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US 6,333,319 B1Granted
Synthetic metal-substituted bacteriochlorophyll derivatives and use thereof
AssigneeYeda Research and Development Co. Ltd.
InventorsAvigdor Scherz, Yoram Salomon, Hugo Scheer, Gerhard Hartwich, Alexander Brandis
Life of this patent
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Abstract
The present invention relates to a new method of preparation of metalated bacteriochlorophyll derivatives for use in methods of in vivo photodynamic therapy (PDT) and diagnosis and in vitro photodynamic killing of viruses and microorganisms, and to some novel metal-substituted bacteriochlorophyll derivatives.
Claims17
A metalated bacteriochlorophyll of the formula I′, II′ or III′:
- wherein
- R′1 is selected from the group consisting of:
- (a) a C1-C25 hydrocarbyl moiety optionally substituted by halogen, OH, oxo, CHO, COOH, or NH2, or such a moiety interrupted by one or more heteroatoms selected from O, S and NH, or by a phenyl ring;
- (b) an amino acid or a peptide containing a hydroxy group or a derivative thereof selected from the group consisting of esters and N-protected derivatives, wherein said hydroxylated amino acid or derivative thereof is linked to the COO— residue through the hydroxy group;
- (c) a peptide as defined in (b) linked to the COO— residue via said C1-C25, hydrocarbyl moiety optionally substituted by halogen, OH, oxo, CHO, COOH, or NH2, or such moiety interrupted by one or more heteroatoms selected from O, S and NH, or by a phenyl ring, and further substituted by an end group selected from OH, COOH, or NH2;
- and
- (d) a cell-specific ligand selected from the group consisting of a peptide and a protein directly linked to the COO— moiety or via said C1-C25 hydrocarbyl moiety optionally substituted by halogen, OH, oxo, CHO, COOH, or NH2, or interrupted by one or more heteroatoms selected from O, S and NH, or by a phenyl ring, and fur ther substituted by an end group selected from OH, COOH, or NH2;
- R2 is H, OH or COOR5, wherein R5 is C1-C12 alkyl or C3-C12 cycloalkyl;
- R3 is H, OH or C1-C12 alkyl or alkoxy;
- R4 is each independently selected from the group consisting of vinyl, ethyl, acetyl, 1-hydroxyethyl and ethers and esters thereof;
- and
- M represents a metal with an ionic radius smaller than that of Cd (r≅95), said metal M being selected from the group consisting of a divalent metal selected from the group consisting of Pd, Co, Ni and Mn, a trivalent metal selected from the group consisting of Fe, Mn and Cr, and a tetravalent metal selected from the group consisting of Sn and Pt;
- but excluding the compounds of formula I′ wherein R2 is COOCH3, R3 is H, R4 at position 3 is acetyl and at position 8 is ethyl, R′1 is phytyl or ethyl and M is Pd.
10 more elements
A process for the preparation of a synthetic metalated bacteriochlorophyll of the formula:
- [M]—BChl
- wherein
- BChl represents a demetalated natural or synthetic bacteriochlorophyll carrying at position 173 a group —COOR1 wherein R1 is a C1-C25 hydrocarbyl moiety, and
- M represents a metal with an ionic radius smaller than that of Cd (r 95), said metal M being selected from the group consisting of a divalent metal selected from the group consisting of Pd, Co, Ni, Cu, Zn and Mn, a trivalent metal selected from the group consisting of Fe, Mn and Cr, and a tetravalent metal selected from the group consisting of Sn and Pt, which process comprises:
- (i) reacting a bacteriopheophytin , dissolved in dimethyl formamide, with dehydrated Cd acetate in argon atmosphere, and recovering the [Cd]—BChl complex from the reaction mixture by chromatography under reducing conditions;
- (ii) reacting the [Cd]—BChl complex produced in step (i), dissolved in dry acetone, with an appropriate dehydrated metal M salt selected from metal M chloride, acetate and acetylacetonate in argon atmosphere;
- and
- (iii) recovering the metalated [M]—B—Chl from the reaction mixture.
5 more elements
Dependencies are inferred from the claim text.