CN101039910A - 适合制备药物组合物的多奈哌齐盐 - Google Patents
适合制备药物组合物的多奈哌齐盐 Download PDFInfo
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- CN101039910A CN101039910A CNA2005800348076A CN200580034807A CN101039910A CN 101039910 A CN101039910 A CN 101039910A CN A2005800348076 A CNA2005800348076 A CN A2005800348076A CN 200580034807 A CN200580034807 A CN 200580034807A CN 101039910 A CN101039910 A CN 101039910A
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- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical class O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
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- 238000000034 method Methods 0.000 claims abstract description 24
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- 150000001875 compounds Chemical class 0.000 claims abstract description 13
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 229960003530 donepezil Drugs 0.000 claims description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 19
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 17
- -1 1-benzyl-4-piperidyl Chemical group 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 14
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 12
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
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- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 6
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 claims description 5
- 229960004373 acetylcholine Drugs 0.000 claims description 5
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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Abstract
本发明涉及利用有机酸形成的多奈哌齐盐及其制备方法。所述盐可以用于制备药物组合物。本发明还涉及制备所述盐的方法、包含它们的药物组合物和所述化合物在治疗疾病中的应用。
Description
发明领域
本发明涉及在制备药物组合物中有用的多奈哌齐盐。此外,本发明也涉及制备所述盐的方法,包含它们的药物组合物和所述组合物在治疗疾病中的应用。
更特别地,本发明涉及通式(I)的1-苄基-4-[(5,6-二甲氧基-1-茚满酮-2-基)-甲基]-哌啶)(INN名称:多奈哌齐)的盐
其是与通式H-X的有机酸形成的,其中X代表有机酸根。
发明的技术背景
多奈哌齐是一种治疗老年痴呆的药物成分,其以盐酸盐的形式用于药物的制备。
人口中老年人比例迅速增加,需要发展出有效的疗法来治疗和预防老年痴呆,例如其所导致的阿尔茨海默病的发展。
已经在试验中使用了数种成分来治疗痴呆,但是使用它们仅仅能达到部分的结果。然而,已经观测到在阿尔茨海默病的患者机体中,乙酰胆碱的浓度显著低于健康人。在此基础上,可以推测,治疗所述疾病的方法可以是施用提高乙酰胆碱水平,特别是提高脑中的乙酰胆碱水平的药物。实际上,为实现该目的提供了两种方法。
根据两种方法中的一种,将乙酰胆碱前体递送到机体中,所述前体通过复杂的生化过程在机体中形成乙酰胆碱物质。因此,这些物质可以认为是前药。通过施用它们,可以在机体中达到较高的乙酰胆碱浓度。
根据另一种方法,将一种对负责分解乙酰胆碱的酶具有抑制作用的物质—即所谓乙酰胆碱酯酶抑制剂—递送到机体中。在该方法中,乙酰胆碱的分解受到了抑制。这些乙酰胆碱酯酶抑制剂是毒扁豆碱和四氢吖啶。但是,这些成分具有令人不快的副作用,因为它们不仅在脑中,而且也在整个机体中抑制乙酰胆碱分解。
多奈哌齐是第一种长效、强力并高度选择性的乙酰胆碱酯酶抑制性药物成分,其增强了脑中的乙酰胆碱水平,程度比在机体的其他部分要高得多。在记忆丧失和临床适用症中,该物质的效力比毒扁豆碱更为有利,这一点已经通过模型试验得到了证明。
多奈哌齐适合治疗和预防由乙酰胆碱缺乏引起的大脑疾病。这些疾病包括,例如阿尔茨海默病、霍廷顿综合症、共济失调或匹克病。
多奈哌齐是在匈牙利专利说明书214,592中提供的。在匈牙利专利说明书211,165中披露了它与盐酸形成的盐的医药用途。已经发明出了该活性成分的盐酸盐的四种其他的多态晶体形式,并申请了专利保护。不同于基础专利中特定的晶体形式的所述晶体形式是在国际专利申请WO97/46526中提供的。
不同机构对市场上销售的药物提出了很多更高的要求。所述要求越来越严格,并需要用适当的文件来证明。一部分说明书涉及活性成分,其余部分涉及药物组合物,其在组合物的发展和销售文件的评价期间是紧密相关的。
对药物活性成分的最严格要求包括纯度在内。在大多数情况下,活性成分是较高摩尔重量的有机碱,其不溶于水并不能用水润湿。活性成分的疏水性是有问题的,特别是在配制单位剂量的时候。一种有用的方法是用药物可接受的有机盐将碱性活性成分转换成盐,并使用这样获得的盐来制备药物组合物。使用盐的进一步优点是基于下列的事实:与相应的碱相比,它们在水中更易溶解,而且用水润湿要容易的多。除此以外,由于它们的熔点高于碱,因此它们更容易和有效地纯化。
对市场上销售的药物组合物提出的要求中最重要的是,当根据药物说明书检查时,它们应当保持稳定。稳定性是指在制备或贮存时药物组合物中活性成分的减少应当不超过允许的水平。
确保药物组合物的稳定性是一项复杂的工作,这是因为在制造过程中会发生一些机械效应和受热。在制备药物组合物期间,通常遇到下列的问题:使用的是适合配制较大比表面积和在湿气影响下可能溶胀的物质。在较大的表面上,一些化学过程—其可能是不希望的分解、氧化或水解反应—可能会变得快得多,这是因为在这些情况中,活性成分以较大的表面与空气和湿气接触。这是一个问题,特别是在使用较小粒径的药物成分的时候,也就是说在活性物质是微粒形式的时候。
为了证明药物组合物的稳定性,根据批准机构的要求对它们进行严格检查,其间考虑到了分解反应事实上无法预测的情况。稳定性检查的基本部分是在高湿度含量下于恒定的高温(50℃到70℃)下贮存该药物组合物,确定在预定时间(通常是数月以后)时活性成分的含量并进行定量和定性分析来检查分解过程导致的组合物中形成的杂质。为此目的,确定预期以超过一定水平的量存在的最重要杂质的结构,并由它们来合成可用做参照物质的样品。
在包含盐酸多奈哌齐的片剂的稳定性检查期间,发现存在不同浓度的数种杂质,其可以通过质谱(MS)来检测、鉴定,并可以通过高效液相色谱法(HPLC)确定它们的浓度。
为了证明具有已鉴定结构的杂质和所合成的参照物质是相当的,必须进行单独的试验,例如MS或HPLC-MS联合法。
在用具有不同组成但包含盐酸多奈哌齐作为活性成分的片剂进行的稳定性检查的过程中,可以在样品中检测到不同的杂质。本发明人已经通过质谱(MS)确定了所述杂质的摩尔重量。在MS检查的基础上,推测一种杂质应当是通式(III)的化合物
它是多奈哌齐通过部分脱甲基化而获得的。本发明人已经制备出了通式(III)的(±)-2-[(1-苄基-4-哌啶基)甲基]-5-羟基-6-甲氧基-1-茚满酮,并通过HPLC法证明了,在包含盐酸多奈哌齐的片剂的稳定性检查过程中形成了相同的化合物。
当研究技术文献时,已经发现,也存在于多奈哌齐分子中的邻位的芳香甲氧基容易在强无机酸存在下部分水解。在较高温度下,芳香甲氧基衍生物的脱甲基作用会在盐酸水溶液(Pyman,J.J.Chem.Soc.97,275(1910))或在乙酸中的溴化氢(Tomit等人,Yakugaku Zasshi,76,1122(1956))存在下进行。在强烈条件下,通常会使两个甲氧基都脱离,但令人惊奇地,依靠芳香环的取代基,甚至在非常温和的条件下邻位的一个甲氧基也会脱甲基化而形成羟基。根据文献,在无机酸存在下邻位的芳香甲氧基的部分脱甲基化甚至可以在室温下发生(Blaskó,G.等人.,Tetrahedron Lett.22,3135-3138(1981))。当在特定条件下多奈哌齐与无机酸反应时发生的邻位脱甲基化会改变片剂的性质。为了达到比较的目的,根据比较实施例1和2(见下文)也制备了多奈哌齐与溴化氢和硫酸形成的盐。这就可以确定,由这些盐制备的片剂的稳定性与由盐酸制备的片剂的稳定性实际上是相当的。
本发明的目的是制备适合制备稳定的药物组合物的多奈哌齐盐,其基本上不含通式(III)的(±)-2-[(1-苄基-4-哌啶基)甲基]-5-羟基-6-甲氧基-1-茚满酮。
发明简述
本发明是基于下列令人惊奇的认识:在用有机酸形成的多奈哌齐的盐来制备片剂时,在稳定性检查的过程中不会检测到通式(III)的化合物。
发明详述
根据本发明的一个方面,提供通式(II)的多奈哌齐盐,
其中X代表有机酸根,例如甲酸、乙酸、丙酸、马来酸、延胡索酸、琥珀酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、丙二酸、草酸、扁桃酸、羟乙酸、邻苯二甲酸、苯磺酸、甲苯磺酸、萘磺酸或甲磺酸的酸根,优选延胡索酸、马来酸、甲磺酸、苯磺酸或甲苯磺酸的酸根,其与文献已知的无机酸形成的多奈哌齐盐相比能产生更加有利的稳定性。
在根据本发明的利用有机酸形成的多奈哌齐盐中,延胡索酸盐具有显著的性质。该盐的物理性质、稳定性和溶解性对于制备药物组合物是特别有利的。其在水中的溶解性与文献已知的盐酸盐几乎相等。其熔点在150℃以上,这对于制备药物例如片剂是特别有利的。根据本发明的多奈哌齐的延胡索酸盐基本上不含通式(III)的杂质。
根据本发明的另一个方面,提供一种制备利用有机酸形成的通式(II)的多奈哌齐盐的方法,包括将多奈哌齐的碱在适当的有机溶剂中与需要的有机酸反应,分离结晶的多奈哌齐盐,并任选用有机溶剂洗涤。
作为溶剂,可以使用C1-4醇、醚或酯,优选二乙醚、乙酸乙酯、甲醇、乙醇、2-丙醇或其混合物。
相对于多奈哌齐的碱的量,为形成盐而使用的有机酸的量是1.0-1.3摩尔当量,优选是等摩尔量。
根据本发明进一步的方面,提供药物组合物,其包含通式(II)的化合物作为活性成分,并与一种或多种在制药工业中常规使用的载体或辅助物质混合。根据本发明的药物组合物实质上不包含通式(III)的(±)-2-[(1-苄基-4-哌啶基)甲基]-5-羟基-6-甲氧基-1-茚满酮。
根据本发明的进一步的方面,提供一种制备包含作为活性成分的通式(II)的多奈哌齐盐的药物组合物的方法,包括将所述活性成分与一种或多种在制药工业中常规使用的载体或辅助物质混合,将该混合物制成盖仑剂型。
根据本发明的药物组合物通常包括0.1-95%重量,优选1-50%重量,特别是5-30%重量的活性成分。
本发明的药物组合物可以适合口服(例如,粉末、片剂、包衣片、胶囊、微胶囊、丸剂、溶液、混悬液或乳剂)、胃肠外(例如静脉内、肌内、皮下或腹膜内使用的注射溶液)、直肠(例如,栓剂)、经皮(例如膏剂)或局部(例如软膏或膏剂)给药或以植入物的形式使用。根据本发明的固体、柔软或液体药物组合物可以通过制药工业中常规使用的方法来制备。
包含通式(I)的化合物或其药学可接受的酸加成盐的口服固体药物组合物可以包含填充剂或载体(例如乳糖、葡萄糖、淀粉、磷酸钙、微晶纤维素)、结合剂(例如明胶、山梨醇、聚乙烯吡咯烷酮)、崩解剂(例如交联羧甲基纤维素钠、羧甲基纤维素钠、交聚维酮)、压片辅剂(例如硬脂酸镁、滑石、聚乙二醇、硅酸、二氧化硅)和表面活性剂(例如月桂硫酸钠)。
包含通式(II)的化合物的适合口服的液体组合物可以是溶液、混悬液或乳剂。这些组合物可以包含助悬剂(例如明胶、羧甲基纤维素)、乳化剂(例如单油酸山梨聚糖)、溶剂(例如水、油、甘油、丙二醇、乙醇)、缓冲剂(例如乙酸、磷酸、柠檬酸缓冲液)和防腐剂(例如甲基-4-羟苯酸酯等)。
适合胃肠外给药的液体药物组合物一般是无菌的等张溶液,除了溶剂外,任选包含缓冲剂和防腐剂。
包含通式(I)的化合物或其药学可接受的酸加成盐的柔软药物组合物,例如栓剂,包含平均分散在栓剂基质中(例如在聚乙二醇或可可脂中)的活性成分。
根据本发明的包含通式(II)的化合物的药物组合物可以通过制药工业中已知的方法来制备。活性成分与药学可接受的固体或液体载体和/或辅剂混合,将该混合物制成盖仑剂型。可以在制药工业中使用的载体和辅剂以及方法已经在文献(Remington′s PharmaceuticalSciences,Edition 18,Mack Publishing Co.,Easton,USA,1990)中公开。
根据本发明的药物组合物通常包含单位剂量的通式(II)的活性成分。
根据本发明的进一步的方面,提供通式(II)的化合物作为药物成分的用途。
在下列的实施例中将发现对本发明的进一步详述,但所述实施例并不是限制保护范围。
实施例1
多奈哌齐延胡索酸盐的制备
在能够强烈搅拌的设备中,测量550ml的无水乙醇,在搅拌下将38.0g(0.10mole)的多奈哌齐的碱溶解于其中。在60℃下向该溶液中加入11.6g(0.10mole)的延胡索酸,溶液加热到沸点,用2.5g的活性碳使其变澄清,并在2小时内冷却至室温。在60℃下开始结晶。混悬液在0℃下搅拌2小时,过滤并用0℃的乙醇在过滤器上洗涤直至不含母液。
收率:47.2g(95.4%)的白色晶体
熔点:170-171℃
分析通式C24H29NO3·C4H4O4(495.5):
计算值 C:67.86% H:6.71% N:2.83%
测定值:C:67.74% H:6.65% N:2.83%
根据HPLC,产品的纯度总计99.8%。
实施例2
多奈哌齐马来酸盐的制备
在能够强烈搅拌的设备中,测量100ml的2-丙醇,在搅拌下将7.6g(20mmoles)的多奈哌齐的碱溶解于其中。在60℃下向该溶液中加入2.32g(20mmoles)的马来酸,溶液加热到沸点,用活性碳使其变澄清,并在1小时内冷却至室温。混悬液在0℃下搅拌2小时,过滤并用0℃的乙酸乙酯在过滤器上洗涤直至不含母液。
收率:9.04g(91.2%)的白色晶体。
熔点:116-118℃
分析通式C24H29NO3·C4H4O4(495.5):
计算值 C:67.86% H:6.71% N:2.83%
测定值:C:67.24% H:6.85% N:2.79%
根据HPLC,产品的纯度总计99.8%。
实施例3
多奈哌齐甲磺酸盐的制备
在能够强烈搅拌的设备中,测量100ml的2-丙醇,在搅拌下将7.6g(20mmoles)的多奈哌齐的碱溶解于其中。向该溶液中加入1.92g(20mmoles)的甲磺酸,溶液加热到沸点,用2.5g的活性碳使其变澄清,并冷却至室温。混悬液在0℃下过滤,并用0℃的乙酸乙酯在过滤器上洗涤直至不含母液。
收率:9.34g(89.2%)的白色晶体。
熔点:180-182℃
分析通式C25H33NO6S(475.6):
计算值 C:63.14% H:6.99% N:2.95% S:6.74%
测定值:C:62.98% H:7.02% N:2.94% S:6.70%
实施例4
多奈哌齐苯磺酸盐的制备
在能够强烈搅拌的设备中,测量100ml的2-丙醇,在搅拌下将7.6g(20mmoles)的多奈哌齐的碱溶解于其中。向该溶液中加入3.16g(20mmoles)的苯磺酸,溶液加热到沸点,用2.5g的活性碳使其变澄清,并冷却至室温。混悬液在0℃下过滤,并用0℃的乙酸乙酯在过滤器上洗涤直至不含母液。
收率:9.41g的(87.5%)的白色晶体。
熔点:175-176
分析通式C30H35NO6S(537.7):
计算值 C:67.02% H:6.56% N:2.61% S:5.96%
测定值:C:66.94% H:6.53% N:2.58% S:5.91%
实施例5
多奈哌齐对甲苯磺酸盐的制备
在能够强烈搅拌的设备中,测量100ml的2-丙醇,在搅拌下将7.6g(20mmoles)的多奈哌齐的碱溶解于其中。向该溶液中加入3.45g(20mmoles)的甲磺酸,溶液加热到沸点,用活性碳使其变澄清,并冷却至室温。混悬液在0℃下过滤,并用0℃的乙酸乙酯在过滤器上洗涤直至不含母液。
收率:9.29g(84.2%)的白色晶体。
熔点:171-173℃
分析通式C31H37NO6S(551.7):
计算值 C:67.49% H:6.76% N:2.54% S:5.81%
测定值:C:67.54% H:6.83% N:2.54% S:5.76%
实施例6
(±)-2-[(1-苄基-4-哌啶基)甲基]-5-羟基-6-甲氧基-1-茚满酮盐酸盐[通式(III)的化合物]的制备
在水浴中将7.6g(20mmoles)的多奈哌齐的碱在50ml的48%的溴化氢水溶液和10ml的乙酸的混合物中搅拌20小时。该溶液倾倒在500g的冰上,用碳酸钾中和,用乙酸乙酯萃取产品,减压蒸发该溶液。在二乙醚和2-丙醇的5∶1(v/v)混合物中,由残留的油形成了盐酸盐。
收率:2.85g(35.4%)的白色晶体。
熔点:159-160℃
分析通式C23H28ClNO3(401.9):
计算值:C:68.73% H:7.02% N:3.48% Cl:8.82%
测定值:C:68.63% H:7.12% N:3.45% Cl:8.95%
实施例7
(±)-2-[(1-苄基-4-哌啶基)甲基]-5-羟基-6-甲氧基-1-茚满酮盐酸盐[通式(III)的化合物]的制备
在80℃的水浴中将7.6g(20mmoles)的多奈哌齐的碱在50ml的36.5%的溴化氢水溶液和10ml的乙酸的混合物中搅拌24小时。该溶液倾倒在500g的冰上,用碳酸钾中和,用乙酸乙酯萃取产品,减压蒸发该溶液。在乙酸乙酯中,由残留的油形成了盐酸盐。
收率:2.10g的(26.1%)的白色晶体。
熔点:158-160℃
分析通式C23H28ClNO3(401.9):
计算值:C:68.73% H:7.02% N:3.48% Cl:8.82%
测定值:C:68.55% H:6.94% N:3.54% Cl:8.71%
实施例8
药物组合物的制备
为制备总重量100mg、包含5mg活性成分的片剂,测量下列的物质(涉及一个片剂):
多奈哌齐延胡索酸盐 5mg
乳糖 47mg
玉米淀粉 47mg
硬脂酸镁 1mg
将粉末混合物均质化,并压制成片。
实施例9
药物组合物的制备
为制备总重量100mg、包含10mg活性成分的片剂,测量下列的物质(涉及一个片剂):
多奈哌齐延胡索酸盐 10mg
乳糖 30mg
玉米淀粉 59mg
硬脂酸镁 1mg
将粉末混合物均质化,并压制成片。
实施例10
药物组合物的制备
为制备总重量100mg、包含25mg活性成分的片剂,测量下列的物质(涉及一个片剂):
多奈哌齐延胡索酸盐 25mg
乳糖 50mg
玉米淀粉 24mg
硬脂酸镁 1mg
将粉末混合物均质化,并压制成片。
实施例11(比较试验)
多奈哌齐氢溴酸盐的制备
在能够强烈搅拌的设备中,测量100ml的2-丙醇,将7.6g(20mmoles)的多奈哌齐的碱溶解于其中。向该溶液中加入包含1.62g(20mmoles)的溴化氢的2-丙醇。混悬液在0℃下过滤,并用乙酸乙酯在过滤器上洗涤直至不含母液。
收率:8.28g的(89.9%)的白色晶体。
熔点:246-247℃
分析通式C24H30BrNO3(460.7):
计算值:C:62.61% H:6.57% Br:17.35% N:3.04%
测定值:C:62.33% H:6.55% Br:17.57% N:3.00%
实施例12(比较实施例)
多奈哌齐硫酸盐(1∶1)的制备
在能够强烈搅拌的设备中,测量100ml的2-丙醇,将7.6g(20mmoles)的多奈哌齐的碱溶解于其中。向该溶液中加入包含2.45g(20mmoles)的硫酸的2-丙醇。混悬液在0℃下搅拌2小时,并用乙酸乙酯在过滤器上洗涤直至不含母液。
收率:8.83g的(92.4%)的白色晶体。
熔点:190-195℃
分析通式C24H31NO7S(477.6):
计算值:C:60.36% H:6.54% N:2.93% S:6.71%
测定值:C:59.95% H:6.52% N:2.87% S:6.64%
Claims (17)
2.根据权利要求1的通式(II)的盐,其中X代表有机酸根,例如甲酸、乙酸、丙酸、马来酸、延胡索酸、琥珀酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、丙二酸、草酸、扁桃酸、羟乙酸、邻苯二甲酸、苯磺酸、甲苯磺酸、萘磺酸或甲磺酸的酸根,优选延胡索酸、马来酸、甲磺酸、苯磺酸或甲苯磺酸的酸根。
3.多奈哌齐延胡索酸盐(1∶1)。
4.多奈哌齐马来酸盐(1∶1)。
5.多奈哌齐甲磺酸盐。
6.多奈哌齐苯磺酸盐。
7.多奈哌齐甲苯磺酸盐。
8.如权利要求1到7任一项所要求的利用有机酸形成的多奈哌齐的酸加成盐,其基本上不含通式(III)的(±)-2-[(1-苄基-4-哌啶基)甲基]-5-羟基-6-甲氧基-1-茚满酮。
9.一种制备如权利要求1到7任一项所要求的多奈哌齐盐的方法,包括将多奈哌齐的碱在适当的有机溶剂中与需要的有机酸反应,分离所得到的多奈哌齐盐,并任选用有机溶剂洗涤。
10.如权利要求9所要求的方法,其包括使用量为1.0-1.3摩尔当量,优选1.0摩尔当量的所述有机酸。
11.如权利要求9和10所要求的方法,包括使用作为溶剂的C1-4醇、醚或酯,优选二乙醚、乙酸乙酯、甲醇、乙醇、2-丙醇或其混合物。
12.药物组合物,包含根据权利要求1到8的多奈哌齐盐作为活性成分,与一种或多种在制药工业中常规使用的载体或辅助物质混合。
13.制备根据权利要求12的药物组合物的方法,包括将根据权利要求1到8任一项的通式(II)的化合物与药学可接受的载体和任选的其他辅剂混合,并将该混合物制成盖仑剂型。
14.根据权利要求1到8任一项的多奈哌齐盐在制备适合预防或治疗与大脑乙酰胆碱的缺乏有关的疾病、阿尔茨海默病或老年痴呆的药物组合物中的应用。
15.预防或治疗与大脑乙酰胆碱的缺乏有关的疾病、阿尔茨海默病或老年痴呆的方法,包括以对需要治疗的患者的药学有效量给患者施用如权利要求1到8任一项所要求的至少一种通式(II)的多奈哌齐盐。
16.通式(III)的(±)-2-[(1-苄基-4-哌啶基)-甲基]-5-羟基-6-甲氧基-1-茚满酮。
17.与无机酸,例如硫酸、盐酸或氢溴酸形成的(±)-2-[(1-苄基-4-哌啶基)甲基]-5-羟基-6-甲氧基-1-茚满酮的盐。
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HU0401850A HUP0401850A3 (en) | 2004-09-15 | 2004-09-15 | Donepezil salts for producing pharmaceutical composition |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2009049479A1 (fr) * | 2007-09-28 | 2009-04-23 | Tianjin Hemay Bio-Tech Co., Ltd. | Polymorphes de sels de donepezil, leurs procédés de préparation et leurs utilisations |
WO2013005094A1 (en) * | 2011-07-05 | 2013-01-10 | Torrent Pharmaceuticals Ltd | Acid addition salt of donepezil and pharmaceutical composition thereof |
WO2018153315A1 (zh) * | 2017-02-23 | 2018-08-30 | 上海华汇拓医药科技有限公司 | 一种多奈哌齐半帕莫酸盐的粉针剂、包含其的组合物及它们的制备方法 |
CN113164392A (zh) * | 2018-11-26 | 2021-07-23 | 益霸生物公司 | 多奈哌齐共熔混合物及其用途 |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
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DE102004046497A1 (de) * | 2004-09-23 | 2006-04-06 | Helm Ag | Donepezil-Salze |
US7592459B2 (en) * | 2004-09-29 | 2009-09-22 | Chemagis Ltd. | Use of purified donepezil maleate for preparing pharmaceutically pure amorphous donepezil hydrochloride |
WO2007010910A1 (en) * | 2005-07-15 | 2007-01-25 | Eisai R & D Management Co., Ltd. | 1-benzyl-4-[(5, 6-dimethoxy-1-indanon)-2-yl]-methyl piperidine p-toluenesulfonate or crystal thereof |
US20100113793A1 (en) * | 2006-03-20 | 2010-05-06 | Ind-Swift Laboratories Limited | Process for the Preparation of Highly Pure Donepezil |
GB0609835D0 (en) * | 2006-05-18 | 2006-06-28 | Pliva Istrazivanje I Razvoj D | Impurities of a pharmaceutical product |
CN101167697B (zh) * | 2006-10-26 | 2011-03-30 | 中国科学院上海药物研究所 | 多奈哌齐类化合物长效缓控释组合物及其制备方法 |
WO2010033045A1 (en) * | 2008-09-16 | 2010-03-25 | Igor Anatolievich Pomytkin | Compositions and methods for prevention or treatment of beta amyloid deposition |
EP2586436A1 (en) | 2011-10-31 | 2013-05-01 | Commissariat à l'Énergie Atomique et aux Énergies Alternatives | Use of anti-connexin agents for enhancing the therapeutic effect of acetylcholinesterase inhibitor |
WO2013078608A1 (en) | 2011-11-29 | 2013-06-06 | Ziqiang Gu | Donepezil pamoate and methods of making and using the same |
KR101811797B1 (ko) * | 2013-04-03 | 2017-12-22 | 동국제약 주식회사 | 도네페질을 포함하는 비경구투여용 약제학적 조성물 |
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FI95572C (fi) * | 1987-06-22 | 1996-02-26 | Eisai Co Ltd | Menetelmä lääkeaineena käyttökelpoisen piperidiinijohdannaisten tai sen farmaseuttisen suolan valmistamiseksi |
US6372760B1 (en) * | 1999-03-31 | 2002-04-16 | Eisai Co., Ltd. | Stabilized composition comprising antidementia medicament |
DK1209151T3 (da) * | 1999-09-01 | 2007-08-20 | Eisai R&D Man Co Ltd | 4-substituerede piperidinderivativer |
EP1285656A4 (en) * | 2000-04-13 | 2006-07-12 | Eisai Co Ltd | ACETYLCHOLINESTERASE HEMMER CONTAINING 1-BENZYLPYRIDINIUM SALT |
US7439365B2 (en) * | 2003-11-17 | 2008-10-21 | Usv, Ltd. | Pharmaceutical salt of (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl] methyl piperidine (Donepezil) |
-
2004
- 2004-09-15 HU HU0401850A patent/HUP0401850A3/hu unknown
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2005
- 2005-09-12 UA UAA200704106A patent/UA88481C2/ru unknown
- 2005-09-12 CN CNA2005800348076A patent/CN101039910A/zh active Pending
- 2005-09-12 EA EA200700637A patent/EA200700637A1/ru unknown
- 2005-09-12 WO PCT/HU2005/000102 patent/WO2006030249A1/en active Application Filing
- 2005-09-12 PL PL382842A patent/PL382842A1/pl not_active Application Discontinuation
- 2005-09-12 RU RU2007114082/04A patent/RU2382032C2/ru not_active IP Right Cessation
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- 2005-09-12 SK SK5034-2007A patent/SK50342007A3/sk not_active Application Discontinuation
- 2005-09-12 EP EP05787910A patent/EP1817286A1/en not_active Withdrawn
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2009049479A1 (fr) * | 2007-09-28 | 2009-04-23 | Tianjin Hemay Bio-Tech Co., Ltd. | Polymorphes de sels de donepezil, leurs procédés de préparation et leurs utilisations |
US8501779B2 (en) | 2007-09-28 | 2013-08-06 | Tianjin Hemay Bio-Tech Co., Ltd. | Polymorphs of donepezil salts, preparation methods and uses thereof |
WO2013005094A1 (en) * | 2011-07-05 | 2013-01-10 | Torrent Pharmaceuticals Ltd | Acid addition salt of donepezil and pharmaceutical composition thereof |
WO2018153315A1 (zh) * | 2017-02-23 | 2018-08-30 | 上海华汇拓医药科技有限公司 | 一种多奈哌齐半帕莫酸盐的粉针剂、包含其的组合物及它们的制备方法 |
CN109803654A (zh) * | 2017-02-23 | 2019-05-24 | 上海华汇拓医药科技有限公司 | 一种多奈哌齐半帕莫酸盐的粉针剂、包含其的组合物及它们的制备方法 |
US11197850B2 (en) | 2017-02-23 | 2021-12-14 | Shanghai Synergy Pharmaceutical Sciences Co., Ltd. | Powder injection of the donepezil semi palmoxiric acid salt, composition containing same and preparation method therefor |
CN109803654B (zh) * | 2017-02-23 | 2022-06-28 | 上海华汇拓医药科技有限公司 | 一种多奈哌齐半帕莫酸盐的粉针剂、包含其的组合物及它们的制备方法 |
US11801239B2 (en) | 2017-02-23 | 2023-10-31 | Shanghai Synergy Pharmaceutical Sciences Co., Ltd. | Powder injection of the donepezil semi palmoxiric acid salt, composition containing same and preparation method therefor |
CN113164392A (zh) * | 2018-11-26 | 2021-07-23 | 益霸生物公司 | 多奈哌齐共熔混合物及其用途 |
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Publication number | Publication date |
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NO20071912L (no) | 2007-06-07 |
UA88481C2 (ru) | 2009-10-26 |
HU0401850D0 (en) | 2004-11-29 |
EA200700637A1 (ru) | 2007-08-31 |
IL181827A0 (en) | 2007-07-04 |
RU2382032C2 (ru) | 2010-02-20 |
HUP0401850A3 (en) | 2008-03-28 |
RU2007114082A (ru) | 2008-10-27 |
WO2006030249A1 (en) | 2006-03-23 |
PL382842A1 (pl) | 2008-01-21 |
US20080194628A1 (en) | 2008-08-14 |
EP1817286A1 (en) | 2007-08-15 |
CZ2007248A3 (cs) | 2007-06-20 |
BG109855A (bg) | 2008-04-30 |
SK50342007A3 (sk) | 2007-07-06 |
HUP0401850A2 (en) | 2006-11-28 |
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