CN1244123A - 用于抑制癌生长的药盒,含有化疗剂和苯并咪唑并任选地含有增效剂 - Google Patents
用于抑制癌生长的药盒,含有化疗剂和苯并咪唑并任选地含有增效剂 Download PDFInfo
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- CN1244123A CN1244123A CN98802043A CN98802043A CN1244123A CN 1244123 A CN1244123 A CN 1244123A CN 98802043 A CN98802043 A CN 98802043A CN 98802043 A CN98802043 A CN 98802043A CN 1244123 A CN1244123 A CN 1244123A
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Abstract
本发明涉及抑制哺乳动物中肿瘤和癌生长的方法,该方法包括,施用化疗剂以明显缩小肿块中的肿瘤,然后施用苯并咪唑衍生物。该苯并咪唑衍生物中还可以含有增效剂。
Description
技术领域
本发明涉及在哺乳动物、特别是人和温血动物中抑制癌和肿瘤生长的方法。该方法包括，按顺序施用可以缩小肿瘤大小的化疗剂和苯并咪唑衍生物、优选苯咪氨甲酯或2-甲氧羰基氨基苯并咪唑，上述两类药物可以以任何顺序施用。
发明背景
癌症是动物和人类的主要死因。引起癌症的确切原因并不清楚，但大量研究人员已经证实了某些活动如吸烟或接触致癌物和某些类型的癌症和肿瘤发生率之间的联系。
已证实了许多种类型的化疗剂对癌症和肿瘤细胞是有效的，但不幸的是，许多这样的药物也会破坏正常的细胞。尽管在癌症治疗领域取得了进展，但目前的主要治疗方法仍是手术、放疗和化疗。化疗方法用于对抗转移的癌症或特别具有攻击性的癌症。杀细胞剂或细胞生长抑制剂对具有大量生长因子的癌症、即细胞迅速***的癌症特别有效。这些化疗剂的确切作用机制通常并不清楚。此外，尽管某些化疗剂在给药一次后可以明显减小肿瘤的体积，但不幸的是，当肿瘤复发(经常会出现的情况)时不能将其再次施用给同一患者。某些药物一生只能给药一次，其它药物则需要在各次治疗之间间断数月或数年。
很明显，开发出由于对肿瘤细胞具有特异性而可以靶向肿瘤细胞的物质将是突破性的。或者，对肿瘤细胞具有细胞毒性而对正常细胞仅有轻微影响的物质也将是适宜的。现已发现，苯并咪唑类化合物对于抑制癌症和肿瘤的生长特别有效。将这些苯并咪唑类化合物与其它可以有效减小肿瘤体积的化疗剂顺序并用是一种新的治疗方法。优选的方法包括，首先用细胞毒剂减小肿瘤的质量，然后施用苯并咪唑类化合物。
本发明的目的是提供一种抗癌疗法，该方法包括，首先施用化疗剂以减小肿瘤的质量，然后施用本文所定义的苯并咪唑衍生物以维持或破坏癌瘤。也可以先施用苯并咪唑，然后施用化疗剂。
可将苯并咪唑与增效剂一起给药。
通过以下对本发明的详细描述，这些以及其它的目的将更为明显。
发明概述
本发明涉及一种在哺乳动物、特别是温血动物和人中治疗癌症的方法，该方法包括，施用可以明显减小肿瘤或癌质量的化疗剂，然后施用安全、有效量的苯并咪唑衍生物，所述苯并咪唑衍生物选自：
其中X是氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基；n是小于4的正整数；Y是氢、氯、硝基、甲基或乙基；R是氢、1-8个碳原子的烷基或CONHR3并且R3是少于7个碳原子的烷基，优选丁基或异丁基；R2是4-噻唑基、NHCOOR1，其中R1是少于7个碳原子的脂族烃基，优选少于7个碳原子的烷基。
优选的苯并咪唑类化合物是：
其中R是氢、CONHR3并且R3是少于7个碳原子的烷基，优选丁基或异丁基或1-8个碳原子的烷基；R2选自4-噻唑基、NHCOOR1，其中R1是甲基、乙基或异丙基，及其与有机或无机酸形成的无毒的可药用酸加成盐。最优选的化合物是2-(4-噻唑基)苯并咪唑、甲基-(丁基氨基甲酰基)-2-苯并咪唑氨基甲酸酯和2-甲氧羰基氨基-苯并咪唑以及其中Y是氯的化合物。
可以将有效量的所述化合物通过口服、直肠、局部或胃肠外、静脉内给药或通过注射到肿瘤内部来抑制人或动物中癌症和其它肿瘤的生长。可将增效剂与该化合物一起使用。
发明详述
A.定义
本文所用的术语“含有”指的是可将各种成分联合用于本发明的药物组合物。因此，术语“基本由……组成”和“由……组成”是术语“含有”具体化的形式。
本文所用术语“可药用”成分是指该成分适用于人和/或动物而不会引起超出了与合理的有益效果/危险性比相称的不利副反应(例如毒性、刺激和过敏反应)。
本文所用术语“安全和有效量”是指当以本发明的方式使用时，足以产生所需的治疗效果而不会引起超出了与合理的有益效果/危险性比相称的不利副反应(例如毒性、刺激和过敏反应)的某成分的量。很明显，具体的“安全和有效量”随所治疗的具体病情、患者的生理状况、所治疗的哺乳动物的种类、治疗的持续时间、同时进行的治疗(如果有的话)的性质、所用的具体制剂以及化合物或其衍生物的结构等因素而改变。
本文所用的“可药用加成盐”是苯并咪唑类化合物及其衍生物与有机或无机酸形成的盐。优选的酸加成盐是氯盐、溴盐、硫酸盐、硝酸盐、磷酸盐、磺酸盐、甲酸盐、酒石酸盐、马来酸盐、苹果酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等。
本文所用的“可药用载体”是指用于向动物或人传递抗癌剂的可药用溶剂、悬浮剂或赋形剂，包括脂质体。载体可以是液体或固体的并且根据准备采用的给药方式进行选择。
本文所用术语“癌症”指的是见于哺乳动物的各种类型的癌症或肿瘤或恶性肿瘤，包括瘤和白血病。
本文所用的“苯并咪唑类化合物及其盐”将在以下详细说明。优选的物质是由BASF和Hoechst、DuPont和MSD-AgVet以商品名“噻苯咪唑”“Benomyl”和“苯咪氨甲酯”出售的产品。
本文所用的“化疗剂”包括与DNA相互作用的药物、抗代谢剂、与微管蛋白相互作用的药物、激素药物以及其它药物如天冬酰胺酶或羟基脲。
本文所用的“增效剂”是指与化疗剂和苯并咪唑类化合物联用的物质如吡咯吡胺及其顺式异构体以及苯咪唑丙酸。
本文所用的“明显减小”是指使肿瘤的质量明显减小。通常小于其最初质量的50％，优选使质量减小至不可检测的量。
B.苯并咪唑类化合物
已知苯并咪唑衍生物具有抗真菌活性。令人惊奇的是，现已发现这些化合物还可以引起癌细胞系的程序性死亡。程序性死亡是不同于坏死的特殊的细胞死亡。大部分的癌细胞均可以无限制的存活，癌细胞通常被称为是不死的细胞系。因此，引起细胞程序性死亡的能力是非常重要的。
所述化合物具有如下结构：
其中X是氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基；n是小于4的正整数；Y是氢、氯、硝基、甲基或乙基；R是氢、1-8个碳原子的烷基或CONHR3并且R3是少于7个碳原子的烷基，优选丁基或异丁基；R2是4-噻唑基、NHCOOR1，其中R1是少于7个碳原子的脂族烃基，优选少于7个碳原子的烷基。优选的苯并咪唑类化合物是：
其中R是氢、1-8个碳原子的烷基或CONHR3并且R3是少于7个碳原子的烷基，优选丁基或异丁基；R2选自4-噻唑基、NHCOOR1，其中R1是甲基、乙基或异丙基，及其与有机或无机酸消除的无毒的可药用酸加成盐。
最优选的化合物是2-(4-噻唑基)苯并咪唑、甲基-(丁基氨基甲酰基)-2-苯并咪唑氨基甲酸酯和2-甲氧羰基氨基-苯并咪唑以及其中Y是氯并且X是氢的化合物。
这些化合物根据1973年6月12日授权的Adams等的专利US3,738,995中描述的方法制备。噻唑基衍生物根据Brown等，美国化学会杂志(J.Am.Chem.Soc.)，83，1764(1961)和Grenda等，有机化学杂志(J.Org.Chem.)，30，259(1965)描述的方法制备。
C.化疗剂
化疗剂通常分为与DNA相互作用的药物、抗代谢剂、与微管蛋白相互作用的药物、激素药物以及其它药物如天冬酰胺酶或羟基脲。各组化疗剂又可以活性或化合物的种类进一步分类。在与苯并咪唑类化合物并用的顺序给药的方法中使用的化疗剂主要包括与DNA相互作用的药物、抗代谢剂、与微管蛋白相互作用的药物。关于化疗剂及其给药方法的详细讨论参见Dorr等，癌症化疗手册(Cancer Chemotherapy Handbook)，第2版，15-34页，Appleton & Lange(Connecticut，1994)，该文献引入本文作为参考。
为了减少肿瘤的质量或停止癌细胞的生长，化疗剂必需能够防止细胞的复制，并且还必需能够干扰细胞维持其自身的能力。可以起到这种作用的试剂主要是与DNA相互作用的药物如顺铂，以及与微管蛋白相互作用的药物。
与DNA相互作用的药物包括烷化剂如顺铂、环磷酰胺、六甲密胺；DNA-链断裂剂，例如博来霉素；嵌入型拓扑异构酶II抑制剂，例如放线菌素D和阿霉素；非嵌入型拓扑异构酶II抑制剂，例如依托泊苷和替尼泊苷；以及DNA小沟结合剂如普卡霉素。
烷化剂可与细胞的DNA、RNA和蛋白质分子以及更小的氨基酸、谷胱甘肽和类似的化学物质形成共价的化学加合物。通常，这些烷化剂与细胞组分中的亲核性原子如核酸、蛋白质、氨基酸或谷胱甘肽中的氨基、羧基、磷酸根、巯基反应。这些烷化剂在癌症治疗中的机制和作用还不十分清楚。典型的烷化剂包括：
氮芥，例如苯丁酸氮芥、环磷酰胺、isofamide、氮芥(Mechlorethamine)、美法仑、尿嘧啶氮芥；
氮丙啶类化合物如噻替派；
甲磺酸酯如白消安；
亚硝基脲，例如卡莫司汀、环己亚硝脲、链佐星；
铂配合物，例如顺铂、碳铂；
生物还原性烷化剂，例如丝裂霉素、丙卡巴肼、达卡巴嗪和六甲蜜胺；
DNA链断裂剂如博来霉素；
DNA拓扑异构酶II抑制剂，包括：
嵌入剂，例如安吖啶、放线菌素D、柔红霉素、阿霉素、去甲氧柔红霉素、米托蒽醌；
非嵌入剂，例如依托泊苷和替尼泊苷。
DNA小沟结合剂为Plcamydin。
抗代谢物通过两种主要机制中的一种干扰核酸的生产。某些药物可以抑制DNA合成的中间体前体脱氧核糖核苷三磷酸的生产，从而抑制DNA的复制。某些化合物与嘌呤或嘧啶充份相似，从而可以在合成代谢核苷酸途径中取而代之。因此，这些类似物可以取代其正常的对应物而进入DNA和RNA中。可用于本发明的抗代谢物包括：
叶酸盐拮抗剂如甲氨蝶呤和曲美沙特；
嘧啶拮抗剂，例如氟尿嘧啶、氟脱氧尿苷(fluorodeoxyuridine)、CB3717、氮胞苷、阿糖孢苷和氟尿苷；
嘌呤拮抗剂，包括巯基嘌呤、6-硫代鸟嘌呤、氟达拉滨、喷司他丁；
糖修饰的类似物，包括cyctrabine和氟达拉滨；
核糖核苷还原酶抑制剂，包括羟基脲。
与微管蛋白相互作用的药物通过结合微管蛋白上的特异性位点来起作用，微管蛋白是聚合形成细胞微管的蛋白。微管是重要的细胞结构单元。当与微管蛋白相互作用的药物与蛋白结合时，细胞就不能形成微管。与微管蛋白相互作用的药物包括长春新碱和长春花碱，两种生物碱以及Pacliatxel。
肾上腺皮质类固醇是从天然的肾上腺皮质醇或氢化可的松衍生得到的。它们具有抗炎活性，有些还可以抑制有丝***并阻止DNA的合成而可以使用。这些化合物包括，***、***、甲泼尼龙和***龙。
羟基脲似乎主要是通过抑制核糖核苷还原酶来起作用。
天冬酰胺酶是一种可以将天冬酰胺转变成无功能的天冬氨酸的酶，从而阻断了肿瘤中蛋白质的合成。
激素药物和促黄体激素并不常用于明显减少肿瘤的质量。但是，可将它们与化疗剂或苯并咪唑类化合物联用。
激素阻断剂可用于治疗癌症和肿瘤。它们用于对激素敏感的肿瘤并且通常是从天然途径得到的。它们包括：
***、缀合的***、炔雌醇、己烯雌酚、氯烯雌醚和Idenestrol；
孕激素如羟孕酮己酸酯、甲羟孕酮和甲地孕酮；
雄激素如睾酮、丙酸睾酮、氟***、***；
促黄体激素释放激素或促性腺素释放素拮抗剂主要用于治疗***癌。它们包括醋酸亮丙瑞林和醋酸性瑞林。它们可以阻断睾丸中甾体化合物的生物合成。
抗激素抗原包括：
抗***药物如他莫昔芬；
抗雄激素药物如氟他胺；和
抗肾上腺药物如米托坦和氨鲁米特。
D.增效剂
“增效剂”可以是能够改善或增强药物组合物的效力和/或对免疫***的作用的物质。所述增效剂之一是吡咯吡胺(triprolidine)及其顺式异构体，可将它们与化疗剂和苯并咪唑类化合物联合使用。曲普利啶记载于US5,114,951(1992)。另一种增效剂是苯咪唑丙酸，1H-苯并咪唑-2-丙酸；[β-(2-苯并咪唑)-丙酸；2-(2-羧乙基)苯并咪唑；propazol]。苯咪唑丙酸是一种对抗病毒和细菌感染的非特异性活性免疫保护剂，可与本文所述的组合物一起使用。
增效剂可以改善苯并咪唑类化合物的效力并可以以安全有效量使用。这种联合形式可以通过口服、直肠、局部或胃肠外给药施用给患者或动物。
抗氧化维生素如抗坏血酸、β-胡萝卜素、维生素A和维生素E也可以与本发明的组合物一起给药。
E.剂量
任何适宜的剂量均可用于本发明的方法。化合物及载体的类型和用量将随着温血动物或人的种类、体重、所治疗的癌症或肿瘤而变化。所用的化疗剂和苯并咪唑类化合物及其衍生物的范围和比例取决于化疗剂的类型和所治疗的癌症。通常，对于苯并咪唑类化合物，适宜的剂量范围是约2mg/kg体重-约4000mg/kg体重。也可以更高的剂量，最高达6000mg/kg。对于苯并咪唑类化合物，优选的剂量是15mg-约3000mg/kg体重。对于化疗剂，优选较低的剂量，即约0.01mg/kg体重-约400mg/kg体重，尽管也可以使用高达1500mg/kg体重的剂量。通常，对于人的剂量低于小的温血哺乳动物如小鼠的剂量。剂量单位可以含有单一的化合物或其与其它化合物或其它癌症抑制化合物的混合物。剂量单位还可以含有稀释剂、填料、载体等。剂量单位可以是固体或凝胶形式的，例如丸剂、片剂、胶囊、脂质体等，或是适于口服、直肠给药、局部给药、静脉内注射或胃肠外给药或用于注射到肿瘤内部或周围的液体形式。
F.剂量传递形式
苯并咪唑类化合物及其衍生物和化疗剂通常与可药用载体混合。这些载体可以是固体、液体或脂质体形式的，其类型的选择通常取决于所采用的给药方式。可将活性药物以片剂或胶囊、脂质体的形式，或以聚集的粉末或液体的形式随同给药。适宜的固体载体的例子包括乳糖、蔗糖、明胶和琼脂。胶囊或片剂很容易制备并且可以制成易于吞咽或咀嚼的形式；其它固体剂型包括颗粒剂和整装粉剂。片剂可以含有适宜的粘合剂、润滑剂、稀释剂、崩解剂、着色剂、矫味剂、助流剂和助熔剂(melting agent)。适宜的液体剂型的例子包括在水、可药用脂肪和油、醇或其它有机溶剂包括酯中的溶液或混悬液；乳剂；糖浆或酏剂；混悬液；从非泡腾颗粒剂再建的溶液和/或混悬液以及从泡腾颗粒剂再建的泡腾制剂。所述液体剂型可以含有，例如适宜的溶剂、防腐剂、乳化剂、助悬剂、稀释剂、甜味剂、增稠剂和助熔剂。口服剂型可任选地含有矫味剂和着色剂。胃肠外和静脉内给药剂型还可以含有使其与选定注射或传递***类型相适应的矿物质和其它材料。
可用于配制本发明口服剂型的可药用载体和赋形剂的具体例子记载于1975年9月2日授予Robert的专利US3,903,297。制备本发明所用剂型的方法和组合物记载于如下参考文献：现代药学(Modern Pharmaceutics)，第9和第10章(Banker & Rhodes编，1979)；Lieberman等，药物剂型：片剂(Pharmaceutical Dosage Forms：Tablets)；和Ansel，药物剂型介绍(Introduction to Pharmaceutical Dosage Forms)，第二版(1976)。
G.治疗方法
治疗方法可以是任何能够有效地治疗所需治疗的具体癌症或肿瘤的方法。可以通过口服、直肠、局部、胃肠外或静脉内给药或注射到肿瘤内部等进行治疗。施用有效量的方法也随着所治疗的肿瘤而改变。据信通过静脉内、皮下或肌肉内施用与适宜载体、其它癌症抑制化合物或有助于给药的化合物或稀释剂一起配制的苯并咪唑类化合物进行胃肠外治疗是对温血动物施用化合物的优选方法。
优选首先施用化疗剂来明显缩小癌或肿瘤的大小。该过程通常需要3-约14天。肿瘤或癌细胞的量减少到最初水平的50％以下。可将放疗与化疗一同进行。
当肿瘤缩小后，立即施用苯并咪唑。由于该物质相对较为安全，可根据需要将其施用14天至365天以有效地抑制癌的生长。
以下实施例是说明性的，并非想要限定本发明。
实施例1
在乳腺癌的小鼠模型中，向动物施用环磷酰胺以明显缩小肿瘤质量。在另一条腿以4000、5000和6000mg/kg体重的剂量向小鼠施用苯咪氨甲酯。肿瘤的体积持续缩小，在用苯咪氨甲酯治疗180天后，肿瘤的再生长仍被限制。生长是剂量依赖性的。用环磷酰胺处理的对照组在100天后出现肿瘤的再生长；当用***在第115天刺激时，出现迅速的再生长。即使用***进行刺激，用苯咪氨甲酯处理的动物的肿瘤大小没有明显的改变。130天后，向已用环磷酰胺处理的小鼠施用苯咪氨甲酯(剂量为4000、5000和6000mg/kg体重)。肿瘤的体积持续缩小，180天后，肿瘤的再生长仍被限制。
Claims (10)
1.用于治疗癌症的药盒，该药盒含有药盒形式的两种药物的组合，第一种药物是安全有效量的化疗剂，其剂量应使得首先施用该药物可明显缩小癌症；第二种药物是用于对癌症继续进行治疗的安全有效量的第二种药物组合物，该组合物含有选自如下一组化合物的苯并咪唑类化合物或其可药用有机或无机酸加成盐：
其中X是氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基；n是小于4的正整数；Y是氢、氯、硝基、甲基或乙基；R是氢、CONHR3其中R3是少于7个碳原子的烷基或1-8个碳原子的烷基；R2是4-噻唑基、NHCOOR1，其中R1是少于7个碳原子的脂族烃基。
2.权利要求1的药盒，其中，所述药盒含有约0.5mg/kg体重-约400mg/kg体重的所述化疗剂药物和约2mg/kg体重-约4000mg/kg体重的所述苯并咪唑药物。
3.权利要求1或2的药盒，其中，所述苯并咪唑药物选自如下一组化合物或其可药用有机或无机酸加成盐：
其中R是氢，R2选自NHCOOR1，其中R1是甲基、乙基或异丙基。
4.权利要求1、2或3的药盒，其中，所述化疗剂药物选自与DNA相互作用的药物、抗代谢物或与微管蛋白相互作用的药物。
5.权利要求4的药盒，其中，所述化疗剂药物选自天冬酰胺酶、羟脲、顺铂、环磷酰胺、六甲密胺；博来霉素、放线菌素D、阿霉素、依托泊苷、替尼泊苷和Plcamydin。
6.权利要求4的药盒，其中，所述化疗剂药物选自甲氨蝶呤、氟尿嘧啶、氟脱氧尿苷、CB3717、氮胞苷、阿糖孢苷、氟尿苷、巯基嘌呤、6-硫代鸟嘌呤、氟达拉滨、喷司他丁、cyctrabine、氟达拉滨。
7.权利要求4、5或6的药盒，其中，所述化疗剂药物是脂质体的形式。
8.权利要求7的药盒，其中，所述苯并咪唑药物是液体形式，所述液体形式选自含水溶液、醇溶液、乳液、混悬液以及从非泡腾制剂和泡腾制剂再建的混悬液和在可药用脂肪或油中的混悬液。
9.权利要求7的药盒，其中，所述化疗剂药物选自紫杉酚或顺铂，所述的第二种药物是含有2-甲氧羰基氨基苯并咪唑或其可药用有机或无机酸加成盐的药物组合物，并且所述药盒用于在温血哺乳动物中治疗乳腺癌。
10.权利要求9的药盒，其中，所述化疗剂药物的剂量可用于约3-14天的治疗，所述的2-甲氧碳基氨基苯并咪唑的剂量可用于约3-365天的治疗。
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| BR9604973A (pt) | 1995-04-12 | 1998-06-09 | Procter & Gamble | Uma composição farmacêutica contendo carbamatos de n-cloro fenila e tiocarbamatos de n-cloro fenila para inibição de crescimento de vírus e cânceres |
| US5629341A (en) * | 1995-04-12 | 1997-05-13 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of viruses and cancers |
| ZA962879B (en) | 1995-04-12 | 1997-03-17 | Procter & Gamble | A pharmaceutical composition for inhibiting the growth of viruses and cancers |
| US5656615A (en) * | 1995-04-12 | 1997-08-12 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of cancers and viruses in mammals |
| ZA962880B (en) | 1995-04-12 | 1997-03-17 | Procter & Gamble | A pharmaceutical composition for inhibiting the growth of viruses and cancers |
| US5665713A (en) | 1995-04-12 | 1997-09-09 | Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of viruses and cancers |
| MX9707809A (es) * | 1995-06-07 | 1998-01-31 | Procter & Gamble | Una composicion farmaceutica que contiene bencimidazol para inhibir el crecimiento de canceres. |
| US6200992B1 (en) | 1995-06-07 | 2001-03-13 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of cancers |
| SK168697A3 (en) | 1995-06-07 | 1998-12-02 | Procter & Gamble | A medicament for the treatment of leukemia |
| US5770616A (en) | 1995-06-07 | 1998-06-23 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of cancers |
| US5665751A (en) | 1995-06-07 | 1997-09-09 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of cancers |
| WO1997005870A2 (en) | 1995-08-03 | 1997-02-20 | The Procter & Gamble Company | Use of griseofulvin for inhibiting the growth of cancers |
| US5908855A (en) | 1996-07-16 | 1999-06-01 | The Procter & Gamble Company | Compositions for treating viral infections |
| WO1997005873A2 (en) | 1995-08-04 | 1997-02-20 | The Procter & Gamble Company | Use of fluconazole for inhibiting the growth of cancers |
| US5900429A (en) * | 1997-01-28 | 1999-05-04 | The Procter & Gamble Company | Method for inhibiting the growth of cancers |
| US6506783B1 (en) | 1997-05-16 | 2003-01-14 | The Procter & Gamble Company | Cancer treatments and pharmaceutical compositions therefor |
| PE11499A1 (es) | 1997-05-16 | 1999-03-01 | Procter & Gamble | Tratamiento del hiv y cancer |
| US6245789B1 (en) | 1998-05-19 | 2001-06-12 | The Procter & Gamble Company | HIV and viral treatment |
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1997
- 1997-01-28 US US08/788,482 patent/US5900429A/en not_active Expired - Fee Related
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1998
- 1998-01-21 IL IL13109798A patent/IL131097A0/xx unknown
- 1998-01-21 WO PCT/US1998/001147 patent/WO1998032440A1/en not_active Application Discontinuation
- 1998-01-21 KR KR1019997006797A patent/KR20000070551A/ko not_active Application Discontinuation
- 1998-01-21 JP JP53211098A patent/JP2001509164A/ja active Pending
- 1998-01-21 SK SK991-99A patent/SK99199A3/sk unknown
- 1998-01-21 HU HU0001939A patent/HUP0001939A3/hu unknown
- 1998-01-21 CN CN98802043A patent/CN1244123A/zh active Pending
- 1998-01-21 BR BR9807003-7A patent/BR9807003A/pt not_active IP Right Cessation
- 1998-01-21 TR TR1999/01768T patent/TR199901768T2/xx unknown
- 1998-01-21 CA CA002277166A patent/CA2277166A1/en not_active Abandoned
- 1998-01-21 CZ CZ992654A patent/CZ265499A3/cs unknown
- 1998-01-21 ID IDW990746A patent/ID23507A/id unknown
- 1998-01-21 PL PL98335054A patent/PL335054A1/xx unknown
- 1998-01-21 AU AU60343/98A patent/AU729099B2/en not_active Ceased
- 1998-01-21 EP EP98903620A patent/EP0967977A1/en not_active Withdrawn
- 1998-01-27 ZA ZA98643A patent/ZA98643B/xx unknown
- 1998-01-28 AR ARP980100378A patent/AR011583A1/es not_active Application Discontinuation
- 1998-12-22 US US09/218,884 patent/US6271217B1/en not_active Expired - Fee Related
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1999
- 1999-07-27 NO NO993654A patent/NO993654L/no not_active Application Discontinuation
-
2000
- 2000-04-19 US US09/552,408 patent/US6329355B1/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1543356B (zh) * | 2001-06-25 | 2011-09-28 | 味之素株式会社 | 抗肿瘤剂 |
| CN100350975C (zh) * | 2005-02-03 | 2007-11-28 | 山东蓝金生物工程有限公司 | 抗癌药物组合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| US5900429A (en) | 1999-05-04 |
| KR20000070551A (ko) | 2000-11-25 |
| HUP0001939A2 (hu) | 2001-01-29 |
| WO1998032440A1 (en) | 1998-07-30 |
| AU729099B2 (en) | 2001-01-25 |
| HUP0001939A3 (en) | 2002-08-28 |
| JP2001509164A (ja) | 2001-07-10 |
| AR011583A1 (es) | 2000-08-30 |
| CA2277166A1 (en) | 1998-07-30 |
| SK99199A3 (en) | 2000-05-16 |
| NO993654D0 (no) | 1999-07-27 |
| EP0967977A1 (en) | 2000-01-05 |
| US6329355B1 (en) | 2001-12-11 |
| AU6034398A (en) | 1998-08-18 |
| CZ265499A3 (cs) | 1999-12-15 |
| ID23507A (id) | 2000-04-27 |
| NO993654L (no) | 1999-09-28 |
| PL335054A1 (en) | 2000-03-27 |
| ZA98643B (en) | 1998-07-30 |
| IL131097A0 (en) | 2001-01-28 |
| BR9807003A (pt) | 2000-03-14 |
| US6271217B1 (en) | 2001-08-07 |
| TR199901768T2 (xx) | 1999-09-21 |
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