CN101006090A - 4[[(7r)－8－环戊基－7－乙基－5,6,7,8－四氢－5－甲基－4－6－氧代－2－哌啶基]氨基]－3－甲氧基－n－(1－甲基－4－哌啶基)－苯甲酰胺的水合物及多晶型物，其制造方法及其作为药物的用途 - Google Patents
4[[(7r)－8－环戊基－7－乙基－5,6,7,8－四氢－5－甲基－4－6－氧代－2－哌啶基]氨基]－3－甲氧基－n－(1－甲基－4－哌啶基)－苯甲酰胺的水合物及多晶型物，其制造方法及其作为药物的用途 Download PDFInfo
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- CN101006090A CN101006090A CNA2005800276839A CN200580027683A CN101006090A CN 101006090 A CN101006090 A CN 101006090A CN A2005800276839 A CNA2005800276839 A CN A2005800276839A CN 200580027683 A CN200580027683 A CN 200580027683A CN 101006090 A CN101006090 A CN 101006090A
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Images
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-
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
本发明是关于新颖4[[(7R)－8－环戊基－7－乙基－5，6，7，8－四氢－5－甲基－6－氧代－2－蝶啶基]氨基]－3－甲氧基－N－(1－甲基－4－哌啶基)－苯甲酰胺的水合物及多晶型物、其制造方法及其作为药物的用途。
Description
本发明是关于新颖4[[(7R)-8-环戊基-7-乙基-5，6，7，8-四氢-5-甲基-6-氧代-2-蝶啶基]氨基]-3-甲氧基-N-(1-甲基-4-哌啶基)-苯甲酰胺的水合物及多晶型物、其制造方法及其作为药物的用途。
现有技术
化合物4[[(7R)-8-环戊基-7-乙基-5，6，7，8-四氢-5-甲基-6-氧代-2-蝶啶基]氨基]-3-甲氧基-N-(1-甲基-4-哌啶基)-苯甲酰胺为一种类polo激酶(PLK)，在调节真核细胞周期中起重要作用。
化合物4[[(7R)-8-环戊基-7-乙基-5，6，7，8-四氢-5-甲基-6-氧代-2-蝶啶基]氨基]-3-甲氧基-N-(1-甲基-4-哌啶基)-苯甲酰胺具有下式(I)的结构
类似的二氢蝶啶酮描述于WO03/020722中。
发明详述
本发明是具有抗增生活性的式(I)化合物的新颖的水合物及新颖的多晶型形式。
因此，本发明是关于式(I)化合物的水合物：
式(I)化合物的水合物优选为单水合物。
又优选的式(I)化合物的水合物为三水合物。
本发明进一步是关于式(I)化合物的无水合物。
又优选的式(I)化合物的无水合物是以I型的无水合物存在。
又优选的式(I)化合物的无水合物是以II型的无水合物存在。
又优选的式(I)化合物的无水合物是以III型的无水合物存在。
本发明进一步关于一种药物组合物，其含有一种治疗有效量的上述本发明式(I)化合物的水合物及多晶型形式，及一种或多种医药上可接受的赋形剂。
本发明进一步关于本发明式(I)化合物的水合物及多晶型形式，以用作具有抗增生活性的药物制剂。
本发明进一步关于本发明式(I)化合物的水合物及多晶型形式在制备供治疗及/或预防癌症、感染、炎症及自体免疫性疾病的药物制剂中的用途。
本发明进一步关于本发明式(I)化合物的水合物及多晶型形式在制备供抑制类polo激酶的药物制剂中的用途。
根据本发明，优选是使用式(I)化合物的水合物及多晶型形式以制备供抑制类polo激酶PLK-1的药物制剂。
特别优选的是使用本发明式(I)化合物的水合物及多晶型形式，其中活性物质，是以口服、胃肠内、静脉内、腹腔内或通过注射给药。
本发明进一步是关于制备式(I)化合物的方法，其特征为将式4化合物
与式
9化合物反应，
本发明进一步是关于制备式9化合物的方法，
其通过与碳酸二甲酯在有碱的存在下于升高的温度(介于80℃及180℃)，优选为130℃下进行甲基化。
本发明进一步关于式
3化合物
本发明进一步是关于式
4化合物
本发明进一步是关于制备式(I)化合物的单水合物的方法，其包含下列步骤：
(a)制备式(I)化合物在异丙醇/水或丙酮/水的溶剂混合物中的溶液；
(b)由溶剂混合物中结晶出式(I)化合物的单水合物；及
(c)分离式(I)化合物的单水合物。
本发明进一步关于制备式(I)化合物的三水合物的方法，因而将式(I)化合物的单水合物置于至少70％相对湿度下。
本发明进一步关于制备式(I)化合物的III型无水合物的方法，其中
(a)将式(I)化合物的单水合物用干燥氮气冲洗，或
(b)将式(I)化合物的单水合物置于约70℃，优选的70至120℃，特佳为70至90℃的温度下。
本发明进一步关于制备式(I)化合物的I型无水合物的方法，其中将式(I)化合物的III型无水合物熔解，然后将熔解物于至少140℃的温度，较佳为140至160℃下进行结晶。
本发明进一步关于制备式(I)化合物的I型无水合物的方法，其包括下列步骤：
(a)制备式(I)化合物在乙酸乙酯及甲基叔丁基醚的溶剂混合物中的溶液，或在甲基-异丁基酮/环己烷的溶剂混合物中的溶液，优选乙酸乙酯/甲基叔丁基醚的比例为3∶5(v/v)；
(b)由溶剂混合物中结晶式(I)化合物的I型无水合物；
(c)分离式(I)化合物的I型无水合物。
本发明进一步关于制备式(I)化合物的II型无水合物的方法，其包括下列步骤：
(a)制备式(I)化合物在乙酸乙酯中的溶液；
(b)由乙酸乙酯中结晶出式(I)化合物的II型无水合物，随后加入二乙醚；
(c)分离式(I)化合物的II型无水合物。
本发明进一步关于制备式(I)化合物的I型无水合物的方法，其包括下列步骤：
(a)熔解式(I)化合物的II型无水合物；
(b)将熔解物置于至少185℃的温度下，优选为185至200℃的温度下进行结晶。
式(I)化合物可使用下文所述的合成方法来制备。该合成示于流程图(1)中并说明本发明用于了解而非限制其内容。
制备苯胺片段
4
制备化合物
3
方案1A：
将100g(0.507mol)的3-甲氧基-4-硝基苯甲酸
2，163g(0.508mol)O-(苯并三唑-1-基)-N，N，N’，N’-四甲基四氟硼酸及192mL(1.1mol)乙基二异丙基胺在1.2L二氯甲烷中的悬浮液于25℃下搅拌一小时。将58g(0.508mol)1-甲基-4-氨基哌啶
1加到生成的溶液中，并于20℃搅拌混合物16小时。将溶液蒸发至600mL并将有机层以80mL的1摩尔氨液洗涤五次。将有机层蒸发浓缩并将残余物在硅胶上使用二氯甲烷/甲醇/浓氨水(15∶1∶0.1)层析。合并产物馏分，蒸发溶剂并由乙酸乙酯/甲醇中结晶。得到123g的产物
3。
方案1B：
将4.00kg(20.3mol)3-甲氧基-4-硝基苯甲酸
2置于54L甲苯中。将16L甲苯于正常压力下蒸馏。将混合物冷却至105℃并加入40ml二甲基甲酰胺在2L甲苯中的溶液。于120℃的夹套温度下，于30分钟内使2.90kg(24.3mol)亚硫酰氯流入并以4L甲苯洗涤混合物。将反应混合物于回流下搅拌1小时。然后于正常压力下蒸馏出12L甲苯。将反应器的内含物冷却。于55-65℃使2.55kg(22.3mol)1-甲基-4-氨基哌啶
1在2L甲苯中的溶液及2.46kg(24.3mol)三乙胺在2L甲苯中溶液流入。以4L甲苯冲洗混合物。将悬浮液搅拌1小时。使20L水流入并于35-40℃下加入3.08kg(30.4mol)浓盐酸(36％)。以2L水冲洗混合物。于35-40℃下形成2层。分离有机层并将含有产物的水层转入反应器中。以4L水冲洗。于50℃、减压蒸馏出3.2L的水。于40℃下将4.87kg(60.9mol)氢氧化钠溶液(50％)加到剩余的溶液中。以4L水冲洗混合物。将产物悬浮液冷却至22℃并于该温度下搅拌30分钟。抽气过滤悬浮液并以40L水冲洗滤饼。于40℃在真空干燥柜中干燥并得到5.65kg的产物。
制备化合物4
方案2A
将145g(0.494mol)
3的2L甲醇溶液在有2g碳上钯(10％)的存在下，于4巴(bar)压力下氢化。滤出催化剂并将滤液蒸发浓缩得到128g的产物
4。
方案2B
将25L去离子水加到5.00kg(17.0mol)
3及600g活性碳(工业级)中。然后加入2.05kg(34.1mol)的乙酸。将悬浮液于22-25℃下搅拌15分钟。加入悬浮于3L去离子水中的500g碳上钯(10％)并以2L去离子水冲洗混合物。将反应器的内含物加热至40℃并于该温度下将混合物氢化直到氢吸收停止。过滤反应混合物并将滤饼以10L去离子冲洗。将滤液转移至反应器中以进行结晶，并以5L的去离子水洗涤转置的容器。将反应器的内含物加热至50℃。加入5.45kg(68.2mol)氢氧化钠溶液(50％，工业级)及7L去离子水的混合物。将混合物于45-50℃搅拌10分钟。冷却悬浮液至20℃并于该温度下搅拌1-1.5小时。将产物抽气过滤，以30L去离子水冲洗并于45℃下在真空干燥柜中干燥。得到4.13kg的产物
4。
制备二氢蝶啶酮片段
9
制备氨基酸酯
6a-
d
按文献所描述的方法，例如WO03/020722，制备甲酯
6a、乙酯
6b及2-丙酯
6c。通过在过氯酸的存在下与乙酸叔丁酯进行酯交换反应来制备叔丁酯
6d(J.Med.Chem.，Vol 37，No 20，1994，3294-3302)。
氨基酸可以碱或盐酸盐的形式用于下列亲核性取代反应。
制备氨基酸酰胺
6e，
f
以40％甲基胺的水溶液于环境温度下氨解甲酯
6a，来制备氨基酸酰胺6e。
以五倍过量的2摩尔二甲胺在四氢呋喃中的溶液，在有O-(苯并三唑-1-基)-N，N，N’，N’-四甲基四氟硼酸作为偶合剂存在下，使游离氨基酸形成酰胺，来制备氨基酸酰胺
6f。
制备化合物7
制备甲酯
7a
将457g(2.06mol)的氨基酸甲酯
6a及693g(8.25mol)碳酸氢钠粉末在10L环己烷中的悬浮液于环境温度下搅拌15分钟。加入440g(2.27mol)2，4-二氯-5-硝基嘧啶5及1.5L环己烷，并将混合物于环境温度下搅拌3天。以HPLC监测反应。将4L的二氯甲烷加到悬浮液中以再溶解结晶出的产物。加入335g的硫酸镁后，抽气过滤悬浮液并将无机的滤饼再次以二氯甲烷冲洗。将滤液于减压下蒸发浓缩至3.1kg并将得到的悬浮液加热回流。使溶液缓慢冷却并于10-15℃搅拌一小时。抽气过滤悬浮液，并以环己烷冲洗滤饼。将产物于40℃下在真空干燥柜中干燥。得到582g的
7a(X＝OCH3)的深黄色固体。
亲脂性溶剂例如环己烷、甲基环己烷、甲苯及其混合物特别适合用于获得在进行化合物
5的亲核性取代中的高区域选择性。
化合物
7b-
f是以该类似方法进行制备。在氨基酸酰胺
7e，
f反应期间，加入一种有些极性的溶剂例如乙酸乙酯或二氯甲烷以增进溶解性。
制备化合物
8
将新制备的560g(1.63mol)
7a及185g阮内镍(Raney nickel)的2.8L乙酸的悬浮液，于75℃下进行氢化。当氢气吸收结束后滤出催化剂并于减压下蒸发氢化溶液。将4L去离子水及4L乙酸乙酯加到残留物中。在二相间形成一种含有产物的沉淀。分离出水层。将2L乙酸乙酯加到有机层中并抽气过滤沉淀。将该沉淀悬浮于600mL去离子水中，于环境温度下搅拌1小时，抽气过滤并以去离子水冲洗。得到110g的潮湿产物A。
将滤液以氯化钠溶液冲洗三次。将有机层蒸发浓缩。得到380g红棕色的残余物B，将其与湿产物A合并。将合并的粗产物A和B于回流下溶于1.5L乙醇中。将溶液过滤净化并以150mL乙醇冲洗滤饼。将550mL去离子水于回流温度下加到溶液中。放置冷却混合物并于环境温度下搅拌16小时及于0-5℃下搅拌3小时。将沉淀抽气过滤并以去离子水/甲醇(1∶1)洗涤，然后以去离子水洗涤。将产物置于50℃下在真空干燥柜中干燥。得到266g产物
8的固体。
制备化合物
9(方案3A)
于一小时内，4-10℃下分批将38g(0.95mol)氢化钠(60％分散于矿物油中)加到264g(0.94mol)的
8及161g(1.13mol)碘代甲烷的2L二甲基乙酰胺溶液中。移除冷却浴并使混合物于2小时内上升至20℃。冷却至10℃并再加入0.38g(9.5mmol)氢化钠。将混合物于10-15℃下搅拌4小时。于反应溶液中加入100mL乙酸乙酯及1kg冰。将生成的悬浮液以3L去离子水稀释。搅拌悬浮液2小时，以抽气过滤沉淀并以去离子水洗涤滤饼。将产物于50℃下在真空干燥柜中干燥。得到273g的产物
9的无色结晶。
制备化合物
9(方案3B)
将100g(356mmol)
8及73.8g(534mmol)碳酸钾在400mL碳酸二甲酯中的悬浮液于高压釜中加热至130℃6小时。放置冷却混合物并搅拌加入300mL去离子水及200mL乙酸乙酯。分离出水层与不溶解的盐类。由有机层于180mbar的压力及70℃温度的加热浴下蒸馏出500mL的溶剂。将600mL去离子水加到残余物中并于150mbar的压力及温度80℃的加热浴下蒸馏出100mL的溶剂。将350mL乙醇加到悬浮液中然后加热至65℃。放置冷却溶液并接晶种。冷却至10℃，将沉淀抽气过滤并以去离子水及乙醇(2.5∶1)的混合物洗涤。将产物在50℃下在真空干燥柜中干燥。得到95.5g的产物
9。
制备式(I)化合物
将201g(1.06mmol)对甲苯磺酸水合物、209g(706mmol)
9及183g(695mmol)
4在800mL 2-甲基-4-戊醇中的悬浮液加热回流。蒸馏出100mL溶剂。将混合物回流3小时，加入200mL的2-甲基-4-戊醇并蒸馏出120mL溶剂。于回流下加热2小时后，再蒸馏出280mL溶剂。将混合物冷却至100℃并于反应溶液中加入1L去离子水然后再加入0.5L乙酸乙酯。分离出有机相并将水相再次以0.5L乙酸乙酯洗涤。将1.5L二氯甲烷及0.5L乙酸乙酯加到酸性水相中。以260mL的6N氢氧化钠溶液将水相的pH值调整至pH9.2。分离出水相并各以1L的1N的碳酸氢钠溶液洗涤有机相三次。将有机相以硫酸钠干燥，过滤并减压下蒸发溶剂。得到406g的粗产物。
将粗产物溶于1.5L乙酸乙酯中。于50-55℃的温度下加入2.5L甲基叔丁基醚。在45℃下接晶种并冷却至环境温度搅拌16小时。将悬浮液于0-5℃下搅拌3.5小时并抽气过滤沉淀。再次以甲基叔丁基醚/乙酸乙酯(2∶1)和甲基叔丁基醚洗涤滤饼。将产物在50℃下在真空干燥柜中干燥。得到236g式(I)化合物结晶产物的I型无水合物。
结晶：
将46.5g的上述I型无水合物晶体溶于310mL的1-丙醇中并过滤澄清。将混合物加热至70℃并加入620mL去离子水。将溶液冷却至环境温度，冷却至0-10℃并加入晶种。将生成的悬浮液于0-10℃搅拌3小时。抽气过滤并以冷的1-丙醇/去离子水(1∶2)洗涤。将产物于50℃下在真空干燥柜中干燥。得到40.5g式(I)化合物结晶产物的单水合物。
亦可将上述反应的粗产物从1-丙醇/去离子水中直接结晶出晶体单水合物。
制备式(I)化合物的水合物及无水合物可根据下述方法进行。这些方法示于流程2，且作为理解而说明发明而非限制其内容。
流程2
式(I)化合物的多晶型特性
本发明的水合物及无水合物是通过DSC/TG(差示扫描量热计/差热重量分析法)及XRD(X-射线粉末衍射图)(表1-5，图1a至5a)来表征。
所有的XRD粉末衍射图是使用现有技术中已知的方法，其使用X-射线粉末衍射仪(Bruker D8 Advance)而得到的。衍射图是在下列测量条件下得到：CuKα放射线(λ＝1.5418)，40kV，40mA.
DSC/TG的测量是使Mettler Toledo公司所生产的仪器(DSC821及TGA851)来进行。对DSC测量所用的样品量是介于2至10mg间，对TG测量使用10-30mg。加热的速率为10K/min，且测量是于惰性气氛下进行(通入氮气)。
表1
于正常环境条件下式(I)化合物单水合物的X-射线粉末反射及其强度(标准化)。
| 2Θ[°] | dhkl[] | 强度I/Io[％] |
| 6,07 | 14,54 | 62 |
| 8,06 | 10,96 | 15 |
| 9,11 | 9,7 | 100 |
| 12,23 | 7,23 | 24 |
| 12,93 | 6,84 | 50 |
| 13,81 | 6,41 | 13 |
| 14,29 | 6,2 | 76 |
| 14,94 | 5,92 | 18 |
| 16,29 | 5,44 | 18 |
| 17,01 | 5,21 | 15 |
| 17,8 | 4,98 | 8 |
| 18,29 | 4,85 | 69 |
| 18,6 | 4,77 | 32 |
| 19,71 | 4,5 | 18 |
| 19,94 | 4,45 | 13 |
| 20,43 | 4,34 | 7 |
| 20,76 | 4,27 | 17 |
| 21,8 | 4,07 | 5 |
| 22,64 | 3,92 | 65 |
| 23,21 | 3,83 | 29 |
| 23,67 | 3,76 | 22 |
| 24,38 | 3,65 | 7 |
| 25,4 | 3,5 | 14 |
| 25,98 | 3,43 | 2 |
| 27,01 | 3,3 | 3 |
| 27,78 | 3,21 | 27 |
| 28,49 | 3,13 | 11 |
| 30,41 | 2,94 | 9 |
表2
于环境温度及90％相对湿度下，式(I)化合物三水合物的X-射线粉末反射及其强度(标准化)。
| 2Θ[°] | dhkl[] | 强度I/Io[％] |
| 5,93 | 14,89 | 39 |
| 6,45 | 13,68 | 34 |
| 8,69 | 10,17 | 100 |
| 9,45 | 9,35 | 26 |
| 11,43 | 7,74 | 85 |
| 12,5 | 7,08 | 8 |
| 13,06 | 6,77 | 32 |
| 13,89 | 6,37 | 7 |
| 14,57 | 6,08 | 19 |
| 15,38 | 5,76 | 9 |
| 16,18 | 5,47 | 7 |
| 17,04 | 5,2 | 25 |
| 17,34 | 5,11 | 10 |
| 18,07 | 4,91 | 37 |
| 18,59 | 4,77 | 21 |
| 18,85 | 4,71 | 16 |
| 19,81 | 4,48 | 5 |
| 20,52 | 4,32 | 15 |
| 21,18 | 4,19 | 57 |
| 22,06 | 4,03 | 5 |
| 22,96 | 3,87 | 15 |
| 23,46 | 3,79 | 51 |
| 24,79 | 3,59 | 21 |
| 25,74 | 3,46 | 7 |
| 27,23 | 3,27 | 6 |
| 28,04 | 3,18 | 7 |
| 28,8 | 3,1 | 15 |
| 29,52 | 3,02 | 7 |
| 29,88 | 2,99 | 7 |
| 30,58 | 2,92 | 5 |
表3
于正常环境条件下，式(I)化合物无水合物I的X-射线粉末反射及其强度(标准化)。
| 2Θ[°] | dhkl[] | 强度I/Io[％] |
| 5,48 | 16,11 | 22 |
| 6,47 | 13,65 | 51 |
| 7,88 | 11,21 | 31 |
| 8,93 | 9,89 | 100 |
| 9,5 | 9,31 | 5 |
| 10,74 | 8,23 | 22 |
| 11,06 | 7,99 | 5 |
| 13,06 | 6,78 | 19 |
| 13,81 | 6,41 | 9 |
| 14,95 | 5,92 | 4 |
| 15,86 | 5,58 | 14 |
| 16,71 | 5,3 | 10 |
| 16,94 | 5,23 | 17 |
| 18,27 | 4,85 | 5 |
| 18,65 | 4,75 | 20 |
| 19,14 | 4,63 | 9 |
| 20,12 | 4,41 | 29 |
| 21,32 | 4,16 | 5 |
| 21,81 | 4,07 | 4 |
| 22,57 | 3,94 | 11 |
| 23,44 | 3,79 | 4 |
| 23,78 | 3,74 | 7 |
| 24,66 | 3,61 | 3 |
| 25,28 | 3,52 | 7 |
| 25,55 | 3,48 | 4 |
| 27,21 | 3,27 | 8 |
| 28,03 | 3,18 | 2 |
| 29,35 | 3,04 | 3 |
| 30,04 | 2,97 | 3 |
表4
于正常环境条件下，式(I)化合物无水合物II的X-射线粉末反射及其强度(标准化)。
| 2Θ[°] | dhkl[] | 强度I/Io[％] |
| 4,76 | 18,55 | 50 |
| 6,64 | 13,3 | 100 |
| 7,92 | 11,15 | 1 |
| 9,03 | 9,79 | 3 |
| 9,51 | 9,29 | 39 |
| 11,29 | 7,83 | 1 |
| 12,39 | 7,14 | 37 |
| 13,41 | 6,6 | 2 |
| 14,31 | 6,18 | 16 |
| 17,1 | 5,18 | 1 |
| 17,58 | 5,04 | 1 |
| 18,72 | 4,74 | 3 |
| 19 | 4,67 | 7 |
| 19,23 | 4,61 | 17 |
| 20,04 | 4,43 | 5 |
| 20,39 | 4,35 | 2 |
| 21,15 | 4,2 | 4 |
| 21,57 | 4,12 | 2 |
| 22,18 | 4 | 1 |
| 23,07 | 3,85 | 4 |
| 23,54 | 3,78 | 1 |
| 24,2 | 3,67 | 3 |
| 24,65 | 3,61 | 1 |
| 25,37 | 3,51 | 2 |
| 26,28 | 3,39 | 1 |
| 26,74 | 3,33 | 1 |
| 27,01 | 3,3 | 2 |
| 27,95 | 3,19 | 1 |
| 28,13 | 3,17 | 1 |
表5
于100℃，式(I)化合物无水合物III型的X-射线粉末反射及其强度(标准化)。
| 2Θ[°] | dhkl[] | 强度I/Io[％] |
| 6,49 | 13,61 | 41 |
| 9,74 | 9,07 | 81 |
| 10,99 | 8,04 | 29 |
| 12,56 | 7,04 | 21 |
| 14,44 | 6,13 | 13 |
| 14,95 | 5,92 | 8 |
| 15,72 | 5,63 | 59 |
| 17,5 | 5,06 | 14 |
| 17,89 | 4,95 | 11 |
| 18,8 | 4,72 | 29 |
| 19,14 | 4,63 | 46 |
| 19,68 | 4,51 | 100 |
| 21,58 | 4,12 | 50 |
| 22,19 | 4 | 43 |
| 23,09 | 3,85 | 40 |
| 25,99 | 3,43 | 29 |
| 27,66 | 3,22 | 17 |
| 30,74 | 2,91 | 12 |
本发明的式(I)化合物的无水合物I、无水合物II及单水合物可单独使用或与本发明其他活性物质结合使用，视需要也可与其他药学上活性物质组合。
适合的制剂形式包括例如片剂、胶囊、栓剂、溶液，特别是注射溶液(s.c.，i.v.，i.m.)及输液，酏剂、乳液或可分散的粉剂。医药上活性化合物的比例在0.01至90重量％的范围内，优选的为0.1至50重量％的组合物总量，即其是足以达到所规定剂量范围的量。若需要，该规定剂量可按一天给予多次。
适合的片剂，例如可通过将活性物质与已知的赋型剂，例如惰性稀释剂(如碳酸钙、磷酸钙或乳糖)、崩解剂(例如玉米淀粉或藻酸)、粘合剂(例如淀粉或明胶)、润滑剂(例如硬脂酸镁或滑石)及/或延迟释放剂(例如羧甲基纤维素、纤维醋酸苯二甲酸酯(cellulose acetate phthalate)或聚醋酸乙烯酯)混合而制得。片剂亦可包含多层。
包衣片可由以类似片剂所产生的片芯，涂覆一般常用于片剂包衣的物质来制备，例如可力酮(collidone)或虫胶、阿拉伯胶、滑石、二氧化钛或糖。为了达到延迟释放效果或预防不相容性，片芯也可包含多层。同样的，片剂包衣可包含多层以达到延迟释放目的，同时可使用上述所提及的用于片剂的赋型剂。
含有本发明的活性物质或活性物质组合物的糖浆可另含有一种甜味剂，例如糖精、环己氨磺酸盐(cyclamate)、甘油或糖，及味道增进剂例如芳香物质如香草醛或橙提取物。其也可含有悬浮助剂或增稠剂例如羧甲基纤维素钠、湿润剂例如脂肪醇与环氧乙烷的缩合产物或保存剂例如对羟基苯甲酸盐。
注射溶液或输液可以常用的方法来制备，例如加入等张剂、保存剂例如对羟基苯甲酸盐或稳定剂例如乙二胺四乙酸的碱金属盐类，视需要可使用乳化剂及/或分散剂，其中例如使用水作为稀释剂则视需要可使用有机溶剂作为溶剂化剂或助溶剂，并转置于注射瓶或安瓿或输液瓶中。
含有一种或多种活性物质或活性物质组合物的胶囊，可例如通过将活性物质与惰性载剂例如乳糖或山梨糖醇混合，并将其包装入明胶胶囊内而制备。
适合的栓剂可例如通过与适合本目的的载剂例如中性脂肪或聚乙二醇或其衍生物混合而制造。
可使用的赋形剂包括，例如水、医药上可接受的有机溶剂例如石蜡(石油分馏物)、植物源油(例如花生或芝麻油)、单或多功能醇类(例如乙醇或甘油)，载剂例如天然矿物粉末(例如高岭土、粘土、滑石、白垩)、合成的矿物粉(例如高分散性硅酸及硅酸盐)、糖(例如蔗糖、乳糖及葡萄糖)、乳化剂(例如木质素、亚硫酸盐废液、甲基纤维素、淀粉及聚乙烯吡咯烷酮)及润滑剂(例如硬脂酸镁、滑石、硬脂酸及月桂基硫酸钠)。
给药可以常用的方法来进行，优选的为口服、注射或透皮给药。以口服给药而言，片剂当然除上述载剂外还可含有添加剂，例如柠檬酸钠、碳酸钙及磷酸氢钙与各种添加剂例如淀粉，优选的为马铃薯淀粉、明胶及类似物。再者，在制片中，同时可使用润滑剂例如硬脂酸镁、月桂基硫酸钠及滑石。以水性悬浮液而言，除了上述的赋形剂外，活性物质可与各种增味剂或调色剂组合。
就不经胃肠用途而言，活性物质的溶液可与适合的液体载剂一起使用。
用于静脉内的剂量为每小时1-1000mg，优选的为每小时5至500mg。
然而依体重、给药途径、个体对药物的反应、调配物的性质及投药的时间或给药时间间隔，有时候需要时可将给定的量分开。因此，在某些案例中使用低于上所给予的最小剂量可能就足够，而在一些案例中可能必须超过上限。当给药量较大时，建议将其分成在一天中的多个单剂量中。
下列剂型实例说明本发明但并非限制其范围：
医药制剂的实例
A)
片剂
每片
活性物质 100mg
乳糖 140mg
玉米淀粉 240mg
聚乙烯吡咯烷酮 15mg
硬脂酸镁
5mg
500mg
将磨成细粉的活性物质、乳糖及部分玉米淀粉共同混合。将混合物过筛，然后以聚乙烯吡咯烷酮的水溶液润湿，捏和湿式造粒并干燥。将颗粒、剩余的玉米淀粉及硬脂酸镁过筛并共同混合。将混合物压制成适当形状及大小的片剂。
B)
片剂
每片
活性物质 80mg
乳糖 55mg
玉米淀粉 190mg
微晶纤维素 35mg
聚乙烯吡咯酮 15mg
羧甲基淀粉钠 23mg
硬脂酸镁
2mg
400mg
将磨成细粉的活性物质、部分玉米淀粉、乳糖、微晶纤维素及聚乙烯吡咯烷酮共同混合，将混合物过筛，然后与剩余的玉米淀粉及水加工成颗粒，将其干燥并过筛。加入羧甲基淀粉钠及硬脂酸镁，混合并将混合物制成适当大小的片剂。
C)
安瓿溶液
活性物质 50mg
氯化钠 50mg
注射用水 5ml
将活性物质以其本身的pH或视需要调整至pH3.5至6.5溶解于水中，加入氯化钠作为等张溶液。将生成的溶液过滤除热原，并将滤液于无菌的条件下注入安瓿中，将其灭菌并熔封。该安瓿含有5mg、25mg及50mg的活性物质。
Claims (19)
1.一种式(I)化合物的水合物：
2.如权利要求1的式(I)化合物的水合物，其特征在于该水合物为式(I)化合物的单水合物。
3.如权利要求1的式(I)化合物的水合物，其特征在于该水合物为式(I)化合物的三水合物。
4.一种式(I)化合物的无水合物：
5.如权利要求4的无水合物，其特征在于该无水合物是以式(I)化合物的I型无水合物存在。
6.如权利要求4的无水合物，其特征在于该无水合物是以式(I)化合物的II型的无水合物存在。
7.如权利要求4的无水合物，其特征在于该无水合物是以式(I)化合物的III型的无水合物存在。
8.一种医药组合物，其特征在于该医药组合物含有一种治疗上有效量的权利要求1至2或4至6中任一项的式(I)化合物的水合物或无水合物，及一种或多种医药上可接受的赋形剂。
9.如权利要求1至2或4至6中任一项的式(I)化合物的水合物或无水合物，其是作为具抗增生活性的药物组分。
10.一种如权利要求1至2或4至6中任一项的式(I)化合物的水合物或无水合物的用途，其用于制备供治疗及/或预防癌症、感染、炎症及自体免疫性疾病的药物制剂。
11.一种如权利要求1至2或4至6中任一项的式(I)化合物的水合物或无水合物的用途，其用于制备抑制类polo激酶的药物制剂。
12.如权利要求11的用途，其特征在于该类polo激酶为PLK-1。
13.如权利要求10至12中的用途，其中该活性物质是以口服、胃肠道内、静脉内、腹腔内或通过注射给药。
14.一种制备式(I)化合物的方法，
其特征在于将式4化合物
与式9化合物反应
15.一种式3化合物，
16.一种式4化合物，
17.一种制备如权利要求2的式(I)化合物的单水合物的方法，其包括下列步骤：
(a)制备式(I)化合物在一种异丙醇及水的溶剂混合物中的溶液；
(b)由溶剂混合物中结晶出式(I)化合物的单水合物；及
(c)分离式(I)化合物的单水合物。
18.一种制备如权利要求5的式(I)化合物的I型无水合物的方法，其包括下列步骤：
(a)制备式(I)化合物在乙酸乙酯及甲基叔丁基醚中的溶液；
(b)由溶剂混合物中结晶出式(I)化合物的I型无水合物；及
(c)分离式(I)化合物的I型无水合物。
19.一种制备如权利要求6的式(I)化合物的II型无水合物的方法，其包括下列步骤：
(a)制备式(I)化合物在乙酸乙酯中的溶液；
(b)由乙酸乙酯中结晶出式(I)化合物的II型无水合物，随后加入二乙醚；
(c)分离式(I)化合物的II型无水合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP04019366.6 | 2004-08-14 | ||
| EP04019366 | 2004-08-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101006090A true CN101006090A (zh) | 2007-07-25 |
Family
ID=35311878
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| CNA2005800276839A Pending CN101006090A (zh) | 2004-08-14 | 2005-08-11 | 4[[(7r)－8－环戊基－7－乙基－5,6,7,8－四氢－5－甲基－4－6－氧代－2－哌啶基]氨基]－3－甲氧基－n－(1－甲基－4－哌啶基)－苯甲酰胺的水合物及多晶型物，其制造方法及其作为药物的用途 |
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| Country | Link |
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| US (3) | US7728134B2 (zh) |
| EP (1) | EP1778691A1 (zh) |
| JP (1) | JP2008509953A (zh) |
| KR (1) | KR101221864B1 (zh) |
| CN (1) | CN101006090A (zh) |
| AR (1) | AR052404A1 (zh) |
| AU (1) | AU2005274340B2 (zh) |
| BR (1) | BRPI0514351A2 (zh) |
| CA (1) | CA2578098A1 (zh) |
| EA (1) | EA011407B1 (zh) |
| EC (1) | ECSP077249A (zh) |
| IL (1) | IL181302A0 (zh) |
| MX (1) | MX2007001854A (zh) |
| NO (1) | NO20070752L (zh) |
| NZ (1) | NZ553649A (zh) |
| PE (1) | PE20060424A1 (zh) |
| TW (1) | TWI370131B (zh) |
| UA (1) | UA87865C2 (zh) |
| WO (1) | WO2006018222A1 (zh) |
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| CN102076690A (zh) * | 2008-06-23 | 2011-05-25 | 维泰克斯制药公司 | 蛋白激酶抑制剂 |
| CN102762568A (zh) * | 2009-12-23 | 2012-10-31 | 伊兰药品公司 | 作为polo样激酶的抑制剂的蝶啶酮 |
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- 2005-08-11 KR KR1020077005956A patent/KR101221864B1/ko not_active IP Right Cessation
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- 2009-06-04 US US12/478,183 patent/US8034816B2/en active Active
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102076690A (zh) * | 2008-06-23 | 2011-05-25 | 维泰克斯制药公司 | 蛋白激酶抑制剂 |
| CN102762568A (zh) * | 2009-12-23 | 2012-10-31 | 伊兰药品公司 | 作为polo样激酶的抑制剂的蝶啶酮 |
Also Published As
| Publication number | Publication date |
|---|---|
| US20090298840A1 (en) | 2009-12-03 |
| ECSP077249A (es) | 2007-03-29 |
| UA87865C2 (en) | 2009-08-25 |
| CA2578098A1 (en) | 2006-02-23 |
| AR052404A1 (es) | 2007-03-21 |
| AU2005274340A1 (en) | 2006-02-23 |
| IL181302A0 (en) | 2007-07-04 |
| TW200619220A (en) | 2006-06-16 |
| EA200700387A1 (ru) | 2007-08-31 |
| TWI370131B (en) | 2012-08-11 |
| NO20070752L (no) | 2007-05-10 |
| US20060035902A1 (en) | 2006-02-16 |
| WO2006018222A8 (de) | 2006-06-15 |
| KR101221864B1 (ko) | 2013-01-14 |
| WO2006018222A1 (de) | 2006-02-23 |
| EA011407B1 (ru) | 2009-02-27 |
| US8034816B2 (en) | 2011-10-11 |
| AU2005274340B2 (en) | 2012-04-05 |
| EP1778691A1 (de) | 2007-05-02 |
| MX2007001854A (es) | 2007-03-28 |
| JP2008509953A (ja) | 2008-04-03 |
| BRPI0514351A2 (pt) | 2012-10-30 |
| US7728134B2 (en) | 2010-06-01 |
| NZ553649A (en) | 2010-11-26 |
| PE20060424A1 (es) | 2006-06-09 |
| KR20070050967A (ko) | 2007-05-16 |
| US20090318457A1 (en) | 2009-12-24 |
| US8202867B2 (en) | 2012-06-19 |
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