CN1329499A - 包含环肽和化学治疗剂或血管生成抑制剂的药用制剂 - Google Patents
包含环肽和化学治疗剂或血管生成抑制剂的药用制剂 Download PDFInfo
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- CN1329499A CN1329499A CN99813387A CN99813387A CN1329499A CN 1329499 A CN1329499 A CN 1329499A CN 99813387 A CN99813387 A CN 99813387A CN 99813387 A CN99813387 A CN 99813387A CN 1329499 A CN1329499 A CN 1329499A
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Abstract
本发明涉及药用制剂环－(Arg－Gly－Asp－D－Phe－NMe－Val)和/或其一种生理上安全的盐。本发明也涉及至少一种化学治疗剂和/或其一种生理上安全盐和/或一种血管生成抑制剂和/或其一种生理上安全的盐。
Description
本发明涉及新的药用制剂，所述药用制剂包含环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐和至少一种化学治疗剂和/或其一种生理上可接受的盐和/或血管生成抑制剂和/或其一种生理上可接受的盐。
这种新制剂可以用来控制病理性血管生成性疾病、血栓形成、心肌梗塞、冠心病、动脉硬化、肿瘤、骨质疏松、炎症和感染。
本发明基于这样一个目的：提供药用制剂形式的、其特性优于用于相同目的的已知药用制品的新药用制品。
通过发现所述新制剂，已经达到该目的。
环(Arg-Gly-Asp-D-Phe-NMe-Val)公开于EP0770622中，具体用作整联蛋白抑制剂，特别是抑制αv、β3或β5整联蛋白受体与配体之间的相互作用，例如血纤蛋白原与αvβ3整联蛋白受体的结合。在整联蛋白αvβ3、αvβ5、αIIbβ3和αvβ1、αvβ6和αvβ8的情况下，该化合物显示出特别的活性。
这种效应可以例如通过J.W.Smith等描述的方法(J.Biol.Chem.265，12267-12271(1990))检测。
本发明将被认为是与EP0770622有关的选择发明。
WO98/14192提及包含非肽玻连蛋白受体拮抗剂与化学治疗剂的组合的药用制品。J.Folkman在Nature Medicine 1，27-30中描述了抗血管生成疗法与化学疗法联合的效应。
在Lewis肺癌系统中可以显示出环(Arg-Gly-Asp-D-Phe-NMe-Val)与化学治疗剂联合的效应。常规化学治疗剂对Lewis肺癌的影响仅是不充分的(Y.Kakeji和B.A.Teicher，Invest.New Drugs 15：39-48(1997))。与Kakeji类似地进行了延迟肿瘤生长的方法(F.Mitjans等，J.Cell Sci.108：2825-2838(1995))。
本发明还涉及一种药用制剂，其包含环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐和至少一种化学治疗剂和/或其一种生理上可接受的盐。
本发明具体涉及所述的药用制剂，其特征在于，使用选自以下的一种化学治疗剂：
a)烷化剂，
b)抗生素，
c)抗代谢药物，
d)生物制剂和免疫调节剂，
e)激素及其拮抗剂，
f)芥子气衍生物，
g)生物碱，
h)基质金属蛋白酶的抑制剂(MMP抑制剂)，
i)蛋白激酶抑制剂，
k)其它化学治疗剂。
优选的烷化剂的实例为白消安、卡铂、卡莫司汀、顺铂、环磷酰胺、达卡巴嗪、异环磷酰胺或洛莫司汀。优选的抗生素的实例为博来霉素、阿霉素、伊达比星或普卡霉素。优选的抗代谢药物的实例为磺胺或叶酸拮抗剂，例如5-氟尿嘧啶(5-FU)、巯基嘌呤、甲氨蝶呤或硫鸟嘌呤或5-FU与亚叶酸钙(亚叶酸)。生物制剂和免疫调节剂的实例是干扰素a2A、白介素2或左旋咪唑。优选的激素及其拮抗剂的实例包括氟他胺、戈舍瑞林、米托坦或他莫昔芬。优选的芥子气衍生物的实例是美法仑、卡莫司汀或氮芥。优选的生物碱的实例是taxane，例如docetaxel或paclitaxel，也包括依托泊苷、长春碱或vinovelbine[sic]。其它化学治疗剂是指不能分配到上述组的化学治疗剂，例如六甲蜜胺、克拉屈滨、吉西他滨、亚叶酸、左旋咪唑、喷司他丁或伊立替康。
在例如M.Wittaker[sic]等在Current Opinion in Drug Discovery &Development 1，157-164(1998)中也描述的基质金属蛋白酶抑制剂(MMP抑制剂)中，优选以下化合物，例如baltimastat(BB-94)、marimastat(BB-2516)、BB-3644、ilomastat、metastat、AG-3340、BAY-12-9566、AE-941/neovastat、CGS-27023A、RS-113456、RS-130830、Ro-32-3555、Ro-31-9790、CT-1746、CT-1418、D-1927、D-2163。
例如G.McMahon等在Current Opinion in Drug Discovery &Development1，131-146(1998)中和L.M.Strawn等在Exp.Opin.Invest.Drugs7，533-573(1998)中描述了蛋白激酶抑制剂。在按照本发明的制剂中，特别优选以下受体酪氨酸激酶抑制剂：CGP 79787、SU-101(HWA 486、来氟米特、Arava)、SU-5416、SU-5271(PD-153035)、PD-173074、SU-6668、ZD-1839、CP-358774。
在按照本发明的制剂中，也包括所述血管生成抑制剂和/或所述化学治疗剂所谓的前体药物衍生物，即例如用烷基或酰基修饰的化合物，糖或寡肽在机体中容易被切割，产生按照本发明的活性化合物。所述前体药物衍生物包括例如也为5-FU前体药物的化学治疗剂capecitabine，如例如Inpharma No.1142，13-14(1998)中所述。
特别优选所述的药用制剂，其特征在于使用选自以下的一种化学治疗剂：docetaxel、paclitaxel、卡铂、顺铂、5-FU和亚叶酸钙、伊立替康、环磷酰胺、卡莫司汀、阿霉素、长春瑞滨、戈舍瑞林或吉西他滨。
例如B.J.Braakhuis等在Semin-Oncol.1995 Aug；22(4suppl.11)：42-6中或R.M.Mohammed等在Pancreas 1998 Jan；16(1)；19-25中描述了使用吉西他滨治疗肿瘤。
本发明还涉及一种药用制剂，其包含环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐和吉西他滨和/或其一种生理上可接受的盐。
本发明还涉及药用制剂，其包含环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐和至少一种血管生成抑制剂和/或其一种生理上可接受的盐。
优选的血管生成抑制剂描述于例如WO9741844的表1中。
特别优选αvβ3和αvβ5整联蛋白抑制剂，例如EP0770622中提及的化合物。
通过将环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐和至少一种化学治疗剂和/或其一种生理上可接受的盐和/或一种血管生成抑制剂和/或其一种生理上可接受的盐与至少一种固体、液体或半液体赋形剂或辅助物质一起，转化为合适的一日剂型(daily doseform)，可以生产新的药用制剂。以该方式获得的制剂可以在人类医学或兽医学中用作药用制品，特别是用于治疗肿瘤的药用制品。合适的载体物质是适用于肠内(例如口服、舌下或直肠)、胃肠外或局部(例如经皮)给药且不与所述化合物反应的有机或无机物质，例如水、植物油、苯甲醇、聚乙二醇、乙酸甘油酯和其它脂肪酸甘油酯、明胶、大豆卵磷脂、碳水化合物例如乳糖或淀粉、硬脂酸镁、滑石粉、纤维素。具有用于口服的是片剂、包衣片、胶囊、糖浆、悬浮剂或滴剂，用于直肠给药的是栓剂，用于胃肠外给药的是溶液、优选油性溶液或水溶液，也包括悬浮剂、乳剂或植入物，用于局部给药的是软膏、乳膏或膏药。也可以将所述有效成分冻干，所得的冻干粉例如用于产生注射用制品。可以将所述制剂灭菌和/或所述制剂含有辅助物质，例如防腐剂、稳定剂和/或润湿剂、乳化剂、影响渗透压的盐、缓冲物质、着色剂和/或香料。它们也可以包含另外的有效成分，例如降低血压或具有利尿效应的其它物质，但也含有维生素和/或无机盐，特别是有利于代谢过程的那些物质。
按照本发明的制剂用于控制病理性血管生成性疾病、血栓形成、心肌梗塞、冠心病、动脉硬化、肿瘤、骨质疏松、炎症和感染。通常，用它们来控制肿瘤，亦即抑制肿瘤生长或肿瘤转移。
有可能与在控制其中涉及αv整联蛋白(特别是αvβ3和αvβ5整联蛋白)并且其抑制形成治疗一部分的疾病方面所用制品联合使用环(Arg-Gly-Asp-D-Phe-NMe-Val)。在非肿瘤性病症的情况下，将环(Arg-Gly-Asp-D-Phe-NMe-Val)与通常用于该病症治疗剂联用。所述病状包括血栓形成、心肌梗塞、动脉硬化、炎症、中风、心绞痛、肿瘤病、溶骨性疾病例如骨质疏松、病理性血管生成性疾病例如炎症、眼科疾病、糖尿病性视网膜病、黄斑变性、近视、眼部组织胞浆病、类风湿性关节炎、骨关节炎、发红性青光眼(mbeotic glaucoma)、溃疡性结肠炎、节段性回肠炎、动脉硬化、牛皮癣、血管成形术后的再狭窄、病毒感染、细菌感染、真菌感染、炎性肠病和急性肾衰竭。
在肿瘤治疗中有可能将环(Arg-Gly-Asp-D-Phe-NMe-Val)结合另一种血管生成抑制剂用于以下方面：
a)手术去除肿瘤，
b)放射疗法，
c)光动力疗法，
d)与抗肿瘤选择性表位的单克隆抗体一起使用，
e)与融合蛋白一起使用，
f)与肽疫苗一起使用，和
g)基因治疗。
环(Arg-Gly-Asp-D-Phe-NMe-Val)或其盐和所述化学治疗剂和/或血管生成抑制剂的剂量优选为每剂量单位约0.1-100mg，特别优选0.2-20mg，尤其是0.1-10mg。日剂量优选约0.001-1mg/kg体重，特别是0.002-0.2mg/kg体重。
在化学治疗期间，所述肽的给药也可以为例如1-10mg/kg，每周2次。所述化学治疗剂的给药剂量可以例如也为1-10mg/kg，每周1次至每3-4周1次。然而，每个患者的具体剂量取决于各种各样的因素，例如取决于具体使用的化合物的效力、年龄、体重、一般健康状况、性别、饮食、给药时间和给药途径、排泄速率、药物组合和应用所述疗法的具体病症的严重程度。优选口服。
因此，本发明也涉及应用所述药用制剂生产用于控制以下病症的药用制品：病理性血管生成性病症、血栓形成、心肌梗塞、冠心病、动脉硬化、肿瘤、骨质疏松、炎症和感染。
本发明还涉及应用所述药用制剂控制病理性血管生成性病症、血栓形成、心肌梗塞、冠心病、动脉硬化、肿瘤、骨质疏松、炎症和感染。
本发明特别涉及环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐与一种化学治疗剂和/或其一种生理上可接受的盐和/或一种血管生成抑制剂和/或其一种生理上可接受的盐连续应用或在物理上组合应用，来生产控制肿瘤的药用制品。
本发明也涉及环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐与一种化学治疗剂和/或其一种生理上可接受的盐连续应用或在物理上组合应用，来生产用于控制肿瘤的药用制品。
此外，本发明涉及环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐与一种化学治疗剂和/或其一种生理上可接受的盐连续应用或在物理上组合应用，来控制肿瘤。
所述新的药用制剂的组分优选组合给予。然而，它们也可以单独、同时或连续给予。
本发明也涉及包含以下独立包装的试剂盒：
(a)有效量的环(Arg-Gly-Asp-D-Phe-NMe-Val)和
(b)有效量的一种化学治疗剂。
所述试剂盒包含合适的容器，例如盒、单独的瓶、袋或安瓿。所述试剂盒可以例如包含分开的安瓿，在每个瓶中有溶解形式或冻干[sic]形式的有效量的环(Arg-Gly-Asp-D-Phe-NMe-Val)和所述化学治疗剂。
WO9814192公开了各种适用于测定具有药理学活性的化合物的生物测试。
如果存在酸性官能性，则将环(Arg-Gly-Asp-D-Phe-NMe-Val)、所述治疗剂或所述血管生成抑制剂与一种基质一起，例如通过使等量的所述酸和所述碱在惰性溶剂例如乙醇中反应，然后蒸发，转化为相关的酸加成盐。
特别适用于该反应中的碱是提供生理上可接受的盐的那些碱。因此，可以用碱(例如氢氧化钠或氢氧化钾或碳酸钠或碳酸钾)将酸转化为相应的金属盐，特别是碱金属盐或碱土金属盐，也可以转化为相应量的铵盐。
另一方面，例如通过使等量的所述碱和所述酸在惰性溶剂例如乙醇中反应，然后蒸发，可以将碱性官能性转化为相关的酸加成盐。特别适用于该反应的酸是提供生理上可接受的盐的那些酸。因此，有可能使用无机酸，例如硫酸、硝酸、氢卤酸例如盐酸或氢溴酸、磷酸如正磷酸、氨基磺酸，也有可能使用有机酸，特别是脂族、脂环族、芳脂族或芳族或杂环的一元或多元羧酸、磺酸或硫酸，例如甲酸、乙酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、柠檬酸、葡糖醛酸、抗坏血酸、烟酸、异烟酸、甲磺酸或乙磺酸、乙二磺酸、2-羟基乙磺酸、苯磺酸、对甲苯磺酸、萘一磺酸和二磺酸、十二烷基硫酸。具有生理上不可接受的盐的盐例如为苦味酸盐，可以用来分离和/或纯化式I化合物[sic]。
本发明还涉及药用制剂，其包含一种αvβ3和/或αvβ5整联蛋白抑制剂和/或其一种生理上可接受的盐和至少一种MMP抑制剂和/或其一种生理上可接受的盐，还涉及药用制剂，其包含一种αvβ3和/或αvβ5整联蛋白抑制剂和/或其一种生理上可接受的盐和至少一种酪氨酸激酶抑制剂和/或其一种生理上可接受的盐。
优选的αvβ3和αvβ5整联蛋白抑制剂描述于例如EP0770622、EP0710657、EP0820988、EP0820991、WO94/12181、WO94/08577、EP0518586、EO95/32710、WO96/00574、WO96/00730或DE19850131中。
在MMP抑制剂和酪氨酸激酶抑制剂中，优选上述提及的那些抑制剂。联合疗法的测试实施例
类似于Kakeji的方法进行肿瘤生长的延迟(F.Mitjans等，J.Cell Sci.108：2825-2838(1995))：
给8-10周龄的C57BL小鼠注射Lewis肺癌细胞(2×10E6)。第4天，每日腹膜内给予环(Arg-Gly-Asp-D-Phe-NMe-Val)(30mg/kg)[sic]。每日测量肿瘤生长(B.A.Teicher等，Int.J.Cancer 57：920-925(1994))。一旦肿瘤达到约100mm3的特定体积后，在肿瘤接种后第7天通过腹膜内注射开始各种细胞毒性联合疗法。实例为：从第7-11天，每天给予5-氟尿嘧啶(30mg/kg)或阿霉素(1.8mg/kg)。在第7、9和11天，给予环磷酰胺(150mg/kg)、卡莫司汀(15mg/kg)或吉西他滨(2.5mg/kg)。第7天给予顺铂(10mg/kg)。
每周3次测量肿瘤，直至达到约500mm3的体积。肿瘤生长的延迟以与未治疗的对照相比，各个肿瘤达到500mm3所需的时间来计算。
以下实施例涉及药用制剂：实施例A：管形瓶
用2N盐酸，将100g环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐、100g所述化学治疗剂和5g磷酸氢二钠在6L双蒸水中的溶液调至pH6.5，除菌过滤，分装到管形瓶中，在无菌条件下冻干，并无菌密封。每个管形瓶含有5mg所述有效成分。实施例B：栓剂
将20g环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐、20g所述化学治疗剂的混合物与100g大豆卵磷脂和1400g可可脂一起熔融，注入模中，让其冷却。每个栓剂含有20mg有效成分。实施例C：溶液
在940ml双蒸水中，由1g环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐、lg所述化学治疗剂、9.38gNaH2PO4·2H2O、28.48gNa2HPO4·12H2O和0.1g苯扎氯铵制备溶液。将pH调至6.8，使体积为1L，经辐射将溶液灭菌。该溶液可以以滴眼剂形式使用。实施例D：软膏
在无菌条件下，将500mg环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐、500mg所述化学治疗剂与99.5g凡士林一起混合。实施例E：片剂
将1kg环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐、1kg所述化学治疗剂和4kg乳糖、1.2kg马铃薯淀粉、0.2kg滑石粉和0.1kg硬脂酸镁的混合物以常规方法压制成片剂，使得每片片剂含有10mg有效成分。实施例F：包衣片
以类似于实施例E的方式，压制片剂，然后将片剂以常规方式用蔗糖、马铃薯淀粉、滑石粉、西黄蓍胶和色素的包衣进行包衣。实施例G：胶囊
将2kg环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐、2kg所述化学治疗剂以常规方式包装到硬明胶胶囊中，使得每个胶囊含有20mg所述有效成分。实施例H：安瓿
将1kg环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐、1kg所述化学治疗剂在60L双蒸水中的溶液除菌过滤，分装到安瓿中，在无菌条件下冻干，并无菌密封。每个安瓿含有10mg的每种所述有效成分。实施例I：试剂盒
对于胃肠外给药的制剂(试剂盒)
该制剂含有500mg环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐和500mg吉西他滨盐酸盐，并且如下生产：
将两种化合物各500mg溶于40ml蒸馏水中。将溶液在无菌条件下过滤，分装到10ml安瓿中并冻干。
对于静脉内注射或肌内注射，加入10ml5％葡萄糖水溶液。
Claims (15)
1.药用制剂，其包含环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐和至少一种化学治疗剂和/或其一种生理上可接受的盐和/或一种血管生成抑制剂和/或其一种生理上可接受的盐。
2.按照权利要求1的药用制剂，其包含环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐和至少一种化学治疗剂和/或其一种生理上可接受的盐。
3.按照权利要求1的药用制剂，其包含环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐和至少一种血管生成抑制剂和/或其一种生理上可接受的盐。
4.按照权利要求1或2的药用制剂，其特征在于使用选自以下的一种化学治疗剂：
a)烷化剂，
b)抗生素，
c)抗代谢药物，
d)生物制剂和免疫调节剂，
e)激素及其拮抗剂，
f)芥子气衍生物，
g)生物碱，
h)基质金属蛋白酶的抑制剂(MMP抑制剂)，
i)蛋白激酶抑制剂，
k)其它化学治疗剂。
5.按照权利要求1、2或4的药用制剂，其特征在于使用选自以下的一种化学治疗剂：docetaxel、paclitaxel、卡铂、顺铂、5-FU和亚叶酸钙、伊立替康、环磷酰胺、卡莫司汀、阿霉素、长春瑞滨、戈舍瑞林或吉西他滨。
6.按照权利要求1、2、4或5的药用制剂，其包含环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐和吉西他滨和/或其一种生理上可接受的盐。
7.按照权利要求1或3的药用制剂，其特征在于使用一种选自αvβ3和αvβ5整联蛋白抑制剂的血管生成抑制剂。
8.按照权利要求1-5的药用制剂用于生产控制以下病症的药用制品的用途：病理性血管生成性疾病、血栓形成、心肌梗塞、冠心病、动脉硬化、肿瘤、骨质疏松、炎症和感染。
9.按照权利要求1-5的药用制剂用于控制以下病症的用途：病理性血管生成性疾病、血栓形成、心肌梗塞、冠心病、动脉硬化、肿瘤、骨质疏松、炎症和感染。
10.环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐和一种化学治疗剂和/或其一种生理上可接受的盐和/或一种血管生成抑制剂和/或其一种生理上可接受的盐的连续应用或在物理上组合应用，用于生产控制肿瘤的药用制品。
11.环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐和一种化学治疗剂和/或其一种生理上可接受的盐的连续应用或在物理上组合应用，用于生产控制肿瘤的药用制品。
12.环(Arg-Gly-Asp-D-Phe-NMe-Val)和/或其一种生理上可接受的盐和一种化学治疗剂和/或其一种生理上可接受的盐的连续应用或在物理上组合应用，用于控制肿瘤。
13.试剂盒，包括以下独立的包装：
(a)有效量的环(Arg-Gly-Asp-D-Phe-NMe-Val)和
(b)有效量的一种化学治疗剂。
14.药用制剂，其包含一种αvβ3和/或αvβ5整联蛋白抑制剂和/或其一种生理上可接受的盐和至少一种MMP抑制剂和/或其一种生理上可接受的盐。
15.药用制剂，其包含一种αvβ3和/或αvβ5整联蛋白抑制剂和/或其一种生理上可接受的盐和至少一种酪氨酸激酶抑制剂和/或其一种生理上可接受的盐。
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| CA2277273C (en) | 1997-01-17 | 2008-03-25 | Merck & Co., Inc. | Integrin antagonists |
| DE19850131A1 (de) | 1998-10-30 | 2000-05-04 | Merck Patent Gmbh | Chromenon- und Chromanonderivate |
-
1998
- 1998-09-16 DE DE19842415A patent/DE19842415A1/de not_active Withdrawn
-
1999
- 1999-09-09 CA CA002344151A patent/CA2344151A1/en not_active Abandoned
- 1999-09-09 PT PT99969031T patent/PT1113809E/pt unknown
- 1999-09-09 JP JP2000569828A patent/JP2002524526A/ja active Pending
- 1999-09-09 AT AT04006076T patent/ATE432707T1/de active
- 1999-09-09 AU AU59758/99A patent/AU765073B2/en not_active Ceased
- 1999-09-09 TR TR2001/00765T patent/TR200100765T2/xx unknown
- 1999-09-09 RU RU2001110104/15A patent/RU2227041C2/ru not_active IP Right Cessation
- 1999-09-09 EP EP04006076A patent/EP1466615B1/de not_active Expired - Lifetime
- 1999-09-09 ID IDW20010746A patent/ID29226A/id unknown
- 1999-09-09 EP EP99969031A patent/EP1113809B1/de not_active Expired - Lifetime
- 1999-09-09 DK DK04006076T patent/DK1466615T3/da active
- 1999-09-09 WO PCT/EP1999/006654 patent/WO2000015244A2/de active IP Right Grant
- 1999-09-09 IL IL14151699A patent/IL141516A0/xx unknown
- 1999-09-09 CN CNB998133876A patent/CN1201812C/zh not_active Expired - Fee Related
- 1999-09-09 DK DK99969031T patent/DK1113809T3/da active
- 1999-09-09 US US09/787,374 patent/US6683051B1/en not_active Expired - Lifetime
- 1999-09-09 SK SK337-2001A patent/SK287012B6/sk not_active IP Right Cessation
- 1999-09-09 DE DE59911881T patent/DE59911881D1/de not_active Expired - Lifetime
- 1999-09-09 AT AT99969031T patent/ATE292470T1/de active
- 1999-09-09 HU HU0103521A patent/HUP0103521A3/hu unknown
- 1999-09-09 NZ NZ510040A patent/NZ510040A/en not_active IP Right Cessation
- 1999-09-09 PL PL348026A patent/PL201902B1/pl not_active IP Right Cessation
- 1999-09-09 ES ES99969031T patent/ES2241363T3/es not_active Expired - Lifetime
- 1999-09-09 KR KR1020017003238A patent/KR100703253B1/ko not_active IP Right Cessation
- 1999-09-09 SI SI9930792T patent/SI1113809T1/xx unknown
- 1999-09-09 CN CNB2004100834955A patent/CN100352494C/zh not_active Expired - Fee Related
- 1999-09-09 BR BR9913737-2A patent/BR9913737A/pt not_active Application Discontinuation
- 1999-09-09 CZ CZ20010932A patent/CZ302908B6/cs not_active IP Right Cessation
- 1999-09-09 ES ES04006076T patent/ES2327331T3/es not_active Expired - Lifetime
- 1999-09-09 PT PT04006076T patent/PT1466615E/pt unknown
- 1999-09-09 DE DE59915033T patent/DE59915033D1/de not_active Expired - Lifetime
- 1999-09-13 MY MYPI99003955A patent/MY129572A/en unknown
- 1999-09-13 PE PE1999000926A patent/PE20001046A1/es not_active Application Discontinuation
- 1999-09-15 AR ARP990104617A patent/AR022382A1/es not_active Application Discontinuation
- 1999-09-16 CO CO99058733A patent/CO5140070A1/es unknown
- 1999-09-16 TW TW088116003A patent/TW576744B/zh not_active IP Right Cessation
-
2001
- 2001-02-19 IL IL141516A patent/IL141516A/en not_active IP Right Cessation
- 2001-03-15 NO NO20011308A patent/NO331734B1/no not_active IP Right Cessation
- 2001-04-12 ZA ZA200103073A patent/ZA200103073B/en unknown
-
2010
- 2010-09-15 AR ARP100103356A patent/AR078175A2/es not_active Application Discontinuation
-
2011
- 2011-08-12 JP JP2011176480A patent/JP2011252012A/ja active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102223915A (zh) * | 2008-11-20 | 2011-10-19 | 默克专利有限公司 | 应用整联蛋白配体治疗癌症的新疗法和药物 |
| CN103333227A (zh) * | 2013-06-07 | 2013-10-02 | 东南大学 | 转移肿瘤缺失蛋白小分子环肽抑制剂及其制备方法与应用 |
| CN103333227B (zh) * | 2013-06-07 | 2015-10-07 | 东南大学 | 转移肿瘤缺失蛋白小分子环肽抑制剂及其制备方法与应用 |
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