KR960022526A - Novel carbapenem antibiotics and preparation method thereof - Google Patents

Novel carbapenem antibiotics and preparation method thereof Download PDF

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KR960022526A
KR960022526A KR1019940039916A KR19940039916A KR960022526A KR 960022526 A KR960022526 A KR 960022526A KR 1019940039916 A KR1019940039916 A KR 1019940039916A KR 19940039916 A KR19940039916 A KR 19940039916A KR 960022526 A KR960022526 A KR 960022526A
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alkyl
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KR100246948B1 (en
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김충렬
정원희
남기평
문광율
김미리
오성호
손희성
김용주
송혜경
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성재갑
주식회사 Lg 화학
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D477/16—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 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
    • C07D477/20—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D477/02—Preparation
    • C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

본 발명은 항균제로 유용한 다음 일반식(I)의 신규한 카바페넴 유도체, 그의 염, 에스테르, 용매화물 및 그의 이성체에 관한 것이다.The present invention relates to novel carbapenem derivatives of the following general formula (I), salts, esters, solvates and isomers thereof, useful as antimicrobial agents.

상기 식에서, R1은 1-히드록시에틸, 1-아미노에틸, 1-플루오로에틸 또는 히드록시메틸을 나타내며, R2는 수소, C1-4알킬기, 아미노메틸 또는 2-아미노에틸기를 나타내고, R3는 수소, C1-4알킬기, C3-6알케닐기, C3-7시클로알킬기 또는 아실옥시알킬기를 나타내며, R4및 R5는 각각 독립적으로 수소, C1-4알킬기, 아르알킬기 또는 -NBR′(여기서 R과 R′은 각각 독립적으로 수소, C1-4알킬기, C3-6알케닐기, C3-7시클로알킬기 또는 아실옥시알킬기를 나타낸다)를 나타내며, R6는 수소, C1-4알킬기, C3-6알케닐기, C3-7시클로알킬기 또는 아실옥시알킬기를 나타낸다.Wherein R 1 represents 1-hydroxyethyl, 1-aminoethyl, 1-fluoroethyl or hydroxymethyl, R 2 represents hydrogen, a C 1-4 alkyl group, aminomethyl or 2-aminoethyl group, R 3 represents hydrogen, a C 1-4 alkyl group, a C 3-6 alkenyl group, a C 3-7 cycloalkyl group or an acyloxyalkyl group, and R 4 and R 5 each independently represent hydrogen, a C 1-4 alkyl group, or an aralkyl group. Or —NBR ′ wherein R and R ′ each independently represent hydrogen, a C 1-4 alkyl group, a C 3-6 alkenyl group, a C 3-7 cycloalkyl group, or an acyloxyalkyl group, and R 6 represents hydrogen, C 1-4 alkyl group, C 3-6 alkenyl group, C 3-7 cycloalkyl group or acyloxyalkyl group.

Description

신규 카바페넴계 항생제 및 그의 제조방법Novel carbapenem antibiotics and preparation method thereof

본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음As this is a public information case, the full text was not included.

Claims (11)

다음 일반식(I)로 표시되는 카바페넴 화합물, 약제학적으로 허용가능한 그의 무독성염, 생리학적으로 가수분해 가능한 그의 에스테르, 수화물, 용매화물 또는 그의 이성질체.Carbapenem compound represented by the following general formula (I), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates, solvates or isomers thereof. 상기 식에서, R1은 1-히드록시에틸, 1-아미노에틸, 1-플루오로에틸 또는 히드록시메틸을 나타내며, R2는 수소, C1-4알킬기, 아미노메틸 또는 2-아미노에틸기를 나타내고, R3는 수소, C1-4알킬기, C3-6알케닐기, C3-7시클로알킬기 또는 아실옥시알킬기를 나타내며, R4및 R5는 각각 독립적으로 수소, C1-4알킬기, 아르알킬기 또는 -NRR′(여기서 R과 R′은 각각 독립적으로 수소, C1-4알킬기, C3-6알케닐기, C3-7시클로알킬기 또는 아실옥시알킬기를 나타낸다)를 나타내며, R6는 수소, C1-4알킬기, C3-6알케닐기, C3-7시클로알킬기 또는 아실옥시알킬기를 나타낸다.Wherein R 1 represents 1-hydroxyethyl, 1-aminoethyl, 1-fluoroethyl or hydroxymethyl, R 2 represents hydrogen, a C 1-4 alkyl group, aminomethyl or 2-aminoethyl group, R 3 represents hydrogen, a C 1-4 alkyl group, a C 3-6 alkenyl group, a C 3-7 cycloalkyl group or an acyloxyalkyl group, and R 4 and R 5 each independently represent hydrogen, a C 1-4 alkyl group, or an aralkyl group. Or —NRR ′ wherein R and R ′ each independently represent hydrogen, a C 1-4 alkyl group, a C 3-6 alkenyl group, a C 3-7 cycloalkyl group, or an acyloxyalkyl group, and R 6 represents hydrogen, C 1-4 alkyl group, C 3-6 alkenyl group, C 3-7 cycloalkyl group or acyloxyalkyl group. 제1항에 있어서, R′이 1-히드록시에틸인 화합물.The compound of claim 1, wherein R ′ is 1-hydroxyethyl. 제1항에 있어서, R2가 수소 또는 메틸인 화합물.The compound of claim 1, wherein R 2 is hydrogen or methyl. 제1항에 있어서, 다음의 화학식(IV)의 구조를 갖는 화합물.The compound of claim 1 having the structure of formula (IV) 상기 식에서, R3, R4, R5및 R6는 제1항에서 언급된 바와 같다.Wherein R 3 , R 4 , R 5 and R 6 are as mentioned in claim 1. 제1항에 있어서, 상기 일반식(I)의 화합물이 다음 (I-a) 내지 (I-e) 중에서 선택된 것인 화합물, 또는 약제학적으로 허용가능한 그의 무독성염, 생리학적으로 가수분해 가능한 그의 에스테르, 수화물, 용매화물 또는 이의 이성질체:The compound according to claim 1, wherein the compound of formula (I) is selected from (Ia) to (Ie), or a pharmaceutically acceptable nontoxic salt thereof, a physiologically hydrolysable ester thereof, a hydrate, Solvates or Isomers thereof: I-a:(4R,5S,6S)-3-〔2-(4-아미노피리미디니움-I-일)에틸티오〕-6-〔(1′R)-히드록시에틸)-4-메틸-7-옥소-1-아자바이시클로〔3.2.0〕헵트-2-엔-카르복실레이트.Ia: (4R, 5S, 6S) -3- [2- (4-aminopyrimidinium-I-yl) ethylthio] -6-[(1'R) -hydroxyethyl) -4-methyl-7 Oxo-1-azabicyclo [3.2.0] hept-2-ene-carboxylate. I-b:(4R,5S,6S)-3-〔2-(4-메틸아미노피리미디니움-1-일)에틸티오〕-6-〔(1′R)-히드록시에틸)-4-메틸-7-옥소-1-아자바이시클로〔3.2.0〕헵트-2-엔-2-카르복실레이트.Ib: (4R, 5S, 6S) -3- [2- (4-methylaminopyrimidin-1-yl) ethylthio] -6-[(1'R) -hydroxyethyl) -4-methyl- 7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate. I-c:(4R,5S,6S)-3-〔2-(4-아미노-6-메틸피리미디니움-1-일)에틸티오〕-6-〔(1′R)-히드록시에틸)-4-메틸-7-옥소-1-아자바이시클로〔3.2,0〕헵트-2-엔-2-카르복실레이트.Ic: (4R, 5S, 6S) -3- [2- (4-amino-6-methylpyrimidin-1-yl) ethylthio] -6-[(1'R) -hydroxyethyl) -4 -Methyl-7-oxo-1-azabicyclo [3.2,0] hept-2-ene-2-carboxylate. I-d:(4R,5S,6S)-3-(2-(4-아미노-5,6-디메틸피리미디니움-1-일)에틸티오〕-6-〔(1′R)-히드록시에틸〕-4-메틸-7-옥소-1-아자바이시클로〔3.2.0〕헵트-2-엔-2-카르복실레이트.Id: (4R, 5S, 6S) -3- (2- (4-amino-5,6-dimethylpyrimidin-1-yl) ethylthio] -6-[(1'R) -hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate. I-e:(4R,5S,6S)-3-〔2-(4-메틸아미노-5,6-디메틸피리미디니움-1-일)에틸티오〕-6-〔(1′R)-히드록시에틸)-4-메틸-7-옥소-1-아자바이시클로〔3.2.0〕헵트-2-엔-2-카르복실레이트.Ie: (4R, 5S, 6S) -3- [2- (4-methylamino-5,6-dimethylpyrimidin-1-yl) ethylthio] -6-[(1'R) -hydroxyethyl ) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate. 다음 일반식(II)의 화합물을 용매 존재하에서 다음 일반식(III)의 화합물과 반응시킴을 특징으로 하는 다음 인반식(I)의 화합물, 약제학적 허용가능한 그의 무독성염, 생리학적으로 가수분해 가능한 그의 에스테르, 수화물 또는 용매화물을 제조하는 방법.A compound of formula (I), a pharmaceutically acceptable non-toxic salt thereof, physiologically hydrolysable, characterized by reacting a compound of formula (II) with a compound of formula (III) in the presence of a solvent Process for preparing esters, hydrates or solvates thereof. 상기 식에서, R1은 1-히드록시에틸, 1-아미노에틸, 1-플루오로에틸 또는 히드록시메틸을 나타내며, R2는 수소, C1-4알킬기, 아미노메틸 또는 2-아미노에틸기를 나타내고, R3는 수소, C1-4알킬기, C3-6알케닐기, C3-7시클로알킬기 또는 아실옥시 알킬기를 나타내며, R4및 R5는 각각 독렵 적으로 수소, C1-4알킬기, 아르알킬기 또는 -NRR′(여기서 R과 R′은 각각 독립적으로 수소, C1-4알킬기, C3-6알케닐기, C3-7시클로알킬기 또는 아실옥시알킬기를 나타낸다)를 나타내며, R6는 수소, C1-4알킬기, C3-6알케닐기, C3-7시클로알킬기 또는 아실옥시알킬기를 나타내고, R7는 수소, C1-4알킬기, C3-6알케닐기 C3-7시클로알킬기 또는 아실옥시알킬기 또는 카르복실 보호기로서, 통상적으로 온화한 조건에서 쉽게 제거되는 것이며, R8는 1-플로오로에틸 또는 -CH(Ra)-ORb기이고, Ra는 수소 또는 C1-4알킬기를 나타내며, Rb는 수소 또는 히드록시 보호기이고, L은 이탈기를 나타낸다.Wherein R 1 represents 1-hydroxyethyl, 1-aminoethyl, 1-fluoroethyl or hydroxymethyl, R 2 represents hydrogen, a C 1-4 alkyl group, aminomethyl or 2-aminoethyl group, R 3 represents hydrogen, C 1-4 alkyl group, C 3-6 alkenyl group, C 3-7 cycloalkyl group or acyloxy alkyl group, R 4 and R 5 are each independently hydrogen, C 1-4 alkyl group, An alkyl group or —NRR ′ wherein R and R ′ each independently represent hydrogen, a C 1-4 alkyl group, a C 3-6 alkenyl group, a C 3-7 cycloalkyl group, or an acyloxyalkyl group, and R 6 represents hydrogen , C 1-4 alkyl group, C 3-6 alkenyl group, C 3-7 cycloalkyl group or acyloxyalkyl group, R 7 is hydrogen, C 1-4 alkyl group, C 3-6 alkenyl group C 3-7 cycloalkyl group Or an acyloxyalkyl group or carboxyl protecting group, which is usually easily removed under mild conditions, and R 8 is 1-fluoroethyl or -C Is a H (R a ) -OR b group, R a represents hydrogen or a C 1-4 alkyl group, R b is hydrogen or a hydroxy protecting group, and L represents a leaving group. 제6항에 있어서, R7는 가지가 있거나 없는, 알킬(C1-12)기, 저급알콕시저급알킬기, 저급지방족알콕시저급알킬기, 저급알콕시카르보닐옥시저급알킬기, 아릴저급알킬기, 트리(저급알킬)실릴기, 디아릴(저급알킬)실릴기, 트리(저급알킬)실릴저급알킬기 또는 알케닐(C2-6)기이고, Rb는 저급알케닐기, 저급알카노일기, 저급알콕시카르보닐기, 저급알케닐옥시카르보닐기, 아릴저급알콕시카르보닐기, 트리저급알킬실리기 또는 아릴저급알킬이고, L은 할로겐, 알카노일옥시기, 알칸술포닐옥시기, 아릴술포닐옥시, 알콕시카르보닐옥시 또는 포스포릭에스테르를 나타내는 일반식(I) 화합물의 제조방법. 7. An alkyl (C 1-12 ) group, lower alkoxy lower alkyl group, lower aliphatic alkoxy lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, aryl lower alkyl group, tri (lower alkyl) according to claim 6 ) Silyl group, diaryl (lower alkyl) silyl group, tri (lower alkyl) silyl lower alkyl group or alkenyl (C 2-6 ) group, R b is lower alkenyl group, lower alkanoyl group, lower alkoxycarbonyl group, lower Alkenyloxycarbonyl group, aryl lower alkoxycarbonyl group, trilower alkylsilyl group or aryl lower alkyl, L represents a halogen, alkanoyloxy group, alkanesulfonyloxy group, arylsulfonyloxy, alkoxycarbonyloxy or phosphoric ester Process for the preparation of the compound of formula (I). 제7항에 있어서, R7이 이소프로필, t-부틸, 메톡시메틸, 에톡시메틸, 이소부톡시메틸, 아세톡시메틸, 프로피오닐옥시메틸, 부티릴옥시메틸, 피바로일옥시메틸, 메톡시카르보닐옥시메틸, 1-에톡시카르보닐옥시메틸, p-메톡시벤질, o-니트로벤질, p-니트로벤질, 벤즈히드릴, 프타리딜, 트리메틸실릴, t-부틸디메틸실릴, t-부틸디페닐실릴, 트리메틸실릴에틸, 알릴 또는 비닐에틸이고, Rb는 알릴, 아세틸, t-부톡시카르보닐, 알릴옥시카르보닐, 벤조일옥시카르보닐, p-메톡시벤조일옥시카르보닐, 트리메틸실릴, t-부틸디메틸실릴 또는 벤질이고, L은 염소, 브롬, 요오드, 아세톡시, 메탄술포닐옥시, 트리플루오로메탄술포닐옥시 또는 파라톨루엔술포닐옥시를 나타내는 일반식(I) 화합물의 제조방법.The method of claim 7 wherein, R 7 is isopropyl, t- butyl, methoxymethyl, ethoxymethyl, isobutoxy methyl, acetoxymethyl, propionyloxy-methyl, butyryl oxymethyl, pivaloyl oxymethyl, methoxymethyl Carbonyloxymethyl, 1-ethoxycarbonyloxymethyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl, phthalidyl, trimethylsilyl, t-butyldimethylsilyl, t-butyl Diphenylsilyl, trimethylsilylethyl, allyl or vinylethyl, R b is allyl, acetyl, t-butoxycarbonyl, allyloxycarbonyl, benzoyloxycarbonyl, p-methoxybenzoyloxycarbonyl, trimethylsilyl, t-butyldimethylsilyl or benzyl, and L represents chlorine, bromine, iodine, acetoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy or paratoluenesulfonyloxy. 제6항에 있어서, 반응이 끝난후 히드록시 보호기 및 카르복실기 보호기를 제거함을 특징으로 하는 일반식(I) 화합물의 제조방법.The method for preparing a compound of formula (I) according to claim 6, wherein the hydroxy protecting group and the carboxyl protecting group are removed after the reaction. 제6항이 있어서, 반응을 요모드화나트륨, 요오드화칼륨, 브로모나트륨, 브로모칼륨 및 칼륨 티오시아네이트로 구성된 군에서 선택된 1종 또는 1종 이상의 안정화제 존재하에서 수행하는 것을 특징으로 하는 방법.The method of claim 6, wherein the reaction is carried out in the presence of one or more stabilizers selected from the group consisting of sodium iodide, potassium iodide, bromosodium, bromopotassium and potassium thiocyanate. 제1항 내지 5항 중의 어느 한 항의 화합물을 유효성분으로 함유하는 항생제 조성물.Antibiotic composition containing the compound of any one of Claims 1-5 as an active ingredient. ※ 참고사항:최초출원 내용에 의하여 공개하는 것임.※ Note: The disclosure is based on the initial application.
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