JP2019534323A - ナフチリジン化合物、薬物組成物およびそれらの応用 - Google Patents
ナフチリジン化合物、薬物組成物およびそれらの応用 Download PDFInfo
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
Description
R1とR2はH、C1-C3アルキル基から選ばれ、
R3はH、C1-C3アルコキシ基から選ばれ、
R4はH、C1-C6アルキル基、3-8員全炭素単環式シクロアルキル基、3-8員ヘテロ脂環基から選ばれ、そのうちC1-C6アルキル基、3-8員全炭素単環式シクロアルキル基、3-8員ヘテロ脂環基はさらに、C1-C6アルキル基、C1-C6アルコキシ基、3-8員ヘテロ脂環基、C6-C10アリール基、C5-C10ヘテロアリール基またはヒドロキシ基から選ばれる1つまたは複数の置換基によって置換されてもよく、
R5はH、F、Cl、Br、I、CN、C1-3アルキル基またはC1-3ハロアルキル基から選ばれる。
別の局面によれば、本発明の薬物組成物は、式(I)の化合物、本発明に挙げられた化合物、または実施例1〜18の化合物、および薬学的に許容可能な担体、佐剤、または賦形剤を含むことを特徴とする。本発明の組成物における化合物の量は、生物モデルまたは患者の体内のプロテインキナーゼを効果的且つ検出可能に阻害できる。
本発明の薬物組成物は、式(I)に示す化合物または本発明に挙げられた化合物、および薬学的に許容可能な担体、佐剤または賦形剤を含むことを特徴とする。本発明の組成物における化合物の量は、プロテインキナーゼ、たとえばc-Met、VEGFR-2、AxlまたはRETの活性を効果的且つ検出可能に阻害できる。本発明の化合物またはその組成物は、抗腫瘍薬として、患者の治療またはc-Met、VEGFR-2、AxlまたはRETシグナル応答による有害作用の軽減に用いられる。
室温条件において、2-メトキシ-5-ニトロフェノール(5g、29.6mmol)をN,N-ジメチルホルムアミド(DMF)60mLに溶解して、磁気撹拌し、無水K2CO3(6.1g、44.2mmol)を加えた。次に、この系に臭化ベンジル(5.56g、32.5mmol)をゆっくりと加えて、40℃に昇温し、一晩反応させて、TLCモニタリング(石油エーテル:アセトン=20:5、Rf=0.4)を行った。減圧蒸留により大部分のDMFを除去して、撹拌しながら、残った系を氷水に注入して、大量の固体を析出させた。濾過して、濾液が無色になるまで濾過ケーキをアルカリ溶液で洗浄し、濾過ケーキを乾燥して、暗赤色の固体を得た。収率は99%であった。
2-ベンジルオキシ-1-メトキシ-4-ニトロベンゼン(7.1g、23.3mmol)、NH4Cl(4.4g、82.2mmol)を200mLナシフラスコに投入して、それにエタノール(72mL)、水(24mL)を加えた。室温下、磁気撹拌の条件において、鉄粉(12.3g、219mmol)を加えた。1時間還流反応させて、TLCモニタリング(石油エーテル:アセトン=20:7、Rf=0.4)を行った。50℃に冷却して、珪藻土で濾過し、濾液を減圧濃縮してエタノールをできるだけ除去し、水を加えて酢酸エチルで抽出した。有機相を飽和K2CO3で2回洗浄して、水で2回洗浄し、無水硫酸ナトリウムで乾燥して濃縮し、黒色固体を得た。収率は84%であった。
3-ベンジルオキシ-4-メトキシアニリン(5g、21.7mmol)、イソプロピリデンマロネート(3.756g、26mmol)を無水エタノール(55mL)に溶解した。磁気撹拌しながら、それにオルトギ酸トリエチル(3.86g、26mmol)をゆっくりと加えて、次に加熱して1時間還流し、大量の茶緑色固体を析出させた。氷浴下で2時間撹拌し続け、濾過して、濾過ケーキを冷却した無水エタノールで洗浄して、茶緑色の固体を得た。収率は92%であった。
5-(((3-ベンジルオキシ)-4-メトキシフェニル)メチン)-2,2-ジメチル-1,3-ジオキサン-4,6-ジオン(5g、13mmol)をo-ジクロロベンゼン(40mL)に加えて、懸濁液を得た。180℃に加熱して、7時間反応させ、TLCモニタリング(ジクロロメタン:メタノール=20:1、Rf=0.2)を行った。室温まで冷却した後、氷浴下で2時間撹拌し続け、濾過して、濾過ケーキを冷却したo-ジクロロベンゼンで洗浄し、さらにエーテルで洗浄し、乾燥して浅褐色の固体を得た。収率は54%であった。
7-ベンジルオキシ-6-メトキシ-キノリン-4-オール(2g、7.1mmol)を再蒸留トルエン(10mL)に加えて、懸濁液を得て、再蒸留POCl3(1.1g、7.2mmol)をゆっくりと加えた。120℃に加熱して、1.5時間反応させ、TLCモニタリング(石油エーテル:アセトン=20:6、Rf=0.4)を行った。室温まで冷却して、水を加え、3M NaOH溶液でpH=8に調整して、濾過し、水洗して乾燥し、浅褐色の固体を得た。収率は90%であった。
7-ベンジルオキシ-4-クロロ-6-メトキシ-キノリン(1.675、5.58mmol)、氷酢酸(10mL)を50mLナシフラスコに加え、磁気撹拌しながら、大量の白色固体を発生させた。次に、系に臭化水素水溶液(40%、10mL)を加えて、80℃に昇温して3時間反応させた。反応系を45℃程度に冷却して、エーテル80mLに注入して撹拌し、大量の白色固体を析出させ、吸引濾過、エーテル洗浄、真空乾燥を行って白色固体を得た。収率は80%であった。
4-クロロ-6-メトキシキノリン-7-オール(50mg、0.24mmol)をTHF/H2O混合溶媒(3mL、THF/H2O=1:1、V/V)に溶解して、それにNaOH(30mg、0.75mmol)とメチルプロピレンオキサイド(172mg、2.4mmol)を順次加えた。45℃で72時間撹拌し、酢酸エチルで希釈した後、1N NaOH(10mL×4)で母液を洗浄し、次に飽和食塩水で洗浄して、有機相を無水硫酸ナトリウムで乾燥した。カラムクロマトグラフィー精製(TLC、石油エーテル:アセトン=20:5、Rf=0.45)を行って白色固体を得た。収率は42.4%であった。
1-((4-クロロ-6-メトキシキノリン-7-イル)オキソ)-2-メチルプロパン-2-オール(570mg、2.02mmol)と2-フルオロ-4-ニトロフェノール(475mg、3.02mmol)を再蒸留トルエン(10mL)に懸濁させ、次に反応系にN,N-ジイソプロピルエチルアミン(DIPEA、520mg、4.03mmol)を加えた。油浴温度が120℃の条件において、48時間反応させた。酢酸エチルで反応系を希釈して、次に1N NaOHで有機相を洗浄して、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。カラムクロマトグラフィー精製(TLC、石油エーテル:アセトン=20:8、Rf=0.3)を行って灰色固体を得た。収率は53%であった。
1-(4-(2-フルオロ-4-ニトロフェノキシ-6-メトキシキノリン-7-イル)オキソ)2-メチルプロパン-2-オール(410mg、1.02mmol)、塩化アンモニウム(163mg、3.05mmol)、エタノール:水=3:1(12mL)を25mLナシフラスコに加えて、鉄粉(399mg、7.125mmol)を加え、油浴温度80℃で、1時間反応させた。50℃程度に冷却した後、珪藻土で吸引濾過し、濾過ケーキを酢酸エチルで洗浄した。母液を酢酸エチルで抽出して、有機相を合わせた後、無水硫酸ナトリウムで乾燥し、カラムクロマトグラフィー精製を行って浅褐色の固体を得た。収率は84%であった。
1-((4-(4-アミノ-2-フルオロフェニル)-6-メトキシキノリン-7-イル)オキソ)2-メチルプロパン-2-オール(60mg、0.16mmol)と5-クロロ-3-(4-フルオロフェニル)-1,6-ナフチリジン-4(1H)-オン(44mg、0.16mmol)を25mLナシフラスコに加え、次にイソプロパノール(6mL)を加えて、磁気撹拌しながら、p-トルエンスルホン酸一水和物(PTSA・H2O、37mg、0.195mmol)を加え、90℃に昇温して1時間反応させた。不溶分を濾過して、濾過ケーキをイソプロパノールで洗浄した後、乾燥して白色固体を得た。1H NMR (600 MHz, DMSO-d6): δ 13.40 (s, 1H), 12.96 (s, 1H), 8.88 (d, J = 6.3 Hz, 1H), 8.23 - 8.33 (m, 2H), 8.11 (d, J = 6.0 Hz, 1H), 7.79 (s, 1H), 7.77 - 7.71 (m, 2H), 7.69 (s, 1H), 7.68 - 7.63 (m, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.29 (t, J = 8.4 Hz, 2H), 7.17 (d, J = 4.2 Hz, 1H), 7.01 (d, J = 5.7 Hz, 1H), 4.07 (s, 3H), 3.99 (s, 2H), 1.29 (s, 6H).
7-ベンジルオキシ-4-クロロ-6-メトキシキノリン(2.5g、8.3mmol)、2-フルオロ-4-ニトロフェノール(2.6g、16.6mmol)に再蒸留トルエン(25mL)を加え、磁気撹拌しながら、DIPEA(2.7g、20.9mmol)を加え、120℃に加熱して48時間還流し、TLCモニタリング(石油エーテル:アセトン=20:8、Rf=0.4)をした。室温まで冷却した後、酢酸エチル200mLを加え、1M NaOH溶液で有機相を、水相が無色になるまで洗浄し、有機相を無水硫酸ナトリウムで乾燥して、有機相を濃縮させ、エーテルを加えて再結晶化し、浅褐色の固体を得た。収率は80%であった。
7-ベンジルオキシ-4-(2-フルオロ-4-ニトロフェノキシ)-6-メトキシキノリン(1.5g、3.6mmol)に氷酢酸10mLを加えて撹拌し、大量の白色固体を発生させた。次に、それに臭化水素水溶液(40%、10mL)を加えて、80℃に加熱し、4時間反応させて、TLCモニタリング(ジクロロメタン:メタノール=40:1、Rf=0.2)を行った。室温まで冷却した後、この系をエーテル100mLに注入し、2時間撹拌した。濾過して、濾過ケーキをエーテルで洗浄し、白色固体を得た。収率は90%であった。
4-(2-フルオロ-4-ニトロフェノキシ)-6-メトキシキノリン-7-オール(500mg、1.51mmol)、無水炭酸カリウム(627mg、4.54mmol)を25mLナシフラスコに加え、次にDMF(13mL)、エピクロロヒドリン(700mg、7.56mmol)を加えて、80℃に昇温して、10時間反応させた。室温まで冷却した後、水中に注入し、酢酸エチルで抽出して、有機相を合わせてから乾燥し、カラムクロマトグラフィーを行って化合物を得た。収率は30%であった。
4-(2-フルオロ-4-ニトロフェノキシ)-6-メトキシ-7-(エチレンオキシド-2-イルメトキシ)キノリン(146mg、0.378mmol)をメタノール(10mL)とジクロロメタン(15mL)の混合溶媒に溶解した。撹拌しながら、それにPd/C(30mg)を加えて、水素雰囲気下で、室温で一晩反応させた。反応液から溶媒を除去した後、カラムクロマトグラフィー精製を行って浅黄色の固体を得た。収率は63%であった。
1-((4-(4-アミノ-2-フルオロフェニル)キノリンー7-イル)オキソ)プロパン-2-オールと5-クロロ-3-(4-フルオロフェニル)-1,6-ナフチリジン-4(1H)-オン(44mg、0.16mmol)を10mLナシフラスコに加え、次にイソプロパノール(4mL)を加え、磁気撹拌しながら、PTSA・H2O(38mg、0.2mmol)を加え、90℃に昇温して1時間反応させた。室温まで冷却した後、固体を析出させないと、イソプロパノールを除去し、カラムクロマトグラフィー精製を行って黄色の固体を得た。収率は47%であった。1H NMR (400 MHz, DMSO-d6): δ 13.22 (s, 1H), 12.49 (s, 1H), 8.67 (d, J = 6.0 Hz, 1H), 8.44 (d, J = 13.6 Hz, 1H), 8.17 (d, J = 5.6 Hz, 2H), 7.74 - 7.68 (m, 2H), 7.67 (s, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.50 (s, 1H), 7.47 (d, J = 6.8 Hz, 1H), 7.24 (t, J = 8.0 Hz, 2H), 6.88 (d, J = 5.4 Hz, 1H), 6.79 (d, J = 6.0 Hz, 1H), 5.01 (s, 1H), 4.07 - 4.08-4.00 (m, 5H), 1.95 - 1.87 (m, 1H), 1.23 (d, J = 5.2 Hz, 3H).
5-クロロ-3-(4-フルオロフェニル)-1,6-ナフチリジン-4(1H)-オンを5-クロロ-3-フェニル-1,6-ナフチリジン-4(1H)-オンに変更する以外、製造方法は実施例1と同様である。1H NMR (600 MHz, DMSO-d6): δ 13.45 (s, 1H), 12.93 (s, 1H), 8.89 (d, J = 6.6 Hz, 1H), 8.25 - 8.34 (m, 2H), 8.11 (d, J = 4.8 Hz, 1H), 7.79 (s, 1H), 7.67 - 7.72 (m, 3H), 7.65 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 7.8 Hz, 2H), 7.38 (t, J = 7.2 Hz, 1H), 7.17 (d, J = 4.2 Hz, 1H), 7.01 (d, J = 5.7 Hz, 1H), 4.07 (s, 3H), 3.99 (s, 2H), 1.29 (s, 6H).
窒素保護下で、-70℃の条件において、4-クロロ-7-メトキシキノリン(0.95g、4.9mmol)のジクロロメタン(45mL)溶液にBBr3(4.9g、19.6mmol)のジクロロメタン(15mL)希釈溶液をゆっくりと滴下した。次に反応系を室温まで昇温して、それにベンジルトリエチルアンモニウムクロライド(TEBA、0.19g、0.83mmol)のジクロロメタン(5mL)希釈溶液を加え、室温で20時間撹拌した。TLCモニタリング(石油エーテル:アセトン=20:5、Rf=0.4)を行った。氷浴で冷却して撹拌しながら、この系に氷水(25mL)をゆっくりと加えてBBr3をクエンチした。大部分のジクロロメタンを除去して、1N NaOHで残りの溶液をpH=7に調整し、大量の白色固体を析出させて、吸引濾過し、真空(45℃)乾燥を24時間行って化合物を得た。収率は90%であった。1H NMR (600 MHz, DMSO-d6): δ 10.54 (s, 1H), 8.69 (d, J = 4.8 Hz, 1H), 8.06 (d, J = 9.6 Hz, 1H), 7.51 (d, J = 4.8 Hz, 1H), 7.30 - 7.36 (m, 2H).
4-クロロキノリン-7-オール(100mg、0.56mmol)をTHF/H2Oの混合溶媒(8mL、THF/H2O=1:1、V/V)に溶解して、それにNaOH(66.6mg、1.67mmol)とメチルプロピレンオキシド(400mg、5.56mmol)を順次加えた。45℃で24時間撹拌して、酢酸エチルで希釈し、次に1N NaOH(10mL×4)で母液を洗浄し、さらに飽和食塩水で洗浄し、有機相を無水硫酸ナトリウムで乾燥した。カラムクロマトグラフィー精製(TLC、石油エーテル:アセトン=20:5、Rf=0.45)を行って、白色固体を得た。収率は63%であった。1H NMR (600 MHz, DMSO-d6): δ 7.88 (d, J = 4.8 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 6.70 (d, J = 4.8 Hz, 1H), 6.52 - 6.57 (m, 2H), 3.88 (s, 1H), 3.06 (s, 2H), 0.41 (s, 6H).
1-((4-クロロキノリン-7-イル)オキソ)-2-メチルプロパン-2-オール(0.456g、1.8mmol)と2-フルオロ-4-ニトロフェノール(0.568g、3.6mmol)を再蒸留トルエン(20mL)に懸濁させ、次に反応系にN,N-ジイソプロピルエチルアミン(0.583g、4.5mmol)を加えた。油浴の温度が120℃の条件において、30時間反応させた。酢酸エチルで反応系を希釈して、次に1N NaOHで有機相を洗浄して、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。カラムクロマトグラフィー精製(TLC、石油エーテル:アセトン=20:8、Rf=0.3)を行って、灰色固体を得た。収率は90%であった。1H NMR (600 MHz, DMSO-d6): δ 8.72 (d, J = 4.8 Hz, 1H), 8.48 (d, J = 10.2 Hz, 1H), 8.20 (d, J = 9.0 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.64 (t, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.36 (d, J = 9.0 Hz, 1H), 6.80 (d, J = 4.8 Hz, 1H), 4.76 (s, 1H), 3.93 (s, 2H), 1.27 (s, 6H).
1-((4-(2-フルオロ-4-ニトロフェニル)キノリン-7-イル)オキソ)-2-メチルプロパン-2-オール(54mg、0.145mmol)をメタノール(10mL)に溶解した。撹拌しながら、それにPd/C(11mg)を加え、水素雰囲気下で、室温で5時間反応させた。溶媒を除去してカラムクロマトグラフィー精製(TLC、石油エーテル:アセトン=20:10、Rf=0.3)を行って灰色固体を得た。収率は90%であった。1H NMR (400 MHz, DMSO-d6): δ 8.55 (d, J = 4.2Hz, 1H), 8.18 (d, J = 9.0 Hz, 1H), 7.33 (s, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.06 (t, J = 12.0 Hz, 1H), 6.53 (d, J = 12.8 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 4.8 Hz, 1H), 5.51 (s, 2H), 4.72 (s, 1H), 3.89 (s, 2H), 1.26 (s, 6H).
1-((4-(4-アミノ-2-フルオロフェニル)キノリン-7-イル)オキソ)-2-メチルプロパン-2-オール(40mg、0.117mmol)と5-クロロ-3-(4-フルオロフェニル)-1,6-ナフチリジン-4(1H)-オン(33mg、0.12mmol)を25mLナシフラスコに加え、次にイソプロパノール(8mL)を加え、磁気撹拌しながら、濃塩酸(1滴)を加えて、90℃に昇温して1時間反応させた。不溶分を濾過して、濾過ケーキをジクロロメタンとメタノールの混合溶媒10mLに溶解して、等当量のトリエチルアミンを加え、室温で0.5時間撹拌し、析出した固体を吸引濾過した後に乾燥し、白色固体を得た。収率は88%であった。1H NMR (600 MHz, DMSO-d6): δ 13.41 (s, 2H), 9.03 (d, J = 6.0 Hz, 1H), 8.54 (d, J = 9.0 Hz, 1H), 8.30 (d, J = 3.6 Hz, 1H), 8.21 (s, 1H), 8.06 (d, J = 4.8 Hz, 1H), 7.78 (s, 1H), 7.77 - 7.72 (m, 2H), 7.72 - 7.63 (m, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.29 (t, J = 8.4 Hz, 2H), 7.10 (d, J = 5.4 Hz, 1H), 4.00 (s, 2H), 1.29 (s, 6H).
5-クロロ-3-(4-フルオロフェニル)-1,6-ナフチリジン-4(1H)-オンを5-クロロ-3-(2-フルオロフェニル)-1,6-ナフチリジン-4(1H)-オンに変更する以外、製造方法は実施例4と同様である。1H NMR (600 MHz, DMSO-d6): δ 13.22 (s, 1H), 13.08 (s, 1H), 8.98 (d, J = 3.0 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.43 (d, J = 11.4 Hz, 1H), 8.15 - 8.24 (m, 2H), 7.79 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.55 - 7.75 (m, 2H), 7.48 - 7.54 (m 1H), 7.43 - 7.47 (m, 1H), 7.26 - 7.33 (m, 2H), 7.07 - 7.12 (m, 1H), 7.01 - 7.06 (m, 1H), 4.00 (s, 2H), 1.29 (s, 6H).
5-クロロ-3-(4-フルオロフェニル)-1,6-ナフチリジン-4(1H)-オンを5-クロロ-3-(3-フルオロフェニル)-1,6-ナフチリジン-4(1H)-オンに変更する以外、製造方法は実施例4と同様である。1H NMR (600 MHz, DMSO-d6): δ 13.35 (s, 2H), 9.03 (d, J = 6.6 Hz, 1H), 8.54 (d, J = 9.0Hz, 1H), 8.37 (d, J = 5.4 Hz, 1H), 8.25 (d, J = 12.6 Hz, 1H), 8.09 (d, J = 6.0 Hz, 1H), 7.77 (s, 1H), 7.63 - 7.72 (m, 2H), 7.57 - 7.66 (m, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.49 (dd, J = 14.4, 7.2 Hz, 1H), 7.25 - 7.33 (m, 1H), 7.21 (t, J = 8.4 Hz, 1H), 7.10 (d, J = 6.3 Hz, 1H), 4.00 (s, 2H), 1.29 (s, 6H).
5-クロロ-3-(4-フルオロフェニル)-1,6-ナフチリジン-4(1H)-オンを5-クロロ-3-フェニル-1,6-ナフチリジン-4(1H)-オンに変更する以外、製造方法は実施例4と同様である。1H NMR (600 MHz, DMSO-d6): δ 13.45 (s, 1H), 13.27 (s, 1H), 9.03 (d, J = 6.6 Hz, 1H), 8.54 (d, J = 9.3 Hz, 1H), 8.28 (d, J = 5.4 Hz, 1H), 8.24 (d, J = 9.3 Hz, 1H), 8.07 (d, J = 6.0 Hz, 1H), 7.77 (s, 1H), 7.68 - 7.73 (m, 3H), 7.66 (d, J = 9.6Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 7.5, 7.5 Hz, 2H), 7.38 (t, J = 7.2, 1H), 7.24 - 7.33 (m, 1H), 7.08 (d, J = 6.0 Hz, 1H), 4.00 (s, 2H), 1.29 (s, 6H).
2-メトキシ-5-ニトロフェノールを2-メトキシ-4-ニトロフェノールに変更する以外、製造方法は実施例1と同様である。1H NMR (600 MHz, DMSO-d6): δ 13.38 (s, 1H), 12.90 (s, 1H), 8.87 (d, J = 6.0 Hz, 1H), 8.31 (d, J = 9.0 Hz, 1H), 8.26 (d, J = 3.6 Hz, 1H), 8.12 (d, J = 4.2 Hz, 1H), 7.81 (s, 1H), 7.71 - 7.76 (m, 1H), 7.68 (s, 1H), 7.58 - 7.64 (m, 1H), 7.49 (d, J = 7.2 Hz 1H), 7.28 (t, J = 8.4 Hz, 2H), 7.10 - 7.16 (m, 2H), 7.00 (d, J = 4.8 Hz, 1H), 4.07 (s, 3H), 4.02 (s, 2H), 1.27 (s, 6H).
2-メトキシ-5-ニトロフェノールを2-メトキシ-4-ニトロフェノール、5-クロロ-3-(4-フルオロフェニル)-1,6-ナフチリジン-4(1H)-オンを5-クロロ-3-フェニル-1,6-ナフチリジン-4(1H)-オンに変更する以外、製造方法は実施例1と同様である。1H NMR (400 MHz, DMSO-d6): δ 13.39 (s, 1H), 12.85 (s, 1H), 8.85 (d, J = 6.8 Hz, 1H), 8. 03 - 8.23 (m, 2H), 8.08 (d, J = 6.4 Hz, 1H), 7.78 (s, 1H), 7.67 - 7.59 (m, 4H), 7.46 - 7.40 (m, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.15 - 7.09 (m, 2H), 6.97 (d, J = 6.4 Hz, 1H), 4.06 (s, 3H), 4.01 (s, 2H), 1.27 (s, 6H).
5-((3-フルオロ-4-((7-(2-ヒドロキシプロピル)-6-メトキシキノリン-4-イル)オキソ)フェニル)アミノ)-3-(4-フルオロフェニル)-1,6-ナフチリジン-4(1H)-オン(100mg、0.13mmol)と無水炭酸カリウム(95mg、0.69mmol)を10mLナシフラスコに加え、DMF(3mL)を加え、30分間磁気撹拌して、次にヨードメタン(71mg、0.52mmol)を加え、4時間撹拌し続けた。この系を水(12mL)に注入して、撹拌し、不溶分を濾過して、濾過ケーキを水で洗浄し、真空乾燥して、淡黄色の固体を得た。収率は73.5%であった。1H NMR (400 MHz, DMSO-d6): δ 13.57 (s, 1H), 8.97 (d, J = 6.8 Hz, 1H), 8.50 (d, J = 9.2 Hz, 1H), 8.40 (s, 1H), 8.35 (d, J = 12.8 Hz, 1H), 8.23 (d, J = 6.4 Hz, 1H), 7.83 - 7.69 (m, 3H), 7.68 - 7.54 (m, 3H), 7.38 - 7.23 (m, 2H), 7.14 (d, J = 5.2 Hz, 1H), 7.04 (d, J = 6.4 Hz, 1H), 3.98 (s, 2H), 3.89 (s, 3H), 1.28 (s, 6H).
ヨードメタンをヨードエタンに変更する以外、製造方法は実施例10と同様である。1H NMR (400 MHz, DMSO-d6): δ 13.47 (s, 1H), 8.58 (d, J = 5.2 Hz, 1H), 8.37 (dd, J = 13.6, 2.0 Hz, 1H), 8.34 (s, 1H), 8.27 (d, J = 6.4 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 5.6 Hz, 1H), 7.72 (d, J = 5.6 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.41 - 7.36 (m, 2H), 7.32 (dd, J = 9.0, 2.4 Hz, 1H), 7.26 (t, J = 8.8 Hz, 2H), 7.04 (d, J = 6.4Hz, 1H), 6.48 (d, J = 5.2 Hz, 1H), 4.74 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 3.91 (s, 2H), 1.39 (t, J = 7.2 Hz, 3H), 1.27 (s, 6H).
ヨードメタンをヨードプロパンに変更する以外、製造方法は実施例10と同様である。1H NMR (400 MHz, DMSO-d6): δ 13.45 (s, 1H), 8.58 (d, J = 3.6 Hz, 1H), 8.30 - 8.40 (m, 2H ), 8.18 - 8.28 (m, 2H), 7.66 - 7.76 (m, 2H), 7.49 (d, J = 7.0 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.20 - 7.33 (m, 3H), 7.04 (d, J = 4.8 Hz, 1H), 6.48 (d, J = 5.2 Hz, 1H), 4.71 (s, 1H), 4.17 - 4.30 (m, 2H), 3.90 (s, 2H), 1.74 - 1.88 (m, 2H), 1.27 (s, 6H), 0.90 - 1.02 (m, 3H).
ヨードメタンを2-ヨードプロパンに変更する以外、製造方法は実施例10と同様である。1H NMR (400 MHz, DMSO-d6): δ 13.56 (s, 1H), 8.58 (d, J = 5.2 Hz, 1H), 8.36 (dd, J = 13.6, 2.0 Hz, 1H), 8.26 (d, J = 6.4 Hz, 1H), 8.19 - 8.24 (m, 2H), 7.75 - 7.66 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.43 - 7.34 (m, 2H), 7.31 (dd, J = 9.2, 2.2 Hz, 1H), 7.23 - 7.28 (m, 2H), 7.18 (d, J = 6.6 Hz, 1H), 6.47 (d, J = 5.0 Hz, 1H), 5.06 - 4.95 (m, 1H), 4.72 (s, 1H), 3.90 (s, 2H), 1.53 (d, J = 6.4 Hz, 6H), 1.27 (s, 6H).
ヨードメタンをブロモシクロプロパンに変更する以外、製造方法は実施例10と同様である。1H NMR (400 MHz, DMSO-d6): δ 13.46 (s, 1H), 8.57 (d, J = 5.2 Hz, 1H), 8.40 - 8.32 (m, 2H), 8.26 (d, J = 6.0 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 5.6 Hz, 1H), 7.69 (d, J = 5.8 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 9.2, 2.0 Hz, 1H), 7.20 - 7.28 (m, 2H), 7.13 (d, J = 6.2 Hz, 1H), 6.47 (d, J = 5.0 Hz, 1H), 4.71 (s, 1H), 4.17 (d, J = 6.8 Hz, 1H), 3.90 (s, 2H), 1.41 - 1.32 (m, 1H), 1.26 (s, 6H), 0.53 - 0.60 (m, 2H), 0.48 - 0.52 (m, 2H).
ヨードメタンをエピブロモヒドリンに変更する以外、製造方法は実施例10と同様である。1H NMR (400 MHz, DMSO-d6): δ 13.14 (s, 1H), 8.55 (d, J = 5.2 Hz, 1H), 8.34 - 8.16 (m, 3H), 7.56 (s, 1H), 7.54 (d, J = 5.4 Hz, 1H), 7.52 (d, J = 5.4 Hz, 1H), 7.46 - 7.40 (m, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.28 - 7.21 (m, 2H), 7.20 - 7.14 (m, 1H), 7.13 - 7.09 (m, 1H), 6.63 (d, J = 6.2 Hz, 1H), 6.44 (d, J = 5.2 Hz, 1H), 4.51 (dd, J = 15.6, 5.6 Hz, 1H), 4.03 (dd, J = 15.6, 5.6 Hz, 1H), 3.96 (s, 2H), 3.42 - 3.35 (m, 1H), 2.97 - 2.92 (m, 1H), 2.62 - 2.56 (m, 1H), 1.40 (s, 6H).
ヨードメタンを2-ブロモエチルメチルエーテルに変更する以外、製造方法は実施例10と同様である。1H NMR (400 MHz, DMSO-d6): δ 13.44 (s, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.37 (dd, J = 13.6, 2.0 Hz, 1H), 8.26 (d, J = 6.0 Hz, 1H), 8.24 - 8.19 (m, 2H), 7.71 (d, J = 5.6 Hz, 1H), 7.69 (d, J = 6.0 Hz, 1H), 7.51 (dd, J = 9.2, 1.2 Hz, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 9.2, 2.4 Hz, 1H), 7.23 - 7.29 (m, 2H), 7.08 (d, J = 6.4 Hz, 1H), 6.48 (d, J = 5.2 Hz, 1H), 4.73 (s, 1H), 4.49 (t, J = 4.2, 4.0 Hz, 2H), 3.91 (s, 2H), 3.70 (t, J = 4.2, 4.0 Hz, 2H), 3.26 (s, 3H), 1.27 (s, 6H).
ヨードメタンをブロモエタノールに変更する以外、製造方法は実施例10と同様である。1H NMR (400 MHz, DMSO-d6): δ 13.65 (s, 1H), 8.99 (d, J = 6.4 Hz, 1H), 8.50 (d, J = 9.2 Hz, 1H), 8.37 - 8.26 (m, 2H), 8.16 (d, J = 6.2 Hz, 1H), 7.73 (d, J = 6.2 Hz, 1H), 7.71 (d, J = 5.6 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 4.8 Hz, 1H), 7.32 - 7.23 (m, 2H), 7.19 (d, J = 6.4 Hz, 1H), 7.14 (d, J = 6.0 Hz, 1H), 5.15 ( br ), 4.51 - 4.37 (m, 2H), 3.98 (s, 2H), 3.82 - 3.71 (m, 2H), 1.27 (s, 6H).
ヨードメタンを臭化ベンジルに変更する以外、製造方法は実施例10と同様である。1H NMR (400 MHz, DMSO-d6): δ 13.37 (s, 1H), 8.61 - 8.53 (m, 2H), 8.32 (d, J = 13.6 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 8.16 (d, J = 6.0 Hz, 1H), 7.80 - 7.71 (m, 2H), 7.49 (d, J = 8.2 Hz, 1H), 7.42 - 7.32 (m, 4H), 7.32 - 7.22 (m, 6H), 6.86 (d, J = 5.4 Hz, 1H), 6.46 (d, J = 5.0 Hz, 1H), 5.56 (s, 2H), 4.70 (s, 1H), 3.90 (s, 2H), 1.26 (s, 6H).
ステップ1):3-フルオロ-4-((7-(2-メトキシ-2-メチルプロポキシ)キノリン-4-イル)オキソ)アニリンの合成
1-((4-(4-アミノ-2-フルオロフェニル)キノリン-7-イル)オキソ)-2-メチルプロパン-2-オール(324mg、0.84mmol)と無水炭酸カリウム(170mg、1.23mmol)を25mLナシフラスコに加え、DMF(10mL)を加え、磁気撹拌しながら、ヨードメタン(310mg、2.18mmol)を加えて、2.5時間撹拌し続けた。この系を水(40mL)に注入して撹拌し、不溶分を濾過して、濾過ケーキを水で洗浄し、真空乾燥して、淡黄色固体を得た。
3-フルオロ-4-((7-(2-メトキシ-2-メチルプロポキシ)キノリン-4-イル)オキソ)アニリン(42mg、0.117mmol)と5-クロロ-3-(4-フルオロフェニル)-1,6-ナフチリジン-4(1H)-オン(33mg、0.12mmol)を25mLナシフラスコに加え、次にイソプロパノール(8mL)を加えて、磁気撹拌しながら、濃塩酸(1滴)を加えて、90℃に昇温して1時間反応させた。不溶分を濾過して、濾過ケーキをジクロロメタンとメタノールの混合溶媒10mLに溶解し、等当量のトリエチルアミンを加えて、室温で0.5時間撹拌し、析出した固体を吸引濾過した後、乾燥して白色固体を得た。1H NMR (600 MHz, DMSO-d6): δ 13.34 (s, 1H), 12.86 (s, 1H), 8.84 (d, J = 6.4 Hz, 1H), 8.24 - 8.29 (m, 2H), 8.08 (d, J = 6.4 Hz, 1H), 7.67 - 7.76 (m, 3H ), 7.56 - 7.62 (m, 2H ), 7.46 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.8 Hz, 2H), 7.13 (d, J = 6.8 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 6.0 Hz, 1H), 4.10 (s, 2H), 3.27 (s, 3H), 1.30 (s, 6H).
材料および方法:c-Met、VEGFR-2、AxlおよびRETなどのキナーゼは、Invitrogen製のものである。HTRF KinEASE;TK kit(Cisbio社);384ウェルプレート(Greiner社);ATP(sigma社)、MgCl2(sigma社);PHERAstar FS多機能マイクロプレートリーダー(BMG社);低速遠心分離機(StaiteXiangyi社);恒温槽(Binder社)。使用される対照化合物はWO2013097753に開示されているモデル化合物AとBであり、構造は以下のとおりである。
化合物作業溶液の調製:試験前に、分包した化合物を冷蔵庫から取り出して、純粋なDMSOで50×所望の濃度に希釈した後、脱イオン水で化合物を4×所望の濃度に希釈した。
Optic module HTRF(登録商標)
積分遅延(Integration delay、lag time) 50 μs
積分時間(Integration time)400 μs
フラッシュの数(Number of flashes)200
ウェルごとに読み出した生データについて、比=665nm/620 nm;
化合物濃度の対数を横座標、阻害率を縦座標として、GraphPad Prism 5において、非線形曲線:log(inhibitor)vs.response--Variable slopeをフィッティングし、IC50を酵素活性阻害率が50%であるときの被測定化合物濃度として求めた。
実験結果:c-Met、VEGFR-2、AxlおよびRETキナーゼ活性半数阻害濃度(IC50、nM)
本発明に係る式(I)に示す構造を有する化合物によるc-MetとVEGFR-2への半数阻害濃度(IC50)を表1に示す。
比較のために、実施例4と比較化合物Cをポリエチレングリコール400水溶液(70%)としてラットに投与した。静脈内投与の場合、ラットに1mg/kgの用量を投与した。経口投与の場合、ラットに5mg/kgの用量を投与した。実施例4と比較化合物Cの経口投与群については、投与してから15、30、45分、1、2、4、6、8、10、24時間後に、それぞれ血液サンプルを約0.3mL収集してヘパリン化エッペンドロフチューブに投入し、実施例4と比較化合物Cの静脈内投与群については、投与してから5、15、30分、1、2、4、6、8、10および24時間後に、それぞれ血液サンプルを約0.3mL収集してヘパリン化エッペンドロフチューブに投入し、氷上に仮貯蔵した後に遠心処理した。全血8000rpmで5分遠心処理した後、血漿を収集して血漿を96ウェルプレートに移し、-20℃でLC-MS/MS検出まで保存した。
ピーク濃度Cmax:実測値を用いた。
薬物濃度時間曲線下面積AUC0-t値:台形法で計算した。AUC0-∞=AUC0-t+Ct/ke、ここで、Ctは時間点を測定可能な最後の血中薬物濃度、keは消失速度定数であった。
消失半減期t1/2=0.693/ke
絶対バイオアベイラビリティF=Doseiv*AUC0-t、ig/Doseig*AUC0-t、iv×100%
本発明の化合物の薬効については、腫瘍を移植した標準マウスモデルによって評価した。ヒト腫瘍細胞(U87MG神経膠腫細胞、MKN45胃腺癌細胞、Caki-1腎臓癌細胞、HUH 7肝癌細胞、NCI-H441肺腺癌上皮細胞、MDA-MB-231乳癌細胞、SMMC-7721肝癌細胞、ATCC)を培養して収集した後、後腹側皮下から6-7週齢の雌性ヌードマウス(BALB/cA nu/nu、上海SLAC動物実験室)に接種した。腫瘍体積が150mm3になったとき、動物をランダムに溶媒対照群(70%PEG-400の水溶液)と化合物群(群ごとに6匹の動物)に分けた。その後、腫瘍細胞を接種してから0-22日間のいずれかの時点から、化合物を動物に強制的経口投与し(3-10mpk/dose、70%PEG-400の水溶液に溶解した)、通常、試験中に1日ごとに1回行った。
腫瘍の進化は腫瘍体積と時間の関係によって評価した。皮下腫瘍の長軸(L)と短軸(W)はキャリパーで1週間あたり2回測定し、腫瘍の体積(TV)は式(L×W2)/2)に従って計算した。TGIは溶媒群マウスの腫瘍体積の中央値と薬物群マウスの腫瘍体積の中央値との差値で計算し、溶媒対照群の腫瘍体積中央値の百分率として示し、下式により計算した。
元の統計分析は反復測定分散分析(RMANOVA)によって行った。次に、Scheffe psot hoc試験方法を用いて多重比較を行った。独立溶媒(70%PEG-400など)を陰性対照とした。
その他、本発明の様々な異なる実施形態も任意に組み合わせてもよく、本発明の主旨に逸脱しない限り、本発明に開示されているものと考えるべきである。
Claims (10)
- 式(I)に示す構造を有するナフチリジン化合物、または、その立体異性体、幾何異性体、互変異性体、窒素酸化物、水和物、溶媒和物、代謝産物、薬学的に許容可能な塩またはそのプロドラッグ。
(ただし、
R1とR2はH、C1-C3アルキル基から選ばれ、
R3はH、C1-C3アルコキシ基から選ばれ、
R4はH、C1-C6アルキル基、3-8員全炭素単環式シクロアルキル基、3-8員ヘテロ脂環基から選ばれ、そのうち、C1-C6アルキル基、3-8員全炭素単環式シクロアルキル基、3-8員ヘテロ脂環基はさらに、C1-C6アルキル基、C1-C6アルコキシ基、3-8員ヘテロ脂環基、C6-C10アリール基、C5-C10ヘテロアリール基またはヒドロキシ基から選ばれる1つまたは複数の置換基によって置換されてもよく、
R5はH、F、Cl、Br、I、CN、C1-3アルキル基またはC1-3ハロアルキル基から選ばれる。) - R1とR2はH、C1-C3アルキル基から選ばれ、且つR1とR2は同時に水素でない請求項2に記載の化合物。
- R4はH、C1-C6アルキル基、3-8員全炭素単環式シクロアルキル基、3-8員ヘテロ脂環C1-C6アルキレン基、C1-C6アルコキシC1-C6アルキレン基またはC6-C10アリールC1-C6アルキレン基から選ばれる請求項1に記載の化合物。
- 薬物組成物であって、
薬学的に許容可能な担体、賦形剤または希釈剤、および活性成分である請求項1〜6のいずれかに定義された化合物を含む薬物組成物。 - 請求項1〜6のいずれかに記載の化合物または請求項7に記載の組成物の、プロテインキナーゼ媒介疾患の治療薬の製造における応用。
- 前記プロテインキナーゼ媒介疾患はc-Met、VEGFR-2、AxlまたはRETに関連する疾患から選ばれることを特徴とする請求項8に記載の応用。
- 前記疾患は、結腸直腸癌、膀胱癌、乳癌、肝癌、肺癌、膵臓癌、消化器癌、白血病、卵巣癌、頭頸部癌、前立腺癌、腎臓癌、鼻咽頭癌、神経膠芽細胞腫、扁平上皮細胞癌、星細胞腫、カポジ肉腫、黒色腫、神経膠腫、泌尿生殖器癌、骨髄増殖性疾患;アテローム性動脈硬化症または肺繊維化から選ばれることを特徴とする請求項9に記載の応用。
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TW201932464A (zh) | 2018-01-18 | 2019-08-16 | 美商亞雷生物製藥股份有限公司 | 作為ret激酶抑制劑之經取代吡唑基[4,3-c]吡啶化合物 |
AU2019247766A1 (en) | 2018-04-03 | 2020-10-15 | Blueprint Medicines Corporation | RET inhibitor for use in treating cancer having a RET alteration |
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CN111961045A (zh) * | 2020-08-07 | 2020-11-20 | 南京纳丁菲医药科技有限公司 | 1,6-萘啶-4(1h)-酮化合物的合成方法 |
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