CN1148042A - 新的杂环取代的假肽 - Google Patents
新的杂环取代的假肽 Download PDFInfo
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- CN1148042A CN1148042A CN96111429A CN96111429A CN1148042A CN 1148042 A CN1148042 A CN 1148042A CN 96111429 A CN96111429 A CN 96111429A CN 96111429 A CN96111429 A CN 96111429A CN 1148042 A CN1148042 A CN 1148042A
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- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及通式(I)新的杂环取代的假肽，其制备方法以及它们作为抗逆转录病毒剂的用途。式中取代基的定义见说明书。
Description
本发明涉及新的杂环取代的假肽、其制备方法以及它们作为抗逆转录病毒剂的用途。
EP 528242中描述了含三氟甲基的假肽作为抗逆转录病毒剂。
本发明涉及通式(I)新的杂环取代的假肽及其盐：
式中R1代表下式基团
或R4-O-CO-，式中R3和R4相同或不同，代表下式杂环基团：或
R2代表氢或具有至多20个碳原子的直链或支链酰基，该酰基可任选地被羧基或者具有至多6个碳原子的直链或支链烷氧基羰基取代。
按照本发明的通式(I)化合物具有多个不对称碳原子。有代表性的通式(Ia)基团
具有5个不对称碳原子(*)，它们相互独立地以R-或S-构型形式存在。1(R)、2(R)、3(S)、4(S)、5(S)和6(S)构型是优选的。
在按照本发明的通式(I)化合物中使用的氨基酸可以以L-或D-式存在。
具有三氟甲基取代的2-氮杂二环辛烷的杂环取代的假肽的生理上可接受的盐可以是按照本发明的物质与无机酸、羧酸或磺酸形成的盐。特别优选的盐是例如与下列酸形成的盐：氢氯酸，氢溴酸，硫酸，磷酸，甲磺酸，乙磺酸，甲苯磺酸，苯磺酸，萘二磺酸，乙酸，丙酸，乳酸，酒石酸，柠檬酸，富马酸，马来酸或苯甲酸。
优选的按照本发明的通式(I)化合物是式中取代基如下定义的化合物及其盐：R1代表下式基团或R4-O-CO-，式中R3和R4相同或不同，代表下式杂环基团：
或
R2代表氢或具有至多6个碳原子的直链或支链酰基。
特别优选的按照本发明的通式(I)化合物是式中取代基如下定义的化合物及其盐：R1代表下式基团
或R4-O-CO-，式中R3和R4相同或不同，代表下式杂环基团：或
R2代表氢或具有至多5个碳原子的直链或支链酰基。
更优选的按照本发明的通式(I)化合物是式中R2代表氢或具有至多4个碳原子的直链或支链酰基的那些化合物。
此外还发现了按照本发明的通式(I)化合物的制备方法，其特征在于：使式(II)或(III)化合物在惰性溶剂中并在碱和/或助剂存在下与通式(IV)化合物反应，若合适，预先将该羧酸活化，所述通式(IV)如下：
R1-OH (IV)式中R1的定义同上，和在第二步中，若R2≠H，则在惰性溶剂中进行酰化，若合适，在碱和/或助剂存在下进行。
按照本发明的方法可用下面的反应图解举例说明：
适用于所有步骤的溶剂是在反应条件下不变化的常规惰性溶剂，最好包括有机溶剂，例如醚类，例如乙醚、乙二醇一甲醚或二甲醚、二氧六环或四氢呋喃，或烃类，例如苯、甲苯、二甲苯、环己烷或石油馏份，或卤代烃类，例如二氯甲烷、氯仿、四氯化碳，或二甲亚砜，二甲基甲酰胺，六甲基磷酸三酰胺，乙酸乙酯，吡啶，三乙胺或甲基吡啶。也可以使用所述溶剂的混合物。二氯甲烷、二甲基甲酰胺或四氢呋喃是特别优选的。
视各方法步骤而定的适宜的碱是常规的无机或有机碱，最好包括碱金属氢氧化物，例如氢氧化钠或氢氧化钾，或碱金属碳酸盐，例如碳酸钠或碳酸钾，或碱金属醇盐，例如甲醇钠或甲醇钾、或乙醇钠或乙醇钾，或有机胺，例如乙基二异丙基胺、三乙胺、甲基吡啶、吡啶、二甲氨基吡啶或N-甲基哌啶，或氨基化物，例如氨基化钠或二异丙基氨基化锂，或N-甲硅烷基烷基氨基化锂，例如N-(双)三苯基甲硅烷基氨基化锂，或烷基锂，例如正丁基锂。
碱的用量为每摩尔式(II)或(III)化合物1-10mol，优选1-3mol。
适宜的助剂最好是缩合剂，还可以是碱，特别是当羧基以活化形式作为酐存在时。这里优选常规缩合剂，例如碳化二亚胺类，例如N，N’-二乙基、N，N’-二异丙基或N，N’-二环己基碳化二亚胺，N-(3-二乙基氨基异丙基)-N’-乙基碳化二亚胺盐酸盐，N-环己基-N’-(2-吗啉代乙基)碳化二亚胺metho-对甲苯磺酸盐(CMCT或morpho-CDI)，或羰基化合物，例如碳酰二咪唑，或1，2-噁唑鎓化合物，例如2-乙基-5-苯基-1，2-噁唑鎓-3-磺酸盐，2-叔丁基-5-甲基噁唑鎓高氯酸盐，或酰氨基化合物，例如2-乙氧基-1-乙氧基羰基-1，2-二氢喹啉，或丙烷膦酸酐，或氯甲酸异丁酯，或六氟磷酸苯并三唑基氧基-三-(二甲氨基)鏻，1-羟基苯并三唑或二甲氨基吡啶。
该反应可在大气压或者加压或减压下(例如在0.5-5巴)进行，最好是在大气压下进行。
该反应一般在-20℃至+40℃的温度范围内进行，最好是在0℃至室温的温度范围内进行。
酰化反应一般在一种上述的醚或卤代烃、最好是四氢呋喃或二氯甲烷中在-30℃至+50℃、最好是-10℃至室温的温度范围内进行。
适宜于酰化反应的碱和/或助剂一般是上述的有机胺和吡啶。优选三乙胺或二甲氨基吡啶。
碱的用量为每摩尔相应的醇1-10mol，最好是1-3mol。
通式(II)化合物是已知的。
式(III)化合物是新的，可例如按下述制备：将通式(V)化合物首先用环氧化反应转化成通式(VI)化合物，若合适，借助于碱或相转移催化剂，然后与(VII)3-三氟甲基-2-氮杂二环[3.3.0]辛烷在溶剂中反应，并用常规方法除去保护基团；所述通式(V)、(VI)和式(VII)如下：式中W代表氨基保护基团，优选叔丁氧基羰基，
式中W的定义同上，
适宜的溶剂是在反应条件下不变化的常规有机溶剂，最好包括有机溶剂，例如醇类，例如甲醇、乙醇或正丙醇，醚类，例如乙醚、乙二醇一甲醚或二甲醚、二氧六环或四氢呋喃，或烃类，例如苯、甲苯、二甲苯、环己烷或石油馏份，或卤代烃类，例如二氯甲烷、二氯乙烷(DCE)、氯仿、四氯化碳，或二甲亚砜，二甲基甲酰胺，六甲基磷酸三酰胺，乙酸乙酯，吡啶，三乙胺或甲基吡啶。也可以使用所述溶剂的混合物。二氯甲烷、二氯乙烷、二甲基甲酰胺或正丙醇是特别优选的。
环氧化反应适宜的试剂是由文献中得知的化合物，例如间氯过苯甲酸，单过氧邻苯二甲酸镁，二甲基二氧丙环(dioxirane)或甲基(三氟甲基)二氧丙环。间氯过苯甲酸和单过氧邻苯二甲酸镁是优选的(参见P.Brongham等人，Synthesis(1987)，1015；W.Adam等人，J.Org.Chem.52，2800(1987)和R.Curci等人，J.Org.Chem.53，3890(1988))。
若环氧化反应借助于相转移催化剂，则所用的助剂是例如氯化或溴化有机铵例如氯化或溴化苄基三乙基铵，氯化甲基三辛基铵，溴化四丁基铵或氯化三辛基甲基铵(Aliquat 336)。优选氯化和溴化苄基三乙基铵。
环氧化反应在-10℃至+90℃的温度范围内进行，最好是在0℃至+60℃的温度范围内进行。
环氧化反应可在大气压或者加压或减压下(例如在0.5-5巴)进行，最好是在大气压下进行。
通式(IV)化合物本身是已知的，或可用常规方法来制备。
通式(V)和(VI)化合物基本上是已知的[参见EP 528242]。
通式(VII)化合物是新的，可例如通过将相应构型的2-氮杂二环[3.3.0]辛烷-3-羧酸用HF和SF4氟化来制备。
现已令人惊异地发现通式(I)化合物对逆转录病毒有极强的作用。这用HIV-特异性蛋白酶试验得到证实。
下述实施例的效果按照下列文献中所述的HIV测试系统进行测定[参见Hansen，J.，Billich，S.，Schulze，T.，Sukrow，S.和Molling，K.(1988)，EMBOJournal，第7卷，第6期，第1785-1791页]：将精制的HIV蛋白酶与能模拟箝制前体蛋白(gag precursor protein)中的裂解位点并且是HIV蛋白酶在体内的裂解位点的合成肽一起培养。用反相高效液相色谱(RP-HPLC)分析所得到的该合成肽的裂解产物。所显示的IC50值表示在上述试验条件下能对该蛋白酶活性产生50％抑制的物质浓度。酶测定，HIV-1
表I
| 实施例序号 | HIV-1蛋白IC50[mol/l] | 酶甲制作用IC95[mol/l] |
| 1 | 3.0×10-8 | 3.8×10-7 |
| 2 | 2.7×10-10 | 3.6×10-9 |
| 3 | 9.5×10-9 | n.t. |
| 4 | 2.1×10-9 | 3.9×10-9 |
| 5 | 4.1×10-9 | 4.7×10-8 |
| 6 | 2.5×10-8 | 5.0×10-8 |
| 7 | 2.5×10-8 | n.t. |
| 8 | 3.2×10-9 | 4.1×10-8 |
按照本发明的化合物还在慢病毒(lentivirus)感染的细胞培养物中显示出作用。可以以HIV病毒作为实例来显示这一作用。在细胞培养中感染HIV
HIV试验用Pauwels等人的方法[参见Journal of VirologicalMethods 20，(1988)，309-321]进行，略有改动。
用Ficoll-Hypaque富集正常人血淋巴细胞(PBLs)，并在RPMI1640，20％牛胎儿血清中用植物凝血素(90μg/ml)和白介素-2(40U/ml)刺激。为感染HIV，将PBLs制成粒状，然后将此细胞粒悬浮于1ml HIV病毒吸附溶液中，并于37℃培养1小时。
将该病毒吸附溶液离心，并将该感染的细胞粒吸收至生长培养基中，使其浓度达到每毫升1×105个细胞。将用这种方法感染的细胞按1×104个细胞/孔用移液管吸移至96孔微滴板的孔中。
该微滴板的第一纵列只含有生长培养基和未被感染的细胞，然而在别的方面却准确按上述进行了处理(细胞对照组)。微滴板的第二纵列在生长培养基中只含有HIV-感染的细胞(病毒对照组)。其它的孔含有不同浓度的本发明化合物，由微滴板的第三纵列的孔起，试验物质以2倍为一级被稀释210倍。
将各试验组于37℃培养直至在未处理的病毒对照组中出现HIV的特征性的合胞体生成(感染后3至6天之间)，然后用显微镜测定。在未处理的病毒对照组中，在这些试验条件下产生大约20个合胞体，而未处理的细胞对照组未显示出合胞体。
将50％(大约10个合胞体)的病毒诱发的合胞体被用本发明化合物处理所抑制的处理的和感染的细胞的浓度定为IC50值。
现已发现，按照本发明的化合物能保护HIV感染的细胞免受病毒所致细胞破坏。细胞培养测定，PBL
表II
| 实施例序号 | PBLIC50[mol/l] | IC95[mol/l] |
| 1 | 2.2×10-6 | 3.5×10-6 |
| 2 | 2.0×10-6 | 3.5×10-6 |
| 3 | 1.2×10-6 | 1.9×10-6 |
| 4 | ＞1.6×10-5 | n.t. |
| 5 | 1.4×10-5 | 2.2×10-5 |
| 6 | 2.8 ×10-6 | 1.3×10-5 |
| 7 | 6.2×10-6 | n.t. |
| 8 | 1.7×10-5 | ＞2×10-5 |
按照本发明的化合物可作为活性物质用在治疗和预防由逆转录病毒引起的疾病的人用和兽用药中。
可提及的人用药适应症方面的实例有：
1)治疗和预防人逆转录病毒感染。
2)治疗或预防由HIV I(人类免疫缺陷病毒；早期称作HTLVIII/LAV)和HIV II引起的疾病(AIDS)和与此有关的阶段例如ARC(AIDS相关复症)和LAS(淋巴结病综合征)以及由此病毒引起的免疫缺陷和脑病。
3)治疗或预防HTLV-I或HTLV-II感染。
4)治疗或预防AIDS带菌状态(AIDS传递状态)。
可提及的兽用药方面适应症的实例有：
a)梅迪-维斯那病毒感染(绵羊和山羊中)
b)进行性肺炎病毒(PPV)(绵羊和山羊中)
c)山羊关节炎脑炎病毒感染(绵羊和山羊中)
d)泽沃格齐克特病毒感染(绵羊中)
e)传染性贫血(anaemia)病毒感染(马)
f)由猫白血病病毒所致感染
g)由猫免疫缺陷病毒(FIV)所致感染
h)由猿猴免疫缺陷病毒(SIV)所致感染
在人用药方面的适应症中，上述第2、3和4项是优选的。
本发明包括药用制剂和这些制剂的制备方法，所述药用制剂中除无毒、惰性的适宜药用的赋形剂外，还含有一种或多种式(I)化合物，或者该制剂由一种或多种式(I)活性化合物组成。
式(I)活性化合物在上述药用制剂中存在的浓度应为该混合物总重量的大约0.1-99.5％(重量)，优选大约0.5-95％(重量)。
除式(I)化合物外，上述药用制剂还可以含有其它的药用活性化合物。
上述药用制剂按常规方法用已知方法例如将活性化合物(一种或多种)与赋形剂(一种或多种)混合来制备。
业已证明，为获得期望的效果，一般在人用和兽用药方面，每24小时使用所述活性化合物(一种或多种)的总量大约为0.5-500mg/kg，体重有利，优选1-100mg/kg体重，若合适，以多个单剂量形式使用。单剂量最好含约1-80、特别是1-30mg/kg体重活性化合物(一种或多种)。然而，可能有必要改变所述剂量，即根据待治疗的对象的种类和体重、疾病的类型和严重程度、药物的制剂类型和使用形式以及使用药物的时间或间隔改变剂量。
按照本发明的化合物是酶抑制剂，可直接用于可以使用酶抑制剂的所有实用场合。可提及的实例有用作亲和层析的标记，用作测定酶结构和反应机制的助剂，和用作诊断用试剂。
实施例1
(2S，3S)-3-(四氢呋喃-3-基-氧基羰基-L-天冬酰胺酰基)氨基-1-{(S，S，S)-3-三氟甲基-2-氮杂二环[3.3.0]半烷-2-基}-2-羟基-4-苯基丁烷
将0.1g(0.22mmol)(2R，3S)-3-(L-天冬酰胺酰基)氨基-1-{(S，S，S)-3-三氟甲基-2-氮杂二环[3.3.0]辛烷-2-基}-2-羟基-4-苯基丁烷和0.11g(0.44mmol)四氢呋喃-3-基4-硝基苯基碳酸酯(类似于Daniel F.Veber等人，J.Org.Chem.，第42卷，第20期，1977，第3286-3288页)溶于3ml THF中，并在氩气氛下于RT搅拌过夜。然后将混合物蒸发至干，并将残余物用柱层析分离(硅胶60，二氯甲烷/甲醇＝100∶5，Rf＝0.4)。产量：120mg(收率为96.0％)无色泡沫状物。
按类似于实施例1的方法制得表1中所列的化合物：表1
实施例5
(2R，3S)-3-(四氢呋喃-3-基-氧基羰基)氨基-1-{(S，S，S)-3-三氟甲基-2-氮杂二环[3.3.0]半烷-2-基}-2-羟基-4-苯基丁烷
将0.1g(0.29mmol)(2R，3S)-3-氨基-1-{(S，S，S)-3-三氟甲基-2-氮杂二环[3.3.0]辛烷-2-基}-2-羟基-4-苯基丁烷和0.11g(0.44mmol)四氢呋喃-3-基4-硝基苯基碳酸酯(类似于Daniel F.Veber等人，J.Org.Chem.，第42卷，第20期，第3286-3288页)溶于3ml无水THF中，并在氩气氛下于RT搅拌过夜。然后将混合物蒸发至干，并将残余物用柱层析分离(硅胶60；二氯甲烷/乙酸乙酯＝4∶1)。Rf＝0.5(二氯甲烷/乙酸乙酯＝1∶1)产量：50mg(收率为37.5％)无色泡沫状物
按类似于实施例5的方法制得表2中所列的化合物：
表2 
实施例9
(2S，3S)-3-(四氢呋喃-3-基-氧基羰基-L-天冬酰胺酰基)氨基-1-{(S，S，S)-3-三氟甲基-2-氮杂二环[3.3.0]辛烷-2-基}-2-乙酰氧基-4-苯基丁烷
将50mg(0.0876mmol)实施例1化合物、25mg(0.035ml)三乙胺和13mg(0.13mmol)乙酸酐在氩气氛下溶于2ml干燥的四氢呋喃(THF)中，用一刮铲尖的二甲氨基吡啶(DMAP)处理并搅拌过夜。
将混合物真空蒸发至干，并与5ml水和15ml乙酸乙酯一起搅拌。分出有机相，用硫酸钠干燥，并用柱层析分离(硅胶60，洗脱剂：二氯甲烷/乙酸乙酯＝4∶1)。无色结晶，m.p.＝191℃；Rf＝0.4(二氯甲烷/乙酸乙酯＝4∶1)产量：35mg(收率为65.2％)
实施例10
(2S，3S)-3-[四氢呋喃-(3S)-3-基-氧基羰基]-氨基-1-{(S，S，S)-3-三氟甲基-2-氮杂二环[3.3.0]辛烷-2-基}-2-异丁酰氧基-4-苯基丁烷
按类似于实施例9的方法，由50mg(0.11mmol)得自实施例6的化合物、20mg(0.027ml/0.2mmol)三乙胺和15mg(0.14mmol)丁酸酐使用一刮铲尖的二甲氨基吡啶制得标题化合物。无色泡沫状物；Rf＝0.6(二氯甲烷/乙酸乙酯＝4∶1)产量：40mg(收率为69.3％)
Claims (7)
1.通式(I)杂环取代的假肽及其盐
式中R1代表下式基团或R4-O-CO-，式中R3和R4相同或不同，代表下式杂环基团：
或
R2代表氢或具有至多20个碳原子的直链或支链酰基，该酰基可任选地被羧基或者具有至多6个碳原子的直链或支链烷氧基羰基取代。
2.按照权利要求1的通式(I)化合物及其盐，其中R1代表下式基团
或R4-O-CO-，式中R3和R4相同或不同，代表下式杂环基团：或
R2代表氢或具有至多6个碳原子的直链或支链酰基。
3.按照权利要求1的通式(I)化合物及其盐，其中R1代表下式基团或R4-O-CO-，式中R3和R4相同或不同，代表下式杂环基团：或R2代表氢或具有至多5个碳原子的直链或支链酰基。
4.按照权利要求1的通式(I)化合物，其中R2代表氢或具有至多4个碳原子的直链或支链酰基。
5.按照权利要求1的通式(I)化合物的制备方法，其特征在于：使式(II)或(III)化合物
在惰性溶剂中并在碱和/或助剂存在下与通式(IV)化合物反应，若合适，预先将该羧酸活化，所述通式(IV)如下：
R1-OH (IV)式中R1的定义同权利要求1中给出的定义，和在第二步中，若R2≠H，则在惰性溶剂中进行酰化，若合适，在碱和/或助剂存在下进行。
6.含有一种或多种权利要求1至4的化合物的药物。
7.权利要求1至4的化合物在制备抗逆转录病毒药物方面的用途。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19531685A DE19531685A1 (de) | 1995-08-29 | 1995-08-29 | Neue heterocyclisch substituierte Pseudopeptide |
| DE19531685.1 | 1995-08-29 |
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| CN1148042A true CN1148042A (zh) | 1997-04-23 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN96111429A Pending CN1148042A (zh) | 1995-08-29 | 1996-08-29 | 新的杂环取代的假肽 |
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| EP (1) | EP0761667A1 (zh) |
| JP (1) | JPH09124642A (zh) |
| KR (1) | KR970010765A (zh) |
| CN (1) | CN1148042A (zh) |
| AU (1) | AU6421496A (zh) |
| CA (1) | CA2184146A1 (zh) |
| CZ (1) | CZ253396A3 (zh) |
| DE (1) | DE19531685A1 (zh) |
| HR (1) | HRP960376A2 (zh) |
| HU (1) | HUP9602374A3 (zh) |
| IL (1) | IL119136A0 (zh) |
| MX (1) | MX9603722A (zh) |
| NO (1) | NO963598L (zh) |
| PL (1) | PL315851A1 (zh) |
| SK (1) | SK110996A3 (zh) |
| ZA (1) | ZA967278B (zh) |
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| EP1604662A1 (en) * | 2004-06-08 | 2005-12-14 | Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft | 1-[(3R)-Amino-4-(2-fluoro-phenyl)-butyl]-pyrrolidine-(2R)-carboxylic acid benzyl amine derivatives and related compounds as dipeptidyl peptidase IV (DPP-IV) inhibitors for the treatment of type 2 diabetes mellitus |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1340588C (en) * | 1988-06-13 | 1999-06-08 | Balraj Krishan Handa | Amino acid derivatives |
| DE4126485A1 (de) * | 1991-08-10 | 1993-02-11 | Bayer Ag | Trifluormethyl-haltige pseudopeptide |
| WO1993008184A1 (en) * | 1991-10-23 | 1993-04-29 | Merck & Co., Inc. | Hiv protease inhibitors |
-
1995
- 1995-08-29 DE DE19531685A patent/DE19531685A1/de not_active Withdrawn
-
1996
- 1996-08-13 HR HR19531685.1A patent/HRP960376A2/hr not_active Application Discontinuation
- 1996-08-16 EP EP96113160A patent/EP0761667A1/de not_active Withdrawn
- 1996-08-22 AU AU64214/96A patent/AU6421496A/en not_active Abandoned
- 1996-08-22 JP JP8238618A patent/JPH09124642A/ja active Pending
- 1996-08-26 IL IL11913696A patent/IL119136A0/xx unknown
- 1996-08-26 CA CA002184146A patent/CA2184146A1/en not_active Abandoned
- 1996-08-27 PL PL96315851A patent/PL315851A1/xx unknown
- 1996-08-28 SK SK1109-96A patent/SK110996A3/sk unknown
- 1996-08-28 CZ CZ962533A patent/CZ253396A3/cs unknown
- 1996-08-28 MX MX9603722A patent/MX9603722A/es unknown
- 1996-08-28 NO NO963598A patent/NO963598L/no unknown
- 1996-08-28 KR KR1019960036115A patent/KR970010765A/ko not_active Withdrawn
- 1996-08-28 ZA ZA967278A patent/ZA967278B/xx unknown
- 1996-08-29 CN CN96111429A patent/CN1148042A/zh active Pending
- 1996-08-29 HU HU9602374A patent/HUP9602374A3/hu unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PL315851A1 (en) | 1997-03-03 |
| HUP9602374A3 (en) | 1998-01-28 |
| HUP9602374A2 (en) | 1997-09-29 |
| IL119136A0 (en) | 1996-11-14 |
| CZ253396A3 (en) | 1997-03-12 |
| NO963598D0 (no) | 1996-08-28 |
| JPH09124642A (ja) | 1997-05-13 |
| DE19531685A1 (de) | 1997-03-06 |
| KR970010765A (ko) | 1997-03-27 |
| EP0761667A1 (de) | 1997-03-12 |
| ZA967278B (en) | 1997-04-16 |
| NO963598L (no) | 1997-03-03 |
| MX9603722A (es) | 1997-03-29 |
| HU9602374D0 (en) | 1996-10-28 |
| HRP960376A2 (en) | 1998-02-28 |
| SK110996A3 (en) | 1997-03-05 |
| AU6421496A (en) | 1997-03-06 |
| CA2184146A1 (en) | 1997-03-01 |
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