CN1170584C - 利用精氨酸衍生物增强噁唑烷酮抗菌剂的活性 - Google Patents
利用精氨酸衍生物增强噁唑烷酮抗菌剂的活性 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明提供利用一种精氨酸衍生物增强噁唑烷酮抗菌剂的抗革兰氏阴性生物感染的功效的方法和组合物。
Description
发明领域
本发明涉及利用一种精氨酸衍生物增强噁唑烷酮抗菌剂的抗革兰氏阴性生物功效的方法和组合物。
发明背景
噁唑烷酮抗菌剂是一类新颖的合成抗微生物剂，具有强有力的抗多种人和动物病原体的活性，包括革兰氏阳性需氧菌，例如多耐受性葡萄球菌和链球菌，厌氧生物，例如拟杆菌和梭状芽胞杆菌类，和耐酸性生物，例如结核分枝杆菌和鸟分枝杆菌。特别是已经发现结构I-V的噁唑烷酮化合物是尤其有效的。
不过，某些噁唑烷酮在有用的浓度下，抗需氧的革兰氏阴性生物的活性一般较差，例如大肠埃希氏杆菌、流感嗜血菌、粘膜炎莫拉氏菌、铜绿假单胞菌或肺炎克雷伯氏菌。因此，这些噁唑烷酮抗菌剂的单独使用仅限于由革兰氏阳性菌引起的感染状态。因此，本发明的目的之一是提供用于增强噁唑烷酮抑菌谱的方法。我们现已发现，当噁唑烷酮抗菌剂与一种精氨酸衍生物给药时，产生显著的抗革兰氏阴性生物的协同作用。噁唑烷酮抗菌剂完全有效地抗需氧革兰氏阴性生物的有效量大大低于噁唑烷酮不与这些精氨酸衍生物一起给药时所需的量。
信息的公开
国际专利公报WO96/33285公开了用于筛选微生物外向通量泵抑制剂的方法，包括输出抗生素的那些。该筛选方法是当细菌细胞与外向通量泵抑制剂接触时，以一种化合物的细胞内浓度为基础的，例如抗生素或染料。另外，该发明提供了药物组合物，含有这样的外向通量泵抑制剂，包括某些精氨酸衍生物，还提供了用于治疗微生物感染和增强某些抗微生物剂的抗微生物活性的方法。
由Pharmacia and Upjohn，Inc.提出的第36次ICAAC摘要公开了大肠埃希氏杆菌中AcrAB抗生素外向通量泵的突变带来对噁唑烷酮抗菌剂的敏感性。
发明概述
本发明提出一种用于治疗哺乳动物革兰氏阴性生物感染的方法和组合物，包括给以有效量的噁唑烷酮抗菌剂和一种式A的精氨酸衍生物或药学上可接受的盐，
其中
R1是
a)芳基，可选地被C1-4烷基、C1-4烷氧基、C1-4烷硫基、卤素或-NH2取代，
b)-(CH2)i-芳基，其中的芳基被被C1-4烷基、C1-4烷氧基、C1-4烷硫基、卤素或-NH2取代，
c)噻吩基、呋喃基、吡啶基、苯并呋喃基或苯并噻吩基；
Z是R2或-CHWR2；
R2是
a)芳基，可选地被一个或两个C1-4烷基、C1-4烷氧基、C1-4烷硫基、卤、-NH2、C1-4烷基氨基、C1-4二烷基氨基或-NHOH取代，
b)C1-4烷基，可选地被氟原子取代，
c)C1-4烷氧基、C1-4烷硫基，
d)卤素，
e)噻吩基、呋喃基或吡啶基；
W是H、-NH2、C1-4烷基氨基、C1-4二烷基氨基、卤素、羟基、C1-4烷氧基、烷硫基或氮杂环；
芳基是苯基或萘基；
氮杂环是正吗啉基、正哌嗪基、正吡咯烷基、正咪唑基、正吡咯基、正吡唑基、正三唑基或正四唑基；
i是0、1或2。
发明的详细说明
本发明教导，当噁唑烷酮抗菌剂与一种精氨酸衍生物给药时，噁唑烷酮有效地抗需氧的革兰氏阴性生物，例如大肠埃希氏杆菌、流感嗜血菌、粘膜炎莫拉氏菌、铜绿假单胞菌或肺炎克雷伯氏菌，以及革兰氏阳性需氧菌，例如多耐受性葡萄球菌和链球菌，厌氧生物，例如拟杆菌和梭状芽胞杆菌类，和耐酸性生物，例如结核分枝杆菌和鸟分枝杆菌。噁唑烷酮抗菌剂完全有效地抗需氧革兰氏阴性生物的有效量大大低于噁唑烷酮不与这些精氨酸衍生物一起给药时所需的量。
出于本发明的目的，术语“C1-4烷基”指具有一至四个碳原子的烷基，例如甲基、乙基、丙基、丁基和它们的异构形式。
术语“C1-4烷氧基”指与一个羟基氧原子连接的具有一至四个碳原子的烷基，例如甲氧基、乙氧基、丙氧基、丁氧基和它们的异构形式。
术语“C1-4烷硫基”指与一个硫原子连接的具有一至四个碳原子的烷基和它们的异构形式。
术语“C1-4烷基氨基”指与一个氨基部分连接的具有一至四个碳原子的烷基，例如甲氨基、乙氨基、正丙氨基、正丁氨基和它们的异构形式。
术语“C1-4二烷基氨基”指与一个氨基部分连接的具有一至四个碳原子的两个烷基，例如二甲氨基、甲乙氨基、二乙氨基、二丙氨基、甲基丙氨基、乙基丙氨基、二丁氨基和它们的异构形式。
术语“卤素”指氟、氯、溴或碘，优选为氟、氯或溴。
术语“芳基”指苯基或萘基。
术语“氮杂环”指正吗啉基、正哌嗪基、正吡咯烷基、正咪唑基、正吡咯基、正吡唑基、正三唑基或正四唑基。
术语“药学上可接受的盐”指可用于将本发明化合物给药的盐，包括氢氯酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、乙酸盐、丙酸盐、乳酸盐、甲磺酸盐、马来酸盐、苹果酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、2-羟基乙磺酸盐、富马酸盐等。这些盐可以是水合的形式。
术语“哺乳动物”指人或兽医意义上的动物。
噁唑烷酮抗菌剂指式B化合物
其中R1是甲基、乙基、环丙基或二氯甲基；R2是氢或氟；Het是一个6元饱和杂环部分，具有一至两个选自硫、氮和氧原子的原子。可选地，杂环的氮原子可以被适当的基团取代，例如羟基乙酰基，硫原子可以是被氧化的。另外，式Y化合物包括所有可能的立体异构体和几何形式。优选地，噁唑烷酮抗菌剂是如上所述的式I-V化合物。
本领域有多篇参考文献公开了各种噁唑烷酮衍生物及其制备方法。上述噁唑烷酮抗菌剂可以按照美国专利5652238与5688792、国际专利公报WO93/23384、WO97/09328与WO98/54161中所述操作加以制备，它们引用在此作为参考文献。
式A的精氨酸衍生物是已知的，易于获得或者可以通过本领域技术人员已知的合成化学方法加以制备。优选地，式A的精氨酸衍生物是L-苯丙氨酰-L-精氨酰-β-萘酰胺。
本发明的药物组合物包含噁唑烷酮抗菌剂和式A的精氨酸衍生物，以及一种或多种固体或液体药学上可接受的载体和可选的药学上可接受的佐剂和赋形剂。固体形式的组合物包括粉末、片剂、可分散颗粒、胶囊和栓剂。固体载体可以是至少一种这样的物质，它也可以充当稀释剂、矫味剂、增溶剂、润滑剂、悬浮剂、粘合剂、片剂崩解剂和包封剂。惰性固体载体包括碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、纤维素材料、低熔点蜡、可可脂等。液体形式的组合物包括溶液、悬浮液和乳液。例如，可以提供的有本发明化合物溶解在水、水-丙二醇和水-聚乙二醇系统中的溶液，可选地含有常规的着色剂、矫味剂、稳定剂和增稠剂。
药物组合物是利用常规工艺提供的。优选地，组合物是含有有效量的噁唑烷酮抗菌剂、即式B化合物的单位剂量形式。
药物组合物及其单位剂量形式中噁唑烷酮抗菌剂的量可以是不同的，或者可以根据特定的用药方法、特定化合物的效力、所治疗的状态和所需浓度加以广泛调整。一般来说，噁唑烷酮抗菌剂的量将在0.5％至90％的范围内，以全体组合物的重量计。
在用于治疗已经诊断为需氧革兰氏阴性生物感染的人和其他动物的细菌感染的治疗用途中，噁唑烷酮抗菌剂和精氨酸衍生物或本发明的药物组合物将通过口服、肠胃外、透皮和/或局部给药，给药剂量可达到并保持活性组分在接受治疗的哺乳动物中的浓度、也就是量、或血液水平将是抗菌有效的。优选的给药方式是口服。一般来说，这种抗菌有效量的活性噁唑烷酮抗菌剂的剂量将在约0.1至约100mg/kg正常体重的范围内，更优选为约3.0至约50mg/kg体重/天。不言而喻的是，剂量可以因患者的需要、所治疗细菌感染的严重性和所使用的特定化合物而异。也不言而喻的是，为了快速达到所需血液水平，最初的给药剂量可以超过上述上限，或者最初的剂量可以小于最优值，每日剂量可以在治疗过程中根据具体情况逐渐增加。如果需要的话，每日剂量也可以分为多剂给药，例如每天二至四次。
式A精氨酸衍生物的用量随着特定精氨酸衍生物的活性增加和所治疗生物的吸收作用而改变。应当使用足量的精氨酸衍生物，以使所治疗的哺乳动物中需氧革兰氏阴性生物对药学上可接受水平的噁唑烷酮抗菌剂敏感。足量的特定精氨酸衍生物可以如下简单地加以确定：试验噁唑烷酮抗菌剂的最小抑制浓度(MIC)，比较单用抗菌剂的MIC与结合使用抗菌剂与精氨酸衍生物的MIC。一般来说，精氨酸衍生物与噁唑烷酮抗菌剂的给药摩尔比可以是约0.01至10，优选为约0.1至1.0。因此，用于增强哺乳动物中噁唑烷酮抗菌剂抗需氧革兰氏阴性生物的功效的精氨酸衍生物的每日剂量可以从约0.01至100mg/kg正常体重，优选为约0.3至50mg/kg体重。精氨酸衍生物可以在噁唑烷酮抗菌剂给药前一至四小时给药，或者与噁唑烷酮抗菌剂同时给药。
生物学试验
噁唑烷酮抗菌剂当与式A精氨酸衍生物结合时抗需氧革兰氏阴性生物的活性加强作用使用两种测定工艺：
a)常规的棋盘法，和
b)用于定量大肠埃希氏杆菌中放射性标记的噁唑烷酮抗菌剂的硅油离心法。
I.利用棋盘法测定分级抑制浓度(FIC)指数。
“棋盘”法是评定抗微生物组合的最常用的体外工艺(Lorian，V.，editor.Antibiotics in Laboratory Medicine，Third Edition，p.432，Williams & Wilkins.Baltimore，Maryland 21202，USA)。在微量稀释法中，棋盘模式是在微量滴定盘的小孔内形成的，小孔内含有多份供试试剂的2-倍稀释液。供试稀释液所跨越的浓度范围在用于供试生物的每种供试试剂的最小抑制浓度(MIC)之上和之下。在每种试验比例下的反应(生长或没有生长)用于计算分级抑制浓度(FIC)指数。当两种药物一起使用所得到的结果等于分别使用两种药物所得到的结果之和时(FIC指数＝1.0)，把药物-药物相互作用定义为加和作用。当两种药物的结果显著小于加和性反应时(FIC指数＞1.0)，把相互作用描述为拮抗作用。当两种药物组合的结果显著大于加和性反应时(FIC指数＜0.50)，把相互作用描述为协同作用。
II.定量放射性标记的式I噁唑烷酮抗菌剂
用式A精氨酸衍生物预处理细菌细胞后大肠埃希氏杆菌中的蓄积作用
放射性标记的式I噁唑烷酮抗菌剂在大肠埃希氏杆菌中的蓄积作用的测量按照Thanassi，D.G.，G.S.B.Suh，H.Nikaido《细菌学杂志》1995，p.177，(4)：998-1007所述操作进行。简单地说，使细胞在37℃LB/0.2％葡萄糖中生长至对数中期(OD530 0.5-0.7)，用离心法收获，洗涤两次，再次在50mM磷酸钾pH7.0、1mM MgSO4和0.2％葡萄糖中悬浮至OD530为8.0。在加入精氨酸衍生物之前，将1.0ml等分试样的细胞悬浮液在37℃下预培养10分钟。使用羰基氰间氯苯腙(CCCP)作为阳性对照。加入精氨酸衍生物、L-苯丙氨酰-L-精氨酰-β-萘酰胺后，将细胞培养30分钟，然后加入放射性标记的式I噁唑烷酮抗菌剂，至最终浓度为25TM。然后再将细胞培养15分钟。取出50Tl等分试样，在300Tl硅油垫(70％550号流体和30％510号流体的硅油，DowCorning Corp.Midland，MI)上分层。将试管在22℃、12000rpm下离心3分钟，然后浸入液N2进行冷冻。除去含有细胞颗粒的每支试管顶端，放置在闪烁小瓶内。融化后，将细胞颗粒悬浮在200Tl蒸馏水中，加入4ml闪烁流体。将样本充分混合，在液体闪烁计数器中计数。为了校正所标记的药物与细胞表面的非特异性粘着，用自始至终仅加入载体和放射性标记的式I噁唑烷酮抗菌剂进行培养的细胞做对照实验。
III.结果
单用式I噁唑烷酮抗菌剂证明抗菌活性非常差，抑制大肠埃希氏杆菌31700需要256mg/ml的浓度。单用L-苯丙氨酰-L-精氨酰-β-萘酰胺也证明抗菌活性非常差，直到高达256mg/ml的浓度也没有生长抑制作用。不过，当在“棋盘”模式中将这两种试剂组合使用时，戏剧性地证明式I噁唑烷酮抗菌剂的活性被L-苯丙氨酰-L-精氨酰-β-萘酰胺加强了。例如，在16mg/ml L-苯丙氨酰-L-精氨酰-β-萘酰胺的存在下，式I噁唑烷酮抗菌剂对细菌生长的抑制浓度是16mg/ml。FIC指数的计算值为0.23，显然说明具有协同性相互作用。
Claims (19)
1、噁唑烷酮抗菌剂和式A的化合物或其药学上可接受的盐在制备用于治疗哺乳动物革兰氏阴性生物感染的药物中的用途，
其中
R1是
a)芳基，可选地被C1-4烷基、C1-4烷氧基、C1-4烷硫基、卤素或-NH2取代，或
b)-(CH2)i-芳基，其中的芳基被C1-4烷基、C1-4烷氧基、C1-4烷硫基、卤素或-NH2取代，或
c)噻吩基、呋喃基、吡啶基、苯并呋喃基或苯并噻吩基；
Z是R2或-CHWR2；
R2是
a)芳基，可选地被一个或两个C1-4烷基、C1-4烷氧基、C1-4烷硫基、卤素、-NH2、C1-4烷基氨基、C1-4二烷基氨基或-NHOH取代，或
b)C1-4烷基，可选地被氟原子取代，或
c)C1-4烷氧基、C1-4烷硫基，或
d)卤素，或
e)噻吩基、呋喃基或吡啶基；
W是H、-NH2、C1-4烷基氨基、C1-4二烷基氨基、卤素、羟基、C1-4烷氧基、C1-4烷硫基或氮杂环；
芳基是苯基或萘基；
氮杂环是n-吗啉基、n-哌嗪基、n-吡咯烷基、n-咪唑基、n-吡咯基、n-吡唑基、n-三唑基或n-四唑基；
i是0、1或2。
2、权利要求1的用途，其中该噁唑烷酮抗菌剂是结构为B的化合物
其中R1是甲基、乙基、环丙基或二氯甲基；
R2是氢或氟；
Het是一个6元饱和杂环部分，具有一至两个选自硫、氮和氧原子的原子。
3、权利要求2的用途，其中该噁唑烷酮抗菌剂是结构为I、II、III、IV或V的化合物
4、权利要求2的用途，其中该噁唑烷酮抗菌剂是结构II的化合物
5、权利要求1的用途，其中该式A的化合物是L-苯丙氨酰-L-精氨酰-β-萘酰胺。
6、权利要求1的用途，其中噁唑烷酮抗菌剂和式A化合物的比例为10∶0.01。
7、权利要求1的用途，其中噁唑烷酮抗菌剂和式A化合物的比例为1∶1。
8、权利要求1的用途，其中该噁唑烷酮抗菌剂的有效量是0.1至100mg/kg体重/天。
9、权利要求1的用途，其中该噁唑烷酮抗菌剂的有效量是3至50mg/kg体重/天。
10、权利要求1的用途，其中该式A化合物的量是0.01至100mg/kg体重/天。
11、权利要求1的用途，其中该式A化合物的量是0.3至50mg/kg体重/天。
12、权利要求1的用途，其中该噁唑烷酮抗菌剂和式A化合物是同时给药的。
13、权利要求1的用途，其中该式A化合物是在该噁唑烷酮抗菌剂给药前一至四小时给药的。
14、权利要求1的用途，其中该有效量的噁唑烷酮抗菌剂和式A化合物是口服、肠胃外、透皮或局部给药的。
15、权利要求1的用途，其中该革兰氏阴性生物是需氧的革兰氏阴性生物。
16、权利要求15的用途，其中该需氧的革兰氏阴性生物是大肠埃希氏杆菌、流感嗜血菌、粘膜炎莫拉氏菌、铜绿假单胞菌或肺炎克雷伯氏菌。
17、用于治疗哺乳动物革兰氏阴性生物感染的组合物，包含如权利要求2中所定义的式B的噁唑烷酮抗菌剂、如权利要求1中所定义的式A的化合物或其药学上可接受盐，和药学上可接受的载体。
18、权利要求17的组合物，其中该噁唑烷酮抗菌剂是结构I、II、III、IV或V的化合物
19、权利要求17的组合物，其中该式A的化合物是L-苯丙氨酰-L-精氨酰-β-萘酰胺。
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| DE10129725A1 (de) * | 2001-06-20 | 2003-01-02 | Bayer Ag | Kombinationstherapie substituierter Oxazolidinone |
| US20050255538A1 (en) * | 2002-03-15 | 2005-11-17 | Buxser Stephen E | Methods for screening for AcrAB efflux pump inhibitors |
| DE10300111A1 (de) * | 2003-01-07 | 2004-07-15 | Bayer Healthcare Ag | Verfahren zur Herstellung von 5-Chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid |
| DE10355461A1 (de) | 2003-11-27 | 2005-06-23 | Bayer Healthcare Ag | Verfahren zur Herstellung einer festen, oral applizierbaren pharmazeutischen Zusammensetzung |
| KR100854211B1 (ko) * | 2003-12-18 | 2008-08-26 | 동아제약주식회사 | 신규한 옥사졸리디논 유도체, 그의 제조방법 및 이를유효성분으로 하는 항생제용 약학 조성물 |
| CN1976703A (zh) * | 2004-06-30 | 2007-06-06 | 诺瓦提斯公司 | 通过使用外排泵抑制剂增加肽脱甲酰基酶抑制剂敏感性的方法 |
| DE102004062475A1 (de) * | 2004-12-24 | 2006-07-06 | Bayer Healthcare Ag | Feste, oral applizierbare pharmazeutische Darreichungsformen mit modifizierter Freisetzung |
| EP1685841A1 (en) | 2005-01-31 | 2006-08-02 | Bayer Health Care Aktiengesellschaft | Prevention and treatment of thromboembolic disorders |
| DE102005045518A1 (de) | 2005-09-23 | 2007-03-29 | Bayer Healthcare Ag | 2-Aminoethoxyessigsäure-Derivate und ihre Verwendung |
| EP1934208B1 (de) | 2005-10-04 | 2011-03-23 | Bayer Schering Pharma Aktiengesellschaft | Neue polymorphe form von 5-chlor-n-({ ( 5s )-2-0x0-3-[4-( 3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl} -methyl)-2-thiophencarboxamid |
| DE102005047558A1 (de) * | 2005-10-04 | 2008-02-07 | Bayer Healthcare Ag | Kombinationstherapie substituierter Oxazolidinone zur Prophylaxe und Behandlung von cerebralen Durchblutungsstörungen |
| DE102005047561A1 (de) | 2005-10-04 | 2007-04-05 | Bayer Healthcare Ag | Feste, oral applizierbare pharmazeutische Darreichungsformen mit schneller Wirkstofffreisetzung |
| DE102006051625A1 (de) * | 2006-11-02 | 2008-05-08 | Bayer Materialscience Ag | Kombinationstherapie substituierter Oxazolidinone |
| US20170258816A1 (en) | 2014-09-12 | 2017-09-14 | Antibiotx Aps | Antibacterial Use of Halogenated Salicylanilides |
| GB201509326D0 (en) | 2015-05-29 | 2015-07-15 | Antibio Tx Aps | Novel use |
| US11419834B2 (en) | 2019-02-25 | 2022-08-23 | Rhode Island Hospital | Methods for treating diseases or infections caused by or associated with H. pylori using a halogenated salicylanilide |
| WO2020176067A1 (en) | 2019-02-25 | 2020-09-03 | Rhode Island Hospital | Methods for treating diseases or infections caused by or associated with h. pylori using a halogenated salicylanilide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5989832A (en) * | 1995-04-21 | 1999-11-23 | Microcide Pharmaceuticals, Inc. | Method for screening for non-tetracycline efflux pump inhibitors |
| KR20010021645A (ko) * | 1997-07-11 | 2001-03-15 | 로렌스 티. 마이젠헬더 | 티아디아졸릴 및 옥사디아졸릴 페닐 옥사졸리디논 항균제 |
| US6068972A (en) * | 1997-10-03 | 2000-05-30 | Trustees Of Tufts College | Methods and compositions for reducing bacterial tolerance to antibacterials, disinfectants and organic solvents |
| US6790856B2 (en) * | 2002-01-31 | 2004-09-14 | Boehringer Ingelheim Pharma Kg | Fluorenecarboxylic acid esters, process for the manufacture thereof, and use thereof as medicaments |
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- 1999-05-13 AT AT99921365T patent/ATE222115T1/de not_active IP Right Cessation
- 1999-05-13 JP JP2000549280A patent/JP2002515450A/ja active Pending
- 1999-05-13 HU HU0101958A patent/HUP0101958A3/hu unknown
- 1999-05-13 AU AU38601/99A patent/AU746606B2/en not_active Ceased
- 1999-05-13 TR TR2000/03384T patent/TR200003384T2/xx unknown
- 1999-05-13 PL PL99344049A patent/PL344049A1/xx not_active Application Discontinuation
- 1999-05-13 KR KR1020007012910A patent/KR20010043695A/ko not_active Application Discontinuation
- 1999-05-13 CN CNB998052183A patent/CN1170584C/zh not_active Expired - Fee Related
- 1999-05-13 ES ES99921365T patent/ES2182521T3/es not_active Expired - Lifetime
- 1999-05-13 SK SK1625-2000A patent/SK283038B6/sk unknown
- 1999-05-13 EP EP99921365A patent/EP1077718B1/en not_active Expired - Lifetime
- 1999-05-13 PT PT99921365T patent/PT1077718E/pt unknown
- 1999-05-13 EA EA200001197A patent/EA003458B1/ru not_active IP Right Cessation
- 1999-05-13 IL IL13943799A patent/IL139437A0/xx unknown
- 1999-05-13 WO PCT/US1999/007038 patent/WO1999059616A1/en not_active Application Discontinuation
- 1999-05-13 CZ CZ20004259A patent/CZ291945B6/cs not_active IP Right Cessation
- 1999-05-13 BR BR9910443-1A patent/BR9910443A/pt not_active IP Right Cessation
- 1999-05-13 DE DE69902526T patent/DE69902526T2/de not_active Expired - Fee Related
- 1999-05-13 DK DK99921365T patent/DK1077718T3/da active
- 1999-05-13 NZ NZ508256A patent/NZ508256A/en unknown
- 1999-05-17 US US09/313,465 patent/US6251869B1/en not_active Expired - Fee Related
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2000
- 2000-10-23 ZA ZA200005923A patent/ZA200005923B/xx unknown
- 2000-11-17 NO NO20005813A patent/NO20005813L/no not_active Application Discontinuation
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| Publication number | Publication date |
|---|---|
| DK1077718T3 (da) | 2002-11-11 |
| JP2002515450A (ja) | 2002-05-28 |
| WO1999059616A1 (en) | 1999-11-25 |
| ATE222115T1 (de) | 2002-08-15 |
| EP1077718B1 (en) | 2002-08-14 |
| BR9910443A (pt) | 2001-01-02 |
| US6251869B1 (en) | 2001-06-26 |
| NO20005813D0 (no) | 2000-11-17 |
| CZ291945B6 (cs) | 2003-06-18 |
| NZ508256A (en) | 2003-08-29 |
| HUP0101958A2 (hu) | 2001-10-28 |
| ES2182521T3 (es) | 2003-03-01 |
| EA200001197A1 (ru) | 2001-04-23 |
| TR200003384T2 (tr) | 2001-03-21 |
| IL139437A0 (en) | 2001-11-25 |
| KR20010043695A (ko) | 2001-05-25 |
| DE69902526T2 (de) | 2003-04-03 |
| CZ20004259A3 (en) | 2001-05-16 |
| SK283038B6 (sk) | 2003-02-04 |
| AU746606B2 (en) | 2002-05-02 |
| PT1077718E (pt) | 2002-12-31 |
| PL344049A1 (en) | 2001-09-24 |
| DE69902526D1 (de) | 2002-09-19 |
| EP1077718A1 (en) | 2001-02-28 |
| HK1036222A1 (en) | 2001-12-28 |
| CN1297355A (zh) | 2001-05-30 |
| EA003458B1 (ru) | 2003-06-26 |
| NO20005813L (no) | 2000-11-17 |
| AU3860199A (en) | 1999-12-06 |
| HUP0101958A3 (en) | 2003-07-28 |
| SK16252000A3 (sk) | 2001-06-11 |
| CA2327100A1 (en) | 1999-11-25 |
| ZA200005923B (en) | 2001-10-23 |
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