Hydrophobic cis-platinum complexes efficiently incorporated into

Details Hydrophobic cis-platinum complexes efficiently incorporated into Hydrophobic cis-platinum complexes efficiently incorporated into

1988-08-22

1992-05-26

Shaver, Paul F.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heavy metal containing

424450, 514492, C07F 1500

Patent

active

051170221

ABSTRACT:
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.

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