申请人:The Board of Regents, The University of Texas System
公开号:US05117022A1
公开(公告)日:1992-05-26
The present invention concerns a platinum (II) four-coordinant complex having the formula: ##STR1## wherein R.sub.1 is an alkyl diamine or cycloalkyl diamine and R.sub.2 and R.sub.3 are an alkylcarboxylato containing from five to ten carbon atoms. The R.sub.1 is preferably trans-D,L-1,2-diaminocyclohexane, trans-R,R-1,2-diaminocyclohexane, trans-S,S-1,2-diaminocyclohexane, cis-1,2-diaminocyclohexane ethylene diamine or 1,1-bis(aminomethyl)cyclohexane. The R.sub.2 and R.sub.3 are preferably neohexanoato, neoheptanoato, neononanoato, neodecanoato, neooctanoato, neopentanoato, 2-ethylhexanoato, 2-ehtylbutyrato, 2-propylpropanoato, 2-methyl-2-ethylheptanoato, 2,2-diethylhexanoato, 2,2-dimethyl-4-ethylhexanoato, 2,2-diethyl-4-methylpentanoato, 2,2-dimethyloctanoato, 2-methyl-2-ethylheptanoato, 2,2-diethylhexanoato, 2,2-diethyl-4-methylpentanoato or 2,2,4,4-tetramethylpentanoato. In an important further aspect, the present invention involves preparation and therapeutic use of a liposome comprising a phospholipid and a four-coordinate platinum complex having the formula: ##STR2## wherein R.sub.1 is an alkyl diamine or cycloalkyl diamine and R.sub.2 and R.sub.3 are an alkylcarboxylato containing from about five to about fourteen carbon atoms. The R.sub.1, R.sub.2 and R.sub.3 functions are preferably as described above with the exception that R.sub.2 and R.sub.3 may have even longer alkyl chains such as myristate and laurate, i.e., up to fourteen carbon atoms. For therapeutic use, a pharmaceutical composition comprising this liposome and a pharmaceutically acceptable carrier or diluent may be readily prepared by methods well known to those skilled in the art. The liposomes are useful vehicles for solubilizing the otherwise aqueously insoluble complexes of the present invention. The phospholipids of the liposomes may be one or more of phosphatidylglycerol, phosphatidylcholine, sphingomyelin, phosphatidic acid or phosphatidylserine. The liposomes more preferably consist essentially of phosphatidylglycerol, phosphatidylcholine or a combination thereof and may also comprise cholesterol. The liposomes of the present most preferably comprise phospholipid consisting essentially of dimyristoylphosphatidylglycerol, dimyristoylphosphatidylcholine or a combination thereof.
本发明涉及一种铂(II)四配位配合物,其化学式为:##STR1##其中,R.sub.1是一种含有五到十个碳原子的烷基二胺或环烷基二胺,R.sub.2和R.sub.3是一种含有五到十个碳原子的烷基羧酸盐。其中,R.sub.1最好是顺反-1,2-环己烷二胺、顺顺-1,2-环己烷二胺、顺反-1,2-环己烷二胺、顺-1,2-环己烷二胺、乙二胺或1,1-双(氨甲基)环己烷。R.sub.2和R.sub.3最好是新己酸盐、新庚酸盐、新壬酸盐、新癸酸盐、新辛酸盐、新戊酸盐、2-乙基己酸盐、2-乙基丁酸盐、2-丙基丙酸盐、2-甲基-2-乙基庚酸盐、2,2-二乙基己酸盐、2,2-二甲基-4-乙基己酸盐、2,2-二乙基-4-甲基戊酸盐、2,2-二甲基辛酸盐、2-甲基-2-乙基庚酸盐、2,2-二乙基己酸盐、2,2-二乙基-4-甲基戊酸盐或2,2,4,4-四甲基戊酸盐。在另一个重要方面,本发明涉及制备和治疗使用一种脂质体,该脂质体包括磷脂和一种具有以下化学式的四配位铂配合物:##STR2##其中,R.sub.1是一种含有五到十四个碳原子的烷基二胺或环烷基二胺,R.sub.2和R.sub.3是一种含有约五到十四个碳原子的烷基羧酸盐。其中,R.sub.1、R.sub.2和R.sub.3的功能最好如上所述,但R.sub.2和R.sub.3可以具有更长的烷基链,例如肉豆蔻酸盐和月桂酸盐,即长达十四个碳原子。对于治疗用途,可以通过已知的方法轻松制备包含该脂质体和药学上可接受的载体或稀释剂的制药组合物。脂质体是用于溶解本发明中否则水不溶性配合物的有用载体。脂质体的磷脂可以是磷酸甘油酸、磷酸胆碱、鞘磷脂、磷酸或磷酸酰丝氨酸中的一种或多种。脂质体更好地由磷酸甘油酸、磷酸胆碱或它们的组合基本构成,并且还可以包括胆固醇。本发明中的脂质体最好由基本构成的二肌酰磷脂酰甘油酸、二肌酰磷脂酰胆碱或它们的组合构成。