JP7372740B2 - 細胞生存性及び/又は細胞増殖を低減するための薬物の組み合わせ - Google Patents
細胞生存性及び/又は細胞増殖を低減するための薬物の組み合わせ Download PDFInfo
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- JP7372740B2 JP7372740B2 JP2018559826A JP2018559826A JP7372740B2 JP 7372740 B2 JP7372740 B2 JP 7372740B2 JP 2018559826 A JP2018559826 A JP 2018559826A JP 2018559826 A JP2018559826 A JP 2018559826A JP 7372740 B2 JP7372740 B2 JP 7372740B2
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
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Description
ここで、X日目は任意の測定日である。
Claims (42)
- N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩を含む、肝細胞癌の治療剤であって、前記N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩が、EGFR阻害剤又はその薬学的に許容される塩と組み合わせて投与され、
前記N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩及びEGFR阻害剤又はその薬学的に許容される塩が肝細胞癌の増殖を相乗的に阻害し、
前記EGFR阻害剤が、4-キナゾリンアミンN-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-[3-(4-モルホリニル)プロポキシ]、N-[4-[(3-クロロ-4-フルオロフェニル)アミノ]-7-[[(3S)-テトラヒドロ-3-フラニル]オキシ]-6-キナゾリニル]-4(ジメチルアミノ)-2-ブテンアミド、N-(3-クロロ-4-{[(3-フルオロフェニル)メチル]オキシ}フェニル)-6-[5-({[2-(メチルスルホニル)エチル]アミノ}メチル)-2-フラニル]-4-キナゾリンアミンビス(4-メチルベンゼンスルホナート)一水和物、及びセツキシマブから成る群から選択される、治療剤。 - 前記N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩が、50mg~600mgの間の1日当たりの投与量で投与される、請求項1に記載の治療剤。
- 前記N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩が、200mg~400mgの間の1日当たりの投与量で投与される、請求項2に記載の治療剤。
- 前記N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩が、300mgの1日当たりの投与量で投与される、請求項3に記載の治療剤。
- 前記EGFR阻害剤が、ゲフィチニブである、請求項1に記載の治療剤。
- 前記ゲフィチニブが、250mgの1日当たりの投与量で投与される、請求項5に記載の治療剤。
- 前記N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩及び前記ゲフィチニブが、Loewe相加性の方程式による算出で17~134の範囲において肝細胞癌の増殖を相乗的に阻害する、請求項5に記載の治療剤。
- 前記Loewe相加性の方程式による算出値が36~134の範囲である、請求項7に記載の治療剤。
- 前記Loewe相加性の方程式による算出値が59~134の範囲である、請求項7に記載の治療剤。
- 前記Loewe相加性の方程式による算出値が100~134の範囲である、請求項7に記載の治療剤。
- 前記EGFR阻害剤が、アファチニブである、請求項1に記載の治療剤。
- 前記アファチニブが、20mg/日の1日当たりの投与量で投与される、請求項11に記載の治療剤。
- 前記アファチニブが、30mg/日の1日当たりの投与量で投与される、請求項11に記載の治療剤。
- 前記アファチニブが、40mg/日の1日当たりの投与量で投与される、請求項11に記載の治療剤。
- 前記N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩及び前記アファチニブが、Loewe相加性の方程式による算出で5~126の範囲において肝細胞癌の増殖を相乗的に阻害する、請求項11に記載の治療剤。
- 前記Loewe相加性の方程式による算出値が24~126の範囲である、請求項15に記載の治療剤。
- 前記Loewe相加性の方程式による算出値が50~126の範囲である、請求項15に記載の治療剤。
- 前記Loewe相加性の方程式による算出値が114~126の範囲である、請求項15に記載の治療剤。
- 前記EGFR阻害剤が、ラパチニブである、請求項1に記載の治療剤。
- 前記ラパチニブが、1000mg~1500mgの間の1日当たりの投与量で投与される、請求項19に記載の治療剤。
- 前記ラパチニブが、1000mgの1日当たりの投与量で投与される、請求項20に記載の治療剤。
- 前記ラパチニブが、1250mgの1日当たりの投与量で投与される、請求項20に記載の治療剤。
- 前記ラパチニブが、1500mgの1日当たりの投与量で投与される、請求項20に記載の治療剤。
- 前記N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩及び前記ラパチニブが、Loewe相加性の方程式による算出で6~139の範囲において肝細胞癌の増殖を相乗的に阻害する、請求項19に記載の治療剤。
- 前記Loewe相加性の方程式による算出値が27~139の範囲である、請求項24に記載の治療剤。
- 前記Loewe相加性の方程式による算出値が56~139の範囲である、請求項24に記載の治療剤。
- 前記Loewe相加性の方程式による算出値が123~139の範囲である、請求項24に記載の治療剤。
- 前記EGFR阻害剤が、セツキシマブである、請求項1に記載の治療剤。
- 前記セツキシマブが、200~300mg/m2の間の週当たりの投与量で投与される、請求項28に記載の治療剤。
- 前記セツキシマブが、250mg/m2の週当たりの投与量で投与される、請求項29に記載の治療剤。
- 前記N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩及び前記EGFR阻害剤が、別個の製剤として投与される、請求項1~30のいずれか一項に記載の治療剤。
- 前記N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩及び前記EGFR阻害剤が、単一製剤として投与される、請求項1~30のいずれか一項に記載の治療剤。
- 前記N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩及び前記EGFR阻害剤が、連続的に投与される、請求項1~31のいずれか一項に記載の治療剤。
- 前記N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩及び前記EGFR阻害剤が、同時に投与される、請求項1~31のいずれか一項に記載の治療剤。
- 遊離塩基形態のN-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミドを含む、請求項1~34のいずれか一項に記載の治療剤。
- N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミドの前記薬学的に許容される塩が、塩酸塩形態のN-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミドである、請求項1~34のいずれか一項に記載の治療剤。
- N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩及びEGFR阻害剤又はその薬学的に許容される塩を含む、医薬製剤であって、
前記医薬製剤が肝細胞癌の増殖を相乗的に阻害するために用いられ、
前記EGFR阻害剤が、4-キナゾリンアミンN-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-[3-(4-モルホリニル)プロポキシ]、N-[4-[(3-クロロ-4-フルオロフェニル)アミノ]-7-[[(3S)-テトラヒドロ-3-フラニル]オキシ]-6-キナゾリニル]-4(ジメチルアミノ)-2-ブテンアミド、N-(3-クロロ-4-{[(3-フルオロフェニル)メチル]オキシ}フェニル)-6-[5-({[2-(メチルスルホニル)エチル]アミノ}メチル)-2-フラニル]-4-キナゾリンアミンビス(4-メチルベンゼンスルホナート)一水和物、及びセツキシマブから成る群から選択される、医薬製剤。 - 遊離塩基形態のN-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミドを含む、請求項37に記載の医薬製剤。
- N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミドの前記薬学的に許容される塩が、塩酸塩形態のN-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミドである、請求項37に記載の医薬製剤。
- 肝細胞癌の治療のための薬剤の調製におけるN-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩及びEGFR阻害剤の組み合わせの使用であって、
前記N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩及びEGFR阻害剤又はその薬学的に許容される塩が肝細胞癌の増殖を相乗的に阻害し、
前記EGFR阻害剤が、4-キナゾリンアミンN-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-[3-(4-モルホリニル)プロポキシ]、N-[4-[(3-クロロ-4-フルオロフェニル)アミノ]-7-[[(3S)-テトラヒドロ-3-フラニル]オキシ]-6-キナゾリニル]-4(ジメチルアミノ)-2-ブテンアミド、N-(3-クロロ-4-{[(3-フルオロフェニル)メチル]オキシ}フェニル)-6-[5-({[2-(メチルスルホニル)エチル]アミノ}メチル)-2-フラニル]-4-キナゾリンアミンビス(4-メチルベンゼンスルホナート)一水和物、及びセツキシマブから成る群から選択される、使用。 - 1つ又は複数の細胞にN-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩及びEGFR阻害剤又はその薬学的に許容される塩の組み合わせを投与するステップを含む、インビトロにおいて細胞生存性又は細胞増殖を相乗的に低減する方法であって、
前記EGFR阻害剤が、4-キナゾリンアミンN-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-[3-(4-モルホリニル)プロポキシ]、N-[4-[(3-クロロ-4-フルオロフェニル)アミノ]-7-[[(3S)-テトラヒドロ-3-フラニル]オキシ]-6-キナゾリニル]-4(ジメチルアミノ)-2-ブテンアミド、N-(3-クロロ-4-{[(3-フルオロフェニル)メチル]オキシ}フェニル)-6-[5-({[2-(メチルスルホニル)エチル]アミノ}メチル)-2-フラニル]-4-キナゾリンアミンビス(4-メチルベンゼンスルホナート)一水和物、及びセツキシマブから成る群から選択される、方法。 - インビトロにおいて細胞生存性又は細胞増殖を相乗的に低減するための、N-(2-((6-(3-(2,6-ジクロロ-3,5-ジメトキシフェニル)-1-メチルウレイド)ピリミジン-4-イル)アミノ)-5-(4-エチルピペラジン-1-イル)フェニル)アクリルアミド又はその薬学的に許容される塩及びEGFR阻害剤の組み合わせの使用であって、
前記EGFR阻害剤が、4-キナゾリンアミンN-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-[3-(4-モルホリニル)プロポキシ]、N-[4-[(3-クロロ-4-フルオロフェニル)アミノ]-7-[[(3S)-テトラヒドロ-3-フラニル]オキシ]-6-キナゾリニル]-4(ジメチルアミノ)-2-ブテンアミド、N-(3-クロロ-4-{[(3-フルオロフェニル)メチル]オキシ}フェニル)-6-[5-({[2-(メチルスルホニル)エチル]アミノ}メチル)-2-フラニル]-4-キナゾリンアミンビス(4-メチルベンゼンスルホナート)一水和物、及びセツキシマブから成る群から選択される、使用。
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Family Cites Families (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4679363A (en) * | 1986-01-28 | 1987-07-14 | Adams George W | Township, city and regional land arrangement |
AU763839B2 (en) | 1998-05-26 | 2003-07-31 | Warner-Lambert Company | Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation |
EP1651648A4 (en) | 2003-07-29 | 2009-09-02 | Irm Llc | COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS |
GB0512324D0 (en) | 2005-06-16 | 2005-07-27 | Novartis Ag | Organic compounds |
WO2006038112A1 (en) | 2004-10-01 | 2006-04-13 | Warner-Lambert Company Llc | Use of kinase inhibitors to promote neochondrogenesis |
WO2007071752A2 (en) | 2005-12-21 | 2007-06-28 | Novartis Ag | Pyrimidinyl aryl urea derivatives being fgf inhibitors |
EP1918376A1 (en) | 2006-11-03 | 2008-05-07 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | FGFR4 promotes cancer cell resistance in response to chemotherapeutic drugs |
CN101808648B (zh) * | 2007-07-25 | 2013-04-03 | 博洛尼亚大学阿尔玛母校研究室 | 用于治疗肝细胞癌的药物组合物和药剂盒 |
US20090062320A1 (en) | 2007-08-28 | 2009-03-05 | Vito Guagnano | Method of Treating Disorders Mediated by the Fibroblast Growth Factor Receptor |
NZ624345A (en) | 2008-06-27 | 2016-07-29 | Celgene Avilomics Res Inc | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
EP2169071A1 (en) | 2008-09-29 | 2010-03-31 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Rodent cancer model for human FGFR4 Arg388 polymorphism |
AR079257A1 (es) | 2009-12-07 | 2012-01-04 | Novartis Ag | Formas cristalinas de 3-(2,6-dicloro-3-5-dimetoxi-fenil)-1-{6-[4-(4-etil-piperazin-1-il)-fenil-amino]-pirimidin-4-il}-1-metil-urea y sales de las mismas |
US9180127B2 (en) | 2009-12-29 | 2015-11-10 | Dana-Farber Cancer Institute, Inc. | Type II Raf kinase inhibitors |
SG181850A1 (en) | 2010-01-14 | 2012-08-30 | Univ Yale | Inhibitors of receptor tyrosine kinases (rtk) and methods of use thereof |
WO2011153553A2 (en) | 2010-06-04 | 2011-12-08 | The Regents Of The University Of California | Methods and compositions for kinase inhibition |
WO2012136732A1 (en) | 2011-04-08 | 2012-10-11 | Ab Science | Treatment of multiple myeloma with masitinib |
CN102816162B (zh) | 2011-06-10 | 2016-04-27 | 中国科学院广州生物医药与健康研究院 | 嘧啶并嘧啶酮类化合物及其药用组合物和应用 |
CN103106630A (zh) * | 2011-11-10 | 2013-05-15 | 李红彬 | 生态城市规划 |
RU2014133547A (ru) | 2012-01-18 | 2016-03-10 | Дженентек, Инк. | Способы применения модуляторов fgf19 |
EP2821402B1 (en) | 2012-02-28 | 2019-08-21 | Astellas Pharma Inc. | Nitrogen-containing aromatic heterocyclic compound |
CN103306509A (zh) * | 2012-03-06 | 2013-09-18 | 李尚喜 | 未来城市区域定向建设与施工 |
RU2496937C1 (ru) * | 2012-03-12 | 2013-10-27 | Лев Иванович Гаранин | Способ обустройства антарктиды |
KR102163776B1 (ko) | 2012-07-11 | 2020-10-12 | 블루프린트 메디신즈 코포레이션 | 섬유아세포 성장인자 수용체의 저해제 |
WO2014149164A1 (en) | 2013-03-15 | 2014-09-25 | Celgene Avilomics Research, Inc. | Mk2 inhibitors and uses thereof |
AU2014228746B2 (en) | 2013-03-15 | 2018-08-30 | Celgene Car Llc | Heteroaryl compounds and uses thereof |
CA2917667A1 (en) | 2013-07-09 | 2015-01-15 | Dana-Farber Cancer Institute, Inc. | Kinase inhibitors for the treatment of disease |
AR097455A1 (es) | 2013-08-28 | 2016-03-16 | Astellas Pharma Inc | Composición farmacéutica que contiene compuesto de pirimidina como un ingrediente activo |
AU2014337291B9 (en) | 2013-10-18 | 2020-05-07 | Eisai R&D Management Co., Ltd. | Pyrimidine FGFR4 inhibitors |
JP6458023B2 (ja) | 2013-10-25 | 2019-01-23 | ブループリント メディシンズ コーポレイション | 繊維芽細胞成長因子受容体の阻害剤 |
WO2015108992A1 (en) | 2014-01-15 | 2015-07-23 | Blueprint Medicines Corporation | Heterobicyclic compounds and their use as fgfr4 receptor inhibitors |
CN104099840B (zh) * | 2014-07-28 | 2016-07-13 | 池昭新 | 一种添加自然地貌的城镇规划模式 |
MX2017013248A (es) | 2015-04-14 | 2018-07-06 | Eisai R&D Man Co Ltd | Compuesto del inhibidor fgfr4 cristalino y usos del mismo. |
TWI669300B (zh) | 2016-05-20 | 2019-08-21 | 浙江海正藥業股份有限公司 | 嘧啶類衍生物、其製備方法、其藥物組合物以及其在醫藥上的用途 |
CN113105454B (zh) | 2016-05-20 | 2022-10-11 | 江苏豪森药业集团有限公司 | Fgfr4抑制剂、其制备方法和应用 |
-
2017
- 2017-05-09 EP EP17725014.9A patent/EP3454898B1/en active Active
- 2017-05-09 WO PCT/US2017/031771 patent/WO2017196854A1/en unknown
- 2017-05-09 US US16/300,313 patent/US11357769B2/en active Active
- 2017-05-09 JP JP2018559826A patent/JP7372740B2/ja active Active
- 2017-05-12 WO PCT/US2017/032343 patent/WO2017197226A1/en active Application Filing
-
2022
- 2022-08-10 JP JP2022127803A patent/JP2022160654A/ja active Pending
Non-Patent Citations (4)
Title |
---|
Cancer Research、2008年、Vol.68、No.7、p.2391-2399 |
Cancer、2008年、Vol.112、No.12、p.2733-2739 |
Front.Pharmacol.、2015年、6:181 |
国際公開第2015/57938号 |
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