CN106083960B - 新型紫杉类化合物及其制备方法和应用 - Google Patents
新型紫杉类化合物及其制备方法和应用 Download PDFInfo
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- CN106083960B CN106083960B CN201610426133.4A CN201610426133A CN106083960B CN 106083960 B CN106083960 B CN 106083960B CN 201610426133 A CN201610426133 A CN 201610426133A CN 106083960 B CN106083960 B CN 106083960B
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Abstract
本发明公开了一种新型紫杉类化合物及其制备方法和应用，该新型紫杉类化合物的制备方法具有以下步骤：先对吉西他滨中的两个羟基进行保护，然后与氯甲酸烷基酯进行缩合反应，接着脱除羟基保护基团，得到中间体G1；先对中间体G1其中一个羟基进行保护，然后再对另一个羟基进行保护，接着脱除第一个羟基脱保基团，得到中间体G2；将7,10‑二（三氯乙氧基甲酰）多西他赛与二酸酐反应得到中间体D1；将中间体D1与中间体G2进行缩合反应得到中间体D2；对中间体D2进行羟基脱保护得到目标产物。本发明的新型紫杉类化合物毒性较小，抗肿瘤活性较高，尤其是对于胃肠道癌、肺癌、乳腺癌以及白血病等实体肿瘤具有很好的抑制率。
Description
技术领域
本发明涉及一种新型紫杉类化合物及其制备方法和应用。
背景技术
现有的紫杉类化合物大多存在毒性较大、抗肿瘤活性较低等不足，尤其是对于胃肠道癌、肺癌、乳腺癌以及白血病等实体肿瘤的抑制效果不佳。
发明内容
本发明的目的在于解决现有技术的不足，提供一种毒性较小、抗肿瘤活性较高、尤其是对于胃肠道癌、肺癌、乳腺癌以及白血病等实体肿瘤具有很好的抑制率的新型紫杉类化合物及其制备方法和应用。
实现本发明上述目的的技术方案是：一种新型紫杉类化合物，其结构如通式（Ⅰ）所示：
（Ⅰ）。
通式（Ⅰ）中，R1为C1～C6烷基或取代烷基，优选为乙基、正丁基或者正己基，更优选为正丁基。
n为0～6，优选为0～2，更优选为1。
上述新型紫杉类化合物的制备方法具有以下步骤：
S1：先对吉西他滨中的两个羟基进行保护，然后与氯甲酸烷基酯进行缩合反应，接着脱除羟基保护基团，得到中间体G1；
S2：先对步骤S1制得的中间体G1其中一个羟基进行保护，然后再对另一个羟基进行保护，接着脱除第一个羟基脱保基团，得到中间体G2；
S3：将7,10-二（三氯乙氧基甲酰）多西他赛与二酸酐反应得到中间体D1；
S4：将步骤S3制得的中间体D1与步骤S2制得的中间体G2进行缩合反应得到中间体D2；
S5：对步骤S4制得的中间体D2进行羟基脱保护得到目标产物。
上述步骤S1中采用的羟基保护试剂为六甲基二硅氮烷、六甲基二硅氧烷、三甲基氯硅烷或者三甲基碘硅烷，优选为六甲基二硅氮烷。
上述步骤S1中所述的氯甲酸烷基酯为氯甲酸甲酯、氯甲酸乙酯、氯甲酸正丙酯、氯甲酸异丙酯、氯甲酸正丁酯、氯甲酸正戊酯、氯甲酸正己酯中的一种，优选为氯甲酸乙酯、氯甲酸正丁酯或者氯甲酸正己酯，更优选为氯甲酸正丁酯。
上述步骤S2中第一个羟基保护采用的保护试剂为叔丁基二甲基氯硅烷、异丙基二甲基氯硅烷、乙基二甲基氯硅烷或者三甲基氯硅烷，优选为叔丁基二甲基氯硅烷。
上述步骤S2中第二个羟基保护采用的保护试剂为氯甲酸-2,2,2-三氯乙酯。
上述步骤S3中采用的二酸酐为丁二酸酐、戊二酸酐或者己二酸酐，优选为戊二酸酐。
上述步骤S4中采用的缩合试剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（EDCI）、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐（EDC）、二环己基碳二亚胺（DCC）或者N,N-二异丙基碳二亚胺（DIC），优选为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐或者1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐，更优选为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
上述步骤S4的缩合反应优选在4-二甲氨基吡啶的存在下进行。
上述步骤S5的羟基脱保护是在锌粉和乙酸钠的存在下进行的。
上述新型紫杉类化合物在制备抗肿瘤药物中的应用。
上述肿瘤为血液瘤或者恶性实体瘤；具体来说，上述肿瘤包括结肠癌、直肠癌、胃癌、肺癌、乳腺癌、前列腺癌、胰腺癌、肝癌、食道癌、脑肿瘤、卵巢癌、子宫癌、肾癌、头颈癌、皮肤癌、膀胱癌、外阴癌、睾丸瘤、绒毛癌、生殖细胞瘤、恶性淋巴瘤、白血病和多发性骨髓瘤；优选包括结肠癌、直肠癌、胃癌、肺癌、乳腺癌以及白血病。
一种药物组合物，其含有作为活性成分的上述新型紫杉类化合物以及一种或者多种药用载体/赋形剂。
上述药物组合物的剂型为注射剂型或者是口服剂型，其中注射剂型为溶液型注射剂、混悬型注射剂、乳剂型注射剂、或注射用无菌粉末；口服剂型为片剂、散剂、颗粒剂、胶囊剂、微丸制剂、溶液剂、混悬剂、乳剂、糖浆剂或者酏剂。
本发明具有的积极效果：本发明的新型紫杉类化合物毒性较小（MTD剂量只有250mg/kg），抗肿瘤活性较高，尤其是对于胃肠道癌、肺癌、乳腺癌以及白血病等实体肿瘤具有很好的抑制率（结肠癌TGI可达85.69%）。
附图说明
图1为中间体G1的1H-NMR谱图。
图2为中间体G2的1H-NMR谱图。
图3为中间体D1的1H-NMR谱图。
图4为中间体D2的1H-NMR谱图。
图5为新型紫杉类化合物Z1的1H-NMR谱图。
图6为新型紫杉类化合物Z1的13C-NMR谱图。
图7为新型紫杉类化合物Z1的HSQC图（异核单量子相关谱图）。
具体实施方式
（实施例1）
本实施例的新型紫杉类化合物Z1的结构式如下：
。
该新型紫杉类化合物Z1的制备方法具有以下步骤：
S1：制备中间体G1，合成路线如下：
。
具体方法如下：
S11：在1L的圆底烧瓶中加入30g的吉西他滨（0.114mol）、143mL的六甲基二硅氮烷（0.68mol、6eq.）、0.569g的硫酸铵（4mmol、0.038eq.）以及143mL的二氧六环，然后将混合物至于130℃的油浴中，回流1.5h，直至不再有氨气产生。
待挥发物蒸发后，先将半结晶固体真空干燥10min，剩余物用干燥的甲苯共蒸发二次后于60℃真空干燥，得到53.99g的白色结晶固体。
S12：0℃的温度下，向含有28.05g上述S11制得的白色结晶固体（59mmol）和8.02mL的N-甲基咪唑（101mmol、1.7eq.）的296mL二氯甲烷溶液中加入11.3mL的氯甲酸正丁酯（89mmol、1.5eq.），此时无沉淀产生，将反应混合物室温（15～25℃，下同）下搅拌4h，然后在30℃的温度下蒸除溶剂，向剩余物中加入197mL的甲醇和41mL的三乙胺（0.27mol、5eq），将反应混合物室温下搅拌过夜，第二天TLC表明几乎都是产物。
将反应混合物蒸除溶剂，剩余物溶解在500mL的乙酸乙酯/二氯甲烷混合溶液（1∶3）中，然后与300mL的柠檬酸溶液（含42g柠檬酸）在分液漏斗中混合摇晃，将有机层直接倒入含有100g硅胶的过滤漏斗中，将水相用200mL的乙酸乙酯/二氯甲烷混合溶剂（1∶3）提取3次，再依次用100mL的乙酸乙酯/二氯甲烷混合溶剂（1∶3）和300mL的甲醇/二氯甲烷混合溶剂（1∶20）进行洗脱，产物用1300mL的甲醇/二氯甲烷混合溶剂（1∶20）洗脱。蒸除溶剂后于60℃真空干燥，得到19.8g白色固体泡沫中间体G1，收率为92.0%（以吉西他滨计）。
中间体G1的1H-NMR谱图见图1。
1H NMR (399.86 MHz, DMSO-d 6 ): δ = 0.90 (t, 3H, 3 J = 7.42 Hz, CH3),1.30-1.41 (m, 2H, CH2CH2CH2CH3), 1.54-1.64 (m, 2H, CH2CH2CH2CH3), 3.65 (dm, 1H, 2 J = 12.69 Hz, 3 J = 3.22 Hz, H-5a'), 3.81 (dm, 1H, 2 J = 12.69 Hz, H-5b'),3.86-3.91 (m, 1H, H-4'), 4.12 (t, 2H, 3 J = 6.64 Hz, CH2CH2CH2CH3), 4.13-4.25(m, 1H, H-3'), 5.30 (t, 1H, 3 J = 5.37 Hz, OH-5'), 6.17 (t, 1H, 3 J (H-F) = 7.52Hz, H-1'), 6.32 (d, 1H, 3 J = 6.45 Hz, OH-3'), 7.10 (d, 1H, 3 J = 7.71 Hz, H-5),8.22 (d, 1H, 3 J = 7.71 Hz, H-6), 10.84 (br s, 1H, NH)。
LC/MS（ESI）[M+H]+ 理论值：364.13，实测值：364.17。
S2：制备中间体G2，合成路线如下：
。
具体方法如下：
将1.5g步骤S1制得的中间体G1（4.1mmol）、0.653g的叔丁基二甲基氯硅烷（4.3mmol、1.05eq.）和0.765mL的吡啶（9.5mmol，2.3eq.）溶解在15mL的二氯甲烷中，室温搅拌1h，TLC表明反应进行了一半。将反应混合物搅拌过夜，仍有较多中间体G1存在，再添加0.187g的叔丁基二甲基氯硅烷（1.24mmol、0.3eq.），将反应混合物室温搅拌6h，TLC表明仍然存在中间体G1，再加入0.124g的叔丁基二甲基氯硅烷（0.83mmol、0.2eq.），继续搅拌过夜，第二天TLC表明没有中间体G1，随后加入0.2-33mL的吡啶（2.9mmol、0.7eq.），接着在0℃下加入0.625mL的氯甲酸-2,2,2-三氯乙酯（4.5mmol、1.1eq.），将反应混合物室温搅拌0.5h，TLC表明反应完全。
将反应混合物与3.90g的柠檬酸（18.6mmol，4.5eq.）一起摇晃，蒸除溶剂后的提取物无需干燥，将剩余物在40℃下进行高真空干燥，然后溶解在27mL的四氢呋喃中，将溶液冷却至0℃，加入三乙胺以及3倍的氢氟酸，将溶液置于5℃的冰箱中过夜，第二天将反应混合物置于20℃保持3h，然后在该温度下蒸除溶剂。将剩余物经硅胶柱层析（含55g硅胶），然后依次用500mL的乙酸乙酯/二氯甲烷混合溶剂（1∶5）以及450mL的乙酸乙酯/二氯甲烷混合溶剂（1∶2）洗脱。合并相同组分，蒸除溶剂后于60℃真空干燥，得到1.904g的白色固体泡沫中间体G2，收率为86%。
中间体G2的1H-NMR谱图见图2。
1H NMR (399.86 MHz, DMSO-d 6 ): δ = 0.90 (t, 3H, 3 J = 7.32 Hz,CH2CH2CH2CH3), 1.30-1.41 (m, 2H, CH2CH2CH2CH3), 1.55-1.64 (m, 2H, CH2CH2CH2CH3),3.68-3.76 (m, 1H, H-5a'), 3.78-3.85 (m, 1H, H-5b'), 4.12 (t, 2H, 3 J = 6.64Hz, CH2CH2CH2CH3), 4.34-4.39 (m, 1H, H-4'), 5.01 (d, 1H, 2 J = 12.20 Hz, Troc),5.09 (d, 1H, 2 J = 12.20 Hz, Troc), 5.31-5.41 (m, 2H, H-3', OH-5'), 6.34 (t,1H, 3 J (H-F) = 8.60 Hz, H-1'), 7.13 (d, 1H, 3 J = 7.62 Hz, H-5), 8.15 (d, 1H, 3 J =7.62 Hz, H-6), 10.87 (br s, 1H, NH)。
LC/MS（ESI）[M+H]+ 理论值：538.0，实测值：538.2。
S3：制备中间体D1，合成路线如下：
。
具体方法如下：
将0.95g的7,10-二（三氯乙氧基甲酰）多西他赛（0.82mmol）和0.935g的戊二酸酐（8.2mmol、10eq.）溶解在10.6mL的吡啶（131mmol、160eq.）中，将反应混合物室温搅拌2.5h，然后置于-20℃的冰箱中过夜，第二天再将反应混合物室温搅拌3h以上，TLC表明反应基本完成。
在30℃下蒸除吡啶，并将剩余物在该温度下真空干燥，将剩余物溶解在5.5g的柠檬酸（26mmol、32eq.）溶液中，然后用二氯甲烷提取，将提取物直接倒入硅胶柱（含20g硅胶），将杂质用110mL的甲醇/二氯甲烷混合溶剂（1∶100）洗去，将产物用143mL的甲醇/二氯甲烷混合溶剂（1∶100）以及102mL的甲醇/二氯甲烷混合溶剂（1∶50）洗出，蒸除溶剂后于40℃真空干燥，得到1.055g白色固体中间体D1粗品。
将粗品经硅胶柱层析（含35g硅胶），然后依次用50mL的二氯甲烷、210mL的乙酸乙酯/二氯甲烷混合溶剂（1∶20）以及220mL的乙酸乙酯/二氯甲烷混合溶剂（1∶10）洗去杂质，将洗脱后的组分收集于试管中，并用乙酸乙酯/二氯甲烷混合溶剂（1∶5）进行柱洗脱。合并相同组分，蒸除溶剂后于40℃真空干燥，得到0.623g白色固体中间体D1成品，收率为60%。
中间体D1的1H-NMR谱图见图3。
1H NMR (399.86 MHz, DMSO-d 6 ): δ = 0.98 (s, 3H, CH3), 1.03 (s, 3H,CH3), 1.38 (s, 9H, BOC), 1.51-1.65 (m, 1H), 1.68 (s, 3H, CH3), 1.72-1.91 (m,4H), 1.80 (s, 3H, CH3), 2.26 (s, 3H, OAc), 2.28 (t, 2H, 3 J = 7.42 Hz,COCH2CH2CH2COOH), 2.46 (t, 2H, 3 J = 7.23 Hz, COCH2CH2CH2COOH), 2.56-2.50 (m,1H), 3.65 (d, 1H, 3 J = 6.83 Hz, CH), 4.03-4.10 (m, 2H), 4.77 (d, 1H, 2 J =12.01 Hz, Troc-a), 4.81 (s, 1H), 4.93 (d, 1H, 2 J = 12.01 Hz, Troc-a), 4.95(d, 1H, 2 J = 12.10 Hz, Troc-b), 4.98-5.02 (m, 1H), 5.00 (d, 1H, 2 J = 12.10 Hz,Troc-b), 5.01-5.07 (m, 1H), 5.09 (d, 1H, 3 J = 8.40 Hz), 5.38-5.47 (m, 2H),5.79 (t, 1H, 3 J = 8.89 Hz, CH), 6.09 (s, 1H), 7.18 (t, 1H, 3 J = 7.32 Hz,CH p-Ph), 7.37 (d, 2H, 3 J = 7.62 Hz, CH o-Ph), 7.41-7.47 (m, 2H, CH m-Ph), 7.65-7.72(m, 2H, CH m-Bz), 7.76 (t, 1H, 3 J = 7.32 Hz, CH p-Bz), 7.88 (d, 1H, 3 J = 8.98 Hz,NH-BOC), 7.99 (d, 2H, 3 J = 7.22 Hz, CH o-Bz), 12.13 (br s, 1H, COOH)。
LC/MS（ESI）[M+Na]+ 理论值：1292.2，实测值：1292.2。
S4：制备中间体D2，合成路线如下：
。
具体方法如下：
0℃的温度下，将0.277mg步骤S2制得的中间体G2（0.51mmol、1.1eq.）、0.594mg步骤S3制得的中间体D1（0.47mmol、1eq）、98mg的碳化二亚胺（0.51mmol、1.1eq.）以及11.4mg的4-二甲氨基吡啶（95·10–6 mol、0.2eq.）溶解在0.934mL的二氯甲烷中，将反应混合物缓慢加热至室温，搅拌过夜，第二天，TLC表明为主要产品和一些轻微的杂质。
将反应混合物直接倒入硅胶柱（含35g硅胶）中，依次用50mL的二氯甲烷、205mL的乙酸乙酯/二氯甲烷混合溶剂（1∶40）、210mL的乙酸乙酯/二氯甲烷混合溶剂（1∶20）以及220mL的乙酸乙酯/二氯甲烷混合溶剂（1∶10）将杂质洗去，将洗脱后的组分收集于试管中，用360mL的乙酸乙酯/二氯甲烷混合溶剂（1∶5）进行柱洗脱，合并相同组分，蒸除溶剂后于40℃真空干燥，得到0.636g无色透明中间体D2，收率为76%。
中间体D2的1H-NMR谱图见图4。
1H NMR (399.86 MHz, DMSO-d 6 ): δ = 1H NMR (399.86 MHz, DMSO-d 6 ): δ =0.90 (t, 3H, 3 J = 7.32 Hz, CH2CH2CH2CH3), 0.98 (s, 3H, CH3), 1.02 (s, 3H, CH3),1.30-1.41 (m, 2H, CH2CH2CH2CH3), 1.37 (s, 9H, BOC), 1.51-1.66 (m, 4H,CH2CH2CH2CH3, CH2-a, CH2-a), 1.68 (s, 3H, CH3), 1.75-1.89 (m, 4H), 1.80 (s, 3H,CH3), 2.26 (s, 3H, OAc), 2.43 (t, 2H, 3 J = 7.52 Hz, COCH2CH2CH2CO), 2.46 (t,2H, 3 J = 8.01 Hz, COCH2CH2CH2CO), 3.65 (d, 1H, 3 J = 6.64 Hz, CH), 4.03-4.10 (m,2H), 4.12 (t, 2H, 3 J = 6.64 Hz, CH2CH2CH2CH3), 4.43 (dd, 1H, 2 J = 12.10 Hz, 3 J= 6.25 Hz, H-5'a), 4.51 (dd, 1H, 2 J = 12.10 Hz, 3 J = 2.84 Hz, H-5'b), 4.55-4.62 (m, 1H, H-4'), 4.77 (d, 1H, 2 J = 12.11 Hz, Troc-a), 4.80 (s, 1H), 4.93(d, 1H, 2 J = 12.11 Hz, Troc-a), 4.94 (d, 1H, 2 J = 12.10 Hz, Troc-b), 4.97-5.20(m, 3H), 5.01-5.10 (m, 2H), 5.09 (d, 1H, 2 J = 12.30 Hz, Troc-c), 5.37-5-57(m, 3H), 5.80 (t, 1H, 3 J = 8.98 Hz, CH), 6.09 (s, 1H), 6.36 (t, 2H, 3 J (H-F) =8.30 Hz, H-1'), 7.16 (d, 1H, 3 J = 7.61 Hz, H-5), 7.18 (t, 1H, 3 J = 7.42 Hz,CH p-Ph), 7.37 (d, 2H, 3 J = 7.62 Hz, CH o-Ph), 7.40-7.47 (m, 2H, CH m-Ph), 7.65-7.72(m, 2H, CH m-Bz), 7.76 (t, 1H, 3 J = 7.42 Hz, CH p-Bz), 7.87 (d, 1H, 3 J = 8.98 Hz,NH-BOC), 7.99 (d, 2H, 3 J = 7.42 Hz, CH o-Bz), 8.07 (d, 1H, 3 J = 7.42 Hz, H-6),10.90 (br s, 1H, NH)。
LC/MS（ESI）[M+H–Troc]+理论值：1617.3，实测值：1617.6。
S5：制备新型紫杉类化合物Z1，合成路线如下：
。
具体方法如下：
将1.101g的乙酸钠（13.4mmol、40eq.）溶解在12mL甲醇和12mL醋酸的混合溶液中，然后将该溶液加入到装有0.602g步骤S4制得的中间体D2（0.34mmol）的烧瓶中，待其完全溶解后，加入1.756g的锌粉（27mmol、40eq.），将反应混合物在5℃超声振动15min并剧烈摇晃，TLC表明中间体D2消失，只有微量的二（三氯乙氧基甲酰）产物和一定量的单（三氯乙氧基甲酰）产物，绝大部分是目标产物。继续超声振动并剧烈摇晃持续15min，TLC显示没有二（三氯乙氧基甲酰）产物，但仍有一部分单（三氯乙氧基甲酰）存在，将反应混合物第三次超声振动并剧烈摇晃15min，然后倒入50mL含有19.44g的碳酸氢钠（0.23mol）水悬浮液中，接着加入乙酸乙酯，过滤，滤液用乙酸乙酯提取，提出物于25℃蒸干。
将剩余物溶于二氯甲烷后经硅胶柱层析（含35g硅胶），然后依次用203.3mL的甲醇/二氯甲烷混合溶剂（1∶60）以及615mL的甲醇/二氯甲烷混合溶剂（1∶40）洗脱，将洗脱后的组分收集于试管中，依次用206.7mL的甲醇/二氯甲烷混合溶剂（1∶30）以及208mL的甲醇/二氯甲烷（1∶25）混合溶剂进行洗脱。合并相同组分，蒸除溶剂后于40℃真空干燥，得到0.244g无色透明目标产物Z1，收率为57%，纯度为95.0%（HPLC）。
目标产物Z1的1H-NMR谱图、13C-NMR谱图以及HSQC谱图分别见图5～图7。
1H NMR (399.86 MHz, DMSO-d 6 ): δ = 0.90 (t, 3H, 3 J = 7.13 Hz,CH2CH2CH2CH3), 0.97 (s, 6H, CH3×2), 1.29-1.41 (m, 2H, CH2CH2CH2CH3), 1.36 (s,9H, BOC), 1.51 (s, 3H, CH3), 1.53-1.67 (m, 4H, CH2CH2CH2CH3, CH2-a, CH2-a),1.70 (s, 3H, CH3), 1.76-1.89 (m, 3H, COCH2CH2CH2CO, CH2-b), 2.23 (s, 3H, OAc),2.25-2.33 (m, 1H, CH2-b), 2.38-2.48 (m, 4H, COCH2CH2CH2CO), 3.63 (d, 1H, 3 J =6.44 Hz, CH), 3.97-4.07 (m, 3H, CH, CH2O), 4.06-4.12 (m, 1H, H-4'), 4.12 (t,2H, 3 J = 6.44 Hz, CH2CH2CH2CH3), 4.18-4.31 (m, 1H, H-3'), 4.32-4.47 (m, 3H, H-5', t-OH), 4.86-4.95 (m, 2H, CH, OH), 5.00 (d, 1H, 3 J = 6.64 Hz, OH), 5.03-5.14 (m, 3H, CH×3), 5.40 (d, 1H, 3 J = 6.83 Hz, CH), 5.77 (t, 1H, 3 J = 8.59Hz, CH), 6.22 (t, 2H, 3 J (H-F) = 7.52 Hz, H-1'), 6.49 (d, 1H, 3 J = 6.06 Hz, OH-3'), 7.10-7.20 (m, 2H, H-5, H p-Ph), 7.31-7.45 (m, 4H, H o-Ph×2, H m-Ph×2), 7.61-7.69 (m, 2H, H m-Ph), 7.73 (t, 1H, 3 J = 7.42 Hz, H p-Ph), 7.85 (d, 1H, 3 J = 8.98Hz, NH-BOC), 7.93-8.04 (m, 3H, H o-Ph×2, H-6), 10.86 (br s, 1H, NH)。
13C NMR (100.56 MHz, DMSO-d 6 ): δ = 9.8 (CH3), 13.5 (CH2CH2CH2CH3), 13.6(CH3), 18.4 (CH2CH2CH2CH3), 19.7 (COCH2CH2CH2CO), 20.7 (CH3), 22.4 (OAc), 26.4(CH3), 28.1 (t-BOC, primary), 30.2 (CH2CH2CH2CH3), 32.1 (COCH2CH2CH2CO), 32.3(COCH2CH2CH2CO), 34.7 (CH2), 36.4 (CH2), 42.9, 45.9 (CH), 55.1 (CH), 57.0, 62.8(CH2-5'), 65.1 (CH2CH2CH2CH3), 70.1 (t, 2 J (C-F) = 23.0 Hz, CH-3'), 70.7 (CH),71.2 (CH), 73.7 (CH), 74.8 (CH), 75.0 (CH), 75.4 (CH2), 76.8, 77.9 (CH-4'),78.5, 80.3 (t-BOC, quaternary), 83.7 (CH), 84.5 (br s, CH-1'), 95.2 (CH-5),122.5 (t, 1 J (C-F) = 259.2 Hz, C-2'), 127.3 (CH o-Ph), 128.0 (CH p-Ph), 128.5(CH m-Ph), 128.6 (CH m-Ph), 129.5 (CH o-Ph), 130.0, 133.3 (CH p-Ph), 135.9, 136.9,137.5, 144.9 (CH-6), 153.1 (NHCOO), 153.9 (COAr), 155.1 (NHCOO), 163.5 (C-4),165.3 (COO), 169.0 (COO), 169.5 (COO), 171.8 (COCH2CH2CO), 172.1 (COCH2CH2CO),209.3 (CO)。
LC/MS（ESI）[M+H]+理论值：1267.5，实测值：1267.8。
（实施例2～实施例9）
各实施例的制备方法与实施例1基本相同，不同之处在于步骤S1中采用的氯甲酸烷基酯、步骤S3中采用的二酸酐以及最后得到的新型紫杉类化合物，具体见表1。
表1
| 实施例编号 | 化合物编号 | 氯甲酸烷基酯 | 二酸酐 | R<sup>1</sup> | n |
| 实施例1 | Z1 | 氯甲酸正丁酯 | 戊二酸酐 | 正丁基 | 1 |
| 实施例2 | Z2 | 氯甲酸正丁酯 | 己二酸酐 | 正丁基 | 2 |
| 实施例3 | Z3 | 氯甲酸正丁酯 | 丁二酸酐 | 正丁基 | 0 |
| 实施例4 | Z4 | 氯甲酸正己酯 | 戊二酸酐 | 正己基 | 1 |
| 实施例5 | Z5 | 氯甲酸正己酯 | 己二酸酐 | 正己基 | 2 |
| 实施例6 | Z6 | 氯甲酸正己酯 | 丁二酸酐 | 正己基 | 0 |
| 实施例7 | Z7 | 氯甲酸乙酯 | 戊二酸酐 | 乙基 | 1 |
| 实施例8 | Z8 | 氯甲酸乙酯 | 己二酸酐 | 乙基 | 2 |
| 实施例9 | Z9 | 氯甲酸乙酯 | 丁二酸酐 | 乙基 | 0 |
（实施例10）
本实施例为含有实施例1的新型紫杉类化合物Z1的药物组合物的制备方法。
其中，注射剂型以冻干粉针剂为例，包括：30g的新型紫杉类化合物Z1、甘露醇（20%，w/v）300g、缓冲剂二水合磷酸二氢钠7g、表面活性剂泊洛沙姆188（F68）4.0g。
将按照上述处方量准确称取的二水合磷酸二氢钠、泊洛沙姆188（F68）、甘露醇（20%，w/v）加入300g预冷至10℃以下的注射用水中溶解后，用0.1mol/L 的NaOH调节溶液pH值为7.3～7.5；再向上述溶液中加入30g的新型紫杉类化合物Z1混合均匀，用0.1mol/L的NaOH溶液或0.1mol/L 的HCl调节pH值为7.3±0.2（本实施例为7.5）；加水至2000g，溶液用0.22μm微孔滤膜过滤除菌；按每瓶2.0g将滤液分装于管制瓶中，半加塞后置于冷冻干燥机中冻干，待干燥后真空压塞，轧盖，贴标签，即得冻干粉针剂1000支，保存在2～8℃温度下。
除了上述冻干粉针剂即注射用无菌粉末外，本发明的新型紫杉类化合物还可制备成其他形式的注射剂型，如溶液型注射剂、混悬型注射剂、乳剂型注射剂。
药物组合物的适用剂型除了上述涉及的片剂形式外，还可以被制成口服的散剂、颗粒剂、胶囊剂、微丸制剂、溶液剂、混悬剂、乳剂、糖浆剂或者酏剂，或者是口服形式的缓释及控释制剂，或者是其他口服形式的药物组合物，这些口服剂型含有常见的相应的辅料（根据不同的作用分为添加剂、附加物等），如添加剂有药物等级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精盐、纤维素或硫酸镁等。
在实现上述口服剂型中，可以选择药学上的附加物作为药物活性组分的载体，包括已有技术成熟的物质，例如：惰性固体稀释液、水溶剂、脂质体、微球体或/和无毒有机溶剂等；优选的附加物有：加湿剂、乳化剂、pH缓冲液、人血清白蛋白、抗氧化剂、防腐剂、抑菌剂、葡萄糖、蔗糖、海藻糖、麦芽糖、卵磷脂、甘氨酸、山梨酸、丙烯醇、聚乙烯、鱼精蛋白、硼酸、氯化钠、或者氯化钾、矿物油、植物油等；可从中选择一种或几种组合作为药物载体。
本发明的药物组合物的靶肿瘤包括血液瘤或者恶性实体瘤。具体的，靶肿瘤包括结肠癌、直肠癌、胃癌、肺癌、乳腺癌、前列腺癌、胰腺癌、肝癌、食道癌、脑肿瘤、卵巢癌、子宫癌、肾癌、头颈癌、皮肤癌、膀胱癌、外阴癌、睾丸瘤、绒毛癌、生殖细胞瘤、恶性淋巴瘤、白血病和多发性骨髓瘤，并且甚至更优选的靶肿瘤可包括结肠癌、直肠癌、胃癌、肺癌、胰腺癌、肝癌、卵巢癌、肾癌、恶性淋巴瘤、乳腺癌以及白血病，但本发明不限于此。
（应用例1、单次腹腔给药新型紫杉类化合物在ICR小鼠的最大耐受量实验）
本应用例是研究实施例1的新型紫杉类化合物Z1单次腹腔给药对ICR小鼠的毒性反应，以确其最大耐受量（maximal tolerance dose，MTD）。
最大耐受量是指动物不会发生死亡，动物的体重降低不会超过10%（与Day 0相比），或者不产生明显毒副作用的剂量。
1、受试物的配制。
受试物溶解所用溶剂来源如下：
无水乙醇，批号10009218，厂商：国药集团化学试剂有限公司。
Cremophor EL，批号27963，厂商：Sigma。
0.9%生理盐水，批号13083004，厂商：华裕制药有限公司。
称取定量对应的受试物于5mL玻璃试管中，在5mm的磁力搅拌子搅拌下溶解于乙醇中，全部溶解后加入Cremophor EL，保持搅拌，临用前加入标示量的生理盐水搅拌均匀，配置时乙醇、Cremophor EL、生理盐水的体积比为5∶5∶90。
2、实验动物。
品种和品系：ICR 小鼠。
级别：SPF。
性别：雌性。
来源：上海斯莱克实验动物有限公司。
合格证号：0130749。
实验开始动物体重：18-20g。
数量和性别：41只。
适应环境时间：5-7天，与实验时相同饲养条件。
动物房环境保持温度18-26℃，相对湿度30-70%，12小时光照。
实验动物用水采用过滤灭菌水，动物自由饮食及饮水。
3、实验方法。
给药方式：IP。如动物死亡则减低剂量，直至动物存活，如无动物死亡，则增加剂量；如在给给定高剂量下动物正常存活则实验结束。最终根据实验结果确定小鼠对受试物的MTD；急性给药后连续观察动物7天。
实验过程中所有动物，对所有的受试动物进行详细临床观察，给药后每天两次（上10：00、下午16：00各一次），连续观察14天，观察包括但不仅限于：皮肤，毛，眼，耳，鼻，口腔，胸腔，腹部，外生殖器，四肢和脚，呼吸道及循环系统，自主效应（如流涎），神经系统（如震颤，抽搐，应激反应以及反常行为）。
给药前称重动物的体重，随后每天在同一时间称量动物的体重并记录。
每天详细记录观察结果、动物体重以及给药一周后动物存活情况。
4、实验结果。
新型紫杉类化合物Z1的MTD剂量为250mg/kg。
（应用例2、单次腹腔注射新型紫杉类化合物对肿瘤的生长抑制作用）
本应用例是研究单次腹腔注射实施例1的新型紫杉类化合物Z1对结肠癌HCT-116荷瘤裸小鼠移植瘤的生长抑制作用。
1、受试物的配制。
受试物溶解所用溶剂来源如下：
无水乙醇，批号10009218，厂商：国药集团化学试剂有限公司。
Cremophor EL，批号27963，厂商：Sigma。
0.9%生理盐水，批号13083004，厂商：华裕制药有限公司。
称取定量对应的受试物于5mL玻璃试管中，在5mm的磁力搅拌子搅拌下溶解于乙醇中，全部溶解后加入Cremophor EL，保持搅拌，临用前加入标示量的生理盐水搅拌均匀，配置时乙醇、Cremophor EL、生理盐水的体积比为5∶5∶90。
2、实验动物。
品种和品系：Balb/c Nude 小鼠。
级别：SPF。
性别：雌性。
来源：上海西普尔-毕凯实验动物有限公司。
动物合格证号：0123627。
实验开始时动物年龄：7-9 周龄。
实验开始时动物体重：18-22克。
适应环境时间：5-7天，与实验时相同饲养条件。
动物房环境保持温度23±2℃，湿度40-70%，12小时明暗交替。
动物饲料（SLAC-M01）购自北京科澳协力有限公司。
实验动物用水采用过滤灭菌水，动物自由饮食和饮水。
3、实验方法。
3.1、肿瘤细胞：结肠癌HCT-116细胞，购于中科院细胞生物研究所。用F-12培养基（含10%的FBS）培养在37℃，饱和湿度，含体积分数为5%CO2 、95%空气的二氧化碳培养箱内。接种前取对数生长期细胞，以0.25%胰蛋白酶消化后，PBS洗涤1次，PBS重新悬浮计数，用不含血清的培养基重新悬浮细胞，调整细胞浓度至约3×107cell/mL。
3.2、动物接种及分组：每个裸鼠在无菌状态下，右侧后肢皮下接种0.1mL细胞悬液（3×106cell/mouse）。待肿瘤长至体积60-150mm3左右时，选出肿瘤体积相近、形状较好的裸鼠（形状尽量为单一圆球形，无不规则的形状或多个肿瘤聚在一起），每组6只。
3.3、动物给药和观察。
（1）观察各组裸鼠接种部位肿瘤的形成状况，每周3次用圆洞尺测量肿瘤结节的直径（D）， 并按如下公式计算肿瘤结节的体积（V）：
V =3/4π（D/2）3。
（2）抗肿瘤活性的评价指标为肿瘤生长抑制率TGI（%），其计算公式为：
TGI（%） = （Vcontrol-VTreatment）/Vcontrol） × 100%。
每周3次称量小鼠体重。
3.4、临床症状。
在实验开始和实验过程中每个动物所有的临床症状都应记录。观察应在每天的同一时间进行。
给予受试物后如出现体重减低＞20%，濒死动物或肿瘤体积超过 2800mm3，则CO2处死，分离肿瘤并称重，尸检，肉眼观察是否有病变器官并记录。
3.5、数据统计。
实验数据除特别指出外，均以Mean±SEM 表示；两组间数据采用非配对T检验，P＜0.05认为有显著性差异。
4、实验结果。
新型紫杉类化合物Z1对人结肠癌HCT-116荷瘤小鼠肿瘤的生长抑制率（TGI%）为85.69%。
Claims (8)
1.一种新型紫杉类化合物，其特征在于其结构如通式（Ⅰ）所示：
（Ⅰ）；
通式（Ⅰ）中，R1为C1～C6烷基；n为0～6。
2.根据权利要求1所述的新型紫杉类化合物，其特征在于：通式（Ⅰ）中，R1为乙基、正丁基或者正己基；n为0～2。
3.根据权利要求2所述的新型紫杉类化合物，其特征在于：通式（Ⅰ）中，R1为正丁基；n为1。
4.权利要求1至3之一所述的新型紫杉类化合物的制备方法，其特征在于具有以下步骤：
S1：先对吉西他滨中的两个羟基进行保护，然后与氯甲酸烷基酯进行缩合反应，接着脱除羟基保护基团，得到中间体G1；
S2：先对步骤S1制得的中间体G1其中一个不与四氢呋喃直接连接的羟基进行保护，采用的保护试剂为叔丁基二甲基氯硅烷，然后再对另一个与四氢呋喃直接连接的羟基进行保护，采用的保护试剂为氯甲酸-2,2,2-三氯乙酯，接着脱除第一个不与四氢呋喃直接连接的羟基脱保基团，得到中间体G2；
S3：将7,10-二（三氯乙氧基甲酰）多西他赛与二酸酐反应得到中间体D1；
S4：将步骤S3制得的中间体D1与步骤S2制得的中间体G2进行缩合反应得到中间体D2；
S5：对步骤S4制得的中间体D2进行羟基脱保护得到目标产物。
5.根据权利要求4所述的新型紫杉类化合物的制备方法，其特征在于：步骤S1中所述的氯甲酸烷基酯为氯甲酸正丁酯。
6.根据权利要求4所述的新型紫杉类化合物的制备方法，其特征在于：步骤S3中所述的二酸酐为戊二酸酐。
7.根据权利要求4所述的新型紫杉类化合物的制备方法，其特征在于：步骤S1中采用的羟基保护试剂为六甲基二硅氮烷。
8.权利要求1至3之一所述的新型紫杉类化合物在制备抗结肠癌药物中的应用。
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| CN102264396A (zh) * | 2008-10-07 | 2011-11-30 | 瑞沙恩医药公司 | Hpma-多西他赛或吉西他滨缀合物及其用途 |
| WO2012004005A1 (en) * | 2010-07-09 | 2012-01-12 | Fresenius Kabi Deutschland Gmbh | Conjugates comprising hydroxyalkyl starch and a cytotoxic agent and process for their preparation |
| CN103002891A (zh) * | 2010-05-10 | 2013-03-27 | 加利福尼亚大学董事会 | 比例计量型组合药物递送 |
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| CN102264396A (zh) * | 2008-10-07 | 2011-11-30 | 瑞沙恩医药公司 | Hpma-多西他赛或吉西他滨缀合物及其用途 |
| CN103002891A (zh) * | 2010-05-10 | 2013-03-27 | 加利福尼亚大学董事会 | 比例计量型组合药物递送 |
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