JP7350336B2 - MEK/PI3K、JAK/MEK、JAK/PI3K/mTORおよびMEK/PI3K/mTORの生物学的経路の阻害剤、および治療化合物のリンパ取り込み、生物学的利用能、および溶解性を改善する方法 - Google Patents
MEK/PI3K、JAK/MEK、JAK/PI3K/mTORおよびMEK/PI3K/mTORの生物学的経路の阻害剤、および治療化合物のリンパ取り込み、生物学的利用能、および溶解性を改善する方法 Download PDFInfo
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- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
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- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Description
本発明は、米国国立衛生研究所によって授与されたCA197701およびCA085878の下で政府の支援を受けてなされた。政府は、本発明におけるある特定の権利を有する。
本出願は、その全体が参照により本明細書に組み込まれる、2017年8月11日に出願された米国仮特許出願第62/544,332号の利益を主張する。
表1.薬物に結合することができるマルチエチレングリコール(mEG)機能的リンパ系標的リンカーの例
表2.mEGリンカーの官能基結合(Y)。
表3.MEKのトリグリセリドプロドラッグ阻害剤および二価阻害剤プロドラッグの例。
MEKのトリグリセリドプロドラッグ阻害剤(PD0316684)
表5.MEK、PI3K、およびmTOR/PI3Kリンパ系指向性mEGプロドラッグの例。
阻害剤化合物は、リンパ系への取り込みに必要な物理化学的特性を有する薬物を提供するために、薬物分子への結合に適合する化学修飾剤の開発に必要な基礎となるパラメーターを発見するために合成された。表9に示すように、6つの異なるツール分子(化合物1~6)または構造の3つのペア(ペア1~2、3~4および5~6)であって、3つのペアはそれぞれ化学リンカー(mEGまたはアルキルのみが異なる)チェーン)が調製された。表9に示す化合物1~4を、分子のヒトへの経口送達のために開発された賦形剤材料であるマイシンと混合した。この賦形剤は、長鎖脂肪酸を含み、疎水性化合物の可溶化のために使用される。合計10mgの各化合物1~4を200マイクロリットルのマイシンに加えた。化合物1と3は完全にマイシンに溶解したが、化合物2と4は白い濁った懸濁液を生成することがわかったため、溶解が不完全であった。このデータは、短いmEG化学修飾剤によって提供されるユニークな化学的属性、すなわち、結合後の薬物の改善された溶解性の直接的な証拠を提供する。化合物2および4は、この投薬量レベルで完全に溶解するために十分な溶解度を有さないため、生物学的利用能ははるかに制限される。このデータは、アルキル鎖部分が結合化合物の改善された溶解性を提供するために最適ではなく、mEG部分がこの目的のために必要とされることを明らかにした。化合物1~4からなる各混合物をマウスに経口投与し、投与後0.5、2、4時間の時点で組織を採取し、LC-MS/MS組織分析を使用して、宿主血漿、腸間膜リンパ節、および腸間膜脂肪組織の化合物濃度の定量化を可能にした。
表9.経口投与後のマウスにおけるcLogPおよびリンパ管取り込みに対するmEG対アルキルリンカーの影響を実証する化合物。
表10A
表11
表12
表13.ST-65および活性mTORおよびMEK阻害剤のインビトロ阻害データ
表14
Anighoro,A.,J.Bajorath and G.Rastelli(2014).“Polypharmacology:challenges and opportunities in drug discovery.” J Med Chem 57(19):7874-7887.
Claims (3)
- 疾患または状態を治療するための薬学的組成物であって、治療薬物を含み、前記治療薬物はリンカーを前記治療薬物に共有結合させることにより改変されて改変薬物が提供されるものであり、
前記治療薬物がMEK阻害剤であり、
前記改変薬物は、それを必要とする個体における標的への送達のために、前記個体のリンパ系によって送達または吸収されるものであり、
前記改変薬物が、
前記改変薬物は、前記治療薬物と比較してリンパ指向吸収が増加している、
薬学的組成物。 - 必要とする個体において疾患または状態を治療するための薬学的組成物であって、mTOR、MEK、およびPI3Kのうちの少なくとも1つの阻害が前記個体に利益を提供するものであり、請求項1に記載の前記改変薬物の有効量を含む、薬学的組成物。
- 前記疾患または状態が、
癌;
肺疾患、線維性疾患、炎症性疾患、慢性疼痛、および神経変性疾患;並びに
慢性閉塞性肺疾患、IPF、自己免疫疾患、多発性硬化症、およびアルツハイマー病
からなる群から選択される、請求項2に記載の薬学的組成物。
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US201762544332P | 2017-08-11 | 2017-08-11 | |
US62/544,332 | 2017-08-11 | ||
PCT/US2018/045703 WO2019032640A1 (en) | 2017-08-11 | 2018-08-08 | MEK / P13K, JAK / MEK, JAK / P13K / MTOR AND MEK / P13K / MTOR BIKE INHIBITORS AND METHODS FOR ENHANCING LYMPHATIC ABSORPTION, BIOAVAILABILITY AND SOLUBILITY OF THERAPEUTIC COMPOUNDS |
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JP2020530471A JP2020530471A (ja) | 2020-10-22 |
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JP7350336B2 true JP7350336B2 (ja) | 2023-09-26 |
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US (1) | US11311624B2 (ja) |
EP (1) | EP3664808A1 (ja) |
JP (1) | JP7350336B2 (ja) |
KR (1) | KR20200039756A (ja) |
CN (1) | CN111065397A (ja) |
AU (1) | AU2018316175B2 (ja) |
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JP2020530471A (ja) | 2020-10-22 |
KR20200039756A (ko) | 2020-04-16 |
EP3664808A1 (en) | 2020-06-17 |
AU2018316175A1 (en) | 2020-02-27 |
US20200164081A1 (en) | 2020-05-28 |
WO2019032640A1 (en) | 2019-02-14 |
CN111065397A (zh) | 2020-04-24 |
CA3072080A1 (en) | 2019-02-14 |
AU2018316175B2 (en) | 2023-02-23 |
US11311624B2 (en) | 2022-04-26 |
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