公开(公告)号：EP0566142A1

公开(公告)日：1993-10-20

申请号：EP93106236.8

申请日：1993-04-16

申请人： LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d.

发明人： Fercej-Temeljotov, Darja, Mag.-Ing. ,  Zmitek, Janko, Dr.-Ing. ,  Husu-Kovacevic, Breda, Mag.-Ing. ,  Kotnik, Sonja, Dipl.-Ing. ,  Jerala-Strukelj, Zdenka, Dipl.-Ing.

IPC分类号： A61K47/48 ,  A61K31/44

CPC分类号： B82Y5/00 ,  A61K31/4422 ,  A61K47/6951 ,  C08B37/0015

摘要： Novel inclusion complexes of racemic 1,4-dihydropyridines and enantiomers thereof of the formula

wherein
R represents a phenyl group, substituted with nitro, trifluoromethyl, difluoromethoxy group or with one or two halo atoms (especially chlorine),
R₁ and R₂, if the same, represent methyl groups and if one of them has the meaning of a 2-aminoethoxymethyl or cyano group, the other represents a methyl group,
R₃ and R₄, if different, stand each time for a hydrogen, linear or branched C₁-C₆-alkyl, 2-methoxyethyl, 1-(phenylmethyl)-3-piperidinylphenyl, styryl, furyl, piperidino, 4-diphenylmethyl-1-piperazinylethyl, 5-phenyl-3-pirazolyloxy, 1-phenyl-methyl-3-pyrrolidinyl group or a group of the formula

or, if the same, stand each time C₁-C₄ alkyl group,
and of acid addition salts thereof with methyl-β-cyclodextrin, hydroxy-ethyl-β-cyclodextrin or hydroxypropyl-β-cyclodextrin, with the exception of inclusion complexes of racemic dihydropyridines with HP-β-CD, or, in case of amlodipine and enantiomeric nicardipine, also with β-cyclodextrin, are disclosed.
Whilst inclusion complexes of racemic dihydropyridines with the cited cyclodextrins are prepared in a well-known manner disclosed in the literature, enantiomerically pure dihydropyridines and inclusion complexes thereof with cyclodextrins are prepared in a novel way by means of preparative column chromatography.
The invention also relates to a pharmaceutical formulation containing novel inclusion complexes and to the use thereof as calcium antagonists for the treatment of hypertension, angina pectoris and cerebrovascular disorders.

摘要翻译： 其中R表示苯基，被硝基，三氟甲基，二氟甲氧基或与一个或两个卤原子（特别是氯）取代的外消旋1,4-二氢吡啶的新型包合络合物及其对映异构体，其中R表示苯基， 如果相同，表示甲基，如果其中一个具有2-氨基乙氧基甲基或氰基的含义，另一个表示甲基，如果不同，则R 3和R 4各自代表氢，直链或支链C1- C6-烷基，2-甲氧基乙基，1-（苯基甲基）-3-哌啶基苯基，苯乙烯基，呋喃基，哌啶子基，4-二苯基甲基-1-哌嗪基乙基，5-苯基-3-吡咯烷氧基，1-苯基 - 甲基-3-吡咯烷基 或式CHEM的基团，或者如果相同，则每次保持C1-C4烷基，及其与甲基-β-环糊精，羟基 - 乙基-β-环糊精或羟丙基-β-环糊精的酸加成盐 ，除外消旋二氢吡啶与HP-β-CD的包合物外， 或者在使用氨氯地平和对映体尼卡地平的情况下，也可以使用β-环糊精。 尽管外消旋二氢吡啶与所引用的环糊精的包合物以文献中公开的众所周知的方式制备，但通过制备型柱色谱以新的方式制备对映体纯的二氢吡啶类及其与环糊精的包合络合物。 本发明还涉及含有新型包合物的药物制剂及其作为治疗高血压，心绞痛和脑血管障碍的钙拮抗剂的用途。