CN101142200A - 甲苯哌丙酮的加成盐,其制备方法和其用途 - Google Patents
甲苯哌丙酮的加成盐,其制备方法和其用途 Download PDFInfo
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- CN101142200A CN101142200A CNA2006800088995A CN200680008899A CN101142200A CN 101142200 A CN101142200 A CN 101142200A CN A2006800088995 A CNA2006800088995 A CN A2006800088995A CN 200680008899 A CN200680008899 A CN 200680008899A CN 101142200 A CN101142200 A CN 101142200A
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
本发明描述了2,4′-二甲基-3-哌啶子基苯丙酮(甲苯哌丙酮)的加成盐,所述盐是与酸R-COOH形成的,其中R是生理可相容的有机酸的有机基团。还描述了制备该加成盐的方法,该加成盐用于制备药物的用途和含有该加成盐的药物。
Description
本发明涉及甲苯哌丙酮(Tolperison)的加成盐,其制备方法,其用于药物组合物的用途和含有该加成盐的药物。
甲苯哌丙酮是总式C16H23NO的肌肉松弛剂(RS)-2,4′二甲基-3-哌啶子基苯丙酮的国际自由命名。
甲苯哌丙酮和其盐用于:疼痛性痉挛、肌肉系统紧张、颈椎综合征、颈臂综合征、腰部综合征、骨质疏松症、大关节的炎症、风湿病、纤维肿瘤痛(Fibromyalgie)综合征、慢性多关节炎、职业和运动引起的负荷过重。
甲苯哌丙酮在低pH值下经长时间保持稳定。在碱性pH范围内出现颜色改变,并且该活性物质降解。为了保证甲苯哌丙酮在药物制剂中的稳定性,使用甲苯哌丙酮与药物可接受的酸的加成盐。
JP 51128418描述了加成盐甲苯哌丙酮盐酸盐的制备。
WO 2004/050648描述了一种制备甲苯哌丙酮加成盐的方法,其中,使用4-甲基苯丙酮、哌啶盐酸盐和1,2-二氧杂环戊烷以及无机酸作为起始物。
在JP 53040779中公开了旋光性甲苯哌丙酮的制备。其中描述了甲苯哌丙酮的对映体不同的药物学作用。
目前市场上存在的甲苯哌丙酮制剂具有最长3年的耐久性。如果更长时间存放甲苯哌丙酮盐酸盐,则会因蒸发而造成氯化氢损失。因而不能保持所希望的pH值,不再能保证甲苯哌丙酮的稳定性。
本发明的目的在于,提供稳定的甲苯哌丙酮加成盐,与甲苯哌丙酮盐酸盐相比,该加成盐具有更大的长时间稳定性,可以在药物制剂中毫无疑虑地使用。
该目的是通过根据主权利要求的甲苯哌丙酮加成盐实现的。本发明加成盐有利的技术方案记载在从属权利要求中。
因此,本发明的一个主题是式(A)的甲苯哌丙酮(2,4′-二甲基-3-哌啶子基苯丙酮)的加成盐
其中
R是生理可相容的有机酸的有机基团。
根据本发明优选,R是具有多至5个碳原子的饱和或不饱和的脂族基团,其任选被一个或多个羟基、氧代和/或羧基所取代。
根据本发明还优选,R是芳基或芳烷基,其中所述基团含有5到9个碳原子,并任选被一个或多个羟基和/或羧基所取代。
根据本发明还特别优选,所述生理可相容的有机酸选自乙酸、丙酸、丙二酸、草酸、葡糖酸、琥珀酸、马来酸、富马酸、乳酸、酒石酸、苹果酸、柠檬酸、丙酮酸、羟基丁酸、己二酸、水杨酸、邻苯二甲酸、扁桃酸和苯甲酸。
根据本发明更特别优选,所述生理可相容的有机酸是柠檬酸。
尤其优选通式(A)的根据本发明的盐,即甲苯哌丙酮柠檬酸盐,(S)-甲苯哌丙酮柠檬酸盐或(R)-甲苯哌丙酮柠檬酸盐。
更特别优选其中甲苯哌丙酮以光学纯形式作为(R)-或(S)-对映体存在的盐。
甲苯哌丙酮在2位具有不对称中心,这导致相应的(R)-或(S)-对映体。因此本发明的主题还在于与有机酸的所有根据本发明的盐,其中甲苯哌丙酮的不对称中心以光学纯或光学富集的形式存在,以及它们所有的混合物,包括外消旋体。
显然,由甲苯哌丙酮和本身带有不对称中心的酸组成的所有非对映异构体也是本申请的主题,属于本发明的范畴。这样的酸例如是扁桃酸、羟基丁酸、乳酸和苹果酸。
本发明另一主题还在于一种制备式(A)的2,4′-二甲基-3-哌啶子基苯丙酮(甲苯哌丙酮)的本发明加成盐的方法,
其中,式(B)的甲苯哌丙酮
与式(C)的有机酸
R-COOH
(C)
在溶剂2-丙醇中反应成甲苯哌丙酮的加成盐。
特别优选其中使用柠檬酸作为有机酸的本发明方法。在此优选,使用甲苯哌丙酮作为外消旋体。特别优选使用甲苯哌丙酮的(S)-对映体。但是还特别优选使用甲苯哌丙酮的(R)-对映体。
所述方法能够将甲苯哌丙酮外消旋的混合物以及纯的对映体转变成相应的加成盐。
文中使用的术语生理可相容的有机酸是技术人员熟悉的术语。在此是指所有的有机酸,其以所使用的浓度和量以加成盐形式是生理学上毫无疑虑的,亦即例如既无毒性,也无刺激性,也不以其它方式具有影响患者健康的作用。
本发明方法可以描述如下:
作为起始物,使用作为外消旋混合物的甲苯哌丙酮或甲苯哌丙酮的对映体以及有机酸和溶剂2-丙醇。
在本发明方法中有利的是使用有机酸,优选柠檬酸,其盐比甲苯哌丙酮盐酸盐基本上更稳定。向含有甲苯哌丙酮盐酸盐的商用制剂中添加柠檬酸盐作为助剂,以便达到低的pH值。通过使用甲苯哌丙酮-柠檬酸盐作为活性物质,取消了作为助剂的柠檬酸盐。
用目前所述的方法不能合成甲苯哌丙酮与有机酸的加成盐。令人惊讶地,在使用溶剂2-丙醇情况下能够使甲苯哌丙酮盐酸盐结晶。
本发明方法能够制备(R)-甲苯哌丙酮、(S)-甲苯哌丙酮或两种对映体的外消旋混合物的加成盐。这样能够将甲苯哌丙酮-对映体的盐以纯形式或以任意的混合物用于治疗性制剂中。通过使用旋光活性的形式,可以提高药物作用的选择性。
本发明的另一主题是本发明的加成盐用于治疗疼痛性痉挛、肌肉系统紧张、颈椎综合征、颈臂综合征、腰部综合征、骨质疏松症、大关节的炎症、风湿病、纤维肿瘤痛综合征、慢性多关节炎、职业和运动引起的负荷过重的用途。
本发明的另一主题是本发明的加成盐用于制备治疗疼痛性痉挛、肌肉系统紧张、颈椎综合征、颈臂综合征、腰部综合征、骨质疏松、大关节的炎症、风湿病、纤维肿瘤痛综合征、慢性多关节炎、职业和运动引起的负荷过重的药物的用途。
本发明的主题还在于除了药物可接受的助剂和/或载体外还含有甲苯哌丙酮的至少一种本发明的加成盐的药物。
本发明的主题尤其还在于用于口服、直肠、局部(皮肤上,经皮,局部)、皮下、静脉内或肌内给药的药物,其除了常见的载体和稀释剂外还含有通式(A)化合物活性物质。
在此特别优选,可以使用无需其它渗透增强剂的有机酸形成本发明的甲苯哌丙酮盐。通常向经皮体系中加入多元酸,如酒石酸或柠檬酸,起到渗透增强剂的作用。现在令人惊讶地发现,使用与所述多元酸形成的相应的甲苯哌丙酮盐可以省略增强剂。这在制备和使用这种经皮体系时带来显著的优点。
以已知方式,将本发明的药物与常用的固态或液态载体或稀释剂和通常使用的制药技术的助剂相应地制成具有合适剂量的所希望的给药类型。优选的制剂在于适合于口服的给药剂型。这种给药剂型例如是片剂、膜片、糖丸、胶囊、药丸、粉末、溶液或悬浮液或贮存形式。
局部应用例如可以以油膏、霜剂、凝胶、溶液形式或通过膏药进行。
显然还可考虑肠胃外制剂如注射液。此外作为制剂例如还可提及栓剂。
相应的片剂例如可以通过混合活性物质与已知的助剂,例如惰性稀释剂如右旋糖、糖、山梨糖醇、甘露醇、聚乙烯吡咯烷酮、崩解剂如玉米淀粉或藻酸,粘合剂如淀粉或明胶,润滑剂如硬脂酸镁或滑石和/或用于达到贮存效果的试剂如羧基聚亚甲基,羧甲基纤维素,乙酸邻苯二甲酸纤维素或聚乙酸乙烯酯而得到。所述片剂也可以由多层组成。
相应地,糖丸可以通过用在糖丸涂敷中通常使用的试剂例如聚乙烯吡咯烷酮或虫胶、阿拉伯胶、滑石、二氧化钛或糖涂敷由类似片剂制得的核而制得。在此糖丸壳也可以由多层组成,在此可以使用以上在片剂情况下提及的助剂。
含有本发明使用的活性物质的溶液或悬浮液可以额外含有改善味道的试剂如糖精、环己氨磺酸盐或糖以及例如芳香物如香草醛或橙桔提取物。此外还可以含有悬浮助剂如钠羧基甲基纤维素或防腐剂如p-羟基苯甲酸盐。含有活性物质的胶囊例如可以通过将活性物质与惰性载体如乳糖或山梨糖醇混合并封装在明胶胶囊中而制得。
合适的栓剂例如可以通过与为此安排的载剂如中性脂肪或聚乙二醇或其衍生物进行混合而制得。
局部给药的本发明药物的制备是技术人员已知的。在制备经皮应用的本发明药物时,使用已知的助剂和增强剂。
本发明药物制剂的制备是已知的,并描述在技术人员已知的手册中,例如Hager′s Handbuch(5.)2,622-1045;List等人,Arzneiformenlehre,Stuttgart:Wiss.Verlagsges.1985;Sucker等人,Pharmazeutische Technologie,Stuttgart:Thieme 1991;Ullmann′s Enzyklopdie(5.)A19,241-271;Voigt,Pharmazeutische Technologie,Berlin:Ullstein Mosby 1995。
以下实施例更详细地描述本发明:
实施例1:
甲苯哌丙酮-柠檬酸盐的制备
在反应容器中,3.84g柠檬酸(无水),4.91g甲苯哌丙酮碱和25ml 2-丙醇在回流下加热并搅拌3分钟。将这样得到的澄清溶液冷却到室温并混入25ml 2-丙醇。在室温下搅拌该溶液15分钟,然后在-15℃下培育一小时。沉淀物用3ml 2-丙醇抽滤洗涤,并空气干燥。
产率:7.45g白色晶体
熔点:128.7℃
1H-NMR:1H-NMR-分析的结果证实产物的同一性,证实纯度>99%。
实施例2:
(S)-甲苯哌丙酮-柠檬酸盐的制备
在反应容器中,1.87g柠檬酸(无水),2.39g(S)-甲苯哌丙酮碱和13ml 2-丙醇在回流下加热并搅拌3分钟。将这样得到的澄清溶液冷却到室温。通过用玻璃棒在容器壁上摩擦而诱发结晶。然后加入8ml 2-丙醇。溶液在-15℃下过夜培育。沉淀物用3ml 2-丙醇抽滤洗涤,并空气干燥。
产率:2.65g白色晶体
熔点:125.2℃
旋光度:2.0°
1H-NMR:1H-NMR-分析的光谱证实产物的同一性。
实施例3:
(R)-甲苯哌丙酮-柠檬酸盐的制备
在反应容器中,1.92g柠檬酸(无水)和25ml 2-丙醇在回流下加热并搅拌5分钟。向所形成的澄清溶液中加入2.39g(R)-甲苯哌丙酮碱。反应混合物在搅拌下在10分钟内冷却到室温。反应混合物在冰上再搅拌30分钟。沉淀物用3ml 2-丙醇抽滤洗涤,并空气干燥。
产率:2.4′5g白色晶体
熔点:124.6℃
旋光度:-2.9°
1H-NMR:1H-NMR-分析的光谱证实产物的同一性。
实施例4
甲苯哌丙酮-苹果酸盐的制备
在反应容器中,将15ml乙酸乙酯加热至沸。在沸腾的乙酸乙酯中溶解0.67g L-苹果酸。然后加入1.23g甲苯哌丙酮碱。将该溶液加热到回流温度,并加入5ml乙酸乙酯。这样得到的澄清溶液在没有再加热的情况下搅拌30分钟,然后在-15℃下培育30分钟。沉淀物被抽滤,用4ml乙醇洗涤并干燥。
产率:1.6g白色晶体
熔点:103.9℃
1H-NMR:1H-NMR-分析结果证实产物的同一性,证实纯度>99%。
Claims (15)
2.根据权利要求1的加成盐,其特征在于,R是带有多至5个碳原子的饱和或不饱和的脂族基团,其任选被一个或多个羟基、氧代和/或羧基所取代。
3.根据权利要求1的加成盐,其特征在于,R是芳基或芳烷基,其中所述基团含有5到9个碳原子,并任选被一个或多个羟基和/或羧基所取代。
4.根据权利要求1的加成盐,其特征在于,所述生理可相容的有机酸选自乙酸、丙酸、丙二酸、草酸、葡糖酸、琥珀酸、马来酸、富马酸、乳酸、酒石酸、苹果酸、柠檬酸、丙酮酸、羟基丁酸、己二酸、水杨酸、邻苯二甲酸、扁桃酸和苯甲酸。
5.根据权利要求1的加成盐,其特征在于,所述生理可相容的有机酸是柠檬酸。
6.根据权利要求1的加成盐,即甲苯哌丙酮-柠檬酸盐、(S)-甲苯哌丙酮-柠檬酸盐或(R)-甲苯哌丙酮-柠檬酸盐。
8.根据权利要求7的方法,其特征在于,使用柠檬酸作为有机酸。
9.根据权利要求7的方法,其特征在于,以外消旋体使用甲苯哌丙酮。
10.根据权利要求7的方法,其特征在于,使用甲苯哌丙酮的(S)-对映体。
11.根据权利要求7的方法,其特征在于,使用甲苯哌丙酮的(R)-对映体。
12.根据权利要求1的加成盐用于治疗疼痛性痉挛、肌肉系统紧张、颈椎综合征、颈臂综合征、腰部综合征、骨质疏松症、大关节的炎症、风湿病、纤维肿瘤痛综合征、慢性多关节炎、职业和运动引起的负荷过重的用途。
13.根据权利要求1的加成盐用于制备治疗疼痛性痉挛、肌肉系统紧张、颈椎综合征、颈臂综合征、腰部综合征、骨质疏松症、大关节的炎症、风湿病、纤维肿瘤痛综合征、慢性多关节炎、职业和运动引起的负荷过重的药物的用途。
14.药物,除了药物可接受的助剂和/或载体外含有根据权利要求1的加成盐。
15.根据权利要求14的药物,其特征在于,该药物以经皮体系的形式存在,不含有其它渗透增强剂。
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US20100249423A1 (en) * | 2009-03-09 | 2010-09-30 | Sanochemia Pharmazeutika Ag | Tolperisone controlled release tablet |
KR101156054B1 (ko) * | 2011-09-05 | 2012-06-20 | 주식회사 네비팜 | 안정한 에페리손 함유 서방성 의약조성물 |
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CN102311407A (zh) * | 2010-06-30 | 2012-01-11 | 北京润德康医药技术有限公司 | S(+)托哌酮的制备方法及其医药用途 |
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EA200701962A1 (ru) | 2008-04-28 |
US20090298893A1 (en) | 2009-12-03 |
DE102005014080B4 (de) | 2007-11-22 |
CA2602208A1 (en) | 2006-09-28 |
WO2006099862A1 (de) | 2006-09-28 |
EP1863779A1 (de) | 2007-12-12 |
MX2007011523A (es) | 2008-01-14 |
JP2008537935A (ja) | 2008-10-02 |
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