Platinum(II) complexes

Details Platinum(II) complexes Platinum(II) complexes

1982-03-02

1984-10-16

Sneed, Helen M. S.

Chemistry of carbon compounds

Miscellaneous organic carbon compounds

C-metal

424287, C07F 1500

Patent

active

044773870

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION



Technical Field

The present invention relates to novel platinum(II) complexes and antineoplastic agents containing the same as effective ingredients.


Background Art

It has been found by the studies of Barnett Rosenberg et. al. that a certain kind of platinum(II) complex has an antineoplastic activity in that they bond with a DNA of a neoplasm, particularly malignant neoplasm to prevent the synthesis of its DNA.
However, many platinum(II) complexes in the primary stage do not have enough maximum antineoplastic activities but have quite strong toxicities for humans.


DISCLOSURE OF INVENTION

As a result of extensive and thorough researches, the inventors had found the fact that platinum(II) complexes represented by the general formula: ##STR1## wherein --B--B-- is ##STR2## (in which R.sub.1 and R.sub.2 are the same or different and each is hydrogen, an alkyl group or an aryl group, and n, m and l are 0 or is an integer of from 1 to 3), at least one of A.sub.1 and A.sub.2 is ##STR3## (hereinafter referred to as a ligand of D-gluconic acid) and the other is the ligand of D-gluconic acid, Cl.sup.-, Br.sup.-, I.sup.-, F.sup.-, XCH.sub.2 COO.sup.- (in which X is a halogen atom), NO.sub.3.sup.-, SO.sub.4.sup.--, H.sub.2 PO.sub.4.sup.- or H.sub.2 O or, when taken together, A.sub.1 and A.sub.2 may form a ring together with Pt(II), in the latter case --A.sub.1 --A.sub.2 -- being the ligand of D-gluconic acid
In comparison with the known platinum(II) complexes which are of a ligand of glucuronic acid as A.sub.1 and/or A.sub.2 in the above-mentioned general formula, the platinum(II) complexes of the invention have superior medical effects that the present complexes show their maximum antineoplastic activities in the dose of about one-fourth of the known complexes and are effective as antineoplastics in a wide range of doses.
The --B--B-- in the platinum(II) complexes of the invention is roughly classified into the following two diamines. ##STR4## wherein n and m are as defined above.
Examples of such type are, for instance, 1,2-diaminocyclohexane (hereinafter referred to as dach), 1-amino-2-aminomethylcyclohexane (hereinafter referred to as aamch), and the like. ##STR5## wherein R.sub.1, R.sub.2 and l are as defined above.
Examples of such type are, for instance, ethylenediamine, trimethylenediamine, 1,2-diphenylethylenediamine (hereinafter referred to as stien), 1-phenylethylenediamine (hereinafter referred to as C-phenen), and the like.
There are isomers of dach and aamch in the type(A) and stien and C-phenen in the type(B), and among them cis-form, trans-d-form and trans-l-form of dach; cis-d-form, cis-l-form, trans-d-form and trans-l-form of aamch; trans-d-form, trans-l-form and meso-form of stien; and d-form and l-form of C-phenen have preferable antineoplastic activities.
A.sub.1 and A.sub.2 are groups which are liberated when the platinum(II) complex bonds with DNA, and are roughly classified into the following two groups.
(C) At least one of A.sub.1 and A.sub.2 is the ligand of D-gluconic acid, and the other is Cl.sup.-, Br.sup.-, I.sup.-, F.sup.-, XCH.sub.2 COO.sup.- (in which X is as defined above), NO.sub.3.sup.-, SO.sub.4.sup.--, H.sub.2 PO.sub.4.sup.- or H.sub.2 O.
(D) A.sub.1 and A.sub.2, when taken together, form a ring together with Pt(II) and --A.sub.1 --A.sub.2 -- is the ligand of D-gluconic acid.
Examples of the platinum(II) complexes are, for instance, shown in Table 1. In Table 1 D-gluco represents the ligand of D-gluconic acid.


TABLE 1 ______________________________________ Complex No. Platinum (II) complexes ______________________________________ 1 Pt(D-gluco)H.sub.2 O(cis-dach).NO.sub.3 2 Pt(D-gluco)H.sub.2 O(trans-d-dach).NO.sub.3 3 Pt(D-gluco)H.sub.2 O(trans-l-dach).NO.sub.3 4 Pt(D-gluco)H.sub.2 O(cis-dach).1/2 SO.sub.4 5 Pt(D-gluco)H.sub.2 O(trans-d-dach).1/2 SO.sub.4 6 Pt(D-gluco)H.sub.2 O(trans-l-dach).1/2 SO.sub.4 7 Pt(D-gluco).sub.2 (cis-dach) 8 Pt(D-gluco).sub.2 (trans-d-dach) 9 Pt(D-gluco).sub.2 (trans-l-dach) 10 Pt(D-gluco)H.

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Heilbron et al., Dictionary of Organic Compounds, Oxford Univ. Press, NY, p. 598 (1953).

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