N,O-amidomalonate platinum complexes

Details N,O-amidomalonate platinum complexes N,O-amidomalonate platinum complexes

2001-01-04

2004-02-17

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Solid synthetic organic polymer as designated organic active...

Aftertreated polymer

C424S078080, C424S078160, C424S078170, C424S078180, C424S078220, C424S078230

Reexamination Certificate

active

06692734

ABSTRACT:

BACKGROUND OF THE INVENTION
Following the discovery of the anti-tumor activity of cisplatin (Rosenburg et al, 1969) extensive research has been conducted into areas related to the use of platinum complexes for the treatment of cancer. The anti-tumor activity of platinum compounds is believed to result from the loss of the labile chlorine ligand(s) in vivo to form a reactive mono- or di-aqua complex, which is able to form intra- and inter-strand DNA crosslinks in tumor cells. These crosslinks can result in cell death. Cisplatin (cDDP or cis-diamminedichloroplatinum(II) is the most widely used of the platinum compounds approved for use in human subjects, and is indicated for the treatment of solid tumors, including testicular, ovarian, and head and neck, and in combination with other agents in use against squamous cell carcinoma and small cell lung carcinoma (Sur, et al., 1983).
However, there are significant limitations to the use of cisplatin due to its toxicity. Nephrotoxicity and ototoxicity are typically its dose limiting toxicities. Because of this problem, many researchers have made and tested novel small molecule platinum chelates in the hope of finding new compounds in which the therapeutic index (the ratio between the maximum dose that can be tolerated due to toxicity and the dose which provides efficacy) is improved. Changes in platinum chelate structure might also extend the spectrum of tumor types for which platinum therapy could be effective, and/or alter the toxicity profile. As noted above, labile leaving groups are required for tumorcidal activity, but these functional groups can also contribute to the toxicity of the molecule. Research conducted at the Institute for Cancer Research in the U.K. demonstrated that by replacing the chlorine atoms with other leaving groups, compounds could be obtained with lower nephrotoxicity (Harrap, 1985). This work led to the discovery of carboplatin, a cisplatin analog in which the two coordinated chloride ions are replaced by a chelate of 1,1-cyclobutane-dicarboxylic acid. This chelating group is less labile compared with the chlorine atoms of cisplatin. As a result, compared to cisplatin, higher doses of carboplatin are required for a similar tumorcidal effect, but carboplatin has a higher therapeutic index, and the dose limiting toxicity is myelosuppression rather than nephrotoxicity.
Oxaliplatin is another small platinum chelate approved for human use in Europe. This platinum chelate was the result of research investigating the effect of changes in both the non-labile (amine) ligand of cisplatin as well as the labile ligands. In oxaliplatin, the coordinated ammonia ligands are replaced by a trans-1R,2R-diaminocyclohexane (DACH) chelate, while the labile chlorine ligands are replaced by an oxalic acid chelate. It has been shown that oxaliplatin (and other DACH platinum compounds) have a different activity spectrum when compared with cisplatin and carboplatin in the NCI human tumor screen (Paull et al. 1989), and oxaliplatin was subsequently developed for the treatment of colorectal cancer. The dose limiting toxicity of oxaliplatin is sensory neuropathy.
Many other small platinum complexes have been investigated as potential chemotherapeutic agents, but at best, only slight improvements to efficacy and therapeutic index have been achieved. Many of these newer small platinum chelates are inactive or have formulation problems (for example, low solubility in water or poor aqueous stability), and most induce severe toxic side effects including nephrotoxicity, neurotoxicity, myelosuppression, nausea and vomiting. A number of attempts to improve the therapeutic index of the approved platinum complexes have involved either combination therapy, for example, the co-administration of cisplatin and paclitaxel; (Posner et al, 2000) or formulation changes, such as entrapment in liposomes (Steerenberg et al, 1988). There remains a distinct need for new platinum chelates with further improvements in therapeutic index compared with the currently-approved platinum chelates. Such chelates would ideally be water soluble and stable in an aqueous environment, but sufficiently labile in tumor cells to provide species capable of crosslinking DNA and ultimately causing tumor cell death.
Furthermore, improvements to therapeutic index might be achieved by targeting of platinum complexes to tumor cells. Conventional small molecule platinum complexes such as cisplatin, carboplatin, and oxaliplatin are not specifically targeted to tumor cells, and following intravenous administration, they can diffuse into normal cells as readily as they diffuse into tumor cells. Also, their doses are rapidly cleared. At 3 hour post injection 90% of plasma platinum from cisplatin is irreversibly protein bound (Physican's. Desk Ref. 1997). For cisplatin and carboplatin 25% and 65%, respectively, of the dose is renally secreted within 12 h (DeVita et al. 1993). Improvements in therapeutic index might be possible if platinum complexes are more readily delivered to tumors and/or more readily taken up by tumor cells than normal cells.
One method of tumor targeting which has been extensively reported in the literature involves the labile attachment of a chemotherapeutic compound to a polymer or other macromolecular structure. It has been demonstrated that the concentration of polymers and nanoparticles in tumors exceeds their concentration in normal tissue following intravenous administration (Seymour 1992; Veronese et al. 1999). The mechanism for this preferred tumor accumulation has been termed the “enhanced permeability and retention” (or “EPR”) effect (Seymour et al. 1995). Essentially, tumor endothelial cells are more ‘leaky’ than normal endothelial cells, so polymers and nanoparticles more readily cross the endothelial cell layer in tumors than is the case in normal tissue. Thus, following intravenous administration, polymers and nanoparticles can enter the extracellular fluid of tumor cells much more readily than that of normal cells. Furthermore, lymphatic drainage of the extracellular fluid in tumor cells is much less efficient compared with normal cells. These two factors account for the greater concentration of polymers and nanoparticles in tumors relative to normal tissue relative to small, freely diffusible molecules.
There are already several examples of constructs which provide for the passive targeting of chemotherapeutic agents to tumors through the EPR effect. For example, doxorubicin was attached to a polyhydroxypropylmethacrylamide, (poly(HPMA)), linear polymer backbone via a tetrapeptide designed to be cleaved by lysosomal enzymes. The water-soluble conjugate was termed ‘PK1’, and has been subject of numerous publications describing its chemistry, pre-clinical testing, and clinical evaluation (for example, Seymour et al, 1990; Pimm et al, 1996; Duncan et al. 1998; Thomson et al. 1999; Minko et al. 2000). Similarly, HPMA was conjugated to paclitaxel and camptothecin for enhanced delivery of these chemotherapeutic molecules to tumors (Fraier et al, 1998; Caiolfa et al. 2000). Both paclitaxel and camptothecin have been attached to other water-soluble polymers for the purpose of improving tumor targeting and drug water solubility (for example, Li et al. 2000 and Conover et al. 1998).
It has been proposed that polymer-platinum conjugates might be used to benefit patients in treating cancer by increasing the solubility of platinum complexes, reducing systemic toxicity, and targeting tumors by the EPR effect (Duncan 1992). Several examples of polymer-platinum conjugates have been reported. For example, U.S. Pat. No. 5,965,118 describes various platinum chelates attached to the HPMA polymer backbone via a peptide which is potentially cleavable by lysosomal enzymes (see also Gianasi et al. 1999). Additional examples include polyphosphazene platinum (II) conjugates (Sohn et al. 1997; U.S. Pat. No. 5,665,343), poly(glutamate) platinum complexes (Schechter et al. 1987), and others (Bogdanov, Jr., et al., 1996; Han, et al., 1994; Johnsson et al. 1996; Fiebig, et

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