CN1050196A - 用作C17-20裂解酶抑制剂的4-取代的17β-(环丙基氨基)雄甾-5-烯-3β-醇和相关的化合物 - Google Patents
用作C17-20裂解酶抑制剂的4-取代的17β-(环丙基氨基)雄甾-5-烯-3β-醇和相关的化合物 Download PDFInfo
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- CN1050196A CN1050196A CN90107580A CN90107580A CN1050196A CN 1050196 A CN1050196 A CN 1050196A CN 90107580 A CN90107580 A CN 90107580A CN 90107580 A CN90107580 A CN 90107580A CN 1050196 A CN1050196 A CN 1050196A
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- androstane
- alkene
- compound
- hydrogen
- methyl
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Abstract
本发明涉及4-取代的17β-(环丙基氨基)雄甾
-5-烯-3β-醇及其它的相关化合物，以及应用上述
化合物治疗与雄性激素有关病症的方法。通过适宜
的甾体亚胺或烯胺的氢化物还原反应，制备这些化合
物。
Description
本发明涉及4-取代的17β-（环丙基氨基）雄甾-5-烯-3β-醇及其它的相关化合物，还涉及应用上述化合物治疗与雄性激素有关病症的方法。更具体地说，本发明涉及下述通式的一组化合物
式中R是氢或甲基;R1是氢、C1-4的烷基或环丙基;且Q是
式中Z是＝O、β-OH或β-OZ′，其中Z′是1-10个碳原子的链烷酰基或取代的C2-4链烷酰基，其中的取代基是环戊烷或苯;Y′是氢或卤素;且Y″是甲基或卤素。在上面的结构式中，Z是二价的基团，在这些定义中Z仅是单一取代基（β），第二个价键被氢占有。含1-10个碳原子的链烷酰基团实例有乙酰基、丙酰基、丁酰基和癸酰基;取代的C2-4链烷酰基团实例是环戊烷丙酰基和苯丙酰基。上述优选的卤原子是氟、氯或溴。优选的化合物Q结构为Ⅰ，更具体地说，这些化合物中Q为结构Ⅰ且Y′和Y″都是卤素。更为优选的化合物是那些Q为结构Ⅰ且Y′和Y″都是氟。
对于本发明来说，上述化合物与适于药用的酸形成酸加成盐与上述胺的效果相同。这些盐可以是无机酸的盐、有机羧酸盐和有机磺酸盐。无机酸有氢氯酸、氢溴酸、硫酸、磷酸和其它的酸;有机羧酸有乙酸、丙酸、乙醇酸、乳酸、丙酮酸、顺丁烯二酸、丁二酸、反丁烯二酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸和二羟基马来酸、苯甲酸、苯乙酸、4-氨基苯甲酸、4-羟基苯甲酸、邻氨基苯甲酸、肉桂酸、水杨酸、4-氨基水杨酸、2-苯氧基苯甲酸、2-乙酰氧基苯甲酸、苯乙醇酸和其它的酸;有机磺酸有甲磺酸和P-甲苯磺酸。
在本发明范围内，具体实例的化合物如下：
17β-（环丙基氨基）-4，4-二氟雄甾-5-烯-3β-醇。
4，4-二氟-17β-（1-甲基环丙基氨基）雄甾-5-烯-3β-醇。
3β-乙酰氧基-17β-（环丙基氨基）-4，4-二氟雄甾-5-烯。
4，4-二氟-17β-〔N-甲基（环丙基氨基）〕雄甾-5-烯-3β-醇。
17β-（环丙基氨基）-4，4-二氟雄甾-5-烯-3-酮。
17β-（环丙基氨基）-4，4-二氯雄甾-5-烯-3β-醇。
17β-（环丙基氨基）-4β-氟雄甾-5-烯-3β-醇。
17β-（环丙基氨基）-4β-甲基雄甾-5-烯-3β-醇。
17β-（环丙基氨基）-4-氟雄甾-4-烯-3-酮。
17β-（环丙基氨基）-4-甲基雄甾-4-烯-3-酮。
使用一种氢化物还原剂还原适当的甾体化合物亚胺或烯胺，可以方便地制备本发明的化合物，其采用的化合物是3-羟基或3-链烷酰基羟基-△5甾族化合物。这里的起始物是亚胺，这个反应可如下用图解反应式说明：
在这种情况，用氢化物还原剂进行还原反应，优选的是在醇溶剂中的硼氢化钠试剂。为了得到含有酯化了的3-羟基基团化合物，把上述胺与苄酯基氯反应，得到相应的N-苄酯基化合物。而后，把该化合物酰化，例如用乙酐酰化，得到相应的3-乙酰氧基甾族化合物。用溴化氢和乙酸处理或者通过催化转移氢化处理，除去N-苄酯基保护基团。另一方面，3-乙酰氧基团或一些其它的保护氧基团，如3-（2-四氢吡喃氧）基团在17-亚氨基团被引入之前能存在于甾核上。在上述所有情况里，产物是一种二级胺，通过使用甲醛和甲酸的Eschweiler-Clarke反应处理或用甲醛溶液和硼氢化钠反应处理，二级胺可以转化成相应的N-甲基化合物。在此，3-羟基以一种四氢吡喃醚酯的形式存在，这些保护基团可以通过常规的步骤除去。即酯基团可以通过碱水解除去，醚能用稀酸处理除去。
那些R1是C2-4烷基的化合物可从17-环丙基氨基甾族化合物中获得。例如，用乙酰氯反应得到相应的乙酰胺，再用氰基硼氢钠还原，得到N-乙基化合物。在上述与酰氯反应也得到3-酯的情况里，还原反应后，通过碱水解该化合物，如用碳酸钾、甲醇和四氢呋喃组合物，或用酸水解化合物，如用氢氯酸，能除去这种酯基团。在后者得到氢氯化物的盐。
通过奥本诺尔（Oppenauer）氧化作用，使用异丙醇铝可以任意地把上述所得的3-羟基-△5-化合物转化成相应的3-酮-△5-化合物。
在本方法中使用的亚胺起始物，可以通过适当的4-取代的3-氧化的雄甾-5-烯-17酮与适当的环丙基胺在甲醇中回流反应得到。当亚胺生成后在脱水剂存在下进行反应，以便从反应混合物中除去水。对于在起始物产物中使用的“3-氧化的”一词意味着起始产物在3-位能含有一个游离羟基团，或者该羟基团能以与最多6个碳原子的链烷酸形成一种酯的形态存在，或者该3-羟基团可以是一种保护的醇基团，如四氢吡喃氧基团。
在二氯甲烷中，从相应的醇，通过使用氯铬酸吡啶鎓盐氧化作用，能够得到上一段中涉及的17-酮。尤其是，使用这种方法氧化4，4-二氟-3β-（2-四氢吡喃氧）雄甾-5-烯-17β-醇，得到4，4-二氟-3β-（2-四氢吡喃氧）雄甾-5-烯-17-酮。为了得到4，4-二氟-3β-（2-四氢吡喃氧）雄甾-5-烯-17β-醇，可使4，4-二氟-17β-羟基雄甾-3-酮在三乙胺存在下与二氯甲烷中的酰氯反应，得到相应的17-乙酸酯，然后用在乙醇中的硼氢化钠还原该17-乙酸酯，得到相应的3β-羟基化合物。在二氯甲烷中使该3β-羟基化合物与二氢吡喃和氯化氢反应，得到相应的3-（2-四氢吡喃氧）化合物。在二噁烷和水的混合物中，使用氢氧化锂水解上述化合物，得到所需的4，4-二氟-3β-（2-四氢吡喃氧）雄甾-5-烯-17β-醇。采用类似的步骤，可以得到在4-位仅有一个甲基或卤素取代基的化合物。
当最初的还原反应在烯胺上进行时，可以使用硼烷或硼氢化钠这样的硼氢化物作为还原剂。通过脱氢表雄甾酮与二环丙胺这样的适当二级胺缩合制得所需要的烯胺起始物。在这种方法中，所得的最终醇产物可被适当的酸酐酰化，如被乙酸酐酰化，得到相应的3-乙酰氧基化合物，或把该醇通过奥本诺尔氧化作用，能够氧化生成相应的3-酮-△5-化合物。
本发明化合物用作C17-20甾族化合物裂解酶的抑制剂。C17-20甾族化合物裂解酶催化C21甾族化合物孕烯酮和孕酮，使它转变成C19甾族化合物脱氢表雄甾酮和雄甾烯二酮，它是雄性激素、睾酮和5α-二氢睾酮的前体。因此，使用本发明的化合物抑制C17-20裂解酶可以降低雌酮，也可以降低雄性激素的形成。因此，本发明的化合物可用于治疗与各种雄性激素有关的病症。因此，本发明也包括一种治疗与雄性激素有关病症的方法，包括对患病症的个体服用一种有效量的本发明化合物。更具体地说，本发明的化合物在治疗前列腺癌、良性前列腺增生、男性脱发和妇女男性化现象和女性多毛症上是有用的。本发明化合物在治疗与雌性激素有关的病症，如与雌性激素有关的乳房癌上也是有用的。
现已充分确定，在治疗多种前列腺癌中，降低血清睾酮水平是有用的。在临床实践中，通过睾丸切除术或者通过二乙基乙烯雌酚的处理治疗前列腺癌，但是手术常出现生理不适现象，而后者服药会带来多种副作用。因而，另一种减少睾丸激素的方法是很需要的，并且这种方法可以通过服用本发明化合物来实现。前列腺癌的程度是与雄性激素有关的，本发明的化合物能阻断雄性激素来源并且对于这种病况是一种适宜的处理方法。
使用来自人体或实验室动物的C17-20甾族化合物裂解酶的微粒体制剂确定本发明化合物作为C17-20甾族化合物裂解酶抑制剂的活性;为此目的，人体实验可以从睾丸切除术治疗中获得。使用NADPH并且在5×10-8M至3×10-6M浓度范围间的供试化合物来培养这种裂解酶。随着接触暴露在供试化合物的时间，采用酶活性下降建立的抑制的时间关系决定该酶的抑制程度。抑制的时间关系通常指该酶的不可逆的灭活作用，在保持天然酶活性的条件下，通过透析分离通过不能恢复酶活性特定地建立了不可逆性。
在治疗前述的各种与雄性激素有关的病症中，把本发明的化合物口服到要治疗的患者可以得到所要求的特定效果。服用化合物的量可以在很宽的范围内变化且可为任意的有效量。根据治疗的对象和要治疗的具体条件和疾病的程度，服用化合物有效量每公斤体重每天约为0.625至62.5mg，优选的是5mg到30mg。每单位口服剂量可含有25到500mg本发明的化合物。另外，本发明化合物也可以通过非肠道途径或通过植入管用药。
在实际使用本发明的方法中，最好把活性成分组配在组合物中，这种组合物含有药用载体，和大约5%至90%重量的环丙基氨基甾族化合物或它的一种药用盐。“药用的载体”一词意指已知的药用赋形剂，它在配制动物体内用药的药学活性化合物上有用，它基本上无毒且在使用条件下不敏感。该组合物可以用已知技术制成片剂或胶囊并且在用于制备所需的特定类型组合物时，可以含有已知的适宜的赋形剂。采用常规的实验方法，如在一般的教科书中Remingtons Pharmaceutical Sciences，Mack出版公司Easton，Pennsylvania，可以找到配制组合物适宜的药用载体。
以下的实施例是本发明的例证，但它们不是以任何方式解释为限制本发明。
实施例1
对于在175ml环丙基胺和150ml甲醇混合溶液中的21g的4，4-二氟-3β-（2-四氢吡喃氧）雄甾-5-烯-17-酮溶液加入5g的分子筛。回流反应混合物48小时，冷却到室温，通过硫酸镁过滤。用乙酸乙酯洗涤硫酸镁，在减压条件下，从合并的滤液中除去溶剂，得到17-（环丙基亚氨基）-4，4-二氟-3β-（2-四氢吡喃氧）雄甾-5-烯。
实施例2
对于在200ml干燥乙醇中的9.1g的17-（环丙基亚氨基）-4，4-二氟-3β-（2-四氢吡喃氧）雄甾-5-烯溶液加入2g的硼氢化钠。室温条件下搅拌反应混合物3小时，然后在减压下从该混合物中除去100ml溶剂。随后用稀乙酸骤冷反应混合物，用600ml水稀释，用氢氧化钠调节溶液PH到14。把水混合物用600ml一份的乙酸乙酯提取3次，用硫酸镁干燥合并的有机提取液。减压除溶剂，得到所要的白色固态的17β-（环丙基氨基）-4，4-二氟-3β-（2-四氢吡喃氧）雄甾-5-烯。在二噁烷中使用催化量的氢氯酸处理产物，除去四氢吡喃基保护基团。该物具有如下的结构式：
实施例3
根据在实施例1中描述的过程，使4，4-二氟-3β-（2-四氢吡喃氧）雄甾-5-烯-17-酮与1-甲基环丙基胺反应，生成4，4-二氟-17-（1-甲基环丙烷基亚氨）-3β-（2-四氢吡喃氧）雄甾-5-烯-3β-醇。用硼氢化钠还原该产物，根据实施例2描述的过程除去四氢吡喃基团，得到4，4-二氟-17β-（1-甲基环丙基氨基）雄甾-5-烯-3β-醇。
实施例4
把17-（环丙基亚氨基）-4，4-二氟-3-（2-四氢吡喃氧）雄甾-5-烯-3β-醇在碱存在下（吡啶）与过量的乙酸酐反应，接着除去过量的酸酐和乙酸，得到3β-乙酰氧基-17-（环丙基亚氨基）-4，4-二氟-3-（2-四氢吡喃氧）雄甾-5-烯。用硼氢化钠还原这个酯并根据实施例2描述的过程，除去四氢吡喃基团，得到3β-乙酰氧基-17β-（环丙基氨基）-4，4-二氟雄甾-5-烯。以相似的方法，使用适当的酸的氯化物，可以制得3β-（环戊烷丙酰氧基）-17β-（环丙基氨基）-4，4-二氟雄甾-5-烯和3β-（苯丙酰氧基）-17β-（环丙基氨基）-4，4-二氟雄烷-5-烯。
实施例5
对于在10ml的甲酸和5ml甲醛的混合物中，加入1.4g的17β-（环丙基氨基）-4，4-二氟雄甾-5-烯-3β-醇。加热回流混合物5小时，真空条件下使混合物体积减至7.5ml，加入10ml50%（W/W）的氢氧化钠溶液。分离出水层，用乙酸乙酯提取水层并把合并的有机溶液在硫酸镁上干燥。真空除去溶剂，把残留物用快速色谱法提纯，得到4，4-二氟-17β-〔N-甲基（环丙基氨基）〕雄甾-5-烯-3β-醇。
实施例6
在80ml甲苯中的1.5g17β-（环丙基氨基）-4，4-二氟雄甾-5-烯-3β-醇溶液，浓缩到起始体积的75%，加入20ml的环己酮。把混合物浓缩到原体积的75%，加入1.5g异丙醇铝。把反应混合物回流45分钟，冷却至室温，在混合物中加入50ml的水和5ml的浓盐酸。然后用11g氢氧化钠处理溶液，并分离两相。用50ml乙酸乙酯提取水相，合并有机提取物，并在硫酸钠上干燥。真空条件下除去溶剂，用己烷/乙酸乙酯结晶残留物，得到17β-（环丙基氨基）-4，4-二氟雄甾-5-烯-3-酮。
Claims (8)
1、一种下式的化合物
式中R是氢或甲基；R1是氢、C1-C4烷基或环丙基；且Q是
式中Z是=0、β-OH或β-OZ′，其中Z′是1-10个碳原子的链烷酰基或取代的C2-4链烷酰基，其中取代基是环戊烷或苯；Y′是氢或卤素；且Y″是甲基或卤素。
2、根据权利要求1的一种化合物，它的通式是
式中Z是＝O、β-OH或β-OZ′，其中Z′是1-10个碳原子的链烷酰基或取代的C2-4链烷酰基，其中的取代基是环戊烷或苯;R是氢或甲基;R1是氢或C1-4烷基;Y′是卤素;且Y″是甲基或卤素。
3、根据权利要求1的一种化合物，它的通式是
式中Z是＝O、β-OH或β-OZ′，其中Z′是1-10个碳原子的链烷酰基或取代的C2-4链烷酰基，其中的取代基是环戊烷或苯基;R是氢或甲基;R1是氢或C1-4烷基。
4、根据权利要求1的一种化合物是17β-（环丙基氨基）-4，4-二氟雄甾-5-烯-3β-醇。
5、根据权利要求1的一种化合物是17β-（环丙基氨基）-4，4-二氟雄甾-4-烯-3-酮。
6、一种治疗与雄性激素有关病症的方法，其中包括对患病的个体服用一种有效量的下式化合物
式中R是氢或甲基;R1是氢，C1-4烷基或环丙基，且Q是
式中Z是＝O、β-OH或β-OZ′，其中Z′是1-10个碳原子的链烷酰基或取代的C2-4链烷酰基，其中的取代基是环戊烷或苯;Y′是氢或卤素;且Y″是甲基或卤素。
7、一种根据权利要求6的治疗与雄性激素有关病症的方法，其中包括对患病的个体服用一种有效量的下式化合物
式中Z是＝O、β-OH或β-OZ′，其中Z′是1-10个碳原子的链烷酰基或取代的C2-4链烷酰基，其中的取代基是环戊烷或苯基;R是氢或甲基;R1是氢或C1-4烷基;Y′是卤素;且Y″是甲基或卤素。
8、一种根据权利要求6的治疗与雄性激素有关病症的方法，其中包括对患者服用有效量的17β-（环丙基氨基）-4，4-二氟雄甾-5-烯-3β-醇。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US394,025 | 1989-08-15 | ||
| US07/394,025 US4966898A (en) | 1989-08-15 | 1989-08-15 | 4-substituted 17β-(cyclopropylamino)androst-5-en-3β-ol and related compounds useful as C17-20 lyase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1050196A true CN1050196A (zh) | 1991-03-27 |
Family
ID=23557240
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN90107580A Pending CN1050196A (zh) | 1989-08-15 | 1990-08-15 | 用作C17-20裂解酶抑制剂的4-取代的17β-(环丙基氨基)雄甾-5-烯-3β-醇和相关的化合物 |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US4966898A (zh) |
| EP (1) | EP0413270B1 (zh) |
| JP (1) | JP2879703B2 (zh) |
| KR (1) | KR910004649A (zh) |
| CN (1) | CN1050196A (zh) |
| AT (1) | ATE137761T1 (zh) |
| AU (1) | AU628209B2 (zh) |
| CA (1) | CA2023012C (zh) |
| DD (1) | DD299650A5 (zh) |
| DE (1) | DE69026881T2 (zh) |
| ES (1) | ES2088928T3 (zh) |
| FI (1) | FI95804C (zh) |
| HU (1) | HUT55029A (zh) |
| IE (1) | IE72516B1 (zh) |
| IL (1) | IL95358A (zh) |
| NO (1) | NO903564L (zh) |
| NZ (1) | NZ234856A (zh) |
| PH (1) | PH27098A (zh) |
| PT (1) | PT94993B (zh) |
| ZA (1) | ZA906308B (zh) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4966897A (en) * | 1989-08-15 | 1990-10-30 | Merrell Dow Pharmaceuticals Inc. | 4-substituted 17β-(cyclopropyloxy)androst-5-en-3β-ol and related compounds useful as C17-20 lyase inhibitors |
| US5604213A (en) * | 1992-03-31 | 1997-02-18 | British Technology Group Limited | 17-substituted steroids useful in cancer treatment |
| JP2742331B2 (ja) * | 1992-03-31 | 1998-04-22 | ブリテイツシユ・テクノロジー・グループ・リミテツド | 癌治療に有用な１７位置換ステロイド |
| TW369521B (en) * | 1993-09-17 | 1999-09-11 | Smithkline Beecham Corp | Androstenone derivative |
| US5541322A (en) * | 1994-10-14 | 1996-07-30 | Glaxo Wellcome Inc. | Synthesis of 6-azaandrostenones |
| US6365597B1 (en) | 1996-02-14 | 2002-04-02 | Aventis Pharmaceuticals Inc. | 4-aza steroids |
| CA2407839C (en) * | 2000-06-09 | 2009-09-08 | Bayer Cropscience S.A. | Process for the preparation of substituted pyrazole pesticidal compounds |
| CN100572363C (zh) | 2000-11-17 | 2009-12-23 | 武田药品工业株式会社 | 咪唑衍生物、其制备方法及其用途 |
| US6960586B2 (en) | 2000-11-20 | 2005-11-01 | Takeda Pharmaceutical Company Limited | Imidazole derivatives, process for their preparation and their use |
| CA2431171A1 (en) | 2000-12-08 | 2002-06-13 | Takeda Chemical Industries, Ltd. | Substituted thiazole derivatives bearing 3-pyridyl groups, process for preparing the same and use thereof |
| US20080051380A1 (en) | 2006-08-25 | 2008-02-28 | Auerbach Alan H | Methods and compositions for treating cancer |
| GEP20156250B (en) | 2009-06-26 | 2015-02-25 | Novartis Ag | 1,3-disubstituted imidazolidin-2-one derivatives as inhibitors of cyp 17 |
| JP2011098893A (ja) * | 2009-11-04 | 2011-05-19 | Sumitomo Chemical Co Ltd | テストステロンの生合成を抑制するための化合物の使用およびその化合物 |
| JP5998137B2 (ja) | 2010-08-04 | 2016-09-28 | ペルフィキュア ファーマシューティカルズ，インコーポレイテッド | 前立腺癌を処置するための併用療法 |
| EP2627648A1 (en) | 2010-09-16 | 2013-08-21 | Novartis AG | 17aHYDROXYLASE/C17,20-LYASE INHIBITORS |
| ES2656218T3 (es) | 2011-04-28 | 2018-02-26 | Novartis Ag | Inhibidores de 17 alfa-hidroxilasa/C17,20-liasa |
| WO2014158875A1 (en) | 2013-03-14 | 2014-10-02 | Pellficure Pharmaceuticals Inc. | Novel therapy for prostate carcinoma |
| US10093620B2 (en) | 2014-09-12 | 2018-10-09 | Pellficure Pharmaceuticals, Inc. | Compositions and methods for treatment of prostate carcinoma |
| CA3031705A1 (en) | 2016-07-29 | 2018-02-01 | Janssen Pharmaceutica Nv | Treatment of prostate cancer with niraparib |
| EP3528799A1 (en) | 2016-10-24 | 2019-08-28 | Pellficure Pharmaceuticals, Inc. | Pharmaceutical compositions of 5-hydroxy-2-methylnaphthalene-1, 4-dione |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3107254A (en) * | 1960-10-05 | 1963-10-15 | Upjohn Co | 17beta-dialkylamino-17-cyanosteroids and their 17alpha-alkyl, alkylene and alkyne derivatives |
| US3097200A (en) * | 1962-01-03 | 1963-07-09 | Syntex Corp | 17-aminoandrostanes |
| NL302932A (zh) * | 1962-12-31 | |||
| AU606677B2 (en) * | 1987-04-22 | 1991-02-14 | Merrell Dow Pharmaceuticals Inc. | 17 beta -(cyclopropylimino) androst-5-EN-3 beta- Ol and related compounds useful as C17-20 lyase inhibitors |
| US4966897A (en) * | 1989-08-15 | 1990-10-30 | Merrell Dow Pharmaceuticals Inc. | 4-substituted 17β-(cyclopropyloxy)androst-5-en-3β-ol and related compounds useful as C17-20 lyase inhibitors |
-
1989
- 1989-08-15 US US07/394,025 patent/US4966898A/en not_active Expired - Fee Related
-
1990
- 1990-08-09 CA CA002023012A patent/CA2023012C/en not_active Expired - Fee Related
- 1990-08-09 ZA ZA906308A patent/ZA906308B/xx unknown
- 1990-08-09 JP JP2209389A patent/JP2879703B2/ja not_active Expired - Fee Related
- 1990-08-09 AU AU60877/90A patent/AU628209B2/en not_active Ceased
- 1990-08-10 EP EP90115391A patent/EP0413270B1/en not_active Expired - Lifetime
- 1990-08-10 ES ES90115391T patent/ES2088928T3/es not_active Expired - Lifetime
- 1990-08-10 DE DE69026881T patent/DE69026881T2/de not_active Expired - Fee Related
- 1990-08-10 NZ NZ234856A patent/NZ234856A/en unknown
- 1990-08-10 AT AT90115391T patent/ATE137761T1/de not_active IP Right Cessation
- 1990-08-13 IL IL9535890A patent/IL95358A/en not_active IP Right Cessation
- 1990-08-14 NO NO90903564A patent/NO903564L/no unknown
- 1990-08-14 IE IE294290A patent/IE72516B1/en not_active IP Right Cessation
- 1990-08-14 KR KR1019900012533A patent/KR910004649A/ko not_active Application Discontinuation
- 1990-08-14 HU HU905004A patent/HUT55029A/hu unknown
- 1990-08-14 PT PT94993A patent/PT94993B/pt not_active IP Right Cessation
- 1990-08-15 PH PH41034A patent/PH27098A/en unknown
- 1990-08-15 FI FI904035A patent/FI95804C/fi not_active IP Right Cessation
- 1990-08-15 CN CN90107580A patent/CN1050196A/zh active Pending
- 1990-08-15 DD DD90343476A patent/DD299650A5/de unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE69026881T2 (de) | 1996-09-12 |
| NO903564D0 (no) | 1990-08-14 |
| NZ234856A (en) | 1992-08-26 |
| EP0413270A3 (en) | 1992-05-20 |
| US4966898A (en) | 1990-10-30 |
| JPH0383998A (ja) | 1991-04-09 |
| HUT55029A (en) | 1991-04-29 |
| DD299650A5 (de) | 1992-04-30 |
| IL95358A (en) | 1995-03-30 |
| FI95804B (fi) | 1995-12-15 |
| DE69026881D1 (de) | 1996-06-13 |
| CA2023012C (en) | 2001-07-03 |
| EP0413270A2 (en) | 1991-02-20 |
| KR910004649A (ko) | 1991-03-29 |
| IE72516B1 (en) | 1997-04-23 |
| FI904035A0 (fi) | 1990-08-15 |
| PH27098A (en) | 1993-02-26 |
| ZA906308B (en) | 1991-06-26 |
| IL95358A0 (en) | 1991-06-30 |
| FI95804C (fi) | 1996-03-25 |
| ES2088928T3 (es) | 1996-10-01 |
| PT94993B (pt) | 1997-07-31 |
| PT94993A (pt) | 1991-04-18 |
| EP0413270B1 (en) | 1996-05-08 |
| IE902942A1 (en) | 1991-02-27 |
| CA2023012A1 (en) | 1991-02-16 |
| JP2879703B2 (ja) | 1999-04-05 |
| ATE137761T1 (de) | 1996-05-15 |
| NO903564L (no) | 1991-02-18 |
| HU905004D0 (en) | 1991-01-28 |
| AU628209B2 (en) | 1992-09-10 |
| AU6087790A (en) | 1991-02-21 |
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