JP7124006B2 - アミロイド標的剤及びその使用方法 - Google Patents
アミロイド標的剤及びその使用方法 Download PDFInfo
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- JP7124006B2 JP7124006B2 JP2020081012A JP2020081012A JP7124006B2 JP 7124006 B2 JP7124006 B2 JP 7124006B2 JP 2020081012 A JP2020081012 A JP 2020081012A JP 2020081012 A JP2020081012 A JP 2020081012A JP 7124006 B2 JP7124006 B2 JP 7124006B2
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Images
Classifications
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- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
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- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07C255/43—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms the carbon skeleton being further substituted by singly-bound oxygen atoms
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07C311/31—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
- C07C311/35—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
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Description
本出願は、全体として及び全ての目的のために、内容が参照により本明細書に組み込まれる、米国特許商標庁に2014年3月19日に出願された米国仮出願第61/955,366号の優先権の利益を主張する。
各R26、R27、及びR28は独立して、水素またはハロゲンであり;R29は、ハロゲン、水素、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、C1~C10アリーレン、またはC1~C10ヘテロアリーレンであり、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリーレン、またはヘテロアリーレンは、1つ以上のR31と任意に置換され;R30は、水素、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、C1~C10アリーレン、またはC1~C10ヘテロアリーレンであり、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリーレン、またはヘテロアリーレンは、1つ以上のR32と任意に置換され;各R31及びR32は独立して、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、C1~C10アリーレン、またはC1~C10ヘテロアリーレンである。
各R33は独立して、ハロゲン、-OR34、-NR35R36、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、C1~C10アリーレン、またはC1~C10ヘテロアリーレンであり、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリーレン、またはヘテロアリーレンは、1つ以上のR37と任意に置換され;
各R34、R35、及びR36は独立して、水素、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、C1~C10アリーレン、またはC1~C10ヘテロアリーレンであり、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリーレン、またはヘテロアリーレンは、1つ以上のR37と任意に置換され;各R37は独立して、ハロゲン、-OR38、-NR39R40、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、-(C1~C6アルキル)(C1~C10ヘテロシクロアルキル)、C1~C10アリーレン、またはC1~C10ヘテロアリーレンであり;R38、R39、及びR40のそれぞれは独立して、水素またはC1~C10アルキルである。
各R33は独立して、ハロゲン、-OR34、-NR35R36、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、C1~C10アリーレン、またはC1~C10ヘテロアリーレンであり、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリーレン、またはヘテロアリーレンは、1つ以上のR37と任意に置換され;
各R34、R35、及びR36は独立して、水素、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、C1~C10アリーレン、またはC1~C10ヘテロアリーレンであり、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリーレン、またはヘテロアリーレンは、1つ以上のR37と任意に置換され;各R37は独立して、ハロゲン、-OR38、-NR39R40、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、C1~C10アリーレン、またはC1~C10ヘテロアリーレンであり;R38、R39、及びR40のそれぞれは独立して、水素またはC1~C10アルキルである。
一部の場合では、式Iの化合物は、
一部の実施形態では、本開示は、対象の1つ以上の疾患または状態の有無を判定する方法を提供する。一部の場合では、疾患または状態は、タンパク質の凝集またはタンパク質のミスフォールディングを特徴とする疾患または状態である。一部の態様では、方法は、有効量の式I若しくは式IIによる化合物またはその医薬組成物を対象に投与すること、を含み、疾患または状態の存在下で、投与される化合物は、検出可能な複合体を形成し、さらに、検出可能な複合体の有無が疾患または状態の有無と相関性があるような検出可能な複合体を検出すること、を含む。一部の場合では、疾患または状態は、対象におけるアミロイドの蓄積を特徴とするアミロイド系疾患または状態である。一部の場合では、疾患または状態は、アミロイド様形態構造を生じるタンパク質を伴う。一部の場合では、疾患または状態は、アルツハイマー病(AD)、パーキンソン病、ハンチントン病、筋萎縮性側索硬化症(ALS)、レビー小体認知症(LBD)、またはダウン症である。一部の場合では、疾患または状態は、アルツハイマー病である。一部の場合では、疾患または状態は、プリオン疾患または状態、例えば、クロイツフェルト・ヤコブ病(CJD)、である。一部の場合では、投与は、全身または局所である。一部の場合では、化合物は、対象の眼に投与される。一部の場合では、検出は、式Iまたは式IIの化合物の対象への投与から、約1秒、約5秒、約1分、約10分、約30分、または約60分以内に実施される。一部の場合では、検出は、式Iまたは式IIの化合物の対象への投与から、約1~5分以内である。一部の場合では、検出可能な複合体の形成の検出は、検出可能な複合体により生じるシグナルを測定することにより実施される。一部の場合では、シグナルは、電磁シグナルである。一部の場合では、シグナルは、蛍光シグナルである。一部の場合では、有効量の化合物は、成体対象当たり約50~500mg、例えば、50mg、60mg、70mg、80mg、90mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、280mg、290mg、300mg、310mg、320mg、330mg、340mg、350mg、360mg、370mg、380mg、390mg、400mg、410mg、420mg、430mg、440mg、450mg、460mg、470mg、480mg、490mg、または500mg、の化合物に相当する。
別の態様では、本開示は、式Iまたは式IIによる化合物を含むキットを提供する。一部の場合では、キットは、アミロイドまたはアミロイド様タンパク質に結合して、検出可能な複合体を形成するための化合物を使用するための、及び、検出可能な複合体の有無が、アミロイドまたはアミロイド様タンパク質の有無と相関性があるような検出可能な複合体の形成を検出するための、使用説明書をさらに含む。一部の場合では、キットは、アミロイドまたはアミロイド様タンパク質に結合して、検出可能な複合体を形成するための化合物を使用するための、及び、検出可能な複合体の存在量の経時的な変化が、アミロイドまたはアミロイド様タンパク質の存在量の経時的な変化と関連しているような検出可能な複合体の存在量の経時的な変化を検出するための、使用説明書をさらに含む。一部の場合では、キットは、検出可能な複合体の存在量の変化を、疾患の進行の監視に関連づけるための使用説明書をさらに含む。一部の場合では、式Iまたは式IIの化合物は、滅菌液体製剤として1つ以上の容器に含まれる。一部の場合では、式Iまたは式IIの化合物は、滅菌フリーズドライ製剤として1つ以上の容器に含まれる。一部の場合では、容器は、バイアルである。一部の場合では、バイアルは、アンバーバイアルである。一部の場合では、容器はまた、感光性化合物または製剤を保護できる。
本明細書に記載される全ての刊行物及び特許出願は、各個々の刊行物または特許出願が、参照により組み込まれることが具体的及び個別的に示されるような程度と同程度に本明細書に参照により組み込まれる。
本明細書で使用される略称は、化学及び生物学の技術分野内の従来の意味を有する。本明細書に記載される化学構造及び式は、当該化学分野で既知の化学価の標準規則に従って作図される。
一部の場合では、本開示は、タンパク質凝集またはタンパク質ミスフォールディングと関連する疾患または状態の検出、診断、治療、及び監視に用いられる新規化合物を提供する。一部の場合では、本開示の化合物はまた、アミロイド系疾患または状態の検出、診断、治療、及び監視に用いられる。本開示は、これら化合物を含む医薬組成物、及び、このような疾患または状態の治療のための薬品を調製するためのこれら化合物の使用、をさらに提供する。
一態様では、本開示は、式I:
R6、R7、及びR8は独立して、水素またはC1~C10アルキルである。
各R33は独立して、ハロゲン、-OR34、-NR35R36、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、C1~C10アリーレン、またはC1~C10ヘテロアリーレンであり、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリーレン、またはヘテロアリーレンは、1つ以上のR37と任意に置換され;各R34、R35、及びR36は独立して、水素、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、C1~C10アリーレン、またはC1~C10ヘテロアリーレンであり、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリーレン、またはヘテロアリーレンは、1つ以上のR37と任意に置換され;各R37は独立して、ハロゲン、-OR38、-NR39R40、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、C1~C10アリーレン、またはC1~C10ヘテロアリーレンであり;
R38、R39、及びR40のそれぞれは独立して、水素またはC1~C10アルキルである。
式Iの一部の化合物では、WSGは、-CH3-R33-R37である。
各R73は独立して、ハロゲン、-OR74、-NR75R76、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、C1~C10アリーレン、またはC1~C10ヘテロアリーレンであり、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリーレン、またはヘテロアリーレンは、1つ以上のR77と任意に置換され;各R74、R75、及びR76は独立して、水素、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、C1~C10アリーレン、またはC1~C10ヘテロアリーレンであり、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリーレン、またはヘテロアリーレンは、1つ以上のR77と任意に置換され;各R77は独立して、ハロゲン、-OR78、-NR79R80、C1~C10アルキル、C1~C10ヘテロアルキル、C1~C10シクロアルキル、C1~C10ヘテロシクロアルキル、C1~C10アリーレン、またはC1~C10ヘテロアリーレンであり、R78、R79、及びR80のそれぞれは独立して、水素またはC1~C10アルキルである。
一部の場合では、本開示の製剤は、多くの好適な投与様式を利用する。一部の場合では、送達は、局所投与または全身投与のいずれかにより、達成される。好適な投与経路は、経口、静脈内、経直腸、エアゾール、非経口、点眼、経肺、経粘膜、経皮、膣内、点耳、経鼻、及び局所投与を含むが、これらに限定されない。加えて、単なる例として、非経口送達は、筋肉内注射、皮下注射、静脈内注射、髄内注射、ならびに、髄腔内注射、直接脳室内注射、腹腔内注射、リンパ管内注射、及び鼻腔内注射を含む。一部の場合では、本開示の化合物は、全身方式で投与される。一部の場合では、投与は、非経口である。一部の場合では、投与は、静脈内である。一部の場合では、投与は、経皮である。一部の場合では、投与は、筋肉内である。一部の場合では、投与は、髄腔内である。投与は、経腸投与(消化管を経た薬物の吸収)、または、非経口投与、例えば、注射、注入、またはインプラントによるもの、で行うことができる。一部の場合では、投与は、経粘膜、例えば、経口、口内、舌下、経鼻、経肺、または経直腸、である。一部の場合では、投与は、経口である。一部の場合では、投与は、口内である。一部の場合では、投与は、舌下である。一部の場合では、投与は、経鼻である。一部の場合では、投与は、経肺である。一部の場合では、投与は、経直腸である。一部の場合では、投与は、経皮である。一部の場合では、投与は、皮内である。一部の場合では、投与は、局所である。一部の場合では、投与は、眼局所である。
一部の場合では、本明細書に記載される化合物は、医薬組成物に製剤化される。一部の場合では、医薬組成物は、薬学的に使用できる活性化合物を製剤に加工することを容易にする賦形剤及び補助剤を含む、1つ以上の生理学的に許容される担体を使用する従来方式で製剤化される。適切な製剤は、選択される投与経路に依存している。任意の薬学的に許容される手法、担体、及び賦形剤は、本明細書に記載される医薬組成物を製剤化するために好適なものとして使用される:Remington: The Science and Practice of Pharmacy, 第19版(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.及びLachman, L.,編, Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980;ならびにPharmaceutical Dosage Forms and Drug Delivery Systems, 第7版(Lippincott Williams & Wilkins1999)。
本開示は、本開示による化合物を含むキットも提供する。一部の場合では、本開示の化合物は、製剤として容器に含まれる。一部の場合では、キットは、滅菌液体製剤として容器に含まれる本開示の化合物を含む。一部の場合では、化合物はまた、滅菌フリーズドライ製剤として容器に入れられる。一部の場合では、容器は、バイアルである。一部の場合では、容器は、アンバーバイアルである。一部の場合では、容器はまた、感光性化合物または製剤を保護できる。
一態様では、本開示は、1つ以上のアミロイドまたはアミロイド様タンパク質を検出するための方法を提供し、アミロイドまたはアミロイド様タンパク質を潜在的に含むサンプルと、式I若しくは式IIのいずれか1つによる化合物またはその医薬組成物を接触させること、を含み、アミロイドまたはアミロイド様タンパク質の存在下で、化合物は、検出可能な複合体を形成し、さらに、検出可能な複合体の有無が、アミロイドまたはアミロイド様タンパク質の有無と相関性があるような検出可能な複合体の形成を検出すること、を含む。
本明細書で開示される主題の具体的な実施形態は、次の実施形態に記載される。
R38、R39、及びR40のそれぞれが独立して、水素またはC1~C10アルキルである、実施形態P1に記載の化合物。
合成スキームのための図1Aを参照のこと。
合成スキームのための図5を参照のこと。
合成スキームのための図7を参照のこと。
合成スキームのための図9を参照のこと。
合成スキームのための図11を参照のこと。
合成スキームのための図14を参照のこと。
合成スキームのための図16を参照のこと。
広範なインビトロ研究により、化合物1(図13A)が、アミロイドに選択的に結合する能力の観点から、特権的な特性を示し、アルツハイマー病関連アミロイドに結合する際に、特徴的な蛍光を発光することが、実証された。図2A及び図2Bは、溶液中で遊離する化合物1の吸光及び発光プロファイル(実線)、ならびに、凝集したアルツハイマー関連ペプチド(Aβ42)に結合した化合物1の吸光及び発光プロファイル(破線)を示す。図2Cは、凝集したAβ(1-42)ペプチドの存在下での、蛍光強度対化合物1の濃度のプロットを示す。10μMの最終濃度(モノマーの分子量に基づく)で凝集したAβ(1-42)を、5%のDMSOのPBS中の増加する濃度の化合物1(0、0.25、0.5、1、2、4、8μM)と混合した。データを、1部位特異的結合アルゴリズム:Y=Bmax・X/(Kd+X)、(式中、Xはプローブの濃度であり、Yは特異的結合蛍光強度であり、Bmaxは、プローブが凝集したAβ(1-42)ペプチドに結合する際の、見かけの最大の観察可能な蛍光に相当する)にフィッティングさせることにより、Kdを決定した。
HPLCによる、25℃での、(溶解性を促進する5%のDMSOを入れた)PBS中の、化合物1の加水分解速度を検査した。図19Aは、24時間にわたる、化合物1の相対的な存在量を示す。これらの研究は、化合物1が、150時間までの、加水分解に対するt1/2を有することを表す。比較のために、ANCA-11((E)-2-(2-(2-メトキシエトキシ)エトキシ)エチル2-シアノ-3-(6-(ピペリジン-1-イル)ナフタレン-2-イル)アクリレート)は、同じ条件下で、11時間までの加水分解に対するt1/2を示した。特定のインビボの環境(特に、高pH若しくは低pH、または、エステラーゼの存在下)では、ANCA-11は、そのエステル官能基の不十分な安定性のために、非常に速く分解すると予想される。化合物1のアミド官能基は、ANCA-11に特有の加水分解不安定性の問題を軽減する。
化合物1の溶解度を、HCl、酢酸、クエン酸、コハク酸、及び乳酸緩衝液(20~50mM)中で、かつpH2~6で試験した。より低いpH及びより高い緩衝液濃度で、溶解度は、3μg/mLである水に対し、350μg/mLまで増加し、100倍の増加に相当する。クエン酸緩衝液に対する代表例を、図19Cに示す。
HCl塩の調製:
化合物1は、0℃の3モル当量のメタノール性HClに溶解し、27℃で4時間撹拌した。メタノールを除去し、固体を乾燥エチルエーテル(5×10mL)で粉末にし、一晩高真空で乾燥した。構造及び純度を、分析用HPLC(標準物質に対する保持時間を比較する)、プロトンNMR、及び質量分光分析により決定した。化合物1対化合物1-HCl塩の質量分析:(ES、m/z):[M+H]+452(図24A)。化合物1-HCl塩の1H-NMR(500MHz、CDCl3)分析:プロトンNMRにより、NMRスペクトルにおけるシフトを分析することによって、ピペラジンのプロトン化を確認した。
化合物1. 1H NMR (500 MHz, CDCl3) δ 8.33 (s, 1H), 8.11 (s, 1H), 8.00-8.02 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 7.69-7.71 (d, J = 9.5 Hz, 1H), 7.60-7.62 (d, J = 8.5 Hz, 1H), 7.24-7.26 (m, 1H), 7.01 (bs, 1H), 6.84 (m, 1H), 3.64-3.66 (m, 6H), 3.62-3.63 (m, 4H), 3.54-3.55 (m, 2H), 3.35 (s, 3H), 3.12-3.34 (m, 4H), 1.69 (m, 4H), 1.61-1.62 (m, 2H)
化合物1-HCl: 1H-NMR (500 MHz, CDCl3): δ 8.59 (s, 1H), 8.44 (s, 1H), 8.37 (s, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 9 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 6.94-6.95 (m, 1H), 3.64-3.68 (m, 11H), 3.55-3.57 (m, 5H), 3.36 (s, 3H), 2.37 (bd. s, 4H), 1.83 (bd, m, 2H)
化合物1を、1.2モル当量のクエン酸を加えたエタノールに溶解させた。混合物を、溶解させるために超音波処理し、2時間室温で撹拌し、-4℃まで冷却した。沈殿物を濾過し、冷えたエチルエーテルで洗浄し、高真空下で乾燥させた。サンプルを、分析用HPLCで分析し、保持時間を、元の化合物の保持時間であると確認して、塩の同一性を立証した。
クエン酸塩の溶解度は、0.25mg/mlであり、pH3.5の水に対して140倍の増加である。比較により、化合物1のHCl塩は、1.96mg/mlの水溶性を有する。
アミロイド前駆体タンパク質(APP)のスウェーデン及びインディアナ変異型を過剰発現させ、ヒトアミロイドβを産生するトランスジェニックマウス(J20)は、アルツハイマー病の病因をもつ便利なマウスモデルとして役立つ。繁殖されて21ヶ月齢の6匹のJ20マウス(及び6匹のwtの同腹子対照)に、化合物1(試験製剤:インビボ注射のための500μMの化合物1の80%プロピレングリコール/20%DMSO溶液を100~150μL)、または、単独のビヒクル、を(尾静脈より)全身投薬した。注射後、全てのマウスを、30分間ケージ内で自由にさせた。次に、マウスを死亡させ、網膜組織を採取して、化合物1の染色により可視化した。
図20A及び図20Bは、死亡の30分前に化合物1を注射されたJ20マウスの網膜の3次元Zスタックの再構築を示す。図20Aの白矢印は、化合物1で染色された網膜のニューロン層内のいくつかの明るい物体を強調する。ADに罹患するtgマウス及びヒトの網膜のアミロイド沈着物は、疾患進行に応じてニューロン層内に出現すると報告されている(Neuroimage 2011、54、S204-S217)。図20Bは、図20Aで示されるものと同じ網膜のイメージであるが、抗Aβ抗体(続いて、蛍光標識二次抗体)により染色されたアミロイド沈着物の場所(白矢印)のみを強調する。抗Aβ抗体(図20Bにおいて白矢印で強調される)、及び、化合物1(図20Aにおいて白矢印で強調される)は、網膜に共局在化し、化合物1が、血液網膜関門を通過でき、インビボでの全身投与後に網膜中のアミロイドを特異的に染色する、という非常に強力な証拠を提供した。
組織の採取及びエクスビボイメージングによるアミロイド沈着物の可視化に加えて、最近の取り組みにより、生きた動物のアミロイド沈着物をイメージングする技量が示されている。3匹のトランスジェニックADマウス(hAPP/PS1、J20、及び5XFADマウス)は、イメージングのために繁殖されて年をとっている。これらのADtgマウスモデルが年をとるのに対し、アミロイド沈着物の蓄積のための、はるかに短いタイムラインを有するCJDの動物モデルが、化合物1のIP投与後の網膜のアミロイド蓄積をライブイメージングするために研究されている。マウスを、ケタミンで麻酔し、37℃に加熱したパッドが取付けられたステージに置いた。基準イメージを確立するために、Phoenix LaboratoryのMicron IV齧歯類用網膜顕微鏡を使用して、網膜を、明視野及び蛍光でメージングした。
Claims (30)
- 式:
EDGは、
各R17は、独立して、ハロゲン、-OR18、-NR19R20、C1~C10アルキル、またはC1~C10ヘテロアルキルであり、
R18、R19、及びR20のそれぞれは、独立して、水素、C1~C10アルキル、C1~C10ヘテロアルキル、または最大で炭素原子が10個のシクロアルキルであり、水素を除くこれらのそれぞれは、1つ以上のR21と任意に置換され;
各R21は、独立して、ハロゲン、-OR22、-NR23R24、C1~C10アルキル、C1~C10ヘテロアルキル、最大で炭素原子が10個のシクロアルキル、最大で炭素原子が10個のヘテロシクロアルキル、最大で炭素原子が10個のアリーレン、または最大で炭素原子が10個のヘテロアリーレンであり;
R22、R23、及びR24のそれぞれは、独立して、水素またはC1~C10アルキルであり;
WSGは、
nは、2~10の整数であり、
R81は、水素、メチルまたはCH 2 -C≡CHであり、
Xは、C=Oであり;及び
Yは、NHである)
の化合物、またはその塩若しくは溶媒和物。 - R81 がCH2-C≡CHである、請求項1または2に記載の化合物。
- R81がメチルである、請求項1または2に記載の化合物。
- R81が水素である、請求項1または2に記載の化合物。
- nが3または6である、請求項1~5のいずれか1項に記載の化合物。
- nが3である、請求項1~5のいずれか1項に記載の化合物。
- 請求項1~10のいずれか1項に記載の化合物を含み、任意選択的に、さらに、1つ以上の薬学的に許容される添加剤、担体、または賦形剤を含む、医薬組成物であって、
前記賦形剤が、エタノール、DMSO、ポリエチレングリコール、ポリプロピレングリコール、水性酢酸緩衝液、水性クエン酸緩衝液、水性リン酸緩衝液、水性炭酸緩衝液、シクロデキストリン、トウモロコシ油、ビタミンE、ポリソルベート、ソルトール、及び胆汁酸からなる群から選択される、医薬組成物。 - 請求項1~10のいずれか1項に記載の化合物、並びに、アミロイドまたはアミロイド様タンパク質を含む、組成物。
- 前記アミロイドまたはアミロイド様タンパク質が、Aβペプチド、プリオンペプチド、α-シヌクレイン、またはスーパーオキシドジスムターゼである、請求項12に記載の組成物。
- アミロイドまたはアミロイド様タンパク質を検出する方法であって、
a. 前記アミロイドまたはアミロイド様タンパク質を潜在的に含むサンプルと、請求項1~10のいずれか1項に記載の化合物とを接触させ、アミロイドまたはアミロイド様タンパク質の存在下で、前記化合物の検出可能な複合体を形成させること、及び
b. 前記検出可能な複合体の形成を検出すること(ここで、前記検出可能な複合体の有無が、前記アミロイドまたはアミロイド様タンパク質の有無と相関する)、
を含む、前記方法。 - 前記アミロイドまたはアミロイド様タンパク質が、Aβペプチド、プリオンペプチド、α-シヌクレイン、またはスーパーオキシドジスムターゼであり、任意選択的に、前記アミロイドまたはアミロイド様タンパク質が、アミロイドβ(1-42)(Aβ(1-42))である、請求項14に記載の方法。
- 対象の1つ以上の疾患または状態の有無を判定するために、請求項1~10のいずれか1項に記載の化合物またはその医薬組成物の検出可能な複合体を検出する方法であって、
a. 有効量の前記化合物またはその医薬組成物を投与された対象において、検出可能な複合体を形成させること、及び
b. 前記検出可能な複合体により生じるシグナルを測定することによって、前記検出可能な複合体の形成を検出すること(ここで、前記検出可能な複合体の有無が、前記疾患または状態の有無と相関する)、
を含む、前記方法。 - 前記検出可能な複合体により生じる前記シグナルが、電磁シグナルである、請求項16に記載の方法。
- 前記電磁シグナルが、蛍光シグナルである、請求項17に記載の方法。
- 前記蛍光シグナルが、450~650nmの波長で測定される、請求項18に記載の方法。
- 前記検出可能な複合体の形成の検出が、化合物の接触または化合物若しくは医薬組成物投与から、1秒、5秒、1分、10分、30分、または60分以内に実施される、請求項14~19のいずれか1項に記載の方法。
- 少なくとも1つの疾患または状態の治療に使用するための、またはそれらの症状の改善に使用するための、またはそれらの予防に使用するための、請求項1~10のいずれか1項に記載の治療的有効量の化合物を含有する組成物。
- 請求項1~10のいずれか1項に記載の有効量の化合物またはその医薬組成物を投与された対象において、前記化合物が検出可能な複合体を形成する、スクリーニング法。
- 前記疾患または状態が、タンパク質凝集またはタンパク質ミスフォールディングを特徴とする、請求項16に記載の方法。
- 前記疾患または状態が、アミロイド系疾患または状態である、請求項16に記載の方法。
- 前記疾患または状態が、アルツハイマー病(AD)、パーキンソン病、ハンチントン病、筋萎縮性側索硬化症(ALS)、レビー小体認知症(LBD)、またはダウン症である、請求項16に記載の方法。
- 前記疾患または状態が、プリオン疾患または状態であり、任意選択的に、前記プリオン疾患または状態が、クロイツフェルト・ヤコブ病(CJD)である、請求項16に記載の方法。
- 前記疾患または状態が、タンパク質凝集またはタンパク質ミスフォールディングを特徴とする、請求項21に記載の組成物。
- 前記疾患または状態が、アミロイド系疾患または状態である、請求項21に記載の組成物。
- 前記疾患または状態が、アルツハイマー病(AD)、パーキンソン病、ハンチントン病、筋萎縮性側索硬化症(ALS)、レビー小体認知症(LBD)、またはダウン症である、請求項21に記載の組成物。
- 前記疾患または状態が、プリオン疾患または状態であり、任意選択的に、前記プリオン疾患または状態が、クロイツフェルト・ヤコブ病(CJD)である、請求項21に記載の組成物。
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