CN1148596A - 新晶形无水7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐 - Google Patents
新晶形无水7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐 Download PDFInfo
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- 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
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Abstract
无水7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐在配制抗菌剂中有优良的稳定性。
Description
本发明涉及新晶形无水7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐,用所说化合物治疗哺乳动物(特别是人)的细菌感染的方法,和涉及为此使用的药物组合物。
本发明涉及新晶形无水7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐,它具有有价值的非显而易见的性质。由于此无水盐基本是疏水稳定的,因而在制片剂或制胶囊期间该活性组分配制问题易于解决。
在美国专利NO.5229396中所提及的7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐由下述X-射线粉末衍射图的主峰表征,
它基本是吸湿的而且能从空气吸水生成一水合物。该一水合物由下述X-射线粉末衍射图的主峰表征。
峰号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
2θ(°)Cu | 5.0 | 9.8 | 13.0 | 14.8 | 19.7 | 20.9 | 22.0 | 23.0 | 28.1 | 29.3 |
d间距 | 17.9 | 9.0 | 6.8 | 6.0 | 4.5 | 4.2 | 4.0 | 3.9 | 3.2 | 3.0 |
峰号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
2θ(°)Cu | 4.7 | 9.4 | 12.4 | 13.1 | 13.6 | 14.2 | 17.0 | 17.9 |
d间距 | 18.7 | 9.4 | 7.1 | 6.7 | 6.5 | 6.3 | 5.2 | 5.0 |
峰号 | 9 | 10 | 11 | 12 | 12 | 14 | 15 | |
2θ(°)Cu | 18.7 | 21.0 | 22.0 | 24.2 | 24.2 | 26.6 | 27.2 | |
d间距 | 4.7 | 4.2 | 4.0 | 3.7 | 3.7 | 3.5 | 3.3 |
新晶形7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐(以下称为“无水盐”)基本是疏水稳定的并且由下述X-射线粉末衍射图的主峰表征。
峰号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
2θ(°)Cu | 4.5 | 7.7 | 9.1 | 13.6 | 15.0 | 18.2 | 18.6 | 22.8 |
d间距 | 19.5 | 11.5 | 9.7 | 6.5 | 5.9 | 4.9 | 4.8 | 3.9 |
此无水盐可按下述方法制备:在有机溶剂或其与非质子传递共溶剂的混合物(如异丙醇、二甲基亚砜、正丙醇、四氢呋喃或正丁醇,优选正丁醇或四氢呋喃/正丁醇)中,将7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐或它衍生的一水合物加热至回流或至约70℃至约90℃之间,优选约85℃。取决于反应温度和其他条件,反应时间通常在约1小时至约20小时范围内,优选约2小时至约16小时。
将生成的晶体浆液冷至约20℃至约30℃,优选约25℃,时间范围为约2小时至约24小时,优选约2小时至约12小时。然后从母液中滤出结晶产物并真空干燥至除去所有溶剂。
此无水盐可如上面提及的美国专利NO.5229396中所述作为抗菌剂使用。可以给受治者单独给药,但是此无水盐通常应与药学上可接受的载体以混合形式给药,这些载体的选择应考虑予定的给药途径和标准的药学实践。例如,它可以按下述形式口服给药:含如淀粉或乳糖赋形剂的片剂形式;单独或与赋形剂混合的胶囊形式;或含调味剂或着色剂的酏剂或悬浮剂形式。在动物情况下,将其含于动物饲料中为好。
本发明也提供含有抗菌有效量无水盐同时还有药学上可接受的稀释剂或载体的药物组合物。
用口服或肠胃外途径可给人施用此无水盐以治疗细菌疾病,口服给药的剂量水平可以是约0.1至500mg/kg/日,0.5-50mg/kg/日为好,可以一剂或分至3剂给药。肌内或静脉内给药时,剂量水平为约0.1-200mg/kg/日,0.5-50mg/kg/日为好。当肌内给药时可以一剂或分至3剂,静脉内给药时可包括连续滴注。根据进行治疗的受治者的体重和症状和按本专业技术人员所熟知的知识选择的特定给药途径,用药必然会有所差异。
按Steer复制子技术试验证明了此无水盐的抗菌活性,所述试验方法是由E.Steers等在Antibiotics andChemotherapy,9,307(1959)中描述的标准的体外细菌测试方法。
在相对温度范围内按重量测定了该水合性,采用VT1微量天平系统吸湿分析(MB300W型)。
制备例A
7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-],4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐
将7-([1α,5α,6α]-6-叔丁氧羰基氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸乙酯(25g)和甲磺酸(11g)加入水(250ml)和四氢呋喃(250ml)的混合物中。将所得浆液加热至回流温度(约66℃)并于此温度保持20小时,此后得到清彻的溶液。将此溶液冷至35-40℃并减压浓缩至约原体积的一半。将所得晶体浆液慢慢冷至室温(约20℃),然后再于10℃搅拌2小时。过滤分离结晶产物7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐,用四氢呋喃(12.5ml)和水(12.5ml)的混合物洗涤。于30-35℃真空干燥该晶体至晶体的残留水含量低于0.2%。产量21.2g,90%。
该7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐由下述X-射线粉末衍射图主峰表征。
峰号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
2θ(°)Cu | 5.0 | 9.8 | 13.0 | 14.8 | 19.7 | 20.9 | 22.0 | 23.0 | 28.1 | 29.3 |
d间距 | 17.9 | 9.0 | 6.8 | 6.0 | 4.5 | 4.2 | 4.0 | 3.9 | 3.2 | 3.0 |
该7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐晶体能从空气中吸收水分形成一水合物。此一水合物由下述X-射线粉末衍射图主峰表征。
峰号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
2θ(°)Cu | 4.7 | 9.4 | 12.4 | 13.1 | 13.6 | 14.2 | 17.0 | 17.9 |
d间距 | 18.7 | 9.4 | 7.1 | 6.7 | 6.5 | 6.3 | 5.2 | 5.0 |
峰号 | 9 | 10 | 11 | 12 | 12 | 14 | 15 | |
2θ(°)Cu | 18.7 | 21.0 | 22.0 | 24.2 | 24.2 | 26.6 | 27.2 | |
d间距 | 4.7 | 4.2 | 4.0 | 3.7 | 3.7 | 3.5 | 3.3 |
实施例1
无水7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐
将7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐或其一水合物(20g)与异丙醇(220ml)一起搅拌。将晶体悬浮液回流16小时或至显微镜观察其晶形已转变成六方形。将此晶体浆液冷至20-25℃并于此温度下搅拌约1小时。从母液中滤出结晶产物,用异丙醇(约50ml)洗涤,于40℃真空干燥至除去全部溶剂。产率98%。
此产物是无水新多晶型物7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐,其由下述X-射线粉末衍射图主峰表征。
峰号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
2θ(°)Cu | 4.5 | 7.7 | 9.1 | 13.6 | 15.0 | 18.2 | 18.6 | 22.8 |
d间距 | 19.5 | 11.5 | 9.7 | 6.5 | 5.9 | 4.9 | 4.8 | 3.9 |
实施例2
无水7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐
将7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐或其一水合物(7g)溶于二甲基亚砜(DMSO)(21ml)中,加热至80-85℃直到完全溶解。向此85℃溶液中滴加入异丙醇(150ml),以诱发结晶。将此晶体悬浮液保持在回流温度约85℃2-16小时或至显微镜观察其晶形已转变成六方形。将所得晶体浆液冷至20-25℃。从母液中滤出结晶产物,用异丙醇(约50ml)洗涤并于50℃真空干燥至除去全部溶剂。产率77%。
此产物与实施例1中的产物相同。
实施例3
无水7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐
将7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐或其一水合物(55.6g)溶于二甲基亚砜(DMSO)(159ml)中,加热至80-85℃直到完全溶解。将所得溶液冷至20-25℃并搅拌2小时,直至形成晶体浆液。于约25℃将二氯甲烷(1200ml)滴加入此溶液以充分诱导结晶。将此晶体悬浮液于室温保持过夜或至显微镜观察其晶形已转变成六方形。从母液中滤出结晶产物,用二氯甲烷(3×119ml)洗涤,并于50℃真空干燥至除去全部溶剂。产率91%。
此产物与实施例1中的产物相同。
实施例4
无水7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐
将7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐或其一水合物(1g)与正丙醇(44ml)一起搅拌。将晶体悬浮液回流3小时或至显微镜观察其晶形已转变成六方形。将晶体浆液冷至20-25℃并搅拌过夜。从母液中滤出结晶产物,用正丙醇(约10ml)洗涤,于50-55℃真空干燥至除去全部溶剂。产率68%。
此产物与实施例1中的产物相同。
实施例5
无水7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-.,8-二氮杂萘-3-羧酸甲磺酸盐
将7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐或其一水合物(70g)与四氢呋喃(175ml)和正丁醇(525ml)的混合物一起搅拌。将晶体悬浮液加热16小时或至显微镜观察其晶形已转变成六方形。将晶体浆液冷至20-25℃并搅拌过夜。从母液中滤出结晶产物,用四氢呋喃(25ml)和正丁醇(75ml)的混合物洗涤,于80℃真空干燥至除去全部溶剂。产率95%。
此产物与实施例1中的产物相同。
实施例6
无水7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐
将7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐或其一水合物(5g)与含最多1%水的正丁醇(220ml)一起搅拌。将晶体悬浮液加热至回流5小时或至显微镜观察其晶形已转变成六方形。将该晶体浆液冷至20-25℃并搅拌过夜。从母液中滤出结晶产物,用正丁醇(约20ml)洗涤,于50-55℃真空干燥至除去全部溶剂。产率92%。
此产物与实施例1中的产物相同。
Claims (4)
1. 7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐,其特征在于在它的X-射线粉末衍射图中具有下述主峰
峰号
1
2
3
4
5
6
7
8
2θ(°)Cu
4.5
7.7
9.1
13.6
15.0
18.2
18.6
22.8
d间距
19.5
11.5
9.7
6.5
5.9
4.9
4.8
3.9
2.具有抗菌活性的药物组合物,其含有治疗细菌感染有效量的按照权利要求1的化合物和药学上可接受的载体。
3.治疗细菌感染的方法,包括向需要治疗的受治者施用抗菌量的按照权利要求1的化合物。
4.制备权利要求1化合物的方法,包括在醇或其与非质子传递共溶剂的混合物存在下加热7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]己-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐或它衍生的一水合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1995/007211 WO1996039406A1 (en) | 1995-06-06 | 1995-06-06 | NOVEL CRYSTAL FORM OF ANHYDROUS 7-([1α, 5α, 6α]-6-AMINO-3-AZABICYCLO[3.1.0]HEX-3-YL)-6-FLUORO-1-(2,4-DIFLUOROPHENYL)-1,4-DIHYDRO-4-OXO-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACID, METHANESULFONIC ACID SALT |
WOPCT/US95/07211 | 1995-06-06 |
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CN1148596A true CN1148596A (zh) | 1997-04-30 |
CN1055474C CN1055474C (zh) | 2000-08-16 |
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CN96110060A Expired - Fee Related CN1055474C (zh) | 1995-06-06 | 1996-05-29 | 新晶形无水7-([1α,5α,6α]-6-氨基-3-氮杂二环[3.1.0]已-3-基)-6-氟-1-(2,4-二氟苯基)-1,4-二氢-4-氧代-1,8-二氮杂萘-3-羧酸甲磺酸盐 |
Country Status (38)
Country | Link |
---|---|
US (1) | US5763454A (zh) |
EP (1) | EP0789697B1 (zh) |
JP (1) | JP3145715B2 (zh) |
KR (1) | KR100191989B1 (zh) |
CN (1) | CN1055474C (zh) |
AR (1) | AR002753A1 (zh) |
AU (1) | AU703634B2 (zh) |
BG (1) | BG62443B1 (zh) |
BR (1) | BR9602630A (zh) |
CA (1) | CA2223404C (zh) |
CZ (1) | CZ285878B6 (zh) |
DE (1) | DE69503066T2 (zh) |
DK (1) | DK0789697T3 (zh) |
DZ (1) | DZ2046A1 (zh) |
ES (1) | ES2117426T3 (zh) |
FI (1) | FI974441A (zh) |
HR (1) | HRP960267B1 (zh) |
HU (1) | HUP9601540A3 (zh) |
IL (1) | IL118488A (zh) |
IS (1) | IS4351A (zh) |
LV (1) | LV11619B (zh) |
MA (1) | MA23892A1 (zh) |
NO (1) | NO305599B1 (zh) |
NZ (1) | NZ286735A (zh) |
OA (1) | OA10293A (zh) |
PE (1) | PE38097A1 (zh) |
PL (1) | PL314604A1 (zh) |
RU (1) | RU2125571C1 (zh) |
SG (1) | SG54339A1 (zh) |
SI (1) | SI9600185A (zh) |
SK (1) | SK280535B6 (zh) |
TN (1) | TNSN96084A1 (zh) |
TW (2) | TW580389B (zh) |
UA (1) | UA44718C2 (zh) |
UY (1) | UY25459A1 (zh) |
WO (1) | WO1996039406A1 (zh) |
YU (1) | YU34596A (zh) |
ZA (1) | ZA964647B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1315825C (zh) * | 1998-09-18 | 2007-05-16 | 史密丝克莱恩比彻姆有限公司 | 一种制备二氮杂萘羧酸衍生物(甲磺酸盐倍半水合物)的方法 |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MA24500A1 (fr) | 1997-03-21 | 1998-10-01 | Lg Life Sciences Ltd | Derive du sel d'acide carboxylique de naphthyridine . |
US20020032216A1 (en) | 1997-03-21 | 2002-03-14 | Lg Chemical Ltd. | Salt of naphthyridine carboxylic acid derivative |
HN1998000106A (es) | 1997-08-01 | 1999-01-08 | Pfizer Prod Inc | Composiciones parenterales de alatroflaxacino |
DE19800214A1 (de) * | 1998-01-06 | 1999-07-15 | Knoll Ag | Verfahren zur Herstellung von Doxazosin-Mcsylat in einer als Form A bezeichneten Kristallmodifikation und ein Zwischenprodukt dafür |
US7019142B2 (en) * | 1998-01-16 | 2006-03-28 | Pfizer Inc. | Process for preparing naphthyridones and intermediates |
GB9818258D0 (en) * | 1998-08-21 | 1998-10-14 | Pfizer Ltd | Antifungal compositions |
HN1999000141A (es) * | 1998-09-03 | 2000-06-19 | Pfizer Prod Inc | Procedimiento para preparar sales de trovafloxacina de adicion de acidos. |
ES2164520B1 (es) * | 1999-03-16 | 2003-04-01 | Medichem Sa | "procedimiento de obtencion del polimorfo a del mesilato de doxazosina" |
US6239141B1 (en) | 1999-06-04 | 2001-05-29 | Pfizer Inc. | Trovafloxacin oral suspensions |
GB9920919D0 (en) | 1999-09-03 | 1999-11-10 | Sb Pharmco Inc | Novel compound |
GB9920917D0 (en) | 1999-09-03 | 1999-11-10 | Sb Pharmco Inc | Novel process |
US6596871B2 (en) | 2001-06-29 | 2003-07-22 | Grayson Walker Stowell | Polymorphic forms of 6-[4-(1-cyclohexyl-1h-tetraol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone |
US6573382B2 (en) | 2001-06-29 | 2003-06-03 | Grayson Walker Stowell | Polymorphic forms of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone |
US6657061B2 (en) | 2001-06-29 | 2003-12-02 | Grayson Walker Stowell | Polymorphic forms of 6-[4-1(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone |
US6660864B2 (en) | 2001-06-29 | 2003-12-09 | Grayson Walker Stowell | Polymorphic forms of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone |
US6388080B1 (en) | 2001-06-29 | 2002-05-14 | Grayson Walker Stowell | Polymorphic forms of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone |
US6531603B1 (en) | 2001-06-29 | 2003-03-11 | Grayson Walker Stowell | Polymorphic forms of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone |
KR100517638B1 (ko) | 2002-04-08 | 2005-09-28 | 주식회사 엘지생명과학 | 게미플록사신 산염의 새로운 제조방법 |
CN102512364A (zh) * | 2011-12-30 | 2012-06-27 | 天津市嵩锐医药科技有限公司 | 一种供注射用的甲磺酸阿拉曲伐沙星药物组合物 |
JP6420544B2 (ja) * | 2013-01-11 | 2018-11-07 | 参天製薬株式会社 | 中栓とその中栓を備えた液体収容容器、及びノズルの先端構造とその構造を備えた液体収容容器 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5164402A (en) * | 1989-08-16 | 1992-11-17 | Pfizer Inc | Azabicyclo quinolone and naphthyridinone carboxylic acids |
RU2049777C1 (ru) * | 1989-08-16 | 1995-12-10 | Пфайзер Инк. | Азабицикло-хинолон-карбоновые кислоты или их фармацевтически приемлемые кислотно-аддитивные соли и промежуточные продукты для их получения |
BR9408490A (pt) * | 1994-01-18 | 1997-08-26 | Pfizer | Processo e intermediários para a preparação de sais do ácido nafftiridonocarboxílico |
GB2289674A (en) * | 1994-05-23 | 1995-11-29 | Pfizer | Antibacterial naphthyridine |
-
1995
- 1995-06-06 CA CA002223404A patent/CA2223404C/en not_active Expired - Fee Related
- 1995-06-06 EP EP95922240A patent/EP0789697B1/en not_active Expired - Lifetime
- 1995-06-06 DE DE69503066T patent/DE69503066T2/de not_active Expired - Fee Related
- 1995-06-06 DK DK95922240T patent/DK0789697T3/da active
- 1995-06-06 ES ES95922240T patent/ES2117426T3/es not_active Expired - Lifetime
- 1995-06-06 US US08/849,300 patent/US5763454A/en not_active Expired - Fee Related
- 1995-06-06 JP JP50037497A patent/JP3145715B2/ja not_active Expired - Fee Related
- 1995-06-06 SK SK719-96A patent/SK280535B6/sk unknown
- 1995-06-06 WO PCT/US1995/007211 patent/WO1996039406A1/en active IP Right Grant
-
1996
- 1996-05-13 TW TW089107609A patent/TW580389B/zh not_active IP Right Cessation
- 1996-05-13 TW TW085105632A patent/TW403751B/zh not_active IP Right Cessation
- 1996-05-29 CN CN96110060A patent/CN1055474C/zh not_active Expired - Fee Related
- 1996-05-30 IL IL11848896A patent/IL118488A/en not_active IP Right Cessation
- 1996-05-31 AR ARP960102817A patent/AR002753A1/es unknown
- 1996-06-03 IS IS4351A patent/IS4351A/is unknown
- 1996-06-04 BR BR9602630A patent/BR9602630A/pt not_active Application Discontinuation
- 1996-06-04 PL PL96314604A patent/PL314604A1/xx unknown
- 1996-06-04 LV LVP-96-172A patent/LV11619B/en unknown
- 1996-06-04 UA UA96062190A patent/UA44718C2/uk unknown
- 1996-06-05 DZ DZ960090A patent/DZ2046A1/fr active
- 1996-06-05 KR KR1019960020171A patent/KR100191989B1/ko not_active IP Right Cessation
- 1996-06-05 HU HU9601540A patent/HUP9601540A3/hu unknown
- 1996-06-05 CZ CZ961625A patent/CZ285878B6/cs not_active IP Right Cessation
- 1996-06-05 NO NO962321A patent/NO305599B1/no not_active IP Right Cessation
- 1996-06-05 ZA ZA9604647A patent/ZA964647B/xx unknown
- 1996-06-05 RU RU96111026A patent/RU2125571C1/ru not_active IP Right Cessation
- 1996-06-05 NZ NZ286735A patent/NZ286735A/en unknown
- 1996-06-05 AU AU54749/96A patent/AU703634B2/en not_active Ceased
- 1996-06-05 TN TNTNSN96084A patent/TNSN96084A1/fr unknown
- 1996-06-05 SG SG1996009972A patent/SG54339A1/en unknown
- 1996-06-05 YU YU34596A patent/YU34596A/sh unknown
- 1996-06-05 BG BG100639A patent/BG62443B1/bg unknown
- 1996-06-05 MA MA24262A patent/MA23892A1/fr unknown
- 1996-06-06 PE PE1996000421A patent/PE38097A1/es not_active Application Discontinuation
- 1996-06-06 OA OA60835A patent/OA10293A/fr unknown
- 1996-06-06 HR HR960267A patent/HRP960267B1/xx not_active IP Right Cessation
- 1996-06-06 SI SI9600185A patent/SI9600185A/sl not_active IP Right Cessation
-
1997
- 1997-12-05 FI FI974441A patent/FI974441A/fi unknown
-
1999
- 1999-04-06 UY UY25459A patent/UY25459A1/es not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1315825C (zh) * | 1998-09-18 | 2007-05-16 | 史密丝克莱恩比彻姆有限公司 | 一种制备二氮杂萘羧酸衍生物(甲磺酸盐倍半水合物)的方法 |
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