Organic compounds -- part of the class 532-570 series – Organic compounds – Heavy metal containing
Patent
1997-11-03
1999-12-28
Geist, Gary
Organic compounds -- part of the class 532-570 series
Organic compounds
Heavy metal containing
C07F 1500
Patent
active
060083956
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/JP96/00463 filed Feb. 26, 1996.
TECHNICAL FIELD
This invention relates to a novel platinum(IV) complex which shows strong antitumor activity, a process for the production thereof and a carcinostatic agent that contains the same.
BACKGROUND ART
Since the development and practical use of cisplatin as an effective antitumor agent, a broad range of studies have been conducted with the aim of finding a new platinum complex which possesses more effective antitumor activity than cisplatin, and of improving properties thereof other than the antitumor action, such as reduction of toxicity and other undesirable side effects.
Carboplatin is known as a platinum(II) complex, as well as recently developed oxaliplatin. With regard to platinum(IV) complexes, iproplatin is known, and tetraplatin has been subjected to clinical trial but its clinical development has been suspended due to the side effects, such as toxicity.
Each of these platinum complexes is for parenteral administration use and is hydrophilic. In order to improve quality of life of cancer patients, great concern has been directed toward the development of an oral preparation for use in the treatment of cancer patients at the terminal stage.
DISCLOSURE OF THE INVENTION
The present invention provides platinum(IV) complexes having high antitumor activity, particularly for use in oral administration. Many of these complexes show high solubility in both water and organic solvents, have high partition coefficient and are stable in strongly acidic solution.
The present invention is a platinum(IV) complex represented by the general formula (I): ##STR2## wherein R.sub.1 and R.sub.2 independently represent ammonia, an alkylamine or a cycloalkylamine, or R.sub.1 and R.sub.2 may together form a cycloalkyldiamine; X.sub.1 and X.sub.2 independently represent a halogen, nitrate ion, sulfate ion or a monocarboxylic acid, or X.sub.1 and X.sub.2 may together form a glycolate or a dicarboxylic acid; Y.sub.1 represents formic acid, a C.sub.1 -C.sub.8 alkyl-, alkenyl-, aryl-, aralkyl-, alkylamino- or alkoxyl-monocarboxylic acid or sulfonic acid; and Y.sub.2 represents a halogen.
In the general formula (I), the alkylamine includes normal and iso forms, and examples of the cycloalkyldiamine include cyclopentyldiamine, cyclohexyldiamine, cycloheptyldiamine and cyclooctyldiamine, each of which may be a cis, trans-d or trans-l isomer of 1,2-, 1,3- or 1,4-form, 1,1-diaminomethylcyclohexane, 1,1-diaminocyclopentane, 1,1-diaminocycloheptane, 1,1-diaminocyclooctane, cis-d, cis-l, trans-d and trans-l isomers of 1-aminomethyl-2-aminomethylcyclohexane and cis-dl and trans-dr isomers thereof, cis-d, cis-l, trans-d and trans-l isomers of 1-aminomethyl-2-aminomethylcyclopentane and cis-dl and trans-dl isomers thereof, cis-d, cis-l, trans-d and trans-l isomers of 1-aminomethyl-2-aminomethylcycloheptane and cis-dl and trans-dl isomers thereof, cis-d, cis-l , trans-d and trans-e isomers of 1-aminomethyl-2-aminomethylcyclooctane and cis-dl and trans-dl isomers thereof and the like.
In the general formula (I), examples of the monocarboxylic acid include gluconic acid, glucuronic acid and the like sugar carboxylic acids and an alkyl monocarboxylic acid, and examples of the dicarboxylic acid include oxalic acid, malonic acid and derivatives thereof (such as of methyl, ethyl, benzyl, benzoyl or the like) and 1,1-cyclobutanedicarboxylic acid.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a reaction scheme regarding the process for the production of the platinum(IV) complex of the present invention.
FIG. 2 is a chart showing infrared absorption spectrum of C6-OHP.Cl as a member of the platinum(IV) complex of the present invention.
BEST MODE OF CARRYING OUT THE INVENTION
A preferred platinum complex of the present invention is a complex represented by the general formula (II): ##STR3## wherein Y.sub.1 and Y.sub.2 are as defined in the general formula (I).
A more preferred platinum complex of the present invention is a platinum complex represe
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patent: 5393909 (1995-02-01), Khokhar
Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy, Edited by Stephen B. Howell pp. 93-100 (1991).
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Barnard, Inor Chem "Studies on the Oral Anticancer Drug JM216: Synthesis and Characterization of Isomers and Related Complexes", 35, pp. 3280-3284, Feb. 1996.
Geist Gary
Vollano Jean F
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