JP2015502926A - 癌治療における使用のためのモルホリニルベンゾトリアジン - Google Patents
癌治療における使用のためのモルホリニルベンゾトリアジン Download PDFInfo
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- JP2015502926A JP2015502926A JP2014541555A JP2014541555A JP2015502926A JP 2015502926 A JP2015502926 A JP 2015502926A JP 2014541555 A JP2014541555 A JP 2014541555A JP 2014541555 A JP2014541555 A JP 2014541555A JP 2015502926 A JP2015502926 A JP 2015502926A
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Abstract
Description
で表される化合物、ならびに/またはそれらの生理学的に許容し得る塩、互変異性体および立体異性体、ならびにすべての比率でのそれらの混合物に関する。式(I)で表される化合物を、セリン/トレオニンプロテインキナーゼの阻害のために、ならびに癌細胞の抗癌剤および/または電離放射線に対する増感のために使用することができる。本発明はまた、式(I)で表される化合物の、放射線療法および/または抗癌剤と組み合わせての癌、腫瘍、転移または血管新生障害の予防、治療または進行抑制における使用に関する。本発明はさらに、式(I)で表される化合物の、式(II)および(III)で表される化合物の反応ならびに任意に式(I)で表される化合物の塩基または酸のそれらの塩への変換による製造方法に関する。
R1はHet1またはArを示し;
R2、R3は、互いに独立してYもしくはOYを示すか、または一緒にまた−O−(CH2)n−を示し;
R4はAまたは(CH2)nOAを示し;
YはHまたはAを示し;
Cycは、3〜7個のC原子を有する環状アルキルを示し、ここで、互いに独立して、1〜4個のH原子はHalによって置き換えられていてもよく;
Arは、非置換であるか、またはHal、(CH2)pOY、R4、(CH2)pOR4、COOY、NY2、NYCOYおよび/もしくはCNによって単置換もしくは二置換されているフェニルを示し;
Het2は、2〜7個のC原子ならびに1〜4個のN、Oおよび/またはS原子を有し、非置換であるか、またはAによって単置換されていてもよい、単環式の飽和複素環を示し;
mは0、1または2を示し;ならびに
n、pは、互いに独立して0、1、2、3、4または5を示す、
ならびに/またはそれらの生理学的に許容し得る塩、互変異性体および/もしくは立体異性体、ならびにすべての比率でのそれらの混合物。
式(I)で表される基本構造は、本発明の意味におけるあらゆるラジカル、例えばAr、Het1またはHet2が、本発明の式(I)で表される化合物を得るために結合することができるあらゆる包括的であるかまたは包括的でない構造である。
ラジカルR2、R3は、特に、互いに独立してYもしくはOY、または一緒にまた−O−(CH2)n−を示す。
ラジカルR2は、好ましくはYまたはOY、特に好ましくはYまたはOH、非常に特に好ましくはY、同様に非常に特に好ましくはOH、最も好ましくはHを示す。
ラジカルR3は、好ましくはYまたはOY、特に好ましくはOYまたはA、非常に特に好ましくはOY、最も好ましくはOHを示す。
ラジカルR4は、特にAまたは(CH2)nOAを示す。
基−L−R1は、好ましくはピロリジン、ピペリジンまたはアゼパン上のメタ位において配置される。
指数nは、好ましくは0、1、2、3または4、特に好ましくは1、2または3を示す。「n」のそれぞれの意味が本発明の式で表されるラジカルにおいて互いに独立していることは、言うまでもない。
R1はHet1またはArを示し;
R2はYまたはOYを示し;
R3はOYまたはAを示し;
R2、R3は一緒にまた−O−(CH2)n−を示し;
YはHまたはAを示し;
Aは1〜6個のC原子を有する非分枝状または分枝状アルキルを示し、ここで、互いに独立して、1〜5個のH原子はHalによって置き換えられていてもよく;
Arは、非置換であるか、またはHalおよび/もしくは(CH2)pOYによって単置換もしくは二置換されているフェニルを示し;
HalはF、Cl、BrまたはIを示し;ならびに
n、pは、互いに独立して0、1、2、3または4を示す、
で表されるモルホリニルベンゾトリアジン誘導体ならびに/またはそれらの生理学的に許容し得る塩、互変異性体および/もしくは立体異性体、ならびにすべての比率でのそれらの混合物を提供する。
YはHまたはAを示し;
Aは1〜6個のC原子を有する非分枝状または分枝状アルキルを示し、ここで、互いに独立して、1〜3個のH原子はHalによって置き換えられていてもよく;
pは0、1または2を示す、
で表されるモルホリニルベンゾトリアジン誘導体ならびに/またはそれらの生理学的に許容し得る塩、互変異性体および/もしくは立体異性体、ならびにすべての比率でのそれらの混合物を提供する。
で表される化合物を反応させて、
で表される化合物を得ること、
(b)式(I)で表される化合物の塩基または酸をそれらの塩の1種に変換すること
を有する、前記方法に関する。
で表される中間体化合物
ならびに/またはそれらの塩、互変異性体および/もしくは立体異性体、ならびにすべての比率でのそれらの混合物に関する。
の1つ、2つ以上またはすべてのステップに従う、前記方法に関する。
の1つまたはすべてのステップに従う、前記方法に関する。
の1つまたはすべてのステップに従う、前記方法に関する。
の1つ、2つ以上またはすべてのステップに従う、前記方法に関する。
機器:Bruker Avance DRX 500、Bruker Avance 400、Bruker DPX 300
基準:TMS
TD(時間領域=データ点またはデジタル分解能の数):65536
溶媒:DMSO d6
NS(走査の数):32
SF(分光計周波数=透過周波数):500MHz
TE(温度):303K
機器:Agilent Technologies 1200シリーズ
方法:ESI1ROD.MおよびPOLAR.M(3.8分、溶媒勾配)
カラム:ChromolithSpeedROD RP18e50-4.6
溶媒:アセトニトリル+0.05%のHCOOH/脱イオン水+0.04%のHCOOH
検出波長:220nm
MSタイプ:API−ES
例3Aに従って製造した化合物を、表1(ピリダジン類似体番号14〜15なし)および2に示す。
MS(M+H)+=224。
MS(M+H)+=324。
MS(M+H)+=224。
分析は表1を参照。
キナーゼ分析を、ストレプトアビジンで被覆した348ウェルマイクロタイターフラッシュプレート(FlashPlates)(登録商標)中で行った。このために、36.5μlの全容積における1.5μgのDNA−PK/タンパク質複合体および100ngのビオチン化基質、例えばPESQEAFADLWKKビオチン−NH2(「ビオチン−DNA−PKペプチド」)(34.25mMのHEPES/KOH、7.85mMのトリス−HCl、68.5mMのKCl、5μMのATP、6.85mMのMgCl2、0.5mMのEDTA、0.14mMのEGTA、0.69mMのDTT、pH7.4)を、室温で90分間、ウェルあたり500ngのウシ胸腺からのDNA、0.1μCiの33P−ATPおよび1.8%のDMSOと共に、試験化合物と共に、または試験化合物なしでインキュベートした。反応を、50μl/ウェルの200mMのEDTAを使用して停止した。
HCT116細胞を、10%の胎児ウシ血清、1mMのピルビン酸ナトリウムおよび2mMのグルタミンを有するMEMアルファ培地中で、37℃および10%CO2で培養した。細胞を、トリプシン/EDTAの補助によって培養容器の底部から剥離させ、遠心分離管中で遠心分離して除去し、新鮮な培地中に吸収させた。細胞密度を、その後決定した。200,000の細胞を、1mlの培養培地中に12ウェル細胞培養プレートのキャビティあたり播種し、一晩培養した。翌日、新鮮な培養培地中の10μMのブレオマイシンおよび試験物質を、細胞に加え、これらをさらに6時間培養した。
結腸直腸癌細胞株HCT116を、10%の胎児ウシ血清、1mMのピルビン酸ナトリウムおよび2mMのグルタミンを有するMEMアルファ培地中で、37℃および10%CO2で培養した。細胞を、トリプシン/EDTAの補助によって培養容器の底部から剥離させ、遠心分離管中で遠心分離して除去し、新鮮な培地中に吸収させた。細胞密度を、その後決定した。300の細胞を、6ウェル細胞培養プレート中で2mlの培養培地中に播種し、一晩培養した。翌日、細胞を試験物質で1時間処理し、その後細胞培養プレートを、規定された線量のX線(一般的に0、2.4、4.8、12グレイ;照射機器:Faxitron RX-650;Faxitron X-Ray LLC, USA)で処理した。
HCT116細胞を、10%の胎児ウシ血清、1mMのピルビン酸ナトリウムおよび2mMのグルタミンを有するMEMアルファ培地中で、37℃および10%CO2で培養した。細胞を、トリプシン/EDTAの補助によって培養容器の底部から剥離させ、遠心分離管中で遠心分離して除去し、新鮮な培地中に吸収させた。細胞密度を、その後決定した。50,000の細胞を、0.1mlの培養培地中に96ウェル細胞培養プレートのキャビティあたり播種し、一晩培養した。翌日、新鮮な培養培地中の10μMのブレオマイシンおよび試験物質を、細胞に加え、これらをさらに6時間培養した。
例A:注射バイアル
3lの2回蒸留水中の100gの本発明の活性化合物および5gのリン酸水素二ナトリウムの溶液を、2Nの塩酸を使用してpH6.8に調整し、滅菌濾過し、注射バイアル中に移送し、滅菌条件下で凍結乾燥し、滅菌条件下で密封した。各注射バイアルは、5mgの本発明の活性化合物を含んでいた。
100gの大豆レシチンおよび1400gのココアバターとの20gの本発明の活性化合物の混合物を溶融させ、型中に注ぎ、放冷した。各坐剤は、20mgの本発明の活性化合物を含んでいた。
溶液を、1gの本発明の活性化合物、9.38gのNaH2PO4*2H2O、28.48gのNa2HPO4*12H2Oおよび0.1gの塩化ベンザルコニウムから940mlの2回蒸留水中に製造した。pHを6.8に調整し、溶液を1lにし、照射によって滅菌した。この溶液を、点眼薬の形態で使用することができる。
500mgの本発明の活性化合物を99.5gのワセリンと、無菌条件下で混合した。
1kgの本発明の活性化合物、4kgのラクトース、1.2kgのジャガイモデンプン、0.2kgのタルクおよび0.1kgのステアリン酸マグネシウムの混合物を、慣用の方式で押圧して錠剤を得、各錠剤が10mgの本発明の活性化合物を含むようにした。
錠剤を、例Eと同様にして押圧し、次に慣用の方式でスクロース、ジャガイモデンプン、タルク、トラガカントゴムおよび色素のコーティングで被覆した。
2kgの本発明の活性化合物を、硬質ゼラチンカプセル中に慣用の方式で、各カプセルが20mgの本発明の活性化合物を含むように導入した。
60lの2回蒸留水中の1kgの本発明の活性化合物の溶液を滅菌濾過し、アンプル中に移送し、滅菌条件下で凍結乾燥し、滅菌条件下で密封した。各アンプルは、10mgの本発明の活性化合物を含んでいた。
14gの本発明の活性化合物を、10lの等張NaCl溶液に溶解し、溶液を、ポンプ機構を有する標準的な商業的スプレー容器中に移送した。溶液を、口または鼻中に噴霧することができる。1回のスプレー噴射(約0.1ml)は、約0.14mgの用量に相当した。
Claims (15)
- 式(I)
R1はHet1またはArを示し;
R2、R3は、互いに独立してYもしくはOYを示すか、または一緒にまた−O−(CH2)n−を示し;
R4はAまたは(CH2)nOAを示し;
Lは、−CR2R3−、単結合、−(CH2)n−、−CH(Hal)−、−C(Hal)2−、−(CH2)nCH(OY)−、−(CH2)nCO−、−(CH2)nNH−、−(CH2)nCONY2−、−NYCO−、−NHCO−NH−、−NR4CO−、−NYSO2−、−C(=NR4)−、−C(=NCN)−、−CY(NY2)−、−CY(CN)−、−CY(O−(CH2)nCN)−、−CY(Het2)−または−CY(O−(CH2)nHet2)−を示し;
YはHまたはAを示し;
Aは、1〜10個のC原子を有する非分枝状または分枝状アルキルを示し、ここで、互いに独立して、1〜7個のH原子はHalによって置き換えられていてもよく;
Cycは、3〜7個のC原子を有する環状アルキルを示し、ここで、互いに独立して、1〜4個のH原子はHalによって置き換えられていてもよく;
Arは、非置換であるか、またはHal、(CH2)pOY、R4、(CH2)pOR4、COOY、NY2、NYCOYおよび/もしくはCNによって単置換もしくは二置換されているフェニルを示し;
Het1は、2〜9個のC原子ならびに1〜4個のN、Oおよび/またはS原子を有し、非置換であるか、またはHal、(CH2)pOY、R4、(CH2)pOR4、=O、COOY、NY2、NYCOY、CONY2、Cyc、Het2および/もしくはCNによって単置換もしくは二置換されていてもよい、単環式の、または二環式のヘテロアリールを示し;
Het2は、2〜7個のC原子ならびに1〜4個のN、Oおよび/またはS原子を有し、非置換であるか、またはAによって単置換されていてもよい、単環式の飽和複素環を示し;
HalはF、Cl、BrまたはIを示し;
mは0、1または2を示し;ならびに
n、pは、互いに独立して0、1、2、3、4または5を示す、
で表される化合物、またはそれらの生理学的に許容し得る塩、互変異性体もしくは立体異性体、あるいはすべての比率でのそれらの混合物。 - R1がHet1を示す、
請求項1に記載の化合物。 - R2、R3が互いに独立してYまたはOYを示す、
請求項1または2に記載の化合物。 - Lが−CR2R3−を示す、
請求項1〜3のいずれか一項に記載の化合物。 - Het1が2〜8個のC原子および1〜3個のN、Oおよび/またはS原子を有し、非置換であるかまたはHal、(CH2)pOY、Aおよび/もしくは=Oによって単置換もしくは二置換されていてもよい単環式または二環式ヘテロアリールを示す、
請求項1〜4のいずれか一項に記載の化合物。 - 従属式(IA)
R1はHet1またはArを示し;
R2はYまたはOYを示し;
R3はOYまたはAを示し;
R2、R3は一緒にまた−O−(CH2)n−を示し;
Lは−CR2R3−を示し;
YはHまたはAを示し;
Aは1〜6個のC原子を有する非分枝状または分枝状アルキルを示し、ここで、互いに独立して、1〜5個のH原子はHalによって置き換えられていてもよく;
Arは、非置換であるか、またはHalおよび/もしくは(CH2)pOYによって単置換もしくは二置換されているフェニルを示し;
Het1は、2〜8個のC原子ならびに1〜3個のN、Oおよび/またはS原子を有し、非置換であるかまたはHal、(CH2)pOY、Aおよび/もしくは=Oによって単置換もしくは二置換されていてもよい、単環式または二環式ヘテロアリールを示し;
HalはF、Cl、BrまたはIを示し;ならびに
n、pは、互いに独立して0、1、2、3または4を示す、
を有する、請求項1に記載の化合物、またはそれらの生理学的に許容し得る塩、互変異性体もしくは立体異性体、あるいはすべての比率でのそれらの混合物。 - 従属式(IB)
YはHまたはAを示し;
Aは1〜6個のC原子を有する非分枝状または分枝状アルキルを示し、ここで、互いに独立して、1〜3個のH原子はHalによって置き換えられていてもよく;
Het1は、非置換であるかまたはHal、(CH2)pOY、Aおよび/もしくは=Oによって単置換もしくは二置換されていてもよい、以下の群から選択されるヘテロアリールを示し;
pは0、1または2を示す、
を有する、請求項1に記載の化合物、またはそれらの生理学的に許容し得る塩、互変異性体もしくは立体異性体、あるいはすべての比率でのそれらの混合物。 - 以下の群:
- 請求項1に記載の式(I)で表される化合物、またはそれらの生理学的に許容し得る塩、互変異性体もしくは立体異性体の製造方法であって、以下のステップ:
(a)式(II)
で表される化合物と反応させ、
式(I)
で表される化合物を得ること、
ならびに任意に
(b)式(I)で表される化合物の塩基または酸をそれらの塩の1種に変換すること
を有する、前記方法。 - 式(II)、(III)、(IIIA)、(IIIB)、(IV)、(IVA)、(IVB)、(VIA)、(VIB)、VIC)および/または(VID)
で表される中間体化合物、またはそれらの塩、互変異性体もしくは立体異性体、あるいはすべての比率でのそれらの混合物。 - 請求項1〜8のいずれか一項に記載の化合物、またはそれらの生理学的に許容し得る塩、互変異性体もしくは立体異性体、あるいはすべての比率でのそれらの混合物の、in vitroでのセリン/トレオニンプロテインキナーゼ、好ましくはPIKKおよび/またはATM、特に好ましくはDNA−PKの阻害のための使用。
- 請求項1〜8のいずれか一項に記載の少なくとも1種の化合物、またはそれらの生理学的に許容し得る塩、互変異性体もしくは立体異性体、あるいはすべての比率でのそれらの混合物の、癌細胞の抗癌剤および/または電離放射線に対する感作、ただし感作が人体上でin vivoで起こらない、のための使用。
- 請求項1〜8のいずれか一項に記載の少なくとも1種の化合物、またはそれらの生理学的に許容し得る塩、互変異性体もしくは立体異性体、あるいはすべての比率でのそれらの混合物を含む、医薬。
- 活性化合物として、有効量の請求項1〜8のいずれか一項に記載の少なくとも1種の化合物、またはそれらの生理学的に許容し得る塩、互変異性体もしくは立体異性体、あるいはすべての比率でのそれらの混合物を、薬学的に耐容される補助剤と一緒に、少なくとも1種の抗癌剤と組み合わせて含む、医薬組成物。
- 放射線治療と、および/または少なくとも1種の抗癌剤と組み合わせて癌、腫瘍、転移および/または血管新生障害の予防、治療および/または進行抑制において使用するための、請求項1〜8のいずれか一項に記載の化合物、またはそれらの生理学的に許容し得る塩、互変異性体もしくは立体異性体、あるいはすべての比率でのそれらの混合物。
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PCT/EP2012/004542 WO2013072015A1 (de) | 2011-11-18 | 2012-10-30 | Morpholinylbenzotriazine zur anwendung in der krebstherapie |
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DE102013008118A1 (de) | 2013-05-11 | 2014-11-13 | Merck Patent Gmbh | Arylchinazoline |
PE20161022A1 (es) | 2013-10-17 | 2016-11-12 | Vertex Pharma | Cocristales de (s)-n-metil-8-(1-((2'-metil-[4,5´-bipirimidin]-6-il)amino)propan-2-il)quinolina-4-carboxamida y sus derivados deuterados como inhibidores de proteinas quinasa dependientes de adn |
US11110108B2 (en) | 2016-09-27 | 2021-09-07 | Vertex Pharmaceuticals Incorporated | Method for treating cancer using a combination of DNA-damaging agents and DNA-PK inhibitors |
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ZA201404438B (en) | 2015-12-23 |
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JP6096792B2 (ja) | 2017-03-15 |
HK1199875A1 (en) | 2015-07-24 |
MX2014005838A (es) | 2014-07-30 |
BR112014011805A2 (pt) | 2017-05-16 |
PL2780332T3 (pl) | 2016-07-29 |
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EP2780332A1 (de) | 2014-09-24 |
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AU2012339196B2 (en) | 2017-04-27 |
IL232577A (en) | 2017-05-29 |
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US9187469B2 (en) | 2015-11-17 |
CA2856103C (en) | 2020-08-25 |
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