CN1062353A - 新氨烷基酮衍生物的制备程序以及在治疗中的应用 - Google Patents
新氨烷基酮衍生物的制备程序以及在治疗中的应用 Download PDFInfo
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- CN1062353A CN1062353A CN91111558A CN91111558A CN1062353A CN 1062353 A CN1062353 A CN 1062353A CN 91111558 A CN91111558 A CN 91111558A CN 91111558 A CN91111558 A CN 91111558A CN 1062353 A CN1062353 A CN 1062353A
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- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
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- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pyrrole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
本发明涉及的化合物的通式为:
其中A从吡咯烷子 基、哌啶子基、吗啉代、1-咪
唑基、六亚甲基亚氨基、及1-哌嗪基中选择,这些基
为非取代的,或它们可能含1个或2个从含1至3个
碳原子的烷基和含1至3个碳原子的羟烷基中选择
的取代基;本发明还涉及这些化合物与适于药用的酸
生成的盐。
这些化合物具有作为外周血管扩张剂的治疗功
效。
Description
本发明涉及新的氨烷基酮衍生物、涉及它们的制备方法,以及它们的治疗功用,特别是作为外周血管扩张剂的治疗作用。
法国专利申请2,134,218中描述了氨烷基酮衍生物的外周血管扩张活性,特别是甲氧吡丁苯的外周血管扩张活性。
本发明的目的在于制备不仅具有外周血管扩张活性,而且具有有利的代谢活性的新化合物。
本发明的目的是通式为
的化合物,其中A从吡咯烷子基、哌啶子基、吗啉代、1-咪唑基、六亚甲基亚氨基和1-哌嗪基选择,这些基为非取代的或它们可含1个或2个从含1至3个碳原子的烷基和含1至3个碳原子的羟烷基中选择的取代基,以及这些化合物与适于药用的酸生成的盐。
作为基团A的例子,吡咯烷子基、2,4-二甲基吡咯烷子基、2. 5-二甲基吡咯烷子基、哌啶子基、3-(羟甲基)-哌啶子基、吗啉代、1-咪唑基、六亚甲基亚氨基和N-甲基哌啶子基可被提及。
与“适于药用的酸加合的盐”指那些能产生游离碱的生物学性质,而没有副作用的盐。这些盐可以特指与无机酸,例如盐酸、氢溴酸、硫酸、硝酸和磷酸生成的盐,与金属的酸盐,例如与正磷酸钠、硫酸氢钾生成的盐,与有机酸,例如甲酸、乙酯、丙酸、乙醇酸、草酸、顺丁烯二酸、反丁烯二酸、柠檬酸、丙二酸、甲磺酸、乳酸、丁二酸、和洒石酸,生成的盐。
本发明的化合物可以通过将通式为
的氯化衍生物与通式为HA(Ⅲ)的环胺缩合而制得。A具有上面给出的含义。
该缩合反应可以在通常的缩合反应溶剂中完成..;作为一种变形,本发明的化合物可以通过通式为NC-(CH2)3-A(Ⅳ)的腈与2-或3-溴噻吩的锂衍生物反应,接着水解,来制备。
该反应可以在使用锂衍生物的常规条件下进行。
按照常规方法,把通式Ⅰ的化合物与适于药用的酸在合适的溶 剂中反应,便可制得所需的盐。
下面的实施例说明了根据本发明的化合物的制备。
实施例1
4-吡咯烷子基-1-(2-噻吩基)丁酮盐酸盐(CRL41687)的制备。
18.85g(0.10mol)4-氯-1-(2-噻吩基)丁酮在30分钟内加入到18.5ml(0.22mol)吡咯烷和35ml甲苯保温于100℃的溶液之中,混合物加热回流2小时。反应介质用乙烯稀释,混合物用水洗。有机层有2N的盐酸溶液萃取,盐酸层碱化之后,反过来再用乙醚萃取。有机层用无水硫酸钠干燥,并用氯化氢的异丙醇溶液处理。
所得的沉淀逐次用CXA活性碳在异丙醇和绝对乙醇中两次结晶纯化,得11.1g稍微灰色的粉末,该粉末在水中可溶达20%的浓度。
熔点仪器(kofler):177℃;
收率:46.3%。
实施例2
4-哌啶子基-1-(2-噻吩基)丁酮盐酸盐(CRL41696)的制备。
18.9g(0.10mol)4-氯-1-(2-噻吩基)丁酮在30分钟内加入到18.7g(0.22mol)哌啶与35ml甲苯的回流溶液中,保持加热2小时。反应介质用乙醚稀释,混合物用水洗。有机层用稀盐酸溶液萃取,水相有氢氧化钠碱化。水相用乙醚萃取,用无水硫酸钠干燥后,有机相用氯化氢的异丙醇溶液处理。
滤出的沉淀在绝对乙醇中结晶纯化,得22.5g水溶性浅米色粉末。
熔点仪器(kofler):178℃
收率:82.3%。
实施例3
4-(3-甲基哌啶子基)-1-(2-噻吩基)丁酮盐酸盐(CRL41686)的制备。
18.85g(0.10mol)4-氯-1-(2-噻吩基)丁酮在30分钟内加入到21.8g(0.22mol)3-甲基哌啶和35ml甲苯保温于100℃的溶液之中,混合物加热回流2小时。反应介质用乙醚稀释,混合物用水洗。有机层用稀盐酸溶液萃取,盐酸溶液层用氢氧化钠碱化后反过来用乙醚萃取。有机层用无水硫酸钠干燥,并用氯化氢的异丙醇溶液处理。
所得沉淀在异丙醇中结晶纯化,得18g白色粉末,该粉末在水中可溶解达20%的浓度。
熔点仪器(kofler):164℃
收率:62.6%
实施例4
4-吗啉代-1-(2-噻吩基)丁酮盐酸盐(CRL41698)的制备。
18.9g(0.20mol)4-氯-1-(2-噻吩基)丁酮在15分钟内加入到19.2g(0.22mol)吗啉与35ml甲苯的回流溶液中,继续加热2小时。反应介质用乙醚稀释,混合物用水洗。有机层用稀盐酸萃取,水相用氢氧化钠碱化。水相用乙醚萃取,用无水硫酸钠干燥之后,有机相用氯化氢的异丙醇溶液处理。
滤得的沉淀在甲醇中结晶纯化,得12.7g水溶性米色粉末。
熔点仪器(kofler):210℃
收率:46.1%
实施例5
4-〔3-(羟甲基)哌啶子基〕-1-(2-噻吩基)丁酮盐酸盐(CRL41697)的制备。
28.3g(0.15mol)4-氯-1-(2-噻吩基)丁酮在30分钟内加入到38g(0.33mol)3-哌啶基甲醇和55ml甲苯的回流溶液中,保持 加热2.5小时。反应介质用乙酸乙酯稀释,混合物用水洗。有机相用稀盐酸溶液萃取,水相用氢氧化钠碱化。水相用乙酸乙酯萃取,用无水硫酸钠干燥后,有机相用氯化氢的异丙醇溶液处理。
滤得的沉淀在乙醇中结晶精制,得26g水溶性浅灰色粉末。
熔点仪器(kofler):160℃
收率:57.1%。
实施例6
4-(1-咪唑基)-1-(2-噻吩基)丁酮盐酸盐(CRL41703)的制备。
18.9g(0.10mol)4-氯-1-(2-噻吩基)丁酮加入到15g(0.22mol)咪唑和35ml甲苯,保温约90℃的溶液中,混合物加热回流4小时。反应介质用乙酸乙酯稀释,混合物用水洗,并用稀盐酸溶液萃取。水相用氢氧化钠碱化并用乙酸乙酯萃取,萃取液用硫酸钠干燥。溶液用氯化氢的乙醇溶液处理,不溶物用丙酮洗涤纯化,得6g水溶性的米色粉末。
熔点仪器(kofler):132℃,
收率:23.4%。
实施例7
4-六亚甲基亚氨基-1-(2-噻吩基)丁酮盐酸盐(CRL41683)的制备。
28.3g(0.15mol)4-氯-1-(2-噻吩基)丁酮在30分钟内加入到32.7g(0.33mol)六亚甲基亚氨和50ml甲苯的保温于100℃的溶液之中。继续回流3小时,反应介质用150ml乙醚稀释,滤去不溶物,滤液用稀盐酸溶液萃取。水相用浓氢氧化钠碱化,并反过来用乙醚萃取。有机相用无水硫酸钠干燥后,用氯化氢的异丙醇溶液处理。
过滤分离沉淀,然后在绝对乙醇中用CXA活性碳处理,结晶纯化,得33.1g水溶性米色粉末。
熔点仪器(kofler):181℃
收率:76.75%。
实施例8
4-吡咯烷子基-1-(3-噻吩基)丁酮盐酸盐(CL41724)的制备。
16.3g(0.10mol)3-溴噻吩与50ml乙醚的溶液在10分钟内,在-70℃,氮气流下,加入到69ml(0.11mol)1.6M用150ml乙醚稀释的丁基锂己烷溶液中。
当温度保持于-50℃时,在15分钟内加入12.5g4-吡咯烷子基丁腈,所得的混合物搅拌2小时,使回复到室温。反应介质注到85g水和42.5ml12N的盐酸内,反应混合物搅拌1小时,分层之后分出水相,用氢氧化钠碱化,并用乙醚萃取。
有机相用水洗,无水硫酸钠干燥,然后用氯化氢的异丙醇溶液处理。
所得沉淀在125∶40乙酸乙酯/异丙醇混合溶液中用CXA活性碳处理,结晶纯化,得15g水溶性米色粉末。
熔点仪器(kofler):124℃
收率:6412%。
实施例9
4-六亚甲基亚氨基-1-(3-噻吩基)丁酮盐酸盐(CRL41725)的制备。
16.3g(0.10mol)3-溴噻吩与50ml乙醚的溶液在15分钟内,加到用氮气流保护,保温于-70℃的69ml(0.11mol)1.6M用150ml乙醚稀释的丁基锂的己烷溶液之中。
在保温-50℃下,在10分钟内加入16.6g(0.10mol)(六亚甲基亚氨基)丁腈,混合物搅拌4小时,使温度回复到室温。反应介质注入到85g冰和41.5ml12N的盐酸中,混合物搅拌1小时,分层之后分出水相,用氢氧化钠碱化并用乙醚萃取。
有机相用水洗,无水硫酸钠干燥,然后用氯化氢的异丙醇溶液处理。
所得沉淀在绝对乙醇中用CXA活性碳处理,结晶纯化,得19.5g水溶性微灰色粉末。
熔点仪器(kofler):200-202℃,
收率:67.8%。
实施例10
4-(3-甲基哌啶子基)-1-(3-噻吩基)丁酮盐酸盐(CRL41726)的制备。
a)4-(3-甲基哌啶子基)丁腈的制备。
27.2g(0.25mol)4-氯丁腈在25分钟内加入到58.8ml(0.50mol)3-甲基哌啶和65ml苯的回流溶液中。继续回流2小时,滤去沉淀,滤液减压至干。
残留物减压蒸馏纯化,得29.2g无色油状物。
沸点5.6mm:100℃
收率:70.3%。
b)4-(3-甲基哌啶子基)-1-(3-噻吩基)丁酮的制备。
16.3g(0.10mol)3-溴噻吩与50ml乙醚的溶液,在10分钟内,加入到-70℃氮气流保护的69ml(0.11mol)1.6M用150ml乙醚稀释的丁基锂的己烷溶液之中。
在-50℃下于15分钟内加入16.6g(0.10ml)自a)中获得的产物,混合物搅拌2小时,同时使温度回复到室温。反应介质注入到85g冰和42.5ml12N的盐酸中,混合物搅拌1小时,分层之后分离出水层,用氢氧化钠碱化,并用乙醚萃取。
有机层用水洗,无水硫酸钠干燥,然后用氯化氢的异丙醇溶液处理。
所得沉淀在绝对乙醇中用CXA活性碳处理,结晶纯化,得16g水溶性微粉色粉末。
溶点仪器(kofler):184℃
收率:56%
总收率:39.4%。
实施例11
4-吡咯烷子基-1-(2-噻吩基)丁酮2,4,6-三甲氧苯甲酸盐(CRL41784)的制备。
9.9g(0.044mol)4-吡咯烷子基-1-(2-噻吩基)丁酮和9.4g(0.044)mol)2,4,6-三甲氧苯甲酸在50ml丙酮中混合。混合物室 温搅拌1小时,反应介质用25ml丙酮稀释并加热至沸,使有效地溶解。
冷却以后,滤出12.3米色沉淀,该产品在水中加热时可溶。
熔点仪器(kofler):115℃
收率:64.2%。
实施例12
4-哌啶子基-1-(2-噻吩基)丁酮2,4,6-三甲氧苯甲酸盐(CRL41777)的制备。
往10g(0.0365mol)4-哌啶子基-1-(2-噻吩基)丁酮与50ml甲醇的溶液中,加入7.7g(0.0365mol)2,4,6-三甲氧苯甲酸。反应介质在室温下搅拌30分钟并挥发至干,残留物用丙酮溶解。用乙醚析出不溶性产物,过滤分离出沉淀。
产品先在丙酮中洗,然后在丙酮中用CXA活性碳处理结晶,而纯化。得到6.8g在水中加热可溶的白色粉末。
熔点:100℃(熔融为胶状)
收率:41.5%。
下面给出证实根据本发明的化合物的有利性质的药理和毒理结果。
a)急性毒性
急性毒性用小鼠(NMRI)口服给药测定。
b)血管扩张活性
静脉给药的化合物的活性用麻醉的狗进行研究。
实施例1的化合物(CRL41687)
在每公斤1mg或高于此剂量下,该化合物明显地增加股脉流速。在4mg/kg剂量下,股脉流速增加170%。
作为对照组的甲氧吡丁苯在4mg/kg的剂量下,股脉流速增加106%。
在相同的试验中,即使在4mg/kg的剂量下,实施例1的化合物也不明显改变动脉血压。
实施例2的化合物(CRL41696)
在1mg/kg或高于此剂量下,该化合物明显增加股脉流速。2mg/kg的剂量下它产生的股脉流速增加与4mg/kg的甲氧吡丁基相同,不改变动脉血压。实施例2的化合物的作用比甲氧吡丁苯的作用延续时间更长。
实施例7的化合物(CRL41683)
在1.14mg/kg和更高的剂量下,该化合物明显而又持续增加股脉流速。这种股脉流速增加效应比4mg/kg剂量下甲氧吡丁苯的效应大。
c)与微循环有关的活性
静脉给药的化合物的微循环活性用兔耳腔进行研究。
静脉1mg/kg的剂量下,实施例1和7的化合物(CRL41687)和CRL41683)明显和持续地增加非末端动脉直径。
d)代谢作用
化合物对新鲜血液中ATP的影响通过13p核磁共振光谱体内实验测定。
下表中以百分数变化的形式给出结果。
用甲氧吡丁苯完成的相同测试,未能揭示ATP水平的任何变化。
本发明的目标也在于包含通式Ⅰ的化合物或该化合物与药用的酸的加成合盐为主要活性化合物的,具有治疗作用的制剂。
根据本发明的治疗制剂可以经口服或胃肠外给药用于人和动物。
它们可以是固体、半固体或液体制品,作为范例,可以提及片剂、硬质明胶胶囊、栓剂、可以注射的溶液或悬浮剂,以及阻滞剂或缓释植入剂。
在这些制剂中,主要活性化合物一般都与一种以上普通适于药用的赋型剂接照技术上熟为人知的技艺混合。
服用的活性成分的量自然取决于被治疗的病人,给药途径和病的严重性。
一般而言,根据本发明的化合物可以按每天100至800mg的剂量的口服给药。
Claims (4)
2、根据权利要求1的方法,其中A为吡咯烷子基。
3、根据权利要求1的方法,其中A从哌啶子基、3-甲基哌啶子基如3-(羟甲基)哌啶子基中选择。
4、根据权利要求1的方法制得4-吡咯烷子基-1-(2-噻吩基)丁酮以及它与适于药用的酸加合的盐类。
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DE1217396B (de) * | 1963-07-04 | 1966-05-26 | Laboratorie Roger Bellon, Neuilly-sur-Seine (Frankreich) | Verfahren zur Herstellung von 1 - (Thienyl-21) - l-oxo-2-amino-propanen |
US3417087A (en) * | 1965-12-27 | 1968-12-17 | Research Corp | 3(aminopropionyl)benzothiophenes |
FR2134218A1 (en) * | 1971-04-27 | 1972-12-08 | Penciolelli Madeleine | Phloroglucinol aminoketones - vasodilators and antispasmodics |
FR2184503A2 (en) * | 1972-05-19 | 1973-12-28 | Cluzel Roger | Alkyl 2-amino-3-(2-thenoyl)propionates - with antibacterial activity |
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FR2291755A2 (fr) * | 1974-11-21 | 1976-06-18 | Delalande Sa | Nouveaux benzoyl-2' eth-1' yl)-1 (cinnamyl-4'' piperazin-1'' yl methyl)-2 benzimidazoles, leur procede de preparation et leur application en therapeutique |
FR2305981A1 (fr) * | 1975-04-03 | 1976-10-29 | Innothera Lab Sa | Nouvelles benzothienyl aminoethyl cetones, leur procede de preparation et leur application en therapeutique |
FR2305982A1 (fr) * | 1975-04-03 | 1976-10-29 | Innothera Lab Sa | Nouvelles benzothienyl amino (propyl et butyl) cetones, leur procede de preparation et leur application en therapeutique |
FR2453172A1 (fr) * | 1979-04-06 | 1980-10-31 | Innothera Lab Sa | Nouvelles (thienyl-2) amino-1 butyl cetones, leur procede de preparation et leur application en therapeutique |
US4299769A (en) * | 1980-04-28 | 1981-11-10 | American Cyanamid Company | ω-Heteroaroyl(propionyl or butyryl)-L-prolines |
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-
1990
- 1990-12-12 FR FR9015591A patent/FR2670492B1/fr not_active Expired - Fee Related
-
1991
- 1991-11-29 NZ NZ240809A patent/NZ240809A/en unknown
- 1991-12-05 CA CA002057138A patent/CA2057138A1/en not_active Abandoned
- 1991-12-09 KR KR1019910022474A patent/KR920012074A/ko not_active Application Discontinuation
- 1991-12-09 PT PT99726A patent/PT99726A/pt not_active Application Discontinuation
- 1991-12-10 FI FI915809A patent/FI915809A/fi not_active Application Discontinuation
- 1991-12-10 NO NO91914845A patent/NO914845L/no unknown
- 1991-12-10 AU AU88940/91A patent/AU648126B2/en not_active Ceased
- 1991-12-11 ZA ZA919754A patent/ZA919754B/xx unknown
- 1991-12-11 MX MX9102514A patent/MX9102514A/es unknown
- 1991-12-11 IE IE431191A patent/IE914311A1/en unknown
- 1991-12-11 HU HU913903A patent/HUT62002A/hu unknown
- 1991-12-11 CS CS913755A patent/CS375591A3/cs unknown
- 1991-12-11 CN CN91111558A patent/CN1029737C/zh not_active Expired - Fee Related
- 1991-12-11 JP JP3327752A patent/JPH04334379A/ja active Pending
- 1991-12-12 EP EP91403374A patent/EP0490769B1/fr not_active Expired - Lifetime
- 1991-12-12 ES ES91403374T patent/ES2071955T3/es not_active Expired - Lifetime
- 1991-12-12 AT AT91403374T patent/ATE121397T1/de not_active IP Right Cessation
- 1991-12-12 DE DE69109072T patent/DE69109072T2/de not_active Expired - Fee Related
- 1991-12-12 DK DK91403374.1T patent/DK0490769T3/da active
-
1993
- 1993-06-04 LT LTIP614A patent/LTIP614A/xx unknown
- 1993-06-15 LV LVP-93-587A patent/LV10266B/xx unknown
-
1994
- 1994-01-21 US US08/183,904 patent/US5446060A/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CA2057138A1 (en) | 1992-06-13 |
CS375591A3 (en) | 1992-06-17 |
FI915809A (fi) | 1992-06-13 |
LV10266A (lv) | 1994-10-20 |
NZ240809A (en) | 1992-11-25 |
ATE121397T1 (de) | 1995-05-15 |
FI915809A0 (fi) | 1991-12-10 |
DK0490769T3 (da) | 1995-07-17 |
EP0490769A1 (fr) | 1992-06-17 |
HU913903D0 (en) | 1992-02-28 |
LV10266B (en) | 1995-04-20 |
ZA919754B (en) | 1993-06-11 |
HUT62002A (en) | 1993-03-29 |
FR2670492B1 (fr) | 1994-11-04 |
DE69109072D1 (de) | 1995-05-24 |
AU648126B2 (en) | 1994-04-14 |
DE69109072T2 (de) | 1995-09-14 |
ES2071955T3 (es) | 1995-07-01 |
KR920012074A (ko) | 1992-07-25 |
FR2670492A1 (fr) | 1992-06-19 |
CN1029737C (zh) | 1995-09-13 |
NO914845L (no) | 1992-06-15 |
PT99726A (pt) | 1992-10-30 |
AU8894091A (en) | 1992-07-09 |
US5446060A (en) | 1995-08-29 |
EP0490769B1 (fr) | 1995-04-19 |
JPH04334379A (ja) | 1992-11-20 |
LTIP614A (en) | 1994-12-27 |
NO914845D0 (no) | 1991-12-10 |
IE914311A1 (en) | 1992-06-17 |
MX9102514A (es) | 1992-09-01 |
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