CN104086554B - 一种新型的完全水溶的光敏剂单体及其制备方法及应用 - Google Patents
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Abstract
本发明涉及一种新型的完全水溶的光敏剂单体，其以叶绿素-a为原料通过脱镁叶绿酸-a直接合成3-去乙烯基-3-（1’-己羟）乙基-脱镁叶绿酸-a甲酯，并经碱金属氢氧化物处理获得结构式所示的水溶性盐，其中，R1、R2、R3为：H或M，且R1、R2、R3不同时为H，M选自Na、K或NH4 +。上述水溶性盐并不改变具备光敏性的大环结构，水溶性好，因而在应用上带来诸多方便，适宜制备用于光动力疗法的药物，用于治疗或诊断：恶性肿瘤（特别是所有管腔内浅表性恶性肿瘤）、癌前病变、良性病变。
Description
技术领域
本发明涉及光动力疗法的药物—光敏剂，具体涉及一种新型的完全水溶的光敏剂单体及其制备方法及应用。
背景技术
作为光动力疗法的新的药物，第二代光敏剂受到普遍关注。以叶绿素为原料制备第二代光敏剂的方法及所得的产品也已经有了很多。ZL01823093.8涉及提取螺旋藻生物质制造二氢卟酚e6、紫红素5和紫红素18的混合物光敏剂。
美国专利第5198460号及其引用的参考文献,通过低温破碎螺旋藻细胞，再进行萃取，层析纯化和再结晶分离得到脱镁叶绿酸-a甲酯，然后在回流温度下在三甲基吡啶中进行热脱羧分离。由此得到的焦脱镁叶绿酸-a甲酯用正己醇和酸处理形成二己基醚基团(部分)。最后皂化去除甲酯，得到3–去乙烯基-3(1'-己羟)乙基-焦脱镁叶绿酸-α，或称为HPPH。HPPH是比二氢卟酚e6更好的光敏剂。但是其过程复杂。
美国7053210B2首先用一种碱性物三甲基酯来处理二氢卟酚e6，加热得到焦脱镁叶绿酸a，在酸性环境中用正己醇处理将其转化为HPPH。其步骤减少，控制条件容易满足，产率高。然而获得二氢卟酚e6也还是要经过一些过程的(如ZL01823093.8)。
发明内容
为了通过简单高效的方法获得新的光敏剂，本发明目的在于以叶绿素-a为原料通过脱镁叶绿酸-a直接合成获得可满足光动力疗法的新物质，以克服已有技术过程复杂的弊端。
本发明首先要实现的目的是提供一种新型的完全水溶的光敏剂。
本发明提供的新型的完全水溶的光敏剂是式Ⅲ、式Ⅳ所示的水溶性盐，
其中，R1、R2、R3为：H或M，且R1、R2、R3不同时为H，M选自Na、K或NH4。
上述的水溶性盐由式Ⅰ、式Ⅱ所示的化合物制备的。由式Ⅰ所示的化合物制得式Ⅲ所示的水溶性盐，由式Ⅱ所示的化合物制得式Ⅳ所示的水溶性盐。
式Ⅰ所示的化合物式和Ⅱ所示的化合物为一对手性化合物，其名称均为3-去乙烯基-3-(1’-己羟)乙基-脱镁叶绿酸-a甲酯，其脱羧后与已有技术所述的HPPH即3–去乙烯基-3(1'-己羟)乙基-焦脱镁叶绿酸-α略有不同。HPPH的结构式如下。
式Ⅰ、式Ⅱ所示的化合物与HPPH具有相同的大环结构，因而同样具有很好的光敏性。但是本发明并不将其作为直接应用的药物，因其水溶性不好，带来应用上的很多限制。因此本发明侧重在将其作为一种中间原料而获得式Ⅲ、式Ⅳ所示的水溶性盐。
式Ⅲ、式Ⅳ所示的水溶性盐也是一对手性化合物，其结构并不改变具备光敏性的大环结构，水溶性好，因而在应用上带来诸多方便，可以极大地促进叶绿素基本结构这一类新光敏剂的发展。
式Ⅲ、式Ⅳ所示的水溶性盐溶解后的水溶液不再有手性特征，为方便计，故可用下述式Ⅴ统一表示。
式Ⅲ或式Ⅳ所示的水溶性盐包含一钠(钾、铵)盐、二钠(钾、铵)盐和三钠(钾、铵)盐，且前两种钠(钾、铵)盐都具有三个同分异构体。考虑手性的话就有六个。
二钠盐的六个同分异构体如下(二钾盐、二铵盐的的情况相同)：
在另一方面，本发明还提供式Ⅰ、式Ⅱ所示的化合物的制备方法，其包括下述步骤：
A)以叶绿素-a为原料制备脱镁叶绿酸-a甲酯；
B)由脱镁叶绿酸-a甲酯制得3-去乙烯基-3-(1’-己羟)乙基-脱镁叶绿酸-a甲酯，即为式Ⅰ和式Ⅱ所示的化合物；
C)纯化，得式Ⅰ和式Ⅱ所示的化合物单体。
上述方法中，在步骤A)，将叶绿素-a浸膏溶解于预先配制好的H2SO4/甲醇混合溶液中，在室温下搅拌3～5h后，将其倒入水中，用有机溶剂萃取，用水洗涤萃取液，去除有机溶剂后的残余物用乙酸乙酯/植物油抽提溶剂结晶；在步骤B)，将脱镁叶绿酸-a甲酯溶解于CH2Cl2中，加入20～40％溴化氢/乙酸溶液，反应混合物在18～25℃搅拌反应3～5h，然后在低于50℃下去除CH2Cl2，所得物用植物油抽提溶剂处理，然后将其溶解于无水CH2Cl2中，加入正己醇、碳酸钾，在室温下搅拌2～5h，将其倒入水中，用有机溶剂萃取，用水洗涤萃取液，去除有机溶剂，残留物经硅胶柱层析分离纯化得黑色固体粉末；在步骤C)，将步骤B)所得用正已烷溶解，压入手性层析柱中，用正已烷/乙醇＝70/30～95/5进行洗脱，将洗脱液分段接收，定性检测后，相应部分分别合并浓缩至干，得式Ⅰ、式Ⅱ所示的化合物。
上述的植物油抽提溶剂为国家标准(GB16629-2008)所指的物质。
具体地，在步骤A)，所述H2SO4/甲醇的体积比浓度为H2SO4占3％～8％；所述用于萃取有机溶剂为CH2Cl2或CHCl3；所述结晶包括先用乙酸乙酯溶解，然后再加入植物油抽提溶剂，乙酸乙酯/植物油抽提溶剂的体积比为3/7～7/3；在步骤B)，所述用植物油抽提溶剂处理包括析晶，洗晶过程。重复2～3次；所述用于萃取有机溶剂为CH2Cl2或CHCl3；所述硅胶柱层析包括：用200～300目硅胶作固定相，用二氯甲烷/乙酸乙酯的体积比为8/1～20/1的混合溶剂作层析的流动相。
另一方面，本发明还提供式Ⅲ、式Ⅳ所示的水溶性盐的制备方法，其包括下述步骤：
D)由式Ⅰ或式Ⅱ所示的化合物单体制得3-去乙烯基-3-(1’-己羟)乙基-脱镁叶绿酸-a甲酯水溶性盐，即分别为式Ⅲ或式Ⅳ所示的化合物；
E)精制纯化，得式Ⅲ或式Ⅳ所示的化合物单体。
上述方法中，在步骤D)将式Ⅰ或式Ⅱ所示的化合物单体溶解于乙腈或丙酮、或四氢呋喃中，加入氢氧化钠、氢氧化钾或氢氧化铵水溶液，混合物在热水浴下超声反应2～3h，将反应液过滤，固体物以水/乙腈、或水/丙酮、或水/四氢呋喃结晶；在步骤E)将步骤D)所得晶体用甲醇溶解，压入反相柱，用碱调PH≥7的甲醇/水或乙腈/水混合液进行洗脱，将洗脱液分段接收，定性检测后，相应部分分别合并浓缩至干，再将浓缩物真空干燥24～36h，得黑色单体产物。
具体地，在步骤D)所述氢氧化钠或氢氧化钾水溶液浓度为0.5～4mol·L-1,氢氧化铵浓度为4.0～8.0mol·L-1；所述热水浴温度为45～55℃；所述以水/乙腈、或水/丙酮、或水/四氢呋喃结晶包括将前述过滤的固体物溶解在水中，之后加入乙腈、或丙酮、或四氢呋喃，搅拌后静置，加入乙腈或丙酮、或四氢呋喃的量为溶解用水量的20～100/1ml/ml，具体比例以产物是三钠(钾、铵)盐、二钠(钾、铵)盐或一钠(钾、铵)盐为基础来衡量。
这里，碱液的浓度、以及反应温度和时间会对产物中成盐的钠(钾、铵)的个数产生影响。因此可以通过控制上述因素和条件来获取不同的反应产物。
在步骤E)所述反相柱使用的填料为C18；所述甲醇/水或乙腈/水混合液的体积比为7/3～3/7。
上述从叶绿素-a开始到最后制得式Ⅲ所示的水溶性盐的反应式如下(以所得产品为3-去乙烯基-3-(1’-己羟)乙基-脱镁叶绿酸-a二钠盐为例)：
其中，Chl-a即Chlorophyll-a，为叶绿素-a，MPPB为脱镁叶绿酸-a甲酯。
本发明还提供用于光动力疗法的药物组合物，其包含式Ⅲ、式Ⅳ所示的水溶性盐和至少一种可药用的辅料。
本发明还提供式Ⅲ、式Ⅳ所示的水溶性盐和上述所述的药物组合物在制备药物中的用途，所述药物用于光动力疗法治疗或诊断：恶性肿瘤、癌前病变、良性病变。
其中所述的恶性肿瘤是实体瘤，特别是所有管腔内浅表性恶性肿瘤。所述的癌前病变是巴雷特氏食管和口腔粘膜白斑；所述的良性病变选自老年性眼底黄斑病变、动脉粥样硬化斑块、类风湿性关节炎、皮肤微血管畸形、牛皮癣和红斑狼疮皮损。
而上述所述的实体瘤选自膀胱癌、食管癌、支气管癌、口腔颌面部癌、鼻咽癌、肋膜间皮瘤、肝癌、胰腺癌、皮肤癌、阴茎癌、宫颈癌、乳腺癌及乳腺癌切除术后皮下转移结节、肛周肿瘤及肛周肿瘤扩大切除术后癌残留、卡波西肉瘤、肺癌、胃癌、胆管癌、前列腺癌、黑色素瘤和脑肿瘤。
根据本发明的式Ⅲ或式Ⅳ所示的水溶性盐的性质，式Ⅲ或式Ⅳ所示的水溶性盐和前述所述的药物组合物制备的药物，其剂型最方便制成：溶液的形式，或者冻干制剂的形式，并且还包含用于将该冻干制剂进行重新配制以进行施用的溶剂。
本发明最后还提供式Ⅰ、式Ⅱ所示的化合物以及式Ⅲ或式Ⅳ所示的水溶性盐的检测方法，
1)、对式Ⅰ、式Ⅱ所示的化合物，用稀释剂超声溶解，用高效液相色谱法，使用手性柱，检测波长407nm，洗脱液为正己烷：无水乙醇(94：6)，稀释剂为正己烷/无水乙醇(94：6)。
具体试验条件：仪器：Agilemt1100高效液相色谱仪，色谱柱：OZ-H手性柱；柱温：35℃，流速：1.0ml/min。试验操作：取本品适量，用稀释剂超声溶解使成2mg/ml的溶液，0.45μ滤膜过滤后，待用。取滤液20μl注入高效液相色谱仪，按上述色谱条件进行洗脱，采集色谱图。
2)、对式Ⅲ或式Ⅳ所示的水溶性盐，用高效液相色谱法，使用反相色谱柱，检测波长为395nm，梯度洗脱，流动相A：K2HPO4水溶液，流动相B：甲醇，稀释剂：水。
对式Ⅲ或式Ⅳ所示的水溶性盐方法使用反相色谱柱，检测波长为395nm，梯度洗脱，流动相A：K2HPO4水溶液，流动相B：甲醇，稀释剂：水。
梯度洗脱按表1洗脱程序进行。
表1
| 时间(min) | 流动相A(％) | 流动相B(％) |
| 0 | 50 | 50 |
| 5 | 50 | 50 |
| 20 | 30 | 70 |
| 25 | 30 | 70 |
| 25.5 | 50 | 50 |
流动相A最好选用浓度为0.016M的K2HPO4水溶液。
具体试验用仪器：Agilent1200高效液相色谱系统；色谱柱ZORBOXSB-AQ250mm×4.6mm5μm；柱温：35℃；流速：1.0ml/min；稀释剂：水；检测波长：395nm。检验操作过程：取本品适量，用水超声溶解使成0.5mg/ml的溶液，0.45μ滤膜过滤后，待用。取滤液5μl注入高效液相色谱仪，按洗脱程序进行洗脱，采集图谱。在同样色谱条件下，出峰顺序为三钠(钾、铵)盐、二钠(钾、铵)盐、一钠(钾、铵)盐。
附图说明
图1是本发明的水溶性盐的一种二钠盐的HPLC图谱。
图2是本发明的水溶性盐的另一种二钠盐的HPLC图谱。
图3是式Ⅰ、式Ⅱ所示的化合物的混合物的HPLC图谱。
图4是式Ⅰ所示的化合物的HPLC图谱。主峰保留时间在10.316min。
图5是式Ⅱ所示的化合物的HPLC图谱。主峰保留时间在14.742min。
具体实施方式
一、脱镁叶绿酸-a甲酯(MPPB)的制备
将叶绿素-a浸膏(100g)溶解于预先配制好的体积比浓度为H2SO4占5％的H2SO4/甲醇混合溶液中，反应混合物在室温下搅拌4h，待原料及中间产物反应完全后，将其倒入水中，用CH2Cl2萃取，用水洗涤有机层，减压蒸除溶剂后的残余物用乙酸乙酯/植物油抽提溶剂(体积比为1/1)结晶。
二、3-去乙烯基-3-(1'-己羟)乙基-脱镁叶绿酸-a甲酯的制备及粗制
将脱镁叶绿酸-a甲酯50g溶解于CH2Cl2(350ml)中，加入30％溴化氢/乙酸溶液(300ml)，反应混合物在20℃左右搅拌反应3～5h，然后真空蒸除溶剂(水浴温度低于40℃)，将其用植物油抽提溶剂处理2次(包括析晶，洗晶过程)，然后将其重新溶解于无水CH2Cl2(750ml)中，加入正己醇(300ml)、碳酸钾(40g)，混合物在室温下搅拌3h，将反应液倒入水中，用CH2Cl2萃取，用水洗涤有机层，减压蒸除溶剂，残留物以200-300目硅胶作固定相，用二氯甲烷/乙酸乙酯的混合溶剂(体积比为10/1)作层析的流动相，层析分离纯化得黑色固体粉末。
三、3-去乙烯基-3-(1’-己羟)乙基-脱镁叶绿酸-a甲酯单体制备
将3-去乙烯基-3-(1’-己羟)乙基-脱镁叶绿酸-a甲酯用正已烷溶解，压入手性层析柱中，用正已烷/乙醇＝9/1进行洗脱，将洗脱液分段接收，定性检测后，相应部分分别合并浓缩至干，得式Ⅰ、式Ⅱ所示的化合物的单体物。检测结果见图3～5。
四、3-去乙烯基-3-(1'-己羟)乙基-脱镁叶绿酸-a钠盐的制备
将柱分离出的3-去乙烯基-3-(1'-己羟)乙基-脱镁叶绿酸-a甲酯同分异构单体(式Ⅰ所示的化合物，或者式Ⅱ所示的化合物，或者式Ⅰ和式Ⅱ所示的化合物的混合物)(200mg)溶解于乙腈(10ml)中，加入2mol·L-1氢氧化钠水溶液0.4ml，混合物在热水浴(设置温度50℃)下超声反应3h，将反应液过滤，过滤晶体以水/乙腈结晶，得钠盐绿色固体。
五、3-去乙烯基-3-(1’-己羟)乙基-脱镁叶绿酸-a甲酯钠盐纯化
将反应所得3-去乙烯基-3-(1’-己羟)乙基-脱镁叶绿酸-a甲酯钠盐，用甲醇溶解，压入反相柱头中，用甲醇/水(体积比为1/1，碱调PH≥7)进行洗脱，将洗脱液分段接收，定性检测后，相应部分分别合并浓缩至干，将浓缩物用真空干燥箱进行干燥24h，得黑色单体3-去乙烯基-3-(1’-己羟)乙基-脱镁叶绿酸-a甲酯单体钠盐，分别可得各种钠盐的化合物单体，取样检测，纯度≥99.5％。见图1和图2。
3-去乙烯基-3-(1’-己羟)乙基-脱镁叶绿酸-a甲酯二钠盐的HRESI-MS测定分子量为743.33699[M+H]+，确定分子式为C40H48N4O7Na2。
紫外吸收光谱的紫外最大吸收峰在λMeOH：204,286,319,396,498,598,652nm。
红外吸收光谱证实见表2：
表2
1H核磁共振谱各个氢的化学位移和偶合常数值(见表3)
表31HNMR数据(MeOD,500MHz)
13C碳核磁共振谱和DEPT谱显示化合物分子中共有40个碳原子，其中：伯碳(CH3)7个，仲碳(CH2)9个，叔碳(CH)6个，季碳(C)18个。
Claims (2)
1.式Ⅲ、式Ⅳ所示的水溶性盐，
其中，R1、R2、R3为：H或M，且R1、R2、R3不同时为H，M选自Na、K或NH4。
2.权利要求1中式Ⅲ或式Ⅳ所示的水溶性盐的制备方法，其特征在于：包括下述步骤：
A)以叶绿素-a为原料制备脱镁叶绿酸-a甲酯：
将叶绿素-a浸膏溶解于预先配制好的H2SO4/甲醇混合溶液中，在室温下搅拌3～5h后，将其倒入水中，用有机溶剂萃取，用水洗涤萃取液，去除有机溶剂后的残余物用乙酸乙酯/植物油抽提溶剂结晶；所述H2SO4/甲醇的体积比浓度为H2SO4占3％～8％；所述用于萃取有机溶剂为CH2Cl2或CHCl3；所述结晶包括先用乙酸乙酯溶解，然后再加入植物油抽提溶剂，乙酸乙酯/植物油抽提溶剂的体积比为3/7～7/3；
B)由脱镁叶绿酸-a甲酯制得3-去乙烯基-3-(1’-己羟)乙基-脱镁叶绿酸-a甲酯，即为式Ⅰ和式Ⅱ所示的化合物：
将脱镁叶绿酸-a甲酯溶解于CH2Cl2中，加入20～40％溴化氢/乙酸溶液，反应混合物在18～25℃搅拌反应3～5h，然后在低于50℃下去除CH2Cl2，所得物用植物油抽提溶剂处理，然后将其溶解于无水CH2Cl2中，加入正己醇、碳酸钾，在室温下搅拌2～5h，将其倒入水中，用有机溶剂萃取，用水洗涤萃取液，去除有机溶剂，残留物经硅胶柱层析分离纯化得黑色固体粉末；所述用植物油抽提溶剂处理包括析晶，洗晶过程，重复2～3次；所述用于萃取有机溶剂为CH2Cl2或CHCl3；所述硅胶柱层析包括：用200～300目硅胶作固定相，用二氯甲烷/乙酸乙酯体积比为8/1～20/1的混合溶剂作流动相；
C)纯化，得式Ⅰ和式Ⅱ所示的化合物单体：
将步骤B)所得物用正已烷溶解，压入手性层析柱中，用正已烷/乙醇＝70/30～95/5进行洗脱，将洗脱液分段接收，定性检测后，相应部分分别合并浓缩至干，得式Ⅰ和式Ⅱ所示的化合物；
D)由式Ⅰ或式Ⅱ所示的化合物单体制得3-去乙烯基-3-(1’-己羟)乙基-脱镁叶绿酸-a甲酯水溶性盐，即分别为式Ⅲ或式Ⅳ所示的化合物：
将式Ⅰ或式Ⅱ所示的化合物单体溶解于乙腈或丙酮、或四氢呋喃中，加入氢氧化钠、氢氧化钾或氢氧化铵水溶液，混合物在热水浴下超声反应2～3h，将反应液过滤，固体物以水/乙腈、或水/丙酮、或水/四氢呋喃结晶；所述氢氧化钠或氢氧化钾水溶液浓度为0.5～4mol·L-1，氢氧化铵浓度为4.0～8.0mol·L-1；所述热水浴温度为45～55℃；所述以水/乙腈、或水/丙酮、或水/四氢呋喃结晶包括将前述过滤的固体物溶解在水中，之后加入乙腈、或丙酮、或四氢呋喃，搅拌后静置，加入乙腈、或丙酮、或四氢呋喃的量为溶解用水量的20～100/1ml/ml；
E)精制纯化，得式Ⅲ或式Ⅳ所示的化合物单体：
将步骤D)所得晶体用甲醇或乙腈溶解，压入反相柱，用碱调PH≥7的甲醇/水或乙腈/水混合液进行洗脱，将洗脱液分段接收，定性检测后，相应部分分别合并浓缩至干，再将浓缩物真空干燥24～36h，得黑色单体产物；所述反相柱使用的填料为C18；所述甲醇/水或乙腈/水混合液的体积比为3/7～7/3；
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| WO1990000895A1 (en) * | 1988-07-20 | 1990-02-08 | Health Research, Inc. | New photosensitizing agents |
| CN1102412A (zh) * | 1994-06-03 | 1995-05-10 | 中国人民解放军第二军医大学 | 二氢卟吩e6醚衍生物及其合成方法 |
| CN101638411A (zh) * | 2001-06-01 | 2010-02-03 | 塞拉莫普泰克工业公司 | 用于光动力学治疗的水溶性卟啉盐的制备方法 |
| CN102268004A (zh) * | 2011-06-21 | 2011-12-07 | 北京普瑞博思投资有限公司 | 一种叶绿酸盐化合物及其制备方法 |
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| WO1990000895A1 (en) * | 1988-07-20 | 1990-02-08 | Health Research, Inc. | New photosensitizing agents |
| CN1102412A (zh) * | 1994-06-03 | 1995-05-10 | 中国人民解放军第二军医大学 | 二氢卟吩e6醚衍生物及其合成方法 |
| CN101638411A (zh) * | 2001-06-01 | 2010-02-03 | 塞拉莫普泰克工业公司 | 用于光动力学治疗的水溶性卟啉盐的制备方法 |
| CN102268004A (zh) * | 2011-06-21 | 2011-12-07 | 北京普瑞博思投资有限公司 | 一种叶绿酸盐化合物及其制备方法 |
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