公开(公告)号：US11820805B2

公开(公告)日：2023-11-21

申请号：US16771818

申请日：2018-12-13

申请人： Merck Sharp & Dohme Corp. ,  Lin Yan ,  Pei Huo ,  Ahmet Kekec ,  Danqing D. Feng ,  Yuping Zhu ,  Dmitri Pissarnitski ,  Chris Moyes ,  Songnian Lin

发明人： Lin Yan ,  Pei Huo ,  Ahmet Kekec ,  Danqing D. Feng ,  Yuping Zhu ,  Dmitri Pissarnitski ,  Chris Moyes ,  Songnian Lin

IPC分类号： C07K14/62 ,  A61K47/61 ,  A61K47/54 ,  A61K38/00

CPC分类号： C07K14/62 ,  A61K47/549 ,  A61K47/61 ,  A61K38/00

摘要： The present disclosure provides conjugates that comprise an insulin molecule conjugated via a conjugate framework to two or more separate ligands that each include a saccharide, wherein the framework, ligand, saccharide and insulin molecule optionally comprise a fatty chain (e.g., a C8-30 fatty chain), wherein when said insulin molecule is conjugated both to a C8-30 fatty chain and one or more separate ligands that each include a saccharide, said C8-30 fatty chain is linked to insulin molecule only, and wherein when the framework or ligand comprises a fatty chain the insulin molecule is conjugated to two or more separate ligands. In certain embodiments, a conjugate is characterized in that, when the conjugate is administered to a mammal, at least one pharmacokinetic (PK) and/or pharmacodynamic (PD) property of the conjugate is sensitive to serum concentration of a second saccharide. In certain embodiments, a conjugate is also characterized by having a protracted PK profile. Exemplary conjugates and sustained release formulations are provided in addition to methods of use and preparation.

公开(公告)号：US20160251407A1

公开(公告)日：2016-09-01

申请号：US15025912

申请日：2014-10-02

申请人： Songnian LIN ,  Lin YAN ,  Ahmet KEKEC ,  Yuping ZHU ,  David N. HUNTER ,  Pei HUO ,  Danqing FENG ,  Ravi P. NARGUND ,  Christopher R. MOYES ,  Zhiqiang ZHAO ,  Brenda PIPIK ,  Dimitri PISSARNITSKI ,  Joseph L. DUFFY ,  Erin N. GUIDRY ,  MERCK SHARP & DOHME CORP.

发明人： Songnian Lin ,  Lin Yan ,  Ahmet Kekec ,  Yuping Zhu ,  David N. Hunter ,  Pei Huo ,  Danqing Feng ,  Ravi P. Nargund ,  Christopher R. Moyes ,  Zhiqiang Zhao ,  Brenda Pipik ,  Dmitri Pissarnitski ,  Joseph L. Duffy ,  Erin Guidry

IPC分类号： C07K14/62 ,  A61K38/28 ,  A61K47/48

CPC分类号： A61K47/61 ,  A61K38/28 ,  A61K47/549 ,  A61K47/64 ,  C07K14/62

摘要： Insulin conjugates comprising an insulin molecule covalently attached to at least one bi-dentate linker having two arms, each arm independently attached to a ligand comprising a saccharide and wherein at least one ligand of the linker is fucose are disclosed. The insulin conjugates display a pharmacokinetic (PK) and/or pharmacodynamic (PD) profile that is responsive to the systemic concentrations of a saccharide such as glucose or alpha-methylmannose even when administered to a subject in need thereof in the absence of an exogenous multivalent saccharide-binding molecule such as Con A.

摘要翻译： 胰岛素缀合物包含共价连接到具有两个臂的至少一个双齿连接体的胰岛素分子，每个臂独立地连接到包含糖的配体，并且其中至少一个连接体的配体是岩藻糖。 胰岛素缀合物显示药代动力学（PK）和/或药效学（PD）谱，其对糖类如葡萄糖或α-甲基甘露糖的全身浓度有反应，即使在不存在外源多价的情况下施用于有需要的受试者时 糖结合分子如Con A.

公开(公告)号：US09056859B2

公开(公告)日：2015-06-16

申请号：US13881574

申请日：2011-10-24

申请人： Alexander Pasternak ,  Reynalda K. deJesus ,  Yuping Zhu ,  Lihu Yang ,  Shawn Walsh ,  Haifeng Tang ,  Dooseop Kim ,  Barbara Pio ,  Aurash Shahripour ,  Kevin Belyk

发明人： Alexander Pasternak ,  Reynalda K. deJesus ,  Yuping Zhu ,  Lihu Yang ,  Shawn Walsh ,  Haifeng Tang ,  Dooseop Kim ,  Barbara Pio ,  Aurash Shahripour ,  Kevin Belyk

IPC分类号： C07D257/04 ,  C07D405/12 ,  C07D405/14 ,  C07D413/12 ,  C07D413/14 ,  C07D495/04 ,  A61K31/496 ,  C07D311/76 ,  C07D311/80 ,  C07D403/10 ,  C07D307/88 ,  C07D311/02 ,  C07D405/06 ,  C07D471/08 ,  C07D487/08

CPC分类号： C07D405/12 ,  A61K31/496 ,  C07D257/04 ,  C07D307/88 ,  C07D311/02 ,  C07D311/76 ,  C07D311/80 ,  C07D403/10 ,  C07D405/06 ,  C07D405/14 ,  C07D413/12 ,  C07D413/14 ,  C07D471/08 ,  C07D487/08 ,  C07D495/04

摘要： This invention relates to compounds having structural Formula (I); and pharmaceutically acceptable salts thereof which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (Kir 1.1). The compounds of Formula I are useful as diuretics and natriuretics and therefore are useful for the therapy and prophylaxis of disorders resulting from excessive salt and water retention, including cardiovascular diseases such as hypertension and chronic and acute heart failure.

摘要翻译： 本发明涉及具有结构式（I）的化合物; 和它们的药学上可接受的盐，它们是肾外
膜髓质（ROMK）通道（Kir1.1）的抑制剂。 式I的化合物可用作利尿剂和利尿钠，因此可用于治疗和预防由过度的盐和水分滞留引起的疾病，包括心血管疾病如高血压和慢性和急性心力衰竭。

公开(公告)号：US07179802B2

公开(公告)日：2007-02-20

申请号：US10697547

申请日：2003-10-30

申请人： Steven H. Olson ,  James M. Balkovec ,  Yuping Zhu

发明人： Steven H. Olson ,  James M. Balkovec ,  Yuping Zhu

IPC分类号： A61K31/55 ,  A61P3/06 ,  C07D487/02

CPC分类号： C07D249/08

摘要： Compounds having Formula I, including pharmaceutically acceptable salts, hydrates and solvates thereof: are selective inhibitors of the 11β-HSD1 enzyme. The compounds are useful for the treatment of diabetes, such as noninsulin-dependent diabetes (NIDDM), hyperglycemia, obesity, insulin resistance, dylsipidernia, hyperlipidemia, hypertension, Syndrome X, and other symptoms associated with NIDDM.

摘要翻译： 具有式I的化合物，包括其药学上可接受的盐，水合物和溶剂化物：是11beta-HSD1酶的选择性抑制剂。 这些化合物可用于治疗糖尿病，例如非胰岛素依赖性糖尿病（NIDDM），高血糖症，肥胖症，胰岛素抵抗，二亚型癫痫，高脂血症，高血压，综合征X和与NIDDM相关的其他症状。

公开(公告)号：US20140057893A1

公开(公告)日：2014-02-27

申请号：US14110332

申请日：2012-04-05

申请人： Scott Edmondson ,  Zhiqiang Guo ,  Harold B. Wood ,  Andrew W. Stamford ,  Michael W. Miller ,  Duane E. DeMong ,  Gregori J. Morriello ,  Rajan Anand ,  Vincent J. Colandrea ,  Megan Macala ,  Milana Maletic ,  Cheng Zhu ,  Yuping Zhu ,  Wanying Sun ,  Kake Zhao ,  Yong Huang ,  Joel M. Harris ,  Lehua Chang ,  Nam Fung Kar ,  Zhiyong Hu ,  Liping Wang ,  Bowei Wang ,  Ping Liu ,  Jason W. Szewczyk ,  William B. Geiss

发明人： Scott Edmondson ,  Zhiqiang Guo ,  Harold B. Wood ,  Andrew W. Stamford ,  Michael W. Miller ,  Duane E. DeMong ,  Gregori J. Morriello ,  Rajan Anand ,  Vincent J. Colandrea ,  Megan Macala ,  Milana Maletic ,  Cheng Zhu ,  Yuping Zhu ,  Wanying Sun ,  Kake Zhao ,  Yong Huang ,  Joel M. Harris ,  Lehua Chang ,  Nam Fung Kar ,  Zhiyong Hu ,  Liping Wang ,  Bowei Wang ,  Ping Liu ,  Jason W. Szewczyk ,  William B. Geiss

IPC分类号： C07D513/04 ,  C07D413/14 ,  C07D413/04 ,  C07D498/04 ,  C07D405/04 ,  C07D471/04 ,  C07D487/04 ,  C07D401/12 ,  C07D211/22

CPC分类号： C07D513/04 ,  A61K9/4858 ,  C07D211/22 ,  C07D401/12 ,  C07D405/04 ,  C07D413/04 ,  C07D413/14 ,  C07D417/14 ,  C07D471/04 ,  C07D487/04 ,  C07D495/04 ,  C07D498/04

摘要： Substituted cyclopropyl compounds of the formula I: and pharmaceutically acceptable salts thereof are disclosed as useful for treating or preventing type 2 diabetes and similar conditions. The compounds are useful as agonists of the G-protein coupled receptor GPR-119. Pharmaceutical compositions and methods of treatment are also included

摘要翻译： 公开了取代的式I的环丙基化合物及其药学上可接受的盐可用于治疗或预防2型糖尿病和类似病状。 该化合物可用作G蛋白偶联受体GPR-119的激动剂。 还包括药物组合物和治疗方法

公开(公告)号：US20130217680A1

公开(公告)日：2013-08-22

申请号：US13881574

申请日：2011-10-24

申请人： Alexander Pasternak ,  Reynalda K. deJesus ,  Yuping Zhu ,  Lihu Yang ,  Shawn Walsh ,  Haifeng Tang ,  Dooseop Kim ,  Barbara Pio ,  Aurash Shahripour ,  Kevin Belyk

发明人： Alexander Pasternak ,  Reynalda K. deJesus ,  Yuping Zhu ,  Lihu Yang ,  Shawn Walsh ,  Haifeng Tang ,  Dooseop Kim ,  Barbara Pio ,  Aurash Shahripour ,  Kevin Belyk

IPC分类号： C07D405/12 ,  C07D405/14 ,  C07D471/08 ,  C07D413/14 ,  C07D487/08 ,  C07D413/12 ,  C07D257/04

CPC分类号： C07D405/12 ,  A61K31/496 ,  C07D257/04 ,  C07D307/88 ,  C07D311/02 ,  C07D311/76 ,  C07D311/80 ,  C07D403/10 ,  C07D405/06 ,  C07D405/14 ,  C07D413/12 ,  C07D413/14 ,  C07D471/08 ,  C07D487/08 ,  C07D495/04

摘要： This invention relates to compounds having structural Formula (I); and pharmaceutically acceptable salts thereof which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (Kir 1.1). The compounds of Formula I are useful as diuretics and natriuretics and therefore are useful for the therapy and prophylaxis of disorders resulting from excessive salt and water retention, including cardiovascular diseases such as hypertension and chronic and acute heart failure.

摘要翻译： 本发明涉及具有结构式（I）的化合物; 和它们的药学上可接受的盐，它们是肾外
膜髓质（ROMK）通道（Kir1.1）的抑制剂。 式I的化合物可用作利尿剂和利尿钠，因此可用于治疗和预防由过度的盐和水保持引起的疾病，包括心血管疾病如高血压和慢性和急性心力衰竭。

公开(公告)号：US20100286123A1

公开(公告)日：2010-11-11

申请号：US12768209

申请日：2010-04-27

申请人： Alexander Pasternak ,  Aurash Shahripour ,  Haifeng Tang ,  Nardos H. Teumelsan ,  Lihu Yang ,  Yuping Zhu ,  Shawn P. Walsh

发明人： Alexander Pasternak ,  Aurash Shahripour ,  Haifeng Tang ,  Nardos H. Teumelsan ,  Lihu Yang ,  Yuping Zhu ,  Shawn P. Walsh

IPC分类号： A61K31/55 ,  C07D493/04 ,  A61K31/496 ,  A61P7/10 ,  A61P9/12 ,  A61P9/04 ,  A61P1/16 ,  A61P13/12 ,  A61P3/10 ,  A61P7/02 ,  A61P9/10 ,  C07D405/12 ,  A61K31/551 ,  C07D487/08 ,  A61K31/4375 ,  C07D471/08 ,  A61K31/407 ,  C07D295/092 ,  A61K31/445 ,  C07D413/14

CPC分类号： C07D307/88 ,  C07D295/135 ,  C07D295/155 ,  C07D405/08 ,  C07D407/08 ,  C07D413/08 ,  C07D487/08 ,  C07D493/04

摘要： This invention relates to compounds having structural Formula I: and pharmaceutically acceptable salts thereof which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (Kir1.1). The compounds of Formula I are useful as diuretics and natriuretics and therefore are useful for the therapy and prophylaxis of disorders resulting from excessive salt and water retention, including cardiovascular diseases such as hypertension and chronic and acute heart failure.

摘要翻译： 本发明涉及具有结构式I的化合物及其药学上可接受的盐，它们是肾外
膜（ROMK）通道（Kir1.1）的抑制剂。 式I的化合物可用作利尿剂和利尿钠，因此可用于治疗和预防由过度的盐和水保持引起的疾病，包括心血管疾病如高血压和慢性和急性心力衰竭。

公开(公告)号：US20220273770A1

公开(公告)日：2022-09-01

申请号：US17629501

申请日：2020-07-23

申请人： Danqing FENG ,  Erin N. GUIDRY ,  Pei HUO ,  Andrew J. KASSICK ,  Ahmet KEKEC ,  Songnian LIN ,  Christopher R MOYES ,  Dmitri A. PISSARNITSKI ,  Lin YAN ,  Yuping ZHU ,  Merck Sharp & Dohme Corp.

发明人： Danqing Feng ,  Erin N. Guidry ,  Pei Huo ,  Andrew J. Kassick ,  Ahmet Kekec ,  Songnian Lin ,  Christopher R. Moyes ,  Dmitri A. Pissarnitski ,  Lin Yan ,  Yuping Zhu

IPC分类号： A61K38/28 ,  A61K47/54 ,  A61P3/10

摘要： Glucose-responsive insulin conjugates that contain one or more trisaccharides are provided. Such insulin conjugates may display a pharmacokinetic (PK) and/or pharmacodynamic (PD) profile that is responsive to the systemic concentrations of a saccharide such as glucose or alpha-methylmannose, even when administered to a subject in need thereof in the absence of an exogenous multivalent saccharide-binding molecule.

公开(公告)号：US20210198339A1

公开(公告)日：2021-07-01

申请号：US16771818

申请日：2018-12-13

申请人： Lin YAN ,  Pei HUO ,  Ahmet KEKEC ,  Danqing D. FENG ,  Yuping ZHU ,  Dmitri PISSARNITSKI ,  Chris MOYES ,  Songnian LIN ,  Merck Sharp & Dohme Corp.

发明人： Lin Yan ,  Pei Huo ,  Ahmet Kekec ,  Danqing D. Feng ,  Yuping Zhu ,  Dmitri Pissarnitski ,  Chris Moyes ,  Songnian Lin

IPC分类号： C07K14/62 ,  A61K47/54 ,  A61K47/61

摘要： The present disclosure provides conjugates that comprise an insulin molecule conjugated via a conjugate framework to two or more separate ligands that each include a saccharide, wherein the framework, ligand, saccharide and insulin molecule optionally comprise a fatty chain (e.g., a C8-30 fatty chain), wherein when said insulin molecule is conjugated both to a C8-30 fatty chain and one or more separate ligands that each include a saccharide, said C8-30 fatty chain is linked to insulin molecule only, and wherein when the framework or ligand comprises a fatty chain the insulin molecule is conjugated to two or more separate ligands. In certain embodiments, a conjugate is characterized in that, when the conjugate is administered to a mammal, at least one pharmacokinetic (PK) and/or pharmacodynamic (PD) property of the conjugate is sensitive to serum concentration of a second saccharide. In certain embodiments, a conjugate is also characterized by having a protracted PK profile. Exemplary conjugates and sustained release formulations are provided in addition to methods of use and preparation.

公开(公告)号：US08957062B2

公开(公告)日：2015-02-17

申请号：US14110332

申请日：2012-04-05

申请人： Scott Edmondson ,  Zhiqiang Guo ,  Harold B. Wood ,  Andrew W. Stamford ,  Michael W. Miller ,  Duane E. DeMong ,  Gregori J. Morriello ,  Rajan Anand ,  Vincent J. Colandrea ,  Megan Macala ,  Milana Maletic ,  Cheng Zhu ,  Yuping Zhu ,  Wanying Sun ,  Kake Zhao ,  Yong Huang ,  Joel M. Harris ,  Lehua Chang ,  Nam Fung Kar ,  Zhiyong Hu ,  Liping Wang ,  Bowei Wang ,  Ping Liu ,  Jason W. Szewczyk ,  William B. Geiss

发明人： Scott Edmondson ,  Zhiqiang Guo ,  Harold B. Wood ,  Andrew W. Stamford ,  Michael W. Miller ,  Duane E. DeMong ,  Gregori J. Morriello ,  Rajan Anand ,  Vincent J. Colandrea ,  Megan Macala ,  Milana Maletic ,  Cheng Zhu ,  Yuping Zhu ,  Wanying Sun ,  Kake Zhao ,  Yong Huang ,  Joel M. Harris ,  Lehua Chang ,  Nam Fung Kar ,  Zhiyong Hu ,  Liping Wang ,  Bowei Wang ,  Ping Liu ,  Jason W. Szewczyk ,  William B. Geiss

IPC分类号： C07D513/04 ,  C07D401/12 ,  C07D413/14 ,  C07D413/04 ,  C07D211/22 ,  C07D405/04 ,  C07D471/04 ,  C07D487/04 ,  C07D498/04 ,  A61K9/48 ,  C07D417/14 ,  C07D495/04

CPC分类号： C07D513/04 ,  A61K9/4858 ,  C07D211/22 ,  C07D401/12 ,  C07D405/04 ,  C07D413/04 ,  C07D413/14 ,  C07D417/14 ,  C07D471/04 ,  C07D487/04 ,  C07D495/04 ,  C07D498/04

摘要： Substituted cyclopropyl compounds of the formula I: and pharmaceutically acceptable salts thereof are disclosed as useful for treating or preventing type 2 diabetes and similar conditions. The compounds are useful as agonists of the G-protein coupled receptor GPR-119. Pharmaceutical compositions and methods of treatment are also included.

摘要翻译： 公开了取代的式I的环丙基化合物及其药学上可接受的盐可用于治疗或预防2型糖尿病和类似病症。 该化合物可用作G蛋白偶联受体GPR-119的激动剂。 还包括药物组合物和治疗方法。