JP6207625B2 - チロシンキナーゼ阻害剤としてのインドリノン誘導体 - Google Patents
チロシンキナーゼ阻害剤としてのインドリノン誘導体 Download PDFInfo
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- JP6207625B2 JP6207625B2 JP2015545634A JP2015545634A JP6207625B2 JP 6207625 B2 JP6207625 B2 JP 6207625B2 JP 2015545634 A JP2015545634 A JP 2015545634A JP 2015545634 A JP2015545634 A JP 2015545634A JP 6207625 B2 JP6207625 B2 JP 6207625B2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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Description
一般式(I)に示される化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体:
R1は水素原子またはプロドラッグ官能基であり;
R2、R4とR5はそれぞれ独立して水素原子、ヒドロキシ、アミノ、ハロゲン原子、C1−6アルキルまたはC1−6アルコキシであり;
R3は水素原子、カルボキシ、未置換または1−3個のQ1で置換されるC1−6アルキル−OC(O)−、C1−6アルキル−SC(O)−、3−14員シクロアルキル−OC(O)−、カルバモイル、C1−3アルキルカルバモイル、ジ(C1−3アルキル)カルバモイル、6−14員アリール−OC(O)−または6−14員アリール(C1−3アルキル)−OC(O)−であり、
Q1はハロゲン原子、ヒドロキシ、アミノ、6−14員アリール、3−14員シクロアルキル、3−14員複素環基、カルボキシ、C1−3アルコキシ、C1−3アルコキシカルボニル、C1−3アルキルアミノ、ジ(C1−3アルキル)アミノ、カルバモイル、C1−3アルキルカルバモイルまたはジ(C1−3アルキル)カルバモイルであり;
R6は水素原子、未置換または1−3個のQ2で置換されるC1−6アルキル、3−14員シクロアルキル、6−14員アリール、7−12員架橋環基C0−3アルキル、7−12員スピロ環基C0−3アルキルまたは3−14員複素環基C0−3アルキルであり、
Q2はハロゲン原子、ヒドロキシ、シアノ、カルボキシ、アミノ、ニトロ、トリフルオロメチル、C1−3アルキル、C1−3アルコキシ、ヒドロキシC1−3アルキル、アミノC1−3アルキル、C1−3アルコキシC1−3アルキル、カルボキシC1−3アルコキシ、C1−3アルキルアミノ、ジ(C1−3アルキル)アミノ、C1−3アルコキシカルボニル、カルバモイル、C1−3アルキルカルバモイル、ジ(C1−3アルキル)カルバモイル、C1−3アルキルカルボニルアミノ、N−(C1−3アルキル)C1−3アルキルカルボニルアミノ、C1−3アルキルスルホニルアミノ、N−(C1−3アルキル)C1−3アルキルスルホニルアミノまたは6−14員アリールC1−3アルキルスルホニルアミノであり;
R7は水素原子、未置換または1−3個のQ3で置換されるC1−3アルキル、3−14員シクロアルキルまたは3−14員複素環基であり;
環Aはフェニルまたは5−7員複素環基であり;
R8は式(IIa)に示され、
Ra、Rb、RcとRdはそれぞれ独立して水素原子、C1−3アルキル、C1−3アルコキシ、アミノ、C1−3アルキルアミノ、ジ(C1−3アルキル)アミノ、フェニルアミノ、N−(C1−3アルキル)フェニルアミノ、ベンジルアミノまたはN−(C1−3アルキル)ベンジルアミノであり、
Reは水素原子、C1−3アルキル、C1−3アルコキシ、アミノ、C1−3アルキルアミノ、ジ(C1−3アルキル)アミノ、フェニルアミノ、N−(C1−3アルキル)フェニルアミノ、ベンジルアミノ、N−(C1−3アルキル)ベンジルアミノ、フェニルまたは3−8員単環複素環基であり、
前記3−8員単環複素環基上の炭素原子は1−3個の同じまたは異なるS(O)m、C(O)で代替されても良い、
前記C1−3アルキル、3−8員単環複素環基は1−3個のQ3で置換されても良い、
Q3はハロゲン原子、ヒドロキシ、シアノ、カルボキシ、アミノ、ニトロ、トリフルオロメチル、C1−3アルキル、C1−3アルコキシ、ジ(C1−3アルキル)アミノ、C1−3アルコキシカルボニル、カルバモイル、C1−3アルキルカルバモイル、ジ(C1−3アルキル)カルバモイルまたはC1−3アルキルカルボニルアミノであり;
R9は水素原子、ハロゲン原子、ヒドロキシ、シアノ、カルボキシ、アミノ、ニトロ、C1−3アルキル、トリフルオロメチル、C1−3アルコキシ、C1−3アルコキシカルボニル、アセチルアミノ、C1−3アルキルスルホニルアミノ、カルバモイル、C1−3アルキルカルバモイル、ジ(C1−3アルキル)カルバモイル、アミノスルホニル、C1−3アルキルアミノスルホニルまたはジ(C1−3アルキル)アミノスルホニルであり;
aとbはそれぞれ独立して0、1、2または3であり;
nは0、1または2であり、nは2である場合、R9で表される置換基は同じでも異なっていても良い;
n1は0、1、2または3であり;
n2は0または1であり;
n3は0、1、2または3であり;
mは1または2である。
一般式(I)に示される化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体である:
そのうち、Xは酸素原子または硫黄原子であり;
R1は水素原子またはプロドラッグ官能基であり;
R2、R4とR5はそれぞれ独立して水素原子であり;
R3はカルボキシ、未置換または1−3個のQ1で置換されるC1−3アルキル−OC(O)−、3−8員単環シクロアルキルOC(O)−、カルバモイルまたはベンジル−OC(O)−であり、
Q1はハロゲン原子、ヒドロキシ、アミノ、フェニル、3−6員シクロアルキル、C1−3アルコキシ、C1−3アルキルアミノまたはジ(C1−3アルキル)アミノであり;
R6は未置換または1−3個のQ2で置換される下記の官能基である:
(1)C1−3アルキル、3−8員単環シクロアルキル、アリールであり、前記シクロアルキル、アリール上の炭素原子は1−3個の同じまたは異なるN、NH、N(C1−3アルキル)、O、S(O)m、C(O)で代替されても良い、
(2)
且つ環上の炭素原子は1−3個の同じまたは異なるNH、N(C1−3アルキル)、O、S(O)m、C(O)で代替されても良い、
pは0、1、2または3であり、
rは0、1または2であり、
sは0、1または2であり、
Q2はハロゲン原子、ヒドロキシ、シアノ、カルボキシ、アミノ、ニトロ、トリフルオロメチル、C1−3アルキル、C1−3アルコキシ、ヒドロキシC1−3アルキル、アミノC1−3アルキル、C1−3アルコキシC1−3アルキル、カルボキシC1−3アルコキシ、C1−3アルキルアミノ、ジ(C1−3アルキル)アミノ、C1−3アルコキシカルボニル、カルバモイル、C1−3アルキルカルバモイル、ジ(C1−3アルキル)カルバモイル、C1−3アルキルカルボニルアミノ、N−(C1−3アルキル)C1−3アルキルカルボニルアミノ、C1−3アルキルスルホニルアミノ、N−(C1−3アルキル)C1−3アルキルスルホニルアミノまたはフェニルC1−3アルキルスルホニルアミノであり;
R7は水素原子、未置換または1−3個のQ3で置換されるC1−3アルキル、3−6員単環シクロアルキルまたは3−8員単環複素環基であり;
環Aはフェニル、ピロリル、ピリジル、ピリミジニル、ピロリジニル、ピペリジニル、ピペラジニルまたはモルホリニルであり;
R8は式(IIa)に示され、
Ra、Rb、RcとRdはそれぞれ独立して水素原子、C1−3アルキル、C1−3アルコキシ、アミノまたはC1−3アルキルアミノであり、
Reは水素原子、C1−3アルキル、C1−3アルコキシ、アミノ、C1−3アルキルアミノ、ジ(C1−3アルキル)アミノ、フェニルアミノ、N−(C1−3アルキル)フェニルアミノ、ベンジルアミノ、N−(C1−3アルキル)ベンジルアミノ、フェニルまたは5−7員単環複素環基であり、
前記5−7員単環複素環基上の炭素原子は1−3個の同じまたは異なるS(O)m、C(O)で代替されても良い、
前記C1−3アルキル、5−7員単環複素環基は1−3個のQ3で置換されても良い、
Q3はハロゲン原子、ヒドロキシ、シアノ、カルボキシ、アミノ、ニトロ、トリフルオロメチルまたはC1−3アルキルであり;
R9は水素原子、ハロゲン原子、ヒドロキシ、シアノ、カルボキシ、アミノ、ニトロ、C1−3アルキル、トリフルオロメチルまたはC1−3アルコキシであり;
aとbはそれぞれ独立して0、1または2であり;
nは0、1または2であり、nは2である場合、R9で表される置換基は同じでも異なっていても良い;
n1は0、1または2であり:
n2は0または1であり;
n3は0、1または2であり;
mは1または2である。
Xは酸素原子であり;
R1は水素原子であり;
R2、R4とR5はそれぞれ独立して水素原子であり;
R3は未置換または1−2個のQ1で置換されるC1−3アルキルOC(O)−またはカルバモイルであり、
Q1はハロゲン原子、ヒドロキシ、アミノ、C1−3アルコキシ、C1−3アルキルアミノまたはジ(C1−3アルキル)アミノであり;
R6は未置換または1−3個のQ2で置換される下記の官能基である:
(1)4−7員単環シクロアルキル、フェニルであり、前記フェニル、シクロアルキル上の炭素原子は1−3個の同じまたは異なるN、NH、N(C1−3アルキル)、O、S(O)m、C(O)で代替されても良い、
(2)
且つ環上の炭素原子は1−3個の同じまたは異なるNH、N(C1−3アルキル)、O、S(O)m、C(O)で代替されても良い、
pは0、1、2または3であり、
rは1であり、
sは1であり、
Q2はハロゲン原子、ヒドロキシ、シアノ、カルボキシ、アミノ、ニトロ、トリフルオロメチル、C1−3アルキル、C1−3アルコキシ、ヒドロキシC1−3アルキル、アミノC1−3アルキルまたはC1−3アルコキシC1−3アルキルであり;
R7は水素原子または3−5員単環シクロアルキルであり;
環Aはフェニルまたはピリジルであり;
R8は式(IIa)に示され、
Ra、Rb、RcとRdはそれぞれ独立して水素原子、メチルまたはエチルであり;
Reは水素原子、C1−3アルキル、C1−3アルコキシ、アミノ、C1−3アルキルアミノ、ジ(C1−3アルキル)アミノ、フェニルアミノ、N−(C1−3アルキル)フェニルアミノ、ベンジルアミノ、N−(C1−3アルキル)ベンジルアミノ、フェニルまたは5−7員単環複素環基であり、
前記5−7員単環複素環基上の炭素原子は1−3個の同じまたは異なるS(O)m、C(O)で代替されても良い、
前記C1−3アルキル、5−7員単環複素環基は1−3個のQ3で置換されても良い、
Q3はハロゲン原子、ヒドロキシ、シアノ、カルボキシ、アミノ、ニトロ、トリフルオロメチルまたはメチルであり;
R9は水素原子、ハロゲン原子、ヒドロキシ、シアノ、カルボキシ、アミノまたはメチルであり;
aとbはそれぞれ独立して0、1または2であり;
nは0または1であり;
n1は0または1であり;
n2は1であり;
n3は0または1または2であり;
mは1または2である。
R1は水素原子であり;
R2、R4とR5はそれぞれ独立して水素原子であり;
R3はCH3OC(O)−、CH3CH2OC(O)−、(CH3)2CHOC(O)−またはNH3C(O)−であり;
R6は未置換または1−3個のQ2で置換される下記の官能基である:
フェニル、テトラヒドロフラン、テトラヒドロピラン、
Q2はハロゲン原子、ヒドロキシ、シアノ、カルボキシ、アミノ、ニトロ、トリフルオロメチル、メチル、メトキシまたはメトキシメチルであり;
R7は水素原子またはシクロプロピルであり;
R8は式(IIb)に示され、
前記ピロリル、ピラゾリル、イミダゾリル、トリアゾリル、ピリジル、ピリミジニル、ピロリジニル、ピロリドニル、ピペリジニル、ピペラジニル、モルホリニルは1−3個のQ3で置換されても良い、
Q3はハロゲン原子、ヒドロキシ、アミノ、トリフルオロメチルまたはメチルであり;
R9は水素原子であり;
aとbはそれぞれ独立して0、1または2であり;
nは0であり;
n3は1または2である。
Xは酸素原子であり;
R1は水素原子であり;
R2、R4とR5はそれぞれ独立して水素原子であり;
R3はCH3OC(O)−またはCH3CH2OC(O)−であり;
R6は未置換または1−3個のハロゲン原子、トリフルオロメチルまたはメトキシで置換される下記の官能基である:
フェニル、テトラヒドロフラニル、テトラヒドロピラニルまたは
環Aはフェニルであり;
R8は式(IIb)に示され、
前記ピロリル、ピラゾリル、イミダゾリル、トリアゾリル、ピリジル、ピリミジニル、ピロリジニル、ピロリドニル、ピペリジニル、ピペラジニル、モルホリニルは1−2個のQ3で置換されても良い、
Q3はヒドロキシ、トリフルオロメチルまたはメチルであり;
R9は水素原子であり;
aは0であり;
bは2であり;
nは0であり;
n3は1または2である。
Xは酸素原子であり;
R1は水素原子であり;
R2、R4とR5はそれぞれ独立して水素原子であり;
R3はCH3OC(O)−またはCH3CH2OC(O)−であり;
R6はフェニル、4−フルオロフェニル、4−トリフルオロメチルフェニルまたは4−メトキシフェニルであり;
R7は水素原子であり;
R8は式(IIb)に示され、
R9は水素原子であり;
aは0であり;
bは2であり;
nは0であり;
n3は1または2である。
中間体4はJ.Med.Chem. 2009、 52、 4466−4480に従って合成する
ステップ1 中間体1の製造
原料1と有機塩基をDCMに溶かし、氷浴で原料2を滴下し、室温まで昇温して30分間反応させ、水を加え、DCMで抽出し、乾燥し、蒸留乾燥し、固体を真空乾燥して中間体1を得る。
中間体1と有機塩基をDCMに溶かし、原料3を滴下し、室温で12h反応させ、DCMで抽出し、有機層を無水硫酸ナトリウムで乾燥し、蒸留乾燥して中間体2を得る。
中間体2をDCMに溶かし、TFAを加え、室温下で反応終了後,濃縮して中間体3を得る。または中間体2をメタノールに溶かし、オーバーナイトでPd/C水素化反応させ、濾過し、濃縮して中間体3を得、精製しないで直接に次のステップに用いる。
中間体4と中間体3をDMFに溶かし、80℃に加熱して5h反応させ、室温まで冷却して更に2h反応させた後、水を加え、濾過し、固体を真空乾燥して式(I)化合物を得る。
(1)本発明化合物は小分子のチロシンキナーゼ阻害剤として、繊維化疾患を予防または治療でき、細胞増殖及び血管新生を抑制し、優れた抗腫瘍活性を有し、各種哺乳類動物(ヒトを含む)の繊維化疾患及び/又は腫瘍疾患の治療及び/又は予防に対して優れた効果を有する;
(2)本発明化合物の毒性及び副作用は比較的低く、安全域が広い;
(3)本発明化合物の製造プロセスが簡単で、理化学性質が良く、品質が安定していて、大規模な工業生産が行い易い。
試験材料:
(1)試薬及び化合物の製造
[1]1倍のMnCl2を含まないキナーゼ緩衝液(50 mM HEPES、 pH= 7.5、0.0015% Brij−35、10 mM MgCl2、2 mM DTT);
[2]1倍のMnCl2を含むキナーゼ緩衝液(50 mM HEPES、 pH= 7.5、0.0015% Brij−35、10 mM MgCl2、10 mM MnCl2、2 mM DTT);
[3]停止液(100 mM HEPES、 pH=7.5、0.015% Brij−35、0.2% Coating Reagent #3、50 mM EDTA);
[4]2.5倍のキナーゼ溶液(1倍のキナーゼ緩衝液に相応するキナーゼを加えて2.5倍のVEGFR2、FGFR1、 FGFR3、PDGFRβキナーゼ溶液を製造する);
[5]2.5倍の基質溶液(1倍のキナーゼ緩衝液にFAMで標識したペプチドとATPを加えてペプチド溶液を製造する);
[6]4倍希釈の化合物溶液:化合物を正確に量り、DMSOを加えて溶かし、充分に均一に混合し、10mMに製造する。次にDMSOで500μMに希釈し、更に4倍希釈して10個の濃度の溶液に製造し、最大濃度が50μMであり、使用に供する。
(2)5倍希釈された化合物溶液5μLを取り384ウェルプレートに加える:
(3)2.5倍のキナーゼ溶液10μLを加えて10min培養する;
(4)2.5倍の基質溶液10μLを加え、28℃で1h反応させる;PGDFRβキナーゼを有するものは、5h反応させる。
(5)最後に停止液25μLを加えて反応を終了させ、Caliper機器でデータを読み取る。
(6)曲線あてはめからIC50を得る
計算抑制率(%)=(最大転換率−試料転換率)/(最大転換率−最小転換率)×100
Xlfitソフトを用いて曲線あてはめして、IC50値を得る。
表1
本発明の一部の化合物のin vitroでの酵素学的な抑制活性
試料:
(1)細胞の蘇生、成長。
Net OD=化合物OD−MinOD、化合物の濃度−Net OD曲線を描き、下記公式でED50を計算する:
Conc.ED50(x)=(y−b)/a、y=IC50に対して計算されたO.D.(Calculated Net O.D.forIC50)、a=傾き(slope)、b=切片(intercept)。
表2
本発明の一部の化合物のin vitroでの細胞学的な抑制活性
試料:
1.溶液及び化合物の調製
細胞外液(mM):N−2−ヒドロキシエチルピペラジン−N’−2−エタンスルホン酸(N−2−hydroxyethylpiperazine−N′−2−ethanesulfonic acid)(HEPES)10、NaCl145、KCl4、CaCl22、MgCl21、Glucose10を、1Nの水酸化ナトリウム溶液でpHが7.4になるように調整する;浸透圧を290−300mOsmに調整する;濾過した後4℃で保存する。
手動パッチクランプ技術を用いて、hERGチャンネルを安定して発現するCHO−K1細胞株でhERG電流を記録する;hERG尾電流に基づいて各濃度の抑制率を計算する;各化合物を5個の濃度を測定し、IC50値を推定する;各濃度において2個の細胞を測定する;1個の陽性対照薬物を用いる。
Digidata1440(Molecular Devices)及びpCLAMPソフト(10.2版、Molecular Devices)A/D−D/Aアナログデジタル変換を用いて、刺激及び信号収集を行う。Clampfit(10.2版、Molecular Devices)とPrismを用いて更にデータ分析及び曲線あてはめを行う。データは全て平均値±標準偏差で表示する。IC50値はLogistic方程式によりあてはめて得る:
表4 CHO−K1安定細胞株において記録された化合物のhERG電流に対するIC50値
以下は実施例形式の発明を実施するための形態により、本発明の前記内容について更なる詳細な説明を行うが、本発明は前記主題の範囲が下記の実施例に限ると理解してはならない。
1H NMR (400M、 DMSO−d6、 δppm):12.16 (s、 1H)、 10.93 (s、 1H)、 7.77 (d、 1H)、 7.56 (m、 3H)、 7.48 (d、 2H)、 7.40 (s、 1H)、 7.17 (d、 1H)、 6.79 (s、 1H)、 6.66 (d、 1H)、 5.79 (d、 1H)、 4.09 (t、 2H)、 3.75 (s、 3H)、 3.16 (t、 2H)、 2.95 (t、 2H)、 2.30 (m、 4H)、 2.29 (m、 4H)、 2.12 (s、 3H)。
1H NMR (400MHz,、塩酸塩、DMSO-d6, δppm) : 12.16 (s, 1H), 10.96 (s, 1H), 9.77 (br. s., 1H), 7.79 (d, J = 8.8 1H), 7.56 (m, 3H), 7.45 (m, 2H), 7.26 (s, 1H), 7.17(m, 1H), 6.88 (s, 1H), 6.74 (s, 1H),5.81(d, J = 8.4, 1H), 4.25 (m, 2H), 3.96(m, 2H),3.76 (s, 3H), 3.04 (m, 2H), 2.83 (m, 6H).
1H NMR (塩酸塩、DMSO-d6, 400MHz, δppm): 12.10 (s, 1H), 11.5(br s、1H)、10.97 (s, 1H), 7.80 (d, 1H), 7.51-7.55 (m, 2H), 7.36-7.42 (m, 3H), 7.22-7.25 (m, 1H), 6.89 (s, 1H), 6.73 (d, 1H), 5.89 (d, 1H), 4.39-4.05 (m, 2H), 3.76 (s, 3H), 3.25-3.27 (m, 10H), 3.04 (t, 2H), 2.79 (s, 3H).
1HNMR (塩酸塩、DMSO-d6, 400MHz, δppm): 1.25(m, 3H), 2.80(s, 3H), 3.02(m, 2H),3.45(m, 8H),4.01(m, 2H), 4.25(m, 4H), 5.80(d, 1H),6.73(d, 1H), 6.87(s, 1H),7.16 (m, 1H),7.44 (m, 3H),7.55 (m, 3H),7.77 (d, 1H),10.94 (s, 1H),11.5(br s、1H),12.13 (s, 1H).
1H NMR (塩酸塩、DMSO-d6, 400MHz, δppm): 12.14 (s, 1H), 10.94 (s, 1H), 10.2(br m、1H)、7.79 (d, 1H), 7.51-7.66 (m, 3H), 7.40-7.45 (m, 3H), 7.16 (d, 1H), 6.80 (s, 1H), 6.65 (d, 1H), 5.79 (d, 1H), 3.98-4.05 (m, 2H), 3.75 (s, 3H), 2.86-2.97 (m, 4H),2.67-2.71(m, 4H), 2.34 (d, 2H), 1.84-2.01 (m, 4H), 1.44-1.51 (m, 2H).
1H NMR (DMSO-d6, 400MHz, δppm): 12.15 (s, 1H), 10.91 (s, 1H), 7.76 (d, 1H), 7.53-7.55 (m, 3H), 7.40-7.46 (m, 3H), 7.17 (d, 1H), 6.80 (s, 1H), 6.64 (d, 1H), 5.80 (d, 1H), 4.06 (t, 2H), 3.75 (s, 3H), 2.97 (m, 5H), 2.78 (s, 3H), 2.56(s, 4H).
1H NMR (塩酸塩、DMSO-d6, 400MHz, δppm): 3.15(s,2H), 3.20(t,4H), 3.75(s,3H), 3.80(t,2H), 4.00(t, 4H), 4.35(m,2H), 5.80(d, 1H), 6.75(d, 1H), 6.87(s, 1H) ,7.18(d, 1H) ,7.44 (s, 1H) ,7.46 (d, 2H) ,7.59 (m, 3H) ,7.79 (d, 1H) ,10.49 (s, 1H) ,10.97 (s, 1H),12.16 (s, 1H).
1H NMR (塩酸塩、DMSO-d6, 400MHz, δppm): 1.72(m,2H), 1.94(m,2H), 3.03(m,4H), 3.25(m,2H), 3.45(m,1H), 3.75(s,3H), 3.99(s,2H), 4.29(m,2H),5.05(d,1H), 5.80(d, 1H), 6.75(d, 1H), 6.87(s, 1H) ,7.18(d, 1H) ,7.44 (s, 1H) ,7.46 (d, 2H) ,7.59 (m, 3H) ,7.79 (d, 1H) ,10.49 (s, 1H) ,10.97 (s, 1H),12.16 (s, 1H).
1H NMR (400MHz, 塩酸塩、DMSO-d6, δppm): 12.10 (s, 1H), 10.97 (s, 1H), 10.45(br s、1H)、7.81 (d, 1H), 7.51-7.55 (m, 2H), 7.39 (t, 3H), 7.22 (d, 1H), 6.90 (s, 1H), 6.75 (d, 1H), 5.89 (d, 1H), 4.37 (s, 2H), 3.93-4.02 (m, 5H), 3.76-3.83 (m, 5H), 3.15-3.19 (m, 3H), 3.07 (t, 2H).
1H NMR (400MHz, 塩酸塩、DMSO-d6, δppm): 12.11 (s, 1H), 10.93 (s, 1H), 10.25(br s、1H)、7.78 (d, 1H), 7.51-7.57 (m, 3H), 7.41-7.45(m, 3H), 7.17(d, 1H), 6.87 (s, 1H), 6.72-6.75 (m, 1H), 5.79 (d, 1H), 4.35 (s, 2H), 4.17-4.23 (m, 2H), 3.96-4.00 (m, 2H), 3.76-3.79 (br, 6H), 3.14-3.19 (br, 2H), 3.03 (t, 2H), 1.24 (t, 3H).
1HNMR(400MHz、DMSO, 塩酸塩, δppm): 12.13(s, 1H), 10.95(s 1H), 10.50(s, 1H), 7.79(s, 1H), 7.51(m, 6H), 7.18(s, 1H), 6.89(s, 1H), 6.74(s, 1H), 5.81(s, 1H), 4.29(s, 2H), 3.98(s, 4H), 3.76(m, 3H), 3.16(s, 2H), 3.06(t, 2H), 2.74(d, 2H), 1.09(d, 6H).
1H NMR (400MHz, DMSO-d6, δppm): 12.15 (s, 1H), 10.93(s, 1H),7.73 (d, 1H), 7.55 (m, 3H), 7.43-7.40 (m, 2H), 7.41 (d, 1H), 7.17 (d, 1H), 6.83 (d, 1H), 6.67 (d, 1H), 5.81 (d, 1H), 4.10 (s, 2H), 4.04(t, 2H), 3.75(s, 3H), 3.00 (t, 2H), 2.24 (m, 2H), 1.95(m, 2H)、1.22(m、2H).
1H NMR (400MHz, 塩酸塩、DMSO-d6, δppm): 12.17(s, 1H), 10.93(s, 1H), 7.80(d, 1H), 7.50(m, 6H), 7.19(m, 1H), 6.83(s, 1H), 6.69(m, 1H), 5.83(d, 1H), 4.09(s, 2H), 3.92(t, 3H), 3.76(s, 3H), 2.96(t, 2H)(活性水素が示されていない)。
1H NMR (400MHz, DMSO-d6, δppm): 12.09 (s, 1H), 10.93 (s, 1H), 7.69 (d, 1H), 7.64 (d, 1H), 7.52-7.54 (m, 3H), 7.42 (d, 4H), 7.14-7.18 (m, 1H), 6.83 (s, 1H), 6.65 (d, 1H), 6.26 (t, 1H), 5.80 (d, 1H), 5.14 (s, 2H), 4.09 (t, 2H), 3.74 (s, 3H), 3.01 (t, 2H).
Claims (14)
- 一般式(I)に示される化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体:
そのうち、Xは酸素原子であり;
R1は水素原子であり;
R2、R4とR5はそれぞれ独立して水素原子またはC1−6アルキルであり;
R3はC1−6アルキル−OC(O)−であり;
R6は未置換または1−3個のハロゲン原子で置換されるフェニルであり;
R7は水素原子またはC1−3アルキルであり;
環Aはフェニルであり;
R8は式(IIa)に示され、
そのうち、
Ra、Rb、RcとRdはそれぞれ独立して水素原子であり、
Reはアミノ、C1−3アルキルアミノ、ジ(C1−3アルキル)アミノ、ジ(C1−3アルキル)カルバモイルまたは3−8員単環複素環基であり、
前記3−8員単環複素環基上の炭素原子は1−3個のC(O)で代替されても良い、
前記C1−3アルキル、3−8員単環複素環基は1−3個のQ3で置換されても良い、
Q3はハロゲン原子、ヒドロキシまたはC1−3アルキルであり;
R9は水素原子、ハロゲン原子またはヒドロキシであり;
aは0であり;
bは2であり;
nは0、1または2であり、nは2である場合、R9で表される置換基は同じでも異なっていても良い;
n1は0であり;
n2は1であり;
n3は1、2または3である。 - Xは酸素原子であり;
R1は水素原子であり;
R2、R4とR5はそれぞれ独立して水素原子であり;
R3はC1−3アルキル−OC(O)−であり;
R6は未置換または1−3個のハロゲン原子で置換されるフェニルであり;
R7は水素原子であり;
環Aはフェニルであり;
R8は式(IIa)に示され、
そのうち、
Ra、Rb、RcとRdはそれぞれ独立して水素原子であり、
Reはアミノ、C1−3アルキルアミノ、ジ(C1−3アルキル)アミノ、ジ(C1−3アルキル)カルバモイルまたは5−7員単環複素環基であり、
前記5−7員単環複素環基上の炭素原子は1−3個のC(O)で代替されても良い、
前記C1−3アルキル、5−7員単環複素環基は1−3個のQ3で置換されても良い、
Q3はハロゲン原子、ヒドロキシまたはC1−3アルキルであり;
R9は水素原子、ハロゲン原子またはヒドロキシであり;
aは0であり;
bは2であり;
nは0、1または2であり、nは2である場合、R9で表される置換基は同じでも異なっていても良い;
n1は0であり;
n2は1であり;
n3は1または2である請求項1の化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体。 - Xは酸素原子であり;
R1は水素原子であり;
R2、R4とR5はそれぞれ独立して水素原子であり;
R3はC1−3アルキル−OC(O)−であり;
R6は未置換または1−3個のハロゲン原子で置換されるフェニルであり;
R7は水素原子であり;
環Aはフェニルであり;
R8は式(IIa)に示され、
そのうち、
Ra、Rb、RcとRdはそれぞれ独立して水素原子であり;
Reはアミノ、C1−3アルキルアミノ、ジ(C1−3アルキル)アミノ、ジ(C1−3アルキル)カルバモイルまたは5−7員単環複素環基であり、
前記5−7員単環複素環基上の炭素原子は1−3個のC(O)で代替されても良い、
前記C1−3アルキル、5−7員単環複素環基は1−3個のQ3で置換されても良い、
Q3はハロゲン原子、ヒドロキシまたはメチルであり;
R9は水素原子、ハロゲン原子またはヒドロキシであり;
aは0であり;
bは2であり;
nは0または1であり;
n1は0であり;
n2は1であり;
n3は1または2である請求項2の前記化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体。 - 下記一般式(II)に示される構造式を有する請求項3の前記化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体、
式中、Xは酸素原子であり;
R1は水素原子であり;
R2、R4とR5はそれぞれ独立して水素原子であり;
R3はCH3OC(O)−、CH3CH2OC(O)−または(CH3)2CHOC(O)−であり;
R6は未置換または1−3個のハロゲン原子で置換されるフェニルであり;
R7は水素原子であり;
R8は式(IIb)に示され、
式中、Reはジ(C1−3アルキル)アミノ、ジ(C1−3アルキル)カルバモイル、ピロリル、ピラゾリル、イミダゾリル、トリアゾリル、ピリジル、ピリミジニル、ピロリジニル、ピロリドニル、ピペリジニル、ピペラジニルまたはモルホリニルであり、
前記ピロリル、ピラゾリル、イミダゾリル、トリアゾリル、ピリジル、ピリミジニル、ピロリジニル、ピロリドニル、ピペリジニル、ピペラジニル、モルホリニルは1−3個のQ3で置換されても良い、
Q3はハロゲン原子、ヒドロキシまたはメチルであり;
R9は水素原子であり;
aは0であり;
bは2であり;
nは0であり;
n3は1または2である。 - Xは酸素原子であり;
R1は水素原子であり;
R2、R4とR5はそれぞれ独立して水素原子であり;
R3はCH3OC(O)−またはCH3CH2OC(O)−であり;
R6は未置換または1−3個のハロゲン原子で置換されるフェニルであり;
R7は水素原子であり;
R8は式(IIb)に示され、
式中、Reはジメチルアミノ、ピロリル、ピラゾリル、イミダゾリル、トリアゾリル、ピリジル、ピリミジニル、ピロリジニル、ピロリドニル、ピペリジニル、ピペラジニルまたはモルホリニルであり、
前記ピロリル、ピラゾリル、イミダゾリル、トリアゾリル、ピリジル、ピリミジニル、ピロリジニル、ピロリドニル、ピペリジニル、ピペラジニル、モルホリニルは1−2個のQ3で置換されても良い、
Q3はヒドロキシまたはメチルであり;
R9は水素原子であり;
aは0であり;
bは2であり;
nは0であり;
n3は1または2である請求項4の化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体。 - Xは酸素原子であり;
R1は水素原子であり;
R2、R4とR5はそれぞれ独立して水素原子であり;
R3はCH3OC(O)−またはCH3CH2OC(O)−であり;
R6はフェニルまたは4−フルオロフェニルであり;
R7は水素原子であり;
R8は式(IIb)に示され、
式中、Reはジメチルアミノ、ピラゾリル、トリアゾリル、ピロリジニル、ピロリドニル、ピペリジニル、N−メチルピペリジニル、4−ヒドロキシピペリジニル、N−メチルピペラジニル、モルホリニルまたは3,5−ジメチルモルホリニルであり;
R9は水素原子であり;
aは0であり;
bは2であり;
nは0であり;
n3は1または2である請求項5の前記化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体。 - 下記から選ばれる化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体、
。 - 式(III)に示される化合物と式(IV)に示される化合物を反応させて式(I)に示される化合物を得ることが含まれることを特徴とする請求項1−7のいずれか1項の化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体を製造する方法。
式中、X、R1、R2、R3、R4、R5、R6、R7、R8、R9、環A、n、aとbは請求項1に定義されるとおりである。 - 塩は、塩酸塩、硫酸塩、エタンスルホン酸塩、メタンスルホン酸塩、マレイン酸塩、p−トルエンスルホン酸塩、ベンゼンスルホン酸塩、およびシュウ酸塩から選ばれる請求項1−7のいずれか1項の化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体。
- 請求項1−7のいずれか1項の前記化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体、及び任意に含有される一種または数種の薬剤用キャリヤーを含む医薬組成物。
- 更に抗腫瘍剤と免疫阻害剤から選ばれる第二治療薬剤を含み、前記第二治療薬剤は、代謝拮抗薬(カペシタビン、ゲムシタビンを含む)、成長因子阻害剤(ゲフィチニブ、ラパチニブ、パゾパニブ、イマチニブを含む)、抗体(トラスツズマブ、ベバシズマブを含む)、有糸分裂阻害剤(パクリタキセル、ビノレルビン、ドセタキセル、ドキソルビシンを含む)、抗腫瘍ホルモン剤(レトロゾール、タモキシフェン、フルベストラントを含む)、アルキル化剤(シクロホスファミド、カルムスチンを含む)、プラチナ製剤(カルボプラチン、シスプラチン、オキサリプラチンを含む)、トポイソメラーゼ阻害剤(トポテカンを含む)、免疫阻害剤類(エベロリムスを含む)、抗コリン作動薬、β−コリンミメティック、ステロイド、PDE−IV阻害剤、p38MAPキナーゼ阻害剤、NK1拮抗剤、LTD4拮抗剤、EGFR阻害剤及びエンドセリン拮抗剤から選ばれる請求項10に記載の医薬組成物。
- 請求項1−7のいずれか1項の化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体及び一種または数種の薬剤用キャリヤーを含み、製剤上許容される任意の剤型である医薬製剤。
- 慢性閉塞性肺疾患における肺組織の線維化及び再構築;慢性気管支炎における肺組織の線維化及び再構築;肺気腫における肺組織の線維化及び再構築;肺線維化及び線維化成分を有する肺疾患;喘息における線維化及び再構築;リウマチ性関節炎における線維化;ウイルス性肝硬変;放射線による線維化;血管形成術後の再狭窄;慢性糸球体腎炎;シクロスポリン投与患者の腎線維化及び高血圧による腎線維化;線維化成分を有する皮膚疾患及び過剰瘢痕化から選ばれる線維化疾患を予防または治療するための薬物、脳癌;肺癌;非小細胞性肺癌;扁平上皮癌;膀胱癌;胃癌;卵巣癌;腹膜癌;膵臓癌;乳癌;頭頸部癌;子宮頸癌;子宮内膜癌;結腸直腸癌;肝癌;腎癌;食道腺癌;食道扁平上皮癌;固形腫瘍;非ホジキンリンパ腫;中枢神経系腫瘍(神経膠腫、多形膠芽腫、神経膠肉腫から選ばれる)、前立腺癌または甲状腺癌から選ばれる癌性疾患及び皮膚または前立腺の良性増生から選ばれる非癌性疾患を含む過剰増殖性疾患を治療するための薬物、或いは抗血管新生及び/又は血管透過性を低下させるための薬物の製造における請求項1−7のいずれか1項の化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体の使用。
- 前記肺線維化と線維化成分を含む肺疾患は、特発性肺線維症、巨細胞性間質性肺炎、類肉腫症、嚢胞性線維症、呼吸窮迫症候群、薬物由来の肺線維症、肉芽腫、珪肺症、石綿症、全身性硬化症、ウイルス性肝硬変(C型肝炎による肝硬変から選ばれる)、線維化成分を含む皮膚疾患(強皮症、類肉腫症、全身性エリテマトーデスから選ばれる)を含む線維化疾患を予防または治療するための薬物、過剰増殖性疾患を治療するための薬物、或いは抗血管新生及び/又は血管透過性を低下させるための薬物の製造における請求項1−7のいずれか1項の化合物、その製薬学的に許容される塩、その重水素化物またはその立体異性体の使用。
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