Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1985-09-04
1988-05-31
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
556 40, 556137, C07F 1500
Patent
active
047482540
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to complex platinum compounds and, more specifically, to mixed carboxylate platinum(II) complexes and to a process for preparing same.
Mixed carboxylate platinum complexes are biologically active compounds which exhibit antitumor activity.
BACKGROUND OF THE INVENTION
Known in the art is a complex platinum compound, viz. cis-dichlorodiamine platinum(II) (DDP) (Nature; vol. 222, 1969 (Macmillan (Journals) LTD, London) B. Rosenberg, L. Van Camp, J. E. Trosko, V. H. Mansour: "Platinum Compounds; A New Class of Antitumor Agents", p. 385).
This platinum compound has the formula: ##STR2## and reveals a high antitumor activity.
It possesses a remarkably wide spectrum of action on diverse tumors, activity in respect of rapidly growing and slowly developing neoplasms, as well as activity in respect of not only early-formed (small-size) neoplasms but also in respect of well-formed and even far-gone and disseminated neoplasms; it is also characterized by the absence of typical specificity.
Nevertheless, likewise all antitumor compounds, in addition to the effect on neoplasms, DDP exhibits a toxic effect the organism, thus limiting dosage of this compound and frequently forcing discontinuation of the treatment due to a toxic effect of the compound on kidney. The LD.sub.50 of this platinum complex (the dose at which 50% of the test animals are dead) is the same for mice and rats--about 13 mg/kg (Vestnik AMN SSSR, No. 2, 1979 (Medicina, Moscow); M. A. Presnov, A. L. Konovalova, V. P. Koral'chuk "Complex Compounds of Platinum in Chemotherapy of Malignant Tumors", p. 72).
Furthermore, an insufficient solubility of DDP in water (0.25 mass % at 25.degree. C.) complicates the use of this preparation in clinics and makes it impossible to carry out a local treatment of the tumor with a solution containing a high concentration of the preparation.
Also known in the art are platinum(II) dichlorocomplexes with two molecules of primary alicyclic amines, beginning with cyclopropylamine and ending with cyclooctylamine also revealing antitumor properties and corresponding to the formula: ##STR3## wherein n is 1 to 6 (Chem.-Biol. Interaction, vol. 5, 1972, Elsevier, Netherlands): T. A. Connors, M. Jones, W. C. J. Ross, P. D. Braddock, A. R. Khokhar, M. L. Tobe "New platinum complexes with antitumor activity", see p. 421-422). Chem.-Biol. Interaction, vol. 11, 1975 (Elsevier, Netherlands): P. D. Braddock, T. A. Connors, M. Jones, A. R. Khokhar, D. H. Melzack, M. L. Tobe "Structure and activity relationships of platinum complexes with antitumor activity", p. 153).
On regrafted plasmacytoma of mice ADJ/PC6A these complexes show a high antitumor activity, the highest selectivity of their action is observed for complexes with cyclopentyl- and cyclohexylamine (therapeutical indexes (TI/equal to the ratio of the LD.sub.50 to the inhibiting dose (ID) suppressing growth of the tumor by 90%, TI=LD.sub.50 /ID.sub.90 are equal to 200 and above 267 respectively). These very high therapeutical index values have caused clinical tests of cis-[PtCl.sub.2 (cyclo-C.sub.5 H.sub.9 NH.sub.2).sub.2 ] (cf. Cancer Treatment Reports, vol. 63, No. 9-10, September-October 1979 (national Cancer Institute, Bethesda); J. M. Hill, E. Loeb, A. Pardue, A. Khan, J. J. King, C. Aleman, N. O. Hill "Platinum Analogs of Clinical Interest", see p. 1510, 1512).
This compound, however, is substantially insoluble in water, wherefore it should be administered in the form of fine suspensions in sesame oil or in the form of aqueous solloids stabilized by polyvinylpyrrolidone. The administration of the compound in these forms has shown that it substantially remains at the spot of the injection and no therapeutic response or a side effect, apart from a local irritation upon administration of an oily suspension, is observed, wherefore further tests were stopped.
Known in the art is also a mixed chloride platinum(II) complex containing ammonia and cyclopentylamine having formula: cis-[PtCl.sub.2 NH.sub.3 (cyclo-C.sub.5 H.sub.9 NH
REFERENCES:
patent: 4115418 (1978-09-01), Gale et al.
patent: 4140707 (1979-02-01), Cleare et al.
patent: 4225529 (1980-09-01), Hydes et al.
patent: 4329299 (1982-05-01), Hydes
patent: 4614811 (1986-09-01), Gandolfi
Cheltsov-Bebutov Petr A.
Ivanov Viktor B.
Konovalova Alexandra L.
Kravchenko Alexandr N.
Presnov Mikhail A.
Institut Obschei I Neorganicheskoi Khimii Imeni N.S. Kurnakova A
Raymond Richard L.
Vsesojuzny Onkologichesky Nauchny Tsentr Akademii Meditsinskikh
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