JP6860585B2 - 非環状抗ウイルス 優先出願の参照による組み込み - Google Patents
非環状抗ウイルス 優先出願の参照による組み込み Download PDFInfo
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- JP6860585B2 JP6860585B2 JP2018547294A JP2018547294A JP6860585B2 JP 6860585 B2 JP6860585 B2 JP 6860585B2 JP 2018547294 A JP2018547294 A JP 2018547294A JP 2018547294 A JP2018547294 A JP 2018547294A JP 6860585 B2 JP6860585 B2 JP 6860585B2
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Description
特に定義されない限り、本明細書で用いられる技術用語及び科学用語は全て、当業者によって一般的に理解されているものと同じ意味を有する。本明細書に引用する全ての特許、特許出願、公開出願及び他の刊行物は、別段に明記しない限り、その全体が参照により本明細書に組み込まれる。本明細書の用語について複数の定義が存在する場合、別段に明記しない限り、本項の定義が優先する。
本明細書に開示されたいくつかの実施形態は、式(I)の化合物、又はその薬学的に許容される塩に関する。
式(I)の化合物又はその薬学的に許容される塩、及び本明細書に記載された化合物は、多様な方法で調製することができる。式(I)の化合物又はその薬学的に許容される塩への一般的な合成経路、及び式(I)の化合物又はその薬学的に許容される塩を合成するために使用される出発物質のいくつかの例は、スキーム1に示され、本明細書に記載されている。本明細書に図示及び説明される経路は、単なる例示であり、たとえいかなる方法であっても特許請求の範囲を限定することを意図するものではなく、またそのように解釈すべきでもない。当業者は、開示する合成の変形例を認識し、本明細書の開示に基づく代替経路を考案することができるであろう。このような変形例及び代替経路は全て、本特許請求の範囲内である。
本明細書に記載するいくつかの実施形態は、有効量の本明細書に記載する1つ以上の化合物(例えば、式(I)の化合物又はその薬学的に許容される塩)と、薬学的に許容される担体、希釈剤、賦形剤又はこれらの組み合わせと、を含み得る医薬組成物に関する。
本明細書に開示されるいくつかの実施形態は、被験体に、有効量の、式(I)の化合物若しくはその薬学的に許容される塩、又は本明細書に記載された化合物を含む医薬組成物若しくはその薬学的に許容される塩などの1種又は2種以上の化合物を投与することを含むことができる疾病又は病状を治療し、かつ/又は寛解させる方法に関する。本明細書に開示される他の実施形態は、疾病に罹患しているとして特定された被験体に、有効量の、式(I)の化合物若しくはその薬学的に許容される塩、又は本明細書に記載された化合物若しくはその薬学的に許容される塩を含む医薬組成物などの本明細書に記載された1種又は2種以上の化合物を投与することを含むことができる、疾病又は病状を治療し、かつ/又は寛解させる方法に関する。
いくつかの実施形態では、式(I)の化合物若しくはその薬学的に許容される塩などの本明細書に開示された化合物、又は本明細書に記載された化合物若しくはその薬学的に許容される塩を含む医薬組成物は、1種又は2種以上の付加的な作用剤と組み合わせて使用することができる。式(I)の化合物若しくはその薬学的に許容される塩、又は式(I)の化合物若しくはその薬学的に許容される塩を含む医薬組成物と組み合わせて使用することができる付加的な作用剤の例は、HIV、HBV、及び/又はHDVを治療するための従来の標準治療において現在使用されている作用剤であり得る。いくつかの実施形態において、式(I)の化合物若しくはその薬学的に許容される塩、又は式(I)の化合物若しくはその薬学的に許容される塩を含む医薬組成物は、本明細書に記載された1種、2種、3種以上の付加的な作用剤と共に使用することができる。
(2−((4−アミノピロロ[2,1−f][1,2,4]トリアジン−7−イル)メトキシ)エチル)ホスホン酸
(化合物1)
(R)−(((1−(4−アミノピロロ[2,1−f][1,2,4]トリアジン−7−イル)プロパン−2−イル)オキシ)メチル)ホスホン酸(化合物2)
((2−(4−アミノピロロ[2,1−f][1,2,4]トリアジン−7−イル)エトキシ)メチル)ホスホン酸(化合物3)
(R)−(((1−(8−アミノ−[1,2,4]トリアゾロ[3,4−f][1,2,4]トリアジン−3−イル)プロパン−2−イル)オキシ)メチル)ホスホン酸(化合物4)
(R)−(((1−(4−アミノイミダゾ[2,1−f][1,2,4]トリアジン−7−イル)プロパン−2−イル)オキシ)メチル)ホスホン酸(化合物5)
(R)−(((1−(4−アミノイミダゾ[5,1−f][1,2,4]トリアジン−7−イル)プロパン−2−イル)オキシ)メチル)ホスホン酸(化合物6)
(1−(4−アミノピラゾロ[1,5−a][1,3,5]トリアジン−8−イル)プロパン−2−イルオキシ)メチルホスホン酸(化合物7)
(((1−(4−アミノ−2−フルオロピロロ[2,1−f][1,2,4]トリアジン−7−イル)プロパン−2−イル)オキシ)メチル)ホスホン酸
(化合物8)
(((1−(2,4−ジアミノピロロ[2,1−f][1,2,4]トリアジン−7−イル)プロパン−2−イル)オキシ)メチルホスホン酸
(化合物9)
(1−(4−アミノピラゾロ[1,5−a][1,3,5]トリアジン−8−イル)−3−フルオロプロパン−2−イルオキシ)メチルホスホン酸
(化合物10)
(1−(4−アミノピラゾロ[1,5−a][1,3,5]トリアジン−8−イル)プロパン−2−イルオキシ)メチルホスホン酸(化合物11)
表3における以下の化合物を、11と同様にして調製した。
(((1−(4−オキソ−3,4−ジヒドロピロロ[2,1−f][1,2,4]トリアジン−7−イル)プロパン−2−イル)オキシ)メチル)ホスホン酸(化合物47)
(((1−(2−アミノ−4−オキソ−3,4−ジヒドロイミダゾ[2,1−f][1,2,4]トリアジン−7−イル)プロパン−2−イル)オキシ)メチル)ホスホン酸(化合物48)
(S)−(((1−(4−アミノピロロ[2,1−f][1,2,4]トリアジン−7−イル)−3−フルオロプロパン−2−イル)オキシ)メチル)ホスホン酸(化合物49)
(((1−(2−アミノ−4−オキソ−3,4−ジヒドロピロロ[2,1−f][1,2,4]トリアジン−7−イル)プロパン−2−イル)オキシ)メチル)ホスホン酸(化合物50)
(化合物52)
以下の表4の化合物を、52と同様にして調製した。
((1−((4−アミノピラゾロ[1,5−a][1,3,5]トリアジン−8−イル)メチル)シクロプロポキシ)メチル)ホスホン酸(化合物64)
(S)(((3−(4−アミノピラゾロ[1,5−a][1,3,5]トリアジン−8−イル)−1,1−ジフルオロプロパン−2−イル)オキシ)メチル)ホスホン酸(化合物65)
(R)−(((3−(4−アミノピラゾロ[1,5−a][1,3,5]トリアジン−8−イル)−1,1−ジフルオロプロパン−2−イル)オキシ)メチル)ホスホン酸(化合物66)
(S)−(((1−(4−アミノイミダゾ[2,1−f][1,2,4]トリアジン−7−イル)−3−フルオロプロパン−2−イル)オキシ)メチル)ホスホン酸(化合物67)
(R)−(((1−(4−アミノイミダゾ[2,1−f][1,2,4]トリアジン−7−イル)−3−フルオロプロパン−2−イル)オキシ)メチル)ホスホン酸(化合物68)
((1−((2−アミノ−4−オキソ−3、4−ジヒドロピラゾロ[1,5−a][1,3,5]トリアジン−8−イル)メチル)シクロプロポキシ)メチル)ホスホン酸(22)
(((1−(2−アミノ−4−オキソ−3,4−ジヒドロピラゾロ[1,5−a][1,3,5]トリアジン−8−イル)−2−メチルプロパン−2−イル)オキシ)メチル)ホスホン酸(84)
ジホスフェート
アシクロヌクレオシドホスホネート(0.05mmol)を、0.5M TEAB緩衝液をその水性懸濁液に添加することによって、トリエチルアンモニウム塩に変換した。得られた透明な溶液を固体残渣に濃縮し、これを無水アセトニトリルで数回共蒸発させること、及び高真空化で保持することによって無水にした。固体材料をDMF(1.0mL)に溶解し、CDI(40mg、0.25mmol)を添加した。混合物を室温で7時間で撹拌し、次いでDMF(0.2mL)中のピロリン酸テトラブチルアンモニウム(0.25g、約0.25mmol)の溶液を添加した。この混合物を2日間室温で撹拌し、次いで酢酸トリエチルアンモニウム緩衝液で急冷し、水(10mL)で希釈し、HiPrep Q HP16/10カラム上に載置した。50mM TRIS−緩衝液(pH7.5)中0〜1NのNaClの線形勾配において、分離を行った。対応する画分を濃縮した。Synergy 4μ Hydro−RPカラム(Phenomenex)上でRP HPLCによって、脱塩を行った。50mM酢酸トリエチルアンモニウム緩衝液(pH7.5)中0〜30%の線形勾配のアセトニトリルを溶出に用いた。対応する画分を合わせ、濃縮し、凍結乾燥して過剰の緩衝液を除去した。得られたホスホノジホスフェートを表5に提供する。
式(I)の化合物
いくつかの化合物について、上記合成は例示的であり、式(I)の付加的な化合物を調製する出発点として使用することができる。式(I)の付加的な化合物の例を以下に示す。これらの化合物は、本明細書に示され、記載される合成スキームを含む、様々な方法で調製することができる。当業者は、開示した合成の変形例を認識し、本明細書の開示に基づく経路を考案することができるであろう。このような変形例及び代替経路は全て、本特許請求の範囲内である。
HIV単一サイクルアッセイ
感染の24時間前に、CEMヒトTリンパ球細胞(ATCC、Manassas、VA)をアッセイ培地(10%FBS、1%ペニシリン/ストレプトマイシンで補充したMEM(全てMediatech、Manassas、VA))に播種し、1% DMSO(Sigma−Aldrich、St Louis、MO)を、5×105細胞/mL(5×104細胞/ウェル)の密度で白色96ウェルプレートに播種した。連続希釈化合物を細胞に添加し、37℃、5% CO2で終夜インキュベートした。次の日に、細胞を、env及びnefの部分がRenilla−ルシフェラーゼで置き換えられたVSV−G偽型HIV NL4−3に感染させ、感染した細胞を37℃、5%CO2で72時間インキュベートした。ウイルス接種を滴定して、バックグラウンドでおよそ100x倍のRenilla−ルシフェラーゼシグナルを達成した。抗ウイルス活性は、100μLのRenilla−Glo(登録商標)試薬(Promega、Madison、WI)を感染した細胞に添加することによって測定した。室温で10分のインキュベーション後、発光を、Victor X3マルチラベルプレートリーダ(Perkin Elmer、Waltham、MA)上で測定した。非感染平行培養物の細胞毒性を、100μLのCellTiter−Glo(登録商標)試薬(Promega、Madison、WI)の添加及び室温で10分間のインキュベーションによって判定した。輝度は、Victor X3マルチラベルプレートリーダ上で測定した。
HIV逆転写酵素の阻害
組み換え全長HIV−1逆転写酵素(HIVrt)は、Abcam(カタログ番号ab63979)から購入した。5’非翻訳領域(c5’UTR)に相補的なHCV抗ゲノムの最後の385ヌクレオチド領域は、Ambion(カタログ番号AM1333)からのT7 RNAポリメラーゼMegascriptキットを使用して合成した。DNAオリゴを内部開始プライマーとして用い、IDTから購入した。別途特定されない限り、反応試料は、20nM c5’UTR RNA、100nM DNAプライマー及び1nM HIVrtからなり、50mM Tris pH7.5、100mM KCl、4mMジチオスレイトール(DTT)及び12.5mM MgCl2を含有する緩衝液中で一緒に混合した。反応を、30℃で、0.1μMのアデノシン三リン酸塩(dATP)、0.1μMのシトシン三リン酸塩(dCTP)、1μMのグアノシン三リン酸塩(dGTP)及び0.32μMの3H−チミジン三リン酸塩(3H−TTP)を、50μLの最終容量で添加することによって開始した。40分のインキュベーション後、60μLの冷却した20%(w/v)トリクロロ酢酸を500μMのATPと共に添加することによって反応を終了させて、核酸を沈殿させた。4℃で1時間のインキュベーション後、試料を、マルチスクリーンBV1.2−μmの96ウェルプレート(Millipore)上で濾過した。40μLのMicroscint−20(Perkin Elmer)をウェルに添加し、試料中の数を、Trilux Microbetaマイクロプレートシンチレーションリーダー(Wallac)によって判定した。
HBVの阻害
HepG2.117細胞(25継代より少ない)を、10% FBS(Coning、REF 35−011CV)、250μg/mL G418 Sulfate(Corning、REF30−234−CI)、2μg/mLテトラシクリン(TEKNOVA、カタログ番号T3325)及び1倍P/S(Corning、30−002−CI)を含むDMEM/F12 50/50培地(Corning、REF10−092−CM)中で培養した。各アッセイのために、細胞をアッセイ培地:DMEM/F12 50/50(Corning、REF10−092−CM)、2% Tet−system承認FBS(Clontech、カタログ番号631106)及び1倍P/S(Corning、30−002−CI)に播種した。
HCVレプリコン細胞における化合物の50%抑制濃度(EC50)を、以下の手順によって測定した。初日に、細胞を、Biocoatコラージュコーティングされた平底96ウェルプレートに100μLあたり30,000細胞で播種した。次の日、100%DMSOにおいて、100x所望の最終試験濃度に試験化合物を可溶化した。次いで、各化合物を9つの異なる濃度まで連続希釈した(1:3)。100%DMSO中の化合物を、アッセイ培地中で1:10に希釈することによって10%DMSOまで低減させた。最終DMSO濃度は1%だった。細胞を37℃で72時間インキュベートした。
Claims (25)
- 以下の構造を有する式(I)
任意に置換された
R1及びR2が、各々独立して、O−、−OH、任意に置換された−O−C1〜24アルキル、任意に置換された−O−C2〜24アルケニル、任意に置換された−O−C2〜24アルキニル、任意に置換された−O−C3〜6シクロアルキル、任意に置換された−O−C3〜6シクロアルケニル、任意に置換された−O−アリール、任意に置換された−O−ヘテロアリール、任意に置換された−O−アリール(C1〜6アルキル)、任意に置換された*−O−(CR4R5)p−O−C1〜24アルキル、任意に置換された*−O−(CR6R7)q−O−C1〜24アルケニル、
R1が、
R1及びR2が一緒になって、任意に置換された
R3a及びR3bが、各々独立して、水素、ハロゲン、非置換C1〜4アルキル、非置換C3〜6シクロアルキル、シアノ、ハロゲン(C1〜4アルキル)、ヒドロキシ(C1〜4アルキル)、アルコキシ基(C1〜4アルキル)、アシル(C1〜4アルキル)及びシアノ(C1〜4アルキル)からなる群から選択されるか、又は
R3a及びR3bが、それらが結合される前記炭素と一緒になって、任意に置換されたC3〜6シクロアルキルを形成し、
各R4、各R5、各R6及び各R7が、独立して、水素、任意に置換されたC1〜24アルキル又はアルコキシであり、
R8、R9、R11及びR12が、各々独立して、水素、任意に置換されたC1〜24アルキル及び任意に置換されたアリールからなる群から選択され、
R10及びR13が、各々独立して、水素、任意に置換されたC1〜24アルキル、任意に置換されたアリール、任意に置換された−O−C1〜24アルキル、任意に置換された−O−アリール、任意に置換された−O−ヘテロアリール及び任意に置換された−O−単環式ヘテロシクリルからなる群から選択され、
R14が、水素、任意に置換されたC1〜24アルキル及び任意に置換されたアリールからなる群から選択され、
R15及びR16が、各々独立して、−C≡N、任意に置換されたC2〜8オルガニルカルボニル、任意に置換されたC2〜8アルコキシカルボニル及び任意に置換されたC2〜8オルガニルアミノカルボニルからなる群から選択され、
R17が、水素、任意に置換されたC1〜24アルキル、任意に置換されたC2〜24アルケニル、任意に置換されたC2〜24アルキニル、任意に置換されたC3〜6シクロアルキル及び任意に置換されたC3〜6シクロアルケニルからなる群から選択され、
R19、R20、及びR21が、各々独立して、存在しないか又は水素であり、
mが、0又は1であり、
nが、1又は2であり、
p及びqが、各々独立して、1、2及び3からなる群から選択され、
rが、1又は2であり、
sが、0又は1であり、
Z1が、酸素(O)又は硫黄(S)である)の化合物、又はその薬学的に許容される塩。 - R1及びR2の一方が、O−又は−OHであり、R1及びR2のもう一方が、任意に置換された−O−C1〜24アルキル、任意に置換された−O−C2〜24アルケニル、任意に置換された−O−C2〜24アルキニル、任意に置換された−O−C3〜6シクロアルキル、任意に置換された−O−O−C3〜6シクロアルケニル、任意に置換された−O−アリール、任意に置換された−O−ヘテロアリール及び任意に置換された−O−アリール(C1〜6アルキル)からなる群から選択される、請求項1または2に記載の化合物。
- R1及びR2の両方が、各々独立して、任意に置換された−O−C1〜24アルキル、任意に置換された−O−C2〜24アルケニル、任意に置換された−O−C2〜24アルキニル、任意に置換された−O−C3〜6シクロアルキル、任意に置換された−O−C3〜6シクロアルケニル、任意に置換された−O−アリール、任意に置換された−O−ヘテロアリール及び任意に置換された−O−アリール(C1〜6アルキル)からなる群から選択される、または、R 1 及びR 2 の少なくとも一方が、任意に置換された * −O−(CR 4 R 5 ) p −O−C 1〜24 アルキルもしくは任意に置換された * −O−(CR 6 R 7 ) q −O−C 1〜24 アルケニルである、請求項1または2に記載の化合物。
- R1が、任意に置換された−O−アリールまたは任意に置換された−O−ヘテロアリールであり、R2が、任意に置換されたN−結合型アミノ酸又は任意に置換されたN−結合型アミノ酸エステル誘導体である、請求項1または2に記載の化合物。
- R2が、
R 1 及びR 2 が、各々独立して、
請求項7に記載の化合物。 - R1及びR2が、各々独立して、任意に置換されたN−結合型アミノ酸又は任意に置換されたN−結合型アミノ酸エステル誘導体であり、前記N−結合型アミノ酸が、アラニン、アスパラギン、アスパラギン酸塩、システイン、グルタミン酸塩、グルタミン、グリシン、プロリン、セリン、チロシン、アルギニン、ヒスチジン、イソロイシン、ロイシン、リシン、メチオニン、フェニルアラニン、スレオニン、トリプトファン及びバリンからなる群より選択される、請求項1または2に記載の化合物。
- R3a及びR3bの各々が、水素である、または、R 3a 及びR 3b の一方が、水素であり、R 3a 及びR 3b のもう一方が、ハロゲン(C 1〜4 アルキル)である、または、R 3a 及びR 3b の一方が、水素であり、R 3a 及びR 3b のもう一方が、CH 2 Fである、または、R 3a 及びR 3b の一方が、水素であり、R 3a 及びR 3b のもう一方が、CHF 2 である、または、R 3a 及びR 3b が、それらが結合している炭素と一緒になって、任意に置換されたC 3〜4 シクロアルキルを形成する、請求項1〜10のいずれか一項に記載の化合物。
- R3a及びR3bの一方が、水素であり、R3a及びR3bのもう一方が、フルオロである、または、R 3a 及びR 3b の一方が、水素であり、R 3a 及びR 3b のもう一方が、非置換C 1〜4 アルキルである、または、R 3a 及びR 3b の各々が、非置換C 1〜4 アルキルである、または、R 3a 及びR 3b の一方が、水素であり、R 3a 及びR 3b のもう一方が、メチルである、または、R 3a 及びR 3b の各々が、メチルである、または、R 3a 及びR 3b の一方が、水素であり、R 3a 及びR 3b のもう一方が、非置換C 3〜6 シクロアルキルである、または、R 3a 及びR 3b の一方が、水素であり、R 3a 及びR 3b のもう一方が、シアノである、または、R 3a 及びR 3b の一方が、水素であり、R 3a 及びR 3b のもう一方が、ヒドロキシ(C 1〜4 アルキル)である、または、R 3a 及びR 3b の一方が、水素であり、R 3a 及びR 3b のもう一方が、−CH 2 OHである、または、R 3a 及びR 3b の一方が、水素であり、R 3a 及びR 3b のもう一方が、アルコキシ(C 1〜4 アルキル)である、または、R 3a 及びR 3b の一方が、水素であり、R 3a 及びR 3b のもう一方が、−CH 2 OCH 3 である、または、R 3a 及びR 3b の一方が、水素であり、R 3a 及びR 3b のもう一方が、アシル(C 1〜4 アルキル)である、または、R 3a 及びR 3b の一方が、水素であり、R 3a 及びR 3b のもう一方が、シアノ(C 1〜4 アルキル)である、請求項1〜10のいずれか一項に記載の化合物。
- nが1であり、mが1である、または、nが2であり、mが1である、または、nが2であり、mが0である、請求項1〜12のいずれか一項に記載の化合物。
- 有効量の請求項1〜17のいずれか一項に記載の化合物又はその薬学的に許容される塩と、薬学的に許容される担体、希釈剤、賦形剤又はこれらの組み合わせと、を含む、医薬組成物。
- HBV及び/又はHDV感染症を治療するための、請求項18に記載の医薬組成物。
- HBV及び/又はHDV感染症の再発を低減するための、請求項18に記載の医薬組成物。
- HBV及び/又はHDVウイルスの複製を阻害するための、請求項18に記載の医薬組成物。
- HBV及び/又はHDVポリメラーゼ阻害剤、免疫調節剤、インターフェロン、ペグ化インターフェロン、ウイルス融合/侵入阻害剤、ウイルス成熟阻害剤、カプシド形成変調剤、逆転写阻害剤、NS5A阻害剤、シクロフィリン/TNF阻害剤、FXRアゴニスト、TLR−アゴニスト、iRNA又はASO cccDNA阻害剤、遺伝子サイレンシング剤、HBx阻害剤、sAg分泌阻害剤、及びHBVワクチンからなる群から選択される1種若しくは2種以上の作用剤、又は上記のうちのいずれかの薬学的に許容される塩を更に含む、請求項18〜21のいずれか一項に記載の医薬組成物。
- HIV感染症を寛解させるか又は治療するための、請求項18に記載の医薬組成物。
- HIVウイルスの複製を阻害するための、請求項18に記載の医薬組成物。
- 非ヌクレオシド逆転写酵素阻害剤(NNRTI)、ヌクレオシド逆転写酵素阻害剤(NRTI)、プロテアーゼ阻害剤(PI)、融合/侵入阻害剤(CCR5アンタゴニストとも呼ばれる)、インテグラーゼ鎖転移阻害剤(INSTI)及び他のHIV抗レトロウイルス療法からなる群から選択される1種若しくは2種以上の抗レトロウイルス療法(ART)剤、又は上記のうちのいずれかの薬学的に許容される塩を更に含む、請求項23又は24に記載の医薬組成物。
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