CN1341116A - 8－氰基－1－环丙基－7－(1s,6s－2,8－二氮杂双环(4.3.0)壬－8－基)－6－氟－1,4－二氢－4－氧代－3－喹啉羧酸的结晶变体d - Google Patents
8－氰基－1－环丙基－7－(1s,6s－2,8－二氮杂双环(4.3.0)壬－8－基)－6－氟－1,4－二氢－4－氧代－3－喹啉羧酸的结晶变体d Download PDFInfo
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Abstract
本发明涉及一种界定的8－氰基－1－环丙基－7－(1S,6S－2,8－二氮杂双环[4.3.0]壬－8－基)－6－氟－1,4－二氢－4－氧代－3－喹啉羧酸的结晶变体,涉及其制备方法并涉及其在药物制剂方面的应用。该结晶变体与式(I)的8－氰基－1－环丙基－7－(1S,6S－2,8－二氮杂双环[4.3.0]壬－8－基)－6－氟－1,4－二氢－4－氧代－3－喹啉羧酸的其它结晶变体的区别在于其特征X射线粉末衍射图及其差热分析图。
Description
本发明涉及一种界定的8-氰基-1-环丙基-7-(1S，6S-2，8-二氮杂双环[4.3.0]壬-8-基)-6-氟-1，4-二氢-4-氧代-3-喹啉羧酸的结晶变体，涉及其制备方法并涉及其在药物制备方面的应用。
在下文中，将式(I)的8-氰基-1-环丙基-7-(1S，6S-2，8-二氮杂双环[4.3.0]壬-8-基)-6-氟-1，4-二氢-4-氧代-3-喹啉羧酸称作CCDC。
CCDC由DE-A 19 633 805或PCT申请97 903 260.4可知。根据这些出版物，它是通过使7-氯-8-氰基-1-环丙基-6-氟-1，4-二氢-4-氧代-3-喹啉羧酸与(1S，6S)-2，8-二氮杂双环[4.3.0]壬烷在二甲基甲酰胺和乙腈的混合物中于辅助碱存在下反应而制备的。将水加入到混合物中，然后用二氯甲烷从水中提取出CCDC并通过除去萃取剂进行分离。这样得到结晶变体不明显的粉末。相反，粉末主要是无定形的并可包含不同结晶变体的混合物。如果偶然形成了一种均匀的结晶变体，则尚不清楚如何提取并确切地得到它。但是，制备药物的先决条件是，对于一种可以不同结晶变体存在的活性化合物，可以明确指出其哪一个结晶变体可用于制备药物。
而且由上述制备方法获得的部分无定形粉末是易吸湿的。但是，无定形固体，并且特别是易吸湿固体，在进行药物加工时难以处理，因为例如它们具有低的本体密度和不能令人满意的流动性能。而且，处理易吸湿固体需要特殊工艺和设备以获得可重复性结果，例如活性化合物含量或所产生固体制剂的稳定性。
因此，本发明的目的是制备所界定的CCDC变体的结晶形式，由于其物理性能，特别是其结晶性能，而易于在药物制剂中进行处理。
根据本发明，该目的是通过一种CCDC的新型结晶形式实现的，该形式在下文中被称作变体D。
因此，本发明提供了CCDC的结晶变体D，其特征在于其具有带有列于下表1中的高和中等强度(＞30％相对强度)反射信号(2θ)的X射线粉末衍射图。
表1：
CCDC的变体D的X射线粉末衍射图
2θ(2theta)
7.6
9.5
12.8
14.2
17.5
19
19.3
19.5
20.4
21
21.8
22.6
25.2
27.5
变体D的X射线粉末衍射图还示于图1中。
而且，根据本发明的CCDC变体D在许多其它性能方面也不同于其它形式的CCDC。这些性能本身或与其它参数一起还可用于表征根据本发明的CCDC变体D。
CCDC变体D以通过差热分析(DTA)测定的261-265℃的熔点为特征。特征差热图谱示于图2中。
CCDC变体D的特征在于其具有如图3所示的在KBr中测定的红外图谱。
CCDC的结晶变体D是通过将未知变体CCDC或无定形CCDC以1-3wt％的浓度溶解在水中，放置该溶液直到沉淀出固体，过滤出该固体，干燥所得含水产物，随后加热到重排温度之上的温度而获得的。
含水产物可通过常规方法干燥。因此例如可在减压下于高温干燥含水产物。也可以在常规干燥剂如五氧化二磷存在下进行干燥。
将干燥样品重排成变体D所需的温度可由干燥物质的DTA确定。一般为130-160℃。
CCDC的结晶变体D令人惊讶地稳定，即使长期储存也不变成另一种结晶变体或无定形形式。由于这些原因，其高度适于制备片剂或其它固体制剂。由于其稳定性，它赋予这些制剂所需的长期储存稳定性。因此使用结晶变体D可以以界定的和目标的方式制备稳定的CCDC固体制剂。
CCDC的结晶变体D在人类或兽医药品领域对病原菌是高度活性的。其广泛的使用范围对应于相应的CCDC。
表征CCDC结晶变体D的X射线粉末衍射图是使用来自Stoe公司的带有位置敏感探测仪(PSD2)的传动衍射仪STADI-P获得的。
差热分析的熔点是使用来自Mettler-Toledo公司的DSC820装置获得的。在此CCDC结晶变体D样品在铝坩埚中暴露于大气中以5K/min被加热。
IR光谱是使用来自Perkin-Elmer的881装置在KBr中获得的。
下列实施例非限制性地说明了本发明。下面实施例中所用溶剂/碱体系是特别优选的。对比例
将3.07g 7-氯-8-氰基-1-环丙基-6-氟-1，4-二氢-4-氧代-3-喹啉羧酸、1.39g(1S，6S)-2，8-二氮杂双环[4.3.0]壬烷、2.24g 1，4-二氮杂双环[2.2.2]辛烷(DABCO)、29.5ml二甲基甲酰胺和29.5ml乙腈的混合物在室温搅拌16小时。使用旋转蒸发器在60℃的水浴下将反应混合物浓缩，并将残余物吸收在10ml水中。使用稀盐酸将所得溶液pH调节为7并过滤掉固体。每次使用20ml二氯甲烷将滤液提取3次。有机相经硫酸钠干燥、过滤并使用旋转蒸发器在60℃的水浴下将滤液浓缩。得到2.4g浅棕色固体，其X射线粉末衍射图示于图4中，主要是无定形的。
实施例1
先将1012g 7-氯-8-氰基-1-环丙基-6-氟-1，4-二氢-4-氧代-3-喹啉羧酸加入到3300ml乙醇、1980ml N-甲基吡咯烷酮和534gHünig碱的混合物中。将该混合物加热回流，并随后滴加459g(1S，6S)-2，8-二氮杂双环[4.3.0]壬烷。滴加完毕后，将混合物在回流下再搅拌3小时，然后冷却至室温，抽滤过滤掉固体并用总共1800ml乙醇洗涤。
将所得固体悬浮在4650ml乙醇和41g Hünig碱的混合物中，并将该反应混合物加热回流3小时。再次将反应混合物冷却至室温，并抽滤过滤掉固体，用总共1000ml EtOH洗涤并在真空干燥箱中于60-70℃干燥直至恒重。得到1130g浅褐色固体，其X射线粉末衍射图示于图5中。
由450g该固体和29 450g二次蒸馏水制备浓度为1.5％(w/w)的水溶液，通过0.2μm过滤器过滤除去任何不溶的颗粒。然后将该溶液在室温无光照的聚乙烯罐中储存4周。经过这一时间后，通过0.8μm过滤器过滤沉淀出的固体并在75℃干燥过夜。
得到2g固体，根据X射线粉末衍射图其主要是无定形的(图6)并具有图7所示的DTA。
将30mg如此获得的固体在160℃于氮气氛下加热2小时。得到28mg固体，其X射线粉末衍射图示于图1，差热分析图示于图2且IR光谱图示于图3。
Claims (7)
1. 8-氰基-1-环丙基-7-(1S，6S-2，8-二氮杂双环[4.3.0]壬-8-基)-6-氟-1，4-二氢-4-氧代-3-喹啉羧酸(CCDC)结晶变体D，其特征在于其具有带有下列高和中等强度反射信号(2θ)的X射线粉末衍射图：
2θ(2theta)
7.6
9.5
12.8
14.2
17.5
19
19.3
19.5
20.4
21
21.8
22.6
25.2
27.5 。
2. 8-氰基-1-环丙基-7-(1S，6S-2，8-二氮杂双环[4.3.0]壬-8-基)-6-氟-1，4-二氢-4-氧代-3-喹啉羧酸(CCDC)结晶变体D，其特征在于其具有带有下列高和中等强度反射信号(2θ)的X射线粉末衍射图和由DTA测定的261-265℃的熔点：
2θ(2theta)
7.6
9.5
12.8
14.2
17.5
19
19.3
19.5
20.4
21
21.8
22.6
25.2
27.5 。
3. 8-氰基-1-环丙基-7-(1S，6S-2，8-二氮杂双环[4.3.0]壬-8-基)-6-氟-1，4-二氢-4-氧代-3-喹啉羧酸(CCDC)结晶变体D，可通过将未知变体CCDC或无定形CCDC以1-3wt％的浓度溶解在水中，过滤掉放置一会儿后沉淀出的固体，干燥该固体并加热到重排温度之上而获得。
4.制备CCDC变体D的方法，其特征在于将未知变体CCDC或无定形CCDC以1-3wt％的浓度溶解在水中，过滤掉放置一会儿后沉淀出的固体，干燥并加热到重排温度之上。
5.药物，其特征在于，除了常规助剂和赋形剂外，它还包含根据权利要求1或2的CCDC变体D。
6.权利要求1或2的CCDC变体D在制备药物方面的应用。
7.权利要求1或2的CCDC变体D在抗菌组合物中的应用。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19908448A DE19908448A1 (de) | 1999-02-26 | 1999-02-26 | Kristallmodifikation D von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicylo[4.3.0)nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chino incarbonsäure |
| DE19908448.3 | 1999-02-26 |
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| CN1341116A true CN1341116A (zh) | 2002-03-20 |
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| DE19854356A1 (de) | 1998-11-25 | 2000-05-31 | Bayer Ag | Kristallmodifikation A von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-/4.3.0/nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
| DE19854355A1 (de) | 1998-11-25 | 2000-05-31 | Bayer Ag | Kristallmodifikation B von 8-Cyan-1-cyclopropyl-7-(1S, 6S-2,8-diazabicyclo-/4.3.O/nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
| DE19908449A1 (de) | 1999-02-26 | 2000-08-31 | Bayer Ag | Kristallmodifikation C von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicylo-[4.3.0]nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chino/incarbonsäure |
| DE102004015981A1 (de) * | 2004-04-01 | 2005-10-20 | Bayer Healthcare Ag | Neue kirstalline Form von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
| SG11201907073TA (en) | 2017-02-13 | 2019-08-27 | Bayer Animal Health Gmbh | Liquid composition containing pradofloxacin |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2676521B2 (ja) | 1988-03-22 | 1997-11-17 | 北陸製薬株式会社 | キノロンカルボン酸化合物ｉ型結晶の製造法 |
| CA2201735A1 (en) | 1994-11-18 | 1996-05-30 | The Upjohn Company | A new physically stable solid form of a fluoroquinolone |
| BR9707606B1 (pt) * | 1996-02-23 | 2010-08-10 | ácidos 8-ciano-1-ciclopropil-7-(2,8-diazabiciclo(4.3.0) nonan-8-il)-6-flúor-1,4-diidro-4-oxo-3-quinolinocarbo xìlicos, bem como medicamentos que os compreendem. | |
| DE19854356A1 (de) | 1998-11-25 | 2000-05-31 | Bayer Ag | Kristallmodifikation A von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-/4.3.0/nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
| DE19854355A1 (de) | 1998-11-25 | 2000-05-31 | Bayer Ag | Kristallmodifikation B von 8-Cyan-1-cyclopropyl-7-(1S, 6S-2,8-diazabicyclo-/4.3.O/nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
| DE19908449A1 (de) | 1999-02-26 | 2000-08-31 | Bayer Ag | Kristallmodifikation C von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicylo-[4.3.0]nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chino/incarbonsäure |
| JP2001242582A (ja) * | 2000-02-25 | 2001-09-07 | Fuji Photo Film Co Ltd | ハロゲン化銀写真感光材料およびその現像処理方法 |
-
1999
- 1999-02-26 DE DE19908448A patent/DE19908448A1/de not_active Withdrawn
-
2000
- 2000-02-14 HU HU0200053A patent/HUP0200053A3/hu unknown
- 2000-02-14 PL PL00349394A patent/PL349394A1/xx not_active Application Discontinuation
- 2000-02-14 RU RU2001126301/04A patent/RU2248357C2/ru not_active IP Right Cessation
- 2000-02-14 UA UA2001096577A patent/UA71606C2/uk unknown
- 2000-02-14 EP EP00909167A patent/EP1159277A1/de not_active Withdrawn
- 2000-02-14 NZ NZ513749A patent/NZ513749A/en unknown
- 2000-02-14 AU AU31544/00A patent/AU760710B2/en not_active Ceased
- 2000-02-14 CZ CZ20013065A patent/CZ20013065A3/cs unknown
- 2000-02-14 JP JP2000602236A patent/JP2002538159A/ja not_active Withdrawn
- 2000-02-14 WO PCT/EP2000/001203 patent/WO2000052010A1/de not_active Application Discontinuation
- 2000-02-14 TR TR2001/02435T patent/TR200102435T2/xx unknown
- 2000-02-14 IL IL14452800A patent/IL144528A0/xx not_active IP Right Cessation
- 2000-02-14 CN CN00804306XA patent/CN1217944C/zh not_active Expired - Fee Related
- 2000-02-14 KR KR1020017009632A patent/KR100756474B1/ko not_active IP Right Cessation
- 2000-02-14 SK SK1194-2001A patent/SK11942001A3/sk not_active Application Discontinuation
- 2000-02-14 CA CA002362804A patent/CA2362804A1/en not_active Abandoned
- 2000-02-14 BR BR0008520-0A patent/BR0008520A/pt not_active IP Right Cessation
- 2000-02-14 US US09/914,031 patent/US6492391B1/en not_active Expired - Fee Related
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2001
- 2001-07-24 ZA ZA200106050A patent/ZA200106050B/en unknown
- 2001-08-21 NO NO20014059A patent/NO320314B1/no unknown
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2002
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Also Published As
| Publication number | Publication date |
|---|---|
| KR100756474B1 (ko) | 2007-09-07 |
| CN1217944C (zh) | 2005-09-07 |
| BR0008520A (pt) | 2001-12-18 |
| HK1045158B (zh) | 2006-04-21 |
| WO2000052010A1 (de) | 2000-09-08 |
| TR200102435T2 (tr) | 2002-01-21 |
| RU2248357C2 (ru) | 2005-03-20 |
| JP2002538159A (ja) | 2002-11-12 |
| EP1159277A1 (de) | 2001-12-05 |
| HUP0200053A3 (en) | 2003-01-28 |
| HK1045158A1 (en) | 2002-11-15 |
| NO20014059D0 (no) | 2001-08-21 |
| SK11942001A3 (sk) | 2001-12-03 |
| DE19908448A1 (de) | 2000-08-31 |
| ZA200106050B (en) | 2002-07-24 |
| PL349394A1 (en) | 2002-07-15 |
| UA71606C2 (uk) | 2004-12-15 |
| HUP0200053A2 (hu) | 2002-05-29 |
| AU760710B2 (en) | 2003-05-22 |
| NO20014059L (no) | 2001-08-21 |
| US6492391B1 (en) | 2002-12-10 |
| CZ20013065A3 (cs) | 2002-01-16 |
| CA2362804A1 (en) | 2000-09-08 |
| IL144528A0 (en) | 2002-05-23 |
| NZ513749A (en) | 2003-10-31 |
| NO320314B1 (no) | 2005-11-21 |
| AU3154400A (en) | 2000-09-21 |
| KR20010093300A (ko) | 2001-10-27 |
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