CN1034073C - 取代的吡啶基－二羟基o庚烯酸的钠盐的制法 - Google Patents

取代的吡啶基－二羟基o庚烯酸的钠盐的制法 Download PDF

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CN1034073C
CN1034073C CN91107973A CN91107973A CN1034073C CN 1034073 C CN1034073 C CN 1034073C CN 91107973 A CN91107973 A CN 91107973A CN 91107973 A CN91107973 A CN 91107973A CN 1034073 C CN1034073 C CN 1034073C
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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
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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HMG-CoA还原酶抑制剂而用于治疗高脂蛋白血症和动脉硬化。

Description

取代的吡啶基－二羟基O庚烯酸的钠盐的制法
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(HMG-CoA还原酶)的抑制剂(麦维诺林(mevinolin)； EP22,478，US-4,231,938)。
此外还了解到，吡啶取代的二羟基庚烯酸是HMG-CoA还原酶的抑制剂(EP325,130；EP307,342；EP306,929)。
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HMG-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 C9110797300041
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 C9110797300051
赤式苏式优选赤式构型。
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，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 C9110797300071
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 C9110797300081
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(HMG-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O.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，pH7.2)匀浆三次，缓冲液中含有0.1M蔗糖、0.05MKCl、0.04MKxHy磷酸盐(K2HPO4和KH2PO4的混合物，pH7.2)、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) IN 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(pH7.2)、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 0.25 M 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
Figure C9110797300152
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13ml1N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％)(+)-对映异构体钠盐(实施例1)。
1H-NMR(DMSO-d5)：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)：[a]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)：(a]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非对映体A2
Figure C9110797300172
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360(2.6摩尔)S-(+)-苯基氨基乙醇溶于1升无水四氨呋喃中，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乙迷。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RP18柱(长40cm，直径3cm，RP18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 (5)

1.制备式(I)的取代的吡啶基-二羟基-庚烯酸的钠盐及必要时为异构体形式的方法，
Figure C9110797300021
其特征在于，
[A]如果要制备外消旋产物，则水解式(II)的相应外消旋酯，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(II)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 C9110797300031
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。
2.根据权利要求1的方法，其中所制备的是赤式构型的式(I)的取代的吡啶基-二羟基-庚烯酸的钠盐。
3.根据权利要求1的方法，其中所制备的是式(I)的取代的吡啶基-二羟基-庚烯酸的(+)对映体的钠盐。
4.根据权利要求1的方法，其中所制备的是赤式构型的式(I)的取代的吡啶基-二羟基-庚烯酸的(+)对映体的钠盐。
5.根据权利要求1的方法，其中所制备的是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。
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IE914350A1 (en) 1992-06-17
PT99776B (pt) 1999-05-31
FI915854A (fi) 1992-06-15
JPH04308573A (ja) 1992-10-30
KR100192625B1 (en) 2002-02-19
HU913945D0 (en) 1992-02-28
IE75691B1 (en) 1997-09-10
NO1998025I1 (no) 1998-10-22
CZ282642B6 (cs) 1997-08-13
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