Method and compositions for treating hematological malignancies

Abstract

A compound of formula 1 and / or its salts, tautomers or solvates is used to treat hematological malignancies. In an embodiment, an organic acid salt of compound 1 is provided for general use in treatment of neoplasms, and in a further embodiment the salt is stabilized with carbohydrate.

Description

BACKGROUND OF THE INVENTION [0001] N-6 cyclopropylPMEDAP (“cpr-PMEDAP”) has been shown to be effective producing an antiproliferative and differentiation-inducing effect in in vitro cell culture against a variety of tumor cell lines (Naessens et al., “Biochem. Pharmacol.” 1999 Jul. 15; 58(2):311-23). However, when cpr-PMEDAP and other N6-substituted PMEDAP compounds were employed in an in vivo model of haematological malignancy of inbred Sprague-Dawley rats (Valerianova et al. “Anticancer Res.” 2001 May-June; 21(3B):2057-64), the authors concluded that the “acyclic nucleoside phosphonates substituted at the 6-position of 2,6-diaminepurine ring do not seem to be promising drugs for the treatment of haematological malignancies” due to “high toxicity”. [0002] Various bis- and mono-amino acid amidate esters of cpr-PMEDAP (and their use as antiproliferative agents) have been disclosed. See WO 05 / 066189. WO 02 / 08241 discloses a method for screening methoxyphosphonate nucleotide analogue p...

AI Technical Summary

Benefits of technology

[0013] Applicants have found that the nature of the alkyl ester on the carboxyl group of the amino acid ester of the cpr-PMEDAP bisamidate class of compounds is instrumental in preferentially distributing the compound into PBMCs. Unexpectedly, it was found that administering the bis(ethyl) ester (i.e., compound 1) resulted in a highly preferential distribution of cpr-PMEDAP into the PBMCs over plasma. The distribution was far superior to that obtained with the otherwise closely related bis(isopropyl) ester. In addition, it was determined that the organic acid salts of compound 1 were less hygroscopic than the free base, thereby facilitating the manufacture of products containing compound 1. Finally, it was determined that the stability of these salts (particularly in parenteral formulations) was enhanced by including a carbohydrate in the formulations.

Problems solved by technology

“Anticancer Res.” 2001 May-June; 21(3B):2057-64), the authors concluded that the “acyclic nucleoside phosphonates substituted at the 6-position of 2,6-diaminepurine ring do not seem to be promising drugs for the treatment of haematological malignancies” due to “high toxicity”.

While the introduction of novel agents such as imatinib (Gleevec®), bortezomib (Velcade®) and rituximab (Rituxin®) has improved the outcome of several hematological malignancies, there remains an unmet medical need for novel, efficacious therapeutics.

However, there remains substantial unmet medical need, for example for the treatment of acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL), as illustrated by poor 5-year survival rates.

However, existing therapies have limitations with regard to, for example, safety, efficacy and ease of use.

It is not uncommon for treatments to be successful initially, then have the hematological malignancies frequently relapse over time.

However, applicants determined that the free base is not commercially optimal for formulation into a dosage form because the free base is hygroscopic.

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