CN101326191B - 膦过渡金属配合物、其制造方法和含有该配合物的抗癌剂 - Google Patents
膦过渡金属配合物、其制造方法和含有该配合物的抗癌剂 Download PDFInfo
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- CN101326191B CN101326191B CN2006800458668A CN200680045866A CN101326191B CN 101326191 B CN101326191 B CN 101326191B CN 2006800458668 A CN2006800458668 A CN 2006800458668A CN 200680045866 A CN200680045866 A CN 200680045866A CN 101326191 B CN101326191 B CN 101326191B
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- Prior art keywords
- gold
- phosphine transition
- formula
- title complex
- phosphine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 Phosphine transition metal Chemical class 0.000 title claims abstract description 75
- 229910052723 transition metal Inorganic materials 0.000 title claims abstract description 47
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 45
- 238000004519 manufacturing process Methods 0.000 title description 13
- 239000002246 antineoplastic agent Substances 0.000 title 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229910052737 gold Inorganic materials 0.000 claims abstract description 19
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 9
- 150000001450 anions Chemical group 0.000 claims abstract description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 45
- 239000003795 chemical substances by application Substances 0.000 claims description 30
- RJHLTVSLYWWTEF-UHFFFAOYSA-K gold trichloride Chemical class Cl[Au](Cl)Cl RJHLTVSLYWWTEF-UHFFFAOYSA-K 0.000 claims description 21
- 229910003803 Gold(III) chloride Inorganic materials 0.000 claims description 20
- 229940076131 gold trichloride Drugs 0.000 claims description 20
- 230000003327 cancerostatic effect Effects 0.000 claims description 19
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 4
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract description 18
- 239000010931 gold Substances 0.000 abstract description 15
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 abstract description 13
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 abstract description 13
- 229910052709 silver Inorganic materials 0.000 abstract description 13
- 239000004332 silver Substances 0.000 abstract description 13
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- 239000010949 copper Substances 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 11
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 11
- 230000000259 anti-tumor effect Effects 0.000 abstract description 8
- 125000004437 phosphorous atom Chemical group 0.000 abstract description 6
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 125000001118 alkylidene group Chemical group 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
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- 229910052697 platinum Inorganic materials 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 10
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- 125000000217 alkyl group Chemical group 0.000 description 8
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- 238000002360 preparation method Methods 0.000 description 8
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- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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- 239000011574 phosphorus Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- UCOBJOONLGFYMF-UHFFFAOYSA-L Cl[Au]Cl Chemical compound Cl[Au]Cl UCOBJOONLGFYMF-UHFFFAOYSA-L 0.000 description 4
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Abstract
本发明提供一种具有优异的抗癌活性且副作用小的新颖的膦过渡金属配合物。本发明的新颖的膦过渡金属配合物是下述通式(1)所示的膦过渡金属配合物。式中,A表示亚烷基、亚苯基或顺式亚乙烯基;M表示金、银、铜或铂原子;B1和B2分别表示含有能够与A共价结合并与M配位结合的3价磷原子的可以具有取代基的杂环基;C表示阴离子原子。
Description
技术领域
本发明涉及新颖的膦过渡金属配合物、其制造方法和含有该配合物的抗癌剂。
背景技术
顺铂(顺式二氯二氨合铂(II))、卡铂(顺式1,1-环丁烷二羧酸二氨合铂(II))、奈达铂(顺式O,O′-乙醇酸二氨合铂(II))等铂配合物具有很强的抗癌活性,用作现在主要的抗癌剂。
另外,已知在下述通式(4)中,R1′~R8′是相同或不同的苯基、取代苯基或吡啶基,A′是直链状的亚烷基或顺式亚乙烯基,M′是金、银或铜原子,B′是阴离子类的膦过渡金属配合物(参照专利文献1);和R1′~R8′是相同的苯基、取代苯基或乙基,或者R1′、R2′、R7′和R8′是苯基,R3′~R6′是乙基,A是直链状的亚烷基或顺式亚乙烯基,M′是金、银或铜原子,B′是阴离子类的膦过渡金属配合物(参照专利文献2),具有与顺铂相同的抗癌作用。
专利文献1:日本专利特表平10-509957号公报
专利文献2:日本专利特开昭61-10594号公报
发明内容
但是已知,通常化合物的抗癌活性和抗癌谱很大程度上依存于化学结构,微小的结构不同会给这些特性带来很大的差异。并且,抗癌剂的效果因人而异,例如,即使是作为最高抗癌剂的泰素,有效率也是30%左右。因此,希望开发化学结构不同的各种新颖的抗癌剂。
本发明是鉴于这种情况完成的,其目的在于,提供具有优异抗癌性的新颖的膦过渡金属配合物、其制造方法和含有该配合物的抗癌剂。
本发明人等对于具有抗癌作用的新颖的膦过渡金属配合物反复进行深入研究,结果,发现具有特定结构的膦过渡金属配合物具有优异的抗癌性,至此完成本发明。
即,本发明是下述通式(1)所示的膦过渡金属配合物。
(式中,A表示亚烷基、亚苯基或顺式亚乙烯基;M表示金、银、铜或铂原子;B1和B2分别表示含有能够与A共价结合并与M配位结合的3价磷原子的可以具有取代基的杂环基;C表示阴离子原子。)
另外,本发明的上述膦过渡金属配合物,用下述通式(2)表示。
(式中,A、M和C同上述定义,D1和D2分别表示亚烷基,R1、R2、R3和R4分别表示氢原子、烷基、羟烷基、苯基、苄基、羰基、氨基或羟基。)
另外,本发明的上述膦过渡金属配合物,D1和D2是四亚甲基,R1、R2、R3和R4分别为低级烷基。
另外,本发明的上述膦过渡金属配合物,M为金原子。
另外,本发明的上述膦过渡金属配合物,为双(1,2-双(2,5-二甲基膦基)乙烷)氯化金(I)、双(1,2-双(2,5-二乙基膦基)乙烷)氯化金(I)、双(1,2-双(2,5-二异丙基膦基)乙烷)氯化金(I)、双(1,2-双(2,5-(二甲基膦基)苯))氯化金(I)、双(1,2-双(2,5-(二乙基膦基)苯))氯化金(I)、双(1,2-双(2,5-(二异丙基膦基)苯))氯化金(I)、双(1,2-双(2,5-(二甲基)-3,4-(二羟基)膦基)苯))氯化金(I)或双(1,2-双(2,5-(二甲基)-3,4-(二苄氧基)膦基)苯))氯化金(I)。
另外,本发明是上述膦过渡金属配合物的光学活性体。
另外,本发明为膦过渡金属配合物的制造方法,该膦过渡金属配合物由下述通式(1)表示,其特征在于,使下述通式(3)所示的双膦衍生物与金、银、铜或铂的金属盐反应,
B1-A-B2 (3)
(式中,A表示亚烷基、亚苯基或顺式亚乙烯基;B1和B2分别表示含有能够与A共价结合的3价磷原子的可以具有取代基的杂环基),
(式中,A、B1和B2同上述定义,M表示金、银、铜或铂原子,C表示阴离子类)。
并且,本发明还是一种抗癌剂,含有下述通式(1)所示的膦过渡金属配合物,
(式中,A表示亚烷基、亚苯基或顺式亚乙烯基;M表示金、银、铜或铂原子;B1和B2分别表示含有能够与A共价结合并与M配位结合的3价磷原子的可以具有取代基的杂环基;C表示阴离子原子)。
具体实施方式
下面,根据优选实施方式对本发明进行详细说明。
本发明的膦过渡金属配合物如下述通式(1)所示。
(式中,A表示亚烷基、亚苯基或顺式亚乙烯基;M表示金、银、铜或铂原子;B1和B2分别表示含有能够与A共价结合并与M配位结合的3价磷原子的可以具有取代基的杂环基;C表示阴离子原子。)
在通式(1)中,A是亚烷基、亚苯基或顺式亚乙烯基。其中,作为亚烷基,可以列举亚甲基、亚乙基、三亚甲基、四亚甲基、五亚甲基、亚丙基、乙基亚乙基等直链状或支链状的亚烷基。其中特别优选亚乙基或亚苯基。
另外,M是金、银、铜或铂原子。其中,特别优选金原子。
并且,B1和B2分别为含有能够与A共价结合并与M配位结合的3价磷原子的可以具有取代基的杂环基。作为这种杂环基的例子,可以列举磷杂环丁基、磷杂环戊基、磷杂环己基、磷杂环庚基、磷杂环辛基等。作为取代基,例如可以列举羰基、氨基、羟基等官能基,和甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基等烷基,羟甲基、羟乙基等羟烷基,苄基等。
其中,B1和B2由于取代基的种类和位置,可以采取立体上不同的结构,B1和B2的立体结构可以相同,也可以不同。例如,B1具有1个或多个不对称点,其立体标记分别标记为R或RR等时,B2可以是与B1相同结构的R、RR,也可以是其相反结构的S、SS。但是,本发明的膦过渡金属配合物是光学活性物时,B1和B2特别优选为立体上相同的结构。
另外,C是阴离子类,具体而言可以列举氯、溴、碘等卤原子,四氟化硼、六氟磷酸、高氯酸等。其中,特别优选氯、溴、碘等卤原子。
在本发明的膦过渡金属配合物中,特别优选下述通式(2)所示的膦过渡金属配合物。
(式中,A、M和C同上述定义,D1和D2分别表示亚烷基,R1、R2、R3和R4分别表示氢原子、烷基、羟烷基、苯基、苄基、羰基、氨基或羟基)。
在通式(2)中,D1和D2是相同或彼此不同的亚烷基。作为亚烷基,可以列举亚乙基、三亚甲基、四亚甲基、五亚甲基等碳原子数2~10、优选碳原子数3~6的直链状的亚烷基,其中优选四亚甲基。
另外,R1、R2、R3和R4是相同或彼此不同的氢原子、烷基、羟烷基、苯基、苄基、羰基、氨基或羟基。其中,作为烷基,可以列举甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基、异戊基、新戊基等碳原子数1~10、优选碳原子数1~5的直链状或支链状的烷基。作为羟烷基,可以列举羟甲基、羟乙基等。其中特别优选甲基。
作为本发明的膦过渡金属配合物的优选化合物的例子,可以列举双(1,2-双(2,5-二甲基膦基)乙烷)氯化金(I)、双(1,2-双(2,5-二乙基膦基)乙烷)氯化金(I)、双(1,2-双(2,5-二异丙基膦基)乙烷)氯化金(I)、双(1,2-双(2,5-(二甲基膦基)苯))氯化金(I)、双(1,2-双(2,5-(二乙基膦基)苯))氯化金(I)、双(1,2-双(2,5-(二异丙基膦基)苯))氯化金(I)、双(1,2-双(2,5-(二甲基)-3,4-(二羟基)膦基)苯))氯化金(I)、双(1,2-双(2,5-(二甲基)-3,4-(二苄氧基)膦基)苯))氯化金(I)等。
另外,本发明的膦过渡金属配合物可以是光学活性体,作为特别优选的光学活性体,可以列举下述通式(5)~(10)的膦过渡金属配合物的(S,S)-体、(R,R)-体、内消旋体。
(式中,M、R1、R2、R3、R4和C同上述定义)。
下面,对本发明的膦过渡金属配合物的制造方法进行说明。本发明的膦过渡金属配合物通过使下述通式(3)所示的双膦衍生物与金、银、铜或铂的金属盐反应而制造。
B1-A-B2 (3)
(式中,A、B1和B2同上述定义)。
原料通式(3)所示的双膦衍生物是公知的化合物,可以采用公知的方法制造。表示其一个例子,按照下述反应式(I)(式中,A、B1和B2同上述定义,R5表示甲基、乙基、异丙基等低级烷基,D3表示碳原子数1~5的亚烷基),首先使二元醇(化合物(11))与亚硫酰氯反应,生成对应二元醇的环状亚硫酸酯,接着,在催化剂量的RuCl3的存在下,使其与NaIO4反应,得到原料二元醇环状硫酸酯(化合物(12))。然后,使双膦化合物(化合物(13))与正丁基锂等强碱反应,然后在反应液中加入上述配制的二元醇环硫酸酯(化合物(12)),再加入正丁基锂等强碱进行反应,由此能够制造目的双膦衍生物(化合物(14))(例如,参照日本专利特表平6-508848号公报、J.Am.Chem.Soc.,Vol.115,No.22,1993,p10125,Tetrahedron Lett.,Vol.38,1997,p2947,Synlett,1997,p1975,J.Org.Chem.,Vol63,1998,p8031,Chem.Euro.J.,Vol5,1999,p1160,Eur.J.Org.Chem.,2000,p4615,J.Org.Chem.,Vol65,2000,p600,J.Org.Chem.,Vol65,2000,p3489等)。
另外,在本发明中,为了得到通式(1)所示的双膦过渡金属配合物的光学活性体,可以使用通式(2)所示的双膦衍生物的光学活性体作为原料,进行该光学活性体与后述的金、铜、铂或银的过渡金属盐的反应。其中,为了得到通式(2)所示的双膦衍生物的光学活性体,在反应式(1)中,使用起始原料1,4-二元醇(化合物(11))的光学活性体即可。
另一种原料的金、银、铜或铂的金属盐,例如,可以使用这些金属的卤化物或硝酸盐、高氯酸盐、四氟硼酸盐、六氟磷酸盐等。作为优选的金的金属盐,例如,可以列举氯金(I)酸、氯化金(I)或四丁基氯化铵·氯化金(I)等(参照社团法人日本化学会编“第5版 实验化学讲座21”,平成16年3月30日,丸善株式会社发行,p366~380;Aust.J.Chemm.,1997,50,775~778页)。作为优选的铜的金属盐,例如,可以列举氯化铜(I)、溴化铜(I)、碘化铜(I)等(参照社团法人日本化学会编“第5版 实验化学讲座21”,平成16年3月30日,丸善株式会社发行,p349~361)。作为优选的铂的金属盐,例如,可以列举氯化铂(II)、四氯铂(II)酸钠、四氯铂(II)酸钾等(参照社团法人日本化学会编“第5版 实验化学讲座21”,平成16年3月30日,丸善株式会社发行,p327~348)。另外,作为优选的银的金属盐,例如,可以列举氯化银(I)、溴化银(I)、碘化银(I)等(参照社团法人日本化学会编“第5版 实验化学讲座21”,平成16年3月30日,丸善株式会社发行,p361~366)。其中,这些金属盐可以是无水物,也可以是含水物。
通常,通式(2)所示的双膦衍生物与上述过渡金属盐的反应,通过与相对于上述金属盐的摩尔比为1~5倍摩尔、优选为1.8~2.2倍摩尔量的上述通式(2)所示的双膦衍生物,在反应温度-20~60℃、优选为0~25℃,反应时间0.5~48小时、优选为1~3小时,多数情况下在丙酮、乙腈、甲醇、乙醇等溶剂中反应而制造。反应结束后,根据需要,进行通常方法的精制,得到制品。
另外,本发明的膦过渡金属配合物,通过合成通式(1)所示的膦过渡金属配合物的式中的C为卤原子的配合物,然后使所希望的无机酸、有机酸或它们的碱金属盐在溶剂中反应,将式中的C诱导为其它的阴离子(参照日本专利特开平10-147590号公报、日本专利特开平10-114782号公报、日本专利特开昭61-10594号公报)。
如后所述,本发明的膦过渡金属配合物具有优异的抗癌作用,可以用作抗癌剂。
即,本发明的抗癌剂是含有上述通式(1)所示的膦过渡金属配合物或其光学活性体的1种或2种以上的抗癌剂。
本发明的抗癌剂适用的癌的种类没有特别限定,例如,可以列举恶性黑色素瘤、恶性淋巴瘤、消化器官癌、肺癌、食道癌、胃癌、大肠癌、直肠癌、结肠癌、尿管肿瘤、胆囊癌、胆管癌、胆道癌、乳腺癌、肝脏癌、胰腺癌、睾丸肿瘤、上颚癌、舌癌、口唇癌、口腔癌、咽头癌、喉头癌、卵巢癌、子宫癌、前列腺癌、甲状腺癌、脑肿瘤、卡波西肉瘤、血管瘤、白血病、真性多红血球症、神经母细胞瘤、视网膜母细胞瘤、骨髓瘤、膀胱瘤、肉瘤、骨肉瘤、肌肉瘤、皮肤癌、基底细胞癌、皮肤附件癌、皮肤转移癌、皮肤黑色素瘤等,并且,不仅适用于恶性肿瘤,还适用于良性肿瘤。另外,本发明的抗癌剂也可以用于抑制癌转移,特别是可以有效作为手术后的癌转移抑制剂。
本发明的抗癌剂可以以各种形态对人或动物给药,可以口服给药,也可以向静脉内、肌肉内、皮下或皮内等注射、直肠内给药、经粘膜给药等的非口服给药。作为适合于口服给药的制剂形态,例如,可以列举片剂、丸剂、颗粒剂、散剂、胶囊剂、液剂、悬浊剂、乳剂、糖浆剂等;作为适合于非口服给药的医药组合物,例如,可以列举注射剂、点滴剂、滴鼻剂、喷雾剂、吸入剂、栓剂或软膏、膏剂、粉状涂布剂、液状涂布剂、贴剂等经皮吸收剂等。并且,可以为埋入用颗粒或利用公知技术制成持续性制剂。上述中优选的给药形态和制剂形态等,根据患者的年龄、性别、体质、症状、处理时期等,由医生适当选择。
在将本剂制成片剂、丸剂、散剂、粉剂、颗粒剂等固态制剂的情况下,可以按照通常的方法,将上述膦过渡金属配合物与适当的添加剂例如乳糖、蔗糖、D-甘露糖醇、玉米淀粉、合成或天然橡胶、结晶纤维素等赋形剂,淀粉、羟丙基纤维素、羟丙基甲基纤维素、阿拉伯胶、明胶、聚乙烯基吡咯烷酮等粘合剂,羧甲基纤维素钙、羧甲基纤维素钠、淀粉、玉米淀粉、褐藻酸钠等崩解剂,滑石、硬脂酸镁、硬脂酸钠等润滑剂,碳酸钙、碳酸钠、磷酸钙、磷酸钠等填充剂或稀释剂等适当混合制造。根据需要,片剂等可以使用羟丙基甲基纤维素、白糖、聚乙二醇、氧化钛等糖衣剂,实施糖衣、明胶、肠溶包覆、膜涂敷等。
在将本制剂制成注射剂、滴眼剂、滴鼻剂、吸入剂、喷雾剂、洗发剂、糖浆剂、液剂、悬浊剂、乳剂等液态制剂的情况下,将上述膦过渡金属配合物溶解于精制水,磷酸缓冲液等适当的缓冲液,生理盐水、林格试液、洛克氏溶液等生理盐类溶液,可可乳脂、芝麻油、橄榄油等植物油,矿物油、高级醇、高级脂肪酸、乙醇等有机溶剂等中,根据需要,适当添加:胆甾醇等乳化剂,阿拉伯胶等悬浊剂,分散助剂,浸润剂,聚氧化乙烯固化蓖麻子油系、聚乙二醇系等表面活性剂,磷酸钠等助溶剂,糖、糖醇、白蛋白等稳定剂,对羟基苯甲酸酯等保存剂,氯化钠、葡萄糖、甘油等等渗剂,缓冲剂,无痛化剂,防吸附剂,保湿剂,抗氧化剂,着色剂,甜味剂,调味剂,芳香物质等,调制为经过灭菌的水溶液、非水溶液、悬浊液、微脂粒或乳化液等。此时,优选注射剂具有生理学的pH,优选为6~8范围内的pH。
在将本制剂制成洗发剂、乳膏剂、软膏等半固态制剂时,将上述膦过渡金属配合物与脂肪、脂肪油、羊毛脂、凡士林、石蜡、蜡、硬膏剂、树脂、塑料、甘醇类、高级醇、甘油、水、乳化剂、悬浊剂等适当混合而制造。
本发明的抗癌剂中所含的上述膦过渡金属配合物的含量,根据给药形态、病重度和目的给药量等而不同,通常相对于制剂总重量为0.001~80重量%,优选为0.1~50重量%。
本发明的抗癌剂的给药量,例如,根据患者的年龄、性别、体重、症状和给药途径等条件,由医生适当决定,通常作为成人每日的有效成分的量,为从1μg/kg至1000mg/kg左右的范围,优选为从10μg/kg至10mg/kg左右的范围。上述给药量的药剂,可以1日1次给药,也可以分为数次(例如2~4次左右)给药。
本发明的抗癌剂,可以与已知的化学疗法、外科治疗法、放射线疗法、温热疗法和免疫疗法等组合使用。
实施例1
下面,利用实施例进一步详细地说明本发明,但本发明不限于这些实施例。
[实施例1]
双((+)-1,2-双((2R,5R)-2,5-二甲基膦基)乙烷)氯化
金(I)的合成
在氮气流下,在充分脱气干燥的2口烧瓶中称量436mg(1.69mmol)(+)-1,2-双((2R,5R)-2,5-二甲基膦基)乙烷(Strem社生产),在其中加入25mL经过脱气的氯仿并溶解。接着,一次性加入430mg(0.84mmol)四丁基铵二氯化金(I),在室温(25℃)搅拌3小时,使之反应。将该反应液移入50mL分液漏斗中,依次用5mL的1当量盐酸水溶液、10mL纯水×3、10mL饱和食盐水洗净,用无水硫酸钠脱水。用蒸发器蒸馏除去溶剂,得到白色粉末的590mg标题化合物。收率是94%。
(鉴定数据)
1H NMR(CDCl3):δ=1.0-1.3(m,24H),1.2-1.4(m,4H),1.3-1.5(m,4H),1.5-1.7(m,4H),1.9-2.1(m,8H),2.1-2.3(m,8H),2.2-2.4(m,4H)
13C NMR:δ=13.78(s),21.3(m),25.1(m),34.1,34.7,36.5(m),36.9(m)
31P NMR(1H decoupled,CDCl3):δ=37.2(s)
IR(KBr):2927,2865,1454,1407,1375cm-1
MS(FAB,POS):m/z 713.(M+-Cl-)
[实施例2]
双((-)-1,2-双((2S,5S)-2,5-二甲基膦基)乙烷)氯化
金(I)
在氮气流下,在充分脱气干燥的2口烧瓶中称量423mg(1.64mmol)(-)-1,2-双((2S,5S)-2,5-二甲基膦基)乙烷(Strem社生产),在其中加入25mL经过脱气的氯仿并溶解。接着,一次性加入418mg(0.82mmol)四丁基铵二氯化金(I),在室温(25℃)搅拌3小时,使之反应。将该反应液移入50mL分液漏斗中,依次用5mL的1当量盐酸水溶液、10mL纯水×3、10mL饱和食盐水洗净,用无水硫酸钠脱水。用蒸发器蒸馏除去溶剂,得到白色粉末的566mg标题化合物。收率是94%。
(鉴定数据)
1H NMR(CDCl3):δ=1.0-1.3(m,24H),1.2-1.4(m,4H),1.3-1.5(m,4H),1.5-1.7(m,4H),1.9-2.1(m,8H),2.1-2.3(m,8H),2.2-2.4(m,4H)
13C NMR:δ=13.78(s),21.3(m),25.1(m),34.1,34.7,36.5(m),36.9(m)
31P NMR(1H decoupled,CDCl3):δ=37.2(s)
IR(KBr):2927,2865,1454,1407,1375cm-1
MS(FAB,POS):m/z 713.(M+-Cl-)
[实施例3]
双(1,2-双((2S,5S)-2,5-(二甲基膦基)苯))氯化金(I)
在以氮气置换的50ml 2口烧瓶中加入0.50g(1.60mmol)1,2-双((2S,5S)-2,5-(二甲基膦基)苯(Strem社生产)的脱气氯仿溶液。在其中加入0.42g(0.80mmol)四丁基铵二氯化金,在室温(25℃)搅拌4小时。干燥得到的溶液,用甲醇-二乙醚重结晶。洗净得到的浅黄色针状结晶,减压干燥后,得到0.64g标题化合物(收率是93%)。
(鉴定数据)
1H NMR(300.4MHz,CDCl3):δ=0.74-0.81(m,12H),1.16-1.25(m,12H),1.52-1.63(m,4H),1.74-1.88(m,4H),2.21-2.34(m,8H),2.54-2.68(m,8H),7.58-7.62(m,4H),7.71-7.74(m,4H)
13C NMR(75.5MHz,CDCl3):δ=14.4(s),21.3(m),35.7(s),35.9(s),37.5(m),40.3(m),130.6(s),133.2(m),142.2(s)
31P NMR(121.5MHz,CDCl3):δ=38.9(s)
Mass(FAB,POS):m/z 809.(M+-Cl-)
[实施例4]
双(1,2-双((2R,5R)-2,5-(二甲基膦基)苯))氯化金(I)
在以氮气置换的50ml 2口烧瓶中加入0.50g(1.60mmol)1,2-双((2R,5R)-2,5-(二甲基膦基)苯(Strem社生产)的脱气氯仿溶液。在其中加入0.42g(0.80mmol)四丁基铵二氯化金,在室温(25℃)搅拌4小时。干燥得到的溶液,用甲醇-二乙醚重结晶。洗净得到的浅黄色针状结晶,减压干燥后,得到0.61g标题化合物(收率是89%)。
(鉴定数据)
Mass(FAB,POS):m/z 809.(M+-Cl-)
其中,在下述通式(15)和表1中汇总实施例1~4中得到的化合物。
[表1]
[实施例5]
抗癌性评价
用下述方法评价实施例中1~4得到的膦金配合物对肿瘤细胞的活性。其中,作为比较例,也对顺铂(比较例1)同样进行评价。
作为癌细胞,使用HL-60(人急性骨髓性白血病细胞),在补充有10%胎牛血清和1%抗生物质、抗真菌剂的Rosewell Park MemorialInstitute培养基(RPMI1640)中,在5%二氧化碳气氛下,在湿润恒温箱中,以37℃进行培养。
细胞用PBS洗净,算出细胞数后,使用同样的培养基,配制1×106细胞/ml悬浊液。在灭菌的96孔微量培养板中加入上述悬浊液,以得到50000细胞/孔的密度。
接着,加入完全溶解于水或二甲亚砜中的实施例1~4中配制的膦金配合物溶液或顺铂溶液(比较例1),继续在恒温箱中培养24小时。
然后,采用Mosmann(T.Mosmann,J.Immunnol.Method(1983)65,55-63)法评价生存细胞数。即,加入四鎓盐(3,[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide,MTT)溶液,再以同样的条件培养3小时。用0.04mol/HCl/异丙醇溶解由细胞内的线粒体酶活性生成的甲结晶,使用微量培养板酶标仪(Bio-Rad550),测定595nm的吸光度。为了排除基底,测定630nm的吸光度,从实际测定值减去。将其作为生存细胞数进行评价,算出50%细胞发育抑制浓度(IC50)。其中,在算出IC50值时,采用同样实施的至少3次以上的实验值的平均值。在表2表示该结果。
[表2]
IC50(μM/L) | |
实施例1 | 2.75 |
实施例2 | 1.66 |
实施例3 | 3.55 |
实施例4 | 0.542 |
比较例1 | 23.6 |
从表2的结果可知,本发明的膦过渡金属配合物具有比顺铂更优异的抗癌作用。
[实施例5]
毒性试验
对在实施例4中得到的膦金配合物试样,大鼠单次口服给药进行与顺铂(比较例1)的毒性比较试验。
对Sprauge-Dawley系SPF雌性大鼠(CrJ:CD(SD))进行约1周的检疫、驯化饲养后,选出健康的8周龄大鼠,将选出的5只大鼠作为1组。对于给药前一晚断食的大鼠,使用玉米油作为溶剂,单次口服给药20、50、100和300mg/kg的膦金配合物,10、20、50和100mg/kg的顺铂,给药后,在10分钟、30分钟、1小时、2小时、4小时和以后每日到第14日进行观察,从大鼠的生存率求出50%致死量(LD50)。在表3中表示该结果。
[表3]
LD50值 | |
实施例4 | 300mg/kg以上 |
比较例1 | 20~50mg/kg |
由表3的结果可以确认,给与了本发明的膦金配合物的大鼠经过14日后也没有死亡,另外,此期间,在一般状态、体重推移和内脏所见中,也没有应该特别记载的变化,所以,暗示本发明的膦金配合物是低毒性的。
产业上的可利用性
本发明的膦过渡金属配合物具有优异的抗癌活性,作为各种癌的预防和抗癌剂极其有用。另外,本发明的膦过渡金属配合物的副作用小,可以极其安全地利用。另外,根据本发明的制造方法,能够采用工业上有利的方法提供这种膦过渡金属配合物。
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EP1958951A4 (en) | 2011-05-04 |
US7655810B2 (en) | 2010-02-02 |
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