JP2008527048A - 2,4−ピリミジンジアミン化合物のプロドラッグおよびそれらの使用 - Google Patents
2,4−ピリミジンジアミン化合物のプロドラッグおよびそれらの使用 Download PDFInfo
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- JP2008527048A JP2008527048A JP2007552272A JP2007552272A JP2008527048A JP 2008527048 A JP2008527048 A JP 2008527048A JP 2007552272 A JP2007552272 A JP 2007552272A JP 2007552272 A JP2007552272 A JP 2007552272A JP 2008527048 A JP2008527048 A JP 2008527048A
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Abstract
本開示は、多彩な生物活性を有するので、治療用途を有する2,4−ピリミジンジアミン化合物のプロドラッグ、該プロドラッグを含む組成物、該プロドラッグを合成するのに有用な方法及び中間体、並びに、少なくとも部分的に、Fc受容体のシグナル伝達カスケードの活性化が介在する疾患の治療及び予防を含めた種々のインビトロ及びインビボのコンテキストで該プロドラッグを使用する方法を提供する。
Description
本出願は、米国特許法第119条(e)に基づき、米国仮特許出願第60/645,424号(2005年1月19日出願)および米国仮特許出願第60/654,620号(2005年2月18日出願)に対する利益を主張する。これらの仮特許出願の両方の開示は、その全体が参考として本明細書に援用される。
本開示は、生物学的に活性のある2,4−ピリミジンジアミン化合物のプロドラッグ、該プロドラッグを含む医薬組成物、該プロドラッグを作製するための中間体及び合成方法、並びに、たとえば、種々の疾患の治療又は予防のような種々のコンテキストにおいて該プロドラッグ及び組成物を使用する方法に関する。
たとえば、IgEに対する高親和性受容体(FcεRI)及び/又はIgGに対する高親和性受容体(FcγRI)のようなFc受容体の架橋は、多数の有害事象を担う化学メディエータの放出を生じる、肥満細胞、好塩基球及びそのほかの免疫細胞におけるシグナル伝達カスケードを活性化する。たとえば、そのような架橋は、脱顆粒によって顆粒の貯蔵部位から、たとえばヒスタミンのようなI型(即時型)アナフィラキシー過敏反応の前もって形成されたメディエータの放出を導く。それはまた、ロイコトリエン、プロスタグランジン及び血小板活性化因子(PAF)を含むそのほかのメディエータの合成及び放出を導き、それらは、炎症反応において重要な役割を演じる。Fc受容体を架橋する際、合成され、放出される追加のメディエータには、サイトカイン及び一酸化窒素が挙げられる。
本開示は、多彩な生物活性を有するので、治療用途を有する2,4−ピリミジンジアミン化合物のプロドラッグ、該プロドラッグを含む組成物、該プロドラッグを合成するのに有用な方法及び中間体、並びに、少なくとも部分的に、Fc受容体のシグナル伝達カスケードの活性化が介在する疾患の治療及び予防を含めた種々のインビトロ及びインビボのコンテキストで該プロドラッグを使用する方法を提供する。
Yは、CH2、NR24、O、S、S(O)、及びS(O)2から選択され;
Z1及びZ2はそれぞれ、互いに独立してCH及びNから選択され;
R2は、任意で置換された低級アルキル、低級シクロアルキル、低級へテロアルキル、低級シクロへテロアルキル、アリール、フェニル又はヘテロアリール基であり;
R5は、たとえば、ハロ、フルオロ、シアノ、ニトロ、トリハロメチル又はトリフルオロメチル基のような負の電荷を有する基であり;
R17は、水素、ハロゲン、フルオロ、低級アルキル及びメチルから選択されるか、或いは、R17は、R18と一緒になってオキソ(=O)基を形成し、若しくはそれらが結合する炭素原子と一緒になって3〜7の炭素原子を含有するスピロ環を形成してもよく;
R18は、水素、ハロゲン、フルオロ、低級アルキル及びメチルから選択されるか、或いは、R18は、R17と一緒になってオキソ(=O)基を形成し、若しくはそれらが結合する炭素原子と一緒になって3〜7の炭素原子を含有するスピロ環を形成してもよく;
R19は、水素、低級アルキル及びメチルから選択されるか、或いは、R19は、R20と一緒になってオキソ(=O)基を形成し、若しくはそれらが結合する炭素原子と一緒になって3〜7の炭素原子を含有するスピロ環を形成してもよく;
R20は、水素、低級アルキル及びメチルから選択されるか、或いは、R20は、R19と一緒になってオキソ(=O)基を形成し、若しくはそれらが結合する炭素原子と一緒になって3〜7の炭素原子を含有するスピロ環を形成してもよく;
R21、R22及びR23は、互いに独立して水素及び本明細書で記載されるようなプロ基Rpから選択され;
R24は、R21、R22、R23及びR24の少なくとも1つがプロ基Rpでなければならないという条件で、本明細書で記載されるような水素、低級アルキル及びプロ基Rpから選択される。いくつかの実施態様では、R21、R22及びR23のそれぞれが、上記で例示された具体的なプロ基の1つであり、R24は水素である。いくつかの実施態様では、R21が上記で例示された具体的なプロ基の1つであり、R22、R23及びR24は水素である。いくつかの実施態様では、R21、R22及びR23が、上記で例示された具体的なプロ基の1つであり、R24は低級アルキルである。
Rpが−CRdRd−AR3である実施態様は、従来の方法を用いて相当する2,4−ピリミジンジアミン薬剤から調製することができる。たとえば、AがOである場合、活性型2,4−ピリミジンジアミン化合物を、Rdが以前定義されたとおりである式、Rd−C(O)−Rdのアルデヒド又はケトンと反応させて相当するヒドロキシメチルアミン中間体(Rpが−CRdRd−OHである場合)を得ることによって、中間体を合成することができる。次いで、標準的な技法を用いて、ヒドロキシメチルアミン中間体をプロドラッグに変換することができる。Rpの定義に従って、ヒドロキシメチルアミン中間体も本発明のプロドラッグである。たとえば、2級アミンを含有するそのほかの薬剤物質をホルムアルデヒドに添加して相当する単離可能なヒドロキシメチルアミン付加体を得ている、Bansal et al.,J.Pharmaceutical Sci.,70(8):850−854,1981;Bansal et al.,J.Pharmaceutical Sci.,70(8):855−856,1981;Khan et al.,J.Pharmaceutical and Biomedical Analysis,7(6):685−691,1989。或いは、ヒドロキシアルキル含有のプロドラッグは、先ず、活性型2,4−ピリミジンジアミンを、ビス−官能性の求電子性物質、たとえば、式、X1−CRdRd−X2(X1は第1のハライドであり、X2は第2のハライドであり、Rdは以前定義したとおりである)のハライドと反応させることによって2工程において調製することができる。具体的な例示となる実施態様では、ハライドは、式I−CRdRd−Clのものである。次いで標準的な技法を用いて反応しなかったハライドをヒドロキシル化してヒドロキシアルキル含有のプロドラッグを得る。
6.1.定義
本明細書で使用するとき、以下の用語は、以下の意味を有するように意図される。
要約に記載したように、本開示は、たとえば、その開示を参照によって本明細書に組み入れる、2003年1月31日に出願された米国特許出願、出願番号第10/355,543号(US2004/0029902A1)、2003年1月31日に出願された国際出願、出願番号PCT/US03/03022(WO03/063794)、2003年7月29日に出願された米国特許出願、出願番号第10/631,029号(____)、国際出願、出願番号PCT/US03/24087(WO2004/014382)、2004年7月30日に出願された米国特許出願、出願番号第10/903,263号(US2005/0234049)及び国際出願、出願番号PCT/US2004/24716(____)に記載される種々の2,4−ピリミジンジアミン化合物のような生物学的に活性のある2,4−ピリミジンジアミン化合物のプロドラッグを提供する。これら2,4−ピリミジンジアミン化合物のプロドラッグは、これらの化合物がSykキナーゼ及びSykキナーゼ依存性のシグナル伝達カスケードと同様にFc受容体のシグナル伝達カスケードの上流を阻害するので、特に興味深い。プロドラッグは一般に、1以上の利用可能な1級又は2級アミン基が、インビボで代謝して活性型2,4−ピリミジンジアミン薬剤を生じるプロ基Rpで覆い隠されるそのような活性型2,4−ピリミジンジアミン化合物を含む。要約の区分でも議論したように、及び以下でさらに詳細に議論するように、プロ基の性質は、変化することができ、そのほかの因子の間で、プロドラッグの水溶解性、投与の意図される方式及び/又は意図されるメカニズム又は活性型2,4−ピリミジンジアミン化合物への代謝の部位に依存するであろう。
Yは、CH2、NR24、O、S、S(O)及びS(O)2から選択され;
Z1及びZ2は、互いに独立してCH及びNから選択され;
R2は、1以上の同一のもしくは異なったR8基によって任意で置換された低級アルキル、1以上の同一のもしくは異なったR8基によって任意で置換された低級シクロアルキル、1以上の同一のもしくは異なったR8基によって任意で置換されたシクロヘキシル、1以上の同一のもしくは異なったR8基によって任意で置換された3〜8員のシクロヘテロアルキル、1以上の同一のもしくは異なったR8基によって任意で置換された(C6〜C14)のアリール、1以上の同一のもしくは異なったR8基によって任意で置換されたフェニル及び1以上の同一のもしくは異なったR8基によって任意で置換された5〜15員のヘテロアリールから選択され;
R5は、ハロ、フルオロ、シアノ、ニトロ、トリハロメチル及びトリフルオロメチルから選択され;
R8は、Ra、Rb、1以上の、たとえば、1〜4の同一のもしくは異なったRa又はRbによって置換されたRa、1以上の同一のもしくは異なったRa又はRbによって置換された−ORa、−B(ORa)2、−B(NRcRc)2、−(CH2)m−Rb、−(CHRa)m−Rb、−O−(CH2)m−Rb、−S−(CH2)m−Rb、−O−CHRaRb、−O−CRa(Rb)2、−O−(CHRa)m−Rb、−O−(CH2)mCH[(CH2)mRb]Rb、−S−(CHRa)m−Rb、−C(O)NH−(CH2)m−Rb、−C(O)NH−(CHRa)m−Rb、−O−(CH2)m−C(O)NH−(CH2)m−Rb、−S−(CH2)m−C(O)NH−(CH2)m−Rb、−O−(CHRa)m−C(O)NH−(CHRa)m−Rb、−S−(CHRa)m−C(O)NH−(CHRa)m−Rb、−NH−(CH2)m−Rb、−NH−(CHRa)m−Rb、−NH[(CH2)mRb]、−N[(CH2)mRb]2、−NH−C(O)NH−(CH2)m−Rb、−NH−C(O)−(CH2)m−CHRbRb及び−NH−(CH2)m−C(O)−NH−(CH2)m−Rbから選択され;
R17は、水素、ハロゲン、フルオロ、低級アルキル及びメチルから選択されるか、或いは、R17は、R18と一緒になってオキソ(=O)基を形成し、若しくはそれらが結合する炭素原子と一緒になって3〜7の炭素原子を含有するスピロ環を形成してもよく;
R18は、水素、ハロゲン、フルオロ、低級アルキル及びメチルから選択されるか、或いは、R18は、R17と一緒になってオキソ(=O)基を形成し、若しくはそれらが結合する炭素原子と一緒になって3〜7の炭素原子を含有するスピロ環を形成してもよく;
R19は、水素、低級アルキル及びメチルから選択されるか、或いは、R19は、R20と一緒になってオキソ(=O)基を形成し、若しくはそれらが結合する炭素原子と一緒になって3〜7の炭素原子を含有するスピロ環を形成してもよく;
R20は、水素、低級アルキル及びメチルから選択されるか、或いは、R20は、R19と一緒になってオキソ(=O)基を形成し、若しくはそれらが結合する炭素原子と一緒になって3〜7の炭素原子を含有するスピロ環を形成してもよく;
各Raは、ほかとは独立して、水素、低級アルキル、低級シクロアルキル、シクロヘキシル、(C4〜C11)のシクロアルキルアルキル、(C6〜C10)のアリール、フェニル、(C7〜C16)のアリールアルキル、ベンジル、2〜6員のヘテロアルキル、3〜8員のシクロヘテロアルキル、モルホリニル、ピペラジニル、ホモピペラジニル、ピペリジニル、4〜11員のシクロヘテロアルキルアルキル、5〜10員のヘテロアリール及び6〜16員のヘテロアリールアルキルから選択され;
各Rbは、=O、−ORa、(C1〜C3)のハロアルキルオキシ、=S、−SRa、=NRa、=NORa、ハロゲン、−CF3、−CN、−NC、−OCN、−SCN、−NO、−NO2、=N2、−N3、−S(O)Ra、−S(O)2Ra、−S(O)2QRa、−S(O)NRcRc、−S(O)2NRcRc、−OS(O)Ra、−OS(O)2Ra、−OS(O)2ORa、−OS(O)2NRcRc,−C(O)Ra、−C(O)ORa、−C(O)NRcRc、−C(NH)NRcRc、−C(NRa)NRcRc、−C(NOH)Ra、−C(NOH)NRcRc、−OC(O)Ra、−OC(O)ORa、−OC(O)NRcRc、−OC(NH)NRcRc、−OC(NRa)NRcRc、−[NHC(O)]nRa、−[NRaC(O)]nRa、−[NHC(O)]nORa、−[NRaC(O)]nORa、−[NHC(O)]nNRcRc、[NRaC(O)]nNRcRc,−[NHaC(NH)]nNRcRc及び−[NRaC(NRa)]nNRcRcから独立して選択される好適な基であり;
各Rcは、ほかとは独立して、保護基及びRaから選択されるか、或いは、同一の窒素原子に結合する2つのRcがその窒素原子と一緒になって、必要に応じて1以上の同一又は異なった追加のヘテロ原子を含んでもよく、必要に応じて1以上の、たとえば、1〜4の同一のもしくは異なったRa基で置換されてもよい5〜8員のシクロヘテロアルキル又はヘテロアリールを形成し;
R21、R22及びR23は、互いに独立して水素及びプロ基Rpから選択され;
R24は、水素、低級アルキル及びプロ基Rpから選択され;
R21、R22、R23及びR24の少なくとも1つがプロ基であるという条件で、
各mは、ほかとは独立して1〜3の整数であり;
各nは、ほかとは独立して0〜3の整数である。
(i)R5がフルオロである;
(ii)R2が1以上の同一のもしくは異なったR8基によって任意で置換されるフェニルである;
(iii)R2が3,4,5−トリ(低級アルコキシ)フェニルである;
(iv)R2が3,4,5−トリメトキシフェニルである;
(v)Y又はY1がOであり、Z1がCHであり、Z2がNであり、R17及びR18がそれぞれメチルであり、R19及びR20が一緒になってオキソ基を形成する;
(vi)Rpが、式−CH2OHのヒドロキシアルキル含有のプロ基、又は式−(CRdRd)y−O−P(O)(OH)2のホスフェート含有のプロ基、又はそのリン酸エステル、亜リン酸塩若しくは亜リン酸エステルの類縁体であり、式中、yが1又は2であり、各Rdがほかとは独立して水素及び非置換の低級アルキルから選択される;或いは
(vii)Rpが、−CH2OH、−CH2SH、−CH2NH2、−CH2−NHR50、−CH2−N(R50)2、−CH2−A−Rf、−CH2−A−C(O)Rf、−CH2−A−C(O)ORf、及び−CH2−A−C(O)NRfRfから選択され、式中、A、R50及びRfは以前定義されたとおりである。
本明細書に記載されるプロドラッグは、そのための中間体と同様に、市販の出発物質及び/又は従来の合成の方法によって調製された出発物質を用いた種々の様々な合成経路を介して合成されてもよい。活性型2,4−ピリミジンジアミン化合物を合成するのに日常的に使用されてもよい及び/又は適用されてもよい好適な例示となる方法は、参照によってその開示が本明細書に組み入れられる米国特許第5,958,935号、2003年1月31日に出願された米国特許出願、出願番号第10/355,543号(US2004/0029902A1)、2003年1月31日に出願された国際出願、出願番号PCT/US03/03022(WO03/063794)、2003年7月29日に出願された米国特許出願、出願番号第10/631,029号(____)、国際出願、出願番号PCT/US03/24087(WO2004/014382)、2004年7月30日に出願された米国特許出願、出願番号第10/903,263号(US2005/0234049)及び国際出願、出願番号PCT/US2004/24716(____)に見い出すことができる。これらの活性型2,4−ピリミジンジアミン化合物は、プロドラッグを合成するための出発物質として使用することができる。ホスフェートプロドラッグ化合物4、同様にそのための合成中間体の合成を記載する具体例は、実施例の区分に提供される。本明細書に記載されるプロドラッグはすべて本方法の日常的な適応によって合成されてもよい。
本明細書に記載されるプロドラッグの多くは、特に構造式(I)及び(Ia)によるプロドラッグは、とりわけ、細胞の脱顆粒をもたらすFc受容体によるシグナル伝達カスケードを阻害する活性型2,4−ピリミジンジアミン化合物に代謝する。具体例として、これらの活性型化合物は、たとえば、好中球、好酸球、肥満細胞及び/又は好塩基球のような免疫細胞の脱顆粒をもたらすFcεRI及び/又はFcγRIによるシグナル伝達カスケードを阻害する。肥満細胞及び好塩基球の双方は、たとえば、アレルギー性の鼻炎及び喘息を含むアレルゲンが誘発する障害で中心的な役割を担う。とりわけ、花粉又は寄生虫であってもよいアレルゲンへの曝露の際、IL−4(又はIL−13)及びIgEクラス特異的な抗体合成に切り換えるそのほかのメッセンジャによって活性化されたB細胞によりアレルゲン特異的なIgE抗体が合成される。これらのアレルゲン特異的なIgEは、高親和性のFcεRIに結合する。抗原の結合の際、FcεRIに結合したIgEは架橋し、IgE受容体のシグナル伝達経路が活性化され、それは、細胞の脱顆粒をもたらし、その結果、ヒスタミン、プロテアーゼ(たとえば、トリプターゼ及びキマーゼ)、ロイコトリエン(たとえば、LTC4)のような脂質、メディエータ、血小板活性化因子(PAF)及びプロスタグランジン(たとえば、PGD2)のような宿主の化学メディエータ、並びにTNF−α、IL−4、IL−13、IL−5、IL−6、IL−8、GMCSF、VEGF及びTGF−βを含む一連のサイトカインの放出及び/又は合成をもたらす。肥満細胞及び/又は好塩基球からのこれらメディエータの放出及び/又は合成は、アレルゲンによって誘導される早期の及び後期の応答の原因であり、持続する炎症状態に導く下流の事象に直接連結する。
以前議論したように、たとえば、構造式(I)及び(Ia)によるプロドラッグのような、本明細書に記載されるプロドラッグは、動物及びヒトに投与された場合、とりわけ、脱顆粒又はそのほかの過程のいずれかを介して細胞からの化学メディエータの放出及び/又は合成をもたらすFc受容体によるシグナル伝達カスケード、特に、γ−ホモダイマーを含むFc受容体、たとえば、FcεRI及び/又はFcγRIによるシグナル伝達カスケードを阻害する活性型化合物に代謝する。また議論したように、活性型化合物は、Sykキナーゼの強力な阻害剤である。これらの活性の結果、これら活性型化合物のプロドラッグは、インビトロ、インビボ及び生体外の様々なコンテキストで、Sykキナーゼ、Sykキナーゼが役割を担うシグナル伝達カスケード、Fc受容体によるシグナル伝達カスケード及びそのようなシグナル伝達カスケードによって達成される生物反応を調節する又は阻害するのに使用されてもよい。たとえば、実施態様の1つでは、プロドラッグを使用して、Sykキナーゼを発現している実際上のいかなる細胞種でもインビトロ又はインビボのいずれかでSykキナーゼを阻害してもよい。それらを用いて、Sykキナーゼが役割を担うシグナル伝達カスケードを調節してもよい。そのようなSyk依存性のシグナル伝達カスケードには、FcεRI、FcγRI、FcγRIII、BCR及びインテグリンによるシグナル伝達カスケードが挙げられるが、これらに限定されない。インビトロで又はインビボでプロドラッグを使用して、そのようなSyk依存性のシグナル伝達カスケードによって達成される細胞性の反応又は生物反応を調節してもよく、特に阻害してもよい。そのような細胞性の反応又は生物反応には、呼吸バースト、細胞接着、細胞の脱顆粒、細胞の拡散、細胞の移動、細胞の凝集、貪食作用、サイトカインの合成及び放出、細胞の成熟並びにCa2+の流入が挙げられるが、これらに限定されない。重要なことに、全体的に又は部分的にかのいずれかでSykキナーゼ活性が介在する疾患の治療又は予防に向けた治療的アプローチとして、プロドラッグを使用してインビボでSykキナーゼを阻害してもよい。プロドラッグによって治療されてもよく、又は予防されてもよいSykキナーゼが介在する疾患の非限定例は、以下でさらに詳細に議論されるものである。
本明細書に記載されるプロドラッグ、又はその組成物は一般に、意図される結果を達成するのに有効な量、たとえば、治療される特定の疾患を治療又は予防するのに有効な量で使用される。プロドラッグを治療的に投与して治療的利益を達成し、予防的に投与して予防的利益を達成する。治療的利益によって、患者が依然として基礎を成す障害に悩まされているにもかかわらず、患者が感覚又は状態における改善を報告するような、治療される基礎を成す障害の根絶又は改善、及び/又は基礎を成す障害に関係する1以上の症状の根絶又は改善を意味する。たとえば、アレルギーに苦しむ患者への化合物の投与は、基礎を成すアレルギー反応が根絶される又は改善される場合だけではなく、患者が、アレルゲンへの曝露の後のアレルギーに関係した症状の重症度又は持続時間の低下を報告する場合も、治療的利益を提供する。別の例として、喘息のコンテキストでの治療的利益には、喘息発作の発症に続く呼吸の改善、又は喘息症状の頻度及び重症度の低下が挙げられる。RAのコンテキストでの治療的利益には、以前記載したようなACR20、ACR50又はACR70が挙げられる。治療的利益にはまた、一般に、改善が実感されるかどうかにかかわりなく、疾患の進行を中断すること又は遅らせることも含まれる。
7.1.プロドラッグ化合物4の合成
7.1.1.N4−(2,2−ジメチル1−4−[(ジ−tert−ブチルホスホノキシ)メチル]−3−オキソ−5−ピリド[1,4]オキサジン−6−イル)−5−フルオロ−N2−(3,4,5−トリメトキシフェニル)−2,4−ピリミジンジアミン(化合物3)
窒素雰囲気下で0℃にてCH2Cl2(10mL)に溶解したN4−(2,2−ジメチル−4−[(ジ−tert−ブチルホスホノキシ)メチル]−3−オキソ−5−ピリド[1,4]オキサジン−6−イル)−5−フルオロ−N2−(3,4,5−トリメトキシフェニル)−2,4−ピリミジンジアミン(化合物3、120mg、0.173ミリモル)に、トリフルオロ酢酸(1.5mL)を原液として一滴ずつ5分間で加えた。内容物を1.5時間撹拌した。反応混合物の進行をLC/MSでモニターした。出発物質を完全に消費した後、反応混合物を濃縮し、乾燥してエーテルで粉砕した。エーテルの入った層を静かに注ぎ、乾燥して、粗精製の固形物を提供した。粗精製物のLC/MS解析は、M++H581、471及び501の3つのピークを示した。調製用HPLCによるクロマトグラフィ精製によってM++H581に相当するピークを回収した。分画を凍結乾燥し、乾燥して53mg(52%)の白っぽい綿毛状の固形物を得、N4−(2,2−ジメチル−4−[(二水素ホスホノキシ)メチル]−3−オキソ−5−ピリド[1,4]オキサジン−6−イル)−5−フルオロ−N2−(3,4,5−トリメトキシフェニル)−2,4−ピリミジンジアミン(化合物4)とみなされた。
カラムクロマトグラフィ及びHPLC精製の必要性を軽減する、プロドラッグ化合物4を合成する代替的方法が以下に提供される。
1)内容物を30時間撹拌する際(92%の消費)、反応混合物を氷水(400mL)に注ぎ、ブライン溶液(200mL)を加えることによって内容物を撹拌した。形成された微細な黄褐色の固形物をろ過し、水で洗浄し、一晩乾燥した。
2)固形物(35g)をMTBE(500mL)に溶解し、水(400mL)で洗浄した。TLCでUVがなくなるまで、水性層をMTBE(2x350mL)で抽出した。集めた有機層を無水Na2SO4上で乾燥し、静かに注いだ。
注)工程2は直接行うことができるが、溶液に戻るDMF抽出は、結晶化工程に困難をもたらす。
3)暗赤色の透明の溶液を10gの活性炭処理に供し、加熱して沸騰させ、ろ過した。
4)通常の加熱によって暗赤色の透明の溶液を400mLの容積まで濃縮し、静置して結晶化させた。顆粒として結晶化した固形物をろ過し、顆粒を粉末に粉砕し、MTBE(400mL)で洗浄し、高真空にて乾燥した。母液のワークアップについては工程7を参照のこと。固形物の重量:17g、純度:90%(化合物3)、6.26%(化合物1)、1.8%(副次的M+693)。
5)この段階で500mLのエチルエーテルに固形物を入れ、加熱して沸騰させた。冷却し、ろ過して非溶解物質を除いた。ろ液を濃縮した。
6)上記の濃縮物をMTBE(300mL)での結晶化に供した。形成された白色の固形物をろ過し、MTBE(100mL)で洗浄し、高真空にて乾燥して、純度97%の所望のN4−(2,2−ジメチル−4−[(ジ−tert−ブチルホスホノキシ)メチル]−3−オキソ−5−ピリド[1,4]オキサジン−6−イル)−5−フルオロ−N2−(3,4,5−トリメトキシフェニル)−2,4−ピリミジンジアミン(化合物3)を得た。
7)母液を濃縮し、工程5及び6を繰り返して化合物3を得た。
AcOH/H2O(225mL、4:1)に溶解したN4−(2,2−ジメチル−4−[(ジ−tert−ブチルホスホノキシ)メチル]−3−オキソ−5−ピリド[1,4]オキサジン−6−イル)−5−フルオロ−N2−(3,4,5−トリメトキシフェニル)−2,4−ピリミジンジアミン(化合物3)(15.0g、21.67ミリモル)を65℃(油浴槽の温度)で加熱した。反応の進行を進行中のLC/MSによってモニターした。1時間加熱した後、反応混合物は、かすかに黄褐色の白色固形物に変わった。この時点で、ほとんどの化合物3は、モノデスt−ブチル生成物に変換した。3時間の加熱後、SMの消費及び中間体(モノデスt−ブチル化)の生成物への完全な変換が認められた。
動物において毒性を示すものより低い用量でその活性を発揮する、多数の生物学的に活性のある2,4−ピリミジンジアミン化合物の能力は、以前、立証されている(たとえば、2003年1月31日に出願された米国特許出願、出願番号第10/355,543号(US2004/0029902A1)、2003年1月31日に出願された国際出願、出願番号PCT/US03/03022(WO03/063794)、2003年7月29日に出願された米国特許出願、出願番号第10/631,029号(____)、国際出願、出願番号PCT/US03/24087(WO2004/014382)、2004年7月30日に出願された米国特許出願、出願番号第10/903,263号(US2005/0234049)及び国際出願、出願番号PCT/US2004/24716(____)を参照のこと)。
脱顆粒の際放出されるトリプターゼの活性を測定することによって評価するとき、化合物1は、臍帯血由来のヒト一次肥満細胞(CHMC)のFcεRI依存性の活性化を用量依存性に遮断し、EC50はおよそ43nMである。化合物1は、CHMCのイオノマイシン誘導の脱顆粒を阻害しない。イオノマイシンは、FcRのシグナル伝達を早期に迂回してCHMCの脱顆粒を誘導するカルシウムイオノフォアなので、化合物1は、脱顆粒自体ではなく、FcRのシグナル伝達に特異的であることを示している。化合物1は、また、FcεRI依存性のLTC4(EC50=39nM)及び調べたすべてのサイトカイン(EC50は158〜462nMの範囲)の産生及び放出を阻害する。
ICが介在する血管浮腫(ラットにおけるアルツス反応)、マウスにおけるコラーゲン抗体誘導の関節炎、及びコラーゲン誘導の関節炎のラットモデルにおける化合物1の生物活性。
ICが介在する急性の炎症性の組織傷害は、血管炎、血清病、全身性エリテマトーデス、RA及び糸球体腎炎を含む種々のヒト自己免疫疾患に関係しているとみなされている。ICが介在する組織傷害の古典的な実験モデルは、逆受動アルツス(RPA)反応である。OVAに特異的な抗体(ウサギ抗OVAIgG)の皮内注射に続く抗原(オボアルブミン、OVA)の静脈内注射は、血管周囲のICの沈着並びに注射部位での浮腫、好中球の浸潤及び出血を特徴とする迅速な炎症反応を生じる(Szalai et al.,J.Immunol.,164(1);463−468,2000)。
抗コラーゲンII型抗体カクテルを適用して関節炎を誘導するマウスのコラーゲン抗体誘導関節炎(CAIA)モデル(Teroto et al.,J.Immunol.,148(7):2103−2108,1992;McCoy et al.,J.Clin.Invest.,110(5):651−658,2002;Kagari et al.,J.Immunol.,169(3)1459−1466,2002)にて化合物 1の抗炎症性活性を評価した。この受身モデルは、疾患の症状が迅速に現れる(抗体のIV注射後24〜48時間で発生する)、関節炎は、CIA感受性及びCIA抵抗性のマウス系統の双方で誘導可能であり、抗体産生とは独立する炎症を評価することができるという点で、従来のげっ歯類のコラーゲン誘導の関節炎(CIA)とは異なる。
ICが介在する組織傷害の実験モデルの1つは、げっ歯類におけるCIAである(Kleinau et al.,J.Exp.Med.,191:1611−1616,2000)。げっ歯類へのコラーゲンII型(CII)の注射は、付随する周辺組織の腫脹と共に末端の関節の軟骨と骨の免疫的破壊が特徴的に関与する免疫反応を生じる。ラットにおけるCIAは、関節リウマチ及びそのほかの慢性的炎症状態を治療するための薬剤としての使用の可能性がある化合物を評価するのに一般に用いられ、CIAは、不完全フロインドアジュバント(IFA)と共にCIIを注射することによってマウス又はラットのいずれかの感受性の系統で誘導される。このエマルションの投与は、滑膜の過形成、単核細胞の浸潤、パンヌスの形成、及び軟骨及び骨の破壊を特徴とする多発性関節炎を生じる。B細胞欠損マウスが関節炎を発生しないので、CIIに対する抗体が、マウスのCIAの前提条件であることは以前よく立証された(Svensson et al.,Clin.Exp.Immunol.,111:521−526,1998)。
経口の生体利用率についてプロドラッグ化合物4を調べた。試験のために、ラットにおける静脈内投与用及び経口投与用の種々のビヒクル(たとえば、PEG−400溶液及びCMC懸濁液)にプロドラッグを溶解した。指示された場合、活性型代謝産物化合物1(薬剤)を同一ビヒクルで製剤化し、投与した。プロドラッグ及び/又は薬剤の投与に続いて、血漿試料を得て、抽出した。高速液体クロマトグラフィ/直列質量分光計(LC/MS/MS)によってプロドラッグ及び/又は薬剤の血漿濃度を測定した。血漿濃度のデータに基づいて薬物力学的解析を行った。関心のある薬物力学的パラメータには、クリアランス(CL)、定常状態での分布の容積(Vss)、最終半減期(t1/2)及び経口生体利用率(%F)が挙げられる。
図10は、プロドラッグ化合物4がラットの血漿中では不安定であることを説明し、−薬剤化合物1への加水分解が認められ、化合物1への変換は、ホスファターゼ酵素によって触媒されると考えられる。ホスファターゼの既知の基質であるリン酸p−ニトロフェニルを用いて、ラットの血漿におけるホスファターゼ活性の存在を確認した。
Claims (40)
- 2,4−ピリミジンジアミン部分及び少なくとも1つのプロ基Rpを含むプロドラッグ化合物、又はその塩、溶媒和物、水和物もしくはN−オキシドであって、該プロ基Rpが該2,4−ピリミジンジアミン部分の1級又は2級のアミノ窒素原子に共有結合している、プロドラッグ化合物。
- 請求項1に記載のプロドラッグ化合物であって、その塩、溶媒和物、水和物およびN−オキシドを含む構造式(I):
式中、
Yは、CH2、NR24、O、S、S(O)、及びS(O)2から選択され;
Z1及びZ2はそれぞれ、互いに独立してCH及びNから選択され;
R2は、1以上の同一のもしくは異なったR8基によって任意で置換された(C1〜C6)のアルキル、1以上の同一のもしくは異なったR8基によって任意で置換された(C3〜C8)のシクロアルキル、1以上の同一のもしくは異なったR8基によって任意で置換されたシクロヘキシル、1以上の同一のもしくは異なったR8基によって任意で置換された3〜8員のシクロヘテロアルキル、1以上の同一のもしくは異なったR8基によって任意で置換された(C6〜C14)のアリール、1以上の同一のもしくは異なったR8基によって任意で置換されたフェニル及び1以上の同一のもしくは異なったR8基によって任意で置換された5〜15員のヘテロアリールから選択され;
R5は、ハロ、フルオロ、シアノ、ニトロ、トリハロメチル及びトリフルオロメチルから選択され;
R8は、Ra、Rb、1以上の同一のもしくは異なったRa又はRbによって置換されたRa、1以上の同一のもしくは異なったRa又はRbによって置換された−ORa、−B(ORa)2、−B(NRcRc)2、−(CH2)m−Rb、−(CHRa)m−Rb、−O−(CH2)m−Rb、−S−(CH2)m−Rb、−O−CHRaRb、−O−CRa(Rb)2、−O−(CHRa)m−Rb、−O−(CH2)mCH[(CH2)mRb]Rb、−S−(CHRa)m−Rb、−C(O)NH−(CH2)m−Rb、−C(O)NH−(CHRa)m−Rb、−O−(CH2)m−C(O)NH−(CH2)m−Rb、−S−(CH2)m−C(O)NH−(CH2)m−Rb、−O−(CHRa)m−C(O)NH−(CHRa)m−Rb、−S−(CHRa)m−C(O)NH−(CHRa)m−Rb、−NH−(CH2)m−Rb、−NH−(CHRa)m−Rb、−NH[(CH2)mRb]、−N[(CH2)mRb]2、−NH−C(O)NH−(CH2)m−Rb、−NH−C(O)−(CH2)m−CHRbRb及び−NH−(CH2)m−C(O)−NH−(CH2)m−Rbから選択され;
R17は、水素、ハロゲン、フルオロ、低級アルキル及びメチルから選択されるか、或いは、R17は、R18と一緒になってオキソ(=O)基を形成し、若しくはそれらが結合する炭素原子と一緒になって3〜7の炭素原子を含有するスピロ環を形成してもよく;
R18は、水素、ハロゲン、フルオロ、低級アルキル及びメチルから選択されるか、或いは、R18は、R17と一緒になってオキソ(=O)基を形成し、若しくはそれらが結合する炭素原子と一緒になって3〜7の炭素原子を含有するスピロ環を形成してもよく;
R19は、水素、低級アルキル及びメチルから選択されるか、或いは、R19は、R20と一緒になってオキソ(=O)基を形成し、若しくはそれらが結合する炭素原子と一緒になって3〜7の炭素原子を含有するスピロ環を形成してもよく;
R20は、水素、低級アルキル及びメチルから選択されるか、或いは、R20は、R19と一緒になってオキソ(=O)基を形成し、若しくはそれらが結合する炭素原子と一緒になって3〜7の炭素原子を含有するスピロ環を形成してもよく;
各Raは、ほかとは独立して、水素、低級アルキル、低級シクロアルキル、シクロヘキシル、(C4〜C11)のシクロアルキルアルキル、(C6〜C10)のアリール、フェニル、(C7〜C16)のアリールアルキル、ベンジル、2〜6員のヘテロアルキル、3〜8員のシクロヘテロアルキル、モルホリニル、ピペラジニル、ホモピペラジニル、ピペリジニル、4〜11員のシクロヘテロアルキルアルキル、5〜10員のヘテロアリール及び6〜16員のヘテロアリールアルキルから選択され;
各Rbは、=O、−ORa、(C1〜C3)のハロアルキルオキシ、=S、−SRa、=NRa、=NORa、ハロゲン、−CF3、−CN、−NC、−OCN、−SCN、−NO、−NO2、=N2、−N3、−S(O)Ra、−S(O)2Ra、−S(O)2ORa、−S(O)NRcRc、−S(O)2NRcRc、−OS(O)Ra、−OS(O)2Ra、−OS(O)2ORa、−OS(O)2NRcRc、−C(O)Ra、−C(O)ORa、−C(O)NRcRc、−C(NH)NRcRc、−C(NRa)NRcRc、−C(NOH)Ra、−C(NOH)NRcRc、−OC(O)Ra、−OC(O)ORa、−OC(O)NRcRc、−OC(NH)NRcRc、−OC(NRa)NRcRc、−[NHC(O)]nRa、−[NRaC(O)]nRa、−[NHC(O)]nORa、−[NRaC(O)]nORa、−[NHC(O)]nNRcRc、[NRaC(O)]nNRcRc、−[NHC(NH)]nNRcRc及び−[NRaC(NRa)]nNRcRcから独立して選択される好適な基であり;
各Rcは、ほかとは独立して、保護基及びRaから選択されるか、或いは、同一の窒素原子に結合する2つのRcがその窒素原子と一緒になって、5〜8員のシクロヘテロアルキル又はヘテロアリールを形成し、該シクロヘテロアルキル又はヘテロアリールは、必要に応じて1以上の同一又は異なった追加のヘテロ原子を含んでもよく、必要に応じて1以上の同一のもしくは異なったRa基で置換されてもよく;
R21、R22及びR23はそれぞれ、互いに独立して水素及びプロ基Rpから選択され;
R24は、水素、低級アルキル及びプロ基Rpから選択され;
R21、R22、R23及びR24の少なくとも1つがプロ基であるという条件で、
各mは、ほかとは独立して1〜3の整数であり;
各nは、ほかとは独立して0〜3の整数である、プロドラッグ化合物。 - R5がフルオロである、請求項2に記載のプロドラッグ化合物。
- R2が1以上の同一のもしくは異なったR8基で任意で置換されるフェニルである、請求項2に記載のプロドラッグ化合物。
- R2が3,4,5−トリ(低級アルコキシ)フェニルである、請求項4に記載のプロドラッグ化合物。
- R2が3,4,5−(トリメトキシ)フェニルである、請求項5に記載のプロドラッグ化合物。
- YがOであり、Z1がCHであり、Z2がNであり、R17及びR18がそれぞれメチルであり、R19とR20が一緒になってオキソ基を形成する、請求項2に記載のプロドラッグ化合物。
- R2が1以上の同一のもしくは異なったR8基で任意で置換されるフェニルである、請求項7に記載のプロドラッグ化合物。
- R2が3,4,5−トリ(低級アルコキシ)フェニルである、請求項8に記載のプロドラッグ化合物。
- R2が3,4,5−(トリメトキシ)フェニルである、請求項9に記載のプロドラッグ化合物。
- R21のみがプロ基Rpである、請求項10に記載のプロドラッグ化合物。
- 前記プロ基Rpが、エステル、チオエステル、エーテル、チオエーテル、シリルエーテル、チオシリルエーテル、カーボネート、チオ尿素、アミド、チオアミド、カルバメート及び尿素結合のうちの少なくとも1つを含む、請求項11に記載のプロドラッグ化合物。
- 前記プロ基Rpが、ホスフェート基を含む、請求項11に記載のプロドラッグ化合物。
- 前記プロ基Rpが、式−(CRdRd)y−O−P(O)(OH)2、もしくはそれらの塩を有し、式中、yは1〜3の範囲の整数であり、各Rdは、他とは独立して、水素、任意で置換された低級アルキル、任意で置換された(C6〜C14)のアリール及び任意で置換された(C7〜C20)のアリールアルキルから選択され、ここで、任意の置換基が、互いに独立してヒドロキシル、低級アルコキシ、(C6〜C14)のアリールオキシ、低級アルコキシアルキル、メトキシメチル、メトキシエチル、エトキシメチル、エトキシエチル及びハロゲンから選択されるか、あるいは同じ炭素原子に結合する2つのRdはそれらが結合する炭素原子と一緒になって3〜8の炭素原子を含有するシクロアルキル基を形成する、請求項13に記載のプロドラッグ化合物。
- 前記プロ基Rpが、−CH2−O−P(O)(OH)2、−CH2CH2−O−P(O)(OH2)及びそれらの塩から選択される、請求項14に記載のプロドラッグ化合物。
- 前記プロ基Rpが、リン酸エステル基を含む、請求項11に記載のプロドラッグ化合物。
- 前記プロ基Rpが、−(CRdRd)y−O−P(O)(ORe)(OH)、−(CRdRd)y−O−P(O)(ORe)(ORe)、
各Rgは、ほかとは独立して、水素及び低級アルキルから選択され、各Rhは、ほかとは独立して、水素、置換又は非置換の低級アルキル、置換又は非置換の低級シクロへテロアルキル、置換又は非置換の(C6〜C14)のアリール、置換又は非置換の(C7〜C20)のアリールアルキル及び置換又は非置換の5〜14員のヘテロアリールから選択され;zは0〜2の範囲の整数であり、Rd及びyは、請求項14に定義されるとおりである、請求項16に記載のプロドラッグ化合物。 - Rpが、−CH2−O−P(O)(OH)2、−CH2CH2−O−P(O)(OH)2、−CH2OH及びそれらの塩から選択される、請求項11に記載のプロドラッグ化合物。
- 構造(III):
式中、各R30、R31及びR32は、互いに独立して、水素、低級アルキル、低級アルケニル、低級アルキニル、(C6〜C14)のアリール、フェニル、5〜14員のヘテロアリール、(C7〜C20)のアリールアルキル、ベンジル、7〜20員のヘテロアリールアルキル、−OR、クロロ、フルオロ、ブロモ、シアノ、ニトロ、−C(O)R、−C(O)OR、−NRR、−S(O)2NRR、−C(O)NRR、−N(R)S(O)2R及び−NC(O)ORから選択され、ここで、各Rは、ほかとは独立して、水素及び低級アルキルから選択され、Rpは、−CH2−O−P(O)(OH)2、−CH2CH2−O−P(O)(OH)2、−CH2OH及びそれらの塩から選択される、プロドラッグ化合物。 - 各R30、R31及びR32がそれぞれメトキシである、請求項19に記載のプロドラッグ化合物。
- 請求項1に記載のプロドラッグ化合物及び許容可能なキャリア、賦形剤及び/又は希釈剤を含む、組成物。
- 脱顆粒を阻害するのに有効な量の請求項2に記載のプロドラッグ化合物を被験体に投与することを含む、被験体において細胞の脱顆粒を阻害する方法。
- 疾患が、アレルギー疾患、軽度の瘢痕、組織の破壊に関連する疾患、組織の炎症に関連する疾患、炎症及び瘢痕から選択される、請求項23に記載の方法。
- 疾患が関節リウマチである、請求項23に記載の方法。
- Sykキナーゼの活性を阻害するのに有効な量の請求項2に記載のプロドラッグ化合物を被験体に投与することを含む、被験体においてSykキナーゼの活性を阻害する方法。
- Fc受容体によるシグナル伝達カスケードを阻害するのに有効な量の請求項2に記載のプロドラッグ化合物を被験体に投与することを含む、被験体においてFc受容体によるシグナル伝達カスケードを阻害する方法。
- 前記Fc受容体が、FcαRI、FcγRI,FcγRIII及びFcεRIから選択される、請求項27に記載の方法。
- 自己免疫疾患を治療又は予防するのに有効な量の請求項1に記載のプロドラッグ化合物を被験体に投与することを含む、被験体における自己免疫疾患、及び/又はそれと関連した1つ以上の症状を治療又は予防する方法。
- 自己免疫疾患が、単一臓器又は単一細胞型の自己免疫障害と呼ばれることが多い自己免疫疾患、及び全身性の自己免疫障害が関与すると呼ばれることが多い自己免疫疾患から選択される、請求項29に記載の方法。
- 前記自己免疫疾患が、ハシモト甲状腺炎、自己免疫性溶血性貧血、悪性貧血の自己免疫性アトピー性胃炎、自己免疫性脳脊髄炎、自己免疫性精巣炎、グッドパスチャー疾患、自己免疫性血小板減少症、交感神経性眼炎、重症筋無力症、グラーベ病、原発性胆汁性肝硬変、慢性活動性肝炎、潰瘍性大腸炎、膜性糸球体腎炎、全身性エリテマトーデス、関節リウマチ、シェーグレン症候群、ライター症候群、多発性筋炎−皮膚筋炎、全身性硬化症、結節性多発性動脈炎、多発性硬化症及び水疱性類天疱瘡から選択される、請求項29に記載の方法。
- 関節リウマチに罹患している被験体に、治療利益を提供するのに有効な量の請求項2に記載のプロドラッグ化合物を投与することを含む、被験体において関節リウマチを治療する方法。
- 投与されるプロドラッグ化合物の量が、インビトロアッセイで測定されるとき、薬剤のSyk阻害のIC50以上である対応する薬剤の血清濃度を達成するのに有効である、請求項32に記載の方法。
- R26が、−CH2−O−P(O)(ORf)2及び−CH2CH2−O−P(O)(ORf)2及びそれらの塩から選択され、各Rfは、同一であるか又は異なる低級アルキルである、請求項35に記載の化合物。
- N4−(2,2−ジメチル−4−[(二水素ホスホノキシ)メチル]−3−オキソ−5−ピリド[1,4]オキサジン−6−イル)−5−フルオロ−N2−(3,4,5−トリメトキシフェニル)−2,4−ピリミジンジアミンならびにその塩及び溶媒和物。
- N4−(2,2−ジメチル−4−[ヒドロキシメチル]−3−オキソ−5−ピリド[1,4]オキサジン−6−イル)−5−フルオロ−N2−(3,4,5−トリメトキシフェニル)−2,4−ピリミジンジアミンならびにその塩及び溶媒和物。
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WO2010027002A1 (ja) * | 2008-09-05 | 2010-03-11 | 塩野義製薬株式会社 | Pi3k阻害活性を有する縮環モルホリン誘導体 |
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JP2016041700A (ja) * | 2010-04-13 | 2016-03-31 | ライジェル ファーマシューティカルズ, インコーポレイテッド | 2,4−ピリミジンジアミン化合物およびそのプロドラッグならびにそれらの使用 |
JP2014521630A (ja) * | 2011-07-28 | 2014-08-28 | ライジェル ファーマシューティカルズ, インコーポレイテッド | (トリメトキシフェニルアミノ)ピリミジニル製剤 |
JP2017503018A (ja) * | 2013-12-20 | 2017-01-26 | ライジェル ファーマシューティカルズ, インコーポレイテッド | 薬学的方法および中間体 |
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