JP2023551741A - 二重標的化化合物及びその調製方法と応用 - Google Patents
二重標的化化合物及びその調製方法と応用 Download PDFInfo
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Classifications
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Abstract
Description
100mLフラスコ中のN,N-ジメチルホルムアミド30mLに、化合物1(6-ヒドロキシキノリン-4-カルボン酸、1.89g、10.0mmol)、グリシンtert-ブチルエステル(1.89g、10.0mmol)、HATU(3.8g、10.0mmol)及びN,N-ジイソプロピルエチルアミン(2.6g、20.0mmol)をそれぞれ順に加えた。反応混合物を一晩撹拌し、溶媒を減圧蒸留により除去して粗生成物を得た。シリカゲルカラム(ジクロロメタン/メタノール=30:1)で精製して、化合物2を白色固体として87%の収率で得た。
100mLフラスコ中のN,N-ジメチルホルムアミド50mLに、化合物2(1.51g、5.0mmol)、1-ブロモ-3-クロロプロパン(1.55g、10.0mmol)、及び炭酸カリウム(1.38g、10.0mmol)をそれぞれ順に加えた。系の温度を60℃に上げ、60℃に維持して一晩撹拌し、溶媒を減圧蒸留により除去して粗生成物を得た。シリカゲルカラム(ジクロロメタン/メタノール=50:1)で精製して、化合物3を白色固体として63%の収率で得た。
100mLフラスコ中のアセトニトリル30mLに、化合物3(0.76g、2.0mmol)、1-tert-ブトキシカルボニルピペラジン(0.55g、3.0mmol)、及びヨウ化カリウム(0.49g、3.0mmol)をそれぞれ順に加えた。系の温度を60℃に上げ、60℃に維持して一晩撹拌し、溶媒を減圧蒸留により除去して粗生成物を得た。シリカゲルカラム(ジクロロメタン/メタノール=30:1)で精製して、化合物4を白色固体として58%の収率で得た。
氷浴条件下で化合物4(0.52g、1.0mmol)をジクロロメタンとトリフルオロ酢酸の混合溶液10mL(体積比9:1)に溶解し、系の温度を室温に上げて2時間反応させ、反応終了後、溶媒を減圧蒸留により除去し、N,N-ジメチルホルムアミド10mLに溶解して化合物5を得て次の反応に備えた。
化合物5のN,N-ジメチルホルムアミド溶液に、二炭酸ジ-tert-ブチル(0.22g、1.0mmol)とN,N-ジイソプロピルエチルアミン(0.39g、3.0mmol)をそれぞれ加え、室温で一晩撹拌し、溶媒を減圧蒸留により除去して粗生成物を得た。シリカゲルカラム(ジクロロメタン/メタノール=10:1)で精製して、化合物6を白色固体として72%の収率で得た。
100mLフラスコ中のN,N-ジメチルホルムアミド10mLに、化合物6(0.47g、1.0mmol)、(S)-ピロリジン-2-カルボニトリル塩酸塩(0.13g、1.0mmol)、HATU(0.38g、1.0mmol)、及びN,N-ジイソプロピルエチルアミン(0.26g、2.0mmol)をそれぞれ順に加えた。反応混合物を室温で反応終了まで撹拌し、溶媒を減圧蒸留により除去して粗生成物を得た。シリカゲルカラム(ジクロロメタン/メタノール=50:1)で精製して、化合物7を白色固体として85%の収率で得た。図1は化合物7の水素核磁気共鳴スペクトルであり、図2は化合物7の炭素核磁気共鳴スペクトルであり、図3は化合物7のマススペクトルである。
化合物7(2.50g、4.5mmol)、p-トルエンスルホン酸一水和物(2.58g、13.6mmol)、及びアセトニトリル25mLを反応フラスコに加え、65℃で1時間反応させ、TLCで化合物7の反応の完了をモニタリングし(メタノール:ジクロロメタン=5:1)、減圧下、40℃で蒸発乾固した。DMF14mL及びDIPEA(3.05g、23.6mmol)を加え、25℃で撹拌した。この反応を番号(1)とする。即ち、化合物7のピペラジン脱保護により中間体を得た。別の反応フラスコにN-tert-ブトキシカルボニル-ジエチレングリコール-カルボン酸(1.62g、4.8mmol)、HATU(2.60g、6.8mmol)、及びDMF10mLを加え、25℃で30分間反応させた。この反応を番号(2)とする。反応(2)の反応溶液系を反応(1)系に滴下し、1時間反応させた。減圧下、40℃で蒸発乾固し、精製水50mLを加え、DCMで2回、各回50mLで抽出し、DCMを合わせ、無水硫酸ナトリウムで乾燥し、濾過し、蒸発乾固して粗生成物を得て、粗生成物をカラムクロマトグラフィーで精製し、目的物1.68gを得た。理論分子量は709.3799、測定分子量は709.38801であり、マススペクトル結果は目的物と一致した。図4は化合物8のマススペクトルである。
化合物8、p-トルエンスルホン酸一水和物(1.61g、8.5mmol)、及びアセトニトリル20mLを反応フラスコに加え、65℃で1時間反応させ、減圧下、40℃で蒸発乾固した。DMF20mL及びDIPEA(1.83g、14.2mmol)を加え、25℃で撹拌した。この反応を番号(1)とする。別の反応フラスコにFmoc-O-tert-ブチル-L-グルタミン酸(1.43g、3.4mmol)、HATU(1.29g、3.4mmol)、及びDMF20mLを加え、25℃で30分間反応させた。この反応を番号(2)とする。反応(2)の反応溶液系を反応(1)系に滴下し、1時間反応させた。減圧下、40℃で蒸発乾固して粗生成物を得て、粗生成物をカラムクロマトグラフィーで精製し、目的物1.19gを得た。理論分子量は1016.5008、測定分子量は1016.51094であり、マススペクトル結果は目的物と一致した。図5は化合物9のマススペクトルである。
c(RGDfK)(1.00g、1.7mmol)、アミノtert-ブチルエステル-ジポリエチレングリコール-スクシンイミドエステル(0.74g、1.9mmol)、DIPEA(0.44g、3.4mmol)、及びDMF20mLを反応フラスコに加え、30℃で20時間反応させた。減圧下、40℃で蒸発乾固し、メタノール10mLを加え、MTBE60mLを滴加し、固体を沈殿させて中間体11を得て、この中間体を吸引濾過し、40℃で真空下で2時間乾燥した。固体の中間体11を反応フラスコに加え、TFA30mL及び精製水1.5mLを加え、30℃で1時間反応させ、0~5℃に冷却し、MTBE200mLを滴下し、0~5℃で30分間撹拌し、吸引濾過し、MTBEですすぎ、40℃で真空下で乾燥して生成物を得た。理論分子量は762.4024、測定分子量は762.40768であり、マススペクトル結果は目的物と一致した。図6は化合物12のマススペクトルである。
化合物9、p-トルエンスルホン酸一水和物(0.34g、1.8mmol)、及びアセトニトリル20mLを反応フラスコに加え、65℃で4時間反応させ、減圧下、40℃で蒸発乾固した。DMF20mL、DIPEA(0.36g、2.8mmol)、DCC(0.14g、0.7mmol)、及びNHS(0.08g、0.7mmol)を加え、35℃で15~20時間反応させて中間体10を得た。次に、25℃に冷却し、化合物12を加え、1時間反応させ、減圧下、40℃で蒸発乾固して粗生成物を得て、粗生成物を分取液体クロマトグラフィーで精製して目的物66.5mgを得た。理論分子量は1704.8300、測定分子量は1704.84518であり、マススペクトル結果は目的物と一致した。図7は化合物13のマススペクトルである。
化合物13、ピペリジン0.5mL、及びDMF2mLを反応フラスコに加え、25℃で1時間反応させ、酢酸エチル10mLを滴下して結晶化させ、30分間撹拌し、吸引濾過した。固体を40℃で真空下で2時間乾燥し、生成物50.8mgを得た。Fmoc保護が除去された化合物13をDMF2mLに溶解し、NOTA-2 tert-ブチルエステル-NHS活性化エステル及びDIPEA(0.010g、0.08mmol)を加え、25℃で1時間反応させ、減圧下、40℃で蒸発乾固し、酢酸エチル2mLとMTBE2mLを加えて結晶化させ、20分間撹拌し、吸引濾過した。固体を40℃で真空下で乾燥し、生成物43.2mgを得た。理論分子量は1880.0196、測定分子量は1880.0369であり、マススペクトル結果は目的物と一致した。図8は化合物14のマススペクトルである。
化合物14及びトリフルオロ酢酸2mLを反応フラスコに加え、25℃で1時間反応させ、減圧下、40℃で蒸発乾固して粗生成物を得て、粗生成物を分取液体クロマトグラフィーで精製し、凍結乾燥して、生成化合物15を42%の収率で得た。理論分子量は1767.8944、測定分子量は1767.91036であり、マススペクトル結果は目的物と一致した。図9は化合物15のマススペクトルである。
実施例2の調製方法については、実施例1を参照し、上記の実施例におけるNOTA-2 tert-ブチルエステル-NHS活性化エステルをDOTA-3 tert-ブチルエステル-NHS活性化エステルに置き換えて、以下の構造を得た。
Claims (11)
- 二重標的化化合物であって、その構造が同時にFAPとインテグリンαvβ3の特異的結合リガンド構造を含み、前記化合物の構造が以下の式(I)に示すとおりである、ことを特徴とする二重標的化化合物。
- 放射性核種で標識できる二重標的化化合物であって、その構造が同時にFAPとインテグリンαvβ3の特異的結合リガンド及び核種キレート構造を含み、前記化合物の構造が以下の式(I-1)又は式(I-2)に示すとおりである、ことを特徴とする放射性核種で標識できる二重標的化化合物。
- 請求項2に記載の放射性核種で標識できる二重標的化化合物の調製方法であって、まず6-ヒドロキシキノリン-4-カルボン酸のカルボキシル基をグリシンtert-ブチルエステルのアミノ基とアミド縮合反応させるステップと、アミド縮合生成物のヒドロキシル基の位置でアルキル鎖を介してBocで保護されたピペラジニル基を連結するステップと、酸性条件下でBoc保護基及びtert-ブチル保護基を除去し、縮合生成物のピペラジン環にBoc保護基を導入するステップと、(S)-ピロリジン-2-カルボニトリル塩酸塩とアミド縮合反応させるステップと、Boc保護基を除去し、N-Boc-3-[2-(2-アミノエトキシ)エトキシ]プロピオン酸と縮合反応させるステップと、Boc保護基を除去し、Fmoc-O-tert-ブチル-L-グルタミン酸と反応させるステップと、tert-ブチルエステルを除去し、活性化エステルを調製し、アミノ-ジポリエチレングリコールを含むc(RGDfK)と反応させて、二重標的化化合物を得るステップと、Fmoc保護を除去し、核種キレート剤(核種キレート剤は、1,4,7,10-テトラアザシクロドデカン-N,N’,N,N’-四酢酸又は1,4,7-トリアザシクロノナン-1,4,7-三酢酸である)と反応させるステップと、キレート基のtert-ブチルエステル保護を除去して、放射性核種で標識できる二重標的化化合物を得るステップとを含む、ことを特徴とする調製方法。
- 放射性核種標識二重標的化化合物であって、請求項2に記載の放射性核種で標識できる二重標的化化合物のいずれかを放射性核種で標識することによって得られるものであり、前記放射性核種は、α線放出同位体、β線放出同位体、γ線放出同位体、オージェ電子放出同位体又はX線放出同位体から選択される、ことを特徴とする放射性核種標識二重標的化化合物。
- 前記放射性核種は、18F、51Cr、64Cu、67Cu、67Ga、68Ga、89Zr、111In、99mTc、186Re、188Re、139La、140La、175Yb、153Sm、166Ho、86Y、90Y、149Pm、165Dy、169Er、177Lu、47Sc、142Pr、159Gd、212Bi、213Bi、72As、72Se、97Ru、109Pd、105Rh、101mRh、119Sb、128Ba、123I、124I、131I、197Hg、211At、151Eu、153Eu、169Eu、201Tl、203Pb、212Pb、198Au、225Ac、227Th又は199Agのいずれかから選択される、ことを特徴とする請求項4に記載の放射性核種標識二重標的化化合物。
- 前記放射性核種は、18F、64Cu、68Ga、89Zr、90Y、111In、99mTc、177Lu、188Re又は225Acから選択される、ことを特徴とする請求項4に記載の放射性核種標識二重標的化化合物。
- 請求項4に記載の放射性核種標識二重標的化化合物の調製方法であって、湿式標識法又は凍結乾燥標識法に従って請求項2に記載の放射性核種で標識できる二重標的化化合物を放射性核種を含む化合物と反応させて、前記放射性核種標識二重標的化化合物を得るステップを含む、ことを特徴とする調製方法。
- 請求項1に記載の二重標的化化合物、請求項2に記載の放射性核種で標識できる二重標的化化合物、請求項4に記載の放射性核種標識二重標的化化合物、又はそれらの薬学的に許容される水和物、溶媒和物若しくは塩を含む、ことを特徴とする医薬組成物。
- 動物又はヒト対象におけるFAP及び/又はインテグリンαvβ3の過剰発現を特徴とする疾患を診断又は治療するための薬物の調製における、請求項1に記載の二重標的化化合物、請求項2に記載の放射性核種で標識できる二重標的化化合物、請求項4に記載の放射性核種標識二重標的化化合物、それらの薬学的に許容される水和物、溶媒和物若しくは塩、又は請求項8に記載の医薬組成物のいずれかの応用。
- 前記FAP及び/又はインテグリンαvβ3の過剰発現を特徴とする疾患は、癌、慢性炎症、アテローム性動脈硬化症又は瘢痕疾患を含む、ことを特徴とする請求項9に記載の応用。
- 前記前記癌は、乳癌、膵臓癌、小腸癌、結腸癌、直腸癌、肺癌、頭頸部癌、卵巣癌、肝細胞癌、食道癌、下咽頭癌、鼻咽頭癌、喉頭癌、骨髄腫細胞、膀胱癌、胆管癌、淡明細胞型腎細胞癌、神経内分泌腫瘍、発癌性骨軟化症、肉腫、原発不明癌、胸腺癌、神経膠腫、神経膠腫、星状細胞腫、子宮頸癌、又は前立腺癌から選択される、ことを特徴とする請求項10に記載の応用。
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