CN115385875A - 一类紫杉醇衍生物及其制备方法和用途 - Google Patents
一类紫杉醇衍生物及其制备方法和用途 Download PDFInfo
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- CN115385875A CN115385875A CN202210841952.0A CN202210841952A CN115385875A CN 115385875 A CN115385875 A CN 115385875A CN 202210841952 A CN202210841952 A CN 202210841952A CN 115385875 A CN115385875 A CN 115385875A
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- taxol
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Abstract
本发明涉及医药领域,具体涉及一类水溶性紫杉醇衍生物及其制备方法和用途。一类可在血浆中降解,水溶性明显增加的紫杉醇衍生物。通过共价键将含有磷酸和磺酸基团的小分子羧酸与难溶性药物紫杉醇结合,因磷酸和磺酸基团具有极强的亲水性,得到的紫杉醇衍生物水溶性明显增强;而且此种衍生物可在血浆中降解成原料紫杉醇。
Description
技术领域
本发明涉及医药领域,具体涉及一类紫杉醇衍生物及其制备方法和用途。
背景技术
紫杉醇是从太平洋红豆杉又称短叶红豆杉(Taxus brevifolia)树皮中提取分离出的一种天然产物。1992年12月29日,美国食品药品管理局(FDA)批准紫杉醇上市,商品名为Taxol,用于治疗卵巢癌。紫杉醇由于其复杂的化学结构和众多的疏水性基团致使其水溶性很差,水中溶解度为0.25μg/mL(Bioorganic&Medicinal Chemistry.1993,3,1357),限制了其临床应用;市售处方以无水乙醇与聚氧乙烯蓖麻油(Cremphor EL)的等体积混合溶液来提高紫杉醇的溶解度,注射给药时,仍需要以5%葡萄糖溶液或生理盐水稀释,而聚氧乙烯蓖麻油降解时,使机体释放组胺,患者使用后,会产生面红、心跳过速、呼吸困难等严重过敏反应。
一种增加紫杉醇溶解性的方法是在其2’位引入含二硫键的结构以形成自组装纳米粒(Nat Commun.2019.19,3211),但此种解决方案需要引入较大基团进而导致紫杉醇衍生物的降解过程复杂,降解产物种类较多,因此存在潜在的安全风险。另一种常用的方法是在紫杉醇的2’或7位通过酯键连接各种有机酸或氨基酸;这类改性技术的优点是得到的紫杉醇衍生物水溶性有一定提高,但同时其在体内过于稳定,不易降解产生紫杉醇。通过增加有机酸的极性以期得到水溶性明显增加的紫杉醇衍生物,同时其降解速率或可大幅提高。但有机酸的大极性又会使其很难通过直接的酯化等缩合反应得到相应的紫杉醇衍生物;所以大极性的有机酸对紫杉醇的修饰很难进行,需要对大极性有机酸进行特别的修饰并找到合适的纯化方法。
发明内容
为了解决上述技术问题,本发明通过对不易形成酯键的大极性小分子羧酸进行修饰得到小极性羧酸,进而与紫杉醇缩合并脱保护基得到了一类可在血浆中快速降解,水溶性明显增加的紫杉醇衍生物。
其中磷酸和磺酸有极强的亲水性,通过共价键将磷酸或磺酸基团与紫杉醇结合,可明显增强其水溶性。
本发明的目的在于提供一类如下通式(Ⅰ)所示的紫杉醇衍生物,其药学上可接受的盐或其溶剂化物;
本发明的另一个目的是提供含有上述紫杉醇衍生物的钠盐、钾盐、锂盐、钙盐、铵盐;
本发明的还一目的在于提供上述紫杉醇衍生物的制备方法和上述紫杉醇衍生物在注射制剂中的用途。
本发明人设计和合成了一系列新的如下面通式(Ⅰ)所示的含有紫杉醇衍生物、其药学上可接受的盐或其溶剂化物:
其中R3取自C1-C6烷基、C3-C5链烯基、C3-C6环烷基、-OH、-COOH、-CN;
m取自0、2、3、4、5;
n取0、1、2、3、4、5。
进一步的本发明所述的一类紫杉醇衍生物,其中R3取自C1-C3烷基、C3-C5链烯基、C3-C5环烷基、-OH、-COOH、-CN;
m取自0、2、3;
n取自0、1、2、3。
m取自0、2、3;
n取自0、1、2、3。
在本发明最优选的实施方案中,所述的一类紫杉醇衍生物为如下化合物:
本发明涉及的化合物可以按如下路线制备:
R3和n的定义与权利要求4的定义相同
1)以具有通式B2所示的已知原料,分别与甲醇和苯甲醇反应,然后用碱水解得以通式B1所示的中间体;
2)以具有通式B1所示的中间体与A2缩合,后经还原脱苄基得到通式C1所示化合物;
3)以具有通式B1所示的中间体与D2缩合,后经还原脱苄基得到通式D1所示化合物;其中碱选自氢氧化钠、氢氧化钾、氢氧化镁、氢氧化钙;还原剂选自氢气、甲酸铵;
有益效果
本发明合成全新的化合物,该化合物未见文献报道。同时本发明发现对紫杉醇取代都在2’或7位取代为形成酯键,但只有特定的羧酸才可以实现代谢速度合适、生物相容性好的功能。
附图说明
图1:小鼠存活率a)注射化合物C1,b)注射化合物A1,c)注射紫杉醇注射液,d)注射白蛋白结合型紫杉醇。
图2:紫杉醇衍生物体外血浆降解a)化合物A1,b)化合物C1
具体实施方式
为了使本发明的目的和技术方案更加清楚,下面对本发明的优选实施例进行详细的描述。要说明的是:以下实施例只用于对本发明进行进一步的说明,而不能理解为对本发明保护范围的限制。本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。
实施例1紫杉醇-2’-磺基乙酸酯(A1)的合成
冰浴条件下,依次将4-二甲氨基吡啶(0.8eq,22.9mg)、A3(1.0eq,32.8mg)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.0eq,44.9mg)、1-羟基苯并三唑(0.8eq,25.3mg)以及二氯甲烷加入应瓶中;氩气置换并氩气保护,冰浴搅拌2小时后加入原料A2;升至室温反应2天;分别用稀盐酸和水洗涤,蒸干有机相后制备液相纯化得产物A1。1HNMR(500MHz,DMSO-d6)δ9.13(d,J=8.1Hz,1H),8.00(d,J=7.3Hz,2H),7.89(d,J=7.4Hz,2H),7.73(t,J=7.3Hz,1H),7.66(t,J=7.5Hz,2H),7.57-7.36(m,7H),7.21-7.14(m,1H),6.31(s,1H),5.85(t,J=8.8Hz,1H),5.52(t,J=8.4Hz,1H),5.42(d,J=7.1Hz,1H),5.38(d,J=8.4Hz,1H),4.92(d,J=9.3Hz,1H),4.13(m,1H),4.01(dd,J=16.1,8.3Hz,2H),3.70-3.51(m,3H),2.39-2.28(m,1H),2.23(s,3H),2.10(s,3H),1.85(dd,J=15.3,9.9Hz,1H),1.80(s,3H),1.68-1.55(m,2H),1.50(s,3H),1.02(d,J=7.0Hz,6H).
实施例2 3-(双(苄基氧基)磷基)丙酸(B1)的合成
第一步
室温条件下,依次将原料B2(500.0mg),甲醇10mL加入反应瓶中;室温搅拌3天后将甲醇蒸干,得白色固体。
室温条件下,依次向上述固体中加入5mL SOCl2和5滴DMF,60℃反应1小时后蒸干得油状物。用12.5mL二氯甲烷将上述油状物转入50mL反应瓶中,冰浴降温;冰浴条件下,依次向其中滴加吡啶(1.0eq,256.7mg)的二氯甲烷溶液5.5mL和溶液A(N,N-二异丙基乙胺(6.0eq,2516.0mg)和苯甲醇(2.5eq,877.2mg)溶于15mL二氯甲烷);
滴毕,撤去冰浴并继续搅拌12小时,向反应液中补加二氯甲烷至40mL,用稀盐酸洗涤反应液至洗出的水层显酸性;将有机相蒸干,柱层析得中间体B3。MS m/z[M+H]+349.1205.
第二步
室温,依次将中间体B3(1.0eq,836.0mg)、30mL四氢呋喃加入反应瓶中,冰浴降温,滴加3mL 40mg/mL的氢氧化钠溶液;撤去冰浴后继续搅拌3.5小时;补加30mL水后蒸去四氢呋喃,得到溶液用二氯甲烷洗涤,水层用稀盐酸调pH小于1;得到的溶液用20mL二氯甲烷萃取蒸干有机相得到产物B1。MS m/z[M-H]-333.0890.1HNMR(500MHz,CDCl3)δ7.38-7.28(m,10H),5.08-5.01(m,2H),4.96(dd,J=11.7,8.3Hz,2H),2.63-2.52(m,2H),2.15-2.04(m,2H).
实施例3紫杉醇-2’-磷酸乙基酯的合成
第一步
室温条件下,将中间体B1(0.8eq,162.0mg)、100mL二氯甲烷加入反应瓶中,冰浴降温;向上述反应中加入1-羟基苯并三唑(1.1eq,90.0mg)、4-二甲氨基吡啶(1.5eq,111.0mg)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.5eq,174.1mg);冰浴条件下继续搅拌5小时;加入原料A2(1.0eq,517.1mg)并撤去冰浴,室温反应3小时。分别用稀氢氧化钠溶液,稀盐酸以及水洗有机相,蒸干有机相后经柱层析纯化得中间体C2。1HNMR(500MHz,MeOD)δ8.12(d,J=7.7Hz,2H),7.81(d,J=7.8Hz,2H),7.66(t,J=7.3Hz,1H),7.57(t,J=7.6Hz,2H),7.51(t,J=7.4Hz,1H),7.48-7.38(m,7H),7.37-7.24(m,11H),6.45(s,1H),6.11(t,J=9.1Hz,1H),5.87(d,J=5.6Hz,1H),5.65(d,J=7.1Hz,1H),5.45(d,J=5.6Hz,1H),4.95(m,5H),4.34(dt,J=17.4,8.6Hz,1H),4.20(s,2H),3.83(d,J=7.1Hz,1H),2.74-2.60(m,2H),2.52-2.43(m,1H),2.39(s,3H),2.24(dd,J=15.5,9.4Hz,1H),2.19-2.09(m,5H),1.97-1.87(m,4H),1.81(t,J=12.6Hz,1H),1.66(s,3H),1.14(d,J=4.3Hz,6H).
第二步
室温,依次将中间体C2(1.0eq,51.2mg),甲醇加入反应瓶中;再加入甲酸铵(10.0eq,27.6mg)的水溶液、10%Pb/C(10.2mg);氩气置换并氩气保护,升至50℃反应30分钟后过滤,滤液经制备液相纯化得产物C1。1HNMR(400MHz,DMSO-d6加重水)δ7.96(d,J=7.6Hz,2H),7.83(d,J=7.5Hz,2H),7.75-7.61(m,3H),7.59-7.37(m,7H),7.21-7.10(m,1H),6.27(s,1H),5.81(t,J=9.2Hz,1H),5.53-5.46(m,1H),5.39(d,J=7.1Hz,1H),5.30(d,J=9.0Hz,1H),4.90(d,J=9.4Hz,1H),4.09(dd,J=10.8,6.9Hz,1H),3.99(s,2H),3.57(d,J=7.1Hz,1H),2.42-2.26(m,1H),2.21(s,3H),2.08(s,3H),1.85-1.71(m,4H),1.68-1.56(m,3H),1.56-1.49(m,1H),1.47(s,3H),0.99(s,3H),0.98(s,3H).
31PNMR(162MHz,DMSO-d6)δ20.09.MS m/z[M-H]–988.3145.
实施例4紫杉醇-7-磷酸乙基酯(D1)的合成
第一步
室温,将苯甲氧羰酰琥珀酰亚胺(4.0eq,116.7mg)的5mL四氢呋喃溶液滴入含有原料A2(1.0eq,100.0mg)、三乙胺(8.0eq,94.8mg)的3mL四氢呋喃溶液中;室温反应2天,蒸干,柱层析纯化得中间体D2。
第二步
室温,将4-二甲氨基吡啶(1.0eq,12.4mg)、中间体D2(1.0eq,100.0mg)、N,N'-二环己基碳二亚胺(2.5eq,52.2mg)、中间体B1(2.5eq,84.6mg),二氯甲烷加入反应瓶中,氩气置换并氩气保护,室温反应1小时。
过滤滤液依次用稀盐酸,稀氢氧化钠溶液及水洗,蒸干有机相后柱层析纯化得中间体D3。1H NMR(400MHz,DMSO-d6)δ9.30(d,J=8.2Hz,1H),7.99(d,J=7.5Hz,2H),7.84(d,J=7.4Hz,2H),7.75(t,J=7.2Hz,1H),7.67(t,J=7.5Hz,2H),7.61-7.28(m,22H),7.20(t,J=6.5Hz,1H),6.03(s,1H),5.82(t,J=8.8Hz,1H),5.51(t,J=8.7Hz,1H),5.48-5.34(m,3H),5.23(q,J=12.2Hz,2H),5.09-4.88(m,5H),4.74(s,1H),4.05(s,2H),3.67(d,J=6.9Hz,1H),2.45-2.32(m,3H),2.27(s,3H),2.12-1.96(m,5H),1.85-1.56(m,8H),1.50(dd,J=15.1,8.9Hz,1H),1.00(d,J=17.7Hz,6H).
第三步
室温条件下,向反应瓶中加入中间体D3(1.0eq,100.0mg),甲醇及甲酸铵(15.0eq,72.6mg)的水溶液,再加入10%Pb/C 40.0mg;氩气置换后升温至50℃反应1小时,过滤,蒸干滤液,制备液相纯化得产物D1。
实施例5细胞毒性测定
采用CCK8法考察产物对4T1细胞和A549细胞的细胞毒性,将细胞(3000个/孔)接种到96孔板中,37℃二氧化碳培养箱内培养24小时。弃去培养液,加入用新鲜培养液稀释的不同浓度的白蛋白结合紫杉醇、产物A1或产物C1。于加药后24小时或48小时,将96孔板取出,每孔加入10μL CCK8后继续于37℃二氧化碳培养箱内培养3小时,使用酶标仪在450nm处测定各孔的吸光度值并计算存活率。通过SPSS软件计算半数抑制浓度(IC50值)。
表1
以上结构显示,化合物C1对4T1细胞的IC50值是对照药白蛋白紫杉醇的1/6,对A549细胞的IC50值是对照药白蛋白紫杉醇的2倍,表明化合物C1对部分癌细胞的毒性要好于白蛋白结合型紫杉醇。
实施例6溶解度测定
称取本发明化合物20.0mg,加入0.5mL水,超声30分钟,19800g离心30分钟后经高效液相测定。
表2
化合物 | 溶解度(mg/ml) |
A1 | 28.3 |
C1 | 28.7 |
D1 | 0.35 |
紫杉醇 | 0.00025 |
实施例7考察样品在各注射用溶剂中的降解情况
称取化合物5.0mg,用不同注射用溶剂配制成浓度100μg/mL的溶液;于特定时间点取样,高效液相测定有关物质含量,进而计算各物质的水解反应速率常数。
表3
注:紫杉醇是原料药,在上述溶剂中不溶,故其反应速率常数无法测定
实施例8考察样品在血浆中的降解情况
向360μL血浆中加入40μL紫杉醇衍生物(A1或C1)的水溶液(1mg/mL),涡旋混匀后放入摇床37℃,100rpm;于特定时间点取样,样品加入2倍体积乙腈后涡旋1min;15000rpm,4℃离心15min后取上清液经液相测定。
结果显示:化合物A1和C1在血浆中的降解主要产物为紫杉醇;化合物A1在3小时内降解近97%,化合物C1在10小时内降解近90%。
实施例9考察样品在小鼠体内的毒性
使用18-22g Balb/c小鼠用于样品的毒性研究,每个剂量6只小鼠;将A1、C1溶解在5%葡萄糖中分别配制成2.0mg/mL和5.0mg/mL溶液,将白蛋白结合紫杉醇、紫杉醇注射液用5%葡萄糖稀释成的浓度分别为5.0mg/mL和1.2mg/mL;白蛋白结合紫杉醇和产物C1的给药量为100、132、174、229、302、400mg/kg;产物A1的给药量为50、63、79、100、126、160mg/kg;紫杉醇注射液的给药量为10、15、22、33、48、72mg/kg。结果表明A1、C1、白蛋白结合紫杉醇和紫杉醇注射液的最大耐受剂量分别为160mg/kg、174mg/kg、174mg/kg和23mg/kg。
对比例1
Luo等(Small.2016.12,635)报道了紫杉醇2’位引入油酸基团得到的PTX-OA和PTX-S-S-OA的紫杉醇的羧酸衍生物。但这种衍生物并不能直接增加水溶性,而且PTX-OA体外并不能降解产生紫杉醇;而PTX-S-S-OA需要加入特定的物质二硫苏糖醇才能促进其降解。
对比例2
Sun等(Nat Commun.2019.19,3211)报道了紫杉醇2’位引入不同基团得到的紫杉醇羧酸衍生物。但此紫杉醇衍生物只能形成纳米粒,并不能增加其水溶性。并且PTX-C-CIT和PTX-C-C-CIT体外几乎不降解,而PTX-S-CIT、PTX-S-S-CIT、PTX-Se-CIT和PTX-Se-Se-CIT体外降解需要加入特定物质二硫苏糖醇或双氧水。
对比例3
冰浴条件下,将4-二甲氨基吡啶(4.0eq,57.2mg)、B2(4.0eq,72.2mg)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(4.0eq,87.8mg)、1-羟基苯并三唑(2.0eq,31.7mg)以及二氯甲烷加入应瓶中;氩气置换并氩气保护,冰浴活化2小时后加入原料A2(1.0eq,100.0mg);升至室温反应4天;分别用稀盐酸和水洗涤,液相检测并未发现主产物生成。
Claims (7)
2.根据权利要求1所述的一类紫杉醇衍生物及药效可接受的盐,其特征在于:其中R3取自C1-C3烷基、C3-C5链烯基、C3-C5环烷基、-OH、-COOH、-CN;
m取自0、2、3;
n取自0、1、2、3。
7.根据权利要求6的方法,其特征在于,步骤1)所述碱选自氢氧化钠、氢氧化钾、氢氧化镁、氢氧化钙;还原剂选自氢气、甲酸铵。
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CN111777577A (zh) * | 2020-07-01 | 2020-10-16 | 天津仁雨生物科技有限公司 | 一类紫杉醇衍生物及其在制备防治人恶性肿瘤药物中的用途 |
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