JP2008510719A - Chk1の阻害に有用な化合物 - Google Patents
Chk1の阻害に有用な化合物 Download PDFInfo
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- JP2008510719A JP2008510719A JP2007528037A JP2007528037A JP2008510719A JP 2008510719 A JP2008510719 A JP 2008510719A JP 2007528037 A JP2007528037 A JP 2007528037A JP 2007528037 A JP2007528037 A JP 2007528037A JP 2008510719 A JP2008510719 A JP 2008510719A
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- cancer
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- alkylene
- heteroaryl
- cell
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- 229910000166 zirconium phosphate Inorganic materials 0.000 description 1
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- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Description
X2が、-O-、-S-、または-N(R1)-であり;
Yが、酸素または硫黄であり;または、=Yは、共通する炭素原子に結合している二つの水素原子を表し;
Wが、ヘテロアリール、アリール、ヘテロシクロアルキル、シクロアルキル、およびヘテロアリールまたはアリール基で置換されたC1-6アルキルからなるグループから選択され、(a)前記W基でのアリール基またはヘテロアリール基が、少なくとも一つのCF3およびヘテロアリールで置換されており、(b)前記W基でのアリール基が、R2で表される1個〜3個の置換基で任意に置換されており、および、(c)前記W基でのヘテロアリール基が、R5で表される1個〜3個の置換基で任意に置換されており;
R1が、ヒドロ、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、およびアリールからなるグループから選択され;
R2が、ヘテロアリール、ハロ、任意に置換されたC1-6アルキル、C2-6アルケニル、OCF3、NO2、CN、NC、N(R3)2、OR3、CO2R3、C(O)N(R3)2、C(O)R3、N(R1)COR3、N(R1)C(O)OR3、N(R1)C(O)C1-6アルキレンC(O)R3、N(R1)C(O)C1-6アルキレンC(O)R3、N(R1)C(O)C1-6アルキレンOR3、N(R1)C(O)C1-6アルキレンNHC-(O)OR3、N(R1)C(O)C1-6アルキレンSO2NR3、C1-6アルキレンOR3、およびSR3からなるグループから選択され;
R3が、ヒドロ、ハロ、C1-6アルキル、C2-6アルケニル、シクロアルキル、アリール、ヘテロアリール、CO2R4、SO2R4、ハロ、ヒドロキシ、アリール、ヘテロアリール、ヘテロシクロアルキル、N(R4)2、およびSO2R4の一つまたはそれ以上で置換されたC1-6アルキル、C1-6アルキレンアリール、C1-6アルキレンヘテロアリール、C1-6アルキレンC3-8ヘテロシクロアルキル、C1-6アルキレンSO2アリール、任意に置換されたC1-6アルキレンN(R4)2、OCF3、C1-6アルキレンN(R4)3 +、C3-8ヘテロシクロアルキル、およびCH(C1-6アルキレンN(R4)2)2からなるグループから選択され、または、二つのR3基をもってして、任意に置換された三員〜六員の脂肪族環が形成され;
R4が、ヒドロ、C1-6アルキル、シクロアルキル、アリール、ヘテロアリール、C1-6アルキレンアリール、およびSO2C1-6アルキルからなるグループから選択され、または、二つのR4基をもってして、任意に置換された三員〜六員の環が形成され;
R5が、C1-6アルキル、アリール、ヘテロアリール、ヘテロシクロアルキル、N(R3)2、OR3、ハロ、N3、CN、C1-6アルキレンアリール、C1-6アルキレンN(R3)2、C(O)R3、C(O)OR3、C(O)N(R3)2、N(R1)C(O)R3、N(R1)CO2R3、CF3、および以下の式、
R6が、OR11、-C≡C-R7、およびヘテロアリールからなるグループから選択され;
R7が、ヒドロ、C1-6アルキル、アリール、C1-6アルキレンアリール、ヘテロアリール、C1-6アルキレンヘテロアリール、およびアルコキシからなるグループから選択され;
R8、R9およびR10が、独立して、ヒドロ、ハロ、任意に置換されたC1-6アルキル、C2-6アルケニル、C2-6アルキニル、OCF3、CF3、NO2、CN、NC、N(R3)2、OR3、CO2R3、C(O)N(R3)2、C(O)R3、N(R1)COR3、N(R1)C(O)OR3、N(R8)C(O)OR3、N(R1)C(O)C1-6アルキレンC(O)R3、N(R1)C(O)C1-6アルキレンC(O)OR3、N(R1)C(O)C1-3アルキレンOR3、N(R1)C(O)C1-6アルキレンNHC(O)OR3、N(R1)C(O)C1-6アルキレンSO2NR3、C1-6アルキレンOR3、およびSR3からなるグループから選択され;
R11が、ヒドロ、C1-6アルキル、C2-6アルケニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、SO2R4、ハロ、ヒドロキシ、ヘテロアリール、N(R4)2、およびSO2R4の一つまたはそれ以上で置換されたC1-6アルキル、C1-6アルキレンアリール、C1-6アルキレンヘテロアリール、C1-6アルキレン-C3-8ヘテロシクロアルキル、C1-6アルキレンSO2アリール、任意に置換されたC1-6アルキレンN(R4)2、OCF3、C1-6アルキレンN(R4)3 +、C3-8ヘテロシクロアルキル、およびCH(C1-6アルキレン-N(R4)2)2からなるグループから選択される、化学構造式で表される化合物であり、薬学的に許容可能なその塩、またはプロドラッグ、または溶媒和物をも意図している。
X2が、-O-、-S-、または-N(R1)-であり;
Yが、酸素または硫黄であり;または、=Yは、共通する炭素原子に結合している二つの水素原子を表し;
Wが、ヘテロアリール、アリール、ヘテロシクロアルキル、シクロアルキル、およびヘテロアリールまたはアリール基で置換されたC1-6アルキルからなるグループから選択され、(a)前記W基でのアリール基またはヘテロアリール基が、少なくとも一つのCF3およびヘテロアリールで置換されており、(b)前記W基でのアリール基が、R2で表される1個〜3個の置換基で任意に置換されており、および、(c)前記W基でのヘテロアリール基が、R5で表される1個〜3個の置換基で任意に置換されており;
R1が、ヒドロ、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、およびアリールからなるグループから選択され;
R2が、ヘテロアリール、ハロ、任意に置換されたC1-6アルキル、C2-6アルケニル、OCF3、NO2、CN、NC、N(R3)2、OR3、CO2R3、C(O)N(R3)2、C(O)R3、N(R1)COR3、N(R1)C(O)OR3、N(R1)C(O)C1-6アルキレンC(O)R3、N(R1)C(O)C1-6アルキレンC(O)R3、N(R1)C(O)C1-6アルキレンOR3、N(R1)C(O)C1-6アルキレンNHC-(O)OR3、N(R1)C(O)C1-6アルキレンSO2NR3、C1-6アルキレンOR3、およびSR3からなるグループから選択され;
R3が、ヒドロ、ハロ、C1-6アルキル、C2-6アルケニル、シクロアルキル、アリール、ヘテロアリール、CO2R4、SO2R4、ハロ、ヒドロキシ、アリール、ヘテロアリール、ヘテロシクロアルキル、N(R4)2、およびSO2R4の一つまたはそれ以上で置換されたC1-6アルキル、C1-6アルキレンアリール、C1-6アルキレンヘテロアリール、C1-6アルキレンC3-8ヘテロシクロアルキル、C1-6アルキレンSO2アリール、任意に置換されたC1-6アルキレンN(R4)2、OCF3、C1-6アルキレンN(R4)3 +、C3-8ヘテロシクロアルキル、およびCH(C1-6アルキレンN(R4)2)2からなるグループから選択され、または、二つのR3基をもってして、任意に置換された三員〜六員の脂肪族環が形成され;
R4が、ヒドロ、C1-6アルキル、シクロアルキル、アリール、ヘテロアリール、C1-6アルキレンアリール、およびSO2C1-6アルキルからなるグループから選択され、または、二つのR4基をもってして、任意に置換された三員〜六員の環が形成され;
R5が、C1-6アルキル、アリール、ヘテロアリール、ヘテロシクロアルキル、N(R3)2、OR3、ハロ、N3、CN、C1-6アルキレンアリール、C1-6アルキレンN(R3)2、C(O)R3、C(O)OR3、C(O)N(R3)2、N(R1)C(O)R3、N(R1)CO2R3、CF3、および以下の式、
R6が、OR11、-C≡C-R7、およびヘテロアリールからなるグループから選択され;
R7が、ヒドロ、C1-6アルキル、アリール、C1-6アルキレンアリール、ヘテロアリール、C1-6アルキレンヘテロアリール、およびアルコキシからなるグループから選択され;
R8、R9およびR10が、独立して、ヒドロ、ハロ、任意に置換されたC1-6アルキル、C2-6アルケニル、C2-6アルキニル、OCF3、CF3、NO2、CN、NC、N(R3)2、OR3、CO2R3、C(O)N(R3)2、C(O)R3、N(R1)COR3、N(R1)C(O)OR3、N(R8)C(O)OR3、N(R1)C(O)C1-6アルキレンC(O)R3、N(R1)C(O)C1-6アルキレンC(O)OR3、N(R1)C(O)C1-3アルキレンOR3、N(R1)C(O)C1-6アルキレンNHC(O)OR3、N(R1)C(O)C1-6アルキレンSO2NR3、C1-6アルキレンOR3、およびSR3からなるグループから選択され;
R11が、ヒドロ、C1-6アルキル、C2-6アルケニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、SO2R4、ハロ、ヒドロキシ、ヘテロアリール、N(R4)2、およびSO2R4の一つまたはそれ以上で置換されたC1-6アルキル、C1-6アルキレンアリール、C1-6アルキレンヘテロアリール、C1-6アルキレン-C3-8ヘテロシクロアルキル、C1-6アルキレンSO2アリール、任意に置換されたC1-6アルキレンN(R4)2、OCF3、C1-6アルキレンN(R4)3 +、C3-8ヘテロシクロアルキル、およびCH(C1-6アルキレン-N(R4)2)2からなるグループから選択される、化学構造式で表される化合物であり、薬学的に許容可能なその塩、またはプロドラッグ、または溶媒和物をも意図している。
本願発明の化合物は、以下の合成スキームに従って調製することができる。 出発物質は、市販品から入手することもできるし、あるいは、当業者が熟知している既に確立された方法によって調製することもできる。 以下の官能基X、R1、R3、R4、R5、R6、R7、R8、R9、R10およびR11は、先に定義した通りのものである。 R2は、先に定義した通りのものであり、また、以下の合成スキームにあっては、CF3やヘテロアリールをも含む。
室温の窒素雰囲気下で攪拌した5-メチル-ピラジン-2-カルボン酸(25g、181mmol)を含む540mlのTHFの懸濁液に対して、DIEA(31.7ml、181mmol)を加えたところ、茶褐色の溶液が生成した。 次いで、ジフェニルフォスフォリルアジド(39.2ml、181mmol)を、50mlのTHF溶液として、1時間かけて、防護柵内で滴下して加えた。 一晩かけて攪拌を継続して反応を行った。 次いで、得られた反応物を、室温下で、回転式濃縮機で濃縮して、ジエチルエーテル相(1リットル)と水相(1リットル)に分離した。 この水相を、2×250mlのジエチルエーテルで逆抽出して、合わせて得た有機相を、2×1リットルの飽和重炭酸ナトリウムで洗浄した。 有機相を、乾燥(MgSO4)、濾過、および濃縮して固形物を取得し、これをジエチルエーテルを用いて砕いて黄色固形物の産物(15g、50%)を得た。 1gの粗産物を20mlのジエチルエーテルに採り、1〜2gの漂白炭素を用いて、室温下で、数分間かけてこれを処理することで、より純度の高い化合物を単離することができた。 濾過と濃縮を終えた後に、この物質を、酢酸エチルを用いた薄層クロマトグラフィーで均質化したところ、純白の産物が得られた。 通常の回収率は、65%であった。
-3-(5-トリフルオロメチル-ピラジン-2-イル)-尿素塩酸塩
工程1:3-[2-(4-ニトロ-フェノキシカルボニルアミノ)-4-トリフルオロメチル-フェノキシメチル]-ピペリジン-1-カルボン酸 tert-ブチルエステル
窒素雰囲気下、0℃にて攪拌した3-(2-アミノ-4-トリフルオロメチル-フェノキシメチル)-ピペリジン-1-カルボン酸 tert-ブチルエステル(240mg、0.64mmol)を含む2mlのCH2Cl2の溶液に対して、ピリジン(57μl、0.71mmol)を加え、次いで、クロロギ酸p-ニトロフェニル(130mg、0.64mmol)を加えた。 0℃で、1時間置いた後に、得られた反応混合物を、CH2Cl2で30mlの溶液になるまで希釈し、次いで、2×30mlの2Nの塩酸、1×30mlの水、そして、1×30mlの塩水で洗浄した。 有機相を、乾燥(MgSO4)、濾過および濃縮したところ、灰白色の泡状物が得られた。
3-[2-(4-ニトロ-フェノキシカルボニルアミノ)-4-トリフルオロメチル-フェノキシメチル]-ピペリジン-1-カルボン酸 tert-ブチルエステル(217mg、0.4mmol)および(米国特許第4,293,552号の方法に従って調製した)5-トリフルオロメチル-ピラジン-2-イルアミン(66mg、0.4mmol)を、5ml容の反応用ガラス瓶内で、固体のままで混合し、400μlのNMPで希釈し、閉蓋し、そして、攪拌を行い、次いで、得られた暗黄色の溶液を、85℃の油浴に浸して、6時間かけて攪拌を行った。 得られた反応混合物を、室温にまで冷却し、そして、一晩かけて攪拌を行った。 そして、0.5mmおよび800℃の条件で、クーゲルロール蒸留装置を稼働させてNMPを除去した。 褐色の残留物を、30mlのCH2Cl2の溶液に加えて希釈し、次いで、3×30mlのNa2CO3で洗浄して、p-ニトロフェノールを除去した。 有機相を、乾燥(MgSO4)、濾過および濃縮したところ、固体の粗製物が生成し、次いで、得られた粗製物を、酢酸エチルを用いて粉砕し、そして、濾過したところ、所望の産物が白色の固形物として得られた。
-3-(5-トリフルオロメチル-ピラジン-2-イル)-尿素塩酸塩
工程1:3-[4-メチル-2-[3-(5-トリフルオロメチル-ピラジン-2-イル)-ウレイド]-フェノキシメチル]-ピペリジン-1-カルボン酸 tert-ブチルエステル
化合物1の工程2に記載した手順に従って、3-[4-メチル-2-(4-ニトロ-フェノキシカルボニルアミノ)-フェノキシメチル]-ピペリジン-1-カルボン酸 tert-ブチルエステル(WO 02/070494)から調製した。 この産物は、白色の固形物として分離された。
-3-(5-トリフルオロメチル-ピラジン-2-イル)-尿素
化合物1の工程2に記載した手順に従って、[5-メチル-2-(1-メチル-ピペリジン-3-イルメトキシ)-フェニル]-カルバミン酸 4-ニトロ-フェニルエステル(WO 02/070494)から、白色固形物として得た。 1H-NMR (400 MHz, CDCl3) δ: 11.01 (br s, 1H), 8.87 (br s, 1H), 8.82 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 6.84 (d, 1H), 6.76 (d, 1H), 3.84 (m, 2H), 3.16 (m, 1H), 2.81 (m, 1H), 2.37 (s, 3H), 2.29 (m, 1H), 2.20 (s, 3H), 1.99 (m, 1H), 1.87-1.62 (m, 4H), 1.11 (m, 1H). LRMS (apci, ポジティブ) m/e 424.3 (M+l).
本願発明のその他の化合物を以下に記載するが、これらに限定されない。
本願発明の化合物は、ヒトおよびその他の動物の真核細胞が関与する癌やその他の細胞増殖障害の治療で用いられている放射線および/または化学療法剤の効果を増大させるために使用することができる。 例えば、本願発明の化合物は、例えば、通常は、メソトレキセートまたは5-フルオロウラシル(5-FU)のような代謝拮抗剤で治療される腫瘍の治療効果を増強するために使用することができる。 一般的には、本願発明の化合物は、癌性および非癌性の細胞の異常増殖を阻害する。
1998年9月4日に出願された国際出願の国際公開パンフレット第WO 99/11795号に記載の手順に従い、ヒトChk1 cDNAを同定およびクローニングした。 全長Chk1のアミノ末端を有するフレーム内にFLAG(登録商標)タグを挿入した。 5'プライマーは、EcoRI部位、コザック配列を含み、また、M2抗体(シグマ社、セントルイス、イリノイ州)を利用するアフィニティー精製のためのFLAR(登録商標)タグもコードする。 3'プライマーは、SalI部位を含む。 PCR増幅した断片を、EcoRI-SalI断片(インビトロゲン、カールスバッド、カリフォルニア州)として、pCI-Neoにクローニングし、次いで、EcoRI-NotI断片として、FastBacI(ギブコ-BRL、ベセスダ、メリーランド州)にサブクローニングした。 ギブコ-BRL Bac-to-Bacマニュアルに記載の手順に従って組換えバキュロウィルスを調製し、そして、FLAG(登録商標)タグが付いたChk1タンパク質を発現するために、CCM3培地(ハイクローンラボラトリーズ、ローガン、ユタ州)で生育せしめたSf-9細胞を感染させるために用いた。
一つまたは一つ以上のその他のプロテインキナーゼ、すなわち、DNA-PK、Cdc2、カゼインキナーゼI(CKI)、Chk2、p38 MAPキナーゼ、ERKキナーゼ、プロテインキナーゼA(PKA)、および/またはカルシウム-カルモジュリンプロテインキナーゼII(CaM KII)に対する選択性に関して、本願発明のChk1阻害剤を試験した。 Chk2以外のすべてのキナーゼに関する分析手順は、本明細書の一部を構成するものとしてその内容を援用する米国公開特許公報第2002-016521号および1994年1月21日に出願された米国特許出願第08/184,605号に開示されたものを含めて、すでに文献に記載されている。
本願発明のChk1阻害剤が、細胞内でChk1機能を阻害することを確認するために、分子細胞レベルにて阻害剤を分析することもできる。 哺乳動物Chk1が、in vitroでCdc25Cをリン酸化することが知られており、また、DNA損傷に応じたサイクリンB/cdc2の調節能力をうかがうこともできるので、サイクリンB/cdc2の活性向上に関してChk1阻害剤を分析することができる。 次のような実験手順が利用できる。 すなわち、800ラドの放射線をHeLa細胞に照射し、次いで、37℃で、7時間かけてインキュベーションを行う。 これら細胞は、p53機能を欠いているため、細胞周期は専らG2期で停止する。 次いで、ノコダゾールを0.5μg/mlの濃度で加えてから、37℃で、15時間かけて細胞のインキュベーションを行う。 ノコダゾールの添加は、停止していたG2期からM期に進行する細胞を捕捉する目的で行われる。 最後に、8時間にわたってChk1阻害剤を添加し、そして、製造業者の指示に従って、細胞を、回収し、溶解し、そして、サイクリンB1(ニューイングランドバイオラブス社)に対する抗体を含む当量のタンパク質で免疫沈降させる。 次いで、ヒストンH1キナーゼ活性を分析することで、サイクリンB関連cdc2キナーゼ活性に関してIPが分析されることとなる(Yu et al., J Biol Chem., 1998年12月11日; 273(50):pp.33455-64)。
本願発明の化合物によってChk1が阻害されることで、DNA損傷物質の殺傷効果に対して標的細胞が感作されることを実証するために、本願発明のChk1阻害剤の存在下で細胞をインキュベーションし、次いで、放射線またはDNA損傷薬剤のいずれかに曝すことができる。 96穴マイクロ滴定用プレートに、1000〜2000個/穴の密度で配置した細胞を、5%二酸化炭素が給気される加湿型インキュベーター内で、37℃で、18時間、10%のFBS、100U/mlのペニシリン、および100μg/mlのストレプトマイシンを含有するRMPI 1640で成長せしめる。 試験に供する細胞として、HeLa、ACHN、786-0、HCT116、SW620、HT29、Colo205、SK-MEL-5、SK-MEL-28、A549、H322、OVCAR-3、SK-OV-3、MDA-MB-231、MCF-7、PC-3、HL-60、K562、およびM0LT4などを含めた、任意の細胞または細胞系が利用可能である。 前述した細胞系の名称は、以下のヒト細胞系に対応している。
DNA損傷物質によって発生したマウス腫瘍の殺傷性を改善する本願発明のChk1阻害剤の効果を試験するために、結腸癌細胞系を用いた異種移植腫瘍モデルを樹立する。 5-フルオロウラシル(5-FU)またはゲムシタビンを、DNA損傷物質として使用することができる。 6〜8週齢の雌の胸腺Balb/c(nu/nu)マウスでの異種移植腫瘍を増殖させるために、HT29とColo205(ヒト結腸癌)およびH460とCalu-6(非小細胞癌)細胞を用いることができる。 病原体が排除された条件下で層流が供給される個室にマウスを収容して、滅菌した食餌と浄水を制限無く与えた。 10%のFBS、100U/mlのペニシリン、100μg/mlのストレプトマイシン、および1.5mMのL-グルタミンが加えられたRMPI 1640において、5%二酸化炭素の湿潤条件下で、細胞系を略集密状態にまで成長せしめる。 単一細胞の懸濁液をCMF-PBSを用いて調製し、次いで、細胞濃度を1×108細胞/mlに調整する。
Claims (28)
- 以下の構造式;
X2が、-O-、-S-、または-N(R1)-であり;
Yが、酸素または硫黄であり;または、=Yは、共通する炭素原子に結合している二つの水素原子を表し;
Wが、ヘテロアリール、アリール、ヘテロシクロアルキル、シクロアルキル、およびヘテロアリールまたはアリール基で置換されたC1-6アルキルからなるグループから選択され、(a)前記W基でのアリール基またはヘテロアリール基が、少なくとも一つのCF3およびヘテロアリールで置換されており、(b)前記W基でのアリール基が、R2で表される1個〜3個の置換基で任意に置換されており、および、(c)前記W基でのヘテロアリール基が、R5で表される1個〜3個の置換基で任意に置換されており;
R1が、ヒドロ、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、およびアリールからなるグループから選択され;
R2が、ヘテロアリール、ハロ、任意に置換されたC1-6アルキル、C2-6アルケニル、OCF3、NO2、CN、NC、N(R3)2、OR3、CO2R3、C(O)N(R3)2、C(O)R3、N(R1)COR3、N(R1)C(O)OR3、N(R1)C(O)C1-6アルキレンC(O)R3、N(R1)C(O)C1-6アルキレンC(O)R3、N(R1)C(O)C1-6アルキレンOR3、N(R1)C(O)C1-6アルキレンNHC-(O)OR3、N(R1)C(O)C1-6アルキレンSO2NR3、C1-6アルキレンOR3、およびSR3からなるグループから選択され;
R3が、ヒドロ、ハロ、C1-6アルキル、C2-6アルケニル、シクロアルキル、アリール、ヘテロアリール、CO2R4、SO2R4、ハロ、ヒドロキシ、アリール、ヘテロアリール、ヘテロシクロアルキル、N(R4)2、およびSO2R4の一つまたはそれ以上で置換されたC1-6アルキル、C1-6アルキレンアリール、C1-6アルキレンヘテロアリール、C1-6アルキレンC3-8ヘテロシクロアルキル、C1-6アルキレンSO2アリール、任意に置換されたC1-6アルキレンN(R4)2、OCF3、C1-6アルキレンN(R4)3 +、C3-8ヘテロシクロアルキル、およびCH(C1-6アルキレンN(R4)2)2からなるグループから選択され、または、二つのR3基をもってして、任意に置換された三員〜六員の脂肪族環が形成され;
R4が、ヒドロ、C1-6アルキル、シクロアルキル、アリール、ヘテロアリール、C1-6アルキレンアリール、およびSO2C1-6アルキルからなるグループから選択され、または、二つのR4基をもってして、任意に置換された三員〜六員の環が形成され;
R5が、C1-6アルキル、アリール、ヘテロアリール、ヘテロシクロアルキル、N(R3)2、OR3、ハロ、N3、CN、C1-6アルキレンアリール、C1-6アルキレンN(R3)2、C(O)R3、C(O)OR3、C(O)N(R3)2、N(R1)C(O)R3、N(R1)CO2R3、CF3、および以下の式、
R6が、OR11、-C≡C-R7、およびヘテロアリールからなるグループから選択され;
R7が、ヒドロ、C1-6アルキル、アリール、C1-6アルキレンアリール、ヘテロアリール、C1-6アルキレンヘテロアリール、およびアルコキシからなるグループから選択され;
R8、R9およびR10が、独立して、ヒドロ、ハロ、任意に置換されたC1-6アルキル、C2-6アルケニル、C2-6アルキニル、OCF3、CF3、NO2、CN、NC、N(R3)2、OR3、CO2R3、C(O)N(R3)2、C(O)R3、N(R1)COR3、N(R1)C(O)OR3、N(R8)C(O)OR3、N(R1)C(O)C1-6アルキレンC(O)R3、N(R1)C(O)C1-6アルキレンC(O)OR3、N(R1)C(O)C1-3アルキレンOR3、N(R1)C(O)C1-6アルキレンNHC(O)OR3、N(R1)C(O)C1-6アルキレンSO2NR3、C1-6アルキレンOR3、およびSR3からなるグループから選択され;
R11が、ヒドロ、C1-6アルキル、C2-6アルケニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、SO2R4、ハロ、ヒドロキシ、ヘテロアリール、N(R4)2、およびSO2R4の一つまたはそれ以上で置換されたC1-6アルキル、C1-6アルキレンアリール、C1-6アルキレンヘテロアリール、C1-6アルキレン-C3-8ヘテロシクロアルキル、C1-6アルキレンSO2アリール、任意に置換されたC1-6アルキレンN(R4)2、OCF3、C1-6アルキレンN(R4)3 +、C3-8ヘテロシクロアルキル、およびCH(C1-6アルキレン-N(R4)2)2からなるグループから選択される、化学構造式で表される化合物または薬学的に許容可能なその塩、またはプロドラッグ、または溶媒和物。 - X1およびX2が、-N(H)-であり;
Yが、酸素または硫黄であり;
Wが、窒素、酸素および硫黄からなるグループから選択される少なくとも二つのヘテロ原子を含む任意に置換されたヘテロアリールであり、前記環が、C1-6アルキル、アリール、ヘテロアリール、N(R3)2、OR3、C(O)N(R3)2、CO2R3、CN、CF3、およびハロからなるグループから選択された一つまたは二つの置換基で任意に置換する請求項1に記載の化合物。 - Wが、任意に置換されたC1-6アルキル、アリール、ヘテロアリール、N(R3)2、OR3、C(O)OR3、C(O)N(R3)2、およびハロからなるグループから選択された1個または2個の置換基で任意に置換されたピリダジニル、ピリミジニル、ピラジニル、およびトリアジニルからなるグループから選択される請求項2に記載の化合物。
- Wが、ピラジニルである請求項2に記載の化合物。
- R6が、OR11である請求項1に記載の化合物。
- R7が、ヘテロアリールである請求項1に記載の化合物。
- 請求項1に記載の化合物および薬学的に許容可能な担体を含む組成物。
- 有効量の請求項1に記載の化合物と細胞とを接触する工程を含む、細胞内でチェックポイントキナーゼ1を阻害する方法。
- 治療上有効量の請求項1に記載の化合物を、化学療法剤、放射線療法剤、またはこれらの組み合わせと共に個体に投与することを含む、医学的病態のために化学療法または放射線療法を受けている個体の細胞を感作する方法。
- 個体に対して、サイトカイン、リンフォカイン、成長因子、その他の造血因子、またはこれらの組み合わせを投与する工程をさらに含む請求項13に記載の方法。
- 前記化学療法剤が、アルキル化薬、代謝拮抗物質、ホルモンまたはそのアンタゴニスト、放射性同位元素、抗体、およびこれらの組み合わせからなるグループから選択される請求項12に記載の方法。
- 前記放射線療法剤が、γ線、X線、紫外線、可視光線、赤外線、およびマイクロ波からなるグループから選択される請求項13に記載の方法。
- 前記病態が、直腸癌、頭部および頸部癌、膵臓癌、乳癌、胃癌、膀胱癌、外陰部癌、白血病、リンパ腫、黒色腫、腎細胞癌腫、卵巣癌、脳腫瘍、骨肉腫、および肺癌からなるグループから選択される癌である請求項13に記載の方法。
- 前記病態が、粘液型および円形細胞腫、局所進行性腫瘍、転移性癌、ユーイング肉腫、癌転移、リンパ性転移、扁平上皮細胞癌、食道扁平上皮細胞癌、口腔癌、多様性骨髄腫、急性リンパ性白血病、急性非リンパ性白血病、慢性リンパ性白血病、慢性骨髄球性腫瘍、有毛細胞白血病、浸出リンパ腫(体腔由来リンパ腫)、胸腺リンパ腫肺癌、小細胞癌、皮膚T細胞リンパ腫、ホジキンリンパ腫、非ホジキンリンパ腫、副腎皮質癌、ACTH産生腫瘍、非小細胞癌、乳癌、小細胞癌、浸潤性導管癌、胃癌、大腸癌、直腸癌、直腸腫瘍に関連するポリープ、膵臓癌、肝臓癌、膀胱癌、原発性表在性膀胱腫瘍、膀胱の浸潤性移行細胞癌、筋浸潤性膀胱癌、前立腺癌、卵巣腫瘍、原発性腹膜上皮性腫瘍、子宮頚癌、子宮内膜癌、膣癌、外陰部癌、子宮癌、卵胞内固形腫瘍、精巣癌、陰茎癌、腎細胞癌、内因性脳腫瘍、神経芽細胞腫、星状細胞脳腫瘍、神経膠腫、中枢神経系の転移腫瘍細胞浸潤、骨腫および骨肉腫、悪性黒色腫、ヒト皮膚ケラチン生成細胞の腫瘍進行、扁平上皮癌、甲状腺癌、網膜芽細胞腫、神経芽細胞腫、腹膜浸出、悪性胸膜浸潤、中皮腫、ウィルムス腫瘍、ニワトリ膀胱癌、栄養膜腫瘍、血管外皮細胞腫、およびカポジ肉腫からなるグループから選択される癌である請求項13に記載の方法。
- 関節リウマチ、乾癬、白斑症、ウェグナー肉芽腫症、および全身性紅斑からなるグループから選択される炎症病態に対して処置がなされる請求項12に記載の方法。
- 請求項1に記載の化合物が、プロテインキナーゼA、プロテインキナーゼC、cdc2、およびpp60v-srcと比較して、Chk1に対して少なくとも20倍の選択的阻害性を示す請求項13に記載の方法。
- 請求項1に記載の化合物が、プロテインキナーゼA、プロテインキナーゼC、cdc2、およびpp60v-srcと比較して、Chk1に対して少なくとも75倍の選択的阻害性を示す請求項13に記載の方法。
- 請求項1に記載の化合物が、プロテインキナーゼA、プロテインキナーゼC、cdc2、およびpp60v-srcと比較して、Chk1に対して少なくとも100倍の選択的阻害性を示す請求項13に記載の方法。
- 前記化学療法剤が、ゲムシタビン、ペメトレキセド、シスプラチン、カルボプラチン、パクリタキセール、またはこれらの組み合わせを含む請求項13に記載の方法。
- 異常な細胞増殖を阻害する方法であって、異常増殖する細胞を含む細胞集団と異常増殖する当該細胞の実質的な同期性細胞周期を停止するChk1活性剤とを接触させ、および、当該細胞集団と請求項1に記載の化合物とを接触させて停止した当該細胞周期を実質的に廃除する、ことを含む異常な細胞増殖を阻害する方法。
- 前記Chk1活性剤が、少なくとも一つの化学療法剤を含む請求項24に記載の方法。
- 前記Chk1活性剤が、電離放射線または紫外線を含む請求項24に記載の方法。
- 前記電離放射線が、放射線感受性増強物質、感光性増強物質、またはこれらの組み合わせを利用して照射される請求項24に記載の方法。
- 前記異常増殖細胞が、非癌性細胞である請求項24に記載の方法。
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US60296804P | 2004-08-19 | 2004-08-19 | |
PCT/US2005/029518 WO2006021002A2 (en) | 2004-08-19 | 2005-08-18 | Compounds useful for inhibiting chk1 |
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JP2008510719A true JP2008510719A (ja) | 2008-04-10 |
JP2008510719A5 JP2008510719A5 (ja) | 2008-10-02 |
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JP2007528037A Pending JP2008510719A (ja) | 2004-08-19 | 2005-08-18 | Chk1の阻害に有用な化合物 |
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US (1) | US20080318974A1 (ja) |
EP (1) | EP1778648A2 (ja) |
JP (1) | JP2008510719A (ja) |
KR (1) | KR20070054205A (ja) |
CN (1) | CN101115727A (ja) |
AU (1) | AU2005272586A1 (ja) |
BR (1) | BRPI0514466A (ja) |
CA (1) | CA2577880A1 (ja) |
MX (1) | MX2007002040A (ja) |
WO (1) | WO2006021002A2 (ja) |
Families Citing this family (13)
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GB201008005D0 (en) | 2010-05-13 | 2010-06-30 | Sentinel Oncology Ltd | Pharmaceutical compounds |
GB201119799D0 (en) | 2011-11-16 | 2011-12-28 | Sentinel Oncology Ltd | Pharmaceutical compounds |
GB201402277D0 (en) | 2014-02-10 | 2014-03-26 | Sentinel Oncology Ltd | Pharmaceutical compounds |
EP3778584A1 (en) | 2014-06-19 | 2021-02-17 | ARIAD Pharmaceuticals, Inc. | Production process of 2-chloro-4-heteroaryl-pyrimidine derivatives |
CN104628659A (zh) * | 2015-01-27 | 2015-05-20 | 广西师范大学 | 具有抗肿瘤作用的吡嗪-芳基脲衍生物及其制备方法与应用 |
WO2017123588A1 (en) | 2016-01-11 | 2017-07-20 | Merrimack Pharmaceuticals, Inc. | Inhibiting ataxia telangiectasia and rad3-related protein (atr) |
EP3411036B1 (en) | 2016-02-04 | 2021-12-29 | Pharmaengine, Inc. | 3,5-disubstituted pyrazoles useful as checkpoint kinase 1 (chk1) inhibitors, and their preparations and applications |
CA3058457A1 (en) | 2017-03-31 | 2018-10-04 | Seattle Genetics, Inc. | Combinations of chk1- and wee1 - inhibitors |
EP3793993A4 (en) | 2018-05-14 | 2022-01-05 | Takeda Pharmaceutical Company Limited | PHARMACEUTICAL SALTS OF PYRIMIDINE DERIVATIVES AND METHOD OF TREATMENT OF CONDITIONS |
EP4067351A4 (en) * | 2019-11-29 | 2023-11-22 | Medshine Discovery Inc. | DIAZAINDOLE DERIVATIVE AND ITS USE AS CHK1 INHIBITOR |
WO2021119236A1 (en) | 2019-12-10 | 2021-06-17 | Seagen Inc. | Preparation of a chk1 inhibitor compound |
GB202107924D0 (en) | 2021-06-03 | 2021-07-21 | Sentinel Oncology Ltd | A pharmaceutical salt |
GB202107932D0 (en) | 2021-06-03 | 2021-07-21 | Sentinel Oncology Ltd | Preparation of a CHK1 Inhibitor Compound |
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JP2008505112A (ja) * | 2004-07-02 | 2008-02-21 | イコス・コーポレイション | Chk1の阻害に有用な化合物 |
-
2005
- 2005-08-18 JP JP2007528037A patent/JP2008510719A/ja active Pending
- 2005-08-18 BR BRPI0514466-3A patent/BRPI0514466A/pt not_active IP Right Cessation
- 2005-08-18 KR KR1020077006216A patent/KR20070054205A/ko not_active Application Discontinuation
- 2005-08-18 US US11/659,389 patent/US20080318974A1/en not_active Abandoned
- 2005-08-18 WO PCT/US2005/029518 patent/WO2006021002A2/en active Application Filing
- 2005-08-18 CA CA002577880A patent/CA2577880A1/en not_active Abandoned
- 2005-08-18 CN CNA2005800353820A patent/CN101115727A/zh active Pending
- 2005-08-18 AU AU2005272586A patent/AU2005272586A1/en not_active Abandoned
- 2005-08-18 EP EP05810303A patent/EP1778648A2/en not_active Withdrawn
- 2005-08-18 MX MX2007002040A patent/MX2007002040A/es not_active Application Discontinuation
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JP2001526258A (ja) * | 1997-12-22 | 2001-12-18 | バイエル コーポレイション | 対称および非対称置換ジフェニル尿素を用いるrafキナーゼの阻害 |
JP2004523568A (ja) * | 2001-03-02 | 2004-08-05 | アイコス コーポレイション | 放射線増感剤および化学増感剤としてのアリールおよびヘテロアリール尿素Chk1阻害剤の使用 |
WO2003093297A2 (en) * | 2002-05-03 | 2003-11-13 | Exelixis, Inc. | Protein kinase modulators and methods of use |
JP2007519609A (ja) * | 2003-09-17 | 2007-07-19 | アイコス コーポレイション | 細胞増殖を制御するためのchk1インヒビターの使用 |
JP2008504283A (ja) * | 2004-06-25 | 2008-02-14 | イコス・コーポレイション | Chk1の阻害に有用なビスアリール尿素誘導体 |
JP2008505112A (ja) * | 2004-07-02 | 2008-02-21 | イコス・コーポレイション | Chk1の阻害に有用な化合物 |
Also Published As
Publication number | Publication date |
---|---|
AU2005272586A1 (en) | 2006-02-23 |
MX2007002040A (es) | 2008-01-11 |
KR20070054205A (ko) | 2007-05-28 |
CA2577880A1 (en) | 2006-02-23 |
EP1778648A2 (en) | 2007-05-02 |
WO2006021002A3 (en) | 2006-04-20 |
US20080318974A1 (en) | 2008-12-25 |
BRPI0514466A (pt) | 2008-06-10 |
WO2006021002A2 (en) | 2006-02-23 |
CN101115727A (zh) | 2008-01-30 |
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