KR101767602B1 - Novel N-phenylpyrimidin-2-amine derivatives compound, Manufacturing method thereof, Pharmaceutical composition for preventing and treating cancer containing the same and Methods for preventing and treating cancer using the same - Google Patents
Novel N-phenylpyrimidin-2-amine derivatives compound, Manufacturing method thereof, Pharmaceutical composition for preventing and treating cancer containing the same and Methods for preventing and treating cancer using the same Download PDFInfo
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- KR101767602B1 KR101767602B1 KR1020160041198A KR20160041198A KR101767602B1 KR 101767602 B1 KR101767602 B1 KR 101767602B1 KR 1020160041198 A KR1020160041198 A KR 1020160041198A KR 20160041198 A KR20160041198 A KR 20160041198A KR 101767602 B1 KR101767602 B1 KR 101767602B1
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- cancer
- phenylpyrimidin
- derivative
- pyrimidin
- amino
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
Description
본 발명은 N-페닐피리미딘-2-아민계 화합물, 이의 제조방법, 이를 포함하는 암 예방 및 치료용 약학 조성물 및 이를 이용하여 암을 예방 또는 치료하는 방법에 관한 것이다.The present invention relates to a N-phenylpyrimidin-2-amine compound, a process for preparing the same, a pharmaceutical composition for preventing and treating cancer, and a method for preventing or treating cancer using the same.
항암 치료를 위해 자주 사용되는 항암제나 방사선은 세포가 어느 주기 단계에 속해 있는가에 따라 반응이 매우 다르며, G2기나 M기에 있는 세포가 S기 세포보다 항암제에 3배 이상 민감한 것으로 보고되어 있다. 세포주기는 다양한 Cyclin/CDK complex의 발현 및 활성화에 의해서 정밀하게 조절되는데, 세포 성장이 활발한 암세포의 경우 Cyclin 및 CDK 단백질들의 발현이 높게 유지되어 계속적인 세포 분열이 일어난다. 세포는 DNA의 정확한 복제를 위해 각 세포주기마다 이를 점검하는 체크포인트(checkpoint)가 존재하며, 세포주기를 표적으로 하는 항암제의 경우, 이 checkpoint의 기능을 교란시키는 것이 주된 목표이다.It is reported that chemotherapeutic agents and radiation often used for chemotherapy differ in response to the stage of the cell, and cells in the G2 or M phase are three times more sensitive than anticancer drugs in the S phase. The cell cycle is precisely regulated by the expression and activation of various Cyclin / CDK complexes. In cancer cells with active cell growth, the expression of cyclin and CDK proteins is maintained high, resulting in continuous cell division. Cells have a checkpoint that checks each cell cycle for accurate replication of the DNA, and for cell-cycle-targeted anticancer drugs, the primary goal is to disrupt the function of this checkpoint.
세포주기는 다양한 자극제 (주로는 세포 성장 인자)에 의해 시작되어 G1기 동안 Cyclin D/CDK4, 6 complex가 전사인자 E2F를 억제하는 망막아종(Rb: retinoblastoma) 단백질을 유리시킴으로써, 순차적인 Cyclin E/CDK2, Cyclin A/CDK2의 활성화를 통해 DNA 합성이 유도되어 S기로 진입한다. 또한 각 CDK들은 p21, p27, p53과 같은 CKI(cyclin kinase inhibitor) 단백질에 의해 억제되어 있다가 CKI의 유리에 의해 활성화되어 다음 세포주기로 진행된다. G2-M기로의 전환은 Wee1 kinase, CAK(Cdc2-activating kinase)와 Cdc25 phosphatase에 의해 정교하게 조절되는데, Cyclin B/CDK1 complex에서 Wee1에 의해 CDK1 (Y15)가 인산화되어 불활성 상태로 존재하다가 CAK에 의해 CDK (T161)의 인산화가 진행되고, 최종적으로 Cdc25에 의한 CDK1 (Y15)의 탈인산화가 Cyclin B/CDK1 (T161) complex를 활성화시켜 M기로 진행된다. The cell cycle is initiated by a variety of stimulants (primarily cell growth factors), releasing the retinoblastoma protein, a cyclin D / CDK4, 6 complex that inhibits the transcription factor E2F during the G1 phase, Activation of CDK2, Cyclin A / CDK2 induces DNA synthesis and enters the S phase. In addition, each CDK is inhibited by CKI (cyclin kinase inhibitor) proteins such as p21, p27, and p53, and is activated by the release of CKI and proceeds to the next cell cycle. The conversion to G2-M is precisely regulated by Wee1 kinase, CAK (Cdc2-activating kinase) and Cdc25 phosphatase. CDK1 (Y15) is phosphorylated by Wee1 in the cyclin B / (T161) complex is activated by the activation of the Cyclin B / CDK1 (T161) complex and finally the CDK1 (Y15) dephosphorylation by Cdc25 proceeds to the M group.
기존의 세포주기를 표적으로 한 항암제의 경우, Rb, p21(CKI), Wee1 들의 세포주기 억제 단백질을 저해함으로써 불안정한 세포주기의 진행을 유발하여 암세포의 사멸을 유도하는 것이 주요 목적이었다. 하지만 이 경우, 이미 활발한 세포주기로 적응된 암세포의 경우 오히려 더 활발한 세포분열을 유도할 수 있어 조심스러운 접근이 필요하다. 그 예로, 세포내에서 세포주기 외에 다양한 역할을 하는 Rb는 대표적인 종양 억제 유전자로, 염색체 한 copy의 돌연변이를 가지고 태어난 경우 나머지 한 copy 마저 기능을 상실(loss of function)하게 되면 매우 높은 빈도로 망막아종을 유발하는 것으로 알려져 있다. 이런 이유로 항암제 개발을 위해서 Rb 억제는 적절한 표적이 될 수 없고, 이러한 세포주기 억제인자의 저해는 조심스럽고 더욱 정밀한 접근이 요구된다.In the case of anticancer drugs targeting the existing cell cycle, the main purpose was to induce the cell cycle inhibition of Rb, p21 (CKI) and Wee1 by inhibiting the cell cycle inhibition protein, thereby inducing the death of cancer cells. In this case, however, cancer cells adapted to an already active cell cycle may induce more active cell division, requiring careful approach. For example, Rb, which plays a role in the cell cycle outside of the cell cycle, is a typical tumor suppressor gene. When a chromosomal copy mutant is born, even if the other copy is loss of function, ≪ / RTI > For this reason, Rb inhibition is not a suitable target for the development of anticancer drugs, and inhibition of these cell cycle inhibitors requires a careful and more precise approach.
방사선 치료는 세포 분열이 활발한 암 세포에 방사선을 조사함으로써 핵산 (DNA)의 절단이나 손상을 직접 유발하거나, 다양한 프리 래디칼 (자유기)을 발생시켜 세포막 구성 단백질을 변형하고 생존 신호를 교란함으로써 암세포의 성장을 억제하고 사멸을 유도한다. 이러한 과정에서 방사선이 조사된 암 세포는 손상된 핵산을 수선하기 위해 세포주기의 정지 (cell cycle arrest)가 G1기, S기, 초기 G2기에 일어나지만 암세포의 G1 checkpoint 관련 분자들은 대부분 변이가 발생되거나 제대로 기능을 담당하지 못하는 경우가 많아 G2 checkpoint에 의존하게 되므로 G2 checkpoint를 조절하는 방법이 G1 checkpoint가 정상적으로 작동되는 정상세포와의 차별성을 부여하게 되어 좋은 항암치료기술의 타겟이 되고 있다. DNA 합성 및 복제가 일어나는 S기의 세포들은 핵산 손상복구 인자들이 복합체 형성을 쉽게 함으로써 방사선에 저항성을 나타낸다. G2/M기에 정지 (G2/M arrest)된 세포군이 방사선에 민감한 이유는 이미 S기를 거쳐 초기 G2 checkpoint를 지났기 때문에 DNA 손상복구 능력을 상실했기 때문으로 해석할 수 있다. 따라서 세포 주기를 교란하는 전략, 즉 방사선에 민감한 G2/M기로 세포를 정체시키는 약물이나 저항성을 보이는 S기의 세포들을 제거하는 약물 개발이 시도하고 있다. 이러한 세포주기 교란 약물의 개발은 항암제나 방사선 조사와 병용하여 처리하였을 때 항암 치료 효과를 증진시킬 수 있을 것으로 기대된다.Radiation therapy is the treatment of cancer cells by irradiating cancer cells that are actively dividing cells to directly cause the breakage or damage of DNA (DNA), or by generating various free radicals (free radicals) It inhibits growth and induces death. In this process, cancer cells exposed to radiation have cell cycle arrest during G1, S, and early G2 to repair damaged nucleic acid, but most of the G1 checkpoint-related molecules of cancer cells are mutated The G2 checkpoints are differentiated from the normal cells in which the G1 checkpoint is normally operated, which is a target of good chemotherapy technology. S-phase cells in which DNA synthesis and replication occur are resistant to radiation by facilitating complex formation of nucleic acid damage repair factors. The reason why the G2 / M arrested cell group in G2 / M group is sensitive to radiation can be interpreted as the loss of DNA damage repair ability since it passed the initial G2 checkpoint through S phase. Therefore, there is a strategy to disturb the cell cycle, that is, drugs that stagnate the cells with the radiation-sensitive G2 / M group, or drugs that eliminate the S-cells that show resistance. It is expected that the development of such a cell cycle disturbance drug may improve the chemotherapeutic effect when it is treated in combination with an anticancer drug or radiation.
한편, 대한민국 특허공개공보 제2004-0095155호에는 N-페닐-2-피리미딘아민 유도체가 개시되어 있으나, 방사선 치료와 병용하였을 때 보다 효과를 나타내는 유도체의 개선이 필요한 실정이다.On the other hand, Korean Patent Laid-Open Publication No. 2004-0095155 discloses N-phenyl-2-pyrimidineamine derivatives, but it is necessary to improve derivatives that are more effective when used in combination with radiation therapy.
본 발명의 하나의 목적은 N-페닐 피리미딘-2-아민계 유도체 화합물 또는 그의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 암 예방 또는 암 치료용 약학 조성물을 제공하는 것이다. It is an object of the present invention to provide a pharmaceutical composition for preventing cancer or treating cancer comprising an N-phenylpyrimidin-2-amine derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명의 다른 목적은 N-페닐 피리미딘-2-아민계 유도체 또는 그의 약제학적으로 허용가능한 염과 항암제를 포함하는 항암용 약학 조성물을 제공하는 것이다.Another object of the present invention is to provide an anticancer pharmaceutical composition comprising an N-phenylpyrimidin-2-amine derivative or a pharmaceutically acceptable salt thereof and an anticancer agent.
또한, 본 발명은 상기 조성물을 인간을 제외한 개체에 투여하는 단계 및 상기 조성물을 투여한 개체에 선택적으로 방사선을 조사하는 단계를 포함하는 암 예방 또는 암 치료 방법을 제공하는 것이다.The present invention also provides a method for preventing or treating cancer, comprising administering the composition to a subject other than a human and irradiating the subject to which the composition is administered with radiation.
아울러, 본 발명은 N-페닐 피리미딘-2-아민계 유도체 화합물 또는 그의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 암 예방 또는 개선용 식품 조성물을 제공하는 것이다.In addition, the present invention provides a food composition for preventing or improving cancer comprising an N-phenylpyrimidin-2-amine derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 목적을 달성하기 위한 하나의 양태로서, 본 발명은 하기 화학식 1로 표기되는 N-페닐피리미딘-2-아민계 유도체 또는 그의 약제학적으로 허용 가능한 염을 유효성분으로 포함하는 암 예방 또는 치료용 약학 조성물을 제공한다: In one aspect, the present invention provides a method for preventing or treating cancer comprising an N-phenylpyrimidin-2-amine derivative represented by the following
상기 화학식 1에서, R1은 수소, 할로겐, 알킬, 알콕시, 사이클로알킬, 헤테로사이클로알킬, -(CH2)n사이클로알킬, -(CH2)n헤테로사이클로알킬, 아릴, 헤테로아릴, -NO2, 아미노술포닐, -C(O)알킬, -CO2알킬, -CO2H, -C(O)사이클로알킬, -C(O)헤테로사이클로알킬, -C(O)NH(알킬), -C(O)NH(할로알킬), -C(O)N(알킬)2 또는 NHC(O)알킬이며, 상기 알킬은 C1~C6 알킬, 상기 알콕시는 C1~C6 알콕시, 상기 사이클로알킬은 C3~C6 사이클로알킬, 상기 헤테로사이클로알킬은 N 또는 O를 함유하는 5 내지 6원의 헤테로사이클로알킬이고, 상기 n은 0, 1 또는 2이며, 상기 아릴은 페닐, 나프틸, 안트릴 또는 페난트릴이고, 상기 아릴은 할로겐, C1~C3 알킬 또는 C1~C3 알콕시로 치환될 수 있으며, 상기 헤테로아릴은 피리딜, 피라지닐, 피리미디닐, 피리다지닐 또는 트리아지닐이고;Wherein R 1 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, - (CH 2 ) n cycloalkyl, - (CH 2 ) n heterocycloalkyl, aryl, heteroaryl, -NO 2 , aminosulfonyl, -C (O) alkyl, -CO 2 alkyl, -CO 2 H, -C (O) cycloalkyl, -C (O) heterocycloalkyl, -C (O) NH (alkyl), - C (O) NH (haloalkyl), -C (O) N (alkyl) 2 or NHC (O) alkyl, said alkyl being C 1 -C 6 alkyl, said alkoxy being C 1 -C 6 alkoxy, Alkyl is C 3 -C 6 cycloalkyl, said heterocycloalkyl is 5- or 6-membered heterocycloalkyl containing N or O, said n is 0, 1 or 2, said aryl is phenyl, naphthyl, Trityl or phenanthryl, said aryl being optionally substituted with halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy, said heteroaryl being selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl ego;
상기 R2는 수소, 할로겐, C1~C6 알킬, C1~C6 알콕시, -NO2, -C(O)사이클로알킬 또는 C(O)헤테로사이클로알킬이며, 상기 사이클로알킬 및 헤테로사이클로알킬은 상기 R1에서와 동일하고;Said R 2 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO 2 , -C (O) cycloalkyl or C (O) heterocycloalkyl, said cycloalkyl and heterocycloalkyl Is the same as R < 1 >
상기 R3는 수소, 할로겐, C1~C6 알킬 또는 C1~C6 알콕시이며;R 3 is hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
상기 R4 및 R6는 수소, 할로겐, C1~C6 알킬, C1~C6 알콕시, 아릴, NH아릴, 헤테로아릴 또는 -NH헤테로아릴이고, 이때 상기 아릴은 치환되거나 비치환된 아릴이며, 상기 아릴은 페닐, 나프틸, 안트릴 또는 페난트릴이고, 상기 치환된 아릴은 할로겐, C1~C3 알킬, C1~C3 알콕시, 아미노설포닐, NO2, -NHC(O)알킬, -NHC(O)사이클로알킬 또는 NHC(O)헤테로사이클로알킬로 치환된 아릴이며, 상기 헤테로아릴은 피리딜, 피라지닐, 피리미디닐, 피리다지닐 또는 트리아지닐이고, 상기 사이클로알킬 및 헤테로사이클로알킬은 R1에서와 동일하며;Wherein R 4 and R 6 are hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, NHaryl, heteroaryl or -NH heteroaryl, wherein said aryl is substituted or unsubstituted aryl Wherein said aryl is phenyl, naphthyl, anthryl or phenanthryl, said substituted aryl being optionally substituted with one or more substituents selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, aminosulfonyl, NO 2 , -NHC , Aryl substituted with -NHC (O) cycloalkyl or NHC (O) heterocycloalkyl, said heteroaryl being pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl, said cycloalkyl and heterocyclo Alkyl is the same as in R < 1 & gt ;;
상기 R5는 수소, 할로겐, C1~C6 알킬 또는 C1~C6 알콕시이고; 및Wherein R 5 is hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; And
상기 R4 또는 R6와 상기 R5는 이들이 결합되어 있는 원자와 함께 6원 내지 8원의 불포화 사이클릭 고리를 형성할 수 있는데, 이때 상기 고리는 할로겐, C1~C3 알킬 또는 C1~C3 알콕시로 치환될 수 있다.Wherein R 4 or R 6 and the R 5 is can form a cyclic ring among 6-to 8-membered unsaturated together with the atom to which they are attached, wherein said ring is halogen, C 1 ~ C 3 alkyl or C 1 ~ It may be substituted with C 3 alkoxy.
본 발명의 화합물은 염, 특히 약학적으로 허용 가능한 염의 형태로 존재할 수 있다. The compounds of the present invention may exist in the form of a salt, particularly a pharmaceutically acceptable salt.
본 발명의 용어, "약학적으로 허용 가능한 염"은 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기 또는 무기부가염을 의미한다. 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산부가염과 같이, 당 업계에서 통상적으로 사용되는 염을 제한 없이 사용할 수 있다.The term "pharmaceutically acceptable salts" of the present invention refers to those salts which are relatively non-toxic to a patient and which have a harmless effective action, wherein the side-effect of the salt is not adversely affecting the efficacy of the compound of formula Quot; means any organic or inorganic addition salt. Salts include, without limitation, salts commonly used in the art, such as acid addition salts formed by pharmaceutically acceptable free acids.
산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올(예, 글리콜 모노메틸에테르)을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.
이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄설폰산, p-톨루엔설폰산, 아세트산, 트리플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 요오드화수소산(hydroiodic acid) 등을 사용할 수 있으나, 이에 제한되지 않는다.As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. As organic acids, methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid Maleic, succinic, oxalic, benzoic, tartaric, fumaric, mandelic, propionic, citric, lactic, glycolic, Gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like can be used But is not limited thereto.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속 염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상 적합하나, 이에 제한되지 않는다. 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal salt or the alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the non-soluble salt salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically acceptable to produce sodium, potassium, or calcium salt, but not limited thereto. The corresponding silver salt can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).
본 발명의 화합물의 약학적으로 허용 가능한 염은, 달리 지시되지 않는 한, 상기 화학식 1의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용 가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용 가능한 염으로는 히드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄술포네이트(메실레이트) 및 p-톨루엔술포네이트(토실레이트) 염 등이 있으며, 당 업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the compounds of this invention include, unless otherwise indicated, salts of acidic or basic groups that may be present in the compounds of formula (I). For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxy groups, and the other pharmaceutically acceptable salts of amino groups include hydrobromides, sulphates, sulphates, phosphates, hydrogen phosphates (Hydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts and the like, ≪ / RTI >
본 발명의 화학식 1로 표시되는 화합물의 약학적으로 허용 가능한 염으로는 화학식 1로 표시되는 화합물과 동등한 암세포의 증식을 억제하고 사멸을 유도하는 효과를 나타내는 화합물의 염이면 제한없이 모두 사용 가능하다.As the pharmaceutically acceptable salt of the compound represented by the formula (1) of the present invention, any salt of a compound which has the effect of inhibiting the proliferation and inducing the death of cancer cells equivalent to the compound represented by the formula (1) can be used without limitation.
또한, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은, 이의 약학적으로 허용 가능한 염뿐만 아니라 이로부터 제조될 수 있는 가능한 수화물 등의 용매화물을 제한 없이 포함한다. 상기 화학식 1로 표시되는 화합물의 용매화물은 당업계에 공지된 방법을 사용하여 화학식 1로 표시되는 화합물로부터 제조할 수 있다.In addition, the compound represented by Formula 1 according to the present invention includes not only pharmaceutically acceptable salts thereof but also solvates such as possible hydrates which can be prepared therefrom. The solvate of the compound represented by the formula (1) can be prepared from the compound represented by the formula (1) using methods known in the art.
아울러, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 결정 형태 또는 비결정 형태로 제조될 수 있으며, 결정 형태로 제조될 경우 임의로 수화되거나 용매화될 수 있다. 본 발명에서는 상기 화학식 1로 표시되는 화합물의 화학양론적 수화물뿐만 아니라 다양한 양의 물을 함유하는 화합물이 포함될 수 있다. 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 용매화물은 화학양론적 용매화물 및 비화학양론적 용매화물 모두를 포함한다.In addition, the compound represented by Formula 1 according to the present invention may be prepared in crystalline form or amorphous form, and may be optionally hydrated or solvated when prepared in crystalline form. In the present invention, compounds containing various amounts of water as well as stoichiometric hydrates of the compound represented by the formula (1) may be included. Solvates of the compounds of formula (I) according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.
본 발명의 용어, "예방"은 본 발명의 조성물의 투여로 암의 발생, 확산 및 재발을 억제시키거나 지연시키는 모든 행위를 의미하고, "치료"는 본 발명의 조성물의 투여로 상기 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.The term "prophylactic" of the present invention means any action that inhibits or delays the development, spread and recurrence of cancer by administration of the composition of the present invention, and "treatment" Means any act that improves or is beneficially modified.
본 발명의 약학적 조성물은 암세포의 증식을 억제하고 사멸을 유도함으로써 암을 예방 또는 치료할 수 있다. 구체적으로, 본 발명의 약학적 조성물을 이용하여 예방 또는 치료할 수 있는 암의 비제한적인 예는 폐암, 급성 골수성 백혈병, 만성 골수성 백혈병, 급성 림프구성 백혈병, 만성 림프구성 백혈병, 유방암, 위암, 간암, 대장암, 피부암, 두부 또는 경부암, 자궁암, 난소암, 유방암, 뇌암, 후두암, 전립선암, 방광암, 식도암, 갑상선암, 방광암, 신장암, 혈액암 또는 직장암일 수 있으며, 더욱 구체적으로 폐암, 유방암, 뇌암, 난소암, 전립선암일 수 있으나, 이에 제한되지 않는다.The pharmaceutical composition of the present invention can prevent or treat cancer by inhibiting proliferation of cancer cells and inducing death. Specific examples of the cancer that can be prevented or treated by the pharmaceutical composition of the present invention include lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, Cancer of the lungs, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, breast cancer, brain cancer, larynx cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer or rectal cancer, , Ovarian cancer, prostate cancer, but are not limited thereto.
본 발명의 구체적인 일 실시예에서는, 본 발명의 N-페닐피리미딘-2-아민계 유도체 화합물 중 6-클로로-N-(4-니트로페닐)-4-페닐퀴나졸린-2-아민(유도체 4), 4-(4-플루오로페닐)-N-(4-니트로페닐)-6-페닐피리미딘-2-아민(유도체 5), 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)-3-메톡시-N-메틸-벤즈아마이드(유도체 13), 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드(유도체 14), 4-((4-(2-클로로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드(유도체 15) 또는 N-(4-((4-(2-클로로페닐)피리미딘-2-일)아미노)페닐)아세트아마이드(유도체 17)를 인간 폐암 세포주인 A549에 처리하였을 때 세포의 생존율을 50% 이상 억제하거나 사멸을 유도하였으며(도 1), G2/M기 세포가 20% 이상 현저히 증가되고 4n 이상의 유전물질을 가지는 다핵세포도 증가된 것으로 볼 때 G2/M기 정지 효과를 가져 세포 분열을 억제하거나 비정상적인 세포 분열을 초래함을 알 수 있었으며(도 2), 나아가 사이클린 B1과 사이클린 의존 키나아제인 CDK의 발현 증가 및 CHK2의 억제를 확인하였다(도 3). 또한, 방사선과 병용처리 하였을 때 생존 콜로니수를 현저히 감소시킴으로써 항암치료효과를 증진시켰다(도 4 내지 도 6). 이는, 본 발명의 유도체가 암의 예방 또는 치료에 유용하게 사용될 수 있음을 시사하는 것이다. 하기 화학식 2는 본 발명의 N-페닐피리미딘-2-아민계 유도체 화합물 중 항암 효과를 나타내는 유도체들 중 하나인 4-((4-(2-클로로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드(유도체 15)의 구조식을 나타낸다.In one specific embodiment of the present invention, 6-chloro-N- (4-nitrophenyl) -4-phenylquinazoline-2-amine (derivative 4 (4-fluorophenyl) -6-phenylpyrimidin-2-amine (derivative 5), 4- (4-fluorophenyl) (4-fluorophenyl) pyrimidin-2-yl) amino) benzenesulfonamide (Compound 13) (4- (2-chlorophenyl) pyrimidin-2-yl) amino) benzenesulfonamide (derivative 15) or N- (4- (FIG. 1), G2 / M group cells were treated with 20% or less of G2 / M-group cells (FIG. 1) , And the number of polynuclear cells with a genetic material of 4n or more was also increased, indicating that the G2 / It was found to be the inhibition of cleavage or result in abnormal cell-dividing cells import (Fig. 2), and further confirmed the cyclin B1 and cyclin-dependent increased expression of the CDK kinase and inhibition of CHK2 (Fig. 3). In addition, when the combination treatment with radiation was performed, the number of viable colonies was remarkably decreased, thereby enhancing the effect of chemotherapy (Figs. 4 to 6). This suggests that the derivatives of the present invention can be usefully used for the prevention or treatment of cancer. (2-chlorophenyl) pyrimidin-2-yl) amino) -1,2,4-thiadiazole derivatives which are one of the derivatives exhibiting anticancer activity among N-phenylpyrimidin- Benzene sulfonamide (derivative 15).
화학식 1로 표시되는 페닐피리미딘계 유도체는 예를 들어, 4-(4-플루오로페닐)-N-페닐피리미딘-2-아민, N-(4-메톡시페닐)-4-페닐피리미딘-2-아민, N-페닐-4-(피리딘-2-일)피리미딘-2-아민, 6-클로로-N-(4-니트로페닐)-4-페닐퀴나졸린-2-아민, 4-(4-플루오로페닐)-N-(4-니트로페닐)-6-페닐피리미딘-2-아민, N-(4-((4-메틸-6-(페닐아미노)피리미딘-2-일)아미노)페닐)아세트아마이드, (3-((6-클로로-4-페닐퀴나졸린-2-일)아미노)페닐)(몰폴리노)메타논, 에틸-4-((4-(4-플루오로페닐)-6-페닐피리미딘-2-일)아미노)벤조에이트, 4-(4-플루오로페닐)-N-(4-니트로페닐)피리미딘-2-아민, 4-(4-플루오로페닐)-N,6-디페닐피리미딘-2-아민, 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)-N-메틸벤즈아마이드, 4-(4-플루오로페닐)-N-(4-(4-메틸피페라진-1-일)페닐)피리미딘-2-아민, 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)-3-메톡시-N-메틸-벤즈아마이드, 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드, 4-((4-(2-클로로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드, 4-(2-클로로페닐)-N-(3-니트로페닐)피리미딘-2-아민 및 N-(4-((4-(2-클로로페닐)피리미딘-2-일)아미노)페닐)아세트아마이드로 이루어진 군에서 선택된 어느 하나일 수 있으며, 보다 바람직하게는 4-((4-(2-클로로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드일 수 있다.The phenylpyrimidine derivatives represented by the formula (1) include, for example, 4- (4-fluorophenyl) -N-phenylpyrimidin-2-amine, N- (4-methoxyphenyl) 2-amine, 6-chloro-N- (4-nitrophenyl) -4-phenylquinazoline-2-amine, 4- (4-fluorophenyl) -N- (4-nitrophenyl) -6-phenylpyrimidin- ) Amino) phenyl) acetamide, ethyl-4 - ((4- (4- (4-fluorophenyl) (4-fluorophenyl) -6- phenylpyrimidin-2-yl) amino) benzoate, 4- (4-fluorophenyl) pyrimidin-2-yl) amino) -N-methylbenzamide, 4- ( (4- (4-fluorophenyl) pyrimidin-2- (4-fluorophenyl) pyridin-2- (4 - ((4- (4-fluorophenyl) pyrimidin-2-yl) amino) benzenesulfonamide; N- (4 - ((4- (4-fluorophenyl) pyrimidin-2-yl) amino) benzenesulfonamide; (2-chlorophenyl) pyrimidin-2-yl) amino) phenyl) acetamide, and more preferably 4 - ( -Yl) amino) benzenesulfonamide. ≪ / RTI >
상기 화학식 1로 표시되는 N-페닐피리미딘-2-아민계 유도체는 Abl, Aurora-A, Aurora-B, Aurora-C, B-Raf(V599E), CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, DDR1, FAK, FGFR1, FGFR2, FGFR3, Flt1, Flt3, Flt4, JAK1, JAK2, JAK3, KDR, Met, MST1 및 Tie2로 이루어진 군에서 선택된 어느 하나 이상의 카이네이즈 활성을 효과적으로 저해함을 확인할 수 있었다.The N-phenylpyrimidine-2-amine derivative represented by the above-mentioned formula (1) can be used in combination with Abl, Aurora-A, Aurora-B, Aurora-C, B-Raf (V599E), CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 , CDK7, CDK9, DDR1, FAK, FGFR1, FGFR2, FGFR3, Flt1, Flt3, Flt4, JAK1, JAK2, JAK3, KDR, Met, MST1 and Tie2 I could.
또한, 본 발명은 상기 화학식 1로 표시되는 N-페닐피리미딘-2-아민계 유도체 또는 그의 약학적으로 허용 가능한 염과 항암제를 혼합하여 사용할 수 있는데, 상기 항암제는 메토트렉세이트(Methotrexate), 독소루비신(Doxorubicin), 젬시타빈(Gemcitabine), 아라-C(Ara-C), 5-플루오로우라실(5-Fluorouracil), 하이드록시우레아(Hydroxyurea), 빈크리스틴(Vincristine), 빈블라스틴(Vinblastine), 캄토테신(Camptothecin), 블레오마이신(Bleomycin), 파클리탁셀(Paclitaxel) 및 도세탁셀(Docetaxel)로 이루어진 군에서 선택된 어느 하나 이상이다.Also, the present invention can be used by mixing an N-phenylpyrimidin-2-amine derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof with an anticancer agent, wherein the anticancer agent is methotrexate, doxorubicin ), Gemcitabine, ara-C, 5-fluorouracil, hydroxyurea, vincristine, vinblastine, camptothecin, Or at least one selected from the group consisting of Camptothecin, Bleomycin, Paclitaxel and Docetaxel.
또한, 본 발명의 N-페닐피리미딘-2-아민계 유도체 및 항암제를 포함하는 조성물은 상기 항암제 1 내지 99 중량% 및 N-페닐피리미딘-2-아민계 유도체 1 내지 99 중량%를 포함할 수 있다.Further, the composition comprising the N-phenylpyrimidin-2-amine derivative of the present invention and the anticancer agent comprises 1 to 99% by weight of the anticancer agent and 1 to 99% by weight of the N-phenylpyrimidine-2-amine derivative .
본 발명의 조성물은 각각의 사용 목적에 맞게 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁제, 에멀젼, 시럽, 에어로졸 등의 경구 제형, 멸균 주사용액의 주사제 등 다양한 형태로 제형화하여 사용할 수 있으며, 경구 투여하거나 정맥내, 복강내, 피하, 직장, 국소 투여 등을 포함한 다양한 경로를 통해 투여될 수 있다. 이러한 조성물에 포함될 수 있는 적합한 담체, 부형제 또는 희석제의 예로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸셀룰로즈, 미정질셀룰로스, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 들 수 있다. 또한, 본 발명의 조성물은 충전제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.The composition of the present invention may be formulated into various forms such as powders, granules, tablets, capsules, oral formulations such as suspensions, emulsions, syrups and aerosols, injections of sterilized injection solutions, and the like, And can be administered via various routes including oral administration or intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like. Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The composition of the present invention may further include a filler, an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, and the like.
경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면 전분, 탄산칼슘, 수크로스, 락토즈, 젤라틴 등을 혼합하여 제형화한다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크와 같은 윤활제가 사용될 수 있다.Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, Are mixed and formulated. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.
경구용 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 예시될 수 있으며, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Examples of the oral liquid preparation include suspensions, solutions, emulsions and syrups. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included .
비경구 투여를 위한 제제에는 멸균된 수용액제, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. 한편, 주사제에는 용해제, 등장화제, 현탁화제, 유화제, 안정화제, 방부제 등과 같은 종래의 첨가제가 포함될 수 있다.Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of suppository bases include withexol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like. On the other hand, injecting agents may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives and the like.
본 발명의 조성물은 약학적으로 유효한 양으로 투여할 수 있다. 본 발명의 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효 용량 수준은 환자의 건강상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The composition of the present invention may be administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" of the present invention means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, , The type of disease, the severity, the activity of the drug, the sensitivity to the drug, the method of administration, the time of administration, the route of administration and the rate of release, the duration of the treatment, Can be determined. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.
구체적으로, 본 발명의 조성물에서 화합물의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 kg 당 0.001 내지 100mg, 구체적으로 0.01 내지 10mg을 매일 또는 격일 투여하거나 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex, and body weight of the patient. Generally, 0.001 to 100 mg, specifically 0.01 to 10 mg per kg of body weight per day or every other day, Three doses can be administered. However, the dosage may not be limited in any way because it may be increased or decreased depending on route of administration, severity of disease, sex, weight, age, and the like.
본 발명은 다른 양태로서, 상기 조성물을 인간을 제외한 개체에 투여하는 단계를 포함하는 암 예방 또는 치료방법을 제공하며, 상기 방법은 상기 조성물을 투여한 개체에 방사선을 조사하는 단계를 추가로 포함할 수 있다.In another aspect, the present invention provides a method of preventing or treating cancer, comprising administering the composition to a subject other than a human, the method further comprising irradiating the subject to which the composition is administered with radiation .
본 발명의 용어, "개체"는 암이 발병하였거나 발병할 수 있는 인간을 포함한 원숭이, 소, 말, 양, 돼지, 고양이, 개, 쥐, 토끼 또는 기니아 피그를 포함한 모든 동물을 의미한다.The term "individual" of the present invention means all animals including monkeys, cows, horses, sheep, pigs, cats, dogs, mice, rabbits or guinea pigs, including humans who have developed or are capable of developing cancer.
본 발명의 약학적 조성물을 개체에게 투여함으로써 암을 효과적으로 예방 또는 치료할 수 있으며, 본 발명의 약학적 조성물은 기존의 치료제와 병행하여 투여될 수 있다.The cancer composition can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to an individual, and the pharmaceutical composition of the present invention can be administered concurrently with existing therapeutic agents.
본 발명의 용어, "투여"는 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비내 투여, 폐내 투여, 직장내 투여될 수 있으나, 이에 제한되지 않는다. 또한, 본 발명의 약학적 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 바람직한 투여방식 및 제제는 정맥 주사제, 피하 주사제, 피내 주사제, 근육 주사제, 점적 주사제 등이다. 주사제는 생리식염액, 링겔액 등의 수성 용제, 식물유, 고급 지방산 에스테르(예, 올레인산에틸 등), 알코올 류(예, 에탄올, 벤질알코올, 프로필렌글리콜, 글리세린 등) 등의 비수성 용제 등을 이용하여 제조할 수 있고, 변질 방지를 위한 안정화제(예, 아스코르빈산, 아황산수소나트륨, 피로아황산나트륨, BHA, 토코페롤, EDTA 등), 유화제, pH 조절을 위한 완충제, 미생물 발육을 저지하기 위한 보존제(예, 질산페닐수은, 치메로살, 염화벤잘코늄, 페놀, 크레솔, 벤질알코올 등) 등의 약학적 담체를 포함할 수 있다.The term "administering" of the present invention means providing the patient with the desired material in any suitable manner, and the administration route of the composition of the present invention can be administered through any conventional route so long as it can reach the target tissue have. But are not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrathecal, rectal. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to the target cell. The preferred modes of administration and formulations are intravenous, subcutaneous, intradermal, intramuscular, and drip injections. Injections may be prepared by using aqueous solvents such as physiological saline solution and ring gel solution, non-aqueous solvents such as vegetable oils, higher fatty acid esters (e.g., ethyl oleate), alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) (For example, ascorbic acid, sodium hydrogen sulfite, sodium pyrophosphate, BHA, tocopherol, EDTA and the like), emulsifiers, buffers for pH control, preservatives for inhibiting microbial growth (For example, mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).
본 발명에서 유효성분과 결합하여 사용된 "치료학적으로 유효한 양"이란 용어는 대상 질환을 예방 또는 치료하는데 유효한 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의 양을 의미한다.The term "therapeutically effective amount " used in combination with the active ingredient in the present invention means an amount of a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof effective for preventing or treating a target disease.
본 발명의 약학적 조성물은 예방 또는 치료하고자 하는 질환의 종류에 따라, 유효성분으로서 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염 이외의 공지된 각 질환의 예방 또는 치료에 사용되는 공지의 약물을 추가로 포함할 수 있다. 예컨대, 암질환의 예방 또는 치료에 사용되는 경우 유효성분으로서 N-페닐피리미딘-2-아민계 유도체 화합물 또는 이의 약학적으로 허용 가능한 염 이외에 상술한 바와 같은 공지된 항암제를 추가로 포함할 수 있고, 이들 질환의 치료를 위해 공지된 다른 치료와 병용될 수 있다. 다른 치료에는 화학요법, 방사선 치료, 호르몬 치료, 골수 이식, 줄기-세포 대체치료, 다른 생물학적 치료, 면역치료 등이 포함되지만, 이에 제한되지 않는다.The pharmaceutical composition of the present invention can be administered orally or dermatologically effective to prevent or treat any known disease other than the compound represented by the formula (1) or its pharmaceutically acceptable salt as an active ingredient depending on the type of disease to be prevented or treated May further comprise a drug. For example, when it is used for the prophylactic or therapeutic treatment of cancer, it may further comprise a known anticancer agent as described above in addition to the N-phenylpyrimidin-2-amine derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient , And other treatments known for the treatment of these diseases. Other therapies include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem cell replacement therapy, other biological therapies, immunotherapy, and the like.
본 발명은 다른 양태로서, 상기 화학식 1로 표시되는 화합물인 N-페닐피리미딘-2-아민계 유도체 또는 그의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 암 예방 또는 개선용 식품 조성물을 제공한다.In another aspect, the present invention provides a food composition for preventing or improving cancer, which comprises an N-phenylpyrimidin-2-amine derivative or a pharmaceutically acceptable salt thereof as an active ingredient .
이때, 상기 화학식 1로 표시되는 화합물, 약학적으로 허용 가능한 염, 및 예방의 정의는 전술한 바와 같다.Herein, the definition of the compound represented by the formula (1), the pharmaceutically acceptable salt and the prevention is as described above.
본 발명의 용어, "개선"은 본 발명의 조성물의 투여로 암이 호전 또는 이롭게 변경되는 모든 행위를 의미한다.The term "improvement" of the present invention means any action in which the administration of the composition of the present invention improves or alleviates cancer.
본 발명의 용어 "식품"은 육류, 소시지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료, 비타민 복합제, 건강 기능 식품 및 건강 식품 등이 있으며, 통상적인 의미에서의 식품을 모두 포함한다.The term "food" of the present invention is intended to encompass all kinds of foods, such as meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Vitamin complex, health functional food, and health food, all of which include foods in a conventional sense.
상기 건강 기능(성) 식품(functional food)이란, 특정보건용 식품(food for special health use, FoSHU)과 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미한다. 여기서 "기능(성)"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 식품은 당 업계에서 통상적으로 사용되는 방법에 의하여 제조 가능하며, 상기 제조시에는 당 업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 식품의 제형 또한 식품으로 인정되는 제형이면 제한 없이 제조될 수 있다. 본 발명의 식품용 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 식품은 암의 예방 또는 개선의 효과를 증진시키기 위한 보조제로 섭취가 가능하다.The term "functional food" as used herein means the same term as "food for special health use" (FoSHU). In addition to nutrition, It means food. Here, the term "function (surname)" means that the structure and function of the human body have a beneficial effect for health use such as controlling nutrients or physiological action. The food of the present invention can be prepared by a method commonly used in the art and can be prepared by adding raw materials and ingredients which are conventionally added in the art. In addition, the formulations of the food can also be produced without restrictions as long as they are formulations recognized as food. The composition for food of the present invention can be manufactured in various forms, and unlike general pharmaceuticals, it has the advantage that there is no side effect that may occur when a drug is used for a long period of time, and is excellent in portability, Can be ingested as an adjuvant to promote the effect of preventing or improving cancer.
상기 건강식품(health food)은 일반식품에 비해 적극적인 건강유지나 증진 효과를 가지는 식품을 의미하고, 건강보조식품(health supplement food)은 건강보조 목적의 식품을 의미한다. 경우에 따라, 건강기능식품, 건강식품, 건강보조식품의 용어는 호용된다.The health food refers to a food having an active health promotion or promotion effect compared with a general food, and a health supplement food refers to a food for health assistance. In some cases, the terms health functional foods, health foods, and health supplements are used.
구체적으로, 상기 건강기능식품은 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용 가능한 염을 음료, 차류, 향신료, 껌, 과자류 등의 식품소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과를 가져오는 것을 의미하나, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용이 없는 장점이 있다.Specifically, the health functional food may be prepared by adding the compound represented by the formula (1), or a pharmaceutically acceptable salt thereof, to food materials such as beverage, tea, spice, gum and confectionery, or by encapsulating, As a food, it means to have a certain health effect when ingested, but unlike general medicine, there is an advantage that there is no side effect that can occur when a drug is taken for a long time by using food as a raw material.
본 발명의 식품 조성물은, 일상적으로 섭취하는 것이 가능하기 때문에 우수한 암의 예방 또는 개선 효과를 기대할 수 있어 매우 유용하다.Since the food composition of the present invention can be ingested routinely, excellent effects of preventing or improving cancer can be expected.
상기 조성물은 약학적으로 허용 가능한 담체를 추가로 포함할 수 있는데, 담체의 종류는 특별히 제한되지 않으며 당해 기술 분야에서 통상적으로 사용되는 담체라면 어느 것이든 사용할 수 있다.The composition may further comprise a pharmaceutically acceptable carrier. The carrier is not particularly limited and any carrier conventionally used in the art may be used.
또한, 상기 조성물은 식품 조성물에 통상 사용되어 냄새, 맛, 시각 등을 향상시킬 수 있는 추가 성분을 포함할 수 있다. 예들 들어, 비타민 A, C, D, E, B1, B2, B6, B12, 니아신(niacin), 비오틴(biotin), 폴레이트(folate), 판토텐산(panthotenic acid) 등을 포함할 수 있다. 또한, 아연(Zn), 철(Fe), 칼슘(Ca), 크롬(Cr), 마그네슘(Mg), 망간(Mn), 구리(Cu), 크륨(Cr) 등의 미네랄을 포함할 수 있다. 또한, 라이신, 트립토판, 시스테인, 발린 등의 아미노산을 포함할 수 있다. In addition, the composition may contain additional ingredients which are commonly used in food compositions and which can improve odor, taste, vision and the like. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid and the like. In addition, it may include minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu) It may also include amino acids such as lysine, tryptophan, cysteine, valine, and the like.
또한, 상기 조성물은 방부제(소르빈산 칼륨, 벤조산나트륨, 살리실산, 데히드로초산나트륨 등), 살균제(표백분과 고도 표백분, 차아염소산나트륨 등), 산화방지제(부틸히드록시아니졸(BHA), 부틸히드록시톨루엔(BHT) 등), 착색제(타르색소 등), 발색제(아질산나트륨, 아초산나트륨 등), 표백제(아황산나트륨), 조미료(MSG 글루타민산나트륨 등), 감미료(둘신, 사이클레메이트, 사카린, 나트륨 등), 향료(바닐린, 락톤류 등), 팽창제(명반, D-주석산수소칼륨 등), 강화제, 유화제, 증점제(호료), 피막제, 검기초제, 거품억제제, 용제, 개량제 등의 식품 첨가물(food additives)을 포함할 수 있다. 상기 첨가물은 식품의 종류에 따라 선별되고 적절한 양으로 사용될 수 있다.In addition, the composition can be used in combination with a preservative (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate), a disinfectant (such as bleaching powder and highly bleached white powder, sodium hypochlorite), an antioxidant (butylhydroxy anisole (BHA) (Sodium hypophosphite, etc.), coloring agent (tar color, etc.), coloring agent (sodium nitrite, sodium nitrate), bleaching agent (sodium sulfite), seasoning (MSG sodium glutamate, etc.), sweetener (hypodermic, cyclamate, saccharin, sodium Etc.), flavorings (vanillin, lactones, etc.), swelling agents (alum, potassium hydrogen D-tartrate etc.), enhancers, emulsifiers, thickeners (foams), encapsulating agents, gum bases, foam inhibitors, food additives. The additives may be selected and used in appropriate amounts depending on the type of food.
상기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용 가능한 염은 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조시에 본 발명의 식품 조성물은 식품 또는 음료에 대하여 50 중량부 이하, 구체적으로 20 중량부 이하의 양으로 첨가될 수 있다. 그러나 건강 및 위생을 목적으로 장기간 섭취할 경우에는 상기 범위 이하의 함량을 포함할 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The compound represented by the formula (1), or a pharmaceutically acceptable salt thereof, may be added as it is or may be used together with other food or food ingredients, and may be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to its intended use (prevention, health or therapeutic treatment). Generally, the food composition of the present invention may be added in an amount of not more than 50 parts by weight, specifically not more than 20 parts by weight, based on the food or beverage, when the food or drink is prepared. However, in case of long-term ingestion for health and hygiene purposes, the active ingredient may be contained in an amount not exceeding the above range and there is no problem in terms of safety.
본 발명의 식품 조성물의 일 예로 건강음료 조성물로 사용될 수 있으며, 이 경우 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드; 말토스, 슈크로스와 같은 디사카라이드; 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드; 자일리톨, 소르비톨, 에리트리톨 등의 당알콜일 수 있다. 감미제는 타우마틴, 스테비아 추출물과 같은 천연 감미제; 사카린, 아스파탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 mL 당 일반적으로 약 0.01 ∼ 0.04 g, 구체적으로 약 0.02 ∼ 0.03 g이 될 수 있다.As an example of the food composition of the present invention, it can be used as a health beverage composition. In this case, various flavors or natural carbohydrates can be added as an additional ingredient like ordinary beverages. The above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose; Disaccharides such as maltose, sucrose; Polysaccharides such as dextrin, cyclodextrin; Xylitol, sorbitol, erythritol, and the like. Sweeteners include natural sweeteners such as tau Martin and stevia extract; Synthetic sweetening agents such as saccharin and aspartame, and the like. The ratio of the natural carbohydrate may be generally about 0.01 to 0.04 g, specifically about 0.02 to 0.03 g per 100 mL of the composition of the present invention.
상기 외에 건강음료 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산, 펙트산의 염, 알긴산, 알긴산의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올 또는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일주스, 과일주스 음료, 또는 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 혼합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부당 0.01 ~ 0.1 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the health beverage composition may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acid, protective colloid thickener, pH adjuster, stabilizer, Alcohols or carbonating agents, and the like. It may also contain flesh for the production of natural fruit juices, fruit juice drinks, or vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not critical, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
본 발명의 식품 조성물은 암의 예방 또는 개선 효과를 나타낼 수 있다면 다양한 중량%로 포함할 수 있으나, 구체적으로 상기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용 가능한 염을 식품 조성물의 총 중량 대비 0.00001 내지 100 중량% 또는 0.01 내지 80 중량%로 포함할 수 있다.The food composition of the present invention may be contained at various weight percentages as long as it can exhibit the preventive or ameliorative effect of cancer. Specifically, the food composition of the present invention may contain the compound of
본 발명에 따르면, 폐암, 유방암, 뇌암, 난소암, 전립선암 등을 포함하는 다양한 암 세포주에 N-페닐피리미딘-2-아민계 유도체들을 처리하는 경우 세포가 G2기에 정체되면서 세포사멸이 증가될 뿐만 아니라, 방사선 조사와 병용 처리하는 경우 세포 증식 억제 또는 세포사멸이 증가되는 효과를 보이므로, 본 발명에 따른 N-페닐피리미딘-2-아민계 유도체는 암 예방 또는 치료용 약학조성물, 항암치료 효과 증진용 조성물로 유용하게 활용될 수 있다.According to the present invention, when N-phenylpyrimidine-2-amine derivatives are treated in various cancer cell lines including lung cancer, breast cancer, brain cancer, ovarian cancer, prostate cancer and the like, cells are stuck in the G2 phase and cell death is increased In addition, since the N-phenylpyrimidine-2-amine derivative according to the present invention has an effect of inhibiting cell proliferation or increasing cell death when treated with radiation, the pharmaceutical composition for preventing or treating cancer, It can be usefully used as a composition for enhancing effects.
도 1은 인체 폐암세포주에서 N-페닐피리미딘-2-아민계 화합물들의 세포생존 억제능을 확인한 결과이다.
도 2는 인체 폐암세포주에서 N-페닐피리미딘-2-아민계 화합물들의 세포주기 교란 효과를 확인한 결과이다.
도 3은 인체 폐암세포주에서 N-페닐피리미딘-2-아민계 화합물들의 세포주기 관련 분자들의 발현 변화를 확인한 결과이다.
도 4는 인체 폐암세포주에서 N-페닐피리미딘-2-아민계 화합물들의 방사선 병용 처리시 G2/M기 정지 상승효과를 확인한 결과이다.
도 5는 인체 폐암, 유방암, 뇌암, 난소암 및 전립선암에서 N-페닐피리미딘-2-아민계 화합물들과 방사선의 병용처리시 클론 형성능을 확인한 결과이며 방사선 민감효과가 있음을 나타내는 도면이다.
도 6은 A549 인체 폐암세포 이식 마우스 모델에서 N-페닐피리미딘-2-아민계 화합물은 항암 및 방사선 민감효능을 확인한 결과이다.FIG. 1 shows the results of confirming the ability of N-phenylpyrimidin-2-amine compounds to inhibit cell survival in human lung cancer cell lines.
2 shows the result of confirming cell cycle disturbance effect of N-phenylpyrimidin-2-amine compounds in a human lung cancer cell line.
FIG. 3 shows the results of confirming the expression of cell cycle-related molecules of N-phenylpyrimidin-2-amine compounds in human lung cancer cell lines.
FIG. 4 shows the result of confirming the synergistic effect of G2 / M group stoppage in combination with radiation of N-phenylpyrimidin-2-amine compounds in a human lung cancer cell line.
FIG. 5 is a graph showing the results of confirming the ability of the N-phenylpyrimidin-2-amine compound and radiation to treat clonal formation in human lung cancer, breast cancer, brain cancer, ovarian cancer and prostate cancer, and showing a radiation sensitive effect.
FIG. 6 shows the results of confirming the anti-cancer and radiation-sensitive effects of the N-phenylpyrimidin-2-amine compound in A549 human lung cancer cell transplantation mouse model.
이하, 실시예를 통하여 본 발명을 더욱 상세하게 설명하기로 한다. 이들 실시예는 단지 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는다.Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for illustrating the present invention, and the scope of the present invention is not construed as being limited by these embodiments.
[실시예][ Example ]
N-N- 페닐피리미딘Phenylpyrimidine -- 2아민계2 amine series 유도체 화합물의 합성조건 Synthesis conditions of derivative compounds
이하 실시예에서 언급되는 모든 화학적 시약들은 상업적으로 입수 가능한 것들을 사용했으며, 추가 정제없이 사용했다. 본 실험에서 얻은 생성물의 구조 확인을 위해 사용된 기기는 하기와 같다. 핵자기 공명 스펙트럼 (H-NMR, C-NMR)은 300 MHz 또는 400MHz를, 용매는 CDC, DMSO-d6를 사용하였다. 짝지음(Coupling) 상수 ( J )는 Hz 로 표시하였다. 질량(Mass) 스펙트럼은 ESI를 사용하였으며 m/z 형태로 표시하였다.All of the chemical reagents mentioned in the following examples were commercially available and used without further purification. The equipment used to identify the structure of the product obtained in this experiment is as follows. The nuclear magnetic resonance spectrum (H-NMR, C-NMR) was 300 MHz or 400 MHz, and the solvent was CDC and DMSO-d6. The coupling constant (J) is expressed in Hz. The mass spectrum was expressed in m / z form using ESI.
페닐피리미딘-2-아민 유도체 1~8번까지 화합물은 아래 표 1에서와 같이 구매(유도체 1~5, 7~8은 Chembridge 시약사, 유도체 6은 ChemDiv 시약사에서 구매)하여 실험에 사용하였으며, 유도체 9~17번까지의 화합물은 하기 실시예를 통해 합성하여 사용하였다.Phenylpyrimidin-2-amine derivatives The
유도체 1
4-(4-플루오로페닐)-N-페닐피리미딘-2-아민
4- (4-fluorophenyl) -N-phenylpyrimidin-2-amine
유도체 2
N-(4-메톡시페닐)-4-페닐피리미딘-2-아민
N- (4-methoxyphenyl) -4-phenylpyrimidin-2-amine
유도체 3
N-페닐-4-(피리딘-2-일)피리미딘-2-아민
N-phenyl-4- (pyridin-2-yl) pyrimidin-2-amine
유도체 4
6-클로로-N-(4-니트로페닐)-4-페닐퀴나졸린-2-아민
6-Chloro-N- (4-nitrophenyl) -4-phenylquinazoline-2-amine
유도체 5
4-(4-플루오로페닐)-N-(4-니트로페닐)-6-페닐피리미딘-2-아민
4- (4-fluorophenyl) -N- (4-nitrophenyl) -6-phenylpyrimidin-
유도체 6
N-(4-((4-메틸-6-(페닐아미노)피리미딘-2-일)아미노)페닐)아세트아마이드
N- (4 - ((4-methyl-6- (phenylamino) pyrimidin-2- yl) amino) phenyl) acetamide
유도체 7
(3-((6-클로로-4-페닐퀴아졸린-2-일)아미노)페닐)(몰폴리노)메타논
(3 - ((6-chloro-4-phenylquiazolin-2-yl) amino) phenyl) (morpholino)
유도체 8
에틸-4-((4-(4-플루오로페닐)-6-페닐피리미딘-2-일)아미노)벤조에이트
Ethyl-4 - ((4- (4-fluorophenyl) -6-phenylpyrimidin-2- yl) amino) benzoate
실시예 1 : 4-(4-플루오로페닐)-N-(4-니트로페닐)피리미딘-2-아민(유도체 9) Example 1 : 4- (4-Fluorophenyl) -N- (4-nitrophenyl) pyrimidin-2-amine (Derivative 9)
다음 반응식 1로 상기 유도체 9를 합성하였다.The above-mentioned
[반응식 1][Reaction Scheme 1]
상기 1a로 표시된 1-(4-니트로페닐)구아니딘 나이트레이트 (250 ㎎, 1.04 mM)와 상기 2a로 표시된 (E)-3-(디메틸아미노)-1-(4-플루오로페닐)프롭-2-펜-1-논 (200 ㎎, 1.04 mM)을 NaOH 조건하에서 이소프로필알코올(IPA) 용액 (40 ㎖)으로 밤새 환류 교반하였다. 냉각 후, 반응 혼합물을 진공에서 농축시켰다. 잔류황색 고체로서 목적하는 4-(4-플루오로페닐)-N-(4-니트로페닐)피리미딘-2-아민 (60 ㎎)을 31% 수율로 CH2Cl2 중 Et2O 에서 재결정하여 정제하여 얻었다. (E) -3- (dimethylamino) -1- (4-fluorophenyl) prop-2-ene represented by the above 2a and 1- (4-nitrophenyl) guanidine nitrate (200 mg, 1.04 mM) was refluxed overnight with isopropyl alcohol (IPA) solution (40 mL) under NaOH conditions. After cooling, the reaction mixture was concentrated in vacuo. The desired 4- (4-fluorophenyl) -N- (4-nitrophenyl) pyrimidin-2-amine (60 mg) was recrystallized from Et 2 O in CH 2 Cl 2 in a yield of 31% Purified.
상기 수득된 유도체 9 화합물의 NMR 분석 결과는 다음과 같다.NMR analysis results of the obtained derivative 9 compound are as follows.
1H NMR (DMSO-d6, 400 MHz): δ 10.5 (1H, s), 8.68 (1H, d, J = 4.0 Hz), 8.52 (1H, s), 8.23-8.32 (3H, m), 8.10 (2H, d, J = 8.0 Hz), 7.62 (1H, d, J = 8.0 Hz), 7.42 (2H, t, J = 8.0 Hz). 1 H NMR (DMSO-d6, 400 MHz): δ 10.5 (1H, s), 8.68 (1H, d, J = 4.0 Hz), 8.52 (1H, s), 8.23-8.32 (3H, m), 8.10 ( 8.0 Hz), 7.62 (1H, d, J = 8.0 Hz), 7.42 (2H, t, J = 8.0 Hz).
실시예 2 : 4-(4-플루오로페닐)-N,6-디페닐피리미딘-2-아민(유도체 10) Example 2 : 4- (4-Fluorophenyl) -N, 6-diphenylpyrimidin-2-amine (Derivative 10)
다음 반응식 2-1로 중간체 3b인 2-클로로-4-(4-플루오로페닐)-6-페닐피리미딘을 합성하였다.2-chloro-4- (4-fluorophenyl) -6-phenylpyrimidine, intermediate 3b, was synthesized by the following reaction scheme 2-1.
[반응식 2-1][Reaction Scheme 2-1]
상기 1b로 표시된 2,4-디클로로-6-페닐피리미딘(900 ㎎, 3.99 mM) 및 상기 2b로 표시된 (4-플루오로페닐)보론산(560 ㎎, 3.99 mM)의 혼합물을 Na2CO3 (1.30g, 11.9mM), PPh3(100 ㎎, 0.399 mM) 및 Pd(OAc)2(50.0 ㎎, 0.200 mM)과 THF (45 mL) 및 H2O ( 4.5 ㎖)의 혼합물에 넣고 하룻밤 동안 60℃에서 교반하였다. 반응 혼합물을 물(20 mL)로 희석 하고, EtOAc (3 x 20 mL)로 추출한 후, 실온에서 냉각시켰다. 합한 유기층을 MgSO4로 건조시키고 여과한 다음, 진공에서 농축시켰다. 잔사를 SiO2상에서 플래시 컬럼 크로마토그래피(헥산 : EtOAc = 30 : 1 내지 20 : 1)를 이용하여 화합물을 담황색 고체로서 상기 3b로 표시된 2-클로로-4-(4-플루오로페닐)-6-페닐피리미딘 (660 ㎎, 62 % )을 얻었다.A mixture of 4-dichloro-6-phenyl-pyrimidine (900 ㎎, 3.99 mM) and marked with the 2b (4-fluorophenyl) boronic acid (560 ㎎, 3.99 mM) indicated by the 1b Na 2 CO 3 (1.30 g, 11.9 mM), PPh3 (100 mg, 0.399 mM) and Pd (OAc) 2 (50.0 mg, 0.200 mM) in THF (45 mL) and H 2 O (4.5 mL) Lt; 0 > C. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (3 x 20 mL) and then cooled to room temperature. The combined organic layers were dried with MgSO 4 and filtered and the concentrated in vacuo. The residue was purified by flash column chromatography on SiO 2 (hexane: EtOAc = 30: 1 to 20: 1) to give 2-chloro-4- (4- fluorophenyl) -6- Phenyl pyrimidine (660 mg, 62%).
상기 수득된 중간체 3b의 NMR 분석 결과는 다음과 같다.NMR analysis results of the obtained intermediate 3b are as follows.
1H NMR (CDCl3, 400MHz): δ 8.15-8.21 (4H, m), 8.00 (1H, s), 7.54-7.58 (3H, m), 7.24 (2H, d, J = 10.0 Hz). 1 H NMR (CDCl 3 , 400 MHz):? 8.15-8.21 (4H, m), 8.00 (1H, s), 7.54-7.58 (3H, m), 7.24 (2H, d, J = 10.0 Hz).
다음 반응식 2-2로 4-(4-플루오로페닐)-N,6-디페닐피리미딘-2-아민을 합성하였다.4- (4-fluorophenyl) -N, 6-diphenylpyrimidin-2-amine was synthesized by the following reaction formula 2-2.
[반응식 2-2][Reaction Scheme 2-2]
중간체 3b인 2-클로로-4-(4-플루오로페닐)-6-페닐피리미딘(80.0 ㎎, 0.280 mM) 및 아닐린(26.0 ㎎, 0.280 mM) 혼합물을 Cs2CO3(228 ㎎, 0.700 mM), BINAP(35.0 ㎎, 0.060 mM) 및 Pd(OAc)2(6.00㎎, 0.030 mM)와 디옥산(3 mL)하에 밤새 100℃에서 교반하였다. 반응 혼합물을 물(5 mL)로 희석하고, EtOAc (3 × 5 mL)로 추출한 다음, 실온에서 냉각시켰다. 합한 유기층을 MgSO4로 건조시키고 여과한 다음, 진공에서 농축시켰다. 잔류물을 SiO2 상에서 플래시컬럼크로마토그래피(헥산 : EtOAc = 20 : 1 내지 10 : 1)를 이용하여 황색 고체의 상기 유도체 10으로 표시된 4-(4-플루오로페닐)-N,6-디페닐피리미딘-2-아민(30 ㎎, 24 %)을 얻었다.A mixture of Intermediate 3b 2-chloro-4- (4-fluorophenyl) -6-phenylpyrimidine (80.0 mg, 0.280 mM) and aniline (26.0 mg, 0.280 mM) was treated with Cs 2 CO 3 (228 mg, ), BINAP (35.0 mg, 0.060 mM) and Pd (OAc) 2 (6.00 mg, 0.030 mM) and dioxane (3 mL) overnight at 100 ° C. The reaction mixture was diluted with water (5 mL), extracted with EtOAc (3 x 5 mL) and then cooled to room temperature. The combined organic layers were dried with MgSO 4 and filtered and the concentrated in vacuo. The residue was purified by flash column chromatography over SiO 2 (hexane: EtOAc = 20: 1 to 10: 1) to give 4- (4-fluorophenyl) -N, Pyrimidin-2-amine (30 mg, 24%).
상기 수득된 유도체 10 화합물의 NMR 분석 결과는 다음과 같다.NMR analysis results of the obtained derivative 10 compound are as follows.
1H NMR (DMSO-d6, 400 MHz): δ 9.75 (1H, s), 8.38-8.42 (2H, m), 8.32-8.34 (2H, m), 8.00 (1H, s), 7.91 (2H, d, J = 8.0 Hz), 7.57-7.59 (3H, m), 7.42 (2H, t, J = 10.0 Hz), 7.35 (2H, t, J = 8.0 Hz), 6.99 (1H, t, J = 8.0 Hz). 1 H NMR (DMSO-d6, 400 MHz): δ 9.75 (1H, s), 8.38-8.42 (2H, m), 8.32-8.34 (2H, m), 8.00 (1H, s), 7.91 (2H, d (2H, t, J = 8.0 Hz), 7.57-7.59 (3H, m), 7.42 ).
실시예 3 : 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)-N-메틸벤즈아마이드 (유도체 11) Example 3 ) 4 - ((4- (4-fluorophenyl) pyrimidin-2- yl) amino) -N-methylbenzamide (derivative 11)
다음 반응식 3으로 상기 유도체 11 화합물을 합성하였다.The above-mentioned derivative 11 compound was synthesized by the following
[반응식 3] [Reaction Scheme 3]
상기 1c로 표시된 4-아미노-N-메틸벤즈아마이드(50.0 ㎎, 0.335 mM) 및 상기 2c로 표시된 2-클로로-4-(4-플루오로페닐)피리미딘(69.3 ㎎, 0.335 mM)의 혼합물을 Cs2CO3(273 ㎎, 0.837 mM), BINAP(41.7 ㎎, 0.067 mM) 및 Pd(OAc)2(7.53 ㎎, 0.033 mM)와 디옥산 (3 mL)하에 밤새 100℃에서 교반하였다. 반응 혼합물을 물 (5 mL)로 희석 하고, EtOAc (3 × 5 mL)로 추출한 다음, 실온으로 냉각시켰다. 유기층을 합하여 Na2SO4상에서 건조시키고, 여과한 후, 진공에서 농축시켰다. 황색 고체로서 상기 유도체 11로 표시된 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)-N-메틸벤즈아마이드(23 ㎎, 21 %)를 Prep-TLC(EtOAc : 헥산 = 1 : 2)로 정제하여 얻었다. A mixture of 4-amino-N-methylbenzamide (50.0 mg, 0.335 mM) and 2-chloro-4- (4-fluorophenyl) pyrimidine (69.3 mg, 0.335 mM) Was stirred overnight at 100 ° C under Cs 2 CO 3 (273 mg, 0.837 mM), BINAP (41.7 mg, 0.067 mM) and Pd (OAc) 2 (7.53 mg, 0.033 mM) and dioxane (3 mL). The reaction mixture was diluted with water (5 mL), extracted with EtOAc (3 x 5 mL) and then cooled to room temperature. The combined organic layers were dried over Na 2 SO 4, filtered, and concentrated in vacuo. Prep-TLC (EtOAc: ethyl acetate) was added to a solution of 4 - ((4- (4-fluorophenyl) pyrimidin- Hexane = 1: 2).
상기 수득된 유도체 11 화합물의 NMR 분석 결과는 다음과 같다.NMR analysis results of the obtained derivative 11 compound are as follows.
1H NMR (CDCl3, 400MHz): δ 8.35-8.40 (3H, m), 7.54 (2H, d, J = 8.0 Hz), 7.37 (2H, d, J = 12.0 Hz), 7.18 (1H, brs), 7.13 (2H, t, J = 8.0 Hz), 6.75 (1H, brs), 6.53 (1H, d, J = 8.0 Hz), 2.20 (3H, s). 1 H NMR (CDCl 3, 400MHz ): δ 8.35-8.40 (3H, m), 7.54 (2H, d, J = 8.0 Hz), 7.37 (2H, d, J = 12.0 Hz), 7.18 (1H, brs) , 7.13 (2H, t, J = 8.0 Hz), 6.75 (1H, brs), 6.53 (1H, d, J = 8.0 Hz), 2.20 (3H, s).
실시예 4 : 4-(4-플루오로페닐)-N-(4-(4-메틸피페라진-1-일)페닐)피리디민-2-아민(유도체 12) Example 4 : 4- (4-fluorophenyl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-
다음 반응식 4로 상기 유도체 12 화합물을 합성하였다.The compound of the
[반응식 4][Reaction Scheme 4]
상기 1d로 표시된 4-(4-메틸피레라진-1-일)아닐린(138 ㎎, 0.720 mM) 및 상기 2d로 표시된 2-클로로-4-(4-플루오로페닐)피리미딘(150 ㎎, 0.720 mM)의 혼합물을 Cs2CO3(590 ㎎, 1.80 mM), BINAP (90.0 ㎎, 0.144 mM) 및 Pd(OAc)2 (16.0 ㎎, 0.072 mM), 디옥산 (7 mL)하에 밤새 100℃에서 교반하였다. 반응 혼합물을 물 (10 mL)로 희석 하고, EtOAc (3 × 10 mL)로 추출한 후, 실온으로 냉각시켰다. 유기층을 합하여 Na2SO4상에서 건조시키고, 여과한 다음, 진공에서 농축시켰다. 잔류화합물을 Et2O 에서 플래시 칼럼의 SiO2상에서 크로마토그래피 및 재결정에 의해 정제하여 황색고체인 상기 유도체 12로 표시된 4-(4-플루오로페닐)-N-(4-(4-메틸피페라진-1-일)페닐)피리미딘-2-아민(50 ㎎, 23 %)을 얻었다. (138 mg, 0.720 mmol) and 2-chloro-4- (4-fluorophenyl) pyrimidine (150 mg, 0.720 mmol) The reaction mixture was stirred at 100 ° C overnight under Cs 2 CO 3 (590 mg, 1.80 mM), BINAP (90.0 mg, 0.144 mM) and Pd (OAc) 2 (16.0 mg, 0.072 mM) Lt; / RTI > The reaction mixture was diluted with water (10 mL), extracted with EtOAc (3 x 10 mL) and then cooled to room temperature. The combined organic layers were dried over Na 2 SO 4, filtered and then concentrated in vacuo. The residue compound was purified by chromatography and recrystallization on SiO 2 of the flash column in Et 2 O indicated by the derivative 12 of a yellow solid of 4- (4-fluorophenyl) -N- (4- (4-methylpiperazine Yl) phenyl) pyrimidin-2-amine (50 mg, 23%).
상기 수득된 유도체 12 화합물의 NMR 분석 결과는 다음과 같다.NMR analysis results of the obtained derivative 12 compound are as follows.
1H NMR (CDCl3,400MHz): δ 8.35-8.41 (2H, m), 8.30 (1H, d, J = 4.0 Hz), 7.24-7.28 (2H, m), 7.13 (2H, t, J = 8.0 Hz), 6.97 (2H, d, J = 8.0 Hz), 6.68 (1H, brs), 6.45 (1H, d, J = 4.0 Hz), 3.23 (4H, t, J = 6.0 Hz), 2.60 (4H, d, J = 6.0 Hz), 2.37 (3H, s). 1 H NMR (CDCl 3, 400MHz ): δ 8.35-8.41 (2H, m), 8.30 (1H, d, J = 4.0 Hz), 7.24-7.28 (2H, m), 7.13 (2H, t, J = 8.0 (1H, d, J = 4.0 Hz), 6.97 (2H, d, J = 8.0 Hz), 6.68 (1H, brs), 6.45 d, J = 6.0 Hz), 2.37 (3H, s).
실시예 5 : 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)-3-메톡시-N-메틸 벤즈아마이드(유도체 13) Example (5 -fluorophenyl) pyrimidin-2-yl) amino) -3-methoxy-N-methylbenzamide (derivative 13)
다음 반응식 5로 상기 유도체 13 화합물을 합성하였다.The above-described derivative 13 compound was synthesized by the following
[반응식 5][Reaction Scheme 5]
상기 1e로 표시된 4-아미노-3-메톡시-N-메틸벤즈아마이드(100 ㎎, 0.554 mM) 및 상기 2e로 표시된 2-클로로-4-(4-플루오로페닐)피리미딘(116 ㎎, 0.554 mM)의 혼합물을 Cs2CO3(452 ㎎, 1.39 mM), BINAP(69.1 ㎎, 0.111 mM) 및 Pd(OAc)2(12.4 ㎎, 0.055 mM)과 디옥산 (5 mL)에 넣고 밤새 100℃에서 교반하였다. 반응 혼합물을 물(10 mL)로 희석하고, EtOAc (3 × 10 mL)로 추출한 다음, 실온으로 냉각시켰다. 유기층을 합하여 Na2SO4상에서 건조시키고, 여과한 후, 진공에서 농축시켰다. 잔류화합물을 Prep-TLC(EtOAc만 사용)에 의해 정제하여 황색 고체인 상기 유도체 13으로 표시된 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)-3-메톡시-N-메틸벤즈아마이드(72 ㎎, 37 %)을 얻었다.To a solution of 4-amino-3-methoxy-N-methylbenzamide (100 mg, 0.554 mmol) and 2-chloro-4- (4- fluorophenyl) pyrimidine was added to Cs 2 CO 3 (452 mg, 1.39 mM), BINAP (69.1 mg, 0.111 mM) and Pd (OAc) 2 (12.4 mg, 0.055 mM) and dioxane (5 mL) Lt; / RTI > The reaction mixture was diluted with water (10 mL), extracted with EtOAc (3 x 10 mL), and then cooled to room temperature. The combined organic layers were dried over Na 2 SO 4, filtered, and concentrated in vacuo. The residual compound was purified by Prep-TLC (EtOAc only) to give 4 - ((4- (4-fluorophenyl) pyrimidin-2- yl) amino) -3-methoxy -N-methylbenzamide (72 mg, 37%).
상기 수득된 유도체 13 화합물의 NMR 분석 결과는 다음과 같다.NMR analysis results of the obtained
1H NMR (CDCl3, 400MHz): δ 8.35-8.41 (2H, m), 8.30 (1H, d, J = 4.0 Hz), 7.24-7.28 (2H, m), 7.13 (2H, t, J = 8.0 Hz), 6.97 (2H, d, J = 8.0 Hz), 6.68 (1H, brs), 6.45 (1H, d, J = 4.0 Hz), 3.23 (4H, t, J = 6.0 Hz), 2.60 (4H, d, J = 6.0 Hz), 2.37 (3H, s). 1 H NMR (CDCl 3, 400MHz ): δ 8.35-8.41 (2H, m), 8.30 (1H, d, J = 4.0 Hz), 7.24-7.28 (2H, m), 7.13 (2H, t, J = 8.0 (1H, d, J = 4.0 Hz), 6.97 (2H, d, J = 8.0 Hz), 6.68 (1H, brs), 6.45 d, J = 6.0 Hz), 2.37 (3H, s).
실시예 6 : 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드(유도체 14) Example 6: 4 - ((4- (4-phenyl) pyrimidin-2-yl) amino-fluorophenoxy) benzenesulfonamide (derivative 14)
다음 반응식 6-1을 통해 중간체 3f 화합물인 2-클로로-4-(4-플루오로페닐)피리미딘을 합성하였다.2-chloro-4- (4-fluorophenyl) pyrimidine, which is an intermediate 3f compound, was synthesized through the following reaction scheme 6-1.
[반응식 6-1][Reaction Scheme 6-1]
톨루엔 수용액(60㎖)에 상기 1f로 표시된 2,4-디클로로피리미딘(1.00g, 6.71 mM) 및 상기 2f로 표시된 (4-플루오로페닐)보론산(1.00 g, 7.35 mM)의 혼합물 K2CO3 (2.80 g, 20.1 mM) 및 Pd(PPh3)4 (400 ㎎, 0.340 mM)를 EtOH (20 mL) 및 H2O (20 mL)하에서 밤새 60℃에서 교반하였다. 반응 혼합물을 물 (50 mL)로 희석하고, EtOAc (3 × 30 mL)로 추출한 다음, 실온으로 냉각시켰다. 유기층을 합하여 Na2SO4상에서 건조시키고, 여과한 후, 진공에서 농축시켰다. 잔류물을 MPLC (헥산 : EtOAc = 1 : 10, 열 울트라 100g SNAP)에 의해 정제하여 엷은 황색 고체인 상기 3f로 표시된 2-클로로-4-(4-플루오로페닐)피리미딘(1.50 g , 89 % )을 얻었다.A mixture of K 2 (1.00 g, 7.35 mM) of the above-mentioned 2f (4-fluorophenyl) boronic acid (1.00 g, 6.71 mmol) and 2,4-dichloropyrimidine CO 3 (2.80 g, 20.1 mmol) and Pd (PPh 3 ) 4 (400 mg, 0.340 mM) were stirred at 60 ° C under EtOH (20 mL) and H 2 O (20 mL) overnight. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (3 x 30 mL) and then cooled to room temperature. The combined organic layers were dried over Na 2 SO 4, filtered, and concentrated in vacuo. The residue was purified by MPLC (hexane: EtOAc = 1:10, column Ultra 100 g SNAP) to give 2-chloro-4- (4-fluorophenyl) pyrimidine as a pale yellow solid (1.50 g, 89 %).
상기 수득된 중간체 화합물 3f의 NMR 분석 결과는 다음과 같다.The NMR analysis results of the obtained intermediate compound 3f are as follows.
1H NMR (CDCl3, 400MHz): δ 8.64 (1H, d, J = 8.0 Hz), 8.10-8.14 (2H, m), 7.61 (1H, d, J = 8.0 Hz), 7.18-7.23 (2H, m). 1 H NMR (CDCl 3, 400MHz ): δ 8.64 (1H, d, J = 8.0 Hz), 8.10-8.14 (2H, m), 7.61 (1H, d, J = 8.0 Hz), 7.18-7.23 (2H, m).
다음 반응식 6-2로 유도체 14 화합물인 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드를 합성하였다.4 - ((4- (4-fluorophenyl) pyrimidin-2-yl) amino) benzenesulfonamide was synthesized by the following reaction scheme 6-2.
[반응식 6-2][Reaction Scheme 6-2]
중간체 3f 화합물인 2-클로로-4-(4-플루오로페닐)피리미딘(200 ㎎, 0.960 mM) 및 상기 4f로 표시된 4-아미노벤젠설폰아마이드(170 ㎎, 0.960 mM)의 혼합물에 K2CO3(400 ㎎, 2.88 mM), Xphos(46.0 ㎎, 0.100 mM) 및 Pd2(dba)3(44.0 ㎎, 0.050 mmol)을 t-BuOH의 현탁액(5mL)에서 하룻밤 동안 환류 교반 하였다. 반응 혼합물을 물 (10 mL)로 희석하고, EtOAc(3 × 10 mL)로 추출한 다음, 실온으로 냉각시켰다. 유기층을 합하여 Na2SO4상에서 건조시키고, 여과한 후, 진공에서 농축시켰다. 잔류물을 Prep-TLC 크로마토그래피(CH2Cl2 중 : 메탄올 = 10 : 1)를 통해 담황색 고체인 상기 유도체 14로 표시된 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드(56 ㎎, 23 %)를 얻었다. 상기 수득된 유도체 14 화합물의 NMR 분석 결과는 다음과 같다.To a mixture of intermediate compound 3f 2-chloro-4- (4-fluorophenyl) pyrimidine (200 ㎎, 0.960 mM) and 4-amino-benzenesulfonamide (170 ㎎, 0.960 mM) indicated by the K 2 CO 4f 3 (400 mg, 2.88 mM), Xphos (46.0 mg, 0.100 mM) and Pd 2 (dba) 3 (44.0 mg, 0.050 mmol) were stirred at reflux overnight in a suspension of t-BuOH (5 mL). The reaction mixture was diluted with water (10 mL), extracted with EtOAc (3 x 10 mL), and then cooled to room temperature. The combined organic layers were dried over Na 2 SO 4, filtered, and concentrated in vacuo. The residue was purified via Prep-TLC chromatography (in CH 2 Cl 2 : methanol = 10: 1) to give 4 - ((4- (4- fluorophenyl) pyrimidin- ) Amino) benzenesulfonamide (56 mg, 23%). The NMR analysis results of the obtained
1H NMR (DMSO-d6, 400 MHz): δ 10.1 (1H, s), 8.62 (1H, d, J = 4.0 Hz), 8.26 (2H, dd, J = 10.0, 4.0 Hz), 7.99 (2H, d, J = 8.0 Hz), 7.77 (2H, d, J = 8.0 Hz), 7.52 (1H, d, J = 4.0 Hz), 7.41 (2H, t, J = 10.0 Hz), 7.19 (2H, s). 1 H NMR (DMSO-d6, 400 MHz): δ 10.1 (1H, s), 8.62 (1H, d, J = 4.0 Hz), 8.26 (2H, dd, J = 10.0, 4.0 Hz), 7.99 (2H, J = 8.0 Hz), 7.77 (2H, d, J = 8.0 Hz), 7.52 (1H, d, J = 4.0 Hz), 7.41 .
실시예 7 : 4-((4-(2-클로로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드(유도체 15) Example 7 ) 4 - ((4- (2-chlorophenyl) pyrimidin-2-yl) amino) benzenesulfonamide (derivative 15)
다음 반응식 7-1을 통해 중간체 화합물 3g인 2-브로모-4-(2-클로로페닐)피리미딘을 합성하였다.2-bromo-4- (2-chlorophenyl) pyrimidine, 3g of the intermediate compound, was synthesized through the following reaction scheme 7-1.
[반응식 7-1][Reaction Scheme 7-1]
톨루엔 수용액(6 ㎖)에 상기 1g로 표시된 2,4-디브로모피리미딘(400 ㎎, 1.68 mM) 및 상기 2g로 표시된 (2-클로로페닐)보론산(289 ㎎, 1.85 mM)의 혼합물에 K2CO3(465 mg, 3.36 mM)과 Pd(PPh3)4(97.1 ㎎, 0.084 mM)을 EtOH (2 mL) 및 H2O (2 mL)에 가한 다음 밤새 60℃에서 교반하였다. 반응 혼합물을 물 (10 mL)로 희석하고, EtOAc (3 × 10 mL)로 추출한 후, 실온으로 냉각시켰다. 유기층을 합하여 Na2SO4상에서 건조시키고 여과한 다음, 진공에서 농축시켰다. 잔사를 SiO2 상에서 플래시 컬럼 크로마토 그래피(헥산 : EtOAc = 5 : 1)를 이용하여 헥산에서 재결정하여 백색 고체인 상기 3g로 표시된 2-브로모-4-(2-클로로페닐)피리미딘(160mg , 35 %)을 얻었다.To a mixture of 2,4-dibromopyrimidine (400 mg, 1.68 mM) and 2g (2-chlorophenyl) boronic acid (289 mg, 1.85 mM) shown above as 1g in an aqueous toluene solution (6 ml) K 2 CO 3 (465 mg, 3.36 mM) and Pd (PPh 3 ) 4 (97.1 mg, 0.084 mM) were added to EtOH (2 mL) and H 2 O (2 mL) and stirred overnight at 60 ° C. The reaction mixture was diluted with water (10 mL), extracted with EtOAc (3 x 10 mL) and then cooled to room temperature. The combined organic layers were dried over Na 2 SO 4, filtered and then concentrated in vacuo. The residue was recrystallized in hexane using flash column chromatography on SiO 2 (hexane: EtOAc = 5: 1) to obtain 2-bromo-4- (2- chlorophenyl) pyrimidine (160 mg, 35%).
상기 수득된 중간체 화합물 3g의 NMR 분석 결과는 다음과 같다.The NMR analysis results of the obtained intermediate compound 3g are as follows.
1H NMR (CDCl3,400MHz): δ 8.62 (1H, d, J = 4.0 Hz), 7.77 (1H, dd, J = 8.0, 4.0 Hz), 7.70-7.75 (1H, m), 7.48-7.53 (1H, m), 7.41-7.45 (2H, m). 1 H NMR (CDCl 3, 400MHz ): δ 8.62 (1H, d, J = 4.0 Hz), 7.77 (1H, dd, J = 8.0, 4.0 Hz), 7.70-7.75 (1H, m), 7.48-7.53 ( 1H, < / RTI > m), 7.41-7.45 (2H, m).
다음 반응식 7-2로 유도체 15 화합물인 4-((4-(2-클로로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드를 합성하였다.4 - ((4- (2-chlorophenyl) pyrimidin-2-yl) amino) benzenesulfonamide was synthesized by the following reaction scheme 7-2.
[반응식 7-2][Reaction Scheme 7-2]
상기 중간체 화합물 3g인 2-브로모-4-(2-클로로페닐)피리미딘(50.0 ㎎, 0.185 mM) 및 상기 4g로 표시된 4-아미노벤젠설폰아마이드(35.1 ㎎, 0.204 mM)의 혼합물에 K2CO3(51.3 ㎎, 0.371 mM), Xphos(8.84 ㎎, 0.018 mM) 및 Pd2(dba)3 (8.49 ㎎, 0.009 mmol)을 t-BuOH의 현탁액(2 mL)에서 하룻밤 동안 환류 교반하였다. 반응 혼합물을 물 (5 mL)로 희석 하고, EtOAc (3 × 5 mL)로 추출한 다음, 실온으로 냉각시켰다. 유기층을 합하여 Na2SO4 상에서 건조시키고, 여과한 후, 진공에서 농축시켰다. 잔류물을 메탄올을 사용하여 재결정, 정제하고 옅은 황색 고체인 상기 유도체 15로 표시된 4-((4-(2-클로로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드(27 ㎎, 40 %)를 얻었다. To a mixture of the intermediate compound 3g of 2-bromo-4- (2-chlorophenyl) pyrimidine (50.0 ㎎, 0.185 mM) and 4-amino-benzenesulfonamide (35.1 ㎎, 0.204 mM) indicated by the K 2 4g CO 3 and stirred under reflux overnight (51.3 ㎎, 0.371 mM), Xphos (8.84 ㎎, 0.018 mM) and Pd 2 (dba) 3 (8.49 ㎎, 0.009 mmol) and the suspension (2 mL) in t-BuOH. The reaction mixture was diluted with water (5 mL), extracted with EtOAc (3 x 5 mL) and then cooled to room temperature. The combined organic layers were dried over Na 2 SO 4, filtered, and concentrated in vacuo. The residue was recrystallized and recrystallized using methanol to give 4 - ((4- (2-chlorophenyl) pyrimidin-2-yl) amino) benzenesulfonamide (27 mg, 40%) as a pale yellow solid, ).
상기 수득된 유도체 15 화합물의 NMR 분석 결과는 다음과 같다.NMR analysis results of the obtained derivative 15 compound are as follows.
1H NMR (DMSO-d6, 400 MHz): δ 10.2 (1H, s), 8.66 (1H, d, J = 8.0 Hz), 7.96 (2H, d, J = 8.0 Hz), 7.72 (2H, d, J = 8.0 Hz), 7.62-7.69 (2H, m), 7.52-7.56 (2H, m), 7.20 (1H, d, J = 4.0 Hz), 7.28 (2H, s). 1 H NMR (DMSO-d6, 400 MHz): δ 10.2 (1H, s), 8.66 (1H, d, J = 8.0 Hz), 7.96 (2H, d, J = 8.0 Hz), 7.72 (2H, d, J = 8.0 Hz), 7.62-7.69 (2H, m), 7.52-7.56 (2H, m), 7.20 (1H, d, J = 4.0 Hz), 7.28 (2H, s).
실시예 8 : 4-(2-클로로페닐)-N-(3-니트로페닐)피리미딘-2-아민(유도체 16) Example 8 : 4- (2-Chlorophenyl) -N- (3-nitrophenyl) pyrimidin-2-amine (Derivative 16)
다음 반응식 8로 상기 유도체 16 화합물을 합성하였다.The above-described derivative 16 compound was synthesized by the following
[반응식 8][Reaction Scheme 8]
상기 반응식 7의 중간체 3g인 2-브로모-4-(2-클로로페닐)피리미딘 (70.0 ㎎, 0.259 mM)과 상기 4h로 표시된 3-니트로아닐린 (39.4 ㎎, 0.285 mM)의 혼합물에 K2CO3 (71.7 ㎎, 0.519 mM), Xphos (12.3 ㎎, 0.025 mM) 및 Pd2(dba)3 (11.8 ㎎, 0.012 mM)을 t-BuOH의 현탁액 (3 mL)에서 하룻밤 동안 환류 교반하였다. 반응 혼합물을 물 (5 mL)로 희석하고, EtOAc (3 × 5 mL)로 추출한 다음, 실온으로 냉각시켰다. 합한 유기층을 Na2SO4로 건조시키고, 여과한 후, 진공에서 농축시켰다. 잔류물을 메탄올로부터 재결정시켜 정제하였으며 녹색 고체인 상기 유도체 16으로 표시된 4-(2-클로로페닐)-N-(3-니트로페닐)피리미딘-2-아민(27 ㎎, 29 %)을 얻었다.To a mixture of 2-bromo-4- (2-chlorophenyl) of Intermediate 3g of
상기 수득된 유도체 16 화합물의 NMR 분석 결과는 다음과 같다.NMR analysis results of the obtained
1H NMR (DMSO-d6, 400 MHz): δ 10.3 (1H, s), 8.95 (1H, s), 8.69 (1H, d, J = 4.0 Hz), 8.08-8.15 (1H, m), 7.79-7.81 (1H, m), 7.70-7.73 (1H, m), 7.63-7.66 (1H, m), 7.52-7.59 (3H, m), 7.24 (1H, d, J = 4.0 Hz). 1 H NMR (DMSO-d6, 400 MHz): δ 10.3 (1H, s), 8.95 (1H, s), 8.69 (1H, d, J = 4.0 Hz), 8.08-8.15 (1H, m), 7.79- 7.81 (1H, m), 7.70-7.73 (1H, m), 7.63-7.66 (1H, m), 7.52-7.59 (3H, m), 7.24 (1H, d, J = 4.0 Hz).
실시예 9 : N-(4-((4-(2-클로로페닐)피리미딘-2-일)아미노)페닐)아세트아마이드(유도체 17) Example 9 : Synthesis of N- (4 - ((4- (2-chlorophenyl) pyrimidin-2-yl) amino)
다음 반응식 9로 상기 유도체 17 화합물을 합성하였다.The above-mentioned derivative 17 compound was synthesized by the following
[반응식 9][Reaction Scheme 9]
상기 반응식 7의 중간체 3g인 2-브로모-4-(2-클로로페닐)피리미딘 (70.0 ㎎, 0.259 mM)과 상기 4i로 표시된 N-(4-아미노페닐)아세트아마이드 (42.9 ㎎, 0.285 mM)의 혼합물에 K2CO3 (71.7 ㎎, 0.519 mM), Xphos (12.3 ㎎, 0.025 mM) 및 Pd2(dba)3 (11.8 ㎎, 0.012 mM)을 t-BuOH의 현탁액 (3 mL)에서 하룻밤 동안 환류 교반 하였다. 반응 혼합물을 물 (5 mL)로 희석하고, EtOAc (3 × 5 mL)로 추출한 후, 실온으로 냉각시켰다. 합한 유기층을 Na2SO4로 건조시키고, 여과한 다음, 진공에서 농축시켰다. 잔류물을 Prep-TLC(헥산 : EtOAc = 1 : 1)로 정제하여 백색 고체인 상기 유도체 17로 표시된 N-(4-((4-(2-클로로페닐)피리미딘-2-일)아미노)페닐)아세트아마이드(21 ㎎, 24 %)를 얻었다.(4-aminophenyl) acetamide (42.9 mg, 0.285 mM) represented by the above 4i and 2-bromo-4- (2- chlorophenyl) pyrimidine (70.0 mg, 0.259 mM) ) Was added to a mixture of K 2 CO 3 (71.7 mg, 0.519 mM), Xphos (12.3 mg, 0.025 mM) and Pd 2 (dba) 3 (11.8 mg, 0.012 mM) in a suspension of t- Lt; / RTI > The reaction mixture was diluted with water (5 mL), extracted with EtOAc (3 x 5 mL) and then cooled to room temperature. Dry the combined organic layers with Na 2 SO 4, filtered and then concentrated in vacuo. The residue was purified by Prep-TLC (hexane: EtOAc = 1: 1) to give N- (4 - ((4- (2- chlorophenyl) pyrimidin- Phenyl) acetamide (21 mg, 24%).
상기 수득된 유도체 17 화합물의 NMR 분석 결과는 다음과 같다.NMR analysis results of the obtained
1H NMR (DMSO-d6, 400 MHz): δ 10.0 (1H, s), 8.64 (1H, d, J = 8.0 Hz), 8.21-8.26 (1H, m), 7.87 (2H, d, J = 12.0 Hz), 7.76 (2H, d, J = 8.0 Hz), 7.62-7.68 (2H, m), 7.51-7.54 (2H, m), 7.16 (1H, d, J = 4.0 Hz), 2.75 (3H, d, J = 4.0 Hz). 1 H NMR (DMSO-d6, 400 MHz): δ 10.0 (1H, s), 8.64 (1H, d, J = 8.0 Hz), 8.21-8.26 (1H, m), 7.87 (2H, d, J = 12.0 (2H, m), 7.16 (1H, d, J = 4.0 Hz), 2.75 (3H, d), 7.76 , J = 4.0 Hz).
상기 유도체 1~8 및 실시예 1~9로 합성된 유도체 9~17을 정리하면 아래 표 2와 같다.
유도체1
-
-
-
-
-
-
-
-
구매화합물
Purchase compound
유도체2
-OCH3
-OCH 3
-
-
-
-
-
-
구매화합물
Purchase compound
유도체3
-
-
-
-
-
-
-
-
구매화합물
Purchase compound
유도체4
-NO2
-NO 2
-
-
구매화합물
Purchase compound
유도체5
-NO2
-NO 2
-
-
-
-
구매화합물
Purchase compound
유도체6
-NH-CO-CH3
-NH-CO-CH 3
-
-
-CH3
-CH 3
-
-
구매화합물
Purchase compound
유도체7
-
-
구매화합물
Purchase compound
유도체8
-COO-
C2H5
-COO-
C 2 H 5
-
-
구매화합물
Purchase compound
유도체9
(실시예1)
(Example 1)
-NO2
-NO 2
-
-
-
-
-
-
m/z 311.1 (MH+).Yellow solid, 1 H NMR (DMSO-d6 , 400 MHz): δ 10.5 (1H, s), 8.68 (1H, d, J = 4.0 Hz), 8.52 (1H, s), 8.23-8.32 (3H, m) , 8.10 (2H, d, J = 8.0Hz), 7.62 (1H, d, J = 8.0Hz), 7.42 (2H, t, J = 8.0Hz).
m / z 311.1 (MH < + & gt ; ).
유도체10
(실시예2)
(Example 2)
-
-
-
-
-
-
m/z 342.1 (MH+).Yellow solid, 1 H NMR (DMSO-d6 , 400MHz): δ 9.75 (1H, s), 8.38-8.42 (2H, m), 8.32- 8.34 (2H, m), 8.00 (1H, s), 7.91 (2H J = 8.0 Hz), 6.99 (1H, t, J = 8.0 Hz), 7.57-7.59 (3H, m), 7.42 (2H, t, J = 10.0 Hz), 7.35 8.0 Hz).
m / z 342.1 (MH < + & gt ; ).
유도체11
(실시예3)
(Example 3)
-NH-CO-CH3
-NH-CO-CH 3
-
-
-
-
-
-
유도체12
(실시예4)
(Example 4)
-
-
-
-
-
-
유도체13
(실시예5)
(Example 5)
-CO-NH-CH3
-CO-NH-CH 3
-
-
-OCH3
-OCH 3
-
-
-
-
유도체14
(실시예6)
The derivative 14
(Example 6)
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-
-
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-
m/z 345.1 (MH+).Light yellow solid, 1 H NMR (DMSO- d6, 400 MHz): δ 10.1 (1H, s), 8.62 (1H, d, J = 4.0 Hz), 8.26 (2H, dd, J = 10.0, 4.0 Hz), 7.99 (2H, d, J = 8.0 Hz), 7.77 (2H, d, J = 8.0 Hz), 7.52 , s).
m / z 345.1 (MH < + & gt ; ).
유도체15
(실시예7)
(Example 7)
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-
유도체16
(실시예8)
(Example 8)
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-NO2
-NO 2
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-
m/z 327.1 (MH+).Green solid, 1 H NMR (DMSO-d6 , 400 MHz): δ 10.3 (1H, s), 8.95 (1H, s), 8.69 (1H, d, J = 4.0 Hz), 8.08-8.15 (1H, m) , 7.79-7.81 (1H, m), 7.70-7.73 (1H, m), 7.63-7.66 (1H, m), 7.52-7.59 (3H, m), 7.24 (1H, d, J = 4.0 Hz).
m / z 327.1 (MH < + & gt ; ).
유도체17
(실시예9)
(Example 9)
-CO-NH-CH3
-CO-NH-CH 3
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-
-
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-
m/z 339.1 (MH+).White solid, 1 H NMR (DMSO-d6 , 400 MHz): δ 10.0 (1H, s), 8.64 (1H, d, J = 8.0 Hz), 8.21-8.26 (1H, m), 7.87 (2H, d, J = 12.0 Hz), 7.76 (2H, d, J = 8.0Hz), 7.62-7.68 (2H, m), 7.51-7.54 3H, d, J = 4.0 Hz).
m / z 339.1 (MH < + & gt ; ).
실험예 1 : N-페닐피리미딘-2-아민계 유도체화합물들의 세포 생존 억제 효과 Experimental Example 1 : Inhibitory effect of N-phenylpyrimidin-2-amine derivative compounds on cell survival
인체 폐암 세포주인 A549를 10% 우태혈청 및 페니실린-스트렙토마이신 (10,000 U/ml)이 첨가된 RPMI-1640 (Rosewell Park Memorial Institute Medium-1640) 배지에서 5% CO2 및 37℃의 조건 하에서 배양하였다. 96-웰 플레이트 (96-well plate)에 상기 A549 세포를 1,000 개씩 분주하고 24 시간 배양한 후, 유도체 1 ~ 유도체 17의 N-페닐피리미딘-2-아민계 유도체를 10 μM (micromole) 농도로 처리하여 72 시간 동안 추가 배양하였다. 다음으로 0.5 mg/ml의 MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) 용액을 각각의 웰에 첨가하고 37℃에서 3 시간 동안 추가로 배양한 후, 상등액을 제거하고, 형성된 포름아잔 결정을 DMSO (dimethyl sulfoxide)에 용해시켰다. 이 후, 540 nm에서의 흡광도를 마이크로플레이트 리더 (microplate reader)를 이용하여 측정하였으며, 결과는 독립적으로 3회 반복 수행하여 얻은 값으로부터 대조군에 대한 세포 생존률 (%)로 나타내었다.Human lung cancer cell line A549 was cultured in RPMI-1640 medium (Rosewell Park Memorial Institute Medium-1640) supplemented with 10% fetal calf serum and penicillin-streptomycin (10,000 U / ml) under the condition of 5% CO 2 and 37 ° C . Each of the A549 cells was dispensed into a 96-well plate and cultured for 24 hours. Then, N-phenylpyrimidine-2-amine derivatives of
그 결과 도 1에서, 유도체 2, 유도체 10을 제외한 모든 N-페닐피리미딘-2-아민 유도체에서 세포 생존율의 감소가 확인되었다. 그 중에서도 유도체 4, 유도체 5, 유도체 13, 유도체 14, 유도체 15 및 유도체 17이 A549 세포주의 생존율을 50% 이상 억제하는 것으로 나타났다. 상기 결과는 17종의 N-페닐피리미딘-2-아민 유도체 중 유도체 4, 유도체 5, 유도체 13, 유도체 14, 유도체 15 및 유도체 17의 6 종의 유도체가 효과적으로 폐암 세포의 성장을 억제하거나 사멸을 유도하는 것을 시사한다.As a result, in FIG. 1, a decrease in cell viability was confirmed in all N-phenylpyrimidin-2-amine derivatives except for
실험예 2 : N-페닐피리미딘-2-아민계 화합물들의 G2/M 기 정지 효과 Experimental Example 2 : G2 / M group termination effect of N-phenylpyrimidine-2-amine compounds
유도체 1 ~ 유도체 17 화합물들의 세포 주기에 미치는 효과를 조사하기 위해 A549 세포를 대상으로 유세포 분석기 (flow cytometry)를 이용하여 세포 주기 변화를 확인하였다. 1 x 105 개의 A549 세포를 6-웰 플레이트 (6-well plate)에 분주하여 24 시간 동안 안정화하고, 유도체 1 ~ 유도체 17의 N-페닐피리미딘-2-아민계 화합물들을 10 μM 농도로 처리하여 72 시간 동안 추가 배양하였다. 다음으로 세포를 획득하여, 70% 에탄올로 고정한 후, 최종적으로 800 μl의 인산완충용액 (PBS)에 1 mg/ml 농도의 RNase 100 μl와 400 μg/ml 농도의 PI (propidium iodide)를 100 μl 처리하여 세포내 DNA를 염색하고, 유세포 분석기로 측정하였다.In order to investigate the effects of the
도 2에서 나타나듯이, 유도체 5, 유도체 13, 유도체 14, 유도체 15, 유도체 16 및 유도체 17에서 대조군과 비교하여 G2/M기 세포가 20% 이상 현저히 증가되었다. 그 중 유도체 13, 유도체 14, 유도체 15 및 유도체 17은 4n 이상의 유전물질을 가지는 다핵 세포(혹은 aneuploid 세포)도 증가시켜 G2/M arrest 유발과 더불어 세포 분열을 억제하거나 비정상적인 세포 분열을 초래하는 것으로 나타났다. 또한 유도체 14와 유도체 15는 sub-G1기의 세포가 현저히 증가되었으며, 세포 주기의 교란을 통해 세포사멸이 유발됨을 확인하였다.As shown in FIG. 2, in the
실험예 3 : N-페닐피리미딘-2-아민계 화합물에 의한 세포주기조절 단백질발현 변화 Experimental Example 3 : Changes in cell cycle regulatory protein expression by N-phenylpyrimidin-2-amine compounds
세포 주기는 다양한 cyclin 단백질 및 CDK (cyclin-dependent kinase)의 발현과 인산화를 통해 조절되는데, G2/M 기 정지와 관련된 인자인 cyclin B1, p-cdc2 (Y15), p-CDK2 및 이를 조절 할 수 있는 P53, P21 단백질의 발현을 웨스턴 블럿 분석 실험을 통해 확인하였다.The cell cycle is regulated through the expression and phosphorylation of various cyclin proteins and cyclin-dependent kinases (CDKs), which regulate cyclin B1, p-cdc2 (Y15), p-CDK2 and the factors involved in G2 / Expression of P53 and P21 protein was confirmed by Western blot analysis.
A549 세포에 10 μM의 유도체 1 ~ 유도체 17의 페닐피리미딘-2-아민계 화합물들을 처리하고 5% CO2 및 37℃의 조건 하에서 48 시간 동안 배양한 다음 프로테아제 저해제 (1 mM 페닐메틸설포닐 플루오라이드 (PMSF), 1 μg/ml 아프로티닌 (aprotinin), 1 μg/ml 루펩틴 (leupeptin) 및 1 mM Na3VO4)가 첨가된 TNN 용해 완충액(1 M Tris-HCl, 5M NaCl 및 10% NP-40)으로 단백질을 추출하여 세포 용출물 (lysates)을 획득하였다. 단백질의 양은 Bradford 방법을 사용하여 정량하였으며, 동일한 양의 단백질을 SDS-폴리아크릴아미드 겔에 의해 분리하고, 나이트로셀룰로즈 막으로 이동시켰다. 다음으로, 나이트로셀룰로즈 막을 Tris-완충 염수에서 5% 탈지 분유로 블로킹하고, 4℃에서 일차 항체를 가하여 밤새 반응시켰다. 나이트로셀룰로즈 막을 퍼옥시다제가 결합된 이차 항체와 함께 반응시키고, 증강 화학발광 시약을 이용하여 면역반응 밴드를 검출했다. 이때, 단백질 발현 분석의 내부 대조군으로는 Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) 단백질을 사용하였다. 결과는 3회의 독립적인 실험의 대표 값으로 표시하였다.A549 cells were treated with 10 μM of
도 3의 결과에서, 유도체 13, 유도체 17에 의해 P53의 발현이 현저하게 증가되는 것을 확인할 수 있었고, P53의 하위 유전자로 알려져 있는 P21의 발현은 유도체 13에 의해 현저하게 증가되었다. 이는 유도체 13 화합물이 P53 및 P21 신호전달 기전을 통해 세포 주기 억제를 유발함을 시사한다. 또한, 유도체 14, 유도체 15, 유도체 17의 경우 cyclin B1과 p-cdc2 (Y15)의 발현이 현저하게 증가되어있으나 P21의 발현은 큰 변화가 없었다. 따라서 유도체 14, 유도체 15, 유도체 17의 화합물들의 경우 P21-비의존성 경로로 cyclin B1의 발현을 증가시키고, p-cdc2의 인산화를 유발하여 G2/M 기 정지를 유발하였다.3, it was confirmed that the expression of P53 was significantly increased by the
실험예 4 : N-페닐피리미딘-2-아민계 화합물들의 방사선 병용 효과 Experimental Example 4 : Combined effect of radiation of N-phenylpyrimidin-2-amine compounds
1 x 105 개의 A549 세포를 6-웰 플레이트 (6-well plate)에 분주하여 24 시간 안정화하고, 유도체 5, 유도체 13, 유도체 14, 유도체 15, 유도체 16, 유도체 17의 화합물들을 10 μM 농도로 24 시간 처리한 후, 8 Gy의 방사선을 조사하고 추가로 24 시간 동안 더 배양하였다. 다음으로 세포를 획득하여, 70% 에탄올로 고정한 후, 최종적으로 800 μl의 인산완충용액 (PBS)에 1 mg/ml 농도의 RNase 100 μl와 400 μg/ml 농도의 PI (propidium iodide)를 100 μl 처리하여 세포내 DNA를 염색하고, 유세포 분석기로 측정하였다.1 x 10 5 A549 cells were seeded in a 6-well plate and stabilized for 24 hours. Compounds of the
도 4에서 보여주듯이 유도체 5, 유도체 13, 유도체 14, 유도체 15, 유도체 16 및 유도체 17 화합물들과 방사선을 병용처리한 실험군에서 방사선을 조사하지 않은 실험군과 비교하여 더 현저하게 G2/M기 세포가 증가되는 것을 확인하였다. 실험예 2에서와 마찬가지로 유도체 13, 유도체 14, 유도체 16, 유도체 17 화합물들은 4n 이상의 유전물질을 가지는 다핵세포도 증가되었기에, G2/M arrest 유발과 더불어 세포분열을 억제하는 것으로 나타났다. 또한 유도체 14, 유도체 15는 사멸된 세포를 나타내는 sub-G1기의 세포가 현저히 증가되었다. 따라서 상기 N-페닐피리미딘-2-아민계 화합물들은 방사선과 병용처리 하였을 경우 각각의 단독 처리군보다 상승효과가 있음을 확인할 수 있었다.As shown in FIG. 4, G2 / M cells were more prominently observed in the experimental group treated with the combination of the derivative 5, the derivative 13, the derivative 14, the derivative 15, the derivative 16, Respectively. As in Experimental Example 2, the
실험예 5 : N-페닐피리미딘-2-아민계 화합물들의 방사선 민감 효과 Experimental Example 5 : Radiation-sensitive effect of N-phenylpyrimidin-2-amine compounds
N-페닐피리미딘-2-아민계 화합물들에 의한 방사선 민감 효능을 확인하기 위하여, 인체 폐암세포주인 A549, 인체 난소암세포주인 SK-OV-3, 인체 유방암세포주인 MDA-MB-231, 인체 뇌암 세포주인 U87, 인체 전립선암세포주인 DU-145를 대상으로 클로노제닉 분석법(Clonogenic assay)을 통해 클론 형성능을 평가하였다. 60 mm 플레이트에 각각의 세포주를 접종하고 유도체 5, 유도체 13, 유도체 14, 유도체 15, 유도체 16, 유도체 17 화합물들을 1μM 농도로 24시간 동안 처리한 후, 3~6 Gy 선량의 방사선을 조사하였다. 이후 5% CO2 및 37℃의 조건 하에서 10일간 배양한 다음, 형성된 세포 집락(콜로니)을 인산완충용액 (Phosphate Buffered Saline; PBS)로 세척하고 1% 메틸렌 블루가 포함된 100% 메탄올 혼합액으로 염색하였다.In order to confirm radiation-sensitive efficacy by N-phenylpyrimidin-2-amine compounds, A549 human lung cancer cell line, SK-OV-3 human ovarian cancer cell line, MDA-MB-231 human breast cancer cell line, The clonogenic ability of the cell line U87 and human prostate cancer cell line DU-145 was evaluated by Clonogenic assay. Each of the cell lines was inoculated on a 60 mm plate, and the
도 5의 결과에서, A549, U87, MDA-MB-231, DU-145 및 SK-OV-3 세포에서 화합물 또는 방사선 단독처리에 비해, 화합물과 방사선 병용처리시 암세포의 클론 형성을 효과적으로 억제 할 수 있음을 확인하였다. 특히, 유도체 5, 유도체 14, 유도체 15의 경우 우수한 방사선 치료 민감 효능을 나타내었다.The results of FIG. 5 show that the combination of compound and radiation can effectively inhibit the formation of clones of cancer cells when administered in combination with a compound or radiation in A549, U87, MDA-MB-231, DU-145 and SK-OV- Respectively. In particular, derivative 5, derivative 14 and derivative 15 showed excellent radiotherapeutic efficacy.
실험예 6 : A549 폐암세포주 이식 마우스 모델에서의 항암 및 방사선 민감 효능 Experimental Example 6 : Anti-cancer and radiation-sensitive efficacy in A549 lung cancer cell line transplantation mouse model
6주령의 암컷 Balb-c/nu/nu 마우스를 오리엔트바이오에서 구입하여, 7일간의 순화기간을 거친 다음, 1 × 106 개의 A549 세포를 마우스 뒷다리에 피하주사를 통해 이식하고 종양의 크기가 100 mm3 정도에 도달하였을 때 아래와 같이 5 마리씩 4개의 실험군으로 구분하였다. 6-week old female Balb-c / nu / purchase a nu mice by Orient Bio, implanted through subcutaneous injection a rough purification period of 7 days, and then, 1 × 10 6 of A549 cells in the mouse hind limb and the size of the
[A] 정상대조군, [B] 6 Gy 방사선 조사군, [C] 유도체 5 (U2-A005) 처리군 (10 mg/kg, 복강주사) [D] 유도체 5 투여 후 3시간 째 6 Gy 방사선 조사군으로 나누었다. 종양의 크기와 체중은 2 또는 3일 간격으로 측정하였다.[6] Gy irradiation at 3 hours after 5 doses of [D] derivative [5] (10 mg / kg, intraperitoneal injection) [A] normal control group, [B] 6 Gy irradiation group, . Tumor size and body weight were measured at 2 or 3 day intervals.
도 6의 결과에서 보듯이, 유도체 5를 투여한 군이 정상 대조군에 비해 종양 크기가 7.27% 감소하였고, 유도체 5와 방사선을 병행 처리한 군은 54.93% 감소를 나타내었다. 또한 종양의 크기가 500 mm3에 도달하기까지의 시간을 계산해봤을 때 대조군은 17.2일이 소요된 반면, 유도체 5 단독 처리군은 20일로 1.16배 지연되었으며, 방사선 조사와 유도체 5 병용처리군에서는 실험종료까지 종양의 크기가 500 mm3에 도달하지 못하고 388 mm3를 기록하였다. 6 Gy 조사 용량의 방사선 단독 조사군도 대조군 대비 31.18%의 종양크기 감소를 나타냈다. 본 결과를 바탕으로, 유도체 5 화합물은 단독 처리시에도 항암효과를 나타내지만, 방사선 치료와 병행할 경우 암세포 살상 능력이 상승하여 방사선치료 효능을 현저하게 증가시킬 수 있음을 확인하였다.As shown in the results of FIG. 6, the tumor size in the group treated with the derivative 5 was 7.27% smaller than that in the normal control group, and 54.93% in the group treated with the
실험예 7 : 단백질 인산화 저해활성 Experimental Example 7 : Protein phosphorylation inhibitory activity
N-페닐피리미딘-2-아민계 유도체의 표적 단백질을 확인하기 위하여 활성이 우수한 유도체 15 화합물을 대상으로 Millipore(Upstate)의 106종의 카이네이즈(kinase) 프로파일링 서비스(IC50 profiler express)를 이용하여 분석하였다. 표 3에서 보듯이 유도체 15 화합물(4-((4-(2-클로로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드)을 10 μM 농도로 처리하고 다양한 카이네이즈의 저해 활성을 측정한 결과, 유도체 15 화합물은 Abl, Aurora-A, Aurora-B, Aurora-C, B-Raf(V599E), CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, DDR1, FAK, FGFR1, FGFR2, FGFR3, Flt1, Flt3, Flt4, JAK1, JAK2, JAK3, KDR, Met, MST1, Tie2를 효과적으로 저해하는 것으로 확인되었다.In order to identify the target protein of the N-phenylpyrimidin-2-amine derivative, 15 derivatives having excellent activity were tested using IC 50 profiler express of 106 kinds of Millipore (Upstate) Respectively. As shown in Table 3, when the derivative 15 compound (4 - ((4- (2-chlorophenyl) pyrimidin-2-yl) amino) benzenesulfonamide was treated at a concentration of 10 μM and various kanase inhibitory activities , The derivative 15 compound is selected from the group consisting of Abl, Aurora-A, Aurora-B, Aurora-C, B-Raf (V599E), CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, DDR1, FAK, FGFR1, FGFR3, Flt1, Flt3, Flt4, JAK1, JAK2, JAK3, KDR, Met, MST1 and Tie2.
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로서 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. In this regard, it should be understood that the above-described embodiments are to be considered in all respects as illustrative and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention without departing from the scope of the present invention as defined by the appended claims.
Claims (11)
상기 N-페닐피리미딘-2-아민계 유도체는 6-클로로-N-(4-니트로페닐)-4-페닐퀴나졸린-2-아민, 4-(4-플루오로페닐)-N-(4-니트로페닐)-6-페닐피리미딘-2-아민, 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)-3-메톡시-N-메틸-벤즈아마이드, 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드, 4-((4-(2-클로로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드 또는 N-(4-((4-(2-클로로페닐)피리미딘-2-일)아미노)페닐)아세트아마이드인 것을 특징으로 하는 약학 조성물.
A pharmaceutical composition for preventing or treating lung cancer, ovarian cancer, breast cancer, brain cancer, prostate cancer or colon cancer, which comprises an N-phenylpyrimidin-2-amine derivative or a pharmaceutically acceptable salt thereof as an active ingredient,
The N-phenylpyrimidin-2-amine derivative is obtained by reacting 6-chloro-N- (4-nitrophenyl) -4- phenylquinazolin- (4-fluorophenyl) pyrimidin-2-yl) amino) -3-methoxy-N-methyl-benzamide, (4-fluorophenyl) pyrimidin-2-yl) amino) benzenesulfonamide was prepared in accordance with the general method of example 1 from 4 - ((4- Or N- (4 - ((4- (2-chlorophenyl) pyrimidin-2-yl) amino) phenyl) acetamide.
상기 N-페닐피리미딘-2-아민계 유도체는 Abl, Aurora-A, Aurora-B, Aurora-C, B-Raf(V599E), CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, DDR1, FAK, FGFR1, FGFR2, FGFR3, Flt1, Flt3, Flt4, JAK1, JAK2, JAK3, KDR, Met, MST1 및 Tie2로 이루어진 군에서 선택된 어느 하나 이상의 카이네이즈 활성을 저해하는 것을 특징으로 하는 약학 조성물.The method according to claim 1,
The N-phenylpyrimidine-2-amine derivative may be selected from the group consisting of Abl, Aurora-A, Aurora-B, Aurora-C, B-Raf (V599E), CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, Wherein the composition inhibits one or more kinase activity selected from the group consisting of DDR1, FAK, FGFR1, FGFR2, FGFR3, Flt1, Flt3, Flt4, JAK1, JAK2, JAK3, KDR, Met, MST1 and Tie2.
상기 조성물은 항암제를 추가로 포함하는 것인 약학 조성물.The method according to claim 1,
Wherein the composition further comprises an anti-cancer agent.
상기 항암제는 메토트렉세이트(Methotrexate), 독소루비신(Doxorubicin), 젬시타빈(Gemcitabine), 아라-C(Ara-C), 5-플루오로우라실(5-Fluorouracil), 하이드록시우레아(Hydroxyurea), 빈크리스틴(Vincristine), 빈블라스틴(Vinblastine), 캄토테신(Camptothecin), 블레오마이신(Bleomycin), 파클리탁셀(Paclitaxel) 및 도세탁셀(Docetaxel)로 이루어진 군에서 선택된 어느 하나 이상인 것을 특징으로 하는 약학 조성물.The method according to claim 6,
The anticancer agent may be selected from the group consisting of Methotrexate, Doxorubicin, Gemcitabine, Ara-C, 5-Fluorouracil, Hydroxyurea, Vincristine, Wherein the pharmaceutical composition is at least one selected from the group consisting of Vinblastine, Camptothecin, Bleomycin, Paclitaxel and Docetaxel.
상기 조성물은 항암제 1 내지 99 중량% 및 N-페닐피리미딘-2-아민계 유도체 1 내지 99 중량%를 포함하는 것을 특징으로 하는 약학 조성물.The method according to claim 6,
Wherein the composition comprises 1 to 99% by weight of an anti-cancer agent and 1 to 99% by weight of an N-phenylpyrimidine-2-amine derivative.
상기 방법은 상기 조성물을 투여한 개체에 방사선을 조사하는 단계를 추가로 포함하는 것을 특징으로 하는 폐암, 난소암, 유방암, 뇌암, 전립선암 또는 대장암 예방 또는 치료방법.10. The method of claim 9,
Wherein the method further comprises the step of irradiating the subject to which the composition is administered with radiation. The method for preventing or treating lung cancer, ovarian cancer, breast cancer, brain cancer, prostate cancer or colorectal cancer.
상기 N-페닐피리미딘-2-아민계 유도체는 6-클로로-N-(4-니트로페닐)-4-페닐퀴나졸린-2-아민, 4-(4-플루오로페닐)-N-(4-니트로페닐)-6-페닐피리미딘-2-아민, 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)-3-메톡시-N-메틸-벤즈아마이드, 4-((4-(4-플루오로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드, 4-((4-(2-클로로페닐)피리미딘-2-일)아미노)벤젠설폰아마이드 또는 N-(4-((4-(2-클로로페닐)피리미딘-2-일)아미노)페닐)아세트아마이드인 것을 특징으로 하는 식품 조성물.The present invention relates to a food composition for preventing or ameliorating lung cancer, ovarian cancer, breast cancer, brain cancer, prostate cancer or colon cancer, which comprises an N-phenylpyrimidin-2-amine derivative or a pharmaceutically acceptable salt thereof as an active ingredient,
The N-phenylpyrimidin-2-amine derivative is obtained by reacting 6-chloro-N- (4-nitrophenyl) -4- phenylquinazolin- (4-fluorophenyl) pyrimidin-2-yl) amino) -3-methoxy-N-methyl-benzamide, (4-fluorophenyl) pyrimidin-2-yl) amino) benzenesulfonamide was prepared in accordance with the general method of example 1 from 4 - ((4- Or N- (4 - ((4- (2-chlorophenyl) pyrimidin-2-yl) amino) phenyl) acetamide.
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