JP5999816B2 - ミトコンドリア病および関連した様態の治療ならびに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剤のテイル改変体 - Google Patents
ミトコンドリア病および関連した様態の治療ならびに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剤のテイル改変体 Download PDFInfo
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- 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
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 239000011782 vitamin Chemical class 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Chemical class 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Chemical class 0.000 description 1
- 235000019195 vitamin supplement Nutrition 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
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Description
本願は、2005年9月15日に出願された、米国仮特許出願番号60/717,678の優先権の利益を主張する。この仮特許出願の全内容は、その全体が本明細書中に参考として援用される。
本出願は、ミトコンドリア病による疾患、例えば、フリードライヒ失調症、レーベル遺伝性眼性ニューロパシー、カーンズ・セイアー症候群、およびミトコンドリアミオパシー、脳症、ラクトアシドーシス、発作(MELAS)の治療または抑制、被験体における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、真核細胞の細胞小器官であり、一般に、該細胞の「パワーハウス」と呼ばれている。分子であるアデノシン三リン酸(adenosine triphosphate:ATP)は、該細胞において、エネルギー「通貨」またはエネルギーキャリアとして機能し、真核細胞は、ミトコンドリアによって行われる生化学的プロセスからそれらのATPの大部分を得る。これらの生化学的プロセスには、クエン酸回路(トリカルボン酸回路、またはクレブス回路)が含まれ、該回路は、酸化ニコチンアミド・アデニン・ジヌクレオチド(NAD+)から還元ニコチンアミド・アデニン・ジヌクレオチド(NADH+H+)、および酸化的リン酸化を生じさせ、その最中に、NADH+H+はNAD+に酸化されて元に戻る。(クエン酸回路はまた、フラビン・アデニン・ジヌクレオチド、即ち、FADをFADH2に還元する;FADH2は、酸化的リン酸化にも関与する。)
NADH+H+の酸化によって放出される電子は、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)の下方に向かって受け渡しされる。これらの複合体は、ミトコンドリアの内膜に埋め込まれている。複合体IVは、この鎖の末端にあり、電子を酸素に移動させ、水に還元する。これらの電子が複合体を横断するときに放出されるエネルギーは、ミトコンドリアの内膜を横切って電気化学ポテンシャルを発生する、該内膜を横切るプロトン勾配を生じさせるために用いられる。別のタンパク質複合体である複合体V(複合体I、II、IIIおよびIVと直接的には関係しない)は、ADPをATPに変換するための電気化学的勾配によって貯蔵されるエネルギーを使用する。
エネルギーの生物学的生成を調整する能力は、上述した疾患を超える用途を有する。種々の他の障害は、結果として、ATPレベルなどのエネルギーバイオマーカー(エネルギー機能の指標とも呼ばれることがある)の次善レベルをもたらす可能性がある。これらの障害の治療はさらに、患者の健康を改善する1以上のエネルギーバイオマーカーを調節するために必要とされる。他の用途では、疾患に苦しんでいない個体の正常値から離れているある種のエネルギーバイオマーカーを調節することが望まれる。例えば、個体が過度の激しい仕事を請け負っている場合、その個体においてATPレベルを上昇させることが望まれる。
一態様では、本化合物は、下記:
から成る式Iで表される基から選択される化合物、並びにその全ての塩、立体異性体、立体異性体の混合物、プロドラッグ、代謝産物、溶媒和物、および水和物である。全てのR1、R2、およびR3基は、直線状、分岐状、または環状であってもよい。R20基は、直線状または分岐状であってもよい。C1〜C20アルケニルは、少なくとも1つの二重結合を含む。C1〜C20アルキニルは、少なくとも1つの三重結合を含む。
本発明は例えば、以下の項目を提供する:
(項目1)
ミトコンドリア病を治療するか、1以上のエネルギーバイオマーカーを調節するか、1以上のエネルギーバイオマーカーを正常化するか、または1以上のエネルギーバイオマーカーを増進する方法であって、治療的有効量または有効量の式:
式中、R 1 、R 2 、およびR 3 は、独立して、−C 1 〜C 4 アルキル、−C 1 〜C 4 ハロアルキル、−CN、−F、−Cl、−Br、および−Iから選択され;
R 20 は、独立して、−C 1 〜C 20 アルキル、−C 1 〜C 20 アルケニル、−C 1 〜C 20 アルキニル、ならびに少なくとも1つの二重結合および少なくとも1つの三重結合を含む−C 1 〜C 20 から選択される、
方法。
(項目2)
R 20 が、C 6 n−アルキル、C 7 n−アルキル、およびC 11 n−アルキルを除くという条件である、項目1に記載の方法。
(項目3)
R 1 が、独立して、メチル、エチル、n−プロピル、イソプロピル、シクロプロピル、n−ブチル、イソブチル、sec−ブチル、t−ブチル、シクロブチル、シクロプロピル−メチル、およびメチル−シクロプロパンから選択され、R 1 によるこの分子の残り部分への結合点が、該アルキル断片上の任意の位置であり得;
R 2 が、独立して、メチル、エチル、n−プロピル、イソプロピル、シクロプロピル、n−ブチル、イソブチル、sec−ブチル、t−ブチル、シクロブチル、シクロプロピル−メチル、およびメチル−シクロプロパンから選択され、R 2 によるこの分子の残り部分への結合点が、該アルキル断片上の任意の位置であり得;
R 3 が、独立して、メチル、エチル、n−プロピル、イソプロピル、シクロプロピル、n−ブチル、イソブチル、sec−ブチル、t−ブチル、シクロブチル、シクロプロピル−メチル、およびメチル−シクロプロパンから選択され、R 3 によるこの分子の残り部分への結合点が、該アルキル断片上の任意の位置であり得;
R 20 が、独立して、−C 1 〜C 20 アルキル、−C 1 〜C 20 アルケニル、−C 1 〜C 20 アルキニル、ならびに少なくとも1つの二重結合および少なくとも1つの三重結合を含む−C 1 〜C 20 から選択され、その全ての塩、立体異性体、立体異性体の混合物、プロドラッグ、代謝産物、溶媒和物、および水和物である、項目1に記載の方法。
(項目4)
R 20 が、C 6 n−アルキル、C 7 n−アルキル、およびC 11 n−アルキルを除くという条件である、項目3に記載の方法。
(項目5)
R 1 、R 2 、およびR 3 のうちの少なくとも1つが、メチルではない、項目1に記載の方法。
(項目6)
R 1 、R 2 、およびR 3 のうちの少なくとも1つが、メチルではない、項目2に記載の方法。
(項目7)
R 1 、R 2 、およびR 3 のうちの少なくとも1つが、メチルではない、項目3に記載の方法。
(項目8)
R 1 、R 2 、およびR 3 のうちの少なくとも1つが、メチルではない、項目4に記載の方法。
(項目9)
前記ミトコンドリア病が、遺伝性ミトコンドリア疾患;赤色ぼろ線維を伴うミオクローヌス癲癇(MERRF);ミトコンドリアミオパシー、脳症、ラクトアシドーシス、発作(MELAS);レーベル遺伝性眼性ニューロパシー(LHON);リー病;カーンズ・セイアー症候群(KSS);フリードライヒ失調症(FA);他のミオパシー;心筋症;脳ミオパシー;尿細管性アシドーシス;神経変性病;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);運動ニューロン疾患;他の神経系疾患;癲癇;遺伝病;ハンチントン病;気分障害;統合失調症;双極性障害;加齢性疾患;黄斑変性症;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10)
前記ミトコンドリア病が、遺伝性ミトコンドリア疾患;赤色ぼろ線維を伴うミオクローヌス癲癇(MERRF);ミトコンドリアミオパシー、脳症、ラクトアシドーシス、発作(MELAS);レーベル遺伝性眼性ニューロパシー(LHON);リー病;カーンズ・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1に記載の方法。
(項目11)
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における乳酸(ラクテート)レベル;全血、血漿、脳脊髄液、または脳室液のいずれかにおけるピルビン酸(ピルベート)レベル;全血、血漿、脳脊髄液、または脳室液のいずれかにおけるラクテート/ピルベート比;ホスホクレアチンレベル、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;全補酵素Q(CoQ tot )レベル;酸化型シトクロムCレベル;還元型シトクロムCレベル;酸化型シトクロムC/還元型シトクロムC比;アセトアセテートレベル、β−ヒドロキシブチレートレベル、アセトアセテート/β−ヒドロキシブチレート比、8−ヒドロキシ−2’−デオキシグアノシン(8−OHdG)レベル;反応性酸素種のレベル;酸素消費量(VO2)レベル;二酸化炭素放出量(VCO2)レベル;呼吸指数(VCO2/VO2);運動耐性;および無酸素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12)
前記被験体が、ミトコンドリア疾患を有する被験体;激しいかまたは長期の肉体活動を被っている被験体;慢性エネルギー問題を有する被験体;慢性呼吸問題を有する被験体;妊婦;分娩中の妊婦;新生児;未熟児;厳しい環境に晒されている被験体;高温環境に晒されている被験体;低温環境に晒されている被験体;酸素量が平均を下回っている環境に晒されている被験体;二酸化炭素量が平均を上回っている環境に晒されている被験体;平均レベルを上回る空気汚染の環境に晒されている被験体;肺疾患を有する被験体;肺活量が平均を下回っている被験体;結核患者;肺癌患者;肺気腫患者;嚢胞性線維症患者:外科手術から回復中の被験体;病気から回復中の被験体;急性外傷性傷害を被っている被験体;ショック状態にある被験体;緊急酸素投与を必要としている被験体;長期酸素投与を必要としている被験体;高齢被験体;エネルギー低下にある高齢被験体;および慢性疲労に苦しんでいる被験体からなる群から選択される、項目1に記載の方法。
(項目13)
式:
式中、R 1 、R 2 、およびR 3 は、独立して、−C 1 〜C 4 アルキル、−C 1 〜C 4 ハロアルキル、−CN、−F、−Cl、−Br、および−Iから選択され;
R 20 は、独立して、−C 1 〜C 20 アルキル、−C 1 〜C 20 アルケニル、−C 1 〜C 20 アルキニル、ならびに少なくとも1つの二重結合および少なくとも1つの三重結合を含む−C 1 〜C 20 から選択され;
ただし、R 1 、R 2 、およびR 3 が全てメチルである場合、R 20 は、C 6 n−アルキル、C 7 n−アルキル、およびC 11 n−アルキルを除き、さらに、R 3 がブロモであり、R 1 およびR 2 のうちの1つがメチルであり、R 1 およびR 2 のその他の1つがブロモである場合、R 20 はC 6 n−アルキルを除く、
化合物。
(項目14)
R 1 、R 2 、およびR 3 のいずれの選択に対しても、R 20 が、C 6 n−アルキル、C 7 n−アルキル、およびC 11 n−アルキルを除く、項目13に記載の化合物。
(項目15)
R 1 が、独立して、メチル、エチル、n−プロピル、イソプロピル、シクロプロピル、n−ブチル、イソブチル、sec−ブチル、t−ブチル、シクロブチル、シクロプロピル−メチル、およびメチル−シクロプロパンから選択され、R 1 によるこの分子の残り部分への結合点が、該アルキル断片上の任意の位置であり得;
R 2 が、独立して、メチル、エチル、n−プロピル、イソプロピル、シクロプロピル、n−ブチル、イソブチル、sec−ブチル、t−ブチル、シクロブチル、シクロプロピル−メチル、およびメチル−シクロプロパンから選択され、R 2 によるこの分子の残り部分への結合点が、該アルキル断片上の任意の位置であり得;
R 3 は、独立して、メチル、エチル、n−プロピル、イソプロピル、シクロプロピル、n−ブチル、イソブチル、sec−ブチル、t−ブチル、シクロブチル、シクロプロピル−メチル、およびメチル−シクロプロパンから選択され、R 3 によるこの分子の残り部分への結合点が、該アルキル断片上の任意の位置であり得る、項目13に記載の化合物、その全ての塩、立体異性体、立体異性体の混合物、プロドラッグ、代謝産物、溶媒和物、および水和物。
(項目16)
R 1 、R 2 、およびR 3 のうちの少なくとも1つがメチルではない、項目13に記載の化合物、その全ての塩、立体異性体、立体異性体の混合物、プロドラッグ、代謝産物、溶媒和物、および水和物。
(項目17)
R 1 、R 2 、およびR 3 が、独立して、C 2 〜C 4 アルキルから選択される、項目16に記載の化合物、その全ての塩、立体異性体、立体異性体の混合物、プロドラッグ、代謝産物、溶媒和物、および水和物。
(項目18)
R 1 、R 2 、およびR 3 のうちの1つのみが、メチルである、項目13に記載の化合物、その全ての塩、立体異性体、立体異性体の混合物、プロドラッグ、代謝産物、溶媒和物、および水和物。
(項目19)
R 1 、R 2 、およびR 3 のうちの2つのみが、メチルである、項目13に記載の化合物、その全ての塩、立体異性体、立体異性体の混合物、プロドラッグ、代謝産物、溶媒和物、および水和物。
(項目20)
R 1 、R 2 、およびR 3 の全てが、メチルである、項目13に記載の化合物、その全ての塩、立体異性体、立体異性体の混合物、プロドラッグ、代謝産物、溶媒和物、および水和物。
(項目21)
医薬として許容されるキャリアをさらに含む、項目13に記載の化合物。
本発明は、ミトコンドリア病の治療または抑制に有用な化合物、エネルギーバイオマーカーの調節のためにこのような化合物を用いる方法を包含する。本発明のミトコンドリア疾患および関連した様態の治療または抑制のための酸化還元活性療法は、より詳細には本明細書中に記載されている。
本明細書中に開示されている化合物の合成は、当業者によって容易に達成される。ベンゾキノン系化合物の合成は、米国特許第4,393,075号に開示されている。対象とする他の方法は、米国特許第5,229,385号及び米国特許第4,310,465号に見出される。
73(4):1068(1990)に記載されている;2−アルキル−3,5,6−トリメチル−1,4−ベンゾキノン(105)への3,6−ジメトキシ−1−アルキル−2,4,5−トリメチル−1,4−シクロヘキサジエン(104)の変換に関する化学は、Shiraishiら,Journal of Medicinal Chemistry 32(9):2214(1989)に記載されている。この反応は、R1、R2、およびR3としてメチルを用いて図示されているが、他のR1、R2、およびR3置換基が、環上のメチル置換された位置で用いられ得ることに留意されたい。
本明細書中に開示される化合物のキノンおよびジヒドロキノン形態は、適切な試薬を用いて容易に相互交換される。例えば、化合物のキノン形態は、亜ジチオン酸ナトリウム(Na2S2O4)などの還元剤を用いてジヒドロキノン形態に還元され得る。ヒドロキノン形態は、硝酸セリウムアンモニウムまたは塩化第二鉄などの酸化剤を用いてキノン形態に酸化され得る。キノン形態およびヒドロキノン形態はまた、当該技術分野において周知であるように、電気化学的に容易に変換される。例えば、Streitweiser & Heathcockの33.4節、Introduction to Organic Chemistry,New York:Macmillan,1976を参照されたい。
で表される化合物、ならびにその全ての塩、立体異性体、溶媒和物および水和物である。
様々な疾患は、ミトコンドリア病および機能しなくなったエネルギープロセッシングによって引き起こされるかまたは悪化すると考えられ、本明細書中に開示されている化合物、および本発明の方法を用いて治療または抑制されることができる。このような疾患には、限定されないが、遺伝性ミトコンドリア疾患、例えば、赤色ぼろ線維を伴うミオクローヌス癲癇(MERRF)、ミトコンドリアミオパシー、脳症、ラクトアシドーシス、発作(MELAS)、レーベル遺伝性眼性ニューロパシー(LHON、レーベル病、レーベル視神経萎縮(LOA)、またはレーベル眼性ニューロパシー(LON)とも呼ばれる)、リー病またはリー症候群、カーンズ・セイアー症候群(KSS)、フリードライヒ失調症(FA)、他のミオパシー(心筋症および脳ミオパシーを含む)、および尿細管性アシドーシス;神経変性病、例えば、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・ゲーリック(Lou Gehrig)病としても知られている)、運動ニューロン疾患;他の神経系疾患、例えば、癲癇;遺伝病、例えば、ハンチントン病(神経系疾患でもある);気分障害、例えば、統合失調症および双極性障害;ある種の加齢性疾患、特に、CoQ10が治療に提案される疾患、例えば、黄斑変性症、糖尿病、および癌が挙げられる。
いくつかの容易に測定可能な臨床マーカーは、ミトコンドリア病を有する患者の代謝状態を評価するために用いられる。これらのマーカーは、所定の治療の効果のマーカーとしても用いることができ、これは、マーカーのレベルが病理的な値から健常値まで動くからである。これらの臨床マーカーには、限定されないが、前記で検討された1以上のエネルギーバイオマーカー、例えば、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(ラクテート)レベル;全血、血漿、脳脊髄液、または脳室液のいずれかにおけるピルビン酸(ピルベート)レベル;全血、血漿、脳脊髄液、または脳室液のいずれかにおけるラクテート/ピルベート比;ホスホクレアチンレベル、NADH(NADH+H+)またはNADPH(NADPH+H+)レベル;NADまたはNADPレベル;ATPレベル;無酸素閾値;還元型補酵素Q(CoQred)レベル;酸化型補酵素Q(CoQox)レベル;全補酵素Q(CoQtot)レベル;酸化型シトクロムCレベル;還元型シトクロムCレベル;酸化型シトクロムC/還元型シトクロムC比;アセトアセテートレベル、β−ヒドロキシブチレートレベル、アセトアセテート/β−ヒドロキシブチレート比、8−ヒドロキシ−2’−デオキシグアノシン(8−hydroxy−2’−deoxyguanosine:8−OHdG)レベル;反応性酸素種のレベル;酸素消費量(VO2)のレベル、二酸化炭素放出量(VCO2)のレベル、および呼吸指数(VCO2/VO2)が挙げられる。これらの臨床マーカーのいくつかは、運動生理学研究所で日常的に測定され、被験体の代謝状態の簡易な評価を提供する。本発明の一態様では、フリードライヒ失調症、レーベル遺伝性眼性ニューロパシー、MELAS、またはKSSなどのミトコンドリア疾患に苦しんでいる患者における1以上のエネルギーバイオマーカーのレベルが、健常被験体における平均レベルの2標準偏差以内に改善される。本発明の別の態様では、フリードライヒ失調症、レーベル遺伝性眼性ニューロパシー、MELAS、またはKSSなどのミトコンドリア疾患に苦しんでいる患者における1以上のエネルギーバイオマーカーのレベルが、健常被験体における平均レベルの1標準偏差以内に改善される。運動不耐性は、所定の治療の有効性の指標として用いられても良く、運動耐性の改善(即ち、運動不耐性の減少)は、所定の治療の有効性を指す。
下記の表1は、種々の機能不全が、生化学およびエネルギーバイオマーカーに与える影響を例示する。それは、身体的効果(例えば、機能不全の疾患症状または他の影響)が、典型的には、所定の機能不全を伴うことも示す。他の箇所で列挙されているエネルギーバイオマーカーに加えて、表に列挙されているエネルギーバイオマーカーのいずれかはまた、本明細書中に開示されている化合物および本発明の方法によって調節され、増進され、または正常化し得ることに留意されたい。RQ=呼吸指数;BMR(basal metabolic rate)=基礎代謝率;HR(CO)=心拍数(heart rate)(心拍出量(cardiac output));T=体温(好ましくは、中核体温として測定される);AT(anaerobic threshold)=無酸素閾値;pH=血液pH(静脈および/または動脈)。
ミトコンドリア疾患の治療または抑制の状態を評価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、本明細書中に開示されている化合物は、1以上のエネルギーバイオマーカーを調節するために、被験体または患者に用いることができる。被験体においてエネルギーバイオマーカーを正常化するかまたは被験体においてエネルギーバイオマーカーを増進するために、エネルギーバイオマーカーの調節を行うことができる。
本明細書中に開示されている化合物は、研究用途において用いることもできる。例えば、本明細書中に開示されている化合物は、実験系において1以上のエネルギーバイオマーカーを調節するために、インビトロ、インビボ、またはエクスビボの実験のために用いることができる。このような実験系は、細胞試料、組織試料、細胞成分もしくは細胞成分の混合物、部分的な臓器、全臓器、または生物であり得る。本明細書中に開示されている任意の1以上の化合物は、実験系または研究用途に用いることができる。このような研究用途には、限定されないが、アッセイ試薬としての使用、生化学的経路の解明、または本明細書中に開示されている1以上の化合物の有無での実験系の代謝状態における他の試薬の影響の評価が含まれる。
本明細書中に開示されている化合物は、医薬として許容される賦形剤、医薬として許容されるキャリア、医薬として許容されるベヒクルなどの添加剤とともに製剤化によって医薬組成物として調合することができる。適切な医薬として許容される賦形剤、キャリアおよびベヒクルには、加工剤および薬物送達変性剤および増強剤、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、スターチ、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、ポリビニルピロリジノン、低融点ワックス、イオン交換樹脂など、ならびにそれらの任意の2つ以上の組み合わせが含まれる。他の適切な医薬として許容される賦形剤は、参照により本明細書中に援用される“Remington’s Pharmaceutical Sciences”,Mack Pub.Co.,New Jersey(1991)および“Remington:The Science and Practice of Pharmacy”,Lippincott Williams & Wilkins,Philadelphia,第20版(2003)および第21版(2005)に記載されている。
(脱炭酸化カップリング)
(実施例2A)
Claims (9)
- 以下の式:
の化合物であって、
式中、R1、R2、およびR3は、独立して、−C1〜C4アルキル、−C1〜C4ハロアルキル、−CN、および−Fからなる群より選択され;
R20は、独立して、−C1〜C20アルキル、−C2〜C20アルケニル、および−C2〜C20アルキニルからなる群より選択され;
ただし、R1、R2、およびR3が全てメチルである場合、R20は、C6n−アルキル、C7n−アルキル、およびC11n−アルキルを除く、
化合物、あるいはその立体異性体、立体異性体の混合物、溶媒和物、または水和物。 - R1、R2、およびR3のいずれの選択に対しても、R20が、C6n−アルキル、C7n−アルキル、およびC11n−アルキルを除く、請求項1に記載の化合物、あるいはその立体異性体、立体異性体の混合物、溶媒和物、または水和物。
- R1が、独立して、メチル、エチル、n−プロピル、イソプロピル、シクロプロピル、n−ブチル、イソブチル、sec−ブチル、t−ブチル、シクロブチル、シクロプロピル−メチル、およびメチル−シクロプロピルからなる群より選択され、R1によるこの分子の残り部分への結合点が、アルキル断片上の任意の位置であり得;
R2が、独立して、メチル、エチル、n−プロピル、イソプロピル、シクロプロピル、n−ブチル、イソブチル、sec−ブチル、t−ブチル、シクロブチル、シクロプロピル−メチル、およびメチル−シクロプロピルからなる群より選択され、R2によるこの分子の残り部分への結合点が、アルキル断片上の任意の位置であり得;
R3は、独立して、メチル、エチル、n−プロピル、イソプロピル、シクロプロピル、n−ブチル、イソブチル、sec−ブチル、t−ブチル、シクロブチル、シクロプロピル−メチル、およびメチル−シクロプロピルからなる群より選択され、R3によるこの分子の残り部分への結合点が、アルキル断片上の任意の位置であり得る、請求項1に記載の化合物、あるいはその立体異性体、立体異性体の混合物、溶媒和物、または水和物。 - R1、R2、およびR3のうちの少なくとも1つがメチルではない、請求項1に記載の化合物、あるいはその立体異性体、立体異性体の混合物、溶媒和物、または水和物。
- R1、R2、およびR3が、独立して、C2〜C4アルキルから選択される、請求項4に記載の化合物、あるいはその立体異性体、立体異性体の混合物、溶媒和物、または水和物。
- R1、R2、およびR3のうちの1つのみが、メチルである、請求項1に記載の化合物、あるいはその立体異性体、立体異性体の混合物、溶媒和物、または水和物。
- R1、R2、およびR3のうちの2つのみが、メチルである、請求項1に記載の化合物、あるいはその立体異性体、立体異性体の混合物、溶媒和物、または水和物。
- R1、R2、およびR3の各々が、メチルである、請求項1に記載の化合物、あるいはその立体異性体、立体異性体の混合物、溶媒和物、または水和物。
- 前記化合物が、
からなる群より選択される、請求項1に記載の化合物、またはその溶媒和物、もしくは水和物。
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Publication number | Publication date |
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JP2015078224A (ja) | 2015-04-23 |
JP2016040311A (ja) | 2016-03-24 |
SI1933821T1 (sl) | 2020-11-30 |
HUE052377T2 (hu) | 2021-04-28 |
WO2007035496A1 (en) | 2007-03-29 |
PL1933821T3 (pl) | 2021-01-11 |
EP1933821B1 (en) | 2020-07-29 |
PT1933821T (pt) | 2020-10-15 |
CA2622523A1 (en) | 2007-03-29 |
ES2823728T3 (es) | 2021-05-10 |
US20070072943A1 (en) | 2007-03-29 |
EP1933821A1 (en) | 2008-06-25 |
EA200800819A1 (ru) | 2008-08-29 |
CA2622523C (en) | 2014-02-18 |
US7432305B2 (en) | 2008-10-07 |
JP2017193570A (ja) | 2017-10-26 |
EA021818B1 (ru) | 2015-09-30 |
JP2013155194A (ja) | 2013-08-15 |
JP2009508867A (ja) | 2009-03-05 |
LT1933821T (lt) | 2020-11-10 |
DK1933821T3 (da) | 2020-10-26 |
CY1123740T1 (el) | 2022-03-24 |
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