CN1711086A - 用于治疗眼的退化性疾病的组蛋白脱乙酰酶抑制剂 - Google Patents
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Abstract
本发明公开了用组蛋白脱乙酰酶抑制剂来治疗眼的退化性病症和疾病的组合物及方法。
Description
本发明涉及用作组蛋白脱乙酰酶(HDAC)抑制剂来治疗患有急性或慢性眼退化性病症或疾病的患者的化合物。
发明背景
本申请要求于2002年11月12日提交的U.S.S.N.60/425,576的优先权。
青光眼是一组疾病,其中每种疾病通过该疾病形式的具体特征而相互区分。原发性开角型青光眼(POAG)的特征是:视神经乳头地形图有典型的青光眼变化,视野中出现弓形盲点,开角,并且通常伴随着眼内压(IOP)升高。正常眼压性青光眼(NTG)或低眼压性青光眼与POAG非常相似,除了这些患者的IOP处于正常范围。其它类型的青光眼包括闭角型青光眼和色素分散性青光眼(pigmentary dispersion glaucoma)。所有这些类型的青光眼的相似之处是:患者出现有神经纤维层和视野的连续丢失。现行的治疗青光眼、特别是POAG和NTG的疗法致力于通过降低和控制眼内压来延缓视野丢失的发展。这可通过降IOP药物或氩激光小梁成形术(ALT)和/或通过青光眼滤过术(GFS)来进行。对降低IOP的效果(即使在NTG患者中)进行长期研究已经证明:其在某些患者中可有效减缓疾病的发展。不幸的是,有些患者尽管降低了IOP,但是仍继续丢失视野。
已经研发出降低IOP且对视网膜和视神经乳头提供额外保护的药物疗法。化合物如倍他洛尔和溴莫尼定已经在动物模型中被证明有神经保护作用。已经提出,上述两种化合物在局部施用于眼后通过直接渗入眼后部而在青光眼中提供神经保护。倍他洛尔的神经保护性质被认为源自其钙通道阻滞活性和刺激关键神经保护因子如CNTF、bFGF和BDNF表达的能力。溴莫尼定是α2激动剂,其被认为可刺激bFGF的生成。
年龄相关性黄斑变性(AMD)是引起老年人失明的主要原因,发病率由在65周岁成年人中为约20%升至在75周岁或以上成年人中为37%。非渗出性AMD(干性AMD)的特点是在外视网膜、视网膜色素上皮(RPE)、布鲁赫膜和脉络膜血管层中玻璃疣(drusen)聚集和视杆及视锥光感受器萎缩;而渗出性AMD导致脉络膜新血管形成(Green和Enger,Ophthalmol.Vol.100:1519-1535,1993;Green等人,Ophthalmol,Vol.92:615-627,1985;Green和Key,Trans Am Ophthalmol Soc.,Vol.75:180-254,1977;Bressler等人,Retina,Vol.14:130-142,1994;Schneider等人,Retina,Vol.18:242-250,1998;Green和Kuchle,In:Yannuzzi,L.A.,Flower,R.W.,Slakter,J.S.(Eds.),Indocyanine Green Angiography,St.Louis:Mosby,第151-156页,1997)。色素性视网膜炎(RP)代表一组以视杆光感受器退化、继而视锥光感受器及其下的色素上皮萎缩为特征的遗传性营养不良。(Pruett.Trans Am Ophthalmol Soc.,Vol.81:693-735,1983;Heckenlively,Trans AmOphthalmol Soc.,Vol.85:438-470,1987;Pagon,Sur Ophthalmol,Vol.33:137-177,1988;Berson,Invest Ophthalmol Vis Sci,Vol.34:1659-1676,1993;Nickells和Zack,Ophthalmic Genet,Vol.17:145-165,1996)。视网膜退化性疾病如AMD和RP的发病原理是多方面的,其可在正常个体或在遗传学上易患病的个体中由环境因素引起。迄今为止,已经绘制或克隆了多于100个与各种外视网膜退化相关的基因。
光照射是已经被确定为引起视网膜退化性疾病如AMD发展的环境因素(Young,Sur Ophthal,Vol.32:252-269,1988;Taylor等人,ArchOphthal,Vol.110:99-104,1992;Cruickshank等人,Arch Ophthal,Vol.111:514-518,1993)。导致视网膜细胞光损伤的光氧化应激已经被证明是研究视网膜退化性疾病的有用模型,原因如下:损伤主要发生于外视网膜的光感受器和视网膜色素上皮(RPE),这些细胞与在遗传性变性病中所影响的细胞相同(Noell等人,Invest Ophthal Vis Sci,Vol.5:450-472,1966;Bressler等人,Sur Ophthal,Vol.32:375-413,1988;Curcio等人,InvestOphthal Vis Sci,Vol.37:1236-1249,1996);细胞凋亡是在通过在干性AMD和RP中光感受器和RPE细胞丢失以及之后的光氧化引起的细胞损伤的细胞死亡机制(Ge-Zhi等人,Trans AM Ophthal Soc,Vol.4:411-430,1996;Abler等人,Res Commun Mol Pathol Pharmacol,Vol.92:177-189,1996;Nickells和Zack,Ophthalmic Genet,Vol.17:145-165,1996);已经提示光是AMD和RP发展的环境危险因子(Taylor等人,Arch Ophthalmol,Vol.110:99-104,1992;Naash等人,Invest Ophthal Vis Sci,Vol.37:775-782,1996);并且抑制光氧化损伤的治疗性介入也已经在遗传性退化性视网膜疾病的动物模型中被证明是有效的(LaVail等人,Proc Nat Acad Sci,Vol.89:11249-11253,1992;Fakforovich等人,Nature,Vol.347:83-86,1990;Frasson等人,Nat.Med.Vol.5:1183-1187,1990)。
已经在各种动物模型中确定多种不同种类的化合物可使视网膜光氧化损伤最小。它们包括:抗氧化剂如抗坏血酸盐/酯(Organisciak等人,Invest Ophthal Vis Sci,Vol.26:1589-1598,1985)、二甲基硫脲(Organisciak等人,Invest Ophthal Vis Sci,Vol.33:1599-1609,1992;Lam等人,ArchOphthal,Vol.108:1751-1752,1990)、α-生育酚(Kozaki等人,Nippon GankaGakkai Zasshi,Vol.98:948-954,1994)和β-胡萝卜素(Rapp等人,Cur EyeRes,Vol.15:219-232,1995);钙拮抗剂如氟桂利嗪(Li等人,Exp Eye Res.Vol.56:71-78,1993;Edward等人,Arch Ophthal,Vol.109:554-622,1992;Collier等人,Invest Ophthal Vis Sci,Vol.36:S516);生长因子如碱性成纤维细胞生长因子、脑衍生的神经因子、睫状神经营养因子和白介素-1-β(LaVail等人,Proc Nat Acad Sci,Vol.89:11249-11253,1992);糖皮质激素如甲泼尼龙(Lam等人,Graefes Arch Clin Exp Ophthal,Vol.231:729-736,1993)和地塞米松(Fu等人,Exp Eye Res,Vol.54:583-594,1992);铁螯合剂如去铁胺(Li等人,Cur Eye Res,Vol.2:133-144,1991);NMDA-拮抗剂如依利罗地知MK-801(Collier等人,Invest Ophthal Vis Sci,Vol.40:S159,1999)。
组蛋白乙酰转移酶/脱乙酰酶在较高级的染色质设计及基因转录中扮演着重要角色。组蛋白乙酰化与染色质的转录活性状态相关;反之,去乙酰化与染色质的闭合状态(可导致基因阻遏)相关。已经证明:HDAC抑制剂可使基因表达重新活化并抑制肿瘤细胞的生长和存活(Johnstone,Nature Reviews,Drug Discovery,第1卷,2002年4月)。目前正在测试HDAC抑制剂作为抗癌剂的有效性(例如,Fujisawa的FR-901228;ScheringAG的MS-275;Pfizer的乙酰地那林(CI-994;PD-123654);MethylGene的MG-2856;Vertex的VX-563)。HDAC抑制剂尚未被建议用于治疗患有眼退化性病症或疾病的患者。
发明概述
本发明涉及HDAC抑制剂或(“化合物”)在治疗患有急性或慢性眼退化性病症或疾病的患者中的用途,所述病症或疾病特别是青光眼;干性AMD;RP及其它形式的遗传性退化性视网膜疾病;视网膜脱离和裂孔;黄斑皱褶;影响外视网膜的缺血;与糖尿病性视网膜病和视网膜缺血相关的细胞损伤;与激光疗法、包括光动力疗法(PDT)相关的损伤(格子样变性部位、病灶和全视网膜);创伤;外科手术(视网膜易位、视网膜下手术或玻璃体切割术)或光诱导的医原性视网膜病;以及视网膜移植物的保藏。
优选的实施方案
导致青光眼中视野丢失的因素是多种多样的。多年来已经提出多种假设来解释青光眼,然而,没有一种被证明是青光眼的成因。视野丢失是神经视网膜、特别是视网膜神经节细胞死亡(或功能紊乱)导致的直接后果。因此,保护视网膜神经节细胞的药物疗法被认为是有效的。鉴于对青光眼了解甚少的事实,对该疾病尚无充分建立的动物模型是不足为奇的。由此,将可提供洞察其机理并可提供保护神经视网膜的药物种类的模型用作青光眼模型的替代品。光诱导的视网膜病模型是这几种模型中的一种。该模型有助于鉴别测试对象保护神经视网膜的能力,照此,在该模型中具有活性的化合物被认为具有神经保护作用。
除青光眼外,急性或慢性眼退化性病症或疾病还包括在正常或遗传学上易患病的个体中光感受器和RPE细胞的环境(创伤、缺血、光氧化应激)诱导的急性和慢性退化性病症。其包括但不限于干性AMD、RP及其它形式的遗传性退化性视网膜疾病、视网膜脱离、裂孔、黄斑皱褶、影响外视网膜的缺血、与糖尿病性视网膜病和视网膜缺血相关的细胞损伤、与激光疗法、包括与光动力疗法(PDT)相关的损伤(格子样变性部位、病灶和全视网膜)、热疗法或冷冻疗法、创伤、外科手术(视网膜易位、视网膜下手术或玻璃体切割术)或光诱导的医原性视网膜病,以及视网膜移植物的保藏。
通常,对于退化性疾病,本发明的化合物以约0.001至约500毫克的每日剂量经口服给药。优选的每日总剂量为约1至约100毫克。对于非口服给药,如玻璃体内给药、眼局部给药、透皮贴剂给药、皮下给药、胃肠道外给药、眼内给药、结膜下给药、眼球后或subtenon’s注射、经巩膜(包括离子电渗疗法)或缓释可生物降解聚合物或脂质体给药,需要对每日总剂量进行必要调节,以提供治疗有效量的化合物。化合物还可以在眼冲洗液中被传送。浓度应当为约0.001μM至约100μM,优选约0.01μM至约10μM。
如上所指出的,该化合物可掺在各种类型的眼用制剂中以传送至眼(例如局部、intracamerally、玻璃体内或经植入剂传送)。它们可结合有可眼用的防腐剂、表面活性剂、增粘剂、胶凝剂、渗透促进剂、缓冲剂、氯化钠和水,以形成水性无菌的眼用悬浮液或溶液,或者已制好的凝胶或原位形成的凝胶。眼用溶液制剂可通过将化合物溶于生理可接受的等张水性缓冲液中而制备。此外,眼用溶液可包含可眼用的表面活性剂以有助于溶解该化合物。眼用溶液可含有增粘剂以改善制剂在结膜囊中的滞留,所述增粘剂例如是羟甲基纤维素、羟乙基纤维素、羟丙基甲基纤维素、甲基纤维素或聚乙烯吡咯烷酮等。为了制备无菌的眼用软膏制剂,将活性成分与防腐剂在适宜载体中混合,所述载体例如是矿物油、液态羊毛脂或白凡士林。无菌眼用凝胶制剂可根据相似眼用制剂已公开的处方、通过将活性成分悬浮于亲水基质中来制备,所述的亲水基质由例如卡波普-940等的组合而制备;可加入防腐剂和张力剂(tonicity agent)。
如果是局部给药,该化合物优选制备成局部眼用悬浮液或溶液,其pH为约4至8。该化合物在所述制剂中通常所含的量为0.001%至5%重量,优选为0.01%至2%重量。因此,对于局部施用,可根据熟练医生的医嘱向眼表面滴1至2滴所述制剂,每日1至4次。
可用于本发明的优选HDAC抑制剂包括:suberoylanilide hydroxamicacid(SAHA)、MS-275、oxamflatin、曲古抑菌素A、缩肽和subericbishydroxamate(SBHA)。
所述化合物还可与用于治疗青光眼的其它药物组合使用,所述的其它药物例如但不局限于是β-阻滞剂(例如噻吗洛尔、倍他洛尔、左倍他洛尔、卡替洛尔、左布诺洛尔和美替洛尔)、碳酸酐酶抑制剂(例如布林唑胺、多佐胺和乙酰唑胺)、α1拮抗剂(例如尼普地洛)、α2激动剂(例如艾普罗里定和溴莫尼定)、缩瞳药(例如毛果云香碱)和肾上腺素能药物(肾上腺素)。前列腺素类似物(例如拉坦前列素、曲伏前列素、乌诺前列酮、比马前列素和美国专利US5,889,052、5,296,504、5,422,368、5,688,819和5,151,444中所列出的化合物、“降压脂类(hypotensive lipids)”(例如US5,352,708中所列出的化合物)以及神经保护剂(例如美国专利US4,690,931中的化合物,特别是依利罗地和R-依利罗地,如悬而未决的申请U.S.S.N.06/203350中所列出的,以及WO94/13275中的适宜化合物,例如美金刚,以及5-羟色胺能化合物(5-HT2激动剂)如S-(+)-1-(2-氨丙基)-吲唑-6-醇及其它5-HT2激动剂。
下述局部眼用制剂可用于本发明,根据熟练医生的医嘱,每日施用1至4次。
实施例1
成分 | 含量(wt%) |
化合物,特别是SAHA | 0.01-2% |
羟丙基甲基纤维素 | 0.5% |
磷酸氢二钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠(依地酸二钠) | 0.01% |
聚山梨酯80 | 0.05% |
苯扎氯铵 | 0.01% |
氢氧化钠/盐酸 | 用于将pH调节至7.3-7.4 |
纯净水 | 适量至100% |
实施例2
成分 | 含量(wt%) |
化合物,特别是SAHA | 0.01-2% |
甲基纤维素 | 4.0% |
磷酸氢二钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠(依地酸二钠) | 0.01% |
聚山梨酯80 | 0.05% |
苯扎氯铵 | 0.01% |
氢氧化钠/盐酸 | 用于将pH调节至7.3-7.4 |
纯净水 | 适量至100% |
实施例3
成分 | 含量(wt%) |
化合物,特别是SAHA | 0.01-2% |
瓜尔胶 | 0.4-6.0% |
磷酸氢二钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠(依地酸二钠) | 0.01% |
聚山梨酯80 | 0.05% |
苯扎氯铵 | 0.01% |
氢氧化钠/盐酸 | 用于将pH调节至7.3-7.4 |
纯净水 | 适量至100% |
实施例4
成分 | 含量(wt%) |
化合物,特别是SAHA | 0.01-2% |
白凡士林和矿物油和羊毛脂 | 软膏稠度 |
磷酸氢二钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠(依地酸二钠) | 0.01% |
聚山梨酯80 | 0.05% |
苯扎氯铵 | 0.01% |
氢氧化钠/盐酸 | 用于将pH调节至7.3-7.4 |
实施例5
10mM IV溶液w/v% | |
化合物,特别是SAHA | 0.384% |
L-酒石酸 | 2.31% |
氢氧化钠 | pH3.8 |
盐酸 | pH3.8 |
纯净水 | 适量至100% |
实施例6
5mg胶囊 | |
成分 | mg/胶囊(总重量mg) |
化合物,特别是SAHA | 5 |
乳糖,无水 | 55.7 |
羧甲基淀粉钠 | 8 |
微晶纤维素 | 30 |
胶态二氧化硅 | 0.5 |
硬脂酸镁 | 0.8 |
Claims (4)
1.治疗患有急性或慢性眼退化性病症或疾病的患者的方法,该方法包括给予药物有效量的组蛋白脱乙酰酶抑制剂。
2.权利要求1的方法,其中所述病症或疾病选自青光眼;干性AMD;RP及其它形式的遗传性退化性视网膜疾病;视网膜脱离和裂孔;黄斑皱褶;影响外视网膜的缺血;与糖尿病性视网膜病和视网膜缺血相关的细胞损伤;与激光疗法、包括光动力疗法(PDT)相关的损伤(格子样变性部位、病灶和全视网膜);创伤;外科手术(视网膜易位、视网膜下手术或玻璃体切割术)或光诱导的医原性视网膜病;以及视网膜移植物的保藏。
3.权利要求2的方法,其中所述病症或疾病是干性AMD。
4.权利要求2的方法,其中所述病症或疾病是青光眼。
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US42557602P | 2002-11-12 | 2002-11-12 | |
US60/425,576 | 2002-11-12 |
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CN1711086A true CN1711086A (zh) | 2005-12-21 |
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CNA2003801029350A Pending CN1711086A (zh) | 2002-11-12 | 2003-10-27 | 用于治疗眼的退化性疾病的组蛋白脱乙酰酶抑制剂 |
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US (2) | US20070088045A1 (zh) |
EP (1) | EP1562592A4 (zh) |
JP (1) | JP2006508120A (zh) |
KR (1) | KR20050074547A (zh) |
CN (1) | CN1711086A (zh) |
AU (1) | AU2003286686B2 (zh) |
BR (1) | BR0316163A (zh) |
CA (1) | CA2504226A1 (zh) |
MX (1) | MXPA05004738A (zh) |
RU (1) | RU2324483C2 (zh) |
WO (1) | WO2004043348A2 (zh) |
ZA (1) | ZA200503230B (zh) |
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CN107362148A (zh) * | 2017-07-27 | 2017-11-21 | 东曜药业有限公司 | 一种治疗肿瘤的药物组合物及其制备方法和应用 |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080004311A1 (en) * | 2002-11-12 | 2008-01-03 | Alcon, Inc. | Histone deacetylase inhibitors for treating degenerative diseases of the eye |
EP1562592A4 (en) * | 2002-11-12 | 2009-01-21 | Alcon Inc | HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF DEGENERATIVE DISEASES OF THE EYE |
US20060074100A1 (en) * | 2002-11-12 | 2006-04-06 | Klimko Peter G | Histone deacetylase inhibitors for the treatment of ocular neovascular or edematous disorders and diseases |
US20050197336A1 (en) * | 2004-03-08 | 2005-09-08 | Miikana Therapeutics Corporation | Inhibitors of histone deacetylase |
US7345043B2 (en) * | 2004-04-01 | 2008-03-18 | Miikana Therapeutics | Inhibitors of histone deacetylase |
GB2417682A (en) * | 2004-08-18 | 2006-03-08 | Univ East Anglia | Histone deacetylse inhibitor for treating connective tissue disorders |
CA2596015A1 (en) | 2005-02-14 | 2006-08-24 | Sampath K. Anandan | Fused heterocyclic compounds useful as inhibitors of histone deacetylase |
EA200800321A1 (ru) | 2005-07-14 | 2008-06-30 | Такеда Сан Диего, Инк. | Ингибиторы гистондеацетилазы |
AU2006272497B2 (en) * | 2005-07-27 | 2012-07-19 | University Of Florida Research Foundation, Inc. | Small compounds that correct protein misfolding and uses thereof |
WO2008117861A1 (ja) * | 2007-03-28 | 2008-10-02 | Santen Pharmaceutical Co., Ltd. | フェニレンジアミン誘導体を有効成分とする眼圧下降剤 |
CN101646460A (zh) * | 2007-03-28 | 2010-02-10 | 参天制药株式会社 | 含有具有组蛋白脱乙酰化酶抑制作用的化合物作为有效成分的降眼压剂 |
EP2133339A4 (en) | 2007-03-28 | 2010-04-21 | Santen Pharmaceutical Co Ltd | NOVEL (2-AMINOPHENYL) PYRIDINECARBOXAMIDE DERIVATIVE HAVING UREA STRUCTURE |
JP2010001289A (ja) | 2008-05-23 | 2010-01-07 | Santen Pharmaceut Co Ltd | ウレア構造を有する新規チオフェンジアミン誘導体 |
KR20130123301A (ko) * | 2010-05-27 | 2013-11-12 | 더 리젠츠 오브 더 유니버시티 오브 콜로라도, 어 바디 코포레이트 | 히스톤 디아세틸라아제의 저해제들로서 유용한 거대고리 화합물들 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2534580A1 (fr) * | 1982-10-13 | 1984-04-20 | Synthelabo | Derives de phenyl-1 piperidino-2 propanol, leur preparation, et medicaments qui les contiennent |
US5151444B1 (en) * | 1987-09-18 | 1999-07-06 | R Tech Ueno Ltd | Ocular hypotensive agents |
US5321128A (en) * | 1988-09-06 | 1994-06-14 | Kabi Pharmacia Ab | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
ES2213504T1 (es) * | 1988-09-06 | 2004-09-01 | Pfizer Health Ab | Derivados de prostaglandina para el tratamiento del glaucoma o hipertension ocular. |
US5296504A (en) * | 1988-09-06 | 1994-03-22 | Kabi Pharmacia | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US5464866A (en) * | 1992-08-17 | 1995-11-07 | Alcon Laboratories, Inc. | Substituted hydrindanes for the treatment of angiogenesis-dependent diseases |
US5352708A (en) * | 1992-09-21 | 1994-10-04 | Allergan, Inc. | Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
US5688819A (en) * | 1992-09-21 | 1997-11-18 | Allergan | Cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
US5510383A (en) * | 1993-08-03 | 1996-04-23 | Alcon Laboratories, Inc. | Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension |
US5681854A (en) * | 1995-11-22 | 1997-10-28 | Alcon Laboratories, Inc. | Use of aliphatic carboxylic acid derivatives in ophthalmic disorders |
AUPP505798A0 (en) * | 1998-08-04 | 1998-08-27 | Fujisawa Pharmaceutical Co., Ltd. | Novel compound fr225497 substance |
US6905669B2 (en) * | 2001-04-24 | 2005-06-14 | Supergen, Inc. | Compositions and methods for reestablishing gene transcription through inhibition of DNA methylation and histone deacetylase |
US7154002B1 (en) * | 2002-10-08 | 2006-12-26 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
US7250514B1 (en) * | 2002-10-21 | 2007-07-31 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
US20080004311A1 (en) * | 2002-11-12 | 2008-01-03 | Alcon, Inc. | Histone deacetylase inhibitors for treating degenerative diseases of the eye |
EP1562592A4 (en) * | 2002-11-12 | 2009-01-21 | Alcon Inc | HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF DEGENERATIVE DISEASES OF THE EYE |
WO2009002941A1 (en) * | 2007-06-22 | 2008-12-31 | Board Of Regents, The University Of Texas System | Composition and method for the treatment of diseases affected by histone deacetylase inhibitors |
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2003
- 2003-10-27 EP EP03777895A patent/EP1562592A4/en not_active Withdrawn
- 2003-10-27 US US10/531,747 patent/US20070088045A1/en not_active Abandoned
- 2003-10-27 CN CNA2003801029350A patent/CN1711086A/zh active Pending
- 2003-10-27 CA CA002504226A patent/CA2504226A1/en not_active Abandoned
- 2003-10-27 KR KR1020057008066A patent/KR20050074547A/ko not_active Application Discontinuation
- 2003-10-27 AU AU2003286686A patent/AU2003286686B2/en not_active Ceased
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- 2003-10-27 JP JP2004551572A patent/JP2006508120A/ja not_active Withdrawn
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Cited By (2)
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CN107362148A (zh) * | 2017-07-27 | 2017-11-21 | 东曜药业有限公司 | 一种治疗肿瘤的药物组合物及其制备方法和应用 |
CN107362148B (zh) * | 2017-07-27 | 2020-04-21 | 东曜药业有限公司 | 一种治疗肿瘤的药物组合物及其制备方法和应用 |
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ZA200503230B (en) | 2006-06-28 |
US20040092431A1 (en) | 2004-05-13 |
WO2004043348A2 (en) | 2004-05-27 |
US20070088045A1 (en) | 2007-04-19 |
BR0316163A (pt) | 2005-09-27 |
AU2003286686A1 (en) | 2004-06-03 |
MXPA05004738A (es) | 2005-08-03 |
AU2003286686B2 (en) | 2009-07-16 |
EP1562592A4 (en) | 2009-01-21 |
KR20050074547A (ko) | 2005-07-18 |
RU2324483C2 (ru) | 2008-05-20 |
RU2005118108A (ru) | 2006-01-20 |
JP2006508120A (ja) | 2006-03-09 |
WO2004043348A3 (en) | 2004-07-15 |
EP1562592A2 (en) | 2005-08-17 |
CA2504226A1 (en) | 2004-05-27 |
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