KR100772426B1 - Oxazolidinone derivatives, processes for the preparation thereof, and compositions comprising the same - Google Patents

Oxazolidinone derivatives, processes for the preparation thereof, and compositions comprising the same Download PDF

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KR100772426B1
KR100772426B1 KR1020060039382A KR20060039382A KR100772426B1 KR 100772426 B1 KR100772426 B1 KR 100772426B1 KR 1020060039382 A KR1020060039382 A KR 1020060039382A KR 20060039382 A KR20060039382 A KR 20060039382A KR 100772426 B1 KR100772426 B1 KR 100772426B1
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enyl
oxazolidin
butyldimethylsilyloxyhexadec
hydroxyhexadec
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하현준
이원구
박중찬
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하현준
한국외국어대학교 산학협력단
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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
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione

Abstract

본 발명은 신규의 옥사졸리딘온 유도체 또는 그의 염, 그의 제조방법, 및 이를 유효성분으로 포함하는 조성물을 제공한다. 또한, 본 발명은 상기 옥사졸리딘온 유도체 또는 그의 염의 합성용 중간체를 제공한다.The present invention provides a novel oxazolidinone derivative or a salt thereof, a preparation method thereof, and a composition comprising the same as an active ingredient. The present invention also provides an intermediate for synthesizing the oxazolidinone derivative or a salt thereof.

본 발명의 옥사졸리딘온 유도체 또는 그의 염은 우수한 항암활성을 가진다. Oxazolidinone derivatives or salts thereof of the present invention have excellent anticancer activity.

옥사졸리딘온, 항암제 Oxazolidinone, an anticancer agent

Description

옥사졸리딘온 유도체, 그의 제조방법, 및 이를 포함하는 조성물{Oxazolidinone derivatives, processes for the preparation thereof, and compositions comprising the same}Oxazolidinone derivatives, a method for preparing the same, and a composition comprising the same {Oxazolidinone derivatives, processes for the preparation, and compositions comprising the same}

도 1은 본 발명의 화합물들의 백혈병 세포에 대한 활성 측정 결과를 나타낸다.1 shows the results of measuring activity of leukemia cells of the compounds of the present invention.

본 발명은 우수한 항암활성을 갖는 옥사졸리딘온 유도체 또는 그의 염, 그의 제조방법, 및 이를 포함하는 조성물에 관한 것이다. 또한, 본 발명은 상기 옥사졸리딘온 유도체 또는 그의 염의 합성용 중간체에 관한 것이다.The present invention relates to an oxazolidinone derivative or salt thereof having excellent anticancer activity, a preparation method thereof, and a composition comprising the same. The present invention also relates to an intermediate for synthesis of the oxazolidinone derivative or salt thereof.

생체내 분비 지질의 일종인 세라마이드의 합성과 대사는 항암제 개발의 표적(target)의 하나로서 알려져 있으며 (Cancer Letter, 206, 169-180 (2004)), 외부에서 세라마이드를 가함으로써 세포 사멸을 유도하여 항암 기능을 발휘할 수 있음이 공지되어 있다 (Biochem. Pharmacol. 65, 1633 - 1642 (2003). Synthesis and metabolism of ceramide, a type of secreted lipid in vivo, is known as one of the targets of anticancer drug development (Cancer Letter, 206, 169-180 (2004)), and induces cell death by adding ceramide externally. It is known that it can exert anticancer function (Biochem. Pharmacol. 65, 1633-1642 (2003).

또한, 항암활성을 갖는 다양한 구조의 세라마이드 유도체가 알려져 있으며, 예를 들면, J. Pharmacol. Exp. Therapeutics, 309, 523 - 532 (2004); Org. Lett. 7, 1645 - 1648 (2005); J. Med. Chem. 46, 3445 - 3447, (2003); 및 JP2005041828 는 일차 알코올을 가진 세라마이드 유도체를 개시하고 있고, J. Med. Chem. 44, 3994 - 4000, (2001) 및 US 2005020533 는 유라실 또는 싸이오유라실 고리를 갖는 세라마이드 유사체를 개시하고 있다.In addition, ceramide derivatives of various structures having anticancer activity are known, for example, J. Pharmacol. Exp. Therapeutics, 309, 523-532 (2004); Org. Lett. 7, 1645-1648 (2005); J. Med. Chem. 46, 3445-3447, (2003); And JP2005041828 disclose ceramide derivatives with primary alcohols, and J. Med. Chem. 44, 3994-4000, (2001) and US 2005020533 disclose ceramide analogs having uracil or thiurauracil rings.

이러한 노력에도 불구하고, 생체 분비물인 세라마이드의 생체 대사에 부작용을 최소화 하면서도 우수한 항암활성을 갖는 새로운 물질의 개발이 필요하다.Despite these efforts, there is a need for the development of new substances with excellent anticancer activity while minimizing side effects in the biometabolism of ceramide, a biosecretion.

본 발명은, 세라마이드 분자의 1번 탄소의 하이드록시기와 2번 위치의 아민기 사이를 아실기를 매개로 결합시킨 옥사졸리딘온 유도체로서, 우수한 항암 활성을 갖는 3-아실-4-(1-하이드록시헥사덱-2-엔일)-옥사졸리딘-2-온 유도체를 제공한다.The present invention is an oxazolidinone derivative in which an acyl group is bonded between a hydroxyl group of carbon 1 of the ceramide molecule and an amine group of position 2 through an acyl group, and 3-acyl-4- (1-hydroxy) having excellent anticancer activity. Hexadec-2-enyl) -oxazolidin-2-one derivative is provided.

따라서, 본 발명은 옥사졸리딘온 유도체 또는 그의 염을 제공하는 것을 목적으로 한다.Accordingly, an object of the present invention is to provide an oxazolidinone derivative or a salt thereof.

또한, 본 발명의 목적은 상기 옥사졸리딘온 유도체의 합성 중간체로서 유용한 화합물을 제공하는 것을 포함한다.It is also an object of the present invention to provide a compound useful as a synthetic intermediate of said oxazolidinone derivatives.

또한, 본 발명의 목적은 상기 옥사졸리딘온 유도체의 제조방법을 제공하는 것을 포함한다.It is also an object of the present invention to provide a method for preparing the oxazolidinone derivative.

또한, 본 발명의 목적은 상기 옥사졸리딘온 유도체를 유효성분으로 포함하는 약제학적 조성물을 제공하는 것을 포함한다.It is also an object of the present invention to provide a pharmaceutical composition comprising the oxazolidinone derivative as an active ingredient.

본 발명의 일 태양에 따라, 하기 화학식 1의 옥사졸리딘온 유도체 또는 그의 염이 제공된다:According to one aspect of the present invention, there is provided an oxazolidinone derivative of formula (I) or a salt thereof:

Figure 112006030859960-pat00001
Figure 112006030859960-pat00001

식 중, R1은 C1∼C15 알킬; C3∼C7 시클로알킬; 페닐; C1∼C5 알킬, C1∼C5 알콕시, 또는 나이트로로 치환된 페닐; 벤질; 3,4-(메틸렌다이옥시)페닐; 나프틸; 퓨란일; 또는 2-페닐-에텐-1-일이고,Wherein, R 1 is C 1 ~C 15 alkyl; C 3 -C 7 cycloalkyl; Phenyl; Phenyl substituted with C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or nitro; benzyl; 3,4- (methylenedioxy) phenyl; Naphthyl; Furanyl; Or 2-phenyl-ethen-1-yl,

R2는 C1∼C15 알킬이다.R 2 is C 1 -C 15 alkyl.

상기 화학식 1의 화합물 중, R1은 C1∼C6 알킬, 펜타데칸일, C3∼C7 시클로알킬, 페닐, 메틸페닐, 에틸페닐, 메톡시페닐, 에톡시페닐, 나이트로페닐, 벤질, 3,4-(메틸렌다이옥시)페닐, 나프틸, 퓨란일, 또는 2-페닐-에텐-1-일이고, R2는 트리데칸일인 옥사졸리딘온 유도체 또는 그의 염이 더욱 바람직하다.In the compound of Formula 1, R 1 is C 1 -C 6 alkyl, pentadecanyl, C 3 -C 7 cycloalkyl, phenyl, methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, nitrophenyl, benzyl, More preferred is an oxazolidinone derivative or a salt thereof, wherein 3,4- (methylenedioxy) phenyl, naphthyl, furanyl, or 2-phenyl-ethen-1-yl, and R 2 is tridecanyl.

또한, 상기 화학식 1의 화합물 중, 더욱 바람직한 화합물을 열거하면, 다음과 같다:In addition, among the compounds of the formula (1), more preferable compounds are listed as follows:

3-아세틸-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-acetyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-프로피오닐-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-propionyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-헥사데칸오일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-hexadecane oil- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-benzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-p-메틸벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-p-methylbenzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-피페론일오일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-piperonyloil- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-o-메틸벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-o-methylbenzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-p-에틸벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-p-ethylbenzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-p-에톡시벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-p-ethoxybenzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-아이소뷰탄오일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-isobutanoil- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-(1-나프탈렌오일)-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3- (1-naphthalenoyl)-(4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-p-나이트로벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-p-nitrobenzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-(2-페닐에탄오일)-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온; 3- (2-phenylethanoyl)-(4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-피발로일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-pivaloyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-(2-퓨로일)-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3- (2-furoyl)-(4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-o-메톡시벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-o-methoxybenzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-시클로펜탄오일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-cyclopentanoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one;

3-신남오일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온.3-cinna-oil- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one.

본 발명의 화합물은 약제학적으로 허용 가능한 염, 수화물, 또는 용매화물의 형태일 수 있다. 본 발명의 화합물에 적용될 수 있는 약제학적으로 허용 가능한 염은 염산염, 브롬산염, 황산염, 메틸설폰산염, p-톨루엔설폰산염, 인산염, 초산염, 시트르산염, 석신산염, 락트산염, 타르타르산염, 푸마르산염, 말레산염, 나트륨염, 칼륨염, 마그네슘염, 및 칼슘염 등이 포함된다. 본 발명의 화합물의 약제학적으로 허용 가능한 염, 수화물, 또는 용매화물은 항암제 분야에서 통상적으로 사용되는 방법에 따라 제조될 수 있다.The compounds of the present invention may be in the form of pharmaceutically acceptable salts, hydrates, or solvates. Pharmaceutically acceptable salts that can be applied to the compounds of the present invention include hydrochloride, bromate, sulfate, methylsulfonate, p-toluenesulfonate, phosphate, acetate, citrate, succinate, lactate, tartarate, fumarate, Maleate, sodium salt, potassium salt, magnesium salt, calcium salt and the like. Pharmaceutically acceptable salts, hydrates, or solvates of the compounds of the present invention may be prepared according to methods commonly used in the field of anticancer agents.

또한, 본 발명의 화합물은 부재탄소를 함유함으로써, 라세믹체 또는 광학이성질체의 형태일 수 있다. 따라서, 본 발명의 화합물은 이러한 라세믹체 및 광학이성질체 모두를 포함한다.In addition, the compounds of the present invention may be in the form of racemic or optical isomers by containing the carbon free. Accordingly, the compounds of the present invention include both such racemates and optical isomers.

본 발명은 상기 화학식 1의 옥사졸리딘온 유도체 또는 그의 염의 합성 중간체로서, 하기 화학식 2의 화합물 또는 그의 염을 포함한다:The present invention is a synthetic intermediate of the oxazolidinone derivative of Formula 1 or a salt thereof, and includes a compound of Formula 2 or a salt thereof:

Figure 112006030859960-pat00002
Figure 112006030859960-pat00002

식 중, R1 및 R2는 상기에서 정의한 바와 동일하며, R3는 히드록시 보호기이다.In the formula, R 1 and R 2 are the same as defined above, and R 3 is a hydroxy protecting group.

상기 히드록시 보호기는 공지되어 사용되는 히드록시 보호기를 모두 포함하며, 예를 들면, t-뷰틸다이메틸실릴, 트라이메틸실릴, 트라이에틸실릴, 트라이아이 소프로필실릴, 다이메틸다이아이소프로필실릴, 트리스(트라이메틸실릴)실릴 등의 실릴기, 메톡시메틸, 아릴, t-뷰틸, 또는 테트라하이드로피라닐 등을 포함한다.The hydroxy protecting group includes all known hydroxy protecting groups, for example, t-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethyldiisopropylsilyl, tris Silyl groups such as (trimethylsilyl) silyl, methoxymethyl, aryl, t-butyl, tetrahydropyranyl and the like.

화학식 2의 화합물 중 바람직한 화합물을 열거하면, 다음과 같다:Preferred compounds among the compounds of the formula (II) are as follows:

3-아세틸-(4S)-[(1R)-1-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온;3-acetyl- (4S)-[(1R) -1-t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one;

3-프로피오닐-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온;3-propionyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one;

3-헥사데칸오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온;3-hexadecanoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one;

3-벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온;3-benzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one;

3-p-메틸벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온;3-p-methylbenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one;

3-피페론일오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-piperonyloil- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one;

3-o-메틸벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-o-methylbenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one;

3-p-에틸벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-p-ethylbenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one;

3-p-에톡시벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사 졸리딘-2-온;3-p-ethoxybenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxa zolidin-2-one;

3-아이소뷰탄오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-isobutanoil- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one;

3-(1-나프탈렌오일)-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3- (1-naphthalenyl)-(4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one;

3-p-나이트로벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-p-nitrobenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one;

3-(2-페닐에탄오일)-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3- (2-phenylethanoyl)-(4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one;

3-피발로일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-pivaloyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one;

3-(2-퓨로일)-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3- (2-furoyl)-(4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one;

3-o-메톡시벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-o-methoxybenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one;

3-시클로펜탄오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-cyclopentanoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one;

3-신남오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온.3-cinnamyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one.

본 발명은 상기 화학식 1의 옥사졸리딘온 유도체 또는 그의 염의 제조방법을 포함한다. 구체적으로, 화학식 1의 옥사졸리딘온 유도체 또는 그의 염은 화학식 3의 화합물을 R1COX 과 반응시켜 화학식 2의 화합물을 제조하는 단계 및 화학식 2의 화합물의 탈보호기 반응을 수행하는 단계를 포함하는 제조방법으로 제조할 수 있다. 이를 반응식으로 나타내면 반응식 1과 같다:The present invention includes a method for preparing an oxazolidinone derivative of Formula 1 or a salt thereof. Specifically, an oxazolidinone derivative or a salt thereof is prepared by reacting a compound of Formula 3 with R 1 COX to prepare a compound of Formula 2 and performing a deprotection group reaction of the compound of Formula 2 It can manufacture by a method. This is shown in Scheme 1:

Figure 112006030859960-pat00003
Figure 112006030859960-pat00003

식 중, R1, R2, 및 R3는 상기에서 정의한 바와 동일하고, X는 할로겐이다.In the formula, R 1 , R 2 , and R 3 are the same as defined above, and X is halogen.

화학식 3의 화합물과 R1COX 과의 반응은 소듐 헥사메틸다이실라잔 (Sodium hexamethyldisilazane), 리튬 다이아이소프로필아마이드 (Lithium diisopropylamide), n-BuLi, NaH, CeCO3, K2CO3, 트리에틸아민, 피리딘, N,N-다이메틸아닐린, N,N-다이소프로필에틸아민 등의 염기 존재하에서 수행될 수 있다. 또한, 상기 반응은 테트라히드로퓨란, 다이에틸 에테르, 디클로로메탄, 디메틸포름아마이드, 에틸 아세테이트, 또는 이들의 혼합용매 중에서 수행될 수 있다.The reaction between the compound of formula 3 and R 1 COX is carried out by sodium hexamethyldisilazane, lithium diisopropylamide, n-BuLi, NaH, CeCO 3 , K 2 CO 3 , triethylamine , Pyridine, N, N-dimethylaniline, N, N-diisopropylethylamine, and the like. In addition, the reaction may be carried out in tetrahydrofuran, diethyl ether, dichloromethane, dimethylformamide, ethyl acetate, or a mixed solvent thereof.

화학식 2의 화합물의 탈보호기 반응은 사용된 히드록시 보호기(R3)에 의존한다. 예를 들어, 히드록시 보호기로서 상기한 바와 같은 실릴기가 사용된 경우, 테 트라부틸암모늄 플루오라이드(tetrabutylammonium fluoride), 플루오릭산(hydrofluoric acid), KF3, BF3 등의 불소-함유 탈보호제 또는 Al2O3, KO2, LiBr 등을 사용하여 탈보호기 반응을 수행할 수 있다. 또한, 화학식 2의 화합물이 알킬 에스테르 형태의 보호기를 갖는 경우에는 적절한 탈 보호제, 예를 들면 로듐 금속 (알릴 에스테르 형태의 경우) 또는 루이스 산 (알콕시메틸 에스테르의 경우)을 사용하여 탈보호기 반응을 수행할 수 있다. 상기 탈보호기 반응은 디클로로메탄, 테트라히드로퓨란, 디메틸포름아마이드, 에틸 아세테이트, 메탄올, 디메틸술폭사이드, 또는 이들의 혼합용매 중에서 수행될 수 있다The deprotection group reaction of the compound of formula 2 depends on the hydroxy protecting group (R 3 ) used. For example, when a silyl group as described above is used as the hydroxy protecting group, fluorine-containing deprotectants such as tetrabutylammonium fluoride, hydrofluoric acid, KF 3 , BF 3 or Al 2 O 3 , KO 2 , LiBr and the like can be used to carry out the deprotection group reaction. In addition, when the compound of the formula (2) has a protecting group in the form of an alkyl ester, the deprotecting group reaction is carried out using a suitable deprotecting agent such as rhodium metal (for allyl ester form) or Lewis acid (for alkoxymethyl ester). can do. The deprotection group reaction may be carried out in dichloromethane, tetrahydrofuran, dimethylformamide, ethyl acetate, methanol, dimethyl sulfoxide, or a mixed solvent thereof.

반응식 1에서 출발물질로 사용되는 화학식 3의 화합물은, 하기 반응식 2에 따라, 화학식 4의 화합물을 환원시키고 히드록시 보호기를 도입시켜 화학식 5의 화합물을 제조하는 단계, 화학식 5의 화합물을 아세트산과 반응시켜 화학식 6의 화합물을 제조하는 단계, 및 화학식 6의 화합물을 가수분해하고, 다이카보닐다이이미다졸을 반응시킨 후 아민 보호기(예를 들어, 페닐에틸기)의 탈보호기 반응을 수행하는 단계를 포함하는 제조방법으로 제조할 수 있다.Compound of Formula 3 used as a starting material in Scheme 1, according to Scheme 2 to reduce the compound of Formula 4 and to introduce a hydroxy protecting group to prepare a compound of Formula 5, the compound of Formula 5 reacts with acetic acid To prepare a compound of Formula 6, and to hydrolyze the compound of Formula 6, to react the dicarbonyldiimidazole, and to perform a deprotection group reaction of an amine protecting group (eg, a phenylethyl group). It can manufacture by a manufacturing method.

Figure 112006030859960-pat00004
Figure 112006030859960-pat00004

식 중, R2 및 R3는 상기에서 정의한 바와 동일하다.In the formula, R 2 and R 3 are the same as defined above.

상기 화학식 4의 화합물은 공지의 방법에 따라 제조될 수 있다 (J. Org. Chem. 2003, 68, 7675-7680).The compound of Formula 4 may be prepared according to a known method (J. Org. Chem. 2003, 68, 7675-7680).

화학식 4의 화합물을 리튬 알루미늄 하이드라이드(LAH) 등의 환원제를 사용하여 환원시킴으로써, 트란스 알릴릭 알코올 형태의 화합물을 제조할 수 있다. 또한, 얻어진 반응산물과 클로로 tert-뷰틸다이메틸실레인 등의 클로로 알킬실레인, 알킬 할라이드, 알킬 에스테르, 또는 알킬 에테르 등을 반응시킴으로써 상응하는 히드록시 보호기를 갖는 화학식 5의 화합물을 얻을 수 있다.By reducing the compound of formula 4 with a reducing agent such as lithium aluminum hydride (LAH), a compound in the form of transallylic alcohol can be prepared. In addition, a compound of formula (5) having a corresponding hydroxy protecting group can be obtained by reacting the obtained reaction product with chloro alkylsilane, such as chloro tert-butyldimethylsilane, alkyl halide, alkyl ester, alkyl ether, or the like.

화학식 5의 화합물을 아세트산과 반응시킴으로써 아지리딘 고리를 개환시키며, 생성되는 알코올기는 아세틸기가 보호기로서 도입된다.The aziridine ring is opened by reacting the compound of formula 5 with acetic acid, and the resulting alcohol group is introduced with an acetyl group as a protecting group.

화학식 6의 화합물의 아세틸기 가수분해는 KOH 또는 NaOH 등의 염기를 반응시킴으로써 수행할 수 있으며, 얻어진 가수분해 산물을 다이카보닐다이이미다졸을 반응시켜 옥사졸리딘-2-온 고리를 형성시킨다. 또한, 옥사졸리딘-2-온 고리의 페닐에틸 보호기 제거반응은 Na-함유 NH3 를 가함으로써 수행할 수 있다.The acetyl group hydrolysis of the compound of formula 6 can be carried out by reacting a base such as KOH or NaOH, and the obtained hydrolysis product is reacted with dicarbonyldiimidazole to form an oxazolidin-2-one ring. Further, phenylethyl protecting group removing reaction of the oxazolidin-2-one ring can be carried out by the addition of Na- containing NH 3.

본 발명은 치료학적 유효량의 상기 화학식 1의 옥사졸리딘온 유도체 또는 그의 염 및 약제학적으로 허용 가능한 담체를 포함하는 항암 조성물을 포함한다. 본 발명의 조성물은 감염환자 또는 동물에게 투여하거나, 감염된 외피에 사용하여 암을 치료하는데 사용될 수 있다. The present invention includes an anticancer composition comprising a therapeutically effective amount of an oxazolidinone derivative of Formula 1 or a salt thereof and a pharmaceutically acceptable carrier. The composition of the present invention can be used to treat cancer by administration to an infected patient or animal, or used in an infected envelope.

본 발명의 조성물은 경구 또는 비경구로 투여될 수 있다. 경구투여용 조성물은 정제, 캅셀제, 산제, 과립제, 액제, 현탁제, 겔제 등의 다양한 형태일 수 있으며, 부형제, 붕해제, 활택제 등의 통상의 첨가제를 포함할 수 있다. 상기 첨가제에는 시럽, 아라비아고무, 젤라틴, 솔비톨, 락토오스, 당분, 옥수수-전분, 인산칼슘, 글리신, 스테아르산마그네슘, 탈크, 폴리에틸렌글리콜, 실리카, 감자전분, 또는 황산라우릴나트륨 등의 통상적인 부형제와 통상의 향미제 또는 착색제를 포함한다.The compositions of the present invention can be administered orally or parenterally. The composition for oral administration may be in various forms such as tablets, capsules, powders, granules, solutions, suspensions, gels, and the like, and may include conventional additives such as excipients, disintegrants, lubricants, and the like. The additives include conventional excipients such as syrup, gum arabic, gelatin, sorbitol, lactose, sugar, corn-starch, calcium phosphate, glycine, magnesium stearate, talc, polyethylene glycol, silica, potato starch, or sodium lauryl sulfate. Conventional flavoring or coloring agents are included.

또한 본 발명에 따른 조성물의 비경구 투여용 조성물(예, 주사제)은 등장용액일 수 있으며, 또한 멸균시킬 수 있으며 및/또는 보존제, 안정화제 등과 같은 통상의 첨가제를 포함할 수 있다.In addition, compositions for parenteral administration (eg, injections) of the compositions according to the invention may be isotonic solutions, may also be sterilized and / or may contain conventional additives such as preservatives, stabilizers and the like.

화학식 1의 옥사졸리딘온 유도체 또는 그의 염은 환자에게 약 0.1 mg/kg 내지 약 500 mg/kg per day의 용량으로 투여될 수 있다. 물론, 상기 용량은 환자의 나이, 체중, 감수성, 또는 증상에 따라 변경될 수 있다.The oxazolidinone derivative of Formula 1 or a salt thereof may be administered to a patient at a dose of about 0.1 mg / kg to about 500 mg / kg per day. Of course, the dose may vary depending on the age, weight, sensitivity, or symptoms of the patient.

이하, 본 발명을 실시예를 통하여 더욱 상세히 설명하지만, 본 발명이 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

실시예 1. 3-아세틸-(4S)-[(1R)-1-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온Example 1. 3-acetyl- (4S)-[(1R) -1-t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one

단계 1. 1-[(1R)-페닐에틸]-(2S)-[(1R)-t-뷰틸다이메틸실릴옥시-헥사덱-2-엔일]-아지리딘Step 1. 1-[(1R) -Phenylethyl]-(2S)-[(1R) -t-butyldimethylsilyloxy-hexadec-2-enyl] -aziridine

Figure 112006030859960-pat00005
Figure 112006030859960-pat00005

1-[(1R)-페닐에틸]-(2S)-[(1R)-하이드록시-헥사덱-2-인일]-아지리딘 (510 mg, 1.33 mmol)를 3㎖의 테트라히드로퓨란에 녹인 용액을 LiAlH4 (252 mg, 6.65 mmol)를 테트라히드로퓨란 3 ㎖에 상온에서 용해시킨 용액에 서서히 가하였다. 반응 혼합물을 60∼65 ℃에서 8시간 동안 교반하고, KHSO4 수용액을 가하여 반응을 종결시켰다. 반응혼합물을 무수 MgSO4 상에서 건조한 다음, 갑압농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피로 정제하여(에틸아세테이트/n-헥산, 40/60, v/v), 무색 오일상의 1-[(1R)-페닐에틸]-(2S)-[(1R)-하이드록시-헥사덱-2-엔일]-아지리딘 440 mg을 제조하였다(수율: 86 %). A solution of 1-[(1R) -phenylethyl]-(2S)-[(1R) -hydroxy-hexadec-2-ynyl] -aziridine (510 mg, 1.33 mmol) in 3 ml of tetrahydrofuran Was slowly added to a solution of LiAlH 4 (252 mg, 6.65 mmol) dissolved in 3 ml of tetrahydrofuran at room temperature. The reaction mixture was stirred for 8 h at 60-65 ° C. and aqueous KHSO 4 solution was added to terminate the reaction. The reaction mixture was dried over anhydrous MgSO 4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane, 40/60, v / v) to give 1-[(1R) -phenylethyl]-(2S)-[(1R)-as a colorless oil. 440 mg of hydroxy-hexadec-2-enyl] -aziridine were prepared (yield: 86%).

상기 과정을 2회 반복하여 얻어진 1-[(1R)-페닐에틸]-(2S)-[(1R)-하이드록시 -헥사덱-2-엔일]-아지리딘 (850 mg, 2.2 mmol) 및 4,4'-다이메틸아미노피리딘 (DMAP) (1.35 g, 11.02 mmol)을 5 ㎖의 다이클로로메탄에 용해시킨 후, 0 ℃에서 15분 동안 교반하였다. 클로로 tert-뷰틸다이메틸실레인 (TBDMSCl) (665 mg, 4.4 mmol)을 3 ㎖의 다이클로로메탄에 녹인 용액을 0 ℃에서 반응혼합물에 서서히 가한 후, 상온에서 7시간 동안 교반하였다. 출발물질이 없어진 것을 확인하고 K2CO3 수용액을 반응혼합물에 천천히 가하여 반응을 종결시킨 다음, 다이클로로메탄(10 ㎖)으로 4회 추출하였다. 얻어진 유기층을 소금물로 세척한 후, 무수 MgSO4 상에서 건조한 다음, 갑압농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피로 정제하여(에틸 아세테이트/n-헥산, 15/85, v/v), 무색 오일상의 표제화합물 1.033 g을 제조하였다 (수율: 94%).1-[(1R) -phenylethyl]-(2S)-[(1R) -hydroxy-hexadec-2-enyl] -aziridine (850 mg, 2.2 mmol) and 4 obtained by repeating the above procedure twice. , 4'-dimethylaminopyridine (DMAP) (1.35 g, 11.02 mmol) was dissolved in 5 mL of dichloromethane and stirred at 0 ° C for 15 minutes. Chloro tert-butyldimethylsilane (TBDMSCl) (665 mg, 4.4 mmol) in 3 ml of dichloromethane was slowly added to the reaction mixture at 0 ° C., and then stirred at room temperature for 7 hours. Confirming that the starting material disappeared, and was then extracted four times with dichloromethane (10 ㎖) was complete the reaction was slowly added to K 2 CO 3 aqueous solution to the reaction mixture. The organic layer obtained was washed with brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane, 15/85, v / v) to give 1.033 g of the title compound as a colorless oil (yield: 94%).

1H NMR (500 MHz, CDCl3) 7.25 (m, 5H), 5.41 (dt, J= 15.5 Hz, 1H), 4.94 (dd, J= 15.5 Hz, 1H), 2.39 (q, J= 6.59 Hz, 1H), 1.83 (m, 1H), 1.68 (m, 1H), 1.58 (m, 1H), 1.41 (d, J= 6.59 Hz, 3H), 1.26 (m, 24H), 0.84 (s, 12H), 0.01 (s, 3H), 0.00 (s, 3H); 1 H NMR (500 MHz, CDCl 3 ) 7.25 (m, 5H), 5.41 (dt, J = 15.5 Hz, 1H), 4.94 (dd, J = 15.5 Hz, 1H), 2.39 (q, J = 6.59 Hz, 1H), 1.83 (m, 1H), 1.68 (m, 1H), 1.58 (m, 1H), 1.41 (d, J = 6.59 Hz, 3H), 1.26 (m, 24H), 0.84 (s, 12H), 0.01 (s, 3 H), 0.00 (s, 3 H);

C32H57NOSi에 대한 계산치: C, 76.89; H, 11.49; N, 2.80. Calcd for C 32 H 57 NO Si: C, 76.89; H, 11.49; N, 2.80.

C32H57NOSi에 대한 실측치: C, 76.95; H, 11.46; N, 2.81. Found for C 32 H 57 NOSi: C, 76.95; H, 11. 46; N, 2.81.

단계 2. 1-아세틸옥시-(3R)-t-뷰틸다이메틸실릴옥시-(2S)-[(1R)-페닐에틸]아 미노옥타덱-4-엔 Step 2. 1-Acetyloxy- (3R) -t-butyldimethylsilyloxy- (2S)-[(1R) -phenylethyl] aminooctadec-4-ene

Figure 112006030859960-pat00006
Figure 112006030859960-pat00006

단계 1에서 제조한 1-[(1R)-페닐에틸]-(2S)-[(1R)-t-뷰틸다이메틸실릴옥시-헥사덱-2-엔일]-아지리딘을 4 ㎖ 의 다이클로로메탄에 용해시키고, 초산 0.59 ㎖를 가한 후, 24시간 동안 상온에서 교반하였다. NaHCO3 수용액(1 ㎖)을 반응 혼합물에 가하여 반응을 종결시킨 다음, 다이클로로메탄(10 ㎖)으로 4회 추출하였다. 얻어진 유기층을 소금물로 세척하고, 무수 MgSO4 상에서 건조한 다음, 갑압농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피로 정제하여(에틸 아세테이트/n-헥산, 15/85, v/v), 무색 오일상의 표제 화합물 840 mg 을 제조하였다 (수율: 73%).4 mL of 1-[(1R) -phenylethyl]-(2S)-[(1R) -t-butyldimethylsilyloxy-hexadec-2-enyl] -aziridine prepared in step 1 was dichloromethane. It was dissolved in, 0.59 ml of acetic acid was added, and then stirred at room temperature for 24 hours. Aqueous NaHCO 3 solution (1 mL) was added to the reaction mixture to terminate the reaction, followed by extraction four times with dichloromethane (10 mL). The organic layer obtained was washed with brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane, 15/85, v / v) to give 840 mg of the title compound as a colorless oil (yield: 73%).

1H NMR (500 MHz, CDCl3) 7.26 (m, 5H), 5.62 (dt, J= 15.4 Hz, 1H), 5.30 (dd, J= 14.7 Hz, 1H), 4.15 (m, 3H), 3.91 (q, J= 6.6 Hz, 1H), 2.51 (m, 1H), 2.08 (m, 5H), 1.27 (m, 25H), 0.85 (s, 12H), 0.00 (s, 3H), -0.02 (s, 3H). 1 H NMR (500 MHz, CDCl 3 ) 7.26 (m, 5H), 5.62 (dt, J = 15.4 Hz, 1H), 5.30 (dd, J = 14.7 Hz, 1H), 4.15 (m, 3H), 3.91 ( q, J = 6.6 Hz, 1H), 2.51 (m, 1H), 2.08 (m, 5H), 1.27 (m, 25H), 0.85 (s, 12H), 0.00 (s, 3H), -0.02 (s, 3H).

C34H61NO3Si에 대한 계산치: C, 72.93; H, 10.98; N, 2.50. Calcd for C 34 H 61 N0 3 Si: C, 72.93; H, 10.98; N, 2.50.

C34H61NO3Si에 대한 실측치: C, 72.91; H, 11.00; N, 2.50Found for C 34 H 61 NO 3 Si: C, 72.91; H, 11.00; N, 2.50

단계 3. (4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온Step 3. (4S)-[(1R) -T-Butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one

Figure 112006030859960-pat00007
Figure 112006030859960-pat00007

단계 2에서 제조한 1-아세틸옥시-(3R)-t-뷰틸다이메틸실릴옥시-(2S)-[(1R)-페닐에틸]아미노옥타덱-4-엔 (840 mg)을 5 ㎖의 에탄올에 용해시키고, 168 mg 의 KOH를 가하였다. 반응혼합물을 상온에서 1시간 동안 교반한 다음, 물 1 ㎖를 가하여 반응을 종결시켰다. 반응혼합물을 다이클로로메탄(7 ㎖)으로 4회 추출하였다. 얻어진 유기층을 소금물로 세척하고, 무수 MgSO4 상에서 건조한 다음, 갑압농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피로 정제하여(에틸 아세테이트/n-헥산, 3/7, v/v), 무색 오일상의 (3R)-t-뷰틸다이메틸실릴옥시-1-하이드록시-(2R)-[(1R)-페닐에틸]아미노-옥타덱-4-엔 633 mg 을 제조하였다 (수율: 82 %).5 ml of ethanol of 1-acetyloxy- (3R) -t-butyldimethylsilyloxy- (2S)-[(1R) -phenylethyl] aminooctadec-4-ene (840 mg) prepared in step 2 Was dissolved in and 168 mg of KOH was added. The reaction mixture was stirred at room temperature for 1 hour, and then 1 ml of water was added to terminate the reaction. The reaction mixture was extracted four times with dichloromethane (7 mL). The organic layer obtained was washed with brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane, 3/7, v / v) to give (3R) -t-butyldimethylsilyloxy-1-hydroxy- (2R) as a colorless oil. 633 mg of-[(1R) -phenylethyl] amino-octadec-4-ene were prepared (yield: 82%).

얻어진 화합물을 4 ㎖ 의 다이클로로메탄에 용해시킨 후, 1.03 g의 다이카보닐다이이미다졸을 가하였다. 반응 혼합물을 1시간 동안 교반한 후, 0.56 ㎖의 1,8-다이아자바이싸이클로[5,4,0]운덱-7-엔(DBU)을 반응혼합물에 가하고 다시 상온에서 하루 동안 교반하였다. 반응혼합물을 감압농축한 후, 얻어진 잔사를 다이클로로메탄(10 ㎖)으로 4회 추출하였다. 얻어진 유기층을 소금물로 세척하고, 무수 MgSO4 상에서 건조한 다음, 갑압농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피로 정제하여(에틸 아세테이트/n-헥산, 60/40, v/v), 무색 오일상의 옥사졸리딘 고 리의 질소에 페닐에틸기가 결합된 옥사졸리딘 유도체 580 mg을 제조하였다 (수율: 87 %).After dissolving the obtained compound in 4 ml of dichloromethane, 1.03 g of dicarbonyldiimidazole was added. After the reaction mixture was stirred for 1 hour, 0.56 mL of 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) was added to the reaction mixture and stirred at room temperature again for 1 day. The reaction mixture was concentrated under reduced pressure, and then the obtained residue was extracted four times with dichloromethane (10 mL). The organic layer obtained was washed with brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane, 60/40, v / v) to prepare 580 mg of an oxazolidine derivative having a phenylethyl group bonded to nitrogen of an oxazolidine ring in a colorless oil. (Yield 87%).

얻어진 생성물(580 mg)을 7 ㎖ 의 테트라히드로퓨란에 용해시킨 용액을 -78 ℃에서 123 mg의 Na을 함유한 NH3 용액에 서서히 가하였다. 반응혼합물을 -78 ℃에서 1 시간 동안 교반한 다음, 상온으로 온도를 높였다. 1 ㎖의 물을 반응혼합물에 가한 다음, 유기층을 분리하였다. 수층을 에틸 아세테이트(10 ㎖)로 3회 추출하여 상기 유기층과 합하였다. 얻어진 유기층을 소금물로 세척하고, 무수 MgSO4 상에서 건조한 다음, 갑압농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피로 정제하여(에틸 아세테이트/n-헥산, 35/65, v/v), 무색 오일상의 표제화합물 363 mg을 제조하였다 (수율: 77 %).The resulting product (580 mg) dissolved in 7 ml of tetrahydrofuran was slowly added to a NH 3 solution containing 123 mg of Na at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 hour, and then the temperature was raised to room temperature. 1 ml of water was added to the reaction mixture, and then the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate (10 mL) and combined with the organic layer. The organic layer obtained was washed with brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane, 35/65, v / v) to give 363 mg of the title compound as a colorless oil (yield: 77%).

1H NMR (500 MHz, CDCl3) 5.64 (dt, J= 15, 5 Hz, 1H), 5.59 (s, 1H), 5.38 (dd J= 15, 5 Hz, 1H), 4.32 (dd, J = 19, 9 Hz, 1H), 4.27 (m, 1H), 4.00 (t, J = 6 Hz, 1H), 3.85 (m, 1H), 2.04 (m, 2H), 1.36 (m, 22H), 0.92 (s, 12H), 0.07 (s, 3H), 0.04 (s, 3H). 1 H NMR (500 MHz, CDCl 3 ) 5.64 (dt, J = 15, 5 Hz, 1H), 5.59 (s, 1H), 5.38 (dd J = 15, 5 Hz, 1H), 4.32 (dd, J = 19, 9 Hz, 1H), 4.27 (m, 1H), 4.00 (t, J = 6 Hz, 1H), 3.85 (m, 1H), 2.04 (m, 2H), 1.36 (m, 22H), 0.92 ( s, 12H), 0.07 (s, 3H), 0.04 (s, 3H).

C25H49NO3Si에 대한 계산치: C, 68.3; H, 11.2; N, 3.19. Calcd for C 25 H 49 N0 3 Si: C, 68.3; H, 11.2; N, 3.19.

C25H49NO3Si에 대한 실측치: C, 68.1; H, 11.4; N, 3.22.Found for C 25 H 49 NO 3 Si: C, 68.1; H, 11.4; N, 3.22.

단계 4. 3-아세틸-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸 리딘-2-온Step 4. 3-Acetyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazole lidin-2-one

Figure 112006030859960-pat00008
Figure 112006030859960-pat00008

단계 3에서 제조한 (4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온 85 mg을 0.4 ㎖의 테트라히드로퓨란에 용해시키고, 0.2 ㎖의 1.0 M 소듐 헥사메틸다이실라잔을 0 ℃에서 가하였다. 반응혼합물을 30분 동안 상온에서 교반하고, 아세틸 클로라이드 0.02 ㎖를 가하였다. 반응혼합물을 3시간 동안 상온에서 교반한 다음, 감압농축하였다. 얻어진 잔사를 다이클로로메탄(3 ㎖)으로 3회 추출하였다. 얻어진 유기층을 소금물로 세척하고, 무수 MgSO4 상에서 건조한 다음, 갑압농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피로 정제하여(에틸 아세테이트/n-헥산, 20/80, v/v), 무색 오일상의 표제화합물 81 mg을 제조하였다 (수율: 87 %).85 mg of (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one prepared in step 3 was dissolved in 0.4 ml of tetrahydrofuran, and 0.2 ML 1.0 M sodium hexamethyldisilazane was added at 0 ° C. The reaction mixture was stirred for 30 minutes at room temperature and 0.02 ml of acetyl chloride was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The obtained residue was extracted three times with dichloromethane (3 mL). The organic layer obtained was washed with brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane, 20/80, v / v) to give 81 mg of the title compound as a colorless oil (yield: 87%).

1H NMR (300 MHz, CDCl3) 5.84 (dt, J= 15, 4 Hz, 1H), 5.31 (dd J= 15, 5 Hz, 1H), 4.79 (m, 1H), 4.41 (m, 1H), 4.39 (m, 1H), 4.11 (t, J = 6Hz, 1H), 2.54 (s, 3H), 1.84 (dt, J = 7, 3 Hz, 2H), 1.30 (m, 22H), 0.87 (s, 12H), 0.06 (s, 3H), 0.03 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) 5.84 (dt, J = 15, 4 Hz, 1H), 5.31 (dd J = 15, 5 Hz, 1H), 4.79 (m, 1H), 4.41 (m, 1H) , 4.39 (m, 1H), 4.11 (t, J = 6 Hz, 1H), 2.54 (s, 3H), 1.84 (dt, J = 7, 3 Hz, 2H), 1.30 (m, 22H), 0.87 (s , 12H), 0.06 (s, 3H), 0.03 (s, 3H).

아세틸 클로라이드 대신 프로피온일 클로라이드, 헥사데칸오일 클로라이드, 벤조일 클로라이드, p-메틸벤조일 클로라이드를 사용하여, 실시예 1의 단계 4와 동일한 방법으로 실시예 2 내지 5의 화합물을 제조하였다.Compounds of Examples 2 to 5 were prepared in the same manner as Step 4 of Example 1, using propionyl chloride, hexadecanoyl chloride, benzoyl chloride, p-methylbenzoyl chloride instead of acetyl chloride.

실시예 2. 3-프로피오닐-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온Example 2. 3-propionyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one

1H NMR (300 MHz, CDCl3) 5.83 (dt, J= 15, 6 Hz, 1H), 5.31 (dd J= 15, 5 Hz, 1H), 4.71 (m, 1H), 4.41 (m, 1H), 4.35 (m, 1H), 4.16 (t, J = 6 Hz, 1H), 2.97 (q, J = 7 Hz, 2H), 2.05 (m, 2H), 1.30 (m, 22H), 1.17 (t, J = 7 Hz, 3H), 0.87 (s, 12H), 0.06 (s, 3H), 0.03 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) 5.83 (dt, J = 15, 6 Hz, 1H), 5.31 (dd J = 15, 5 Hz, 1H), 4.71 (m, 1H), 4.41 (m, 1H) , 4.35 (m, 1H), 4.16 (t, J = 6 Hz, 1H), 2.97 (q, J = 7 Hz, 2H), 2.05 (m, 2H), 1.30 (m, 22H), 1.17 (t, J = 7 Hz, 3H), 0.87 (s, 12H), 0.06 (s, 3H), 0.03 (s, 3H).

실시예 3. 3-헥사데칸오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온Example 3. 3-hexadecaneoil- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one

1H NMR (300 MHz, CDCl3) 5.81 (dt, J= 15, 5 Hz, 1H), 5.38 (dd J= 15, 5 Hz, 1H), 4.72 (m, 1H), 4.41 (m, 1H), 4.34 (m, 1H), 4.19 (t, J = 9 Hz, 1H), 2.96 (m, 2H), 2.04 (m, 2H), 1.27 (m, 48H), 0.89 (s, 15H), 0.04 (s, 3H), 0.03 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) 5.81 (dt, J = 15, 5 Hz, 1H), 5.38 (dd J = 15, 5 Hz, 1H), 4.72 (m, 1H), 4.41 (m, 1H) , 4.34 (m, 1H), 4.19 (t, J = 9 Hz, 1H), 2.96 (m, 2H), 2.04 (m, 2H), 1.27 (m, 48H), 0.89 (s, 15H), 0.04 ( s, 3H), 0.03 (s, 3H).

실시예Example 4. 3-벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사 4. 3-benzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxa 졸리딘Zolidine -2-온2-on

1H NMR (300 MHz, CDCl3) 7.43 - 8.14 (m, 5H), 5.92 (dt, J= 15, 5 Hz, 1H), 5.48 (dd J= 15, 5 Hz, 1H), 4.82 (m, 1H), 4.56 (m, 2H), 4.30 (t, J = 6 Hz, 1H), 2.06 (m, 2H), 1.38 (m, 22H), 0.90 (s, 12H), 0.06 (s, 3H), 0.03 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) 7.43-8.14 (m, 5H), 5.92 (dt, J = 15, 5 Hz, 1H), 5.48 (dd J = 15, 5 Hz, 1H), 4.82 (m, 1H), 4.56 (m, 2H), 4.30 (t, J = 6 Hz, 1H), 2.06 (m, 2H), 1.38 (m, 22H), 0.90 (s, 12H), 0.06 (s, 3H), 0.03 (s, 3 H).

실시예 5. 3-p-메틸벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온Example 5. 3-p-methylbenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one

1H NMR (300 MHz, CDCl3) 7.42 - 8.14 (m, 5H), 5.88 (dt, J= 15, 4 Hz, 1H), 5.39 (dd J= 15, 5 Hz, 1H), 4.84 (m, 1H), 4.55 (m, 2H), 4.30 (t, J = 6 Hz, 1H), 2.18 (s, 3H), 2.05 (m, 2H), 1.38 (m, 22H), 0.90 (s, 12H), 0.06 (s, 3H), 0.03 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) 7.42-8.14 (m, 5H), 5.88 (dt, J = 15, 4 Hz, 1H), 5.39 (dd J = 15, 5 Hz, 1H), 4.84 (m, 1H), 4.55 (m, 2H), 4.30 (t, J = 6 Hz, 1H), 2.18 (s, 3H), 2.05 (m, 2H), 1.38 (m, 22H), 0.90 (s, 12H), 0.06 (s, 3H), 0.03 (s, 3H).

아세틸 클로라이드 대신 3-피페론일오일 클로라이드, 3-o-메틸벤조일 클로라이드, 3-p-에틸벤조일 클로라이드, 3-p-에톡시벤조일 클로라이드, 3-아이소뷰탄오일 클로라이드, 3-(1-나프탈렌오일) 클로라이드, 3-p-나이트로벤조일 클로라이드, 3-(2-페닐에탄오일) 클로라이드, 3-피발로일 클로라이드, 3-(2-퓨로일) 클로라이 드, 3-o-메톡시벤조일 클로라이드, 3-시클로펜탄오일 클로라이드 및 3-신남오일 클로라이드를 사용하여, 실시예 1의 단계 4와 동일한 방법으로 하기 표1의 화합물(화학식 6 내지 18의 화합물)을 제조하였으며, 이들을 별도의 분리 없이 다음 반응에 사용하였다.3-piperonyloil chloride, 3-o-methylbenzoyl chloride, 3-p-ethylbenzoyl chloride, 3-p-ethoxybenzoyl chloride, 3-isobutanyl chloride, 3- (1-naphthalene oil) instead of acetyl chloride ) Chloride, 3-p-nitrobenzoyl chloride, 3- (2-phenylethanoyl) chloride, 3-pivaloyl chloride, 3- (2-furoyl) chloride, 3-o-methoxybenzoyl chloride Using 3-cyclopentanoyl chloride and 3-cinnamic oil chloride, the compounds of the following Table 1 (compounds 6 to 18) were prepared by the same method as Step 4 of Example 1, and these were separated without any separate separation. Used for reaction.

실시예Example 화합물명Compound name Mass (M+)Mass (M +) 66 3-피페론일오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온3-piperonyloil- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one 587.36587.36 77 3-o-메틸벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온3-o-methylbenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one 557.39557.39 88 3-p-에틸벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온3-p-ethylbenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one 571.40571.40 99 3-p-에톡시벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온3-p-ethoxybenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one 587.40587.40 1010 3-아이소뷰탄오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온3-isobutanyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one 509.39509.39 1111 3-(1-나프탈렌오일)-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온3- (1-naphthalenyl)-(4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one 593.39593.39 1212 3-p-나이트로벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온3-p-nitrobenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one 588.35588.35 1313 3-(2-페닐에탄오일)-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온3- (2-phenylethanoyl)-(4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one 557.39557.39 1414 3-피발로일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온3-pivaloyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one 523.40523.40 1515 3-(2-퓨로일)-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온3- (2-Puroyl)-(4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one 533.35533.35 1616 3-o-메톡시벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온3-o-methoxybenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one 571.40571.40 1717 3-시클로펜탄오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온3-cyclopentanoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one 535.40535.40 1818 3-신남오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온3-cinna-oil- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one 569.39569.39

실시예 19. 3-아세틸-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온Example 19. 3-Acetyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one

Figure 112006030859960-pat00009
Figure 112006030859960-pat00009

실시예 1에서 제조한 (4S)-3-아세틸-4-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온 132 mg을 0.4 ㎖ 의 테트라히드로퓨란에 용해시킨 용액에 1.0M 테트라부틸암모늄 플루오라이드(TBAF) 용액 0.29 ㎖를 0 ℃에서 적가하였다. 반응혼합물을 상온에서 4시간 동안 교반하고, 아세틸 클로라이드 0.02 ㎖를 가하였다. 반응혼합물을 3시간 동안 상온에서 교반한 다음, 감압농축하였다. 얻어진 잔사를 다이클로로메탄(5 ㎖)으로 2회 추출하였다. 얻어진 유기층을 소금물로 세척하고, 무수 MgSO4 상에서 건조한 다음, 갑압농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피로 정제하여(에틸 아세테이트/n-헥산, 30/70, v/v), 백색 고체상의 표제화합물 60 mg을 제조하였다 (수율: 55 %).132 mg of (4S) -3-acetyl-4-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one prepared in Example 1 was 0.4 ml of tetra To the solution dissolved in hydrofuran, 0.29 ml of 1.0M tetrabutylammonium fluoride (TBAF) solution was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 4 hours, and 0.02 ml of acetyl chloride was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The obtained residue was extracted twice with dichloromethane (5 mL). The organic layer obtained was washed with brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane, 30/70, v / v) to give 60 mg of the title compound as a white solid (yield: 55%).

1H NMR (300 MHz, CDCl3) 5.89 (dt, J= 11, 5 Hz, 1H), 5.27 - 5.37 (m, 2H), 4.47 (t, J = 8 Hz, 1H), 4.28 (m, 1H), 4.02 (m, 1H), 2.11 (s, 3H), 1.37 (m, 25H), 0.89 (t, J = 6 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 5.89 (dt, J = 11, 5 Hz, 1H), 5.27-5.37 (m, 2H), 4.47 (t, J = 8 Hz, 1H), 4.28 (m, 1H ), 4.02 (m, 1H), 2.11 (s, 3H), 1.37 (m, 25H), 0.89 (t, J = 6 Hz, 3H).

(4S)-3-아세틸-4-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온 대신 실시예 2 내지 18에서 제조한 화합물을 출발물질로 사용하여, 실시예 19와 동일한 방법으로 실시예 20 내지 36의 화합물을 제조하였다.(4S) -3-acetyl-4-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one was used as starting material for the compound prepared in Examples 2 to 18 instead. In the same manner as in Example 19, the compounds of Examples 20 to 36 were prepared.

실시예 20. 3-프로피오닐-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온Example 20. 3-propionyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one

1H NMR (200 MHz, CDCl3) 5.88 (dt, J= 11, 4 Hz, 1H), 5.23 - 5.32 (m, 2H), 4.47 (t, J = 9 Hz, 1H), 4.28 (m, 1H), 4.03 (m, 1H), 2.35 (q, J = 5 Hz, 2H), 2.08 (q, J = 5 Hz, 2H), 1.37 (m, 23H), 1.14 (t, J = 7 Hz, 3H), 0.89 (t, J = 5 Hz, 3H). 1 H NMR (200 MHz, CDCl 3 ) 5.88 (dt, J = 11, 4 Hz, 1H), 5.23-5.32 (m, 2H), 4.47 (t, J = 9 Hz, 1H), 4.28 (m, 1H ), 4.03 (m, 1H), 2.35 (q, J = 5 Hz, 2H), 2.08 (q, J = 5 Hz, 2H), 1.37 (m, 23H), 1.14 (t, J = 7 Hz, 3H ), 0.89 (t, J = 5 Hz, 3H).

실시예 21. 3-헥사데칸오일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온Example 21. 3-hexadecane oil- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one

1H NMR (200 MHz, CDCl3) 5.88 (dt, J= 12, 4 Hz, 1H), 5.19 - 5.33 (m, 3H), 4.44 (t, J = 9 Hz, 1H), 4.26 (m, 1H), 4.01 (m, 1H), 2.34 (t, J = 7 Hz, 2H), 2.07 (q, J = 7 Hz, 2H), 1.68 (m, 3H), 1.24 (m, 48H), 0.89 (t, J = 7 Hz, 3H). 1 H NMR (200 MHz, CDCl 3 ) 5.88 (dt, J = 12, 4 Hz, 1H), 5.19-5.33 (m, 3H), 4.44 (t, J = 9 Hz, 1H), 4.26 (m, 1H ), 4.01 (m, 1H), 2.34 (t, J = 7 Hz, 2H), 2.07 (q, J = 7 Hz, 2H), 1.68 (m, 3H), 1.24 (m, 48H), 0.89 (t , J = 7 Hz, 3H).

실시예 22. 3-벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온Example 22. 3-Benzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one

1H NMR (200 MHz, CDCl3) 8.04 (d, J = 8 Hz, 2H), 7.59 (t, J = 8 Hz, 1H), 7.46 (t, J = 8 Hz, 2H), 5.96 (m, 2H), 5.55 (m, 2H), 4.49 (t, J = 8 Hz, 1H), 4.38 (m, 1H), 4.05 (m, 1H), 2.08 (q, J = 7 Hz, 2H), 1.24 (m, 22H), 0.89 (t, J = 7 Hz, 3H). 1 H NMR (200 MHz, CDCl 3 ) 8.04 (d, J = 8 Hz, 2H), 7.59 (t, J = 8 Hz, 1H), 7.46 (t, J = 8 Hz, 2H), 5.96 (m, 2H), 5.55 (m, 2H), 4.49 (t, J = 8 Hz, 1H), 4.38 (m, 1H), 4.05 (m, 1H), 2.08 (q, J = 7 Hz, 2H), 1.24 ( m, 22H), 0.89 (t, J = 7 Hz, 3H).

실시예Example 23. 3-p-메틸벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리 23. 3-p-methylbenzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazoli 딘Dean -2-온2-on

1H NMR (300 MHz, CDCl3) 7.93 (d, J = 8 Hz, 1H), 7.26 (d, J = 8 Hz, 2H), 6.16 (s, 1H), 5.98 (m, 1H), 5.50 (m, 2H), 4.49 (t, J = 8 Hz, 1H), 4.35 (m, 1H), 4.05 (m, 1H), 2.41 (s, 3H), 2.07 (q, J = 7 Hz, 2H), 1.25 (m, 22H), 0.89 (t, J = 7 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 7.93 (d, J = 8 Hz, 1H), 7.26 (d, J = 8 Hz, 2H), 6.16 (s, 1H), 5.98 (m, 1H), 5.50 ( m, 2H), 4.49 (t, J = 8 Hz, 1H), 4.35 (m, 1H), 4.05 (m, 1H), 2.41 (s, 3H), 2.07 (q, J = 7 Hz, 2H), 1.25 (m, 22 H), 0.89 (t, J = 7 Hz, 3 H).

실시예Example 24. 3- 24. 3- 피페론일오일Piperonyl Oil -(4S)-[(1R)--(4S)-[(1R)- 하이드록시헥사덱Hydroxyhexadec -2-엔일)]--2-yen)]- 옥사졸리딘Oxazolidine -2-온2-on

1H NMR (300 MHz, CDCl3) 7.89 (s, d = 8 Hz, 1H), 7.45 (t, J = 8 Hz, 1H), 6.82 (s, J = 8 Hz, 1H), 6.21 (s, 1H), 6.06 (s, 2H), 5.95 (m, 1H), 5.47 (m, 2H), 4.47 (t, J = 8 Hz, 1H), 4.29 (m, 1H), 4.15 (m, 1H), 2.08 (q, J = 7 Hz, 2H), 1.26 (m, 22H), 0.89 (t, J = 7 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 7.89 (s, d = 8 Hz, 1H), 7.45 (t, J = 8 Hz, 1H), 6.82 (s, J = 8 Hz, 1H), 6.21 (s, 1H), 6.06 (s, 2H), 5.95 (m, 1H), 5.47 (m, 2H), 4.47 (t, J = 8 Hz, 1H), 4.29 (m, 1H), 4.15 (m, 1H), 2.08 (q, J = 7 Hz, 2H), 1.26 (m, 22H), 0.89 (t, J = 7 Hz, 3H).

실시예Example 25. 3-o- 25. 3-o- 메틸벤조일Methylbenzoyl -(4S)-[(1R)--(4S)-[(1R)- 하이드록시헥사덱Hydroxyhexadec -2-엔일)]--2-yen)]- 옥사졸리딘Oxazolidine -2-온2-on

1H NMR (300 MHz, CDCl3) 7.94 (d, J = 8 Hz, 1H), 7.46 (t, J = 8 Hz, 1H), 7.27 (m, 2H), 5.98 (m, 2H), 5.51 (m, 2H), 4.49 (t, J = 8 Hz, 1H), 4.38 (m, 1H), 4.13 (m, 1H), 2.56 (s, 3H), 2.06 (q, J = 7 Hz, 2H), 1.31 (m, 22H), 0.89 (t, J = 7 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 7.94 (d, J = 8 Hz, 1H), 7.46 (t, J = 8 Hz, 1H), 7.27 (m, 2H), 5.98 (m, 2H), 5.51 ( m, 2H), 4.49 (t, J = 8 Hz, 1H), 4.38 (m, 1H), 4.13 (m, 1H), 2.56 (s, 3H), 2.06 (q, J = 7 Hz, 2H), 1.31 (m, 22 H), 0.89 (t, J = 7 Hz, 3 H).

실시예Example 26. 3-p-에틸벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리 26. 3-p-ethylbenzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazoli 딘Dean -2-온2-on

1H NMR (300 MHz, CDCl3) 7.95 (d, J = 8 Hz, 1H), 7.26 (d, J = 8 Hz, 2H), 6.01 (m, 1H), 5.62 (s, 1H), 5.50 (m, 2H), 4.51 (t, J = 8 Hz, 1H), 4.39 (m, 1H), 4.13 (m, 1H), 2.73 (q, J = 7 Hz, 2H), 2.06 (m, 3H), 1.26 (m, 22H), 0.90 (t, J = 7 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 7.95 (d, J = 8 Hz, 1H), 7.26 (d, J = 8 Hz, 2H), 6.01 (m, 1H), 5.62 (s, 1H), 5.50 ( m, 2H), 4.51 (t, J = 8 Hz, 1H), 4.39 (m, 1H), 4.13 (m, 1H), 2.73 (q, J = 7 Hz, 2H), 2.06 (m, 3H), 1.26 (m, 22 H), 0.90 (t, J = 7 Hz, 3 H).

실시예Example 27. 3-p- 27. 3-p- 에톡시벤조일Ethoxybenzoyl -(4S)-[(1R)--(4S)-[(1R)- 하이드록시헥사덱Hydroxyhexadec -2-엔일)]--2-yen)]- 옥사졸리딘Oxazolidine -2-온2-on

1H NMR (300 MHz, CDCl3) 7.98 (d, J = 8 Hz, 1H), 6.90 (d, J = 8 Hz, 2H), 6.02 (m, 2H), 5.48 (m, 2H), 4.48 (t, J = 8 Hz, 1H), 4.36 (m, 1H), 4.10 (m, 1H), 2.07 (m, 3H), 1.44 (t, J = 8 Hz, 3H), 1.26 (m, 22H), 0.90 (t, J = 7 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 7.98 (d, J = 8 Hz, 1H), 6.90 (d, J = 8 Hz, 2H), 6.02 (m, 2H), 5.48 (m, 2H), 4.48 ( t, J = 8 Hz, 1H), 4.36 (m, 1H), 4.10 (m, 1H), 2.07 (m, 3H), 1.44 (t, J = 8 Hz, 3H), 1.26 (m, 22H), 0.90 (t, J = 7 Hz, 3H).

실시예Example 28. 3-아이소뷰탄오일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸 28. 3-Isobutan oil- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazole 리딘Lidin -2-온2-on

1H NMR (300 MHz, CDCl3) 5.88 (dt, J = 8.4, 6.6 Hz, 1H), 5.4-5.25 (m, 2H), 4.43 (t, J = 9.0 Hz, 1H), 4.26 (dd, J = 9.0, 5.1 Hz, 1H), 4.03-3.97 (m, 1H), 2.63-2.53 (m, 1H), 2.08 (d, J = 6.0 Hz, 1H), 2.03 (d, J = 6.6 Hz, 2H), 1.4-1.2 (m, 22H), 1.19 (d, J = 3.3 Hz, 3H), 1.17 (d, J = 3.3 Hz, 3H), 0.88 (t, J = 6.6 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 5.88 (dt, J = 8.4, 6.6 Hz, 1H), 5.4-5.25 (m, 2H), 4.43 (t, J = 9.0 Hz, 1H), 4.26 (dd, J = 9.0, 5.1 Hz, 1H), 4.03-3.97 (m, 1H), 2.63-2.53 (m, 1H), 2.08 (d, J = 6.0 Hz, 1H), 2.03 (d, J = 6.6 Hz, 2H) , 1.4-1.2 (m, 22H), 1.19 (d, J = 3.3 Hz, 3H), 1.17 (d, J = 3.3 Hz, 3H), 0.88 (t, J = 6.6 Hz, 3H).

실시예Example 29. 3-(1-나프탈렌오일)-(4S)-[(1R)- 29. 3- (1-naphthalene oil)-(4S)-[(1R)- 하이드록시헥사덱Hydroxyhexadec -2-엔일)]--2-yen)]- 옥사졸리딘Oxazolidine -2-온2-on

1H NMR (300 MHz, CDCl3) 8.89 (d, J = 7.2 Hz, 1H), 8.20 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 7.1 Hz, 1H), 7.92 (d, J = 7.1 Hz, 1H), 7.68-7.51 (m, 4H), 6.06 (dt, J = 15.0, 6.6 Hz, 1H), 5.76 (bs, 1H), 5.64-5.50 (m, 2H), 4.55 (t, J = 9.0 Hz, 1H), 4.40 (dd, J = 9.0, 4.8 Hz, 1H), 4.25-4.19 (m, 1H), 2.12 (dd, J = 13.8, 6.9 Hz, 2H), 1.45-1.25 (m, 22H), 0.88 (t, J = 6.6 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 8.89 (d, J = 7.2 Hz, 1H), 8.20 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 7.1 Hz, 1H), 7.92 (d, J = 7.1 Hz, 1H), 7.68-7.51 (m, 4H), 6.06 (dt, J = 15.0, 6.6 Hz, 1H), 5.76 (bs, 1H), 5.64-5.50 (m, 2H), 4.55 (t , J = 9.0 Hz, 1H), 4.40 (dd, J = 9.0, 4.8 Hz, 1H), 4.25-4.19 (m, 1H), 2.12 (dd, J = 13.8, 6.9 Hz, 2H), 1.45-1.25 ( m, 22H), 0.88 (t, J = 6.6 Hz, 3H).

실시예Example 30. 3-p- 30. 3-p- 나이트로벤조일Nitrobenzoyl -(4S)-[(1R)--(4S)-[(1R)- 하이드록시헥사덱Hydroxyhexadec -2-엔일)]--2-yen)]- 옥사졸리딘Oxazolidine -2-온2-on

1H NMR (300 MHz, CDCl3) 8.28 (dd, J = 6.9, 1.8 Hz, 2H), 8.20 (dd, J = 6.9, 1.8 Hz, 2H), 6.1-5.9 (m, 2H), 5.6-5.4 (m, 2H), 4.53 (t, J = 9.0 Hz, 1H), 4.37 (dd, J = 9.0, 4.5 Hz, 1H), 4.2-4.1 (m, 1H), 2.09 (q, J = 6.9 Hz, 2H), 1.4-1.2 (m, 22H), 0.88 (t, J = 6.9 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 8.28 (dd, J = 6.9, 1.8 Hz, 2H), 8.20 (dd, J = 6.9, 1.8 Hz, 2H), 6.1-5.9 (m, 2H), 5.6-5.4 (m, 2H), 4.53 (t, J = 9.0 Hz, 1H), 4.37 (dd, J = 9.0, 4.5 Hz, 1H), 4.2-4.1 (m, 1H), 2.09 (q, J = 6.9 Hz, 2H), 1.4-1.2 (m, 22H), 0.88 (t, J = 6.9 Hz, 3H).

실시예Example 31. 3-(2-페닐에탄오일)-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사 31. 3- (2-phenylethanoyl)-(4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxa 졸리딘Zolidine -2-온2-on

1H NMR (300 MHz, CDCl3) 5.86-5.76 (m, 1H), 5.34-5.22 (m, 2H), 5.09 (bs, 1H), 4.35 (t, J = 9.0 Hz, 1H), 4.12 (dd, J = 9.0, 5.1 Hz, 1H), 3.98-3.92 (m, 1H), 3.65 (s, 2H), 2.02 (q, J = 6.9 Hz, 2H), 1.35-1.24 (m, 22H), 0.88 (t, J = 6.6 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 5.86-5.76 (m, 1H), 5.34-5.22 (m, 2H), 5.09 (bs, 1H), 4.35 (t, J = 9.0 Hz, 1H), 4.12 (dd , J = 9.0, 5.1 Hz, 1H), 3.98-3.92 (m, 1H), 3.65 (s, 2H), 2.02 (q, J = 6.9 Hz, 2H), 1.35-1.24 (m, 22H), 0.88 ( t, J = 6.6 Hz, 3H).

실시예Example 32. 3- 32. 3- 피발로일Pivaloyl -(4S)-[(1R)--(4S)-[(1R)- 하이드록시헥사덱Hydroxyhexadec -2-엔일)]--2-yen)]- 옥사졸리딘Oxazolidine -2-온2-on

1H NMR (300 MHz, CDCl3) 5.91-5.81 (m, 1H), 5.44 (bs, 1H), 5.37-5.27 (m, 2H), 4.42 (t, J = 9.0 Hz, 1H), 4.27 (dd, J = 9.0, 5.1 Hz, 1H), 4.03-4.96 (m, 1H), 2.08 (d, J = 6.6 Hz, 1H), 2.03 (d, J = 4.5 Hz, 2H), 1.36-1.22 (m, 22H), 1.21 (s, 9H), 0.88 (t, J = 6.6 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 5.91-5.81 (m, 1H), 5.44 (bs, 1H), 5.37-5.27 (m, 2H), 4.42 (t, J = 9.0 Hz, 1H), 4.27 (dd , J = 9.0, 5.1 Hz, 1H), 4.03-4.96 (m, 1H), 2.08 (d, J = 6.6 Hz, 1H), 2.03 (d, J = 4.5 Hz, 2H), 1.36-1.22 (m, 22H), 1.21 (s, 9H), 0.88 (t, J = 6.6 Hz, 3H).

실시예Example 33. 3-(2- 33. 3- (2- 퓨로일Puroyl )-(4S)-[(1R)-)-(4S)-[(1R)- 하이드록시헥사덱Hydroxyhexadec -2-엔일)]--2-yen)]- 옥사졸리딘Oxazolidine -2-온2-on

1H NMR (300 MHz, CDCl3) 7.62 (d, J = 0.6 Hz, 1H), 7.27 (d, J = 3.3 Hz, 1H), 6.55 (dd, J = 3.3, 1.5 Hz, 1H), 6.06-5.95 (m, 1H), 5.86 (bs, 1H), 5.52-5.40 (m, 2H), 4.51 (t, J = 3.3 Hz, 2H), 4.33 (dd, J = 9.0, 4.2 Hz, 1H), 4.2-4.1 (m, 2H), 2.12 (d, J = 6.9 Hz, 1H), 2.08 (d, J = 6.9 Hz, 1H), 1.45-12.5 (m, 22H), 0.88 (t, J = 6.6 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 7.62 (d, J = 0.6 Hz, 1H), 7.27 (d, J = 3.3 Hz, 1H), 6.55 (dd, J = 3.3, 1.5 Hz, 1H), 6.06- 5.95 (m, 1H), 5.86 (bs, 1H), 5.52-5.40 (m, 2H), 4.51 (t, J = 3.3 Hz, 2H), 4.33 (dd, J = 9.0, 4.2 Hz, 1H), 4.2 -4.1 (m, 2H), 2.12 (d, J = 6.9 Hz, 1H), 2.08 (d, J = 6.9 Hz, 1H), 1.45-12.5 (m, 22H), 0.88 (t, J = 6.6 Hz, 3H).

실시예Example 34. 3-o- 34. 3-o- 메톡시벤조일Methoxybenzoyl -(4S)-[(1R)--(4S)-[(1R)- 하이드록시헥사덱Hydroxyhexadec -2-엔일)]--2-yen)]- 옥사졸리딘Oxazolidine -2-온2-on

1H NMR (300 MHz, CDCl3) 7.88 (dd, J = 4.8, 1.8 Hz, 1H), 7.52 (td, J = 9.0, 1.8 Hz, 1H), 7.1-6.9 (m, 2H), 6.1-5.9 (m, 2H), 5.6-5.4 (m, 3H), 4.51 (t, J = 9.0 Hz, 1H), 4.37 (dd, J = 9.0, 4.8 Hz, 1H), 4.2-4.1 (m, 1H), 3.94 (s, 3H), 2.12 (d, J = 6.6 Hz, 1H), 2.07 (d, J = 7.2 Hz, 1H), 1.4-1.2 (m, 22H), 0.88 (t, J = 6.6 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 7.88 (dd, J = 4.8, 1.8 Hz, 1H), 7.52 (td, J = 9.0, 1.8 Hz, 1H), 7.1-6.9 (m, 2H), 6.1-5.9 (m, 2H), 5.6-5.4 (m, 3H), 4.51 (t, J = 9.0 Hz, 1H), 4.37 (dd, J = 9.0, 4.8 Hz, 1H), 4.2-4.1 (m, 1H), 3.94 (s, 3H), 2.12 (d, J = 6.6 Hz, 1H), 2.07 (d, J = 7.2 Hz, 1H), 1.4-1.2 (m, 22H), 0.88 (t, J = 6.6 Hz, 3H ).

실시예Example 35. 3- 35. 3- 시클로펜탄오일Cyclopentane oil -(4S)-[(1R)--(4S)-[(1R)- 하이드록시헥사덱Hydroxyhexadec -2-엔일)]--2-yen)]- 옥사졸리딘Oxazolidine -2-온2-on

1H NMR (300 MHz, CDCl3) 5.9-5.8 (m, 1H), 5.44 (bs, 1H), 5.4-5.2 (m, 2H), 4.45 (t, J = 9.0 Hz, 1H), 4.28 (dd, J = 9.0, 5.1 Hz, 1H), 4.1-3.9 (m, 1H), 2.8-2.7 (m, 1H), 2.11 (d, J = 6.3 Hz, 1H), 2.06 (d, J = 7.5 Hz, 1H), 2.0-1.6 (m, 8H), 1.28 (bs, 22H), 0.88 (t, J = 6.6 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 5.9-5.8 (m, 1H), 5.44 (bs, 1H), 5.4-5.2 (m, 2H), 4.45 (t, J = 9.0 Hz, 1H), 4.28 (dd , J = 9.0, 5.1 Hz, 1H), 4.1-3.9 (m, 1H), 2.8-2.7 (m, 1H), 2.11 (d, J = 6.3 Hz, 1H), 2.06 (d, J = 7.5 Hz, 1H), 2.0-1.6 (m, 8H), 1.28 (bs, 22H), 0.88 (t, J = 6.6 Hz, 3H).

실시예Example 36. 3-신남오일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온 36. 3-cinna-oil- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one

1H NMR (300 MHz, CDCl3) 7.71 (d, J = 16.2 Hz, 1H), 7.55-7.5 (m, 1H), 7.45-7.38 (m, 2H), 6.43 (d, J = 16.2 Hz, 1H), 6.0-5.9 (m, 1H), 5.5-5.3 (m, 2H), 5.27 (bs, 1H), 4.48 (t, J = 9.0 Hz, 1H), 4.30 (dd, J = 9.0, 5.1 Hz, 1H), 4.12-4.0 (m, 1H), 2.10 (d, J = 5.1 Hz, 1H), 2.05 (d, J = 7.5 Hz, 1H), 1.25 (bs, 22H), 0.88 (t, J = 6.6 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) 7.71 (d, J = 16.2 Hz, 1H), 7.55-7.5 (m, 1H), 7.45-7.38 (m, 2H), 6.43 (d, J = 16.2 Hz, 1H ), 6.0-5.9 (m, 1H), 5.5-5.3 (m, 2H), 5.27 (bs, 1H), 4.48 (t, J = 9.0 Hz, 1H), 4.30 (dd, J = 9.0, 5.1 Hz, 1H), 4.12-4.0 (m, 1H), 2.10 (d, J = 5.1 Hz, 1H), 2.05 (d, J = 7.5 Hz, 1H), 1.25 (bs, 22H), 0.88 (t, J = 6.6 Hz, 3H).

시험예. 백혈병 세포 HL-60에 대한 항암활성Test example. Anticancer Activity against Leukemia Cell HL-60

본 발명의 화합물 및 대조군으로서 C2-DHCer (N-아세틸-D-에리쓰로-다이하이드로스핀고신)을 사용하여, 항암활성을 평가하였다. HL-60 세포(한국세포주은행, KCLB No. 10240)을 시험물질(본 발명의 화합물 및 C2-DHCer)을 에탄올 및 헥산의 혼합용매(1:1)에 용해시켜 20 μM 농도로 처리한 후, 16시간 동안 37℃, 5% CO2 배양기에서 배양하였다. J. Immunol. Methods 174, 311-320, (1994) 에 따라, MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] 분석을 수행하여 세포의 사멸 정도를 측정하였으며, 그 결과는 도 1과 같다.Anticancer activity was evaluated using C2-DHCer (N-acetyl-D-erythro-dihydropinosine) as a compound of the present invention and a control. After HL-60 cells (Korea Cell Line Bank, KCLB No. 10240) were dissolved in a test solvent (compound of the present invention and C2-DHCer) in a mixed solvent of ethanol and hexane (1: 1) and treated at 20 μM concentration, Incubated for 16 hours at 37 ℃, 5% CO 2 incubator. J. Immunol. According to Methods 174, 311-320, (1994), MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] analysis was performed to determine the degree of cell death. Is the same as FIG.

도 1에서 확인할 수 있는 바와 같이, 본 발명에 따른 옥사졸리딘온 유도체는 우수한 항암활성을 가짐을 알 수 있다.As can be seen in Figure 1, it can be seen that the oxazolidinone derivative according to the present invention has excellent anticancer activity.

화학식 1의 옥사졸리딘온 유도체 또는 그의 염은 우수한 항암활성을 가진다. 또한, 화학식 2의 화합물은 상기 화학식 1의 화합물을 제조하는데 유용한 합성 중간체이다.Oxazolidinone derivatives of formula (1) or salts thereof have excellent anticancer activity. In addition, the compound of formula 2 is a synthetic intermediate useful for preparing the compound of formula 1 above.

Claims (7)

화학식 1의 옥사졸리딘온 유도체 또는 그의 염:Oxazolidinone derivatives of formula 1 or salts thereof: <화학식 1><Formula 1>
Figure 112006030859960-pat00010
Figure 112006030859960-pat00010
 식 중, R1은 C1∼C15 알킬; C3∼C7 시클로알킬; 페닐; C1∼C5 알킬, C1∼C5 알콕시, 또는 나이트로로 치환된 페닐; 벤질; 3,4-(메틸렌다이옥시)페닐; 나프틸; 퓨란일; 또는 2-페닐-에텐-1-일이고,Wherein, R 1 is C 1 ~C 15 alkyl; C 3 -C 7 cycloalkyl; Phenyl; Phenyl substituted with C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or nitro; benzyl; 3,4- (methylenedioxy) phenyl; Naphthyl; Furanyl; Or 2-phenyl-ethen-1-yl, R2는 C1∼C15 알킬이다.R 2 is C 1 -C 15 alkyl. 제1항에 있어서, R1은 C1∼C6 알킬, 펜타데칸일, C3∼C7 시클로알킬, 페닐, 메틸페닐, 에틸페닐, 메톡시페닐, 에톡시페닐, 나이트로페닐, 벤질, 3,4-(메틸렌다이옥시)페닐, 나프틸, 퓨란일, 또는 2-페닐-에텐-1-일이고, R2는 트리데칸일인 것을 특징으로 하는 옥사졸리딘온 유도체 또는 그의 염.The compound of claim 1, wherein R 1 is C 1 -C 6 alkyl, pentadecaneyl, C 3 -C 7 cycloalkyl, phenyl, methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, nitrophenyl, benzyl, 3 Or 4- (methylenedioxy) phenyl, naphthyl, furanyl, or 2-phenyl-ethen-1-yl, and R 2 is tridecanyl, or an oxazolidinone derivative or salt thereof. 제1항에 있어서, 3-아세틸-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리 딘-2-온;The compound of claim 1, wherein 3-acetyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-프로피오닐-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-propionyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-헥사데칸오일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-hexadecane oil- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-benzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-p-메틸벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-p-methylbenzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-피페론일오일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-piperonyloil- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-o-메틸벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-o-methylbenzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-p-에틸벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-p-ethylbenzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-p-에톡시벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-p-ethoxybenzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-아이소뷰탄오일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-isobutanoil- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-(1-나프탈렌오일)-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3- (1-naphthalenoyl)-(4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-p-나이트로벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-p-nitrobenzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-(2-페닐에탄오일)-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온; 3- (2-phenylethanoyl)-(4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-피발로일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-pivaloyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-(2-퓨로일)-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3- (2-furoyl)-(4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-o-메톡시벤조일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-o-methoxybenzoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; 3-시클로펜탄오일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온; 및3-cyclopentanoyl- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one; And 3-신남오일-(4S)-[(1R)-하이드록시헥사덱-2-엔일)]-옥사졸리딘-2-온으로 이루어진 군으로부터 선택된 옥사졸리딘온 유도체 또는 그의 염.An oxazolidinone derivative or a salt thereof selected from the group consisting of 3-cinnam oil- (4S)-[(1R) -hydroxyhexadec-2-enyl)]-oxazolidin-2-one. 화학식 2의 옥사졸리딘온 유도체 또는 그의 염:Oxazolidinone derivatives of Formula 2 or salts thereof: <화학식 2><Formula 2>
Figure 112007016900209-pat00011
Figure 112007016900209-pat00011
 식 중, R1 및 R2는 제1항에서 정의한 바와 동일하며, R3는 t-뷰틸다이메틸실릴이다.Wherein R 1 and R 2 are the same as defined in claim 1, and R 3 is t-butyldimethylsilyl. 제4항에 있어서, 3-아세틸-(4S)-[(1R)-1-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온;The compound of claim 4, wherein 3-acetyl- (4S)-[(1R) -1-t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one; 3-프로피오닐-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온;3-propionyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one; 3-헥사데칸오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온;3-hexadecanoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one; 3-벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온;3-benzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one; 3-p-메틸벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일]-옥사졸리딘-2-온;3-p-methylbenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl] -oxazolidin-2-one; 3-피페론일오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-piperonyloil- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one; 3-o-메틸벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-o-methylbenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one; 3-p-에틸벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-p-ethylbenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one; 3-p-에톡시벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-p-ethoxybenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one; 3-아이소뷰탄오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-isobutanoil- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one; 3-(1-나프탈렌오일)-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3- (1-naphthalenyl)-(4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one; 3-p-나이트로벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-p-nitrobenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one; 3-(2-페닐에탄오일)-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3- (2-phenylethanoyl)-(4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one; 3-피발로일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-pivaloyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one; 3-(2-퓨로일)-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3- (2-furoyl)-(4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one; 3-o-메톡시벤조일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온;3-o-methoxybenzoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one; 3-시클로펜탄오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온; 및3-cyclopentanoyl- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one; And 3-신남오일-(4S)-[(1R)-t-뷰틸다이메틸실릴옥시헥사덱-2-엔일)]-옥사졸리딘-2-온으로 이루어진 군으로부터 선택된 옥사졸리딘온 유도체 또는 그의 염.An oxazolidinone derivative or a salt thereof selected from the group consisting of 3-cinnam oil- (4S)-[(1R) -t-butyldimethylsilyloxyhexadec-2-enyl)]-oxazolidin-2-one. 화학식 3의 화합물을 R1COX 과 반응시켜 화학식 2의 화합물을 제조하는 단계 및 화학식 2의 화합물의 탈보호기 반응을 수행하는 단계를 포함하는 화학식 1의 옥사졸리딘온 유도체 또는 그의 염의 제조방법:A method for preparing an oxazolidinone derivative or a salt thereof comprising reacting a compound of Formula 3 with R 1 COX to produce a compound of Formula 2 and performing a deprotection group reaction of the compound of Formula 2: <화학식 1><Formula 1>
Figure 112006030859960-pat00012
Figure 112006030859960-pat00012
 <화학식 2><Formula 2>
Figure 112006030859960-pat00013
Figure 112006030859960-pat00013
Figure 112006030859960-pat00014
Figure 112006030859960-pat00014
 식 중, R1 및 R2는 제1항에서 정의한 바와 동일하며, R3는 히드록시 보호기이고, X는 할로겐이다.Wherein R 1 and R 2 are the same as defined in claim 1, R 3 is a hydroxy protecting group and X is a halogen. 제1항 내지 제3항 중 어느 한 항에 따른 옥사졸리딘온 유도체 또는 그의 염 및 약제학적으로 허용가능한 담체를 포함하는 항암 조성물.An anticancer composition comprising the oxazolidinone derivative according to any one of claims 1 to 3 or a salt thereof and a pharmaceutically acceptable carrier.
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JPH11171875A (en) 1997-12-12 1999-06-29 Daiso Co Ltd Production of oxazolidin-2-one derivative

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