KR19990084528A - New anthracycline derivatives and preparation methods - Google Patents
New anthracycline derivatives and preparation methods Download PDFInfo
- Publication number
- KR19990084528A KR19990084528A KR1019980016348A KR19980016348A KR19990084528A KR 19990084528 A KR19990084528 A KR 19990084528A KR 1019980016348 A KR1019980016348 A KR 1019980016348A KR 19980016348 A KR19980016348 A KR 19980016348A KR 19990084528 A KR19990084528 A KR 19990084528A
- Authority
- KR
- South Korea
- Prior art keywords
- compound
- group
- anthracycline
- anticancer
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
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- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
본 발명은 신규 저심독성 안트라사이클린 유도체 및 이를 함유하는 항종양제에 관한 것이다. 퀴논 화학구조를 가진 항암항생물질은 생체내 순환적 산화환원 반응에서 계속적으로 슈퍼옥시드와 같은 산소라디칼을 생성하므로, 퀴논 리닥타제의 기능을 제어하는 방안은 효율적으로 산소라디칼 생성억제 방안이 되어, 안트라사이클린계 항암항생제의 부작용을 줄이는 중요한 방안이 될 수 있음에 착안하여 본 발명자는 심근 독성의 요인이 되는 라디칼생성은 NAD/NADH 비의 보정을 통하여 조절할 수 있음을 알았다. 따라서 본 발명에서는 세포내 NAD/NADH 비의 균형을 보완하여 산소라디칼 생성효소계의 활성을 제어하는 신규 저심독성 항암제인 안트라사이클린계 유도체을 발명하였다. 신규 안트라사이클린 유도체는 공지의 안트라사이클린 항암약물의 14번위치에 L-아스파르테이트 혹은 피루베이트와 에스테르결합으로 제조하고 이들의 화학구조 및 물성과 안정성시험, 심장독성시험, 항암력 평가시험을 실시하였다. 시험결과 본 발명화합물은 안정성이 우수하고 공지의 안트라사이클린계 항암물질과 유사한 항암력을 가지면서도 심장독성이 매우 경감된 우수한 항암약물임이 확인되었다. 이와같은 발명은 심장독성이 경감된 신규 안트라사이클린 유도체를 함유하는 암치료용 약제로 이용될 수 있다.The present invention relates to novel low cardiotoxic anthracycline derivatives and antitumor agents containing the same. Since anti-cancer antibiotics with quinone chemical structure continuously produce oxygen radicals such as superoxide in circulating redox reactions in vivo, the method of controlling the function of quinone reddactase becomes an efficient method of inhibiting oxygen radical generation. In view of the fact that it can be an important way to reduce the side effects of anthracycline-based anticancer antibiotics, the present inventors have found that radical generation, which is a factor of myocardial toxicity, can be regulated through correction of the NAD / NADH ratio. Therefore, the present invention invented an anthracycline derivative, a novel low cardiotoxic anticancer agent that controls the activity of oxygen radical synthase system by compensating the balance of intracellular NAD / NADH ratio. The novel anthracycline derivatives are prepared by ester-bonding with L-aspartate or pyruvate at position 14 of known anthracycline anticancer drugs, and their chemical structure and physical properties, stability tests, cardiotoxicity tests, and anticancer evaluation tests are performed. It was. As a result of the test, it was confirmed that the compound of the present invention is an excellent anticancer drug having excellent stability and anticancer activity similar to a known anthracycline-based anticancer substance, and having very reduced cardiotoxicity. This invention can be used as a drug for the treatment of cancer containing a novel anthracycline derivative with reduced cardiotoxicity.
Description
본 발명은 다음 일반식(Ⅰ)으로 표시되는 신규 안트라사이클린(Athracycline) 유도체 및 이를 함유하는 항종양제에 관한 것이다.The present invention relates to a novel anthracycline derivative represented by the following general formula (I) and an anti-tumor agent containing the same.
(Ⅰ)(Ⅰ)
상기식에서 R1와 R4은 수소원자 혹은 메톡시기 혹은 수산기이고, R는 L-아스파르테이트기 혹은 피루베이트기, R3는 수소원자 혹은 불소를 나타낸다.Wherein R 1 and R 4 represent a hydrogen atom or a methoxy group or a hydroxyl group, R represents an L-aspartate group or pyruvate group, and R 3 represents a hydrogen atom or fluorine.
또한 본 발명은 상기 아스파르테이트- 및 피루베이트-안트라사이클린 글리코사이드 유도체의 제조방법과 이러한 신규 화합물을 유효성분으로 하는 항종양제에 관한 것이다. 안트라사이클린 종류의 물질로서 종래 방사선균의 배양액에서 얻을 수 있는 로도마이신, 다우노마이신 및 아드리아마이신은 그의 화학 구조가 결정된 이후 오랫동안 공지되어 왔으며, 특정의 대표적인 안트라사이클린(예: 다우노마이신, 아드리아마이신, 아클라시노마이신, 4'-에피-아드리아마이신, 4'-메톡시아아드리아마이신, 4'-데옥시아드리아마이신과 이다루비신)은 이미 넓은 항암 스펙트럼을 가지고 암화학요법제로서 임상적 종양치료에 사용해온 것은 공지되어 있다.The present invention also relates to a method for producing the aspartate- and pyruvate-anthracycline glycoside derivatives and an anti-tumor agent comprising the novel compound as an active ingredient. Rhodomycin, daunomycin and adriamycin, which can be obtained from cultures of conventional radiation bacteria as anthracycline species, have long been known since their chemical structures have been determined, and certain representative anthracyclines (eg daunomycin, adriamycin) , Aclacinomycin, 4'-epi-adriamycin, 4'-methoxyadriamycin, 4'-deoxyadriamycin and idarubicin) already have a broad anticancer spectrum and are a clinical chemotherapy agent for cancer It is known to have been used for.
이러한 공지된 안스라사이클린 화학구조을 가진 퀴논계 항암항생제들은 백혈병, 악성임파종을 포함하여 많은 종류의 악성종양에 유효한 광범위하고 강력한 항암작용을 나타내지만, 심근장해, 골수억제, 탈모 등의 부작용을 수반하며, 특히 심한 심장독성이 자주 출현하기 때문에 임상적인 사용에 있어 많은 제한을 받고 있다. 이러한 심장독성은 급성 또는 만성으로 출현하여 심수축기능 저하, 부정맥, 저혈압 등을 일으키고 심하면 심부전증에 의한 사망까지도 초래한다.These quinone-based anticancer antibiotics with the known anthracycline chemical structure exhibit a wide range of potent anticancer effects effective against many types of malignancies including leukemia and malignant lymphomas, but have side effects such as cardiomyopathy, myelosuppression, and hair loss. In particular, severe cardiotoxicity is frequently present, which limits the clinical use. This cardiotoxicity can be acute or chronic, causing cardiac contractility, arrhythmia, hypotension, and even death due to heart failure.
본 발명자들는 이들 화합물의 심장독성을 경감시키기 위해 아스파르트산과 그 염이 생체내 NADH/NAD 비율을 조절함으로써 독소루비신에 의한 심독성을 경감시킬 수있다는 선행 발명특허(한국특허출원번호 94-012769)에 근거하여 신규 아스파르테이트-안트라사이클리논 유도체를 발명하게 되었다. 또한 아스파르트산과 유사하게 생체내 NADH/NAD 비율을 조절할 수 있는 피루베이트와 결합된 안트라사이클린 유도체를 발명하였다. 따라서 본 발명의 주목적은 상기 구조식(Ⅰ)의 기존 다우노마이신,아드리아마이신, 카르미노마이신과 이다루비신등 안트라사이클린 글리코사이드계 항암제보다 심독성이 훨씬 경감된 신규 안트라사이클린 글리코사이드 항암제를 제공하는데 있다.The inventors of the present invention have found that aspartic acid and its salts can mitigate cardiotoxicity by doxorubicin by regulating the in vivo NADH / NAD ratio in order to alleviate the cardiotoxicity of these compounds (Korean Patent Application No. 94-012769). New aspartate-anthracyclinone derivatives have been invented. Also similar to aspartic acid was invented pyruvate-linked anthracycline derivatives that can regulate the in vivo NADH / NAD ratio. Accordingly, the main object of the present invention is to provide a novel anthracycline glycoside anticancer agent with much lower cardiotoxicity than anthracycline glycoside type anticancer agents such as daunomycin, adriamycin, carminomycin and idarubicin of the above formula (I). .
신규 안트라사이클린계 항암항생제는 약물의 대사과정에서 생성되는 산소라디칼이 특히 심근독성의 주요인으로 추정되고 있다. 이러한 산소라디칼이 야기하는 문제점을 해결하기 위해 독성이 다소 적은 새로운 항암항생물질의 유도체를 개발한다거나 항산화제 또는 라디칼제거 효소들의 병용요법이 제안되고 있지만 사용에 많은 제한을 받고 있다. 라디칼제거에 관련되는 효소들을 직접 사용하는 방법은 적절한 조건이 확립되어 있지 않고 라디칼 손상 억제에 이용되는 각종 항산화제들은 그들 자체가 높은 반응성을 가지고 있기 때문이다. 따라서 산소라디칼의 부작용을 감소시키는 효율적인 항산화제의 역할을 하면서도 안정성과 안전성이 높으며 약효 효능을 유지하는 새로운 차원의 신규 안트라사이클린계 항암약물의 개발이 절실히 필요하여 본 발명이 이루어지게 되었다. 본 발명의 또다른 목적은 상기 구조식(Ⅰ)의 신규 안트라사이클린 글리코사이드계 항암제를 제조하는 방법을 제공하는 것이다.Oxygen radicals produced during the metabolism of drugs are believed to be the main cause of myocardial toxicity. In order to solve the problems caused by oxygen radicals, the development of new anti-cancer antibiotic derivatives with less toxicity or a combination therapy of antioxidants or radical scavenging enzymes has been proposed, but the use of them has been limited. The direct use of enzymes involved in radical elimination is because the proper conditions are not established and the various antioxidants used to inhibit radical damage are themselves highly reactive. Therefore, while the role of an effective antioxidant to reduce the side effects of oxygen radicals, the development of a novel anthracycline-based anticancer drug of a high level of stability, safety and high efficacy is urgently needed to achieve the present invention. It is another object of the present invention to provide a method for preparing a novel anthracycline glycoside anticancer agent of the above formula (I).
도 1 은 본 발명의 신규 안트라사이클린 글리코사이드계 항암물질에 대한 제조1 is a preparation for the novel anthracycline glycoside-based anticancer substance of the present invention
경로를 도식으로 나타낸 것이다.The path is shown schematically.
본 발명의 구조식(Ⅰ) 화합물은 하기 일반구조식을 가진 기존의 안트라사이클린 글리코사이드계 항암항생 화합물(Ⅱ)과 L-아스파르테이트 및 피루베이트를 반응시켜 안트라사이클린의 14번 위치에 에스테르결합으로 연결된 상기 신규 화합물(Ⅰ)을 제조한다.Structural formula (I) compound of the present invention is a conventional anthracycline glycoside-based anticancer compound (II) having the following general formula by reacting L-aspartate and pyruvate is linked to the ester position at the 14 position of anthracycline The novel compound (I) is prepared.
(Ⅱ)(Ⅱ)
상기 일반식(Ⅱ)로 표시되는 공지의 안트라사이클린 글리코사이드계 항암물질은 하기 신규 안트라사이클린계 화합물의 제조방법에 관한 도식의 출발물질 1a∼f를 나타낸다.The well-known anthracycline glycoside type anticancer substance represented by the said General formula (II) shows the starting material 1a-f of the schematic of the manufacturing method of the following novel anthracycline-type compound.
신규 안트라사이클린 글리코사이드계 항암물질에 대한 제조경로는 도 1과 같다.The production route for the novel anthracycline glycoside anticancer substance is shown in FIG. 1.
본 발명에 따르는 제조방법은 공지의 제조기술을 활용하였고(예로 3'번 아미노기에 보호기를 도입하는 방법은 Tetrahedron Letters, vol. 27, 5375(1986), 보호기를 제거하는 방법은 Journal of Organic Chemistry, 495(1979)에 공지된 방법을 응용함), 구체적으로 제조하는 실시예는 대표적인 화합물인 아드리아마이신(1a)로 부터 다우노마이신-L-아스파르테이트(7a) 혹은 다우노마이신-피루베이트(8a)를 상세히 설명할 것이나 이로인해 본 발명의 다른 화합물(7b∼f, 8b∼f)의 제조 및 그들의 범위가 제한되는 것은 아니다.The manufacturing method according to the present invention utilizes known manufacturing techniques (for example, the method of introducing a protecting group to the amino group 3 ′ is Tetrahedron Letters, vol. 27, 5375 (1986), and the method of removing the protecting group is described in Journal of Organic Chemistry, 495 (1979) using a method known in the art), specifically, the preparation examples are from the representative compound, adriamycin (1a), daunomycin-L-aspartate (7a) or daunomycin-pyruvate ( 8a) will be described in detail, but this does not limit the preparation of the other compounds (7b-f, 8b-f) of the present invention and their ranges.
< 실시예 1 ><Example 1>
아드리아마이신 (2a)의 제조Preparation of Adriamycin (2a)
삼각플라스크에 1M-초산나트륨수용액과 화합물 1a을 가하고, 30분동안 상온에서 교반시킨뒤, 분액깔대기로 옮겼다. 여기에 메틸렌클로라이드를 가하여 생성물을 추출한뒤 감압 증류로 용매를 제거하고 진공건조 시켜서 순수한 화합물 2a를 98% 수율로 얻었다.Aqueous 1 M-sodium acetate solution and Compound 1a were added to the Erlenmeyer flask, stirred at room temperature for 30 minutes, and then transferred to a separatory funnel. Methylene chloride was added thereto to extract the product, the solvent was removed by distillation under reduced pressure, and dried in vacuo to obtain pure Compound 2a in 98% yield.
< 실시예 2 ><Example 2>
7-O-(N-벤질옥시카르보닐-α-다우노사미닐)14-브로모 다우노아마이시논(3a)을 경유하여 7-O-(N-벤질옥시카르보닐-α-다우노사미닐)아드리아마이시논(4a)의 제조7-O- (N-benzyloxycarbonyl-α-daunosaminyl) via 7-O- (N-benzyloxycarbonyl-α-daunosaminyl via 14-bromo daunoamycinone (3a) ) Production of Adriamycinone (4a)
화합물 2a를 메틸렌클로라이드에 녹인뒤 30% 염화브롬/초산 (4당량)을 가하고, 상온에서 6시간 동안 교반시켰다. 반응물을 10% 황화수소나트륨수용액으로 2번 씻고, 유기층을 분리한뒤, 진공 펌프로 가능한한 용매를 모두 제거시켜서 브롬 화합물 3a을 얻었다. 화합물 3a을 테트라히드로푸란/물(1:1)용매에 넣고 2시간동안 상온에서 가수분해시켜서 알콜화합물4a를 얻었다. 얻어진 생성물을 컬럼크로마토그래피 (실리카겔; 용출제: 메틸렌클로라이드/에틸아세테이트/에테르, 3:2:1)로 분리해서, 2a로부터 화합물 4a까지 총 65% 수율로 얻었다.Compound 2a was dissolved in methylene chloride, 30% bromine chloride / acetic acid (4 equivalents) was added thereto, and the mixture was stirred at room temperature for 6 hours. The reaction was washed twice with 10% aqueous sodium hydrogen sulfide solution, the organic layer was separated, and all solvent was removed by vacuum pump to obtain bromine compound 3a. Compound 3a was added to a tetrahydrofuran / water (1: 1) solvent and hydrolyzed at room temperature for 2 hours to obtain an alcohol compound 4a. The obtained product was separated by column chromatography (silica gel; eluent: methylene chloride / ethyl acetate / ether, 3: 2: 1) to give a total of 65% yield from 2a to compound 4a.
< 실시예 3 ><Example 3>
7-O-(N-벤질옥시카르보닐-α-다우노사미닐)아드리아마이시논(4a)의 제조Preparation of 7-O- (N-benzyloxycarbonyl-α-daunosaminyl) adriamycinone (4a)
다이옥산/물 (4:1)에 수산화나트륨를 넣어 pH 9.0으로 맞춘 뒤에 화합물 2a와 디벤질디카르보네이트를 같은 당량 넣고, 상온에서 2시간 교반시켰다. 용매를 최대한 증발시키고, 메틸렌클로라이드를 가한뒤 분액칼대기로 옮기고 모액과 물로 두번 씻고, 황산마그네슘으로 건조시켰다. 여과하고 용매를 날린뒤 컬럼 크로마토 그래피 (실리카겔; 용출제: 메틸렌클로라이드/에틸아세테이트/에테르, 3:2:1) 분리하여 순수한 화합물 4a를 86% 수율로 얻었다.Sodium hydroxide was added to dioxane / water (4: 1) to adjust the pH to 9.0, and then the same amount of Compound 2a and dibenzyldicarbonate were added thereto, followed by stirring at room temperature for 2 hours. The solvent was evaporated to the maximum, methylene chloride was added, the mixture was transferred to a separating knife, washed twice with the mother liquor and water, and dried over magnesium sulfate. After filtration and blowing the solvent, column chromatography (silica gel; eluent: methylene chloride / ethyl acetate / ether, 3: 2: 1) was isolated to obtain pure Compound 4a in 86% yield.
< 실시예 4 ><Example 4>
7-O-(N-벤질옥시카르보닐-α-다우노사미닐)다우노아마이시논-L-(N-벤질옥시카르보닐)아스파르테이트(5a)의 제조Preparation of 7-O- (N-benzyloxycarbonyl-α-daunosaminyl) daunoamycinone-L- (N-benzyloxycarbonyl) aspartate (5a)
메틸렌클로라이드속에 화합물 4a와 L-아스파르트산를 넣고, 여기에 EEDQ (2-ethoxy-1- ethoxycarbonyl -1,2-dihydroquinoline) 와 DMAP (4-dimetylaminopyridine)를 넣고 상온에서 3시간 교반시켰다. 생성물을 모액과 물로 씻고, 컬럼크로마토그래피(실리카겔; 용출제:메틸렌클로라이드/에틸아세테이트/에테르, 1:2:1)로 분리하여 5a을 80%수율로 얻었다.Compound 4a and L-aspartic acid were added to methylene chloride, and EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) and DMAP (4-dimetylaminopyridine) were added thereto, and the mixture was stirred at room temperature for 3 hours. The product was washed with mother liquor and water, separated by column chromatography (silica gel; eluent: methylene chloride / ethyl acetate / ether, 1: 2: 1) to give 5a in 80% yield.
< 실시예 5 ><Example 5>
7-O-(N-벤질옥시카르보닐-α-다우노사미닐) 다우노아마이시논-피루베이트(6a)의 제조Preparation of 7-O- (N-benzyloxycarbonyl-α-daunosaminyl) daunoamycinone-pyruvate (6a)
메틸렌클로라이드속에 화합물 4a와 피루빅산을 넣고, 여기에 EEDQ (2-ethoxy -1-ethoxycarbonyl-1, 2-dihydroquinoline) 와 DMAP (4-dimetylaminopyridine)를 넣고 상온에서 3시간 교반시켰다. 생성물을 모액과 물로 씻고, 컬럼크로마토그래피(실리카겔; 용출제: 메틸렌클로라이드/에틸아세테이트/에테르, 1:2:1)로 분리하여 6a을 72%수율로 얻었다.Compound 4a and pyruvic acid were added to methylene chloride, and EEDQ (2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline) and DMAP (4-dimetylaminopyridine) were added thereto, followed by stirring at room temperature for 3 hours. The product was washed with mother liquor and water and separated by column chromatography (silica gel; eluent: methylene chloride / ethyl acetate / ether, 1: 2: 1) to give 6a in 72% yield.
< 실시예 6 ><Example 6>
다우노마이신-L-아스파르테이트(7a)의 제조Preparation of daunomycin-L-aspartate (7a)
화합물 5a을 아세토나이트릴에 녹인뒤, 같은 당량의 트리메틸 실릴요오드(Me3SiI)를 넣고, 10분동안 교반시켜서 카르보벤질옥시기(cbz)를 제거시켰다. 카르보벤질옥시기가 제거된 생성물을 메틸렌클로라이드에 녹이고, 3N 염산 수용액을 가하여 pH 3정도로 맞춘 뒤에 3시간 교반시켜서 생성물을 얻고, 생성물을 다시 메틸렌클로라이드에 녹여서 순수한 결정화합물 7a을 78% 수율로 얻었다.After dissolving compound 5a in acetonitrile, the same equivalent of trimethyl silyl iodine (Me 3 SiI) was added and stirred for 10 minutes to remove the carbobenzyloxy group (cbz). The product from which the carbobenzyloxy group was removed was dissolved in methylene chloride, 3N hydrochloric acid aqueous solution was adjusted to pH 3, and then stirred for 3 hours to obtain a product. The product was dissolved in methylene chloride to obtain pure crystalline compound 7a in 78% yield.
[α]D 20= + 61.69(C: 0.022,클로로포름)[a] D 2 ° = + 61.69 (C: 0.022, Chloroform)
IR스펙트럼IR spectrum
3400-3550(수산기), 3000-3050(페닐), 1700-1720(카르보닐)3400-3550 (hydroxyl group), 3000-3050 (phenyl), 1700-1720 (carbonyl)
1H-NMR스펙트럼(CDCl3, ppm) 1 H-NMR spectrum (CDCl 3 , ppm)
13.72(S, 1H, OH), 13.74(s, 1H, OH), 7.84(dd, J=7.5, 1.15 Hz, 1H, C-10)13.72 (S, 1H, OH), 13.74 (s, 1H, OH), 7.84 (dd, J = 7.5, 1.15 Hz, 1H, C-10)
7.56(t, J=8.3Hz, 1H, C-13), 7.42(dd, J=8.3, 1.1Hz, 1H, C-14), 4.88(m, 1H, c-2)7.56 (t, J = 8.3 Hz, 1H, C-13), 7.42 (dd, J = 8.3, 1.1 Hz, 1H, C-14), 4.88 (m, 1H, c-2)
4.89(m, 1H, c-4), 4.78(s, 2H, c-11), 4.04(s, 3H, OMe, c-15), 3.88(m, 1H, c-9), 3.52(m, 1H, c-7)4.89 (m, 1H, c-4), 4.78 (s, 2H, c-11), 4.04 (s, 3H, OMe, c-15), 3.88 (m, 1H, c-9), 3.52 (m, 1H, c-7)
3.37(m, 2H, c-3), 3.37(m, 1H, c-17), 3.05(m, 1H, c-8), 2.59(d, J=6.6Hz, 2H, c-16), 2.02(m, 2H, c-5)3.37 (m, 2H, c-3), 3.37 (m, 1H, c-17), 3.05 (m, 1H, c-8), 2.59 (d, J = 6.6 Hz, 2H, c-16), 2.02 (m, 2H, c-5)
1.67(d, J=6.5Hz, 3H, CH3, c-12), 1.59(m, 1H, c-9), 나머지 OH와 NH2(br. 1-5근방)1.67 (d, J = 6.5 Hz, 3H, CH3, c-12), 1.59 (m, 1H, c-9), remaining OH and NH2 (near Br-5)
< 실시예 7 ><Example 7>
다우노마이신-피루베이트(8a)의 제조Preparation of Daunomycin-Pyruvate (8a)
화합물 6a을 아세토나이트릴에 녹인뒤, 같은 당량의 트리메틸 실릴요오드(Me3SiI)를 넣고, 10분동안 교반시켜서 카르보벤질옥시기 (cbz)기를 제거시켰다. 카르보벤질옥시기가 제거된 생성물을 메틸렌클로라이드에 녹이고, 3N 염산 수용액을 가하여 pH 3정도로 맞춘 뒤에 3시간 교반시켜서 생성물을 얻고, 생성물을 다시 메틸렌클로라이드에 녹여서 순수한 결정화합물 8a을 85%수율로 얻었다.After dissolving compound 6a in acetonitrile, the same equivalent of trimethyl silyl iodine (Me 3 SiI) was added and stirred for 10 minutes to remove the carbobenzyloxy group (cbz). The product from which the carbobenzyloxy group was removed was dissolved in methylene chloride, 3N hydrochloric acid aqueous solution was adjusted to pH 3, and stirred for 3 hours to obtain a product. The product was dissolved in methylene chloride to obtain pure crystalline compound 8a in 85% yield.
[α]D 20= + 57.81(C: 0.025 ,클로로포름)[a] D 2 ° = + 57.81 (C: 0.025, Chloroform)
IR스펙트럼IR spectrum
3400-3550(수산기), 3000-3050(페닐), 1690-1720(카르보닐)3400-3550 (hydroxyl group), 3000-3050 (phenyl), 1690-1720 (carbonyl)
1H-NMR스펙트럼(CDCl3, ppm) 1 H-NMR spectrum (CDCl 3 , ppm)
13.72(s, 1H, OH), 13.74(S, 1H, OH), 7.84(dd, J=7.55, 1.1Hz, 1H, c-10), 7.56(t, J=8.3 Hz, 1H, c-13),13.72 (s, 1H, OH), 13.74 (S, 1H, OH), 7.84 (dd, J = 7.55, 1.1 Hz, 1H, c-10), 7.56 (t, J = 8.3 Hz, 1H, c-13 ),
7.41(dd, J=8.3, 1.1 Hz, 1H, c-14), 4.89(m, 1H, c-2),4.85(s, 2H, c-11), 4.04(s, 3H, OMe, c-15),7.41 (dd, J = 8.3, 1.1 Hz, 1H, c-14), 4.89 (m, 1H, c-2), 4.85 (s, 2H, c-11), 4.04 (s, 3H, OMe, c- 15),
3.91(m, 1H, c-7), 3.36(dd, J=3.9, 13.3 Hz, 2H, c-3), 3.51(m, 1H, c-7), 3.05(m, 1H, c-8),3.91 (m, 1H, c-7), 3.36 (dd, J = 3.9, 13.3 Hz, 2H, c-3), 3.51 (m, 1H, c-7), 3.05 (m, 1H, c-8) ,
2.15(s, 3H, c-16), 2.02(dd, J=13.3, 6.33 Hz, 2H, c-5), 1.68(d, J=6.45Hz, 3H, c-12),1.58(m, 2H, c-6).2.15 (s, 3H, c-16), 2.02 (dd, J = 13.3, 6.33 Hz, 2H, c-5), 1.68 (d, J = 6.45 Hz, 3H, c-12), 1.58 (m, 2H , c-6).
나머지 OH와 NH2(br.1-5근방).Remaining OH and NH 2 (near br. 1-5).
< 실시예 8 ><Example 8>
카르미노마이신-L-아스파르테이트 (7b)의 제조Preparation of Carminomycin-L-Aspartate (7b)
실시예 1, 2, 4, 6와 동일한 방법으로 하여 목적 화합물을 제조한다.In the same manner as in Examples 1, 2, 4, and 6, the target compound was prepared.
총수율: 41%Total yield: 41%
[α]D 20= + 76.89(C: 0.027, 클로로포름)[a] D 2 ° = + 76.89 (C: 0.027, Chloroform)
IR스펙트럼IR spectrum
3400-3550(수산기), 3000-3050(페닐), 1690-1720(카르보닐)3400-3550 (hydroxyl group), 3000-3050 (phenyl), 1690-1720 (carbonyl)
1H-NMR스펙트럼(CDCl3, ppm) 1 H-NMR spectrum (CDCl 3 , ppm)
13.75(S, 1H, OH), 13.79(s, 2H, OH), 7.84(dd, J=7.4, 1.15 Hz, 1H, C-10)13.75 (S, 1H, OH), 13.79 (s, 2H, OH), 7.84 (dd, J = 7.4, 1.15 Hz, 1H, C-10)
7.56(t, J=8.3Hz, 1H, C-13), 7.42(dd, J=8.37, 1.1Hz, 1H, C-14), 4.88(m, 1H, c-2)7.56 (t, J = 8.3 Hz, 1H, C-13), 7.42 (dd, J = 8.37, 1.1 Hz, 1H, C-14), 4.88 (m, 1H, c-2)
4.89(m, 1H, c-4), 4.78(s, 2H, c-11), 4.04(s, 2H, c-15), 3.88(m, 1H, c-9)3.52(m, 1H, c-7)4.89 (m, 1H, c-4), 4.78 (s, 2H, c-11), 4.04 (s, 2H, c-15), 3.88 (m, 1H, c-9) 3.52 (m, 1H, c -7)
3.37(m, 2H, c-3), 3.37(m, 1H, c-17), 3.05(m, 1H, c-8), 2.59(d, J=6.6Hz, 2H, c-16), 2.02(m, 2H, c-5)3.37 (m, 2H, c-3), 3.37 (m, 1H, c-17), 3.05 (m, 1H, c-8), 2.59 (d, J = 6.6 Hz, 2H, c-16), 2.02 (m, 2H, c-5)
1.67(d, J=6.4Hz, 3H, CH3, c-12), 1.59(m, 1H, c-9), 나머지 OH와 NH2(br. 1-5근방)1.67 (d, J = 6.4 Hz, 3H, CH3, c-12), 1.59 (m, 1H, c-9), remaining OH and NH2 (near Br-5)
< 실시예 9 ><Example 9>
카르미노마이신-피루베이트 (8b)의 제조Preparation of Carminomycin-Pyruvate (8b)
실시예 1, 2, 5, 7와 동일한 방법으로 하여 목적 화합물을 제조한다.In the same manner as in Examples 1, 2, 5, and 7, the target compound was prepared.
총수율: 37%Total yield: 37%
[α]D 20= + 51.09(C: 0.024,클로로포름)[a] D 2 ° = + 51.09 (C: 0.024, Chloroform)
IR스펙트럼IR spectrum
3400-3550(수산기), 3000-3050(페닐), 1690-1720(카르보닐)3400-3550 (hydroxyl group), 3000-3050 (phenyl), 1690-1720 (carbonyl)
1H-NMR스펙트럼(CDCl3, ppm) 1 H-NMR spectrum (CDCl 3 , ppm)
13.71(s, 1H, OH), 13.79(S, 2H, OH), 7.84(dd, J=7.55, 1.1Hz, 1H, c-10), 7.56(t, J=8.7 Hz, 1H, c-13),13.71 (s, 1H, OH), 13.79 (S, 2H, OH), 7.84 (dd, J = 7.55, 1.1 Hz, 1H, c-10), 7.56 (t, J = 8.7 Hz, 1H, c-13 ),
7.41(dd, J=8.3, 1.15 Hz, 1H, c-14), 4.89(m, 1H, c-2),4.85(s, 2H, c-11), 4.04(s, 2H, c-15),7.41 (dd, J = 8.3, 1.15 Hz, 1H, c-14), 4.89 (m, 1H, c-2), 4.85 (s, 2H, c-11), 4.04 (s, 2H, c-15) ,
3.91(m, 1H, c-7), 3.36(dd, J=3.9, 13.3 Hz, 2H, c-3), 3.51(m, 1H, c-7), 3.05(m, 1H, c-8),3.91 (m, 1H, c-7), 3.36 (dd, J = 3.9, 13.3 Hz, 2H, c-3), 3.51 (m, 1H, c-7), 3.05 (m, 1H, c-8) ,
2.15(s, 3H, c-16), 2.02(dd, J=13.3, 6.33Hz, 2H, c-5), 1.68(d, J=6.45Hz, 3H, c-12),1.58(m, 2H, c-6).2.15 (s, 3H, c-16), 2.02 (dd, J = 13.3, 6.33 Hz, 2H, c-5), 1.68 (d, J = 6.45 Hz, 3H, c-12), 1.58 (m, 2H , c-6).
나머지 OH와 NH2(br.1-5근방).Remaining OH and NH 2 (near br. 1-5).
< 실시예 10 ><Example 10>
이다루비신-L-아스파르테이트(7c)의 제조Preparation of Idarubicin-L-aspartate (7c)
실시예 8와 동일한 방법으로 하여 목적 화합물을 제조한다.In the same manner as in Example 8, the target compound was prepared.
총수율: 39%Total yield: 39%
[α]D 20= + 81.34(C: 0.023,클로로포름)[a] D 2 ° = + 81.34 (C: 0.023, Chloroform)
IR스펙트럼IR spectrum
3400-3550(수산기), 3000-3050(페닐), 1700-1720(카르보닐)3400-3550 (hydroxyl group), 3000-3050 (phenyl), 1700-1720 (carbonyl)
1H-NMR스펙트럼(CDCl3, ppm) 1 H-NMR spectrum (CDCl 3 , ppm)
13.62(S, 1H, OH), 13.64(s, 1H, OH), 7.84(dd, J=7.55, 1.1 Hz, 1H, C-10)13.62 (S, 1H, OH), 13.64 (s, 1H, OH), 7.84 (dd, J = 7.55, 1.1 Hz, 1H, C-10)
7.56(t, J=8.7Hz, 1H, C-13), 7.42(dd, J=8.37, 1.15Hz, 1H, C-14), 4.88(m, 1H, c-2)7.56 (t, J = 8.7 Hz, 1H, C-13), 7.42 (dd, J = 8.37, 1.15 Hz, 1H, C-14), 4.88 (m, 1H, c-2)
4.89(m, 1H, c-4), 4.78(s, 2H, c-11), 4.04(s, 2H, c-15), 3.88(m, 1H, c-9)3.52(m, 1H, c-7)4.89 (m, 1H, c-4), 4.78 (s, 2H, c-11), 4.04 (s, 2H, c-15), 3.88 (m, 1H, c-9) 3.52 (m, 1H, c -7)
3.37(m, 2H, c-3), 3.37(m, 1H, c-17), 3.05(m, 1H, c-8), 2.59(d, J=6.5Hz, 2H, c-16), 2.02(m, 2H, c-5)3.37 (m, 2H, c-3), 3.37 (m, 1H, c-17), 3.05 (m, 1H, c-8), 2.59 (d, J = 6.5 Hz, 2H, c-16), 2.02 (m, 2H, c-5)
1.67(d, J=6.5Hz, 3H, CH3, c-12), 1.59(m, 1H, c-9), 나머지 OH와 NH2(br. 1-5근방)1.67 (d, J = 6.5 Hz, 3H, CH3, c-12), 1.59 (m, 1H, c-9), remaining OH and NH2 (near Br-5)
< 실시예 11 ><Example 11>
이다루비신-피루베이트 (8c)의 제조Preparation of Idarubicin-Pyruvate (8c)
실시예 9와 동일한 방법으로 하여 목적 화합물을 제조한다.In the same manner as in Example 9, the target compound was prepared.
총수율:42%Total yield: 42%
[α]D 20= + 56.28(C: 0.027,클로로포름)[a] D 2 ° = + 56.28 (C: 0.027, Chloroform)
IR스펙트럼IR spectrum
3400-3550(수산기), 3000-3050(페닐), 1690-1720(카르보닐)3400-3550 (hydroxyl group), 3000-3050 (phenyl), 1690-1720 (carbonyl)
1H-NMR스펙트럼(CDCl3, ppm) 1 H-NMR spectrum (CDCl 3 , ppm)
13.72(s, 1H, OH), 13.70(S, 1H, OH),12.57(S, 1H, OH), 7.84(dd, J=7.5, 1.15Hz, 1H, c-10), 7.56(t, J=8.3 Hz, 1H, c-13),13.72 (s, 1H, OH), 13.70 (S, 1H, OH), 12.57 (S, 1H, OH), 7.84 (dd, J = 7.5, 1.15 Hz, 1H, c-10), 7.56 (t, J = 8.3 Hz, 1H, c-13),
7.41(dd, J=8.3, 1.15 Hz, 1H, c-14), 4.89(m, 1H, c-2),4.85(s, 2H, c-11), 4.04(s, 2H, c-15),7.41 (dd, J = 8.3, 1.15 Hz, 1H, c-14), 4.89 (m, 1H, c-2), 4.85 (s, 2H, c-11), 4.04 (s, 2H, c-15) ,
3.91(m, 1H, c-7), 3.36(dd, J=3.9, 13.3 Hz, 2H, c-3), 3.51(m, 1H, c-7), 3.05(m, 1H, c-8),3.91 (m, 1H, c-7), 3.36 (dd, J = 3.9, 13.3 Hz, 2H, c-3), 3.51 (m, 1H, c-7), 3.05 (m, 1H, c-8) ,
2.15(s, 3H, c-16), 2.02(dd, J=13.3, 6.33 Hz, 2H, c-5), 1.68(d, J=6.4Hz, 3H, c-12),1.58(m, 2H, c-6).2.15 (s, 3H, c-16), 2.02 (dd, J = 13.3, 6.33 Hz, 2H, c-5), 1.68 (d, J = 6.4 Hz, 3H, c-12), 1.58 (m, 2H , c-6).
나머지 OH와 NH2(br.1-5근방).Remaining OH and NH 2 (near br. 1-5).
< 실시예 12 ><Example 12>
4'-메톡시다우노마이신-L-아스파르테이트 (7d)의 제조Preparation of 4'-methoxydanomycin-L-aspartate (7d)
실시예 1,3,4,6와 동일한 방법으로 하여 목적 화합물을 제조한다.In the same manner as in Example 1,3,4,6, the target compound was prepared.
총수율: 32%Total yield: 32%
[α]D 20= + 86.89(C: 0.024,클로로포름)[a] D 2 ° = + 86.89 (C: 0.024, Chloroform)
IR스펙트럼IR spectrum
3400-3550(수산기), 3000-3050(페닐), 1700-1720(카르보닐)3400-3550 (hydroxyl group), 3000-3050 (phenyl), 1700-1720 (carbonyl)
1H-NMR스펙트럼(CDCl3, ppm) 1 H-NMR spectrum (CDCl 3 , ppm)
13.72(S, 1H, OH), 13.74(s, 1H, OH), 7.84(dd, J=7.5, 1.15 Hz, 1H, C-10)13.72 (S, 1H, OH), 13.74 (s, 1H, OH), 7.84 (dd, J = 7.5, 1.15 Hz, 1H, C-10)
7.56(t, J=8.3Hz, 1H, C-13), 7.42(dd, J=8.37, 1.1Hz, 1H, C-14), 4.88(m, 1H, c-2)7.56 (t, J = 8.3 Hz, 1H, C-13), 7.42 (dd, J = 8.37, 1.1 Hz, 1H, C-14), 4.88 (m, 1H, c-2)
4.89(m, 1H, c-4), 4.78(s, 2H, c-11), 4.04(s, 3H, OMe, c-15), 3.94(s, 1H, OMe), 3.88(m, 1H, c-9)3.52(m, 1H, c-7)4.89 (m, 1H, c-4), 4.78 (s, 2H, c-11), 4.04 (s, 3H, OMe, c-15), 3.94 (s, 1H, OMe), 3.88 (m, 1H, c-9) 3.52 (m, 1H, c-7)
3.37(m, 2H, c-3), 3.37(m, 1H, c-17), 3.05(m, 1H, c-8), 2.59(d, J=6.6Hz, 2H, c-16), 2.02(m, 2H, c-5)3.37 (m, 2H, c-3), 3.37 (m, 1H, c-17), 3.05 (m, 1H, c-8), 2.59 (d, J = 6.6 Hz, 2H, c-16), 2.02 (m, 2H, c-5)
1.67(d, J=6.4Hz, 3H, CH3, c-12), 1.59(m, 1H, c-9), 나머지 OH와 NH2(br. 1-5근방)1.67 (d, J = 6.4 Hz, 3H, CH3, c-12), 1.59 (m, 1H, c-9), remaining OH and NH2 (near Br-5)
< 실시예 13 ><Example 13>
4'-메톡시다우노마이신-피루베이트 (8d)의 제조Preparation of 4'-methoxydaunomycin-pyruvate (8d)
실시예 1, 3, 5, 7와 동일한 방법으로 하여 목적 화합물을 제조한다.In the same manner as in Examples 1, 3, 5, and 7, the target compound was prepared.
총수율: 38%Total yield: 38%
[α]D 20= + 79.09(C: 0.022,클로로포름)[a] D 2 ° = + 79.09 (C: 0.022, Chloroform)
IR스펙트럼IR spectrum
3400-3550(수산기), 3000-3050(페닐), 1700-1720(카르보닐)3400-3550 (hydroxyl group), 3000-3050 (phenyl), 1700-1720 (carbonyl)
1H-NMR스펙트럼(CDCl3, ppm) 1 H-NMR spectrum (CDCl 3 , ppm)
13.72(s, 1H, OH), 13.74(S, 1H, OH), 7.84(dd, J=7.5, 1.15Hz, 1H, c-10), 7.56(t, J=8.3 Hz, 1H, c-13),13.72 (s, 1H, OH), 13.74 (S, 1H, OH), 7.84 (dd, J = 7.5, 1.15 Hz, 1H, c-10), 7.56 (t, J = 8.3 Hz, 1H, c-13 ),
7.41(dd, J=8.3, 1.15 Hz, 1H, c-14), 4.89(m, 1H, c-2),4.85(s, 2H, c-11), 4.04(s, 3H, OMe, c-15),3.94(s, 1H, OMe) 3.91(m, 1H, c-7), 3.36(dd, J=3.9, 13.3 Hz, 2H, c-3), 3.51(m, 1H, c-7), 3.05(m, 1H, c-8),7.41 (dd, J = 8.3, 1.15 Hz, 1H, c-14), 4.89 (m, 1H, c-2), 4.85 (s, 2H, c-11), 4.04 (s, 3H, OMe, c- 15), 3.94 (s, 1H, OMe) 3.91 (m, 1H, c-7), 3.36 (dd, J = 3.9, 13.3 Hz, 2H, c-3), 3.51 (m, 1H, c-7) , 3.05 (m, 1H, c-8),
2.15(s, 3H, c-16), 2.02(dd, J=13.3, 6.33 Hz, 2H, c-5), 1.68(d, J=6.5Hz, 3H, c-12),1.58(m, 2H, c-6).2.15 (s, 3H, c-16), 2.02 (dd, J = 13.3, 6.33 Hz, 2H, c-5), 1.68 (d, J = 6.5 Hz, 3H, c-12), 1.58 (m, 2H , c-6).
나머지 OH와 NH2(br.1-5근방).Remaining OH and NH 2 (near br. 1-5).
< 실시예 14 ><Example 14>
4'-데옥시다우노마이신-L-아스파르테이트(7e)의 제조Preparation of 4'-deoxydaomycin-L-aspartate (7e)
실시예 12와 동일한 방법으로 하여 목적 화합물을 제조한다.In the same manner as in Example 12, the target compound was prepared.
총수율: 34%Total yield: 34%
[α]D 20= + 81.34(C: 0.027,클로로포름)[a] D 2 ° = + 81.34 (C: 0.027, Chloroform)
IR스펙트럼IR spectrum
3400-3550(수산기), 3000-3050(페닐), 1690-1720(카르보닐)3400-3550 (hydroxyl group), 3000-3050 (phenyl), 1690-1720 (carbonyl)
1H-NMR스펙트럼(CDCl3, ppm) 1 H-NMR spectrum (CDCl 3 , ppm)
13.72(S, 1H, OH), 13.74(s, 1H, OH), 7.84(dd, J=7.5, 1.15 Hz, 1H, C-10)13.72 (S, 1H, OH), 13.74 (s, 1H, OH), 7.84 (dd, J = 7.5, 1.15 Hz, 1H, C-10)
7.56(t, J=8.3Hz, 1H, C-13), 7.42(dd, J=8.3, 1.15Hz, 1H, C-14), 4.88(m, 1H, c-2)7.56 (t, J = 8.3 Hz, 1H, C-13), 7.42 (dd, J = 8.3, 1.15 Hz, 1H, C-14), 4.88 (m, 1H, c-2)
4.89(m, 1H, c-4), 4.78(s, 2H, c-11), 4.04(s, 3H, OMe, c-15), 3.88(m, 1H, c-9)3.52(m, 1H, c-7)4.89 (m, 1H, c-4), 4.78 (s, 2H, c-11), 4.04 (s, 3H, OMe, c-15), 3.88 (m, 1H, c-9) 3.52 (m, 1H , c-7)
3.37(m, 2H, c-3), 3.37(m, 1H, c-17), 3.05(m, 1H, c-8), 2.59(d, J=6.65Hz, 2H, c-16), 2.02(m, 2H, c-5)3.37 (m, 2H, c-3), 3.37 (m, 1H, c-17), 3.05 (m, 1H, c-8), 2.59 (d, J = 6.65 Hz, 2H, c-16), 2.02 (m, 2H, c-5)
1.67(d, J=6.45Hz, 3H, CH3, c-12), 1.59(m, 1H, c-9), 나머지 OH와 NH2(br. 1-5근방)1.67 (d, J = 6.45 Hz, 3H, CH3, c-12), 1.59 (m, 1H, c-9), remaining OH and NH2 (near Br-5)
< 실시예 15 ><Example 15>
4'-데옥시다우노마이신-피루베이트(8e)의 제조Preparation of 4'-deoxydaomycin-pyruvate (8e)
실시예 13와 동일한 방법으로 하여 목적 화합물을 제조한다.In the same manner as in Example 13, the target compound was prepared.
총수율: 38%Total yield: 38%
[α]D 20= +87.79(C: 0.025,클로로포름)[a] D 2 ° = +87.79 (C: 0.025, Chloroform)
IR스펙트럼IR spectrum
3400-3550(수산기), 3000-3050(페닐), 1690-1720(카르보닐)3400-3550 (hydroxyl group), 3000-3050 (phenyl), 1690-1720 (carbonyl)
1H-NMR스펙트럼(CDCl3, ppm) 1 H-NMR spectrum (CDCl 3 , ppm)
13.72(s, 1H, OH), 13.74(S, 1H, OH), 7.84(dd, J=7.5, 1.15Hz, 1H, c-10), 7.56(t, J=8.3 Hz, 1H, c-13),13.72 (s, 1H, OH), 13.74 (S, 1H, OH), 7.84 (dd, J = 7.5, 1.15 Hz, 1H, c-10), 7.56 (t, J = 8.3 Hz, 1H, c-13 ),
7.41(dd, J=8.3, 1.15 Hz, 1H, c-14), 4.89(m, 1H, c-2),4.85(s, 2H, c-11), 4.04(s, 3H, OMe, c-15),7.41 (dd, J = 8.3, 1.15 Hz, 1H, c-14), 4.89 (m, 1H, c-2), 4.85 (s, 2H, c-11), 4.04 (s, 3H, OMe, c- 15),
3.91(m, 1H, c-7), 3.36(dd, J=3.3, 13.3 Hz, 2H, c-3), 3.51(m, 1H, c-7), 3.05(m, 1H, c-8),3.91 (m, 1H, c-7), 3.36 (dd, J = 3.3, 13.3 Hz, 2H, c-3), 3.51 (m, 1H, c-7), 3.05 (m, 1H, c-8) ,
2.15(s, 3H, c-16), 2.02(dd, J=13.3, 6.33 Hz, 2H, c-5), 1.68(d, J=6.5Hz, 3H, c-12),1.58(m, 2H, c-6).2.15 (s, 3H, c-16), 2.02 (dd, J = 13.3, 6.33 Hz, 2H, c-5), 1.68 (d, J = 6.5 Hz, 3H, c-12), 1.58 (m, 2H , c-6).
나머지 OH와 NH2(br.1-5근방).Remaining OH and NH 2 (near br. 1-5).
< 실시예 16 ><Example 16>
3'-불소다우노마이신-L-아스파르테이트 (7f)의 제조Preparation of 3′-Fluorodaomycin-L-aspartate (7f)
실시예 12와 동일한 방법으로 하여 목적 화합물을 제조한다.In the same manner as in Example 12, the target compound was prepared.
총수율: 28%Total yield: 28%
[α]D 20= + 91.56(C: 0.029,클로로포름)[a] D 2 ° = + 91.56 (C: 0.029, Chloroform)
IR스펙트럼IR spectrum
3400-3550(수산기), 3000-3050(페닐), 1700-1720(카르보닐)3400-3550 (hydroxyl group), 3000-3050 (phenyl), 1700-1720 (carbonyl)
1H-NMR스펙트럼(CDCl3, ppm) 1 H-NMR spectrum (CDCl 3 , ppm)
13.62(S, 1H, OH), 13.71(s, 1H, OH), 7.86(dd, J=7.5, 1.15 Hz, 1H, C-10)13.62 (S, 1H, OH), 13.71 (s, 1H, OH), 7.86 (dd, J = 7.5, 1.15 Hz, 1H, C-10)
7.56(t, J=8.7Hz, 1H, C-13), 7.42(dd, J=8.7, 1.15Hz, 1H, C-14), 4.88(m, 1H, c-2)7.56 (t, J = 8.7 Hz, 1H, C-13), 7.42 (dd, J = 8.7, 1.15 Hz, 1H, C-14), 4.88 (m, 1H, c-2)
4.89(m, 1H, c-4), 4.78(s, 2H, c-11), 4.04(s, 3H, OMe, c-15), 3.88(m, 1H, c-9)3.52(m, 1H, c-7)4.89 (m, 1H, c-4), 4.78 (s, 2H, c-11), 4.04 (s, 3H, OMe, c-15), 3.88 (m, 1H, c-9) 3.52 (m, 1H , c-7)
3.37(m, 2H, c-3), 3.37(m, 1H, c-17), 3.05(m, 1H, c-8), 2.59(d, J=6.5Hz, 2H, c-16), 2.02(m, 2H, c-5)3.37 (m, 2H, c-3), 3.37 (m, 1H, c-17), 3.05 (m, 1H, c-8), 2.59 (d, J = 6.5 Hz, 2H, c-16), 2.02 (m, 2H, c-5)
1.67(d, J=6.5Hz, 3H, CH3, c-12), 1.59(m, 1H, c-9), 나머지 OH와 NH2(br. 1-5근방)1.67 (d, J = 6.5 Hz, 3H, CH3, c-12), 1.59 (m, 1H, c-9), remaining OH and NH2 (near Br-5)
< 실시예 17 ><Example 17>
3'-불소다우노마이신-피루베이트 (8f)의 제조Preparation of 3′-Fluorodaomycin-pyruvate (8f)
실시예 13와 동일한 방법으로 하여 목적 화합물을 제조한다.In the same manner as in Example 13, the target compound was prepared.
총수율: 32%Total yield: 32%
[α]D 20= + 101.09(C: 0.027,클로로포름)[a] D 2 ° = +101.09 (C: 0.027, Chloroform)
IR스펙트럼IR spectrum
3400-3550(수산기), 3000-3050(페닐), 1700-1720(카르보닐)3400-3550 (hydroxyl group), 3000-3050 (phenyl), 1700-1720 (carbonyl)
1H-NMR스펙트럼(CDCl3, ppm) 1 H-NMR spectrum (CDCl 3 , ppm)
13.77(s, 1H, OH), 13.74(S, 1H, OH), 7.80(dd, J=7.55, 1.15Hz, 1H, c-10), 7.56(t, J=8.7 Hz, 1H, c-13),13.77 (s, 1H, OH), 13.74 (S, 1H, OH), 7.80 (dd, J = 7.55, 1.15 Hz, 1H, c-10), 7.56 (t, J = 8.7 Hz, 1H, c-13 ),
7.41(dd, J=8.3, 1.15 Hz, 1H, c-14), 4.89(m, 1H, c-2),4.85(s, 2H, c-11), 4.01(s, 3H, OMe, c-15),7.41 (dd, J = 8.3, 1.15 Hz, 1H, c-14), 4.89 (m, 1H, c-2), 4.85 (s, 2H, c-11), 4.01 (s, 3H, OMe, c- 15),
3.91(m, 1H, c-7), 3.36(dd, J=3.9, 13.3 Hz, 2H, c-3), 3.31(m, 1H, c-7), 3.25(m, 1H, c-8),3.91 (m, 1H, c-7), 3.36 (dd, J = 3.9, 13.3 Hz, 2H, c-3), 3.31 (m, 1H, c-7), 3.25 (m, 1H, c-8) ,
2.15(s, 3H, c-16), 2.02(dd, J=13.3, 6.3 Hz, 2H, c-5), 1.68(d, J=6.4Hz, 3H, c-12),1.58(m, 2H, c-6).2.15 (s, 3H, c-16), 2.02 (dd, J = 13.3, 6.3 Hz, 2H, c-5), 1.68 (d, J = 6.4 Hz, 3H, c-12), 1.58 (m, 2H , c-6).
나머지 OH와 NH2(br.1-5근방).Remaining OH and NH 2 (near br. 1-5).
더욱이 본 발명자는 상기 일반구조식 화합물(Ⅰ)이 기존의 안트라사이클린 글리코사이드계 항암제와 유사한 항종양 활성을 가지면서도 기대한 바와 같이 심장독성이 경감됨을 알게 되었다. 따라서 상기식의 화합물(Ⅰ)은 낮은 심장독성과 후술한 바와 같이 우수한 항종양 활성을 가지므로 항종양제로서의 용도가 고려된다.Furthermore, the present inventors have found that the general structural compound (I) has antitumor activity similar to that of the existing anthracycline glycoside-based anticancer agent, but also reduces cardiac toxicity as expected. Therefore, the compound (I) of the above formula has low cardiotoxicity and excellent anti-tumor activity as described below, so its use as an anti-tumor agent is contemplated.
따라서 첫째로 본 발명의 요지는 상기 일반구조식(Ⅰ) 혹은 도 1의 7과 8화합물로 표시되는 안트라사이클린 유도체에 있다. 즉 본 발명에 의한 일반구조식(Ⅰ)화합물 혹은 도 1의 7과 8화합물은 하기와 같이 명명된다.Therefore, firstly, the gist of the present invention lies in the anthracycline derivative represented by the above general structural formula (I) or 7 and 8 compounds of FIG. That is, the general structural formula (I) compound or 7 and 8 compounds of FIG. 1 according to the present invention are named as follows.
(1) (본 발명화합물 번호1, 도식 7a화합물) 다우노마이신-L-아스파르테이트(1) (Compound No. 1 of the Invention, Compound 7a) Daunomycin-L-Aspartate
(2) (본 발명화합물 번호2, 도식 7b화합물) 카르미노마이신-L-아스파르테이트(2) (Compound No. 2 of the present invention, Scheme 7b Compound) Carminomycin-L-Aspartate
(3) (본 발명화합물 번호3, 도식 7c화합물) 이다루비신-L-아스파르테이트(3) (Compound No. 3 of the present invention, Scheme 7c Compound) Idarubicin-L-aspartate
(4) (본 발명화합물 번호4, 도식 7d화합물) 4'-메톡시다우노마이신-L-아스파르테이트(4) (Compound No. 4 of the present invention, Scheme 7d compound) 4'-methoxy daunomycin-L-aspartate
(5) (본 발명화합물 번호5, 도식 7e화합물) 4'-데옥시다우노마이신-L-아스파르테이트(5) (Compound No. 5 of the present invention, Scheme 7e Compound) 4'-deoxydaomycin-L-aspartate
(6) (본 발명화합물 번호6, 도식 7f화합물) 3'-불소다우노마이신-L-아스파르테이트(6) (Compound No. 6 of the present invention, Scheme 7f compound) 3'-Fluorodaomycin-L-aspartate
(7) (본 발명화합물 번호7, 도식 8a화합물) 다우노마이신-피루베이트(7) (Compound No. 7 of the Invention, Scheme 8a Compound) daunomycin-pyruvate
(8) (본 발명화합물 번호8, 도식 8b화합물) 카르미노마이신-피루베이트(8) (Compound No. 8 of the present invention, Scheme 8b Compound) Carminomycin-pyruvate
(9) (본 발명화합물 번호9, 도식 8c화합물) 이다루비신-피루베이트(9) (Compound No. 9 of the present invention, Scheme 8c Compound) Idarubicin-pyruvate
(10) (본 발명화합물 번호10, 도식 8d화합물) 4'-메톡시다우노마이신-피루베이트(10) (Compound No. 10 of the present invention, Scheme 8d Compound) 4'-methoxydaunmycin-pyruvate
(11) (본 발명화합물 번호11, 도식 8e화합물) 4'-데옥시다우노마이신-피루베이트(11) (Compound No. 11 of the present invention, Scheme 8e Compound) 4'-deoxydaunomycin-pyruvate
(12) (본 발명화합물 번호12, 도식 8f화합물) 3'-불소다우노마이신-피루베이트(12) (Compound No. 12 of the Invention, Scheme 8f) 3'-Fluorodaomycin-pyruvate
생물학적 활성Biological activity
본 발명에 의한 일반식(Ⅰ)의 화합물은 실험동물종양에 대하여 우수한 항종양 활성을 가지면서도, 그 항종양 활성이 공지의 안트라사이클린계 항암물질인 다우노마이신, 아드리아마이신등과 유사하지만 그 심장독성이 매우 경감된 것이 시험에 의해 확인되었다.The compound of general formula (I) according to the present invention has excellent antitumor activity against experimental animal tumors, but its antitumor activity is similar to that of known anthracycline anticancer substances such as daunomycin, adriamycin, and the like. Very low toxicity was confirmed by the test.
이들 신규 항암약물들에 의한 항종양 시험예는 다음과 같이 실시하였다.The antitumor test example by these new anticancer drugs was performed as follows.
< 시험예 1 ><Test Example 1>
실험동물종양에 대한 항종양 효과를 평가하기 위하여, 본 실험에 사용한 L1210생쥐 백혈병에 대한 항암제의 스크리닝법은 미국립 암연구소의 표준 스크리닝 방법으로 행하였다.(Geran,R.T, Cancer Chemother. Rep. part 3)In order to evaluate the antitumor effect on experimental animal tumors, the screening method of anticancer agent against L1210 mouse leukemia used in this experiment was performed by a standard screening method of the American Cancer Institute. (Geran, RT, Cancer Chemother.Rep. Part 3)
L1210복수육종 세포를 이식한 CDF생쥐의 복강으로 부터 L1210생쥐복수 육종세포를 취하여 생리식염수 미리리터당 106개가 되게 현탁하여 생쥐 1마리당 105개의 세포를 복강내 투여하고 1일이 경과한 후부터 9일간 매일 약물을 복강내 투여하고 60일간 관찰하였다. 대조구(생리 식염수 투여)의 마우스 생존 일수와 비교하여 산정한 마우스의 연명율(T/C, 퍼센트)을 구했다. 비교를 하기 위하여 사용한 공지의 아드리아마이신 염산염과 다우노루비신 염산염등 안트라사이클린계 항암약물, 그리고 신규 화합물들은 생리식염수에 용해하여 사용하여 동일하게 실험했다. 그 결과는 약물을 처리한 동물의 중간생존시간대 생리식염수를 처리한 동물의 중간 생존시간에 100을 곱한 비율로서 T/C퍼센트를 제 1표에 표시하였다.L1210 mouse plural sarcoma cells were taken from the abdominal cavity of CDF mice transplanted with L1210 plural sarcoma cells, suspended at 10 6 per ml of saline solution, and 10 5 cells per mouse were injected intraperitoneally for 9 days after 1 day. The drug was administered intraperitoneally daily and observed for 60 days. The survival rate (T / C, percent) of the calculated mice was compared with the number of days of survival of mice in the control group (physiological saline administration). Anthracycline anticancer drugs such as known adriamycin hydrochloride and daunorubicin hydrochloride, and novel compounds used for comparison were tested in the same manner by dissolving in physiological saline. The results are shown in Table 1 as T / C percent as the ratio of the median survival time of the drug-treated animals to the median survival time of the saline-treated animals multiplied by 100.
표 1. L1210생쥐 백혈병에 대한 항종양 효과Table 1. Antitumor Effects on L1210 Mouse Leukemia
약물 처리군의 중간생존기간Interim survival period of drug treatment group
a): --------------------------------------- × 100(%)a): --------------------------------------- × 100 (%)
생리식염수 처리 대조군의 중간생존기간Interim survival period of saline treated control group
b): 5일째 기준(투여 방법: 모든 시료를 생리식염수에 용해시켜 1일 부터 9일 동안 매일 0.1미리리터씩 9회 복강내 투여)b): day 5 (administration method: all samples were dissolved in physiological saline and administered intraperitoneally in a dose of 0.1 ml per day for 9 to 9 days)
상기 시험 예1에서 비교약제로서 사용한 아드리아마이신 경우는 L1210세포를 접종시킨 마우스에 대하여 투여량 2.5mg/kg/일-5mg/kg/일로 투여한 경우에 연명율(T/C, %)이 282-195%인 정도의 항종양효과를 나타내고 있다. 또한 이의 아스파르테이트 및 피루베이트 신규 유도체 경우도 이와 유사한 항암효과를 나타내고 있다. 이는 본 발명의 신규 안트라사이클린 화합물의 항종양활성이 임상에서 실용화 할 수 있는 항종양제로서 극히 유용하거나 기존의 항암제와 같이 각종 종양치료에 유용할 것으로 기대된다.In the case of adriamycin used as a comparative drug in Test Example 1, when the dose of 2.5 mg / kg / day-5 mg / kg / day was administered to mice inoculated with L1210 cells, the elongation rate (T / C,%) was 282. It has antitumor effect of -195%. In addition, aspartate and pyruvate derivatives thereof have similar anticancer effects. This antitumor activity of the novel anthracycline compound of the present invention is expected to be extremely useful as an antitumor agent that can be put to practical use in clinical practice, or to be useful for treating various tumors as conventional anticancer agents.
또한 일반식 (Ⅰ)으로 표시되는 본 발명의 안트라사이클린 화합물은 생체내에서 항종양작용을 할때 세포내의 에스테르 분해효소에 의해 신규화합물의 에스테르결합이 분해되어 기존의 항암제로 존재할 수 있기 때문에 기존의 항암제와 유사한 효능을 나타내는 것으로 생각된다.In addition, since the anthracycline compound of the present invention represented by the general formula (I) may be present as an existing anticancer agent by breaking down the ester bond of the new compound by intracellular esterases during antitumor action in vivo It is thought to show similar efficacy as anticancer drugs.
예를 들어 본 발명화합물 번호1은 세포내 에스테르 분해 효소에 의해 아드리아마이신과 아스파르테이트로 분해되어 생성된 아드리아마이신이 항암작용을 하는 것으로 추정된다.For example, the compound No. 1 of the present invention is estimated to have anti-cancer activity of adriamycin produced by decomposition with adriamycin and aspartate by intracellular esterase.
한편 신규 항암약물들에 대한 심장독성시험은 다음과 같이 실시하였다.Meanwhile, the cardiotoxicity test for new anticancer drugs was conducted as follows.
< 시험예 2 ><Test Example 2>
기존 항암제 대비 신규 항암물질의 심근독성 평가Myocardial Toxicity Evaluation of Novel Anticancer Drugs
1) 실험동물 및 실험군 설정1) Experimental animal and experimental group
실험동물은 체중 200g 내외의 웅성 Sprague-Dawley계 흰쥐를 사용하며, 환경 및 감염에 의한 스트레스를 배제하기 위하여 동물실을 22oC 항온과 SPF 조건으로 유지시킨다.The experimental animals are male Sprague-Dawley rats with a body weight of about 200 g, and the animal room is maintained at 22 o C constant temperature and SPF to exclude stress caused by the environment and infection.
시료를 하기와 같이 제조하여 심장독성시험용으로 사용하였다.Samples were prepared as follows and used for the cardiotoxicity test.
1군 대조군, 2군 아드리아마이신 투여군(20ug/KH 용액 ml) 3군 다우노마이신 투여군(20ug/KH 용액 ml), 4군 본발명 화합물 번호 1 투여군(20ug/KH 용액 ml), 5군 본발명 화합물 번호 7 투여군(20ug/KH 용액 ml), 6군 카르미노마이신 투여군 투여군(20ug/KH 용액 ml), 7군 본발명 화합물 번호 2 투여군(20ug/KH 용액 ml), 8군 본발명 화합물 번호 8 투여군(20ug/KH용액 ml), 9군 이다루비신 투여군 투여군(20ug/KH 용액 ml), 10군 본발명 화합물 번호 3투여군(20ug/KH 용액 ml), 11군 본발명 화합물 번호9 투여군(20ug/KH 용액 ml). 12군 4'-메톡시다우노마이신 투여군 투여군(20ug/KH 용액 ml), 13군 본발명 화합물 번호 4투여군(20ug/KH 용액 ml), 14군 본발명 화합물 번호10 투여군(20ug/KH 용액 ml). 15군 4'-데옥시다우노마이신 투여군 투여군(20ug/KH 용액 ml), 16군 본발명 화합물 번호 5투여군(20ug/KH 용액 ml), 17군 본발명 화합물 번호11 투여군(20ug/KH 용액 ml), 18군 3'-불소다우노마이신 투여군 투여군(20ug/KH 용액 ml), 19군 본발명 화합물 번호 6투여군(20ug/KH 용액 ml), 20군 본발명 화합물 번호12 투여군(20ug/KH 용액 ml).Group 1 Control Group 2 Adriamycin Administration Group (20 ug / KH Solution ml) Group 3 Daunomycin Administration Group (20 ug / KH Solution ml), Group 4 Invention Compound No. 1 Administration Group (20 ug / KH Solution ml), Group 5 Invention Compound No. 7 administration group (20 ug / KH solution ml), Group 6 carminomycin administration group administration group (20 ug / KH solution ml), Group 7 Invention Compound No. 2 administration group (20 ug / KH solution ml), Group 8 Invention Compound No. 8 Administration group (20 ug / KH solution ml), Group 9 idarubicin administered group (20 ug / KH solution ml), group 10 Invention Compound No. 3 administration group (20 ug / KH solution ml), Group 11 Invention Compound No. 9 administration group (20 ug) Ml of KH solution). Group 12 4'-methoxydaunomycin-administered group (20 ug / KH solution ml), Group 13 invention compound No. 4 administration group (20 ug / KH solution ml), Group 14 invention compound No. 10 administration group (20 ug / KH solution ml) ). Group 15 '4'-deoxydaomycin administered group (20 ug / KH solution ml), Group 16 invented compound No. 5 administration group (20 ug / KH solution ml), Group 17 invented compound No. 11 administered group (20 ug / KH solution ml) ), Group 18 3'-fluorodaomycin-administered group (20 ug / KH solution ml), Group 19 invention compound No. 6 administration group (20 ug / KH solution ml), Group 20 invention compound No. 12 administration group (20 ug / KH solution) ml).
2) 적출심장의 심기능 측정2) Measurement of cardiac function of the extracted heart
실험동물을 각군 10마리씩 나누고 각 실험쥐에 30 mg/kg 용량으로 펀토바비탈 나트륨(sodium pentobarbital)을 복강주사하여 마취시킨 후 인공호흡 상태에서 흉부를 절개한다. 대동맥을 절개하고 삽입관을 삽입한 다음 폐장을 포함한 주위조직을 제거하고 곧이어 랑겐도르푸(Langendorff) 관류장치에 대동맥 삽입관을 연결시켜 역방향 관류를 하다. 관류액은 95% O2-5% CO2(Normoxic Condition)로 포화시킨 크렙스-한스라이트(Krebs-Henseleit, KH)완충용액 (염화나트륨 118 mM, 중탄산나트륨 27.2 mM, 염화칼륨 4.8 mM, 황산마그네슘 1.2mM, 중수소인산칼륨 1 mM, 염화칼슘 1.25 mM, 글루코스 10 mM, pH 7.4 )을 80 Cm 물의 일정 압력으로 관류하고, 심장 온도를 37oC로 일정하게 유지한다. KH용액으로 15분 동안 관류하여 심기능이 안정화되면 대동맥 삽입관에 장치된 3-방향 코크를 통해 안트라사이클린계 항암약물(20ug/KH용액 ml)을 1시간 동안 투여한다.Each animal was divided into 10 groups, and anesthetized by intraperitoneal injection of pentobarbital with sodium pentobarbital at a dose of 30 mg / kg. The aorta is dissected, the insertion tube is inserted, the surrounding tissue, including the lung, is removed, and the aortic insertion tube is connected to the Langendorff perfusion device for reverse perfusion. The perfusion solution was buffered with Krebs-Henseleit (KH) saturated with 95% O 2 -5% CO 2 (Normoxic Condition) (sodium chloride 118 mM, sodium bicarbonate 27.2 mM, potassium chloride 4.8 mM, 1.2 mM magnesium sulfate). , Potassium deuterium phosphate 1 mM, calcium chloride 1.25 mM, glucose 10 mM, pH 7.4) is perfused at a constant pressure of 80 Cm water and the heart temperature is kept constant at 37 ° C. When the cardiac function is stabilized by perfusion for 15 minutes with KH solution, anthracycline anticancer drug (20ug / ml of KH solution) is administered for 1 hour through a 3-way cork installed in the aortic intubation tube.
심기능의 지표로서 심박수와 좌심실 압력을 측정한다. 좌심실 압력은 끝에 풍선이 붙은 20G의 플라스틱 삽입관을 승모판을 통해서 좌심실에 삽입하고 압력변환기(Stathan P23XL)에 연결한 후, 생리기록계를 이용해서 측정한다. 이때 안정화된 심장의 좌심실 이완기말 압력(left ventricular end-diastolic pressure, LVEDP)이 2 mmHg가 되도록 풍선을 팽창시킨다. 심박수는 1분간 기록된 수축 횟수로 알 수 있으며 좌심실 압력 중 이완기말 압력은 심근의 수축(contracture) 정도를, 수축기말 압력과 이완기말 압력의 차이(developed pressure)는 심장의 수축력을 나타내는 지표로 사용한다. 심장의 혈액순환 능력(심기능 지수)은 수축기말 압력과 이완기말 압력의 차이에 심박수를 곱하여 산출하여 평가한다.Heart rate and left ventricular pressure are measured as indicators of cardiac function. Left ventricular pressure is measured using a physiological recorder by inserting a 20G plastic insertion tube with a balloon at the end through the mitral valve and connecting it to a pressure transducer (Stathan P23XL). The balloon is inflated so that the left ventricular end-diastolic pressure (LVEDP) of the stabilized heart is 2 mmHg. The heart rate can be measured by the number of contractions recorded for 1 minute, and the diastolic pressure in the left ventricular pressure is used as the index of the myocardial contracture, and the difference between the systolic pressure and the diastolic pressure (developed pressure) is used as an indicator of the contractile force of the heart. do. The heart's blood circulation capacity (cardiac function index) is calculated by multiplying the difference between the systolic and diastolic pressures by the heart rate.
3) 시험결과3) Test result
(1) 기존 항암약물 대비 신규 항암물질의 심근독성 평가(1) Myocardial toxicity evaluation of new anticancer substances compared to existing anticancer drugs
기존 안트라사이클린계 항암약물 단독투여군에 비하여 신규 항암물질을 투여한 군은 심장기능 회복율이 기존 항암약물 대비 20∼40%의 개선되는 효과를 보였다.(표1) 또한 기존 안트라사이클린계 항암약물 단독투여군에 비하여 신규 항암물질을 투여한 군은 세포손상지수인 LDH유출이 50∼80% 감소되는 효과를 보였다.(표2)Compared with the conventional anthracycline-based anticancer drugs alone, the group treated with the new anticancer drug showed a 20 to 40% improvement in cardiac function recovery compared to the existing anticancer drugs (Table 1). Compared to the group treated with the new anticancer substance, LDH leakage, a cell damage index, was reduced by 50-80% (Table 2).
표 1. 기존 항암제 대비 신규 항암물질의 심장기능 개선 효과Table 1.Effect of improving cardiac function of new anticancer substance compared to existing anticancer
표2. 기존 항암약물 대비 신규 항암약물의 LDH방출억제효과Table 2. LDH release inhibitory effect of new anticancer drugs compared to existing anticancer drugs
본 발명의 신규 안트라사이클린 화합물은 항종양활성이 공지의 안트라사이클린 약물과 유사하면서도 공지의 안트라사이클린 약물보다 심장독성이 매우 경감되어 우수한 약물로 평가되고, 임상에서 실용화 할 수 있는 항종양제로서 공지의 안트라사이클린계 항암약물과 같이 각종치료에 유용하다. 또한 일반식(Ⅰ)으로 표시되는 본 발명의 안트라사이클린 화합물은 염상태로 존재하기 때문에 물에 대한 용해도가 매우 좋고 안정성도 높기 때문에 화학적으로 취급이 용이하다.The novel anthracycline compounds of the present invention have similar anti-tumor activity to known anthracycline drugs, but are significantly reduced in cardiotoxicity than known anthracycline drugs, and are evaluated as superior drugs, and are known as antitumor agents that can be put to practical use in clinical practice. It is useful for various treatments such as anthracycline anticancer drugs. In addition, since the anthracycline compound of the present invention represented by the general formula (I) is present in the salt state, the solubility in water is very good and the stability is high, and thus chemical handling is easy.
본 발명에 의하여 제공된 상기 일반식 (Ⅰ)의 화합물은 저심독성을 가지면서도 백혈병 세포 및 실험 동물종양에 대하여 우수한 항종양활성을 나타낸다. 따라서 일반식(Ⅰ)의 화합물은 악성 종양치료제로서 고형암 및 복수암 등의 처치를 위하여 사용될 수 있다. 본 발명 화합물을 실제로 투여하는 경우에는 일반으로 비 경구적으로 투여할 수 있지만 의약제제 분야에서 사용된 통상의 담체와 혼합하여 정제 또는 제제형을 경구적으로 투여할 수 있다.The compound of general formula (I) provided by the present invention has low cardiotoxicity and shows excellent antitumor activity against leukemia cells and experimental animal tumors. Therefore, the compound of general formula (I) can be used for the treatment of solid cancer and ascites cancer as a malignant tumor therapeutic agent. When the compound of the present invention is actually administered, it can be administered orally in general, but can be administered orally in tablet or formulation form by mixing with a conventional carrier used in the pharmaceutical field.
일반적인 투여 방법으로서는 동물의 경우, 복강내 주사, 피하주사, 정맥 또는 동맥의 혈관내 주사 및 국소 투여 등의 주사제로서, 사람의 경우는 정맥 또는 동맥의 혈관내 주사 또는 국소 투여 등의 주사제로서 투여되고, 이러한 투여량은 투여방법, 환자 또는 피처리 동물의 상황, 예를 들면, 연령, 체중, 성별, 감수성, 식이, 투여시간, 병용하는 약제, 환자 또는 그 병의 정도에 따라서 적당하게 변화시켜 투여하여도 좋다. 본 발명 화합물을 항종양제로서 사용하는 경우에, 아드리아마이신과 같은 정도의 투여량으로 할 수 있고, 1일 1회 마다 0.4mg/kg 내지 2mg/kg의 범위내에서 결정된다. 또한 본 발명에 의한 일반식(I)의 화합물은 그람 양성균에 대하여 항균성을 나타내고, 그람 양성군에 유래하는 질병치료제로서 상기 제제형 및 투여량으로 투여 할 수 있다.As a general method of administration, animals are administered as injections such as intraperitoneal injection, subcutaneous injection, intravenous injection and local administration of veins or arteries, and in humans as injections such as intravenous injection or local administration of veins or arteries. These dosages may be appropriately varied depending on the method of administration, the situation of the patient or treated animal, for example, age, weight, sex, sensitivity, diet, time of administration, medication used, patient or degree of disease. You may also do it. When using the compound of this invention as an anti-tumor agent, it can be set as the dose similar to adriamycin, and is determined within 0.4 mg / kg-2 mg / kg once a day. In addition, the compound of the general formula (I) according to the present invention exhibits antimicrobial activity against Gram-positive bacteria, and can be administered in the above-mentioned preparation type and dosage as a disease treatment agent derived from the Gram-positive group.
Claims (4)
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019980016348A KR19990084528A (en) | 1998-05-07 | 1998-05-07 | New anthracycline derivatives and preparation methods |
| PCT/KR1999/000220 WO1999057126A1 (en) | 1998-05-07 | 1999-05-07 | Novel anthracycline derivatives and their preparation |
| KR10-2000-7012427A KR100398289B1 (en) | 1998-05-07 | 1999-05-07 | Novel Anthracycline Derivatives and Their Preparation |
| EP99919679A EP1075484A1 (en) | 1998-05-07 | 1999-05-07 | Novel anthracycline derivatives and their preparation |
| JP2000547095A JP2002513797A (en) | 1998-05-07 | 1999-05-07 | Novel anthracycline derivative and method for producing the same |
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| KR1019980016348A KR19990084528A (en) | 1998-05-07 | 1998-05-07 | New anthracycline derivatives and preparation methods |
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| JPH0742304B2 (en) * | 1986-12-05 | 1995-05-10 | 財団法人微生物化学研究会 | Novel anthracycline derivative and method for producing the same |
| IT1272234B (en) * | 1994-05-02 | 1997-06-16 | Consiglio Nazionale Ricerche | GLUTATIONIC DERIVATIVES OF ANTHRACYCLINES AND PROCEDURE TO OBTAIN THEM. |
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