JP2021527139A - Cd73阻害剤及びその薬学的使用 - Google Patents
Cd73阻害剤及びその薬学的使用 Download PDFInfo
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- 229960001727 tretinoin Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
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- 229960003048 vinblastine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
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Abstract
Description
本出願は、2018年11月30日出願の米国仮特許出願第62/773,267号、及び2018年9月11日出願の中国特許出願第201811057145.X号からの優先権の利益を主張し、そのそれぞれは参照により全体が本明細書に組み込まれる。
の化合物、及びそれらの薬学的に許容される塩又はエステルを提供する。
の化合物、及びそれらの薬学的に許容される塩又はエステルを提供する。
の化合物、及びそれらの薬学的に許容される塩又はエステルを提供する。
の化合物、及びそれらの薬学的に許容される塩又はエステルを提供する。
の化合物、及びそれらの薬学的に許容される塩又はエステルを提供する。
レリン);及び抗ホルモン抗原(例えばタモキシフェン、フルタミド等の抗アンドロゲン剤;ミトタン及びアミノグルテチミド等の抗アドレナリン剤)、が挙げられるがこれらに限定されない、少なくとも1つの化学療法剤を対象に投与する工程を含む、方法を提供する。当技術分野で知られている他の薬剤(例えば、三酸化ヒ素)及び将来開発され得る他の化学療法剤と組み合わせたCD73阻害剤の使用も提供する。
本明細書で使用される用語の明確かつ一貫した理解を提供するために、複数の定義を以下に提供する。更に、他に定義されない限り、本明細書で使用されるすべての技術用語及び科学用語は、本発明が属する技術分野における当業者に一般的に理解されるのと同じ意味を有する。
ニル、チエノチアゾリル、チエノオキサゾリル、チエノイミダゾリル、チオフェニル、トリアジニル、1,2,3-トリアゾリル、1,2,4-トリアゾリル、1,2,5-トリアゾリル、1,3,4-トリアゾリル、キサンテニル等、が挙げられる。複素環という用語は、非置換複素環基と置換複素環基の両方を含む。
(1)無機酸、例として塩酸、臭化水素酸、ヨウ化水素酸、硫酸、スルファミン酸、硝酸、リン酸、炭酸塩形成剤等の付加により、塩基性又は正に帯電した官能基に対して形成された酸付加塩;又は有機酸、例として酢酸、プロピオン酸、乳酸、シュウ酸、グリコール酸、ピバル酸、t-ブチル酢酸、β-ヒドロキシ酪酸、吉草酸、ヘキサン酸、シクロペンタンプロピオン酸、ピルビン酸、マロン酸、コハク酸、リンゴ酸、マレイン酸、フマル酸、酒石酸、クエン酸、安息香酸、3-(4-ヒドロキシベンゾイル)安息香酸、桂皮酸、マンデル酸、メタンスルホン酸、エタンスルホン酸、1,2-エタンジスルホン酸、2-ヒドロキシエタンスルホン酸、シクロヘキシルアミノスルホン酸、ベンゼンスルホン酸、スルファニル酸、4-クロロベンゼンスルホン酸、2-ナフタレンスルホン酸、4-トルエンスルホン酸、カンファースルホン酸、3-フェニルプロピオン酸、ラウリルスルホン酸、ラウリル硫酸、オレイン酸、パルミチン酸、ステアリン酸、ラウリン酸、エンボン(パモ酸)酸、パルモイン酸(palmoic acid)、パントテン酸、ラクトビオン酸、アルギン酸、ガラクタル酸、ガラクツロン酸、グルコン酸、グルコヘプトン酸、グルタミン酸、ナフトエ酸、ヒドロキシナフトエ酸、サリチル酸、アスコルビン酸、ステアリン酸、ムコン酸等、により形成された酸付加塩;
(2)親化合物中に存在する酸性プロトンがアルカリ金属イオン(例えば、リチウム、ナトリウム、カリウム)、アルカリ土類イオン(例えば、マグネシウム、カルシウム、バリウム)、若しくは他の金属イオン、例として、アルミニウム、亜鉛、鉄等の金属イオンで置換される場合;又は親化合物中に存在する酸性プロトンが、有機塩基、例として、アンモニア、エチルアミン、ジエチルアミン、エチレンジアミン、N,N'-ジベンジルエチレンジアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、トロメタミン、N-メチルグルカミン、ピペラジン、クロロプロカイン(chloroprocain)、プロカイン(procain)、コリン、リシン等と配位する場合、のいずれかで形成される塩基付加塩、
が挙げられる。
本明細書で提供される化合物は、従来の方法を使用して、以下の実施例に記載されるように調製することができる。
化合物1の合成
DIEA(ジイソプロピルエチルアミン;7.5mmol、969mg、1.5当量)を、ジオキサン(25mL)中の2,6-ジクロロ-9-(2',3',5'-トリ-O-アセチル-β-D-リボフラノシル)プリン(5.0mmol、2236mg、1.0当量)及びベンジルアミン(5.0mmol、536mg、1.0当量)の溶液に滴加した。反応混合物を、室温で、一晩撹拌した。溶媒を減圧下で蒸発させ、残留物をDCM(100mL)中に溶解し、水(2×30mL)で洗浄した。粗生成物をカラムクロマトグラフィーにより精製した。中間体を、50mLのNH3/CH3OH溶液中に溶解し、35℃で一晩撹拌した。溶媒を減圧下で蒸発させ、残留物質をカラムクロマトグラフィーで精製して、2-クロロプリンヌクレオシド誘導体S-1(1818mg)を得た。
化合物6の合成
DIEA(7.5mmol、969mg、1.5当量)を、ジオキサン(25mL)中の2,6-ジクロロ-9-(2',3',5'-トリ-O-アセチル-β-D-リボフラノシル)プリン(5.0mmol、2.2g、1.0当量)及び1-ナフタレンメタンアミン(5.0mmol、786mg、1.0当量)の溶液に滴加した。反応混合物を、室温で、一晩撹拌した。溶媒を減圧下で蒸発させ、残留物をDCM(100mL)中に溶解し、水(2×30mL)で洗浄した。(ロータリーエバポレーターを使用して)溶媒を除去し、残留物質をカラムクロマトグラフィーにより精製した。中間体を、50mLのNH3/CH3OH溶液中に溶解し、35℃で一晩撹拌した。溶媒を減圧下で蒸発させ、残留物質をカラムクロマトグラフィーにより精製して、S-6(1.3g)を得た。
化合物7の合成
DIEA(7.5mmol、969mg、1.5当量)を、ジオキサン(25mL)中の2,6-ジクロロ-9-(2',3',5'-トリ-O-アセチル-β-D-リボフラノシル)プリン(5.0mmol、2.2g、1.0当量)及び2-ナフタレンメタンアミン(5.0mmol、786mg、1.0当量)の溶液に滴加した。反応物を、室温で、一晩撹拌した。溶媒を減圧下で蒸発させ、残留物をDCM(100mL)中に溶解し、水(2×30mL)で洗浄した。粗生成物をカラムクロマトグラフィーにより精製した。中間体を、50mLのNH3/CH3OH溶液中に溶解し、35℃で一晩撹拌した。溶媒を減圧下で蒸発させ、残留物質をカラムクロマトグラフィーで精製して、2-クロロプリンヌクレオシド誘導体S-7(1.15g)を得た。
化合物8の合成
2-クロロプリンヌクレオシド誘導体S-8(1.0mmol、415mg、1.0当量)をリン酸トリメチル(10mL)中に溶解し;溶液を氷浴で冷却した。氷浴を適用しながら、冷溶液に、リン酸トリメチル(5mL)中のビス(ジクロロホスホリル)メタン(4.0当量)の溶液を加えた。得られた混合物を0℃で2〜4時間撹拌し、反応を、TLCにより監視した。TEAC溶液により反応をクエンチし、反応混合物のpHを7〜8に調整した。混合物をDCMで抽出し;水相を単離して濃縮した。残留物質を精製し(逆相カラムクロマトグラフィー、C18カラム)、生成物を無色の固体(58mg)として得た。1H NMR (500 MHz, D2O) δ ppm 2.12 (t, J = 19.7 Hz, 2H), 4.08 (s, 2H), 4.27 (s, 1H), 4.40 (s, 1H), 4.53 (s, 1H), 4.65 (s, 2H), 5.75 (s, 1H), 7.36 (s, 3H), 7.65 (s, 2H), 7.69 (d, J = 8.0 Hz, 2H), 8.28 (s, 1H); 13C NMR (125 MHz, D2O) δ ppm 44.04, 63.41, 70.06, 74.19, 83.73, 86.90, 125.50, 125.60, 126.00, 126.34, 127.38, 128.15, 132.13, 132.71, 135.18, 139.21, 153.96, 154.73; 31P NMR (202 MHz, D2O) δ ppm 15.86, 19.01; m/z (ES-) 598.4.
化合物9の合成
DIEA(12.5mmol、1.6g、2.5当量)を、25mLのジオキサン中の2,6-ジクロロ-9-(2',3',5'-トリ-O-アセチル-β-D-リボフラノシル)プリン(5.0mmol、2.2g、1.0当量)及びメマンチン塩酸塩(5.0mmol、1.0g、1.0当量)の溶液に滴加した。反応混合物を、室温で、一晩撹拌した。溶媒を減圧下で蒸発させ、残留物をDCM(100mL)中に溶解し、水(2×30mL)で洗浄し、濃縮した。残留物質をカラムクロマトグラフィーにより精製して、中間体を得た。中間体を、50mLのNH3/CH3OH溶液中に溶解し、混合物を35℃で一晩撹拌した。溶媒を減圧下で蒸発させ、残留物質をカラムクロマトグラフィーで精製して、2-クロロプリンヌクレオシド誘導体S-9(1.1g)を得た。
化合物10の合成
2-クロロプリンヌクレオシド誘導体S-10(1.0mmol、451mg、1.0当量)をリン酸トリメチル(10mL)中に溶解し;溶液を氷浴で冷却した。冷溶液に、リン酸トリメチル(5mL)中のビス(ジクロロホスホリル)メタン(4当量)の溶液を加えた。得られた混合物を0℃で2〜4時間撹拌し、反応を、TLCで監視した。TEAC溶液により反応をクエンチし;反応溶液のpHを7〜8に調整した。混合物をDCMで抽出し、水相を単離して濃縮した。残留物質を逆相カラムクロマトグラフィー(C18カラム)により精製して、化合物10を無色の固体(60mg)として得た:1H NMR (500 MHz, D2O) δ ppm 2.27 (t, J = 19.4 Hz, 2H), 4.17 (s, 2H), 4.35 (s, 1H), 4.46 (s, 1H), 6.02 (s, 1H), 7.27 (s, 4H), 7.54 (s, 2H), 7.97 (s, 2H), 8.33 (s, 1H) ; 13C NMR (125 MHz, D2O) δ ppm 16.73, 25.47, 26.48 , 27.50, 57.39, 63.69, 70.09, 74.31, 83.84, 87.70, 113.16, 120.00, 122.84, 124.66, 126.42, 138.03, 143.08, 148.86, 152.70, 154.12 ; 31P NMR (200 MHz, D2O) δ ppm 17.43, 19.35- 19.97; m/z (ES-) 608.0.
化合物11の合成
2-クロロプリンヌクレオシド誘導体S-11(1.0mmol、564mg、1.0当量)をリン酸トリメチル(10mL)中に溶解した。溶液を氷浴で冷却し;冷溶液に、リン酸トリメチル(5mL)中のビス(ジクロロホスホリル)メタン(4当量)の溶液を加えた。得られた混合物を0℃で2〜4時間撹拌し、反応を、TLCで監視した。TEAC溶液によりクエンチした後、反応混合物のpHを7〜8に調整した。この混合物をDCMで抽出し、水相を単離して濃縮した。残留物質を逆相クロマトグラフィー(C18カラム)により精製して、化合物11を無色の固体(100mg)として得た:1H NMR (500 MHz, D2O) δ ppm 0.77 (d, J = 6.5 Hz, 3H), 1.22 (s, 14H), 1.55 (s, 2H), 1.92 (s, 4H), 2.12 (t, J = 19.8 Hz, 2H), 2.67 (d, J = 38.2 Hz, 4H), 4.03 (s, 2H), 4.19 (s, 1H), 4.40 (s, 1H), 4.60 (s, 1H), 5.20 (d, J = 5.6 Hz, 4H), 5.88 (d, J = 4.4 Hz, 1H),8.51 (s, 1H) ; 13C NMR (125 MHz, D2O) δ ppm 13.90 , 22.48 , 24.71 , 25.52 , 27.10 , 29.26 , 29.64 , 31.41, 36.86, 37.49, 63.89 , 70.44 ,74.37, 84.15 , 86.83, 119.95, 127.82, 129.70 , 149.34 , 152.45 , 152.86 , 164.88 ,174.66; 31P NMR (200 MHz, D2O) δ ppm 16.04 ,18.65; m/z (ES-) 720.4.
化合物12の合成
DIEA(7.5mmol、969mg、1.5当量)を、25mLのジオキサン中の2,6-ジクロロ-9-(2',3',5'-トリ-O-アセチル-β-D-リボフラノシル)プリン(5.0mmol、2.23g、1.0当量)及び2-アミノナフタレン(5.0mmol、715mg、1.0当量)の溶液に滴加した。反応混合物を、室温で、一晩撹拌した。溶媒を減圧下で蒸発させ、残留物をDCM(100mL)中に溶解し、水(2×30mL)で洗浄した。DCM溶液を濃縮乾固させ;残留物質をカラムクロマトグラフィーにより精製して、中間体を得た。中間体を、50mLのNH3/CH3OH溶液中に溶解し、混合物を35℃で一晩撹拌した。溶媒を減圧下で蒸発させ、残留物質をカラムクロマトグラフィーにより精製して、化合物S-12(670mg)を得た。
化合物15の合成
2-クロロプリンヌクレオシド誘導体S-15(1.0mmol、513mg、1.0当量)をリン酸トリメチル(10mL)中に溶解した。混合物を氷浴で冷却し、続いて、リン酸トリメチル(5mL)中のビス(ジクロロホスホリル)メタン(4当量)の溶液を加えた。得られた混合物を0℃で2〜4時間撹拌し、反応を、TLCで監視した。TEAC溶液により反応をクエンチし、反応混合物のpHを7〜8に調整した。混合物をDCMで抽出し;水相を単離して濃縮した。残留物質を逆相カラムクロマトグラフィー(C18カラム)により精製して、化合物15を無色の固体(30mg)として得た:1H NMR (500 MHz, D2O) δ ppm 0.70 (t, J = 6.3 Hz, 3H) ,1.06 (s, 16H), 1.27 (s, 2H), 1.58 (s, 2H), 2.10 (t, J = 19.7 Hz, 2H), 4.12 (d, J = 32.1 Hz, 4H), 4.27 (s, 1H), 4.46 (s, 1H), 4.66 (s, 1H), 6.00 (d, J = 4.7 Hz, 1H),8.60 (s, 1H) ; 13C NMR (125 MHz, D2O) δ ppm 13.73, 22.40, 25.51, 27.55, 28.40, 29.07, 29.36, 31.66, 63.64, 66.70, 70.27, 74.36, 83.95, 87.18, 120.57, 142.65, 150.05, 152.38, 153.21; 31P NMR (200 MHz, D2O) δ ppm 15.64,18.89; m/z (ES-) 670.1.
化合物16の合成
2-クロロプリンヌクレオシド誘導体S-16(1.0mmol、478mg、1.0当量)をリン酸トリメチル(10mL)中に溶解し;混合物を氷浴で冷却して、続いて、リン酸トリメチル(5mL)中のビス(ジクロロホスホリル)メタン(4当量)の溶液を加えた。得られた混合物を0℃で2〜4時間撹拌し、反応を、TLCで監視した。TEAC溶液により反応をクエンチし;混合物のpHを7〜8に調整した。混合物をDCMで抽出し;水相を単離して濃縮した。残留物質を逆相クロマトグラフィー(C18カラム)により精製して、化合物16を無色の固体(250mg)として得た:1H NMR (500 MHz, D2O) δ ppm 1.64 (s, 11H), 1.91 (s, 4H), 2.16 (t, J = 19.8 Hz, 2H), 2.29 (s, 2H), 4.14 (dddd, J = 6.8, 5.9, 4.1, 1.6 Hz, 3H), 4.30-4.37 (m, 1H), 4.56 - 4.46 (m, 1H), 6.11 (d, J = 5.1 Hz, 1H),8.72 (s, 1H) ;13C NMR (125 MHz, D2O) δ ppm 16.75 , 27.23 , 28.38 , 33.41 , 36.07 , 42.03 , 51.44 , 63.47 , 70.17 , 74.37 , 84.19, 87.49 , 115.91 , 121.90, 143.36 , 149.28 , 153.15 ,173.66; 31P NMR (200 MHz, D2O) δ ppm 16.37 , 18.85; m/z (ES-) 634.1.
化合物17の合成
DIEA(12.5mmol、1.6g、2.5当量)を、25mLのジオキサン中の2,6-ジクロロ-9-(2',3',5'-トリ-O-アセチル-β-D-リボフラノシル)プリン(5.0mmol、2.23g、1.0当量)及び2-アダマンタナミン塩酸塩(5.0mmol、0.94g、1.0当量)の溶液に滴加した。混合物を、室温で、一晩撹拌した。溶媒を減圧下で蒸発させ、残留物をDCM(100mL)中に溶解し、水(2×30mL)で洗浄した。有機層を濃縮し;残留物質をカラムクロマトグラフィーにより精製して、中間体を得た。この中間体を、50mLのNH3/CH3OH溶液中に溶解し、35℃で一晩撹拌した。溶媒を蒸発させた後、残留物質をカラムクロマトグラフィーにより精製して、2-クロロプリンヌクレオシド誘導体S-17(880mg)を得た。
化合物18の合成
2-クロロプリンヌクレオシド誘導体S-18(1.0mmol、512mg、1.0当量)をリン酸トリメチル(10mL)中に溶解した。混合物を氷浴で冷却し、続いて、リン酸トリメチル(5mL)中のビス(ジクロロホスホリル)メタン(4当量)の溶液を加えた。得られた混合物を0℃で2〜4時間撹拌し、反応を、薄層クロマトグラフィーにより監視した。TEAC溶液により反応をクエンチし;混合物のpHを7〜8に調整した。混合物をDCMで抽出し;水相を単離して濃縮した。残留物質を逆相カラムクロマトグラフィー(C18カラム)により精製して、化合物18を無色の固体(70mg)として得た:1H NMR (500 MHz, CD3OD-d4) δ ppm 0.93 (t, J = 6.8 Hz, 3H), 1.52 (s, 18H), 1.60 - 1.74 (m, 2H), 2.33 (t, J = 19.8 Hz, 2H), 3.43 (t, J = 6.6 Hz, 2H), 4.27 (d, J = 21.4 Hz, 3H), 4.47 - 4.61 (m, 1H), 4.71 (t, J = 5.3 Hz, 1H), 6.13 (d, J = 5.4 Hz, 1H),8.76 (s, 1H); 13C NMR (125 MHz, CD3OD-d4) δ ppm 13.01 , 22.30 , 26.62, 28.98 , 29.28 , 31.63 , 39.56 , 63.95 , 70.57 , 74.91 , 84.44 , 87.86 , 118.78 , 142.32 , 150.79 , 151.78 , 151.97 ,154.17; 31P NMR (200MHz, CD3OD-d4) δ ppm 16.03, 20.25; m/z (ES-), 669.2.
化合物19の合成
DIEA(7.5mmol、969mg、1.5当量)を、25mLのジオキサン中の2,6-ジクロロ-9-(2',3',5'-トリ-O-アセチル-β-D-リボフラノシル)プリン(5.0mmol、2.23g、1.0当量)及びジ-N-ドデシルアミン(5.0mmol、1.8g、1.0当量)の溶液に滴加した。反応混合物を、室温で、一晩撹拌した。溶媒を減圧下で蒸発させ、残留物をDCM(100mL)中に溶解し、水(2×30mL)で洗浄した。有機層を濃縮乾固させた;残留物質をカラムクロマトグラフィーにより精製して、中間体化合物を得た。この中間体を、50mLのNH3/CH3OH溶液中に溶解し、混合物を35℃で一晩撹拌した。溶媒を減圧下で除去した後、残留物質生成物をカラムクロマトグラフィーで精製して、2-クロロプリンヌクレオシド誘導体S-19(1.3g)を得た。
化合物20の合成
DIEA(7.5mmol、969mg、1.5当量)を、25mLのジオキサン中の2,6-ジクロロ-9-(2',3',5'-トリ-O-アセチル-β-D-リボフラノシル)プリン(5.0mmol、2.23g、1.0当量)及び2-アントラセンアミン(5.0mmol、1.0g、1.0当量)の溶液に滴加した。反応混合物を、室温で、一晩撹拌した。溶媒を減圧下で蒸発させ、残留物をDCM(100mL)中に溶解し、水(2×30mL)で洗浄した。有機層を濃縮乾固させた;残留物質をカラムクロマトグラフィーにより精製して、中間体化合物を得た。この中間体を、50mLのNH3/CH3OH溶液中に溶解し、35℃で一晩撹拌した。溶媒を減圧下で蒸発させ、残留物質をカラムクロマトグラフィーで精製して、2-クロロプリンヌクレオシド誘導体S-20(770mg)を得た。
化合物22の合成
DIEA(7.5mmol、969mg、1.5当量)を、ジオキサン(25mL)中の2,6-ジクロロ-9-(2',3',5'-トリ-O-アセチル-β-D-リボフラノシル)プリン(5.0mmol、2.23g、1.0当量)及び1-アダマンタナミン(5.0mmol、756mg、1.0当量)の溶液に滴加した。反応混合物を、室温で、一晩撹拌した。溶媒を減圧下で蒸発させ、残留物をDCM(100mL)中に溶解し、水(2×30mL)で洗浄した。溶媒を除去した後、残留物質をカラムクロマトグラフィーにより精製して、中間体化合物を得た。この中間体を、50mLのNH3/CH3OH溶液中に溶解し、混合物を35℃で一晩撹拌した。溶媒を減圧下で蒸発させ、残留物質をカラムクロマトグラフィーで精製して、2-クロロプリンヌクレオシド誘導体S-22(770mg)を得た。
化合物23の合成
2-クロロプリンヌクレオシド誘導体S-23(1.0mmol、481mg、1.0当量)をリン酸トリメチル(10mL)中に溶解し、混合物を氷浴で冷却した。冷混合物に、リン酸トリメチル(5mL)中のビス(ジクロロホスホリル)メタン(4当量)の溶液を加えた。得られた混合物を0℃で2〜4時間撹拌し、反応を、TLCで監視した。TEAC溶液により反応をクエンチし、反応混合物のpHを7〜8に調整した。混合物をDCMで抽出し;水相を単離して濃縮した。残留物質を逆相カラムクロマトグラフィー(C18カラム)により精製して、化合物23を無色の固体(141mg)として得た:1H NMR (D2O, 500 MHz) δ ppm 0.90-0.97 (m, 9H), 1.18-1.20 (m, 1 H), 1.36-1.40 (m, 1 H), 1.75-1.80 (m, 1H), 1.90-1.97 (m, 1H), 2.00-2.30 (m, 2H), 2.40-2.45 (m, 1H), 4.20-4.25 (m, 2H), 4.40-4.44 (m, 1H), 4.44-4.57 (m, 1H), 4.72-4.73 (m,1 H), 4.91-5.05 (m, 1H), 6.43-6.45 (m, 1H), 9.02 (m, 1H); 13C NMR (D2O, 125 MHz) δ 12.74, 18.03, 18.90, 35.91, 44.47, 47.41, 48.45, 63.50, 70.16, 74.34, 83.22, 84.06, 84.13, 87.37, 120.84, 142.72, 150.23, 152.41, 153.24, 153.45 ppm; 31P NMR (D2O, 200 MHz) δ ppm 16.49, 18.79; m/z (ES-) 638.0.
化合物31の合成
DIEA(7.5mmol、969mg、1.5当量)を、ジオキサン(25mL)中の2,6-ジクロロ-9-(2',3',5'-トリ-O-アセチル-β-D-リボフラノシル)プリン(5.0mmol、2.23g、1.0当量)及び3-アザスピロ[4.5]デカン(5.0mmol、696mg、1.0当量)の溶液に滴加した。反応混合物を、室温で、一晩撹拌した。溶媒を減圧下で蒸発させ、残留物をDCM(100mL)中に溶解し、水(2×30mL)で洗浄した。有機層を蒸発乾固させ;残留物質をカラムクロマトグラフィーにより精製して、中間体化合物を得た。この中間体を、50mLのNH3/CH3OH溶液中に溶解し、35℃で一晩撹拌した。溶媒を減圧下で蒸発させ、残留物質をカラムクロマトグラフィーで精製して、対応する2-クロロプリンヌクレオシド誘導体S-31(1.1g)を得た。
化合物51の合成
DIEA(7.5mmol、969mg、1.5当量)を、ジオキサン(25mL)中の2,6-ジクロロ-9-(2',3',5'-トリ-O-アセチル-β-D-リボフラノシル)プリン(5.0mmol、2.23g、1.0当量)及びノルトロピン(5.0mmol、636mg、1.0当量)の溶液に滴加した。反応混合物を、室温で、一晩撹拌した。溶媒を減圧下で蒸発させ、残留物をDCM(100mL)中に溶解し、水(2×30mL)で洗浄した。残留物質をカラムクロマトグラフィーにより精製して、中間体化合物を得た。この中間体を、50mLのNH3/CH3OH溶液中に溶解し、混合物を35℃で一晩撹拌した。溶媒を(減圧下)で除去した後、残留物質をカラムクロマトグラフィーで精製して、2-クロロプリンヌクレオシドの誘導体S-51(1.2g)を得た。
1. CD73阻害剤スクリーニングアッセイ
CD73に対する化合物の阻害効果を評価するために、マラカイトグリーンリン酸塩検出キット(R&D社、カタログ番号DY996)を使用した。要約すると、化合物を溶解し、リン酸塩不含有バッファー(トリス-HCl、pH7.3)を使用して所望の濃度に希釈した。25μLの化合物溶液を等量のCD73タンパク質溶液(2×濃度、0.5μg/mL、Novoprotein社、カタログ番号C446)に加え、次に室温で5分間インキュベートした。10μLのマラカイトグリーン試薬Aを各ウェルに加え、完全に混合し、室温で10分間インキュベートした。次に、10μLのマラカイトグリーン試薬Bを各ウェルに加え、完全に混合し、室温で20分間インキュベートした。最後に、各ウェルの光学密度を、620nmに設定されたマイクロプレートリーダーを使用して決定した。選択した化合物の阻害活性を表2に示す。
1μM AMPを含む無血清RMPI-1640培地を使用して化合物を所望の濃度に溶解及び希釈することにより、5×の化合物溶液を調製する。A375細胞を収集し、PBSで2回洗浄した後、無血清RMPI-1640培地中に1.125x105/mLの密度で懸濁する。96ウェルプレートに80μLの細胞懸濁液を分注し、次に5x化合物溶液20μLを加え、穏やかに混合し、37℃、5%CO2で16時間培養する。インキュベーション後、50μLの上清を各ウェルから新しい96ウェルプレートに移す。次に、2μLの2.5μM ATPと50μLのCelltiter Glo試薬を、各ウェルに順次加える。PheraStar(BMG社)を使用して発光を測定する。
次に、絶食させた雄型SDラットに、化合物を単回i.v.(1mg/kg)又はi.g.(3mg/kg)投与し、投与後、0.08、0.25、0.5、1、2、4、6、8及び24時間目に血液試料を採取した。血漿を遠心分離(8000rpm)で分離し、試料が分析されるまで凍結(-20℃)した。ラット血漿中の化合物の濃度を、HPLC-MS/MSによって定量した。血漿を、内部標準及びメタノール又はアセトニトリルを含む適切なチューブに分注した。チューブを3分間激しく混合して除タンパクを行い、8000rpmで5分間遠心分離した。上清をオートサンプラバイアルに移し、クロマトグラフィーシステムに注入した。WinNonlin6.3ソフトウェアを使用して、AUC0-t、Cmax、tmax t1/2、MRT、Cl、及びVdを含む薬物動態パラメータを計算した。絶対生物学的利用能を、以下のように計算した:F=[AUC(i.g.)*用量(i.v.)]/[AUC(i.v.)*用量(i.g.)]*100%。
Claims (51)
- 式I
Wは、酸素、硫黄、窒素、又はメチレン基であり;
Xは、ホスホニル(-P(=O)(OR)-)、スルホニル(-S(=O)2-)、及びカルボニル(-C(=O)-)から選択される部分であり、Rは水素、エステル形成基、又は保護基であり;
Yは、ホスホネート(-PO3R2)、スルホネート(-SO3R)、及びカルボキシレート(-CO2R)から選択され、Rは水素、エステル形成基、又は保護基であり;
R1はヒドロキシル基又は水素であり;
R2は塩素又は水素であり;
R3及びR4は、水素、アルキル基、アルケニル基及びアルキニル基から独立して選択され、R3及びR4のうちの少なくとも1つは、11〜30個の炭素原子を有するか;或いは
R3及びR4は、水素及び炭素環式環系又は複素環式環系を含む二環、三環、らせん環、縮合環又は架橋環である環系から独立して選択され、前記炭素環式環系は芳香族又は非芳香族であり、ただし、R3とR4の両方が水素であることはない)
の化合物、又はその薬学的に許容されるエステル若しくは塩。 - R3が、水素又は低級アルキルであり;R4が、-C(=O)R5又は-C(=O)OR5であり、R5が、C11〜C30のアルキル基、アルケニル基、又はアルキニル基である、請求項1に記載の化合物。
- R3が、水素又は低級アルキルであり;R4が、-C(=O)R5又は-C(=O)OR5であり、R5が、炭素環式環系又は複素環式環系を含む二環、三環、らせん環、縮合環又は架橋環を有する環系であり、前記炭素環式環系は芳香族又は非芳香族であり、前記複素環式環系は置換又は非置換である、請求項1に記載の化合物。
- 式IX:
Rは水素、エステル形成基、又は保護基であり;
R1はヒドロキシル基又は水素であり;
R2は水素又は塩素であり;
R3は、水素又は低級アルキルであり、R4は、11〜30個の炭素原子を有するアルキル、アルケニル、又はアルキニルであり;或いは、
R3は、水素又は低級アルキルであり、R4は、二環式、三環式、又は多環式環系を含む置換基であり、前記環系は縮合、らせん、架橋、又は平行であり、前記環系は、炭素環式、脂肪族、芳香族、複素環式、又はそれらの組み合わせであり;或いは、
R3は、水素又は低級アルキルであり、R4は、-C(=O)R5又は-C(=O)OR5であり、R5は、11〜30個の炭素原子を有するアルキル基、アルケニル基、又はアルキニル基であり;或いは、
R3は、水素又は低級アルキルであり、R4は、-C(=O)R5又は-C(=O)OR5であり、R5は、炭素環式環系又は複素環式環系を含む二環、三環、らせん環、縮合環又は架橋環を含む置換基であり、前記炭素環式環系は芳香族又は非芳香族であり、前記複素環式環系は置換又は非置換であり、前記環は、炭素環式、脂肪族、芳香族、複素環式、又はそれらの組み合わせであり;或いは、
R3は、水素又は低級アルキルであり、R4は、非置換若しくは置換1-アダマンチル、α-ナフチルメチル、又はβ-ナフチルメチルであり;或いは、
R3、R4、及びそれらが結合している窒素原子は、縮合三環構造を形成している)
のもの、又はその薬学的に許容される塩若しくはエステルである、請求項1から3のいずれか一項に記載の化合物。 - R、R1、及びR2が、請求項8に規定のとおりであり;R3が、水素又は低級アルキルであり;R4が、アダマンチル部分を含む基である、請求項8に記載の化合物。
- R4が、置換若しくは非置換1-アダマンチル、又は置換若しくは非置換2-アダマンチルである、請求項9に記載の化合物。
- R4が、置換若しくは非置換1-アダマンチルメチルである、請求項9に記載の化合物。
- R4が、置換若しくは非置換1-アダマンチルエチル、置換若しくは非置換1-アダマンチルプロピル、又は置換若しくは非置換1-アダマンチルブチルである、請求項9に記載の化合物。
- R、R1、及びR2が、請求項8に規定のとおりであり;R3が、水素又は低級アルキルであり;R4が、ナフチル部分を含む基である、請求項8に記載の化合物。
- R4が、置換若しくは非置換α-ナフチル、又は置換若しくは非置換β-ナフチルである、請求項13に記載の化合物。
- R4が、置換若しくは非置換α-ナフチルメチル、又は置換若しくは非置換β-ナフチルメチルである、請求項13に記載の化合物。
- R4が、置換若しくは非置換ナフチルエチル、置換若しくは非置換ナフチルプロピル、及び置換若しくは非置換ナフチルブチルから選択される、請求項13に記載の化合物。
- 前記縮合三環構造が、置換又は非置換カルバゾリル部分である、請求項8に記載の化合物。
- 表1に列挙された化合物、又はその薬学的に許容される塩若しくはエステルである、請求項1から17のいずれか一項に記載の化合物。
- 前記化合物中のC、H、O、及びN原子がそれぞれ、天然存在比の原子及び同位体濃縮原子から独立して選択される、請求項1から18のいずれか一項に記載の化合物。
- 前記同位体濃縮原子が、炭素の場合は12C、13C、及び14Cから選択され;水素の場合は1H、2H、及び3Hから選択され;酸素の場合は16O、17O、及び18Oから選択され;並びに窒素の場合は14N及び15Nから選択される、請求項19に記載の化合物。
- 請求項1から20のいずれか一項に記載の化合物又はその薬学的に許容される塩若しくはエステルと、薬学的に許容される担体とを含む、医薬組成物。
- 前記薬学的に許容される担体が、クリーム、エマルション、ゲル、リポソーム、又はナノ粒子を含む、請求項21に記載の医薬組成物。
- 前記組成物が、経口投与に好適である、請求項21又は22に記載の医薬組成物。
- 硬質シェルゼラチンカプセル剤、軟質シェルゼラチンカプセル剤、カシェ剤、丸剤、錠剤、ロゼンジ剤、散剤、顆粒剤、ペレット剤、トローチ剤、又は糖衣錠の形態である、請求項23に記載の医薬組成物。
- 液剤、水性液体懸濁剤、非水性液体懸濁剤、水中油型液体乳剤、油中水型液体乳剤、エリキシル剤、又はシロップ剤の形態である、請求項23に記載の医薬組成物。
- 腸溶コーティングされている、請求項23から25のいずれか一項に記載の医薬組成物。
- 制御放出用に製剤化されている、請求項23から26のいずれか一項に記載の医薬組成物。
- 注射用である、請求項20又は21に記載の医薬組成物。
- 処置又は予防を必要とする対象におけるCD73に関係する疾患、障害若しくは状態を処置又は予防する方法であって、治療有効量の請求項1から20のいずれか一項に記載の化合物又は請求項21から28のいずれか一項に記載の医薬組成物を、前記対象に投与する工程を含み、それにより前記対象において前記CD73に関係する疾患、障害又は状態を処置又は予防する、方法。
- 前記化合物を、前記対象におけるCD73媒介免疫抑制の進行を逆転、遅延、又は停止するのに有効な量で投与する、請求項29に記載の方法。
- 前記CD73関連疾患、障害又は状態が、がんである、請求項29又は30に記載の方法。
- 前記がんが、前立腺がん、結腸がん、直腸がん、膵臓がん、子宮頸がん、胃がん、子宮内膜がん、脳がん、肝臓がん、膀胱がん、卵巣がん、精巣がん、頭部がん、頸部がん、皮膚がん、中皮内層がん、白血球のがん、食道がん、乳がん、筋肉のがん、結合組織のがん、肺がん、副腎がん、甲状腺がん、腎臓がん、又は骨がん、である、請求項31に記載の方法。
- 前記がんが、膠芽腫、中皮腫、腎細胞癌、胃癌、肉腫、絨毛癌、皮膚基底細胞癌、又は精巣セミノーマ、である、請求項31に記載の方法。
- 前記がんが、黒色腫、結腸がん、膵臓がん、乳がん、前立腺がん、肺がん、白血病、脳腫瘍、リンパ腫、卵巣がん、及びカポジ肉腫からなる群から選択される、請求項31に記載の方法。
- 前記CD73に関係する疾患、障害又は状態が、関節リウマチ、腎不全、ループス、喘息、乾癬、大腸炎、膵炎、アレルギー、線維症、貧血、線維筋痛、アルツハイマー病、うっ血性心不全、脳卒中、大動脈弁狭窄症、動脈硬化症、骨粗鬆症、パーキンソン病、感染症、クローン病、潰瘍性大腸炎、アレルギー性接触皮膚炎、湿疹、全身性硬化症、及び多発性硬化症、からなる群から選択される免疫関連疾患、障害又は状態である、請求項29又は30に記載の方法。
- 少なくとも1つの追加の治療剤を更に含む、請求項21から28のいずれか一項に記載の医薬組成物。
- 前記少なくとも1つの追加の治療剤が、化学療法剤、免疫及び/又は炎症調節剤、抗高コレステロール血症剤、又は抗感染症剤である、請求項36に記載の医薬組成物。
- 前記少なくとも1つの追加の治療剤が、免疫チェックポイント阻害剤である、請求項36に記載の医薬組成物。
- 前記対象への少なくとも1つの追加の治療剤の投与を更に含む、請求項29から35のいずれか一項に記載の方法。
- 前記少なくとも1つの追加の治療剤及び前記化合物又は組成物を、併用して又は順次に投与する、請求項39に記載の方法。
- 前記少なくとも1つの追加の治療剤が、化学療法剤、免疫及び/又は炎症調節剤、抗高コレステロール血症剤、又は抗感染症剤である、請求項39又は40に記載の方法。
- 請求項1から20のいずれか一項に記載の化合物又はその薬学的に許容される塩若しくはエステルと、少なくとも1つの追加の治療剤とを含むキット。
- 前記少なくとも1つの追加の治療剤が、化学療法剤、免疫及び/又は炎症調節剤、抗高コレステロール血症剤、抗感染症剤、又は免疫チェックポイント阻害剤である、請求項42に記載のキット。
- 緩衝液又は賦形剤、及び/又はそれらの使用説明書を更に含む、請求項42又は43に記載のキット。
- 対象におけるがんを処置する方法であって、有効量の請求項1から20のいずれか一項に記載の化合物又はその薬学的に許容される塩若しくはエステル、及び免疫チェックポイント阻害剤を、前記対象に投与する工程を含み、それにより前記対象においてがんを処置する、方法。
- 前記投与する工程を、放射線処置の前、放射線処置と同時に、又は放射線処置の後に実施する、請求項42に記載の方法。
- 前記化合物及び前記免疫チェックポイント阻害剤を、組み合わせて投与する、請求項45に記載の方法。
- 前記化合物及び前記免疫チェックポイント阻害剤を、順次に投与する、請求項45に記載の方法。
- 前記化合物を、前記免疫チェックポイント阻害剤の後に投与する、請求項48に記載の方法。
- 前記化合物を、前記免疫チェックポイント阻害剤の前に投与する、請求項48に記載の方法。
- 前記免疫チェックポイント阻害剤が、イプリムマブ(ipulimumab)、ニボルマブ及びランブロリズマブからなる群から選択される、請求項38に記載の医薬組成物、請求項43に記載のキット、又は請求項45及び47から50のいずれか一項に記載の方法。
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WO2023201267A1 (en) | 2022-04-13 | 2023-10-19 | Gilead Sciences, Inc. | Combination therapy for treating trop-2 expressing cancers |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017120508A1 (en) * | 2016-01-08 | 2017-07-13 | Arcus Biosciences, Inc. | Modulators of 5'-nucleotidase, ecto and the use thereof |
JP2019535720A (ja) * | 2016-11-18 | 2019-12-12 | アーカス バイオサイエンシズ インコーポレイティド | Cd73媒介免疫抑制の阻害剤 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017120508A1 (en) * | 2016-01-08 | 2017-07-13 | Arcus Biosciences, Inc. | Modulators of 5'-nucleotidase, ecto and the use thereof |
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Non-Patent Citations (1)
Title |
---|
BHATTARAI, SANJAY ET AL.: "α,β-Methylene-ADP(AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5'-Nu", JOURNAL OF MEDICINAL CHEMISTRY, vol. 58, no. 15, JPN6021040082, 2015, pages 6248 - 6263, ISSN: 0004747024 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2022526147A (ja) * | 2019-04-28 | 2022-05-23 | アビスコ セラピューティクス カンパニー リミテッド | Cd73阻害剤、その製造方法と応用 |
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