CN1128991A - N-取代的氮杂环羧酸及其酯 - Google Patents
N-取代的氮杂环羧酸及其酯 Download PDFInfo
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- CN1128991A CN1128991A CN94193060A CN94193060A CN1128991A CN 1128991 A CN1128991 A CN 1128991A CN 94193060 A CN94193060 A CN 94193060A CN 94193060 A CN94193060 A CN 94193060A CN 1128991 A CN1128991 A CN 1128991A
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- Prior art keywords
- compound
- phenyl
- formula
- carboxylic acid
- ethyl
- Prior art date
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- 150000002148 esters Chemical class 0.000 title description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims abstract description 15
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
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Abstract
本发明涉及有治疗活性的通式(I)氮杂环化合物,该化合物的制备方法,以及含有该化合物的药物组合物。这类新型化合物可用于治疗与GABA摄取有关的中枢神经系统失调。在通式(I)中,A是一个饱和或不饱和的5元或6元碳环,任选地可被一个苯基、亚苄基、苯基取代的C1-4烷基或苯基取代的C2-4链烯基取代,所述苯基或亚苄基可任选地被卤素、C1-4烷基、C1-4烷氧基或三氟甲基取代,且所述饱和或不饱和的5元或6元碳环可以任选地与一个苯并环稠合。
Description
发明领域
本发明涉及新型N-取代的氮杂环羧酸及其酯,其中一条有取代的烷基链形成该N-取代基及其盐的组成部分,涉及其制备方法,涉及含有这类化合物的组合物,及其在临床治疗γ-氨基丁酸神经传导系统的功能异常方面的用途。
发明背景
近年来,关于γ-氨基丁酸(以下简称GABA)这种哺乳动物中枢神经系统中的抑制性神经传递质,已经进行了大量药理学研究。
GABA摄取的抑制导致这种抑制性神经传递质在突触裂中的可得性提高,从而提高GABA能的活性(ergic activity)。GABA能的活性的提高可能有利于治疗诸如焦虑、疼痛和癫痫,以及肌肉和运动失调(例如,参阅P.Krogsgaard-Larsen et al.,Progress inMedicinal Chemistry,1985,22,68-112)。
从突触裂进入前突触神经末稍和胶质细胞的GABA摄取的一种众所周知和强力抑制剂,是诸如3-哌啶羧酸(3-哌啶甲酸)。然而,由于是一种相当极性的化合物,因而不能穿越血-脑屏障,3-哌啶羧酸本身不能发挥作为药物的实际效用。
在美国专利No.4,383,999和No.4,514,414以及EP236342和EP231996中,提出了N-(4,4-二取代-3-丁烯基)氮杂环羧酸的一些衍生物作为GABA摄取抑制剂的专利权。在EP342635和EP374801中,提出了肟醚基和乙烯醚基分别构成其N-取代基组成部分的N-取代杂环羧酸作为GABA摄取抑制剂的专利权。此外,在WO9107389和WO9220658中,提出了N-取代氮杂环羧酸作为GABA摄取抑制剂的专利权。EP221572声称1-芳氧烷基吡啶-3-羧酸是GABA摄取抑制剂。
按照Yunger,L.M.et al.,J.Pharm.Exp.Ther.,1984,228,109,N-(4,4-二苯基-3-丁烯-1-基)3-哌啶甲酸(取名为SK&F 89976A),N-(4,4-二苯基-3-丁烯-1-基)四氢烟酸(取名为SK&F 100330A),N-(4,4-二苯基-3-丁烯-1-基)高-β-脯氨酸(取名为SK&F 100561)和N-(4-苯基-4-(2-噻吩基)-3-丁烯-1-基)3-哌啶甲酸(取名为SK&F 100604J)是经口活性的GABA摄取抑制剂。这些资料已综合于Krogsgaard-Larsen,P.et al.,Epilepsy Res.,1987,1,77-93。
发明描述
式中:
A是一个饱和或不饱和的5元或6元碳环,任选地可被一个苯基、亚苄基、苯基取代的C1-4烷基或苯基取代的C2-4链烯基取代,所述苯基或亚苄基可任选地被卤素、C1-4烷基、C1-4烷氧基或三氟甲基取代,且所述饱和或不饱和的5元或6元碳环可以任选地与一个苯并环稠合;
R1和R2代表氢,或可合在一起代表一个键;
X是羟基或C1-4烷氧基;
n是2、3、4或5;或其药物上可接受的盐。
通式I的化合物可以作为几何异构体和光学异构体存在,所有异构体及其混合物均包括在本发明范围内。异构体可借助于标准方法如色谱技术或适用盐的分级结晶进行分离。
按照本发明的化合物可从任选地以药物上可接受的酸加成盐形式存在,或当羧酸基团未被酯化时以药物上可接受金属盐形式存在,或任选地被烷基化时以铵盐形式存在。
这样的盐的实例包括无机酸和有机酸加成盐,例如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、乙酸盐、酞酸盐、富马酸盐、马为酸盐、柠檬酸盐、乳酸盐、酒石酸盐、草酸盐,或类似的药物上可接受的无机酸或有机酸加成盐,并包括列为本文参考文献的Tournal ofPharmaceutical Science,66,2(1977)中所列的药物上可接受的盐。
在本发明的一个较好实施方案中,C1-4烷基是甲基或乙基,C2-4链烯基是亚乙基,C1-4烷氧基是甲氧基或乙氧基,X包括甲氧基、乙氧基、异丙氧基或正丙氧基,且n包括2或3。
通式I化合物比无N-取代基的母体化合物(即哌啶甲酸和四氢烟酸)有更大的亲油性,因而对大脑有更大的有效性。
业已证明,对从突触裂摄取GABA有抑制作用的通式I新型化合物之所以在中枢神经系统中具有有用的药理学性质,是因为它们引起GABA的能活性的选择性增强。通式I化合物可以用来治疗诸如疼痛、焦虑、嘧啶过多性运动障碍、癫痫和某些肌肉与运动失调。它们也可用作镇静剂、安眠药和抗抑郁药。
通式I化合物是用如下方法制备的:
通式II的化合物,式中A的定义同上,可以与通式III的氮杂环化合物反应,式中R1、R2、n和X的定义同上,且Z是一个适用离去基团如卤素、对甲苯磺酸根或甲磺酸根。这个烷基化反应可以在一种溶剂如丙酮、二丁基醚、2-丁酮、四氢呋喃、甲基异丁基酮或甲苯中,在一种碱如碳酸钾的存在下,在可高达所用溶剂的回流温度的温度,进行诸如1~120小时。如果已制备了其中X为烷氧基的酯,则其中X为OH的通式I化合物可以通过该酯基的水解来制备,较好在室温下,在碱金属氢氧化物水溶液和醇如甲醇或乙醇的混合物中进行诸如约0.5~6小时。
通式II的化合物可以容易地用技术熟练人员所熟悉的方法制备。通式III的化合物可以按照EP374801中描述的步骤制备。
在某些情况下,可能有必要用适用的保护基团来保护以上方法中使用的中间体,如通式III的化合物。例如,可以使该羧酸基团酯化。这样的基团的引进和脱除详见“Protective Groups in OrganicSynthesis”,T.W.Greene and P.G.M.Wuts,2ed.(John Wiley,1991)。
药理学方法
本发明化合物的[3H]-GABA摄取的离体抑制值基本上是用Fjalland的方法(Acta Pharmacol.Toxicol.1978,42,73-76)评价的。
雄性Wistar品系大鼠皮质组织用一台玻璃/PTFE匀化器,以10倍体积的0.32M蔗糖,用手徐徐匀化。用一种含有120nM NaCl、9.2nM KCl、4mM MgSO4、2.3nMCaCl2和10mM葡萄糖的40mMTRIS HCl缓冲剂(30℃ pH7.5)在30℃培养60分钟。
表1列出了一些代表性化合物的GABA摄取抑制值。
表1
[3H]-GABA摄取抑制值
实例号 离体IC50(μM)
1 332
2 417
3 9500
4 819
5 1380
对于以上指示值,剂量将因所采用的通式I化合物、给药方式和所希望的治疗而异。然而,一般来说,能得到令人满意的结果的剂量是约0.5mg~约1000mg、较好约1mg~约500mg通式I化合物,方便地每天给药1~5次,任选地以缓释形式。通常,适用于经口给药的剂量形式包含与药物载体或稀释剂掺合的约0.5mg~约1000mg、较好约1mg~约500mg通式I化合物。
通式I化合物可以以药物上可接受的酸加成盐形式,或在可能的情况下以金属盐或低级烷基铵盐形式给药。
本发明也涉及含有通式I化合物或其药物上可接受的盐的药物组合物,且通常这样的组合物也含有药物载体或稀释剂。含有本发明化合物的组合物可以用常用技术制备,并呈常用形式,例如胶囊、片剂、溶液或悬浮液。
采用的药物载体可以是常用固体载体或液体载体。固体载体的实例是乳糖、白土、蔗糖、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁和硬脂酸。液体载体的实例是糖浆、花生油、橄榄油和水。
类似地,载体或稀释剂可以包括任何一种技术上已知的延时材料,例如,甘油基一硬脂酸酯或甘油基二硬脂酸酯,单独或与蜡混合使用。
如果使用经口给药用的固体载体,则该制剂可制成片剂、以粉末或小丸形式放进硬胶囊胶中,也可以将其制成含片或糖锭形式。固体载体的用量差异很大,但通常将是约25mg~约1g。如果使用液体载体,则该制剂可制成糖浆、乳液、软胶囊或无菌可注射液体如水或非水液体悬浮液或溶液剂等形式。
一般来说,本发明的化合物是配制成单元剂量形式的,每单元剂量包含50~200mg活性组分或同时含有药物上可接受的载体。
按照本发明的化合物的剂量,当以药物形式对患者如人给药时,是1~500mg/日,例如,每剂约100mg。
一种可通过常用压片技术制备的典型片剂包含:
片芯:
活性化合物(游离化合物或其盐) 100mg
胶体二氧化硅(Aerosil) 1.5mg
微晶纤维素(Avicel) 70mg
改性纤维素胶(Ac-Di-Sol) 7.5mg
硬脂酸镁
包衣:
HPMC 大约9mg
*Mywacett9-40T 大约0.9mg
*酰化单甘油酯,用作薄膜包衣增塑剂。
给药途径可以是能有效地将该活性化合物输送到适当或预期作用部位的任何一种途径,例如经口或非经肠,如经直肠、经皮、经皮下、经静脉内、经肌内或经鼻内,较好是经口途径。
实例
以下实例进一步说明通式I化合物的制备方法,然而不要将其理解为限制。
下文中,TLC是薄层色谱法,THF是四氢呋喃,CDCl3是氘化氯仿,DMSO-d6是六氘二甲基亚砜。这些化合物的结构或者用元素分析法或者用NMR(核磁共振法)证实,在此情况下,只要适当,就列出标题化合物中特征质子对应的峰。NMR位移(δ)用ppm表示。M.p.是熔点,用℃表示。柱色谱法是用W.C.Still et al.,J.Org.Chem.,1978,43,2923-2925所述的技术(Art.9385)用Merck硅胶60进行的。用作起始原料的化合物或者是已知化合物,或者是可以容易地用本身已知的方法制备的化合物。
实例1
(R)-1-(2-(((2-苯基亚环己基)氨基)氧乙基)-3-哌啶羧酸盐酸盐
往搅拌着的2-苯基环乙酮(5.0g,29mmol)和氯化羟胺(6.0g,86mmol)在乙醇(20ml)和水(10ml)的混合物中的悬浮液中加入碳酸钾(11.9g,86mmol)的水(50ml)溶液。反应混合物在室温下搅拌5小时,过滤分离出沉淀;然后用水洗涤。在空气中干燥后得到5.1g固体状2-苯基环乙酮肟,m.p.159-160℃。
将上面的肟(2.0g,11mmol)、(R)-1-(2-溴乙基)-3-哌啶羧酸乙酯氢溴酸盐(3.7g,11mmol,EP374801)、碳酸钾(4.6g,33mmol)和丙酮(50ml)的混合物在室温下搅拌6天。将混合物过滤,溶剂进行真空蒸发。残留物用柱色谱法在硅胶上提纯两次(环己烷/乙酸乙酯,梯度3/1-1/1)得到0.65g(R)-1-2-(((2-苯基亚环己基)氨基)氧)乙基)-3-哌啶羧酸乙酯油状物。
将上面的酯(0.6g,1.6mmol)溶解在乙醇(5ml)中,加入4N氢氧化钠(1.6ml)。将混合物在室温下搅拌20小时,放在冰浴上,然后加入过量的浓盐酸。将混合物进行真空浓缩,然后加入二氯甲烷(300ml)。将各相分离,有机相用水(5ml)洗涤,然后干燥(MgSO4)。经真空蒸发掉溶剂后得到0.52g无定形固体标题化合物。M.p.43-45℃.计算值C20H28N2O3·HCl·1/4H2O:C,62.3%;H,7.7%;N,7.3%;实测值:C,62.4%;H,7.8%;N,7.2%。
实例2
(R)-1-(2-(((2-苯基亚环己-2-烯基)氨基)氧)乙基-3-哌啶羧酸盐酸盐
将2-苯基-2-环乙烯-1-酮(0.6g,3.5mmol,Tetrahedron1972,28,2369)、氯化羟铵(0.5g,7mmol)和无水吡啶(15ml)的混合物加热回流3小时。主反应混合物冷却,溶剂进行真空蒸发。将残留物溶于乙酸乙酯和水的混合物中。加入10%柠檬酸溶液直至显酸性pH为止,然后分离两相。有机相用10%柠檬酸溶液萃取,然后干燥(MgSO4)。在真空中蒸发掉溶剂后得到0.55g 2-苯基-2-环己烯-1-酮肟。m.p.144-146℃。
将上面的肟(0.55g,2.9mmol)、(R)-1-(2-溴乙基)-3-哌啶羧酸乙酯氢溴酸盐(1.0g,2.9mmol,EP374801A)、碳酸钾(1.0g,7.3mmol)和丙酮(25ml)的混合物在室温下搅拌14天。将混合物过滤,溶剂进行真空蒸发。残留物用柱色谱法在硅胶125g,(庚烷/乙酸乙酯=1∶1)上提纯得到0.4g(R)-1-(2-(((2-苯基亚环己2-烯基)氨基)氧)乙基-3-哌啶羧酸乙酯油状物。
将上面的酯(0.4g,1.1mmol)溶解在乙醇(10ml)中,然后加入4N氢氧化钠(1ml)。该混合物在室温下搅拌3小时,然后加入过量的浓盐酸,接着加入二氯甲烷(400ml)。该悬浮液用MgSO4干燥,溶剂经真空蒸发。残留物与丙酮一起再蒸发,将其溶于丙酮(10ml)中,进行重结晶,得到1.7g固体标题化合物。M.p.171-172℃.计算值C20H25N2O3·HCl·1/4H2O:C,62.7%;H,7.2%;N,7.3%;实测值:C,63.0%;H,7.4%:N,6.9%。
实例3
(R)-1-(2-(((2-(亚苄基)亚环己基)氨基)氧)乙基)-3-哌啶羧酸盐酸盐
将2-亚苄基环己酮(3.5g,18.8mmol,J.Chem.Soc.1949,2957)、氯化羟铵(3.9g,56mmol)和乙醇(50ml)的混合物在室温下搅拌3天,在真空下蒸发掉溶剂,将残留物溶于乙酸乙酯(200ml)和水(50ml)的混合物中。将两相分离,水相用乙酸乙酯(50ml)萃取。合并的有机萃取物用水洗涤,用MgSO4干燥。在真空中蒸发掉溶剂后得到3.7g固体状2-亚苄基环己酮肟。m.p.114-115℃。
将上面的肟(3.7g,18.4mmol)、(R)-1-(2-溴乙基)-3-哌啶羧酸乙酯氢溴酸盐(7.0g,20.2mmol,EP374801)、碳酸钾(10.2g,73.5mmol)和丙酮(150ml)的混合物在室温下搅拌11天。将混合物过滤,溶剂进行真空蒸发。残留物用柱色谱法在硅胶(200g,庚烷/乙酸乙酯=3/2)上提纯得到2.5g(R)-1-(2-(((2-(亚苄基)亚环己基)氨基)氧)乙基)-3-哌啶羧酸乙酯油状物。
将上面的酯(2.5g,6.5mmol)溶解在乙醇(20ml)中,然后加入4N氢氧化钠(4.9ml)。该混合物在室温下搅拌3小时,然后加入过量的浓盐酸,接着加入二氯甲烷(300ml)和水(15ml)。将两相分离,有机相用MgSO4干燥,溶剂经真空蒸发。残留物与丙酮一起再蒸发,然后用丙酮(180ml)重结晶,得到1.5g固体标题化合物。M.p.116℃分解.计算值C21H30N2O3·HCl:C,63.9%;H,7.9%;N,7.1%;实测值:C,63.9%:H,7.6%;N,6.9%。
实例4
(R)-1-(2-(((2-苯基-1,2,3,4-四氢-1-亚萘基)氨基)氧)乙基)-3-哌啶羧酸盐酸盐
将2-苯基-1-四氢萘酮(1.1g,5mmol,J.Am.Chem.Soc.1949,71,1092)、氯化羟铵(0.7g,10mmol)和无水吡啶(30ml)的混合物加热回流4小时,然后在室温下搅拌过夜。在真空中蒸发掉溶剂后将残留物在乙酸乙酯(50ml)和10%柠檬酸(50ml)的混合物中搅拌。将两相分离,有机相用水洗涤,然后用MgSO4干燥。在真空中蒸发掉溶剂后得到1.2g固体状2-苯基-1-四氢萘酮肟。m.p.156-157℃。
将上面的肟(1.0g,4.2mmol)、(R)-1-(2-溴乙基)-3-哌啶羧酸乙酯氢溴酸盐(2.2g,6.3mmol,EP374801)、碳酸钾(1.5g,11mmol)和丙酮(25ml)的混合物在室温下搅拌10天。将混合物过滤,溶剂进行真空蒸发。残留物用柱色谱在硅胶(150g,庚烷/乙酸乙酯=7/3)上提纯得到0.6g(R)-1-(2-(((2-苯基-1,2,3,4-四氢-1-亚萘基)氨基)氧)乙基)-3-哌啶羧酸乙酯油状物。
将上面的酯(0.6g,1.51mmol)溶解在乙醇(10ml)中,然后加入4N氢氧化钠(1.1ml)。该混合物在室温下搅拌4小时,然后加入过量的浓盐酸,接着加入二氯甲烷(300ml)。混合物用MgSO4干燥,溶剂经真空蒸发。得到的残留物与丙酮一起再蒸发,然后用丙酮重结晶,得到0.5g固体标题化合物。M.p.160-162℃.计算值C24H28N2O3·HCl·H2O:C,66.5%;H,6.9%;N,6.5%;实测值:C,66.4%;H,6.8%;N,6.1%。
实例5
(R)-1-(2-(((3-苯基-1-(2,3-二氢化亚茚基))氨基)氧)乙基)-3-哌啶羧酸盐酸盐
将3-苯基-1-(2,3-二氢茚酮)(4.2g,20mmol,J.Chem.Soc.1949,2957)、氯化羟铵(2.8g,40mmol)和吡啶(30ml)的混合物加热回流加夜。让反应混合物冷却,在真空中蒸发掉溶剂。将残留物溶于乙酸乙酯中,然后用过量的10%柠檬酸溶液洗涤。有机相用MgSO4干燥。在真空中蒸发掉溶剂后得到的固体物用环己烷和乙酸乙酯的混合物研制。过滤分离出固体物,在空气中干燥后得到2.8g3-苯基-1-(2,3-二氢茚酮肟)。m.p.123-125℃。
将上面的肟(1.1g,5mmol)(R)-1-(2-溴乙基)-3-哌啶羧酸乙酯氢溴酸盐(1.7g,5mmol,EP374801)、碳酸钾(1.7g,13mmol)和丙酮(25ml)的混合物在室温下搅拌11天。将混合物过滤,溶剂进行真空蒸发。残留物用柱色谱法在硅胶(100g,庚烷/乙酸乙酯=1/1)上提纯得到1.1g(R)-1-(2-(((3-苯基-1-(2,3-二氢化亚茚基)氨基)氧)乙基)-3-哌啶羧酸乙酯油状物。
将上面的酯(0.6g,1.5mmol)溶解在乙醇(15ml)中,然后加入4N氢氧化钠(1.1ml)。该混合物在室温下搅拌5小时,然后加入过量的浓盐酸,接着加入二氯甲烷(300ml)。将两相分离,有机相用MgSO4干燥,溶剂经真空蒸发。将残留物溶于丙酮(15ml)中,进行重结晶,得到0.6g固体标题化合物。M.p.204-205℃,计算值C23H26N2O3·HCl:C,66.6%;H,6.6%;N,6.8%;实测值:C,66.3%;H,6.6%:N,6.4%。
Claims (9)
1.式I的化合物或其药物上可接受的盐:
式中:
A是一个饱和或不饱和的5元或6元碳环,任选地可被一个苯基、亚苄基、苯基取代的C1-4烷基或苯基取代的C2-4链烯基取代,所述苯基或亚苄基可任选地被卤素、C1-4烷基、C1-4烷氧基或三氟甲基取代,且所述饱和或不饱和的5元或6元碳环可以任选地与一个苯并环稠合;
R1和R2代表氢,或可合在一起代表一个键;
X是羟基或C1-4烷氧基;
n是2、3、4或5。
2.按照权利要求1的化合物,该化合物是:
(R)-1-(2-(((2-苯基亚环己基)氨基)氧)乙基)-3-哌啶羧酸;
(R)-1-(2-(((2-苯基亚环己-2-烯基)氨基)氧)乙基)-3-哌啶羧酸;
(R)-1-(2-(((2-亚苄基)亚环己基)氨基)氧)乙基)-3-哌啶羧酸;
(R)-1-(2-(((2-苯基-1,2,3,4-四氢-1-亚萘基)氨基)氧)乙基)-3-哌啶羧酸;
(R)-1-(2-(((3-苯基-1-(2,3-二氢化亚茚基)氨基)氧)乙基)-3-哌啶羧酸;
或这些化合物的药物上可接受的盐。
4.以按照权利要求1的化合物为活性成分同时含有药物上可接受的载体或稀释剂的药物组合物。
5.含有有效量的权利要求1的化合物和药物上可接受的载体或稀释剂、适用于治疗与GABA摄取有关的中枢神经系统失调的药物组合物。
6.按照权利要求4或5的药物组合物,其中每单元剂量含有0.5mg~1000mg按照权利要求1的化合物。
7.对需要治疗的患者进行与GABA摄取有关中枢神经系统失调的治疗的方法,包括对所述患者施用有效量的按照权利要求1的化合物。
8.对需要治疗的患者进行与GABA摄取有关的中枢神经系统失调的治疗的方法,包括对所述患者施用按照权利要求5的药物组合物。
9.按照权利要求1的化合物用于制备治疗与GABA摄取有关的中枢神经系统失调的药剂的用途。
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FI (1) | FI956175A (zh) |
HU (1) | HUT73242A (zh) |
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DK93791D0 (da) * | 1991-05-17 | 1991-05-17 | Novo Nordisk As | Nye heterocykliske carboxylsyrer |
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1993
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1994
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- 1994-06-22 CZ CZ953355A patent/CZ335595A3/cs unknown
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- 1994-06-22 WO PCT/DK1994/000251 patent/WO1995000484A1/en not_active Application Discontinuation
- 1994-06-22 US US08/263,863 patent/US5639766A/en not_active Expired - Fee Related
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CA2165948A1 (en) | 1995-01-05 |
WO1995000484A1 (en) | 1995-01-05 |
ZA944468B (en) | 1995-12-22 |
HUT73242A (en) | 1996-07-29 |
AU6996094A (en) | 1995-01-17 |
DK74493D0 (da) | 1993-06-23 |
BG100245A (en) | 1996-05-31 |
CZ335595A3 (en) | 1996-07-17 |
NO955261L (no) | 1996-02-22 |
IL110076A0 (en) | 1994-10-07 |
FI956175A0 (fi) | 1995-12-21 |
HU9503754D0 (en) | 1996-02-28 |
US5639766A (en) | 1997-06-17 |
FI956175A (fi) | 1996-02-21 |
JPH08511781A (ja) | 1996-12-10 |
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