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    CYCLIC PRODRUGS OF DUOCARMYCIN ANALOGS
    4.
    发明申请
    CYCLIC PRODRUGS OF DUOCARMYCIN ANALOGS 有权
    环孢霉素类似物的循环作用

    公开(公告)号：US20150057270A1

    公开(公告)日：2015-02-26

    申请号：US14389448

    申请日：2013-03-26

    Applicant: The Scripps Research Institute

    Inventor： Dale L. Boger

    IPC: C07D498/06 ,  C07D209/62

    CPC classification number: C07D498/06 ,  A61K45/06 ,  C07D209/62

    Abstract: The invention provides prodrugs of DNA-reactive analogs of duocarmycin and CC-1065 anticancer agents, wherein a cyclic prodrug form, such as carbamate, thionocarbamate, or carbamimidate, can be hydrolyzed by the patient in vivo to yield a respective bioactive agent comprising a DNA-alkylating moiety and a binding/targeting moiety. The DNA-reactive moiety is a γ-spiro-cyclohexenone fused to a heterocyclyl group which can be produced by endogenous hydrolysis of a cyclic carbamate prodrug of the invention. The cyclic carbamate prodrug produces no residual byproduct during activation in vivo. Methods of synthesis and biological methods and data are also provided.

    Abstract translation: 本发明提供了杜卡霉素和CC-1065抗癌剂的DNA反应性类似物的前药，其中环状前体药物形式如氨基甲酸酯，硫代氨基甲酸酯或氨基甲酰亚胺酯可以在体内由患者水解，得到包含DNA的相应生物活性剂 - 烷基化部分和结合/靶向部分。 DNA反应性部分是融合到可以通过本发明的环状氨基甲酸酯前药的内源性水解产生的杂环基的γ-螺环己烯酮。 环状氨基甲酸酯前体体在体内活化期间不产生残留副产物。 还提供了合成方法和生物学方法和数据。

    Cyclic prodrugs of duocarmycin analogs
    5.
    发明授权
    Cyclic prodrugs of duocarmycin analogs 有权
    杜卡霉素类似物的环状前药

    公开(公告)号：US09139596B2

    公开(公告)日：2015-09-22

    申请号：US14389448

    申请日：2013-03-26

    Applicant: The Scripps Research Institute

    Inventor： Dale L. Boger

    IPC: C07D498/06 ,  A61K31/5365 ,  C07D209/62 ,  A61K45/06

    CPC classification number: C07D498/06 ,  A61K45/06 ,  C07D209/62

    Abstract: The invention provides prodrugs of DNA-reactive analogs of duocarmycin and CC-1065 anticancer agents, wherein a cyclic prodrug form, such as carbamate, thionocarbamate, or carbamimidate, can be hydrolyzed by the patient in vivo to yield a respective bioactive agent comprising a DNA-alkylating moiety and a binding/targeting moiety. The DNA-reactive moiety is a γ-spirocyclohexenone fused to a heterocyclyl group which can be produced by endogenous hydrolysis of a cyclic carbamate prodrug of the invention. The cyclic carbamate prodrug produces no residual byproduct during activation in vivo. Methods of synthesis and biological methods and data are also provided.

    Abstract translation: 本发明提供了杜卡霉素和CC-1065抗癌剂的DNA反应性类似物的前药，其中环状前体药物形式如氨基甲酸酯，硫代氨基甲酸酯或氨基甲酰亚胺酯可以在体内由患者水解，得到包含DNA的相应生物活性剂 - 烷基化部分和结合/靶向部分。 DNA反应性部分是融合到可通过本发明的环状氨基甲酸酯前药的内源性水解产生的杂环基的γ-螺环烯酮。 环状氨基甲酸酯前体体在体内活化期间不产生残留副产物。 还提供了合成方法和生物学方法和数据。

    Diprovocims: a new and potent class of TLR agonists
    6.
    发明授权
    Diprovocims: a new and potent class of TLR agonists 有权

    公开(公告)号：US11040959B2

    公开(公告)日：2021-06-22

    申请号：US16303043

    申请日：2017-06-29

    Applicant: The Scripps Research Institute ,  The Board of Regents of the University of Texas System ,  Bruce Beutler ,  Dale L. Boger

    Inventor： Bruce Beutler ,  Dale L. Boger

    IPC: C07D403/10 ,  A61P37/04

    Abstract: A diprovocim compound that corresponds in structure to structural Formula V is disclosed, wherein A, W, Z, R1, R2, R3 and R4 (when present) are defined within. A diprovocim compound has immune-adjuvant properties on human and mouse cells in culture and on in vivo immunization of mice. A composition containing a diprovocim and a method of using a compound are also disclosed. The immunostimulatory activity of a diprovocim compound is similar to that of LPS, to which there is no apparent structural similarity. A contemplated compound bears no structural similarity to either the TLR1/TLR2 lipoprotein agonists nor to any other synthetic TLR agonist, and is remarkably easy to prepare and synthetically modify.

    DIPROVOCIMS: A NEW AND POTENT CLASS OF TLR AGONISTS
    7.
    发明申请
    DIPROVOCIMS: A NEW AND POTENT CLASS OF TLR AGONISTS 审中-公开

    公开(公告)号：US20200207742A1

    公开(公告)日：2020-07-02

    申请号：US16303043

    申请日：2017-06-29

    Applicant: Bruce BEUTLER ,  Dale L. BOGER ,  The Scripps Research Institute ,  The Board of Regents of the University of Texas System

    Inventor： Bruce Beutler ,  Dale L. Boger

    IPC: C07D403/10 ,  A61P37/04

    Abstract: A diprovocim compound that corresponds in structure to structural Formula V is disclosed, wherein A, W, Z, R1, R2, R3 and R4 (when present) are defined within. A diprovocim compound has immune-adjuvant properties on human and mouse cells in culture and on in vivo immunization of mice. A composition containing a diprovocim and a method of using a compound are also disclosed. A The immunostimulatory activity of a diprovocim compound is similar to that of LPS, to which there is no apparent structural similarity. A contemplated compound bears no structural similarity to either the TLR1/TLR2 lipoprotein agonists nor to any other synthetic TLR agonist, and is remarkably easy to prepare and synthetically modify.

    PERIPHERAL MODIFICATIONS ON POCKET-REDESIGNED VANCOMYCIN ANALOGS SYNERGISTICALLY IMPROVE ANTIMICROBIAL POTENCY AND DURABILITY
    9.
    发明申请
    PERIPHERAL MODIFICATIONS ON POCKET-REDESIGNED VANCOMYCIN ANALOGS SYNERGISTICALLY IMPROVE ANTIMICROBIAL POTENCY AND DURABILITY 审中-公开

    公开(公告)号：US20200071359A1

    公开(公告)日：2020-03-05

    申请号：US16344300

    申请日：2017-10-31

    Applicant: The Scripps Research Institute

    Inventor： Dale L. Boger

    IPC: C07K9/00 ,  C07K7/54 ,  A61P31/04

    Abstract: A C-terminus modification to a binding pocket-modified vancomycin introduces a quaternary ammonium salt that provides a binding pocket-modified vancomycin analog with a second mechanism of action that is independent of D-Ala-D-Ala/D-Ala-D-Lac binding. The modification disrupts cell wall integrity and induces cell wall permeability complementary to the glycopeptide inhibition of cell wall synthesis, and provides synergistic improvements in antimicrobial potency (200-fold) against vancomycin-resistant bacteria. Combining the C-terminus and binding pocket modifications with an orthogonal (4-chlorobiphenyl) methyl addition to the vancomycin disaccharide provides even more potent antimicrobial agents whose activity can be attributed to three independent and synergistic mechanisms of action, only one of which requires D-Ala-D-Ala/D-Ala-D-Lac binding. The resulting modified vancomycins display little propensity for acquired resistance through serial exposure of vancomycin-resistant Enterococci and their durability against such challenges as well as their antimicrobial potency follow predicable trends. Methods of treatment with and compositions containing the modified vancomycins are disclosed.

    N-(hydrophobe-substituted) vancosaminyl [Ψ-[C(=NH) NH] Tpg4] vancomycin and [Ψ-[CH2NH]Tpg4] vancomycin
    10.
    发明授权
    N-(hydrophobe-substituted) vancosaminyl [Ψ-[C(=NH) NH] Tpg4] vancomycin and [Ψ-[CH2NH]Tpg4] vancomycin 有权

    公开(公告)号：US10577395B2

    公开(公告)日：2020-03-03

    申请号：US15322605

    申请日：2015-07-10

    Applicant: THE SCRIPPS RESEARCH INSTITUTE

    Inventor： Dale L. Boger

    IPC: A61K38/00 ,  C07K9/00

    Abstract: The total synthesis and evaluation of key analogs of vancomycin containing single atom changes in the binding pocket are disclosed as well as their peripherally modified, N-(hydrophobe-substituted) derivatives exemplified by a N-4-(4′-chlorobiphenyl)-methyl derivative and their pharmaceutically acceptable salts are disclosed. Their evaluation indicates the combined pocket and peripherally modified analogs exhibit a remarkable spectrum of antimicrobial activity and truly impressive potencies against both vancomycin-sensitive and -resistant bacteria, and likely benefit from two independent and synergistic mechanisms of action. A pharmaceutical composition containing a contemplated compound or its pharmaceutically acceptable salt is disclosed, as is a method of treating a bacterial infection in a mammal by administering an antibacterial amount of a contemplated compound or its salt as above to an infected mammal in need of treatment.

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