公开(公告)号：US08394969B2

公开(公告)日：2013-03-12

申请号：US12563782

申请日：2009-09-21

申请人： Brett C. Bookser ,  Qun Dang ,  Tony S. Gibson ,  Hongjian Jiang ,  De Michael Chung ,  Jianming Bao ,  Jinlong Jiang ,  Andy Kassick ,  Ahmet Kekec ,  Ping Lan ,  Huagang Lu ,  Gergely M. Makara ,  F. Anthony Romero ,  Iyassu Sebhat ,  David Wilson ,  Dariusz Wodka

发明人： Brett C. Bookser ,  Qun Dang ,  Tony S. Gibson ,  Hongjian Jiang ,  De Michael Chung ,  Jianming Bao ,  Jinlong Jiang ,  Andy Kassick ,  Ahmet Kekec ,  Ping Lan ,  Huagang Lu ,  Gergely M. Makara ,  F. Anthony Romero ,  Iyassu Sebhat ,  David Wilson ,  Dariusz Wodka

IPC分类号： A61K31/4184 ,  C07D235/26 ,  C07D235/28 ,  C07D235/30

CPC分类号： C07D235/26 ,  C07D235/28 ,  C07D401/12 ,  C07D403/12 ,  C07D405/12 ,  C07D413/12

摘要： Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

公开(公告)号：US11530250B2

公开(公告)日：2022-12-20

申请号：US16980579

申请日：2019-03-18

申请人： Merck Sharp & Dohme Corp. ,  Ahmet Kekec ,  Nancy Jo Kevin ,  Bing Li ,  Songnian Lin ,  Craig A. Parish ,  Weijuan Tang

发明人： Ahmet Kekec ,  Nancy Jo Kevin ,  Bing Li ,  Songnian Lin ,  Craig A. Parish ,  Weijuan Tang

IPC分类号： C07K14/62 ,  C07K1/107

摘要： The present invention relates to tyrosine-specific functionalized insulin analogs and processes of making such tyrosine-specific functionalized insulin analogs using R-3H-1,2,4-triazoline-3,5-(4H)diones (PTAD).

公开(公告)号：US20110263533A1

公开(公告)日：2011-10-27

申请号：US13124898

申请日：2009-10-12

申请人： Qun Dang ,  Tony S. Gibson ,  Hongjian Jiang ,  De Michael Chung ,  Jianming Bao ,  Jinlong Jiang ,  Andy Kassick ,  Ahmet Kekec ,  Ping Lan ,  Huagang Lu ,  Gergely M. Makara ,  F. Anthony Romero ,  Iyassu Sebhat ,  David Wilson ,  Dariusz Wodka ,  Brett C. Bookser

发明人： Qun Dang ,  Tony S. Gibson ,  Hongjian Jiang ,  De Michael Chung ,  Jianming Bao ,  Jinlong Jiang ,  Andy Kassick ,  Ahmet Kekec ,  Ping Lan ,  Huagang Lu ,  Gergely M. Makara ,  F. Anthony Romero ,  Iyassu Sebhat ,  David Wilson ,  Dariusz Wodka ,  Brett C. Bookser

IPC分类号： A61K31/675 ,  C07F9/40 ,  C07F9/6574 ,  A61P35/00 ,  A61P3/04 ,  A61P3/06 ,  A61P9/12 ,  C07F9/6506 ,  A61P3/10

CPC分类号： C07F9/65068 ,  C07F9/65583 ,  C07F9/657181

摘要： Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, Metabolic Syndrome, obesity, hypercholesterolemia, and hypertension.

摘要翻译： 结构式（I）的新型化合物是AMP-蛋白激酶的活化剂，可用于治疗，预防和抑制AMPK活化蛋白激酶介导的疾病。 本发明的化合物可用于治疗2型糖尿病，高血糖症，代谢综合征，肥胖，高胆固醇血症和高血压。

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：US20150284411A1

公开(公告)日：2015-10-08

申请号：US14419774

申请日：2013-08-19

申请人： James M. APGAR ,  Ashok ARASAPPAN ,  Tesfaye BIFTU ,  Ping CHEN ,  Danqing FENG ,  Erin GUIDRY ,  Jacqueline HICKS ,  Ahmet KEKEC ,  Kenneth LEAVITT ,  Bing LI ,  Troy MCCRACKEN ,  Iyassu SEBHAT ,  Xiaoxia QIAN ,  Lan WEI ,  Robert WILKENING ,  Zhicai WU ,  Merck Sharp & Dohme Corp.

发明人： James M. Apgar ,  Ashok Arasappan ,  Tesfaye Biftu ,  Ping Chen ,  Danqing Feng ,  Erin Guidry ,  Jacqueline D. Hicks ,  Ahmet Kekec ,  Kenneth J. Leavitt ,  Bing Li ,  Troy McCracken ,  Iyassu Sebhat ,  Xiaoxia Qian ,  Lan Wei ,  Robert R. Wilkening ,  Zhicai Wu

IPC分类号： C07D519/00 ,  A61K31/438 ,  A61K45/06 ,  A61K31/501 ,  A61K31/5377 ,  A61K31/541 ,  A61K31/437 ,  A61K31/506

CPC分类号： C07D519/00 ,  A61K31/366 ,  A61K31/397 ,  A61K31/437 ,  A61K31/438 ,  A61K31/4985 ,  A61K31/501 ,  A61K31/506 ,  A61K31/5377 ,  A61K31/541 ,  A61K45/06 ,  A61K2300/00

摘要： Novel compounds of the structural formula (I) are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPK activated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

摘要翻译： 结构式（I）的新型化合物是AMP-蛋白激酶的活化剂，可用于治疗，预防和抑制AMPK活化蛋白激酶介导的疾病。 本发明的化合物可用于治疗2型糖尿病，高血糖症，代谢综合征，肥胖症，高胆固醇血症和高血压。

公开(公告)号：US20100081643A1

公开(公告)日：2010-04-01

申请号：US12563782

申请日：2009-09-21

申请人： BRETT C. BOOKSER ,  Qun Dang ,  Tony S. Gibson ,  Hongjian Jiang ,  De Michael Chung ,  Jianming Bao ,  Jinlong Jiang ,  Andy Kassick ,  Ahmet Kekec ,  Ping Lan ,  Huagang Lu ,  Gergely M. Makara ,  F. Anthony Romero ,  Iyassu Sebhat ,  David Wilson ,  Dariusz Wodka

发明人： BRETT C. BOOKSER ,  Qun Dang ,  Tony S. Gibson ,  Hongjian Jiang ,  De Michael Chung ,  Jianming Bao ,  Jinlong Jiang ,  Andy Kassick ,  Ahmet Kekec ,  Ping Lan ,  Huagang Lu ,  Gergely M. Makara ,  F. Anthony Romero ,  Iyassu Sebhat ,  David Wilson ,  Dariusz Wodka

IPC分类号： A61K31/4184 ,  C07D235/26 ,  C07D403/12 ,  C07D401/12 ,  C07D413/10 ,  A61K31/397 ,  A61K31/44 ,  A61K31/5025 ,  A61K31/4439 ,  A61P3/00 ,  A61P9/00

CPC分类号： C07D235/26 ,  C07D235/28 ,  C07D401/12 ,  C07D403/12 ,  C07D405/12 ,  C07D413/12

摘要： Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

摘要翻译： 结构式（I）的新型化合物是AMP-蛋白激酶的活化剂，可用于治疗，预防和抑制AMPK活化蛋白激酶介导的疾病。 本发明的化合物可用于治疗2型糖尿病，高血糖症，代谢综合征，肥胖症，高胆固醇血症和高血压。

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：US20210002345A1

公开(公告)日：2021-01-07

申请号：US16980579

申请日：2019-03-18

申请人： Ahmet KEKEC ,  Nancy Jo KEVIN ,  Bing LI ,  Songnian LIN ,  Craig A. PARISH ,  Weijuan TANG ,  Merck Sharp & Dohme Corp.

发明人： Ahmet Kekec ,  Nancy Jo Kevin ,  Bing Li ,  Songnian Lin ,  Craig A. Parish ,  Weijuan Tang

IPC分类号： C07K14/62 ,  C07K1/107

摘要： The present invention relates to tyrosine-specific functionalized insulin analogs and processes of making such tyrosine-specific functionalized insulin analogs using R-3H-1,2,4-triazoline-3,5-(4H)diones (PTAD).