JP2021515809A - 一組の抗薬剤耐性細菌活性を有する糖ペプチド化合物、その調製方法および応用 - Google Patents
一組の抗薬剤耐性細菌活性を有する糖ペプチド化合物、その調製方法および応用 Download PDFInfo
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- JP2021515809A JP2021515809A JP2020570620A JP2020570620A JP2021515809A JP 2021515809 A JP2021515809 A JP 2021515809A JP 2020570620 A JP2020570620 A JP 2020570620A JP 2020570620 A JP2020570620 A JP 2020570620A JP 2021515809 A JP2021515809 A JP 2021515809A
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- benzaldehyde
- phenyl
- compound
- drug
- glycopeptide
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- 229940079593 drug Drugs 0.000 title claims abstract description 44
- 239000003814 drug Substances 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical class NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 title claims abstract description 17
- 230000001580 bacterial effect Effects 0.000 title claims abstract description 12
- -1 glycopeptide compound Chemical class 0.000 claims abstract description 70
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- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 58
- 150000001875 compounds Chemical class 0.000 claims description 31
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- MRSVODWJJPXUDV-UHFFFAOYSA-N 9H-fluoren-9-ylmethyl N-[(4-chlorophenyl)methyl]-N-(4-formylphenyl)carbamate Chemical compound ClC1=CC=C(CN(C(=O)OCC2C3=CC=CC=C3C3=CC=CC=C23)C2=CC=C(C=O)C=C2)C=C1 MRSVODWJJPXUDV-UHFFFAOYSA-N 0.000 claims description 2
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- C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
- C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Landscapes
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- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Rは、次の式で表され:−A−D−E−G、
Aは、ベンゼン環であり、
Dは、−O−、または−S−、または−NH−であり、
Eは、−(CH2)m−であり、mは、1〜3であり、
Gは、構造式:
(1)Dが−O−または−S−である場合、具体的に、Rが4−ベンジルオキシフェニル、4−フェニルエトキシフェニル、4−フェニルプロポキシフェニル、4−(4’−メチルベンジルオキシ)フェニル、4−(4’−クロロベンジルオキシ)フェニル、4−(4’−メチルフェネトキシ)フェニル、4−(4’−フルオロフェネトキシ)フェニル、4−(4’−クロロフェネトキシ)フェニル、4−(4’−ブロモフェネトキシ)フェニル、4−(3’−ブロモフェネトキシ)フェニル、4−(4’−トリフルオロメチルフェネトキシ)フェニル、4−(4’−メトキシフェネトキシ)フェニル、4−(4’−クロロフェニルプロポキシ)フェニル、4−ベンジルチオフェニル、4−(4’−クロロベンジルチオ)フェニルおよび4−(4’−クロロフェネチルチオ)フェニルである場合、構造式IIに示される化合物をアルデヒド、ボランtert−ブチルアミンと反応させて、一般式Iに示される化合物を獲得する:
(2)Dが−NH−である場合、具体的に、Rが4−ベンジルアミノフェニル、4−(4’−メチルベンジルアミノ)フェニル、4−(4’−クロロベンジルアミノ)フェニル、4−フェネチルアミノフェニル、4−(4’−クロロフェネチルアミノ)フェニル、4−(4’−トリフルオロメチルフェネチルアミノ)フェニル、4−(4’−メトキシフェネチルアミノ)フェニル、4−アンフェタミンフェニルおよび4−(4’−クロルアンフェタミン)フェニルである場合、構造式IIに示される化合物をアルデヒド、ボランtert−ブチルアミンおよびジエチルアミンと反応させて、一般式Iに示される化合物を獲得する:
DIEA N,N−ジイソプロピルエチルアミン
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
ESI エレクトロスプレイイオン化質量分析
Fmoc 9−フルオレニルメトキシカルボニル
H 時間
LD50 50%致死量
MRSA メチシリン耐性黄色ブドウ球菌
MIC 最小発育阻止濃度
MS 質量分析
TFA トリフルオロ酢酸
VRE バンコマイシン耐性腸球菌
C87H100Cl2N10O27分子量計算値:1786.61、実際の測定値:m/z=1787.60[M+H]+。
実施例二、化合物2の調製
C88H102Cl2N10O27分子量計算値:1800.63、実際の測定値:m/z=1801.63[M+H]+。
実施例三、化合物3の調製
C89H104Cl2N10O27分子量計算値:1814.64、実際の測定値:m/z=1815.64[M+H]+。
実施例四、化合物4の調製
C88H102Cl2N10O27分子量計算値:1800.63、実際の測定値:m/z=1801.63[M+H]+。
実施例五、化合物8の調製
C88H101Cl3N10O27分子量計算値:1834.59、実際の測定値:m/z=1835.60[M+H]+。
実施例六、化合物10の調製
C88H101BrCl2N10O27分子量計算値:1878.54、実際の測定値:m/z=1879.54[M+H]+。
実施例七、化合物11の調製
C89H101Cl2F3N10O27分子量計算値:1868.62、実際の測定値:m/z=1869.64[M+H]+。
実施例八、化合物12の調製
C89H104Cl2N10O28分子量計算値:1830.64、実際の測定値:m/z=1831.64[M+H]+。
実施例九、化合物13の調製
C89H103Cl3N10O27分子量計算値:1848.61、実際の測定値:m/z=1849.62[M+H]+。
実施例十、化合物16の調製
C88H101Cl3N10O26S分子量計算値:1850.57、実際の測定値:m/z=1851.57[M+H]+。
実施例十一、化合物18の調製
C88H103Cl2N11O26分子量計算値:1799.65、実際の測定値:m/z=1800.65[M+H]+。
実施例十二、化合物20の調製
C88H103Cl2N11O26分子量計算値:1799.65、実際の測定値:m/z=1800.65[M+H]+。
実施例十三、化合物21の調製
C88H102Cl3N11O26分子量計算値:1833.61、実際の測定値:m/z=1834.60[M+H]+。
実施例十四、化合物23の調製
C89H105Cl2N11O27分子量計算値:1829.66、実際の測定値:m/z=1830.65[M+H]+。
実施例十五、化合物25の調製
C89H104Cl3N11O26分子量計算値:1847.62、実際の測定値:m/z=1848.63[M+H]+。
実施例十六、塩形成実施例
さらに、臭化水素酸、硫酸、硝酸、リン酸、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエン酸、ピクリン酸、メタンスルホン酸、アスパラギン酸またはグルタミン酸を使用して、上記飽和塩化水素メタノール溶液中の塩化水素を置き換え、対応する塩を得た。
実施例十七、製剤実施例
有効成分 100 mg
等張食塩水 1000 mL
上記の成分の溶液は、通常、患者に1 mL/分の速度で静脈内投与する。
実施例十八、化合物の抗菌活性の測定
Claims (10)
- Rは、4−ベンジルオキシフェニル、4−フェニルエトキシフェニル、4−フェニルプロポキシフェニル、4−(4’−メチルベンジルオキシ)フェニル、4−(4’−クロロベンジルオキシ)フェニル、4−(4’−メチルフェネトキシ)フェニル、4−(4’−フルオロフェネトキシ)フェニル、4−(4’−クロロフェネトキシ)フェニル、4−(4’−ブロモフェネトキシ)フェニル、4−(3’−ブロモフェネトキシ)フェニル、4−(4’−トリフルオロメチルフェネトキシ)フェニル、4−(4’−メトキシフェネトキシ)フェニル、4−(4’−クロロフェニルプロポキシ)フェニル、4−ベンジルチオフェニル、4−(4’−クロロベンジルチオ)フェニル、4−(4’−クロロフェネチルチオ)フェニル、4−ベンジルアミノフェニル、4−(4’−メチルベンジルアミノ)フェニル、4−(4’−クロロベンジルアミノ)フェニル、4−フェネチルアミノフェニル、4−(4’−クロロフェネチルアミノ)フェニル、4−(4’−トリフルオロメチルフェネチルアミノ)フェニル、4−(4’−メトキシフェネチルアミノ)フェニル、4−アンフェタミンフェニルおよび4−(4’−クロルアンフェタミン)フェニルを含むことを特徴とする
請求項1に記載の糖ペプチド化合物。 - 医薬製剤であって、
請求項1に記載の抗薬剤耐性細菌活性を有する糖ペプチド化合物を有効成分として含有することを特徴とする、前記医薬製剤。 - 前記製剤は、注射剤、経口剤、点滴剤または外用剤であることを特徴とする
請求項3に記載の医薬製剤。 - 前記糖ペプチド化合物の重量パーセントは、0.1%〜99.9%であることを特徴とする
請求項3に記載の医薬製剤。 - 前記アルデヒドは、4−ベンジルオキシベンズアルデヒド、4−フェニルエトキシベンズアルデヒド、4−フェニルプロポキシベンズアルデヒド、4−(4’−メチルベンジルオキシ)ベンズアルデヒド、4−(4’−クロロベンジルオキシ)ベンズアルデヒド、4−(4’−メチルフェネトキシ)ベンズアルデヒド、4−(4’−フルオロフェネトキシ)ベンズアルデヒド、4−(4’−クロロフェネトキシ)ベンズアルデヒド、4−(4’−ブロモフェネトキシ)ベンズアルデヒド、4−(3’−ブロモフェネトキシ)ベンズアルデヒド、4−(4’−トリフルオロメチルフェネトキシ)ベンズアルデヒド、4−(4’−メトキシフェネトキシ)ベンズアルデヒド、4−(4’−クロロフェニルプロポキシ)ベンズアルデヒド、4−ベンジルチオベンズアルデヒド、4−(4’−クロロベンジルチオ)ベンズアルデヒド、4−(4’−クロロフェネチルチオ)ベンズアルデヒド、4−(N−Fmoc−ベンジルアミノ)ベンズアルデヒド、4−(4’−メチル−N−Fmoc−ベンジルアミノ)ベンズアルデヒド、4−(4’−クロロ−N−Fmoc−ベンジルアミノ)ベンズアルデヒド、4−(N−Fmoc−フェネチルアミノ)ベンズアルデヒド、4−(4’−クロロ−N−Fmoc−フェネチルアミノ)ベンズアルデヒド、4−(4’−トリフルオロメチル−N−Fmoc−フェネチルアミノ)ベンズアルデヒド、4−(4’−メトキシ−N−Fmoc−フェネチルアミノ)ベンズアルデヒド、4−(N−Fmoc−アンフェタミン)ベンズアルデヒドおよび4−(4’−クロロ−N−Fmoc−アンフェタミン)ベンズアルデヒドから選択されるいずれかの1つであることを特徴とする
請求項6に記載の調製方法。 - 薬剤耐性細菌感染症の治療のための薬物の調製における、請求項1または2に記載の抗薬剤耐性細菌活性を有する糖ペプチド化合物の応用。
- 前記薬剤耐性細菌は、グラム陽性薬剤耐性細菌であることを特徴とする
請求項8に記載の応用。 - 前記薬剤耐性細菌は、メチシリン耐性黄色ブドウ球菌またはバンコマイシン耐性腸球菌であることを特徴とする
請求項9に記載の応用。
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EP1276759B1 (en) | 2000-05-02 | 2008-07-30 | Theravance, Inc. | Reductive alkylation process on glycopeptides |
UA75083C2 (uk) * | 2000-06-22 | 2006-03-15 | Тераванс, Інк. | Похідні глікопептидфосфонатів |
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