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    Antibody-enzyme conjugates in combination with prodrugs for the delivery of cytotoxic agents to tumor cells
    1.
    发明授权
    Antibody-enzyme conjugates in combination with prodrugs for the delivery of cytotoxic agents to tumor cells 失效
    抗体 - 酶缀合物与用于向肿瘤细胞递送细胞毒性剂的前药组合

    公开(公告)号：US4975278A

    公开(公告)日：1990-12-04

    申请号：US211301

    申请日：1988-06-29

    申请人： Peter D. Senter ,  Mark G. Saulnier ,  Joseph P. Brown ,  David E. Kerr

    发明人： Peter D. Senter ,  Mark G. Saulnier ,  Joseph P. Brown ,  David E. Kerr

    IPC分类号： A61K47/48

    CPC分类号： B82Y5/00 ,  A61K47/48761

    摘要： This invention relates to a novel method for the delivery of cytotoxic drugs to tumor cells by the administration of a tumor-specific antibody-enzyme conjugate that binds to the tumor cells, and the additional administration of a prodrug that is converted at the tumor site, in the presence of the antibody-bound enzyme, to an active cytotoxic drug. According to preferred embodiments of this invention, antibody-enzyme conjugates containing the enzyme, alkaline phosphatase ("AP"), have been used in conjunction with the novel prodrug, etoposide-4'-phosphate or 7-(2'-aminoethyl phosphate)mitomycin or a combination thereof, to effect killing of tumor cells. According to another embodiment of the invention, an antibody-enzyme conjugate containing the enzyme, penicillin V amidase ("PVA"), has been used in conjunction with a novel prodrug, N-(p-hydroxyphenoxyacetyl)adriamycin to effect killing of tumor cells. Still another embodiment of the invention relates to the use of an antibody-enzyme conjugate containing the enzyme, cytosine deaminase ("CD"), in combination with the prodrug, 5-fluorocytosine, to effect killing of tumor cells. The method, antibody-enzyme conjugates, prodrugs, pharmaceutical compositions and combinations of this invention provide for enhanced selective killing of tumor cells and are thus useful in the treatment of cancers and other tumors.

    摘要翻译： 本发明涉及通过施用与肿瘤细胞结合的肿瘤特异性抗体 - 酶结合物向肿瘤细胞递送细胞毒性药物的新方法，以及额外施用在肿瘤部位转化的前体药物， 在抗体结合酶存在下，与活性细胞毒性药物接触。 根据本发明的优选实施方案，含有酶碱性磷酸酶（“AP”）的抗体 - 酶缀合物已经与新的前药，依托泊苷-4'-磷酸或7-（2'-氨基乙基磷酸酯）结合使用， 丝裂霉素或其组合，以杀死肿瘤细胞。 根据本发明的另一个实施方案，含有酶青霉素V酰胺酶（“PVA”）的抗体 - 酶结合物已经与新的前体药物N-（对羟基苯氧基乙酰基）阿霉素结合使用，以杀死肿瘤细胞 。 本发明的另一个实施方案涉及含有酶，胞嘧啶脱氨酶（“CD”）与前体药物5-氟胞嘧啶组合的抗体 - 酶偶联物用于杀死肿瘤细胞的用途。 本发明的方法，抗体 - 酶缀合物，前药，药物组合物和组合提供增强的肿瘤细胞的选择性杀伤，因此可用于治疗癌症和其它肿瘤。

    Substituted azaindazole compounds
    5.
    发明授权
    Substituted azaindazole compounds 有权
    取代的氮杂咔唑化合物

    公开(公告)号：US09266880B2

    公开(公告)日：2016-02-23

    申请号：US13884676

    申请日：2011-11-09

    申请人： Joel F. Austin ,  David B. Frennesson ,  Mark G. Saulnier

    发明人： Joel F. Austin ,  David B. Frennesson ,  Mark G. Saulnier

    IPC分类号： C07D487/04 ,  C07D471/04

    CPC分类号： C07D471/04 ,  C07D487/04

    摘要： Disclosed are azaindazole compounds of Formula (I): or pharmaceutically acceptable salts thereof, wherein: Q is: (i) 5-membered heteroaryl comprising at least one nitrogen heteroatom and substituted with zero to 2 Rg; or (ii) 9- to 10-membered bicyclic heteroaryl selected from Formula (II) and; wherein Ring A is a 5- to 6-membered aryl or heteroaryl fused ring substituted with zero to 2 Rg; and R1, R2, R3, and Rg are defined herein. Also disclosed are methods of using such compounds in the treatment of at least one CYP17 associated condition, such as, for example, cancer, and pharmaceutical compositions comprising such compounds.

    摘要翻译： 公开了式（I）的氮杂咔唑化合物或其药学上可接受的盐，其中：Q为：（i）包含至少一个氮杂原子并被0至2个R g取代的5元杂芳基; 或（ii）选自式（II）的9至10元双环杂芳基; 其中环A是被0至2个R g取代的5至6元芳基或杂芳基稠环; 并且R1，R2，R3和Rg在本文中定义。 还公开了使用这些化合物治疗至少一种CYP17相关病症例如癌症的方法，以及包含这些化合物的药物组合物。

    MACROCYCLES AND MACROCYCLE STABILIZED PEPTIDES
    7.
    发明申请
    MACROCYCLES AND MACROCYCLE STABILIZED PEPTIDES 有权
    MACROCYCLES和MACROCYCLE STABILIZED PEPTIDES

    公开(公告)号：US20130281657A1

    公开(公告)日：2013-10-24

    申请号：US13879513

    申请日：2011-10-13

    申请人： Mark G. Saulnier ,  Dolatrai M. Vyas ,  David R. Langley ,  David B. Frennesson

    发明人： Mark G. Saulnier ,  Dolatrai M. Vyas ,  David R. Langley ,  David B. Frennesson

    IPC分类号： C07K7/64 ,  C07K5/12

    CPC分类号： C07K7/64 ,  C07D277/42 ,  C07D417/04 ,  C07K1/1136 ,  C07K5/123 ,  C07K5/126

    摘要： The invention provides methods of preparing macrocycles including macrocycle stabilized peptides (MSPs). Macrocycles and MSPs are prepared according to nucleophilic capture of an iminoquinomethide type intermediate generated from a suitably substituted 2-amino-thiazol-5-yl carbinol. The preferred nucleophile may be selected from an electron rich aromatic moiety in the case of macrocycles and, in the case of MSPs, at least one amino acid comprises an electron rich aromatic moiety. In addition, the concept can be extended to other related 5-membered heterocyclic systems in place of the thiazole, such as imidazole or oxazole. The conditions for the generation of the corresponding iminoquinomethide type intermediates may be similar or different than the conditions used for the 2-amino-thiazol-5-yl carbinol.

    摘要翻译： 本发明提供了制备大环化合物包括大环稳定肽（MSP）的方法。 根据由适当取代的2-氨基 - 噻唑-5-基甲醇产生的亚氨基喹喔啉型中间体的亲核捕获制备大环和MSP。 在大环化合物的情况下，优选的亲核试剂可以选自富含电子的芳族部分，在MSP的情况下，至少一个氨基酸包含富电子的芳族部分。 此外，该概念可以扩展到其它相关的5元杂环体系代替噻唑，例如咪唑或恶唑。 产生相应的亚氨基喹喔啉型中间体的条件可以与用于2-氨基 - 噻唑-5-基甲醇的条件相似或不同。