公开(公告)号：WO2010135569A1

公开(公告)日：2010-11-25

申请号：PCT/US2010/035641

申请日：2010-05-20

Applicant: PHARMASSET, INC. ,  ROSS, Bruce, S. ,  SOFIA, Michael, Joseph ,  PAMULAPATI, Ganapati, Reddy ,  RACHAKONDA, Suguna ,  ZHANG, Hai-ren ,  CHUN, Byoung-kwon ,  WANG, Peiyuan

Inventor： ROSS, Bruce, S. ,  SOFIA, Michael, Joseph ,  PAMULAPATI, Ganapati, Reddy ,  RACHAKONDA, Suguna ,  ZHANG, Hai-ren ,  CHUN, Byoung-kwon ,  WANG, Peiyuan

IPC: C07H19/10 ,  C07H19/073 ,  A61K31/7072 ,  A61P31/14

CPC classification number: C07H19/10 ,  A61K31/7072 ,  A61K31/716 ,  A61K45/00 ,  C07F9/24 ,  C07F9/242 ,  C07F9/65586 ,  C07H1/00 ,  C07H17/02 ,  Y02A50/463 ,  Y02P20/55

Abstract: Disclosed herein are nucleoside phosphoramidates of formula 4 and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. Disclosed is also a process for preparing compound represented by formula 4: (Formula 4) wherein P* represents a chiral phosphorus atom, which comprises: a) reacting an isopropyl-alanate, (Formula A), a di-X'-phenylphosphate, (Formula B), 2'-deoxy-2f-fluoro-2'-C-methyluridine, (Formula 3), and a base to obtain a first mixture comprising 4; wherein X is a conjugate base of an acid, n is 0 or 1, and X' is a halogen, b) reacting the first mixture with a protecting compound to obtain a second mixture comprising 4; and c) optionally subjecting the second mixture to crystallization, chromatography or extraction in order to obtain 4.

Abstract translation: 本文公开了式4的核苷氨基磷酸酯及其作为治疗病毒性疾病的试剂的用途。 这些化合物是RNA依赖性5 RNA病毒复制的抑制剂，可用作HCV NS5B聚合酶的抑制剂，作为HCV复制的抑制剂和用于治疗哺乳动物的丙型肝炎感染。 还公开了制备由式4表示的化合物的方法：（式4）其中P *表示手性磷原子，其包括：a）使异丙基 - 铝酸酯，（式A），二-X'-苯基磷酸酯， （式B），2'-脱氧-2f-fluor-2'-C-甲基尿苷，（式3）和碱，得到包含4的第一混合物; 其中X是酸的共轭碱，n是0或1，X'是卤素，b）使第一混合物与保护化合物反应，得到包含4的第二混合物; 和c）任选地使第二混合物进行结晶，色谱或提取，以获得4。

公开(公告)号：WO2009152095A3

公开(公告)日：2010-11-04

申请号：PCT/US2009046619

申请日：2009-06-08

Applicant: PHARMASSET INC ,  DU JINFA ,  NAGARATHNAM DHANAPALAN ,  PAMULAPATI GANAPATI REDDY ,  ROSS BRUCE S ,  SOFIA MICHAEL JOSEPH

Inventor： DU JINFA ,  NAGARATHNAM DHANAPALAN ,  PAMULAPATI GANAPATI REDDY ,  ROSS BRUCE S ,  SOFIA MICHAEL JOSEPH

IPC: C07H19/10 ,  C07D473/18 ,  C07H19/20

CPC classification number: C07D473/18 ,  C07H19/10 ,  C07H19/20

Abstract: Cyclic phosphate of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof, represented by the following structure: Formula (I)

Abstract translation: 用于治疗哺乳动物中的病毒感染的核苷衍生物的环磷酸酯，其为化合物，其立体异构体，由以下结构表示的盐（酸或碱加成盐），水合物，溶剂化物或其结晶形式：式（I）

公开(公告)号：WO2009152095A2

公开(公告)日：2009-12-17

申请号：PCT/US2009/046619

申请日：2009-06-08

Applicant: PHARMASSET, INC. ,  DU, Jinfa ,  NAGARATHNAM, Dhanapalan ,  PAMULAPATI, Ganapati, Reddy ,  ROSS, Bruce, S. ,  SOFIA, Michael, Joseph

Inventor： DU, Jinfa ,  NAGARATHNAM, Dhanapalan ,  PAMULAPATI, Ganapati, Reddy ,  ROSS, Bruce, S. ,  SOFIA, Michael, Joseph

IPC: A61K31/712

CPC classification number: C07D473/18 ,  C07H19/10 ,  C07H19/20

Abstract: Cyclic phosphate of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof, represented by the following structure: Formula (I)

Abstract translation: 用于治疗哺乳动物中的病毒感染的核苷衍生物的环磷酸酯，其为化合物，其立体异构体，由以下结构表示的盐（酸或碱加成盐），水合物，溶剂化物或其结晶形式：式（I）

公开(公告)号：WO2011123668A2

公开(公告)日：2011-10-06

申请号：PCT/US2011030762

申请日：2011-03-31

Applicant: PHARMASSET INC ,  ROSS BRUCE S ,  SOFIA MICHAEL JOSEPH ,  PAMULAPATI GANAPATI REDDY ,  RACHAKONDA SUGUNA ,  ZHANG HAI-REN

Inventor： ROSS BRUCE S ,  SOFIA MICHAEL JOSEPH ,  PAMULAPATI GANAPATI REDDY ,  RACHAKONDA SUGUNA ,  ZHANG HAI-REN

IPC: C07H19/10

CPC classification number: C07H19/10 ,  C07F7/1856 ,  C07F9/242 ,  C07F9/2458 ,  C07F9/65517 ,  C07F9/65586 ,  C07F9/65616 ,  C07H19/04 ,  C07H19/044 ,  C07H19/052 ,  C07H19/06 ,  C07H19/20 ,  C07H19/207 ,  C07H19/24

Abstract: Disclosed herein are phosphorus-containing actives, their use as actives for treating diseases, and a stereoselective process for preparing the same. Also disclosed herein are useful synthetic intermediates and processes for preparing the same.

Abstract translation: 本文公开了含磷活性物质，它们作为治疗疾病的活性物质的用途和用于制备它们的立体选择性方法。 本文还公开了有用的合成中间体及其制备方法。

公开(公告)号：WO2011123645A2

公开(公告)日：2011-10-06

申请号：PCT/US2011/030725

申请日：2011-03-31

Applicant: PHARMASSET, INC. ,  ROSS, Bruce, S. ,  SOFIA, Michael, Joseph ,  PAMULAPATI, Ganapati, Reddy ,  RACHAKONDA, Suguna ,  ZHANG, Hai-Ren ,  CHUN, Byoung-Kwon ,  WANG, Peiyuan

Inventor： ROSS, Bruce, S. ,  SOFIA, Michael, Joseph ,  PAMULAPATI, Ganapati, Reddy ,  RACHAKONDA, Suguna ,  ZHANG, Hai-Ren ,  CHUN, Byoung-Kwon ,  WANG, Peiyuan

IPC: C07H19/06 ,  C07H19/207 ,  A61K31/7072 ,  C07F9/26 ,  A61P31/14

CPC classification number: C07H19/10 ,  C07F7/1856 ,  C07F9/242 ,  C07F9/2458 ,  C07F9/65517 ,  C07F9/65586 ,  C07F9/65616 ,  C07H19/04 ,  C07H19/044 ,  C07H19/052 ,  C07H19/06 ,  C07H19/20 ,  C07H19/207 ,  C07H19/24

Abstract: Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

Abstract translation: 本文公开了核苷氨基磷酸酯及其作为治疗病毒性疾病的药剂的用途。 这些化合物是RNA依赖性RNA病毒复制的抑制剂，可用作HCV NS5B聚合酶的抑制剂，作为HCV复制的抑制剂和用于治疗哺乳动物的丙型肝炎感染。

公开(公告)号：WO2005108411A2

公开(公告)日：2005-11-17

申请号：PCT/US2005/015240

申请日：2005-05-03

Applicant: ISIS PHARMACEUTICALS, INC. ,  GRIFFEY, Richard, H. ,  ROSS, Bruce, S. ,  QUANLAI, Song

Inventor： GRIFFEY, Richard, H. ,  ROSS, Bruce, S. ,  QUANLAI, Song

IPC: C07H

CPC classification number: C07H19/06 ,  C07H21/00 ,  Y02P20/55

Abstract: The present invention is directed to amidites useful in the synthesis of oligonucleotides comprising at least one RN moiety, and to methods of using such amidites in the synthesis of such oligonucleotides. The inventive amidites possess surprising coupling efficiency as compared to prior art amidites, while providing convenient intermediates in the synthesis of oligonucleotides possessing at least one free 2'-OH moiety.

Abstract translation: 本发明涉及可用于合成包含至少一个RN部分的寡核苷酸的脒基，以及在合成这些寡核苷酸时使用这种脒基的方法。 与现有技术的脒基相比，本发明的脒基具有惊人的偶联效率，同时在合成具有至少一个游离2'-OH部分的寡核苷酸的合成中提供方便的中间体。

公开(公告)号：WO2005077966A1

公开(公告)日：2005-08-25

申请号：PCT/US2005/004875

申请日：2005-02-10

Applicant: ISIS PHARMACEUTICALS, INC. ,  SONG, Quanlai ,  KHAMMUNGKHUNE, Sak ,  ROSS, Bruce, S. ,  GRIFFEY, Richard, H.

Inventor： SONG, Quanlai ,  KHAMMUNGKHUNE, Sak ,  ROSS, Bruce, S. ,  GRIFFEY, Richard, H.

IPC: C07H19/06

CPC classification number: C07H19/06 ,  C07H21/00 ,  Y02P20/55

Abstract: The present invention describes an improved hydroxyl protecting group of formula (1), wherein R 2 and R 7 are specified substituents and Q is O, S, NR 10 or N(C=O)R 10 .

Abstract translation: 本发明描述了一种改进的式（1）羟基保护基，其中R 2和R 7是指定的取代基，Q是O，S，NR 10或N（C = O）R 10 。

公开(公告)号：WO2004072234A3

公开(公告)日：2005-03-31

申请号：PCT/US2004002807

申请日：2004-02-02

Applicant: ISIS PHARMACEUTICALS INC ,  SONG QUANLAI ,  ROSS BRUCE S

Inventor： SONG QUANLAI ,  ROSS BRUCE S

IPC: C07H1/00 ,  C07H19/048 ,  C07H19/22 ,  C12N20060101

CPC classification number: C07H19/22 ,  C07H19/048

Abstract: A process of manufacturing protected nucleosides comprises reacting a nucleoside with a protecting reagent in the presence of a regioselective activator to produce a regioselectively protected nucleoside. In some embodiments of the inventive method, an optionally substituted trityl or optionally substituted pixyl group is selectively added to the 5'-O-position of a nucleoside in the presence of lutidine as activator or activator/solvent. The inventive method results in improved selectivity of the 5'-O- position over the 3'-0-position, thereby improving overall product yield and purity, and permitting simplified purification protocols, in some cases obviating the need for chromatography to produce a purified protected nucleoside suitable for automated synthesis of oligonucleotides, such as primers, probes and antisense molecules.

Abstract translation: 制备受保护核苷的方法包括在区域选择性活化剂存在下使核苷与保护试剂反应以产生区域选择性保护的核苷。 在本发明方法的一些实施方案中，在作为活化剂或活化剂/溶剂的二甲基吡啶存在下，将任选取代的三苯甲基或任选取代的吡啶基选择性地加入到核苷的5'-O-位。 本发明的方法导致5'-O-位置在3'- 0位上的选择性提高，从而提高总体产物产率和纯度，并且允许简化的纯化方案，在一些情况下，不需要色谱法来产生纯化的 保护的核苷适用于自动合成寡核苷酸，如引物，探针和反义分子。

公开(公告)号：WO2004072234A2

公开(公告)日：2004-08-26

申请号：PCT/US2004/002807

申请日：2004-02-02

Applicant: ISIS PHARMACEUTICALS, INC. ,  SONG, Quanlai ,  ROSS, Bruce, S.

Inventor： SONG, Quanlai ,  ROSS, Bruce, S.

IPC: C12N

CPC classification number: C07H19/22 ,  C07H19/048

Abstract: A process of manufacturing protected nucleosides comprises reacting a nucleoside with a protecting reagent in the presence of a regioselective activator to produce a regioselectively protected nucleoside. In some embodiments of the inventive method, an optionally substituted trityl or optionally substituted pixyl group is selectively added to the 5'-O-position of a nucleoside in the presence of lutidine as activator or activator/solvent. The inventive method results in improved selectivity of the 5'-O- position over the 3’-0-position, thereby improving overall product yield and purity, and permitting simplified purification protocols, in some cases obviating the need for chromatography to produce a purified protected nucleoside suitable for automated synthesis of oligonucleotides, such as primers, probes and antisense molecules.

Abstract translation: 制备受保护的核苷的方法包括在区域选择性活化剂存在下使核苷与保护试剂反应以产生区域选择性保护的核苷。 在本发明方法的一些实施方案中，在作为活化剂或活化剂/溶剂的二甲基吡啶存在下，将任选取代的三苯甲基或任选取代的吡啶基选择性地加入到核苷的5'-O-位上。 本发明的方法导致5'-O-位置在3'- 0位上的选择性提高，从而提高总体产物产率和纯度，并且允许简化的纯化方案，在一些情况下，不需要色谱法来产生纯化的 保护的核苷适用于自动合成寡核苷酸，如引物，探针和反义分子。

公开(公告)号：WO2010075554A1

公开(公告)日：2010-07-01

申请号：PCT/US2009/069475

申请日：2009-12-23

Applicant: PHARMASSET, INC. ,  CHUN, Byoung-kwon ,  DU, Jinfa ,  RACHAKONDA, Suguna ,  ROSS, Bruce, S. ,  SOFIA, Michael, Joseph ,  PAMULAPATI, Ganapati, Reddy ,  CHANG, Wonsuk ,  ZHANG, Hai-ren ,  NAGARATHNAM, Dhanapalan

Inventor： CHUN, Byoung-kwon ,  DU, Jinfa ,  RACHAKONDA, Suguna ,  ROSS, Bruce, S. ,  SOFIA, Michael, Joseph ,  PAMULAPATI, Ganapati, Reddy ,  CHANG, Wonsuk ,  ZHANG, Hai-ren ,  NAGARATHNAM, Dhanapalan

IPC: C07H19/167 ,  C07H19/20 ,  C07H19/213 ,  A61K31/7076 ,  A61P31/14

CPC classification number: C07H19/20 ,  C07H1/00 ,  C07H5/02 ,  C07H15/04 ,  C07H19/167 ,  C07H19/213 ,  Y02P20/55

Abstract: A process for preparing phosphoramidate prodrugs or cyclic phosphate prodrugs of nucleoside derivatives, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof.

Abstract translation: 制备核苷衍生物的氨基磷酸酯前药或环磷酸酯前药的方法，其为化合物，其立体异构体，盐（酸或碱加成盐），水合物，溶剂合物或其结晶形式。