CN107801379B - 抗癌剂 - Google Patents

抗癌剂 Download PDF

Info

Publication number
CN107801379B
CN107801379B CN201680035322.7A CN201680035322A CN107801379B CN 107801379 B CN107801379 B CN 107801379B CN 201680035322 A CN201680035322 A CN 201680035322A CN 107801379 B CN107801379 B CN 107801379B
Authority
CN
China
Prior art keywords
cancer
catenin
cbp
inhibitor
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201680035322.7A
Other languages
English (en)
Other versions
CN107801379A (zh
Inventor
小田上刚直
小路弘行
小泽阳一
堀优作
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eisai R&D Management Co Ltd
Original Assignee
Eisai R&D Management Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eisai R&D Management Co Ltd filed Critical Eisai R&D Management Co Ltd
Publication of CN107801379A publication Critical patent/CN107801379A/zh
Application granted granted Critical
Publication of CN107801379B publication Critical patent/CN107801379B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Abstract

本发明的目的在于提供具有优异的治疗效果的癌症治疗药。通过联合应用CBP/连环蛋白抑制剂及免疫检查点抑制剂来对癌症进行治疗，不仅能够增强对于癌症的治疗效果，而且针对在仅有免疫检查点抑制剂时敏感性低的癌症患者也能够进行有效治疗。

Description

抗癌剂
技术领域
本发明涉及联合应用CBP/连环蛋白(catenin)抑制剂和免疫检查点抑制剂(immune checkpoint inhibitor)来对癌症进行治疗的方法及癌症治疗药。
背景技术
最近，在癌症治疗中，对免疫检查点抑制剂的开发愈发活跃，其中，抗CTLA-4抗体、抗PD-1抗体正作为癌症治疗药而被销售。
PD-1(程序性死亡分子1，programmed death 1)与在抗原呈递细胞中表达的其配体PD-L1及PD-L2结合，向细胞毒性T细胞(CD8阳性T细胞)转导抑制性信号，对细胞毒性T细胞的活化状态进行负向调节。已知强制表达有PD-L1的癌细胞可使抗原特异性CD8阳性T细胞的细胞损伤活性减弱、或诱导凋亡。人们已知：PD-L1在多数癌细胞中表达，而表达水平越高则癌症预后越差。抗PD-1抗体纳武单抗(nivolumab)可阻断抑制性信号的转导，从而维持细胞毒性T细胞的活化状态，对癌细胞进行攻击。
另外，CTLA(细胞毒性T淋巴细胞相关抗原，cytotoxic T lymphocyte associatedantigen)-4与存在于抗原呈递细胞中的共刺激分子CD80(B7-1)或CD86(B7-2)结合后，细胞毒性T细胞的活化被抗原呈递细胞抑制。抗CTLA-4抗体伊匹单抗(ipilimumab)通过抑制该结合而使细胞毒性T细胞活化并增殖(参见图1)。
另外，对于PD-L1而言，在胆道癌的癌症干细胞的研究中，报道了PD-L1的表达水平降低的细胞具有各种癌症干细胞的特征(致瘤能力·静止期·ALDH活性等)(非专利文献1)。多数癌症干细胞的HLA I类的表达为阴性，不被细胞毒性T细胞识别。
另一方面，可以认为，多数癌细胞利用Wnt信号来激活β-连环蛋白，结果造成，细胞增殖的控制机构崩溃，细胞的癌化进展。虽然出于这样的考虑而将Wnt信号途径的抑制剂作为抗癌剂进行了研究，但未能实用化。
本申请的发明人已发现，较之以往的其他机制的Wnt抑制剂而言，作为抗癌剂正在进行临床开发的CBP/连环蛋白抑制剂PRI-724对于人具有明显更低的毒性(非专利文献2)。作为其机制，CBP与连环蛋白的结合被抑制，由此使得连环蛋白与同CBP相似性高的P300结合，而非与CBP结合。认为这样的变化可抑制癌的增殖以及诱导分化(非专利文献3)。
最近已发现，对于胆管癌而言，肿瘤经由Wnt-β-连环蛋白途径增殖是主要的途径，并公开了作为CBP/连环蛋白抑制剂的ICG-001在动物模型中具有强效的增殖抑制效果(非专利文献4)。
以往的Wnt抑制剂的机制为基于抑制Wnt配体的产生、阻碍受体的功能、促进连环蛋白的分解等机制来阻断信号，因此，几乎均在临床前试验、临床试验中发生毒性方面的问题而导致开发中止。这是因为，Wnt途径被认为对于生命维持而言是必需的。另一方面，CBP/连环蛋白抑制剂并不阻断信号，而是通过从CBP切换至P300来体现效果，因此，可以推测其安全性高。
此外，β-连环蛋白通过抑制T细胞分化来抑制T细胞的活化也是已知的(非专利文献5)。因此，认为CBP/β-连环蛋白抑制剂促进T细胞的分化、活化T细胞。
在临床中对抗PD-1抗体、抗CTLA-4抗体呈现显著效果的患者是有限的。其理由是，癌症患者中，CD-8阳性细胞数量与β-连环蛋白的表达呈完全逆相关，已发现在β-连环蛋白的表达水平高的组织中T细胞少，反之，β-连环蛋白的表达水平低的组织中T细胞多，并且，上述抗体在T细胞多的组织中呈现显著效果(非专利文献6)。
现有技术文献
非专利文献
非专利文献1：Cancer Sci(105)667-674，2014
非专利文献2：J Clin Oncol 31，2013(suppl；abstr 2501)
非专利文献3：The EMBO Journal 2013，1-13
非专利文献4：J Clin Invest.2015Mar 2；125(3)：1269-85.doi：10.1172/JCI76452
非专利文献5：J Immunol 2011；186：784-790
非专利文献6：Nature.2015May 11.doi：10.1038/nature14404.
发明内容
发明所要解决的课题
在临床中对抗PD-1抗体、抗CTLA-4抗体呈现显著效果的患者是有限的，尽管已在尝试了将其与既往使用的各种癌症治疗药联合应用，但却不一定能得到令人满意的效果。
用于解决课题的手段
本发明中，发现通过联合应用PD-1-PD-L1抑制剂等免疫检查点抑制剂和CBP/连环蛋白抑制剂，能够得到优异的治疗效果，从而完成了本发明。
即，本发明的主要内容如下所述：
(1)癌症治疗药，其包含联合的CBP/连环蛋白抑制剂和免疫检查点抑制剂。
(2)如上述(1)所述的癌症治疗药，其中，免疫检查点抑制剂为选自PD-1拮抗剂、PD-L1拮抗剂、PD-L2拮抗剂、CTLA-4拮抗剂、KIR拮抗剂、CD137拮抗剂、LAG3拮抗剂及OX40拮抗剂中的一种以上的免疫检查点抑制剂。
(3)如上述(1)所述的癌症治疗药，其中，免疫检查点抑制剂为选自抗PD-1抗体、抗PD-L1抗体、抗PD-L2抗体、抗CTLA-4抗体、抗KIR抗体、抗LAG3抗体及抗OX40抗体中的一种以上的免疫检查点抑制剂。
(4)如上述(1)～(3)所述的癌症治疗药，其中，CBP/连环蛋白抑制剂为具有CBP/连环蛋白抑制活性的α-螺旋模拟化合物。
(5)如上述(4)所述的癌症治疗药，其中，上述α-螺旋模拟化合物为WO2003/031448、WO2004/093828、WO2005/116032、WO2009/148192、WO2010/044485、WO2010/128685、WO2012/115286及/或WO2015/098853中记载的α-螺旋模拟化合物中的任意一种以上的化合物。
(6)如上述(1)～(4)所述的癌症治疗药，其中，CBP/连环蛋白抑制剂为选自下述化合物中的一种以上的CBP/连环蛋白抑制剂，
(6S，9aS)-N-苄基-6-[(4-羟基苯基)甲基]-8-(萘-1-基甲基)-4，7-二氧代-3，6，9，9a-四氢-2H-吡嗪并[1，2-a]嘧啶-1-甲酰胺(ICG-001)、二氢磷酸4-(((6S，9S，9aS)-1-(苄基氨基甲酰基)-2，9-二甲基-4，7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2，1-c][1，2，4]三嗪-6-基)甲基)苯基酯、(6S，9S，9aS)-N-苄基-6-(4-羟基苄基)-2，9-二甲基-4，7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2，1-c][1，2，4]三嗪-1-甲酰胺、及(6S，9aS)-N-苄基-8-((6-(3-(4-乙基哌嗪-1-基)氮杂环丁烷-1-基)吡啶-2-基)甲基)-6-((2-氟-4-羟基苯基)甲基)-4，7-二氧代-2-(丙-2-烯-1-基)-八氢-1H-吡嗪并[2，1-c][1，2，4]三嗪-1-甲酰胺。
(7)癌症的治疗方法，所述方法包括下述步骤：将有效量的CBP/连环蛋白抑制剂和有效量的免疫检查点抑制剂施予至需要所述CBP/连环蛋白抑制剂和所述免疫检查点抑制剂的对象。
(8)如上述(7)所述的方法，其中，免疫检查点抑制剂为选自PD-1拮抗剂、PD-L1拮抗剂、PD-L2拮抗剂、CTLA-4拮抗剂、KIR拮抗剂、CD137拮抗剂、LAG3拮抗剂及OX40拮抗剂中的一种以上的免疫检查点抑制剂。
(9)如上述(7)所述的方法，其中，免疫检查点抑制剂为选自抗PD-1抗体、抗PD-L1抗体、抗PD-L2抗体、抗CTLA-4抗体、抗KIR抗体、抗LAG3抗体及抗OX40抗体中的一种以上的免疫检查点抑制剂。
(10)如上述(7)～(9)所述的方法，其中，CBP/连环蛋白抑制剂为具有CBP/连环蛋白抑制活性的α-螺旋模拟化合物。
(11)如上述(10)所述的方法，其中，上述α-螺旋模拟化合物为WO2003/031448、WO2004/093828、WO2005/116032、WO2009/148192、WO2010/044485、WO2010/128685、WO2012/115286及/或WO2015/098853中记载的α-螺旋模拟化合物中的任意一种以上的化合物。
(12)如上述(7)～(10)所述的方法，其中，CBP/连环蛋白抑制剂为选自下述化合物中的一种以上的CBP/连环蛋白抑制剂，
(6S，9aS)-N-苄基-6-[(4-羟基苯基)甲基]-8-(萘-1-基甲基)-4，7-二氧代-3，6，9，9a-四氢-2H-吡嗪并[1，2-a]嘧啶-1-甲酰胺(ICG-001)、二氢磷酸4-(((6S，9S，9aS)-1-(苄基氨基甲酰基)-2，9-二甲基-4，7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2，1-c][1，2，4]三嗪-6-基)甲基)苯基酯、(6S，9S，9aS)-N-苄基-6-(4-羟基苄基)-2，9-二甲基-4，7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2，1-c][1，2，4]三嗪-1-甲酰胺、及(6S，9aS)-N-苄基-8-((6-(3-(4-乙基哌嗪-1-基)氮杂环丁烷-1-基)吡啶-2-基)甲基)-6-((2-氟-4-羟基苯基)甲基)-4，7-二氧代-2-(丙-2-烯-1-基)-八氢-1H-吡嗪并[2，1-c][1，2，4]三嗪-1-甲酰胺。
发明效果
本发明的效果并非是免疫检查点抑制剂的癌症治疗效果与CBP/β-连环蛋白抑制剂的癌症治疗效果的单纯叠加效果，本发明中，CBP/β-连环蛋白抑制剂在促进细胞毒性T细胞的活化及其向癌症组织中的迁移从而增强癌症治疗效果的同时，还抑制CBP/β-连环蛋白的癌细胞增殖效果。CBP/β-连环蛋白抑制剂促进癌症干细胞的分化、增强抗原性，但另一方面，存在通过PD-L1的表达来抑制细胞毒性T细胞的功能的可能性，而免疫检查点抑制剂可通过抑制PD-1与PD-L1的结合来增强CBP/β-连环蛋白抑制剂的癌症治疗效果。
附图说明
[图1]图1为示出了免疫检查点抑制剂的作用机制的示意图。
[图2]图2为示出了CBP/β-连环蛋白抑制剂的作用机制的示意图。
[图3]图3为示出了实施例1中CBP/β-连环蛋白抑制剂使乳腺癌干细胞消失的图。
[图4]图4为示出了实施例3中CBP/β-连环蛋白抑制剂抑制了结肠直肠癌的增殖的图。
[图5]图5为示出了实施例4中CBP/β-连环蛋白抑制剂使IL-10减少的图。
具体实施方式
本发明提供联合应用CBP/连环蛋白抑制剂及免疫检查点抑制剂的癌症治疗药。以下，进行详细说明。
(CBP/连环蛋白抑制剂)
β-连环蛋白作为Wnt信号转导的介体而发挥作用，其与作为转录因子的Tcf/Lef(T细胞因子/淋巴细胞增强因子)结合，促进与Wnt信号转导有关的各种基因(cyclin D1、c-Myc等)的表达，控制细胞的增殖、分化(He等，1998Science 281 1509-1512：Kolligs等，1999Mol.Cell.Biol.19，5696-5706：Crawford等，1999，Oncogene 18，2883-2891：Shtutman等，1999，Proc.Natl.Acad.Sci.USA.，11，5522-5527：Tetsu and McCormick，1999Nature，398，422-426)(参见图2)。
CBP(环磷腺苷效应元件结合蛋白(cyclic AMP response element bindingprotein)(CREB)结合蛋白)在CREB结合域与β-连环蛋白直接相互作用，促进Tcf/Lef的转录激活(Ken-Ichi Takemaru and Randall T.Moon，2000J.Cell.Biol.，149，2，249-254)。
所谓CBP/连环蛋白抑制剂，只要是能抑制CBP与连环蛋白、尤其是与β-连环蛋白的相互作用的抑制剂即可，没有特别限定，优选如下的方式，即，抑制β-连环蛋白与CBP的结合，从而对介由β-连环蛋白复合体的基因表达进行抑制的方式。
对于CBP/β-连环蛋白抑制而言，可通过自身已知的结合分析(放射结合分析等)、报告基因分析法等进行测定，优选地，可以利用WO2009/148192中记载的报告基因分析法测定Wnt信号转导的基因表达，由此进行确认。
本发明的CBP/连环蛋白抑制剂只要为上文所定义的抑制剂即可，没有特别限定，优选为具有CBP/连环蛋白抑制活性的α-螺旋模拟化合物，可举出例如WO2003/031448、WO2004/093828、WO2005/116032、WO2009/148192、WO2010/044485、WO2010/128685、WO2012/115286等中记载的α-螺旋模拟化合物、其药物上允许的盐等。
可优选举出(6S，9aS)-N-苄基-6-[(4-羟基苯基)甲基]-8-(萘-1-基甲基)-4，7-二氧代-3，6，9，9a-四氢-2H-吡嗪并[1，2-a]嘧啶-1-甲酰胺(ICG-001)、二氢磷酸4-(((6S，9S，9aS)-1-(苄基氨基甲酰基)-2，9-二甲基-4，7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2，1-c][1，2，4]三嗪-6-基)甲基)苯基酯(化合物1)、及(6S，9S，9aS)-N-苄基-6-(4-羟基苄基)-2，9-二甲基-4，7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2，1-c][1，2，4]三嗪-1-甲酰胺(化合物2)等。
作为本发明的CBP/连环蛋白抑制剂，还可举出WO2015/098853中记载的具有Wnt途径调节作用的化合物、其药物上允许的盐等。
可优选举出(6S，9aS)-N-苄基-8-((6-(3-(4-乙基哌嗪-1-基)氮杂环丁烷-1-基)吡啶-2-基)甲基)-6-((2-氟-4-羟基苯基)甲基)-4，7-二氧代-2-(丙-2-烯-1-基)-八氢-1H-吡嗪并[2，1-c][1，2，4]三嗪-1-甲酰胺(化合物A)等。
CBP/连环蛋白抑制剂可作为利用常规方法制剂化而成的医药制剂(例如，注射剂、胶囊剂、片剂、散剂、颗粒剂等)进行施予。例如，可每天一次或分成数次，以换算为有效成分的量计为每天约0.01～1000mg/kg(体重)、优选每天约0.1～500mg/kg(体重)的施予量进行施予，其施予量、施予方法、施予次数可根据症状、年龄等而适宜变更。例如，制剂化为注射剂时，可使用蒸馏水、生理盐水等载体，制剂化为胶囊剂、片剂、散剂、颗粒剂时，可使用淀粉、乳糖、白糖、碳酸钙等赋形剂；淀粉糊液、***胶、明胶、海藻酸钠、羧甲基纤维素、羟丙基纤维素等粘合剂；硬脂酸镁、滑石等润滑剂等；淀粉、琼脂、结晶纤维素、碳酸钙、碳酸氢钠、海藻酸钠等崩解剂等。可使制剂中的有效成分的含有率在1～99重量％之间变动。例如，采用片剂、胶囊剂、颗粒剂、散剂等形态时，优选含有5～80重量％的有效成分，为注射剂时，优选含有1～10重量％的有效成分。
(免疫检查点抑制剂)
作为免疫检查点抑制剂，可举出例如针对T细胞抑制受体的阻断剂。针对T细胞抑制受体的阻断剂通常是特异性地与T细胞抑制受体的细胞外结构域或T细胞抑制受体配体的细胞外结构域相结合的分子，并通过阻断例如T细胞抑制受体与其配体(CD80、CD86、PD-L1、PD-L2等)的结合来阻止T细胞抑制受体的活化。具体而言，可举出PD-1拮抗剂(纳武单抗、派姆单抗(pembrolizumab)等抗PD-1抗体等)、PD-L1拮抗剂(皮地珠单抗(pidilizumab)、MPDL-3280A、MEDI4736、MSB0010718C、MEDI0680等抗PD-L1抗体等)、PD-L2拮抗剂(抗PD-L2抗体等)、CTLA-4拮抗剂(伊匹单抗、曲美木单抗(tremelimumab)等抗CTLA-4抗体等)、KIR拮抗剂(立鲁单抗(lirilumab)等抗杀伤细胞免疫球蛋白样受体抗体(抗KIR抗体)等)、CD137拮抗剂(乌瑞鲁单抗(urelumab)、PF-05082566等抗CD137抗体等)、LAG3拮抗剂(BMS-986016等抗淋巴细胞活化因子3抗体(抗LAG3抗体)等)及OX40拮抗剂(MEDI6469等抗OX40抗体)。优选抗PD-1抗体、抗PD-L1抗体、抗CTLA-4抗体。
免疫检查点抑制剂可利用常规方法制成医药组合物。对于该医药组合物而言，在多数情况下，根据需要而进一步含有一种以上的缓冲液(例如，已缓冲至中性的生理盐水或磷酸缓冲盐水)、糖类(例如，葡萄糖、甘露糖、蔗糖、或葡聚糖)、甘露糖醇、蛋白质、多肽、或甘氨酸等氨基酸、抗氧化剂(例如，抗坏血酸、二亚硫酸钠、丁基羟基甲苯、丁基羟基苯甲醚等)、抑菌剂、EDTA或谷胱甘肽等螯合剂、使组合物相对于受体的血液而言为等渗、低渗或略微高渗的溶质、悬浮剂、增稠剂、防腐剂、香料、甜味料及/或着色化合物。
(癌症治疗药、癌症的治疗方法)
本发明为对患有癌症的患者进行治疗的方法，所述方法包括向患者施予包含CBP/连环蛋白抑制剂和免疫检查点抑制剂的组合的癌症治疗药的步骤。本说明书中记载的方法以癌症治疗、例如白血病及实体肿瘤(例如黑色素瘤、癌症、肉瘤、淋巴瘤等)作为对象。具体而言，可举出肾癌、肾细胞癌、膀胱癌、尿路上皮癌、泌尿生殖器肿瘤、肺癌、肺鳞状细胞癌、小细胞性肺癌、非小细胞性肺癌、恶性黑色素瘤、葡萄膜黑色素瘤、眼黑色素瘤、胃癌、食道癌、胶质母细胞瘤(glioblastoma)、神经胶质肉瘤(gliosarcoma)、转移性脑肿瘤、肝癌、转移性肝癌、肝细胞癌、肝细胞上皮癌、大肠癌、结肠癌、胰腺癌、转移性胰腺癌、转移性头部鳞状细胞癌、乳腺癌、转移性乳腺癌、恶性胸膜间皮瘤、转移性颈部鳞状细胞癌、转移性鼻咽癌、HPV-16阳性实体癌、骨髓纤维化、原发性骨髓纤维化(Primary myelofibrosis，PMF)、转移自真性红细胞增多症(Polycythemia vera，PV)或特发性血小板增多症(Essentialthrombocythemia，ET)的骨髓纤维化和原发性骨髓纤维化、复发性上皮卵巢癌、输卵管癌、腹膜癌、转移性肉瘤、激素抵抗性***癌、肾上腺皮质癌、非霍奇金淋巴瘤、B细胞淋巴瘤、B细胞非霍奇金淋巴瘤、霍奇金淋巴瘤、急性髓细胞性白血病、慢性髓细胞性白血病、慢性淋巴细胞性淋巴瘤、小淋巴细胞性淋巴瘤、T-细胞白血病、T-细胞淋巴瘤、滤泡性淋巴瘤、骨髓增生异常综合征等。
另外，上述癌症患者中，尤其对于β-连环蛋白被激活的癌症是有效的。
对于本发明的包含CBP/连环蛋白抑制剂和免疫检查点抑制剂的组合的癌症治疗药而言，可以将CBP/连环蛋白抑制剂及免疫检查点抑制剂各自分别、或一同利用适合于例如经口、经鼻、粘膜、直肠、***内、局部、静脉内、腹膜内、皮内、皮下、及肌肉内施予等任意施予方式的方法进行配方。
本发明中，在本领域技术人员的知识范围内足以确定包含CBP/连环蛋白抑制剂和免疫检查点抑制剂的组合的癌症治疗药的各自的施予量及治疗上有效的量的施予时间。例如，最初的有效量可根据细胞培养或其他的体外(in vitro)分析进行推测。对于施予量而言，可以以在动物模型中实现由细胞培养分析求得的IC50的浓度等循环浓度或组织浓度的方式，来进行设定。
为实现本发明的目的，施予的方法可根据接受治疗的状态及治疗药来选择。CBP/连环蛋白抑制剂及免疫检查点抑制剂的施予可通过多种方法进行，例如，不受限定，可优选举出皮下、静脉内、腹膜内、肌肉内、及全身施予，根据情况而直接注入至特定的器官或肿瘤，等等。CBP/连环蛋白抑制剂及免疫检查点抑制剂的施予可通过单一的途径、或同时利用数种途径进行。
CBP/连环蛋白抑制剂及免疫检查点抑制剂尤其可根据治疗适应性及处方医师的判断而以每天1次、每天2次～数次、或每天多数次进行施予。
对于得到治疗效果而言必需的CBP/连环蛋白抑制剂及免疫检查点抑制剂的量，可基于特定的目的、按照以往的方法凭经验决定。一般而言，基于治疗目的向细胞施予时，细胞被施予药理学上有效的施予量。所谓“药理学上有效的量”或“药理学上有效的施予量”，是指为治疗特定的障碍或疾病状态而足以产生所期望的生理学效果(例如减轻或消除障碍或疾病的一种以上的症状或征兆等)的量、或能够达成所期望的结果的量。
本发明的包含CBP/连环蛋白抑制剂和免疫检查点抑制剂的组合的癌症治疗药还可与其他的癌症治疗(例如为外科切除、放射疗法、化学疗法、免疫疗法、以及支持疗法(例如镇痛剂、利尿药、抗利尿药、抗病毒药、抗生素、营养剂、贫血治疗、血液凝固治疗、骨治疗、以及精神病理学及心理学治疗))等联合。
以下，示出实施例更详细地说明本发明，但本发明的范围不限于这些实施例。
实施例
实施例1
使用Hoechst Blue和Hoechst Red对人乳腺癌细胞株(MDA-MB-231)进行二维分选，对于得到的侧群细胞(Side Population)组分(认为癌症干细胞已被浓缩)，向培养液中添加0.3μM的CBP/连环蛋白抑制剂(化合物2)，在4天后，侧群细胞组分基本消失(未使用药剂处理的情况下，检测到1.6％的SP细胞，化合物2处理组中为0％)，认为癌症干细胞已经分化(图3)。
治疗例1
对于无法根治切除的恶性黑色素瘤患者，以每1次2mg/kg(体重)、3周间隔静脉滴注纳武单抗，同时，以30mg/m2/天静脉滴注CBP/β-连环蛋白抑制剂(化合物1)。
治疗例2
对于无法根治切除的恶性黑色素瘤患者，以每1次3mg/kg(体重)、3周间隔静脉滴注伊匹单抗，同时，以100mg/m2/天静脉滴注CBP/β-连环蛋白抑制剂(化合物1)。
实施例2
传代移植了转基因小鼠(MMTV-Wnt-1)的原发性乳腺癌的模型动物中的CBP/连环蛋白抑制剂(化合物A)与抗小鼠PD-1(CD279)抗体的联用效果
采集Wnt-1在乳腺上皮细胞中局部性表达的转基因小鼠(MMTV-Wnt-1)的原发性乳腺癌，使用套管针传代移植至成为背景品系的小鼠(C57BL/6J)。在移植传代后的肿瘤成为1.5g左右时将其摘出，切成30mg左右的片段，移植至各组为5例的小鼠(C57BL/6J)的体侧皮下。确认肿瘤的成活后，将化合物A(50mg/kg，每天2次，21天，经口施予)及抗小鼠PD-1抗体(克隆：RMP1-14，BioXCell)(10mg/kg，每周2次，3周，腹腔施予)以各自单独或者合用的方式施予。
将施予开始日作为第0天，之后，在第4、7、11、14、18及21天，用电子数显卡尺(Mitsutoyo)测定在各小鼠中长出的肿瘤的长径及短径。
根据下式，算出肿瘤体积。
肿瘤体积TV(mm3)＝肿瘤长径(mm)×肿瘤短径2(mm2)/2
将TV的结果总结示于表1。通过将化合物A及抗小鼠PD-1抗体合用，呈现出较之分别单独施予的情况而言统计上显著(*p＜0.05)优异的抗肿瘤效果(在重复测量方差分析(Repeated measures ANOVA)之后进行Dunnett多重比较(Dunnett’s type multiplecomparison))。
Figure BDA0001510192980000131
实施例3
向BALB/C小鼠移植结肠直肠癌细胞所得模型动物中的CBP/连环蛋白抑制剂(化合物1)与抗小鼠PD-L1抗体的合用效果
将作为结肠直肠癌细胞的CT26细胞皮下移植至雌性BALB/C小鼠的右腹部。饲养至平均肿瘤大小成为80mm3后，按照以下方式，以每组10例进行分组。
组1：背景介质(vehicle)组
组2：抗小鼠PD-L1抗体单独施予组
组3：化合物1单独施予组
组4：化合物1及抗小鼠PD-L1抗体的联合施予组
将化合物1(80mg/kg，每天1次，21天，腹腔内施予)及抗小鼠PD-L1抗体(目录编号：BE0101-100MG，BioXCell)(2mg/kg，每周2次，2周，腹腔施予)以各自单独或者联合的方式施予。
将施予开始日作为第0天，之后，在第3、6、9、12及15天，测定在各小鼠中长出的肿瘤的长径及短径。
根据下式，算出肿瘤体积。
肿瘤体积(mm3)＝肿瘤长径(mm)×肿瘤短径2(mm2)/2
将肿瘤体积的结果总结示于图4。通过将化合物1及抗小鼠PD-L1抗体合用，呈现出较之分别单独施予的情况而言统计上显著(*p＜0.01)优异的抗肿瘤效果(重复测量双因素方差分析(Repeated measurement Two-Way ANOVA))。
实施例4
CBP/连环蛋白抑制剂(化合物1)的抑制IL-10产生的作用
使用了由美国NIH基于人恶性黑色素瘤患者构建的细胞株(黑色素瘤)624mel细胞及928mel细胞。这些细胞已被活化，具有IL-10产生能力。
在培养液(含有10％FCS的RPMI 1640，添加有青霉素及链霉素)中，以1×105个细胞/2ml/孔的浓度将各黑色素瘤细胞接种于6孔培养板中。接种后，以成为规定的浓度的方式添加化合物1，培养24小时。在24小时后将培养上清液回收，测定上清液中的IL-10的浓度。IL-10浓度的测定使用了人IL10 OptEIA ELISA试剂盒(Human IL10 OptEIA ELISAset)(BD公司，#555157)。
将结果示于图5。
添加了1μM化合物1的情况下，在任一种细胞中均确认到化合物1对于增殖的影响，添加了0.2μM化合物1的情况下，在任一种细胞中均未确认到其对于增殖的影响。即使在对于增殖没有产生影响的条件下(0.2μM)，IL-10的产生也受到了抑制，由此可知，化合物1具有抑制IL-10产生的作用。
作为免疫检查点抑制剂的抗PD-1抗体、抗CTLA-4抗体在临床中呈现显著效果的患者是有限的，已知该效果依赖于癌症患者中的CD-8阳性T细胞数量。尤其是CD-8阳性细胞数与β-连环蛋白的表达呈完全逆相关，在β-连环蛋白的表达水平高的组织中，T细胞少，反之，在β-连环蛋白的表达水平低的组织中，T细胞多。
CBP/连环蛋白抑制剂在β-连环蛋白的表达水平高的组织中呈现了更高的效果，另一方面，其抑制IL-10产生的作用能够使CD-8阳性T细胞数量增加。因此，可知通过将CBP/连环蛋白抑制剂与免疫检查点抑制剂联合应用，能够得到更高的抗癌效果。
本申请以在日本提出申请的日本特愿2015-121479(申请日为2015年6月16日)为基础，上述申请的内容全部包括在本说明书中。

Claims (2)

1.癌症治疗药，其包含联合的CBP/连环蛋白抑制剂和免疫检查点抑制剂，
所述CBP/连环蛋白抑制剂为(6S,9aS)-N-苄基-8-((6-(3-(4-乙基哌嗪-1-基)氮杂环丁烷-1-基)吡啶-2-基)甲基)-6-((2-氟-4-羟基苯基)甲基)-4,7-二氧代-2-(丙-2-烯-1-基)-八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺，
所述免疫检查点抑制剂为抗PD-1抗体，且
所述癌症是β-连环蛋白被激活的癌症。
2.CBP/连环蛋白抑制剂和免疫检查点抑制剂的组合用于制造癌症治疗药的用途，
所述CBP/连环蛋白抑制剂为(6S,9aS)-N-苄基-8-((6-(3-(4-乙基哌嗪-1-基)氮杂环丁烷-1-基)吡啶-2-基)甲基)-6-((2-氟-4-羟基苯基)甲基)-4,7-二氧代-2-(丙-2-烯-1-基)-八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺，
所述免疫检查点抑制剂为抗PD-1抗体，且
所述癌症是β-连环蛋白被激活的癌症。
CN201680035322.7A 2015-06-16 2016-06-15 抗癌剂 Active CN107801379B (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2015121479 2015-06-16
JP2015-121479 2015-06-16
PCT/JP2016/067843 WO2016204193A1 (ja) 2015-06-16 2016-06-15 抗がん剤

Publications (2)

Publication Number Publication Date
CN107801379A CN107801379A (zh) 2018-03-13
CN107801379B true CN107801379B (zh) 2021-05-25

Family

ID=57545297

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201680035322.7A Active CN107801379B (zh) 2015-06-16 2016-06-15 抗癌剂

Country Status (14)

Country Link
US (1) US11369623B2 (zh)
EP (1) EP3311841B1 (zh)
JP (1) JP6757959B2 (zh)
KR (1) KR20180018695A (zh)
CN (1) CN107801379B (zh)
AU (1) AU2016279474B2 (zh)
BR (1) BR112017027227B1 (zh)
CA (1) CA2988707C (zh)
ES (1) ES2886107T3 (zh)
IL (1) IL256148B (zh)
MX (1) MX2017015896A (zh)
RU (1) RU2729936C2 (zh)
SG (1) SG11201710198YA (zh)
WO (1) WO2016204193A1 (zh)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2841809T3 (es) 2011-06-03 2021-07-09 Eisai R&D Man Co Ltd Biomarcadores para pronosticar y evaluar el grado de respuesta de sujetos con cáncer de tiroides y de riñón a compuestos de lenvatinib
US10441654B2 (en) 2014-01-24 2019-10-15 Children's Hospital Of Eastern Ontario Research Institute Inc. SMC combination therapy for the treatment of cancer
HRP20221047T1 (hr) 2014-08-28 2022-11-11 Eisai R&D Management Co., Ltd. Derivat kinolina visoke čistoće i postupak za njegovu proizvodnju
FI3263106T3 (fi) 2015-02-25 2024-01-03 Eisai R&D Man Co Ltd Menetelmä kinoliinijohdannaisen kitkeryyden tukahduttamiseksi
CA2978226A1 (en) 2015-03-04 2016-09-09 Merck Sharpe & Dohme Corp. Combination of a pd-1 antagonist and a vegfr/fgfr/ret tyrosine kinase inhibitor for treating cancer
CA2988707C (en) 2015-06-16 2023-10-10 Eisai R&D Management Co., Ltd. Combination of cbp/catenin inhibitor and immune checkpoint inhibitor for treating cancer
EP3581183B1 (en) * 2017-02-08 2023-11-29 Eisai R&D Management Co., Ltd. Tumor-treating pharmaceutical composition
MX2020007066A (es) * 2018-01-05 2020-09-09 Dicerna Pharmaceuticals Inc Reduccion de la expresion de beta-catenina e ido para potenciar la inmunoterapia.
CN110522926A (zh) * 2019-08-06 2019-12-03 天津大学 一种可视化纳米免疫制剂及其制备方法、应用
AU2020374883A1 (en) 2019-10-29 2022-05-26 Eisai R&D Management Co., Ltd. Combination of a PD-1 antagonist, a VEGFR/FGFR/RET tyrosine kinase inhibitor and a CBP/beta-catenin inhibitor for treating cancer
EP4129282A4 (en) * 2020-03-31 2024-05-01 Natural Medicine Inst Zhejiang Yangshengtang Co Ltd PHARMACEUTICAL COMBINATION AND USE THEREOF

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014061826A1 (en) * 2012-10-19 2014-04-24 Hiroyuki Kouji Treatment of hyperproliferative and pre-cancerous skin diseases using an inhibitor of cbp/catenin

Family Cites Families (374)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CU22545A1 (es) 1994-11-18 1999-03-31 Centro Inmunologia Molecular Obtención de un anticuerpo quimérico y humanizado contra el receptor del factor de crecimiento epidérmico para uso diagnóstico y terapéutico
GB1458148A (en) 1974-04-19 1976-12-08 Wyeth John & Brother Ltd Carbocyclic-fused ring quinoline derivatives
JPS57123267A (en) 1981-01-23 1982-07-31 Kansai Paint Co Ltd Thermosetting paint composition
US4526988A (en) 1983-03-10 1985-07-02 Eli Lilly And Company Difluoro antivirals and intermediate therefor
DE3587022T2 (de) 1984-02-17 1993-06-17 Genentech Inc Menschlicher transformationswachstumsfaktor und vorlaeufer oder fragment hiervon, zellen, dna, vektoren und verfahren zu ihrer herstellung, zusammensetzungen und produkte, die diese enthalten, sowie davon abgeleitete antikoerper und diagnostizierverfahren.
US4582789A (en) 1984-03-21 1986-04-15 Cetus Corporation Process for labeling nucleic acids using psoralen derivatives
DE8411409U1 (de) 1984-04-11 1984-08-30 Dr.-Ing. Walter Frohn-Betriebe, 8000 München Entgasungsventil fuer lager- und/oder transportbehaelter
US4563417A (en) 1984-08-31 1986-01-07 Miles Laboratories, Inc. Nucleic acid hybridization assay employing antibodies to intercalation complexes
ATE37196T1 (de) 1984-11-22 1988-09-15 Holsten Brauerei Ag Bier und verfahren zu dessen herstellung.
EP0184365B1 (en) 1984-12-04 1993-08-04 Eli Lilly And Company Improvements in the treatment of tumors in mammals
JPS61148115A (ja) 1984-12-21 1986-07-05 Tooa Eiyoo Kk 難溶性薬物の徐放性製剤及びその製造法
JPS62168137A (ja) 1985-12-20 1987-07-24 Fuji Photo Film Co Ltd ハロゲン化銀カラ−写真感光材料およびその処理方法
CH656535A5 (en) 1986-01-24 1986-07-15 Spirig Ag Process for the production of stable pharmaceutical tablets which disintegrate rapidly in water
JPH07106295B2 (ja) 1986-07-22 1995-11-15 エーザイ株式会社 調湿剤
US4743450A (en) 1987-02-24 1988-05-10 Warner-Lambert Company Stabilized compositions
CA1339136C (en) 1987-07-01 1997-07-29 Sailesh Amilal Varia Amorphous form of aztreonam
US5009894A (en) 1988-03-07 1991-04-23 Baker Cummins Pharmaceuticals, Inc. Arrangement for and method of administering a pharmaceutical preparation
AU4128089A (en) 1988-09-15 1990-03-22 Rorer International (Overseas) Inc. Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same
US5143854A (en) 1989-06-07 1992-09-01 Affymax Technologies N.V. Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof
US4983615A (en) 1989-06-28 1991-01-08 Hoechst-Roussel Pharmaceuticals Inc. Heteroarylamino- and heteroaryloxypyridinamine compounds which are useful in treating skin disorders
EP0408496A3 (en) 1989-07-12 1992-07-01 Ciba-Geigy Ag Solid dosage form for pharmaceutical substances
US5120548A (en) 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US5180818A (en) 1990-03-21 1993-01-19 The University Of Colorado Foundation, Inc. Site specific cleavage of single-stranded dna
US5210015A (en) 1990-08-06 1993-05-11 Hoffman-La Roche Inc. Homogeneous assay system using the nuclease activity of a nucleic acid polymerase
DE69132843T2 (de) 1990-12-06 2002-09-12 Affymetrix Inc N D Ges D Staat Identifizierung von Nukleinsäuren in Proben
GB9105677D0 (en) 1991-03-19 1991-05-01 Ici Plc Heterocyclic compounds
US5367057A (en) 1991-04-02 1994-11-22 The Trustees Of Princeton University Tyrosine kinase receptor flk-2 and fragments thereof
US5710158A (en) 1991-05-10 1998-01-20 Rhone-Poulenc Rorer Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
US5721237A (en) 1991-05-10 1998-02-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties
ES2108120T3 (es) 1991-05-10 1997-12-16 Rhone Poulenc Rorer Int Compuestos bis arilicos y heteroarilicos mono- y biciclicos que inhiben tirosina quinasa receptora de egf y/o pdgf.
JPH04341454A (ja) 1991-05-16 1992-11-27 Canon Inc シート収納装置
US5750376A (en) 1991-07-08 1998-05-12 Neurospheres Holdings Ltd. In vitro growth and proliferation of genetically modified multipotent neural stem cells and their progeny
US5211951A (en) 1991-07-24 1993-05-18 Merck & Co., Inc. Process for the manufacture of bioerodible poly (orthoester)s and polyacetals
JPH05194259A (ja) 1991-08-30 1993-08-03 Mitsubishi Kasei Corp 抗消化性潰瘍剤
US5200194A (en) 1991-12-18 1993-04-06 Alza Corporation Oral osmotic device
JPH08501203A (ja) 1992-06-03 1996-02-13 ケイス・ウエスタン・リザーブ・ユニバーシティー 生理活性物質を連続的に適用するための包帯
TW271400B (zh) 1992-07-30 1996-03-01 Pfizer
GB9221220D0 (en) 1992-10-09 1992-11-25 Sandoz Ag Organic componds
JPH06153952A (ja) 1992-11-26 1994-06-03 Nobuaki Tamamaki 微量未知二重鎖ｄｎａ分子の増幅、標識を行うための前処理方法
GB9323290D0 (en) 1992-12-10 1994-01-05 Zeneca Ltd Quinazoline derivatives
CA2150372C (en) 1993-01-19 2002-08-20 Nancy L. Mills Stable oral ci-981 formulation and process of preparing same
US6027880A (en) 1995-08-02 2000-02-22 Affymetrix, Inc. Arrays of nucleic acid probes and methods of using the same for detecting cystic fibrosis
US6156501A (en) 1993-10-26 2000-12-05 Affymetrix, Inc. Arrays of modified nucleic acid probes and methods of use
JPH07176103A (ja) 1993-12-20 1995-07-14 Canon Inc 光磁気記録再生システムならびにこれに用いる磁気ヘッド及び光磁気記録媒体
GB9326136D0 (en) 1993-12-22 1994-02-23 Erba Carlo Spa Biologically active 3-substituted oxindole derivatives useful as anti-angiogenic agents
IL112249A (en) 1994-01-25 2001-11-25 Warner Lambert Co Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds
US6811779B2 (en) 1994-02-10 2004-11-02 Imclone Systems Incorporated Methods for reducing tumor growth with VEGF receptor antibody combined with radiation and chemotherapy
JP3660391B2 (ja) 1994-05-27 2005-06-15 株式会社東芝 半導体装置の製造方法
JPH0848078A (ja) 1994-08-05 1996-02-20 Nippon Paper Ind Co Ltd 感熱記録体
GB9510757D0 (en) 1994-09-19 1995-07-19 Wellcome Found Therapeuticaly active compounds
US5656454A (en) 1994-10-04 1997-08-12 President And Fellows Of Harvard College Endothelial cell-specific enhancer
JP3207058B2 (ja) 1994-11-07 2001-09-10 財団法人国際超電導産業技術研究センター 超電導体薄膜及びその製造方法
IL115256A0 (en) 1994-11-14 1995-12-31 Warner Lambert Co 6-Aryl pyrido (2,3-d) pyrimidines and naphthyridines and their use
JPH08176138A (ja) 1994-12-19 1996-07-09 Mercian Corp イソクマリン誘導体
US5948438A (en) 1995-01-09 1999-09-07 Edward Mendell Co., Inc. Pharmaceutical formulations having improved disintegration and/or absorptivity
US5658374A (en) 1995-02-28 1997-08-19 Buckman Laboratories International, Inc. Aqueous lecithin-based release aids and methods of using the same
US5624937A (en) 1995-03-02 1997-04-29 Eli Lilly And Company Chemical compounds as inhibitors of amyloid beta protein production
US6579314B1 (en) 1995-03-10 2003-06-17 C.R. Bard, Inc. Covered stent with encapsulated ends
WO1996030347A1 (en) 1995-03-30 1996-10-03 Pfizer Inc. Quinazoline derivatives
GB9508538D0 (en) 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivatives
US5654005A (en) 1995-06-07 1997-08-05 Andrx Pharmaceuticals, Inc. Controlled release formulation having a preformed passageway
DK0831829T3 (da) 1995-06-07 2003-12-15 Pfizer Heterocykliske, ringkondenserede pyrimidinderivater
US5880141A (en) 1995-06-07 1999-03-09 Sugen, Inc. Benzylidene-Z-indoline compounds for the treatment of disease
JPH0923885A (ja) 1995-07-12 1997-01-28 Dai Ichi Seiyaku Co Ltd 遺伝子発現ライブラリー及びその製造法
GB9514265D0 (en) 1995-07-13 1995-09-13 Wellcome Found Hetrocyclic compounds
AR004010A1 (es) 1995-10-11 1998-09-30 Glaxo Group Ltd Compuestos heterociclicos
GB9520822D0 (en) 1995-10-11 1995-12-13 Wellcome Found Therapeutically active compounds
US6346398B1 (en) 1995-10-26 2002-02-12 Ribozyme Pharmaceuticals, Inc. Method and reagent for the treatment of diseases or conditions related to levels of vascular endothelial growth factor receptor
AU7340096A (en) 1995-11-07 1997-05-29 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives inhibiting autophosphorylation of growth factor receptor originating in platelet and pharmaceutical compositions containing the same
US5849759A (en) 1995-12-08 1998-12-15 Berlex Laboratories, Inc. Naphthyl-substituted benzimidazole derivatives as anti-coagulants
GB9604361D0 (en) 1996-02-29 1996-05-01 Pharmacia Spa 4-Substituted pyrrolopyrimidine compounds as tyrosine kinase inhibitors
JPH09234074A (ja) 1996-03-04 1997-09-09 Sumitomo Electric Ind Ltd アダプター二本鎖ｄｎａ及びそれを用いたｄｎａ増幅方法
DE69729583T2 (de) 1996-04-17 2005-06-09 Bristol-Myers Squibb Pharma Co. N-(amidinophenyl)-n'-(subst.)-3h-2,4-benzodiazepin-3-on derivative als faktor xa inhibitoren
WO1997046313A1 (en) 1996-06-07 1997-12-11 Eos Biotechnology, Inc. Immobilised linear oligonucleotide arrays
CA2258093A1 (en) 1996-06-28 1998-01-08 Mark E. Duggan Fibrinogen receptor antagonists
DE69716916T2 (de) 1996-07-13 2003-07-03 Glaxo Group Ltd Kondensierte heterozyklische verbindungen als protein kinase inhibitoren
HRP970371A2 (en) 1996-07-13 1998-08-31 Kathryn Jane Smith Heterocyclic compounds
ID19430A (id) 1996-07-13 1998-07-09 Glaxo Group Ltd Senyawa senyawa heterosiklik
JPH10147524A (ja) 1996-09-20 1998-06-02 Nippon Kayaku Co Ltd フォルスコリン誘導体含有経口製剤及び医薬製剤の製法
CN1252054C (zh) 1996-09-25 2006-04-19 曾尼卡有限公司 抑制生长因子的作用的喹啉衍生物
CN1072657C (zh) 1996-09-30 2001-10-10 日本农药株式会社 1,2,3－噻二唑衍生物和其盐以及农业园艺病毒防治剂及其使用方法
JPH10114655A (ja) 1996-10-09 1998-05-06 Kyowa Hakko Kogyo Co Ltd 固形製剤
EP0837063A1 (en) 1996-10-17 1998-04-22 Pfizer Inc. 4-Aminoquinazoline derivatives
KR20000057228A (ko) 1996-11-27 2000-09-15 디. 제이. 우드, 스피겔 알렌 제이 축합된 비사이클릭 피리미딘 유도체
TW486370B (en) 1996-12-25 2002-05-11 Yamanouchi Pharma Co Ltd Rapidly disintegrable pharmaceutical composition
AU6248798A (en) 1997-01-29 1998-08-18 Eli Lilly And Company Treatment for premenstrual dysphoric disorder
JP3040486U (ja) 1997-02-13 1997-08-19 有限会社ザップ フィッシングジャケット
CO4950519A1 (es) 1997-02-13 2000-09-01 Novartis Ag Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion
ES2277382T3 (es) 1997-02-19 2007-07-01 Berlex, Inc. Derivados n-heterociclicos como inhibidores de nos.
US6090556A (en) 1997-04-07 2000-07-18 Japan Science & Technology Corporation Method for quantitatively determining the expression of a gene
WO1998050346A2 (en) 1997-04-18 1998-11-12 Smithkline Beecham Plc Acetamide and urea derivatives, process for their preparation and their use in the treatment of cns disorders
JPH10316576A (ja) 1997-05-13 1998-12-02 Nissui Pharm Co Ltd キトサン含有錠剤
ES2151467T3 (es) 1997-05-23 2005-03-01 Bayer Corporation Arilureas para el tratamiento de enfermedades inflamatorias o inmunomoduladoras.
PL188450B1 (pl) 1997-06-10 2005-02-28 Synthon Bv Pochodne 4-fenylopiperydyny, sposób wytwarzania pochodnych 4-fenylopiperydyny, zastosowanie pochodnej 4-fenylopiperydyny oraz środek farmaceutyczny
US6093742A (en) 1997-06-27 2000-07-25 Vertex Pharmaceuticals, Inc. Inhibitors of p38
AU8283898A (en) 1997-06-30 1999-01-25 University Of Maryland At Baltimore Heparin binding-epidermal growth factor in the diagnosis of interstitial cystitis
BE1011251A3 (fr) 1997-07-03 1999-06-01 Ucb Sa Compositions pharmaceutiques administrables par voie orale, comprenant une substance active et une cyclodextrine.
GB9714129D0 (en) 1997-07-04 1997-09-10 Pfizer Ltd Azetidines
CO4940418A1 (es) 1997-07-18 2000-07-24 Novartis Ag Modificacion de cristal de un derivado de n-fenil-2- pirimidinamina, procesos para su fabricacion y su uso
JP3765918B2 (ja) 1997-11-10 2006-04-12 パイオニア株式会社 発光ディスプレイ及びその駆動方法
JP4194678B2 (ja) 1997-11-28 2008-12-10 キリンファーマ株式会社 キノリン誘導体およびそれを含む医薬組成物
TR200100874T2 (tr) 1997-12-22 2001-06-21 Bayer Corporation Simetrik ve simetrik olmayan sübstitüe edilmiş difenil üreler kullanılarak raf kinazın inhibe edilmesi
DE69836563T2 (de) 1997-12-22 2007-05-16 Bayer Pharmaceuticals Corp., West Haven INHIBIERUNG DER p38 KINASE-AKTIVITÄT DURCH DIE VERWENDUNG VON ARYL- UND HETEROARYL-SUBSTITUIERTEN HARNSTOFFEN
ATE529109T1 (de) 1997-12-22 2011-11-15 Bayer Healthcare Llc Hemmung der p38 kinase aktivität durch substituierte heterocyclische harnstoffe
TR200002618T2 (tr) 1997-12-22 2001-04-20 Bayer Corporation Sübstitüe edilmiş heterosiklik üreler kullanılarak raf kinazın inhibe edilmesi
RS49779B (sr) 1998-01-12 2008-06-05 Glaxo Group Limited, Biciklična heteroaromatična jedinjenja kao inhibitori protein tirozin kinaze
GB9800575D0 (en) 1998-01-12 1998-03-11 Glaxo Group Ltd Heterocyclic compounds
TR200002447T2 (tr) 1998-02-25 2000-11-21 Genetics Institute, Inc. Fosfolinaz enzimlerinin inhibitörleri
AU741992B2 (en) 1998-03-06 2001-12-13 Adare Pharmaceuticals S.R.L. Fast disintegrating tablets
DE19814257A1 (de) 1998-03-31 1999-10-07 Asta Medica Ag Brauseformulierungen
JPH11322596A (ja) 1998-05-12 1999-11-24 Shionogi & Co Ltd 白金錯体および環状リン酸エステルアミドを含有する抗癌剤
UA60365C2 (uk) 1998-06-04 2003-10-15 Пфайзер Продактс Інк. Похідні ізотіазолу, спосіб їх одержання, фармацевтична композиція та спосіб лікування гіперпроліферативного захворювання у ссавця
US8097648B2 (en) 1998-06-17 2012-01-17 Eisai R&D Management Co., Ltd. Methods and compositions for use in treating cancer
US6653341B1 (en) 1998-06-17 2003-11-25 Eisai Co., Ltd. Methods and compositions for use in treating cancer
PT1087960E (pt) 1998-06-17 2011-06-17 Eisai R&D Man Co Ltd Análogos macrocíclicos e métodos de sua utilização e preparação
ID27504A (id) 1998-10-01 2001-04-12 Novartis Ag Formulasi oral baru
BR9915487A (pt) 1998-11-19 2001-07-31 Warner Lambert Co N-[4-(3-cloro-4-flúor-fenilamino) - 7 - (3-morfolin-4-il-propóxi)-quinazolin-6-il]-acrilamida, um inibidor irreversìvel de tirosina quinases
WO2000042012A1 (en) 1999-01-13 2000-07-20 Bayer Corporation φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS
UA73492C2 (en) 1999-01-19 2005-08-15 Aromatic heterocyclic compounds as antiinflammatory agents
ES2208261T3 (es) 1999-01-22 2004-06-16 Kirin Beer Kabushiki Kaisha Derivados de quinolina y derivados de quinazolina.
JP3270834B2 (ja) 1999-01-27 2002-04-02 ファイザー・プロダクツ・インク 抗がん剤として有用なヘテロ芳香族二環式誘導体
UA71945C2 (en) 1999-01-27 2005-01-17 Pfizer Prod Inc Substituted bicyclic derivatives being used as anticancer agents
DK1154774T3 (da) 1999-02-10 2005-09-26 Astrazeneca Ab Quinazolinderivater som angiogenesisinhibitorer
GB9904103D0 (en) 1999-02-24 1999-04-14 Zeneca Ltd Quinoline derivatives
JP2000328080A (ja) 1999-03-12 2000-11-28 Shin Etsu Chem Co Ltd シートベルト用低摩擦化処理剤
YU13200A (sh) 1999-03-31 2002-10-18 Pfizer Products Inc. Postupci i intermedijeri za dobijanje anti-kancernih jedinjenja
US6342221B1 (en) 1999-04-28 2002-01-29 Board Of Regents, The University Of Texas System Antibody conjugate compositions for selectively inhibiting VEGF
AU4778500A (en) 1999-05-20 2000-12-12 Takeda Chemical Industries Ltd. Composition containing ascorbic acid salt
JP4304357B2 (ja) 1999-05-24 2009-07-29 独立行政法人理化学研究所 完全長ｃＤＮＡライブラリーの作成法
PE20010306A1 (es) 1999-07-02 2001-03-29 Agouron Pharma Compuestos de indazol y composiciones farmaceuticas que los contienen utiles para la inhibicion de proteina kinasa
JP2001047890A (ja) 1999-08-06 2001-02-20 Toyota Motor Corp 車両用パワープラントの制御装置
AU6762400A (en) 1999-08-12 2001-03-13 Cor Therapeutics, Inc. Inhibitors of factor xa
DOP2000000070A (es) 1999-09-28 2002-02-28 Bayer Healthcare Llc Piridinas y piridacinas sustituidas con actividad de inhibición de angiogénesis
US6762180B1 (en) 1999-10-13 2004-07-13 Boehringer Ingelheim Pharma Kg Substituted indolines which inhibit receptor tyrosine kinases
UA75054C2 (uk) 1999-10-13 2006-03-15 Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг Заміщені в положенні 6 індолінони, їх одержання та їх застосування як лікарського засобу
JP2001131071A (ja) 1999-10-29 2001-05-15 Meiji Seika Kaisha Ltd 非晶質および非晶質を含有する医薬組成物
JP2003525595A (ja) 1999-11-01 2003-09-02 キュラゲン コーポレイション 脈管形成に含まれる差動発現遺伝子、それにコードされるポリペプチド、及びそれを用いた方法
US20080241835A1 (en) 1999-11-01 2008-10-02 Genentech, Inc. Differentially expressed genes involved in angiogenesis, the polypeptides encoded thereby, and methods of using the same
AU1617901A (en) 1999-11-16 2001-05-30 Boehringer Ingelheim Pharmaceuticals, Inc. Urea derivatives as anti-inflammatory agents
UA75055C2 (uk) 1999-11-30 2006-03-15 Пфайзер Продактс Інк. Похідні бензоімідазолу, що використовуються як антипроліферативний засіб, фармацевтична композиція на їх основі
CO5271715A1 (es) 1999-12-21 2003-04-30 Sugen Inc 7-aza-indolin-2-onas sustituidas en 4 y su uso como inhibidores de proteiuna quinasa
US20020010203A1 (en) 1999-12-22 2002-01-24 Ken Lipson Methods of modulating c-kit tyrosine protein kinase function with indolinone compounds
TWI281915B (en) 1999-12-24 2007-06-01 Kirin Brewery Quinoline and quinazoline derivatives and drugs containing the same
AU2223501A (en) 1999-12-24 2001-07-09 Kyowa Hakko Kogyo Co. Ltd. Fused purine derivatives
PT1255752E (pt) 2000-02-15 2007-10-17 Pharmacia & Upjohn Co Llc Inibidores de proteína quinases: 2-indolinonas substituídas com pirrolo
JP3657203B2 (ja) 2000-04-21 2005-06-08 エーザイ株式会社 銅クロロフィリン塩含有液剤組成物
CN1116047C (zh) 2000-06-05 2003-07-30 华中科技大学 用泥鳅制成的护肝功能食品及其制备方法
US20020040127A1 (en) 2000-06-09 2002-04-04 Yuqiu Jiang Compositions and methods for the therapy and diagnosis of colon cancer
AU2001277621A1 (en) 2000-08-09 2002-03-04 Astrazeneca Ab Antiangiogenic bicyclic derivatives
ATE355275T1 (de) 2000-10-20 2006-03-15 Eisai R&D Man Co Ltd Stickstoff-enthaltende aromatische ringverbindungen zur behandlung von tumorerkrankungen
TWI283575B (en) 2000-10-31 2007-07-11 Eisai Co Ltd Medicinal compositions for concomitant use as anticancer agent
PT1339458E (pt) 2000-11-22 2007-11-09 Novartis Ag Combinação compreendendo um agente para diminuir a actividade do vegf e um agente para diminuir a actividade do egf
WO2002044156A2 (en) 2000-11-29 2002-06-06 Glaxo Group Limited Benzimidazole derivatives useful as tie-2 and/or vegfr-2 inhibitors
US6544552B2 (en) 2001-01-11 2003-04-08 Particle And Coating Technologies, Inc. Method of producing porous tablets with improved dissolution properties
CN100523216C (zh) 2001-03-02 2009-08-05 匹兹堡大学 Pcr方法
US6960580B2 (en) 2001-03-08 2005-11-01 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic substituted quinoline compounds
CA2442849A1 (en) 2001-04-06 2002-10-17 Wyeth Antineoplastic combinations such as rapamycin together with gemcitabine or fluorouracil
US20040171068A1 (en) 2001-04-19 2004-09-02 Juergen Wehland Method for producing stable, regeneratable antibody arrays
EP1382604B1 (en) 2001-04-27 2005-12-28 Kirin Beer Kabushiki Kaisha Quinoline derivative having azolyl group and quinazoline derivative
JP3602513B2 (ja) 2001-04-27 2004-12-15 麒麟麦酒株式会社 アゾリル基を有するキノリン誘導体およびキナゾリン誘導体
JP2003026576A (ja) 2001-05-09 2003-01-29 Eisai Co Ltd 味覚改善製剤
US6812341B1 (en) 2001-05-11 2004-11-02 Ambion, Inc. High efficiency mRNA isolation methods and compositions
PT1392313E (pt) 2001-05-16 2007-07-17 Novartis Ag Combinação que compreende n - ( 5- [ 4- ( metil-piperazinomrtil ) - benxoilamido ] - 2 -metilfenil ) - 4 -( 3 - piridil ) - 2 - pirimidina-amina e um agente quimioterapêutico
PE20030062A1 (es) 2001-05-30 2003-02-08 Sugen Inc Derivados aralquilsulfonil-3-(pirrol-2-ilmetiliden)-2-indolinona como inhibidores de quinasas
DE60233736D1 (de) 2001-06-22 2009-10-29 Kirin Pharma K K Chinolinderivat und chinazolinderivat, die die selbstphosphorylierung des hepatocytus-proliferator-rezeptors hemmen, und diese enthaltende medizinische zusammensetzung
GB0117144D0 (en) 2001-07-13 2001-09-05 Glaxo Group Ltd Process
US20030013208A1 (en) 2001-07-13 2003-01-16 Milagen, Inc. Information enhanced antibody arrays
JP4827154B2 (ja) 2001-07-25 2011-11-30 株式会社オーイズミ 遊技装置
JP3088018U (ja) 2001-08-02 2002-08-30 ユーエス工業株式会社 垂木支持用ブラケットを備えたパイプバンド
GB0119467D0 (en) 2001-08-09 2001-10-03 Smithkline Beecham Plc Novel compound
US7063946B2 (en) 2001-09-10 2006-06-20 Meso Scale Technologies, Llc. Methods, reagents, kits and apparatus for protein function analysis
JP2005511506A (ja) 2001-09-20 2005-04-28 アブ サイエンス 間質性膀胱炎を治療するための強力で選択的かつ非毒性のｃ−ｋｉｔ阻害剤の使用方法
US6765012B2 (en) 2001-09-27 2004-07-20 Allergan, Inc. 3-(Arylamino)methylene-1,3-dihydro-2H-indol-2-ones as kinase inhibitors
JP4130179B2 (ja) 2001-09-27 2008-08-06 ノバルティス アクチエンゲゼルシャフト 骨髄腫を処置するためのｃ−ｋｉｔ阻害剤の使用
WO2003030908A2 (en) 2001-10-09 2003-04-17 The University Of Cincinnati Inhibitors of the egf receptor for the treatment of thyroid cancer
US7658924B2 (en) 2001-10-11 2010-02-09 Amgen Inc. Angiopoietin-2 specific binding agents
US7521053B2 (en) 2001-10-11 2009-04-21 Amgen Inc. Angiopoietin-2 specific binding agents
US7576084B2 (en) 2001-10-12 2009-08-18 Choongwae Pharma Corporation Reverse-turn mimetics and method relating thereto
US7671054B1 (en) 2001-10-12 2010-03-02 Choongwae Pharma Corporation Reverse-turn mimetics and method relating thereto
US8080657B2 (en) 2001-10-12 2011-12-20 Choongwae Pharma Corporation Compounds of reverse turn mimetics and the use thereof
US20040072831A1 (en) 2001-10-12 2004-04-15 Choongwae Pharma Corporation Reverse-turn mimetics and method relating thereto
KR100910307B1 (ko) 2001-10-12 2009-08-03 주식회사 중외제약 리버스-턴 유사체 및 이와 관련된 방법
EP1447405A4 (en) 2001-10-17 2005-01-12 Kirin Brewery QUINOLINE OR QUINAZOLINE DERIVATIVES INHIBITING THE AUTOPHOSPHORYLATION OF FIBROBLAST GROWTH FACTOR RECEPTORS
PL370137A1 (en) 2001-11-27 2005-05-16 Wyeth Holdings Corporation 3-cyanoquinolines as inhibitors of egf-r and her2 kinases
GB0201508D0 (en) 2002-01-23 2002-03-13 Novartis Ag Organic compounds
CA2478169C (en) 2002-03-04 2013-04-16 Imclone Systems Incorporated Human antibodies specific to kdr and uses thereof
JP2003252737A (ja) 2002-03-04 2003-09-10 Shin Etsu Chem Co Ltd 口腔用組成物
AU2003211594A1 (en) 2002-03-05 2003-09-16 Eisai Co., Ltd. Antitumor agent comprising combination of sulfonamide-containing heterocyclic compound with angiogenesis inhibitor
JP4619658B2 (ja) 2002-03-12 2011-01-26 富山化学工業株式会社 快い味の経口懸濁液および方法
US20050233991A1 (en) 2002-03-20 2005-10-20 Ravi Salgia Methods and compositions for the identification, assessment, and therapy of small cell lung cancer
US6790852B2 (en) 2002-04-18 2004-09-14 Hoffmann-La Roche Inc. 2-(2,6-dichlorophenyl)-diarylimidazoles
US7598258B2 (en) 2002-05-01 2009-10-06 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives inhibiting autophosphorylation of macrophage colony stimulating factor receptor
TW200406374A (en) 2002-05-29 2004-05-01 Novartis Ag Diaryl urea derivatives useful for the treatment of protein kinase dependent diseases
UA77303C2 (en) 2002-06-14 2006-11-15 Pfizer Derivatives of thienopyridines substituted by benzocondensed heteroarylamide useful as therapeutic agents, pharmaceutical compositions and methods for their use
WO2004006862A2 (en) 2002-07-16 2004-01-22 Children's Medical Center Corporation A method for the modulation of angiogenesis
JP2005533893A (ja) 2002-07-22 2005-11-10 アスペン・エアロジェルズ・インコーポレーテッド ポリイミドエーロゲル、炭素エーロゲル、及び金属炭化物エーロゲル並びにこれらの製造方法。
US7169936B2 (en) 2002-07-23 2007-01-30 Boehringer Ingelheim Pharma Gmbh & Co. Kg Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments
US7252976B2 (en) 2002-08-28 2007-08-07 Board Of Regents The University Of Texas System Quantitative RT-PCR to AC133 to diagnose cancer and monitor angiogenic activity in a cell sample
JP4183193B2 (ja) 2002-08-30 2008-11-19 エーザイ・アール・アンド・ディー・マネジメント株式会社 含窒素芳香環誘導体
JP2006504745A (ja) 2002-10-09 2006-02-09 コーザン バイオサイエンシス インコーポレイテッド エポｄ及び５−ｆｕ／ゲムシタビン
GB0223380D0 (en) 2002-10-09 2002-11-13 Astrazeneca Ab Combination therapy
CA2502219C (en) 2002-10-16 2012-05-29 Takeda Pharmaceutical Company Limited A process for producing an amorphous isomer of lansoprazole
JP4749660B2 (ja) 2002-10-16 2011-08-17 武田薬品工業株式会社 安定な固形製剤
ATE327977T1 (de) 2002-10-21 2006-06-15 Warner Lambert Co Tetrahydrochinolin-derivate als crth2 antagonisten
EP1566379A4 (en) 2002-10-29 2005-11-09 Kirin Brewery QUINOLINE AND QUINAZOLINE DERIVATIVES INHIBITING THE AUTOPHOSPHORYLATION OF FLT3 AND MEDICAL COMPOSITIONS CONTAINING SAME
DE10250711A1 (de) 2002-10-31 2004-05-19 Degussa Ag Pharmazeutische und kosmetische Zubereitungen
CA2502979A1 (en) 2002-11-06 2004-05-21 Cyclacel Limited Pharmaceutical composition comprising a cdk inhibitor and gemcitabine
GB0226434D0 (en) 2002-11-13 2002-12-18 Astrazeneca Ab Combination product
ITSV20020056A1 (it) 2002-11-14 2004-05-15 Alstom Transp Spa Dispositivo e metodo di verifica di motori software logici di comando di impianti ferroviari, in particolare di impianti di stazione
AR042042A1 (es) 2002-11-15 2005-06-08 Sugen Inc Administracion combinada de una indolinona con un agente quimioterapeutico para trastornos de proliferacion celular
US7399866B2 (en) 2003-01-14 2008-07-15 Cytokinetics, Inc. Compounds, compositions, and methods
JP3581361B1 (ja) 2003-02-17 2004-10-27 株式会社脳機能研究所 脳活動測定装置
AU2004212976A1 (en) 2003-02-19 2004-09-02 Biovail Laboratories Inc. Rapid absorption selective 5-HT agonist formulations
DK1603570T5 (da) 2003-02-26 2013-12-09 Sugen Inc Aminoheteroarylforbindelser som proteinkinaseinhibitorer
ZA200507321B (en) 2003-03-05 2007-03-28 Celgene Corp Diphenylethylene compounds and uses thereof
EP1604665B1 (en) 2003-03-10 2011-05-11 Eisai R&D Management Co., Ltd. C-kit kinase inhibitor
MXPA05009751A (es) 2003-03-14 2005-10-26 Taisho Pharmaceutical Co Ltd Anticuerpo monoclonal e hibridoma que lo produce.
EP1604981A4 (en) 2003-03-14 2008-12-24 Ono Pharmaceutical Co NITROGENIC HETEROCYCLIC DERIVATIVES AND MEDICAMENTS CONTAINING THEM AS AN ACTIVE SUBSTANCE
EP1608333A1 (en) 2003-04-02 2005-12-28 Pliva Istrazivanje i Razvoj d.o.o. Pharmaceutical compositions having reduced bitter taste
US20050014753A1 (en) 2003-04-04 2005-01-20 Irm Llc Novel compounds and compositions as protein kinase inhibitors
US20070117842A1 (en) 2003-04-22 2007-05-24 Itaru Arimoto Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same
EP1473043A1 (en) 2003-04-29 2004-11-03 Boehringer Ingelheim Pharma GmbH & Co.KG Pharmaceutical combination for the treatment of diseases involving cell proliferation, migration or apotosis of myeloma cells, or angiogenesis
US7107104B2 (en) 2003-05-30 2006-09-12 Medtronic, Inc. Implantable cortical neural lead and method
JP2005008534A (ja) 2003-06-17 2005-01-13 Soc De Conseils De Recherches & D'applications Scientifiques (Scras) 抗癌剤及び癌の治療方法
KR20120093411A (ko) 2003-07-10 2012-08-22 아스트라제네카 아베 백금 화합물 및 임의적으로 이온화 방사능과 조합된 퀴나졸린 유도체 ｚｄ6474의 혈관신생 및/또는 증가된 혈관 투과성 관련 질환 치료 용도
CA2535242A1 (en) 2003-08-15 2005-02-24 Ab Science Use of c-kit inhibitors for treating type ii diabetes
US7485658B2 (en) 2003-08-21 2009-02-03 Osi Pharmaceuticals, Inc. N-substituted pyrazolyl-amidyl-benzimidazolyl c-Kit inhibitors
AP2006003549A0 (en) 2003-08-21 2006-04-30 Osi Pharm Inc N-substituted benzimidazolyl C-kit inhibitors.
AP2006003553A0 (en) 2003-08-21 2006-04-30 Osi Pharm Inc N-substituted pyrazolyl-amidyl-benzimidazolyl C- kit inhibitors.
US7312243B1 (en) 2003-08-29 2007-12-25 Jay Pravda Materials and methods for treatment of gastrointestinal disorders
CA2537991A1 (en) 2003-09-23 2005-03-31 Novartis Ag Combination of a vegf receptor inhibitor with a chemotherapeutic agent
ATE517091T1 (de) 2003-09-26 2011-08-15 Exelixis Inc C-met-modulatoren und verwendungsverfahren
KR200340552Y1 (ko) 2003-10-08 2004-02-11 주식회사 엘지화학 창틀 내부에 블라인드 및 방범창 설치가 용이한 이중창틀
JP2005124034A (ja) 2003-10-20 2005-05-12 Nippon Telegr & Teleph Corp <Ntt> 発信者の特定及び発信者への呼び返しを可能とする回線設定方法
WO2005044788A1 (ja) 2003-11-11 2005-05-19 Eisai Co., Ltd. ウレア誘導体およびその製造方法
TW200529849A (en) 2003-11-28 2005-09-16 Novartis Ag Diaryl urea derivatives in the treatment of protein kinase dependent diseases
US6984403B2 (en) 2003-12-04 2006-01-10 Pfizer Inc. Azithromycin dosage forms with reduced side effects
CN1946417A (zh) 2003-12-05 2007-04-11 阿德内克休斯治疗公司 2型血管内皮生长因子受体的抑制剂
PL1698623T3 (pl) 2003-12-25 2015-08-31 Eisai R&D Man Co Ltd Postać krystaliczna soli 4-(3-chloro-4-(cyklopropyloaminokarbonylo)aminofenoksy)-7-metoksy-6-chinolinokarboksamidu lub jej solwatu i sposoby ich wytwarzania
US7435823B2 (en) 2004-01-23 2008-10-14 Amgen Inc. Compounds and methods of use
JP4457108B2 (ja) 2004-02-27 2010-04-28 エーザイ・アール・アンド・ディー・マネジメント株式会社 新規ピリジン誘導体およびピリミジン誘導体（１）
KR20050091462A (ko) 2004-03-12 2005-09-15 한국과학기술연구원 푸로피리미딘 화합물 및 이를 포함하는 ｄｄｒ2 티로신키나아제 활성 저해제
US7459562B2 (en) 2004-04-23 2008-12-02 Bristol-Myers Squibb Company Monocyclic heterocycles as kinase inhibitors
AU2005245492A1 (en) 2004-05-21 2005-12-01 Novartis Vaccines And Diagnostics, Inc. Substituted quinoline derivatives as mitotic kinesin inhibitors
RU2006146619A (ru) 2004-06-03 2008-07-20 Ф.Хоффманн-Ля Рош Аг (Ch) Лечение гемцитабином и ингибитором рецептора эпидермального фактора роста(egfr)
AU2005265027A1 (en) 2004-06-18 2006-01-26 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Methods for the identification and use of compounds suitable for the treatment of drug resistant cancer cells
US7173031B2 (en) 2004-06-28 2007-02-06 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
US20050288521A1 (en) 2004-06-29 2005-12-29 Phytogen Life Sciences Inc. Semi-synthetic conversion of paclitaxel to docetaxel
JP5368701B2 (ja) 2004-07-02 2013-12-18 エクセリクシス、インコーポレイテッド ｃ−Ｍｅｔモジュレーター及び使用方法
US8772269B2 (en) 2004-09-13 2014-07-08 Eisai R&D Management Co., Ltd. Use of sulfonamide-including compounds in combination with angiogenesis inhibitors
EP2364699A1 (en) 2004-09-13 2011-09-14 Eisai R&D Management Co., Ltd. Joint use of sulfonamide based compound with angiogenesis inhibitor
US7306807B2 (en) 2004-09-13 2007-12-11 Wyeth Hemorrhagic feline calicivirus, calicivirus vaccine and method for preventing calicivirus infection or disease
AU2005283422C1 (en) 2004-09-17 2017-02-02 Eisai R & D Management Co., Ltd. Medicinal composition
WO2006036941A2 (en) 2004-09-27 2006-04-06 Kosan Biosciences Incorporated Specific kinase inhibitors
KR20070057901A (ko) 2004-10-01 2007-06-07 에자이 알앤드디 매니지먼트 가부시키가이샤 미립자 함유 조성물 및 그의 제조 방법
CN101495513B (zh) 2004-10-19 2014-08-06 安姆根有限公司 促血管生成素-2特异性结合剂
EP1827445A2 (en) 2004-11-22 2007-09-05 King Pharmaceuticals Research and Development Inc. Enhancing treatment of cancer and hif-1 mediated disoders with adenosine a3 receptor antagonists
BRPI0517396A (pt) 2004-11-23 2008-10-14 Dong Wha Pharm Ind Co Ltd preparação oral com melhor biodisponibilidade
MX2007006230A (es) 2004-11-30 2007-07-25 Amgen Inc Quinolinas y analogos de quinazolinas y su uso como medicamentos para tratar cancer.
CN100341504C (zh) 2004-12-01 2007-10-10 鲁南制药集团股份有限公司 佐米曲普坦速释制剂
EP1824843A2 (en) 2004-12-07 2007-08-29 Locus Pharmaceuticals, Inc. Inhibitors of protein kinases
NZ556029A (en) 2004-12-21 2010-04-30 Astrazeneca Ab Antibodies directed to angiopoietin-2 and uses thereof
JP2006230816A (ja) 2005-02-25 2006-09-07 H & A Investment:Kk サンダル用ホルダー
WO2006090931A1 (ja) 2005-02-28 2006-08-31 Eisai R & D Management Co., Ltd. スルホンアミド化合物の抗癌剤との新規併用
EP1859793B1 (en) 2005-02-28 2011-04-20 Eisai R&D Management Co., Ltd. Novel combinational use of a sulfonamide compound in the treatment of cancer
US20080286282A1 (en) 2005-02-28 2008-11-20 Eisai R & D Management Co., Ltd. Novel Use of Sulfonamide Compound in Combination with Angiogenesis Inhibitor
WO2006123517A1 (ja) 2005-04-26 2006-11-23 Kissei Pharmaceutical Co., Ltd. ヒドロキシノルエフェドリン誘導体塩酸塩の結晶多形
AU2006244885B2 (en) 2005-05-09 2011-03-31 E. R. Squibb & Sons, L.L.C. Human monoclonal antibodies to programmed death 1(PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
CA2608733A1 (en) 2005-05-17 2007-02-01 Plexxikon, Inc. Pyrrol (2,3-b) pyridine derivatives protein kinase inhibitors
DE602006011150D1 (de) 2005-05-17 2010-01-28 Actelion Pharmaceuticals Ltd Dispergierbare bosertan-tablette
EP3088400A1 (en) 2005-06-22 2016-11-02 Plexxikon Inc. Pyrrolo[2,3-b]pyridine derivatives as protein kinase inhibitors
JP4733700B2 (ja) 2005-06-23 2011-07-27 エーザイ・アール・アンド・ディー・マネジメント株式会社 ４−（３−クロロ−４−（シクロプロピルアミノカルボニル）アミノフェノキシ）−７−メトキシ−６−キノリンカルボキサミドの塩のアモルファスおよびその製造方法
US7550483B2 (en) 2005-06-23 2009-06-23 Eisai R&D Management Co., Ltd. Amorphous salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and process for preparing the same
EP1926494A2 (en) 2005-06-29 2008-06-04 Carlo Pedone Agonistic and antagonistic peptide mimetics of the vegf alpha-helix binding region for use in therapy
AU2006230974C1 (en) 2005-07-11 2012-02-02 Takeda Pharma A/S Benzimidazole formulation
US8101799B2 (en) 2005-07-21 2012-01-24 Ardea Biosciences Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK
US7820664B2 (en) 2007-01-19 2010-10-26 Bayer Schering Pharma Ag Inhibitors of MEK
WO2007014335A2 (en) 2005-07-27 2007-02-01 The University Of Texas System Combinations comprising gemcitabine and tyrosine kinase inhibitors for the treatment of pancreatic cancer
EP1925941B1 (en) 2005-08-01 2012-11-28 Eisai R&D Management Co., Ltd. Method for prediction of the efficacy of vascularization inhibitor
EP1925676A4 (en) 2005-08-02 2010-11-10 Eisai R&D Man Co Ltd TEST METHOD FOR THE EFFECT OF A VASCULARIZATION INHIBITOR
ES2424651T3 (es) 2005-08-24 2013-10-07 Eisai R&D Management Co., Ltd. Nuevo derivado de piridina y derivado de pirimidina (3)
WO2007026864A1 (ja) 2005-09-01 2007-03-08 Eisai R & D Management Co., Ltd. 崩壊性の改善された医薬組成物の製造方法
CN1308012C (zh) 2005-11-02 2007-04-04 广州中医药大学第二附属医院 一种治疗脑出血的中药组合物及其制备方法
CA2627598C (en) 2005-11-07 2013-06-25 Eisai R & D Management Co., Ltd. Use of combination of anti-angiogenic substance and c-kit kinase inhibitor
AU2006311433B2 (en) 2005-11-08 2012-06-28 Choongwae Pharma Corporation Alpha-helix mimetics and method relating to the treatment of cancer stem cells
EP1964837A4 (en) 2005-11-22 2010-12-22 Eisai R&D Man Co Ltd Antitumor agent against multiple myeloma
DK1959955T3 (da) 2005-12-05 2011-02-07 Pfizer Prod Inc Fremgangsmåde til behandling af abnorm cellevækst
AR059066A1 (es) 2006-01-27 2008-03-12 Amgen Inc Combinaciones del inhibidor de la angiopoyetina -2 (ang2) y el inhibidor del factor de crecimiento endotelial vascular (vegf)
KR100728926B1 (ko) 2006-03-20 2007-06-15 삼성전자주식회사 3축 힌지 구조를 갖는 휴대용 전자기기
CN101443009A (zh) 2006-05-18 2009-05-27 卫材R&D管理有限公司 针对甲状腺癌的抗肿瘤剂
WO2008023698A1 (fr) 2006-08-23 2008-02-28 Eisai R & D Management Co., Ltd. Sel de dérivé de phénoxypyridine ou son cristal et procédé de production
EP2065372B1 (en) 2006-08-28 2012-11-28 Eisai R&D Management Co., Ltd. Antitumor agent for undifferentiated gastric cancer
US7790885B2 (en) 2006-08-31 2010-09-07 Eisai R&D Management Co., Ltd. Process for preparing phenoxypyridine derivatives
AU2007293280A1 (en) 2006-09-07 2008-03-13 Astrazeneca Ab Method for evaluating patients for treatment with drugs targeting RET receptor tyrosine kinase
BRPI0719276A2 (pt) 2006-10-12 2014-04-29 Ptc Therapeutics Inc Métodos para tratar, prevenir ou controlar uma doença associada com uma mutação sem sentido, para tratar, prevenir ou reduzir tosse, para aumentar expressão de distrofina em músculo de um paciente e para administrar um composto.
JP2009184925A (ja) 2006-11-02 2009-08-20 Dai Ichi Seiyaku Co Ltd ５−（１ｈ−１，２，３−トリアゾール−４−イル）−１ｈ−ピラゾール誘導体
WO2008088088A1 (ja) 2007-01-19 2008-07-24 Eisai R & D Management Co., Ltd. 膵癌治療用組成物
WO2008093855A1 (ja) 2007-01-29 2008-08-07 Eisai R & D Management Co., Ltd. 未分化型胃癌治療用組成物
JPWO2008102870A1 (ja) 2007-02-23 2010-05-27 エーザイ・アール・アンド・ディー・マネジメント株式会社 Ｈｇｆｒ遺伝子増幅細胞株に優れた細胞増殖阻害効果および抗腫瘍効果を示すピリジン誘導体またはピリミジン誘導体
US20100098690A1 (en) 2007-03-05 2010-04-22 Kyowa Hakko Kirin Co., Ltd. Pharmaceutical composition
US20100104567A1 (en) 2007-03-05 2010-04-29 Kyowa Hakko Kirin Co., Ltd. Pharmaceutical composition
GB2448181B (en) 2007-04-05 2011-11-09 Ford Global Tech Llc Vehicle headlight beam controls
US7807172B2 (en) 2007-06-13 2010-10-05 University Of Washington Methods and compositions for detecting thyroglobulin in a biological sample
PE20090368A1 (es) 2007-06-19 2009-04-28 Boehringer Ingelheim Int Anticuerpos anti-igf
CA2694646C (en) 2007-07-30 2017-09-05 Ardea Biosciences, Inc. Combinations of mek inhibitors and raf kinase inhibitors and uses thereof
CA2704000C (en) 2007-11-09 2016-12-13 Eisai R&D Management Co., Ltd. Combination of anti-angiogenic substance and anti-tumor platinum complex
JP2009132660A (ja) 2007-11-30 2009-06-18 Eisai R & D Management Co Ltd 食道癌治療用組成物
CA2713930A1 (en) 2008-01-29 2009-08-06 Eisai R & D Management Co., Ltd. Combined use of angiogenesis inhibitor and taxane
GB2456907A (en) 2008-01-30 2009-08-05 Astrazeneca Ab Method for determining subsequent VEGFR2 inhibitor therapy comprising measuring baseline VEGF level.
EP2259844A4 (en) 2008-03-05 2012-02-01 Vicus Therapeutics Llc COMPOSITIONS AND METHODS FOR MUCOSITIS AND ONCOLOGY THERAPIES
US8044240B2 (en) 2008-03-06 2011-10-25 Ardea Biosciences Inc. Polymorphic form of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide and uses thereof
EP2262837A4 (en) 2008-03-12 2011-04-06 Merck Sharp & Dohme PD-1 BINDING PROTEINS
KR20110014149A (ko) 2008-04-14 2011-02-10 아디아 바이오사이언스즈 인크. 조성물 및 이것의 제조 및 사용 방법
WO2009137649A2 (en) 2008-05-07 2009-11-12 The Trustees Of The University Of Pennsylvania Methods for treating thyroid cancer
CA2723617A1 (en) 2008-05-14 2009-11-19 Amgen Inc. Combinations vegf(r) inhibitors and hepatocyte growth factor (c-met) inhibitors for the treatment of cancer
EP2303887B1 (en) 2008-06-06 2015-08-05 Prism Biolab Corporation Alpha helix mimetics and methods relating thereto
WO2009150256A1 (en) 2008-06-13 2009-12-17 Institut National De La Sante Et De La Recherche Medicale (Inserm) Markers for predicting response and survival in anti-egfr treated patients
BRPI0915901A2 (pt) 2008-07-11 2015-10-27 Novartis Ag combinação de (a) um inibidor de fosfoinositídeo 3-quinase e (b) um modulador da via ras/raf/mek
US8691819B2 (en) 2008-10-14 2014-04-08 Prism Biolab Corporation Alpha helix mimetic compositions for treating cancer and other CBP/catenin-mediated diseases and conditions
EP2350663A2 (en) 2008-10-21 2011-08-03 Bayer HealthCare LLC Identification of signature genes associated with hepatocellular carcinoma
WO2010086964A1 (ja) 2009-01-28 2010-08-05 株式会社 静岡カフェイン工業所 がん治療のための併用療法
UA103918C2 (en) 2009-03-02 2013-12-10 Айерем Элелси N-(hetero)aryl, 2-(hetero)aryl-substituted acetamides for use as wnt signaling modulators
BRPI1014574A2 (pt) 2009-04-15 2015-08-25 Jw Pharmaceutical Corp Compostos inéditos de imitadores de ligação revesa, método para fabricar os mesmos e uso destes
US9040531B2 (en) 2009-05-07 2015-05-26 Prism BioLab Co., Ltd. Alpha helix mimetics and methods relating thereto
AU2010279359A1 (en) 2009-08-07 2012-02-16 The Wistar Institute Compositions containing JARID1B inhibitors and methods for treating cancer
HUE026957T2 (en) 2009-08-19 2016-07-28 Eisai R&D Man Co Ltd A pharmaceutical composition comprising a quinoline derivative
US20120207753A1 (en) 2009-08-21 2012-08-16 Centre Hospitalier Universitaire Vaudois Methods of using cd44 fusion proteins to treat cancer
EP2293071A1 (en) 2009-09-07 2011-03-09 Universität Zu Köln Biomarker for colorectal cancer
US9174988B2 (en) * 2009-10-27 2015-11-03 Trustees Of Boston University Small molecule inhibitors of hepatitis C virus
ES2573515T3 (es) 2010-06-25 2016-06-08 Eisai R&D Management Co., Ltd. Agente antitumoral que emplea compuestos con efecto inhibitorio de cinasas combinados
KR20130091331A (ko) 2010-07-16 2013-08-16 교와 핫꼬 기린 가부시키가이샤 함질소 방향족 복소환 유도체
BR112013001431A2 (pt) 2010-07-19 2016-05-31 Hoffmann La Roche método de identificação de pacientes com maior probabilidade de reação a terapia anticâncer
RU2013106938A (ru) 2010-07-19 2014-08-27 Ф.Хоффманн-Ля Рош Аг Биомаркеры в плазме крови, предназначенные для комбинированных терапий с использованием бевацизумаба при лечении рака молочной железы
SG187012A1 (en) 2010-07-19 2013-02-28 Hoffmann La Roche Blood plasma biomarkers for bevacizumab combination therapies for treatment of pancreatic cancer
KR20130126576A (ko) 2010-07-19 2013-11-20 에프. 호프만-라 로슈 아게 항암요법에 반응할 가능성이 증가된 환자를 확인하는 방법
WO2012019300A1 (en) 2010-08-10 2012-02-16 Siu K W Michael Endometrial cancer biomarkers and methods of identifying and using same
US20120077837A1 (en) 2010-09-24 2012-03-29 Eisai R&D Management Co., Ltd. Anti-tumor agent
CN103209982B (zh) 2010-10-14 2016-03-16 Jw制药公司 反转模拟物的化合物、其制造方法及其用途
US20140051706A1 (en) 2011-02-25 2014-02-20 Prism Pharma Co., Ltd. Alpha helix mimetics and methods relating thereto
JP5707518B2 (ja) 2011-02-28 2015-04-30 カリトル サイエンシズ， エルエルシー 置換型キノリン化合物及び使用方法
CA2864394C (en) 2011-03-02 2021-10-19 Jack Roth A method of predicting a response to a tusc2 therapy
ES2699965T3 (es) 2011-03-10 2019-02-13 Provectus Pharmatech Inc Una combinación de rosa de bengala y anticuerpo anti-CTLA4 para su uso en el tratamiento del cáncer
KR102289394B1 (ko) 2011-03-31 2021-08-13 머크 샤프 앤드 돔 코포레이션 인간 프로그램화된 사멸 수용체 pd-1에 대한 항체의 안정한 제제 및 관련된 치료
RU2580609C2 (ru) 2011-04-18 2016-04-10 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Противоопухолевое терапевтическое средство
WO2012154935A1 (en) 2011-05-12 2012-11-15 Eisai R&D Management Co., Ltd. Biomarkers that are predictive of responsiveness or non-responsiveness to treatment with lenvatinib or a pharmaceutically acceptable salt thereof
US20140148483A1 (en) 2011-05-17 2014-05-29 Eisai R&D Management Co., Ltd. Method For Predicting Effectiveness Of Angiogenesis Inhibitor
ES2841809T3 (es) 2011-06-03 2021-07-09 Eisai R&D Man Co Ltd Biomarcadores para pronosticar y evaluar el grado de respuesta de sujetos con cáncer de tiroides y de riñón a compuestos de lenvatinib
MY193562A (en) 2011-08-01 2022-10-19 Genentech Inc Methods of treating cancer using pd-1 axis binding antagonists and mek inhibitors
US20130071403A1 (en) 2011-09-20 2013-03-21 Vical Incorporated Synergistic anti-tumor efficacy using alloantigen combination immunotherapy
AR090263A1 (es) 2012-03-08 2014-10-29 Hoffmann La Roche Terapia combinada de anticuerpos contra el csf-1r humano y las utilizaciones de la misma
PH12017500997A1 (en) 2012-04-04 2018-02-19 Samumed Llc Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof
SG11201407190TA (en) 2012-05-15 2014-12-30 Bristol Myers Squibb Co Cancer immunotherapy by disrupting pd-1/pd-l1 signaling
WO2013171287A1 (en) 2012-05-16 2013-11-21 Boehringer Ingelheim International Gmbh Combination of cd37 antibodies with ice (ifosfamide, carboplatin, etoposide)
LT2904011T (lt) 2012-10-02 2017-11-10 Bristol-Myers Squibb Company Anti-kir antikūnų ir anti-pd-1 antikūnų derinys, akirtas vėžio gydymui
MX2015007185A (es) 2012-12-04 2017-09-05 Eisai R&D Man Co Ltd Uso de eribulina en el tratamiento de cancer de pecho.
EP2945652B1 (en) 2013-01-18 2021-07-07 Foundation Medicine, Inc. Methods of treating cholangiocarcinoma
US11083743B2 (en) 2013-02-21 2021-08-10 Michele Maio DNA hypomethylating agents for cancer therapy
PT2968249T (pt) 2013-02-22 2019-02-06 Samumed Llc Gama-dicetonas como ativadores da via de sinalização wnt/beta-catenina
RS57602B1 (sr) 2013-02-28 2018-11-30 Eisai R&D Man Co Ltd Derivat tetrahidroimidazo[1,5-d][1,4]oksazepina
MY197809A (en) 2013-03-15 2023-07-18 Genentech Inc Biomarkers and methods of treating pd-1 and pd-l1 related conditions
US10517861B2 (en) 2013-05-14 2019-12-31 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds
JP6404242B2 (ja) 2013-06-26 2018-10-10 エーザイ・アール・アンド・ディー・マネジメント株式会社 がんの治療のための併用療法としてのエリブリンおよびレンバチニブの使用
US9174998B2 (en) 2013-12-25 2015-11-03 Eisai R&D Management Co., Ltd. (6S,9aS)-N-benzyl-6-[(4-hydroxyphenyl)methyl]-4,7-dioxo-8-({6-[3-(piperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide compound
JOP20200094A1 (ar) 2014-01-24 2017-06-16 Dana Farber Cancer Inst Inc جزيئات جسم مضاد لـ pd-1 واستخداماتها
EP3102237B1 (en) 2014-02-04 2020-12-02 Incyte Corporation Combination of a pd-1 antagonist and an ido1 inhibitor for treating cancer
HRP20221047T1 (hr) 2014-08-28 2022-11-11 Eisai R&D Management Co., Ltd. Derivat kinolina visoke čistoće i postupak za njegovu proizvodnju
CA2978226A1 (en) 2015-03-04 2016-09-09 Merck Sharpe & Dohme Corp. Combination of a pd-1 antagonist and a vegfr/fgfr/ret tyrosine kinase inhibitor for treating cancer
EP3265179A4 (en) * 2015-03-04 2018-07-18 The University of Chicago Beta-catenin inhibitors in cancer immunotherapy
WO2016180781A1 (en) * 2015-05-08 2016-11-17 Michele Maio Combination therapy of mesothelioma
CA2988707C (en) 2015-06-16 2023-10-10 Eisai R&D Management Co., Ltd. Combination of cbp/catenin inhibitor and immune checkpoint inhibitor for treating cancer
EP3315499B1 (en) * 2015-06-23 2021-04-07 Eisai R&D Management Co., Ltd. Crystal of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
US20200375975A1 (en) 2016-04-15 2020-12-03 Eisai R&D Management Co., Ltd. Treatment of Renal Cell Carcinoma with Lenvatinib and Everolimus
EP3581183B1 (en) 2017-02-08 2023-11-29 Eisai R&D Management Co., Ltd. Tumor-treating pharmaceutical composition
AU2020374883A1 (en) 2019-10-29 2022-05-26 Eisai R&D Management Co., Ltd. Combination of a PD-1 antagonist, a VEGFR/FGFR/RET tyrosine kinase inhibitor and a CBP/beta-catenin inhibitor for treating cancer

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014061826A1 (en) * 2012-10-19 2014-04-24 Hiroyuki Kouji Treatment of hyperproliferative and pre-cancerous skin diseases using an inhibitor of cbp/catenin

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma;Kathleen M.Mahoney等;《Clinical Therapeutics》;20150401;第37卷(第4期);第764-782页 *

Also Published As

Publication number Publication date
JP6757959B2 (ja) 2020-09-23
ES2886107T3 (es) 2021-12-16
BR112017027227A2 (pt) 2018-08-21
BR112017027227B1 (pt) 2023-12-12
IL256148B (en) 2022-04-01
AU2016279474B2 (en) 2021-09-09
US11369623B2 (en) 2022-06-28
WO2016204193A1 (ja) 2016-12-22
EP3311841B1 (en) 2021-07-28
IL256148A (en) 2018-02-28
MX2017015896A (es) 2018-08-09
RU2018100944A3 (zh) 2019-12-18
EP3311841A1 (en) 2018-04-25
RU2729936C2 (ru) 2020-08-13
CN107801379A (zh) 2018-03-13
AU2016279474A1 (en) 2018-02-01
JPWO2016204193A1 (ja) 2018-04-05
CA2988707A1 (en) 2016-12-22
RU2018100944A (ru) 2019-07-16
EP3311841A4 (en) 2019-02-13
KR20180018695A (ko) 2018-02-21
US20180185395A1 (en) 2018-07-05
SG11201710198YA (en) 2018-01-30
CA2988707C (en) 2023-10-10

Similar Documents

Publication Publication Date Title
CN107801379B (zh) 抗癌剂
Jiang et al. Exhausted CD8+ T cells in the tumor immune microenvironment: new pathways to therapy
Massari et al. PD-1 blockade therapy in renal cell carcinoma: current studies and future promises
Antonia et al. Immuno-oncology combinations: a review of clinical experience and future prospects
CN110996952A (zh) 用于治疗癌症的方法
CA3063715A1 (en) Combination therapies for treating cancer
Sunami et al. Immunotherapy for Pancreatic Cancer
CA3101340A1 (en) Compositions comprising bisfluoroalkyl-1,4-benzodiazepinone compounds and immunotherapeutics and methods of use thereof
CN112292128A (zh) Ep4抑制剂和其用途
US20210315909A1 (en) Polymorphic compounds and uses thereof
TWI747868B (zh) 含有免疫調節劑之抗腫瘤劑及抗腫瘤效果增強劑
WO2019072220A1 (zh) Pd-1抗体和表观遗传调节剂联合在制备***的药物中的用途
Liao et al. The common costimulatory and coinhibitory signaling molecules in head and neck squamous cell carcinoma
JP6942726B2 (ja) クロメン化合物および第２活性薬剤の併用薬
JP2023517534A (ja) Ｉｌ－２タンパク質およびｃｄ８０タンパク質を含む融合タンパク質および抗癌剤を含む癌治療用薬学組成物
KR20190098995A (ko) 면역 반응의 조절을 위한 옥사바이사이클로헵탄
EP3755371A1 (en) Combination cancer therapy with anti-cancer agents and antibodies targeting a complex comprising non-classical hla-i and neoantigen
CN115227695A (zh) 包含靶向治疗剂的联合疗法
Li et al. Current status and future challenges of CAR-T cell therapy for osteosarcoma
Singh et al. TGF-β in correlation with tumor progression, immunosuppression and targeted therapy in colorectal cancer
WO2023210042A1 (ja) Ｉｌ－３４を発現する腫瘍を治療および／または予防するための医薬
Cheng Review of the Combination Strategies Used in Anti-PD1/PD-L1 Monoclonal Antibody Treatment
Li et al. The potential and promise for clinical application of adoptive T cell therapy in cancer
TW202313091A (zh) 烏苯美司與免疫檢查點抑制劑的併用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant