Platinum complex, its preparation and therapeutic application

Details Platinum complex, its preparation and therapeutic application Platinum complex, its preparation and therapeutic application

2000-11-16

2002-02-26

Vollano, Jean F. (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S492000, C536S103000, C556S137000

Reexamination Certificate

active

06350737

ABSTRACT:

FIELD OF THE INVENTION
The invention deals with a new platinum complex of oxidation number II which is useful in medicinal practice for a therapy of oncological diseases. The invention further discloses use of the complex as a pharmaceutical and pharmaceutical compositions containing that platinum complex as the active substance.
BACKGROUND OF THE INVENTION
Platinum complexes effective as cytostatic agents were introduced into medicinal practice by the end of seventieths of this century. The first pharmaceutical product of this type was cisplatin (cis-diammine-dichloroplatinum(II) complex). During further development, tens of platinum complexes were synthetised and tested; among them, carboplatin (cis-diammine-/1,1-cyclobutanedicarboxylato/platinum(II) complex) attained the biggest importance in oncology. Further, there were described assymetric complexes of platinum in which one ammino-ligand has been replaced by an alkylamine group (U.S. Pat. No. 4,329,299).
At present, platinum complexes which would express higher antitumor efficiacy and lower side effects in comparison with known platinum complexes are still being searched.
Now, within the present invention, certain new platinum complexes which possess higher antitumor efficiacy in comparison with platinum complexes of the prior art and lower undesired side effects in comparison with cited known complexes were found. These new complexes represent the principle of the present invention.
SUMMARY OF THE INVENTION
The first aspect of the present invention is a platinum complex with oxidation number II of formula (I)
wherein
X represents a halogen atom, and
A represents a primary tricyclic amine containing
10
to
14
carbon atoms, which may be optionally substituted on the tricyclic ring by one or two alkyl group(s) each containing 1 to 4 carbon atoms, and, furthermore, an inclusion complex of the above platinum complex with beta- or gamma-cyclodextrin which may be optionally substituted by hydroxyalkyl groups containing 1 to 6 carbon atoms.
Especially advantageous complex of the present invention is a platinum complex of formula (I) wherein A represents an adamantylamino group and X has the above defined meaning. Furthermore, another advantageous platinum complex of the present invention is a complex of formula (I) wherein A represents a 3,5-dimethyladamantylamino group and X has the above defined meaning.
Another aspect of the present invention is a process for the preparation of the platinum complex of the formula (I) which is characterized in that a solution of an alkali metal salt of amminetrihalogenoplatinate (1−) in a polar organic solvent or in water is subjected to a reaction. with a primary amine of formula NH
2
—R, wherein R is a tricyclic hydrogen moiety containing 10 to 14 carbon atoms which may be optionally substituted on the tricyclic ring by one or two alkyl groups of one to four carbon atoms, at the temperature of 0 to 100° C.
The invention also provides a process for the preparation of an inclusion complex of the platinum complex of formula (I) with beta- or gamma-cyclodextrin which may be optionally substituted by hydroxyalkyl groups containing 1 to 6 carbon atoms said process being characterized in that solution of the platinum complex of formula (I) in an organic solvent is mixed with an aqueous solution of beta- or gamma-cyclodextrin which is optionally substituted by hydroxyalkyl groups containing 1 to 6 carbon atoms, and, in the following step, the solvents are evaporated from the obtained solution.
Still another aspect of the invention is the platinum complex of formula (I) above or its inclusion complex with beta- or gamma-cyclodextrin for use as a pharmaceutical.
The next aspect of the invention provides a pharmaceutical composition for therapy of oncological diseases, characterized in that it contains, as the active substance thereof, at least one platinum complex of above formula (I) or its inclusion complex with beta- or gamma-cyclodextrin, and at least one pharmaceutical excipient.
Moreover, the platinum complexes of formula (I) may be further used as starting substances for production of analogically substituted platinum complexes with oxidation number IV which are useful for peroral application.
The platinum complexes of the present invention are novel chemical compounds as until now neither these compounds have been specifically disclosed in any document of the prior art nor their properties have been characterized herein nor a method of their production has been disclosed. The utility of these compounds as active substances in the therapy of oncological diseases is likewise novel and inventive as it was not possible to deduce from the prior art by an obvious way that the presence of primary tricyclic amine ligand in divalent platinum complexes would lead to a substantial increase of antitumor activity of the novel compounds of the present invention.


REFERENCES:
patent: 5225207 (1993-07-01), Barreau et al.
CA:119-84501 abs of Inorg Chem 32(12) pp 2717-23 by Rochon et al, 1993.*
CA:115:63438 abs of EP3893338, Sep. 1990.*
CA:83:141759 abs of Chem-Biol Interact. 11(3) pp 145-161 by Braddock et al, 1975.*
CA:110:375 abs of Khim.-Farm. Zh. 22(7) pp 808-810 by Stetsenko, 1988.

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