CN1312115C - 手性1,4-二胺及其铂(ⅱ)配合物 - Google Patents
手性1,4-二胺及其铂(ⅱ)配合物 Download PDFInfo
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Abstract
本发明公开了一类手性1,4-二胺化合物和以这类手性1,4-二胺为配体的具有有效体外抗肿瘤活性的铂(II)配位化合物,其特征在于应用手性1,4-二胺制备的铂胺配阳离子与多种配阴离子反应形成的铂(II)配位化合物,披露了手性1,4-二胺及其铂(II)配合物的制备方法和典型铂(II)配合物对人体结肠癌细胞和肺癌细胞的体外抑制作用。
Description
技术领域
本发明涉及一类手性1,4-二胺和含有这类手性l,4-二胺为配体的新型铂(II)配合物及其制备方法,以及所述铂(II)配合物中典型化合物的体外抗肿瘤性质。
背景技术
由于手性分子具有不同的光学构型,导致了它们与一些生物体作用时存在着巨大的差异,所以在药物分子结构中引入手性中心得到了人们极大的关注。在抗肿瘤铂类药物的研究中,手性二胺作为配体与金属铂(II)离子形成配合物后,其立体和空间上的差异,往往可改善药物的性质和疗效。诸如已上市的药物奥沙利铂(Oxaliplatin)和庚铂(Sunpla,SKI-2053R)以及一些正在临床试验的药物都含有手性二胺,因此设计和制备新型的手性二胺作为配体应用于铂类抗癌药物的研发中是十分有益的。
发明内容
本发明的目的是在于提供一类手性1,4-二胺化合物和以这类手性1,4-二胺为配体的铂(II)类配合物,这些配合物具有低毒、较好水溶性和有效的抗肿瘤活性,可用于治疗人类肿瘤。本发明公开了一类手性1,4-二胺化合物和以这类1,4-手性二胺为配体的铂(II)配位化合物,其特征在于应用手性1,4-二胺制备的铂胺配阳离子与多种配阴离子反应形成的铂(II)配位化合物。该类手性1,4-二胺化合物由下面式(1)表示:
其中式(1)中的手性1,4-二胺可以是旋光异构体(2R)-2-烷氧基-1,4-丁二胺或其对映异构体(2S)-2-烷氧基-1,4-丁二胺,其中R基团为C1-5的烷基。
以上述手性1,4-二胺为配体形成的铂(II)配合物由下面式(2)和式(3)表示:
其中式(2)和式(3)中的手性1,4-二胺可以是(I)-2-烷氧基-1,4-丁二胺或[(2S)-2-烷氧基-1,4-丁二胺,其中R基团为C1-5的烷基;式(2)中的L基团分别为氯离子、氯乙酸根或乙醇酸根;式(3)中的R’基团为二齿羧酸类配体,分别为草酸根、丙二酸根、1,1-环丁二酸根或螯合乙醇酸根。本发明的铂(II)配合物包括上述化学式所示的所有立体异构体。
本发明的另一个目的是提供制备式(2)和式(3)所示的铂(II)配合物的方法。在这些二价铂配合物的合成中,它们首先是由四氯合铂酸钾与手性二胺配体作用得到含二卤离子二胺配位的铂化合物,由式(4)代表;然后在避光通氮气条件下,通过方法A:使用银离子(I)除去二卤二胺合铂(II)的卤离子,所得中间体与一价碱金属阳离子的相关羧酸盐作用得到顺-酸根·二胺合铂(II)化合物;或通过方法B:使用含有银离子(I)的相关羧酸盐与二卤二胺合铂(II)作用得到顺-酸根·二胺合铂(II)化合物。式(4)中的Hal代表Cl-、Br-和r离子,其中的R基团为C1-5的烷基。
本发明还有一个目的是公开上述铂(II)配合物中典型化合物对人结肠癌细胞和人肺癌细胞的体外抑制作用。
本发明有代表性的手性1,4-二胺化合物包括:
(2R)-2-甲氧基-1,4-丁二胺;(2R)-2-乙氧基-1,4-丁二胺;(2R)-2-异丙氧基-1,4-丁二胺;(2R)-2-丁氧基-1,4-丁二胺;(2R)-2-叔丁氧基-1,4-丁二胺;(2R)-2-新戊氧基-1,4-丁二胺;(2S)-2-甲氧基-1,4-丁二胺;(2S)-2-乙氧基-1,4-丁二胺;(2S)-2-异丙氧基-1,4-丁二胺];(2S)-2-丁氧基-1,4-丁二胺;(2S)-2-叔丁氧基-1,4-丁二胺);(2S)-2-新戊氧基-1,4-丁二胺。
本发明有代表性的铂(II)配合物包括:
顺-二氯[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)(略为:D1a);顺-二氯[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)(略为:D2a);顺-二氯[(2R)-2-异丙氧基-1,4-丁二胺]合铂(II)(略为:D3a);顺-二氯[(2R)-2-丁氧基-1,4-丁二胺]合铂(II)(略为:D4a);顺-二氯[(2R)-2-叔丁氧基-1,4-丁二胺]合铂(II)(略为:D5a);顺-二氯[(2R)-2-新戊氧基-1,4-丁二胺]合铂(II)(略为:D6a);顺-二氯[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)(略为:L1a);顺-二氯[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)(略为:L2a);顺-二氯[(2S)-2-异丙氧基-1,4-丁二胺]合铂(II)(略为:L3a);顺-二氯[(2S)-2-丁氧基-1,4-丁二胺]合铂(II)(略为:L4a);顺-二氯[(2S)-2-叔丁氧基-1,4-丁二胺]合铂(II)(略为:L5a);顺-二氯[(2S)-2-新戊氧基-1,4-丁二胺]合铂(II)(略为:L6a);顺-草酸根[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)(略为:D1b);顺-草酸根[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)(略为:D2b);顺-草酸根[(2R)-2-异丙氧基-1,4-丁二胺]合铂(II)(略为:D3b);顺-草酸根[(2R)-2-丁氧基-1,4-丁二胺]合铂(II)(略为:D4b);顺-草酸根[(2R)-2-叔丁氧基-1,4-丁二胺]合铂(II)(略为:D5b);顺-草酸根[(2R)-2-新戊氧基-1,4-丁二胺]合铂(II)(略为:D6b);顺-草酸根[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)(略为:L1b);顺-草酸根[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)(略为:L2b);顺-草酸根[(2S)-2-异丙氧基-1,4-丁二胺]合铂(II)(略为:L3b);顺-草酸根[(2S)-2-丁氧基-1,4-丁二胺]合铂(II)(略为:L4b);顺-草酸根[(2S)-2-叔丁氧基-1,4-丁二胺]合铂(II)(略为:L5b);顺-草酸根[(2S)-2-新戊氧基-1,4-丁二胺]合铂(II)(略为:L6b);顺-丙二酸根[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)(略为:D1c);顺-丙二酸根[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)(略为:D2c);顺-丙二酸根[(2R)-2-异丙氧基-1,4-丁二胺]合铂(II)(略为:D3c);顺-丙二酸根[(2R)-2-丁氧基-1,4-丁二胺]合铂(II)(略为:D4c);顺-丙二酸根[(2R)-2-叔丁氧基-1,4-丁二胺]合铂(II)(略为:D5c);顺-丙二酸根[(2R)-2-新戊氧基-1,4-丁二胺]合铂(II)(略为:D6c);顺-丙二酸根[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)(略为:L1c);顺-丙二酸根[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)(略为:L2c);顺-丙二酸根[(2S)-2-异丙氧基-1,4-丁二胺]合铂(II)(略为:L3c);顺-丙二酸根[(2S)-2-丁氧基-1,4-丁二胺]合铂(II)(略为:L4c);顺-丙二酸根[(2S)-2-叔丁氧基-1,4-丁二胺]台铂(II)(略为:L5c);顺-丙二酸根[(2S)-2-新戊氧基-1,4-丁二胺]合铂(II)(略为:L6c);顺-1,1-环丁二酸根[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)(略为:D1d);顺-1,1-环丁二酸根[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)(略为:D2d);顺-1,1-环丁二酸根[(2R)-2-异丙氧基-1,4-丁二胺]合铂(II)(略为:D3d);顺-1,1-环丁二酸根[(2R)-2-丁氧基-1,4-丁二胺]合铂(II)(略为:D4d);顺-1,1-环丁二酸根[(2R)-2-叔丁氧基-1,4-丁二胺]合铂(II)(略为:D5d);顺-1,1-环丁二酸根[(2R)-2-新戊氧基-1,4-丁二胺]合铂(II)(略为:D6d);顺-1,1-环丁二酸根[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)(略为:L1d);顺-1,1-环丁二酸根[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)(略为:L2d);顺-1,1-环丁二酸根[(2S)-2-异丙氧基-1,4-丁二胺]合铂(II)(略为:L3d);顺-1,1-环丁二酸根[(2S)-2-丁氧基-1,4-丁二胺]合铂(II)(略为:L4d);顺-1,1-环丁二酸根[(2S)-2-叔丁氧基-1,4-丁二胺]合铂(II)(略为:L5d);顺-1,1-环丁二酸根[(2S)-2-新戊氧基-1,4-丁二胺]合铂(II)(略为:L6d);顺-乙醇酸根[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)(略为:D1e);顺-乙醇酸根[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)(略为:D2e);顺-乙醇酸根[(2R)-2-异丙氧基-1,4-丁二胺]合铂(II)(略为:D3e);顺-乙醇酸根[(2R)-2-丁氧基-1,4-丁二胺]合铂(II)(略为:D4e);顺-乙醇酸根[(2R)-2-叔丁氧基-1,4-丁二胺]合铂(II)(略为:D5e);顺-乙醇酸根[(2R)-2-新戊氧基-1,4-丁二胺]合铂(II)(略为:D6e);顺-乙醇酸根[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)(略为:L1e);顺-乙醇酸根[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)(略为:L2e);顺-乙醇酸根[(2S)-2-异丙氧基-1,4-丁二胺]合铂(II)(略为:L3e);顺-乙醇酸根[(2S)-2-丁氧基-1,4-丁二胺]合铂(II)(略为:L4e);顺-乙醇酸根[(2S)-2-叔丁氧基-1,4-丁二胺]合铂(II)(略为:L5e);顺-乙醇酸根[(2S)-2-新戊氧基-1,4-丁二胺]合铂(II)(略为:L6e); 顺-二乙醇酸根[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)(略为:D1g);顺-二乙醇酸根[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)(略为:D2g);顺-二乙醇酸根[(2R)-2-异丙氧基-1,4-丁二胺]合铂(II)(略为:D3g);顺-二乙醇酸根[(2R)-2-丁氧基-1,4-丁二胺]合铂(II)(略为:D4g);顺-二乙醇酸根[(2R)-2-叔丁氧基-1,4-丁二胺]合铂(II)(略为:D5g);顺-二乙醇酸根[(2R)-2-新戊氧基-1,4-丁二胺]合铂(Ⅱ)(略为:D6g);顺-二乙醇酸根[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)(略为:L1g);顺-二乙醇酸根[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)(略为:L2g);顺-二乙醇酸根[(2S)-2-异丙氧基-1,4-丁二胺]合铂(II)(略为:L3g);顺-二乙醇酸根[(2S)-2-丁氧基-1,4-丁二胺]合铂(II)(略为:L4g);顺-二乙醇酸根[(2S)-2-叔丁氧基-1,4-丁二胺]合铂(II)(略为:L5g);顺-二乙醇酸根[(2S)-2-新戊氧基-1,4-丁二胺]合铂(II)(略为:L6g)。
手性2-烷氧基-1,4-丁二胺类化合物按下列合成路线制备,起始原料分别为具有光学活性的D-苹果酸或L-苹果酸。
由于使用了具有光学活性的起始原料,并且手性碳原子在所有反应中得到保持,所以最终产物仍保留了旋光性质。
本发明由下述实施例得到进一步的阐述,但这些说明并不是限制本发明。
按本发明所制备的化合物的结构已被不同的分析方法诸如红外光谱、质子核磁共振光谱和阳离子电喷雾质谱所证实。
以下为本发明方法制备一些代表性化合物的实施例。
具体实施方式
实施例1:(2R)-2-乙氧基-1,4-丁二胺和(2S)-2-乙氧基-1,4-丁二胺的制备
(1)苹果酸二乙酯1的合成
将100.00克D-苹果酸或L-苹果酸溶解在400毫升无水乙醇中,然后加入10毫升浓硫酸,回流反应24小时。冷却到室温,加入120毫升新鲜的氨水,调节溶液pH=7,有大量白色固体沉淀生成,过滤,无水乙醇洗涤,合并滤液和洗涤液,旋转蒸发除去溶剂。减压蒸馏:l20℃(2-3mmHg),得到浅黄色馏分95.15克(64.5%)。
(2)2-乙氧基苹果酸二乙酯2的合成
30.00克1和115.00克碘乙烷混合,然后分批加入氧化银,每次14.50克(共加6次),搅拌,慢慢加热反应。当加入2/3的氧化银时,向反应液中补充加入50.00克碘乙烷。加料结束后继续回流反应2小时,冷却,常压蒸馏回收未反应的碘乙烷,然后加入冷的干***萃取,有机相用无水硫酸钠干燥数小时,旋转蒸发除去***,得棕红色液体,然后减压蒸馏得到无色有机液体22.49克(65.3%)。
(3)2-乙氧基-1,4-丁二醇3的合成
7.10克氢化铝锂加入到300毫升无水四氢呋喃中,回流20分钟,停止加热,滴加20毫升化合物2(23.70克)的四氢呋喃溶液,1小时滴加完毕,继续回流反应4小时。冷却,然后滴加820毫升***,4N NaOH溶液20毫升。然后再加入200毫升***,过滤,用***洗涤沉淀,合并滤液和洗涤液,无水硫酸镁干燥过夜。旋转蒸发除去溶剂,得到11.25克棕红色液体(77.2%)。
(4)2-乙氧基-1,4-丁二对甲苯磺酸酯4的合成
9.50克3溶解在170毫升吡啶中,然后加入28.15克对甲苯磺酰氯,0℃下搅拌反应5小时,溶液呈红色悬浊液。冰箱中冷冻过夜,有大量无色晶体析出,然后在冰水浴条件下加入340毫升蒸馏水,溶液呈橙红色悬浊液,冰箱中冷藏过夜,底部有粘状液体析出,倾析出上层清液过滤,底部粘状液体用丁醇多次重结晶有粉白色固体析出,母液浓缩后继续冷冻结晶可继续得到部分产物,真空干燥后共计10.97克(35.01%)。
(5)2-乙氧基-1,4-丁二胺7的合成
10.97克4溶于100毫升N,N-二甲酰胺中,然后加入3.30克叠氮酸钠,控温60℃反应12小时,冷却到室温,然后加入200毫升水。用***100毫升/次萃取3-4次,然后用水150毫升/次洗涤两次,有机相用无水硫酸镁干燥过夜后,除去溶剂,得到3.65克浅黄色液体5。不做提纯直接用于下步高压氢化,氢化条件:起始氢压50个大气压,0.5克5%的Pd/C,无水乙醇200毫升,反应5-10小时。反应结束后,过滤除去Pd/C催化剂,并用少量无水乙醇洗涤催化剂,合并滤液和洗涤液,浓缩大部分溶剂得到油状物6,然后用浓盐酸调节溶液pH呈酸性,加入丙酮有晶体析出,过滤用丙酮洗涤,真空干燥得到白色晶体3.25克(63.6%)。
IR(KBr):3032(NH3 +),2010,1608,1497(δNH3 +),1163,1076,1032(C-O)cm-1 1H-NMR(D2O/TMS):δ3.74(m,1H),3.55-3.52(m,2H),3.15-3.13(m,1H),3.04-3.00(m,2H),2.94-2.92(m,1H),1.87-1.86(m,2H),1.11-1.07(m,3H)ESI-MS m/z[M-2Cl-H]+=133(100%).
右旋对映体:[α]25D=+10.88(c=1.0,H2O),左旋对映体:[α]25D=-10.82(c=1.0,H2O)。
其它手性1,4-二胺化合物也按实施例1所述的方法制备。
实施例2:合成顺-二氯[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)(1.13克,2毫摩尔)、硝酸银(0.68克,4毫摩尔)混合加入水(50毫升),40℃下避光通氮气反应24小时,硅藻土辅助过滤,滤液中加入氯化钠(0.24克,4毫摩尔),40℃下避光反应24小时,将溶液浓缩,冷却,有浅黄色晶体析出,过滤,用水、乙醇、***反复洗涤,真空干燥,得产品0.21克(27.3%)。
IR(KBr):3456m(br),3256s,3220s,3177m,3132m,2971m,2942m,1601m,1449w,1384m,1210m,1094s
1H-NMR(D2O/TMS):δ211-2.22(m,2H),2.66-2.75(m,2H),2.83(m,2H),3.25(s,3H),3.90(m,1H)
ESI-MS m/z[M-Cl-+H2O]+=366(100%)
实施例3:合成顺-二氯[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)(1.16克,2毫摩尔)、硝酸银(0.68克,4毫摩尔)混合加入水(50毫升),40℃下避光通氮气反应24小时,硅藻土辅助过滤,滤液中加入氯化钠(0.24克,4毫摩尔),40℃下避光反应24小时,将溶液浓缩,冷却,有浅黄色晶体析出,过滤,用水、乙醇、***反复洗涤,真空干燥,得产品0.22克(27.6%)。
IR(KBr):3452m(br),3229s,3207s,3132m,3065m,2985m,2932m,1596m,1562m,1448w,1384s,1227m,1096s
1H-NMR(D2O/TMS):δ1.01-1.05(m,3H),2.08-2.20(m,2H),2.66-2.75(m,2H),2 78-2.86(m,2H),3.48-3.52(m,3H),4.05(m,1H)
ESI-MS m/z[M-Cl-+H2O]+=381(100%)
实施例4:合成顺-二氯[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)(0.57克,1毫摩尔)、硝酸银(0.34克,2毫摩尔)混合加入水(50毫升),40℃下避光通氮气反应24小时,硅藻土辅助过滤,滤液中加入氯化钠(0.12克,2毫摩尔),40℃下避光反应24小时,将溶液浓缩,冷却,有浅黄色晶体析出,过滤,用水、乙醇、***反复洗涤,真空干燥,得产品0.10克(26.0%)。
IR(KBr):3448m(br),3229s,3202s,3131m,3061m,2931m,1595m,1561m,1461w,1330m,1227s,1212s,1107s,1095s
1H-NMR(D2O/TMS):δ2.22-2.25(m,2H),2.68-2.77(m,2H),2.85(m,2H),3.25(m,3H),391(m,1H)
ESI-MS m/z[M-Cl-+H2O]+=366(100%)
实施例5:合成顺-二氯[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)(0.58克,1毫摩尔)、硝酸银(0.34克,2毫摩尔)混合加入水(50毫升),40℃下避光通氮气反应24小时,硅藻土辅助过滤,滤液中加入氯化钠(0.12克,2毫摩尔),40℃下避光反应24小时,将溶液浓缩,冷却,有浅黄色晶体析出,过滤,用水、乙醇、***反复洗涤,真空干燥,得产品0.10克(25.1%)。
IR(KBr):3444m(br),3255s,3220s,3177m,2971w,1601m,1449w,1384vs,1210m,1184m,1094m
1H-NMR(D2O/TMS):δ1.10(m,3H),2.06-2 22(m,2H),2.64-2.76(m,2H),2.83(m,2H),3.48(m,2H),4.04(m,2H)
ESI-MS m/z[M-Cl-+H2O]+=381(100%)
实施例6:合成顺-草酸根[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)(1.13克,2毫摩尔)与新制的草酸银(0.61克,4毫摩尔)混合加入100毫升水,50℃下避光通氮气反应24小时,将溶液浓缩,析出白色固体。冷却,过滤,干燥,得白色粉末0.27克(33.7%)。
IR(KBr):3446m(br),3231m,3138m,2941w,1691s,1669vs,1390s,1241m,1095m
1H-NMR(D2O/TMS):δ2.13-2.21(m,2H),2.70-2.75(m,2H),2.87(m,2H),3.26(m,3H),3.85(m,1H)
ESI-MS m/z[M+Na]+=424(100%)
实施例7:合成顺-草酸根[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)(1.16克,2毫摩尔)与新制的草酸银(0.61克,4毫摩尔)混合加入100毫升水,50℃下避光通氮气反应24小时,将溶液浓缩,析出白色固体。冷却,过滤,干燥,得白色粉末0.15克(18.1%)。
IR(KBr):3441m(br),3230m,3137m,2972w,2941w,2880w,1690s,1668vs,1391s,1236m,1096m
1H-NMR(D2O/TMS):δ1.08(m,3H),2.11-219(m,2H),2.0-2.78(m,2H),2.84-2.87(m,2H),3.48-3.50(m,3H),4.00(m,1H)
ESI-MS m/z[M+Na]+=438(100%)
实施例8:合成顺-草酸根[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)(0.85克,1.5毫摩尔)与新制的草酸银(0.46克,3毫摩尔)混合加入100毫升水,50℃下避光通氮气反应24小时,将溶液浓缩,析出白色固体。冷却,过滤,干燥,得白色粉末0.15克(24.9%)。
IR(KBr):3451m(br),3238m,3193m,3155m,2977w,1692s,1668vs,1388s,1095m
1H-NMR(D2O/TMS):δ2.10-2.17(m,2H),2.67-2.75(m,2H),2.84(m,2H),3.24(m,3H),3.83(m,1H)
ESI-MS m/z[M+Na]+=424(100%)
实施例9:合成顺-草酸根[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)(1.16克,1.5毫摩尔)与新制的草酸银(0.46克,3毫摩尔)混合加入100毫升水,50℃下避光通氮气反应24小时,将溶液浓缩,析出白色固体。冷却,过滤,干燥,得白色粉末0.20克(31.3%)。
IR(KBr):3411m(br),3208s,3112m,3155m,2965w,2921w,1694s,1672vs,1398s,1189m,1098m
1H-NMR(D2O/TMS):δ1.03(m,3H),2.03-2.17(m,2H),2.64-2.85(m,4H),3.45(m,2H),3.96(m,1H)
ESI-MS m/z[M+Na]+=438(100%)
实施例10:合成顺-丙二酸根[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)(1.13克,2毫摩尔)与新制的丙二酸银(0.63克,4毫摩尔)混合加入100毫升水,50℃下避光通氮气反应24小时,将溶液浓缩,析出白色固体。冷却,过滤,干燥,得白色粉末0.20克(24.1%)。
IR(KBr):3441m(br),3219m,3 127m,2947w,1626vs,1387s,1094m
1H-NMR(D2O/TMS):δ2.17(m,2H),2.68-2.70(m,2H),2.87-2.88(m,2H),3.27(m,3H),3.51-3.57(m,2H),3.83(m,1H)
ESI-MS m/z[M+Na]+=438(100%)
实施例11:合成顺-丙二酸根[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)(1.16克,2毫摩尔)与新制的丙二酸银(0.63克,4毫摩尔)混合加入100毫升水,50℃下避光通氮气反应24小时,将溶液浓缩,析出白色固体。冷却,过滤,干燥,得白色粉末0.21克(245%)。
IR(KBr):3442m(br),3212m,3122m,2972m,2940w,1667s,1643vs,1384s,1247m,1097m
1H-NMR(D2O/TMS):δ1.04-1.06m(3H),2.13(m,2H),2.67-2.75(m,2H),281-2.84(m,2H),3.47-3.49(m,2H),351-3.60(m,2H),3.95(m,1H)
ESI-MS m/z[M+Na]+=452(100%)
实施例12:合成顺-丙二酸根[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2S)-2-甲氧基-1,4-丁二胺]合铂(Ⅱ)(1.13克,2毫摩尔)与新制的丙二酸银(0.63克,4毫摩尔)混合加入100毫升水,50℃下避光通氮气反应24小时,将溶液浓缩,析出白色固体。冷却,过滤,干燥,得白色粉末0.10克(12.0%)。
IR(KBr):3441m(br),3219m,3128m,3155m,2947w,1627vs,1387s,1288w,1240m,1227m,1094m
1H-NMR(D2O/TMS):δ2.15(m,2H),2.67-2 73(m,2H),2.85(m,2H),3.26(m,3H),3.59(m,2H)3.93(m,1H)
ESI-MS m/z[M+Na]+=438(100%)
实施例13:合成顺-丙二酸根[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)(1.16克,2毫摩尔)与新制的丙二酸银(0.63克,4毫摩尔)混合加入100毫升水,50℃下避光通氮气反应24小时,将溶液浓缩,析出白色固体。冷却,过滤,干燥,得白色粉末0.27克(31.5%)。
IR(KBr):3441m(br),3219m,3128m,3155m,2947w,1627vs,1387s,1288w,1240m,1227m,1094m
1H-NMR(D2O/TMS):δ1.07(m,3H),2.12(m,2H),2.68-2.85(m,4H),3.49-3.56(m,4H),3.95(m,1H)
ESI-MS m/z[M+H]+=430(100%)
实施例14:合成顺-1,1-环丁二酸根[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)(1.1 3克,2毫摩尔)与新制的1,1-环丁二酸银(0.72克,4毫摩尔)混合加入100毫升水,50℃下避光通氮气反应24小时,将溶液浓缩近干,加入乙醇和***.析出白色固体。冷却,过滤,干燥,得白色粉末0.26克(28.6%)。
IR(KBr):3444s(br),3138m,2947w,1627vs,1459w,1384vs,1252w,1221m,1115m,1096m
1H-NMR(D2O/TMS):δ1.74-1.81(m,2H),2.11-2.15(m,2H),2.71-2.80(m,6H),2.87(m,2H),3.27(m,3H),3.82(m,1H)
ESI-MS m/z[M+H]+=456(100%)
实施例15:合成顺-1,1-环丁二酸根[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)(1.16克,2毫摩尔)与新制的1,1-环丁二酸银(0.72克,4毫摩尔)混合加入100毫升水,50℃下避光通氮气反应24小时,将溶液浓缩近干,加入乙醇和***,析出白色固体。冷却,过滤,干燥,得白色粉末0.22克(23.4%)。
IR(KBr):3444s(br),3138m,2947w,1627vs,1459w,1384vs,1252w,1221m,1115m,1096m
1H-NMR(D2O/TMS):δ1.02-1.06(m,3H),1.70-1.77(m,2H),2.05-2.13(m,2H),2.66-2.78(m,6H),2.84(m,2H),3.46(m,3H),3.95(m,1H)
ESI-MS m/z[M+H]+=470(100%)
实施例16:合成顺-1,1-环丁二酸根[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)(1.13克,2毫摩尔)与新制的1,1-环丁二酸银(0.72克,4毫摩尔)混合加入100毫升水,50℃下避光通氮气反应24小时,将溶液浓缩近干,加入乙醇和***,析出白色固体。冷却,过滤,干燥,得白色粉末0.32克(35.2%)。
IR(KBr):3445m(br),3229s,3138m,2947w,1627vs,1459w,1384vs,1252w,1221m,1115m,1096m
1H-NMR(D2O/TMS):δ1.77(m,2H),2.15(m,2H),2.71-2.82(m,6H),2.87(m,2H),3.27(m,3H),3.82(m,1H)
ESI-MS m/z[M+Na]+=478(100%)
实施例17:合成顺-1,1-环丁二酸根[(2)-2-乙氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)(1.16克,2毫摩尔)与新制的1,1-环丁二酸银(0.72克,4毫摩尔)混合加入1 00毫升水,50℃下避光通氮气反应24小时,将溶液浓缩近干,加入乙醇和***,析出白色固体。冷却,过滤,干燥,得白色粉末0.22克(23.4%)。
IR(KBr):3454br,3237sh,3109m,2967w,1654vs,1614vs,1374vs,1225w,1112m,1098m
1H-NMR(D2O/TMS):δ1.02(m,3H),1.73(m,2H),2.02-2.07(m,2H),2.66-2.86(m,8H),3.46(m,2H),3.94(m,1H)
ESI-MS m/z[M+Na]+=492(100%)
实施例18:合成顺-乙醇酸根[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)(1.13克,2毫摩尔)与硝酸银(0.68克,4毫摩尔)混合加入50毫升水,40℃下避光通氮气反应24小时,硅藻土辅助过滤,滤液中加入乙醇酸(0.15克,2毫摩尔)和氢氧化钠(0.16克,4毫摩尔)的水溶液,40℃下避光反应24小时,将溶液浓缩近干,加入乙醇,析出固体,过滤,将滤液浓缩,为黄色油状物,加入乙醇和***,有大量固体析出,过滤,迅速抽干,得易吸潮的固体0.16克(20 7%)。
IR(KBr):极易吸潮无法压片检测
1H-NMR(D2O/TMS):δ2.20-2.34(m,2H),2.79-2.90(m,2H),2.94-3.02(m,2H),3.39(m,3H),3.94(m,1H),4.09-4.11(m,2H)
ESI-MS m/z[M+Na]+=410(100%);
实施例19:合成顺-乙醇酸根[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)(1.16克,2毫摩尔)与硝酸银(0.68克,4毫摩尔)混合加入50毫升水,40℃下避光通氮气反应24小时,硅藻土辅助过滤,滤液中加入乙醇酸(0.15克,2毫摩尔)和氢氧化钠(0.16克,4毫摩尔)的水溶液,40℃下避光反应24小时,将溶液浓缩近干,加入乙醇,析出固体,过滤,将滤液浓缩,为黄色油状物,加入乙醇和***,有大量固体析出,过滤,迅速抽干,得易吸潮的固体0.25克(31.2%)。
IR(KBr):极易吸潮无法压片检测
1H-NMR(D2O/TMS):δ1.20(m,3H)2.25-2.36(m,2H),2 83(m,2H),2.96-3 00(m,2H),3.58-3.64(m,2H),4.14(m,1H),4.18-4.21(m,2H)
ESI-MS m/z[M+H2O+H]+=420(100%);
实施例20:合成顺-乙醇酸根[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)(1.13克,2毫摩尔)与硝酸银(0.68克,4毫摩尔)混合加入50毫升水,40℃下避光通氮气反应24小时,硅藻土辅助过滤,滤液中加入乙醇酸(0.15克,2毫摩尔)和氢氧化钠(0.16克,4毫摩尔)的水溶液,40℃下避光反应24小时,将溶液浓缩近干,加入乙醇,析出固体,过滤,将滤液浓缩,为黄色油状物,加入乙醇和***,有大量固体析出,过滤,迅速抽干,得易吸潮的固体0.27克(34.9%)。
IR(KBr):极易吸潮无法压片检测
1H-NMR(D2O/TMS):δ2.20-2.35(m,2H),2.79-2.91(m,2H),2.95-3.02(m,2H),3.39(m,3H),3.94(m,1H),4.10-4.11(m,2H)
ESI-MS m/z[M+Na]+=410(100%);
实施例21:合成顺-乙醇酸根[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)(1.16克,2毫摩尔)与硝酸银(0.68克,4毫摩尔)混合加入50毫升水,40℃下避光通氮气反应24小时,硅藻土辅助过滤,滤液中加入乙醇酸(0.15克,2毫摩尔)和氢氧化钠(0.16克,4毫摩尔)的水溶液,40℃下避光反应24小时,将溶液浓缩近干,加入乙醇,析出固体,过滤,将滤液浓缩,为黄色油状物,加入乙醇和***,有大量固体析出,过滤,迅速抽干,得易吸潮的固体0.17克(21.2%)。
IR(KBr):极易吸潮无法压片检测
1H-NMR(D2O/TMS):δ1.03-1.06(m,3H)2.17-2.18(m,2H),2.66-2.67(m,2H),2.76-2.83m,2H),3.47-3.51(m,2H),3.96-4.05(m,3H)
ESI-MS m/z[M+H]+=402(100%);
实施例22:合成顺-二乙醇酸根[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2R)-2-甲氧基-1,4-丁二胺]合铂(II)(1.13克,2毫摩尔)与硝酸银(0.68克,4毫摩尔)混合加入50毫升水,40℃下避光通氮气反应24小时,硅藻土辅助过滤,称取乙醇酸(0.15克,2毫摩尔)溶于少量水,用氢氧化钠水溶液调pH为8-9,加入滤液中,40℃下避光反应24小时,将溶液浓缩近干,加入乙醇,析出固体,过滤,将滤液浓缩,为黄色油状物,加入乙醇和***,有大量固体听出,过滤,迅速抽干,得易吸潮的固体0.16克(34 6%按乙醇酸的量算)。
IR(KBr):极易吸潮无法压片检测
1H-NMR(D2O/TMS):δ2.18-2.26(m,2H),2.66-2.78(m,2H),2.86-2.88(m,2H),3.28(m,3H),3.88(m,1H),3.94-4.00(m,4H)
ESI-MS m/z[M+Na]+=486(100%);[M-OCOCH2OH+H2O]+=406(80%)
实施例23:合成顺-二乙醇酸根[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)(1.16克,2毫摩尔)与硝酸银(0.68克,4毫摩尔)混合加入50毫升水,40℃下避光通氮气反应24小时,硅藻土辅助过滤,称取乙醇酸(0.15克,2毫摩尔)溶于少量水,用氢氧化钠水溶液调pH为8-9,加入滤液中,40℃下避光反应24小时,将溶液浓缩近干,加入乙醇,析出固体,过滤,将滤液浓缩,为黄色油状物,加入乙醇和***,有大量固体析出,过滤,迅速抽干,得易吸潮的固体0.12克(25.1%按乙醇酸的量算)。
IR(KBr):极易吸潮无法压片检测
1H-NMR(D2O/TMS):δ1.08-1.11(m,3H),2.15-2.25(m,2H),2.68-2.72(m,2H),2.81-2.89(m,2H),3.45-3.57(m,2H),3.93-4.12(m,5H)
ESI-MS m/z[M-OCOCH2OH+H2O]+=420(10%);[M+Na]+=500(80%)
实施例24:合成顺-二乙醇酸根[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2S)-2-甲氧基-1,4-丁二胺]合铂(II)(1.13克,2毫摩尔)与硝酸银(0.68克,4毫摩尔)混合加入50毫升水,40℃下避光通氮气反应24小时,硅藻土辅助过滤,称取乙醇酸(0.15克,2毫摩尔)溶于少量水,用氢氧化钠水溶液调pH为8-9,加入滤液中,40℃下避光反应24小时,将溶液浓缩近干,加入乙醇,析出固体,过滤,将滤液浓缩,为黄色油状物,加入乙醇和***,有大量固体析出,过滤,迅速抽干,得易吸潮的固体0.18克(38.9%按乙醇酸的量算)。
IR(KBr):极易吸潮无法压片检测
1H-NMR(D2O/TMS):δ2.17-2.26(m,2H),2.66-2.78(m,2H),2.86(m,2H),3.28(m,3H),3.90-4.00(m,5H)
ESI-MS m/z[M+Na]+=486(100%);[M-OCOCH2OH+H2O]+=406(80%)
实施例25:合成顺-二氯乙酸根[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2R)-2-乙氧基-1,4-丁二胺]合铂(II)(1.16克,2毫摩尔)与新制的二氯乙酸银(0.72克,4毫摩尔)混合加入100毫升水,50℃下避光通氮气反应24小时,将溶液浓缩近干,加入乙醇和***,有大量固体析出,过滤,迅速抽干,得易吸潮的固体0.17克(16.5%)。
IR(KBr):极易吸潮无法压片检测
1H-NMR(D2O/TMS):δ1.04-1.08(m,3H),2.10-2.26(m,2H),2.67-2.69(m,2H),2.77-2.86(m,2H),3.44-3.51(m,2H),3.90-4.11(m,5H)
ESI-MS m/z[M-OCOCH2Cl+H2O]+=438(100%)
实施例26:合成顺-二氯乙酸根[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)
顺-二碘[(2S)-2-乙氧基-1,4-丁二胺]合铂(II)(1.16克,2毫摩尔)与新制的二氯乙酸银(0.72克,4毫摩尔)混合加入100毫升水,50℃下避光通氮气反应24小时,将溶液浓缩近干,加入乙醇和***,有大量固体析出,过滤,迅速抽干,得易吸潮的固体0.12克(11.6%)。
IR(KBr):极易吸潮无法压片检测
1H-NMR(D2O/TMS):δ1.04-1.09(m,3H),2.11-2.26(m,2H),2.68-2.69(m,2H),2.77-2.86(m,2H),3.43-3.51(m,2H),3.90-4.11(m,5H)
ESI-MS m/z[M-OCOCH2Cl+H2O]+=438(100%)
注:因Pt元素丰度较高的同位素有194pt、195pt和196pt,所以上述化合物ESI-MS质谱的准分子离子峰都有三个丰度较高的同位素峰
一些典型铂(II)配合物对A549人肺癌细胞和HCT-116人结肠癌细胞的体外抑制作用
单体化合物疗效评价:
实验方法:SRB比色法
细胞株:A549人肺癌细胞,HCT-116人结肠癌细胞
实验设计:药物浓度分 为100,10,1,0.5,0.1(ug/ml)五组。根据疗效评价计算抑制率。观察在不同浓度下药物 对肿瘤细胞生长的抑制情况。
有关化合物对两种肿瘤细胞的体外抑制率数据分见表1和表2。
表1.化合物对A549细胞的生长抑制作用
ug/ml | 100 | 10 | 1 | 0.5 | 0.1 | IC50 |
样品 | ||||||
D1a | 100% | 100% | 49% | 32% | 8% | 1.01 |
D1b | 100% | 88% | 24% | 20% | -3% | 2.33 |
D1c | 100% | 86% | 26% | 15% | 1% | 2.32 |
D1d | 100% | 64% | 13% | 11% | 2% | 5.86 |
D1f | 93% | 34% | -4% | 1% | 4% | 15.90 |
D2a | 99% | 100% | 82% | 66% | 13% | 0.33 |
D2b | 100% | 100% | 25% | 32% | 30% | 1.28 |
D2c | 100% | 76% | 13% | 11% | 5% | 4.19 |
D2d | 98% | 40% | 2% | 12% | 0% | 12.40 |
D2f | 100% | 91% | 5% | -12% | -21% | 3.63 |
D2g | 100% | 100% | 55% | 26% | 15% | 0.89 |
L1a | 100% | 100% | 61% | 40% | -1% | 0.69 |
L1b | 98% | 90% | 38% | -1% | 14% | 1.52 |
L1c | 100% | 73% | 22% | 17% | 8% | 3.63 |
L1d | 78% | 25% | 13% | 17% | 1% | 29.20 |
L1f | 100% | 94% | 34% | 15% | -6% | 1.56 |
L2a | 99% | 100% | 77% | 62% | 18% | 0.36 |
L2b | 100% | 100% | 58% | 42% | 13% | 0.71 |
L2c | 100% | 90% | 30% | 30% | 7% | 1.89 |
L2d | 94% | 46% | 7% | 16% | 16% | 11.35 |
L2e | 100% | 100% | 57% | 26% | 16% | 0.86 |
顺铂 | 100% | 100% | 100% | 98% | 55% | 0.09 |
卡铂 | 100% | 93% | 14% | -2% | 0% | 2.58 |
表2.化合物对HCT-116细胞的生长抑制作用
ug/ml | 100 | 10 | 1 | 0.5 | 0.1 | IC50 |
样品 | ||||||
Control | ||||||
D1a | 100% | 84% | 23% | 1% | 10% | 2.64 |
D1b | 100% | 72% | 2% | -11% | 46% | 6.38 |
D1c | 99% | 42% | -5% | -12% | -3% | 11.63 |
D1d | 61% | 3% | -2% | 3% | 1% | 76.90 |
D1f | 32% | -5% | -4% | -4% | 1% | 100.00 |
D2a | 100% | 100% | 62% | 38% | -2% | 0.71 |
D2b | 100% | 82% | 19% | 0% | -8% | 3.08 |
D2c | 98% | 37% | 8% | 13% | -3% | 13.20 |
D2d | 67% | 15% | 0% | 0% | -4% | 51.30 |
D2f | 100% | 37% | -9% | 0% | -8% | 11.30 |
D2g | 100% | 80% | 7% | 3% | -2% | 4.47 |
L1a | 100% | 99% | 61% | 29% | 15% | 0.78 |
L1b | 100% | 65% | 8% | 9% | 7% | 6.27 |
L1c | 100% | 46% | 4% | 2% | 7% | 10.40 |
L1d | 49% | 5% | -13% | 20% | 17% | 100.00 |
L1f | 98% | 6% | -8% | 10% | -4% | 25.90 |
L2a | 100% | 100% | 43% | 40% | 5% | 1.07 |
L2b | 100% | 72% | 33% | 13% | 1% | 2.63 |
L2c | 100% | 68% | 11% | 3% | 5% | 5.43 |
L2d | 69% | 10% | -1% | 4% | 17% | 54.10 |
L2e | 100% | 73% | 14% | 10% | 13% | 4.43 |
奥沙利铂 | 100% | 95% | 90% | 47% | 19% | 0.51 |
有关化合物对相应的肿瘤细胞IC50值图见说明书附图,其中:图1为化合物对A549细胞IC50值,图2为化合物对HCT-116细胞IC50值。
Claims (3)
1、一类铂(II)配位化合物,其立体异构体,其特征在于该类化合物由式(1)和式(2)表示:
其中式(1)和式(2)中的手性1,4-二胺是旋光异构体(2R)-2-烷氧基-1,4-丁二胺或其对映异构体(2S)-2-烷氧基-1,4-丁二胺,其中R基团为C1-5的烷基;式(1)中的L基团为氯离子或氯乙酸根或乙醇酸根,式(2)中的R’基团为草酸根、丙二酸根、1,1-环丁二酸根或螯合乙醇酸根。
3、根据权利要求1所述的铂(II)配合物在制备用于治疗人体结肠癌和肺癌的药物中的用途。
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medicinal c hemistry letters,Vol.6 No.6 1996 * |
全文 synthesis and antitumor activity of 2r 3r.2.3dihydroxy.and.2 3.dialkoxy.1 4.diaminobutane platinum ii complexes,Bioorganic & medicinal c hemistry letters,Vol.6 No.6 1996 * |
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