CN1205186C - Ace-抑制剂硝酸盐 - Google Patents
Ace-抑制剂硝酸盐 Download PDFInfo
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Abstract
具有式(I)、(II)、(III)的Ace-抑制剂硝酸盐。
Description
本发明涉及具有抗高血压活性兼有抗血小板凝聚活性的产品,及其药用组合物。
具体地说,本发明涉及与目前市售的抗高血压药剂产品相比具有较好的抗高血压活性和较少的副作用(尤其在支气管方面)的产品。抗高血压活性是与抗血小板凝聚活性有关的。
本领域中已知抗高血压药剂。特别是ACE抑制剂,其在心血管疾病如高血压、心绞痛、心肌缺血、充血性心力衰竭等的治疗中代表首选的药物学措施。ACE抑制剂作用于肾素-血管紧张素系统,该系统释放血管紧张素II,其是已知最有效的升压剂之一。更确切地说,这些药物抑制血管紧张素转化酶的活性,该酶是主要存在于肺、肾和血管中的一种羧肽酶。这种酶的作用是非特异性的。它灭活血浆缓激肽,缓激肽具有血管舒张活性,并且也有助于利尿,尤其是促尿钠排出。换言之,血浆缓激肽具有与血管紧张素II相反的作用。因此,ACE抑制剂阻止血管紧张素II的形成,同时阻止缓激肽的降解。因而,ACE抑制剂肯定代表了过去几十年最重要的药理学创新之一。
然而,ACE抑制剂的应用常常伴有呼吸系统的副作用(大约病例的20-30%),如咳嗽、呼吸困难、支气管收缩。此外,这些药物还显示出颇受限制的治疗模式,例如它们没有抗血小板凝聚活性,所以在上述心血管疾病的治疗中,它们常与其它的具有抗血小板凝聚活性的药物联合使用。例如,在心肌梗塞的治疗和复发的预防中,需要采用多种心血管药物治疗,其中包括抗高血压药与抗凝剂的联合使用。
因此需要有较好的治疗效果和较少副作用(尤其是呼吸系统,如支气管副作用)的药物。
本申请人意外和惊奇地发现一类特殊的ACE-抑制剂盐,其特征在于这一事实,即与同样化合物的其它盐相比,它们具有较好的抗高血压活性和较少的支气管的副作用。
因此,本发明的目标的是具有下式的ACE抑制剂的硝酸盐:
Y=CH3、苯基;
RIII=H,
RIII与RIV一起形成在4位碳上的下列环
RIII与RV一起(在4和5位碳上)形成环己烷或环戊烷环
RIV=H,或RIV和RIII形成环(IVa);
RV=H,或一个自由价,或者RV和RIII形成环(IIIa)或(IIIb);
RVI=H,或当RV是一个自由价时,为单键-O,以便与5位的碳原子形成酮基团。
优选的式(I)的硝酸盐包括:
当如上述所定义的X=C(RIII)(RIV)时,Y=苯基,RIII=RIV=RV=RVI=H,构成依那普利(Enalapril)的残基;
如在依那普利中那样,但是RIII与RIV一起形成环(IVa),构成斯哌普利(Spirapril)的残基;
如在依那普利中那样,但是RIII与RV一起形成环(IIIb),构成雷米普利的残基;
如在依那普利中那样,但是Y=CH3,并且RIII与RV一起形成环(IIIa),构成培哚普利(Perindopril)的残基;
如在依那普利中那样,但是X=N-CH3,RV是一个自由价和RIV=-O,以便与碳原子C5形成酮基团,构成咪哒普利的残基。
本发明的这类化合物(其为所述盐的前体)是作为旋光活性的单一异构体或作为其混合物或者以外消旋体的形式使用的。
已知类型II的前体称作赖诺普利,类型III的前体称作阿拉普利。按照在“The Mercx Index,Ed.12”中所描述的方法制备所述前体,该文通过引用结合到本文中。
按照下列方法制备本发明的所述盐。将待成盐的物质溶于不含有分子游离羟基基团的有机溶剂中,然后加入化学计量的浓硝酸。通过过滤回收所述盐,并用溶剂(如在反应中所使用的溶剂)洗涤几次。优选极性有机溶剂,例如,乙腈、乙酸乙酯等等。
已惊奇地发现,与同样的物质和普通ACE盐相比,本发明的所述化合物改善了上述ACE抑制剂的药理学模式,并且显示了更为满意的全身和局部的可耐受性。
本发明的所述化合物能作为心血管药物使用,具体地说,能用于高血压、心绞痛、心肌缺血、充血性心力衰竭的治疗。
按照本领域技术人员已熟知的方法,例如在Remington’sPharmaceutical Science,Ed.15中所描述的方法,将本发明的所述盐配制成相应的药用组合物。
以下实施例意味着对本发明的描述,而不应理解为限制本发明。
实施例1
(S)-1-[N-[1-(乙氧羰基)-3-苯丙基]-L-丙氨酰基]-L-脯氨酸(依那普利)
的合成,和乙腈中硝酸盐的获得
在室温下用氰基氢硼化钠(0.4g)的乙醇/水1/1的溶液缓慢处理乙基-2-氧代-4-苯基丁酸酯(2.1g)和L-丙氨酰基-L-脯氨酸(0.4g)的乙醇/水1/1的混合物。
在反应结束时,将该产物吸收在强酸离子交换树脂上,并用含有2%(v/v)吡啶的水溶液洗脱。冷冻干燥含有该产物的部分,获得粗制化合物。然后层析使分离的所需异构体(-)纯化(0.24g)。
然后将该异构体溶于乙腈中,并用溶于乙腈中的化学计量的浓硝酸处理,维持该反应物在冰浴中。冷却和过滤后,用冷乙腈洗涤该固体,回收97%-纯的(HPLC:高压液相层析)依那普利硝酸盐。通过从乙腈中结晶可获得99%-纯的(HPLC)盐。
实施例2
依那普利的合成,和乙酸乙酯中硝酸盐的获得
在室温和大约3个大气压下将乙基-2-氧代-4-苯基丁酸酯(15g)、L-丙氨酰基-L-脯氨酸(9g)、3A°分子筛(40g)和阮内镍(10.8g)的乙醇(300ml)混合物氢化,直到氢不再被消耗。在不溶解的物质滤出后(用乙醇充分洗涤),真空下蒸发该溶剂,获得85%由所需产物形成的非对映异构体的混合物(通过HPLC)。将获得的产物溶于200ml水和70ml乙酸甲酯制成的混合物中。持续搅拌该溶液,用50%NaOH调节pH至8.6。分离有机相,并用乙酸乙酯(3×50ml)充分洗涤含水相。用盐酸调节该含水相至pH 4.3,用氯化钠饱和,然后用乙酸乙酯(4×100ml)萃取。在用硫化钠干燥和真空蒸发该溶剂以后,将残余物溶于乙酸乙酯中,维持该反应物在冰浴中,通过用化学计量的浓硝酸处理成盐。搅拌2小时后,将其冷却、过滤、用乙酸乙酯洗涤并从乙腈中再结晶,获得12.5g大约99%-纯(通过HPLC)的硝酸盐异构体(-)。
实施例3
急性毒性试验
一组10只小鼠(体重15到25g)接受100mg/Kg的单次口服剂量。在观察期间(14天)所有动物均存活。没有观察到毒性症状。
实施例4
抗高血压活性
按照Laubie等的方法(J.Cardiovasc.Pharmacol.6,1076,1984年)测定本发明化合物硝酸盐的抗高血压活性。每个试验组采用6只体重约200到250g的大鼠。共分四组,如下所示,每组分别腹腔内给予:
-依那普利马来酸盐 100μg/Kg
-依那普利马来酸盐 300μg/Kg
-依那普利硝酸盐 100μg/Kg
-依那普利硝酸盐 300μg/Kg
该剂量是参照依那普利(阳离子)在盐中的量。如以上文章中所描述的,通过静脉注射给予100μg/Kg剂量的血管紧张素I诱导高血压,以高血压抑制的百分比来评估抗高血压作用。
结果显示于表I
表I
化合物 剂量 血管紧张素I诱导的
(μg/Kg/i.p.) 高血压抑制%
依那普利马来酸盐 100 18
依那普利马来酸盐 300 55
依那普利硝酸盐 100 35
依那普利硝酸盐 300 67
实施例5
本发明的盐对由给予P物质而诱导的支气管痉挛的药理学作用
按照Subissi等(Br.J.Pharmacol.100,502-6,1990年)确立的方法,通过测定由P物质诱导的支气管痉挛的强度来评估其活性。Subissi描述的模型可预测因给予ACE抑制剂而引起的支气管副作用。
四组雌性豚鼠(6只动物/组),体重约300到400g,在人工压力下以恒定的正压用氨基甲酸乙酯(200mg/Kg)麻醉。在给予P物质以前30分钟腹腔内给予所述化合物。给予的所述盐的剂量与实施例4中的相同。然后按照Konzett的方法(Arch.Exp.Pathol.Pharmacol.195,71,1940年),在给予P物质(200μg/Kg)以前和以后,使用或未使用受试盐(即依那普利马来酸盐和硝酸盐),测定潮气流(tidal air)的变化。
结果显示于表II
从数据中可以看出,在两个试验剂量中,依那普利硝酸盐均比依那普利马来酸盐具有更好的呼吸效用。
表II
化合物 剂量 P物质诱导的支气管
(μg/Kg/i.p.) 痉挛中潮流气变化%
依那普利马来酸盐 100 +16
依那普利马来酸盐 300 +28
依那普利硝酸盐 100 -5
依那普利硝酸盐 300 -7
实施例6
抗血小板凝聚活性
采用Pinon等描述的活体模型(J.Pharm.Methods 12,79-84,1984年)。
两组大鼠,每组6只,体重约200到250g,分别口服给予10mg/Kg/日剂量的依那普利马来酸盐或硝酸盐(该剂量参照依那普利阳离子在盐中的量)进行处理,连续5天,而第三组作为对照组。在最后一次给药前大约18小时,动物禁食。这次给药后1小时,用10%氨基甲酸乙酯(1g/Kg腹腔内注射)麻醉动物,在左颈静脉和右颈动脉中插管。然后以2mg/Kg的剂量静脉给予胶原蛋白(6型,Sigma)。三分钟后,从每只动物的颈动脉采集两个血样,A和B。
将1.6ml的EDTA/福尔马林缓冲液(24mM EDTA四钠盐、1.3mM KH2PO4、13.4mM Na2HPO4)加入到第一个含有0.4ml血液的样本(样本A)中。
第二个血样(样本B)具有与前一样本相同的体积(0.4ml血液),但是加入1.6ml的生理盐水(生理NaCl溶液)来代替缓冲液。
然后将所述样本转移到5-ml试管中,并允许在室温放置15分钟。
然后进行显微镜血小板计数。样本B和A中的血小板计数分别代表血小板的总数和凝聚的血小板的总数。结果显示于表III,以血小板凝聚的%表示,并且参照对照组中获得的%值。
表III
化合物 剂量/die 抗凝聚活性%
(mg/Kg/os)
依那普利马来酸盐 10 5
依那普利硝酸盐 10 58
综上所述,本发明提供的一部分方案是:
具有下式的ACE抑制剂的硝酸盐:
Y=CH3、苯基;
RIII=H,
RIII与RIV一起形成在4位碳上的下列环
RIII与RV一起,在4和5位碳上,形成环己烷或环戊烷环
RIV=H,或RIV和RIII形成环(IVa);
RV=H,或一个自由价,或者RV和RIII形成环(IIIa)或(IIIb);
RVI=H,或当RV是一个自由价时为单键-O,以便与5位的碳原子形成酮基团。
一种技术方案是:其中,在式(I)中,X=C(RIII)(RIV),Y=苯基,RIII=RIV=RV=RVI=H,构成依那普利的残基;
如在依那普利中那样,但是RIII与RIV一起形成环(IVa),构成斯哌普利的残基;
如在依那普利中那样,但是RIII与RV一起形成环(IIIb),构成雷米普利的残基;
如在依那普利中那样,但是Y=CH3,并且RIII与RV一起形成(IIIa),构成培哚普利的残基;
如在依那普利中那样,但是X=N-CH3,RV是一个自由价和RIV=-O,以便与碳原子C5形成一个酮基团,构成咪哒普利的残基。
一种技术方案是:上述硝酸盐中,在式(I)中,X=C(III)(RIV),Y=苯基,RIII=RIV=RV=RVI=H,构成依那普利的残基。
本发明还提供了以下技术方案,包括:
上述硝酸盐用于制备作为抗高血压药的药用组合物的用途。
上述硝酸盐用于制备作为抗凝剂的药用组合物。
上述硝酸盐用于制备作为抗高血压和抗凝剂的药用组合物。
上述硝酸盐用于制备作为治疗高血压、心绞痛、心肌缺血、充血性心力衰竭的心血管药的药用组合物。
Claims (7)
2.按照权利要求1的硝酸盐,其中,在式(I)中,X=C(RIII)(RIV),Y=苯基,RIII=RIV=RV=RVI=H,构成依那普利的残基;
如在依那普利中那样,但是RIII与RIV一起形成环(IVa),构成斯哌普利的残基;
如在依那普利中那样,但是RIII与RV一起形成环(IIIb),构成雷米普利的残基;
如在依那普利中那样,但是Y=CH3,并且RIII与RV一起形成(IIIa),构成培哚普利的残基;
如在依那普利中那样,但是X=N-CH3,RV是一个自由价和RIV=-O,以便与碳原子C5形成一个酮基团,构成咪哒普利的残基。
3.按照权利要求2的硝酸盐,其中,在式(I)中,X=C(RIII)(RIV),Y=苯基,RIII=RIV=RV=RVI=H,构成依那普利的残基。
4.权利要求1到3之一的硝酸盐的用途,其中所述用途是用于制备作为抗高血压药的药用组合物。
5.按照权利要求1到3之一的硝酸盐的用途,其中所述用途是用于制备作为抗凝剂的药用组合物。
6.按照权利要求1到3之一的硝酸盐的用途,其中所述用途是用于制备作为抗高血压和抗凝剂的药用组合物。
7.按照权利要求1到3之一的硝酸盐的用途,其中所述用途是用于制备作为治疗高血压、心绞痛、心肌缺血、充血性心力衰竭的心血管药的药用组合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI97A001523 | 1997-06-27 | ||
IT97MI001523A IT1292426B1 (it) | 1997-06-27 | 1997-06-27 | Sali nitrati di ace-inibitori |
Publications (2)
Publication Number | Publication Date |
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CN1260780A CN1260780A (zh) | 2000-07-19 |
CN1205186C true CN1205186C (zh) | 2005-06-08 |
Family
ID=11377450
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CNB988062763A Expired - Fee Related CN1205186C (zh) | 1997-06-27 | 1998-06-24 | Ace-抑制剂硝酸盐 |
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US (1) | US6218417B1 (zh) |
EP (1) | EP1019370B1 (zh) |
JP (1) | JP2002506456A (zh) |
KR (1) | KR100512892B1 (zh) |
CN (1) | CN1205186C (zh) |
AT (1) | ATE230393T1 (zh) |
AU (1) | AU740411B2 (zh) |
BR (1) | BR9810459A (zh) |
CA (1) | CA2292794A1 (zh) |
DE (1) | DE69810498T2 (zh) |
DK (1) | DK1019370T3 (zh) |
ES (1) | ES2190095T3 (zh) |
HU (1) | HUP0003133A3 (zh) |
IL (1) | IL132691A (zh) |
IT (1) | IT1292426B1 (zh) |
RU (1) | RU2194037C2 (zh) |
WO (1) | WO1999000361A1 (zh) |
Families Citing this family (30)
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IT1301759B1 (it) * | 1998-06-19 | 2000-07-07 | Nicox Sa | Sali nitrati di farmaci antiipertensivi |
IT1303672B1 (it) * | 1998-07-28 | 2001-02-23 | Nicox Sa | Sali nitrati di farmaci attivi nei disordini ossei |
WO2001017528A1 (en) | 1999-09-08 | 2001-03-15 | Nitromed, Inc. | Methods of treating and preventing congestive heart failure with hydralazine compounds and isosorbide dinitrate or isosorbide mononitrate |
US7708989B2 (en) * | 1999-10-29 | 2010-05-04 | Nitromed, Inc. | Methods of treating vascular diseases characterized by nitric oxide insufficiency |
DE60042611D1 (de) | 1999-10-29 | 2009-09-03 | Nitromed Inc | Verfahren zur behandlung von gefässerkrankungen, dxid auszeichnen |
US7235237B2 (en) | 1999-10-29 | 2007-06-26 | Nitromed, Inc. | Methods of treating vascular diseases characterized by nitric oxide insufficiency |
US7537785B2 (en) | 1999-10-29 | 2009-05-26 | Nitromed, Inc. | Composition for treating vascular diseases characterized by nitric oxide insufficiency |
EP1406608B1 (en) | 2001-05-02 | 2009-07-29 | Nitromed, Inc. | Nitrosated and nitrosylated nebivolol and its metabolites, compositions and methods of use |
GB0111872D0 (en) * | 2001-05-15 | 2001-07-04 | Northwick Park Inst For Medica | Therapeutic agents and methods |
US20080026984A1 (en) * | 2002-02-04 | 2008-01-31 | Alfama - Investigacao E Desenvolvimento De Productos Farmaceuticos Lda | Methods for treating inflammatory disease by administering aldehydes and derivatives thereof |
US7968605B2 (en) * | 2002-02-04 | 2011-06-28 | ALFAMA—Investigação e Desenvolvimento de Produtos Farmacêuticos, Lda. | Methods for treating inflammatory disease by administering aldehydes and derivatives thereof |
EP2319518A1 (en) * | 2002-02-04 | 2011-05-11 | ALFAMA-Investigacao e Desenvolvimento de Produtos Farmaceuticos Lda. | Use of CO-releasing compounds for the manufacture of a medicament for the treatment of inflammatory diseases |
US20060247216A1 (en) * | 2002-10-25 | 2006-11-02 | Haj-Yehia Abdullah I | Steroid compounds comprising superoxide dismutase mimic groups and nitric oxide donor groups, and their use in the preparation of medicaments |
GB2395432B (en) * | 2002-11-20 | 2005-09-14 | Northwick Park Inst For Medica | Therapeutic delivery of carbon monoxide to extracorporeal and isolated organs |
US20070207217A1 (en) * | 2003-02-03 | 2007-09-06 | Alfama - Investigacao E Desenvolvimento De Productos Farmaceuticos Lda | Method for treating a mammal by administration of a compound having the ability to release CO |
US7169805B2 (en) * | 2003-05-28 | 2007-01-30 | Nicox S.A. | Captopril derivatives |
JP2008506716A (ja) * | 2004-07-16 | 2008-03-06 | ニトロメッド インコーポレーティッド | 心不全に関連する組成物および方法 |
DE602005020314D1 (de) | 2004-08-25 | 2010-05-12 | Actelion Pharmaceuticals Ltd | Bicyclononen-derivate als renin-inhibitoren |
EP1679072B9 (en) * | 2005-01-06 | 2009-09-02 | IPCA Laboratories Limited | Process for for synthesis of (2S,3aS,7aS)-1-(S)-alanyl-octahydro-1H-indole-2- carboxylic acid derivatives and use in the synthesis of perindopril |
WO2006121853A1 (en) * | 2005-05-05 | 2006-11-16 | Keryx Biopharmaceuticals, Inc. | Combination therapy with sulodexide and a blood pressure reducing agent in the treatment of diabetic nephropathy |
EP1893578A2 (en) * | 2005-05-27 | 2008-03-05 | Actelion Pharmaceuticals Ltd. | Novel piperidine carboxylic acid amide derivatives |
JP2009514809A (ja) * | 2005-10-18 | 2009-04-09 | ニコックス エス エイ | レニン阻害剤のニトロ誘導体 |
GB0601394D0 (en) | 2006-01-24 | 2006-03-01 | Hemocorm Ltd | Therapeutic delivery of carbon monoxide |
AU2007210813A1 (en) | 2006-02-02 | 2007-08-09 | Actelion Pharmaceuticals Ltd | Secondary amines as renin inhibitors |
EP1984010A4 (en) * | 2006-02-17 | 2010-09-08 | Nitromed Inc | METHOD FOR USE OF HYDRALAZIN COMPOUNDS AND ISOSORBIDE DINITRATE OR ISOSORBIDE MONONITRATE |
JP2009529033A (ja) * | 2006-03-08 | 2009-08-13 | アクテリオン ファーマシューティカルズ リミテッド | 新規アミン |
WO2007136626A1 (en) * | 2006-05-16 | 2007-11-29 | Nitromed, Inc. | Solid dosage formulations of hydralazine compounds |
CN102015682B (zh) | 2008-05-05 | 2014-07-16 | 埃科特莱茵药品有限公司 | 作为肾素抑制剂的3,4-取代的哌啶衍生物 |
ES2656237T3 (es) | 2011-04-19 | 2018-02-26 | Alfama, Inc. | Moléculas liberadoras de monóxido de carbono y usos de las mismas |
WO2013013179A1 (en) | 2011-07-21 | 2013-01-24 | Alfama, Inc. | Ruthenium carbon monoxide releasing molecules and uses thereof |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
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SE463851B (sv) | 1988-09-02 | 1991-02-04 | Amsu Ltd | Komposition foer behandling av erektil dysfunktion via uretra |
US5352708A (en) | 1992-09-21 | 1994-10-04 | Allergan, Inc. | Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
US5328933A (en) | 1992-10-28 | 1994-07-12 | Allergan, Inc. | Cyclopentane heptenylnitro and heptanylnitro-2-aliphatic or aryl aliphatic derivatives and homologues |
KR100387359B1 (ko) | 1994-05-10 | 2003-08-27 | 니콕스 에스. 에이. | 항-염증성,비알러지성및항-혈전성을가지는니트로화합물들과그들의조성물들 |
US5625083A (en) | 1995-06-02 | 1997-04-29 | Bezuglov; Vladimir V. | Dinitroglycerol esters of unsaturated fatty acids and prostaglandins |
US5645839A (en) * | 1995-06-07 | 1997-07-08 | Trustees Of Boston University | Combined use of angiotensin inhibitors and nitric oxide stimulators to treat fibrosis |
CN1141771A (zh) * | 1995-08-02 | 1997-02-05 | 贾力 | 巯-亚硝基化合物及其医学用途 |
-
1997
- 1997-06-27 IT IT97MI001523A patent/IT1292426B1/it active IP Right Grant
-
1998
- 1998-06-24 CA CA002292794A patent/CA2292794A1/en not_active Abandoned
- 1998-06-24 CN CNB988062763A patent/CN1205186C/zh not_active Expired - Fee Related
- 1998-06-24 ES ES98938668T patent/ES2190095T3/es not_active Expired - Lifetime
- 1998-06-24 HU HU0003133A patent/HUP0003133A3/hu unknown
- 1998-06-24 KR KR10-1999-7011984A patent/KR100512892B1/ko not_active IP Right Cessation
- 1998-06-24 US US09/423,287 patent/US6218417B1/en not_active Expired - Fee Related
- 1998-06-24 JP JP50529499A patent/JP2002506456A/ja not_active Ceased
- 1998-06-24 DE DE69810498T patent/DE69810498T2/de not_active Expired - Fee Related
- 1998-06-24 AU AU87300/98A patent/AU740411B2/en not_active Ceased
- 1998-06-24 EP EP98938668A patent/EP1019370B1/en not_active Expired - Lifetime
- 1998-06-24 BR BRPI9810459-4A patent/BR9810459A/pt not_active IP Right Cessation
- 1998-06-24 AT AT98938668T patent/ATE230393T1/de not_active IP Right Cessation
- 1998-06-24 IL IL13269198A patent/IL132691A/en not_active IP Right Cessation
- 1998-06-24 WO PCT/EP1998/003946 patent/WO1999000361A1/en active IP Right Grant
- 1998-06-24 RU RU2000100825/04A patent/RU2194037C2/ru not_active IP Right Cessation
- 1998-06-24 DK DK98938668T patent/DK1019370T3/da active
Also Published As
Publication number | Publication date |
---|---|
EP1019370B1 (en) | 2003-01-02 |
RU2194037C2 (ru) | 2002-12-10 |
EP1019370A1 (en) | 2000-07-19 |
HUP0003133A2 (en) | 2001-03-28 |
US6218417B1 (en) | 2001-04-17 |
CN1260780A (zh) | 2000-07-19 |
ITMI971523A1 (it) | 1998-12-27 |
BR9810459A (pt) | 2006-10-03 |
ATE230393T1 (de) | 2003-01-15 |
KR20010013958A (ko) | 2001-02-26 |
IL132691A0 (en) | 2001-03-19 |
CA2292794A1 (en) | 1999-01-07 |
ES2190095T3 (es) | 2003-07-16 |
DE69810498D1 (de) | 2003-02-06 |
IL132691A (en) | 2004-06-01 |
ITMI971523A0 (zh) | 1997-06-27 |
DE69810498T2 (de) | 2003-10-30 |
DK1019370T3 (da) | 2003-05-05 |
IT1292426B1 (it) | 1999-02-08 |
AU8730098A (en) | 1999-01-19 |
AU740411B2 (en) | 2001-11-01 |
KR100512892B1 (ko) | 2005-09-07 |
WO1999000361A1 (en) | 1999-01-07 |
HUP0003133A3 (en) | 2002-10-28 |
JP2002506456A (ja) | 2002-02-26 |
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