JP2020050676A - 抗菌性治療薬及び予防薬 - Google Patents
抗菌性治療薬及び予防薬 Download PDFInfo
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- JP2020050676A JP2020050676A JP2019239163A JP2019239163A JP2020050676A JP 2020050676 A JP2020050676 A JP 2020050676A JP 2019239163 A JP2019239163 A JP 2019239163A JP 2019239163 A JP2019239163 A JP 2019239163A JP 2020050676 A JP2020050676 A JP 2020050676A
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- 229940126573 antibacterial therapeutic Drugs 0.000 title 1
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- 125000000217 alkyl group Chemical group 0.000 claims description 130
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 85
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical class NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 claims description 17
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- 125000002947 alkylene group Chemical group 0.000 claims description 3
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- LJAXTAOSOVPBQH-UHFFFAOYSA-N n-methylpiperidin-3-amine Chemical compound CNC1CCCNC1 LJAXTAOSOVPBQH-UHFFFAOYSA-N 0.000 claims description 3
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- WAXIREISPYMGCW-UHFFFAOYSA-N piperidine;piperidin-4-ol Chemical compound C1CCNCC1.OC1CCNCC1 WAXIREISPYMGCW-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
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Abstract
Description
本出願は、その内容がその全体で引用により本明細書中に組み込まれている、2015年7月28日に出願されたインド特許出願第2298/DEL/2015号の米国特許法(35USC)第119(a)−119(d)条の1又は複数の条項の下での恩恵を主張するものである。
本開示は概して、一般に細菌感染症を、より具体的には抗生物質耐性病原菌による細菌感染症を、治療するための新規の分子、組成物、及び製剤に関する。
今日の世界的な健康シナリオにおける重大な懸念事項は、ごく最近に開発された世代の抗生物質であっても回避可能な薬剤耐性菌株が広範に拡散していることである(Fait及びTor、2014, Perspect Medicin Chem 6: 25;Michaelら、2014, Front Public Health 2: 145.)。細菌は、薬物耐性表現型を獲得するために、様々な戦略をとる(Dever及びDermody、1991, Arch Intern Med 151: 886)。細菌の遺伝要素は、病原菌に対し数多くの抵抗様式を提供する(Davies及びDavies、2010, Microbiol Mol Biol Rev 74: 417)。抗生物質の修飾又は分解を担当する酵素をコードする遺伝子もあるし、結果的に抗生物質の標的タンパク質との相互作用を妨害する抗生物質の標的酵素又は代謝経路の変異を生じさせる遺伝子もある。他の遺伝的な要素が、抗生物質の透過性又は取込みを減少させることもある。時には、排出機構を活性化し、抗生物質をその取込み後に外部へ押し出すことが可能な微生物もいる。バイオフィルム内に存在することで、細菌は、保護的マトリクスを障害物(hindrance)として使用し、抗生物質の接近を効率的に遅延することも可能である(Hoibyら、2010, Int J Antimicrob Agents 35: 322)。このことは、「耐性の拡散を助長する」様々な抗生物質を確立してしまうことを引き起こす。したがって、様々な感染症に関与した多剤耐性の超強力な細菌からの脅威に対処するための新規戦略の開発は、必須である。前向きで巧妙な方策は、現存する薬物耐性菌に対して作用させるのみではなく、標的細菌が耐性菌に進化する機会を減少させる分子を設計することであろう。薬物耐性菌が耐性を拡散する作用するのを妨げるのみではなく、耐性を発達させることをも妨げる特徴を有するこのような効果的な分子が、高感受性及び/又は耐性の細菌により引き起こされる微生物疾患の治療を大きく進展させることとなり得る。
高感受性及び耐性の標的タンパク質のゲノムデータに加え、生物学的標的高分子及びリガンド−標的複合体構造に関する大量の利用可能な結晶学情報からの細菌耐性の機械的及び構造的態様の理解により、細菌の耐性の出現に対抗し現存の耐性「病原菌」に対しても作用する優れた分子が設計可能になる。本明細書において、本発明者らは、複数の機序により抗生物質耐性を迂回及び/又は抑制することにより、論理にかないながらも創造性に富む新たな特性を薬物分子に組み込むことが可能な戦略である「二重作用論的治療薬(Dual Action Rational Therapeutics)」に基づく、理論的な構造ベースの創薬アプローチについて説明する。本発明者らは、この戦略を用いて、フラグメントベースのインシリコ薬物設計アプローチを採用し、選択された標的タンパク質の全く新規なまたは既知の活性部位もしくはアロステリック部位に対する新たな最先端の分子を作製する一方、現存する抗生物質に新規かつ非自明である化学修飾を行って構造的かつ機能的に新規な分子を得た。
(式中:
(a)nは、1であり;
X及びYは、酸素原子であり;
Wは、炭素原子であり;
Zは、存在せず;
R1は、水素原子、ヒドロキシル、メトキシ、アミノ、−NH−(CH2)p−Rであり、ここで、pは、0、1、2、3、4もしくは5であり;Rは、水素原子、アミン、グアニジン、ピペラジン、モルホリン、NHCOCH3、NHSO2CH3、NHSO2−C6H5もしくは−L1−B−R7であり;
L1は、−(CH2)q−、−(CH2)q−CH=CH−(CH2)q−、−(CH2)q−O−(CH2)q−、−(CH2)q−NH−(CH2)q−であり、ここで、qは、0、1、2もしくは3であり;
A及びBは、独立して、シクリル、ヘテロシクリル、アリール又はヘテロアリールであり、ここで、シクリル、ヘテロシクリル、アリール又はヘテロアリールは、1、2又は3個の置換基により任意に置換されることができ;
R7は、水素原子、ヒドロキシル、ハロ、ニトロ、カルボン酸、カルボン酸メチルエステル、OMe、ニトリル、C(NH)−NH2、アミノ、−NHCOCH3、NHSO2CH3、NHSO2−ベンゼンであり、ここで、ベンゼンは、オルト、メタもしくはパラ位で、任意にかつ独立して置換されることができ;
R2は、−L1−A−R7であり;
R3は、Hであり;
R4及びR5は、独立して、水素、ハロゲン、ヒドロキシル、又は−O−(CH2)t−R8であり、ここで、R8は、C1−C6アルキル、アミノ、ジ(C1−C6アルキル)アミノ、アミノシクロプロパン、アミノシクロペンタン、ピペラジノ、又はモルホリンであり、並びに、tは、0〜10であり;或いは
(b)nは、1であり;
X及びWは、炭素原子であるか、又はXは炭素原子でありかつWは窒素原子であり;
Yは、−NH(CH2)q−R6又は(CH2)q−R6であり、ここで、q=0〜10であり;
R6は、−COOH、アミン、グアニジン、ピペラジン、モルホリンであり;
Zは、水素、メチル、NHR、COCH3、SO2CH3、又は−NH−(CH2)l−COOHであり、ここで、lは、0〜10であり;
R1及びR3は、独立して、水素原子、ヒドロキシル、メトキシ、アミノ、又は−L1−A−R6であり;
Rは、CH3、−(CH2)p−CH3であり、ここで、p=0〜10であり;
L1は、−(CH2)n−、−(CH2)t−CH=CH−(CH2)t−、−(CH2)t−O−(CH2)t−、−(CH2)t−NH−(CH2)t−であり、ここで、tは、0、1、2、又は3であり;
Aは、シクリル、ヘテロシクリル、アリール又はヘテロアリールであり、ここでシクリル、ヘテロシクリル、アリール又はヘテロアリールは、1、2又は3個の置換基により任意に置換されることができ;
R6は、水素原子、ヒドロキシル、ハロ、ニトロ、カルボン酸、カルボン酸メチルエステル、OMe、ニトリル、C(NH)−NH2、アミノ、−NHCOCH3、NHSO2CH3、NHSO2−ベンゼンであり、ここで、ベンゼンは、オルト、メタもしくはパラ位で、任意にかつ独立して置換されることができ;
R2は、水素原子であり;
R4及びR5は、独立して、水素、ハロゲン、ヒドロキシル、又は−O(CH2)x−R8であり、ここで、R8は、C1−C6アルキル、アミノ、ジ(N(CH3)2、N(C2H5)2、N(i−Pr)2、アミノシクロプロパン、アミノシクロペンタン、ピペラジノ、又はモルホリンであり、並びに、xは、0〜10であり;或いは、
(c)nは、2であり;
X及びWは、炭素原子であり;
Yは、−NH(CH2)q−R6又は(CH2)q−R6であり、ここで、q=0〜10であり;
R6は、−COOH、アミン、グアニジン、ピペラジン、モルホリンであり;
Zは、水素、メチル、NHR、COCH3、SO2CH3、又は−NH−(CH2)l−COOHであり、ここでlは、0〜10であり;
R1及びR3は、独立して水素原子、ヒドロキシル、メトキシ、アミノ、又は−L1−A−R6であり;
Rは、CH3、−(CH2)p−CH3であり、ここでp=0〜10であり;
L1は、−(CH2)n−、−(CH2)t−CH=CH−(CH2)t−、−(CH2)t−O−(CH2)t−、−(CH2)t−NH−(CH2)t−であり、ここでtは、0、1、2、又は3であり;
Aは、シクリル、ヘテロシクリ、アリール又はヘテロアリールであり、ここでシクリル、ヘテロシクリ、アリール又はヘテロアリールは、1、2又は3個の置換基により任意に置換されることができ;
R6は、水素原子、ヒドロキシル、ハロ、ニトロ、カルボン酸、カルボン酸メチルエステル、OMe、ニトリル、C(NH)−NH2、アミノ、−NHCOCH3、NHSO2CH3、NHSO2−ベンゼンであり、ここで、ベンゼンは、オルト、メタもしくはパラ位で、任意にかつ独立して置換されることができ;
R2は、水素原子であり;
R4及びR5は、独立して、水素、ハロゲン、ヒドロキシル、又は−O(CH2)x−R8であり、ここで、R8は、C1−C6アルキル、アミノ、ジ(N(CH3)2、N(C2H5)2、N(i−Pr)2、アミノシクロプロパン、アミノシクロペンタン、ピペラジノ、又はモルホリンであり、及び、xは、0〜10である)、並びに、
合成された新規抗生物質の前述の特性を達成するために、複数の戦略が考慮された。分子は、単独又はそれらの組合せで、複製(DNA合成)、翻訳(タンパク質発現)、及び細胞ホメオスタシス(細胞壁/膜の完全性)のプロセスを標的化する1又は複数の作用機序(複数可)を持つように、設計された。一つの戦略は、新規相互作用を通じてより高い親和性で、標的(複数可)に結合する分子をつくることであった。微生物は、該分子の結合を防止するために標的部位での複数の変異を発生するので、相互作用の多様性は、耐性発達の機会を減少する。加えて、新規相互作用は、存在する耐性菌株における変異した標的へさえもの結合を可能にすることができる。第二に、空間的及び/又は時間的に無関係であっても、複数の標的部位への結合を可能にする個別のモチーフを持つ分子を有することである。これらの場合、一つの標的での変異は、他の標的が効率的に阻害されない場合、このバグを二重作用する分子に対し耐性としない。かかる二重作用する分子はまた、一部の細胞は一つの標的で変異され、かつ他の細胞は第二の標的で変異されている耐性菌株の混合集団による感染シナリオにおいても有効である。二重作用する分子は、以前に文献において説明されているが(WO2002059116、US20060105941、US9149536、US56416139、Pokrovskaya及びBaasov、2010, Expert Opin Drug Discov 5: 883)、依然、各標的に対する特異性及び感受性に関するそれらの活性の釣り合いが鍵である。構造は、細菌標的に作用する一方で、同時に細菌により分泌される抗生物質分解酵素を阻害するための特異的部分によりはっきりと(sensibly)概説されている。後者は、抗生物質分解酵素の活性部位残基及びそれらの作用様式の先行する知識を基にしているであろう。第三に、抗生物質作用に加えバイオフィルム阻害特性を持つ分子は、バイオフィルムマトリクスの形成を防止することを助け、好適な阻害濃度の該分子への標的化されたバグの曝露、及び結果としての耐性の回避を確実にするであろう。第四の戦略は、存在するバイオフィルムを通じた分子の透過を可能にし、かつ微生物上/内の作用部位に到達するための、一部の二重作用分子においてバイオフィルム破壊特性を含むことであった。別の戦略は、グラム陰性菌及びグラム陽性菌の両方に対する抗生物質の広範なスペクトル活性を保証するために、慎重に選択された標的に対する分子を設計することであった。対照的に、ある種の分子は、特異的病原菌を標的化し、他のものを標的化しない(狭いスペクトル)ように、選択的に開発された。第七のアプローチにおいて、分子は、炎症、創傷治癒などの、ある種の感染症の他の局面に対処するために、抗生物質作用を超える特徴を持つように設計された。かかる場合において、本分子は、感染宿主組織上で発揮されることを意味する特性を包含するように構築された。一部の分子は、前述の戦略のふたつ以上を対象とした。
便宜のために、本明細書、実施例及び添付された請求項においてここで使用される特定の用語を、ここでまとめる。別に言及しないか又は状況から暗喩されない限り、以下の用語及び語句は、以下に提供される意味を含む。別に明確に言及されないか又は状況から明らかでない限り、以下の用語及び語句は、その用語又は語句は、それが関与する技術分野において獲得される意味を排除しない。これらの定義は、特定の実施態様の説明を補助するために提供され、かつ本発明の範囲は、請求項によってのみ限定されるので、請求された発明を限定することを意図するものではない。さらに状況により別に必要とされない限りは、単数の用語は、複数を含み、かつ複数の用語は、単数を含むとされるべきである。
実施例1:化合物2の合成
実施例2:化合物6の合成
実施例3:化合物10の合成
実施例4:化合物11の合成
実施例5:化合物16の合成
実施例6:化合物18の合成
実施例7:化合物19の合成
実施例8:化合物20の合成
実施例9:化合物21の合成
実施例10:化合物31の合成
実施例11:化合物32の合成
実施例12:化合物33の合成
実施例13:化合物34の合成
実施例14:化合物43の合成
実施例15:化合物44の合成
実施例16:化合物48の合成
実施例17:化合物55の合成
実施例18:化合物57の合成
実施例19:化合物58の合成
実施例20:化合物65の合成
実施例21:化合物66の合成
実施例22:化合物68の合成
実施例23:化合物75の合成
実施例24:化合物76の合成
実施例25:化合物77の合成
実施例26:化合物78の合成
実施例27:化合物80の合成
実施例28:化合物84の合成
実施例29:化合物107の合成
実施例30:化合物108の合成
実施例31:化合物110の合成
実施例32:化合物111の合成
実施例33:化合物112の合成
実施例34:化合物113の合成
例示的な本発明の化合物を、様々な高感受性及び耐性のグラム陽性細菌株に対し、インビトロにおいて試験した。
試薬:ブレインハートインフュージョンブロス、細菌培養物、96ウェル−プレート、オートクレーブ、インキュベーター、アラマーブルー。
前記MIC結果は、最終的に得られる有効抗菌薬と、変動する官能基を伴う様々なクラスの抗生物質との間の、いくつかの興味深い構造活性相関(SAR)を強調している。変動するY及びZ置換基を伴う5員の複素環式部分で官能基化されたフルオロキノロンは全て、高感受性及び耐性黄色ブドウ球菌種に対し、同等に活性があることがわかる。例えば、類似のR4及びB基を伴うフルオロキノロンは、式Iに示したように、5員の複素環のY及びZ置換基を変化しながら、異なるように挙動する。これらの新規フルオロキノロン1、2、6、10及び11は全て、高感受性黄色ブドウ球菌及びMRSAの両方において、並びにE.フェシウムに対して、同等に活性がある。類似のBを伴う異なるY及びZ置換基は、特定の病原菌に対する特定の分子の特異性を変化させる。例えば、化合物6は、高感受性大腸菌及びエンテロバクター・アエロゲネスに対し活性があることを除き、化合物2及び6は、グラム陰性病原菌に対してと比べ、グラム陽性病原菌に対し特異性があることが、わかる。ほとんどのグラム陰性病原菌において、化合物2は、4〜8μg/mlの範囲の活性を示す。驚くべきことに、Y=S、Z=Nを伴う化合物(化合物6)並びにY=C及びZ=Oを伴う化合物(化合物10)は、キノロン耐性黄色ブドウ球菌株並びにキノロン及びエリスロマイシン耐性表皮ブドウ球菌株に対してさえ活性がある。化合物6及び10の間で、化合物10は、キノロン耐性黄色ブドウ球菌株及び表皮ブドウ球菌株に対しより活性があることがわかる。化合物10及び化合物11は、異なるB基を有するが、依然これらは、高感受性及び耐性の両方のグラム陽性病原菌に対し類似の活性を有する。
PMMAビーズに関する逐次ZIBアッセイ
材料:ブレインハートインフュージョン寒天、表皮ブドウ球菌S5−2、ペトリ皿、オートクレーブ、インキュベーター、UV分光光度計。
インプラントに関連した骨感染症は、骨セメントに負荷することができる化合物PMMAを必要とする。これらの化合物は、骨におけるそれらの作用のために、必ずセメントからの良好な放出特性を有さなければならず、治療は長期間にわたるので、この放出は持続されなければならず、かつ一般に黄色ブドウ球菌のような骨感染症に関連した微生物表皮ブドウ球菌、アクネ菌のような日和見病原菌などに対して極めて強力でなければならない。前述の微生物に対し良好な効能を有する化合物2及び10を、好適な比で、SmartSet HV(FDA承認済みPMMA)に負荷し、かつ骨感染症において主に使用される抗生物質バンコマイシンが負荷されたセメントと比べた。インビトロ阻害ゾーン(ZOI)アッセイは、表皮ブドウ球菌株S5−2を用いて行った。図1のZOIから認められるように、持続放出が化合物2及び10において得られた。この進行性の放出は、これら2種の化合物について、バンコマイシンよりも高いことがわかった。したがってこれらの化合物は、骨インプラント関連感染症に対する作用に関して、可能性のあるリード分子である。
簡単に述べると、本方法は、均質な透明な溶液を得るための、正確に秤量した量のジエチレングリコールモノエチルエーテル、ポリエチレングリコール400及びプロピレングリコールの均質な混合に関与している。活性物質(化合物2)の特定の量を、前記混合物へ、撹拌しながら少しずつ添加し、相Aを形成した。別に、ヒドロキシエチルセルロースを、30〜40分かけて撹拌しながら、水中に可溶化し、透明なゲル基剤(相B)を形成した。
簡単には、この方法は、シクロペントシロキサン、セトステアリルアルコール、イソソルビドジメチル、ステアレス2及びステアレス21のような、様々な相A成分を均質に混合しながら、同時に60℃で加熱し、透明な溶液を形成することを含む。正確に秤量した量の活性化合物2を、温度を60℃に維持することにより、相Aの透明な溶液に、少量ずつ添加した。相Bを、カルボポール980を水へ添加する(撹拌しながら)ことにより調製し、かつpHを5に調節し、均一なゲル基剤を形成した。プロピレングリコール及びポリエチレングリコール400のような保湿剤を、カルボポールゲル基剤に添加し、この混合物を60℃で加熱し、相Bを得た。相Aを、攪拌しながら、60℃で相Bに添加し、この混合物を40℃に冷却した。次に相C成分(ベンジルアルコール)を、先の混合物へ添加し、撹拌し、室温まで冷却させ、クリーム製剤を調製した。
試薬:ブレインハートインフュージョンブロス、黄色ブドウ球菌MTCC 6908及び表皮ブドウ球菌S5−2、96ウェルプレート、オートクレーブ、インキュベーター、マルチウェルリーダー、UV分光光度計
材料:ブレインハートインフュージョンブロス、表皮ブドウ球菌ATCC 35984、96ウェルプレート、オートクレーブ、インキュベーター、MTT、マルチウェルプレートリーダー。
インビボにおけるラット足浮腫モデルを使用する抗炎症性作用。宿主炎症は、細菌感染症に関連したほとんどの適応症の重大な臨床特徴の一つである。本発明者らは、本発明の例示的な化合物(化合物2)を使用し、インビボにおいてラット足浮腫モデルを使用し、抗炎症作用を試験した。炎症は、インプラント関連感染症において蔓延する日和見病原菌アクネ菌の1種を用いて、誘導した。スプラーグダルウェイラットを、本試験に使用し、かつ感染症は、アクネ菌CCARM 9010により誘導した。加熱により死滅させた細菌1×109CFU/mlの接種材料を、右後肢の足底側に注射し(〜2×107CFU/足)、それ以外にシャム対照には、食塩水を注射した。処置は、右後肢の足底表面に化合物2(30mg)の被験製剤を1日2回塗布し、かつ人差し指で50回優しく擦り込むことにより、注射後8時間で開始した。比較例のAcnedap(ダプソン5%ゲル)及びアダパレンゲル(Adaferin(登録商標))を、1日2回、及び臨床処方用量を基に1日1回塗布した。足のサイズは、感染の開始時、感染後8時間、及び処置開始後24時間(炎症誘導後32時間)に、Vernierキャリパーを使用しミリメートルで測定した。炎症に起因した足サイズの変化を、各時点で測定した足サイズと浮腫誘導直前に測定した基本足サイズの間の差異として評価した。誘導後32時間での炎症の阻害を、下記式を用い計算した:
阻害率(%)=100×(1−X/Y)
(式中、X=処置したラットの足サイズの平均増加(mm)、及びY=対照ラットの足サイズの平均増加(mm))。
長い間、β−ラクタム系は、黄色ブドウ球菌により引き起こされた感染症のための薬物の選択肢であった。しかし、これらの抗生物質の広範な使用は、古いβ−ラクタム系抗生物質に対する耐性の出現により時代遅れとなったが、セフタロリン、セフタビプロールのような新世代β−ラクタム系が、MRSAに対して働くことが分かっている。現在、バンコマイシン、ダプトマイシン及びリネゾリドが、MRSA、並びにセフタロリン耐性MRSA病原菌に対して働く利用可能な薬物である。しかし世界規模でのこれらの抗生物質全てに対する蔓延した抗生物質耐性は、特に耐性MRSAにより引き起こされた細菌感染症を根絶するための、新規戦略の開発を必要としている。
典型的には、SmartsetHV(登録商標)粉末40gmを、1gmの化合物10と、無菌条件下で、適宜混合し、均一な混合物を得た。次に、密封したモノマー溶液20mlを、PMMAポリマー及び活性物質の混合物へ添加し、かつ室温で混合を30秒間継続し、均質な混合物を形成した。前記混合物を、ゴム性グローブに最早接着しない必要なような粘度で柔らかい均質な混合物を得るために、2分間静置した。この柔らかい軟性混合物を、4.8mmビーズ金型に広げた。充填した金型を、セメントを室温で硬化させるために、25℃で7〜8分間静置した。硬化したセメントビーズを、金型から取りだし、無菌条件下で室温で貯蔵した。各ビーズの薬物含量を、HPLCにより測定し、これは計算された薬物含量と合致した。抗生物質負荷されたセメントビーズは、インビトロ薬物放出アッセイ、インビトロ逐次ZIBアッセイ及びインビトロバイオフィルム阻害試験について、さらに試験した。しかし世界規模でこれらの抗生物質全てに対する猛威を奮っている抗生物質耐性は、特に耐性MRSAにより引き起こされる細菌感染症を退治するための新規戦略を開発する課題を有す。
典型的には、stimulan rapid cure(登録商標)粉末40gmを、1gmの化合物2と、無菌条件下で、適宜混合し、均一な混合物を得た。次に混合溶液12.48mlを、薬物−ポリマー混合物へ添加し、かつ30秒間混合し、均質な軟性の柔らかい混合物を形成した。この軟性混合物を、4.8mmビーズ金型に広げた。充填した金型を、セメントを室温で硬化させるために、25℃で3〜5分間静置した。硬化した骨セメントビーズを、金型から取りだし、無菌条件下で室温で貯蔵した。各ビーズの薬物含量を、HPLCにより測定し、これは計算された薬物含量と合致した。抗生物質負荷されたセメントビーズは、インビトロ薬物放出アッセイ、インビトロ逐次ZIBアッセイ及びインビトロバイオフィルム阻害試験について、さらに試験した。
化合物2及び化合物10による薬物放出試験を、1.5mlの溶解培地、すなわちPBS緩衝液(pH6.8):アセトニトリル(9:1)を含有する試料バイアルにおいて行った。この試料は、インキュベーターローター内に、32℃で、40rpmで保持した。この放出培地を、特定の時間間隔(2時間、4時間、6時間、1日、2日、3日、4日、5日、6日、7日)で採取し、各時点で新鮮な溶解培地1.5mlと置き換えた。全ての試料を、分析を行うまで、−20℃で保存した。薬物放出の測定は、HPLCにより行った。
典型的には、キトサン1.5gmを、0.1N HClの75gmに溶解した。この混合物を、キトサンが完全に溶解するまで、完全に撹拌した。このキトサン溶液を、4℃に冷却した。β−グリセロリン酸塩5gmを秤量し、水17.5gmに溶解した。薬物溶液を、4℃に冷却したβ−グリセロリン酸塩溶液中に、1gmの化合物55を分散することにより調製した。化合物55−β−グリセロリン酸塩溶液を、無菌条件下で撹拌しながら、キトサン混合液(予め冷却した)に滴加した。安息香酸ナトリウム0.07gmを、この製剤に添加し、均一な溶液が形成されるまで撹拌した。製剤を、さらに使用するまで、4℃で貯蔵した。最終的な100ml製剤は、0.082Mに相当する1.5%キトサン、及び0.163Mに相当する5%のβ−グリセロリン酸塩を含有し、これは、中性pHでの固体状態(4〜10℃)から、体温37℃でのゲル状態へのシステムの転換を補助した。
簡単には、15gmのPLGAを、クエン酸トリエチル82.3gmに入れ、かつこの混合物を、900rpmで撹拌しながら、70℃で1時間維持した。得られた溶液を、4℃まで冷却した。正確に秤量した1gmの化合物2を、PLGA溶液へ添加し、適宜混合した。この製剤を、4℃までゾル状態の形状で冷却し、これは34℃でゲル形状へと転換した。製剤を、さらに使用するまで、4℃で貯蔵した。
典型的には、精製水73.9gmを秤量し、4℃まで冷却した。20gmのポロキサマー407を秤量し、撹拌しながら、予め冷却した水へ溶解した。正確に1gmの化合物6を秤量し、ジエチレングリコールモノエチルエーテル5gm中に分散させた。薬物−ジエチレングリコールモノエチルエーテル混合物を、予め冷却したポロキサマー407溶液へ、攪拌しながらゆっくり添加した。次に、メチルパラベン0.1gm及びプロピルパラベン0.01gmを添加し、かつ温度を4℃に維持することにより、均一な溶液が形成されるまで、撹拌した。製剤を、均質な分散を得るように撹拌し、4〜10℃ではゾル状態を維持したが、体温37℃でゲル化した。製剤を、さらに使用するまで、4℃で貯蔵した。
典型的には、パルミチン酸アスコルビル0.4gmを秤量し、ジエチレングリコールモノエチルエーテル5gmに溶解した。1gmの化合物6を、パルミチン酸アスコルビル溶液へ添加し、適宜混合した。個別に、ヒドロキシエチルセルロースゲル基剤を、ヒドロキシエチルセルロース1.5gmを、水76gm中に、撹拌しながら溶解することにより調製した。ヒドロキシエチルセルロースゲル基剤に、コラーゲン(水5gm中0.1gm)及びポロキサマー407(水10gm中1gm)を、連続攪拌しながら添加した。薬物−パルミチン酸アスコルビル混合物を、ゲル基剤混合物へ、攪拌しながら添加した。この製剤混合物を、均一なゲルが形成されるまで、撹拌した。この製剤を、更なる使用まで、4℃で貯蔵した。
多層リポソーム負荷された化合物33及びパルミチン酸アスコルビルを、薄フィルム水和技術により調製した。簡単には、化合物33の0.2gm、レシチン1gm、コレステロール0.4gm及びパルミチン酸アスコルビル0.1gmを、クロロホルム:メタノール(2:1)混合液20mlへ添加した。有機溶媒の真空下での蒸発により(45℃、50rpm)、薄い脂質フィルムが形成された。得られた薄いフィルムを、6時間真空乾燥させ、0.5%ポロキサマー407を含有する水5mlにより再水和させ、安定したリポソーム分散液を形成した。リポソームゲルを、予め膨潤した1.7%ヒドロキシエチルセルロースゲル(水12.96gm中0.34gm)中への、リポソーム分散液の添加及び適宜混合により調製し、均一なゲルを形成した。
典型的には、アルギン酸ナトリウム(Manucol LKX(登録商標))溶液2gmを正確に秤量し、水30gm中に、撹拌しながら溶解した。正確に1gmの化合物55(トランスキトール又はDMI又は任意の他の可溶化剤中に分散された)を、アルギン酸ナトリウム溶液へ添加し、適宜混合した。別に、ヒドロキシエチルセルロースゲル基剤を、ヒドロキシエチルセルロース1.5gmを、水60.3gm中に、撹拌しながら溶解することにより調製し、溶解するまで攪拌した。ヒドロキシエチルセルロースゲル基剤に、コラーゲン(水5gm中0.1gm)を、室温での撹拌を維持しながら、ゆっくり添加した。化合物55−アルギン酸ナトリウム混合物を、コラーゲン及びヒドロキシエチルセルロースを含有するゲル基剤混合物へ、撹拌条件下で添加した。完全な混合物を、均一なゲルが形成されるまで、撹拌した。保存剤である安息香酸ナトリウム0.07gmを、前記製剤混合物へ、撹拌しながら添加した。この混合物を、均一なヒドロゲルが形成されるまで、撹拌した。調製した製剤を、更なる使用まで、4℃で貯蔵した。
典型的には、1gのアルギン酸ナトリウム(Manucol LKX(登録商標)))を秤量し、水50ml中に撹拌しながら溶解した。化合物2を、アルギン酸ナトリウム溶液へ、撹拌しながら添加した。3%塩化カルシウム溶液を、ペトリプレートに注ぎ、これがプレート表面上に薄層を形成した後、過剰な分を廃棄した。化合物2−アルギン酸ナトリウム(Manucol LKX(登録商標)))溶液(50ml)を、ペトリプレートへ注ぎ、45℃で6〜8時間乾燥させた。架橋剤塩化カルシウムは、アルギン酸塩溶液の凝固を助け、ヒドロゲルフィルムを形成するであろう。適切に乾燥させた後、フィルムをプレートから取りだし、更なる使用のために貯蔵した。所望の厚さのフィルムを、様々な濃度のアルギン酸塩溶液を調製することにより、制御することができる。
Claims (18)
- (i)式(I)の化合物:
(式中:
Xは、C、N、又はCR8であり;R1は、シクロプロピルであるか、もしくはR8がHであるとき、R1はR2への連結を形成しメチルチアゼタン環を形成する;
R2は、H、SH又はアルキルであり;
R3は、H又はハロであり;
R8は、H、C1−C6アルキル、C1−C6アルコキシ又はハロであり(但し、R8がHであるとき、R1はシクロプロピルではない);
Aは、存在しないか、又はリンカーであり(ここで、リンカーは結合であるか、又は以下からなる群より選択される:
ピペラジニル;3-メチルアミノピペリジン;ピロリジニル[3,4-b]ピペリジン;ピペリンド-4-オール;1-H-ベンゾイミダゾール-2-イル;(1-H-ベンゾイミダゾール-2-イル)−アミノ;2-アミノ-1-H-ベンゾイミダゾリル;
場合により以下で置換される5,6-モノおよびジ置換1-H-ベンゾイミダゾール-2-イル:アルキルC1−C11アルキル、ハロ、ニトロ、カルボキシル、アミノ、チオール、モノもしくはジもしくはポリグアニジノ基:−NH[C(M)NHC(M1)]n−D(ここで、M1はNH、O、S又はCHであり;nは1−10であり;DはNH2、COOH又はCONH2である)、アミノ酸類似体、スペルミン、ノルスペルミジン、スペルミジン類似体、グアニジノアミノ酸、アミド結合を介して結合されたスペルミン、アミド結合を介して結合されたノルスペルミジン、アミド結合を介して結合されたスペルミジン類似体、又はそれらの任意の組み合わせ;又は、
6-カルボキシル-2-ピリジル環;5-ブロモ-2-ピリジル環又は5もしくは6モノもしくはジ置換2-ピリジル環、ここで、それぞれの3、4、5又は6位は独立して以下で置換されてもよい:水素原子、-CH3、CH3-(CH2)m-(ここで、m=1−10)、ハロ、ニトロ、アミノ、カルボキシル、メチルアミノ、チオール、-R7(CH2)oNHCO-、-R7(CH2)oCONH-、-R7(CH2)o-OCO−、-R7(CH2)o-COO-、又はモノもしくはジもしくはポリグアニジノ基-NH[C(M)NHC(M2)]t-D、アミノ酸類似体、スペルミン、ノルスペルミジン、スペルミジン類似体、グアニジノアミノ酸、スペルミン、ノルスペルミジン、又はアミド結合を介したスペルミジン類似体、ここで、R7=NH又はS、かつo=0−10、M2=NH、酸素原子、硫黄原子、又はCH、D=NH2、COOH、CONH2、かつt=1−10;ここで、Aは(CO−RL−CY’)q−Z’又は(CS−R4−CY’)q−Z’により官能化され、ここでqは1−10;RLはNH;Y’はNH、O、S又はCH;かつZ’はNH2、COOH、CONH2、OH、SH又はアルキル基である);
Bは、存在しないか、又はリンカーであり(ここで、リンカーは結合であるか、又は以下からなる群より選択される:
直鎖もしくは分岐アルキル鎖、官能化アルキル鎖、エステルもしくはアミド結合を有するアルキル鎖、-C(O)CH2-、-C(O)CH2NH-、-NHC(O)CH2-、-C(O)-、-C(O)NH(CH2)rC(O)-(rは1、2、3、4又は5)、-CH=N-、-NH-、-OCH2CH2-、(OH)NHC(O)CH2、[(HO)NHC(O)]CH[{CH3(OH)}CH]、[(HO)NHC(O)]CH[CH2(OH)CH]、−CH2CH2NHCH2CH2−、又は−CH2(CO)NH(CO)NH−Ar、ここで、Arはアリールもしくはフェニル置換もしくは非置換、−CO−システイン−CO−(S−ドデカンシステイン)、−CO−S−(N−アセチルシステイン)、及び−CO−S−(N−アセチルドデカンシステイン));
但し、
Aがピペラジニルであるとき、Bが存在し;
AおよびBが存在しないとき、R4はインドール環でも1,8-ナフチリドン環でもピリドチアジニル環系でもピリドオキサジニル環系でもなく;
R1がシクロプロピルであるとき、Bは2-ヒドロキシプロピル基ではない;並びに
R4は、1又は2個の置換基により任意に置換されてもよい5員のアリール又はヘテロアリールであるか;もしくは、R4は、1、2又は3個の置換基により任意に置換されてもよい6員のアリール又はヘテロアリールであるか;もしくは、R4は、1、2又は3個の置換基により任意に置換されてもよい縮合環9−10員のアリール又はヘテロアリールである
但し、
R1がシクロプロピルでありかつXが水素であるとき、R4は2-クロロ-4-ニトロイミダゾリル環系でも1,8-ナフチリドン環系でもピリドチアジニル環系でもピリドオキサジニル環系でもなく;
Aがピペラジニルであるとき、Bは存在しかつR4はフェニルでもフェニル置換基でもない;もしくは、
R4は、1、2又は3個の置換基により任意に置換されてもよい縮合環9−10員のアリール又はヘテロアリールである
ここで、
Aがピペラジニルであり、BがC=Oであるとき、R4はフラニル環系ではない;もしくは、
R4は:
- 下記からなる群から選択される化合物:
- 請求項1又は2に記載の化合物、及び医薬として許容し得る担体又は賦形剤を含有する、医薬組成物。
- 請求項1又は2に記載の化合物を含有する、外用適用のための組成物。
- 請求項1又は2に記載の化合物を含有する、経口投与のための組成物。
- 請求項1又は2に記載の化合物を含有する、注射による投与のための組成物。
- ポリマーマトリクス及び請求項1又は2に記載の化合物を含有する、組成物。
- 請求項1又は2に記載の化合物の治療的有効量を含む、感染症を治療するための医薬組成物。
- 前記感染症が、耐性病原菌により引き起こされる、請求項8に記載の医薬組成物。
- 前記感染症が、メチシリン耐性又はバンコマイシン耐性病原菌により引き起こされる、請求項8に記載の医薬組成物。
- 前記感染症が、キノロン耐性病原菌により引き起こされる、請求項8に記載の医薬組成物。
- 請求項1又は2に記載の化合物の創傷にとっての治療的有効量を含む、創傷を治療するための医薬組成物。
- 請求項1又は2に記載の化合物の治療的有効量をインプラントへ適用することを含む、インプラントにより引き起こされる感染症を軽減するための医薬組成物。
- 請求項1又は2に記載の化合物の治療的有効量を含む、肺炎の治療するための医薬組成物。
- 請求項1又は2に記載の化合物の治療的有効量を含む、尿路感染症の治療するための医薬組成物。
- 請求項1又は2に記載の化合物の治療的有効量を含む、膿痂疹の治療するための医薬組成物。
- 請求項1又は2に記載の化合物の治療的有効量を含む、座瘡の治療するための医薬組成物。
- 請求項1又は2に記載の化合物の治療的有効量を表面又はバイオフィルムへ適用することを含む、バイオフィルム形成を阻害又は減少するための医薬組成物。
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JP2019239163A Pending JP2020050676A (ja) | 2015-07-28 | 2019-12-27 | 抗菌性治療薬及び予防薬 |
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US10995097B2 (en) * | 2016-03-11 | 2021-05-04 | The Board Of Trustees Of The University Of Illinois | Small molecules active against gram-negative bacteria |
WO2018042367A2 (en) * | 2016-08-31 | 2018-03-08 | Vyome Biosciences Pvt. Ltd. | Compounds, compositons and methods related to antimicrobial applications |
EP3515497A4 (en) * | 2016-09-23 | 2020-05-13 | Klox Technologies Inc. | BIOPHOTONIC COMPOSITIONS, METHODS AND KITS FOR INHIBITING AND DISRUPTIONING ORGANIC FILMS |
EP3638681A1 (en) * | 2017-06-13 | 2020-04-22 | Quretech Bio AB | Ring-fused thiazolino 2-pyridones, methods for preparation thereof and their use in the treatment and/or prevention of a disease involving gram-positive bacteria |
WO2018237140A1 (en) | 2017-06-23 | 2018-12-27 | The Board Of Trustees Of The University Of Illinois | TOPOISOMERASE INHIBITORS HAVING ANTIBACTERIAL ACTIVITY AND ANTI-CANCER ACTIVITY |
CN111087390B (zh) * | 2017-11-10 | 2022-07-05 | 西南大学 | 氟喹诺酮类胺基衍生物及其用途 |
CN107721924B (zh) * | 2017-11-10 | 2021-10-22 | 西南大学 | 加替沙星衍生物及其制备方法和用途 |
CN107827815B (zh) * | 2017-11-10 | 2021-08-03 | 西南大学 | 氟喹诺酮类氨基衍生物及其防治柑橘病害的用途 |
JP7370251B2 (ja) * | 2017-12-28 | 2023-10-27 | マルホ株式会社 | 抗炎症剤 |
CN111808090B (zh) * | 2019-04-12 | 2023-05-02 | 中国医学科学院医药生物技术研究所 | 一种新德里金属-β-内酰胺酶-1抑制剂 |
CN111559985A (zh) * | 2020-05-13 | 2020-08-21 | 河南科技大学第一附属医院 | 具有杀菌作用的噁唑酮类化合物及其制备方法 |
CN112355034B (zh) * | 2020-11-17 | 2021-08-06 | 同济大学 | 基于水热钙离子调配的有机固体废弃物无害化预处理方法 |
CN114230516A (zh) * | 2021-12-23 | 2022-03-25 | 中国海洋大学 | 多功能抗菌化合物及其制备与应用方法及中间体 |
WO2024046409A1 (zh) * | 2022-08-31 | 2024-03-07 | 江苏恒瑞医药股份有限公司 | 杂环类化合物、其制备方法及其在医药上的应用 |
US11807640B1 (en) | 2023-03-28 | 2023-11-07 | King Faisal University | 7-isopropyl 1-ethyl/methyl 3-(substituted benzoyl)-2-substituted indolizine-1,7-dicarboxylates as anti-tubercular agents |
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US20200140460A1 (en) | 2020-05-07 |
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