CN1211980A - 吡咯基喹喔啉二酮类化合物,它们的制备及应用 - Google Patents
吡咯基喹喔啉二酮类化合物,它们的制备及应用 Download PDFInfo
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- CN1211980A CN1211980A CN97192480.5A CN97192480A CN1211980A CN 1211980 A CN1211980 A CN 1211980A CN 97192480 A CN97192480 A CN 97192480A CN 1211980 A CN1211980 A CN 1211980A
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- quinoxalindiones
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- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明提供了式Ⅰ吡咯基喹喔啉二酮类化合物及其互变异构和同分异构形式,以及它们的生理上可耐受的盐:其中各变量的定义如下:R1为氢,被羟基或羧基取代的C1－C6－烷基,R2为氢,C1－C6－烷基,C2－C6－链烯基,C2－C6－炔基,氯,氟或溴原子,三卤代甲基,氰基或硝基或SO2－C1－C4－烷基,R3为COOH或为可水解成羧基的基团,n为1或2。
Description
本发明涉及式Ⅰ吡咯基喹喔啉二酮类化合物及其互变异构和同分异构形式，以及它们的生理上可耐受的盐：
其中各变量的定义如下：R1为氢，被羟基或羧基取代的C1-C6-烷基，R2为氢，C1-C6-烷基，C2-C6-链烯基，C2-C6-炔基，氯，氟或溴原子，三卤代甲基，氰基或硝基或SO2-C1-C4-烷基，R3为COOH或为能水解成羧基的基团，n为1或2。
本发明进一步涉及这些化合物的制备方法以及它们在控制疾病方面的应用。
一些文献如EP-A-374534和EP-A-260467中已经公开了一类可用作谷氨酸拮抗剂的式A喹喔啉-2,3(1H,4H)-二酮衍生物：
许多已知衍生物的喹喔啉杂环部分是未取代的(即R1,R2=氢的式A化合物)。此外，人们还已知一些式A中R1为非氢基团的衍生物。例如，EP-A-377112和EP-A-374534中已经公开了一些N-羟基喹喔啉化合物(式A；R1=OR4)。EP-A-315959,DE-A-4135871,WO91/13878以及WO92/07847中已经描述了式A中R1为烷基的衍生物，此烷基链还可被酸，酯或酰胺取代。
取代基R3代表杂环的式A喹喔啉二酮衍生物同样是已知的。例如，EP-A-556393提到了咪唑，三唑和吡唑。EP-A-572852和WO95/35289中公开了R3为吡咯基的喹喔啉二酮衍生物。DE-A-4340045中提到了具有脲基的吡咯衍生物为谷氨酸拮抗剂。
就其药理作用而言，已知的吡咯基喹喔啉二酮类化合物始终仍不能令人完全满意。本发明的目的是提供具有改进活性、同时还具有良好的生理耐受性的吡咯基喹喔啉二酮衍生物。
我们已发现，本发明的这一目的可由本文开头所提及的式Ⅰ吡咯基喹喔啉二酮类化合物实现。
式Ⅰ中的基团R1-R3具有如下含义：
R1为氢或被羟基或羧基取代的直链或支链C1-C6-烷基，如羟乙基或羧甲基。例如，C1-C6-烷基包括甲基，乙基，丙基，异丙基，丁基，仲丁基，叔丁基。对于羟基取代的化合物，烷基优选为C2-C6-烷基。
R2为氢，C1-C6-烷基(如上文提及的基团)，C2-C6-链烯基或-炔基(如乙烯基，乙炔基，丙烯基，异丙烯基)，氟，氯，溴，三卤代甲基(如三氯甲基或三氟甲基)，氰基或硝基，以及SO2-C1-C4-烷基，其中烷基的含义同上。特别优选R2为氢，氯，三氟甲基或硝基。
R3为羧基(COOH)或能水解成羧基的基团(如酰胺基，羧酸酐基或者特别是酯基COOR4，其中R4为C1-C4-烷基，如COOCH3或COOC2H5)。在存在两个邻近羧基时，它们可以形成环酐。考虑到药理作用，特别优选游离COOH或其盐。
变量n为1或2，特别是1。
取代基R3可以位于脲残基的间位、对位或邻位。优选位于对位和/或间位。
特别优选的化合物为这些，其中R1为氢，R2为氢，氯，三氟甲基或硝基，R3为COOH，和n为1或2。
更特别优选的化合物为这些化合物，其中R1为-CH2COOH或-CH2CH2OH，R2为氢，氯，三氟甲基或硝基，R3为COOH，和n为1或2。
本发明化合物Ⅰ可按反应流程1中所示的路线制备。
反应流程1
该流程要求将式Ⅱ氨基取代的喹喔啉二酮与1,4-二羰基化合物或其环状缩醛衍生物(Ⅲ和Ⅵ)反应，脱水得到吡咯Ⅰ和Ⅳ。用于此流程的方法为常规方法，例如，A.R.Katritzky和C.W.Rees“Comprehensive Heterocyclic Chemistry”,Vol.4,Part306,P.313et seq.,C.Ferri,“Reaktionen der organischen Synthese”,Thieme Verlag1978,p.708et seq，或EP-A-572,852和DE-A-4340045中所描述的方法。吡咯合成通常需用酸催化，并在有乙酸或甲苯磺酸存在下进行。如果酸的用量较大，其本身也可用作溶剂。但是，一般习惯在溶剂(如甲苯)或溶剂混合物中进行所述反应，例如在50-150℃，优选100-150℃的温度下在甲苯/二甲基甲酰胺中进行，或者在50℃-沸点的温度下在浓乙酸中进行。
如果所用的二羰基化合物(例如流程1中的化合物Ⅲ)含有氨基，则需要在反应之前对氨基加以保护。这可以使用已知保护基如酰胺，尿烷或苄基，不过优选使用三氟乙酰基。Th.W.Green和P.G.M.Wuts在《有机合成中的保护基》(Wiley&Sons1991)，第7章中描述了其它可能的保护基和保护基的引入方法。吡咯环合成之后，用常规方法除去保护基，得到胺Ⅴ。酰胺保护基的消去优选在10-60℃，更优选20-30℃的温度下，在溶剂或溶剂混合物(如四氢呋喃/水)中采用酸或碱如氢氧化锂来进行。
随后，式Ⅴ胺按照常规方式与异氰酸酯反应，得到本发明式Ⅰ化合物。也可以使用相应的苯胺化合物代替异氰酸酯，在这种情形下，相应的苯胺化合物按照已知方式与光气或类似化合物(如羰基二咪唑)反应，就地产生异氰酸酯。这些方法及其类似方法在例如Houbeh-Wey的“Methoden der organischen Chemie”,Vol.E4,p.334et seq中都有描述。
也可以使用相应的醛来代替酰胺Ⅲ，醛随后可通过还原性胺化作用转化成胺Ⅴ。
利用缩醛Ⅵ，可以由起始物质苯胺化合物Ⅱ直接制得本发明的吡咯基喹喔啉二酮类化合物。这一反应步骤类似于制备吡咯Ⅴ的步骤。
利用酸或碱，可以将脲衍生物Ⅰ中的酯转化为相应的酸。该过程优选在20-30℃下，利用碱(如氢氧化锂)在溶剂混合物(如四氢呋喃/水)中进行。
下表中举例说明的本发明化合物可用上述合成路线制备。
表1:
R3=COOH
| R1 | R2 | n | Position |
| CH2CH2OH | H | 1 | para |
| CH2CH2OH | H | 1 | meta |
| CH2CH2OH | H | 1 | ortho |
| CH2CH2OH | Cl | 1 | para |
| CH2CH2OH | Cl | 1 | meta |
| CH2CH2OH | Cl | 1 | ortno |
| CH2CH2OH | CF3 | 1 | para |
| CH2CH2OH | CF3 | 1 | meta |
| CH2CH2OH | CF3 | 1 | ortho |
| CH2CH2OH | NO2 | 1 | para |
| CH2CH2OH | NO2 | 1 | meta |
| CH2CH2OH | NO2 | 1 | ortho |
| CH2CH2OH | H | 2 | para/meta |
| CH2CH2OH | Cl | 2 | para/meta |
| CH2CH2OH | CF3 | 2 | para/meta |
| CH2CH2OH | NO2 | 2 | para/meta |
| CH2CH(OH)CH3 | H | 1 | para |
| CH2CH(OH)CH3 | H | 1 | meta |
| CH2CH(OH)CH3 | Cl | 1 | para |
| CH2CH(OH)CH3 | Cl | 1 | meta |
| CH2CH(OH)CH3 | CF3 | 1 | para |
| CH2CH(OH)CH3 | CF3 | 1 | meta |
| CH2CH(OH)CH3 | NO2 | 1 | para |
| CH2CH(OH)CH3 | NO2 | 1 | meta |
| CH2CH(OH)CH3 | H | 2 | para/meta |
| CH2CH(OH)CH3 | Cl | 2 | para/meta |
| CH2CH(OH)CH3 | CF3 | 2 | para/meta |
| CH2CH(OH)CH3 | NO2 | 2 | para/meta |
| CH2CH2CH2OH | H | 1 | para |
| CH2CH2CH2OH | H | 1 | meta |
| CH2CH2CH2OH | Cl | 1 | para |
| CH2CH2CH2OH | Cl | 1 | meta |
| CH2CH2CH2OH | CF3 | 1 | para |
| CH2CH2CH2OH | CF3 | 1 | meta |
| R1 | R2 | n | Position |
| CH2CH2CH2OH | NO2 | 1 | para |
| CH2CH2CH2OH | NO2 | 1 | meta |
| CH2CH2CH2OH | H | 2 | para/meta |
| CH2CH2CH2OH | Cl | 2 | para/meta |
| CH2CH2CH2OH | CF3 | 2 | para/meta |
| CH2CH2CH2OH | NO2 | 2 | para/meta |
| CH2CH(OH)CH2CH3 | H | 1 | para |
| CH2CH(OH)CH2CH3 | H | 1 | meta |
| CH2CH(OH)CH2CH3 | Cl | 1 | para |
| CH2CH(OH)CH2CH3 | Cl | 1 | meta |
| CH2CH(OH)CH2CH3 | CF3 | 1 | para |
| CH2CH(OH)CH2CH3 | CF3 | 1 | meta |
| CH2CH(OH)CH2CH3 | NO2 | 1 | para |
| CH2CH(OH)CH2CH3 | NO2 | 1 | meta |
| CH2CH(OH)CH2CH3 | H | 2 | para/meta |
| CH2CH(OH)CH2CH3 | Cl | 2 | para/meta |
| CH2CH(OH)CH2CH3 | CF3 | 2 | para/meta |
| CH2H(OH)CH2CH3 | NO2 | 2 | para/meta |
| CH2CH2CH(OH)CH3 | H | 1 | para |
| CH2CH2CH(OH)CH3 | H | 1 | meta |
| CH2CH2CH(OH)CH3 | Cl | 1 | para |
| CH2CH2CH(OH)CH3 | Cl | 1 | meta |
| CH2CH2CH(OH)CH3 | CF3 | 1 | para |
| CH2CH2CH(OH)CH3 | CF3 | 1 | meta |
| CH2CH2CH(OH)CH3 | NO2 | 1 | para |
| CH2CH2CH(OH)CH3 | NO2 | 1 | meta |
| CH2CH2CH(OH)CH3 | H | 2 | para/meta |
| CH2CH2CH(OH)CH3 | Cl | 2 | para/meta |
| CH2CH2CH(OH)CH3 | CF3 | 2 | para/meta |
| CH2CH2CH(OH)CH3 | NO2 | 2 | para/meta |
| (CH2)4OH | H | 1 | para |
| (CH2)4OH | H | 1 | meta |
| (CH2)4OH | Cl | 1 | para |
| (CH2)4OH | Cl | 1 | meta |
| (CH2)4OH | CF3 | 1 | para |
| (CH2)4OH | CF3 | 1 | meta |
| (CH2)4OH | NO2 | 1 | para |
| (CH2)4OH | NO2 | 1 | meta |
| (CH2)4OH | H | 2 | para/meta |
| (CH2)4OH | Cl | 2 | para/meta |
| (CH2)4OH | CF3 | 2 | para/meta |
| (CH2)4OH | NO2 | 2 | para/meta |
| (CH2)6OH | H | 1 | para |
| (CH2)6OH | H | 1 | meta |
| (CH2)6OH | Cl | 1 | para |
| (CH2)6OH | Cl | 1 | meta |
| (CH2)6OH | CF3 | 1 | para |
| (CH2)6OH | CF3 | 1 | meta |
| (CH2)6OH | NO2 | 1 | para |
| (CH2)6OH | NO2 | 1 | meta |
| R1 | R2 | n | Position |
| (CH2)6OH | H | 2 | para/meta |
| (CH2)6OH | Cl | 2 | para/meta |
| (CH2)6OH | CF3 | 2 | para/meta |
| (CH2)6OH | NO2 | 2 | para/meta |
| CH2COOH | H | 1 | para |
| CH2COOH | H | 1 | meta |
| CH2COOH | H | 1 | ortho |
| CH2COOH | Cl | 1 | para |
| CH2COOH | Cl | 1 | meta |
| CH2COOH | Cl | 1 | ortho |
| CH2COOH | CF3 | 1 | para |
| CH2COOH | CF3 | 1 | meta |
| CH2COOH | CF3 | 1 | ortho |
| CH2COOH | NO2 | 1 | para |
| CH2COOH | NO2 | 1 | meta |
| CH2COOH | NO2 | 1 | ortho |
| CH2COOH | H | 2 | para/meta |
| CH2COOH | Cl | 2 | para/meta |
| CH2COOH | CF3 | 2 | para/meta |
| CH2COOH | NO2 | 2 | para/meta |
| CH2CH2COOH | H | 1 | para |
| CH2CH2COOH | H | 1 | meta |
| CH2CH2COOH | Cl | 1 | para |
| CH2CH2COOH | Cl | 1 | meta |
| CH2CH2COOH | CF3 | 1 | para |
| CH2CH2COOH | CF3 | 1 | meta |
| CH2CH2COOH | NO2 | 1 | para |
| CH2CH2COOH | NO2 | 1 | meta |
| CH2CH2COOH | H | 2 | para/meta |
| CH2CH2COOH | Cl | 2 | para/meta |
| CH2CH2COOH | CF3 | 2 | para/meta |
| CH2CH2COOH | NO2 | 2 | para/meta |
| (CH2)3COOH | H | 1 | para |
| (CH2)3COOH | H | 1 | meta |
| (CH2)3COOH | Cl | 1 | para |
| (CH2)3COOH | Cl | 1 | meta |
| (CH2)3COOH | CF3 | 1 | para |
| (CH2)3COOH | CF3 | 1 | meta |
| (CH2)3COOH | NO2 | 1 | para |
| (CH2)3COOH | NO2 | 1 | meta |
| (CH2)3COOH | H | 2 | para/meta |
| (CH2)3COOH | Cl | 2 | pa.ra/meta |
| (CH2)3COOH | CF3 | 2 | para/meta |
| (CH2)3COOH | NO2 | 2 | para/meta |
本发明化合物为兴奋性氨基酸谷氨酸的拮抗剂，特别是NMDA受体(NMDA=N-甲基-D-天冬氨酸)、AMPA受体(AMPA=2-氨基-3-羟基-5-甲基-4-异恶唑丙酸)和红藻氨酸受体的甘氨酸结合位点的拮抗剂。
在许多神经病性疾病或心理障碍过程中，谷氨酸的活性升高，这样导致中枢神经系统(CNS)处于过度兴奋状态或发生毒性作用。
因此，谷氨酸受体亚型的拮抗剂可用于治疗这些疾病。谷氨酸拮抗剂特别包括NMDA拮抗剂及其调节剂(如甘氨酸拮抗剂)和AMPA拮抗剂，它们适于用作神经变性疾病(如Huntington舞蹈病和Parkinson病)，低氧、缺氧或局部缺血之后的神经毒性失调(如中风后发生的疾病)的治疗药物，或者还可用作抗癫痫药，抗抑郁药和抗焦虑药(参见Arzneim.Forschung40(1990),511-514；TIPS11(1990)334-338和Drugs of the Future14(1989)1059-1071)。
本发明化合物的药理作用采用大鼠大脑离体膜材料加以研究。为达到此目的，在有本发明化合物存在下用放射性标记物质3H-2-氨基-3-羟基-5-甲基-4-异恶唑丙酸(3H-AMPA)，[3H]-甘氨酸或[3H]-红藻氨酸处理膜材料，后三种化合物结合于特定受体(AMPA,NMDA或红藻氨酸受体)。采用闪烁计数法测定处理膜的放射性强度。根据结合放射性，可以测定结合3H-AMPA、[3H]-甘氨酸或[3H]-红藻氨酸的量，或测定每种情形下这些置换的放射性标记物质的量。此方法类似于T.Honore等人在科学241(1988)701-703中描述的方法。
根据这些测定数值，采用IBM计算机统计分析系统(SAS)(类似于P.J.Munson和D.Rodbard(Analytical Biochem.107(1980)220,Ligand:Versatile Computerized Approach for Characterizationof Ligand Binding Systems)的“配体”程序)进行重复非线性回归分析，得到离解常数KI(I=抑制剂)，即本发明化合物的置换作用能力的量度。
按照下面所述进行体外试验：1． 3H-2-氨基-3-羟基-5-甲基-4-异恶唑丙酸(3H-AMAP)的结合
膜材料的制备如下：采用Ultra-Turrax，将新切出的大鼠大脑与15倍体积量缓冲液A一起匀浆，缓冲液A包括30mM三(羟甲基)甲胺盐酸盐(TRIS-HCl)和0.5mM乙二胺四乙酸(EDTA,pH7.4。48000g离心所得悬浮液20分钟。除去上清液，存在于沉降物中的蛋白膜材料通过悬浮到缓冲液A中的方式洗涤三次，每次洗涤之后以48000g离心20分钟。然后将膜材料悬浮在15倍体积量缓冲液A中，在37℃温育30分钟。随后通过离心和悬浮洗涤蛋白物两次，-70℃储存备用。
对于结合测定，在37℃解冻蛋白物，并通过在48000g离心(20分钟)和其后悬浮在缓冲液B中的方式洗涤两次，缓冲液B包括50mMTRIS-HCl,0.1M硫氰酸钾和2.5mM氯化钙，pH7.1。其后将0.25mg膜材料，0.1μCi 3H-AMPA(60Ci/mmol)和化合物Ⅰ溶于1ml缓冲液B内，冰上培养60分钟。培养液通过CF/B滤器(Whatman)过滤(滤器预先用0.5％浓度聚乙烯亚胺水溶液处理至少2小时)。
为将结合和游离的3H-AMPA彼此分离，随后将膜残留物用5ml冷缓冲液B洗涤。通过闪烁计数法测定膜材料中结合3H-AMPA的放射性强度，然后回归分析置换曲线测定KI值。
N-(1-(6-三氟甲基喹喔啉-2,3(1H,4H)-二酮-7-基)吡咯-3-基甲基)-N′-(4-羧基苯基)脲(实施例2)的KI值＜10M。因此，该化合物的活性明显大于D-A-4340045中实施例4所提及的脲衍生物，该衍生物的苯环为未取代的。2． [3H]-甘氨酸的结合
按下所述制备供3H-甘氨酸结合用膜材料：用Potter匀浆器将新切除的大鼠海马在10倍体积量制备缓冲液(50mM Tris-HCl,10mMEDTA)中匀浆。以48000g离心匀浆物20分钟。弃去上清液，通过悬浮和48000g离心(每次20分钟)洗涤沉淀中的膜物质。用液氮冷冻再悬浮膜，并在37℃再次解冻。经另一洗涤步骤后，将膜悬浮液在振荡水浴中于37℃温育15分钟。再经过4次洗涤步骤(每次以48000g离心20分钟并再悬浮在制备缓冲液中)之后，将膜物质在-70℃储存备用。
将冷冻膜物质在37℃解冻，并通过48000g离心(20分钟)接着再悬浮于结合缓冲液(50mM Tris-HCl pH7.4,10mM MgCl2)方式洗涤两次。培养混合物内含有0.25mg蛋白质(膜物质)，25nM 3H-甘氨酸(16Ci/mmol)和位于总量为0.5ml结合缓冲液中的受试物质。加入1mM甘氨酸测定非特异性结合。
在4℃培养60分钟，然后通过GF/B滤器过滤，其后用约5ml冰冷结合缓冲液洗涤，以便将结合及游离的配体彼此分离。利用液体闪烁计数法测定滤器保留的放射性强度。采用重复非线性拟合程序或按照Cheng和Prusoff方程(Biochem.Pharmacol.22(1993)3099)，由置换曲线计算离解常数。3． [3H]-红藻氨酸的结合
按下所述制备供[3H]-红藻氨酸结合用膜材料：利用Ultra-TurraxR将新切除的大鼠大脑在15倍体积量制备缓冲液(30mMTris-HCl-pH7.4-0.5mM EDTA)中匀浆。以48000g离心匀浆物20分钟。弃去上清液，通过再悬浮于制备缓冲液和48000g离心(每次20分钟)形式洗涤存在于沉淀物中的膜物质3次。第三次洗涤步骤之后，将膜物质在-70℃储存备用。
将冷冻膜物质在37℃下解冻，悬浮于结合缓冲液(50mMTris-HCl,pH7.4)并在48000g下离心20分钟。将存在于沉淀中的膜物质再悬浮于结合缓冲液内。一种培养混合物内含有0.25mg蛋白质(膜物质)，0.058Ci(58Ci/mmol)[3H]-红藻氨酸和在总量1ml结合缓冲液中的受试物质。在0.1mM谷氨酸存在下测定非特异性结合。在冰上培养60分钟，然后通过CF/B滤器过滤，其后用5ml冰冷结合缓冲液洗涤，以便将结合和游离的配体彼此分离。CF/B滤器预先用0.5％聚乙烯亚胺处理至少2小时。采用非线性拟合程序或按照Cheng和Prusoff方程，分析置换曲线并计算离解常数。
可以采用下列试验设计的结果来证实本发明新化合物的体内活性：4． 抗惊厥作用(小鼠最大电休克试验)
通过最大电休克诱导小鼠后肢强直性痉挛。用试验化合物预处理可以对抗痉挛发生。这种镇痉作用说明试验化合物有可能用作镇癫药。
试验发现，腹膜内给药N-(1-(1-羧甲基-6-三氟甲基喹喔啉-2,3(1H,4H)-二酮-7-基)吡咯-3-基甲基)-N′-(4-羧基苯基)脲(实施例4)后，其ED50％(=保护50％受试动物的剂量)＜46mg/kg。这表明，本发明化合物的活性明显高于DE-A-4340045中实施例10所记载的脲衍生物。5． 对兴奋性氨基酸引起的大脑过度兴奋的保护作用(体内NMDA和
AMPA拮抗剂，小鼠)
大脑内给药兴奋性氨基酸(EAA)诱导大面积过度兴奋，以导致动物短时间惊厥和死亡。这些症状可通过系统(腹膜内)给药中枢作用EAA拮抗剂而抑制。由于中枢神经系统中的EAA受体的过度活化在各种神经病症的致病机理中起着重要作用，因而有关EAA体内拮抗作用的论证说明，本发明化合物可用于治疗这些类型的CNS病症，包括病灶性和全身性局部缺血，创伤，癫痫以及各种神经变性疾病如Huntington舞蹈病，特别是Parkinson病。
腹膜内给药N-(1-(1-羧甲基-6-三氟甲基喹喔啉-2,3(1H,4H)-二酮-7-基)吡咯-3-基甲基)-N′-(4-羧基苯基)脲(实施例4)后，发现其ED50％(=保护50％受试动物的剂量)＜30mg/kg。这表明，本发明化合物的活性明显高于DE-A-4340045中公开的脲衍生物。6． 对试验性大脑梗塞的(大鼠MCA阻塞；MCA=大脑中动脉)的治
疗作用
大鼠大脑中动脉的永久性阻塞引起试验性大脑梗塞，其程度根据24小时后死亡组织的量测定。试验物质可以减少皮质阻塞的面积，即使在血管阻塞90分钟之后开开始处理也如此。据此可以认为，本发明化合物对人中风具有治疗作用。
本发明化合物适合于治疗其中谷氨酸拮抗剂对其有有益治疗作用的所有病症。
适当的适应症包括神经毒性失调，尤其是中枢神经系统的急性和慢性氧/营养素缺乏状态。这些疾病包括因例如大脑阻塞，蛛网膜下出血或其它起因造成的血管痉挛，以及在诸如心动停止，心律失常或循环性休克中因心血管障碍而发生的缺氧和局部缺血状态；因产期窒息而导致低血糖以及在下列疾病之后引发的CNS损伤：颅脑创伤，脊髓创伤，短暂性缺血发作(TIAs)，延长型可逆局部缺血神经短缺(PRINDs)，多梗塞性痴呆和动脉粥样硬化性痴呆，这些疾病还包括片头痛。
其它可能的适应症为神经变性病症，如Parkinson病，Huntington舞蹈病，Alzheimer病，肌萎缩性侧索硬化(ALS)。
此外，谷氨酸拮抗剂还适于用作镇癫药，抗焦虑药和抗抑郁药，并适合于治疗疼痛，以及用于治疗成瘾者戒断症状性精神分裂症。谷氨酸拮抗剂还适于用作治疗如多发性硬化(MS)中骨骼肌痉挛状态的肌肉松弛药。
本发明的药物组合物中除常规药用助剂外，还包括治疗有效量化合物Ⅰ。
对于外部局部用药的制剂，如撒粉剂和油膏剂，活性成分以常规浓度存在。一般地，活性成分的量为0.0001-1％重量，优选0.001-0.1％重量。
对于体内使用，制剂可以单剂量形式施用。单剂量为0.1-100mg/kg体重。每天可给药一个或多个剂量单位组合物，这取决于病情的性质和严重程度。
适合于所需施用方式，本发明的药物组合物中除活性成分之外，还包括常规赋形剂和稀释剂。对于外部局部使用，可以使用诸如乙醇，异丙醇，乙氧基化蓖麻油，乙氧基化氢化蓖麻油，聚丙烯酸，聚乙二醇，聚乙二醇硬脂酸酯，乙氧基化脂肪醇，液体石蜡，石油醚和羊毛脂之类的药用助剂。适合体内使用的实例有乳糖，丙二醇，乙醇，淀粉，滑石和聚乙烯吡咯烷酮。
其中还可以存在有抗氧化剂如生育酚和丁基化羟基苯甲醚和丁基化羟基甲苯，调味剂，稳定剂，乳化剂和润滑剂。
除活性成分外，组合物中的其它物质，以及生产药物组合物过程中所用的物质都为毒性可接受的，并与特定的活性成分相容。药物组合物用常规方式生产，例如混合活性成分和常规赋形剂和稀释剂。
本发明药物组合物可通过不同途径施用，例如通过口服、非肠道、皮下、腹膜内和局部途径施用。因此，本发明组合物的可能存在形式包括片剂，乳液，输注液和注射液，糊剂，油膏剂，凝胶剂，霜剂，洗剂，撒粉剂和喷雾剂。
实施例实施例1：N′-(4-乙氧羰基苯基)-N-(1-(6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮-7-基)-吡咯-3-基)-甲基脲
a)7-(3-三氟乙酰氨基甲基-1-吡咯基)-1-三氟甲基喹喔啉-2,3-(1H,4H)-二酮
将7.0g(32.8mmol)7-氨基-6-三氟甲基喹喔啉-2,3(1H,4H)-二酮[见EP-A-572852中所述]，和8.5g(33mmol)2,5-二甲氧基-3-三氟乙酰氨基甲基四氢呋喃[见WO95/35289中所述]在200ml冰乙酸中回流20分钟。冷却后，将反应混合物倾入水中，抽滤出所形成的沉淀物，用大量水洗涤，得到9.6g(70％)产物。1H-NMR(D6-DMSO):δ=4.2(2H),6.2(1H),6.8(2H),7.1(1H),7.5(1H),9.9(1H)和约12.5(宽峰)ppm.b)7-(3-氨基甲基-1-吡咯基)-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮
室温下，将9.4g(22.4mmol)实施例1a产物与2.1g(89.5mmol)氢氧化锂在150ml水中搅拌1小时。然后用1M盐酸中和反应混合物，抽滤出所形成的沉淀物，得到6.7g(93％)产物。1H-NMR(D6-DMSO):δ=3.8(2H),6.2(1H),6.8(1H),6.9(1H),7.0(1H)和7.4(1H)ppm.c)N′-(4-乙氧羰基苯基)-N-(1-(6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮-7-基)-吡咯-3-基)-甲基脲
将2g(6.2mmol)实施例1b产物和1.24g(6.5mmol)4-乙氧羰基苯基异氰酸酯在50ml无水二甲基甲酰胺中于50℃搅拌30分钟。然后将反应混合物倾入1M盐酸中，抽滤出所形成的沉淀，得到3.6g(81％)产物。1H-NMR(D6-DMSO):δ=1.3(3H),4.2-4.5(4H),6.2(1H),6.7(1H),6.9(2H),7.1(1H),7.4-8.0(5H),9.1(1H)和约12.5(2H)ppm.实施例2：N′-(4-羧基苯基)-N-(1-(6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮-7-基)-吡咯-3-基)-甲基脲
室温下，将1.6g(3.1mmol)实施例1的化合物和0.3g(12.4mmol)氢氧化锂在40ml水中搅拌2小时。然后过滤混合物，滤液用1M盐酸中和。抽滤出所形成的沉淀物，得到1.1g(74％)产物。1H-NMR(D6-DMSO):δ=4.2(2H),6.2(2H),6.8(2H),7.2(1H),7.4-8.0(5H),9.5(1H)和约12.5(宽峰)ppm.实施例3N-(1-(1-羧甲基-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮-7-基)-吡咯-3-基)-甲基-N′-(4-乙氧羰基苯基)脲
a)N-(2-硝基-4-三氟甲基苯基)草氨酸乙酯
氮气氛下，将51.5g(0.25mol)2-硝基-4-三氟甲基苯胺，45ml(0.32mol)三乙胺和0.1gN,N-二甲氨基吡啶溶于500ml无水四氢呋喃。在0-5℃下，逐滴加入44.4g(0.32mol)草酸一乙酯酰氯。然后在室温下搅拌混合物至转化完全(薄层色谱监测)。减压浓缩后，将残留物分配在水和乙酸乙酯之中。干燥有机相并减压浓缩。粗产物用乙醇重结晶，得到68.2g(89％)产物。1H-NMR(CDCl3):δ=1.5(3H),4.5(2H),8.0(1H),8.6(1H),9.05(1H)和12.2(1H)ppm.b)N-(乙氧羰基甲基)-N-(2-硝基-4-三氟甲基苯基)草氨酸乙酯
氮气氛下，将70g(0.23mol)实施例3a的产物溶于1升无水四氢呋喃中。室温下，分批加入34.8g(0.31mol)叔丁醇钾。搅拌30分钟之后，逐滴加入42.1g(0.25mol)溴乙酸乙酯，并搅拌混合物2小时。然后减压浓缩反应混合物，残留物分批在乙酸乙酯和水之间。干燥有机相并减压浓缩。得到63g(70％)粗产物，并立即进行下一步反应。c)1-(乙氧羰基甲基)-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮
将63g(0.16mol)实施例3b的产物溶于1升乙酸中，并沸腾回流。向此溶液中分批加入54g(0.97mol)铁粉。加热1小时后，冷却反应混合物并过滤。减压浓缩滤液，残留物用水处理。抽滤出所得固体并用乙醇重结晶。得到48.2g(95％)产物。熔点：250-251℃1H-NMR(D6-DMSO):δ=1.25(3H),4.7(2H),5.0(2H),7.5(3H),和12.4(1H)ppm.d)1-(乙氧羰基甲基)-7-硝基-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮
将47g(0.15mol)实施例3c产物溶于500ml浓硫酸中，然后在0℃下分批加入15g(0.149mol)硝酸钾。进一步搅拌反应混合物30分钟，然后倾入冰水中。水相用乙酸乙酯提取，抽滤出所产生的沉淀物，并用乙醇重结晶。得到45.9g(89％)产物。1H-NMR(D6-DMSO):δ=1.25(3H),4.2(2H)；5.0(2H),7.7(1H),8.25(1H)和12.7(1H)ppm.e)7-氨基-1-(乙氧羰基甲基)-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮
将43g(0.12mol)实施例3d产物溶于300ml二甲基甲酰胺中，加入2g钯/碳(10％)，然后在1巴氢气压下室温氢化。随后过滤混合物，并减压浓缩滤液。残留物用乙醇处理，再抽滤，得到37.1g(95％)产物。熔点＞250℃1H-NMR(D6-DMSO):6=1.25(3H),4.2(2H),4.85(2H),5.5(2H),6.6(1H),7.2(1H)和12.0(1H)ppm.f)1-乙氧羰基甲基-7-(3-三氟乙酰氨基甲基-1-吡咯基)-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮
将4.0g(12.1mmol)实施例3e的产物和3.1g(12.1mmol)实施例4a产物在75ml冰乙酸中回流10分钟。然后减压浓缩反应混合物，并用乙醇处理所得残留物，接着抽滤。收率：4.8g(79％)，熔点＞200℃(分解)1H-NMR(D6-DMSO):δ=1.2(3H),4.2(2H),4.3(2H),5.0(2H),6.2(1H),6.8(2H),7.5-7.7(2H),9.9(1H)和12.5(1H)ppm.g)7-(3-氨基甲基-1-吡咯基)-1-羧甲基-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮
将4.7g(9.3mmol)实施例3f的产物加到50ml四氢呋喃中，接着加入75ml 0.5M氢氧化锂溶液。混合物在室温下搅拌1小时。随后减压除去四氢呋喃，所余水相用1M盐酸中和。抽滤出所形成的沉淀物。收率：3.3g(94％)，熔点＞250℃1H-NMR(CD3COOD):δ=4.2(2H),5.0(2H),6.45(1H),6.95(1H),7.1(1H),7.4(1H)和7.8(1H)ppm.h)N-(1-(1-羧甲基-6-三氟甲基喹喔啉-2,3(1H,4H)-二酮-7-基)-吡咯-3-基)-甲基-N′-(4-乙氧羰基苯基)脲
将2g(5.2mmol)实施例3g产物和1.1g(5.8mmol)异氰酸4-乙氧羰基苯酯在30ml无水二甲基甲酰胺中于50℃加热5分钟。然后将反应混合物加到1M盐酸中，抽滤出沉淀物，得到1.8g(69％)产物。1H-NMR(D6-DMSO):
δ=1.3(3H),4.1-4.4(4H),5.0(2H),6.2(1H),6.5(1H),
6.9(2H),7.4-8.0(6H),8.9(1H)和12.5(1H)ppm.实施例4N-(1-(1-羧甲基-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮-7-基)-吡咯-3-基)-甲基-N′-(4-羧基苯基)脲
按照实施例2的方法，反应1.2g(2.1mmol)实施例3的化合物和0.2g(8.6mmol)氢氧化锂，得到1.0g(87％)产物。1H-NMR(D6-DMSO):δ=4.2(2H),4.9(2H),6.2(1H),6.5(1H),6.9(2H),7.4-7.9(6H),8.9(1H)和约12.5(2H)ppm.实施例5N-(1-(1-羧甲基-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮-7-基)-吡咯-3-基)-甲基-N′-(3-乙氧羰基苯基)脲
按照实施例3h的方法，反应2g(5.2mmol)实施例3g产物和1.1g(5.8mmol)并氰酸3-乙氧羰基苯酯，得到1.7g(66％)产物。1H-NMR(D6-DMSO):
δ=1.3(2H),4.2(2H),4.3(2H),4.9(2H),6.2(1H),6.4
(1H),6.9(2H),7.3-7.8(5H),8.1(1H),8.7(1H),12.5
(1H)和约13(宽峰)ppm.实施例6N-(1-(1-羧甲基-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮-7-基)-吡咯-3-基)-甲基-N′-(3-羧基苯基)脲
按照实施例4的方法，反应1.1g(2mmol)实施例5的化合物和0.19g(7.8mmol)氢氧化锂，得到0.9g(82％)产物。1H-NMR(D6-DMSO):δ=4.2(2H),5.0(2H),6.2(1H),6.3(1H),6.9(2H)；7.2-7.7(5H),8.0(1H),8.7(1H),12.5(1H)和约13(宽峰)ppm.实施例7N′-(4-乙氧羰基苯基)-N-(1-(1-(2-羟基乙基)-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮-7-基)-吡咯-3-基)-甲基-脲a)4-(2-羟乙基)氨基-3-硝基-三氟甲基苯
将112.8g(0.5mol)4-氯-3-硝基-三氟甲基苯和61.1g(1mol)2-乙醇胺在50ml二甲基甲酰胺中于100℃加热2小时。然后减压浓缩反应混合物，向残留物中加入水。抽滤出沉淀物，并用环己烷重结晶。收率：116g(46％)，熔点68-70℃1H-NMR(D6-DMSO):δ=3.5(2H),3.7(2H),5.0(1H),7.3(1H),7.8(1H),8.3(1H)和8.6(1H)ppm.b)3-氨基-4-(2-羟乙基)-氨基-三氟甲基苯
将115g(0.46mol)实施例7a产物溶于1升异丙醇中，加入悬浮在200ml水中的11.5g钯/碳(10％)，加热混合物至80℃。然后迅速滴加入91g(1.4mol)甲酸铵的175ml水溶液。反应完成之后，过滤混合物，并减压除去滤液中的乙醇。抽滤出所得沉淀物，用甲苯处理，并再次抽滤。收率：68.4g(68％)，熔点92-94℃1H-NMR(D6-DMSO):δ=3.2(2H),3.6(2H),4.8(1H),4.9(2H),5.1(1H),6.5(1H),和8.6(2H)ppm.c)1-(2-羟乙基)-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮
将60g(0.27mol)实施例7b产物在500ml草酸乙酯中回流3小时。冷却后，抽滤出沉淀物。收率：55g(74％)，熔点275-276℃1H-NMR(D6-DMSO):δ=3.7(2H),4.2(2H),4.9(1H),7.4(1H)和12.2(1H)ppm.d)1-(2-羟乙基)-7-硝基-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮
0℃下，将50g(0.18mol)实施例7c产物溶于500ml浓硫酸中，分批加入21g(0.21mol)硝酸钾。然后搅拌混合物30分钟。随后将反应混合物倾入冰中，抽滤出沉淀物。收率：25g(44％)，熔点254-256℃1H-NMR(D6-DMSO):δ=3.6(2H),4.1(2H),4.5(1H)；7.6(1H)；8.3(1H)和约12(宽峰)ppm.e)7-氨基-1-(2-羟乙基)-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮
如方法7b那样，用50g(0.79mol)甲酸铵还原25g(78mmol)实施例7d产物。收率：13.2g(58％)，熔点278℃(分解)1H-NMR(D6-DMSO):δ=3.6(2H),4.1(H),4.4(宽峰),5.5(2H),6.9(1H),7.1(1H)和11.8(宽峰)ppm.f)N-(2,5-二甲氧基-四氢呋喃-3-基)甲基-N′-(4-乙氧羰基苯基)脲
将2.9g(18mmol)3-氨基甲基-2,5-二甲氧基四氢呋喃(DE-A26 45 234)溶于20ml无水四氢呋喃。0℃下，逐滴加入2.9g(815mmol)异氰酸4-乙氧羰基苯酯的10ml无水四氢呋喃溶液。然后在室温下搅拌混合物1小时，随后减压浓缩，得到5.5g粗产物。1H-NMR(CDCl3):δ=1.4(3H),3.2-3.6(8H),4.4(2H),4.8-5.2(2H),5.9(1H),7.4(2H)和7.9(2H)ppm.g)N′-(4-乙氧羰基苯基)-N-(1-(1-(2-羟基乙基)-6-三氟甲基喹喔啉-2,3(1H,4H)-二酮-7-基)-吡咯-3-基)-甲基-脲
将2.5g(8.7mmol)实施例7e产物和3.4g(9.6mmol)实施例7f产物在50ml冰乙酸中回流15分钟。然后将混合物倾入水中，抽滤出沉淀物，随后通过硅胶色谱纯化，洗脱剂为甲苯/丙酮/冰乙酸=30/20/1，得到1.0g(22％)产物。1H-NMR(D6-DMSO):
δ=1.3(3H),4.2-4.6(8H),6.2(1H)；6.5(1H),6.9(2H),
7.4-8.0(6H),8.9(1H)和约12.5(宽峰)ppm.实施例8
N′-(4-羧基苯基)-N-(1-(1-(2-羟基乙基)-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮-7-基)-吡咯-3-基)-甲基脲
按照实施例4的方法，反应0.66g(1.2mmol)实施例7化合物和0.14g(8.6mmol)氢氧化锂，得到0.6g(89％)产物。1H-NMR(D6-DMSO):δ=3.7(2H),4.2(4H),4.9(1H),6.2(1H),6.5(1H),6.9(2H),7.4-8.0(6H),8.9(1H),12.3(1H)和约12.5(宽峰)ppm.
Claims (12)
1．式Ⅰ吡咯基喹喔啉二酮类化合物或其互变异构和同分异构形式，或其生理上可耐受的盐：
其中各变量的定义如下：
R1为氢，被羟基或羧基取代的C1-C6-烷基，
R2为氢，C1-C6-烷基，C2-C6-链烯基，C2-C6-炔基，氯，氟或溴原子，三卤代甲基-，氰基-或硝基或SO2-C1-C4-烷基，
R3为COOH或为能水解成羧基的基团，
n为1或2。
2．权利要求1的吡咯基喹喔啉二酮类化合物，其中各基团的定义如下：
R1为氢，
R2为氢，氯，三氟甲基或硝基，
R3为COOH。
3．权利要求1的吡咯基喹喔啉二酮类化合物，其中各基团具有下列定义：
R1为-CH2COOH或-CH2CH2OH，
R2为氢，氯，三氟甲基或硝基，
R3为COOH。
4．用于控制疾病的权利要求1-3中任一项所述的式Ⅰ吡咯基喹喔啉二酮类化合物。
5．权利要求1-3中任一项所述的式Ⅰ吡咯基喹喔啉二酮类化合物在生产用于控制中枢神经系统中谷氨酸活性升高的疾病的药物方面的应用。
6．权利要求1-3中任一项所述的式Ⅰ吡咯基喹喔啉二酮类化合物在生产控制因低氧、缺氧或局部缺血造成的氧和营养素缺乏而引起的疾病的药物方面的应用。
7．权利要求1-3中任一项所述的式Ⅰ吡咯基喹喔啉二酮类化合物在生产控制神经变性疾病的药物中的应用。
8．权利要求7中所述的式Ⅰ吡咯基喹喔啉二酮类化合物用于控制Huntington舞蹈病或Parkinson病的应用。
9．权利要求1-3中任一项所述的式Ⅰ吡咯基喹喔啉二酮类化合物在生产用作镇癫痫药的药物中的应用。
l0．权利要求1-3中任一项所述的式Ⅰ吡咯基喹喔啉二酮类化合物在生产用作抗抑郁药、抗焦虑药、肌肉松弛药或防感受伤害药的药物中的应用。
11．供口服、非肠道和腹膜内使用的药物组合物，该组合物的单剂量形式包括每千克体重0.1-100mg至少一种权利要求1-3中所述的吡咯基喹喔啉二酮Ⅰ，以及常规药用助剂。
12．供静脉内使用的药物组合物，该组合物包括0.0001-10％重量至少一种权利要求1-3中所述的吡咯基喹喔啉二酮Ⅰ，和常规药用助剂。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19624808.6 | 1996-06-21 | ||
| DE19624808A DE19624808A1 (de) | 1996-06-21 | 1996-06-21 | Pyrrolylchinoxalindione, ihre Herstellung und Verwendung |
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| CN1211980A true CN1211980A (zh) | 1999-03-24 |
| CN1081636C CN1081636C (zh) | 2002-03-27 |
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| US (1) | US6277850B1 (zh) |
| EP (1) | EP0906306A1 (zh) |
| JP (1) | JP2000513345A (zh) |
| CN (1) | CN1081636C (zh) |
| AU (1) | AU3032397A (zh) |
| DE (1) | DE19624808A1 (zh) |
| WO (1) | WO1997049701A1 (zh) |
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| BR9811739A (pt) * | 1997-09-01 | 2000-09-19 | Kyorin Seiyaku Kk | Derivados de ácido quinoxalinacarbóxilico assimetricamente dissubstituìdo em 6,7, seus sais de adição, e processos para a preparação de ambos |
| EP1100504A2 (en) | 1998-07-02 | 2001-05-23 | Eisai Co., Ltd. | Pharmaceutical compositions and their uses for treatment of demyelinating disorders |
| JP2000309585A (ja) * | 1999-02-26 | 2000-11-07 | Kyorin Pharmaceut Co Ltd | ６−置換ヘテロキノリンカルボン酸誘導体とその付加塩及びそれらの製造方法 |
| JP2000309586A (ja) * | 1999-02-26 | 2000-11-07 | Kyorin Pharmaceut Co Ltd | ６−置換−７−ヘテロキノキサリンカルボン酸誘導体とその付加塩及びそれらの製造方法 |
| US7470718B2 (en) * | 2000-10-03 | 2008-12-30 | Albert Einstein College Of Medicine Of Yeshiva University | Method for treating a demyelinating condition |
| DE10306202A1 (de) * | 2003-02-13 | 2004-08-26 | Grünenthal GmbH | Arzneimittel enthaltend substituierte 2-Aryl-Aminoessigsäure-Verbindungen und/oder substituierte 2-Heteroaryl-Aminoessigsäure-Verbindungen |
| WO2010053757A1 (en) | 2008-10-29 | 2010-05-14 | Gilead Palo Alto, Inc. | 2 -oxoquinoxalin blockers of the late sodium channel |
| US20100113514A1 (en) | 2008-10-30 | 2010-05-06 | Gilead Palo Alto, Inc. | Fused heterocyclic compounds as ion channel modulators |
| US11376294B2 (en) | 2016-07-19 | 2022-07-05 | Nektium Pharma S.L. | Mangiferin-containing compositions for improving sports performance |
| US20220392645A1 (en) * | 2021-06-08 | 2022-12-08 | Exocad Gmbh | Automated treatment proposal |
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| IE66149B1 (en) | 1986-09-16 | 1995-12-13 | Novo Nordisk As | Quinoxaline compounds and their preparation and use |
| NO179551C (no) | 1987-11-10 | 1996-10-30 | Novo Nordisk As | Analogifremgangsmåte for fremstilling av terapeutisk virksomme kinoxalinforbindelser |
| DK716188D0 (da) | 1988-12-22 | 1988-12-22 | Ferrosan As | Quinoxalinforbindelser, deres fremstilling og anvendelse |
| DK715888D0 (da) | 1988-12-22 | 1988-12-22 | Ferrosan As | Quinoxalinforbindelser, deres fremstilling og anvendelse |
| DK69790D0 (da) | 1990-03-16 | 1990-03-16 | Novo Nordisk As | Heterocykliske forbindelser, deres fremstilling af anvendelse |
| EP0556393B1 (en) | 1990-11-06 | 2000-07-26 | Yamanouchi Pharmaceutical Co. Ltd. | Fused pyrazine derivative |
| DE4135871A1 (de) | 1991-10-26 | 1993-04-29 | Schering Ag | Chinoxalinderivate, deren herstellung und verwendung in arzneimitteln |
| PT101004B (pt) | 1991-10-26 | 1999-10-29 | Schering Ag | Derivados da quinoxalina, processo para a sua preparacao e composicoes farmaceuticas que os contem |
| DE4217952A1 (de) | 1992-05-30 | 1993-12-02 | Basf Ag | Chinoxalin-2,3(1H,4H)-dione |
| DE4340045A1 (de) * | 1993-11-24 | 1995-06-01 | Basf Ag | Neue Chinoxaline und Arzneimittel daraus |
| DE4428152A1 (de) * | 1994-06-22 | 1996-01-04 | Basf Ag | Neue Amido-chinoxalindione, ihrer Herstellung und Verwendung |
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1996
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1997
- 1997-06-05 JP JP10502186A patent/JP2000513345A/ja active Pending
- 1997-06-05 CN CN97192480A patent/CN1081636C/zh not_active Expired - Fee Related
- 1997-06-05 AU AU30323/97A patent/AU3032397A/en not_active Abandoned
- 1997-06-05 EP EP97925046A patent/EP0906306A1/de not_active Withdrawn
- 1997-06-05 WO PCT/EP1997/002913 patent/WO1997049701A1/de not_active Application Discontinuation
- 1997-06-05 US US09/202,153 patent/US6277850B1/en not_active Expired - Fee Related
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| WO1997049701A1 (de) | 1997-12-31 |
| EP0906306A1 (de) | 1999-04-07 |
| JP2000513345A (ja) | 2000-10-10 |
| DE19624808A1 (de) | 1998-01-02 |
| AU3032397A (en) | 1998-01-14 |
| CN1081636C (zh) | 2002-03-27 |
| US6277850B1 (en) | 2001-08-21 |
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