公开(公告)号：WO2014088657A1

公开(公告)日：2014-06-12

申请号：PCT/US2013/056459

申请日：2013-08-23

Applicant: THE SCRIPPS RESEARCH INSTITUTE

Inventor： BOGER, Dale, L.

IPC: C07D471/22 ,  C07D471/14 ,  A61K31/4375 ,  A61P35/00

CPC classification number: C07D487/18 ,  C07D471/14 ,  C07D471/22 ,  C07D519/04

Abstract: A vinca alkaloid compound that is substituted at the 20'-position with a urea or thiourea group is disclosed. The urea's proximal nitrogen atom bonded to the 20'-position carbon atom is secondary, whereas the distal nitrogen atom can be unsubstituted only when the compound contains an optionally present 10'-fluoro substituent, and is otherwise preferably mono- or di-substituted. Methods of preparing the compounds are disclosed as are compositions for their use and methods of treatment using a compound.

Abstract translation: 公开了用脲或硫脲基团在20'位被取代的长春花生物碱化合物。 结合到20'-位碳原子上的尿素的近端氮原子是二级的，而远端氮原子只有当化合物含有任选存在的10'-氟取代基时才可以是未被取代的，并且另外优选是单取代或二取代的。 公开了制备化合物的方法，就是使用它们的组合物和使用化合物的处理方法。

公开(公告)号：WO2011103007A2

公开(公告)日：2011-08-25

申请号：PCT/US2011/024230

申请日：2011-02-09

Applicant: THE SCRIPPS RESEARCH INSTITUTE ,  BOGER, Dale, L.

Inventor： BOGER, Dale, L.

IPC: C07D471/14 ,  C07D471/12 ,  A61K31/437 ,  A61P35/00

CPC classification number: C07D519/04

Abstract: A 10'-fluoro-vinca alkaloid compound or its pharmaceutically acceptable salt is disclosed, as are methods of its preparation and use. A disclosed 10'-fluoro-vinca alkaloid compound has better cytotoxic potency against leukemia and cancer cell lines, and is about 8-times more cytotoxic to a multiple drug resistant cancer cell line than is a parental 10'-unsubstituted vinca alkaloid.

Abstract translation: 公开了10'-氟 - 长春花生物碱化合物或其药学上可接受的盐，以及其制备和使用的方法。 公开的10'-氟 - 长春花碱生物碱化合物对白血病和癌细胞系具有更好的细胞毒性效力，并且比无亲本的10'-未取代的长春花生物碱多数药物抗性癌细胞系的细胞毒性高约8倍。

公开(公告)号：WO2006044617A1

公开(公告)日：2006-04-27

申请号：PCT/US2005/036963

申请日：2005-10-14

Applicant: THE SCRIPPS RESEARCH INSTITUTE ,  BOGER, Dale, L.

Inventor： BOGER, Dale, L.

IPC: C07D413/04

CPC classification number: C07D271/10 ,  C07D413/04

Abstract: Certain oxadiazole ketone compounds are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as MS).

Abstract translation: 某些恶二唑酮化合物可用作FAAH抑制剂。 此类化合物可用于治疗由脂肪酰胺水解酶（FAAH）活性介导的疾病状态，病症和病症的药物组合物和方法。 因此，可以施用化合物以治疗焦虑，疼痛，炎症，睡眠障碍，进食障碍或运动障碍（例如MS）。

公开(公告)号：WO2006002895A3

公开(公告)日：2006-01-12

申请号：PCT/EP2005/007007

申请日：2005-06-29

Applicant: NOVARTIS AG ,  NOVARTIS PHARMA GMBH ,  THE SCRIPPS RESEARCH INSTITUTE ,  JANDA, Kim, D. ,  WIRSCHING, Peter ,  BOGER, Dale, L.

Inventor： JANDA, Kim, D. ,  WIRSCHING, Peter ,  BOGER, Dale, L.

IPC: A61K47/48 ,  C07D487/10 ,  C07D403/06 ,  C07D403/14 ,  A61P35/00

Abstract: Methods for treating a neoplastic disease with an antibody-cytotoxin conjugate molecule, methods of synthesizing an antibody-cytotoxin conjugate molecule are provided. Compounds that are useful as antibody-cytotoxin conjugate molecule or useful in the synthesis of these molecules are also provided.

公开(公告)号：WO2021216323A1

公开(公告)日：2021-10-28

申请号：PCT/US2021/027133

申请日：2021-04-13

Applicant: THE SCRIPPS RESEARCH INSTITUTE

Inventor： BOGER, Dale, L. ,  WU, Zhi-Chen

IPC: C07K9/00 ,  A61K38/14 ,  A61P31/04

Abstract: A series of vancomycin C-terminus guanidine modifications are disclosed that improve antimicrobial activity, enhance the durability of antimicrobial action against selection or induction of resistance, and provide two synergistic mechanisms of action independent of D-Ala-D-Ala binding that cause inhibition of cell wall biosynthesis, while inducing bacterial cell permeability. A contemplated compound contains two combined peripheral modifications, a (4-chlorobiphenyl)methyl (CBP) and C-terminus guanidine modification, that provide new treatments against not only vancomycin-sensitive, but especially vancomycin- resistant bacteria. The data demonstrate that the synergistic behavior of the peripheral modifications requires the presence of both the CBP and guanidine modifications in a single molecule versus their combined use as an equimolar mixture of singly modified compounds. A prototypical member of the series, G3- CBP-vancomycin (15), exhibits no hemolytic activity, displays no mammalian cell growth inhibition, and possesses improved and especially attractive in vivo pharmacokinetic (PK) properties.

公开(公告)号：WO2018081797A1

公开(公告)日：2018-05-03

申请号：PCT/US2017/059289

申请日：2017-10-31

Applicant: THE SCRIPPS RESEARCH INSTITUTE

Inventor： BOGER, Dale, L.

IPC: C07K7/54 ,  A61K38/00

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.

Abstract translation: 对结合口袋修饰的万古霉素的C-末端修饰引入季铵盐，其提供具有第二作用机制的结合口袋修饰的万古霉素类似物，所述第二作用机制独立于D-Ala-D- Ala / D-Ala-D-Lac结合。 该修饰破坏细胞壁完整性并诱导与细胞壁合成的糖肽抑制互补的细胞壁渗透性，并且对抗万古霉素抗性细菌的抗微生物效力（200倍）提供协同改善。 将C-末端和结合口袋修饰与正交（4-氯联苯）甲基加到万古霉素二糖中的组合提供了甚至更有效的抗微生物剂，其活性可归因于三种独立且协同的作用机制，其中仅一种需要D- Ala-D-Ala / D-Ala-D-Lac结合。 所得修饰的万古霉素通过连续暴露万古霉素耐药肠球菌显示出获得性耐药的很小倾向，并且它们对这些挑战的耐受性以及它们的抗微生物效力遵循可预测的趋势。 公开了用含有改性万古霉素的组合物治疗的方法。

公开(公告)号：WO2014131023A1

公开(公告)日：2014-08-28

申请号：PCT/US2014/018380

申请日：2014-02-25

Applicant: THE SCRIPPS RESEARCH INSTITUTE ,  THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM ,  BEUTLER, Bruce ,  BOGER, Dale, L.

Inventor： BEUTLER, Bruce ,  BOGER, Dale, L.

IPC: C07C237/20 ,  A61K31/166 ,  A61P37/00

CPC classification number: A61K39/39 ,  A61K31/166 ,  A61K45/06 ,  C07C237/20 ,  C07C237/36 ,  C07C237/44 ,  A61K2300/00

Abstract: A MD-2:TLR4 complex agonist compound is disclosed whose structure corresponds to Formula (I), as defined within. Also disclosed are a method of its preparation and use, as well as a pharmaceutical composition containing the same.

Abstract translation: 公开了MD-2：TLR4复合激动剂化合物，其结构对应于如上所定义的式（I）。 还公开了其制备和使用的方法，以及含有该组合物的药物组合物。

公开(公告)号：WO2009154785A2

公开(公告)日：2009-12-23

申请号：PCT/US2009/003680

申请日：2009-06-19

Applicant: THE SCRIPPS RESEARCH INSTITUTE ,  BOGER, Dale, L.

Inventor： BOGER, Dale, L.

IPC: C07D263/38 ,  C07D263/02 ,  A61K31/42 ,  A61P29/00

CPC classification number: C07D263/40 ,  A61K31/42 ,  C07D263/32 ,  C07D413/04

Abstract: The invention provides a series of C4-substituted oxazole compounds having an alpha keto side chain at the 2 position, for example, compounds of formula I. The compounds can inhibit fatty acid amide hydrolase and can be useful for treatment of malconditions modulated by fatty acid amide hydrolase. The invention further provides methods of making compounds of formula I, useful intermediates in the preparation of compounds of formula I, and methods of using compounds of formula I and compositions thereof.

Abstract translation: 本发明提供了一系列在2位具有α酮侧链的C4-取代的恶唑化合物，例如式I化合物。该化合物可以抑制脂肪酸酰胺水解酶，并且可用于治疗由脂肪酸调节的malcondition 酰胺水解酶。 本发明还提供了制备式I化合物的方法，制备式I化合物的有用中间体，以及使用式I化合物及其组合物的方法。

公开(公告)号：WO2008030532A2

公开(公告)日：2008-03-13

申请号：PCT/US2007/019471

申请日：2007-09-07

Applicant: THE SCRIPPS RESEARCH INSTITUTE ,  BOGER, Dale, L.

Inventor： BOGER, Dale, L.

IPC: A61K31/421

CPC classification number: C07D263/34 ,  C07D263/32 ,  C07D263/46

Abstract: Certain oxazole ketone compounds are described, which are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat, e.g., anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as multiple sclerosis).

Abstract translation: 描述了某些恶唑酮化合物，其可用作FAAH抑制剂。 此类化合物可用于治疗由脂肪酸酰胺水解酶（FAAH）活性介导的疾病状态，病症和病症的药物组合物和方法中。 因此，可以施用化合物以治疗例如焦虑，疼痛，炎症，睡眠障碍，进食障碍或运动障碍（例如多发性硬化症）。

公开(公告)号：WO2007084507A2

公开(公告)日：2007-07-26

申请号：PCT/US2007/001142

申请日：2007-01-16

Applicant: THE SCRIPPS RESEARCH INSTITUTE ,  BOGER, Dale, L.

Inventor： BOGER, Dale, L.

IPC: A61K38/14

CPC classification number: A61K38/14 ,  C07K7/02 ,  C07K9/008

Abstract: [ψ[CH 2 NH]PG 4 ] glycopeptide antibiotic analogs are reengineered forms of glycopeptides that exhibit antimicrobial activity against both wild type and glycopeptide antibiotic resistant strains of microorganisms. For example, [Ψ[CH 2 NH]Tpg 4 ] vancomycin aglycon is a reengineered form of vancomycin that exhibits antimicrobial activity (MIC = 31 µg/mL) against both wild type and VanA resistant organism ( E. faecalis BM4166). The VanA resistant organism achieves its resistance, upon glycopeptide antibiotic challenge, by remodeling its D-Ala-D-Ala peptidoglycan cell wall precursor to D-Ala-D-Lac. [ψ[CH 2 NH]PG 4 ] glycopeptide antibiotic analogs have an altered glycopeptide backbone wherein the carbonyl of the fourth amino acid residue of the glycopeptide backbone has been replaced with a methylene. This alteration of the glycopeptide backbone imparts dual binding affinities for both D-Ala-D-Ala and D-Ala-D-Lac and dual antimicrobial activities for both wild type and resistant strains. For example, [Ψ[CH 2 NH]Tpg 4 ]vancomycin aglycon displays a antimicrobial potency that reflects its altered binding characteristics.

Abstract translation: 糖肽抗生素类似物是显示对微生物的野生型和糖肽抗生素抗性菌株都具有抗微生物活性的糖肽的重新设计形式的[α[CH 2 NH] PG 4]。 例如，[α[CH 2 NH] T pg 4]万古霉素糖苷配基是万古霉素的重新设计形式，其对野生型显示出抗微生物活性（MIC =31μg/ mL） 型和VanA抗性生物体（粪肠球菌BM4166）。 VanA抗性生物体通过将其D-Ala-D-Ala肽聚合物细胞壁前体重组为D-Ala-D-Lac，达到抗糖肽抗生素攻击时的抗性。 糖肽抗生素类似物具有改变的糖肽主链，其中糖肽主链的第四个氨基酸残基的羰基已被 亚甲基。 糖肽骨架的这种改变赋予D-Ala-D-Ala和D-Ala-D-Lac两者的双重结合亲和力，并且对野生型和抗性菌株均具有双重抗菌活性。 例如，[α[CH 2 NH] T pg 4]万古霉素糖苷配基显示反映其改变的结合特征的抗微生物效力。