CN1751051B - 结晶形式的头孢菌素 - Google Patents
结晶形式的头孢菌素 Download PDFInfo
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- CN1751051B CN1751051B CN2004800042140A CN200480004214A CN1751051B CN 1751051 B CN1751051 B CN 1751051B CN 2004800042140 A CN2004800042140 A CN 2004800042140A CN 200480004214 A CN200480004214 A CN 200480004214A CN 1751051 B CN1751051 B CN 1751051B
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- 229930186147 Cephalosporin Natural products 0.000 title abstract description 4
- 229940124587 cephalosporin Drugs 0.000 title abstract description 4
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/48—Methylene radicals, substituted by hetero rings
- C07D501/56—Methylene radicals, substituted by hetero rings with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及式(I)的结晶形式的头孢菌素。结晶形式的式(I)化合物可以用作具有高效广谱抗菌活性的抗生素；这些抗生素对于甲氧西林耐药葡萄球菌(MRSA)和绿脓杆菌特别有效。
Description
本发明涉及结晶形式的头孢菌素及其制备方法。本发明还涉及上述结晶形式的头孢菌素单独或连同结晶形式的所述头孢菌素的其它化合物或制剂作为抗生素化合物的用途。
从EP 1087980和EP 0849269中获知式I的头孢菌素和制备它的非晶形的方法。
上式的头孢菌素以及它的钠盐(式III的头孢菌素)由于是非晶形结构所以具有低稳定性的缺点。这个问题将由本发明来解决，本发明将提供更稳定形式的头孢菌素。
本发明的目的之一是提供具有更高稳定性的结晶形式的式I的头孢菌素。
令人惊奇地发现，在酸存在的情况下，将头孢菌素结晶能够得到稳定结晶形式的头孢菌素盐。
本发明涉及结晶形式的式I的头孢菌素：
本发明还涉及式I的头孢菌素的氢溴酸盐或氢溴酸盐水合物。
此外，本发明还涉及式II的头孢菌素：
本发明也涉及结晶形式的式I和式II的头孢菌素。
另外，本发明还涉及结晶形式的头孢菌素，该头孢菌素在粉末X-射线衍射图形中的衍射角2θ(CuKα照射)下的峰强度如下表1所示。
| 衍射角2θ(°) | 相对强度 |
| 6.9 | (m) |
| 7.3 | (s) |
| 9.3 | (m) |
| 9.8 | (w) |
| 11.5 | (m) |
| 13.1 | (m) |
| 13.8 | (w) |
| 14.5 | (vs) |
| 14.9 | (m) |
| 15.4 | (m) |
| 15.7 | (m) |
| 16.6 | (m) |
| 17.2 | (m) |
| 18.2 | (m) |
| 18.5 | (m) |
| 衍射角2θ(°) | 相对强度 |
| 18.7 | (m) |
| 19.2 | (w) |
| 19.6 | (m) |
| 20.3 | (m) |
| 20.9 | (s) |
| 21.4 | (m) |
| 21.8 | (m) |
| 22.2 | (s) |
| 22.7 | (s) |
| 23.0 | (m) |
| 24.8 | (m) |
| 27.1 | (m) |
| 28.6 | (m) |
(vs)＝极强；(s)＝强；(m)＝中等；(w)＝弱；(vw)＝极弱
可以理解为由于实验细节的微小改变，在粉末X-射线衍射图形中2θ的特征性峰可能出现微小的偏离。
本发明还涉及制备头孢菌素的方法，该方法包括：
a)将酸和有机溶剂混合，将同业加至式III的头孢菌素中，并搅拌混合物；或
b)将酸和有机溶剂混合，向其中加入式III的头孢菌素，并搅拌混合物；或
c)将式III的头孢菌素悬浮于水和酸中并搅拌混合物。
本发明还涉及由上述方法获得的头孢菌素。
本发明也涉及含有上述头孢菌素的组合物。
本发明还涉及作为药物的上述头孢菌素化合物。
本发明也涉及上述头孢菌素化合物在制备抗感染药物中的用途。
本发明还涉及上述头孢菌素的制剂，该制剂含有：
1)碱式盐(如碳酸盐、碳酸氢盐)。使用助溶剂，如PEG、PPG、乙醇、丙二醇、苄醇或它们的混合物。
2)使用缓冲剂和就地形成的盐(如柠檬酸盐、乙酸盐、磷酸盐、碳酸盐、赖氨酸、精氨酸、氨丁三醇、葡甲胺、乙二胺、三乙醇胺)或者与1)中所描述的助溶剂或碱式盐结合。
3)使用络合剂(如PVP、环糊精、葡萄糖)或者与1)和2)中所描述的成分结合。
4)使用表面活性剂(如聚山梨酯、泊洛沙姆、卵磷脂)或者1)、2)和3)中所描述的成分结合。
5)1)、2)和3)中所描述的成分可直接用于组合中或者作为单独成分(如复制溶液)用于头孢菌素盐的复制。
本发明也涉及组合物，该组合物包括根据权利要求1-5或7-8中任一项的式I和/或式II的非结晶形式的头孢菌素、式III的非结晶形式的头孢菌素以及根据权利要求2-5或7-8中任一项的式II的结晶形式的头孢菌素，总计100％。
本发明还涉及上述结晶形式的头孢菌素单独或连同结晶形式的所述头孢菌素的其它化合物或制剂作为抗生素化合物的用途。
本发明也涉及药物制剂，该药物制剂包括上述化合物和治疗上惰性的载体，特别适合用于治疗和预防感染性疾病。
术语“结晶度”或“结晶”是相对于非晶形物质对结晶物质的描述并且通过例如XRPD图形中排列形状和背景强度以及DSC测定来评价。
根据这些方法，测得结晶度为90％-100％。在更优选的实施方案中，结晶度在92％至100％之间。在最优选的实施方案中，结晶度在95％至100％之间。
式II化合物的制备方法既可在溶解于有机溶剂的酸中进行也可在酸的水溶液中进行。优选在酸的水溶液中进行该过程。
本发明所用术语“酸”意指如HBr或HCl的酸，优选HCl。所用酸既可为气态也可为溶解的形式(溶解于水溶液或者溶解于有机溶剂)。
本发明所用术语“有机溶剂”意指如C1-4链烷醇(CH3OH、C2H5OH、正C3H7OH、异C3H7OH、异C4H9OH、正C4H9OH、仲C4H9OH)、酮(丙酮、甲基乙基酮)、醚(THF、二氧杂环己烷)、乙腈的有机溶剂，优选CH3OH、C2H5OH、正C3H7OH、异C3H7OH、异C4H9OH、正C4H9OH、仲C4H9OH、丙酮或乙腈，更优选甲醇。
本发明所用术语“酸溶液”意指HBr或HCl溶液，优选HBr或HCl水溶液。HCl水溶液的浓度为1％-30％，优选浓度为5％-25％，更优选浓度为10％-20％。HBr水溶液的浓度为1％-62％，优选浓度为5％-55％，更优选浓度为8％-20％。
式I、II和III化合物为具有高效广谱抗菌活性的抗生素，尤其用于甲氧西林耐药葡萄球菌和绿脓杆菌。
实验
从酸饱和有机溶剂中结晶：
根据EP 1087980和EP 0849269中所描述的方法制备式III的头孢菌素钠盐。
在溶解于上述有机溶剂(最优选甲醇)的酸(或为气态或为水溶液；优选HBr或HCl；更优选HCl)中进行结晶实验，将溶液加至式III的头孢菌素中并搅拌24小时(优选3-20小时，更优选4-7小时)。将所得的悬浮液过滤，用有机溶剂(优选丙酮)洗涤并在流动的空气中干燥几分钟。
表2：
| 编号 | 式III化合物 | 溶剂 | 产量 | 结果 |
| 1 | 60.8mg | 5ml甲醇，盐酸饱和的，1ml水，23℃ | 32mg | 结晶 |
| 2 | 60.8mg | 6ml甲醇，盐酸饱和的，23℃ | 25mg | 结晶 |
| 3 | 103mg | 15ml甲醇，盐酸饱和的，室温 | 73mg | 结晶 |
在0-30℃的温度范围内进行反应，优选5-25℃，更优选15-25℃。
所得结晶物至少含有50％结晶物质。
根据DSC、元素微量分析、粉末X-射线衍射和拉曼光谱表明，在溶解于上述有机溶剂(更优选甲醇)的酸(优选HBr或HCl；更优选HCl)中结晶实验生成式II的结晶形式的头孢菌素。
如下实施例和图1用于帮助理解本发明。
图1显示了式II的结晶形式的头孢菌素的粉末X-射线衍射图(CuKα照射)
从酸溶液结晶
下表显示了一系列在悬浮液中的结晶实验。
将式III的头孢菌素悬浮于水和酸(气态或为水溶液；优选HBr或HCl；更优选HCl)中进行结晶实验。将所得悬浮液搅拌24小时(优选3-20小时，更优选4-7小时)，过滤，用有机溶剂(优选丙酮)洗涤并在流动的空气中干燥几分钟。
表3：
| 编号 | 式III化合物 | 溶剂 | 产量<sup>★</sup> | 结果 |
| 4 | 100mg | 1.6ml水+0.4ml HBr(48％的水溶液) | 40mg | 结晶 |
| 5 | 61mg | 0.3ml水+6ml HCl(25％)外加4×1ml水，23℃ | 27mg | 结晶 |
| 6 | 112mg | 0.5ml水+10ml HCl(25％)，15℃ | 56mg | 结晶 |
| 7 | 69mg | 0.3ml水+4ml HCl(25％)，20℃+4mlHCl(32％)，23℃ | 26mg | 结晶 |
| 编号 | 式III化合物 | 溶剂 | 产量<sup>★</sup> | 结果 |
| 8 | 81mg | 1.4ml水+HCl(25％)，23℃ | 49mg | 结晶 |
| 9 | 201mg | 20ml HCl(7.4％/2N)，23℃ | 181mg | 结晶 |
| 10 | 151mg | 30ml HCl(12.5％)，23℃ | 136mg | 结晶 |
| 11 | 150mg | 30ml HCl(12.5％)，5℃ | 187mg | 结晶 |
| 12 | 150mg | 15ml HCl(12.5％)，20℃ | 161mg | 结晶 |
| 13 | 150mg | 30ml HCl(7.4％/2N)，23℃ | 125mg | 结晶 |
| 14 | 100mg | 50ml HCl(7.4％/2N)，23℃ | 70mg | 结晶 |
| 15 | 101mg | 25ml水，25ml HCl(25％)，23℃ | 81mg | 结晶 |
| 16 | 102mg | 50ml HCl(12.5％)，23℃ | 82mg | 结晶 |
| 17 | 202mg | 20ml HCl(7.4％/2N)，15℃ | 186mg | 结晶 |
★产量＝无论是盐形式或者水合物形式，均为过滤后质量，不包括残留溶剂(水)。
在0-30℃的温度范围内进行反应，优选5-25℃，更优选15-25℃。
根据DSC、元素微量分析和粉末X-射线衍射表明，在水和酸(优选HBr或HCl；更优选HCl)中结晶实验生成式II的结晶形式的头孢菌素。
表征头孢菌素的方法：
动态蒸汽吸附：
通常，DVS测定表明，所观察的结晶样品以三水合物形式存在。
元素微量分析
元素微量分析表明存在(6R，7R)-7-[(Z)-2-(5-氨基-[1，2，4]噻二唑-3-基)-2-羟基亚氨基-乙酰基氨基]-8-氧代-3-[(E)-(R)-1’-(5-甲基-2-氧代-[1，3]间二氧杂环戊烯-4-基甲氧基羰基)-2-氧代-[1，3’]联吡咯烷基-3-叉甲基]-8-氧代-5-硫杂-1-氮杂-双环[4.2.0]辛-2-烯-2-甲酸盐酸盐三水合物
表4：所观察的No.17样品(化合物II)的分析结果如下：
| 元素 | C | H | N | S | Cl | O |
| 原子量 | 12.01 | 1.00 | 14.01 | 32.07 | 35.45 | 16.00 |
| 原子数 | 26 | 33 | 8 | 2 | 1 | 14 |
| 元素 | C | H | N | S | Cl | O |
| mr(原子) | 312.26 | 33.00 | 112.08 | 64.14 | 35.45 | 224.00 |
| 标示值％ | 39.99 | 4.23 | 14.35 | 8.21 | 4.54 | 28.68 |
| 实测得％ | 39.23 | 4.20 | 14.06 | 7.86 | 4.56 | 29.20 |
| 差％ | -1.89 | -0.61 | -2.04 | -4.30 | 0.45 | 1.80 |
假设组成为C26H26N8O11S2·HCl·3H2O，那么总质量为780.93
证明或鉴定所制备的头孢菌素中存在结晶的方法：
差示扫描量热法(DSC)：
DSC测定用于证明盐酸盐样品中存在非晶形物质。
所选样品的DSC观察以及粉末X-射线衍射
通过DSC观察所选样品中是否存在非晶形物质。通常，观察两种不同的样品：一种为在约100℃-140℃之间分解的样品，另一种为吸热峰约在149℃并同时分解的样品。
对根据DSC带有吸热量的样品并可能有很少的非晶形物质，用粉末X-射线衍射进一步观察。通常，这些样品显示相同的衍射图但结晶度不同。
式I的结晶物质储存稳定性的测定
分别在不同的温度下储存(6R，7R)-7-[(Z)-2-(5-氨基-[1，2，4]噻二唑-3-基)-2-羟基亚氨基-乙酰基氨基]-8-氧代-3-[(E)-(R)-1’-(5-甲基-2-氧-[1，3]二氧杂环戊烯-4-基甲氧基羰基)-2-氧代-[1，3’]联吡咯烷基-3-叉甲基]-8-氧代-5-硫杂-1-氮杂-双环[4.2.0]辛-2-烯-2-甲酸的晶形和非晶形样品24小时、28天和3个月。HPLC分析结果如表4至表6所示。
表5：非晶形式I和晶形式II储存24小时
表6：非晶形的化合物I和结晶形式的化合物II储存28天
表7：非晶形的化合物I和结晶形式的化合物II储存3个月
储存24小时，在整个观察的温度变化区间内结晶形式的化合物II都表现出很好的稳定性。在5℃以上非晶形的化合物I明显分解。
储存28天，在25℃观察到结晶形式的化合物II轻微分解。与此相比，在5℃非晶形的化合物I的含量下降而且在25℃下降的更多。
3个月后，非晶形的化合物I甚至在5℃就出现轻微分解。在25℃非晶形的化合物I的含量出现明显下降。与此相反，结晶形式的化合物II在5℃下与-20℃下相比未出现分解，在25℃仅观察到轻微的分解。
根据本发明的产物可用作药物，例如，可以为药物制剂形式用于经胃肠(口服)给药。根据本发明的产物可以经例如口服(如片剂、包衣片剂、糖衣片剂、硬和软明胶胶囊、溶液、乳液或混悬液形式)或直肠(栓剂形式)给药。
采用本领域技术人员熟知的常规方法，可以制备含有这些化合物的药物组合物，例如可以将所述成分与适当、无毒、惰性、治疗上可接受的固体或液体载体(如果需要可加入常用的药物辅助剂)一起配制成剂型。
可以理解，所述化合物最终被配制成适于口服或胃肠外给药剂型的组合物。本发明组合物可含有药物制剂中常用的各种辅助剂中的任一种(作为任选成分)。因此，例如，在将本发明组合物配制为所需的口服给药的剂型时，可采用填充剂(如共沉淀的氢氧化铝、碳酸钙、磷酸二钙、甘露醇或乳糖)；崩解剂(如玉米淀粉)；以及润滑剂(如滑石粉、硬脂酸钙)等作为任选成分。然而，也应该理解，在此所说的任选成分仅仅作为示例，本发明中所使用的成分并不限于这些成分。本领域所知的其他辅助剂也用于本发明中。
因此，适合的载体物质既可以为无机的也可为有机的载体物质。对于片剂、包衣片剂、糖衣片剂、硬明胶胶囊，可采用例如乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐。对于软明胶胶囊，适合的载体为例如植物油、石蜡、脂肪以及半固体和液体的多元醇(根据活性物质的性质加以选择；然而对于软明胶胶囊，可不需要载体)。对于溶液和糖浆剂，适当的载体物质为例如水、多元醇、蔗糖、转化糖以及葡萄糖。对于栓剂，适当的载体物质为例如天然油和硬化油、石蜡、脂肪以及半液体或者液体多元醇。
可以理解，药用辅助剂包括常规的防腐剂、增溶剂、稳定剂、湿润剂、乳化剂、甜味剂、着色剂、香味剂、调节渗透压的盐、缓冲剂、包衣剂和抗氧化剂等。
根据本发明的产物可以用作药物，例如以药物制剂形式用于胃肠外给药，为此，最好将其制备成冻干或干燥粉末，使用时用常规溶剂(如水或者等渗盐或碳水化合物(如葡萄糖)溶液)进行稀释。
根据药理学活性化合物的性质，所述药物制剂可包括用于预防和治疗哺乳动物(人及除人外的哺乳动物)感染性疾病的化合物，该化合物的日剂量为约10mg-约4000mg，优选约50mg-约3000mg。本领域普通技术人员可以理解，根据哺乳动物的年龄、病情以及所预防或治疗的疾病种类，可以对日剂量进行调整。每日可单次或多次给药。平均单次剂量为约50mg、100mg、250mg、500mg、1000mg和2000mg。
Claims (6)
1.结晶形式的式II的头孢菌素：
它的CuKα照射的粉末X-射线衍射图形具有如下表所示的不同的衍射角下的峰：
其中(vs)＝极强；(s)＝强；(m)＝中等；(w)＝弱；(vw)＝极弱。
2.根据权利要求1的结晶形式的式II的头孢菌素，它具有基本上如说明书附图1所示的粉末X-射线衍射图形。
3.制备权利要求1或2中任一项的结晶形式的式II的头孢菌素的方法，该方法包括：
a)将HCl和甲醇混合，将溶液加至式III的头孢菌素中，并搅拌混合物；
b)将HCl和甲醇混合，向其中加入式III的头孢菌素，并搅拌混合物；或
c)将式III的头孢菌素悬浮于水和HCl中并搅拌混合物。
4.根据权利要求1或2中任一项的结晶形式的式II的头孢菌素在制备抗感染药物的用途。
5.药物制剂，该制剂包括根据权利要求1或2中任一项的结晶形式的式II的头孢菌素以及治疗上惰性的载体。
6.组合物，该组合物包括非结晶形式的式I、式II和式III的头孢菌素以及根据权利要求1的结晶形式的式II的头孢菌素，总计100％：
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| US3697506A (en) * | 1970-08-07 | 1972-10-10 | Pfizer | Crystalline alkali metal salts of {60 -carboxybenzylpenicillin and process therefor |
| JPS5579393A (en) * | 1978-12-11 | 1980-06-14 | Takeda Chem Ind Ltd | Cephalosporin derivative and its preparation |
| GR78221B (zh) | 1980-02-01 | 1984-09-26 | Ciba Geigy Ag | |
| US4432987A (en) * | 1982-04-23 | 1984-02-21 | Pfizer Inc. | Crystalline benzenesulfonate salts of sultamicillin |
| FR2532315A1 (fr) | 1982-08-27 | 1984-03-02 | Rhone Poulenc Sante | Formes cristallisees de sels d'addition avec des acides, de l'((amino-2-thiazolyl-4)-2 methoxyimino-2 acetamido)-7 carboxy-2 (dioxo-5,6 formylmethyl-4 tetrahydro-1,4,5,6 triazine-1,2,4 yl-3) thio-2 vinyl)-3 oxo-8 thia-5 aza-1 bicyclo(4.2.0) octene-2 isomere syn, forme e et leur preparation |
| US4634556A (en) * | 1985-05-10 | 1987-01-06 | Schering Corporation | Crystalline sodium (5R, 6S, 8R)-6-(1-hydroxyethyl)-2-(2-carbamoyloxyethylthio)-penem-3-carboxylate and process for making same |
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| JP2575590B2 (ja) * | 1992-07-31 | 1997-01-29 | 塩野義製薬株式会社 | トリアゾリルチオメチルチオセファロスポリン塩酸塩およびその水和物結晶ならびにそれらの製法 |
| ES2115725T3 (es) | 1992-07-31 | 1998-07-01 | Shionogi & Co | Hidrocloruro de triazoliltiometiltiocefalosporina, su hidrato cristalino y la preparacion de este. |
| SK283674B6 (sk) * | 1993-03-12 | 2003-11-04 | Pharmacia & Upjohn Company | Kryštalická voľná kyselina ceftiofuru a spôsob jej prípravy a farmaceutická kompozícia, ktorá ju obsahuje |
| CN1116299C (zh) * | 1996-09-20 | 2003-07-30 | 明治制果株式会社 | 头孢地托伦新戊酰氧甲酯晶体及其生产方法 |
| TW415949B (en) | 1996-12-19 | 2000-12-21 | Hoffmann La Roche | Vinyl pyrrolidine cephalosporin derivatives with basic substituents |
| US6232306B1 (en) | 1998-06-15 | 2001-05-15 | Hoffmann-La Roche Inc. | Derivatives of 3-(2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl)-cephams |
| US6504025B2 (en) * | 2000-05-24 | 2003-01-07 | Basilea Pharmaceutica Ag | Process for the preparation of vinyl-pyrrolidinone cephalosporin derivatives |
| USRE40794E1 (en) * | 2001-09-26 | 2009-06-23 | Merck & Co., Inc. | Crystalline forms of carbapenem antibiotics and methods of preparation |
-
2004
- 2004-03-15 EP EP04720595A patent/EP1606293B1/en not_active Expired - Lifetime
- 2004-03-15 BR BRPI0408716-0A patent/BRPI0408716B1/pt active IP Right Grant
- 2004-03-15 PL PL04720595T patent/PL1606293T3/pl unknown
- 2004-03-15 US US10/547,648 patent/US7531650B2/en not_active Expired - Lifetime
- 2004-03-15 JP JP2006504690A patent/JP5230934B2/ja not_active Expired - Lifetime
- 2004-03-15 CN CN2004800042140A patent/CN1751051B/zh not_active Expired - Lifetime
- 2004-03-15 AU AU2004224181A patent/AU2004224181B2/en not_active Ceased
- 2004-03-15 DK DK04720595T patent/DK1606293T3/da active
- 2004-03-15 MX MXPA05010083A patent/MXPA05010083A/es active IP Right Grant
- 2004-03-15 DE DE602004022643T patent/DE602004022643D1/de not_active Expired - Lifetime
- 2004-03-15 WO PCT/EP2004/002667 patent/WO2004085444A1/en active Application Filing
- 2004-03-15 ES ES04720595T patent/ES2329244T3/es not_active Expired - Lifetime
- 2004-03-15 SI SI200431215T patent/SI1606293T1/sl unknown
- 2004-03-15 AT AT04720595T patent/ATE440101T1/de active
- 2004-03-15 PT PT04720595T patent/PT1606293E/pt unknown
- 2004-03-15 CA CA2519272A patent/CA2519272C/en not_active Expired - Fee Related
- 2004-03-26 TW TW093108308A patent/TWI346117B/zh not_active IP Right Cessation
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2005
- 2005-09-26 ZA ZA200507760A patent/ZA200507760B/en unknown
- 2005-09-26 KR KR1020057018075A patent/KR101121942B1/ko active IP Right Grant
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2006
- 2006-05-15 HK HK06105568.5A patent/HK1085479A1/xx not_active IP Right Cessation
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2009
- 2009-04-01 US US12/416,461 patent/US8093377B2/en active Active
- 2009-11-12 CY CY20091101186T patent/CY1109615T1/el unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1087980B1 (en) * | 1998-06-15 | 2003-01-29 | Basilea Pharmaceutica AG | Derivatives of 3-(2-oxo- 1,3']bipyrrolidinyl-3-ylidenemethyl)-cephems |
Also Published As
| Publication number | Publication date |
|---|---|
| SI1606293T1 (sl) | 2009-10-31 |
| US8093377B2 (en) | 2012-01-10 |
| DE602004022643D1 (de) | 2009-10-01 |
| AU2004224181A1 (en) | 2004-10-07 |
| WO2004085444A1 (en) | 2004-10-07 |
| AU2004224181B2 (en) | 2011-06-02 |
| BRPI0408716B8 (zh) | 2021-05-25 |
| EP1606293B1 (en) | 2009-08-19 |
| US20060167242A1 (en) | 2006-07-27 |
| ATE440101T1 (de) | 2009-09-15 |
| PL1606293T3 (pl) | 2010-01-29 |
| CY1109615T1 (el) | 2014-08-13 |
| BRPI0408716B1 (pt) | 2017-08-29 |
| DK1606293T3 (da) | 2009-10-05 |
| JP2006521309A (ja) | 2006-09-21 |
| US20090192306A1 (en) | 2009-07-30 |
| CA2519272C (en) | 2010-06-08 |
| EP1606293A1 (en) | 2005-12-21 |
| KR101121942B1 (ko) | 2012-03-09 |
| CA2519272A1 (en) | 2004-10-07 |
| JP5230934B2 (ja) | 2013-07-10 |
| KR20050111787A (ko) | 2005-11-28 |
| US7531650B2 (en) | 2009-05-12 |
| ES2329244T3 (es) | 2009-11-24 |
| PT1606293E (pt) | 2009-10-14 |
| TWI346117B (en) | 2011-08-01 |
| CN1751051A (zh) | 2006-03-22 |
| MXPA05010083A (es) | 2005-11-23 |
| ZA200507760B (en) | 2007-06-27 |
| BRPI0408716A (pt) | 2006-03-07 |
| TW200502237A (en) | 2005-01-16 |
| HK1085479A1 (en) | 2006-08-25 |
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