JP2017537097A - 新規なシストバクタミド - Google Patents
新規なシストバクタミド Download PDFInfo
- Publication number
- JP2017537097A JP2017537097A JP2017528464A JP2017528464A JP2017537097A JP 2017537097 A JP2017537097 A JP 2017537097A JP 2017528464 A JP2017528464 A JP 2017528464A JP 2017528464 A JP2017528464 A JP 2017528464A JP 2017537097 A JP2017537097 A JP 2017537097A
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- Prior art keywords
- formula
- group represented
- hydrogen
- compound
- alkyl
- Prior art date
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- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 70
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 22
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- NSFFHOGKXHRQEW-AIHSUZKVSA-N thiostrepton Chemical compound C([C@]12C=3SC=C(N=3)C(=O)N[C@H](C(=O)NC(/C=3SC[C@@H](N=3)C(=O)N[C@H](C=3SC=C(N=3)C(=O)N[C@H](C=3SC=C(N=3)[C@H]1N=1)[C@@H](C)OC(=O)C3=CC(=C4C=C[C@H]([C@@H](C4=N3)O)N[C@H](C(N[C@@H](C)C(=O)NC(=C)C(=O)N[C@@H](C)C(=O)N2)=O)[C@@H](C)CC)[C@H](C)O)[C@](C)(O)[C@@H](C)O)=C\C)[C@@H](C)O)CC=1C1=NC(C(=O)NC(=C)C(=O)NC(=C)C(N)=O)=CS1 NSFFHOGKXHRQEW-AIHSUZKVSA-N 0.000 description 1
- 229930188070 thiostrepton Natural products 0.000 description 1
- 229940063214 thiostrepton Drugs 0.000 description 1
- NSFFHOGKXHRQEW-OFMUQYBVSA-N thiostrepton A Natural products CC[C@H](C)[C@@H]1N[C@@H]2C=Cc3c(cc(nc3[C@H]2O)C(=O)O[C@H](C)[C@@H]4NC(=O)c5csc(n5)[C@@H](NC(=O)[C@H]6CSC(=N6)C(=CC)NC(=O)[C@@H](NC(=O)c7csc(n7)[C@]8(CCC(=N[C@@H]8c9csc4n9)c%10nc(cs%10)C(=O)NC(=C)C(=O)NC(=C)C(=O)N)NC(=O)[C@H](C)NC(=O)C(=C)NC(=O)[C@H](C)NC1=O)[C@@H](C)O)[C@](C)(O)[C@@H](C)O)[C@H](C)O NSFFHOGKXHRQEW-OFMUQYBVSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 239000012137 tryptone Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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- C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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Abstract
Description
(I)
(式(I)において、R1は、水素、OH、または式−O−C1−6アルキルで表される基であり、
R2は、水素、OH、または式−O−C1−6アルキルで表される基であり、
R3は、水素、OH、または式−O−C1−6アルキルで表される基であり、
R4は、水素、OH、または式−O−C1−6アルキルで表される基であり、
R5は、水素原子、または下記式で表される基であり、
または
ここで、R6はOHまたはNH2である。
R2は、水素、OH、または式−O−C1−4アルキルで表される基であり、
R3は、水素、OH、または式−O−C1−4アルキルで表される基であり、
R4は、水素、OH、または式−O−C1−4アルキルで表される基であり、
R5は下記式で表される基であり、
または
ここでR6はOHまたはNH2である、
式(I)の化合物、あるいは前記化合物の医薬的に許容される塩、溶媒和物または水和物、もしくは医薬的に許容される製剤が好ましい。
ここで、R6は、OHまたはNH2である。
ここで、R6は、OHまたはNH2である。
(II)
ここで、R1、R2、R3、およびR5は、上記式(I)の化合物で定義されたものと同様である。
(III)
ここで、R2、R3、R4、およびR5は上記式(I)の化合物で定義されたものと同様である。
(IV)
ここで、R1、R3、R4、およびR5は、上記式(I)の化合物で定義されたものと同様である。
または
ここで、R6は、OHまたはNH2である。
生成条件
生成のための系統種
この系統種MCy8071は、酵母菌−寒天(VY/2:0.5%の出芽酵母、0.14%のCaCl2×2H2O、0.5μgビタミンB12/l、1.5%の寒天、pH:7.4)、CY寒天(カシトン(casitone):0.3%、酵母菌抽出物:0.1%、CaCl2×2H2O:0.1%、寒天:1.5%、pH:7.2)、およびP寒天(peptone Marcor:0.2%、澱粉:0.8%、単細胞タンパク質probione:0.4%、酵母菌抽出物:0.2%、CaCl2×2H2O:0.1%、MgSO4:0.1%、Fe−EDTA:8mg/l、1.5%:寒天、pH:7.5)でよく成長する。実際の培養は、液体培地CY/H(50%のCY培地+50mMのHEPES、50%のH培地:大豆粉が0.2%、グルコースが0.8%、澱粉が0.2%、酵母菌抽出物が0.2%、CaCl2×2H2Oが0.1%、MgSO4が0.1%、Fe−EDTAが8mg/l、HEPESが50mM、pH:7.4)中で育成した。液体培地を30℃、180rpmで振とうした。保存のため、3日目の培地の一部(2ml)を−80℃で保存した。上記の寒天プレート上または20mlのCY/H培地(プラグおよびアルミニウムキャップ付きの100mlの三角フラスコ中)で数年後に再活性化しても問題はなかった。1日または2日後に20mlの培地を100mlにスケールアップしてもよい。
液体培地CY/Hに入れて2日後に、系統種MCy8071の棒状細胞の長さは9.0〜14.5μm、幅は0.8〜1.0μmであった。上記寒天プレート上での遊走は円形である。VY/2−寒天上では、遊走は薄く透明である。VY/2−寒天上では酵母菌の分解が見られる。CY−寒天上では、培地は透明なオレンジ色に見える。P寒天上では、細胞の大量生産が際立っており、遊走挙動は減少する。コロニーの色はオレンジがかった茶色である。P寒天の澱粉は分解される。
この系統種は、複合媒体で産生する。この系統種は、窒素を含む栄養素(例えば、単細胞タンパク質(Probion)、およびタンパク質分解物の生成物(例えば、ペプトン、トリプトン)、酵母菌抽出物、大豆粉、および肉抽出物)を好む。本明細書では、この生成物は、1種よりも上記タンパク質混合物の数種を含む方がよい。
シストバクタミド935−2:
抗細菌活性
シストバクタミド(Cys)919−2、920−1、934−2、935−2、891−2、および905−2を既に記載した誘導体(861−2、877−2、920−2)と共にグラム陰性菌の選択された集合に対して評価した。誘導体861−2、877−2、919−1、および920−2は、WO2015/003816に記載されているシストバクタミドF、H、A、およびBに対応する。最小発育阻止濃度(minimum inhibitory concentration、MIC)値を、μg/mlで示す。シプロフロキサシン(CP)を参照として用いた。
シストバクタミド861−2および919−2について4倍のMIC値で大腸菌DSM−1116を用いて決定した抵抗性頻度は10−7〜10−8であった。
シストバクタミド919−2およびシプロフロキサシン(CP)と比較してシストバクタミド861−2の大腸菌ギラーゼおよび緑膿菌ギラーゼのDNA超らせん形成(supercoiling、sc)活性を決定した。
20μg/mlのシストバクタミド861−2、シストバクタミド919−2、およびシプロフロキサシンについてCHO−K1細胞株との小核形成アッセイでは検出可能な遺伝毒性の影響は観察されなかった。マイトマイシンC(100ng/ml)を陽性対照として用いた。すべての実験は、同じものを3つ用意して行い、染色した核の顕微鏡画像を評価した。小核形成は、マイトマイシンCで処理したCHO−K1細胞でははっきりと観察されたが、未処理の対照、シプロフロキサシンで処理した細胞、およびシストバクタミドで処理した細胞では観察されなかった。
MICの決定
感受性アッセイに用いた指示系統種は、本発明者らの収集した系統種の一部か、あるいはGerman Collection of Microorgansims and Cell Cultures (DSMZ)またはアメリカ培養細胞系統保存機関(American Type Culture Collection, ATCC)から購入したものであった。大腸菌系統種WTおよび対応する大腸菌変異体は、ハンブルグ大学医薬生物学および微生物学部教授のP. Heisig博士の厚意により提供を受けた。大腸菌系統種JW0401−1(WT)およびΔtsxはE. coli Genetic Stock Center (CGSC)のコレクションから得た。
CHO−K1細胞をDSMZから入手して、供託者により推奨された条件で培養した。細胞を、96ウェルプレートの180μlの完全培地に6×103細胞/ウェルで播種して、2時間の平衡後に一連の希釈をした化合物で処理した。各試料と内部DMSO対照を、同じ物を2つ用意して検査した。5日間インキュベーションした後、ウェルあたり、5mg/mlのMTT(チアゾリルブルーテトラゾリウムブロミド)のPBS溶液20μlを加えて、さらに37℃で2時間インキュベートした。次いで、この培地を捨てて、100μlのPBSで細胞を洗浄した。その後、ホルマザン顆粒を溶解するために100μlの2−プロパノール/10NのHCl(250:1)を加えた。マイクロプレートリーダー(Tecan Infinite M200Pro)を用いて570nmでの吸光度を測定し、細胞生存率を各メタノール対照に対する百分率として表した。
シストバクタミドに対する自然抵抗性頻度を決定するため、対数期の細菌細胞懸濁液をMuller-Hintonブロスで最終濃度を1010CFU/mLに調整し、異なる体積の液を大腸菌DSM−1116に対するMICの4倍の濃度のシストバクタミドを含む二つの同じ寒天プレート上に流し込んだ。また、大腸菌培地を数回希釈したものを抗生物質を含まないプレートに流し込んだ。1日後、シストバクタミドを含むプレートのCFU数を抗生物質を含まないプレートのCFU数で除して抵抗性頻度を決定した。
シストバクタミドの抗ギラーゼ活性を試験するため、市販の大腸菌ギラーゼおよび緑膿菌ギラーゼ超らせん形成キット(Inspiralis、英国ノリッジ)を用いた。標準反応として、0.5μgの弛緩プラスミドを1倍の反応緩衝液中で1単位のギラーゼと混合して(キットのマニュアルを参照のこと)、37℃で30分間インキュベートした。反応を、10%(w/v)のSDSを含むDNAゲルローディングバッファーを加えて停止した。試料を1%(w/v)のアガロースゲル上で分離して、EtBrを用いてDNAを可視化した。すべての天然生成物原液および希釈液を100%のDMSOで調製して、超らせん形成反応物に添加し、最終DMSO濃度を2%(v/v)にした。
チャイニーズハムスター卵巣CHO−K1細胞(ACC−110)をDSMZから入手して、供託者により推奨された条件で保持した。遺伝毒性研究では、光学底部を有する黒色96ウェルプレートに細胞を5×103細胞/ウェルで播種して、化合物を添加する前に1日間付着させた。CP、シストバクタミド、およびマイトマイシンCを添加して、最終濃度20μg/ml(ギラーゼ阻害剤)および100ng/ml(マイトマイシンC)とした。細胞を48時間処理して、リン酸緩衝生理食塩水(PBS、pH:7.4)で二度洗浄し、AcO/MeOH(1:1、−20℃)を用いて室温で10分間固定した。PBSによる洗浄を繰り返した後、光を遮断して室温で15分間、核を5μg/mLのHoechst33342のPBS溶液で染色した。洗浄後、Hoechstに適した1組のフィルターを有する自動顕微鏡(Pathway855, BD Biosciences)を用いて試料を画像観察(200倍)した。すべての試料を、2つの独立した実験で同じものを3つ調製して小核形成について分析した。
ここで、シストバクタミドC誘導体の合成に用いられた異なる個々の環の調製について記載する。
環Cの調製
3.5.1.実験の一般情報
出発物質および溶媒は、供給業者から購入して、さらなる精製は行わずに用いた。すべての化学収率は、精製された化合物について言及しており、最適化されていない。反応の進行は、TLCシリカゲル60F254アルミニウムシートを用いて追跡し、254nmのUVにより可視化した。フラッシュクロマトグラフィーはシリカゲル60Å(40〜63μm)を用いて行った。分取RP−HPLCを2767試料マネジャー、2545二元グラジエントモジュール、2998PDA検出器、および3100エレクトロンスプレー質量分析計を備えたウォーターズ社のセットアップで実施した。精製はWaters XBridgeカラム(C18、150×19mm、5μm)、溶離液として二元溶媒系AおよびB(A=0.1%のギ酸を含む水、B=0.1%のギ酸を含むMeCN)を用いて行い、流量を20mL/分、60%〜95%のBを8分間のグラジエントで行った。融点は、Stuart Scientific融点装置SMP3(Bibby Sterilin, 英国)で決定して、補正は行っていない。NMRスペクトルは、Bruker DRX-500(1H、500MHz;13C、126MHz)分光計またはBruker Fourier 300(1H、300MHz;13C、75MHz)分光計のいずれかを用いて300Kで記録した。内部標準物質としての重水素化物溶媒の水素化残留物(CDCl3:δ=7.26、77.02;DMSO−d6:δ=2.50、39.99)を参照して化学シフトをδ値(単位:ppm)で記録した。分裂パターンは明らかな多重度を記述し、s(一重線)、br s(ブロード一重線)、d(二重線)、dd(二重線の二重線)、t(三重線)、q(四重線)、m(多重線)として表される。カップリング定数(J)は、ヘルツ(Hz)で表される。生物学的アッセイで用いられるすべての化合物の純度は、LC/MS Finnigan Surveyor MSQ Plus(Thermo Fisher Scientific, 独国ドライアイヒ)で測定したところ、95%以上であった。このシステムは、LCポンプ、オートサンプラー、PDA検出器、およびシングル四重極MS検出器、および操作のための標準ソフトウェアXcaliburからなる。RP C18 Nucleodur 100-5(125×3mm)カラム(Macherey-Nagel GmbH, 独国ディーレン)を固定相として、二元溶媒系AおよびB(A=0.1%のTFAを含む水;B=0.1%のTFAを含むMeCN)を移動相として用いた。グラジエント操作では、Bの百分率を、0分での初期濃度0%から15分で100%まで上げ、5分間100%を維持した。注入量は10μLであり、流量は800μL/分に設定した。MS(ESI)分析をスプレー電圧3800V、細管温度350℃、およびソース衝突誘起解離(collision- induced dissociation, CID)10Vで行った。スペクトルを正モードで100〜1000m/zの範囲で取得し、UVでのトレースは254nmで行った。
a)当該酸(25mmol)、臭化イソプロピル(52mmol)、および炭酸カリウム(52mmol)の混合物のDMF(100ml)溶液を90℃で一晩加熱した。次いで、過剰のDMFを減圧下で除去して、残留物を水と酢酸エチルで分離した。有機層を硫酸ナトリウムで脱水して、次いで、過剰な溶媒を減圧下で除去して純粋な生成物を得た。
酢酸2−ホルミル−6−メトキシフェニル
収率94%(オフホワイト固体)、m/z(ESI+)195[M+H]+
4−(4−(4−アミノベンズアミド)−2−ヒドロキシ−3−メトキシベンズアミド)−3−イソプロポキシ安息香酸(1s)
1) Alina Fomovska, Richard D. Wood, Ernest Mui, Jitenter P. Dubey, Leandra R. Ferreira, Mark R. Hickman, Patricia J. Lee, Susan E. Leed, Jennifer M. Auschwitz, William J. Welsh, Caroline Sommerville, Stuart Woods, Craig Roberts, and Rima McLeod. Salicylanilide Inhibitors of Toxoplasma gondii(トキソプラズマ原虫のサリチルアニド阻害剤). J. Med. Chem., 2012, 55(19), pp 8375-8391.
2) Valeria Azzarito, Panchami Prabhakaran, Alice I. Bartlett, Natasha Murphy, Michaele J. Hardie, Colin A. Kilner, Thomas A. Edwards, Stuart L. Warriner, Andrew J. Wilson. 2-O-Alkylated Para-Benzamide α-Helix Mimetics: The Role of Scaffold Curvature(2-O-アルキル化パラベンズアミドα−ヘリックス模倣物:足場曲率の役割). Org. Biomol. Chem., 2012, 10, 6469.
Claims (16)
- 式(I)の化合物:
(I)
R2は、水素、OH、または式−O−C1−6アルキルで表される基であり、
R3は、水素、OH、または式−O−C1−6アルキルで表される基であり、
R4は、水素、OH、または式−O−C1−6アルキルで表される基であり、
R5は、水素原子または下記式で表される基であり、
(ここで、R6はOHまたはNH2である)、
または、前記化合物の医薬的に許容される塩、溶媒和物または水和物、あるいは医薬的に許容される製剤。 - R1は、水素、OH、または式−O−C1−4アルキルで表される基であり、
R2は、水素、OH、または式−O−C1−4アルキルで表される基であり、
R3は、水素、OH、または式−O−C1−4アルキルで表される基であり、
R4は、水素、OH、または式−O−C1−4アルキルで表される基であり、
R5は、下記式で表される基である、
または
(ここで、R6はOHまたはNH2である)、
請求項1に記載の化合物、前記化合物の医薬的に許容される塩、溶媒和物または水和物、あるいは医薬的に許容される製剤。 - R1はOHである、請求項1または2に記載の化合物。
- R1は、式−O−C1−4アルキルで表される基であり、特に、R1は式−O−CH(CH3)2で表される基である、請求項1または2に記載の化合物。
- R2は水素である、請求項1〜4の何れか一項に記載の化合物。
- R2はOHである、請求項1〜4の何れか一項に記載の化合物。
- R3は水素である、請求項1〜6の何れか一項に記載の化合物。
- R3はOHである、請求項1〜6の何れか一項に記載の化合物。
- R3は式−O−C1−4アルキルで表される基である、請求項1〜6の何れか一項に記載の化合物。
- R4は水素である、請求項1〜9の何れか一項に記載の化合物。
- R4はOHである、請求項1〜9の何れか一項に記載の化合物。
- R5は下記式で表される基である、請求項1〜11の何れか一項に記載の化合物:
または
(ここで、R6は、OHまたはNH2である)。 - 以下の化合物から選択される化合物:
- 以下の化合物から選択される化合物:
および
- 請求項1〜14の何れか一項に記載の化合物、および任意で1種以上の担体物質および/または1種以上のアジュバントを含む、医薬品組成物。
- バクテリア感染の治療または予防に用いられる請求項1〜15の何れか一項に記載の化合物または医薬品組成物。
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