JP6309995B2 - トリアゾール含有マクロライドを用いた耐性疾患の治療方法 - Google Patents
トリアゾール含有マクロライドを用いた耐性疾患の治療方法 Download PDFInfo
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Description
本出願は、米国特許法第119条(e)項の下で、2008年10月24日に出願された米国仮特許出願第61/108,110号、2008年10月24日に出願された米国仮特許出願第61/108,112号、2008年10月24日に出願された米国仮特許出願第61/108,134号、2008年10月24日に出願された米国仮特許出願第61/108,137号、2008年10月24日に出願された米国仮特許出願第61/108,168号、および2009年3月20日に出願された米国仮特許出願第61/162,109号に対する恩典を主張するものであり、これらの各々の開示全体が参照により本明細書に組み込まれる。
実施例。CEM−101のインビトロ活性を、HEp−2細胞において、10の肺炎クラミジア分離株および10のC.トラコマチス株に対するAZI、CLR、TELおよびドキシサイクリンのインビトロ活性と比較する。これらの肺炎クラミジア分離株の50%および90%がCEM−101で阻害されるMICは、0.25μg/ml(範囲:0.25〜1.0μg/ml)であった。C.トラコマチス株の50%および90%が阻害されるMICは、0.25μg/ml(範囲:0.125〜0.5μg/ml)であった。AZI、CLR、TEL、およびドキシサイクリンに対するC.トラコマチスと肺炎クラミジアの両方のMIC90は、それぞれ、0.125、0.06、0.06、0.06μg/mlであった。CEM−101のMICは、分離株間で差がなく、1または2希釈分しか違わず、これは、試験した分離株の広範な地理的分布を考慮すると、とりわけ印象的である。これらの結果は、CEM−101および本明細書に記載の化合物が、C.トラコマチスと、肺炎クラミジアによって引き起こされる気道感染症とを治療するための効果的な抗生物質であることを示している。
1−ブロス(細胞外)または感染マクロファージ(細胞内)で行なわれた最初の貪食後種菌と比べた(用量−効果応答の非線形回帰[シグモイド]から計算された)細胞内cfuの最大減少。2−見かけの静菌効果をもたらす細胞外濃度(mg/Lで示したCs)。用量−効果研究から得られた比較薬理学的記述子(Emaxおよび静菌濃度[Cs])。ミュラー−ヒントンブロスでの用量−応答研究。黄色ブドウ球菌ATCC 25923に対しておよびpH7.4のブロス中で、CEM−101は、AZI、CLRおよびTELよりも体系的に活性が高く、pH5.5では、AZI、CLRおよびTELはその効力の有意な減少を示すが、CEM−101はあまり変化を示さない。
関連する回帰パラメータa(信頼区間[CI]を含む)、および図2に示す用量−応答曲線の統計解析。
a図4に示す全てのデータ点(抗生物質の細胞外濃度が0.01倍のMICよりも低いときは抗生物質なしの試料からのデータ)を用いた(5)
+もとの種菌[時間=0時間]:0.97±0.24×106CFU/mL(n=3)
++もとの(貪食後)種菌[時間=0時間]:2.74±0.55×106CFU/mgタンパク質(n=3)
◆抗生物質濃度=∞に関して外挿されたときの、対応するもとの種菌からの時間=24時間の時点でのCFU減少(log10単位で示す);5未満のカウントを生じる試料は、検出レベル未満とみなされた。
◇(傾斜因子1を用いて)ヒル方程式から得られる、初期値(E0)と最大値(Emax)の中間にまで種菌を低下させる濃度(mg/Lまたは×MICで示す);
◇◇グラフ内挿法によって決定される、細菌増殖が見られないようになる濃度(mg/Lまたは×MICで示す)(CFUの数は、もとの種菌と同じである);統計解析。抗生物質間の違いの解析(対応する行の列ごとに;全ての薬物の各パラメータ間の複数の比較についてのテューキー検定による一元配置ANOVA):様々な小文字を伴う数字は、互いに有意に異なる(p<0.05)。ブロスとTHP−1マクロファージの違いの解析(対応する列の行ごとに;対応のない両側t検定):様々な小文字を伴う数字は、互いに有意に異なる(p<0.05)。
関連する回帰パラメータa(信頼区間[CI]を含む)、および図4に示す用量−応答曲線の統計解析。
a図4に示す全てのデータ点(抗生物質の細胞外濃度が0.01倍のMICよりも低いときは抗生物質なしの試料からのデータ)を用いた(5)。+もとの(貪食後)種菌[時間=0時間;CFU/mgタンパク質]:L.モノサイトゲネス、1.67±0.22×106(n=3);L.ニューモフィラ、0.94±0.60×106。◆抗生物質濃度∞に関して外挿されたときの、対応するもとの種菌からの時間=24時間(L.モノサイトゲネス)または48時間(N.ニューモフィラ)の時点でのCFU減少(log10単位で示す);5未満のカウントを生じる試料は、検出レベル未満とみなされた。◇(傾斜因子1を用いて)ヒル方程式から得られる、初期値(E0)と最大値(Emax)の中間にまで種菌を低下させる濃度(mg/Lまたは×MICで示す)。◇◇グラフ内挿法によって決定される、細菌増殖が見られないようになる濃度(mg/Lまたは×MICで示す)(CFUの数は、もとの種菌と同じである)。統計解析:2つの抗生物質間の違いの解析(対応する行の列ごとに;対応のない両側t検定):様々な小文字を伴う数字は、互いに有意に異なる(p<0.05)。
本明細書に記載の化合物のインビトロ研究のスクリーニングは、TEL、ERY、AZIおよびCLRと同等かまたはこれらよりも優れた効力ならびに立証されたマクロライドまたはリンコサミド耐性を有するグラム陽性分離株に対する活性を示している。CEM−101活性は、通常、グラム陽性病原体に対して焦点を当てたものであるが、偏好性グラム陰性種(ヘモフィルス、モラクセラ)、いくつかの腸内細菌科(サルモネラ菌、赤痢菌)および様々な性感染症(STD)を引き起こす病原体に対する測定可能な効力も有する。CARTI(レンサ球菌、ヘモフィルス種、カタラリス菌、レジオネラ・ニューモフィラ)、新興耐性サブセット(血清群19Aの肺炎レンサ球菌)および試験したレンサ球菌内での様々なパターンのMLSB−ケトライド耐性と関連する生物を試験するとき、CEM−101活性は、標準的な臨床検査標準協会(CLSI)法によって測定された。
a.S=感受性およびNS=非感受性(例えば、中間株および耐性株を含む)。
b.ストレプトコッカス・アンギノスス(9株)、S.コンステラツス(8株)、S.インテルメディウス(7株)、S.ミティス(2株)、S.オラリス(3株)、肺炎レンサ球菌(61株)、A群レンサ球菌(29株)、B群レンサ球菌(17株)、C群レンサ球菌(11株)、F群レンサ球菌(6株)およびG群レンサ球菌(11株)を含む。
c.ストレプトコッカス・アンギノスス(2株)、S.コンステラツス(2株)、S.インテルメディウス(3株)、S.ミティス(7株)、 S.オラリス(7株)、肺炎レンサ球菌(14株)、A群レンサ球菌(1株)、B群レンサ球菌(7株)、およびG群レンサ球菌(5株)を含む。
d.ストレプトコッカス・アンギノスス(1株)、肺炎レンサ球菌(75株)、B群レンサ球菌(7株)、C群レンサ球菌(2株)、およびF群レンサ球菌(3株)を含む。
Claims (13)
- ペニシリン、セファロスポリン、キノロン、テトラサイクリン、クリンダマイシン、トリメトプリム、スルファメトキサゾール、アジスロマイシン、ケトライド、バンコマイシン、又はそれらの組合せの1つ以上に耐性のある気道感染症治療用又は***症治療用医薬組成物であって、前記組成物は治療有効量の下記式の化合物又はその薬学的に許容可能な塩を含有し、
Wは水素又はフッ素であり;
AはCH2であり;
Bは(CH2)nであって、ここでnは0〜10の範囲の整数であって、又はBは炭素数2〜10の不飽和炭素鎖であって;且つ
Cはアシル、カルバモイル、ウレイド、アルキル、アリールアルキル、任意に置換されたアリール又は任意に置換されたヘテロアリールである、組成物。 - Bは(CH2)3である請求項1に記載の組成物。
- Cは任意に置換されたアリールである請求項1又は請求項2に記載の組成物。
- Cは3−アミノフェニルである請求項1又は請求項2に記載の組成物。
- Wはフッ素である請求項1〜4のいずれか1項に記載の組成物。
- 前記感染症は肺炎球菌、黄色ブドウ球菌、インフルエンザ菌、K.ニューモニエ、M.カタラリス、大腸菌、肺炎クラミジア、肺炎マイコプラズマ又はそれらの組合せによって少なくとも部分的に引き起こされる請求項1〜7のいずれか1項に記載の組成物。
- 前記感染症はケトライド耐性のある感染症である請求項1〜8のいずれか1項に記載の組成物。
- 前記感染症はアジスロマイシン耐性のある感染症である請求項1〜8のいずれか1項に記載の組成物。
- 前記感染症はペニシリン、セファロスポリン、キノロン、バンコマイシン又はそれらの組合せに耐性のある感染症である請求項1〜8のいずれか1項に記載の組成物。
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