JP4410553B2 - Mifアンタゴニスト活性を有するイソオキサゾリン化合物 - Google Patents
Mifアンタゴニスト活性を有するイソオキサゾリン化合物 Download PDFInfo
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- JP4410553B2 JP4410553B2 JP2003503159A JP2003503159A JP4410553B2 JP 4410553 B2 JP4410553 B2 JP 4410553B2 JP 2003503159 A JP2003503159 A JP 2003503159A JP 2003503159 A JP2003503159 A JP 2003503159A JP 4410553 B2 JP4410553 B2 JP 4410553B2
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- Prior art keywords
- mif
- compound
- isoxazoline
- methyl ester
- activity
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Description
マクロファージ遊走阻止因子(MIF)は、最も早期に記述されたサイトカインの一つであり、極めて多様な細胞および生物活性を有する免疫調節タンパク質である(総説については:Swopeら、Rev. Physiol. Biochem. Pharmacol. 139, 1〜32(1999);Metzら、Adv. Immunol. 66, 197〜223(1997);およびBucala, FASEB J. 14, 1607〜1613(1996)参照)。最初に、MIFは、活性化リンパ系細胞によって分泌され、マクロファージのランダムな移動を阻止し、遅延型過敏症反応に結びつくことが、見出された(Georgeら、Proc. Soc. Exp. Biol. Med., 111, 514〜521(1962);Weiserら、J. Immunol. 126, 1958〜1962(1981);Bloomら、Science, 153:80〜82(1966);David, Proc. Natl. Acad. Sci. USA, 56, 72〜77(1966))。MIFは、また、マクロファージの接着、食作用および殺腫瘍作用を増強することが示された(Nathanら、J. Exp. Med., 137, 275〜288(1973);Nathanら、J. Exp. Med., 133, 1356〜1376(1971);Churchillら、J. Immunol., 115, 781〜785(1975))。残念ながら、初期のMIF試験の多くは混合培養上清を使用しており、それらは、後に、同じくマクロファージ移動阻止活性を有するIFN−γおよびIL−4などの他のサイトカインを含有することが示された(McInnesら、J. Exp. Med., 167, 598〜611(1988);Thurmanら、J. Immunol., 134,305〜309(1985))。組換えMIFが使用できるようになったことは、これらの生物活性の確認と付加的な活性の特定を可能にした。
MIFの酵素活性(互変異性化酵素)およびそれを受容する基質は、MIFに結合してその生物活性を分断する低分子量薬剤を設計するための酵素活性アッセイを提供する。本発明は、イソオキサゾリン構造を有するそのような化合物属についての使用方法を提供する。
R1〜4は、独立して、R、ハロ、N3、CN、OH、NRR′またはSHであり;
RおよびR′は、独立して、HまたはC1〜6アルキルであり;
Xは、R、ハロ、N3、CN、OR、NRR′、SH、=O、=CH2またはAであり;
Aは、置換または非置換芳香環であり;
Yは、R、NRR′、NRR″または(CH2)n−Aであり;
Zは、R、OR、OR″、NRR′、NRR″またはAであり;
R″は、飽和または不飽和の、直鎖または分枝鎖C2〜C18であり;そして
nは、0または1である]
である、関節炎、増殖性血管病、ARDS(急性呼吸窮迫症候群)、サイトカインが介在する毒性、敗血症、敗血症性ショック、乾癬、インターロイキン−2毒性、喘息、MIFが介在する状態、自己免疫疾患(慢性関節リウマチ、インスリン依存性糖尿病、多発性硬化症、対宿主性移植片病、および狼瘡症候群を含むが、これらに限定されない)、腫瘍増殖または血管新生、もしくは局所または全身性MIF放出または合成を特徴とする何らかの状態を含むが、これらに限定されない、炎症性疾患を治療するための方法を提供する。
好ましくは、該化合物は、上記式中、R、R1〜4、XおよびYの各々が、Hまたは−CH2−Aであり、そしてZが、ORである、p−ヒドロキシフェニルイソオキサゾリン含有化合物である。より好ましくは、該化合物は、(R)−3−(4−ヒドロキシフェニル)−4,5−ジヒドロ−5−イソオキサゾリン酢酸のエステル、特にp−ヒドロキシフェノルイソオキサゾリンメチルエステルとしても知られるそのメチルエステル酸(ここでは「ISO−1」と特定する)である。更に一層好ましくは、該化合物は、(2−[3−(4−ヒドロキシフェニル)−4,5−ジヒドロイソオキサゾール−5−イル]−3−フェニルプロピオン酸のエステル、特にそのメチルエステル(「ISO−2」と特定する)である。
R1〜4は、独立して、R、ハロ、N3、CN、OH、NRR′またはSHであり;
RおよびR′は、独立して、HまたはC1-6アルキルであり;
Xは、R、ハロ、N3、CN、OR、NRR′、SH、=O、=CH2またはAであり;
Aは、置換または非置換芳香環であり;
Yは、R、NRR′、NRR″または(CH2)n−Aであり;
Zは、R、OR、OR″、NRR′、NRR″またはAであり;
R″は、飽和または不飽和の、直鎖または分枝鎖C2〜C18であり;そして
nは0または1であり、
ただし、下記のいずれかまたは全部を条件とする:
(i)Z=OCH3であるとき、R、R1〜4、XおよびYの少なくとも1つが、Hではない;
(ii)R1=R2=tert−ブチルであり、各々が、ORに対してオルトであるとき、R、R3、R4、XおよびYの少なくとも1つが、HではないかまたはZが、OCH3ではない;
(iii)Z=OHおよびR=Hまたはメチルであるとき、R1〜4、XおよびYの少なくとも1つが、Hではない(すなわち、該化合物は[3−(4−ヒドロキシフェニル)−4,5−ジヒドロイソオキサゾール−5−イル]酢酸または[3−(4−メトキシフェニル)−4,5−ジヒドロイソオキサゾール−5−イル]酢酸ではない);および
(iv)Z=OCH3およびR=メチルであるとき、R1〜4、XおよびYの少なくとも1つが、Hではない(すなわち、該化合物は[3−(4−メトキシフェニル)−4,5−ジヒドロイソオキサゾール−5−イル]酢酸メチルエステルではない)]
である、医薬組成物を提供する。
先に記述されている(米国特許出願通し番号第09/699,258号、前記参照)アミノ酸シッフ塩基型化合物との構造的類似性に基づき、本発明者らは、潜在的MIFアンタゴニストについての活性基として付加的なフェニルイミン骨格を探索した。いくつかの代表的なフェニルイミン化合物を合成し、MIFのドパクロム互変異性化酵素活性の阻止因子として試験して、イソオキサゾリンが、さらなる注目に値する魅力的な骨格であると結論付けた。したがって、本発明者らによるフェニルピルビン酸:MIFの共結晶化およびアミノ酸/ベンズアルデヒドシッフ塩基型化合物に関するSAR結果の以前の分析(米国特許出願通し番号第09/699,258号)(例えば会合遠位エステル官能基とのイミン結合を担うp−ヒドロキシル化フェニル骨格)に基づき、(S,R)−3−(4−ヒドロキシフェニル)−4,5−ジヒドロ−5−イソオキサゾール−酢酸メチルエステルは、MIF互変異性化酵素活性部位への結合のために重要であると思われるある種の構造要素である。
MIFは、互変異性化(すなわちケト−エノール異性化)反応を触媒する(Rosengrenら、Molecular Medicine,2,143〜149(1996))。同定された最も活性な基質は、ドパクロムの非生理的D−異性体である。この反応は治療的MIF阻止因子を予測する(その全体が、参照として本明細書に組み入れられる、1996年2月16日に出願された審理中の米国特許出願通し番号第08/602,929号および2000年10月27日に出願された米国特許出願通し番号第09/699,258号参照)。MIF互変異性化酵素活性の阻止は、MIF生物活性の阻止の予測となる。
実施例1で使用したMIF互変異性化酵素アッセイは、ある種のイソオキサゾリン含有化合物がMIF酵素活性を阻止することを示す。実施例2は、ある種のイソオキサゾリンベースの化合物が、MIF酵素活性(すなわち互変異性化酵素)を特異的に阻止するだけでなく、MIF生物活性のアッセイにおいて測定したときMIFの免疫調節作用も阻止することを示している。最後に、実施例3は、MIF:イソオキサゾリン複合体の共結晶構造を示し、p−ヒドロキシフェニルイソオキサゾリンのS−異性体の3つの分子だけが、MIF三量体内の3つの活性部位に化学量論的に結合することを明らかにしている。これらのX線データは、次の世代のMIF活性阻止因子を予測する上で貴重な情報を表す。
R1〜4は、独立して、R、ハロ、N3、CN、OH、NRR′またはSHであり;
RおよびR′は、独立して、HまたはC1〜6アルキルであり;
Xは、R、ハロ、N3、CN、OR、NRR′、SH、=O、=CH2またはAであり;
Aは、置換または非置換芳香環であり(例えばR、ハロ、N3、CN、OH、NRR′またはSHから選択される1つまたはそれ以上の基で置換された);
Yは、R、NRR′、NRR″または(CH2)n−Aであり;
Zは、R、OR、OR″、NRR′、NRR″またはAであり;
R″は、飽和または不飽和の、直鎖または分枝鎖C2〜C18であり;そして
nは0または1である]
である。好ましくは、該化合物は、上記式中、R、R1〜4、XおよびYの各々が、Hまたは−CH2−Aであり、そしてZが、ORである、p−ヒドロキシフェニルイソオキサゾリン含有化合物である。より好ましくは、該化合物は、(R)−3−(4−ヒドロキシフェニル)−4,5−ジヒドロ−5−イソオキサゾリン酢酸のエステル、特にそのメチルエステル(ISO−1)である。更に一層好ましくは、該化合物は、(2−[3−(4−ヒドロキシフェニル)−4,5−ジヒドロイソオキサゾール−5−イル]−3−フェニルプロピオン酸のエステル、特にそのメチルエステル(ISO−2)である。
R1〜4は、独立して、R、ハロ、N3、CN、OH、NRR′またはSHであり;
RおよびR′は、独立して、HまたはC1〜6アルキルであり;
Xは、R、ハロ、N3、CN、OR、NRR′、SH、=O、=CH2またはAであり;
Aは、置換または非置換芳香環であり;
Yは、R、NRR′、NRR″または(CH2)n−Aであり;
Zは、R、OR、OR″、NRR′、NRR″またはAであり;
R″は、飽和または不飽和の、直鎖または分枝鎖C2〜C18であり;そして
nは0または1である]
である、関節炎、増殖性血管病、ARDS(急性呼吸窮迫症候群)、サイトカインが介在する毒性、敗血症、敗血症性ショック、乾癬、インターロイキン−2毒性、喘息、MIFが介在する状態、自己免疫疾患(慢性関節リウマチ、インスリン依存性糖尿病、多発性硬化症、対宿主性移植片病、および狼瘡症候群を含むが、これらに限定されない)、腫瘍増殖もしくは血管新生、または局所もしくは全身性MIF放出もしくは合成を特徴とする何らかの状態を含むが、これらに限定されない、炎症性疾患を治療するための方法を提供する。
R1〜4は、独立して、R、ハロ、N3、CN、OH、NRR′またはSHであり;
RおよびR′は、独立して、HまたはC1〜6アルキルであり;
Xは、R、ハロ、N3、CN、OR、NRR′、SH、=O、=CH2またはAであり;
Aは、置換または非置換芳香環であり;
Yは、R、NRR′、NRR″または(CH2)n−Aであり;
Zは、R、OR、OR″、NRR′、NRR″またはAであり;
R″は、飽和または不飽和の、直鎖または分枝鎖C2〜C18であり;そして
nは0または1であり、
ただし、下記のいずれかまたは全部を条件とする:
(i)Z=OCH3であるとき、R、R1〜4、XおよびYの少なくとも1つが、Hではない;
(ii)R1=R2=tert−ブチルであり、各々が、ORに対してオルトであるとき、R、R3、R4、XおよびYの少なくとも1つが、HではないかもしくはZが、OCH3ではない;
(iii)Z=OHおよびR=Hまたはメチルであるとき、R1〜4、XおよびYの少なくとも1つが、Hではない(すなわち、該化合物は[3−(4−ヒドロキシフェニル)−4,5−ジヒドロイソオキサゾール−5−イル]酢酸または[3−(4−メトキシフェニル)−4,5−ジヒドロイソオキサゾール−5−イル]酢酸ではない);および
(iv)Z=OCH3およびR=メチルであるとき、R1〜4、XおよびYの少なくとも1つが、Hではない(すなわち、該化合物は[3−(4−メトキシフェニル)−4,5−ジヒドロイソオキサゾール−5−イル]酢酸メチルエステルではない)]
である、医薬組成物を提供する。
本発明の化合物は、それによってMIFが細胞ソースから放出され、MIF産生が増強されるMIF応答を特徴とする、多くの疾患および障害の治療および予防のための薬理学的組成物において有用性を持つ。本発明の化合物は、単独でまたは適切な担体または賦形剤と混合された医薬組成物中で、MIF放出を特徴とする様々な状態を治療するまたは改善する用量でヒト患者に投与することができる。治療上の有効用量は、更に、MIF互変異性化酵素活性およびMIF生物活性を阻止するのに十分な化合物の量を指し、そのような阻止は、当業者が標的MIF活性を阻止するために必要な化合物の用量を決定することができるような種々の濃度で起こりうることは明白である。治療上の有効用量は、単独でまたはステロイド系または非ステロイド系抗炎症薬もしくは抗腫瘍薬などの他の治療と組み合わせた補助療法として投与しうる。本出願の化合物の製剤および投与のための手法は、Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 最新版に認められる。
合成。下記の合成の例において、使用したすべての試薬および溶媒は、市販の最高品質のものを購入した。使用したすべての溶媒は、FisherからのHPLCグレードであった。1H(270MHz)および13CNMR(67.5MHz)のNMRスペクトルは、JEOL Eclipse 270分光計で記録した。結合定数は、Hertz(Hz)で報告し、化学シフトは、CDCl3、DMSOまたはCD3ODを溶媒として、テトラメチルシラン(TMS、0.0ppm)に対して100万分の1(ppm)で報告した。薄層クロマトグラフィー(TLC)およびフラッシュカラムクロマトグラフィーは、それぞれSelecto ScientificおよびFisher Scientific Basic alumina Brockman acitivity IからのAlumina B,F-254 TLCプレートを使用して実施した。反応をTLCおよび1HNMRによって監視し、1HNMRに従って粗生成物の収率が90〜95%になったときに停止した。
Claims (7)
- (R)−3−(4−ヒドロキシフェニル)−4,5−ジヒドロ−5−イソオキサゾリン酢酸メチルエステルを含む、医薬組成物。
- 2−[3−(4−ヒドロキシフェニル)−4,5−ジヒドロイソオキサゾール−5−イル]−3−フェニルプロピオン酸メチルエステルを含む、医薬組成物。
- ヒトMIFの酵素的及び生物学的活性を阻害するための、請求項1又は2記載の医薬組成物。
- アトピー性皮膚炎、関節炎、増殖性血管病、ARDS(急性呼吸窮迫症候群)、敗血症、敗血症性ショック、乾癬、喘息、自己免疫疾患、腫瘍増殖または血管新生から成る群より選択される疾患または状態を処置するための、請求項1又は2記載の医薬組成物。
- 上記自己免疫疾患が、慢性関節リウマチ、インスリン依存性糖尿病、多発性硬化症、移植片対宿主病および狼瘡症候群から成る群より選択される、請求項4記載の医薬組成物。
- (R)−3−(4−ヒドロキシフェニル)−4,5−ジヒドロ−5−イソオキサゾリン酢酸メチルエステルの化合物。
- 2−[3−(4−ヒドロキシフェニル)−4,5−ジヒドロイソオキサゾール−5−イル]−3−フェニルプロピオン酸メチルエステルの化合物。
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US20150064221A1 (en) | 2012-04-17 | 2015-03-05 | Niranjan Y. Sardesai | Compounds having immunomudulator activity |
US9567306B2 (en) * | 2014-06-17 | 2017-02-14 | The Feinstein Institute For Medical Research | Inhibition of macrophage migration inhibitory factor in melanoma and colon cancer |
BR112017000922A2 (pt) | 2014-07-17 | 2018-01-16 | Chdi Foundation, Inc. | métodos e composições para tratar distúrbios relacionados ao hiv |
WO2016057702A2 (en) | 2014-10-07 | 2016-04-14 | Cornell University | Methods for prognosing and preventing metastatic liver disease |
CN108707204B (zh) * | 2018-07-04 | 2020-09-15 | 吉林大学 | 过氧化氢响应型靶向载药纳米材料及制备方法 |
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US4933464A (en) | 1988-04-25 | 1990-06-12 | W. R. Grace & Co.-Conn. | Process for forming 3-phenylisoxazolines and 3-phenylisoxazoles |
JP2787602B2 (ja) * | 1990-01-24 | 1998-08-20 | 大鵬薬品工業株式会社 | イソキサゾリン誘導体 |
US5849736A (en) | 1993-11-24 | 1998-12-15 | The Dupont Merck Pharmaceutical Company | Isoxazoline and isoxazole fibrinogen receptor antagonists |
HUT76784A (en) * | 1993-11-26 | 1997-11-28 | Pfizer | Antiinflammatory isoxazoline compounds and pharmaceutical compositions containing them |
WO1995024398A1 (en) * | 1994-03-09 | 1995-09-14 | Pfizer Inc. | Isoxazoline compounds as inhibitors of tnf release |
US6335445B1 (en) * | 1997-03-24 | 2002-01-01 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them |
US6809088B2 (en) * | 1997-03-24 | 2004-10-26 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them |
FR2764889B1 (fr) * | 1997-06-20 | 2000-09-01 | Sod Conseils Rech Applic | Nouveaux derives du 2-(iminomethyl)amino-phenyle, leur preparation, leur application a titre de medicaments et les compositions pharmaceutiques les contenant |
CA2450589C (en) * | 2001-06-08 | 2011-12-20 | Cytokine Pharmasciences, Inc. | Isoxazoline compounds having mif antagonist activity |
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- 2002-06-10 WO PCT/US2002/017898 patent/WO2002100332A2/en active Application Filing
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AU2002314944B2 (en) | 2008-03-06 |
WO2002100332A3 (en) | 2003-04-03 |
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CA2450589C (en) | 2011-12-20 |
EP1411930A4 (en) | 2007-04-04 |
US20040204464A1 (en) | 2004-10-14 |
CA2450589A1 (en) | 2002-12-19 |
US7928130B2 (en) | 2011-04-19 |
US8552040B2 (en) | 2013-10-08 |
JP2004534054A (ja) | 2004-11-11 |
EP1411930B1 (en) | 2013-01-16 |
US7491740B2 (en) | 2009-02-17 |
WO2002100332A2 (en) | 2002-12-19 |
US20030008908A1 (en) | 2003-01-09 |
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