JP2013518867A - ランチビオティックの塩 - Google Patents
ランチビオティックの塩 Download PDFInfo
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- JP2013518867A JP2013518867A JP2012551673A JP2012551673A JP2013518867A JP 2013518867 A JP2013518867 A JP 2013518867A JP 2012551673 A JP2012551673 A JP 2012551673A JP 2012551673 A JP2012551673 A JP 2012551673A JP 2013518867 A JP2013518867 A JP 2013518867A
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- salt
- organic amine
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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Abstract
Description
の塩であって、
式中、
R1と、それが結合している炭素ならびにα-窒素およびα-カルボニルとが一緒になってアミノ酸残基となり;
R2と、それが結合している炭素ならびにα-窒素およびα-カルボニルとが一緒になってアミノ酸残基となり;かつ
pが、0または1であり、
少なくとも1個のヒドロキシル基を含む低分子有機アミンで形成される、塩、が提供される。
一態様では、pは1である。
デオキシアクタガルジンB [DAB] (200mg)、3,5-ジクロロベンジルアミン(38mg)およびジイソプロピルエチルアミン(35μL)を乾燥ジメチルホルムアミド(1mL)に溶解させた。ベンゾトリアゾール-1-イル-オキシ-トリス-ピロリジノ-ホスホニウムヘキサフルオロホスフェート(PyBOP) (84mg)の乾燥DMF (2mL)溶液を小分けして加えた。反応後に分析hplcを行い(表1参照)、出発原料が消費されるまでPyBOPを加えた。
カラム: Zorbax 5μ C18(2) 150 x 4.6 mm
移動相A: 20mMリン酸カリウム緩衝液pH 7.0中30%アセトニトリル
移動相B: 20mMリン酸カリウム緩衝液pH 7.0中65%アセトニトリル
流量: 1mL/分
勾配:
時間0分 100% A 0% B
時間10分 0% A 100% B
時間11分 0% A 100% B
時間11.2分 100% A 0% B
サイクル時間 15分
注入容積: 10μL
検出: 210nm
カラム: Zorbax 5μ C18(2) 150 x 4.6 mm
移動相A: 10%アセトニトリル、0.1%ギ酸
移動相B: 90%アセトニトリル、0.1%ギ酸
流量: 1mL/分
勾配:
時間0分 100% A 0% B
時間10分 0% A 100% B
時間11分 0% A 100% B
時間11.1分 100% A 0% B
サイクル時間 15分
注入容積: 20μL
質量分析計パラメータ
イオン化 エレクトロスプレー+ve
質量範囲 250〜1500mu
キャピラリー電圧 3.10KV
コーン電圧 40V
スキマーレンズオフセット 5V
イオンエネルギー 1.4V
化合物1(500mg)をt-ブタノール(250ml)に懸濁させ、すべての固体が溶解するまで懸濁液を45℃で4時間攪拌した。N-メチルグルカミン溶液(1M水溶液、492ul)を加え、混合物をさらに1時間攪拌した。反応混合物を-80℃で瞬間冷凍させた後、材料を終夜凍結乾燥させて白色固体(587mg)を得た。
肺炎連鎖球菌以外の感受性試験を、50μg/mL Ca2+を補充したミュラー・ヒントン培地中にて連続2倍希釈で行った。肺炎連鎖球菌の感受性試験を、50μg/mL Ca2+を補充したブレインハートインフュージョン培地中にて連続2倍希釈で行った。
最大6回の決定によるモーダル値
体重24±2gの6匹の雄CD-1(Crl.)由来マウスの群を使用した。5%ムチンを含有するBHI培地0.5mL中のLD90〜100のメチシリン耐性黄色ブドウ球菌ATCC 33591(1.1x107 CFU/マウス)をマウスに腹腔内(IP)接種した。実施例1およびバンコマイシンを15% HPβCD/4.4%グルコース/0.5mM KH2PO4(pH 5.0)に溶解させ、1、3、5、10および20mg/Kgの用量を皮下(SC)投与して、細菌接種の0、2および24時間後の時点で動物を試験した。投与量は5mL/Kgとした。死亡率を毎日1回、7日間記録した(図1)。各化合物のED50を非線形回帰により決定した。
細菌による組織感染症の処置における本発明の化合物のインビボ有効性を、好中球減少マウス大腿部モデルを使用して評価した。
マウスにおける化合物1のインビボ半減期を、静脈内投与後の様々な時点でのその血漿中濃度の測定によって決定した。18匹の7〜9週齢の雄CD-1マウスに、15%ヒドロキシプロピル-β-シクロデキストリン/4.4%グルコース/1mMリン酸カリウム(pH=7.6)中、実施例1の3.2mg/mL溶液を、用量9.3mL/Kgで静脈内投与した。血漿試料を、投与後10、20、30、60、120および240分の時点に、各時点で3匹の動物より試料採取することで得た。血漿中の化合物1の濃度をLC-MS定量化によって決定した。
実施例1(10mg)をWFI(注射用水1または2mL)に溶解させた。溶液をMillex GP 0.2μmフィルターを通じて濾過した。
Claims (37)
- pが1である、請求項1記載の塩。
- R1と、それが結合している炭素ならびにα-窒素およびα-カルボニルとが一緒になってロイシンまたはバリンとなる、請求項1または2のいずれか一項記載の塩。
- R2と、それが結合している炭素ならびにα-窒素およびα-カルボニルとが一緒になってイソロイシンまたはバリンとなる、請求項1〜3のいずれか一項記載の塩。
- R1と、それが結合している炭素ならびにα-窒素およびα-カルボニルとが一緒になってバリンとなり、R2と、それが結合している炭素ならびにα-窒素およびα-カルボニルとが一緒になってイソロイシンとなる、請求項1〜2のいずれか一項記載の塩。
- R1と、それが結合している炭素ならびにα-窒素およびα-カルボニルとが一緒になってロイシンとなり、R2と、それが結合している炭素ならびにα-窒素およびα-カルボニルとが一緒になってバリンとなる、請求項1〜2のいずれか一項記載の塩。
- 塩を形成する際の化合物が有機アミンである、請求項1〜7のいずれか一項記載の塩。
- 前記化合物が10% w/w以下、例えば5% w/w以下、例えば4% w/w以下、特に3% w/w以下の水を含む、請求項1〜8のいずれか一項記載の塩。
- 5% w/w以下、例えば4% w/w以下、例えば3% w/w以下、特に2% w/w以下のt-ブタノールを含む、請求項1〜9のいずれか一項記載の塩。
- 塩を形成する際の有機アミン化合物が、6個以下の炭素原子を含む、請求項8記載の塩。
- 有機アミンが1個、2個、3個、4個または5個のヒドロキシル基を含む、請求項8〜11のいずれか一項記載の塩。
- 少なくとも、塩を形成する際の出発原料において、有機アミン中のヒドロキシルがその中のカルボニルに結合して酸を形成する、請求項12記載の塩。
- 有機アミンがN-メチルグルカミンまたはN-エチルグルカミンなどのグルカミン、エタノールアミン、ジエタノールアミンおよびアルギニンより選択される、請求項12〜13のいずれか一項記載の塩。
- 有機アミンがグルカミン、例えばN-メチルグルカミンまたはN-エチルグルカミンである、請求項14記載の塩。
- 有機アミンがN-メチルグルカミンである、請求項14記載の塩。
- 有機アミンがN-エチルグルカミンである、請求項14記載の塩。
- 有機アミンがエタノールアミンである、請求項14記載の塩。
- 有機アミンがアルギニンである、請求項14記載の塩。
- 請求項1〜19のいずれか一項記載の塩の、水和物などの溶媒和物。
- (a) 親化合物を好適な溶媒に、適量の塩形成パートナーの存在下で溶解させる工程; および
(b) 工程(a)の生成物を凍結乾燥させる工程; または
(c) 溶媒を蒸発させる工程
を含む、請求項1〜20のいずれか一項記載の塩を生成するための方法。 - 前記溶媒がt-ブタノールおよび/またはDMSOである、請求項21記載の方法。
- 前記溶媒がt-ブタノールおよび水である、請求項21記載の方法。
- 塩形成パートナーが1〜2当量として与えられる、請求項21〜23のいずれか一項記載の方法。
- 請求項21における工程(a)の溶液を1つまたは複数の賦形剤と共に噴霧乾燥させることによって、塩と賦形剤との凝集物である粒子を得る、方法。
- 治療有効量の請求項1〜19のいずれか一項記載の塩と、薬学的に許容される賦形剤、希釈剤および/または担体とを含む、薬学的組成物。
- 治療における使用のための、特に抗菌化合物による回復の見込みがある状態のヒトまたは動物対象の処置における使用のための、請求項26記載の薬学的組成物。
- 請求項1〜19のいずれか一項記載の塩と、薬学的に許容される賦形剤、希釈剤および/または担体とを一緒に混合する工程を含む、請求項26または27記載の薬学的組成物を調製するための方法。
- さらなる治療薬と組み合わせた、請求項1〜19、26または27のいずれか一項記載の塩または薬学的組成物。
- 処置または予防における使用のための、請求項1〜19、26、27または29のいずれか一項記載の塩または薬学的組成物。
- 医薬の製造のための、請求項1〜19、26、27または29のいずれか一項記載の塩または薬学的組成物。
- 治療有効量の請求項1〜19、26、27または29のいずれか一項記載の塩または薬学的組成物を、それを必要とする患者(ヒトまたは動物)に投与する段階を含む、処置方法。
- 皮膚感染症、特に細菌による皮膚および軟部組織感染症の処置における使用のための、請求項1〜19、26、27または29のいずれか一項記載の塩または薬学的組成物。
- グラム陽性微生物感染症の処置における使用のための、請求項1〜19、26、27または29のいずれか一項記載の塩または薬学的組成物。
- MRSAを含む黄色ブドウ球菌(S. aureus)、フェカリス菌(E. faecalis)、フェシウム菌(E. faecium)、化膿性連鎖球菌(S. pyogenes)、肺炎連鎖球菌(S. pneumoniae)および/またはC. ディフィシル(C. difficile)などの微生物感染症の処置における使用のための、請求項34記載の塩または薬学的組成物。
- 黄色ブドウ球菌の処置における使用のための、請求項35記載の塩または薬学的組成物。
- メチシリン耐性黄色ブドウ球菌の処置における使用のための、請求項36記載の塩または薬学的組成物。
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PCT/GB2010/000188 WO2010089544A1 (en) | 2009-02-04 | 2010-02-02 | Actagardine derivatives |
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