CN1272494A - 抗骨质疏松药制备方法 - Google Patents
抗骨质疏松药制备方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/16—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
公开了一种制备CD环片断的式A的新三乙基甲硅烷基醚类似物的方法,其中R2为甲硅烷基保护基团;和制备这些类似物的新的中间体。
Description
本发明提供了一种制备式A的CD环片断的新三乙基甲硅烷基醚类似物的方法，
其中R2为甲硅烷基保护基团；本发明进一步涉及用于制备这些类似物的新的中间体。
式III的维生素D3类似物(见下面)对骨质疏松症的疗效目前正在评估之中。如欧洲专利申请EP 808833所描述，目前的制备依赖于lythgoe氧化膦方法，其中CD-环片断I和式II的A-环片断结合，随后通过产物去保护，得到式III的维生素D3类似物。
本发明提供了一种用于制备式A的CD环片断的新三乙基甲硅烷基醚类似物的新方法，反应方案归纳如下：
反应方案
(化合物A，其中R2为TES)用于上面方案的化合物3，可以按照下面的方案合成：
已知起始化合物1，可以按照Daniewsiki，A.R.；Kiegel，J.在有机化学杂志(J.Org.Chem.1988，53，5534)提出的方法合成。化合物1在适当的条件下，通过Wittig-Horner反应，保留环氧化物环的完整，转化为α，β-未饱和酯2(E∶Z异构体为6∶1的混合物)。然后α，β-未饱和酯2去质子化，得到的烯醇盐中间体用烯丙基氯3立体选择性烷基化，因此在β，γ-未饱和酯4上引入一个新的手性中心C-20和Δ16双键(甾族化合物编号)。侧链片断3从商业途径可得到的3-乙基-1-戊炔-3-醇经过四步制得。对于α，β-未饱和酯2的烷基化，在最佳条件下，通过在六甲基磷酰胺(HMPA)存在下使用锂二环己氨(LCA)，在最少分解底物的条件下，完成去质子化。从不需要的(20R)-差向异构体(10％)通过色谱分离得到产率为73％得所需要的(20S)-差向异构体4。化合物4的酯和环氧化物官能度同时还原得到二醇5。二醇5中得到的伯醇官能度然后进行两步选择性还原，得到所需的C-21甲基基团。氧化产物7得到标题化合物8。三个中间产物2，4和7全部经过色谱纯化。
在本发明的下面描述中，术语“低级烷基”的含义包括甲基、乙基、丙基、丁基。下面的词可以被缩写为：三甲基甲硅烷基(TMS)，三乙基甲硅烷基(TES)，叔丁基二甲基(TBS)，对甲苯磺酰基(Ts)，甲基磺酰基(Ms)，二环己氨(DCHA)，丁基锂(BuLi)，六甲基磷酰胺(HMPA)。其它的词可以按照其它任何地方所规定的进行缩写。
下面实施例中使用的试剂可以从供应商得到的如下：从Aldrich化学有限公司得到的丁基锂(BuLi)，叔丁基锂，氯三乙基硅烷(TESCl)，4-二甲基氨基吡啶(DMAP)，二环己基氨(DCHA)，二异丁基氢化铝(DIBALH)，六甲基磷酰胺(HMPA)，氢化锂铝(LAH)，吡啶二铬酸盐(PDC)，Red-Al[钠二(2-甲氧基乙氧基)氢化铝]，钠乙醇盐，和Super-Hydride(LiBEt3H)；从Fluka得到的三乙基膦酰基醋酸酯；从TCIAmerican得到的3-乙基-1-戊炔-3-醇；从Engelhard得到的钌三氯水合物；从Fluka得到的低聚甲醛。本发明提供了一种式B的化合物
其中R1为低级烷基。本发明还提供了一种式C的化合物
其中R1为低级烷基，R2为甲硅烷基保护基团。本发明进一步提供了一种式D的化合物
其中R2为甲硅烷基保护基团。本发明进一步提供了一种式E的化合物
其中R1为对甲苯磺酰基，苯磺酰基，甲基磺酰基；R2为甲硅烷基保护基团。
本发明还提供了上面提出的每一个化合物的制备方法。
实施例1：[1aS-(1aα，3aβ，6aα，6bα)]-[八氢-3a-甲基-2H-茚并[4，5-b]环氧乙烯-4-叉基]乙酸乙酯(E∶Z异构体的混合物)2的制备。
配有机械搅拌、温度计、充氮器的250mL、三颈、圆底烧瓶中装有87.4g(390mmol)的三乙基膦酰基醋酸酯。升温至40℃后，分5部分加入26.3g(387mmol)的固体钠乙醇盐。在加入过程中，由于放热使反应混合物的温度升至70℃。在46-49℃(水浴温度49℃)下搅拌1小时后，几乎所有的乙醇钠已经溶解。向得到的棕色溶液中在50℃下加入13.0g(78.2mmol)的1。温和的放热使反应混合物的温度升至55℃。得到的暗棕色溶液中在46-49℃下搅拌2小时。薄层色谱(TLC)分析表明已完全反应。冷却至室温后，反应混合物通过加入300mL冰水骤冷，得到的混合物用150mL、再用100mL 8∶1的己烷∶乙酸乙酯提取。合并有机相在减压下浓缩至干燥状态，用200mL己烷溶解残渣。得到的溶液通过TLC硅胶垫过滤(直径10cm，高度3cm)，垫用100mL己烷和250mL8∶1的己烷∶乙酸乙酯洗涤。合并滤液和洗涤液在减压下浓缩至干燥状态，得到15.4g粗品2。残渣溶解于50mL戊烷中，溶液在冰箱中冷却30分钟。得到的沉淀通过过滤过滤收集，用冷戊烷洗涤，得到7.6g反式异构体2。合并母液和洗涤液在减压下浓缩至干燥状态，残渣溶解于20mL戊烷中，在冰箱中放置2小时。得到2.7g反式异构体2的第二部分。合并母液和洗涤液硅胶色谱得到3.7g顺反混合物2。合并三部分总共得到14.0g顺反混合物2。实施例2：环氧酯4的制备。
配有磁力搅拌、温度计、充氮器的250mL、三颈、圆底烧瓶中装有10.2mL(51.4mmol)的二环己基氨和46mL的四氢呋喃(THF)。用干冰丙酮浴冷却至-40℃后，加入34.6mL(46.3mmol)的1.35M丁基锂己烷溶液，混合物升温至0℃。
配有机械搅拌、温度计、充氮器和滴液漏斗的分离的500mL、三颈、圆底烧瓶中装有9.45g(40.0mmol)的2，46mL和128mL的THF。溶液冷却至-65℃后，缓慢加入上面制备的锂二环己氨溶液，并维持反应混合物温度在-60至-65℃之间。反应混合物在-70℃下搅拌1小时，然后加入14.5g(52.3mmol)的3。反应混合物在45分钟之内缓慢升温至-30℃。TLC分析表明已完全反应。反应混合物通过加入20mL水骤冷，浓缩至体积大约100mL，用150mL 8∶1的己烷∶乙酸乙酯稀释，然后用2×150mL＝300mL水洗涤。合并水洗涤液，用100mL8∶1的己烷∶乙酸乙酯后提取两次，合并有机相，用50mL水洗涤，硫酸钠干燥，在减压下浓缩至干燥状态。得到的残渣用100mL己烷溶解，硅胶色谱纯化，用50∶1-20∶1的己烷∶乙酸乙酯洗脱。合并适当馏分，浓缩得到13.9g无色油状的4。实施例3：[3aS-[3(1S*，2E)，3aα，7α，7aβ]]-β-[4-乙基-4-(三乙基甲硅烷氧基)-2-己烯基]-β-[7-羟基-3a，4，5，6，7，7a-六氢-3a-甲基-1H-茚-3-基]乙醇5的制备。
配有机械搅拌、温度计、加液漏斗和充氮器的500mL、三颈、圆底烧瓶中装有60mL(60mmol)的1M氢化锂铝THF溶液。然后加入16.5g(34.7mmol)的4的120mL THF溶液。放热使反应混合物的温度升至20℃-65℃。在周围温度下搅拌1小时后，反应混合物通过小心地加入20mL乙酸乙酯骤冷，然后加入20mL水。搅拌0.5小时后，加入20g硫酸钠，搅拌混悬液15分钟。通过硅藻土垫过滤除去固体，垫和收集的固体用100mL乙酸乙酯洗涤。合并滤液和洗涤液在减压下浓缩至干燥状态，得到16.6g无色油状粗品5。该物质不经过进一步纯化可以直接用于下一步。实施例4：[3aS-[3(1S*，2E)，3aα，7α，7aβ]]-β-[4-乙基-4-(三乙基甲硅烷氧基)-2-己烯基]-β-[7-羟基-3a，4，5，6，7，7a-六氢-3a-甲基-1H-茚-3-基]乙醇4-甲基苯磺酸酯6的制备。
配有磁力搅拌和充氮器的500mL圆底烧瓶中装有16.6g粗品5和100mL吡啶。得到的溶液加入7.9g(41.6mmol)的对甲苯磺酰氯，混合物在室温下搅拌16小时。然后加入170mL水，混合物用200mL 4∶1的己烷∶乙酸乙酯提取。有机相用100mL水洗涤两次。硫酸钠干燥，减压下浓缩，然后在高真空下干燥得到20.6g浅黄色粘浆状粗品6。该物质不经过进一步纯化可以直接用于下一步。实施例5：[3aS-[3(1S*，2E)，3aα，7α，7aβ]]-3-(5-乙基-5-(三乙基甲硅烷氧基)-1-甲基-3-庚烯基)-3a，4，5，6，7，7a-六氢-3a-甲基-1H-茚-7-醇7的制备。
配有磁力搅拌、冷凝器和充氮器的500mL圆底烧瓶中装有20.6g的粗品6和70mL THF。向得到的溶液中加入100mL(139mmol)的1MSuper-Hydride的THF溶液。TLC分析表明已完全反应。冷却至室温后，反应混合物通过小心加入20mL甲醇骤冷，然后加入200mL水。得到的混合物用100mL己烷提取两次。合并有机相，用100mL碳酸氢钾饱和水溶液洗涤，在减压下浓缩至干燥状态。残渣溶于80mL己烷中，硅胶色谱纯化，用20∶1己烷∶乙酸乙酯洗脱。合并适当馏分，在减压下浓缩至干燥状态，得到11.7g无色油状粗品7。实施例6：[3aR-[1(1S*，3E)，3aα，7aβ]]-1-[5-乙基-1-甲基-5-[(三乙基甲硅烷基)氧基]-3-庚烯基)-3，3a，5，6，7，7a-六氢-7a-甲基-4H-茚-4-酮8的制备。
配有磁力搅拌和充氮器的100mL圆底烧瓶中装有3.64g(8.66mmol)的7，40mL二氯甲烷和9.04g(24.0mmol)的吡啶盐重铬酸盐(PDC)。反应混合物在室温下搅拌16小时。TLC分析表明已完全反应。反应混合物用100mL己烷稀释，通过TLC硅胶过滤。然后将硅胶塞用150mL20∶1己烷∶乙酸乙酯洗涤。合并滤液和洗涤液，在减压下浓缩至干燥状态，得到3.1g(85.6％)无色油状粗品8。下列过程阐明侧链片断3的合成。实施例7：3-乙基-1-戊炔-3-醇TES酯的制备
配有磁力搅拌和充氮器的2升圆底烧瓶中装有67.3g(300mmol)的3-乙基-1-戊炔-3-醇，88.2g(720mmol)的二甲基氨基吡啶(DMAP)和300mL的DMF。用冰浴冷却至0-5℃后，加入106mL(640mmol)的氯三乙基硅烷(TESCl)。除去冰浴，混合物在室温下搅拌16小时。TLC表明已完全反应。然后加入250g冰，混合物用500mL己烷提取。有机相用200mL水洗涤两次，100mL饱和氯化钠水溶液洗涤两次，硫酸钠干燥，在减压和周围温度下浓缩，得到149g浅黄色粘状液体3-乙基-1-戊炔-3-醇TES酯粗品。该物质不经过进一步纯化可以直接用于下一步。实施例8：4-乙基-2-己炔-1，4-二醇TES酯的制备
配有磁力搅拌和充氮器的2升圆底烧瓶中装有149g(300mmol)的4-乙基-2-己炔-1，4-二醇TES酯粗品和500mL THF溶液。用干冰-丙酮浴冷却至-70℃后，加入360mL(720mmol)2.0M的丁基锂己烷溶液，混合物在-70℃下搅拌30分钟。升温至周围温度后，烧瓶装上回流浓缩器，加入5.0g(167mmol，对于甲醛)低聚甲醛。几分钟后，放热反应开始。当最初的放热反应减退，总共45.0g(1.45mol，对于甲醛)低聚甲醛，分每次5g加入，为了维持通常的回流。放热很容易被加入多聚甲醛的速率和冷却(通常不需要)控制。在固体溶解和放热减退后，得到澄清的黄色溶液，加热回流2小时，然后冷却至室温。反应混合物用冰水浴冷却，然后通过加入400mL氯化铵水溶液骤冷。水层用200mL二乙醚后-提取两次。合并有机相，用200mL饱和氯化钠溶液洗涤两次，硫酸钠干燥，在减压下浓缩至干燥状态。残渣溶于200mL 1∶9的二乙醚∶己烷中，通过200g的硅胶60(230-400目)过滤。然后将硅胶塞用2升1∶9的二乙醚∶己烷洗脱。合并洗脱液，在减压下浓缩，然后在高真空下得到168 g浅黄色粘状液体4-乙基-2-己炔-1，4-二醇TES酯粗品。该物质不经过进一步纯化可以直接用于下一步。实施例9：(E)-4-乙基-1-己烯-1，4-二醇TES酯的制备
配有机械搅拌、滴液漏斗、温度计和充氮器的3升圆底烧瓶中装有168g的4-乙基-2-己炔-1，4-二醇TES酯粗品和1L THF。用干冰-丙酮浴冷却至-70℃后，缓慢加入200mL(600mmol)商品名Red-AlR的65+wt.％甲苯溶液，在加入开始的50％试剂过程中，控制生成的剧烈气体和泡沫。然后混合物升温至0℃，冰浴下搅拌1小时。TLC表明已完全反应。混合物冷却至-70℃，通过加入240mL 30％的氢氧化铵溶液仔细骤冷，同时维持内部温度低于-50℃。混合物在减压下浓缩除去THF，得到的稀浆用400mL二乙醚稀释。通过过滤除去固体，用200mL二乙醚洗涤两次。合并滤液和洗涤液用200mL水洗涤两次，200mL饱和氯化钠溶液洗涤两次，硫酸钠干燥，在减压下浓缩，然后在高真空下得到160g浅黄色粘状液体(E)-4-乙基-1-己烯-1，4-二醇TES酯粗品。该物质不经过进一步纯化可以直接用于下一步。实施例10：烯丙基氯3的制备
配有磁力搅拌和充氮器的2升圆底烧瓶中装有147g(550mmol，理论上)的4-乙基-2-己烯-1，4-二醇TES酯粗品，75.0g(620mmol)的二甲基氨基吡啶(DMAP)和500mL亚甲基氯。混合物在0-5℃下搅拌30分钟，在室温下搅拌16小时，然后加入1升己烷。通过过滤除去得到的沉淀，用300mL己烷完全洗涤两次。合并滤液和洗涤液连续用200mL10％的硫酸铜溶液洗涤两次，200mL水洗涤两次，200mL饱和碳酸氢钠溶液洗涤两次，200mL氯化钠溶液洗涤两次，硫酸钠干燥，在减压下浓缩至干燥状态。残渣溶于250mL己烷，通过750g的硅胶60(230-400目)过滤。硅胶塞子然后用1.25升己烷洗脱。合并洗脱液，在减压下浓缩，残渣在高真空下蒸馏。开始收集到含有副产品更易蒸发的馏分，随后是无色液体的72.8g纯品3。
Claims (15)
1.具有式B的化合物
其中R1为低级烷基。
2.如权利要求1的化合物，其中R1为乙基。
3.具有式C的化合物
其中R1为低级烷基，R2为甲硅烷基保护基团。
4.如权利要求3的化合物，其中R1为甲基、乙基、丙基、丁基或叔丁基；R2为三乙基甲硅烷基(TES)。
5.具有式4的化合物
6.具有式D的化合物
其中R2为甲硅烷基保护基团。
7.如权利要求6的化合物，其中R2为三乙基甲硅烷基(TES)。
8.具有式E的化合物
其中R1为对甲苯磺酰基(Ts)，苯磺酰基，甲基磺酰基(Ms)，R2为甲硅烷基保护基团。
9.具有式6的化合物
10.制备具有式8化合物的方法
包括1)将具有式2的化合物
和具有式3的化合物
在二环己基氨(DCHA)，丁基锂(BuLi)，和六甲基磷酰胺(HMPA)存在的条件下反应，得到式4的化合物，
2)将化合物4和LiAlH4反应制备式5化合物，
3)将化合物5和TsCl、吡啶反应制备式6化合物
4)式6化合物在THF存在条件下，和LiBEt3H反应制备式7化合物，
5)式7化合物在CH2Cl2存在条件下，和PDC反应制备式8化合物。
11.制备具有式4的化合物的方法
包括将具有式2的化合物
和具有式3的化合物
在DCHA、BuLi和HMPA存在条件下反应。
12.制备具有式5化合物的方法
包括将化合物4和LiAlH3反应。
13.制备具有式6化合物的方法
包括将化合物5和TsCl、吡啶反应。
14.制备具有式7化合物的方法
包括将化合物6和LiBEt3H在THF存在条件下反应。
15.制备具有式III化合物的方法
包括将按照权利要求10制备的式8化合物
和式II化合物
通过维悌希反应结合，随后进行羟基去保护。
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| CH698144B1 (fr) * | 2003-09-24 | 2009-05-29 | Bioxell Spa | Analogue de la vitamine D3 |
| US20090137828A1 (en) * | 2005-08-18 | 2009-05-28 | Bioxell S.P.A. | Synthesis of 1A-Fluoro-25-Hydroxy-16-23E-Diene-26,27-Bishomo-20-Epi-Cholecalciferol |
| US20100009949A1 (en) * | 2006-03-24 | 2010-01-14 | Bioxell S.P.A. | Novel method |
| ES2366077B2 (es) * | 2010-03-30 | 2012-06-25 | Universidade De Vigo | Compuestos quirales, procedimientos de obtención y uso. |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG70009A1 (en) * | 1996-05-23 | 2000-01-25 | Hoffmann La Roche | Vitamin d3 analogs |
| US5872113A (en) * | 1997-05-16 | 1999-02-16 | Syntex (U.S.A.) Inc. | Fluorinated vitamin D3 analogs |
| US8830885B2 (en) * | 2008-08-21 | 2014-09-09 | Qualcomm Incorporated | Multichannel architecture for high throughput modems |
-
2000
- 2000-04-13 US US09/548,471 patent/US6255501B1/en not_active Expired - Fee Related
- 2000-04-19 ES ES00108504T patent/ES2251905T3/es not_active Expired - Lifetime
- 2000-04-19 EP EP00108504A patent/EP1048661B1/en not_active Expired - Lifetime
- 2000-04-19 DK DK00108504T patent/DK1048661T3/da active
- 2000-04-19 DE DE60024353T patent/DE60024353T2/de not_active Expired - Lifetime
- 2000-04-19 AT AT00108504T patent/ATE311375T1/de not_active IP Right Cessation
- 2000-04-23 JO JO200061A patent/JO2176B1/en active
- 2000-04-24 KR KR1020000021572A patent/KR100697491B1/ko not_active IP Right Cessation
- 2000-04-25 MX MXPA00003993 patent/MX221794B/es unknown
- 2000-04-25 CA CA002306573A patent/CA2306573C/en not_active Expired - Fee Related
- 2000-04-26 JP JP2000125034A patent/JP2000336094A/ja active Pending
- 2000-04-26 CN CN00106141A patent/CN1272494A/zh active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CA2306573A1 (en) | 2000-10-26 |
| JP2000336094A (ja) | 2000-12-05 |
| EP1048661A2 (en) | 2000-11-02 |
| EP1048661B1 (en) | 2005-11-30 |
| KR20010014811A (ko) | 2001-02-26 |
| KR100697491B1 (ko) | 2007-03-20 |
| JO2176B1 (en) | 2003-04-23 |
| DK1048661T3 (da) | 2006-03-27 |
| ATE311375T1 (de) | 2005-12-15 |
| US6255501B1 (en) | 2001-07-03 |
| DE60024353T2 (de) | 2006-08-03 |
| EP1048661A3 (en) | 2002-10-09 |
| CA2306573C (en) | 2009-09-29 |
| MXPA00003993A (es) | 2002-03-08 |
| ES2251905T3 (es) | 2006-05-16 |
| MX221794B (es) | 2004-07-27 |
| DE60024353D1 (de) | 2006-01-05 |
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