JP2007516228A - 新規なアルキル化処置剤としての水溶性shp - Google Patents
新規なアルキル化処置剤としての水溶性shp Download PDFInfo
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- JP2007516228A JP2007516228A JP2006533183A JP2006533183A JP2007516228A JP 2007516228 A JP2007516228 A JP 2007516228A JP 2006533183 A JP2006533183 A JP 2006533183A JP 2006533183 A JP2006533183 A JP 2006533183A JP 2007516228 A JP2007516228 A JP 2007516228A
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Abstract
Description
Katzung、In Basic & Clinical Pharmacology、7th edition、1998、Appleton & Lange、Stamford、881 RajskiとWilliams、Chem Reviews 1998、98:2723
DeVita他、Cancer Res.1965、25:1876 Nissen他、Cancer 1979、43:31 Panasci他、Cancer Res.1977、37:2615 GibsonとHickman、Biochem Pharmacol.1982、31:2795
Kohn、In Recent Results in Cancer Research,Eds.Carter他、1981,Springer,Berlin、vol.76:141 Shealy他、J.Med.Chem.1984、27:664 Baril他、Cancer Res.1975:35:1 Kann他、Cancer Res.1974、34:398 Kann他、Cancer Res.1974、34:1982 Swenson他、J.Natl.Cancer Inst.1979、63:1469
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Finch他、Cancer Biochem Biophys、2001、61:3033
Penketh他、J.Med.Chem.1994、37:2912 Penketh他、Biochem Pharmacol.2000、59:283 Baril他、Cancer Res.1975、35:1
Lin他、J.Med.Chem.1986、29:84
Wolfe他、Bioconjug Chem.1999、10:38 Huennekens、Adv Enzyme Regul.1997、37:77 Vitols他、Cancer Res.1995、55:478
R’はC1−C7アルキルまたは−CH2CH2Clであり、
R2またはR4のいずれか一方、両方ではない、がOPO3H2、NO2、OCO(Glu)、NHCO(Glu)およびNHR7から選ばれ他方は割り当てられず、
R2〜R6の少なくとも2つがHであるという条件で、R3、R5、R6は独立にH、F、Cl、Br、I、OH、OPO3H2、OCH3、CF3、OCF3、NO2、CN、SO2CH3、SO2CF3、COCH3、COOCH3、SCH3、SF5、NHR8、N(R9)2、OPO3H2、C1−C7アルキルから選ばれ、
R7はH、グルタミル、好ましくはα−グルタミル(−COCH(NH2)CH2CH2CO2H)またはポリグルタミン酸ポリペプチド残基、(−COCH(NHR7a)CH2CH2CO2Hであり、
R7aはグルタミル(好ましくはα−グルタミル)または1〜50ペプチド連鎖、好ましくは2〜10ペプチド連鎖を有したポリグルタミン酸ポリペプチド残基)であり、
R8はHまたはC1−C7アルキルであり、
R9はCH3またはCH2CH3である。
リン酸および/またはグルタミン酸置換基は遊離酸またはその薬学的に受容可能な塩である。
Rは−CH2CH2Clであり、R’は−CH3であり、R2は遊離酸またはその薬学的に受容可能な塩(好ましくはNa)であるリン酸塩基である。特に好ましきオルト−リン酸塩−帯同SHPにあっては、R3、R5、R6がHのときにR4はCl、FまたはBr(好ましくはCl)である。
R’はC1−C7アルキルまたは−CH2CH2Clであり、
R2またはR4の一方、両方ではない、はOPO3H2、NO2、OCO(Glu)、NHCO(Glu)およびNHR7から選ばれ、
その他方は割り当てられず、
R2〜R6の少なくとも2つがHであるとの条件下で、R3、R5およびR6は独立にH、F、Cl、Br、I、OH、OPO3H2、OCH3、CF3、OCF3、NO2、CN、SO2CH3、SO2CF3、COCH3、COOCH3,SCH3、SF5、NHR8、N(R9)2、OPO3H2およびC1−C7アルキルから選ばれ、
R7はH、グルタミル、好ましくは、α−グルタミル(−COCH(NH2)CH2CH2CO2H)またはポリグルタミン酸ポリペプチド残基−COCH(NHR7a)CH2CH2CO2Hであり、
R7aはグルタミル(好ましくはα−グルタミル)または1〜50のペプチド連鎖、好ましくは2〜10のペプチド連鎖を有したポリグルタミン酸ポリペプチド残基であり、
R8はHまたはC1−C7アルキルであり、
R9はCH3またはCH2CH3である。リン酸およびグルタミン酸(グルタミル)は遊離酸またはその薬学的に受容可能な塩である。
Majer他、J.Org.Chem.1994,59:1937 Pridgen他、J.Org.Chem.1989,54:3231
Matulic−Adamic他、J.Org.Chem.1995、60:2563
Kasmai他、J.Org.Chem.1995、60:2267
Mann他、Tetrahedron、1990、46:5377
Jones他、Bio−org.Med.Chem.Lett.2000,10:1987
Kanno他、Tetrahedron Lett.2002、43:7337
31P NMR (121 MHz, CDC13) δ 5.0。TOF ESMS calculated for (M+H) = 259.07, observed 259.07。
Krishna他、AAPS PharmsciTech 2001、2:14巻
Almassian他、Proceedings AACR、2001、42:326、1756巻
Claims (33)
- 下記の構造式を有し、
R’はC1−C7アルキルまたは−CH2CH2Cl;R2またはR4の一方、双方ではない、はOPO3H2、NO2、OCO(Glu)、NHCO(Glu)およびNHR7から選ばれ、他のR2またはR4は割り当てられず、
R2、R3、R4、R5およびR6の少なくとも2つがHであるとの前提で、R3、R5およびR6は独立にH、F、Cl、Br、I、OH、OPO3H2、OCH3、CF3、OCF3,NO2、CN、SO2CH3、SO2CF3、COCH3、COOCH3、SCH3、SF5、NHR8、N(R9)2およびC1−C7アルキルから選ばれ、
R7は1〜50のペプチド連鎖を有したグルタミルまたはポリグルタミン酸ポリペプチド残基であり、
R8はHまたはC1−C7アルキルであり、
R9はCH3またはCH2CH3である
ことを特徴とする化合物またはその薬学的に受容可能な塩。 - Rが−CH2CH2Clであることを特徴とする請求項1に記載の化合物。
- R’がメチル、エチル、n−プロピル、イソプロピル、n−ブチル、イソブチル、t−ブチル、n−ペンチル、イソペンチル、n−ヘキシル、イソヘキシルまたは置換へキシルであることを特徴とする請求項1または2に記載の化合物。
- R’がメチルであることを特徴とする請求項1〜3のいずれかひとつに記載の化合物。
- R2がOPO3H2基またはその薬学的に受容可能な塩であることを特徴とする請求項1〜4のいずれかひとつに記載の化合物。
- R3、R5およびR6がそれぞれHのときに、R4がF、ClまたはOCH3であることを特徴とする請求項1〜5のいずれかひとつに記載の化合物。
- R3、R4、R6がそれぞれHのときに、R5がF、Cl、OCH3またはOCF3であることを特徴とする請求項1〜5のいずれかひとつに記載の化合物。
- R3、R4、R5またはR6の2つが独立にFまたはClであることを特徴とする請求項1〜5のいずれかひとつに記載の化合物。
- R4とR5が独立にFまたはClであることを特徴とする請求項1〜5および8のいずれかひとつに記載の化合物。
- R5とR6が独立にFまたはClであることを特徴とする請求項1〜5、8または9のいずれかひとつに記載の化合物。
- R4とR5がClであることを特徴とする請求項1〜5または8〜10のいずれかひとつに記載の化合物。
- R5とR6がClであることを特徴とする請求項1〜5または8〜10のいずれかひとつに記載の化合物。
- R5がOPO3H2基またはその薬学的に受容可能な塩であることを特徴とする請求項1〜4のいずれかひとつに記載の化合物。
- R2がNO2であり、R3、R4、R6がそれぞれHであることを特徴とする請求項1〜4および6〜8のいずれかひとつに記載の化合物。
- R4がNO2であり、R2、R3、R6がそれぞれHであることを特徴とする請求項1〜5、8に記載の化合物。
- R4がOCO(Glu)であり、R2、R3、R5、R6がそれぞれHである
ことを特徴とする請求項1〜5、8のいずれかひとつに記載の化合物。 - OCO(Glu)が薬学的に受容可能な塩の形態であることを特徴とする請求項16に記載の化合物。
- R4がNHCO(Glu)であり、R2、R3、R5、R6がそれぞれHであることを特徴とする請求項1〜4のいずれかひとつに記載の化合物。
- NHCO(Glu)が薬学的に受容可能な塩の形態であることを特徴とする請求項18に記載の化合物。
- R4がNHR7であり、R2、R3、R5、R6がそれぞれHであることを特徴とする請求項1〜4のいずれかひとつに記載の化合物。
- R7がH、α−グルタミルまたはその薬学的に受容可能な塩または1〜50のペプチド連鎖を有したポリグルタミン酸ポリペプチド残基またはその薬学的に受容可能な塩であることを特徴とする請求項20に記載の化合物。
- R7がα−グルタミルまたはその薬学的に受容可能な塩または2〜10のペプチド連鎖を有したポリグルタミン酸ポリペプチド残基またはその薬学的に受容可能な塩であることを特徴とする請求項21に記載の図4の化合物IVのための化合物。
- 選択的に薬学的に受容可能な添加剤、キャリアーまたは賦形剤と組み合わせた請求項1〜22のいずれかひとつの化合物またはその薬学的に受容可能な塩の有効量を含んだ薬学的組成物。
- 薬学的に受容可能な添加剤、キャリアーまたは賦形剤と組み合わせた請求項1〜22のいずれかひとつの化合物またはその薬学的に受容可能な塩の有効量を患者に投与することを特徴とする治療を要する患者中の癌処置方法。
- 癌が胃、結腸、直腸、肝臓、膵臓、肺、乳房、子宮頸部、子宮体部、卵巣、前立腺、精巣、膀胱、腎臓、脳/CNS、頭部と首部、咽喉、多発性骨髄腫、黒色素細胞腫、急性リンパ白血病、急性骨髄性白血病、ユーウィング肉腫、小胞肺癌、絨毛腫、平滑筋組織腫瘍、ウィルムス腫瘍、神経芽細胞腫、ヘアリー細胞白血病、口/咽喉、食道、喉頭、腎臓またはリンパ腫からなる群から選ばれることを特徴とする請求項24に記載の方法。
- リンパ腫瘍がホジキン病または非ホジキンリンパ腫であることを特徴とする請求項25に記載の方法。
- 必要なら患者中の抗薬性癌を処置する方法であって、請求項1〜22のいずれかひとつの化合物の有効量を患者に投与することを特徴とする方法。
- 少なくともひとつの追加的な抗癌剤と組み合わせて請求項1〜22のいずれかひとつの化合物の有効量を患者に投与することを特徴とする患者中の癌を処置する方法。
- 代謝拮抗物質、シタラビン(Ara C)、エトポシド、ドキソルビシン、タクソール、ヒドロキシウレア、ビンクリスチン、サイトキサン、マイトマイシンC、アドリアマイシン、トポテカン、カンポセシン(campothecin)、イリノテカン、ゲムシタビン、カンポセシン(campothecin)、シスプラチン(cis−platin)からなる群から選ばれた少なくともひとつの追加的抗癌剤と組み合わせて請求項1〜22のいずれかひとつの化合物の有効量を患者に投与することを特徴とする患者中の癌を処置する方法。
- 選択的に薬学的に受容可能な添加剤、キャリアーまたは賦形剤と組み合わせて請求項1〜22のいずれかひとつの化合物の有効量を患者に投与することを含んでいることを特徴とする患者中の腫瘍形成を処置する方法。
- 選択的に薬学的に受容可能な添加剤、キャリアーまたは賦形剤と組み合わせた少なくとも1種の追加的な抗癌剤と組み合わせた請求項1〜22のいずれかの化合物の有効量を含んでいることを特徴とする薬学的組成物。
- 代謝拮抗物質、シタラビン(Ara C)、エトポシド、ドキソルビシン、タクソール、ヒドロキシウレア、ビンクリスチン、サイトキサン、マイトマイシンC、アドリアマイシン、トポテカン、カンポセシン、イリノテカン、ゲムシタビン、カンポセシン、シスプラチンからなる群から選ばれた少なくともひとつの追加的抗癌剤と組み合わせて請求項1〜22のいずれかひとつの化合物の有効量を含んでいることを特徴とする薬学的組成物。
- 選択的に薬学的に受容可能な添加剤、キャリアーまたは賦形剤と組み合わせた化合物の有効量を含んだ抗癌剤の製造のための請求項1〜22のいずれかひとつの化合物の使用。
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US20080181852A1 (en) * | 2007-01-29 | 2008-07-31 | Nitto Denko Corporation | Multi-functional Drug Carriers |
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