JP5603881B2 - プロテインキナーゼc阻害剤とその使用 - Google Patents
プロテインキナーゼc阻害剤とその使用 Download PDFInfo
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- JP5603881B2 JP5603881B2 JP2011546310A JP2011546310A JP5603881B2 JP 5603881 B2 JP5603881 B2 JP 5603881B2 JP 2011546310 A JP2011546310 A JP 2011546310A JP 2011546310 A JP2011546310 A JP 2011546310A JP 5603881 B2 JP5603881 B2 JP 5603881B2
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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Description
本出願は、2009年1月15日に出願された米国仮特許出願第61/145,021号および2009年1月26日に出願された米国仮特許出願第61/147,353号に対して、特許法§119(e)に基づいて優先権の利益を主張するものであり、前記米国仮特許出願はその内容を参照により本明細書に完全に組み込んだものとする。
Ra、Rb、RcおよびRdは、独立に、水素およびアルキルから選択され;
mは、1〜5の整数であり;
pは、0〜6の整数であり;
R2は、アシルオキシ、ヒドロキシ、チオール、アシル、アルキル、アルコキシ、置換アルキル、置換アルコキシ、アミノ、置換アミノ、アミノアシル、アシルアミノ、アジド、カルボキシル、カルボキシルアルキル、シアノ、ハロゲン、ニトロ、アミノアシルオキシ、オキシアシルアミノ、チオアルコキシ、置換チオアルコキシ、−SO−アルキル、−SO−置換アルキル、−SO−アリール、−SO−ヘテロアリール、−SO2−アルキル、−SO2−置換アルキル、−SO2−アリール、−SO2−ヘテロアリールおよびトリハロメチルから選択され;
X1、X2およびX3はCR5であるか、または、X1、X2およびX3のうちの1つはNであり、そして残りはCR5であり;
R5は、水素、ハロゲン、アルキルおよび置換アルキルから選択され;
R3およびR4は、各生成に関して、独立に、水素、アルキル、置換アルキル、アルコキシ、置換アルコキシ、アシル、アシルアミノ、アシルオキシ、アミノ、置換アミノ、アミノアシル、アミノアシルオキシ、オキシアミノアシル、アジド、シアノ、ハロゲン、ヒドロキシル、オキソ、チオケト、カルボキシル、カルボキシルアルキル、チオール、チオアルコキシ、置換チオアルコキシ、アリール、アリールオキシ、ヒドロキシアミノ、アルコキシアミノ、ニトロ、−SO−アルキル、−SO−置換アルキル、−SO−アリール、−SO−ヘテロアリール、−SO2−アルキル、−SO2−置換アルキル、−SO2−アリールおよび−SO2−ヘテロアリールから選択されるか;またはR3およびR4は、それらが結合されている炭素原子と一緒になって、炭素環式もしくは複素環式の4〜8員環を形成し;
nは、1〜3の整数であり;
Z1、Z2およびZ3は、CR6R6a、N、OおよびSから選択され;
Z4およびZ5は、N、CおよびCR6から選択され;
R6は、水素、ハロゲン、アルキルおよび置換アルキルから選択され;
R6aは、水素、ハロゲン、アルキルおよび置換アルキルから選択されるか、または、原子価要件を満たすために不存在であり;かつ
点線は、単結合もしくは二重結合を表わす)によって表わされる化合物であるか;または、それらの塩もしくは溶媒和物または立体異性体である。
以下の用語は、特に明記しない限り、下記の意味を有する。未定義の用語は、それらの業界で認識されている意味を有する。
以下の置換基および数値は、様々な態様および実施形態の代表的な実施例を提供することを意図している。これらの代表値は、そのような態様および実施形態を更に定義し、そして例示することを意図しており、他の実施形態を除外することまたは本発明の範囲を限定することを意図していない。この点に関しては、特定の値または置換基が好ましいという表現は、特に断りがなければ、本発明から他の数値または置換基を除外することを決して意図していない。
Ra、Rb、RcおよびRdは、独立に、水素およびアルキルから選択され;
mは、1〜5の整数であり;
pは、0〜6の整数であり;
R2は、アシルオキシ、ヒドロキシ、チオール、アシル、アルキル、アルコキシ、置換アルキル、置換アルコキシ、アミノ、置換アミノ、アミノアシル、アシルアミノ、アジド、カルボキシル、カルボキシルアルキル、シアノ、ハロゲン、ニトロ、アミノアシルオキシ、オキシアシルアミノ、チオアルコキシ、置換チオアルコキシ、−SO−アルキル、−SO−置換アルキル−、−SO−アリール、−SO−ヘテロアリール、−SO2−アルキル、−SO2置換アルキル、−SO2−アリール、−SO2−ヘテロアリール、およびトリハロメチルから選択され;
X1、X2およびX3はCR5であるか、または、X1、X2およびX3のうちの1つはNであり、そして残りはCR5であり;
R5は、各生成に関して、水素、ハロゲン、アルキルおよび置換アルキルから選択され;
R3およびR4は、各生成に関して、独立に、水素、アルキル、置換アルキル、アルコキシ、置換アルコキシ、アシル、アシルアミノ、アシルオキシ、アミノ、置換アミノ、アミノアシル、アミノアシルオキシ、オキシアミノアシル、アジド、シアノ、ハロゲン、ヒドロキシル、オキソ、チオケト、カルボキシル、カルボキシルアルキル、チオール、チオアルコキシ、置換チオアルコキシ、アリール、アリールオキシ、ヒドロキシアミノ、アルコキシアミノ、ニトロ、−SO−アルキル、−SO−置換アルキル−、−SO−アリール、−SO−ヘテロアリール、−SO2−アルキル、−SO2置換アルキル、−SO2−アリールおよびSO2−ヘテロアリールから選択されるか;またはR3およびR4は、それらが結合されている炭素原子と一緒になって、炭素環式もしくは複素環式の4〜8員環を形成し;
nは、0〜3の整数であり;
Z1、Z2およびZ3は、CR6R6a、N、O、およびSから選択され;
Z4およびZ5は、N、CおよびCR6から選択され;
R6は、水素、ハロゲン、アルキルおよび置換アルキルから選択され;
R6aは、水素、ハロゲン、アルキルおよび置換アルキルから選択されるか、または、原子価要件を満たすために不存在であり;かつ
点線は、単結合もしくは二重結合を表わす)の化合物;または
それらの塩もしくは溶媒和物もしくは立体異性体を提供する。
N2−(4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(4H−ベンゾ[b]ピロロ[1,2−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(4H−ベンゾ[b]ピロロ[1,2−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(4,4−ジフルオロ−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(4,4−ジフルオロ−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(5,5−ジメチル−5H−ベンゾ[e]テトラゾロ[1,5−c][1,3]オキサジン−9−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(5,5−ジメチル−5H−ベンゾ[e]テトラゾロ[1,5−c][1,3]オキサジン−9−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(8,9−ジヒドロスピロ[ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−4,1´−シクロブタン]−8−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(8,9−ジヒドロスピロ[ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−4,1´−シクロブタン]−8−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
5−フルオロ−N2−(4−メチル−8,9−ジヒドロ−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
5−フルオロ−N2−(4−メチル−8,9−ジヒドロ−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−((1,2,2,5,5−ペンタメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミン;
N2−(4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−((2,2,5,5−テトラメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミン;
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−((1,2,2,5,5−ペンタメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミン;
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−((2,2,5,5−テトラメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミン;
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(((3S)−2,2,5−トリメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミン;および
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(((3R)−2,2,5−トリメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミンが挙げられる。
Rpは、−CH2−O−P(O)(OH)2、−CH2CH2−O−P(O)(OH)2、−CH2OHから選択される)を有することができる。
式:
開示される化合物を合成するのに有用な公知の化学合成スキームと条件を提供する多数の一般的な参考文献が利用できる(例えば、Smith and March, March’s Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, Fifth Edition, Wiley−Interscience,2001;またはVogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978を参照されたい)
スキーム1
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スキーム3
スキーム4
スキーム5
スキーム6
スキーム7
スキーム8
開示化合物は、少なくとも、PKC活性の阻害に有用であり、また、PKC活性の作用によって媒介される疾患または障害の治療に有用である。したがって、少なくとも一種の開示化合物を含む医薬組成物も、本明細書に記載する。
被験化合物はプロテインキナーゼC活性を阻害することが出来る。従って、被験化合物は被験者のPKC活性の作用により媒介される疾患または障害の治療に有効である。従って、被験化合物は被験者のT細胞の活性化に関連した疾患または障害の治療に有効である。
プロテインキナーゼ C
PKCはセリン/スレオニンキナーゼとして機能する酵素ファミリーである。PKCのアイソザイムは、組織分布、酵素選択性、Ca2+の必要性、および調節性の点で異なっている。PKCは細胞−細胞間信号伝達、遺伝子発現、および細胞分化と成長の制御で重要な役割を担っている。
PKC θは、主にリンパ組織および骨格筋に発現する。PKC θは選択的にT細胞中に発現し、成熟T細胞活性化の役割を担う。PKC θはT細胞受容体(TCR)媒介T細胞活性化に関わるが、TCR依存胸腺細胞発生には必要ではないことが明らかになっている。他のPKCイソ型にはない機能であるが、PKC θは、抗原特異性T細胞と抗原提示細胞(APC)との間の細胞接触部位に移行し、そこでT細胞活性化の中核としてTCRと共に局在化する。α、ε、またはζアイソザイムにはない機能であるが、PKC θは、FasLプロモーター−レポーター遺伝子を選択的に活性化でき、mRNAまたは内在性FasLの細胞表面発現を上方制御することが出来る。他方、PKC θおよびεは、Fas誘導アポトーシスから細胞を防御することによりT細胞生存を促進することができ、この防御効果はBCL−2ファミリーメンバーのBADのp90Rsk依存リン酸化の促進により媒介されたものである。このように、PKC θはT細胞のアポトーシスにおいて二重に調節する役割を果たしているようである。
本明細書に開示されているように、被験化合物は、Sykキナーゼ阻害剤等の他のタンパク質キナーゼ阻害剤と組み合わせて投与可能である
被験化合物は、治療の必要な被験者のPKCの活性により媒介される、または悪化する疾患または障害の治療に有用である。また、この化合物は、被験者の異常な、もしくは望ましくないT細胞活性化に関連した疾患または障害の治療に有用である。
以下は、目的化合物の活性評価に有用な代表的アッセイである。
A.インビトロ
蛍光偏光法を使って種々の阻害剤濃度でリン酸化ペプチドの産生をモニターしてPKC活性の阻害を測定した。合計容量20μLの96ウェルプレートフォーマットを用い、20mMのHEPES、pH7.4、5mMのMgCl2、0.2mMのCaCl2、1mMのDTT、0.02%Brij−35、0.1mg/mLのホスファチジルセリン、0.02mg/mLのジオレオイル−sn−グリセロール、ならびに各ATPを5μMおよびペプチド基質を入れて反応を実施した。最初に化合物を連続的にDMSOで希釈し、次いで上記濃度のHEPES、MgCl2、CaCl2、DTT、およびBrij−35を含む溶液に移し、5xの2%DMSO化合物溶液を得、これを反応溶液に添加した。下記の表に記載の代表的濃度でPKCを添加して反応を開始し、次いで室温で20分間インキュベートした。この時間の最後に、反応停止試薬(EDTA)と検出試薬(ペプチドトレーサーおよび抗体)を組み合わせて添加した。これには、Invitrogen P2748(カールズバッド、CA)、タンパク質キナーゼC蛍光偏光アッセイキットを使用した。30分のインキュベーションの後、生成したリン酸化ペプチドの量を、Tecan Polarian instrument(スイス)を用いて蛍光偏光(Ex=485nm、Em=535nm)で測定した。
ヒト一次T細胞の単離と培養:
ヒト一次T細胞を次のように調製した。全血を健康なボランティアから得て、PBSと1:1に混合し、2:1の血液/PBS:フィコール比率でフィコールハイパック(Amersham Pharmacia Biotech、Piscataway、NJ、カタログ#17−1440−03)上に層状に入れ、4℃、1750rpmで30分間遠心分離した。血清:フィコール界面で細胞を回収し、5容積のPBSで2回洗浄した。これら新しく単離されたヒト抹消血中単核細胞を、1μg/mLのαCD3と5μg/mLのαCD28(抗ヒトCD3、BD Pharmingen カタログ#555336、抗ヒトCD28、Beckman Coulter カタログ#IM1376)とをプレコートしたフラスコ中で、40U/mLのIL2を含むYssel’s培地で培養した。この細胞を3〜4日刺激し、新しいフラスコに移した後、10%FBSと40U/mLのIL−2とを含むRPMI(L−グルタミン含有RPMI−1640;Mediatech、Inc.、Herndon VA、カタログ#10−040−CM)とで維持した。次に、一次T細胞をPBSで2回洗浄しIL−2を除去した。
試験化合物を添加した場合と添加しない場合について、ヒト一次T細胞(100、000細胞/ウェル)をYssel’s培地中、37℃で1時間プレインキュベートした。次に、1μg/mlのαCD3および5μg/mlのαCD28でプレコートした丸底96ウェルプレートに移すことにより細胞を刺激した。カウンターアッセイのために、細胞をPMAの8X保存液とYssel’s培地に入れたイオノマイシン(最終濃度は、0.5ng/ml:PMAおよび0.1μM:イオノマイシン;両方ともCalbiochemから入手)を添加して刺激した。細胞を37℃で24時間インキュベーション後、100μLの上澄みを回収し、Human IL−2 Duoset ELISAキット(R and D Systems、カタログ#DY202Eから入手)を使ってELISA法でIL−2を定量した。
被験化合物の異なるPKCイソ型に対する活性を以下の方法で試験できる。白色透明底の384ウェルを備えたノンバインディング表面のマイクロタイタープレートでアッセイを実施する。反応混合物(25μl)には、20mMTris−HClバッファpH7.4+0.1%BSA中に入れる成分として、Ala→Ser置換のあるPKCα疑似基質配列を模倣した1.5μMのトリデカペプチド受容体基質、10μMの33P−ATP、10mMのMg(NO3)2、0.2mMのCaCl2、タンパク質濃度25〜400ng/mlのPKG(使われたアイソタイプに依存)、最終脂質濃度で0.5mMの脂質小胞(30mol%ホスファチジルセリン、5mol%DAGおよび65mol%ホスファチジルコリンを含む)、が含まれる。インキュベーションは室温で60分行う。50μlの停止混合物(100mM EDTA、200μM ATP、0.1%TritonX−100、Ca、Mgを含まないリン酸塩緩衝生理食塩水に入れた0.375mg/ウェルのストレプトアビジン被覆SPAビーズ)を加えて反応を停止させる。室温で10分のインキュベーション後、懸濁液を300gで10分間遠心沈降させる。組み込まれた放射能をTriluxカウンターで1分間計測する。IC50の測定は、1−1000μMの濃度範囲の阻害剤希釈系列をインキュベーションして通例の手法で行う。IC50値は、XLFit(登録商標)ソフトウェアを使ってグラフのカーブフィッティングにより求める。
ヒト組換えPKCαをOxford Biomedical Researchより入手し、上記A.1項で記載したアッセイ条件下で使用する。
ヒト組換えPKCβ1をOxford Biomedical Researchより入手し、上記A.1項で記載したアッセイ条件下で使用する。
ヒト組換えPKCδをOxford Biomedical Researchより入手し、上記A.1項で記載したアッセイ条件下で使用する。
ヒト組換えPKCεをOxford Biomedical Researchより入手し、上記A.1項で記載したアッセイ条件下で使用する。
ヒト組換えPKCηをPanVeraより入手し、上記A.1項で記載したアッセイ条件下で使用する。
ヒト組換えPKCθを上述のアッセイ条件下で使用する。
このアッセイは、Baumann G et al.、Transplant.Proc.1992;24:43−8に記載の、ヒトインターロイキン−2プロモーター/レポーター遺伝子構築物を形質移入したJurkat細胞を使って実施する。ここでβ−ガラクトシダーゼレポーター遺伝子は、ルシフェラーゼ遺伝子で置き換えられている(de Wet J.,et al.,Mol.Cell.Biol.1987,7(2),725−737)。細胞を固相結合抗体またはホルボールミリスタートアセタート(PMA)およびCa++イオノフォアのイオノマイシンにより以下の通りに刺激する。抗体媒介性刺激のために、Microlite TM1マイクロタイタープレート(Dynatech)を、1ウェルにつきリン酸緩衝食塩水(PBS)55μl中の3μg/mlヤギ抗マウスIgG Fc抗体(Jackson)により、3時間室温で被覆する。抗体を除去した後、PBS中の2%ウシ血清アルブミン(BSA)(1ウェルにつき300μl)と共に2時間室温でインキュベートすることにより、プレートをブロックする。1ウェル当たり300μlのPBSで3回洗浄した後、2%BSA/PBS50μl中に入れた10ng/mlの抗T細胞受容体抗体(WT31、Becton&Dickinson)および300ng/mlの抗CD28抗体(15E8)を刺激抗体として添加し、一晩4℃でインキュベートする。最後にプレートを1ウェルにつき300μlのPBSで3回洗浄する。アッセイ培地(50μM 2−メルカプトエタノール、100ユニット/mlペニシリンおよび100μg/mlストレプトマイシンを含有する、RPMI1640/10%ウシ胎児血清(FCS))中で、試験化合物の3倍連続希釈物7個を二通り別々のプレートに調製し、形質移入したJurkat細胞(クローンK22 290_H23)と混合し、30分間、37℃、5%CO2中でインキュベートする。次いで1x105細胞を含有するこの混合物100μlを、抗体被覆アッセイプレートに移す。並行して100μlを40ng/mlPMAおよび2μM イオノマイシンとインキュベートする。5.5時間、37℃、5%CO2中でインキュベートした後、ルシフェラーゼレベルをバイオルミネセンス測定により測定する。プレートを10分間500gで遠心分離し、上清を振り落として除去する。25mM Tris−リン酸塩、pH7.8、2mM DTT、2mM 1.2−ジアミノシクロヘキサン−N,N,N',N−四酢酸、10%(v/v)グリセロールおよび1%(v/v)Triton X−100を含有する溶解バッファを添加する(1ウェルにつき20μl)。プレートを室温で10分間、一定の震盪を加えながらインキュベートする。20mMトリシン、1.07mM(MgCO3)4Mg(OH)2x5H2O、2.67mM MgSO4、0.1mM EDTA、33.3mM DTT、270μM補酵素A、470μMルシフェリン(Chemie Brunschwig AG)、530μM ATP、pH7.8を含有するルシフェラーゼ反応バッファを1ウェルにつき50μl自動的に添加した後、ルシフェラーゼ活性をバイオルミネセンスリーダー(Labsystem、ヘルシンキ、フィンランド)で評価する。遅延時間は0.5秒であり、総測定時間は1または2秒である。低い対照値は抗T細胞受容体またはPMAにより刺激された細胞からの発光単位であり、高い対照値は、試験サンプル無しで抗T細胞受容体/抗CD28またはPMA/イオノマイシンで刺激された細胞からのものである。低い対照を、全値から差し引く。試験化合物の存在下で得られる阻害を、高い対照に対する阻害パーセントとして算出する。50%阻害(IC50)をもたらす試験化合物の濃度を、用量反応曲線から決定する。
CBAマウスからの骨髄細胞(平底組織培養マイクロタイタープレート中、1ウェル当たり2.5x104細胞)を、10%FCS、100U/mlペニシリン、100μg/mlストレプトマイシン(GibcoBRL、バーゼル、スイス)、50μM 2−メルカプトエタノール(Fluke、Buchs、スイス)、増殖因子源としてのWEHI−3ならし培地(7.5%v/v)およびL929ならし培地(3%v/v)、および連続希釈化合物、を含んだ100μlのRPMI培地中でインキュベートする。3倍希釈操作を試験化合物当たり2部ずつ7回実施する。4日間のインキュベーション後、1μCi 3H−チミジンを添加する。さらに5時間インキュベーション後、細胞を回収し、取り込まれた3H−チミジンを標準手法で測定する。ならし培地は次のようにして調製する。WEHI−3細胞l(ATCC TIB68)およびL929細胞(ATCC CCL1)を集密になるまで、それぞれ4日および1週間、RPMI培地中で増殖させる。細胞を回収し、同じ培養フラスコ中で、WEHI−3細胞に対しては1%FCS(Schreier and Tees 1981)、L929細胞に対してはRPMI培地、を含む培地C再懸濁後、2日間(WEHI−3)または1週間(L929)インキュベーションする。上澄みを集め、0.2μmで濾過して−80℃で一定分量を保存する。試験化合物を含まず、WEHI−3とL929上澄みを含まない培養物を低い対照値として使用する。低い対照値をすべての値から差し引く。試料を含まない高い対照値を100%増殖として採用する。試料による阻害パーセンを計算し、50%阻害に必要な濃度(IC50値)を決定する。
双方向MLRを標準方法に従って実施する(J. Immunol. Methods、 1973、 2、 279 および Meo T. et al.、 Immunological Methods、 New York、 Academic Press、 1979、 227−39)。簡単に説明すると、CBAおよびBALB/cマウス由来の脾臓細胞(平底組織培養マイクロタイタープレート中、1ウェルにつき各系統から1.6x105細胞、全部で3.2x105)を、10%FCS、100U/mlペニシリン、100μg/mlストレプトマイシン(GibcoBRL、バーゼル、スイス)、50μM 2−メルカプトエタノール(Fluka、Buchs、スイス)および連続希釈した化合物を含有するRPMI培地中でインキュベートする。各試験化合物につき7回の3倍希釈操作を2部実施する。4日間のインキュベーションの後、1μCiの3H−チミジンを添加する。さらに5時間インキュベーションした後、細胞を回収し、組み込まれた3H−チミジンを標準方法に従って測定する。MLRのバックグラウンド値(低い対照)は、BALB/c細胞単独の増殖である。低い対照は、すべての値から差し引く。どのサンプルも含まない高い対照を、100%増殖とする。各サンプルによるパーセント阻害を算出し、50%阻害に必要とされる濃度(IC50値)を決定する。
心臓移植モデル
使用した系統の組合せ:雄Lewis(RT1ハプロタイプ)およびBN(RT1ハプロタイプ)。吸入イソフルランを使用して、動物を麻酔する。腹部の下大静脈を通してドナーラットをヘパリン化し、同時に大動脈から全採血し、続いて、胸部を切開し、心臓を急速に冷却する。大動脈を結紮し、最初の分岐の遠位で切断し、腕頭動脈を最初の分岐で切断する。左肺動脈を結紮し、切離し、右側は切離するが開口のままにする。他の全血管を切り離して遊離させ、結紮し、切断し、ドナーの心臓を氷冷食塩水に移す。
Wistar/F ラット由来の脾臓細胞(2x107)を、(Wistar/F x Fischer 344)F1ハイブリッドラットの右後肢の足蹠に皮下注射する。左足蹠は処理せずにおく。動物を4日続けて(0〜3日目)試験化合物で治療する。膝窩リンパ節を7日目に取りだし、2つの相応するリンパ節の重量差を測定する。結果は、実験群のリンパ節重量差を、試験化合物で治療しなかった動物群由来の相応するリンパ節間の重量差と比較して、リンパ節拡大の阻害として表す(パーセント表示)。特定の例では、試験化合物は選択的PKC阻害剤である。例えば、移植片対宿主病と関連障害の治療に特に有用な開示化合物は、選択的PKCαとθ阻害剤である。
被験化合物はPKC活性を阻害することが可能であるから、このような化合物は研究用ツールとしても有用である。また、本開示は、生物学的システムまたは試料の研究、またはPKC活性を阻害することが出来る新化学化合物の開発のための研究ツールとして、式(I)の化合物またはそれの塩または溶媒和物または立体異性体の使用方法を提供する。
以下の実施例は、当業者に実施形態の作成と使用方法の完全な開示と記述を提供するために提示されており、発明者が自らの発明と見なす範囲を制限する意図のものでもなく、また、下記の実験が実施したすべて、あるいは唯一の実験であることを示す意図のものでもない。使われている数値(例えば、量、温度、等)には正確を期しているつもりであるが、いくばくかの実験誤差と偏差は考慮されるべきである。特に他に指示がなければ、部は重量部、分子量は重量平均分子量、温度はセ氏、圧力は大気圧またはその近傍である。標準的な略号を使う場合もある。
実施例1および2
1−(2−フルオロ−5−ニトロフェニル)−1H−ピロール(P−1)の合成
250mLの丸底フラスコ中で、5−ニトロ−2−フルオロアニリン(7.0g、44.8mmol)を酢酸(60mL)に溶解させ、2、5−ジメトキシテトラヒドロフラン(6.3mL、49.8mmol)で処理した。得られた混合物を110℃で4時間加熱した。TLC分析により、4時間後には出発物質が完全に生成物に転換していることが示された。次いで、反応混合物を周囲温度まで冷却し、分液漏斗に移して分配した(CH2Cl2//H2O)。有機相をH2O(3x50mL)、食塩水(3x50mL)で洗浄し、Na2SO4上で乾燥後、減圧下蒸発させ薄茶色の残渣を得た。残渣をフラッシュクロマトグラフィー(ヘキサン→1:9EtOAc/ヘキサン)で精製して淡黄色固体の標記化合物(7.2g、78%)を得た。
1H NMR (DMSO−d6, 300 MHz) 8.34 (dd, 1H), 8.16−8.20 (m, 1H), 7.69 (t, 1H), 7.27 (d, 2H), 6.32 (d, 2H) ppm; MS (ES) 207 (M+H).
1−(2−フルオロ−5−ニトロフェニル)−1H−ピロール−2−カルボアルデヒド(P−2)の合成
50mL丸底フラスコ中、0℃で無水DMF(0.82mL、10.67mmol)とPOCl3(0.96mL、10.67mmol)を混合した。この懸濁液を周囲温度まで暖め、無水DMF(8mL)中の淡黄色溶液として1−(2−フルオロ−5−ニトロフェニル)−1H−ピロール(2.0g、9.7mmol)で処理した。得られた混合物を室温で5時間激しく攪拌した。この混合物のTLC分析により、5時間後には出発物質が完全に生成物に転換していることが示された。この反応混合物を分液漏斗に移し分配した(EtOAc//H2O)。有機相をH2O(3x50mL)、食塩水(3x50mL)で洗浄し、Na2SO4上で乾燥後、減圧下蒸発させ茶色の残渣を得た。残渣をフラッシュクロマトグラフィー(ヘキサン→1:1EtOAc/ヘキサン)で精製して白色固体の標記化合物(1.2g、54%)を得た。
8−ニトロ−4H−ベンゾ[b]ピロロ[1,2−d][1,4]オキサジン(P−3)の合成
250mL丸底フラスコ中で、1−(2−フルオロ−5−ニトロフェニル)−1H−ピロール−2−カルボアルデヒド(3.95g、16.9mmol)をエタノール(100mL)に懸濁し、水素化ホウ素ナトリウム(767mg、20.3mmol、1.2当量)で処理した。得られた混合物を60℃で5時間攪拌した。この反応混合物を周囲温度まで冷却した後、分液漏斗に移し分配した(CH2Cl2//H2O)。有機相をH2O(3x50mL)、食塩水(3x50mL)で洗浄し、Na2SO4上で乾燥後、減圧下蒸発させ淡黄色の残渣を得た。残渣をフラッシュクロマトグラフィー(ヘキサン→1:9EtOAc/ヘキサン)で精製して淡黄色固体の標記化合物(2.5g、68%)を得た。
1H NMR (DMSO−d6 , 300 MHz) 8.53 (d, 1H), 7.96 (dd, 1H), 7.77 (s, 1H), 7.26 (d, 1H), 6.35 (t, 1H), 6.14 (s, 1H), 5.33 (s, 2H); MS (ES) 217 (M+H).
4H−ベンゾ[b]ピロロ[1,2−d][1,4]オキサジン−8−アミン(P−4)の合成
1H NMR (DMSO−d6 , 300 MHz) 7.21 (t, 1H), 6.76 (s, 1H), 6.74 (d, 1H), 6.29 (dd, 1H), 6.23 (t, 1H), 6.01 (s, 1H), 4.97 (s, 2H), 4.88 (s, 2H); MS (ES) 187 (M+H).
N2−(4H−ベンゾ[b]ピロロ[1,2−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン(化合物1〜4)の合成
1H NMR (DMSO−d6 , 300 MHz) 8.88 (s, 1H), 8.34 (s, 1H), 7.85 (d, 1H), 7.46 (d, 1H), 7.18−7.19 (m, 2H), 6.86 (d, 1H), 6.23−6.28 (m, 2H), 6.05 (s, 1H), 5.05 (s, 2H), 4.35−4.40 (m, 1H), 1.78 (d, 2H), 1.35 (t, 2H), 1.20 (s, 6H), 1.17 (s, 6H); MS (ES) 437 (M+H).
N2−(4H−ベンゾ[b]ピロロ[1,2−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン(化合物1〜3)のスペクトルデータ
1H NMR (DMSO−d6 , 300 MHz) 8.83 (s, 1H), 7.83 (d, 1H), 7.66 (d, 1H), 7.52 (dd, 1H), 7.23 (s, 1H), 7.14 (d, 1H), 6.86 (d, 1H), 6.25 (t, 1H), 6.05 (s, 1H), 5.06 (s, 2H), 4.31−4.33 (m, 1H), 2.15 (s, 3H), 1.67 (dd, 2H), 1.43 (t, 2H), 1.05 (s, 6H), 0.97 (s, 6H); MS (ES) 451 (M+H).
N2−(4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−((1,2,2,5,5−ペンタメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミンの合成
N2−(4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−((2,2,5,5−テトラメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミンの合成
1H NMR (DMSO−d6, 300 MHz) 9.39 (s, 1H), 8.60 (s, 1H), 7.88 (s, 1H), 7.55 (d, 1H), 7.45 (s, br, 1H), 7.19 (d, 1H), 5.75 (s, 2H), 3.48 (m, br, 1H), 2.10 (m, 1H), 1.90 (m, 1H), 1.65 (m, 1H), 1.30 (dd, 2H), 1.20 (s, 6H), 1.15 (s, 3H), 1.10 (s, 3H) ppm; MS (ES) 440.49 (M+H).
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−((1,2,2,5,5−ペンタメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミンの合成
1H NMR (DMSO−d6, 300 MHz) 9.32 (s, 1H), 8.60 (s, 1H), 7.88 (s, 1H), 7.58 (d, 1H), 7.44 (s, br, 1H), 7.10 (d, 1H), 3.50 (m, 1H), 2.10 (m, 1H), 2.05 (s, 3H), 1.80 (m, 1H), 1.72 (s, 6H), 1.42 (t, 1H), 1.04 (m, 1H), 1.00 (s, 6H), 0.92 (s, 3H), 0.80 (s, 3H) ppm; MS (ES) 482.57 (M+H).
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−((2,2,5,5−テトラメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミンの合成
1H NMR (DMSO−d6, 300 MHz) 9.34 (s, 1H), 8.62 (s, 1H), 7.88 (s, 1H), 7.56 (d, 1H), 7.46 (s, br, 1H), 7.12 (d, 1H), 3.45 (m, 1H), 2.24 (m, 1H), 1.80 (m, 1H), 1.70−1.75 (m, 7H), 1.56 (t, 2H), 1.09 (s, 3H), 1.06 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H) ppm; MS (ES) 468.54 (M+H).
化合物1−1および1−2を次のスキームに従って合成した。
N2−(4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン(化合物1−1)の合成
1H NMR (DMSO−d6, 300 MHz) 8.65 (d, 1H), 8.26 (d, 1H), 8.01 (d, 1H), 7.81 (bs, 1H), 7.76 (bs, 1H), 7.63 (dd, 1H), 7.19 (d, 1H), 5.72 (s, 2H), 4.47 (m, 1H), 2.05−1.85 (d, 2H), 1.65−1.51 (t, 2H), 1.42 (d, 12H) ppm; MS (ES) 440 (M+H)9
N2−(4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン(化合物1−2)の合成
1H NMR (DMSO−d6, 300 MHz) 9.51 (s, 1H), 8.32 (s, 1H), 8.01 (d, 1H), 7.91 (d, 1H), 7.36 (d, 1H), 7.09 (d, 1H), 5.72 (s, 2H), 4.47 (m, 1H), 2.28 (s, 3H), 2.11−2.05 (d, 2H), 1.85−1.71 (t, 2H), 1.35 (d, 12H) ppm; MS (ES) 454 (M+H).
この実施例は化合物1−11および1−12の合成に関して記載している。この合成は実施例7と8で示されたものと類似である。次のスキームはこの化合物に使用される合成法の概要を示す。
2,1−スピロ−ブタン−6−ニトロ−2H−ベンゾ[b][1,4]オキサジン−3(4H)−オン(P−5)の合成
1H NMR (DMSO, 300 MHz) 11.0 (s, 1H), 8.4−8.1 (d, J=8.7Hz, 1H), 7.7 (s, 1H), 7.21−7.18 (d, J=8.7Hz, 1H), 2.54 (bs (2H), 2.34−2.24 (m, 2H), 1.96−1.89 (m, 1H), 1.84−1.75 (m, 1H)ppm; MS (ES) 235.23 (M+H)
2,1−スピロ−ブタン−6−ニトロ−2H−ベンゾ[b][1,4]オキサジン−3(4H)−チオン(P−6)の合成
1H NMR (DMSO, 300 MHz) 7.95−7.93 (d, J=8.7Hz, 1H), 7.89 (s, 1H), 7.29−7.26 (d, J=9.0Hz, 1H), 2.78−2.71 (m, 2H), 2.4−2.3 (m, 2H), 1.99−1.85 (m, 2H)ppm; MS (ES) 251.23 (M+H)
2,1−スピロ−ブタン−8−ニトロ−4H−テトラゾロ[5,1−c][1,4]ベンゾオキサジン(P−7)の合成
1H NMR (DMSO, 300 MHz) 8.57 (s, 1H), 8.29−8.26 (d, J=9.3Hz, 1H), 7.5−7.47 (d, J=9.0Hz, 1H), 2.78−2.73 (t, J=8.1Hz, 4H), 2.1−2.05 (m, 2H)ppm; MS (ES) 260.27 (M+H)
8−アミノ−2、1−スピロ−ブタン−4H−テトラゾロ[5,1−c][1,4]ベンゾオキサジン(P−8)の合成
1H NMR (DMSO, 300 MHz) 7.09 (s, 1H), 7.0−6.97 (d, J=8.7Hz, 1H), 6.59−6.56 (d, J=9.0Hz, 1H), 5.36 (s, 2H), 2.61−2.55 (m, 4H), 2.02−1.96 (m, 2H)ppm; MS (ES) 230.24 (M+H)
N2−{2,1−スピロ−ブタン−4H−テトラゾロ[5,1−c][1,4]ベンゾオキサジン−8−イル}−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)−2,4−ピリミジンジアミン(化合物1−12)の合成
1H NMR (DMSO, 300 MHz) 9.25 (s, 1H), 8.24 (s, 1H), 7.88−7.87 (d, J=3.6Hz, 1H), 7.77−7.74 (d, J=9.0Hz, 1H), 7.23−7.2 (d, J=8.4Hz, 1H), 7.13−7.1 (d, J=8.7Hz, 1H), 4.36 (bs, 1H), 2.66−2.61 (t, J=8.1Hz, 4H), 2.13 (s, 3H), 2.05−2.02 (m, 2H), 1.7−1.67 (d, J=10.2Hz, 2H), 1.47−1.39 (t, J=12.3Hz, 2H), 1.04 (s, 6H), 0.97 (s, 6H)ppm; MS (ES) 495.58 (M+H)
N2−{2,1−スピロ−ブタン−4H−テトラゾロ[5,1−c][1,4]ベンゾオキサジン−8−イル}−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)−2,4−ピリミジンジアミン(化合物1−13)の合成
1H NMR (DMSO, 300 MHz) 9.25 (s, 1H), 8.24 (s, 1H), 7.88−7.86 (d, J=3.9Hz, 1H), 7.76−7.73 (d, J=9.0Hz, 1H), 7.23−7.2 (d, J=8.7Hz, 1H), 7.13−7.1 (d, J=9.0Hz, 1H), 4.38 (bs, 1H), 2.65−2.6 (t, J=7.5, 4H), 2.03−2.01 (m, 2H), 1.71−1.68 (d, J=9.9Hz, 2H), 1.19−1.14 (t, J=7.5Hz, 2H), 1.1 (s, 6H), 1.01 (s, 6H)ppm; MS (ES) 480.50 (M+H)
2,2−ジフルオロ−6−ニトロ−2H−ベンゾ[b][1,4]オキサジン−3(4H)−チオン(P−9)の合成
1H NMR (DMSO, 300 MHz) 8.1−8.07 (d, J=9.0Hz, 1H), 8.05−8.04 (d, J=2.7Hz, 1H), 7.63−7.6 (d, J=9.0Hz, 1H)ppm; MS (ES) 247.18 (M+H)
4,4−ジフルオロ−8−ニトロ−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン(P−10)の合成
1H NMR (DMSO, 300 MHz) 8.82 (s, 1H), 8.49−8.46 (d, J=9.3Hz, 1H), 7.95−7.92 (d, J=9.0Hz, 1H)ppm; MS (ES) 256.12 (M+H)
4,4−ジフルオロ−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−アミン(P−11)の合成
1H NMR (DMSO, 300 MHz) 7.3−7.27 (d, J=9.0Hz, 1H), 7.26 (s, 1H), 6.75−6.72 (d, J=9.0Hz, 1H), 5.7 (s, 2H)ppm; MS (ES) 226.19 (M+H)
N2−(4,4−ジフルオロ−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミンの合成
1H NMR (DMSO, 300 MHz) 9.45 (s, 1H), 8.5 (s, 1H), 7.98−7.92 (m, 2H), 7.47−7.44 (d, J=9.0Hz, 1H), 7.31−7.29 (d, J=7.5Hz, 1H), 4.36 (bs, 1H), 2.18 (s, 3H), 1.73−1.69 (d, J=11.7Hz, 2H), 1.51−1.43 (t, J=11.7Hz, 2H), 1.07 (s, 6H), 1.03 (s, 6H)ppm; MS (ES) 490.07 (M+H)
N2−(4,4−ジフルオロ−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミンの合成
1H NMR (DMSO, 300 MHz) 9.47 (s, 1H), 8.52 (s, 1H), 7.95−7.92 (m, 2H), 7.49−7.46 (d, J=9.0Hz, 1H), 7.42−7.39 (d, J=8.4Hz, 1H), 4.46 (bs, 1H), 1.82−1.76 (d, J=9.9Hz, 2H), 1.38−1.3 (t, J=12.3Hz, 2H), 1.26 (s, 6H), 1.16 (s, 6H)ppm; MS (ES) 476.10 (M+H)
2,2−ジメチル−6−ニトロ−2H−ベンゾ[b][1,4]オキサジン−3(4H)−チオン(P−12)の合成
1H NMR (DMSO, 300 MHz) 7.95−7.92 (m, 2H), 7.19−7.17 (d, J=8.1Hz, 1H), 1.59 (s, 6H)ppm; MS (ES) 239.20 (M+H)
4,4−ジメチル−8−ニトロ−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン(P−13)の合成
1H NMR (DMSO, 300 MHz) 8.6 (s, 1H), 8.3−8.27 (d, J=9.3Hz, 1H), 7.48−7.45 (d, J=9.0Hz, 1H), 1.83 (s, 6H)ppm; MS (ES) 248.22 (M+H)
4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−アミン(P−14)の合成
1H NMR (DMSO, 300 MHz) 7.1 (s, 1H), 6.94−6.91 (d, J=8.7Hz, 1H), 6.59−6.57 (d, J=8.7Hz, 1H), 5.34 (s, 2H), 1.67 (s, 6H)ppm; MS (ES) 218.28 (M+H)
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミンの合成
1H NMR (DMSO, 300 MHz) 9.25 (s, 1H), 8.27 (s, 1H), 7.88−7.86 (d, J=3.9Hz, 1H), 7.74−7.71 (d, J=9.0Hz, 1H), 7.21−7.19 (d, J=7.8Hz, 1H), 7.08−7.05 (d, J=9.0Hz, 1H), 4.35 (bs, 1H), 2.12 (s, 3H), 1.72−1.67 (m, 8H), 1.47−1.39 (t, J=12.3Hz, 2H), 1.04 (s, 6H), 0.95 (s, 6H)ppm; MS (ES) 482.34 (M+H)
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミンの合成
1H NMR (DMSO, 300 MHz) 9.25 (s, 1H), 8.27 (s, 1H), 7.88−7.87 (d, J=3.6Hz, 1H), 7.74−7.7 (d, J=9.3Hz, 1H), 7.25−7.22 (d, J=8.1Hz, 1H), 7.08−7.05 (d, J=9.0Hz, 1H), 4.39 (bs, 1H), 1.71 (bs, 8H), 1.23−1.14 (t, J=12.6Hz, 2H), 1.11 (s, 6H), 1.04 (s, 6H)ppm; MS (ES) 468.10 (M+H)
代表的化合物のアッセイ
いくつかの被験化合物で「機能特性評価」節の手順に従って試験を行った。適切なイソ型を伴ったA.1項(プロテインキナーゼCアッセイ)手順を使ってPKCキナーゼ活性を測定した。全細胞アッセイをA.2項(IL−2ELISA、ヒト一次T細胞、抗CD3+CD28+アッセイ)の手順に従って実施した。表1および表2から抜き出した特定の化合物のアッセイデータを表5に示した。この表で「A」は指定されたアッセイ法によるIC50値が0.25μM未満;「B」は0.25〜0.5μM;「C」は0.5〜1μM;および「D」は1μM〜5μMを意味する。ブランクはIC50を測定しなかったことを意味する。
Claims (25)
- 式(I)
式中、
R1は水素、アルキル、アルケニル、アルキニル、シクロアルキル、−C(O)OR1a、−S(O)R1b、および−S(O)2R1cから選択され;ここで各R1a、R1b、およびR1cは独立に水素、アルキルまたはフェニル−アルキルであり;
Ra、Rb、RcおよびRdは水素およびアルキルから独立に選択され;
mは1〜5の整数であり;
pは0〜6の整数であり;
R2はアシルオキシ、ヒドロキシ、チオール、アシル、アルキル、アルコキシ、置換アルキル、置換アルコキシ、アミノ、置換アミノ、アミノアシル、アシルアミノ、アジド、カルボキシル、カルボキシルアルキル、シアノ、ハロゲン、ニトロ、アミノアシルオキシ、オキシアシルアミノ、チオアルコキシ、置換チオアルコキシ、−SO−アルキル、−SO−置換アルキル、−SO−アリール、−SO−ヘテロアリール、−SO2−アルキル、−SO2−置換アルキル、−SO2−アリール、−SO2−ヘテロアリール、およびトリハロメチルから選択され;
X1、X2、およびX3はCR5または、X1、X2、およびX3の1つがNで残りがCR5であり;
R5は水素、ハロゲン、アルキルおよび置換アルキルから選択され;
R3およびR4は、各生成に関して、独立に、水素、アルキル、置換アルキル、アルコキシ、置換アルコキシ、アシル、アシルアミノ、アシルオキシ、アミノ、置換アミノ、アミノアシル、アミノアシルオキシ、オキシアミノアシル、アジド、シアノ、ハロゲン、ヒドロキシル、オキソ、チオケト、カルボキシル、カルボキシルアルキル、チオール、チオアルコキシ、置換チオアルコキシ、アリール、アリールオキシ、ヒドロキシアミノ、アルコキシアミノ、ニトロ、−SO−アルキル、−SO−置換アルキル、−SO−アリール、−SO−ヘテロアリール、−SO2−アルキル、−SO2−置換アルキル、−SO2−アリールおよび-SO2−ヘテロアリールから選択され;または、R3およびR4はこれらと結合した炭素原子と共に炭素環式または複素環式4〜8員環を形成しており;
nは1〜3の整数であり;
Z1、Z2、およびZ3はCR6R6a、N、O、およびSから選択され;
Z4およびZ5はN、C、およびCR6から選択され;
R6は水素、ハロゲン、アルキルおよび置換アルキルから選択され;
R6aは水素、ハロゲン、アルキルおよび置換アルキルから選択されるか、または原子価要件を満たすために欠けており;かつ
Z 1 とZ 2 、Z 2 とZ 3 、Z 3 とZ 4 、Z 4 とZ 5 、およびZ 5 とZ 1 の間の結合はそれぞれ単結合または二重結合である化合物。 - Ra、Rb、RcおよびRdが1〜6個の炭素原子を有するアルキル基である請求項1に記載の化合物。
- R1が水素およびアルキルから選択される請求項1に記載の化合物。
- mが1および2から選択された整数である請求項1に記載の化合物。
- pが0および1から選択された整数である請求項1に記載の化合物。
- R2がヒドロキシ、アルキル、アルコキシ、シアノ、ハロゲン、ニトロ、およびトリハロメチルから選択される請求項1に記載の化合物。
- R2がハロゲンである請求項1に記載の化合物。
- X1、X2、およびX3がCHである請求項1に記載の化合物。
- X1、X2、およびX3の内の1つがNで残りがCHである請求項1に記載の化合物。
- nが1である請求項1に記載の化合物。
- nが2である請求項1に記載の化合物。
- R3およびR4が各出現に関して独立に、水素、アルキル、置換アルキル、アルコキシ、置換アルコキシ、シアノ、ハロゲン、ヒドロキシル、およびニトロから選択される請求項1に記載の化合物。
- R3およびR4が各出現に関して独立に、水素、アルキル、およびハロゲンから選択される請求項1に記載の化合物。
- Z1、Z2、およびZ3が独立にCR6およびNから選択され、ここでR6が水素、ハロゲン、アルキル、および置換アルキルから選択される請求項1に記載の化合物。
- Z1、Z2、およびZ3がそれぞれNである請求項1に記載の化合物。
- Z1、Z2、およびZ3がそれぞれCHである請求項1に記載の化合物。
- Z4がNである請求項1に記載の化合物。
- Z4がCである請求項1に記載の化合物。
- Z5がNである請求項1に記載の化合物。
- Z5がCである請求項1に記載の化合物。
- N2−(4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2、4−ジアミン;
N2−(4H−ベンゾ[b]ピロロ[1,2−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(4H−ベンゾ[b]ピロロ[1,2−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(4,4−ジフルオロ−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(4,4−ジフルオロ−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(5,5−ジメチル−5H−ベンゾ[e]テトラゾロ[1,5−c][1,3]オキサジン−9−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(5,5−ジメチル−5H−ベンゾ[e]テトラゾロ[1,5−c][1,3]オキサジン−9−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(8,9−ジヒドロスピロ[ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−4,1'−シクロブタン]−8−イル)−5−フルオロ−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
N2−(8,9−ジヒドロスピロ[ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−4,1'−シクロブタン]−8−イル)−5−フルオロ−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
5−フルオロ−N2−(4−メチル−8,9−ジヒドロ−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−N4−(2,2,6,6−テトラメチルピペリジン−4−イル)ピリミジン−2,4−ジアミン;
5−フルオロ−N2−(4−メチル−8,9−ジヒドロ−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−N4−(1,2,2,6,6−ペンタメチルピペリジン−4−イル)ピリミジン−2、4−ジアミン;
N2−(4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−((1,2,2,5,5−ペンタメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミン;
N2−(4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−((2,2,5,5−テトラメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミン;
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−((1,2,2,5,5−ペンタメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミン;
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−((2,2,5,5−テトラメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミン;
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(((3S)−2,2,5−トリメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミン;および
N2−(4,4−ジメチル−4H−ベンゾ[b]テトラゾロ[1,5−d][1,4]オキサジン−8−イル)−5−フルオロ−N4−(((3R)−2,2,5−トリメチルピロリジン−3−イル)メチル)ピリミジン−2,4−ジアミン;
から選択される請求項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医薬組成物。
- 請求項1に記載の化合物を含有する、生物学的試料または患者においてプロテインキナーゼC(PKC)活性を阻害するための医薬組成物。
- 有効量のSykキナーゼ阻害化合物と共に被験者に投与される請求項23に記載の医薬組成物。
- 式(I)
式中、
R1は水素、アルキル、アルケニル、アルキニル、シクロアルキル、−C(O)OR1a、−S(O)R1b、および−S(O)2R1cから選択され;ここで各R1a、R1b、およびR1cは独立に水素、アルキルまたはフェニル−アルキルであり;
Ra、Rb、RcおよびRdは水素およびアルキルから独立に選択され;
mは1〜5の整数であり;
pは0〜6の整数であり;
R2はアシルオキシ、ヒドロキシ、チオール、アシル、アルキル、アルコキシ、置換アルキル、置換アルコキシ、アミノ、置換アミノ、アミノアシル、アシルアミノ、アジド、カルボキシル、カルボキシルアルキル、シアノ、ハロゲン、ニトロ、アミノアシルオキシ、オキシアシルアミノ、チオアルコキシ、置換チオアルコキシ、−SO−アルキル、−SO−置換アルキル、−SO−アリール、−SO−ヘテロアリール、−SO2−アルキル、−SO2−置換アルキル、−SO2−アリール、−SO2−ヘテロアリール、およびトリハロメチルから選択され;
X1、X2、およびX3はCR5または、X1、X2、およびX3の1つがNで残りがCR5であり;
R5は水素、ハロゲン、アルキルおよび置換アルキルから選択され;
R3およびR4は、各生成に関して、独立に、水素、アルキル、置換アルキル、アルコキシ、置換アルコキシ、アシル、アシルアミノ、アシルオキシ、アミノ、置換アミノ、アミノアシル、アミノアシルオキシ、オキシアミノアシル、アジド、シアノ、ハロゲン、ヒドロキシル、オキソ、チオケト、カルボキシル、カルボキシルアルキル、チオール、チオアルコキシ、置換チオアルコキシ、アリール、アリールオキシ、ヒドロキシアミノ、アルコキシアミノ、ニトロ、−SO−アルキル、−SO−置換アルキル、−SO−アリール、−SO−ヘテロアリール、−SO2−アルキル、−SO2−置換アルキル、−SO2−アリールおよび-SO2−ヘテロアリールから選択され;または、R3およびR4はこれらと結合した炭素原子と共に炭素環式または複素環式4〜8員環を形成しており;
nは1〜3の整数であり;
Z1、Z2、およびZ3はCR6R6a、N、O、およびSから選択され;
Z4およびZ5はN、C、およびCR6から選択され;
R6は水素、ハロゲン、アルキルおよび置換アルキルから選択され;
R6aは水素、ハロゲン、アルキルおよび置換アルキルから選択されるか、または原子価要件を満たすために欠けており;かつ
Z 1 とZ 2 、Z 2 とZ 3 、Z 3 とZ 4 、Z 4 とZ 5 、およびZ 5 とZ 1 の間の結合はそれぞれ単結合または二重結合であり、
前記調製方法が:
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RU2014130214A (ru) | 2011-12-23 | 2016-02-10 | Целльзом Лимитид | Пиримидин-2, 4-диаминовые производные в качестве ингибиторов киназы |
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CN107106517A (zh) | 2014-08-25 | 2017-08-29 | 堪培拉大学 | 用于调节癌干细胞的组合物及其用途 |
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US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
WO2020168197A1 (en) | 2019-02-15 | 2020-08-20 | Incyte Corporation | Pyrrolo[2,3-d]pyrimidinone compounds as cdk2 inhibitors |
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US11919904B2 (en) | 2019-03-29 | 2024-03-05 | Incyte Corporation | Sulfonylamide compounds as CDK2 inhibitors |
US11440914B2 (en) | 2019-05-01 | 2022-09-13 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
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US11981671B2 (en) | 2021-06-21 | 2024-05-14 | Incyte Corporation | Bicyclic pyrazolyl amines as CDK2 inhibitors |
US11976073B2 (en) | 2021-12-10 | 2024-05-07 | Incyte Corporation | Bicyclic amines as CDK2 inhibitors |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
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US7122542B2 (en) * | 2003-07-30 | 2006-10-17 | Rigel Pharmaceuticals, Inc. | Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds |
JP4741491B2 (ja) * | 2003-08-07 | 2011-08-03 | 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 | 抗増殖剤としての2,4−ピリミジンジアミン化合物および使用 |
US7601714B2 (en) * | 2004-07-08 | 2009-10-13 | Boehringer Ingelheim Pharmaceuticals, Inc. | Pyrimidine derivatives useful as inhibitors of PKC-theta |
CN1998221A (zh) | 2004-08-03 | 2007-07-11 | 诺基亚公司 | 移动通信和/或游戏终端 |
KR20070085407A (ko) * | 2004-10-21 | 2007-08-27 | 버텍스 파마슈티칼스 인코포레이티드 | 단백질 키나아제의 억제제로서 유용한 트리아졸 |
US8227455B2 (en) * | 2005-04-18 | 2012-07-24 | Rigel Pharmaceuticals, Inc. | Methods of treating cell proliferative disorders |
WO2006129100A1 (en) * | 2005-06-03 | 2006-12-07 | Glaxo Group Limited | Novel compounds |
NZ563454A (en) * | 2005-06-08 | 2011-03-31 | Rigel Pharmaceuticals Inc | 2,4-diaminopyrimidine derivatives for inhibition of the JAK pathway |
EP1896368B1 (en) | 2005-06-28 | 2013-05-01 | Afognak Native Corporation | Method and apparatus for automated, modular, biomass power generation |
WO2007028445A1 (en) * | 2005-07-15 | 2007-03-15 | Glaxo Group Limited | 6-indolyl-4-yl-amino-5-halogeno-2-pyrimidinyl-amino derivatives |
AU2007257650A1 (en) | 2006-06-15 | 2007-12-21 | Boehringer Ingelheim International Gmbh | 2-anilino-4-(heterocyclic)amino-pyrimidines as inhibitors of protein kinase C-alpha |
DE602007013399D1 (de) | 2006-06-28 | 2011-05-05 | Univ Alberta | Titanium-silicat-materialien, verfahren zu deren herstellung und verfahren zur verwendung der titanium-silicat-materialien für adsorptive flüssigkeitstrennungen |
WO2008024634A1 (en) * | 2006-08-25 | 2008-02-28 | Smithkline Beecham Corporation | Pyrimdine compounds useful as kinase inhibitors |
ITVI20070184A1 (it) | 2007-06-27 | 2008-12-28 | Simec Spa | Puleggia per macchine utensili multifilo. |
AU2008275918B2 (en) * | 2007-07-17 | 2014-01-30 | Rigel Pharmaceuticals, Inc. | Cyclic amine substituted pyrimidinediamines as PKC inhibitors |
CA2749248A1 (en) * | 2009-01-14 | 2010-07-22 | Rigel Pharmaceuticals, Inc. | Methods for treating inflammatory disorders using 2,4-pyrimidinediamine compounds |
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CA2749195C (en) | 2017-03-07 |
US20130143875A1 (en) | 2013-06-06 |
EP2387572A2 (en) | 2011-11-23 |
US8394951B2 (en) | 2013-03-12 |
EP2387572B1 (en) | 2015-09-16 |
WO2010083207A3 (en) | 2010-11-04 |
CN102292333A (zh) | 2011-12-21 |
ES2555982T3 (es) | 2016-01-12 |
US20150376203A1 (en) | 2015-12-31 |
CA2749195A1 (en) | 2010-07-22 |
US9453028B2 (en) | 2016-09-27 |
JP2012515206A (ja) | 2012-07-05 |
CN102292333B (zh) | 2015-05-13 |
US20100184755A1 (en) | 2010-07-22 |
US9095593B2 (en) | 2015-08-04 |
WO2010083207A2 (en) | 2010-07-22 |
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