CN1394860A - 3－苯基－3,7－二氮杂双环[3,3,1]壬烷化合物及其制法和含有它的药物 - Google Patents
3－苯基－3,7－二氮杂双环[3,3,1]壬烷化合物及其制法和含有它的药物 Download PDFInfo
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- CN1394860A CN1394860A CN02124963A CN02124963A CN1394860A CN 1394860 A CN1394860 A CN 1394860A CN 02124963 A CN02124963 A CN 02124963A CN 02124963 A CN02124963 A CN 02124963A CN 1394860 A CN1394860 A CN 1394860A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
一种通式I的药物活性化合物其中R1为1－6个碳原子的烷基或4－7个碳原子的环烷基烷基，R2为低级烷基和R3为低级烷基或R2和R3共同形成3－6个碳原子的亚烷基链，R4代表在邻位或对位被硝基、氰基或低级烷酰基单取代或在邻位和对位被硝基双取代的苯基，和其生理上可接受的酸加成盐。
Description
发明领域
本发明涉及新的3，7，9，9-四取代的3，7-二氮杂双环[3，3，1]壬烷化合物，在3位带有一个取代的苯基，和其盐以及含有这种化合物的药物制剂和该化合物的制法。
背景技术
从EP-A 0 665 014已知有抗心律失常性质的3-苯甲酰基-3，7-二氮杂双环[3，3，1]壬烷衍生物。
从EP-A 0 665 228还已知有抗心律失常性质的3-苯基磺酰基-3，7-二氮杂双环[3，3，1]壬烷衍生物以及含有它们的药物。
发明内容
本发明的任务是开发有改善作用方式的新的抗心律失常作用的活性物质。本发明的另一任务是开发具有价值的药理学性质的新的-3，7-二氮杂双环[3，3，1]壬烷化合物。
现已发现，新的在3位带有一个取代的苯基的3，7，9，9-四取代的3，7-二氮杂双环[3，3，1]壬烷化合物具有用于治疗和/或预防心律失常的有价值的药理学性质，并显示出抗心律失常的作用方式，特别适合于治疗心律干扰，尤其是心动过速性心律失常。
因此，本发明涉及一种新的通式I的化合物其中R1为1-6个碳原子的烷基或4-7个碳原子的环烷基烷基，R2为低级烷基和R3为低级烷基或R2和R3共同形成3-6个碳原子的亚烷基链，R4代表在邻位或对位被硝基、氰基或低级烷酰基单取代或在邻位和对位被硝基双取代的苯基，和其生理上可接受的酸加成盐。
如果在式I化合物中R1代表烷基，它可以是直链或支化的并含有1-6，优选3-5，尤其4个碳原子。一个环烷基烷基R1可优选为环丙基甲基。特别适合的R1基团证明是有3-5个碳原子的烷基。
如果取代基R2和R3是低级烷基，该烷基可以是直链或支化的并含有1-4，优选1-3个碳原子，特别是甲基。如果R2和R3共同形成一个亚烷基，它可以含有3-6，优选4-5个碳原子。尤其证明合适的化合物是其中R2和R3共同为一个4-5个碳原子的亚烷基链。
取代基R4是一个取代的苯基，其中苯基上的取代基安排在邻位或对位。一个低级烷酰基取代基可以含有2-5，优选2-3个碳原子。优选地，R4是一个在对位被氰基或低级烷酰基，尤其是氰基取代的苯基。
根据本发明，式I的新化合物和它的酸加成盐是经下列方法得到，通式II的化合物
其中R1、R2和R3具有上述含义，与通式III的化合物以已知的方法反应，
R4-X III其中R4有上述含义，X为卤素，和必要时将式I的自由化合物转变成其酸加成盐或将这种酸加成盐转变成式I的自由化合物。
式II的化合物与式III的化合物的反应可通过已知的方式在用胺取代芳族卤化物的常见条件下进行。式II化合物中的卤素合适的特别是氯或氟。该反应在于反应条件下呈惰性的有机溶剂中在室温至反应混合物沸点之间的温度下进行。适合的有机溶剂例如是醚类，特别是环醚如四氢呋喃，低级烷醇如丁醇，低级脂族酮如丙酮，二甲亚砜，二甲基甲酰胺，芳族烃如苯或甲苯或者上述溶剂的混合物。有利的是，反应在碱性条件下，例如在至少等当量的一种碱存在下进行。合适碱的例子是无机碱如碱金属氢氧化物，碱金属碳酸盐，碱金属氨化物或碱金属氢化物或有机碱如低级烷基叔胺。
式I化合物可经已知的方式从反应混合物中分离和纯化。酸加成盐可以常见的方式转变成游离碱和它可按需要以已知的方式转变成药理学相容性的酸加成盐。
适合的式I化合物的药理学可接受酸加成盐例如是它与无机酸例如氢卤酸尤其盐酸，硫酸或磷酸，或与有机酸，例如低级脂族一元、二元或三元羧酸如马来酸、富马酸、乳酸、酒石酸、乙酸或柠檬酸，或与磺酸，例如低级烷基磺酸如甲磺酸或在苯环上任选被卤素或低级烷基取代的苯磺酸如对甲苯磺酸的常见盐。
如果式I化合物中的取代基R2和R3不同，该化合物含有一个手性中心并可以两种旋光形式或作为外消旋体存在。本发明既包括式I化合物的外消旋体混合物也包括其光学异构体。旋光化合物可从外消旋混合物中以本身已知的方式通过常见的拆分方法得到，例如通过在手性拆分材料上的色谱法或用旋光性酸分级结晶适合的盐。对映异构体纯的化合物也可以通过从相应的对映异构体纯的式II起始化合物合成来制备。
式II起始化合物从DE-OS 2 658 558，EP-A 0 103 833和EP-A 0306 871知道和/或根据这些专利中描述的方法或类似于这些专利中描述的方法以本身已知的方式制备。式III的起始化合物是已知的和/或可按照本身已知的方法或类似于本身已知的方法制备。
现在意外地发现，本发明的式I化合物和其生理相容性酸加成盐具有特别好的抗心律失常作用。它们特别显示出III级抗心律失常性质，可导致EKG中的QT间隔延长并有延长心脏有效不应期的作用。该化合物具有有利的作用方式，有好的相容性、作用持续时间长和对降血压性质很高选择性的抗心律失常作用，使得在抗心律作用的剂量范围内不会出现治疗上不希望的对血压的影响。该化合物的特征是，抗心律失常作用在心动过速状况下特别显著。另外，本发明的化合物具有其抗心律失常性只有意外较低的致前心律失常副作用的性质。
该化合物的抗心律失常作用在药理学标准试验方法中得到验证。在试验方法中对单个受测物质给出的实施例号分别基于后面的制备实施例。
药理学检测方法描述。
1.测定最小毒性剂量。
20-25g重的雄性大鼠经口服给药最大剂量300mg/kg的受测物质。对动物认真观察中毒症状3小时。给药后经72小时另外记录各种症状和死亡情况。同时观察伴发症状并记录。当观察到死亡或强中毒症状时，对其它大鼠给药逐步减少的剂量，直到不再出现中毒症状。引起死亡或强中毒症状时的最低剂量在下表A中作为最小毒性剂量列出。
| 受测物质实施例号 | 最小毒性剂量mg/kg大鼠，口服 |
| 12 | 300300 |
2.在麻醉的海豚体上在心动过速条件下进行受测物质抗心律失常特性的活体内试验。
将海豚麻醉后静脉内给药后，在提高心率的条件下，检测受测物质对有效不应期(＝ERP)和血压的作用。全麻下将双极刺激导管经颈静脉插入动物右心室。电刺激经过导管传导使动物心率在整个试验过程中保持在其正常心率的约150％。在另一颈静脉内插入导管用于静脉内注射受测物质。在试验过程中用血压计(＝Statham-Drucktransdicer)在一侧颈动脉测量收缩期和舒张期血压(SAP和DAP)。受测物质以增加的剂量静脉内给药(蓄积性)。在第一次给药前和每个剂量给药后8分钟，分别用双脉冲记录仪测定ERP。ERP延长到起始值的115％时的剂量作为有效剂量(ERP-ED115)。降压作用的有效剂量为，SAP降低至其起始值的85％的剂量(SAP-ED85)和DAP降低至其起始值的85％的剂量(DAP-ED85)。
在下面的表B中列出了按照上述方法所获得的结果。
表B
| 实施例号 | 抗心律失常作用ERP-ED115μmg/kg，静脉内给药 | 降压作用*ED85，μmg/kg，静脉内给药DAP SAP |
| 12 | 0.41 | ＞＞10 ＞＞105 5 |
*＞＞表示：在测试剂量下没有任何降压的迹象。3.在电刺激后的海豚心脏乳头肌上体外测定受测物质对功能不应期的作用。
受测物质延长不应期的作用，也可以通过体外试验，在离体的海豚右心室乳头肌上测定功能不应期(＝FRP)得以证实。
击颈处死海豚，迅速取出其心脏，然后将右心室乳头肌固定在器官浴池中，该浴池中流动着经过保温和氧化的营养液。以3Hz的频率电刺激肌肉标本。将受测物质以不断提高的浓度(蓄积性)添加在进浴池中。每次在添加受测物质后20分钟，用双脉冲记录仪测定功能不应期。由所测得的数值分别演示出蓄积浓度-作用曲线。由该曲线找出使FRP延长12毫秒的浓度作为有效浓度(＝FRP-EC+12MS)。
在下面的表C中列出了按照上述方法所获得的结果。
表C
4.离体灌注大白兔心脏上体外测定受测物质的致前心律失常潜能
| 实施例号 | 抗心律失常作用FRP-EC+12MS，μmol/l |
| 1234 | 0.60.70.60.8 |
可以借助于在离体灌注大白兔心脏上诱导的单相动作电位，测量电生理参数如“不稳定性”和“三角化”(见以下)，以此来估计III级抗心律失常作用物质的致前心律失常潜能的尺度。以下说明的药理学试验是按照L.M.Hondeghem等，循环
103期(2001年)2004-2013页(以下标注为Hondeghem等)，与L.M.Hondeghem相关联，心血管电生理学杂志，
5期(8)(1994年)711-721页(以下标注为Hondeghem)，所说明的方法进行的。
击颈处死大白兔，迅速取出其心脏，然后立即在朗根多夫装置中在恒定压力(80cm H2O)下用经过保温和氧化的营养液灌注。将二个诱发电极分别置于左和右希氏束侧枝区域内，由此可以不同的诱发程序刺激心脏(对照Hondeghem等)。另外二个电极(一个心内膜电极在左心室室间隔区域，一个参考电极在左心室心包膜下)用于导出单相动作电位。
借助于各种再极化过程中的单相动作电位持续时间(APD10-90；直至出现10％再极化的动作电位持续时间被视为APD10)得出以下参数作为前心律失常致原指数：
(1)不稳定性：由心动周期至心动周期的APD60的改变称为不稳定性。在对照条件下该数值平均为约7毫秒(＝ms)。如果较明显偏离该平均值直至较长的持续时间(＞7ms)，说明由受测物质所致前心律失常的可能性较大。
(2)三角化：以ms为单位由ADP30至ADP90再极化时间称为三角化。在对照条件下该数值通常为约90ms。因受测物质影响，再极化时间明显延长超过该对照数值时，说明再极化过程速度减慢，这样又会使后极化的比率(＝前心律失常)提高。
在以下的表D中列举了分别在三个心脏(n＝3)上按照上述方法所得结果。
表D
5.对快速和慢速整流减缓的钾流的阻滞作用(iKr以及iKs)
| 实施例号 | 浓度 | 不稳定性(ms) | 三角化(ms) |
| 4 | 0.3μM1μM | 6/3/36/25/7 | 48/64/6252/79/79 |
所谓的III级抗心律失常作用物质(按照Vaughan-Williams)的作用原理，是以对各种不同的、参与心肌动作电位再极化过程的、细胞的钾外流的阻滞作用为基础的。它又导致心脏不应期的延长，由此可以防止心律失常。在此，III级抗心律失常作用物质的致前心律失常危机与以下有关：被阻滞的是哪种钾流或哪些钾流组合被阻滞。由文献已知，选择性的iKr阻滞潜藏着较高的致前心律失常危机，而同时阻滞iKr和iKs时致前心律失常危机明显减少。
可以按照以下说明的方法选择性地测量iKs：迅速取出麻醉后的狗的心脏，将左心室的肌肉切片用富含胶原酶的溶液通过一动脉血管灌注。将分离好的组织切碎，然后用“全细胞片-夹”方法(参见O.P.Hamill等，普夫吕格氏文献
391(2)(1981年)85-100页)对那些零星的细胞进行电生理学试验：为了选择性地试验对iKs的阻滞作用，通过添加1μMNisoldipine(＝钙内流的选择性阻滞剂)以阻滞钙内流，对于iKr则通过添加2μM E-4031(＝选择性iKr阻滞剂)，通过-40mV的静止电位阻滞快速的钠内流和瞬间钾外流。这样借助于电流幅度可以在由-40mV静止电位至最大+50mV去极化作用5秒钟脉冲记录后立即得出iKs。
可以按照以下说明的方法选择性地测量iKr(HERG)：测量iKr时应用一种细胞系(人类胚胎肾细胞，HEK293；例如可参见美国组织文化汇集(＝ATCC)-Nr.：CRL-1573)，它可以稳固地与用于iKr(HERG)的基因进行转化(参见Z.Zhou等，生物物理学杂志
74(1)(1998年)230-241页)。由于所应用的细胞没有干扰测量的其它离子流，因而可以放弃添加相关的通道阻滞剂。根据-40mV静止电位时的电流幅度，可以在由-75mV静止电位至最大+10mV去极化作用的500毫秒脉冲记录后立即得出iKr。
根据各种不同的物质浓度下相应电流的阻滞作用，可以得出最大电流的50％受阻滞的各个物质浓度(IC50％)。在下列表E中显示了按照上述方法所获得的结果：
表E
| 实施例号 | IC50％-iKs | IC50％-iKr |
| 34 | 0.7μM0.7μM | 0.09μM0.02μM |
在另外一例麻醉后的猫上所做的体内试验中，实施例4的化合物在口服和静脉内给药后显示出与剂量相关的、明显而持续提高的颤动波，并且在心房较在心室显著。这样一种心房选择性的颤动波提高提示：受测化合物具有有益的作用方式而致前心律失常危险性减小。
上述结果表明：通式I化合物具备抗心律失常作用、可以明显延长心肌有效不应期，并且只是在受测物质的剂量明显高于延长不应期的有效剂量时，才出现有效降血压作用。上述试验结果还显示了：本发明物质原本用于发挥其致前心律失常副作用的令人惊异的微小倾向，与其影响较大哺乳动物和人类心细胞的各种不同的外向钾流，例如影响iKr和iKs的特殊作用方式之间所存在的关系。
根据其上述作用方式，本发明物质适合于抑制心动过速性质的心律失常，并且可以应用于较大哺乳动物和人类预防和治疗心律失常。该物质尤其适合于防止过速型心律失常，即伴有心率加快的心律失常的出现。
所应用的剂量可以存在个体差异，根据所治疗的病状、所应用的物质和给药方式的不同自然有所变化。但是一般来说较大哺乳动物特别是人类用药时，每单次剂量的有效作用物质含量为0.5至100，特别是1至25mg。
作为治疗药物，通式I化合物可以与通常的制药助剂一起制成盖伦氏制剂如片剂、胶囊、栓剂或溶剂。生产这些盖伦氏制剂可以按照已知的方法、应用通常的固体的或液体的载体例如乳糖、淀粉或滑石粉或液态石蜡、和/或应用通常的制药学助剂，例如片剂崩解、增溶剂或防腐剂。
下列实施例用于进一步解释本发明，但不以任何方法限制其范围。
实施例1：
7-正丁基-3-(2，4-二硝基苯基)-9，9-二甲基-3，7-二氮杂双环[3，3，1]壬烷
向4.2g 2，4-二硝基氟苯在40ml丙酮中的溶液中搅拌下滴入4.7g 7-正丁基-9，9-二甲基-3，7-二氮杂双环[3，3，1]壬烷在10ml丙酮中的溶液。反应混合物在室温下继续搅拌并放置过夜。然后蒸去丙酮，残余物与柠檬酸水溶液混合，该混合物用乙酸乙酯萃取两次。为进一步加工，将含水残余物用稀释的苛性钠溶液碱化。混合物再用乙酸乙酯萃取两次。合并的有机相用硫酸镁干燥并浓缩。残余物从乙醚/己烷中重结晶。得到5.5g 7-正丁基-3-(2，4-二硝基苯基)-9，9-二甲基-3，7-二氮杂双环[3，3，1]壬烷，熔点为119℃。
0.61g目标化合物在油浴加热下溶于10ml异丙醇中。向溶液中加入0.7ml 3.8N盐酸异丙醇溶液。然后冷却反应混合物，滤出形成的结晶。得到0.5g目标化合物的盐酸盐，熔点为136-138℃。
根据上述实施例中描述或与其类似的方法，也可以制备下表F中列出的式I化合物。
表F
Cyp＝环丙基，n＝正，i＝异，HTa＝酒石酸氢盐，HCl＝盐酸盐，B＝碱，am＝无定形
| 实施例 | R1 | R2 | R3 | R4 | 盐 | Fp.℃ |
| 2 | n-C4H9- | CH3- | CH3- | 4-NO2-phen | B | 116-118 |
| 3 | n-C4H9 | -(CH2)4- | 4-CH3-CO-pher | 1HTa | 111 | |
| 4 | n-C4H9- | -(CH2)4- | 4-CN-phen | 1HTa | 115 | |
| 5 | n-C4H9- | n-C3H7- | CH3- | 4-CN-phen | 1HTa | am |
| 6 | n-C6H13- | CH3- | CH3- | 4-CN-phen | 1HTa | am |
| 7 | Cyp-CH2- | -(CH2)4- | 4-CN-phen | B | 101-103 | |
| 8 | i-C4H9- | -(CH2)5- | 4-CN-phen | 1HCl | 138-142 | |
| 9 | CH3- | -(CH2)5- | 4-CN-phen | 1HCl | 270 |
实施例I
含有7-正丁基-3-(4-氰基苯基)-9，9-四亚甲基-3，7-二氮杂双环[3，3，1]壬烷-酒石酸氢盐的片剂
制备每片有以下组成的片剂：7-正丁基-3-(4-氰基苯基)-9，9-四亚甲基-3，7-
二氮杂双环[3，3，1]壬烷-酒石酸氢盐 20mg玉米淀粉 60mg乳糖 135mg明胶(10％溶液) 6mg
将活性物质，玉米淀粉和乳糖与10％的明胶溶液增稠。将糊料粉碎，形成的颗粒加到合适的金属片上并在45℃干燥。干燥后的颗粒通过粉碎机并在混合机中与下列其它助剂混合：
滑石 5mg
硬脂酸镁 5mg
玉米淀粉 9mg然后压成240mg的片剂。
Claims (8)
1.一种通式I的药物活性化合物
其中R1为1-6个碳原子的烷基或4-7个碳原子的环烷基烷基，R2为低级烷基和R3为低级烷基或R2和R3共同形成3-6个碳原子的亚烷基链，R4代表在邻位或对位被硝基、氰基或低级烷酰基单取代或在邻位和对位被硝基双取代的苯基，和其生理上可接受的酸加成盐。
2.如权利要求1的化合物，其中R4是在对位被氰基或低级烷酰基单取代的苯基。
3.如前述权利要求之一的化合物，其中R1是3-5个碳原子的烷基，R2和R3共同形成3-6个碳原子的亚烷基链。
4.如权利要求1的7-正丁基-3-(4-氰基苯基)-9，9-四亚甲基-3，7-二氮杂双环并[3，3，1]壬烷。
5.如权利要求1的7-正丁基-3-(4-乙酰基苯基)-9，9-四亚甲基-3，7-二氮杂双环并[3，3，1]壬烷。
6.药物，其特征是，包括药物活性量的权利要求1的化合物和制药助剂和/或赋形剂。
7.权利要求1的化合物用于制备治疗和/或预防心律失常的药物制剂的用途。
8.一种通式I的药物活性化合物的制法
其中R1为1-6个碳原子的烷基或4-7个碳原子的环烷基烷基，R2为低级烷基和R3为低级烷基或R2和R3共同形成3-6个碳原子的亚烷基链，R4代表在邻位或对位被硝基、氰基或低级烷酰基单取代或在邻位和对位被硝基双取代的苯基，和其生理上可接受的酸加成盐。其特征为：通式II的化合物
其中R1、R2和R3具有上述含义，与通式III的化合物反应，
R4-X III其中R4有上述含义，X为卤素，和必要时将式I的自由化合物转变成其酸加成盐或将这种酸加成盐转变成式I的自由化合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10131217A DE10131217A1 (de) | 2001-06-28 | 2001-06-28 | 3-Phenyl-3,7-diazabicyclo 3,3,1 nonan-Verbindungen sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel |
| DE10131217.2 | 2001-06-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1394860A true CN1394860A (zh) | 2003-02-05 |
| CN1303082C CN1303082C (zh) | 2007-03-07 |
Family
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| Application Number | Title | Priority Date | Filing Date |
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| CNB021249636A Expired - Fee Related CN1303082C (zh) | 2001-06-28 | 2002-06-27 | 3－苯基－3,7－二氮杂双环[3,3,1]壬烷化合物及其制法和含有它的药物 |
Country Status (30)
| Country | Link |
|---|---|
| US (1) | US6602880B2 (zh) |
| EP (1) | EP1270576B1 (zh) |
| JP (1) | JP4223237B2 (zh) |
| KR (1) | KR20030002304A (zh) |
| CN (1) | CN1303082C (zh) |
| AR (1) | AR033772A1 (zh) |
| AT (1) | ATE276254T1 (zh) |
| AU (1) | AU781333B2 (zh) |
| BR (1) | BR0202419A (zh) |
| CA (1) | CA2391915C (zh) |
| CZ (1) | CZ296878B6 (zh) |
| DE (2) | DE10131217A1 (zh) |
| DK (1) | DK1270576T3 (zh) |
| DZ (1) | DZ3235A1 (zh) |
| ES (1) | ES2229020T3 (zh) |
| HK (1) | HK1051860A1 (zh) |
| HU (1) | HUP0202057A3 (zh) |
| IL (1) | IL150431A0 (zh) |
| MX (1) | MXPA02006225A (zh) |
| NO (1) | NO20023112L (zh) |
| NZ (1) | NZ519811A (zh) |
| PL (1) | PL207995B1 (zh) |
| PT (1) | PT1270576E (zh) |
| RU (1) | RU2299210C2 (zh) |
| SI (1) | SI1270576T1 (zh) |
| SK (1) | SK5862002A3 (zh) |
| TR (1) | TR200402391T4 (zh) |
| TW (1) | TWI256393B (zh) |
| UA (1) | UA76707C2 (zh) |
| ZA (1) | ZA200204063B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875550A (zh) * | 2011-07-12 | 2013-01-16 | 上海药明康德新药开发有限公司 | 1,3,7-三取代-3,7-二氮杂双环[3,3,1]壬烷衍生物及制备方法 |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200418468A (en) * | 2002-11-18 | 2004-10-01 | Solvay Pharm Gmbh | Liquid pharmaceutical formulations containing 3,7-diazabicyclo[3,3,1]nonane compounds and method of treatments relating to anti-arrhytmic events |
| ES2603856T3 (es) * | 2004-03-29 | 2017-03-01 | Les Laboratoires Servier | Procedimiento para preparar una composición farmacéutica sólida |
| SI21800A (sl) * | 2004-05-14 | 2005-12-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Nov postopek sinteze perindoprila |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2658558A1 (de) | 1976-12-23 | 1978-06-29 | Bayer Ag | Diazabicyclo(3,3,1)nonane, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
| DE3234697A1 (de) * | 1982-09-18 | 1984-03-22 | Kali-Chemie Pharma Gmbh, 3000 Hannover | Neue diazabicyclo-(3,3,1)-nonane |
| US4742217A (en) * | 1986-06-02 | 1988-05-03 | Honeywell Inc. | Projection alignment and focusing aid |
| PT88381B (pt) | 1987-09-09 | 1995-07-06 | Kali Chemie Pharma Gmbh | Processo para a preparacao de novos compostos 3,7-diazabiciclo{3,3,1} nonano, e de composicoes farmaceuticas que contem estes compostos |
| DE4402931A1 (de) | 1994-02-01 | 1995-08-03 | Kali Chemie Pharma Gmbh | Neue 3-Phenylsulfonyl-3,7-diazabicyclo[3,3,1] nonan-Verbindungen enthaltende Arzneimittel |
| DE4402933A1 (de) | 1994-02-01 | 1995-08-03 | Kali Chemie Pharma Gmbh | Neue 3-Benzoyl-3,7-diazabicyclo[3,3,1] nonan-Verbindungen enthaltende Arzneimittel |
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- 2002-05-27 AR ARP020101975A patent/AR033772A1/es not_active Application Discontinuation
- 2002-05-27 KR KR1020020029155A patent/KR20030002304A/ko not_active Application Discontinuation
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- 2002-06-22 EP EP02013861A patent/EP1270576B1/de not_active Expired - Lifetime
- 2002-06-22 ES ES02013861T patent/ES2229020T3/es not_active Expired - Lifetime
- 2002-06-22 SI SI200230027T patent/SI1270576T1/xx unknown
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- 2002-06-26 IL IL15043102A patent/IL150431A0/xx unknown
- 2002-06-26 DZ DZ020152A patent/DZ3235A1/fr active
- 2002-06-26 AU AU50644/02A patent/AU781333B2/en not_active Ceased
- 2002-06-26 UA UA2002065292A patent/UA76707C2/uk unknown
- 2002-06-26 NZ NZ519811A patent/NZ519811A/en unknown
- 2002-06-26 BR BR0202419-5A patent/BR0202419A/pt not_active IP Right Cessation
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875550A (zh) * | 2011-07-12 | 2013-01-16 | 上海药明康德新药开发有限公司 | 1,3,7-三取代-3,7-二氮杂双环[3,3,1]壬烷衍生物及制备方法 |
| CN102875550B (zh) * | 2011-07-12 | 2016-01-06 | 常州合全药业有限公司 | 1,3,7-三取代-3,7-二氮杂双环[3,3,1]壬烷衍生物及制备方法 |
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