Miravant Pharmaceuticals, Inc.

Pdt Pharmaceuticals, Inc.

Byron C Robinson

Avinash S Phadke

Hugh L Narciso, Jr

Alan R Morgan

Dipanjan Sengupta

Barbara A Garcia

G Patrick Stahly

Stephanie Greene

Ian M Leitch

Shwn-Ji Susie Lee

Steve Rychnovsky

The present invention provides a process of preparation of naphthochlorins and other chlorins with annelated ring systems useful for photodynamic therapy and the compounds themselves. The method for producing naphthochlorin compounds include contacting compounds such as meso-(2'-hydroxymethyl)phenyl porphyrin or meso-(2&#x2032;-N,N,N-trialkylaminomethyl)phenyl porphyrin precursors with at least one acid catalyst at sufficient temperature for a sufficient time to yield the desired conversion. In a similar manner chlorins possessing annelated ring systems may be made from compounds such as meso-(2&#x2032;-hydroxymethyl)aryl porphyrins or meso-(2&#x2032;-N,N,N-trialkylaminomethyl)phenyl porphyrin. The procedures described herein provide new routes for synthesizing naphthochlorins and chlorins with annelated ring systems.

Chlorins possessing fused ring systems useful as photoselective compounds for photodynamic therapy

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

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

Metallotetrapyrrolic compounds having photherapeutic properties useful in photodetection and phototherapy of target issues, particularly porphyrins and azaporphyrins that including gallium in the central pyrrolic core. Also disclosed are methods of using metallotetrapyrrolic compounds for the treatment or detection of cardiovascular disease.

Metallotetrapyrrolic photosensitizing agents for use in photodynamic therapy

The present invention provides a process of preparation of naphthochlorins and other chlorins with annelated ring systems useful for photodynamic therapy and the compounds themselves. The method for producing naphthochlorin compounds include contacting compounds such as meso-(2&prime;-hydroxymethyl)phenyl porphyrin or meso-(2&prime;-N,N,N-trialkylaminomethyl)phenyl porphyrin precursors with at least one acid catalyst at sufficient temperature for a sufficient time to yield the desired conversion. In a similar manner chlorins possessing annelated ring systems may be made from compounds such as meso-(2&prime;-hydroxymethyl)aryl porphyrins or meso-(2&prime;-N,N,N-trialkylaminomethyl)phenyl porphyrin. The procedures described herein provide new routes for synthesizing naphthochlorins and chlorins with annelated ring systems.

Solid forms of tin ethyl etiopurpurin (SnET2), including crystalline form I, crystalline Form II, disordered Form II, and an amorphous form are disclosed. Also disclosed are the 1,2-dichloroethane solvate of SnET2 and the N,N-dimethylformamide solvate of SnET2. These solid forms of SnET2 are useful as pharmaceuticals that exhibit pharmacological activity when irradiated with light and thus are useful in photodynamic therapy. Also disclosed are methods for making these solid forms of SnET2 and pharmaceuticals including these solid forms of SnET2.

Solid forms of tin ethyl etiopurpurin and processes for producing such forms

Processes for the large scale production of tetrapyrrolic compounds useful as photosensitizers in photodynamic therapy, such as meso-formyl porphyrins, meso-acrylate porphyrins, purpurins and benzochlorins. In particular, tin ethyl etiopurpurin (SnET2) and the intermediates necessary for its production without chromatography are disclosed.

Processes for large scale production of tetrapyrroles

The invention disclosed herein involves a phototherapeutic pyrrolic core complexed with a non-radioactive Indium atom. Complexation of Indium by the pyrrolic core forms a metalopyrrolic compound which influences enables these compounds to localize at target sites a phototherapy. Such functionally aids in both detection and phototherapy of disease sites, or provides functionality that binds to site specific receptors of a target area such that the therapy is improved.

Indium photosensitizers for PDT

Bacteriochlorins and bacteriopurpurins useful for photodynamic therapy and methods for their manufacture are described herein. Methods for producing the claimed compounds include contacting meso-diacrylate porphyrin precursors with a solvent and a base catalyst at sufficient temperature and time to yield the desired conversion. Reduced bacteriochlorins can be produced by contacting unsaturated bacteriochlorins or bacteriopurpurins with a hydrogenation catalyst and hydrogen. These methods provide new routes for synthesizing bacteriochlorins and bacteriopurpurins from symmetrical and asymmetrical meso-diacrylate porphyrins.

Bacteriochlorins and bacteriopurpurins useful as photoselective compounds for photodynamic therapy and a process for their production

A broad class of photosensitive compounds having enhanced in vivo target tissue selectivity and versatility in photodynamic therapy. Many furocoumarin compounds, such as psoralens, exhibit cytostatic activity when photoactivated but exhibit little in vivo specificity for selectively accumulating in any particular target tissue such as atheromatous plaques. Reactive Oxygen Producing Photosensitizers ('ROPPs') are photoactivatable compounds having an affinity for hyperproliferating cells (such as atheromatous plaque cells), which when photoactivated, produce cytotoxic reaction products. The photoactivity of a ROPP, such as a porphyrin, may be reduced by metalating the porphyrin while the selective affinity of the metalized ROPP for hyperproliferating tissue remains substantially unchanged. By linking a furocoumarin compound to a ROPP to form a F-ROPP, the cytostatic properties of the furocoumarin portion of the F-ROPP can be exploited while the selective affinity of the ROPP portion of the compound for hyperproliferating cells such as atheromatous plaque provides enhanced tissue selectivity without cytotoxicity. In vivo, certain F-ROPPs may be forced to selectively accumulate in a target tissue by illuminating only the target tissue with light having a wavelength operable for photoactivating the F portion of the F-ROPP thereby causing the F-ROPP to either form a monoadduct with or crosslink the cellular DNA in the target tissue. Light of a second wavelength can then be delivered to the target tissue to photoactivate the ROPP portion causing further interference with cellular activity.

Compounds and method for PDT of intimal hyperplasia and other diseases

Photoactivatable compounds comprising benzochlorin and furocoumarin

An improved method for the demethoxycarbonylation of porphyrinic compounds such as pheophorbides involving reacting the starting porphyrinic compound with a high boiling point solvent to which a selected amount of water has been added.

Method for the demethoxycarbonylation of porphyrinic compounds such as

A method for preparing functionalized derivatives of organic or inorganic compounds and tetrapyrrolic compounds in particular, all of which compounds have at least one sulfonic acid group, by first preparing a sulfonyl halide intermediate of the compound then reacting the intermediate with a second compound having a reactive hydroxyl or amine group to yield the desired sulfonylamide or sulfonic esters thereof. The method may be used to produce a variety of photosensitive compounds having different functionality. For example, sulfonamide or sulfonic ester reaction products of the tetrapyrrolic compounds or other photosensitive organic molecules may exhibit an enhanced ability to localize at a particular target site for phototherapy. The method provides means for altering the functionality of sulfonic acid-containing photosensitive compounds to produce derivatives thereof which may aid in the detection and/or phototherapy of diseased sites or provide functionality having enhanced affinity and exhibiting improved binding to site specific receptors within a diseased target tissue such that the therapy is improved.

Growing community of inventors

Santa Barbara, CA, United States of America

Byron C Robinson