JP2017105729A - ミトコンドリア病の治療剤 - Google Patents
ミトコンドリア病の治療剤 Download PDFInfo
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- JP2017105729A JP2017105729A JP2015240970A JP2015240970A JP2017105729A JP 2017105729 A JP2017105729 A JP 2017105729A JP 2015240970 A JP2015240970 A JP 2015240970A JP 2015240970 A JP2015240970 A JP 2015240970A JP 2017105729 A JP2017105729 A JP 2017105729A
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- erythropoietin
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Abstract
Description
〔1〕式(1)
〔2〕式(1)で表される化合物が、以下のいずれかの式(2)〜(6)であることを特徴とする上記〔1〕に記載の治療剤。
〔3〕式(1)で表される化合物が、以下のいずれかの化合物であることを特徴とする上記〔1〕に記載の治療剤。
〔5〕式(1)
〔6〕式(1)で表される化合物が、以下のいずれかの式(2)〜(6)であることを特徴とする上記〔5〕に記載のエリスロポエチン発現増強剤。
〔7〕式(1)で表される化合物が、以下のいずれかの化合物であることを特徴とする上記〔5〕に記載のエリスロポエチン発現増強剤。
〔9〕式(1)で表される化合物が、以下のいずれかの式(2)〜(6)であることを特徴とする上記〔8〕に記載の化合物又はその塩。
〔10〕式(1)で表される化合物が、以下のいずれかの化合物であることを特徴とする上記〔8〕に記載の化合物又はその塩。
本発明の化合物は、以下の式(1)で表される化合物である。
本発明における式(1)で表される化合物は、公知の有機化学反応を用いる有機合成手法によって得ることができる。例えば、以下に示すように(E)−4−(2,4−ジフルオロフェニル)−4−オキソ−2−ブテン酸と式(7)で表されるインドール誘導体とをマイケル反応させることにより、式(1)で表される化合物を得ることができる。
1H-NMR(400MHz, CDCl3) δ 10.31 (s, 1H), 8.01 (m, 1H), 7.47 (dd, J=8.8, 5.2, 1H), 7.34 (d, J=2.0, 2H), 7.12-7.20 (m, 3H), 6.92 (td, J=9.6, 2.4, 1H), 4.54 (dd, J=10.4, 4.0, 1H), 4.01 (ddd, J=18.8, 10.8, 3.2, 1H), 3.38 (td, J=18.8, 3.2, 1H);
13C-NMR (100MHz, CDCl3) δ 195.18, 174.85, 166.28 JC-F(dd, 254, 13 Hz), 163.42 JC-F (dd, 254, 13 Hz), 161.74, 159.4, 137.54 JC-F (d, 13 Hz), 133.47 JC-F (dd, 11, 3 Hz), 123.35 JC-F(d, 4Hz), 123.02 JC-F (dd, 13, 4 Hz), 120.97 JC-F (d, 11 Hz), 113.51, 112.94 JC-F (dd, 10, 2 Hz) , 108.27 JC-F (d, 24 Hz), 105.59 JC-F (t, 27 Hz), 98.27 JC-F (d, 26 Hz), 46.68 JC-F (d, 7Hz) ,38.47;
FAB-MS m/z = 348 [M+H]+
1H-NMR(400MHz, acetone-d6) δ 10.34 (s, 1H), 8.02 (m, 1H), 7.47 (dd, J=10.4, 2.8, 1H), 7.39-7.43 (m, 2H), 7.13-7.21 (m, 2H), 6.93 (td, J=9.2 , 2.8, 1H), 4.52 (dd, J=10.4, 3.6, 1H), 4.03 (ddd, 18.4, 10.8, 3.6, 1H), 3.40 (td, 18.4, 3.6, 1H);
13C-NMR (100MHz, acetone-d6) δ 195.17, 174.86, 166.52 JC-F(dd, 254, 13 Hz), 163.58 JC-F (dd, 254, 13 Hz), 159.52, 157.21, 134.25, 133.46 JC-F (dd, 11, 4 Hz), 127.66 JC-F (d, 11 Hz), 123.01 JC-F (dd, 10, 4 Hz), 113.42 JC-F (d, 5 Hz), 113.28 JC-F(d, 10 Hz), 113.51 JC-F (dd, 21, 4 Hz), 110.56 JC-F (d, 27 Hz), 105.61 JC-F (t, 27 Hz), 104.65 JC-F (d, 24 Hz), 46.68 JC-F (d, 8Hz), 38.48;
FAB-MS m/z = 348 [M+H]+
1H-NMR(400MHz, acetone-d6) δ 10.55 (s, 1H), 8.01 (m, 1H), 7.75 (d, J=8.4, 1H), 7.45 (d, J=2.8, 1H), 7.06-7.14 (m, 4H), 7.08 (t. J=7.6, 1H), 4.57 (dd, J=10.4 , 3.6, 1H), 4.03 (ddd, 18.4, 10.8, 3.6, 1H), 3.41 (td, 18.4, 3.6, 1H);
13C-NMR(100MHz, acetone-d6) δ 195.06, 74.67, 166.53, JC-F(dd, 252, 12 Hz), 163.63 JC-F (dd, 252, 12 Hz), 134.45, 133.46 JC-F(dd, 11, 5 Hz), 129.25, 124.97, 122.98 JC-F (dd, 13, 4 Hz), 121.91, 120.84, 119.03, 117.22, 114.73, 112.99 JC-F (dd, 21, 3 Hz), 105.61 JC-F(t, 27 Hz), 46.71 JC-F (d, 8 Hz) , 38.50;
FAB-MS m/z = 364 [M+H]+
1H-NMR(400MHz, acetone-d6) δ 10.45 (s, 1H), 8.02 (q, J=8.3, 1H), 7.80 (d, J=1.6, 1H), 7.44 (m, 2H), 7.11-7.22 (m, 3H), 4.54 (dd, J=10.4, 3.8, 1H), 4.01 (ddd, J=18.7, 10.7, 3.2, 1H), 3.41 (td, J=18.7, 3.2, 1H);
13C-NMR (100MHz, acetone-d6) δ 195.10, 174.76, 166.52 JC-F(dd, 253, 12Hz), 163.62 JC-F (dd, 253, 12 Hz), 136.06, 133.44 JC-F(dd, 12, 4 Hz), 128.47, 125.62, 122.96 JC-F (dd, 13, 4 Hz), 122.48, 119.33, 113.77, 113.12, 112.96 JC-F (dd, 22, 3 Hz), 105.61 JC-F(t, 27 Hz), 46.72 JC-F (d, 8 Hz), 38.35;
FAB-MS m/z = 364 [M+H]+
1H-NMR(400MHz, acetone-d6) δ 10.24 (s, 1H), 8.01 (m, 1H), 7.77 (d, J=8.4, 1H), 7.42 (d, J=8.0, 1H), 7.21〜7.03 (m, 4H), 4.57 (dd, J=10.8, 3.6, 1H), 4.03 (ddd 18.8, 10.8, 3.2, 1H), 3.38 (td, 18.8, 3.2, 1H);
13C-NMR (100MHz, acetone-d6) δ 195.28, 174.97, 166.55 JC-F(dd, 254, 12 Hz), 163.62 JC-F (dd, 254, 12 Hz), 137.646, 137.49, 133.46 JC-F (dd, 11, 4 Hz), 127.37, 123.70, 123.54, 123.05 JC-F(dd, 13, 4 Hz), 122.39, 119.88, 119.79, 112.95 JC-F (dd, 22, 4 Hz), 105.58 JC-F (t, 26 Hz), 46.95 JC-F (d, 8 Hz), 38.47;
FAB-MS m/z = 364 [M+H]+
1H-NMR(400MHz, acetone-d6) δ 10.10 (s, 1H), 8.01 (m, 1H), 7.54 (s, 1H), 7.20-7.31 (m, 2H), 7.13-7.20 (m, 1H), 7.96 (d, J=6.8, 1H), 4.53 (dd, J=10.6, 3.6, 1H), 4.01 (ddd 18.8, 10.6, 3.2, 1H), 3.36 (td, 18.8, 3.2, 1H), 2.40 (s, 3H);
13C-NMR (100MHz, acetone-d6) δ 195.33, 175.08, 166.54 JC-F(dd, 254, 12 Hz), 163.49 JC-F (dd, 254, 12 Hz), 136.01, 133.45 JC-F(dd, 11, 4 Hz), 128.59, 127.63, 124.02, 123.72, 123.05 JC-F (dd, 13, 4 Hz), 119.43, 112.94 JC-F (dd, 22, 4 Hz), 112.74, 112.03, 105.59 JC-F(t, 26 Hz), 47.01 JC-F (d, 7 Hz), 38.45, 21.64;
FAB-MS m/z = 344 [M+H]+
1H-NMR(400MHz, acetone-d6) δ 8.00 (m, 1H), 7.75 (d, J=7.6, 1H) , 7.37 (d, J=8.4, 1H), 7.12-7.22 (m, 4H), 7.07 (t, J=7.6, 1H), 4.54 (dd, J=10.8, 3.6, 1H), 4.00 (ddd, 18.8, 10.4, 3.6, 1H), 3.79 (s, 3H), 3.36 (td, 18.8, 3.6, 1H);
13C-NMR (100MHz, acetone-d6) δ 195.22, 174.94, 166.52 JC-F(dd, 253, 13 Hz), 163.57 JC-F (dd, 253, 13 Hz), 138.08, 133.46 JC-F(dd, 11, 4 Hz), 128.00, 127.79, 123.03 JC-F (dd, 13, 4 Hz), 122.36, 120.07, 119.72, 112.94 JC-F (d, 22, 4 Hz), 112.33, 110.32, 105.60 JC-F(t, 27 Hz), 47.01 JC-F (d, 8 Hz), 38.36, 32.72;
FAB-MS m/z = 344 [M+H]+
1H-NMR(400MHz, acetone-d6) δ 10.26 (s, 1H), 8.01 (m, 1H), 7.35 (d, J=8.0, 1H), 7.28 (d, J=2.8, 1H), 7.12-7.20 (m, 2H), 6.98 (t, J=7.8, 1H), 6.67 (d, J=7.8, 1H), 4.54 (dd, J=10.8, 3.6, 1H), 4.03 (ddd 18.8, 10.6, 3.3, 1H), 3.92 (s, 3H), 3.36 (td, 18.6, 3.2, 1H);
13C-NMR (100MHz, acetone-d6) δ 1195.28, 174.98, 166.54 JC-F(dd, 252, 12 Hz), 163.48 JC-F (dd, 252, 12 Hz), 147.35, 133.44 JC-F(dd, 11, 4 Hz), 128.81, 127.83, 123.22, 123.05 JC-F (dd, 13, 4 Hz) , 120.43, 113.76, 112.94 JC-F (dd, 22, 4 Hz), 112.7, 105.59 JC-F(t, 27 Hz), 102.52, 55.52, 46.97 JC-F (d, 8 Hz) , 38.59;
FAB-MS m/z = 360 [M+H]+
1H-NMR(400MHz, acetone-d6) δ 10.09 (s, 1H), 8.02 (m, 1H), 7.27-7.31 (m, 3H), 7.13-7.20 (m, 2H), 6.79 (dd, J=8.8, 2.4, 1H), 4.52 (dd, J=10.8, 3.6, 1H), 4.00 (ddd, 18.8, 10.4, 3.4, 1H), 3.80 (s, 3H), 3.38 (td, 18.6, 3.4, 1H;
13C-NMR (100MHz, acetone-d6) δ 195.35, 175.03, 166.53, JC-F(dd, 253, 12 Hz), 163.61 JC-F (dd, 253, 12 Hz), 154.84, 133.45 JC-F(dd, 11, 4 Hz), 132.72, 127.78, 124.22, 123.04 JC-F (dd, 12, 4 Hz), 112.95 JC-F (dd, 22, 4 Hz), 112.96, 112.68, 105.61 JC-F (t, 26 Hz), 101.58, 55.79, 46.9 JC-F (d, 8 Hz), 38.67;
FAB-MS m/z = 360 [M+H]+
1H-NMR(400MHz, acetone-d6) δ 10.0 4(s, 1H), 8.01 (m, 1H), 7.65 (d, J=8.8, 1H), 7.48 (d, J-7.6, 2H), 7.38 (t, J=7.2, 2H), 7.31 (m, 1H), 7.13-7.20 (m, 3H), 7.03 (d, J=2.0, 1H), 6.83 (dd, J=8.4 , 2.0, 1H), 4.51 (dd, J=10.4 , 3.6, 1H), 4.01 (ddd, 18.1, 10.4, 3.3, 1H), 3.36 (td, 18.1, 3.3, 1H);
13C-NMR (100MHz, acetone-d6) δ 195.29, 175.00, 166.54 JC-F(dd, 254, 12 Hz), 163.52 JC-F (dd, 254, 12 Hz), 156.33, 138.85, 138.45, 133.45, JC-F (dd, 11, 4 Hz), 129.17, 128.37, 128.23, 123.01 JC-F(dd, 13, 4 Hz), 122.49, 121.97, 120.54, 113.24, 113.06 JC-F (dd, 21, 4 Hz), 110.73, 105.59 JC-F (t, 27 Hz), 96.89, 70.70, 46.94 JC-F(d, 8 Hz), 38.57;
FAB-MS m/z = 436 [M+H]+
(E)−4−(2,4−ジフルオロフェニル)−4−オキソ−2−ブテン酸
1H-NMR(400MHz, acetone-d6) δ 7.98 (m, 1H), 7.72 (dd, J=15.6 , 3.6, 1H), 7.20-7.28 (m, 2H), 6.75 (d, J=15.6, 2H);
13C-NMR(100MHz, acetone-d6) δ 187.13, 166.86 JC-F(dd, 254, 12 Hz), 166.35, 163.33 JC-F (dd, 254, 12 Hz), 139.95 JC-F(d, 7 Hz), 133.98 JC-F (dd, 66, 59 Hz), 132.91, 123.22 JC-F(d, 9 Hz), 113.33 JC-F (dd, 22 , 3 Hz), 105.76, JC-F (t, 22 Hz)
[方法]
実施例1で合成した本件化合物#6を用い、以下の手順〔1〕〜〔4〕にしたがってLeber病患者由来線維芽細胞の酸化ストレスによる細胞死抑制効果を検討した。
〔1〕24ウェル細胞培養プレートに1ウェルあたり3×104個のLeber病患者由来線維芽細胞を撒いた後、24時間培養した。
〔2〕グルタチオン合成阻害剤BSO(L-Buthionine sulphoximine)(Sigma-Aldrich社製)を、100μMとなるように培養液中に混和し、24時間培養した。
〔3〕本件化合物#6及び比較例化合物#4を、各種濃度(0.1、0.3、1、3、及び10μM)となるように培養液中に混和し、48時間培養した(n=4)。なお、対照として化合物非存在下(DMSOを0.01%となるように添加)で培養した。
〔4〕細胞生存率を、Cell Counting Kit-8(同仁化学研究所社製)を用いたMTTアッセイにより測定した。すなわち、各ウェルにCell Count Reagent SFを100μLずつ添加し、2時間インキュベートし、マイクロプレートリーダーで3秒間撹拌した後、吸光度450nm(リファレンス750nm)を測定した。また、細胞障害レベルは、Cytotoxicity LDH Assay Kit-WST(同仁化学研究所社製)を用いて細胞外に放出された乳酸脱水素酵素(LDH)活性を測定することにより検出した。すなわち、各ウェルに調製したWorking Solutionを100μLずつ添加し、30分間インキュベーションし、Stop Solutionを50μLずつ添加し、マイクロプレートリーダーで3秒間撹拌した後、吸光度490nm(リファレンス750nm)を測定した。
まず、BSO存在下でLeber病患者由来線維芽細胞を培養すると、細胞生存率が低下することを確認した(図1A参照)。次に、かかる条件で本件化合物#6を添加すると、少なくとも1μMの濃度で細胞生存率低下が抑制され(図1Bの左図参照)、細胞障害レベルが低下することが示された(図1Cの左図参照)。一方、比較例化合物#4は、細胞生存率低下を抑制させ、細胞障害レベルを低下させるためには、少なくとも10μMの濃度を必要とすることが示された(図1B及びCの右図参照)。この結果は、本件化合物#6は比較例化合物#4よりも低濃度で、Leber病患者由来線維芽細胞の酸化ストレスによる細胞死を抑制することができることを示している。また、同様の解析法を用いて、本件化合物#1〜5、及び7〜10についても、Leber病患者由来線維芽細胞の酸化ストレスによる細胞死抑制効果を有することを確認した。さらに、KSS患者由来線維芽細胞を用いた同様の解析法により、本件化合物#1〜10は、KSS患者由来線維芽細胞の酸化ストレスによる細胞死抑制効果を有することも確認した。
以上の結果は、本発明の化合物は、Leber病、KSS等のミトコンドリア病患者の酸化ストレスによる細胞死を抑制し、ミトコンドリア病の治療効果を有することを示している。
[方法]
12ウェル細胞培養プレートに1ウェルあたり1×105個のエリスロポエチン産生ヒト肝臓癌細胞株Hep3B(ATCC[American Type Culture Collection]より入手)を撒いた後、24時間正常酸素(20%O2)下で培養し、実施例1で合成した3種類の化合物(本件化合物#1、5及び6)と、リコンビナントヒトTNFα(Roche社製)とを、それぞれ3μM及び220μg/mLとなるようにRPMI1640通常培養液に混和し、さらに24時間正常酸素(20%O2)下で培養した後、培養液中に産生されたエリスロポエチンの濃度(mIU/mL)をヒトエリスロポエチンELISAキット(Bender MedSystems社製)を用いて測定した(図2の「A1」、「A5」、及び「A6」)。なお、ネガティブコントロールとして化合物非存在(DMSO添加[1%])下で培養したHep3B細胞(図2の「DMSO」)を用いた。
Hep3B細胞におけるエリスロポエチン産生はTNFα存在下で抑制されるが、3種類の化合物(本件化合物#1、5及び6)存在下で培養すると、エリスロポエチンの発現量は増加することが明らかとなった(図2参照)。この結果は、本発明の化合物は、TNFα等の炎症性サイトカインによるエリスロポエチン産生抑制を解除し、エリスロポエチン産生を促進する効果を有することを示している。
Claims (10)
- 式(1)
- 式(1)で表される化合物が、以下のいずれかの式(2)〜(6)であることを特徴とする請求項1に記載の治療剤。
- 式(1)で表される化合物が、以下のいずれかの化合物であることを特徴とする請求項1に記載の治療剤。
- ミトコンドリア病が、Leber病、カーンズ・セイヤー症候群(KSS)、又はLeigh脳症であることを特徴とする請求項1〜3のいずれかに記載の治療剤。
- 式(1)
- 式(1)で表される化合物が、以下のいずれかの式(2)〜(6)であることを特徴とする請求項5に記載のエリスロポエチン発現増強剤。
- 式(1)で表される化合物が、以下のいずれかの化合物であることを特徴とする請求項5に記載のエリスロポエチン発現増強剤。
- 式(1)表される化合物又はその塩。
- 式(1)で表される化合物が、以下のいずれかの式(2)〜(6)であることを特徴とする請求項8に記載の化合物又はその塩。
- 式(1)で表される化合物が、以下のいずれかの化合物であることを特徴とする請求項8に記載の化合物又はその塩。
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JP7219387B1 (ja) | 2021-08-06 | 2023-02-08 | 国立大学法人東北大学 | 4-(2,4-ジフルオロフェニル)-2-(1h-インドール-3-イル)-4-オキソ-ブタン酸のr体 |
WO2023013756A1 (ja) * | 2021-08-06 | 2023-02-09 | 国立大学法人東北大学 | 4-(2,4-ジフルオロフェニル)-2-(1h-インドール-3-イル)-4-オキソ-ブタン酸のr体 |
JP2023024389A (ja) * | 2021-08-06 | 2023-02-16 | 国立大学法人東北大学 | 4-(2,4-ジフルオロフェニル)-2-(1h-インドール-3-イル)-4-オキソ-ブタン酸のr体 |
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