University of Toledo

Medical College of Ohio

St. Vincent Medical Center

Pdt Pharmaceuticals, Inc.

Other

Miravant Pharmaceuticals, Inc.

Alan R Morgan

Steven H Selman

Hugh L Narciso, Jr

Byron C Robinson

Martha Kreimer-Birnbaum

James A Hampton

Dimitris Skalkos

Greta M Garbo

Rick W Keck

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

Families of Diels Alder adducts and of metal complexes of Diels Alder adducts, which are useful as particularly active compounds for use in photodynamic therapy, are disclosed. The Diels Alder adducts and a preferred family of metal complexes have the structures of Formulas 3 and 4, below: ##STR1## where R1, R2, R3 and R4 can be the same or different, and each is methyl, ethyl, an amino acid moiety which is a part of an amide produced by reaction between an amine function of a naturally occurring amino acid and a carbonyl function of the adduct, or a monoclonal antibody moiety which is attached to the adduct moiety through a carbonyl which is a part of an amide produced by reaction between an amine function of a monoclonal antibody and a CO.sub.2 R', CH.sub.2 CO.sub.2 R' or CH.sub.2 CH.sub.2 CO.sub.2 R'group of the adduct, and wherein the moiety is of a monoclonal antibody which selectively binds to malignant tumors, R5, R6 and R7 can be the same or different, and each is ethyl, an amino acid moiety which is a part of an amide produced by reaction between an amine function of a naturally occurring amino acid and a carbonyl function of the adduct, or a monoclonal antibody moiety which is attached to the adduct moiety through a carbonyl which is a part of an amide produced by reaction between an amine function of a monoclonal antibody and a CO.sub.2 R', CH.sub.2 CO.sub.2 R' or CH.sub.2 CH.sub.2 CO.sub.2 R'group of the adduct, and wherein the moiety is of a monoclonal antibody which selectively binds to malignant tumors, M comprises 2H or a metal cation, e.g., Sn or Zn, that is complexed with two of the nitrogens of the adduct, and R8 is an alkyl group other than t-butyl having from one to four carbon atoms. The use of the adducts and complexes in PHD is also disclosed.

Method of treating blood which comprises use of diels alder adducts of

Photoactivatable compounds comprising benzochlorin and furocoumarin

Photoactivatable compositions and to methods for the diagnosis and

Purified imines of porphyrins, chlorins, bateriochlorins, chlorophylls, bacteriochlorophylls, purpurins, reduced purpurins, verdins, Diels Alder adducts, benzochlorins and metal complexes of the foregoing imines are disclosed. The formulas of the benzochlorinimines and of the benzochlorinimine metal complexes are set forth below: ##STR1## In specific examples, M in the metal complexes is a copper cation that is complexed with two of the nitrogens of the benzochlorinimine R' and R'' are methyl, and R1 through R8 are ethyl.

Imines of porphyrins, of porphyrin derivatives, and of related

Families of Diels Alder adducts and of metal complexes of Diels Alder adducts, which are useful as particularly active compounds for use in photodynamic therapy, are disclosed. The Diels Alder adducts and a preferred family of metal complexes have the structures of Formulas 1, 2, 3 and 4, below: ##STR1## where R1, R2, R3 and R4 can be the same or different, and each is methyl, ethyl or an amino acid moiety which is a part of an amide produced by reaction between an amine function of a naturally occurring amino acid and a carbonyl function of the adduct, R5, R6 and R7 can be the same or different, and each is ethyl or an amino acid moiety which is a part of an amide produced by reaction between an amine function of a naturally occurring amino acid and a carbonyl function of the adduct, M comprises metal cation.

Method of use of diels alder adducts of vinyl porphyrin metal complexes

Families of Diels Alder adducts and of metal complexes of Diels Alder adducts, which are useful as particularly active compounds for use in photodynamic therapy, are disclosed. The Diels Alder adducts and a preferred family of metal complexes have the structures of Formulas 1, 2, 3 and 4, below: ##STR1## where R1, R2, R3 and R4 can be the same or different, and each is methyl, ethyl or an amino acid moiety which is a part of an amide produced by reaction between an amine function of a naturally occurring amino acid and a carbonyl function of the adduct, R5, R6 and R7 can be the same or different, and each is ethyl or an amino acid moiety which is a part of an amide produced by reaction between an amine function of a naturally occurring amino acid and a carbonyl function of the adduct.

Production and use of diels alder adducts of vinyl porphyrins, of metal

Families of Diels Alder adducts and of metal complexes of Diels Alder adducts, which are useful as particularly active compounds for use in photodynamic therapy, are disclosed. The Diels Alder adducts and a preferred family of metal complexes have the structures of Formulas 1, 2, 3 and 4, below: ##STR1## where R1, R2, R3 and R4 can be the same or different, and each is methyl, ethyl or an amino acid moiety which is a part of an amide produced by reaction between an amine function of a naturally occurring amino acid and a carbonyl function of the adduct, R5, R6 and R7 can be the same or different, and each is ethyl or an amino acid moiety which is a part of an amide produced by reaction between an amine function of a naturally occurring amino acid and a carbonyl function of the adduct, M comprises a metal cation, e.g., Sn or Zn, that is complexed with two of the nitrogens of the adduct, and R8 is an alkyl group other than t-butyl having from one to four carbon atoms. The use of the adducts and complexes in PHD is also disclosed.

Diels alder adducts of vinyl porphyrins

A family of benzochlorins, a family of verdins, a family of porphyrin derivatives and metal complexes thereof are disclosed. The benzochlorins have the formula of FIG. 3 of the attached drawings; their metal complexes have the formula of FIG. 1. The verdins have the formula of FIG. 4 of the attached drawings; their metal complexes have the formula of FIG. 2. The porphyrin derivatives have the formula of FIG. 7 of the attached drawings; their metal complexes have the formula of FIG. 8. Solutions of the benzochlorins, verdins, porphyrin derivatives and metal complexes which are physiologically acceptable for intravenous administration are also disclosed, as are emulsions or suspensions of the solutions, and compositions which additionally include cyclodextrin, and wherein the molecules of the benzochlorin, verdin, porphyrin derivative or metal complex are encapsulated within the molecules of the cyclodextrin. The solvent for the solutions can be a product of the reaction of ethylene oxide with castor oil. A method for detecting and diseased tissue in human and animal patients is also disclosed. The method comprises administering one of the benzochlorins, verdins, porphyrin derivatives or metal complexes to the patient. For detection, the diseased tissue is then illuminated with ultra violet light or light at which the benzochlorin or the like administered has an absorption peak; for treatment, the diseased tissue is illuminated with visible light of a wavelength at which the benzochlorin or the like administered shows an absorption peak. A method for treating blood and other body fluids and tissues is also disclosed. The method comprises in vitro irradiation of the body fluid or tissue and an effective amount of a benzochlorin or the like with light of a wavelength at which the benzochlorin or the like has an absorbance peak.

Uses of benzochlorins, verdins and porphyrin derivatives and of

The treatment of blood and other body fluids and tissues, the detection of tumors and the treatment of patients is disclosed. The treatment and detection involve the use of families of chlorins, families of purpurins and families of metal complexes of chlorins and purpurins. The purpurins and their metal complexes have the structures of FIGS. 1 , 7, 14-18, 29-38, 44-48 and 54-58 of the attached drawings. The chlorins and their metal complexes have the formulas of FIGS. 2 , 8, 19, 20, 22, 23, 24, 25, 27, 28, 39, 40, 42, 43 and 49-53 of the attached drawings. Solutions of the purpurins, of the foregoing and other chlorins and of the metal complexes which are physiologically acceptable for intravenous administration are also disclosed, as are emulsions or suspensions of the solutions. The solvent for the solutions can be a product of the reaction of ethylene oxide with castor oil. Families of purpurins, chlorins and metal complexes which can be detected by nuclear magnetic resonance or by an instrument that detects ionizing radiation are also disclosed. These compounds have the formula of one of FIGS. 1 , 2, 7, 8, or 14-58 and a structure which is enriched in an atom that can be detected by nuclear magnetic resonance, e.g., .sup.13 C or .sup.15 N, or by an instrument that detects ionizing radiation, e.g., .sup.14 C or .sup.131 I.

Use of purpurins, chlorins and purpurin- and chlorin-containing

A family of benzochlorins, a family of verdins, a family of porphyrin derivatives and metal complexes thereof are disclosed. The benzochlorins have the formula of FIG. 3 of the attached drawings; their metal complexes have the formula of FIG. 1 . The verdins have the formula of FIG. 4 of the attached drawings; their metal complexes have the formula of FIG. 2. The porphyrin derivatives have the formula of FIG. 7 of the attached drawings; their metal complexes have the formula of FIG. 8. Solutions of the benzochlorins, verdins, porphyrin derivatives and metal complexes which are physiologically acceptable for intravenous administration are also disclosed, as are emulsions or suspensions of the solutions, and compositions which additionally include cyclodextrin, and wherein the molecules of the benzochlorin, verdin, porphyrin derivative or metal complex are encapsulated within the molecules of the cyclodextrin. The solvent for the solutions can be a product of the reaction of ethylene oxide with castor oil. A method for detecting and treating tumors in human and animal patients is also disclosed. The method comprises administering one of the benzochlorins, verdins, porphyrin derivatives or metal complexes to the patient. For detection, the tumor area is then illuminated with ultra violet light; for treatment, the tumor area is illuminated with visible light of a wavelength at which the benzochlorin, verdin, porphyrin derivative or complex administered shows an absorption peak.

Compositions of porphyrin derivatives

Families of Diels Alder adducts and of metal complexes of Diels Alder adducts, which are useful as particularly active compounds for use in photodynamic therapy, are disclosed. The Diels Alder adducts and a preferred family of metal complexes have the structures of Formula 1, Formula 2, Formula 3 and Formula 4, below: ##STR1## where R1, R2, R3 and R4 can be the same or different, and each is methyl or ethyl, R5, R6 and R7 are ethyl, R8 is an alkyl group other than t-butyl having from one to four carbon atoms and M comprises a metal cation, e.g., Sn or Zn, that is complexed with two of the nitrogens of the adduct. The use of the adducts and complexes in photodynamic therapy is also disclosed.

Production and use of Diels Alder adducts of vinyl porphyrins and of

A family of benzochlorins, a family of verdins, a family of porphyrin derivatives and metal complexes thereof are disclosed. The benzochlorins have the formula of FIG. 3 of the attached drawings; their metal complexes have the formula of FIG. 1 . The verdins have the formulas of FIGS. 4 and 6 of the attached drawings; their metal complexes have the formulas of FIGS. 2 and 5. The porphyrin derivatives have the formula of FIG. 9 of the attached drawings; their metal complexes have the formula of FIG. 10 . Solutions of the benzochlorins, verdins, porphyrin derivatives and metal complexes which are physiologically acceptable for intravenous administration are also disclosed, as are emulsions or suspensions of the solutions, and compositions which additionally include cyclodextrin, and wherein the molecules of the benzochlorin, verdin, porphyrin derivative or metal complex are encapsulated within the molecules of the cyclodextrin. The solvent for the solutions can be a product of the reaction of ethylene oxide with castor oil. A method for detecting and treating tumors in human and animal patients is also disclosed. The method comprises administering one of the benzochlorins, verdins, porphyrin derivatives or metal complexes to the patient. For detection, the tumor area is then illuminated with ultra violet light; for treatment, the tumor area is illuminated with visible light of a wavelength at which the benzochlorin, verdin, porphyrin derivative or complex administered shows an absorption peak.

Production and use of porphyrin derivatives and of compositions

Families of chlorins, families of purpurins and metal complexes thereof are disclosed. The purpurins and their metal complexes have the structures of FIGS. 1, 7, 14-18, 29-38, 44-48 and 54-58 of the attached drawings. The chlorins and their metal complexes have the formulas of FIGS. 2, 8, 19, 20, 22, 23, 24, 25, 27, 28, 39, 40, 42, 43 and 49-53 of the attached drawings. Solutions of the purpurins, of the foregoing and other chlorins and of the metal complexes which are physiologically acceptable for intravenous administration are also disclosed, as are emulsions or suspensions of the solutions. The solvent for the solutions can be a product of the reaction of ethylene oxide with castor oil. A method for detecting and treating tumors in human and animal patients is also disclosed. The method comprises administering one of the purpurins, chlorins or metal complexes to the patient. For detection, the patient is then illuminated with ultra violet light; for treatment, the patient is illuminated with visible light of a wavelength at which the purpurin, chlorin or complex administered shows an absorption peak. Families of purpurins, chlorins and metal complexes which can be detected by nuclear magnetic resonance or by an instrument that detects ionizing radiation are also disclosed. These compounds have the formula of one of FIGS. 1, 2, 7, 8, or 14-58 and a structure which is enriched in an atom that can be detected by nuclear magnetic resonance, e.g., C-13 or N-15, or by an instrument that detects ionizing radiation, e.g., C-14.

Production and use of purpurins, chlorins and purpurin- and

A family of benzochlorins, a family of verdins, a family of porphyrin derivatives and metal complexes thereof are disclosed. the benzochlorins have the formula of FIG. 3 of the attached drawings; their metal complexes have the formula of FIG. 1. The verdins have the formula of FIG. 4 of the attached drawings; their metal complexes have the formula of FIG. 2. The porphyrin derivatives have the formula of FIG. 9 of the attached drawings; their metal complexes have the formula of FIG. 10. Solutions of the benzochlorins, verdins, porphyrin derivatives and metal complexes which are physiologically acceptable for intravenous administration are also disclosed, as are emulsions or suspensions of the solutions, and compositions which additionally include cyclodextrin, and wherein the molecules of the benzochlorin, verdin, prophyrin derivative or metal complex are encapsulated within the molecules of the cyclodextrin. The solvent for the solutions can be a product of the reaction of ethylene oxide with castor oil. A method for detecting and treating tumors in human and animal patients is also disclosed. The method comprises administering one of the benzochlorins, verdins, porphyrin derivatives or metal complexes to the patient. For detection, the tumor area is then illuminated with ultra violet light; for treatment, the tumor area is illuminated with visible light of a wavelength at which the benzochlorin, verdin, porphyrin derivative or complex administered shows an absorption peak.

Growing community of inventors

Santa Barbara, CA, United States of America

Alan R Morgan