CN100345840C - 毒蕈碱性受体拮抗剂的稳定水合物 - Google Patents
毒蕈碱性受体拮抗剂的稳定水合物 Download PDFInfo
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- CN100345840C CN100345840C CNB038070847A CN03807084A CN100345840C CN 100345840 C CN100345840 C CN 100345840C CN B038070847 A CNB038070847 A CN B038070847A CN 03807084 A CN03807084 A CN 03807084A CN 100345840 C CN100345840 C CN 100345840C
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- hydrate
- solvate
- treatment
- bladder
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Abstract
本发明涉及毒蕈碱性受体拮抗剂的稳定的固体水合物,可用于治疗肠易激惹综合征、憩室病、食管弛缓不能、慢性阻塞性气道疾病、膀胱过动(包括尿失禁、尿急和尿频症状)、尿失禁、神经性尿急或频尿,治疗膀胱功能障碍、尿漏、由神经性膀胱、痉挛性或高张性膀胱导致的排尿疼痛或排尿困难,功能障碍性膀胱综合征、包括肠胃活动过强在内的肠胃障碍,以及对肠平滑肌细胞发挥松弛作用。
Description
本发明涉及毒蕈碱性受体拮抗剂(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺的稳定固体水合物,所述拮抗剂也公知为达非那新(VII):
另外,本发明还涉及含有本发明水合物的药物组合物和所述水合物在药物中的用途。这类药物组合物与以下情形特别相关:治疗需要毒蕈碱性受体拮抗剂的病症如肠易激惹综合征、憩室病、食管弛缓不能、慢性阻塞性气道疾病、包括尿失禁、尿急和尿频症状的膀胱过动、尿失禁、神经性尿急或频尿,治疗膀胱功能障碍、尿漏(urinary leakage)、由神经性膀胱、痉挛性或高张性膀胱导致的排尿疼痛或排尿困难,功能障碍性膀胱综合征、包括肠胃活动过强在内的肠胃障碍,以及对肠平滑肌细胞的松弛效果。
欧洲专利0388054描述了一族作为毒蕈碱性受体拮抗剂的3-取代的吡咯烷衍生物,包括达非那新及其可药用盐。这类可药用盐包括酸加成盐,具体而言是盐酸盐、氢溴酸盐、氢氟酸盐、硫酸盐或硫酸氢盐、磷酸盐或磷酸氢盐、乙酸盐、苯磺酸盐(besylate)、柠檬酸盐、富马酸盐、葡糖酸盐、乳酸盐、马来酸盐、甲磺酸盐、琥珀酸盐和酒石酸盐。
达非那新的氢溴酸盐对于医疗用途而言是优选的化合物。该盐由相应的无水游离碱制备。然而,与游离碱相关的问题在于它非常不稳定,贮存期仅为1个月。另外,就药用而言足够纯的形式的游离碱可能难以制备。
令人惊讶的是,已经发现该问题可通过合成达非那新的水合物以转化成氢溴酸盐而不是采用该游离碱来制备氢溴酸盐得以解决。已发现该固体水合物可保持稳定远远超过1年。此外,还可达到适于药用的纯度水平。固体水合物向可药用氢溴酸盐的转化可经由容易的转化过程而实现。
因此,本发明提供达非那新的稳定固体水合物。X-射线结晶学已显示,本发明的水合物可被分离为达非那新∶水化学计量比为1∶0.6至1∶1的化合物。
更具体而言,本发明提供了式(IX)化合物:
在一个优选实施方案中,式(IX)化合物通过使用单反射ATR(衰减全反射)进行的红外光谱而表征,该光谱在下列νmax(cm-1)处显示显著的吸收带:3625、3516、3440、2948、2806、1699、1622、1597、1578、1488、1471、1445、1378、1353、1325、1312、1280、1242、1196、1152、1119、1102、1086、1024、981、939、925、900。
式(IX)化合物还可通过使用铜辐射(λ=0.15405nm)获得的X-射线粉末衍射图而表征,该衍射图在下列2θ角显示主峰:8.39、10.519、13.272、13.693、15.908、16.289、16.855、19.637、21.135、21.55、21.722、23.006和26.284度。
此外,还可通过差示扫描量热法(DSC)曲线表征,该曲线在101℃、20℃/min的扫描速率下显示陡峭的吸热峰。
红外光谱法使用Nicolet Avatar 360FT-IR分光光度计进行。
使用单反射ATR(衰减全反射)对样品进行检测,其中分光光度计的扫描光谱范围为650cm-1至4000cm-1。
使用SIEMENS D5000X-射线粉末衍射仪获得PXRD数据,该衍射仪装配有自动样品转换装置、θ-θ测角器、自动光束发散狭缝、二次单色仪(secondary monochromator)和闪烁计数器。通过将粉末压实到硅片样品装置上而制备用于分析的样品。旋转每一样品,同时使用铜K-α1X-射线(波长=1.5406埃)辐照,X-射线管在40kV/40mA下操作。
使用以步进扫描模式运行的测角器进行分析,其中该模式设定为在2°-45°的2θ范围内,每步0.02°,计数5秒。
使用装配有自动样品转换装置的PerkinElmer DSC-7仪器进行DSC。精确称量约3mg样品,置于50微升铝盘中,并用穿孔盖卷边密封。在氮气吹扫下将样品以20℃/min的速率在40℃-250℃内加热。
本发明还提供包含如上所述的本发明水合物以及可药用赋形剂、稀释剂或载体的药物组合物。
另外,本发明提供如上所述的本发明水合物或如上所述的包含本发明水合物的药物组合物作为药物的用途。
再进一步,本发明提供如上所述的本发明水合物或如上所述的包含本发明水合物的药物组合物在制备用于治疗性或预防性治疗毒蕈碱性受体拮抗剂适用的医学病症的药物中的用途。这类病症为肠易激惹综合征、憩室病、食管弛缓不能、慢性阻塞性气道疾病、包括尿失禁、尿急和尿频症状的膀胱过动,尿失禁、神经性尿急或频尿、治疗膀胱功能障碍、尿漏、由神经性膀胱、痉挛性或高张性膀胱导致的排尿疼痛或排尿困难,功能障碍性膀胱综合征、包括肠胃活动过强在内的肠胃障碍以及对肠平滑肌细胞的松弛影响。
本发明还提供一种治疗哺乳动物以治疗或预防毒蕈碱性受体拮抗剂适用的医学病症的方法,其包括向所述哺乳动物施用有效量的如上所述的本发明水合物或如上所述的包含本发明水合物的药物组合物。
本发明还包括如上所述的本发明水合物的所有合适的同位素变体。如上所述的“本发明水合物的同位素变体”定义为其中至少一个原子被具有相同原子数但原子质量与自然界中通常发现的原子质量不同的原子替代。可引入如上所述的本发明水合物中的同位素的实例包括氢、碳、氮和氧的同位素,分别如2H、3H、13C、14C、15N、17O和18O。如上所述的本发明水合物的某些同位素变体,例如其中引入了具有放射性同位素如3H或14C的那些,可用于药物和/或底物组织分布研究。氚,即3H和碳-14,即14C同位素由于它们易于制备和检测而特别优选。此外,用同位素如氘,即2H取代可提供某些治疗优点,这些优点源于更高的代谢稳定性,例如体内半衰期增加或剂量要求降低,因此在某些情况下是优选的。如上所述的本发明水合物的同位素变体通常可通过常规方法如通过示例性方法或通过随后使用合适试剂的适当同位素变体的实施例和制备例中描述的制备方法而制备。
如上所述的本发明水合物可单独施用,但通常以与根据预计使用途径和标准药学实践而选择的合适的药物赋形剂、稀释剂或载体的混合物施用。例如,如上所述的本发明水合物可以以片剂、胶囊剂、多粒子剂(multiparticulate)、凝胶剂、薄膜剂、卵剂(ovule)、酏剂、溶液剂或混悬剂形式经口服、口含或经舌下施用,所述剂型可含有矫味剂或着色剂,用于即释、延迟释放、调节释放、缓释或控释施用。如上所述的本发明水合物还可作为快速分散或快速溶解剂型或以高能分散体形式或作为包衣颗粒施用。如上所述的本发明水合物的合适制剂可根据需要呈包衣或非包衣形式。
这些固体药物组合物,例如片剂,可含有赋形剂,如微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸氢钙和甘氨酸;崩解剂如淀粉(优选玉米、马铃薯或木薯淀粉)、羟基乙酸淀粉、交联羧甲基纤维素钠和某些复合硅酸盐;以及制粒粘合剂,例如聚乙烯吡咯烷酮、羟丙甲基纤维素(HPMC)、羟丙基纤维素(HPC)、蔗糖、明胶和阿拉伯树胶。另外,还可包含润滑剂如硬脂酸镁、硬脂酸、山嵛酸甘油酯和滑石。
还可将类似类型的固体组合物用作明胶或HPMC胶囊剂中的填充物。在这方面,优选的赋形剂包括乳糖(lactose)、淀粉、纤维素、乳糖(milk sugar)或高分子量聚乙二醇。对于水悬剂和/或酏剂,可将如上所述的本发明水合物与各种甜味剂或矫味剂、着色物质或染料、与乳化剂和/或悬浮剂、与稀释剂如水、乙醇、丙二醇和甘油及其组合相混合。
如上所述的本发明水合物还可经肠胃外施用,例如经静脉内、经动脉内、经腹膜内、经鞘内、经心室内、经尿道内、经胸骨内、经颅内、经肌肉内或经皮下施用,或者它们可通过输注或无针注射技术施用。对于这类肠胃外施用,它们最好以可含有其它物质如使该溶液与血液等张的足够的葡萄糖盐的无菌水溶液形式使用。必要时应将水溶液适当地缓冲(优选缓冲至pH 3-9)。在无菌条件下制备合适的肠胃外制剂可容易地通过本领域熟练技术人员熟知的标准制药技术而完成。
对于向人类患者的口服和肠胃外施用,如上所述的本发明水合物的日剂量水平通常为1.5至30mg(以一剂或分剂施用)。在任何情况下内科医生将确定最适合任何个体患者的实际剂量,并且该剂量会因特定患者的年龄、体重和响应而异。上述剂量为平均情况的举例。当然也存在其中应当使用更高或更低剂量范围的个别情况,这类情况包括在本发明范围内。
如上所述的本发明水合物还可经鼻内或经吸入施用,并且方便地以干粉吸入剂形式或以来自加压容器、泵、喷射器、雾化器或喷雾器的气雾喷雾形式递送,其中任选使用合适的抛射剂,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、氢氟链烷烃如1,1,1,2-四氟乙烷(HFA134ATM)或1,1,1,2,3,3,3-七氟丙烷(HFA227EATM)、二氧化碳或其它合适的气体。在加压气雾剂的情况下,剂量单位可通过提供递送计量药量的阀来确定。加压容器、泵、喷射器、雾化器或喷雾器可含有活性化合物的溶液或悬液,例如使用乙醇和抛射剂的混合物作为溶剂,其可额外含有润滑剂,例如失水山梨醇三油酸酯。用于吸入器或吹入器中的胶囊剂和药筒(例如由明胶制成)可配制成含有如上所述的本发明水合物与合适的粉末基质如乳糖或淀粉的粉末混合物。
优选将气雾剂或干粉制剂设置为每次定量剂量或“喷出(puff)”含有0.2mg至3.0mg如上所述的本发明水合物,以递送至患者。气雾剂的总日剂量为0.5mg至10.0mg如上所述的本发明水合物,该剂量可以单剂施用,或更通常地在一日内以分剂量施用。
或者,如上所述的本发明水合物可以以栓剂或阴道栓剂的形式施用,或者可以以凝胶剂、水凝胶剂、洗剂、溶液剂、霜剂、软膏剂或撒粉剂形式局部施用。如上所述的本发明水合物还可例如通过使用皮肤帖剂而经皮或透皮施用。它们还可通过肺部或直肠途径施用。
或者,如上所述的本发明水合物可例如以凝胶剂、水凝胶剂、洗剂、溶液剂、霜剂、软膏剂、撒粉剂、裹敷剂(dressing)、泡沫剂、薄膜剂、皮肤帖剂(例如但不限于下列类型:贮库、骨架、粘合剂包合药物(drug-in-adhesive)、多层压制(multilaminate)聚合物体系)、糯米纸囊剂(wafer)、植入物、海绵、纤维、绷带、微乳剂形式及其组合局部经皮或透皮施用于皮肤、粘膜。对于这些施用,可将如上所述的本发明水合物混悬或溶解在例如一种或多种下列物质的混合物中:矿物油、液体石蜡、白凡士林、丙二醇、聚氧乙烯聚氧丙烯复合物、乳化蜡、甘油、硅酮液、固定油类—包括合成的单或二甘油酯,以及脂肪酸和脂肪酸酯—包括油酸、水、失水山梨醇单硬脂酸酯、聚乙二醇、液体石蜡、聚山梨酯60、十六烷基酯蜡(cetyl ester wax)、棕榈醇(cetearyl alcohol)、2-辛基十二烷醇、苄醇、醇类如乙醇。或者,还可使用渗透增强剂,例如但不限于如下文献中公开的那些:Finnin和Morgan,Journal of Pharm.Sciences,1999年10月,“透皮渗透促进剂:应用、局限和潜力”。还可以使用下列物质:聚合物、碳水化合物、蛋白质、呈纳米颗粒形式(如niosome或脂质体)或悬浮或溶解的磷脂。另外,它们可使用离子导入法、电穿孔法、超声导入法(phonophoresis,sonophoresis)和无针注射递送。
如上所述的本发明水合物还可与环糊精结合使用。环糊精公知与药物分子形成包合和非包合配合物。药物-环糊精配合物的形成可改变药物分子的溶解性、溶解速率、生物利用度和/或稳定性性能。药物-环糊精配合物通常可用于大多数剂型和施用途径。作为与药物直接配合的替代,可将环糊精用作辅助添加剂,例如用作载体、稀释剂或增溶剂。α-、β-和γ-环糊精最常使用,并且合适的实例描述于WO-A-91/11172、WO-A-94/02518和WO-A-98/55148。
本发明化合物可如下所示制备:
方案1
令人惊讶的是,已经发现达非那新可由达非那新溶液以药学纯形式获得,对所述溶液进行树脂处理,然后经由甲苯溶剂合物转化成水合物(见方案1中的步骤A和B)。可将达非那新甲苯溶剂合物直接转化为氢溴酸盐,但该转化不允许生产厂家在进度方面具备灵活性,因为甲苯溶剂合物在中至长期贮存期间不稳定。对制造工艺的该额外负担可通过将达非那新甲苯溶剂合物转化成达非那新水合物而得以克服,该水合物长期稳定,这样,当需要时可转化成达非那新氢溴酸盐,而不必担心这期间化合物(IX)的质量下降。
因此,本发明通过对达非那新进行树脂处理、然后转化成甲苯溶剂合物、之后再将该甲苯溶剂合物转化成所述水合物,进一步提供了一种提供呈药学纯形式的如上所述本发明水合物的方法。将达非那新在合适的有机溶剂或水-有机溶剂混合物中的溶液与树脂混合,并将所得混合物在环境温度和回流温度之间搅拌。随后,通过过滤将达非那新溶液与树脂分离。优选该树脂是氢氧化季铵树脂。树脂处理可以以分批模式或以连续加工模式进行。可将水合物进一步精制,得到达非那新的酸加成盐。优选该酸加成盐是氢溴酸盐。
此外,本发明还提供一种呈达非那新甲苯溶剂合物形式的、用于提供如上所述的本发明水合物的新中间体。应理解达非那新的其它溶剂合物如乙酸乙酯溶剂合物可以用以替代甲苯溶剂合物。
X-射线晶体学已表明:化合物(VIII)具有1∶1的化学计量比,即在非对称单元中有1分子达非那新和1分子甲苯。
式(VIII)化合物通过使用单反射ATR(衰减全反射)进行的红外光谱表征,该光谱在下列νmax(cm-1)处显示显著的吸收带:3463、3342、3299、3285、3022、2925、2825、1673、1614、1490、1440、1384、1333、1319、1243、1195、1152、1130、1115、1102、1028、1003、980、939、926、907。
该化合物还可通过使用铜辐射(λ=0.15405nm)得到的X-射线粉末衍射图表征,该衍射图在下列2θ角显示主峰:12.572、12.754、15.978、17.419、18.537、18.889、20.78、21.562、22.437、22.736、23.767、24.075、24.266、25.35、25.762、27.214和29.716度。
所述化合物进一步通过其差示扫描量热法(DSC)曲线表征,该曲线在20℃/min的扫描速率下于92℃下显示陡峭的吸热峰。
下列实施例说明公开于方案1中的化合物的制备:
实施例1:
(S)-2,2-二苯基-2-(3-吡咯烷基)乙腈氢溴酸盐(II)
将(S)-2,2-二苯基-2-(1-甲苯磺酰基-3-吡咯烷基)乙腈(I)[见欧洲专利公开0388054](83.8kg,201.2mol)、48%氢溴酸水溶液(419L,5L/kg化合物1)和苯酚(16.8kg,0.2kg/kg化合物I)的混合物加热回流3小时。将混合物冷却并用二氯甲烷萃取(1×560kg,1×523kg)。合并萃取液并用氯化钠水溶液洗涤(15kg,在150kg水中)。浓缩有机层并用乙酸乙酯基本替代至总体积为约440L。在40℃加入己烷(276kg),通过过滤在0-5℃下收集产物。将(S)-2,2-二苯基-2-(3-吡咯烷基)乙腈氢溴酸盐用冷乙酸乙酯洗涤并在真空下在60℃下干燥。产量:52.8kg(76%)。
ν=3441,2940,2745,2455,2246,1972,1886,1806,1596,1585,1561,1494,1450,1392,1289,1255,1217,1159,1104,1070,1034,1002,967,917,899,833,766,750,702,664,645,546,496,472cm-1。
1HMR(300MHz,CDCl3):δ=2.12(2H,m),3.15(1H,m),2.96(3H,m),3.76(1H,五重峰,J 8Hz),7.25-7.41(6H,m),7.47(4H,t,J 8Hz),9.23(1H,br.s),9.43(1H,br)。
LRMS(电喷雾,正离子):m/z[MH+]263。
旋光度:[α]365 25=-55.9°
实施例2
(S)-3-(氰基二苯基甲基)-1-[2-(2,3-二氢苯并呋喃-5-基)乙酰基]吡咯烷(IV)
向冷却(0-5℃)的2-(2,3-二氢苯并呋喃-5-基)乙酸(III)(9.85kg,55.3mol)在乙酸乙酯(115L)中的浆液中加入羰基二咪唑(8.97kg,55.3mol)。将该反应在5-10℃下搅拌1小时,然后加入(S)-2,2-二苯基-2-(3-吡咯烷基)乙腈氢溴酸盐(II)(17.25kg,50.2mol)。使反应温热至20-25℃并再搅拌3小时。将反应混合物先后用2N盐酸水溶液(42L)和碳酸氢钠水溶液(2.1kg在42L水中)洗涤。浓缩乙酸乙酯溶液并用甲苯基本替代,使产物在甲苯中的溶液的总体积为约43L。假定(S)-3-(氰基二苯基甲基)-1-[2-(2,3-二氢苯并呋喃-5-基)乙酰基]吡咯烷的产率为100%(21.2kg),并直接用于制备化合物V。
ν=3448,3059,3026,2973,2948,2878,2236,1959,1890,1811,1719,1643,1600,1491,1449,1421,1362,1336,1297,1241,1219,1198,1159,1125,1102,1034,1002,983,944,917,892,836,804,764,752,701,667,646,618,576,550,469,424,405cm-1。
对于该化合物,存在两种结构构型,产生一些共振的“双峰(doubled-up)”信号。1HMR(300MHz,CDCl3):δ=1.85-2.20(2H,m),3.16&3.18(2H,t,J 9Hz),3.20-3.85(7H,m),4.54&4.55(2H,t,J 9Hz),6.68&6.70(1H,d,J 9Hz),6.83&6.94(1H,d,J 9Hz),7.05&7.12(1H,s),7.22-7.48(10H,m)。
LRMS(电喷雾,正离子):m/z[MH+]423。
旋光度:[α]365 25=+85.9°
实施例3
(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙腈(V)
向(S)-3-(氰基二苯基甲基)-1-[2-(2,3-二氢苯并呋喃-5-基)乙酰基]吡咯烷(IV)的甲苯溶液(7.43kg活性成分,17.59mol)与硼氢化钠(0.87kg,23mol)在四氢呋喃(29.7L)中的冷却(0℃)混合物中,以保持反应温度低于10℃的速率加入三氟化硼四氢呋喃复合物(4.31kg,30.81mol)。将反应温热至环境温度并再搅拌4小时。加入哌嗪水溶液,并将混合物加热至回流达8小时。分离水层并在40℃下用1%氯化钠水溶液(22.3L)洗涤。在大气压下浓缩有机层并用异丙醇基本替代至总体积为约30L。产物于冷却时结晶并在0-5℃下过滤收集。将(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙腈(V)用冷异丙醇洗涤并在真空下在50℃下干燥。产量:6.34kg(88%)。
ν=3441,3088,3056,3032,2947,2924,2884,2856,2790,2744,2237,1955,1883,1809,1614,1596,1489,1448,1385,1353,1338,1322,1290,1245,1216,1195,1148,1130,1101,1076,1033,1016,1003,980,944,921,891,847,819,799,764,750,701,674,658,646,573,563,540,504,491,427,403cm-1。
1HMR(300MHz,CDCl3):1.86(1H,m),2.10(1H,m),2.38(1H,t,J 9Hz),2.52(1H,q,J 8Hz),2.59-2.75(4H,m),2.84(1H,m),3.02(1H,dt,J 4&9Hz),3.16(2H,t,J 9Hz),3.47(1H,m),4.53(2H,t,J 9Hz),6.67(1H,d,J 8Hz),6.90(1H,d,J 8Hz),7.00(1H,s),7.23-7.40,(6H,m),7.46(4H,t,J 8Hz)。
LRMS(电喷雾,正离子):m/z[MH+]409。
旋光度:[α]365 25=+31.8°
实施例4
(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙腈氢溴酸盐(VI)
向(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙腈(V)(30.0g,0.073mol)在甲醇(150mL)中的浆液加入48%氢溴酸水溶液(13.6g,0.081mol),保持温度低于40℃。将混合物加热回流1小时。将批料冷却至0℃,过滤收集产物,用甲醇(60mL)洗涤并在真空下在50℃下干燥,得到(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙腈氢溴酸盐(VI)(33.5g,93%)。
ν=3440,3059,3002,2931,2893,2856,2653,2624,2548,2496,2471,2239,1960,1888,1812,1615,1599,1493,1450,1394,1363,1332,1294,1242,1159,1129,1106,1088,1073,1035,1003,981,941,889,830,766,751,725,703,666,645,582,548,534,500,476,423cm-1。
1HMR(300MHz,CDCl3):2.08(1H,m),2.46(1H,m),2.75(1H,q,J10Hz),2.69-3.33(7H,m),3.70(1H,m),3.83(1H,m),4.09(1H,m),4.54(2H,t,J 9Hz),6.69(1H,d,J 8Hz),6.92(1H,d,J 8Hz),7.06(1H,s),7.27-7.50(10H,m),12.08(1H,br)。
LRMS(电喷雾,正离子):m/z[MH+]409。
旋光度:[α]365 25=+90.0°
实施例5
(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺甲苯溶剂合物(VIII)
方法1:将氢氧化钾(48.7g,0.87mol)在2-甲基丁-2-醇(175mL)中的浆液在50-60℃下加热。1小时后,加入(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙腈氢溴酸盐(VI)(25.0g,0.051mol),并将所得混合物加热回流20小时。将反应混合物冷却至环境温度并加入水(125mL),保持温度低于30℃。将混合物搅拌15分钟,然后静置,分离有机相。将有机相用氯化钠水溶液(125mL 5重量%溶液)洗涤,得到(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺(VII)在2-甲基丁-2-醇中的溶液。将该溶液在Amberlite树脂(37.5g)存在下加热回流22小时,然后冷却至环境温度。过滤除去Amberlite树脂,并用2-甲基丁-2-醇(25mL)洗涤。浓缩合并的2-甲基丁-2-醇相,并用甲苯基本替代至最终体积为约140mL。将甲苯溶液冷却至0℃,期间发生结晶。过滤收集(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺甲苯溶剂合物(VIII),用冷甲苯(25mL)洗涤,并在真空下在35℃下干燥。产量(22.2g,84%)。
方法2:将氢氧化钾(40g,0.71mol)在2-甲基丁-2-醇(140mL)中的浆液在50-60℃下加热。1小时后,加入(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙腈(V)(20g,0.049mol),并将所得混合物加热回流约20小时。将反应混合物冷却并加入水(100mL),保持温度低于34℃。将混合物搅拌30分钟并分离有机相。将有机相用氯化钠水溶液(100mL 5重量%溶液)洗涤,得到产物在2-甲基丁-2-醇中的产物溶液。将该溶液在Amberlite树脂(30g)存在下加热回流9小时,然后冷却至环境温度。过滤除去Amberlite树脂,并用2-甲基丁-2-醇(20mL)洗涤。浓缩合并的2-甲基丁-2-醇相,并用甲苯基本替代至最终体积为约80mL。将甲苯溶液冷却至0℃,期间发生结晶。过滤收集(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺甲苯溶剂合物(VIII),用冷甲苯(70mL)洗涤,并在真空下在35℃下干燥。产量(17.2g,68%)。
ν=3463,3342,3299,3285,3022,2925,2825,1673,1614,1490,1440,1384,1333,1319,1243,1195,1152,1130,1115,1102,1028,1003,980,939,926,907cm-1。
1HMR(300MHz,d6-DMSO):δ=1.57(1H,m);1.93(2H,m);2.3-2.5(6H,m);2,82(1H,t,J 9);3.11(2H,t,J 9);3.62(1H,m);4.47(2H,t,J 9);6.62(1H,d,J 8);6.82(1H,d,J 8);6.99(1H,s);7.08(2H,m);7.2-7.4(10H,m)。在2.3下观察到对应于摩尔比为1的甲苯的信号,并且该信号位于(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺的芳族区域之下。
旋光度:[α]365 25=-119.0°
实施例6
(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺水合物(IX)
将(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺甲苯溶剂合物(VIII)(16g,0.031mol)在乙腈(320mL)中的溶液在减压下在环境温度下浓缩。将所得泡沫溶解于乙腈(48mL)中,在环境温度下向其中滴加水(1.1mL)。将溶液在环境温度下搅拌直到发生结晶并且搅拌过夜。过滤收集(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺水合物(IX),并在真空下在环境温度下干燥。产量(10.4g,76%)。
ν=3625,3516,3440,2948,2806,1699,1622,1597,1578,1488,1471,1445,1378,1353,1325,1312,1280,1242,1196,1152,1119,1102,1086,1024,981,939,925,900cm-1。
1HMR(300MHz,d6-DMSO):δ=1.57(1H,m),1.93(2H,m),2.3-2.5(6H,m),2,82(1H,t,J 9),3.11(2H,t,J 9),3.62(1H,m),4.46(2H,t,J 9),6.62(1H,d,J 8),6.81(1H,d,J 8),6.99(1H,s),7.07(2H,m),7.2-7.4(10H,m)。
Karl Fischer水含量:2.7重量%
旋光度:[α]365 25=-120.7°
实施例7
(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺氢溴酸盐(X)
方法1:将(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺甲苯溶剂合物(VIII)(30.4g,0.059mol)在丁-2-酮(213mL)中的溶液温热至33℃,得到溶液,然后冷却至15℃。然后加入48%氢溴酸水溶液(9.9g,0.059mol),并将混合物在15℃下搅拌1小时和在0℃下搅拌2小时。过滤收集(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺氢溴酸盐(X),用丁-2-酮(65mL)洗涤并在真空下在50℃下干燥18小时。产量(24.6g,83%)。
方法2:向(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺水合物(IX)(3.60g,0.0081mol)在丁-2-酮(30mL)中的溶液中加入48%氢溴酸水溶液(1.36g,0.0081mol)。将混合物在20℃下搅拌1小时和在0℃下搅拌1小时。过滤收集(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺氢溴酸盐(X),用丁-2-酮(10mL)洗涤并在真空下在50℃下干燥18小时。产量(3.90g,95%)。m.p.=232℃。
ν=3468,3211,3052,2995,2870,2693,2586,1668,1585,1492,1442,1243,983,850cm-1。
1HMR(300MHz,CDCl3):δ=2.10-2.23(1H,m),2.81-2.99(2H,m),3.00-3.15(4H,m),3.15(2H,t),3.18-3.29(1H,m),3.48(1H,t),3.69(1H,s),3.80-3.95(1H,m),4.52(2H,t),5.58(1H,bs),5.62(1H,bs),6.63(1H,d),6.84(1H,d),7.01(1H,s),7.19-7.40(10H,m),11.48(1H,bs)。
旋光度:[α]365 25=+46.0°
Claims (21)
1.达非那新的稳定的固体水合物,其具有化学计量比为1∶0.6至1∶1的达非那新∶水。
3.根据权利要求1或2的水合物,其通过使用单反射ATR(衰减全反射)进行的红外光谱表征,该光谱在下列νmax(cm-1)处显示显著的吸收带:3625、3516、3440、2948、2806、1699、1622、1597、1578、1488、1471、1445、1378、1353、1325、1312、1280、1242、1196、1152、1119、1102、1086、1024、981、939、925、900。
4.根据权利要求1或2的水合物,其通过使用铜辐射(λ=0.15405nm)获得的X-射线粉末衍射图表征,该衍射图在下列2θ角显示出主峰:8.39、10.519、13.272、13.693、15.908、16.289、16.855、19.637、21.135、21.55、21.722、23.006和26.284度。
5.根据权利要求1或2的水合物,其通过差示扫描量热法(DSC)曲线表征,该曲线在101℃、20℃/min的扫描速率下显示陡峭的吸热峰。
6.药物组合物,其包含根据前述权利要求中任一项的水合物以及可药用赋形剂、稀释剂或载体。
7.根据权利要求中1至5中任一项的水合物在制备用于治疗性或预防性治疗毒蕈碱性受体拮抗剂适用的医学病症的药物中的用途。
8.根据权利要求7的用途,其中所述医学病症选自肠易激惹综合征、憩室病、食管弛缓不能、慢性阻塞性气道疾病、膀胱过动、尿失禁、神经性尿急或频尿,治疗膀胱功能障碍、尿漏、由神经性膀胱、痉挛性或高张性膀胱导致的排尿疼痛或排尿困难,功能障碍性膀胱综合征、肠胃障碍以及对肠平滑肌细胞的松弛效果。
9.根据权利要求8的用途,用于制备用于治疗性或预防性治疗膀胱过动的尿失禁、尿急和尿频症状的药物。
10.根据权利要求8的用途,用于制备用于治疗性或预防性治疗肠胃活动过强的药物。
11.根据权利要求7至10任一项的用途,其中所述药物适于局部经皮施用。
12.根据权利要求7至10任一项的用途,其中所述药物适于口含施用。
14.根据权利要求13的溶剂合物,其通过使用单反射ATR(衰减全反射)进行的红外光谱表征,该光谱在下列νmax(cm-1)处显示显著的吸收带:3463、3342、3299、3285、3022、2925、2825、1673、1614、1490、1440、1384、1333、1319、1243、1195、1152、1130、1115、1102、1028、1003、980、939、926、907。
15.根据权利要求13或权利要求14的溶剂合物,其通过使用铜辐射(λ=0.15405nm)获得的X-射线粉末衍射图表征,该衍射图在下列2θ角显示主峰:12.572、12.754、15.978、17.419、18.537、18.889、20.78、21.562、22.437、22.736、23.767、24.075、24.266、25.35、25.762、27.214和29.716度。
16.根据权利要求13或14的溶剂合物,其通过差示扫描量热法(DSC)曲线表征,该曲线在92℃、20℃/min的扫描速率下显示陡峭的吸热峰。
17.根据权利要求15的溶剂合物,其通过差示扫描量热法(DSC)曲线表征,该曲线在92℃、20℃/min的扫描速率下显示陡峭的吸热峰。
18.一种提供根据权利要求13的式(VIII)的溶剂合物的方法,其包括对(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺进行离子交换树脂处理,随后与甲苯混合。
19.一种提供呈药学纯形式的如权利要求1至5中任一项所定义的水合物的方法,其包括对(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺进行离子交换树脂处理,随后将其转化成甲苯溶剂合物,再将该溶剂合物转化成所述水合物。
20.一种提供达非那新酸加成盐的方法,包括将权利要求19的方法所制备的水合物转化成(S)-2-{1-[2-(2,3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2,2-二苯基乙酰胺的酸加成盐。
21.根据权利要求20的方法,其中所述酸加成盐为氢溴酸盐。
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US7244765B2 (en) * | 2004-06-25 | 2007-07-17 | Cytokine Pharmasciences, Inc | Guanylhydrazone salts, compositions, processes of making and methods of using |
AU2006239941A1 (en) * | 2005-04-24 | 2006-11-02 | Wyeth | Methods for modulating bladder function |
US20070197630A1 (en) * | 2005-12-27 | 2007-08-23 | Valeriano Merli | Pure darifenacin hydrobromide substantially free of oxidized darifenacin and salts thereof and processes for the preparation thereof |
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US20090005431A1 (en) * | 2007-06-30 | 2009-01-01 | Auspex Pharmaceuticals, Inc. | Substituted pyrrolidines |
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CZ200845A3 (cs) | 2008-01-28 | 2009-09-02 | Zentiva, A. S. | Zpusob prípravy Darifenacinu |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1045580A (zh) * | 1989-03-17 | 1990-09-26 | 美国辉瑞有限公司 | 吡咯烷衍生物 |
WO1995019164A1 (en) * | 1994-01-14 | 1995-07-20 | Pfizer Limited | Use of m3 muscarinic antagonists for the treatment of motion sickness |
CN1195984A (zh) * | 1995-09-15 | 1998-10-14 | 辉瑞研究及发展公司 | 含有达非那新的药物制剂 |
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