JP5631428B2 - ミトコンドリア病および他の状態の治療、およびエネルギーバイオマーカーの調節のための酸化還元活性治療薬 - Google Patents
ミトコンドリア病および他の状態の治療、およびエネルギーバイオマーカーの調節のための酸化還元活性治療薬 Download PDFInfo
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- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 229940040064 ubiquinol Drugs 0.000 description 1
- QNTNKSLOFHEFPK-UPTCCGCDSA-N ubiquinol-10 Chemical compound COC1=C(O)C(C)=C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)C(O)=C1OC QNTNKSLOFHEFPK-UPTCCGCDSA-N 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 235000019195 vitamin supplement Nutrition 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
- 239000002478 γ-tocopherol Substances 0.000 description 1
- GZIFEOYASATJEH-VHFRWLAGSA-N δ-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-VHFRWLAGSA-N 0.000 description 1
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Description
本願は、2005年6月1日に出願された、米国仮特許出願第60/686,826号、2005年7月21日に出願された、米国仮特許出願第60/701,815号、および2006年2月22日に出願された、米国仮特許出願第60/776,028号に対する利益を主張する。これらの出願の全内容は、本明細書中に参考として援用される。
本出願は、対象におけるフリードライヒ失調症、レーバー遺伝性視神経障害、キーンズセイアー症候群、および乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症などのミトコンドリア障害の治療または抑制に、ならびにエネルギーバイオマーカーの調節に有用な組成物および方法を開示する。
ミトコンドリアは、真核細胞における細胞小器官であり、一般に細胞の「発電所」と呼ばれる。分子であるアデノシン三リン酸(ATP)は細胞中のエネルギー「通貨」すなわちエネルギー担体として機能し、真核細胞は、ミトコンドリアによって遂行された生化学過程からそのATPの大部分を得る。これらの生化学過程には、酸化型ニコチンアミドアデニンジヌクレオチド(NAD+)から還元型ニコチンアミドアデニンジヌクレオチド(NADH+H+)を発生するクエン酸回路(トリカルボン酸回路またはクレブス回路)、およびNADH+H+がNAD+に酸化し戻される酸化的リン酸化がある。(クエン酸回路は、フラビンアデニンジヌクレオチド(FAD)をFADH2にも還元する。FADH2もまた酸化的リン酸化に関与している。)
NADH+H+の酸化により放出される電子は、呼吸鎖として知られている一連のタンパク質複合体(複合体I、複合体II、複合体III、および複合体IV)を下向きに移動する。これらの複合体はミトコンドリア内膜に埋め込まれている。呼吸鎖の最後にある複合体IVは電子を酸素に伝達し、その酸素は水に還元される。これらの電子がこれらの複合体を行き来するときに放出されるエネルギーは、ミトコンドリア内膜を隔てたプロトン勾配を発生するために使用され、その勾配は内膜を隔てた電気化学的ポテンシャルを生み出す。別のタンパク質複合体である複合体V(この複合体は複合体I、II、III、およびIVと直接関連していない)は、電気化学的勾配により貯蔵されたエネルギーを使用してADPをATPに変換する。
したがって、フリードライヒ失調症、レーバー遺伝性視神経障害、MELAS、およびキーンズセイアー症候群などのミトコンドリア障害の有効な治療法への深刻でまだ対処されていない必要性がある。
一実施形態では、本発明は、式I/III:
例えば、本発明は以下の項目を提供する。
(項目1)
ミトコンドリア障害を治療するか、1つもしくは複数のエネルギーバイオマーカーを調節するか、1つもしくは複数のエネルギーバイオマーカーを正常化するか、または1つまたは複数のエネルギーバイオマーカーを強化する方法であって、式:
(項目2)
前記1つまたは複数の化合物が、式:
(項目3)
前記化合物が
(項目4)
R 11 、R 12 、およびR 13 のいずれもHではなく、R 11 、R 12 、およびR 13 の少なくとも1つがメチルではない、項目1に記載の方法。
(項目5)
式:
(項目6)
ミトコンドリア障害を治療するか、1つもしくは複数のエネルギーバイオマーカーを調節するか、1つもしくは複数のエネルギーバイオマーカーを正常化するか、または1つまたは複数のエネルギーバイオマーカーを強化する方法であって、項目5に記載の1つまたは複数の化合物の治療有効量または有効量を対象に投与することを含む方法。
(項目7)
式:
(項目8)
ミトコンドリア障害を治療するか、1つもしくは複数のエネルギーバイオマーカーを調節するか、1つもしくは複数のエネルギーバイオマーカーを正常化するか、または1つまたは複数のエネルギーバイオマーカーを強化する方法であって、項目7に記載の1つまたは複数の化合物の治療有効量または有効量を対象に投与することを含む方法。
(項目9)
式:
(項目10)
ミトコンドリア障害を治療するか、1つもしくは複数のエネルギーバイオマーカーを調節するか、1つもしくは複数のエネルギーバイオマーカーを正常化するか、または1つまたは複数のエネルギーバイオマーカーを強化する方法であって、項目9に記載の化合物の治療有効量または有効量を対象に投与することを含む方法。
(項目11)
ミトコンドリア障害を治療するか、1つもしくは複数のエネルギーバイオマーカーを調節するか、1つもしくは複数のエネルギーバイオマーカーを正常化するか、または1つまたは複数のエネルギーバイオマーカーを強化する方法であって、式IV:
(項目12)
式:
(項目13)
項目12に記載の1つまたは複数の化合物の治療有効量または有効量を対象に投与することにより、ミトコンドリア障害を治療するか、1つもしくは複数のエネルギーバイオマーカーを調節するか、1つもしくは複数のエネルギーバイオマーカーを正常化するか、または1つまたは複数のエネルギーバイオマーカーを強化する方法。
(項目14)
式VI:
(項目15)
式:
(項目16)
項目15に記載の1つまたは複数の化合物の治療有効量または有効量を対象に投与することにより、ミトコンドリア障害を治療するか、1つもしくは複数のエネルギーバイオマーカーを調節するか、1つもしくは複数のエネルギーバイオマーカーを正常化するか、または1つまたは複数のエネルギーバイオマーカーを強化する方法。
(項目17)
ミトコンドリア障害を治療するか、1つもしくは複数のエネルギーバイオマーカーを調節するか、1つもしくは複数のエネルギーバイオマーカーを正常化するか、または1つまたは複数のエネルギーバイオマーカーを強化する方法であって、式X−O、式X−R、式XI−O、式XI−R、式XII−O、または式XII−R:
(項目18)
前記化合物が、
(項目19)
前記ミトコンドリア障害が、遺伝性ミトコンドリア病;もじゃもじゃ赤色線維ミオパシーを伴うミオクローヌスてんかん(MERRF)、乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症(MELAS)、レーバー遺伝性視神経障害(LHON)、リー病、キーンズセイアー症候群(KSS)、フリードライヒ失調症(FA)、その他の筋症、心筋症、脳筋症、尿細管性アシドーシス、神経変性疾患、パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症(ALS)、運動ニューロン疾患、その他の神経系疾患、てんかん、遺伝性疾患、ハンチントン病、気分障害、統合失調症、双極性障害、加齢関連疾患、黄斑変性、糖尿病、および癌からなる群から選択される、項目6に記載の方法。
(項目20)
前記ミトコンドリア障害が、遺伝性ミトコンドリア病、もじゃもじゃ赤色線維ミオパシーを伴うミオクローヌスてんかん(MERRF)、乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症(MELAS)、レーバー遺伝性視神経障害(LHON)、リー病、キーンズセイアー症候群(KSS)、およびフリードライヒ失調症(FA)からなる群から選択される、項目19に記載の方法。
(項目21)
前記エネルギーバイオマーカーが、全血、血漿、脳脊髄液、または脳室液のいずれかの中の乳酸(乳酸塩)濃度;全血、血漿、脳脊髄液、または脳室液のいずれかの中のピルビン酸(ピルビン酸濃度)濃度;全血、血漿、脳脊髄液、または脳室液のいずれかにおける乳酸/ピルビン酸比;クレアチンリン酸レベル、NADH(NADH+H + )レベル;NADPH(NADPH+H + )レベル;NADレベル;NADPレベル;ATPレベル;還元型補酵素Q(CoQ red )レベル;酸化型補酵素Q(CoQ ox )レベル;総補酵素Q(CoQ tot )レベル;酸化型チトクロームCレベル;還元型チトクロームCレベル;酸化型チトクロームC/還元型チトクロームC比;アセト酢酸レベル、β−ヒドロキシ酪酸レベル、アセト酢酸/β−ヒドロキシ酪酸比、8−ヒドロキシ−2’−デオキシグアノシン(8−OHdG)レベル;活性酸素種レベル;酸素消費量(VO2)のレベル;二酸化炭素産出量(VCO2)のレベル;呼吸商(VCO2/VO2);運動耐性;および無酸素性作業閾値からなる群から選択される、項目1に記載の方法。
(項目22)
薬学的に許容できる賦形剤をさらに含む、項目5に記載の化合物。
(項目23)
前記対象が、ミトコンドリア病を有する対象、激しい身体活動もしくは持続する身体活動を行っている対象、慢性的なエネルギーの問題を有する対象、慢性的な呼吸の問題を有する対象、妊婦、分娩中の妊婦;新生児、未熟児、極限環境に曝されている対象、暑熱環境に曝されている対象、寒冷環境に曝されている対象、平均よりも低い酸素含量の環境に曝されている対象、平均よりも高い二酸化炭素含量の環境に曝されている対象、平均よりも高い大気汚染レベルの環境に曝されている対象、肺疾患を有する対象、平均よりも低い肺活量を有する対象、結核患者、肺癌患者、気腫患者、嚢胞性線維症患者、手術から回復中の患者、疾病から回復中の対象;急性外傷を受けている対象、ショック状態の対象、急性酸素投与を必要とする対象、慢性酸素投与を必要とする対象、高齢の対象、エネルギー減退を経験している高齢の対象、および慢性疲労を患う対象からなる群から選択される、項目1に記載の方法。
(項目24)
前記ミトコンドリア障害が、遺伝性ミトコンドリア病、もじゃもじゃ赤色線維ミオパシーを伴うミオクローヌスてんかん(MERRF)、乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症(MELAS)、レーバー遺伝性視神経障害(LHON)、リー病、キーンズセイアー症候群(KSS)、フリードライヒ失調症(FA)、その他の筋症、心筋症、脳筋症、尿細管性アシドーシス、神経変性疾患、パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症(ALS)、運動ニューロン疾患、その他の神経系疾患、てんかん、遺伝性疾患、ハンチントン病、気分障害、統合失調症、双極性障害、加齢関連疾患、黄斑変性、糖尿病、および癌からなる群から選択される、項目1に記載の方法。
(項目25)
前記ミトコンドリア障害が、遺伝性ミトコンドリア病、もじゃもじゃ赤色線維ミオパシーを伴うミオクローヌスてんかん(MERRF)、乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症(MELAS)、レーバー遺伝性視神経障害(LHON)、リー病、キーンズセイアー症候群(KSS)、フリードライヒ失調症(FA)、その他の筋症、心筋症、脳筋症、尿細管性アシドーシス、神経変性疾患、パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症 ALS)、運動ニューロン疾患、その他の神経系疾患、てんかん、遺伝性疾患、ハンチントン病、気分障害、統合失調症、双極性障害、加齢関連疾患、黄斑変性、糖尿病、および癌からなる群から選択される、項目8に記載の方法。
(項目26)
前記ミトコンドリア障害が、遺伝性ミトコンドリア病、もじゃもじゃ赤色線維ミオパシーを伴うミオクローヌスてんかん(MERRF)、乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症(MELAS)、レーバー遺伝性視神経障害(LHON)、リー病、キーンズセイアー症候群(KSS)、フリードライヒ失調症(FA)、その他の筋症、心筋症、脳筋症、尿細管性アシドーシス、神経変性疾患、パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症(ALS)、運動ニューロン疾患、その他の神経系疾患、てんかん、遺伝性疾患、ハンチントン病、気分障害、統合失調症、双極性障害、加齢関連疾患、黄斑変性、糖尿病、および癌からなる群から選択される、項目10に記載の方法。
(項目27)
前記ミトコンドリア障害が、遺伝性ミトコンドリア病、もじゃもじゃ赤色線維ミオパシーを伴うミオクローヌスてんかん(MERRF)、乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症(MELAS)、レーバー遺伝性視神経障害(LHON)、リー病、キーンズセイアー症候群(KSS)、フリードライヒ失調症(FA)、その他の筋症、心筋症、脳筋症、尿細管性アシドーシス、神経変性疾患、パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症(ALS)、運動ニューロン疾患、その他の神経系疾患、てんかん、遺伝性疾患、ハンチントン病、気分障害、統合失調症、双極性障害、加齢関連疾患、黄斑変性、糖尿病、および癌からなる群から選択される、項目11に記載の方法。
(項目28)
前記ミトコンドリア障害が、遺伝性ミトコンドリア病、もじゃもじゃ赤色線維ミオパシーを伴うミオクローヌスてんかん(MERRF)、乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症(MELAS)、レーバー遺伝性視神経障害(LHON)、リー病、キーンズセイアー症候群(KSS)、フリードライヒ失調症(FA)、その他の筋症、心筋症、脳筋症、尿細管性アシドーシス、神経変性疾患、パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症(ALS)、運動ニューロン疾患、その他の神経系疾患、てんかん、遺伝性疾患、ハンチントン病、気分障害、統合失調症、双極性障害、加齢関連疾患、黄斑変性、糖尿病、および癌からなる群から選択される、項目13に記載の方法。
(項目29)
前記ミトコンドリア障害が、遺伝性ミトコンドリア病、もじゃもじゃ赤色線維ミオパシーを伴うミオクローヌスてんかん(MERRF)、乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症(MELAS)、レーバー遺伝性視神経障害(LHON)、リー病、キーンズセイアー症候群(KSS)、フリードライヒ失調症(FA)、その他の筋症、心筋症、脳筋症、尿細管性アシドーシス、神経変性疾患、パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症(ALS)、運動ニューロン疾患、その他の神経系疾患、てんかん、遺伝性疾患、ハンチントン病、気分障害、統合失調症、双極性障害、加齢関連疾患、黄斑変性、糖尿病、および癌からなる群から選択される、項目14に記載の方法。
(項目30)
前記ミトコンドリア障害が、遺伝性ミトコンドリア病、もじゃもじゃ赤色線維ミオパシーを伴うミオクローヌスてんかん(MERRF)、乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症(MELAS)、レーバー遺伝性視神経障害(LHON)、リー病、キーンズセイアー症候群(KSS)、フリードライヒ失調症(FA)、その他の筋症、心筋症、脳筋症、尿細管性アシドーシス、神経変性疾患、パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症(ALS)、運動ニューロン疾患、その他の神経系疾患、てんかん、遺伝性疾患、ハンチントン病、気分障害、統合失調症、双極性障害、加齢関連疾患、黄斑変性、糖尿病、および癌からなる群から選択される、項目16に記載の方法。
(項目31)
前記ミトコンドリア障害が、遺伝性ミトコンドリア病、もじゃもじゃ赤色線維ミオパシーを伴うミオクローヌスてんかん(MERRF)、乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症(MELAS)、レーバー遺伝性視神経障害(LHON)、リー病、キーンズセイアー症候群(KSS)、フリードライヒ失調症(FA)、その他の筋症、心筋症、脳筋症、尿細管性アシドーシス、神経変性疾患、パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症(ALS)、運動ニューロン疾患、その他の神経系疾患、てんかん、遺伝性疾患、ハンチントン病、気分障害、統合失調症、双極性障害、加齢関連疾患、黄斑変性、糖尿病、および癌からなる群から選択される、項目17に記載の方法。
本発明は、ミトコンドリア障害の治療または抑制に有用な化合物、およびエネルギーバイオマーカーの調節のために当該化合物を使用する方法を包含する。ミトコンドリア病の治療または抑制のための酸化還元活性治療薬および関連する本発明の態様を本明細書にさらに詳細に記載する。
式Iおよび式IIの化合物の合成
式Iおよび式IIの化合物は、様々な方法により容易に合成することができる。α−トコフェロールキノンの合成は、いくつかの参考文献、例えばUS3406188(GB1059155)およびUS4310465に詳細に述べられている。ベンゾキノン型化合物の合成は、US5229385およびUS4393075に開示されている。
式IIIおよび式IVの化合物は、「頭部基」が1,4−ベンゾキノンの代わりにベンゼン−1,4−ジオール部分である以外は、式Iおよび式IIの化合物と同様である。すなわち、式IIIおよびIVの頭部基は、式IおよびIIの頭部基の還元形態である。したがって、式IIIおよびIVの化合物は、式IおよびIIの化合物の単純な還元により容易に調製することができる。この還元は、当技術分野で周知のように、化学的(例えばNa2S2O4を用いて)または電気化学的に行うことができる。
式Vおよび式VIの化合物の合成
式Vおよび式VIの化合物は、Omura、J.Org.Chem.54巻:1987頁(1989年)に論じられたように以下の手順により合成することができる。
式VII−iの化合物に関する情報は、以下の刊行物に見い出すことができる:US2004/0116715;Storozhokら、Biomeditsinskaya Khimiya(2003年)、49巻(1)、96〜104頁;Bertalanら、Olaj,Szappan,Kozmetika(2000年)、49巻(Kulonszam)、40〜45頁;Dompertら、Fette,Seifen,Anstrichmittel(1976年)78巻(3)、108〜11頁;Berndorfer−Krasznerら、Elelmezesi Ipar(1971年)、25巻(11)、339〜45頁;およびWhittleら、Biochemical Journal(1967年)103巻(3)、21C〜22C頁。
キノン、ジヒドロキノン形態の相互変換性
本明細書に開示されたキノンおよびジヒドロキノン型の化合物は、適切な試薬で容易に相互変換される。例えば、亜ジチオン酸ナトリウムなどの還元剤で、キノン形態の化合物をジヒドロキノン形態に還元することができる。硝酸アンモニウムセリウムまたは塩化第二鉄などの酸化剤で、ヒドロキノン形態をキノン形態に酸化することができる。当技術分野で周知のように、キノンおよびヒドロキノン形態もまた電気化学的に容易に変換することができる。例えば、Streitweiser & Heathcock、Introduction to Organic Chemistry、ニューヨーク;Macmillan、1976年の33.4節を参照されたい。
本発明の化合物および方法を用いて治療または抑制しやすい疾患
多様な疾患が、ミトコンドリア障害およびエネルギー処理障害により起きるか、または増悪すると考えられ、本発明の化合物および方法を使用し、それらの疾患を治療または抑制することができる。当該疾患には、もじゃもじゃ赤色線維ミオパシーを伴うミオクローヌスてんかん(MERRF)、乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症(MELAS)、レーバー遺伝性視神経障害(LHON、レーバー病、レーバー視神経萎縮(LOA)、またはレーバー視神経症(LON)とも呼ばれる)、リー病またはリー症候群、キーンズセイアー症候群(KSS)、フリードライヒ失調症(FA)、その他の筋症(心筋症および脳筋症を含む)、および尿細管性アシドーシスなどの遺伝性ミトコンドリア病;パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症(ALS、ルーゲーリッグ病とも知られている)、運動ニューロン疾患などの神経変性疾患;てんかんなどのその他の神経系疾患;アシドーシスなどの遺伝性疾患;パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症(ALS、ルーゲーリッグ病とも知られている)、運動ニューロン疾患などの神経変性疾患;てんかんなどのその他の神経系疾患;ハンチントン病などの遺伝性疾患(神経系疾患でもある);統合失調症および双極性障害などの気分障害;およびある種の加齢関連疾患、特に黄斑変性、糖尿病、ならびに癌などの、CoQ10が治療に提案されている疾患があるが、それに限定されるわけではない。
ミトコンドリア機能不全および治療の有効性の臨床判定
ミトコンドリア障害を有する患者の代謝状態を判定するために、いくつかの容易に測定できる臨床マーカーが使用される。マーカーのレベルが病的値から健常値に移動するときに、これらのマーカーは与えられた治療法の有効性の指標としても使用することができる。これらの臨床マーカーには、全血、血漿、脳脊髄液、または脳室液のいずれかの中の乳酸(乳酸塩)濃度;全血、血漿、脳脊髄液、または脳室液のいずれかの中のピルビン酸(ピルビン酸塩)濃度;全血、血漿、脳脊髄液、または脳室液のいずれかにおける乳酸/ピルビン酸比;クレアチンリン酸レベル、NADH(NADH+H+)またはNADPH(NADPH+H+)レベル;NADまたはNADPレベル;ATPレベル;無酸素性作業閾値;還元型補酵素Q(CoQred)レベル;酸化型補酵素Q(CoQox)レベル;総補酵素Q(CoQtot)レベル;酸化型チトクロームCレベル;還元型チトクロームCレベル;酸化型チトクロームC/還元型チトクロームC比;アセト酢酸レベル;β−ヒドロキシ酪酸レベル;アセト酢酸/β−ヒドロキシ酪酸比;8−ヒドロキシ−2’−デオキシグアノシン(8−OHdG)レベル;活性酸素種のレベル;ならびに酸素消費量(VO2)のレベル、二酸化炭素産出量(VCO2)のレベル、および呼吸商(VCO2/VO2)などのこれまでに論じたエネルギーバイオマーカーの1つまたは複数があるが、それに限定されるわけではない。これらの臨床マーカーのうちいくつかは、運動生理学の研究室で日常的に測定され、対象の代謝状態を便利に判定する。本発明の一実施形態では、フリードライヒ失調症、レーバー遺伝性視神経障害、MELAS、またはKSSなどのミトコンドリア病を患う患者における1つまたは複数のエネルギーバイオマーカーのレベルは、健常対象における平均レベルから2標準偏差内に改善する。本発明の別の実施形態では、フリードライヒ失調症、レーバー遺伝性視神経障害、MELAS、またはKSSなどのミトコンドリア病を患う患者における1つまたは複数のこれらのエネルギーバイオマーカーのレベルは、健常対象における平均レベルから1標準偏差内に改善する。運動不耐性もまた、与えられた治療の有効性の指標として使用することができ、ここで、運動耐性の改善(すなわち運動不耐性の減少)は、与えられた治療法の有効性を示す。
(NADH+H+)またはNADPH(NADPH+H+)の測定は、多様な蛍光技法、酵素技法、または電気化学的技法、例えばUS2005/0067303に記載されている電気化学的アッセイにより測定することができる。
次の表1は、様々な機能不全が生化学バイオマーカーおよびエネルギーバイオマーカーに及ぼしうる作用を示している。この表は、典型的には与えられた機能不全に伴う物理作用(疾患の症状または機能不全の他の作用など)もまた示す。他の箇所に列挙したエネルギーバイオマーカーに加えて、この表に挙げたエネルギーバイオマーカーのうち任意のものもまた、本発明の化合物および方法により調節、強化、または正常化できることに留意すべきである。RQ=呼吸商、BMR=基礎代謝率、HR(CO)=心拍数(心拍出量)、T=体温(好ましくは核心温度として測定されたもの)、AT=無酸素性作業閾値、pH=血液pH(静脈および/または動脈)。
エネルギーバイオマーカーの調節のための化合物の使用
ミトコンドリア病の治療または抑制の状態を判定するためにエネルギーバイオマーカーをモニターすることに加えて、本発明の化合物を対象または患者に使用して、1つまたは複数のエネルギーバイオマーカーを調節することができる。エネルギーバイオマーカーの調節は、対象におけるエネルギーバイオマーカーを正常化するために行うことができるし、対象におけるエネルギーバイオマーカーを強化するために行うこともできる。
研究応用、実験系、およびアッセイへの化合物の使用
本発明の化合物は、研究応用に使用することもまたできる。例えば、α−トコフェロールキノンをin vitro、in vivo、またはex vivo実験に使用して、実験系における1つまたは複数のエネルギーバイオマーカーを調節することができる。当該実験系は、細胞試料、組織試料、細胞成分もしくは細胞成分の混合物、部分器官、器官全体、または生物のことがある。式I、Ia、Ib、II、IIa、IIb、III、IIIa、IIIb、IV、IVa、IVb、V、Va、Vb、VI、VIa、VIb、VII−O、VII−R、VIII−O、VIII−R、IX−O、IX−R、X−O、X−R、XI−O、XI−R、XII−O、および/またはXII−Rの任意の1つまたは複数の化合物を実験系または研究応用に使用することができる。当該研究応用には、アッセイ試薬としての使用、生化学経路の解明、または本発明の1つもしくは複数の化合物の存在/不在下で他の薬剤が実験系の代謝状態に及ぼす効果の評価がありうるが、それに限定されるわけではない。
薬学的製剤
本明細書に記載した化合物は、薬学的に許容できる賦形剤、薬学的に許容できる担体、および薬学的に許容できるビヒクルなどの添加剤と共に製剤することにより医薬組成物として製剤することができる。薬学的に許容できる適切な賦形剤、担体、およびビヒクルには、例えばリン酸カルシウム、ステアリン酸マグネシウム、タルク、単糖類、二糖類、デンプン、ゼラチン、セルロース、メチルセルロース、カルボキシメチルセルロースナトリウム、デキストロース、ヒドロキシプロピル−β−シクロデキストリン、ポリビニルピロリドン、低融点ロウ、イオン交換樹脂など、およびその任意の2つ以上の組み合わせなどの加工剤および薬物送達調節剤および促進剤がある。その他の適切な薬学的に許容できる賦形剤は、参照により本明細書に組み込まれている「Remington’s Pharmaceutical Sciences」Mack Pub.Co.、ニュージャージー(1991年)および「Remington: The Science and Practice of Pharmacy」Lippincott Williams & Wilkins、フィラデルフィア、第20版(2003年)および第21版(2005年)に記載されている。
化合物の合成
実施例1A
化合物VIII−iである(R/S,R,R)−2,3,5−トリメチル−6−(3,7,11,15−テトラメチル−ヘキサデシル)−[1,4]ベンゾキノンの立体異性体混合物の合成
化合物IX−iである2,3,5−トリメチル−6−(3,7,11,15−テトラメチル−ヘキサデカ−2,6,10、14−テトラエニル)−[1,4]ベンゾキノンの合成
(R,R,R)−2−ブチル−3−(3−ヒドロキシ−3,7,11,15−テトラメチル−ヘキサデシル)−5,6−ジメチル−[1、4]ベンゾキノン
(R,R,R)−2−(3−ヒドロキシ−3,7,11,15−テトラメチル−ヘキサデシル)−5,6−ジメチル−3−プロピル−[1、4]ベンゾキノン
(R,R,R)−3−(3−ヒドロキシ−3,7,11,15−テトラメチル−ヘキサデシル)−5−メチル−2−プロピル−[1,4]ベンゾキノン
(R,R,R)−2−(3−ヒドロキシ−3,7,11,15−テトラメチル−ヘキサデシル)−3−イソブチル−5,6−ジメチル−[1,4]ベンゾキノン
有効な酸化還元化合物のための初回スクリーニング
酸化還元障害の改善に有効な化合物を同定するために初回スクリーニングを行った。Jauslinら、Hum.Mol.Genet.11巻(24):3055頁(2002年)、Jauslinら、FASEB J.17巻:1972〜4頁(2003年)、および国際特許出願WO2004/003565に記載されているように、被験試料、4つの参照化合物(イデベノン、デシルユビキノン、トロロックス、および酢酸α−トコフェロール)、および溶媒対照が、L−ブチオニン−(S,R)−スルホキシイミン(BSO)の添加によりストレスを与えられたFRDA線維芽細胞を救出する能力について試験した。フリードライヒ失調症患者由来のヒト皮膚線維芽細胞は、グルタチオン(GSH)シンテターゼの特異的阻害剤であるL−ブチオニン−(S,R)−スルホキシイミン(BSO)を用いたGSHのde novo合成阻害に過敏であることが示されている(Jauslinら、Hum.Mol.Genet.11巻(24):3055頁(2002年))。この特異的なBSO介在性細胞死は、抗酸化物経路に関与する、α−トコフェロール、短鎖キノン、セレン、またはグルタチオンペルオキシダーゼの小分子模倣体などの抗酸化物または分子の投与により阻止することができる。しかし、抗酸化物はその効力が様々であり、すなわち抗酸化物がBSOによりストレスを与えられたFRDA線維芽細胞を救出できる濃度は様々である。このアッセイでは被験化合物のEC50濃度を決定し、公知の参照抗酸化物と比較した。
本発明の化合物のスクリーニング
本発明の化合物がFRDA患者由来のヒト皮膚線維芽細胞を酸化ストレスから救出する能力について、実施例2に記載したスクリーニングを使用して試験する。このデーターは、疾患治療薬としてのこれらの化合物の潜在性を推定するために使用する。
本発明の化合物の投与
α−トコフェロールキノンなどの本発明の化合物は、薬学的に許容できる担体中の化合物300mgを含有するカプセルに入れて提示される。カプセルは1日1回、好ましくは朝食または昼食時に経口服用される。ごく幼い小児の場合は、カプセルを割って、中身を食物と混合する。
Claims (27)
- 式:
式:
- 前記化合物が、
- 前記化合物が、
- 前記化合物が、
- 前記化合物が、
- 前記化合物が、
- 前記ミトコンドリア障害が遺伝性ミトコンドリア病である、請求項3に記載の組成物。
- 前記ミトコンドリア障害がリー病またはリー症候群である、請求項3に記載の組成物。
- 前記ミトコンドリア障害がもじゃもじゃ赤色線維ミオパシーを伴うミオクローヌスてんかん(MERRF)である、請求項3に記載の組成物。
- 前記ミトコンドリア障害が乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症(MELAS)である、請求項3に記載の組成物。
- 前記ミトコンドリア障害がレーバー遺伝性視神経障害(LHON)である、請求項3に記載の組成物。
- 前記ミトコンドリア障害がキーンズセイアー症候群(KSS)である、請求項3に記載の組成物。
- 前記ミトコンドリア障害がフリードライヒ失調症(FA)である、請求項3に記載の組成物。
- 前記ミトコンドリア障害が遺伝性ミトコンドリア病である、請求項4に記載の組成物。
- 前記ミトコンドリア障害がリー病またはリー症候群である、請求項4に記載の組成物。
- 前記ミトコンドリア障害がもじゃもじゃ赤色線維ミオパシーを伴うミオクローヌスてんかん(MERRF)である、請求項4に記載の組成物。
- 前記ミトコンドリア障害が乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症(MELAS)である、請求項4に記載の組成物。
- 前記ミトコンドリア障害がレーバー遺伝性視神経障害(LHON)である、請求項4に記載の組成物。
- 前記ミトコンドリア障害がキーンズセイアー症候群(KSS)である、請求項4に記載の組成物。
- 前記ミトコンドリア障害がフリードライヒ失調症(FA)である、請求項4に記載の組成物。
-
前記ミトコンドリア障害が遺伝性ミトコンドリア病である、請求項6に記載の組成物。 - 前記ミトコンドリア障害がリー病またはリー症候群である、請求項6に記載の組成物。
- 前記ミトコンドリア障害がもじゃもじゃ赤色線維ミオパシーを伴うミオクローヌスてんかん(MERRF)である、請求項6に記載の組成物。
- 前記ミトコンドリア障害が乳酸アシドーシスと脳卒中様症状を伴うミトコンドリア脳筋症(MELAS)である、請求項6に記載の組成物。
- 前記ミトコンドリア障害がレーバー遺伝性視神経障害(LHON)である、請求項6に記載の組成物。
- 前記ミトコンドリア障害がキーンズセイアー症候群(KSS)である、請求項6に記載の組成物。
- 前記ミトコンドリア障害がフリードライヒ失調症(FA)である、請求項6に記載の組成物。
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SI (1) | SI1888059T1 (ja) |
WO (1) | WO2006130775A2 (ja) |
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