KR100463111B1 - Oxazolidinone derivatives, methods for producing the same and antibacterial composition containing the said compounds - Google Patents
Oxazolidinone derivatives, methods for producing the same and antibacterial composition containing the said compounds Download PDFInfo
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- KR100463111B1 KR100463111B1 KR1019970056574A KR19970056574A KR100463111B1 KR 100463111 B1 KR100463111 B1 KR 100463111B1 KR 1019970056574 A KR1019970056574 A KR 1019970056574A KR 19970056574 A KR19970056574 A KR 19970056574A KR 100463111 B1 KR100463111 B1 KR 100463111B1
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- 0 CC(C*CC(*)C(N1CCCC1)=O)=CC* Chemical compound CC(C*CC(*)C(N1CCCC1)=O)=CC* 0.000 description 4
- LQERCXTUDKGZSU-UHFFFAOYSA-N CC(CN1C(CCC2C3C4OCCOC4C3)CC2C=C)OC1O Chemical compound CC(CN1C(CCC2C3C4OCCOC4C3)CC2C=C)OC1O LQERCXTUDKGZSU-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
본원에서는 그람양성균 및 내성균에 우수한 항균활성을 나타내는 하기 화학식 1의 신규한 옥사졸리디논 유도체 또는 그의 염, 수화물 또는 광학이성체, 이의 제조방법 및 그를 유효성분으로 함유한 항균제 조성물이 기재된다:Disclosed herein are novel oxazolidinone derivatives of formula (1) or salts, hydrates or optical isomers thereof, methods for their preparation, and antimicrobial compositions containing them as active ingredients, which exhibit excellent antimicrobial activity against Gram-positive and resistant bacteria.
[화학식 1][Formula 1]
상기식에서, R1, R4 및 R5는 각각 독립적으로 (i) 수소, (ii) 불소, 염소, 히드록시, C1-C3 알킬, C1-C6 알콕시 및 C1-C6 아실옥시 중에서 선택된 하나 이상의 그룹에 의해 치환되거나 비치환된 C1-C6 알킬 또는 (iii) C3-C6 시클로알킬이며; R2는 독립적으로 수소, 불소, 염소 또는 메톡시이고; R3는 (i) 수소, (ii) 불소, 염소, 히드록시, C1-C3 알킬, C1-C6 알콕시 및 C1-C6 아실옥시중에서 선택된 하나 이상의 그룹에 의해 치환되거나 비치환된 C1-C6 알킬 또는 (iii) C3-C6 시클로알킬, (iv) 아미노, (v) C1-C6 알킬아미노, (vi) C1-C6 디알킬아미노 또는 (vii) C1-C6 알콕시이며; X는 히드록시이다.Wherein R 1, R 4 and R 5 are each independently selected from (i) hydrogen, (ii) fluorine, chlorine, hydroxy, C 1 -C 3 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 acyloxy C 1 -C 6 alkyl or (iii) C 3 -C 6 cycloalkyl unsubstituted or substituted by one or more groups; R 2 is independently hydrogen, fluorine, chlorine or methoxy; R 3 is unsubstituted or substituted by one or more groups selected from (i) hydrogen, (ii) fluorine, hydroxy, C 1 -C 3 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 acyloxy C 1 -C 6 alkyl or (iii) C 3 -C 6 cycloalkyl, (iv) amino, (v) C 1 -C 6 alkylamino, (vi) C 1 -C 6 dialkylamino or (vii) C 1 -C 6 alkoxy; X is hydroxy.
Description
본 발명은 신규한 페닐옥사졸리디논 유도체, 이를 제조하는 방법 및 그를 함유한 항균제 조성물에 관한 것이다.The present invention relates to a novel phenyloxazolidinone derivative, a method for preparing the same and an antimicrobial composition containing the same.
국제특허공개 제WO96/15130호 및 제WO95/25106은 항균활성을 갖는 옥사졸리디논 유도체를 기술하고 있다. 이들 화합물가운데 1환 또는 2환고리 유도체의 일부 화합물은 스타필로코카스 아우레우스, 스트렙토코카스 뉴모니아 등 그람 양성균에 반코마이신과 비교하여 동등 및 다소 열등하지만 유효한 약효를 나타냄을 알 수 있다.WO 96/15130 and WO 95/25106 describe oxazolidinone derivatives having antimicrobial activity. Among these compounds, some compounds of monocyclic or bicyclic derivatives are equivalent to and somewhat inferior to vancomycin but effective in Gram-positive bacteria such as Staphylococcus aureus and Streptococcus pneumoniae.
본 발명자들은 그람 양성균에 대하여 반코마이신과 비교하여 동등이상의 약효를 갖는 옥사졸리디논 항균제를 찾기위해 오랜기간에 걸쳐 집중적인 연구를 수행하였으며, 그 결과 신규한 2환고리를 도입한 신규한 옥사졸리디논 유도체를 발명하였고, 이들 화합물은 여러종의 그람양성균들에 대해 반코마이신보다 동등 이상의 강력한 항균활성을 나타냄을 발견하여 본 발명을 완성하게 되었다.The present inventors conducted intensive studies for a long time to find an oxazolidinone antimicrobial agent having an equivalent or more efficacy compared to vancomycin against gram-positive bacteria, and as a result, a novel oxazolidinone derivative introduced with a new bicyclic ring The present invention has been found that these compounds exhibit a stronger antimicrobial activity than that of vancomycin against a variety of Gram-positive bacteria, thereby completing the present invention.
본 발명은 하기 화학식 1로 나타내는 신규한 옥사졸리디논 유도체 및 이의 염 및 수화물을 제공한다:The present invention provides novel oxazolidinone derivatives represented by the following formula (1) and salts and hydrates thereof:
[화학식 1][Formula 1]
상기식에서,In the above formula,
R1, R4 및 R5는 각각 독립적으로 (i) 수소, (ii) 불소, 염소, 히드록시, C1-C3 알킬, C1-C6 알콕시 및 C1-C6 아실옥시중에서 선택된 하나 이상의 그룹에 의해 치환되거나 비치환된 C1-C6 알킬 또는 (iii) C3-C6 시클로알킬이며;R 1, R 4 and R 5 are each independently one or more groups selected from (i) hydrogen, (ii) fluorine, chlorine, hydroxy, C 1 -C 3 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 acyloxy C 1 -C 6 alkyl unsubstituted or substituted by (iii) C 3 -C 6 cycloalkyl;
R2는 독립적으로 수소, 불소, 염소 또는 메톡시이고;R 2 is independently hydrogen, fluorine, chlorine or methoxy;
R3는 (i) 수소, (ii) 불소, 염소, 히드록시, C1-C3 알킬, C1-C6 알콕시 및 C1-C6 아실옥시중에서 선택된 하나 이상의 그룹에 의해 치환되거나 비치환된 C1-C6 알킬 또는 (iii) C3-C6 시클로알킬, (iv) 아미노, (v) C1-C6 알킬아미노, (vi) C1-C6 디알킬아미노 또는 (vii) C1-C6 알콕시이며;R 3 is unsubstituted or substituted by one or more groups selected from (i) hydrogen, (ii) fluorine, hydroxy, C 1 -C 3 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 acyloxy C 1 -C 6 alkyl or (iii) C 3 -C 6 cycloalkyl, (iv) amino, (v) C 1 -C 6 alkylamino, (vi) C 1 -C 6 dialkylamino or (vii) C 1 -C 6 alkoxy;
X는 히드록시이다.X is hydroxy.
본 발명에 따라 페닐기에 치환된 하기 화학식 2로 표시된 3-아자-비시클로[3.1.1]헵탄 형태 유도체들은 광학활성을 가질 수 있는 헤테로 고리 화합물로서, R1, R4, R5, X에 따라, 라세믹체, 광학적으로 순수한 (-)체, (+)체 등이 가능하다.The 3-aza-bicyclo [3.1.1] heptane derivatives represented by the following Chemical Formula 2 substituted with phenyl groups according to the present invention are heterocyclic compounds which may have optical activity, according to R1, R4, R5, X, Lase Mixtures, optically pure (-) bodies, (+) bodies and the like are possible.
[화학식 2][Formula 2]
화학식1에서 사용된 용어중에 C1-C6는 탄소수가 1개 내지 6개의 탄화수소골격 구조를 의미하고, 다른 예로서 C1-C5는 탄소수가 1개에서 5개임을 의미하고, 이들은 또한 그것의 구조이성질체형태를 가질 수 있다.In terms used in Chemical Formula 1, C 1 -C 6 means a hydrocarbon skeleton having 1 to 6 carbon atoms, and as another example, C 1 -C 5 means 1 to 5 carbon atoms, which are also The structural isomer may have the form.
알킬기는 지방족 탄화수소기라 일컫고 여기에는 직쇄형(unbranched)과 측쇄형(branched)이 가능하다. 예로서 메틸, 에틸, n-프로필, i-프로필, n-부틸, s-부틸, t-부틸, n-펜틸, neo-펜틸 등을 들수 있다.Alkyl groups are referred to as aliphatic hydrocarbon groups, which can be unbranched and branched. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, neo-pentyl and the like.
아실기는 예로서 포르밀, 아세틸, 프로피오닐 등과 그들의 이성체를 일컫는다.Acyl groups refer to, for example, formyl, acetyl, propionyl and the like, and their isomers.
R2 치환체는 페닐기의 양쪽에 수소 또는 불소가 될 수 있으나, 특히, 바람직하게는 한쪽에는 수소원자로 치환되고 다른 쪽에는 불소로 치환되는 것이다.The R2 substituent may be hydrogen or fluorine on both sides of the phenyl group, but is particularly preferably substituted with a hydrogen atom on one side and fluorine on the other side.
R3 치환체는 바람직하게는 수소, 메틸, 디플루오로메틸, 디클로로메틸, 히드록시메틸 또는 메톡시가 될 수 있고, 가장 좋은 효과를 주는 것은 R3가 메틸기이다.The R3 substituent may preferably be hydrogen, methyl, difluoromethyl, dichloromethyl, hydroxymethyl or methoxy, with R3 being a methyl group giving the best effect.
본 발명에 있어서 옥사졸리디논 환의 C-5탄소의 가장 바람직한 절대배치(absolute configuration)는 Cahn-Ingold-Prelog명명법 하에서 (S)-에난티오머를 가지는 것이다. 약리적으로 우수한 항균활성을 지니는 것은 (S)-에난티오머이다. 라세믹체도 항생항균제로서 사용될 수 있는데, 그것의 항균력 차이는 순수한 (S)-에난티오머의 절반 정도이다. 따라서, 본 발명의 근간을 이루는 바람직한 화합물은 광학적으로 활성을 가지는 2환고리 헤테로화합물로 치환된 C-5가 (S)-에난티오머인 옥사졸리디논 유도체이다.In the present invention, the most preferred absolute configuration of the C-5 carbon of the oxazolidinone ring is to have (S) -enantiomer under Cahn-Ingold-Prelog nomenclature. It is (S) -enantiomer which has pharmacologically excellent antimicrobial activity. Racemics can also be used as antibiotics, with a difference in antimicrobial activity of about half that of pure (S) -enantiomers. Accordingly, a preferred compound underlying the present invention is an oxazolidinone derivative wherein C-5 is (S) -enantiomer substituted with an optically active bicyclic hetero compound.
또한, 본 발명은 (i) 하기 화학식(17)의 화합물을 하기화학식(2)의 화합물과 반응시켜 하기 화학식(3)의 화합물을 생성하고; (ii) 이를 환원시켜 하기 화학식(4)의 화합물을 생성하고; (iii) 이를 (R)-(-)-글리시딜 부틸레이트와 반응시켜 하기 화학식(5)의 화합물을 생성하고; (iv) 이를 메실 또는 토실화하여 하기 화학식(7)의 화합물을 생성하고; (v) 이를 아민화하고 아실화하고 탈보호하여 목적하는 화학식(1)의 화합물을 수득하는 단계를 포함함을 특징으로하여 상기 화학식(1)의 화합물을 제조하는 방법을 제공한다:In addition, the present invention (i) reacting a compound of formula (17) with a compound of formula (2) to produce a compound of formula (3); (ii) reduction to give the compound of formula (4); (iii) reacting it with (R)-(-)-glycidyl butyrate to yield the compound of formula (5); (iv) mesyl or tosylate to yield the compound of formula (7); (v) amination, acylating and deprotecting the same to obtain the desired compound of formula (1) to provide a process for preparing the compound of formula (1):
상기식에서, R1, R2, R4 및 R5는 상기 정의된 바와 같고, R6은 메틸 또는 벤질이며, R7은 메틸 또는 4-메틸페닐이며, Y는 X가 불필요한 반응에 참여하는 것을 방지하는 보호기이며, Z는 할로겐 또는 트리플루오로메탄 술포네이트이다.Wherein R1, R2, R4 and R5 are as defined above, R6 is methyl or benzyl, R7 is methyl or 4-methylphenyl, Y is a protecting group that prevents X from participating in unwanted reactions and Z is Halogen or trifluoromethane sulfonate.
또한, 본 발명에 따른 옥사졸리디논 유도체는 유기산 또는 무기산이 결합되어서 독성이 없는 약제학적으로 허용되는 염을 형성할 수 있다. 이때의 유기 및 무기산은 황산, 질산, 인산, 염산, 브롬산, 초산, 젖산, 타르타르산, 파모산, 숙신산, 에탄디설폰산, 설팜산, 벤조산 등이 가능하다.In addition, the oxazolidinone derivative according to the present invention may be combined with an organic acid or an inorganic acid to form a non-toxic pharmaceutically acceptable salt. The organic and inorganic acids at this time may be sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, bromic acid, acetic acid, lactic acid, tartaric acid, pamo acid, succinic acid, ethanedisulfonic acid, sulfamic acid, benzoic acid and the like.
본 발명의 화합물은 기존 항생항균제에 내성을 가지는 스타필로코카이, 스트렙토코카이, 엔테로코카이와 같은 그람양성 호기성 박테리아 뿐만 아니라 박테로이데스종, 클로스티리디아종 같은 혐기성 미생물과 마이코박테리움 투베르클로시스, 마이코박테리움 아비움 등의 마이코박테리움종 같은 항산성 미생물을 포함한 사람 및 동물 병원균에 효과적이다. 따라서, 본 발명은 또한 상기 화학식 1의 신규한 페닐옥사졸리디논 유도체를 유효성분으로 함유한 항균 약재 조성물을 제공한다.Compounds of the present invention are not only Gram-positive aerobic bacteria such as Staphylococcus, Streptococcus and Enterococcus, which are resistant to existing antibiotics, but also anaerobic microorganisms such as Bacteroides and Clostridia species and Mycobacterium tuberculosis. It is effective against human and animal pathogens including acidic microorganisms such as mycobacterium species such as Mycobacterium avium. Accordingly, the present invention also provides an antimicrobial pharmaceutical composition containing the novel phenyloxazolidinone derivative of Formula 1 as an active ingredient.
본 발명에 따른 화합물은 그대로 사용해도 좋으나, 제제용 담체와 배합하여 경구, 비경구 및 국소투여에 적합한 액체, 고체 또는 반고체 형태로 제형화시켜 투여할 수 있는데 예를들면 정제, 액제, 캅셀제, 과립제, 세립제, 산제, 시럽제, 주사제 및 연고제등이 가능하다.The compound according to the present invention may be used as it is, but may be formulated into a liquid, solid or semisolid form suitable for oral, parenteral and topical administration in combination with a carrier for preparation, for example, tablets, liquids, capsules, granules. , Fines, powders, syrups, injections and ointments.
본 발명에서 약제학적으로 받아질 수 있는 구성성분으로는, 약제학적으로 허용된, 고체나 액체의 전달매개체(carrier), 보조제(adjuvants), 첨가제(excipients) 등이 혼합될 수 있는데, 혼합방법으로는 표준방법이거나 편리한 기술적 방법으로서 적용될 수 있다.Pharmaceutically acceptable components in the present invention, pharmaceutically acceptable, solid or liquid carriers, adjuvants, excipients, etc. may be mixed. May be applied as a standard method or as a convenient technical method.
이렇게 얻어진 성분은 사람이나 동물에 미생물감염치료에 사용될 수 있고 투여경로는 경구제나 주사제로서 가능하다.The components thus obtained can be used for the treatment of microbial infections in humans or animals and the route of administration can be oral or injection.
투여상 바람직한 양은 치료되어야 할 환자의 연령, 체중, 증상, 투여경로 등에 따라 가변적이나 일반적으로 1mg/체중kg/일 내지 1000mg/체중kg/일이고, 바람직하게는 10mg/체중kg/일 내지 500mg/체중kg/일이다.The preferred amount for administration varies depending on the age, weight, symptoms, route of administration, etc. of the patient to be treated, but is generally 1 mg / kg / day to 1000 mg / kg / day, preferably 10 mg / kg / day to 500 mg / Weight kg / day.
본 발명의 조성물은 통상의 방법으로 고체 또는 액체로 제형될 수 있다. 고형제제는 분제, 정제, 캡슐제, 좌제, 카세(cachet) 등을 포함한다. 고형제제에 사용되는 담체는 중량제, 감미제, 융해보조제, 활택제, 현탁제, 결합제, 붕해제, 포합제로서 기능을 할 수 있는 최소한 1가지 이상의 물질이 될 수 있다. 비활성 고체 담체로서는 탄산마그네슘, 스테아린산마그네슘, 탈크, 당, 락토오스, 펙틴, 덱스트린, 전분, 젤라틴, 저융점의 왁스, 코코아버터, 그리고 그들과 유사한 것들을 포함한다.The compositions of the present invention may be formulated in a solid or liquid manner in conventional manner. Solid form preparations include powders, tablets, capsules, suppositories, cachets and the like. The carrier used in the solid preparation may be at least one substance capable of functioning as a weighting agent, sweetening agent, fusion aid, lubricant, suspending agent, binder, disintegrant, binder. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, low melting wax, cocoa butter, and the like.
액체제제는 용액, 현탁액 및 에멀젼을 포함하다. 담체의 예로서 물, 물과 프로필렌글리콜의 혼합물, 물과 폴리프로필렌글리콜의 혼합물이 사용될 수 있고, 추가로 색소, 감미제, 안정화제, 점도증가제 등의 첨가제가 사용 가능하다.Liquid formulations include solutions, suspensions, and emulsions. As examples of the carrier, water, a mixture of water and propylene glycol, a mixture of water and polypropylene glycol may be used, and additives such as colorants, sweeteners, stabilizers, viscosity increasing agents, etc. may be used.
액제 또는 연고제는 이비인후과나 안과에서 치료목적으로 특히 사용될 수 있다. 바람직하게는 약제학적 구성은 본 발명의 항균활성을 가지는 물질의 효과적이거나, 적절한 투여량이 포함된 단위복용량을 통상의 방법으로 적용하는 것이라 할 수 있다. 사람이나 동물의 미생물 감염에 대한 치료에 있어서, 항균활성을 갖는 화합물이나 그것의 약제학적 구성성분은 경구나 주사제로서 가능하고, 항균활성을 주기 위한 혈중농도를 유지하기 위해 투여량 및 투여횟수를 조절할 수 있다.Liquids or ointments may be used particularly for therapeutic purposes in otolaryngology or ophthalmology. Preferably, the pharmaceutical composition may be said to apply in a conventional manner a unit dose containing an effective or appropriate dosage of the substance having the antimicrobial activity of the present invention. In the treatment of microbial infections in humans or animals, a compound having an antimicrobial activity or a pharmaceutical component thereof may be oral or injectable, and the dosage and frequency of administration are controlled to maintain blood concentration for giving antimicrobial activity. Can be.
주사제로서 가능한 투여경로는 정맥주사, 근육주사나 기타 다른 종래의 투여 경로가 가능하다. 주사제로서의 약제학적으로 가능한 구성성분은 화합물 그 자체뿐아니라 화합물들의 물에 녹을 수 있는 염이 가능하다. 이때 염은 산염이나 염기염이 가능하다.Possible routes of administration as injections are intravenous, intramuscular or other conventional routes of administration. Pharmaceutically possible constituents as injectables are not only the compounds themselves, but also salts which are soluble in the water of the compounds. The salt may be an acid salt or a base salt.
항균활성을 지닌 화합물이나 그의 약제학적으로 유용한 염은 약제학적으로 유용한 담체를 사용하여 용액으로서 사용할 수 있는데, 그 예로서, 주사제에 사용되는 담체로는 약제학적으로 허용되는 물, 생리식염수 및 pH를 약 3 내지 7까지 조절할 수 있는 적당한 완충등장용액이 가능하다. 적당한 완충제의 예로서 오르토-인산나트륨, 중탄산나트륨, 시트르산나트륨, N-메틸글루카민, L-(+)-라이신, L(+)-아르기닌 뿐아니라 그외에 약제학적으로 통용되는 완충물질들이 가능하다.The compound having an antimicrobial activity or a pharmaceutically useful salt thereof may be used as a solution using a pharmaceutically useful carrier. For example, as a carrier used for injection, a pharmaceutically acceptable water, physiological saline and pH may be used. Appropriate buffering solutions are possible which can be adjusted up to about 3-7. Examples of suitable buffers include ortho-sodium phosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L-(+)-lysine, L (+)-arginine as well as other pharmaceutically acceptable buffers. .
본 발명에 따른 광학적으로 순수한 에난티오머 옥사졸리디논 유도체는 문헌[J. Med. Chem., 39, (1996), p 9673] 및 [J. Med. Chem., 35, (1992), p 1156]을 참고로 하여 합성할 수 있으며, 하기 도식1 및 도식2는 화학식 1에 관계된 광학적으로 순수한 에난티오머 옥사졸리디논 유도체 합성에 관한 제법을 보여주고 있다. 화학식 17에서 보여준 3-아자비시클로-[3.1.1]-헵탄 헤테로고리 아민 유도체(화학식 17)는 문헌[Heterocycle, 25.,(1989), p 29]을 참고로하여 합성할 수 있다.Optically pure enantiomeric oxazolidinones derivatives according to the invention are described in J. Med. Chem., 39, (1996), p 9673] and [J. Med. Chem., 35, (1992), p 1156], and Scheme 1 and Scheme 2 below show a method for the synthesis of optically pure enantiomer oxazolidinone derivatives related to formula (1). . The 3-azabicyclo- [3.1.1] -heptane heterocyclic amine derivative (Formula 17) shown in Formula 17 can be synthesized with reference to Heterocycle, 25., (1989), p 29.
[도식 1]Scheme 1
[도식 2]Scheme 2
(상기식에서, R1, R2, R4, R5, R6, R7, Y 및 Z는 위에서 정의한 바와 같다)(Wherein R1, R2, R4, R5, R6, R7, Y and Z are as defined above)
[도식 3]Scheme 3
(상기식에서, R1, R4 및 R5는 상기 화학식(1)에서 정의한 바와 같다)(Wherein R1, R4 and R5 are as defined in formula (1) above)
도식 1은 광학적으로 순수한 에난티오머 옥사졸리디논 유도체의 합성에 관한 제법을 나타낸 것이다. 이에 관련된 합성제법은 문헌[J. Med. Chem., 39, (1996), p 9673] 및 [J. Med. Chem., 35, (1992), p 1156]을 참고로 하여 합성할 수 있다.Scheme 1 shows a process for the synthesis of optically pure enantiomeric oxazolidinone derivatives. Synthesis methods related thereto are described in J. Chem. Med. Chem., 39, (1996), p 9673] and [J. Med. Chem., 35, (1992), p 1156].
도식 2에서 보여주는 바와 같이, 화학식(17)의 3-아자-[3.1.1]헵탄 헤테로고리아민 유도체는 방향족 친핵반응을 이룰 수 있는 기능화된 화학식(2)의 니트로벤젠 유도체(Z는 할로겐, 혹은 트리플루오로 메탄 술포네이트)와 적절한 염기의 존재하에, 적절한 용매조건에서 반응하여 화학식(3)의 화합물을 얻을 수 있다. 예로서, 디메틸술폭사이드 용매에서 2염기성 인산칼륨 염기조건, 혹은 아세토니트릴, 테트라히드로퓨란 또는 클로로포름같은 할로겐화 알칸용매에서 N,N-디이소프로필에틸아민이나 트리에틸아민 같은 유기염기조건에서 반응시켜 화학식(3)의 화합물 유도체를 얻을 수 있다. 이때, 전형적으로 적절한 반응온도는 실온에서 약 80℃까지이다.As shown in Scheme 2, the 3-aza- [3.1.1] heptane heterocyclic amine derivative of formula (17) is a nitrobenzene derivative of formula (2) which is capable of aromatic nucleophilic reaction (Z is halogen, or Trifluoro methane sulfonate) and the appropriate base can be reacted under appropriate solvent conditions to obtain the compound of formula (3). As an example, the reaction may be carried out under basic conditions such as dibasic potassium phosphate in a dimethyl sulfoxide solvent or in an organic base such as N, N-diisopropylethylamine or triethylamine in a halogenated alkane solvent such as acetonitrile, tetrahydrofuran or chloroform. The compound derivative of (3) can be obtained. Typically, a suitable reaction temperature is from room temperature to about 80 ° C.
도식1에 도시된 반응 전반에 있어서 만일 X나 R1, R4 또는 R5가 불필요한 반응에 참여하여 부반응 물질이 생성될 경우를 방지하기 위하여 통상적으로 사용되는 적절한 보호기로서 보호할 수 있다. 이때 Y는 X의 일반적인 적절한 보호기이다. 예로서 Y가 케탈인 경우에 반응중에 생성될 1차 아민과의 반응을 사전에 방지하며, 필요시에 카르보닐로 탈보호시킨 후, 환원시켜서 히드록시기로 변형시킬 수 있다. 기능기의 보호 및 탈보호에 관련된 반응들은 통상적인 것으로 예를들면 문헌 Greene, T.W.,등 "Protective Group in Organic Synthesis" 2nd edition; John Wiley & Sons; New York, 1991을 참조로하여 수행할 수 있다.Throughout the reaction shown in Scheme 1, it can be protected with appropriate protecting groups commonly used to prevent the case where X or R1, R4 or R5 participate in unwanted reactions to produce side reactions. Where Y is a general suitable protecting group of X. For example, when Y is ketal, the reaction with the primary amine to be produced during the reaction can be prevented in advance, deprotected with carbonyl if necessary, and then reduced to transform into a hydroxy group. Reactions related to the protection and deprotection of functional groups are conventional and are described, for example, in Greene, T.W., et al. "Protective Group in Organic Synthesis" 2nd edition; John Wiley &Sons; New York, 1991, may be referred to.
화학식(3)의 화합물의 니트로 기능기는 적절한 촉매, 예로서 5% 내지 10% 팔라듐/카본, W-2라니니켈 등의 존재하에서 적당한 용매, 예로서 테트라히드로퓨란/물 같은 용매조건에서 수소반응으로 환원시킴으로서 니트로기를 아민기로 변환시킬 수 있다. 수소반응으로서 환원 이외에 기타 그에 해당하는 통용의 방법으로도 환원시킬 수 있다. 상기방법을 사용하여 생성된 아민 유도체는 정제과정을 거치지 않고 잔여 촉매를 여과하거나, 필요시 농축과정을 통해 용매를 변환시킨 후 모액에 적절한 염기와 알킬 혹은 아릴 클로로포메이트를 사용하여 화학식(4)의 우레탄 유도체를 만들 수 있다. 예로서, 중탄산나트륨과 벤질 혹은 메틸 클로로포메이트를 사용할 수 있다. 생성된 화학식(4)의 우레탄 유도체는 n-부틸리튬, 리튬 디이소프로필아미드(LDA)나 리튬 비스(트리메틸실릴)아미드 등의 염기를 사용하고, 테트라히드로퓨란, 에테르같은 적절한 용매와 -78℃에서 -60℃까지 적당한 온도조건에서 탈수소반응을 시키고 이어서 곧바로 분리하지 않고, 상용 시판되는 (R)-(-)-글리시딜부틸레이트와 함께 리튬화된 중간체를 얻고, 온도를 상승시키고, 물과 클로로포름, 에틸아세테이트와 같은 물에 불용인 유기용매를 첨가, 추출하여 화학식(5)의 5-(히드록시메틸)옥사졸리디논 모핵의 순수한 에난티오머를 얻을 수 있다.The nitro functional group of the compound of formula (3) is subjected to hydrogen reaction under a suitable solvent such as tetrahydrofuran / water in the presence of a suitable catalyst such as 5% to 10% palladium / carbon, W-2 nickel, etc. By reducing the nitro group can be converted to an amine group. In addition to reduction as a hydrogen reaction, it can also be reduced by other commonly used methods. The amine derivatives produced using the above method can be obtained by filtration of the remaining catalyst without purification or by concentrating the solvent if necessary by converting the solvent and then using an appropriate base and alkyl or aryl chloroformate in the mother liquor. The urethane derivative of can be made. As an example, sodium bicarbonate and benzyl or methyl chloroformate can be used. The resulting urethane derivative of formula (4) uses a base such as n-butyllithium, lithium diisopropylamide (LDA) or lithium bis (trimethylsilyl) amide, and is suitable at -78 ° C with an appropriate solvent such as tetrahydrofuran and ether. Dehydrogenation at moderate temperature conditions from to -60 ° C. and then immediately without separation, to obtain lithiated intermediates with commercially available (R)-(-)-glycidylbutylate, raise the temperature, and And insoluble organic solvents in water such as chloroform and ethyl acetate can be added and extracted to obtain the pure enantiomer of the 5- (hydroxymethyl) oxazolidinone nucleus of the formula (5).
화학식(5)의 화합물은 메탄술포닐클로라이드/피리딘, 메탄술포닐클로라이드/트리에틸아민/디클로로메탄이나 p-톨루엔술포닐클로라이드/피리딘 같은 반응조건에서 대응하는 화학식(7)의 메실레이트나 아릴술포네이트(예, p-톨루엔술포닐)로 기능기를 바꿀 수 있다. 이 술포네이트 유도체는 N,N-디메틸포름아미드나 1-메틸-2-피롤리디논같은 아프로틱용매에서 50℃ 내지 90℃ 온도 상에서 아지드나트륨 또는 아지드칼륨을 사용하여 아지드 중간체를 얻을 수 있다. 이때 18-크라운-6같은 촉매를 사용하여 반응 속도를 증가시킬 수 있다. 아지드 중간체는 에틸아세테이트 또는 메탄올 같은 적당한 용매를 사용하고, 팔라듐/카본, 백금 촉매 등을 사용하여 수소 반응시켜 대응하는 화학식(8)의 아민유도체로 변환시킬 수 있다. 다른 방법으로서, 아지드에서 아민으로의 변환은 아지드 중간체를 트리페닐포스핀과 같은 인화합물에 물/테트라히드로퓨란과 같은 적절한 용매조건에서 변환시킬 수 있고, 니켈클로라이드 촉매하에 수소화붕소나트륨을 사용하여 달성할 수 있다.Compounds of formula (5) are mesylates or arylsulfos of corresponding formula (7) under reaction conditions such as methanesulfonylchloride / pyridine, methanesulfonylchloride / triethylamine / dichloromethane or p-toluenesulfonylchloride / pyridine Nate (eg p-toluenesulfonyl) can be used to change functional groups. The sulfonate derivatives can be used to obtain azide intermediates using sodium azide or azide potassium at temperatures between 50 ° C. and 90 ° C. in aprotic solvents such as N, N-dimethylformamide or 1-methyl-2-pyrrolidinone. have. At this time, a catalyst such as 18-crown-6 can be used to increase the reaction rate. The azide intermediate can be converted to the corresponding amine derivative of formula (8) by hydrogen reaction using a suitable solvent such as ethyl acetate or methanol and using a palladium / carbon, platinum catalyst or the like. Alternatively, the azide to amine conversion can convert the azide intermediate to a phosphorus compound such as triphenylphosphine under appropriate solvent conditions such as water / tetrahydrofuran, and using sodium borohydride under a nickel chloride catalyst. Can be achieved.
또한, 화학식(7)의 술포네이트 유도체에서 아민으로의 변환은 프탈이미드 중간체를 경유하여 달성할 수 있다. 예를들면, 술포네이트 유도체를 아세토니트릴 용매에서 프탈이미드칼륨과 가열환류로 반응시켜 화학식(9)의 프탈이미드 중간체를 경유하여 화학식(8)의 아민을 얻을 수 있다.In addition, the conversion of the sulfonate derivatives of formula (7) to amines can be achieved via phthalimide intermediates. For example, the sulfonate derivative may be reacted with potassium phthalimide by heating under reflux in an acetonitrile solvent to obtain the amine of formula (8) via the phthalimide intermediate of formula (9).
또한, 화학식(7)의 메실레이트에서 물/이소프로판올/테트라히드로퓨란과 같은 적절한 용매에서 직접 화학식(8)의 아민으로 변환시킬 수도 있다.It is also possible to convert the mesylate of formula (7) directly into an amine of formula (8) in a suitable solvent such as water / isopropanol / tetrahydrofuran.
생성된 화학식(8)의 아민은 -50℃ 내지 50℃의 온도 범위에서 피리딘과 같은 염기성 용매에서 산클로라이드 또는 산 무수화물 등과 반응시켜 통상적인 방법으로 화학식(10)의 아실화 화합물을 얻을 수 있다.The resulting amine of formula (8) may be reacted with an acid chloride or an acid anhydride in a basic solvent such as pyridine in a temperature range of -50 ° C to 50 ° C to obtain an acylated compound of formula (10) in a conventional manner. .
도식 3은 아실화 반응 후 케탈로 보호된 카르보닐기를 탈보호시킴으로서, 생성된 카르보닐 유도체들(11)을 히드록시 화합물로의 변환을 도식화한 것이다. 예로서, 화학식 1의 히드록시 유도체는 카르보닐 유도체(11)을 통상의 방법인 수소화 붕소나트륨과 환원반응 시킴으로서 얻을 수 있다.Scheme 3 illustrates the conversion of the resulting carbonyl derivatives (11) to hydroxy compounds by deprotecting the carbonyl groups protected with ketals after the acylation reaction. As an example, the hydroxy derivative of the formula (1) can be obtained by reducing the carbonyl derivative (11) with sodium borohydride which is a conventional method.
상기 합성 경로와 관련된 반응이나 반응 조건은 문헌 Greene, T.W. "Protective Groups in Organic Synthesis", 2nd edition; John Wiley & Sons: New York, 1991; Francis A. Carey "Advanced Organic Chemistry" 3rd edition; Plenum Press, March J. "Advanced Organic Chemistry" 4th edition; John Wiley & sons; New York, 1992 등의 문헌 및 이들 문헌에 인용된 논문이나 특허를 참고로 할 수 있다.Reactions or reaction conditions associated with such synthetic routes are described in Greene, T.W. "Protective Groups in Organic Synthesis", 2nd edition; John Wiley & Sons: New York, 1991; Francis A. Carey "Advanced Organic Chemistry" 3rd edition; Plenum Press, March J. "Advanced Organic Chemistry" 4th edition; John Wiley &Sons; See New York, 1992, et al., And articles or patents cited therein.
본 발명의 화합물은 기존항생항균제에 내성을 가지는 스타필로코카이, 스트렙토코카이, 엔테로코카이와 같은 그람양성 호기성 박테리아 뿐만아니라, 박테로이데스종, 클로스티리디아종과 같은 혐기성 미생물과 마이코박테리움 투베르쿨로시스, 마이코박테리움 아비움 등의 마이코박테리움종과 같은 항산성 미생물들을 포함하여 각종 사람 및 동물 병원균에 효과적이다.The compounds of the present invention are not only Gram-positive aerobic bacteria such as Staphylococcus, Streptococcus, and Enterococcus, which are resistant to conventional antibiotics, but also anaerobic microorganisms such as Bacteroides and Clostridia species and Mycobacterium tuber It is effective against various human and animal pathogens, including antimicrobial microorganisms such as mycobacterium species such as coulosis and mycobacterium avium.
본 발명은 유효성분으로서 상기 화학식1의 화합물을 함유하여 항생항균제로 사용할 수 있는 약제학적 조성물을 제공한다.The present invention provides a pharmaceutical composition that can be used as an antibiotic antibiotic containing the compound of Formula 1 as an active ingredient.
본 발명의 항균제 조성물은 사람 또는 동물을 대상으로 직접 사용함은 물론이고 어병약, 농약, 식품의 보존제등으로서도 사용가능하다. 인간이나 동물에서의 미생물감염을 치료하는 경우 그의 투여경로는 경구제 또는 주사제가 바람직하다. 경구제 또는 주사제로서, 이러한 투여량은 하루에 일회 내지 수회로 투여할 수 있다.The antimicrobial composition of the present invention can be used not only directly for humans or animals, but also as a fish disease drug, pesticide, food preservative, and the like. When treating microbial infections in humans or animals, the route of administration is preferably oral or injection. As oral or injection, such dosages may be administered once to several times a day.
본 발명의 항균제 조성물은 고체나 액체의 담체, 보조제(adjuvant), 부형제(excipient)등이 유효성분과 혼합되어 구성될수 있는데, 혼합방법으로는 표준방법이거나 통상적인 편리한 기술적 방법으로서 적용될 수 있다.The antimicrobial composition of the present invention may be composed of a solid or a liquid carrier, an adjuvant, an excipient, and the like mixed with an active ingredient. The mixing method may be a standard method or a conventional convenient technical method.
본 발명은 이하 실시예를 통해 좀더 구체적으로 설명될 것이다. 그러나, 이들 실시예는 본 발명을 단지 예시하고자하는 것이며 본 발명이 이들 실시예에 의해 한정되는 것으로 이해되어서는 안된다.The invention will be explained in more detail through the following examples. However, these examples are only intended to illustrate the invention and should not be construed as limiting the invention to these examples.
[실시예]EXAMPLE
참고예 1Reference Example 1
7-엑소-메틸-스피로[3-(파라-톨루엔술포닐)-3-아자비시클로[3.1.1]헵탄-6,2'-퍼히드로[1.3]디옥소란7-exo-methyl-spiro [3- (para-toluenesulfonyl) -3-azabicyclo [3.1.1] heptan-6,2'-perhydro [1.3] dioxolane
공지의 화합물인 7-엑소-메틸-6-옥소-3-(파라-톨루엔술포닐)-3-아자비시클로[3.1.1]헵탄 (참고 ; Heterocycles, 1989, 25, p 29) 13.3 g, 에틸렌글리콜 3.54 g과 파라톨루엔술포닐산.일수화물 0.2 g을 벤젠 250 ㎖에 가하고 딘-스탁기구를 이용하여 물을 제거하면서 24시간동안 가열환류하였다. 반응 완료후, 반응액에 에틸아세테이트 200 ㎖와 포화 탄산나트륨 수용액 200 ㎖를 가했다. 유기층을 물층으로부터 추출하고 유기층을 무수황산 나트륨으로 건조하고, 여과후 농축하여 표제 화합물 15g을 수득하였다.13.3 g, ethylene, known compound 7-exo-methyl-6-oxo-3- (para-toluenesulfonyl) -3-azabicyclo [3.1.1] heptane (cf. Heterocycles, 1989, 25 , p 29) 3.54 g of glycol and 0.2 g of paratoluenesulfonyl acid monohydrate were added to 250 ml of benzene and heated to reflux for 24 hours while removing water using a Dean-Stark apparatus. After the reaction was completed, 200 ml of ethyl acetate and 200 ml of saturated aqueous sodium carbonate solution were added to the reaction solution. The organic layer was extracted from the water layer and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 15 g of the title compound.
참고예 2Reference Example 2
7-엑소-메틸-스피로[3-아자비시클로[3.1.1]헵탄-6,2'-퍼히드로[1.3]디옥소란7-exo-methyl-spiro [3-azabicyclo [3.1.1] heptan-6,2'-perhydro [1.3] dioxolane
참고예 1의 화합물 8 g을 n-아밀알코올 60 ㎖에 가하고 가열환류시켰다. 그후, 나트륨 10 g을 조각조각 반응액에 가하면서 3시간동안 가열 환류시켰다. 반응액을 5℃로 냉각시키고 물 100 ㎖를 서서히 가했다. 반응액에 에틸아세테이트 100 ㎖를 가하고 추출하여 유기층을 물층에서 분리하였다. 유기층을 무수황산나트륨으로 건조시키고 여과후 감압농축하여 표제 화합물 4 g을 수득하였다.8 g of the compound of Reference Example 1 was added to 60 ml of n-amyl alcohol and heated to reflux. Thereafter, 10 g of sodium was added to the fragment reaction solution and heated to reflux for 3 hours. The reaction solution was cooled to 5 ° C. and 100 ml of water was slowly added. 100 ml of ethyl acetate was added to the reaction mixture, followed by extraction. The organic layer was separated from the water layer. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4 g of the title compound.
참고예 3Reference Example 3
7-엑소-메틸-스피로[3-(2-플루오로-4-니트로페닐)-3-아자비시클로[3.1.1]헵탄-6,2'-퍼히드로[1.3]디옥소란7-exo-methyl-spiro [3- (2-fluoro-4-nitrophenyl) -3-azabicyclo [3.1.1] heptan-6,2'-perhydro [1.3] dioxolane
참고예 2의 화합물 9.2 g을 1,2-디클로로에탄 150 ㎖에 녹이고 N,N-디이소프로필에틸아민 7.1 g을 반응액에 가하고 5℃로 냉각시킨후, 3,4-디플루오로니트로벤젠 8.7 g을 서서히 가했다. 반응액을 24시간동안 가열환류한 후, 서서히 25℃로 방치한 다음 반응액을 감압농축하였다. 농축된 잔사에 메탄올 50 ㎖를 가하고 5℃로 냉각하였다. 이때, 생성된 노란 고체를 여과 건조하여서 표제화합물 5 g을 수득하였다.9.2 g of the compound of Reference Example 2 was dissolved in 150 ml of 1,2-dichloroethane, and 7.1 g of N, N-diisopropylethylamine was added to the reaction solution, which was cooled to 5 ° C., followed by 3,4-difluoronitrobenzene. 8.7 g was added slowly. After the reaction solution was heated to reflux for 24 hours, the reaction solution was slowly allowed to stand at 25 ° C and the reaction solution was concentrated under reduced pressure. 50 ml of methanol was added to the concentrated residue, and the mixture was cooled to 5 deg. At this time, the resulting yellow solid was filtered and dried to obtain 5 g of the title compound.
참고예 4Reference Example 4
N-카보벤족시-3-플루오로-4-(7-엑소-메틸스피로-[3-아자비시클로[3.1.1]헵탄-6,2'-퍼히드로[1,3]디옥소란]-3일)아닐린N-carbobenzoxi-3-fluoro-4- (7-exo-methylspiro- [3-azabicyclo [3.1.1] heptan-6,2'-perhydro [1,3] dioxolane]- 3 days) aniline
참고예 3의 화합물 4.6 g을 테트라히드로푸란 80 ㎖와 메탄올 80 ㎖의 혼합용매에 녹이고, 암모늄포메이트 3.8 g과 10%-팔라듐/카본 0.2 g을 가한 후, 3시간동안 가열환류한 다음 25℃로 냉각시키고 여과하였다. 여과한 모액을 감압농축하여 얻어진 잔사에 아세톤 100㎖를 가하여 녹이고, 중탄산나트륨 3.8 g이 녹은 수용액 100 ㎖를 가했다. 5℃로 반응액을 냉각하고 벤질클로로포메이트 3.2 ㎖를 서서히 가한 다음 25℃에서 24시간동안 반응시켰다. 반응완료후, 에틸아세테이트 200 ㎖를 가하여 유기층을 분리하고, 포화 소금물로 세척한 다음 무수황산나트륨으로 건조시켰다. 이어서, 감압여과하고 농축하여 표제화합물 7 g을 수득하였다.4.6 g of the compound of Reference Example 3 was dissolved in a mixed solvent of 80 ml of tetrahydrofuran and 80 ml of methanol, and 3.8 g of ammonium formate and 0.2 g of 10% -palladium / carbon were added, followed by heating to reflux for 3 hours, followed by 25 ° C. Cooled to and filtered. 100 ml of acetone was added to the residue obtained by concentrating the filtered mother liquid under reduced pressure, and 100 ml of aqueous solution in which 3.8 g of sodium bicarbonate was melt | dissolved was added. The reaction solution was cooled to 5 ° C. and 3.2 ml of benzylchloroformate was added slowly, followed by reaction at 25 ° C. for 24 hours. After completion of the reaction, 200 ml of ethyl acetate was added to separate the organic layer, washed with saturated brine, and dried over anhydrous sodium sulfate. Subsequent filtration under reduced pressure and concentration yielded 7 g of the title compound.
참고예 5Reference Example 5
(R)-[N-3-[3-플루오로-4-(7-엑소-메틸스피로-[3-아자비시클로[3.1.1]헵탄-6,2'-퍼히드로[1,3]디옥소란]-3일)페닐]-2-옥소-5-옥사졸리디닐]메탄올(R)-[N-3- [3-fluoro-4- (7-exo-methylspiro- [3-azabicyclo [3.1.1] heptan-6,2'-perhydro [1,3] di Oxolane] -3yl) phenyl] -2-oxo-5-oxazolidinyl] methanol
참고예 4의 화합물 7 g을 무수 테트라히드로퓨란 200 ㎖에 녹이고 반응액을 -78℃로 건조된 질소하에서 냉각시켰다. 2.5 M n-부틸리튬 11 ㎖를 서서히 가하고 같은 온도에서 1.5시간 반응시켰다. 반응액에 R-(-)-글리시딜 부틸레이트 2.88 ㎖를 서서히 적가하고, 같은 온도에서 2시간동안 반응시키고, 서서히 25℃로 방치하면서 24시간동안 반응시켰다. 반응완료후, 5℃로 냉각하고, 포화 염화암모늄 수용액 50㎖를 서서히 가한 다음 에틸아세테이트 200 ㎖와 물 20 ㎖를 차례로 가했다. 유기층을 물층으로부터 분리하고, 유기층을 무수 황산나트륨으로 건조한 후, 여과하고 감압농축하였다. 농축한 잔사를 실리카겔 상에서 칼럼 크로마토그라피(에틸아세테이트:메탄올=7:1)하여 표제화합물 4 g을 수득하였다.7 g of the compound of Reference Example 4 was dissolved in 200 ml of anhydrous tetrahydrofuran and the reaction solution was cooled under nitrogen dried at -78 deg. 11 ml of 2.5 M n-butyllithium was slowly added and reacted at the same temperature for 1.5 hours. 2.88 mL of R-(-)-glycidyl butyrate was slowly added dropwise to the reaction solution, reacted at the same temperature for 2 hours, and allowed to react for 24 hours while slowly standing at 25 ° C. After completion of the reaction, the reaction mixture was cooled to 5 DEG C, 50 mL of saturated aqueous ammonium chloride solution was slowly added thereto, followed by 200 mL of ethyl acetate and 20 mL of water. The organic layer was separated from the water layer, and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrated residue was subjected to column chromatography on silica gel (ethyl acetate: methanol = 7: 1) to obtain 4 g of the title compound.
참고예 6Reference Example 6
(R)-[N-3-[3-플루오로-4-(7-엑소-메틸스피로-[3-아자비시클로[3.1.1]헵탄-6,2'-퍼히드로[1,3]디옥소란]-3일)페닐]-2-옥소-5-옥사졸리디닐]메틸 매탄술포네이트(R)-[N-3- [3-fluoro-4- (7-exo-methylspiro- [3-azabicyclo [3.1.1] heptan-6,2'-perhydro [1,3] di Oxolane] -3yl) phenyl] -2-oxo-5-oxazolidinyl] methyl methanesulfonate
참고예 5의 화합물 4 g을 디클로로메탄 50㎖에 녹이고 트리에틸아민 3.25 ㎖를 가했다. 반응액을 5℃로 냉각시키고, 메탄술포닐클로라이드 1 ㎖를 서서히 가한후 25 ℃에서 24시간동안 반응시켰다. 반응완료를 확인하고 (TLC: 에틸아세테이트 R불소=0.6), 반응액에 물 50 ㎖와 디클로로메탄 50 ㎖를 가했다. 유기층을 물층으로부터 분리하고, 포화 소금물로 세척하고, 무수황산나트륨으로 건조시킨 후, 여과하고, 감암농축하여 표제화합물 5 g을 수득하였다.4 g of the compound of Reference Example 5 was dissolved in 50 ml of dichloromethane, and 3.25 ml of triethylamine was added. The reaction solution was cooled to 5 ° C., and 1 ml of methanesulfonyl chloride was slowly added, followed by reaction at 25 ° C. for 24 hours. After completion of the reaction (TLC: ethyl acetate R fluoride = 0.6), 50 mL of water and 50 mL of dichloromethane were added to the reaction solution. The organic layer was separated from the water layer, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 5 g of the title compound.
참고예 7Reference Example 7
(R)-[N-3-[3-플루오로-4-(7-엑소-메틸스피로-[3-아자비시클로[3.1.1]헵탄-6,2'-퍼히드로[1,3]디옥소란]-3일)페닐]-2-옥소-5-옥사졸리디닐]메틸 아지드(R)-[N-3- [3-fluoro-4- (7-exo-methylspiro- [3-azabicyclo [3.1.1] heptan-6,2'-perhydro [1,3] di Oxolane] -3yl) phenyl] -2-oxo-5-oxazolidinyl] methyl azide
참고예 6의 화합물 5.2 g을 N,N-디메틸포름아미드 30㎖에 녹이고 아지드나트륨 3.2 g을 가한 후, 75℃로 24시간동안 가열하여 반응시켰다. 반응완료 후에 반응액을 25℃로 방치하고 에틸아세테이트 200 ㎖와 물 100 ㎖를 가하여 유기층을 분리하고, 유기층을 물 100 ㎖와 포화 소금물로 차례로 세척하고, 무수 황산나트륨으로 건조시킨 후, 여과하고, 감압농축하여 표제화합물 3.5 g을 수득하였다.5.2 g of the compound of Reference Example 6 was dissolved in 30 ml of N, N-dimethylformamide, 3.2 g of sodium azide was added, and the mixture was heated and reacted at 75 ° C. for 24 hours. After completion of the reaction, the reaction solution was left at 25 ° C, 200 ml of ethyl acetate and 100 ml of water were added to separate the organic layer. The organic layer was washed sequentially with 100 ml of water and saturated brine, dried over anhydrous sodium sulfate, filtered and depressurized. Concentration gave 3.5 g of the title compound.
참고예 8Reference Example 8
(S)-[N-3-[3-플루오로-4-(7-엑소-메틸스피로-[3-아자비시클로[3.1.1]헵탄-6,2'-퍼히드로[1,3]디옥소란]-3일)페닐]-2-옥소-5-옥사졸리디닐]메틸]아세트아미드(S)-[N-3- [3-fluoro-4- (7-exo-methylspiro- [3-azabicyclo [3.1.1] heptan-6,2'-perhydro [1,3] di Oxolane] -3yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide
참고예 7의 화합물 3 g을 에틸아세테이트 50 ㎖에 녹이고 10%-팔라듐/카본 0.7 g을 가한 후 50 psi 수소압력으로 수소반응을 시켰다. 반응완결은 TLC로 수시로 확인하였다 (TLC; 클로로포름:메탄올=2:1에서 R불소=0.3). 반응이 미완결될 때, 필요시 10%-팔라듐/카본을 촉매량씩 더 가했다. 반응완료 후에 여과하고, 여과한 모액에 피리딘 1.3 g을 가하고 5℃로 냉각시킨다음 아세트산무수물 3.0 g을 가하여 25℃에서 24시간 반응시켰다. 반응완결을 확인하고 (TLC; 에틸아세테이트:메탄올=7:1에서 R불소=0.3), 물 20 ㎖와 에틸아세테이트 50 ㎖를 가하여 유기층을 분리한다음, 유기층을 물과 포화소금물로 차례로 세척하고, 무수황산나트륨으로 건조시킨 후, 여과하고, 감압농축하였다. 잔사를 에틸 에테르와 n-헥산으로 고체화하여 백색고체상태의 표제화합물 3.5 g을 수득하였다.3 g of the compound of Reference Example 7 was dissolved in 50 ml of ethyl acetate, and 0.7 g of 10% -palladium / carbon was added thereto, followed by hydrogen reaction at 50 psi hydrogen pressure. Completion of the reaction was frequently confirmed by TLC (TLC; R fluorine = 0.3 at chloroform: methanol = 2: 1). When the reaction was incomplete, 10% -palladium / carbon was added in catalytic amounts, if necessary. After completion of the reaction, the resultant was filtered, 1.3 g of pyridine was added to the filtered mother liquor, cooled to 5 ° C., 3.0 g of acetic anhydride was added, and the reaction was carried out at 25 ° C. for 24 hours. After completion of the reaction (TLC; ethyl acetate: methanol = R fluorine at 0.3: 0.3), 20 ml of water and 50 ml of ethyl acetate were added to separate the organic layer, and the organic layer was washed with water and saturated brine in that order. After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was solidified with ethyl ether and n-hexane to obtain 3.5 g of the title compound as a white solid.
녹는점=170℃Melting point = 170 ℃
참고예 9Reference Example 9
(S)-N-[[3-[3-플루오로-4-(6-엑소-메틸-7-옥소-3-아자비시클로[3.1.1]헵탄-3일)페닐]-2-옥소-5-옥사졸리디닐]메틸]아세트아미드(S) -N-[[3- [3-fluoro-4- (6-exo-methyl-7-oxo-3-azabicyclo [3.1.1] heptan-3yl) phenyl] -2-oxo- 5-oxazolidinyl] methyl] acetamide
참고예 8의 화합물 1.4 g을 아세톤 60 ㎖와 물 4 ㎖에 녹이고, 파라톨루엔술폰산 일수화물 1 g을 가하고 7시간동안 가열환류시켰다. 반응완료후 에틸아세테이트 100 ㎖와 포화 탄산나트륨 수용액 50 ㎖를 가하고 추출하여 유기층을 분리하고, 물층을 다시 클로로포름 50 ㎖로 세척하였다. 분리된 유기층들을 무수황산나트륨으로 건조시킨 후, 여과하고, 감암농축하였다. 농축한 잔사를 실리카겔 상에서 칼럼 크로마토그라피 (에틸아세테이트:메탄올=5:1)하여 표제화합물 500 mg을 수득하였다.1.4 g of the compound of Reference Example 8 was dissolved in 60 ml of acetone and 4 ml of water, and 1 g of paratoluenesulfonic acid monohydrate was added and heated to reflux for 7 hours. After completion of the reaction, 100 ml of ethyl acetate and 50 ml of saturated aqueous sodium carbonate solution were added and extracted to separate the organic layer, and the water layer was washed with 50 ml of chloroform again. The separated organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The concentrated residue was subjected to column chromatography on silica gel (ethyl acetate: methanol = 5: 1) to obtain 500 mg of the title compound.
녹는점=152∼155℃Melting Point = 152 ~ 155 ℃
참고예 10Reference Example 10
(S)-N-[[3-[3-플루오로-4-(스피로[3-아자비시클로[3.1.1]헵탄-6,2'-퍼히드로[1,3]디옥소란]-3일)]페닐]2-옥소-5-옥사졸리디닐]메틸]아세트아미드(S) -N-[[3- [3-fluoro-4- (spiro [3-azabicyclo [3.1.1] heptan-6,2'-perhydro [1,3] dioxolane] -3 Il)] phenyl] 2-oxo-5-oxazolidinyl] methyl] acetamide
공지의 화합물인 6-옥소-3-(파라-톨루엔술포닐)-3-아자비시클로[3.1.1]헵탄 (참고; Heterocycles, 1989, 25, p 29 400MHz-1H-NMR(CDCl3); 7.7(2H,d), 7.3(2H,d), 3.7∼4.0(4H,m), 3.1(2H,m), 2.4(3H,s), 1.7∼2.1(2H,m)) 10 g을 출발물질로하여 참고예 1에서 참고예 8 까지의 일련의 반응들과 같은 방법 및 반응조건으로 표제화합물 1.5 g을 수득하였다.Known compound 6-oxo-3- (para-toluenesulfonyl) -3-azabicyclo [3.1.1] heptane (see Heterocycles, 1989, 25 , p 29 400 MHz- 1 H-NMR (CDCl 3 )); 7.7 (2H, d), 7.3 (2H, d), 3.7-4.0 (4H, m), 3.1 (2H, m), 2.4 (3H, s), 1.7-2.1 (2H, m)) starting 10 g 1.5 g of the title compound was obtained in the same manner and under the same reaction conditions as the reaction from Reference Example 1 to Reference Example 8 as a substance.
녹는점=155∼160℃Melting Point = 155 ~ 160 ℃
참고예 11Reference Example 11
(S)-N-[[3-[3-플루오로-4-(6-옥소-3-아자비시클로[3.1.1]헵탄-3일)페닐]-2-옥소-5-옥사졸리디닐]메틸]아세트아미드(S) -N-[[3- [3-fluoro-4- (6-oxo-3-azabicyclo [3.1.1] heptan-3yl) phenyl] -2-oxo-5-oxazolidinyl] Methyl] acetamide
참고예 10의 화합물 1 g을 가지고 참고예 9와 같은 방법으로, 반응에 필요한 화합물 및 시약을 동일한 비율의 당량을 가하여 표제 화합물 200 mg을 수득하였다.In the same manner as in Reference Example 9 with 1 g of the compound of Reference Example 10, the same ratio of the compound and the reagent required for the reaction was added to obtain 200 mg of the title compound.
녹는점=140∼145℃Melting Point = 140 ~ 145 ℃
참고예 12Reference Example 12
(S)-N-[[3-[3-플루오로-4-(1-메틸-스피로[3-아자비시클로[3.1.1]헵탄-6,2'-퍼히드로[1,3]디옥소란]-3-일)페닐]-2-옥소-5-옥사졸리디닐]메틸]아세트아미드(S) -N-[[3- [3-fluoro-4- (1-methyl-spiro [3-azabicyclo [3.1.1] heptan-6,2'-perhydro [1,3] dioxo Lan] -3-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide
공지의 화합물인 1-메틸-6-옥소-3-(파라-톨루엔술포닐)-3-아자비시클로[3.1.1]헵탄 (참고; Heterocycles, 1989, 25, p 29 400MHz-1H-NMR(CDCl3); 7.7(2H,d ), 7.3(2H,d), 3.6∼4.0(4H,m), 2.7(1H,m), 2.4(3H,s), 1.7∼2.0(2H,m)1.2(3H,s)) 10 g을 출발물질로 하여 참고예 1에서 참고예 8까지의 일련의 반응들과 같은 방법 및 반응조건으로 표제화합물 1.5 g을 수득하였다.Known compound 1-methyl-6-oxo-3- (para-toluenesulfonyl) -3-azabicyclo [3.1.1] heptane (see Heterocycles, 1989, 25 , p 29 400 MHz- 1 H-NMR ( CDCl 3 ); 7.7 (2H, d), 7.3 (2H, d), 3.6-4.0 (4H, m), 2.7 (1H, m), 2.4 (3H, s), 1.7-2.0 (2H, m) 1.2 (3H, s)) 1.5 g of the title compound were obtained by the same method and reaction conditions as the series of reactions from Reference Example 1 to Reference Example 8 using 10 g as a starting material.
녹는점=135∼140℃Melting Point = 135 ~ 140 ℃
참고예 13Reference Example 13
(S)-N-[[3-[3-플루오로-4-(1-메틸-6-옥소-3-아자비시클로[3.1.1]헵탄-3-일)페닐]-2-옥소-5-옥사졸리디닐]메틸]아세트아미드(S) -N-[[3- [3-fluoro-4- (1-methyl-6-oxo-3-azabicyclo [3.1.1] heptan-3-yl) phenyl] -2-oxo-5 -Oxazolidinyl] methyl] acetamide
참고예 12의 화합물 1 g을 가지고 참고예 9와 같은 방법으로, 반응에 필요한 화합물 및 시약을 동일한 비율의 당량을 가하여 표제의 화합물 200mg을 수득하였다.In the same manner as in Reference Example 9 with 1 g of the compound of Reference Example 12, the same ratio of the compound and the reagent required for the reaction was added to obtain 200 mg of the title compound.
녹는점=120∼125℃Melting Point = 120 ~ 125 ℃
실시예 1Example 1
(S)-N-[[3-[3-플루오로-4-(6-히드록시-7-엑소메틸-3-아자비시클로[3.1.1]헵탄-3일)페닐]-2-옥소-5-옥사졸리디닐]메틸]아세트아미드(S) -N-[[3- [3-fluoro-4- (6-hydroxy-7-exomethyl-3-azabicyclo [3.1.1] heptan-3yl) phenyl] -2-oxo- 5-oxazolidinyl] methyl] acetamide
참고예 9의 (S)-N-[[3-[3-플루오로-4-(7-엑소메틸-6-옥소-3-아자비시클로[3.1.1]헵탄-3일)페닐]-2-옥소-5-옥사졸리디닐]메틸]아세트아미드 10g에 메탄올 250ml와 테트라히드로퓨란 200ml에 NaBH4 1.1g이 녹아있는 용액을 가하였다. 이 혼합물을 60℃에서 1시간 교반하여 출발물질을 모두 환원시켰다. 이를 TLC로 확인하였다. 반응완료 후 초산으로 혼합용액을 pH=6.0으로 조절하고 물 500ml를 가한 후 감압농축하여 메탄올과 테트라히드로퓨란을 제거하고, 에틸아세테이트 500ml로 혼합물을 추출하였다. 유기층을 분리하여 MgSO4로 건조시키고 농축하여 생성된 고체를 에틸아세테이트와 헥산으로 재결정하여 표제화합물 5g을 수득하였다.(S) -N-[[3- [3-fluoro-4- (7-exomethyl-6-oxo-3-azabicyclo [3.1.1] heptan-3yl) phenyl] in Reference Example 9 To 10 g of oxo-5-oxazolidinyl] methyl] acetamide, a solution of 1.1 g of NaBH 4 dissolved in 250 ml of methanol and 200 ml of tetrahydrofuran was added. The mixture was stirred at 60 ° C. for 1 hour to reduce all starting materials. This was confirmed by TLC. After completion of the reaction, the mixture was adjusted to pH = 6.0 with acetic acid, 500 ml of water was added thereto, concentrated under reduced pressure to remove methanol and tetrahydrofuran, and the mixture was extracted with 500 ml of ethyl acetate. The organic layer was separated, dried over MgSO 4 , concentrated, and the resulting solid was recrystallized from ethyl acetate and hexane to obtain 5 g of the title compound.
녹는점=185℃Melting Point = 185 ℃
실시예 2Example 2
(S)-N-[[3-[3-플루오로-4-(6-히드록시-3-아자비시클로[3.1.1]헵탄-3일)페닐]-2-옥소-5-옥사졸리디닐]메틸]아세트아미드(S) -N-[[3- [3-fluoro-4- (6-hydroxy-3-azabicyclo [3.1.1] heptan-3yl) phenyl] -2-oxo-5-oxazolidinyl ] Methyl] acetamide
참고예 11의 (S)-N-[[3-[3-플루오로-4-(6-옥소-3-아자비시클로[3.1.1]헵탄-3일)페닐]-2-옥소-5-옥사졸리디닐]메틸]아세트아미드 500mg을 가지고 수소화붕소나트륨 65mg을 사용하여 실시예 1과 같은 방법 및 당량으로 표제화합물 200mg을 수득하였다.(S) -N-[[3- [3-fluoro-4- (6-oxo-3-azabicyclo [3.1.1] heptan-3yl) phenyl] of Reference Example 11] -2-oxo-5- Using 500 mg of oxazolidinyl] methyl] acetamide and 65 mg of sodium borohydride, 200 mg of the title compound were obtained by the same method and equivalent as in Example 1.
녹는점=175℃Melting Point = 175 ℃
실시예 3Example 3
(S)-N-[[3-[3-플루오로-4-(6-히드록시-1-메틸-3-아자비시클로[3.1.1]헵탄-3일)페닐]-2-옥소-5-옥사졸리디닐]메틸]아세트아미드(S) -N-[[3- [3-fluoro-4- (6-hydroxy-1-methyl-3-azabicyclo [3.1.1] heptan-3yl) phenyl] -2-oxo-5 -Oxazolidinyl] methyl] acetamide
참고예 13의 (S)-N-[[3-[3-플루오로-4-(6-옥소-3-아자비시클로[3.1.1]헵탄-3일)페닐]-2-옥소-5-옥사졸리디닐]메틸]아세트아미드 500mg을 가지고 수소화붕소나트륨 65mg을 사용하여 실시예 1과 같은 방법 및 당량으로 표제화합물 200mg을 수득하였다.(S) -N-[[3- [3-fluoro-4- (6-oxo-3-azabicyclo [3.1.1] heptan-3yl) phenyl] of Reference Example 13] -2-oxo-5- Using 500 mg of oxazolidinyl] methyl] acetamide and 65 mg of sodium borohydride, 200 mg of the title compound were obtained by the same method and equivalent as in Example 1.
녹는점=165℃Melting Point = 165 ℃
실험예 1Experimental Example 1
시험관내 항균활성측정In vitro antibacterial activity measurement
문헌(Chemotheraphy, 29(1), 76, (1981))에 기재된 방법에 따라 실시예 1에서 실시예 8까지의 화합물에 대해 한천희석법(agar dilution)에 의한 최소발육저지 농도(MIC: mcg/㎖)를 구하였으며, 이때 반코마이신을 대조군으로 하여 비교하였다. 측정결과는 하기 표 1에 나타낸 바와 같다.Minimum growth inhibition concentration (MIC: mcg / ml) by agar dilution for the compounds of Examples 1 to 8 according to the method described in Chemotheraphy, 29 (1), 76, (1981) ), And vancomycin was compared as a control. The measurement results are shown in Table 1 below.
[표 1]TABLE 1
상기 표 1의 결과로부터 알 수 있듯이, 본발명에 따른 화학식(1)의 화합물은 공지의 항생제인 반코마이신에 비해 거의 대등하거나 탁월한 항균활성을 나타냄을 알 수 있다.As can be seen from the results of Table 1, it can be seen that the compound of formula (1) according to the present invention shows almost the same or superior antimicrobial activity compared to vancomycin, a known antibiotic.
본 발명에 따른 화학식(1)의 신규한 옥사졸리디논 유도체는 대부분의 그람양성균 및 내성균에 대해서 탁월한 항균활성을 나타내고 있으므로 항균제로서 유용하게 사용할 수 있을 것으로 기대된다.The novel oxazolidinone derivatives of the general formula (1) according to the present invention show excellent antimicrobial activity against most Gram-positive bacteria and resistant bacteria, and thus are expected to be useful as antibacterial agents.
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| KR19990034862A (en) | 1999-05-15 |
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