Manufacturing Process For the Synthesis of Odanacatib, Merck’s Closed Watched Osteoporosis Drug 默沙东骨质疏松症药物奥当卡替的化学合成 2014年7月2日| Synthesis 合成Leave a comment
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Merck’s Odanacatib (MK-0822, Chinese Name:奥当卡替) is a selective cathepsin K inhibitor under development for the treatment of osteoporosis, the most common type of bone disease, in which bones become fragile and more likely to fracture. In May 2014, Merck announced that it plans to seek marketing approvals in the U.S. for the osteoporosis drug odanacatib in the second half of the year. Data from the pivotal, Phase III POWER trial and the POWER extension trial will be included in the regulatory filings of odanacatib. At one point odanacatib was the closely watched drug in Merck’s late-stage pipeline. In June 2012, Merck & Co halted a phase III trial of odanacatib early after seeing “robust efficacy and a favorable benefit-risk profile” in an interim analysis and had hoped to submit its application to the U.S. Food and Drug Administration, with clinical trials results, in the first half of 2013. Instead, the company announced in February 2013 that it was delaying its FDA submission of odanacatib to await additional data from a clinical trial. In a company meeting with investors in Boston in May 2014, Merck research and development chief Roger Perlmutter acknowledged that a numerically higher incidence of stroke and atrial fibrillation – a type of irregular heartbeat most common in the elderly – was seen in patients taking odanacatib than those taking placebos in studies. Roger Perlmutter also said a type of skin thickening and itching called morphea was seen in 0.2 percent of patients taking odanacatib. He said 0.1 percent of patients had fractures in the shaft of the femur, or thigh bone, a greater incidence than seen in the placebo group. Merck is leading the pack among pharma companies developing cathepsin K (cat-K) inhibitors for osteoporosis, but the class as a whole has suffered a number of setbacks. Other companies that have tried to develop such treatments include Novartis, whose balicatib (AAE581) had reached phase II testing but was discontinued due to skin-related adverse events including rashes and scleroderma-like lesion similar to morphea, with Ono Pharmaceuticals’ also electing to drop its own candidate ONO-5334 in 2012 blaming competitiveness and marketing conditions in the osteoporosis sector. Clinical trials with GlaxoSmithKline’s Relacatib (SB-462795) were discontinued after phase I because of drug–drug interactions with the commonly prescribed medications acetaminophen, ibuprofen and atorvastatin. Analysts predict that odanacatib, if approved, could reap Merck annual sales of $1 billion by 2020. Manufacturing Process For the Synthesis of Odanacatib (MK-0822), Merck’s Investigational Osteoporosis drug 默沙东治疗骨质疏松症药物奥当卡替的化学合成Trade Name:N/A, C$ d, m( i8 ^. c9 [' [8 C2 t2 G
Generic Name:Odanacatib
- e) y% `2 q. [3 @1 j! dSynonym:MK-0822; {6 Y2 [+ z5 ?
Chinese Name:奥当卡替
. }: @ s9 N. s: R6 cChemial Name: (S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4′-(methylsulfonyl) -[1,1′-biphenyl]-4-yl)ethyl)amino)pentanamide6 u/ G- f: @8 c( r* N
CAS number: 603139-19-1
5 z! C, @$ i. f$ |" n7 s2 e. KMechanism of Action:selective cathepsin-K inhibitor
- n3 x1 B. Q" ]0 z- ~. MIndication ostmenopausal osteoporosis
# u0 O: w5 Q7 C8 G! y6 J( VDevelopment Statushase II
% }: Z) }' j- G( K" ZDrug Company:Merck 默沙东治疗骨质疏松症药物奥当卡替 (Odanacatib)默沙东治疗骨质疏松症新药奥当卡替(Odanacatib)是一种高度选择性的组织蛋白酶K抑制剂, 2014年5月6日，默沙东宣称计划2014年下半年递交奥当卡替(Odanacatib)用于治疗绝经后妇女骨质疏松症在美国的上市申请。 然而，默沙东研发主管Roger Perlmutter在公司与投资者召开的一个研究项目审查会议中表示，试验中奥当卡替用药患者与安慰剂患者相比，中风及房颤（老年人中一种常见的不规则心跳）的发生率更高。Perlmutter还表示，在0.2%的奥当卡替用药患者中发现一种叫做硬斑病的皮肤增厚及搔痒症状。他表示，0.1%的患者发生股骨轴骨折，相比安慰剂组有更高的发生率。 奥当卡替通过一种新的作用机制而起作用，它能阻止一种叫组织蛋白酶K（Cathespin K)的蛋白，其将会与包括默沙东自己的福善美（Fosamax）在内普遍应用的二磷酸盐类老药进行竞争。二磷酸盐类药物主要治疗骨质疏松症，这类药物由于罕见的颌骨衰变及股骨骨折病例已引起关注。默沙东表示，奥当卡替未发现有颌骨症状。 默沙东2013年表示，奥当卡替的上市申请由于需要额外临床试验数据而被推迟。分析师曾预测，如果奥当卡替获得批准，这款药物到2020年可能会为默沙东带来10亿美元的年销售额。 商品名称：暂无
3 B5 Q( L$ X+ K+ S8 Z9 I通用名称：Odanacatib （奥当卡替）
- x/ F# Z/ s# d' z中文名:奥当卡替0 N5 W6 h1 `( m7 u' p3 [
别名：MK-0822
4 v: b z' x. n7 N' t6 zCAS 登录号:603139-19-1- R- r6 s8 A7 \! V( t1 G0 N! u) h
英文化学名称：(S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)ethyl)amino)pentanamide7 g0 }# \4 V6 t& n
中文化学名称：(2S)-N-(1-氰基环丙基)-4-氟-4-甲基-2-[[(1S)-2,2,2-三氟-1-[4′-(甲基磺酰基)[1,1′-联苯]-4-基]乙基]氨基]戊酰胺6 o9 j; K# b" j C- s' v
药物机理：组织蛋白酶K抑制剂# J5 p; y/ u7 N2 j8 o/ i* A
适应症:骨质疏松症7 o/ M8 H+ P; g! U( T. E: @, i
研发进展：Ⅲ期临床
' O* d. `$ C: h* ^" k1 K o& N药企:默沙东 一般名 オダナカチブ
1 n+ N) i! i4 P* C6 I2 [. ]2 F* B欧文一般名 Odanacatib
3 R6 J+ K* l. I8 a3 m2 b製造会社 MSD株式会社
" U0 {; t7 q# G. d% F Z薬効分類名 カテプシンK阻害剤
8 ^+ z) u! p; `4 Q# B効能 骨粗鬆症治療薬1 Q+ G$ N1 T( v; t$ {& ^
開発段階 第ＩＩＩ相2 K: t5 C0 s# ~# q% ?6 C
承認状況 未承認 Sources:Lems, Willem F.; Geusens, Piet. Established and forthcoming drugs for the treatment of osteoporosis. Current Opinion in Rheumatology (2014), 26(3), 245-251. Schwarz, Peter; Jorgensen, Niklas Rye; Abrahamsen, Bo. Status of drug development for the prevention and treatment of osteoporosis. Expert Opinion on Drug Discovery (2014), 9(3), 245-253. Anderson, Matt S.; Gendrano, Isaias Noel; Liu, Chengcheng; Jeffers, Steven; Mahon, Chantal; Mehta, Anish; Mostoller, Kate; Zajic, Stefan; Morris, Denise; Lee, Jessie; et al. Odanacatib, a selective cathepsin K inhibitor, demonstrates comparable pharmacodynamics and pharmacokinetics in older men and postmenopausal women.Journal of Clinical Endocrinology and Metabolism (2014), 99(2), 552-560. Nelo Rivera, Yadagiri R. Pendri, Sreenivas MENDE, Bramhananda N. REDDY. Process for preparing fluoroleucine alkyl esters. PCT Int. Appl., WO2013148554 A1,Oct 3, 2013 Humphrey, Guy and Yong, Kelvin. Improved amidation process for the preparation of dipeptide nitriles from fluorinated amino acids in the absence of HOBt coupling agent. PCT Int. Appl., WO2012148555, 01 Nov 2012 Kassahun, Kelem et al. Cathepsin cysteine protease inhibitors. PCT Int. Appl., WO2012112363, 23 Aug 2012 Qiu, Xiao-Long; Yue, Xuyi; Qing, Feng-Ling. Fluorine-containing chiral drugs. Chiral Drugs (2011), 195-251. O’Shea, Paul D. et al. A Practical Enantioselective Synthesis of Odanacatib, a Potent Cathepsin K Inhibitor, via Triflate Displacement of an α-Trifluoromethylbenzyl Triflate. Journal of Organic Chemistry, 74(4), 1605-1610; 2009 O’Shea, Paul and Gosselin, Francis. Amidation process for the preparation of cathepsin K inhibitor 4-fluoro-N-[(S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl]-L-leucine 1-cyanocyclopropylamide. PCT Int. Appl., WO2008119176, 09 Oct 2008 Gauthier, Jacques Yves et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorganic & Medicinal Chemistry Letters, 18(3), 923-928; 2008 Sarah J. Dolman, Francis Gosselin, Paul D. O’Shea, Ian W. Davies. Selective metal-halogen exchange of 4,4′-dibromobiphenyl mediated by lithium tributylmagnesiate. Tetrahedron, 2006, 62, 5092–5098 Gauthier, Jacques Yves and Truong, Vouy Linh. Preparation of amino acid derivatives as cathepsin cysteine protease inhibitors. PCT Int. Appl., WO2005019161, 03 Mar 2005 Bayly, Christopher et al. Preparation of amino acid derivatives as cathepsin inhibitors. PCT Int. Appl., WO2005021487, 10 Mar 2005 Limanto, John et al. An Efficient Chemoenzymatic Approach to (S)-γ-Fluoroleucine Ethyl Ester. Journal of Organic Chemistry, 70(6), 2372-2375; 2005 Devine, Paul et al. Process for preparing fluoroleucine alkyl esters. U.S. Pat. Appl. Publ., US20050234128, 20 Oct 2005 Bayly, Christopher I. et al. Cathepsin cysteine protease inhibitors and their therapeutic use. PCT Int. Appl., WO2003075836, 18 Sep 2003 ' F* o% e- @5 D; ]/ m4 P% [0 ]
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