CN1041939A - 新的氟甲氧苯基二氢吡啶、其制备方法和其在药物方面的应用 - Google Patents
新的氟甲氧苯基二氢吡啶、其制备方法和其在药物方面的应用 Download PDFInfo
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- CN1041939A CN1041939A CN88107637A CN88107637A CN1041939A CN 1041939 A CN1041939 A CN 1041939A CN 88107637 A CN88107637 A CN 88107637A CN 88107637 A CN88107637 A CN 88107637A CN 1041939 A CN1041939 A CN 1041939A
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- compound
- dihydropyridine
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- -1 fluorine methoxyphenyl dihydropyridine Chemical compound 0.000 title claims abstract description 15
- 239000003814 drug Substances 0.000 title claims abstract description 9
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- 239000011737 fluorine Chemical group 0.000 claims abstract description 5
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- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 9
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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Abstract
本发明涉及新的通式(I)的氟甲氧苯基二氢吡啶，其几种制备方法和其在药物方面，特别是在具有增强心肌收缩力作用的血液循环促进剂方面的应用。
Description
本发明涉及新的通式（Ⅰ）的氟甲氧苯基二氢吡啶，其几种制备方法和其在药物方面，特别是在具有增强心肌收缩力作用的血液循环促进剂方面的应用。
业已公开1，4-二氢吡啶具有血管扩张性质并可用作冠状动脉扩张剂和抗高血压药（对比文献：英国专利1，173，062和1，358，951;DE-OS（德国已公布的说明书）2，629，892和2，752，820）。此外，已知1，4-二氢吡啶能抑制平滑肌和心肌的收缩力并可用于治疗冠状动脉疾病和血管疾病（对比文献Fleckenstein，Ann.Rev.Pharmacol，Toxicol.17，149-166（1977）。
又知道3-硝基二氢吡啶除了增强心肌收缩力作用外，通常还对冠状血管具有不期望的缩窄作用的缺陷〔Schramm et al.，Nature 303，535-537（1983）〕）也参见DE-OS（German PuPlished Specification）3，447，169）。
仅知道二氢吡啶的上述这些性质，并不能预见到本发明化合物具有增强心肌收缩力而对血管实际上并无影响的作用。
本发明涉及通式（Ⅰ）的新的氟甲氧苯基二氢吡啶，
式中，R为氢或氟。
R具有上述定义的本发明式（Ⅰ）的化合物，可通过下列反应制得：
〔A〕使式（Ⅱ）的醛和式（Ⅲ）的硝基丙酮或其式（Ⅳ）的诺文葛耳缩合产物和通式（Ⅴ）的氨基巴豆酸酯反应，如在有惰性溶剂存在下反应，则更为合适，
式中，R具有上述定义，
或
〔B〕按已知方法，通过使式（Ⅵ）的二氢吡啶同式（Ⅶ）的任意活性的癸醇反应，如用活性酸衍生物反应，则更为合适，
式中，R具有上述定义。
式中，Y为羟基或诸如卤素、-O-SO2O-（CH2）9-CH3等之类的一种活性基团，或通过
〔C〕使式（Ⅱ）的醛和式（Ⅷ）的乙酰乙酸酯或其式（Ⅸ）的诺文葛耳缩合产物同硝基丙酮和铵盐如乙酸铵反应，如在有惰性溶剂存在下反应，则更为合适，如有需要，可用常规方法如在手性固定相上进行色谱层析，以拆解所得到的二氢吡啶，
式中，R具有上述定义。
根据所用起始物质的类型，用A-C的方法，通过下列各反应式，可说明外消旋化合物的合成：
＊＝二环己基碳化二亚胺
本发明化合物以立体异构体存在，它呈镜像构型（对映体）。本发明既涉及具有增强心肌收缩力作用的对映体又涉及外消旋体。外消旋体可用已知方法拆解为立体异构的均相成分（对比文献E.L.Eliel，Stereochemistry of Carbon Compounds.McGraw Hill，1962，或DE-OS（German Puplished Specification）3，447，169）。
适用于方法A和C的稀释剂都是惰性有机溶剂，最优选的溶剂包括诸如甲醇、乙醇、正丙醇或异丙醇之类的醇;诸如乙醚、四氢呋喃、二噁烷或乙二醇-乙醚或乙二醇乙醚之类的醚;冰醋酸、吡啶、二甲基甲酰胺、二甲基亚砜、乙腈或六甲基磷三酰胺或甲苯等。
适用于方法B的稀释剂，除了醇类之外，其它有机溶剂都与方法A和C的相同。方法B中优选使癸醇（Y＝OH）同任意活性的二氢吡啶酸衍生物反应或使活性癸醇（Y≠OH）同二氢吡啶酸或其盐反应。
方法A-C的反应温度可在相对宽的范围内变化，反应通常在10℃-200℃，最好为20℃-150℃下进行。
按本发明方法反应时，参与反应的各物质可以任意比例，但是，通常采用摩尔量的反应剂进行反应。
用作起始物质的氟甲氧苯甲醛（Ⅱ），可按氟化学中常规方法，从水杨醛和含氯氟代甲烷制得。
硝基丙酮（Ⅲ）为已知物质〔见N.Levy，C.W.Scoufen，J.Chem.Soc.1946，1100）;C.D.Huret，M.E.Nilson，J.Org.Chem.20，927（1955）〕。
式（Ⅳ）的内鎓烯盐（ylidene）化合物虽是新物质，但可按已知方法制得（对比文献H.Dornow and W.Sassenberg，Liebigs Ann.Chem.602，14（1957））。
式（Ⅴ）的氨基巴豆酸酯亦为已知物质〔对比文献S.A.Glickmann，A.C.Cope，J.Am.Chem.Soc.67，1017（1945）〕。
本发明式Ⅷ的乙酰乙酸酯为已知物质〔对比文献D.Borrman，“Umsetzung von Diketen mit Alkoholen，Phenolen und Mercaptanen”（Reactions of diketene with alcohols，phenols and mercaptans'），in Houben-Weyl，Methoden der organischen Chemie，（Methods of organic chemistry），Vol.Ⅶ/4，230 ff（1968）〕。
本发明可利用的式（Ⅸ）内鎓烯盐化合物为已知物质或可用已知方法制得〔Organic Reactions ⅩⅤ，204 ff，1967〕。
DHP羧酸（Ⅵ）为新物质，可用已知方法制得（对比文献EP718，819）。
上述各制备方法仅用于说明本发明，式（Ⅰ）化合物的制备并不限于这些方法，但是可利用制备本发明化合物的相似方法，对上述各种方法作出任何改进。
本发明化合物，在药理学上，显示出未预见的，有价值的广谱作用。它们能影响心肌收缩力和平滑肌的紧张，因此，在药物上，它们适用于影响病理性血压的变化，如可治疗冠状动脉疾病和心机能不全。此外还可用于治疗心律不齐、低血糖、使粘液膜消肿、影响盐液平衡等。
在离体灌注的豚鼠心胶上发现了本发明化合物对心脏和心血的作用。此实验选用体重为250-350g的豚鼠进行试验。先对着豚鼠头部吹气使鼠致死，接着剖开胸部，把一支金属套管连结到暴露的主动脉上，自胸部连同肺一起分离出心脏，并经主动脉套管将其连接到灌注器上，以便进行连续灌注，而后自肺的根部分离出肺。配制CaCl2含量为1.2mmol/l的克汉氏溶液（1）（其中含有118.5mmol/l的NaCl、4.75mmol/l的KCl、1.19mmol/l的KH2PO4、1.19mmol/l的MgSO4、25mmol/l的NaHCO3和0.013mmol/l的Na2EDTA）作为灌注介质。用10mmol/l葡萄糖作为产生能量的基质。灌注前，先过滤上述溶液，使其不含颗粒，再用95%O2和5%CO2的混合气向溶液鼓气，以使其pH维持为7.4。于32℃，经蠕动泵，采用恒定流速（10ml/分）对心脏进行灌注。
将一充有液体的胶乳囊，经一液柱，与一个压力转换器连接，再经左心房被导入左心室，在一个快速记录器上记录等容量收缩数据，以测定心脏功能（Opie，L.，physiol，180（1965），529-541）。灌注压力由压力转换器记录，该压力转换器先与灌注系统连接，再与心脏连接。在这些条件下，灌注压力降低即表明冠状动脉扩张;左心室收缩幅度增大或减小即表明心脏收缩力有相应的减小或增大。在分离心脏之前，立即将适当稀释度的本发明化合物灌注到灌注系统中。
本发明化合物对分离的豚鼠心房的收缩幅度的效应是在活性化合物浓度为10-3g/l下进行试验的。
实施例号 变化%
1 +45
用常规方法，采用惰性的、无毒性的、药物上适合的赋形剂或溶剂，可将新的活性化合物转化为各种常用的剂型，诸如片剂、糖衣药丸、丸剂、粒剂、气溶胶、糖浆、乳剂、悬浮剂和溶液剂。在每种剂型中，治疗用的活性化合物浓度应为总混合物重量的约0.5%-90%，即应载有足够量的所指定的剂量范围的活性化合物含量。
各种剂型的制备，例如，可将活性化合物加入溶剂和/或赋形剂中，如适合，还可加入乳化剂和/或分散剂中，例如，用水作稀释剂时，如适合，还可用各种有机溶剂作为辅助剂。
上述提及的各种辅助剂，例如有水、无毒性的有机溶剂如液体石蜡（例如各种矿物油组分）、植物油（例如花生油/芝麻油）、醇类（例如乙醇、丙三醇）、赋形剂例如天然矿物质（例如高岭土、矾土、滑石、白垩）、合成矿物质（例如高分散度的硅石、硅酸盐）、糖（例如蔗糖、乳糖和葡萄糖）、乳化剂（例如聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚，烷基磺酸酯和芳基磺酸酯）、分散剂（例如木素亚磺酸酯废液、甲基纤维素、淀粉、聚乙烯吡咯烷酮）和润滑剂（例如硬脂酸镁、滑石、硬脂酸和十二烷基磺酸钠）。
本发明化合物可以常规方法给药，嗫好为口服或肠胃外，特别是经舌部或静脉内给药为宜。口服给药时，片剂除含有上述赋形剂外，当然还可含有各种添加剂，例如含有与诸如淀粉（最好是马铃薯淀粉）、明胶等混合的柠檬酸钠、碳酸钙和磷酸二钙等各种添加剂。此外，诸如硬脂酸镁、十二烷基磺酸钠和滑石之类的润滑剂可用于制备片剂。制备水悬浮剂时，除含有上述辅助剂外，还可含有加入活性化合物中的各种调味剂和着色剂。
肠胃外使用时，可用各种适合的液体赋形剂以制备含活性化合物的溶液剂。
一般说来，已证明静脉内给药是有利的，取得良好效果的给药剂量约为0.001-1mg/kg体重，最好约为0.01-0.5mgkg体重;口服给药剂量约为0.01-20mg/kg体重，最好为0.1-10mg/kg体重。
尽管如此，如合适，可根据患者体重或给药途径类型、药物性质、剂型种类、给药时间或时间间隔等因素，对上述剂量仍需作出改变。因此，在某些情况下，可采用低于上述的最小剂量，以便有效地控制疾病;而在另外一些情况下，又必须采用上述剂量的上限。采用较大给药剂量时，可将这些剂量，在一天内，分成几个单剂量服用更为合适。
制备例1
方法A
4-（2-二氟甲氧苯基）-1，4-二氢-2，6-二甲基-3-硝基吡啶-5-羧酸癸酯
将10.28g（40mmol）2-二氟甲氧亚苄基硝基丙酮的50ml乙醇溶液同9.5g（40mmol）β-氨基巴豆酸癸酯和2.4ml（40mmol）乙酸共沸3小时。混合物浓缩，油状蒸发残余物溶于乙酸乙酯，用水、碳酸氢钠溶液洗涤，再用水洗涤、干燥和浓缩。将10∶1的己烷/乙醚加入蒸发残余物中，待生成结晶后，空吸过滤混合物，用10∶1的己烷/乙醚洗涤，制得熔点为94-95℃的桔黄色晶体17.5g（为理论值的91%）。
用类似方法制得下列化合物。
制备例2
4-（2-三氟甲氧苯基）-1，4-二氢-2，6-二甲基-3-硝基吡啶-5-羧酸癸酯
熔点108℃。
制备例3（方法B）
4-（2-二氟甲氧苯基-）-1，4-二氢-2，6-二甲基-3-硝基吡啶-5-羧酸癸酯
将由2-二氟甲氧亚苄基硝基丙酮和β-氨基巴豆酸1-（R）-（1-异丙氧羰基乙基）酯制得的1.14g（2.5mmol）4-（2-二氟甲氧苯基-）-1，4-二氢-2，6-二甲基-3-硝基吡啶-5-羧酸1-（R）-（1-异丙氧羰基乙基）酯的40ml二噁烷和50ml 1.5N氢氧化钠溶液搅拌48小时，混合物与二氯甲烷一起震摇萃取两次。用10%盐酸酸化水相，乙酸乙酯震摇萃取两次，用水洗涤、干燥和浓缩，所得到的产物在硅胶柱上纯化。
所制得的（+）-对映体4-（2-二氟甲氧苯基-）-1，4-二氢-2，6-二甲基-3-硝基吡啶-5-羧酸（〔α〕20 589＝+17.6（C＝0.512，丙酮））溶于1.5g的10ml无水二甲基甲酰胺中，并依次与10g癸醇、0.44g 4-二甲基氨基吡啶和2.55g 1-环己基-3-（2-吗啉代乙基）碳化二亚胺-对-甲氧甲苯硫酸酯一起共搅拌44小时。然后空吸滤除沉淀盐、滤液浓缩、油状残余物溶于乙酸乙酯中，用水、5%盐酸、水、碳酸氢钠溶液洗涤，再用水洗涤，干燥和浓缩。蒸发残余物经闪色谱法纯化，用环己烷/甲苯混合物洗脱。浓缩各组分，用乙醚/庚烷1∶10搅拌结晶，空吸过滤，制得熔点为87-88℃的黄色晶体。
〔α〕20 589＝-27.8（C＝0.71，氯仿）（-）-对映体。
用类似方法制得下列化合物。
制备例4
4-（2-三氟甲氧苯基-）-1，4-二氢-2，6-二甲基-3-硝基吡啶-5-羧酸癸酯
熔点：106℃
〔α〕20 589＝-23.6（氯仿）
Claims (8)
1、通式(Ⅰ)的氟甲氧苯基二氢吡啶，
式中，R为氢或氟。
2、根据权利要求1的通式（Ⅰ）的化合物用于防治心机能紊乱。
3、通式（Ⅰ）的化合物的制备方法，
式中，R为氢或氟，该方法的特征在于，
〔A〕式（Ⅱ）的醛和式（Ⅲ）的硝基丙酮或其式（Ⅳ）的诺文葛耳缩合产物和式（Ⅴ）的氨基巴豆酸酯一起反应，如在有惰性溶剂存在下反应，更为合适，
式中，R具有上述定义，
或其特征在于：
〔B〕用已知方法，使式（Ⅵ）的二氢吡啶同任意活性的式（Ⅶ）的癸醇反应，如用活性酸衍生物反应，更为合适，
式中，R具有上述定义，
式中，Y为羟基或诸如卤素，-O-SO2O-（CH2）9-CH3等一种活性基团，或其特征在于：
〔C〕使式（Ⅱ）的醛和式（Ⅷ）的乙酰乙酸酯或其式（Ⅸ）的诺文葛耳缩合产物同硝基丙酮和例如乙酸铵的铵盐一起反应，如在有惰性溶剂存在下反应，更为合适，如有需要，所得到的二氢吡啶可通过常规方法例如通过在手性固定相上色谱层析进行拆解，
式中，R具有上述定义。
4、根据权利要求3的方法，其特征在于：反应和拆解是在有惰性有机溶剂存在下，于10-200℃之间进行的。
5、含有至少一种权利要求1的化合物的药物。
6、药物的制备方法，其特征在于：将权利要求1的通式（Ⅰ）的化合物转化为给药的一种适合的剂型，如适合，可用各种常规的辅助剂和赋形剂。
7、权利要求1的通式（Ⅰ）的化合物所制备的药物用于影响血液循环，各种心脏疾病、糖平衡和盐液平衡。
8、权利要求1的通式（Ⅰ）的化合物用于防治各种血管疾病。
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|---|---|---|---|---|
| DE2752820A1 (de) * | 1977-11-26 | 1979-05-31 | Bayer Ag | Neue nitrosubstituierte 1,4-dihydropyridine, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
| DE3447169A1 (de) * | 1984-12-22 | 1986-07-03 | Bayer Ag, 5090 Leverkusen | Optisch aktive nitrodihydropyridine, verfahren zur herstellung und ihre verwendung in arzneimitteln |
| US4868181A (en) * | 1986-08-04 | 1989-09-19 | E. I. Du Pont De Nemours And Company | 1,4-dihydropyridine derivatives with calcium agonist and alpha1 -antagonist activity |
-
1987
- 1987-11-04 DE DE19873737341 patent/DE3737341A1/de not_active Withdrawn
-
1988
- 1988-10-20 NO NO88884672A patent/NO884672L/no unknown
- 1988-10-20 AU AU24099/88A patent/AU2409988A/en not_active Abandoned
- 1988-10-25 EP EP88117703A patent/EP0315019A3/de not_active Withdrawn
- 1988-10-31 IL IL88238A patent/IL88238A0/xx unknown
- 1988-11-02 FI FI885057A patent/FI885057A/fi not_active Application Discontinuation
- 1988-11-02 PT PT88919A patent/PT88919A/pt not_active Application Discontinuation
- 1988-11-03 ZA ZA888235A patent/ZA888235B/xx unknown
- 1988-11-03 DK DK613988A patent/DK613988A/da not_active Application Discontinuation
- 1988-11-03 KR KR1019880014438A patent/KR890008098A/ko not_active Application Discontinuation
- 1988-11-03 CN CN88107637A patent/CN1041939A/zh active Pending
- 1988-11-04 JP JP63279183A patent/JPH01151556A/ja active Pending
- 1988-11-04 HU HU885712A patent/HU199797B/hu not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408483A (zh) * | 2013-07-17 | 2013-11-27 | 张家港威胜生物医药有限公司 | 钙离子通道拮抗剂马尼地平的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| HUT48592A (en) | 1989-06-28 |
| AU2409988A (en) | 1989-05-04 |
| EP0315019A3 (de) | 1990-07-18 |
| NO884672L (no) | 1989-05-05 |
| ZA888235B (en) | 1989-08-30 |
| DK613988D0 (da) | 1988-11-03 |
| HU199797B (en) | 1990-03-28 |
| NO884672D0 (no) | 1988-10-20 |
| IL88238A0 (en) | 1989-06-30 |
| PT88919A (pt) | 1989-09-14 |
| JPH01151556A (ja) | 1989-06-14 |
| DE3737341A1 (de) | 1989-05-18 |
| DK613988A (da) | 1989-05-05 |
| EP0315019A2 (de) | 1989-05-10 |
| FI885057A0 (fi) | 1988-11-02 |
| FI885057A (fi) | 1989-05-05 |
| KR890008098A (ko) | 1989-07-08 |
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