JP2011518228A - 真菌感染症の治療法 - Google Patents
真菌感染症の治療法 Download PDFInfo
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- JP2011518228A JP2011518228A JP2011506420A JP2011506420A JP2011518228A JP 2011518228 A JP2011518228 A JP 2011518228A JP 2011506420 A JP2011506420 A JP 2011506420A JP 2011506420 A JP2011506420 A JP 2011506420A JP 2011518228 A JP2011518228 A JP 2011518228A
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Abstract
【選択図】図8B
Description
(式中、各R1は独立して、−OH、−OC(O)H、−OC(O)アルキル、−NH2、−NH−アルキル、−N(アルキル)2、−NH−アミノ酸、−NHC(O)アルキル、−NHC(O)アリール、−NH(S(O)2)アルキル(ここで、アルキルは場合によって置換されている)、−NH(S(O)2)アリール(ここで、アリールは場合によって置換されている)、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換された5員ヘテロアリール、または場合によってアルキル、ハロゲン、OH、NH2、もしくはカルボニルで置換された5員もしくは6員複素環、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換されたアルキルである)と接触させ、
これによって真菌の成長を阻害するか、または真菌を殺すことを含む。
(式中、各R1は独立して−OH、−OC(O)H、−OC(O)アルキル、−NH2、−NH−アルキル、−N(アルキル)2、−NH−アミノ酸、−NHC(O)アルキル、−NHC(O)アリール、−NH(S(O)2)アルキル(ここで、アルキルは場合によって置換されている)、−NH(S(O)2)アリール(ここで、アリールは場合によって置換されている)、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換された5員ヘテロアリール、または場合によってアルキル、ハロゲン、OH、NH2、もしくはカルボニルで置換された5員もしくは6員複素環、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換されたアルキルである)と組み合わせて対象に投与し、これによって真菌感染症を治療することを含む。
式中、R1は、−OH、−OC(O)H、−OC(O)アルキル、−NH2、−NH−アルキル、−N(アルキル)2、−NH−アミノ酸、−NHC(O)アルキル、−NHC(O)アリール、−NH(S(O)2)アルキル(ここで、アルキルは場合によって置換されている)、−NH(S(O)2)アリール(ここで、アリールは場合によって置換されている)、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換された5員ヘテロアリール、または場合によってアルキル、ハロゲン、OH、NH2、もしくはカルボニルで置換された5員もしくは6員複素環である)。
(式中、各R1は独立して−OH、−OC(O)H、−OC(O)アルキル、−NH2、−NH−アルキル、−N(アルキル)2、−NH−アミノ酸、−NHC(O)アルキル、−NHC(O)アリール、−NH(S(O)2)アルキル(ここで、アルキルは場合によって置換されている)、−NH(S(O)2)アリール(ここで、アリールは場合によって置換されている)、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換された5員ヘテロアリール、または場合によってアルキル、ハロゲン、OH、NH2、もしくはカルボニルで置換された5員もしくは6員複素環、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換されたアルキルである)と組み合わせて投与し、これによって対象における再発性膣炎を治療することを含む。いくつかの実施形態において、再発性膣炎は、カンジダ・アルビカンスを含む。他の実施形態において、再発性膣炎はカンジダ・アルビカンス存続細胞を含む。
(式中、各R1は独立して、−OH、−OC(O)H、−OC(O)アルキル、−NH2、−NH−アルキル、−N(アルキル)2、−NH−アミノ酸、−NHC(O)アルキル、−NHC(O)アリール、−NH(S(O)2)アルキル(ここで、アルキルは場合によって置換されている)、−NH(S(O)2)アリール(ここで、アリールは場合によって置換されている)、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換された5員ヘテロアリール、または場合によってアルキル、ハロゲン、OH、NH2、もしくはカルボニルで置換された5員もしくは6員複素環、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換されたアルキルである)と接触させ、これにより真菌の成長を阻害するか、または真菌を殺すことを含む。
(式中、各R1は独立して−OH、−OC(O)H、−OC(O)アルキル、−NH2、−NH−アルキル、−N(アルキル)2、−NH−アミノ酸、−NHC(O)アルキル、−NHC(O)アリール、−NH(S(O)2)アルキル(ここで、アルキルは場合によって置換されている)、−NH(S(O)2)アリール(ここで、アリールは場合によって置換されている)、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換された5員ヘテロアリール、または場合によってアルキル、ハロゲン、OH、NH2、もしくはカルボニルで置換された5員もしくは6員複素環、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換されたアルキルである)と組み合わせて投与し、これによって真菌感染症を治療することを含む。
本開示の化合物は、そのあらゆる可能な異性体、立体異性体、エナンチオマ、ジアステレオマ、互変異性体、薬剤的に許容される塩、および溶媒和物を包含する。したがって、本開示で用いられる「化合物」および「(複数の)化合物」という用語は、本開示の化合物ならびにそのあらゆる可能な異性体、立体異性体、エナンチオマ、ジアステレオマ、互変異性体、薬剤的に許容される塩、および溶媒和物を意味する。
増強剤の同定法
式Iの化合物
アダマンタン誘導体の調製法
スキーム1
MeCN、室温(RT)で0.5時間
両ヒドロキシ置換アダマンタンは、スキーム1に示す化学反応にしたがって、またAlonsoら、Tetrahedron,64(8)、1847−1852(2008)で記載されているようにして製造することができる。
スキーム2
2.NaBH4、3時間、室温
3.NH4OH、H2O
スキーム2(「AC17」)のアミノアダマンタンは、Miriyalaら、Tetrahedron,60(7)、1463−1472,(2004)で記載される方法に従って合成することができる。
スキーム3
スキーム4
スキーム5
スキーム6
スキーム8
2.H2O、冷却
3.NaHCO3、塩基性化
スキーム10
本明細書で記載するいくつかの増強剤化合物を、様々な真菌感染症を治療するための、それ自体は抗真菌薬活性を有さない既知の抗真菌薬と組み合わせて用いることができる。さらに、ある増強剤化合物は抗真菌薬活性を有するが、抗真菌薬の活性を増強する働きもする。
真菌感染症は、多くの真菌種が原因であり、本明細書で記載する化合物を用いて、かかる真菌種の成長を阻害するか、またはかかる真菌種を殺すことができる。これらの真菌としては、これらに限定されるものではないが、アスペルギルス属の構成要素(たとえば、アスペルギルス・フラバス、アスペルギルス・フミガタス、アスペルギルス・グラウカス、アスペルギルス・ニデュランス、アスペルギルス・ニガー、およびアスペルギルス・テレウス)、ブラストミセス・デルマチチジス、カンジダ属の構成要素(たとえば、カンジダ・アルビカンス、カンジダ・グラブラタ、カンジダ・トロピカリス、カンジダ・パラプシロシス、カンジダ・クルセイ、およびカンジダ・ギリエルモンディ、コクシジオイデス・イミチス、クリプトコッカス属の構成要素(たとえば、クリプトコッカス・ネオフォルマンス、クリプトコッカス・アルビダス、およびクリプトコッカス・ローレンティ)、ヒトプラズマ・カプスラーツム・カプスラーツム変異株、ヒトプラズマ・カプスラーツム・ズボアジ変異株、パラコクシジオイデス・ブラジリエンシス、スポロスリックス・シェンキー、アブシジア・コリムビフェラ、リゾムコール・プシルス、およびリゾープス・アリズスが挙げられる。
抗真菌薬
本明細書で記載する抗真菌薬および増強剤化合物の投与経路および/または様式は、所望の結果に応じて様々であり得る。たとえば、本明細書で記載する抗真菌薬および化合物の用量は、治療効果が、抗真菌薬単独を用いて(すなわち、本明細書に記載する化合物の非存在下で)得られるよりも少なくとも10%、20%、25%、30%、40%、50%、60%、70%、80%、90%、100%、125%、150%、175%、または200%高くなるように選択することができる。このような効果は、たとえば真菌感染症に関連する標準的パラメータを用いて当業者には認識することができる。投薬計画を調節して、所望の反応、たとえば治療応答もしくは組み合わせ治療効果を得ることができる。一般的に、抗真菌薬と本明細書に記載する化合物との用量の任意の組み合わせ(別個もしくは同時処方のいずれか)を、生物学的に利用可能な量で両薬剤を対象に提供するために、用いることができる。
プランクトン様およびバイオフィルム集団の両方を、存続細胞の存在の可能性について調べた。アムホテリシンB、クロルヘキシジン、およびカスポファンギンをはじめとするいくつかの化合物はカンジダバイオフィルムを殺し、これらは用量に依存した実験で試験した。生存細胞の亜集団を明示する二相性殺菌曲線は、存続細胞の存在を示す。
既知の抗真菌薬が存続細胞に対して不活性であるならば(高レベルのクロルヘキシジンを除く)、通常の抗真菌薬との組み合わせで存続形成を無効にし感染を根絶する潜在的な存続細胞を同定するスクリーンを開発した。特に、スクリーンは、準阻害濃度のミコナゾールで処理されたシー・アルビカンス細胞を用い、これに対して候補増強剤化合物を添加して開発された。バイオフィルムをマイクロタイタープレート中で成長させ、アラマーブルーの減少を定量的読み出しとして使用した。アラマーブルーは、生きている細胞によって減少し、青から赤への色の変化として視覚的に検出できる蛍光指示薬を産生する。この一次スクリーンは、直接作用する化合物と、ミコナゾールを増強する化合物とを識別しなかった。以下に記載するような、その後の一次ヒットの検証によって、相乗的に作用する化合物が同定された。
Z’=1−(3SD++3SD−)/(Ave+−Ave−)
(式中、SD+=正の対照標準偏差、SD−=負の対照標準偏差、Ave+=正の対照平均、およびAve−=負の対照平均)。
AC17を、高存続突然変異体の効力、毒性、バイオフィルムを根絶する能力のインビトロ評価に付した。
ミコナゾールの存在下で、バイオフィルムを殺し、存続細胞を根絶するために必要なAC17の最低濃度を決定した。野生型成熟シー・アルビカンス・バイオフィルムをAC17で48時間攻撃した。バイオフィルムを洗浄し、こすり取り、PBS中に再懸濁させ、30秒間ボルテックスし、コロニー計数のためにプレートした。ミコナゾールが100μg/mlで存在していた。
高濃度の殺菌性抗生物質を定期的に適用することは、インビトロでの大腸菌(E.coli)における高存続「hip」突然変異体の選択につながる。hip突然変異体の同様の選択がインビボで起こるかどうかを確認するために、シー・アルビカンスの131臨床分離株のコレクションを、それらの存続レベルについて試験した。これらの株は、抗癌化学療法の結果として口腔カンジダ症を発症した患者から得た。患者を局所クロルヘキシジンで毎日治療した。
前述のように、AC17はカンジダバイオフィルムをミコナゾールとの組み合わせで殺すことが判明した。AC17がバイオフィルム形成に対して直接影響を及ぼすかどうかを確認した。
どのようにしてAC17がバイオフィルム形成を阻害し、直接成長阻害活性を有さなかったかをよりよく理解するために、AC17の繊維状生育に対する影響を決定した。顕微鏡検査を用いて、AC17が酵母菌の菌糸への推移を特異的に阻害するか、または菌糸伸長を防止するかどうかを分析した。
カンジダによる浸潤性成長は発病およびインビボでの感染の確立に関与する。AC17が固体培地中への浸潤を防止する能力を分析した。いくつかの遺伝経路がフィラメンテ−ションおよび浸潤性成長を活性化する。たとえば、転写因子CZF1は埋め込み成長状態における浸潤に関与し、一方、CPH1の突然変異の結果、ある培地では繊維状生育不良となるが、寒天内では軽度の不良を示す。このように、いくつかの条件下で様々な培地中への浸潤を阻害するAC17の能力を試験した。
UME6は、菌糸成長の維持に必要とされる転写因子であることが知られている。Δume6突然変異の結果、AC17で処理した細胞と類似した短縮された菌糸表現型が得られるので、UME6は、AC17の推定標的であり得る。AC17がUME6経路を標的とするかどうかを試験するために、AC17で処理された細胞をUME6突然変異体と比較した。
シー・アルビカンスに感染したカテーテルを処理するために、2%のミコナゾールおよび1%のAC17を含むカテーテルロック溶液を調製する。カテーテルを使用しない状態で、カテーテル管腔をロッキングし、溶液を7日間、1日につき2時間投与することによって、カテーテルを処理する。次いで、すすいだ後に使用する。カテーテルをミコナゾール/AC17溶液で処理することによって、バイオフィルムおよび存続細胞が除去され、カテーテルの連続使用が可能になる。
対象における口腔カンジダ症を治療するために、10mgのクロトリマゾールおよび5mgのAC17を含むロゼンジを調製する。ロゼンジを7日間、1日につき5回投与する。AC17とクロトリマゾールとの組み合わせを含むロゼンジの使用は、バイオフィルムおよび存続細胞を除去し、疾患の再発を予防する。
対象においてカンジダが原因の膣内酵母菌感染症を治療するために、2%ミコナゾール、硬化植物油基剤、安息香酸、セチルアルコール、ミリスチン酸イソプロピル、ポリソルベート60、水酸化カリウム、プロピレングリコール、純水、およびステアリルアルコールを含むクリーム(たとえば、Monistat(登録商標)クリーム)に1%のAC17をを添加する。クリームを膣の患部に7日間、1日1回投与する。ミコナゾール含有クリームにAC17を添加することによって、ミコナゾールの効能が増大し、再発性疾患を予防する。
本発明をその詳細な説明と関連して記載したが、先の記載は、添付の特許請求の範囲によって規定される本発明の範囲を説明することを意図するものであって、限定するものではない。他の態様、利点、および修正は、以下の特許請求の範囲内に含まれる。
Claims (42)
- 真菌の成長を阻害するか、または真菌を殺す方法であって、前記真菌を有効量の
(a)抗真菌薬と、
(b)式I:
- 前記増強剤化合物が前記抗真菌薬の活性を増強する、請求項1に記載の方法。
- 前記増強剤化合物が抗真菌薬化合物でない、請求項1に記載の方法。
- 真菌の成長を阻害するか、または真菌を殺す方法であって、前記真菌を、有効量の
(a)抗真菌薬と、
(b)式Ia:
- 前記増強剤化合物が前記抗真菌薬の活性を増強する、請求項4に記載の方法。
- 前記増強剤化合物が抗真菌薬化合物でない、請求項4に記載の方法。
- 真菌の成長を阻害するか、または真菌を殺す方法であって、前記真菌を
(a)抗真菌薬と、
(b)式Ib:
- 前記増強剤化合物が前記抗真菌薬の活性を増強する、請求項11に記載の方法。
- 前記増強剤化合物が抗真菌薬化合物でない、請求項11に記載の方法。
- これを必要とする対象における真菌感染症を治療する方法であって、前記対象に、有効量の
(a)抗真菌薬を、
(b)有効量の1以上の式I:
(式中、各R1は独立して−OH、−OC(O)H、−OC(O)アルキル、−NH2、−NH−アルキル、−N(アルキル)2、−NH−アミノ酸、−NHC(O)アルキル、−NHC(O)アリール、−NH(S(O)2)アルキル(前記アルキルは場合によって置換されている)、−NH(S(O)2)アリール(前記アリールは場合によって置換されている)、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換された5員ヘテロアリール、または場合によってアルキル、ハロゲン、OH、NH2、もしくはカルボニルで置換された5員もしくは6員複素環、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換されたアルキルである)と組み合わせて投与し、これによって前記真菌感染症を治療することを含む、方法。 - 前記増強剤化合物が抗真菌薬の活性を増強する、請求項16に記載の方法。
- 前記増強剤化合物が抗真菌薬化合物でない、請求項16に記載の方法。
- これを必要とする対象における真菌感染症を治療する方法であって、前記対象に、有効量の
(a)抗真菌薬を、
(b)有効量の1以上の式Ia:
(式中、各R1は独立して−OH、−OC(O)H、−OC(O)アルキル、−NH2、−NH−アルキル、−N(アルキル)2、−NH−アミノ酸、−NHC(O)アルキル、−NHC(O)アリール、−NH(S(O)2)アルキル(前記アルキルは場合によって置換されている)、−NH(S(O)2)アリール(前記アリールは場合によって置換されている)、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換された5員ヘテロアリール、または場合によってアルキル、ハロゲン、OH、NH2、もしくはカルボニルで置換された5員もしくは6員複素環、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換されたアルキルである)と組み合わせて投与し、これによって前記真菌感染症を治療することを含む、方法。 - 前記増強剤化合物が前記抗真菌薬の活性を増強する、請求項19に記載の方法。
- 前記増強剤化合物が抗真菌薬化合物でない、請求項19に記載の方法。
- これを必要とする対象における真菌感染症を治療する方法であって、前記対象に、有効量の
(a)抗真菌薬を
(b)有効量の1以上の式Ib:
(式中、各R1は独立して−OH、−OC(O)H、−OC(O)アルキル、−NH2、−NH−アルキル、−N(アルキル)2、−NH−アミノ酸、−NHC(O)アルキル、−NHC(O)アリール、−NH(S(O)2)アルキル(前記アルキルは場合によって置換されている)、−NH(S(O)2)アリール(前記アリールは場合によって置換されている)、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換された5員ヘテロアリール、または場合によってアルキル、ハロゲン、OH、NH2、もしくはカルボニルで置換された5員もしくは6員複素環、または場合によってアルキル、ハロゲン、OH、もしくはNH2で置換されたアルキルである)と組み合わせて投与し、これによって前記真菌感染症を治療することを含む、方法。 - 前記増強剤化合物が、前記抗真菌薬の活性を増強する、請求項26に記載の方法。
- 前記増強剤化合物が抗真菌薬化合物でない、請求項26に記載の方法。
- シー・アルビカンス真菌の成長を阻害するか、シー・アルビカンス真菌を殺す方法であって、有効量の
(a)抗真菌薬と、
(b)式I:
- シー・アルビカンス真菌の成長を阻害するか、シー・アルビカンス真菌を殺す方法であって、有効量の
(a)抗真菌薬と、
(b)式Ia:
- シー・アルビカンス真菌の成長を阻害するか、シー・アルビカンス真菌を殺す方法であって、前記真菌を
(a)抗真菌薬および
(b)式Ib:
- これを必要とする対象においてシー・アルビカンス真菌感染症を治療する方法であって、前記対象に、有効量の
(a)抗真菌薬を、
(b)有効量の式I:
と組み合わせて投与して、これにより前記真菌感染症を治療することを含む、方法。 - これを必要とする対象においてシー・アルビカンス真菌感染症を治療する方法であって、前記対象に、有効量の
(a)抗真菌薬を
(b)有効量の1以上の式Ia:
と組み合わせて投与し、これにより真菌感染症を治療することを含む、方法。 - これを必要とする対象においてシー・アルビカンス真菌感染症を治療する方法であって、前記対象に有効量の
(a)抗真菌薬を、
(b)有効量の1以上の式Ib:
と組み合わせて投与し、これによって前記真菌感染症を治療することを含む方法。
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