Substituted porphyrin and azaporphyrin derivatives and their use in photodynamic therapy, radioimaging and MRI diagnosis

Abstract

Substituted porphyrin and azaporphyrin deviations with various substitutents in the 12- and 17-positions of the prophyrin skeleton as pharmaceutical agents for use in photodynamic therapy, MRI diagnosis, and radiodiagnostics.

Description

DESCRIPTION OF THE INVENTION [0001] 1. Field of the Invention [0002] This invention is directed to substituted porphyrin and azaporphyrin derivatives with various substituents in the 13- and 17-positions of the porphyrin skeleton suitable as pharmaceutical agents for use in photodynamic therapy, MRI diagnosis, and radiodiagnostics. The invention is also directed to pharmaceutical agents that contain these compounds, as well as a process for the production of these compounds and agents. [0003] 2. Background of the Invention [0004] Photodynamic therapy (“PDT”) is a new modality for the treatment of malignancies, diseased tissue, hyperproliferating tissues, pathogens or unwanted normal tissues. PDT involves a localized or systemic administration of a photosensitizing compound followed by exposure of target tissue to photoactivating light. The photoactivating light excites the photosensitizer which, in turn, interacts with singlet oxygen causing the production of cytotoxic oxygen specie...

AI Technical Summary

Benefits of technology

"The present invention provides phototherapeutic compositions of metallo-tetrapyrrolic compounds that can be used as MRI, radiodiagnostic and PDT agents. These compounds have the formula I and can be selected from a variety of different groups, such as H, halide, alkyl, haloalkyl, cyano, aryl, and more. The compounds can be used in various applications, such as in the diagnosis and treatment of medical conditions. The invention also provides methods for synthesizing these compounds and their use in various medical procedures."

Problems solved by technology

Indeed, the biological factors that result in the preferential uptake of some photosensitizers in certain tissue types compared to other tissue types are not well understood either.

Surprisingly, it has been found that short wavelength photosensitizers (with activation absorptions 600 nm) have shown ineffective clinical outcomes.

While several of the photosensitizers described above have been used to treat atheromatous plaques and some are able to display some inhibition of intimal hyperplasia in animal models, many if not all have characteristics that will limit the usefulness of these drugs in a clinical setting.

A photosensitizer delivered systemically with a long half-life (CASPc, Photofrin, SnET2) may have phototoxic side effects if exposed to direct light, within days of the procedure.

Experiments that we have performed in pig arteries with new photosensitizer candidates at light activation >600 nm have resulted in unacceptable levels of damage to myocardial or cardiac muscle tissue surrounding the treatment area.

Attempts to lower the light dosimetry in order to limit treatments to the target tissue (media / intima) leads to long treatment times and less efficacy.

In addition, long treatment times in the artery exposes the patient to additional risks with inflation and deflation of the balloon devices.

Thus, it is believed that, long wavelength absorbing molecules (>600 nm), unless highly selective to target myocardial and intimal tissues (which has not to date been reported with any photosensitizer in cardiovascular tissues), may cause unacceptable normal cardiac tissue damage.

In addition, protoporphyrin IX and photofrin do not display absorption maximas at 532 nm, thus they may be inefficient at absorbing treatment light at this wavelength and have very low molar extinction coefficients at 575 nm (˜7000 cm−1 / M−1).

Furthermore, because long wavelength photosensitizers by design have red absorption peaks, operating room lighting in an emergency situation may cause serious photosensitivity in light exposed tissues.

Attempts to use red light filters on operating room lights results in poor tissue contrast and sub-optimal lighting conditions, making surgical procedures under these conditions extremely difficult, if not impossible.

Another significant drawback of the above long wavelength absorbing compounds mentioned is that they are only suitable for therapy; prior or simultaneous MRI-diagnostic monitoring of the success of the therapy is not possible with them, nor is radiodiagnostic imaging.

This requirement often cannot be met.

5, 1986). However, the compounds so far described are far from being able to satisfactorily meet the desired requirements to be effective PDT, MRI and radiodiagnostic imagi

While these compounds show a good concentration behavior in various target organs, the described compounds used as NMR diagnostic agents are not satisfacatory because they require a dose necessary for optimal imaging that is too close to the lethal dose.

Hematoporphyrin derivatives have the drawback that they can eliminate both pseudobenzylic OH groups in the hydroxyethyl side chains.

However, such porphyrin esters are not very suitable for parenteral use in patients, especially for NMR or radiodiagnostic diagnosis, since the injection solutions obtained from them can neither be heat-sterilized nor stored for a sufficiently long time.

However, all of these approaches using deuteroporphyrins are suboptimal with respect to design of short wavelength PDT photosensitizers for use as MRI or radiodiagnostic agents for reasons detailed below.

This synthetic approach carries with it significant manufacturing problems.

The separation of the two porphyrins is often difficult (if not impossible) and complicates both the manufacturing process and the cost of the final product.

If one of the isomers is not optimal therapeutically due to any one of these parameters, then the route to regulatory approval is often more complex, time consuming and costly than pursuing a single defined isomer.

A second limiting factor that has been highlighted previously, is the instability of the various linking groups to aqueous hydrolysis, elimination at sterilization temperatures, or prolonged storage in solution.

Additionally, the use of diastereotopic mixtures as occurs with —CH(OR)CH3 groups in porphyrins complicates the analysis of the molecules for development.

Niedballa and Platzek's approach also has the same synthetic manufacturing problems as explained for Sakata (except when R1═H), i.e., multiple compounds are produced when a single linking moiety is attached to the molecule.

The limitation of R1═H symmetry does not, however, allow for modification of this molecule with other functionality that may enhance localization or uptake in tissues or target organelle, or changes in pharmacokinetic or elimination profiles for singly linked molecules.

Compounds with high water solubility are often not taken up efficiently by tumors or cells.

An additional problem, that has been overlooked by all of the prior workers (Sakata, Niedballa, and Platzek) in the development of short wavelength porphyrin photosensitizers, is the limited absortion profile of the porphyrin ring system metallated tetrapyrroles.

Hence, photosensitizers with low molar extinction coefficients capture photons less efficiently than molecules with high molar extinction coefficients and are thus less efficient.

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