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CN1051310C - 呋喃基或噻吩基羰基取代的紫杉烷及含它们的药用组合物 - Google Patents

呋喃基或噻吩基羰基取代的紫杉烷及含它们的药用组合物 Download PDF

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CN1051310C
CN1051310C CN93114654A CN93114654A CN1051310C CN 1051310 C CN1051310 C CN 1051310C CN 93114654 A CN93114654 A CN 93114654A CN 93114654 A CN93114654 A CN 93114654A CN 1051310 C CN1051310 C CN 1051310C
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taxane derivative
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R·A·霍尔顿
K·伦根
H·纳迪扎德
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Abstract

结构如下所示的紫杉烷衍生物可用作抗肿瘤剂，式中R1、R3、T1、T2、Ac、E1和E2的定义见说明书：

Description

呋喃基或噻吩基羰基取代的紫杉烷及含它们的药用组合物
本发明涉及可用作抗白血病及抗肿瘤剂的新的紫杉烷(taxanes)。
紫杉烷萜类在生物和化学领域均引起了人们极大的兴趣。紫杉醇(taxol)是其中之一。紫杉醇是一个有希望的具广谱抗白血病和抑制肿瘤活性的癌症化疗剂。紫杉醇具2′R，3′S构型，其结构式如下式(1)示：其中Ac是乙酰基。由于其有前途的活性，目前法国和美国都在对紫杉醇进行临床试验。
Colin等人在美国专利第4814470中报道，具下式(2)结构的紫杉醇衍生物，其活性远远大于紫杉醇(1)的活性。所述式(2)结构如下：
Figure C9311465400071
式中R′代表氢或乙酰基，以及R″和R中一个代表羟基，而另一个代表叔丁氧基羰基氨基及其立体异构形式和它们的混合物。式中R″是羟基、R是叔丁氧基羰基氨基并具2′R、3′S构型的式(2)化合物通常称为taxotere。
尽管紫杉醇和taxotere是有希望的化疗剂，但它们并不是普遍奏效的。因此仍有必要开发其它的化疗剂。
因此，本发明的目的之一是提供新的紫杉烷衍生物，它们是有效的抗白血病和抗肿瘤剂。
因此概括地说，本发明涉及下式(3)紫杉烷衍生物：
Figure C9311465400072
式中R1是苯基或对硝基苯基，R3是呋喃基或噻吩基，T1是氢、羟基保护基团或-COT2，
其中T2是H、C1-C6烷基、C2-C6链烯基、C2-C6链炔基或单环芳基，Ac是乙酰基，以及E1和E2分别选自氢、羟基保护基团和能增加紫杉烷衍生物水溶性的功能基。
本发明的其它目的和特征将在下文中做部分叙述。
根据本发明，现已发现：一般具式(3)以及尤其是具式(4)、(5)和(6)结构的化合物在体外显示出显著的特性，是有效的抗白血病和抗肿瘤剂。其生物活性已在体外用微管蛋白测定法(tubulinassays)和人癌细胞系进行了测定，并将该活性与紫杉醇和taxotere的作了比较；所述测定方法是按照Parness等人的方法，见J.CellBiology，91：479-487(1981)；所述式(4)、(5)和(6)的结构如下：
Figure C9311465400081
具2′R、3′S构型的式(4)、(5)和(6)紫杉烷可通过下述方法获得：使β-内酰胺与具紫杉烷四环核及C-13金属氧化物取代基的金属醇盐反应，生成在C-13位具β-酰氨基酯取代基的化合物。所述的β-内酰胺具下式(7)结构：
Figure C9311465400092
式中R1是苯基或对硝基苯基，R2是羟基保护基团，以及R3是呋喃基或噻吩基。
β-内酰胺(7)可由易得的原料，按下图所示的反应路线来制备：
Figure C9311465400101
试剂
(a)二异丙基氨基化锂，四氢呋喃(“THF”)，-78℃-
   -50℃；
(b)六甲基二硅氮杂烷(disilazane)锂，THF，-78-
   0℃；
(c)THF，-78-25℃，(2小时)；和
(d)三乙胺和酰基氯。
以上反应路线中所示的3-羟基保护基团是SiR5，式中R5是三烷基或三芳基，如三乙基。3-羟基可用其它标准的保护基团如1-乙氧基乙基或2，2，2-三氯乙氧基甲基来保护。更多的羟基保护基团及其合成可见“Protective Groups in Organic Synthesis”，T.W.Greene，John Wiley & Sons，1981。
外消旋β-内酰胺可以通过将其相应的2-甲氧基-2-(三氟甲基)苯基乙酸酯重结晶，而在保护前被拆分成纯的对映体。然而在下文所述的连接有β-酰氨基酯侧链的反应具很高的非对映选择性的优点，因此允许侧链前体的外消旋混合物。
具紫杉烷四环核和C-13金属氧化物取代基的金属醇盐具下式(8)结构：式中T1是氢、羟基保护基团或-COT2，T2是H、C1-C6烷基、C2-C6链烯基、C2-C6链炔基或单环芳基，T3是氢或羟基保护基团，以及M是金属，最好选自IA族、IIA族和过渡金属，以Li、Mg、Na、K或Ti为最佳。
该金属醇盐最好通过使具紫杉烷四环核和C-13羟基基团的醇在合适的溶剂中与有机金属化合物反应来制备。优选的醇是保护的浆果赤霉素III，尤其是7-0-三乙基甲硅烷基浆果赤霉素III(它可按Greene等人在JACS 110：5917(1988)中所述的方法或通过其它途径制得)或7，10-双-0-三乙基甲硅烷基浆果赤霉素III。
根据Greene等人的报道，10-去乙酰基浆果赤霉素III按照以下反应路线转化成7-0-三乙基甲硅烷基-10-去乙酰基浆果赤霉素在据报道是经仔细选择的最佳条件下，10-去乙酰基浆果赤霉素III与20当量(C2H5)3SiCl在23℃及氩气气氛中并在吡啶存在下反应20小时，得反应产物7-三乙基甲硅烷基-10-去乙酰基浆果赤霉素III(10a)，纯化后收率为84-86％；所述吡啶的用量为每mmol 10-去乙酰基浆果赤霉素III 50ml。然后可将反应产物用5当量CH3COCl和吡啶在0℃以及氩气气氛下乙酰化48小时，得7-0-三乙基甲硅烷基浆果赤霉素III(10b)，收率为86％；所述吡啶的用量为每mmol 10a25ml。见Greene等，JACS 110，5917-5918(1988)。
7-0-三乙基甲硅烷基浆果赤霉素III(10b)在溶剂如四氢呋喃(THF)中与有机金属化合物如正丁基锂反应，生成金属醇盐13-0-锂-7-0-三乙基甲硅烷基浆果赤霉素III(11)，如以下反应图解所示：
Figure C9311465400131
如以下反应图解所示，13-0-锂-7-0-三乙基甲硅烷基浆果赤霉素III(11)与式中R2是三乙基甲硅烷基的β-内酰胺(7)反应，得到C-7和C-2′羟基被三乙基甲硅烷基基团保护的中间体；然后在温和的条件下，即不影响酯键或紫杉烷取代基的条件下，将三乙基甲硅烷基基团水解：
Figure C9311465400132
式中R1是苯基或对硝基苯基，R3是呋喃基或噻吩基。
醇向金属醇盐的转化和紫杉烷衍生物的最终合成均可以在同一个反应器中进行，最好是将β-内酰胺在金属醇盐生成后加到反应器中。
本发明式(1)化合物在抑制动物、包括人的肿瘤生长方面有效，它最好以药用组合物的形式来使用；所述药用组合物包含抗肿瘤有效量的本发明化合物和药学上可接受的载体或稀释剂。
本发明抗肿瘤组合物可以配制成适合所需使用途径如口服、非胃肠道或局部给药的任何适宜的形式。非胃肠道给药的例子有肌内、静脉内、腹膜内、直肠和皮下给药。
稀释剂或载体组分不应削弱抗肿瘤化合物的治疗作用。
适宜的口服制型包括片剂、可分散的粉剂、颗粒剂、胶囊剂、悬浮剂、糖浆剂和酏剂。用于片剂的惰性稀释剂和载体包括例如碳酸钙、碳酸钠、乳糖和滑石粉。片剂也可以含有成粒剂和崩解剂如淀粉和藻酸，粘合剂如淀粉、明胶和阿拉伯胶，以及润滑剂如硬脂酸镁、硬脂酸和滑石粉。片剂可以不包衣，或可用已知技术包衣，制成延缓崩解和吸收的包衣片。可用在胶囊剂中的惰性稀释剂和载体包括例如碳酸钙、磷酸钙和高岭土。悬浮剂、糖浆剂和酏剂可含有常规赋形剂如甲基纤维素、黄蓍胶、藻酸钠，润湿剂如卵磷脂和聚氧乙烯硬脂酸酯以及防腐剂如对羟基苯甲酸乙酯。
适宜于非胃肠道给药的剂型包括溶液、悬浮剂、分散剂、乳剂等。也可将其制成可在使用前立即溶于或悬浮于灭菌注射用介质中的灭菌固体组合物。它们可以含有本领域公知的助悬剂或分散剂。
式(3)化合物的水溶性可以通过将C2′和/或C7取代基改性，与适宜的功能基E1和E2结合而得到改善。为增加水溶性，E1和E2各自可以是氢和-COGCOR1，其中G是1，2-亚乙基、1，2-亚丙基、-CH＝CH-、1，2-亚环己基或1，2-亚苯基，R1是OH碱、NR2R3、OR3、SR3、OCH2CONR4R5或OH，R2是氢、甲基，R3是(CH2)nNR6R7、(CH2)nN+R6R7R8X-，n是1-3，R4是氢、具1-4个碳原子的低级烷基，R5是氢、具1-4个碳原子的低级烷基、苄基、羟基乙基、CH2CO2H、二甲基氨基乙基，R6R7是具1或2个碳原子的低级烷基、苄基或者R6与R7和NR6R7中的氮
原子一起形成下列环：
Figure C9311465400151
R8是具1或2个碳原子的低级烷基、苄基，X-是卤离子，碱为NH3、(HOC2H4)3N、N(CH3)3、CH3N(C2H4OH)2、NH2(CH2)6NH2、N-甲基葡萄糖胺、NaOH、KOH。式中E1或E2是-COGCOR1的化合物的制备见Haugwitz。美国专利4942184，该文献被并入本文作参考。
以下实施例将举例说明本发明。
                  实施例1
N-去苯甲酰基-N-(呋喃甲酰)-3′-去苯基-3′-(4-硝基苯基)紫杉醇的制备
将0.174ml 1.63M nBuLi的己烷溶液于-45℃滴加至7-三乙基甲硅烷基浆果赤霉素III(200mg，0.286mmol)的THF(2ml)溶液中。在-45℃ 0.5小时后，将顺式-1-(呋喃甲酰)-3-三乙基甲硅烷氧基-4-(4-硝基苯)氮杂环丁-2-酮(596mg，1.43mmol)的THF(2ml)溶液滴加至该混合物中。将溶液温热至0℃，并在该温度下保持1小时，然后加入1ml 10％AcOH的THF溶液。将混合物分配于NaHCO3饱和溶液和60/40乙酸乙酯/己烷中。将有机层蒸发后得到的残留物经硅胶过滤纯化，得320mg混合物，该混合物含有(2′R，3′S)-2′7-(双)三乙基甲硅烷基-N-去苯甲酰基-N-(呋喃甲酰)-3′-去苯基-3′-(4-硝基苯基)紫杉醇和少量的(2′S，3′R)异构体。
将2.8ml 48％HF水溶液于0℃加至由上述反应所得的混合物(320mg，0.286mmol)的乙腈(18ml)和吡啶(0.93ml)溶液中。将混合物于0℃搅拌3小时，然后于25℃搅拌13小时后将混合物分配于碳酸氢钠饱和溶液和乙酸乙酯中。将乙酸乙酯溶液蒸发后得254mg残留物，将其用闪层析纯化，用甲醇/水重结晶，得187mg(74％)N-去苯甲酰基-N-(呋喃甲酰)-3′-去苯基-3′-(4-硝基苯基)紫杉醇。m.p.184-185℃；[α]25 Na-60.0°(c 0.006，CHCl3)。1H NMR(CDCl3，300MHz)δ8.26(d，J＝8.79Hz，2H，Ar-NO2)，8.12(d，J＝7.2Hz，2H，苯甲酸酯，邻位)，7.68(d，J＝8.8Hz 2H，苯甲酰胺，邻位)，7.7-7.47(m，6H，芳族的)，7.3(d，J＝9.3Hz，1H，NH)，7.02(d，J＝3.3Hz，1H，呋喃基)，6.48(dd，J＝3.3Hz，1.65Hz，1H，呋喃基)，6.27(s，1H Hz，H10)，6.26(dd，J＝8.5，8.5Hz，1H，H13)，5.87(dd，J＝8.8，1.65Hz，1H，H3′)，5.65 (d，J＝6.6Hz，1H，H2β)，4.93(d，J＝8.2Hz，1H，H5)，4.79(dd，J＝2.7，1.4Hz，1H，H2′)，4.38(m，1H，H7)，4.29(d，J＝8.4Hz，1H，H20α)，4.18(d，J＝8.4Hz，1H，H20β)，3.97(d，J＝3.3Hz，1H，2′OH)，3.79(d，J＝6.6Hz，1H，H3)，2.5(m，1H，H6α)，2.4(m，1H，7OH)，2.38(s，3H，4Ac)，2.27(m，2H，H14)，2.22(s，3H，10Ac)，1.88(m，1H，H6β)，1.81(br s，3H，Me18)，1.78(s，1H，1OH)，1.68(s，3H，Me19)，1.21(s，3H，Me17)，1.13(s，3H，Me16)。
              实施例2N-去苯甲酰基-N-(2-呋喃甲酰)紫杉醇的制备
将0.174ml 1.63M nBuLi的己烷溶液于-45℃滴加至7-三乙基甲硅烷基浆果赤霉素III(200mg，0.286mmol)的THF(2ml)溶液中。于-45℃0.5小时后，将顺式-1-(2-呋喃甲酰)-3-三乙基甲硅烷氧基-4-苯基氮杂环丁-2-酮(531mg，1.43mmol)的THF(2ml)溶液滴加至该混合物中。将溶液温热至0℃并在该温度下保持1小时，然后加入1ml 10％AcOH的THF溶液。将混合物分配于NaHCO3饱和溶液和60/40乙酸乙酯/己烷中。将有机层蒸发后得到的残留物用硅胶过滤纯化，得306mg混合物，该混合物含有(2′R，3′S)-2′7-(双)三乙基甲硅烷基-N-去苯甲酰基-N-(2-呋喃甲酰)紫杉醇和少量的(2′S，3′R)异构体。
将2.8ml 48％HF水溶液于0℃加至由上述反应所得的混合物(306mg，0.286mmol)的乙腈(18ml)和吡啶(0.93ml)溶液中。将混合物于0℃搅拌3小时，然后于25℃搅拌13小时后将混合物分配于碳酸氢钠饱和溶液和乙酸乙酯中。将乙酸乙酯溶液蒸发后得240mg残留物，将其用闪层析纯化，用甲醇/水重结晶，得192mg(80％)N-去苯甲酰基-N-(2-呋喃甲酰)紫杉醇。m.p.172-174℃；[α]25 Na-49.6°(c 0.0103，CHCl3)。1H NMR(CDCl3，300MHz)δ8.12(d，J＝7.1Hz，2H，苯甲酸酯，邻位)，7.64-7.33(m，9H，芳族的)，7.19(d，J＝8.8Hz，1H，NH)，7.01 (d，J＝3.3Hz，1H，呋喃基)，6.45(dd，1H，呋喃基)，6.26(s，1H，H10)，6.21(dd，J＝8.8，8.8Hz，1H，H13)，5.72(dd，J＝8.8，1.7Hz，1H，H3′)，5.66(d，J＝7.1Hz，1H，H2β)，4.92(d，J＝8.2Hz，1H，H5)，4.75(brs，1H，H2′)，4.40(m，1H，H7)，4.28(d，J＝8.2Hz，1H，H20α)，4.18(d，J＝8.2Hz，1H，H20β)，3.78(d，J＝6.6Hz，1H，H3)，3.69(d，J＝3.8Hz，1H，2′OH)，2.53(m，1H，H6α)，2.47(br s，1H，7OH)，2.3 6(s，3H，4Ac)，2.32(m，2H，H14)，2.22(s，3H，10Ac)，1.84 (m，1H，H6β)，1.79(br s，3H，Me18)，1.67(s，3H，Me19)，1.22(s，3H，Me17)，1.13(s，3H，Me16)。
                  实施例3N-去苯甲酰基-N-(2-噻吩甲酰)紫杉醇的制备
Figure C9311465400191
将0.174ml 1.63M nBuLi的己烷溶液于-45℃滴加至7-三乙基甲硅烷基浆果赤霉素III(200mg，0.286mmol)的THF(2ml)溶液中。于-45℃ 0.5小时后，将顺式-1-(2-噻吩甲酰)-3-三乙基甲硅烷氧基-4-苯基氮杂环丁-2-酮(554mg，1.43mmol)的THF(2ml)溶液滴加至该混合物中。将溶液温热至0℃并在该温度下保持1小时，然后加入1ml 10％AcOH的THF溶液。将混合物分配于NaHCO3饱和溶液和60/40乙酸乙酯/己烷中。将有机层蒸发后得到的残留物用硅胶过滤纯化，得311mg混合物，该混合物含有(2′R，3′S)-2′7-(双)三乙基甲硅烷基-N-去苯甲酰基-N-(2-噻吩甲酰)紫杉醇和少量的(2′S，3′R)异构体。
将2.8ml 48％HF水溶液于0℃加至由上述反应所得的混合物(311mg，0.286mmol)的乙腈(18ml)和吡啶(0.93ml)溶液中。将混合物于0℃搅拌3小时，然后于25℃搅拌13小时后将混合物分配于碳酸氢钠饱和溶液和乙酸乙酯中。将乙酸乙酯溶液蒸发后得246mg残留物，将其用闪层析纯化，用甲醇/水重结晶，得195mg(80％)N-去苯甲酰基-N-(2-噻吩甲酰)紫杉醇。m.p.218-219℃；[α]25 Na-47.6°(c 0.0103，CHCl3)。1H NMR(CDCl3，300MHz)δ8.12(d，J＝7.1Hz，2H，苯甲酸酯邻位)，7.64-7.31(m，10H，芳族的)，7.05(dd，1H，噻吩基环)，6.86(d，J＝9.3Hz，1H，NH)，6.23(s，1H，H10)，6.21(dd，J＝8.8，8.8Hz，1H，H13)，5.75(dd，J＝8.8，2.2Hz，1H，H3′)，5.66(d，J＝7.1Hz，1H，H2β)，4.93(dd，J＝9.3，1.65Hz，1H，H5)，4.78(dd，J＝5.0，2.7Hz，1H，H2′)，4.41(m，1H，H7)，4.28(d，J＝8.2Hz，1H，H20α)，4.18(d，J＝8.2Hz，1H，H20β)，3.78(d，J＝6.6Hz，1H，H3)，3.63(d，J＝4.9Hz，1H，2′OH)，2.53(m，1H，H6α)，2.48(d，J＝4.4Hz，1H，7OH)，2.36(s，3H，4Ac)，2.30(m，2H，H14)，2.23(s，3H，10Ac)，1.85(m，1H，H6β)，1.78(br s，3H，Me18)，1.68(s，3H，Me19)，1.23(s，3H，Me17)，1.13(s，3H，Me16)。实施例4
用化合物(4)、(5)和(6)，基本上按照Parness等人在J.Cell Biology 91：479-487(1981)中所述的方法进行微管蛋白结合测定(Tubulin binding assay)，并与紫杉醇和taxotere进行了比较，结果见表1。
           表1
                 微管蛋白测定化合物              Init，    Rel.名称/式             Peak      Rate4                 2195                 926                 114紫杉醇              100        98Taxotere            100        -
                      实施例5
将紫杉烷4、5和6在体外评价它们抗人结肠癌细胞HCT-116和HCT-116/VM46的细胞毒活性。HCT116/VM细胞是已经选择teniposide抗性的细胞并表示出多药物抗性表型(multidrug resitancephenotype)，包括对紫杉醇的抗性。细胞毒性在HCT 116和HCT VM46人结肠癌细胞中通过下述测定来评价：XTT(氢氧化2，3-双(2-甲氧基-4-硝基-5-磺苯基)-5-[(苯基氨基)羰基]-2H-四唑鎓测定(Scudiero等，“用人和其它肿瘤细胞系评价用于培养物中细胞生长和药物敏感性的可溶性四唑鎓/甲测定”，Cancer Res.48：4827-4833，1988)。将细胞以4000细胞/孔置于96孔微量滴定盘中。24小时后加入药物并连续稀释。将细胞于37℃培养72小时，同时加入四唑鎓染料XTT。在活细胞中的脱氢酶将XTT还原成在450nm处吸光的形式，它可用分光光度法定量。吸收越强，则活细胞的数目就越多。结果用IC50来表示，IC50是抑制细胞繁殖(即在450nm处的吸收)达未处理的对照细胞的50％时所需的药物浓度。结果见表2，数字越小表示活性越强。
                  表2
                      IC50
                  HCT      HCT化合物名称/式
                  116      VM46
 4                0.002    0.883
 5                0.003    0.300
 6                0.002    0.202紫杉醇              0.004    0.536Taxotere            0.007    0.246
鉴于以上所述，可以看出：本发明的几个目的已经达到。
由于不背离本发明的范围可对上述组合物进行各种改变，因此，以上说明书中所包含的所有内容均被理解为举例说明，并不具限定意义。

Claims (8)

1.下式紫杉烷衍生物：
Figure C9311465400021
式中R1是苯基或对硝基苯基，R3是呋喃基或噻吩基，T1是氢或-COT2基团，其中
T2是H、C1-C6烷基、C2-C6链烯基、C2-C6链炔基或单环芳基，Ac是乙酰基，以及E1和E2分别选自氢、羟基保护基团和基团-COGCOR1，其中
G是1，2-亚乙基、1，2-亚丙基、-CH＝CH-、1，2-亚环己基或1，2-
 亚苯基，
R1是NR2R3、OR3、SR3、OCH2CONR4R5或OH，
R2是氢、甲基，
R3是(CH2)nNR6R7、(CH2)nN+R6R7R8X-，
n是1-3，
R4是氢、具1-4个碳原子的低级烷基，
R5是氢、具1-4个碳原子的低级烷基、苄基、羟基乙基、
CH2CO2H、二甲基氨基乙基，R6R7是具1或2个碳原子的低级烷基、苄基或者R6与R7和
NR6R7中的氮原子一起形成下列环：
Figure C9311465400031
R8是具1或2个碳原子的低级烷基、苄基，
X-是卤离子。
2.权利要求1的紫杉烷衍生物，其中，T1是-COCH3，以及E1和E2是氢。
3.权利要求1的紫杉烷衍生物，其中，紫杉烷衍生物具2′R，3′S构型。
4.权利要求1的紫杉烷衍生物，其中，R1是苯基，T1是-COCH3，以及E1和E2中至少有一个是-COGCOR1，其中G是1，2-亚乙基、1，2-亚丙基、-CH＝CH-、1，2-亚环己基或1，2-亚苯基，R1是NR2R3、OR3、SR3、OCH2CONR4R5或OH，R2是氢、甲基，R3是(CH2)nN6R7、(CH2)nN+R6R7R8X-，n是1-3，R4是氢、具1-4个碳原子的低级烷基，R5是氢、具1-4个碳原子的低级烷基、苄基、羟基乙基、CH2CO2H、二甲基氨基乙基，R6R7是具1或2个碳原子的低级烷基、苄基或者R6与R7和NR6R7中的氮原子一起形成下列环：
Figure C9311465400041
R8是具1或2个碳原子的低级烷基、苄基，X-是卤离子。
5.权利要求1的紫杉烷衍生物，其中，T1是H或-COT2，T2是C1-C6烷基，以及E1和E2是氢，
6.权利要求1的紫杉烷衍生物，它具有下列结构：
Figure C9311465400042
7.权利要求1的紫杉烷衍生物，它具有下式结构：
Figure C9311465400051
8.一种药用组合物，它含有权利要求1的紫杉烷衍生物和一种或多种药学上可接受的、惰性或生理学上活性稀释剂或辅助剂。
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US5283253A (en) 1994-02-01
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