CN1092641C - 含取代的吡啶基二羟基庚烯酸或其盐的药物的制法 - Google Patents

含取代的吡啶基二羟基庚烯酸或其盐的药物的制法 Download PDF

Info

Publication number
CN1092641C
CN1092641C CN95106818A CN95106818A CN1092641C CN 1092641 C CN1092641 C CN 1092641C CN 95106818 A CN95106818 A CN 95106818A CN 95106818 A CN95106818 A CN 95106818A CN 1092641 C CN1092641 C CN 1092641C
Authority
CN
China
Prior art keywords
acid
salt
dihydroxy
salts
reaction
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 - Fee Related
Application number
CN95106818A
Other languages
English (en)
Other versions
CN1113485A (zh
Inventor
R·安格包尔
P·费
W·胡什
T·菲利普斯
H·比索夫
D·佩津纳
D·施米特
G·托马斯
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.)
Bayer AG
Original Assignee
Bayer AG
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
Priority claimed from DE4040026A external-priority patent/DE4040026A1/de
Priority claimed from IT002125A external-priority patent/ITMI912125A1/it
Application filed by Bayer AG filed Critical Bayer AG
Publication of CN1113485A publication Critical patent/CN1113485A/zh
Application granted granted Critical
Publication of CN1092641C publication Critical patent/CN1092641C/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Valve Device For Special Equipments (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

取代的吡啶基-二羟基庚烯酸及其盐(必要时为异构体形式)可用以下方法制备：如果要制备外消旋产物，则水解适当的外消旋酯；如果要制备均一的立体异构体产物，则使外消旋酯与对映异构的胺反应，分离非对映体酰胺，然后水解这些酰胺。这些产物具有非常好的药理性质。它们可作为HMC-CoA还原酶抑制剂而用于治疗高脂蛋白血症和动脉硬化。本发明还涉及含有所述化合物的药物产品及其制备方法。

Description

含取代的吡啶基二羟基庚烯酸或其盐的药物的制法
本发明涉及取代的吡啶基-二羟基-庚烯酸、它的盐、它的制备方法、以及它在药物中的应用。
已经有人公开了从真菌培养物中分离出来的某些内酯衍生物是3-羟基-3-甲基-戊二酰辅酶A还原酶(HMC-CoA还原酶)的抑制剂(麦维诺林(mevinolin)；EP 22,478；US-4,231,938)。
此外还了解到，吡啶取代的二羟基庚烯酸是HMC-CoA还原酶的抑制剂(EP 326,130；EP 307,342；EP 306,929)。
现已发现，具有下式的取代的吡啶基-二羟基-庚烯酸及其盐(必要时为异构体形式)，对HMC-CoA还原酶具有优异的抑制作用，因而产生了出人意料好的降低血液中胆固醇含量的作用。
Figure C9510681800031
本发明的取代的吡啶基-二羟基-庚烯酸可以以其盐的形式存在。一般来说，这里可以举出有机碱盐或无机碱盐。
在本发明的文本中，优选生理上可接受的盐。就本发明的取代的吡啶基-二羟基-庚烯酸而言，其生理上可接受的盐可以是金属盐或铵盐。可以举出的优选盐有钠盐、钾盐、镁盐或钙盐，还有由氨或有机胺衍生的铵盐。有机胺的例子有甲胺、乙胺、丙胺、异丙胺、二乙胺或三乙胺、二异丙胺、二乙醇胺或三乙醇胺、二环己胺、精氨酸、赖氨酸或1，2-乙二胺。特别优选的是钠盐和钾盐。
本发明的取代的吡啶基-二羟基-庚烯酸及其盐有两个不对称碳原子，即与羟基键接的两个碳原子。因此可以以各种立体化学形式存在。本发明既涉及单个异构体，也涉及其混合物。这样，根据羟基的相对位置，本发明的物质可以以赤式构型或苏式构型存在：
Figure C9510681800041
赤式
Figure C9510681800042
苏式优选赤式构型。
反过来，两种对映体的存在形式都既有苏式构型，又有赤式构型，即3R，5S-异构体或3S，5R-异构体(赤式)和3R，5R-异构体和3S，5S-异构体(苏式)，其中优选3R，5S/3S，5R外消旋体和3R，5S对映体。
本发明的物质由于具有双键，还可以以E构型或Z构型存在。优选具有E构型的那些化合物。
特别优选的是赤式(E)构型的取代的吡啶基-二羟基-庚烯酸的(+)对映体及其盐。
式(I)的取代的吡啶基-二羟基-庚烯酸及其盐(必要时为异构体形式)的制备方法是：
(A)如果要制备外消旋产物，则水解式(II)的相应外消旋酯，
Figure C9510681800051
其中R1代表C1-C4烷基或苄基；或
(B)如果要制备均一的立体异构体产物，则先用式(III)的(+)或(-)对映异构的胺将式(II)的外消旋酯转化为式(IV)的相应的非对映异构的酰胺，用层析法或结晶法把该非对映异构的酰胺分离成单个非对映体后，再将纯的非对映异构的酰胺水解，得到对映异构纯的产物。
Figure C9510681800061
其中R2代表可被羟基任意取代的C1-C4烷基，R3代表氢、卤素、C1-C4烷基或C1-C4烷氧基。
该方法将以下列反应式举例说明：
Figure C9510681800071
酯(II)的水解反应一般通过在惰性溶剂中用碱处理该酯来进行，一般先形成盐，而后在第二步用酸处理将之转化成游离酸(I)。
合适的酯水解反应的溶剂为水或酯水解反应惯用的有机溶剂。其中优选溶剂包括醇类(如甲醇、乙醇、丙醇、异丙醇或丁醇)或醚类(如四氢呋喃或二噁烷)或二甲基甲酰胺或二甲亚砜。特别优选的是象甲醇、乙醇、丙醇或异丙醇这样一些醇。也可以使用上述溶剂的混合物。
合适的酯水解反应的碱为惯用的无机碱。其中优选的碱包括碱金属氢氧化物或碱土金属氢氧化物(如氢氧化钠、氢氧化钾或氢氧化钡)、或碱金属碳酸盐(如碳酸钠或碳酸钾或碳酸氢钠)、或碱金属醇盐(如乙醇钠、甲醇钠、甲醇钾、乙醇钾、或叔丁醇钾)。特别优选的是氢氧化钠或氢氧化钾。
酯的水解反应一般在-10℃至+100℃，优选+20℃至+80℃的温度范围内进行。
酯水解反应一般在常压下进行。但也可在减压或加压(例如0.5至5巴)下进行。
进行水解反应时，碱的用量相对于1摩尔酯来说一般为1-3摩尔，优选1-5摩尔。特别优选的是使用摩尔量的反应物。
进行水解反应时，第一步形成本发明酸的盐，可以分离出该盐。用惯用无机酸处理该盐就得到了本发明的酸。其中优选的无机酸包括象例如盐酸、氢溴酸、硫酸或磷酸等这样一些无机酸。在这种情况下已经证明，在羧酸制备反应中，在不分离盐的情况下在第二步将由水解反应得到的碱性反应混合物酸化，是有利的。然后可以以惯用方式分离出酸。
酯(II)与对映异构纯的胺(III)反应生成非对映异构的酰胺(IV)的反应一般在惰性溶剂中进行。
适于此目的的溶剂为酰胺化反应惯用的有机溶剂。其中优选的溶剂包括象乙醚、二噁烷或四氢呋喃这样的醚，或者象二氯甲烷或氯仿这样的氯代烃，或者二甲基甲酰胺。但特别优选的是使用过量的相应胺(III)，如果需要则用四氢呋喃或二噁烷作溶剂。
该反应一般在0℃至100℃。优选+20℃至+80℃的温度范围内进行。
该反应一般在常压下进行，但也可在减压或加压下进行。
现已证明，在该反应中，最好是或者直接采用大大过量的胺作溶剂，或者采用最高过量10倍的另一种溶剂进行反应。
非对映异构的酰胺(IV)的水解反应用惯用方法进行，例如，在惰性溶剂中用碱或酸处理该酰胺。
适于此目的的惰性溶剂为水和/或有机溶剂。可以举出的优选有机溶剂是象甲醇、乙醇、丙醇或异丙醇这样的醇，或者象乙醚、二噁烷或四氢呋喃这样的醚。特别优选的是水和水/醇混合物。
适于酰胺水解反应的酸是惯用的无机酸或有机酸。此处优选盐酸、氢溴酸、硫酸和甲磺酸或甲苯磺酸。
适于酰胺水解反应的碱是惯用的无机碱。例如氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、甲醇钾、乙醇钾、碳酸钠或碳酸钾。
在苯乙基酰胺的情况下，酰胺水解反应最好在盐酸乙醇溶液中进行；在苯基氨基乙醇酰胺的情况下，最好用氢氧化钠溶液进行水解，必要时在醇存在下进行。
非对映异构的酰胺(IV)的水解反应一般在0℃至150℃，优选+20℃至+100℃的温度范围内进行。
该酰胺的水解反应一般在常压下进行，但也可在加压或减压下进行。
此外，还可以用惯用的层析方法分离相应的外消旋体来制备对映异构纯的式(I)盐。
作为起始物质使用的胺(III)是已知的，或者可以用本身已知的方法来制备。最好使用本发明中R3代表氢，R2代表甲基或羟甲基的式(III)胺。
非对映异构的酰胺(IV)是新化合物。它们是可用于制备对映异构纯的取代的吡啶基-二羟基-庚烯酸及其盐的中间体。
本发明的取代的吡啶基-二羟基-庚烯酸、它的盐及各种异构形式，具有优于先有技术的有用药理性质，特别是，它们是具有高度活性的3-羟基-3-甲基-戊二酰辅酶A(HMC-CoA)还原酶抑制剂，因此也是胆固醇生物合成的抑制剂。所以，它们可用于治疗高脂蛋白血症或动脉硬化。此外，本发明的活性化合物还能产生降低血液中胆固醇含量的作用。
本发明物质的药理作用用下列试验来确定：
A)用改进的C.C.Ness等人的方法(Archives ofBiochemistry and Biophysics 197：493-499，1979)进行酶活性测定。取雄性Rico大鼠(体重300至400克)，用阿托明(altromin)饲料粉处理11天，每千克饲料中加入了40克消胆胺。断头处死后，从动物体内取出肝脏并置于冰上。将肝脏捣碎，用Potter-Elvejem匀浆器加3倍体积的SPE缓冲液(蔗糖-磷酸盐-乙二胺四乙酸缓冲液，pH 7.2)匀浆三次，缓冲液中含有0.1M蔗糖、0.05M KCl、0.04M KxHy磷酸盐(K2HPO4和KH2PO4的混合物，pH 7.2)、0.03M乙二胺四乙酸、0.002M二硫苏糖醇。然后将匀浆液离心15分钟，弃去沉降物。上清液以100,000g沉降75分钟。将沉淀物悬浮于1/4体积的SPE缓冲液中，再次匀浆，而后再次离心60分钟。将沉淀物悬浮于5倍体积的SPE缓冲液中，匀浆后冷冻，于-70℃贮存(酶溶液)。
测试时，把试验化合物(或作为参比物质的麦维诺林)溶解在二甲基甲酰胺中，同时加入5％(体积)1N NaOH，在酶测试以各种不同的浓度使用，体积为10μl。于37℃下将化合物与酶一起预保温20分钟，然后开始测试。每批测试的体积为0.380ml，其中含有4微摩尔葡萄糖-6-磷酸、1.1mg牛血清清蛋白、2.1微摩尔二硫苏糖醇、0.35微摩尔NADP(β-烟酰胺腺嘌呤二核苷酸磷酸)、1单位葡萄糖-6-磷酸脱氢酶、35微摩尔KxHy磷酸盐(pH 7.2)、20μl酶制备物、56毫微摩尔3-羟基-3-甲基-戊二酰辅酶A(戊二酰-3-14C，100,000dpm)。将该混合物于37℃下保温60分钟，加入300μl 0.25M HCl停止反应。于37℃下后保温60分钟后，将该批反应液离心，取600μl上清液加到装填有粒度为100-200目的5-氯阴离子交换剂的0.7×4cm柱上。用2ml蒸馏水洗柱。将流出液和洗脱液用3ml闪烁液处理，用闪烁计数器计数。画出抑制百分比与试验化合物浓度关系曲线，用内推法确定IC50值。为确定相对抑制效力，将参比物质麦维诺林的IC50值设为100，并与同时测定的试验化合物的IC50值作比较。
B)用持续若干周的饲喂实验测试本发明化合物对狗血液胆固醇值的亚慢性作用。为此，在持续若干周的时间内，将所要研究的物质以胶囊的形式与饲料一起每天给健康比哥猎狗口服一次。在整个实验期间，即，在服用所要研究的物质之前、期间和之后，饲料中还混合有消胆胺(4g/100g饲料)作为棓酸螯合剂。每周从狗体内取静脉血两次，用商品测试试剂盒以酶法测定血清胆固醇。将服用期间的血清胆固醇值与服用期前的血清胆固醇值(对照)作比较。
本发明还包括一些药物制剂，这些制剂除含有惰性无毒药用助剂和赋形剂外还含有一种或多种通式I化合物，或者，这些制剂由一种或多种式I活性化合物组成。本发明还包括制备这些制剂的方法。
这些制剂中式(I)活性化合物的浓度按混合物总重量计应为0.1-99.5％，优选0.5-95％。
除式(I)活性化合物外，这些药物制剂还可含有其他活性药物化合物。
上述药物制剂可以用已知方法以惯用方式制备，例如使用助剂或赋形剂。
一般来说，已经证明，式(I)活性化合物的总服用量最好为每24小时每千克体重约0.1-100μg，优选1-50μg，适当的话，可以若干单个剂量的形式服用，以达到所希望的效果。
然而，偏离上述剂量也可能是有利的，具体来说这取决于治疗对象的种属和体重、对药物的个体反应、疾病的本质和严重程度、制剂类型和服药方式、以及服药时间或间隔。
                        实施例1
3R，5S-(+)-赤式-(E)-7-〔4-(4-氟苯基)-2，6-二异丙基-5-甲氧基甲基-吡啶-3-基〕-3，5-二羟基庚-6-烯酸钠
Figure C9510681800131
和
            实施例2
3S，5R-(-)-赤式-(E)-7-〔4-(4-氟苯基)-2，6-二异丙基-5-甲氧基甲基-吡啶-3-基〕-3，5-二羟基庚-6-烯酸钠方法变式A：用R-(+)-苯乙胺进行外消旋体分离a)非对映异构的苯乙基酰胺的制备和分离
                        非对映异构体A1
                        非对映异构体B1
将4.7g(10毫摩尔)赤式-(E)-4-(4-氟苯基)-2，6-二异丙基-5-甲氧基甲基吡啶-3-基〕-3，5-二羟基庚-6-烯酸甲酯溶于20ml R-(+)苯乙胺中，于40℃下加热72小时。将该反应液倒入150ml水中，用1N盐酸将溶液调至pH4。然后用乙醚萃取几次。合并有机萃取液，用饱和氯化钠溶液洗涤，用硫酸镁干燥，浓缩。在63-200μ硅胶上预纯化后(洗脱剂为乙酸乙酯/石油醚4∶6→6∶4)，将残留物置于预先装填好的15μ硅胶柱上进行分离(洗脱剂为乙酸乙酯/石油醚1∶1)。
产量：2.1g非对映体A1(理论值的37.4％)
      1.5g非对映体B1(理论值的26.6％)
b)对映异构纯钠盐(实施例1/2)的制备
将2.1g(3.7毫摩尔)非对映体A1溶解在70ml 15％乙醇中，加入13ml 1N盐酸后，加热回流48小时。冷却后，滤掉上清液，残余物加乙醇搅拌几次。合并乙醇溶液并浓缩，将残余物溶于50ml水和50ml二氯甲烷中。用1N盐酸将溶液的pH调至3.5，然后用二氯甲烷萃取该溶液几次。合并有机溶液，用硫酸钠干燥，浓缩。将残余物溶于50ml四氢呋喃/水(1∶1)中，用1N氢氧化钠溶液将溶液的pH调至7.5。用旋转蒸发器蒸发四氢呋喃，剩余的水溶液进行冰冻干燥。粗制冻干物在RP18上进行纯化(洗脱剂∶乙腈/水30∶70)。将各产物级分冰冻干燥后，得到850mg(理论值的48％)(+)一对映异构体钠盐(实施例1)
1H-NMR(DMSO-d6)：δ(ppm)＝1.0(m，1H)；1.23(d，
6H)；1.28(d，6H)；1.3(m，1H)；1.75(dd，1H)；1.98
(dd，1H)；3.07(s，3H)；3.2-3.4(m，3H)；3.52(m，
1H)；4.02(m，2H)；5.28(dd，1H)；6.17(d，1H)；7.1-
7.3(m，4H).
            比旋(EtOH)：[α]D 20＝24.1°(c＝1.0).
如上所述由1.5g(2.6毫摩尔)非对映体B1制得800mg(理论值的61.5％)(-)-对映异构体钠盐(实施例2)。
比旋(EtOH)：[α]D 20＝-23.2°(c＝1.0).方法变式B：用S-(+)-苯基氨基乙醇进行外消旋体分离a)非对映异构的苯基氨基乙醇酰胺的制备
Figure C9510681800161
                            非对映体A2
                            非对映体B2
将418g(0.88摩尔)赤式-(E)-7-〔4-(4-氟苯基)-2，6-二异丙基-5-甲氧基甲基吡啶-3-基〕-3，5-二羟基庚-6-烯酸甲酯和360g(2.6摩尔)S-(+)-苯基氨基乙醇溶于1升无水四氢呋喃中，将该混合物于50℃下加热96小时。冷却至室温后，加入1升水，用5N盐酸将溶液的pH调至4，用乙醚萃取3次，每次用400ml乙醚。合并有机相，用400ml饱和氯化钠溶液洗涤，用硫酸钠干燥，用旋转蒸发器浓缩。将残余物(500g粗产物)在层析柱(每次操作用约1.8kg硅胶)上预分离为两部分(洗脱剂为乙酸乙酯/石油醚8∶2)。由此得到350g经过预纯化的粗产物，该产物几乎完全由两种非对映异构的酰胺组成。将经过预纯化的粗产物在硅胶柱(Büchi柱，长63cm，直径7cm，20μ硅胶，经100ml样品环管加样)上分离成7份，每份50g。得到195g(理论值的38.2％)非对映体A2。未分离出纯的非对映体B2，只在洗涤硅胶柱时回收到其粗产物，该粗产物可供以后使用。
b)对映异构纯钠盐(实施例1/2)的制备
将195g(0.34摩尔)非对映异构纯的酰胺A2溶解在1升乙醇(p.A.)中，加入1.2升1N氢氧化钠溶液后，将该混合物加热回流过夜。冷却至室温后，倾出上清液，油状残留物用无水乙醇搅拌3次，每次用50ml乙醇(p.A.)。将这些溶液合并并浓缩。将残余物溶于500ml水和500ml二氯甲烷中，用1N盐酸将溶液的pH调至3.5。然后分离出有机相，水相用二氯甲烷萃取3次，每次用400ml二氯甲烷。合并有机相，干燥(Na2SO4)后浓缩。将残余物溶解于100ml  四氢呋喃中，用500ml水稀释该溶液。然后用1N氢氧化钠溶液调至pH7.5，用旋转蒸发器蒸除四氢呋喃，留下的水溶液进行冰冻干燥。
得到142g粗制冰冻干燥物，为使其脱盐，在RP 18柱(长40cm，直径3cm，RP 18硅胶，30μ，洗脱剂为乙腈/水30∶70)上分批进行进一步纯化和脱盐，其中每份5g的27份，每份3.5g的2份。合并所有产物级分，用旋转蒸发器蒸除乙腈，含水残留物进行冰冻干燥，得到102g(理论值的62.5％)(+)-对映异构体钠盐(实施例1)。

Claims (4)

1.制备含有下式的取代的吡啶基二羟基庚烯酸的钠盐的药物组合物的方法，所述方法包括借助惯用的助剂将其中所述的化合物转化成适宜的给药形式，其中如果必要所述化合物可以是其异构体。
2.根据权利要求1的方法，其中所述化合物以赤式构型存在。
3.根据权利要求1的方法，其中所述化合物为其(+)对映体。
4.根据权利要求1的方法，其中所述化合物为其(+)对映体，它以赤式构型存在。
CN95106818A 1990-12-14 1995-05-26 含取代的吡啶基二羟基庚烯酸或其盐的药物的制法 Expired - Fee Related CN1092641C (zh)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE4040026A DE4040026A1 (de) 1990-12-14 1990-12-14 Substituierte pyridyl-dihydroxy-heptensaeure und deren salze
DEP4040026.3 1990-12-14
ITMI91A002125 1991-07-31
ITMI91A0021* 1991-07-31
IT002125A ITMI912125A1 (it) 1991-07-31 1991-07-31 Acidi piridil-diidrossi-eptenoici sostituiti e loro sali

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN91107973A Division CN1034073C (zh) 1990-12-14 1991-12-14 取代的吡啶基－二羟基o庚烯酸的钠盐的制法

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN00127089A Division CN1329888A (zh) 1990-12-14 2000-09-08 含取代的吡啶基二羟基庚烯酸或其盐的药物的制法

Publications (2)

Publication Number Publication Date
CN1113485A CN1113485A (zh) 1995-12-20
CN1092641C true CN1092641C (zh) 2002-10-16

Family

ID=25899340

Family Applications (3)

Application Number Title Priority Date Filing Date
CN91107973A Expired - Fee Related CN1034073C (zh) 1990-12-14 1991-12-14 取代的吡啶基－二羟基o庚烯酸的钠盐的制法
CN95106818A Expired - Fee Related CN1092641C (zh) 1990-12-14 1995-05-26 含取代的吡啶基二羟基庚烯酸或其盐的药物的制法
CN00127089A Pending CN1329888A (zh) 1990-12-14 2000-09-08 含取代的吡啶基二羟基庚烯酸或其盐的药物的制法

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN91107973A Expired - Fee Related CN1034073C (zh) 1990-12-14 1991-12-14 取代的吡啶基－二羟基o庚烯酸的钠盐的制法

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN00127089A Pending CN1329888A (zh) 1990-12-14 2000-09-08 含取代的吡啶基二羟基庚烯酸或其盐的药物的制法

Country Status (26)

Country Link
US (1) US5177080A (zh)
EP (1) EP0491226B1 (zh)
JP (1) JP2786363B2 (zh)
KR (1) KR100192625B1 (zh)
CN (3) CN1034073C (zh)
AT (1) ATE141261T1 (zh)
AU (1) AU652977B2 (zh)
CA (1) CA2057444C (zh)
CZ (1) CZ282642B6 (zh)
DE (1) DE59108081D1 (zh)
DK (1) DK0491226T3 (zh)
ES (1) ES2091852T3 (zh)
FI (1) FI101069B (zh)
GR (1) GR3020826T3 (zh)
HK (1) HK1004552A1 (zh)
HU (2) HU221293B1 (zh)
IE (1) IE75691B1 (zh)
IL (1) IL100327A (zh)
LU (1) LU90230I2 (zh)
MY (1) MY107492A (zh)
NL (1) NL970033I1 (zh)
NO (2) NO177140C (zh)
NZ (1) NZ240946A (zh)
PL (1) PL169757B1 (zh)
PT (1) PT99776B (zh)
SK (1) SK280115B6 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8114328B2 (en) 2001-09-28 2012-02-14 Mcneil-Ppc, Inc. Method of coating a dosage form comprising a first medicant

Families Citing this family (230)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5506219A (en) * 1988-08-29 1996-04-09 E. R. Squibb & Sons, Inc. Pyridine anchors for HMG-CoA reductase inhibitors
DE4243279A1 (de) 1992-12-21 1994-06-23 Bayer Ag Substituierte Triole
DE4244029A1 (de) * 1992-12-24 1994-06-30 Bayer Ag Neue substituierte Pyridine
DE4309553A1 (de) * 1993-03-24 1994-09-29 Bayer Ag Verfahren zur Herstellung von 3R,5S-(+)-Natrium-erythro-(E)-7-(4-(4-flurophenyl)-2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl)-3,5-dihydroxy-hept-6-enoat
DE69527684T2 (de) * 1994-09-06 2002-11-28 Ube Industries Herstellung von 3-oxy-5-oxo-6-Heptensäurederivaten
PT902777E (pt) 1996-04-16 2001-11-30 Bayer Ag D-manitol e sua preparacao
DE19627420A1 (de) * 1996-07-08 1998-01-15 Bayer Ag 6-(Hydroxymethyl-ethyl)pyridine
DE19714343A1 (de) 1997-04-08 1998-10-15 Bayer Ag Chromatographische Enantiomerentrennung von Lactonen
US20060141036A1 (en) * 1997-12-12 2006-06-29 Andrx Labs Llc HMG-CoA reductase inhibitor extended release formulation
US20030078211A1 (en) * 1998-06-24 2003-04-24 Merck & Co., Inc. Compositions and methods for inhibiting bone resorption
EP1088333A4 (en) 1998-06-24 2005-08-10 Merck & Co Inc METHOD AND COMPOSITIONS FOR CONNECTING OSTEOPROSIS
DE19858789A1 (de) 1998-12-18 2000-06-21 Bayer Ag Kombination von Cerivastatin und Fibraten
US6569461B1 (en) 1999-03-08 2003-05-27 Merck & Co., Inc. Dihydroxy open-acid and salts of HMG-CoA reductase inhibitors
GB0003305D0 (en) * 2000-02-15 2000-04-05 Zeneca Ltd Pyrimidine derivatives
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
CA2406383A1 (en) * 2000-04-13 2001-10-25 Mayo Foundation For Medical Education And Research A.beta.42 lowering agents
US6627636B2 (en) 2000-06-15 2003-09-30 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US20020013334A1 (en) * 2000-06-15 2002-01-31 Robl Jeffrey A. HMG-CoA reductase inhibitors and method
US6620821B2 (en) 2000-06-15 2003-09-16 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US6812345B2 (en) 2000-06-15 2004-11-02 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
JO2654B1 (en) * 2000-09-04 2012-06-17 شركة جانسين فارماسوتيكا ان. في Multiple aryl caroxa amides are useful as lipid - lowering agents
US20030162829A1 (en) * 2000-10-06 2003-08-28 George Kindness Combination of treatment of cancer utilizing a COX-2 inhibitor and a 3-hydroxy-3-methylglutaryl-coenzyme-a (HMG-CoA) reductase inhibitor
US6534540B2 (en) 2000-10-06 2003-03-18 George Kindness Combination and method of treatment of cancer utilizing a COX-2 inhibitor and a 3-hydroxy-3-methylglutaryl-coenzyme-a (HMG-CoA) reductase inhibitor
ATE401886T1 (de) * 2000-10-12 2008-08-15 Nissan Chemical Ind Ltd Wirkstoffe zur vorbeugung und behandlung von komplikationen im zusammenhang mit diabetes
US6777552B2 (en) * 2001-08-16 2004-08-17 Teva Pharmaceutical Industries, Ltd. Processes for preparing calcium salt forms of statins
JO2409B1 (en) 2000-11-21 2007-06-17 شركة جانسين فارماسوتيكا ان. في Second-phenyl carboxy amides are useful as lipid-lowering agents
EP1345903A1 (en) * 2000-12-21 2003-09-24 Ciba SC Holding AG Crystalline forms of cerivastatin sodium
JO2390B1 (en) 2001-04-06 2007-06-17 شركة جانسين فارماسوتيكا ان. في Diphenylcarboxamides act as lipid-lowering agents
JP2004536047A (ja) 2001-04-11 2004-12-02 ブリストル−マイヤーズ　スクイブ　カンパニー 糖尿病処置用ｃ−アリールグルコシドのアミノ酸複合体および方法
WO2002085382A1 (en) * 2001-04-18 2002-10-31 Genzyme Corporation Methods of treating syndrome x with aliphatic polyamines
US20040092565A1 (en) * 2001-07-25 2004-05-13 George Kindness Composition and method of sustaining chemotherapeutic effect while reducing dose of chemotherapeutic agent using cox-2 inhibitor and statin
PL377687A1 (pl) * 2001-10-18 2006-02-06 Bristol-Myers Squibb Company Środki naśladujące ludzki peptyd glukagonopodobny typu 1 i ich zastosowanie w leczeniu cukrzycy i stanów związanych z cukrzycą
US7238671B2 (en) * 2001-10-18 2007-07-03 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US6806381B2 (en) * 2001-11-02 2004-10-19 Bristol-Myers Squibb Company Process for the preparation of aniline-derived thyroid receptor ligands
AU2002348276A1 (en) * 2001-11-16 2003-06-10 Bristol-Myers Squibb Company Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein
US6831102B2 (en) * 2001-12-07 2004-12-14 Bristol-Myers Squibb Company Phenyl naphthol ligands for thyroid hormone receptor
US7482366B2 (en) 2001-12-21 2009-01-27 X-Ceptor Therapeutics, Inc. Modulators of LXR
ES2421511T3 (es) * 2001-12-21 2013-09-03 X Ceptor Therapeutics Inc Moduladores de LXR
WO2003060078A2 (en) * 2001-12-21 2003-07-24 X-Ceptor Therapeutics, Inc. Heterocyclic modulators of nuclear receptors
AU2003217676B2 (en) 2002-02-22 2009-06-11 Takeda Pharmaceutical Company Limited Active agent delivery systems and methods for protecting and administering active agents
US20050113577A1 (en) * 2002-04-16 2005-05-26 Karki Shyam B. Solid forms of slats with tyrosine kinase activity
DE10216967A1 (de) * 2002-04-16 2003-11-13 Bayer Ag Verfahren zur Herstellung spezieller aromatischer Aldehyde
US6747048B2 (en) 2002-05-08 2004-06-08 Bristol-Myers Squibb Company Pyridine-based thyroid receptor ligands
EP1504525A2 (de) * 2002-05-14 2005-02-09 Siemens Aktiengesellschaft Verfahren zum erzeugen eines sendesignals
US7057046B2 (en) * 2002-05-20 2006-06-06 Bristol-Myers Squibb Company Lactam glycogen phosphorylase inhibitors and method of use
CA2488498A1 (en) 2002-06-10 2003-12-18 Elan Pharma International Limited Nanoparticulate polycosanol formulations and novel polycosanol combinations
JP2006506464A (ja) * 2002-07-23 2006-02-23 ニュートリノヴァ ニュートリション スペシャリティーズ アンド フード イングリーディエンツ ゲゼルシャフト ミット ベシュレンクテル ハフツング 食事性繊維およびコレステロール低下物質で造られたコレステロール低下剤
UA79300C2 (en) 2002-08-12 2007-06-11 Janssen Pharmaceutica Nv N-aryl piperidine substituted biphenylcarboxamides as inhibitors of apolipoprotein b secretion
US20080293750A1 (en) * 2002-10-17 2008-11-27 Anna Helgadottir Susceptibility Gene for Myocardial Infarction, Stroke, Paod and Methods of Treatment
WO2004037181A2 (en) * 2002-10-23 2004-05-06 Bristol-Myers Squibb Company Glycinenitrile-based inhibitors of dipeptidyl peptidase iv and methods
US7098235B2 (en) 2002-11-14 2006-08-29 Bristol-Myers Squibb Co. Triglyceride and triglyceride-like prodrugs of glycogen phosphorylase inhibiting compounds
US20040110241A1 (en) * 2002-12-06 2004-06-10 Segal Mark S. Materials and methods for monitoring vascular endothelial function
US20040132771A1 (en) * 2002-12-20 2004-07-08 Pfizer Inc Compositions of choleseteryl ester transfer protein inhibitors and HMG-CoA reductase inhibitors
AU2003283769A1 (en) 2002-12-20 2004-07-14 Pfizer Products Inc. Dosage forms comprising a cetp inhibitor and an hmg-coa reductase inhibitor
DE10261061A1 (de) * 2002-12-24 2004-07-15 Nutrinova Nutrition Specialties & Food Ingredients Gmbh Diätetisches Lebensmittel zur positiven Beeinflussung der kardiovaskulären Gesundheit
DE10261067A1 (de) * 2002-12-24 2004-08-05 Nutrinova Nutrition Specialties & Food Ingredients Gmbh Cholesterinsenkendes Mittel, enthaltend eine n-3-Fettsäure
TW200504021A (en) * 2003-01-24 2005-02-01 Bristol Myers Squibb Co Substituted anilide ligands for the thyroid receptor
EP1603548A4 (en) * 2003-02-05 2007-10-10 Myriad Genetics Inc COMPOSITION AND METHOD FOR TREATING NEURODEGENERATIVE DISORDERS
US20040186046A1 (en) * 2003-03-17 2004-09-23 Pfizer Inc Treatment of type 1 diabetes with PDE5 inhibitors
US20040254238A1 (en) * 2003-04-07 2004-12-16 Osteoscreen Bone growth stimulation with NO/statin and other NO modulating combinations
US7557143B2 (en) 2003-04-18 2009-07-07 Bristol-Myers Squibb Company Thyroid receptor ligands
US7459474B2 (en) * 2003-06-11 2008-12-02 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor and method
DE602004018494D1 (de) * 2003-06-18 2009-01-29 Teva Pharma Fluvastatin-natrium in der kristallform xiv, verfahren zu deren herstellung, diese enthaltende zusammensetzungen und enstprechende anwendungsverfahren
US7368468B2 (en) * 2003-06-18 2008-05-06 Teva Pharmaceutical Industries Ltd. Fluvastatin sodium crystal forms XIV, LXXIII, LXXIX, LXXX and LXXXVII, processes for preparing them, compositions containing them and methods of using them
US20050042284A1 (en) * 2003-07-11 2005-02-24 Myriad Genetics, Incorporated Pharmaceutical methods, dosing regimes and dosage forms for the treatment of Alzheimer's disease
US6995183B2 (en) 2003-08-01 2006-02-07 Bristol Myers Squibb Company Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
WO2005019161A1 (en) 2003-08-21 2005-03-03 Merck Frosst Canada Ltd. Cathepsin cysteine protease inhibitors
WO2005023778A2 (en) * 2003-08-28 2005-03-17 Teva Pharmaceutical Industries Ltd. Process for preparation of rosuvastatin calcium
RU2358734C2 (ru) * 2003-08-29 2009-06-20 Кова Ко., Лтд. Способ стабилизации бляшки с высоким содержанием липидов и способ профилактики ее разрушения
US20050171207A1 (en) * 2003-09-26 2005-08-04 Myriad Genetics, Incorporated Method and composition for combination treatment of neurodegenerative disorders
US7576121B2 (en) * 2003-11-12 2009-08-18 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
KR100918322B1 (ko) * 2003-11-12 2009-09-22 페노믹스 코포레이션 헤테로시클릭 보론산 화합물
US7767828B2 (en) * 2003-11-12 2010-08-03 Phenomix Corporation Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7317109B2 (en) * 2003-11-12 2008-01-08 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
EP2428516A1 (en) 2003-11-19 2012-03-14 Metabasis Therapeutics, Inc. Novel phosphorus-containing thyromimetics
TW200526596A (en) * 2003-11-24 2005-08-16 Teva Pharma Crystalline ammonium salts of rosuvastatin
US8415364B2 (en) * 2003-11-26 2013-04-09 Duke University Method of preventing or treating glaucoma
EP1689723B1 (en) * 2003-12-02 2011-04-27 Teva Pharmaceutical Industries, Ltd. Reference standard for characterization of rosuvastatin
KR20060135712A (ko) * 2003-12-24 2006-12-29 테바 파마슈티컬 인더스트리즈 리미티드 높은 ｓｙｎ형 대 ａｎｔｉ형 비율을 지닌 스타틴의 제조방법
US20070179166A1 (en) * 2003-12-24 2007-08-02 Valerie Niddam-Hildesheim Process for preparation of statins with high syn to anti ratio
US7851624B2 (en) * 2003-12-24 2010-12-14 Teva Pharamaceutical Industries Ltd. Triol form of rosuvastatin and synthesis of rosuvastatin
US20070161700A1 (en) * 2004-12-28 2007-07-12 Kowa Company, Ltd. Inhibitor for the formation of y-secretase complex
EP1559419A1 (en) * 2004-01-23 2005-08-03 Fournier Laboratories Ireland Limited Pharmaceutical formulations comprising metformin and a fibrate, and processes for their obtention
US20100216863A1 (en) * 2004-01-30 2010-08-26 Decode Genetics Ehf. Susceptibility Gene for Myocardial Infarction, Stroke, and PAOD; Methods of Treatment
US8158362B2 (en) * 2005-03-30 2012-04-17 Decode Genetics Ehf. Methods of diagnosing susceptibility to myocardial infarction and screening for an LTA4H haplotype
EP1563837A1 (en) * 2004-02-03 2005-08-17 Ferrer Internacional, S.A. Hypocholesterolemic compositions comprising a statin and an antiflatulent agent
US8309574B2 (en) * 2004-02-25 2012-11-13 Kowa Company, Ltd. Nuclear transfer promoter for Rac protein and method of screening the same
JP4728226B2 (ja) 2004-02-25 2011-07-20 興和株式会社 Ｃｄｃ４２タンパク質の核内移行促進剤及びそのスクリーニング方法
US20060211752A1 (en) 2004-03-16 2006-09-21 Kohn Leonard D Use of phenylmethimazoles, methimazole derivatives, and tautomeric cyclic thiones for the treatment of autoimmune/inflammatory diseases associated with toll-like receptor overexpression
WO2006001877A2 (en) * 2004-04-13 2006-01-05 Myriad Genetics, Inc. Combination treatment for neurodegenerative disorders comprising r-flurbiprofen
CN1946906A (zh) * 2004-04-29 2007-04-11 吉斯通护岸系统股份有限公司 用于墙、护墙和类似物的饰面
CA2568542A1 (en) * 2004-05-27 2005-12-08 Dexcel Pharma Technologies Ltd. Localized controlled absorption of statins in the gastrointestinal tract for achieving high blood levels of statins
UA87854C2 (en) 2004-06-07 2009-08-25 Мерк Энд Ко., Инк. N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators
TW200611704A (en) * 2004-07-02 2006-04-16 Bristol Myers Squibb Co Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions
US7534763B2 (en) 2004-07-02 2009-05-19 Bristol-Myers Squibb Company Sustained release GLP-1 receptor modulators
US7145040B2 (en) * 2004-07-02 2006-12-05 Bristol-Myers Squibb Co. Process for the preparation of amino acids useful in the preparation of peptide receptor modulators
EP1778220A1 (en) * 2004-07-12 2007-05-02 Phenomix Corporation Constrained cyano compounds
WO2006017357A1 (en) * 2004-07-13 2006-02-16 Teva Pharmaceutical Industries Ltd. A process for the preparation of rosuvastatin involving a tempo-mediated oxidation step
US7572805B2 (en) 2004-07-14 2009-08-11 Bristol-Myers Squibb Company Pyrrolo(oxo)isoquinolines as 5HT ligands
BRPI0513082A (pt) * 2004-08-06 2008-04-22 Transform Pharmaceuticals Inc formulações de fenofibrato e métodos de tratamento relacionados
US7642287B2 (en) * 2004-08-06 2010-01-05 Transform Pharmaceuticals, Inc. Statin pharmaceutical compositions and related methods of treatment
US20090042979A1 (en) * 2004-08-06 2009-02-12 Transform Pharmaceuticals Inc. Novel Statin Pharmaceutical Compositions and Related Methods of Treatment
CA2618985A1 (en) * 2004-08-11 2006-02-23 Myriad Genetics, Inc. Pharmaceutical composition and method for treating neurodegenerative disorders
WO2006020850A2 (en) * 2004-08-11 2006-02-23 Myriad Genetics, Inc. Pharmaceutical composition and method for treating neurodegenerative disorders
WO2006020852A2 (en) * 2004-08-11 2006-02-23 Myriad Genetics, Inc. Pharmaceutical composition and method for treating neurodegenerative disorders
AR051446A1 (es) * 2004-09-23 2007-01-17 Bristol Myers Squibb Co Glucosidos de c-arilo como inhibidores selectivos de transportadores de glucosa (sglt2)
US7517991B2 (en) * 2004-10-12 2009-04-14 Bristol-Myers Squibb Company N-sulfonylpiperidine cannabinoid receptor 1 antagonists
CA2584740A1 (en) * 2004-10-19 2006-04-27 Cargill, Incorporated Meat systems
EP1817010A4 (en) * 2004-11-22 2009-06-17 Dexcel Pharma Technologies Ltd CONTROLLED ABSORPTION OF STATINS IN THE INTESTINE
BRPI0518874A2 (pt) 2004-12-09 2008-12-16 Merck & Co Inc composto, composiÇço farmacÊutica, e, usos de um composto, e de uma composiÇço
TW200619204A (en) * 2004-12-10 2006-06-16 Kowa Co Method for reduction, stabilization and prevention of rupture of lipid rich plaque
US7635699B2 (en) * 2004-12-29 2009-12-22 Bristol-Myers Squibb Company Azolopyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US7589088B2 (en) * 2004-12-29 2009-09-15 Bristol-Myers Squibb Company Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US7314882B2 (en) * 2005-01-12 2008-01-01 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
WO2006076568A2 (en) 2005-01-12 2006-07-20 Bristol-Myers Squibb Company Thiazolopyridines as cannabinoid receptor modulators
WO2006076597A1 (en) * 2005-01-12 2006-07-20 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
US20060160850A1 (en) * 2005-01-18 2006-07-20 Chongqing Sun Bicyclic heterocycles as cannabinoid receptor modulators
ES2319461T3 (es) * 2005-02-10 2009-05-07 Bristol-Myers Squibb Company Dihidroquinazolinonas como moduladores de 5ht.
US20070167625A1 (en) * 2005-02-22 2007-07-19 Anna Balanov Preparation of rosuvastatin
US20070037979A1 (en) * 2005-02-22 2007-02-15 Valerie Niddam-Hildesheim Preparation of rosuvastatin
WO2006091771A2 (en) * 2005-02-22 2006-08-31 Teva Pharmaceutical Industries Ltd. Preparation of rosuvastatin
US20070293535A1 (en) * 2005-02-24 2007-12-20 Kowa Company, Ltd. Nuclear Transfer Promoter for Ddc42 Protein and Method of Screening the Dame
CA2599572A1 (en) 2005-03-02 2007-04-26 Merck & Co., Inc. Composition for inhibition of cathepsin k
CA2603105A1 (en) * 2005-03-28 2006-10-05 Dexcel Pharma Technologies Ltd. Controlled absorption of statins in the intestine
EP1879881A2 (en) 2005-04-14 2008-01-23 Bristol-Myers Squibb Company Inhibitors of 11-beta hydroxysteroid dehydrogenase type i
EP1888050B1 (en) 2005-05-17 2012-03-21 Merck Sharp & Dohme Ltd. cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanepropanoic acid for the treatment of cancer
US7521557B2 (en) 2005-05-20 2009-04-21 Bristol-Myers Squibb Company Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods
US7825139B2 (en) * 2005-05-25 2010-11-02 Forest Laboratories Holdings Limited (BM) Compounds and methods for selective inhibition of dipeptidyl peptidase-IV
CN101282991A (zh) * 2005-05-26 2008-10-08 布里斯托尔-迈尔斯斯奎布公司 N-端修饰的胰高血糖素样肽-1受体调节剂
US7632837B2 (en) * 2005-06-17 2009-12-15 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid-1 receptor modulators
US20060287342A1 (en) * 2005-06-17 2006-12-21 Mikkilineni Amarendra B Triazolopyrimidine heterocycles as cannabinoid receptor modulators
US7629342B2 (en) * 2005-06-17 2009-12-08 Bristol-Myers Squibb Company Azabicyclic heterocycles as cannabinoid receptor modulators
US7452892B2 (en) * 2005-06-17 2008-11-18 Bristol-Myers Squibb Company Triazolopyrimidine cannabinoid receptor 1 antagonists
US7572808B2 (en) * 2005-06-17 2009-08-11 Bristol-Myers Squibb Company Triazolopyridine cannabinoid receptor 1 antagonists
US7317012B2 (en) * 2005-06-17 2008-01-08 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoind-1 receptor modulators
CA2615063A1 (en) * 2005-07-22 2007-02-01 Myriad Genetics, Inc. High drug load formulations and dosage forms
CA2617102A1 (en) * 2005-07-28 2007-02-08 Bristol-Myers Squibb Company Substituted tetrahydro-1h-pyrido[4,3,b]indoles as serotonin receptor agonists and antagonists
AU2006278444A1 (en) * 2005-08-04 2007-02-15 Transform Pharmaceuticals, Inc. Novel formulations comprising fenofibrate and a statin, and related methods of treatment
WO2007022488A2 (en) * 2005-08-16 2007-02-22 Teva Pharmaceutical Industries Ltd. Crystalline rosuvastatin intermediate
US7795436B2 (en) * 2005-08-24 2010-09-14 Bristol-Myers Squibb Company Substituted tricyclic heterocycles as serotonin receptor agonists and antagonists
EP1919393A2 (en) * 2005-09-01 2008-05-14 Prescient Medical, Inc. Drugs coated on a device to treat vulnerable plaque
US20080139457A1 (en) * 2005-09-16 2008-06-12 Virginia Commonwealth University Therapeutic compositions comprising chorionic gonadotropins and HMG CoA reductase inhibitors
DE102005049293A1 (de) * 2005-10-15 2007-04-26 Bayer Healthcare Ag Kombinationspräparate von Salzen oder o-Acetylsalicylsäure
US7741317B2 (en) 2005-10-21 2010-06-22 Bristol-Myers Squibb Company LXR modulators
US8618115B2 (en) * 2005-10-26 2013-12-31 Bristol-Myers Squibb Company Substituted thieno[3,2-d]pyrimidinones as MCHR1 antagonists and methods for using them
US7488725B2 (en) 2005-10-31 2009-02-10 Bristol-Myers Squibb Co. Pyrrolidinyl beta-amino amide-based inhibitors of dipeptidyl peptidase IV and methods
US7888376B2 (en) 2005-11-23 2011-02-15 Bristol-Myers Squibb Company Heterocyclic CETP inhibitors
US7592461B2 (en) 2005-12-21 2009-09-22 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
EP1976873A2 (en) * 2006-01-11 2008-10-08 Brystol-Myers Squibb Company Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions
US7553836B2 (en) * 2006-02-06 2009-06-30 Bristol-Myers Squibb Company Melanin concentrating hormone receptor-1 antagonists
US8367112B2 (en) * 2006-02-28 2013-02-05 Alkermes Pharma Ireland Limited Nanoparticulate carverdilol formulations
US20070238770A1 (en) * 2006-04-05 2007-10-11 Bristol-Myers Squibb Company Process for preparing novel crystalline forms of peliglitazar, novel stable forms produced therein and formulations
US8288339B2 (en) 2006-04-20 2012-10-16 Amgen Inc. GLP-1 compounds
US7659281B2 (en) * 2006-04-25 2010-02-09 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors
WO2007139589A1 (en) * 2006-05-26 2007-12-06 Bristol-Myers Squibb Company Sustained release glp-1 receptor modulators
US7919598B2 (en) 2006-06-28 2011-04-05 Bristol-Myers Squibb Company Crystal structures of SGLT2 inhibitors and processes for preparing same
US20080044326A1 (en) * 2006-07-04 2008-02-21 Esencia Co., Ltd. Sterilizer for baby products
EP2046119A2 (en) * 2006-07-07 2009-04-15 Myriad Genetics, Inc. Treatment of psychiatric disorders
US7727978B2 (en) 2006-08-24 2010-06-01 Bristol-Myers Squibb Company Cyclic 11-beta hydroxysteroid dehydrogenase type I inhibitors
US20080161324A1 (en) * 2006-09-14 2008-07-03 Johansen Lisa M Compositions and methods for treatment of viral diseases
WO2008044236A2 (en) * 2006-10-10 2008-04-17 Dexcel Pharma Technologies Ltd. Improved release of statins in the intestine
US20080118572A1 (en) * 2006-10-10 2008-05-22 Harold Richard Hellstrom Methods and compositions for reducing the risk of adverse cardiovascular events associated with the administration of artificial blood
US20110218176A1 (en) 2006-11-01 2011-09-08 Barbara Brooke Jennings-Spring Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
EP2089355A2 (en) 2006-11-01 2009-08-19 Brystol-Myers Squibb Company Modulators of glucocorticoid receptor, ap-1, and/or nf- kappa b activity and use thereof
TW200904405A (en) 2007-03-22 2009-02-01 Bristol Myers Squibb Co Pharmaceutical formulations containing an SGLT2 inhibitor
TWI407955B (zh) 2007-03-29 2013-09-11 Kowa Co 高脂血症之預防及／或治療劑
CN101687873A (zh) 2007-04-17 2010-03-31 百时美施贵宝公司 具有稠合杂环的11β-羟基类固醇Ⅰ型脱氢酶抑制剂
PE20090696A1 (es) 2007-04-20 2009-06-20 Bristol Myers Squibb Co Formas cristalinas de saxagliptina y procesos para preparar las mismas
US20080287529A1 (en) * 2007-05-18 2008-11-20 Bristol-Myers Squibb Company Crystal structures of sglt2 inhibitors and processes for preparing same
EP2581081A3 (en) 2007-06-01 2013-07-31 The Trustees Of Princeton University Treatment of viral infections by modulation of host cell metabolic pathways
US20090011994A1 (en) * 2007-07-06 2009-01-08 Bristol-Myers Squibb Company Non-basic melanin concentrating hormone receptor-1 antagonists and methods
JP2010534722A (ja) * 2007-07-27 2010-11-11 ブリストル−マイヤーズ スクイブ カンパニー 新規グルコキナーゼ活性化薬およびその使用方法
ES2448839T3 (es) 2007-11-01 2014-03-17 Bristol-Myers Squibb Company Compuestos no esteroideos útiles como moderadores de la actividad del receptor de glucocorticoides AP-1 y/o NF-kappa b y uso de los mismos
US20090163452A1 (en) * 2007-12-20 2009-06-25 Schwartz Janice B Compositions and methods for lowering serum cholesterol
US8354446B2 (en) * 2007-12-21 2013-01-15 Ligand Pharmaceuticals Incorporated Selective androgen receptor modulators (SARMs) and uses thereof
PE20091928A1 (es) * 2008-05-29 2009-12-31 Bristol Myers Squibb Co Tienopirimidinas hidroxisustituidas como antagonistas de receptor-1 de hormona concentradora de melanina no basicos
WO2010093601A1 (en) 2009-02-10 2010-08-19 Metabasis Therapeutics, Inc. Novel sulfonic acid-containing thyromimetics, and methods for their use
CA2756786A1 (en) 2009-03-27 2010-09-30 Bristol-Myers Squibb Company Methods for preventing major adverse cardiovascular events with dpp-iv inhibitors
WO2010114780A1 (en) 2009-04-01 2010-10-07 Merck Sharp & Dohme Corp. Inhibitors of akt activity
US8470805B2 (en) * 2009-04-30 2013-06-25 Kaohsiung Medical University Processes for preparing piperazinium salts of KMUP and use thereof
CN102648184B (zh) 2009-05-28 2015-09-30 埃克塞利希斯专利有限责任公司 Lxr调节剂
EA023838B1 (ru) 2009-10-14 2016-07-29 Мерк Шарп Энд Домэ Корп. ЗАМЕЩЕННЫЕ ПИПЕРИДИНЫ, КОТОРЫЕ ПОВЫШАЮТ АКТИВНОСТЬ p53, И ИХ ПРИМЕНЕНИЕ
CA2780939C (en) 2009-11-13 2018-06-12 Bristol-Myers Squibb Company Bilayer tablet formulations
RS57926B1 (sr) 2009-11-13 2019-01-31 Astrazeneca Ab Formulacije tablete sa trenutnim oslobađanjem
RU2564901C2 (ru) 2009-11-13 2015-10-10 Бристол-Майерс Сквибб Кампани Композиции метформина с уменьшенной массой
AR079336A1 (es) * 2009-12-11 2012-01-18 Irm Llc Antagonistas de la pro-proteina convertasa-subtilisina/quexina tipo 9 (pcsk9)
TWI562775B (en) 2010-03-02 2016-12-21 Lexicon Pharmaceuticals Inc Methods of using inhibitors of sodium-glucose cotransporters 1 and 2
WO2011130459A1 (en) 2010-04-14 2011-10-20 Bristol-Myers Squibb Company Novel glucokinase activators and methods of using same
US8372877B2 (en) 2010-04-16 2013-02-12 Cumberland Pharmaceuticals Stabilized statin formulations
WO2011145022A1 (en) 2010-05-21 2011-11-24 Pfizer Inc. 2-phenyl benzoylamides
EP2584903B1 (en) 2010-06-24 2018-10-24 Merck Sharp & Dohme Corp. Novel heterocyclic compounds as erk inhibitors
MX342120B (es) 2010-07-09 2016-09-14 William Owen Wilkison Combinación de sistema de liberación prolongada/inmediata para productos farmacéuticos de vida media corta como el remogliflozin.
US8946216B2 (en) 2010-09-01 2015-02-03 Merck Sharp & Dohme Corp. Indazole derivatives useful as ERK inhibitors
EP2615916B1 (en) 2010-09-16 2017-01-04 Merck Sharp & Dohme Corp. Fused pyrazole derivatives as novel erk inhibitors
EP2626069A4 (en) 2010-10-06 2014-03-19 Univ Tokyo A MEDICINAL PRODUCT FOR THE PREVENTION AND TREATMENT OF A DERY LYMPH
TWI462739B (zh) 2010-11-02 2014-12-01 Univ Kaohsiung Medical Ｓｉｌｄｅｎａｆｉｌ－同族物四級銨哌嗪鹽類之製備及醫療用途
EP2654748B1 (en) 2010-12-21 2016-07-27 Merck Sharp & Dohme Corp. Indazole derivatives useful as erk inhibitors
TWI631963B (zh) 2011-01-05 2018-08-11 雷西肯製藥股份有限公司 包含鈉－葡萄糖共同輸送體１與２之抑制劑的組合物與應用方法
WO2012112363A1 (en) 2011-02-14 2012-08-23 Merck Sharp & Dohme Corp. Cathepsin cysteine protease inhibitors
EP2680874A2 (en) 2011-03-04 2014-01-08 Pfizer Inc Edn3-like peptides and uses thereof
TW201242953A (en) 2011-03-25 2012-11-01 Bristol Myers Squibb Co Imidazole prodrug LXR modulators
US8586527B2 (en) 2011-10-20 2013-11-19 Jaipal Singh Cerivastatin to treat pulmonary disorders
US9023865B2 (en) 2011-10-27 2015-05-05 Merck Sharp & Dohme Corp. Compounds that are ERK inhibitors
KR101466617B1 (ko) 2011-11-17 2014-11-28 한미약품 주식회사 오메가-3 지방산 및 HMG-CoA 환원효소 억제제를 포함하는 안정성이 증가된 경구용 복합 제제
KR20140108705A (ko) 2011-12-29 2014-09-12 트러스티즈 오브 터프츠 칼리지 재생 및 염증 반응을 제어하기 위한 생체물질의 기능화
US8729092B2 (en) * 2012-09-24 2014-05-20 Terence J. Scallen Rosuvastatin enantiomer compounds
JP6280554B2 (ja) 2012-09-28 2018-02-14 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Ｅｒｋ阻害剤である新規化合物
KR102165224B1 (ko) 2012-11-20 2020-10-13 렉시컨 파마슈티컬스 인코퍼레이티드 나트륨 글루코스 공동수송체 1의 억제제
ME02925B (me) 2012-11-28 2018-04-20 Merck Sharp & Dohme Kompozicije i postupci za liječenje kancera
TW201429969A (zh) 2012-12-20 2014-08-01 Merck Sharp & Dohme 作爲ｈｄｍ２抑制劑之經取代咪唑吡啶
EP2951180B1 (en) 2013-01-30 2018-05-02 Merck Sharp & Dohme Corp. 2,6,7,8 substituted purines as hdm2 inhibitors
EP2968275B1 (en) 2013-03-15 2017-11-29 Bristol-Myers Squibb Company Lxr modulators
WO2014170786A1 (en) 2013-04-17 2014-10-23 Pfizer Inc. N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases
WO2015027021A1 (en) 2013-08-22 2015-02-26 Bristol-Myers Squibb Company Imide and acylurea derivatives as modulators of the glucocorticoid receptor
WO2015051479A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Cathepsin cysteine protease inhibitors
WO2015054089A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Cathepsin cysteine protease inhibitors
EP3613418A1 (en) 2014-01-17 2020-02-26 Ligand Pharmaceuticals, Inc. Methods and compositions for modulating hormone levels
WO2015120580A1 (en) 2014-02-11 2015-08-20 Merck Sharp & Dohme Corp. Cathepsin cysteine protease inhibitors
WO2015181676A1 (en) 2014-05-30 2015-12-03 Pfizer Inc. Carbonitrile derivatives as selective androgen receptor modulators
ES2822561T3 (es) 2014-09-15 2021-05-04 Univ Leland Stanford Junior Direccionamiento a enfermedad por aneurisma modulando las vías de fagocitosis
WO2016055901A1 (en) 2014-10-08 2016-04-14 Pfizer Inc. Substituted amide compounds
EP3261671B1 (en) 2015-02-27 2020-10-21 The Board of Trustees of the Leland Stanford Junior University Combination therapy for treatment of atherosclerosis
TW201702271A (zh) 2015-04-30 2017-01-16 哈佛大學校長及研究員協會 治療代謝病症之抗－ａｐ２抗體及抗原結合劑
WO2019094311A1 (en) 2017-11-08 2019-05-16 Merck Sharp & Dohme Corp. Prmt5 inhibitors
US11993602B2 (en) 2018-08-07 2024-05-28 Merck Sharp & Dohme Llc PRMT5 inhibitors
EP3833667B1 (en) 2018-08-07 2024-03-13 Merck Sharp & Dohme LLC Prmt5 inhibitors
AU2019346497A1 (en) 2018-09-26 2021-04-08 Lexicon Pharmaceuticals, Inc. Crystalline forms of n-(1 -((2-(dimethylamino)ethyl)amino)-2-m ethyl-1 -oopropan-2-yl)-4-(4-(2-methyl-5- (2s,3r,4r,5s,6r)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2h-pyran-2-yl)benzyl) phenl)butanamide and methods of their synthesis
CN113574055A (zh) 2019-01-18 2021-10-29 阿斯利康(瑞典)有限公司 Pcsk9抑制剂及其使用方法
WO2021126731A1 (en) 2019-12-17 2021-06-24 Merck Sharp & Dohme Corp. Prmt5 inhibitors
WO2023275715A1 (en) 2021-06-30 2023-01-05 Pfizer Inc. Metabolites of selective androgen receptor modulators

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0325130A2 (de) * 1988-01-20 1989-07-26 Bayer Ag Substituierte Pyridine

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4231938A (en) 1979-06-15 1980-11-04 Merck & Co., Inc. Hypocholesteremic fermentation products and process of preparation
FI90236C (fi) * 1987-07-10 1994-01-10 Hoechst Ag Menetelmä terapeuttisesti käyttökelpoisten 3-desmetyylimevalonihappojohdannaisten valmistamiseksi
US4906624A (en) * 1987-09-08 1990-03-06 Warner-Lambert Company 6-(((Substituted)pyridin-3-yl)alkyl)-and alkenyl)-tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
NZ230121A (en) * 1988-08-29 1993-08-26 Squibb & Sons Inc Pyridine and quinoline terminal groups for hmg-coenzyme a reductase inhibitors and pharmaceutical compositions for lowering blood serum cholesterol levels

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0325130A2 (de) * 1988-01-20 1989-07-26 Bayer Ag Substituierte Pyridine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8114328B2 (en) 2001-09-28 2012-02-14 Mcneil-Ppc, Inc. Method of coating a dosage form comprising a first medicant

Also Published As

Publication number Publication date
NO914696D0 (no) 1991-11-29
CA2057444A1 (en) 1992-06-15
KR100192625B1 (en) 2002-02-19
GR3020826T3 (en) 1996-11-30
NL970033I1 (nl) 1997-10-01
ATE141261T1 (de) 1996-08-15
MY107492A (en) 1995-12-30
KR920012035A (ko) 1992-07-25
SK280115B6 (sk) 1999-08-06
PT99776B (pt) 1999-05-31
DE59108081D1 (de) 1996-09-19
CN1062350A (zh) 1992-07-01
FI915854A (fi) 1992-06-15
PT99776A (pt) 1992-11-30
HU211695A9 (en) 1995-12-28
AU8961591A (en) 1992-06-18
JP2786363B2 (ja) 1998-08-13
DK0491226T3 (da) 1997-01-06
HU913945D0 (en) 1992-02-28
CS360291A3 (en) 1992-06-17
NO177140B (no) 1995-04-18
HU221293B1 (en) 2002-09-28
IE75691B1 (en) 1997-09-10
CN1329888A (zh) 2002-01-09
IE914350A1 (en) 1992-06-17
PL292764A1 (en) 1992-08-24
JPH04308573A (ja) 1992-10-30
IL100327A (en) 1995-12-08
CA2057444C (en) 1998-05-26
NO177140C (no) 1995-07-26
NO1998025I1 (no) 1998-10-22
FI101069B (fi) 1998-04-15
LU90230I2 (fr) 1998-05-18
HUT61282A (en) 1992-12-28
US5177080A (en) 1993-01-05
EP0491226B1 (de) 1996-08-14
NZ240946A (en) 1993-09-27
CN1113485A (zh) 1995-12-20
AU652977B2 (en) 1994-09-15
CN1034073C (zh) 1997-02-19
CZ282642B6 (cs) 1997-08-13
PL169757B1 (pl) 1996-08-30
HK1004552A1 (en) 1998-11-27
EP0491226A1 (de) 1992-06-24
NO914696L (no) 1992-06-15
ES2091852T3 (es) 1996-11-16
FI915854A0 (fi) 1991-12-12

Similar Documents

Publication Publication Date Title
CN1092641C (zh) 含取代的吡啶基二羟基庚烯酸或其盐的药物的制法
US4342767A (en) Hypocholesteremic fermentation products
US8318933B2 (en) Process for preparing rosuvastatin calcium
Yang et al. Asymmetric total synthesis of (+)-desoxoprosophylline
WO2009092702A2 (en) ((2s,4r)-4,6-dihydroxytetrahydro-2h-pyran-2-yl)methyl carboxylate and process for the production thereof
US8269001B2 (en) Process for the synthesis of HMG-CoA reductase inhibitors
CN1433393A (zh) 新方法
HU203318B (en) Process for producing levodopa active component for pharmaceutical compositions
JP2012507506A (ja) （３ｓ，４ｓ）−４−（（ｒ）−２−（ベンジルオキシ）トリデシル）−３−ヘキシル−２−オキセタノンの製造方法及びそれに用いられる新規な中間体
US8546114B2 (en) Processes for the preparation of optically active cyclopentenones and cyclopentenones prepared therefrom
JP3187905B2 (ja) ラセミおよび光学活性１，２，３，４−テトラヒドロイソキノリン−３−カルボン酸およびその前駆体の製造方法
CN105566228B (zh) 一种瑞舒伐他汀的合成方法
Amino Concise Synthesis of (2R, 4R)-Monatin
US6573392B1 (en) Process for manufacturing simvastatin and the novel intermediates
JPH06279280A (ja) エステル化合物
US5217886A (en) Method for the production of (-)-4-difluoromethyl-ornithine
CN1080286A (zh) 具有抗过敏和止喘作用的新的氨基羧酸衍生物及其制备方法
KR100951490B1 (ko) 락톤류의 제조방법
JP3503904B2 (ja) Ｅ型プロスタグランジン類の製造方法
CN105461636A (zh) 一种瑞舒伐他汀甲酯的合成方法
EP0357029A2 (en) Method for the production of (-) 2-difluoromethyl-ornithine
CN105646369A (zh) 一种瑞舒伐他汀的制备方法
JPH0745482B2 (ja) （Ｒ）−（＋）−γ−ブチロラクトン−γ−３−プロピオン酸の製造方法
JPS6134797B2 (zh)
JPH0959217A (ja) 新規光学活性ハロゲン含有カルボン酸誘導体及びそれを製造する方法

Legal Events

Date Code Title Description
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C06 Publication
PB01 Publication
C14 Grant of patent or utility model
GR01 Patent grant
C19 Lapse of patent right due to non-payment of the annual fee
CF01 Termination of patent right due to non-payment of annual fee