U.S. patent application number 10/548793 was filed with the patent office on 2008-01-10 for boronated metal-phthalocyanines, process for their preparation, pharmaceutical compositions comprising them and use thereof.
This patent application is currently assigned to L. Molteni & C. dei Fratelli Alitti Societa di Esercizio S.p.A.. Invention is credited to Giacomo Chiti, Donata Dei, Clara Fabris, Francesca Giuntini, Giulio Jori, Moira Municchi, Gabrio Roncucci.
Application Number | 20080009464 10/548793 |
Document ID | / |
Family ID | 32983184 |
Filed Date | 2008-01-10 |
United States Patent
Application |
20080009464 |
Kind Code |
A9 |
Roncucci; Gabrio ; et
al. |
January 10, 2008 |
Boronated metal-phthalocyanines, process for their preparation,
pharmaceutical compositions comprising them and use thereof
Abstract
The present invention relates to meta 1-phthalocyanines bearing
at least a group containing boron isotopes .sup.11B or .sup.10B,
covalently bound to the peripheral positions of meta
1-phthalocyanine nucleus; moreover it refers to the processes for
their preparation, the pharmaceutical compositions comprising them
and their use for the treatment of neoplastic and dysplastic
pathologies.
Inventors: |
Roncucci; Gabrio; (Colle Val
D'elsa, IT) ; Jori; Giulio; (Padova, IT) ;
Giuntini; Francesca; (Marcatale Val Di Pesa, IT) ;
Fabris; Clara; (Padova, IT) ; Chiti; Giacomo;
(Montemurlo, IT) ; Municchi; Moira; (Pelago,
IT) ; Dei; Donata; (San Gimignano, IT) |
Correspondence
Address: |
WOLF GREENFIELD & SACKS, P.C.
600 ATLANTIC AVENUE
BOSTON
MA
02210-2206
US
|
Assignee: |
L. Molteni & C. dei Fratelli
Alitti Societa di Esercizio S.p.A.
Strada Statale 67 Tosco-Romagnola
Scandicci
IT
1-50018
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20060135478 A1 |
June 22, 2006 |
|
|
Family ID: |
32983184 |
Appl. No.: |
10/548793 |
Filed: |
March 11, 2004 |
PCT Filed: |
March 11, 2004 |
PCT NO: |
PCT/EP04/02505 |
371 Date: |
September 12, 2005 |
Current U.S.
Class: |
514/64;
540/128 |
Current CPC
Class: |
C09B 47/08 20130101;
A61K 41/0095 20130101; C07C 255/54 20130101; A61P 35/00 20180101;
A61K 41/0071 20130101; C07F 5/022 20130101; C09B 47/067 20130101;
C07F 7/025 20130101; C07C 317/18 20130101; C09B 47/045 20130101;
C07F 5/069 20130101; C07D 487/22 20130101; C07B 2200/05
20130101 |
Class at
Publication: |
514/064;
540/128 |
International
Class: |
A61K 31/69 20060101
A61K031/69; C07F 5/02 20060101 C07F005/02; C07D 487/22 20060101
C07D487/22 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 11, 2003 |
IT |
FI2003A 00063 |
Claims
1. A compound of general formula (I) ##STR12## in which: Me is
selected from the group consisting of Zn, AlOR.sub.4 and
Si(OR.sub.4), wherein R.sub.4 is selected from the group consisting
of H and C1-C15 alkyl, R, R.sub.1, R.sub.2 and R.sub.3, equal or
different from one other, are selected from H and groups
(G).sub.s--(X).sub.t--(Y-Z).sub.u wherein: G is selected from the
group consisting of O, S, SO, CH.sub.2 and N; X is selected from
the group consisting of phenyl, linear or branched C1-C10 alkyl,
C1-C10 alkenyl and C1-C.sub.10 alkynyl; Y is selected from the
group consisting of S, (CH.sub.2).sub.n, phenyl,
O--(CH.sub.2).sub.n, (CH.sub.2).sub.n--O--,
(CH.sub.2CH.sub.2O).sub.n, CONH, NHCO, COO, COS, and
3-mercapto-pyrrolidine-2,5-dione; Z is selected from the group
consisting of .sup.11B-(o,m,p-carborane),
.sup.11B-undecahydrododecaboromercaptyl,
.sup.11B-undecahydrododecaborate, .sup.10B-(o,m,p-carborane),
.sup.10B-undecahydrododecaboromercaptyl and
.sup.10B-undecahydrododecaborate; n is an integer comprised between
1 and 10; s is 0, 1; t is 0, 1; u is an integer comprised between 1
and 3; with the proviso that at least one among R, R.sub.1, R.sub.2
and R.sub.3 is different from H, and when only one amongst R,
R.sub.1, R.sub.2 and R.sub.3 is different from H, u is different
from 1; and pharmaceutically acceptable salts thereof.
2. The compound of general formula (I) according to claim 1, in
which R.sub.1=R.sub.2=H and R and R.sub.3 are different from H and
equal between each other.
3. The compound according to claim 1, wherein Me is Zn.
4. The compound according to claim 1, wherein G is O, X is phenyl
and Y is CH.sub.2.
5. The compound according to claim 1, selected from the following
compounds:
1,8(11),15(18),22(25)-tetrakis-{[4-(.sup.11B1-o-carboran-1-yl)methyl]phen-
oxy}-phthalocyaninate zinc(II); 2,9(10),16(17),23
(24)-tetrakis-{[4-(.sup.11B-o-carboran-1-yl)methyl]phenoxy}-phthalocyanin-
ate zinc(II);
1,8(11),15(18),22(25)-tetrakis-{[4-(.sup.10B-o-carboran-1-yl)methyl]pheno-
xy}-phthalocyaninate zinc(II);
2,9(10),16(17),23(24)-tetrakis-{[3,5-bis-(.sup.11B-o-carboran-1-yl)methyl-
]phenoxy}-phthalocyaninate zinc(II);
1,8(11),15(18),22(25)-tetrakis-{[3,5-bis-(.sup.10B-o-carboran-1-yl)methyl-
]phenoxy}-phthalocyaninate zinc(II);
1,8(11),15(18),22(25)-tetrakis-{[3,5-bis-(.sup.11B-o-carboran-1-yl)methyl-
]phenoxy}-phthalocyaninate zinc(II);
2,9(10),16(17),23(24)-tetrakis-{[3,5-bis-(.sup.10B-o-carboran-1-yl)methyl-
]phenoxy}-phthalocyaninate zinc(II);
2,3,9,10,16,17,23,24-octakis-{[4-(.sup.11B-o-carboran-1-yl)methyl]phenoxy-
}-phthalocyaninate zinc(II);
2,3,9,10,16,17,23,24-octakis-{[4-(.sup.10B-o-carboran-1-yl)methyl]phenoxy-
}-phthalocyaninate zinc(II);
2,9(10),16(17),23(24)-tetrakis-{[4-(.sup.10B-o-carboran-1-yl)methyl]pheno-
xy}-phthalocyaninate zinc(II);
2-{3,5-[bis-(.sup.11B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II);
2-{3,5-[bis-(.sup.10B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II);
1-{3,5-[bis-(.sup.11B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II);
1-{3,5-[bis-(.sup.10B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II);
2,3-bis-{[4-(.sup.11B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II);
2,3-bis-{[4-(.sup.10B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II);
2-{2,4,6-[tris(.sup.11B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II);
2-{2,4,6-[tris(.sup.10B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II);
1-{2,4,6-[tris(.sup.11B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II); and
1-{2,4,6-[tris(.sup.10B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II).
6. A compound of general formula (II) ##STR13## wherein T is a
group (G).sub.s-(X).sub.t--(Y-Z).sub.u wherein G, X, Y, Z, s, t,
and u are as defined in claim 1; and r is 1, 2.
7. The compound according to claim 6, selected from the following
compounds:
3-{4-[(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile;
4-{4-[(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile;
3-{4-[(.sup.10B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile;
3-{3,5-[bis-(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile;
4-{3,5-[bis-(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile;
3-{3,5-[bis-(.sup.10B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile;
4-{3,5-[bis-(.sup.10B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile;
4-{2,4,6-[tris(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile;
3-{2,4,6-[tris(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile;
4-{2,4,6-[tris(.sup.10B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile;
3-{2,4,6-[tris(.sup.10B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile;
4,5-bis-{4-[(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile;
4,5-bis-{4-[(.sup.10B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile;
and
4-{4-[(.sup.10B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile.
8. A process for the preparation of compounds of general formula
(I) as defined in claim 1, comprising the tetramerization of the
functionalized compounds of formula (II) ##STR14## wherein T is a
group (G).sub.s-(X).sub.t--(Y-Z).sub.u wherein G, X, Y, Z, s, t,
and u are as defined in claim 1; and r is 1, 2, alone or in the
presence of dicyanobenzene, possibly in the presence of a reactant
suitable for introducing the metal into the phthalocyanine nucleus,
to obtain a compound of formula (I).
9. A process for the preparation of compounds of general formula
(I) as defined in claim 1, comprising the insertion of boronated
chains onto previously functionalized metal-phthalocyanines bearing
from 1 to 8 functional groups by means of coupling reactions.
10. A process for the preparation of compounds of general formula
(II) as defined in claim 6, comprising replacing the group
(W).sub.r by the group (T).sub.r by reacting a compound of formula
(III) with a suitable boron cluster derivative: ##STR15## wherein T
and r are as defined in claim 6, and W is selected from the group
consisting of NO.sub.2, NH.sub.2, Cl, Br, I, OH, and
(G).sub.s-(X).sub.t--(P).sub.u, wherein G, X, s, t and u are as
defined in claim 6, and P is selected from the group consisting of
Br, Cl, I, C.ident.CH, CHO, COOH, NH.sub.2, OH, methansulfonyloxy,
tosyloxy and Y, wherein Y is as defined in claim 6.
11. A compound of formula (III) as defined in claim 10, selected
from the following compounds:
-3-[4-(methansulfonylmethyl)phenoxy]phthalonitrile;
-4-[4-(methansulfonylmethyl)phenoxy]phthalonitrile;
-3-[4-(bromomethyl)phenoxy]phthalonitrile;
-4-[4-(bromomethyl)phenoxy]phthalonitrile;
-3-[3,5-bis-(bromomethyl)phenoxy]phthalonitrile; and
-4-[3,5-bis-(bromomethyl)phenoxy]phthalonitrile.
12. A pharmaceutical composition containing as the active principle
at least a compound of general formula (I) as defined in claim 1,
or mixtures thereof, optionally in combination with
pharmaceutically acceptable excipients and/or diluents.
13.-16. (canceled)
17. A diagnostic agent containing as the active principle a
compound of general formula (I) as defined in claim 1, optionally
in combination with a pharmaceutically acceptable carrier.
18. (canceled)
19. A method for the treatment of pathologically affected tissues
by PhotoDynamic Therapy, comprising administering to a patient in
need of such a treatment an effective amount of at least a compound
of general formula (I) as defined in claim 1.
20. The method according to claim 19, wherein said tissues are
affected by tumors, pre-cancerous conditions and pathological
diseases characterized by cellular hyperproliferation.
21. A method of treating pathologically affected tissues by Boron
Neutron Capture Therapy, comprising administering to a patient in
need of such a treatment an effective amount of at least a compound
of general formula (I) as defined in claim 1.
22. The method according to claim 21, wherein said tissues are
affected by tumors, pre-cancerous conditions and pathological
diseases characterized by cellular hyperproliferation.
23. A method of treating pathologically affected tissues by
sequential application of PhotoDynamic Therapy and Boron Neutron
Capture Therapy, comprising administering to a patient in need of
such a treatment an effective amount of at least a compound of
general formula (I) as defined in claim 1.
24. The method according to claim 23, wherein said tissues are
affected by tumors, pre-cancerous conditions and pathological
diseases characterized by cellular hyperproliferation.
25. A method for localizing pathologically affected areas by
PhotoDynamic Therapy, comprising administering to a patient an
effective amount of at least a compound of general formula (I) as
defined in claim 1.
26. A method for localizing pathologically affected areas by Boron
Neutron Capture Therapy, comprising administering to a patient an
effective amount of at least a compound of general formula (I) as
defined in claim 1.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to metal-phthalocyanines
bearing at least one group containing boron isotopes .sup.11B or
.sup.10B covalently bound to the peripheral positions of the
metal-phthalocyanine nucleus; moreover it refers to the processes
for their preparation, the pharmaceutical compositions comprising
them and their use for the treatment of neoplastic and dysplastic
pathologies.
STATE OF THE ART
[0002] It is known that organic molecules, originating from the
phthalocyanines macrocycle complexed with a diamagnetic metal and
bearing proper substituents, once photo-activated by irradiation
with light, are capable of generating reactive oxygen species
(ROS).
[0003] Such compounds, developed for therapeutic purposes, have
been recently widely described in the scientific literature and in
the U.S. Pat. No. 5,965,598, in the European Patent Application No.
906 758 and in the European Patent No. 1 164 135, all in the name
of the Applicant, where the use of these molecules in the
photodynamic therapy of microbial infections, tumour and
proliferative pathologies, as well as in the photodiagnosis and ex
vivo sterilization procedures, is claimed, according to their
distinctive selectivity for the above mentioned targets.
[0004] The derivatives described in the above cited patents and
patent applications combine high quantum yields of singlet oxygen
production, high absorptions in the red region of visible spectrum
and optimum solubility in aqueous medium or formulations, suitable
for topical administrations. The side chains, from one side provide
the physical-chemical features required for the photosensitising
efficiency, from the other guarantee the high bio-availability of
the products, the fast metabolism of the derivatives and thus the
final clearance for an optimal localization of the active molecules
in the target, thus limiting their toxicity. It is also worth
mentioning that the by-products, that may originate from the
photobleaching process of the original derivatives after
interaction with the light, are not toxic and could facilitate
their clearance after the photodynamic treatment, the skin toxicity
damage due to a potential delayed phototoxicity resulting
limited.
[0005] Moreover, a therapy for the treatment of particularly
aggressive neoplastic and displastic pathologies, known as Boron
Neutron Capture Therapy (hereinafter called BNCT), has been
recently described and is based on the administration of
non-radioactive isotope .sup.10B in conjunction with thermal
neutrons. As reported in the state of the art, the interaction of
(non-radioactive) .sup.10B isotope with thermal neutrons generates
high linear energy transfer particles such as .sup.4.sub.2He
(.alpha. particles) and .sup.7.sub.3Li, causing cellular damage
through ionization processes at subcellular level. Since those
fission fragments have a mean free pathway which is approximately
equivalent to the average diameter of mammalian cells, the success
of BNCT therapy in the inactivation of tumour or hyperproliferative
cells is dependent upon the possibility to achieve a sufficiently
large endocellular concentration of boron atoms, that is a
consequence of the localization of the carriers they are bound to,
in neoplastic or dysplastic tissues.
[0006] .sup.10B isotope derivatives bound to carriers having tumour
targeting selectivity has been recently described (Stephan B. Kahl
et al., Inorg. Chem. 1996, 35 3878-3880; M. G. Vicente et. al.,
Tetrahedron Letters 41 (2000) 7623-7627, Spryshkova R et al.
Frontiers in Neutron Capture Therapy (2001) 1027-1032, Bregadze V.
I. Journal Porphyrin and Phthalocyanine (2001) 5, 767-781); in
these papers the effectiveness of phthalocyanines and porphyrins
derivatives as regards BNCT treatment is demonstrated.
[0007] Moreover, in the article Fabris C. et al., J. Photochem.
Phobiol. 64 (2001) 1-7 the synthesis of a mono-substituted
zinc-phthalocyanine with a single boron cluster
(undecahydro-closo-dodecaboromercaptocarbonylphenoxy) group is
described, and it has been found that localization of this product
is particularly efficient due to the optimal ratio between the
phthalocyanine moiety and the substituent boron derivative. This
compound showed remarkable biological characteristics and
photodynamic efficiency, however the amount of boron carried to
tumour cells proved to be less than the minimum dose of boron
required for the BNCT treatment to be effective, which is 20 .mu.g
per g of tissue.
[0008] According to what has been previously discussed, there is a
strong need for the availability of products having both
photodynamic enhanced properties and specific cellular and
subcellular uptake and bearing substituents with a sufficient
number of boron atoms, in order to provide suitable boron
concentration in tumor tissues or in areas affected by other
pathologies characterised by cell hyperproliferation; such
compounds will allow the sequential application of PDT and BNCT
with all the advantages of selectivity and activity related to
these treatments (Hill J. S. at al. Proc. Natl. Acad. Sci. USA 92
12126-12130). Toward this aim the preparation of the corresponding
.sup.11B-boronated derivatives is also of paramount importance, for
the following reasons: 1) as .sup.10B intermediates are quite
expensive and hard to find, the synthetic procedures must be
optimised on the products having the natural isotopic abundance; 2)
many biological experiments, such as accumulation in tissues,
permeability of biological barriers, metabolic pathway
determination, etc, can be performed by using .sup.11B-boronated
derivatives in advance; 3) .sup.11B containing phthalocyanines are
themselves useful photosensitizers for PDT applications.
SUMMARY OF THE INVENTION
[0009] The Applicant has now surprisingly found that novel
boronated metal-phthalocyanines, bearing up to eight peripheral
substituents containing boron isotopes .sup.10B, may be used as
products for both BNCT and PDT. These products are able to carry
amounts of boron greater than the minimum dose needed for the
success of BNCT treatment into the tumour cells, while still
showing a high photodynamic efficiency and a selective uptake in
rapidly proliferating cells. This finding was unexpected on the
light of the previously cited literature and know-how, where good
uptake and localizing properties as well as optimal photodynamic
characteristics were found for phthalocyanine derivatives having
only one boron cluster substituent
(undecahydro-closo-dodecaboromercaptocarbonylphenoxy).
[0010] Subject of the present invention are therefore compounds of
general formula (I) ##STR1## in which: Me is chosen in the group
consisting of Zn, AlOR.sub.4 and Si(OR.sub.4), wherein R.sub.4 is
chosen in the group consisting of H and C1-C15 alkyl, R, R.sub.1,
R.sub.2 and R.sub.3, equal or different from one other, are
selected from H and groups (G).sub.s--(X).sub.t--(Y-Z).sub.u
wherein: G is selected from the group consisting of O, S, SO,
CH.sub.2 and N; X is selected from the group consisting of phenyl,
linear or branched C1-C10 alkyl, C1-C10 alkenyl and C1-C10 alkinyl;
Y is selected from the group consisting of S, (CH.sub.2).sub.n,
phenyl, O--(CH.sub.2).sub.n, (CH.sub.2).sub.n--O--,
(CH.sub.2CH.sub.2O).sub.n, CONH, NHCO, COO, COS, and, and
3-mercapto-pyrrolidine-2,5-dione; Z is selected from the group
consisting of .sup.11B-(o,m,p-carborane),
.sup.11B-undecahydrododecaboromercaptyl,
.sup.11B-undecahydrododecaborate, .sup.10B-(o,m,p-carborane),
.sup.10B-undecahydrododecaboromercaptyl and
.sup.10B-undecahydrododecaborate; n is an integer comprised between
1 and 10; s is 0, 1; t is 0, 1; U is an integer comprised between 1
and 3; with the proviso that at least one among R, R.sub.1, R.sub.2
and R.sub.3 is different from H. and when only one amongst R,
R.sub.1, R.sub.2 and R.sub.3 is different from H, u is different
from 1; and pharmaceutically acceptable salts thereof.
[0011] Further subject of the present invention are the
intermediates of general formula (II) hereinafter reported, the
preparation processes for compounds of the above reported formula
(I), the pharmaceutical compositions comprising them and their use
in PDT and/or BNCT therapy.
[0012] Features and advantages of the present invention will be
illustrated in details in the following description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1: Photooxydation kinetics of 9,10-dimethylantracene
(DMA) with tetrasubstituted boronated phhalocyanine prepared as
described in Example 21 in DMF, after irradiation with 600-700 nm
light at 100 mW/cm.sup.2.
[0014] FIG. 2A: Absorption spectrum and determination of the
degraded unsubstituted zinc phthalocyanine, irradiated according to
the experimental conditions described above for FIG. 1.
[0015] FIG. 2B: Absorption spectrum and determination of degraded
boronated phthalocyanine, prepared according the Example 21,
irradiated according to the experimental conditions described in
FIG. 1.
[0016] FIG. 3: Percentage survival of transformed B16F1 murine
melanocites as a function of the irradiation time after 24 hours
incubation with boronated phthalocyanine prepared according to
Example 21, as a DL .alpha.-dipalmitoyl phosphatidylcoline (DPPC)
liposomal preparation (3A) or a DOPC liposomal preparation (3B).
Irradiations were performed as described above for FIG. 1.
[0017] FIG. 4: Time-dependence of boronated phthalocyanine
(B.sub.4Pc) recovery from plasma and selected tissues of B16-F1
pigmented melanoma bearing C57/BL6 mice (4A) as well as from tumour
and skin (4B), after intravenous administration of 0.75 mg/Kg of
boronated phthalocyanine according to Example 21 as DPPC liposomal
preparation.
[0018] FIG. 5: Time-dependence of boronated phthalocyanine
(B.sub.4Pc) recovery from plasma and selected tissues of B16-F1
pigmented melanoma bearing C57/BL6 mice (5A), as well as from
tumour and skin (5B) after iv administration of 3.0 mg/Kg of
boronated phthalocyanine according to Example 21 as DOPC liposomal
preparation.
[0019] FIG. 6: Rate of tumour growth as a function of
post-irradiation time in C57/BL6 mice bearing a B16F1 transplanted
pigmented melanoma which have been intravenously injected with 6.0
mg/kg boronated phthalocyanine prepared according to Example 21 as
a DOPC liposomal preparation and then irradiated by red visible
light (670 nm from a diode laser) at a fluence-rate of 200
mW/cm.sup.2 and a total light dose of 250 J/cm.sup.2.
[0020] FIG. 7: Rate of tumour growth as a function of
post-irradiation time in C57/BL6 mice bearing a B16F1 transplanted
pigmented melanoma which have been intravenously injected with 6.0
mg/kg boronated phthalocyanine prepared according to Example 23, as
a DOPC liposomal preparation, and at 24 hours from injection were
irradiated by thermal neutrons for 20 and 30 min. The growth
profile of the radiosensitized pigmented melanoma is compared with
that obtained for untreated control mice.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The present invention allows one to meet the above-mentioned
requirements thanks to the compounds of formula (I) as above
described.
[0022] On the contrary to what it is expected from the molecular
structure and taking into consideration that both side chains
number and/or bulkiness may interfere with optimal behaviour of the
phthalocyanines macrocycle, by reducing the in vivo stability, the
photodynamic features and the tumour-localizing properties, the
Applicant has surprisingly found that the products subject of the
present invention maintain the physical-chemical properties linked
with the photosensitising features, particularly the wavelength,
the fluorescence and quantum yield of singlet-oxygen production and
the molar extinction coefficient. These products are also able to
efficiently localize into tumours after systemic administration as
well and can efficiently sensitize a hard-to-treat tumour, such as
the pigmented melanoma, to both PDT and BNCT.
[0023] The presence of at least one substituent bearing at least
two or more .sup.11B or .sup.10B isotopes clusters on the
peripheral position of the macrocycle, neither interferes with
cellular localization estimated on model cells, nor with the
photobleaching processes, while it provides optimal
characteristics.
[0024] Thanks to the products herein described, a substantial
improvement of the specific toxicity on the therapeutic target is
achieved for synergic effect, while sparing healthy cells. Cells
may thus be inactivated through a photodynamic mechanism related to
the phtahlocyanine and is also possible to inactivate tumour cells
by means of BNCT, due to the presence of a sufficiently large
number of boron atoms on the phthalocyanine carrier, as well as to
the sufficiently high affinity of the boronated phthalocyanine for
an experimental tumour model.
[0025] Resistance associated to cells mutation and/or
transformation as a result of PDT/BNCT combined action is not
expected; in fact the cellular inactivation due to photodynamic
process is the result of a cellular membrane damage without
involvement of the nuclear material; moreover, the inactivation
promoted by BNCT is too energetic to induce the selection of
radioresistant cell clones.
[0026] Preferred compounds according to the present invention are
the compounds of is formula (I) in which Me is Zn.
[0027] The present compounds of formula (I) may carry from one to
eight groups bearing .sup.11B or .sup.10B Isotopes in the alpha or
beta positions on the phthalocyanine molecule, preferably at the
positions 1(4),8(11),15(18),22(25) or 2(3),9(10),16(17),23(24).
Preferred are the present compounds (I) wherein R.sub.1=R.sub.2=H
and R=R.sub.3 are different from H. Preferably, in the present
compounds (I) G is O, X is phenyl and Y Is CH.sub.2. The compounds
of the present invention can be prepared according to reaction
schemes known in organic chemistry, for example by using one of the
following general procedures: a) process comprising the
tetramerization of the functionalised phthalonitriles of general
formula (II) ##STR2## wherein T is a group
(G).sub.s--(X).sub.t--(Y-Z).sub.u wherein G, X, Y, Z, s, t, and u
are as defined above; and r is 1, 2; alone or in the presence of
dicyanobenzene, possibly in the presence of a reactant suitable for
introducing the metal into the phthalocyanine nucleus, thus
obtaining a compound of formula (I). In the following Scheme 1 the
tetramerization of compound (II), alone or with dicyanobenzene, in
the presence of Zn(OAc).sub.2 is illustrated. ##STR3## b) process
comprising the insertion of boronated chains as above defined onto
previously functionalised metal-phthalocyanines bearing from 1 to 8
functional groups, by coupling reactions known in the state of the
art.
[0028] The phthalonitriles of formula (II) reported above can be
prepared starting from commercially available materials according
to the following Scheme 2. ##STR4## wherein T and r are as defined
above, and W is selected from the group consisting of NO.sub.2,
NH.sub.2, Cl, Br, I, OH, and (G).sub.s--(X).sub.t--(P).sub.u,
wherein G, X, s, t and u are as defined above, and P is selected
from the group consisting of Br, Cl, O, C.ident.CH, CHO, COOH,
NH.sub.2, OH, methansulfonyloxy, tosyloxy and Y, wherein Y is as
defined above.
[0029] The compounds of formula (III) wherein W is selected from
the group consisting of NO.sub.2, NH.sub.2, Cl, Br, I and OH are
commercially available, whereas the remaining compounds of formula
(III) can be prepared starting from these commercial products by
means of procedures known in the art.
[0030] The schemes reported below show the synthetic pathway
followed for the preparation of several boronated phthalocyanines
of formula (I) according to the invention (Scheme 4, 6, 7 and 9),
and of the corresponding intermediates (Scheme 3, 5 and 8). The
schemes are reported to illustrate, but are not limited at,
examples of the synthetic procedures suitable to obtain the present
compounds of formula (I) and (II), as above defined. ##STR5##
##STR6## ##STR7## ##STR8## ##STR9## ##STR10## ##STR11##
[0031] The following examples are reported as a non-limiting
illustration of the invention.
EXAMPLE 1
Synthesis of 3-[4-(methansulfonylmethyl)phenoxy]phthalonitrile
[0032] To a solution of 3-[4-(hydroxymethyl)phenoxy]phthalonitrile
(900 mg, 3.9 mmol) prepared according to procedures described in
literature, and triethylamine (0.75 ml, 5.8 mmol) in anhydrous
CH.sub.2Cl.sub.2 (50 ml), kept at 0.degree. C. under stirring and
in an inert atmosphere, methylsulfonylchloride was added (0.33 ml,
4.3 mmol). The mixture was stirred at 0.degree. C. for 1 hour, then
it was diluted with CH.sub.2Cl.sub.2 (50 ml) and washed with 1% HCl
solution (60 ml), then with brine (50 ml), the organic layer was
dried on Na.sub.2SO.sub.4 and the solvent was evaporated. 1.1 g
(93%) of the title compound were obtained as a viscous fluid that
crystallized on standing.
[0033] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.69 (1H, dd,
J.sub.1=J.sub.2=8.4 Hz), 7.53-7.49 (3H, m), 7.15-7.11 (3H, m), 5.26
(2H, s), 3.01 (3H, s).delta.
[0034] .sup.13C-NMR (75 MHz, CDCl.sub.3): 160.46, 154.98, 134.90,
131.65, 131.43, 127.84, 121.35, 120.79, 117.64, 115.28, 112.80,
106.89, 70.48, 38.52 .delta.
[0035] EI.sup.+-MS: m/z 328
[(C.sub.15H.sub.10N.sub.2O.sub.4S)].sup.+, 250
[(C.sub.15H.sub.10N.sub.2O.sub.4S)--CH.sub.3SO.sub.2].sup.+, 233
[(C.sub.15H.sub.10N.sub.2O.sub.4S)--CH.sub.3SO.sub.3].sup.+
EXAMPLE 2
Synthesis of 4-[4-(methansulfonylmethyl)phenoxy]phthalonitrile
[0036] To a solution of 4-[4-(hydroxymethyl)phenoxy]phthalonitrile
(1.0 g, 3.9 mmol) prepared according to procedures described in
literature, and triethylamine (0.80 ml, 5.8 mmol) in anhydrous
CH.sub.2Cl.sub.2 (50 ml), kept at 0.degree. C. under stirring and
in an inert atmosphere, methylsulfonylchloride was added (0.33 ml,
4.3 mmol). The mixture was stirred at 0.degree. C. for 1 hour, then
ft was diluted with CH.sub.2Cl.sub.2 (50 ml) and washed with 1% HCl
solution (60 ml), then with brine (50 ml), the organic layer was
dried on Na.sub.2SO.sub.4 and the solvent was evaporated. 1.2 g
(92%) of the title compound were obtained as a viscous fluid that
crystallised on standing.
[0037] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.75 (1H, d, J=8.4 Hz),
7.53 (2H, d, J=8.7 Hz), 7.30-7.24 (2H, m), 7.12 (2H, d, J=8.7 Hz),
5.26 (2H, s), 3.03 (3H, s) 3
[0038] .sup.13C-NMR (75 MHz, CDCl.sub.3): 161.50, 154.66, 135.82,
131.81, 131.52, 122.04, 121.95, 121.17, 917.93, 115.59, 115.16,
109.64, 70.22, 38.46 .delta.
[0039] EI.sup.+-MS: m/z 250
[(C.sub.15H.sub.10N.sub.2O.sub.4S)--CH.sub.3SO.sub.2].sup.+, 233
[(CO.sub.15H.sub.10N.sub.2O.sub.4S)--CH.sub.3SO.sub.3].sup.+
EXAMPLE 3
Synthesis of 3-[4-(bromomethyl)phenoxy]phthalonitrile
[0040] To a solution of
3-[4-(methansulfonylmethyl)phenoxy]phthalonitrile (1.1 g, 3.1 mmol)
prepared according to Example 2, in anhydrous THF (15 ml) kept in
an inert atmosphere, LiBr (0.4 g, 4.6 mmol) was added. The solution
was refluxed for 1 hour, during which a white precipitate formed,
then it was allowed to cool at room temperature. The white
precipitate was filtered off and the solvent was evaporated. From
the crude mixture the desired product was isolated by filtration on
silica gel (eluent: chloroform). (900 mg, 93%).
[0041] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.59 (1H, dd,
J.sub.1=J.sub.2=8.4 Hz), 7.49-7.63 (3H, m), 7.14-7.06 (3H, m), 4.51
(2H, s) 8
[0042] .sup.13C-NMR (75 MHz, CDCl.sub.3): 160.67, 154.05, 136.07,
134.93, 131.57, 127.68, 121.20, 120.80, 117.50, 115.36, 112.91,
106.52, 32.59 .delta.
[0043] EI.sup.+-MS: m/z 313 [C.sub.15H.sub.10N.sub.2OBr].sup.+, 233
[(C.sub.15H.sub.10N.sub.2OBr)--Br].sup.+
[0044] m.p.: 130-132.degree. C.
[0045] Anal. Calcd. for C.sub.15H.sub.10N.sub.2OBr (%): C (57.53),
H (2.90), N (8.95); Found (%): C (57.40), H (2.92), N (8.96)
EXAMPLE 4
Synthesis of 4-[4-(bromomethyl)phenoxy]phthalonitrile
[0046] To a solution of
4-[4-(methansulfonylmethyl)phenoxy]phthalonitrile (1.2 g, 3.3 mmol)
prepared according to Example 2, in anhydrous THF (15 ml) kept in
an inert atmosphere, LiBr (0.4 g, 4.6 mmol) was added. The solution
was refluxed for 1 hour, during which a white precipitate formed,
then it was allowed to cool at room temperature. The white
precipitate was filtered off and the solvent was evaporated. From
the crude mixture the desired product was isolated by filtration on
silica gel (eluent: chloroform). (1.0 g, 95%)
[0047] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.74 (1H, d, J=8.4 Hz),
7.49 (2H, d, J=8.6 Hz), 7.30-7.24 (2H, m), 7.05 (2H, d, J=8.6),
4.52 (2H, s) 8
[0048] .sup.13C-NMR (75 MHz, CDCl.sub.3): 161.63, 153.80, 136.20,
135.73, 131.68, 121.97, 121.88, 121.08, 117.97, 115.54, 115.11,
109.44, 32.39 .delta.
[0049] EI.sup.+-MS: m/z 233
[(C.sub.15H.sub.10N.sub.2OBr)--Br].sup.+
[0050] m.p.: 100.8-102.2.degree. C.
[0051] Anal. Calcd. for C.sub.15H.sub.10N.sub.2OBr (%): C (57.53),
H (2.90), N (8.95); Found (%): C (57.86), H (2.79), N (8.65)
[0052] p.f.: 100.8-102.2.degree. C.
EXAMPLE 5
Synthesis of
3-{4-[(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
[0053] n-butyl lithium (1.40 ml, 1.6M in hexanes, 2.2 mmol) was
added dropwise to a solution of 1,2-closo-carborane (366 mg, 2.0
mmol) in anhydrous THF (10 ml) kept in an inert atmosphere at
-78.degree. C. The solution was stirred at -78.degree. C. for 10
min. then it was kept at room temperature for 40 min. and cooled
again at -78.degree. C., and
3-[4-(bromomethyl)phenoxy]phthalonitrile (500 mg, 1.6 mmol),
prepared according to Example 3. The mixture was stirred for 1 hour
while being warmed to room temperature, then it was quenched with
water, and the mixture was extracted with ethyl acetate. The
organic layer was washed with brine (30 ml.times.2) then it was
dried on Na.sub.2SO.sub.4, and the solvent was evaporated. The
crude product was purified by flash chromatography (eluent:
petroleum spirit/ethyl acetate=3/1) to yield 333 mg (55%) of the
title compound.
[0054] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.63 (1H, dd,
J.sub.1=J.sub.2=7.9 Hz), 7.51 (1H, d, J=7.9 Hz), 7.26-7.22 (2H, m),
7.14-7.08 (3H, m), 3.54 (2H, s), 3.35 (1H, bs), 2.94-1.25 (10H, bm)
.delta.
[0055] .sup.13C-NMR (75 MHz, CDCl.sub.3): 160.39, 154.40, 134.81,
132.53, 132.24, 127.84, 121.34, 120.82, 117.77, 115.20, 112.67,
74.26, 59.94, 43.10 .delta. (selected data)
[0056] EI.sup.+-MS: m/z 376
[C.sub.17H.sub.20N.sub.2OB.sub.10].sup.+, 233
[(C.sub.17H.sub.20N.sub.2OB.sub.10)--C.sub.2B.sub.10H.sub.11].sup.+
[0057] m.p.: 182-184.degree. C.
[0058] Anal. Calcd. for C.sub.17H.sub.20N.sub.2OB.sub.10 (%): C
(54.24), H (5.36), N (7.44); Found (%): C (54.10), H (5.30), N
(7.18).
EXAMPLE 6
Synthesis of
4-{4-[(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
[0059] n-butyl lithium (1.40 ml, 1.6M in hexanes, 2.2 mmol) was
added dropwise to a solution of 1,2-closo-carborane (366 mg, 2.0
mmol) in anhydrous THF (10 ml) kept in an inert atmosphere at
-78.degree. C. The solution was stirred at -78.degree. C. for 10
min. then it was kept at room temperature for 40 min. and cooled
again at -78.degree. C., and
4-[4-(bromomethyl)phenoxy]phthalonitrile (500 mg, 1.6 mmol),
prepared according to Example 4. The mixture was stirred for 1.5
hours while being warmed to room temperature, then it was quenched
with water, and the mixture was extracted with ethyl acetate. The
organic layer was washed with brine (30 ml.times.2) then it was
dried on Na.sub.2SO.sub.4, and the solvent was evaporated. The
crude product was purified by flash chromatography (eluent:
petroleum spirit/ethyl acetate=3/1) to yield 287 mg (48%) of the
title compound.
[0060] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.76 (1H, d, J=9.0Hz),
7.31-7.23 (4H, m), 7.07 (2H, d, J=8.4 Hz), 3.55 (2H, s), 3.37 (1H,
bs), 2.95-1.39 (10H, bm) 8
[0061] .sup.13C-NMR (75 MHz, CDCl.sub.3): 161.36, 154.05, 135.80,
132.69, 132.40, 122.13, 121.99, 121.16, 118.04, 115.49, 115.08,
109.67, 74.22, 59.92, 43.10 .delta.
[0062] EI.sup.+-MS: m/z 376 .sup.+, 233
[(C.sub.17H.sub.20N.sub.2OB.sub.10)--C.sub.2B.sub.10H.sub.11].sup.30
[0063] m.p.: 183.0-185.0.degree. C.
[0064] Anal. Calcd. for C.sub.17H.sub.20N.sub.2OB.sub.10 (%): C
(54.24), H (5.36), N (7.44); Found (%): C (54.50), H (5.08), N
(7.70)
EXAMPLE 7
Synthesis of
3-{4-[(.sup.10B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
[0065] Starting from 1,2-closo-carborane (235 mg, 1.7 mmol) and
3-[4-(bromomethyl)phenoxy]phthalonitrile (500 mg, 1.6 mmol),
prepared as showed in Example 3, 300 mg (yield=47%) of desired
compound are obtained, following the procedure described in Example
5.
[0066] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.63 (1H, dd,
J.sub.1=J.sub.2=7.8 Hz), 7.51 (1H, d, J=7.8 Hz), 7.26-7.22 (2H, m),
7.14-7.08 (3H, m), 3.54 (2H, s), 3.38 (1H, bs), 2.50-1.82 (10H, bm)
.delta.
[0067] .sup.13C-NMR (75 MHz, CDCl.sub.3): 160.38, 154.37, 134.84,
132.54, 132.24, 127.84, 121.33, 120.84, 117.75, 115.22, 112.71,
106.92, 74.32, 59.98, 43.11 .delta.
[0068] ESI.sup.--MS: m/z 367
[C.sub.17H.sub.20N.sub.2OB.sub.10].sup.-
[0069] p.f.: 179-181.degree. C.
EXAMPLE 8
Synthesis of 3-[3,5-bis-(bromomethyl)phenoxy]phthalonitrile
[0070] N-bromosuccinimide (790 mg, 4.4 mmol) was dissolved in
dichloroethane and the mixture was warmed to reflux.
3-[3,5-bis-(methyl)phenoxy]phthalonitrile (500 mg, 2 mmol),
prepared according to procedures described in literature, and a
catalytic amount of benzoyl peroxide were added and the mixture was
refluxed for 1.15 hours. After cooling to room temperature, the
reaction mixture was diluted with dichloromethane, washed with
saturated solution of NaHCO.sub.3 and water and dried on
Na.sub.2SO.sub.4. The solvent was evaporated and the crude was
purified by flash chromatography (eluent: petroleum spiritlethyl
acetate=4/1) to yield 350 mg (43%) of the title compound.
[0071] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.63 (1H, dd,
J.sub.1=J.sub.2=8 Hz), 7.52 (1H, d, J=8 Hz), 7.33 (1H, s), 7.15
(1H, d, J=8 Hz), 7.08 (2H, s), 4.45 (4H, s)
EXAMPLE 9
Synthesis of 4-[3,5-bis-(bromomethyl)phenoxy]phthalonitrile
[0072] N-bromosuccinimide (394 mg, 2.2 mmol) was dissolved in
dichloroethane. The mixture was warmed to reflux,
4-[3,5-bis-(methyl)phenoxy]phthalonitrile (250 mg, 1 mmol) prepared
according to procedures described in literature, and a catalytic
amount of benzoyl peroxide were added and the mixture was refluxed
for 1 hour. After cooling to room temperature, the reaction mixture
was diluted with dichloromethane, washed with saturated solution of
NaHCO.sub.3 and water and dried on Na.sub.2SO.sub.4. The solvent
was evaporated and the crude was purified by flash chromatography
(eluent: petroleum spirit/ethyl acetate=4/1) to obtain 150 mg
(yield=37%) of the title compound.
[0073] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.76 (1H, d J=8 Hz),
7.35-7.25 (3H, m), 7.06 (2H, s), 4.45 (4H, s) .delta.
EXAMPLE 10
Synthesis of
3-{3.5-[bis-(11B-carboran-1-yl)methyl]phenoxy}phthalonitrile
[0074] n-butyl lithium (0.97 ml, 1.6M in hexanes, 1.54 mmol) was
added dropwise to a solution of 1,2-closo-carborane (200 mg, 1.4
mmol) in anhydrous THF (10 ml) kept in an inert atmosphere at
-78.degree. C. The solution was stirred at -78.degree. C. for 10
min. then it was kept at room temperature for 40 min. and cooled
again at -78.degree. C., and
3-[3,5-bis-(bromomethyl)phenoxy]phthalonitrile (227 mg, 0.56 mmol)
prepared according to Example 8. The mixture was stirred for 1 hour
while being warmed to room temperature, then it was quenched with
water, and the mixture was extracted with ethyl acetate. The
organic layer was washed with brine (30 ml.times.2) then it was
dried on Na.sub.2SO.sub.4, and the solvent was evaporated. The
crude product was purified by flash chromatography (eluent:
petroleum spirit/ethyl acetate=4/1 to 1/2) to obtain 58 mg
(yield=19%) of the title compound.
[0075] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.69 (1H, dd,
J.sub.1=J.sub.2-8 Hz), 7.57 (1H, d, J=8 Hz), 7.12 (1H, d, J=8 Hz),
6.88-6.86 (3H, m), 3.52 (4H, s), 3.45 (2H, bs), 3.00-1.00 (10H, bm)
.delta.
[0076] ESI.sup.+-MS: m/z 532
[C.sub.20H.sub.32N.sub.2OB.sub.20].sup.+
EXAMPLE 11
Synthesis of
4-{3,5-[bis-(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
[0077] n-butyl lithium (0.97 ml, 1.6M in hexanes, 1.54 mmol) was
added dropwise to a solution of 1,2-closo-carborane (200 mg, 1.4
mmol) in anhydrous THF (10 ml) kept in an inert atmosphere at
-78.degree. C. The solution was stirred at -78.degree. C. for 10
min. then it was kept at room temperature for 40 min. and cooled
again at -78.degree. C., and
4-[3,5-bis-(bromomethyl)phenoxy]phthalonitrile (227 mg, 0.56 mmol)
prepared according to Example 9. The mixture was stirred for 1 hour
while being warmed to room temperature, then it was quenched with
water, and the mixture was extracted with ethyl acetate. The
organic layer was washed with brine (30 ml.times.2) then it was
dried on Na.sub.2SO.sub.4, and the solvent was evaporated. The
crude product was purified by flash chromatography (eluent:
petroleum spiritlethyl acetate=1/1) to obtain 82 mg (yield=28%) of
the title compound.
[0078] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 7.79 (1H, d, J=8
Hz), 7.29-7.21 (2H, m), 6.87 (3H, s), 3.52 (4H, s), 3.45 (2H, bs),
3.10-1.00 (10H, bm)
[0079] ESI.sup.+-MS: m/z 532
[C.sub.20H.sub.32N.sub.2OB.sub.20].sup.+
[0080] According with the two alternative procedures reported above
in Examples 1-11, the following compounds were also obtained:
EXAMPLE 12
3-{3,5-[bis-(.sup.10B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
[0081] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.69 (1H, dd,
J.sub.1=J.sub.2=8.0 Hz), 7.57 (1H, d, J=8.0 Hz), 7.12 (1H, d, J=8.0
Hz), 6.88-6.86 (3H, m), 3.52 (4H, s), 3.40 (2H, bs), 2.750-1.20
(10H, bm) .delta.
[0082] ESI.sup.+-MS: m/z 516
[C.sub.20H.sub.32N.sub.2OB.sub.20].sup.+
EXAMPLE 13
4-{3,5-[bis-(.sup.10B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
[0083] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.79 (1H, d, J=8.0 Hz),
7.29-7.21 (2H, m), 6.87 (3H, s), 3.52 (4H, s), 3.39 (2H, bs),
2.97-1.13 (10H, bm) .delta.
[0084] ESI.sup.+-MS: m/z 516
[C.sub.20H.sub.32N.sub.2OB.sub.20].sup.+
EXAMPLE 14
4-{2,4,6-[tris(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
[0085] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.65 (1H, d, J=8.0 Hz),
7.40 (2H, s), 7.07-7.05 (3H, m), 3.61, (4H, s), 3.52 (2H, s), 3.43
(2H, bs), 3.40 (1H, bs), 2.84-1.76 (30H, bm) .delta.
[0086] ESI.sup.+-MS: m/z 688
[C.sub.23H.sub.44N.sub.2OB.sub.30].sup.+
EXAMPLE 15
3-{2,4,6-[tris(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
[0087] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.67 (1H, dd,
J.sub.1=J.sub.2=8.0 Hz), 7.60 (1H, d, J=8.0 Hz), 7.40 (2H, s), 7.12
(1H, d, J=8.0 Hz), 3.64, (4H, s), 3.54 (2H, s), 3.41 (2H, bs), 3.38
(1H, bs), 2.80-1.77 (30H, bm) .delta.
[0088] ESI.sup.+-MS: m/z 688
[C.sub.23H.sub.44N.sub.2OB.sub.30].sup.+
EXAMPLE 16
4-{2,4,6-[tris(10B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
[0089] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.65 (1H, d, J=8.0 Hz),
7.40 (2H, s), 7.07-7.05 (3H, m), 3.61, (4H, s), 3.52 (2H, s), 3.40
(2H, bs), 3.36 (1H, bs), 2.75-1.79 (30H, bm) .delta.
[0090] ESI.sup.+-MS: m/z 664
[C.sub.23H.sub.44N.sub.2OB.sub.30].sup.+
EXAMPLE 17
3-{2,4,6-[tris(.sup.10B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
[0091] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.67 (1H, dd,
J.sub.1=J.sub.2=8.0 Hz), 7.60 (1H, d, J=8.0 Hz), 7.40 (2H, s), 7.12
(1H, d, J=8.0 Hz), 3.64, (4H, s), 3.51 (2H, s), 3.36 (2H, bs), 3.38
(1H, bs), 2.80-1.77 (30H, bm) .delta.
[0092] ESI.sup.+-MS: m/z 664
[C.sub.23H.sub.44N.sub.2OB.sub.30].sup.+
EXAMPLE 18
4,5-bis-{4-[(11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
[0093] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.61 (2H, s), 7.37-7.24
(8H, m), 3.55 (4H, s), 3.32 (4H, bs), 2.91-1.06 (20H, bm)
.delta.
[0094] ESI.sup.+-MS: m/z 624
[C.sub.26H.sub.36N.sub.2O.sub.2B.sub.20].sup.+
EXAMPLE 19
4,5-bis-{4-[(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
[0095] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.61 (2H, s), 7.37-7.25
(8H, m), 3.55 (4H, s), 3.37 (4H, bs), 2.98-1.00 (20H, bm)
.delta.
[0096] ESI.sup.+-MS: m/z 608
[C.sub.26H.sub.36N.sub.2O.sub.2B.sub.20].sup.+
EXAMPLE 20
4-{4-[(.sup.10B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
[0097] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.76 (1H, d, J=9.0 Hz),
7.31-7.23 (4H, m), 7.07 (2H, d, J=8.4 Hz), 3.55 (2H, s), 3.37 (1H,
bs), 2.95-1.39 (10H, bm) .delta.
[0098] ESI.sup.--MS: m/z 367
[C.sub.17H.sub.20N.sub.2OB.sub.10].sup.-
EXAMPLE 21
Synthesis of
1,8(11),15(18),22(25)-tetrakis-{[4-(.sup.11B-o-carboran-1-yl)methyl]pheno-
xy}-phthalocyaninate zinc(II)
[0099] A mixture of
3-{4-[(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile (120
mg, 0.3 mmol), prepared according to Example 5, and Zn(OAc).sub.2
(59 mg, 0.3 mmol) was finely ground and heated to 200.degree. C. in
an inert atmosphere for 5.5 hours. The dark solid was then allowed
to cool to room temperature, and was taken up in ethyl acetate. The
suspension was filtered through celite and the solvent was
evaporated. From the crude mixture the title compound was isolated
by flash chromatography (eluent: petroleum spirit/THF 3/1 to 1/1).
54 mg of the title compound are obtained (yield=43%).
[0100] .sup.1H-NMR (300 MHz, d.sub.6-DMSO): 9.07 (d, J=7.2 Hz),
8.90-8.79 (m), 8.68-8.56 (m), 8.45 (d, J=7.2 Hz), 8.11-7.77 (m),
7.65 (d, J=7.8 Hz), 7.52-7.40 (m), 7.43-7.10 (m), 5.21-5.17 (m),
4.89 (bs), 3.68-3.59 (m), 3.48 (bs), 2.71-1.18 (bm) .delta.
[0101] .sup.13C-NMR (75 MHz, d.sub.6-DMSO): 159.80, 159.53, 159.40,
157.50, 157.43, 157.13, 156.97, 154.66, 154.48, 154.11, 153.97,
153.55, 153.36, 153.05, 152.82, 152.63, 151.75, 151.60, 151.42,
151.25, 150.42, 150.26, 141.47, 141.41, 141.34, 141.10, 140.93,
132.95, 132.24, 132.13, 132.07, 132.00, 131.65, 131.47, 131.25,
129.93, 129.84, 129.76, 129.10, 129.02, 128.79, 127.64, 127.53,
127.33, 123.79, 123.43, 123.21, 121.03, 120.67, 120.52, 120.21,
119.88, 119.66, 119.37, 119.11, 118.67, 118.09, 116.77, 116.69,
116.55, 77.45, 77.33, 63.59, 63.08, 42.18, 41.94 .delta.(selected
data)
[0102] ESI.sup.+-MS: m/z 1571 [C.sub.68H.sub.80N.sub.8
O.sub.4B.sub.40Zn].sup.+
[0103] UV-vis.(DMF): nm (%) 690 (100), 622 (16), 329 (18)
.epsilon..sub.690=230000 M.sup.-1 cm.sup.-1
EXAMPLE 22
Synthesis of
2,9(10),16(17),23(24)-tetrakis-{[4(.sup.11B-o-carboran-1-yl)methyl]phenox-
y}-phthalocyaninate zinc(II)
[0104] A mixture of
4-{4-[(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile (70
mg, 0.2 mmol) prepared according to Example 6, and Zn(OAc).sub.2
(34 mg, 0.2 mmol) was finely ground and heated to 200.degree. C. in
an inert atmosphere for 5 hours. The dark solid was then allowed to
cool to room temperature, and was taken up in ethyl acetate. The
suspension was filtered through celite and the solvent was
evaporated. From the crude mixture the title compound was isolated
by flash chromatography (eluent: petroleum spirit/THF 3/1 to 1/1).
30 mg of the title compound are obtained (yield=40%).
[0105] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) 8.98-8.91 (2H, m),
8.68-8.69 (2H, m), 8.45-8.41 (2H, m), 8.27-8.23 (2H, m), 7.79-7.40
(2H, m), 5.31 and 5.18 (4H, 2 bs), 3.76 and 3.68 (8H, 2 bs),
2.90-1.18 (40H, bm) .delta.
[0106] .sup.13C-NMR (75 MHz, d.sub.6-DMSO) 159.70, 158.71, 158.57,
157.34, 156.53, 156.41, 151.80, 140.03, 139.92, 132.99, 132.90,
132.68, 132.11, 124.40, 121.17, 119.98, 111.73, 77.45, 77.26,
63.76, 63.51, 42.15 .delta. (selected data)
[0107] ESI.sup.+-MS: m/z 1571 [C.sub.68H.sub.80N.sub.8
O.sub.4B.sub.40Zn].sup.+
[0108] UV-vis.(DMF): nm (%) 677 (100), 609 (17), 357 (34)
.delta..sub.677=240000 M.sup.-1 cm.sup.-1
EXAMPLE 23
Synthesis of
1,8(11),15(18),22(25)-tetrakis-{[4-(.sup.10B-o-carboran-1-yl)methyl]pheno-
xy}phthalocyaninate zinc(II)
[0109] A mixture of
3-{4-[(.sup.10B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile (200
mg, 0.5 mmol) prepared according to Example 7, and Zn(OAc).sub.2
(100 mg, 0.5 mmol) was finely ground and heated to 210.degree. C.
in an inert atmosphere for 4.5 hours. The dark solid was then
allowed to cool to room temperature, and was taken up in ethyl
acetate. The suspension was filtered through celite and the solvent
was evaporated. From the crude mixture the title compound was
isolated by flash chromatography (eluent: petroleum spirit/THF 3/1
to 1/1). 83 mg (yield=40%).
[0110] .sup.1H-NMR (300 MHz, d.sub.6DMSO): 9.13 (d, J=7.2 Hz),
9.01-8.98 (m), 8.68-8.56 (m), 8.75 (d, J=7.2 Hz), 8.65 (dd,
J.sub.1=J.sub.2=7.2 Hz), 8.52 (d, J=7.2 Hz), 8.15-7.82 (m), 7.73
(d, J=7.5 Hz), 7.47-7.22 (m), 5.24-5.18 (m), 4.92 (bs), 3.68-3.64
(m), 3.50 (bs), 2.71-1.18 (bm) .delta.
[0111] .sup.13C-NMR (75 MHz, d.sub.6-DMSO): 159.81, 159.51, 159.39,
157.46, 157.39, 157.08, 154.46, 154.09, 153.94, 153.55, 153.07,
152.81, 150.38, 141.46, 141.39, 136.86, 132.95, 132.29, 132.06,
131.86, 131.67, 131.49, 129.95, 129.11, 128.78, 127.62, 127.50,
127.27, 121.07, 120.68, 120.52, 120.19, 116.65, 116.50, 77.50,
77.38, 63.65, 63.14, 42.17, 41.93 .delta. (selected data)
[0112] ESI.sup.+-MS: m/z 1540 [C.sub.68H.sub.80N.sub.8
O.sub.4B.sub.40Zn].sup.+
[0113] UV-vis.(DMF): nm (%) 690 (100), 622 (16), 326 (17)
.epsilon..sub.690=250000 M.sup.-1 cm.sup.-1
EXAMPLE 24
Synthesis of
2,9(10),16(17),23(24)tetrakis-{[3,5-bis-(.sup.11B-o-carboran-1-yl)methyl]-
phenoxy}-phthalocyaninate zinc(II)
[0114] A mixture of
4-(3,5-bis-[(.sup.11B-o-carboran-1-yl)methyl]phenoxyphthalonltrile
(83 mg, 0.15 mmol) prepared according to Example 11, and
Zn(OAc).sub.2 (28 mg, 0.15 mmol) was finely ground and heated to
260.degree. C. in an inert atmosphere for 4 hours. The dark solid
was then allowed to cool to room temperature, and was taken up in
ethyl acetate. The suspension was filtered through celite and the
solvent was evaporated. From the crude mixture the title compound
was isolated by flash chromatography (eluent: petroleum spirit(THF
1/1), thus obtaining 54 mg of the title compound (yield=43%).
[0115] .sup.1H-NMR (300 MHz, d.sub.6DMSO) 9.11-9.02 (4H, m),
8.55-8.48 (4H, m), 7.85-7.60 (4H, m), 7.36-7.06 (12H, m), 5.18 and
5.12 (8H, 2 bs), 3.73 and 3.68 (16H, 2 bs), 2.90-1.00 (80H, bm)
.delta.
[0116] UV-vis.(DMF): nm (%) 677 (100), 610 (18), 355 (30)
[0117] ESI.sup.+-MS: m/z 2197
[C.sub.80H.sub.129N.sub.8O.sub.4B.sub.80Zn].sup.+
EXAMPLE 25
Synthesis of
1,8(11),15(18),22(25)-tetrakis-{[3,5-bis-(.sup.11B-o-carboran-1-yl)methyl-
]phenoxy}-phthalocyaninate zinc(II)
[0118] A mixture of
3-{3,5-bis-[(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
(53 mg, 0.1 mmol) prepared according to Example 10, and
Zn(OAc).sub.2 (19 mg; 0.1 mmol) was finely ground and heated to
260.degree. C. in an inert atmosphere for 4 hours. The dark solid
was then allowed to cool to room temperature, and was taken up in
ethyl acetate. The suspension was filtered through celite and the
solvent was evaporated. From the crude mixture the title compound
was isolated by flash chromatography (eluent: petroleum spirit/THF
1/1), thus obtaining 54 mg of the title compound (yield=43%).
[0119] UV-vis.(DMF): nm (%) 690 (100), 624(15), 332 (27)
[0120] ESI.sup.+-MS: m/z 2197
[C.sub.80H.sub.129N.sub.8O.sub.4B.sub.80Zn].sup.+
[0121] According with the procedures reported in Examples 21-25,
the following compounds were also obtained:
EXAMPLE 26
1,8(11),15(18),22(25)-tetrakis-{[3,5-bis-(.sup.10B-o-carboran-1-yl)methyl]-
phenoxy}-phthalocyaninate zinc(II)
[0122] ESI.sup.+-MS: m/z 2136
[C.sub.80H.sub.129N.sub.8O.sub.4B.sub.80Zn].sup.+
[0123] UV-vis (DMF): nm (%) 691 (100), 623 (17), 332 (21)
EXAMPLE 27
2,9(10),16(17),23(24)-tetrakis-{[3,5-bis-(.sup.10B-o-carboran-1-yl)methyl]-
phenoxy}-phthalocyaninate zinc(II)
[0124] ESI.sup.+-MS: m/z 2136
[C.sub.80H.sub.129N.sub.8O.sub.4B.sub.80Zn].sup.+
[0125] UV-vis (DMF): nm (%) 685 (100), 611 (16), 354 (40)
EXAMPLE 28
2,3,9,10,16,17,23,24-octakis-{[4-(.sup.11B-o-carboran-1-yl)methyl]phenoxy}-
-phthalocyaninate zinc(II)
[0126] ESI.sup.+-MS: m/z 2564
[C.sub.104H.sub.144N.sub.8O.sub.8B80Zn].sup.+
[0127] UV-vis (DMF): nm (%) 680 (100), 613 (16), 361 (33)
EXAMPLE 29
2,3,9,10,16,17,23,24-octakis-{[4-(.sup.10B-o-carboran-1-yl)methyl]phenoxy}-
-phthalocyaninate zinc(II)
[0128] ESI.sup.+-MS: m/z 2503
[C.sub.104H.sub.144N.sub.8O.sub.8B.sub.80Zn].sup.+
[0129] UV-vis (DMF): nm (%) 680 (100), 615 (15), 360 (34)
EXAMPLE 30
2,9(10),16(17),23(24)-tetrakis{[4-(.sup.10B-o-carboran-1-yl)methyl]phenoxy-
}-phthalocyaninate zinc(II)
[0130] ESI.sup.+-MS: m/z 1540 [C.sub.68H.sub.80N.sub.8
O.sub.4B.sub.40Zn].sup.+
[0131] UV-vis.(DMF): nm (%) 677 (100), 609 (20), 357 (33)
EXAMPLE 31
Synthesis of
2-{3,5-[bis-(.sup.11B-o-carboran-1-yl)methyl]phenoxy}}-phthalocyaninate
zinc(II)
[0132] A mixture of
4-{3,5-bis-[(.sup.11B-o-carboran-1-yl)methyl]phenoxy}phthalonitrile
(70 mg, 0.2 mmol) prepared according to Example 11, dicyanobenzene
(77 mg, 0.6 mmol) and Zn(OAc).sub.2 (34 mg, 0.2 mmol) was finely
ground and heated to 200.degree. C. in an inert atmosphere for 5
hours. The dark solid was then allowed to cool to room temperature,
and was taken up in THF. The suspension was filtered through celite
and the solvent was evaporated. From the crude mixture the title
compound was isolated by flash chromatography (eluent: petroleum
spirit/THF 5/1 to 1/1). 15 mg of the title compound were obtained
(yield=7.6%).
[0133] ESI.sup.+-MS: m/z 983
[C.sub.44H.sub.45N.sub.8OB.sub.20Zn].sup.+
[0134] UV-vis (DMF): nm (%) 672(100), 609(16), 344(24)
[0135] UV-vis (DMF): nm (%) 680 (100), 613(16), 361(33)
[0136] According to the procedure described in Example 31, the
following compounds where obtained:
EXAMPLE 32
2-{3,5-[bis-(.sup.10B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II)
[0137] ESI.sup.+-MS: m/z 968
[C.sub.44H.sub.45N.sub.8OB.sub.20Zn].sup.+
[0138] UV-vis (DMF): nm (%) 672(100), 606(16), 344(25)
EXAMPLE 33
1-{3,5-[bis-(11B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II)
[0139] ESI.sup.+-MS: m/z 983
[C.sub.44H.sub.45N.sub.8OB.sub.20Zn].sup.+
[0140] UV-vis (DMF): nm (%) 677(100), 335(21), 609(15)
EXAMPLE 34
1-{3,5-[bis-(.sup.10B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II)
[0141] ESI.sup.+-MS: m/z 968
[C.sub.44H.sub.45N.sub.8OB.sub.20Zn].sup.+
[0142] UV-vis (DMF): nm (%) 678 (100), 610 (16), 336(23)
EXAMPLE 35
2,3-bis-{[4-(.sup.11B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II)
[0143] ESI.sup.+-MS: m/z 1074
[C.sub.50H.sub.48N.sub.8O.sub.2B.sub.20Zn].sup.+
[0144] UV-vis (DMF): nm (%) 672 (100), 606 (15), 342 (23)
EXAMPLE 36
2,3-bis-{[4-(10B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II)
[0145] ESI.sup.+-MS: m/z 1059
[C.sub.50H.sub.48N.sub.8O.sub.2B.sub.20Zn].sup.+
[0146] UV-vis (DMF): nm (%) 671 (100), 608 (13), 344 (23)
EXAMPLE 37
2-{2,4,6-[tris(.sup.11B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II)
[0147] ESI.sup.+-MS: m/z 1140
[C.sub.47H.sub.57N.sub.8OB.sub.30Zn].sup.+
[0148] UV-vis (DMF): nm (%) 672 (100), 606 (16), 344 (24)
EXAMPLE 38
2-{2,4,6-[tris(.sup.10B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II)
[0149] ESI.sup.+-MS: m/z 1117
[C.sub.47H.sub.57N.sub.8OB.sub.30Zn].sup.+
[0150] UV-vis (DMF): nm (%) 672 (100), 606 (16.0), 344 (25.1)
EXAMPLE 39
1-{2,4,6-[tris(.sup.11B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II)
[0151] ESI.sup.+-MS: m/z 1117
[C.sub.47H.sub.57N.sub.8OB.sub.30Zn].sup.+
[0152] UV-vis (DMF): nm (%) 677 (100), 336 (23), 611 (15)
EXAMPLE 40
1-{2,4,6-[tris(.sup.10B-o-carboran-1-yl)methyl]phenoxy}-phthalocyaninate
zinc(II)
[0153] ESI.sup.+-MS: m/z 0.1117
[C.sub.47H.sub.57N.sub.8OB.sub.30Zn].sup.+
[0154] UV-vis (DMF): nm (%) 677 (100), 608 (14), 335 (22)
Assessment of Photodynamic Efficiency
[0155] Singlet oxygen is produced through an electron energy
transfer from the phthalocyanines in their excited triplet state to
molecular oxygen. For its high reactivity and its relatively long
life time (in the microseconds time-scale, with consequent
possibility of diffusion within relatively wide distance before
decaying), it represents the main phototoxic intermediate in the
photosensitising processes. Therefore, defining the photodynamic
efficiency of these compounds through the measurement of the
efficiency of singlet oxygen production is particularly useful.
Measurement of singlet oxygen has been performed following the
photooxidation kinetics of 9,10-dimethylantracene (DMA)
spectrophotometrically; as reported in FIG. 1, the production of
singlet oxygen by the boronated phthalocyanine described in Example
21 is similar to that of a not-substituted phthalocyanine. This
leads to the conclusion that the presence of boronated substituents
does not affect the photodynamic efficiency of the phthalocyanine
in the products subject of the present invention.
Assessment of Photostability
[0156] It is known that most phthalocyanines are subjected to a
more or less extensive photobleaching under visible light
irradiation. It is therefore important to define if the rate
constant of this process is too fast, so that the active principle
is photodegraded at a high rate, which could negatively interfere
with the photosensitization of cells or other substrates. The
photostability of tetra-substituted boronated phthalocyanine,
prepared as described in Example 21, has been performed
spectrophotometrically and the results shown in FIG. 2B. Results
obtained with a not substituted phthalocyanine are reported. In
FIG. 2A as a reference. From comparison of the plots shown in FIGS.
2A and 2B it may be concluded that
1--the boron substituted molecules prepared according to the
present invention are as useful photosensitizers able to absorb red
visible light as the unsubstituted ones;
[0157] 2--the photobleaching kinetics undergoes only limited
changes when the phthalocyanine structure is modified by
introduction of boronated groups. Indeed, the more extensive
photobleaching found for the boronated compound has the advantage
to induce an easier elimination of excess drug, thereby avoiding
the onset of delayed photosensitization, obviously compared to its
control represented by a not-boronated compound.
Assessment of Activity on Biological Substrates
[0158] The tetra-substituted boronated phthalocyanine prepared as
described in Example 21 has been used for the photosensitization of
melanocytes deriving from murine pigmented melanoma B16-F1.
Melanocytes were incubated (24 hrs) with a DPCC or DOPC liposomal
phthalocyanine preparation (7 microM). After incubation, the cells
were washed with PBS and irradiated with red visible light (600-750
nm, 50 mW/cm.sup.2). Survival was determined after the
photo-treatment (18-24 hrs) by the Trypan Blue exclusion test.
Results for delivered phthalocyanine are summarised in FIG. 3A
(DPPC liposomes) and in FIG. 3B (DOPC liposomes). It can be
concluded that an almost complete cell mortality is achieved with
irradiation times as low as 10 min.
[0159] Through pharmacokinetic experiments on B16-F1 pigmented
melanoma bearing mice, a number of studies such as tissue affinity,
uptake kinetics on various organs, clearance from the body and
selectivity for the tumour tissues have been evaluated, using the
product described in Example 21. Toward this aim, once tumours had
reached the volumes of 0.81 cm.sup.2, the boronated phthalocyanine
as DPPC liposomal preparation (0.75 mg/kg) or as a DOPC liposomal
preparation (3 mg/kg) was systemically administered. Animals were
sacrified (after 3, 24, 48 hrs) and the phthalocyanine
concentration determined in plasma and selected tissues
spectrophotometrically. The results are shown in FIG. 4 (DPPC
liposomes) and in FIG. 5 (DOPC liposomes) and indicate that the
clearance of this product from plasma is rapid with no product
residue at 24 hrs after the treatment. The large recovery of
phthalocyanine from the components of the reticuloendothelial
system, such as liver and spleen, is to be expected for compounds
which are delivered via liposomes.
[0160] Moreover, as one can see in FIG. 6, the boronated
phthalocyanine is able to induce a significant delay in the rate of
tumour growth, when the mice bearing a subcutaneously transplanted
pigmented melanoma are exposed to red light. The tumour response is
most evident if the irradiations are carried out at 3 h after
injection of the photosensitizer.
[0161] A significant delay in tumour growth is also observed for
the mice which are irradiated with thermal neutrons at 24 h, after
intravenous injection of the boronated phthalocyanine reported in
Example 23 incorporated in DOPC liposomes. This shows that the
amount of phthalocyanine accumulated in the tumour under our
experimental conditions is sufficient to achieve the BNCT effect.
As a consequence, an extensive tumour necrosis is caused.
[0162] The boron substituted phthalocyanines of the present
invention are able to localize in the melanoma at appreciable
concentrations, in which a reduction of the tumour, as result of
photoinactivation, was obtained.
[0163] The tetra-substituted phthalocyanine, reported in Example 21
is accumulated in large amounts, both in the liver and in the
spleen, and, at least the phthalocyanine delivered via DOPC
liposomes, is largely cleared from liver and spleen after 1 week
from injection. This would indicate that no persistent general
photosensitivity can be expected beyond one week after the
administration of the phthalocyanine. Very limited amounts of
phthalocyanine are recovered from the kidneys, which suggests that
the photosensitizer is cleared from the organism almost exclusively
via the bile-gut pathway.
[0164] The selectivity of tetra-substituted phthalocyanine (Example
21) localization in the tumour is, on the whole, acceptable, since
small amounts of photosensitizer were found in the skin that, in
this animal model, represents the peritumoural tissue. This
circumstance clearly favours the application of either PDT or BNCT
treatments, since an extensive damage of the tumour tissue can be
achieved with minimal damage at the level of the surrounding
healthy tissues, as shown by our experimental results.
[0165] The compounds of formula (I), reported in the present
invention, are therefore useful for treatment of tumours,
pre-cancerous and hyperproliferative conditions, using a combined
PDT/BNCT approach, further benefiting from their fluorescence
emission properties, that allow the identification of the
pathological areas before and during the therapeutic treatment.
[0166] The products can be administered parenterally, by using
pharmaceutical formulations known in the state of the art, and
proceeding with the BNCT/PDT treatment, after localization has
taken place.
* * * * *