development by Novartis for the treatment of osteoarthritis (OA), rheumatoid arthritis (RA) and pain (Press release, Novartis, 21 May 2002). The chemical structure is different from rofecoxib and celecoxib (both qv) (Invest conf, Novartis, Sep 1999). Marketing
Regulatory filings have been submitted in the EU and the US for OA, RA, acute pain and dysmenorrhoea (Press release, Novartis, 27 Nov 2002). Launch is expected in mid-2004 (Scrip Daily Online, 18 Oct 2002, S00775256). A 400mg formulation will be indicated for short-term use in acute pain and dysmenorrhoea, and a 200mg formulation for chronic use in OA and RA (Company Web Page, 12 Nov 2002). Launches of paediatric suspension and parenteral formulations are expected in 2005 (Company Web Page, Novartis, 18 Oct 2002).
Clinical Phase III
It is in a 1yr multinational, multicentre, stratified, randomized, double-blind, double-dummy, active-controlled, parallel-group Phase III trial in >18000 OA patients >50yr old (the TARGET study) to compare lumiracoxib 400mg once-daily with ibuprofen and naproxen. Perforation, obstruction and bleeding will be primary safety endpoints, with cardiovascular and gastrointestinal events as secondary endpoints. Results are expected by mid-2004 (Press releases, Novartis, 21 May & 22 Jul 2002). It is also in a pivotal trial in RA to support US approval (Press release, Novartis, 23 Jan 2003). In a 13wk Phase III study in 1042 OA patients, lumiracoxib 200-400mg once-daily produced a significantly lower gastroduodenal ulcer rate cf ibuprofen 800mg tid, and a gastroduodenal ulcer rate similar to celecoxib (qv) 200mg once-daily (Digestive Dis Wk (San Francisco), 2002, Abs M1732). It is in a Phase III long-term GI safety outcome study in >14000 patients. This included trials in multiple pain indications with once-daily dosing. In 2 trials (300-400 patients each) in OA and RA, lumiracoxib 400mg/day was comparable to diclofenac after 4wk in reducing pain and stiffness. In a 13wk Phase III trial, lumiracoxib was significantly more effective at controlling pain in arthritis of the knee cf celecoxib at 2, 4 and 8wk of treatment (Pharmaceutical Marketing, 2002, 14, 22).
Phase II
In a Phase II trial in 150 patients, lumiracoxib 400mg was more potent cf ibuprofen 400mg. In 60 GI endoscopy patients, lumiracoxib 200mg bid x9 days reduced the incidence of ulcers and erosions to 0%, cf 65% on naproxen and 5% on placebo (Company Web Page, Novartis, 16 Jan 2001). Phase I
Initial Phase I results showed lumiracoxib was well tolerated up to 800mg with no serious side-effects (Invest conf, Novartis, Sep 1999). Licensing
Novartis plans to decide whether it will seek a marketing partner by mid-to-late 2003 (Scrip Daily Online, 18 Oct 2002, S00775256). Updated by JB on 28/1/2003.
结构式及分子式
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OONFCl[2-(2-Chloro-6-fluoro-phenylamino)-5-methyl-phenyl]-acetic acidMolecular Weight =293.73Exact Mass =293Molecular Formula =C15H13ClFNO2
合成方法：
经文献检索有两种方法，如下： 合成路线1
OOHII IIBH3/THFIIII OHBrHIBrClI VI OSOCl2INH2VFOOHNaOHIIVCNNH(Me)2ClNIVIIO VIII ONHClNNaOHFClONHOHCu,Cu2I2,K2CO3F IX
5—6
路线2：
NH2ClNa,Liq,NH3OXClTHF,EtOHXIFI2,AcOHXVIIIONHXVIIXIXCl90°ClOFNOVIIITiCl4ClFOH XIIOClNHOFNHNaOMeCl ClFXIIIXIVOHONHClFNaOH,HClClONFAlCl3NOClXVI XV
涉及的中间体
FNH2Cl2-Chloro-6-fluoro-phenylamineMolecular Weight =145.56Molecular Formula =C6H5ClFN 例2
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Prucalopride制备中涉及的中间体
1、Prucalopride概况
1．1，化学名称及化学结构式
4-Amino-5-chloro-2,3-dihydro-N(1-(3-methoxypropyl)-4-piperidinyl)-7-benzofurancarboxamide- [CAS]
OHNNOCH3OClNH21．2，开发公司，适应症及市场预测 Originator Johnson & Johnson Market Size US$ 501-2000 million
Janssen (Johnson & Johnson (J&J)) has suspended development of prucaloprides an orally-administered colon-specific gastroprokinetic, as a 5-HT4 agonist with potential in the treatment of gastrointestinal disorders involving decreased colon mobility (Company Web Page, J&J, 23 Jan 2001). It is an N-substituted piperidinyl bicyclic benzoate derivative. 2、合成路线
由其结构式经文献检索合成路线如下：
OHOOEtOOOEtOOH
OClHNOCH3ClHNOOOHCH3OClHNOClCH3OOClNH2OHNOClNH2NOCH3H2NNOCH3
3、涉及的中间体
5—8
OHOOEtClHNOCH3 H2NN
OCH3
4、中间体的合成路线
略
五、已经开展的工作
1、研究开发一些专利即将到期的品种
对于专利即将到期的药物已进行许多调研工作，积累和筛选的一批品种，与国外有关专家建立了联系，组织FDA所需的文件和符合GMP的车间，我们希望与国内企业合作共同开发。
2、小规模开发了一些临床药物中间体
已经与国外合作有几年时间，开发了一些国外制药企业临床药物正在应用的一些中间体，正由小批量向生产过渡，同时也筛选一些Ⅲ期临床所需中间体在研发中。 我们体会到与国外合作中速度要快、产品质量要高，那么所得回报也高。 但我们在工作中也有困难，放大能力差，希望与有兴趣的企业合作。 3、对期临床药物中间体欲进一步开展的工作
我们从Ⅲ期临床药物筛选了一些中间体。希望建立一个专门研究开发临床药物中间体的研究室，专门从事此项工作。并有一个初步设想，希望在优势互不、资源共享、互惠互利的前提下，建立一个专门从事临床药物中间体的合作联盟 同时我们希望为大家提供一些有意义的信息
我们一些粗浅看法，希望各位专家同仁批评指正。
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