JP7455353B2 - Pharmaceutical composition for treatment of acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia - Google Patents
Pharmaceutical composition for treatment of acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia Download PDFInfo
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- JP7455353B2 JP7455353B2 JP2019218270A JP2019218270A JP7455353B2 JP 7455353 B2 JP7455353 B2 JP 7455353B2 JP 2019218270 A JP2019218270 A JP 2019218270A JP 2019218270 A JP2019218270 A JP 2019218270A JP 7455353 B2 JP7455353 B2 JP 7455353B2
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Description
本発明は、急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病治療用医薬組成物に関するものである。 The present invention relates to a pharmaceutical composition for treating acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia.
急性リンパ芽球性白血病（Acute Lymphoblastic Leukemia：ＡＬＬ）は、小児における発症率が最も高いがんの１つである。ＡＬＬと急性骨髄性白血病（ＡＭＬ）の比は、成人では３：７であるのに対して、小児では８：２と逆転する。ＡＬＬには、Ｂ細胞系統のＢ－ＡＬＬとＴ細胞系統のＴ－ＡＬＬとがあり、ＡＬＬ全体での割合は、それぞれ７５％と２５％である。 Acute lymphoblastic leukemia (ALL) is one of the cancers with the highest incidence in children. The ratio of ALL to acute myeloid leukemia (AML) is reversed, from 3:7 in adults to 8:2 in children. ALL includes B-ALL, which is a B-cell lineage, and T-ALL, which is a T-cell lineage, and their proportions in the total ALL are 75% and 25%, respectively.
かつては不治の病と言われていたＡＬＬも、新しい分子標的薬が開発されたことで、治療成績は改善している。例えば、ＢＣＲ－ＡＢＬ融合遺伝子を標的としたイマチニブは、フィラデルフィア染色体（Ｐｈ）陽性ＡＬＬ患者に対して、また、Ｂ細胞マーカーＣＤ２０に対する抗体薬リツキサンと化学療法の組み合わせは、Ｂ－ＡＬＬ患者に対して、それぞれ高効率で完全寛解をもたらしている。さらに最近、Ｂ細胞マーカーＣＤ１９を認識する抗体の細胞外ドメインとＣＤ３ζの細胞内ドメインのキメラ遺伝子を導入した患者由来Ｔ細胞（ＣＡＲ－Ｔ）を利用する細胞療法製剤キムリアが開発され、Ｂ－ＡＬＬの治療成績の更なる改善が期待されている。 Treatment results for ALL, which was once considered an incurable disease, are improving with the development of new molecular target drugs. For example, imatinib, which targets the BCR-ABL fusion gene, is used for patients with Philadelphia chromosome (Ph)-positive ALL, and the combination of Rituxan, an antibody against the B cell marker CD20, and chemotherapy is used for patients with B-ALL. Each of these treatments is highly efficient and leads to complete remission. Furthermore, recently, Kymriah, a cell therapy product that uses patient-derived T cells (CAR-T) into which a chimeric gene of the extracellular domain of an antibody that recognizes the B cell marker CD19 and the intracellular domain of CD3ζ was introduced, has been developed. Further improvements in treatment outcomes are expected.
その一方、Ｔ－ＡＬＬやＴ細胞由来のリンパ芽球性リンパ腫（T-Lymphoblastic Lymphoma：Ｔ－ＬＢＬ）に対しては、様々な候補薬の開発が進められているが（非特許文献１及び２）、未だ実用化には至っていない。日本国におけるＴ－ＡＬＬの発症頻度は、約１０万人に１人と低いが、再発率が非常に高く、成人では、再発患者の約６０％が死亡するという予後不良の白血病である。従って、Ｔ－ＡＬＬ患者を救うためには、腫瘍化したＴ前駆細胞に特異的に作用する薬剤の開発が急務な状況にある。
On the other hand, various candidate drugs are being developed for T-ALL and T-cell-derived lymphoblastic lymphoma (T-LBL) (Non-Patent
このような状況下、本発明者らは、Ｔ－ＡＬＬ細胞の増殖の仕組みについて研究する過程で、転写制御因子Ｌｈｘ２がＣＣＲＦ－ＣＥＭを含む複数のヒトＴ－ＡＬＬ由来白血病細胞株の増殖を強力に抑制することを発見した（非特許文献３）。これは、主にＬｈｘ２の過剰発現によって、Ｔ－ＡＬＬ細胞の自己複製に必須なＬＭＯ２タンパク質の分解が急速に誘導されることに因る。なお、Ｌｈｘ２は、Ｂリンフォーマ細胞株Ｒａｊｉや複数の上皮性癌細胞株の増殖には影響を与えない。 Under these circumstances, in the process of researching the mechanism of proliferation of T-ALL cells, the present inventors found that the transcriptional regulator Lhx2 strongly inhibits the proliferation of multiple human T-ALL-derived leukemia cell lines, including CCRF-CEM. (Non-Patent Document 3). This is mainly due to the fact that overexpression of Lhx2 rapidly induces the degradation of LMO2 protein, which is essential for self-renewal of T-ALL cells. Note that Lhx2 does not affect the proliferation of the B lymphoma cell line Raji or multiple epithelial cancer cell lines.
しかしながら、上記のＬｈｘ２のような核内タンパク質を抗がん剤としてＴ－ＡＬＬ患者へ投与することは不可能であり、遺伝子治療も不確定要素が多過ぎて現実的ではない。仮に、上記のＬｈｘ２活性を模倣するような化合物が存在するならば、該化合物は新しいＴ－ＡＬＬ治療薬になる可能性がある。 However, it is impossible to administer nuclear proteins such as the above-mentioned Lhx2 as anticancer agents to T-ALL patients, and gene therapy is also impractical due to too many uncertainties. If a compound that mimics the above-mentioned Lhx2 activity exists, this compound has the potential to become a new therapeutic agent for T-ALL.
そこで、本発明者らは、天然化合物ライブラリーの中から、Ｌｈｘ２感受性のＴ－ＡＬＬ細胞株ＣＣＲＦ－ＣＥＭの増殖を阻害し、Ｌｈｘ２抵抗性のＢリンフォーマ細胞株Ｒａｊｉの増殖に影響を与えない天然化合物を探索した。その結果、本発明者らは、基準を満たすヒット天然化合物として、以下の３種の化合物の発見に至った。
しかしながら、これらの天然化合物は、構造が複雑であり、工業的に合成することは困難である。また、前記天然化合物は、細菌やカビに由来するが、細菌やカビから前記天然化合物を抽出、単離、精製することも、コストの観点から困難である。更には、前記天然化合物は、低濃度でＬｈｘ２感受性のＴ－ＡＬＬ細胞株ＣＣＲＦ－ＣＥＭの増殖を阻害し、同一濃度ではＬｈｘ２抵抗性のＢリンフォーマ細胞株Ｒａｊｉの増殖に影響を与えないとの基準を満たすものの、その阻害活性、選択性には、依然として改良の余地がある。 However, these natural compounds have complex structures and are difficult to synthesize industrially. Furthermore, although the natural compounds are derived from bacteria and fungi, it is also difficult to extract, isolate, and purify the natural compounds from bacteria and fungi from the viewpoint of cost. Furthermore, the natural compound inhibits the proliferation of the Lhx2-sensitive T-ALL cell line CCRF-CEM at low concentrations, and does not affect the proliferation of the Lhx2-resistant B lymphoma cell line Raji at the same concentration. Although it meets the criteria, there is still room for improvement in its inhibitory activity and selectivity.
そこで、本発明者らは、前記天然化合物と類似した増殖抑制活性を有する類縁化合物の有機合成を試み、以下の２種の化合物の発見に至った。
しかしながら、これらの合成化合物は、阻害活性、選択性が低く、依然として改良の余地がある。 However, these synthetic compounds have low inhibitory activity and low selectivity, and there is still room for improvement.
そこで、本発明は、活性及び選択性に優れた、急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病治療用医薬組成物を提供することを課題とする。 Therefore, an object of the present invention is to provide a pharmaceutical composition for treating acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia, which has excellent activity and selectivity.
上記課題を解決する本発明の要旨構成は、以下の通りである。 The gist of the present invention for solving the above problems is as follows.
本発明の急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病治療用医薬組成物は、下記一般式（I）：
かかる本発明の医薬組成物は、急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病に対する活性及び選択性に優れる。
The pharmaceutical composition for treating acute T lymphoblastic leukemia or lymphoma or acute myeloid leukemia of the present invention has the following general formula (I):
The pharmaceutical composition of the present invention has excellent activity and selectivity against acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia.
本発明の医薬組成物の好適例においては、上記一般式（I）中のＲ２が、炭素数１～４のアルキル基又はベンジル基である。この場合、一般式（I）の化合物の合成が容易であり、また、急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病に対する活性及び選択性が向上する。 In a preferred example of the pharmaceutical composition of the present invention, R 2 in the above general formula (I) is an alkyl group having 1 to 4 carbon atoms or a benzyl group. In this case, the compound of general formula (I) can be easily synthesized, and the activity and selectivity against acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia are improved.
本発明の医薬組成物の他の好適例においては、上記一般式（I）中のＲ１がハロゲン元素であり、ｍが２又は３である。この場合も、一般式（I）の化合物の合成が容易であり、また、急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病に対する活性及び選択性が向上する。 In another preferred example of the pharmaceutical composition of the present invention, R 1 in the above general formula (I) is a halogen element, and m is 2 or 3. In this case as well, the compound of general formula (I) is easily synthesized, and the activity and selectivity against acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia is improved.
本発明の医薬組成物の他の好適例においては、上記一般式（I）で表わされる化合物が、下記構造式（II）、（III）、（IV）、（V）又は（VI）：
また、本発明の他の態様によれば、下記一般式（I）：
かかる本発明のキットは、急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病に対する活性及び選択性に優れる。
Further, according to another aspect of the present invention, the following general formula (I):
The kit of the present invention has excellent activity and selectivity against acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia.
本発明によれば、活性及び選択性に優れた、急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病治療用医薬組成物を提供することができる。 According to the present invention, it is possible to provide a pharmaceutical composition for treating acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia, which has excellent activity and selectivity.
以下に、本発明の急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病治療用の医薬組成物及びキットを、その実施形態に基づき、詳細に例示説明する。 Below, the pharmaceutical composition and kit for treating acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia of the present invention will be illustrated in detail based on the embodiments thereof.
＜医薬組成物＞ <Pharmaceutical composition>
本発明の急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病治療用医薬組成物は、下記一般式（I）：
一般式（I）で表わされる化合物は、急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病に対する活性及び選択性に優れ、該一般式（I）で表わされる化合物を有効成分として含む本発明の医薬組成物は、急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病の治療に有用である。
The pharmaceutical composition for treating acute T lymphoblastic leukemia or lymphoma or acute myeloid leukemia of the present invention has the following general formula (I):
The compound represented by the general formula (I) has excellent activity and selectivity against acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia, and the compound represented by the general formula (I) has excellent activity and selectivity against acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia. The pharmaceutical compositions of the invention are useful in the treatment of acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia.
上記一般式（I）中、Ｒ１は、水素又はハロゲン元素である。ここで、ハロゲン元素としては、フッ素、塩素、臭素、ヨウ素等が挙げられる。これらの中でも、塩素が好ましい。なお、Ｒ１が水素又は塩素である化合物は、合成が容易である。 In the above general formula (I), R 1 is hydrogen or a halogen element. Here, examples of the halogen element include fluorine, chlorine, bromine, and iodine. Among these, chlorine is preferred. Note that compounds in which R 1 is hydrogen or chlorine are easy to synthesize.
上記一般式（I）中、Ｒ２は、置換基を有していてもよい炭化水素基（即ち、置換又は非置換の炭化水素基）である。ここで、炭化水素基は、飽和でも不飽和でもよく、また、環式でも非環式でもよい。炭化水素基としては、炭素数１～１０のアルキル基、炭素数２～１０のアルケニル基、炭素数２～１０のアルキニル基、炭素数４～１０のアルカジエニル基、炭素数６～２０のアリール基、炭素数７～２０のアラルキル基、炭素数３～１０のシクロアルキル基、炭素数３～１０のシクロアルケニル基等が挙げられる。 In the above general formula (I), R 2 is a hydrocarbon group that may have a substituent (ie, a substituted or unsubstituted hydrocarbon group). Here, the hydrocarbon group may be saturated or unsaturated, and may be cyclic or acyclic. Examples of the hydrocarbon group include an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, an alkadienyl group having 4 to 10 carbon atoms, and an aryl group having 6 to 20 carbon atoms. , an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, and the like.
炭素数１～１０のアルキル基としては、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、各種ペンチル基、各種ヘキシル基等が挙げられる。
炭素数２～１０のアルケニル基としては、ビニル基、アリル基、プロペニル基、イソプロペニル基、２－メチル－１－プロペニル基、２－メチルアリル基等が挙げられる。
炭素数２～１０のアルキニル基としては、エチニル基、プロピニル基、ブチニル基等が挙げられる。
炭素数４～１０のアルカジエニル基としては、１，３－ブタジエニル基、ペンタジエニル基、ヘキサジエニル基等が挙げられる。
炭素数６～２０のアリール基としては、フェニル基、１－ナフチル基、２－ナフチル基、インデニル基、ｏ－トリル基、ｍ－トリル基、ｐ－トリル基、２，３－キシリル基、２，５－キシリル基、ｏ－クメニル基、ｍ－クメニル基、ｐ－クメニル基等が挙げられる。
炭素数７～２０のアラルキル基としては、ベンジル基、フェネチル基、１－ナフチルメチル基、２－ナフチルメチル基、１－フェニルエチル基、フェニルプロピル基等が挙げられる。
炭素数３～１０のシクロアルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等が挙げられる。
炭素数３～１０のシクロアルケニル基としては、シクロプロペニル基、シクロブテニル基、シクロペンテニル基、シクロヘキセニル基等が挙げられる。
Examples of the alkyl group having 1 to 10 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, various pentyl groups, various hexyl groups, etc. It will be done.
Examples of the alkenyl group having 2 to 10 carbon atoms include vinyl group, allyl group, propenyl group, isopropenyl group, 2-methyl-1-propenyl group, and 2-methylallyl group.
Examples of the alkynyl group having 2 to 10 carbon atoms include ethynyl group, propynyl group, butynyl group, and the like.
Examples of the alkadienyl group having 4 to 10 carbon atoms include a 1,3-butadienyl group, a pentadienyl group, and a hexadienyl group.
Examples of the aryl group having 6 to 20 carbon atoms include phenyl group, 1-naphthyl group, 2-naphthyl group, indenyl group, o-tolyl group, m-tolyl group, p-tolyl group, 2,3-xylyl group, , 5-xylyl group, o-cumenyl group, m-cumenyl group, p-cumenyl group and the like.
Examples of the aralkyl group having 7 to 20 carbon atoms include benzyl group, phenethyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 1-phenylethyl group, and phenylpropyl group.
Examples of the cycloalkyl group having 3 to 10 carbon atoms include cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.
Examples of the cycloalkenyl group having 3 to 10 carbon atoms include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group.
また、前記炭化水素基の置換基としては、フッ素、塩素、臭素、ヨウ素等のハロゲン元素、アルコキシ基、ニトロ基、シアノ基、ヒドロキシル基、チオール基、アシル基、カルボキシル基、アミノ基、アルコキシカルボニル基等が挙げられる。なお、前記炭化水素基は、置換基を有しても、有しなくてもよく、また、置換基を有する場合において、置換基の数は、１つても、複数でもよい。 Substituents for the hydrocarbon group include halogen elements such as fluorine, chlorine, bromine, and iodine, alkoxy groups, nitro groups, cyano groups, hydroxyl groups, thiol groups, acyl groups, carboxyl groups, amino groups, and alkoxycarbonyl groups. Examples include groups. Note that the hydrocarbon group may or may not have a substituent, and when it has a substituent, the number of substituents may be one or more.
上記一般式（I）中のＲ２は、炭素数１～４のアルキル基又はベンジル基であることが好ましい。一般式（I）で表され、Ｒ２が炭素数１～４のアルキル基又はベンジル基である化合物は、合成が容易であり、また、急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病に対する活性及び選択性に優れる。 R 2 in the above general formula (I) is preferably an alkyl group having 1 to 4 carbon atoms or a benzyl group. The compound represented by the general formula (I), in which R 2 is an alkyl group having 1 to 4 carbon atoms or a benzyl group, is easy to synthesize and is useful for acute T lymphoblastic leukemia, lymphoma, or acute myeloid leukemia. Excellent activity and selectivity against leukemia.
上記一般式（I）中、Ｒ３は、水素、又は、置換基を有していてもよい炭化水素基（即ち、置換又は非置換の炭化水素基）である。ここで、炭化水素基は、飽和でも不飽和でもよく、また、環式でも非環式でもよい。炭化水素基としては、炭素数１～１０のアルキル基、炭素数２～１０のアルケニル基、炭素数２～１０のアルキニル基、炭素数４～１０のアルカジエニル基、炭素数６～２０のアリール基、炭素数７～２０のアラルキル基、炭素数３～１０のシクロアルキル基、炭素数３～１０のシクロアルケニル基等が挙げられる。 In the above general formula (I), R 3 is hydrogen or a hydrocarbon group that may have a substituent (ie, a substituted or unsubstituted hydrocarbon group). Here, the hydrocarbon group may be saturated or unsaturated, and may be cyclic or acyclic. Examples of the hydrocarbon group include an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, an alkadienyl group having 4 to 10 carbon atoms, and an aryl group having 6 to 20 carbon atoms. , an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, and the like.
炭素数１～１０のアルキル基としては、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、各種ペンチル基、各種ヘキシル基等が挙げられる。
炭素数２～１０のアルケニル基としては、ビニル基、アリル基、プロペニル基、イソプロペニル基、２－メチル－１－プロペニル基、２－メチルアリル基等が挙げられる。
炭素数２～１０のアルキニル基としては、エチニル基、プロピニル基、ブチニル基等が挙げられる。
炭素数４～１０のアルカジエニル基としては、１，３－ブタジエニル基、ペンタジエニル基、ヘキサジエニル基等が挙げられる。
炭素数６～２０のアリール基としては、フェニル基、１－ナフチル基、２－ナフチル基、インデニル基、ｏ－トリル基、ｍ－トリル基、ｐ－トリル基、２，３－キシリル基、２，５－キシリル基、ｏ－クメニル基、ｍ－クメニル基、ｐ－クメニル基等が挙げられる。
炭素数７～２０のアラルキル基としては、ベンジル基、フェネチル基、１－ナフチルメチル基、２－ナフチルメチル基、１－フェニルエチル基、フェニルプロピル基等が挙げられる。
炭素数３～１０のシクロアルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等が挙げられる。
炭素数３～１０のシクロアルケニル基としては、シクロプロペニル基、シクロブテニル基、シクロペンテニル基、シクロヘキセニル基等が挙げられる。
Examples of the alkyl group having 1 to 10 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, various pentyl groups, various hexyl groups, etc. It will be done.
Examples of the alkenyl group having 2 to 10 carbon atoms include vinyl group, allyl group, propenyl group, isopropenyl group, 2-methyl-1-propenyl group, and 2-methylallyl group.
Examples of the alkynyl group having 2 to 10 carbon atoms include ethynyl group, propynyl group, butynyl group, and the like.
Examples of the alkadienyl group having 4 to 10 carbon atoms include a 1,3-butadienyl group, a pentadienyl group, and a hexadienyl group.
Examples of the aryl group having 6 to 20 carbon atoms include phenyl group, 1-naphthyl group, 2-naphthyl group, indenyl group, o-tolyl group, m-tolyl group, p-tolyl group, 2,3-xylyl group, , 5-xylyl group, o-cumenyl group, m-cumenyl group, p-cumenyl group, etc.
Examples of the aralkyl group having 7 to 20 carbon atoms include benzyl group, phenethyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 1-phenylethyl group, and phenylpropyl group.
Examples of the cycloalkyl group having 3 to 10 carbon atoms include cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.
Examples of the cycloalkenyl group having 3 to 10 carbon atoms include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group.
また、前記炭化水素基の置換基としては、フッ素、塩素、臭素、ヨウ素等のハロゲン元素、アルコキシ基、ニトロ基、シアノ基、ヒドロキシル基、チオール基、アシル基、カルボキシル基、アミノ基、アルコキシカルボニル基等が挙げられる。なお、前記炭化水素基は、置換基を有しても、有しなくてもよく、また、置換基を有する場合において、置換基の数は、１つても、複数でもよい。 Substituents for the hydrocarbon group include halogen elements such as fluorine, chlorine, bromine, and iodine, alkoxy groups, nitro groups, cyano groups, hydroxyl groups, thiol groups, acyl groups, carboxyl groups, amino groups, and alkoxycarbonyl groups. Examples include groups. Note that the hydrocarbon group may or may not have a substituent, and when it has a substituent, the number of substituents may be one or more.
上記一般式（I）中のＲ３は、水素又は炭素数１～４のアルキル基であることが好ましい。一般式（I）で表され、Ｒ３が水素又は炭素数１～４のアルキル基である化合物は、合成が容易であり、また、急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病に対する活性及び選択性に優れる。 R 3 in the above general formula (I) is preferably hydrogen or an alkyl group having 1 to 4 carbon atoms. The compound represented by the general formula (I), in which R 3 is hydrogen or an alkyl group having 1 to 4 carbon atoms, is easy to synthesize, and is also used for acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia. Excellent activity and selectivity for
上記一般式（I）中、ｍは、ビニレン単位（－ＣＨ＝ＣＨ－）の繰り返し数を示し、２、３又は４である。但し、Ｒ１が水素の場合、ｍは４である。一般式（I）で表され、Ｒ１が水素で、ｍが３以下である化合物は、上述のように、活性、選択性が低い。これに対し、一般式（I）で表され、Ｒ１が水素で、ｍが４である化合物は、活性及び選択性に優れる。 In the above general formula (I), m represents the number of repeating vinylene units (-CH=CH-), and is 2, 3 or 4. However, when R 1 is hydrogen, m is 4. A compound represented by the general formula (I) in which R 1 is hydrogen and m is 3 or less has low activity and selectivity, as described above. On the other hand, a compound represented by the general formula (I) in which R 1 is hydrogen and m is 4 has excellent activity and selectivity.
上記一般式（I）中のＲ１がハロゲン元素である場合、ｍは２、３、４のいずれでもよいが、ｍは２又は３であることが好ましく、３であることが更に好ましい。一般式（I）で表され、Ｒ１がハロゲン元素で、ｍが２又は３である化合物は、合成が容易であり、また、急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病に対する活性及び選択性に優れる。 When R 1 in the above general formula (I) is a halogen element, m may be 2, 3, or 4, but m is preferably 2 or 3, and more preferably 3. The compound represented by the general formula (I), in which R 1 is a halogen element and m is 2 or 3, is easy to synthesize and is effective against acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia. Excellent activity and selectivity.
上記一般式（I）で表わされる化合物としては、下記構造式（II）、（III）、（IV）、（V）又は（VI）：
上記一般式（I）で表わされる化合物は、任意の方法で合成することができる。
例えば、まず、ホルミルピロールやハロゲン化ホルミルピロールを出発物質とし、Ｗｉｔｔｉｇ反応によりニトリル化してニトリル体を合成し、更に、ニトリル体をＤＩＢＡＬ還元することによりホルミル体を合成する。次に、得られたホルミル体に対し、Ｗｉｔｔｉｇ反応によるニトリル化と、ＤＩＢＡＬ還元とを繰り返し、所望のビニレン単位（－ＣＨ＝ＣＨ－）の繰り返し数を有するホルミル体を合成し、最後に、所望の置換基を有するＷｉｔｔｉｇ試薬を用いることにより、一般式（I）で表わされる化合物を合成することができる。
The compound represented by the above general formula (I) can be synthesized by any method.
For example, first, formylpyrrole or halogenated formylpyrrole is used as a starting material, and a nitrile compound is synthesized by nitrification by a Wittig reaction, and then a formyl compound is synthesized by subjecting the nitrile compound to DIBAL reduction. Next, the obtained formyl compound is subjected to repeated nitrification by Wittig reaction and DIBAL reduction to synthesize a formyl compound having the desired repeating number of vinylene units (-CH=CH-), and finally, the desired formyl compound is synthesized. By using a Wittig reagent having a substituent, a compound represented by general formula (I) can be synthesized.
本発明の医薬組成物は、経口投与及び非経口投与のいずれの剤形でもよい。これらの剤形は、常法に従って製剤化することができる。本発明の医薬組成物は、上記一般式（I）の化合物の他、医薬的に許容される担体、添加剤等を含むことができる。 The pharmaceutical composition of the present invention may be administered either orally or parenterally. These dosage forms can be formulated according to conventional methods. The pharmaceutical composition of the present invention can contain, in addition to the compound of general formula (I) above, a pharmaceutically acceptable carrier, additives, and the like.
前記担体及び添加剤としては、水、酢酸、医薬的に許容される有機溶剤、コラーゲン、ポリビニルアルコール、ポリビニルピロリドン、カルボキシビニルポリマー、カルボキシメチルセルロースナトリウム、ポリアクリル酸ナトリウム、アルギン酸ナトリウム、水溶性デキストラン、カルボキシメチルスターチナトリウム、ペクチン、メチルセルロース、エチルセルロース、キサンタンガム、アラビアゴム、カゼイン、寒天、ポリエチレングリコール、ジグリセリン、グリセリン、プロピレングリコール、ワセリン、パラフィン、ステアリルアルコール、ステアリン酸、ヒト血清アルブミン、マンニトール、ソルビトール、ラクトース、医薬添加剤として許容される界面活性剤等が挙げられる。
前記添加剤は、本発明の医薬組成物の剤形に応じて、１種又は２種以上を組み合わせて使用することができる。
The carrier and additives include water, acetic acid, a pharmaceutically acceptable organic solvent, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethyl cellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, carboxy Methyl starch sodium, pectin, methyl cellulose, ethyl cellulose, xanthan gum, gum arabic, casein, agar, polyethylene glycol, diglycerin, glycerin, propylene glycol, vaseline, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, lactose, Examples include surfactants and the like that are acceptable as pharmaceutical additives.
The additives may be used alone or in combination of two or more, depending on the dosage form of the pharmaceutical composition of the present invention.
前記剤形としては、経口投与の場合は、錠剤、カプセル剤、細粒剤、粉末剤、顆粒剤、液剤、シロップ剤等が挙げられる。また、非経口投与の場合、剤形としては、注射剤、噴霧剤、塗布剤、外用剤等が挙げられる。ここで、注射剤形の場合、例えば、点滴等の静脈内注射、皮下注射、腹腔内注射等により、全身又は局所的に投与することができる。例えば、注射用製剤の場合、本発明の医薬組成物を溶剤（例えば、生理食塩水、緩衝液、ブドウ糖溶液等）に溶解し、更に適切な添加剤（ヒト血清アルブミン、ポリエチレングリコール、マンノース修飾デンドリマー、シクロデキストリン結合体等）を加えたものを使用することができる。また、使用前に溶解する剤形とするために、凍結乾燥したものであってもよい。凍結乾燥用賦形剤としては、例えば、マンニトール、ブドウ糖等の糖アルコールや糖類を使用することができる。 In the case of oral administration, the dosage forms include tablets, capsules, fine granules, powders, granules, liquids, syrups, and the like. In the case of parenteral administration, dosage forms include injections, sprays, liniments, and external preparations. Here, in the case of an injection dosage form, it can be administered systemically or locally, for example, by intravenous injection such as drip, subcutaneous injection, intraperitoneal injection, etc. For example, in the case of an injectable formulation, the pharmaceutical composition of the present invention is dissolved in a solvent (e.g., physiological saline, buffer, glucose solution, etc.), and suitable additives (human serum albumin, polyethylene glycol, mannose-modified dendrimer, etc.) are further added. , cyclodextrin conjugate, etc.) can be used. It may also be freeze-dried to form a dosage form that is dissolved before use. As the excipient for freeze-drying, for example, sugar alcohols and saccharides such as mannitol and glucose can be used.
本発明の医薬組成物又は上記一般式（I）化合物の投与量は、対象者の年齢、性別、症状、投与経路、投与回数、剤形等に応じて適宜選択できる。該投与量は、例えば、成人（６０ｋｇ）の場合、１日当り通常０．００６～６００ｍｇ、好ましくは０．０６～６０ｍｇ、より好ましくは０．６～６ｍｇである。投与方法は、患者の年齢、症状により選択することが好ましい。また、投与は、数日間隔で、１日当り１回投与するか、或いは１日当り２～４回に分けて投与することが好ましい。 The dosage of the pharmaceutical composition of the present invention or the above compound of general formula (I) can be appropriately selected depending on the age, sex, symptoms, route of administration, frequency of administration, dosage form, etc. of the subject. For example, the dosage for an adult (60 kg) is usually 0.006 to 600 mg, preferably 0.06 to 60 mg, and more preferably 0.6 to 6 mg per day. The administration method is preferably selected depending on the patient's age and symptoms. Furthermore, it is preferable to administer once per day, or in divided doses 2 to 4 times per day, at intervals of several days.
本発明の医薬組成物は、抗がん剤として用いることができる。対象になるがんの種類は、急性Ｔリンパ芽球性白血病（Ｔ－ＡＬＬ）、Ｔリンパ芽球性リンパ腫（Ｔ－ＬＢＬ）、又は急性骨髄性白血病（ＡＭＬ）である。 The pharmaceutical composition of the present invention can be used as an anticancer agent. The target cancer types are acute T-lymphoblastic leukemia (T-ALL), T-lymphoblastic lymphoma (T-LBL), or acute myeloid leukemia (AML).
＜キット＞
本発明の急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病治療用キットは、上述した、上記一般式（I）で表わされる化合物を含むことを特徴とする。
本発明のキットは、上記一般式（I）で表わされる化合物を含むため、急性Ｔリンパ芽球性白血病若しくはリンパ腫、又は急性骨髄性白血病に対する活性及び選択性に優れる。
<Kit>
The kit for treating acute T lymphoblastic leukemia or lymphoma or acute myeloid leukemia of the present invention is characterized by containing the compound represented by the above general formula (I).
Since the kit of the present invention contains the compound represented by the above general formula (I), it has excellent activity and selectivity against acute T lymphoblastic leukemia or lymphoma, or acute myeloid leukemia.
本発明のキットは、上記一般式（I）で表わされる化合物に加えて、医薬的に許容される担体や添加剤、試薬類、補助剤、専用容器、その他の必要なアクセサリー、取扱説明書等を含むことができる。本発明のキットは、癌治療用キットや、研究試薬キットとしても使用することができる。 In addition to the compound represented by the general formula (I), the kit of the present invention includes pharmaceutically acceptable carriers, additives, reagents, auxiliary agents, special containers, other necessary accessories, instruction manuals, etc. can include. The kit of the present invention can also be used as a cancer treatment kit or a research reagent kit.
以下に、実施例を挙げて本発明を更に詳しく説明するが、本発明は下記の実施例に何ら限定されるものではない。 EXAMPLES The present invention will be described in more detail below with reference to Examples, but the present invention is not limited to the Examples below.
＜材料と方法＞
（細胞培養）
ヒト白血病由来細胞株（ＣＣＲＦ－ＣＥＭ、Ｒａｊｉ、ＴＦ－１、ＴＨＰ－１、ＨＬ－６０、ＭＫＰＬ－１、Ｋ５６２）の培養は、１０％ fetal bovine serum（ＦＢＳ；Invitrogen）、Penicillin-Streptomycin（ＰＳ；Sigma）、５０μＭの２－メルカプトエタノールを含むRPMI-1640 Medium（Sigma）を用いて、３７℃－５％ ＣＯ２の条件下で行った。なお、ＴＦ－１細胞の培養には、上記の培地にＧＭ－ＣＳＦ（5 ng/ml, Peprotech）を添加した。
また、ヒト皮膚線維芽細胞（ＨＤＦ）、接着性ヒト癌細胞株（ＨＳＣ－３、Ｈｅｌａ）、ヒト腎上皮細胞株（２９３Ｔ）の培養には、１０％ ＦＢＳとＰＳを含むDulbecco’s Modified Eagle’s Medium（Sigma）を用いた。
<Materials and methods>
(Cell culture)
Human leukemia-derived cell lines (CCRF-CEM, Raji, TF-1, THP-1, HL-60, MKPL-1, K562) were cultured in 10% fetal bovine serum (FBS; Invitrogen), Penicillin-Streptomycin (PS). ; Sigma) and RPMI-1640 Medium (Sigma) containing 50 μM 2-mercaptoethanol under the conditions of 37° C. and 5% CO 2 . For culturing TF-1 cells, GM-CSF (5 ng/ml, Peprotech) was added to the above medium.
In addition, Dulbecco's Modified Eagle's Medium (containing 10% FBS and PS) was used for culturing human dermal fibroblasts (HDF), adherent human cancer cell lines (HSC-3, Hela), and human renal epithelial cell lines (293T). Sigma) was used.
（in vitro増殖抑制アッセイ）
増殖抑制アッセイでは、まず、細胞を96 well plateに3,000 cells/wellになるように入れ、それぞれの化合物を段階希釈して添加した。３日間培養した後、Cell Counting Kit-8を添加し４時間培養し、生存細胞数を４５０ｎｍの吸光度測定によって比較定量した。
(in vitro growth inhibition assay)
In the growth inhibition assay, cells were first placed in a 96-well plate at 3,000 cells/well, and each compound was serially diluted and added. After culturing for 3 days, Cell Counting Kit-8 was added and cultured for 4 hours, and the number of viable cells was comparatively quantified by absorbance measurement at 450 nm.
（Ｔ－ＡＬＬ細胞のin vivoゼノグラフトモデル）
１２－１６週齢の雌NOD-SCID-γc-KO（ＮＳＧ）マウスに、ルシフェラーゼ遺伝子を導入したＣＣＲＦ－ＣＥＭ細胞を１０５個／１００μｌずつ皮下注入した。４週間後にルシフェラーゼ発光基質を腹腔投与し、腫瘍部の発光強度をIVIS Spectrum-FM（Caliper）を用いて測定した（０日）。マウスを２群に分け、２５０μＭの構造式（II）の化合物、又は溶媒２．５％ ＤＭＳＯ－ＰＢＳを２０μlずつ１日１回４日間腫瘍内投与した（０日～４日）。５日目に再びルシフェラーゼ発光基質を腹腔投与し、IVIS Spectrum-FMを用いて発光強度を測定した。その後、上記のマウス群を３週間飼育し、生存日数を記録した。
また、構造式（VI）の化合物のin vivo投与実験では、ＣＣＲＦ－ＣＥＭ細胞（１０５個）を皮下移植して３週間飼育したＮＳＧマウスの腫瘍内に、５００μＭの構造式（VI）の化合物、又は溶媒２０％ ２－ヒドロキシプロピル－γ－シクロデキストリン－５％ ＤＭＳＯを２０μlずつ朝夕合計９回投与した（０日～４日）。５日目に再びルシフェラーゼ発光基質を腹腔投与し、IVIS Spectrum-FMを用いて発光強度を測定した。
(In vivo xenograft model of T-ALL cells)
CCRF-CEM cells into which the luciferase gene had been introduced were subcutaneously injected into 12- to 16-week-old female NOD-SCID-γ c -KO (NSG) mice at a rate of 10 5 cells/100 μl. Four weeks later, a luciferase luminescent substrate was administered intraperitoneally, and the luminescence intensity of the tumor area was measured using IVIS Spectrum-FM (Caliper) (day 0). The mice were divided into two groups, and 20 μl of 250 μM of the compound of structural formula (II) or the solvent 2.5% DMSO-PBS was intratumorally administered once a day for 4 days (
In addition, in an in vivo administration experiment of the compound of structural formula (VI), 500 μM of the compound of structural formula (VI) was administered into the tumor of NSG mice subcutaneously implanted with CCRF-CEM cells (10 5 cells) and kept for 3 weeks. , or solvent 20% 2-hydroxypropyl-γ-cyclodextrin-5% DMSO was administered in 20 μl doses in the morning and evening for a total of 9 times (
＜Auxarconjugatin B類縁化合物の有機合成＞
（エステル体８及びエステル体９の合成）
エステル体８及びエステル体９の合成経路は、以下の通りである。
(Synthesis of ester body 8 and ester body 9)
The synthetic route of ester body 8 and ester body 9 is as follows.
まず、市販のピロール－２－カルボキシアルデヒド（１）をＷｉｔｔｉｇ反応によりニトリル化しニトリル体２を合成した。次に、ニトリル体２をＤＩＢＡＬ還元することによりホルミル体３を得た。また、ホルミル体３にＷｉｔｔｉｇ試薬を用いることでニトリル体４を得た。次に、ニトリル体４をＤＩＢＡＬ還元によりホルミル体５を合成し、Ｗｉｔｔｉｇ反応によりニトリル体６へと誘導した。次に、ニトリル体６をＤＩＢＡＬ還元によりホルミル体７へと誘導し、最後に、２種類のＷｉｔｔｉｇ試薬を用いることにより、目的化合物であるエステル体８、エステル体９を合成した。
First, commercially available pyrrole-2-carboxaldehyde (1) was nitrified by Wittig reaction to synthesize nitrile compound 2. Next,
（構造式（II）の化合物、構造式（IV）の化合物、構造式（V）の化合物、及び構造式（VI）の化合物の合成）
構造式（II）の化合物、構造式（IV）の化合物、構造式（V）の化合物、及び構造式（VI）の化合物の合成経路は、以下の通りである。
The synthetic routes for the compound of structural formula (II), the compound of structural formula (IV), the compound of structural formula (V), and the compound of structural formula (VI) are as follows.
まず、市販の４－クロロピリジン Ｎ－オキサイド（１０）と硫酸銅五水和物を用いて混合水溶液を作製し、高圧水銀ランプによる光照射で光反応を行い、ホルミル体１１を得た。また、ホルミル体１１をＷｉｔｔｉｇ反応によりニトリル化し、ニトリル体１２を合成した。次に、ニトリル体１２をＤＩＢＡＬ還元することにより、ホルミル体１３を得た。また、ホルミル体１３にＷｉｔｔｉｇ試薬を用いることで、ニトリル体１４を得た。次に、ニトリル体１４にＤＩＢＡＬ還元を行うことで、ホルミル体１５を合成し、Ｗｉｔｔｉｇ反応により構造式（V）の化合物を合成した。また、ホルミル体１５にＷｉｔｔｉｇ試薬を用いることで、ニトリル体１６へと誘導した。次に、ニトリル体１６をＤＩＢＡＬ還元によりホルミル体１７へと誘導した。また、ホルミル体１７に３種類のＷｉｔｔｉｇ試薬をそれぞれ用いることで、構造式（II）の化合物と構造式（IV）の化合物と構造式（VI）の化合物をそれぞれ合成した。 First, a mixed aqueous solution was prepared using commercially available 4-chloropyridine N-oxide (10) and copper sulfate pentahydrate, and a photoreaction was performed by light irradiation with a high-pressure mercury lamp to obtain formyl compound 11. Further, the formyl compound 11 was nitrile-formed by Wittig reaction to synthesize the nitrile compound 12. Next, the formyl compound 13 was obtained by subjecting the nitrile compound 12 to DIBAL reduction. Further, by using a Wittig reagent for the formyl compound 13, a nitrile compound 14 was obtained. Next, formyl compound 15 was synthesized by subjecting nitrile compound 14 to DIBAL reduction, and a compound of structural formula (V) was synthesized by Wittig reaction. Further, the formyl compound 15 was induced into the nitrile compound 16 by using a Wittig reagent. Next, the nitrile compound 16 was induced into the formyl compound 17 by DIBAL reduction. Furthermore, by using three types of Wittig reagents for formyl compound 17, a compound of structural formula (II), a compound of structural formula (IV), and a compound of structural formula (VI) were synthesized, respectively.
（構造式（III）の化合物の合成）
構造式（III）の化合物の合成経路は、以下の通りである。
The synthetic route for the compound of structural formula (III) is as follows.
まず、市販のピロール－２－カルボキシアルデヒド（１）をＷｉｔｔｉｇ反応によりニトリル化し、ニトリル体２を合成した。次に、ニトリル体２をＤＩＢＡＬ還元することによりホルミル体３を得た。また、ホルミル体３にＷｉｔｔｉｇ試薬を用いることで、ニトリル体４を得た。次に、ニトリル体４をＤＩＢＡＬ還元によりホルミル体５を合成し、Ｗｉｔｔｉｇ反応によりニトリル体６へと誘導した。次に、ニトリル体６をＤＩＢＡＬ還元により、ホルミル体７へと誘導した。
また、ホルミル体７にＷｉｔｔｉｇ試薬を用いることで、ニトリル体１８に誘導し、ニトリル体１８をＤＩＢＡＬ還元することにより、ホルミル体１９を得た。そして、最後に、Ｗｉｔｔｉｇ反応を行うことで、構造式（III）の化合物を合成した。
First, commercially available pyrrole-2-carboxaldehyde (1) was nitrified by Wittig reaction to synthesize nitrile compound 2. Next,
Further, the formyl compound 7 was induced to the nitrile compound 18 by using a Wittig reagent, and the formyl compound 19 was obtained by reducing the nitrile compound 18 by DIBAL. Finally, a compound of structural formula (III) was synthesized by performing a Wittig reaction.
＜Ｔ－ＡＬＬ細胞株の増殖を選択的に抑制する天然化合物の同定＞
約１５万種類の天然化合物ライブラリーを用いて、ヒトＴ－ＡＬＬ細胞株ＣＣＲＦ－ＣＥＭの増殖を阻害し、ヒトＢリンフォーマ細胞株Ｒａｊｉの増殖に影響を与えない物質をハイスループットスクリーニングによって探索した。その結果、以下の３種類の天然化合物が、ＣＣＲＦ－ＣＥＭ細胞の増殖を選択的に抑制することを見出した（図１参照）。
Using a library of approximately 150,000 natural compounds, we conducted high-throughput screening to search for substances that inhibit the proliferation of the human T-ALL cell line CCRF-CEM and do not affect the proliferation of the human B lymphoma cell line Raji. . As a result, we found that the following three natural compounds selectively suppress the proliferation of CCRF-CEM cells (see Figure 1).
これらの中でも、RumbrinとAuxarconjugatin Bは、共通の化学構造を有している。 Among these, Rumbrin and Auxarconjugatin B have a common chemical structure.
次に、ヒト皮膚線維芽細胞（ＨＤＦ）の増殖に対するRumbrinとAuxarconjugatin Bの影響を調べた。
その結果、Rumbrinは１μＭの濃度でさえＨＤＦに毒性を示したが、Auxarconjugatin Bは１～５μＭの濃度でＨＤＦに毒性を示さなかった。
Next, we investigated the effects of Rumbrin and Auxarconjugatin B on the proliferation of human dermal fibroblasts (HDFs).
As a result, Rumbrin was toxic to HDF even at a concentration of 1 μM, but Auxarconjugatin B was not toxic to HDF at a concentration of 1 to 5 μM.
そこで、Auxarconjugatin Bをシード化合物に選定して、詳細な解析を実施した。
Auxarconjugatin BのＣＣＲＦ－ＣＥＭ細胞に対するＩＣ50は０．５１μＭであり、Ｒａｊｉ細胞に対するＩＣ50はその約１１倍の５．７μＭであった（図１（ｃ）参照）。
また、Auxarconjugatin Bは、ヒト赤芽球系（Ｍ６クラス）急性骨髄性白血病（Acute myeloid leukemia：ＡＭＬ）細胞株ＴＦ－１や、ヒト単球系（Ｍ５クラス）ＡＭＬ細胞株ＴＨＰ－１の増殖を、それぞれ０．７２μＭと１．３μＭのＩＣ50値にて抑制した（図２（ａ）、図２（ｂ）参照）。
Therefore, we selected Auxarconjugatin B as a seed compound and conducted detailed analysis.
The IC 50 of Auxarconjugatin B against CCRF-CEM cells was 0.51 μM, and the IC 50 against Raji cells was 5.7 μM, about 11 times that value (see FIG. 1(c)).
Auxarconjugatin B also inhibits the proliferation of the human erythroid (M6 class) acute myeloid leukemia (AML) cell line TF-1 and the human monocytic (M5 class) AML cell line THP-1. were suppressed with IC 50 values of 0.72 μM and 1.3 μM, respectively (see FIGS. 2(a) and 2(b)).
＜リード化合物類縁体の評価＞
以上の結果から、Auxarconjugatin BがＴ－ＡＬＬやＡＭＬに対して有効である（即ち、リード化合物として有望である）ことが示唆されたが、Auxarconjugatin Bはカビ由来の天然化合物であるため、大量に製造することができない。
そこで、Auxarconjugatin Bと類似の構造を持つ、エステル体８及びエステル体９に対して、ヒトＴ－ＡＬＬ細胞株ＣＣＲＦ－ＣＥＭ、ヒトＢリンフォーマ細胞株Ｒａｊｉの増殖阻害活性を評価した。結果を図３に示す。
<Evaluation of lead compound analogs>
The above results suggested that Auxarconjugatin B is effective against T-ALL and AML (that is, it is promising as a lead compound). However, since Auxarconjugatin B is a natural compound derived from fungi, cannot be manufactured.
Therefore, ester form 8 and ester form 9, which have a similar structure to Auxarconjugatin B, were evaluated for growth inhibition activity in human T-ALL cell line CCRF-CEM and human B lymphoma cell line Raji. The results are shown in Figure 3.
更に、エステル体９に対して、ヒト赤芽球系（Ｍ６クラス）ＡＭＬ細胞株ＴＦ－１、ヒト単球系（Ｍ５クラス）ＡＭＬ細胞株ＴＨＰ－１、ヒト赤芽球系慢性骨髄性白血病（Chronic myeloid leukemia：ＣＭＬ）細胞株Ｋ５６２の増殖阻害活性を評価した。結果を図４に示す。 Furthermore, for ester 9, human erythroid (M6 class) AML cell line TF-1, human monocytic (M5 class) AML cell line THP-1, human erythroblastic chronic myeloid leukemia ( The growth inhibitory activity of Chronic myeloid leukemia (CML) cell line K562 was evaluated. The results are shown in Figure 4.
その結果、エステル体９は、ヒト赤芽球系（Ｍ６クラス）ＡＭＬ細胞株ＴＦ－１、ヒト単球系（Ｍ５クラス）ＡＭＬ細胞株ＴＨＰ－１の増殖を強力に抑制することが分かった。
但し、エステル体８は、ＣＣＲＦ－ＣＥＭ細胞に対するＩＣ50が１．７μＭで、Ｒａｊｉ細胞に対するＩＣ50が８．８μＭであり、また、エステル体９は、ＣＣＲＦ－ＣＥＭ細胞に対するＩＣ50が１．３μＭで、Ｒａｊｉ細胞に対するＩＣ50が４．１μＭであり、Auxarconjugatin Bよりも活性及び選択性に劣っていた。
As a result, it was found that ester 9 strongly suppresses the proliferation of the human erythroblastoid (M6 class) AML cell line TF-1 and the human monocytic (M5 class) AML cell line THP-1.
However, ester form 8 has an IC 50 of 1.7 μM for CCRF-CEM cells and 8.8 μM for Raji cells, and ester form 9 has an IC 50 of 1.3 μM for CCRF-CEM cells. The IC 50 against Raji cells was 4.1 μM, indicating inferior activity and selectivity to Auxarconjugatin B.
次に、Auxarconjugatin Bと類似の構造を持つ、構造式（II）の化合物、構造式（III）の化合物、構造式（IV）の化合物、構造式（V）の化合物、構造式（VI）の化合物に対して、ヒトＴ－ＡＬＬ細胞株ＣＣＲＦ－ＣＥＭ、ヒトＢリンフォーマ細胞株Ｒａｊｉの増殖阻害活性を評価した。結果を図５に示す。 Next, compounds of structural formula (II), compound of structural formula (III), compound of structural formula (IV), compound of structural formula (V), and compound of structural formula (VI), which have a structure similar to Auxarconjugatin B, are The compound was evaluated for growth inhibitory activity in the human T-ALL cell line CCRF-CEM and the human B lymphoma cell line Raji. The results are shown in Figure 5.
更に、これらの化合物に対して、ヒト赤芽球系（Ｍ６クラス）ＡＭＬ細胞株ＴＦ－１、ヒト単球系（Ｍ５クラス）ＡＭＬ細胞株ＴＨＰ－１、ヒト骨髄球系（Ｍ２クラス）ＡＭＬ細胞株ＨＬ－６０、ヒト巨核球系（Ｍ７クラス）ＡＭＬ細胞株ＭＫＰＬ－１、ヒト赤芽球系ＣＭＬ細胞株Ｋ５６２の増殖阻害活性を評価した。構造式（II）の化合物の結果を図６に、構造式（III）の化合物の結果を図７に、構造式（IV）の化合物の結果を図８に、構造式（V）の化合物の結果を図９に、構造式（VI）の化合物の結果を図１０に示す。 Furthermore, for these compounds, human erythroid (M6 class) AML cell line TF-1, human monocytic (M5 class) AML cell line THP-1, human myeloid (M2 class) AML cell line The growth inhibitory activity of cell line HL-60, human megakaryocytic (M7 class) AML cell line MKPL-1, and human erythroblast CML cell line K562 was evaluated. The results for the compound of structural formula (II) are shown in Figure 6, the results for the compound of structural formula (III) are shown in Figure 7, the results for the compound of structural formula (IV) are shown in Figure 8, and the results for the compound of structural formula (V) are shown in Figure 6. The results are shown in FIG. 9, and the results for the compound of structural formula (VI) are shown in FIG.
構造式（II）の化合物のＣＣＲＦ－ＣＥＭ細胞に対するＩＣ50は０．２７μＭであるのに対し、Ｒａｊｉ細胞に対する増殖抑制効果はほとんど検出されなかった（図５（ａ）参照）。
また、ヒト赤芽球系ＣＭＬ細胞株Ｋ５６２細胞に対する構造式（II）の化合物の増殖抑制効果もほとんど検出でされなかった（図６（ｅ）参照）。
また、構造式（II）の化合物は、Auxarconjugatin Bと同様、ヒト赤芽球系（Ｍ６クラス）ＡＭＬ細胞株ＴＦ－１、ヒト単球系（Ｍ５クラス）ＡＭＬ細胞株ＴＨＰ－１、ヒト骨髄球系（Ｍ２クラス）ＡＭＬ細胞株ＨＬ－６０、ヒト巨核球系（Ｍ７クラス）ＡＭＬ細胞株ＭＫＰＬ－１の増殖を、それぞれ０．２３μＭ、１．２μＭ、０．２７μＭ、０．４２μＭのＩＣ50値にて抑制した（図６（ａ）、図６（ｂ）、図６（ｃ）、図６（ｄ）参照）。
While the IC 50 of the compound of structural formula (II) against CCRF-CEM cells was 0.27 μM, almost no growth-inhibitory effect on Raji cells was detected (see FIG. 5(a)).
Further, the growth-inhibiting effect of the compound of structural formula (II) on the human erythroid CML cell line K562 cells was hardly detected (see FIG. 6(e)).
Similarly to Auxarconjugatin B, the compound of structural formula (II) can be used in human erythroid (M6 class) AML cell line TF-1, human monocytic (M5 class) AML cell line THP-1, human myeloid cell line IC 50 values of 0.23 μM, 1.2 μM, 0.27 μM, and 0.42 μM were observed for the proliferation of AML cell line HL-60 (M2 class) and MKPL-1, human megakaryocytic (M7 class) AML cell line, respectively. (See FIGS. 6(a), 6(b), 6(c), and 6(d)).
また、構造式（III）の化合物、構造式（IV）の化合物、構造式（V）の化合物、及び構造式（VI）の化合物にも、構造式（II）の化合物に類似したＴ－ＡＬＬ及びＡＭＬに選択的な細胞死滅活性が検出された（図５（ｂ）、図５（ｃ）、図５（ｄ）、図５（ｅ）、図７、図８、図９、図１０参照）。 In addition, compounds of structural formula (III), compounds of structural formula (IV), compounds of structural formula (V), and compounds of structural formula (VI) also include T-ALL, which is similar to the compound of structural formula (II). and AML-selective cell killing activity was detected (see Fig. 5(b), Fig. 5(c), Fig. 5(d), Fig. 5(e), Fig. 7, Fig. 8, Fig. 9, Fig. 10). ).
次に、構造式（II）の化合物に対して、ヒト上皮性癌細胞株ＨｅｌａとＨＳＣ－３の増殖阻害活性を評価し、更に、ヒト腎上皮細胞株２９３Ｔの増殖阻害活性を評価した。結果を図１１に示す。
Next, the compound of structural formula (II) was evaluated for growth inhibitory activity on human epithelial cancer cell lines Hela and HSC-3, and further evaluated for growth inhibitory activity on human renal
その結果、構造式（II）の化合物は、ヒト上皮性癌細胞株ＨｅｌａとＨＳＣ－３の増殖にまったく影響を与えなかった（図１１（ａ）参照）。
また、構造式（II）の化合物は、ヒト腎上皮細胞株２９３Ｔに対するＩＣ50値が３．５μＭと、ＣＣＲＦ－ＣＥＭより１３倍高かった（図１１（ｂ）参照）。
As a result, the compound of structural formula (II) had no effect on the proliferation of human epithelial cancer cell lines Hela and HSC-3 (see FIG. 11(a)).
Furthermore, the compound of structural formula (II) had an IC 50 value of 3.5 μM against the human renal
以上の実験の結果から、本発明に係る上記一般式（I）で表される化合物は、Auxarconjugatin Bと共通の標的分子を認識していると推察され、Ｔ－ＡＬＬ及びＡＭＬに対するがん種選択的な治療薬として有効であることが分かった。また、本発明に係る上記一般式（I）で表される化合物は、Auxarconjugatin Bよりも、活性及び選択性に優れることが分かった。 From the results of the above experiments, it is inferred that the compound represented by the above general formula (I) according to the present invention recognizes a common target molecule with Auxarconjugatin B, and can be used to select cancer types for T-ALL and AML. It was found to be effective as a therapeutic drug. Furthermore, it was found that the compound represented by the above general formula (I) according to the present invention has superior activity and selectivity to Auxarconjugatin B.
＜in vivo抗白血病活性＞
次に、活性とＴ－ＡＬＬ選択性が最も優れていた構造式（II）の化合物及び構造式（VI）の化合物を用いて、in vivo抗腫瘍活性を検討した。ＮＳＧマウスの皮下で増殖したＣＣＲＦ－ＣＥＭ由来腫瘍の内部に構造式（II）の化合物又は構造式（VI）の化合物を連続投与してみたところ、構造式（II）の化合物又は構造式（VI）の化合物投与マウス群では溶媒コントロール群と比べて腫瘍増殖が抑えられ、マウスが延命する傾向が観察された（図１２、図１３）。この結果から、本発明に係る上記一般式（I）で表される化合物には、in vivo抗白血病活性もあることが分かった。
<In vivo antileukemia activity>
Next, in vivo antitumor activity was investigated using the compound of structural formula (II) and the compound of structural formula (VI), which had the best activity and T-ALL selectivity. When we continuously administered the compound of structural formula (II) or the compound of structural formula (VI) into the subcutaneously grown CCRF-CEM-derived tumors of NSG mice, we found that the compound of structural formula (II) or the compound of structural formula (VI) ) In the compound-administered mouse group, tumor growth was suppressed and the survival of the mice tended to be prolonged compared to the vehicle control group (Figures 12 and 13). From this result, it was found that the compound represented by the above general formula (I) according to the present invention also has in vivo anti-leukemia activity.
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| Journal of Chemical Research: Synopses，1986年，Vol.40，p.440-441 |
| Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999)，1984年，Vol.7，p.1577-1579 |
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