JP2018505909A - ウィルス感染の処置又は予防において使用する為のキノリン誘導体 - Google Patents
ウィルス感染の処置又は予防において使用する為のキノリン誘導体 Download PDFInfo
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Classifications
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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Abstract
Description
(i) 多くのウィルス、例えばレトロウィルス、例えばHIV又はヘルペスウィルス科のDNAウィルス、はウィルス潜伏によって特徴付けられており、それは細胞内で休眠状態になるウィルスの能力であり、従ってウィルスライフサイクルの溶原性部分を定義する、という事実。潜伏は、初期感染後に、完全に根絶すること無しに、ウィルス粒子の増殖が止まるウィルス複製サイクルの段階である。ウィルス潜伏の現象は、宿主内の所謂「リザーバ」の出現に関連しており、それは、一般的に到達しにくく、且つそれはまた、HIVの為の治癒を提供することの困難性の主な理由の一つである;
(ii) 特に長期処置を必要とするウィルス感染についての、薬物耐性株の出現。突然変異株の出現の見込みは特に、レトロウィルス、例えばHIV、にとって重要である。実際、抗HIV薬物に対する耐性は、下記の通り、生物学的レベルで説明されることができる。レトロウィルスとして、HIVは、酵素 逆転写酵素を使用してそのRNAゲノムからDNAを合成し、及び、そのゲノムを再生している間になされた誤りを訂正する為のメカニズムが欠けている。その結果、HIVは、何らかの「生きている」有機体の最高の既知の突然変異率でそのゲノムを複製する。これは、遺伝的変異が自然選択の為の原材料であるので、HIV集団に対して作用する為の自然選択についての理想的な状況を作り出す。
− それらのウィルス量が制御されるか又は減少さえされている;
− CD4+細胞数のそれらのレベルが維持されるか又は回復さえされている;及び/又は、
− ウィルス関連状態、例えばAIDS、に一般的に関連付けられている臨床的徴候が安定化されているか又は消失さえされている。AIDSの臨床的徴候は、感染の段階に応じて変化する。
(i) HIVがレトロウィルスであり、及び、以前に述べた通り、新規な突然変異株の出現がウィルスのこのクラスについて特に重要であるという事実;
(ii) HIVが潜在相に入り、従って現在利用可能な処置によって効率的に標的化されていない「潜在性の」リザーバを形成する為の能力を有するという事実;
(iii) 現在利用可能な処置がまた、時間の経過とともにHIV突然変異株を選択する傾向があり、それは長期的において薬物耐性の出現における主要な役割を有するという事実。
(i) ヌクレオシド類似体とまた呼ばれるヌクレオシド/ヌクレオチド逆転写酵素阻害剤、例えばアバカビル、エムトリシタビン、及びテノホビル;
(ii) 非ヌクレオシド逆転写酵素阻害剤(NNRTIs:non-nucleoside reverse transcriptase inhibitors)、例えばエファビレンツ、エトラビリン、及びネビラピン;
(iii) プロテアーゼ阻害剤(PIs:protease inhibitors)、例えばアタザナビル、ダルナビル、及びリトナビル;
(iv) 侵入阻害剤、例えばエンフビルチド、及びマラビロク;
(v) インテグラーゼ阻害剤、例えばドルテグラビル及びラルテグラビル。
− 所定の期間中にウィルス量を減少させる際の抗HIV剤の作用、しかし上記処置の終了後に該ウィルス量の持続的な低下を必ずしも示さない;及び/又は、
− HIV感染されている患者におけるCD4+細胞数のレベルを増加させる際の抗HIV剤の作用、しかし、上記処置の終了後に、上記細胞の持続的な増加又は安定化を必ずしも示さない。
Rは独立に、水素原子、ハロゲン原子、又は、-CN基、水酸基、-COOR1基、(C1〜C3)フルオロアルキル基、(C1〜C3)フルオロアルコキシ基、(C3〜C6)シクロアルキル基、-NO2基、-NR1R2基、(C1〜C4)アルコキシ基、フェノキシ基、-NR1-SO2-NR1R2基、-NR1-SO2-R1基、-NR1-C(=O)-R1基、-NR1-C(=O)-NR1R2基、-SO2-NR1R2基、-SO3H基、-O-SO2-OR3基、-O-P(=O)-(OR3)(OR4)基、-O-CH2-COOR3基、及び(C1〜C3)アルキル基のうちから選択される基を表し、上記アルキルは任意的に、水酸基によって一置換されていてもよく、
QはN又はOであり、ただし、Qが Oである場合にR’’は存在しない、
R1及びR2は独立に、水素原子又は(C1〜C3)アルキル基であり、
R3及びR4は独立に、水素原子、Li+、Na+、K+、N+(Ra)4、又はベンジル基を表し、
nは1、2又は3であり、
n’は1、2又は3であり、
R’は独立に、水素原子、又は、(C1〜C3)アルキル基、ハロゲン原子、水酸基、-COOR1基、-NO2基、-NR1R2基、モルホリニル基若しくはモルホリノ基、N-メチルピペラジニル基、(C1〜C3)フルオロアルキル基、(C1〜C4)アルコキシ基、及び-CN基のうちから選択される基を表し、及びさらに下記のうちから選択される基であることができる:
Bは、共有結合又はNHであり、
mは、1、2、3、4又は5であり、
pは、1、2又は3であり、
Ra及びRbは独立に、水素原子、(C1〜C5)アルキル基、又は(C3〜C6)シクロアルキル基を表し、
Ra及びRbはさらに、それらが結合している窒素原子と一緒に、N、O及びSのうちから選択されるさらなるヘテロ原子を任意的に含む飽和5又は6員複素環を形成することができ、上記複素環は任意的に、1以上のRaによって置換されていてもよく、ただし、R’が(IIa)基又は(IIIa)基である場合には、他のR’基が上記(IIa)基又は(IIIa)基と異なる場合にのみ、n’は2又は3であってもよく、
R’’は、水素原子、(C1〜C4)アルキル基、又は上で定義された通りの(IIa)基である。
− (1) 8-クロロ-3-メチル-N-2-(4-(トリフルオロメチル)ピリジン-2-イル)キノリン-2,5-ジアミン
− (2) 8-クロロ-N-2-(4-(トリフルオロメチル)ピリジン-2-イル)キノリン-2,5-ジアミン
− (3) 8-クロロ-5-(2-モルホリノエトキシ)-N-(4-(トリフルオロメチル)ピリジン-2-イル)キノリン-2-アミン
− (4) 8-クロロ-N4-(3-(ピペリジン-1-イル)プロピル)-N-2-(4-(トリフルオロメチル)ピリジン-2-イル)キノリン-2,4-ジアミン
− (5) 8-クロロ-6-(2-モルホリノエトキシ)-N-(4-(トリフルオロメチル)ピリジン-2-イル)キノリン-2-アミン
− (6) 8-クロロ-N-メチル-N-(4-(トリフルオロメチル)ピリジン-2-イル)キノリン-2-アミン
− (7) 8-クロロ-N-(4-(トリフルオロメチル)ピリジン-2-イル)キノリン-2-アミン
− (8) 4,8-ジクロロN-(4-(トリフルオロメチル)ピリジン-2-イル)キノリン-2-アミン
− (9) 8-クロロ-N-(3-モルホリノプロピル)-N-(4-(トリフルオロメチル)ピリジン-2-イル)キノリン-2-アミン
− (10) 8-クロロ-5-(2-(ピペリジン-1-イル)エトキシ)-N-(4-(トリフルオロメチル)ピリジン-2-イル)キノリン-2-アミン
− (11) (8-クロロ-キノリン-2-イル)-(4-メチル)ピリジン-2-イル)-アミン
− (12) 8-クロロ-N-(5-フルオロピリジン-2-イル)キノリン-2-アミン
− (13) N-(3-メトキシピリジン-2-イル)キノリン-2-アミン
− (14) N-(6-(トリフルオロメチル)ピリジン-2-イル)キノリン-2-アミン
− (15) 6-クロロ-N-(5-フルオロピリジン-2-イル)キノリン-2-アミン
− (16) N-(3-フルオロピリジン-2-イル)キノリン-2-アミン
− (17) 8-クロロ-N-(6-(トリフルオロメチル)ピリジン-2-イル)キノリン-2-アミン
− (18) 8-クロロ-N-(3-クロロ-4-メトキシフェニル)キノリン-2-アミン
− (19) 8-クロロ-N-(4-(メトキシ)フェニル)キノリン-2-アミン
− (20) 3-メチル-N-(4-(トリフルオロメトキシ)フェニル)キノリン-2-アミン
− (21) 8-クロロ-N-(3-(ピペリジン-1-イル)プロピル)-N-(4-(トリフルオロメトキシ)フェニル)キノリン-2-アミン
− (22) 8-クロロ-N-(4-(トリフルオロメトキシ)フェニル)キノリン-2-アミン
− (23) 4,8-ジクロロN-(4-(トリフルオロメトキシ)フェニル)キノリン-2-アミン
− (24) 8-クロロ-N-メチル-N-(4-(トリフルオロメトキシ)フェニル)キノリン-2-アミン
− (25) 8-クロロ-N-(2-モルホリノエチル)-N-(4-(トリフルオロメトキシ)フェニル)キノリン-2-アミン
− (26) 8-クロロ-N-(ピラジン-2-イル)キノリン-2-アミン
− (27) 8-クロロ-2-((4-(トリフルオロメチル)ピリジン-2-イル)オキシ)キノリン
− (28) 4-(2-((8-クロロ-2-((4-(トリフルオロメチル)ピリジン-2-イル)オキシ)キノリン-6-イル)オキシ)エチル)モルホリン
− (29) 8-クロロ-2-(4-(トリフルオロメトキシ)フェノキシ)キノリン
− (30) 4-(2-((8-クロロ-2-(4-(トリフルオロメトキシ)フェノキシ)キノリン-5-イル)オキシ)エチル)モルホリン
− 「ハロゲン」は、塩素、フッ素、臭素又はヨウ素、特に塩素、フッ素又は臭素、を意味すると理解される、
− 「(C1〜C5)アルキル」はそれぞれ、本明細書において使用される場合に、C1〜C5の直鎖、第2級又は第3級の飽和炭化水素を言及する。例が、制限されるものではないが、メチル、エチル、1−プロピル、2−プロピル、ブチル、ペンチルである、
− 「(C3〜C6)シクロアルキル」はそれぞれ、本明細書において使用される場合に、環状飽和炭化水素を言及する。例が、制限されるものではないが、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルである、
− 「(C1〜C4)アルコキシ」はそれぞれ、本明細書において使用される場合に、O-(C1〜C4)アルキル残基を言及し、ここでアルキルは上記に定義された通りである例が、制限されるものではないが、メトキシ、エトキシ、1-プロポキシ、2-プロポキシ、ブトキシである、
− 「フルオロアルキル基」及び「フルオロアルコキシ」はそれぞれ、上記に定義された通りのアルキル基及びアルコキシ基を言及し、当該基は少なくとも1つのフッ素原子によって置換されている。例が、ペルフルオロアルキル基、例えばトリフルオロメチル又はペルフルオロプロピル、である、
− 「飽和5又は6員複素環」はそれぞれ、本明細書において使用される場合に、少なくとも1つのヘテロ原子を含む飽和環を言及する。例が、制限されるものではないが、モルホリン、ピペラジン、チオモルホリン、ピペリジン、及びピロリジン.である。
− HIVウィルス量の増加;及び/又は、
− CD4+細胞数のレベルの減少;
− AIDSに一般的に関連付けられている臨床的徴候の増加又は出現。
− 上記患者が、複製及び/又は感染性が安定化されている又はそれどころか減少されていると考えられていたウィルス株、特にHIV株、で感染されているが、それは処置、例えばART及びHAARTの処置、に対してもはや応答しない;及び/又は、
− 上記患者が、薬物耐性株で感染されている。
− HIVウィルス量の増加;及び/又は、
− CD4+細胞数のレベルの減少;
ここで、HIVウィルス量及び/又はCD4+細胞数のレベルが、好ましくは血漿サンプルにおいて確立されている。
− 上記に開示された通り、従来の処置後に上記患者からの薬物耐性株を選択すること;及び/又は、
− 薬物耐性株で上記患者の初感染をすること。
(i) ヌクレオシド類似体とまた呼ばれるヌクレオシド/ヌクレオチド逆転写酵素阻害剤、例えばアバカビル、エムトリシタビン、及びテノホビル;
(ii) 非ヌクレオシド逆転写酵素阻害剤(NNRTIs:non-nucleoside reverse transcriptase inhibitors)、例えばエファビレンツ、エトラビリン、及びネビラピン;
(iii) プロテアーゼ阻害剤(Pis:protease inhibitors),例えばアタザナビル、ダルナビル、及びリトナビル;
(iv) 侵入阻害剤、例えばエンフビルチド、及びマラビロク;
(v) インテグラーゼ阻害剤、例えばドルテグラビル、及びラルテグラビル;並びに、
それらの組み合わせ。
− M41;K65;D67;K70;L74;Y115;M184(M184 V/Iを含む);L210;T215;K219;主なNRTI耐性突然変異として;
− M41;A62;D67;T69;K70;V75;F77;F116;Q151;L210;T215;K219;マルチNTRI耐性突然変異として;
− V90;A98;L100;K101;K103;V106;V108;E138;V179;Y181;Y188;G190;H221;P225;F227;M230;主なNNRTI耐性突然変異として;
− L10;V11;G16;K20;L24;D30;V32;L33;E34;M36;K43;M46;I47;G48;I50;F53;I54;Q58;D60;I62;L63;I64;H69;A71;G73;L74;L76;V77;V82;N83;I84;I85;N88;L89;L90;I93;主なプロテアーゼ阻害剤耐性突然変異として;
− T66;L74;E92;T97;E138;G140,Y143;S147;Q148;N155;主なインテグラーゼ阻害剤耐性突然変異として;
− G36;I37;V38;Q39;Q40;N42;N43;主な侵入阻害剤耐性突然変異として;並びに
それらの組み合わせ。
− 血漿サンプルの1mL当たりのウィルスRNA又はDNAのコピーの数;
− 血漿サンプルの1mL当たりのウィルス粒子の数;及び/又は、
− 血漿サンプル中のウィルス関連タンパク質の活性。
− 血漿サンプルの1mL当たりのHIV RNAのコピーの数;及び/又は、
− 血漿サンプルの1mL当たりのHIV粒子の数;及び/又は、
− 血漿サンプル中のHIV関連タンパク質の活性、それは例えば、該血漿サンプル中の逆転写酵素(RT)活性を決定することを含みうる。
− サンプルの1mL当たりのHIV RNAのコピーの数を決定すること;
− サンプルの1mL当たりのHIV粒子の数を決定すること;及び/又は、
− サンプル中のHIV関連タンパク質の活性を決定すること。
(i) 患者から得られた全血サンプルを用意すること;
(ii) 遠心分離によって当該サンプルから細胞を除去し、血漿を用意すること;
(iii) 例えば逆転写酵素ポリメラーゼ連鎖反応(RT-PCR)、分岐DNA(bDNA)、又は核酸配列ベースの増幅(NASBA)解析によって血漿の1ml当たりのHIV RNAのコピーの数を決定すること;
(iv) 任意的に、工程(iii)で得られた上記結果を参照値及び/又はベースライン測定値と比較すること。
(i) それを必要とする患者に、式(1)のキノリン誘導体の有効量を投与し、それによって上記患者を処置すること;
(ii) 上記処置を終了すること;
(iii) 任意的に、処置の終了後に、上記患者におけるウィルス量及び/又はCD4+細胞数を測定すること;ここで好ましくは:処置終了後に、
− 低い又は検出できないウィルス量が維持されること;及び/又は、
− CD4+細胞数が安定し又は増加していること;
(iv)任意的に、上記ウィルス量が低くないか又は検出できなくはない場合に及び/又はCD4+細胞数が減少している場合に、それを必要とする患者に、式(1)のキノリン誘導体の有効量を投与すること。
式(I)の化合物、又はその医薬的に許容される塩及び代謝物のいずれか一つが、1以上の抗レトロウィルス化合物、例えばART及びHAART処置、例えば下記から選択される一つと組み合わせて投与されうる:ジドブジン、ラミブジン、エムトリシタビン、ジダノシン、スタブジン、アバカビル、ザルシタビン、テノホビル、ラシビル、アムドキソビル、アプリシタビン、エルブシタビン、エファビレンツ、ネビラピン、エトラビリン、デラビルジン、リルピビリン、テノホビル、フォスアルブジン、アンプレナビル、チプラナビル、インジナビル、サクイナビル、ホスアンプレナビル、リトナビル、ダルナビル、アタザナビル、ネルフィナビル、ロピナビル、ラルテグラビル、エルビテグラビル、ドルテグラビル、エンフビルチド、マラビロク、ビクリビロック、及びそれらの組み合わせ。
シーケンシング・アプローチ(deep sequencing approach)を適用した。4人の異なるドナーの、処置された及び処置されていない感染した初期マクロファージから得られたウィルスが配列決定され、且つヒトゲノムに整列してない読み取りが、Wu等(Fast and SNP-tolerant detection of complex variants and splicing in short reads. Bioinformatics、第26巻、第873〜881頁、(2010年))に詳述されている通り、gsnapを使用してYU2配列に整列された。低く且つ高い頻度の変異体の大部分は、処置された及び処置されていないサンプルにおいて等しく存在し、化合物22が特定の変異体を選択しないことを示す。
Claims (11)
- ウィルス感染又はウィルス関連状態、特に従来の抗ウィルス処置有効性における非有効性又は低下が言及された患者におけるHIV感染又はHIV関連状態、を処置又は予防する為に使用する為の、下記の式(I)のキノリン誘導体、又はその医薬的に許容される塩の一つ若しくはその代謝物の一つ
Rは独立に、水素原子、ハロゲン原子、又は、-CN基、水酸基、-COOR1基、(C1〜C3)フルオロアルキル基、(C1〜C3)フルオロアルコキシ基、(C3〜C6)シクロアルキル基、-NO2基、-NR1R2基、(C1〜C4)アルコキシ基、フェノキシ基、-NR1-SO2-NR1R2基、-NR1-SO2-R1基、-NR1-C(=O)-R1基、-NR1-C(=O)-NR1R2基、-SO2-NR1R2基、-SO3H基、-O-SO2-OR3基、-O-P(=O)-(OR3)(OR4)基、-O-CH2-COOR3基、及び(C1〜C3)アルキル基のうちから選択される基を表し、上記アルキルは任意的に、水酸基によって一置換されていてもよく、
QはN又はOであり、ただし、Qが Oである場合にR’’は存在しない、
R1及びR2は独立に、水素原子又は(C1〜C3)アルキル基であり、
R3及びR4は独立に、水素原子、Li+、Na+、K+、N+(Ra)4、又はベンジル基を表し、
nは、1、2又は3であり、
n’は、1、2又は3であり、
R’は独立に、水素原子、又は(C1〜C3)アルキル基、ハロゲン原子、水酸基、-COOR1基、-NO2基、-NR1R2基、モルホリニル基若しくはモルホリノ基、N-メチルピペラジニル基、(C1〜C3)フルオロアルキル基、(C1〜C4)アルコキシ基、及び-CN基のうちから選択される基を表し、及びさらに下記のうちから選択される基であることができる:
Bは、共有結合又はNHであり、
mは、1、2、3、4又は5であり、
pは、1、2又は3であり、
Ra及びRbは独立に、水素原子、(C1〜C5)アルキル基、又は(C3〜C6)シクロアルキル基を表し、
Ra及びRbはさらに、それらが結合している窒素原子と一緒に、N、O及びSのうちから選択されるさらなるヘテロ原子を任意的に含む飽和5又は6員複素環を形成することができ、上記複素環は任意的に、1以上のRaによって置換されていてもよく、ただし、R’が(IIa)基又は(IIIa)基である場合には、他のR’基が上記(IIa)基又は(IIIa)基と異なる場合にのみ、n’は2又は3であってもよく、
R’’は、水素原子、(C1〜C4)アルキル基、又は上で定義された通りの(IIa)基である。 - 上記患者は、薬物耐性ウィルス株によって、より特には薬物耐性HIV株によって、感染されている、ウィルス感染又はウィルス関連状態、特に患者におけるHIV感染又はHIV関連状態、を処置又は予防する為に使用する為の、請求項1に記載の式(I)のキノリン誘導体、又はその医薬的に許容される塩若しくは代謝物の一つ。
- ウィルス感染又はウィルス関連状態、特に患者におけるHIV感染又はHIV関連状態、を処置又は予防し、そして次に、ウィルス量が低い又は検出できない場合に及び/又はCD4+細胞数のレベルが維持又は回復される場合に、上記処置を終了する為に使用する為の、請求項1に記載の式(I)のキノリン誘導体、又はその医薬的に許容される塩若しくは代謝物の一つ。
- 上記ウィルス量が、500コピー/血漿mL未満ならば、低い、上記ウィルス量が、40コピー/血漿mL未満ならば、検出できない、及び上記CD4+細胞数のレベルが、500 CD4+細胞/血漿mm3以上ならば、回復される、請求項3の記載に従って使用する為の、請求項1に記載の式(I)のキノリン誘導体、又はその医薬塩及び代謝物のいずれか一つ。
- 上記HIV株が、ART及び/又はHAART処置から選択される薬物に対して耐性である、請求項2の記載に従って使用する為の、請求項1に記載の式(I)のキノリン誘導体、又はその医薬塩及び代謝物のいずれか一つ。
- 上記HIV株が、ジドブジン、ラミブジン、エムトリシタビン、ジダノシン、スタブジン、アバカビル、ザルシタビン、テノホビル、ラシビル、アムドキソビル、アプリシタビン、エルブシタビン、エファビレンツ、ネビラピン、エトラビリン、デラビルジン、リルピビリン、テノホビル、フォスアルブジン、アンプレナビル、チプラナビル、インジナビル、サクイナビル、ホスアンプレナビル、リトナビル、ダルナビル、アタザナビル、ネルフィナビル、ロピナビル、ラルテグラビル、エルビテグラビル、ドルテグラビル、エンフビルチド、マラビロク、ビクリビロック、及びそれらの組み合わせから選択される薬物に対して耐性である、請求項2の記載に従って使用する為の、請求項1に記載の式(I)のキノリン誘導体、又はその医薬塩及び代謝物のいずれか一つ。
- 上記患者は、抗レトロウィルス処置によって予め処置されていない、請求項1又は2の記載に従って使用する為の、請求項1に記載の式(I)のキノリン誘導体、又はその医薬塩及び代謝物のいずれか一つ。
- 上記キノリン誘導体又はその代謝物が、処置期間中又は連続的な処置として、1日に1回、3日に1回、1週間に1回、2週間に1回、毎月1回、特に投与量25〜500mg、特に25〜300mg、より特には25〜200mg、例えば25〜150mg、で投与される、請求項1〜8のいずれか一項の記載に従って使用する為の、請求項1に記載の式(I)のキノリン誘導体、又はその医薬塩及び代謝物のいずれか一つ。
- 上記処置期間が2〜8週間である、請求項1〜8のいずれか一項の記載に従って使用する為の、請求項1に記載の式(I)のキノリン誘導体、又はその医薬塩及び代謝物のいずれか一つ。
- 上記キノリン誘導体が下記の式(Ib)を有し、
- 8-クロロ-N-(4-(トリフルオロメトキシ)フェニル)キノリン-2-アミン、特にそのN-グルクロニド代謝物、である、請求項1〜10のいずれか一項の記載に従って使用する為の、請求項1に記載の式(I)のキノリン誘導体、又はその医薬塩及び代謝物のいずれか一つ。
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