KR100948408B1 - 4-o-Carboran-1-ylphenol derivatives, a process for the preparation thereof and a pharmaceutical composition comprising the same - Google Patents
4-o-Carboran-1-ylphenol derivatives, a process for the preparation thereof and a pharmaceutical composition comprising the same Download PDFInfo
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- KR100948408B1 KR100948408B1 KR1020080016994A KR20080016994A KR100948408B1 KR 100948408 B1 KR100948408 B1 KR 100948408B1 KR 1020080016994 A KR1020080016994 A KR 1020080016994A KR 20080016994 A KR20080016994 A KR 20080016994A KR 100948408 B1 KR100948408 B1 KR 100948408B1
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- South Korea
- Prior art keywords
- ortho
- phenol
- carbonan
- formula
- bis
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- 238000000034 method Methods 0.000 title claims description 13
- 238000002360 preparation method Methods 0.000 title abstract description 13
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 41
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- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 19
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/009—Neutron capture therapy, e.g. using uranium or non-boron material
- A61K41/0095—Boron neutron capture therapy, i.e. BNCT, e.g. using boronated porphyrins
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
본 발명은 4-(오쏘-카보란-1-일)페놀 유도체, 이의 제조방법 및 이를 포함하는 약학적 조성물에 관한 것으로서, 더욱 상세하게는 4-(오쏘-카보란-1-일)-2-(N,N-다이알킬아미노메틸)페놀 유도체와 비스{4-(오쏘-카보란-1-일)-2-하이드록시벤질}-l,4,10,13-테트라옥사-7,16-다이아자싸이클로옥타데케인 및 이의 제조방법, 그리고 이의 약학적 허용 가능한 염, 그리고 이를 유효성분으로 포함하는 약학적 조성물 특히, 붕소중성자포획요법을 위한 약학적 조성물에 관한 것이다.The present invention relates to 4- ( ortho - carbonan -1-yl) phenol derivative, a preparation method thereof, and a pharmaceutical composition comprising the same, and more particularly 4- ( ortho - carbonan -1-yl) -2. -( N, N -dialkylaminomethyl) phenol derivatives Bis {4- ( ortho -carbonan-1-yl) -2-hydroxybenzyl} -l, 4,10,13-tetraoxa-7,16-diazacyclooctadecane and its preparation, and its preparation A pharmaceutically acceptable salt and a pharmaceutical composition comprising the same as an active ingredient, in particular, a pharmaceutical composition for boron neutron capture therapy.
본 발명의 4-(오쏘-카보란-1-일)페놀 유도체는 세포 독성이 비교적 낮으며, 암세포에 대한 붕소 원자의 높은 선택적 축적을 보이므로, 암 치료를 위한 붕소 중성자 포획 치료요법제로서 유용하다.The 4- ( ortho - carbonan -1-yl) phenol derivative of the present invention is relatively low in cytotoxicity and exhibits high selective accumulation of boron atoms in cancer cells, and thus is useful as a boron neutron capture therapy for the treatment of cancer. Do.
4-(오쏘-카보란-1-일)페놀, 4-(오쏘-카보란-1-일)-2-(N,N-다이알킬아미노메틸)페놀, 중성자포획, 붕소뭉치화합물, 오쏘-카보란 4- (ortho-carbonan-1-yl) phenol, 4- (ortho-carbonan-1-yl) -2- (N, N-dialkylaminomethyl) phenol, neutron capture, boron compound, ortho- Caboran
Description
본 발명은 4-(오쏘-카보란-1-일)페놀 유도체 및 이의 제조방법, 그리고 이를 포함하는 약학적 조성물에 관한 것으로서 더욱 상세하게는 4-(오쏘-카보란-1-일)-2-(N,N-다이알킬아미노메틸)페놀 유도체 및 비스{4-(오쏘-카보란-1-일)-2-하이드록시벤질}-l,4,10,13-테트라옥사-7,16-다이아자싸이클로옥타데케인, 이의 제조방법, 이의 약학적 허용 가능한 염, 그리고 이를 유효성분으로 포함하는 약학적 조성물 특히, 붕소중성자포획요법을 위한 약학적 조성물에 관한 것이다.The present invention relates to 4- ( ortho - carbonan -1-yl) phenol derivatives and methods for preparing the same, and to pharmaceutical compositions comprising the same. More specifically, 4- ( ortho - carbonan -1-yl) -2 -( N, N -dialkylaminomethyl) phenol derivatives and Bis {4- ( ortho -carbonan-1-yl) -2-hydroxybenzyl} -l, 4,10,13-tetraoxa-7,16-diazacyclooctadecane, preparation method thereof, and pharmaceutical preparation thereof An acceptable salt, and a pharmaceutical composition comprising the same as an active ingredient, in particular, a pharmaceutical composition for boron neutron capture therapy.
오늘날 인간 질병의 하나로서 가장 큰 관심이 모이고 있는 암 치료 기술에는 수술 등의 외과적 방법, 약물 투여 등에 의한 내과적 방법 및 감마선 조사에 의한 방사선치료법 등이 있다. 이러한 암 치료방법은 암세포뿐만 아니라 암세포 주위의 정상세포들까지 손상을 입히게 될 뿐만 아니라 화학요법(chemotherapy)의 경우는 내성을 갖는 암세포를 생성하는 문제점이 있다. The cancer treatment technology that is attracting the most attention as one of human diseases today includes surgical methods such as surgery, medical methods such as drug administration, and radiation therapy by gamma irradiation. Such a cancer treatment method not only damages cancer cells but also normal cells around the cancer cells, and in the case of chemotherapy, there is a problem of generating cancer cells with resistance.
따라서, 최근에는 암세포가 증식된 곳에 집중적으로 다량의 방사선을 조사할 수 있는 방법으로서 붕소 등 특정 원소를 포함하고 있는 화합물을 적당한 운반 생화학 물질을 이용하여 암 세포에 선택적으로 축적시키고, 적당한 양의 열중성자를 암세포 증식 부위에 조사하여 해당 원소의 핵분열을 유발함으로써 이러한 핵분열에서 방출되는 에너지로 암세포만을 파괴하여 암을 치료하는 방법이 시도되고 있다.Therefore, recently, as a method of intensively irradiating a large amount of radiation where cancer cells have proliferated, a compound containing a specific element such as boron is selectively accumulated in cancer cells by using a suitable transport biochemical, and an appropriate amount of heat. A method of treating cancer by destroying only cancer cells with energy released from the nuclear fission by neutron irradiation to the cancer cell proliferation site to induce nuclear fission of the element has been attempted.
이러한 이원성 치료법을 중성자포획 치료요법(neutron capture therapy, NCT)이라고 하며, 특히 붕소 원소를 이용한 방법을 붕소 중성자포획 치료요법(boron neutron capture therapy, BNCT)이라 한다. 또한 이러한 목적에 이용되는 시약을 붕소 중성자포획 치료요법제(boron neutron capture therapy agent, BNCT agent)라고 한다.Such dual therapy is called neutron capture therapy (NCT), and in particular, the method using boron element is called boron neutron capture therapy (BNCT). The reagent used for this purpose is also called a boron neutron capture therapy agent (BNCT agent).
자연에서 발견되는 붕소 원자는 11B와 10B의 두 동위원소가 약 81.17:18.8의 비율로 존재하는데, 이 중 동위원소 10B에 열중성자를 조사하면 붕소 원자가 중성자를 포획하고 이어서 붕소 원자의 핵붕괴가 일어나며, 이어서 암세포를 파괴할 수 있는 에너지가 발생된다.Boron atoms found in nature exist in a ratio of about 81.17: 18.8 to two isotopes of 11 B and 10 B. Among them, when the thermal neutrons are irradiated on the isotope 10 B, the boron atoms capture neutrons and then the nuclear decay of the boron atoms. Occurs, followed by energy that can destroy cancer cells.
따라서, 환자에게 붕소(10B) 화합물을 투여한 후 중성자를 그 환자의 종양부위에 조사하게 되면, 그 종양세포가 상기 중성자의 핵심 표적이 됨으로써 결국 종양세포만을 선별적이고 안전하게 제거할 수 있게 되는 것이다. 이때 원하는 효과를 달성하기 위해서는 중성자 조사를 받는 종양조직 대 정상조직의 붕소 축적 선택성은 가능한 한 커야 한다.Therefore, if the patient is irradiated with a boron ( 10 B) compound and the neutron is irradiated to the tumor site of the patient, the tumor cells become a key target of the neutrons, so that only tumor cells can be selectively and safely removed. . In order to achieve the desired effect, the boron accumulation selectivity of tumor tissue to normal tissue subjected to neutron irradiation should be as large as possible.
제1세대 붕소 중성자 포획 치료요법제로서 무기 붕소 화합물이 사용되었으나 세포막의 통과와 독성에 문제점이 있었다. 그러나 제 2세대 붕소 중성자포획 치료요법제인 BSH(Na2 10B12H11SH, mercaptoborane)를 이용하여 뇌암의 일종인 신경교아종(glioblastoma)을 성공적으로 치료함에 따라, 붕소 중성자포획 치료요법의 개념은 뇌암 치료에 대하여 새로운 전기를 맞게 되었다. Inorganic boron compounds were used as the first generation boron neutron capture therapy, but there was a problem in the passage and toxicity of the cell membrane. However, with the successful treatment of glioblastoma, a type of brain cancer, using BSH (Na 2 10 B 12 H 11 SH, mercaptoborane), a second-generation boron neutron capture therapy, the concept of boron neutron capture therapy A new biography has emerged for the treatment of brain cancer.
1950년대 후반과 1960년대에 발견된 붕소 뭉치화합물과 다양한 생화학적 경로를 가진 생물활성 물질의 결합은 암세포에 대한 붕소 원자의 선택적 축적을 가능하게 하고 있다. 붕소 뭉치화합물의 한 예로는 하기 화학식으로 표시되는 오쏘-카보란(1,2-디카바-클로소-도데카보란, dicarba-closo-dodecacarborane)(1)이 있다.The combination of boron compounds found in the late 1950s and 1960s with bioactive materials with various biochemical pathways has enabled the selective accumulation of boron atoms in cancer cells. One example of the boron aggregate compound is ortho -carborane (1,2 - dicarba- closo -dodecaborane, dicarba- closo- dodecacarborane) represented by the following formula (1).
오쏘-카보란(1)은 C2B10H12의 분자식을 가지며, 상기 식에서 정이십면체의 모서리에 문자로 표시되지 않은 꼭지점은 B-H 결합을 나타낸다. BSH와 타이로신의 유 사체인 BPA(L-4-boronophenylalanine)로 대표되는 붕소 중성자포획 치료요법제의 연구는 임상 응용에서도 큰 성과를 거두었다. 현재 붕소 화학의 큰 발전과 생화학적 대사경로의 발달이 서로 결합되어 암세포에 대한 높은 선택적 흡수와 정상 세포에 대한 낮은 독성을 목표로 제 4세대 시약의 개발로 진행되고 있다. Ortho - carborane (1) has the molecular formula of C 2 B 10 H 12 , Vertices in the equation, not marked with letters at the corners of the icosahedron, represent BH bonds. The study of boron neutron capture therapy represented by BPA (L-4-boronophenylalanine), an analog of BSH and tyrosine, has also been successful in clinical applications. At present, the development of boron chemistry and the development of biochemical metabolic pathways have been combined to develop the fourth generation of reagents aiming at high selective absorption of cancer cells and low toxicity to normal cells.
따라서, 적당한 수용성, 낮은세포독성, 그리고 암세포에 대한 붕소 원자의 축적의 선택성이 뛰어난 새로운 붕소 중성자포획 치료요법제의 계속적인 개발이 요구되고 있다. Therefore, there is a need for the continuous development of new boron neutron capture therapy that has good water solubility, low cytotoxicity and selectivity for the accumulation of boron atoms in cancer cells.
본 발명은 적당한 수용성, 낮은세포독성 및 암세포에 대한 붕소 원자의 축적의 선택성이 뛰어난 4-(오쏘-카보란-1-일)페놀 유도체 및 이의 제조 방법, 그리고 이의 약학적으로 허용 가능한 염을 제공함에 목적이 있다.The present invention provides 4- ( ortho - carbolan -1-yl) phenol derivatives having excellent water solubility, low cytotoxicity and selectivity for the accumulation of boron atoms on cancer cells, methods for their preparation, and pharmaceutically acceptable salts thereof. There is a purpose.
본 발명은 적당한 수용성, 낮은세포독성 및 암세포에 대한 붕소 원자의 축적의 선택성이 뛰어난 4-(오쏘-카보란-1-일)페놀 유도체 및 이의 약학적 허용 가능한 염을 유효성분으로 포함하는 약학적 조성물 특히, 붕소중성자포획요법을 위한 약학적 조성물을 제공함에 또 다른 목적이 있다.The present invention provides a pharmaceutical composition comprising 4- ( ortho - carbolan -1-yl) phenol derivative and its pharmaceutically acceptable salts thereof having excellent water solubility, low cytotoxicity and selectivity for the accumulation of boron atoms in cancer cells. It is another object to provide a composition, in particular a pharmaceutical composition for boron neutron capture therapy.
상기와 같은 목적을 달성하기 위한 본 발명은 하기 화학식 1 또는 2로 표시되는 화합물 및 이의 제조방법, 그리고 이의 약학적으로 허용 가능한 염을 제공한다.The present invention for achieving the above object provides a compound represented by the following formula (1) or (2), a preparation method thereof, and a pharmaceutically acceptable salt thereof.
[화학식 1] [Formula 1]
[화학식 2][Formula 2]
(상기 화학식 1에서, R1은 수소, 벤질, C1 ~5의 알킬기 또는 알코올기 및 알콕시기를 가진 C1 ~5의 알킬기, 그리고 C1 ~5의 알콕시기를 가진 알콕시카보닐메틸 및 알콕시카보닐에틸기이며, R2는 수소, 메틸, 페닐이다. 상기 정이십면체의 문자가 없는 꼭지점은 B-H 결합을 나타낸다.)(In Formula 1, R 1 is hydrogen, benzyl, C 1 ~ 5 alkoxy-carbonyl-methyl and alkoxycarbonyl having alkoxy groups of the alkyl group of C 1 ~ 5 with an alkyl group or an alcohol group and an alkoxy group, and C 1 ~ 5 of carbonyl Is an ethyl group, R 2 is Hydrogen, methyl, phenyl. The vertices without the letters of the icosahedron represent BH bonds.)
그리고, 본 발명은 상기 화학식 1 또는 2로 표시되는 4-(오쏘-카보란-1-일)페놀 유도체 또는 약학적으로 허용 가능한 이의 염을 유효성분으로 포함하는 붕소중성자포획요법을 위한 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for boron neutron capture therapy comprising 4- ( ortho - carbonan -1-yl) phenol derivative represented by Chemical Formula 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. To provide.
이하, 본 발명을 상세히 설명하기에 앞서, 본 명세서 및 청구범위에 사용된 용어나 단어는 통상적이거나 사전적인 의미로 한정해서 해석되어서는 아니 되며, 발명자는 그 자신의 발명을 가장 최선의 방법으로 설명하기 위해 용어의 개념을 적절하게 정의할 수 있다는 원칙에 입각하여 본 발명의 기술적 사상에 부합하는 의미와 개념으로 해석되어야만 한다. Before describing the present invention in detail, the terms or words used in the present specification and claims should not be construed as being limited to the common or dictionary meanings, and the inventors explain their own invention in the best way. In order to properly define the concept of the term in order to be interpreted as meanings and concepts in accordance with the technical spirit of the present invention.
본 발명의 상기 화학식 1 또는 2로 표시되는 화합물에 있어서, 더욱 바람직한 구체적인 예는 다음과 같다.In the compound represented by Formula 1 or 2 of the present invention, more preferable specific examples are as follows.
1) 4-(오쏘-카보란-1-일)페놀1) 4- ( ortho - carbonan -1-yl) phenol
(4-(o-carboran-1-yl)phenol),(4- ( o -carboran-1-yl) phenol),
2) 4-(오쏘-카보란-1-일)-2-{N,N-비스(에톡시카복시메틸)아미노메틸}페놀2) 4- ( ortho - carbonan -1-yl) -2- { N, N -bis (ethoxycarboxymethyl) aminomethyl} phenol
(4-(o-carboran-1-yl)-2-{N,N-bis(ethoxycarboxymethyl)aminomethyl}- phenol),(4- ( o -carboran-1-yl) -2- { N, N -bis (ethoxycarboxymethyl) aminomethyl} -phenol),
3) 4-(오쏘-카보란-1-일)-2-{N,N-비스(카복시메틸)아미노메틸}페놀3) 4- ( ortho - carbonan -1-yl) -2- { N, N -bis (carboxymethyl) aminomethyl} phenol
(4-(o-carboran-1-yl)-2-{N,N-bis(carboxymethyl)aminomethyl}phenol),(4- ( o -carboran-1-yl) -2- { N, N -bis (carboxymethyl) aminomethyl} phenol),
4) 4-(오쏘-카보란-1-일)-2-{N,N-비스(2-메톡시에틸)아미노메틸}페놀4) 4- ( ortho - carbonan -1-yl) -2- { N, N -bis (2-methoxyethyl) aminomethyl} phenol
(4-(o-carboran-1-yl)-2-{N,N-bis(2-methoxyethyl)aminomethyl}phenol),(4- ( o -carboran-1-yl) -2- { N, N -bis (2-methoxyethyl) aminomethyl} phenol),
5) 4-(오쏘-카보란-1-일)-2-{N,N-비스(2-하이드록시에틸)아미노메틸}페놀5) 4- ( ortho - carbonan -1-yl) -2- { N, N -bis (2-hydroxyethyl) aminomethyl} phenol
(4-(o-carboran-1-yl)-2-{N,N-bis(2-hydroxyethyl)aminomethyl}phenol),(4- ( o -carboran-1-yl) -2- { N, N -bis (2-hydroxyethyl) aminomethyl} phenol),
6) 비스{4-(오쏘-카보란-1-일)-2-하이드록시벤질}-l,4,10,13-테트라옥사-7,16-다이아자싸이클로옥타데케인6) Bis {4- ( ortho -carbonan-1-yl) -2-hydroxybenzyl} -l, 4,10,13-tetraoxa-7,16-diazacyclooctadecane
(Bis{4-(o-carboranyl-1-yl)-2-hydroxybenzyl}-l,4,10,13-tetraoxa-7,16-(Bis {4- ( o -carboranyl-1-yl) -2-hydroxybenzyl} -l, 4,10,13-tetraoxa-7,16-
diazacyclooctadecane) diazacyclooctadecane)
본 발명의 화학식 1 또는 2로 표시되는 화합물은 약학적으로 허용되는 염의 형태로 사용될 수 있으며, 이러한 염으로는 약학적으로 허용되는 유리산(free acid)에 의해 형성되는 산부가염이 있다. 상기 유리산으로는 무기산과 유기산이 사용될 수 있으며 무기산으로는 염산, 황산, 브롬산, 아황산 또는 인산 등이 사용될 수 있고 유기산으로는 구연산, 초산, 말레인산, 후마린산, 글루콘산, 메탄술폰산 등이 사용될 수 있다. The compound represented by Formula 1 or 2 of the present invention may be used in the form of a pharmaceutically acceptable salt, and such salts include acid addition salts formed by pharmaceutically acceptable free acid. The free acid may be an inorganic acid and an organic acid, and the inorganic acid may be hydrochloric acid, sulfuric acid, bromic acid, sulfurous acid or phosphoric acid, and the organic acid may be citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, or the like. Can be used.
또한, 본 발명은 하기 반응식 1과 같이 오쏘-카보란-1-일페놀(2)과 이차 아민 유도체와 반응시키는 단계를 포함하는 화학식 1의 유도체 또는 이의 염의 제조방법을 제공한다.In addition, the present invention is a derivative of formula (1) comprising the step of reacting with ortho - carborane -1- ylphenol (2) and the secondary amine derivative as shown in Scheme 1 below Or a method for preparing a salt thereof.
(R1은 수소, 메틸, 페닐이고, R2는 수소, 벤질, C1 ~5의 알킬기 또는 알콕시기 및 알코올기를 가진 C1 ~5의 알킬기이고, 정이십면체의 문자가 없는 꼭지점은 B-H 결합을 나타낸다.)(R 1 is hydrogen, methyl, phenyl, R 2 is hydrogen, benzyl, an alkyl group of C 1 ~ 5 with an alkyl group or an alkoxy group and an alcohol of C 1 ~ 5, the vertices that do not have the regular icosahedron characters BH bond Indicates.)
상기 반응식 1에서 오쏘-카보란-1-일페놀(2), 포름알데히드(3), 그리고 이차아민 4을 적당한 용매에서 반응시키면 화학식 1의 생성물을 제조할 수 있다. In Scheme 1, the product of Formula 1 may be prepared by reacting ortho - carbonan -1- ylphenol (2), formaldehyde (3), and secondary amine 4 in a suitable solvent.
구체적으로는 상기 반응식 1에서 포름알데히드(3)는 포르마린 또는 파라포름 알데히드를 사용할 수 있으며, 반응용매로는 테트라하이드로퓨란(THF), N,N-디메틸포름아미드(DMF), 디메틸술폭사이드(DMSO), 다이옥산, N,N-아메틸아세트아마이드, 벤젠, 톨루엔, 자일렌(xylene) 등을 사용할 수 있으며, 반응 온도는 -20 ℃ 내지 환류 온도에서 수행될 수 있다.Specifically, in the reaction scheme 1, formaldehyde (3) may be used forformin or paraformaldehyde, and the reaction solvent is tetrahydrofuran (THF), N, N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO ), Dioxane, N, N -methylacetamide, benzene, toluene, xylene, and the like may be used, and the reaction temperature may be performed at -20 ° C to reflux temperature.
또한, 반응 시간은 충분한 시간 동안 수행하는 것이 바람직하며, 48시간 이상 수행할 수 있다.상기 반응식 1에서 오쏘-카보란-1-일페놀(2), 포름알데히드(3), 그리고 이차 아민(4)을 같은 당량비를 사용하여 적당한 용매를 사용하여 반응시키면 화학식 1의 생성물을 얻을 수 있다. In addition, the reaction time is preferably performed for a sufficient time, and may be performed for 48 hours or more. In Scheme 1, ortho - carbonan -1- ylphenol (2), formaldehyde (3), and secondary amine (4). ) Is reacted with a suitable solvent using the same equivalent ratio to give the product of formula (1).
또한 본 발명에 따른 제조방법에 있어서, 상기 반응식 1의 출발물질로 사용되는 오쏘-카보란-1-일페놀(2)은 이미 공지된 화합물이다(Tetrahedron Letters, 2000, 41(36), 7065-7070.). 본 발명에서는 반응식 2와 같이 (오쏘-카보란-1일)아닐린(5)으로부터 제조하는 방법을 제공한다. 구체적으로 아닐린 유도체(5)를 황산 수용액에 녹이고 0-5oC에서 아질산소듐과 반응시키고 이어서 서서히 온도를 90oC까지 올리면 페놀 유도체 2가 얻어진다. In addition, in the preparation method according to the present invention, ortho -carbonan-1-ylphenol (2) used as a starting material of Scheme 1 is a known compound (Tetrahedron Letters, 2000, 41 (36) , 7065- ) . 7070.). The present invention provides a process for preparing from ( ortho - carborane -1 yl) aniline (5) as in Scheme 2. Specifically, the phenol derivative 2 is obtained by dissolving aniline derivative 5 in an aqueous sulfuric acid solution and reacting with sodium nitrite at 0-5 ° C. and then gradually raising the temperature to 90 ° C.
[반응식 2]Scheme 2
상기 반응식 2에서 사용되는 산은 염산, 아세트산, 포름산, 인산, 그리고 브롬산을 사용할 수 있다. 아질산 소듐의 반응온도는 0oC에서 실온까지 범위이며, 반응시간은 반응물의 양에 따라 충분하게 진행되어야 한다. The acid used in Scheme 2 may use hydrochloric acid, acetic acid, formic acid, phosphoric acid, and bromic acid. The reaction temperature of sodium nitrite ranges from 0 o C to room temperature, and the reaction time should proceed sufficiently depending on the amount of reactants.
본 발명의 화학식 1의 유도체 중 R1이 알콕시카보닐알킬기, 구체적 예로서 에톡시카보닐메틸기일 경우, 하기 반응식 3의 산 또는 염기에 의한 가수분해반응을 더 수행하여, 화학식 1의 유도체에 포함되는 이미노다이아세트산 유도체(7)를 얻을 수 있다.When R 1 of the derivatives of general formula (I) of the present invention is an alkoxy-carbonyl group, an ethoxycarbonyl methyl group in a specific example, to further perform the hydrolysis with an acid or a base in scheme 3, comprising a derivative of the general formula (I) The imino diacetic acid derivative (7) can be obtained.
[반응식 3]Scheme 3
(R2는 수소, 메틸, 페닐이며, 그리고 R3는 C1 ~5의 알킬기이고, 정이십면체의 문자가 없는 꼭지점은 B-H 결합을 나타낸다.)(R 2 is hydrogen, methyl, phenyl, and R 3 is an alkyl group of C 1 ~ 5, the vertices that do not have the regular icosahedron characters BH represents a bond.)
구체적으로 반응식 3의 가수분해반응은 염산, 브롬산, 황산, 인산, 파라톨루엔술폰산, 그리고 벤젠술폰산 등을 촉매로 사용하여 수행될 수 있으며, 용매는 물이고, 반응온도는 실온내지 환류 온도에서 수행될 수 있다. 또한, 반응 시간은 충분한 시간 동안 수행하는 것이 바람직하며, 24시간 이상 수행할 수 있다. 또한 NaOH, KOH, Ca(OH)2 등을 사용하여 가수분해한 후에 위에서 언급된 산으로 중화시켜서 화학식 1의 유도체에 포함되는 이미노다이아세트산기를 가진 유도체(8)를 얻을 수 있다. Specifically, the hydrolysis reaction of Scheme 3 may be performed using hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, paratoluenesulfonic acid, and benzenesulfonic acid as catalysts, the solvent is water, and the reaction temperature is performed at room temperature to reflux temperature. Can be. In addition, the reaction time is preferably carried out for a sufficient time, can be carried out for more than 24 hours. In addition, it is possible to obtain a derivative (8) having an iminodiacetic acid group included in the derivative of Formula 1 by hydrolysis with NaOH, KOH, Ca (OH) 2 and the like and then neutralizing with the acid mentioned above.
본 발명의 화학식 1의 유도체 중 R1이 알콕시알킬기, 구체적 예를로서 2-메톡시에틸기일 경우, 하기 반응식 4의 탈알킬화 반응을 더 수행하여, 화학식 1의 유도체에 포함되는 비스(2-하이드록시에틸)아미노 유도체(10)를 얻을 수 있다.If derivative formula R 1 is an alkoxyalkyl group, 2-methoxy-ethyl as a concrete example of the date of the present invention, by performing more dealkylation reaction of Scheme 4, bis (2-hydroxy included in the derivatives of formula (I) Oxyethyl) amino derivative (10) can be obtained.
[반응식 4]Scheme 4
(R2는 수소, 메틸, 페닐이며, 그리고 R4는 C1 ~5의 알킬기이고, 정이십면체의 문자가 없는 꼭지점은 B-H 결합을 나타낸다.)(R 2 is hydrogen, methyl, phenyl, and R 4 is an alkyl group of C 1 ~ 5, the vertices that do not have the regular icosahedron characters BH represents a bond.)
더욱 구체적으로는, R4에 메톡시기를 가진 화학식 1 화합물은 BBr3, HBr, HI 또는 (CH3)3SiI와 반응시킴으로써 탈알킬화 반응을 수행할 수 있다. 상기 탈알킬화 반응은 통상의 유기 용매, 예를 들면, 디클로로메탄, 클로로포름, 디클로로에탄, 아세트산 등을 사용할 수 있으며, 나아가 이들의 혼합용매를 사용하는 것도 가능하다. 또한, 상기 탈알킬화 반응은 실온에서 충분한 시간 동안 수행하는 것이 바람직하며, 24시간 이상 수행하는 것이 더욱 바람직하다.More specifically, the compound of formula 1 having a methoxy group in R 4 may be subjected to dealkylation reaction by reacting with BBr 3 , HBr, HI or (CH 3 ) 3 SiI. As the dealkylation reaction, a conventional organic solvent such as dichloromethane, chloroform, dichloroethane, acetic acid, or the like may be used, and further, a mixed solvent thereof may be used. In addition, the dealkylation reaction is preferably carried out for a sufficient time at room temperature, more preferably 24 hours or more.
본 발명의 화학식 2의 화합물은 구체적 예를로서 2-메톡시에틸기일 경우, 하기 반응식 4의 탈알킬화 반응을 더 수행하여, 화학식 1의 유도체에 포함되는 비 스(2-하이드록시에틸)아미노 유도체(10)를 얻을 수 있다.As a specific example of the compound of the present invention, in the case of 2-methoxyethyl group, the benzo (2-hydroxyethyl) amino derivative included in the derivative of Formula 1 is further subjected to the dealkylation reaction of Scheme 4 below. (10) can be obtained.
또한, 본 발명의 화학식 2의 화합물은 하기 반응식 5의 Mannich반응의 아미노메메틸화 반응으로 제조될 수 있다. 반응식 5와 같이 오쏘-카보란-1-일페놀(2), 포름알데히드(3), 그리고 이차아민(11)을 적당한 용매에서 반응시키면 화학식 1에 포함되어 있는 생성물을 제조할 수 있다. In addition, the compound of formula 2 of the present invention can be prepared by the amino methylation reaction of the Mannich reaction of Scheme 5. As in Scheme 5, ortho - carbonan -1- ylphenol (2), formaldehyde (3), and secondary amine (11) may be reacted in a suitable solvent to prepare a product included in Chemical Formula 1.
[반응식 5]Scheme 5
(R2는 수소, 메틸, 페닐이며, 정이십면체의 문자가 없는 꼭지점은 B-H 결합을 나타낸다.)(R 2 is hydrogen, methyl, phenyl, and the vertices without icosahedron represent BH bonds.)
구체적으로는 상기 반응식 5에서 4-(오쏘-카보란-1-일)페놀(2), 2당량의 포름알데히드(3), 그리고 이차 아민 11은 1당량을 사용하여 적당한 용매를 사용하여 반응시키면 화학식 1의 생성물 12를 얻을 수 있다. 포름알데히드는 포르마린 또는 파라포름알데히드를 사용할 수 있으며, 반응용매로는 테트라하이드로퓨란(THF), N,N-디메틸포름아미드(DMF), 디메틸술폭사이드(DMSO), 다이옥산, N,N-아메틸아세트아마이드, 벤젠, 톨루엔, 자일렌(xylene) 등을 사용할 수 있으며, 반응 온도는 -20 ℃ 내지 환류 온도에서 수행될 수 있다. 또한, 반응 시간은 충분한 시간 동안 수행하는 것이 바람직하며, 48시간 이상 수행할 수 있다.Specifically, in Scheme 5, 4- ( ortho - carbonan -1-yl) phenol ( 2 ), 2 equivalents of formaldehyde ( 3 ), and secondary amine 11 are reacted with an appropriate solvent using 1 equivalent. Product 12 of Formula 1 can be obtained. Formaldehyde may be used formalin or paraformaldehyde, and the reaction solvent is tetrahydrofuran (THF), N, N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dioxane, N, N -methyl Acetamide, benzene, toluene, xylene, and the like may be used, and the reaction temperature may be performed at -20 ° C to reflux temperature. In addition, the reaction time is preferably carried out for a sufficient time, can be carried out for more than 48 hours.
또한, 본 발명은 상기 화학식 1 또는 상기 화학식 2로 표시되는 화합물 또는 이의 염을 포함하는 항암용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for anticancer comprising the compound represented by Formula 1 or Formula 2 or a salt thereof.
그리고, 본 발명의 조성물은 붕소 원자를 암세포에 선택적으로 축적시켜 열중성자를 조사하였을 때 암세포를 효과적으로 파괴할 수 있는 붕소 중성자포획 치료요법제로 유용하게 사용될 수 있다.In addition, the composition of the present invention can be usefully used as a boron neutron capture therapy for effectively destroying cancer cells when the boron atoms are selectively accumulated in cancer cells and irradiated with thermal neutrons.
본 발명의 유도체 및 이의 염은 과립제, 산제, 액제, 정제, 캅셀제 또는 건조시럽제 등의 경구용 제제 또는 주사제 등의 비경구용 제제로 제형화 할 수 있으나 이러한 제형에 한정되는 것은 아니다. 바람직하게는 본 발명의 조성물은 정제 또는 캅셀제의 형태이거나, 액제 또는 주사제의 형태이다. Derivatives and salts thereof of the present invention may be formulated into oral preparations such as granules, powders, solutions, tablets, capsules or dry syrups or parenteral preparations such as injections, but are not limited thereto. Preferably the compositions of the present invention are in the form of tablets or capsules or in the form of solutions or injections.
본 발명의 유도체 및 이의 염을 제형화할 경우 통상적으로 사용되는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 1종 이상 사용할 수 있다. 부형제로는 미결정 셀룰로오즈, 유당, 저치환도 히드록시셀룰로오즈 등이 사용될 수 있고, 붕해제로는 전분글리콜산 나트륨, 무수인산일수소 칼슘 등이 사용될 수 있다. 결합제로는 폴리비닐피롤리돈, 저치환도 히드록시프로필셀룰로오즈, 히드록시프로필셀룰로오즈 등이 사용될 수 있고, 활택제로는 스테아린산 마그네슘, 이산화규소, 탈크 등으로부터 선택하여 사용될 수 있다.When formulating the derivative of the present invention and salts thereof, one or more diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used may be used. As the excipient, microcrystalline cellulose, lactose, low-substituted hydroxycellulose, and the like may be used, and as the disintegrant, sodium starch glycolate, calcium monohydrogen phosphate, and the like may be used. As the binder, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose and the like may be used, and the lubricant may be selected from magnesium stearate, silicon dioxide, talc and the like.
또한, 본 발명의 유도체 및 이의 염을 액제 또는 주사제로 제형화 하는 경우, 필요시 10~40%의 프로필렌글리콜 및 용혈현상을 방지하는데 충분한 양의 염화나트륨이 포함될 수 있다.In addition, when the derivative of the present invention and salts thereof are formulated as a solution or injection, 10 to 40% of propylene glycol and sodium chloride in an amount sufficient to prevent hemolysis may be included if necessary.
본 발명의 유도체 및 이의 염의 인체에 대한 투여량은 환자의 나이, 몸무게, 성별, 투여 형태, 건강 상태 및 질환 정도에 따라 달라질 수 있으며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.Dosage of the derivative of the present invention and salts thereof to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and once a day at regular intervals according to the judgment of the doctor or pharmacist It may be administered in several divided doses.
이와 같이 본 발명에 따른 4-(오쏘-카보란-1-일)페놀 유도체 및 이의 약학적으로 허용 가능한 염은 세포 독성이 비교적 낮으며, 암세포에 대한 붕소 원자의 높은 선택적 축적을 보이므로, 암 치료를 위한 붕소 중성자 포획 치료요법제(BNCT agent)로 유용하게 사용할 수 있는 효과가 있다.As such, the 4- ( ortho - carboran -1-yl) phenol derivative and the pharmaceutically acceptable salt thereof according to the present invention have relatively low cytotoxicity and show high selective accumulation of boron atoms in cancer cells. There is an effect that can be useful as a boron neutron capture therapy (BNCT agent) for the treatment.
이하 본 발명을 실시예를 들어 더욱 상세히 설명하면 다음과 같고, 하기에 기재된 실시예는 본 발명의 가장 바람직한 실시예에 불과할 뿐이고 본 발명의 기술적 사상을 모두 대변하는 것은 아니므로, 본 출원시점에 있어서 이들을 대체할 수 있는 다양한 균등물과 변형 예들이 있을 수 있음을 이해하여야 한다.Hereinafter, the present invention will be described in more detail with reference to the following examples, and the following examples are only the most preferred embodiments of the present invention, and do not represent all of the technical ideas of the present invention. It should be understood that there may be various equivalents and variations that can replace these.
[[ 실시예Example 1] 4-( 1] 4- ( 오쏘Ortho -- 카보란Caboran -1일)페놀의 제조-1 day) Preparation of phenol
1M 황산 수용액(5 mL)에 4-(오쏘-카보란-1-일)아닐린(1.20 g, 5.0 mmol)을 녹인 후에 0~5℃에서 아질산 소듐(0.40 g, 6.0 mmol)을 물 10 mL에 녹여 서서히 가한다. 반응 혼합물을 0~5℃를 유지 하면서 10분간 교반 시킨 후에 45℃에서 12시간 더 교반한다. 과량의 물을 가하고 에틸 아세테이트로 추출한다. 유기층을 증류수로 씻어 주고, 무수 황산 소듐으로 건조하고 농축 시키면 4-(오쏘-카보란-1일)페놀 0.52 g(43%)이 연한 갈색의 분말로 얻어진다. Dissolve 4- ( ortho - carbolan -1-yl) aniline (1.20 g, 5.0 mmol) in 1 M aqueous sulfuric acid solution (5 mL), and then add 10 mL of water with sodium nitrite (0.40 g, 6.0 mmol) at 0-5 ° C. Melt and add slowly. The reaction mixture was stirred for 10 minutes while maintaining 0 ~ 5 ℃ and then further stirred at 45 ℃ 12 hours. Excess water is added and extracted with ethyl acetate. The organic layer was washed with distilled water, dried over anhydrous sodium sulfate and concentrated to give 0.52 g (43%) of 4- ( ortho - carborane -1 yl) phenol as a light brown powder.
녹는점; 89-91℃.Melting point; 89-91 ° C.
IR (KBr) ν 2595 cm-1. IR (KBr) ν 2595 cm -1 .
1H NMR (Acetone-D6); δ 4.51 (s, 1 H), 5.0 (s, 1 H), 6.82-6.81 (td, J = 2.55 및 J = 6.45 Hz, 2 H), 7.46-7.44 (td, J = 1.8 및 J = 6.9 Hz, 2 H) ppm. 1 H NMR (Acetone-D 6 ); δ 4.51 (s, 1H), 5.0 ( s , 1H), 6.82-6.81 (td, J = 2.55 and J = 6.45 Hz, 2H), 7.46-7.44 (td, J = 1.8 and J = 6.9 Hz , 2 H) ppm.
13C NMR (Acetone-D6); δ 61.59, 77.77, 115.49, 124.50, 129.30, 159.0 ppm. 13 C NMR (Acetone-D 6 ); δ 61.59, 77.77, 115.49, 124.50, 129.30, 159.0 ppm.
[[ 실시예Example 2] 4-( 2] 4- ( 오쏘Ortho -- 카보란Caboran -1-일)-2-{-1-yl) -2- { N,NN, N -비스(-Vis ( 에톡시카복시메틸Ethoxycarboxymethyl )) 아미노메Aminome 틸}페놀의 제조Preparation of Tyl} phenol
건조된 질소 분위기 하에서, 건조된 톨루엔(30 mL)에 4-(오쏘-카보란-1-일)페놀 (1.00 g, 4.2 mmol), 다이에틸 이미노다이아세테이트(1.5 ml, 8.6 mmol), 그리고 파라포름알데하이드(0.03 g, 0.9 mmol)을 가한 후 48시간 동안 환류를 시킨다. 반응용액을 물로 씻어주고, 무수 황산 소듐으로 건조하여 감압농축 시킨다. 잔유물을 크로마토그라피 법으로 분리하면 1.31 g(71%)의 4-(오쏘-카보란-1-일)-2- {N,N-비스(에톡시카복시메틸)아미노메틸}페놀이 얻어진다.In a dry nitrogen atmosphere, 4- (ortho-carbonan-1-yl) phenol (1.00 g, 4.2 mmol), diethyl iminodiacetate (1.5 ml, 8.6 mmol), and para in dried toluene (30 mL) Formaldehyde (0.03 g, 0.9 mmol) is added and refluxed for 48 hours. The reaction solution is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is separated by chromatography to give 1.31 g (71%) of 4- ( ortho - carbonan -1-yl) -2- { N, N -bis (ethoxycarboxymethyl) aminomethyl} phenol.
녹는점; 68-70℃. Melting point; 68-70 ° C.
IR (KBr) ν 2595 cm-1.IR (KBr) ν 2595 cm -1 .
1H NMR (Acetone-D6); δ 1.24-1.22 (t, J = 14.2 Hz, 2 H), 3.44 (s, 1 H), 3.5 (s, 2H), 3.95 (s, 2H), 4.18-4.15 (q, J = 14.2 Hz, 2 H), 5.0 (s, 2H), 6.76-6.75 (d, J = 8.7 Hz 2 H), 7.33-7.32 (d, J = 2.75 Hz 2 H), 7.44-7.42 (dd, J = 2.75 and J = 8.45 Hz 2 H) ppm. 1 H NMR (Acetone-D 6 ); δ 1.24-1.22 (t, J = 14.2 Hz, 2H), 3.44 (s, 1H), 3.5 (s, 2H), 3.95 (s, 2H), 4.18-4.15 (q, J = 14.2 Hz, 2 H), 5.0 (s, 2H), 6.76-6.75 (d, J = 8.7 Hz 2 H), 7.33-7.32 (d, J = 2.75 Hz 2 H), 7.44-7.42 (dd, J = 2.75 and J = 8.45 Hz 2 H) ppm.
13C NMR (Acetone-D6); δ 13.64, 55.15, 53.80, 60.61, 61.52, 77.69, 116.29, 122.54, 124.07, 128.72, 129.32, 159.17, 170.84 ppm. 13 C NMR (Acetone-D 6 ); δ 13.64, 55.15, 53.80, 60.61, 61.52, 77.69, 116.29, 122.54, 124.07, 128.72, 129.32, 159.17, 170.84 ppm.
[[ 실시예Example 3] 4-( 3] 4- ( 오쏘Ortho -- 카보란Caboran -1-일)-2-{-1-yl) -2- { N,NN, N -비스(-Vis ( 카복시메틸Carboxymethyl )) 아미노메틸Aminomethyl }페놀의 제조} Production of Phenol
에탄올 (10 mL)에 4-(오쏘-카보란-1-일)-2-{N,N-비스(에톡시카복시메틸)아-미노메틸}페놀(0.40 g, 0.9 mmol)과 수산화 나트륨 (0.11 g, 2.7 mmol)을 물(3 mL)에 녹여 가하고 실온에서 24시간 교반시킨다. 반응용액을 1N 염산 수용액으로 pH 2.0으로 조절하여 농축 시키고 과량의 아세톤을 가하면 0.22 g (63%)의 4-(오쏘-카보란-1-일)-2-{N,N-비스(카복시메틸)아미노메틸}페놀이 얻어진다. In ethanol (10 mL) 4- ( ortho - carbolan -1-yl) -2- { N, N -bis (ethoxycarboxymethyl) a-minomethyl} phenol (0.40 g, 0.9 mmol) and sodium hydroxide ( 0.11 g, 2.7 mmol) is dissolved in water (3 mL) and stirred at room temperature for 24 hours. The reaction solution with 1 N hydrochloric acid aqueous solution adjusted to p H 2.0 with concentrated and 4 of 0.22 g (63%) Applying a large excess of acetone (ortho-carborane-1-yl) -2- {N, N-bis ( Carboxymethyl) aminomethyl} phenol is obtained.
녹는점; 105-107℃. Melting point; 105-107 ° C.
IR (KBr); ν 2594 cm-1 IR (KBr); ν 2594 cm -1
1H NMR (Acetone-d6); δ 3.87 (s, 1 H) 4.47-4.41 (d, J = 25.65 Hz, 2 H), 4.87 (s, 2 H), 5.53 (s, 1 H), 7.15-7.14 (d, J = 8.7 Hz, 2 H), 7.59-7.56 (dd, J = 2.3 and J= 8.7 Hz, 2 H), 7.93-7.92 (d, J = 2.3 Hz, 2 H) ppm. 1 H NMR (Acetone-d 6 ); δ 3.87 (s, 1H) 4.47-4.41 (d, J = 25.65 Hz, 2H), 4.87 (s, 2H), 5.53 (s, 1H), 7.15-7.14 (d, J = 8.7 Hz, 2H), 7.59-7.56 (dd, J = 2.3 and J = 8.7 Hz, 2H), 7.93-7.92 (d, J = 2.3 Hz, 2H) ppm.
13C NMR (Acetone-d6); δ 54.00, 53.65, 55.73, 62.60, 77.13, 116.52, 125.01, 131.58, 133.17, 158.48, 166.86, 166.53 ppm. 13 C NMR (Acetone-d 6 ); δ 54.00, 53.65, 55.73, 62.60, 77.13, 116.52, 125.01, 131.58, 133.17, 158.48, 166.86, 166.53 ppm.
[실시예 4] 4-( 오쏘 - 카보란 -1-일)-2-{ N,N -비스(2- 메톡시에틸 ) 아미노메틸 }페놀 Example 4 4- (ortho-carborane-1-yl) -2- {N, N-bis (2-methoxyethyl) amino} methyl phenol
건조된 질소 분위기 하에서, 건조된 톨루엔(20 mL)에 4-(오쏘-카보란-1-일)페놀 (0.21 g, 0.9 mmol), 비스(메톡시에틸)아민(0.18 ml, 1.3 mmol), 그리고 파라포름알데하이드(0.04 g, 1.3 mmol)을 가한 후 48시간 동안 환류를 시킨다. 반응용액을 물로 씻어주고, 무수 황산 소듐으로 건조하여 감압농축 시킨다. 잔유물을 크로마토그라피 법으로 분리하면 0.23 g(67%)의 4-(오쏘-카보란-1-일)-2-{N,N-비스(메톡시에틸)아미노메틸}페놀이 얻어진다. In a dry nitrogen atmosphere, 4- ( ortho - carbonan -1-yl) phenol (0.21 g, 0.9 mmol), bis (methoxyethyl) amine (0.18 ml, 1.3 mmol) in dried toluene (20 mL), Paraformaldehyde (0.04 g, 1.3 mmol) was added thereto, and the mixture was refluxed for 48 hours. The reaction solution is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is separated by chromatography to give 0.23 g (67%) of 4- ( ortho - carbonan -1-yl) -2- { N, N -bis (methoxyethyl) aminomethyl} phenol.
녹는점; 84-86℃ Melting point; 84-86 ℃
IR (KBr); v 2595 cm-1.IR (KBr); v 2595 cm -1 .
1H NMR (Acetone-D6); δ 2.77-2.75 (t, J = 11 Hz, 4 H), 3.26-3.25 (d, J = 2.75 Hz, 6 H), 3.50-3.48 (t, J = 11 Hz, 4 H), 3.50-3.48 (t, J = 11 Hz, 4 H), 3.89 (s, 1 H), 5.03 (s, 1 H), 6.68-6.66 (d, J = 8.7 Hz, 1 H), 7.32-7.31 (d, J = 2.75 Hz, 1 H), 738-7.36 (dd, J = 2.75 및 J = 8.72 Hz, 1 H) ppm. 1 H NMR (Acetone-D 6 ); δ 2.77-2.75 (t, J = 11 Hz, 4 H), 3.26-3.25 (d, J = 2.75 Hz, 6 H), 3.50-3.48 (t, J = 11 Hz, 4 H), 3.50-3.48 ( t, J = 11 Hz, 4 H), 3.89 (s, 1 H), 5.03 (s, 1 H), 6.68-6.66 (d, J = 8.7 Hz, 1 H), 7.32-7.31 (d, J = 2.75 Hz, 1 H), 738-7.36 (dd, J = 2.75 and J = 8.72 Hz, 1 H) ppm.
13C NMR (Acetone-D6); δ 44.60, 51.37, 52.33, 60.56, 77.62, 111.62, 113.60, 115.63, 129.58, 134.38, 148.44, 171.13 ppm. 13 C NMR (Acetone-D 6 ); δ 44.60, 51.37, 52.33, 60.56, 77.62, 111.62, 113.60, 115.63, 129.58, 134.38, 148.44, 171.13 ppm.
[실시예 5] 4-( 오쏘 - 카보란 -1-일)-2-{ N,N -비스(2-하이드록시에틸) 아미노메 틸}페놀의 제조 Example 5 4- (ortho-carborane-1-yl) -2- {N, N-bis (2-hydroxyethyl) amino methyl} phenol Preparation of
건조된 질소 분위기 하에서, 건조된 다이클로로메탄(20 mL)에 4-(오쏘-카보란-1-일)-2-{N,N-비스(메톡시에틸)아미노메틸}페놀(0.20 g, 0.5 mmol)을 녹인 후에 트리브롬오보레인(1.5 mL, 1.5 mmol) 첨가한 후 0℃에서 2시간 동안 교반시킨다. 반응용액에 과량의 물을 가하면 0.13 g(74%)의 4-(오쏘-카보란-1-일)-2-{N,N-비스(하이드록시에틸)아미노메틸}페놀이 얻어진다. Under a dry nitrogen atmosphere, 4- (ortho-carbolan-1-yl) -2- { N, N -bis (methoxyethyl) aminomethyl} phenol (0.20 g, in dried dichloromethane (20 mL) 0.5 mmol) is dissolved and tribrom-oborone (1.5 mL, 1.5 mmol) is added, followed by stirring at 0 ° C. for 2 hours. When excess water is added to the reaction solution, 0.13 g (74%) of 4- ( ortho - carbonan -1-yl) -2- { N, N -bis (hydroxyethyl) aminomethyl} phenol is obtained.
녹는점; 126-128℃ Melting point; 126-128 ℃
IR (KBr) v 2591 cm-1.IR (KBr) v 2591 cm -1 .
1H NMR (Acetone-D6); δ 2.77-2.75 (t, J = 5.5 Hz, 4 H), 3.50-3.48 (t, J = 5.5 Hz, 4 H), 3.88 (s, 1 H), 5.04 (s, 1 H), 6.68-6.66 (d, J = 8.7 Hz, 1 H), 7.31-7.30 (d, J = 2.75Hz, 1 H), 7 38-7.36 (dd, J= 2.75 및 J = 8.72 Hz, 1 H) ppm. 1 H NMR (Acetone-D 6 ); δ 2.77-2.75 (t, J = 5.5 Hz, 4H), 3.50-3.48 (t, J = 5.5 Hz, 4H), 3.88 (s, 1H), 5.04 (s, 1H), 6.68-6.66 (d, J = 8.7 Hz, 1 H), 7.31-7.30 (d, J = 2.75Hz, 1 H), 7 38-7.36 (dd, J = 2.75 and J = 8.72 Hz, 1 H) ppm.
13C NMR (CDCl3); δ 55.17, 59.96, 60.54, 66.11, 77.53, 12.29, 113.84, 115.16, 129.67, 134.52, 148.03 ppm. 13 C NMR (CDCl 3 ); δ 55.17, 59.96, 60.54, 66.11, 77.53, 12.29, 113.84, 115.16, 129.67, 134.52, 148.03 ppm.
[[ 실시예Example 6] 6] 비스Vis {4-({4-( 오쏘Ortho -- 카보란Caboran -1-일)-2--1-yl) -2- 하이드록시벤질Hydroxybenzyl }-l,4,10,13-} -l, 4,10,13- 테트라Tetra -옥사-7,16--Oxa-7,16- 다이아자싸이클로옥타데케인의Of the diamond cyclooctadecane 제조 Produce
건조된 질소 분위기 하에서, 건조된 톨루엔(40 mL)에 4-(오쏘-카보란-1-일)- 페놀 (0.3 g, 1.2 mmol), 1,4,10,13-테트라옥사-7,16-다이아자싸이클로옥타데케인(0.16 g, 0.6 mmol), 그리고 파라포름알데하이드(0.05 g, 1.6 mmol)를 가하고 48시간 동안 환류시킨다. 반응용액을 물로 씻어 주고, 무수 황산 소듐으로 건조하고, 농축을 시킨다. 이어서 잔유물을 크로마토그라피 법으로 분리하면 0.11 g (11%)의 비스{4-(오쏘-카보란-1-일)-2-하이드록시벤질}-l,4,10,13-테트라옥사-7,16-다이아자싸이클로옥타데케인이 얻어진다.Under dry nitrogen atmosphere, 4- (ortho-carbolan-1-yl) -phenol (0.3 g, 1.2 mmol), 1,4,10,13-tetraoxa-7,16 in dried toluene (40 mL) -Diacyclooctadecane (0.16 g, 0.6 mmol), and paraformaldehyde (0.05 g, 1.6 mmol) are added and refluxed for 48 hours. The reaction solution is washed with water, dried over anhydrous sodium sulfate and concentrated. Subsequently, the residue was separated by chromatographic method and 0.11 g (11%) of bis {4- ( ortho -carbonan-1-yl) -2-hydroxybenzyl} -1,4,10,13-tetraoxa-7 16-diazacyclooctadecane is obtained.
녹는점; 168-170℃ IR (KBr) 2608 cm-1.Melting point; 168-170 ° C. IR (KBr) 2608 cm −1 .
1H NMR (Acetone-d6); δ 2.80 (t, J = 5.5 Hz 8 H), 3.56 (s, 8 H), 3.66-3.64 (t, J = 5.5 Hz 8 H), 3.86 (s, 8 H), 5.04 (s, 1 H), 6.69-6.68 (d, J = 8.25 Hz, 1 H), 7.33-7.32 (d, J = 2.75 Hz, 1 H), 7.38-7.36 (dd, J = 2.75 and J = 8.75 Hz, 1 H) ppm. 1 H NMR (Acetone-d 6 ); δ 2.80 (t, J = 5.5 Hz 8 H), 3.56 (s, 8 H), 3.66-3.64 (t, J = 5.5 Hz 8 H), 3.86 ( s , 8 H), 5.04 (s, 1 H) , 6.69-6.68 (d, J = 8.25 Hz, 1 H), 7.33-7.32 (d, J = 2.75 Hz, 1 H), 7.38-7.36 ( dd , J = 2.75 and J = 8.75 Hz, 1 H) ppm .
13C NMR (Acetone-d6) δ 53.6, 57.6, 61.5, 68.6, 70.6, 77.9, 116. 1123.6, 128.0, 128.3, 131.9, 160.0 ppm. 13 C NMR (Acetone-d 6 ) δ 53.6, 57.6, 61.5, 68.6, 70.6, 77.9, 116. 1123.6, 128.0, 128.3, 131.9, 160.0 ppm.
[[ 실험예Experimental Example 1] One] HeLaHeLa 세포 독성 실험Cytotoxicity experiment
실시예 3에서 제조한 화합물 100 mg을 1.0 ㎖의 DMSO에 녹인 용액을 배양액(Eagle's MEM; Eagle's Minimum Essential Medium)(10% FCS(Fetal Calf Serum))으로 희석하여 1000 ppm의 용액을 제조하였다. 배양접시(Falcon 3072; 92-well)에서, Hela 세포(자궁경 암종에서 채취되어 계속 배양되고 있는 연구용 세포, 5 x 103cells/well)을 여러 가지 농도의 붕소 화합물을 포함하는 배양액으로 37 ℃의 CO2 배양기에서 3일 동안 다섯 개의 접시에서 배양시켰다. DMSO는 0.5% 이하의 농도에서는 독성이 없는 것으로 알려져 있으며, 위의 농도에서 DMSO가 독성을 나타내지 않는 것을 실험으로 확인하였다. 배양액을 제거하고 세포를 인산 완충용액으로 세 번 세척한 후에 크리스탈 바이올렛(crystal violet; 메틸 알코올의 0.4% 용액)으로 염색하고 마이크로플레이트 판독 장치로서 세포를 계수하였다. A solution of 100 mg of the compound prepared in Example 3 in 1.0 ml of DMSO was diluted with culture solution (Eagle's MEM; Eagle's Minimum Essential Medium) (10% FCS (Fetal Calf Serum)) to prepare a 1000 ppm solution. In a culture dish (Falcon 3072; 92-well), Hela cells (5 x 10 3 cells / well, a research cell taken from a cervical carcinoma and still in culture) were cultured at 37 ° C. in a culture solution containing various concentrations of boron compounds. Incubated in five dishes for 3 days in a CO 2 incubator. DMSO is known to be nontoxic at concentrations below 0.5%, and experimentally confirmed that DMSO is not toxic at the above concentrations. The cultures were removed and the cells washed three times with phosphate buffer, followed by staining with crystal violet (0.4% solution of methyl alcohol) and counting the cells with a microplate reading device.
얻어진 결과는 50%의 세포가 살아남은 농도(IC50)로서 나타내었으며, 그 결과를 표 1에 나타내었다.The results obtained are shown as the concentration of 50% cells survived (IC 50 ), the results are shown in Table 1.
[표 1] HeLa 세포 독성 실험 (IC50 (μM) = 5.87±1.16 (SEM) Table 1 HeLa cytotoxicity experiment (IC 50 (μM) = 5.87 ± 1.16 (SEM)
[[ 실험예Experimental Example 2] 2] HeLaHeLa 세포의 붕소 흡수 Boron Absorption of Cells
HeLa 세포는 Falcon 접시(150 mmf)에서 배양하였다. 세포가 접시(1.62 x 106 cells/dish)에서 충분히 자란 것을 확인한 후, 붕소가 10.8 ppm인 BSH 및 실시예 3에서 제조된 화합물을 함유하는 Eagle-MEM 배양액에서 3시간 동안 배양하였다. 배양된 세포를 PBS(-)로 3회 세척하고, 흡수된 붕소 농도를 ICP-AES(Shimadzu, ICP-100-III)를 사용하여 측정하였다. 각 실험은 3회 반복 수행하였고, 평균 붕소 흡수율은 표 2에 나타낸 것과 같다.HeLa cells were cultured in a Falcon dish (150 mmf). After confirming that the cells had grown sufficiently in a dish (1.62 x 10 6 cells / dish), and incubated for 3 hours in Eagle-MEM culture medium containing BSH with 10.8 ppm boron and the compound prepared in Example 3. Cultured cells were washed three times with PBS (−) and the absorbed boron concentration was measured using ICP-AES (Shimadzu, ICP-100-III). Each experiment was repeated three times, and the average boron absorption rate is shown in Table 2.
[표 2] TABLE 2 HeLaHeLa 세포의 붕소 흡수 Boron Absorption of Cells
상기 표 1 및 표 2에 나타낸 바와 같이, 본 발명에 따른 실시예 3의 화합물은 HeLa 암세포에 대한 붕소 흡수율이 0.3290 ppm B/106세포로서 종래의 붕소 중성자포획 치료요법제인 BSH(0.2681±0.0038 ppm B/106세포)보다 더 높은 것을 확인하였다.As shown in Table 1 and Table 2, the compound of Example 3 according to the present invention has a boron uptake rate of 0.3290 ppm B / 10 6 cells for HeLa cancer cells, BSH (0.2681 ± 0.0038 ppm) which is a conventional boron neutron capture therapy B / 10 6 cells).
따라서, 본 발명에 따른 4-(오쏘-카보란-1-일)-2-(N,N-알킬아미노메틸)페놀유도체 및 이의 약학적으로 허용 가능한 염은 HeLa 암세포에 대한 붕소 원자의 높은 축적을 보이는 것으로 나타났다.Thus, the 4- ( ortho - carboran -1-yl) -2- ( N, N -alkylaminomethyl) phenol derivatives and their pharmaceutically acceptable salts according to the present invention have a high accumulation of boron atoms on HeLa cancer cells. Appeared to look.
본 발명은 이상에서 살펴본 바와 같이 바람직한 실시예를 들어 설명하였으 나, 상기한 실시예에 한정되지 아니하며, 본 발명의 정신을 벗어나지 않는 범위 내에서 당해 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 다양한 변경과 수정이 가능할 것이다.The present invention has been described with reference to the preferred embodiment as described above, but is not limited to the above-described embodiment, to those of ordinary skill in the art to which the present invention pertains without departing from the spirit of the present invention. Various changes and modifications will be possible.
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| US5462724A (en) | 1992-02-24 | 1995-10-31 | Schinazi; Raymond F. | Sensitizing agents for use in boron neutron capture therapy |
| KR20050119943A (en) * | 2004-06-17 | 2005-12-22 | 한국원자력연구소 | A 3,4-o-carboranylenepiperidine derivative, a process for the preparation thereof and a pharmaceutical composition comprising the same |
| KR100715358B1 (en) | 2005-08-17 | 2007-05-08 | 한국원자력연구소 | 2-o-carboran-1-ylmethylpiperidine derivative, a process for the preparation thereof and a pharmaceutical composition comprising the same |
| KR20080015209A (en) * | 2006-08-14 | 2008-02-19 | 한국원자력연구원 | O-carboran-1-yl-1,3,5-triazine derivative, a process for the preparation thereof and a pharmaceutical composition comprising the same |
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| US5462724A (en) | 1992-02-24 | 1995-10-31 | Schinazi; Raymond F. | Sensitizing agents for use in boron neutron capture therapy |
| KR20050119943A (en) * | 2004-06-17 | 2005-12-22 | 한국원자력연구소 | A 3,4-o-carboranylenepiperidine derivative, a process for the preparation thereof and a pharmaceutical composition comprising the same |
| KR100715358B1 (en) | 2005-08-17 | 2007-05-08 | 한국원자력연구소 | 2-o-carboran-1-ylmethylpiperidine derivative, a process for the preparation thereof and a pharmaceutical composition comprising the same |
| KR20080015209A (en) * | 2006-08-14 | 2008-02-19 | 한국원자력연구원 | O-carboran-1-yl-1,3,5-triazine derivative, a process for the preparation thereof and a pharmaceutical composition comprising the same |
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