公开(公告)号：WO2008128056A1

公开(公告)日：2008-10-23

申请号：PCT/US2008/060051

申请日：2008-04-11

Applicant: THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS ,  OLDFIELD, Eric ,  ZHANG, Yonghui

Inventor： OLDFIELD, Eric ,  ZHANG, Yonghui

IPC: C07F9/576 ,  C07F9/6503

CPC classification number: C07F9/3865 ,  C07F9/386 ,  C07F9/3873 ,  C07F9/5414 ,  C07F9/581 ,  C07F9/587 ,  C07F9/65061 ,  C07F9/65517 ,  C07F9/655345 ,  C07F9/65583 ,  C07F9/6561 ,  C07F9/723 ,  G01N33/5011

Abstract: The disclosure provides, inter alia, novel bisphosphonate compounds and methods of making and using such compounds. In certain embodiments, compounds of the invention include bisphosphonates that are capable of selectively inhibiting one or more of farnesyl diphosphate synthase (FPPS), geranylgeranyl diphosphate synthase (GGPPS), and decaprenyl pyrophosphate synthase (DPPS). In preferred embodiments, compounds of the invention are capable of selectively inhibiting two or more of FPPS, GGPPS, and DPPS. In embodiments, compounds and methods of the invention demonstrate superior activity levels, such as in the anti-cancer context, immunostimulation context, and other contexts, which in several cases exceed the activity levels of previous generation bisphosphonate drugs by orders of magnitude. In embodiments, the invention provides compounds and methods in connection with research and therapeutic applications, e.g., for tumor or cancer cell growth inhibition, activation of gammadelta T cells, inhibition of certain enzymes related to the mevalonate metabolic pathway, bone resorption diseases, cancer, immune disorders, immunotherapy, and infectious diseases.

Abstract translation: 本公开尤其提供了新的双膦酸盐化合物以及制备和使用这些化合物的方法。 在某些实施方案中，本发明的化合物包括能够选择性抑制法呢基二磷酸合成酶（FPPS），香叶基香叶基二磷酸合成酶（GGPPS）和癸酰焦磷酸合酶（DPPS）中的一种或多种的双膦酸盐。 在优选的实施方案中，本发明的化合物能够选择性地抑制FPPS，GGPPS和DPPS中的两种或更多种。 在实施方案中，本发明的化合物和方法表现出优异的活性水平，例如在抗癌情境，免疫刺激背景和其他情况下，其在若干情况下超过前一代二膦酸药物的活性水平达数量级。 在实施方案中，本发明提供了与研究和治疗应用相关的化合物和方法，例如用于肿瘤或癌细胞生长抑制，Gammadelta T细胞的活化，与甲羟戊酸代谢途径相关的某些酶的抑制，骨吸收疾病，癌症， 免疫疾病，免疫治疗和传染病。

公开(公告)号：WO2010123599A2

公开(公告)日：2010-10-28

申请号：PCT/US2010021800

申请日：2010-01-22

Applicant: UNIV ILLINOIS ,  OLDFIELD ERIC ,  SONG YONGCHENG

Inventor： OLDFIELD ERIC ,  SONG YONGCHENG

CPC classification number: C07F9/3808 ,  C07F9/098 ,  C07F9/3821 ,  C07F9/3882 ,  C07F9/5728 ,  C07F9/65515 ,  C07F9/65517

Abstract: This disclosure relates to compositions and methods including for the inhibition, prevention, and/or treatment of microbial infections, including infections from such pathogens as Staphylococcus aureus.

Abstract translation: 本公开涉及包括用于抑制，预防和/或治疗微生物感染的组合物和方法，包括来自诸如金黄色葡萄球菌的病原体的感染。

公开(公告)号：WO2007133712A3

公开(公告)日：2007-11-22

申请号：PCT/US2007/011466

申请日：2007-05-11

Applicant: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA ,  UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN ,  NIZET, Victor ,  LIU, George, Y. ,  OLDFIELD, Eric ,  SONG, Yongcheng

Inventor： NIZET, Victor ,  LIU, George, Y. ,  OLDFIELD, Eric ,  SONG, Yongcheng

IPC: A01N57/10 ,  A61K31/66

Abstract: The disclosure provides compounds and methods to treat bacterial pathogenesis, and demonstrates that the S. aureus pigment is a virulence factor and potential novel target for antimicrobial therapy.

公开(公告)号：WO2006039721A2

公开(公告)日：2006-04-13

申请号：PCT/US2005/036425

申请日：2005-10-07

Applicant: THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS ,  SANDERS, John M. ,  SONG, Yongcheng ,  CHAN, Julian M. W. ,  OLDFIELD, Eric ,  ZHANG, Yonghui

Inventor： SANDERS, John M. ,  SONG, Yongcheng ,  CHAN, Julian M. W. ,  OLDFIELD, Eric ,  ZHANG, Yonghui

IPC: H05B33/04 ,  H05B33/00

CPC classification number: C07F9/3873 ,  C07F9/581 ,  C07F9/582 ,  C07F9/60 ,  C07F9/62 ,  C07F9/65061 ,  C07F9/65583

Abstract: Bishosphonate compounds and related methods of making and using are disclosed, including pyridinium-1-yl, quinolinium-1-yl, and related compounds. The activity of compounds is disclosed in the context of functional assays such as Leishmania major farnesyl diphosphate synthase (FPPS) inhibition, Dictyostelium discoideum growth inhibition, human gamma delta T cell activation, and bone resorption. The applicability of bisphosphonate compounds in the context of parasitic infections, for example against trypanosomes, is disclosed. Further potential applications of the invention are disclosed regarding the treatment of one or more conditions such as bone resorption disorders, cancer, bone pain, infectious diseases, and in immunotherapy.

Abstract translation: 公开了二膦酸盐化合物及其制备和应用的相关方法，包括吡啶鎓-1-基，喹啉鎓-1-基和相关化合物。 在功能测定的上下文中公开了化合物的活性，例如

公开(公告)号：WO2005023270A2

公开(公告)日：2005-03-17

申请号：PCT/US2004/029375

申请日：2004-09-09

Applicant: UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION ,  UNIVERSITY OF ILLINOIS ,  PARNIAK, Michael ,  MELLORS, John, W. ,  OLDFIELD, Eric ,  TOVIAN, Zev ,  CHAN, Julian, Mun, Weng

Inventor： PARNIAK, Michael ,  MELLORS, John, W. ,  OLDFIELD, Eric ,  TOVIAN, Zev ,  CHAN, Julian, Mun, Weng

IPC: A61K31/663

CPC classification number: A61K31/663 ,  A61K31/66 ,  A61K31/7072 ,  A61K45/06 ,  A61K2300/00

Abstract: The present invention relates to novel compositions comprising an excisioninhibiting bisphosphonate and a nucleoside reverse transcriptase inhibitor. The present invention also relates to methods for preventing or treating retrovirus-related diseases using a composition comprising a bisphosphonate and a nucleoside reverse transcriptase inhibitor. In a specific embodiment, the invention provides methods for preventing or treating AIDS by administering a bisphosphonate-based compound in combination with 3'-azido-3'-deoxythymidine (AZT) to patients infected with AZT­resistant HIV to improve the effectiveness of AZT therapy.

Abstract translation: 本发明涉及包含切除抑制双膦酸盐和核苷逆转录酶抑制剂的新型组合物。 本发明还涉及使用包含双膦酸盐和核苷逆转录酶抑制剂的组合物预防或治疗逆转录病毒相关疾病的方法。 在一个具体实施方案中，本发明提供了通过将双膦酸盐类化合物与3'-叠氮基-3'-脱氧胸苷（AZT）组合施用于感染耐AZ抗药性HIV的患者来提高AZT疗法的有效性来预防或治疗AIDS的方法。

公开(公告)号：WO2014089226A1

公开(公告)日：2014-06-12

申请号：PCT/US2013/073148

申请日：2013-12-04

Applicant: THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS ,  THE REGENTS OF THE UNIVERSITY OF CALIFORNIA ,  ZHU, Wei ,  LINDERT, Steffen ,  ZHANG, Yonghui ,  SINKO, William ,  LI, Kai ,  MCCAMMON, James Andrew ,  OLDFIELD, Eric

Inventor： ZHU, Wei ,  LINDERT, Steffen ,  ZHANG, Yonghui ,  SINKO, William ,  LI, Kai ,  MCCAMMON, James Andrew ,  OLDFIELD, Eric

IPC: C07C257/18 ,  C07D403/12 ,  C07D403/14 ,  C07H15/203 ,  A61K31/4178 ,  A61K31/551 ,  A61K31/7034 ,  A61P31/04

CPC classification number: C07H15/26 ,  A61K31/167 ,  A61K31/4178 ,  A61K31/43 ,  A61K31/4439 ,  A61K31/506 ,  A61K31/551 ,  A61K31/7034 ,  A61K31/7056 ,  C07D209/08 ,  C07D233/24 ,  C07D239/06 ,  C07D239/28 ,  C07D243/04 ,  C07H15/203

Abstract: With the rise in resistance to antibiotics such as methicillin, there is a need for new drugs. The invention provides small molecules that inhibit cellular drug targets such as UPPS and FPPS by interacting with binding pockets, thereby preventing enzyme function. Compounds described herein are also active against Staphylococcus aureus (MIC90 ~0.25 µg/mL), can potently synergize with methicillin (fractional inhibitory concentration index = 0.25), and are protective in a mouse infection model. The invention therefore provides numerous compounds for anti-bacterial treatments and for restoring sensitivity to drugs such as methicillin, using combination therapies.

Abstract translation: 随着抗生素如甲氧西林的抗药性上升，需要新药。 本发明提供了通过与结合袋相互作用来抑制细胞药物靶标如UPPS和FPPS的小分子，从而防止酶功能。 本文所述的化合物对金黄色葡萄球菌（MIC90〜0.25μg/ mL）也具有活性，可以与甲氧西林（分数抑制浓度指数= 0.25）有效协同，并且在小鼠感染模型中是保护性的。 因此，本发明提供了许多用于抗菌处理的化合物，并且使用联合疗法来恢复药物如甲氧西林的敏感性。

公开(公告)号：WO2011044505A3

公开(公告)日：2011-08-18

申请号：PCT/US2010052049

申请日：2010-10-08

Applicant: UNIV ILLINOIS ,  OLDFIELD ERIC ,  WANG KE ,  WANG WEIXUE ,  ZHANG YONGHUI

Inventor： OLDFIELD ERIC ,  WANG KE ,  WANG WEIXUE ,  ZHANG YONGHUI

IPC: C07F9/09 ,  A61K31/6615 ,  A61K31/663 ,  A61P31/04 ,  C07F9/40

CPC classification number: C07F9/65502 ,  A61K31/6615 ,  A61K31/663 ,  C07F9/098 ,  C07F9/141 ,  C07F9/1411 ,  C07F9/142 ,  C07F9/143 ,  C07F9/581 ,  C07F9/582

Abstract: The invention provides compounds, compositions, and methods for studying the Rohmer pathway and for treating bacterial infections or parasitic infections. The parasitic infection can be a protozoan infection, such as malaria. The compounds and compositions can also be used as antibiotics, for example, to kill bacteria or parasites, or to inhibit bacterial or parasite growth. The invention further provides inhibitors of isoprenoid biosynthesis enzymes, and methods of inhibiting the activity of isoprenoid biosynthesis enzymes. The compounds can be, for example, alkynes or allenes that bind to a unique Fe of an Fe4S4 cluster of an isoprenoid biosynthesis enzyme.

Abstract translation: 本发明提供了研究Rohmer途径和治疗细菌感染或寄生虫感染的化合物，组合物和方法。 寄生虫感染可以是原生动物感染，例如疟疾。 化合物和组合物也可以用作抗生素，例如杀死细菌或寄生虫，或抑制细菌或寄生虫生长。 本发明进一步提供了类异戊二烯生物合成酶的抑制剂和抑制类异戊二烯生物合成酶活性的方法。 所述化合物可以是例如结合异戊二烯生物合成酶的Fe 4 S 4簇的独特Fe的炔烃或联烯。

公开(公告)号：WO2007109585A3

公开(公告)日：2008-11-06

申请号：PCT/US2007064239

申请日：2007-03-16

Applicant: UNIV ILLINOIS ,  OLDFIELD ERIC ,  SONG YONGCHENG ,  ZHANG YONGHUI ,  SANDERS JOHN M

Inventor： OLDFIELD ERIC ,  SONG YONGCHENG ,  ZHANG YONGHUI ,  SANDERS JOHN M

IPC: A61K31/663 ,  C07F9/38 ,  C07F9/40

CPC classification number: C07F9/4037 ,  C07F9/3843 ,  C07F9/3856 ,  C07F9/3865 ,  C07F9/3869 ,  C07F9/3873 ,  C07F9/4028 ,  C07F9/404 ,  C07F9/4046 ,  C07F9/5414 ,  C07F9/5728 ,  C07F9/581 ,  C07F9/65061 ,  C07F9/655345 ,  C07F9/655363 ,  C07F9/723

Abstract: The invention provides, inter alia, novel bisphosphonate compounds and methods of making and using. In embodiments, the invention provides compounds and methods in connection with research and therapeutic applications, e.g., for tumor cell growth inhibition, activation of gammadelta T cells, inhibition of farnesyldiphosphate (FPPS) and/or undecaprenyldiphosphate synthase enzymes, bone resorption diseases, cancer, immune disorders, immunotherapy, and infectious diseases. In regards to certain embodiments, a surprising advance has been the recognition that certain structural features can significantly enhance the activity of the compounds. For example, the presence of particular cationic species e.g., phosphonium, sulfonium, and arsonium moieties can contribute to desirable functional activity when positioned near a bisphosphonate moiety. In other embodiments of non-nitrogen containing bisphosphonates, terphenyl and benzyl bisphosphonate compounds and methods are provided. Further variations are also provided.

Abstract translation: 本发明尤其提供新的双膦酸盐化合物及其制备和使用方法。 在实施方案中，本发明提供了与研究和治疗应用相关的化合物和方法，例如用于肿瘤细胞生长抑制，Gammadelta T细胞的活化，法呢基二磷酸（FPPS）和/或十一烷基二磷酸合成酶的抑制，骨吸收疾病，癌症， 免疫疾病，免疫治疗和传染病。 关于某些实施方案，令人惊奇的进步是认识到某些结构特征可以显着增强化合物的活性。 例如，当位于二膦酸盐部分附近时，特定的阳离子物质例如鏻，锍和钍部分的存在可以有助于所需的功能活性。 在非含氮双膦酸盐的其它实施方案中，提供了三联苯基和苄基二膦酸盐化合物和方法。 还提供了进一步的变化。

公开(公告)号：WO2007133712A2

公开(公告)日：2007-11-22

申请号：PCT/US2007011466

申请日：2007-05-11

Applicant: UNIV CALIFORNIA ,  UNIV ILLINOIS ,  NIZET VICTOR ,  LIU GEORGE Y ,  OLDFIELD ERIC ,  SONG YONGCHENG

Inventor： NIZET VICTOR ,  LIU GEORGE Y ,  OLDFIELD ERIC ,  SONG YONGCHENG

IPC: B05B1/14

CPC classification number: A61K38/14 ,  A61K9/0014 ,  A61K9/127 ,  A61K31/4174 ,  A61K31/496 ,  A61K31/662 ,  A61K45/06 ,  A61K2039/522 ,  A61K2300/00 ,  C07F9/098 ,  C07F9/113 ,  C07F9/3808 ,  C12N9/1085

Abstract: The disclosure provides compounds and methods to treat bacterial pathogenesis, and demonstrates that the S. aureus pigment is a virulence factor and potential novel target for antimicrobial therapy.

Abstract translation: 本公开提供了治疗细菌发病机理的化合物和方法，并且证明金黄色葡萄球菌色素是抗毒素治疗的毒力因子和潜在的新靶标。

公开(公告)号：WO2007109585A2

公开(公告)日：2007-09-27

申请号：PCT/US2007/064239

申请日：2007-03-16

Applicant: THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS ,  OLDFIELD, Eric ,  SONG, Yongcheng ,  ZHANG, Yonghui ,  SANDERS, John M.

Inventor： OLDFIELD, Eric ,  SONG, Yongcheng ,  ZHANG, Yonghui ,  SANDERS, John M.

IPC: A61K31/663

CPC classification number: C07F9/4037 ,  C07F9/3843 ,  C07F9/3856 ,  C07F9/3865 ,  C07F9/3869 ,  C07F9/3873 ,  C07F9/4028 ,  C07F9/404 ,  C07F9/4046 ,  C07F9/5414 ,  C07F9/5728 ,  C07F9/581 ,  C07F9/65061 ,  C07F9/655345 ,  C07F9/655363 ,  C07F9/723

Abstract: The invention provides, inter alia, novel bisphosphonate compounds and methods of making and using. In embodiments, the invention provides compounds and methods in connection with research and therapeutic applications, e.g., for tumor cell growth inhibition, activation of gammadelta T cells, inhibition of farnesyldiphosphate (FPPS) and/or undecaprenyldiphosphate synthase enzymes, bone resorption diseases, cancer, immune disorders, immunotherapy, and infectious diseases. In regards to certain embodiments, a surprising advance has been the recognition that certain structural features can significantly enhance the activity of the compounds. For example, the presence of particular cationic species e.g., phosphonium, sulfonium, and arsonium moieties can contribute to desirable functional activity when positioned near a bisphosphonate moiety. In other embodiments of non-nitrogen containing bisphosphonates, terphenyl and benzyl bisphosphonate compounds and methods are provided. Further variations are also provided.

Abstract translation: 本发明尤其提供新的双膦酸盐化合物及其制备和使用方法。 在实施方案中，本发明提供了与研究和治疗应用相关的化合物和方法，例如用于肿瘤细胞生长抑制，Gammadelta T细胞的活化，法呢基二磷酸（FPPS）和/或十一烷基二磷酸合成酶的抑制，骨吸收疾病，癌症， 免疫疾病，免疫治疗和传染病。 关于某些实施方案，令人惊奇的进步是认识到某些结构特征可以显着增强化合物的活性。 例如，当位于二膦酸盐部分附近时，特定的阳离子物质例如鏻，锍和钍部分的存在可以有助于所需的功能活性。 在非含氮双膦酸盐的其它实施方案中，提供了三联苯基和苄基双膦酸盐化合物和方法。 还提供了进一步的变化。