CN1081632C - (R－(R*,R*)－2－(4－氟苯基)－β－δ－二羟基－5－(1－甲基－乙基)－3－苯基－4－[(苯基氨基)羰基]－1H－吡咯－1－庚酸半钙盐的Ⅲ型结晶 - Google Patents

(R－(R*,R*)－2－(4－氟苯基)－β－δ－二羟基－5－(1－甲基－乙基)－3－苯基－4－[(苯基氨基)羰基]－1H－吡咯－1－庚酸半钙盐的Ⅲ型结晶 Download PDF

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CN1081632C
CN1081632C CN96195632A CN96195632A CN1081632C CN 1081632 C CN1081632 C CN 1081632C CN 96195632 A CN96195632 A CN 96195632A CN 96195632 A CN96195632 A CN 96195632A CN 1081632 C CN1081632 C CN 1081632C
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A·T·麦肯泽
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Abstract

描述了新的定义为III型的(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯基氨基)羰基)]-1H-吡咯-1-庚酸半钙盐晶体，其特征在于其X-射线粉末衍射图和/或固态13C核磁共振谱(NMR)，和描述了上述晶体的制法和其药物组合物，它们可用作低脂血症和低胆固醇血症的治疗剂。

Description

(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基-乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸半钙盐的III型结晶
本发明涉及新的阿托坦汀(atorvastatin)晶形，已知其可作为药物使用，化学名称为(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯基氨基)羰基)]-1H-吡咯-1-庚酸半钙盐，本发明也涉及这种晶形的生产和分离方法，涉及包括这种化合物和可药用载体的药物组合物，和涉及药物治疗方法。本发明新的结晶化合物可用作酶3-羟基-3-甲基-戊二酰-辅酶A还原酶(HMG-CoA还原酶)的抑制剂，因而可用作低脂血症和低胆固醇血症的(治疗)剂。
US专利4,681,193(这里引入本文作为参考)公开了一些反式-6-[2-(3-或4-甲酰氨基-取代的-吡咯-1-基)烷基]-4-羟基-吡喃-2-酮，包括反式(±)-5-(4-氟苯基)-2-(1-甲基乙基)-N，4-二苯基-1-[(2-四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1H-吡咯-3-甲酰胺。
US专利5,273,995(这里引入本文作为参考)公开了具有反式-5-(4-氟苯基)-2-(1-甲基乙基)-N，4-二苯基-1-[(2-四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1 H-吡咯-3-甲酰胺的开环酸的R构型的对映体，即(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯基氨基)羰基)]-1H-吡咯-1-庚酸。
US专利5,003,080；5,097,045；5,103,024；5,124,482；5,149,837；5,155,251；5,216,174；5,245,047；5,248,793；5,280,126；5,397,792；和5,342,952(这里均引入本文作为参考)公开了制备阿托坦汀的多种方法和主要中间体。
阿托坦汀是以其钙盐的形式制备的，即(R-(R*，R*)-2-(4-氟苯基)β-δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯基氨基)羰基)]-1H-吡咯-1-庚酸钙盐(2∶1)。钙盐是需要的，因为它使得阿托坦汀易于制剂，制成例如适合口服的片剂，胶囊，锭剂，粉剂等。此外，也需要制备纯的和结晶形式的阿托坦汀以满足特定的药物和处方的需要。
此外，生产阿托坦汀的方法应当是适合大规模生产的。而且产物应当是易于过滤和容易干燥的形式。最后出于经济上的需要产物应当是长时间稳定的，不需要特定的储存条件。
上述US专利的方法公开了无定形阿托坦汀，它具有于大规模生产不适合的过滤和干燥特征，并且必须与热，光，氧气和湿气隔绝方可保护。
令人惊异和意想不到的是我们发现了阿托坦汀可以结晶形式制备。因此本发明提供了新的阿托坦汀的III型结晶形式。与以前的无定形产物比较，III型阿托坦汀具有不同的物理性质。
因此，本发明涉及III型阿托坦汀结晶及其水合物，其特征在于下述的X-射线粉末衍射图，它们是以2θ，d-晶格，和相对强度(相对强度大于25％，在Siemens D-500衍射仪上用CuKα辐射测量的)表示的。2θ                    d           相对强度
                               (＞25％)4.123                 21.4140       49.204.993                 17.6832       30.825.768                 15.3099       28.697.670                 11.5173       25.498.451                 10.4538       100.0015.962                5.5478        32.5916.619                5.3298        62.3417.731                4.9981        49.2918.267                4.8526        45.1218.870                4.6989        39.5219.480                4.5531        36.5919.984                4.4393        70.3420.294                4.3722        69.5421.105                4.2061        37.3921.670                4.0976        36.5023.318                3.8117        38.6324.405                3.6442        65.5424.967                3.5635        27.2025.397                3.5041        33.75
进一步的，本发明涉及III型阿托坦汀结晶及其水合物，其特征在于下述的固态13C核磁共振谱，其中化学位移是在Bruker AX-250波谱仪上测量以每百万分之几表示的：分布
                               化学位移自旋侧谱带
                                214.8
                                209.3
                                202.3C12或C25                            184.9C12或C25                            166.7C16                                 161.0(弱，宽)原子碳C2-C5，C13-C18，C19-C24，C27-C32    140.1
                                135.2
                                131.8
                                128.9
                                124.3
                                122.2
                                117.2
                                114.9C8，C10                             69.8
                                67.3
                                65.6亚甲基碳C6，C7，C9，C11                     44.1
                                40.4
                                35.4C33                                 27.0
                                24.1C34                                 22.1
                                19.9
作为HMG-CoA的抑制剂，新的阿托坦汀结晶可用作低脂血症和低胆固醇血症的(治疗)剂。
本发明进一方面涉及药物组合物，该药物组合物是以含有效量III型阿托坦汀结晶的单位剂量形式在上述治疗方法中施用的。最后本发明涉及III型阿托坦汀的生产方法。
通过在附图1-2中提及的下述非限制性实施例进一步说明本发明，其中的特征简要说明如下。
附图1
III型阿托坦汀的衍射(Y-轴＝0至最大计数2815/秒(cps))。附图2
固态13C核磁共振谱，其自旋侧谱带(side bands)通过III型阿托坦汀的星号识别。
III型阿托坦汀结晶以其X-射线粉末衍射图和/或固态13C核磁共振谱(NMR)为特征。
X-射线粉末衍射图III型阿托坦汀
III型阿托坦汀的特征为X-射线粉末衍射图。这样，III型阿托坦汀的X-射线粉末衍射图是在Siemens D-500衍射仪上用CuKα辐射测量的。仪器
具有与IBM兼容界面的Siemens D-500衍射仪-Kristalloflex，软件为DIFFRAC AT(SOCABIM 1986，1992)。
CuKα辐射(20mA，40kV，λ＝1.5406A)光隙I和II之间是1°)，通过Kevex Psi Peltier Cooled Silicon[Si(Li)]检测器电过滤(光隙：III是1°和IV是0.15°)。方法学
每天运行二氧化硅标准器(silicon standard)以检查X-射线管的校准情况。
连续以θ/2θ成对扫描：在2θ时4.00°-40.00°，
扫描速率6°/分钟：0.4秒/0.04°步
将样品放出管瓶并压制到无背景噪音的石英A1容器中。
样品在室温下保存和在室温下测试。
表1列出了III型阿托坦汀结晶未磨样品所有谱线的2θ，d-晶格，和相对强度大于25％的相对强度。也应当注意计算机产生的没有四舍五入的数字也列在表中。表1 III型阿托坦汀所有衍射谱线相对强度大于25％的强度和峰位置2θ                   d                   相对强度
                                      (＞25％)4.123                   21.4140            49.204.993                   17.6832            30.825.768                   15.3099            28.697.670                   11.5173            25.498.451                   10.4538            100.0015.962                  5.5478             32.5916.619                  5.3298             62.3417.731                  4.9981             49.2918.267                  4.8526             45.1218.870                  4.6989             39.5219.480                  4.5531             36.5919.984                  4.4393             70.3420.294                  4.3722             69.5421.105                  4.2061             37.3921.670                  4.0976             36.5023.318                  3.8117             38.6324.405                  3.6442             65.5424.967                  3.5635             27.2025.397                  3.5041             33.75
固态核磁共振谱NMR)方法学
所有固态13C NMR均是在Bruker AX-250，250MHz NMR波谱仪上测量的。高分辨率谱是采用高能质子去耦和交叉-极化CP)在磁-角自旋(MAS)约5kHz时获得的。如Frye和Maciel(Frye J.S.和MacielG.E.，J.Mag.Res.，1982；48：125)所述，通过监测侧谱带采用KBr的Br信号调整磁-角。在各试验中采用约300-450mg样品，上述样品被装填入canister-设计回旋器的。化学位移是指外部的tetrakis(三甲基甲硅烷基)硅烷(甲基信号在3.50ppm)(Muntean J.V.和Stock L.M.，J.Mag.Res.，1988；76：54)。
表2表示III型阿托坦汀结晶的固态NMR谱。
Figure C9619563200111
表2 III型阿托坦汀的碳原子排布和化学位移分布                                   化学位移自旋侧谱带                              214.8
                                    209.3
                                    202.3C12或C25                                184.9C12或C25                                166.7C16                                     161.0(弱，宽)原子碳C2-C5，C13-C18，C19-C24，C27-C32        140.1
                                    135.2
                                    131.8
                                    128.9
                                    124.3
                                    122.2
                                    117.2
                                    114.9C8，C10                                 69.8
                                    67.3
                                    65.6亚甲基碳C6，C7，C9，C11                         44.1
                                    40.4
                                    35.4C33                                     27.0
                                    24.1C34                                     22.1
                                    19.9
本发明的III型阿托坦汀可以无水和水合形式存在。总的来说，水合形式等同于无水形式并且也被包括在本发明的范围之内。
本发明也提供了III型阿托坦汀结晶的制备方法，该方法包括在可产生III型阿托坦汀结晶的条件下将阿托坦汀暴露在高相对湿度的环境中。
产生III型阿托坦汀结晶的具体条件根据经验确定，这里只可能提供在实践中发现适当的方法。
因此，例如，当起始原料是II型阿托坦汀结晶时，它在名称为“结晶体(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯基氨基)羰基])-1H-吡咯-1-庚酸钙盐(2∶1)”的同时申请的美国专利申请No.60/001452公开，律师案例号PD-5250-01-FJT，相应中国专利申请号为96195564.3(I型和IV型阿托坦汀结晶也在该申请中公开)，所需的III型阿托坦汀结晶可通过将固体暴露在相对湿度大于95％的环境中11天获得。
II型阿托坦汀可从无定形的，从无定形和I型阿托坦汀的混合物或从I型阿托坦汀制备。这样，例如，当起始原料是无定形的，无定形和I型阿托坦汀的混合物或I型阿托坦汀结晶时，所需的II型阿托坦汀结晶可通过将固体悬浮于含有约40％-约50％水的甲醇中直到向所需类型的转化完成，接着过滤。
在控制条件下重结晶可以制备I型阿托坦汀。具体的，它可由相应碱性盐的水溶液制备，碱性盐如碱金属盐如锂盐，钾盐，钠盐等；氨或胺盐；优选是加入钙盐如乙酸钙等的钠盐，或通过将无定形阿托坦汀悬浮于水中制备。总的来说，采用羟基助溶剂如低级链烷醇，例如甲醇等，是优选的。
可以制备本发明化合物和以多种口服和非肠道剂量形式给药。因此，本发明化合物可通过注射如静脉，肌内，皮内，皮下，十二指肠内或腹膜内注射。而且本发明化合物也可通过吸入施用，例如通过鼻内吸入。此外，本发明化合物也可经皮施用。下述剂量形式中可含有本发明化合物或其相应的可药用盐作为活性成分对本领域熟练技术人员而言是显而易见的。
采用本发明化合物制备药物组合物时，可药用载体可以是固体或液体。固体制剂包括粉剂，片剂，丸剂，胶囊，扁囊剂，栓剂和可分散颗粒。固体载体是也可充当稀释剂，调味剂，增溶剂，润滑剂，悬浮剂，粘合剂，防腐剂，片剂崩解剂或包封物的一种或多种物质。
在粉剂中，载体是与细分活性组分混合的细分固体。
在片剂中，活性组分与在适当比例时具有必要粘合性质的载体混合并且压制成所需的形状和大小。
优选的，粉剂和片剂含有约2或10至约70％的活性化合物。合适的载体为碳酸镁，硬脂酸镁，滑石，糖，乳糖，果胶，糊精，淀粉，明胶，黄蓍胶，甲基纤维素，羧甲基纤维素钠，低熔点石蜡，可可脂等。术语“制剂”是指包括这样一种制剂，其中活性化合物与作为载体的包封物质混合得到胶囊，其中的活性组分(有或没有其它载体)是被载体包围的，因此也是与载体结合的。类似的，扁囊剂和锭剂也包括在内。片剂，粉剂，胶囊，丸剂和锭剂可作为适于口服的固体剂量形式。
在制备栓剂时，低熔点石蜡如脂肪酸甘油酯或可可脂的混合物首先融化，并且通过搅拌活性组分均匀分散其中。然后将融化的均一混合物倾入到适当大小的塑模中，使之冷却，然后固化。
液体剂型包括溶液，悬浮液，潴留(retention)灌肠剂，和乳剂，例如水和水聚乙二醇溶液。非肠道注射时，液体制剂可被制成含水聚乙二醇的溶液。
适于口服的水溶液可通过将活性组分溶于水中并加入所需的合适的着色剂，调味剂，稳定剂和增稠剂来制备。
适于口服的悬浮液可通过将细分活性组分与粘稠物质以及其它熟知的悬浮剂溶于水中制备，粘稠物质如天然或合成树胶，树脂，甲基纤维素，羧甲基纤维素钠。
在口服施用前不久可转化为液体剂型的固体剂型也包括在内。这种液体剂型包括溶液，悬浮液和乳液。除了活性组分外，这些制剂还可包括着色剂，调味剂，稳定剂，缓冲液，人工和天然甜味剂，分散剂，增稠剂，增溶剂等。
药物组合物优选采用单位剂量形式。采用这种形式时，制剂被分成含有合适量活性化合物的单位剂量。单位剂量可以是包装的(packaged)制剂，这种制剂含有分割量的制剂，如包装的片剂，胶囊，和在管瓶或安瓿中的粉剂。而且，单位剂量也可以是胶囊，片剂，扁囊剂或锭剂本身，或者，单位剂量可以是适当数目的任何这些包装的剂量形式的(的组合)。
根据具体的应用和活性组分的效力，单位剂量制剂中活性组分的量可在0.5mg-100mg，优选2.5mg-80mg范围内变化或调节。如果需要，组合物也可含有其它治疗剂
在作为低脂血症和低胆固醇血症的(治疗)剂的医疗用途中，本发明药物制备方法中采用的III型阿托坦汀结晶是以每天约2.5mg-约80mg的初始剂量施用的。日剂量范围在约2.5mg-约20mg是优选的。但是，根据病人的需要，所治疗疾病的严重程度和采用的化合物，剂量可以进行变化。针对具体情况确定合适的剂量是在现有技术范围内的。总的来说，以低于化合物理想剂量的小剂量开始进行治疗，之后，少量逐步增加剂量直到达到这种情况下的理想效果。为方便起见，如果需要，一天的总剂量可按比例分割和施用。
下述非限制性实施例说明了制备本发明化合物的优选的方法。
                      实施例1(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯基氨基)羰基)]-1H-吡咯-1-庚酸半钙盐(I型阿托坦汀)
在48-58℃使(2R-反式)-5-(4-氟苯基)-2-(1-甲基乙基)-N，4-二苯基-1-[(2-(四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1H-吡咯-3-甲酰胺(阿托坦汀内酯)(US专利号5,273,995)(75kg)，甲基叔丁基醚(MTBE)(308kg)，甲醇(190L)的混合物与氢氧化钠(5.72kg/950L)反应40-60分钟形成开环钠盐。冷却到25-35℃后，弃去有机层，和再用MTBE(230kg)提取水层。弃去有机层，并加热钠盐的MTBE饱和水溶液至47-52℃。在至少30分钟内向此溶液中加入溶于水(410L)中的乙酸钙半水合物(11.94kg)。在加入乙酸钙溶液溶液不久，采用I型阿托坦汀(1.1kg于1L水和5L甲醇中)接种混合物。然后在51-57℃加热混合物至少10分钟，接着冷却到15-40℃。过滤混合物，用水(300L)和甲醇(150L)溶液洗涤，接着用水(450L)洗涤。在60-70℃真空干燥固体3-4天得到I型阿托坦汀(72.2kg)。
                     实施例2(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯基氨基)羰基)]-1H-吡咯-1-庚酸半钙盐(II型阿托坦汀)
将无定形和I型阿托坦汀结晶(100g)的混合物悬浮于甲醇(1200ml)和水(800ml)的混合物中并搅拌3天。过滤所得物质，70℃下减压干燥得到II型阿托坦汀结晶。
                     实施例3(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯基氨基)羰基)]-1H-吡咯-1-庚酸半钙盐(III型阿托坦汀)
将II型阿托坦汀(实施例2)通过50目筛到100目筛摇筛并置于湿度罐中相对湿度95％下11天，得到III型阿托坦汀。

Claims (8)

1.III型(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基-乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸半钙盐结晶水合物，其特征在于下述的X-射线粉末衍射图，它们是以2θ，d-晶格，和相对强度，相对强度大于25％，在Siemens D-500衍射仪上用CuKα辐射测量的，表示的：2θ              d         相对强度
                         (＞25％)4.123         21.4140       49.204.993         17.6832       30.825.768         15.3099       28.697.670         11.5173       25.498.451         10.4538       100.0015.962        5.5478        32.5916.619        5.3298        62.3417.731        4.9981        49.2918.267        4.8526        45.1218.870        4.6989        39.5219.480        4.5531        36.5919.984        4.4393        70.3420.294        4.3722        69.5421.105        4.2061        37.3921.670        4.0976        36.5023.318        3.8117        38.6324.405        3.6442        65.5424.967        3.5635        27.2025.397        3.5041        33.75
2.权利要求1的III型(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基-乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸半钙盐)结晶水合物，其特征在于下述的固态13C核磁共振谱，其中化学位移是在Bruker AX-250波谱仪上测量以每百万分之几表示的：分布                                化学位移自旋侧谱带                          214.8
                                209.3
                                202.3C12或C25                            184.9C12或C25                            166.7C16                                 161.0(弱，宽)原子碳C2-C5，C13-C18，C19-C24，C27-C32    140.1
                                135.2
                                131.8
                                128.9
                                124.3
                                122.2
                                117.2
                                114.9C8，C10                             69.8
                                67.3
                                65.6亚甲基碳C6，C7，C9，C11                     44.1
                                40.4
                                35.4C33                                 27.0
                                24.1C34                                 22.1
                                19.9
3.片剂形式的药物组合物，该组合物含有权利要求1定义的III型(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基-乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸半钙盐结晶水合物以及至少一种可药用赋形剂，稀释剂，或载体。
4.胶囊形式的药物组合物，该组合物含有权利要求1定义的III型(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基-乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸半钙盐结晶水合物以及至少一种惰性可药用赋形剂，稀释剂，或载体。
5.粉剂形式的药物组合物，该组合物含有权利要求1定义的III型(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基-乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸半钙盐结晶水合物以及至少一种惰性可药用赋形剂，稀释剂，或载体。
6.锭剂形式的药物组合物，该组合物含有权利要求1定义的III型(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基-乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸半钙盐结晶水合物以及至少一种惰性可药用赋形剂，稀释剂，或载体。
7.栓剂形式的药物组合物，该组合物含有权利要求1定义的III型(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基-乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸半钙盐结晶水合物以及至少一种惰性可药用赋形剂，稀释剂，或载体。
8.潴留灌肠剂形式的药物组合物，该组合物含有权利要求1定义的III型(R-(R*，R*)-2-(4-氟苯基)-β-δ-二羟基-5-(1-甲基-乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸半钙盐结晶水合物以及至少一种惰性可药用赋形剂，稀释剂，或载体。
CN96195632A 1995-07-17 1996-07-08 (R－(R*,R*)－2－(4－氟苯基)－β－δ－二羟基－5－(1－甲基－乙基)－3－苯基－4－[(苯基氨基)羰基]－1H－吡咯－1－庚酸半钙盐的Ⅲ型结晶 Expired - Lifetime CN1081632C (zh)

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