KR100240778B1 - Novel genipin derivative and therapeutic composition for liver disease comprising the same as an active ingredient - Google Patents
Novel genipin derivative and therapeutic composition for liver disease comprising the same as an active ingredient Download PDFInfo
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- KR100240778B1 KR100240778B1 KR1019970067407A KR19970067407A KR100240778B1 KR 100240778 B1 KR100240778 B1 KR 100240778B1 KR 1019970067407 A KR1019970067407 A KR 1019970067407A KR 19970067407 A KR19970067407 A KR 19970067407A KR 100240778 B1 KR100240778 B1 KR 100240778B1
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- 0 COC(C1=COC(*)C2C(CO)=CCC12)=O Chemical compound COC(C1=COC(*)C2C(CO)=CCC12)=O 0.000 description 3
- AZKVWQKMDGGDSV-UHFFFAOYSA-N COC(C(C1C2C(CO)=CC1)=COC2O)=O Chemical compound COC(C(C1C2C(CO)=CC1)=COC2O)=O AZKVWQKMDGGDSV-UHFFFAOYSA-N 0.000 description 1
- DMUVVXZULJHYQU-UHFFFAOYSA-N COC(C1=COCC2C(C=O)=CCC12)=O Chemical compound COC(C1=COCC2C(C=O)=CCC12)=O DMUVVXZULJHYQU-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
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- A—HUMAN NECESSITIES
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/06—Peri-condensed systems
Abstract
본 발명은 우수한 간질환 예방 및 치료효과를 갖는 하기 화학식 1의 신규한 제니핀 유도체 및 그의 제조방법에 관한 것이다 :The present invention relates to a novel genipine derivative of the formula (1) having a superior liver disease prevention and treatment effect and a method for preparing the same:
상기식에서In the above formula
R1은 수소원자, 저급알킬 또는 알칼리금속을 나타내고,R 1 represents a hydrogen atom, lower alkyl or an alkali metal,
R2는 저급알킬 또는 벤질을 나타내며,R 2 represents lower alkyl or benzyl,
R3는 수소원자 또는 저급알킬을 나타내고,R 3 represents a hydrogen atom or lower alkyl,
R4는 하이드록시, 저급알콕시, 벤질옥시, 니코티노일옥시 등을 나타낸다.R 4 represents hydroxy, lower alkoxy, benzyloxy, nicotinoyloxy and the like.
Description
본 발명은 우수한 간질환 예방 및 치료효과를 갖는 하기 화학식 1의 신규한 제니핀 유도체, 그의 약제학적으로 허용되는 염 또는 입체이성체에 관한 것이다 :The present invention relates to a novel genipine derivative of Formula 1, a pharmaceutically acceptable salt or stereoisomer thereof having excellent liver disease prevention and treatment effects:
화학식 1Formula 1
상기식에서In the above formula
R1은 수소원자, 저급알킬 또는 알칼리금속을 나타내고,R 1 represents a hydrogen atom, lower alkyl or an alkali metal,
R2는 저급알킬 또는 벤질을 나타내며,R 2 represents lower alkyl or benzyl,
R3는 수소원자 또는 저급알킬을 나타내고,R 3 represents a hydrogen atom or lower alkyl,
R4는 하이드록시, 저급알콕시, 벤질옥시, 니코티노일옥시, 이소니코티노일옥시, 2-피리딜메톡시 또는 하이드록시카보닐메톡시를 나타내거나,R 4 represents hydroxy, lower alkoxy, benzyloxy, nicotinoyloxy, isnicotinoyloxy, 2-pyridylmethoxy or hydroxycarbonylmethoxy, or
R3및 R4는 이들이 부착되어 있는 질소원자 및 탄소원자와 함께
단, R1이 메틸을 나타내고, R3가 수소원자를 나타내는 경우에 R4는 하이드록시 또는 메톡시가 아니다.Provided that when R 1 represents methyl and R 3 represents a hydrogen atom, R 4 is not hydroxy or methoxy.
본 발명은 또한, 상기 화학식 1의 화합물을 유효성분으로 함유함으로써 간질환의 예방 및 치료에 효과적으로 사용될 수 있는 약제학적 조성물에 관한 것이다.The present invention also relates to a pharmaceutical composition that can be effectively used for the prevention and treatment of liver disease by containing the compound of Formula 1 as an active ingredient.
인간의 신체장기중 생체내 대사가 가장 활발하게 일어나는 간에 바이러스나 각종 약품과 같은 유해물질, 영양부족 등 여러 다양한 원인에 의해 급성 또는 만성의 장애가 일어나면 지방간, 간염, 황달, 간경변, 간경화, 간암등이 야기될 수 있다. 이러한 간질환을 치료하는 공지의 치료제로는 실리마린(참조: Biotech, Therapeutics, 4, 263-270, 1993), 말로틸레이트(참조: Japan, J. Exp. Med., 56, 235-245, 1986; Biochem. Biophy. Res. Comm., 200, 1414, 1994), 디디비(참조: Biochem. Biophy. Res. Comm., 103, 1131-1137, 1981), 플루메시놀(참조: USP 4,039,589 호) 등이 보고되어 있다. 또한, 식사요법, 대중요법, 스테로이드제, 면역제제 등의 약물요법을 이용하여 간질환을 치료하고자 하는 시도가 있으나 그 치료효능은 미미한 실정이며, 천연물에서 분리된 이리도이드 유도체인 피크로리브(피크로시드 I과 쿠루아를 함유하는 엑기스)에 간보호활성이 있다고 보고된 바 있으나(참조: Indian, J. Med. Res., 92, 195-200, 1990; USP 5,145,955 호), 간보호활성을 갖는 이리도이드 유도체로서 본 발명에 따른 신규한 제니핀 유도체는 지금까지 공지된 바가 없다.Liver metabolism is the most active in the human organs, and acute or chronic disorders occur due to various causes such as viruses, various drugs, and malnutrition. Fatty liver, hepatitis, jaundice, cirrhosis, cirrhosis, liver cancer, etc. May be caused. Known therapeutic agents for treating such liver diseases include silymarin (Biotech, Therapeutics, 4, 263-270, 1993), malolate (Japan, J. Exp. Med., 56, 235-245, 1986). Biochem.Biophy.Res.Comm., 200, 1414, 1994), dividi (Biochem. Biophy.Res.Comm., 103, 1131-1137, 1981), flumesinol (US Pat. No. 4,039,589); And the like have been reported. In addition, there are attempts to treat liver disease using medication therapy such as diet therapy, mass therapy, steroids, and immunologic agents, but the therapeutic effect is insignificant, and pyrrolib, an iridoid derivative isolated from natural products, is peaked. Hepatoprotective activity has been reported in extracts containing Rosid I and kurua (Indian, J. Med. Res., 92, 195-200, 1990; USP 5,145,955). As the iridoid derivative having, the novel jennypin derivative according to the present invention is not known until now.
한편, 하기 화학식 2의 제니핀 및 화학식 3의 오쿠빈은 이리도이드 계통의 천연물로서 B형 간염 바이러스의 복제를 억제하는 기작을 통해 B형 간염의 치료제로 작용한다고 보고되어 있다(참조: 대한민국 특허공개 제 94-1886 호).On the other hand, it is reported that the phenine of formula 2 and the okubin of formula (3) is a natural product of the iridoid line and acts as a therapeutic agent for hepatitis B through a mechanism that inhibits the replication of hepatitis B virus (see: Korean Patent Publication 94-1886).
상기 구조의 제니핀 및 오쿠빈은 항 바이러스 활성을 비롯하여 간보호작용, RNA 및 단백질 생합성의 억제, 해독활성 등의 생체활성을 갖고 있으며, 특히 제니핀의 경우 항암제로서의 유효성도 보고되어 있다(일본국 특허 공개 제 80/164625 호). 그러나, 이들 화합물은 또한 생체내에서 분해되어 디알데히드를 생성하는데, 생성된 디알데히드는 알부민 등 생체내 단백질의 아미노산 잔기와 결합함으로써, 뇨, 변 및 각종 장기를 푸른 빛으로 변화시키고 면역독성을 유발시키는 등의 부작용을 나타낸다.In addition to the antiviral activity, zenpin and okubin have the biological activities such as hepatoprotective activity, inhibition of RNA and protein biosynthesis, detoxification activity, and especially in the case of jennypin, its effectiveness as an anticancer agent has been reported. Patent Publication No. 80/164625). However, these compounds are also degraded in vivo to produce dialdehydes, which combine with amino acid residues of proteins in vivo such as albumin to change urine, stools and various organs to bluish light and induce immunotoxicity. Side effects such as
본 발명에 따른 화합물과 유사한 구조를 갖는 화합물로는 상기 제니핀 및 오쿠빈 이외에도 하기 화학식 4의 화합물을 언급할 수 있으며(참조: 국제 특허 공개 제 WO 92/06061 호 및 유럽 특허 공개 제 EP 0505572 호), 이들은 고지혈증 치료제나 이담제로서 유용하게 사용될 수 있다고 보고되어 있다.As compounds having a structure similar to that of the compound according to the present invention, in addition to the above-mentioned nippin and ucvin, compounds of the following formula (4) may be mentioned (see, for example, WO 92/06061 and EP 0505572). It is reported that they can be usefully used as a drug for treating hyperlipidemia or as a diarrhea agent.
상기식에서In the above formula
R1은 벤조일옥시, 하이드록시, 아세톡시 또는 에톡시에톡시를 나타내고,R 1 represents benzoyloxy, hydroxy, acetoxy or ethoxyethoxy,
R2는 벤조일옥시메틸, 메톡시메틸, t-부틸디메틸실릴옥시메틸, 카복시 또는 하이드록시메틸을 나타낸다.R 2 represents benzoyloxymethyl, methoxymethyl, t-butyldimethylsilyloxymethyl, carboxy or hydroxymethyl.
한편, 본 발명자들은 상기 언급한 선행기술을 바탕으로 하여 B 형 간염 바이러스의 억제에 있어서 종래 화합물들보다 우수한 활성을 갖는 화합물을 개발하기 위해 오쿠빈 및 제니핀의 유도체로서 신규한 일련의 화합물을 합성하고 이들의 항바이러스 활성 및 세포독성을 확인한 결과 이를 대한민국 특허출원 제 95-38181 호, 96-46732 호 및 97-14907 호로 출원한 바 있다.On the other hand, the present inventors have synthesized a new series of compounds as derivatives of okubin and jennypin in order to develop compounds having superior activity to conventional compounds in the inhibition of hepatitis B virus based on the above-mentioned prior art. As a result of confirming their antiviral activity and cytotoxicity, it has been filed as Korean Patent Application Nos. 95-38181, 96-46732 and 97-14907.
그러나, 본 발명자들은 이에 그치지않고 신규한 제니핀 유도체의 합성 및 그의 약리활성에 대한 연구를 지속적으로 수행하였으며, 그 결과 상기 화학식 1로 나타낸 바와 같이 옥사인덴환의 2, 5, 및 7 위치가 치환된 본 발명의 화합물을 새로이 합성하였다. 그리고, 이 화합물이 우수한 간질환 예방 및 치료효과를 나타냄을 확인함으로써 본 발명을 완성하게 되었다.However, the present inventors continued to study the synthesis and pharmacological activity of the novel nippine derivatives, and as a result, the positions 2, 5, and 7 of the oxaindene ring are substituted as shown in Formula 1 above. Synthesized compounds of the present invention were newly synthesized. In addition, the present invention was completed by confirming that the compound exhibited an excellent liver disease prevention and treatment effect.
따라서 본 발명의 목적은 간질환 예방 및 치료효과가 우수한 화학식 1의 신규한 제니핀 유도체를 제공하는 것이다.Therefore, it is an object of the present invention to provide a novel genipine derivative of formula (1) excellent in the prevention and treatment of liver disease.
본 발명은 또한, 이러한 화학식 1의 화합물을 유효성분으로 함유함을 특징으로 하는 간질환 치료제 조성물을 제공하는 것을 목적으로 한다.It is another object of the present invention to provide a therapeutic agent for liver disease, which comprises the compound of formula 1 as an active ingredient.
이하, 본 발명의 구성을 상세히 설명한다.Hereinafter, the configuration of the present invention will be described in detail.
본 발명은 간질환 예방 및 치료효과가 우수한 하기 화학식 1의 제니핀 유도체, 그의 약제학적으로 허용되는 염 또는 입체이성체에 관한 것이다.The present invention relates to a genipine derivative of Formula 1, a pharmaceutically acceptable salt or stereoisomer thereof having excellent liver disease prevention and treatment.
화학식 1Formula 1
상기식에서In the above formula
R1은 수소원자, 저급알킬 또는 알칼리금속을 나타내고,R 1 represents a hydrogen atom, lower alkyl or an alkali metal,
R2는 저급알킬 또는 벤질을 나타내며,R 2 represents lower alkyl or benzyl,
R3는 수소원자 또는 저급알킬을 나타내고,R 3 represents a hydrogen atom or lower alkyl,
R4는 하이드록시, 저급알콕시, 벤질옥시, 니코티노일옥시, 이소니코티노일옥시, 2-피리딜메톡시 또는 하이드록시카보닐메톡시를 나타내거나,R 4 represents hydroxy, lower alkoxy, benzyloxy, nicotinoyloxy, isnicotinoyloxy, 2-pyridylmethoxy or hydroxycarbonylmethoxy, or
R3및 R4는 이들이 부착되어 있는 질소원자 및 탄소원자와 함께
단, R1이 메틸을 나타내고, R3가 수소원자를 나타내는 경우에 R4는 하이드록시 또는 메톡시가 아니다.Provided that when R 1 represents methyl and R 3 represents a hydrogen atom, R 4 is not hydroxy or methoxy.
우수한 간질환 예방 및 치료효과를 나타내는 상기 화학식 1의 화합물 중에서도 바람직한 화합물은 R1은 수소원자, 메틸, 이소프로필 또는 나트륨을 나타내고, R2는 메틸 또는 벤질을 나타내며, R3는 수소원자 또는 메틸을 나타내고, R4는 하이드록시, 메톡시, t-부톡시, 벤질옥시, 니코티노일옥시, 이소니코티노일옥시, 2-피리딜메톡시 또는 하이드록시카보닐메톡시를 나타내거나, R3및 R4는 이들이 부착되어 있는 질소원자 및 탄소원자와 함께
상기 화학식 1의 화합물에서 -OR2그룹이 부착되어 있는 탄소원자는 비대칭 중심(asymmetric center)을 이루고 있으므로, 본 발명에 따른 화합물은 R 또는 S 형태이거나 R 및 S 형태의 혼합물로 존재할 수 있다. 따라서, 본 발명에는 이들 각각의 입체이성체 및 이들의 혼합물도 포함된다.Since the carbon atom to which the —OR 2 group is attached in the compound of Formula 1 forms an asymmetric center, the compound according to the present invention may be present in R or S form or as a mixture of R and S form. Accordingly, the present invention also encompasses each of these stereoisomers and mixtures thereof.
본 발명에 따른 화학식 1 화합물의 약제학적으로 허용되는 염으로는 아스파라긴산염, 글루콘산염, 염산염, p-톨루엔설폰산염 또는 구연산염 등과 같이 약제학적으로 허용되는 산부가염, 피리딘염 또는 암모니아염 등과 같이 약제학적으로 허용되는 염기부가염, 그밖에 이리도이드계 화합물의 기술분야에서 공지되어 사용되고 있는 다른 산 또는 염기와의 염을 언급할 수 있다. 이들은 통상의 전환공정에 의하여 제조된다.Pharmaceutically acceptable salts of the compounds of formula 1 according to the present invention include pharmaceutically acceptable acid addition salts, pyridine salts or ammonia salts, such as aspartinates, gluconates, hydrochlorides, p-toluenesulfonates or citrates Mention may be made of pharmaceutically acceptable base addition salts, as well as salts with other acids or bases known and used in the art of iridoid-based compounds. These are manufactured by the usual conversion process.
한편, 본 발명에 따른 화학식 1의 화합물은 다음에 설명하는 바와 같은 방법에 따라 제조할 수 있다. 그러나, 본 발명에 따른 화합물의 제조방법이 하기에 설명하는 것으로만 한정되는 것은 아니며, 본 명세서에 기재되거나 선행문헌에 개시된 여러 가지 합성방법을 임의로 조합함으로써 극히 용이하게 제조할 수 있고 이러한 조합은 본 발명이 속하는 기술 분야의 당업자에게 범용화된 통상의 기술이다.On the other hand, the compound of formula 1 according to the present invention can be prepared according to the method as described below. However, the preparation method of the compound according to the present invention is not limited to the following description, and can be prepared very easily by arbitrarily combining various synthesis methods described in this specification or disclosed in the prior literature, and such combinations are It is a common technique generalized to those skilled in the art to which the invention belongs.
1) 먼저, R1이 메틸이고 R2가 저급알킬 또는 벤질이며, R3가 수소원자이고, R4가 t-부톡시, 벤질옥시, 하이드록시카보닐메톡시 또는 2-피리딜메톡시인 화학식 1의 화합물은 하기 반응식 1에 나타낸 바와 같이 제조할 수 있다. 즉, 단계 1에서 트리플루오로보란 디에틸에테르 존재하에 제니핀을 메탄올, 에탄올 등의 저급알콜 또는 벤질알콜과 반응시켜 제니핀의 5번 탄소에 위치한 하이드록시를 저급알콕시 또는 벤질옥시로 전환시키고, 단계 2에서 피리디늄클로로크로메이트(PCC)를 사용하여 7번 탄소에 위치한 하이드록시메틸을 포르밀로 산화시킨 후 생성된 화합물을 단계 3에서 t-부톡실아민 하이드로클로라이드, 벤질옥시아민 하이드로클로라이드, 하이드록시카보닐메톡실아민 헤미하이드로클로라이드 또는 2-피리딜메톡실아민 디하이드로클로라이드와 반응시켜 목적화합물을 제조한다.1) First, Formula 1 wherein R 1 is methyl, R 2 is lower alkyl or benzyl, R 3 is a hydrogen atom, R 4 is t-butoxy, benzyloxy, hydroxycarbonylmethoxy or 2-pyridylmethoxy The compound of can be prepared as shown in Scheme 1 below. That is, in step 1, phenyl is reacted with lower alcohols such as methanol and ethanol or benzyl alcohol in the presence of trifluoroborane diethyl ether to convert hydroxy at position 5 carbon of the phenyl to lower alkoxy or benzyloxy, In step 2, pyridinium chlorochromate (PCC) was used to oxidize hydroxymethyl at position 7 to formyl, followed by oxidation of the resulting compound in step 3 with t-butoxylamine hydrochloride, benzyloxyamine hydrochloride, hydroxy The desired compound is prepared by reacting with carbonylmethoxylamine hemihydrochloride or 2-pyridylmethoxylamine dihydrochloride.
상기 반응식 1에서In Scheme 1
R2는 저급알킬 또는 벤질을 나타내고,R 2 represents lower alkyl or benzyl,
R4' 는 t-부톡시, 벤질옥시, 하이드록시카보닐메톡시 또는 2-피리딜메톡시를 나타낸다.R 4 ′ represents t-butoxy, benzyloxy, hydroxycarbonylmethoxy or 2-pyridylmethoxy.
반응식 1로부터 알 수 있듯이, 단계 2 반응 후에 생성되는 제니핀 유도체는 5번 탄소에 부착된 -OR2그룹의 입체화학적 배열에 따라 R 또는 S 형태의 입체이성체로 존재한다. 따라서, 단계 2 반응을 수행한 후에 각각의 이성체로 분리하여 각 이성체를 다음 반응에 이용한다.As can be seen from Scheme 1, the jennypin derivative produced after the step 2 reaction exists as a stereoisomer in R or S form depending on the stereochemical arrangement of the -OR 2 group attached to carbon 5. Therefore, after performing the step 2 reaction, each isomer is separated and used for the next reaction.
2) R1이 메틸이고, R2가 저급알킬 또는 벤질이며, R3가 수소원자이고, R4가 니코티노일옥시 또는 이소니코티노일옥시인 화학식 1의 화합물은 하기 반응식 2에 나타낸 바와 같이, 단계 1에서 포르밀화합물을 하이드록실아민 하이드로클로라이드와 반응시킨 후, 생성된 화합물을 단계 2에서 니코티노일할라이드 또는 이소니코티노일할라이드와 반응시킴으로써 제조할 수 있다.2) A compound of Formula 1 wherein R 1 is methyl, R 2 is lower alkyl or benzyl, R 3 is a hydrogen atom, and R 4 is nicotinoyloxy or isnicotinoyloxy, as shown in Scheme 2 below, After reacting the formyl compound with hydroxylamine hydrochloride in step 1, the resulting compound is reacted with nicotinoyl halide or isicotinoyl halide in step 2.
상기 반응식 2에서In Scheme 2
R2는 저급알킬 또는 벤질을 나타내고,R 2 represents lower alkyl or benzyl,
R4" 는 니코티노일옥시 또는 이소니코티노일옥시를 나타낸다.R 4 ″ represents nicotinoyloxy or isnicotinoyloxy.
3) R1이 메틸이고, R2가 저급알킬 또는 벤질이며, R3및 R4는 이들이 부착되어 있는 질소원자 및 탄소원자와 함께 4-(p-톨루엔설포닐옥시카보닐)티아졸린-2-일 또는 4-에톡시카보닐티아졸-2-일인 화학식 1의 화합물은 하기 반응식 3에 나타낸 바와 같이, 단계 1에서 포르밀 화합물을 L-시스테인 또는 L-시스테인 에틸에스테르와 반응시킨 다음, 생성된 화합물을 트리에틸아민의 존재하에 p-톨루엔설포닐클로라이드와 반응시키거나(단계 2a) 망간디옥사이드와 함께 반응시켜(단계 2b) 각각 제조한다.3) R 1 is methyl, R 2 is lower alkyl or benzyl, and R 3 and R 4 together with the nitrogen and carbon atoms to which they are attached 4- (p-toluenesulfonyloxycarbonyl) thiazoline-2 The compound of formula 1, which is -yl or 4-ethoxycarbonylthiazol-2-yl, reacts the formyl compound with L-cysteine or L-cysteine ethylester in step 1, as shown in Scheme 3 below. The prepared compounds are each prepared by reacting with p-toluenesulfonylchloride in the presence of triethylamine (step 2a) or with manganese dioxide (step 2b).
상기 반응식 3에서In Scheme 3 above
R2는 저급알킬 또는 벤질을 나타내고,R 2 represents lower alkyl or benzyl,
R5' 는 수소 또는 에틸을 나타낸다.R 5 ′ represents hydrogen or ethyl.
4) R1이 메틸이고, R2가 저급알킬 또는 벤질이며, R3가 저급알킬이고, R4가 하이드록시, 저급알콕시, 벤질옥시, 하이드록시카보닐알콕시, 니코티노일옥시, 이소니코티노일옥시 또는 2-피리딜메톡시인 화학식 1의 화합물은 하기 반응식 4에 나타낸 바와 같이 제조한다. 즉, 단계 1에서 포르밀 화합물을 메틸마그네슘클로라이드나 에틸마그네슘클로라이드와 같은 저급알킬마그네슘클로라이드와 반응시켜 2차 알콜화합물을 제조하고, 단계 2에서 알콜화합물을 PCC등의 산화제로 처리하여 케톤화합물을 제조한 다음, 단계 3에서 반응식 1의 단계 3에서와 같이 상응하는 아민화합물과 반응시켜 목적화합물을 제조한다.4) R 1 is methyl, R 2 is lower alkyl or benzyl, R 3 is lower alkyl, R 4 is hydroxy, lower alkoxy, benzyloxy, hydroxycarbonylalkoxy, nicotinoyloxy, isicotinoino Compound of formula 1, which is monooxy or 2-pyridylmethoxy, is prepared as shown in Scheme 4 below. That is, in step 1, the formyl compound is reacted with a lower alkyl magnesium chloride such as methylmagnesium chloride or ethylmagnesium chloride to prepare a secondary alcohol compound, and in step 2, the ketone compound is prepared by treating the alcohol compound with an oxidizing agent such as PCC. Then, in step 3, the target compound is prepared by reacting with the corresponding amine compound as in step 3 of Scheme 1.
상기 반응식 4에서In Scheme 4
R2는 저급알킬 또는 벤질을 나타내고,R 2 represents lower alkyl or benzyl,
R3' 는 저급알킬을 나타내며,R 3 ′ represents lower alkyl,
R4"' 는 하이드록시, 저급알콕시, 벤질옥시, 하이드록시카보닐알콕시, 니코티노일옥시, 이소니코티노일옥시 또는 2-피리딜메톡시를 나타낸다.R 4 "'represents hydroxy, lower alkoxy, benzyloxy, hydroxycarbonylalkoxy, nicotinoyloxy, isnicotinoyloxy or 2-pyridylmethoxy.
5) R1이 이소프로필이고, R2, R3, 및 R4가 상기 화학식 1에 대해 정의한 바와 같은 화학식 1의 화합물은 하기 반응식 5에 나타낸 바와 같이, 제니핀의 5-번 위치가 치환된 화합물을 용매로도 작용하는 이소프로판올과 함께 티타늄이소프로폭사이드와 같은 루이스산 존재하에 반응시켜 2-번 위치의 메톡시카보닐을 이소프로필옥시카보닐로 전환시킨 후 반응식 1 내지 4에 나타낸 것과 동일한 방법으로 제조한다.5) A compound of Formula 1, wherein R 1 is isopropyl and R 2 , R 3 , and R 4 are defined for Formula 1 above is substituted with the 5-position of Zenipin, as shown in Scheme 5 below. The compound is reacted with isopropanol, which also acts as a solvent, in the presence of a Lewis acid such as titanium isopropoxide to convert methoxycarbonyl at 2-position to isopropyloxycarbonyl and then the same as shown in Schemes 1-4. It is prepared by the method.
상기 반응식 5에서In Scheme 5
R2, R3, 및 R4는 화학식 1에 대해 정의한 바와 같다.R 2 , R 3 , and R 4 are as defined for Formula (1).
6) R1이 수소원자 또는 알칼리금속이고, R2가 저급알킬 또는 벤질이며, R3가 수소원자 또는 저급알킬이고, R4가 하이드록시, 저급알콕시, 벤질옥시, 하이드록시카보닐알콕시, 니코티노일옥시, 이소니코티노일옥시 또는 2-피리딜메톡시인 화학식 1의 화합물은 하기 반응식 6에 나타낸 바와 같이 제조한다. 즉, 반응식 1, 2, 및 4에서 제조된 화합물을 물과 아세토니트릴의 혼합용매중에서 3당량의 수산화나트륨과 반응시킨 후 진한 염산으로 처리하여 R1이 수소원자인 화합물을 제조한 다음, 이 화합물을 1 당량의 알칼리금속 수산화물로 처리하여 R1이 알칼리금속인 목적화합물을 제조한다.6) R 1 is a hydrogen atom or an alkali metal, R 2 is lower alkyl or benzyl, R 3 is hydrogen atom or lower alkyl, R 4 is hydroxy, lower alkoxy, benzyloxy, hydroxycarbonylalkoxy, nico Compounds of formula (1) which are tinoyloxy, isicotinoyloxy or 2-pyridylmethoxy are prepared as shown in Scheme 6 below. That is, the compound prepared in Schemes 1, 2, and 4 was reacted with 3 equivalents of sodium hydroxide in a mixed solvent of water and acetonitrile, and then treated with concentrated hydrochloric acid to prepare a compound having R 1 as a hydrogen atom. Is treated with 1 equivalent of alkali metal hydroxide to prepare a target compound wherein R 1 is an alkali metal.
상기 반응식 6에서In Scheme 6
R1' 는 알칼리금속을 나타내고,R 1 ′ represents an alkali metal,
R2는 저급알킬 또는 벤질을 나타내며,R 2 represents lower alkyl or benzyl,
R3는 수소 또는 저급알킬을 나타내고,R 3 represents hydrogen or lower alkyl,
R4"' 는 하이드록시, 저급알콕시, 벤질옥시, 하이드록시카보닐알콕시, 니코티노일옥시, 이소니코티노일옥시 또는 2-피리딜메톡시를 나타낸다.R 4 "'represents hydroxy, lower alkoxy, benzyloxy, hydroxycarbonylalkoxy, nicotinoyloxy, isnicotinoyloxy or 2-pyridylmethoxy.
화학식 1의 화합물을 제조하는 상기 방법 1 내지 6에서 출발물질로 사용된 공지의 화합물들은 대한민국 특허출원 제 95-38181 호 및 96-46732 호에 개시되어 있는 방법을 참조하여 제조할 수 있다.Known compounds used as starting materials in the above methods 1 to 6 for preparing the compounds of Formula 1 may be prepared by referring to the methods disclosed in Korean Patent Applications Nos. 95-38181 and 96-46732.
한편, 본 발명에 따른 상기 화학식 1의 신규 제니핀 유도체의 간보호효과는 사염화탄소 모델과 D-갈락토사민 모델을 이용하여 조사하였다.On the other hand, the hepatoprotective effect of the novel Zenithine derivative of Formula 1 according to the present invention was investigated using a carbon tetrachloride model and D-galactosamine model.
사염화탄소 모델(참조: Philippe letteron et al., Biochemical Pharma- cology, 39, 12, 2027-2034, 1990; Tips, 10, 1989; Kyoichi Kagawa et al., Japan J. Pharmacol., 42, 19-26, 1986; K. T. Liu and P. Lesca, Chem. Biol. Interactions, 41, 39-47, 1982; Richard O. et al., J. Biological Chemistry, 236, 2, 1961)은 실험적 간장해 모델중 가장 일반적으로 사용되는 것으로서, 사염화탄소가 체내 사이토크롬 P-450에 의해 독성이 강한 대사물인 트리클로로메틸 자유라디칼(CCl3·)로 전환되고 이 대사물이 간 마이크로좀의 막단백 티올기와 강하게 결합하여 지질라디칼(lipid radical)을 형성하며 산소 존재시 과산화라디칼(peroxy radical)로 되어 막의 지질 과산화반응을 촉진하는 현상을 기초로하여 확립된 것이다. 즉, 사염화탄소는 간에서의 단백질 생합성을 억제하고, 혈중 ALT, AST 치의 증가를 야기시키며, 조직학적으로는 간세포의 소엽중심성 괴사를 일으킨다.Carbon tetrachloride model (Philippine letteron et al., Biochemical Pharmacology, 39, 12, 2027-2034, 1990; Tips, 10, 1989; Kyoichi Kagawa et al., Japan J. Pharmacol., 42, 19-26, 1986; KT Liu and P. Lesca, Chem. Biol.Interactions, 41, 39-47, 1982; Richard O. et al., J. Biological Chemistry, 236, 2, 1961) are the most commonly used models of experimental liver injury. As used, carbon tetrachloride is converted into trichloromethyl free radical (CCl 3 ·), a highly toxic metabolite by cytochrome P-450 in the body, and this metabolite binds strongly to the membrane protein thiol of the liver microsomes to bind lipid radicals ( It forms lipid radicals and becomes a peroxy radical in the presence of oxygen and is established based on the phenomenon of promoting lipid peroxidation reaction of membrane. That is, carbon tetrachloride inhibits protein biosynthesis in the liver, causes an increase in blood ALT and AST levels, and histologically causes lobular central necrosis of hepatocytes.
또한, 본 발명화합물의 간보호작용을 D-갈락토사민 모델(참조: Koji Hase et al., Biol. Pharm. Bull., 20, 4, 381-385, 1997; Jun-ichi Nagakawa et al., J. Pharmacology and Experimental Therapeutics, 264, 1, 1992; Toxicology of the Liver, Raven Press, New York, 1985)에 의해서도 확인하였다. D-갈락토사민을 과량 투여하는 경우 생성되는 N-아실 갈락토사민은 UDP-갈락토사민, UDP-N-아실갈락토사민의 기질로 작용하는데, UDP-글루코스, UDP-헥소사민의 과잉합성은 간세포내 UTP의 결합과 UDP-글루코스, UDP-갈락토스 생합성을 저해하므로 결국은 간세포막 구조의 변화와 기능변화를 야기시켜 소엽산재성 괴사 및 혈중 ALT, AST치의 상승을 일으키게 된다. D-갈락토사민에 의한 독성의 발현은 바이러스성 간염과 유사하여 이에 대한 모델로도 많이 이용되고 있다.In addition, the hepatoprotective action of the compounds of the present invention can be described in the D-galactosamine model (Koji Hase et al., Biol. Pharm. Bull., 20, 4, 381-385, 1997; Jun-ichi Nagakawa et al., J. Pharmacology and Experimental Therapeutics, 264, 1, 1992; Toxicology of the Liver, Raven Press, New York, 1985). N-acyl galactosamine produced when an overdose of D-galactosamine acts as a substrate of UDP-galactosamine and UDP-N-acylgalactosamine. The oversynthesis of UDP-glucose and UDP-hexamine Inhibits the binding of UTP and UDP-glucose and UDP-galactose biosynthesis in hepatocytes, resulting in changes in hepatocellular membrane structure and functional changes, resulting in lobular necrosis and elevation of blood ALT and AST levels. The expression of toxicity by D-galactosamine is similar to viral hepatitis and has been widely used as a model.
본 발명에서는 랫트를 실험동물로 하여 본 발명에 따른 신규화합물을 4일간 경구투여한 후 사염화탄소 및 D-갈락토사민 유발 간장해에 대한 본 발명 화합물의 억제효과를 측정하였다.In the present invention, rats were used as experimental animals for 4 days after oral administration of a novel compound according to the present invention, and the inhibitory effect of the compound of the present invention on carbon tetrachloride and D-galactosamine-induced liver injury was measured.
각 실험동물의 간 손상정도는 혈청중 ALT, AST 치를 측정함으로써 확인하였으며(참조: Biol. Pharm. Bull., 20, 4, 381-385, 1997; Toxicology and Applied Pharmacology, 95, 1-11, 1988), 본 발명 화합물의 간 보호활성은 하기 수학식 1에 의거하여 측정하였다(참조: Planta Medica, 55, 127-132, 1989). 이때, ALT 값 대신에 AST 값을 사용하여서도 동일한 수식에 의거하여 간보호활성을 구하는 것이 가능하다.Liver damage of each experimental animal was determined by measuring serum ALT and AST levels (Biol. Pharm. Bull., 20, 4, 381-385, 1997; Toxicology and Applied Pharmacology, 95, 1-11, 1988). ), The hepatoprotective activity of the compounds of the present invention was measured based on the following equation (Planta Medica, 55, 127-132, 1989). At this time, it is possible to obtain hepatoprotective activity based on the same formula using AST value instead of ALT value.
상기 수학식에서 정상군(Normal)은 용제만 투여받은 군을 나타내며, 대조군(Control)은 사염화탄소 및 D-갈락토사민을 투여받아 간손상이 유발된 군을 나타내고, 화합물 투여군은 본 발명에 따른 화합물을 4회 투여하고 마지막으로 투여한지 30분 후에 사염화탄소 또는 D-갈락토사민을 투여한 군을 나타낸다.In the above equation, the normal group (Normal) represents a group receiving only a solvent, the control group (Control) represents a group induced liver damage by administration of carbon tetrachloride and D-galactosamine, and the compound administration group is a compound according to the present invention. The group administered with carbon tetrachloride or D-galactosamine after 4 administrations and 30 minutes after the last administration is shown.
이러한 실험을 수행한 결과, 본 발명에 따른 화학식 1의 화합물은 간보호제로서 널리 공지되어있는 실리마린에 비해서도 우수한 간보호효과를 가지고 있는 것으로 나타났다. 또한, 본 발명에 따른 화합물의 일반적인 독성을 평가하기 위하여 마우스를 사용하여 급성독성시험을 실시한 결과, 1 회 경구투여시 각 화합물의 LD50은 2,000mg/kg 이상으로서 상당히 안전한 화합물로 평가되었다.As a result of the experiment, the compound of formula 1 according to the present invention was found to have an excellent hepatoprotective effect compared to the well-known silymarin as a hepatoprotectant. In addition, as a result of conducting an acute toxicity test using a mouse to evaluate the general toxicity of the compound according to the present invention, the LD 50 of each compound at once oral administration was evaluated as a fairly safe compound as 2,000 mg / kg or more.
이러한 결과를 종합해볼 때 본 발명에 따른 화학식 1의 화합물은 안전하면서도 우수한 간질환 예방 및 치료효과를 지니고 있으므로, 본 발명은 상기 화학식 1의 화합물 또는 그의 약제학적으로 허용되는 염을 유효성분으로 함유하는 간질환치료제 조성물을 제공함을 또다른 목적으로 한다.In summary, the compound of formula 1 according to the present invention has a safe and excellent prevention and treatment effect of liver disease, the present invention contains the compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient Another object is to provide a liver disease therapeutic composition.
본 발명에 따른 치료제 조성물은 임상학적으로 투여시에 약제학적으로 허용되는 불활성담체와 화학식 1의 화합물을 배합하여 경구 또는 비경구 투여에 적합한 고체, 반고체 또는 액체 형태의 약제학적 제제로 제형화시켜 투여할 수 있다.The therapeutic composition according to the present invention is administered in a solid, semi-solid or liquid form suitable for oral or parenteral administration by combining the pharmaceutically acceptable inert carrier and the compound of formula 1 at the time of clinical administration. can do.
이러한 목적으로 적합하게 사용할 수 있는 약제학적으로 허용되는 불활성 담체는 고체이거나 액체일 수 있으며 희석제, 향미제, 가용화제, 윤활제, 현탁제, 결합제, 정제팽화제로 작용할 수 있는 물질중의 어느 하나 또는 그 이상일 수 있다. 본 발명에서 사용하기에 적당한 고체 또는 액체 담체의 구체적인 예로는 유당, 전분, 만니톨, 면실유 등을 언급할 수 있다.Pharmaceutically acceptable inert carriers which can be suitably used for this purpose can be solid or liquid and can be any of the substances which can act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, tableting agents, or the like. It may be abnormal. Specific examples of solid or liquid carriers suitable for use in the present invention may include lactose, starch, mannitol, cottonseed oil, and the like.
간질환의 예방 및 치료목적으로 사용됨에 있어서 본 발명의 약제학적 조성물은 활성화합물을 기준으로 하여 초기에는 하루에 체중 킬로그람당 0.1 내지 100㎎의 투여량이 바람직하다. 그러나, 투약량은 환자의 필요정도, 치료되어야할 상태의 정도, 사용될 화합물에 따라 변할 수 있으며 특정한 상태에서 바람직한 투약량을 결정하는 것은 본 분야의 전문가에게 공지되어 있는 기술이다. 일반적으로 치료는 화합물의 최적량보다 적은 투약량으로 시작한다. 그런 다음 상황에 따라 최적의 효과가 나타날 때까지 조금씩 투약량을 증가시킨다. 필요에 따라 하루 총 투약량을 몇회로 나누어 하루 동안 투여할 수도 있다.For use in the prophylaxis and treatment of liver disease, the pharmaceutical composition of the present invention is preferably at a dose of 0.1 to 100 mg / kg body weight per day based on the active compound. However, the dosage may vary depending on the needs of the patient, the degree of condition to be treated, the compound to be used and determining the desired dosage in a particular condition is a technique known to those skilled in the art. In general, treatment begins with a dosage less than the optimal amount of the compound. Then increase the dosage in small increments until the optimal effect occurs. If necessary, the total daily dose may be divided into several daily doses.
이하, 본 발명을 하기 실시예에 의거하여 보다 구체적으로 설명한다. 그러나, 이들 실기예는 본 발명에 대한 이해를 돕기 위한 것이며, 어떤 의미로든 본 발명의 범위가 이들 실시예로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples. However, these practical examples are provided to help the understanding of the present invention, and the scope of the present invention is not limited to these examples in any sense.
실시예 1: 메틸 (1S,5R,6S)-5-벤질옥시-7-(t-부톡시이미노메틸)-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 1: Methyl (1S, 5R, 6S) -5-benzyloxy-7- (t-butoxyiminomethyl) -4-oxa-bicyclo [4.3.0] nona-2,7-diene-2- Synthesis of Carboxylate
메틸 (1S,5R,6S)-5-벤질옥시-7-포르밀-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트(0.63g, 2.00mmol)를 메탄올과 물의 혼합액(11㎖, 10/1, v/v)에 용해시킨 다음, 여기에 t-부톡실아민 하이드로클로라이드(0.34g, 2.71mmol)를 가하여 실온에서 1시간동안 교반하다가 반응혼합물을 농축시켰다. 잔류물을 에틸아세테이트에 용해시킨 후, 포화식염수로 세척하고 무수 마그네슘설페이트로 건조시키고, 여과하고, 농축시켰다. 잔류물을 실리카겔 칼럼 크로마토그래피(용출제: n-헥산/에틸아세테이트=10/1, v/v)로 정제하여 흰색 고체상의 표제화합물(0.64g, 수율 83%)을 수득하였다.Methyl (1S, 5R, 6S) -5-benzyloxy-7-formyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate (0.63 g, 2.00 mmol) Dissolve in a mixture of methanol and water (11 ml, 10/1, v / v), add t-butoxylamine hydrochloride (0.34 g, 2.71 mmol), and stir at room temperature for 1 hour, then concentrate the reaction mixture. I was. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluant: n-hexane / ethyl acetate = 10/1, v / v) to give the title compound (0.64 g, 83% yield) as a white solid.
1H NMR (300MHz, CDCl3) : δ 1.19(s, 9H), 2.37-2.45(m, 1H), 2.82-2.92(m, 1H), 3.38-3.40(m, 2H), 3.75(s, 3H), 4.63(d, 1H, J=12.3Hz), 4.83(d, 1H, J=12.3 Hz), 5.70(d, 1H, J=2.6㎐), 6.06(s, 1H), 7.29-7.37(m, 5H), 7.50(s, 1H), 7.83 (s, 1H) 1 H NMR (300MHz, CDCl 3 ): δ 1.19 (s, 9H), 2.37-2.45 (m, 1H), 2.82-2.92 (m, 1H), 3.38-3.40 (m, 2H), 3.75 (s, 3H ), 4.63 (d, 1H, J = 12.3 Hz), 4.83 (d, 1H, J = 12.3 Hz), 5.70 (d, 1H, J = 2.6 Hz), 6.06 (s, 1H), 7.29-7.37 (m , 5H), 7.50 (s, 1H), 7.83 (s, 1H)
13C NMR(CDCl3) : δ 27.84, 33.09, 39.34, 47.54, 51.51, 70.53, 79.13, 97.04, 112.04, 128.19, 128.26, 128.83, 136.79, 137.65, 138.21, 145.09, 152.33, 168.11 13 C NMR (CDCl 3 ): δ 27.84, 33.09, 39.34, 47.54, 51.51, 70.53, 79.13, 97.04, 112.04, 128.19, 128.26, 128.83, 136.79, 137.65, 138.21, 145.09, 152.33, 168.11
MASS : 386[M+1]+ MASS: 386 [M + 1] +
실시예 2: 메틸 (1S,5R,6S)-5-벤질옥시-7-벤질옥시이미노메틸-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 2 Synthesis of Methyl (1S, 5R, 6S) -5-benzyloxy-7-benzyloxyiminomethyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate
t-부톡실아민 하이드로클로라이드 대신에 벤질옥시아민 하이드로클로라이드를 사용하는 점을 제외하고는 실시예 1에서와 동일하게 실시하여 표제화합물(수율 83%)을 수득하였다.The title compound (yield 83%) was obtained in the same manner as in Example 1 except for using benzyloxyamine hydrochloride instead of t-butoxylamine hydrochloride.
1H NMR (300 MHz, CDCl3) : δ 2.36-2.43(m, 1H), 2.86-2.94(m, 1H), 3.34- 3.39(m, 2H), 3.76(s, 3H), 4.60(d, 1H, J=12.1Hz), 4.84(d, 1H, J=12.1Hz), 5.03(s, 2H), 5.53(d, 1H, J=3.9㎐), 6.15(s, 1H), 7.29-7.40(m, 5H), 7.52(s, 1H), 7.94(s, 1H)13 1 H NMR (300 MHz, CDCl 3 ): δ 2.36-2.43 (m, 1H), 2.86-2.94 (m, 1H), 3.34- 3.39 (m, 2H), 3.76 (s, 3H), 4.60 (d, 1H, J = 12.1 Hz, 4.84 (d, 1H, J = 12.1 Hz), 5.03 (s, 2H), 5.53 (d, 1H, J = 3.9 Hz), 6.15 (s, 1H), 7.29-7.40 ( m, 5H), 7.52 (s, 1H), 7.94 (s, 1H) 13
C NMR(CDCl3) : δ 33.52, 39.61, 47.08, 51.51, 70.79, 76.61, 97.72, 111.77, 128.16, 128.23, 128.29, 128.38, 128.43, 128.76, 136.26, 137.68, 137.92, 139.61, 146.61, 152.44, 168.06C NMR (CDCl 3 ): δ 33.52, 39.61, 47.08, 51.51, 70.79, 76.61, 97.72, 111.77, 128.16, 128.23, 128.29, 128.38, 128.43, 128.76, 136.26, 137.68, 137.92, 139.61, 146.61, 152.0644
MASS : 420[M+1]+, 442[M+23]+ MASS: 420 [M + 1]+, 442 [M + 23]+
실시예 3: 메틸 (1S,5R,6S)-5-벤질옥시-7-하이드록시카보닐메톡시이미노메틸-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 3: Methyl (1S, 5R, 6S) -5-benzyloxy-7-hydroxycarbonylmethoxyiminomethyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxyl Rate Synthesis
t-부톡실아민 하이드로클로라이드 대신에 하이드록시카보닐메톡실아민 하이드로클로라이드를 사용하는 점을 제외하고는 실시예 1에서와 동일하게 실시하여 표제화합물(수율 44%)을 수득하였다.The title compound (yield 44%) was obtained in the same manner as in Example 1 except for using hydroxycarbonylmethoxylamine hydrochloride instead of t-butoxylamine hydrochloride.
1H NMR (300 MHz, CDCl3) : δ 2.31-2.39(m, 1H), 2.86-2.95(m, 1H), 3.23- 3.27(m, 1H), 3.31-3.36(m, 1H), 3.75(s, 3H), 4.55(s, 2H), 4.62(d, 1H, J=12.1 Hz), 4.86(d, 1H, J=12.1Hz), 5.34(d, 1H, J=4.8㎐), 6.23(bs, 1H), 7.29-7.36(m, 5H), 7.52(s, 1H), 7.98(s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 2.31-2.39 (m, 1H), 2.86-2.95 (m, 1H), 3.23- 3.27 (m, 1H), 3.31-3.36 (m, 1H), 3.75 ( s, 3H), 4.55 (s, 2H), 4.62 (d, 1H, J = 12.1 Hz), 4.86 (d, 1H, J = 12.1 Hz), 5.34 (d, 1H, J = 4.8 Hz), 6.23 ( bs, 1H), 7.29-7.36 (m, 5H), 7.52 (s, 1H), 7.98 (s, 1H)
13C NMR(75 MHz, CDCl3) : δ 33.94, 39.75, 51.65, 70.56, 70.79, 97.65, 111.49, 128.31, 128.39, 128.77, 128.91, 135.72, 137.35, 141.57, 148.23, 152.63, 168.11, 174.75 13 C NMR (75 MHz, CDCl 3 ): δ 33.94, 39.75, 51.65, 70.56, 70.79, 97.65, 111.49, 128.31, 128.39, 128.77, 128.91, 135.72, 137.35, 141.57, 148.23, 152.63, 168.11, 174.75
MASS : 388[M+1]+, 410[M+23]+ MASS: 388 [M + 1]+, 410 [M + 23]+
실시예 4: 메틸 (1S,5R,6S)-5-벤질옥시-4-옥사-7-(2-피리딜메톡시이미노메틸)-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 4: Methyl (1S, 5R, 6S) -5-benzyloxy-4-oxa-7- (2-pyridylmethoxyiminomethyl) -bicyclo [4.3.0] nona-2,7-diene-2 Synthesis of Carboxylate
2-피리딜카빈올(2.41㎖, 24.98mmol)을 메틸렌클로라이드(120㎖)에 용해시킨 후 트리에틸아민(9.40㎖, 67.44mmol)을 가하고 0℃로 냉각시켰다. 여기에 메탄설포닐클로라이드(3.48㎖, 67.44mmol)를 적가하고 동온도에서 30분간 교반하였다. 반응혼합물을 포화중조수와 포화식염수로 세척해주고 무수 마그네슘설페이트로 건조시킨 후, 여과하고 농축시켰다. 잔류물을 실리카겔 칼럼 크로마토그래피(용출제: n-헥산/에틸아세테이트=1/1, v/v)로 정제하여 2-(메탄설포닐옥시메틸)피리딘(3.34g, 수율 71%)을 수득하였다.2-pyridylcarbinol (2.41 mL, 24.98 mmol) was dissolved in methylene chloride (120 mL), then triethylamine (9.40 mL, 67.44 mmol) was added and cooled to 0 ° C. Methanesulfonyl chloride (3.48 mL, 67.44 mmol) was added dropwise thereto and stirred at the same temperature for 30 minutes. The reaction mixture was washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1, v / v) to give 2- (methanesulfonyloxymethyl) pyridine (3.34 g, 71% yield). .
상기 수득한 화합물을 아세토니트릴(200㎖)에 용해시킨 후, 포타슘카보네이트(4.94g, 35.74mmol) 및 N-(t-부톡시카보닐)하이드록실아민(2.8g, 21.41mmol)을 가하여 3시간동안 환류교반하였다. 반응혼합물을 농축시키고 잔류물을 에틸아세테이트에 용해시킨 후, 포화중조수로 세척하고 무수 마그네슘설페이트로 건조시키고, 여과하고 농축시켰다. 잔류물을 실리카겔 칼럼 크로마토그래피(용출제: n-헥산/에틸아세테이트=2/1, v/v)로 정제하여 N-(t-부톡시카보닐)-O-(2-피리딜메틸)하이드록실아민(1.67g, 7.45mmol, 수율 42%)을 수득하였다.The obtained compound was dissolved in acetonitrile (200 mL), and then potassium carbonate (4.94 g, 35.74 mmol) and N- (t-butoxycarbonyl) hydroxylamine (2.8 g, 21.41 mmol) were added thereto for 3 hours. Was refluxed for a while. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate water, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2/1, v / v) to give N- (t-butoxycarbonyl) -O- (2-pyridylmethyl) hydride. Oxylamine (1.67 g, 7.45 mmol, yield 42%) was obtained.
상기 수득한 화합물(1g, 4.46mmol)에 염산가스로 포화된 에틸아세테이트(50㎖)를 가해 실온에서 2시간동안 교반하다가 농축시켜 O-(2-피리딜메틸)하이드록실아민 디하이드로클로라이드를 수득하였다. 이 후, t-부톡실아민 하이드로클로라이드 대신에 O-(2-피리딜메틸)하이드록실아민 디하이드로클로라이드를 사용하는 점을 제외하고는 실시예 1에서와 동일하게 실시하여 표제화합물(0.86g, 수율 46%)을 수득하였다.Ethyl acetate (50 ml) saturated with hydrochloric acid gas was added to the obtained compound (1 g, 4.46 mmol), stirred at room temperature for 2 hours, and concentrated to obtain O- (2-pyridylmethyl) hydroxylamine dihydrochloride. It was. Thereafter, the same procedure as in Example 1 was carried out except for the use of O- (2-pyridylmethyl) hydroxylamine dihydrochloride instead of t-butoxylamine hydrochloride to give the title compound (0.86 g, Yield 46%).
1H NMR (300㎒, CDCl3) : δ 2.35-2.42(m, 1H), 2.84-2.94(m, 1H), 3.27-3.39(m, 2H), 3.74(s, 3H), 4.55(d, 1H, J=12.1㎐), 4.79(d, 1H, J=12.1㎐), 5.17(s, 2H), 5.48(d, 1H, J=4.1Hz), 6.18(bs, 1H), 7.21(dd, 1H, J=5.4, 7.1Hz), 7.28-7.40(m, 6H), 7.49(s, 1H), 7.67(dt, 1H, J=1.7, 7.7Hz), 8.01(s, 1H), 8.60(d, 1H, J=4.5Hz) 1 H NMR (300MHz, CDCl 3 ): δ 2.35-2.42 (m, 1H), 2.84-2.94 (m, 1H), 3.27-3.39 (m, 2H), 3.74 (s, 3H), 4.55 (d, 1H, J = 12.1 ㎐, 4.79 (d, 1H, J = 12.1 ㎐), 5.17 (s, 2H), 5.48 (d, 1H, J = 4.1 Hz), 6.18 (bs, 1H), 7.21 (dd, 1H, J = 5.4, 7.1 Hz), 7.28-7.40 (m, 6H), 7.49 (s, 1H), 7.67 (dt, 1H, J = 1.7, 7.7 Hz), 8.01 (s, 1H), 8.60 (d , 1H, J = 4.5Hz)
13C NMR(75MHz, CDCl3) : δ 33.53, 39.58, 47.08, 51.52, 70.79, 77.07, 97.64, 111.72, 122.30, 122.81, 128.14, 128.74, 136.07, 136.83, 137.56, 140.07, 147.15, 149.61, 152.43, 158.41, 168.03 13 C NMR (75 MHz, CDCl 3 ): δ 33.53, 39.58, 47.08, 51.52, 70.79, 77.07, 97.64, 111.72, 122.30, 122.81, 128.14, 128.74, 136.07, 136.83, 137.56, 140.07, 147.15, 149.61, 152.43, 152.43 , 168.03
MASS : 420[M]+ MASS: 420 [M] +
실시예 5: 메틸 (1S,5R,6S)-5-벤질옥시-7-(니코티노일옥시이미노메틸)-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 5: Methyl (1S, 5R, 6S) -5-benzyloxy-7- (nicotinoyloxyiminomethyl) -4-oxa-bicyclo [4.3.0] nona-2,7-diene-2- Synthesis of Carboxylate
메틸 (1S,5R,6S)-5-벤질옥시-7-포르밀-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트(1.0g, 3.18mmol)를 메탄올과 물의 혼합액(11㎖, 10/1, v/v)에 용해시키고 하이드록실아민 하이드로클로라이드(0.44g, 6.36mmol)를 가하여 실온에서 1시간동안 교반하다가 과량의 물을 넣으면 흰색 고체가 생성되었다. 생성된 흰색 고체를 감압하에 여과하고 물로 여러번 세척한 후 감압하에 건조시키 흰색 고체상의 메틸 (1S,5R,6S)-5-벤질옥시-7-하이드록시이미노메틸-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트(1g, 수율 95%)가 수득되었다.Methyl (1S, 5R, 6S) -5-benzyloxy-7-formyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate (1.0 g, 3.18 mmol) Dissolve in a mixture of methanol and water (11 mL, 10/1, v / v), add hydroxylamine hydrochloride (0.44 g, 6.36 mmol), stir at room temperature for 1 hour, and add excess water to give a white solid. . The resulting white solid was filtered under reduced pressure, washed several times with water and dried under reduced pressure to afford methyl (1S, 5R, 6S) -5-benzyloxy-7-hydroxyiminomethyl-4-oxa-bicyclo [4.3 on white solid. .0] nona-2,7-diene-2-carboxylate (1 g, yield 95%) was obtained.
니코틴산(1.12g, 9.11mmol)을 메틸렌클로라이드(20㎖)에 현탁시키고 옥살릴클로라이드(1.59㎖, 18.22mmol)를 가한 다음 2시간동안 환류교반한 후 감압하에 농축시켰다. 농축된 잔류물을 메틸렌클로라이드(20㎖)에 녹이고 피리딘(5㎖)을 가한 다음 앞에서 수득한 메틸 (1S,5R,6S)-5-벤질옥시-7-하이드록시이미노메틸-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트(1g, 3.04mmol)를 가하고 1시간동안 교반하였다. 반응 혼합물을 감압하에 농축시킨 다음 에틸아세테이트에 녹이고 포화중조수, 포화식염수 순으로 세척하였다. 무수 마그네슘설페이트로 건조시킨 후 농축시키고 농축된 잔류물은 실리카겔 칼럼 크로마토그래피(용출제: n-헥산/에틸아세테이트=1/2, v/v)로 정제하여 연한 노란색 오일상의 표제화합물(1.12g, 수율 85%)을 수득하였다.Nicotinic acid (1.12 g, 9.11 mmol) was suspended in methylene chloride (20 mL), oxalyl chloride (1.59 mL, 18.22 mmol) was added, and the mixture was stirred under reflux for 2 hours and then concentrated under reduced pressure. The concentrated residue was dissolved in methylene chloride (20 mL), pyridine (5 mL) was added, and the methyl (1S, 5R, 6S) -5-benzyloxy-7-hydroxyiminomethyl-4-oxa-r ratio obtained above was obtained. Cyclo [4.3.0] nona-2,7-diene-2-carboxylate (1 g, 3.04 mmol) was added and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate and washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous magnesium sulfate and concentrated, the concentrated residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/2, v / v) to give the title compound (1.12 g, pale yellow oil). Yield 85%) was obtained.
1H NMR (300㎒, CDCl3) : δ 2.49(m, 1H), 3.00(m, 1H), 3.33(m, 1H), 3.78(s, 3H), 4.70(d, 1H, J=11.8㎐), 4.92(d, 1H, J=11.7㎐), 5.61(d, 1H, J=3.2 ㎐), 6.59(s, 1H), 7.32(m, 5H), 7.47(dd, 1H, J=5.1, 7.8Hz), 7.57(s, 1H), 8.32(s, 1H), 8.37(d, 1H, J=7.9Hz), 8.86(bs, 1H), 9.29(bs, 1H) 1 H NMR (300MHz, CDCl 3 ): δ 2.49 (m, 1H), 3.00 (m, 1H), 3.33 (m, 1H), 3.78 (s, 3H), 4.70 (d, 1H, J = 11.8 Hz ), 4.92 (d, 1H, J = 11.7 kPa), 5.61 (d, 1H, J = 3.2 kPa), 6.59 (s, 1H), 7.32 (m, 5H), 7.47 (dd, 1H, J = 5.1, 7.8 Hz), 7.57 (s, 1H), 8.32 (s, 1H), 8.37 (d, 1H, J = 7.9 Hz), 8.86 (bs, 1H), 9.29 (bs, 1H)
13C NMR(75MHz, CDCl3) : δ 34.13, 39.97, 47.01, 51.62, 71.37, 98.44, 111.30, 123.89, 125.26, 128.17, 128.73, 134.94, 137.54, 137.56, 145.86, 151.12, 152.17, 154.18, 154.45, 162.85, 167.90 13 C NMR (75 MHz, CDCl 3 ): δ 34.13, 39.97, 47.01, 51.62, 71.37, 98.44, 111.30, 123.89, 125.26, 128.17, 128.73, 134.94, 137.54, 137.56, 145.86, 151.12, 152.17, 154.18, 154.18, 154.18. , 167.90
실시예 6: 메틸 (1S,5R,6S)-5-벤질옥시-7-이소니코티노일옥시이미노메틸-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 6: Methyl (1S, 5R, 6S) -5-benzyloxy-7-isonicotinoyloxyiminomethyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxyl Rate Synthesis
니코틴산 대신에 이소니코틴산을 사용하는 점을 제외하고는 실시예 5에서와 동일하게 실시하여 표제화합물(수율 87%)을 수득하였다.The title compound (yield 87%) was obtained in the same manner as in Example 5 except that isonicotinic acid was used instead of nicotinic acid.
1H NMR (300㎒, CDCl3) : δ 2.48(m, 1H), 3.01(m, 1H), 3.42(m, 2H), 3.78 (s, 3H), 4.68(d, 1H, J=11.8㎐), 4.92(d, 1H, J=11.8㎐), 5.59(d, 1H, J=4.4㎐), 6.60(s, 1H), 7.38(m, 5H), 7.54(s, 1H), 7.89(d, 1H, J=6.0㎐), 7.89(d, 1H, J=2.8㎐), 8.33(s, 1H), 8.84(d, 1H, J=6.0Hz), 8.84(d, 1H, J=2.9Hz) 1 H NMR (300MHz, CDCl 3 ): δ 2.48 (m, 1H), 3.01 (m, 1H), 3.42 (m, 2H), 3.78 (s, 3H), 4.68 (d, 1H, J = 11.8 Hz ), 4.92 (d, 1H, J = 11.8 Hz), 5.59 (d, 1H, J = 4.4 Hz), 6.60 (s, 1H), 7.38 (m, 5H), 7.54 (s, 1H), 7.89 (d , 1H, J = 6.0 Hz), 7.89 (d, 1H, J = 2.8 Hz), 8.33 (s, 1H), 8.84 (d, 1H, J = 6.0 Hz), 8.84 (d, 1H, J = 2.9 Hz )
실시예 7: 이소프로필 (1S,5R,6S)-5-벤질옥시-7-하이드록시이미노메틸-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 7: Isopropyl (1S, 5R, 6S) -5-benzyloxy-7-hydroxyiminomethyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate synthesis
메틸 (1S,5R,6S)-5-벤질옥시-7-하이드록시메틸-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트(1.45g, 4.58㎜ol)를 이소프로판올(30㎖)에 용해시키고 티타늄이소프로폭사이드(2.73㎖, 9.16mmol)를 가하여 하룻밤동안 환류교반하였다. 반응혼합물을 0℃로 냉각시킨 후 1N-염산을 적가해 반응을 종결시키고 농축시켰다. 잔류물을 에틸아세테이트에 용해시킨 후, 유기층을 분리하여 포화중조수와 포화식염수로 세척해주었다. 무수 마그네슘설페이트로 건조시키고 여과하고 농축시켜 이소프로필 (1S,5R,6S)-5-벤질옥시-7-하이드록시메틸-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트(1.47g, 4.27mmol, 수율 93%)를 수득하였다.Methyl (1S, 5R, 6S) -5-benzyloxy-7-hydroxymethyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate (1.45 g, 4.58 mmol) ) Was dissolved in isopropanol (30 mL) and titanium isopropoxide (2.73 mL, 9.16 mmol) was added and the mixture was stirred under reflux overnight. After cooling the reaction mixture to 0 ° C., 1 N hydrochloric acid was added dropwise to terminate the reaction and concentrated. The residue was dissolved in ethyl acetate, and then the organic layer was separated and washed with saturated sodium bicarbonate water and brine. Dried over anhydrous magnesium sulfate, filtered and concentrated to isopropyl (1S, 5R, 6S) -5-benzyloxy-7-hydroxymethyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene- 2-carboxylate (1.47 g, 4.27 mmol, yield 93%) was obtained.
상기 수득한 화합물(1.47g, 4.27mmol)을 메틸렌클로라이드(150㎖)에 용해시키고 셀라이트(1.84g)와 피리디늄클로로크로메이트(1.84g, 8.54mmol)를 가하였다. 혼합물을 실온에서 2시간동안 교반하다가 셀라이트를 통과하여 여과한 다음 여액을 농축시켰다. 잔류물을 실리카겔 칼럼 크로마토그래피(용출제: n-헥산/에틸아세테이트=7/1, v/v)로 정제하여 노란색 오일상의 이소프로필 (1S,5R,6S)-5-벤질옥시-7-포르밀-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트(1.02g, 수율 70%)를 수득하였다.The obtained compound (1.47 g, 4.27 mmol) was dissolved in methylene chloride (150 mL), and celite (1.84 g) and pyridinium chloro chromate (1.84 g, 8.54 mmol) were added thereto. The mixture was stirred at room temperature for 2 hours, filtered through celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluant: n-hexane / ethyl acetate = 7/1, v / v) to give isopropyl (1S, 5R, 6S) -5-benzyloxy-7-form as yellow oil. Mil-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate (1.02 g, yield 70%) was obtained.
1H NMR (300㎒, CDCl3) : δ 1.29(d, 6H, J=6.2㎐), 2.51-2.59(m, 1H), 2.98-3.07(m, 1H), 3.35-3.41(m, 2H), 4.66(d, 1H, J=12.0㎐), 4.88(d, 1H, J=12.0 ㎐), 5.11(Sep, 1H, J=6.3Hz), 5.40(d, 1H, J=4.4㎐), 6.98(t, 1H, J=2.5㎐), 7.31-7.48(m, 5H), 7.57(s, 1H), 9.79(s, 1H) 1 H NMR (300MHz, CDCl 3 ): δ 1.29 (d, 6H, J = 6.2 Hz), 2.51-2.59 (m, 1H), 2.98-3.07 (m, 1H), 3.35-3.41 (m, 2H) , 4.66 (d, 1H, J = 12.0 Hz), 4.88 (d, 1H, J = 12.0 Hz), 5.11 (Sep, 1H, J = 6.3 Hz), 5.40 (d, 1H, J = 4.4 Hz), 6.98 (t, 1H, J = 2.5 Hz), 7.31-7.48 (m, 5H), 7.57 (s, 1H), 9.79 (s, 1H)
메틸 (1S,5R,6S)-5-벤질옥시-7-포르밀-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트 및 t-부톡실아민 하이드로클로라이드 대신에 이소프로필 (1S, 5R,6S)-5-벤질옥시-7-포르밀-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트 및 하이드록실아민 하이드로클로라이드를 사용하는 점을 제외하고는 실시예 1에서와 동일하게 실시하여 표제화합물(수율 70%)을 수득하였다.Methyl (1S, 5R, 6S) -5-benzyloxy-7-formyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate and t-butoxylamine hydrochloride Instead isopropyl (1S, 5R, 6S) -5-benzyloxy-7-formyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate and hydroxylamine hydro The title compound (yield 70%) was obtained in the same manner as in Example 1 except for using chloride.
1H NMR (300㎒, CDCl3) : δ 1.28(d, 6H, J=6.2㎐), 2.23-2.31(m, 1H), 2.88-2.98(m, 1H), 3.18-3.23(m, 1H), 3.28-3.33(m, 1H), 4.67(d, 1H, J=12.2㎐), 4.91(d, 1H, J=12.1㎐), 5.11(Sep, 1H, J=6.2Hz), 6.20(s, 1H), 7.27-7.37(m, 5H), 7.52(s, 1H), 7.89(bs, 1H), 7.94(s, 1H) 1 H NMR (300MHz, CDCl 3 ): δ 1.28 (d, 6H, J = 6.2 Hz), 2.23-2.31 (m, 1H), 2.88-2.98 (m, 1H), 3.18-3.23 (m, 1H) , 3.28-3.33 (m, 1H), 4.67 (d, 1H, J = 12.2 Hz), 4.91 (d, 1H, J = 12.1 Hz), 5.11 (Sep, 1H, J = 6.2 Hz), 6.20 (s, 1H), 7.27-7.37 (m, 5H), 7.52 (s, 1H), 7.89 (bs, 1H), 7.94 (s, 1H)
실시예 8: 이소프로필 (1S,5R,6S)-5-벤질옥시-7-메톡시이미노메틸-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 8: Isopropyl (1S, 5R, 6S) -5-benzyloxy-7-methoxyiminomethyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate synthesis
하이드록실아민 하이드로클로라이드 대신에 메톡실아민 하이드로클로라이드를 사용하는 점을 제외하고는 실시예 7의 마지막 단계에서와 동일하게 실시하여 표제화합물(수율 89%)을 수득하였다.The title compound (yield 89%) was obtained in the same manner as in the last step of Example 7, except that methoxylamine hydrochloride was used instead of hydroxylamine hydrochloride.
1H NMR (300㎒, CDCl3) : δ 1.29(d, 6H, J=6.3㎐), 2.33-2.40(m, 1H), 2.80-2.86(m, 1H), 3.28-3.33(m, 1H), 3.34-3.37(m, 1H), 3.81(s, 1H), 4.65(d, 1H, J=12.0㎐), 4.90(d, 1H, J=12.0㎐), 5.11(Sep, 1H, J=6.2㎐), 5.46(d, 1H, J=4.7㎐), 6.16(bs, 1H), 7.30-7.38(m, 5H), 7.57(s, 1H), 7.85(s, 1H) 1 H NMR (300MHz, CDCl 3 ): δ 1.29 (d, 6H, J = 6.3 Hz), 2.33-2.40 (m, 1H), 2.80-2.86 (m, 1H), 3.28-3.33 (m, 1H) , 3.34-3.37 (m, 1H), 3.81 (s, 1H), 4.65 (d, 1H, J = 12.0 μs), 4.90 (d, 1H, J = 12.0 μs), 5.11 (Sep, 1H, J = 6.2 I), 5.46 (d, 1H, J = 4.7 Hz), 6.16 (bs, 1H), 7.30-7.38 (m, 5H), 7.57 (s, 1H), 7.85 (s, 1H)
13C NMR(75MHz, CDCl3) : δ 22.35, 22.41, 33.94, 39.68, 46.83, 62.19, 67.54, 70.86, 98.12, 112.19, 128.10, 128.21, 128.70, 136.38, 137.67, 139.33, 146.19, 152.06, 167.15 13 C NMR (75 MHz, CDCl 3 ): δ 22.35, 22.41, 33.94, 39.68, 46.83, 62.19, 67.54, 70.86, 98.12, 112.19, 128.10, 128.21, 128.70, 136.38, 137.67, 139.33, 146.19, 152.06, 167.15
MASS : 372[M+1]+ MASS: 372 [M + 1] +
실시예 9: 메틸 (1S,5R,6S)-5-벤질옥시-7-[(4-에톡시카보닐)티아졸-2-일]-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 9: Methyl (1S, 5R, 6S) -5-benzyloxy-7-[(4-ethoxycarbonyl) thiazol-2-yl] -4-oxa-bicyclo [4.3.0] nona- Synthesis of 2,7-diene-2-carboxylate
메틸 (1S,5R,6S)-5-벤질옥시-7-포르밀-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트(1.0g, 3.18mmol)를 벤젠(100㎖)에 용해시킨 후, L-시스테인 에틸에스테르 하이드로클로라이드(1.43g, 7.70mmol), 피리딘(0.78㎖, 9.64mmol), 및 p-톨루엔설폰산(0.62g, 3.26mmol)을 가하여 실온에서 하룻밤 동안 교반하고 반응혼합물을 농축시켰다. 잔류물을 에틸아세테이트에 용해시켜 포화중조수와 포화식염수로 세척해준 후 무수 소듐카보네이트로 건조시키고 여과하고 농축시켰다. 잔류물을 실리카겔 칼럼 크로마토그래피(용출제: n-헥산/에틸아세테이트=3/1, v/v)로 정제하여 메틸 (1S,5R,6S)-7-[4-(에톡시카보닐)-티아졸리딘-2-일]-4-옥사-5-벤질옥시-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트(0.75g, 1.68mmol, 수율 53%)를 수득하였다.Methyl (1S, 5R, 6S) -5-benzyloxy-7-formyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate (1.0 g, 3.18 mmol) After dissolving in benzene (100 ml), L-cysteine ethyl ester hydrochloride (1.43 g, 7.70 mmol), pyridine (0.78 ml, 9.64 mmol), and p-toluenesulfonic acid (0.62 g, 3.26 mmol) were added to room temperature. Stir overnight at and concentrate the reaction mixture. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium carbonate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/1, v / v) to give methyl (1S, 5R, 6S) -7- [4- (ethoxycarbonyl)- Obtain thiazolidin-2-yl] -4-oxa-5-benzyloxy-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate (0.75 g, 1.68 mmol, 53% yield). It was.
상기 수득한 화합물(0.45g, 1.0mmol)을 벤젠(25㎖)에 용해시키고 망간옥사이드(3.4g, 40mmol)를 가하여 하룻밤 동안 환류교반한 후 실온으로 냉각시켰다. 반응액을 셀라이트를 통과하여 여과하고 농축시켰다. 잔류물을 실리카겔 칼럼 크로마토그래피(용출제: n-헥산/에틸아세테이트=3/1, v/v)로 정제하여 표제화합물(0.08g, 수율 18%)을 수득하였다.The obtained compound (0.45 g, 1.0 mmol) was dissolved in benzene (25 mL), and manganese oxide (3.4 g, 40 mmol) was added thereto, and the mixture was stirred under reflux overnight, and then cooled to room temperature. The reaction solution was filtered through celite and concentrated. The residue was purified by silica gel column chromatography (eluant: n-hexane / ethyl acetate = 3/1, v / v) to give the title compound (0.08 g, 18% yield).
1H NMR (300㎒, CDCl3) : δ 1.34(t, 3H, J=7.1㎐), 2.23-2.33(m, 1H), 2.95- 3.05(m, 1H), 3.27-3.39(m, 2H), 3.68(s, 3H), 4.36(q, 2H, J=7.1Hz), 4.50(d, 1H, J=11.6㎐), 4.81(d, 1H, J=11.7㎐), 5.13(d, 1H, J=6.2Hz), 6.71(t, 1H, J=2.4Hz), 7.01-7.05(m, 2H), 7.15-7.20(m, 3H), 7.48(s, 1H), 7.96(s, 1H) 1 H NMR (300MHz, CDCl 3 ): δ 1.34 (t, 3H, J = 7.1 Hz), 2.23-2.33 (m, 1H), 2.95- 3.05 (m, 1H), 3.27-3.39 (m, 2H) , 3.68 (s, 3H), 4.36 (q, 2H, J = 7.1 Hz), 4.50 (d, 1H, J = 11.6 Hz), 4.81 (d, 1H, J = 11.7 Hz), 5.13 (d, 1H, J = 6.2 Hz), 6.71 (t, 1H, J = 2.4 Hz), 7.01-7.05 (m, 2H), 7.15-7.20 (m, 3H), 7.48 (s, 1H), 7.96 (s, 1H)
실시예 10: 이소프로필 (1S,5R,6S)-5-벤질옥시-7-[4-(p-톨루엔설포닐옥시카보닐)티아졸린-2-일]-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 10 Isopropyl (1S, 5R, 6S) -5-benzyloxy-7- [4- (p-toluenesulfonyloxycarbonyl) thiazolin-2-yl] -4-oxa-bicyclo [4.3 .0] Synthesis of Nona-2,7-diene-2-carboxylate
이소프로필 (1S,5R,6S)-5-벤질옥시-7-포르밀-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트(1.90g, 5.55mmol)를 톨루엔(20㎖)에 용해시키고 L-시스테인(1.35g, 11.14mmol)과 촉매량의 피리디늄-p-톨루엔설포네이트를 가한 후 딘스탁 장치를 사용하여 2시간동안 환류교반하였다. 반응혼합물을 실온으로 냉각시켜 농축시켰다. 잔류물을 메틸렌클로라이드(30㎖)에 용해시킨 다음 트리에틸아민(3.47㎖, 24.9mmol)과 p-톨루엔설포닐클로라이드(2.12g, 11.12mmol)를 가하여 실온에서 3시간동안 교반하였다. 반응혼합물을 0.1N 염산수용액, 포화중조수 및 포화식염수로 세척해준 다음, 무수 마그네슘설페이트로 건조시키고 여과하고 농축시켰다. 잔류물을 실리카겔 칼럼 크로마토그래피(용출제: n-헥산/에틸아세테이트=4/1, v/v)로 정제하여 표제화합물(0.40g, 수율 12%)을 수득하였다.Isopropyl (1S, 5R, 6S) -5-benzyloxy-7-formyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate (1.90 g, 5.55 mmol) Was dissolved in toluene (20 mL), L-cysteine (1.35 g, 11.14 mmol) and a catalytic amount of pyridinium-p-toluenesulfonate were added, and the mixture was stirred under reflux for 2 hours using a Deanstock apparatus. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in methylene chloride (30 mL), triethylamine (3.47 mL, 24.9 mmol) and p-toluenesulfonyl chloride (2.12 g, 11.12 mmol) were added and stirred at room temperature for 3 hours. The reaction mixture was washed with 0.1N aqueous hydrochloric acid solution, saturated sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluant: n-hexane / ethyl acetate = 4/1, v / v) to give the title compound (0.40 g, 12% yield).
1H NMR (300㎒, CDCl3) : δ 1.18(d, 6H, J=6.2㎐), 1.85-1.93(m, 1H), 2.30- 2.35(m, 1H), 2.33(s, 3H), 2.63-2.72(m, 1H), 2.83-2.88(m, 1H), 3.52-3.58(m, 1H), 3.67-3.74(m, 1H), 4.46(d, 1H, J=8.3㎐), 4.52(d, 1H, J=11.3㎐), 4.70(t, 1H, J=6.3Hz), 4.86(d, 1H, J=11.3Hz), 4.99(Sept, 1H, J=6.2Hz), 5.64(s, 1H), 7.17(d, 2H, J=8.0Hz), 7.25-7.31(m, 1H), 7.41(s, 1H), 7.54(d, 2H, J=8.3㎐) 1 H NMR (300MHz, CDCl 3 ): δ 1.18 (d, 6H, J = 6.2 Hz), 1.85-1.93 (m, 1H), 2.30- 2.35 (m, 1H), 2.33 (s, 3H), 2.63 -2.72 (m, 1H), 2.83-2.88 (m, 1H), 3.52-3.58 (m, 1H), 3.67-3.74 (m, 1H), 4.46 (d, 1H, J = 8.3 Hz), 4.52 (d , 1H, J = 11.3 Hz, 4.70 (t, 1H, J = 6.3 Hz), 4.86 (d, 1H, J = 11.3 Hz), 4.99 (Sept, 1H, J = 6.2 Hz), 5.64 (s, 1H ), 7.17 (d, 2H, J = 8.0 Hz), 7.25-7.31 (m, 1H), 7.41 (s, 1H), 7.54 (d, 2H, J = 8.3 Hz)
실시예 11: 이소프로필 (1S,5R,6S)-5-메톡시-7-[4-(p-톨루엔설포닐옥시카보닐)티아졸린-2-일]-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 11: Isopropyl (1S, 5R, 6S) -5-methoxy-7- [4- (p-toluenesulfonyloxycarbonyl) thiazolin-2-yl] -4-oxa-bicyclo [4.3 .0] Synthesis of Nona-2,7-diene-2-carboxylate
이소프로필 (1S,5R,6S)-5-벤질옥시-7-포르밀-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트 대신에 이소프로필 (1S,5R,6S)-7-포르밀-5-메톡시-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트를 사용하는 점을 제외하고는 실시예 10에서와 동일하게 실시하여 표제화합물(수율 12%)을 수득하였다.Isopropyl (1S, 5R, 6S) -5-benzyloxy-7-formyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate instead of isopropyl (1S, In Example 10, except that 5R, 6S) -7-formyl-5-methoxy-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate is used In the same manner as in the title compound (yield 12%) was obtained.
1H NMR (300㎒, CDCl3) : δ 1.18(d, 6H, J=6.2㎐), 1.89-1.97(m, 1H), 2.23- 2.29(m, 1H), 2.36(s, 3H), 2.65-2.73(m, 1H), 2.82-2.87(m, 1H), 3.45(s, 3H), 3.63-3.71(m, 1H), 4.25(d, 1H, J=8.2㎐), 4.77(t, 1H, J=6.1㎐), 4.99(Sept, 1H, J=6.2Hz), 5.65(bs, 1H), 7.23(d, 2H, J=8.2Hz), 7.38(s, 1H), 7.67(d, 2H, J=8.2㎐) 1 H NMR (300MHz, CDCl 3 ): δ 1.18 (d, 6H, J = 6.2 Hz), 1.89-1.97 (m, 1H), 2.23- 2.29 (m, 1H), 2.36 (s, 3H), 2.65 -2.73 (m, 1H), 2.82-2.87 (m, 1H), 3.45 (s, 3H), 3.63-3.71 (m, 1H), 4.25 (d, 1H, J = 8.2 Hz), 4.77 (t, 1H , J = 6.1 Hz), 4.99 (Sept, 1H, J = 6.2 Hz), 5.65 (bs, 1H), 7.23 (d, 2H, J = 8.2 Hz), 7.38 (s, 1H), 7.67 (d, 2H , J = 8.2㎐)
실시예 12: 메틸 (1S,5R,6S)-5-벤질옥시-7-[1-(하이드록시이미노)에틸]-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 12 Methyl (1S, 5R, 6S) -5-benzyloxy-7- [1- (hydroxyimino) ethyl] -4-oxa-bicyclo [4.3.0] nona-2,7-diene- Synthesis of 2-carboxylate
메틸 (1S,5R,6S)-5-벤질옥시-7-포르밀-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트(1.2g, 4.08mmol)를 테트라하이드로푸란(5㎖)에 용해시키고 -78℃로 냉각시켰다. 여기에 메틸마그네슘클로라이드(3M, 1.63㎖, 4.90mmol)를 적가하여 동온도에서 2시간동안 교반하다가 0℃로 승온시켰다. 포화 암모늄클로라이드 수용액을 이용하여 반응을 종결시키고 에틸아세테이트로 추출한 다음 무수 마그네슘설페이트로 건조시키고 여과하고 농축시켰다. 잔류물을 실리카겔 칼럼 크로마토그래피(용출제: n-헥산/에틸아세테이트=4/1, v/v)로 정제하여 메틸 (1S,5R, 6S)-5-벤질옥시-7-(1-하이드록시에틸)-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트(1.17g, 3.55mmol, 수율 87%)를 수득하였다.Methyl (1S, 5R, 6S) -5-benzyloxy-7-formyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate (1.2 g, 4.08 mmol) It was dissolved in tetrahydrofuran (5 mL) and cooled to -78 ° C. Methyl magnesium chloride (3M, 1.63 mL, 4.90 mmol) was added dropwise thereto, stirred at the same temperature for 2 hours, and then heated to 0 ° C. The reaction was terminated with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1, v / v) to give methyl (1S, 5R, 6S) -5-benzyloxy-7- (1-hydroxy Ethyl) -4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate (1.17 g, 3.55 mmol, yield 87%) was obtained.
1H NMR (300㎒, CDCl3) : δ 1.20(d, 3H, J=6.6Hz), 1.95(m, 1H), 2.35(d, 1H, J=4.5Hz), 2.52(m, 1H), 2.75(m, 1H), 3.10(m, 1H), 3.60(s, 3H), 4.28(bs, 1H), 4.50-4.62(m, 2H), 4.90(d, 1H, J=11.8㎐), 5.70(s, 1H), 7.15-7.30(m, 5H), 7.42(s, 1H) 1 H NMR (300 MHz, CDCl 3 ): δ 1.20 (d, 3H, J = 6.6 Hz), 1.95 (m, 1H), 2.35 (d, 1H, J = 4.5 Hz), 2.52 (m, 1H), 2.75 (m, 1H), 3.10 (m, 1H), 3.60 (s, 3H), 4.28 (bs, 1H), 4.50-4.62 (m, 2H), 4.90 (d, 1H, J = 11.8 Hz), 5.70 (s, 1H), 7.15-7.30 (m, 5H), 7.42 (s, 1H)
13C NMR(75㎒, CDCl3) : δ 20.19, 34.45, 36.71, 45.01, 49.10, 63.97, 69.47, 98.70, 109.00, 124.57, 126.19, 126.51, 134.00, 145.48, 149.82, 165.56 13 C NMR (75 MHz, CDCl 3 ): δ 20.19, 34.45, 36.71, 45.01, 49.10, 63.97, 69.47, 98.70, 109.00, 124.57, 126.19, 126.51, 134.00, 145.48, 149.82, 165.56
상기 수득한 화합물(2.55g, 7.72mmol)을 메틸렌클로라이드(30㎖)에 용해시키고 규조토(3.5g)와 피리디늄클로로크로메이트(3.32g, 15.4mmol)를 가하여 실온에서 1시간동안 교반하였다. 규조토를 이용하여 여과한 후 농축시키고 잔류물을 실리카겔 칼럼 크로마토그래피(용출제: n-헥산/에틸아세테이트=7/1, v/v)로 정제하여 흰색 고체상의 메틸 (1S,5R,6S)-7-아세틸-5-벤질옥시-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트(1.65g, 수율 65%)를 수득하였다.The obtained compound (2.55 g, 7.72 mmol) was dissolved in methylene chloride (30 mL), diatomaceous earth (3.5 g) and pyridinium chloro chromate (3.32 g, 15.4 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Filtration was carried out using diatomaceous earth and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 7/1, v / v) to give methyl (1S, 5R, 6S)-as a white solid. 7-acetyl-5-benzyloxy-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate (1.65 g, yield 65%) was obtained.
1H NMR (300㎒, CDCl3) : δ 2.32(s, 3H), 2.50(m, 1H), 2.90-3.10(m, 1H), 3.30-3.40(m, 2H), 3.75(s, 3H), 4.65(d, 1H, J=11.9Hz), 4.85(d, 1H, J=11.9Hz), 5.42(m, 1H), 6.85(s, 1H), 7.22-7.42(m, 5H), 7.50(s, 1H) 1 H NMR (300MHz, CDCl 3 ): δ 2.32 (s, 3H), 2.50 (m, 1H), 2.90-3.10 (m, 1H), 3.30-3.40 (m, 2H), 3.75 (s, 3H) , 4.65 (d, 1H, J = 11.9 Hz), 4.85 (d, 1H, J = 11.9 Hz), 5.42 (m, 1H), 6.85 (s, 1H), 7.22-7.42 (m, 5H), 7.50 ( s, 1 H)
13C NMR(75㎒, CDCl3) : δ 27.71, 33.80, 39.82, 46.61, 51.59, 71.06, 98.18, 111.26, 128.16, 128.23, 128.79, 137.50, 143.81, 146.57, 152.70, 167.91, 196.58 13 C NMR (75 MHz, CDCl 3 ): δ 27.71, 33.80, 39.82, 46.61, 51.59, 71.06, 98.18, 111.26, 128.16, 128.23, 128.79, 137.50, 143.81, 146.57, 152.70, 167.91, 196.58
메틸 (1S,5R,6S)-5-벤질옥시-7-포르밀-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트 및 t-부톡실아민 하이드로클로라이드 대신에 상기 수득한 화합물 및 하이드록실아민 하이드로클로라이드를 사용하는 점을 제외하고는 실시예 1에서와 동일하게 실시하여 표제화합물(수율 80%)을 수득하였다.Methyl (1S, 5R, 6S) -5-benzyloxy-7-formyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate and t-butoxylamine hydrochloride The title compound (yield 80%) was obtained in the same manner as in Example 1 except for using the obtained compound and hydroxylamine hydrochloride instead.
1H NMR (300㎒, CDCl3) : δ 1.83(s, 3H), 2.05(m, 1H), 2.62-2.80(m, 1H), 3.00-3.15(m, 2H), 3.58(s, 3H), 4.45(d, 1H, J=12.2Hz), 4.68(d, 1H, J=12.0Hz), 4.85(m, 1H), 6.00(s, 1H), 7.00-7.15(m, 5H), 7.35(s, 3H)13 1 H NMR (300MHz, CDCl 3 ): δ 1.83 (s, 3H), 2.05 (m, 1H), 2.62-2.80 (m, 1H), 3.00-3.15 (m, 2H), 3.58 (s, 3H) , 4.45 (d, 1H, J = 12.2 Hz), 4.68 (d, 1H, J = 12.0 Hz), 4.85 (m, 1H), 6.00 (s, 1H), 7.00-7.15 (m, 5H), 7.35 ( s, 3 H) 13
C NMR(75㎒, CDCl3) : δ 11.98, 34.98, 39.64, 46.08, 51.56, 71.31, 99.79, 111.45, 128.19, 128.68, 134.99, 137.55, 140.19, 152.66, 153.70, 168.16C NMR (75 MHz, CDCl 3 ): δ 11.98, 34.98, 39.64, 46.08, 51.56, 71.31, 99.79, 111.45, 128.19, 128.68, 134.99, 137.55, 140.19, 152.66, 153.70, 168.16
실시예 13: 메틸 (1S,5R,6S)-5-벤질옥시-7-[1-(메톡시이미노)에틸]-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 13: Methyl (1S, 5R, 6S) -5-benzyloxy-7- [1- (methoxyimino) ethyl] -4-oxa-bicyclo [4.3.0] nona-2,7-diene- Synthesis of 2-carboxylate
하이드록실아민 하이드로클로라이드 대신에 메톡실아민 하이드로클로라이드를 사용하는 점을 제외하고는 실시예 12에서와 동일하게 실시하여 표제화합물(수율 78%)을 수득하였다.The title compound (yield 78%) was obtained in the same manner as in Example 12 except for using methoxylamine hydrochloride instead of hydroxylamine hydrochloride.
1H NMR (300㎒, CDCl3) : δ 1.90(s, 3H), 2.25(m, 1H), 2.78(m, 1H), 3.25 (m, 2H), 3.65(s, 3H), 3.66(s, 3H), 4.53(d, 1H, J=12.2Hz), 4.75(d, 1H, J=12.2 Hz), 5.45(d, 1H, J=3.8Hz), 6.05(m, 1H), 7.15-7.30(m, 5H), 7.42(s, 1H)13 1 H NMR (300MHz, CDCl 3 ): δ 1.90 (s, 3H), 2.25 (m, 1H), 2.78 (m, 1H), 3.25 (m, 2H), 3.65 (s, 3H), 3.66 (s , 3H), 4.53 (d, 1H, J = 12.2 Hz), 4.75 (d, 1H, J = 12.2 Hz), 5.45 (d, 1H, J = 3.8 Hz), 6.05 (m, 1H), 7.15-7.30 (m, 5 H), 7.42 (s, 1 H) 13
C NMR(75㎒, CDCl3) : δ 33.49, 39.34, 47.09, 51.54, 62.08, 70.67, 98.19, 111.97, 128.09, 128.16, 128.74, 134.72, 137.76, 139.49, 152.44, 152.61, 168.18C NMR (75 MHz, CDCl 3 ): δ 33.49, 39.34, 47.09, 51.54, 62.08, 70.67, 98.19, 111.97, 128.09, 128.16, 128.74, 134.72, 137.76, 139.49, 152.44, 152.61, 168.18
실시예 14: 메틸 (1S,5R,6S)-7-[1-(하이드록시이미노)에틸]-5-메톡시-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 14 Methyl (1S, 5R, 6S) -7- [1- (hydroxyimino) ethyl] -5-methoxy-4-oxa-bicyclo [4.3.0] nona-2,7-diene- Synthesis of 2-carboxylate
메틸 (1S,5R,6S)-5-벤질옥시-7-포르밀-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트 대신에 메틸 (1S,5R,6S)-7-포르밀-5-메톡시-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트를 사용하는 점을 제외하고는 실시예 12에서와 동일하게 실시하여 표제화합물(수율 85%)을 수득하였다.Methyl (1S, 5R, 6S) -5-benzyloxy-7-formyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate in place of methyl (1S, 5R, Same as in Example 12, except that 6S) -7-formyl-5-methoxy-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate is used To give the title compound (yield 85%).
1H NMR (300㎒, CDCl3) : δ 2.25(s, 3H), 2.42(m, 1H), 2.88(m, 1H), 3.25 (m, 1H), 3.38(s, 3H), 3.65(s, 3H), 5.12(d, 1H, J=7.0Hz), 6.72(s, 1H), 7.20(s, 1H), 7.40(s, 1H) 1 H NMR (300MHz, CDCl 3 ): δ 2.25 (s, 3H), 2.42 (m, 1H), 2.88 (m, 1H), 3.25 (m, 1H), 3.38 (s, 3H), 3.65 (s , 3H), 5.12 (d, 1H, J = 7.0 Hz), 6.72 (s, 1H), 7.20 (s, 1H), 7.40 (s, 1H)
실시예 15: (1S,5R,6S)-5-벤질옥시-7-메톡시이미노메틸-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실산의 합성Example 15 Synthesis of (1S, 5R, 6S) -5-benzyloxy-7-methoxyiminomethyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylic acid
메틸 (1S,5R,6S)-5-벤질옥시-7-메톡시이미노메틸-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트(15g, 43.68mmol)를 아세토니트릴과 물의 혼합액(2/1, v/v, 300㎖)에 녹이고 수산화나트륨(5.24g, 131.04mmol)을 가한 다음 3시간동안 환류교반하였다. 반응용기를 실온으로 냉각시킨 후 감압하에 유기용매를 제거하고 클로로포름으로 추출하였다. 추출액을 무수 마그네슘설페이트로 건조시키고 농축시키면 갈색 고체가 수득되었다. 수득된 갈색 고체를 에틸아세테이트와 n-헥산으로 재결정하여 흰색 고체상의 표제화합물(12.9g, 수율 90%)을 수득하였다.Methyl (1S, 5R, 6S) -5-benzyloxy-7-methoxyiminomethyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate (15 g, 43.68 mmol) Was dissolved in a mixed solution of acetonitrile and water (2/1, v / v, 300 mL), sodium hydroxide (5.24 g, 131.04 mmol) was added, and the mixture was stirred under reflux for 3 hours. After cooling the reaction vessel to room temperature, the organic solvent was removed under reduced pressure and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated to give a brown solid. The obtained brown solid was recrystallized from ethyl acetate and n-hexane to give the title compound (12.9 g, 90% yield) as a white solid.
1H NMR (300㎒, CDCl3) : δ 2.42(m, 1H), 2.93(m, 1H), 3.32(m, 2H), 3.82 (s, 3H), 4.68(d, 1H, J=11.9㎐), 4.90(d, 1H, J=11.9㎐), 5.57(d, 1H, J=4.2㎐), 6.13(s, 1H), 7.32(m, 5H), 7.68(s, 1H), 7.89(s, 1H) 1 H NMR (300MHz, CDCl 3 ): δ 2.42 (m, 1H), 2.93 (m, 1H), 3.32 (m, 2H), 3.82 (s, 3H), 4.68 (d, 1H, J = 11.9㎐ ), 4.90 (d, 1H, J = 11.9 kPa), 5.57 (d, 1H, J = 4.2 kPa), 6.13 (s, 1H), 7.32 (m, 5H), 7.68 (s, 1H), 7.89 (s , 1H)
MASS : 330[M+H]+, 352[M+Na]+ MASS: 330 [M + H]+, 352 [M + Na]+
실시예 16: 소듐 (1S,5R,6S)-5-벤질옥시-7-메톡시이미노메틸-4-옥사-비사이클로[4.3.0]노나-2,7-디엔-2-카복실레이트의 합성Example 16: Synthesis of Sodium (1S, 5R, 6S) -5-benzyloxy-7-methoxyiminomethyl-4-oxa-bicyclo [4.3.0] nona-2,7-diene-2-carboxylate
실시예 15에서 수득한 화합물(2g, 6.07mmol)을 물(20㎖)에 현탁시키고 5℃에서 1N-NaOH(6.1㎖, 6.10mmol)을 가한 다음 30분간 교반하면 화합물이 모두 용해되었다. 맑게된 용액을 감압하에 농축시키고 잔류물에 뜨거운 에탄올을 가하여 녹인 다음 0℃로 냉각시키고 흰색 고체가 생길 때까지 에틸아세테이트를 적가하였다. 생성된 흰색 고체를 여과한 후 건조시켜 흰색 고체상의 표제화합물(2.1g, 수율 99%)을 수득하였다.The compound (2 g, 6.07 mmol) obtained in Example 15 was suspended in water (20 mL), 1N-NaOH (6.1 mL, 6.10 mmol) was added at 5 ° C, and stirred for 30 minutes to completely dissolve the compound. The cleared solution was concentrated under reduced pressure, dissolved by adding hot ethanol to the residue, cooled to 0 ° C. and ethyl acetate was added dropwise until a white solid formed. The resulting white solid was filtered and dried to give the title compound (2.1 g, 99% yield) as a white solid.
1H NMR (300㎒, D2O) : δ 2.19(m, 1H), 2.82(m, 1H), 3.01(m, 1H), 3.21(m, 1H), 3.68(s, 3H), 4.59(d, 1H, J=11.7㎐), 4.82(d, 1H, J=11.7㎐), 5.11(d, 1H, J=6.3㎐), 6.32(s, 1H), 7.19(s, 1H), 7.37(m, 5H), 7.89(s, 1H) 1 H NMR (300MHz, D 2 O): δ 2.19 (m, 1H), 2.82 (m, 1H), 3.01 (m, 1H), 3.21 (m, 1H), 3.68 (s, 3H), 4.59 ( d, 1H, J = 11.7 kPa, 4.82 (d, 1H, J = 11.7 kPa), 5.11 (d, 1H, J = 6.3 kPa), 6.32 (s, 1H), 7.19 (s, 1H), 7.37 ( m, 5H), 7.89 (s, 1H)
MASS : 352[M+H]+, 374[M+Na]+ MASS: 352 [M + H] + , 374 [M + Na] +
생물학적 실험예 1: 사염화탄소 유발 간장해에 대한 억제효과Biological Experimental Example 1 Inhibitory Effect on Carbon Tetrachloride-Induced Liver Injury
공지의 방법(참조: Philippe letteron et al., Biochemical Pharmacology, 39, 12, 2027-2034, 1990)에 따라 본 발명에 따른 화합물의 간보호효과를 확인하기 위하여 실험하였으며, 그 과정을 간단히 기술하면 다음과 같다.Experiments were carried out to determine the hepatoprotective effects of the compounds according to the invention according to known methods (see Philippe letteron et al., Biochemical Pharmacology, 39, 12, 2027-2034, 1990). Same as
A. 시험동물A. Test Animal
실험에 사용한 랫트(SD, male, 180∼200g)는 온도 22±1℃, 습도 60±5%의 환경에 두었으며, 12시간 간격으로 명암을 바꿔주면서 사료와 물은 마음껏 섭취하도록 하였다.Rats (SD, male, 180 ~ 200g) used in the experiment were placed in an environment of temperature 22 ± 1 ℃ and humidity 60 ± 5%, and the feed and water were ingested freely while changing the contrast every 12 hours.
B. 약물투여B. Drug Administration
본 발명에 따른 화합물을 용제인 옥수수유에 현탁시켰으며 현탁액은 2㎖/kg의 양으로 투여하였다. 각 8 마리의 랫트를 한군으로 하고, 시험화합물을 50mg/kg의 용량으로 1일 1회, 4일간 경구투여하였으며, 마지막 시험화합물을 투여한지 30분 후에 옥수수유에 현탁된 10% 사염화탄소 용액을 2㎖/kg 의 용량으로 복강내 주사하였다. 시험 화합물에 대한 대조화합물로는 실리마린을 사용하였다.The compound according to the present invention was suspended in a solvent corn oil and the suspension was administered in an amount of 2 ml / kg. Each group of 8 rats was used as a group, and the test compound was orally administered once a day for 4 days at a dose of 50 mg / kg, and 2 ml of a 10% carbon tetrachloride solution suspended in corn oil 30 minutes after the last test compound was administered. Intraperitoneal injection at a dose of / kg. Silymarin was used as a control compound for the test compound.
C. 혈청분리 및 혈액의 생화학적 분석C. Serum Separation and Biochemical Analysis of Blood
각 시험동물에 사염화탄소를 투여한 후 24시간 절식시켰으며 음수는 마음껏 섭취하게 하였다. 각 시험동물을 에테르로 가볍게 마취시킨 후 개복하여 하대정맥에서 채혈하는 방법으로 혈액을 채취하였으며, 채취한 혈액을 원심분리하여 혈청을 얻었다. 혈청중 ALT, AST 치는 혈액생화학 분석기(Vitalab, Spectra II, Merck)를 이용하여 측정하였다. 각 군별 측정치에 대한 통계학적 유의성은 스튜던트 t-검정법(Student's t-test)으로 검정하였으며 P 값이 5% 미만인 경우에 통계적으로 유의성이 있다고 판정하였다.Each test animal was fasted for 24 hours after the administration of carbon tetrachloride, and the drinking water was ingested freely. Each test animal was lightly anesthetized with ether, and then opened and blood was collected from the inferior vena cava, and blood was collected and centrifuged to obtain serum. Serum levels of ALT and AST were measured using a blood biochemical analyzer (Vitalab, Spectra II, Merck). The statistical significance for each group of measurements was tested by Student's t-test and determined to be statistically significant when P value was less than 5%.
주요 화합물을 랫트에 경구투여한 경우, 사염화탄소 유발 간장해에 대한 억제효과는 하기 표 1에 요약하여 나타내었다.When the main compound was orally administered to rats, the inhibitory effect on carbon tetrachloride-induced liver injury is summarized in Table 1 below.
생물학적 실험예 2 : D-갈락토사민 유발 간장해에 대한 억제효과Biological Experimental Example 2: Inhibitory effect on D-galactosamine-induced liver injury
공지의 방법(참조: Koji Hase et al., Biol. Pharm. Bull., 20, 4, 381-385, 1997)에 따라 본 발명에 따른 화합물의 간보호효과를 확인하기 위하여 실험하였으며, 그 과정을 간단히 기술하면 다음과 같다.In accordance with known methods (see Koji Hase et al., Biol. Pharm. Bull., 20, 4, 381-385, 1997), experiments were conducted to confirm the hepatoprotective effect of the compounds according to the present invention. In short,
A. 시험동물A. Test Animal
실험에 사용한 랫트(SD, male, 180∼200g)는 온도 22±1℃, 습도 60±5%의 환경에 두었으며, 12시간 간격으로 명암을 바꿔주면서 사료와 물은 마음껏 섭취하도록 하였다.Rats (SD, male, 180 ~ 200g) used in the experiment were placed in an environment of temperature 22 ± 1 ℃ and humidity 60 ± 5%, and the feed and water were ingested freely while changing the contrast every 12 hours.
B. 약물투여B. Drug Administration
본 발명에 따른 화합물을 용제인 옥수수유에 현탁시켰으며 현탁액은 2㎖/kg의 양으로 투여하였다. 각 8 마리의 랫트를 한군으로 하고, 시험화합물을 50mg/kg의 용량으로 1일 1회, 4일간 경구투여하였으며, 마지막 시험화합물을 투여한지 30분 후에 생리식염수에 용해시킨 D-갈락토사민 용액을 2㎖/kg의 용량으로 복강내 주사하였다. 시험 화합물에 대한 대조화합물로는 실리마린을 사용하였다.The compound according to the present invention was suspended in a solvent corn oil and the suspension was administered in an amount of 2 ml / kg. Each group of 8 rats was used as a group, and the test compound was orally administered once a day for 4 days at a dose of 50 mg / kg, and D-galactosamine solution dissolved in physiological saline 30 minutes after the last test compound was administered. Was injected intraperitoneally at a dose of 2 ml / kg. Silymarin was used as a control compound for the test compound.
C. 혈청분리 및 혈액의 생화학적 분석C. Serum Separation and Biochemical Analysis of Blood
각 시험동물에 D-갈락토사민을 투여한 후 24시간 절식시켰으며 음수는 마음껏 섭취하게 하였다. 각 시험동물을 에테르로 가볍게 마취시킨 후 개복하여 하대정맥에서 채혈하는 방법으로 혈액을 채취하였으며, 채취한 혈액을 원심분리하여 혈청을 얻었다. 혈청중 ALT, AST 치는 혈액생화학 분석기(Vitalab, Spectra II, Merck)를 이용하여 측정하였다. 각 군별 측정치에 대한 통계학적 유의성은 스튜던트 t-검정법(Student's t-test)으로 검정하였으며 P 값이 5% 미만인 경우에 통계적으로 유의성이 있다고 판정하였다.Each test animal was fasted for 24 hours after D-galactosamine was administered, and the drinking water was ingested freely. Each test animal was lightly anesthetized with ether, and then opened and blood was collected from the inferior vena cava, and blood was collected and centrifuged to obtain serum. Serum levels of ALT and AST were measured using a blood biochemical analyzer (Vitalab, Spectra II, Merck). The statistical significance for each group of measurements was tested by Student's t-test and determined to be statistically significant when P value was less than 5%.
주요 화합물을 랫트에 경구투여한 경우, D-갈락토사민 유발 간장해에 대한 억제효과는 하기 표 2에 요약하여 나타내었다.When the main compound was orally administered to rats, the inhibitory effect on D-galactosamine-induced liver injury is summarized in Table 2 below.
생물학적 실험예 3 : 급성독성시험Biological Experiment 3: Acute Toxicity Test
급성독성시험이란 시험화합물을 시험동물에 1 회 투여하였을 때, 단기간에 나타나는 독성을 질적, 양적으로 검사하는 시험이다.An acute toxicity test is a test that qualitatively and quantitatively examines the toxicity in a short period of time when a test compound is administered to a test animal once.
본 실험예에서는 "국립보건안전연구원 고시 제 94-3호" 「의약품등의 독성시험기준」을 참고로하여, 마우스를 사용한 급성독성시험을 수행하였다. 마우스는 대한실험동물센타에서 4주령 ICR 품종의 수컷 특정병원균부재동물(SPF)을 구입하여 1주일간 실험실 환경에 순화시킨 후 사용하였으며, 실험전 절식기간을 제외하고 사료와 물은 자유섭식시켰다.In the present experimental example, acute toxicity test using mice was performed with reference to "National Health and Safety Institute Notice No. 94-3" "Toxicity Test Standards for Drugs". Mice were purchased from the Korean Experimental Animal Center for 4 weeks old ICR varieties of male-specific pathogen-free animals (SPF) and allowed to acclimate to the laboratory environment for one week. Feed and water were freely fed except for the fasting period before the experiment.
화합물을 투여하기 전일 오후 6시부터 투여당일 오전 9시까지 마우스를 절식시킨 후, 각 화합물을 옥수수유에 마쇄·현탁하여 250mg/kg, 500mg/kg, 1,000 mg/kg, 및 2,000mg/kg 용량으로 조제하여 투여하였으며, 마우스당 투여부피는 체중 kg당 10㎖ 또는 20㎖로 하였다. 각 용량군의 수는 5마리로 하였다. 화합물은 투여당일 조제하여 사용하였으며, 경구투여용 바늘을 사용하여 일회 경구투여하였다. 투여후 2주간 관찰하였고, 관찰기간동안 매일 임상증상을 기록하고 체중은 3회이상 기록하였다. 또한, 관찰기간 종료 후 부검을 실시하여 육안적 해부소견을 기록하였다. 본 발명에 따른 화합물중 대표적으로 실시예 12번 화합물을 선택하여 급성독성실험을 수행한 결과는 하기 표 3에 나타내었다.The mice were fasted from 6 pm on the day before compound administration to 9 am on the day of administration, and each compound was ground and suspended in corn oil at 250 mg / kg, 500 mg / kg, 1,000 mg / kg, and 2,000 mg / kg doses. Prepared and administered, the volume of administration per mouse was 10ml or 20ml / kg body weight. The number of dose groups was five. The compound was prepared and used on the day of administration, and orally administered once using an oral administration needle. Two weeks after the administration, the clinical symptoms were recorded daily and the body weight was recorded three times or more during the observation period. An autopsy was performed after the end of the observation period to record gross anatomical findings. Among the compounds according to the present invention, the results of the acute toxicity test by selecting the compound of Example 12 are shown in Table 3 below.
Claims (4)
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| KR1019970067407A KR100240778B1 (en) | 1997-12-10 | 1997-12-10 | Novel genipin derivative and therapeutic composition for liver disease comprising the same as an active ingredient |
| EP98944315A EP1045841B1 (en) | 1997-11-05 | 1998-09-04 | Novel genipin derivative having liver protection activity |
| DE69809967T DE69809967T2 (en) | 1997-11-05 | 1998-09-04 | GENIPIN DERIVATIVES WITH AN ACTIVITY PROTECTING LIVER |
| ES98944315T ES2189238T3 (en) | 1997-11-05 | 1998-09-04 | NEW DERIVATIVE OF GENIPINA THAT HAS LIVER PROTECTIVE ACTIVITY. |
| AU91886/98A AU9188698A (en) | 1997-11-05 | 1998-09-04 | Novel genipin derivative having liver protection activity |
| PCT/KR1998/000273 WO1999023090A1 (en) | 1997-11-05 | 1998-09-04 | Novel genipin derivative having liver protection activity |
| US09/530,796 US6262083B1 (en) | 1997-11-05 | 1998-09-04 | Genipin derivative having liver protection activity |
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