Phthalocyanine derivatives, process for their preparation, pharmaceutical compositions containing them and their use
View Patent ↗Phthalocyanine derivatives are described having photosensitizing characteristics and high solubility in water, useful for photodynamic treatment of bacterial infections, in particular infections generated by Gram-negative bacteria.
1. A phthalocyanine compound of formula (I)
in which the substituents are in positions 1,8(11), 15(18), 22(25) or in positions 2,9(10), 16(17), 23(24) of the phthalocyanine ring.
2. Process for preparing a phthalocyanine compound of formula (I) as defined in claim 1 , comprising the following steps:
i) performing nucleophilic substitution of the amino alcohol of formula (III) onto the phthalonitrile of formula (II) to obtain the compound of formula (IV)
(ii) performing reductive methylation of the amino nitrogen on the compound of formula (IV) coming from step i) to obtain the compound of formula (V)
iii) performing base catalysed tetramerization of the compound of formula (V) coming from step ii) and simultaneous metal insertion with a suitable Zinc(II) salt to obtain the Zinc(II) phthalocyanine of formula (VI)
iv) performing quaternarization of the amino groups of the phthalocyanine of formula (VI) coming from step iii) by treatment with methyl iodide to obtain the corresponding phthalocyanine of formula (VII) substituted with quaternary ammonium groups and in iodide form:
v) performing treatment of the phthalocyanine of formula (VII) in iodide form coming from step iv) with a suitable ion exchange resin to obtain the corresponding phthalocyanine of formula (I) in chloride form:
3. Pharmaceutical compositions comprising as active principle a phthalocyanine compound of formula (I) as defined in claim 1 , in combination with pharmaceutically acceptable excipients and/or diluents.
4. The pharmaceutical compositions according to claim 3 , further comprising a metal chelating agent.
5. The pharmaceutical compositions according to claim 4 , wherein said metal chelating agent is chosen from metal chelating agents having specificity for Ca 2+ and Mg 2+ ions.
6. The pharmaceutical compositions according to claim 4 , wherein said metal chelating agent is selected from the group consisting of citric acid, 1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid (CDTA), diethylenetriaminepentaacetic acid (DTPA) and ethylenediamine-N,N,N′,N′-tetraacetic acid (EDTA).
7. The pharmaceutical compositions according to claim 4 , wherein said metal chelating agent is EDTA.
8. Compounds of formula (V), (VI) and (VII) as intermediates of the process as defined in claim 2 .
9. The process according to claim 2 , wherein said step ii) of reductive methylation is carried out by treating said compound of formula (II), dissolved in acetonitrile, with 30% aqueous formaldehyde in the presence of sodium cyanoborohydride.
10. The process according to claim 2 , wherein said step iii) is carried out at a temperature between 100 and 250° C.
11. The process according to claim 10 , wherein said temperature is between 130 and 180° C.
12. The process according to claim 2 , wherein said step iii) is carried out in an organic solvent, using as the base a base chosen from 1,5-diazabicyclo[5.4.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2-dimethylamino-ethanol (DMAE).
13. The process according to claim 2 , wherein said step iii) is carried out in the absence of solvent, using as the base a base chosen from 1,5-diazabicyclo[5.4.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2-dimethylamino-ethanol (DMAE).
14. The process according to claim 2 , wherein said step iii) is carried out in the absence of solvent with DBU as base, and at a temperature of 140° C.
15. The process according to claim 2 , wherein the crude product of formula (VI) obtained in step iii) is precipitated by treating the reaction mixture with water, filtering or centrifuging the suspension and washing the recovered solid several times with water and methanol.
16. The process according to claim 2 , further comprising the purification of the intermediate of formula (VI) coming from step iii) by column chromatography followed by re-precipitation from solvent, prior to undergoing step iv).
17. The process according to claim 16 , wherein said column chromatography is carried out using silica gel as the stationary phase and a mixture of dichloromethane and methanol as the mobile phase; said re-precipitation is carried out using dichloromethane as the solvent and n-hexane as the precipitant.
18. The process according to claim 2 , wherein said methylating agent in step iv) is methyl iodide.
19. The process according to claim 18 , wherein said methyl iodide is used in a quantity between 1 and 20 equivalents per amino group to be methylated in the product of formula (VI).
20. The process according to claim 18 , wherein said methyl iodide is used in a quantity between 5 and 11 equivalents per amino group to be methylated in the product of formula (VI).
21. The process according to claim 2 , wherein said methylation reaction in step iv) is carried out in a solvent chosen from dimethylformamide, dimethylsulfoxide and N-methylpyrrolidone.
22. The process according to claim 21 , wherein said solvent is N-methylpyrrolidone.
23. The process according to claim 2 , wherein said methylation reaction in step iv) is carried out using methyl iodide as the methylating agent in a quantity between 5 and 11 equivalents per amino group to be methylated in the product of formula (VI), and N-methylpyrrolidone as solvent.
24. The process according to claim 23 , wherein the reaction product in step iv) is precipitated from the solution in N-methylpyrrolidone with ethyl ether or isopropyl ether in a quantity of 8 volumes with respect to the volume of N-methylpyrrolidone, after having diluted the solution in N-methylpyrrolidone with methanol in a quantity of 2 volumes with respect to the volume of N-methylpyrrolidone.
25. The process according to claim 2 , wherein said Zinc(II) salt in step iii) is chosen from Zinc(II) chloride and Zinc(II) acetate.
26. The process according to claim 2 , wherein said Zinc(II) salt in step iii) is Zinc(II) acetate.
27. The process according to claim 2 , wherein said ion exchange resin in step v) is chosen from strong basic resins with quaternary ammonium functional groups.
28. The process according to claim 27 , wherein said resin is a resin based on polystyrene with a degree of cross-linking between 4 and 10%.
29. The process according to claim 2 , wherein said treatment of the phthalocyanine (VII) in step v) is achieved by a chromatography process by using a solution of said phthalocyanine (VII) and said ion exchange resin, and recovering the phthalocyanine of formula (I) by evaporation, lyophilisation or precipitation.
30. The process according to claim 29 , wherein said chromatography is undertaken by passing a solution of the phthalocyanine of formula (VII) in methanol through the ion exchange resin, then treating the eluate with ethyl ether to precipitate the phthalocyanine of formula (I) in chloride form, or by passing a solution of the phthalocyanine of formula (VII) in methanol/dimethylsulfoxide through the resin, then treating the eluate with ethyl ether to precipitate the phthalocyanine (I) which is then purified by dissolving in methanol and re-precipitating by adding ethyl ether.
31. A method for treating, by means of photodynamic therapy, bacterial infections caused by Gram-negative bacteria, alone or in the presence of other bacterial species, the method comprising subjecting said bacteria to a phthalocyanine compound of formula (I) as defined in claim 1 .