JP5978291B2 - 一酸化炭素放出分子およびその使用 - Google Patents
一酸化炭素放出分子およびその使用 Download PDFInfo
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- JP5978291B2 JP5978291B2 JP2014506550A JP2014506550A JP5978291B2 JP 5978291 B2 JP5978291 B2 JP 5978291B2 JP 2014506550 A JP2014506550 A JP 2014506550A JP 2014506550 A JP2014506550 A JP 2014506550A JP 5978291 B2 JP5978291 B2 JP 5978291B2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F11/00—Compounds containing elements of Groups 6 or 16 of the Periodic Table
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本開示は、一酸化炭素放出分子(CO-RM)、ならびに、肝臓疾患および炎症性状態を処置するためのその使用に関する。
一酸化炭素(CO)は、最も一般的に遭遇する毒物である。逆説的に、半世紀以上前に、一酸化炭素が常にヒトにおいて少量形成されること、および、特定の病態生理学的条件下においてこの一酸化炭素の内部産生が増大することが見出された(Sjostrand, Scan J Clin Lab Invest. (1949) 1: 201−214)。したがって、一酸化炭素がヒトの体内において産生されることについては長い間知られていたが、科学者がこの気体分子の潜在的な生物学的活性を研究し始めたのは、つい近年になってからである。一酸化炭素の主要な内部ソースは、ヘムオキシゲナーゼであり、これは、常在型(HO-2およびHO-3)ならびに誘導型(HO-1)のアイソフォームにおいて存在する。ヘムは、一酸化炭素、遊離の二価の鉄およびビリベルジンの形成におけるHO-1およびHO-2のための基質として働き、ビリベルジンは、ビリベルジンレダクターゼによりビリルビンへと迅速に変換される(例えば、Maines, Annu Rev Pharmacol Toxicol. (1997) 37:517−554を参照)。一般に、HO-1が、UVA照射、発癌物質、虚血−再灌流傷害、エンドトキシンショック、および酸素により誘導されるフリーラジカルの産生により特徴づけられる幾つかの他の状態を含むストレス刺激に対する、中心的な誘導型防御システムを代表すると考えられている(例えば、Abraham et al., Cell Physiol Biochem. (1996) 6: 129−168を参照)。その生理学的および細胞保護的作用の一部として、ヘムオキシゲナーゼにより誘導される一酸化炭素は、神経伝達物質、類洞の緊張の調節因子、血小板凝集の阻害剤、および急性高血圧応答の抑制因子として、主要な役割を果たすと考えられる。外因的に適用される一酸化炭素は、動物の疾患モデルにおける一酸化炭素の有益な効果を明らかにするために、非常に有用な実験的手法となっている(例えば、US 2002155166、US 2003039638、US 2003219496、US 2003219497、US 2004052866、WO 03/103585、WO 04/043341を参照)。したがって、一貫する知見は、一酸化炭素についての多目的な役割を支持する一連の重要な細胞機能を明らかとする。
本出願は、発明のモリブデンCO-RM化合物、その医薬組成物、ならびに調製、使用および処置の方法を提供する。
式中:
R1の各々の場合は、独立して、水素、未置換のC1−3アルキル、または−CO2RA1もしくは−C(=O)N(RA1)2で置換されたC1−3アルキルであり、ここで、RA1の各々の場合は、独立して、水素またはC1−10アルキルであり;
R2の各々の場合は、独立して、水素、未置換のC1−3アルキル、または−CO2RA2もしくは−C(=O)N(RA2)2で置換されたC1−3アルキルであり、ここで、RA2の各々の場合は、独立して、水素またはC1−10アルキルである;
あるいは、R1およびR2ならびにそれらが結合している炭素は、独立して、連結されてC3−4カルボシクリルを形成する;
ただし、同じ炭素に結合しているR1およびR2の各々の場合は、両方がともに水素であることはない。
のもの、またはその塩、溶媒和物もしくは水和物、またはそれらの組み合わせである。
のもの、またはその塩、溶媒和物もしくは水和物、またはそれらの組み合わせである。
特許または出願のファイルは、少なくとも1つのカラーで実行された図面を含む。この特許または特許出願の刊行物のカラー図面を含むコピーは、請求および必要な手数料の支払いにより、庁により提供される。
本開示は、少なくとも部分的に、式(I):
一側面において、本開示は、式(I):
式中:
R1の各々の場合は、独立して、水素、未置換のC1−3アルキル、または−CO2RA1もしくは−C(=O)N(RA1)2で置換されたC1−3アルキルであり、ここで、RA1の各々の場合は、独立して、水素またはC1−10アルキルであり;
R2の各々の場合は、独立して、水素、未置換のC1−3アルキル、または−CO2RA2もしくは−C(=O)N(RA2)2で置換されたC1−3アルキルであり、ここで、RA2の各々の場合は、独立して、水素またはC1−10アルキルである;
あるいは、R1およびRならびにそれらが結合している炭素は、独立して、連結されてC3−4カルボシクリルを形成する;
ただし、同じ炭素に結合しているR1およびR2の各々の場合は、両方がともに水素であることはない。
のうちの1または2以上を含む化合物が挙げられる。
の1または2以上を含む化合物が挙げられる。
ある態様において、R1およびRならびにそれらが結合している炭素の少なくとも1つの場合は、連結されてC3−4カルボシクリルを形成する。ある態様において、R1およびRならびにそれらが結合している炭素の少なくとも1つの場合は、連結されてシクロプロパニル(C3)環を形成する。ある態様において、R1およびRならびにそれらが結合している炭素の少なくとも1つの場合は、連結されてシクロブタニル(C4)環を形成する。
ある態様において、R2の各々の場合は、水素である。この場合、ある態様において、R1の各々の場合は、独立して、未置換のC1−3アルキルまたは−CO2RA1もしくは−C(=O)N(RA1)2で置換されたC1−3アルキルである。ある態様において、R1の少なくとも1つの場合は、−CO2RA1で置換されたC1−3アルキルである。ある態様において、R1の少なくとも1つの場合は、−C(=O)N(RA1)2で置換されたC1−3アルキルである。ある態様において、R1の少なくとも1つの場合は、未置換のC1−3アルキルである。ある態様において、R1の少なくとも2つの場合は、未置換のC1−3アルキルまたは−CO2RA1で置換されたC1−3アルキルである。ある態様において、R1の少なくとも2つの場合は、−CO2RA1で置換されたC1−3アルキルである。ある態様において、R1の少なくとも2つの場合は、−C(=O)N(RA1)2で置換されたC1−3アルキルである。ある態様において、R1の少なくとも2つの場合は、未置換のC1−3アルキルである。
ある態様において、R2の各々の場合は、独立して、未置換のC1−3アルキルまたは−CO2RA2もしくは−C(=O)N(RA2)2で置換されたC1−3アルキルであり、R1の各々の場合は、独立して、未置換のC1−3アルキルまたは−CO2RA1もしくは−C(=O)N(RA1)2で置換されたC1−3アルキルである。この場合、ある態様において、R1の少なくとも1つの場合は、−CO2RA1で置換されたC1−3アルキルである。ある態様において、R1の少なくとも1つの場合は、−C(=O)N(RA1)2で置換されたC1−3アルキルである。ある態様において、R1の少なくとも1つの場合は、未置換のC1−3アルキルである。ある態様において、R1の少なくとも2つの場合は、−CO2RA1で置換されたC1−3アルキルである。ある態様において、R1の各々の場合は、未置換のC1−3アルキルである。ある態様において、R1の各々の場合は、−CO2RA1で置換されたC1−3アルキルである。ある態様において、R1の各々の場合は、−C(=O)N(RA1)2で置換されたC1−3アルキルである。ある態様において、R1の各々の場合は、独立して、未置換のC1−2アルキルまたは−CO2RA1もしくは−C(=O)N(RA1)2で置換されたC1−2アルキルである。ある態様において、R1の各々の場合は、独立して、未置換のC2−3アルキルまたは−CO2RA1もしくは−C(=O)N(RA1)2で置換されたC2−3アルキルである。ある態様において、R1の各々の場合は、独立して、未置換のC1アルキルまたは−CO2RA1もしくは−C(=O)N(RA1)2で置換されたC1アルキルである。ある態様において、R1の各々の場合は、独立して、未置換のC2アルキルまたは−CO2RA1もしくは−C(=O)N(RA1)2で置換されたC2アルキルである。ある態様において、R1の各々の場合は、独立して、未置換のC3アルキルまたは−CO2RA1もしくは−C(=O)N(RA1)2で置換されたC3アルキルである。ある態様において、R1の各々の場合は、独立して、−CH3、−CH2CH3、−CH2CH2CH3、−CH(CH3)2、−CH2CO2RA1、−CH2CH2CO2RA1、−CH(CO2RA1)CH3、−CH2CH2CH2CO2RA1、−CH2CH(CO2RA1)CH3、−CH(CO2RA1)CH2CH3、−CH(CH3)(CHCO2RA1)、−C(CO2RA1)(CH3)2、−CH2C(=O)N(RA1)2、−CH2CH2C(=O)N(RA1)2、−CH(C(=O)N(RA1)2)CH3、−CH2CH2CH2C(=O)N(RA1)2、−CH2CH(C(=O)N(RA1)2)CH3、−CH(C(=O)N(RA1)2)CH2CH3、−CH(CH3)(CHC(=O)N(RA1)2)および−C(C(=O)N(RA1)2)(CH3)2。ある態様において、R1の各々の場合は、独立して、−CH3、−CH2CO2RA1または−CH2C(=O)N(RA1)2である。ある態様において、R1の各々の場合は、−CH3である。ある態様において、R1の各々の場合は、独立して、−CH2CO2RA1である。ある態様において、R1の各々の場合は、−CH2CO2Hである。ある態様において、R1の各々の場合は、独立して、−CH2C(=O)N(RA1)2である。ある態様において、R1の各々の場合は、独立して、−CH2C(=O)NH2である。
上の議論から、上記のような式(I)の化合物、およびそのサブセット(例えば式(II)の化合物)が、そのリガンド(i):
提供されるのは、本開示の化合物、すなわち、式(I)、(II)および(III)の化合物を製造する方法である。
を製造する方法であって、方法は、モリブデントリ−CO複合体を、式:
のイソシアニドと反応させて、式(II)の化合物を提供することを含む。
Mo(CO)3L3
のものであって、式中、L3は、3個の単座のリガンド、1個の二座のリガンドおよび1個の単座のリガンド、または1個の三座のリガンドのいずれかを表わす。
Mo(CO)3L3
のものであって、式中、L3は、3個の単座のリガンドのいずれかを表わす。ある態様において、3個の単座のリガンドは、COリガンドである。ある態様において、3個の単座のリガンドは、有機ニトリルリガンドである。
Mo(CO)3L3
のものであって、式中、L3は、1個の二座のリガンドおよび1個の単座のリガンドを表わす。
Mo(CO)3L3
のものであって、式中、L3は、1個の三座のリガンドを表わす。ある態様において、三座のリガンドは、環式トリエンである。ある態様において、環式トリエンは、シクロヘプタトリエンである。
ある態様において、本開示は、本開示の化合物またはその塩、エステル、アミド、溶媒和物もしくは水和物またはそれらの組み合わせならびに薬学的に受容可能な賦形剤を含む医薬組成物を提供する。ある態様において、本開示の化合物またはその薬学的に受容可能な塩は、医薬組成物中で有効量において提供される。
本開示は、少なくとも部分的に、式(I)の化合物が一酸化炭素(CO)の有効量を肝臓において優先的に放出するという知見に基づく。これらの化合物はまた、肝臓において抗炎症活性および再生活性を示す。
本明細書において記載される開示がより完全に理解され得るように、以下の例を記載する。これらの例は、単に説明を目的とするものであって、決して本開示を限定するものとして解釈されるべきではないことが理解されるべきである。
Mo(CO)3(η6−C7H8)の合成
モリブデントリ−CO複合体Mo(CO)3(η6−C7H8)の調製は、文献において記載されている(例えばW. A. HerrmannおよびA. Salzer、Synthetic Methods of Organometallic and Inorganic Chemistry、第1巻、Georg Thieme Verlag、New York、1996年、p129;および Abelら、J. Chem. Soc. (1958) 4559を参照)。
方法A
Beckら(Achatz et al., Anorg. Allg. Chem (2005) 631:2339−2346)により記載される手順に従って、化合物(3−a)または(3−c)のNaOHによる?化、およびその後の水溶液中での酸(例えばHClまたはH2SO4)によるプロトン化は、トリカルボニル[トリス(2−イソシアノ−2−メチル−プロピオン酸)]Mo(0)(3−b)の形成をもたらした。化合物(3−b)は、褐色のバイアル中で常温においてN2下で保存した場合、6か月間またはそれより長く安定であった。
化合物(3−a)(1.914g;3.41mmol;561.3939g/mol)を、36mLのTHF中に溶解し、氷槽中に置いた。NaOH(10当量;1.364g;34.1mmol;40g/mol)を、9mLのH2O中に溶解し、先の黄色の溶液にゆっくり添加した。黄色の濁った溶液を得、これを室温までゆっくり温めながら1時間撹拌した。ヘキサン:酢酸エチル(1:1)中でのTLC分析は、この時点の最後におけるRf=0による1つのスポットのみを示した。溶媒をTHFが無くなるまで濃縮した。次いで27mLの水を添加し、その後17.05mLの1MのH2SO4酸を添加した。白色の沈澱が形成され、これは次いで黄色のオイルへと変化した。白色の粉末が再形成されるまで水を蒸発させた。濾過した後、無色の溶液のpHは1であった。固体を5×20mLの量の水で洗浄した。洗浄用液のpHは、連続的に3、4、4、4および4であった。最後に洗浄された生成物を、真空下で乾燥させた。1.0×10−2トルで30時間、および2.0×10−5トルで9時間の乾燥の後で、IRスペクトル(840mgのKBr中1.2mgの化合物(3−b))およびNMR(10mg/600μLのアセトン−d6)は、複合体が純粋であったことを示した。収量:1.600g(90.3%)。C18H21O9N3Mo(519.31g/mol)。
I型の完全にプロトン化された複合体を得るための、第2の方法を開発した。
化合物1b、2b、3b、4bおよび5bのCO放出のダイナミクスを、in vitroで、HEPESバッファー(pH7.4)中またはリン酸バッファー(pH7.4)中で、肝臓ミクロソームの存在下において行った。放出されたCOの素量化を、Vreman et al. Anal. Biochem. (2005) 341: 280-289に従って、気体混合物中の1〜2ppbもの低い濃度におけるCOを定量することを可能にする還元性化合物分光検出器(Reducing Compound Photometric detector)を備えたガスクロマトグラフィー(GC-RCP;Peak Laboratories, Mountain View, CA)を用いて行った。
全ての化合物のCO放出のダイナミクスを、密封された8mLのバイアル中の50mMのHEPESバッファー(pH7.4)中で評価した。化合物のストック溶液(5mM)を、PBSバッファー中で調製し(各化合物は、3当量のNaOHの添加の後でPBS中で可溶性であった)、10μLを、990μLの50mMのHEPESバッファーに添加した(バッファーの最終濃度は50μMであった)。光活性化によりモリブデンカルボニル化合物からCOを放出させることができるので、密封された、透明なガラスバイアル中の溶液により、明所において(研究室のベンチにおいて、通常の研究室の照明の下で)、または暗所において(アルミニウムホイル中に包んで、およびボール紙の箱の中に保って)、CO放出を決定することができた。バイアルのヘッドスペース(7mLの容積)の気体試料(10μLから500μLまで)を、気密シリンジで、インキュベーションの開始の15、30、60、120、240、360分、および24時間後に取り除いた。気体試料を、希釈のために、空気を含有する密封バイアル(8mL)中に注入した。バイアルの全気体容積(8mL)を、キャリアガスと共にGC-RCPに移し、COについて分析した。GC-RCPは、既知の量のCOを含む気体によりカリブレーションされていた。30ppmのCOを含む合成空気を含むシリンダーからの気体から始めて、上記のような8mLのバイアル中で希釈物を調製し、カリブレーション曲線を確立した。
化合物1b、2b、3b、4bおよび5bのCO放出のダイナミクスもまた、ラットまたはヒトの肝臓ミクロソームの存在下において評価した。8mLバイアル中で、以下の試薬を組み合わせた:
713μLの精製水
200μLの0.5Mのカリウムリン酸バッファー、pH7.4
50μLのNADPH再生システム溶液A(BD、カタログ番号451220)
10μLのNADPH再生システム溶液B(BD、カタログ番号451200)
2μLのDMSO(10μMの最終濃度)中の化合物の5mMの溶液
既知のCO濃度に対するGC-RCPにおいて得られるピーク面積を推定することを可能にするために、COのカリブレーション曲線を確立した。異なる気体容積の30ppmのCOガスボトル(Linde、カタログ番号14960013)を、8mLのバイアル中に注入した。GC-RCPにおいて得られたピーク面積の値および対応する各試料中のCOのppmまたはpmolを、グラフ中にプロットした。0.857ppm(または268pmol)までのCO濃度について、直線的な応答曲線が得られた。これらの値より上では、GC-RCPの読み取りは正確ではない。
50mMのHEPES(pH7.4)バッファー中の化合物1bのCO放出のダイナミクスを、図1Aにおいて表わす。CO放出の半減期は、暗所においておよそ4時間であり、明所においては約1時間である。50mMのHEPESバッファー中に24時間あった化合物1bは、明所においては1.6当量のCOを、暗所では1.4当量のCOを、それぞれ放出する。
50mMのHEPES(pH7.4)バッファー中の化合物2bのCO放出のダイナミクスを、図2Aにおいて表わす。化合物2bの場合のCO放出の半減期は、暗所においてはおよそ4時間であるが、明所においては、それは0.5当量のCOを放出するために約90分間を要する。50mMのHEPESバッファー中での24時間のインキュベーションの後で、化合物2bは、明所においては1.5当量のCOを、暗所では1.2当量のCOを、それぞれ放出する。
50mMのHEPES(pH7.4)バッファー中の化合物3bのCO放出のダイナミクスを、図4Dにおいて表わす。CO放出の半減期は、暗所においておよそ2時間であり、明所においては約1時間である。50mMのHEPESバッファー中に24時間あった化合物3bは、明所においては1.8当量のCOを、暗所においては1.3当量のCOを、それぞれ放出する。
50mMのHEPES(pH7.4)バッファー中の化合物4bのCO放出のダイナミクスを、図5Aにおいて表わす。RCPを備えたGCを用いてin vitroでの50mMのHepesバッファー(pH7.4)中でのCOの放出を測定することにより、化合物4bの安定性を決定した。化合物4bの濃度は、50μMであった。CO放出についての半減期は、0.5モル当量のCOを放出するために必要とする時間として定義され、化合物4bについては約1時間であることが見出された(光の不在において)。CO放出についての半減期はまた、オキシメーターを用いてヒツジの血液中でも測定した。632.1μg/mLの濃度の化合物4bを用いた。この濃度は、マウスにおいて50mg/kgの用量について計算されたCmaxに対応する。血液中でのCO放出についての半減期は、約2.5時間であることが見出された。
50mMのHEPES(pH7.4)バッファー中の化合物5bのCO放出のダイナミクスを、図6Aにおいて表わす。RCPを備えたGCを用いてin vitroでの50mMのHepesバッファー(pH7.4)中でのCOの放出を測定することにより、化合物5bの安定性を決定した。化合物5bの濃度は、50μMであった。CO放出についての半減期は、0.5モル当量のCOを放出するために必要とする時間として定義され、化合物5bについては約6時間であることが見出された(光の不在において)。
表5は、ミクロソームの存在下における、50mMのHEPESバッファー(pH7.4)中、またはカリウムリン酸バッファー(pH7.4)中の、モリブデンカルボニルイソシアノ化合物のCO放出の半減期をまとめる。化合物4bは、最も安定性が低く、pH7.4の溶液中での自発的CO放出について1時間の半減期を有する。化合物1bおよび2bは、4時間の自発的CO放出の半減期を有する。
一酸化炭素放出分子(CO-RM)は、一酸化炭素(CO)のキャリアであり、in vivoでCOを放出することができる。COは、血液中でヘモグロビンに、および細胞において多様なヘムタンパク質に結合することができる。Vreman et al. Anal Biochem 341:280-289は、組織に結合したCOを気相へと放出させ、それをGC-RCPクロマトグラフィーを用いて定量する方法を記載する。本発明者らは、この方法論を、CO-RMで処置されたマウスの多様な組織におけるCOをアッセイするために適用した(本明細書において例2を参照)。しかし、VremanのCO放出方法(スルホサリチル酸と共のin vitroインキュベーション)はまた、CO-RMからCOを放出させるので、組織試料から放出されたCOは、組織タンパク質に結合したCO、および組織中に蓄積したCO-RM化合物からのCOを表わす。in vivoで低いCO放出速度を有するCO-RM化合物について、最初のサンプリングの時点(CO-RM投与の5分後)において測定されたCOは、したがって、主に、完全なCO-RMの組織分布についての指標であり得る。
化合物を、PBS中に溶解し、酸を、3当量のNaOH(2.5MのNaOHストック溶液から)で中和した。pHを、HCl(1Mのストック溶液から)を添加することにより、約7.5まで下げた。化合物を、次いで、i.v.で(150μL中50mg/kg)CD-1メスマウス(Charles River)に投与した。マウスを、尾静脈からのi.v.投与を容易にするために赤外ランプの下で温めた。投与の5分後および20分後に、2個体のマウスをIsoFluoraneで麻酔し、約20μLのヘパリン溶液を含有するパスツールピペットを用いて、後眼窩神経叢(retro-orbital plexus)から血液を収集した。動物を開腹し、門脈を切開し、心臓の左心室において10〜15mLの冷たいPBSを注入することにより器官を灌流した。次いで、心臓、腎臓、肝臓および肺を収集し、カリウムリン酸バッファーで簡単に洗浄し、ペーパータオルで乾燥させ、液体窒素中で迅速凍結した。新たに収集した血液の試料を、AVOXimeter 4000キュベット(ITC)に移し、カルボキシヘモグロビン(COHb)、オキシヘモグロビン(O2Hb)およびメトヘモグロビン(MetHb)のレベルを、ポータブルのAVOXimeter 4000 CO−オキシメーターを用いて測定した。結果を、循環中の総ヘモグロビン種の平均パーセンテージとして示す。器官および血液を、CO素量化が行われるまで−20℃で保存した。
マウスにおける事前の安全性の研究
マウスにおける事前の安全性の研究は、1g/kgまでの用量は何らの毒性も示さないことを示す。図7は、CD-1マウスにおける化合物3bの薬物動態学を表わす。化合物3bを、静脈内で(i.v.)100mg/kgの用量において投与した。投与の1、5、10、20および30分後に、血液試料を収集した。血清中の化合物3bの濃度を、HPLCによりアッセイした。実験的曲線は、循環からの排出およびCO放出を通しての減衰を表わす。
化合物3bが迅速に肝臓に分布されることを見出した。化合物3bのi.v.注射の5分後に、COの濃度は、肝臓において、血液におけるものよりも5倍高い。20分後、アッセイされた非血液組織の中で、COの濃度は肝臓においてなお最も高い。
図8は、リン酸バッファー(pH7.4)(「バッファー」)、ヒト肝臓ミクロソーム(「ヒト」)またはラット肝臓ミクロソーム(「ラット」)の存在下におけるリン酸バッファー(pH7.4)中の、COの当量において表わされた、化合物3bから放出されたCOの量を表わす。アッセイは、1時間37℃で密封されたバイアル中で行った。気体のアリコートをバイアルの気体空間から取り除き、異なる時点におけるCO濃度をGC-RCPにより決定した。
図9は、CD-1メスマウスにおいて、化合物3bの300mg/kgにおける静脈内での投与の後で測定されたカルボキシヘモグロビン(CO-Hb)のパーセンテージを表わす。CO-Hbを、オキシメーター(A-vox Instruments製のAVOXimeter 4000)を用いて80分間にわたり測定した。この装置を用いて測定されたCO-Hbのベースラインは、3〜4%である。化合物3bでi.v.で300mg/kgの用量において処置されたマウスは、血液中で7.5%のCOHbを超えず、化合物3bの治療的用量は、マウスの血液中のCOHbの徴候性レベルを引き起こさなかったことを見出した。
化合物3bを、アセトアミノフェン(APAP)誘導性の肝臓の傷害についての致死量以下のモデルにおいて研究した。
化合物3bをまた、より高い用量において治療的利益が存在するか否かを確認するために研究した。3群の5個体のマウスを、2回の用量の化合物で、APAP負荷の1時間および3時間後に処置し:(1)化合物3b、2×60mg/kg;(2)化合物3b、2×120mg/kg;および(3)NAC、2×300mg/kg、APAPの22時間後に効果を評価した。
図13は、APAP誘導性の急性肝不全(ALF)モデルにおける血清ALTに対するNACまたは化合物3bによる処置の効果を表わす。C57Bl/6オスマウスにおいて、i.p.注射によるアセトアミノフェンの1回用量(300mg/kg)を用いて、ALFを誘導した。APAP注射の5時間または7時間後に、動物を、NAC(150mg/kg)もしくは化合物3b(120mg/kg)により、または両方の化合物の組み合わせにより処置した。アラニンアミノトランスフェラーゼ(ALT)を、APAP注射の22時間後に測定した(各群についてn=4またはn=5マウス)。*マウスへのNAC投与は、ヒトの用量を模倣し、これは、21時間にわたり300mgの合計のために、60分間にわたる150mg/kg(負荷用量);4時間にわたる50mg(第2の用量);16時間にわたる100mg(第3の用量)である。
図15A〜15Bは、ALFモデルにおける血清ALTに対するNACと化合物3bとによる組み合わせ処置の効果を表わす。C57Bl/6オスマウスにおいて、i.p.注射によるアセトアミノフェンの1回用量(300mg/kg)を用いて、ALFを誘導した。NAC(300mg/kg)および化合物3b(120mg/kg、図15A、または60mg/kg、図15B)を、マウスに、別々にまたは組み合わせて、APAP注射の1時間後または3時間後に投与した。実験1および2は、2回の独立した実験を表わす。アラニンアミノトランスフェラーゼ(ALT)を、APAP注射の22時間後に測定した(各群についてn=4またはn=5マウス)。ALTレベル、および、APAPのみを注射されたマウスにおいて観察された増大と比較しての、対応するALT増大のパーセンテージを、表7において表わす。
図16は、アセトアミノフェンにより誘導される肝臓の損傷におけるNACおよび化合物3bの効果を表わす。C57Bl/6オスマウスにおいて、i.p.注射によるアセトアミノフェンの1回用量(300mg/kg)を用いて、ALFを誘導した。NACおよび化合物3bを、APAP投与の1および3時間後に投与した。APAP注射の22時間後に、血清ALTを測定し、マウス肝臓の小葉中心切片を作製し、ヘマトキシリンおよびエオジンで染色した。A:ナイーブなマウス;BおよびC:APAP対照マウス(複製実験);DおよびE:APAPプラス化合物3b、2×100mg/kg(複製実験);FおよびG:APAPプラス化合物3b、2×300mg/kg(複製実験);HおよびI:APAPプラスNAC、2×300mg/kg(複製実験)。
図24は、0.3、3、10または30mg/kgの用量において、APAP(300mg/kg)投与の3時間および5時間(+3h、+5h)後に投与された(i.p.)マウスにおけるALFモデルにおける化合物4bの効果を表わす。APAP投与の22時間後に血清ALTレベルを評価した。化合物4bは、APAPにより誘導されたALTレベルを、用量依存的な様式において、低下させることができた;30mg/kgの用量において、ALTレベルは、未処置の対照動物と比較して、75%低下した。
図25は、10、30または120mg/kgの用量においてAPAP(300mg/kg)投与の3時間および5時間(+3h、+5h)後に投与された(i.p.)マウスにおけるALFモデルにおける化合物5bの効果を表わす。APAP投与の22時間後に血清ALTレベルを評価した。化合物5bAPAPにより誘導されたALTレベルを、用量依存的な様式において、低下させることができた;120mg/kgの用量において、ALTレベルは、未処置の対照動物と比較して、70%低下した。
化合物3bを、致死性APAP肝不全モデルにおいて試験した(例えばImaeda et al. J Clin Invest (2009) 119:305-14を参照)。
C57BL/6マウスにおける肝臓虚血−再灌流モデル。麻酔したC57BL/6マウスにおいて、肝動脈および門脈を30分間クランプし;24時間後に血清ALTレベルを決定した。化合物3bを、i.p.で30mg/kgにおいて、各々、手術の1時間前および1時間後に投与した。
図21A〜21Bは、アポトーシスのex-vivoモデルにおける化合物3bの効果を表わす。C57BL/6マウスからの初代培養肝細胞のアポトーシスを、アクチノマイシンD(ActD;200ng/mL)および腫瘍壊死因子−α(TNF−α;10ng/mL)により誘導した。アポトーシス誘導因子ActD/TNF−αの添加の1時間前および1時間後に、化合物3bを培養に添加した。化合物3bを、0.5mLのウェルあたり25、50、100および150μgの濃度で試験した。アポトーシス誘導因子の添加の24時間後に、肝細胞の生存率を決定した。図21A:アポトーシス誘導因子のみにより処置された細胞と比較しての、化合物3bの存在下におけるActD/TNF−α処置細胞の生存の増大のパーセンテージ。図21B:マウス肝細胞(アポトーシス誘導因子により処置されていないもの)に対する化合物3bの用量の毒性。データは、3〜5回の独立した実験(異なるマウスからの3〜5個の肝臓)の平均±S.D.である。
再生活性について試験するためのマウス部分肝切除モデルにおける肝臓再生。モデル:マウスにおける部分的(70%)肝臓摘除およびその後の再生の速度。
図23A〜23Cは、TNBSにより誘導される大腸炎のモデルにおける化合物3bの効果を表わす。Balb/Cマウスにおいて、4mgのTNBS(2,4,6−トリニトロベンゼンスルホン酸)を含む100mLの40%エタノールの1回の大腸内投与により、大腸炎を誘導した。デキサメタゾン(Dex:0.3mg/kg)、化合物3b(120mg/kg)またはそのビヒクルを、大腸炎誘導の1日前(第1日)から始まる連続した3日間の間、毎日投与した。大腸炎誘導の4日後において、マウスを安楽死させ、大腸を単離し、洗浄し、遠位大腸の7cmのセグメントを摘除し、計量した(図23A)。以下のスコアを用いて便のコンシステンシーを決定した:0、よく形成されたペレット;1、軟便;2、液状便または血便(図23B)。研究全体を通して、動物を計量した(図23C)。
本明細書において引用される全ての特許、特許出願、および参考文献は、本明細書において参考として援用される。
Claims (31)
- 式(I):
R1の各々の場合は、独立して、水素、未置換のC1−3アルキル、または−CO2RA1もしくは−C(=O)N(RA1)2で置換されたC1−3アルキルであり、ここで、RA1の各々の場合は、独立して、水素またはC1−10アルキルであり;
R2の各々の場合は、独立して、水素、未置換のC1−3アルキル、または−CO2RA2もしくは−C(=O)N(RA2)2で置換されたC1−3アルキルであり、ここで、RA2の各々の場合は、独立して、水素またはC1−10アルキルである;
あるいは、R1およびR2ならびにそれら両方が結合している炭素は、独立して、連結されてC3−4カルボシクリルを形成する;
ただし、同じ炭素に結合しているR1およびR2の各々の場合は、両方がともに水素であることはない
の化合物、またはその塩、エステル、アミド、溶媒和物もしくは水和物であって、さらにここで、
式(I)の化合物のエステルが、分子中のカルボン酸基の酸性の水素原子のうちの1または2以上が、C 1−10 アルキル基により置き換えられた化合物であり、
式(I)の化合物のアミドが、分子中のカルボン酸基のOH基のうちの1または2以上が、アミノ、C 1−10 アルキルアミノ、およびC 1−10 ジアルキルアミノから選択される基により置き換えられた化合物である、
前記化合物、またはその塩、エステル、アミド、溶媒和物もしくは水和物。 -
- 式(I−a):
式(I−b):
の化合物、あるいは
式(I−e):
の化合物、あるいは
式(I−g):
の化合物、あるいは
式(I−i):
の化合物である、請求項1に記載の化合物、またはその塩、エステル、アミド、溶媒和物もしくは水和物。 - R2の各々の場合は、水素である、請求項1に記載の化合物。
- R2の各々の場合は、水素であり、R1の各々の場合は、独立して、未置換のC1−3アルキル、または−CO2RA1もしくは−C(=O)N(RA1)2で置換されたC1−3アルキルである、請求項4に記載の化合物。
- R1の各々の場合は、独立して、未置換のC1−3アルキルであるか、あるいは、R1の各々の場合は、−CO2RAで置換されたC1−3アルキルである、請求項5に記載の化合物。
- R2の各々の場合は、独立して、未置換のC1−3アルキル、または−CO2RA2もしくは−C(=O)N(RA2)2で置換されたC1−3アルキルであり、R1の各々の場合は、独立して、未置換のC1−3アルキル、または−CO2RA1もしくは−C(=O)N(RA1)2で置換されたC1−3アルキルである、請求項1に記載の化合物。
- R1の各々の場合は、独立して、未置換のC1−3アルキルであり;R2の各々の場合は、独立して、未置換のC1−3アルキル、または−CO2RA2で置換されたC1−3アルキルであるか、あるいは、
R1の各々の場合は、独立して、−CO2RA1で置換されたC1−3アルキルであり;R2の各々の場合は、独立して、−CO2RA2で置換されたC1−3アルキルである、請求項7に記載の化合物。 - 請求項1に記載の式(I):
- 化合物のエステルが、式(II):
R 3 の各々の場合は、独立して、C 1−6 アルキルであり;
R 1 の各々の場合は、独立して、水素、未置換のC 1−3 アルキル、または−CO 2 R A1 もしくは−C(=O)N(R A1 ) 2 で置換されたC 1−3 アルキルであり、ここで、R A1 の各々の場合は、独立して、水素またはC 1−10 アルキルであり;
R 2 の各々の場合は、独立して、水素、未置換のC 1−3 アルキル、または−CO 2 R A2 もしくは−C(=O)N(R A2 ) 2 で置換されたC 1−3 アルキルであり、ここで、R A2 の各々の場合は、独立して、水素またはC 1−10 アルキルである;
あるいは、R 1 およびR 2 ならびにそれら両方が結合している炭素は、独立して、連結されてC 3−4 カルボシクリルを形成する;
ただし、同じ炭素に結合しているR 1 およびR 2 の各々の場合は、両方がともに水素であることはない
の化合物である、請求項1に記載の化合物、またはその塩、溶媒和物もしくは水和物。 - 化合物のアミドが、式(III):
R 4 の各々の場合は、独立して、水素またはC 1−6 アルキルであり;
R 1 の各々の場合は、独立して、水素、未置換のC 1−3 アルキル、または−CO 2 R A1 もしくは−C(=O)N(R A1 ) 2 で置換されたC 1−3 アルキルであり、ここで、R A1 の各々の場合は、独立して、水素またはC 1−10 アルキルであり;
R 2 の各々の場合は、独立して、水素、未置換のC 1−3 アルキル、または−CO 2 R A2 もしくは−C(=O)N(R A2 ) 2 で置換されたC 1−3 アルキルであり、ここで、R A2 の各々の場合は、独立して、水素またはC 1−10 アルキルである;
あるいは、R 1 およびR 2 ならびにそれら両方が結合している炭素は、独立して、連結されてC 3−4 カルボシクリルを形成する;
ただし、同じ炭素に結合しているR 1 およびR 2 の各々の場合は、両方がともに水素であることはない
の化合物である、請求項1に記載の化合物、またはその塩、溶媒和物もしくは水和物。 - 請求項1〜11のいずれか一項に記載の化合物および薬学的に受容可能な賦形剤を含む、医薬組成物。
- それを必要とする対象における肝臓疾患の処置における使用のための、請求項1〜11のいずれか一項に記載の化合物を含む、医薬組成物。
- 肝臓疾患が肝臓細胞の死を引き起こす、請求項13に記載の医薬組成物。
- 化合物が肝臓細胞の再生を刺激する、請求項14に記載の医薬組成物。
- 肝臓疾患が、薬物に誘導される肝臓の傷害、肝炎、非アルコール性脂肪肝疾患、アルコールに誘導される肝臓疾患、肝硬変、肝臓癌、原発性胆汁性肝硬変、胆汁うっ滞、肝臓の嚢胞性疾患および原発性硬化性胆管炎からなる群より選択される、請求項13に記載の医薬組成物。
- 肝炎が、慢性肝炎、ウイルス性肝炎、アルコールに誘導される肝炎、自己免疫性肝炎または脂肪性肝炎である、請求項16に記載の医薬組成物。
- アルコールに誘導される肝臓疾患が、アルコール性脂肪肝、アルコール性肝炎またはアルコール関連性硬変である、請求項16に記載の医薬組成物。
- 薬物に誘導される肝臓の傷害が、アセトアミノフェンにより誘導される肝臓の傷害である、請求項16に記載の医薬組成物。
- さらなる治療剤をさらに含む、請求項13に記載の医薬組成物。
- さらなる治療剤がN−アセチルシステイン(NAC)である、請求項20に記載の医薬組成物。
- それを必要とする対象における炎症性疾患の処置における使用のための、請求項1〜11のいずれか一項に記載の化合物を含む、医薬組成物。
- 炎症性疾患が胃腸障害に関連する炎症である、請求項22に記載の医薬組成物。
- 胃腸障害が、消化性潰瘍、限局性腸炎、憩室炎、胃腸出血、好酸球性胃腸障害、胃炎、下痢、胃食道逆流性疾患、炎症性腸疾患、クローン病、ベーチェット症候群、大腸炎および炎症性腸症候群から選択される、請求項23に記載の医薬組成物。
- 請求項1に記載の式(I):
R 1 の各々の場合は、独立して、水素、未置換のC 1−3 アルキル、または−CO 2 R A1 もしくは−C(=O)N(R A1 ) 2 で置換されたC 1−3 アルキルであり、ここで、R A1 の各々の場合は、独立して、水素またはC 1−10 アルキルであり;
R 2 の各々の場合は、独立して、水素、未置換のC 1−3 アルキル、または−CO 2 R A2 もしくは−C(=O)N(R A2 ) 2 で置換されたC 1−3 アルキルであり、ここで、R A2 の各々の場合は、独立して、水素またはC 1−10 アルキルである;
あるいは、R 1 およびR 2 ならびにそれら両方が結合している炭素は、独立して、連結されてC 3−4 カルボシクリルを形成する;
ただし、同じ炭素に結合しているR 1 およびR 2 の各々の場合は、両方がともに水素であることはない
の化合物、またはその塩、溶媒和物もしくは水和物を調製する方法であって、
(i)モリブデントリ−CO複合体を、式:
式中、R3の各々の場合は、独立して、C1−6アルキルである;
と反応させて、式(II):
を提供すること;
ならびに、
(ii)式(II)の化合物を加水分解して、式(I):
を提供すること
を含む、前記方法。 - 工程(ii)が、式(II)の化合物を塩基で加水分解して式(I)の化合物を提供することを含む、請求項25に記載の方法。
- 塩基が水酸化物である、請求項26に記載の方法。
- 塩基が、NaOH、KOHまたはLiOHである、請求項27に記載の方法。
- 工程(ii)が、式(II)の化合物を酸で加水分解して式(I)の化合物を提供することを含む、請求項25に記載の方法。
- モリブデントリ−CO複合体が、式:
Mo(CO)3L3
式中、L3は、3個の単座のリガンド、1個の二座のリガンドおよび1個の単座のリガンド、または1個の三座のリガンドのいずれかを表わす
のものである、請求項25に記載の方法。 - モリブデントリ−CO複合体が、
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- 2012-04-19 EP EP12774004.1A patent/EP2699242B1/en not_active Not-in-force
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- 2012-04-19 US US14/112,786 patent/US9163044B2/en not_active Expired - Fee Related
- 2012-04-19 PT PT127740041T patent/PT2699242T/pt unknown
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2015
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US20140142176A1 (en) | 2014-05-22 |
PT2699242T (pt) | 2018-01-22 |
WO2012145520A3 (en) | 2012-12-27 |
JP2014512389A (ja) | 2014-05-22 |
EP2699242A2 (en) | 2014-02-26 |
ES2656237T3 (es) | 2018-02-26 |
US20160137679A1 (en) | 2016-05-19 |
WO2012145520A2 (en) | 2012-10-26 |
EP2699242B1 (en) | 2017-11-01 |
EP2699242A4 (en) | 2015-03-11 |
US9163044B2 (en) | 2015-10-20 |
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