Gilead’s Sofosbuvir (brand name; Sovaldi, previously known as GS-7977, PSI-7977) was approved on December 6, 2013 by the U.S. Food and Drug Administration (FDA) as a new treatment for chronic infection with the liver-destroying hepatitis C virus (HCV).

吉利德公司的丙型肝炎药物索非布韦(商品名：Sovaldi,通用名：Sofosbuvir,别名为GS-7977,PSI-7977, 400mg片剂）2013年12月6日获得美国食品药品监督管理局（FDA）批准用于基因1型，2型，3型和4型慢性丙型肝炎（Hepatitis C）成人患者的治疗。索非布韦(Sovaldi)是首个获批可用于丙型肝炎全口服治疗方案的药物，在用于特定基因型(2型，3型)慢性丙型肝炎治疗时，可消除对传 统注射药物干扰素（IFN）的需求。

For patient with genotypes 2 and 3 of the virus, Sovaldi (sofosbuvir) offers first approved all-oral hepatitis C treatment with an interferon-free drug regimen. Those with genotypes 1 and 4, however, will still require the injectable interferon that is the backbone of standard treatment but causes flu-like side effects. Sovaldi must be taken in combination with ribavirin regardless of genotype. Recommended treatment duration is 12 weeks for genotypes 1, 2 and 4, and 24 weeks for genotype 3.

The duration of treatment and other medications used with Sovaldi is dependent upon genotype:

Sovaldi (sofosbuvir), the first in a new class of medications knows as nucleotide NS5B polymerase inhibitors or “nukes”, is a direct-acting agent that interferes with the NS5B RNA-dependent polymerase in the HCV life cycle by suppressing viral replication. Sofosbuvir (aka GS-7977, PSI-7977) was first discovered by New Jersey-based Pharmasset.  Gilead, the world’s largest maker of HIV medicines Atripla and Truvada, acquired an exclusive license on sofosbuvir when it acquired Pharmasset for $11 billion in 2011. Analysts have projected Sovaldi to be a mega-blockbuster generating $1.9 billion in revenue next year and $6.6 billion in 2016.

Sovaldi(Sofosbuvir)是NS5B聚合酶抑制剂，由Pharmasset公司研制后被吉利德2011年以110亿美元收购。对于 HCV基因型2(HCV GT2)、HCV基因型3(HCV GT3)感染，Sovaldi(Sofosbuvir)只需与利巴韦林（ribavirin)日联用即可，sofosbuvir因此成为用于丙型肝炎治疗 的全球首个无需同时使用干扰素的全口服组合治疗. FDA同时也批准Sovaldi(Sofosbuvir联合聚乙二醇干扰素(peg-interferon alfa）、利巴韦林（ribavirin)用于基因型1和4（HCV GT1,HCV GT4)的感染。

Sovaldi(Sofosbuvir) 的获批源于6个III期临床实验结果（NEUTRINO, FISSION, POSITRON, FUSION, VALENCE, PHOTON-1）的支持，其中两个结果（VALENCE和PHOTON-1）支持了FDA授予其“突破性药物资格”。

分析师们预测Sovaldi(sofosbuvir)会成为一款超级重磅炸弹级产品,2014年的销售额将达到19亿美元，2016年的销售额将达到66亿美元。

Preparation of Gilead’s Mega-blockbuster Hepatitis C Drug Sovaldi (Sofosbuvir, GS-7977, PSI-7977) 吉利德丙肝重磅新药索非布韦的制备方法

Commerically available isopropylidine protected D-glyceraldehyde was reacted with (carbethoxyethylidene)triphenylmethylphosphorane gave the chiral pentenoate ester YP-1. Permanganate dihydroxylation of YP-1 in acetone gave the D-isomer diol YP-2. The cyclic sulfate YP-3 was obtained by first making the cyclic sulfite with thionyl chloride and then oxidizing to cyclic sulfate with sodium hypochlorite. Fluorination of YP-3 with triethylamine-trihydrofluoride(TEA-3HF) in the presence of triethylamine, followed by the hydrolysis of sulfate ester in the presence of concentrated HCl provided diol YP-4 which was benzoylated to give ribonolactone YP-5. Reduction of YP-5 with Red-Al followed by chlorination with sulfuryl chloride in the presence of catalytic amount of tetrabutylammonium bromide yielded YP-6. The conversion of YP-6 to benzoyl protected 2′-deoxyl-2′-alpha-F-2′-Beta-C-methylcytidine (YP-7) was achieved by using O-trimethyl silyl-N4-benzoylcytosine and stannic chloride. Preparation of the uridine nucleoside YP-8 was accomplished by first heating benzoyl cytidine YP-7 in acetic acid then treating with methoanolic ammonia to provide YP-8 in 78% yield.

The phosphoramidating reagent YP-9 was obtained by first reacting phenyldichlorophosphate with L-Alanine isopropyl ester hydrochloride and then with pentafluorophenol. Isolation of single Sp diastereomer YP-9 was achieved via crystallization-induced dynamic resolution in the presence of 20% MTBE/hexane at room temperature.

The uridine nucleoside YP-8 was treated with tert-butylmagnesium chloride in dry THF, followed by pentafluorophenyl Sp diastereomer YP-9 to furnish the Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate (Sovaldi, sofosbuvir, GS-7977, PSI-7977)。

Brand Name:Sovaldi
Generic Name: Sofosbuvir
Synonym:GS-7977, PSI-7977
Chinese Name:索非布韦(索法布韦, 索发布韦, 索氟布韦）
Chemical Name:Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate
CAS Number: 1190307-88-0
Mechanism of Action: nucleotide NS5B polymerase inhibitor that interferes with viral replication by binding to the active site of NS5B RNA-dependent RNA polymerase
Clinical Trial Studies(PhaseIII):FISSION, POSITRON, FUSION, NEUTRINO, VALENCE, PHOTON-1
Indication:chronic Heaptitis C Virus (HCV) Infection
Date of Approval: December 6, 2013
Manufacturer:Gilead
Dose: Oral, Once-Daily, 400 mg tablet
Cost:$84,000(12 weeks), $168,000 (24 weeks)
Sales: $1.9 billion (2014), $6.6 billion (2016)
Patents: US patent number 7964580, US patent number 8415322,  US patent number 8334270,US patent number 7429572
Patent Expiration Date:  March 26, 2029 for US patent number 7964580 and  8334270 (2028 in EU)； April 3, 2025 for US patent number 7429572 and  8415322

商品名：Sovaldi
通用名：Sofosbuvir
别名:GS-7977, PSI-7977
中文名：索非布韦(索法布韦, 索发布韦, 索氟布韦）
中文化学名：(S)-2-((S)_(((2R，3R，4R，5R)-5-(2,4-二氧代-3，4-二氢嘧啶-I (2H)-基）-4-氟代-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基氨基)丙酸异丙酯
英文化学名：Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate
CAS 登录号: 1190307-88-0
适应症：慢性丙型肝炎(HCV GT1,GT2,GT3,GT4)
作用机理:核苷类NS5B聚合酶抑制剂
III期临床实验：FISSION、POSITRON、FUSION、NEUTRINO、VALENCE、PHOTON-1
批准时间：2013年12月6日
美国专利号码: 7964580,8415322,8334270,7429572
相关中国专利:CN101918425A, CN102858790A, CN102906102A,CN101600725A,
专利有效期:2029年3月26日(美国专利号:7964580 和 8334270),2025年4月3日 (美国专利号:7429572和 8415322)
使用方法：每天口服一粒,一粒400mg
花费:8.4万美元(12周疗程),16.8美元(24周疗程)
销售值(预计): 19亿美元(2014年),66亿美元(2016年)
药物公司：吉利德科学公司（Gilead Sciences)

商品名(洋名):Sovaldi
商品名(和名):ソバルディ
一般名(洋名):Sofosbuvir
一般名(和名):ソフォスブビル
開発コード：GS-7977, PSI-7977
CAS登録番号:1190307-88-0
薬効分類名:核酸型NS5B ポリメラーゼ阻害剤
効能・効果:C型肝炎治療薬
費用が1日1000ドル（約10万円）,ソバルディの12週間治療の定価は8万4000ドル
製造会社:ギリアド・サイエンシズ
承認年月:アメリカ, 2013年12月6日

来源：

专利

1a)Jeremy Clark; Modified fluorinated nucleoside analogues; US patent number 7429572B2 (download this patent here); Filing date:Apr 21, 2004; Publication number:US7429572B2; Also published as CA2527657A1, CA2527657C, CA2733842A1, CA2734052A1, CA2734055A1, CA2734066A1, CN1816558A, CN100503628C, EP1633766A2, EP2345657A1, EP2345658A1, EP2345659A1, EP2345661A1, EP2604620A1, US8415322, US20050009737, US20080070861, US20080253995, US20090004135, US20090036666, US20110038833, US20120245335, WO2005003147A2, WO2005003147A3; Pharmasset, Inc.

1b)Jeremy Clark; Modified fluorinated nucleoside analogues; US patent number 8415322 ; Date of Patent: April 9, 2013. Gilead Pharmasset LLC. This patent is subject to a terminal disclaimer.

1c)J·克拉克;修饰的氟化核苷类似物;公开(公告)号：CN1816558A, CN100503628C; 申请号：200480019148.4; 申请(专利权)人：法莫赛特股份有限公司; 申请日：2004.04.21

摘要:本发明提供在宿主，包括动物尤其是人中，使用(2’R)-2’-脱氧-2’-氟 -2’-C-甲基核苷或其药学上可接受的盐或其前药，治疗黄病毒科感染，包括丙 型肝炎病毒、西尼罗病毒、黄热病毒以及鼻病毒感染的组合物的方法。

2a)Michael Joseph Sofia, Jinfa Du, Peiyuan Wang; Nucleoside phosphoramidate prodrugs; US patent number 7964580 B2; Filing date:Mar 21, 2008; Publication number:US7964580B2; Also published as CA2682230A1, CN101918425A, EP2203462A2, US8334270, US20100016251, US20110257122, US20130029929,WO2008121634A2,WO2008121634A3,;Pharmasset, Inc.

2b)迈克尔·J·索菲亚;杜锦发;王培源;达纳帕兰·纳加拉特南; 核苷氨基磷酸酯前药; 公开(公告)号：CN101918425A; 申请号：200880018024.2;申请(专利权)人：法莫赛特股份有限公司;申请日：2008.03.26

摘要:本文公开了用于治疗哺乳动物病毒性感染的核苷衍生物的氨基磷酸酯前药，该氨基磷酸酯前药是由以下结构表示的化合物、它的立体异构体、其盐(酸或碱加成盐)、水合物、溶剂合物或结晶形式：还公开了各自利用式(I)所示化合物的治疗方法、用途以及制备方法。

2c)Michael Joseph Sofia, Jinfa Du, Peiyuan Wang, Dhanapalan Nagarathnam;Nucleoside phosphoramidate prodrugs;US patent US8334270B2; Gilead Pharmasset LLC;  This patent is subject to a terminal disclaimer.

专利申请

3a)Steven D Axt, Keshab Sarma, Justin Vitale, Jiang Zhu, Bruce Ross, Suguna Rachakonda, Qingwu Jin, Byoung-Kwon Chun; Preparation of nucleosides ribofuranosyl pyrimidines; WO2008045419A1, CA2666098A1, CA2666098C, CN101600725A, EP2084174A1, EP2084174B1, US20080139802, US20100056770

3b)B·罗斯, J·朱, J·瓦伊塔尔, K·萨尔曼, S·D·阿克斯特, S·拉卡康达, 牛炳权, 金庆武;制备呋喃核糖基嘧啶核苷;CN101600725A;申请号：200780037855.X;申请(专利权)人：法莫赛特股份有限公司;豪夫迈· 罗氏有限公司;申请日：2007.10.05

摘要:本发明的方法提供了一种改进的制备式(IV)的4-氨基-1-((2R，3R，4R，5R)-3- 氟-4-羟基-5-羟基甲基-3-甲基-四氢-呋喃-2-基)-1H-嘧啶-2-酮的方法，所述化合物是丙肝病毒(HCV)NS5B聚合酶的有力抑制剂。

4)Peiyuan Wang, Wojciech Stec, Byoung-Kwon Chun, Junxing Shi, Jinfa Du;Preparation of alkyl-substituted 2-deoxy-2-fluoro-d-ribofuranosyl pyrimidines and purines and their derivatives; WO2006012440A8; CA2574651A1, CA2574651C, EP2348029A1, WO2006012440A2, WO2006012440A3

5a)Bruce S. Ross, Michael Joseph Sofia, Ganapati Reddy Pamulapati, Suguna Rachakonda, Hai-Ren Zhang, Byoung-Kwon Chun, Peiyuan Wang; Nucleoside phosphoramidates; WO2011123645 A3; CA2794669A1, CA2794671A1, CN102858790A, CN102906102A, EP2552930A2, EP2552931A2, US20110245484, WO2011123645A2, WO2011123668A2, WO2011123668A3

5b)B·S·罗斯;M·J·索菲亚;G·R·帕姆拉帕蒂;S·拉查孔达;张海仁;千炳权;王培源;核苷氨基磷酸酯;公开(公告) 号：CN102858790A; 申请号：201180017181.3;申请(专利权)人：吉利德制药有限责任公司;申请日：2011.03.31

摘要:本文公开核苷氨基磷酸酯和其用作治疗病毒疾病的剂的用途。这些化合物是RNA依赖性RNA病毒复制的抑制剂，并可用作HCVNS5B聚合酶的抑制剂、用作HCV复制的抑制剂和用于治疗哺乳动物中的丙型肝炎感染。

6a)Bruce S. Ross, Michael Joseph Sofia, Ganapati Reddy Pamulapati, Suguna Rachakonda, Hai-Ren Zhang; Stereoselective synthesis of phosphorus containing actives; WO2011123668A2

6b)B·S·罗斯, M·J·索菲亚, G·R·帕姆拉帕蒂, S·拉查孔达, 张海仁;含磷活性物的立体选择性合成;公开(公告)号: CN102906102A; 申 请号：201180023066.7;申请(专利权)人：吉利德制药有限责任公司;申请日：2011.03.31

7)Ross, Bruce S. et al. Stereoselective synthesis of nucleoside phosphoramidates for the treatment of prophylaxis as antiviral agents.PCT Int. Appl., WO2011123668, 06 Oct 2011

8)Cho, Aesop and Wolckenhauer, Scott Alan. Methods for the preparation of diasteromerically pure nucleoside phosphoramidate prodrugs as antiviral agents.PCT Int. Appl., WO2012012465, 26 Jan 2012

9)Ray, Adrian S. et al. Preparation of pyridazinylmethylimidazopyridine derivatives and analogs for use in the treatment of hepatitis C virus using combination chemotherapy.PCT Int. Appl., WO2013040492, 21 Mar 2013

研发和合成

10)Michael J. Sofia,Donghui Bao, Wonsuk Chang, Jinfa Du, Dhanapalan Nagarathnam, Suguna Rachakonda, P. Ganapati Reddy, Bruce S. Ross, Peiyuan Wang, Hai-Ren Zhang, Shalini Bansal, Christine Espiritu, Meg Keilman, Angela M. Lam, Holly M. Micolochick Steuer, Congrong Niu, Michael J. Otto, and Phillip A. Furman; Discovery of a β-D-2^’-Deoxy-2^’-a-fluoro-2^’-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus; J. Med. Chem. 2010, 53, 7202–7218; Pharmasset, Inc.

11)Bruce S. Ross, P. Ganapati Reddy , Hai-Ren Zhang , Suguna Rachakonda , and Michael J. Sofia; Synthesis of Diastereomerically Pure Nucleotide Phosphoramidates; J. Org. Chem., 2011, 76 (20), pp 8311–8319; Pharmasset, Inc.

12)Peiyuan Wang, Byoung-Kwon Chun, Suguna Rachakonda, Jinfa Du, Noshena Khan, Junxing Shi, Wojciech Stec, Darryl Cleary, Bruce S. Ross and Michael J. Sofia; An Efficient and Diastereoselective Synthesis of PSI-6130: A Clinically Efficacious Inhibitor of HCV NS5B Polymerase; J. Org. Chem., 2009, 74 (17), pp 6819–6824;Pharmasset, Inc.

13)Jeremy L. Clark, Laurent Hollecker, J. Christian Mason, Lieven J. Stuyver, Phillip M. Tharnish, Stefania Lostia, Tamara R. McBrayer, Raymond F. Schinazi, Kyoichi A. Watanabe, Michael J. Otto, Phillip A. Furman, Wojciech J. Stec, Steven E. Patterson, and Krzysztof W. Pankiewicz; Design, Synthesis, and Antiviral Activity of 2‘-Deoxy-2‘-fluoro-2‘-C-methylcytidine, a Potent Inhibitor of Hepatitis C Virus Replication; J. Med. Chem., 2005, 48 (17), pp 5504–5508; Pharmasset, Inc

14)Manuel Peifer, Raphaëlle Berger, Valerie W. Shurtleff, Jay C. Conrad, and David W. C. MacMillan. A General and Enantioselective Approach to Pentoses: A Rapid Synthesis of PSI-6130, the Nucleoside Core of Sofosbuvir. J. Am. Chem. Soc., 2014, 136 (16), pp 5900–5903

机理

15)Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.; Espiritu, C.; Bansal, S.; Lam, A. M.; Otto, M. J.; Sofia, M. J.; Furman, P. A. (2010). “Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977″. Journal of Biological Chemistry 285 (45): 34337–34347

III期临床实验

16a)Sofosbuvir Phase III FUSION Study: Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment Experienced Subjects With Chronic Genotype 2 or 3 HCV Infection

ClinicalTrials.gov Identifier: NCT01604850

16b)Sofosbuvir Phase III POSITRON Study:GS-7977 + Ribavirin for 12 Weeks in Subjects With Chronic Genotype 2 or 3 HCV Infection Who Are Interferon Intolerant, Interferon Ineligible or Unwilling to Take Interferon

ClinicalTrials.gov Identifier:NCT01542788

16c)Results for Phase III POSITRON Study and FUSION Study .

Jacobson IM,Nelson DR et al.,Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options; N Engl J Med. 2013 May 16;368(20):1867-77.(free article, download pdf file here)

16d)Sofosbuvir FISSION Study: Phase 3 Study of Sofosbuvir and Ribavirin ; ClinicalTrials.gov Identifier:NCT01497366

16e)Sofosbuvir Phase III NEUTRINO Study: Sofosbuvir With Peginterferon Alfa 2a and Ribavirin for 12 Weeks in Treatment-Naïve Subjects With Chronic Genotype 1, 4, 5, or 6 HCV Infection

ClinicalTrials.gov Identifier:NCT01641640

16f)Results for Phase III FISSION Study and NEUTRINO Study .

Lawitz E, Gane EJ.et al.,Sofosbuvir for previously untreated chronic hepatitis C infection; N Engl J Med. 2013 May 16;368(20):1878-87. (free article, download pdf file here)

16g)Sofosbuvir Phase III VALENCE Study: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and Safety of GS-7977+Ribavirin for 12 Weeks in Treatment Naive and Treatment Experienced Subjects With Chronic Genotype 2 or 3 HCV Infection。 ClinicalTrials.gov Identifier:NCT01682720

16g)Zeuzem S et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC, abstract 1085, 2013.

16h)Sofosbuvir Phase III PHOTON-1 Study: A Phase 3, Open-label Study to Investigate the Efficacy and Safety of GS-7977 Plus Ribavirin in Chronic Genotype 1, 2 and 3 Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) Co-infected Subjects，ClinicalTrials.gov Identifier:NCT01667731

16i)MS Sulkowski, M Rodriguez-Torres, JP Lalezari, et al. All-Oral Therapy With Sofosbuvir Plus Ribavirin For the Treatment of HCV Genotype 1, 2, and 3 Infection in Patients Co-infected With HIV (PHOTON-1). 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract212.