JP6155187B2 - トロンビンの阻害剤としての多置換芳香族化合物 - Google Patents
トロンビンの阻害剤としての多置換芳香族化合物 Download PDFInfo
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- JP6155187B2 JP6155187B2 JP2013502815A JP2013502815A JP6155187B2 JP 6155187 B2 JP6155187 B2 JP 6155187B2 JP 2013502815 A JP2013502815 A JP 2013502815A JP 2013502815 A JP2013502815 A JP 2013502815A JP 6155187 B2 JP6155187 B2 JP 6155187B2
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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Description
本明細書で使用する略語は、化学および生物学の技術の範囲内のその通常の意味を有する。本明細書に記載する化学構造および化学式は、化学業界で知られている化学原子価の標準規則に従って作成したものである。
(A)−OH、−NH2、−SH、−CN、−CF3、−NO2、オキソ、ハロゲン、−COOH、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール、および
(B)(i)および(ii)から選択される少なくとも1個の置換分で置換されているアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、およびヘテロアリール、
(i)オキソ、−OH、−NH2、−SH、−CN、−CF3、−NO2、ハロゲン、−COOH、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール、および
(ii)(a)および(b)から選択される少なくとも1個の置換分で置換されているアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、およびヘテロアリール、
(a)オキソ、−OH、−NH2、−SH、−CN、−CF3、−NO2、ハロゲン、−COOH、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール、および
(b)オキソ、−OH、−NH2、−SH、−CN、−CF3、−NO2、ハロゲン、−COOH、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、および非置換ヘテロアリールから選択される少なくとも1個の置換分で置換されているアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリール。
一態様では、式(Ia)の構造を有する化合物
いくつかの実施形態では、本明細書に記載の化合物は、トロンビンに対して、1μM以上、たとえば、約1、2、3、4、5、6、7、8、9、10、11、12、13、14、16、18、20、22、24、26、28、30、32、34、36、38、40、45、50、55、60、65、70、75、80、85、90、95、100μMまたはこれ以上の活性で、阻害活性を示す。いくつかの実施形態では、化合物は、トロンビンに対して、0.1μM〜1μMの間、たとえば、約0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9または1.0μMの活性で、阻害活性を示す。いくつかの実施形態では、本明細書に記載の化合物は、トロンビンに対して、0.1μM以下、たとえば、約1、2、5、10、15、20、30、40、50、60、70、80、90または100nMの活性で、阻害活性を示す。ここで挙げた値のいずれかの組合せを上限および/または下限として使用する値の範囲は、たとえば、限定されるわけではないが、1〜10nM、10〜100nM、0.1〜1μM、1〜10μM、10〜100μM、100〜200μM、200〜500μMまたはさらに500〜1000μMも考えられる。いくつかの実施形態では、阻害活性は、約1〜10nM、10〜100nM、0.1〜1μM、1〜10μM、10〜100μM、100〜200μM、200〜500μMまたはさらに500〜1000μMの範囲にある。定量化の目的では、本明細書で開示する阻害化合物に関しての用語「活性」、「阻害活性」、「生物学的活性」、「トロンビン活性」などは、当業界で知られている様々な手段で定量化したものでよいと理解される。別段指摘しない限り、本明細書では、このような用語は、通例の意味のIC50(すなわち、最大値の半分の阻害を実現する濃度)を指す。
血栓症。トロンビンの所在が凝固カスケードにあり、その凝固カスケードは、血液凝固過程の進行において重要であるので、血栓性疾患が、トロンビン阻害の第一の適応症である。しかし、推測に囚われるつもりはないが、一般には凝固カスケード、詳細にはトロンビンは、他の様々な疾患状態において重要であると考えられる。
本明細書に記載の化合物は、当業界で知られており、本明細書に記載する様々な方法によって、生物学的活性、たとえば、様々なタンパク質、たとえばトロンビンのプロテアーゼ活性を阻害するか検定することができる。たとえば、そのようなタンパク質、たとえばトロンビンのプロテアーゼ活性は、色素産生基質、たとえば、加水分解されるとp−ニトロアニリドを遊離させ、それによって、分光光度的に測定することのできる色の変化を生じるp−ニトロアニリドペプチド基質を使用してモニターすることができる。たとえば、Lottenberg,R,ら、1983、Biochemica et Biophysica Acta、752:539〜557を参照されたい。したがって、色の変化を、分光光度計によって、たとえば405nmでモニターすると、酵素のタンパク質分解活性に正比例するシグナルを得ることができる。
別の態様では、本明細書で開示する化合物と薬学的に許容される添加剤とを含む医薬組成物が提供される。化合物は、本明細書で開示するような式(Ia)、(Ib)、(IIa)、(IIb)、(IIIa)、(IIIb)、(IV)もしくは(V)のいずれかの化合物、本明細書において表A、BもしくはCのいずれかに記載するような化合物または薬学的に許容されるその塩、エステル、溶媒和物もしくはプロドラッグである。いくつかの実施形態では、化合物は、本明細書において表Aに記載するものである。いくつかの実施形態では、化合物は、本明細書において表Bに記載するものである。いくつかの実施形態では、化合物は、本明細書において表Cに記載するものである。
本明細書で開示する化合物は、広範な種類の経口、非経口、および局所剤形にして調製し、投与することができる。すなわち、化合物は、注射によって(たとえば、静脈内、筋肉内、皮内、皮下、十二指腸内または腹腔内に)投与することができる。また、本明細書に記載の化合物は、吸入によって、たとえば鼻腔内に投与することもできる。加えて、本明細書で開示する化合物は、経皮的に投与することもできる。本明細書で開示する化合物の投与に、複数の投与経路(たとえば、筋肉内、経口、経皮)を使用してよいことも構想される。いくつかの実施形態では、本明細書で開示する化合物は、錠剤、水性もしくは油性の懸濁剤、ロゼンジ剤、トローチ剤、散剤、顆粒剤、乳剤、カプセル剤、シロップ剤またはエリキシル剤として経口投与することができる。経口的に使用する組成物は、医薬として洗練され、口当たりのよい調製物を製造するために、甘味剤、香味剤、着色剤、および保存剤の群から選択される1種または複数の薬類を含有してよい。したがって、薬学的に許容される担体または添加剤と、本明細書で開示する1種または複数の化合物とを含む医薬組成物も提供される。
本明細書で提供する医薬組成物として、活性成分が、治療有効量、すなわち、その目指す目的を実現するのに有効な量で含まれている組成物が挙げられる。特定の適用例に有効な実際の量は、特に、治療対象となる状態に応じて決まる。たとえば、血栓症を治療する方法において投与するとき、そのような組成物は、所望の結果(たとえば、血栓症の程度を軽減すること)を実現するのに有効な量の活性成分を含有する。
特定の化合物の毒性と治療効果の比は、その治療指数であり、LD50(集団の50%において致死的な化合物の量)とED50(集団の50%において有効な化合物の量)の比として示すことができる。高い治療指数を示す化合物が好ましい。in vitroアッセイ、細胞培養アッセイ、および/または動物研究から得た治療指数データは、ヒトにおいて使用する投与量の範囲を策定する際に使用することができる。そのような化合物の投与量は、毒性をほとんどまたは全く伴わない、ED50が算入された血漿濃度の範囲内にあることが好ましい。投与量は、用いる剤形および利用する投与経路に応じて、この範囲内で様々でよい。たとえば、Finglら、出典:THE PHARMACOLOGICAL BASIS OF THERAPEUTICS、第1章、1頁、1975を参照されたい。厳密な製剤、投与経路、および投与量は、患者の状態、および化合物を使用する特定の方法を考慮して、個々の従業者が選択することができる。in vitro製剤では、厳密な製剤および投与量を、患者の状態、および化合物を使用する特定の方法を考慮して、個々の従業者が選択することができる。
以下の実施例は、本発明の特定の実施形態を例示するものであり、本発明の範囲を限定しないものとする。本明細書で使用する略語は、別段指摘しない限り、当業界におけるその通常の意味を有する。個別の略語としては、以下のものが挙げられる。Å=オングストローム、Ac2O=無水酢酸、AcOH=酢酸、aq=水性、Bt=ベンゾトリアゾール、BOC=N−tert−ブトキシカルボニル、br=ブロード、t−BuOH=tert−ブタノール、℃=摂氏度、d=二重線、DABCO=1,4−ジアザビシクロ[2.2.2]オクタン、DCE=1,2−ジクロロエタン、DCM=ジクロロメタン、dd=二重線の二重線、DIEA=ジエチルイソプロピルアミン、DMAP=4−ジメチルアミノピリジン、DMF=N,N−ジメチルホルムアミド、DMSO=ジメチルスルホキシド、δ=化学シフト(別段指摘しない限りppmで示す)、EDCI=1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド、eq=当量、Et2O=ジエチルエーテル、Et3N=トリエチルアミン、EtOAc=酢酸エチル、EtOH=エタノール、g=グラム、h(またはhr)=時間、HOBt=ヒドロキシベンゾトリアゾール、HPLC=高速液体クロマトグラフィー、Hz=ヘルツ、IC50=50%阻害での阻害濃度、J=結合定数(別段指摘しない限りHzで示す)、LC=液体クロマトグラフィー、LHMDS=リチウムヘキサメチルジシラジド、m=多重線、M=モル濃度、[M+H]+=質量スペクトル親ピーク+H+、MS=質量スペクトル、ms=分子ふるい、MP=融点、Me2NH=ジメチルアミン、MeOH=メタノール、mg=ミリグラム、mL=ミリリットル、mM=ミリモル濃度、mmol=ミリモル、min=分、μL=マイクロリットル、μM=マイクロモル濃度、ng=ナノグラム、nM=ナノモル濃度、NMR=核磁気共鳴、ppm=百万分率、q=四重線、Rf=保持係数、RT=室温、s=一重線、t=三重線、TFA=トリフルオロ酢酸、THF=テトラヒドロフラン、TLC=薄層クロマトグラフィー。
一般スキームI.本明細書に記載の化合物の合成に有用な合成スキームを以下の一般スキームIで開示するが、一般スキームIにおいて、用語「Ar」とは、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールを指し、用語「R1」および「R2」は、上で規定したとおりである。
一般手順1
化合物4の合成では、以下の一般手順2の手順に従った。
一般手順2
化合物7の合成では、以下の一般手順3に従った。
一般手順3
化合物17の合成では、以下の一般手順4に従った。
一般手順4
化合物18の合成では、以下の一般手順5に従った。
一般手順5
一般スキームII.本明細書に記載の化合物の合成に有用な合成スキームを以下の一般スキームIIで開示するが、一般スキームIIにおいて、用語「X」は、ハロゲン、たとえば、Cl、Brを指し、「塩基」は、当業界で知られている塩基、たとえば、K2CO3、Et3Nなどであり、「R」は、本明細書で開示するような置換分、たとえば、置換もしくは非置換のアルキル、置換もしくは非置換のヘテロアルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のヘテロシクロアルキル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールである。
一般手順6
化合物22のタイプの化合物の調製に有用なスキームを以下のスキーム1に示す。
中間体6の調製
化合物23のタイプの化合物の調製に有用なスキームを以下のスキーム2に示す。
中間体7の調製
化合物24のタイプの化合物の調製に有用なスキームを以下のスキーム3に示す。
中間体10の調製
トリアゾリル環の生成を含む一般化学スキームを、以下の一般スキームIIIに示すが、「Ar」、「R1」、および「R2」は、実施例1で規定したとおりである。
化合物25の合成では、以下の一般手順7に従った。
一般手順7
化合物28のタイプの化合物の生成についての一般化学スキームを以下の一般スキームIVに示すが、「Ar」、「R1」、および「R2」は、実施例1で規定したとおりである。
中間体17の調製
中間体21の調製
一般スキームVI.化合物33を含む本明細書に記載の化合物の合成に有用な合成スキームを以下の一般スキームVIで開示するが、用語「Ar」、「R1」、および「R2」は、実施例1で規定したとおりである。
中間体23の調製では、一般手順8に従った。
一般手順8
中間体25の調製では、一般手順9に従った。
一般手順9
化合物33の調製では、一般手順10に従った。
一般手順10
一般スキームVII.化合物35を含む本明細書に記載の化合物の合成に有用な合成スキームを以下の一般スキームVIIで開示するが、用語「Ar」、「R1」、および「R2」は、実施例1で規定したとおりである。
中間体29の調製
一般スキームVIII.化合物36を含む本明細書に記載の化合物の合成に有用な合成スキームを以下の一般スキームVIIで開示するが、用語「Ar」、「R1」、および「R2」は、実施例1で規定したとおりである。
中間体31の調製では、一般手順11に従った。
一般手順11
化合物36の調製では、一般手順12に従った。
一般手順12
一般スキームIX.化合物39を含む本明細書に記載の化合物の合成に有用な合成スキームを以下の一般スキームIXで開示するが、用語「Ar」、「R1」、および「R2」は、実施例1で規定したとおりである。
中間体34の調製では、一般手順13に従った。
一般手順13
中間体35の調製では、一般手順14に従った。
一般手順14
中間体36の調製では、一般手順15に従った。
一般手順15
本明細書に記載の化合物の合成に有用な合成スキームを以下の一般スキームXで開示するが、用語「R」は、存在毎に、独立に、実施例1で規定したような「R1」および「R2」であり、「Ar1」および「Ar2」は、実施例1で「Ar」として規定したものである。
化合物42の調製では、一般手順16に従った。
一般手順16
化合物43の調製では、一般手順17に従った。
一般手順17
化合物44の調製では、一般手順18に従った。
一般手順18
化合物45の調製では、一般手順19に従った。
一般手順19
本明細書に記載の化合物の合成に有用な合成スキームを以下の一般スキームXIで開示するが、用語「Ar」、「R1」、および「R2」は、実施例1で規定したとおりである。
化合物48の調製では、一般手順20に従った。
一般手順20
本明細書に記載の化合物の合成に有用な合成スキームを以下の一般スキームXIIで開示するが、用語「Ar」、「R1」、および「R2」は、実施例1で規定したとおりであり、用語「X」は、ハロゲン、たとえば、Cl、Brを指す。
化合物52の調製では、一般手順21に従った。
一般手順21
本明細書に記載の化合物の合成に有用な合成スキームを以下の一般スキームXIIで開示するが、用語「Ar」、「R1」、および「R2」は、実施例1で規定したとおりである。
Claims (19)
- 以下の構造を有する化合物:
(式中、
L1は、結合であり、
L3は、−NH−であり、
L4は、結合であり、
R1は、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールであり、ここで、置換アリールおよび置換ヘテロアリールは、OH、NH 2 、SH、CN、CF 3 、NO 2 、ハロゲン、および非置換アルキルから選択される1以上の置換基を有し、
R2は、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のヘテロシクロアルキル、置換もしくは非置換のヘテロシクロアルケニル、置換もしくは非置換縮合環アリールまたは置換もしくは非置換のヘテロアリールであり、ここで、置換シクロアルキル、置換シクロアルケニル、置換ヘテロシクロアルキル、置換ヘテロシクロアルケニル、置換縮合環アリールおよび置換ヘテロアリールは、OH、NH2、SH、CN、CF3、NO2、オキソ、ハロゲン、および非置換アルキルから選択される1以上の置換基を有し、
R3は、置換アルキルであり、ここで置換アルキルは、置換もしくは非置換アリールまたは置換もしくは非置換ヘテロアリールから選択される1以上の置換基を有するものであり、ここで、置換アリールおよび置換ヘテロアリールは、OH、NH 2 、SH、CN、CF 3 、NO 2 、オキソ、ハロゲン、および非置換アルキルから選択される1以上の置換基を有し、
R4は、水素である)。 - R1がフェニルまたはピリジルである、請求項1に記載の化合物。
- R3が置換メチルである、請求項1に記載の化合物。
- R3が置換アルキルであり、前記置換基がヘテロ原子として窒素を含む置換または非置換のヘテロアリールである、請求項1に記載の化合物。
- R3が置換アルキルであり、前記置換アルキルは置換および非置換アリールならびに置換および非置換ヘテロアリールからなる群から選択される置換基を有するものであり、1以上の前記置換アリールおよび置換ヘテロアリール基は1以上のハロゲンで置換されている、請求項1に記載の化合物。
- 請求項1から5のいずれかに記載の化合物であって、
- 請求項1から6のいずれかに記載の化合物と、薬学的に許容される添加剤とを含む医薬組成物。
- 対象において疾患または障害を治療するための医薬であって、請求項1から6のいずれかに記載の化合物または請求項7に記載の医薬組成物を含む、医薬。
- 前記疾患または障害が血栓性障害である、請求項8に記載の医薬。
- 前記血栓性障害が、急性冠動脈症候群、静脈血栓塞栓症、動脈血栓塞栓症または心原生血栓塞栓症である、請求項9に記載の医薬。
- 前記疾患または障害が線維症である、請求項8に記載の医薬。
- 前記疾患または障害が多発性硬化症である、請求項8に記載の医薬。
- 前記疾患または障害が疼痛である、請求項8に記載の医薬。
- 前記疾患または障害ががんである、請求項8に記載の医薬。
- 対象において疾患または障害を予防するための医薬であって、請求項1から6のいずれかに記載の化合物または請求項7に記載の医薬組成物を含む、医薬。
- 前記疾患または障害が血栓性障害である、請求項15に記載の医薬。
- 前記血栓性障害が、急性冠動脈症候群、静脈血栓塞栓症、動脈血栓塞栓症または心原生血栓塞栓症である、請求項16に記載の医薬。
- 前記血栓性障害が播種性血管内凝固症候群である、請求項16に記載の医薬。
- 前記血栓性障害が、血液凝塊血栓の存在もしくは潜在的形成を伴うものである、請求項16に記載の医薬。
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