Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1990-11-28
1993-08-17
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540145, A61K 3140, C07D48722
Patent
active
052369145
DESCRIPTION:
BRIEF SUMMARY
The subject of the present invention is novel derivatives of metalloporphyrins, their preparation, their application in therapy, and their use for the preparation of hybrid molecules for therapeutic use.
The use of certain hemtoporphyrin derivatives in the treatment of cancers by means of phototherapy has been described, for example, by J. Moan (Photobiol. Photochem. 43, 681 (1986). These molecules possess the characteristic of accumulating at the site of tumors, which makes it possible to use them as biological markers or therapeutic agents. However, the preparation of these derivatives often leads to a mixture of products not always well defined and of variable composition. This established fact justifies the development of porphyrin derivatives prepared by total synthesis and which can be substituted for hematoporphyrins in the treatment of cancers by phototherapy.
Moreover, recent experiments have shown that metalated derivatives of synthetic porphyrins are capable of cleaving nucleic acid (DNA) in vitro by means of an oxidative process (EP-A-118 913; E. Fouquet, G. Pratviel, J. Bernadou and B. Meunier, J. Chem. Soc., Chem. Commun., 1169 (1987). This nuclease activity of water-soluble metalloporphyrins is of a special interest because it can be observed at very low concentrations of the reagents (of the order of 10.sup.-6 to 10.sup.-8 M), lower than those of bleomycin (an antitumoral antibiotic possessing high nuclease activity in the presence of ferric ions, molecular oxygen and reducers). The numerous studies carried out in recent years on the molecular pharmacology of this important drug in anticancer chemotherapy indicate that its cytotoxic and antitumoral activity may be due to its capacity to degrade the DNA of tumor cells.
According to EP-A-0,186,562, tetra-(substituted phenyl)-porphyrins are provided, which are useful in the treatment and the localization of tumors,
According to the present invention the synthesis of metalloporphyrins has been carried out (the coordination sphere of which around the iron or magnesium ions mimics the arrangements of the peptide ligands of bleomycin) having the two following properties: metalloporphyrins. Thus, the invention relates to novel porphyrin derivatives possessing this dual property. Furthermore, it is also shown that this dual property is conserved in hybrid molecules when the porphyrin skeleton is linked to an entity possessing an affinity for the nucleic acids and also capable of modulating the biological activity of these cytotoxic metalloporphyrins (polyamines, polylysine, oligonucleotides . . . ).
The novel metalloporphyrin derivatives according to the invention correspond to the general formula: ##STR3## in which A and B each represents: ##STR4## Z.sup.+ represents N.sup.+ --R.sub.1 or C--N.sup.+ R.sub.1 R.sub.2 R.sub.3 ; R.sub.1 being C.sub.1 -C.sub.10 linear or branched aliphatic, and branched aliphatic, halogen, either linear or branched, acid, m being an integer from 1 to 5 and Y represents a bond, or a --O--, --CO-- or --CPNH-- radical.
Preferably, R.sub.1 represents an alkyl group, in particular methyl or ethyl, and R.sub.2 and R.sub.3 each represents a hydrogen atom or methyl, M represents in particular Cr, Mn, Fe, Co, Ni, Cu, Zn or Ru, and preferably Mn or Fe.
X.sup.- is selected in particular from the anions of the soluble carboxylic acids commonly used in pharmacy, in particular: acetate, propionate, butyrate, ascorbate, benzoate, cinnamate, citrate, fumarate, glycolate, malonate, tartrate, malate, maleate and mandalate.
Preferably, Z.sup.+ is N.sup.+ --R.sub.1.
The compounds of formula I can be prepared by ##STR5## in which n and Y have the same meanings as in formula I and R' is the R group of formula I, protected if appropriate, with an aldehyde of formula; ##STR6## in which Z' is selected from N or ##STR7## R.sub.2 and R.sub.3 have the same meanings as in formula I, and with pyrrole in acid medium so as to obtain a porphyrin (PP) tetrasubstituted at positions 5, 10, 15 and 20 of the general formula: ##STR8## in which R', n, Y and Z'
REFERENCES:
patent: 2740794 (1956-04-01), Bonner
patent: 4386087 (1983-05-01), Lavallee
patent: 4614723 (1986-09-01), Schmidt et al.
Cros Suzy
Ding Li
Etemad-Moghadam Guita
Meunier Bernard
Centre National de la Recherche Scientifique "CNRS"
Page Thurman K.
Venkat Jyothsna
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