U.S. patent application number 11/059557 was filed with the patent office on 2005-10-13 for substituted porphyrin and azaporphyrin derivatives and their use in photodynamic therapy, radioimaging and mri diagnosis.
This patent application is currently assigned to Miravant Pharmaceuticals, Inc.. Invention is credited to Robinson, Byron C..
Application Number | 20050226810 11/059557 |
Document ID | / |
Family ID | 23137288 |
Filed Date | 2005-10-13 |
United States Patent
Application |
20050226810 |
Kind Code |
A1 |
Robinson, Byron C. |
October 13, 2005 |
Substituted porphyrin and azaporphyrin derivatives and their use in
photodynamic therapy, radioimaging and MRI diagnosis
Abstract
Substituted porphyrin and azaporphyrin deviations with various
substitutents in the 12- and 17-positions of the prophyrin skeleton
as pharmaceutical agents for use in photodynamic therapy, MRI
diagnosis, and radiodiagnostics.
Inventors: |
Robinson, Byron C.; (Santa
Barbara, CA) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Assignee: |
Miravant Pharmaceuticals,
Inc.
|
Family ID: |
23137288 |
Appl. No.: |
11/059557 |
Filed: |
February 17, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11059557 |
Feb 17, 2005 |
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10159580 |
May 31, 2002 |
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6906050 |
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60295343 |
May 31, 2001 |
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Current U.S.
Class: |
424/1.11 ;
424/9.362; 514/185; 514/410; 514/63; 534/16; 540/145 |
Current CPC
Class: |
A61K 49/106 20130101;
A61K 51/0451 20130101; C07D 487/22 20130101; A61K 49/085 20130101;
A61K 49/10 20130101; A61K 51/0497 20130101; A61K 47/546 20170801;
A61K 51/0485 20130101; A61P 9/00 20180101 |
Class at
Publication: |
424/001.11 ;
514/185; 514/410; 514/063; 540/145; 534/016; 424/009.362 |
International
Class: |
A61K 051/00; A61K
031/695; C07F 005/00; A61K 031/555 |
Claims
1. A compound of formula I: 31wherein R.sub.1-R.sub.12 can be the
same or different and are selected from: H, halide, substituted or
unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl,
cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, amide, ester, ether, polyether,
alkoxy group, aryloxy group, haloalkoxy, group, amino group,
alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl
group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group,
aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil
group, carbamoyl group, heterocyclic group, nitro group, nitroso
group, formyloxy group, isocyano group, cyanate group, isocyanate
group, thiocyanate group, isothiocyanate group, N(alkyl).sub.2,
N(aryl).sub.2, CH.dbd.CH(aryl), CH.dbd.CHCH.sub.2N(CH.sub-
.3).sub.2, or a functional group of molecular weight of less than
about 100,000 daltons; CH.dbd.CHCH.sub.2N.sup.+(CH.sub.3).sub.3A,
CH.dbd.N(alkyl).sub.2A, or N(alkyl).sub.3.sup.+A, where A is a
charge balancing ion; CN, OH, CHO, COCH.sub.3, CO(alkyl),
CO.sub.2H, CO.sub.2Na, CO.sub.2K, CH(CH.sub.3)OH,
CH(CH.sub.3)O-alkyl, CH(CH.sub.3)-alkoxy, CH(CH.sub.3)O-aryl;
(CH.sub.2).sub.nO-alkoxy, or (CH.sub.2).sub.nO-alkyl, where n is an
integer from 0 to 8; C(X).sub.2C(X).sub.3, where X is a halogen;
CO.sub.2R.sub.13, where R.sub.13 is selected from H, a
physiologically acceptable counter ion, a C1-C20 straight or
branched chain alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, or a functional
group of less than about 100,000 daltons; (CH.sub.2).sub.nOH, or
(CH.sub.2).sub.nOR.sub.14, where R.sub.14 is selected from alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, a protecting group, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4; (CH.sub.2).sub.nCO.sub.2R.sub.15,
(CHX).sub.nCO.sub.2R.sub.15, or (CX.sub.2).sub.nCO.sub.2R.sub.15,
where X is a halogen and R.sub.15 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, or a functional group of
less than about 100,000 daltons, and n is an integer between 1 and
4; CONH(R.sub.16), CONHNH(R.sub.16), CO(R.sub.16),
CON(R.sub.16).sub.2, CON(R.sub.16)(R.sub.17),
(CH.sub.2).sub.nCONH(R.sub.16),
(CH.sub.2).sub.nCON(R.sub.16).sub.2, (CH.sub.2).sub.nCOR.sub.16,
(CH.sub.2).sub.nCON(R.sub.16)(R.sub.17),
(CX.sub.2).sub.nCONH(R.sub.16),
(CX.sub.2).sub.nCON(R.sub.16).sub.2,
(CX.sub.2).sub.nCON(R.sub.16)(R.sub.17),
(CX.sub.2).sub.nCOR.sub.16, (CH.sub.2).sub.nCONHNH(R.sub.16),
(CX.sub.2).sub.nCONHNH(R.sub.16), (CHX).sub.nCONH(R.sub.16),
(CHX).sub.nCONHNH(R.sub.16), (CHX).sub.nCO(R.sub.16),
(CHX).sub.nCON(R.sub.16).sub.2, or
(CHX).sub.nCON(R.sub.16)(R.sub.17), where X is a halogen and
R.sub.16 and R.sub.17 can be the same or different and are selected
from H, NH.sub.2, straight or branched chain C1-C20 alkyl,
haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl,
heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt,
an amino acid ester, an amino acid amide, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons, and n is an
integer between 0 and 4; S(R.sub.18), (CH.sub.2).sub.nS(R.sub.18),
(CH.sub.2).sub.nNH(R.sub.18), (CH.sub.2).sub.nNHNH(R.sub.18),
(CH.sub.2).sub.nN(R.sub.18).sub.2,
(CH.sub.2).sub.nN(R.sub.18)(R.sub.19), or
(CH.sub.2).sub.nN(R.sub.18)(R.sub.19)(R.sub.20).sup.+A, where
R.sub.18, R.sub.19 and R.sub.20 can be the same or different and
are selected from H, NH.sub.2, straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, amino acids (provided --NH(R.sub.18) is part of the
amino acid), an amino acid ester, an amino acid amide, a mono-,
di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl
residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or
polyetheraryl residue, a functional group of less than about
100,000 daltons, or where R.sub.18, R.sub.19 and R.sub.20 together
possess the atoms necessary to constitute an aromatic ring system,
n is an integer between 0 and 4, and A is a physiologically
acceptable counter ion; (CH.sub.2).sub.nOPO.sub.2OR.sub.2- 1,
(CH.sub.2).sub.nPO(OR.sub.21).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.21, or (CH.sub.2).sub.nPOR.sub.21
where R.sub.21 is selected from H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino
acids, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a
mono-, di-, or polyetheraryl residue, or a functional group of less
than about 100,000 daltons, and n is an integer between 0 and 4;
(CH.sub.2).sub.nNHCOR.sub.22, or (CH.sub.2).sub.nNHNHCOR.sub.22,
where R.sub.22 is selected from a straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.23,
SO.sub.2NHR.sub.23, SO.sub.2N(R.sub.23).sub.2,
SO.sub.2NHNHR.sub.23, or SO.sub.2R.sub.23, where R.sub.23 is
selected from H, a physiologically acceptable counter ion, a
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or
polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue,
a mono-, di-, or polyetheralkyl residue, a mono-, di-, or
polyetheraryl residue, or a functional group of less than about
100,000 daltons, and NHR.sub.23 can also be an amino acid, an amino
acid salt, an amino acid ester residue, an amino acid amide
residue[, and n is an integer between 0 and 4]; Aryl or substituted
aryl, which may bear one or more substituents with a molecular
weight of less than or equal to about 100,000 daltons; and
R.sub.1-R.sub.2, R.sub.4-R.sub.5, R.sub.7-R.sub.8,
R.sub.10-R.sub.11, R.sub.2-R.sub.3, R.sub.5-R.sub.6,
R.sub.8-R.sub.9, and R.sub.11-R.sub.12 may also possess the atoms
necessary to form ring systems, which themselves may possess
heteroatoms that may bear one or more functional groups of
molecular weight equal to or less than about 100,000 daltons; with
the proviso that at least one of the R.sub.1-R.sub.23 groups is
linked via an organic group that has as part or all of its
structure a group Q, which is an amine, an ester, an ether or an
amide link, to a complexing agent of general formula 11a, 11b, 11c,
11d, 11e; 32wherein R.sub.24 is selected from a hydrogen, a
straight or branched chain C.sub.1-C.sub.7 alkyl group, a phenyl or
benzyl group; L.sub.1, L.sub.2, L.sub.3, L.sub.4, independently of
one another, are selected from a hydrogen atom or a metal ion
equivalent of an element of the atomic numbers 20-32, 37-39, 42-51,
or 57-83, which may be radioactive, provided that at least two of
L.sub.1, L.sub.2, L.sub.3 and L.sub.4 are metal ion equivalents,
that other anions are present to compensate for optionally present
charges on the porphyrin, and free carboxylic acid groups that are
not required for complexing are optionally present as salts with
physiologically compatible inorganic cations, or organic cations,
or as esters or amides; with the proviso that when R.sub.1 and
R.sub.4 are methyl, R.sub.2 and R.sub.5 cannot be methyl, a
straight chain C1-C6 alkyl, a C7-C12 aralkyl, CH.sub.2O(C1-C3
alkyl), CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2CH.sub.2OH,
CH(NH(CH.sub.2).sub.nNH.sub.2)CH.sub.3,
CH.sub.2CH.sub.2NH(CH.sub.2).sub.- nNH.sub.2 (where n=2, 3, 4, 6),
vinyl, ethyl, CH.sub.2OR.sub.25 (where R.sub.25 is a hydrogen or a
C1-C3 alkyl), CH(O-lower alkanoyl)CH.sub.3, CH(O-lower
alkylene-OR.sub.26)CH.sub.3, or CH(OR.sub.26)CH.sub.3 (where
R.sub.26.dbd.H, lower alkyl, a polyfunctional carbonyl compound
excluding a hydrogen atom therefrom or a metal derivative of a
polyfunctional carbonyl compound); and wherein M is 2H or a
diamagnetic or paramagnetic photoactive metal ion selected from
Ga.sup.3+, Pt.sup.2+, Pd.sup.2+, Sn.sup.4+, In.sup.3+, Ge.sup.4+,
Si.sup.4+, Al.sup.3+, Zn.sup.2+, and Mg.sup.2+.
2. A method of using the compound of claim 1 comprising
administering the compound to a patient and, after a period of
time, imaging targeted tissue of the patient through MRI or
radio-diagnostic imaging.
3. A method of using the compound of claim 1 comprising
administering the compound to a patient and, after a period of
time, irradiating targeted tissue of the patient with an energy
source that excites the compound thereby producing a desired
therapeutic response in the target tissue.
4. A method of using the compound of claim 1 comprising
administering the compound to a patient and, after a period of
time, imaging targeted tissue of the patient through MRI or
radio-diagnostic imaging then, after a second period of time,
irradiating the targeted tissue with an energy source that excites
the compound thereby producing a desired therapeutic response in
the target tissue.
5. A method for the detection or treatment of tissue comprising
administering to a patient a therapeutic amount of the compound of
claim 1 locally, systemically, intramuscularly or interperitoneally
and irradiating said compound with energy at a wavelength able to
excite the molecule, such that a desired therapeutic effect is
observed, whereby said tissue belongs to the hematological system,
lymphatic reticuloendothelial system, nervous system, endocrine and
exocrine system, skeletomuscular system, skin, pulmonary system,
gastrointestinal system, reproductive system, immune system,
cardiovascular system, urinary system, auditory or olfactory
system.
6. The method of claim 2, wherein said method is for diagnosing
disorders in a vessel wall, tissue adjoining the vessel wall, or
material attached to the vessel wall of a coronary, carotid or
peripheral vasculature.
7. The method of claim 6 wherein said vessel is an artery or a
vein.
8. The method of claim 2 wherein the tissue is atherosclerosis,
restenosis or graft disease.
9. The method of claim 3 wherein the tissue is atherosclerosis,
restenosis or graft disease.
10. The method of claim 4 wherein the tissue is atherosclerosis,
restenosis or graft disease.
11. The method of claim 5 wherein the tissue is atherosclerosis,
restenosis or graft disease.
12. The method of claim 4 wherein the therapy is selected from
ablation, reduction and stabilization of vessel wall plaque.
13. The method of claim 4 wherein said energy source is selected
from light, ultrasound, magnetic force, and electromagnetic
radiation in the UV/visible electromagnetic spectrum or near
infrared.
14. The method of claim 4 wherein said administration of the
compound is prior to, concomitant with, or subsequent to adjunctive
interventions, diagnostics or therapies.
15. The method of claim 4 wherein said administration is a single
bolus or plurality of doses administered to the patient.
16. A compound of formula IA: 33wherein R.sub.1-R.sub.7 can be the
same or different and are selected from: H, halide, substituted or
unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl,
cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, amide, ester, ether, polyether,
alkoxy group, aryloxy group, haloalkoxy group, amino group,
alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl
group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group,
aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil
group, carbamoyl group, heterocyclic group, nitro group, nitroso
group, formyloxy group, isocyano group, cyanate group, isocyanate
group, thiocyanate group, isothiocyanate group, N(alkyl).sub.2,
N(aryl).sub.2, CH.dbd.CH(aryl), CH.dbd.CHCH.sub.2N(CH.sub-
.3).sub.2, or a functional group of molecular weight of less than
about 100,000 daltons; CH.dbd.CHCH.sub.2N.sup.+(CH.sub.3).sub.3A,
CH.dbd.N(alkyl).sub.2A, or N(alkyl).sub.3.sup.+A, where A is a
charge balancing ion; CN, OH, CHO, COCH.sub.3, CO(alkyl),
CO.sub.2H, CO.sub.2Na, CO.sub.2K, CH(CH.sub.3)OH,
CH(CH.sub.3)O-alkyl, CH(CH.sub.3)O-alkoxy, CH(CH.sub.3)O-aryl;
(CH.sub.2).sub.nO-alkoxy, or (CH.sub.2).sub.nO-alkyl, where n is an
integer from 0 to 8; C(X).sub.2C(X).sub.3, where X is a halogen;
CO.sub.2R.sub.8, where R.sub.8 is selected from a physiologically
acceptable counter ion, a C1-C20 straight or branched chain alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, a mono-, di-,. or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, ether or polyether, or a
functional group of less than about 100,000 daltons;
(CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.9, where R.sub.9 is
selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocycle, aryl, heteroaryl, a protecting group, a mono-, di-, or
polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue,
or a functional group of less than about 100,000 daltons, and n is
an integer between 0 and 4; (CH.sub.2).sub.nCO.sub.2R.sub.10,
(CHX).sub.nCO.sub.2R.sub.10, or (CX.sub.2).sub.nCO.sub.2R.sub.10,
where X is a halogen and R.sub.10 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, or a functional
group of less than about 100,000 daltons, and n is an integer
between 1 and 4; CONH(R.sub.11), CO(R.sub.11), CON(R.sub.11).sub.2,
CON(R.sub.11)(R.sub.12), (CH.sub.2).sub.nCONH(R.sub.11),
(CH.sub.2).sub.nCON(R.sub.11).sub.2, (CH.sub.2).sub.nCOR.sub.11,
(CH.sub.2).sub.nCON(R.sub.11)(R.sub.12),
(CX.sub.2).sub.nCONH(R.sub.11),
(CX.sub.2).sub.nCON(R.sub.11).sub.2,
(CX.sub.2).sub.nCON(R.sub.11)(R.sub.- 12),
(CX.sub.2).sub.nCOR.sub.11, (CH.sub.2).sub.nCONHNH(R.sub.11),
(CX.sub.2).sub.nCONHNH(R.sub.11), (CHX).sub.nCONH(R.sub.11),
(CHX).sub.nCONHNH(R.sub.11), (CHX).sub.nCON(R.sub.11).sub.2,
(CHX).sub.nCON(R.sub.11)(R.sub.12), where X is a halogen and
R.sub.11 and R.sub.12 can be the same or different and are selected
from H, NH.sub.2, straight or branched chain C1-C20 alkyl,
haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl,
heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt,
an amino acid ester, an amino acid amide, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons, and n is an
integer between 0 and 4; S(R.sub.13), (CH.sub.2).sub.nS(R.sub.13),
(CH.sub.2).sub.nNH(R.sub.13), (CH.sub.2).sub.nNHNH(R.sub.13),
(CH.sub.2).sub.nNR13(CH.sub.2).sub.nN(R.sub.13)(R.sub.14), or
(CH.sub.2).sub.nN(R.sub.13)(R.sub.14)(R.sub.15).sup.+A, where
R.sub.13, R.sub.14 and R.sub.15 can be the same or different and
are selected from H, NH.sub.2, straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, amino acids (provided --NH(R.sub.13 is part of the
amino acid), an amino acid ester, an amino acid amide, a mono-,
di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl
residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or
polyetheraryl residue, a functional group of less than about
100,000 daltons, or where R.sub.13, R.sub.14 and R.sub.15 together
possess the atoms necessary to constitute an aromatic ring system,
n is an integer between 0 and 4, and A is a physiologically
acceptable counter ion; (CH.sub.2).sub.nOPO.sub.2OR.sub.16,
(CH.sub.2).sub.nPO(OR.sub.16).su- b.2,
(CH.sub.2).sub.nPO.sub.2R.sub.16, or (CH.sub.2).sub.nPOR.sub.16
where R.sub.16 is selected from H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl or heteroaryl, heterocycle,
amino acids, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl
residue, a mono-, di-, or polyetheraryl residue, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4; (CH.sub.2).sub.nNHCOR.sub.1- 7,
(CH.sub.2).sub.nNHNHCOR.sub.17, where R.sub.17 is selected from a
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, heterocycle, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4; SO.sub.3R.sub.18, SO.sub.2NHR.sub.18,
SO.sub.2N(R.sub.18).sub.2, SO.sub.2NHNHR.sub.18 or
SO.sub.2R.sub.18, where R.sub.18 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl
or heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, and
NHR.sub.18 can also be an amino acid residue, an amino acid salt,
an amino acid ester residue, an amino acid amide residue, or a
functional group of less than about 100,000 daltons; Aryl or
substituted aryl, which may bear one or more substituents with a
molecular weight of less than or equal to about 100,000 daltons;
and R.sub.1-R.sub.2, and R.sub.3-R.sub.4 may also possess the atoms
necessary to form ring systems, which themselves may possess
heteroatoms that may bear one or more functional groups of
molecular weight equal to or less than about 100,000 daltons; with
the proviso that R.sub.1 and R.sub.4 are the same, R.sub.2 and
R.sub.3 are the same, and that when R.sub.7 is H, R.sub.1-R.sub.4
cannot be methyl; and that at least one of the R.sub.1-R.sub.7
groups is linked via an organic group that has as part or all of
its structure a group Q, which is an amine, a ester, a ether or an
amide link, to a complexing agent of general formula 11a, 11b, 11c,
11d, 11e: 34wherein R.sub.24 is selected from a hydrogen, a
straight or branched chain C.sub.1-C.sub.7 alkyl group, a phenyl or
benzyl group; L.sub.1, L.sub.2, L.sub.3, L.sub.4, independently of
one another, are selected from a hydrogen atom or a metal ion
equivalent of an element of the atomic numbers 20-32, 37-39, 42-51,
or 57-83, which may be radioactive, provided that at least two of
L.sub.1, L.sub.2, L.sub.3 and L.sub.4 are metal ion equivalents,
that other anions are present to compensate for optionally present
charges on the porphyrin, and free carboxylic acid groups that are
not required for complexing are optionally present as salts with
physiologically compatible inorganic cations, or organic cations,
or as esters or amides; and wherein M is 2H or a diamagnetic or
paramagnetic photoactive metal ion selected from Ga.sup.3+,
Pt.sup.2+, Pd.sup.2+, Sn.sup.4+, In.sup.3+, Ge.sup.4+, Si.sup.4+,
Al.sup.3+, Zn.sup.2+, and Mg.sup.2+.
17. A method of using the compound of claim 16 comprising
administering the compound to a patient and, after a period of
time, imaging targeted tissue of the patient through MRI or
radio-diagnostic imaging.
18. A method of using the compound of claim 16 comprising
administering the compound to a patient and, after a period of
time, irradiating targeted tissue of the patient with an energy
source that excites the compound thereby producing a desired
therapeutic response in the target tissue.
19. A method of using the compound of claim 16 comprising
administering the compound to a patient and, after a period of
time, imaging targeted tissue of the patient through MRI or
radio-diagnostic imaging then, after a second period of time,
irradiating the targeted tissue with an energy source that excites
the compound thereby producing a desired therapeutic response in
the target tissue.
20. A method for the detection or treatment of tissue comprising
administering to a patient a therapeutic amount of the compound of
claim 16 locally, systemically, intramuscularly or
interperitoneally and irradiating said compound with energy at a
wavelength able to excite the molecule, such that a desired
therapeutic effect is observed, whereby said tissue belongs to the
hematological system, lymphatic reticuloendothelial system, nervous
system, endocrine and exocrine system, skeletomuscular system,
skin, pulmonary system, gastrointestinal, reproductive system,
immune system, cardiovascular system, urinary system, auditory or
olfactory system.
21. The method of claim 17, wherein said method is for diagnosing
disorders in a vessel wall, tissue adjoining the vessel wall, or
material attached to the vessel wall of a coronary, carotid or
peripheral vasculature.
22. The method of claim 21 wherein said vessel is an artery or a
vein.
23. The method of claim 17 wherein the tissue is atherosclerosis,
restenosis or graft disease.
24. The method of claim 18 wherein the tissue is atherosclerosis,
restenosis or graft disease.
25. The method of claim 19 wherein the tissue is atherosclerosis,
restenosis or graft disease.
26. The method of claim 20 wherein the tissue is atherosclerosis,
restenosis or graft disease.
27. The method of claim 19 wherein the therapy is selected from
ablation, reduction and stabilization of vessel wall plaque.
28. The method of claim 19 wherein said energy source is selected
from light, ultrasound, magnetic force, and electromagnetic
radiation in the UV/visible electromagnetic spectrum or near
infrared.
29. The method of claim 19 wherein said administration of the
compound is prior to, concomitant with, or subsequent to adjunctive
interventions, diagnostics or therapies.
30. The method of claim 19 wherein said administration is a single
bolus or plurality of doses administered to the patient.
31. A compound of formula IB: 35wherein R.sub.1 and R.sub.2 can be
the same or different and are selected from H, NO.sub.2, CN, CHO,
CO-alkyl, SO.sub.3H, SO.sub.3alkyl, SO.sub.3alkylether,
SO.sub.3heteroalkyl, SO.sub.3Na, SO.sub.3K, SO.sub.2NHalkyl,
SO.sub.2N(alkyl).sub.2, SO.sub.2NHheteroalkyl,
SO.sub.2N(heteroalkyl).sub.2, SO.sub.2NHhaloalkyl,
SO.sub.2N(haloalkyl).sub.2, SO.sub.2NHhaloalkylether,
SO.sub.2N(haloalkylether).sub.2, SO.sub.2NHalkylether,
SO.sub.2N(haloalkylether).sub.2, CO-haloalkyl, haloalkyl,
heteroalkyl, hydroxyhaloalkyl, haloalkyl ether, haloalkyl ester, a
halogen, and a alkylcarbonyloxy group; R.sub.3 and R4 can be the
same or different and are selected from: CO.sub.2R.sub.5, where
R.sub.5 is selected from a physiologically acceptable counter ion,
a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heterocycle, heteroaryl, a mono-, di-, or
polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue,
ethers or polyethers, or a functional group of less than about
100,000 daltons; (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.6,
where R.sub.6 is selected from alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, a protecting group, a mono-,
di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl
residue, or a functional group of less than about 100,000 daltons,
and n is an integer between 0 and 4; (CH.sub.2).sub.nCO.sub.2R.s-
ub.7, (CHX).sub.nCO.sub.2R.sub.7, or
(CX.sub.2).sub.nCO.sub.2R.sub.7, where X is a halogen and R.sub.7
is selected from H, a physiologically acceptable counter ion, a
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, a mono-, di-, or
polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue,
or a functional group of less than about 100,000 daltons, and n is
an integer between 1 and 4; CONH(R.sub.8), CO(R.sub.8),
CON(R.sub.8).sub.2, CON(R.sub.8)(R.sub.9),
(CH.sub.2).sub.nCONH(R.sub.8), (CH.sub.2).sub.nCON(R.sub.8).sub.2,
(CH.sub.2).sub.nCOR.sub.8, (CH.sub.2).sub.nCON(R.sub.8)(R.sub.9),
(CX.sub.2).sub.nCONH(R.sub.8), (CX.sub.2).sub.nCON(R.sub.8).sub.2,
(CX.sub.2).sub.nCON(R.sub.8)(R.sub.9)- , (CX.sub.2).sub.nCOR.sub.8,
(CH.sub.2).sub.nCONHNH(R.sub.8), (CX.sub.2).sub.nCONHNH(R.sub.8),
(CHX).sub.nCONH(R.sub.8), (CHX).sub.nCONHNH(R.sub.8),
(CHX).sub.nCON(R.sub.8).sub.2, (CHX).sub.nCON(R.sub.8)(R.sub.9),
where X is a halogen and R.sub.8 and R.sub.9 can be the same or
different and are selected from H, NH.sub.2, straight or branched
chain C1-C20 alkyl, haloalkyl, haloheteroalkyl, heteroalkyl, aryl,
heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino
acid salt, an amino acid ester, an amino acid amide, a mono-, di-,
or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue,
or a functional group of less than about 100,000 daltons, and n is
an integer between 0 and 4; S(R.sub.10),
(CH.sub.2).sub.nS(R.sub.10), (CH.sub.2).sub.nNH(R.sub.10),
(CH.sub.2).sub.nNHNH(R.sub.10),
(CH.sub.2).sub.nNR.sub.10(CH.sub.2).sub.nN(R.sub.10)(R.sub.11), or
(CH.sub.2).sub.nN(R.sub.10)(R.sub.11)(R.sub.12).sup.+A, where
R.sub.10, R.sub.11 and R.sub.12 can be the same or different and
are selected from H, NH.sub.2, straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, amino acids (provided --NH(R.sub.10 is part of the
amino acid), an amino acid ester, an amino acid amide, a mono-,
di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl
residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or
polyetheraryl residue, a functional group of less than about
100,000 daltons, or where R.sub.10, R.sub.11 and R.sub.12 together
possess the atoms necessary to constitute an aromatic ring system,
n is an integer between 0 and 4, and A is a physiologically
acceptable counter ion; (CH.sub.2).sub.nOPO.sub.2OR.sub.13,
(CH.sub.2).sub.nPO(OR.sub.13).su- b.2,
(CH.sub.2).sub.nPO.sub.2R.sub.13, or (CH.sub.2).sub.nPOR.sub.13
where R.sub.13 is selected from H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl or heteroaryl, heterocycle,
amino acids, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl
residue, a mono-, di-, or polyetheraryl residue, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4; (CH.sub.2).sub.nNHCOR.sub.1- 4,
(CH.sub.2).sub.nNHNHCOR.sub.14, where R.sub.14 is selected from a
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, heterocycle, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4; SO.sub.3R.sub.15, SO.sub.2NHR.sub.15,
SO.sub.2N(R.sub.15).sub.2, SO.sub.2NHNHR.sub.15 or
SO.sub.2R.sub.15, where R.sub.15 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl
or heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, and
NHR.sub.15 can also be an amino acid residue, an amino acid salt,
an amino acid ester residue, an amino acid amide residue, or a
functional group of less than about 100,000 daltons; Aryl or
substituted aryl, which may bear one or more substituents with a
molecular weight of less than or equal to about 100,000 daltons;
with the proviso that at least one of the R.sub.1-R.sub.4 groups is
linked via an organic group that has as part or all of its
structure a group Q, which is an amine, an ester, an ether or an
amide link, to a complexing agent of general formula 11a, 11b, 11c,
11d, 11e: 36wherein R.sub.24 is selected from a hydrogen, a
straight or branched chain C.sub.1-C.sub.7 alkyl group, a phenyl or
benzyl group; L.sub.1, L.sub.2, L.sub.3, L.sub.4, independently of
one another, are selected from a hydrogen atom or a metal ion
equivalent of an element of the atomic numbers 20-32, 37-39, 42-51,
or 57-83, which may be radioactive, provided that at least two of
L.sub.1, L.sub.2, L.sub.3 and L.sub.4 are metal ion equivalents,
that other anions are present to compensate for optionally present
charges on the porphyrin, and free carboxylic acid groups that are
not required for complexing are optionally present as salts with
physiologically compatible inorganic cations, or organic cations,
or as esters or amides; and wherein M is 2H or a diamagnetic or
paramagnetic photoactive metal ion selected from Ga.sup.3+,
Pt.sup.2+, Pd.sup.2+, Sn.sup.4+, In.sup.3+, Ge.sup.4+, Si.sup.4+,
Al.sup.3+, Zn.sup.2+, and Mg.sup.2+.
32. A method of using the compound of claim 31 comprising
administering the compound to a patient and, after a period of
time, imaging targeted tissue of the patient through MRI or
radio-diagnostic imaging.
33. A method of using the compound of claim 31 comprising
administering the compound to a patient and, after a period of
time, irradiating targeted tissue of the patient with an energy
source that excites the compound thereby producing a desired
therapeutic response in the target tissue.
34. A method of using the compound of claim 31 comprising
administering the compound to a patient and, after a period of
time, imaging targeted tissue of the patient through MRI or
radio-diagnostic imaging then, after a second period of time,
irradiating the targeted tissue with an energy source that excites
the compound thereby producing a desired therapeutic response in
the target tissue.
35. A method for the detection or treatment of tissue comprising
administering to a patient a therapeutic amount of the compound of
claim 31 locally, systemically, intramuscularly or
interperitoneally and irradiating said compound with energy at a
wavelength able to excite the molecule, such that a desired
therapeutic effect is observed, whereby said tissue belongs to the
hematological system, lymphatic reticuloendothelial system, nervous
system, endocrine and exocrine system, skeletomuscular system,
skin, pulmonary system, gastrointestinal, reproductive system,
immune system, cardiovascular system, urinary system, auditory or
olfactory system.
36. The method of claim 32, wherein said method is for diagnosing
disorders in a vessel wall, tissue adjoining the vessel wall, or
material attached to the vessel wall of a coronary, carotid or
peripheral vasculature.
37. The method of claim 36 wherein said vessel is an artery or a
vein.
38. The method of claim 32 wherein the tissue is atherosclerosis,
restenosis or graft disease.
39. The method of claim 33 wherein the tissue is atherosclerosis,
restenosis or graft disease.
40. The method of claim 34 wherein the tissue is atherosclerosis,
restenosis or graft disease.
41. The method of claim 35 wherein the tissue is atherosclerosis,
restenosis or graft disease.
42. The method of claim 34 wherein the therapy is selected from
ablation, reduction and stabilization of vessel wall plaque.
43. The method of claim 34 wherein said energy source is selected
from light, ultrasound, magnetic force, and electromagnetic
radiation in the UV/visible electromagnetic spectrum or near
infrared.
44. The method of claim 34 wherein said administration of the
compound is prior to, concomitant with, or subsequent to adjunctive
interventions, diagnostics or therapies.
45. The method of claim 34 wherein said administration is a single
bolus or plurality of doses administered to the patient.
46. (canceled)
47. (canceled)
48. (canceled)
49. (canceled)
50. (canceled)
51. (canceled)
52. (canceled)
53. (canceled)
54. (canceled)
55. (canceled)
56. (canceled)
57. (canceled)
58. (canceled)
59. (canceled)
60. (canceled)
61. (canceled)
62. (canceled)
63. (canceled)
64. (canceled)
65. (canceled)
66. (canceled)
67. (canceled)
68. (canceled)
69. (canceled)
70. (canceled)
71. (canceled)
72. (canceled)
73. (canceled)
74. (canceled)
75. (canceled)
76. A compound of formula III: 37wherein R.sub.1-R.sub.10 can be
the same or different and are selected from: H, halide, substituted
or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl,
cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, amide, ester, ether, polyether,
alkoxy group, aryloxy group, haloalkoxy group, amino group,
alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl
group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group,
aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil
group, carbamoyl group, heterocyclic group, nitro group, nitroso
group, formyloxy group, isocyano group, cyanate group, isocyanate
group, thiocyanate group, isothiocyanate group, N(alkyl).sub.2,
N(aryl).sub.2, CH.dbd.CH(aryl), CH.dbd.CHCH.sub.2N(CH.sub-
.3).sub.2, or a functional group having a molecular weight of less
than about 100,000 daltons;
CH.dbd.CHCH.sub.2N.sup.+(CH.sub.3).sub.3A, CH.dbd.N(alkyl).sub.2A,
or N(alkyl).sub.3.sup.+A, where A is a charge balancing ion; CN,
OH, CHO, COCH.sub.3, CO(alkyl), CO.sub.2H, CO.sub.2Na, CO.sub.2K,
CH(CH.sub.3)OH, CH(CH.sub.3)O-alkyl, CH(CH.sub.3)O-alkoxy, or
CH(CH.sub.3)O-aryl; (CH.sub.2).sub.nO-alkoxy, or
(CH.sub.2).sub.nO-alkyl, where n is an integer from 0 to 8;
C(X).sub.2C(X).sub.3, where X is a halogen; CO.sub.2R.sub.11, where
R.sub.11 is selected from a physiologically acceptable counter ion,
a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or
polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue,
or a functional group of less than about 100,000 daltons;
(CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.12, where R.sub.12 is
selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocycle, aryl, heteroaryl, a protecting group, a mono-, di-, or
polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue,
or a functional group of less than about 100,000 daltons, and n is
an integer between 0 and 4; (CH.sub.2).sub.nCO.sub.2R.sub.13,
(CHX).sub.nCO.sub.2R.sub.13, or (CX.sub.2).sub.nCO.sub.2R.sub.13,
where X is a halogen and R.sub.13 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, or a functional
group of less than about 100,000 daltons, and n is an integer
between 1 and 4; CONH(R.sub.14), CONHNH(R.sub.14), CO(R.sub.14),
CON(R.sub.14).sub.2, CON(R.sub.14)(R.sub.15),
(CH.sub.2).sub.nCONH(R.sub.14), (CH.sub.2).sub.nCONHNH(R.sub.14),
(CH.sub.2).sub.nCON(R.sub.14).sub.2, (CH.sub.2).sub.nCOR.sub.14,
(CH.sub.2).sub.nCON(R.sub.14)(R.sub.15),
(CX.sub.2).sub.nCONH(R.sub.14),
(CX.sub.2).sub.nCON(R.sub.14).sub.2,
(CX.sub.2).sub.nCON(R.sub.14)(R.sub.- 15),
(CX.sub.2).sub.nCOR.sub.14, (CH.sub.2).sub.nCONHNH(R.sub.14),
(CX.sub.2).sub.nCONHNH(R.sub.14), (CHX).sub.nCONH(R.sub.14),
(CHX).sub.nCONHNH(R.sub.14), (CHX).sub.nCON(R.sub.14).sub.2,
(CHX).sub.nCON(R.sub.14)(R.sub.15), where X is a halogen and
R.sub.14 and R.sub.15 can be the same or different and are selected
from H, NH.sub.2, straight or branched chain C1-C20 alkyl,
haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl,
heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt,
an amino acid ester, an amino acid amide, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons, and n is an
integer between 0 and 4; S(R.sub.16), (CH.sub.2).sub.nS(R.sub.16),
(CH.sub.2).sub.nNH(R.sub.16), (CH.sub.2).sub.nNHNH(R.sub.16),
(CH.sub.2).sub.nN(R.sub.16).sub.2
(C.sub.2).sub.nN(R.sub.16)(R.sub.17), or
(CH.sub.2).sub.nN(R.sub.16)(R.sub.17)(R.sub.18).sup.+A, where
R.sub.16, R.sub.17 and R.sub.18 can be the same or different and
are selected from H, NH.sub.2, straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, amino acids, an amino acid ester, or an amino acid
amide provided --NHR.sub.16 is part of the amino acid, a mono-,
di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl
residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or
polyetheraryl residue, a functional group of less than about
100,000 daltons, or where R.sub.16, R.sub.17 and R.sub.18 together
possess the atoms necessary to constitute an aromatic ring system,
n is an integer between 0 and 4, and A is a physiologically
acceptable counter ion; (CH.sub.2).sub.nOPO.sub.2OR.sub.1- 9,
(CH.sub.2).sub.nPO(OR.sub.19).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.19, or (CH.sub.2).sub.nPOR.sub.19
where R.sub.19 is selected from H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino
acids, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a
mono-, di-, or polyetheraryl residue, or a functional group of less
than about 100,000 daltons, and n is an integer between 0 and 4;
(CH.sub.2).sub.nNHCOR.sub.20, (CH.sub.2).sub.nNHNHCOR.sub.20, where
R.sub.20 is selected from a straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.21,
SO.sub.2NHR.sub.21, SO.sub.2N(R.sub.21).sub.2, SO.sub.2NHNHR.sub.21
or SO.sub.2R.sub.21, where R.sub.21 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons; and
NHR.sub.21 can be an amino acid residue, an amino acid salt, an
amino acid ester residue, or an amino acid amide residue; Aryl or
substituted aryl, which may bear one or more substituents with a
molecular weight of less than or equal to about 100,000 daltons;
and R.sub.1-R.sub.2, R.sub.3-R.sub.4, R.sub.6-R.sub.7;
R.sub.8-R.sub.9, R.sub.4-R.sub.5, R.sub.5-R.sub.6, R.sub.9-R.sub.10
and R.sub.10-R.sub.1 may also possess the atoms necessary to form
ring systems, which themselves may possess heteroatoms that may
neutral or bear one or more functional groups of molecular weight
equal to or less than about 100,000 daltons; with the proviso that
at least one of the R.sub.1-R.sub.10 groups is linked via an
organic group that has as part or all of its structure a group Q,
which is an amine, an ester, an ether or an amide link, to a
complexing agent of general formula 11a, 11b, 11c, 11d, 11e:
38wherein R.sub.24 is selected from a hydrogen, a straight or
branched chain C.sub.1-C.sub.7 alkyl group, a phenyl or benzyl
group; L.sub.1, L.sub.2, L.sub.3, L.sub.4, independently of one
another, are selected from a hydrogen atom or a metal ion
equivalent of an element of the atomic numbers 20-32, 37-39, 42-51,
or 57-83, which may be radioactive, provided that at least two of
L.sub.1, L.sub.2, L.sub.3 and L.sub.4 are metal ion equivalents,
that other anions are present to compensate for optionally present
charges on the porphyrin, and free carboxylic acid groups that are
not required for complexing are optionally present as salts with
physiologically compatible inorganic cations, or organic cations,
or as esters or amides; and wherein M is 2H or a diamagnetic or
paramagnetic photoactive metal ion selected from Ga.sup.3+,
Pt.sup.2+, Pd.sup.2+, Sn.sup.4+, In.sup.3+, Ge.sup.4+, Si.sup.4+,
Al.sup.3+, Zn.sup.2+, and Mg.sup.2+.
77. A method of using the compound of claim 76 comprising
administering the compound to a patient and, after a period of
time, imaging targeted tissue of the patient through MRI or
radio-diagnostic imaging.
78. A method of using the compound of claim 76 comprising
administering the compound to a patient and, after a period of
time, irradiating targeted tissue of the patient with an energy
source that excites the compound thereby producing a desired
therapeutic response in the target tissue.
79. A method of using the compound of claim 76 comprising
administering the compound to a patient and, after a period of
time, imaging targeted tissue of the patient through MRI or
radio-diagnostic imaging then, after a second period of time,
irradiating the targeted tissue with an energy source that excites
the compound thereby producing a desired therapeutic response in
the target tissue.
80. A method for the detection or treatment of tissue comprising
administering to a patient a therapeutic amount of the compound of
claim 76 locally, systemically, intramuscularly or
interperitoneally and irradiating said compound with energy at a
wavelength able to excite the molecule, such that a desired
therapeutic effect is observed, whereby said tissue belongs to the
hematological system, lymphatic reticuloendothelial system, nervous
system, endocrine and exocrine system, skeletomuscular system,
skin, pulmonary system, gastrointestinal, reproductive system,
immune system, cardiovascular system, urinary system, auditory or
olfactory system.
81. The method of claim 77, wherein said method is for diagnosing
disorders in a vessel wall, tissue adjoining the vessel wall, or
material attached to the vessel wall of a coronary, carotid or
peripheral vasculature.
82. The method of claim 81 wherein said vessel is an artery or a
vein.
83. The method of claim 77 wherein the tissue is atherosclerosis,
restenosis or graft disease.
84. The method of claim 78 wherein the tissue is atherosclerosis,
restenosis or graft disease.
85. The method of claim 79 wherein the tissue is atherosclerosis,
restenosis or graft disease.
86. The method of claim 80 wherein the tissue is atherosclerosis,
restenosis or graft disease.
87. The method of claim 79 wherein the therapy is selected from
ablation, reduction and stabilization of vessel wall plaque.
88. The method of claim 79 wherein said energy source is selected
from light, ultrasound, magnetic force, and electromagnetic
radiation in the UV/visible electromagnetic spectrum or near
infrared.
89. The method of claim 79 wherein said administration of the
compound is prior to, concomitant with, or subsequent to adjunctive
interventions, diagnostics or therapies.
90. The method of claim 79 wherein said administration is a single
bolus or plurality of doses administered to the patient.
91. A compound of formula IIIA: 39wherein R.sub.1-R.sub.4 can be
the same or different and are selected from a functional group of
less than about 100,000 daltons; CO.sub.2R.sub.5, where R.sub.5 is
selected from H, a physiologically acceptable counter ion, a
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heterocycle, heteroaryl, a mono-, di-, or
polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue,
or a functional group of less than about 100,000 daltons;
(CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.6, where R.sub.6 is
selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocycle, aryl, heteroaryl, a protecting group, a mono-, di-, or
polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue,
or a functional group of less than about 100,000 daltons, and n is
an integer between 0 and 4; (CH.sub.2).sub.nCO.sub.2R.sub.7,
(CHX).sub.nCO.sub.2R.su- b.7, or (CX.sub.2).sub.nCO.sub.2R.sub.7,
where X is a halogen and R.sub.7 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, heterocycle, aryl,
heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, or a functional group of less than
about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R.sub.8), (CONHNH(R.sub.8), CO(R.sub.8), CON(R.sub.8).sub.2,
CON(R.sub.8)(R.sub.9), (CH.sub.2).sub.nCONH(R.sub.8),
(CH.sub.2).sub.nCONHNH(R.sub.8),
(CH.sub.2).sub.nCON(R.sub.8).sub.2, (CH.sub.2).sub.nCOR.sub.8,
(CH.sub.2).sub.nCON(R.sub.8)(R.sub.9),
(CX.sub.2).sub.nCONH(R.sub.8), (CX.sub.2).sub.nCON(R.sub.8).sub.2,
(CX.sub.2).sub.nCON(R.sub.8)(R.sub.9)- , (CX.sub.2).sub.nCOR.sub.8,
(CH.sub.2).sub.nCONHNH(R.sub.8), (CX.sub.2).sub.nCONHNH(R.sub.8),
(CHX).sub.nCONH(R.sub.8), (CHX).sub.nCONHNH(R.sub.8),
(CHX).sub.nCON(R.sub.8).sub.2, or (CHX).sub.nCON(R.sub.8)(R.sub.9),
where X is a halogen and R.sub.8 and R.sub.9 can be the same or
different and are selected from H, NH.sub.2, straight or branched
chain C1-C20 alkyl, haloalkyl, haloheteroalkyl, heteroalkyl, aryl,
heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an
amino acid, an amino acid salt, an amino acid ester, an amino acid
amide, or a functional group of less than about 100,000 daltons,
and n is an integer between 0 and 4; S(R.sub.10),
(CH.sub.2).sub.nS(R.sub.10)- , (CH.sub.2).sub.nNH(R.sub.10),
(CH.sub.2).sub.nNHNH(R.sub.10), (CH.sub.2).sub.nN(R.sub.10).sub.2,
(CH.sub.2).sub.nN(R.sub.10)(R.sub.11), or
(CH.sub.2).sub.nN(R.sub.10)(R.sub.11)(R.sub.12).sup.+A, where
R.sub.10, R.sub.11 and R.sub.12 can be the same or different and
are selected from H, NH.sub.2, straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, amino acids, an amino acid ester, or an amino acid
amide provided --NHR.sub.10 is part of the amino acid, a mono-,
di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl
residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or
polyetheraryl residue, a functional group of less than about
100,000 daltons, or where R.sub.10, R.sub.11 and R.sub.12 together
possess the atoms necessary to constitute an aromatic ring system,
n is an integer between 0 and 4, and A is a physiologically
acceptable counter ion; (CH.sub.2).sub.nOPO.sub.2OR.sub.1- 3,
(CH.sub.2).sub.nPO(OR.sub.13).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.13, or (CH.sub.2).sub.nPOR.sub.13
where R.sub.13 is selected from H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino
acids, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a
mono-, di-, or polyetheraryl residue, or a functional group of less
than about 100,000 daltons, and n is an integer between 0 and 4;
(CH.sub.2).sub.nNHCOR.sub.14, or (CH.sub.2).sub.nNHNHCOR.sub.14,
where R.sub.14 is selected from a straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.15,
SO.sub.2NHR.sub.15, SO.sub.2N(R.sub.15).sub.2, SO.sub.2NHNHR.sub.15
or SO.sub.2R.sub.15, where R.sub.15 is selected from H, a
physiologically acceptable counter ion, a, straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heteroaryl, heterocycle; NHR.sub.15 can also be an amino acid
residue, an amino acid salt, an amino acid ester residue, or an
amino acid amide residue; a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons; Aryl or
substituted aryl, which may bear one or more substituents with a
molecular weight of less than or equal to about 100,000 daltons;
with the proviso that at least one of the R.sub.1-R.sub.4 groups is
linked via an organic group that has as part or all of its
structure a group Q, which is an amine, an ester, an ether or an
amide link, to a complexing agent of general formula 11a, 11b, 11c,
11d, 11e: 40wherein R.sub.24 is selected from a hydrogen, a
straight or branched chain C.sub.1-C.sub.7 alkyl group, a phenyl or
benzyl group; L.sub.1, L.sub.2, L.sub.3, L.sub.4, independently of
one another, are selected from a hydrogen atom or a metal ion
equivalent of an element of the atomic numbers 20-32, 37-39, 42-51,
or 57-83, which may be radioactive, provided that at least two of
L.sub.1, L.sub.2, L.sub.3 and L.sub.4 are metal ion equivalents,
that other anions are present to compensate for optionally present
charges on the porphyrin, and free carboxylic acid groups that are
not required for complexing are optionally present as salts with
physiologically compatible inorganic cations, or organic cations,
or as esters or amides; and wherein M is 2H or a diamagnetic or
paramagnetic photoactive metal ion selected from Ga.sup.3+,
Pt.sup.2+, Pd.sup.2+, Sn.sup.4+, In.sup.3+, Ge.sup.4+, Si.sup.4+,
Al.sup.3+, Zn.sup.2+, and Mg.sup.2+.
92. A method of using the compound of claim 91 comprising
administering the compound to a patient and, after a period of
time, imaging targeted tissue of the patient through MRI or
radio-diagnostic imaging.
93. A method of using the compound of claim 91 comprising
administering the compound to a patient and, after a period of
time, irradiating targeted tissue of the patient with an energy
source that excites the compound thereby producing a desired
therapeutic response in the target tissue.
94. A method of using the compound of claim 91 comprising
administering the compound to a patient and, after a period of
time, imaging targeted tissue of the patient through MRI or
radio-diagnostic imaging then, after a second period of time,
irradiating the targeted tissue with an energy source that excites
the compound thereby producing a desired therapeutic response in
the target tissue.
95. A method for the detection or treatment of tissue comprising
administering to a patient a therapeutic amount of the compound of
claim 91 locally, systemically, intramuscularly or
interperitoneally and irradiating said compound with energy at a
wavelength able to excite the molecule, such that a desired
therapeutic effect is observed, whereby said tissue belongs to the
hematological system, lymphatic reticuloendothelial system, nervous
system, endocrine and exocrine system, skeletomuscular system,
skin, pulmonary system, gastrointestinal, reproductive system,
immune system, cardiovascular system, urinary system, auditory or
olfactory system.
96. The method of claim 92, wherein said method is for diagnosing
disorders in a vessel wall, tissue adjoining the vessel wall, or
material attached to the vessel wall of a coronary, carotid or
peripheral vasculature.
97. The method of claim 96 wherein said vessel is an artery or a
vein.
98. The method of claim 92 wherein the tissue is atherosclerosis,
restenosis or graft disease.
99. The method of claim 93 wherein the tissue is atherosclerosis,
restenosis or graft disease.
100. The method of claim 94 wherein the tissue is atherosclerosis,
restenosis or graft disease.
101. The method of claim 95 wherein the tissue is atherosclerosis,
restenosis or graft disease.
102. The method of claim 94 wherein the therapy is selected from
ablation, reduction and stabilization of vessel wall plaque.
103. The method of claim 94 wherein said energy source is selected
from light, ultrasound, magnetic force, and electromagnetic
radiation in the UV/visible electromagnetic spectrum or near
infrared.
104. The method of claim 94 wherein said administration of the
compound is prior to, concomitant with, or subsequent to adjunctive
interventions, diagnostics or therapies.
105. The method of claim 94 wherein said administration is a single
bolus or plurality of doses administered to the patient.
106. A compound of formula IV: 41wherein R.sub.1-R.sub.8 can be the
same or different and are selected from: H, halide, substituted or
unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl,
cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, amide, ester, ether, polyether,
alkoxy group, aryloxy group, haloalkoxy group, amino group,
alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl
group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group,
aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil
group, carbamoyl group, heterocyclic group, nitro group, nitroso
group, formyloxy group, isocyano group, cyanate group, isocyanate
group, thiocyanate group, isothiocyanate group, N(alkyl).sub.2,
N(aryl).sub.2, CH.dbd.CH(aryl), CH.dbd.CHCH.sub.2N(CH.sub-
.3).sub.2, or a functional group of molecular weight of less than
about 100,000 daltons; CH.dbd.CHCH.sub.2N(CH.sub.3).sub.3.sup.+A,
CH.dbd.N(alkyl).sub.2.sup.+A, or N(alkyl).sub.3.sup.+A, where A is
a charge balancing ion; CN, OH, CHO, COCH.sub.3, CO(alkyl),
CO.sub.2H, CO.sub.2Na, CO.sub.2K, CH(CH.sub.3)OH,
CH(CH.sub.3)O-alkyl, CH(CH.sub.3)O-alkoxy, or CH(CH.sub.3)O-aryl;
(CH.sub.2).sub.nO-alkoxy, or (CH.sub.2).sub.nO-alkyl; where n is an
integer from 0 to 8; C(X).sub.2C(X).sub.3, where X is a halogen;
CO.sub.2R.sub.9, where R.sub.9 is selected from a physiologically
acceptable counter ion, a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heterocycle,
heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, or a functional group of less than
about 100,000 daltons; (CH.sub.2).sub.nOH, or
(CH.sub.2).sub.nOR.sub.10, where R.sub.10 is selected from alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heterocycle,
heteroaryl, a protecting group, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4; (CH.sub.2).sub.nCO.sub.2R.sub.11,
(CHX).sub.nCO.sub.2R.sub.11, (CX.sub.2).sub.nCO.sub.2R.sub.11 where
X is a halogen and R.sub.11 is selected from H, a physiologically
acceptable counter ion, a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heterocycle,
heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, or a functional group of less than
about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R.sub.12), CONHNH(R.sub.12)CO(R.sub.12), CON(R.sub.12).sub.2,
CON(R.sub.12)(R.sub.13), (CH.sub.2).sub.nCONH(R.sub.12),
(CH.sub.2).sub.nCONHNH(R.sub.12),
(CH.sub.2).sub.nCON(R.sub.12).sub.2, (CH.sub.2).sub.nCOR.sub.12
(CH.sub.2).sub.nCON(R.sub.12)(R.sub.13),
(CX.sub.2).sub.nCONH(R.sub.12),
(CX.sub.2).sub.nCON(R.sub.12).sub.2,
(CX.sub.2).sub.nCON(R.sub.12)(R.sub.13),
(CX.sub.2).sub.nCOR.sub.12, (CH.sub.2).sub.nCONHNH(R.sub.12),
(CX.sub.2).sub.nCONHNH(R.sub.12), (CHX).sub.nCONH(R.sub.12),
(CHX).sub.nCONHNH(R.sub.12), (CHX).sub.nCON(R.sub.12).sub.2,
(CHX).sub.nCON(R.sub.12)(R.sub.13), where X is a halogen and
R.sub.12 and R.sub.13 can be the same or different and are selected
from H, NH.sub.2, straight or branched chain C1-C20 alkyl,
haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl,
heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt,
an amino acid ester, an amino acid amide, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons, and n is an
integer between 0 and 4; S(R.sub.14), (CH.sub.2).sub.nS(R.sub.14),
(CH.sub.2).sub.nNH(R.sub.14), (CH.sub.2).sub.nNHNH(R.sub.14),
(CH.sub.2).sub.nN(R.sub.14).sub.2,
(CH.sub.2).sub.nN(R.sub.14)(R.sub.15), or
(CH.sub.2).sub.nN(R.sub.14)(R.s- ub.15)(R.sub.16).sup.+A, where
R.sub.14, R.sub.15 and R.sub.16 can be the same or different and
are selected from H, NH.sub.2, straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, amino acids, an amino acid ester, or an amino acid
amide provided --NH(R.sub.14) is part of the amino acid, a mono-,
di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl
residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or
polyetheraryl residue, a functional group of less than about
100,000 daltons, or where R.sub.14, R.sub.15 and R.sub.16 together
possess the atoms necessary to constitute an aromatic ring system,
n is an integer between 0 and 4, and A is a physiologically
acceptable counter ion; (CH.sub.2).sub.nOPO.sub.2OR.sub.17,
(CH.sub.2).sub.nPO(OR.sub.17).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.17, or (CH.sub.2).sub.nPOR.sub.17
where R.sub.17 is selected from H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino
acids, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a
mono-, di-, or polyetheraryl residue, or a functional group of less
than about 100,000 daltons, and n is an integer between 0 and 4;
(CH.sub.2).sub.nNHCOR.sub.1- 8, or (CH.sub.2).sub.nNHNHCOR.sub.18,
where R.sub.18 is selected from a straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.19,
SO.sub.2NHR.sub.19, SO.sub.2N(R.sub.19).sub.2, SO.sub.2NHNHR.sub.19
or SO.sub.2R.sub.19, where R.sub.19 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons, and
NHR.sub.19 can also be an amino acid residue, an amino acid salt,
an amino acid ester residue, or an amino acid amide residue; and
Aryl or substituted aryl, which may bear one or more substituents
selected from hydroxy groups, alkyl groups, carboxyl groups and its
esters and amides and sulfonic acid groups and their esters and
amides, and substitiuents with a molecular weight of less than or
equal to about 100,000 daltons; with the proviso that at least one
of the R.sub.1-R.sub.12 groups is linked via an organic group that
has as part or all of its structure a group Q, which is an amine,
an ester, an ether or an amide link, to a complexing agent of
general formula 11a, 11b, 11c, 11d, 11e: 42wherein R.sub.24 is
selected from a hydrogen, a straight or branched chain
C.sub.1-C.sub.7 alkyl group, a phenyl or benzyl group; L.sub.1,
L.sub.2, L.sub.3, L.sub.4, independently of one another, are
selected from a hydrogen atom or a metal ion equivalent of an
element of the atomic numbers 20-32, 37-39, 42-51, or 57-83, which
may be radioactive, provided that at least two of L.sub.1, L.sub.2,
L.sub.3 and L.sub.4 are metal ion equivalents, that other anions
are present to compensate for optionally present charges on the
porphyrin, and free carboxylic acid groups that are not required
for complexing are optionally present as salts with physiologically
compatible inorganic cations, or organic cations, or as esters or
amides; and A, B, C, and D can be the same or different and are
selected from N, CH, and CR.sub.20 where R.sub.20 is selected from
a halogen, aryl, subsitituted aryl, heteroaryl, alkyl, haloalkyl,
heterohaloalkyl, heterocycle, hydroxyalky, hydroxyhaloalkyl, or a
functional group of molecular weight of less than about 100,000
daltons; and wherein M is selected from 2H or a diamagnetic or
paramagnetic photoactive metal ion selected from Ga.sup.3+,
Pt.sup.2+, Pd.sup.2+, Sn.sup.4+, In.sup.3+, Ge.sup.4+, Si.sup.4+,
Al.sup.3+, Zn.sup.2+, and Mg.sup.2+.
107. A method of using the compound of claim 106 comprising
administering the compound to a patient and, after a period of
time, imaging targeted tissue of the patient through MRI or
radio-diagnostic imaging.
108. A method of using the compound of claim 106 comprising
administering the compound to a patient and, after a period of
time, irradiating targeted tissue of the patient with an energy
source that excites the compound thereby producing a desired
therapeutic response in the target tissue.
109. A method of using the compound of claim 106 comprising
administering the compound to a patient and, after a period of
time, imaging targeted tissue of the patient through MRI or
radio-diagnostic imaging then, after a second period of time,
irradiating the targeted tissue with an energy source that excites
the compound thereby producing a desired therapeutic response in
the target tissue.
110. A method for the detection or treatment of tissue comprising
administering to a patient a therapeutic amount of the compound of
claim 106 locally, systemically, intramuscularly or
interperitoneally and irradiating said compound with energy at a
wavelength able to excite the molecule, such that a desired
therapeutic effect is observed, whereby said tissue belongs to the
hematological system, lymphatic reticuloendothelial system, nervous
system, endocrine and exocrine system, skeletomuscular system,
skin, pulmonary system, gastrointestinal, reproductive system,
immune system, cardiovascular system, urinary system, auditory or
olfactory system.
111. The method of claim 107, wherein said method is for diagnosing
disorders in a vessel wall, tissue adjoining the vessel wall, or
material attached to the vessel wall of a coronary, carotid or
peripheral vasculature.
112. The method of claim 111 wherein said vessel is an artery or a
vein.
113. The method of claim 107 wherein the tissue is atherosclerosis,
restenosis or graft disease.
114. The method of claim 108 wherein the tissue is atherosclerosis,
restenosis or graft disease.
115. The method of claim 109 wherein the tissue is atherosclerosis,
restenosis or graft disease.
116. The method of claim 1 10 wherein the tissue is
atherosclerosis, restenosis or graft disease.
117. The method of claim 109 wherein the therapy is selected from
ablation, reduction and stabilization of vessel wall plaque.
118. The method of claim 109 wherein said energy source is selected
from light, ultrasound, magnetic force, and electromagnetic
radiation in the UV/visible electromagnetic spectrum or near
infrared.
119. The method of claim 109 wherein said administration of the
compound is prior to, concomitant with, or subsequent to adjunctive
interventions, diagnostics or therapies.
120. The method of claim 109 wherein said administration is a
single bolus or plurality of doses administered to the patient.
Description
DESCRIPTION OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention is directed to substituted porphyrin and
azaporphyrin derivatives with various substituents in the 13- and
17-positions of the porphyrin skeleton suitable as pharmaceutical
agents for use in photodynamic therapy, MRI diagnosis, and
radiodiagnostics. The invention is also directed to pharmaceutical
agents that contain these compounds, as well as a process for the
production of these compounds and agents.
[0003] 2. Background of the Invention
[0004] Photodynamic therapy ("PDT") is a new modality for the
treatment of malignancies, diseased tissue, hyperproliferating
tissues, pathogens or unwanted normal tissues. PDT involves a
localized or systemic administration of a photosensitizing compound
followed by exposure of target tissue to photoactivating light. The
photoactivating light excites the photosensitizer which, in turn,
interacts with singlet oxygen causing the production of cytotoxic
oxygen species. The interaction of the cytotoxic oxygen species
with tissues in which the photosensitizer is localized causes a
modification of the tissue, resulting in a desired clinical effect.
The tissue specificity of the resultant phototoxic damage is
determined largely, although not entirely, by the relative
concentrations of the photosensitizer in each tissue at the time of
its exposure to the photoactivating light.
[0005] Following systemic administration, many photosensitizers
accumulate to varying degrees within tissues depending on the
pharmacokinetic and distribution profile of the photosensitizing
compound and the cell types comprising the tissues. The chemical
factors that enable certain photosensitizers to accumulate to a
greater degree at a target site than other photosensitizers is not
well understood. Indeed, the biological factors that result in the
preferential uptake of some photosensitizers in certain tissue
types compared to other tissue types are not well understood
either. It is clear, however, that each photosensitizer has its own
distribution and pharmacokinetic properties within different
tissues and these properties determine the relative usefulness of
the photosensitizer for the desired therapy. Currently, rigorous
screening and biological evaluation in appropriate model systems is
required to identify suitable photosensitizers that display the
characteristics necessary to effect a therapy within the diseased
or target tissues.
[0006] Porphyrins and azaporphyrins and their metallated
derivatives belong to a family of substances that are suitable for
PDT. These compounds accumulate in target tissues and absorb light
in a range in which living tissue is still fairly permeable, namely
between 380-680 nm. Moreover, porphyrins, azaporphyrins and their
photoactive metallated derivatives exhibit high yields of the
excited triplet state, a long lifetime in this state, and good
energy transfer to oxygen with concomittent production of singlet
oxygen. Of the porphyrins and their derivatives, several
photosensitizers have been developed largely for use in oncological
applications, but have also been examined in other disease areas in
the PDT field in humans. (WO 92/06097; WO 97/20846; EP 0 811626;
U.S. Pat. Nos. 5,633,275, 5,654,423, 5,675,001, 5,703,230, and
5,705,622). Such photosensitizers include Photofrin (U.S. Pat. No.
4,882,234), 5-aminolevulinic acid (protoporphyrin IX precursor),
SnET2, Visudyne.RTM. (Benzoporphyrin derivative), Antrin.RTM.,
Optrin.RTM. (Lutetium texaphyrin) and mono-aspartyl chlorin e6
(MACE). All of these compounds were designed specifically for the
treatment of solid tumors. Specifically, many of these compounds
were designed to have large absorptions in the 620-740 nm range so
as to optimize the photoactivation of the drug with a wavelength
that will penetrate to the greatest depths possible all tissue
types. In particular, these drugs were designed to absorb outside
of the blood absorption profile, thus ensuring efficient
photoactivation in most tissue types.
[0007] The excitation light source (usually diode lasers or dye
lasers) has historically been matched to the far-red absorption
bandwidth of the photosensitizer in order to maximize light
penetration through tissues. Indeed, the present inventor believes
that all the tetrapyrrolic photosensitizers used have been designed
for long wavelength absorption of light (>630 nm) to address
this perceived issue. Surprisingly, it has been found that short
wavelength photosensitizers (with activation absorptions <600
nm) are capable of delivering effective localized therapy to many
disease indications where historically long wavelength
photosensitizers (with activation absorptions >600 nm) have
shown ineffective clinical outcomes. One such example is in
coronary artery disease.
[0008] While several of the photosensitizers described above have
been used to treat atheromatous plaques and some are able to
display some inhibition of intimal hyperplasia in animal models,
many if not all have characteristics that will limit the usefulness
of these drugs in a clinical setting. One particular concern is the
half-life of the photosensitizer. A photosensitizer delivered
systemically with a long half-life (CASPc, Photofrin, SnET2) may
have phototoxic side effects if exposed to direct light, within
days of the procedure.
[0009] A second even more pressing concern that has to date escaped
many of the investigators testing new photosensitizers in
cardiovascular disease is photochemically induced damage to
"normal" myocardial tissue surrounding the artery due to
non-selective photosensitizer uptake and long depths of light
penetration, which activates the photosensitizer in the myocardial
tissue. Historically, it has been believed that attenuation of the
photosensitizer excitation light by blood would inhibit the use of
wavelengths of light shorter than 600 nm in the cardiovascular
field. This may have been true several years ago when balloon
catheter technology in PDT was not as advanced as it is today. New
endovascular light ballon catheters, however, can remove most of
the blood from the treatment area. This advance enables the use of
short wavelengths of light that historically may have been
attenuated by blood.
[0010] The use of wavelengths of light lower than 600 nm offers
significant advantages in PDT because such wavelengths have
penetration characteristics that deliver the PDT effect to the
target sites (media and adventicia layers of the vessel) and not to
myocardial tissue. Thus, effective therapy can be afforded at the
target site, while deeper tissues are shielded from a PDT response
by blood absorption within these tissues. Previously reported
cardiovascular experiments performed to date on tetrapyrrolic
molecules have been done at wavelengths >620 nm. Experiments
that we have performed in pig arteries with new photosensitizer
candidates at light activation >600 nm have resulted in
unacceptable levels of damage to myocardial or cardiac muscle
tissue surrounding the treatment area. This has major clinical
implications to patients with existing ischemic myocardial or
muscle tissue due to poor artery perfusion. Attempts to lower the
light dosimetry in order to limit treatments to the target tissue
(media/intima) leads to long treatment times and less efficacy. In
addition, long treatment times in the artery exposes the patient to
additional risks with inflation and deflation of the balloon
devices. Importantly, we have demonstrated in pig arteries that
effective treatment depths can be obtained with shorter wavelengths
of light, with sparing of underlying tissue damage.
[0011] Thus, it is believed that, long wavelength absorbing
molecules (>600 nm), unless highly selective to target
myocardial and intimal tissues (which has not to date been reported
with any photosensitizer in cardiovascular tissues), may cause
unacceptable normal cardiac tissue damage. Therefore, it would
appear that activation of lutetium texaphyrin, BPD-MA, MACE, CASPc,
SnET2, and pheophorbide PH-II26 with red light may be of limited
use in the treatment of cardiovascular disease as all of these
compounds are "red" absorbers by design, in so much as all possess
low energy absorbtion peaks at wavelengths >600 nm. It should be
noted also that chlorins, phthalocyanines and texaphyrin type
photosensitizers in general have little absorption in the 500-600
nm regions, and thus may be suboptimal with regard to light
activation at green and yellow wavelengths in cardiovascular
tissues. In addition, protoporphyrin IX and photofrin do not
display absorption maximas at 532 nm, thus they may be inefficient
at absorbing treatment light at this wavelength and have very low
molar extinction coefficients at 575 nm (.about.7000
cm.sup.-1/M.sup.-1). Furthermore, because long wavelength
photosensitizers by design have red absorption peaks, operating
room lighting in an emergency situation may cause serious
photosensitivity in light exposed tissues. Attempts to use red
light filters on operating room lights results in poor tissue
contrast and sub-optimal lighting conditions, making surgical
procedures under these conditions extremely difficult, if not
impossible. Optical clarity is much better at shorter wavelengths
(500-600 nm) where the depth of light peneration is limited to a
few mm of tissue penetration during the surgical procedure.
[0012] Another significant drawback of the above long wavelength
absorbing compounds mentioned is that they are only suitable for
therapy; prior or simultaneous MRI-diagnostic monitoring of the
success of the therapy is not possible with them, nor is
radiodiagnostic imaging. For this purpose, it is necessary to
administer another paramagnetic substance, which must have a
biodistribution that is as close to that of the therapeutic agent
as possible. This requirement often cannot be met.
[0013] There have been attempts by groups in the field to provide
porphyrin linked MRI or radiodiagnostic compounds. Notable examples
include: Hilgar, C. S., et al, U.S. Pat. No. 5,849,259; Niedballa,
U., et. al., U.S. Pat. No. 5,275,801; Platzek, J., et. al., U.S.
Pat. No. 6,136,841; Niedballa, U., et. al., EP 0355041 A2, A3, and
B1; Sakata, I., et. al., U.S. Pat. No. 4,996,312; Sakata, I., et.
al., U.S. Pat. No. 4,996,312; and Sakata, I., et. al., U.S. Pat.
No. EP 0220686. It has been known for some time that porphyrin
derivatives selectively accumulate in human and animal tumors (D.
Kessel and T.-II. Chu, Cancer Res. 43, pp.1994-1999, 1983; P.
Hambright, Bioinorg. Chem. 5, pp. 87-92, 1975; R. Lipson et al.,
Cancer 20, pp. 2250-2257, 1967; and D. Sanderson et al., Cancer 30,
pp. 1368-1372, 1972). First attempts to use this class of compound
as a diagnostic agent were also described in the literature (J.
Winkelmann et al., Cancer Research 27, pp. 2060-2064, 1967; N. J.
Patronas et al, Cancer Treatment Reports 70, pp. 391-395, 1986).
However, the compounds so far described are far from being able to
satisfactorily meet the desired requirements to be effective PDT,
MRI and radiodiagnostic imaging agents.
[0014] Substituted hematoporphyrin complex compounds used in
diagnosis and treatment are described in patent application EP 0
355 041. While these compounds show a good concentration behavior
in various target organs, the described compounds used as NMR
diagnostic agents are not satisfacatory because they require a dose
necessary for optimal imaging that is too close to the lethal dose.
Hematoporphyrin derivatives have the drawback that they can
eliminate both pseudobenzylic OH groups in the hydroxyethyl side
chains.
[0015] Derivatives of the deuteroporphyrin have been proposed
(Sakata, et. al., U.S. Pat. No. 4,996,312 and EP 0220686) for tumor
imaging with radioisotopes, containing as additional complexing
groups polyaminopolycarboxylic acids bound to the porphyrin
skeleton by ethylene glycol bridges (Photochemistry and
Photobiology Vol. 46, pp. 783-788 (1987)). However, such porphyrin
esters are not very suitable for parenteral use in patients,
especially for NMR or radiodiagnostic diagnosis, since the
injection solutions obtained from them can neither be
heat-sterilized nor stored for a sufficiently long time.
[0016] Other derivatives of deuteroporphyrins have been proposed in
Hilgar, C. S., et al. U.S. Pat. No. 5,849,259; Niedballa, U., et.
al., U.S. Pat. No. 5,275,801; Platzek, J., et. al. U.S. Pat. No.
6,136,841; and Niedballa, U., et. al., EP 0355041 A2, A3, B1 with
striking similarity to overcome certain deficiencies of Sakata's
deuteroporphyrins by providing metalloporphyrin amide linkages.
However, all of these approaches using deuteroporphyrins are
suboptimal with respect to design of short wavelength PDT
photosensitizers for use as MRI or radiodiagnostic agents for
reasons detailed below.
[0017] Sakata's porphyrin-based PDT/MRI/radiodiagnostic compounds
are based on a naturally occurring asymmetrical porphyrin ring
system shown in FIG. 1.
[0018] In his synthetic philosophy, Sakata has linked
polyfunctional carboxyl groups that are capable of binding
radioactive metals or MRI active metals to a) the R.sub.1 and
R.sub.2 positions as shown via ether--alcohol linkages; and b) to
positions R.sub.4 or R.sub.5 via ether linking units. This
synthetic approach carries with it significant manufacturing
problems. First, the linking of one metal chelating moiety to an
asymmetrical porphyrin at R.sub.1 or R.sub.2, R.sub.3 or R.sub.4
(where R.sub.1 and R.sub.2 can be vinyl, ethyl, --CH(O-lower
alkanoyl)CH.sub.3, --CH(OR)CH.sub.3 or --CH(O-loweralklene-OR)CH_,)
generates at least two new chemical porphyrinic entities in the
synthesis process if R.sub.1 and R.sub.2 (or R.sub.3 and R.sub.4)
are the same linking moiety. This is outlined in scheme 1. 12
[0019] Naturally occurring porphyrins like hematoporphyrin or
protoporphyrin cannot be chemically modified such that only one
position, either R.sub.1 or R.sub.2, (or R.sub.3 or R.sub.4) is
selectively modified to form a molecule with a single linking unit
as the only product. In this instance, two compounds are always
formed which must be separated to obtain a pure single molecule
with which to link the metal chelating moiety. The separation of
the two porphyrins is often difficult (if not impossible) and
complicates both the manufacturing process and the cost of the
final product. If one chooses not to separate the isomers, the
isomeric components will each have their own toxicities, and
pharmacokinetic and distribution profiles. If one of the isomers is
not optimal therapeutically due to any one of these parameters,
then the route to regulatory approval is often more complex, time
consuming and costly than pursuing a single defined isomer. A
second limiting factor that has been highlighted previously, is the
instability of the various linking groups to aqueous hydrolysis,
elimination at sterilization temperatures, or prolonged storage in
solution. Additionally, the use of diastereotopic mixtures as
occurs with --CH(OR)CH.sub.3 groups in porphyrins complicates the
analysis of the molecules for development.
[0020] Niedballa and Platzek's approach also has the same synthetic
manufacturing problems as explained for Sakata (except when
R.sub.1.dbd.H), i.e., multiple compounds are produced when a single
linking moiety is attached to the molecule. These molecules may
offer enhanced stability over Sakata's due to the use of amine
linkages. The limitation of R.sub.1.dbd.H symmetry does not,
however, allow for modification of this molecule with other
functionality that may enhance localization or uptake in tissues or
target organelle, or changes in pharmacokinetic or elimination
profiles for singly linked molecules. Compounds with high water
solubility are often not taken up efficiently by tumors or cells.
The ability to enhance the lipophilicity of the molecule is thus
very important.
[0021] An additional problem, that has been overlooked by all of
the prior workers (Sakata, Niedballa, and Platzek) in the
development of short wavelength porphyrin photosensitizers, is the
limited absortion profile of the porphyrin ring system metallated
tetrapyrroles. In general, metallotetrapyrroles have green and
yellow absorptions at about 532 and 575 nm with molar extinction
coefficients of between 15,000-20,000 M.sup.-1cm.sup.-1. In the
field of photodynamic therapy, the depth of light penetration into
tissues is a function of the wavelength of the exciting light. The
theoretical efficacy of a photosensitizer largely correlates to the
molar extinction coefficient of the photosensitizer's absorption
peak and its ability to absorb light. This is due primarily to the
fact that the ability of a photosensitizer to absorb incidental
light is a function of the cross sectional area of the molecule's
absorption profile. Hence, photosensitizers with low molar
extinction coefficients capture photons less efficiently than
molecules with high molar extinction coefficients and are thus less
efficient.
[0022] Therefore, there remains a need for novel photosensitizers
that are easily manufactured, have excellent stability and
solubility, and have more favorable wavelength absorption
characteristics. There is a further need for photosensitizers that
are capable of being modified to contain a wide range of
substituents making biological targeting more possible and
ultimately enabling control of the properties and uses of the
compounds clinically for not only MRI and radiodiagnostic imaging,
but also for treatment using photodynamic therapy.
[0023] The present inventor has found novel metal-free or
metallated functionalized phototherapeutic agents that may be used
for imaging (MRI or radiodiagnostic) before or after photodynamic
therapy. These novel phototherapeutic agents are based on
tetrapyrrolic ring systems such as the porphyrins and azaporphyrins
that can be covalently linked by stable linkages to metal
complexing agents. These new photosensitizers are useful in short
wavelength applications in photodynamic therapy.
SUMMARY OF THE INVENTION
[0024] To achieve these and other advantages, and in accordance
with the purpose of the invention as embodied and broadly described
herein, the present invention in one aspect provides
phototherapeutic compositions of metallo-tetrapyrrolic compounds of
formula I which may be used as MRI, radiodiagnostic and PDT agents:
3
[0025] In formula I, R.sub.1-R.sub.12 can be the same or different
and can be selected from:
[0026] H, halide, substituted or unsubstituted alkyl, heteroalkyl,
haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide,
ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy
group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group,
aryloxycarbonyl group, azo group, arylcarbonyloxy group,
alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group,
sulfonyl group, silil group, carbamoyl group, heterocyclic group,
nitro group, nitroso group, formyloxy group, isocyano group,
cyanate group, isocyanate group, thiocyanate group, isothiocyanate
group, N(alkyl).sub.2, N(aryl).sub.2, CH.dbd.CH(aryl),
CH.dbd.CHCH.sub.2N(CH.sub.3).sub.2, or a functional group of
molecular weight of less than about 100,000 daltons;
CH.dbd.CHCH.sub.2N.sup.+(CH.sub.3).sub.3A, CH.dbd.N(alkyl).sub.2A,
or N(alkyl).sub.3.sup.+A, where A is a charge balancing ion; CN,
OH, CHO, COCH.sub.3, CO(alkyl), CO.sub.2H, CO.sub.2Na, CO.sub.2K,
CH(CH.sub.3)OH, CH(CH.sub.3)O-alkyl, CH(CH.sub.3)O-alkoxy,
CH(CH.sub.3)O-aryl;
[0027] (CH.sub.2).sub.nO-alkoxy, or (CH.sub.2).sub.nO-alkyl, where
n is an integer from 0 to 8;
[0028] C(X).sub.2C(X).sub.3, where X is a halogen;
[0029] CO.sub.2R.sub.13, where R.sub.13 is selected from H, a
physiologically acceptable counter ion, a C1-C20 straight or
branched chain alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, or a functional
group of less than about 100,000 daltons;
[0030] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.14, where
R.sub.14 is selected from alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, heterocycle, a protecting group,
a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, or a functional group of less than about
100,000 daltons, and n is an integer between 0 and 4;
[0031] (CH.sub.2).sub.nCO.sub.2R.sub.15,
(CHX).sub.nCO.sub.2R.sub.15, or (CX.sub.2).sub.nCO.sub.2R.sub.15,
where X is a halogen and R.sub.15 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, or a functional group of
less than about 100,000 daltons, and n is an integer between 1 and
4;
[0032] CONH(R.sub.16), CONHNH(R.sub.16), CO(R.sub.16),
CON(R.sub.16).sub.2, CON(R.sub.16)(R.sub.17),
(CH.sub.2).sub.nCONH(R.sub.- 16),
(CH.sub.2).sub.nCON(R.sub.16).sub.2, (CH.sub.2).sub.nCOR.sub.16,
(CH.sub.2).sub.nCON(R.sub.16)(R.sub.17),
(CX.sub.2).sub.nCONH(R.sub.16),
(CX.sub.2).sub.nCON(R.sub.16).sub.2,
(CX.sub.2).sub.nCON(R.sub.16)(R.sub.- 17),
(CX.sub.2).sub.nCOR.sub.16, (CH.sub.2).sub.nCONHNH(R.sub.16),
(CX.sub.2).sub.nCONHNH(R.sub.16), (CHX).sub.nCONH(R.sub.16),
(CHX).sub.nCONHNH(R.sub.16), (CHX).sub.nCO(R.sub.16),
(CHX).sub.nCON(R.sub.16).sub.2, or
(CHX).sub.nCON(R.sub.16)(R.sub.17), where X is a halogen and
R.sub.16 and R.sub.17 can be the same or different and are selected
from H, NH.sub.2, straight or branched chain C1-C20 alkyl,
haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl,
heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt,
an amino acid ester, an amino acid amide, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons, and n is an
integer between 0 and 4;
[0033] S(R.sub.18), (CH.sub.2).sub.nS(R.sub.18),
(CH.sub.2).sub.nNH(R.sub.- 18), (CH.sub.2).sub.nNHNH(R.sub.18),
(CH.sub.2).sub.nN(R.sub.18).sub.2,
(CH.sub.2).sub.nN(R.sub.18)(R.sub.19), or
(CH.sub.2).sub.nN(R.sub.18)(R.s- ub.19)(R.sub.20).sup.+A, where
R.sub.18, R.sub.19 and R.sub.20 can be the same or different and
are selected from H, NH.sub.2, straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, amino acids (provided --NH(R.sub.18) is part of the
amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl
residue, a mono-, di-, or polyetheraryl residue, a functional group
of less than about 100,000 daltons, or where R.sub.18, R.sub.19 and
R.sub.20 possess the atoms necessary to constitute an aromatic ring
system, n is an integer between 0 and 4, and A is a physiologically
acceptable counter ion;
[0034] (CH.sub.2).sub.nOPO.sub.2OR.sub.21, or
(CH.sub.2).sub.nPO(OR.sub.21- ).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.21, (CH.sub.2).sub.nPOR.sub.21 where
R.sub.21 is selected from H, a physiologically acceptable counter
ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a
mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a
mono-, di-, or polyetheraryl residue, or a functional group of less
than about 100,000 daltons, and n is an integer between 0 and
4;
[0035] (CH.sub.2).sub.nNHCOR.sub.22, or
(CH.sub.2).sub.nNHNHCOR.sub.22, where R.sub.22 is selected from a
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, heterocycle, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0036] SO.sub.3R.sub.23, SO.sub.2NHR.sub.23,
SO.sub.2N(R.sub.23).sub.2, SO.sub.2NHNHR.sub.23, or
SO.sub.2R.sub.23, where R.sub.23 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons, and
NHR.sub.23 can also be an amino acid, an amino acid salt, an amino
acid ester residue, an amino acid amide residue, and n is an
integer between 0 and 4;
[0037] aryl or substituted aryl, which may optionally bear one or
more substituents with a molecular weight of less than or equal to
about 100,000 daltons; and
[0038] R.sub.1-R.sub.2, R.sub.4-R.sub.5, R.sub.7-R.sub.8,
R.sub.10-R.sub.11, R.sub.2-R.sub.3, R.sub.5-R.sub.6,
R.sub.8-R.sub.9, and R.sub.11-R.sub.12 may also possess the atoms
necessary to form ring systems, which themselves may possess
heteroatoms that may bear one or more functional groups of
molecular weight equal to or less than about 100,000 daltons;
[0039] with the proviso that at least one of the R.sub.1-R.sub.16
groups is linked to a complexing agent of general formula IIA, IIB,
IIC, IID, IIE by way of an organic group that has as part or all of
its structure a group Q, which is an amine, an ester, an ether or
an amide link: 4
[0040] wherein R.sub.24 is selected from a hydrogen, a straight or
branched chain C.sub.1-C.sub.7 alkyl group, a phenyl or benzyl
group; L.sub.1, L.sub.2, L.sub.3, L.sub.4, independently of one
another, are selected from a hydrogen atom or a metal ion
equivalent of an element of the atomic numbers 20-32, 37-39, 42-51,
or 57-83, which may be radioactive, provided that at least two of
L.sub.1, L.sub.2, L.sub.3 and L.sub.4 are metal ion equivalents,
that other anions are present to compensate for optionally present
charges on the porphyrin, and free carboxylic acid groups that are
not required for complexing are optionally present as salts with
physiologically compatible inorganic cations, or organic cations,
or as esters or amides; and that when R.sub.1 and R.sub.4 are
methyl, R.sub.2 and R.sub.5 cannot be methyl, a straight chain
C1-C6 alkyl, a C7-C12 aralkyl, CH.sub.2O(C1-C3alkyl), CH.sub.2OH,
CH(OH)CH.sub.3, CH.sub.2CH.sub.2OH, CH(NH(CH.sub.2).sub.nNH.s-
ub.2)CH.sub.3, CH.sub.2CH.sub.2NH(CH.sub.2).sub.nNH.sub.2 (where
n=2, 3, 4, 6), vinyl, ethyl, CH(O-lower alkanoyl)CH.sub.3,
CH(O-lower alkylene-OR)CH.sub.3, or CH(OR)CH.sub.3 (where R.dbd.H,
lower alkyl, a polyfunctional carbonyl compound excluding a
hydrogen atom therefrom or a metal derivative of a polyfunctional
carbonyl compound).
[0041] In formula I, M is 2H or a diamagnetic or paramagnetic metal
ion that may be radioactive or not, photoactive metals being
preferably selected from Ga.sup.3+, Pt.sup.2+, Pd.sup.2+,
Sn.sup.4+, In.sup.3+, Ge.sup.4+, Si.sup.4+, Al.sup.3+, Zn.sup.2+,
Mg.sup.2+ either with or without a physiologically acceptable
charge balancing counter ion.
[0042] In a preferred embodiment of the invention, provided are
phototherapeutic compositions of metallo-tetrapyrrolic compounds of
formula IA: 5
[0043] In formula IA, R.sub.1-R.sub.7 can be the same or different
and can be selected from:
[0044] H, halide, substituted or unsubstituted alkyl, heteroalkyl,
haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide,
ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy
group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group,
aryloxycarbonyl group, azo group, arylcarbonyloxy group,
alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group,
sulfonyl group, silil group, carbamoyl group, heterocyclic group,
nitro group, nitroso group, formyloxy group, isocyano group,
cyanate group, isocyanate group, thiocyanate group, isothiocyanate
group, N(alkyl).sub.2, N(aryl).sub.2, CH.dbd.CH(aryl),
CH.dbd.CHCH.sub.2N(CH.sub.3).sub.2, or a functional group of
molecular weight of less than about 100,000 daltons;
CH.dbd.CHCH.sub.2N.sup.+(CH.sub.3).sub.3A, CH.dbd.N(alkyl).sub.2A,
or N(alkyl).sub.3.sup.+A, where A is a charge balancing ion; CN,
OH, CHO, COCH.sub.3, CO(alkyl), CO.sub.2H, CO.sub.2Na, CO.sub.2K,
CH(CH.sub.3)OH, CH(CH.sub.3)O-alkyl, CH(CH.sub.3)O-alkoxy,
CH(CH.sub.3)O-aryl;
[0045] (CH.sub.2).sub.nO-alkoxy, or (CH.sub.2).sub.nO-alkyl; (where
n is an integer from 0 to 8);
[0046] C(X).sub.2C(X).sub.3, where X is a halogen;
[0047] CO.sub.2R.sub.8, where R.sub.8 is selected from a
physiologically acceptable counter ion, a straight or branched
chain alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle,
aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a
mono-, di-, or polyhydroxyaryl residue, ether or polyether, or a
functional group of less than about 100,000 daltons;
[0048] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.9, where
R.sub.9 is selected from alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group,
a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, or a functional group of less than about
100,000 daltons, and n is an integer between 0 and 4;
[0049] (CH.sub.2).sub.nCO.sub.2R.sub.10,
(CHX).sub.nCO.sub.2R.sub.10, or (CX.sub.2).sub.nCO.sub.2R.sub.10,
where X is a halogen and R.sub.10 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, or a functional
group of less than about 100,000 daltons, and n is an integer
between 1 and 4;
[0050] CONH(R.sub.11), CO(R.sub.11), CON(R.sub.11).sub.2,
CON(R.sub.11)(R.sub.12), (CH.sub.2).sub.nCONH(R.sub.11),
(CH.sub.2).sub.nCON(R.sub.11).sub.2, (CH.sub.2).sub.nCOR.sub.11,
(CH.sub.2).sub.nCON(R.sub.11)(R.sub.12),
(CX.sub.2).sub.nCONH(R.sub.11),
(CX.sub.2).sub.nCON(R.sub.11).sub.2,
(CX.sub.2).sub.nCON(R.sub.11)(R.sub.- 12),
(CX.sub.2).sub.nCOR.sub.11, (CH.sub.2).sub.nCONHNH(R.sub.11),
(CX.sub.2).sub.nCONHNH(R.sub.11), (CHX).sub.nCONH(R.sub.11),
(CHX).sub.nCONHNH(R.sub.11), (CHX).sub.nCON(R.sub.11).sub.2,
(CHX).sub.nCON(R.sub.11)(R.sub.12), where X is a halogen and
R.sub.11 and R.sub.12 can be the same or different and are selected
from H, NH.sub.2, straight or branched chain C1-C20 alkyl,
haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl,
heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt,
an amino acid ester, an amino acid amide, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons, and n is an
integer between 0 and 4;
[0051] S(R.sub.13), (CH.sub.2).sub.nS(R.sub.13),
(CH.sub.2).sub.nNH(R.sub.- 13), (CH.sub.2).sub.nNH(R.sub.13),
(CH.sub.2).sub.nR.sub.13(CH.sub.2).sub.- nN(R.sub.13)(R.sub.14), or
(CH.sub.2).sub.nN(R.sub.13)(R.sub.14)(R.sub.15)- .sup.+A, where
R.sub.13, R.sub.14 and R.sub.15 can be the same or different and
are selected from H, NH.sub.2, straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, amino acids, an amino acid ester, an amino acid amide,
a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a
mono-, di-, or polyetheraryl residue, a functional group of less
than about 100,000 daltons, or where R.sub.13, R.sub.14 and
R.sub.15 possess the atoms necessary to constitute an aromatic ring
system, n is an integer between 0 and 4, and A is a physiologically
acceptable counter ion;
[0052] (CH.sub.2).sub.nOPO.sub.2OR.sub.16, or
(CH.sub.2).sub.nPO(OR.sub.16- ).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.16, (CH.sub.2).sub.nPOR.sub.16 where
R.sub.16 is selected from H, a physiologically acceptable counter
ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl or heteroaryl, heterocycle,
amino acids, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl
residue, a mono-, di-, or polyetheraryl residue, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0053] (CH.sub.2).sub.nNHCOR.sub.17,
(CH.sub.2).sub.nNHNHCOR.sub.17, where R.sub.17 is selected from a
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, heterocycle, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0054] SO.sub.3R.sub.18, SO.sub.2NHR.sub.18,
SO.sub.2N(R.sub.18).sub.2, SO.sub.2NHNHR.sub.18 or
SO.sub.2R.sub.18, where R.sub.18 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl
or heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an
amino acid residue, an amino acid salt, an amino acid ester
residue, an amino acid amide residue, or a functional group of less
than about 100,000 daltons;
[0055] aryl or substituted aryl, which may optionally bear one or
more substituents with a molecular weight of less than or equal to
about 100,000 daltons; and
[0056] R.sub.1-R.sub.2, and R.sub.3-R.sub.4 may also possess the
atoms necessary to form ring systems, either aromatic or not, which
themselves may possess heteroatoms that may be charged or neutral
or bear one or more functional groups of molecular weight equal to
or less than about 100,000 daltons;
[0057] with the proviso that R.sub.1 and R.sub.4 are the same,
R.sub.2 and R.sub.3 are the same, and that when R.sub.7 is H,
R.sub.1-R.sub.4 cannot be methyl; and that at least one of the
R.sub.1-R.sub.7 groups is linked to a complexing agent of general
formula IIA, IIB, IIC, IID, IIE by way of an organic group that has
as part or all of its structure a group Q, which is an amine, a
ester, a ether or an amide link: 6
[0058] wherein R.sub.24 is selected from a hydrogen, a straight or
branched chain C.sub.1-C.sub.7 alkyl group, a phenyl or benzyl
group; L.sub.1, L.sub.2, L.sub.3, L.sub.4, independently of one
another, are selected from a hydrogen atom or a metal ion
equivalent of an element of the atomic numbers 20-32, 37-39, 42-51,
or 57-83, which may be radioactive, provided that at least two of
L.sub.1, L.sub.2, L.sub.3 and L.sub.4 are metal ion equivalents,
that other anions are present to compensate for optionally present
charges on the porphyrin, and free carboxylic acid groups that are
not required for complexing are optionally present as salts with
physiologically compatible inorganic cations, or organic cations,
or as esters or amides.
[0059] In formula IA, M is 2H or a diamagnetic or paramagnetic
metal ion that may be radioactive or not, photoactive metals being
preferably scheduled from Ga.sup.3+, Pt.sup.2+, Pd.sup.2+,
Sn.sup.4+, In.sup.3+, Ge.sup.4+, Si.sup.4+, Al.sup.3+, Zn.sup.2+,
Mg.sup.2+ either with or without a physiologically acceptable
charge balancing counter ion.
[0060] In another preferred embodiment of the invention, provided
are phototherapeutic compositions of metallo-tetrapyrrolic
compounds of the formula IB: 7
[0061] In formula IB, R.sub.1 and R.sub.2 can be the same or
different and can be selected from H, NO.sub.2, CN, CHO, CO-alkyl,
SO.sub.3H, SO.sub.3alkyl, SO.sub.3alkylether, SO.sub.3heteroalkyl,
SO.sub.3Na, SO.sub.3K, SO.sub.2NHalkyl, SO.sub.2N(alkyl).sub.2,
SO.sub.2NHheteroalkyl, SO.sub.2N(heteroalkyl).sub.2,
SO.sub.2NHhaloalkyl, SO.sub.2N(haloalkyl).sub.2,
SO.sub.2NHhaloalkylether, SO.sub.2N(haloalkylether).sub.2,
SO.sub.2NHalkylether, SO.sub.2N(haloalkylether).sub.2,
CO-haloalkyl, haloalkyl, heteroalkyl, hydroxyhaloalkyl, haloalkyl
ether, haloalkyl ester, a halogen, a alkylcarbonyloxy group;
[0062] R.sub.3 and R.sub.4 can be the same or different and are
selected from:
[0063] CO.sub.2R.sub.5, where R.sub.5 is selected from a
physiologically acceptable counter ion, a straight or branched
chain alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heterocycle, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, ethers or polyethers, or
a functional group of less than about 100,000 daltons;
[0064] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.6, where
R.sub.6 is selected from alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, a protecting group, a mono-,
di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl
residue, or a functional group of less than about 100,000 daltons,
and n is an integer between 0 and 4;
[0065] (CH.sub.2).sub.nCO.sub.2R.sub.7, (CHX).sub.nCO.sub.2R.sub.7,
or (CX.sub.2).sub.nCO.sub.2R.sub.7, where X is a halogen and
R.sub.7 is selected from H, a physiologically acceptable counter
ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl, heteroaryl, a mono-, di-, or
polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue,
or a functional group of less than about 100,000 daltons, and n is
an integer between 1 and 4;
[0066] CONH(R.sub.8), CO(R.sub.8), CON(R.sub.8).sub.2,
CON(R.sub.8)(R.sub.9), (CH.sub.2).sub.nCONH(R.sub.8),
(CH.sub.2).sub.nCON(R.sub.8).sub.2, (CH.sub.2).sub.nCOR.sub.8,
(CH.sub.2).sub.nCON(R.sub.8)(R.sub.9),
(CX.sub.2).sub.nCONH(R.sub.8), (CX.sub.2).sub.nCON(R.sub.8).sub.2,
(CX.sub.2).sub.nCON(R.sub.8)(R.sub.9)- , (CX.sub.2).sub.nCOR.sub.8,
(CH.sub.2).sub.nCONHNH(R.sub.8), (CX.sub.2).sub.nCONHNH(R.sub.8),
(CHX).sub.nCONH(R.sub.8), (CHX).sub.nCONHNH(R.sub.8),
(CHX).sub.nCON(R.sub.8).sub.2, (CHX).sub.nCON(R.sub.8)(R.sub.9),
where X is a halogen and R.sub.8 and R.sub.9 can be the same or
different and are selected from H, NH.sub.2, straight or branched
chain C1-C20 alkyl, haloalkyl, haloheteroalkyl, heteroalkyl, aryl,
heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino
acid salt, an amino acid ester, an amino acid amide, a mono-, di-,
or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue,
or a functional group of less than about 100,000 daltons, and n is
an integer between 0 and 4;
[0067] S(R.sub.10), (CH.sub.2).sub.nS(R.sub.10),
(CH.sub.2).sub.nNH(R.sub.- 10), (CH.sub.2).sub.nNH(R.sub.10),
(CH.sub.2).sub.nR.sub.10), (CH.sub.2).sub.nN(R.sub.10)(R.sub.11),
or (CH.sub.2).sub.nN(R.sub.10)(R.s- ub.11)(R.sub.12).sup.+A, where
R.sub.10, R.sub.11 and R.sub.12 can be the same or different and
are selected from H, NH.sub.2, straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, amino acids, an amino acid ester, an amino acid amide,
a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a
mono-, di-, or polyetheraryl residue, a functional group of less
than about 100,000 daltons, or where R.sub.10, R.sub.11 and
R.sub.12 possess the atoms necessary to constitute an aromatic ring
system, n is an integer between 0 and 4, and A is a physiologically
acceptable counter ion;
[0068] (CH.sub.2).sub.nOPO.sub.2OR.sub.13,
(CH.sub.2).sub.nPO(OR.sub.13).s- ub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.13, (CH.sub.2).sub.nPOR.sub.13 where
R.sub.13 is selected from H, a physiologically acceptable counter
ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl or heteroaryl, heterocycle,
amino acids, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl
residue, a mono-, di-, or polyetheraryl residue, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0069] (CH.sub.2).sub.nNHCOR.sub.14,
(CH.sub.2).sub.nNHNHCOR.sub.14, where R.sub.14 is selected from a
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, heterocycle, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0070] SO.sub.3R.sub.15, SO.sub.2NHR.sub.15,
SO.sub.2N(R.sub.15).sub.2, SO.sub.2NHNHR.sub.15 or
SO.sub.2R.sub.15, where R.sub.15 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl
or heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an
amino acid residue, an amino acid salt, an amino acid ester
residue, an amino acid amide residue, or a functional group of less
than about 100,000 daltons;
[0071] aryl or substituted aryl, which may optionally bear one or
more substituents with a molecular weight of less than or equal to
about 100,000 daltons;
[0072] with the proviso that at least one of the R.sub.1-R.sub.4
groups is linked to a complexing agent of general formula IIA, IIB,
IIC, IID, IIE by way of an organic group that has as part or all of
its structure a group Q, which is an amine, an ester, an ether or
an amide link: 8
[0073] wherein R.sub.24 is selected from a hydrogen, a straight or
branched chain C.sub.1-C.sub.7 alkyl group, a phenyl or benzyl
group; L.sub.1, L.sub.2, L.sub.3, L.sub.4, independently of one
another, are selected from a hydrogen atom or a metal ion
equivalent of an element of the atomic numbers 20-32, 37-39, 42-51,
or 57-83, which may be radioactive, provided that at least two of
L.sub.1, L.sub.2, L.sub.3 and L.sub.4 are metal ion equivalents,
that other anions are present to compensate for optionally present
charges on the porphyrin, and free carboxylic acid groups that are
not required for complexing are optionally present as salts with
physiologically compatible inorganic cations, or organic cations,
or as esters or amides.
[0074] In formula IB, M is 2H or a diamagnetic or paramagnetic
metal ion that may be radioactive or not, photoactive metals being
preferably selected from Ga.sup.3+; Pt.sup.2+, Pd.sup.2+,
Sn.sup.4+, In.sup.3+, Ge.sup.4+, Si.sup.4+, Al.sup.3+, Zn.sup.2+,
Mg.sup.2+ either with or without a physiologically acceptable
charge balancing counter ion.
[0075] In another aspect of the invention, provided are
phototherapeutic, MRI and radiodiagnostic compositions of
metallo-tetrapyrrolic compounds of formula II that may be used as
photosensitizers in photodynamic therapy: 9
[0076] In formula II, R.sub.1-R.sub.11 can be the same or different
and can be selected from:
[0077] H, halide, substituted or unsubstituted alkyl, heteroalkyl,
haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide,
ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy
group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group,
aryloxycarbonyl group, azo group, arylcarbonyloxy group,
alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group,
sulfonyl group, silil group, carbamoyl group, heterocyclic group,
nitro group, nitroso group, formyloxy group, isocyano group,
cyanate group, isocyanate group, thiocyanate group, isothiocyanate
group, N(alkyl).sub.2, N(aryl).sub.2, CH.dbd.CH(aryl),
CH.dbd.CHCH.sub.2N(CH.sub.3).sub.2, or a functional group of
molecular weight of less than about 100,000 daltons;
CH.dbd.CHCH.sub.2N.sup.+(CH.sub.3).sub.3A, CH.dbd.N(alkyl).sub.2A,
or N(alkyl).sub.3.sup.+A, where A is a charge balancing ion; CN,
OH, CHO, COCH.sub.3, CO(alkyl), CO.sub.2H, CO.sub.2Na, CO.sub.2K,
CH(CH.sub.3)OH, CH(CH.sub.3)O-alkyl, CH(CH.sub.3)O-alkoxy,
CH(CH.sub.3)O-aryl;
[0078] (CH.sub.2).sub.nO-alkoxy, or (CH.sub.2).sub.nO-alkyl, where
n is an integer from 0 to 8;
[0079] C(X).sub.2C(X).sub.3, where X is a halogen;
[0080] CO.sub.2R.sub.12, where R.sub.12 is selected from a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, or a functional
group of less than about 100,000 daltons;
[0081] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.13, where
R.sub.13 is selected from alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group,
a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, or a functional group of less than about
100,000 daltons, and n is an integer between 0 and 4;
[0082] (CH.sub.2).sub.nCO.sub.2R.sub.14,
(CHX).sub.nCO.sub.2R.sub.14, or (CX.sub.2).sub.nCO.sub.2R.sub.14,
where X is a halogen and R.sub.14 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, or a functional group of
less than about 100,000 daltons, and n is an integer between 1 and
4;
[0083] CONH(R.sub.15), CONHNH(R.sub.15), CO(R.sub.15),
CON(R.sub.15).sub.2, CON(R.sub.15)(R.sub.16),
(CH.sub.2).sub.nCONH(R.sub.- 15), (CH.sub.2).sub.nCONHNH(R.sub.15),
(CH.sub.2).sub.nCON(R.sub.15).sub.2- , (CH.sub.2).sub.nCOR.sub.15,
(CH.sub.2).sub.nCON(R.sub.15)(R.sub.16),
(CX.sub.2).sub.nCONH(R.sub.15),
(CX.sub.2).sub.nCON(R.sub.15).sub.2,
(CX.sub.2).sub.nCON(R.sub.15)(R.sub.16),
(CX.sub.2).sub.nCOR.sub.15, (CH.sub.2).sub.nCONHNH(R.sub.15),
(CX.sub.2).sub.nCONHNH(R.sub.15), (CHX).sub.nCONH(R.sub.15),
(CHX).sub.nCONHNH(R.sub.15), (CHX).sub.nCON(R.sub.15).sub.2,
(CHX).sub.nCON(R.sub.15)(R.sub.16), where X is a halogen and
R.sub.15 and R.sub.16 can be the same or different and are selected
from H, NH.sub.2, straight or branched chain C1-C20 alkyl,
haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl,
heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt,
an amino acid ester, an amino acid amide, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons, and n is an
integer between 0 and 4;
[0084] S(R.sub.17), (CH.sub.2).sub.nS(R.sub.17),
(CH.sub.2).sub.nNH(R.sub.- 17), (CH.sub.2).sub.nNH(R.sub.17),
(CH.sub.2).sub.nR.sub.17, (CH.sub.2).sub.nN(R.sub.17)(R.sub.18), or
(CH.sub.2).sub.nN(R.sub.17)(R.s- ub.18)(R.sub.19).sup.+A, where
R.sub.17, R.sub.18 and R.sub.19 can be the same or different and
are selected from H, NH.sub.2, straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, amino acids, an amino acid ester, an amino acid amide,
a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a
mono-, di-, or polyetheraryl residue, a functional group of less
than about 100,000 daltons, or where R.sub.17, R.sub.18 and
R.sub.19 possess the atoms necessary to constitute an aromatic ring
system, n is an integer between 0 and 4, and A is a physiologically
acceptable counter ion;
[0085] (CH.sub.2).sub.nOPO.sub.2OR.sub.20, or
(CH.sub.2).sub.nPO(OR.sub.20- ).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.20, (CH.sub.2).sub.nPOR.sub.20 where
R.sub.20 is selected from H, a physiologically acceptable counter
ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl or heteroaryl, heterocycle,
amino acids, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl
residue, a mono-, di-, or polyetheraryl residue, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0086] (CH.sub.2).sub.nNHCOR.sub.21, or
(CH.sub.2).sub.nNHNHCOR.sub.21, where R.sub.21 is selected from a
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, heterocycle, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0087] SO.sub.3R.sub.22, SO.sub.2NHR.sub.22,
SO.sub.2N(R.sub.22).sub.2, SO.sub.2NHNHR.sub.22 or
SO.sub.2R.sub.22, where R.sub.22 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl
or heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an
amino acid residue, an amino acid salt, an amino acid ester
residue, an amino acid amide residue, or a functional group of less
than about 100,000 daltons;
[0088] aryl or substituted aryl, which may optionally bear one or
more substituents with a molecular weight of less than or equal to
about 100,000 daltons;
[0089] R.sub.1-R.sub.2, R.sub.3-R.sub.4, R.sub.6-R.sub.7,
R.sub.9-R.sub.10, R.sub.4-R.sub.5, R.sub.5-R.sub.6,
R.sub.7-R.sub.8, R.sub.8-R.sub.9, R.sub.10-R.sub.11, or
R.sub.11-R.sub.1, may also possess the atoms necessary to form ring
systems, either aromatic or not, which themselves may possess
heteroatoms that may be charged or neutral or bear one or more
functional groups of molecular weight equal to or less than about
100,000 daltons; with the proviso that at least one of the
R.sub.1-R.sub.11 groups is linked to a complexing agent of general
formula IIA, IIB, IIC, IID, IIE by way of an organic group that has
as part or all of its structure a group Q, which is an amine, an
ester, an ether or an amide link: 10
[0090] wherein R.sub.24 is selected from a hydrogen, a straight or
branched chain C.sub.1-C.sub.7 alkyl group, a phenyl or benzyl
group; L.sub.1, L.sub.2, L.sub.3, L.sub.4, independently of one
another, are selected from a hydrogen atom or a metal ion
equivalent of an element of the atomic numbers 20-32, 37-39, 42-51,
or 57-83, which may be radioactive, provided that at least two of
L.sub.1, L.sub.2, L.sub.3 and L.sub.4 are metal ion equivalents,
that other anions are present to compensate for optionally present
charges on the porphyrin, and free carboxylic acid groups that are
not required for complexing are optionally present as salts with
physiologically compatible inorganic cations, or organic cations,
or as esters or amides.
[0091] In formula II, M is 2H or a diamagnetic or paramagnetic
metal ion that can be radioactive, photoactive metals being
preferably selected from Ga.sup.3+, Pt.sup.2+, Pd.sup.2+,
Sn.sup.4+, In.sup.3+, Ge.sup.4+, Si.sup.4+, Al.sup.3+, Zn.sup.2+,
Mg.sup.2+, either with or without a physiologically acceptable
charge balancing counter ion.
[0092] In a preferred embodiment of the invention, provided are
phototherapeutic compositions of metallo-tetrapyrrolic compounds of
following formula IIA: 11
[0093] In formula IIA, R.sub.1-R.sub.6 can be the same or different
and can be selected from:
[0094] H, halide, substituted or unsubstituted alkyl, heteroalkyl,
haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide,
ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy
group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group,
aryloxycarbonyl group, azo group, arylcarbonyloxy group,
alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group,
sulfonyl group, silil group, carbamoyl group, heterocyclic group,
nitro group, nitroso group, formyloxy group, isocyano group,
cyanate group, isocyanate group, thiocyanate group, isothiocyanate
group, N(alkyl).sub.2, N(aryl).sub.2, CH.dbd.CH(aryl),
CH.dbd.CHCH.sub.2N(CH.sub.3).sub.2, or a functional group of
molecular weight of less than about 100,000 daltons;
CH.dbd.CHCH.sub.2N.sup.+(CH.sub.3).sub.3A, CH.dbd.N(alkyl).sub.2A,
or N(alkyl).sub.3.sup.+A, where A is a charge balancing ion; CN,
OH, CHO, COCH.sub.3, CO(alkyl), CO.sub.2H, CO.sub.2Na, CO.sub.2K,
CH(CH.sub.3)OH, CH(CH.sub.3)O-alkyl, CH(CH.sub.3)O-alkoxy, or
CH(CH.sub.3)O-aryl;
[0095] (CH.sub.2).sub.nO-alkoxy, or (CH.sub.2).sub.nO-alkyl, where
n is an integer from 0 to 8;
[0096] C(X).sub.2C(X).sub.3, where X is a halogen;
[0097] CO.sub.2R.sub.7, where R.sub.7 is selected from a
physiologically acceptable counter ion, a straight or branched
chain alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, or a functional group of
less than about 100,000 daltons;
[0098] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.8, where
R.sub.8 is selected from alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, heterocycle, a protecting group,
a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, or a functional group of less than about
100,000 daltons, and n is an integer between 0 and 4;
[0099] (CH.sub.2).sub.nCO.sub.2R.sub.9, (CHX).sub.nCO.sub.2R.sub.9,
or (CX.sub.2).sub.nCO.sub.2R.sub.9, where X is a halogen and
R.sub.9 is selected from H, a physiologically acceptable counter
ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a
mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, or a functional group of less than about
100,000 daltons, and n is an integer between 1 and 4;
[0100] CONH(R.sub.10), CONHNH(R.sub.10), CO(R.sub.10),
CON(R.sub.10).sub.2, CON(R.sub.10)(R.sub.11),
(CH.sub.2).sub.nCONH(R.sub.- 10), (CH.sub.2).sub.nCONHNH(R.sub.10),
(CH.sub.2).sub.nCON(R.sub.10).sub.2- , (CH.sub.2).sub.nCOR.sub.10,
(CH2).sub.nCON(R.sub.10)(R.sub.11), (CX.sub.2).sub.nCONH(R.sub.10),
(CX.sub.2).sub.nCON(R.sub.10).sub.2,
(CX.sub.2).sub.nCON(R.sub.10)(R.sub.11),
(CX.sub.2).sub.nCOR.sub.10, (CH.sub.2).sub.nCONHNH(R.sub.10),
(CX.sub.2).sub.nCONHNH(R.sub.10), (CHX).sub.nCONH(R.sub.10),
(CHX).sub.nCONHNH(R.sub.10), (CHX).sub.nCON(R.sub.10).sub.2, or
(CHX).sub.nCON(R.sub.10)(R.sub.11), where X is a halogen and
R.sub.10 and R.sub.11 can be the same or different and are selected
from H, NH.sub.2, straight or branched chain C1-C20 alkyl,
haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl,
heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt,
an amino acid ester, an amino acid amide, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons, and n is an
integer between 0 and 4;
[0101] S(R.sub.12), (CH.sub.2).sub.nS(R.sub.12),
(CH.sub.2).sub.nNH(R.sub.- 12), (CH.sub.2).sub.nNHNH(R.sub.12),
(CH.sub.2).sub.nN(R.sub.12).sub.2,
(CH.sub.2).sub.nN(R.sub.12)(R.sub.13); or
(CH.sub.2).sub.nN(R.sub.12)(R.s- ub.13)(R.sub.14).sup.+A, where
R.sub.12, R.sub.13 and R.sub.14 can be the same or different and
are selected from H, NH.sub.2, straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, amino acids, an amino acid ester, or an amino acid
amide provided --NH(R.sub.13) is part of the amino acid, a mono-,
di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl
residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or
polyetheraryl residue, a functional group of less than about
100,000 daltons, or where R.sub.12, R.sub.13 and R.sub.14 possess
the atoms necessary to constitute an aromatic ring system, n is an
integer between 0 and 4, and A is a physiologically acceptable
counter ion;
[0102] (CH.sub.2).sub.nOPO.sub.2OR.sub.15, or
(CH.sub.2).sub.nPO(OR.sub.15- ).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.15, (CH.sub.2).sub.nPOR.sub.15where
R.sub.15 is selected from H, a physiologically acceptable counter
ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl or heteroaryl, heterocycle,
amino acids and salts, esters, or amides thereof, a mono-, di-, or
polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue,
a mono-, di-, or polyetheralkyl residue, a mono-, di-, or
polyetheraryl residue, or a functional group of less than about
100,000 daltons, and n is an integer between 0 and 4;
[0103] (CH.sub.2).sub.nNHCOR.sub.16, or
(CH.sub.2).sub.nNHNHCOR.sub.16, where R.sub.16 is selected from a
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids and
salts, esters, or amides thereof, or a functional group of less
than about 100,000 daltons, and n is an integer between 0 and
4;
[0104] SO.sub.3R.sub.17, SO.sub.2NHR.sub.17,
SO.sub.2N(R.sub.17).sub.2, SO.sub.2NHNHR.sub.17 or
SO.sub.2R.sub.17, where R.sub.17 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, a
functional group of less than about 100,000 daltons, and NHR.sub.17
can be an amino acid residue, an amino acid salt, an amino acid
ester residue, an amino acid amide residue;
[0105] aryl or substituted aryl, which may optionally bear one or
more substituents with a molecular weight of less than or equal to
about 100,000 daltons; and
[0106] R.sub.1-R.sub.2, and R.sub.3-R.sub.4 may also possess the
atoms necessary to form ring systems, either aromatic or not, which
themselves may possess heteroatoms that may be charged or neutral
or bear one or more functional groups of molecular weight equal to
or less than about 100,000 daltons;
[0107] with the proviso that at least one of the R.sub.1-R.sub.4
groups is linked to a complexing agent of general formula IIA, IIB,
IIC, IID, IIE by way of an organic group that has as part or all of
its structure a group Q, which is an amine, an ester, an ether or
an amide link: 12
[0108] wherein R.sub.24 is selected from a hydrogen, a straight or
branched chain C.sub.1-C.sub.7 alkyl group, a phenyl or benzyl
group; L.sub.1, L.sub.2, L.sub.3, L.sub.4, independently of one
another, are selected from a hydrogen atom or a metal ion
equivalent of an element of the atomic numbers 20-32, 37-39, 42-51,
or 57-83, which may be radioactive, provided that at least two of
L.sub.1, L.sub.2, L.sub.3 and L.sub.4 are metal ion equivalents,
that other anions are present to compensate for optionally present
charges on the porphyrin, and free carboxylic acid groups that are
not required for complexing are optionally present as salts with
physiologically compatible inorganic cations, or organic cations,
or as esters or amides.
[0109] In formula IIA, M is 2H or a diamagnetic or paramagnetic
metal ion that may be radioactive or not, photoactive metals being
preferably selected from Ga.sup.3+, Pt.sup.2+, Pd.sup.2+, S.sup.4+,
In.sup.3+, Ge.sup.4+, Si.sup.4+, Al.sup.3+, Zn.sup.2+, Mg.sup.2+,
either with or without a physiologically acceptable charge
balancing counter ion.
[0110] Additionally and in accordance with the present invention,
provided are phototherapeutic compositions of metallo-tetrapyrrolic
compounds of formula III that may be used as MRI, radiodiagnostic,
or PDT agents: 13
[0111] In formula III, R.sub.1-R.sub.10 can be the same or
different and can be selected from:
[0112] H, halide, substituted or unsubstituted alkyl, heteroalkyl,
haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide,
ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy
group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group,
aryloxycarbonyl group, azo group, arylcarbonyloxy group,
alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group,
sulfonyl group, silil group, carbamoyl group, heterocyclic group,
nitro group, nitroso group, formyloxy group, isocyano group,
cyanate group, isocyanate group, thiocyanate group, isothiocyanate
group, N(alkyl).sub.2, N(aryl).sub.2, CH.dbd.CH(aryl),
CH.dbd.CHCH.sub.2N(CH.sub.3).sub.2, or a functional group having a
molecular weight of less than about 100,000 daltons;
CH.dbd.CHCH.sub.2N.sup.+(CH.sub.3).sub.3A, CH.dbd.N(alkyl).sub.2A,
or N(alkyl).sub.3.sup.+A, where A is a charge balancing ion; CN,
OH, CHO, COCH.sub.3, CO(alkyl), CO.sub.2H, CO.sub.2Na, CO.sub.2K,
CH(CH.sub.3)OH, CH(CH.sub.3)O-alkyl, CH(CH.sub.3)O-alkoxy, or
CH(CH.sub.3)O-aryl;
[0113] (CH.sub.2).sub.nO-alkoxy, or (CH.sub.2).sub.nO-alkyl, where
n is an integer from 0 to 8;
[0114] C(X).sub.2C(X).sub.3, where X is a halogen;
[0115] CO.sub.2R.sub.11, where R.sub.11 is selected from a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, or a functional
group of less than about 100,000 daltons;
[0116] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.12, where
R.sub.12 is selected from alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group,
a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, or a functional group of less than about
100,000 daltons, and n is an integer between 0 and 4;
[0117] (CH.sub.2).sub.nCO.sub.2R.sub.13,
(CHX).sub.nCO.sub.2R.sub.13, or (CX.sub.2).sub.nCO.sub.2R.sub.13,
where X is a halogen and R.sub.13 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, or a functional
group of less than about 100,000 daltons, and n is an integer
between 1 and 4;
[0118] CONH(R.sub.14), CONHNH(R.sub.14), CO(R.sub.14),
CON(R.sub.14).sub.2, CON(R.sub.14)(R.sub.15),
(CH.sub.2).sub.nCONH(R.sub.- 14), (CH.sub.2).sub.nCONHNH(R.sub.14),
(CH.sub.2).sub.nCON(R.sub.14).sub.2- , (CH.sub.2).sub.nCOR.sub.14,
(CH.sub.2).sub.nCON(R.sub.14)(R.sub.15),
(CX.sub.2).sub.nCONH(R.sub.14),
(CX.sub.2).sub.nCON(R.sub.14).sub.2,
(CX.sub.2).sub.nCON(R.sub.14)(R.sub.15),
(CX.sub.2).sub.nCOR.sub.14, (CH.sub.2).sub.nCONHNH(R.sub.14),
(CX.sub.2).sub.nCONHNH(R.sub.14), (CHX).sub.nCONH(R.sub.14),
(CHX).sub.nCONHNH(R.sub.14), (CHX).sub.nCON(R.sub.14).sub.2,
(CHX).sub.nCON(R.sub.14)(R.sub.15), where X is a halogen and
R.sub.14 and R.sub.15 can be the same or different and are selected
from H, NH.sub.2, straight or branched chain C1-C20 alkyl,
haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl,
heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt,
an amino acid ester, an amino acid amide, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons, and n is an
integer between 0 and 4;
[0119] S(R.sub.16), (CH.sub.2).sub.nS(R.sub.16),
(CH.sub.2).sub.nNH(R.sub.- 16), (CH.sub.2).sub.nNHNH(R.sub.16),
(CH.sub.2).sub.nN(R.sub.16).sub.2
(CH.sub.2).sub.nN(R.sub.16)(R.sub.17), or
(CH.sub.2).sub.nN(R.sub.16)(R.s- ub.17)(R.sub.18).sup.+A, where
R.sub.16, R.sub.17 and R.sub.18 can be the same or different and
are selected from H, NH.sub.2, straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, amino acids, an amino acid ester, or an amino acid
amide provided --NHR.sub.16 is part of the amino acid, a mono-,
di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl
residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or
polyetheraryl residue, a functional group of less than about
100,000 daltons, or where R.sub.16, R.sub.17 and R.sub.18 together
possess the atoms necessary to constitute an aromatic ring system,
n is an integer between 0 and 4, and A is a physiologically
acceptable counter ion;
[0120] (CH.sub.2).sub.nOPO.sub.2OR.sub.19, or
(CH.sub.2).sub.nPO(OR.sub.19- ).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.19, (CH.sub.2).sub.nPOR.sub.19 where
R.sub.19 is selected from H, a physiologically acceptable counter
ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino
acids, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a
mono-, di-, or polyetheraryl residue, or a functional group of less
than about 100,000 daltons, and n is an integer between 0 and
4;
[0121] (CH.sub.2).sub.nNHCOR.sub.20,
(CH.sub.2).sub.nNHNHCOR.sub.20, where R.sub.20 is selected from a
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, heterocycle, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0122] SO.sub.3R.sub.21, SO.sub.2NHR.sub.21,
SO.sub.2N(R.sub.21).sub.2, SO.sub.2NHNHR.sub.21 or
SO.sub.2R.sub.21, where R.sub.21 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons; and
NHR.sub.21 can be an amino acid residue, an amino acid salt, an
amino acid ester residue, or an amino acid amide residue;
[0123] aryl or substituted aryl, which may optionally bear one or
more substituents with a molecular weight of less than or equal to
about 100,000 daltons; and
[0124] R.sub.1-R.sub.2, R.sub.3-R.sub.4, R.sub.6-R.sub.7,
R.sub.8-R.sub.9, R.sub.4-R.sub.5, R.sub.5-R.sub.6, R.sub.9-R.sub.10
and R.sub.10-R.sub.1 may also possess the atoms necessary to form
ring systems, either aromatic or not, which themselves may possess
heteroatoms that may be charged or neutral or bear one or more
functional groups of molecular weight equal to or less than about
100,000 daltons;
[0125] with the proviso that at least one of the R.sub.1-R.sub.4
groups is linked to a complexing agent of general formula IIA, IIB,
IIC, IID, IIE by way of an organic group that has as part or all of
its structure a group Q, which is an amine, an ester, an ether or
an amide link: 14
[0126] wherein R.sub.24 is selected from a hydrogen, a straight or
branched chain C.sub.1-C.sub.7 alkyl group, a phenyl or benzyl
group; L.sub.1, L.sub.2, L.sub.3, L.sub.4, independently of one
another, are selected from a hydrogen atom or a metal ion
equivalent of an element of the atomic numbers 20-32, 37-39, 42-51,
or 57-83, which may be radioactive, provided that at least two of
L.sub.1, L.sub.2, L.sub.3 and L.sub.4 are metal ion equivalents,
that other anions are present to compensate for optionally present
charges on the porphyrin, and free carboxylic acid groups that are
not required for complexing are optionally present as salts with
physiologically compatible inorganic cations, or organic cations,
or as esters or amides.
[0127] In formula III, M is 2H or a diamagnetic or paramagnetic
metal ion that may be radioactive or not, photoactive metals being
preferably selected from Ga.sup.3+, Pt.sup.2+, Pd.sup.2+,
Sn.sup.4+, In.sup.3+, Ge.sup.4+, Si.sup.4+, Al.sup.3+, Zn.sup.2+,
Mg.sup.2+ either with or without a physiologically acceptable
charge balancing counter ion.
[0128] In a preferred embodiment of the invention, provided are
phototherapeutic compositions of metal-tetrapyrolic compounds of
formula IIIA: 15
[0129] In formula IIIA, R.sub.1-R.sub.4 can be the same or
different and are selected from:
[0130] a functional group of less than about 100,000 daltons;
[0131] CO.sub.2R.sub.5, where R.sub.5 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heterocycle, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, or a functional group of
less than about 100,000 daltons;
[0132] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.6, where
R.sub.6 is selected from alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group,
a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, or a functional group of less than about
100,000 daltons, and n is an integer between 0 and 4;
[0133] (CH.sub.2).sub.nCO.sub.2R.sub.7, (CHX).sub.nCO.sub.2R.sub.7,
or (CX.sub.2).sub.nCO.sub.2R.sub.7, where X is a halogen and
R.sub.7 is selected from H, a physiologically acceptable counter
ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a
mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, or a functional group of less than about
100,000 daltons, and n is an integer between 1 and 4;
[0134] CONH(R.sub.8), (CONHNH(R.sub.8), CO(R.sub.8),
CON(R.sub.8).sub.2, CON(R.sub.8)(R.sub.9),
(CH.sub.2).sub.nCONH(R.sub.8), (CH.sub.2).sub.nCONHNH(R.sub.8),
(CH.sub.2).sub.nCON(R.sub.8).sub.2, (CH.sub.2).sub.nCOR.sub.8,
(CH.sub.2).sub.nCON(R.sub.8)(R.sub.9),
(CX.sub.2).sub.nCONH(R.sub.8), (CX.sub.2).sub.nCON(R.sub.8).sub.2,
(CX.sub.2).sub.nCON(R.sub.8)(R.sub.9), (CX.sub.2).sub.nCOR.sub.8,
(CH.sub.2).sub.nCONHNH(R.sub.8), (CX.sub.2).sub.nCONHNH(R.sub.8),
(CHX).sub.nCONH(R.sub.8), (CHX).sub.nCONHNH(R.sub.8),
(CHX).sub.nCON(R.sub.8).sub.2, or (CHX).sub.nCON(R.sub.8)(R.sub.9),
where X is a halogen and R.sub.8 and R.sub.9 can be the same or
different and are selected from H, NH.sub.2, straight or branched
chain C1-C20 alkyl, haloalkyl, haloheteroalkyl, heteroalkyl, aryl,
heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an
amino acid, an amino acid salt, an amino acid ester, an amino acid
amide, or a functional group of less than about 100,000 daltons,
and n is an integer between 0 and 4;
[0135] S(R.sub.10), (CH.sub.2).sub.nS(R.sub.10),
(CH.sub.2).sub.nNH(R.sub.- 10), (CH.sub.2).sub.nNHNH(R.sub.10),
(CH.sub.2).sub.nN(R.sub.10).sub.2,
(CH.sub.2).sub.nN(R.sub.10)(R.sub.11), or
(CH.sub.2).sub.nN(R.sub.10)(R.s- ub.11)(R.sub.12).sup.+A, where
R.sub.10, R.sub.11 and R.sub.12 can be the same or different and
are selected from H, NH.sub.2, straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, amino acids, an amino acid ester, or an amino acid
amide provided --NHR.sub.10 is part of the amino acid, a mono-,
di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl
residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or
polyetheraryl residue, a functional group of less than about
100,000 daltons, or where R.sub.10, R.sub.11 and R.sub.12 together
possess the atoms necessary to constitute an aromatic ring system,
n is an integer between 0 and 4, and A is a physiologically
acceptable counter ion;
[0136] (CH.sub.2).sub.nOPO.sub.2OR.sub.13, or
(CH.sub.2).sub.nPO(OR.sub.13- ).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.13, (CH2).sub.nPOR.sub.13 where
R.sub.13 is selected from H, a physiologically acceptable counter
ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino
acids, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a
mono-, di-, or polyetheraryl residue, or a functional group of less
than about 100,000 daltons, and n is an integer between 0 and
4;
[0137] (CH.sub.2).sub.nNHCOR.sub.14, or
(CH.sub.2).sub.nNHNHCOR.sub.14, where R.sub.4 is selected from a
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, heterocycle, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0138] SO.sub.3R.sub.15, SO.sub.2NHR.sub.15,
SO.sub.2N(R.sub.15).sub.2, SO.sub.2NHNHR.sub.15 or
SO.sub.2R.sub.15, where R.sub.15 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, halbheteroalkyl, aryl,
heteroaryl, heterocycle; NHR.sub.15 can also be an amino acid
residue, an amino acid salt, an amino acid ester residue, or an
amino acid amide residue; a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons;
[0139] aryl or substituted aryl, which may optionally bear one or
more substituents with a molecular weight of less than or equal to
about 100,000 daltons;
[0140] with the proviso that at least one of the R.sub.1-R.sub.4
groups is linked to a complexing agent of general formula IIA, IIB,
IIC, IID, IIE by way of an organic group that has as part or all of
its structure a group Q, which is an amine, an ester, an ether or
an amide link: 16
[0141] wherein R.sub.24 is selected from a hydrogen, a straight or
branched chain C.sub.1-C.sub.7 alkyl group, a phenyl or benzyl
group; L.sub.1, L.sub.2, L.sub.3, L.sub.4, independently of one
another, are selected from a hydrogen atom or a metal ion
equivalent of an element of the atomic numbers 20-32, 37-39, 42-51,
or 57-83, which may be radioactive, provided that at least two of
L.sub.1, L.sub.2, L.sub.3 and L.sub.4 are metal ion equivalents,
that other anions are present to compensate for optionally present
charges on the porphyrin, and free carboxylic acid groups that are
not required for complexing are optionally present as salts with
physiologically compatible inorganic cations, or organic cations,
or as esters or amides.
[0142] In formula IIIA, M is 2H or a diamagnetic or paramagnetic
metal ion that may be radioactive or not, photoactive metals being
preferably selected from Ga.sup.3+, Pt.sup.2+, Pd.sup.2+,
Sn.sup.4+, In.sup.3+, Ge.sup.4+, Si.sup.4+, Al.sup.3+, Zn.sup.2+,
Mg.sup.2+ either with or without a physiologically acceptable
charge balancing counter ion.
[0143] In another aspect of the invention, provided are
phototherapeutic compositions of metallo-tetrapyrrolic compounds of
formula IV that may be used as MRI, radiodiagnostic, or PDT agents:
17
[0144] In formula IV, R.sub.1-R.sub.8 can be the same or different
and are selected from:
[0145] H, halide, substituted or unsubstituted alkyl, heteroalkyl,
haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide,
ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy
group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group,
aryloxycarbonyl group, azo group, arylcarbonyloxy group,
alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group,
sulfonyl group, silil group, carbamoyl group, heterocyclic group,
nitro group, nitroso group, formyloxy group, isocyano group,
cyanate group, isocyanate group, thiocyanate group, isothiocyanate
group, N(alkyl).sub.2, N(aryl).sub.2, CH.dbd.CH(aryl),
CH.dbd.CHCH.sub.2N(CH.sub.3).sub.2, or a functional group of
molecular weight of less than about 100,000 daltons;
CH.dbd.CHCH.sub.2N(CH.sub.3).sub.3.sup.+A,
CH.dbd.N(alkyl).sub.2.sup.+A, or N(alkyl).sub.3.sup.+A, where A is
a charge balancing ion; CN, OH, CHO, COCH.sub.3, CO(alkyl),
CO.sub.2H, CO.sub.2Na, CO.sub.2K, CH(CH.sub.3)OH,
CH(CH.sub.3)O-alkyl, CH(CH.sub.3)O-alkoxy, or
CH(CH.sub.3)O-aryl;
[0146] (CH.sub.2).sub.nO-alkoxy, or (CH.sub.2).sub.nO-alkyl; where
n is an integer from 0 to 8;
[0147] C(X).sub.2C(X).sub.3, where X is a halogen;
[0148] CO.sub.2R.sub.9, where R.sub.9 is selected from a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heterocycle, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, or a functional group of
less than about 100,000 daltons;
[0149] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.10, where
R.sub.10 is selected from alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heterocycle, heteroaryl, a protecting group,
a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, or a functional group of less than about
100,000 daltons, and n is an integer between 0 and 4;
[0150] (CH.sub.2).sub.nCO.sub.2R.sub.11,
(CHX).sub.nCO.sub.2R.sub.11, (CX.sub.2).sub.nCO.sub.2R.sub.11,
where X is a halogen and R.sub.11 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heterocycle, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, or a functional group of
less than about 100,000 daltons, and n is an integer between 1 and
4;
[0151] CONH(R.sub.12), CONHNH(R.sub.12)CO(R.sub.12),
CON(R.sub.12).sub.2, CON(R.sub.12)(R.sub.13),
(CH.sub.2).sub.nCONH(R.sub.12), (CH.sub.2).sub.nCONHNH(R.sub.12),
(CH.sub.2).sub.nCON(R.sub.12).sub.2, (CH.sub.2).sub.nCOR.sub.12,
(CH.sub.2).sub.nCON(R.sub.12)(R.sub.13),
(CX.sub.2).sub.nCONH(R.sub.12),
(CX.sub.2).sub.nCON(R.sub.12).sub.2,
(CX.sub.2).sub.nCON(R.sub.12)(R.sub.13),
(CX.sub.2).sub.nCOR.sub.12, (CH.sub.2).sub.nCONHNH(R.sub.12),
(CX.sub.2).sub.nCONHNH(R.sub.12), (CHX).sub.nCONH(R.sub.12),
(CHX).sub.nCONHNH(R.sub.12), (CHX).sub.nCON(R.sub.12).sub.2,
(CHX).sub.nCON(R.sub.12)(R.sub.13), where X is a halogen and
R.sub.12 and R.sub.13 can be the same or different and are selected
from H, NH.sub.2, straight or branched chain C1-C20 alkyl,
haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl,
heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt,
an amino acid ester, an amino acid amide, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons, and n is an
integer between 0 and 4;
[0152] S(R.sub.14), (CH.sub.2).sub.nS(R.sub.14),
(CH.sub.2).sub.nNH(R.sub.- 14), (CH.sub.2).sub.nNHNH(R.sub.14),
(CH.sub.2).sub.nN(R.sub.14).sub.2,
(CH.sub.2).sub.nN(R.sub.14)(R.sub.15), or
(CH.sub.2).sub.nN(R.sub.14)(R.s- ub.15)(R.sub.16).sup.+A, where
R.sub.14, R.sub.15 and R.sub.16 can be the same or different and
are selected from H, NH.sub.2, straight or branched chain C1-C20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocycle, amino acids, an amino acid ester, or an amino acid
amide provided --NH(R.sub.14) is part of the amino acid, a mono-,
di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl
residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or
polyetheraryl residue, a functional group of less than about
100,000 daltons, or where R.sub.14, R.sub.15 and R.sub.16 together
possess the atoms necessary to constitute an aromatic ring system,
n is an integer between 0 and 4, and A is a physiologically
acceptable counter ion;
[0153] (CH.sub.2).sub.nOPO.sub.2OR.sub.17, or
(CH.sub.2).sub.nPO(OR.sub.17- ).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.17, (CH.sub.2).sub.nPOR.sub.17 where
R.sub.17 is selected from H, a physiologically acceptable counter
ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino
acids, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a
mono-, di-, or polyetheraryl residue, or a functional group of less
than about 100,000 daltons, and n is an integer between 0 and
4;
[0154] (CH.sub.2).sub.nNHCOR.sub.18, or
(CH.sub.2).sub.nNHNHCOR.sub.18, where R.sub.18 is selected from a
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, aryl, heteroaryl, heterocycle, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0155] SO.sub.3R.sub.19, SO.sub.2NHR.sub.19,
SO.sub.2N(R.sub.19).sub.2, SO.sub.2NHNHR.sub.19 or
SO.sub.2R.sub.19, where R.sub.19 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue,
a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or
polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or
a functional group of less than about 100,000 daltons, and
NHR.sub.19 can also be an amino acid residue, an amino acid salt,
an amino acid ester residue, or an amino acid amide residue;
and
[0156] aryl or substituted aryl, which may optionally bear one or
more substituents selected from hydroxy groups, alkyl groups,
carboxyl groups and its esters and amides and sulfonic acid groups
and their esters and amides, and substitiuents with a molecular
weight of less than or equal to about 100,000 daltons;
[0157] with the proviso that at least one of the R.sub.1-R.sub.12
groups is linked to a complexing agent of general formula IIA, IIB,
IIC, IID, IIE by way of an organic group that has as part or all of
its structure a group Q, which is an amine, an ester, an ether or
an amide link: 18
[0158] wherein R.sub.24 is selected from a hydrogen, a straight or
branched chain C.sub.1-C.sub.7 alkyl group, a phenyl or benzyl
group; L.sub.1, L.sub.2, L.sub.3, L.sub.4, independently of one
another, are selected from a hydrogen atom or a metal ion
equivalent of an element of the atomic numbers 20-32, 37-39, 42-51,
or 57-83, which may be radioactive, provided that at least two of
L.sub.1, L.sub.2, L.sub.3 and L.sub.4 are metal ion equivalents,
that other anions are present to compensate for optionally present
charges on the porphyrin, and free carboxylic acid groups that are
not required for complexing are optionally present as salts with
physiologically compatible inorganic cations, or organic cations,
or as esters or amides; and
[0159] A, B, C, and D can be the same or different and can be
selected from N, CH, CR.sub.20 where R.sub.20 is selected from a
halogen, aryl, subsitituted aryl, heteroaryl, alkyl, haloalkyl,
heterohaloalkyl, heterocycle, hydroxyalky, hydroxyhaloalkyl, or a
functional group of molecular weight of less than about 100,000
daltons.
[0160] In formula IV, M is selected from 2H or a diamagnetic or
paramagnetic metal ion that can be radioactive, photoactive metals
being preferably selected from Ga.sup.3+, Pt.sup.2+, Pd.sup.2+,
S.sup.4+, In.sup.3+, Ge.sup.4+, Si.sup.4+, Al.sup.3+, Zn.sup.2+,
Mg.sup.2+ the appropriate number of physiologically acceptable
charge balancing counter ions.
[0161] In accordance with a preferred embodiment of the invention,
the metallo-tetrapyrrolic compounds of the invention can be derived
by various procedures from naturally occuring cyclic tetrapyrroles.
The naturally occurring cyclic tetrapyrrolic molecules can have the
basic ring structure of compounds I, II, III, and IV, whose
substituents are outlined in Table 1, and are particularly
preferred as starting materials for the synthesis of the compounds
of structures I-IV. In particular, tetrapyrroles derived from
naturally occuring ring systems that have one linking group are
particularly preferred. These are shown in scheme 1.
[0162] In a second preferred aspect of this invention, the
tetrapyrrole is derived by the coupling of suitably substituted
dipyrromethane, dipyrromethenes, biladienes, builirubins, pyrroles
and functionalized aldehydes, or functionalized maleonitriles. The
cyclic tetrapyrroles that have the basic ring structure of
compounds I-IV, whose substituents are outlined in Table 2, are
particularly preferred as starting materials for the synthesis of
compounds of structures I-IV.
[0163] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the invention as
claimed.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0164] The terms "tetrapyrrole", tetrapyrrolic molecule and
"porphyrin" are used here to designate compounds of the cyclic
structure where four pyrrolic ring systems are linked via either
carbon or nitrogen bonds. Compounds within the scope of the
invention include porphyrins, mono-, di-, tri- and
tetraazaporphyrins, and porphyrin isomers such as porphycenes,
isoporphycenes, hemiporphycenes, corroles, corrphycenes, and the
like.
[0165] Included in the first class of metallated tetrapyrrolic
compounds of the invention are those of the porphyrins. Scheme 1
outlines an example of the synthesis of porphyrins that are derived
from plants. Particularly advantageous are the porphyrins based on
chloroporphyrin e6 (9), chloroporphyrin e4 (10), phylloporphyrin
(11), rhodoporphyrin (7), pyrroporphyrin (8), pheoporphyrin a5 (13)
and phylloerythrin (12) and compounds having similar ring systems.
Such compounds can be synthesized with single linking groups, which
can be modified according to the invention to increase their
biological activity and MRI and radiodiagnostic capacity. In
particular, the propionic esters of (2), (3), (5) and (6) can be
selectively hydrolized to form carboxylic acids, which can then be
linked to the metal coordinating moiety. Alternatively, the
carboxylic acids can be converted to amides with a free amine
linking unit, which can then be linked to the metal co-ordinating
moiety. Porphyrin amide derivatives like (4)
(R.sub.2.dbd.NHR.sub.3) may be synthesized from phylloporphyrin
such that an amine linking group is present. Examples include where
R.sub.2.dbd.NHCH.sub.2CH.sub.2NH.sub.2,
NHCH.sub.2CH.sub.2CH.sub.2NH.sub.2, NHCH.sub.2CH.sub.2NH.sub.2,
NH(CH.sub.2).sub.2O(CH.sub.2).sub.2NH.sub.2 and similar compounds.
These amine groups can then be linked to the metal co-ordinating
moiety.
[0166] While plant derived porphyrins are preferred as starting
materials in the invention due to their abundant availability, a
very large number of synthetic porphyrins are generally applicable
to the invention. Such porphyrins can be made by synthetic methods
known to those skilled in the art, via coupling of pyrrolic
precursors, dipyrromethanes, dipyrromethenes and biladienes to give
the required porphyrins with widely ranging functionality at both
the .beta. and meso positions. The synthesis of porphyrins via the
coupling of pyrrolic intermediates is outlined in detail in
chapters 1, 2, 3 in "The Porphyrin Handbook" Editors, K. M. Kadish,
K. M. Smith, R. Guilard, Volume 1, Academic press, 2000, p. 1-148,
the disclosure of which is hereby incorporated by reference herein.
Such functionality is explained in detail below. This functionality
can be modified by further chemical reactions. Such compounds can
then be modified according to the invention to produce
metalloporphyrins that absorb at or about 400, 532 and 575 nm.
Table 1 outlines some of the preferred porphyrins that may be used
as starting materials in the development of these types of
compounds.
1TABLE 1 19 Tetrapyrrole R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5
R.sub.6 R.sub.7 R.sub.8 Hematoporphyrin IX Me EO Me EO Me PO PO Me
Protoporphyrin IX Me V Me V Me PO PO Me Mesoporphyrin IX Me Et Me
Et Me PO PO Me Deuteroporphyrin IX Me H Me H Me PO PO Me
Hematoporphyrin dialkylethers Me EOE Me EOE Me PO PO Me
Coproporphyrin I PO Me PO Me PO Me PO Me Coproporphyrin II Me PO PO
Me Me PO PO Me Coproporphyrin III Me PO Me PO Me PO PO Me
Uroporphyrin IX Me EO Me EO Me PO PO Me Pentacarboxyporphyrin I PO
Me PO Me PO Me PO AO Pentacarboxyporphyrin III PO Me PO Me PO Me AO
PO 2, 4-dihalodeuteroporphyrin IX Me X Me X Me PO PO Me
Hexacarboxyporphyrin I PO Me PO AO PO Me PO AO Hexacarboxyporphyrin
III PO Me PO Me PO AO PO AO Heptacarboxyporphyrin I PO Me PO AO PO
AO PO AO AO = --CH.sub.2CO.sub.2H; PO =
--CH.sub.2CH.sub.2CO.sub.2H, EO =]--CH(OH)CH.sub.3, EOE =
--CH(OR)CH.sub.3, Me = --CH.sub.3, Et = CH.sub.2CH.sub.3, V =
--CH.dbd.CH.sub.2
[0167] 20 212223
[0168] A second preferred class of compounds according to the
invention are the mono-, di-, tri- and tetra-azaporphyrins. Schemes
3-7 outline the synthesis of mono-, di-, and tetra-azaporphyrins,
examples of which are listed in Table 2.
2TABLE 2 24 Tetrapyrrole A B C D R.sub.1 R.sub.2 R.sub.3 R.sub.4
R.sub.5 R.sub.6 R.sub.7 R.sub.8 5-aza-coproporphyrin II N CH CH CH
Me PO PO Me Me PO PO Me 5-aza-protoporphyrin IX N CH CH CH Me V V
Me Me PO PO Me 5-aza-mesoporphyrin IX N CH CH CH Me Et Me Et Me PO
PO Me 5-aza-mesoporphyrin XIII N CH CH CH Me Et Et Me Me PO PO Me
5-aza-uroporphyrin III N CH CH CH PO AO PO AO PO AO AO PO
5-aza-isomesoporphyrin N CH CH CH Et Me Me Et Me PO PO Me
5-aza-mesoporphyrin III N CH CH CH Me Et Me Et PO Me Me PO
5,15-Diaza-coproporphyrin II N CH N CH Me PO PO Me Me PO PO Me
5,15-diaza-mesoporphyrin III N CH N CH Me Et Me Et PO Me Me PO AO =
--CH.sub.2CO.sub.2H; PO = --CH.sub.2CH.sub.2CO.sub.2H, EO =
--CH(OH)CH.sub.3, EOE = --CH(OR)CH.sub.3, Me = --CH.sub.3, Et =
CH.sub.2CH.sub.3, V = --CH.dbd.CH.sub.2
[0169] Schemes 3-7 outline synthetic routes to novel tetrapyrrolic
molecules that possess a linking group with terminal amine groups.
Such compounds can be linked to a metal complexing reagent (MCR)
and subsequently modified to be phototherapeutic and diagnostic
compounds. 2526
[0170] Mono-azaporphyrins are synthesized efficiently via the
coupling of dibromobiladienes with sodium azide or via the reaction
of oxyporphyrins with ammonia. Copper and metal free
diazaporphyrins can be obtained via the coupling of
5,5'-dibromopyrromethenes with sodium azide. Tetra-azaporphyrins
are synthesized most efficiently via the treatment of substituted
maleonitriles with magnesium powder or magnesium alcoxides. Such
reactions are well known in the art and are outlined in detail by
N. Kobayashi in "The Porphyrin Handbook," K. M. Kadish, K. M.
Smith, R. Guilard, Editors, Volume 2, Chapter 13, Academic Press,
2000, p. 301-360, the disclosure of which is hereby incorporated by
reference herein.
[0171] The peripheral functionality of these compounds is important
with respect to further derivatization to achieve the desired
coupling to the metal complexing reagent (MCR) and the desired
biological effect (both therapeutic and diagnostic). The types of
peripheral functionality applicable to the invention are described
in detail below. It is recognized that small changes in the
peripheral functionality can have pronounced effects on the
biological efficacy of the molecules as does metal co-ordination to
the compounds. Schemes 4-7 outline synthetic routes to the novel
tetrapyrrolic molecules of the invention.
[0172] The new compounds of the invention are based on the
porphyrin, mono-, di-, tri- and tetra-azaporphyrin ring systems
that bear peripheral functionality on the ring system. Such
functionality includes esters, alcohols, amides, amines, ethers,
and phosphates. Such derivatives may also have at least one
hydroxylated residue present, or an amine group with which to
couple the metal co-ordination compound. The new porphyrins
themselves may be photodynamically active as metal free analogs and
therefore useful as PDT agents. In addition, metallated derivatives
of these compounds are also of particular interest for treatment
and diagnosis of disorders of the cardiovascular system, normal or
abnormal conditions of the hematological system, lymphatic
reticuloendothelial system, nervous system, endocrine and exocrine
system, skeletomuscular system including bone, connective tissue,
cartilage and skeletal muscle, pulmonary system, gastrointestinal
system including the liver, reproductive system, skin, immune
system, cardiovascular system, urinary system, ocular system,
auditory or olfactory system, where shorter wavelengths of light
are necessary or advantageous to effect a desired therapy.
[0173] Scheme 4 outlines chemistry that has been undertaken to
produce photosensitizing or diagnostic agents (based on
non-naturally occuring porphyrin systems and azaporphyrins) that
possess pendant terminal amine moieties and is exemplary only and
is not intended to limit the invention. It should be noted that the
functionality and position of the N and C meso atoms can be varied
to produce analogs different from those shown. Additionally, the R
groups in these schemes constitute functional groups that can be
symmetrically substituted and can also, if desired, be modified by
techniques known to those skilled in the art based on the chemistry
described herein without departing from the spirit or scope of the
invention. 27
[0174] In scheme 4, the ester functionality of porphyrins or
azaporphyrins can be hydrolyzed to yield both mono- and di-acid
compounds. It is preferred that the synthesis of mono-acid
compounds via this method occurs on compounds that are symmetrical
in their substitution pattern of R.sub.1-R.sub.4, such that isomers
are not formed. The mono- or di-acid can then be converted to the
desired amide via standard techniques, to produce pendant arm
groups with terminal amine moieties. Alternatively, if R.sub.5
possesses a functional group that can be modified to produce a
reactive linking moiety (for example C.sub.6H.sub.4SO.sub.3H,
C.sub.6H.sub.4CO.sub.2H and the like), these may alternatively be
chemically modified to produce compounds with pendant arm groups
having terminal amine moieties. Such compounds can, if desired, be
reacted with: metals to produce metallotetrapyrrolic complexes. 28
29 30
[0175] Scheme 5 outlines the synthesis of porphyrins and
azaporphyrins possessing two pendant arm terminal amine moieties.
In this instance, the ester functionality of porphyrins or
azaporphyrins can be hydrolyzed to yield di-acid compounds. The
mono-or di-acid can then be converted to its di-acid chloride,
which subsequently can be reacted with sodium azide in acetone to
yield the di-azide compound. The di-azide then can be rearranged in
methanol to give the di-urethane derivative, which can then be
hydrolysed in acid to give protonated amine compounds.
Neutralization with base yields the free amine compound. Such
compounds can, if desired, be reacted with metals to produce
metallo-tetrapyrrolic diamine complexes.
[0176] Scheme 6 outlines the synthesis route of metal-free or
metallated mono- or di-amine porphyrins based on rhodoporphyrin or
pyrroporphyrin. In the case of rhodoporphyrin (R.dbd.CO.sub.2Me),
it is possible to selectively hydrolyze the propionic acid ester
with dilute HCl/water to give the mono acid derivative shown.
Alternatively, both groups can be hydrolyzed with KOH/H.sub.2O to
give the di-acid derivative. The acid groups can then be converted
to the acid chloride derivatives and reacted with the appropriate
amine to give compounds possessing one or two pendant arm terminal
amine moieties. These compounds can, if desired, be reacted with
metals to produce metallo-tetrapyrrolic mono or di-amine
complexes.
[0177] Scheme 7 outlines the synthesis of metal-free or metallated
mono or di-amine di-azaporphyrins. The di-azaporphyrins themselves
can be synthesized via the coupling of appropriate brominated
dipyrromethanes. Once synthesized, the peripheral functionality can
be modified by similar chemistry as outlined in schemes 4 and 5. As
before, it is preferred that if mono-amine functionalized compounds
are to be made, R.sub.1-R.sub.4 should possess a symmetrical
substitution pattern. This preference does not apply if di-amine
substitution is desired.
[0178] The introduction of the desired metals (e.g., Zn, Ga, Al,
Sn, In, Mg, Mn, Fe, etc) into the porphyrins or azaporphyrins can
be carried out according to methods that are known in the
literature (e.g., The Porphyrins, ed. D. Dolphin, Academic Press,
New York 1980, Vol. V, p. 459; DE 4232925). In particular, metal
substitution of pyrrolic NH's can be carried out by heating the
metal-free ligand with the corresponding metal salt, preferably
acetate or halide, optionally with the addition of acid-buffering
agents, such as, for example, sodium acetate in a polar solvent.
Alternatively, such substitutions can be carried out by metal
exchange in which a metal that is already complexed by the
porphyrin or azaporphyrin is displaced by the desired metal. An
example of such a metal is cadmium. In this process, the preferred
solvent is a polar solvent, such as, for example, methanol, glacial
acetic acid, dimethylformamide, chloroform or water. In some
instances where the metal is difficult to remove under acid
conditions (Pt, Pd), it is more practical to generate the
metalloporphyrin or metalloazaporphyrin compounds prior to
modification to form the amine linking units. Additionally, the
introduction of a diamagnetic or paramagnetic metal M into the
porphyrin system can be carried out before or after linkage of the
metal complexing agent radical (MCR). As a result, an especially
flexible procedure for the synthesis of the compounds according to
the invention is made possible.
[0179] The reaction of a metal-free or metallated porphyrin or
azaporphyrin amine with a metal complexing agent (MCA) can be
carried out according to methods that are known in the literature.
Preferable MCA's include diethylenetriaminepentaacetic acid and
1,4,7,10-tetraazacyclodode- cane-1,4,7-triacetic acid, which can be
bonded via a linker to the respective porphyrin or azaporphyrin
derivatives. See, e.g., DE 4232925 for IIa and IId; DE 19507822, DE
19580858 and DE 19507819 for IIb; U.S. Pat. No. 5,053,503, WO
96/02669, WO 96/01655, EP 0430863, EP 255471, U.S. Pat. No.
5,277,895, EP 0232751, and U.S. Pat. No. 4,885,363 for IIc and
IIe.
[0180] In accordance with the invention, an activated MCR can be
reacted with the amine porphyrin or azaporphyrin derivatives such
that a covalent link between the two compounds occurs. As can be
seen in schemes 4-7, the nature of the linking amine moiety on the
porphyrins or azaporphyrins (P) to the MCR compounds may be varied.
Preferable examples include: P-(CH.sub.2).sub.nNH.sub.2, where n is
an integer from 1 to 10; P-(aryl)NH.sub.2, P-CONHNH.sub.2, or
P-(CH.sub.2).sub.nCONHNH.sub.2, where n is an integer from 1 to 10;
P-CONH(CH.sub.2).sub.nNH.sub.2, where n is an integer from 1 to 10;
P-CONH(CH.sub.2).sub.2O(CH.sub.2).sub.2NH.s- ub.2, or
P-CONH[(CH.sub.2).sub.2].sub.nO.sub.n/2[(CH.sub.2).sub.2].sub.nNH-
.sub.2, where n is an integer from 1 to 10; P-SO.sub.2NHNH.sub.2,
or P-SO.sub.2NH(CH.sub.2).sub.nNH.sub.2, where n is an integer from
1 to 10; P-SO.sub.2NH(CH.sub.2).sub.2O(CH.sub.2).sub.2NH.sub.2, or
P-SO.sub.2NH[(CH.sub.2).sub.2].sub.nO.sub.n/2[(CH.sub.2).sub.2].sub.nNH.s-
ub.2, where n is an integer from 1 to 10;
P-(Aryl)-SO.sub.2NHNH.sub.2, or
P-(Aryl)-SO.sub.2NH(CH.sub.2).sub.nNH.sub.2, where n is an integer
from 1 to 10; and
P-(Aryl)-SO.sub.2NH(CH.sub.2).sub.2O(CH.sub.2).sub.2NH.sub.2, or
P-(Aryl)-SO.sub.2NH[(CH.sub.2).sub.2].sub.nO.sub.n/2[(CH.sub.2).sub.2]-
.sub.nNH.sub.2, where n is an integer from 1 to 10. It would be
apparent to those skilled in the art that other suitable linking
amine units could be used in accordance with the teachings of the
specification.
[0181] Alternatively, in accordance with the invention, porphyrin
and azaporphyrin units can be generated that possess alcohol
terminal linking groups. Preferred examples of such groups include
P-(CH.sub.2).sub.nOH, where n is an integer from 1 to 10;
P-(aryl)OH, P-CONHOH, or P-(CH.sub.2).sub.nCONHOH, where n is an
integer from 1 to 10; P-CONH(CH.sub.2).sub.nOH, where n is an
integer from 1 to 10; P-CONH(CH.sub.2).sub.2O(CH.sub.2).sub.2OH, or
P-CONH[(CH.sub.2).sub.2].su-
b.nO.sub.n/2[(CH.sub.2).sub.2].sub.nOH, where n is an integer from
1 to 10; P-SO.sub.2NHOH, or P-SO.sub.2NH(CH.sub.2).sub.nOH, where n
is an integer from 1 to 10;
P-SO.sub.2NH(CH.sub.2).sub.2O(CH.sub.2).sub.2OH, or
P-SO.sub.2NH[(CH.sub.2).sub.2].sub.nO.sub.n/2[(CH.sub.2).sub.2].sub.nOH,
where n is an integer from 1 to 10; P-(Aryl)-SO.sub.2NHOH, or
P-(Aryl)-SO.sub.2NH(CH.sub.2).sub.nOH, where n is an integer from 1
to 10; P-(Aryl)-SO.sub.2NH(CH.sub.2).sub.2O(CH.sub.2).sub.2OH, or
P-(Aryl)-SO.sub.2NH[(CH.sub.2).sub.2].sub.nO.sub.n/2[(CH.sub.2).sub.2].su-
b.nOH, where n is an integer from 1 to 10;
P-CO.sub.2(CH.sub.2).sub.nOH, where n is an integer from 1 to 10;
P-CO.sub.2(CH.sub.2).sub.2O(CH.sub.2)- .sub.2OH, or
P-CO.sub.2[(CH.sub.2).sub.2].sub.nO.sub.n/2[(CH.sub.2).sub.2]-
.sub.nOH, where n is an integer from 1 to 10;
P-SO.sub.3(CH.sub.2).sub.nOH- , where n is an integer from 1 to 10;
P-SO.sub.3(CH.sub.2).sub.2O(CH.sub.2- ).sub.2OH, or
P-SO.sub.3[(CH.sub.2).sub.2].sub.nO.sub.n/2[(CH.sub.2).sub.2-
].sub.nOH, where n is an integer from 1 to 10;
P-(Aryl)-SO.sub.3(CH.sub.2)- .sub.nOH, where n is an integer from 1
to 10; and P-(Aryl)-SO.sub.3(CH.sub- .2).sub.2O(CH.sub.2).sub.2OH,
or P-(Aryl)-SO.sub.3[(CH.sub.2).sub.2].sub.n-
O.sub.n/2[(CH.sub.2).sub.2].sub.nOH, where n is an integer from 1
to 10. Such compounds can then be linked to the MCR group. It would
be apparent to those skilled in the art that other suitable linking
alcohol units or other reactive moieties can be used in accordance
with the teachings of the specification.
[0182] The MCR linking group Q is an organic group that when linked
to the amine or alcohol porphyrin or azaporphyrin results in a
product that is an ester, an amide, an amine, an ether, or a
thiolate. Preferable reactive MCR's are described in, for example,
U.S. Pat. No. 4,885,363, U.S. Pat. No. 5,730,956, U.S. Pat. No.
6,136,841, and U.S. Pat. No. 5,275,801 the disclosures which are
hereby incorporated herein by reference. Examples are illustrated
in FIG. 2.
[0183] Examples of linker groups Q include --CO--, --CS--,
--COCH.sub.2NH--, --CO(CH.sub.2).sub.2NH, --CO(CH.sub.2).sub.2--,
--COCH.sub.2OC.sub.6H.sub.4CO, --COC.sub.6H.sub.4NH--,
--COCH.sub.2OCH.sub.2NH--, --COC.sub.6H.sub.4--,
--COCH.sub.2NHCOCH.sub.2- CH(CH.sub.2COOH)C.sub.6H.sub.4NH--,
phenyleneoxy, a C1-C12 alkylene or a C7-C12 aralkylene group by one
or more oxygen atoms. Obviously a large variety of linker groups
are possible and it would be apparent to those skilled in the art
that other suitable groups can be used in accordance with the
teachings of the specification without deviating from the spirit of
the invention.
[0184] In accordance with the invention, the porphyrin or
azaporphyrin linked MCR compounds can then be modified to produce
PDT/MRI radiodiagnostic compounds. If the compounds are to be used
for NMR diagnosis, paramagnetic metal ions must be present in the
complex. These are preferably divalent or trivalent ions of the
elements of atomic numbers 21-29, 42-44 and 57-71. In this
instance, the paramagnetic metal may be coordinated to either the
inner pyrrolic core of the porphyrin or azaporphyrin, or in the MCR
pendant arm, or in both. Suitable ions include, for example,
chromium, gadolinium, dysprosium, manganese, iron, cobalt, cobalt,
nickel, copper, praseodymium, neodymium, samarium, terbium,
holmium, erbium and ytterbium ions. Because of their high magnetic
moment, the gadolinium, dysprosium, manganese, terbium, holmium,
erbium and iron ions are especially preferred.
[0185] For the use of the agents according to the invention for
photodynamic therapy, the porphyrin or azaporphyrin compound should
be metal free, i.e, M=2H, or should have coordinated photoactive
metals, preferred examples of which include zinc, indium, gallium,
tin, germanium, palladium, platinum, aluminum, silicon, ruthenium,
yttrium, ytterbium, magnesium, lutetium, and cadmium.
[0186] For the use of the agents according to the invention in
nuclear medicine, the metal ions must be radioactive. Examples that
are suitable for the invention include radioisotopes of the
elements copper, cobalt, gallium, zinc, germanium, yttrium,
strontium, technetium, indium, ytterbium, gadolinium, samarium,
thallium, and iridium. In this instance, the radioactive isotope
may be coordinated to the porphyrin or azaporphyrin ligand or
within the MCR, or both. Alternatively, such compounds can be
modified such that they become active or excited using sonotherapy
(e.g., M=gallium) or photothermally.
[0187] Metal chelation to the MCR group can be carried out by
techniques known in the literature (see, e.g., DE3401052) by the
metal oxide or metal salt (e.g., nitrate, acetate, carbonate,
chloride or sulfate) of the metal that is desired. In each case the
metal oxide or salt can be suspended or dissolved in polar solvents
such as water or aqueous alcohols and then reacted with the
corresponding amount of the complexing ligand. If desired, acidic
hydrogen atoms or acid groups that are present can be substituted
by cations of inorganic and/or organic bases or amino acids.
[0188] In accordance with the invention, neutralization can be
carried out with the aid of inorganic bases, such as, e.g., alkali
or alkaline-earth hydroxides, carbonates or bicarbonates and/or
organic bases such as, for example, primary, secondary and tertiary
amines, such as, e.g., ethanolamine, morpholine, glucamine,
N-methyl- and N,N-dimethylglucamine, as well as basic amino acids,
such as, e.g., lysine, arginine and ornithine or amides of
originally neutral or acidic amino acids.
[0189] For the production of neutral complex compounds, a
sufficient amount of the desired bases can be added to, for
example, the acidic complex salts in aqueous solution or suspension
to ensure that the neutral point is reached. The solution that is
obtained can then be evaporated to the dry state in a vacuum. It is
may be advantageous to precipitate the neutral salts that are
formed by adding water-miscible solvents, such as, for example,
lower alcohols (e.g., methanol, ethanol, isopropanol,
acetonitrile), lower ketones (e.g., acetone), polar ethers (e.g.,
tetrahydrofuran, dioxane, 1,2-dimethoxyethane) and thus to obtain
easily isolated and readily purified crystallizates. It has proven
especially advantageous to add the desired base as early as during
the complexing of the reaction mixture and thus eliminate a process
step.
[0190] If the acidic complex compounds contain several free acid
groups, it is often advantageous to produce neutral mixed salts
that contain both inorganic and organic cations as counter-ions.
This can be achieved, for example, by reacting the complexing
ligands in aqueous suspension or solution with the oxide or salt of
the element that yields the central ion and half of the amount of
an organic base that is required for neutralization. The complex
salt that is formed can then be isolated, optionally purified, and
then mixed for complete neutralization with the required amount of
inorganic base. The sequence in which the base is added can also be
reversed. Another way of obtaining neutral complex compounds
consists of converting the remaining acid groups in the complex
completely or partially into esters. This can be achieved by
subsequent reaction on the finished complex, e.g., by exhaustive
reaction of free carboxy groups with dimethylsulfate.
[0191] Pharmaceutical agents of the invention can be produced by
adding to the complex compounds of the invention certain additives
that are commonly used in the pharmaceutical industry to suspend or
dissolve the compounds in an aqueous medium, and then the
suspension or solution can be sterilized by techniques known in the
art. Suitable additives include, for example, physiologically
harmless buffers (such as, e.g., trimethamine), small additions of
complexing agents (such as, e.g., diethylenetriaminepentaacetic
acid) or, if necessary, electrolytes such as, e.g., sodium chloride
or antioxidants such as, e.g., ascorbic acid, butylate hydroxy
toluene, or tocopherol.
[0192] If suspensions or solutions of the agents according to the
invention in water or in physiological salt solution are desired
for enteral administration or other purposes, they can be mixed
with one or more adjuvants that are commonly used in galenicals
(e.g., methylcellulose, lactose, mannitol) and/or surfactant(s)
(e.g., lecithins, Tween, and/or flavoring substances for taste
correction (e.g., ethereal oils).
[0193] In principle, it is possible to produce the pharmaceutical
agents according to the invention even without isolating the
complex salt. In any case, special care must be taken to perform
the chelation such that the salts and salt solutions according to
the invention are virtually free of noncomplexed metal ions that
may have a toxic effect. This can be ensured, for example, by the
use of color indicators such as xylenol orange by control
titrations during the production process. As a final precaution,
there remains purification of the isolated complex salt.
[0194] To avoid undesirable photoreactions of porphyrins and
azaporphyrins, the compounds and agents according to the invention
should be stored and handled as much as possible in a light-free
environment.
[0195] The pharmaceutical agents according to the invention
preferably contain from about 20 .mu.mol/L to about 200 mmol/L of
the complex salt and are generally dosed in amounts of 0.01 .mu.mol
to 2 mmol/kg of body weight, both for their use in PDT and for
therapy monitoring using MRI diagnosis. They are intended for
enteral and parenteral administration or are administered with the
methods of interventional radiology.
[0196] The agents according to the invention are especially
suitable for PDT and as MRI contrast media. After administration,
they can enhance the informational value of the image that is
obtained from a nuclear spin tomograph by increasing the signal
intensity. They are effective without burdening the body with large
amounts of foreign substances.
[0197] The high water-solubility of the agents according to the
invention allows the production of highly concentrated solutions,
so as to keep the volume burden of the circulation within
acceptable limits and to compensate for dilution by bodily fluid.
In addition, the agents according to the invention show not only a
high stability in vitro but also a surprisingly high stability in
vivo, so that a release or an exchange of the ions, which are
inherently toxic and not covalently bonded in the complexes, will
not be harmful within the time that it takes for the contrast media
to be completely excreted.
[0198] Similar reactions can be undertaken on tetrapyrrolic
molecules in which more than two carboxylic acid functionalities
are present, for example, those compounds shown in Tables 1 and 2.
Such reactions on mono-, di- and tetra-azaporphyrin compounds are
particularly preferred because metallo-derivatives of such
compounds have larger molar extinction co-efficents than the
porphyrins in the green and yellow region, and thus theoretically
may be more efficient photosensitizers as a larger cross-sectional
area of light may be absorbed. While the specification describes
several chemical modifications to the tetrapyrrolic compounds,
those skilled in the art would know that additional modifications
can be made to the tetrapyrrolic ring systems in accordance with
the teachings of the specification.
[0199] The scope of the present invention is not limited to the
specific disclosure provided herein. As shown by the above
disclosure, any porphyrinic molecule may be modified according to
the invention to form the desired photoactive compounds with widely
differing functionality as described in the literature (for example
see "Porphyrins and Metalloporphyrins" Ed. K. Smith, Elsevier,
1975, N.Y., "The Porphyrins", Ed. D. Dolphin, Vol I-V, Academic
Press, 1978, and "The Porphyrin Handbook", Eds. K. Kadish, K. M.
Smith, R. Guilard, Academic Press, 2000). These compounds contain
various and ranging substituents on the .beta.-pyrrole positions or
meso-positions of the porphyrin ring, either symmetrically or
asymmetrically substituted on the ring.
[0200] Examples of such functionality include functional groups
having a molecular weight less than about 100,000 daltons and can
be a biologically active group or organic. Examples include, but
are not limited to: (1) hydrogen; (2) halogen, such as fluoro,
chloro, iodo and bromo (3) lower alkyl, such as methyl, ethyl,
n-propyl, butyl, hexyl, heptyl, octyl, isopropyl, t-butyl, n-pentyl
and the like groups; (4) lower alkoxy, such as methoxy, ethoxy,
isopropoxy, n-butoxy, t-pentoxy and the like; (5) hydroxy; (6)
carboxylic acid or acid salts, such as --CH.sub.2COOH,
--CH.sub.2COONa, --CH.sub.2CH.sub.2COOH, --CH.sub.2CH.sub.2COONa,
--CH.sub.2CH.sub.2CH(Br)COOH, --CH.sub.2CH.sub.2CH(CH.sub.3)COOH,
--CH.sub.2CH(Br)COOH, --CH.sub.2CH(CH.sub.3)COOH,
--CH(Cl)CH.sub.2CH(CH.sub.3)COOH,
--CH.sub.2CH.sub.2C(CH.sub.3).sub.2COOH,
--CH.sub.2CH.sub.2C(CH.sub.3).su- b.2COOK,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2COOH, C(CH.sub.3).sub.2COOH,
CH(Cl).sub.2COOH and the like; (7) carboxylic acid esters, such as
--CH.sub.2CH.sub.2COOCH.sub.3,
--CH.sub.2CH.sub.2COOCH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3)COOCH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2COOCH.sub.2C- H.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2COOCH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3)COOCH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2COOCH.sub.2C- H.sub.2OH,
--CH.sub.2CH.sub.2COOCH.sub.2CH.sub.2N(CH.sub.3).sub.2 and the
like, particularly halogenated alkyl esters; (8) sulfonic acid or
acid salts, for example, group I and group II salts, ammonium
salts, and organic cation salts such as alkyl and quaternary
ammonium salts; (9) sulfonylamides such as --SO.sub.2NH(alkyl),
--SO.sub.2N(alkyl).sub.2, --SO.sub.2NH(alkyl-OH),
--SO.sub.2N(alkyl-OH).sub.2, --SO.sub.2NH(alkyl)-N(alkyl).sub.2,
--SO.sub.2N(alkyl-N(alkyl).sub.2).sub- .2,
SO.sub.2(NH(alkyl)-N(alkyl).sub.3.sup.+Z.sup.-) and the like,
wherein Z.sup.- is a counterion, --SO.sub.2NHCH.sub.2CO.sub.2H,
substituted and unsubstituted benzene sulfonamides and
sulfonylamides of aminoacids and the like; (10) sulfonic acid
esters, such as SO.sub.3(alkyl), SO.sub.3(alkyl-OH),
SO.sub.3(alkyl-N(alkyl).sub.2),
SO.sub.3(alkyl-N(alkyl).sub.3.sup.+Z.sup.-) and the like, wherein
Z.sup.- is a counterion, SO.sub.3CH.sub.2CO.sub.2H, and the like;
(11) amino, such as unsubstituted or substituted primary amino,
methylamino, ethylamino, n-propylamino, isopropylamino, butylamino,
sec-butylamino, dimethylamino, trimethylamino, diethylamino,
triethylamino, di-n-propylamino, methylethylamino,
dimethyl-sec-butylamino, 2-aminoethoxy, ethylenediamino,
cyclohexylamino, benzylamino, phenylethylamino, anilino,
N-methylanilino, N,N-dimethylanilino, N-methyl-N-ethylanilino,
3,5-dibromo-4-anilino, p-toluidino, diphenylamino,
4,4'-dinitrodiphenylamino and the like; (12) cyano; (13) nitro;
(14) a biologically active group; (15) amides, such as
--CH.sub.2CH.sub.2CONHCH.sub.3,
--CH.sub.2CH.sub.2CONHCH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CON(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CON(CH.sub.2CH.s- ub.3).sub.2,
--CH.sub.2CONHCH.sub.3, --CH.sub.2CONHCH.sub.2CH.sub.3,
--CH.sub.2CON(CH.sub.3).sub.2,
--CH.sub.2CON(CH.sub.2CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CONHSO.sub.2CH.sub.3; (16) iminium salts, for
example --CH.dbd.N(CH.sub.3).sub.2.sup.+Z.sup.- and the like,
wherein Z.sup.- is a counterion); (17) boron containing complexes;
(18) carbon cage complexes (e.g., C20 and the like); (19)
polyfunctional carboxylic acid groups and their metal cluster
complexes, for example metal complexes of polyfunctional carboxylic
acid moieties such as of EDTA, DTPA, EGTA, crown ethers, cyclams,
cyclens, and the like; (20) other porphyrin, chlorin,
bacteriochlorin, isobacteriochlorin, azaporphyrin,
tetraazaporphyrin, phthalocyanine, naphthalocyanine, texaphyrins,
tetrapyrrolic macrocycles or dye molecules and the like; (21)
alkynyl, including alkyl, aryl, acid and heteroatom substituted
alkynes; (22) leaving or protecting groups; (23) aromatic ring
systems (aryl), such as substituted phenyls, napthalenes,
anthracenes, benzopyrenes, quinolines, benzoquinolines,
benzoperylene, benzofluorenes, fluorenes, benzofurazans,
benzodiphenylenes, benzofluoranthenes, benzanthracenes,
benzacephenanthrylenes, bathophenanthrolines, indans,
benzoquinolines, quinolines, pyrazines, quinolines, quinazoles,
quinoxalines, imidazopyridines, indenes, indolines, thiazolines,
bezopyrimidines, pyrimidines, benzimidazole, triazolopyrimidines,
pyrazoles, tryptophans, phenanthrolines, benzooxadiazoles,
benzoselenadiazole, benzocoumarins, chalcones, fluoranthenes,
pyridoindoles, pentacenes, perylenes, phenatholines, phenazines,
phenoxazines, phenoxathiins, phenothiazines, pyrroles, thiophenes,
or heteroaromatics containing 5, 6, 7, 8, membered ring systems;
24) --NHCS groups or any other substituent that increases the
hydrophilic, amphiphilic or lipophilic nature or stability of the
compounds. It is recognized that such groups can affect the
biological activity of the compounds in vivo.
[0201] The term "biologically active group" can be any group that
selectively promotes the accumulation, elimination, binding rate,
or tightness of binding in a particular biological environment. For
example, one category of biologically active groups is the
substituents derived from sugars, specifically: (1) aldoses such as
glyceraldehyde, erythrose, threose, ribose, arabinose, xylose,
lyxose, allose, altrose, glucose, mannose, gulose, idose,
galactose, and talose; (2) ketoses such as hydroxyacetone,
erythrulose, rebulose, xylulose, psicose, fructose, sorbose, and
tagatose; (3) pyranoses such as glucopyranose; (4) furanoses such
as fructo-furanose; (5) O-acyl derivatives such as
penta-O-acetyl-.alpha.-glucose; (6) O-methyl derivatives such as
methyl .alpha.-glucoside, methyl .beta.-glucoside, methyl
.alpha.-glucopyranoside, and
methyl-2,3,4,6-tetra-O-methyl-glucopyranosid- e; (7) phenylosazones
such as glucose phenylosazone; (8) sugar alcohols such as sorbitol,
mannitol, glycerol, and myo-inositol; (9) sugar acids such as
gluconic acid, glucaric acid and glucuronic acid,
.delta.-gluconolactone, .delta.-glucuronolactone, ascorbic acid,
and dehydroascorbic acid; (10) phosphoric acid esters such as
.alpha.-glucose 1-phosphoric acid, .alpha.-glucose 6-phosphoric
acid, .alpha.-fructose 1,6-diphosphoric acid, and .alpha.-fructose
6-phosphoric acid; (11) deoxy sugars such as 2-deoxy-ribose,
rhammose (deoxy-mannose), and fructose (6-deoxy-galactose); (12)
amino sugars such as glucosamine and galactosamine; muramic acid
and neurarninic acid; (13) disaccharides such as maltose, sucrose
and trehalose; (14) trisaccharides such as raffinose (fructose,
glucose, galactose) and melezitose (glucose, fructose, glucose);
(15) polysaccharides (glycans) such as glucans and mannans; and
(16) storage polysaccharides such as .alpha.-amylose, amylopectin,
dextrins, and dextrans.
[0202] Amino acid derivatives are also useful biologically active
substituents, such as those derived from valine, leucine,
isoleucine, threonine, methionine, phenylalanine, tryptophan,
alanine, arginine, aspartic acid, cystine, cysteine, glutamic acid,
glycine, histidine, proline, serine, tyrosine, asparagine and
glutamine. Also useful are peptides, particularly those known to
have affinity for specific receptors, for example, oxytocin,
vasopressin, bradykinin, LHRH, thrombin and the like.
[0203] Another useful group of biologically active substituents are
those derived from nucleosides, for example, ribonucleosides such
as adenosine, guanosine, cytidine, and uridine; and
2'-deoxyribonucleosides, such as 2'-deoxyadenosine,
2'-deoxyguanosine, 2'-deoxycytidine, and 2'-deoxythymidine.
[0204] Another category of biologically active groups that is
particularly useful is any ligand that is specific for a particular
biological receptor. The term "ligand specific for a biological
receptor" refers to a moiety that binds a receptor at cell
surfaces, and thus contains contours and charge patterns that are
complementary to those of the biological receptor. The ligand is
not the receptor itself, but a substance complementary to it. It is
well understood that a wide variety of cell types have specific
receptors designed to bind hormones, growth factors, or
neurotransmitters. However, while these embodiments of ligands
specific for receptors are known and understood, the phrase "ligand
specific for a biological receptor", as used herein, refers to any
substance, natural or synthetic, that binds specifically to a
receptor.
[0205] Examples of such ligands include: (1) the steroid hormones,
such as progesterone, estrogens, androgens, and the adrenal
cortical hormones; (2) growth factors, such as epidermal growth
factor, nerve growth factor, fibroblast growth factor, and the
like; (3) other protein hormones, such as human growth hormone,
parathyroid hormone, and the like; (4) neurotransmitters, such as
acetylcholine, serotonin, dopamine, and the like; and (5)
antibodies. Any analog of these substances that also succeeds in
binding to a biological receptor is also included within the
invention.
[0206] Particularly useful examples of substituents tending to
increase the amphiphilic nature of the compounds include, but are
not limited to: (1) short or long chain alcohols, such as, for
example, --C.sub.12H.sub.24--OH; (2) fatty acids and their salts,
such as, for example, the sodium salt of the long-chain fatty acid
oleic acid; (3) phosphoglycerides, such as, for example,
phosphatidic acid, phosphatidyl ethanolamine, phosphatidyl choline,
phosphatidyl serine, phosphatidyl inositol, phosphatidyl glycerol,
phosphatidyl 3'-O-alanyl glycerol, cardiolipin, or phosphatidyl
choline; (4) sphingolipids, such as, for example, sphingomyelin;
and (5) glycolipids, such as, for example, glycosyldiacylglycerols,
cerebrosides, sulfate esters of cerebrosides or gangliosides. It
would be known to those skilled in the art what other substituents,
or combinations of the subsituents described, would be suitable for
use in the invention.
[0207] The compounds of the present invention, or their
pharmaceutically acceptable salts, solvates, prodrugs, or
metabolites, can be administered to the host in a variety of forms
adapted to the chosen route of administration, e.g., orally,
intravenously, topically, intramuscularly or subcutaneously.
[0208] The active compound may be orally administered, for example
with an inert diluent or with an assimilable edible carrier, or it
may be enclosed in hard or soft shell gelatin capsule, or it may be
compressed into tablets, or it may be incorporated directly with
food. For oral therapeutic administration, the active compound may
be incorporated with excipients and used in the form of ingestible
tablets, buccal tablets, troches, capsules, elixirs, suspensions,
syrups, wafers, and the like. Such compositions and preparations
should contain at least about 0.1% of active compound. The
percentage of the compositions and preparations may, of course, be
varied and may, for example, conveniently be between about 2 to
about 60% of the weight of the administered product. The amount of
active compound in such therapeutically useful compositions is can
be selected so that a suitable dosage will be obtained. Preferred
compositions or preparations according to the present invention are
prepared so that an oral dosage unit form contains between about 50
and 300 mg of active compound.
[0209] The tablets, troches, pills, capsules and the like may also
contain the following: a binder such as gum tragacanth, acacia,
corn starch or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such as corn starch, potato starch, alginic
acid and the like; a lubricant such as magnesium stearate; a
sweetening agent such as sucrose, lactose or saccharin; or a
flavoring agent such as peppermint, oil of wintergreen, or cherry
flavoring. When the dosage unit form is a capsule, it may contain,
in addition to materials of the above type, a liquid carrier.
Various other materials may be present as coatings or to otherwise
modify the physical form of the dosage unit. For instance, tablets,
pills, or capsules may be coated with shellac, sugar or both. A
syrup or elixir may contain the active compound, sucrose as a
sweetening agent, methyl and propylparabens as preservatives, a dye
and flavoring such as cherry or orange flavor. Of course, any
material used in preparing any dosage unit form should be
pharmaceutically pure and substantially non-toxic in the amounts
employed. In addition, the active compound may be incorporated into
sustained-release preparations and formulations.
[0210] The active compound may also be administered parenterally or
intraperitoneally. Solutions of the active compound as a free base
or pharmacologically acceptable salt can be prepared in water
suitably mixed with a surfactant such as hydroxypropylcellulose.
Dispersions can also be prepared in glycerol, liquid polyethylene
glycols, and mixtures thereof and in oils. Under ordinary
conditions of storage and use, these preparations contain a
preservative to prevent the growth of microorganisms.
[0211] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporanous preparation of sterile injectable solutions,
dispersions, or liposomal or emulsion formulations. In all cases
the form must be sterile and should be fluid to enable
administration by a syringe. The form must be stable under the
conditions of manufacture and storage and must be preserved against
the contaminating action of microorganisms such as bacteria and
fungi. The carrier can be a solvent or dispersion medium
containing, for example, water, ethanol, polyol (for example,
glycerol, propylene glycol, and liquid polyethylene glycol, and the
like), suitable mixtures thereof, and vegetable oils. The proper
fluidity can be maintained, for example, by the use of a coating
such as lecithin, by the maintenance of the required particle size
in the case of dispersions and by the use of surfactants. The
prevention of the action of microorganisms can be brought about by
various antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In
many cases, it will be preferable to include isotonic agents, for
example, sugars or sodium chloride. Prolonged absorption of the
injectable compositions can be brought about by the use of agents
delaying absorption, for example, aluminum monostearate and
gelatin.
[0212] Sterile injectable solutions are prepared by incorporating
the active compound in the required amount in the appropriate
solvent with various other ingredients enumerated above, as
required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the various sterilized
active ingredients into a sterile vehicle which contains the basic
dispersion medium and the required additional ingredients from
those enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation are vacuum drying and the freeze-drying technique,
which yield a powder of the active ingredient plus any additional
desired ingredient from previously sterile-filtered solutions
thereof.
[0213] The new compounds of the invention may also be applied
directly to tumors in the host whether internal or external, in
topical compositions. Exemplary compositions include solutions of
the new compounds in solvents, particularly aqueous solvents, most
preferably water. Alternatively, for topical application
particularly to skin tumors or psoriasis, the present new compounds
may be dispersed in the usual cream or salve formulations commonly
used for this purpose (such as liposomes, ointments, gels,
hydrogels, cremes and oils) or may be provided in the form of spray
solutions or suspensions that may include a propellant usually.
employed in aerosol preparations.
[0214] As used herein, "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents and the like. The use of such media and agents for
pharmaceutical active substances is well known in the art. Any
conventional media or agent that is compatible with the active
ingredient can be used in the therapeutic compositions of the
invention. Supplementary active ingredients can also be
incorporated into the compositions.
[0215] It is especially advantageous to formulate parenteral
compositions in dosage unit form for ease of administration and
uniformity of dosage. Dosage unit form as used herein refers to
physically discrete units suited as unitary dosages for the
mammalian subjects to be treated. Each unit contains a
predetermined quantity of active material calculated to produce the
desired therapeutic effect in association with the required
pharmaceutical carrier. The specifications for the novel dosage
unit forms of the invention are dictated by and directly dependent
on (a) the unique characteristics of the active material and the
particular therapeutic effect to be achieved, and (b) the
limitations inherent in the art of compounding such an active
material for the treatment of cardiovascular diseases, diseases of
the skin, cancers and other superficial disease conditions in
living subjects.
[0216] The present invention provides a method of treating live
cells, which includes, but is not limited to, animals such as
humans and other mammals. The "mammals" also include farm animals,
such as cows, hogs and sheep, as well as pet or sport animals, such
as horses, dogs and cats. The dosage of the pharmaceutical
compositions of the invention is dependent on the method of
administration, the patient's age, severity of the disease, and the
like.
[0217] The compounds of the invention may be taken parentally or
orally, generally being administered intravascularly,
subcutaneously, or intramuscularly or interperitoneally. The
subject compounds may also be administered by inhalation,
perivascular delivery, pericardial delivery (into perivascular
sac), periadvential delivery (e.g., using a hydrogel wrap around
the vessel), endovascular balloon catheters with micropores,
channels, transmural injection ports, and the like.
[0218] For local catheter-based delivery of the compounds of the
invention, an infusate can be placed and pressurized to facilitate
intramural and transmural penetration into the target vessel. Local
delivery can also be enhanced by other mechanical and electrical
means. The depth of the penetration of the subject compounds by
this local delivery method is a function of pressure in the
perfused segment and the dwell time. Although little attention has
been paid to the quantitative characteristics of the compounds of
the invention in this setting, deposition of the substance should
obey the principles governing transmural convection and
diffusion.
[0219] Delivery of the compounds of the invention may also be via
antibody-drug conjugates, internalizing antibodies or antibody
fragments conjugated to compounds into cells using endocytosis. The
subject compounds may also be impregnated into stent struts for
local delivery. The route of administration of these pharmaceutical
preparations is not critical, but may be selected according to the
dosage form, the patient's age, the severity of the disease to be
treated and other factors.
[0220] The compounds of the invention may find use in conjunction
with other interventions, diagnostics and therapies, where lower
levels of other therapies having significant side effects may be
used effectively to reduce the detrimental side effects. Adjunctive
interventions may include, but are not limited to: balloon
angioplasty, invasive and non-invasive surgical procedures, stent
deployment, cutting balloons, embolic protection devices,
rotational and directional atherectomy, eximer lasers and the
like.
[0221] Adjunctive therapies may include, but are not limited to
radiation therapy, chemotherapy, anti-platelet agents,
vasodilators, antihypertensives, anti-arrhythmics, hyperthermia,
cryotherapy, magnetic force, viral and non-viral gene therapy,
pharmacogenetic therapy, antibodies, vaccines, glycoprotein
IIb/IIIa Inhibitors, growth factors, peptides, DNA delivery,
nucleic acids, anticancer drugs, steroid hormones,
anti-inflammatories, proteins, anti-apoptotic therapies, anti-sense
agents, immunotoxins, immunomodulators, antibody-drug conjugates,
anti-proliferative therapies, drug eluting stents containing
pharmacologically active agents, transplant products and processes,
prostaglandins and catheter based devices to detect vulnerable
plaques, hormone products, chelating agents, diuretics, cardiac
glycosides, bronchodilators, antibiotics, antivirals, antitioxins,
cyclosporins, thrombolytic agents, interferons, blood products such
as parental iron and hemin, anti-fungal agents, antianginals,
anticoagulants, analgesics, narcotics, neuromuscular blockers,
sedatives, bacterial vaccines, viral vaccines, DNA or RNA of
natural or synthetic origin including recombinent RNA and DNA,
cytokines and their antagonists/inhibitors, chemokines and their
antagonists/inhibitors,
[0222] Adjunctive diagnostics may include, but are not limited to:
intravascular ultrasound imaging, angiography, quantitative vessel
measurements and the use of radiological contrast agents, hormone
products, chelating agents, diuretics, cardiac glycosides,
bronchodilators, antibiotics, antivirals, antitoxins, cyclosporins,
thrombolytic agents, interferons, blood products such as parental
iron and hemin, anti-fungal agents, antianginals, anticoagulants,
analgesics, narcotics, neuromuscular blockers, sedatives, bacterial
vaccines, viral vaccines, DNA or RNA of natural or synthetic origin
including recombinent RNA and DNA, cytokines and their
antagonists/inhibitors, and chemokines and their
antagonists/inhibitors.
Definitions
[0223] As used in the present application, the following
definitions apply:
[0224] The term "alkyl" as used herein refers to substituted or
unsubstituted, straight or branched chain groups, preferably having
one to twenty, more preferably having one to six, and most
preferably having from one to four carbon atoms. The term
"C.sub.1-C.sub.20 alkyl" represents a straight or branched alkyl
chain having from one to twenty carbon atoms. Exemplary
C.sub.1-C.sub.20 alkyl groups include methyl, ethyl, n-propyl,
isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl,
hexyl, isohexyl, and the like. The term "C.sub.1-C.sub.20 alkyl"
includes within its definition the term "C.sub.1-C.sub.4 alkyl."
Such alkyl groups may themselves be ethers or thioethers, or
aminoethers or dendrimers.
[0225] The term "cycloalkyl" represents a substituted or
unsubstituted, saturated or partially saturated, mono- or
poly-carbocyclic ring, preferably having 5-14 ring carbon atoms.
Exemplary cycloalkyls include monocyclic rings having from 3-7,
preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and the like. An exemplary
cycloalkyl is a C.sub.5-C.sub.7 cycloalkyl, which is a saturated
hydrocarbon ring structure containing from five to seven carbon
atoms.
[0226] The term "aryl" as used herein refers to an aromatic,
monovalent monocyclic, bicyclic, or tricyclic radical containing 6,
10, 14, or 18 carbon ring atoms, which may be unsubstituted or
substituted, and to which may be fused one or more cycloalkyl
groups, heterocycloalkyl groups, or heteroaryl groups, which
themselves may be unsubstituted or substituted by one or more
suitable substituents. Illustrative examples of aryl groups
include, but are not limited to, phenyl, napthalenes, anthracenes,
benzopyrenes, quinolines, benzoquinolines, benzoperylene,
benzofluorenes, fluorenes, benzofurazans, benzodiphenylenes,
benzofluoranthenes, benzanthracenes, benzacephenanthrylenes,
bathophenanthrolines, indans, benzoquinolines, quinolines,
pyrazines, quinolines, quinazoles, quinoxalines, imidazopyridines,
indenes, indolines, thiazolines, benzopyrimidines, pyrimidines,
benzimidazole, triazolopyrimidines, pyrazoles, tryptophans,
phenanthrolines, benzooxadiazoles, benzoselenadiazole,
benzocoumarins, chalcones, fluoranthenes, pyridoindoles,
pentacenes, perylenes, phenatholines, phenazines, phenoxazines,
phenoxathiins, phenothiazines ad the like.
[0227] The term "halogen" represents chlorine, fluorine, bromine or
iodine. The term "halocarbon" or "haloalkyl" represents one or more
halogens bonded to a one or more carbon bearing groups. The term
"heterohaloalkyl" represents for example halogenated alkylethers,
halogenated alkyl amines, halogenated alkyl esters, halogenated
alkyl amides, halogenated alkyl thioesters, halogenated alkyl
thiols, where N, S, O, P atoms are present in the haloalkylated
structure. The term. heteroalkyl represents for example ethers,
alkylamines, alkylated thiols and alkylate phosphorus containing
groups.
[0228] The term "carbocycle" represents a substituted or
unsubstituted aromatic or a saturated or a partially saturated 5-14
membered monocyclic or polycyclic ring, such as a 5- to 7-membered
monocyclic or 7- to 10-membered bicyclic ring, wherein all the ring
members are carbon atoms.
[0229] The term "electron withdrawing group" is intended to mean a
chemical group containing an electronegative element such as
halogen, sulfur, nitrogen or oxygen.
[0230] A "heterocycloalkyl group" is intended to mean a
non-aromatic, monovalent monocyclic, bicyclic, or tricyclic
radical, which is saturated or unsaturated, containing 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, and
which includes 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen,
oxygen and sulfur, wherein the radical is unsubstituted or
substituted, and to which may be fused one or more cycloalkyl
groups, aryl groups, or heteroaryl groups, which themselves may be
unsubstituted or substituted. Illustrative examples of
heterocycloalkyl groups include, but are not limited to azetidinyl,
pyrrolidyl, piperidyl, piperazinyl, morpholinyl,
tetrahydro-2H-1,4-thiazi- nyl, tetrahydrofuryl, dihydrofuryl,
tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl,
1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl,
azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl,
azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl,
1,5,9-triazacyclododecyl, and the like.
[0231] A "heteroaryl group" is intended to mean an aromatic
monovalent monocyclic, bicyclic, or tricyclic radical containing 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms,
including 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen,
oxygen and sulfur, which may be unsubstituted or substituted, and
to which may be fused one or more cycloalkyl groups,
heterocycloalkyl groups, or aryl groups, which themselves may be
unsubstituted or substituted. Illustrative examples of heteroaryl
groups include, but are not limited to, thienyl, pyrrolyl,
imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl,
thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,
benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl,
chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl,
indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,
naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl,
benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl,
carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl,
perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl,
phenothiazinyl, and phenoxazinyl and the like.
[0232] The term "leaving group" as used herein refers to any group
that departs from a molecule in a substitution reaction by breakage
of a bond. Examples of leaving groups include, but are not limited
to, halides, tosylates, arenesulfonates, alkylsulfonates, and
triflates.
[0233] Suitable protecting groups are recognizable to those skilled
in the art. Examples of suitable protecting groups can be found in
T. Green & P. Wuts, Protective Groups in Organic Synthesis (2d
ed. 1991), which is hereby incorporated by reference herein in its
entirety.
[0234] Suitable salt anions include, but are not limited to,
inorganics such as halogens, pseudohalogens, sulfates, hydrogen
sulfates, nitrates, hydroxides, phosphates, hydrogen phosphates,
dihydrogen phosphates, perchlorates, and related complex inorganic
anions; and organics such as carboxylates, sulfonates, bicarbonates
and carbonates.
[0235] Examples of substituents for alkyl and aryl groups include
mercapto, thioether, nitro (NO.sub.2), amino, aryloxyl, halogen,
hydroxyl, alkoxyl, and acyl, as well as aryl, cycloalkyl and
saturated and partially saturated heterocycles. Examples of
substituents for cycloalkyl groups include those listed above for
alkyl and aryl, as well as alkyl.
[0236] Exemplary substituted aryls include a phenyl or naphthyl
ring substituted with one or more substituents, preferably one to
three substituents, independently selected from halo, hydroxy,
morpholino(C.sub.1-C.sub.20)alkoxy carbonyl, pyridyl
(C.sub.1-C.sub.20)alkoxycarbonyl, halo (C.sub.1-C.sub.20)alkyl,
C.sub.1-C.sub.20 alkyl, C.sub.1-C.sub.20 alkoxy, carboxy,
C.sub.1-C.sub.20 alkocarbonyl, carbamoyl,
N-(C.sub.1-C.sub.20)alkylcarbam- oyl, amino,
C.sub.1-C.sub.20alkylamino, di(C.sub.1-C.sub.20)alkylamino or a
group of the formula --(CH.sub.2).sub.a--R.sub.7 where a is 1, 2,
3, 4, 5; and R.sub.7 is hydroxy, C.sub.1-C.sub.20 alkoxy, carboxy,
C.sub.1-C.sub.20 alkoxycarbonyl, amino, carbamoyl, C.sub.1-C.sub.20
alkylamino or di(C.sub.1-C.sub.20)alkylamino, sulfonic acids,
sulfonic esters, sulfonic amides, amides, esters and the like.
[0237] Another substituted alkyl is halo(C.sub.1-C.sub.20)alkyl,
which represents a straight or branched alkyl chain having at least
one halogen atom attached to it. Exemplary
halo(C.sub.1-C.sub.20)alkyl groups include chloromethyl,
2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl,
3-chloroisobutyl, trifluoromethyl, trifluoroethyl, and the
like.
[0238] Another substituted alkyl is hydroxy
(C.sub.1-C.sub.20)alkyl, which represents a straight or branched
alkyl chain having from one to twenty carbon atoms with a hydroxy
group attached to it. Exemplary hydroxy(C.sub.1-C.sub.20)alkyl
groups include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
2-hydroxyisopropyl, 4-hydroxybutyl, and the like.
[0239] Yet another substituted alkyl is C.sub.1-C.sub.20
alkylthio(C.sub.1-C.sub.20)alkyl, which is a straight or branched
C.sub.1-C.sub.20 alkyl group with a C.sub.1-C.sub.20 alkylthio
group attached to it. Exemplary C.sub.1-C.sub.20
alkylthio(C.sub.1-C.sub.20)alk- yl groups include methylthiomethyl,
ethylthiomethyl, propylthiopropyl, sec-butylthiomethyl, and the
like.
[0240] Yet another exemplary substituted alkyl is
heterocycle(C.sub.1-C.su- b.20)alkyl, which is a straight or
branched alkyl chain having from one to twenty carbon atoms with a
heterocycle attached to it. Exemplary
heterocycle(C.sub.1-C.sub.20)alkyls include pyrrolylmethyl,
quinolinylmethyl, 1-indolylethyl, 2-furylethyl, 3-thien-2-ylpropyl,
1-imidazolylisopropyl, 4-thiazolylbutyl and the like.
[0241] Yet another substituted alkyl is
aryl(C.sub.1-C.sub.20)alkyl, which is a straight or branched alkyl
chain having from one to twenty carbon atoms with an aryl group
attached to it. Exemplary aryl(C.sub.1-C.sub.20)alkyl groups
include phenylmethyl, 2-phenylethyl, 3-naphthyl-propyl,
1-naphthylisopropyl, 4-phenylbutyl and the like.
[0242] The heterocycloalkyls and the heteroaryls can, for example,
be substituted with 1, 2 or 3 substituents independently selected
from halo, halo(C.sub.1-C.sub.20)alkyl, C.sub.1-C.sub.20 alkyl,
C.sub.1-C.sub.20 alkoxy, carboxy, C.sub.1-C.sub.20 alkoxycarbonyl,
carbamoyl, --(C.sub.1-C.sub.20)alkylcarbamoyl, amino,
C.sub.1-C.sub.20alkylamino, di(C.sub.1-C.sub.20)alkylamino or a
group having the structure --(CH.sub.2).sub.a--R.sub.7 where a is
1, 2, 3, 4, 5 and R.sub.7 is hydroxy, C.sub.1-C.sub.20 alkoxy,
carboxy, C.sub.1-C.sub.20 alkoxycarbonyl, amino, carbamoyl,
C.sub.1-C.sub.20alkylamino or di(C.sub.1-C.sub.20)alkylamino.
[0243] Examples of substituted heterocycloalkyls include, but are
not limited to, 3-N-t-butyl carboxamide decahydroisoquinolinyl and
6-N-t-butyl carboxamide octahydro-thieno[3,2-c]pyridinyl. Examples
of substituted heteroaryls include, but are not limited to,
3-methylimidazolyl, 3-methoxypyridyl, 4-chloroquinolinyl,
4-aminothiazolyl, 8-methylquinolinyl, 6-chloroquinoxalinyl,
3-ethylpyridyl, 6-methoxybenzimidazolyl, 4-hydroxyfuryl,
4-methylisoquinolinyl, 6,8-dibromoquinolinyl, 4,8-dimethylnaphthyl,
2-methyl-1,2,3,4-tetrahydroisoquinolinyl, N-methyl-quinolin-2-yl,
2-t-butoxycarbonyl-1,2,3,4-isoquinolin-7-yl and the like.
[0244] A "pharmaceutically acceptable solvate" is intended to mean
a solvate that retains the biological effectiveness and properties
of the biologically active components of the inventive
compounds.
[0245] Examples of pharmaceutically acceptable solvates include,
but are not limited to, compounds prepared using water,
isopropanol, ethanol, DMSO, and other excipients generally reffered
to as GRAS ingredients.
[0246] In the case of solid formulations, it is understood that the
compounds of the inventive methods may exist in different polymorph
forms, such as stable and metastable crystalline forms and
isotropic and amorphous forms, all of which are intended to be
within the scope of the present invention.
[0247] A "pharmaceutically acceptable salt" is intended to mean
those salts that retain the biological effectiveness and properties
of the free acids and bases and that are not biologically or
otherwise undesirable.
[0248] Examples of pharmaceutically acceptable salts include, but
are not limited to, sulfates, pyrosulfates, bisulfates, sulfites,
bisulfites, phosphates, monohydrogenphosphates,
dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,
bromides, iodides, acetates, propionates, citrates, decanoates,
caprylates, acrylates, formates, isobutyrates, caproates,
heptanoates, propiolates, oxalates, malonates, succinates,
suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,
hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,
dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,
sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,
phenylbutyrates, citrates, lactates, hydroxybutyrates, glycolates,
tartrates, methanesulfoantes, propanesulfonates,
naphthalene-1-sulfonates- , naphthalene-2-sulfonates, and
mandelates.
[0249] If a compound of the present invention is a base, the
desired salt may be prepared by any suitable method known to the
art, including treatment of the free base with an inorganic acid,
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid and the like, or with an organic acid, such
as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric
acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,
lactic acid, salicylic acid, pyranosidyl acids such as glucuronic
acid and galacturonic acid, alpha-hydroxy acids such as citric acid
and tartaric acid, amino acids such as aspartic acid and glutamic
acid, aromatic acids such as benzoic acid and cinnamic acid,
sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic
acid, or the like.
[0250] If a compound of the present invention is an acid, the
desired salt may be prepared by any suitable method known to the
art, including treatment of the free acid with an inorganic or
organic base, such as an amine (primary, secondary or tertiary), or
an alkali metal or alkaline earth metal hydroxide or the like.
Illustrative examples of suitable salts include organic salts
derived from amino acids such as glycine and arginine; ammonia;
primary, secondary and tertiary amines; cyclic amines such as
piperidine, morpholine and piperazine; and inorganic salts derived
from sodium, calcium, potassium, magnesium, manganese, iron,
copper, zinc, aluminum, and lithium.
[0251] In summary, there is a real need for better "shorter
wavelength" absorbing photodynamic agents that do not display red
absorptions, that are cleared rapidly from normal tissues,
especially skin, and agents that may be used as MRI diagnostics or
radiodiagnostic agents in addition to therapeutics. Additionally,
as more disease indications are realized, shorter wavelength light
may be equally important in other PDT applications that only
require short wavelength excitation to effect a therapy. Such
applications may be, for example, in hollow organ disease (for
example lung cancers, barrets esophagus), or in diseases of the
skin (for example psoriasis, actinic keratosis, acne vulgaris). The
invention disclosed herein describes the synthesis of metallated
photosensitizers having ring systems that have shown excellent
efficacy in advanced animal model systems as well as preferred
uptake in the target tissue, with excellent clearance
characteristics and low toxicity. (See co-pending application filed
on May 31, 2001 entitled "Metallotetrapyrrolic Photosensitizing
Agents For Use In Photodynamic Therapy," inventors Byron C.
Robinson, Ian M. Leitch, Stephanie Greene, and Steve Rychnovsky,
Attorney Docket No. 07328-0015.)
[0252] The compounds of the invention are intended for use not only
for effective photodynamic therapy treatment but also as MRI and
radiodiagnostic diagostic agents. Such compounds may be used to
diagnose, locate or treat cardiovascular disease and normal or
abnormal conditions of the hematological system, lymphatic
reticuloendothelial system, nervous system, endocrine and exocrine
system, skeletomuscular system including bone, connective tissue,
cartilage and skeletal muscle, pulmonary system, gastrointestinal
system including the liver, reproductive system, skin, immune
system, cardiovascular system, urinary system, ocular system,
auditory or olfactory system. In particular, photoactive
derivatives of porphyrins and azaporphyrins are particularly
advantageous where shorter wavelengths of light are necessary to
effect a photodynamic response.
EXAMPLES
[0253] Preparation of compounds according to the invention is
illustrated by reference to the following non-limiting examples. It
will be appreciated by persons skilled in the art with the
teachings of the examples and the rest of the specification (i) how
the chemistry may be applied to other peripheral groups on
tetrapyrrolic ring structures that fall within the scope of this
invention and (ii) that other synthetic routes may be suitable for
preparation of the desired compounds.
Example 1
8,12-Diethyl-3,7,13,17-tetramethylporphyrin-2,18-dipropionylhydrazide
[0254] 1.3 g of
8,12-diethyl-3,7,13,17-tetramethylporphyrin-2,18-diyl-di(m-
ethoxycarbonylpropionic acid) was modified according to H. Fischer,
E. Haarer and F. Stadler, Z. Physiol. Chem. 241, 209 (1936) by
treatment with hydrazine hydrate (7 mL of an 80% water solution) in
pyridine (30 mL) at room temperature overnight. The solvent was
removed by rotoevaporation and the solid suspended/dissolved in
methanol (10 mL). Water (30 mL) was added and the methanol removed
by rotary evaporation. The precipitated porphyrin was collected by
filtration and dried to give the title compound. Yield: 1.25 g of a
reddish-brown powder.
Example 2
Zinc
8,12-Diethyl-3,7,13,17-tetramethylporphyrin-2,18-dipropionylhydrazide
[0255] The compound produced in example 1 (100 mg) was dissolved in
chloroform/methanol (80:20) and zinc acetate (200 mg) was added.
The solution was refluxed until complete by UV. The solution was
evaporated to dryness and redissolved in dichloromethane (50 mL).
Water (100 mL) was added and the dichloromethane removed by rotary
evaporation. The precipitated solid was collected by filtration,
washed with water (50 mL) and dried. Yield of the title
compound=110 mg.
Example 3
Platinum
8,12-Diethyl-3,7,13,17-tetramethylporphyrin-2,18-dipropionylhydra-
zide
[0256] Platinum
8,12-Diethyl-3,7,13,17-tetramethylporphyrin-2,18-dipropion- ic acid
methyl ester (1.2 g) was modified according to H. Fischer, E.
Haarer and F. Stadler, Z. Physiol. Chem. 241, 209 (1936) by
treatment with hydrazine hydrate (7 mL of an 80% water solution) in
pyridine (30 mL) at room temperature. The solution was evaporated
to dryness, dissolved/suspended in methanol (10 mL) and water (30
mL) was added. The methanol was removed by rotary evaporation and
the precipitated porphyrin collected by filtration and dried.
Yield: 1.25 g of an orange-red powder.
Example 4
8,12-Diethyl-3,7,13,17-tetramethylporphyrin-2-{N(6-tert-butoxycarbonylamin-
ohexyl)propionylamide}-18-propionic Acid &
8,12-Diethyl-3,7,13,17-tetramet-
hylporphyrin-2,18-{N,N'-bis-(6-tert-butoxycarbonylaminohexyl)}dipropionyla-
mide
[0257] 8,12-Diethyl-3,7,13,17-tetramethylporphyrin-2,18-dipropionic
acid (1.8 g), 1-hydroxybenzotriazole (810 mg),
N-BOC-1,6-diaminohexane hydrochloride (1.52 g) and triethylamine
(608 mg) is dissolved in dimethylformamide (300 mL). The solution
is stirred under argon and cooled to -10.degree. C.
Dicyclohexylcarbodiimide (1.24 g) is added and the solution is
stirred for 1 hr at -10.degree. C., then left to warm to room
temperature. After three hours the solution is evaporated to
dryness and the residue dissolved in dichloromethane (50 mL). The
solution is washed with a saturated sodium bicarbonate solution.
The dichloromethane layer was dried over sodium sulfate and
filtered and evaporated. The crude residue is chromatographed on
silica using dichloromethane/methanol (0-10%) as eluent and the two
fractions collected. The diamide is eluted first (800 mg), followed
sluggishly by the mono amide title compound (1500 mg).
Example 5
8,12-Diethyl-3,7,13,17-Tetramethylporphyrin-2-{N-(6-Aminohexyl)-Propionyla-
mide}-18-Propionic Acid
[0258] The mono amide produced in example 4 (500 mg) is dissolved
in 2N hydrochloric acid in glacial acetic acid (10 mL). When no
more starting material could be detected, the solution is
evaporated to dryness and dissolved in distilled water. A saturated
sodium bicarbonate solution is added dropwise until the porphyrin
precipitated. The porphyrin is collected by filtration and dried.
Yield of title compound=400 mg.
Example 6
8,12-Diethyl-3,7,13,17-Tetramethylporphyrin-2,18-{N,N'-Bis-(6-Aminohexyl}P-
ropionylamide
[0259] The di-amide produced in example 4 (500 mg) is dissolved in
2N hydrochloric acid in glacial acetic acid (10 mL) and the
solution is stirred overnight. When no more starting material could
be detected, the solution is evaporated to dryness and dissolved in
distilled water. A saturated sodium bicarbonate solution is added
dropwise until the porphyrin precipitated. The porphyrin was
collected by filtration and dried. Yield of title compound=400
mg.
Example 7
Zinc
8,12-Diethyl-3,7,13,17-Tetramethylporphyrin-2-{N-(6-Aminohexyl}Propio-
nylamide-18-Propionic Acid
[0260] The porphyrin prepared in Example 5 (100 mg) is metallated
as described in example 2. Yield of title compound=(100 mg).
Example 8
Zinc
8,12-Diethyl-3,7,13,17-Tetramethylporphyrin-2,18-(N,N'-Bis-(6-Aminohe-
xyl)Propionylamide
[0261] The porphyrin prepared in Example 6 (100 mg) is metallated
as described in example 2. Yield of title compound=(100 mg).
Example 9
Platinum
8,12-diethyl-3,7,13,17-tetramethylporphyrin-2,18-{N,N'-bis-(6-ter-
t-butoxycarbonylaminohexyl}dipropionylamide
[0262] The porphyrin prepared in Example 2 (100 mg) is hydrolyzed
in THF (50 mL) containing KOH/methanol (0.4 g; 5 mL). The solution
is neutralized using acetic acid and evaporated to 10 mL. Water (50
mL) is added and the precipitated porphyrin collected by filtration
and dried under vacuum. The diacid porphyrin is converted to the
protected amide according to example 4, except that the solution is
reacted over night. The diamide protected compound is
chromatographed on silica using 5% methanol/dichloromethane as
eluent. Yield of title compound=85 mg.
Example 10
Platinum
8,12-Diethyl-3,7,13,17-Tetramethylporphyrin-2,18-{N,N'-Bis-(6-Ami-
nohexyl)}Propionylamide
[0263] The porphyrin of example 9 (85 mg) is dissolved in
dichloromethane (20 mL) and trifluoroacetic acid (10 mL) is added.
The solution is stirred for 4 hrs, after which the solvent is
removed by rotary evaporation. The compound is partially dissolved
in methanol and triethylamine (0.4 mL) added. The precipitated
porphyrin is collected and washed with water and dried. Yield of
title compound=72 mg.
Example 11
8,12-Diethyl-3,7,13,17-Tetramethylporphyrin-2,18-{N,N'-Bis-(2-Aminoethyl}P-
ropionylamide
[0264] 8,12-diethyl-3,7,13,17-tetramethylporphyrin-2,18-propionic
acid (250 mg) is suspended in dichloromethane (50 mL) and oxalyl
chloride (5 mL) is added. The solution is refluxed for 2 hrs under
a dry inert atmosphere and the solvent removed by rotary
evaporation. The solid is redissolved in dichloromethane (dry, 20
mL) and ethylenediamine (4 mL) is added all at once. The resulting
solution is stirred at room temperature for 2 hrs and the solvent
removed by rotary evaporation. The solid is suspended in methanol
and triethylamine (5 drops) added. The flocculated porphyrin is
collected by filtration, dissolved in dichloromethane (30 mL) and
chromatographed on silica using 10-15% methanol/dichloromethane
(with 1% triethylamine) and the major red band collected. The
solvent is removed and the porphyrin dissolved in dichloromethane
and precipitated from methanol by slow evaporation of
dichloromethane. The solid is collected and washed with methanol.
Yield of title compound=210 mg.
Example 12
Gallium Hydroxide
8,12-Diethyl-3,7,13,17-Tetramethylporphyrin-2,18-{N,N'-B-
is-(2-Aminoethyl)}Propionylamide
[0265] The porphyrin prepared in Example 11 (100 mg) is metallated
by refluxing a solution of the porphyrin and gallium
acetylacetonate (100 mg) in acetic acid for 1.5 hrs. The solvent is
removed and the solid dissolved in dichloromethane (50 mL) and
washed with a saturated sodium bicarbonate solution. The organic
layer is dried over sodium sulfate, filtered, evaporated to 10 ml,
and hexane (10 mL) is added. The dichloromethane is slowly removed
by rotary evaporation and the precipitated porphyrin collected by
filtration. Yield of title compound=(100 mg).
Example 13
Indium Hydroxide
8,12-diethyl-3,7,13,17-tetramethylporphyrin-2,18-{(N,N'-b-
is-(2-aminoethyl)}propionylamide
[0266] The porphyrin prepared in Example 11 (100 mg) is metallated
by refluxing a solution of the porphyrin, indium chloride (100 mg)
and sodium acetate (100 mg) in acetic acid for 2 hrs. The solvent
is removed and the solid dissolved in dichloromethane (50 mL) and
washed with a saturated sodium bicarbonate solution. The organic
layer is dried over sodium sulfate, filtered, evaporated to 10 ml,
and hexane (10 mL) is added. The dichloromethane is slowly removed
by rotary evaporation and the precipitated porphyrin collected by
filtration. Yield of title compound=(100 mg).
Example 14
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(propionic
Acid Methyl Ester)
[0267] To a solution of
5,5'-dicarboxy-3,3'-di(2-methoxycarbonylethyl)-4,4-
'-dimethylpyrromethane (5 g) in methanol (70 mL) was added ammonium
hydroxide (2.6 ml) and the solution stirred until the
dipyrromethane had dissolved. 2-bromo-5-formyl-3,4-diethylpyrrole
(5.3 g) and HBr (33%, 25 mL) were added. The solution was stirred
at room temperature for 2 hrs after which time the solid
1,19-dibromobiladiene was filtered and dried to yield=7.2 g. A
smaller amount of 1,19-dibromobiladiene (3 g) was refluxed in
methanol containing sodium azide (4 g) for 4 hrs. The solvent was
removed and the residue dissolved in dichloromethane and
chromatographed on silica using dichloromethane as eluent. The
major purple band was collected and evaporated to dryness. The
compound was dissolved in dichloromethane (50 mL) and methanol (50
mL) added. The dichloromethane was removed by rotary evaporation
and the precipitated azaporphyrin collected by filtration. Yield of
title compound=1.7 g.
Example 15
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(propanyl
Hydrazide)
[0268] The azaporphyrin synthesized in example 13 (250 mg) was
modified according to H. Fischer, E. Haarer and F. Stadler, Z.
Physiol. Chem. 241, 209 (1936) by treatment with hydrazine hydrate
(1.5 mL of an 80% water solution) in pyridine (20 mL) at room
temperature. The solution was evaporated to dryness,
dissolved/suspended in methanol (10 mL) and water (30 mL) was
added. The methanol was removed by rotary evaporation and the
precipitated porphyrin collected by filtration and dried. Yield of
title compound: 250 g of a purple powder.
Example 16
Zinc
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(propanyl
Hydrazide)
[0269] The azaporphyrin prepared in example 14 (100 mg) was
metallated according to example 2. Yield of title compound 110
mg.
Example 17
Gallium
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(propan-
yl Hydrazide)
[0270] The azaporphyrin prepared in example 14 (100 mg) was
metallated according to example 12. Yield of title compound=110
mg.
Example 18
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-(N,N'-bis-(2-amin-
oethyl)propionylamide
[0271] 8,12-diethyl-3,7,13,17-tetramethylporphyrin-2,18-propionic
acid potassium salt (250 mg)(prepared by hydrolysis of the
azaporphyrin prepared in example 14 with KOH/methanol) was
converted to the title compound via the procedure described in
example 11. Yield=200 mg.
Example 19
Zinc
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-{N,N'-bis-(2-
-aminoethyl)}propionylamide
[0272] The porphyrin prepared in example 18 (100 mg) was metallated
by the procedure of example 14. Yield of title compound=100 mg.
Example 20
Gallium Hydroxyl
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18--
(N,N'-bis-(2-aminoethyl)propionylamide
[0273] The porphyrin prepared in example 18 (100 mg) was metallated
by the procedure of example 12. Yield of title compound=100 mg.
Example 21
Indium Hydroxyl
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-(-
N,N'-bis-(2-aminoethyl)propionylamide
[0274] The porphyrin prepared in example 18 (100 mg) was metallated
by the procedure of example 13. Yield of title compound=100 mg.
Example 22
8,12-Diethyl-3,8,13,17-tetramethyl-2,18-bis{3,6,16-trioxo-8,11,14-tris(car-
boxymethyl)-17-oxa-4,5,8,11,14-pentaazanonadec-1-yl}porphyrin
[0275] 806.8 mg (2 mmol) of
3-ethoxy-carbonylmethyl-6-[2-(2,6-dioxomorphol-
ino)ethyl]-3,6-diazaoctanedioic acid
(DTPA-monoethylester-monoanhydride) is suspended in 250 ml of
absolute dimethylformamide. It is then covered with a layer of
nitrogen, 1.0 g (10 mmol) of triethylamine and 593 mg (1 mmol) of
the title compound synthesized via Example I are added, and the
resulting reaction mixture is stirred for 3 days at room
temperature. After the reaction is complete, it is filtered, the
solvent is drawn off in a vacuum, and the remaining oil is
pulverized with 500 ml of diethyl ether. The precipitated solid is
filtered off and washed with diethyl ether and n-hexane. For
purification, it is chromatographed on silica gel RP-18 (eluant:
H.sub.2O/tetrahydrofuran: 0-30%). Yield of title compound: 1.30 g
of a reddish-brown powder
Example 23
[8,12-Diethyl-3,8,13,17-tetramethyl-2,18-bis{3,6,16-trioxo-8,11,14-tris(ca-
rboxymethyl)-17-oxa-4,5,8,11,14-pentaazanonadec-1-yl}porphyrinato(2-)]-zin-
c
[0276] The zinc porphyrin (658 mg) of example 2 is reacted as
described in example 22. Yield of title compound=1.0 g
Example 24
[8,12-Diethyl-3,8,13,17-tetramethyl-2,18-bis{3,6,16-trioxo-8,11,14-tris(ca-
rboxymethyl)-17-oxa-4,5,8,11,14-pentaazanonadec-1-yl}porphyrinato(2-)]plat-
inum
[0277] The platinum porphyrin of example 3 (786 mg) is reacted as
described in example 22. Yield of title compound=1.5 g
Example 25
[8,12-Diethyl-3,8,13,17-tetramethyl-2,-propionicacid-18-{3,12,22-trioxo-14-
,17,20-tris(carboxymethyl)-23-oxa-4,11,14,17,20-pentaazapentacosan-1-yl}po-
rphyrin
[0278] The mono-hexylamine porphyrin (663 mg) of example 5 is
reacted analogously as described in example 22, except using
DTPA-monoethylester-monoanhydride (404 mg) and triethylamine (0.5
g). Yield of title compound=900 mg.
Example 26
[8,12-Diethyl-3,8,13,17-tetramethyl-2,18-{3,12,22-trioxo-14,17,20-tris(car-
boxymethyl)-23-oxa-4,11,14,17,20-pentaazapentacosan-1-yl}porphyrin
[0279] The dihexylamine porphyrin (663 mg) of example 5 is reacted
as described in example 22, using DTPA-monoethylester-monoanhydride
(808 mg) and triethylamine (1.0 g). Yield of title compound=1.3
g.
Example 27
[7,8,12,13-Tetraethyl-3,17-dimethyl-2,18-{3,8,18-trioxo-10,13,16-tris(carb-
oxymethyl)-19-oxa-4,7,10,13,16-pentaazaheneicosan-1-yl}-10-azaporphyrin
[0280] The diamine azaporphyrin (663 mg) of example 18 is reacted
as described in example 24, using DTPA-monoethylester-monoanhydride
(808 mg) and triethylamine (1.0 g). Yield of title compound=1.32
g.
Example 28
[7,8,12,13-Tetraethyl-3,17-dimethyl-2,18-{3,6,16-trioxo-8,11,14-tris(carbo-
xymethyl)-17-oxa-4,5,8,11,14-pentaazanonadec-1-yl}-10-azaporphyrinato(2-)]-
zinc
[0281] The zinc dihydrazide azaporphyrin (686 mg) of example 16 is
reacted as described in example 22, using
DTPA-monoethylester-monoanhydride (808 mg) and triethylamine (1.0
g). Yield of title compound=1.22 g.
Example 29
[7,8,12,13-Tetraethyl-3,17-dimethyl-2,18-{3,6,16-trioxo-8,11,14-tris(carbo-
xymethyl)-17-oxa-4,5,8,11,14-pentaazanonadec-1-yl}-10-azaporphyrinato(2-)]-
galliumhydroxide
[0282] The gallium dihydrazide azaporphyrin (707 mg) of example 17
is reacted as described in example 22, using
DTPA-monoethylester-monoanhydri- de (808 mg) and triethylamine (1.0
g). Yield of title compound=1.31 g.
Example 30
[7,8,12,13-Tetraethyl-3,17-dimethyl-2,18-{3,8,18-trioxo-10,13,16-tris(carb-
oxymethyl)-19-oxa-4,7,10,13,16-pentaazaheneicosan-1-yl}-10-azaporphyrinato-
(2-)]zinc
[0283] The zinc azaporphyrin of example 19 (742 mg) is reacted as
described in example 22, using DTPA-monoethylester-monoanhydride
(808 mg) and triethylamine (1.0 g). Yield of title compound=1.35
g.
Example 31
7,8,12,13-tetraethyl-12,17-dimethyl-2-(3-carboxypropyl)-18-(3-methoxycarbo-
nylpropyl)-10-azaporphyrin
[0284] The dimethyl ester azaporphyrin of example 14 (1.0 g, 1.6
mmol) is dissolved in THF (200 ml) and a solution of KOH (100
mg)/MeOH (5 mL) is added. The solution is closely monitored until
only a trace of starting material remains and the major product is
the mono-hydrolyzed azaporphyrin. Acetic acid (107 mg) is added and
the solution diluted with water (100 mL). The THF was removed by
rotary evaporation and the precipitated azaporphyrins were
collected and washed with methanol (20 mL) and dried. The solid was
dissolved in dichloromethane containing 2% methanol and the
solution is chromatographed on silica using 2%
methanol/dichloromethane as eluent. The second major fraction is
collected and evaporated to dryness. Yield of title compound=0.62
g.
Example 32
7,8,12,13-tetraethyl-12,17-dimethyl-2-{N-(2-aminoethyl)propionylamide}-18--
(3-methoxycarbonylpropyl)-10-azaporphyrin
[0285] The monoacid azaporphyrin prepared in example 30 (500 mg) is
dissolved in dichloromethane (50 ml) and oxalyl chloride (5 ml)
added. The solution is refluxed under dry conditions for 2 hrs and
then evaporated to dryness, care being taken not to expose the
crude material to moisture. The residue is dissolved in
dichloromethane (50 mL, dry) and ethylene diamine (3 ml, dry) added
all at once. The resulting solution is washed with a saturated
sodium bicarbonate solution, followed by water and the organic
layer is collected, dried over sodium sulfate, filtered and
evaporated. The crude reaction mixture is chromatographed on silica
using 4% methanol/dichloromethane/0.5% triethylamine as eluent, and
the major fraction collected. The dichloromethane is removed by
rotary evaporation and the precipitated porphyrin collected by
filtration and dried. Yield of title compound=0.51 g.
Example 33
[7,8,12,13-Tetraethyl-3,17-dimethyl-2-(3-methoxycarbonylpropyl)-18-{3,8,18-
-trioxo-10,13,16-tris(carboxymethyl)-19-oxa-4,7,10,13,16-pentaazaheneicosa-
n-1-yl}-10-azaporphyrin
[0286] The azaporphyrin of example 32 (0.5 g, 0.76 mmol) is reacted
as described in example 22, using DTPA-monoethylester-monoanhydride
(404 mg) and triethylamine (0.5 g). Yield of title compound=0.8
g.
Example 34
8,12-Diethyl-3,8,13,17-tetramethyl-2,18-bis{3,6,16-trioxo-8,11,14-tris(car-
boxymethyl)-4,5,8,11,14-pentaazahexadecanoato-1-yl}porphyrin
[0287] The ligand that is produced by Example 22 (1.0 g, 0.74 mmol)
is dissolved in THF (50 mL) and water (350 mL). Sodium hydroxide
solution (10 mol) is added and it is stirred overnight at room
temperature. After the ester groups have been completely
saponified, the THF is removed by rotoevaporation. A pH of 4 is set
with concentrated hydrochloric acid. It is evaporated to the dry
state in a vacuum. The residue is chromatographed on RP 18 (eluant:
H.sub.2O/tetrahydrofuran/gradient). Yield of title compound: 0.90 g
of a reddish-brown powder.
Example 35
[8,12-Diethyl-3,8,13,17-tetramethyl-2,18-bis{3,6,16-trioxo-8,11,14-tris(ca-
rboxymethyl)-4,5,8,11,14-pentaazahexadecanoato-1-yl}porphyrinato(2-)]zinc
[0288] The esters on the ligand produced by Example 23 (1.3 g,
0.885 mmol) are hydrolyzed and acidified as described in example
34. Yield of title compound=1.12 g.
Example 36
[8,12-Diethyl-3,8,13,17-tetramethyl-2,18-bis{3,6,16-trioxo-8,11,14-tris(ca-
rboxymethyl)-4,5,8,11,14-pentaazahexadecanoato-1-yl}porphyrinato(2-)]plati-
num
[0289] The esters on the ligand produced by Example 24 (1.0 g, 0.62
mmol) are hydrolyzed and acidified as described in example 34.
Yield of title compound=1.12 g.
Example 37
[7,8,12,13-Tetraethyl-3,17-dimethyl-2,18-{3,6,16-trioxo-8,11,14-tris(carbo-
xymethyl)-4,5,8,11,14-pentaazahexadecanoato-1-yl}-10-azaporphyrinato(2-)]z-
inc
[0290] The esters on the ligand produced in Example 28 (1.0 g, 0.69
mmol) are hydrolyzed and acidified as described in example 34.
Yield of title compound=0.85 g.
Example 38
[7,8,12,13-Tetraethyl-3,17-dimethyl-2-propionic
acid-18-{3,8,18-trioxo-10,-
13,16-tris(carboxymethyl)-4,7,10,13,16-pentaazaheneicosan-1-yl}-10-azaporp-
hyrin
[0291] The esters on the ligand produced in Example 33 (1.0 g, 1
mmol) are hydrolyzed and acidified as described in example 34.
Yield of title compound=0.85 g.
Example 39
[7,8,12,13-Tetraethyl-3,17-dimethyl-2-18-{3,6,16-trioxo-8,11,14-tris(carbo-
xymethyl)-4,5,8,11,14-pentaazahexadecanoato-1-yl}-10-azaporphyrinato(2-)]g-
allium Chloride
[0292] The esters on the ligand produced in Example 29 (1.0 g, 0.68
mmol) are hydrolyzed and acidified as described in example 34.
Yield of title compound=0.85 g.
Example 40
7,8,12,13-Tetraethyl-3,17-dimethyl-2-18-{3,8,18-trioxo-10,13,16-tris(carbo-
xymethyl)-4,7,10,13,16-pentaazaheneicosan-1-yl}-10-azaporphyrin
[0293] The esters on the ligand produced in Example 27 (1.0 g, 0.7
mmol) are hydrolyzed and acidified as described in example 34.
Yield of title compound=0.82 g.
Example 41
Mu-[(16,16'-[zinc(II)-8,12-Diethyl-3,8,13,17-tetramethylporphyrin-2,18-diy-
l]-bis[3,6,9-tris(carboxymethyl)-11,14-dioxo-3,6,9,12,13-pentaazahexadecan-
oato]}(8-)]}digadolinato(2-), Disodium
[0294] The ligand produced by example 35 (200 mg, 0.14 mmol) is
dissolved in water (100 mL), and gadolinium chloride (74 mg, 0.28
mmol) and 2N aqueous sodium hydroxide solution are added
alternately in portions, such that the pH of the reaction mixture
remains between 6.8 and 7.2. After all of the gadolinium chloride
is added, stirring is continued overnight at room temperature. The
solvent is drawn off in a vacuum, and the residue is
chromatographed on silica gel RP-18 (eluent:water/THF: 0-30%).
Yield of title compound=260 mg.
Example 42
Mu-[(16,16'-[Platinum(II)-8,12-Diethyl-3,8,13,17-tetramethylporphyrin-2,18-
-diyl]-bis[3,6,9-tris(carboxymethyl)-11,14-dioxo-3,6,9,12,13-pentaazahexad-
ecanoato]}(8-)]}digadolinato(2-), Disodium
[0295] The ligand produced by example 36 (200 mg, 0.13 mmol) is
dissolved in water (100 mL), and gadolinium chloride (69 mg, 0.26
mmol) and 2N aqueous sodium hydroxide solution are added
alternately in portions, such that the pH of the reaction mixture
remains between 6.8 and 7.2. After all of the gadolinium chloride
is added, stirring is continued overnight at room temperature. The
solvent is drawn off in a vacuum, and the residue is
chromatographed on silica gel RP-18 (eluent:water/THF: 0-30%).
Yield of title compound 247 mg.
Example 43
{Mu-[(16,16'-[8,12-Diethyl-3,8,13,17-tetramethylporphyrin-2,18-diyl]-bis[3-
,6,9-tris(carboxymethyl)-11,14-dioxo-3,6,9,12,13-pentaazahexadecanoato]}(8-
-)]}digadolinato(2-), Disodium
[0296] The ligand produced by example 34 (200 mg, 0.15 mmol) is
dissolved in water (10 mL), and gadolinium chloride (79 mg, 0.30
mmol) and 2N aqueous sodium hydroxide solution are added
alternately in portions, such that the pH of the reaction mixture
remains between 6.8 and 7.2. After all of the gadolinium chloride
is added, stirring is continued overnight at room temperature. The
solvent is drawn off in a vacuum, and the residue is
chromatographed on silica gel RP-18 (eluent:water/THF: 0-30%).
Yield of title compound=258 mg.
Example 44
{Mu-[(16,16'-[Zinc(II)[7,8,11,12-tetraethyl-13,17-dimethyl-10-azaporphyrin-
-2,18-diyl]-bis[3,6,9-tris(carboxymethyl)-11,14-dioxo-3,6,9,12,13-pentaaza-
hexadecanoato]}(8-)]}digadolinato(2-), Disodium
[0297] The ligand produced by example 37 (200 mg, 0.15 mmol) is
dissolved in water (100 mL), and gadolinium chloride (79 mg, 0.30
mmol) and 2N aqueous sodium hydroxide solution are added
alternately in portions, such that the pH of the reaction mixture
remains between 6.8 and 7.2. After all of the gadolinium chloride
is added, stirring is continued overnight at room temperature. The
solvent is drawn off in a vacuum, and the residue is
chromatographed on silica gel RP-18 (eluent:water/THF: 0-30%).
Yield of title compound=260 mg.
Example 45
{Mu-[18'-[Zinc(II)[7,8,11,12-tetraethyl-13,17-dimethyl-10-azaporphyrin-2-(-
3-carboxypropanyl)-18-yl]-[{3,6,9-tris(carboxymethyl)-11,16-dioxo-3,6,9,12-
,15-pentaazaheneicosanato}](8-)]}digadolinato(2-), Disodium
[0298] The ligand produced by example 38 (200 mg, 0.21 mmol) is
dissolved in water (100 mL), and gadolinium chloride (110 mg, 0.42
mmol) and 2N aqueous sodium hydroxide solution are added
alternately in portions, such that the pH of the reaction mixture
remains between 6.8 and 7.2. After all of the gadolinium chloride
is added, stirring is continued overnight at room temperature. The
solvent is drawn off in a vacuum, and the residue is
chromatographed on silica gel RP-18 (eluent:water/THF: 0-30%).
Yield of title compound=260 mg.
Example 46
8,12-Diethyl-3,7,13,17-tetramethyl-2,18-(3-methoxycarboxylpropyl)-5,15-dia-
zaporphyrin
[0299] This compound was prepared via the method of Neya, S., Hori,
H., Imai, K., Konishi, Y. K., Suzuki, H., Shiro, Y., Lizuka, T.,
Funasaki, N., J. Biochem, 1997, 121, 654. The free bases of
5,5'-dibromo-3,3'-dieth- yldipyrromethene (2.00 g, 5.18 mmol) and
5,5'-dibromo-3,3'-di(methoxycarbo-
nylethyl)-4,4'-dimethyldipyrromethene (2.60 g, 5.18 mmol) and
sodium azide (10 g, 154 mmol) were placed in a round bottom flask
containing methanol (1 L). the mixture was gently refluxed for 72
hrs. After solvent evaporation the residue was chromatographed on
silica using chloroform as eluent. The title compound was eluted as
the middle fraction of the three possible diazaporphyrins. The
middle fraction was collected and recrystallized from
dichloromethane/methanol. Yield=240 mg.
Example 47
8,12-Diethyl-3,7,13,17-tetramethyl-2,18-dipropionylhydrazide-5,15-diazapor-
phyrin
[0300] The compound produced by example 46 (1.0 g) was modified
according to H. Fischer, E. Haarer and F. Stadler, Z. Physiol.
Chem. 241, 209 (1936) by treatment with hydrazine hydrate (7 mL of
an 80% water solution) in pyridine (30 mL) at room temperature
overnight. The solvent was removed by rotoevaporation and the solid
suspended/dissolved in methanol (10 mL). Water (30 mL) was added
and the methanol removed by rotary evaporation. The precipitated
porphyrin was collected by filtration and dried to give the title
compound. Yield: 1.25 g of purple powder.
Example 48
8,12-Diethyl-3,7,13,17-tetramethyl-2,18-{3,6,16-trioxo-8,11,14-tris(carbox-
ymethyl)-17-oxa-4,5,8,11,14-pentaazanonadec-1-yl}-5,15-diazaporphyrin
[0301] The compound produced by example 47 (500 mg, 0.83 mmol) is
modified according to example 22 except using
DTPA-monoethylester-monoanhydride (674 mg, 1.67 mmol) and
triethylamine (1.0 g) Yield of title compound=990 mg.
Example 49
{Mu-[(16,16'-[8,12-Diethyl-3,7,13,17-tetramethyl-5,15-diazaporphyrin-2,18--
diyl]-bis[3,6,9-tris(carboxymethyl)-11,14-dioxo-3,6,9,12,13-pentaazahexade-
canoato]}(8-)]}digadolinato(2-), Disodium
[0302] The compound produced by example 48 (200 mg, 0.148 mmol) is
dissolved in water (100 mL), and gadolinium chloride (78.2 mg,
0.296 mmol) and 2N aqueous sodium hydroxide solution are added
alternately in portions, such that the pH of the reaction mixture
remains between 6.8 and 7.2. After all of the gadolinium
* * * * *