CN1048042A - 晶状头孢烯酸加成盐及其制备方法 - Google Patents
晶状头孢烯酸加成盐及其制备方法 Download PDFInfo
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- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
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- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
通式II的晶状头孢烯酸加成盐，对细菌感染
Description
本发明涉及经肠吸收式Ⅰ的7-〔2-（2-氨基-4-噻唑基）-2-（顺）-羟亚氨-乙酰氨基〕-3-甲氧甲基-3-头孢烯-4-羧酸α-（2，2-二甲基丙酰氧基）乙酯及其制备方法
已经研制了许多临床上适用的，有广谱抗菌作用的头孢菌素。然而，大多数只适宜非肠道给药，如若全给口服，则吸收很差。而在很多情况对高活性的抗菌素希望患者口服用药，因为这种治疗方式简便，治疗费用也相当低。
在某些情况下，头孢菌素4-羧基酯化后就可能提高胃肠道的吸收度。因为头孢菌素酯本身通常没有抗菌活性，要选择的酯，是在其吸收后，经对机体特异的酶-酯酶迅速完全的再裂开成有游离羧基的头孢菌素。
德国专利说明书P3，804，841和P3，809，561中叙述了许多7-〔2-（2-氨基-4-噻唑基）-2-（顺）-羟亚氨基-乙酰氨基-3-甲氧甲基-3-头孢烯-4-羧酸酯对不同的动物都容易在肠道被吸收。发现在德国专利说明书P3，804，841叙述的酯中，式Ⅰ中的酯是特别有趣的。
这个酯在1-新戊酰基的1-位有一个不对称碳原子，因此就存在R-和S-型异构体或其混合物。在德国专利说明书P3，804，841中叙述的式Ⅰ中酯的制备过程，产生的物质为无定形。两个非对映体吸收度相同。
用常规的有机溶剂试图使Ⅰ结晶化，未获成功。此外，在结晶一步两个非对映体因有不同溶解度使得比例改变了。
基于氨基的弱碱性，式Ⅰ的酯制备盐时，只有与强酸反应才能成功。在用上述化合物以专利或其它文献叙述的制备各种头孢菌素酯的结晶盐的方法都未得到所希望的结果。例如制备盐酸盐，硫酸盐或磷酸盐只得到无定形产物。
而根据本发明的方法却意外地得到结晶产物。
然而，制备含有两个异构体大约1∶1的结晶性酯或结晶性盐是很值得努力尝试的。这种操作导致纯度的改善，也改善了不稳定β-内酰胺的稳定度。纯度可由物理化学参数像高熔点、溶解度、稳定性和△3/△2双键异构体的比例等来测定。用这种方法获得规定组成或能重现组成的产物也是可能的，在这种情况下，用于制备盐的溶剂或其他物质掺入或吸收进晶格中。
本发明涉及通式Ⅱ的结晶性的，化学计量的肠可吸收的盐。
其中R代表氢或C1-C4烷基以及顺式位的＝N-OH基。
如果R为C1-C4-烷基，那么它就可代表，例如，甲基，乙基，丙基，异丙基，丁基，异丁基，或叔丁基。R为氢、甲基或乙基较好，若为甲基或乙基更好。R可以在邻位、间位或对位，而在对位最好。酸加成盐最好是苯磺酸盐，甲苯磺酸盐或对乙基苯磺酸盐。
本发明进而涉及通式Ⅱ化合物的制备方法，其中包括式Ⅰ的无定形物与通式Ⅲ的酸在有机溶剂中反应，需要的话，可向该溶液加其它有机溶剂或水以引发和/或完成该结晶作用。
其中R如上述一样含义。
酸部分可稍微过量一些，相对于式Ⅰ中酯来说最好是1～1.5个当量。
溶剂的选择是重要的，为了获得两个异构体大约1∶1的比例，必须选择溶剂系统使实际上定量回收盐。
对反应适宜的溶剂是与水不混溶的有机溶剂，例如乙酸乙酯，乙酸正丁酯或乙酸叔丁酯，但最好是以后可能需要加水时与三相混溶的溶剂。
适宜的与水混溶的有机溶剂是C1-C4醇，如甲醇，乙醇，异丙醇，丙醇，丁醇，2-丁醇，异丁醇，叔丁醇，丙酮，四氢呋喃或这些溶剂的混合物。乙醇，丙醇和丙酮特别适宜。为了完成该结晶化作用，把与水不混溶的溶剂如正己烷，甲苯，乙醚或二异丙醚加到结晶在水和与水混溶的溶剂混合物的悬浮液中。若反应是在与水不混溶的有机溶剂中进行，自然也可加这种溶剂。
在按照本发明加水时，所加水的总量为有机溶液体积的约20倍为宜，但也可加更多的水量。
有机溶液与水或其它有机溶剂合并时要慢慢进行，例如可以滴，其滴加速度以使得到好结晶产物为准。
结晶化在室温下进行为宜。在象0～40℃的温度也可得到好的结果。随后搅拌时间大约3小时或者更长，以完成结晶化作用。
这样得到式Ⅱ的结晶盐用常规实验室方法分离出来，例如低真空过滤，並除去附着的溶剂。
如果于高真空下（＜1mmHg）过滤得到结晶，则，有机液剂和水都被除掉，特别是有干燥剂存在下，例如象浓硫酸，磷酸酐和苛性碱或苛性苏打以及硅胶。
用式Ⅱ的结晶盐进行的稳定性研究表明，其稳定性与碱Ⅰ相比大大改善了。
对各种动物的试验证明，这种盐胃肠吸收良好。
本发明通式Ⅱ的化合物以常规的药物剂型口服给药，如胶囊，片剂，粉剂，糖浆或悬浮液。所用剂量取决于病人的年龄，症状和体重以及疗程。通常每天大约0.2g至5g之间，以每天0.5g-3g间为宜。本化合物最好是分剂量给药，例如每天2-4次，每次剂量含活性物质在50和500mg之间。
口服制剂可含有常规的赋形剂和/或稀释剂。例如适宜胶囊或片剂的有粘合剂像明胶，山梨醇、聚乙烯吡咯烷酮或羧甲基纤维素，稀释剂如乳糖，蔗糖，淀粉，磷酸钙或聚乙二醇，润滑剂如滑石粉或硬脂酸镁，适宜液体制剂的像水或油悬浮剂，糖浆或类似已知剂型。
以下按本发明制备的式Ⅰ的化合物7-〔2-（2-氨基-4-噻唑基）-2-（顺）-羟基亚氨基-乙酰氨基〕-3-甲氧甲基-3-头孢烯-4-羧酸α-（2，2二甲基丙酰氧基）乙酯的盐的操作实例做为本专利的进一步解释，但不限于此。
操作实例
操作实例1
7-〔2-（2-氨基-4-噻唑基）-2-（顺）-羟亚氨基-乙酰氨基〕-3-甲氧甲基-3-头孢烯-4-羧酸α-（2，2-二甲基丙酰氧基）乙酯苯磺酸盐
将0.44g（1份当量）苯磺酸在9ml乙酸乙酯中的溶液滴加到1.5g（2.77mmol）7-〔2-（2氨基-4-噻唑-基）-2-（顺）-羟亚氨基-乙酰氨基〕-3-甲氧甲基-3-头孢烯-4-羧酸α-（2，2-二甲基丙酰氧基）乙酯在21ml乙酸乙酯的溶液中。开始结晶后，混合物再搅拌30分钟，吸滤出结晶，用少量乙醚洗涤。经CaCl2/石蜡真空干燥后，得1.4g所要的标题化合物，在偏振光显微镜下鉴定为结晶物质，根据HPLC测定两个非对映体的组成大约为1∶1的混合物。M.P.198℃（分解）
1H NMR（270MHz，DMSO-d6）：δ（ppm）＝1.15（9H，2 x s，叔丁基），1.48（1H，dd，CH（CH3）），3.2（3H，2 x s，OCH3），3.47-3.7（2H，2 x dd，S-CH2），4.13（2H，bs，3′-CH2），5.21（1H，2 x d，J＝6Hz，6-H），5.83（1H，2 x dd，J＝6HZ，7-H），6.8（1H，2 x s，噻唑），6.9（1H，dq，CH-CH3），7.3（3H，m，芳香.H），7.6（2H，m，arom.H），9.65（1H，d，NH），12.05（1H，bs，肟）.
元素分析
C27H32N5O11S3计算值. C46.3 H4.8 N10.0 O25.1 S13.8
（699.78）试验值 C46.3 H4.8 N10.1 O25.3 S13.5
操作实例2
7-〔2-（2-氨基-4-噻唑基）-2-（顺）-羟亚氨基-乙酰氨基〕-3-甲氧甲基-3-头孢烯-4-羟酸α-（2，2-二甲基丙酰氧基）乙酯甲苯磺酸盐
将570mg（3mmol）对-甲苯磺酸在1ml丙酮中的溶液加到1.08g（2mmol）的7-〔2-（2-氨基4-噻唑-基）-2-（顺）-羟亚氨基-乙酰氨基〕-3-甲氧甲基-3-头孢烯-4-羟酸α-（2，2-二甲基丙酰氧基）乙酯在3ml丙酮的溶液中。然后在搅拌下，慢慢滴加28ml水，迅速形成结晶悬浮液。吸滤出结晶性沉淀，用3ml水洗涤8次，经CaCl2/石蜡真空干燥。得1.08g所要的标题化合物，按HPLC分析，两个非对映体的组成大约为1∶1，在偏振光显微镜下鉴定为结晶。m.p.190℃（分解）
1H NMR（270MHz，DMSO-d6）：δ（ppm）＝1.15（9H，2 x s，tert.-butyl），1.47（1H，dd，CH-CH3），2.3（3H，s，CH3on the 芳环），3.2（3H，2 x s，OCH3），3.47-3.7（2H，2 x dd，S-CH2），4.13（2H，bs，CH2-OCH3），5.23（1H，2 x d，J＝6Hz，6-H），5.83（1H，2 x dd，J＝6Hz，7-H），6.83（1H，2 x s，噻唑），6.9（1H，dq，CH-CH3），7.1 and 7.5（4H，d，芳环.H），9.68（1H，d，NH），12.08（1H，bs，肟）.
元素分析
C28H36N5O11S3计算值. C47.1 H4.9 N9.8 O24.7 S13.5
（713.80）实验值 C47.4 H4.9 N10.0 O24.4 S13.1
操作实例3
7-〔2-（2-氨基-4-噻唑基）-2-（顺）-羟亚氨基-乙酰氨基〕-3-甲氧甲基-3-头孢烯-4-羧酸α-（2，2-二甲基丙酰氧基）乙酯对-乙基苯磺酸盐
将664mg对-乙基苯磺酸（3mmol）在1ml丙酮的溶液加到1.08g（2mmol）7-〔2-（2-氨基-4-噻唑基）-2-（顺）-羟亚氨基-乙酰氨基〕-3-甲氧甲基-3-头孢烯-4-羧酸α-（2，2-二甲基丙酰氧基）乙酯在3ml丙酮的溶液中，然后在搅拌下，慢慢加28ml水。加完以后，放晶种于混合物並搅拌15分钟。结晶性沉淀被吸滤出，用3ml水洗涤8次，用真空经CaCl2/石蜡干燥。得1.28g所要标题化合物，HPLC分析，两个异构体的组成大约为1∶1的混合物，在偏光显微镜下鉴定为结晶。m.p.170℃（分解）。
1H NMR（270MHz，DMSO-d6）：δ（ppm）＝1.15（9H，2 x s，tert.-butyl），1.17（3H，t，CH3CH2-），1.5（3H，dd，CH-CH3），2.6（2H，q，CH3-CH2-），3.2（3H，2 x s，OCH3），3.47-3.7（2H，2 x dd，S-CH2），4.13（2H，d，CH2OCH3），5.23（1H，2 x d，J＝6Hz，6-H），5.83（1H，2 x dd，J＝6Hz，6-H），5.83（1H，2 x dd，J＝6HZ，7-H），6.83（1H，2 x s，噻唑-H），6.9（1H，dq，CH-CH3），7.15 and 7.51（4H，d，芳香 H），9.67（1H，d，NH），12.05（1H，bs，酚-H）.
元素分析
C29H37N5O11S3理论值 C47.9 H5.1 N9.6 O24.2 S13.2
（727.86）实验值 C47.6 H5.2 N9.8 O24.0 S13.3
操作实例4
7-〔2-（2-氨基-4-噻唑基）-2-（顺）-羟亚氨基-乙酰氨基〕-3-甲氧甲基-3-头孢烯-4-羧酸α-（2，2-二甲基丙酰氧基）乙酯甲苯磺酸盐。
将2.1g（11mmol）对-甲苯磺酸在5ml乙醇中的溶液滴加到5g（9.3mmol）7-〔2-（2-氨基-4-噻唑基）-2-（顺）-羟亚氨基-乙酰氨基〕-3-甲氧甲基-3-头孢烯-4-羧酸α-（2，2-二甲基丙酰氧基）乙酯在32ml乙醇的溶液中。室温搅拌30分钟后，将280ml异丙醚加到形成的结晶糊中，混合物搅拌片刻。吸滤出形成的沉淀，用少量异丙醚洗涤，剩余物经CaCl2/石蜡真空干燥，得5.4g所要标题所列化合物的结晶，据HPLC分析两个异构体的混合物的组成大约为1∶1，其物理化学性质与操作实例2的相同。
m.p.190℃（分解）
操作实例5
7-〔2-（2-氨基 基）-2-（顺）-羟亚氨-乙酰氨基〕-3-甲氧甲基-3-头孢烯-4-羧酸α-（2，2-二甲基丙酰氧基）乙酯甲苯磺酸盐
将1.8g（15mmol对甲苯磺酸在5ml丙酮的溶液滴加到5g（9.3mmol）7-〔2-（2-氨基-4-噻唑基-2-（顺）-羟亚氨基-乙酰氨基〕-3-甲氧甲基-3-头孢烯-4-羧酸α-（2，2-二甲基丙酰氧基）乙酯在35ml丙酮的溶液中。搅拌片刻后，形成稠厚的沉淀。搅拌15分钟后，慢慢滴加总体积为185ml二异丙醚，使结晶完全，混合物搅拌短时间。吸滤出沉淀，用少量异丙醚洗涤，经CaCl2/石蜡真空干燥，得5.9g标题化合物结晶，HPLC分析，两个非对映体的混合物组成大约为1∶1，物理化学性质与操作实例2的产物相同。
m.p：190℃（分解）
操作实例6
7-〔2-（2-氨基-4-噻唑基）-2-（顺）-羟亚氨基-乙酰氨基〕-3-甲氧甲基-3-头孢烯-4-羧酸α-（2，2-二甲基丙酰氧基）乙酯甲苯磺酸盐
将2.1g（11mmol）对一甲苯磺酸在5ml丙酮的溶液滴加到7-〔2-（2-氨基-4-噻唑基）-2-（顺）-羟亚氨基-乙酰氨基〕-3-甲氧甲基-3-头孢烯-4-羧酸α-（2，2-二甲基丙酰氧基）乙酯在35ml丙酮的溶液中。搅拌片刻后，慢慢加叔丁甲醚使沉淀完全。搅拌15分钟后，吸滤出结晶产物，用少量叔丁甲醚洗涤，经CaCl2/石蜡真空干燥。得4.6g所要标题列的结晶性化合物，两个非对映体组成比例大约为1∶1，其物化性质与操作实例2中的产物相同
m.p：190℃（分解）
Claims (1)
1、通式Ⅱ的结晶状头孢烯酸加成盐制备方法(其通式Ⅱ
中R代表氢或C1-C4烷基，顺式位的=N-OH，该方法特征是，通式Ⅰ的无定形头孢烯在有机溶剂中与通
式Ⅲ(R代表氢或C1-C4-烷基)的酸反应，随
后酸加成盐直接结晶或加其他有机溶剂或水使结晶化。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3919259A DE3919259A1 (de) | 1989-06-13 | 1989-06-13 | Kristalline cephem-saeureadditionssalze und verfahren zu ihrer herstellung |
| DEP3919259.8 | 1989-06-13 |
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| CN1048042A true CN1048042A (zh) | 1990-12-26 |
| CN1043043C CN1043043C (zh) | 1999-04-21 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN90104242A Expired - Lifetime CN1043043C (zh) | 1989-06-13 | 1990-06-11 | 晶状头孢烯酸加成盐及其制备方法 |
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| US (1) | US5409918A (zh) |
| EP (1) | EP0402806B1 (zh) |
| JP (1) | JPH0730085B2 (zh) |
| KR (1) | KR0158883B1 (zh) |
| CN (1) | CN1043043C (zh) |
| AT (1) | ATE95185T1 (zh) |
| AU (1) | AU645254B2 (zh) |
| CA (1) | CA2018794C (zh) |
| DE (2) | DE3919259A1 (zh) |
| DK (1) | DK0402806T3 (zh) |
| ES (1) | ES2045653T3 (zh) |
| FI (1) | FI96424C (zh) |
| HU (1) | HU207087B (zh) |
| IE (1) | IE64076B1 (zh) |
| IL (1) | IL94701A (zh) |
| NO (1) | NO174258C (zh) |
| NZ (1) | NZ234004A (zh) |
| PT (1) | PT94347B (zh) |
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| YU48484B (sh) * | 1991-05-24 | 1998-09-18 | Hoechst Aktiengesellschaft | Kristalne kiselinske adicione soli diastereomerno čistih 1-(2,2-dimetilpropioniloksi)-etilestara 3-cefem-4-karbonske kiseline |
| US5589593A (en) * | 1991-11-11 | 1996-12-31 | Biochimica Opos Spa | Crystalline form of a cephalosporin antibiotic |
| TW212181B (zh) * | 1992-02-14 | 1993-09-01 | Hoechst Ag | |
| DE59308295D1 (de) * | 1992-05-21 | 1998-04-30 | Hoechst Ag | Verfahren zur Spaltung von Cephalosporin Prodrugestern zu 7-Amino-3-methoxymethylceph-3-em-4-carbonsäure |
| LT3871B (en) | 1993-11-30 | 1996-04-25 | Hoechst Ag | Additive crystalline salts of pure diastereomers of 1-cefem-4-carboxylic acid 1-(2,2-dimethyl-propionyloxy)ethyl esters, process for the preparation thereof, pharmaceutical compositions and process for the preparation thereof |
| AT401651B (de) * | 1994-06-14 | 1996-11-25 | Biochemie Gmbh | 7-(2-(2-aminothiazol-4-yl)-2-(z)- hydroximinoacetamido)-3-n,n- dimethylcarbamoyloxymethyl-3-cephem-4- |
| AT408226B (de) * | 1999-05-05 | 2001-09-25 | Biochemie Gmbh | Kristalliner 7-(2-(2-formylaminothiazol-4-yl)-2 |
| US7842791B2 (en) | 2002-12-19 | 2010-11-30 | Nancy Jean Britten | Dispersible pharmaceutical compositions |
| JP4749194B2 (ja) * | 2006-03-28 | 2011-08-17 | ジャパンパイル株式会社 | オーガー削孔装置における土質試料採取具 |
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| JPS5760345B2 (zh) * | 1974-12-19 | 1982-12-18 | Takeda Chemical Industries Ltd | |
| DK154939C (da) * | 1974-12-19 | 1989-06-12 | Takeda Chemical Industries Ltd | Analogifremgangsmaade til fremstilling af thiazolylacetamido-cephemforbindelser eller farmaceutisk acceptable salte eller estere deraf |
| US4668783A (en) * | 1974-12-19 | 1987-05-26 | Takeda Chemical Industries, Ltd. | Thiazolylacetamido cephalosporin compounds |
| US4203899A (en) * | 1974-12-19 | 1980-05-20 | Takeda Chemical Industries, Ltd. | Thiazolylacetamido compounds |
| US4298606A (en) * | 1974-12-19 | 1981-11-03 | Takeda Chemical Industries, Ltd. | Thiazolylacetamido compounds |
| JPS523091A (en) * | 1975-06-23 | 1977-01-11 | Takeda Chem Ind Ltd | A prcess for preparing cephalosporins |
| DE2760123C2 (de) * | 1976-01-23 | 1986-04-30 | Roussel-Uclaf, Paris | 7-Aminothiazolyl-syn-oxyiminoacetamidocephalosporansäuren, ihre Herstellung und sie enthaltende pharmazeutische Zusammensetzungen |
| JPS6011713B2 (ja) * | 1976-09-08 | 1985-03-27 | 武田薬品工業株式会社 | セフアロスポリン誘導体およびその製造法 |
| DE2714880A1 (de) * | 1977-04-02 | 1978-10-26 | Hoechst Ag | Cephemderivate und verfahren zu ihrer herstellung |
| IT1101437B (it) * | 1978-11-28 | 1985-09-28 | Proter Spa | Procedimento per il recupero di cefaloridina da soluzione acquosa nella quale e'stata prodotta |
| US4409215A (en) * | 1979-11-19 | 1983-10-11 | Fujisawa Pharmaceutical Co., Ltd. | 7-Acylamino-3-substituted cephalosporanic acid derivatives and processes for the preparation thereof |
| FR2476087A1 (fr) * | 1980-02-18 | 1981-08-21 | Roussel Uclaf | Nouvelles oximes derivees de l'acide 3-alkyloxy ou 3-alkyl-thiomethyl 7-amino thiazolyl acetamido cephalosporanique, leur procede de preparation et leur application comme medicaments |
| US4486425A (en) * | 1980-09-30 | 1984-12-04 | Sankyo Company Limited | 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylates |
| JPS5759894A (en) * | 1980-09-30 | 1982-04-10 | Sankyo Co Ltd | Cephalosporin for oral administration |
| FR2532315A1 (fr) * | 1982-08-27 | 1984-03-02 | Rhone Poulenc Sante | Formes cristallisees de sels d'addition avec des acides, de l'((amino-2-thiazolyl-4)-2 methoxyimino-2 acetamido)-7 carboxy-2 (dioxo-5,6 formylmethyl-4 tetrahydro-1,4,5,6 triazine-1,2,4 yl-3) thio-2 vinyl)-3 oxo-8 thia-5 aza-1 bicyclo(4.2.0) octene-2 isomere syn, forme e et leur preparation |
| US4910301A (en) * | 1985-08-05 | 1990-03-20 | Bristol-Myers Company | Cefepime cephalosporin salts |
| DE3804841A1 (de) * | 1988-02-17 | 1989-08-31 | Hoechst Ag | Cephalosporinderivate und verfahren zu ihrer herstellung |
| DE3809561A1 (de) * | 1988-03-22 | 1989-10-05 | Hoechst Ag | Ester der 7-(2-(2-aminothiazol-4-yl)-2-(z)- hydroxyiminoacetamido)-3-methoxymethyl-3-cephem-4-carbonsaeure, verfahren zu ihrer herstellung und sie enthaltende pharmazeutische zubereitungen |
| US5063224A (en) * | 1990-07-09 | 1991-11-05 | Eli Lilly And Company | R-cefuroxime axetil |
-
1989
- 1989-06-13 DE DE3919259A patent/DE3919259A1/de not_active Withdrawn
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1990
- 1990-06-09 EP EP90110945A patent/EP0402806B1/de not_active Expired - Lifetime
- 1990-06-09 ES ES90110945T patent/ES2045653T3/es not_active Expired - Lifetime
- 1990-06-09 DE DE90110945T patent/DE59002880D1/de not_active Expired - Lifetime
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- 1990-06-09 AT AT90110945T patent/ATE95185T1/de not_active IP Right Cessation
- 1990-06-11 CN CN90104242A patent/CN1043043C/zh not_active Expired - Lifetime
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- 1990-06-11 KR KR1019900008498A patent/KR0158883B1/ko not_active Expired - Lifetime
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- 1990-06-12 JP JP2153825A patent/JPH0730085B2/ja not_active Expired - Lifetime
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- 1990-06-12 IE IE211590A patent/IE64076B1/en not_active IP Right Cessation
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- 1990-06-12 ZA ZA904526A patent/ZA904526B/xx unknown
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1992
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