New 5-aminolevulinic acid prodrugs for use in photodynamic therapy and photodynamic diagnosis

Abstract

There is provided a compound of Formulaand salts thereof whereinR1 is an imine or an alkylated imine, said imine or alkylated imine comprising a linear or branched alkyl group of length C1 to C5;R2 are each independently(a) an unsubstituted or substituted linear or branched alkyl group of chain length C1-7;(b) an aryl substituted alkyl group, wherein said aryl group is substituted,(c) an alkoxy substituted alkyl group, wherein said alkoxy group is substituted by a methoxy group or an alkoxy group substituted with an alkoxy group; or(d) an H atom;wherein said substituents in (a) and (b) are selected from hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, nitro, oxo and fluoro groups.R3 and R4 are linear or branched alkyl groups of length C1 to C6 constituting a ketal or a cyclic ketal.The compounds claimed may be used for the manufacture of a medicament.

Description

FIELD OF INVENTION [0001]The present invention relates to derivatives of 5-aminolevulinic acid (5ALA) and in particular to derivatives comprising a hydrolysable group at position C4, for use as medicaments. In particular, the medicaments are used as photosensitizing agents in medical applications such as photochemotherapy and diagnosis of disorders or abnormalities of the body. Moreover, the invention relates to novel derivatives of 5-aminolevulinic acid (5ALA) as such, and in particular to novel derivatives comprising a hydrolysable group at position C4. Pharmaceutical compositions comprising the above derivatives also form part of the invention.BACKGROUND OF THE INVENTION[0002]Photochemotherapy, or photodynamic therapy (PDT) as it is also known, is a technique for the treatment of various abnormalities or disorders of the skin-or other epithelial organs or mucosa, especially cancers or pre-cancerous lesions, as well as certain non-malignant lesions for example skin complaints such...

AI Technical Summary

Benefits of technology

[0019]The compounds according to the invention comprise a hydrolysable functionality at C4 of 5ALA (the keto group of the parent compound 5ALA) or any of its derivatives modified by substituents at the amino- or carboxylic group, in order to enhance membrane penetration and thus shortening the retention time before irradiation.

Problems solved by technology

Such drugs become toxic when exposed to light.

Thus for example, certain photosensitizers become directly toxic when activated by light, whereas others act to generate toxic species, e.g. oxidizing agents such as singlet oxygen or other oxygen-derived free radicals, which are extremely destructive to cellular material and biomolecules such as lipids, proteins and nucleic acids.

The unfortunate drawback of this therapy is that unwanted mutagenic and carcinogenic side effects may occur.

A considerable disadvantage is that since it must be administered parenterally, generally intravenously, it can cause photosensitization of the skin which may last for several weeks following injection.

Similar problems exist with other porphyrin-based photosensitizers such as Foscan (temoporfin) or the so-called “hematoporphyrin derivative” (Hpd) which have also been reported for use in cancer photochemotherapy.

5ALA, which is formed from succinyl CoA and glycine in the first step of heme synthesis, is to a limited extent able to penetrate the skin and lead to a localised build-up of PpIX; since the action of ferrochelatase (the metallating enzyme) is the rate limiting step in heme synthesis, adding an excess amount of exogenous 5ALA (or a derivative thereof) bypasses the natural regulatory mechanisms, and leads to elevated levels of the photosensitizing agent PpIX in the cells, with a notable accumulation in tumorus cells [3,4].

Photochemotherapy with 5ALA is not always entirely satisfactory.

5ALA is not able to penetrate all tumors and other tissues with sufficient efficacy to enable treatment of a wide range of tumors or other conditions and 5ALA also tends to be unstable in pharmaceutical formulations.

However, these compounds still exhibit some limitations for use as pharmaceuticals in PDT, e.g. relatively low efficacy of membrane penetration.

Such a slow penetration hampers efficient clinical treatment by requiring longer retention times before irradiation, and may negatively influence the acceptance of treatment, both by the patient and the medical profession.

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