CN87104026A - 2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮 - Google Patents
2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮 Download PDFInfo
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- CN87104026A CN87104026A CN87104026.3A CN87104026A CN87104026A CN 87104026 A CN87104026 A CN 87104026A CN 87104026 A CN87104026 A CN 87104026A CN 87104026 A CN87104026 A CN 87104026A
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- pyridazine
- triazole
- isophthalic acid
- methyl isophthalic
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- OXKFUMWNEJSNTJ-UHFFFAOYSA-N 1-(8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2,3-dihydropyridin-4-one Chemical compound N=1N2C=NN=C2C(C)=CC=1N1CCC(=O)C=C1 OXKFUMWNEJSNTJ-UHFFFAOYSA-N 0.000 title abstract 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
Abstract
本发明制备了2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮的纯化物并发现其可用于缓解哺乳动物的支气管痉挛,同时还介绍了用苯硒基中间体合成该物质的方法。
Description
在美国专利3,915,968和4,136,182中介绍了8-甲基-6-(1-哌啶基)-1,2,4-三唑[4,3-b]哒嗪和其减轻支气管痉挛作用的应用。实际上,已对该化合物做了临床调查并对它的尿代谢物做了检测。质谱技术被用于研究这些代谢物的结构并且这方面的工作在Bucknell系列讲座(1982,12,1)里,在第三十一次质谱及其有关课题年会上(Boston,1983),在第三十三次质谱及其有关课题年会上(San Diego,1985),以及菲尼根公司MAT系列讨论会上(Cincinnati,1985)都有描述。在这些介绍中讨论了许多可能的代谢物。2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮是这些提出可能的代谢物之一,但该物质仅以小量存在。另外,应注意到分析用的尿样品是代谢物的混合物而不是彼此分开的纯代谢物。因此,虽然2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮被认为是代谢物,但它没被分离成提纯的形式。另外,确定通过独立化学合成来确定的该代谢物结构是不可能的,尤其是因为二氢吡啶酮结构,该化合物不能通过以前专利中描述的合成步骤或其它显而易见的替代步骤获得
本发明涉及2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮,尤其是它的纯品。和制备该化合物的方法。本发明还涉及到将该化合物用作支气管扩张剂。本发明进一步涉及到含该化合物的支气管扩张剂组合物。
现在发现可以通过下面一系列反应制备上述吡啶酮。
具体过程是:6-氯-8-甲基-1,2,4-三唑[4,3-b]哒嗪和4-哌啶醇的乙二醇缩酮反应得到相应的6-取代三唑哒嗪。然后该缩酮基水解得到相应的转变为烯醇酯的酮。然后该烯醇酯与三氟乙酸 苯硒(原地制备)酯反应得到相应的a-苯硒酮。该产物用间一氯过苯甲酸氧化,再用碱处理得所要产物。
另一方法是用四氢吡啶作起始物,具体路线见下面:
将起始物N-取代四氢吡啶与乙酸苯硒酯反应得到相应的4-乙氧基-3-苯硒吡啶,然后用碱水解该化合物得相应的4-哌啶醇。苯硒化合物与琥珀酰氯反应,接着用1,8-二杂双环[5,4,0]十一-7-烯除去苯硒基,在哌啶环引入2,3-双键。然后不饱和的哌啶醇用二氧化锰氧化得所要产物。
上面介绍的2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮化合物是支气管扩张剂,因此对于治疗支气管疾病象支气管哮喘是有用的。因此,本发明包括用该化合物产生支气管扩张的方法。
在本发明方法的应用中,本发明的2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮的有效支气管扩张剂量是根据需要通过将该化合物带至支气管的气管组织的有效途径对哺乳动物内服给药的。给药途径可有非肠道给药(例静脉,腹膜内,皮下或肌内注射),或是经过胃肠道的口服或直肠给药(如为了与血流接触),或采用气管内给药(如喷雾形式的溶液吸入)。
本发明化合物产生支气管扩张的有效量即抑制或减轻支气管痉挛的足够量,它依赖于各种因素,如治疗的动物的体重大小、类型和年龄、使用的具体化合物或药理可用盐、给药途径和频率、任何痉挛的严重程度和引起的因素,及给药时间。在具体条件下,给药剂量可通过常规范围估测技术来确定,如通过观察在不同剂量比率下产生的支气管扩张活性。更具体来讲,服用该化合物的剂量范围是每千克动物体重服0.1至100毫克的2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮尽管更好的范围是每千克体重服0.25到50或1到10毫克。一般希望给个体服用的剂量应为可以提供所需支气管痉挛保护作用的最小剂量,同时给药方案应简便。虽然需要快速作用时,注射用组合物或喷雾剂和气雾剂对于吸收更好,但适于口服的剂型有:片剂,丸剂,锭剂,剂,糖浆等通常更易接受,并且活性化合物组合在能在常规时间释放出来的丸剂或片剂组合物中。在个别剂型中,片剂含100mg活性物质,每天服1至6次,最好是2至4次。
在本发明方法的应用中,活性成份最好掺入含有药物载体的组合物中。2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮化合物占重量的约5%至90%。术语“药物载体”是指熟知的药物赋形剂,用于动物内服给药来形成药物的活性化合物,它在使用时无毒性和无致敏性。组合物可用已知方法制备成片剂,丸剂,锭剂,糖锭,栓剂,酏剂,气雾剂,乳剂,分散剂,湿剂和发泡粉,无菌注射用组合物和喷雾溶液,并含有用于制备具体类型组合物的已知适宜赋形剂。适宜的药物载体和组合技术见标准数科书,如Remington’s PharmaceuticalSciences Mack Publishing Company,Easton,Pennsylvania。
该化合物的支气管扩张活性证据是从雄性荷兰猪分离的气管段的体外试验获得的。具体实验过程是:将该气管切片悬浮在已调整的Burn溶液中,用95%氧气和5%二氧化碳通气,在8g的张力状态放置。组织用其中一种收缩剂[选自:组胺(1×10-5M),5-羟色胺(2×10-6M)。或氯化钾(20mM)]预先收缩,所用浓度为最大反应的70-80%的浓度,并预先测定浓度一收缩曲线。然后用累加方式将实验化合物加到水浴直到得到最大舒张反应。实验化合物每个浓度的舒张作用占用3.2×10-7异丙肾上腺素获得效应的百分比表示,并且这些百分比用来计算实验化合物的ED50。所有数据点至少包括了五个不同组织。两个具有已知支气管扩张活性的化合物(氨茶碱和8-甲基-6-(1-哌啶基)-1,2,4-三唑[4,3-b]哒嗪)同时做实验用作对照。实验发现,本发明化合物翻转由收缩剂产生的收缩,与哌啶化合物具有相似的药物疗效。
另外,为了评价支气管扩张活性,化合物在猴子上实验。在这一方法中,首先将恒河猴麻醉,然后人工换气,做肺力学记录。肺阻力通过静脉输注组胺而增加,并且2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮是以半对数增加剂量的药团静脉给药的。随后产生的肺阻力的最大翻转用来绘制对数剂量一反应曲线。从曲线上,可测出本发明的二氢吡啶酮的ED50大约是0.18mg/kg,ED是指翻转50%人为增加的肺阻力的剂量。
下面实施例是对本发明的描述,但不意味着限制本发明。
实施例1
将42.1g 6-氯-8-甲基-1,2,4-三唑[4,3-b]哒嗪,53.7g 4,4-亚乙二氧基哌啶,50.5g三乙胺和700ml纯乙醇的混合物在氮气中回流24小时。减压除去溶剂,得到的半固体残渣溶在800ml二氯甲烷中,然后用饱和碳酸氢钠洗涤两次。然后有机相用无水硫酸钠干燥,蒸除溶剂得橙色油。将该油溶于大约1200ml乙酸乙酯中,然后浓缩直到析出结晶。然后将混合物冷却到5℃,过滤收集结晶,用新鲜乙酸乙酯洗涤,然后干燥得6-(4,4-亚乙二氧基-1-哌啶基)-8-甲基-1,2,4-三唑[4,3-b]哒嗪,熔点约156-157℃。
实施例2
将含62.5g 6-(4,4-亚乙二氧基-1-哌啶基)-8-甲基-1,2,4-三唑[4,3-b]哒嗪的350ml乙酸溶液回流7小时。然后减压蒸除乙醇,残渣溶于1100ml沸腾乙醇中。乙醇溶液浓缩至600ml,然后用冰浴冷却。过滤分离形成的结晶,用新鲜乙醇洗涤,然后用乙醚洗涤,干燥得呈奶油针状结晶的1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)哌啶酮,熔点196.5-199℃。
实施例3
将含23.1g1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4-哌啶酮的250ml乙酸酐悬浮液在室温搅拌,然后加入22.8g 4-甲苯磺酸。一含得到清澈浅黄色溶液,该溶液在35℃左右加热,10分钟后,当沉淀开始形成时,混合物在油浴140℃加热2小时。加热再继续两小时,此时间内将氮气流通过混合物。这样导致减少一些体积,但大量乙酸酐是通过毛细管(bulb-to-bulb)真空蒸馏(60℃,约0.1mmHg)除去。这样得到的棕色粘稠物溶于二氯甲烷,然后用饱和碳酸氢钠洗一次,接着用无水硫酸钠干燥,蒸除溶剂得棕色油。该油在硅胶柱上层析,硅胶是液相层析用的Water’s arsociater prep.500;洗脱液是95%二氯甲烷/5%乙醇,该乙醇含有10%浓缩氢氧化铵。这样得到呈棕黄色固体的干净产物6-(4-乙酰氧基-1,2,3,6-四氢-1-哌啶基)-8-甲基-1,2,4-三唑[4,3-b]哒嗪。
实施例4
将含18.8g银白色三氟酸乙酯的200ml二氯甲烷悬浮液在氮气下搅拌并短时间回流加热以便尽可能多地溶解固体。可是大部分固体仍不能溶解。冷却该悬浮液,然后往该悬浮液中加入含14.9g苯硒氯的100ml二氯甲烷溶液。该混合物在室温剧烈搅拌90分钟。然后往混合物中分批加入含16.4g 6-(4-乙酰氧基-1,2,3,6-四氢-1-哌啶基)-8-甲基-1,2,4-三唑[4,3-b]哒嗪的100ml二氯甲烷溶液。该混合物在室温搅拌,不久颜色减褪得浅黄色悬浮液。该混合物在硅胶层析前(其中硅胶用Water’sprep.500)首先用粗滤纸过滤,然后用硅胶栓(aplug of silicagel)过滤;洗脱液是97.5%二氯甲烷/2.5%乙醇,其中乙醇含10%浓缩氢氧化铵。由此得到1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-3-(苯硒基)-4-哌啶酮。
实施例5
将含由前面实例中制备的8.8g吡啶酮400ml二氯甲烷溶液和9.4g无水碳酸钾粉末混合得悬浮液。该悬浮液在室温搅拌下滴加含5.9g3-氯过苯甲酸的200ml二氯甲烷溶液,费时2.5小时。滴加完毕后,薄层层析表明反应已完成。反应液用硅藻土过滤后,溶液蒸发至干,残渣用乙醚研磨成粉。由此溶走硒副产物得到固体物质。用甲醇结晶该固体得呈黄色针状的2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮,熔点约268-270℃。该化合物结构式如下:
实施例6
将含84.3g 6-氯-8-甲基-1,2,4-三唑[4,3-b]哒嗪,62.4g1,2,5,6-四氢吡啶和101g三乙胺的一升乙醇溶液在氮气中回流21小时。用旋转蒸发除去大量溶剂。半固体残渣溶于1000ml二氯甲烷中,然后用500ml饱和碳酸氢钠溶液洗涤。然后用新鲜二氯甲烷(2×200ml)洗涤,除去水层,合并有机层,用无水硫酸钠干燥。蒸除溶剂得浅棕色油,该油慢慢凝固。该油溶于230ml热乙酸乙酯中然后冷却。待该混合物慢慢冷却到室温,然后到5℃,收集形成的奶油色结晶,结晶先用乙醚/乙酸乙酯(2/1)洗涤,然后用乙醚洗涤,最后干燥得8-甲基-6-(1,2,5,6-四氢吡啶-1-基)-1,2,4-三唑[4,3-b]哒嗪,熔点约103-106℃。
实施例7
将含3.7g 无水乙酸钾,3.0g二苯联硒化物的25ml冰乙酸混和物在室温搅拌,同时迅速加入含1.5g溴的5ml冰乙酸溶液。注意反应温度是微热的。将深红棕色化合物搅拌10分钟,然后加入4.0g 8-甲基-6-(1,2,5,6-四氢吡啶-1-基)-1,2,4-三唑[4,3-b]哒嗪,继续在室温搅拌。10分钟后,混合物的颜色明显褪色,反应由薄层层析表明已完成[硅胶柱,洗脱液是95%二氯甲烷/5%乙醇(其中乙醇含10%浓氢氧化铵)]。反应液用等体积二氯甲烷稀释并将无机盐滤出。滤液浓缩成粘油,然后该粘油在色谱柱上层析提纯,色谱柱采用Waters Prep.500系统,柱体为硅胶。洗脱剂是上面用于薄层层析的溶剂系统。纯净馏分生成呈粘油状的4-乙酰氧基-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-3-(苯硒基)哌啶。
实施例8
将含3.6g 4-乙酰氧基-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-3-(苯硒基)哌啶的25ml乙醇溶液在室温搅拌,同时加入10ml 1N氢氧还能。在室温搅拌30分钟后,反应液分为水/二氯甲烷层。分离水/二氯甲烷层,水层用新鲜二氯甲烷洗涤,合并有机层,用无水硫酸钠干燥有机层,然后蒸除溶剂得无色玻璃状物。当该物质在50ml乙酸乙酯中煮沸时,形成结晶物质。将反应液冷却至室温,收集产物,干燥产物,得1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-3-(苯硒基)-4-哌啶醇,熔点约157-160℃。
实施例9
将含387mg 1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-3-(苯硒基)-4-哌啶醇的二氯甲烷溶液在室温与含147mg N-琥珀酰氯的3ml二氯甲烷混和,然后在室温搅拌。则白色沉淀形成。15分钟后,加入305mg 1,8-二氮杂双环[5,4,0]十一-7-烯,在室温继续搅拌20小时。由此生成非常暗的溶液。旋转蒸发减少反应体积,将减少后的溶液直接加到硅胶拄(20g)上进行闪式柱层析。用二氯甲烷冲洗柱上物质后,用95%二氯甲烷/5%乙醇(该乙醇含10%浓氢氧化钠)洗脱。合并得到的纯馏分,蒸除溶剂,得到的棕色粘油慢慢析出结晶,从而得到1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-1,4,5,6-四氢-4-哌啶醇,熔点约171-173℃。
实施例10
将含116mg 1-(8-甲基-1,2,4-四氢[4,3-b]哒嗪-6-基)-1,4,5,6-四氢-4-哌啶醇的15ml二氯甲烷溶液与500ml二氧化锰混合,然后加热回流。混合物回流64小时,然后用硅藻土滤除固体,然后用新鲜热二氯甲烷洗涤。蒸除滤液中溶剂得2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮,熔点约264-266℃(分解)。该化合物用甲醇结晶得黄白色针晶的纯化产物,该产物熔点270.5-271.5℃(分解)。该物质与实施例5获得的产物一样。
Claims (9)
1.2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮。
2.2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮的纯化物。
3.制备2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮纯化物的方法,其特征在于:
(a)将6-氯-8-甲基-1,2,4-三唑[4,3-b]哒嗪与4,4-亚乙二氧基哌啶反应得6-(4,4-亚乙二氧基-1-哌啶基)-8-甲基-1,2,4-三唑[4,3-b]哒嗪;
(b)用10%乙酸除去亚乙二氧基保护基得相应的酮;
(c)用乙酸酐和4-甲苯磺酸将酮转变成为相应的烯醇式乙酸酯;
(d)用三氟乙酸苯硒酯将烯醇式酯转变成相应的a-苯硒酮;
(e)将苯硒化合物与3-氯-过苯甲酸反应,接着用碱处理得到所要化合物。
4.制备2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮纯化物的方法,其特征在于:
(a)将8-甲基-6-(1,2,5,6-四氢吡啶-1-基)-1,2,4-三唑[4,3-b]哒嗪与乙酸苯硒酯反应生成4-乙酰氧基-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-3(苯硒基)哌啶;
(b)用碱水解乙酰氧酯基团得相应的4-哌啶醇;
(c)将哌啶醇首先与N-琥珀酰氯反应,然后与1,8-二氮杂环[5,4,0]十一-7-烯反应得相应的1,4,5,6-四氢-吡啶醇;
(d)用二氧化锰氧化四氢吡啶醇得所要产物。
5.2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮由权项3步骤制备。
6.2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮何时都由权项4方法制备。
7.用来减轻哺乳动物支气管痉挛的方法,其特征在于:根据需要给哺乳动物服用产生支气管扩张量的2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮。
8.根据权项7的方法,其中口服该化合物的剂量为每千克动物体重服0.25至50mg。
9.在药剂学上接受的药物载体里,用以治疗支气管痉挛的组合物中含有2,3-二氢-1-(8-甲基-1,2,4-三唑[4,3-b]哒嗪-6-基)-4(1H)-吡啶酮。
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ATE168376T1 (de) * | 1993-04-12 | 1998-08-15 | Takeda Chemical Industries Ltd | Triazolopyridazin-derivate, ihre herstellung und verwendung |
US5869486A (en) * | 1995-02-24 | 1999-02-09 | Ono Pharmaceutical Co., Ltd. | Fused pyrimidines and pyriazines as pharmaceutical compounds |
ATE226936T1 (de) * | 1995-08-08 | 2002-11-15 | Ono Pharmaceutical Co | Hydroxamsäurederivate verwendbar zur hemmung von gelatinase |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3915968A (en) * | 1973-09-21 | 1975-10-28 | Lepetit Spa | Triazolopyridazines |
US4136182A (en) * | 1976-05-26 | 1979-01-23 | The Dow Chemical Company | Triazolopyridazines used to alleviate bronchial spasms |
US4366156A (en) * | 1979-03-05 | 1982-12-28 | Mead Johnson & Company | Antiallergic methods using diazaheterocyclopurines |
US4515791A (en) * | 1980-06-03 | 1985-05-07 | American Cyanamid Company | Substituted phenyl-1,2,4-triazolo[2,3-b]pyridazin-3(2H)ones as anti-asthma agents |
US4489078A (en) * | 1980-11-24 | 1984-12-18 | Mead Johnson & Company | Diazaheterocyclopurines used as anti-broncho spasmatics and vasodilators |
US4578464A (en) * | 1983-11-22 | 1986-03-25 | Merrell Dow Pharmaceuticals Inc. | 6-Hydroxyalkylamino-8-methyl-1,2,4-triazolo-[4,3-b]pyridazine and related compounds |
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1987
- 1987-06-02 FI FI872461A patent/FI85481C/fi active IP Right Grant
- 1987-06-02 ZA ZA873934A patent/ZA873934B/xx unknown
- 1987-06-02 AU AU73728/87A patent/AU593109B2/en not_active Ceased
- 1987-06-02 NZ NZ220521A patent/NZ220521A/xx unknown
- 1987-06-02 AR AR87307742A patent/AR243525A1/es active
- 1987-06-03 DE DE8787108016T patent/DE3776199D1/de not_active Expired - Fee Related
- 1987-06-03 ES ES198787108016T patent/ES2038616T3/es not_active Expired - Lifetime
- 1987-06-03 CA CA000538692A patent/CA1335994C/en not_active Expired - Fee Related
- 1987-06-03 EP EP87108016A patent/EP0248413B1/en not_active Expired - Lifetime
- 1987-06-03 PT PT85001A patent/PT85001B/pt not_active IP Right Cessation
- 1987-06-03 AT AT87108016T patent/ATE71946T1/de not_active IP Right Cessation
- 1987-06-04 IL IL82766A patent/IL82766A/xx not_active IP Right Cessation
- 1987-06-04 HU HU872564A patent/HU196802B/hu not_active IP Right Cessation
- 1987-06-04 NO NO872358A patent/NO165544C/no not_active IP Right Cessation
- 1987-06-04 DK DK289187A patent/DK165923C/da not_active IP Right Cessation
- 1987-06-04 JP JP62139096A patent/JP2527967B2/ja not_active Expired - Fee Related
- 1987-06-04 IE IE148487A patent/IE59611B1/en not_active IP Right Cessation
- 1987-06-04 CN CN87104026A patent/CN1022833C/zh not_active Expired - Fee Related
- 1987-06-04 KR KR1019870005648A patent/KR900005658B1/ko not_active IP Right Cessation
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1992
- 1992-01-27 GR GR920400087T patent/GR3003658T3/el unknown
- 1992-08-17 US US07/931,644 patent/US5374632A/en not_active Expired - Fee Related
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