CN1384817A - 多晶型的n-[3-[[2-(3,4-二甲氧基苯基)乙基]氨基]丙基]-4-硝基苯甲酰胺盐酸化物 - Google Patents
多晶型的n-[3-[[2-(3,4-二甲氧基苯基)乙基]氨基]丙基]-4-硝基苯甲酰胺盐酸化物 Download PDFInfo
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Abstract
本发明涉及一种多晶型的N-[3-[[2-(3,4-二甲氧基苯基)乙基]氨基]丙基]-4-硝基苯甲酰胺盐酸化物、该化合物的制备方法、以及该化合物在医药中的用途。
Description
本发明涉及一种新的药物、制备该药物的方法以及该药物在医疗中的用途。
Ar 代表取代或未取代的芳基,其中该任选取代的取代基选自烷基、羟基或烷氧基或,任何两个取代基,如果与相邻碳原子连接则与连接它们的碳原子一起可形成稠合的5-6个原子的杂环,其中所述原子的二或三个是氧或氮;
A 代表C1-4亚烷基,其中每个碳原子可被1或2个C1-6烷基取代或不取代;
R1 代表氢、烷基、链烯基或环烷基;
R2、R3和R4中的一或两个基团代表硝基,其余基团代表氢;
X 代表-CO-NH-部分;以及
Z 代表C2-4正亚烷基,其中每个碳原子可被1或2个C1-6烷基取代或不取代。
WO96/13479中的实施例2公开的是N-[3-[[2-(3,4-二甲氧基苯基)乙基]氨基]丙基]-4-硝基苯甲酰胺的这种盐酸化物(此后也称其为“该盐酸化物”),所公开的该盐酸化物的熔点是141.2℃。
现在已经发现,N-[3-[[2-(3,4-二甲氧基苯基)乙基]氨基]丙基]-4-硝基苯甲酰胺盐酸化物存在着一种新颖的多晶型物,这种晶型物特别适合于大量制备和处理,并且还显示出具有极好的配制性能。这种新的多晶型物可通过一种特别适合于大规模制备的有效而经济并且可重新组配的方法来制备。
该新颖的多晶型物还具有一些有用的药学性能而被认为是一种具有联合III级/IV级抗心律失常性能的有效的抗心律失常药,因此与单纯的III级抗心律失常药相比改善了药理学性能曲线,尤其是显示出较低的引起或加重心律失常的可能性。该药对治疗房或室的心律失常特别有用。
因此,本发明提供了一种新的N-[3-[[2-(3,4-二甲氧基苯基)乙基]氨基]丙基]-4-硝基苯甲酰胺盐酸化物的多晶型物(此后也称其为‘化合物(I)’),其特征在于:
(i) 固态核磁共振谱的化学位移基本上如表I所示;
(ii) X-射线粉末衍射图基本上如表II所示;和/或
(iii)红外光谱基本上如图(I)所示。
本发明包括分离成为纯形式或不纯形式的化合物(I),后者混有其它物质如该盐酸化物的已知形式或任何其它物质。
优选的化合物(I)是纯形式的,特别优选的是结晶形式的。
本发明还提供了制备N-[3-[[2-(3,4-二甲氧基苯基)乙基]氨基]丙基]-4-硝基苯甲酰胺盐酸化物的该新颖多晶型物的方法,其特征在于使N-[3-[[2-(3,4-二甲氧基苯基)乙基]氨基]丙基]-4-硝基苯甲酰胺盐酸化物从乙腈中结晶,然后将该乙腈从结晶产物中除去。
除去乙腈的方法优选的是通过干燥,以真空干燥为宜。
该结晶物优选的是在高温下干燥,例如在60℃下长期干燥,通常大于12小时,如36小时。
结晶或任何再结晶一般在低于室温下进行,适宜的是在室温下进行。
适宜的是将该盐酸化物熔解在高温(例如该溶剂的回流温度)的乙腈中。然后,一般是将该溶剂冷却到室温来引发结晶。
在该方法的一种优选实施方式中,从该盐酸化物在高温(例如60℃)下的乙腈溶液中制备化合物(I),将该产物冷却结晶,然后将所得产物在60℃下真空干燥。化合物(I)的纯化也是用这个上述的这一方法通过化合物(I)的重结晶来进行的。
该盐酸化物是根据已知的方法制备的,如WO96/13479所公开的方法。WO96/13479的公开内容在此引用作为参考文献。
这里用的“心脏节律失常”是与心脏跳动的正常节律改变有关的一种病,包括但不限于窦性心律失常、早博、心传导阻滞、纤颤、扑动、心动过速、阵发性心动过速和心室早收缩。
如上所述,本发明的化合物具有有效的医疗性能,因此本发明提供了用作治疗活性物质的化合物(I)。
更具体说,本发明提供了用于治疗和/或预防节律失常,特别是如心脏节律失常以及局部缺血性的节律失常。
化合物(I)可以单用其本身或优选也可作为含有药用可接受盐的药物组合物使用。
因此,本发明还提供了一种含有化合物(I)和其药用可接受的盐的药物组合物。
化合物(I)通常以单位剂型用药。
治疗上述疾病有效的用量取决于各种因素,例如所选化合物(I)的疗效、所治疗疾病的性质和严重程度、以及被治疗的哺乳动物的体重。但单位剂量一般含0.1-500mg(如2-50mg)本发明化合物。单位剂量给药每天一次或几次,例如一天2、3、4、5或6次,比较常用的是一天2-4次。这样,每天总剂量范围通常为:70kg体重成年人0.1-2500mg;更通常为1-1000mg,例如1-200mg,这样的用量范围大约相当于0.02-3mg/kg/天,例如0.15-2mg/kg/天。
按上述的剂量范围用药,本发明的化合物没有毒理学的副作用。
在这样的治疗中,服用该活性化合物的途径可以是口服、肠胃外给药或局部给药。这些用途中的本发明化合物一般采用与人用或兽用制药载体、稀释剂和/或赋型剂结合的药物组合物形式,当然,该组合物的恰当形式要根据用药的方式确定。
通过混合制备的并适合于口服、肠胃外或局部给药的药物组合物其剂型可以是片剂、口服液体制剂、粉剂、锭剂、软锭剂、可再配的粉剂、注射和灌注的溶液或混悬液、栓剂和经皮组件。可口服的组合物是优选的,特别是具有形状的口服组合物,因为它们通常便于使用。
口服的片剂和胶囊通常是单位剂量的,并含有常用的赋型剂如粘结剂、填料、稀释剂、成片剂、润滑剂、着色剂、调味剂和湿润剂。这些片剂可以按本领域已知的方法包衣。
适合使用的填料包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物如羟基乙酸淀粉钠。合适的润滑剂例如包括硬脂酸镁。合适的用药可接受的湿润剂包括十二烷基硫酸钠。
固体口服组合物可以用共混、填充、制片等常用方法制备。可以采用反复的共混操作将活性剂全面分布到用大量填料的那些组合物中。这样做法在本领域中自然是很方便的。
口服液体制剂的形式例如可以是水性或油性的混悬液、溶液、乳液、糖浆或酏剂,或者可以是干燥的在使用前可用水或其它适宜的载体再组配的产品。这种液体制剂可以含常用的添加剂例如悬浮剂如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或食用氢化脂肪;乳化剂例如卵磷脂、脱水山梨醇单油酸脂或阿拉伯胶;非水性载体(可包括食用油)例如杏仁油、馏分可可油、油状的酯如甘油、丙二醇或乙醇的酯;防腐剂例如对羟基苯甲酸甲酯或乙酯、或山梨酸,以及如果需要还可包括常用的调味剂或着色剂。
对于非肠胃道给药,将本发明化合物和灭菌载体配制成流体单位剂型。该化合物可以是悬浮的或者也可以是溶解的,非肠胃道给药溶液的配制一般是将活性化合物溶解在载体中,在灌入适当的小瓶或安瓿并进行密封之前先进行过滤灭菌。最好将一些辅剂如局部麻醉剂、防腐剂和缓冲剂也溶在载体中。为了提高药物组合物的稳定性,在灌入小瓶和真空除去水份之后可将其冷冻。
非肠胃道用混悬液用基本上相同的方式配制,只是活性化合物是悬浮在载体里的而不溶解,并在悬浮到灭菌载体里之前通过用环氧乙烷处理使其灭菌。该组合物中最好加有表面活性剂或湿润剂以利于活性化合物的均匀分布。
对于局部给药用的组合物可以是全身传递化合物的经皮软膏或贴片,其制备可以用如标准教科书[‘Dermatological Formulations’-B.W.Barry(Drugs and Pharmaceutical Sciences-Ddkker)或Harrys Cosmeticology(LeonardHill Books)]中所述的常用方法。
另外,这种组合物还可以含另外的活性剂例如抗高血压药和利尿药。
习惯的做法是,该组合物通常附有与治疗用途有关的书写或印刷的说明书。
在此所用的“药用可接受的”一词包括人用和兽用的化合物、组合物和组分,例如‘药用可接受的盐’包括了兽用可接受的盐。
本发明还提供了治疗和/或预防人或非人哺乳动物的节律失常,特别是心脏节律失常如房性心律失常,以及局部缺血性节律失常的方法,该方法包括给需要治疗和/或预防的人或非人哺乳动物服用有效且无毒剂量的化合物(I)。
为方便起见,可将活性组分作为前面所定义的药物组合物服用,并且这也是本发明一个特定的方面。
在治疗和/或预防心律失常和/或局部缺血性心律失常疾病中,用化合物(I)的剂量如上面所述。
类似的剂量方案适用于治疗和/或预防非人哺乳动物的疾病。
本发明再有一方面是提供化合物(I)在制备治疗节律失常,特别是心脏节律失常,如房性心律失常,以及治疗局部缺血性节律失常的药物中的用途。
化合物(I)按上述剂量范围用药时无毒副作用。
下面的实施例说明本发明而不是以任何方式限制本发明。
实施例1
新的多晶体N-[3-[[2-(3,4-二甲氧基苯基)乙基]氨基]丙基]-4-硝基苯甲酰胺盐酸化物(化合物(I))的制备
如WO96/13479的实施例2所公开的方法一样制备该盐酸化物。将173g粗制的盐酸化物在回流下溶解在1.3立升乙腈中。
然后使该溶液在两小时内冷却到室温,在冷却过程中发生结晶。滤出所得到的晶体,用乙腈(IL)洗涤、在60℃下真空(0.5乇)干燥12小时后在同样条件(0.5乇,60℃)再干燥24小时得到125.6g化合物(I),溶点156℃,HPLC显示的主峰为99.8%,主要杂质含量<0.1%。总产率(合成+提纯)为59.9%。谱图数据
(A)固态NMR
表I中列出了9055MHz13C CP-MAS NMR谱的化学位移。在BrukerAMX360WB光谱测量仪上,在室温和10kHz自旋频率下记录这些数据。
表I
C13化学位移(ppm)
28.8 33.4 36.0 49.1 54.6 57.6 107.2 112.7 120.5
126.3 127.9 131.7 137.3 146.8 148.9 164.5
(B)X-射线粉末衍射(XRPD)
表II概述了化合物(I)XRPD角的特征
使用PW1710 X-射线粉末衍射仪(Cu X-射线源)和以下测量条件,产生该谱图。
管电极 Cu
发生器强度 40kv
发生器电流 30mA
起始角 3.5°2θ
结束角 35.0°2θ
分段大小 0.005°2θ
每段时间 0.25s
表II
XRPD衍射角
衍射角(°2θ)
8.7
14.4
18.0
20.7
22.2
22.7
23.9
24.3
24.9
26.6
28.1
29.2
30.8
31.4
32.0
34.0
(C)红外光谱
用Perkin-Elmer PE2000光谱仪在2cm-1分辨率下测得化合物(I)的矿物油分散液的红外吸收光谱。
图(I)
Claims (11)
1.一种新的多晶型N-[3-[[2-(3,4-二甲氧基苯基)乙基]氨基]丙基]-4-硝基苯甲酰胺盐酸化物,其特征在于:
(i)固态核磁共振谱的化学位移基本上如表I所示;
(ii) X-射线粉末衍射图基本上如表II所示;和/或
(iii)红外光谱基本上如图(I)所示。
2.权利要求1的新的多晶型物是纯的形式。
3.一种制备新的多晶型N-[3-[[2-(3,4-二甲氧基苯基)乙基]氨基]丙基]-4-硝基苯甲酰胺盐酸化物的方法,其特征在于使N-[3-[[2-(3,4-二甲氧基苯基)乙基]氨基]丙基]-4-硝基苯甲酰胺从乙腈中结晶,然后从该产物中除去该乙腈。
4.权利要求3的方法,其中该乙腈是通过干燥除去的。
5.权利要求3或4的方法,其中将该最终产物在高温下经过长时间干燥。
6.权利要求3-5的任一项方法,其中该新的多晶型物是从N-[3-[[2-(3,4-二甲氧基苯基)乙基]氨基]丙基]-4-硝基苯甲酰胺盐酸化物的乙腈溶液在60℃下制备的,使该产物在冷却下结晶,然后将所得的产物在60℃真空下干燥。
7.一种药物组合物,含有权利要求1的新的多晶物和其药用可接受的载体。
8.作为治疗活性物质用的权利要求1新的多晶型物。
9.作为治疗和/或预防心脏节律失常或局部缺血性节律失常用的权利要求1新的多晶型物。
10.一种治疗和/或预防人或非人哺乳动物心脏节律失常或局部缺血性节律失常的药物组合物,该组合物包含有效和无毒量的权利要求1新的多晶型物。
11.权利要求1的新多晶型物在制备治疗心脏节律失常或局部缺血性节律失常的药物中的用途。
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CA2386845A1 (en) | 2001-04-19 |
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MXPA02003516A (es) | 2004-09-10 |
HK1049147A1 (zh) | 2003-05-02 |
CZ20021189A3 (cs) | 2002-09-11 |
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