JP2011525906A - 置換されたピリミドン誘導体 - Google Patents
置換されたピリミドン誘導体 Download PDFInfo
- Publication number
- JP2011525906A JP2011525906A JP2011515668A JP2011515668A JP2011525906A JP 2011525906 A JP2011525906 A JP 2011525906A JP 2011515668 A JP2011515668 A JP 2011515668A JP 2011515668 A JP2011515668 A JP 2011515668A JP 2011525906 A JP2011525906 A JP 2011525906A
- Authority
- JP
- Japan
- Prior art keywords
- group
- alkyl group
- hydrogen atom
- phenyl
- pyridin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 22
- 125000005843 halogen group Chemical group 0.000 claims abstract description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000001424 substituent group Chemical group 0.000 claims abstract description 20
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 19
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Classifications
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- 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
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Abstract
式中:R1は4−ピリジン環を表わし;R2は水素原子を表わし;R3は水素原子を表わし;R4は:水素原子;フェニル環を表わし、この環は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されており;R5は、水素原子、C1−6アルキル基、4−ピリジン基、フェニル基を表わし、これらの基は場合により置換されており;R6は、水素原子、C1−6アルキル基、ベンジルオキシ基、フェニルC1−6アルキル基を表わし、これらの基は場合により置換されている、遊離塩基の形態または酸との付加塩の形態である誘導体。治療的使用。
Description
R1は4−ピリジン環を表わし;
R2は水素原子を表わし;
R3は水素原子を表わし;
R4は:
水素原子;
フェニル環を表わし、この環は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されており;
R5は、水素原子、C1−6アルキル基、4−ピリジン基、フェニル基を表わし、これらの基は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されており;
R6は、水素原子、C1−6アルキル基、ベンジルオキシ基、フェニルC1−6アルキル基を表わし、これらの基は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されている。
R1は4−ピリジン環を表わし;
R2は水素原子を表わし;
R3は水素原子を表わし;
R4は:
水素原子;
フェニル環を表わし、この環は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されており;
R5は、水素原子、C1−6アルキル基、4−ピリジン基、フェニル基を表わし、これらの基は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されており;
R6は、水素原子、C1−6アルキル基、ベンジルオキシ基、フェニルC1−6アルキル基を表わし、これらの基は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されているが、
ただし、R4およびR5が水素原子を表わす場合、R6はメチルまたはベンジルではない。
R1は4−ピリジン環を表わし;
R2は水素原子を表わし;
R3は水素原子を表わし;
R4は、水素原子、ハロゲン原子、フェニル基を表わし;
R5は、水素原子、C1−6アルキル基、4−ピリジン環、フェニル基を表わし;
R6は、水素原子、C1−6アルキル基、ベンジルオキシ基、フェニルC1−6アルキル基を表わし、これらの基は場合により、C1−6アルキル基、ハロゲン、C1−6アルコキシ基から選択される1から4個の置換基によって置換されている
化合物を、遊離塩基の形態または酸との付加塩の形態にて提供するが、ただしR4およびR5が水素原子を表わす場合、R6はメチルまたはベンジルではない。
R1は4−ピリジン環を表わし;
R2は水素原子を表わし;
R3は水素原子を表わし;
R4は、水素原子、ハロゲン原子、フェニル基を表わし;
R5は、水素原子、C1−6アルキル基、4−ピリジン環、フェニル基を表わし;
R6は、水素原子、C1−6アルキル基、ベンジルオキシ基、フェニルC1−6アルキル基を表わし、これらの基は場合により、C1−6アルキル基、ハロゲン、C1−6アルコキシ基から選択される1から4個の置換基によって置換されている、遊離塩基の形態または酸との付加塩の形態である化合物を提供する。
R1は4−ピリジン環を表わし;
R2は水素原子を表わし;
R3は水素原子を表わし;
R4は、水素原子、またはフェニル環を表わし、この環は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されており;
R5は、水素原子、C1−6アルキル基、4−ピリジン基、フェニル基を表わし、これらの基は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されており;
R6は、水素原子、C1−6アルキル基、ベンジルオキシ基、フェニルC1−6アルキル基を表わし、これらの基は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されている、遊離塩基の形態または酸との付加塩の形態である化合物を提供する。
R1は4−ピリジン環を表わし;
R2は水素原子を表わし;
R3は水素原子を表わし;
R4は、水素原子、ハロゲン原子またはフェニル環を表わし、この環は、場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されており;
R5は、C1−6アルキル基、4−ピリジン基、フェニル基を表わし、これらの基は、場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されており;
R6は、水素原子、C1−6アルキル基、ベンジルオキシ基、フェニルC1−6アルキル基を表わし、これらの基は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されている
化合物を、遊離塩基の形態または酸との付加塩の形態にて提供する。
R1は4−ピリジン環を表わし、
R2、R2、R3、R4およびR5は水素原子を表わし、
R6は、水素原子、ベンジルオキシ基、フェニルC2−6アルキル基を表わし、これらの基は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されている、遊離塩基の形態または酸との付加塩の形態である化合物を提供する。
1.2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
2.7−フェニル−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
3.8,9−ジメチル−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
4.8−フェニル−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
5.2,8−ジ−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
6.9−ベンジルオキシ−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
7.9−[2−(2−メトキシ−フェニル)−エチル]−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
8.2−ピリジン−4−イル−9−(2−o−トリル−エチル)−ピリド[1,2−a]ピリミジン−4−オン
9.9−(3−フェニル−プロピル)−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
10.9−[2−(2,4−ジフルオロ−フェニル)−エチル]−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
11.9−[2−(2−フルオロ−フェニル)−エチル]−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
12.9−[3−(2−フルオロ−フェニル)−プロピル]−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
上述の式(I)によって表されるピリミドン化合物は、スキーム1に記載される方法に従って調製できる。
(上記スキームにおいてR1、R2、R3、R4、R5およびR6の定義は、式(I)の化合物について既に記載されたものと同一である。)
式(II)および(III)の化合物は市販されているか、または当業者に周知の方法に従って合成されてもよい。
2−ピリジン−4−イル―4H−ピリド[1,2−a]ピリミジン−4−オン
ピリジン−2−アミン0.406g(4.31mmol)およびエチル3−(4−ピリジニル)−3−オキソプロピオナート1.00g(5.17mmol)を、ポリリン酸(84%最小)3gに添加した。反応混合物を、140℃にて12時間加熱した。冷却後、水を添加して、混合物を水酸化ナトリウム水溶液(30%)で中和して、クロロホルムで抽出した。抽出物を塩化ナトリウム飽和水溶液で洗浄し、乾燥し、エバポレートした。得られた残渣を、ジクロロメタン/メタノール/アンモニア水溶液(29%)の混合物を99/1/0.1から85/15/1.5の割合で用いて溶出するシリカゲル上のクロマトグラフィーにより精製して、所望の化合物0.154g(16%)を得て、これを通常の様式によりオキサラート塩に変換し、固体として純粋な生成物を得た。
MP:222−224℃
RMN 1H(DMSO−d6;200MHz)
δ(ppm):9.10(d,1H),8.80(d,2H),8.15(d,2H),8.05(t,1H),7.80(d,1H),7.40(t,1H),7.15(s,1H)。
7−フェニル−2−ピリジン−4−イル―4H−ピリド[1,2−a]ピリミジン−4−オン
5−フェニルピリジン−2−アミン0.20g(1.17mmol)およびエチル−3−(4−ピリジニル)−3−オキソプロピオナート0.227g(1.17mmol)の混合物に、酢酸アンモニウム0.180g(2.34mmol)を添加した。反応混合物を140℃で12時間加熱した。冷却後、水を添加し、混合物をクロロホルムで抽出した。抽出物を塩化ナトリウム飽和水溶液で洗浄し、硫酸ナトリウムで脱水し、エバポレートした。得られた固体をメタノール中に溶解させ、酢酸エチル/エタノールの混合物を95/5の割合で用いて溶出する分取薄層クロマトグラフィーで精製して、所望の化合物0.10g(28%)を得て、これを通常の様式でオキサラート塩に変換して、固体として純粋な生成物を得た。
Mp:220−224℃
RMN 1H(DMSO−d6;200MHz)
δ(ppm):9.20(d,1H),8.80(d,2H),8.45(dd,1H),8.20(d,2H),7.95(s,1H),7.85(m,2H),7.60(m,3H),7.20(s,1H)。
8−フェニル−2−ピリジン−4−イル―4H−ピリド[1,2−a]ピリミジン−4−オン
ピリジン−2−アミンの代わりに、4−フェニルピリジン−2−アミン(Journal of Medicinal chemistry 1978,Vol.21,N°9,pp874−876に記載される合成)を用いて、実施例1に記載の方法と同様の方法によって、生成物を得て、これを通常の様式でオキサラート塩に変換して、固体0.155g(10%)を得た。
Mp:261−262℃
RMN 1H(DMSO−d6;200MHz)
δ(ppm):9.10(d,1H),8.80(d,2H),8.20(m,3H),8.00(m,2H),7.85(dd,1H),7.60(m,3H),7.15(s,1H)。
9−ベンジルオキシ−2−ピリジン−4−イル−4H−ピリド[1,2−a]ピリミジン−4−オン
3−(ベンジルオキシ)ピリジン−2−アミン5.02mmol)およびエチル3−(4−ピリジニル)−3−オキソプロピオナート1.16g(6.02mmol)の混合物に、酢酸アンモニウム0.774(10.04mmol)を添加した。反応混合物を150℃で12時間加熱した。冷却後、水を添加し、混合物をジクロロメタンで抽出した。抽出物を塩化ナトリウム飽和水溶液で洗浄し、硫酸ナトリウムで脱水し、エバポレートした。得られた残渣を、ジクロロメタン/エタノールの混合物を99/1から90/10の割合で用いて溶出するシリカゲル上のクロマトグラフィーによって精製して、所望の化合物0.32g(19%)を得て、これを通常の様式で塩酸塩に変換して、黄色固体として純粋な生成物を得た。
MP:215−217℃
RMN 1H (DMSO−d6;200MHz)
δ(ppm):9.00(d,2H),8.65(d,1H),8.50(d,2H),7.65(m,3H),7.50−7.30(m,5H),5.50(s,2H)。
4つの異なるプロトコルが使用できる。
NH2−YRRAAVPPSPSLSRHSSPHQS(P)EDEE−COOH。(Woodgett,J.R.(1989)Analytical Biochemistry 180,237−241。
(1)錠剤
以下の成分は、通常の方法によって混合され、従来の装置を用いることによって圧縮された。
実施例1の化合物 30mg
結晶性セルロース 60mg
コーンスターチ 100mg
ラクトース 200mg
ステアリン酸マグネシウム 4mg
以下の成分は通常の方法によって混合され、軟カプセルに充填された。
実施例1の化合物 30mg
オリーブ油 300mg
レシチン 20mg
以下の成分は、1mlのアンプルに含有された注射を調製するため通常の方法によって混合された。
実施例1の化合物 3mg
塩化ナトリウム 4mg
注射用の蒸留水 1ml
Claims (15)
- 式(I)によって表わされるピリミドン誘導体であって:
R1は4−ピリジン環を表わし;
R2は水素原子を表わし;
R3は水素原子を表わし;
R4は:
水素原子;
フェニル環を表わし、この環は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されており;
R5は、水素原子、C1−6アルキル基、4−ピリジン基、フェニル基を表わし、これらの基は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されており;
R6は、水素原子、C1−6アルキル基、ベンジルオキシ基、フェニルC1−6アルキル基を表わし、これらの基は場合により、C1−6アルキル基、ハロゲン原子、C1−2ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2ハロゲン化アルコキシ基から選択される1から4個の置換基によって置換されている、
遊離塩基の形態または酸との付加塩の形態であり、
R4およびR5が水素原子を表わす場合、R6はメチルまたはベンジルではない、ピリミドン誘導体。 - 遊離塩基の形態または酸との付加塩の形態において、式(I)によって表わされるピリミドン誘導体であって、
R1は4−ピリジン環を表わし;
R2は水素原子を表わし;
R3は水素原子を表わし;
R4は、水素原子、ハロゲン原子、フェニル基を表わし;
R5は、水素原子、C1−6アルキル基、4−ピリジン環、フェニル基を表わし;
R6は、水素原子、C1−6アルキル基、ベンジルオキシ基、フェニルC1−6アルキル基を表わし、これらの基は場合により、C1−6アルキル基、ハロゲン、C1−6アルコキシ基から選択される1から4個の置換基によって置換されている、
ただしR4およびR5が水素原子を表わす場合、R6はメチルまたはベンジルではない、ピリミドン誘導体。 - 2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
7−フェニル−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
8,9−ジメチル−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
8−フェニル−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
2,8−ジ−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
9−ベンジルオキシ−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
9−[2−(2−メトキシ−フェニル)−エチル]−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
2−ピリジン−4−イル−9−(2−o−トリル−エチル)−ピリド[1,2−a]ピリミジン−4−オン
9−(3−フェニル−プロピル)−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
9−[2−(2,4−ジフルオロ−フェニル)−エチル]−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
9−[2−(2−フルオロ−フェニル)−エチル]−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
9−[3−(2−フルオロ−フェニル)−プロピル]−2−ピリジン−4−イル−ピリド[1,2−a]ピリミジン−4−オン
から成る群から選択される、請求項1および3に記載の、ピリミドン誘導体またはこれらの塩、またはこれらの溶媒和物、またはこれらの水和物。 - 請求項1から3に記載の、式(I)によって表わされるピリミドン誘導体またはこれらの塩、またはこれらの溶媒和物、またはこれらの水和物から成る群から選択される物質を活性成分として含む薬剤。
- 請求項1から3に記載の、式(I)によって表わされるピリミドン誘導体またはこれらの塩から成る群から選択されるGSK3β阻害剤。
- 異常GSK3β活性によって生じる疾患の予防的および/または治療的処置のための、請求項1から3に記載の化合物。
- 神経変性疾患の予防的および/または治療的処置のための、請求項1から3に記載の化合物。
- 神経変性疾患が、アルツハイマー病、パーキンソン病、タウオパシー、血管性認知症;急性脳卒中、外傷;脳血管発作、頭部外傷、脊髄損傷;末梢神経障害;網膜症または緑内障から成る群から選択される、請求項7に記載の化合物。
- インスリン非依存性糖尿病;肥満症;躁鬱病;統合失調症;脱毛症;癌;実質性腎疾患または筋委縮性症の予防的および/または治療的処置のための、請求項1から3に記載の化合物。
- 癌が、乳癌、非小細胞肺癌、甲状腺癌、TまたはB−細胞白血病、およびウイルス誘発腫瘍である、請求項9に記載の化合物。
- マラリアの予防的および/または治療的処置のための、請求項1から3に記載の化合物。
- 骨の疾患の予防的および/または治療的処置のための、請求項1から3に記載の化合物。
- 尋常性天疱瘡の予防的および/または治療的処置のための、請求項1から3に記載の化合物。
- 癌の化学療法によって誘発される好中球減少症の予防的および/または治療的処置のための、請求項1から3に記載の化合物。
- 認知障害および記憶障害を特徴とする疾患の治療的処置のための、請求項1から3に記載の化合物。
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JP2015508075A (ja) * | 2012-02-10 | 2015-03-16 | ピーティーシー セラピューティクス, インコーポレイテッド | 脊髄性筋萎縮症を治療するための化合物 |
JP2017122097A (ja) * | 2012-02-10 | 2017-07-13 | ピーティーシー セラピューティクス, インコーポレイテッド | 脊髄性筋萎縮症を治療するための化合物 |
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WO2009156861A2 (en) | 2009-12-30 |
BRPI0914544A2 (pt) | 2015-12-15 |
KR20110027802A (ko) | 2011-03-16 |
CN102076341A (zh) | 2011-05-25 |
NZ590043A (en) | 2012-03-30 |
IL210176A0 (en) | 2011-03-31 |
TW201006835A (en) | 2010-02-16 |
MX2010013944A (es) | 2011-06-24 |
WO2009156861A3 (en) | 2010-04-01 |
EP2321314A2 (en) | 2011-05-18 |
EP2321314B1 (en) | 2017-05-31 |
WO2009156861A8 (en) | 2012-04-26 |
AR072224A1 (es) | 2010-08-11 |
CA2728694A1 (en) | 2009-12-30 |
EA201170096A1 (ru) | 2011-08-30 |
US20110144133A1 (en) | 2011-06-16 |
JP5501353B2 (ja) | 2014-05-21 |
EP2138493A1 (en) | 2009-12-30 |
US9073915B2 (en) | 2015-07-07 |
AU2009263847A1 (en) | 2009-12-30 |
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