KR19980034032A - Novel Diarylsulfonylimidazolone Derivatives - Google Patents
Novel Diarylsulfonylimidazolone Derivatives Download PDFInfo
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- KR19980034032A KR19980034032A KR1019960051939A KR19960051939A KR19980034032A KR 19980034032 A KR19980034032 A KR 19980034032A KR 1019960051939 A KR1019960051939 A KR 1019960051939A KR 19960051939 A KR19960051939 A KR 19960051939A KR 19980034032 A KR19980034032 A KR 19980034032A
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
본 발명은 하기 화학식 I로 표시되는 4-페닐-1-(N-카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론 유도체, 그의 제조방법 및 이 화합물을 유효성분으로서 함유하는 항암체 조성물에 관한 것이다.The present invention provides 4-phenyl-1- (N-carbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone derivative represented by the following formula (I), a preparation method thereof, and the compound It relates to an anticancer composition containing as an active ingredient.
[화학식][Formula]
상기식에서 X는 산소이거나 황이고, R은 메틸, 에틸, 프로필, 이소프로필, 부틸, 알릴, 사이클로헥실 등의 저급알킬기, 클로로아세틸기 또는 페닐, 벤질 등의 치환 또는 비치환된 방향족이고, R'은 수소이거나 염소이다.Wherein X is oxygen or sulfur, R is lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, allyl, cyclohexyl, chloroacetyl group or substituted or unsubstituted aromatic such as phenyl, benzyl, and R ' Is hydrogen or chlorine.
Description
본 발명은 항암작용을 갖는 신규한 디아릴 설포닐이미다졸론 유도체에 관한 것이다. 더욱 구체적으로, 본 발명은 하기 화학식 I로 표시되는 4-페닐-1-(N-카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론 유도체, 그의 제조방법 및 이 화합물을 유효성분으로서 함유하는 항암제 조성물에 관한 것이다.The present invention relates to novel diaryl sulfonylimidazolone derivatives having anticancer activity. More specifically, the present invention is 4-phenyl-1- (N-carbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone derivative represented by the following general formula (I), and a preparation method thereof And an anticancer composition comprising the compound as an active ingredient.
상기식에서 X는 산소이거나 황이고, R은 메틸, 에틸, 프로필, 이소프로필, 부틸, 알릴, 사이클로헥실 등의 저급 알킬기, 클로로아세틸기 또는 페닐, 벤질 등의 치환 또는 비치환된 방향족이고, R'은 수소이거나 염소이다.Wherein X is oxygen or sulfur, R is lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, allyl, cyclohexyl, chloroacetyl group or substituted or unsubstituted aromatic such as phenyl, benzyl, and R ' Is hydrogen or chlorine.
기존에 사용되는 항암제들은 정상세포이나 급속하게 분열되는 암세포를 많이 함유하는 백혈병과 같은 혈액암에 대한 치료제가 대부분이고 성장속도가 빠른 세포를 극히 적게 함유하고 있는 고형함에 대한 치료제는 드물다. 그러나 실제 암의 90%이상을 차지하고 있는 것은 고형함이다.Conventional anticancer drugs are mostly used for the treatment of blood cancers such as leukemia, which contains a lot of normal cells or rapidly dividing cancer cells, and there is a rare treatment for solids that contain very few fast-growing cells. But it is solid that accounts for more than 90% of the actual cancer.
최근에 디아릴 설포닐 우레아 구조를 갖는 썰로페누어가 대장암, 난소암 등과 같은 고형함에 특히 탁월한 약물로 알려져 있다. 썰로페누어는 그 작용기전이 DNA, RNA, 단백질 합성을 차단하지 않으므로 오심, 구토, 탈모 등의 부작용이 나타나지 않고 다만 과량사용에 따른 빈혈과 대사물로 생성되는 아닐린 유도체에 기인된 약한 신독성이 부작용으로 나타났다.Recently, salopenur with a diaryl sulfonyl urea structure is known to be a particularly excellent drug for solidification such as colorectal cancer, ovarian cancer and the like. Zalofenur does not block the synthesis of DNA, RNA, and protein, so it does not show side effects such as nausea, vomiting, and hair loss, but has weak renal toxicity due to aniline derivatives produced by anemia and metabolites due to overuse. It appeared to be a side effect.
따라서 썰로페뉴어와 같이 설포닐우레아 구조를 기본으로 하는 항암제를 개발하고자 하는 시도가 다양하게 이루어지고 있다.Therefore, various attempts have been made to develop anticancer drugs based on sulfonylurea structures such as saffron.
이에 따라, 본 발명자들은 썰로페뉴어와 유사한 작용기전에 의해 약효를 나타내므로서 특히 고형암에 대한 치료효과가 썰로페누어보다 훨씬 우수하며 또한 썰로페누어의 부작용을 나타내는 아닐린 유도체가 생성되지 않는 화합물을 개발하고자 광범위하고 지속적인 연구를 수행하였으며, 그 결과 다양한 신규의 디아릴설포닐우레아계 유도체를 발명하고 이미 4건의 특허를 출원한 바 있다(참조 : 한국특허원 제93-937호, 95-29425호, 96-8823호 및 96-34920호).Accordingly, the inventors of the present invention have shown that the drug is exhibited by a mechanism similar to that of Zelofenyu, in particular, the therapeutic effect of solid cancer is much better than that of Zalofenur, and also a compound that does not produce aniline derivatives exhibiting the side effects of Zalofenur is produced. Extensive and continuous research has been conducted, and as a result, various novel diarylsulfonylurea derivatives have been invented and four patents have already been filed (see Korean Patent Application Nos. 93-937, 95-29425, 96-). 8823 and 96-34920).
이에 본 발명자들은 좀 더 강력한 항암효과를 설포닐이미다졸론 화합물의 유도체를 개발하기 위하여 집중적인 연구를 수행한 결과 4-페닐-1-(인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론 화합물에서 인돌린의 1번 위치에 카바모일 또는 치오카바모일을 도입시킨 화합물이 썰로페뉴어보다 100배 이상 강력한 항암효과를 나타낼 뿐만 아니라 선출원된 화합물보다 우수한 항암효과를 나타냄을 알 수 있었으며 이에 본 발명을 완성하게 되었다.Accordingly, the present inventors conducted intensive studies to develop derivatives of sulfonylimidazolone compounds having a stronger anticancer effect, resulting in 4-phenyl-1- (indolin-5-sulfonyl) -4,5-di In the hydro-2-imidazolone compound, the compound in which carbamoyl or chiocarbamoyl was introduced at position 1 of indolin showed not only 100-fold stronger anticancer effect than that of sloefenaur, but also superior anticancer effect than the pre-registered compound. It was found that this has been completed the present invention.
따라서 본 발명은 하기 화학식 I의 4-페닐-1-(N-카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론 유도체에 관한 것이다.The present invention therefore relates to 4-phenyl-1- (N-carbamoylindoline-5-sulfonyl) -4,5-dihydro-2-imidazolone derivatives of the general formula (I).
[화학식][Formula]
상기식에서, X는 산소이거나 황이고, R은 메틸, 에틸, 프로필, 이소프로필, 부틸, 알릴, 사이클로헥실 등의 저급 알킬기, 클로로아세틸기 또는 페닐, 벤질 등의 치환 또는 비치환된 방향족이고 R'은 수소이거나 염소이다.Wherein X is oxygen or sulfur, R is lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, allyl, cyclohexyl, chloroacetyl group or substituted or unsubstituted aromatic such as phenyl, benzyl and R ' Is hydrogen or chlorine.
본 발명에 따르는 화학식 I의 화합물중에서 바람직한 것은 X는 산소이거나 황이고, R이 메틸, 에틸, 이소프로필, 프로필, 사이클로헥실, 페닐, 2-메톡시페닐, 4-메틸페닐, 4-아미노페닐을 나타내는 화합물이다.Preferred among the compounds of formula (I) according to the invention are those in which X is oxygen or sulfur and R represents methyl, ethyl, isopropyl, propyl, cyclohexyl, phenyl, 2-methoxyphenyl, 4-methylphenyl, 4-aminophenyl Compound.
특히 바람직한 화합물은 X가 산소이거나 황이고, R이 메틸, 에틸, 사이클로헥실, 페닐, 4-아미노페닐을 나타내는 화학식 I의 화합물이다.Particularly preferred compounds are those of the formula I, wherein X is oxygen or sulfur and R represents methyl, ethyl, cyclohexyl, phenyl, 4-aminophenyl.
본 발명에 따르는 화학식 I의 화합물의 대표적인 예로는 다음과 같은 화합물이 언급될 수 있다. :As representative examples of the compounds of the formula I according to the invention, the following compounds may be mentioned. :
-4-페닐-1-(N-에틸카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론,-4-phenyl-1- (N-ethylcarbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone,
-4-페닐-1-(N-페닐카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론,-4-phenyl-1- (N-phenylcarbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone,
-4-페닐-1-(N-사이클로헥실카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론,-4-phenyl-1- (N-cyclohexylcarbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone,
-4-페닐-1-(N-메틸치오카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론,4-phenyl-1- (N-methylthiocarbamoylindolin-5-sulfonyl) -4, 5-dihydro-2-imidazolone,
-4-페닐-1-[N-(4-아미노-페닐)카바모일인돌린-5-설포닐]-4, 5-디하이드로-2-이미다졸론,-4-phenyl-1- [N- (4-amino-phenyl) carbamoylindoline-5-sulfonyl] -4,5-dihydro-2-imidazolone,
본 발명은 또한 상기 화학식 I의 화합물의 제조방법에 관한 것이다.The invention also relates to a process for the preparation of compounds of formula (I).
본 발명의 방법에 따르면 화학식 I의 화합물은 하기 반응도식 1로 나타낼 수 있다.According to the method of the present invention, the compound of formula I can be represented by Scheme 1 below.
상기식에서, X, R 및 R'은 상기에서 정의한 바와 같다.Wherein X, R and R 'are as defined above.
이하에서는 본 발명의 제조방법을 구체적으로 설명한다.Hereinafter, the manufacturing method of the present invention will be described in detail.
본 발명의 방법에서 출발물질로 사용되는 화학식 Ⅱ의 화합물은 특허출원 제96-8823호에 기술된 방법에 따라 제조할 수 있다.Compounds of formula (II) used as starting materials in the process of the invention may be prepared according to the methods described in patent application 96-8823.
화학식 Ⅱ와 화학식 Ⅲ의 화합물의 반응에 바람직하게 사용되는 용매의 예로는 벤젠, 톨루엔, 디메틸포름아마이드 등이 언급될 수 있으며, 가장 바람직하게는 톨루엔을 사용한다. 반응온도 및 시간은 특별히 제한되지는 않으며, 사용되는 출발물질이나 반응물 등에 의해 적합하게 선택될 수 있다. 일반적으로 50℃-60℃에서 5시간 내지 18시간 동안 반응을 수행하여 목적화합물을 수득한다.Examples of the solvent preferably used for the reaction of the compounds of the formulas (II) and (III) may include benzene, toluene, dimethylformamide, and the like, most preferably toluene. The reaction temperature and time are not particularly limited and may be appropriately selected depending on the starting materials or reactants used. In general, the reaction is carried out at 50 ℃-60 ℃ for 5 to 18 hours to obtain the target compound.
본 발명의 방법에 의해 제조된 화학식 I의 목적화합물은 통상적인 후처리공정, 예를들면 크로마토그라피, 재결정 등과 같은 방법에 의해 분리 및 정제될 수 있다.The desired compound of formula (I) prepared by the process of the present invention can be isolated and purified by conventional post-treatment processes such as chromatography, recrystallization and the like.
본 발명에 따르는 화학식 I의 신규한 4-페닐-1-(N-카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론 및 그의 유도체들은 폐암, 대장암, 림포암, 난소암 등에 대해 강력한 항암효과를 가지고 있어서 임상적으로 유용한 항암제로서 사용될 수 있다. 따라서 본 발명은 화학식 I의 디아릴설포닐이미다졸론 유도체를 활성성분으로 함유하는 항암제 조성물에 관한 것이다.The novel 4-phenyl-1- (N-carbamoylindolin-5-sulfonyl) -4, 5-dihydro-2-imidazolone and derivatives thereof according to the present invention can be used for lung cancer, colorectal cancer, Since it has a strong anticancer effect against lymphocarcinoma, ovarian cancer, etc., it can be used as a clinically useful anticancer agent. Accordingly, the present invention relates to an anticancer composition comprising a diarylsulfonylimidazolone derivative of formula (I) as an active ingredient.
본 발명의 화합물을 활성성분으로서 함유하는 항암제 조성물은 임상적으로 이용시에 약제학적 분야에서 통상적인 담체와 함께 배합하여 약제학적 분야에서 통상적인 제제, 예를들면 정제, 캅셀제, 트로키제, 액제, 현탁제 등의 경구투여용 제제, 주사용 용액 또는 현탁액, 또는 주사시에 주사용 증류수로 제조하여 사용할 수 있는 즉시 사용형 주사용 건조분말 등의 형태인 주사용 제제, 연고제, 크림제, 액제 등의 국소적용형 제제 등의 다양한 제제로 제형화시킬 수 있다.An anticancer composition containing the compound of the present invention as an active ingredient may be combined with a conventional carrier in the pharmaceutical field when used clinically, such as tablets, capsules, troches, liquids, suspensions, etc. Injectable preparations, ointments, creams, liquids, etc., in the form of preparations for oral administration such as preparations, injectable solutions or suspensions, or ready-to-use injectable dry powders which can be prepared and used as injectable distilled water at the time of injection. It may be formulated into a variety of formulations, such as topical formulations.
본 발명의 조성물에서 사용될 수 있는 담체는 약제학적 분야에서 통상적인 것으로, 예를들면 경구투여용 제제의 경우에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등이 있으며, 주사제의 경우에는 보존제, 무통화제, 가용화제, 안정화제 등이 있고, 국소투여용 제제의 경우에는 기제, 부형제, 윤활제 보존제 등이 있다. 이렇게 제조된 약제학적 제제는 경구적으로 투여하거나, 비경구적으로, 예를들면 정맥내, 피하, 복강내 또는 국소적용 할 수 있다. 또한 경구투여시에 약제가 위산에 의해 분해되는 것을 방지하기 위하여 제산제를 병용하거나, 정제 등의 경구투여용 고형제제를 장용피로 피복된 제제로 제형화하여 투여할 수도 있다.Carriers that can be used in the compositions of the present invention are conventional in the pharmaceutical field, for example in the case of oral preparations, binders, suspending agents, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments And fragrances. In the case of injectables, there are preservatives, analgesic agents, solubilizers, stabilizers and the like, and in the case of topical administration preparations, there are bases, excipients, lubricant preservatives and the like. The pharmaceutical preparations thus prepared may be administered orally or parenterally, for example, intravenously, subcutaneously, intraperitoneally or topically. In addition, in order to prevent the decomposition of the drug by gastric acid during oral administration, antacids may be used in combination, or solid dosage forms for oral administration such as tablets may be formulated into a formulation coated with enteric skin.
본 발명에 따르는 화학식 I의 신규한 디아릴설포닐이미다졸론 유도체의 인체에 대한 투여량은 체내에서 활성성분의 흡수도, 불활성화율 및 배설속도, 환자의 연령, 성별 및 상태, 치료할 질병의 중증도 등에 따라 적절히 선택되나, 일반적으로 성인에게 1일에 10 내지 5000㎎, 바람직하게는 10 내지 1000㎎의 양이 투여되도록 한다. 따라서 본 발명의 조성물을 단위투여형으로 제조시에 각각의 단위투여형은 상기 언급된 유효용량 범위를 고려하여 화학식 I의 화합물을 10 내지 5000㎎, 바람직하게는 10 내지 1000㎎을 함유하도록 제형화시킬 수 있다. 이렇게 제형화된 단위투여형은 필요에 따라 약제의 투여를 감시하거나 관찰하는 전문가의 판단과 개인의 요구에 따라 전문화된 투약법을 사용하거나, 일정시간 간격으로 수회, 바람직하게는 1회 내지 6회 투여할 수 있다.The dosage of the novel diarylsulfonylimidazolone derivatives of the formula I according to the present invention to the human body is determined by the absorption rate, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, the severity of the disease to be treated, etc. Although appropriately selected according to the present invention, generally, an adult is administered with an amount of 10 to 5000 mg, preferably 10 to 1000 mg per day. Thus, when preparing a composition of the present invention in unit dosage form, each unit dosage form is formulated to contain 10 to 5000 mg, preferably 10 to 1000 mg of the compound of formula I in view of the above-mentioned effective dosage range. You can. The unit dosage form thus formulated uses a specialized dosage method according to the judgment of the expert who monitors or observes the administration of the drug as required and the needs of the individual, or several times, preferably 1 to 6 times at regular time intervals. May be administered.
본 발명은 하기의 실시예에 의해 더욱 상세히 설명된다. 다음의 실시예는 본 발명을 예시한 것으로 본 발명이 다음의 실시예에 국한되는 것은 아니다.The invention is illustrated in more detail by the following examples. The following examples illustrate the present invention and the present invention is not limited to the following examples.
실시예 1 : 4-페닐-1-(N-에틸카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론의 제조(화합물 (1))Example 1 Preparation of 4-phenyl-1- (N-ethylcarbamoylindolin-5-sulfonyl) -4,5-dihydro-2-imidazolone (Compound (1))
4-페닐-1-(인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론 0.25g을 톨루엔 10㎖에 용해시키고 에틸이소시아네이트 0.1㎖를 가한 후 50-60℃에서 18시간 교반시킨다. 톨루엔을 감압농축 시킨후 반응물을 메틸렌클로라이드 50㎖에 용해시켜서 물 10㎖로 2회 세척하고 무수망초로 건조시킨후 감압하에서 용매를 제거하고 생성물을 메틸렌클로라이드와 메탄올(15:1)을 사용해서 칼럼크로마토그래피하여 목적화합물 0.22g을 수득하였다.0.25 g of 4-phenyl-1- (indoline-5-sulfonyl) -4 and 5-dihydro-2-imidazolone are dissolved in 10 ml of toluene, 0.1 ml of ethyl isocyanate is added, and 18 at 50-60 ° C. Stir for time. The toluene was concentrated under reduced pressure, the reaction was dissolved in 50 ml of methylene chloride, washed twice with 10 ml of water, dried over anhydrous forget-me-not, the solvent was removed under reduced pressure, and the product was purified by using methylene chloride and methanol (15: 1). Chromatography yielded 0.22 g of the target compound.
수율 : 90%Yield: 90%
융점 : 127℃Melting Point: 127 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
1.07(t, 3H, J=9), 6.92(s, 1H, J=7.16), 3.19-3.31(m, 4H), 3.43-3.52(m, 1H), 3.94(t, 2H, J=8.7), 4.22(t, 1H, J=8.99), 4.76(t, 1H, J=7.79), 6.92(s, 1H), 7.19-7.35(m, 5H), 7.63-7.66(m, 2H), 7.93-7.97(m, 1H), 8.15(s, 1H)1.07 (t, 3H, J = 9), 6.92 (s, 1H, J = 7.16), 3.19-3.31 (m, 4H), 3.43-3.52 (m, 1H), 3.94 (t, 2H, J = 8.7) , 4.22 (t, 1H, J = 8.99), 4.76 (t, 1H, J = 7.79), 6.92 (s, 1H), 7.19-7.35 (m, 5H), 7.63-7.66 (m, 2H), 7.93- 7.97 (m, 1 H), 8.15 (s, 1 H)
실시예 1과 같은 방법으로 화합물(2) 내지 화합물(23)를 제조하였다.Compounds (2) to (23) were prepared in the same manner as in Example 1.
화합물(2) : 4-페닐-1-(N-페닐카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론Compound (2): 4-phenyl-1- (N-phenylcarbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone
수율 : 76%Yield: 76%
융점 : 246.7-248.5℃Melting Point: 246.7-248.5 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
3.15-3.60(m, 3H), 4.10-4.40(m, 3H), 4.80-4.90(m, 2H), 7.00-8.30(m, 13H)3.15-3.60 (m, 3H), 4.10-4.40 (m, 3H), 4.80-4.90 (m, 2H), 7.00-8.30 (m, 13H)
화합물(3) : 4-페닐-1-(N-사이클로헥실카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론Compound (3): 4-phenyl-1- (N-cyclohexylcarbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone
수율 : 82%Yield: 82%
융점 : 272.9-274.8℃Melting Point: 272.9-274.8 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
1.15-1.95(m, 10H), 3.18(t, 2H, J=8.8), 3.46(dd, 1H, J=6.6, 7.7), 7.20-8.05(m, 13H)1.15-1.95 (m, 10H), 3.18 (t, 2H, J = 8.8), 3.46 (dd, 1H, J = 6.6, 7.7), 7.20-8.05 (m, 13H)
화합물 (4) : 4-페닐-1-(N-메틸치오카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론Compound (4): 4-phenyl-1- (N-methylthiocarbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone
수율 : 75%Yield: 75%
융점 : 217.4-219.2℃Melting Point: 217.4-219.2 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
2.98(d, 3H, J=3.92), 3.15(t, 2H, J=8.25), 3.44-3.48(m, 1H), 4.14-4.29(m, 2H), 4.78(t, 1H, J=6.53), 7.21-7.39(m, 5H), 7.68-7.71(m, 1H), 8.19(s, 1H), 8.34-8.36(brS, 1H), 8.77(d, 1H, J=8.63)2.98 (d, 3H, J = 3.92), 3.15 (t, 2H, J = 8.25), 3.44-3.48 (m, 1H), 4.14-4.29 (m, 2H), 4.78 (t, 1H, J = 6.53) , 7.21-7.39 (m, 5H), 7.68-7.71 (m, 1H), 8.19 (s, 1H), 8.34-8.36 (brS, 1H), 8.77 (d, 1H, J = 8.63)
화합물 (5) : 4-페닐-1-(N-페닐치오카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론Compound (5): 4-phenyl-1- (N-phenylthiocarbamoylindolin-5-sulfonyl) -4, 5-dihydro-2-imidazolone
수율 : 80%Yield: 80%
융점 : 182-182.7℃Melting Point: 182-182.7 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
3.13-3.27(m, 2H), 3.41-3.51(m, 1H), 4.12-4.3(m, 3H), 4.78(t, 1H, J=7.66), 7.12-8.35(m, 13H), 10.15(s, 1H)3.13-3.27 (m, 2H), 3.41-3.51 (m, 1H), 4.12-4.3 (m, 3H), 4.78 (t, 1H, J = 7.66), 7.12-8.35 (m, 13H), 10.15 (s , 1H)
화합물 (6) : 4-페닐-1-(N-벤질카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론Compound (6): 4-phenyl-1- (N-benzylcarbamoylindolin-5-sulfonyl) -4, 5-dihydro-2-imidazolone
수율 : 72%Yield: 72%
융점 : 253-256℃Melting Point: 253-256 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
3.20(t, 2H, J=8.64), 3.38-3.48(m, 1H), 4.05(t, 2H, J=8.68), 4.22(t, 1H, J=8.92), 4.3-4.5(m, 2H), 4.75(t, 1H, J=7.49), 7.13-7.4(m, 5H), 7.52(t, 1H, J=4.82), 7.62-7.78(m, 1H), 7.95(d, 1H, J=9.17), 8.16(s, 1H)3.20 (t, 2H, J = 8.64), 3.38-3.48 (m, 1H), 4.05 (t, 2H, J = 8.68), 4.22 (t, 1H, J = 8.92), 4.3-4.5 (m, 2H) , 4.75 (t, 1H, J = 7.49), 7.13-7.4 (m, 5H), 7.52 (t, 1H, J = 4.82), 7.62-7.78 (m, 1H), 7.95 (d, 1H, J = 9.17 ), 8.16 (s, 1 H)
화합물 (7) : 4-페닐-1-(N-알킬카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론Compound (7): 4-phenyl-1- (N-alkylcarbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone
수율 : 69%Yield: 69%
융점 : 217.3-218.7℃Melting Point: 217.3-218.7 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
3.16(t, 2H, J=8.62), 3.4-3.5(m, 1H), 3.69-3.82(m, 2H), 3.69(t, 2H, J=8.88), 4.26(t, 1H, J=9.1), 4.76(t, 1H, J=7.5), 5.03-5.21(m, 2H), 5.79-6.0(m, 1H), 7.1-7.42(m, 5H), 7.68-7.73(m, 2H), 7.88-8.02(m, 1H), 8.16(s, 1H)3.16 (t, 2H, J = 8.62), 3.4-3.5 (m, 1H), 3.69-3.82 (m, 2H), 3.69 (t, 2H, J = 8.88), 4.26 (t, 1H, J = 9.1) , 4.76 (t, 1H, J = 7.5), 5.03-5.21 (m, 2H), 5.79-6.0 (m, 1H), 7.1-7.42 (m, 5H), 7.68-7.73 (m, 2H), 7.88- 8.02 (m, 1H), 8.16 (s, 1H)
화합물 (8) : 4-페닐-1-[N-(4-메톡시-페닐)치오카바모일인돌린-5-설포닐]-4, 5-디하이드로-2-이미다졸론Compound (8): 4-phenyl-1- [N- (4-methoxy-phenyl) thiocarbamoylindolin-5-sulfonyl] -4, 5-dihydro-2-imidazolone
수율 : 89%Yield: 89%
융점 : 181-183℃Melting Point: 181-183 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
3.18(t, 2H, J=8.32), 3.43-3.61(m, 1H), 3.75(s, 3H), 4.21-4.40(m, 3H), 4.81(t, 1H, J=7.45), 6.95(d, 2H, J=8.93), 7.23-7.42(m, 5H), 7.64-7.82(m, 2H), 8.17(s, 1H), 8.42(d, 2H, J=8.67), 9.96(s, 1H)3.18 (t, 2H, J = 8.32), 3.43-3.61 (m, 1H), 3.75 (s, 3H), 4.21-4.40 (m, 3H), 4.81 (t, 1H, J = 7.45), 6.95 (d , 2H, J = 8.93), 7.23-7.42 (m, 5H), 7.64-7.82 (m, 2H), 8.17 (s, 1H), 8.42 (d, 2H, J = 8.67), 9.96 (s, 1H)
화합물 (9) : 4-페닐-1-[N-(4-플루오로-페닐)치오카바모일인돌린-5-설포닐]-4, 5-디하이드로-2-이미다졸론Compound (9): 4-phenyl-1- [N- (4-fluoro-phenyl) thiocarbamoylindoline-5-sulfonyl] -4, 5-dihydro-2-imidazolone
수율 : 72%Yield: 72%
융점 : 190.5-192.5℃Melting Point: 190.5-192.5 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
3.15-3.22(m, 2H), 3.46-3.52(m, 1H), 4.23-4.38(m, 3H), 4.79(t, 1H, J=7.32), 7.16-7.44(m, 7H), 7.69-7.86(m, 2H), 8.19(s, 1H), 8.32-8.48(m, 2H), 10.07(s, 1H)3.15-3.22 (m, 2H), 3.46-3.52 (m, 1H), 4.23-4.38 (m, 3H), 4.79 (t, 1H, J = 7.32), 7.16-7.44 (m, 7H), 7.69-7.86 (m, 2H), 8.19 (s, 1H), 8.32-8.48 (m, 2H), 10.07 (s, 1H)
화합물 (10) : 4-페닐-1-(N-클로로아세틸카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론Compound (10): 4-phenyl-1- (N-chloroacetylcarbamoylindolin-5-sulfonyl) -4, 5-dihydro-2-imidazolone
수율 : 57%Yield: 57%
융점 : 228.1-229.1℃Melting Point: 228.1-229.1 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
3.22(m, 2H), 3.51(dd, 1H, J=6.6, 8.2), 4.06-4.21(m, 3H), 4.66(m, 2H), 4.73(dd, 1H, J=8.6, 7.7), 7.20-8.06(m, 13H)3.22 (m, 2H), 3.51 (dd, 1H, J = 6.6, 8.2), 4.06-4.21 (m, 3H), 4.66 (m, 2H), 4.73 (dd, 1H, J = 8.6, 7.7), 7.20 -8.06 (m, 13 H)
화합물 (11) : 4-페닐-1-[N-(2-메톡시-페닐)카바모일인돌린-5-설포닐]-4, 5-디하이드로-2-이미다졸론Compound (11): 4-phenyl-1- [N- (2-methoxy-phenyl) carbamoylindolin-5-sulfonyl] -4, 5-dihydro-2-imidazolone
수율 : 69%Yield: 69%
융점 : 201.9-203.8℃Melting Point: 201.9-203.8 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
3.20-3.58(m, 3H), 3.88(s, 3H), 4.25-4.35(m, 3H), 4.74(dd, 1H, J=6.6, 7.7), 7.05-8.20(m, 13H)3.20-3.58 (m, 3H), 3.88 (s, 3H), 4.25-4.35 (m, 3H), 4.74 (dd, 1H, J = 6.6, 7.7), 7.05-8.20 (m, 13H)
화합물 (12) : 4-페닐-1-[N-(4-메틸-페닐)카바모일인돌린-5-설포닐]-4, 5-디하이드로-2-이미다졸론Compound (12): 4-phenyl-1- [N- (4-methyl-phenyl) carbamoylindoline-5-sulfonyl] -4, 5-dihydro-2-imidazolone
수율 : 82%Yield: 82%
융점 : 222.7-224.2℃Melting Point: 222.7-224.2 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
4.25-4.30(m, 3H), 4.78-4.80(m, 1H), 7.00-8.20(m, 12H)4.25-4.30 (m, 3H), 4.78-4.80 (m, 1H), 7.00-8.20 (m, 12H)
화합물 (13) : 4-페닐-1-(N-부틸치오카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론Compound (13): 4-phenyl-1- (N-butylthiocarbamoylindolin-5-sulfonyl) -4, 5-dihydro-2-imidazolone
수율 : 93%Yield: 93%
융점 : 186.3-187.7℃Melting Point: 186.3-187.7 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
0.91(t, 3H, J=7.27), 1.28-1.37(m, 2H), 1.56-1.62(m, 2H), 3.13(t, 2H, J=8.35), 3.39-3.61(m, 3H), 4.13-4.29(m, 3H), 4.75(t, 1H, J=7.48), 7.22(d, 2H, J=6.17), 7.29-7.42(m, 3H), 7.63-7.79(m, 2H), 8.19(s, 1H), 8.3-8.42(brS, 1H), 8.62(d, 2H, J=6.17)0.91 (t, 3H, J = 7.27), 1.28-1.37 (m, 2H), 1.56-1.62 (m, 2H), 3.13 (t, 2H, J = 8.35), 3.39-3.61 (m, 3H), 4.13 -4.29 (m, 3H), 4.75 (t, 1H, J = 7.48), 7.22 (d, 2H, J = 6.17), 7.29-7.42 (m, 3H), 7.63-7.79 (m, 2H), 8.19 ( s, 1H), 8.3-8.42 (brS, 1H), 8.62 (d, 2H, J = 6.17)
화합물 (14) : 4-페닐-1-(N-에틸치오카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론Compound (14): 4-phenyl-1- (N-ethylthiocarbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone
수율 : 86%Yield: 86%
융점 : 223.1-2224.5℃Melting Point: 223.1-2224.5 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
1.67(t, 3H, J=7.09), 3.08-3.22(m, 2H), 3.42-3.67(m, 3H), 4.05-4.27(m, 3H), 4.72-4.86(m, 1H), 7.13-7.43(m, 5H), 7.62-7.8(m, 2H), 8.20(s, 1H), 8.38(t, 1H, J=4.8), 8.64(d, 1H, J=8.29)1.67 (t, 3H, J = 7.09), 3.08-3.22 (m, 2H), 3.42-3.67 (m, 3H), 4.05-4.27 (m, 3H), 4.72-4.86 (m, 1H), 7.13-7.43 (m, 5H), 7.62-7.8 (m, 2H), 8.20 (s, 1H), 8.38 (t, 1H, J = 4.8), 8.64 (d, 1H, J = 8.29)
화합물 (15) : 4-페닐-1-(N-프로필치오카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론Compound (15): 4-phenyl-1- (N-propylthiocarbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone
수율 : 86%Yield: 86%
융점 : 222.3-223.5℃Melting Point: 222.3-223.5 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
0.87(t, 3H, J=4.12), 1.62(q, 2H, J=4.57), 3.15(t, 2H, J=5.2), 3.45-3.54(m, 3H), 4.78(t, 1H, J=4.42), 7.21-7.36(m, 5H), 7.68-7.71(m, 2H), 8.18(s, 1H), 8.37(t, 1H, J=4.11), 8.63(d, 1H, J=5.47)0.87 (t, 3H, J = 4.12), 1.62 (q, 2H, J = 4.57), 3.15 (t, 2H, J = 5.2), 3.45-3.54 (m, 3H), 4.78 (t, 1H, J = 4.42), 7.21-7.36 (m, 5H), 7.68-7.71 (m, 2H), 8.18 (s, 1H), 8.37 (t, 1H, J = 4.11), 8.63 (d, 1H, J = 5.47)
화합물 (16) : 4-(4-클로로-페닐)-1-(N-에틸카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론Compound (16): 4- (4-chloro-phenyl) -1- (N-ethylcarbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone
수율 : 78%Yield: 78%
융점 : 222.3-223.4℃Melting Point: 222.3-223.4 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
1.07(t, 3H, J=4.57), 3.13-3.18(m, 4H), 3.43-3.45(m, 1H), 3.92-3.97(m, 2H), 4.22(t, 1H, J=5.62), 4.78(t, 1H, J=3.8), 6.93(s, 1H), 7.24(d, 2H, J=5.2), 7.42(d, 2H, J=5.32), 7.62-7.65(m, 2H), 7.95(d, 1H, J=5.35), 8.18(s, 1H)1.07 (t, 3H, J = 4.57), 3.13-3.18 (m, 4H), 3.43-3.45 (m, 1H), 3.92-3.97 (m, 2H), 4.22 (t, 1H, J = 5.62), 4.78 (t, 1H, J = 3.8), 6.93 (s, 1H), 7.24 (d, 2H, J = 5.2), 7.42 (d, 2H, J = 5.32), 7.62-7.65 (m, 2H), 7.95 ( d, 1H, J = 5.35), 8.18 (s, 1H)
화합물 (17) : 4-페닐-1-[N-(4-아미노-페닐)카바모일인돌린-5-설포닐]-4, 5-디하이드로-2-이미다졸론Compound (17): 4-phenyl-1- [N- (4-amino-phenyl) carbamoylindoline-5-sulfonyl] -4, 5-dihydro-2-imidazolone
수율 : 63%Yield: 63%
융점 : 158-160℃Melting Point: 158-160 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
3.15-3.44(m, 2H), 3.45-3.48(m, 1H), 4.12-4.26(m, 3H), 4.75-4.79(m, 1H), 4.87(brS, 2H), 6.54(d, 2H, J=9.15), 7.10-7.37(m, 7H), 7.66-7.70(m, 2H), 7.95(d, 1H, J=5.85), 8.15(s, 1H), 8.37(s, 1H)3.15-3.44 (m, 2H), 3.45-3.48 (m, 1H), 4.12-4.26 (m, 3H), 4.75-4.79 (m, 1H), 4.87 (brS, 2H), 6.54 (d, 2H, J) = 9.15), 7.10-7.37 (m, 7H), 7.66-7.70 (m, 2H), 7.95 (d, 1H, J = 5.85), 8.15 (s, 1H), 8.37 (s, 1H)
화합물 (18) : 4-(4-클로로-페닐)-1-(N-알릴카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론Compound (18): 4- (4-chloro-phenyl) -1- (N-allylcarbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone
수율 : 80%Yield: 80%
융점 : 213-214.3℃Melting Point: 213-214.3 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
3.17-3.20(m, 2H), 3.42-3.46(m, 1H), 3.74-3.76(m, 2H), 4.00(t, 2H, J=5.65), 4.23(t, 1H, J=5.5), 4.76-4.78(m, 1H), 5.04-5.18(m, 2H), 5.82-5.86(m, 1H), 7.12(s, 1H), 7.24(d, 2H, J=5.35), 8.16(s, 1H)3.17-3.20 (m, 2H), 3.42-3.46 (m, 1H), 3.74-3.76 (m, 2H), 4.00 (t, 2H, J = 5.65), 4.23 (t, 1H, J = 5.5), 4.76 -4.78 (m, 1H), 5.04-5.18 (m, 2H), 5.82-5.86 (m, 1H), 7.12 (s, 1H), 7.24 (d, 2H, J = 5.35), 8.16 (s, 1H)
화합물 (19) : 4-페닐-1-[N-(4-메톡시-페닐)카바모일인돌린-5-설포닐]-4, 5-디하이드로-2-이미다졸론Compound (19): 4-phenyl-1- [N- (4-methoxy-phenyl) carbamoylindoline-5-sulfonyl] -4, 5-dihydro-2-imidazolone
수율 : 68%Yield: 68%
융점 : 267.7-269.6℃Melting Point: 267.7-269.6 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
3.20-3.68(m, 3H), 3.75(s, 3H), 4.77(dd, 1H, J=6.5, 7.1), 6.85(d, 2H, J=8.9), 7.30-7.75(m, 7H), 7.73-7.75(m, 2H), 8.08(s, 1H)3.20-3.68 (m, 3H), 3.75 (s, 3H), 4.77 (dd, 1H, J = 6.5, 7.1), 6.85 (d, 2H, J = 8.9), 7.30-7.75 (m, 7H), 7.73 -7.75 (m, 2H), 8.08 (s, 1H)
화합물 (20) : 4-페닐-1-[N-(4-치오메틸-페닐)카바모일인돌린-5-설포닐]-4, 5-디하이드로-2-이미다졸론Compound (20): 4-phenyl-1- [N- (4-thiomethyl-phenyl) carbamoylindolin-5-sulfonyl] -4, 5-dihydro-2-imidazolone
수율 : 88%Yield: 88%
융점 : 260.1-261.3℃Melting Point: 260.1-261.3 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
2.45(s, 3H), 3.17-3.62(m, 3H), 4.20-4.26(m, 3H), 4.75(dd, 1H, J=6.2, 7.9), 7.16-8.11(m, 12H)2.45 (s, 3H), 3.17-3.62 (m, 3H), 4.20-4.26 (m, 3H), 4.75 (dd, 1H, J = 6.2, 7.9), 7.16-8.11 (m, 12H)
화합물 (21) : 4-(4-클로로-페닐)-1-[N-(4-아미노-페닐)카바모일인돌린-5-설포닐]-4, 5-디하이드로-2-이미다졸론Compound (21): 4- (4-chloro-phenyl) -1- [N- (4-amino-phenyl) carbamoylindoline-5-sulfonyl] -4, 5-dihydro-2-imidazolone
수율 : 69%Yield: 69%
융점 : 191-193.2℃Melting Point: 191-193.2 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
3.21-3.29(m, 2H), 3.44-3.48(m, 1H), 4.12-4.26(m, 3H), 4.75-4.79(m, 1H), 4.90(brS, 2H), 6.54(d, 2H, J=8.85), 7.10-7.43(m, 6H), 7.96(d, 1H, J=5.95), 8.15(s, 1H), 8.36(s, 1H)3.21-3.29 (m, 2H), 3.44-3.48 (m, 1H), 4.12-4.26 (m, 3H), 4.75-4.79 (m, 1H), 4.90 (brS, 2H), 6.54 (d, 2H, J = 8.85), 7.10-7.43 (m, 6H), 7.96 (d, 1H, J = 5.95), 8.15 (s, 1H), 8.36 (s, 1H)
화합물 (22) : 4-페닐-1-(N-이소프로필카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론Compound (22): 4-phenyl-1- (N-isopropylcarbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone
수율 : 89%Yield: 89%
융점 : 120-122℃Melting Point: 120-122 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
0.99-1.28(m, 6H), 3.13-3.18(m, 2H), 3.34-3.45(m, 1H), 3.84-3.99(m, 3H), 4.20-4.24(m, 1H), 4.75-4.78(m, 1H), 6.58(d, 1H, J=4.72), 7.21-7.37(m, 5H), 7.63-7.66(m, 2H), 7.95(d, 1H, J=5.2), 8.16(s, 1H)0.99-1.28 (m, 6H), 3.13-3.18 (m, 2H), 3.34-3.45 (m, 1H), 3.84-3.99 (m, 3H), 4.20-4.24 (m, 1H), 4.75-4.78 (m , 1H), 6.58 (d, 1H, J = 4.72), 7.21-7.37 (m, 5H), 7.63-7.66 (m, 2H), 7.95 (d, 1H, J = 5.2), 8.16 (s, 1H)
화합물 (23) : 4-페닐-1-(N-프로필카바모일인돌린-5-설포닐)-4, 5-디하이드로-2-이미다졸론Compound (23): 4-phenyl-1- (N-propylcarbamoylindoline-5-sulfonyl) -4, 5-dihydro-2-imidazolone
수율 : 92%Yield: 92%
융점 : 197-198.6℃Melting Point: 197-198.6 ℃
1H-NMR(DMSO-d6, ppm) : 1 H-NMR (DMSO-d 6 , ppm):
0.86(t, 1H, J=4.62), 1.48(q, 2H, J=4.4), 3.05-3.19(m, 4H), 3.43-3.45(m, 1H), 3.96(t, 2H, J=5.57), 4.22(t, 1H, J=5.55), 4.74-4.78(m, 1H), 6.93(t, 1H, J=3.47), 7.20-7.37(m, 5H), 7.63-7.65(m, 2H), 7.94-7.96(m, 1H), 8.16(s, 1H)0.86 (t, 1H, J = 4.62), 1.48 (q, 2H, J = 4.4), 3.05-3.19 (m, 4H), 3.43-3.45 (m, 1H), 3.96 (t, 2H, J = 5.57) , 4.22 (t, 1H, J = 5.55), 4.74-4.78 (m, 1H), 6.93 (t, 1H, J = 3.47), 7.20-7.37 (m, 5H), 7.63-7.65 (m, 2H), 7.94-7.96 (m, 1 H), 8.16 (s, 1 H)
실험예 1 : 시험관내 세포독성 실험Experimental Example 1 In Vitro Cytotoxicity Test
디아릴설포닐이미다졸론 유도체들의 시험관내 세포독성을 더블(double) 간격으로 암세포균주에 대하여 MTT 검색법으로 측정하였다. MTT법은 생존세포의 미토콘드리아 석시네이트 디하이드로게나제에 의해 MTT가 포르마잔 결정으로 환원되는 정도를 흡광도로 측정하여 이로부터 항암제에 의해 세포가 사멸 또는 증식억제 되는 정도를 결정하는 실험법으로, 암세포의 성장을 50% 억제하는 각 시험약물의 농도(IC50)를 구하여 독소루비신과 세포독성을 비교하였다.In vitro cytotoxicity of the diarylsulfonylimidazolone derivatives was determined by MTT screening for cancer cell strains at double intervals. The MTT method is an experimental method that determines the extent to which cells are killed or inhibited proliferation by anticancer drugs by measuring the degree of absorbance of MTT reduced to formazan crystals by mitochondrial succinate dehydrogenase of living cells. The concentration of each test drug that inhibits growth by 50% (IC 50 ) was determined and compared with doxorubicin and cytotoxicity.
각각의 시험약물을 DMSO(디메틸설폭사이드)에 20㎎/㎖의 농도로 용해시키고 0.22㎛ 필터로 여과한 후, RPMI 1640 배지를 사용하여 200㎍/㎖에서 0.0128㎍/㎖까지 공비를 5로 하여 적정농도로 희석하여 사용하였다.Each test drug was dissolved in DMSO (dimethylsulfoxide) at a concentration of 20 mg / ml and filtered through a 0.22 μm filter, followed by azeotropy of 5 from 200 μg / ml to 0.0128 μg / ml using RPMI 1640 medium. Diluted to the appropriate concentration was used.
본 시험에서는 A549 인간폐암세포, K562 인간림포람세포, SK-OV-3 인간난소암세포 및 Colo205인간대장암세포가 실험용 암세포로 사용되었다. RPMI 1640 배지에 현탁된 각각의 암세포의 현탁액 100㎍(10,000세포/웰)을 96 웰 마이크로플레이트에 접종하여 37℃, 5% CO2에 24시간 동안 배양한 후 각 웰에 상기에서 희석한 시험약물 100㎕를 최종 약물농도가 100㎍/㎖에서 0.0064㎍/㎖가 되도록 가하고 대조군에는 동량의 RPMI 1640 배지를 접종하였다. 여기에서 세포배양에는 10%(v/v) 소태자혈청, 페니실린, 스트렙토마이신이 첨가된 RPMI 1640 배지를 사용하였다. 암세포를 72시간 동안 약물에 노출시킨 후 각 웰에 MTT 용액(2㎎/㎖ 식염수 용액) 25㎍씩을 첨가하고, 다시 4시간 동안 배양한 후 원심분리(1,000rpm, 10분)하여 상등액을 제거하고 생성된 포르마잔 결정을 100㎕의 디메틸설폭사이드에 용액시켰다.In this study, A549 human lung cancer cells, K562 human lymphoma cells, SK-OV-3 human ovarian cancer cells and Colo205 human colon cancer cells were used as experimental cancer cells. 100 μg (10,000 cells / well) of each suspension of cancer cells suspended in RPMI 1640 medium was inoculated in a 96 well microplate, incubated at 37 ° C., 5% CO 2 for 24 hours, and then diluted in each well. 100 μl was added to a final drug concentration of 100 μg / ml to 0.0064 μg / ml and the control group was inoculated with the same amount of RPMI 1640 medium. Here, RPMI 1640 medium containing 10% (v / v) fetal bovine serum, penicillin, and streptomycin was used for cell culture. After exposure of the cancer cells to the drug for 72 hours, 25 μg of MTT solution (2 mg / ml saline solution) was added to each well, followed by incubation for 4 hours, followed by centrifugation (1,000 rpm, 10 minutes) to remove the supernatant. The resulting formazan crystals were solution in 100 μl of dimethylsulfoxide.
이를 마이크로플레이트 판독기를 사용하여 540nm에서 흡광도를 측정하여 대조군에 비해 암세포의 성장을 50% 억제시키는 시험약물의 농도(IC50)를 계산하였다.This was measured by absorbance at 540nm using a microplate reader to calculate the concentration of the test drug (IC 50 ) that inhibits the growth of cancer cells by 50% compared to the control.
MTT 검색법에 의한 화합물들의 인체 암세포에 대한 세포독성이 실험결과는 표 1에 기재하였다.Cytotoxicity of compounds by human MTT screening to human cancer cells is shown in Table 1.
주 : 화합물 A=선특허출원 제93-937호의 35번 화합물(=1-(p-클로로벤젠설포닐)-4-페닐-2-이미다졸리디논)Note: Compound A = Compound 35 of First Patent Application No. 93-937 (= 1- (p-chlorobenzenesulfonyl) -4-phenyl-2-imidazolidinone)
화합물 B = 선특허출원 제93-937호의 36번 화합물(=(1-5-인단설포닐)-4-페닐-2-이미다졸리디논)Compound B = Compound No. 36 of Prior Patent Application 93-937 (= (1-5-Indansulfonyl) -4-phenyl-2-imidazolidinone)
상기 표1에서 보는 바와 같이 본 발명의 화합물은 시험한 네가지 암세포주에 대하여 대조약물인 썰로페뉴어보다 10 내지 100배 이상 강력한 세포특성을 나타내며, 선특허출원 제93-937호의 화합물중 가장 우수한 35 및 36번 화합물보다도 월등히 우수한 세포특성을 나타낸다. 따라서, 본 발명의 화합물은 썰로페뉴어보다 더 강력한 항암제를 사용될 수 있음을 확인할 수 있다.As shown in Table 1, the compound of the present invention exhibits 10 to 100 times more potent cell characteristics than the control drug, sloefenyuer, for the four cancer cell lines tested, and is the most excellent compound among the compounds of the prior patent application No. 93-937. And cell characteristics superior to compound No. 36. Therefore, it can be seen that the compounds of the present invention may use a stronger anticancer agent than saffron.
실험예 2 : 급성독성실험Experimental Example 2: Acute Toxicity Test
실험동물로서 체중 20 내지 40g의 마우스를 각각의 시험화합물당 암수 각각 5마리씩을 사용하여 본 발명의 벤조일로 치환된 인돌린설포닐우레아 유도체의 급성독성을 측정하였다.Acute toxicity of the benzoyl-substituted indolinsulfonylurea derivative of the present invention was measured using 5 males and 20 females of each body weight of each test compound as experimental animals.
실험동물에서 본 발명에 따르는 화학식 I의 화합물중의 대표적인 화합물인 화합물 (1) 및 (2)를 최대 1.5g/kg까지 생리식염수 1㎖에 현탁시켜 경구투여한 후 14일간 관찰한 결과, 사망예를 발견할 수 없었다. 따라서, 본 발명에 따르는 화학식 I의 신규한 벤조일로 치환된 인돌린설포닐이미다졸론 유도체는 약효용량에서는 실질적으로 독성을 나타내지 않음을 알 수 있었다.As a result of death for 14 days after oral administration of compounds (1) and (2), which are representative compounds of the compound of formula (I) according to the present invention, were suspended in 1 ml of saline solution up to 1.5 g / kg in experimental animals. Could not be found. Thus, it was found that the indolinesulfonylimidazolone derivatives substituted with the novel benzoyl of the general formula (I) according to the present invention were not substantially toxic at the drug dose.
Claims (4)
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019960051939A KR100438482B1 (en) | 1996-11-05 | 1996-11-05 | Diarylsulfonyl imidazolone derivative having anticancer activity and preparation method thereof |
| CN97197359A CN1079096C (en) | 1996-08-22 | 1997-08-20 | Arylsulfonylimidazolone derivatives as antimumor agent |
| DE69708340T DE69708340T2 (en) | 1996-08-22 | 1997-08-20 | ARYLSULFONYLIMIDAZOLONE DERIVATIVES AS AN ANTITUARY AGENT |
| AU39529/97A AU709107B2 (en) | 1996-08-22 | 1997-08-20 | Arylsulfonylimidazolone derivatives as an antitumor agent |
| EP97936869A EP1021437B1 (en) | 1996-08-22 | 1997-08-20 | Arylsulfonylimidazolone derivatives as an antitumor agent |
| PCT/KR1997/000154 WO1998007719A1 (en) | 1996-08-22 | 1997-08-20 | Arylsulfonylimidazolone derivatives as an antitumor agent |
| JP51060898A JP3226100B2 (en) | 1996-08-22 | 1997-08-20 | Arylsulfonylimidazolone derivatives as antitumor agents |
| AT97936869T ATE208774T1 (en) | 1996-08-22 | 1997-08-20 | ARYLSULFONYLIMIDAZOLONE DERIVATIVES AS ANTI-TUMOR AGENTS |
| CA002263353A CA2263353C (en) | 1996-08-22 | 1997-08-20 | Arylsulfonylimidazolone derivatives as an antitumor agent |
| US08/915,726 US5929103A (en) | 1996-08-22 | 1997-08-21 | Arylsulfonylimidazolone derivatives as an antitumor agent |
| US09/212,396 US5932742A (en) | 1996-08-22 | 1998-12-16 | Arylsulfonylimidazolone derivatives as an antitumor agent |
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| KR1019960051939A KR100438482B1 (en) | 1996-11-05 | 1996-11-05 | Diarylsulfonyl imidazolone derivative having anticancer activity and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20030082294A (en) * | 2002-04-17 | 2003-10-22 | 주식회사 엘지생명과학 | Novel Arylsulfonylurea Derivatives, Method for Preparation Thereof and Composition for Anti-cancer Comprising the Same |
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| US5270329A (en) * | 1992-12-10 | 1993-12-14 | Eli Lilly And Company | Antitumor compositions and methods of treatment |
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| KR20030082294A (en) * | 2002-04-17 | 2003-10-22 | 주식회사 엘지생명과학 | Novel Arylsulfonylurea Derivatives, Method for Preparation Thereof and Composition for Anti-cancer Comprising the Same |
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