CN1116526A - 因平滑肌细胞增殖引起的疾病的治疗、预防剂 - Google Patents
因平滑肌细胞增殖引起的疾病的治疗、预防剂 Download PDFInfo
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- CN1116526A CN1116526A CN95106317.0A CN95106317A CN1116526A CN 1116526 A CN1116526 A CN 1116526A CN 95106317 A CN95106317 A CN 95106317A CN 1116526 A CN1116526 A CN 1116526A
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- smooth muscle
- muscle cell
- cell proliferation
- therapeutic
- prophylactic agent
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Abstract
以通式(I)的氨基哒嗪衍生物或其盐作为有效成分的因平滑肌细胞增殖引起的疾病的治疗、预防剂(其中各代号意义详见说明书),
由于氨基哒嗪衍生物抑制平滑肌细胞的游走、增殖,故对因平滑肌细胞增殖引起的疾病,如经皮冠状动脉扩张术(PTCA)后的再狭窄、心脏、肝脏、肾脏、血管等内脏器官移植后的血管狭窄,经皮动脉扩张术(PTA)后的再狭窄具有预防和治疗作用。
Description
本发明关于因平滑肌细胞增殖引起的疾病的治疗、预防剂,更具体地说,是以特定的氨基哒嗪衍生物或其盐为有效成分的、因平滑肌细胞增殖引起的疾病的治疗、预防剂。
近些年来,作为狭小化血管的治疗方法,经皮冠状动脉扩张术(Percutaneous Transluminal Coronary Angioplasty:PTCA)、经皮动脉扩张术(Percutaneous Transluminal Angioplasty:PTA)正日益普及。这是从大腿动脉等部位远距离插入气球导管(balloon catheter),在狭窄部位使气球膨胀,使血管物理性扩张的方法。但该治疗方法实施3~6个月后有时会再次出现血管变窄。在这种再狭窄中,观察不到胆固醇的沉积,无疑这几乎都是由平滑肌细胞以及由它们产生的细胞间基质构成,即所谓细胞纤维性内膜肥厚(Journal of AmericanCollege of Cordiology 23,(6),1278-1289,1994,5月)。另外,平滑肌细胞的增殖引起心脏、肝脏、肾脏、血管等内脏器官移植后的血管狭窄(FASEB Journal7,1055~1060,1993,8月)。
为此,作为治疗、预防PTCA及PTA术后的再狭窄与内脏器官移植后的血管狭窄的方法,抑制血管内腔出现的平滑肌细胞的游走、增殖被认为是有效的。
为解决此课题,一直在进行药剂的研究(特开昭57-38715号、特开平2-121922号、特开平3-83923号、特开平3-83957号、特开平3-118383号、特开平4-99775号、特开平4-154720号等),但至今还未开发成功。
另一方面,2,3-二氮杂萘的各种衍生物的各种药理作用已被报导。如特开昭56-53659、特开昭56-53660以及特开昭57-48972报导了1-苯胺基-4-苯基-2,3-二氮杂萘衍生物具有强烈的体外血小板凝集抑制作用,而特开昭60-218377、特开昭60-243074中,也报导了下述2种化合物具有强烈的体外血小板凝集抑制作用。
关于英国专利第1303016号、J.Med.Chem.12,555(1969)等公开的1-氨基-4-苯基-2,3-二氮杂萘衍生物,只记载过它具有消炎及抗锂作用。
此外,欧洲公开专利公报449203(特开平4-211666)中公开了1-α-取代苄氨基-4-苯基-2,3-二氮杂萘衍生物,欧洲公开专利公报534443中公开了3,6-二取代哒嗪衍生物,两者都具有强烈的血小板凝集抑制作用,鉴于这一作用,预计它们对脑血栓、脑塞栓等脑血管障碍、血肌梗塞等缺血性心疾病、末梢循环障碍等循环阻碍有效果。
但是,这些2,3-二氮杂萘衍生物对平滑肌细胞增殖有抑制作用尚不为人所知。
本发明者为解决上述问题经过多次研究,结果首次发现已知对血小板凝集有抑制作用的氨基哒嗪衍生物对血管内腔出现的平滑肌细胞增殖有抑制作用,从而完成了本发明。
R1表示环己基、任选具有1个以上选自C1~C4烷基、C1~C4烷氧基以及卤原子的取代基的苯基、任选具有一个以上选自C1~C4烷基、C1~C4烷氧基及卤原子的取代基的噻吩基,或任选具有1个以上选自C1~C4烷基C1~C4烷氧基及卤原子的取代基的呋喃基;
R2表示-CHR3R4(R3表示氢原子或C1~C4烷基,R4表示C1~C4烷基、环己基、噻吩基或任选具有1个以上选自C1~C4烷基、C1~C4烷氧基及卤原子的取代基的苯基)、或任选具有1个以上选自C1~C4烷基、C1~C4烷氧基及C1~C6亚烷基的取代基的环己基;
环A表示苯环、噻吩环或呋喃环。
以下详细说明本发明。
本发明的因平滑肌细胞增殖引起的疾病的治疗、预防剂以上述通式(I)的氨基哒嗪衍生物或其盐为有效成分。
上述通式中C1~C4烷基可列举甲基、乙基、正丙基、异丙基、正丁基、叔丁基等,C1~C4烷氧基可列举甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基等,卤原子可列举氟原子、氯原子、溴原子等,C1~C6亚烷基可列举任意二个取代基连结的基团,如亚甲基、亚乙基、1,3-亚丙基、1,4-亚丁基、1,5-亚戊基、1,2-亚丙基、乙基亚乙基、二甲基亚甲基等。
R1优选苯基、2-噻吩基或2-呋喃基,特别优选苯基。R2优选-CHR3′R4′(R3′表示C1~C4烷基,R4′表示环己基),特别优选下式基团,
环A优选苯环或噻吩环,优选为苯环。
通式(I)的氨基哒嗪衍生物形成的盐可列举其盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐等无机酸盐,或甲磺酸盐、对甲苯磺酸盐、苯磺酸盐、樟脑磺酸盐、乙酸盐、安息香酸盐、苹果酸盐、乳酸盐、羟基乙酸盐、葡萄糖醛酸盐、马来酸盐、富马酸盐、草酸盐、抗坏血酸盐、柠檬酸盐、水杨酸盐、尼古丁酸盐、酒石酸盐等有机酸盐。因通式(I)的化合物及其盐有时也以水合物或溶剂化物形式存在,故这些水合物、溶剂化物也包括在本发明化合物内。
另外,上述通式(I)的氨基哒嗪衍生物中存在不对称碳原子时,(R)体、(S)体、(RS)体都可以采用,这些均包括在用作本发明的有效成分的化合物中。
因平滑肌细胞增殖引起的疾病具体可列举PTCA术后的再狭窄,心脏、肝脏、肾脏、血管等内脏器官移植后的血管狭窄、PTA术后的再狭窄等。
以下表-1为本发明氨基哒嗪衍生物的具体实例。
表-I(续)
这类氨基哒嗪衍生物就是在欧洲公开专利449203号或534443号所记载的化合物,无论哪种化合物都可根据这些专利中的方法合成。
本发明的因平滑肌细胞增殖引起的疾病的治疗、预防剂对于血管内腔出现的因平滑肌细胞游走、增殖引起的各种疾病有效。具体而言,可用于PTCA术后的再狭窄、经皮动脉扩张术(PTA)后的再狭窄、心脏、肝脏、肾脏、血管等内脏器官移植后的血管狭窄等的预防或治疗。
本发明的氨基哒嗪衍生物作为因平滑肌细胞增殖引起的疾病的治疗、预防剂应用于临床时,经口使用时成人优选一次1~100mg,一日1~3次给药,静脉注射时成人优选一次0.01~10mg,一日2~5次给药,另外直肠内给药时优选一次1~100mg,一日1~3次给药。此外,以上给药量更优选随年龄、病态、症状等作适宜增减。
制成药剂时,将氨基哒嗪衍生物或其1种或2种以上可药用盐与常用的药用载体、赋型剂及其它添加剂混合。载体无论固体还是液体均可,作为固体载体可列举乳糖、白陶土(高岭土)、蔗糖、结晶纤维素、玉米淀粉、滑石粉、琼脂、果胶、阿拉伯胶、硬脂酸、硬脂酸镁、卵磷脂、氯化钠等。
作为液体载体可列举糖浆、甘油、花生油、聚乙烯吡咯烷酮、橄榄油、乙醇、苯甲醇、丙二醇、水等。
医药制剂可采用各种剂型,采用固体载体时,有片剂、散剂、颗粒剂、硬明胶囊剂、栓剂或锭剂。固体载体量可在很宽范围改变,优选约1mg~约1g。
采用液体载体时,可制成糖浆剂、乳液剂、软明胶囊剂,以及装入安瓿瓶的无菌注射液或水性或非水性悬浮液剂。
[实施例]
以下用实施例详细说明本发明,只要不超出本发明的要点,则本发明不限于下述实施例。
合成例
(R)-1-(1-环己基乙基氨基)-4-苯基-2,3-二氮杂萘(表-1化合物No.17的(R)体)富马酸盐的合成(以下简称为化合物A)。
在400ml N-甲基吡咯烷酮中添加144.4g(0.6mol)1-氯-4-苯基-2,3-二氮杂萘和230g(1.8mol)(R)-(-)-1-环己基乙胺后,在120~130℃下加热搅拌混合物6小时。反应终了后,冷却,添加4.0升5%NaOH水溶液,用氯仿萃取。有机层用MgSO4干燥后,浓缩,然后用硅胶柱色谱法(分离液为乙酸乙酯:正己烷:氯仿=1∶3∶1)精制,用乙醚-氯仿重结晶,合成出150.2g(R)-1-(1-环己基乙基氨基)-4-苯基-2,3-二氮杂萘。
熔点:164.0~167.0℃
将得到的(R)-1-(1-环己基乙基氨基)-4-苯基-2,3-二氮杂萘100.0g、富马酸32.0g在1.01的甲醇中搅拌回流16小时。一边搅拌一边自然冷却到20℃,滤取晶体,用200ml甲醇洗涤,在约60℃1~2mmHg下干燥,得到121.5g的富马酸盐。
烷点:240~250℃(分解)
实施例1
对大鼠内膜肥厚模型的作用
将戊巴比妥麻醉下的SD大鼠(20周龄)背位固定,露出左颈动脉。由外颈动脉将用于除去血栓的福格替氏导管(2フレンチ)在气球不膨胀的状态下插入到大动脉分支部位(约5cm)。使气球膨胀,并一边转动一边引入到插入部位。重复操作三次,使颈动脉内皮细胞剥离。操作完毕后,拨出导管,结扎外颈动脉,用医疗用夹子使切开部位闭合。将化合物A悬浮分散在0.7%西黄蓍胶溶液中,采用1mg/kg、3mg/kg或10mg/kg的用量一日一次经口给药。对于对照组,以0.7%西黄蓍胶溶液同样经口给药。第一天给药在颈动脉内膜剥离后进行。
内膜剥离两周后,在戊巴比妥麻醉下,将3%伊凡斯蓝从大腿静脉注入静脉内。30分钟后剖腹,用0.01M磷酸缓冲液从大动脉开始全身灌流后,摘出颈动脉。
将摘出的颈动脉中确认已剥离内皮细胞的部分做成6~8个2mm长的动脉片,用福尔马林固定后用石蜡包覆。由各片制作横断面组织切片,进行弹性组织·范吉逊氏染色。各切片内膜、中膜面积用数字转换器测定,内膜肥厚度用内膜/中膜面积比表示。结果如表-2所示。
表-2
用 量 | 例致 | 内膜/中膜面积比±标准误差 | |
对 照 | 14 | 1.060±0.081 | |
化合物A | 1mg/kg | 7 | 0.853±0.107 |
3mg/kg | 8 | 0.637±0.067* | |
10mg/kg | 9 | 0.462±0.094* |
*;p<0.05(检测法)一元配置分散分析Dunnett型
化合物A对内膜剥离引起的大鼠颈动脉内膜肥厚的抑制情况与其用量相关。
实施例2:
对大鼠内膜肥厚模型的作用
将戊巴比妥麻醉下的SD大鼠(20周龄)背位固定,露出左颈动脉。由外颈动脉将除血栓用福格替氏导管(2フレンチ)在气球不膨胀的状态下插入到大动脉分支部位(约5cm)。使气球膨胀,一边使之旋转一边引入到插入部位。重复操作三次,使颈动脉内皮细胞剥离。操作完毕后,拨出导管,结扎外颈动脉,用医疗用夹子使切开部位闭合。将化合物A悬浮分散在0.7%西黄蓍胶溶液中,采用3mg/kg用量一日一次经口给药,对于对照组,同样地经口给予0.7%西黄蓍胶溶液。A组中第一次给药在颈动脉内膜剥离后立即进行,B组则在颈动脉内膜剥离4日后开始。
内膜剥离2周后,在戊巴比妥麻醉下,将3%伊凡斯蓝由大腿静脉注入静脉内。30分钟后剖腹,用0.01M磷酸缓冲液从大动脉开始全身灌流后摘出颈动脉。
将摘出的颈动脉中确认已剥离内皮细胞的部分制成6~8个长度为2mm的动脉片,用福尔马林固定后,用石蜡包覆。用各片制作横截面组织切片,进行弹性组织·范吉逊氏染色。用数字转换器测定内膜、中膜面积,内膜肥厚度用内膜/中膜面积比表示。其结果列于表-3中。
表-3
*;p<0.05(粒测法)一元配置分散分析Dunnett型
给药时间(日) | 例致 | 内膜/中膜面积比±标准误差 | |
对 照 | 7 | 1.033±0.086 | |
化合物A | A0~14 | 6 | 0.568±0.037* |
B4~14 | 6 | 0.594±0.044* |
化合物以3mg/kg经口给药,可抑制由于内膜剥离引起的大鼠颈动脉内膜肥厚,即或颈动脉内膜剥离4日后给药也有意义。
氨基哒嗪衍生物由于可抑制平滑肌细胞的游走、增殖,故对因平滑肌细胞增殖引起的疾病,例如经皮冠状动脉扩张术(PTCA)后的再狭窄,心脏、肝脏、肾脏、血管等内脏器官移植后的血管狭窄、经皮动脉扩张术(PTA)后的再狭窄的预防或治疗有效。
Claims (11)
其中,
R1表示环己基、任选含有1个以上选自C1~C4烷基、C1~C4烷氧基及卤原子的取代基的苯基、任选含有1个以上选自C1~C4烷基、C1~C4烷氧基及卤原子的取代基的噻吩基或任选含有1个以上选自C4~C4烷基、C1~C4烷氧基及卤原子的取代基的呋喃基;
R2表示-CHR3R4,R3表示氢原子或C1~C4烷基、R4表示C1~C4烷基、环己基、噻吩基或任选含有1个以上选自C1~C4烷基、C1~C4烷氧基及卤原子的取代基的苯基;或任选含有1个以上选自C1~C4烷基、C1~C4烷氧基及C1~C6亚烷基的取代基的环己基;
环A表示苯环、噻吩环或呋喃环。
2.按权利要求1的因平滑肌细胞增殖引起的疾病的治疗、预防剂,其特征在于R2表示-CHR3′R4′、R3′表示C1~C4烷基,R4′表示环己基。
3.按权利要求1或2的因平滑肌细胞增殖引起的疾病的治疗、预防剂,其特征在于R1表示苯基、2-噻吩基或2-呋喃基。
4.按权利要求1或2的因平滑肌细胞增殖引起的疾病的治疗、预防剂,其特征在于R1表示苯基。
5.按权利要求1~4中任一项的因平滑肌细胞增殖引起的疾病的治疗、预防剂,其特征在于环A表示苯环或噻吩环。
6.按权利要求1~4中任一项的因平滑肌细胞增殖引起的疾病的治疗、预防剂,其特征在于环A表示苯环。
8.以(R)-1-(1-环己基乙基氨基)-4-苯基-2,3-二氮杂萘或其可药用盐作为有效成分的因平滑肌细胞增殖引起的疾病的治疗、预防剂。
9.按权利要求1~8中任何一项的治疗、预防剂,其中因平滑肌细胞增殖引起的疾病为经皮冠状动脉扩张术后的再狭窄。
10.按权利要求1~8中任何一项的治疗、预防剂,其中因平滑肌细胞增殖引起的疾病为内脏器官移植后的血管狭窄。
11.按权利权利要求1~8中任何一项的治疗、预防剂,其中因平滑肌细胞增殖引起的疾病为经皮动脉扩张术后的再狭窄。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP105367/94 | 1994-05-19 | ||
JP10536794 | 1994-05-19 |
Publications (1)
Publication Number | Publication Date |
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CN1116526A true CN1116526A (zh) | 1996-02-14 |
Family
ID=14405751
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN95106317.0A Pending CN1116526A (zh) | 1994-05-19 | 1995-05-18 | 因平滑肌细胞增殖引起的疾病的治疗、预防剂 |
Country Status (9)
Country | Link |
---|---|
US (1) | US5643911A (zh) |
EP (1) | EP0682947B1 (zh) |
CN (1) | CN1116526A (zh) |
AT (1) | ATE157871T1 (zh) |
CA (1) | CA2149691A1 (zh) |
DE (1) | DE69500673T2 (zh) |
DK (1) | DK0682947T3 (zh) |
ES (1) | ES2109752T3 (zh) |
GR (1) | GR3025568T3 (zh) |
Cited By (1)
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CN1103591C (zh) * | 1996-05-22 | 2003-03-26 | 永光制药有限公司 | 取代的1,4,5,6-四氢哒嗪并[4,5-c]哒嗪-5-酮类化合物之药物组合物及其应用和制备方法 |
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US5716956A (en) * | 1995-06-07 | 1998-02-10 | Bearsden Bearsden Bio, Inc. | Dihydrophthalazine antagonists of excitatory amino acid receptors |
US6689883B1 (en) | 1999-09-28 | 2004-02-10 | Bayer Pharmaceuticals Corporation | Substituted pyridines and pyridazines with angiogenesis inhibiting activity |
US7977333B2 (en) | 2000-04-20 | 2011-07-12 | Bayer Healthcare Llc | Substituted pyridines and pyridazines with angiogenesis inhibiting activity |
US6903101B1 (en) | 2000-08-10 | 2005-06-07 | Bayer Pharmaceuticals Corporation | Substituted pyridazines and fused pyridazines with angiogenesis inhibiting activity |
KR100915287B1 (ko) * | 2001-12-11 | 2009-09-03 | 교와 핫꼬 기린 가부시키가이샤 | 티아디아졸린 유도체 |
DE60325879D1 (de) | 2002-11-08 | 2009-03-05 | Tyco Healthcare | Selbstverschliessende kanüle |
JPWO2004089412A1 (ja) * | 2003-04-08 | 2006-07-06 | 三菱ウェルファーマ株式会社 | 特異的nad(p)hオキシダーゼ抑制剤 |
WO2004092147A1 (ja) | 2003-04-18 | 2004-10-28 | Kyowa Hakko Kogyo Co., Ltd. | M期キネシン阻害剤 |
CA2528433A1 (en) * | 2003-06-10 | 2004-12-23 | Kyowa Hakko Kogyo Co., Ltd. | Thiadiazoline derivative |
EP1867640A4 (en) * | 2005-03-22 | 2010-07-14 | Kyowa Hakko Kirin Co Ltd | MEANS FOR TREATING SOLID TUMORS |
CA2602559A1 (en) * | 2005-03-22 | 2006-09-28 | Kyowa Hakko Kogyo Co., Ltd. | Agent for treatment of hematopoietic tumor |
WO2006137490A1 (ja) * | 2005-06-24 | 2006-12-28 | Kyowa Hakko Kogyo Co., Ltd. | 再狭窄治療剤 |
US8025640B2 (en) | 2008-06-27 | 2011-09-27 | Tyco Healthcare Group Lp | Pressurized surgical valve |
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US3738371A (en) | 1970-12-11 | 1973-06-12 | Esb Inc | Cardiac pacers with source condition-responsive rate |
JPS5653660A (en) | 1979-10-09 | 1981-05-13 | Mitsubishi Yuka Yakuhin Kk | 4-phenylphthalazine derivative |
JPS5653659A (en) | 1979-10-09 | 1981-05-13 | Mitsubishi Yuka Yakuhin Kk | Blood platelet coagulation suppressing agent |
JPS5748972A (en) | 1980-09-10 | 1982-03-20 | Mitsubishi Yuka Yakuhin Kk | 4-phenylphthalazine derivative |
JPS5738715A (en) | 1980-08-18 | 1982-03-03 | Mochida Pharmaceut Co Ltd | Medical composition having activity of prohibiting artery wall from thickening |
JPS60218377A (ja) | 1984-04-16 | 1985-11-01 | Mitsubishi Yuka Yakuhin Kk | 4−フエニルフタラジン誘導体及びそれを有効成分とする循環改善剤 |
JPS60243074A (ja) | 1985-04-15 | 1985-12-03 | Mitsubishi Yuka Yakuhin Kk | 4−フエニルフタラジン誘導体 |
ZA896851B (en) | 1988-09-14 | 1990-06-27 | Hoffmann La Roche | Use of ace-inhibitors |
DE3926606A1 (de) | 1989-08-11 | 1991-02-14 | Hoechst Ag | Verfahren zur behandlung der cardialen sowie der vasculaeren hypertrophie und hyperplasie |
JPH0383923A (ja) | 1989-08-25 | 1991-04-09 | Terumo Corp | 中膜平滑筋細胞の遊走阻害剤 |
JPH03106873A (ja) * | 1989-09-20 | 1991-05-07 | Morishita Pharmaceut Co Ltd | 1―ピリジルフタラジン誘導体及びそれらを含有する血小板凝集抑制剤 |
JP2852538B2 (ja) | 1989-09-29 | 1999-02-03 | 第一製薬株式会社 | 〔1,2,4〕トリアゾロ〔1,5―a〕ピリミジン誘導体 |
ATE115136T1 (de) * | 1990-03-30 | 1994-12-15 | Mitsubishi Chem Ind | 4-phenylphthalazin-derivate. |
JPH04211666A (ja) | 1990-03-30 | 1992-08-03 | Mitsubishi Kasei Corp | 4−フェニルフタラジン誘導体 |
JP2999808B2 (ja) | 1990-08-20 | 2000-01-17 | 第一製薬株式会社 | 2位置換トリアゾロピリミジン類 |
JPH04154720A (ja) | 1990-10-16 | 1992-05-27 | Terumo Corp | カテコール誘導体及びこれを含有する血管壁肥厚防止薬 |
TW279162B (zh) | 1991-09-26 | 1996-06-21 | Mitsubishi Chem Corp |
-
1995
- 1995-05-16 DK DK95107372.5T patent/DK0682947T3/da active
- 1995-05-16 US US08/441,743 patent/US5643911A/en not_active Expired - Fee Related
- 1995-05-16 EP EP95107372A patent/EP0682947B1/en not_active Expired - Lifetime
- 1995-05-16 DE DE69500673T patent/DE69500673T2/de not_active Expired - Fee Related
- 1995-05-16 AT AT95107372T patent/ATE157871T1/de not_active IP Right Cessation
- 1995-05-16 ES ES95107372T patent/ES2109752T3/es not_active Expired - Lifetime
- 1995-05-18 CN CN95106317.0A patent/CN1116526A/zh active Pending
- 1995-05-18 CA CA002149691A patent/CA2149691A1/en not_active Abandoned
-
1997
- 1997-12-02 GR GR970403218T patent/GR3025568T3/el unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1103591C (zh) * | 1996-05-22 | 2003-03-26 | 永光制药有限公司 | 取代的1,4,5,6-四氢哒嗪并[4,5-c]哒嗪-5-酮类化合物之药物组合物及其应用和制备方法 |
Also Published As
Publication number | Publication date |
---|---|
ES2109752T3 (es) | 1998-01-16 |
DE69500673T2 (de) | 1998-03-19 |
EP0682947A1 (en) | 1995-11-22 |
DE69500673D1 (de) | 1997-10-16 |
US5643911A (en) | 1997-07-01 |
EP0682947B1 (en) | 1997-09-10 |
DK0682947T3 (da) | 1998-05-04 |
ATE157871T1 (de) | 1997-09-15 |
GR3025568T3 (en) | 1998-03-31 |
CA2149691A1 (en) | 1995-11-20 |
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