CN1259346A - 一种旋光纯化合物的药用 - Google Patents
一种旋光纯化合物的药用 Download PDFInfo
- Publication number
- CN1259346A CN1259346A CN99118539A CN99118539A CN1259346A CN 1259346 A CN1259346 A CN 1259346A CN 99118539 A CN99118539 A CN 99118539A CN 99118539 A CN99118539 A CN 99118539A CN 1259346 A CN1259346 A CN 1259346A
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- China
- Prior art keywords
- methoxyl group
- methyl
- salt
- compound
- benzimidazole
- Prior art date
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Abstract
一种旋光纯化合物在制备治疗胃肠疾病的药物中的应用,所述化合物选自(－)－5－甲氧基－2－[[(4－甲氧基－3,5－二甲基－2－吡啶基)甲基]亚磺酰基]－1H－苯并咪唑的Na+、Mg2+、Li+、K+、Ca2+和N+(R)4盐,其中R为有1～4个碳原子的烷基。
Description
本申请是1994年5月27日提交的、题为“旋光纯的吡啶甲基亚磺酰基-1H-苯并咪唑类化合物的盐”的PCT发明专利申请的分案申请(1995年1月27日进入中国国家阶段)，原申请的申请号为94190335.4。
本发明涉及一种旋光纯化合物在制备治疗胃肠疾病的药物中的应用，所述化合物选自(-)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑的Na+、Mg2+、Li+、K+、Ca2+和N+(R)4盐，其中R为有1～4个碳原子的烷基。
EP5129和EP124495中分别讲述了俗名为奥美拉唑的化合物，即5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑，以及其治疗学上适用的碱性盐。奥美拉唑及其碱性盐是有效的胃酸分泌抑制剂，它们可用作抗溃疡剂。该化合物由于是亚砜类化合物，在其硫原子上具有不对称中心，即存在两种旋光异构体(对映体)。人们希望制得具有改善的药代动力学和代谢特性的化合物，这种化合物应能产生改善的治疗特性，例如更低的个体间差异程度。本发明提供了这样的化合物，它们是新的奥美拉唑单一对映体的盐。
1990年的《色谱杂志》(J.Chromatography，532(1990)，305-19)以分析规模而DE4035455以制备规模分别描述了奥美拉唑对映体的分离。后者通过利用非对映体醚，使之分离并随后在酸性溶液中水解而实现。为水解所结合的基团，需要酸性条件，而在这种酸性条件下，奥美拉唑非常敏感，必须用碱快速中和酸，以避免所述的酸敏感化合物的降解。在上述应用中，通过将含有浓硫酸的反应混合物加至NaOH浓溶液中，完成所述的中和操作。但该方法是不利的，因为其在局部有达到pH值为1～6的高风险，这种pH值范围会破坏所述物质。另外，立即中和将会产生热，这在大规模生产中难以操作。
另一方面，本发明提供了大规模制备本发明新化合物的新方法。这种新方法还可用于以中性形式大规模制备奥美拉唑单一对映体。
先有技术中不仅没有任何实例涉及旋光纯的奥美拉唑(即奥美拉唑的单一对映体)的任何分离的或特征化的盐，而且也没任何实例涉及任何旋光纯的奥美拉唑类似物的任何分离的或特征化的盐。发明的详细描述
本发明涉及新的奥美拉噻单一对映体的Na+、Mg2+、Li+、K+、Ca2+和N+(R)4盐，其中R为有1-4个碳原子的烷基。也就是说本发明涉及(+)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑和(-)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑的Na+、Mg2+、Li+、K+、Ca2+和N+(R)4盐，其中R为有1-4个碳原子的烷基。
本发明尤其优选的盐是旋光纯的奥美拉唑的Na+、Ca2+和Mg2+盐，即(+)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑钠盐、(-)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑钠盐、(+)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑镁盐、(-)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑镁盐、(+)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑钙盐和(-)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑钙盐。
本发明最优选的盐是根据化合物Ia和Ib的旋光纯的奥美拉唑Na+盐
Ia(+)-对映体
Ib(-)-对映体以及根据化合物IIa和IIb的旋光纯的奥美拉唑镁盐
IIa(+)-对映体
IIb(-)-对映体
术语“旋光纯的奥美拉唑Na+盐”是指基本上不含有奥美拉唑Na盐(-)对映体的奥美拉唑(+)对映体，以及基本上不含有(+)对映体的奥美拉唑(-)对映体。本发明前制得的奥美拉唑单一对映体只是为浆状物而不是晶体产物。根据本发明的一个方面，通过本发明制备奥美拉唑单一对映体的新的特定方法，很容易制得本发明所定义的盐。另外，作为晶体产物制得了所述的盐，而不是中性形式。因为可以用结晶法纯化奥美拉唑对映体的不纯盐，因此即使从旋光污染的制备产物中，也可以以非常高的旋光纯度(即≥99.8％对映体过量(e.e.))制得其对映体盐。另外，该旋光纯的盐在中性pH和碱性pH中对外消旋化作用均是稳定的，这是令人惊异的，因为原认为在碱性条件下吡啶环和手性硫原子间的碳原子上的去质子化作用会引起外消旋化作用。这种对外消旋化作用的高度稳定性使得在治疗学上可应用本发明的单一对映体。
如上所述，奥美拉唑单一对映体的特定制备方法是本发明的另一方面，该方法可用于制得中性形式的奥美拉唑单一对映体及其盐。
本发明化合物可用于抑制哺乳动物及人的胃酸分泌。更广泛的意义是，本发明化合物可用于治疗哺乳动物及人的与胃酸有关的疾病和胃肠炎性疾病，例如胃溃疡、十二指肠溃疡、消化性食管炎、以及胃炎。另外，本发明化合物还可用于治疗其中需要抗胃酸分泌作用的其它胃肠疾病，例如用于正进行非甾体抗炎药(NSAID)治疗的患者、胃泌素瘤患者、急性上消化道出血患者。本发明化合物还可用于特护情形的患者，在手术前和手术后防止酸吸出并刺激溃疡。本发明化合物还可用于治疗和预防哺乳动物(包括人)的炎症，尤其是涉及溶菌酶的炎症。可特别提到的症状是类风湿性关节炎和痛风。本发明化合物还可用于治疗牛皮癣和螺旋菌(Helicobacter)感染。
本发明的还一方面是在特定的制备方法中使用的下式中间体化合物III。制备
本发明的旋光纯化合物，即单一对映体，可按下述方法制得：分离下面式IV的5-或6-甲氧基-2-[[4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1-[酰氧基甲基]-1H-苯并咪唑的非对映体混合物的两个立体异构体，然后在碱性溶液中将分离到的每个非对映体进行溶剂分解。然后通过用中和试剂(它可以是酸或酯如甲酸甲酯)中和奥美拉唑单一对映体盐的水溶液，分离所形成的奥美拉唑单一对映体。其中苯并咪唑部分上中的甲氧基取代基位于其5和6位，酰基如下文所定义。
非对映体酯的酰基部分可以是手性酰基例如扁桃酰基，且手性酰基的不对称中心可以是R构型或者S构型。
非对映体酯可通过色谱法或分级结晶法分离。
溶剂分解作用通常是与碱一起在质子传递溶剂例如醇或水中进行，但是在非质子传递溶剂例如二甲亚砜或二甲基甲酰胺中，用碱也可水解掉该酰基。反应的碱可以是OH-或R1O-，其中R1可以是任何烷基或芳基。
为制备本发明的旋光纯Na+盐，即奥美拉唑单一对映体的钠盐，将形成的化合物用碱例如NaOH在水或非水介质中处理，或者用NaOR2(其中R2为含有1-4个碳原子的烷基)或用NaNH2处理。其中阳离子为Li+或K+的碱性盐还可用上述提到的碱的锂或钾盐制备。为制备晶形的本发明Na+盐，优选加入非水介质(例如2-丁酮和甲苯混合物)中的NaOH。
为制得本发明的旋光纯Mg2+盐将旋光纯Na+盐用无机镁盐(例如MgCl2)的水溶液处理，因此沉淀出Mg2+盐。通过在非水溶剂例如醇(仅用于醇盐)如ROH中或在醚例如四氢呋喃中用碱例如Mg(OR3)2(其中R3为含有1-4个碳原子的烷基)处理奥美拉唑的单一对映体，也可以制备旋光纯Mg2+盐。以类似的方法，使用无机钙盐(例如CaCl2)的水溶液还能制备其中阳离子为Ca2+的碱性盐。
如上所述，本发明的单一对映体的碱性盐除了钠盐(化合物Ia和Ib)和镁盐(化合物IIa和IIb)之外，还可以例举它们与Li+、K+、Ca2+、和N+(R)4的盐，其中R为有1-4个碳原子的烷基。
用于临床用途时，将本发明单一对映体即旋光纯化合物配制成适于口服、直肠、非胃肠或其它给药方式的药物制剂。该药物制剂含有本发明的单一对映体并通常组合有药学上适用的载体。载体可以是固态、半固态或液态稀释剂，或者是胶囊。这些药物制剂是本发明的另一目的。通常活性化合物的剂量占制剂总重量的0.1～95％，非胃肠道给药的制剂中为0.2～20％，口服给药的制剂中为1～50％。
在口服给药的剂量单元形式的药物制剂制备中，可以将旋光纯化合物与固体粉末载体(例如乳糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、支链淀粉、纤维素衍生物、明胶或其它适用载体)、稳定剂例如碱性化合物(如钠、钾、钙、镁等的碳酸盐、氢氧化物和氧化物等等)以及润滑剂(例如硬脂酸镁、硬脂酸钙、硬脂酰富马酸钠和聚2二醇蜡)混合。然后将混合物制成颗粒或压制成片。可以用肠溶包衣材料将颗粒和片包衣，在剂型停留在胃内期间，这种肠溶包衣能保护活性化合物免遭酸催化降解。这种肠溶包衣选自药学上适用的肠溶包衣材料例如蜂蜡、虫胶、阴离子成膜聚合物等，优选时可与适用的增塑剂组合。为了区别片剂或颗粒剂中存在的活性化合物的不同剂量，可在包衣中加入各种染料。
用含有活性化合物、植物油、脂肪、或软明胶胶囊剂适用的其它载体的胶囊制备软明胶胶囊剂。也可将软明胶胶囊剂如上所述进行肠溶包衣。
硬明胶胶囊剂可含有活性化合物的颗粒或肠溶包衣颗粒。硬明胶胶囊剂还可含有与活性化合物一起组合的固体粉末载体例如乳糖、蔗糖、山梨糖醇、甘露糖醇、土豆淀粉、支链淀粉、纤维衍生物或明胶。该胶囊剂可如上所述进行肠溶包衣。
直肠给药的剂量单元可配制成栓剂形式，其中含有与中性脂肪基质混合的活性物质；或者这种剂量单元可配制成明胶直肠胶囊剂，其中含有与植物油、石蜡油或明胶直肠胶囊剂适用的其它载体混合的活性物质；或者可配制成微灌肠剂现成品形式；或者配制成微灌肠剂干粉形式，在给药前再在合适的溶剂中重新配制。
口服给药的液体制剂可配制成糖浆剂或悬浮液剂的形式，例如含有0.2～20％(重量)活性成分的溶液剂或悬浮液剂，制剂的其余成分由糖或糖醇以及乙醇、水、甘油、丙二醇和/或聚乙二醇的混合物组成。必要时，这种液体制剂可含有着色剂、调味剂、糖精和羧甲基纤维素或其它增稠剂。口服给药的液体制剂还可配制成干粉形式，在使用之前再用合适的溶剂重新配制。
非胃肠道给药的溶液剂可配制成本发明旋光纯化合物在药学适用的溶剂中的溶液剂，优选浓度为0.1～10％(重量)。这些溶液剂还可含有稳定剂和/或缓冲剂，并可制于不同的单元剂量安瓿或小瓶中。非胃肠道给药的溶液剂还可配制成干粉制剂，在使用前再用合适的溶剂即时重新配制。
活性化合物的一段日剂量将取决于各种因素，例如每一患者的个体需要、给药途径和疾病。一般情况下，每天口服和非胃肠道给药剂量为5～500mg活性化合物。
通过下面的实施例进一步阐明本发明。
实施例1
(+)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑钠盐的制备
搅拌下将100mg(0.3mmol)(+)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑(其中含有3％(-)-异构体)溶解在1ml 2-丁酮中。加入60μl5.0M氢氧化钠水溶液和2ml甲苯。所形成的混合物是非均相似的。为制得透明溶液，加入更多的2-丁酮(约1ml)并将混合物在环境温度下搅拌过夜。过滤所形成的沉淀并用乙醚洗涤。制得51mg(46％)标题化合物白色晶体，m.p.(分解)246-248℃。手性柱色谱法分析的旋光纯度(e.e.)≥99.8％。[α]D 20＝+42.8°(c＝0.5％，水)。表1中给出NMR数据
实施例2(-)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑钠盐的制备
搅拌下将100mg(0.3mmol)(-)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑(其中含有3％(+)-异构体)溶解在1ml 2-丁酮中。加入60μl5.0M氢氧化钠水溶液和2ml甲苯。形成的混合物是非均相的。为制得透明溶液，加入更多的2-丁酮(约1ml)并将混合物在环境温度下搅拌过夜。过滤所形成的沉淀并用乙醚洗涤。制得56mg(51％)标题化合物白色结晶，m.p.(分解)247-249℃。手性柱色谱法分析的旋光纯度(e.e.)≥99.8％[α]D 20＝-44.1°(c＝0.5％水)。NMR数据见表1。
实施例3
(+)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑镁盐的制备
将2.9ml 0.1M NaOH溶液加至0.10g(0.29mmol)(+)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑中。向该混合物中加入2ml二氯甲烷，在分液漏斗中混合后，分离掉水溶液。滴加14mg(0.145mmol)MgCl2在水中的溶液。形成的沉淀经离心分离，分离得到52mg(50％)产物，为非晶形粉末。旋光纯度(e.e.)为98％，与原料相同。旋光纯度是在分析用手性柱上经色谱法测定的。[α]D 20＝+101.2(c＝1％，甲醇)。原子吸收光谱法测定样品Mg含量为3.0％。
实施例4(+)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑镁盐的制备
将(-)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑钠盐(0.500g，1.36mmol)溶解在水(10ml)中。向该混合物中滴加10ml MgCl2.xH2O(138mg，0.68mmol)水溶液，形成的沉淀经离心分离。制得418mg(86％)产物，为白色粉末。产物的旋光纯度(e.e.)为99.8％，与原料的旋光纯度相同。旋光纯度是在分析用手性柱上经色谱法测定的。[α]D 20＝+129.9°(c＝1％，甲醇)。
实施例5(-)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺，酰基]-1H-苯并咪唑镁盐的制备
将(+)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺，酰基]-1H-苯并咪唑钠盐(0.165g，0.45mmol)溶解在水(3ml)中。向该混合物中滴加2ml MgCl2.xH2O(46mg，0.23mmol)水溶液，形成的沉淀经离心分离。制得85mg(51％)产物，为白色粉末。产物的旋光纯度(e.e.)为99.9％，与原料的旋光纯度相同或更好。旋光纯度是在分析用手性柱上经色谱法测定的。[α]D 20＝-128.2°(c＝1％，甲醇)。表1：实施例编号 NMR数据 δppm
1.DMSO-d6 2.20(s，3H)，2.22(s，3H)，3.69(s，3H)，3.72(s，3H)，4.37
500MHz (d，1H)，4.75(d，1H)，6.54(dd，1H)，6.96(d，1H) 7.30(d，
1H)，8.21(s，1H).
2.DMSO-d6 2.20(s，3H)，2.22(s，3H)，3.69(s，3H)，3.72(s，3H)，
500MHz 4.38(d，1H)，4.73(d，1H)，6.54(dd，1H)，6.96(d，1H)，7.31
(d，1H)，8.21(s，1H).
下面实施例将说明本发明合成的中间体的制备。
实施例66-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]-(R/S)-亚磺酰基]-1-[(R)-扁桃酰氧基甲基]-1H-咪唑的制备
将3.4g氢氧化钠在40ml水中的溶液加至14.4g(42mmol)硫酸氢(四丁基)铵和6.4g(42mmol)(R)-(-)扁桃酸的混合物中。用400ml氯仿萃取混合物。分离后，将有机萃取物与16.6g(42mmol)6-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]-亚磺酰基]-1-[氯甲基]-1H-苯并咪唑的外消旋体一起加热至回流。溶剂蒸发后，用100ml二氯甲烷和700ml乙酸酯稀释。混合物用3×200ml水洗涤，有机溶液用MgSO4干燥然后蒸馏。粗品在100ml乙腈中用重结晶法纯化，得到8.1g标题化合物(38％)，为非对映体混合物。表2中给出NMR数据。
实施例76-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]-(R/S)-亚磺酰基]-1-[(R)-扁桃酰氧基甲基]-1H-苯并咪唑的较亲水性非对映体的分离。
用反相色谱法(HPLC)分离实施例6中标题化合物的非对映体。将约300mg对映体混合物溶解在10ml热乙腈中，用10ml0.1M乙酸铵水溶液和乙腈(70/30)的混合物稀释。将溶液注入柱中并用0.1M乙酸铵水溶液和乙腈(70/30)的混合物洗脱化合物。与亲水性差的异物体相比，更亲水的异构体较易制得纯品。按下法进行含有纯异物体的级份的后处理步骤：用二氯甲烷萃取，用5％碳酸氢钠水溶液洗涤有机溶液，用Na2SO4干燥并在旋转蒸发仪上蒸馏溶剂(在蒸馏结束时，通过加入更多的二氯甲烷，便于乙腈的除去)。用上述技术，使用1.2g非对映体混合物，制得纯的较亲水性异构体410mg，为无色浆状。表2中给出NMR数据。
实施例86-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]-(R/S)-亚磺酰基]-1-[(S)-扁桃酰氧基甲基]-1H-苯并咪唑的制备
用实施例6相同的方法，由8.1g(202mmol)氢氧化钠在100ml水中的溶液与34.4g(101mmol)硫酸氢(四丁基)铵、15.4g(101mmol)(S)-(+)-扁桃酸和39.9g(101mmol)6-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]-亚磺酰基]-1-[氯甲基]-1H-萃并咪唑的外清旋体反应制得该产物。在100ml乙腈中重结晶，得到21.3g(41％)标题化合物，为非对映体混合物。表2中给出NMR数据。
实施例96-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]-(R/S)-亚磺酰基]-1-[(S)-扁桃酰氧基甲基]-1H-苯并咪唑的较亲水性非对映体的分离。
用反相色谱法(HPLC)，以实施例7的相同方法分离实施例8的标题化合物的非对映体，但用6-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]-(R/S)-亚磺酰基]-1-[(S)-扁桃酰氧基甲基]-1H-苯并咪唑的非对映体混合物代替实施例7中使用的(R)-扁桃酸酯。使用2.1g非对映体混合物，制得760mg纯的较亲水性异构体，为无色浆状物。表2中给出NMR数据。
实施例10(-)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑的制备
将0.23g(0.45mmol)6-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1-[(R)-扁桃酰氧基甲基]-1H-苯并咪唑的较亲水性非对映体溶解在15ml甲醇中。加入36mg(0.9mmol)氢氧化钠在0.45ml水中的溶液，10分钟后在旋转蒸发仪上蒸馏混合物。残余物在15ml水和15ml二氯甲烷之间分配。有机溶液用15ml水萃取，并向合并的水溶液中加入85μl(1.4mmol)甲酸甲酯。15分钟后混合物用3×10ml二氯甲烷萃取。有机溶液用Na2SO4干燥，然后蒸馏。制得0.12g(77％)标题化合物，为无色浆状物。用手性柱色谱法分析的旋光纯度(e.e.)为94％。[α]D 20＝-155°(c＝0.5％，氯仿)。表2中给出NMR数据。
实施例11(+)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑的制备
将0.76g 6-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1-[(S)-扁桃酰氧基甲基]-1H-苯并咪唑的较亲水性非对映体溶解在50ml甲醇中。加入0.12mg(3.0mmol)氢氧化钠在1.5ml水中的溶液，10分钟在旋转蒸发仪上蒸馏混合物。残余物在25ml水和25ml二氯甲烷之间分配。有机溶液用25ml水萃取，并向合并的水溶液中加入200μl(3.2mmol)甲酸甲酯。15分钟后混合物用3×25ml二氯甲烷萃取。有机溶液用Na2SO4干燥然后蒸馏。制得0.42g(81％)标题化合物，为无色浆状物。用手性柱色谱法分析的旋光纯度(e.e.)为98％。[α]D 20＝+157°(c＝0.5％，氯仿)。表2中给出NMR数据。表2：实施例编号 NMR数据δppm
6.CDCl3 2.18(S，3H)，2.20(s，3H)，2.36(s，3H)，2.39(s，3H)，
500MHz 3.77(s，3H)，3.78(s，3H)，3.82(s，3H)，3.87(s，3H)，4.80(d，
1H)，4.88(d，1H)，5.0(m，2H)，534(s，2H)，6.43(d，1H)，
6.54(d，1H)，6.6-6.7(m，2H)6.90(d，1H)，6.95-6.98(m，
2H)，7.01(1H)，7.2-73(m，6H)，7.37(m，2H)，7.44(m，
2H)，7.58(d，1H)，7.62(d，1H)，7.95(s，1H)，7.97(s，1H).
7.CDCl3 2.20(s，3H)，2.36(s，3H)，3.78(s，3H)，3.82(s，3H)，
500MHz 4.80(s，1H)，5.00(d，1H)，5.35(d，1H)，6.43(d，1H)，6.63
(d，1H)，6.90(d，1H)，6.97(dd，1H)，7.2-7.3(m，3H)，7.37
(m，2H)，7.62(d，1H)，7.97(s，1H).
8.CDCl3 2.19(s，3H)，2.20(s，3H)，2.36(s，3H)，2.39(s，3H)，3.77
500MHz (s，3H)，3.78(s，3H)，3.83(s，3H)，3.87(s，3H)，4.80(d，1H)，
4.88(d，1H)，5.0(m，2H)，5.34(s，2H)，6.43(d，1H)，6.54(d，
1H)，6.6-6.7(m，2H)，6.90(d，1H)，6.96-6.98(m，2H)，7.01
(d，1H)，7.2-7.3(m，6H)，7.37(m，2H)，7.44(m，2H)，7.58(d，
1H).7.62(d，1H)，7.95(s，1H)，7.97(s，1H).
9.CDCl3 2.20(s，3H)，2.36(s，3H)，3.78(s，3H)，3.82(s，3H)，4.80
500MHz (d，1H)，5.00(d，1H)，5.35(d，1H)，6.43(d，1H)，6.63
(d，1H)，6.90(d，1H)，6.97(dd，1H)，7.2-7.3(m，3H)，7.37
(m，2H)，7.62(d，1H)，7.97(s，1H).
10.CDCl3 2.18，(s，3H)，2.22(s，3H)，3.68(s，3H)，3.83(s，3H)，
300MHz 4.77(m，2H)，6.93(dd，1H)，＝7.0(b，1H)，＝7.5(b，1H)，8.19
(s，1H).
11.CDCl3 2.21(s，3H)，2.23(s，3H)，3.69(s，3H)，3.84(s，3H)，4.76(m，
2H)，6.94(dd，1H)，＝7.0(b，1H)，＝7.5(b，1H)，8.20(s，1H).
目前已知的实现本发明的最佳方式是使用本发明旋光纯化合物的钠盐，这些化合物描述于实施例1和实施例2中。
下面的制剂说明含有本发明化合物作为活性成分的药物制剂。糖浆剂
由下列成分配制含有1％(重量/体积)活性物质的糖浆剂：根据实施例2的化合物 1.0g糖(粉末) 30.0g糖精 0.6g甘油 5.0g调味剂 0.05g96％乙醇 5.0g蒸馏水 加至最终体积为 100ml
将糖和糖精溶解在60g温水中，冷却后向糖溶液中加入活性化合物，并加入甘油和溶解在乙醇中的调味剂溶液。将混合物用水稀释至100ml的最终体积。包有肠溶衣的片剂
由下列成分配制含有50mg活性化合物的包有肠溶衣的片剂：I.根据实施例3的化合物(作为Mg盐) 500g乳糖 700g甲基纤维素 6g交联的聚乙稀吡咯烷酮 50g硬脂酸镁 15g碳酸钠 6g蒸馏水 适量II.邻苯二甲酸乙酸纤维素 200g鲸蜡醇 15g异丙醇 2000g二氯甲烷 2000g
I、将根据实施例3的化合物粉末与乳糖混合并用甲基纤维素和碳酸钠的水溶液制粒。用力使湿块通过网筛，并在烘箱中干燥颗粒。干燥后将颗粒与聚乙稀吡咯烷酮和硬脂酸镁混合。在压片机中用7mm直径的冲头将干混合物压成片芯(10000片)，每片含有50mg活性物质。
II、在Accela CotaR，Manesty包衣装置中将邻苯二甲酸乙酸纤维素和鲸蜡醇在异丙醇/二氯甲烷中的溶液喷雾于片剂I上。制得最终重110mg的片剂。静脉内给药的溶液剂
由下列成分配制每ml含有4mg活性成分的静脉内使用的非胃肠道给药的制剂：根据实施例2的化合物 4g无菌水 加至最终体积为 1000ml
将活性化合物溶解在水中，加水至最终体积为1000ml。将溶液经0.22μm滤膜过滤并立即分装在10ml无菌安瓿中。将安瓿密封。胶囊剂
由下列成分配制含有30mg活性成分的胶囊剂：根据实施例1的化合物 300g乳糖 700g微晶纤维素 40g低取代的羟丙基纤维素 62g磷酸氢二钠 2g纯水 适量
将活性化合物与干成分混合并用磷酸氢二钠溶液制粒。用力使湿块通过挤压机并团成球状，然后在流化床干燥器中干燥。
用流化床包衣设备，首先将上述500g小丸用30g羟丙基甲基纤维素在750g水中的溶液包衣。干燥后，再将小丸用如下给定的第二种包衣溶液包衣。包衣溶液：羟丙基甲基纤维素邻苯二甲酸酯 70g鲸蜡醇 4g丙酮 200g乙醇 600g
将最终包衣的小丸装入胶囊中。栓剂
用熔合法由下列成分分配制栓剂，每一栓剂含有40mg活性成分。根据实施例2的化合物 4gWitepsol H-15 180g
在41℃的温度下将活性化合物与Witepsol H-15均匀混合。将熔融体装入预制的栓剂外壳至净重为1.84g冷却后将该外壳热密封。每一栓剂含有40mg活性成分。不同pH值下对外消旋化的稳定性
在pH为8、9.3、10和12的缓冲水溶液中，于冰箱内，测定了本发明的旋光纯化合物在低浓度时对外消旋化作用的稳定性。通过比较5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)-甲基]亚磺酰基]-1H-苯并咪唑的(-)-异构体在缓冲溶液中在溶解后即刻和溶解数天后的旋光纯度，测定了其立体化学稳定性。在分析用手性柱上通过色谱法完成测定。在pH11.2时即使21天也未观察到受试化合物的任何外消旋化作用，这一事实说明了本发明化合物在碱性条件下的令人惊异的高度立体化学稳定性。在pH8、9.3和10时，本发明化合物的化学降解较明显，这使得外消旋化作用的测定较难完成，但所有这些pH值条件下溶解的16天后均未检测到外消旋化作用。
在用本发明旋光纯化合物进行的另一外消旋化实验中，将5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑的(+)-异构体的磷酸盐缓冲水溶液在37℃温热26小时，根本未观察到任何外消旋化作用。
Claims (8)
1.一种旋光纯化合物在制备治疗胃肠疾病的药物中的应用，所述化合物选自(-)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑的Na+、Mg2+、Li+、K+、Ca2+和N+(R)4盐，其中R为有1～4个碳原子的烷基。
2.根据权利要求1的应用，其中所述化合物是(-)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑的Na+、Mg2+或Ca2+盐。
3.根据权利要求1的应用，其中所述化合物是(-)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑的Mg2+盐。
4.根据权利要求1的应用，其中所述化合物是晶体形式的(-)-5-甲氧基-2-[[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑的Na+盐。
5.根据权利要求1-4之一的应用，用于制备抑制胃酸分泌的药物。
6.根据权利要求1-4之一的应用，用于制备治疗胃肠炎性疾病的药物。
7.根据权利要求1-4之一的应用，用于制备具有更低的个体间血浆浓度差异程度的药物。
8.根据权利要求1-4之一的应用，用于制备在治疗与胃酸有关的疾病时具有改善的治疗特性的药物。
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| CN102807561A (zh) * | 2011-06-21 | 2012-12-05 | 寿光富康制药有限公司 | S-奥美拉唑铝盐及其制备方法和应用 |
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