JP6410819B2 - 置換オキソピリジン誘導体および第XIa因子/血漿としてのその使用 - Google Patents
置換オキソピリジン誘導体および第XIa因子/血漿としてのその使用 Download PDFInfo
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- JP6410819B2 JP6410819B2 JP2016528481A JP2016528481A JP6410819B2 JP 6410819 B2 JP6410819 B2 JP 6410819B2 JP 2016528481 A JP2016528481 A JP 2016528481A JP 2016528481 A JP2016528481 A JP 2016528481A JP 6410819 B2 JP6410819 B2 JP 6410819B2
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-
- A—HUMAN NECESSITIES
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Description
ここで*はオキソピリジン環への連結点であり、
R6は、臭素、塩素、フッ素、メチル、ジフルオロメチル、トリフルオロメチル、メトキシ、ジフルオロメトキシまたはトリフルオロメトキシを表し、
R7は、水素、臭素、塩素、フッ素、シアノ、ニトロ、ヒドロキシ、メチル、ジフルオロメチル、トリフルオロメチル、メトキシ、エトキシ、ジフルオロメトキシ、トリフルオロメトキシ、エチニル、3,3,3−トリフルオロプロプ−1−イン−1−イルまたはシクロプロピルを表し、
R8は、水素、塩素またはフッ素を表し、
R3は水素を表し、
R4は水素を表し、
R5は、式
ここで#は窒素原子への連結部位であり、
R9は、ヒドロキシカルボニルまたは5員ヘテロシクリルを表し、
ここで、ヘテロシクリルは、互いに独立に、オキソ、ヒドロキシ、チオキソ、スルファニル、メチル、ジフルオロメチル、トリフルオロメチル、2−ヒドロキシカルボニル−1,1,2,2−テトラフルオロエチルおよび2−メトキシカルボニル−1,1,2,2−テトラフルオロエチルからなる群から選択される1から2個の置換基により置換され得、
ここでメチルは、メトキシ置換基により置換され得、
R10は、水素、塩素、フッ素またはメチルを表し、
R11およびR12は、それらが結合される炭素原子と一緒に5員複素環を形成し、
ここで、複素環は、互いに独立に、オキソ、塩素、ヒドロキシ、ヒドロキシカルボニル、メチル、ジフルオロメチル、トリフルオロメチル、1,1,2,2,2−ペンタフルオロエチル、2−ヒドロキシカルボニル−1,1,2,2−テトラフルオロエチルおよび2−メトキシカルボニル−1,1,2,2−テトラフルオロエチルからなる群から選択される1から2個の置換基により置換され得、
R13は、水素、塩素、フッ素、メチルまたはメトキシを表す。)
およびそれらの塩、それらの溶媒和物およびそれらの塩の溶媒和物を提供する。
アルキルは、1から5個の炭素原子、好ましくは1から3個の炭素原子を有する直鎖状または分岐状アルキルラジカルを表し、例となるもの、および好ましいのは、メチル、エチル、n−プロピル、イソプロピル、2−メチルプロプ−1−イル、n−ブチル、tert−ブチルおよび2,2−ジメチルプロプ−1−イルである。
ここで*がオキソピリジン環への連結点であり、
R6が、臭素、塩素、フッ素、メチル、ジフルオロメチル、トリフルオロメチル、メトキシ、ジフルオロメトキシまたはトリフルオロメトキシを表し、
R7が、水素、臭素、塩素、フッ素、シアノ、ニトロ、ヒドロキシ、メチル、ジフルオロメチル、トリフルオロメチル、メトキシ、ジフルオロメトキシ、トリフルオロメトキシ、エチニル、3,3,3−トリフルオロプロプ−1−イン−1−イルまたはシクロプロピルを表し、
R8が、水素、塩素またはフッ素を表し、
R3が水素を表し、
R4が水素を表し、
R5が、式
ここで#が窒素原子への連結部位であり、
R9が、ヒドロキシカルボニルまたは5員ヘテロシクリルを表し、
ここで、ヘテロシクリルが、互いに独立に、オキソ、ヒドロキシ、メチル、ジフルオロメチルおよびトリフルオロメチルからなる群から選択される1から2個の置換基により置換され得、
ここでメチルが、メトキシ置換基により置換され得、
R10が、水素、塩素、フッ素またはメチルを表し、
R11およびR12が、それらが結合される炭素原子と一緒に5員複素環を形成し、
ここで、複素環が、互いに独立に、オキソ、ヒドロキシ、メチル、ジフルオロメチル、トリフルオロメチルおよび1,1,2,2,2−ペンタフルオロエチルからなる群から選択される1から2個の置換基により置換され得、
R13が、水素、塩素、フッ素またはメチルを表す、式(I)の化合物
およびそれらの塩、それらの溶媒和物およびそれらの塩の溶媒和物が好ましい。
R6が塩素を表し、
R7が、水素、臭素、塩素、シアノ、メチル、ジフルオロメチル、トリフルオロメチル、ジフルオロメトキシまたはトリフルオロメトキシを表し、
R8が、水素またはフッ素を表し、
R3が水素を表し、
R4が水素を表し、
R5が、式
ここで#が窒素原子への連結部位であり、
R9が、ヒドロキシカルボニル、オキサジアゾリル、ピラゾリル、イミダゾリル、トリアゾリルまたはテトラゾリルを表し、
ここでオキサジアゾリル、ピラゾリル、イミダゾリルおよびトリアゾリルが、互いに独立に、オキソ、ヒドロキシ、メチルおよびトリフルオロメチルからなる群から選択される1から2個の置換基により置換され得、
R10が水素を表す、式(I)の化合物
およびそれらの塩、それらの溶媒和物およびそれらの塩の溶媒和物も好ましい。
ここで#が窒素原子への連結部位であり、
R9が、ヒドロキシカルボニル、オキサジアゾリル、ピラゾリルまたはテトラゾリルを表し、
ここでオキサジアゾリルおよびピラゾリルが、互いに独立に、オキソ、ヒドロキシおよびトリフルオロメチルからなる群から選択される1から2個の置換基により置換され得、
R10が水素を表す、式(I)の化合物
およびそれらの塩、それらの溶媒和物およびそれらの塩の溶媒和物も好ましい。
ここで*がオキソピリジン環への連結点であり、
R6が塩素を表し、
R7が臭素またはシアノを表し、
R8が水素を表す、式(I)の化合物も好ましい。
R6が塩素を表し、
R7がシアノまたはジフルオロメトキシを表し、
R8が水素を表す、式(I)の化合物も好ましい。
ここで#が窒素原子に対する連結部位であり、
R9がヒドロキシカルボニル、オキサジアゾリル、ピラゾリル、イミダゾリル、トリアゾリルまたはテトラゾリルを表し、
ここでオキサジアゾリル、ピラゾリル、イミダゾリルおよびトリアゾリルが、互いに独立に、オキソ、ヒドロキシ、メチルおよびトリフルオロメチルからなる群から選択される1から2個の置換基により置換され得、
R10が水素を表す、式(I)の化合物も好ましい。
R9がヒドロキシカルボニル、オキサジアゾリル、ピラゾリルまたはテトラゾリルを表し、
ここでオキサジアゾリルおよびピラゾリルが、互いに独立に、オキソ、ヒドロキシおよびトリフルオロメチルからなる群から選択される1から2個の置換基により置換され得、
R10が水素を表す、式(I)の化合物も好ましい。
n、A、R1、R3、R4およびR5は、それぞれ上記で定義されるとおりである。)
を酸化剤と反応させる。
R4およびR10は、それぞれ上記で定義されるとおりであり、
R14はメチル、エチルまたはtert−ブチルを表す。)
と脱水試薬の存在下で反応させることによって調製され得る。本反応は、工程[C]に対して記載のとおりに行われる。
n、A、R1およびR3は、それぞれ上記で定義されるとおりであり、
R15はメチルまたはエチルを表す。)
を塩基と反応させることによって調製され得る。
R3は、上記で与えられる意味を有し、
R15は、メチル、エチルまたはtert−ブチルを表し、
X1は、塩素、臭素、ヨウ素、メタンスルホニルオキシまたはトリフルオロメタンスルホニルオキシを表す。)
と反応させるか、
または
[I]式
R1は上記で定義されるとおりであり、
Qは、−B(OH)2、ボロン酸エステル、好ましくはボロン酸ピナコールエステルまたは−BF3−K+を表す。)
と鈴木カップリング条件下で反応させることにより、調製され得る。
n、R1およびR3は、それぞれ上記で定義されるとおりであり、
R15は、メチル、エチルまたはtert−ブチルを表し、
R16は、メチルまたはエチルを表す。)
を式R2−NH2(XVII)
の化合物(式中、
R2は上記で与えられる意味を有する。)
と反応させて、式
n、R1、R2およびR3は、それぞれ上記で定義されるとおりであり、
R15は、メチル、エチルまたはtert−ブチルを表す。)
を与えることにより、調製され得る。
を第一段階で式(XV)の化合物と反応させ、
場合によっては第二段階で脱水剤と反応させることによって調製され得る。
n、A、R1およびR3は、それぞれ上記で定義されるとおりである。)
を式(IV)の化合物と脱水試薬の存在下で反応させることによって調製され得る。
n、A、R1およびR3は、それぞれ上記で定義されるとおりであり、
R15はメチルまたはエチルを表す。)
を塩基と反応させることによって調製され得る。
n、AおよびR1は、それぞれ上記で定義されるとおりである。)
を酸化剤と反応させることによって調製され得る。
n、AおよびR3は、それぞれ上記で定義されるとおりであり、
R15は、メチル、エチルまたはtert−ブチルである。)
をトリフルオロメタンスルホン酸無水物またはN,N−ビス(トリフルオロメタンスルホニル)アニリンと反応させることによって調製され得る。
・脂質低下物質、特にHMG−CoA(3−ヒドロキシ−3−メチルグルタリル−補酵素A)レダクターゼ阻害剤、例えばロバスタチン(Mevacor)、シンバスタチン(Zocor)、プラバスタチン(Pravachol)、フルバスタチン(Lescol)およびアトルバスタチン(Lipitor);
・冠動脈治療薬/血管拡張薬、特にACE(アンジオテンシン変換酵素)阻害剤、例えばカプトプリル、リシノプリル、エナラプリル、ラミプリル、シラザプリル、ベナゼプリル、ホシノプリル、キナプリルおよびペリンドプリルまたはAII(アンジオテンシンII)受容体アンタゴニスト、例えばエンブサルタン、ロサルタン、バルサルタン、イルベサルタン、カンデサルタン、エプロサルタンおよびテミサルタンまたはβ−アドレナリン受容体アンタゴニスト、例えばカルベジロール、アルプレノロール、ビソプロロール、アセブトロール、アテノロール、ベタキソロール、カルテオロール、メトプロロール、ナドロール、ペンブトロール、ピンドロール、プロパノロールおよびチモロールまたはα−1−アドレナリン受容体アンタゴニスト、例えばプラゾシン、ブナゾシン、ドキサゾシンおよびテラゾシンまたは利尿薬、例えばヒドロクロロチアジド、フロセミド、ブメタニド、ピレタニド、トラセミド、アミロリドおよびジヒドララジンまたはカルシウムチャネルブロッカー、例えばベラパミルおよびジルチアゼム、またはジヒドロピリジン誘導体、例えばニフェジピン(Adalat)およびニトレンジピン(Bayotensin)、またはニトロ製剤、例えば5−一硝酸イソソルビド、二硝酸イソソルビドおよび三硝酸グリセリン、または環状グアノシン一リン酸(cGMP)の増加を引き起こす物質、例えば可溶性グアニル酸シクラーゼの刺激物質、例えばリオシグアト;
・プラスミノーゲン活性化物質(血栓溶解薬/線維素溶解薬)および血栓溶解/線維素溶解を促進する化合物、例えばプラスミノーゲン活性化因子阻害剤の阻害剤(PAI阻害剤)またはトロンビン活性化線維素溶解阻害剤の阻害剤(TAFI阻害剤)、例えば組織プラスミノーゲン活性化因子(t−PA、例えばActilyse(登録商標))、ストレプトキナーゼ、レテプラーゼおよびウロキナーゼまたはプラスミンの形成増加を引き起こすプラスミノーゲン修飾物質;
・抗凝固物質(抗凝固薬)、例えばヘパリン(UFH)、低分子量ヘパリン(LMW)、例えばチンザパリン、セルトパリン、パルナパリン、ナドロパリン、アルデパリン、エノキサパリン、レビパリン、ダルテパリン、ダナパロイド、セムロパリン(AVE5026)、アドミパリン(M118)およびEP−42675/ORG42675;
・直接的トロンビン阻害剤(DTI)、例えばプラダキサ(ダビガトラン)、アテセガトラン(AZD−0837)、DP−4088、SSR−182289A、アルガトロバン、ビバリルジンおよびタノギトラン(BIBT−986およびプロドラッグBIBT−1011)、ヒルジン;
・直接的な第Xa因子阻害剤、例えば、リバーロキサバン、アピキサバン、エドキサバン(DU−176b)、ベトリキサバン(PRT−54021)、R−1663、ダレキサバン(YM−150)、オタミキサバン(FXV−673/RPR−130673)、レタキサバン(TAK−442)、ラザキサバン(DPC−906)、DX−9065a、LY−517717、タノギトラン(BIBT−986、プロドラッグ:BIBT−1011)、イドラパリヌクスおよびフォンダパリヌクス、
・血小板の凝集を阻害する物質(血小板(platelet)凝集阻害剤、血小板(thrombocyte)凝集阻害剤)、例えばアセチルサリチル酸(例えばアスピリン)、P2Y12アンタゴニスト、例えばチクロピジン(Ticlid)、クロピドグレル(Plavix)、プラスグレル、チカグレロル、カングレロル、エリノグレル、PAR−1アンタゴニスト、例えばボラパクサール、PAR−4アンタゴニスト、EP3アンタゴニスト、例えばDG041;
・血小板接着阻害剤、例えばGPVIおよび/またはGPIbアンタゴニスト、例えばレバセプトまたはカプラシズマブ;
・フィブリノーゲン受容体アンタゴニスト(糖タンパク質−IIb/IIIaアンタゴニスト)、例えばアブシキシマブ、エピチフィバチド、チロフィバン、ラミフィバン、レフラダフィバンおよびフラダフィバン;
・組み換えヒト活性化プロテインC、例えばキシグリスまたは組み換えトロンボモジュリン;
・およびまた抗不整脈薬;
・VEGFおよび/またはPDGFシグナル経路の阻害剤、例えばアフリベルセプト、ラニビズマブ、ベバシズマブ、KH−902、ペガプタニブ、ラムシルマブ、スクアラミンまたはベバシラニブ、アパチニブ、アキシチニブ、ブリバニブ、セジラニブ、ドビチニブ、レンバチニブ、リニファニブ、モテサニブ、パゾパニブ、レゴラフェニブ、ソラフェニブ、スニチニブ、チボザニブ、バンデタニブ、バタラニブ、バルガテフおよびE−10030;
・アンジオポエチン−Tieシグナル経路の阻害剤、例えばAMG386;
・Tie2受容体チロシンキナーゼの阻害剤;
・インテグリンシグナル経路の阻害剤、例えばボロシキシマブ、シレンギチドおよびALG1001;
・PI3K−Akt−mTorシグナル経路の阻害剤、例えばXL−147、ペリフォシン、MK2206、シロリムス、テムシロリムスおよびエベロリムス;
・コルチコステロイド、例えばアネコルタブ、ベタメタゾン、デキサメタゾン、トリアムシノロン、フルオシノロンおよびフルオシノロンアセトニド;
・ALK1−Smad1/5シグナル経路の阻害剤、例えばACE041;
・シクロオキシゲナーゼ阻害剤、例えば、ブロムフェナクおよびネパフェナク;
・カリクレイン−キニン系の阻害剤、例えばサフォチバントおよびエカランチド;
・スフィンゴシン1−リン酸シグナル経路の阻害剤、例えばソネプシズマブ;
・補体−C5a受容体の阻害剤、例えばエクリズマブ;
・5HT1a受容体の阻害剤、例えばタンドスピロン;
・Ras−Raf−Mek−Erkシグナル経路の阻害剤;MAPKシグナル経路の阻害剤;FGFシグナル経路の阻害剤;内皮細胞増殖の阻害剤;アポトーシス誘導活性化合物;
・活性化合物および光の作用からなる光線力学的治療、活性化合物は例えばベルテポルフィン。
方法1:機器:Waters ACQUITY SQD UPLCシステム;カラム:Waters Acquity UPLC HSS T3 1.8μ 50mm×1mm;移動相A:1Lの水+0.25mLの99%強度ギ酸、移動相B:1Lのアセトニトリル+0.25mLの99%強度ギ酸;勾配:0.0分90%A→1.2分5%A→2.0分5%A;オーブン:50℃;流速:0.40mL/分;UV検出:208から400nm。
一般的方法1A:HATU/ジイソプロピルエチルアミンとのアミドカップリング
アルゴン下およびRTで、適切なアミン(1.1eq.)、N,N−ジイソプロピルエチルアミン(2.2eq.)および少量のDMF中のHATU(1.2eq.)の溶液をジメチルホルムアミド中の適切なカルボン酸(1.0eq.)の溶液(7から15mL/mmol)に添加した。反応混合物をRTで撹拌した。水/酢酸エチルの添加および相分離後、有機相を水および飽和塩化ナトリウム水溶液で洗浄し、乾燥させ(硫酸ナトリウム)、ろ過し、減圧下で濃縮した。次いで、フラッシュクロマトグラフィー(シリカゲル60、移動相:シクロヘキサン/酢酸エチル混合液またはジクロロメタン/メタノール混合液)または分取HPLC(Reprosil C18、水/アセトニトリル勾配または水/メタノール勾配)の何れかによって、粗製生成物を精製した。
RTで、20eq.のTFAをジクロロメタン中の適切なtert−ブチルエステル誘導体の1.0eq.の溶液(約7mL/mmol)に添加し、混合物をRTで1から8時間撹拌した。次いで、反応混合物を減圧下で濃縮し、残渣をジクロロメタンとともに3回共蒸発させ、減圧下で乾燥させた。次いで、フラッシュクロマトグラフィー(シリカゲル60、移動相:シクロヘキサン/酢酸エチル混合液またはジクロロメタン/メタノール混合液)または分取HPLC(Reprosil C18、水/アセトニトリル勾配または水/メタノール勾配)の何れかによって、粗製生成物を任意に精製した。
RTで、3.0eq.の水酸化リチウムをテトラヒドロフラン/水(3:1、約10mL/mmol)中の適切なメチルまたはエチルエステルの1.0eq.の溶液に添加した。反応混合物をRTから60℃で撹拌し、次いで1N塩酸水溶液を用いてpH1に調整した。水/酢酸エチルの添加および相分離後、水相を酢酸エチルで3回抽出した。合わせた有機相を乾燥させ(硫酸ナトリウム)、ろ過し、減圧下で濃縮した。次いで、フラッシュクロマトグラフィー(シリカゲル60、移動相:シクロヘキサン/酢酸エチル混合液またはジクロロメタン/メタノール混合液)または分取HPLC(Reprosil C18、水/アセトニトリル勾配または水/メタノール勾配)の何れかによって、粗製生成物を精製した。
LC−MS[方法1]:Rt=0.44分;MS(ESIpos):m/z=178(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=7.42(d,2H),6.51(d,2H),5.23(s,2H),4.13(br.s,1H).
[実施例1.2A]
4−ニトロベンゼンカルボキシイミドヒドラジド
LC−MS[方法6]:Rt=1.77分;MS(ESIpos):m/z=181(M+H)+。
LC−MS[方法1]:Rt=0.94分;MS(ESIpos):m/z=259(M+H)+。
LC−MS[方法6]:Rt=1.66分;MS(ESIpos):m/z=229(M+H)+。
LC−MS[方法1]:Rt=1.07分;MS(ESIpos):m/z=306(M+H)+。
GC/MS[方法5]:Rt=4.78分;MS(EI):m/z=97。
LC−MS[方法1]:Rt=0.58分;MS(ESIpos):m/z=212(M+H)+。
LC−MS[方法1]:Rt=0.61分;MS(ESIpos):m/z=226(M+H)+。
[実施例3.1A]
メチル4−(3−クロロフェニル)−2−メチル−6−オキソ−1,4,5,6−テトラヒドロピリジン−3−カルボキシレート(ラセミ体)
LC−MS[方法1]:Rt=0.91分;MS(ESIpos):m/z=280(M+H)+。
LC−MS[方法1]:Rt=1.20分;MS(ESIpos):m/z=394(M+H)+。
LC−MS[方法1]:Rt=0.96分;MS(ESIpos):m/z=416(M+H)+。
LC−MS[方法1]:Rt=0.58分;MS(ESIpos):m/z=321(M+H)+。
2−[4−(3−クロロフェニル)−2,5−ジオキソ−2,3,4,5,6,7−ヘキサヒドロ−1H−ピロロ[3,4−b]ピリジン−1−イル]−N−[4−(1H−テトラゾール−5−イル)フェニル]アセトアミド(ラセミ体)
LC−MS[方法1]:Rt=0.75分;MS(ESIpos):m/z=464(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=10.64(s,1H),8.01(d,2H),7.84−7.80(m,3H),7.43(s,1H),7.37−7.28(m,3H),4.59(d,1H),4.36(d,1H),4.12(dd,2H),3.98(d,1H),3.23(dd,1H),2.63(d,1H).
[実施例3.2A]
メチル4−(2,5−ジクロロフェニル)−2−メチル−6−オキソ−1,4,5,6−テトラヒドロピリジン−3−カルボキシレート(ラセミ体)
LC−MS[方法1]:Rt=0.95分;MS(ESIpos):m/z=314(M+H)+。
メチル1−(2−tert−ブトキシ−2−オキソエチル)−4−(2,5−ジクロロフェニル)−2−メチル−6−オキソ−1,4,5,6−テトラヒドロピリジン−3−カルボキシレート(ラセミ体)
LC−MS[方法2]:Rt=1.31分;MS(ESIpos):m/z=371(M+H−tert−ブチル)+。
メチル2−(ブロモメチル)−1−(2−tert−ブトキシ−2−オキソエチル)−4−(2,5−ジクロロフェニル)−6−オキソ−1,4,5,6−テトラヒドロピリジン−3−カルボキシレート(ラセミ体)
LC−MS[方法2]:Rt=1.01分;MS(ESIpos):m/z=450(M+H−tert−ブチル)+。
tert−ブチル[4−(2,5−ジクロロフェニル)−6−メチル−2,5−ジオキソ−2,3,4,5,6,7−ヘキサヒドロ−1H−ピロロ[3,4−b]ピリジン−1−イル]アセテート(ラセミ体)
LC−MS[方法2]:Rt=1.06分;MS(ESIpos):m/z=425(M+H)+。
LC−MS[方法2]:Rt=1.02分;MS(ESIpos):m/z=423(M+H)+。
LC−MS[方法1]:Rt=0.65分;MS(ESIpos):m/z=367(M+H)+。
1H−NMR(400MHz,DMSO−d6):δ[ppm]=8.40(s,1H),7.78(d,1H),7.64(d,1H),7.59(dd,1H),1.79(s,6H).
[実施例4.1B]
tert−ブチル[4−(2,5−ジクロロフェニル)−2,5−ジオキソ−2,3,4,5,6,7−ヘキサヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]アセテート(ラセミ体)
LC−MS[方法1]:Rt=1.12分;MS(ESIpos):m/z=410(M+H)+。
LC−MS[方法1]:Rt=1.08分;MS(ESIpos):m/z=354(M+H−tert−ブチル)+。
2−[4−(2,5−ジクロロフェニル)−2,5−ジオキソ−2,3,4,5,6,7−ヘキサヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]−N−[4−(1H−テトラゾール−5−イル)フェニル]アセトアミド(ラセミ体)
LC−MS[方法1]:Rt=0.87分;MS(ESIpos):m/z=497(M+H)+。
LC−MS[方法1]:Rt=1.10分;MS(ESIpos):m/z=408(M+H)+。
LC−MS[方法1]:Rt=0.72分;MS(ESIpos):m/z=352(M+H)+。
tert−ブチル4−({[4−(2,5−ジクロロフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]アセチル}アミノ)ベンゾエート
LC−MS[方法1]:Rt=1.14分;MS(ESIpos):m/z=527(M+H)+。
tert−ブチル5−[4−({[4−(2,5−ジクロロフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]アセチル}アミノ)フェニル]−3−オキソ−2,3−ジヒドロ−1H−ピラゾール−1−カルボキシレート
LC−MS[方法1]:Rt=1.12分;MS(ESIpos):m/z=609(M+H)+。
1H−NMR(400MHz,DMSO−d6):δ[ppm]=8.35(s,1H),7.78(d,1H),7.71(d,1H),7.50(dd,1H),1.79(s,6H).
[実施例5.1B]
4−(2−ブロモ−5−クロロフェニル)−3,4,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−2,5−ジオン(ラセミ体)
LC−MS[方法1]:Rt=0.84分;MS(ESIpos):m/z=340(M+H)+。
LC−MS[方法3]:Rt=1.78分;MS(ESIpos):m/z=338(M+H−tert−ブチル)+。
[実施例5.1D]
tert−ブチル[4−(2−ブロモ−5−クロロフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]アセテート
LC−MS[方法1]:Rt=1.11分;MS(ESIpos):m/z=452(M+H−tert−ブチル)+。
[実施例5.1E]
[4−(2−ブロモ−5−クロロフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]酢酸
1H−NMR(400MHz,DMSO−d6):δ[ppm]=8.57(s,1H),7.87(d,1H),7.75(d,1H),7.70(s,1H),1.78(s,6H).
[実施例6.1B]
4−[5−クロロ−2−(トリフルオロメチル)フェニル]−3,4,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−2,5−ジオン(ラセミ体)
LC−MS[方法1]:Rt=0.85分;MS(ESIpos):m/z=330(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=10.85(s,1H),7.74(d,1H),7.52(dd,1H),7.24(d,1H),4.18(t,1H),2.98(dd,1H),2.78(dd,1H),2.67−2.60(m,1H),2.47−2.33(m,3H).
[実施例6.1C]
4−[5−クロロ−2−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−1H−シクロペンタ[b]ピリジン−2,5−ジオン
LC−MS[方法1]:Rt=0.83分;MS(ESIpos):m/z=328(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=12.74(s,1H),7.82(d,1H),7.70(d,1H),7.44(s,1H),6.10(s,1H),2.98−2.92(m,2H),2.40−2.44(m,2H).
[実施例6.1D]
tert−ブチル{4−[5−クロロ−2−(トリフルオロメチル)フェニル]−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル}アセテート
LC−MS[方法1]:Rt=1.11分;MS(ESIpos):m/z=442(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=7.84(d,1H),7.72(dd,1H),7.48(d,1H),6.30(s,1H),4.79(dd,2H),3.07−3.02(m,2H),2.59−2.55(m,2H),1.44(s,9H).
[実施例6.1E]
{4−[5−クロロ−2−(トリフルオロメチル)フェニル]−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル}酢酸
LC−MS[方法1]:Rt=0.79分;MS(ESIpos):m/z=386(M+H)+。
tert−ブチル5−{4−[({4−[5−クロロ−2−(トリフルオロメチル)フェニル]−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル}アセチル)アミノ]フェニル}−3−オキソ−2,3−ジヒドロ−1H−ピラゾール−1−カルボキシレート
LC−MS[方法1]:Rt=1.14分;MS(ESIpos):m/z=643(M+H)+。
LC−MS[方法1]:Rt=0.86分;MS(ESIpos):m/z=280(M+H)+。
[実施例7.1B]
tert−ブチル(2,5−ジオキソ−4−{[(トリフルオロメチル)スルホニル]オキシ}−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]アセテート
1H−NMR(400MHz,DMSO−d6):δ[ppm]=6.64(s,1H),4.76(s,2H),3.10−3.07(m,2H),2.73−2.69(m,2H),1.43(s,9H).
[実施例7.1C]
tert−ブチル[4−(5−クロロ−2−シアノフェニル]−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]アセテート
LC−MS[方法1]:Rt=1.00分;MS(ESIneg):m/z=397[M+H]+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=7.97(d,1H),7.74(dd,1H),7.68(d,1H),6.49(s,1H),4.81(s,2H),3.10−3.05(m,2H),2.64−2.60(m,2H),1.45(s,9H).
[実施例7.1D]
[4−(5−クロロ−2−シアノフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]酢酸
LC−MS[方法1]:Rt=0.65分;MS(ESIpos):m/z=343(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=13.4(br.s,1H),7.97(d,1H),7.74(dd,1H),7.69(d,1H),6.49(s,1H),4.82(s,2H),3.13−3.07(m,2H),2.64−2.59(m,2H).
[実施例7.2A]
tert−ブチル4−({[4−(5−クロロ−2−シアノフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]アセチル}アミノ)ベンゾエート
LC−MS[方法1]:Rt=1.12分;MS(ESIneg):m/z=516(M+H)−
1H−NMR(400MHz,DMSO−d6):δ[ppm]=10.88(s,1H),7.98(d,1H),7.89(d,2H),7.76−7.68(m,4H),6.49(s,1H),4.97(s,2H),3.17−3.12(m,2H),2.65−2.60(m,2H),1.54(s,9H).
[実施例7.3A]
tert−ブチル5−[4−({[4−(5−クロロ−2−シアノフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]アセチル}アミノ)フェニル]−3−オキソ−2,3−ジヒドロ−1H−ピラゾール−1−カルボキシレート
LC−MS[方法1]:Rt=1.04分;MS(ESIpos):m/z=600(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=12.95(d,1H),10.72(s,1H),7.98(d,1H),7.76−7.67(m,6H),6.51−6.49(m,2H),4.97(s,2H),3.17−3.13(m,2H),2.65−2.61(m,2H),1.50(s,9H).
[実施例7.4A]
tert−ブチル(4−ヒドロキシ−2,5−ジオキソ−5,6,7,8−テトラヒドロキノリン−1(2H)−イル)アセテート
LC−MS[方法1]:Rt=0.83分;MS(ESIpos):m/z=294(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=12.75(br.s,1H),5.60(s,1H),4.81(s,2H),2.92−2.87(m,2H),2.61−2.56(m,2H),2.07−1.99(m,2H),1.43(s,9H).
[実施例7.4B]
tert−ブチル[2,5−ジオキソ−4−{[(トリフルオロメチル)スルホニル]オキシ}−5,6,7,8−テトラヒドロキノリン−1(2H)−イル]アセテート
LC−MS[方法1]:Rt=1.07分;MS(ESIneg):m/z=424[M+H]+
1HNMR(400MHz,DMSO−d6)δ=6.55(s,2H),4.86(s,3H),2.99(s,2H),2.54−−2.45(m,2H),2.06−−1.98(m,2H)
(主要な構成要素の特徴的なシグナル)
[実施例7.4C]
tert−ブチル[4−(5−クロロ−2−シアノフェニル)−2,5−ジオキソ−5,6,7,8−テトラヒドロキノリン−1(2H)−イル]アセテート
LC−MS[方法1]:Rt=1.05分;MS(ESIneg):m/z=411(M+H)−
1H−NMR(400MHz,DMSO−d6):δ[ppm]=7.88(d,1H),7.63(dd,1H),7.55(d,1H),6.36(s,1H),4.91(d,2H),3.06−2.88(m,2H),2.44−2.37(m,2H),2.12−1.96(m,2H),1.45(s,9H).
[実施例7.4D]
[4−(5−クロロ−2−シアノフェニル)−2,5−ジオキソ−5,6,7,8−テトラヒドロキノリン−1(2H)−イル]酢酸
LC−MS[方法3]:Rt=1.67分;MS(ESIpos):m/z=357(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=13.39(br.s,1H),7.88(d,1H),7.63(dd,1H),7.56(d,1H),6.36(s,1H),4.97−4.86(m,2H),3.10−2.89(m,2H),2.44−2.39(m,2H),2.10−1.97(m,2H).
[実施例7.5A]
tert−ブチル4−({[4−(5−クロロ−2−シアノフェニル)−2,5−ジオキソ−5,6,7,8−テトラヒドロキノリン−1(2H)−イル]アセチル}アミノ)ベンゾエート
LC−MS[方法3]:Rt=2.46分;MS(ESIneg):m/z=531(M+H)−
1H−NMR(400MHz,DMSO−d6):δ[ppm]=10.86(s,1H),7.89(d,1H),7.88(d,2H),7.72(d,2H),7.64(dd,1H),7.56(d,1H),6.37(s,1H),5.07(q,2H),3.16−2.95(m,2H),2.45−2.38(m,2H),2.10−1.99(m,2H),1.54(s,9H).
作業例
一般的方法1:カルボン酸とのアミドカップリング
アルゴン下およびRTで、適切なアミン(1.1eq.)、N,N−ジイソプロピルエチルアミン(2.2eq.)および少量のDMF中のHATU(1.2eq.)の溶液をジメチルホルムアミド中の適切なカルボン酸(1.0eq.)の溶液(約12mL/mmol)に添加した。反応混合物をRTで撹拌した。水/酢酸エチルの添加および相分離後、有機相を水および飽和塩化ナトリウム水溶液で洗浄し、乾燥させ(硫酸ナトリウム)、ろ過し、減圧下で濃縮した。次いで、分取HPLC(Reprosil C18、水/アセトニトリル勾配または水/メタノール勾配)によって粗製生成物を精製した。
RTで、TFA(20eq.)をジクロロメタン(約25mL/mmol)中の適切なtert−ブチルエステル誘導体またはBoc−保護アミン(1.0eq.)の溶液に添加し、混合物をRTで1から8時間撹拌した。続いて、反応混合物を減圧下で濃縮した。残渣をジクロロメタンとともに3回共蒸発させた。次いで、分取RP−HPLC(移動相:アセトニトリル/水勾配または水/メタノール勾配)によって粗製生成物を精製した。
RTで、水酸化リチウム(2から4eq.)をテトラヒドロフラン/水(3:1、約15mL/mmol)の混合液中の適切なメチルまたはエチルエステル(1.0eq.)の溶液に添加し、混合物をRTで撹拌した。次いで塩酸水溶液(1N)を用いて反応混合物をpH1に調整した。水/酢酸エチルの添加後、水相を酢酸エチルで3回抽出した。合わせた有機相を乾燥させ(硫酸ナトリウム)、ろ過し、減圧下で濃縮した。次いで、フラッシュクロマトグラフィー(シリカゲル60、移動相:シクロヘキサン/酢酸エチル混合液またはジクロロメタン/メタノール混合液)または分取HPLC(Reprosil C18、水/アセトニトリル勾配または水/メタノール勾配)の何れかによって、粗製生成物を精製した。
2−[4−(3−クロロフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−ピロロ[3,4−b]ピリジン−1−イル]−N−[4−(1H−テトラゾール−5−イル)フェニル]アセトアミド
LC−MS[方法4]:Rt=0.86分;MS(ESIpos):m/z=462(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=10.81(s,1H),8.32(s,1H),8.00(d,2H),7.79(d,2H),7.65(s,1H),7.56−7.44(m,3H),6.42(s,1H),4.86(s,2H),4.39(s,2H).
[実施例2]
2−[4−(2,5−ジクロロフェニル)−6−メチル−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−ピロロ[3,4−b]ピリジン−1−イル]−N−[4−(1H−テトラゾール−5−イル)フェニル]アセトアミド
LC−MS[方法1]:Rt=0.79分;MS(ESIneg):m/z=510[M+H]+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=10.87(s,1H),8.02(d,2H),7.82(d,2H),7.57(d,1H),7.53(dd,1H),7.47(d,1H),6.37(s,1H),4.89(s,2H),4.50(s,2H),2.92(s,3H).
[実施例3]
2−[4−(2,5−ジクロロフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]−N−[4−(1H−テトラゾール−5−イル)フェニル]アセトアミド
LC−MS[方法1]:Rt=0.87分;MS(ESIneg):m/z=495[M+H]+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=16.77(br.s,1H),10.88(s,1H),8.02(d,2H),7.83(d,2H),7.56(s,1H),7.54(d,1H),7.45(d,1H),6.34(s,1H),4.97(s,2H),3.19−3.05(m,2H),2.68−2.55(m,2H).
[実施例4]
4−({[4−(2,5−ジクロロフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]アセチル}アミノ)安息香酸
LC−MS[方法1]:Rt=0.86分;MS(ESIneg):m/z=471[M+H]+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=10.87(s,1H),7.93(d,2H),7.72(d,2H),7.57(d,1H),7.52(dd,1H),7.45(d,1H),6.33(s,1H),4.96(s,2H),3.15−3.07(br.s,2H),2.63−2.(br.s,2H).
[実施例5]
2−[4−(2,5−ジクロロフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]−N−[4−(5−オキソ−4,5−ジヒドロ−1,2,4−オキサジアゾール−3−イル)フェニル]アセトアミド
LC−MS[方法1]:Rt=0.91分;MS(ESIpos):m/z=511(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=10.76(s,1H),7.76(d,2H),7.70(d,2H),7.56(d,1H),7.51(dd,1H),7.44(d,1H),6.33(s,1H),4.95(s,2H),3.15−3.07(br.s,2H),2.63−2.55(br.s,2H).
[実施例6]
2−[4−(2,5−ジクロロフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]−N−{4−[3−(トリフルオロメチル)−1H−1,2,4−トリアゾール−5−イル]フェニル}アセトアミド
LC−MS[方法1]:Rt=1.05分;MS(ESIpos):m/z=562(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=15.18(s,1H),10.85(s,1H),8.01(d,2H),7.80(d,2H),7.55(d,1H),7.53(dd,1H),7.44(d,1H),6.33(s,1H),4.97(s,2H),3.16−3.08(br.s,2H),2.64−2.56(br.s,2H).
[実施例7]
2−[4−(2,5−ジクロロフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]−N−[4−(5−オキソ−2,5−ジヒドロ−1H−ピラゾール−3−イル)フェニル]アセトアミド
LC−MS[方法1]:Rt=0.86分;MS(ESIpos):m/z=509(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=11.98(s,1H),10.65(s,1H),9.57(s,1H),7.63(br.s,4H),7.57(d,1H),7.52(dd,1H),7.45(d,1H),6.33(s,1H),5.85(br.s,1H),4.96(s,2H),3.16−3.04(br.s,2H),2.63−2.55(br.s,2H).
[実施例8]
2−[4−(2,5−ジクロロフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]−N−[4−(1H−イミダゾール−5−イル)フェニル]アセトアミド
LC−MS[方法1]:Rt=0.75分;MS(ESIpos):m/z=493(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=10.58(s,1H),7.90(br.s,1H),7.73(d,2H),7.62(d,2H),7.59−7.55(m,2H),7.53(dd,1H),7.44(d,1H),6.33(s,1H),4.94(s,2H),3.12(br.s,2H),2.60(br.s,2H).
[実施例9]
2−[4−(2−ブロモ−5−クロロフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]−N−[4−(1H−テトラゾール−5−イル)フェニル]アセトアミド
LC−MS[方法1]:Rt=0.83分;MS(ESIpos):m/z=539(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=10.88(s,1H),8.02(d,2H),7.83(d,2H),7.72(d,1H),7.44(dd,1H),7.41(d,1H),6.30(s,1H),4.97(s,2H),3.17−3.09(br.s,2H),2.63−2.56(br.s,2H).
[実施例10]
2−[4−(2−ブロモ−5−クロロフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]−N−[4−(5−オキソ−4,5−ジヒドロ−1,2,4−オキサジアゾール−3−イル)フェニル]アセトアミド
LC−MS[方法1]:Rt=0.92分;MS(ESIpos):m/z=555(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=12.86(s,1H),10.90(s,1H),7.79(s,4H),7.72(d,1H),7.44(dd,1H),7.40(d,1H),6.29(s,1H),4.97(s,2H),3.15−3.08(br.s,2H),2.62−2.56(br.s,2H).
[実施例11]
2−{4−[5−クロロ−2−(トリフルオロメチル)フェニル]−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル}−N−[4−(5−オキソ−2,5−ジヒドロ−1H−ピラゾール−3−イル)フェニル]アセトアミド
LC−MS[方法1]:Rt=0.89分;MS(ESIpos):m/z=543(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=11.98(s,1H),10.65(s,1H),9.57(s,1H),7.85(d,1H),7.74(dd,1H),7.64(br.s,4H),7.49(d,1H),6.30(s,1H),5.85(br.s,1H),4.96(q,2H),3.15−3.08(m,2H),2.60−2.56(m,2H).
[実施例12]
4−({[4−(5−クロロ−2−シアノフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]アセチル}アミノ)安息香酸
LC−MS[方法1]:Rt=0.80分;MS(ESIpos):m/z=461(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=12.77(br.s,1H),10.87(s,1H),7.98(d,1H),7.92(d,2H),7.77−7.68(m,4H),6.50(s,1H),4.98(s,2H),3.17−3.12(m,2H),2.66−2.60(m,2H).
[実施例13]
2−[4−(5−クロロ−2−シアノフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]−N−[4−(5−オキソ−4,5−ジヒドロ−1,2,4−オキサジアゾール−3−イル)フェニル]アセトアミド
LC−MS[方法1]:Rt=0.82分;MS(ESIpos):m/z=502(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=12.87(br.s,1H),10.92(s,1H),7.98(d,1H),7.80(br.s,4H),7.74(dd,1H),7.68(d,1H),6.49(s,1H),4.98(br.s,2H),3.17−3.12(m,2H),2.65−2.61(m,2H).
[実施例14]
2−[4−(5−クロロ−2−シアノフェニル)−2,5−ジオキソ−2,5,6,7−テトラヒドロ−1H−シクロペンタ[b]ピリジン−1−イル]−N−[4−(5−オキソ−2,5−ジヒドロ−1H−ピラゾール−3−イル)フェニル]アセトアミド
LC−MS[方法1]:Rt=0.73分;MS(ESIpos):m/z=500(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=10.57(br.s,1H),7.98(d,1H),7.74(dd,1H),7.70(d,1H),7.52(br.s,4H),6.49(s,1H),4.96(br.s,3H),3.18−3.12(m,2H),2.65−2.60(m,2H).2NH−共鳴は見られない。
LC−MS[方法1]:Rt=0.83分;MS(ESIneg):m/z=474(M+H)−
1H−NMR(400MHz,DMSO−d6):δ[ppm]=12.78(br.s,1H),10.83(s,1H),7.92(d,2H),7.89(d,1H),7.71(d,2H),7.63(dd,1H),7.56(d,1H),6.37(s,1H),5.08(q,2H),3.15−2.94(m,2H),2.45−2.35(m,2H),2.05−2.00(m,2H).
[実施例16]
2−[4−(5−クロロ−2−シアノフェニル)−2,5−ジオキソ−5,6,7,8−テトラヒドロキノリン−1(2H)−イル]−N−[4−(5−オキソ−4,5−ジヒドロ−1,2,4−オキサジアゾール−3−イル)フェニル]アセトアミド
LC−MS[方法1]:Rt=0.88分;MS(ESIneg):m/z=516[M+H]+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=12.88(br.s.,1H),10.91(br.s.,1H),7.797.64(m,4H),7.56(d,1H),6.375.09(m,1H),3.15−2.95(m,2H),2.46(d,3H),3個のプロトンが不明瞭であった。
血栓塞栓性障害を処置するための本発明による化合物の適切性を次のアッセイ系において明らかにすることができる。
a.1)FXIa阻害の測定
ヒト第XIa因子の酵素活性を求めるためのペプチド性第XIa因子基質の反応を利用する生化学試験系を用いて、本発明物質の第XIa因子阻害を求める。ここで、第XIa因子は消化性の第XIa因子基質からC末端アミノメチルクマリン(AMC)を切り出し、その蛍光を測定する。マイクロタイタープレートにおいて決定を行う。
FXIa阻害に関して物質の選択性を明らかにするために、試験物質を第Xa因子、トリプシンおよびプラスミンなどの他のヒトセリンプロテアーゼのそれらの阻害について調べる。第Xa因子(1.3nmol/L、Kordiaより)、トリプシン(83mU/mL、Sigmaより)およびプラスミン(0.1μg/mL、Kordiaより)の酵素活性を決定するために、これらの酵素を溶解させ(50mmol/Lのトリス緩衝液[C,C,C−トリス(ヒドロキシメチル)アミノメタン]、100mmol/Lの塩化ナトリウム、0.1%BSA[ウシ血清アルブミン]、5mmol/Lの塩化カルシウム、pH7.4)、ジメチルスルホキシド中の様々な濃度の試験物質およびまた試験物質なしのジメチルスルホキシドとともに15分間温置する。次いで、適切な基質(第Xa因子およびトリプシンに対してはBachemからの5μmol/LのBoc−Ile−Glu−Gly−Arg−AMC、プラスミンに対してはBachemからの50μmol/LのMeOSuc−Ala−Phe−Lys−AMC)の添加によって酵素反応を開始させる。22℃で30分間の温置時間後、蛍光を測定する(励起:360nm、発光:460nm)。試験物質を用いた試験混合物の測定発光を試験物質なしの対照混合物(ジメチルスルホキシド中の試験物質の代わりにジメチルスルホキシドのみ)と比較し、IC50値を濃度/活性相関から計算する。
トロンボグラム(Hemkerによるトロンビン生成アッセイ)における試験物質の効果をヒト血漿(Octaplas(登録商標)、Octapharmaより)中でインビトロで決定する。
試験物質の抗凝固活性をヒト血漿およびラット血漿においてインビトロで求める。この目的のために、0.11モラーのクエン酸ナトリウム溶液をレシーバとして使用して、1:9のクエン酸ナトリウム/血液の混合比で採血する。採血直後に、これを完全に混合し、約4000gで15分間遠心する。上清をピペットで取り出す。
本発明による物質の血漿カリクレイン阻害を決定するために、ペプチド性血漿カリクレイン基質の反応を利用する生化学試験系を使用して、ヒト血漿カリクレインの酵素活性を決定する。ここで、血漿カリクレインは消化性の血漿カリクレイン基質からC末端アミノメチルクマリン(AMC)を切り出し、その蛍光を測定する。マイクロタイタープレートにおいて決定を行う。
本発明による化合物の活性の特徴を「ヒト臍帯静脈性細胞」(HUVEC)におけるインビトロ透過性アッセイによって調べる。EOS装置(EC IS:Electric Cell−substrate Impedance Sensing;Applied Biophysics Inc;Troy,NY)を用いて、金電極上に置かれた内皮細胞単層を横切る経内皮電気抵抗(TEER)の変動を連続的に測定することが可能である。HUVECを96ウェルセンサー電極プレート(96W1 E,Ibidi GmbH,Martinsried,Germany)上に播種する。キニノーゲン、プレカリクレインおよび第XII因子(各100nM)での刺激によって、形成されるコンフルエント細胞単層の過透過性を誘導する。上記で示される物質の添加前に本発明による化合物を添加する。化合物の通例の濃度は1x10−10から1x10−6Mである。
さらなる過透過性モデルにおいて、巨大分子透過性の調節における物質の活性を求める。HUVECをフィブロネクチン被覆Transwellフィルター膜(24ウェルプレート、0.4μMポリカーボネート膜付きの6.5mmインサート;Costar#3413)に播種する。フィルター膜により細胞培養スペースが上部と下部に分けられ、コンフルエント内皮細胞層が上部の細胞培養スペースの床面上にある。250g/mLの40kDa FITCデキストラン(Invitrogen、D1844)を上部チャンバーの培地に添加する。キニノーゲン、プレカリクレインおよび第XII因子(各100nM)での刺激によって、単層の過透過性を誘導する。30分ごとに、培地試料を下部チャンバーから採取し、フルオリメーターを使用して、時間の関数として、巨大分子透過性の変化に対するパラメーターとしての相対蛍光を決定する。上記で示される物質の添加前に本発明による化合物を添加する。化合物の通例の濃度は1x10−10から1x10−6Mである。
b.1)ウサギにおける耳出血時間と組み合わせた動脈血栓症モデル(塩化鉄(II)誘導性血栓症)
動脈血栓症モデルにおいてFXIa阻害剤の抗血栓活性を試験する。ウサギの頸動脈における領域に対して化学的損傷を引き起こすことによってここで血栓形成を誘発する。同時に、耳出血時間を決定する。
c.1)レーザー誘導性脈絡膜血管新生モデルにおける物質の有効性の試験
この試験は、レーザー誘導性脈絡膜血管新生のラットモデルでの血管外漏出/浮腫形成および/または脈絡膜血管新生の減少に対する試験物質の有効性を調べるためのものである。
酸素誘導性網膜症は、病的な網膜血管形成の研究のための有用な動物モデルであることが示されている。このモデルは、網膜における出生後早期の発生中の酸素過剰により、正常な網膜血管の成長の停止または遅延が起こるという観察に基づく。7日間の酸素過剰期後、動物が酸素正常状態の室内大気に戻される場合、網膜が酸素正常状態下の神経組織の的確な供給を確実にするために必要とされる正常血管を欠いているので、これは相対的な低酸素症と同等である。このようにして引き起こされる虚血状態の結果、湿潤型AMDなどの眼の障害における病態生理学的血管新生といくつかの類似点がある異常な血管新生が起こる。さらに、引き起こされる血管新生は非常に再現性があり、定量的であり、疾患機序および網膜障害の様々な形態に対する可能性のある処置を調べるための重要なパラメーターである。
本発明による物質を次のように医薬製剤に変換することができる:
錠剤:
組成:
100mgの実施例1の化合物、50mgのラクトース(一水和物)、50mgのトウモロコシデンプン、10mgのポリビニルピロリドン(PVP25)(BASF、Germanyより)および2mgのステアリン酸マグネシウム。
実施例1の化合物、ラクトースおよびデンプンの混合物を水中のPVPの5%強度溶液(m/m)とともに顆粒化する。乾燥後、5分間にわたり顆粒をステアリン酸マグネシウムと混合する。この混合物を従来の打錠プレス中で圧縮する(錠剤の形式については上記参照)。
組成:
1000mgの実施例1の化合物、1000mgのエタノール(96%)、400mgのRhodigel(キサンタンガム)(FMC、USAより)および99gの水。
エタノール中でRhodigelを懸濁し、実施例1の化合物を懸濁液に添加する。撹拌しながら水を添加する。混合物をRhodigelの膨潤が完了するまで約6時間撹拌する。
滅菌食塩水中で本発明化合物の凍結乾燥物を再構成することによって、眼への局所投与のための滅菌医薬製剤を調製することができる。このような液剤または懸濁液に適切な保存剤は、例えば、0.001から1重量%の範囲の濃度の、塩化ベンザルコニウム、チオメルサールまたは硝酸フェニル水銀である。
Claims (15)
- 式
の化合物(式中、
nは数1または2を表し;
Aは−N(R2)−または−CH2−を表し、
ここで、
R2は水素またはC1−C4−アルキルを表し、
R1は、式
の基を表し、
ここで*はオキソピリジン環への連結点であり、
R6は、臭素、塩素、フッ素、メチル、ジフルオロメチル、トリフルオロメチル、メトキシ、ジフルオロメトキシまたはトリフルオロメトキシを表し、
R7は、水素、臭素、塩素、フッ素、シアノ、ニトロ、ヒドロキシ、メチル、ジフルオロメチル、トリフルオロメチル、メトキシ、エトキシ、ジフルオロメトキシ、トリフルオロメトキシ、エチニル、3,3,3−トリフルオロプロプ−1−イン−1−イルまたはシクロプロピルを表し、
R8は、水素、塩素またはフッ素を表し、
R3は水素を表し、
R4は水素を表し、
R5は、式
または
の基を表し、
ここで#は窒素原子への連結部位であり、
R9は、ヒドロキシカルボニルまたは5員ヘテロシクリルを表し、
ここでヘテロシクリルは、互いに独立に、オキソ、ヒドロキシ、チオキソ、スルファニル、メチル、ジフルオロメチル、トリフルオロメチル、2−ヒドロキシカルボニル−1,1,2,2−テトラフルオロエチルおよび2−メトキシカルボニル−1,1,2,2−テトラフルオロエチルからなる群から選択される1から2個の置換基により置換され得、
ここでメチルは、メトキシ置換基により置換され得、
R10は、水素、塩素、フッ素またはメチルを表し、
R11およびR12は、それらが結合される炭素原子と一緒に5員複素環を形成し、
ここで、前記複素環は、互いに独立に、オキソ、塩素、ヒドロキシ、ヒドロキシカルボニル、メチル、ジフルオロメチル、トリフルオロメチル、1,1,2,2,2−ペンタフルオロエチル、2−ヒドロキシカルボニル−1,1,2,2−テトラフルオロエチルおよび2−メトキシカルボニル−1,1,2,2−テトラフルオロエチルからなる群から選択される1から2個の置換基により置換され得、
R13は、水素、塩素、フッ素、メチルまたはメトキシを表す。)
またはそれらの塩、それらの溶媒和物もしくはそれらの塩の溶媒和物のうち1つ。 - nが数1または2を表し;
Aが−N(R2)−または−CH2−を表し、
ここで、
R2が水素またはメチルを表し、
R1が、式
の基を表し、
ここで*がオキソピリジン環への連結点であり、
R6が塩素を表し、
R7が、水素、臭素、塩素、シアノ、メチル、ジフルオロメチル、トリフルオロメチル、ジフルオロメトキシまたはトリフルオロメトキシを表し、
R8が、水素またはフッ素を表し、
R3が水素を表し、
R4が水素を表し、
R5が、式
の基を表し、
ここで#が窒素原子への連結部位であり、
R9が、ヒドロキシカルボニル、オキサジアゾリル、ピラゾリル、イミダゾリル、トリアゾリルまたはテトラゾリルを表し、
ここでオキサジアゾリル、ピラゾリル、イミダゾリルおよびトリアゾリルが、互いに独立に、オキソ、ヒドロキシ、メチルおよびトリフルオロメチルからなる群から選択される1から2個の置換基により置換され得、
R10が水素を表すことを特徴とする、請求項1に記載の化合物
またはそれらの塩、それらの溶媒和物もしくはそれらの塩の溶媒和物のうち1つ。 - nが数1または2を表し;
Aが−CH2−を表し、
R1が、式
の基を表し、
ここで*がオキソピリジン環への連結点であり、
R6が塩素を表し、
R7が臭素またはシアノを表し、
R8が水素を表し、
R3が水素を表し、
R4が水素を表し、
R5が式
の基を表し、
ここで#が窒素原子への連結部位であり、
R9が、ヒドロキシカルボニル、オキサジアゾリル、ピラゾリルまたはテトラゾリルを表し、
ここでオキサジアゾリルおよびピラゾリルが、互いに独立に、オキソ、ヒドロキシおよびトリフルオロメチルからなる群から選択される1から2個の置換基により置換され得、
R10が水素を表すことを特徴とする請求項1および2の何れかに記載の化合物
またはそれらの塩、それらの溶媒和物もしくはそれらの塩の溶媒和物のうち1つ。 - 請求項1に記載の式(I)の化合物またはそれらの塩、それらの溶媒和物もしくはそれらの塩の溶媒和物のうち1つを調製するための方法であって、
[A]式
の化合物(式中、
n、A、R1、R3、R4およびR10は、それぞれ請求項1で定義されるとおりであり、
R14は、tert−ブチルを表す。)
を酸と反応させて、式
の化合物(式中、
n、A、R1、R3、R4およびR10は、それぞれ請求項1で定義されるとおりであり、
R9はヒドロキシカルボニルを表す。)
を与えるか、
または
[B]式
の化合物(式中、
n、A、R1、R3、R4およびR10は、請求項1で定義されるとおりであり、
R14は、メチルまたはエチルを表す。)
を塩基と反応させて、式
の化合物(式中、
n、A、R1、R3、R4およびR10は、請求項1で定義されるとおりであり、
R9はヒドロキシカルボニルを表す。)
を与えるか、
または
[C]式
の化合物(式中、
n、A、R1およびR3は、それぞれ請求項1で定義されるとおりである。)
を式
の化合物(式中、
R4およびR5は、それぞれ請求項1で定義されるとおりである。)
と脱水剤の存在下で反応させて、式(I)の化合物を与えるか、
または
[D]式
の化合物(式中、n、A、R1、R3、R4およびR5は、それぞれ請求項1で定義されるとおりである。)
を酸化剤と反応させることの何れかを特徴とする、方法。 - 疾患の処置および/または予防のための請求項1から3の何れかに記載の化合物。
- 疾患の処置および/または予防のための薬剤を作製するための請求項1から3の何れかに記載の化合物の使用。
- 血栓性または血栓塞栓性障害の処置および/または予防のための薬剤を作製するための請求項1から3の何れかに記載の化合物の使用。
- 眼の障害の処置および/または予防のための薬剤を作製するための請求項1から3の何れかに記載の化合物の使用。
- 遺伝性血管浮腫または腸の炎症障害の処置および/または予防のための薬剤を作製するための請求項1から3の何れかに記載の化合物の使用。
- 前記腸の炎症障害が、クローン病または潰瘍性大腸炎である、請求項9に記載の使用。
- 不活性で、無毒性で、医薬的に適切な賦形剤と組み合わせて、請求項1から3の何れかに記載の化合物を含む薬剤。
- 血栓性または血栓塞栓性障害の処置および/または予防のための請求項11に記載の薬剤。
- 眼の障害の処置および/または予防のための請求項11に記載の薬剤。
- 遺伝性血管浮腫または腸の炎症障害の処置および/または予防のための請求項11に記載の薬剤。
- 前記腸の炎症障害が、クローン病または潰瘍性大腸炎である、請求項14に記載の製剤。
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EP3024822B1 (de) * | 2013-07-23 | 2017-05-03 | Bayer Pharma Aktiengesellschaft | Substituierte oxopyridin-derivate und ihre verwendung als faktor xia und plasmakallikrein inhibitoren |
PE20210470A1 (es) | 2014-01-31 | 2021-03-08 | Bristol Myers Squibb Co | Macrociclos con grupos p2' heterociclicos como inhibidores del factor xia |
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CN107074821B (zh) | 2014-09-04 | 2020-05-22 | 百时美施贵宝公司 | 为fxia抑制剂的二酰胺大环化合物 |
EP3197891B1 (de) | 2014-09-24 | 2018-11-21 | Bayer Pharma Aktiengesellschaft | Faktor xia hemmende pyridobenzazepin- und pyridobenzazocin-derivate |
ES2722423T3 (es) | 2014-09-24 | 2019-08-12 | Bayer Pharma AG | Derivados de oxopiridina sustituidos |
ES2694189T3 (es) | 2014-09-24 | 2018-12-18 | Bayer Pharma Aktiengesellschaft | Derivados de oxopiridina sustituidos |
ES2716417T3 (es) | 2014-09-24 | 2019-06-12 | Bayer Pharma AG | Derivados de oxopiridina sustituidos con acción antiinflamatoria y antitrombótica |
US10167280B2 (en) | 2014-09-24 | 2019-01-01 | Bayer Pharma Aktiengesellschaft | Substituted oxopyridine derivatives |
US9453018B2 (en) | 2014-10-01 | 2016-09-27 | Bristol-Myers Squibb Company | Pyrimidinones as factor XIa inhibitors |
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WO2017074833A1 (en) | 2015-10-29 | 2017-05-04 | Merck Sharp & Dohme Corp. | Macrocyclic spirocarbamate derivatives as factor xia inhibitors, pharmaceutically acceptable compositions and their use |
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US20220144848A1 (en) | 2018-12-21 | 2022-05-12 | Bayer Aktiengesellschaft | Substituted oxopyridine derivatives |
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CN113135929B (zh) * | 2020-01-17 | 2024-04-19 | 江西济民可信集团有限公司 | 呋喃并吡啶酮酰胺化合物及其制备方法和用途 |
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