[go: up one dir, main page]

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

Info

Publication number
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
Authority
CN
China
Prior art keywords
phenyl
fluorophenyl
carbonyl
methyl
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CN96195632A
Other languages
English (en)
Other versions
CN1190957A (zh
Inventor
A·T·麦肯泽
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=21696105&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN1081632(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of CN1190957A publication Critical patent/CN1190957A/zh
Application granted granted Critical
Publication of CN1081632C publication Critical patent/CN1081632C/zh
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US145495P 1995-07-17 1995-07-17
US60/001,454 1995-07-17

Publications (2)

Publication Number Publication Date
CN1190957A CN1190957A (zh) 1998-08-19
CN1081632C true CN1081632C (zh) 2002-03-27

Family

ID=21696105

Family Applications (1)

Application Number Title Priority Date Filing Date
CN96195632A Expired - Lifetime CN1081632C (zh) 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

Country Status (32)

Country Link
US (1) US6121461A (zh)
JP (1) JP3296563B2 (zh)
KR (1) KR100431039B1 (zh)
CN (1) CN1081632C (zh)
AT (1) ATE207465T1 (zh)
AU (1) AU725368B2 (zh)
BG (1) BG63629B1 (zh)
BR (1) BR9610567A (zh)
CA (1) CA2220458C (zh)
CO (1) CO4700442A1 (zh)
CZ (1) CZ294109B6 (zh)
DK (1) DK0848704T3 (zh)
EA (1) EA000505B1 (zh)
EE (1) EE03607B1 (zh)
ES (1) ES2166456T3 (zh)
GE (1) GEP20002028B (zh)
HR (1) HRP960313B1 (zh)
HU (1) HU223598B1 (zh)
ID (1) ID16158A (zh)
IL (3) IL122162A (zh)
MX (1) MX9708857A (zh)
MY (1) MY118398A (zh)
NO (1) NO309899B1 (zh)
NZ (1) NZ312906A (zh)
PE (1) PE1798A1 (zh)
PL (1) PL192244B1 (zh)
RO (1) RO120068B1 (zh)
SK (1) SK284201B6 (zh)
TW (1) TW401399B (zh)
UA (1) UA44796C2 (zh)
WO (1) WO1997003958A1 (zh)
ZA (1) ZA966045B (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103702982A (zh) * 2011-07-01 2014-04-02 中化帝斯曼制药有限公司荷兰公司 阿托伐他汀半钙的超细晶体

Families Citing this family (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI94339C (fi) 1989-07-21 1995-08-25 Warner Lambert Co Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi
CZ294108B6 (cs) 1995-07-17 2004-10-13 Warner@Lambertácompany Krystalická forma I hydrátu atorvastatinuŹ tj@ semivápenaté soli kyseliny [R@}RgŹRgB]@}@fluorfenylB@betaŹdelta@dihydroxy@Q@}�@methylethylB@fenyl[}fenylaminoBkarbonyl]@�H@pyrrol@�@heptanové
US6569461B1 (en) 1999-03-08 2003-05-27 Merck & Co., Inc. Dihydroxy open-acid and salts of HMG-CoA reductase inhibitors
IN191236B (zh) 1999-05-25 2003-10-11 Ranbaxy Lab Ltd
SK286789B6 (sk) * 1999-11-17 2009-05-07 Teva Pharmaceutical Industries Ltd. Kryštalická forma atorvastatínu vápenatého alebo jeho hydrátu, spôsob jej prípravy a farmaceutická kompozícia s jej obsahom
US7411075B1 (en) 2000-11-16 2008-08-12 Teva Pharmaceutical Industries Ltd. Polymorphic form of atorvastatin calcium
SI20425A (sl) 1999-12-10 2001-06-30 LEK tovarna farmacevtskih in kemi�nih izdelkov d.d. Priprava amorfnega atorvastatina
DE60026737T2 (de) 1999-12-17 2006-09-21 Pfizer Science And Technology Ireland Ltd., Dun Laoghaire Verfahren zur herstellung von kristallin atorvastin kalcium
AU776613B2 (en) * 1999-12-17 2004-09-16 Pfizer Science And Technology Ireland Limited A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt
SK6592003A3 (en) * 2000-11-03 2004-01-08 Teva Pharma Atorvastatin hemi-calcium form VII
RU2344127C2 (ru) * 2000-11-30 2009-01-20 Тева Фамэситикл Индастрис Лтд. Новые кристаллические структуры (полиморфные модификации) полукальциевой соли аторвастатина и способы получения этих и других полиморфных модификаций соли аторвастатина
LT5196B (lt) 2000-11-30 2005-02-25 Teva Pharmaceutical Industries Ltd. Naujos atorvastatino pusiau kalcio kristalinės formos ir jų gavimo būdai, taip pat ir nauji kitų formų gavimo būdai
IL156055A0 (en) 2000-11-30 2003-12-23 Teva Pharma Novel crystal forms of atorvastatin hemi calcium and processes for their preparation as well as novel processes for preparing other forms
US7501450B2 (en) * 2000-11-30 2009-03-10 Teva Pharaceutical Industries Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
CZ20032019A3 (cs) 2000-12-27 2003-10-15 Ciba Specialty Chemicals Holding Inc. Krystalické formy Atorvastatinu
US6476235B2 (en) * 2001-01-09 2002-11-05 Warner-Lambert Company Process for the synthesis of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide
EP1734034A3 (en) 2001-01-09 2007-01-03 Warner-Lambert Company LLC Carboxylic acid salts of beta-alanine esters or -amides
WO2002057229A1 (en) 2001-01-19 2002-07-25 Biocon India Limited FORM V CRYSTALLINE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1- HEPTANOIC ACID HEMI CALCIUM SALT. (ATORVASTATIN)
SI20814A (sl) 2001-01-23 2002-08-31 LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. Priprava amorfnega atorvastatina
SI20848A (sl) * 2001-03-14 2002-10-31 Lek, Tovarna Farmacevtskih In Kemijskih Izdelkov, D.D. Farmacevtska formulacija, ki vsebuje atorvastatin kalcij
IL158790A0 (en) 2001-06-29 2004-05-12 Warner Lambert Co Crystalline forms of [r-(*,r*)]-2-(4-fluorophenyl) -beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1h-pyrrole-1-heptanoic acid calcium salt (2:1) (atorvastatin)
AU2002255479B2 (en) * 2001-07-30 2008-09-11 Dr. Reddy's Laboratories Ltd. Crystalline forms VI and VII of atorvastatin clacium
US7074818B2 (en) 2001-07-30 2006-07-11 Dr. Reddy's Laboratories Limited Crystalline forms VI and VII of Atorvastatin calcium
US20030114497A1 (en) * 2001-07-31 2003-06-19 Laman Alani Pharmaceutical compositions of amlodipine and atorvastatin
RU2334738C2 (ru) * 2001-08-03 2008-09-27 Циба Спешиалти Кемикэлз Холдинг Инк. Кристаллические формы
US20060020137A1 (en) * 2001-11-29 2006-01-26 Limor Tessler Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
UA77990C2 (en) * 2001-12-12 2007-02-15 Crystalline calcium salt of (2:1) [r-(r*,r*)]-2-(4-fluorophenyl)-?,?-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrroleheptanic acid
CZ296967B6 (cs) 2002-02-01 2006-08-16 Zentiva, A.S. Zpusob výroby amorfní formy hemivápenaté soli (3R,5R) 7-[3-fenyl-4-fenylkarbamoyl-2-(4-fluorfenyl)-5-isopropylpyrrol-1-yl]-3,5-dihydroxyheptanové kyseliny (atorvastatinu)
PL372303A1 (en) * 2002-02-15 2005-07-11 Teva Pharmaceutical Industries Ltd. Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation, as well as novel processes for preparing atorvastatin hemi-calcium forms i, viii and ix
CA2475123A1 (en) * 2002-02-19 2003-08-28 Teva Pharmaceutical Industries Ltd. Desolvating solvates of atorvastatin hemi-calcium
IL164020A0 (en) * 2002-03-18 2005-12-18 Biocon Ltd A process for the preparation of amorphous hmg-coareductase inhibitors
RU2309141C2 (ru) * 2002-03-18 2007-10-27 Байокон Лимитид АМОРФНЫЕ ИНГИБИТОРЫ ГМГ-КоА-РЕДУКТАЗЫ И СПОСОБ ИХ ПОЛУЧЕНИЯ
ITMI20020907A1 (it) * 2002-04-29 2003-10-29 Chemi Spa Processo di preparazione della forma amorfa del sale di calcio della atorvastatina
PL375415A1 (en) * 2002-08-06 2005-11-28 Warner-Lambert Company Llc Process for preparing 5-(4-fluorophenyl)-1-[2-((2r,4r)-4-hydroxy -6-oxo-tetrahydro-pyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1h-pyrrole-3-carboxylic acid phenylamide
AU2002330735A1 (en) * 2002-09-03 2004-03-29 Morepen Laboratories Limited Atorvastatin calcium form vi or hydrates thereof
SI21302A (sl) * 2002-10-11 2004-04-30 LEK farmacevtska dru�ba d.d. Stabiliziran farmacevtski izdelek z amorfno aktivno učinkovino
HRP20020885B1 (en) * 2002-11-11 2007-05-31 GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. SUBSTITUTED 9a-N-{N'-[4-(SULFONYL)PHENYLCARBAMOYL]}DERIVATIVES 9-DEOXO-9-DIHYDRO-9a-AZA-9a-HOMOERITHROMYCIN A AND 5-O-DESOZAMINYL-9-DEOXO-9-DIHYDRO-9a-AZA-9a-HOMOERITHRONOLIDE A
CA2508871C (en) * 2002-11-28 2008-09-09 Teva Pharmaceutical Industries Ltd. Crystalline form f of atorvastatin hemi-calcium salt
EP1424324A1 (en) * 2002-11-28 2004-06-02 Teva Pharmaceutical Industries Limited Crystalline form F of Atorvastatin hemi-calcium salt
RU2337905C2 (ru) * 2003-04-14 2008-11-10 Уорнер-Ламберт Компани Ллс Способ получения фениламида 5-(4-фторфенил)-1-[2-((2r,4r)-4-гидрокси-6-оксотетрагидропиран-2-ил)этил]-2-изопропил-4-фенил-1h-пиррол-3-карбоновой кислоты
US7790197B2 (en) * 2003-06-09 2010-09-07 Warner-Lambert Company Llc Pharmaceutical compositions of atorvastatin
US20050271717A1 (en) 2003-06-12 2005-12-08 Alfred Berchielli Pharmaceutical compositions of atorvastatin
US7655692B2 (en) * 2003-06-12 2010-02-02 Pfizer Inc. Process for forming amorphous atorvastatin
US20040253305A1 (en) * 2003-06-12 2004-12-16 Luner Paul E. Pharmaceutical compositions of atorvastatin
KR100781420B1 (ko) * 2003-09-17 2007-12-03 워너-램버트 캄파니 엘엘씨 [Ｒ-(Ｒ*,Ｒ*)]-2-(4-플루오로페닐)-β,δ-다이하이드록시-5-(1-메틸에틸)-3-페닐-4-[(페닐아미노)카보닐]-1Ｈ-피롤-1-헵탄산의 결정성 형태
KR100829268B1 (ko) * 2004-04-16 2008-05-13 화이자 프로덕츠 인코포레이티드 비정질 아토바스타틴 칼슘의 제조 방법
JP2007536373A (ja) 2004-05-05 2007-12-13 ファイザー・プロダクツ・インク アトルバスタチンの塩形態
JP5000502B2 (ja) * 2004-07-16 2012-08-15 レツク・フアーマシユーテイカルズ・デー・デー アトルバスタチンカルシウムの酸化分解生成物
BRPI0513422A (pt) 2004-07-20 2008-05-06 Warner Lambert Co formas de sais cálcio do ácido (r-(r*))-2-(4- fluorfenil)-(beta), (sigma)-diidróxi-5-(1-metiletil) -3-fenil-4-((fenilamino) carbonil)-1h-pirrol-1-heptanóico (2:1)
CA2578722C (en) 2004-08-27 2010-02-02 Biocon Limited Process for atorvastatin calcium amorphous
ES2263407T1 (es) * 2004-09-28 2006-12-16 Teva Pharmaceutical Industries Ltd Procedimiento para la preparacion de formas de atorvastatina calcica sustancialmente libres de impurezas.
EP1716114A1 (en) * 2004-10-18 2006-11-02 Teva Pharmaceutical Industries Ltd. Process for preparing amorphous atorvastatin hemi-calcium by dissolving the salt in an organic solvent which is a mixture of an alcohol and a ketone and/or an ester and removing the solvent
AU2005298383A1 (en) * 2004-10-28 2006-05-04 Warner-Lambert Company Llc Process for forming amorphous atorvastatin
WO2006048894A1 (en) * 2004-11-05 2006-05-11 Morepen Laboratories Limited Novel crystalline forms of atorvastatin calcium and processes for preparing them.
WO2006054308A2 (en) 2004-11-22 2006-05-26 Dexcel Pharma Technologies Ltd. Stable atorvastatin formulations
US20090088465A1 (en) * 2004-12-02 2009-04-02 Stephen Craig Dyar Pharmaceutical Compositions of Amorphous Atorvastatin and Process for Preparing Same
GB2424880A (en) * 2005-04-06 2006-10-11 Generics Crystalline forms of atorvastatin sodium, processes for their preparation and their use in inhibiting HMG-CoA reductase
CA2547216A1 (en) 2005-09-21 2007-03-21 Renuka D. Reddy Process for annealing amorphous atorvastatin
ATE466840T1 (de) * 2005-11-21 2010-05-15 Warner Lambert Co Neue formen von är-(r*,r*)ü-2-(4-fluorphenyl)-b,d-dihydroxy-5-( -methylethyl)-3-phenyl-4- ä(phenylamino)carbonylü-1h-pyrrol-1-heptansäure magnesium
CN101370774A (zh) 2005-12-13 2009-02-18 特瓦制药工业有限公司 阿托伐他汀半钙的晶形及其制备方法
EP1810667A1 (en) 2006-01-20 2007-07-25 KRKA, tovarna zdravil, d.d., Novo mesto Pharmaceutical composition comprising amorphous atorvastatin
CA2640573A1 (en) * 2006-03-01 2007-09-13 Michael Pinchasov Process for preparing a crystalline form of atorvastatin hemi-calcium
US20070265456A1 (en) * 2006-05-09 2007-11-15 Judith Aronhime Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
KR100878140B1 (ko) * 2007-01-29 2009-01-12 한미약품 주식회사 아토바스타틴의 스트론튬염 또는 이의 수화물, 및 이를포함하는 약학 조성물
WO2009007856A2 (en) * 2007-07-11 2009-01-15 Actavis Group Ptc Ehf Novel polymorph of atorvastatin calcium and use thereof for the preparation of amorphous atorvastatin calcium
WO2009013633A2 (en) * 2007-07-20 2009-01-29 Actavis Group Ptc Ehf Amorphous coprecipitates of atorvastatin pharmaceutically acceptable salts
DE102007052071A1 (de) 2007-10-30 2009-05-07 Stada Arzneimittel Ag Stabilisiertes Atorvastatin
US20090124817A1 (en) * 2007-11-09 2009-05-14 The Industry & Academic Cooperation In Chungnam National University Process for Preparing Amorphous Atorvastatin Calcium Nanoparticles
US8115015B2 (en) * 2009-01-26 2012-02-14 Cadila Healthcare Limited Process for the preparation of amorphous atorvastatin calcium
CZ201039A3 (cs) 2010-01-19 2011-07-27 Zentiva, K. S Zpusob prumyslové výroby amorfní formy hemivápenaté soli (3R,5R) 7-[3-fenyl-4-fenylkarbamoyl-2-(4-fluorfenyl)-5-isopropylpyrrol-1-yl]-3,5-dihydroxyheptanové kyseliny (atorvastatinu) s vysokým specifickým povrchem a jeho použití v lékové forme
KR20120011249A (ko) 2010-07-28 2012-02-07 주식회사 경보제약 아토바스타틴 헤미칼슘염의 신규한 결정형, 이의 수화물, 및 그의 제조방법
CN102424663B (zh) * 2010-12-03 2013-08-14 天津滨江药物研发有限公司 一种阿托伐他汀氨基酸盐及其制备方法
US9050342B2 (en) 2011-03-29 2015-06-09 Pfizer Inc. Beneficial effects of combination therapy on cholesterol
CN103483238B (zh) * 2013-08-20 2014-12-31 蚌埠丰原医药科技发展有限公司 阿托伐他汀钙三水合物的制备方法
CN106432033B (zh) * 2016-10-21 2018-07-27 江苏阿尔法药业有限公司 一种无定形阿托伐他汀钙的制备方法
KR101723783B1 (ko) 2017-02-24 2017-04-07 주식회사 경보제약 아토바스타틴 헤미칼슘염의 신규한 결정형, 이의 수화물, 및 그의 제조방법
WO2025147589A1 (en) 2024-01-05 2025-07-10 Osanni Bio, Inc. Implants, compositions, and methods for treating retinal diseases and disorders

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0409281A1 (en) * 1989-07-21 1991-01-23 Warner-Lambert Company (R-(R*R*))-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl-3-phenyl-4((phenylamino)-carbonyl)-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof
US5316765A (en) * 1989-09-07 1994-05-31 Karl Folkers Foundation For Biomedical And Clinical Research Use of coenzyme Q10 in combination with HMG-CoA reductase inhibitor therapies
WO1994016693A1 (en) * 1993-01-19 1994-08-04 Warner-Lambert Company Stable oral ci-981 formulation and process of preparing same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE409281C (de) * 1922-04-26 1925-01-31 Farbenfab Vorm Bayer F & Co Verfahren zur Herstellung von sauren Monoazofarbstoffen fuer Wolle

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0409281A1 (en) * 1989-07-21 1991-01-23 Warner-Lambert Company (R-(R*R*))-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl-3-phenyl-4((phenylamino)-carbonyl)-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof
US5316765A (en) * 1989-09-07 1994-05-31 Karl Folkers Foundation For Biomedical And Clinical Research Use of coenzyme Q10 in combination with HMG-CoA reductase inhibitor therapies
WO1994016693A1 (en) * 1993-01-19 1994-08-04 Warner-Lambert Company Stable oral ci-981 formulation and process of preparing same

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103702982A (zh) * 2011-07-01 2014-04-02 中化帝斯曼制药有限公司荷兰公司 阿托伐他汀半钙的超细晶体

Also Published As

Publication number Publication date
ATE207465T1 (de) 2001-11-15
BR9610567A (pt) 1999-07-06
NO309899B1 (no) 2001-04-17
EA000505B1 (ru) 1999-10-28
EA199800129A1 (ru) 1998-08-27
HU223598B1 (hu) 2004-10-28
SK5998A3 (en) 1998-05-06
IL128863A0 (en) 2000-01-31
DK0848704T3 (da) 2002-02-04
TW401399B (en) 2000-08-11
IL122162A0 (en) 1998-04-05
ES2166456T3 (es) 2002-04-16
AU725368B2 (en) 2000-10-12
GEP20002028B (en) 2000-04-10
PL324532A1 (en) 1998-06-08
UA44796C2 (uk) 2002-03-15
JPH11509229A (ja) 1999-08-17
CA2220458C (en) 2002-09-24
IL128863A (en) 2006-09-05
CA2220458A1 (en) 1997-02-06
HRP960313B1 (en) 2002-08-31
MY118398A (en) 2004-10-30
HUP9901687A3 (en) 2000-04-28
NO980208L (no) 1998-01-16
ZA966045B (en) 1997-02-04
RO120068B1 (ro) 2005-08-30
US6121461A (en) 2000-09-19
PL192244B1 (pl) 2006-09-29
CO4700442A1 (es) 1998-12-29
PE1798A1 (es) 1998-03-04
HUP9901687A2 (hu) 1999-10-28
SK284201B6 (sk) 2004-10-05
NZ312906A (en) 2000-12-22
CZ294109B6 (cs) 2004-10-13
CZ12398A3 (cs) 1998-06-17
HK1018053A1 (zh) 1999-12-10
EE9800016A (et) 1998-08-17
BG63629B1 (bg) 2002-07-31
AU6484196A (en) 1997-02-18
EE03607B1 (et) 2002-02-15
ID16158A (id) 1997-09-11
KR100431039B1 (ko) 2004-08-25
JP3296563B2 (ja) 2002-07-02
BG102186A (en) 1998-10-30
KR19990029044A (ko) 1999-04-15
MX9708857A (es) 1998-03-31
CN1190957A (zh) 1998-08-19
HRP960313A2 (en) 1998-04-30
WO1997003958A1 (en) 1997-02-06
IL177378A0 (en) 2006-12-10
NO980208D0 (no) 1998-01-16
IL122162A (en) 1999-07-14

Similar Documents

Publication Publication Date Title
CN1081632C (zh) (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
JP3296564B2 (ja) 結晶性の〔Ｒ−（Ｒ▲上＊▼，Ｒ▲上＊▼）〕−２−（４−フルオロフェニル）−β，δ−ジヒドロキシ−５−（１−メチルエチル）−３−フェニル−４−〔（フェニルアミノ）カルボニル〕−１Ｈ−ピロール−１−ヘプタン酸ヘミカルシウム塩（アトルバスタチン）
JP2003073353A6 (ja) 結晶性の〔Ｒ−（Ｒ＊，Ｒ＊）〕−２−（４−フルオロフェニル）−β，δ−ジヒドロキシ−５−（１−メチルエチル）−３−フェニル−４−〔（フェニルアミノ）カルボニル〕−１Ｈ−ピロール−１−ヘプタン酸ヘミカルシウム塩（アトルバスタチン）
MXPA97009099A (en) Salt hemi calcium of acid [r- (r *, r *,)] - 2- (4-fluorophenyl) -beta, delta-dihydroxy-5- (1-methylthyl) -3-phenyl-4 - [(phenylamine) carbonil] -1h-pirrole-1-heptanoico (atorvastat
CN1190956A (zh) 制备非晶性[R－(R*,R*)]－2－(4－氟苯基)－β,δ－二羟基－5－(1－甲基乙基)－3－苯基－4－[(苯氨基羰基]－1H－吡咯－1－庚酸钙盐(2∶1)的新方法
CN100471836C (zh) 托伐他汀钙晶型vi和vii
EP2426104A1 (en) Tigecycline crystalline form and process for preparation thereof
CN1898211A (zh) 喹啉化合物的晶形及其生产方法
CN1634869A (zh) 普瑞巴林新晶型及其制备方法
TW200844093A (en) Atorvastatin strontium salt and pharmaceutical composition comprising same
EP0848704B1 (en) Form iii crystalline [r-(r*,r*)]-2-(4-fluorophenyl)-beta-delta-dihydroxy-5-(1-methyl-ethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin)
HK1018053B (zh) (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型结晶
CN1852894A (zh) [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] －1 H－吡咯－1－庚酸的结晶形式
CN1827590A (zh) 一种普瑞巴林新晶型、制备方法及其药用组合物
JP2003073354A6 (ja) 形態ＩＩＩの結晶性の（Ｒ−（Ｒ＊，Ｒ＊））−２−（４−フルオロフェニル）−β，δ−ジヒドロキシ−５−（１−メチル−エチル）−３−フェニル−４−（（フェニルアミノ）カルボニル）−１Ｈ−ピロール−１−ヘプタン酸ヘミカルシウム塩（アトルバスタチン）
CN1030229A (zh) 丁烯酸酰胺类及它们的盐类和包含它们的医药组成物及其制备方法
WO2004011413A1 (en) Sertraline

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
EE01 Entry into force of recordation of patent licensing contract

Assignee: Pfizer Pharmaceuticals Limited

Assignor: Vonil Longbow company (Warner - Lambert) Pfizer, Irish medicine

Contract fulfillment period: Contract performance period from January 10, 2006 to January 10, 2009

Contract record no.: Contract filing No. 061000010077

Denomination of invention: The invention relates to an improved method for the synthesis of protected (S) -3, 4-, two hydroxybutyrate, of type III crystals

Granted publication date: 20020327

Record date: 20060818

LIC Patent licence contract for exploitation submitted for record

Free format text: LICENCE; TIME LIMIT OF IMPLEMENTING CONTACT: 2006.1.10 TO 2009.1.10

Name of requester: PFIZER(WARNER-LAMBERT) PHARMACEUTICAL CO., LTD.

Effective date: 20060818

CX01 Expiry of patent term

Granted publication date: 20020327

EXPY Termination of patent right or utility model