JP2011105738A - バニロイドアンタゴニストとして有用なキナゾリノン誘導体 - Google Patents
バニロイドアンタゴニストとして有用なキナゾリノン誘導体 Download PDFInfo
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- JP2011105738A JP2011105738A JP2011010997A JP2011010997A JP2011105738A JP 2011105738 A JP2011105738 A JP 2011105738A JP 2011010997 A JP2011010997 A JP 2011010997A JP 2011010997 A JP2011010997 A JP 2011010997A JP 2011105738 A JP2011105738 A JP 2011105738A
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- Prior art keywords
- alkyl
- hydroxy
- amino
- formula
- alkoxy
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Abstract
Description
R1は、C1−C6アルキル、(C1−C6アルキル)C1−C6アルキル、ジ−(C1−C6アルキル)C1−C6アルキル、C3−C6シクロアルキル、(C1−C6アルキル)アミノまたはジ−(C1−C6アルキル)アミノであり;
R2は、それぞれ独立して、ハロゲン、C1−C6アルキル、ハロゲン置換C1−C6アルキル、ヒドロキシC1−6アルキル、シアノまたは基−C(=O)−R2a(ここで、R2aは、C1−C6アルキルである。)であり;
R3は、水素、ハロゲン、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、ヒドロキシ、ヒドロキシ置換C1−C6アルキル、C1−C6アルコキシ、C3−C6シクロアルキル、シアノ、−C(=O)H、フェニル、(C3−C6シクロアルキル)C1−C6アルコキシ、(C1−C6アルコキシカルボニルアミノ)C1−C6アルコキシまたは(C1−C6アルキルカルボニルアミノ)C1−C6アルコキシであり;
R4は、ヒドロキシ、エステル化ヒドロキシ、エーテル化ヒドロキシ、アミノ、(C1−C6アルキル)アミノ、基
R5は、水素またはヒドロキシであり;そして
mは、1または2である。]
で示されるキナゾリノン化合物の使用に関する。
〔式中、R1は、C1−C6アルキル、(C1−C6アルキル)C1−C6アルキル、ジ−(C1−C6アルキル)C1−C6アルキルまたはC3−C6シクロアルキルであり;
R2は、それぞれ独立して、ハロ、C1−C6アルキル、トリ−ハロ置換C1−C6アルキル、ヒドロキシC1−C6アルキルまたは基
R3は、水素、ハロ、C1−C6アルキル、ヒドロキシ、C1−C6アルコキシまたは(C3−C6シクロアルキル)C1−C6アルコキシであり;
R4は、ヒドロキシ、エステル化ヒドロキシ、エーテル化ヒドロキシ、アミノ、(C1−C6アルキル)アミノ、基
または基
R5は、水素またはヒドロキシであり;そして
mは、1または2である。〕
で示されるキナゾリノン化合物の使用に関する。
R1は、C1−C6アルキル、(C1−C6アルキル)C1−C6アルキル、ジ−(C1−C6アルキル)C1−C6アルキル、C3−C6シクロアルキル、(C1−C6アルキル)アミノまたはジ−(C1−C6アルキル)アミノであり;
R2は、それぞれ独立して、ハロゲン、C1−C6アルキル、ハロゲン置換C1−C6アルキル、ヒドロキシC1−C6アルキル、シアノまたは基−C(=O)−R2a(ここで、R2aは、C1−C6アルキルである。)であり;
R3は、水素、ハロゲン、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、ヒドロキシ、ヒドロキシ置換C1−C6アルキル、C1−C6アルコキシ、C3−C6シクロアルキル、シアノ、−C(=O)H、フェニル、(C3−C6シクロアルキル)C1−C6アルコキシ、(C1−C6アルコキシカルボニルアミノ)C1−C6アルコキシまたは(C1−C6アルキルカルボニルアミノ)C1−C6アルコキシであり;
R4は、ヒドロキシ、エステル化ヒドロキシ、エーテル化ヒドロキシ、アミノ、(C1−C6アルキル)アミノ、基
mは、1または2である。]
で示される新規なキナゾリノン化合物に関する。
〔式中、R1は、C1−C6アルキル、(C1−C6アルキル)C1−C6アルキル、ジ−(C1−C6アルキル)C1−C6アルキルまたはC3−C6シクロアルキルであり;
R2は、それぞれ独立して、ハロ、C1−C6アルキル、トリ−ハロ置換C1−C6アルキル、ヒドロキシC1−C6アルキルまたは基
R3は、水素、ハロ、C1−C6アルキル、ヒドロキシ、C1−C6アルコキシまたは(C3−C6シクロアルキル)C1−C6アルコキシであり;
R4は、ヒドロキシ、エステル化ヒドロキシ、エーテル化ヒドロキシ、アミノ、(C1−C6アルキル)アミノ、基
または基
mは、1または2である。〕
で示される新規なキナゾリノン化合物に関する。
“C1−C6アルキル”は、直鎖または分枝鎖C1−C6−アルキル、例えば、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、イソブチル、sec−ブチルまたはtert−ブチルを示す。
“C1−C6アルコキシ”は、直鎖または分枝鎖C1−C6−アルキル−オキシ、例えばメトキシ、エトキシ、n−プロポキシまたはイソプロポキシを示す。
“エステル化ヒドロキシ”は、アシルオキシ、好ましくはC1−C6アルカノイルオキシを示し、より好ましくはC1−C4アルカノイルオキシを示す。
“エーテル化ヒドロキシ”は、C1−C6アルコキシ、好ましくはC1−C4アルコキシを示す。
(a)R1は、C1−C4アルキル、(C1−C4アルキル)C1−C4アルキル、ジ−(C1−C4アルキル)C1−C4アルキルまたはシクロプロピルであり;
(b)R2は、それぞれ独立して、クロロ、フルオロ、C1−C4アルキル、トリフルオロ置換C1−C4アルキルであり、より好ましくはトリフルオロメチル、C1−C4アルキルカルボニルであり、より好ましくはメチルカルボニルまたはヒドロキシC1−C4アルキルであり、より好ましくはヒドロキシメチルであり;
(c)R3は、水素、クロロ、ブロモ、C1−C4アルキル、ヒドロキシ、C1−C4アルコキシまたは(C3−C6シクロアルキル)C1−C4アルコキシであり;そして
(d)R4は、ヒドロキシ、アミノ、(C1−C4アルキル)アミノまたは基
A.式(Ia)〔ここで、R1およびR2は上記に定義の通りであり、R3は、式Iの化合物について記載の通りであり、R4はアミノであり、そしてmは1である。〕の化合物を製造するための方法。
スキームAの第一段階は、三塩化リンの存在下、式1のアミド化合物を置換アニリン化合物を用いて縮合/環化し、式2の7−ニトロ置換キナゾリン−4−オン化合物を得ることを含む。
スキームBは、スキームAに記載の通りに製造された式3の7−アミノ置換キナゾリン−4−オン化合物を濃硫酸および亜硝酸ナトリウムを用いてサンドマイヤー反応を行い、式4の7−ヒドロキシ置換キナゾリン−4−オン化合物を得ることを含む。
上記の方法による反応混合物の後処理およびそのようにして得られた化合物の精製を、公知の方法に従い行うことができる。
酸付加塩を、公知の方法で遊離塩基から製造することができ、その逆も可能である。
R1が、C1−C4アルキル、(C1−C4アルキル)C1−C4アルキルまたはC3−C6シクロアルキルであり;
R2が、クロロ、フルオロ、C1−C4アルキル、トリフルオロ置換C1−C4アルキル、C1−C4アルキルカルボニルまたはヒドロキシC1−C4アルキルであり;
R3が、水素、クロロ、ブロモ、C1−C4アルキル、ヒドロキシ、C1−C4アルコキシまたは(C3−C6シクロアルキル)C1−C4アルコキシであり;
R4が、ヒドロキシ、アミノまたは(C1−C4アルキル)アミノであり;
R5が、水素またはヒドロキシであり;そして
mが、1または2であるものである。
R1が、C1−C4アルキル、(C1−C4アルキル)C1−C4アルキルまたはC3−C6シクロアルキルであり;
R2が、クロロ、フルオロ、C1−C4アルキル、トリフルオロメチル、メチルカルボニルまたはヒドロキシメチルであり;
R3が、水素、クロロ、ブロモ、C1−C4アルキル、ヒドロキシまたはC1−C4アルコキシであり;
R4が、ヒドロキシ、アミノまたは(C1−C4アルキル)アミノであり;
R5が、水素またはヒドロキシであり;そして
mが1であるものである。
R1が、C1−C4アルキル、(C1−C4アルキル)C1−C4アルキルまたはC3−C6シクロアルキルであり;
R2が、クロロ、フルオロ、C1−C4アルキル、トリフルオロ置換C1−C4アルキル、C1−C4アルキルカルボニルまたはヒドロキシC1−C4アルキルであり;
R3が、水素、クロロ、ブロモ、C1−C4アルキル、ヒドロキシ、C1−C4アルコキシまたは(C3−C6シクロアルキル)C1−C4アルコキシであり;
R4が、ヒドロキシ、アミノまたは(C1−C4アルキル)アミノであり;そして
mが、1または2であるものである。
R1が、C1−C4アルキル、(C1−C4アルキル)C1−C4アルキルまたはC3−C6シクロアルキルであり;
R2が、クロロ、フルオロ、C1−C4アルキル、トリフルオロメチル、メチルカルボニルまたはヒドロキシメチルであり;
R3が、水素、クロロ、ブロモ、C1−C4アルキル、ヒドロキシ、C1−C4アルコキシまたは(C3−C6シクロアルキル)C1−C4アルコキシであり;
R4が、ヒドロキシ、アミノまたは(C1−C4アルキル)アミノであり;そして
mが1であるものである。
カプサイシン分析の日、培地を吸引し、そして細胞を、100μLの10mM 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](HEPES)緩衝ハンクス平衡塩溶液(HBSS)、pH7.4を用いて洗浄した。その後、細胞を、0.01% pluronic F−127を含むHEPES緩衝HBSS中に調製された、2.3μMのレシオメトリックカルシウム結合色素フラ−2/AM(Molecular Probesから購入)を用いて40分間インキュベートした。pH分析について、HEPESを除き、そしてHBSSのpHを7.4に調節した。100μLの分析緩衝液で2回洗浄後、細胞を、0.001から30μMの間の濃度で、デュプリケートで、100μLの試験化合物(HBSS中に調製、pH7.4)と共に10分間インキュベートした。その後、前記プレートを、Molecular Devices社のFlexstation中に置いた。前記TRPV1受容体を、カプサイシンまたは低pHのいずれかの適用により刺激した。可能性のある拮抗作用について化合物の効果を試験するため、カプサイシンをEC80濃度で用い、それは、ラットTRPV1受容体について0.05μM、そしてヒトおよびモルモットについて0.1μMであった。pH試験のために、低pH緩衝溶液[HBSS中60mM 2−[N−モルホリノ]エタンスルホン酸(MES)]を、分析ウェルに加え、最終pH5.5とした。
(1)バニロイド受容体ブロッカーとしての使用を目的とした、例えば上記の特定の適応症のいずれかにおける使用を目的とした、遊離型または塩形態、および可能なときは薬学的に許容される酸付加塩形態の式(I)または(Ia)の化合物;
7−アミノ−3−(4−クロロフェニル)−2−イソプロピル−3H−キナゾリン−4−オンの製造
a)3−(4−クロロフェニル)−2−イソプロピル−7−ニトロ−3H−キナゾリン−4−オンの製造
トルエン(150mL)中、4−ニトロアントラニル酸イソブチルアミド(4g、15.8mmol)、4−クロロアニリン(2.2g、17.2mmol)および三塩化リン(5.6mL)の懸濁液を、2時間加熱還流する(150℃の浴温度)。反応混合物を室温まで冷却し、その後、乾燥するまで蒸発させる。残渣を、水とEtOAcの間に分配させ、水相をEtOAcで抽出する(2×)。合わせた有機相を水で洗浄し、乾燥させ(Na2SO4)、そして真空で蒸発させる。イソプロピルエーテルで粉末化し、所望の化合物を褐色固体として得る。
上記実施例1aで製造した化合物の混合物(2.4g、6.98mmol)、鉄粉(1.16g、20.8mmol)および氷酢酸(70mL)を、50℃で2.5時間撹拌する。反応混合物を室温まで冷却し、その後、乾燥するまで真空で蒸発させる。残渣を、水とEtOAcの間に分配させ、水相をEtOAcで抽出する(2×)。合わせた有機相を水で洗浄し、乾燥させ(Na2SO4)、そして真空で蒸発させ、褐色固体を得る。自動フラッシュクロマトグラフィー(勾配溶出:EtOAc/DCM0−50%)により精製し、淡黄色固体として表題化合物を得る。
(M+H)+=314.2;HPLC保持時間=3.9分。
3−(4−クロロフェニル)−7−ヒドロキシ−2−イソプロピル−3H−キナゾリン−4−オンの製造
氷浴温度に冷却した、濃硫酸/水972μL/1.4mL中、実施例1の化合物(778mg、2.479mmol)の懸濁液に、水中硝酸ナトリウム(188mg)の溶液(680μL)を添加する。混合物を、0−5℃(内部温度)で45分間撹拌し、次いで硫酸/水 3/2(5mL)を添加し、150℃まで予め加熱する。15分間撹拌後、その混合物を室温まで冷却し、ろ過し、そしてEtOAcで抽出する(3×)。合わせたEtOAc抽出物を水で洗浄し、乾燥させ(Na2SO4)、蒸発させ、黄色−オレンジ色固体とする。自動フラッシュクロマトグラフィー(勾配溶出:EtOAc/ヘキサン0−25%)により精製し、表題化合物を黄色固体として得る。
1H NMR (400 MHz, MeOH-d4): δ 7.91 (1H, d, J=8.7 Hz), 7.49 (2H, d, J=9.5 Hz), 7.25 (2H, J=9.5 Hz), 6.93 (1H, d, J=2.3 Hz), 6.86 (1H, dd, J=2.3, 8.7 Hz), 2.56 (1H, quint, J=6.7 Hz), 1.11 (6H, d, J=6.7 Hz);(M+H)+=315.8;HPLC保持時間=4.2分。
実施例3から28の化合物を、前記実施例に記載の方法と同様に製造することができる。
化合物29.1から29.54を、前記実施例に記載の方法と同様に製造することができる。
軟ゼラチンカプセルの製造
活性成分として0.05gの前記実施例に記載の式(Ia)の化合物のうち1つをそれぞれ含む5000個の軟ゼラチンカプセルを、下記の通りに製造する:
活性成分 250g
Lauroglycol(登録商標) 2l
[1] バニロイド受容体活性化が役割を果たすかまたは関係する疾患または状態の処置または予防のための医薬としての使用を目的とした、遊離型または塩形態、および可能なときは薬学的に許容される酸付加塩形態の、式
R1は、C1−C6アルキル、(C1−C6アルキル)C1−C6アルキル、ジ−(C1−C6アルキル)C1−C6アルキル、C3−C6シクロアルキル、(C1−C6アルキル)アミノまたはジ−(C1−C6アルキル)アミノであり;
R2は、それぞれ独立して、ハロゲン、C1−C6アルキル、ハロゲン置換C1−C6アルキル、ヒドロキシC1−6アルキル、シアノまたは基−C(=O)−R2a(ここで、R2aは、C1−C6アルキルである。)であり;
R3は、水素、ハロゲン、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、ヒドロキシ、ヒドロキシ置換C1−C6アルキル、C1−C6アルコキシ、C3−C6シクロアルキル、シアノ、−C(=O)H、フェニル、(C3−C6シクロアルキル)C1−C6アルコキシ、(C1−C6アルコキシカルボニルアミノ)C1−C6アルコキシまたは(C1−C6アルキルカルボニルアミノ)C1−C6アルコキシであり;
R4は、ヒドロキシ、エステル化ヒドロキシ、エーテル化ヒドロキシ、アミノ、(C1−C6アルキル)アミノ、基
R5は、水素またはヒドロキシであり;そして
mは、1または2である。]
で示されるキナゾリノン化合物。
[2] バニロイド受容体活性化が役割を果たすかまたは関係する疾患または状態の処置または予防のための医薬の製造を目的とした、遊離型または塩形態、および可能なときは薬学的に許容される酸付加塩形態の、式
R1は、C1−C6アルキル、(C1−C6アルキル)C1−C6アルキル、ジ−(C1−C6アルキル)C1−C6アルキル、C3−C6シクロアルキル、(C1−C6アルキル)アミノまたはジ−(C1−C6アルキル)アミノであり;
R2は、それぞれ独立して、ハロゲン、C1−C6アルキル、ハロゲン置換C1−C6アルキル、ヒドロキシC1−6アルキル、シアノまたは基−C(=O)−R2a(ここで、R2aは、C1−C6アルキルである。)であり;
R3は、水素、ハロゲン、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、ヒドロキシ、ヒドロキシ置換C1−C6アルキル、C1−C6アルコキシ、C3−C6シクロアルキル、シアノ、−C(=O)H、フェニル、(C3−C6シクロアルキル)C1−C6アルコキシ、(C1−C6アルコキシカルボニルアミノ)C1−C6アルコキシまたは(C1−C6アルキルカルボニルアミノ)C1−C6アルコキシであり;
R4は、ヒドロキシ、エステル化ヒドロキシ、エーテル化ヒドロキシ、アミノ、(C1−C6アルキル)アミノ、基
R5は、水素またはヒドロキシであり;そして
mは、1または2である。]
で示されるキナゾリノン化合物の使用。
[3] バニロイド受容体活性化が役割を果たすかまたは関係する疾患または状態の処置または予防のための方法であって、遊離型または塩形態、および可能なときは薬学的に許容される酸付加塩形態の、式
R1は、C1−C6アルキル、(C1−C6アルキル)C1−C6アルキル、ジ−(C1−C6アルキル)C1−C6アルキル、C3−C6シクロアルキル、(C1−C6アルキル)アミノまたはジ−(C1−C6アルキル)アミノであり;
R2は、それぞれ独立して、ハロゲン、C1−C6アルキル、ハロゲン置換C1−C6アルキル、ヒドロキシC1−6アルキル、シアノまたは基−C(=O)−R2a(ここで、R2aは、C1−C6アルキルである。)であり;
R3は、水素、ハロゲン、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、ヒドロキシ、ヒドロキシ置換C1−C6アルキル、C1−C6アルコキシ、C3−C6シクロアルキル、シアノ、−C(=O)H、フェニル、(C3−C6シクロアルキル)C1−C6アルコキシ、(C1−C6アルコキシカルボニルアミノ)C1−C6アルコキシまたは(C1−C6アルキルカルボニルアミノ)C1−C6アルコキシであり;
R4は、ヒドロキシ、エステル化ヒドロキシ、エーテル化ヒドロキシ、アミノ、(C1−C6アルキル)アミノ、基
R5は、水素またはヒドロキシであり;そして
mは、1または2である。]
で示されるキナゾリノン化合物の治療的有効量を、それを必要とする哺乳動物に投与することを含む方法。
[4] 遊離型または塩形態、および可能なときは酸付加塩形態の、式
R1は、C1−C6アルキル、(C1−C6アルキル)C1−C6アルキル、ジ−(C1−C6アルキル)C1−C6アルキル、C3−C6シクロアルキル、(C1−C6アルキル)アミノまたはジ−(C1−C6アルキル)アミノであり;
R2は、それぞれ独立して、ハロゲン、C1−C6アルキル、ハロゲン置換C1−C6アルキル、ヒドロキシC1−C6アルキル、シアノまたは基−C(=O)−R2a(ここで、R2aは、C1−C6アルキルである。)であり;
R3は、水素、ハロゲン、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、ヒドロキシ、ヒドロキシ置換C1−C6アルキル、C1−C6アルコキシ、C3−C6シクロアルキル、シアノ、−C(=O)H、フェニル、(C3−C6シクロアルキル)C1−C6アルコキシ、(C1−C6アルコキシカルボニルアミノ)C1−C6アルコキシまたは(C1−C6アルキルカルボニルアミノ)C1−C6アルコキシであり;
R4は、ヒドロキシ、エステル化ヒドロキシ、エーテル化ヒドロキシ、アミノ、(C1−C6アルキル)アミノ、基
mは、1または2である。]
で示されるキナゾリノン化合物。
[5] 遊離型または塩形態、および可能なときは薬学的に許容される酸付加塩形態の[4]に記載の化合物を薬学的担体または希釈剤と合わせて含む、医薬組成物。
[6] a)式(Ia)〔ここで、R1およびR2が、[4]に定義の通りであり、R3が水素であり、R4がアミノであり、そしてmが1である。〕の化合物を製造するために、三塩化リンの存在下、式
b)式(Ia)〔ここで、R1およびR2が、[4]に定義の通りであり、R3が水素であり、R4がヒドロキシであり、そしてmが1である。〕の化合物を製造するために、上記a)で製造した7−アミノ置換キナゾリン−4−オン化合物を、濃硫酸および亜硝酸ナトリウムを用いて還元し、式
ならびに、遊離型または塩形態のa)およびb)で製造した対応する化合物を回収する工程を含む、[4]に記載の式Iaの化合物またはその塩の製造方法。
Claims (1)
- バニロイド受容体活性化が役割を果たすかまたは関係する疾患または状態の処置または予防のための医薬としての使用を目的とした、遊離型または塩形態、および可能なときは薬学的に許容される酸付加塩形態の、式
R1は、C1−C6アルキル、(C1−C6アルキル)C1−C6アルキル、ジ−(C1−C6アルキル)C1−C6アルキル、C3−C6シクロアルキル、(C1−C6アルキル)アミノまたはジ−(C1−C6アルキル)アミノであり;
R2は、それぞれ独立して、ハロゲン、C1−C6アルキル、ハロゲン置換C1−C6アルキル、ヒドロキシC1−6アルキル、シアノまたは基−C(=O)−R2a(ここで、R2aは、C1−C6アルキルである。)であり;
R3は、水素、ハロゲン、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、ヒドロキシ、ヒドロキシ置換C1−C6アルキル、C1−C6アルコキシ、C3−C6シクロアルキル、シアノ、−C(=O)H、フェニル、(C3−C6シクロアルキル)C1−C6アルコキシ、(C1−C6アルコキシカルボニルアミノ)C1−C6アルコキシまたは(C1−C6アルキルカルボニルアミノ)C1−C6アルコキシであり;
R4は、ヒドロキシ、エステル化ヒドロキシ、エーテル化ヒドロキシ、アミノ、(C1−C6アルキル)アミノ、基
R5は、水素またはヒドロキシであり;そして
mは、1または2である。]
で示されるキナゾリノン化合物。
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