CN1163566A - 喹唑酮药物及其应用 - Google Patents
喹唑酮药物及其应用 Download PDFInfo
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- CN1163566A CN1163566A CN95195353A CN95195353A CN1163566A CN 1163566 A CN1163566 A CN 1163566A CN 95195353 A CN95195353 A CN 95195353A CN 95195353 A CN95195353 A CN 95195353A CN 1163566 A CN1163566 A CN 1163566A
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- halofuginone
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Abstract
本发明提供通过抑制血管平滑肌细胞增殖来抑制再狭窄的药用组合物，它包含作为其中活性组分的式I化合物，其中：R1为下列基团：氢，卤素，硝基，苯并，低级烷基，苯基和低级烷氧基；R2为下列基团：羟基，乙酰氧基，和低级烷氧基，并且R3为下列基团：氢和低级链烯氧基-羰基；和可药用载体。
Description
本发明涉及含喹唑酮的组合物。尤其，本发明涉及抑制再狭窄的组合物，其中包含本文称作活性组分的喹唑酮衍生物。
在1967年批准的美国专利3,320,124中描述和公开了用喹唑酮衍生物治疗球虫病的方法。
在所述专利中，首先由美国Cyanamid公司描述和公开了卤夫酮，此外已知为7-溴-6-氯-3-〔3-(3-羟基-2-哌啶基)-2-氧丙基〕-4-(3H)-喹唑酮，并且该化合物是所述专利中提到的优选化合物，是所述专利中描述和公开的衍生物中成为商品化产物的化合物。
随后，美国再批准专利26,833和美国专利4,824,847；4,855,299；4,861,758和5,215,993中都提到了卤夫酮，同时，美国专利4,340,596中提到该化合物也可用于治疗泰累尔梨浆虫病。
最近，在未决的美国专利申请08/181,066中，描述和公开了抗纤维变性的组合物，它包含一定量作为其中活性组分的式I化合物：其中：
R1为下列基团：氢，卤素，硝基，苯并，低级烷基，苯基和低级烷氧基；
R2为下列基团：羟基，乙酰氧基，和低级烷氧基，并且
R3为下列基团：氢和低级链烯氧基-羰基；可有效地抑制I型胶原蛋白的合成。
进一步研究和发展后发现，上述式I化合物在抑制非纤维变性型再狭窄中是有效的。
动脉粥样硬化的发病机理涉及由巨噬细胞将平滑肌细胞浸润并包埋在粘性糖蛋白，蛋白多糖和胶原蛋白组成的细胞外基质(ECM)中引起的平滑肌细胞(SMCs)的异常迁移和增殖〔V.Fuster等人，“冠状动脉病和急性冠状动脉综合症的发病机理”New Eng.J.Med.，326卷，242-250页(1992)；R.Ross，“动脉粥样硬化的发病机理：九十年代的观点”Nature，362卷，801-809页(1993)〕。在生理状态下，大多数动脉SMCs保留在Go相并且通过内源性增殖刺激因子和增殖抑制因子之间的平衡作用来控制细胞的生长。下列内皮细胞紊乱归因于致动脉粥样硬化的危险因素(即高血压，高脂蛋白血症，糖尿病)，血小板和非血小板衍生的生长因子，细胞激动素释放出来并且刺激单核细胞和SMC迁移以及SMC增殖(V.Fuster等人，ibid.；R.Ross，ibid.)。这些生长因子包括血小板衍生的生长因子(PDGF)〔G.A.A.Ferns等人.，“PDGF抗体对血管成形术Neoinitmal平滑肌蓄积的抑制作用，”Science，253卷，1129-1132页(1991)〕，碱性成纤维细胞生长因子(bFGF)〔V.Lindner等人，“碱性成纤维细胞生长因子在血管损伤形成中的作用，”Circ.Res.，68卷，106-113页(1991)〕，和白细胞介素-1(IL-1)〔H.Loppnow和P.Libby，“增殖或白细胞介素-1激活的人血管平滑肌细胞分泌大量白细胞介素-6，”J.Clin.Invest.，85卷，731-738页(1990)〕。巨噬细胞和血小板也释放消化各种ECM中组分的酶，释放bFGF并可释放其它贮存在基膜和ECM中的生长因子(TGFB)〔I.Vlodavsky等人，“与细胞外基质结合的生长因子，酶和血浆蛋白质，”in：Molecular and Cellular Aspects of Basement Membranes，Monographs in Cell Biology，D.H.Rohrbach和R.Timpl，Eds.，AcadmicPress，New York，U.S.A.324-246页(1993)〕。可能的促SMCs生长活性也由在某些情况下可由存在于血管壁中的凝血酶产生〔R.Bar-Shavit等人，“固定在细胞外基质中的凝血酶是粗血管平滑肌细胞分裂的促细胞分裂素：非酶作用方式，”Cell Reg.，1卷，453-463页(1990)；S.M.Schwartz，“血清衍生的生长因子是凝血酶吗？”J.Clin.Invest.，91卷，4页(1993)〕。干扰这些生长因子促生长活性的分子可抑制致动脉粥样硬化过程的进程。
在经皮腔冠状动脉血管成形术(PTCA)后冠状动脉再狭窄过程中，作为对内皮损害的反应，动脉平滑肌细胞增殖是基本反应〔V.Fuster等，ibid.〕。冠状动脉分流术或成形术用于因心脏病引起狭窄的冠状动脉的再扩张。两种方法的主要问题是大约30％经过血管成形术的病人和大约10％分流术的病人很快发生动脉再栓塞。通常，通过由血管内皮细胞构成的平滑的动脉内壁来保护血管SMC。然而，分流术或血管成形术后，通常将SMC暴露出来。在修复伤口无效的情况下，细胞增殖并栓塞动脉。
本发明提供药用组合物，它包含通过抑制血管平滑肌细胞增殖来抑制再栓塞时药用有效量的上述定义的式I化合物和可药用载体。
在优选的本发明组合物中，所述化合物为卤夫酮。
本发明进一步包含上述药用组合物，其中载体为液体并且组合物为溶液。
在实施本发明中，药用组合物中所加入卤夫酮的量可以广泛变化。在测定精确量时所考虑的因素是本领域技术人员已知的。这些因素的实例包括但不限制于所治疗的受试者，特定的药用载体，所使用的给药途径和给予组合物的次数。
如上所述，以包含化合物和药用载体的组合物的形式来给予本发明组合物。本文所使用的术语“药用载体”包含任何标准药用载体，如磷酸盐缓冲的盐水溶液，水，乳浊液如油/水乳浊液或甘油三酯乳浊液和各种湿润剂。在通过静脉和腹膜内给予化合物中所使用的适宜的甘油三酯乳浊液的实例为已知在商业上称作脂肪乳剂(intralipid)的甘油三酯乳浊液。
在实施本发明中，给予药用组合物受任何已知的给药方法的影响，所述给药方法包括但不限制于静脉，腹膜，肌肉或皮下给药。
用下列实施例中的某些优选实例并参考附图来描述本发明，这样可以更完全地了解和评价本发明，但这并不表示将本发明限定在这些特定实例中。相反，如权利要求中所述，所有替换，修改和相当本发明的部分都包括在本发明范围内。因此，包括优选实例的下列实施例用于说明本发明的实施，应该知道，所描述的特例是作为实施例和仅用于说明性讨论本发明优选实例，描述的原因是为了提供被认为是最有用的和容易理解的说明本发明方法，原则和概念的方法，
在图中：
图1是显示卤夫酮对SMC增殖抑制作用的特征曲线；
图2是显示卤夫酮抗SMC增殖作用逆转的特征曲线；
图3a和3b分别是显示卤夫酮对3H-胸苷加入血管SMCs中作用的条形图和特征曲线；
图4是显示卤夫酮对血管内皮细胞增殖作用的特征曲线；
图5a和5b分别是显示卤夫酮对3H-胸苷加入血管内皮细胞中作用的条形图和特征曲线；
图6是显示卤夫酮抗3T3成纤维细胞增殖作用的条形图；
图7是显示卤夫酮对bFGF促有丝分裂活性抑制作用的条形图；
图8a和8b是在粉碎性损伤后，兔子耳中心动脉的彩色光学显微摄影，它们分别显示未处理的动脉和按照本发明处理的动脉；并且
图9是显示卤夫酮对损伤引起的动脉狭窄作用的图。
实施例1)、试验方法
细胞
如上所述从牛主动脉的血管介质中分离出SMC〔例如，见J.J.Castellot等人，“肝素抑制血管平滑肌细胞增殖能力的结构测定：证明是含3-O-硫酸根基的五糖序列，”J.Ceu Biol.，102卷；1979-1984页(1986)；和A.Schmidt等人，“在富含2-O-硫酸化糖醛酸残基的区域中，动脉的硫酸乙酰肝素残基的抗增殖活性，”J.Biol.Chem.，267卷，19242-19247页(1992)〕。
简单地说，取出腹主动脉并在解剖显微镜下将筋膜清除。将主动脉纵向切开，将一小段介质小心地从血管壁上剥离下来。将平均直径为2-3mm的2或3个该小条放到100mm含DMEM(4.5g葡萄糖/升)，10％FCS，100U/ml青霉素和100μl/ml链霉素组织培养皿中。在7-14天内，大片的多层细胞从组织培养块中迁移出来。大约一周后，将细胞传代培养到100mm组织培养盘(4-6×105细胞/盘)中。培养物(3-8代)表现出典型的血管SMC形态学特征并且将细胞与选择性识别肌动蛋白(HF-35)肌形态的单克隆抗体一起染色。该抗体不识别内皮细胞和成纤维细胞。
如上D.Gospodarowicz等人所述，从牛主动脉制备血管内皮细胞培养物〔“牛内皮细胞的克隆生长：成纤维细胞生长因子作为存活剂，”Proc.Natl.Acad.Sci.U.S.A.，73卷，4120页(1979)〕。在10％CO2湿润的37℃保温箱中，将原培养物保持在含10％小牛血清，50U/ml青霉素和50μg/ml链霉素的DMEM(1g葡萄糖/升)中。在活性细胞生长阶段，每隔一天加入部分纯化的脑产生的bFGF(100ng/ml)〔D.Gospodarowicz等人，ibid.，和I.Vlodavsky等人，“在不含成纤维细胞因子下保存的血管内皮细胞经历结构和功能的改变。这与它们体内分化性质是不相容的，”J.Cell Biol.83卷，468-486页(1979)〕。细胞增殖：混入3H-胸苷
将SMCs放在(4×104个细胞/16mm孔)含10％FCS的DMEM中。接种24小时后，将该培养基再放到含0.2％FCS的基质中，并在48小时后将细胞暴露到生长兴奋剂和3H-胸苷(1μCi/孔)中24-48小时。通过测定混入三氯乙酸不溶物的放射活性来测定DNA的合成〔M.Benezra等人，“Reversal of bFGF Autocrine CellTransformation by Aromatic Compound，”Cancer Res.，52卷，5656-5662页(1992)〕。生长速度
将SMCs(1.5×104个细胞/孔)接种在24孔的培养板中并如上所述暴露到生长兴奋剂中。接种1-6天后，用在PBS中的2.5％甲醛固定细胞。将培养板浸在0.1M硼酸盐缓冲液(PH8.5)中，用亚甲兰(1％，在0.1M硼酸盐缓冲液中，PH8.5)染色(1h，24℃)并用水洗涤4次。实际上，该过程除掉所有未结合细胞的染料。用0.5ml 0.1N HCl(1h，25℃)将与特异性细胞结合的亚甲兰溶解并通过测定在620nm下的吸收度来测定(Bar-Shavit等人，ibid.)。选择开始放置的细胞量来确定试验结束时细胞数目和吸收度之间的关系。在每个试验中，在加入试验化合物前固定3个孔来测定开始的吸收度。用该值和下列等式来计算对照和药物处理细胞的倍增时间(DT)：
DT＝In2/IN[(ODt/ODc)/h]其中：DT＝倍增时间，小时；ODt＝试验结束时试验孔的光学密度；ODC＝试验开始时试验孔的光学密度；h＝孵育时间，小时
通过用药物处理细胞的倍增时间来除以对照细胞的倍增时间来计算生长速率〔A.Horowitz等人“脂质体包裹的阿霉素的体外细胞毒性：依赖于脂质体组合物和药物释放，”1109卷，203-209页(1992)〕。细胞数目
将SMCs接种(2.5×103个细胞/孔)到24-孔板中含10％FCS的DMEM(4.5g葡萄糖/升)中并孵育6小时〔A.Schmidt等人“在富含2-O-磺化糖醛酸残基区域中，动脉的硫酸乙酰肝素的抗组织活性，”J.Biol.Chem.，267卷，19242-19247页(1992)〕。除掉培养基并将含10％FCS的试验培养基(含或不含卤夫酮)加到四倍的孔中。孵育4天后，用Counter计数器来测定细胞数目(Schmidt等人，ibid.)。通过下式计算抑制程度：
％抑制＝1-在卤夫酮中的净生长/在对照中的净生长×100
通过用最终细胞数目减去开始细胞数目来测定净生长。2)、试验结果i)、卤夫酮抗SMC增殖的作用生长速度
将稀疏接种的血管SMC暴露到不含和含浓度递增的卤夫酮的10％FCS中。将细胞用STV分离并且每天计数。如图1所示，在含75ng/ml卤夫酮下，80-90％抑制SMC增殖，在125ng/ml下几乎完全抑制。
在另一试验中，将SMCs暴露到卤夫酮中48小时，除掉药物并随后在正规的生长培养基中生长。如图2所证明的，除掉药物使生长速度加快，与未处理SMCs的生长速度类似。混入3H-胸甙
将保持在含10％FCS培养基中的分支血管下(subconfluentvascular)SMCs暴露到不含和含浓度递增的卤夫酮的3H-胸甙中。如图3a所示，在0.15μg/ml卤夫酮下完全抑制NA合成，而在0.05μg/ml浓度下获得65％抑制(图3b)。ii)、抗血管内皮细胞和3T3成纤维细胞增殖的作用血管内皮细胞
将稀疏接种的牛主动脉内皮细胞暴露到不含和含浓度递增的卤夫酮的10％FCS培养基中。将细胞用0.05％胰蛋白酶和0.02％EDTA分离并且每天计数。
主要在最初4天，在用相对高浓度(0.1-0.125μg/ml)的药物处理的细胞中(图4)观察到内皮细胞增殖的抑制作用。与SMCs的结果不同，从第5天开始(图5)，内皮细胞重新获得几乎正常的生长速度(倍增时间)，这表明，与血管SMCs相比，血管EC对卤夫酮的抑制作用不太敏感。混入胸苷的研究表明，在0.05μg/ml卤夫酮下，50％抑制DNA合成(图5)。3T3成纤维细胞
图6表明，混入3H-胸苷时，在0.025μg/ml卤夫酮下即可完全抑制保持在含10％FCS培养基中的3T3成纤维细胞的生长，这说明与SMCs相比，成纤维细胞对药物更敏感。bFGF诱导的细胞增殖作用
在低浓度碱性成纤维细胞生长因子(bFGF)存在下，可以很容易地刺激保持在含0.5％FCS培养基中的静止期，生长停止的3T3成纤维细胞的生长。暴露到卤夫酮(0.025μg/ml)中几乎完全抑制bFGF刺激的、在生长停止期3T3成纤维细胞中混入胸苷(图7)。这说明，卤夫酮可有效的拮抗bFGF的促生长活性。iii)、由物理性损伤引起的动脉狭窄
通过静脉注射氯胺酮(50mg/kg)将新西兰白兔麻醉。将每个兔耳的中心动脉施以物理性损伤30分钟〔Bahai等人，Circulation Res.，69卷，748-756页(1992)〕。然后，按照动物福利条例的规定，将兔子安置在兔笼中。在挤压后1小时和最初4天每隔24小时，通过皮下注射，将卤夫酮给予到物理性损伤区域。在第14天，将动物处死并将兔耳固定在10％缓冲的甲醛中72小时。将1mm长的挤压部位进一步整理，在乙醇和二甲苯中脱水，并包埋在石蜡中。通过Movat五铬(pentachrome)方法，将一系列(5μm)切片染色。在损伤部位和在距离损伤部位2mm处取下的相邻正常动脉部分通过计算机法测面积。选择正常部位是随机的；几乎一半接近和一半远离损伤部位。描记由内部有弹力的薄层所限定的腔和区域(“原腔”)和由外部血管中层边缘所限定的区域(总血管区域)，并计算新内皮和血管中层之间的比率。在所有情况下，选择显示新内皮增殖程度最大的信号区域测定面积。
参照图8a和8，可以看到在外部挤压损伤后14天时兔耳这些动脉的关系显微图(Movat染色的有代表性的截面)。
在图8a中，SMCs通过破裂的内部弹性薄层，从血管中层游走到新内皮中并且由于使未处理动脉的新内皮突出而使得动脉腔狭窄。如图可见明显的内皮形成并且几乎使动脉腔完全消失，
作为对比，在图8b中，可见经过挤压损伤并用卤夫酮处理的兔耳动脉。并看到卤夫酮几乎完全抑制了新内皮形成。
图9显示，在对照兔和用卤夫酮(H)或合成的模拟(mimicking)肝素化合物(M)处理的兔中进行的，新内皮和血管中层之间比率的定量分析。每个点代表一只兔子。结论
目前抑制血管SMC增殖的方法利用了肝素，苏拉明，各种促生长因子抗体，抗凝血酶剂，并且最近又利用了反意义DNA技术。肝素是有效的抗凝血剂，其抗增殖活性相对小并且根据来源和生产公司不同，该活性发生很大改变。苏拉明在有效剂量下毒性很高，而抗体价格昂贵，半衰期短并且可诱发免疫反应。关于反意义方法的信息是新的并且目前其应用受到一定限制。
本发明在其最优选实例中，利用了高效，花费不多和无毒的化合物，该化合物可抑制各种生长因子，包括bFGF的活性，并且可抑制血管SMC和成纤维细胞的autocrine生长。此外，卤夫酮是低分子量的化合物，它可以通过口服给予。F.D.A.已经提出将该化合物用于农场的动物中。这些特性使得卤夫酮最有希望成为临床用于抑制再狭窄的药物。
因此，本发明提供利用卤夫酮作为有效地抑制SMC增殖的无毒化合物，由此提供有效的方法来抑制动脉粥样硬化，冠状动脉血管成形术后再狭窄和在隐静脉移植物中新内皮增殖等病理生理改变。
很明显，对于本领域技术人员来说，本发明并非限制于上述说明性实例的叙述中并且本发明可以包括在不离开其基本特征的其它特定形式中，因此，应该知道，本发明实例和实施例在各个方面都是说明性的而并非限定性的，参见权利要求而并非上述说明书，因此，任何在权利要求含义和范围内的改变都包括在本发明范围内。
Claims (3)
1、通过抑制血管平滑肌细胞增殖来抑制再狭窄的药用组合物，它包括作为其中活性组分的式I化合物：
其中：
R1为下列基团：氢，卤素，硝基，苯并，低级烷基，苯基和低级烷氧基；
R2为下列基团：羟基，乙酰氧基，和低级烷氧基，并且
R3为下列基团：氢和低级链烯氧基-羰基；和可药用载体。
2、权利要求1组合物，其中，所述化合物为卤夫酮。
3、抑制病人再狭窄的方法，它包括给予该病人一定量的权利要求1药用组合物，通过抑制所述病人血管平滑肌细胞增殖来有效地抑制再狭窄。
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| Publication Number | Publication Date |
|---|---|
| CN1163566A true CN1163566A (zh) | 1997-10-29 |
| CN1108797C CN1108797C (zh) | 2003-05-21 |
Family
ID=11066514
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95195353A Expired - Lifetime CN1108797C (zh) | 1994-08-31 | 1995-08-29 | 喹唑酮药物及其应用 |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0787000B1 (zh) |
| JP (1) | JPH10513149A (zh) |
| CN (1) | CN1108797C (zh) |
| AT (1) | ATE197401T1 (zh) |
| AU (1) | AU692307B2 (zh) |
| DE (1) | DE69519385T2 (zh) |
| IL (1) | IL110831A (zh) |
| WO (1) | WO1996006616A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114469956A (zh) * | 2022-01-29 | 2022-05-13 | 中国科学技术大学 | 常山酮在治疗和预防动脉粥样硬化性疾病的药物中的应用 |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL114951A (en) * | 1995-08-15 | 1999-08-17 | Hadasit Med Res Service | Quinazolinone-containing pharmaceutical compositions for prevention of neovascularization |
| EP0936910B1 (en) * | 1996-08-30 | 2002-07-24 | Agricultural Research Organization, Ministry Of Agriculture, State Of Israel | Intracoronary stents containing quinazolinone derivatives |
| US6211188B1 (en) * | 1997-02-11 | 2001-04-03 | Hadasit Medical Research Services And Development Company Ltd | Treatment of skin disorders |
| US6028075A (en) | 1997-02-11 | 2000-02-22 | Pines; Mark | Quinazolinone containing pharmaceutical compositions for prevention of neovascularization and for treating malignancies |
| US6562829B1 (en) | 1997-05-23 | 2003-05-13 | Hadasit Medical Research Services & Development Co., Ltd. | Treatment of hepatic cirrhosis |
| US6159488A (en) * | 1997-08-14 | 2000-12-12 | Agricultural Research Org. Ministry Of Agriculture (Gov.) | Intracoronary stents containing quinazolinone derivatives |
| EP1109559B1 (en) * | 1998-08-13 | 2005-10-26 | Hadasit Medical Research Services & Development Co., Ltd. | Inhibition of pathogenic processes related to tissue trauma |
| EP1162974A1 (en) * | 1999-03-19 | 2001-12-19 | Parker Hughes Institute | Quinazoline formulations and therapeutic use thereof |
| US7064114B2 (en) | 1999-03-19 | 2006-06-20 | Parker Hughes Institute | Gel-microemulsion formulations |
| CA2384331C (en) * | 1999-09-09 | 2008-10-14 | Hadasit Medical Research Services And Development Company Ltd. | The use of halofuginone and related compounds for the treatment of urethral stricture by local administration |
| US6545004B1 (en) | 1999-10-27 | 2003-04-08 | Cytokinetics, Inc. | Methods and compositions utilizing quinazolinones |
| WO2003043995A1 (en) | 2001-11-20 | 2003-05-30 | Cytokinetics, Inc. | Process for the racemization of chiral quinazolinones |
| KR20100024494A (ko) | 2007-06-22 | 2010-03-05 | 아르퀼 인코포레이티드 | 퀴나졸리논 화합물 및 이의 사용 방법 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US26833A (en) * | 1860-01-17 | Improvement in plows | ||
| US3320124A (en) * | 1964-07-20 | 1967-05-16 | American Cyanamid Co | Method for treating coccidiosis with quinazolinones |
| DE2934069A1 (de) * | 1979-08-23 | 1981-03-12 | Hoechst Ag, 6000 Frankfurt | Mittel gegen theileriosen und seine verwendung. |
| DE3703789A1 (de) * | 1987-02-07 | 1988-08-18 | Hoechst Ag | Coccidiozide mittel |
| CA2113229C (en) * | 1994-01-11 | 1999-04-20 | Mark Pines | Anti-fibrotic quinazolinone-containing compositions and methods for the use thereof |
-
1994
- 1994-08-31 IL IL11083194A patent/IL110831A/en not_active IP Right Cessation
-
1995
- 1995-08-29 JP JP8508990A patent/JPH10513149A/ja active Pending
- 1995-08-29 WO PCT/US1995/011186 patent/WO1996006616A1/en active IP Right Grant
- 1995-08-29 AU AU36268/95A patent/AU692307B2/en not_active Ceased
- 1995-08-29 CN CN95195353A patent/CN1108797C/zh not_active Expired - Lifetime
- 1995-08-29 EP EP95933731A patent/EP0787000B1/en not_active Expired - Lifetime
- 1995-08-29 AT AT95933731T patent/ATE197401T1/de not_active IP Right Cessation
- 1995-08-29 DE DE69519385T patent/DE69519385T2/de not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114469956A (zh) * | 2022-01-29 | 2022-05-13 | 中国科学技术大学 | 常山酮在治疗和预防动脉粥样硬化性疾病的药物中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1996006616A1 (en) | 1996-03-07 |
| EP0787000A4 (en) | 1997-11-12 |
| CN1108797C (zh) | 2003-05-21 |
| EP0787000A1 (en) | 1997-08-06 |
| AU3626895A (en) | 1996-03-22 |
| IL110831A0 (en) | 1994-11-11 |
| EP0787000B1 (en) | 2000-11-08 |
| IL110831A (en) | 1998-12-27 |
| AU692307B2 (en) | 1998-06-04 |
| DE69519385D1 (de) | 2000-12-14 |
| JPH10513149A (ja) | 1998-12-15 |
| ATE197401T1 (de) | 2000-11-11 |
| DE69519385T2 (de) | 2001-03-15 |
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| C53 | Correction of patent of invention or patent application | ||
| CB02 | Change of applicant information |
Co-applicant after: Agricultural Research Organization of Ministry of Israel Agriculture Co-applicant after: Kiryat Hadasa Hatta Co-applicant after: Hitler medical research service and Development Co. Ltd. Co-applicant before: CM David Desson Co-applicant before: Agricultural Research Organization of Ministry of Israel Agriculture Co-applicant before: Kiryat Hadasa Hatta Co-applicant before: Hitler medical research service and Development Co. Ltd. |
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Free format text: CORRECT: CO-APPLICANT; FROM: CM DAVIDESON; AGRICULTURAL RESEARCH ORGANIZATION OF ISRAEL MINISTRY OFAGRICULTURE; ALISTAIR CHARLES DE ABEL; HITT MEDICAL RESEARCH SERVICES AND DEVELOPMENT LTD. TO: AGRICULTURAL RESEARCH ORGANIZATION OF ISRAEL MINISTRY OF AGRICULTURE; ALISTAIR CHARLES DE ABEL; HITT MEDICAL RESEARCH SERVICES AND DEVELOPMENT LTD. |
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| C14 | Grant of patent or utility model | ||
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Correction item: Patentee Correct: Agricultural Research Organization of Ministry of Israel Agriculture Kiryat Hadasah Hadasit Medical Research Services & Development Company Ltd. False: C.M.Davidson|Ministry of Agriculture Agriculture Research Organization|Kier Yate Hadasa Hachter Medical Research Services & Development Co., Ltd. Number: 21 Page: 288 Volume: 19 |
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| CI03 | Correction of invention patent |
Correction item: Patentee Correct: Agricultural Research Organization of Ministry of Israel Agriculture Kiryat Hadasah Hadasit Medical Research Services & Development Company Ltd. False: C.M.Davidson|Ministry of Agriculture Agriculture Research Organization|Kier Yate Hadasa Hachter Medical Research Services & Development Co., Ltd. Number: 21 Page: The title page Volume: 19 |
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Free format text: CORRECT: PATENTEE; FROM: C M DAIWEIDESANG AGRICULTURAL RESEARCH ORGANIZATION OF ISRAEL MINISTRY OF AGRICULTURE GEREAT·HADASSAH·HASITE MEDICAL RESEARCH SERVICES AND DEVELOPMENT CO., LTD. TO: AGRICULTURAL RESEARCH ORGANIZATION OF ISRAEL MINISTRY OF AGRICULTURE GEREAT·HADASSAH·HASITE MEDICAL RESEARCH SERVICES AND DEVELOPMENT CO., LTD. |
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Free format text: CORRECT: PATENTEE; FROM: C M DAIWEIDESANG AGRICULTURAL RESEARCH ORGANIZATION OF ISRAEL MINISTRY OF AGRICULTURE GEREAT·HADASSAH·HASITE MEDICAL RESEARCH SERVICES AND DEVELOPMENT CO., LTD. TO: AGRICULTURAL RESEARCH ORGANIZATION OF ISRAEL MINISTRY OF AGRICULTURE GEREAT·HADASSAH·HASITE MEDICAL RESEARCH SERVICES AND DEVELOPMENT CO., LTD. |
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| C19 | Lapse of patent right due to non-payment of the annual fee |