CN1302780C - 烷基胆碱磷酸在制备用抗肿瘤药之前和/或期间***的药物中的应用 - Google Patents
烷基胆碱磷酸在制备用抗肿瘤药之前和/或期间***的药物中的应用 Download PDFInfo
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Abstract
本发明涉及烷基胆碱磷酸与抗肿瘤药联合用于治疗人和哺乳动物的良性和恶性肿瘤病的应用。烷基胆碱磷酸可以在本发明中与一种或多种批准的细胞抑制剂的组合联合使用。优选的烷基胆碱磷酸由式Ⅱ表示。
Description
烷基胆碱磷酸是一类新的有机化合物，其表现多种抗肿瘤活性(M.Lohmeyer和R.Bittman；Antitumor ether lipids andalkylphosphocholines，DOF，
19(11)，1021-1037(1994))。在这一点上烷基胆碱磷酸的作用可能基于不同的分子和生物化学机理，其中的某些在细胞的质膜水平下发生。已知烷基胆碱磷酸影响肌醇代谢，与磷脂酶的相互作用或蛋白激酶C的抑制作用，因而这类物质对细胞信号转导有普遍的影响(K.Maly，F.berall，C.Schubert，E.Kindler，J.Stekar，H.Brachwitz and H.H.Grunicke，Interference of new alkylphospholipid analogues withmitogenic signal transduction，Anti-Cancer Drug Design，
10，411-425(1995))。因此，烷基胆碱磷酸哌立福辛表现与不同的黑素瘤、CNS、肺、结肠、***和乳腺癌细胞系有关的生长抑制性能，且其IC50范围为0.2-20μM(P.Hilgard，T.Klenner，J.Stekar，G.Nssner，B.kutscher and J.Engel；D-21266，a New HeterocyclicAlkylphospholipid with Antitumor Activity，Eur.J.Cancer，33(3)，442-446(1997))。还已知哌立福辛在细胞周期的G1-S和G2-M期阻断肿瘤细胞(V.Patel，T.Lahusen，T.Sy，E.A.Sausville，J.S.Gutkind and A.M.Senderowicz；哌立福辛，a NovelAlkylphospholipid，Induces p21waf1 Expression in SquamousCarcinoma Cells through a p53-independent Pathway，Leading toLoss in Cyclin-dependent Kinase Activity和Cell Cycle Arrest，Cancer Research
62，1401-1409(2002))。
已知在放射治疗之前或一起使用烷基胆碱磷酸导致肿瘤治疗的协同作用(G.A.Ruitter，M.Verheijl，S.F.Zerp and W.J.vanBlitterswijk；Alkyl-Lysophospholipids as Anticancer Agentsand Enhancers of Radiation-Induced Apoptosis，Int.J.Radiation Oncology Biol.Phys.，49(2)，415-420，2001)。还已报道不同的甘油-3-磷脂，例如ET-18-OCH3，与不同的DNA相互作用物质或微管蛋白结合剂联合增加对不同肿瘤细胞系的体外抗肿瘤活性(A.Noseda，M.E.Berens，J.G.White and E.J.Modest；Invitroantiproliferative activity of combinations of ether lipidanalogs and DNA-Interactive agents against human tumor cells，Cancer Res.，
48(7)，1788-1791(1988)；P.Principe，H.Coulomb，C.Broquet and P.Braquet；Evaluation of combinations ofantineoplastic ether phospholipids and chemotherapeutic drugs，Ant-Cancer Drugs，3(6)，577-587(1992)；P.Principe，H.Coulomb，J.-M.Mencia-Huerta，C.Broquet and P.Braquet；Synergistic cytotoxic effect of aza-alkylphospholipids inassociation with chemotherapeutic drugs，J.Lipid MediatorsCell Signalling，
10(1-2)，171-173(1994))。
现已可以令人惊奇地表明通式I和II的直链烷基胆碱磷酸适于根据本发明与其它治疗人和哺乳动物良性和恶性肿瘤病的药品联合应用。在这一点上可以根据本发明将通式I和II的化合物与抗肿瘤物质联合使用。抗肿瘤物质可以是烷基化试剂、抗代谢物、植物生物碱、铂化合物、肿瘤抗生素和天然激素的激动剂或拮抗剂。抗肿瘤物质可以选自但不限于：顺铂、卡铂、奥沙利铂、博来霉素、多柔比星、甲氨蝶呤、紫杉醇、多西他赛、长春新碱、长春花碱、依托泊苷、替尼泊苷、异环磷酰胺、环磷酰胺、5-氟尿嘧啶、氟达拉滨、吉西他滨和阿糖孢苷。
通式I和II的烷基胆碱磷酸更可能用于主张的与高和低分子量受体和/或胞质激酶抑制剂形式的信号转导抑制剂联合。这些抑制剂可以选自但不限于单克隆抗体和杂环化合物。作为本发明基础的通式I和II的烷基胆碱磷酸可以呈制成的药品形成使用。
作为本发明基础的化合物由通式I和II描述：
其中，彼此独立地：
n、m、p、z为0-4的整数；
x为O、S、NH；
R为H、直链或支链(C1-C20)-烷基，所述基团可以是饱和的或1-3个双键和/或叁键不饱和的，并可以未被取代或任选在相同或不同的C原子上被1、2或更多个卤素、硝基、氰基、羟基、(C1-C6)-烷氧基、氨基、单-(C1-C4)-烷基氨基或二-(C1-C4)-烷基氨基取代；
R1、R2、R3彼此独立地为H、直链或支链(C1-C6)-烷基，优选甲基和乙基、(C3-C7)-环烷基，且它可以未被取代或任选在相同或不同的C原子上被1、2或更多个卤素、硝基、氰基、羟基、(C1-C6)-烷氧基、氨基、单-(C1-C4)-烷基氨基或二-(C1-C4)-烷基氨基取代。
根据本发明的另一方面，提供一种控制人和哺乳动物的肿瘤的方法，它包括给人或哺乳动物施用一定数量的至少一种作为本发明基础的通式I和II的化合物，以有效地在用批准的抗肿瘤物质治疗之前或期间进行肿瘤治疗。
待施用以进行治疗的作为本发明基础的通式I和II的特定化合物的治疗有效剂量取决于肿瘤病的性质和阶段，患者的年龄和性别，给药方式和治疗持续时间。
作为本发明基础的化合物可以液体、半固体和固体药物形式的药品给药。采取以下形式以适于每种情况的方式发生：气溶胶、口服散剂、撒粉和撒布粉、未包衣片剂、包衣片剂、乳剂、泡沫、溶液、悬浮液、凝胶、软膏、糊剂、丸剂、锭剂、胶囊或栓剂。
例举性实施方案：
1.哌立福辛(D-21 266)与顺铂联合给药
体内试验：DMBA诱导的大鼠乳腺癌模型
实验动物：Sprague-Dawley大鼠，雌性
方法：
通过单一口服剂量的DMBA诱导乳腺癌。动物在第0天至第14天接受哌立福辛，并观察至第42天。通过触诊并与塑料模型进行比较来估计肿瘤物的重量。最初的重量设为100％。
给药：哌立福辛14×6.81mg/kg p.o.
顺铂 4×1mg/kg i.p。
效果：
通过联合治疗比通过各药物单一治疗导致的肿瘤的减少明显较多和时间较长。
治疗 肿瘤 第21天 相对于对照的p试验
最初重量[g] 变化[％]
对照 1.0 875 -
哌立福辛(D-21266) 0.9 -25 ＜0.001
顺铂 0.9 410 0.120
哌立福辛(D-21266) 0.8 -75 ＜0.001
+顺铂
2.哌立福辛与环磷酰胺联合给药
体内试验：DMBA诱导的大鼠乳腺癌模型
实验动物：Sprague-Dawley大鼠，雌性
方法：
通过单一口服剂量的DMBA诱导乳腺癌。动物在第0天至第14天接受哌立福辛，并观察至第42天。通过触诊并与塑料模型进行比较来估计肿瘤物的重量。最初的重量设为100％。
给药：哌立福辛14×6.81mg/kg p.o.
环磷酰胺 100mg/kg，VZ 0，i.v.
效果：
通过联合治疗比通过各药物单一治疗导致的肿瘤的减少明显较多和时间较长。
治疗 肿瘤 第21天 相对于对照的p
最初重量[g] 变化[％] 试验
对照 1.0 875 -
哌立福辛(D-21266) 0.9 -25 ＜0.001
环磷酰胺 0.9 500 0.011
哌立福辛(D-21266) 0.8 -83.3 ＜0.001
+环磷酰胺
3.哌立福辛与阿霉素联合给药
体内试验：DMBA诱导的大鼠乳腺癌模型
实验动物：Sprague-Dawley大鼠，雌性
方法：
通过单一口服剂量的DMBA诱导乳腺癌。动物在第0天至第14天接受哌立福辛，并观察至第42天。通过触诊并与塑料模型进行比较来估计肿瘤物的重量。最初的重量设为100％。
给药：哌立福辛14×6.81mg/kg p.o.
阿霉素 4×2.15mg/kg i.p.
效果：
通过联合治疗比通过各药物单一治疗导致的肿瘤的减少明显较多和时间较长。
治疗 肿瘤 第21天 相对于对照的p
最初重量[g] 变化[％] 试验
对照 1.0 875 -
哌立福辛(D-21266) 0.9 -25 ＜0.001
阿霉素 1.0 781.3 0.197
哌立福辛(D-21266) 0.10 -70 ＜0.001
+阿霉素
Claims (9)
1.通式II的烷基胆碱磷酸用于制备在用抗肿瘤药治疗之前和/或期间治疗良性和恶性肿瘤病的药物的应用，
其中，彼此独立地：
n、m、p、z为0-4的整数；
x为O、S、NH；
R为H、直链或支链(C1-C20)-烷基，所述基团可以是饱和的或1-3个双键和/或叁键不饱和的，并可以未被取代或任选在相同或不同的C原子上被1、2或更多个卤素、硝基、氰基、羟基、(C1-C6)-烷氧基、氨基、单-(C1-C4)-烷基氨基或二-(C1-C4)-烷基氨基取代；
R1、R2彼此独立地为H、直链或支链(C1-C6)-烷基，优选甲基和乙基、(C3-C7)-环烷基，且它可以未被取代或任选在相同或不同的C原子上被1、2或更多个卤素、硝基、氰基、羟基、(C1-C6)-烷氧基、氨基、单-(C1-C4)-烷基氨基或二-(C1-C4)-烷基氨基取代。
2.如权利要求1所要求的通式II的烷基胆碱磷酸用于制备在用抗肿瘤药治疗之前和/或期间治疗良性和恶性肿瘤病的药物的应用，
其中，彼此独立地：
m、p为整数1；
n、z为整数2；
X为0；
R为H、直链或支链(C1-C17)-烷基，所述基团可以是饱和的或1-3个双键和/或叁键不饱和的；
R1、R2彼此独立地为H、直链或支链(C1-C6)-烷基，优选可以为甲基和乙基、(C3-C7)-环烷基。
3.如权利要求1所要求的1，1-二甲基哌啶子基-4-基磷酸十八烷基酯用于制备在用抗肿瘤药治疗之前和/或期间治疗良性和恶性肿瘤病的药物的应用。
4.如权利要求1-3任一项所要求的通式II的烷基胆碱磷酸的应用，其中抗肿瘤药可以是烷基化试剂、抗代谢物、植物生物碱、铂化合物、肿瘤抗生素和天然激素的激动剂或拮抗剂。
5.如权利要求4所要求的应用，其中抗肿瘤药可以为顺铂、环磷酰胺或阿霉素。
6.如权利要求1-3任一项所要求的通式II的烷基胆碱磷酸的应用，其中抗肿瘤药可以是高和低分子量受体激酶和/或胞质激酶抑制剂形式的信号转导抑制剂。
7.如权利要求6所要求的应用，其中所述抑制剂可以是单克隆抗体或杂环化合物。
8.如权利要求1-3任一项所要求的式II的烷基胆碱磷酸用于制备在用抗肿瘤药治疗之前和/或期间治疗良性和恶性肿瘤病的药品的应用，其中该药品除了包含式II的烷基胆碱磷酸以外，还包含常规的药用载体、赋形剂和/或稀释剂。
9.一种药品，其包含至少一种通式II的烷基胆碱磷酸，还任选包含载体和/或赋形剂，用于在用抗肿瘤药治疗之前和/或期间治疗良性和恶性肿瘤病。
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| US8703179B2 (en) | 2006-05-11 | 2014-04-22 | Kimberly-Clark Worldwide, Inc. | Mucosal formulation |
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| US20120128732A1 (en) * | 2008-12-11 | 2012-05-24 | Vuong Trieu | Combinations and modes of administration of therapeutic agents and combination therapy |
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