JP7179185B2 - 医薬の製造おける単環式β-ラクタム化合物の使用 - Google Patents
医薬の製造おける単環式β-ラクタム化合物の使用 Download PDFInfo
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- JP7179185B2 JP7179185B2 JP2021535115A JP2021535115A JP7179185B2 JP 7179185 B2 JP7179185 B2 JP 7179185B2 JP 2021535115 A JP2021535115 A JP 2021535115A JP 2021535115 A JP2021535115 A JP 2021535115A JP 7179185 B2 JP7179185 B2 JP 7179185B2
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- treating pneumonia
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- -1 monocyclic β-lactam compounds Chemical class 0.000 title description 13
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- 230000008261 resistance mechanism Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229940041007 third-generation cephalosporins Drugs 0.000 description 1
- VAMSVIZLXJOLHZ-QWFSEIHXSA-N tigemonam Chemical compound O=C1N(OS(O)(=O)=O)C(C)(C)[C@@H]1NC(=O)C(=N/OCC(O)=O)\C1=CSC(N)=N1 VAMSVIZLXJOLHZ-QWFSEIHXSA-N 0.000 description 1
- 229950010206 tigemonam Drugs 0.000 description 1
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- 229910052722 tritium Inorganic materials 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
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- 238000005303 weighing Methods 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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Description
CN201811549551.8であり、出願日は2018年12月18日である。
別途に説明しない限り、本明細書で用いられる以下の用語及び連語は以下の意味を有する。一つの特定の用語又は連語は、特別に定義されていない限り、不確定又は不明瞭ではなく、普通の定義として理解されるべきである。本明細書で商品名が出た場合、相応の商品又はその活性成分を指す。本明細書で用いられる用語「薬学的に許容される」は、それらの化合物、材料、組成物及び/又は剤形に対するもので、これらは信頼できる医学的判断の範囲内にあり、ヒト及び動物の組織と接触して使用することに適し、過剰な毒性、刺激性、アレルギー反応又は他の問題又は合併症があまりなく、合理的な利益/リスク比に合う。
aqは水を表し;minは分を表し;FAはギ酸を表し;m-CPBAは3-クロロペルオキシ安息香酸を表し;eqは当量、等量を表し;DCCはN,N′-ジシクロヘキシルカルボジイミドを表し;DCMはジクロロメタンを表し;PEは石油エーテルを表し;DIADはアゾジカルボン酸ジイソプロピルを表し;DMFはN,N-ジメチルホルムアミドを表し;BH3・SMe2はボランジメチルスルフィドを表し;DMSOはジメチルスルホキシドを表し;EtOAcは酢酸エチルを表し;EtOHはエタノールを表し;MeOHはメタノールを表し;Cbzはベンジルオキシカルボニルを表し、アミンの保護基の一つであり;Bocはtert-ブトキシカルボニルを表し、アミンの保護基の一つであり;HOAcは酢酸を表し;ACNはアセトニトリルを表し;BH3はシアノ水素化ホウ素ナトリウムであり;r.t.は室温を表し;THFはテトラヒドロフランを表し;Boc2Oは二炭酸ジ-tert-ブチルを表し;TFAはトリフルオロ酢酸を表し;DIPEAはジイソプロピルエチルアミンを表し;SOCl2は塩化チオニルを表し;iPrOHは2-プロパノールを表し;mpは融点を表し;LDAはリチウムジイソプロピルアミドを表し;TEMPOは2,2,6,6-テトラメチルピペリジン1-オキシルフリーラジカル又は2,2,6,6-テトラメチルピペリジンオキシドを表し;NaClOは次亜塩素酸ナトリウムを表し;NaClO2は亜塩素酸ナトリウムを表し;HOBtは1-ヒドロキシベンゾトリアゾールを表し;psiはポンド/平方インチを表し;DMF・SO3は三酸化硫黄N,N-ジメチルホルムアミドを表し;KH2PO4はリン酸二水素カリウムを表し;Bu4HSO4はテトラブチルアンモニウム硫酸水素塩を表し;PPh3はトリフェニルホスフィンを表し;NH2NH2・H2Oはヒドラジンを表し;DPPFは1,1‘-ビス(ジフェニルホスフィノ)フェロセンを表し;Pd2(dba)3はトリス(ジベンジリデンアセトン)ジパラジウム(0)を表し;MICは最小発育阻止濃度を表し;DMAPは4-ジメチルアミノピリジンを表し;BnBrはベンジルブロミドを表し;H2O2は過酸化水素を表す。
LC-MS(ESI)m/z:283(M-56+1)。
LC-MS(ESI)m/z:321.1(M+1)。
緑膿菌PA14。
(1)試験化合物:式(I)で表される化合物
(2)参照化合物:AiCuris特許WO2018065636の参照化合物I-g、(大連メイルンバイオテック株式会社製)。
ミューラーヒントン寒天培地(MHA)及びTSA培地、いずれもBD社から購入した。
CD-1(ICR)マウスは、北京バイタルリバーラボラトリーアニマルテクノロジー株式会社から提供され、体重は23~27gであり、7週齢、メス、合計46匹のマウスである。
(1)シクロホスファミドの腹腔内注射により免疫抑制マウスを形成させた。
46匹のマウスに1日目、4日目にシクロホスファミド150mg/kgを腹腔内注射して、免疫抑制マウスを形成させた。
本実験は七つの群を設置し、それぞれ式(I)で表される化合物の高、中、低投与量群、化合物I-gの高、中投与量群、アズトレオナム群及びモデル群であり、群あたり6匹の動物であり、残りの4匹の動物は、肺部感染の2時間後に肺組織を取って細菌数をカウントした。群分けの詳細は以下の表を参照できる。
感染の2時間後、群に応じて投与し、2時間、4時間、6時間及び8時間目に1回、計4回腹腔内注射した。
感染の24時間後、頸椎脱臼により、各群のマウスを殺処分し、無菌操作で肺組織と腎臓組織を採取し、滅菌した組織ホモジネートチューブに入れ、秤量し、適量の生理食塩水(NS)を添加し、ホモジナイザーで1分間均質化させ、モデル群の動物の肺組織を104、105、106倍に希釈し、各投与群の肺組織を10、100倍に希釈し、モデル群の動物の腎臓組織を102、103、104倍に希釈し、各投与群の動物の肺組織を10倍に希釈し、TSAプレートにスクリューコーターでコーティングし、37℃で一晩インキュベートし、コロニーカウンターでCFUをカウントした。
試験開始の後、毎日体重を測定し、体重の変化を記録した。
Graphpad Prismマッピングソフトウェアを使用して、肺組織CFUのスキャッタグラムを作成した。SPSS19.0ソフトウェアを使用してCFUと体重の平均値を統計し、分散分析により群間の差を分析した。
(1)免疫抑制マウスの肺部が緑膿菌に感染された後の細菌負荷
シクロホスファミドを2回腹腔内注射した4匹の免疫抑制マウスの肺に緑膿菌PA14を約1.06×104CFU感染させ、2時間後、肺組織を採取して均質化し、細菌をカウントし、マウスの細菌負荷を計算し、この範囲で、平均負荷が5.10×103CFUであった。
感染の2時間、4時間、6時間及び8時間後、式(I)で表される化合物、化合物I-g及びアズトレオナムを腹腔内注射し、24時間後に動物を殺処分し、無菌操作で肺組織を採取し、生理食塩水(NS)に浸入させ、組織を均質化し、適切に希釈した後50μLを取ってTSAプレートで均一に塗布し、37℃のインキュベーターで一晩培養し、コロニー数をカウントし、希釈比に基づいてmlあたりのCFUに換算し、次に細菌負荷の対数値を基数10で計算し、各群はその平均数と標準偏差を比較し、結果を表3と図1に示した。モデル群の24時間の細菌負荷は1.06×104CFUから3.34×108CFUに増加し(細菌負荷のLOG10は8.14である)、各投与群の細菌負荷はモデル群の細菌負荷よりも有意に低く、基本的に除去され、式(I)で表される化合物の高、中、低投与量群は完全にクリアされた。
式(I)で表される化合物は、シクロホスファミドによって引き起こされる免疫抑制マウスにおける肺緑膿菌感染に対して生体内治療効果を有し、肺組織の細菌負荷を有意に減少させ、肺に感染した緑膿菌を排除した。その中で、式(I)で表される化合物の低投与量下で、肺に感染した緑膿菌を完全に排除することができた。又、投与群の動物の体重は有意に変化せず、式(I)で表される化合物の安全性が良好であることを示した。
Claims (8)
- 前記肺炎は緑膿菌の感染によって引き起こされることを特徴とする、請求項1に記載の肺炎治療用医薬組成物。
- 1つ又は複数の薬学的に許容される賦形剤及び/又は薬学的に許容される担体を含む請求項1に記載の肺炎治療用医薬組成物。
- 前記賦形剤は表面安定剤、溶解補助剤、緩衝液、光遮断剤、結合剤、崩壊剤又は潤滑剤であることを特徴とする、請求項3に記載の肺炎治療用医薬組成物。
- 前記表面安定剤は両性界面活性剤、非イオン性界面活性剤、カチオン界面活性剤又はアニオン界面活性剤、又はそれらの組み合わせを含むことを特徴とする、請求項4に記載の肺炎治療用医薬組成物。
- 前記肺炎治療用医薬組成物は経口投与に使用されることを特徴とする、請求項3~5のいずれか1項に記載の肺炎治療用医薬組成物。
- 前記肺炎治療用医薬組成物は錠剤、カプセルであることを特徴とする、請求項6に記載の肺炎治療用医薬組成物。
- 前記肺炎治療用医薬組成物は注射製剤又は吸入製剤の形態であることを特徴とする、請求項3~5のいずれか1項に記載の肺炎治療用医薬組成物。
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JP2017510580A (ja) | 2014-03-24 | 2017-04-13 | ノバルティス アーゲー | 細菌感染を治療するためのモノバクタム有機化合物 |
WO2017155765A1 (en) | 2016-03-07 | 2017-09-14 | Merck Sharp & Dohme Corp. | Bicyclic aryl monobactam compounds and methods of use thereof for the treatment of bacterial infections |
WO2018065636A1 (en) | 2016-12-21 | 2018-04-12 | Aicuris Anti-Infective Cures Gmbh | COMBINATION THERAPY WITH AMIDINE SUBSTITUTED ß-LACTAM COMPOUNDS AND ß-LACTAMASE INHIBITORS FOR INFECTIONS WITH ANTIBIOTIC RESISTANT BACTERIAL STRAINS |
JP2018528241A (ja) | 2015-09-23 | 2018-09-27 | ノバルティス アーゲー | モノバクタム抗生物質の塩および固体形態 |
JP2021512866A (ja) | 2018-01-29 | 2021-05-20 | メッドシャイン ディスカバリー インコーポレイテッド | 細菌感染を治療するための単環β−ラクタム化合物 |
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MX338505B (es) | 2005-12-07 | 2016-04-20 | Basilea Pharmaceutica Ag | Combinaciones utiles de antibioticos de monobactama con inhibidores de beta-lactamasa. |
NZ579375A (en) | 2007-03-23 | 2012-02-24 | Basilea Pharmaceutica Ag | Combination medicaments for treating bacterial infections |
UY34585A (es) | 2012-01-24 | 2013-09-02 | Aicuris Gmbh & Co Kg | Compuestos b-lactámicos sustituidos con amidina, su preparación y uso |
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JP2017510580A (ja) | 2014-03-24 | 2017-04-13 | ノバルティス アーゲー | 細菌感染を治療するためのモノバクタム有機化合物 |
JP2018528241A (ja) | 2015-09-23 | 2018-09-27 | ノバルティス アーゲー | モノバクタム抗生物質の塩および固体形態 |
WO2017155765A1 (en) | 2016-03-07 | 2017-09-14 | Merck Sharp & Dohme Corp. | Bicyclic aryl monobactam compounds and methods of use thereof for the treatment of bacterial infections |
WO2018065636A1 (en) | 2016-12-21 | 2018-04-12 | Aicuris Anti-Infective Cures Gmbh | COMBINATION THERAPY WITH AMIDINE SUBSTITUTED ß-LACTAM COMPOUNDS AND ß-LACTAMASE INHIBITORS FOR INFECTIONS WITH ANTIBIOTIC RESISTANT BACTERIAL STRAINS |
JP2021512866A (ja) | 2018-01-29 | 2021-05-20 | メッドシャイン ディスカバリー インコーポレイテッド | 細菌感染を治療するための単環β−ラクタム化合物 |
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EP3901150A4 (en) | 2022-09-07 |
WO2020125670A1 (zh) | 2020-06-25 |
US20220062244A1 (en) | 2022-03-03 |
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