The platinum (II) complexes, e.g. cisplatin, carboplatin or oxaliplatin, are broadly and long term used cytostatics (further CTS) in the therapy of tumor diseases. Their advantages are very good clinical experience and good antitumor efficacy. A big advantage of platinum CTS is that they kill already existing cancer cells by a direct cross-linking of their cellular DNA, in particular on guanine sites. Further, platinum CTS induce activation of stress kinases, resulting in increased expression of death receptors on the cell surface and increased transcription and translation of soluble death ligand (FAS ligand). This leads to activation of the external receptor apoptotic pathway. Platinum CTS, which preferentially binds to guanine, also inhibits telomeres having frequent sequences TTAGGG rich on guanine. Effects of platinum CTS are therefore surprisingly pluripotent and they are particularly suited to combination therapy of cancer with other CTS agents, including targeted inhibitors of cell signaling pathways. The drawbacks of platinum (II) CTS stem from the same action on cellular DNA in both cancer and healthy cells which result in serious side effects and toxicity. There is also impossibility of oral administration due to their big reactivity and less stability after administration. There is also described an acquired resistance of tumors against cisplatin after its long term use.
The platinum CTS as well as other CTS including targeted inhibitors are xenobiotic and they are rapidly captured, destroyed and eliminated by immune and enzyme systems after their administration to the body. A small residual portion of the administered dosage reaches the targeted cancer tissue as a consequence. So, the improvement of stability of the platinum CTS is of utmost importance. Further, a lipophilic cell membrane fundamentally limits penetration of any drug including platinum CTS into the cell and only a part of the residual portion of the dosage reaches the intracellular environment. Since a DNA-cross linking mechanism of action of the platinum CTS requires entry to cells, the capability of the platinum CTS to cross lipophilic cell membranes is of utmost importance. Once the part of the residual portion of the dosage reaches the intracellular environment, it is concurrently with its therapeutic action reduced and destroyed by the enzyme system with glutathione and degraded metabolites are then removed from the cells by the increased efflux by means of p-glycoprotein. Hence, the therapeutic efficacy of the platinum CTS and its degradation and elimination from the body after its administration is a kinetic competition variable in time.
The platinum (IV) complexes are a relatively new class of platinum anticancer drugs which offer unlike platinum (II) complexes better stability, increased lipophility, less toxicity and oral administration possibility. They also overcome a tumor resistance to cisplatin. The most interesting antitumor efficacy has platinum (IV) complex of the general formula (I) with cis,trans,cis geometric configuration of ligands around central Pt (IV)-ion:

A1 and A2 are equatorial aminoligands which remain in the platinum complex. B1 and B2 are axial ligands which should be reduced to platinum (II) species in the intracellular environment. C1 and C2 are equatorial leaving ligands which are hydrolyzed to reactive aqua-platinum (II) species which then create firm cross-linked complexes with cellular DNA, in particular on guanine sites, which leads to the cell apoptosis.
In further text and examples of embodiment, the “c-t-c” abbreviation is used for “cis-trans-cis” configuration of ligands in order to specify the stereochemistry of ligands around the central Pt (IV)-ion when grouped pairwise in the order written. Basic information about optimized structures of “c-t-c” platinum (IV) complexes, about their antitumor efficacy and about a process for preparation of such complexes are described e.g. in EP 0 328 274 (Johnson Matthey, Inc.), EP 0 423 707 (Bristol-Myers Squibb Co.) and U.S. Pat. No. 6,503,943 (Lachema, a.s.).
The most promising “c-t-c” platinum (IV) complex in the prior has the formula (II):
where R1 is methyl and A2 is either cyclohexylamine (the complex with the trade name “Satraplatin”, see EP 0 328 274) or 1-adamantylamine (the complex has the code name “LA-12”, see U.S. Pat. No. 6,503,943). Cyclohexylamine or 1-adamantylamine is highly lipophilic aminoligand which improves lipophility of the platinum (IV) complex and its penetration through the lipid cell membrane which results in the improvement of antitumor efficacy as a consequence. There is expert opinion that R1 group preferably contains 1 to 10 carbon atoms in the aliphatic chain or 3 to 7 carbon atoms in the carbon cycle (see EP 0 328 274, p. 3, line 12 and further), more preferably 3 (see ibid, claim 3). Satraplatin and LA-12 represent the best state of the art in this type of platinum complexes which offer the possibility of per oral administration and overcome in vitro efficacy of cisplatin and cisplatin resistance, too. However, they are more than ten years in clinical testing with average results which do not confirm their very good in vitro antitumor potential.
Adamantane is tricyclo (3.3.1.13,7) decane which has the unique, highly lipophilic and highly symmetric structure like diamond. Adamantyl derivatives were proposed for improvement of properties of many compounds including drugs in the prior art, e.g. Chem. Rev. 2013, No. 113, 3516. Even though adamantyl derivatives offer excellent tool for the improvement of the stability and lipophility of drugs it was not yet been fully exploited in platinum (IV) complexes. There have been described only very few platinum complexes with 1-adamantyl group in the prior art, moreover, these complexes contained the only one 1-adamantyl group. It was beside LA-12 its Pt (IV) analog with “all trans” configuration of ligands (J. Inorg. Biochem. 2008, No. 102, 1077) and further Pt(II) analogues of cisplatin having 1-adamantylamine in configuration “cis” (Gynecol. Oncol. 2006, No. 102, 32) and “trans” (J. Inorg. Biochem. 2008, No. 102, 1077) which had, however, a low antitumor efficacy.
“c-t-c” platinum (IV) complexes according to formula (I) with different axial carboxylate ligands B1 and B2 are generally prepared by the reaction of abundance of appropriate carboxylic acid anhydride with “c-t-c” PI(C1,C2)(OH)2(A1,A2) intermediate (e.g. EP 0 328 274, examples 1 to 5; J. Med. Chem. 1997, 40, 112). The reaction usually takes several days at room temperature, yields are between 23-87% and purity is between 70-95%. The further purification is necessary to achieve purity above 98% with the yield about 68% in the case of Satraplatin (see CN 1557821). The use of more reactive chloride of carboxylic acid instead of its anhydride to decrease the reaction time is possible but the yield is 14% only (see EP 0 328 274, Example 8).
So, there is still a continuing need for new platinum (IV) complexes with improved antitumor efficacy for the therapy of tumor diseases.
USPTO Backgrounds
USPTO Backgrounds