CN1237969A - 吡啶斯的明及相关化合物的多价盐 - Google Patents
吡啶斯的明及相关化合物的多价盐 Download PDFInfo
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- CN1237969A CN1237969A CN97199841A CN97199841A CN1237969A CN 1237969 A CN1237969 A CN 1237969A CN 97199841 A CN97199841 A CN 97199841A CN 97199841 A CN97199841 A CN 97199841A CN 1237969 A CN1237969 A CN 1237969A
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- compound according
- compound
- anion
- multivalent
- quaternary ammonium
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明涉及将季铵胆碱能药剂与多价阴离子，或与多个单价阴离子配合。配合物可以作为胆碱能药剂对患者口服给药，或者用于某些其它用途。本发明尝试了许多修饰方法，包括修饰化合物的环结构，和取代和环的官能团化。其他尝试的修饰包括使用各种阴离子，包括各种单价和多价阴离子，和有机和无机阴离子。这些化合物具有作为胆碱能药剂的用途，尤其是用于治疗mysastheniagravis，胸痛，和腕管综合征。
Description
发明领域
本发明涉及胆碱能药剂。
发明背景
吡啶斯的明，即3-[[(二甲氨基)羰基]氧基]-1-甲基吡啶鎓(MestinonTM)，和新斯的明，即3-[[(二甲氨基)-羰基]氧基]-N,N,N-三甲基苯铵(新斯的明)，和滕西隆，即N-乙基-3-羟基-N,N-二甲基苯铵都是胆碱能药剂。这些化合物已经具有某些已知用途包括治疗mysasthenia gravis，食管胸痛，和神经化学毒剂的预暴露解毒药。这些化合物也可以用于治疗腕管综合征。
吡啶斯的明和新斯的明通常作为溴化物盐给药，而滕西隆通常作为氯化物盐给药。而这些已知的单价盐通常被认为是适当的，现在，注意到多价盐可能是更稳定的，并且可能具有更好的物理特性，尤其是以固体物理剂量形式。也可能有比单价盐优越的药物动力学。还注意到具有多价季铵位置的化合物可以具有有用的制药好处。
发明概述
本发明的季铵胆碱能药剂与多价阴离子，或与多个单价阴离子配合。配合物可以作为胆碱能药剂口服给药，或者用于某些其它用途。现己想出了许多修饰方法，包括修饰化合物的环结构，和环的取代和官能团化。其他想尝试的修饰包括使用不同的阴离子，包括各种单价和多价阴离子，和有机和无机阴离子。
附图的简要说明
图1是根据本发明的一方面的一类多价季铵胆碱能药剂的通式分子式。
图2是根据本发明的另一方面的第二类多价季铵胆碱能药剂的通式分子式。
图3是根据本发明的另一方面的第三类多价季铵胆碱能药剂的通式分子式。
图4是根据本发明的另一方面的第四类多价季铵胆碱能药剂的通式分子式。
图5是根据本发明的另一方面的第五类多价季铵胆碱能药剂的通式分子式。
图6是根据本发明的另一方面的第六类多价季铵胆碱能药剂的通式分子式。
图7是根据本发明的另一方面的第七类多价季铵胆碱能药剂的通式分子式。
图8是根据本发明的另一方面的第八类多价季铵胆碱能药剂的通式分子式。
图9是根据本发明的另一方面的第九类多价季铵胆碱能药剂的通式分子式。
图10是根据本发明的另一方面的第十类多价季铵胆碱能药剂的通式分子式。
发明详述
本发明使用的术语“季铵胆碱能药剂”通常用于指吡啶斯的明，新斯的明，滕西隆，和这些化合物的取代的或官能化的类似物。因此，在本发明中任何这些化合物的多价盐有时被称为多价季铵胆碱能药剂盐。其他的化学术语具有它们通常被接受的含义。
本发明中有许多被考虑的化合物，其中的一些实例被描述在图1-10中。这些化合物都具有下列结构：其中：
M是单价阴离子，许多单价阴离子，或多价阴离子；
R是环或环系统；
Y是烷基，取代的烷基，芳基，取代的芳基，芳烷基，取代的芳烷基，或NR3R4R5，其中R1,R2,R3,R4和R5各自独立地是H，烷基，取代的烷基，芳基，或取代的芳基；
x是大于1的整数；和
(LINK)是可任选的连接基(linker)。
环或环系统理解为包括至少一个五元或六元环，其可以是未被取代的碳环，或者可以是具有一个或多个硫、氮或其他取代的杂环。环可以是芳族或非芳族环。优选的环包括吡啶，嘧啶，氮杂嘧啶和苯。
优选的阴离子包括无机和有机离子，和特别是包括三溴离子(Br3)-3，碳酸根CO3 -2，硝酸根NO2 -2，硫酸根SO4 -2，磷酸氢根HPO4 -2，亚磷酸根PO3 -2，磷酸根PO4 -3，和有机酸阴离子包括二羧酸阴离子如草酸、丙二酸、琥珀酸和苯二甲酸的阴离子。其中采用大量的单价阴离子，尝试使用的阴离子可以包括卤素，HCO3 -,CH3COO-,CH3SO4 -,CH3SO3 -和C4H5O6 -。
优选的连接基包括1至10个碳原子脂肪族链。该链的骨架可以或者不必完全由碳原子组成，和可以或者不必被取代或者是支链的。但是最优选的(LINK)应该是-S-或-(CH2)n-，其中n是1至4的整数。(LINK)一般不在环原子上直接与基本分子连接，而是通过官能度从环延伸。
图1-10描述了10个不同类型的化合物，它们在本发明中被考虑。其结构本身对其进行了说明。合成
多价季铵胆碱能药剂的合成是直接简单的。在其中的一种方法中，活性部分的多价盐(如溴化吡啶斯的明)流经阳离子交换柱。适用于该用途的树脂是安伯来特。该生产方法根据下列反应：
该方法中3克溴化吡啶斯的明使用将近23meq树脂，23meq≈12毫升树脂床。更详细的方法如下：(1)在带有玻璃绒毛塞的25毫升塑料吸移管中制备12毫升树脂床安伯来特IR-116(NA+形式)。(2)用去离子水漂洗柱子直到澄清。(3)称量6克溴化吡啶斯的明，溶解在10毫升去离子水中，最终的体积约13.5毫升。(4)吸移6.7毫升(3克)溴化吡啶斯的明溶液至漂洗床。(5)让溶液流过该柱(床不能变干)。(6)用将近30毫升去离子水洗漂洗柱子直到收集的液滴用AgNO3溶液试验不再出现沉淀。吸移4毫升(10meq)Na2CO3溶液至漂洗床，用20毫升去离子水彻底漂洗。收集在250毫升烧瓶中。(8)在旋转蒸发仪上快速蒸发溶液至干。(9)在玻璃储藏小瓶中收集固体物料。试验结果
吡啶斯的明碳酸盐的合成如上面所述。当放入盐酸中时，产物变成相应的吡啶斯的明，其被在269nm处的吸收光谱所证实。药物制剂
与其他药物制剂一样，多价季铵胆碱能盐可以采用许多适当的选自下列的给药方式对人体给药，这些给药方式包括口服，静脉给药，肌内给药，腹膜内给药，局部等给药方式。除了含有一种或多种不同的多价季铵胆碱能药剂盐之外，主题药物制剂可以含有一种或多种非-生物活性化合物，即，赋形剂，如稳定剂(有助于长期贮藏)，软化剂，粘结剂，增稠剂，盐，防腐剂等。
多价季铵胆碱能盐可以以一定的剂量和数量形式使用，这种剂量和数量形式在本领域中对于所述的季铵胆碱能药剂或季铵胆碱能药剂类化合物是方便的，但是它们被调整为更有效被吸收、传输和细胞摄取。因此，对于吡啶斯的明，其可以每天以1-3 180mg的片剂口服给药一或两次，其相应的多价季铵胆碱能药剂盐的剂量仍然可以是每天以1-3180mg的片剂给药一或两次。每天的剂量可以一次性给药，或者可以分成多次较少的剂量经过一定的时间间隔给药。
可以采用一定的剂量规则以提供理想的治疗应答。例如，最优选的剂量应该根据所选择的具体药剂变化，在给药期间可以根据治疗情况的紧急程度所指示按比例增加或减少剂量。
多价季铵胆碱能药剂盐可以以任何方便的方式给药，如提供口服，静脉注射，腹膜内，肌内，或者皮下或者其他已知的给药途径给药。对于口服给药，多价季铵胆碱能药剂盐可以与惰性稀释剂或与可同化可食用载体一起给药，或多价季铵胆碱能药剂盐可以直接掺入日常的食物中。口服给药的多价季铵胆碱能药剂盐可以与赋形剂掺合并且以可摄取片剂，口腔片剂，糖锭剂，胶囊，酏剂，混悬液糖浆，纸囊剂等形式使用。
片剂，糖锭剂，丸剂，胶囊等也可以含有下列成分：粘结剂，如黄芪胶，阿拉伯胶，玉米淀粉，或明胶；赋形剂，如磷酸二钙；崩解剂如玉米淀粉，马铃薯淀粉，海藻酸等；润滑剂如硬脂酸镁；和甜味剂，如蔗糖，乳糖或糖精；增香剂如薄荷油，冬青油，樱桃调味料。当剂量单位是胶囊时，其除了含有上述类型的物料之外，还可以含有液体载体。各种其他物料也可以作为包衣剂或者以其他剂量单位的改良的物理形式存在。例如，片剂，丸剂，或胶囊可以用胶或糖或者同时使用两者包衣。糖浆或酏剂可以含有作为甜味剂的蔗糖，作为防腐剂的对羟基苯甲酸甲基和丙基酯，染料和调味剂如樱桃或柑橘香味剂。这种添加剂物料应该以基本上无毒的数量使用。而且，多价季铵胆碱能药剂盐可以掺入持续-释放的制品和制剂中。
非肠道给药的制剂可以包含无菌含水溶液或分散剂，和用于无菌临时制剂的无菌粉末，可注射溶液或分散剂。溶液或分散剂也可以含有缓冲剂，稀释剂，和其他适当的添加剂，可以被设计成以有助于组合物中的多价季铵胆碱能药剂盐的细胞吸收，例如，多价季铵胆碱能药剂盐可以被包胶于适当的微脂粒中。用于非肠道给药的溶液剂和分散剂优选是适当给药的无菌和足够的液体，在生产和使用中是足够稳定的，并且可以防护微生物如细菌和真菌的污染作用。载体可以是溶剂或分散介质，包括，例如，水，乙醇，多元醇(例如，甘油，丙二醇，和液体聚乙二醇等)，及其适当的混合物，和植物油。可以通过例如使用包衣剂如卵磷脂，在分散剂情况下通过保持所需的颗粒度和通过使用表面活性剂保持适当的流动性。
无菌可注射溶液剂通过将所需数量的活性化合物掺入带有一种或多种不同的上述其他成分的适当的溶剂中，然后进行消毒制备得到。分散剂通常可以通过将各种无菌的活性成分掺入无菌载体中制备，上述载体含有基本分散介质和所需的列于上面的其他成分。在制备无菌可注射溶液剂的无菌粉末的情况中，优选的制备方法是真空干燥和冷冻干燥方法，该方法得到含活性成分和来自预先无菌过滤的溶液的其他所需成分的粉末。
局部给药的药物制剂尤其适合于某些用于局部治疗的生物活性化合物。用于局部治疗的制剂包括软膏，喷雾剂，凝胶，悬浮剂，洗剂，乳油剂等。除了主要的多价季铵胆碱能药剂盐之外，局部给药的制剂可以包括已知的载体物料如异丙醇，甘油，石蜡，硬脂醇，聚乙二醇等。可药用载体也可以包括已知的化学吸收促进剂。吸收促进剂的实例是例如二甲基乙酰胺(美国专利US3472931)，三氯-乙醇或三氟乙醇(美国专利US3891757)，某些醇和它们的混合物(英国专利GB1001949)，和英国专利GB1464975。
多价季铵胆碱能药剂盐的溶液剂可以在适当地与表面活性剂如羟基丙基纤维素混合的水中制备。分散剂也可以在甘油，液体聚乙二醇，和它们的混合物中和在油中制备。这些组合物和制剂可以有利地含有防腐剂以防止微生物生长。
避免微生物的作用可以通过使用各种抗菌剂和杀真菌剂进行，例如，使用对羟苯甲酸酯，氯代丁醇，苯酚，山梨酸，硫汞撒等。在许多情况中，优选包含等渗剂如氯化钠。可注射组合物的延续传送可以通过使用延缓吸收的试剂如单硬脂酸铝和明胶实现。
上述的组合物和制剂优选含有至少0.1％的活性多价季铵胆碱能药剂盐。当然，组合物和制剂的百分率可以变化，可以含有约2％至60％(重量)的给药量。在这种用于治疗的组合物和制剂中的活性化合物的数量是应该得到的适当的剂量。
本文中所述的“可药用载体”包括任何和所有溶剂，分散介质，包衣剂，抗菌剂和杀真菌剂，等渗剂和延迟吸收剂等。使用这些用于药物活性物的介质和试剂是本领域中公知的。除了在任何常规介质和试剂的范围内之外的介质或试剂与治疗活性成分不相容，在治疗组合物和制剂中用其进行了尝试。补充的活性成分也可以被掺入到该组合物和制剂中。
本文中使用的术语“治疗”与疾病相关，其指预防和改善在个体中已经存在的病症。本领域中的普通技术人员应该理解的是治疗对于避免疾病发作或减少与疾病有关的病症不必是完全有效的。对患者而言，需要减轻严重的病症，延迟病症的发作，或推迟严重病症的加重。除了主题多价季铵胆碱能药剂盐的治疗用途之外，多价季铵胆碱能药剂盐也可以用作研究吸收、分布、细胞吸收和功效的实验室手段。等同物
前面撰写的说明书被认为是足以使本领域的技术人员能够实施本发明。确实，上述内容的各种变体可以实施本发明，这种变体对于有机化学领域或其他相关的领域的技术人员来说是显而易见并且落入所附的权利要求书的范围之内。
权利要求书
1．具有多个根据式[Y-R-O-CO-NR1R2]+的氨基甲酸酯化学基团的药学上有效的胆碱能化合物，这些基团以下列的任一方式共价连接在一起：
(a)通过氨基甲酸酯碳基的α位的氮原子；和
(b)通过R的环结构中的季氮原子；其中R是环或环系统，Y是烷基，取代的烷基，芳基，取代的芳基，芳烷基，取代的芳烷基，或NR3R4R5，其中R1,R2,R3,R4和R5各自独立地是H，烷基，取代的烷基，芳基，或取代的芳基。
2．根据权利要求1的化合物，其中R是六元杂环。
3．根据权利要求1的化合物，其中R是六元杂环和Y在氮上与R共价连接。
4．根据权利要求1的化合物，其中R是嘧啶。
5．根据权利要求1的化合物，其中R是氮杂嘧啶。
6．根据权利要求1的化合物，其中R是苯基和Y是NR3R4R5。
7．根据权利要求1的化合物，其中R是五元杂环。
8．根据权利要求1-7之一的化合物，其还包括三溴离子。
9．根据权利要求1-7之一的化合物，其还包括选自碳酸根，硝酸根，和硫酸根的阴离子。
10．根据权利要求1-7之一的化合物，其还包括选自磷酸氢根，亚磷酸根，和磷酸根的阴离子。
11．根据权利要求1-7之一的化合物，其还包括有机酸阴离子。
12．根据权利要求1-7之一的化合物，其还包括选自碳酸根，硝酸根，硫酸根，磷酸氢根，亚磷酸根，磷酸根，和有机酸阴离子的阴离子。
13．根据权利要求1-7之一的化合物，其中所述基团通过1至10个原子的脂肪族链共价连接。
14．根据权利要求1-7之一的化合物，其中所述基团通过1至10个原子的脂肪族链共价连接，其还包括选自碳酸根，硝酸根，硫酸根，磷酸氢根，亚磷酸根，磷酸根，和有机酸阴离子的阴离子。
15．一种治疗应答于胆碱能药剂的病症的方法，包括对患者使用有效量的权利要求1-7之一的化合物。
16．一种治疗mysasthenia gravis的方法，包括对患者使用有效量的权利要求1-7之一的化合物。
17．一种治疗腕管综合征的方法，包括对患者使用有效量的权利要求1-7之一的化合物。
18．根据权利要求1-7之一的化合物，其在生理学条件下离解产生吡啶斯的明。
19．根据权利要求1-7之一的化合物，其在生理学条件下离解产生新斯的明。
20．根据权利要求1-7之一的化合物，其在生理学条件下离解产生滕西隆。
Claims (19)
1．具有下列结构的化合物：
其中：
M是单价阴离子，许多单价阴离子，或多价阴离子；
R是环或环系统；
Y是烷基，取代的烷基，芳基，取代的芳基，芳烷基，取代的芳烷基，或NR3R4R5，其中R1,R2,R3,R4和R5各自独立地是H，烷基，取代的烷基，芳基，或取代的芳基；
x是大于1的整数；和
(LINK)是可任选的连接基。
2．根据权利要求1的化合物，其中R是六元杂环。
3．根据权利要求1的化合物，其中R是六元杂环和Y在氮上与X共价连接。
4．根据权利要求1的化合物，其中R是嘧啶。
5．根据权利要求1的化合物，其中R是氮杂嘧啶。
6．根据权利要求1的化合物，其中R是苯基和Y是NR3R4R5。
7．根据权利要求1的化合物，其中R是五元杂环。
8．根据权利要求1-7之一的化合物，其中单价阴离子包括三溴离子。
9．根据权利要求1-7之一的化合物，其中多价阴离子包括碳酸根，硝酸根，和硫酸根之一。
10．根据权利要求1-7之一的化合物，其中多价阴离子包括磷酸氢根，亚磷酸根，和磷酸根之一。
11．根据权利要求1-7之一的化合物，其中多价阴离子包括有机酸阴离子。
12．根据权利要求1-7之一的化合物，其中阴离子包括碳酸根，硝酸根，硫酸根，磷酸氢根，亚磷酸根，磷酸根，和有机酸阴离子之一。
13．根据权利要求1-7之一的化合物，其中(LINK)包括1至10个原子的脂肪族链。
14．根据权利要求1-7之一的化合物，其中(LINK)包括1至10个原子的脂肪族链，阴离子包括碳酸根，硝酸根，硫酸根，磷酸氢根，亚磷酸根，磷酸根，和有机酸阴离子之一。
15．一种治疗应答于胆碱能药剂的病症的方法，包括对患者使用有效量的权利要求1-7之一的化合物。
16．一种治疗mysasthenia gravis的方法，包括对患者使用有效量的权利要求1-7之一的化合物。
17．一种治疗腕管综合征的方法，包括对患者使用有效量的权利要求1-7之一的化合物。
18．一种治疗应答于胆碱能药剂的病症的方法，包括对患者使用有效量的权利要求12的化合物。
19．一种治疗应答于胆碱能药剂的病症的方法，包括对患者使用有效量的权利要求14的化合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3118696P | 1996-11-19 | 1996-11-19 | |
| US60/031186 | 1996-11-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1237969A true CN1237969A (zh) | 1999-12-08 |
Family
ID=21858083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97199841A Pending CN1237969A (zh) | 1996-11-19 | 1997-11-10 | 吡啶斯的明及相关化合物的多价盐 |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US6211201B1 (zh) |
| EP (1) | EP0941224A4 (zh) |
| JP (1) | JP2001505561A (zh) |
| KR (1) | KR20000069028A (zh) |
| CN (1) | CN1237969A (zh) |
| AU (1) | AU717740B2 (zh) |
| BR (1) | BR9713112A (zh) |
| CA (1) | CA2271786A1 (zh) |
| CZ (1) | CZ172799A3 (zh) |
| HU (1) | HUP9904040A3 (zh) |
| IL (1) | IL129619A0 (zh) |
| NO (1) | NO992384L (zh) |
| NZ (1) | NZ335419A (zh) |
| PL (1) | PL333414A1 (zh) |
| SI (1) | SI20018A (zh) |
| SK (1) | SK64399A3 (zh) |
| WO (1) | WO1998022458A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107854428A (zh) * | 2016-12-20 | 2018-03-30 | 成都医学院 | 一种溴吡斯的明糖浆剂及其制备方法 |
| CN113277961A (zh) * | 2021-04-09 | 2021-08-20 | 深圳市新浩瑞医药科技有限公司 | 一种溴新斯的明的合成方法 |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1390032A4 (en) * | 2001-05-11 | 2004-12-29 | Marvin B Bacaner | NOVEL QUATERNARY AMMONIUM COMPOSITIONS COUPLED WITH AUXILIARY ANIONS, USES THEREOF IN KITS AND THE USE THEREOF FOR PREVENTING AND TREATING CERTAIN CONDITIONS |
| MXPA05003715A (es) * | 2002-10-07 | 2005-09-30 | Univ California | Modulacion de ansiedad a traves de bloqueo de hidrolisis de anandamida. |
| US20050182252A1 (en) | 2004-02-13 | 2005-08-18 | Reddy K. R. | Novel 2'-C-methyl nucleoside derivatives |
| JP2017512183A (ja) | 2014-02-13 | 2017-05-18 | リガンド・ファーマシューティカルズ・インコーポレイテッド | プロドラッグ化合物およびそれらの使用 |
| CN106687118A (zh) | 2014-07-02 | 2017-05-17 | 配体药物公司 | 前药化合物及其用途 |
| US11970482B2 (en) | 2018-01-09 | 2024-04-30 | Ligand Pharmaceuticals Inc. | Acetal compounds and therapeutic uses thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4692530A (en) * | 1967-03-07 | 1987-09-08 | The United States Of America As Represented By The Secretary Of The Army | Chemical agents |
| US4686293A (en) * | 1967-05-29 | 1987-08-11 | The United States Of America As Represented By The Secretary Of The Army | Chemical agents |
| US4672120A (en) * | 1967-07-03 | 1987-06-09 | The United States Of America As Represented By The Secretary Of The Army | Chemical agents |
| US4246416A (en) * | 1967-12-01 | 1981-01-20 | The United States Of America As Represented By The Secretary Of The Army | Chemical agents |
| US4677222A (en) * | 1968-01-22 | 1987-06-30 | The United States Of America As Represented By The Secretary Of The Army | Ketobenzylcarbamates |
| US5534623A (en) * | 1993-01-21 | 1996-07-09 | Du Pont (Uk) Limited | Process for preparing a polyunsaturated diazonium compounds |
-
1997
- 1997-11-10 KR KR1019997004410A patent/KR20000069028A/ko not_active Application Discontinuation
- 1997-11-10 JP JP52371598A patent/JP2001505561A/ja active Pending
- 1997-11-10 PL PL97333414A patent/PL333414A1/xx unknown
- 1997-11-10 EP EP97954835A patent/EP0941224A4/en not_active Withdrawn
- 1997-11-10 HU HU9904040A patent/HUP9904040A3/hu unknown
- 1997-11-10 SI SI9720075A patent/SI20018A/sl not_active IP Right Cessation
- 1997-11-10 AU AU62367/98A patent/AU717740B2/en not_active Ceased
- 1997-11-10 CA CA002271786A patent/CA2271786A1/en not_active Abandoned
- 1997-11-10 US US09/308,723 patent/US6211201B1/en not_active Expired - Lifetime
- 1997-11-10 BR BR9713112-1A patent/BR9713112A/pt not_active IP Right Cessation
- 1997-11-10 NZ NZ335419A patent/NZ335419A/xx not_active IP Right Cessation
- 1997-11-10 WO PCT/US1997/020509 patent/WO1998022458A1/en not_active Application Discontinuation
- 1997-11-10 SK SK643-99A patent/SK64399A3/sk unknown
- 1997-11-10 IL IL12961997A patent/IL129619A0/xx unknown
- 1997-11-10 CN CN97199841A patent/CN1237969A/zh active Pending
- 1997-11-10 CZ CZ991727A patent/CZ172799A3/cs unknown
-
1999
- 1999-05-18 NO NO992384A patent/NO992384L/no not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107854428A (zh) * | 2016-12-20 | 2018-03-30 | 成都医学院 | 一种溴吡斯的明糖浆剂及其制备方法 |
| CN113277961A (zh) * | 2021-04-09 | 2021-08-20 | 深圳市新浩瑞医药科技有限公司 | 一种溴新斯的明的合成方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CZ172799A3 (cs) | 1999-10-13 |
| AU6236798A (en) | 1998-06-10 |
| PL333414A1 (en) | 1999-12-06 |
| EP0941224A4 (en) | 2000-01-12 |
| HUP9904040A2 (hu) | 2000-05-28 |
| WO1998022458A1 (en) | 1998-05-28 |
| IL129619A0 (en) | 2000-02-29 |
| NO992384L (no) | 1999-07-16 |
| HUP9904040A3 (en) | 2000-09-28 |
| SI20018A (sl) | 2000-02-29 |
| SK64399A3 (en) | 2000-05-16 |
| EP0941224A1 (en) | 1999-09-15 |
| NO992384D0 (no) | 1999-05-18 |
| AU717740B2 (en) | 2000-03-30 |
| BR9713112A (pt) | 2000-04-11 |
| US6211201B1 (en) | 2001-04-03 |
| CA2271786A1 (en) | 1998-05-28 |
| NZ335419A (en) | 2000-05-26 |
| JP2001505561A (ja) | 2001-04-24 |
| KR20000069028A (ko) | 2000-11-25 |
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