틸실릴, 트리에틸실릴, t-부틸디메틸실릴 또는 알릴옥시 카르보닐을 나타내며, t-부틸디메틸실릴 또는 트리에틸실릴이 바람직하다. R3는 카르복실 보호기로서 알릴, p-니트로벤질, p-메톡시벤질 또는 p-t-부틸벤질이 바람직하고, M은 금속 원자를 나타내며, 마그네슘 또는 리튬 원자가 바람직하다.In the above scheme, R 2 represents trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or allyloxy carbonyl as hydroxy protecting group, with t-butyldimethylsilyl or triethylsilyl being preferred. R 3 is preferably allyl, p-nitrobenzyl, p-methoxybenzyl or pt-butylbenzyl as the carboxyl protecting group, M represents a metal atom, and magnesium or lithium atom is preferred.
본 발명의 제조 방법을 단계별로 설명하면 다음과 같다.Referring to the manufacturing method of the present invention step by step.
(1) 제1단계(1) First step
출발물질인 일반식(2)의 포밀 카르바페넴을 디에틸에테르(이하 에테르라 함), 테트라히드로푸란(이하 THF라 함) 또는 이들의 혼합물 중에서 RM과 반응시켜 일반식(3)의 2차 알코올 화합물을 얻는다. 일반식(2)의 포밀 카르바페넴은 본 발명자의 대한민국 특허출원 제93-26675호(1993. 12. 7.)에 기재된 화합물이다. 반응은 -78℃ 내지 실온에서 5분 내지 2시간동안 반응시키면 충분하다. 얻어진 일반식(3)의 화합물은 1'-위치에 새로운 키랄 중심이 생성되어 R 및 S 이성질체의 혼합물로 얻어지므로 이를 컬럼 크로마토그래피로 분리, 정제하여 제2단계 반응에 사용하는 것이 효과적이다.Formyl carbapenem of general formula (2) as a starting material is reacted with RM in diethyl ether (hereinafter referred to as ether), tetrahydrofuran (hereinafter referred to as THF), or a mixture thereof to form a secondary compound of formula (3). Obtain an alcohol compound. Formyl carbapenem of formula (2) is a compound described in Korean Patent Application No. 93-26675 (Dec. 7, 1993) of the inventor. The reaction is sufficient to react for 5 minutes to 2 hours at -78 ° C to room temperature. Since the obtained compound of the general formula (3) generates a new chiral center at the 1'-position to obtain a mixture of the R and S isomers, it is effective to separate and purify it by column chromatography and use it for the second step reaction.
(2) 제2단계(2) second stage
제1단계에서 얻은 일반식(3)의 2차 알코올로부터 히드록시 보호기 R2와 카르복실 보호기 R3를 제거하는 단계인 제2단계는, 베타락탐 화학분야의 숙련자들에게 공지되어 있는 바와 같이 제거할 보호기의 성질에 좌우된다. 예를 들면 일반식(3)의 R2이 트리에틸실릴옥시기인 경우에는 1M HCl 용액을 사용하여 제거할 수 있다. 히드록시 보호기 제거 반응은 THF와 물의 혼합 용매를 사용하여 빙냉하에서 실시하는 것이 바람직하며, 반응에 소요되는 시간은 1 내지 2시간이다. 반응이 완결되면 목적 생성물을 통상의 방법으로 반응 혼합물로부터 회수하여 정제한 다음 카르복실 보호기를 제거한다.The second step of removing the hydroxy protecting group R 2 and the carboxyl protecting group R 3 from the secondary alcohol of the general formula (3) obtained in the first step is, as is known to those skilled in the beta lactam chemistry. It depends on the nature of the protecting group. For example, when R <2> of General formula (3) is a triethylsilyloxy group, it can remove using 1M HCl solution. The hydroxy protecting group removal reaction is preferably carried out under ice cooling using a mixed solvent of THF and water, and the time required for the reaction is 1 to 2 hours. Upon completion of the reaction, the desired product is recovered from the reaction mixture in a conventional manner to purify and then the carboxyl protecting groups are removed.
일반식(3)의 R3가 p-니트로벤질 또는 p-t-부틸벤질인 경우에는 탄소상 팔라듐, 산화 백금 등의 공지의 촉매를 사용하여 촉매 환원 반응으로 보호기를 제거하여 일반식 (1a) 또는 (1b)의 목적 화합물을 수득한다. 또한 R3가 알릴인 경우에는, THF, 염화메틸렌 등의 용매중에서 테트라키스트리페닐포스핀 팔라듐(0), 트리페닐 포스핀 및 2-에틸헥산온산과 반응시켜 보호기를 제거하여 일반식(1a) 및 (1b)의 목적화합물을 제조할 수 있다. 카르복실 보호기 제거 반응은 15 내지 30℃의 온도에서 수행하는 것이 바람직하며 소요시간은 2 내지 3 이다. 상기 방법으로 제조한 일반식(1a) 및 (1b)의 혼합물은 통상적인 기술에 따라서 분리 및 정제할 수 있으며, 약제학적으로 허용되는 나트륨 또는 칼륨염등으로 전환시킬 수도 있다.When R 3 in formula (3) is p-nitrobenzyl or pt-butylbenzyl, the protecting group is removed by catalytic reduction reaction using a known catalyst such as palladium on carbon, platinum oxide, or the like, to give general formula (1a) or ( The desired compound of 1b) is obtained. In the case where R 3 is allyl, the protecting group is removed by reacting with tetrakistriphenylphosphine palladium (0), triphenyl phosphine and 2-ethylhexanoic acid in a solvent such as THF or methylene chloride. And the desired compound of (1b). The carboxyl protecting group removal reaction is preferably carried out at a temperature of 15 to 30 ℃ and the time required is 2-3. Mixtures of the general formulas (1a) and (1b) prepared by the above method can be separated and purified according to conventional techniques, and can also be converted into pharmaceutically acceptable sodium or potassium salts and the like.
본 발명의 화합물은 병원성 박테리아에 의해 발생되는 국소적 세균 감염에 따른 여러가지 질병을 치료하기 위하여, 하나 또는 그 이상의 생리학적으로 허용되는 담체 또는 부형제와 함께 경구 또는 비경구적으로 사람을 포함한 동물에 사용될 수 있으며, 2.5 내지 100㎎/㎏(체중), 바람직하게는 5 내지 60㎎/㎏(체중)의 양을 1일 1회 또는 분할 투여할 수 있다.The compounds of the present invention can be used orally or parenterally in animals, including humans, with one or more physiologically acceptable carriers or excipients to treat various diseases associated with local bacterial infections caused by pathogenic bacteria. The amount of 2.5 to 100 mg / kg body weight, preferably 5 to 60 mg / kg body weight, may be administered once or in divided doses per day.
이하 실시예를 통하여 본 발명을 더욱 상세히 설명할 것이다.The present invention will be described in more detail with reference to the following examples.
단, 본 발명의 범위가 하기 실시예만으로 한정되는 것은 아니다.However, the scope of the present invention is not limited only to the following Examples.
[제조예 1][Production Example 1]
[알릴 (1S, 5R, 6S)-2-포밀-6-[(1'R)-1'-트리에틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트의 제조]Preparation of Allyl (1S, 5R, 6S) -2-formyl-6-[(1'R) -1'-triethylsilyloxyethyl] -1-methyl-2-carbapenem-3-carboxylate ]
[방법 A][Method A]
알릴 (1S, 5R, 6S)-2-히드록시메틸-6-[(1'R)-1'-트리에틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트 10g을 상온에서 무수 디클로로메탄 200㎖에 용해시킨 후 이산화망간 33g을 첨가하였다. 이 혼합물을 동일한 온도에서 30분간 교반한 후 15시간 가열, 환류시켰다. 이 반응물을 소량의 실리카겔과 셀라이트로 여과한 다음 감압하에서 용매를 증발시켜 제거함으로써 표제 화합물 8.2g을 얻었다.Allyl (1S, 5R, 6S) -2-hydroxymethyl-6-[(1'R) -1'-triethylsilyloxyethyl] -1-methyl-2-carbapenem-3-carboxylate 10 g Was dissolved in 200 ml of anhydrous dichloromethane at room temperature, and then 33 g of manganese dioxide was added. The mixture was stirred at the same temperature for 30 minutes and then heated and refluxed for 15 hours. The reaction was filtered through a small amount of silica gel and celite and then the solvent was evaporated off under reduced pressure to give 8.2 g of the title compound.
[방법 B][Method B]
디에틸술폭시드 5.0㎖를 무수 디클로로메탄 60㎖에 용해시킨후 -78℃에서 트리플루오로무수아세트산 5.5㎖를 적가한 다음 동온도에서 30분동안 교반하였다. 상기 반응물에 알릴(1S, 5R, 6S)-2-히드록시메틸-6-[(1'R)-1'-트리에틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트 5.0g을 무수 디클로로메탄 15㎖에 용해시킨 용액을 천천히 가한 후 트리에틸아민 13.5㎖을 적가하였다. 반응액을 동온도에서 1시간동안 교반시킨후 물로 희석시키고 아세트산에틸로 추출하여 분리한 후 유기층을 1N 염산과 포화 탄산수소나트륨으로 세척하였다. 무수 황산마그네슘으로 건조시키고, 용매를 감압하에서 증류제거하여 얻은 잔류물을 컬럼 크로마토그래피(헥산/아세트산에틸로 용출시킴)로 정제하여 표제 화합물 3.1g을 얻었다.After dissolving 5.0 mL of diethyl sulfoxide in 60 mL of anhydrous dichloromethane, 5.5 mL of trifluoroacetic anhydride was added dropwise at −78 ° C., followed by stirring at the same temperature for 30 minutes. Allyl (1S, 5R, 6S) -2-hydroxymethyl-6-[(1'R) -1'-triethylsilyloxyethyl] -1-methyl-2-carbapenem-3-carramide A solution of 5.0 g of carboxylate dissolved in 15 ml of anhydrous dichloromethane was slowly added, followed by dropwise addition of 13.5 ml of triethylamine. The reaction solution was stirred at the same temperature for 1 hour, diluted with water, extracted with ethyl acetate, separated, and the organic layer was washed with 1N hydrochloric acid and saturated sodium bicarbonate. The residue was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluted with hexane / ethyl acetate) to obtain 3.1 g of the title compound.
[제조예 2][Production Example 2]
[알릴 (1S, 5R, 6S)-2-포밀-6-[(1'R)-1'-(디에틸-t-부틸실릴옥시)에틸]-1-메틸-2-카르바페넴-3-카르복실레이트의 제조[Allyl (1S, 5R, 6S) -2-formyl-6-[(1'R) -1 '-(diethyl-t-butylsilyloxy) ethyl] -1-methyl-2-carbapenem-3 Preparation of Carboxylate
알릴(1S, 5R, 6S)-2-히드록시메틸-6-[(1'R)-1'-디에틸-t-부틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트 10g을 상온에서 무수 디클로로메탄 200㎖에 용해시킨 후 이산화망간 33g을 첨가하였다. 이 혼합물을 동일 온도에서 30분 동안 교반한 후 15시간 동안 가열, 환류시켰다. 참고예 1의 방법 A에서와 같은 과정으로 반응을 종결, 정제하여 표제 화합물 8.2g을 얻었다.Allyl (1S, 5R, 6S) -2-hydroxymethyl-6-[(1'R) -1'-diethyl-t-butylsilyloxyethyl] -1-methyl-2-carbapenem-3- 10 g of carboxylate was dissolved in 200 ml of anhydrous dichloromethane at room temperature, and then 33 g of manganese dioxide was added. The mixture was stirred at the same temperature for 30 minutes and then heated and refluxed for 15 hours. The reaction was terminated and purified in the same manner as in Method A of Reference Example 1 to obtain 8.2 g of the title compound.
[실시예 1]Example 1
[칼륨 (1S, 5R, 6S)-2-[(1'R)-(이소프로필)히드록시메틸]-6-[(1'R)-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실산의 제조][Potassium (1S, 5R, 6S) -2-[(1'R)-(isopropyl) hydroxymethyl] -6-[(1'R) -hydroxyethyl] -1-methyl-2-carbafe Preparation of Nem-3-carboxylic Acid]
[단계 1][Step 1]
알릴 (1S, 5R, 6S)-2-[(1'R)-(이소프로필)히드록시메틸]-6-[(1'R)-1-트리에틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트의 제조]Allyl (1S, 5R, 6S) -2-[(1'R)-(isopropyl) hydroxymethyl] -6-[(1'R) -1-triethylsilyloxyethyl] -1-methyl-2 Preparation of Carbapenem-3-carboxylate]
제조예 1에서 제조한 알릴 (1S, 5R, 6S)-2-포밀-6-[(1'R)-1'-트리에틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트 0.14g을 무수 THF 5㎖에 용해시킨 후 반응용기를 -78℃로 냉각시켰다. 질소 대기하에서 이 반응물에 2M 이소프로필 마그네슘 클로라이드 0.18㎖를 천천히 가하고 동일 온도에서 15분간 교반하였다. 반응액에 염화암모늄 포화 수용액을 첨가하여 반응을 종결시키고 아세트산에틸 40㎖로 희석하였다. 유기층을 물로 세척하고 염화나트륨 포화 수용액으로 세척한 다음 무수 황산 마그네슘으로 건조시켰다. 용매를 증발시켜 제거하고 컬럼 크로마토그래피로 정제하여 표제 화합물 0.11g을 얻었다.Allyl (1S, 5R, 6S) -2-formyl-6-[(1'R) -1'-triethylsilyloxyethyl] -1-methyl-2-carbapenem-3- prepared in Preparation Example 1 0.14 g of carboxylate was dissolved in 5 ml of anhydrous THF, and the reaction vessel was cooled to -78 deg. 0.18 ml of 2M isopropyl magnesium chloride was slowly added to the reaction under a nitrogen atmosphere and stirred at the same temperature for 15 minutes. Saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, and diluted with 40 ml of ethyl acetate. The organic layer was washed with water, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and purified by column chromatography to give 0.11 g of the title compound.
[단계 2][Step 2]
1) 알릴 (1S, 5R, 6S)-2-[(1'R)-(이소프로필)히드록시메틸]-6-(1'R)-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트의 제조1) Allyl (1S, 5R, 6S) -2-[(1'R)-(isopropyl) hydroxymethyl] -6- (1'R) -hydroxyethyl] -1-methyl-2-carbafe Preparation of Nem-3-carboxylate
단계 1에서 알릴 ((1S, 5R, 6S)-2-[(1'R)-(이소프로필)히드록시메틸]-6-[(1'R)-트리에틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트 1.88g을 THF 60㎖와 H2O 60㎖에 용해시키고 빙냉하에서 1M HCl 12.3㎖를 가한 후 동온도에서 1시간동안 교반시켰다. 반응액을 탄산수소나트륨 포화수용액으로 중화하고 아세트산에틸로 유기층을 추출한 다음 물 및 염화나트륨 포화 수용액으로 세척한 후 건조시켰다. 용매를 감압하에 농축 제거한후 컬럼 크로마토그래피(헥산/아세트산에틸)로 정제하여 표제화합물 870㎎을 얻었다.Allyl ((1S, 5R, 6S) -2-[(1'R)-(isopropyl) hydroxymethyl] -6-[(1'R) -triethylsilyloxyethyl] -1-methyl in step 1 1.88 g of 2-carbapenem-3-carboxylate was dissolved in 60 mL of THF and 60 mL of H 2 O, and then 12.3 mL of 1M HCl was added under ice cooling, followed by stirring for 1 hour at the same temperature. The mixture was neutralized with saturated aqueous sodium chloride solution, an organic layer was extracted with ethyl acetate, washed with water, saturated aqueous sodium chloride solution and dried, and the solvent was concentrated under reduced pressure, purified by column chromatography (hexane / ethyl acetate) to obtain 870 mg of the title compound. .
2) 칼륨 (1S, 5R, 6S)-2-[(1'R)-(이소프로필)히드록시메틸]-6-[(1'R)-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실산의 제조2) Potassium (1S, 5R, 6S) -2-[(1'R)-(isopropyl) hydroxymethyl] -6-[(1'R) -hydroxyethyl] -1-methyl-2-car Preparation of Bapenem-3-carboxylic Acid
1)에서 제조한 알릴 (1S, 5R, 6S)-2-[(1'R)-(이소프로필)히드록시메틸]-6-[(1'R)-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트 0.21g을 무수 디클로로메탄 12㎖에 용해시키고 알루미늄 호일로 반응 플라스크를 싼 다음 트리페닐포스핀 0.05g, 칼륨 2-에틸헥산온산 0.13g, 2-에틸헥산온산 0.12g 및 테트라키스(트리페닐포스핀)팔라듐 0.60g을 첨가하고 실온에서 2시간 동안 교반하였다. 반응액에 물 2㎖를 가한 다음 감압하에서 유기용매를 증류제거하였다. 농축수용액을 에테르로 세척한 다음 수층을 MPLC로 분리, 정제후 동결건조하여 표제 화합물 0.14g을 얻었다.Allyl (1S, 5R, 6S) -2-[(1'R)-(isopropyl) hydroxymethyl] -6-[(1'R) -hydroxyethyl] -1-methyl- 0.21 g of 2-carbapenem-3-carboxylate was dissolved in 12 ml of anhydrous dichloromethane, the reaction flask was wrapped with aluminum foil, 0.05 g of triphenylphosphine, 0.13 g of potassium 2-ethylhexanoic acid, 2-ethylhexane 0.12 g of warm acid and 0.60 g of tetrakis (triphenylphosphine) palladium were added and stirred at room temperature for 2 hours. 2 ml of water was added to the reaction solution, and the organic solvent was distilled off under reduced pressure. The concentrated aqueous solution was washed with ether, the aqueous layer was separated by MPLC, purified and lyophilized to obtain 0.14 g of the title compound.
[실시예 2]Example 2
[칼륨 (1S, 5R, 6S)-2-[(1'R)-(시클로프로필)히드록시메틸]-6-[(1'R)-1'-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실산의 제조][Potassium (1S, 5R, 6S) -2-[(1'R)-(cyclopropyl) hydroxymethyl] -6-[(1'R) -1'-hydroxyethyl] -1-methyl-2 Preparation of Carbapenem-3-carboxylic Acid]
[단계 1][Step 1]
알릴 (1S, 5R, 6S)-2-[(1'R)-(시클로프로필)히드록시메틸]-6-[(1'R)-1'-트리에틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트(1a) 및 알릴(1S, 5R, 6S)-2-[(1'S)-(시클로프로필)히드록시메틸]-6-[(1'R)-1'-트리에틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트(1b)의 제조Allyl (1S, 5R, 6S) -2-[(1'R)-(cyclopropyl) hydroxymethyl] -6-[(1'R) -1'-triethylsilyloxyethyl] -1-methyl- 2-carbapenem-3-carboxylate (1a) and allyl (1S, 5R, 6S) -2-[(1'S)-(cyclopropyl) hydroxymethyl] -6-[(1'R) -1 Preparation of '-triethylsilyloxyethyl] -1-methyl-2-carbapenem-3-carboxylate (1b)
잘게 자른 리튬 0.48g을 무수 에테르 50㎖에 첨가하고 시클로프로필브롬 2.46㎖을 빙냉하에서 천천히 가한 다음 실온에서 2시간동안 반응시켰다. 제조예 1에서 제조한 알릴 (1S, 5R, 6S)-2-포밀-6-[(1'R)-1'-트리에틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트 8.0g을 무수에테르에 용해시킨 후 -78℃로 냉각시키고 상기 시클로프로필 리튬 용액을 적가한 다음 동일 온도에서 30분간 교반하였다. 반응액에 염화암모늄 포화 용액을 가하고 에테르로 추출하여 유기층을 건조시키고 감압하에서 증발시켜 얻은 잔류물을 컬럼 크로마토그래피 하여 분리, 정제함으로써 4.5g의 표제화합물 (1a)(TLC Rf=0.31, 용출액 : 헥산/아세트산에틸=3/1)와 2.1g의 표제화합물 (1b)(TLC Rf=0.22, 용출액 : 헥산/아세트산에틸=3/1)를 얻었다. 알릴 (1S, 5R, 6S)-2-[(1'R)-(시클로프로필)히드록시메틸]-6-[(1'R)-트리에틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트(1a)0.48 g of finely chopped lithium was added to 50 ml of anhydrous ether, and 2.46 ml of cyclopropyl bromide was slowly added under ice-cooling, followed by reaction at room temperature for 2 hours. Allyl (1S, 5R, 6S) -2-formyl-6-[(1'R) -1'-triethylsilyloxyethyl] -1-methyl-2-carbapenem-3- prepared in Preparation Example 1 8.0 g of the carboxylate was dissolved in anhydrous ether, cooled to -78 ° C, the cyclopropyl lithium solution was added dropwise, and stirred at the same temperature for 30 minutes. 4.5 g of the titled compound (1a) (TLC R f = 0.31, eluate) by adding a saturated ammonium chloride solution to the reaction solution, extracting with ether, drying the organic layer and evaporating under reduced pressure, column chromatography and separating and purifying the residue. Hexane / ethyl acetate = 3/1) and 2.1 g of the title compound (1b) (TLC R f = 0.22, eluent: hexane / ethyl acetate = 3/1) were obtained. Allyl (1S, 5R, 6S) -2-[(1'R)-(cyclopropyl) hydroxymethyl] -6-[(1'R) -triethylsilyloxyethyl] -1-methyl-2-car Bapenem-3-carboxylate (1a)
알릴 (1S, 5R, 6S)-2-[(1'S)-(시클로프로필)히드록시메틸]-6-[(1'R)-트리에틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트(1b)Allyl (1S, 5R, 6S) -2-[(1'S)-(cyclopropyl) hydroxymethyl] -6-[(1'R) -triethylsilyloxyethyl] -1-methyl-2-carbapenem 3-carboxylate (1b)
[단계 2][Step 2]
1) 알릴 (1S, 5R, 6S)-2-[(1'R)-(시클로프로필)히드록시메틸]-6-[(1'R)-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트의 제조1) Allyl (1S, 5R, 6S) -2-[(1'R)-(cyclopropyl) hydroxymethyl] -6-[(1'R) -hydroxyethyl] -1-methyl-2-car Preparation of Bafenem-3-carboxylate
단계 1에서 제조한 알릴 (1S, 5R, 6S)-2-[(1'R)-(시클로프로필)히드록시메틸]-6-[(1'R)-1'-트리에틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트 0.31g을 사용하고 2시간동안 반응시키는 것을 제외하고는 실시예 1의 단계 2의 1)과 동일한 방법을 수행하여 표제화합물 0.19g을 얻었다.Allyl (1S, 5R, 6S) -2-[(1'R)-(cyclopropyl) hydroxymethyl] -6-[(1'R) -1'-triethylsilyloxyethyl] 0.19 g of the title compound was obtained by the same method as 1) of Example 2, except that 0.31 g of -1-methyl-2-carbapenem-3-carboxylate was reacted for 2 hours. Got it.
2) 칼륨 (1S, 5R, 6S)-2-[(1'R)-(시클로프로필)히드록시메틸]-6-[(1'R)-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실산의 제조2) Potassium (1S, 5R, 6S) -2-[(1'R)-(cyclopropyl) hydroxymethyl] -6-[(1'R) -hydroxyethyl] -1-methyl-2-car Preparation of Bapenem-3-carboxylic Acid
1)에서 제조한 알릴 (1S, 5R, 6S)-2-[(1'R)-(시클로프로필)히드록시메틸]-6-[(1'R)-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트 0.21g을 무수 디클로로메탄 12㎖에 용해시키고 알루미늄 호일로 반응 플라스크를 싼 다음 트리페닐포스핀 0.05g, 칼륨 2-에틸헥사노에이트 0.13g, 2-에틸헥산온산 0.12g 및 테트라키스(트리페닐포스핀)팔라듐 0.60g을 첨가하고 실온에서 2시간동안 교반하였다. 반응액에 물 2㎖를 가한 다음 감압하에서 유기용매를 증류제거하였다. 농축수용액을 에테르로 세척한 다음 수층을 MPLC로 분리, 정제후 동결건조하여 표제 화합물 0.14g을 얻었다.Allyl (1S, 5R, 6S) -2-[(1'R)-(cyclopropyl) hydroxymethyl] -6-[(1'R) -hydroxyethyl] -1-methyl- 0.21 g of 2-carbapenem-3-carboxylate was dissolved in 12 ml of anhydrous dichloromethane, the reaction flask was wrapped with aluminum foil, 0.05 g of triphenylphosphine, 0.13 g of potassium 2-ethylhexanoate, 2-ethyl 0.12 g of hexanoic acid and 0.60 g of tetrakis (triphenylphosphine) palladium were added and stirred at room temperature for 2 hours. 2 ml of water was added to the reaction solution, and the organic solvent was distilled off under reduced pressure. The concentrated aqueous solution was washed with ether, the aqueous layer was separated by MPLC, purified and lyophilized to obtain 0.14 g of the title compound.
[실시예 3]Example 3
[칼륨 (1S, 5R, 6S)-2-[(1'R)-(시클로펜틸)히드록시메틸]-6-[(1'R)-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실산의 제조][Potassium (1S, 5R, 6S) -2-[(1'R)-(cyclopentyl) hydroxymethyl] -6-[(1'R) -hydroxyethyl] -1-methyl-2-carbafe Preparation of Nem-3-carboxylic Acid]
[단계 1][Step 1]
알릴 (1S, 5R, 6S)-2-[(1'R)-(시클로펜틸)히드록시메틸]-6-[(1'R)-트리메틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트의 제조]Allyl (1S, 5R, 6S) -2-[(1'R)-(cyclopentyl) hydroxymethyl] -6-[(1'R) -trimethylsilyloxyethyl] -1-methyl-2-carbafe Preparation of Nem-3-carboxylate]
2M 시클로펜틸클로라이드 1.4㎖을 사용하는 것을 제외하고는 실시예 2의 단계 1과 동일한 방법을 수행하여 표제 화합물 0.802g을 얻었다.0.802 g of the title compound was obtained by the same method as the Step 1 of Example 2, except that 1.4 ml of 2M cyclopentyl chloride was used.
[단계 2][Step 2]
1) 알릴 (1S, 5R, 6S)-2-[(1'R)-(시클로펜틸)히드록시메틸]-6-[(1'R)-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트의 제조]1) Allyl (1S, 5R, 6S) -2-[(1'R)-(cyclopentyl) hydroxymethyl] -6-[(1'R) -hydroxyethyl] -1-methyl-2-car Preparation of Bafenem-3-carboxylate]
단계 1에서 제조한 알릴 (1S, 5R, 6S)-2-[(1'R)-(시클로펜틸)히드록시메틸]-6-[(1'R)-트리메틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트 0.516g을 사용하고 1시간 동안 반응시키는 것을 제외하고는 실시예 1의 단계 2의 1)과 동일한 방법을 수행하여 표제 화합물 0.257g을 얻었다.Allyl (1S, 5R, 6S) -2-[(1'R)-(cyclopentyl) hydroxymethyl] -6-[(1'R) -trimethylsilyloxyethyl] -1-methyl prepared in step 1 0.257 g of the title compound was obtained by the same method as 1) of Step 2 of Example 1, except that 0.516 g of 2-carbapenem-3-carboxylate was reacted for 1 hour.
2) (1S, 5R, 6S)-2-[(1'R)-(시클로펜틸)히드록시메틸]-6-[(1'R)-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실산의 제조2) (1S, 5R, 6S) -2-[(1'R)-(cyclopentyl) hydroxymethyl] -6-[(1'R) -hydroxyethyl] -1-methyl-2-carbafe Preparation of Nem-3-carboxylic Acid
1)에서 제조한 알릴 (1S, 5R, 6S)-2-[(1'R)-(시클로펜틸)히드록시메틸]-6-[(1'R)-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트 0.257g을 사용하는 것을 제외하고는 실시예 1의 단계 2의 2)와 동일한 방법을 수행하여 표제 화합물 0.151g을 얻었다.Allyl (1S, 5R, 6S) -2-[(1'R)-(cyclopentyl) hydroxymethyl] -6-[(1'R) -hydroxyethyl] -1-methyl- 0.151 g of the title compound was obtained by the same method as 2, 2) of Example 1, except that 0.257 g of 2-carbapenem-3-carboxylate was used.
[실시예 4]Example 4
[칼륨 (1S, 5R, 6S)-2-[(1'R)-(1,3-티아졸릴 히드록시메틸]-6-[(1'R)-1'-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실산의 제조][Potassium (1S, 5R, 6S) -2-[(1'R)-(1,3-thiazolyl hydroxymethyl] -6-[(1'R) -1'-hydroxyethyl] -1- Preparation of Methyl-2-carbapenem-3-carboxylic Acid]
[단계 1][Step 1]
[알릴 (1S, 5R, 6S)-2-[(1'R)-(1,3-티아졸릴)히드록시메틸]-6-[(1'R)-1'-트리에틸실릴옥시에틸-1-메틸-2-카르바페넴-3-카르복실레이트의 제조][Allyl (1S, 5R, 6S) -2-[(1'R)-(1,3-thiazolyl) hydroxymethyl] -6-[(1'R) -1'-triethylsilyloxyethyl- Preparation of 1-methyl-2-carbapenem-3-carboxylate]
티아졸 0.6g을 무수 THF 25㎖에 용해시키고 -78℃로 냉각시킨 후 N-부탈리튬(1.6M 헥산용액) 4.4㎖를 천천히 적가하였다. 20분간 교반한 다음 동온도에서 무수 THF 20㎖에 용해시킨 제조예 1의 알릴 (1S, 5R, 6S)-2-포밀-6-[(1'R)-1'-트리에틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트 2.5g을 서서히 적가한 뒤 동온도에서 1시간 교반시켰다. 반응액에 염화암모늄 포화용액을 가하고 감압하에서 THF를 제거한 후 아세트산에틸 200㎖로 추출하여 유기층을 건조시키고 감압하에서 증발시켜 얻은 잔류물을 컬럼 크로마토그래피로 분리 정제하여 표제 화합물 1.2g을 얻었다.0.6 g of thiazole was dissolved in 25 mL of anhydrous THF, cooled to -78 DEG C, and 4.4 mL of N-butalithium (1.6 M hexane solution) was slowly added dropwise. Allyl (1S, 5R, 6S) -2-formyl-6-[(1'R) -1'-triethylsilyloxyethyl] of Preparation Example 1 which was stirred for 20 minutes and dissolved in 20 ml of dry THF at the same temperature. 2.5 g of -1-methyl-2-carbapenem-3-carboxylate was slowly added dropwise, followed by stirring at the same temperature for 1 hour. Saturated ammonium chloride was added to the reaction solution, THF was removed under reduced pressure, extracted with 200 ml of ethyl acetate, the organic layer was dried and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 1.2 g of the title compound.
[단계 2][Step 2]
1) 알릴 (1S, 5R, 6S)-2-[(1'R)-(1,3-티아졸릴)히드록시메틸]-6-[(1'R)-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트의 제조1) Allyl (1S, 5R, 6S) -2-[(1'R)-(1,3-thiazolyl) hydroxymethyl] -6-[(1'R) -hydroxyethyl] -1-methyl Preparation of 2-carbapenem-3-carboxylate
단계 1에서 제조한 알릴 (1S, 5R, 6S)-2-[(1'R)-(1,3-티아졸릴)히드록시메틸]-6-[(1'R)-1'-트리에틸실릴옥시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트 0.13g을 사용하고 1시간동안 반응시키는 것을 제외하고는 실시예 1의 단계 2의 1)과 동일한 방법을 수행하여 표제 화합물 55㎎을 얻었다.Allyl (1S, 5R, 6S) -2-[(1'R)-(1,3-thiazolyl) hydroxymethyl] -6-[(1'R) -1'-triethyl prepared in step 1 The same procedure as in step 2 of 1) of Example 1 was carried out except that 0.13 g of silyloxyethyl] -1-methyl-2-carbapenem-3-carboxylate was reacted for 1 hour. 55 mg of compound was obtained.
2) 칼륨 (1S, 5R, 6S)-2-[(1'R)-(1,3-티아졸릴)히드록시메틸]-6-[(1'R)-히드록시에틸-1-메틸-2-카르바페넴-3-카르복실산의 제조2) Potassium (1S, 5R, 6S) -2-[(1'R)-(1,3-thiazolyl) hydroxymethyl] -6-[(1'R) -hydroxyethyl-1-methyl- Preparation of 2-carbapenem-3-carboxylic acid
1)에서 제조한 알릴 (1S, 5R, 6S)-2-[(1'R)-(1,3-티아졸릴)히드록시메틸]-6-[(1'R)-히드록시에틸]-1-메틸-2-카르바페넴-3-카르복실레이트 30㎎을 사용하는 것을 제외하고는 실시예 1의 단계 2의 2)와 동일한 방법을 수행하여 표제 화합물 10.4㎎을 얻었다.Allyl (1S, 5R, 6S) -2-[(1'R)-(1,3-thiazolyl) hydroxymethyl] -6-[(1'R) -hydroxyethyl]- 10.4 mg of the title compound was obtained by the same method as 2) of Example 1, 2) except that 30 mg of 1-methyl-2-carbapenem-3-carboxylate was used.
상기 실시예들에 의해 제조된 본 발명에 따른 베타메틸카르바페넴계 유도체들의 항균 작용은 뮬러-힌톤 한천(Muller-Hinton agar)을 사용하여 2배수 한천 희석에 의한 한천 배지 희석법(Hoechst 345)에 의거하여 최소 성장 저해 농도(MIC)를 측정하였다. 그 결과를 하기 표 1에 나타내었다. 이 때 균의 접종은 약 107균체 형성 단위/㎖를 포함하며 균의 성장은 트라이박탐, SUN-5555를 대조물질로 사용하여 37℃에서 약 18시간 경과된 후 관찰하였다. 시험균주는 훽스트(Hoechst) 표준 균주를 사용하였다.The antimicrobial activity of the betamethylcarbapenem derivatives according to the present invention prepared by the above examples is based on agar medium dilution method (Hoechst 345) by diluting agar twice with Muller-Hinton agar. Minimal growth inhibition concentration (MIC) was measured. The results are shown in Table 1 below. At this time, the inoculation of the bacterium contained about 10 7 cell formation units / ml and the growth of the bacteria was observed after 18 hours at 37 ° C. using Tribactam, SUN-5555 as a control. Test strains were used Hoechst standard strain.
상기한 표 1에서 알 수 있듯이, 본 발명의 베타메틸 카르바페넴 유도체는 대조 물질인 경구용 페넴 화합물(SUN-5555)과 트라이박탐에 비해 대체로 항균 활성이 우수함을 알 수 있으며, 특히 연쇄상 구균(Streptococcus faecium), 클레브시엘라 아에로게니스(Klebsiella aerogenes) 및 엔테로박터 클로아크(Enterobacter cloacae)균에서는 대조물질에 비해 월등한 항균력을 나타내었다.As can be seen in Table 1, the betamethyl carbapenem derivative of the present invention can be seen that the antibacterial activity is generally superior to the oral penem compound (SUN-5555) and tribactam as a control material, in particular streptococci ( Streptococcus faecium, Klebsiella aerogenes and Enterobacter cloacae showed superior antimicrobial activity compared to the control.
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| KR970027084A (en) | 1997-06-24 |
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