JP6468602B2 - トリアジン系放射性医薬品及び放射線造影剤 - Google Patents
トリアジン系放射性医薬品及び放射線造影剤 Download PDFInfo
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- JP6468602B2 JP6468602B2 JP2015552805A JP2015552805A JP6468602B2 JP 6468602 B2 JP6468602 B2 JP 6468602B2 JP 2015552805 A JP2015552805 A JP 2015552805A JP 2015552805 A JP2015552805 A JP 2015552805A JP 6468602 B2 JP6468602 B2 JP 6468602B2
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Description
本出願は、2013年1月14日に出願された米国仮特許出願番号第61/752,350号及び2013年3月14日に出願された第61/785,788号の利益を主張するものであって、その両方を、全て本明細書に参照として含む。
から選択され、置換基Rcは、−OH、−O(C1−C10)アルキル、−Oベンジル、−O(C3−C10)シクロアルキル、−O(C3−C10)アリール、−O−(C1−C10)アルキレン−(C3−C10)アリール、又は、−O−(C1−C10)アルキレン−(C3−C10)シクロアルキルから選択されることができる。
から選択される。
から選択され、変数R1及びR2は、各々独立に、H、−(C1−C10)アルキル、−C(O)−(C1−C10)アルキル、ベンジル、−(C3−C10)シクロアルキル、又は、−(C3−C10)アリールから選択される。
から選択され、置換基Rcは、−OH、−O(C1−C10)アルキル、−Oベンジル、−O(C3−C10)シクロアルキル、−O(C3−C10)アリール、−O−(C1−C10)アルキレン−(C3−C10)アリール、又は、−O−(C1−C10)アルキレン−(C3−C10)シクロアルキルから選択される。
であり、Lは、−NH−(C1−C10)アルキレン−、−NH−(C1−C10)アルキレン−C(O)−、−C(O)−(C1−C10)アルキレン−、−C(O)−(C1−C10)アルキレン−C(O)−又は
から選択され、置換基Rd及びReは、各々独立に、H、結合、−OH、−(C1−C10)アルキル、又は、−(C3−C10)ヘテロアリール−(C1−C10)アルキレンから選択され、下付きの添字nは、0、1、2、3、4、5、6、7、8、9、又は、10から選択される整数である。
から選択されることができ、置換基Rcは、−OH、−O(C1−C10)アルキル、−Oベンジル、−O(C3−C10)シクロアルキル、−O(C3−C10)アリール、−O−(C1−C10)アルキレン−(C3−C10)アリール、又は、−O−(C1−C10)アルキレン−(C3−C10)シクロアルキルから選択され、R3は、H、ハロゲン、−OH、−NH2、−(CH2)p−COOH、又は、−(CH2)p−NH2から選択される。
表1
表3
−C(O)−(C1−C10)アルキレン−、−C(O)−(C1−C10)アルキレン−C(O)−又は
ヒト前立腺癌LNCaP細胞は、アメリカン・タイプ・カルチャー・コレクションから入手した。細胞培養用品は、特に断りのない限り、インビトロゲンからであった。LNCaP細胞を、37oC/5%CO2の加湿インキュベーター中で、10%ウシ胎児血清(ハイクロン社)、4mMのL−グルタミン、1mMのピルビン酸ナトリウム、10mMのHEPES、2.5mg/mlのDグルコース、及び50μg/mLのゲンタマイシンを補充したRPMI−1640培地中で維持した。細胞をフラスコから取り出し、マウスで継代接種するか、又は0.25%トリプシン/EDTAでそれらを培養することにより、12ウェルアッセイプレートへ転送した。
LNCaP細胞内でPSMAとの結合のために、PSMA阻害剤を含む非放射性ルテチウムが99mTc−((7S,14S,18S)−7−アミノ−1−(1−(カルボキシメチル)−1H−イミダゾル−2−イル)−2−((1−(カルボキシメチル)−1H−イミダゾル−2−イル)メチル)−8,16−ジオキソ−2,9,15,17−テトラアザイコサン−14,18,20−トリカルボン酸)と競合する能力を調べた。LNCaP細胞(三つの、12ウェルプレート内の4×105細胞/ウェル)を、1〜10,000nMの試験化合物の存在下で、0.5%BSAを含有するRPMI培地内で3nMの99mTc錯体を用いて、1時間培養した。細胞を徐徐にピペッティングすることによってエッペンドルフチューブに移し、RPMI+0.5%BSAで2回洗浄し、計数した。
全ての動物研究は、動物管理及び使用委員会によって、実験動物の人道的管理及び使用に関するアメリカ公衆衛生局の政策によって定められた指針に従って承認された。マウスは、承認された施設で標準的な条件下で12時間の明/暗サイクルで飼育し、食物及び水を自由に与えた。雄無胸腺NCr−nu/nuマウスはタコニック社から購入した。マウスに接種するために、LNCaP細胞を、細胞培養培地:マトリゲル(BD Biosciences)の1:1混合物中で107細胞/mlに再懸濁した。各マウスは、0.25mlの細胞懸濁液を右脇腹に注射した。腫瘍が約100〜400mm3に達した時、マウスを組織分布研究のために使用した。
177Lu標識化合物の組織分布の定量分析は、LNCaP細胞の異種移植片を有する雄のNCR−nu/nuマウスの別々のグループで行った。当該化合物を、尾静脈を介して0.05mLの一定の体積にボーラス注射(約10μCi/マウス)で投与した。動物(N=5/時点)は、注射後の示された時点で二酸化炭素で窒息により安楽死させた。組織、例えば、血液、心臓、肺、肝臓、脾臓、腎臓、胃、大腸及び小腸(内容物を含む)、精巣、骨格筋、骨、脳、脂肪、及び腫瘍を、解剖し、切除し、湿潤秤量し、自動γカウンターで計数した。組織時間放射能レベルは、組織のグラムあたり注射用量率(%ID/g)として表した。
平均体積が約100〜500mm3であるLNCaP異種移植片を有するマウスを、無作為に対照群、又は、処置群に割当した(n=群あたり10匹のマウス)。試験群のマウスは、本発明の式(I)若しくは式(II)の化合物の177Lu−錯体を450μCi/マウス受けるが、対照群のマウスには、生理食塩水を投与した。各動物は、0.05mLの量で静脈内に試験物質を投与した。腫瘍の寸法は、デジタルノギスで毎週2回測定し、腫瘍体積は、式(4/3xΠx幅2x長さ)/6を用いて計算した。ビークル群における腫瘍体積がIACUCガイドラインで許容される最大値(1,500mm3)になるまで測定を行った。
式(I)の化合物の合成、及び式(I)の化合物と放射性核種との錯体形成に対する一般的な手順を記載する。ルテチウムと式(I)の化合物との錯体を形成するためのプロトコルが以下に例示されているが、他の放射性核種との錯体を形成するために、同様の合成手順が続くことができることを理解すべきである。したがって、ルテチウムを下記に記載された様々な例で具体的に示すことができるが、In、Y、Zr、Ga、Lu、Cu、Gd、Ac、Fe、Bi、Co、Dy、Ho、Ir、Ra、Re、Rh、Sr、又は、Smなどの他の放射性核種との錯体が、本発明の範囲内である。さらに、これらの要素の様々な同位体は、錯体を形成してもよく、例えば、111In、90Y、68Ga、64Cu、153Gd、155Gd、157Gd、59Fe、225Ac、212Bi、213Bi、55Co、67Cu、165Dy、166Ho、192Ir、223Ra、186Re、188Re、105Rh、212Pb、213Pb、149Tb、227Th、153Sm、89Sr、117mSn、169Yb、90Y、86Y、89Zr、及び、177Luが挙げられることを理解すべきである。
式(I)の化合物のルテチウム錯体は、市販のLuCl3を式(I)に従った化合物と接触させることを含む反応から便利に単離された。簡潔には、密閉バイアル内で、アセトニトリル及びリン酸緩衝液の1:1等量の体積混合物中の、所望の式(I)若しくは式(II)の化合物の10−6M〜10−4M溶液を、LuCl3と接触させた。反応混合物を100Cで、30〜45分間加熱した。冷却時、反応を、逆相高圧液体クロマトグラフィー(RP−HPLC)によって純度及び完了について分析し、必要に応じてRP−HPLC、又は、C18 Sep−Pakカラムを用いて精製した。精製後ルテチウムと錯体を形成した製品の全体の平均収率は、約20%〜約99%の範囲内にあった。しかし、HPLC精製後の放射化学的純度(RCP)は、一貫して、95%以上であった。
図解A、B、及びCは、例示的な式(I)の化合物に対する一般的な合成プロトコルを示す。簡単にいえば、p−アミノベンジルDOTAを、塩化シアヌルと接触させた後、得られた生成物をアミンと反応させた。次いで、このように形成された生成物を、GUG−、又は、GUL−リンカー−ピペラジン部位と接触させて式(I)の化合物を得た。
(2S)−2−(3−((1S)−1−カルボキシ−5−(8−((4−(ジメチルアミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)アミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(18S,22S)−トリ−tert−ブチル1−(9H−フルオレン−9−イル)−3,12,20−トリオキソ−2−オキサ−4,13,19,21−テトラアザテトラコサン−18、22,24−トリカルボキシレート。
(2S)−2−(3−((1S)−1−カルボキシ−5−(8−(4−(ジメチルアミノ)−6−(4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニルアミノ)−1,3,5−トリアジン−2−イルアミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((1S)−1−カルボキシ−5−(8−(4−(ジメチルアミノ)−6−(4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニルアミノ)−1,3,5−トリアジン−2−イルアミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(S)−2−(3−((S)−1−カルボキシ−5−(8−((4−(ピペリジン−1−イル)−6−((4−(((S)−1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)アミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((S)−1−カルボキシ−5−(8−(4−(ピペリジン−1−イル)−6−(4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニルアミノ)−1,3,5−トリアジン−2−イルアミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((S)−1−カルボキシ−5−(8−(4−(ピペリジン−1−イル)−6−(4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニルアミノ)−1,3,5−トリアジン−2−イルアミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(8−(4−モルホリノ−6−(4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニルアミノ)−1,3,5−トリアジン−2−イルアミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(8−(4−モルホリノ−6−(4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニルアミノ)−1,3,5−トリアジン−2−イルアミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((1S)−1−カルボキシ−5−(8−(4−モルホリノ−6−(4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニルアミノ)−1,3,5−トリアジン−2−イルアミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(8−(4−(4−((4−カルボキシ−1,7,10−トリス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニルアミノ)−6−(ピペラジン−1−イル)−1,3,5−トリアジン−2−イルアミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(8−(4−(4−((4−カルボキシ−1,7,10−トリス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニルアミノ)−6−(ピペラジン−1−イル)−1,3,5−トリアジン−2−イルアミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((1S)−1−カルボキシ−5−(8−(4−(4−((4−カルボキシ−1,7,10−トリス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニルアミノ)−6−(ピペラジン−1−イル)−1,3,5−トリアジン−2−イルアミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(8−(4−(4−(3−カルボキシプロピル)ピペリジン−1−イル)−6−(4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニルアミノ)−1,3,5−トリアジン−2−イルアミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(8−(4−(4−(3−カルボキシプロピル)ピペリジン−1−イル)−6−(4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニルアミノ)−1,3,5−トリアジン−2−イルアミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((1S)−1−カルボキシ−5−(8−(4−(4−(3−カルボキシプロピル)ピペリジン−1−イル)−6−(4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニルアミノ)−1,3,5−トリアジン−2−イルアミノ)オクタンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
((2S,2’S)−2,2’−(((((1S,1’S)−((8,8’−((6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2,4−ジイル)ビス(アザンジイル))ビス(オクタノイル))ビス(アザンジイル))ビス(1−カルボキシペンタン−5,1−ジイル))ビス(アザンジイル))ビス(カルボニル))ビス(アザンジイル))ジペンタン二酸ルテチウム錯体。
((2S,2’S)−2,2’−(((((1S,1’S)−((8,8’−((6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2,4−ジイル)ビス(アザンジイル))ビス(オクタノイル))ビス(アザンジイル))ビス(1−カルボキシペンタン−5,1−ジイル))ビス(アザンジイル))ビス(カルボニル))ビス(アザンジイル))ジペンタン二酸。
((2S,2’S)−2,2’−(((((1S,1’S)−((8,8’−((6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2,4−ジイル)ビス(アザンジイル))ビス(オクタノイル))ビス(アザンジイル))ビス(1−カルボキシペンタン−5,1−ジイル))ビス(アザンジイル))ビス(カルボニル))ビス(アザンジイル))ジペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(ジメチルアミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(S)−ジ−tert−ブチル2−(3−((S)−6−(11−(4−((ベンジルオキシ)カルボニル)ピペラジン−1−イル)ウンデカンアミド)−1−(tert−ブトキシ)−1−オキソヘキサン−2−イル)ウレイド)ペンタンジオアート。
(S)−ジ−tert−ブチル2−(3−((S)−1−(tert−ブトキシ)−1−オキソ−6−(11−(ピペラジン−1−イル)ウンデカンアミド)ヘキサン−2−イル)ウレイド)ペンタンジオアート。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(ジメチルアミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(ジメチルアミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(ピペリジン−1−イル)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
((2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(ピペリジン−1−イル)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(ピペリジン−1−イル)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−((2−(2−(2−カルボキシエトキシ)エトキシ)エチル)アミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−((2−(2−(2−カルボキシエトキシ)エトキシ)エチル)アミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−((2−(2−(2−カルボキシエトキシ)エトキシ)エチル)アミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−((26−カルボキシ−3,6,9,12,15,18,21,24−オクタオキサヘキサコシル)アミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−((26−カルボキシ−3,6,9,12,15,18,21,24−オクタオキサヘキサコシル)アミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−((26−カルボキシ−3,6,9,12,15,18,21,24−オクタオキサヘキサコシル)アミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−5−(11−(4−(4−(((S)−5−(ビス((1−(カルボキシメチル)−1H−イミダゾル−2−イル)メチル)アミノ)−1−カルボキシペンチル)アミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)−1−カルボキシペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−5−(11−(4−(4−(((S)−5−(ビス((1−(カルボキシメチル)−1H−イミダゾル−2−イル)メチル)アミノ)−1−カルボキシペンチル)アミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)−1−カルボキシペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((1S)−5−(11−(4−(4−(((S)−5−(ビス((1−(カルボキシメチル)−1H−イミダゾル−2−イル)メチル)アミノ)−1−カルボキシペンチル)アミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)−1−カルボキシペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−5−(11−(4−(4−(ビス(カルボキシメチル)アミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)−1−カルボキシペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−5−(11−(4−(4−(ビス(カルボキシメチル)アミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)−1−カルボキシペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((1S)−5−(11−(4−(4−(ビス(カルボキシメチル)アミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)−1−カルボキシペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(メチルアミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(メチルアミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(メチルアミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−5−(11−(4−(4−(4−(3−アミノプロピル)ピペラジン−1−イル)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)−1−カルボキシペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−5−(11−(4−(4−(4−(3−アミノプロピル)ピペラジン−1−イル)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)−1−カルボキシペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((1S)−5−(11−(4−(4−(4−(3−アミノプロピル)ピペラジン−1−イル)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)−1−カルボキシペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(4−(カルボキシメチル)ピペラジン−1−イル)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(4−(カルボキシメチル)ピペラジン−1−イル)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(4−(カルボキシメチル)ピペラジン−1−イル)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(4−(3−カルボキシプロピル)ピペリジン−1−イル)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(4−(3−カルボキシプロピル)ピペリジン−1−イル)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(4−(3−カルボキシプロピル)ピペリジン−1−イル)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸ルテチウム錯体。
(2S)−2−(3−((1S)−1−カルボキシ−5−(11−(4−(4−(ジメチルアミノ)−6−((4−((1,4,7,10−テトラキス(カルボキシメチル)−1,4,7,10−テトラアザシクロドデカン−2−イル)メチル)フェニル)アミノ)−1,3,5−トリアジン−2−イル)ピペラジン−1−イル)ウンデカンアミド)ペンチル)ウレイド)ペンタン二酸の68Ga標識。
特定の実施態様について例示しかつ説明してきたが、当業者によって、以下の請求項で定義するような広義の態様の技術から逸脱することなく変更及び修正が可能であると解されるべきである。
Claims (24)
- 式(I)で表される化合物であって、
式中、
Aは、(CHR1)m、又は、C(O)であり、
Wは、−C(O)−(CH2)p−、−C(O)[−CH2−CH2−O]n−、−[CH2−CH2−O]n−(CH2)2−、−C(O)−[CHR3]q−、−(CH2)m−O−(CH2)n−、−(CH2)m−S−(CH2)n−、−(CH2)m−S(O)−(CH2)n−、−(CH2)m−S(O)2−(CH2)n−、又は、−(CH2)m−NRa−(CH2)n−であり,
Yは、−NH−、−NR2−、又は、
Xは、−(C1−C10)アルキレン−(C3−C10)アリーレン、−(C3−C10)アリーレン、−(C3−C10)アリーレン−(C1−C10)アルキレン−、−(C1−C10)アルキレン−(C3−C10)シクロアルキレン、−(C3−C10)シクロアルキレン、又は、−(C3−C10)シクロアルキレン−(C1−C10)アルキレン−であり、
R1及びR2は、各々独立に、H、−(C1−C10)アルキル、−C(O)−(C1−C10)アルキル、ベンジル、−(C3−C10)シクロアルキル、又は、−(C3−C10)アリールであり、
Ra及びRbは、各々独立に、H、−OH、−(C1−C10)アルキル、−[CH2−CH2−O]n−(CH2)2−T、−C(O)−(C1−C10)アルキル、−(C1−C10)アルキレン−C(O)−Z、ベンジル、−(C3−C10)シクロアルキル、−(C3−C10)アリール、ハロ−(C1−C10)アルキル、ヒドロキシ−(C1−C10)アルキル、−NH−(C1−C10)アルキル、若しくは、−(C 1 −C 10 )アルキレン−NR d R e であるか、又は、Ra及びRbは、それらが結合する窒素と一緒に、N、S、若しくは、Oから選択される1つ以上のヘテロ原子をさらに含むことができる、(C3−C6)−ヘテロアリール若しくは(C3−C6)−ヘテロシクロアルキルを形成し、
Zは、−OH、−O(C1−C10)アルキル、
Rcは、−OH、−O(C1−C10)アルキル、−O(C3−C10)シクロアルキル、−O(C3−C10)アリール、−O−(C1−C10)アルキレン−(C3−C10)アリール、又は、−O−(C1−C10)アルキレン−(C3−C10)シクロアルキルであり、
R3は、H、ハロゲン、−OH、−NH2、−(CH2)p−COOH、又は、−(CH2)p−NH2であり、
Tは、−H、−OH、−COOH、又は、−NRdReであり、
Rd及びReは、各々独立に、H、−OH、−(C1−C10)アルキル、又は、(C3−C10)ヘテロアリール−(C1−C10)アルキレンであり、
m、n、p、q、及び、rは、各々独立に、0、1、2、3、4、5、6、7、8、9、又は、10であり、
Dは、
任意のアルキル、アルキレン、アリール、アリーレン、ヘテロアリール、ヘテロアリーレン、シクロアルキル、シクロアルキレン、ヘテロシクロアルキル、又は、ヘテロシクロアルキレンは、−(C1−C10)アルキレン−COOH、−COOH、及び、−(C 1 −C 10 )アルキレン−NR d R e からなる群から選択される1個、2個又は3個の置換基で任意に置換される、化合物。 - 前記化合物は、式(II)に従った化合物であり、
Aは、(CHR1)m、又は、C(O)であり、
Wは、−C(O)−(CH2)p−、−C(O)[−CH2−CH2−O]n−、−[CH2−CH2−O]n−(CH2)2−、−C(O)−[CHR3]q−、−(CH2)m−O−(CH2)n−、−(CH2)m−S−(CH2)n−、−(CH2)m−S(O)−(CH2)n−、−(CH2)m−S(O)2−(CH2)n−、及び、−(CH2)m−NRa−(CH2)n−からなる群から選択され、
Yは、−NH−、−NR2−、
R1及びR2は、各々独立に、H、−(C1−C10)アルキル、−C(O)−(C1−C10)アルキル、ベンジル、−(C3−C10)シクロアルキル、又は、−(C3−C10)アリールから選択され、
Ra及びRbは、各々独立に、H、−OH、−(C1−C10)アルキル、−[CH2−CH2−O]n−(CH2)2−T、−C(O)−(C1−C10)アルキル、−(C1−C10)アルキレン−C(O)−Z、ベンジル、−(C3−C10)シクロアルキル、−(C3−C10)アリール、ハロ−(C1−C10)アルキル、ヒドロキシ−(C1−C10)アルキル、−NH−(C1−C10)アルキル、及び、−(C 1 −C 10 )アルキレン−NR d R e からなる群から選択されるか、又は、Ra及びRbは、これらが結合する窒素と一緒に、N、S、又は、Oから選択される1つ以上のヘテロ原子をさらに含むことができる(C3−C6)−ヘテロアリール若しくは(C3−C6)−ヘテロシクロアルキルを形成し、
Zは、−OH、−O(C1−C10)アルキル、
Rcは、−OH、−O(C1−C10)アルキル、−O(C3−C10)シクロアルキル、−O(C3−C10)アリール、−O−(C1−C10)アルキレン−(C3−C10)アリール、又は、−O−(C1−C10)アルキレン−(C3−C10)シクロアルキルから選択され、
R3は、H、ハロゲン、−OH、−NH2、−(CH2)p−COOH、又は、−(CH2)p−NH2から選択され、
Tは、−H、−OH、−COOH、又は、−NRdReから選択され、
Rd及びReは、各々独立に、H、−OH、−(C1−C10)アルキル、又は、(C3−C10)ヘテロアリール−(C1−C10)アルキレンから選択され、
m、n、p、及び、qは、各々独立に、0、1、2、3、4、5、6、7、8、9、又は、10であり、
式(II)中、任意のアルキル、アルキレン、アリール、アリーレン、ヘテロアリール、ヘテロアリーレン、シクロアルキル、シクロアルキレン、ヘテロシクロアルキル、又は、ヘテロシクロアルキレンは、−(C1−C10)アルキレン−COOH、−COOH、及び、−(C 1 −C 10 )アルキレン−NR d R e からなる群から選択される1個、2個又は3個の置換基で任意に置換される、請求項2に記載の化合物。 - Aは(CHR1)mであり、Wは−C(O)−(CH2)p−である、請求項3に記載の化合物。
- Wは、−C(O)−(CH2)7又は−C(O)−(CH2)10−である、請求項4に記載の化合物。
- R1は水素であり、mは2である、請求項4に記載の化合物。
- Ra及びRbは、各々独立に、水素、又は、メチルであり、Rcは、−OHである、請求項3に記載の化合物。
- Ra及びRbは、これらが結合する窒素と一緒に、(C3−C6)−ヘテロシクロアルキルを形成する、請求項3に記載の化合物。
- 前記(C3−C6)−ヘテロシクロアルキルは、ピペリジン、ピペラジン、モルホリン、チオモルホリン、イソチアゾリジン、イソオキサゾリジン、ピロリジン、イミダゾリジン、チアゾリジン、又は、オキサゾリジンから選択される、請求項10に記載の化合物。
- 前記(C3−C6)−ヘテロシクロアルキルは、ピペリジン、又は、4−(ピペリジン−4−イル)ブタン酸である、請求項11に記載の化合物。
- Rd及びReは、各々独立に、(C3−C10)ヘテロアリール−(C1−C10)アルキレンである、請求項13に記載の化合物。
- 放射性核種と、請求項1に記載の化合物とを含む、金属錯体。
- 前記化合物は、
式中、
Aは、(CHR1)m又はC(O)であり、
Wは、−C(O)−(CH2)p−、−C(O)[−CH2−CH2−O]n−、−[CH2−CH2−O]n−(CH2)2−、−C(O)−[CHR3]q−、−(CH2)m−O−(CH2)n−、−(CH2)m−S−(CH2)n−、−(CH2)m−S(O)−(CH2)n−、−(CH2)m−S(O)2−(CH2)n−、及び、−(CH2)m−NRa−(CH2)n−からなる群から選択され、
Yは、−NH−、−NR2−、
R1及びR2は、各々独立に、H、−(C1−C10)アルキル、−C(O)−(C1−C10)アルキル、ベンジル、−(C3−C10)シクロアルキル、又は、−(C3−C10)アリールから選択され、
Ra及びRbは、各々独立に、H、−OH、−(C1−C10)アルキル、−[CH2−CH2−O]n−(CH2)2−T、−C(O)−(C1−C10)アルキル、−(C1−C10)アルキレン−C(O)−Z、ベンジル、−(C3−C10)シクロアルキル、−(C3−C10)アリール、ハロ−(C1−C10)アルキル、ヒドロキシ−(C1−C10)アルキル、−NH−(C1−C10)アルキル、及び、−(C 1 −C 10 )アルキレン−NR d R e からなる群から選択されるか、又は、Ra及びRbは、これらが結合する窒素と一緒に、N、S、又は、Oから選択される1つ以上のヘテロ原子をさらに含むことができる、(C3−C6)−ヘテロアリール若しくは(C3−C6)−ヘテロシクロアルキルを形成し、
Zは、−OH、−O(C1−C10)アルキル、
Rcは、−OH、−O(C1−C10)アルキル、−O(C3−C10)シクロアルキル、−O(C3−C10)アリール、−O−(C1−C10)アルキレン−(C3−C10)アリール、又は、−O−(C1−C10)アルキレン−(C3−C10)シクロアルキルから選択され、
R3は、H、ハロゲン、−OH、−NH2、−(CH2)p−COOH、又は、−(CH2)p−NH2から選択され、
Tは、−H、−OH、−COOH、又は、−NRdReから選択され、
Rd及びReは、各々独立に、H、−OH、−(C1−C10)アルキル、又は、(C3−C10)ヘテロアリール−(C1−C10)アルキレンから選択され、
m、n、p、及び、qは、各々独立に、0、1、2、3、4、5、6、7、8、9、又は、10であり、
式(III)中、任意のアルキル、アルキレン、アリール、アリーレン、ヘテロアリール、ヘテロアリーレン、シクロアルキル、シクロアルキレン、ヘテロシクロアルキル、又は、ヘテロシクロアルキレンは、−(C1−C10)アルキレン−COOH、−COOH、及び、−(C 1 −C 10 )アルキレン−NR d R e からなる群から選択される1個、2個又は3個の置換基で任意に置換され、
前記放射性核種は、111In、90Y、68Ga、64Cu、153Gd、155Gd、157Gd、59Fe、225Ac、212Bi、213Bi、55Co、67Cu、165Dy、166Ho、192Ir、223Ra、186Re、188Re、105Rh、212Pb、213Pb、149Tb、227Th、153Sm、89Sr、117mSn、169Yb、90Y、86Y、89Zr、及び、177Luからなる群から選択される、請求項17に記載の金属錯体。 - 請求項3に記載の化合物、又は、その薬学的に許容される塩と、薬学的に許容されるキャリアとを含む、医薬組成物。
- 請求項18に記載の金属錯体、又は、その薬学的に許容される塩と、薬学的に許容されるキャリアとを含む、医薬組成物。
- 放射性核種と、式(IV)に従った化合物、又は、その薬学的に許容される塩若しくは溶媒和物とを含む金属錯体を含む組成物であって、
式中、
Gは、
Lは、−NH−(C1−C10)アルキレン−、−NH−(C1−C10)アルキレン−C(O)−、−C(O)−(C1−C10)アルキレン−、−C(O)−(C1−C10)アルキレン−C(O)−、又は、
Ra及びRbは、各々独立に、H、−OH、−(C1−C10)アルキル、−[CH2−CH2−O]n−(CH2)2−T、−C(O)−(C1−C10)アルキル、−(C1−C10)アルキレン−C(O)−Z、ベンジル、−(C3−C10)シクロアルキル、−(C3−C10)アリール、ハロ−(C1−C10)アルキル、ヒドロキシ−(C1−C10)アルキル、−NH−(C1−C10)アルキル、若しくは、−(C 1 −C 10 )アルキレン−NR d R e であるか、又は、Ra及びRbは、これらが結合する窒素と一緒に、N、S、又は、Oから選択される1つ以上のヘテロ原子をさらに含むことができる、(C3−C6)−ヘテロアリール若しくは(C3−C6)−ヘテロシクロアルキルを形成し、
Zは、−OH、−O(C1−C10)アルキル、
Rd及びReは、各々独立に、H、−OH、−(C1−C10)アルキル、又は、(C3−C10)ヘテロアリール−(C1−C10)アルキレンであり、
nは、0、1、2、3、4、5、6、7、8、9、又は、10であり、
式(IV)中、任意のアルキル、アルキレン、アリール、アリーレン、ヘテロアリール、ヘテロアリーレン、シクロアルキル、シクロアルキレン、ヘテロシクロアルキル、又は、ヘテロシクロアルキレンは、−(C1−C10)アルキレン−COOH、−COOH、及び、−(C 1 −C 10 )アルキレン−NR d R e からなる群から選択される1個、2個又は3個の置換基で任意に置換される、組成物。 - 前記1つ以上の組織は、前立腺組織、又は、前立腺癌組織から選択される、請求項22に記載の組成物。
- 前記放射性核種は、111In、90Y、68Ga、64Cu、153Gd、155Gd、157Gd、59Fe、225Ac、212Bi、213Bi、55Co、67Cu、165Dy、166Ho、192Ir、223Ra、186Re、188Re、105Rh、212Pb、213Pb、149Tb、227Th、153Sm、89Sr、117mSn、169Yb、90Y、86Y、89Zr、及び、177Luからなる群から選択される、請求項22に記載の組成物。
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