CN87101688A - 4-(2-嘧啶基)-1-嗪基杂环羰基衍生物 - Google Patents
4-(2-嘧啶基)-1-嗪基杂环羰基衍生物 Download PDFInfo
- Publication number
- CN87101688A CN87101688A CN87101688.5A CN87101688A CN87101688A CN 87101688 A CN87101688 A CN 87101688A CN 87101688 A CN87101688 A CN 87101688A CN 87101688 A CN87101688 A CN 87101688A
- Authority
- CN
- China
- Prior art keywords
- pyrimidyl
- alkyl
- piperazinyl
- acid
- tetrahydrochysene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 title abstract 2
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 28
- -1 alkyl propionates Chemical class 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 208000019901 Anxiety disease Diseases 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 8
- 230000036506 anxiety Effects 0.000 claims description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 2
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- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 244000025254 Cannabis sativa Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
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- CINTWGJQDJSXPJ-UHFFFAOYSA-N ethyl 3-amino-3-methylbutanoate Chemical compound CCOC(=O)CC(C)(C)N CINTWGJQDJSXPJ-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明是关于4-(2-嘧啶基)-1-嗪基杂环羰基衍生物、它们的制备方法、和它们用作抗焦虑药的用途。
Description
本发明与某些4-(2-嘧啶基)-1-哌嗪基杂环羰基衍生物及其用作为抗焦虑剂的用途有关。
焦虑症已被定义为对一些未来事件的恐惧和忧虑。大多数人(如果不是全部)偶尔也会对某种适当的刺激反应而患有焦虑的某些症状,但在有些患者中,这种对日常生活的压力所产生的焦虑和恐慌的感觉可成为主要因素,致使该患者成为社会丧失劳动力的成员。当人们之间的劝导成为较好的早期治疗方法时,化学治疗已被证明是进行精神疗法的有效的辅助治疗。从而可使陷于极端痛苦中的患者在进行精神疗法时恢复劳动力。
申请者现在发现了一类新的4-(2-嘧啶基)-1-哌嗪基杂环羰基衍生物,它们是有效的抗焦虑剂并通常没有所不希望的苯并二氮草类的副作用。这里公开的化合物在按本发明的治疗方法治疗时,可减轻如过度的恐惧、担忧、不安静、紧张压迫感、精神抑郁等症状,并可有效地缓解某些人格失常行为。
本发明是针对具有结构式(1)的4-(2-嘧啶基)-1-哌嗪基杂环羰基衍生物
其中n是2~5的整数;x是下列基团和可作药用的酸加成盐类:
基团中R1和R2各为甲基或一起形成四亚甲基或五亚甲基环。
本发明也与上述化合物的制备方法、药物复方和这些化合物用作抗焦虑剂的用途有关。
这里所用的专业术语“可作药用的酸加成的盐”是指用于与结构式Ⅰ所示的碱化合物加成的任一无毒的有机或无机酸加成的盐类,可形成适宜盐类的无机酸的实例包括盐酸,溴氢酸、硫酸,磷酸和酸性金属盐,如原磷酸-氢钠和硫酸氢钾。形成适宜盐类的有机酸包括一元、二元和三元羧酸。这些酸盐的实例包括醋酸,乙醇酸,乳酸,丙酮酸,丙二酸,琥珀酸,戊二酸,富马酸,苹果酸,酒石酸,柠檬酸,抗坏血酸,马来酸,羟基马来酸,苯甲酸,对羟基苯甲酸,苯乙酸,肉桂酸,水杨酸,2-苯氧基苯甲酸磺酸,如甲磺酸或2-羟基-乙磺酸。既可形成一元酸盐或二元酸盐,而这些盐类可以以水合的或基本上无水的形式存在。一般来说,这些化合物的酸加成的盐为结晶物质,可溶于水和各种亲水性有机溶剂中。与它们的游离碱相比,这种加成盐类的熔点一般较高,化学稳定性也较好大。
如上述结构(1)所示,本发明的化合物主要由被2~5碳原子的稀链分离的两个末端杂环部分组成,更特别的是,一个这种杂环部分由4-(2-嘧啶基)-1-哌嗪基组成,而另一个杂环部分是或取代的四氢-嘧啶-2,4-二酮或者四氢-6H-1,3-恶嗪-6-酮。
更为特别的是,本发明的化合物还分成二个特定的而不同的亚类,图示如下:
1-[ω-[4-(2-嘧啶基)-1-哌嗪基]烷基]四氢-嘧啶-2,4-二酮和
2-[ω-[4-(2-嘧啶基)-1-哌嗪基]烷基亚氨基]四氢-6H-1,3恶嗪-6-酮。
n为2~4碳原子的这些亚烷基代表了较好的亚烷基链的长度,R1和R2或为甲基,或在一起形成四亚基或五亚基环,即环戊烷或环己烷环。
结构式(1a)和(1b)的化合物是通过相同的反应过程制备的,即就是说,结构式(1a)的四氢嘧啶-2,-4二酮和结构式(1b)的四氢-6H-1,3,-恶嗪-6-酮都是从同样的反应混合物中得到的。
由3-[(N-烷基)脲基丙酸烷基酯(2)与化合物1-(2-嘧啶基)哌嗪(3)缩合形成3-[N[ω-[4-(2-嘧啶基)-1-哌嗪基]烷基]脲基]丙酸烷基酯(4)。这些烷基酯(4)一般不用分离,但可自动环合形成所需的1-[ω-[4-(2-嘧啶基)-1-哌嗪基]烷基]-四氢-嘧啶-2,4-二酮(1a)和2-[ω-[4-(2-嘧啶基)-1-哌嗪基]-烷基亚氨基]四氢-6H-1,3-恶嗪-6-酮(1b)。这一反应顺序可图示如下,其中n,R1和R2如前所述。R为低级烷基,Y代表一个合适的离去基团。
术语“低级烷基”如R所示,代表1~4碳原子的烷基。低级烷基实例包括甲基,乙基,丙基,异丙基,丁基和仲丁基。术语“离去基团”,如Y所示,代表氯,溴,碘或甲苯磺酸酯和甲磺酸酯基团。
该亲核缩合反应最好用等摩尔量的1-(2-嘧啶基)哌嗪(3)和3-[(N-烷基)脲基]丙酸烷基酯缩合,期间从1小时至24小时,它取决于使用的特定反应剂。反应温度范围大约从25℃至140℃。最好在60℃-125℃温度范围内进行。
最好采用溶剂,适宜的溶剂包括无反应活性的溶剂。最好是沸点范围在60℃~150℃之间的极性溶剂。适于使用的溶剂包括氯代碳氢化合物,如二氯乙烷,二氯甲烷或氯仿;氯代的芳香化合物,如1、2、4-三氯代苯。或邻位二氯代苯;醚性溶剂,如四氢呋喃或对位-二恶烷;芳香溶剂,如苯,甲苯或二甲苯;或醇溶剂,如乙醇或丁醇。特别适用的溶剂是那些已知的可促进亲核反反应的溶剂,如二甲基亚砜,或二甲基甲酰胺。
如上所述,烷基酯(4)能自动环合形成预期的化合物(1a)和(1b),这种环化反应可因催化量的强碱例如叔丁醇钠和钾和极性溶剂例如二甲基亚砜或二甲基甲酰胺的存在下而增强,反应后可得到大约等分子量的异构体(1a)和(1b),反应条件的变化可改变其比例而使其中一种异构体或另一种异构体更多。
通过3-氨基丙酸烷基酯(5)和异氰酸烷酯(6)反应可制备3-[(N-烷基)脲基]丙酸烷基酯(2),该酯含有如下所示的离去基团,下式中的R,R1,R2,n和Y的含有若前述。
采用大约等摩尔量的(5)和(6),由于二种反应剂在室温都为液体,所以反应可通过简单的混合进行。然而,最好采用合适的非质子传递溶剂。合适的非质子传递溶剂包括氯代的碳氢化合物,如二氯甲烷,二氯乙烷或四氯化碳;芳香的碳氢化合物,如苯或甲苯;醚性溶剂,如乙醚,四氢呋喃或对二恶烷和有机酸酯类,如醋酸乙酯。
反应放热,可采用合适的冷却方法在室温下进行。根据所用的反应剂,它们的浓度和所用的特定溶剂,反应温度范围可在-30℃至室温之间,反应时间可在30分钟至3小时。反应温度最好为-20℃至0℃,而反应时间最好为30分钟至1小时。反应混合物中的溶剂一般通过蒸发除去,然后留下所要的3-[(N-烷基)脲基]-丙酯烷基酯,即可按前面所述的方法进行。
或者,也可通过将结构(7)的3-异氰基丙酸烷基酯和如下所示的ω-[4-(2-嘧啶基)-1-哌嗪基]烷基胺(8)的亲核缩合反应制备3-[N-[ω-[4-(2-嘧啶基)-1-哌嗪基]烷基]丙酸烷基酯(4),下面式中的R,R1,R2和n的含意如前述。
这种亲核缩合反应最好采用等摩尔量的3-异氰基丙酸烷基酯(7)和ω-[4-(2-嘧啶基)-1-哌嗪基]烷基胺(8)进行,反应条件基本和前述的反应条件相同,只是将功能基变化了一下,即与3-氨基丙酸烷基酯(5)变为异氰酸烷基酯(6)反应。
结构式(1)的化合物具有有效的抗焦虑性能。抗焦虑作用可采用体外5-羟色胺(5-HT1A)受体结合研究表示,见Middlemiss等,《欧洲药理学杂志》(Eur.J.Phamacol.)90,151-3(1983)和Glaser等《药理学进展》(Arch.Pharmacol.)329,211-215(1985).另外,这里所述的化合物的抗焦虑作用可用体内大鼠舔后趾试验(licking test)来证明,该试验采用文献中的技术,用公认的焦虑动物模型做试验。见Vogel等,《精神药理学》(Psychopharmacologia),21,1-7(1971)。
本发明的化合物可口服,皮下,静脉,肌肉,腹腔内或直肠给药。口服是较好的给药方法。化合物的给药剂量可以是任一有效剂量,当然,要根据被治疗患者的情况、给药方式、焦虑症的严重程度而决定的,每天重复给予该化合物可能是需要的,但也要根据患者的情况和特定的给药物方式而改变。
该化合物抗焦虑作用口服有效剂量范围从0.005~10毫克/公斤体重/天,最好是0.05~5毫克/公斤体重/天。结构式(1a)化合物较好的抗焦虑的剂量大约为0.4毫克/公斤体重/天。单位剂量剂型的药物复方含有1~50毫克的有效成份,可每天用1次或多次。
该化合物可制成固体或液体制剂如胶囊,丸剂,片剂,锭剂,融熔剂,粉剂,溶液剂,混悬剂或乳剂。通常采用的固体剂量单位剂型包括胶囊或片剂。胶囊可为一般的明胶型,含有附加的赋形剂如表面活性剂,润滑剂和惰性填充剂例如乳糖,蔗糖和玉米淀粉。含结构式(1)化合物的片剂可用常规的片剂基质如乳糖,蔗糖,和玉米与粘合剂如阿拉伯胶,玉米淀粉或明胶;分散剂如土豆淀粉或藻酸和润滑剂例如硬脂酸或硬脂酸镁一起压制而成。
该化合物非经胃肠道用的抗焦虑有效剂量范围从0.005~10毫克/公斤体重/天,最好大约为0.05~5毫克/公斤体重/天。非经胃肠道用的单位剂量剂型的复方含有0.1~10毫克有效成份,并可一天使用一次或多次。
该化合物也可作为注射剂给药,注射剂为由生理上可接受的稀释剂配制而成的溶液剂或混悬剂,可有或没有药物载体。合适的稀释剂或载体包括如水或油的消毒液,可加入或不加入表面活性剂或其它可作药用的辅助剂。在本发明的示范例子中采用的各种油为从石油,动物,植物或经合成而得的油,例如花生油,豆油,矿物油。一般来说,水,盐水,含水右旋糖和有关的糖溶液,醇和乙二醇类如丙二醇或聚乙二醇都是较好的液体载体,特别适合于注射溶液。
下面的实施例说明了在本发明实施中采用的代表性化合物的制备方法,但并不限制本发明于这些例子。
例Ⅰ
1-[4-[4-(2-嘧啶基)-1-哌嗪基]丁基]-四氢-6,6-二甲基嘧啶-2,4-二酮(结构式A)和2-[4-[4-(2-嘧啶基)-1-哌嗪基]丁基亚氨基]-四氢-4,4-二甲基-6H-1,3-恶嗪-6-酮(结构式B)
4-溴丁基异氰酸酯的制备
将36.2克-溴戊酸在15.7毫升亚硫酰氯的溶液在室温下搅拌2小时,过量的亚硫酰氯通过蒸发除去。然后将酰基氯残余物溶于50毫升丙酮并在0℃下将该溶液慢慢地加到搅拌的13克叠氮钠在15毫升的水悬浮液中。再搅拌30分钟,用乙醚提取反应混合物。醚层用饱和碳酸氢钠溶液洗涤数次,硫酸镁干燥并蒸发,得到29克5-溴戊酰基叠氮化物,为一种油。将酰基叠氮化物在苯中的溶液回流2小时,然后蒸馏,得到15,1克4-溴丁基异氰酸酯,沸点110℃/15毫米。
3-[(4-溴丁基)-氨基羰基氨基]-3-甲基丁酸乙酯的制备
将15.1克4-溴丁基异氰酸酯在50毫升二氯甲烷的溶液加到搅拌下的12.3克3-氨基-3-甲基丁酸乙酯溶液中,在-20℃将上溶液溶于50毫升二氯甲烷。混合物在-20℃搅拌30分钟,然后再在室温搅拌2小时,蒸发溶剂得到26克3-〔4-溴丁基)氨基羰基氨基〕-3-甲基丁酸乙酯。
1-〔4-〔4-(2-嘧啶基)-1-哌嗪基〕丁基〕-四氢-6,6-二甲基嘧啶-2,4-二酮和2-〔4-〔4-(2-嘧啶基)-1-哌嗪基〕丁基亚氨基〕四氢-4,4-二甲基-6H-1,3-噁嗪-6-酮的制备
将3.21克3-〔(4-溴丁基)氨基羰基氨基〕-3-甲基丁酸乙酯,1.64克1-(2-嘧啶基)哌嗪,1.38克碳酸钾和50毫升二甲基甲酰胺在100℃加热3小时,室温放置过夜,过滤,并蒸发至干。残留物在硅胶上进行色谱层析,用醋酸乙酯-乙醇(90∶10)混合液作洗脱剂,得到2-〔4-〔4-(2-嘧啶基)-1-哌嗪基〕丁基亚氨基〕-四氢-4,4-二甲基-6H-1,3-噁嗪-6-酮(从含水甲醇中结晶时,熔点为124-126℃Rf值为0.3)和1-〔4-〔4-(2-嘧啶基)-1-哌嗪基〕丁基〕四氢-6,6-二甲基嘧啶-2,4-二酮(为一种油,Rf值为0.2)。
将嘧啶-2,4-二酮在乙醚的溶液中用醚的草酸处理,得到相应的草酸盐。熔点128-130℃(从异丙醇结晶)。
例Ⅱ
1-〔4-〔4-(2-嘧啶基)-1-哌嗪基〕丁基〕-四氢-6,6-二甲基嘧啶-2,4-二酮(A)和2-〔4-〔4-(2-嘧啶基)-1-哌嗪基〕丁基亚氨基〕-四氢-4,4-二甲基-6H-1,3-噁嗪-6-酮(B)
2-乙氧羰基-1,1-二甲基乙基异氰酸酯的制备
将4.1克氯甲酸三氯甲酯在15毫升二氯甲烷中的溶液在5℃下慢慢地加到搅拌下的3克3-氨基-3-甲基丁酸乙酯,6.6克三乙胺和30毫升二氯甲烷的混合物中。该混合物于室温搅拌过夜,回流3小时,冷却,再加无水乙醚。过滤除去三乙胺盐酸盐沉淀,滤液蒸发,得到3.5克2-乙氧羰基-1,1-二甲基乙基异氰酸酯,为一种油。
3-〔4-〔4-(2-嘧啶基)-1-哌嗪基〕丁基〕氨基〕氨基羰基氨基-3-甲基丁酸乙酯的制备
将3.5克上述的异氰酸酯在10毫升二氯甲烷中的溶液在室温加到搅拌下的4.15克4-〔4-(2-嘧啶基)-1-哌嗪基〕丁胺在10毫升二氯甲烷的溶液中。可观察到轻微的放热反应。搅拌30分钟后,蒸发二氯甲烷,残留物溶于50毫升1当量的盐酸溶液,用醋酸乙酯提取该溶液,水层用饱和碳酸钾溶液使呈碱性并用乙醚提取,蒸馏干燥的醚提取液,得到5.4克3-〔4-〔4-(2嘧啶基)-1-哌嗪基〕丁基〕氨基羰基氨基-3-甲基丁酸乙酯,为一糖浆。
1-〔4-〔4-(2-嘧啶基)-1-哌嗪基〕丁基〕-四氢-6,6-二甲基嘧啶-2,4-二酮和2-〔4-〔4-(2-嘧啶基)-1-哌嗪基〕丁基亚氨基〕-四氢-4,4-二甲基-6H-1,3-噁嗪-6-酮的制备
将1克叔丁醇钾在5毫升乙醇中的溶液加到5.4克3-〔4-〔4-(2-嘧啶基)-1-哌嗪基〕丁基〕氨基羰基氨基-3-甲基丁酸乙酯在10毫升的溶液中,混合物搅拌回流30分钟。将乙醇蒸发,残留物用50毫升水处理,形成的油用二氯甲烷提取。将二氯甲烷提取合并液干燥并蒸发,得到一种部分结晶的糖浆。该糖浆用乙醚处理并用过滤滤出2克结晶。用活性碳处理在含水甲醇中的结晶溶液,过滤,并重结晶,得到1克2-〔4-〔4-(2-嘧啶基)-1-哌嗪基〕丁基亚氨基〕-四氢-4,4-二甲基-6H-1,3-噁嗪-6-酮,熔点124-126℃。
将醚溶液蒸发留下2克糖浆在硅胶上进行色谱层析,得到1-〔4-〔4-(2-嘧啶基)-1-哌嗪基〕丁基〕-四氢-6,6-二甲基嘧啶-2,4-二酮,为一种油。用醚的草酸处理该油,得到草酸盐,熔点128-130℃。
例Ⅲ
通过5-羟色胺1A结合试验在体外测定
抗焦性能
对5-羟色胺1A识别部位的放射配体结合研究是用以下方法进行。切除正常血压的雄性Sprague-Dawley大鼠的额皮层,并在液氮中冰冻,于-20℃贮存待用。合并从4-8个大鼠切除下的组织并在70份体积的Tris-HCl缓冲剂(50mM,pH7.7)中,用Kinematica Polytron仪(调至2/3最大速度,20秒)均浆化。离心组织均浆(36500xg,10分钟),将沉聚的小片在相同体积的缓冲剂中重新均浆化,并重复此过程二次。在第二和第三次离心之间将组织均浆在37℃孵育10分钟。将最后的小片混悬在相同体积的含有10M优降宁,5.7mM氯化钙和0.1%抗坏血酸的Tris缓冲剂中。此混悬物于37℃孵育10分钟而后贮存在冰中,供结合测定使用。
将组织均浆(0.7毫升),放射性配体(0.1毫升)和合适浓度的试验化合物(0.1毫升)与缓冲剂一起使最终体积为1毫升,在37℃孵育15分钟。通过Whatman GF/B过滤器快速过滤以停止孵育,随后用冰冷的Tris-HCl缓冲剂(50mM,PH7.0)洗涤三次,每次5毫升。放射性的测定是在提取到Aguasol-Z(NEN)后进行的,效率为45-50%。用以标记5-羟色胺1A识别部位及其浓度的放射配体为〔3H〕-8-羟基-2-(二-正丙氨基)-1,2,3,4-四氢化萘,〔3H〕-8-羟基-DPAT,1mM。
基本上按照上述方法测定化合物1-〔-4〔4-(2-嘧啶基)-1-哌嗪基〕丁基〕-四氢-6,6-二甲基嘧啶-2,4-二酮(化合物A)和2-〔4-〔4-(2-嘧啶基)-1-哌嗪基〕丁基亚氨基〕-四氢-4,4-二甲基-6H-1,3-噁嗪-6-酮(化合物B)。结果以PIC50(抑制特异性结合50%的试验化合物浓度的常用对数)表示。
Claims (6)
2、如权利要求1所述的方法,其中X是基团:
3、如权利要求1所述的方法,其中该衍生物是1-〔4〔4-(2-嘧啶基)-1-哌嗪基〕丁基〕-四氢-6,6-二甲基嘧啶-2,4-二酮及其可供药用的盐。
5、如权利要求1所述的方法,其中该衍生物是2-〔4-〔4-(2-嘧啶基)-1-哌嗪基〕-丁基亚氨基〕-四氢-4,4-二甲基-6H-1,3-噁嗪-6-酮及其可供药用的盐。
6、一种抗焦虑组合物的制备方法,它是将抗焦虑有效量的按权利要求1所述的方法制备的化合物或其可供药用的盐与可供药用的载体或稀释剂结合。
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PT84408B (pt) | 1989-10-04 |
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AU588671B2 (en) | 1989-09-21 |
HU197567B (en) | 1989-04-28 |
DE3787109T2 (de) | 1994-02-10 |
FI870925A (fi) | 1987-09-06 |
HUT43591A (en) | 1987-11-30 |
JPS62265285A (ja) | 1987-11-18 |
ATE93523T1 (de) | 1993-09-15 |
DK111987D0 (da) | 1987-03-04 |
EP0238905A3 (en) | 1989-08-09 |
PT84408A (en) | 1987-04-01 |
NO870891D0 (no) | 1987-03-04 |
KR870008874A (ko) | 1987-10-21 |
KR900000413B1 (ko) | 1990-01-30 |
NO167390C (no) | 1991-10-30 |
JPH0778043B2 (ja) | 1995-08-23 |
PH24912A (en) | 1990-12-26 |
CA1286667C (en) | 1991-07-23 |
ES2059316T3 (es) | 1994-11-16 |
NO870891L (no) | 1987-09-07 |
AR242790A1 (es) | 1993-05-31 |
FI870925A0 (fi) | 1987-03-03 |
DK111987A (da) | 1987-09-06 |
AR242678A1 (es) | 1993-04-30 |
NO167390B (no) | 1991-07-22 |
AU6960787A (en) | 1987-09-10 |
CN1023484C (zh) | 1994-01-12 |
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EP0238905A2 (en) | 1987-09-30 |
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