U.S. patent application number 10/965849 was filed with the patent office on 2005-06-23 for metallotetrapyrrolic photosensitizing agents for use in photodynamic therapy.
This patent application is currently assigned to Miravant Pharmaceuticals, Inc.. Invention is credited to Greene, Stephanie, Leitch, Ian M., Robinson, Byron C., Rychnovsky, Steve.
Application Number | 20050137180 10/965849 |
Document ID | / |
Family ID | 23137301 |
Filed Date | 2005-06-23 |
United States Patent
Application |
20050137180 |
Kind Code |
A1 |
Robinson, Byron C. ; et
al. |
June 23, 2005 |
Metallotetrapyrrolic photosensitizing agents for use in
photodynamic therapy
Abstract
Metallotetrapyrrolic compounds having photherapeutic properties
useful in photodetection and phototherapy of target issues,
particularly porphyrins and azaporphyrins that including gallium in
the central pyrrolic core. Also disclosed are methods of using
metallotetrapyrrolic compounds for the treatment or detection of
cardiovascular disease.
Inventors: |
Robinson, Byron C.; (Santa
Barbara, CA) ; Leitch, Ian M.; (Goleta, CA) ;
Greene, Stephanie; (Goleta, CA) ; Rychnovsky,
Steve; (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: |
23137301 |
Appl. No.: |
10/965849 |
Filed: |
October 18, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10965849 |
Oct 18, 2004 |
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10159005 |
May 31, 2002 |
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6827926 |
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60295345 |
May 31, 2001 |
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Current U.S.
Class: |
514/185 ;
540/145 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 37/02 20180101; A61P 19/02 20180101; A61P 31/00 20180101; A61P
29/00 20180101; A61P 41/00 20180101; A61P 17/02 20180101; A61P 7/00
20180101; A61P 17/00 20180101; A61P 9/08 20180101; A61P 17/04
20180101; A61K 41/0071 20130101; A61P 9/10 20180101; A61P 37/08
20180101; A61K 49/0036 20130101 |
Class at
Publication: |
514/185 ;
540/145 |
International
Class: |
A61K 031/555; C07D
487/22 |
Claims
1. A method of using a gallium porphyrin as a medicament to treat
or detect diseases of the cardiovascular system, comprising
administering to a patient an effective amount of a porphyrin
compound that coordinates gallium in the central pyrrolic core, and
irradiating said porphyrin compound with energy at a wavelength
capable of exciting the molecule to achieve the desired detection
or therapeutic effect.
2. A method of using a gallium mono-, di-, tri-, or
tetra-azaporphyrin as a medicament to treat or detect diseases of
the cardiovascular system, comprising administering to a patient an
effective amount of a mono-, di-, tri-, or tetra-azaporphyrin
compound that coordinates gallium in the central pyrrolic core, and
irradiating said mono-, di-, tri-, or tetra-azaporphyrin compound
with energy at a wavelength capable of exciting the molecule to
achieve the desired detection or therapeutic effect.
3. A method of using a metallated porphyrin as a medicament to
treat or detect diseases of the cardiovascular system, comprising
administering to a patient an effective amount of a porphyrin
compound that coordinates a metal in the central pyrrolic core, and
irradiating said porphyrin compound with energy at a wavelength
capable of exciting the molecule to achieve the desired detection
or therapeutic effect.
4. The method of claim 3, wherein the coordinated metal is selected
from Ag, Au, Al, Cd, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Ga, Ge, Gd,
Hf, Ho, In, Ir, La, Lu, Mn, Mg, Mo, Ni, Nd, P, Pb, Pd, Pr, Pt, Rh,
Ru, Sb, Sc, Si, Sm, Sn, Tc, Tb, Th, Ti, TI, Tm, U, V, Y, Yb, W, Zn
and Zr.
5. The method of claim 3, wherein the coordinated metal is selected
from Si, Ga, Pt, Pd, Sn, In, Ge, Al, Zn, Y, and Mg.
6. A method of using a metallated mono-, di-, tri-, or
tetra-azaporphyrin as a medicament to treat or detect diseases of
the cardiovascular system, comprising administering to a patient an
effective amount of a mono-, di-, tri-, or tetra-azaporphyrin
compound that coordinates a metal in the central pyrrolic core, and
irradiating said mono-, di-, tri-, or tetra-azaporphyrin compound
with energy at a wavelength capable of exciting the molecule to
achieve the desired detection or therapeutic effect.
7. The method of claim 6, wherein the coordinated metal is selected
from Ag, Au, Al, Cd, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Ga, Ge, Gd,
Hf, Ho, In, Ir, La, Lu, Mn, Mg, Mo, Ni, Nd, P, Pb, Pd, Pr, Pt, Rh,
Ru, Sb, Sc, Si, Sm, Sn, Tc, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, W, Zn
and Zr.
8. The method of claim 6, wherein the coordinated metal is selected
from In, Pt, Pd, Sn, Al, Mg, Zn, Si, Ge, Y and Ga.
9. A method for the detection or treatment of tissues of the
cardiovascular system, comprising administering to a patient,
locally or systemically, an effective amount of a porphyrin or a
mono-, di-, tri-, or tetra-azaporphyrin, that coordinates a metal
in the central tetrapyrrolic core, and irradiating said porphyrin
or azaporphyrin with energy at a wavelength capable of exciting the
molecule to achieve the desired detection or therapeutic
effect.
10. The method of claim 9, wherein said metal is selected from In,
Pt, Pd, Sn, Al, Mg, Zn, Si, Ge, Y, and Ga.
11. (canceled)
12. The method of claim 1, wherein said porphyrin compound is
selected from gallium (III) mesoporphyrin diacid, gallium (III)
mesoporphyrin dimethyl ester, gallium (III) mesoporphyrin diethyl
ester, and gallium (III) mesoporphyrin dipropyl ester, gallium
(III) mesoporphyrin dibutyl ester, gallium (III) mesoporphyrin
dipentyl ester, gallium (III) mesoporphyrin dihexyl ester, gallium
(III) mesoporphyrin N,N-diethylamide, gallium (III)
deuteroporphyrin diacid, gallium (III) deuteroporphyrin dimethyl
ester, gallium (III) deuteroporphyrin diethyl ester, gallium (III)
deuteroporphyrin dipropyl ester, gallium (III) deuteroporphyrin
dibutyl ester, gallium (III) deuteroporphyrin dipentyl ester,
gallium (III) deuteroporphyrin dihexyl ester, and p-halogenated
derivatives and salts thereof.
13. The method of claim 1, wherein said porphyrin compound is
selected from mesoporphyrin derivatives, deuteroporphyrin
derivatives, coproporphyrin derivatives, uroporphyrin derivatives,
pentacarboxyporphyrin derivatives, hematoporphyrin derivatives,
protoporphyrin derivatives, hexacarboxyporphyrin derivatives,
chloroporphyrin e6 derivatives, chloroporphyrin e4 derivatives,
phylloporphyrin derivatives, rhodoporphyrin derivatives,
pyrroporphyrin derivatives, pheoporphyrin a5 derivatives, and
phylloerythrin derivatives.
14. A method of using a tetrapyrrolic macrocycle that coordinates
gallium in the central pyrrolic core as a medicament to treat or
detect diseases of the cardiovascular system comprising
administering to a patient an effective amount of said
tetrapyrrolic macrocycle, and irradiating said macrocycle with
energy at a wavelength capable of exciting the molecule to achieve
the desired detection or therapeutic effect, wherein said gallium
co-ordinating tetrapyrrolic macrocycle is selected from a
porphyrin, a azaporphyrin, a diazaporphyrin, a triazaporphyrin, a
corrole, a porphycene, a isoporphycene, a hemiporphycene, and a
corrphycene.
15. The method of any of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12,
13 and 14 for treating a vessel wall or tissue adjoining the vessel
wall, or material attached to the vessel wall of a patient's
coronary, carotid or peripheral vasculature.
16. The method of claim 15 wherein said vessel is an artery or a
vein.
17. The method of any of claims 3, 4, 5, 6, 7, 8, 10, 12, 13, and
14 wherein the cardiovascular disease is atherosclerosis,
restenosis or graft disease.
18. The method of claim 9 wherein said therapeutic effect is
achieved by depleting or eliminating normal contractile phenotype
vascular smooth muscle cells (VSMC), neovessels, non-contractile
synthetic phenotype VSMC, myofibroblasts, endothelial cells,
macrophages, leukocytes, monocytes, erthyrocytes, platelets,
(thrombocytes) or combinations thereof.
19. The method of claim 9, wherein said therapeutic effect is
observed on fibronectin, vitronectin, collagen, elastin,
fibrinogen, proteoglycans, or metalloproteinases.
20. The method of claim 9, wherein said treatment involves
ablation, reduction and/or stabilization of the vessel wall
plaque.
21. The method according to claim 9, wherein said treatment is of
restenosis of occlusive tissue formation induced in the vessel wall
or by vascular injury to the vessel wall.
22. The method of claim 21 wherein said restenosis is selected from
vessel wall negative geometric remodelling, intimal thickening,
increased intraluminal shear stress, dysfunctional or absent
endothelium, periadventitial fibrosis, increased motor tone,
fibrotic contracture, scar formation or combinations thereof.
23. The method of claim 21 wherein said injury is via balloon
angioplasty.
24. The method of claim 21 wherein said injury is stent
deployment.
25. The method of claim 21 wherein said injury is from an
endovascular device.
26. The method of claim 21 wherein said occlusive tissue is foreign
tissue.
27. The method of claim 21 wherein said occlusive tissue is host
tissue.
28. The method of claim 21 wherein said occlusive tissue is from an
injury via invasive or non-invasive surgical manipulation of the
vessel.
29. The method of claim 28 wherein said surgical manipulation is
selected from suturing, vascular access, anastomosis, bypass
procedure, or shunt.
30. The method of claim 9 for treatment of arteriovenous
shunts.
31. The method of any of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12,
13 and 14 further including the step of delivering an activatable
agent into tissue of the vessel wall which continues to act
therapeutically with or without exposure to an energy source.
32. The method of claim 9 wherein said energy source is selected
from light, ultrasound, magnetic force, electromagnetic radiation,
LEDs or lasers in the UV/visible electromagnetic spectrum or near
infrared.
33. The method of claim 9 wherein said energy is an illuminating
step of wavelength between about 350 to about 900 nm on the tissue
of the vascular vessel wall.
34. The method of claim 33 wherein said illuminating step comprises
illuminating a plurality of times, each for a duration and in an
area sufficient to impart a treatment effect within the vascular
vessel wall.
35. A method for restructuring the epithelial or endothelial layers
of skin comprising administering to a patient, either topically or
systemically, a therapeutic amount of a tetrapyrrolic molecule that
coordinates gallium in the central tetrapyrrolic core, and
irradiating said molecule with energy at a wavelength capable of
exciting the molecule to achieve the desired therapeutic
effect.
36. The method of claim 35 wherein epithelial or endothelial cell
layer restructuring results in a positive therapeutic response to
scars, wound healing, psoriasis, chronic inflammatory diseases,
eczema, immune modulated diseases, scleraderma, shingles, wrinkles,
actinic keratosis, carcinomas or sarcoma of the skin or other
tissues, fungual infections, viral or bacterial infections, warts,
arthritis, port wine stains, birth marks, stretch marks, hyper
pigmentation, urticaria, allegenic reactions, chronic proliferative
dermatitis, chronic ulcerative dermatitis, disorders of hair or
hair follicles, disorders of skin pigmentation, acne, cutaneous
infections, skin tumors, seborrheic dermatitis, cutaneous
vasculitis, erythema multiforme or nodosum.
37. A method for stopping or arresting hair growth comprising
administering to a patient, either topically or systemically, a
therapeutic amount of a tetrapyrrolic molecule that coordinates
gallium in the central tetrapyrrolic core and irradiating said
molecule with energy at a wavelength capable of exciting the
molecule to achieve the desired therapeutic effect.
38. A method according to claim 37 wherein said gallium
co-ordinating tetrapyrrole is selected from a mesoporphyrin
derivative, deuteroporphyrin derivative, coproporphyrin derivative,
uroporphyrin derivative, pentacarboxyporphyrin derivative,
hematoporphyrin derivative, protoporphyrin derivative,
hexacarboxyporphyrin derivative, chloroporphyrin e6 derivative,
chloroporphyrin e4 derivative, phylloporphyrin derivative,
rhodoporphyrin derivative, pyrroporphyrin derivative, pheoporphyrin
a5 derivative, phylloerythrin derivative, azaporphyrin derivate,
diazaporphyrin derivative, triazaporphyrin derivative and a
tetraazaporphyrin derivative.
39. A method according to claim 37 wherein said gallium
co-ordinating tetrapyrrole is selected from a mesoporphyrin amide
derivative, deuteroporphyrin amide derivative, coproporphyrin amide
derivative, uroporphyrin amide derivative, pentacarboxyporphyrin
amide derivative, hematoporphyrin amide derivative, protoporphyrin
amide derivative, hexacarboxyporphyrin amide derivative,
chloroporphyrin e6 amide derivative, chloroporphyrin e4 amide
derivative, phylloporphyrin amide derivative, rhodoporphyrin amide
derivative, pyrroporphyrin amide derivative, pheoporphyrin a5 amide
derivative phylloerythrin amide derivative, azaporphyrin amide
derivate, diazaporphyrin amide derivative, triazaporphyrin amide
derivative and a tetraazaporphyrin amide derivative.
40. The method of claim 37 wherein said gallium tetrapyrrole is
formulated topically in a gel containing excipients selected from
benzyl alcohol, oleyl alcohol, hydroxypropyl cellulose, ethanol and
water.
41. The method of claim 40 where the formulation comprises benzyl
alcohol 19.6%, oleyl alcohol 2%, hydroxypropylcellulose 1.5% and
ethanol, 76.9%.
42. A method of using a gallium tetrapyrrole molecule for the
detection or treatment of tissue comprising administering to a
patient a therapeutic amount of a gallium tetrapyrrolic molecule
either locally, systemically, intramuscularly or interperitoneally
and irradiating said molecule with energy at a wavelength capable
of exciting the molecule to achieve the desired therapeutic effect,
whereby said tissue belongs to 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, immune system,
cardiovascular system, urinary system, auditory or olfactory
system.
43. The method of claim 9 wherein the detected disease is
atherosclerotic plaque.
44. The method of claim 22, wherein said stabilization involves
collagen cross linking.
45. A method for the treatment of diseases of the cardiovascular
system comprising administering to a graft tissue a therapeutic
amount of a tetrapyrrolic molecule that coordinates gallium in the
central tetrapyrrolic core and irradiating said graft with energy
at a wavelength capable of exciting the tetrapyrrolic molecule,
such that the graft tissue is made less immunogenic to the
host.
46. The method of claim 9 wherein said administration of porphyrin
or azaporphyrin is prior to, concomitant with, or subsequent to,
administration of adjunctive interventions, diagnostics or
therapies.
47. The method of claim 9 wherein said administration is a single
bolus or plurality of doses administered to the patient.
48. A method of claim 9 wherein said local administration is
selected from perivascular delivery, pericardial delivery into
perivascular sac, periadventital delivery, intravascular delivery
using elution from placed stents impregnated with porphyrin or
azaporphyrin, endovascular delivery using balloon catheters with
micropores or channels, or transmural injection ports pressurized
and enhanced by mechanical and electrical means to facilitate
intramural and transmural penetration of the prophyrin or
azaprophyrin into the target tissue.
49. The method of claim 9 wherein said systemic administration is
selected from parenterally, orally, intravascularly,
subcutaneously, intramuscularly, intradermal or by inhalation.
50. The method of claim 46 wherein said adjunctive interventions
are selected from balloon angioplasty, invasive or non-invasive
surgical procedures, stent deployment, cutting balloons, embolic
protection devices, rotational and directional atherectomy, and
eximer laserectomy.
51. A method according to claim 46 wherein said therapies are
selected from radiation therapy, chemotherapy, anti-platelet
agents, vasodilators, antihypertensives, anti-arrhythmics, statins,
anti-adrenergic agents, angiotensin converting enzyme inhibitors,
sonotherapy, hyperthermia, cryotherapy, magnetic force, viral or
non-viral gene therapy, pharmacogenetic therapy, antibodies,
vaccines, glycoprotein IIb/IIa Inhibitors, growth factors,
peptides, DNA delivery, nucleic acids, anticancer drugs, steroid
hormones, anti-inflammatories, proteins, anti-apoptotic therapies,
anti-sense agents, immunosuppressants, immunotoxins,
immunomodulators, antibody-drug conjugates, anti-proliferative
therapies, drug eluting stents containing pharmacologically active
agents, 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 recombinant RNA and DNA,
cytokines and their antagonists/inhibitors, chemokines and their
antagonists/inhibitors, vitamins, and antioxidants.
52. The method of claim 46 wherein said diagnostics are selected
from intra-vascular ultrasound radiofrequency imaging or
elastography, angiography, radiological contrast agents,
electromechanical mapping, fourier transform infrared
microspectroscopy, optical coherance tomography, high resolution
Magnetic Resonance, electron beam tomography, combined raman
spectroscopy and particle induced x-ray emission, radionucleotide
technology, fluorescence based optical analysis, and thermal
mapping.
53. The method of claim 3 wherein said metallated porphyrin is
formulated by encapsulation in carriers selected from water,
deionized water, phosphate buffered saline, aqueous ethanol,
glucose, amino acids, vegetable oils, liposomes, immunoliposomes,
cyclodextrans, microspheres, nanoparticles, lipoproteins,
micellular systems or combinations thereof.
54. The method of claim 53 wherein said formulation is selected
from slow release, a prodrug, tablets, pills, solutions,
suspensions, emulsions, granules or capsules.
55. The method of claims 1 and 9, wherein the gallium porphyrin is
a compound of the following formula I: 23wherein R.sub.1-R.sub.12
can be the same or different and can be 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.13, where
R.sub.13 is selected from H, a physiologically acceptable counter
ion, a C.sub.1-C.sub.20 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 C.sub.1-C.sub.20 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.1- 6),
(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.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, or a functional
group of less than about 100,000 daltons, 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.21,
(CH.sub.2).sub.nPO(OR.sub.21).su- b.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, 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.2N(R.sub.23)(R.sub.24), SO.sub.2NHNHR.sub.23, or
SO.sub.2R.sub.23, where R.sub.23 and R.sub.24 can be the same or
different and are 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, or an amino acid ester 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.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, 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; and wherein M is Ga.sup.3+,
wherein associated with the co-ordinated gallium is a
physiologically acceptable charge balancing counter ion.
56. The method of claims 1 and 9, wherein the gallium porphyrin is
a compound of the following formula IA: 24wherein R.sub.1 and
R.sub.2 can be the same or different and can be selected from:
CO.sub.2R.sub.3, where R.sub.3 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heteroaryl, heterocyclic, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, or a functional
group of less than about 100,000 daltons; CONH(R.sub.4),
CONHNH(R.sub.4), CON(R.sub.4).sub.2, COR.sub.4, or
CON(R.sub.4)(R.sub.5), where R.sub.4 and R.sub.5 can be the same or
different and are selected from H, NH.sub.2, straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocyclic, aryl, heteroaryl, 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 amide 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 a C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, 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 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, 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; (CH.sub.2).sub.nCONH(R.sub.8),
(CH.sub.2).sub.nCO(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.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), (CHX).sub.nCONH(R.sub.9),
(CHX).sub.nCONHNH(R.sub.9), (CHX).sub.nCON(R.sub.9).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, heteroalkyl,
haloalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an
amino acid, an amino acid salt, 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, 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.1)(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, straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocyclic, an amino acid or a salt, ester or amide thereof
(provided --NH(R.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, or a functional group of less than about
100,000 daltons, 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, heterocycle, aryl, heteroaryl, 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 a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, 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.2N(R.sub.15)(R.sub.- 16), SO.sub.2NHNHR.sub.15, or
SO.sub.2R.sub.15, where R.sub.15 and R.sub.16 can be the same or
different and are 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, 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 wherein M is Ga.sup.3+, wherein associated with the
coordinated gallium is a physiologically acceptable charge
balancing counter ion.
57. A compound of the following formula IA: 25wherein R.sub.1 and
R.sub.2 may be the same or different and are selected from:
CO.sub.2R.sub.3 where R.sub.3 is selected from a physiologically
acceptable counter ion, a straight or branched chain C1-C20 alkyl
or heteroalkyl, aryl or heteroaryl, a mono, di-, or
polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue,
or a functional group of less than about 100,000 daltons;
CONH(R.sub.4), CONHNH(R.sub.4), CON(R.sub.4).sub.2, COR.sub.4, or
CON(R.sub.4)(R.sub.5), where R.sub.4 and R.sub.5 are selected from
H, straight or branched chain C1-C20 alkyl or heteroalkyl, aryl or
heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-,
or polyhydroxyaryl residue; a mono, di-, or polyetheralkyl residue,
or a mono, di-, or polyetheraryl residue, an amino acid residue, an
amino acid ester residue, an amino acid amide residue, or a
functional group of less than about 100,000 daltons, with the
proviso that R.sub.4 and R.sub.5 are not pentetic acid (DTPA),
polyfunctional carboxyl compounds or cyclen functional groups that
are capable of binding metal ions with atomic numbers of 20-32,
37-39, 42-51 or 57-83; (CH.sub.2).sub.nOH or
(CH.sub.2).sub.nOR.sub.6 where R.sub.6 is alkyl or heteroalkyl,
aryl or 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 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
H, a physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl or heteroalkyl, an aryl or heteroaryl, a mono,
di-, or polyhydroxyalkyl residue, or 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;
(CH.sub.2).sub.nCONH(R.sub.- 8),
(CH.sub.2).sub.nCON(R.sub.8).sub.2,
(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,
or (CX.sub.2).sub.nCON(R.sub.8)(R.sub.9) where X is a halogen,
R.sub.8 and R.sub.9 can be the same or different and are selected
from H, straight or branched chain C1-C20 alkyl or heteroalkyl,
aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a
mono, di-, or polyhydroxyaryl residue, a mono, di-, or
polyetheralkyl residue, or a mono, di-, or polyetheraryl residue,
or a functional group of less than about 100,000 daltons, and n is
an integer between 1 and 4; (CH.sub.2).sub.nNH(R.sub.10- ),
(CH.sub.2).sub.nN(R.sub.10).sub.2, or
(CH.sub.2).sub.nN(R.sub.10)(R.sub- .11), where R.sub.10 and
R.sub.11 can be the same or different and are selected from H,
straight or branched chain C1-C20 alkyl or heteroalkyl, a aryl or
heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-,
or polyhydroxyaryl residue, a mono, di-, or polyetheralkyl residue,
or 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.12) where R.sub.12 is selected from H, straight or
branched chain C1-C20 alkyl or heteroalkyl, aryl or heteroaryl, a
mono, di-, or polyhydroxyalkyl residue, a mono, di-, or
polyhydroxyaryl residue, a mono, di-, or polyetheralkyl residue, or
a mono, di-, or polyetheraryl residue, or a functional group of
less than about 100,000 daltons; with the proviso that R.sub.12
does not include a carboxyl group; (CH.sub.2).sub.nS(R.sub.13)
where R.sub.13 is selected from H, straight or branched chain
C1-C20 alkyl or heteroalkyl, an aryl or heteroaryl, a mono, di-, or
polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue;
a mono, di-, or polyetheralkyl residue, or 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.nOPO.sub.2OR- .sub.14,
(CH.sub.2).sub.nPO(OR.sub.14).sub.2, (CH.sub.2).sub.nPO.sub.2R.su-
b.14, or (CH.sub.2).sub.nPOR.sub.14 where R.sub.14 is selected from
H, a physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl or heteroalkyl, aryl or heteroaryl, a mono, di-,
or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl
residue; a mono, di-, or polyetheralkyl residue, or 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.15 or (CH.sub.2).sub.nNHNHCOR.sub.15
where R.sub.15 is a straight or branched chain C1-C20 alkyl or
heteroalkyl, aryl or heteroaryl, or a functional group of less than
about 100,000 daltons, and n is an integer between 0 and 4;
SO.sub.3R.sub.16, SO.sub.2NH R.sub.16, SO.sub.2N(R.sub.16).sub.2,
SO.sub.2N(R.sub.16)(R.sub.17), SO.sub.2NHNHR.sub.16, or
SO.sub.2R.sub.16, where R.sub.16 and R.sub.17 can be the same or
different and are selected from H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, aryl or heteroaryl, a mono, di-, or
polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue;
a mono, di-, or polyetheralkyl residue, or 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; and wherein M
is Ga.sup.3+, wherein associated with the coordinated gallium is a
physiologically acceptable charge balancing counter ion; with the
proviso that R.sub.1 and R.sub.2 are not both CO.sub.2H or both
CO.sub.2CH.sub.3.
58. A compound of the following formula: 26wherein R.sub.1 and
R.sub.2 may be the same or different and are selected from:
CO.sub.2R.sub.3 where R.sub.3 is a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl or
heteroalkyl, aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl
residue, a mono, di-, or polyhydroxyaryl residue, or a functional
group of less than about 100,000 daltons; CONH(R.sub.4),
CONHNH(R.sub.4), CON(R.sub.4).sub.2, COR.sub.4, or
CON(R.sub.4)(R.sub.5), where R.sub.4 and R.sub.5 can be the same or
different and are selected from H, straight or branched chain
C1-C20 alkyl or heteroalkyl, aryl or heteroaryl, a mono, di-, or
polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue;
a mono, di-, or polyetheralkyl residue, or a mono, di-, or
polyetheraryl residue, an amino acid residue, an amino acid ester
residue, an amino acid amide 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 alkyl or heteroalkyl,
aryl or 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 0 and 4;
(CH.sub.2).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 H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl or
heteroalkyl, an aryl or heteroaryl, a mono, di-, or
polyhydroxyalkyl residue, or 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; (CH.sub.2).sub.nCONH(R.sub.-
8), (CH.sub.2).sub.nCON(R.sub.8).sub.2,
(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,
or (CX.sub.2).sub.nCON(R.sub.8)(R.sub.9), where X is a halogen and
where R.sub.8 and R.sub.9 can be the same or different and are
selected from H, straight or branched chain C1-C20 alkyl or
heteroalkyl, aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl
residue, a mono, di-, or polyhydroxyaryl residue; a mono, di-, or
polyetheralkyl residue, or a mono, di-, or polyetheraryl residue,
or a functional group of less than about 100,000 daltons, and n is
an integer between 1 and 4; with the proviso that when n=2, R.sub.8
or R.sub.9 is not pentetic acid (DTPA), a polyfunctional carboxyl
compound or a cyclen functional group that is capable of binding
metal ions with atomic numbers of 20-32, 37-39, 42-51 or 57-83;
(CH.sub.2).sub.nNH(R.sub.10), (CH.sub.2).sub.nN(R.sub.10).sub.2- ,
or (CH.sub.2).sub.nN(R.sub.10)(R.sub.11), where R.sub.10 and
R.sub.11 can be the same or different and are selected from H,
straight or branched chain C1-C20 alkyl or heteroalkyl, a aryl or
heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-,
or polyhydroxyaryl residue, a mono, di-, or polyetheralkyl residue,
or 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.nNH(R.sub.10- ),
(CH.sub.2).sub.nN(R.sub.10).sub.2, or
(CH.sub.2).sub.nN(R.sub.10)(R.sub- .11), where R.sub.10 and
R.sub.11 can be the same or different and are selected from H,
straight or branched chain C1-C20 alkyl or heteroalkyl, a aryl or
heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-,
or polyhydroxyaryl residue, a mono, di-, or polyetheralkyl residue,
or 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.12) where R.sub.12 is selected from H, straight or
branched chain C1-C20 alkyl or heteroalkyl, an aryl or heteroaryl,
a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or
polyhydroxyaryl residue, a mono, di-, or polyetheralkyl residue, or
a mono, di-, or polyetheraryl residue, or a functional group of
less than about 100,000 daltons; (CH.sub.2).sub.nS(R.sub.13) where
R.sub.13 is selected from H, straight or branched chain C1-C20
alkyl or heteroalkyl, an aryl or heteroaryl, a mono, di-, or
polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue,
a mono, di-, or polyetheralkyl residue, or 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.nOPO.sub.2OR- .sub.14,
(CH.sub.2).sub.nPO(OR.sub.14).sub.2, (CH.sub.2).sub.nPO.sub.2R.su-
b.14, or (CH.sub.2).sub.nPOR.sub.14 where R.sub.14 is selected from
H, a physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl or heteroalkyl, an aryl or heteroaryl, a mono,
di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl
residue; a mono, di-, or polyetheralkyl residue, or 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.15 where R.sub.15 is a straight or
branched chain C1-C20 alkyl or heteroalkyl, aryl or heteroaryl, or
a functional group of less than about 100,000 daltons, and n is an
integer between 0 and 4; SO.sub.3R.sub.16, SO.sub.2NHR.sub.16,
SO.sub.2N(R.sub.16).sub.2, SO.sub.2N(R.sub.16)(R.sub.- 17),
SO.sub.2R.sub.16, or SO.sub.2NHNHR.sub.16 where R.sub.16 and
R.sub.17 can be the same or different and are selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl
or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono,
di-, or polyhydroxyaryl residue; a mono, di-, or polyetheralkyl
residue, or 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; and wherein M is Ga.sup.3+, wherein associated with the
coordinated gallium is a physiologically acceptable charge
balancing counter ion; with the proviso that R.sub.1 and R.sub.2
are not both (CH.sub.2).sub.2CO.sub.2H or both
(CH.sub.2).sub.2CO.sub.2CH.sub.3.
59. The method of claims 1 and 9 wherein the gallium porphyrin is a
compound of the following formula 1B: 27wherein R.sub.1 and R.sub.2
can be the same or different and are selected from H, CN, CO-alkyl,
haloalkyl, heteroalkyl, hydroxyhaloalkyl, ether haloalkyl, ester
haloalkyl, a C1-C20 alkyl, or a halogen; R.sub.3 and R.sub.4 can be
the same or different and are selected from: 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, heterocyclic, aryl, 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; CONH(R.sub.6),
CONHNH(R.sub.6), CON(R.sub.6).sub.2, or CON(R.sub.6)(R.sub.7),
where R.sub.6 and R.sub.7 can be the same or different and are
selected from H, a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl,
heteroaryl, 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; (CH.sub.2).sub.nOH, or
(CH.sub.2).sub.nOR.sub.8, where R.sub.8 is selected from a straight
or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocyclic, 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 0 and 4; (CH.sub.2).sub.nCO.sub.2R.sub.9,
(CHX.sub.2).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, heterocyclic, 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; (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.nCON(R.sub.10)(R.sub.11),
(CX.sub.2).sub.nCONH(R.sub.10), (CX.sub.2).sub.nCONHNH(R.sub.10),
(CX.sub.2).sub.nCON(R.sub.10).sub.2,
(CX.sub.2).sub.nCON(R.sub.10)(R.sub.11), (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, straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an
amino acid or a salt, ester, or amide thereof (provided
NH(R.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, or a functional group of less than about
100,000 daltons, and n is an integer between 0 and 4; S(R.sub.12),
(CH.sub.2).sub.nS(R.sub.12), (CH.sub.2).sub.nNH(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.sub.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, straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl,
heteroaryl, an amino acid or a salt, ester or amide thereof
(provided --NH(R.sub.12) 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, or a functional group of less than about
100,000 daltons, or where R.sub.12, R.sub.13 and R.sub.14 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.15,
(CH.sub.2).sub.nPO(OR.sub.15).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.15, or (CH.sub.2).sub.nPOR.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, heterocycle, aryl, heteroaryl, 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.16 or (CH.sub.2).sub.nNHNHCOR.sub.16,
where R.sub.16 is a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.17,
SO.sub.2NHR.sub.17, SO.sub.2N(R.sub.17).sub.2,
SO.sub.2N(R.sub.17)(R.sub.18), SO.sub.2NHNHR.sub.17, or
SO.sub.2R.sub.17, where R.sub.17 and R.sub.18 can be the same or
different and are 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, 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; All of the above which may bear one or more substituents
selected from hydroxy groups, alkyl groups, carboxyl groups and
their esters and amides, and sulfonic acid groups and their esters
and amides; and wherein M is Ga.sup.3+, wherein associated with the
coordinated gallium is a physiologically acceptable charge
balancing counter ion.
60. The method of claims 1 and 9 wherein the gallium porphyrin is a
compound of the following formula: 28wherein R.sub.1 and R.sub.2
can be the same or different and are selected from H, CN, CO-alkyl,
haloalkyl, heteroalkyl, hydroxyhaloalkyl, ether haloalkyl, ester
haloalkyl, a C1-C20 alkyl, or a halogen; R.sub.3 and R.sub.4 can be
the same or different and are selected from: 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, heterocyclic, aryl, 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; CONH(R.sub.6),
CONHNH(R.sub.6), CON(R.sub.6).sub.2, or CON(R.sub.6)(R.sub.7),
where R.sub.6 and R.sub.7 can be the same or different and are
selected from H, a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl,
heteroaryl, 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; (CH.sub.2).sub.nOH, or
(CH.sub.2).sub.nOR.sub.8, where R.sub.8 is selected from a straight
or branched chain C.sub.1-C.sub.20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocyclic, 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 0 and 4; (CH.sub.2).sub.nCO.sub.2R.sub.9,
(CHX.sub.2).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, heterocyclic, 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; (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.nCON(R.sub.1-
0)(R.sub.11), (CX.sub.2).sub.nCONH(R.sub.10),
(CX.sub.2).sub.nCONHNH(R.sub- .10),
(CX.sub.2).sub.nCON(R.sub.10).sub.2,
(CX.sub.2).sub.nCON(R.sub.10)(R- .sub.11),
(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, straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an
amino acid or a salt, ester, or amide thereof (provided
NH(R.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, or a functional group of less than about
100,000 daltons, and n is an integer between 0 and 4; S(R.sub.12),
(CH.sub.2).sub.nS(R.sub.12), (CH.sub.2).sub.nNH(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, straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl,
heteroaryl, an amino acid or a salt, ester or amide thereof
(provided --NH(R.sub.12) 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, or a functional group of less than about
100,000 daltons, where R.sub.12, R.sub.13 and R.sub.14 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.2O- R.sub.15,
(CH.sub.2).sub.nPO(OR.sub.15).sub.2, (CH.sub.2).sub.nPO.sub.2R.s-
ub.15, or (CH.sub.2).sub.nPOR.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, heterocycle, aryl, heteroaryl, 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.16 or (CH.sub.2).sub.nNHNHCOR.sub.16,
where R.sub.16 is a straight or branched chain C.sub.1-C.sub.20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.17,
SO.sub.2NHR.sub.17, SO.sub.2N(R.sub.17).sub.2,
SO.sub.2N(R.sub.17)(R.sub.18), SO.sub.2NHNHR.sub.17, or
SO.sub.2R.sub.17, where R.sub.17 and R.sub.18 can be the same or
different and are 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, 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; All of the above 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 wherein M is Ga.sup.3+, wherein associated with the
coordinated gallium is a physiologically acceptable charge
balancing counter ion.
61. A compound of the following formula: 29wherein R.sub.1 and
R.sub.2 can be the same or different and are selected from H,
methyl, CN, CO-alkyl, haloalkyl, heteroalkyl, hydroxyhaloalkyl,
ether haloalkyl, ester haloalkyl, a C1-C20 alkyl, or a halogen;
R.sub.3 and R.sub.4 may be the same or different and are selected
from: CO.sub.2R.sub.5 where R.sub.5 is H, a physiologically
acceptable counter ion, a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl,
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; CONH(R.sub.6),
CONHNH(R.sub.6), CON(R.sub.6).sub.2, or CON(R.sub.6)(R.sub.7),
where R.sub.6 and R.sub.7 can be the same or different and are
selected from H, a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl,
heteroaryl, 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; (CH.sub.2).sub.nOH, or
(CH.sub.2).sub.nOR.sub.8, where R.sub.8 is selected from a straight
or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocyclic, 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 0 and 4; (CH.sub.2).sub.nCO.sub.2R.sub.9,
(CHX.sub.2).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, heterocyclic, 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; (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.nCON(R.sub.10)(R.sub.11),
(CX.sub.2).sub.nCONH(R.sub.10), (CX.sub.2).sub.nCONHNH(R.sub.10),
(CX.sub.2).sub.nCON(R.sub.10).sub.2,
(CX.sub.2).sub.nCON(R.sub.10)(R.sub.11), (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, straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an
amino acid or a salt, ester, or amide thereof (provided
NH(R.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, or a functional group of less than about
100,000 daltons, and n is an integer between 0 and 4; S(R.sub.12),
(CH.sub.2).sub.nS(R.sub.12), (CH.sub.2).sub.nNH(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.sub.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, straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl,
heteroaryl, an amino acid or a salt, ester or amide thereof
(provided --NH(R.sub.12) 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, or a functional group of less than about
100,000 daltons, or where R.sub.12, R.sub.13 and R.sub.14 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.15,
(CH.sub.2).sub.nPO(OR.sub.15).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.15, or (CH.sub.2).sub.nPOR.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, heterocycle, aryl, heteroaryl, 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.16 or (CH.sub.2).sub.nNHNHCOR.sub.16,
where R.sub.16 is a a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.17,
SO.sub.2NHR.sub.17, SO.sub.2N(R.sub.17).sub.2,
SO.sub.2N(R.sub.17)(R.sub.18), SO.sub.2NHNHR.sub.17, or
SO.sub.2R.sub.17, where R.sub.17 and R.sub.18 can be the same or
different and are 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, 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; All of the above 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 wherein M is Ga.sup.3+, wherein associated with the
coordinated gallium is a physiologically acceptable charge
balancing counter ion; with the proviso that when R.sub.1 and
R.sub.2=H or Et and n=2, R.sub.9 cannot be H or CH.sub.3, and when
R.sub.1 and R.sub.2=C1-C7 alkyl and n=2, one of R.sub.10 or
R.sub.11 cannot be a functional group that possesses pentetic acid
(DTPA), polyfunctional carboxyl compounds or cyclen functional
groups that are capable of binding metal ions with atomic numbers
of 20-32, 37-39, 42-51 or 57-83;
62. A compound of the following formula IB: 30wherein R.sub.1 and
R.sub.2 may be the same or different and are selected from H,
methyl, CN, CO-alkyl, haloalkyl, heteroalkyl, hydroxyhaloalkyl,
ether haloalkyl, ester haloalkyl, a C1-C20 alkyl, or a halogen;
R.sub.3 and R.sub.4 may be the same or different and are selected
from: CO.sub.2R.sub.5 where R.sub.5 is H, a physiologically
acceptable counter ion, a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl,
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; CONH(R.sub.6),
CONHNH(R.sub.6), CON(R.sub.6).sub.2, or CON(R.sub.6)(R.sub.7),
where R.sub.6 and R.sub.7 can be the same or different and are
selected from H, a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl,
heteroaryl, 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; (CH.sub.2).sub.nOH, or
(CH.sub.2).sub.nOR.sub.8, where R.sub.8 is selected from a straight
or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocyclic, 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 0 and 4; (CH.sub.2).sub.nCO.sub.2R.sub.9,
(CHX.sub.2).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, heterocyclic, 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; (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.nCON(R.sub.10)(R.sub.11),
(CX.sub.2).sub.nCONH(R.sub.10), (CX.sub.2).sub.nCONHNH(R.sub.10),
(CX.sub.2).sub.nCON(R.sub.10).sub.2,
(CX.sub.2).sub.nCON(R.sub.10)(R.sub.11), (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, straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an
amino acid or a salt, ester, or amide thereof (provided
NH(R.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, or a functional group of less than about
100,000 daltons, and n is an integer between 0 and 4; S(R.sub.12),
(CH.sub.2).sub.nS(R.sub.12), (CH.sub.2).sub.nNH(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.sub.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, straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl,
heteroaryl, an amino acid or a salt, ester or amide thereof
(provided --NH(R.sub.12) 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, or a functional group of less than about
100,000 daltons, or where R.sub.12, R.sub.13 and R.sub.14 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.15,
(CH.sub.2).sub.nPO(OR.sub.15).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.15, or (CH.sub.2).sub.nPOR.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, heterocycle, aryl, heteroaryl, 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.16 or (CH.sub.2).sub.nNHNHCOR.sub.16,
where R.sub.16 is a a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.17,
SO.sub.2NHR.sub.17, SO.sub.2N(R.sub.17).sub.2,
SO.sub.2N(R.sub.17)(R.sub.18), SO.sub.2NHNHR.sub.17, or
SO.sub.2R.sub.17, where R.sub.17 and R.sub.18 can be the same or
different and are 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, 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;
All of the above 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 wherein M is a metal cation selected from Ga.sup.3+, Pt.sup.2+,
Pd.sup.2+, Sn.sup.4+, In.sup.3+, Ge.sup.3+, Si.sup.4+, Al.sup.3+,
Zn.sup.2+, and Y.sup.3+, with the proviso that the compound of
formula IB cannot be zinc deuteroporphyrin dimethylester, zinc
deuteroporphyrin, zinc
[3,7,12,17-tetramethyl-2,18-dipropanolato(2-)- ]porphyrin, zinc
[dimethyl 8-bromo-3,7,12,17-tetramethyl-2-18-dipropanoato-
(2-)]porphyrin, zinc
[2-(2-hydroxyethyl)-18-methyl-3,7,12,17-tetramethyl-2-
,18-dipropanoato(2-)]porphyrin, zincate(1-)
[2-[3,7,-dimethyl-9-(2,6,6-tri-
methyl-1-cyclohexen-1-yl-0-2,4,6,8-nonatetraenyl]3,7,12,17-tetramethyl-2-1-
8-dipropanoato(3-)]porphyrin, Indium deuteroporphyrin dimethyl
ester, palladium deuteroprophyrin diethylester, tin
deuteroporphyrin, tin deuteroprophyrin dimethyl ester,
zinc[[methyl18-[3-[[1-9-1H-imidazol-4-yl-
methyl0-2-methoxy-2-oxoethyl]amino]-3-oxopropyl]-3,7,12,17-2,18-propanoato-
(2-)]porphyrin, Indium 7,12-diiododeuteroporphyrin dimethyl ester,
Tin 7,12-diiododeuteroporphyrin, Zinc 7,12-dibromodeuteroporphyrin
dimethyl ester, Zinc 7-bromodeuteroporphyrin dimethyl ester, Zinc
7-iododeuteroporphyrin dimethyl ester, Zinc
7,12-diiododeuteroporphyrin dimethyl ester, Zinc
7,12-dibromodeuteroporphyrin, palladium deuteroprophyrin, platinum
[2,8,12,17-tetramethyl-3,7-dipropyl-porphyrina- to(2-), platinum
deuteroprophyrin dimethyl ester, Zinc 2,4-diiododeuteroporphyrin
dimethyl ester, or Zinc 7,12-diiododeuteroporphyrin dioctyl
ester.
63. Compounds according to claim 62 wherein M is Ga.sup.3+, where
associated with the coordinated gallium is a physiologically
acceptable charge balancing counter ion; with the proviso that when
R.sub.1 and R.sub.2=H, R.sub.5 cannot be CH.sub.3, and when R.sub.1
and R.sub.2=C.sub.1-C.sub.7 alkyl and n=2, R.sub.10 or R.sub.11
cannot be a functional group that possesses pentetic acid (DTPA),
polyfunctional carboxyl compounds or cyclen functional groups that
are capable of binding metal ions with atomic numbers of 20-32,
37-39, 42-51 or 57-83.
64. The method of claims 2 and 9 wherein said gallium azaporphyrin
is a compound of the following formula II: 31wherein R.sub.1 to
R.sub.11 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 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)0-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.12, where
R.sub.12 is selected from H, a physiologically acceptable counter
ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, 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.13,
where R.sub.13 is selected from alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocyclic, 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.14, (CX.sub.2).sub.nCO.sub.2R.sub.14,
or (CHX).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, heterocyclic, 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.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.nCONHNH(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, (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), or (CHX).sub.nCOR.sub.15, where
X is a halogen and R.sub.15 and R.sub.16 can be the same or
different and are selected from H, 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, 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.17),
(CH.sub.2).sub.nS(R.sub.17), (CH.sub.2).sub.nNH(R.sub.17),
(CH.sub.2).sub.nNHNH(R.sub.17), (CH.sub.2).sub.nN(R.sub.17).sub.2,
(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 (provided --NH(R.sub.17) 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, or a functional
group of less than about 100,000 daltons, where R.sub.17, R.sub.18
and R.sub.19 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.20,
(CH.sub.2).sub.nPO(OR.sub.20).su- b.2,
(CH.sub.2).sub.nPO.sub.2R.sub.20, or (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, heterocycle, aryl, heteroaryl, 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.21 or (CH.sub.2).sub.nNHNHCOR.sub.21,
where R.sub.21 is a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.22,
SO.sub.2NHR.sub.22, SO.sub.2NHNHR.sub.22,
SO.sub.2N(R.sub.22).sub.2, SO.sub.2N(R.sub.22)(R.sub.23), or
SO.sub.2R.sub.22, where R.sub.22 and R.sub.23 can be the same or
different and are 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, 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.22 can also be an amino
acid, 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; 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.8-R.sub.9, R.sub.9-R.sub.10,
R.sub.11-R.sub.12 and R.sub.12-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; and wherein M is Ga.sup.3+
where associated with the metal ion is a physiologically acceptable
charge balancing counter ion.
65. The method of claims 2 and 9 wherein the gallium azaporphyrin
is a compound of the following formula: 32wherein R.sub.1-R.sub.6
can be the same or different and are selected from: H.sub.1 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 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.7, where
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; (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.8,
where R.sub.8 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.9, (CHX).sub.nCO.sub.2R.su- b.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; 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,
(CH.sub.2).sub.nCON(R.sub.10)(R.sub.11),
(CX.sub.2).sub.nCONH(R.sub.10), (CX.sub.2).sub.nCONHNH(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, (CHX).sub.nCONH(R.sub.10),
(CHX).sub.nCONHNH(R.sub.10), (CHX).sub.nCON(R.sub.10).sub.2,
(CHX).sub.nCON(R.sub.10)(R.sub.11), or (CHX).sub.nCOR.sub.10, where
X is a halogen, and R.sub.10 and R.sub.11 can be the same or
different and are selected from H, 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, an amino acid, 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.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.sub.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 (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, or a functional
group of less than about 100,000 daltons, or where R.sub.12,
R.sub.13 and R.sub.14 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.15,
(CH.sub.2).sub.nPO(OR.sub.15).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.15, or (CH.sub.2).sub.nPOR.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, heterocycle, aryl, heteroaryl, 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.16 or (CH.sub.2).sub.nNHNHCOR.sub.16,
where R.sub.16 is a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.17,
SO.sub.2NHR.sub.17, SO.sub.2NHNHR.sub.17,
SO.sub.2N(R.sub.17).sub.2, SO.sub.2N(R.sub.17)(R.sub.18), or
SO.sub.2R.sub.17, where R.sub.17 and R.sub.18 can be the same or
different and are selected from H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, 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.17 can also be an amino
acid, 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; R.sub.1-R.sub.2, 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; and
wherein M is Ga.sup.3+ where associated with the metal ion is the
appropriate number of physiologically acceptable charge balancing
counter ions.
66. A metalloazaporphyrin of the following formula: 33wherein
R.sub.1-R.sub.6 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 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.7, where
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; (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.8,
where R.sub.8 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.9, (CHX).sub.nCO.sub.2R.su- b.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; 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,
(CH.sub.2).sub.nCON(R.sub.10)(R.sub.11),
(CX.sub.2).sub.nCONH(R.sub.10), (CX.sub.2).sub.nCONHNH(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, (CHX).sub.nCONH(R.sub.10),
(CHX).sub.nCONHNH(R.sub.10), (CHX).sub.nCON(R.sub.10).sub.2,
(CHX).sub.nCON(R.sub.10)(R.sub.11), or (CHX).sub.nCOR.sub.10, where
X is a halogen, and R.sub.10 and R.sub.11 can be the same or
different and are selected from H, 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, an amino acid, 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.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.sub.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 (provided --NH(R.sub.12) 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, or a functional
group of less than about 100,000 daltons, or where R.sub.12,
R.sub.13 and R.sub.14 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.15,
(CH.sub.2).sub.nPO(OR.sub.15).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.15, or (CH.sub.2).sub.nPOR.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, heterocycle, aryl, heteroaryl, 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.16 or (CH.sub.2).sub.nNHNHCOR.sub.16,
where R.sub.16 is a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.17,
SO.sub.2NHR.sub.17, SO.sub.2NHNHR.sub.17,
SO.sub.2N(R.sub.17).sub.2, SO.sub.2N(R.sub.17)(R.sub.18) or
SO.sub.2R.sub.17, where R.sub.17 and R.sub.18 are the same or
different and are selected from H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, 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.17 can also be an amino
acid, 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; R.sub.1-R.sub.2, 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; M is
Ga.sup.3+ wherein associated with the metal ion is the appropriate
number of physiologically acceptable charge balancing counter
ions.
67. The method of claims 2 and 9 wherein the gallium azaporphyin is
a compound of the following formula IIA: 34wherein R.sub.1-R.sub.6
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 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.7, where
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; (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.8,
where R.sub.8 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.9, (CHX).sub.nCO.sub.2R.su- b.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; 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,
(CH.sub.2).sub.nCON(R.sub.10)(R.sub.11),
(CX.sub.2).sub.nCONH(R.sub.10), (CX.sub.2).sub.nCONHNH(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, (CHX).sub.nCONH(R.sub.10),
(CHX).sub.nCONHNH(R.sub.10), (CHX).sub.nCON(R.sub.10).sub.2,
(CHX).sub.nCON(R.sub.10)(R.sub.11), or (CHX).sub.nCOR.sub.10, where
X is a halogen, and R.sub.10 and R.sub.11 can be the same or
different and are selected from H, 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, an amino acid, 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.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.sub.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 (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, or a functional
group of less than about 100,000 daltons, where R.sub.12, R.sub.13
and R.sub.14 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.15,
(CH.sub.2).sub.nPO(OR.sub.15).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.15, or (CH.sub.2).sub.nPOR.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, heterocycle, aryl, heteroaryl, 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.16 or (CH.sub.2).sub.nNHNHCOR.sub.16,
where R.sub.16 is a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.17,
SO.sub.2NHR.sub.17, SO.sub.2NHNHR.sub.17,
SO.sub.2N(R.sub.17).sub.2, SO.sub.2N(R.sub.17)(R.sub.18) or
SO.sub.2R.sub.17, where R.sub.17 and R.sub.18 can be the same or
different and are selected from H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, 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.17 can also be an amino
acid, an amino acid salt, an amino acid ester residue, or an amino
acid amide; 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 R.sub.1-R.sub.2, 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; and
wherein M is Ga.sup.3+ where associated with the metal ion is the
appropriate number of physiologically acceptable charge balancing
counter ions.
68. A compound of the following formula II: 35wherein R.sub.1 to
R.sub.11 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,
CH.dbd.CHCH.sub.2N.sup.+(CH.sub.3).su- b.3A,
CH.dbd.N(alkyl).sub.2A, 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, (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.12 where R.sub.12 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocyclic, 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.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; (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,
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.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.nCONHNH(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, (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), or (CHX).sub.nCOR.sub.15, where
X is a halogen, and R.sub.15 and R.sub.16 can be the same or
different and are selected from H, 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, an amino acid, 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.17), (CH.sub.2).sub.nS(R.sub.17),
(CH.sub.2).sub.nNH(R.sub.17), (CH.sub.2).sub.nNHNH(R.sub.17),
(CH.sub.2).sub.nN(R.sub.17).sub.2,
(CH.sub.2).sub.nN(R.sub.17)(R.sub.18), or
(CH.sub.2).sub.nN(R.sub.17)(R.sub.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 (provided --NH(R.sub.17) 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, or a functional
group of less than about 100,000 daltons, where R.sub.17, R.sub.18
and R.sub.19 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.20,
(CH.sub.2).sub.nPO(OR.sub.20).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.20, or (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, heterocycle, aryl, heteroaryl, 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.21 or (CH.sub.2).sub.nNHNHCOR.sub.21,
where R.sub.21 is a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.22,
SO.sub.2NHR.sub.22, SO.sub.2NHNHR.sub.22,
SO.sub.2N(R.sub.22).sub.2, SO.sub.2N(R.sub.22)(R.sub.23), and
SO.sub.2R.sub.22 where R.sub.22 and R.sub.23 can be the same or
different and are selected from H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, 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.22 can also be an amino
acid, 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; All of 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 wherein M is a metal selected from Ga.sup.3+
Pt.sup.2+, Pd.sup.2+, Sn.sup.4+, In.sup.3+, Ge.sup.3+, Si.sup.4+,
Al.sup.3+, and Mg.sup.2+, wherein and where necessary associated
with the metal ion is the appropriate number of physiologically
acceptable charge balancing counter ions; where R.sub.1-R.sub.11
may possess the atoms necessary to form ring systems, either
aromatic or not, which themselves may possess heteroatoms that may
be charged or neutral; with the proviso that formula II excludes
the following compounds: R.sub.1, R.sub.4, R.sub.6, R.sub.9 are
ethyl, R.sub.2, R.sub.3, R.sub.7, R.sub.10 are Me, R.sub.5,
R.sub.8, R.sub.11 are H, and M=Mg; R.sub.1, R.sub.4, R.sub.7,
R.sub.9 are ethyl, R.sub.2, R.sub.3, R.sub.6, R.sub.10 are Me,
R.sub.5, R.sub.8, R.sub.11 are H, and M=Zn; R.sub.1, R.sub.4,
R.sub.6, R.sub.10 are ethyl, R.sub.2, R.sub.3, R.sub.7, R.sub.9 are
Me, R.sub.5, R.sub.8, R.sub.11 are H, and M=Zn; R.sub.1, R.sub.4,
R.sub.7, R.sub.9 are Me, R.sub.2, R.sub.3, R.sub.6, R.sub.10 are
Et, R.sub.5, R.sub.8, R.sub.11 are H, and M=Zn; R.sub.1, R.sub.4,
R.sub.6, R.sub.10 are Me, R.sub.2, R.sub.3, R.sub.7, R.sub.9 are
Et, R.sub.5, R.sub.8, R.sub.11 are H, and M=Zn; R.sub.1, R.sub.3,
R.sub.6, R.sub.10 are Me, R.sub.2, R.sub.4 are vinyl, R.sub.7,
R.sub.9 are CH.sub.2CH.sub.2CO.sub.2Me, R.sub.5, R.sub.8, R.sub.11
are H, and M=Zn; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.6,
R.sub.7, R.sub.9, R.sub.100 are Me, R.sub.5, R.sub.8, R.sub.11 are
H, and M=Zn; R.sub.1, R.sub.3, R.sub.7, R.sub.10 are ethyl,
R.sub.2, R.sub.4, R.sub.6, R.sub.9 are Me, R.sub.5, R.sub.8,
R.sub.1 are H, and M=Zn; R.sub.1, R.sub.3, R.sub.6, R.sub.10 are
Me, R.sub.2, R.sub.4 are Et, R.sub.7, R.sub.9 are
CH.sub.2CH.sub.2CO.sub.2Me, R.sub.5, R.sub.8, R.sub.11 are H, and
M=Zn or Pd; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.6, R.sub.7,
R.sub.9, R.sub.10 are Me, R.sub.5, R.sub.8, R.sub.11 are H, and
M=Pd; and R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8 R.sub.9, R.sub.10, R.sub.11 are H and M=Zn.
69. A compound of the following formula: 36wherein R.sub.1-R.sub.6
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 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.7, where
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; (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.8,
where R.sub.8 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.9, (CHX).sub.nCO.sub.2R.su- b.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; 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,
(CH.sub.2).sub.nCON(R.sub.10)(R.sub.11),
(CX.sub.2).sub.nCONH(R.sub.10), (CX.sub.2).sub.nCONHNH(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, (CHX).sub.nCONH(R.sub.10),
(CHX).sub.nCONHNH(R.sub.10), (CHX).sub.nCON(R.sub.10).sub.2,
(CHX).sub.nCON(R.sub.10)(R.sub.11), or (CHX).sub.nCOR.sub.10, where
X is a halogen, and R.sub.10 and R.sub.11 can be the same or
different and are selected from H, 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, an amino acid, 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.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.sub.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 (provided --NH(R.sub.12) 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, or a functional
group of less than about 100,000 daltons, or where R.sub.12,
R.sub.13 and R.sub.14 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.15,
(CH.sub.2).sub.nPO(OR.sub.15).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.15, or (CH.sub.2).sub.nPOR.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, heterocycle, aryl, heteroaryl, 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.16 or (CH.sub.2).sub.nNHNHCOR.sub.16,
where R.sub.16 is a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.17,
SO.sub.2NHR.sub.17, SO.sub.2NHNHR.sub.17,
SO.sub.2N(R.sub.17).sub.2, SO.sub.2N(R.sub.17)(R.sub.18), or
SO.sub.2R.sub.17, where R.sub.17 and R.sub.18 can be the same or
different and are selected from H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, 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.17 can also be an amino
acid, 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 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; and
wherein M is 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+, Y.sup.3+, Zn.sup.2+,
and Mg.sup.2+ wherein associated with the metal ion is the
appropriate number of physiologically acceptable charge balancing
counter ions; with the proviso that when R.sub.1 and R.sub.3 are
Me, R.sub.2 and R.sub.4 are vinyl, and R.sub.5 and R.sub.6 are
(CH.sub.2).sub.2CO.sub.2Me- , M cannot be Zn; and when R.sub.1 and
R.sub.3 are Me, R.sub.2 and R.sub.4 are Et, and R.sub.5 and R.sub.6
are (CH.sub.2).sub.2CO.sub.2Me, M cannot be Zn.sup.2+, Pd.sup.2+,
or Mn.sup.3+.
70. A compound of the following formula IIA: 37wherein
R.sub.1-R.sub.6 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 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.7, where
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; (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.8,
where R.sub.8 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.9, (CHX).sub.nCO.sub.2R.su- b.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 C.sub.1-C.sub.20 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.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,
(CH.sub.2).sub.nCON(R.sub.10)(R.sub.11),
(CX.sub.2).sub.nCONH(R.sub.10), (CX.sub.2).sub.nCONHNH(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, (CHX).sub.nCONH(R.sub.10),
(CHX).sub.nCONHNH(R.sub.10), (CHX).sub.nCON(R.sub.10).sub.2,
(CHX).sub.nCON(R.sub.10)(R.sub.11), or (CHX).sub.nCOR.sub.10, where
X is a halogen, and R.sub.10 and R.sub.11 can be the same or
different and are selected from H, 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, an amino acid, 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.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.sub.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 (provided --NH(R.sub.12) 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, or a functional
group of less than about 100,000 daltons, where R.sub.12, R.sub.13
and R.sub.14 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.15,
(CH.sub.2).sub.nPO(OR.sub.15).sub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.15, or (CH.sub.2).sub.nPOR.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, heterocycle, aryl, heteroaryl, 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.16 or (CH.sub.2).sub.nNHNHCOR.sub.16,
where R.sub.16 is a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, or a functional group of less than about 100,000
daltons, and n is an integer between 0 and 4; SO.sub.3R.sub.17,
SO.sub.2NHR.sub.17, SO.sub.2NHNHR.sub.17,
SO.sub.2N(R.sub.17).sub.2, SO.sub.2N(R.sub.17)(R.sub.18), or
SO.sub.2R.sub.17, where R.sub.17 and R.sub.18 can be the same or
different and are selected from H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, 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.17 can also be an amino
acid, 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; R.sub.1-R.sub.2, 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. M is
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+, Y.sup.3+, Mg.sup.2+ wherein
associated with the metal ion is the appropriate number of
physiologically acceptable charge balancing counter ions; with the
proviso that when R.sub.1 and R.sub.3 are Me, R.sub.2 and R.sub.4
are vinyl, and R.sub.5 and R.sub.6 are CO.sub.2Me, M cannot be
Zn.sup.2+; and when R.sub.1 and R.sub.3 are Me, R.sub.2 and R.sub.4
are Et and R.sub.5 and R.sub.6 are CO.sub.2Me, M cannot be
Zn.sup.2+, Pd.sup.2+ or Mn.sup.3+.
71. The method of claims 2 and 9 wherein the gallium azaporphyrin
is a compound of formula III: 38wherein R.sub.1 to 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 about
100,000 daltons; CH.dbd.CHCH.sub.2N.sup.+(CH.sub.3).sub.3 A,
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)Oaryl;
(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 H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocyclic, 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, heterocyclic, 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,
heterocyclic, 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.nCONHNH(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, (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), or (CHX).sub.nCOR.sub.14, where
X is a halogen, and R.sub.14 and R.sub.15 can be the same or
different and are selected from H, 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, an amino acid, 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,
(CH.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 (provided --NH(R.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, or a functional
group of less than about 100,000 daltons, 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.19,
(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, heterocycle, aryl, heteroaryl, 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 or (CH.sub.2).sub.nNHNHCOR.sub.20,
where R.sub.20 is a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, 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.2NHNHR.sub.21,
SO.sub.2N(R.sub.21).sub.2, SO.sub.2N(R.sub.21)(R.sub.22), or
SO.sub.2R.sub.21, where R.sub.21 and R.sub.22 can be the same or
different and are 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, 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 also be an amino
acid, 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; 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; and wherein M is Ga.sup.3+,
where associated with the metal ion is the appropriate number of
physiologically acceptable charge balancing counter ions.
72. The method of claims 2 and 9 wherein the gallium azaporphyrin
is a compound of formula IIIA: 39wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4 can be the same or different and are selected from:
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,
heterocyclic, 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.6, where R.sub.6 is selected from alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, 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.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; 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.nCONHNH(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,
(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), or
(CHX).sub.nCOR.sub.8, where X is a halogen, and R.sub.8 and R.sub.9
can be the same or different and are selected from H, 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,
an amino acid, 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.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.1 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), 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, 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).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, heterocycle, aryl, heteroaryl, 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 a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, 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.2NHNHR.sub.15,
SO.sub.2N(R.sub.15).sub.2, SO.sub.2N(R.sub.15)(R.sub.16), or
SO.sub.2R.sub.15, where R.sub.15 and R.sub.16 can be the same or
different and are 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, 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.15 can also be an amino
acid, 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 wherein M is 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+, Y.sup.3+, Mg.sup.2+ wherein associated with
the metal ion is the appropriate number of physiologically
acceptable charge balancing counter ions.
73. A compound of formula IIIA: 40wherein R.sub.1, R.sub.2, R.sub.3
and R.sub.4 can be the same or different and are selected from: a
straight or branched chain C1-C20 alkyl, C1-C20 cycloalkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl,
heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-,
di-, or a polyhydroxyaryl residue; 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, heterocyclic, 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.6, where R.sub.6 is
selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocyclic, 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 C.sub.1-C.sub.20 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.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.nCONHNH(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,
(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), or
(CHX).sub.nCOR.sub.8, where X is a halogen, and R.sub.8 and R.sub.9
can be the same or different and are selected from H, 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,
an amino acid, 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.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 (provided --NH(R.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, or 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).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, heterocycle, aryl, heteroaryl, 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 a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, 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.2NHNHR.sub.15,
SO.sub.2N(R.sub.15).sub.2, SO.sub.2N(R.sub.15)(R.sub.16), or
SO.sub.2R.sub.15, where R.sub.15 and R.sub.16 can be the same or
different and are 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, 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.15 can also be an amino
acid, 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; M is 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+, Y.sup.3+, and Mg.sup.2+ wherein associated with the
metal ion is the appropriate number of physiologically acceptable
charge balancing counter ions; with the proviso that when R.sub.1
and R.sub.2 are Et, and R.sub.3 and R.sub.4 are
(CH.sub.2).sub.2CO.sub.2H or (CH.sub.2).sub.2CO.sub.2Me, M cannot
be Fe.sup.3+; when R.sub.1 and R.sub.2 are
(CH.sub.2).sub.2CO.sub.2Me, M cannot be Fe.sup.3+; and when
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are butyl, M cannot be
Cu.sup.2+.
74. A compound of formula III: 41wherein R.sub.1-R.sub.4,
R.sub.6-R.sub.9, can be the same or different and can be selected
from: H, halogen, a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl; CO.sub.2R.sub.11, where
R.sub.11 is selected from H, a physiologically acceptable counter
ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, 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, heterocyclic, 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.nCONHNH(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, (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), or (CHX).sub.nCOR.sub.14, where
X is a halogen, and R.sub.14 and R.sub.15 can be the same or
different and are selected from H, 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, an amino acid, 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,
(CH.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 (provided --NH(R.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, or a functional
group of less than about 100,000 daltons, 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.19,
(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, heterocycle, aryl, heteroaryl, 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 or (CH.sub.2).sub.nNHNHCOR.sub.20,
where R.sub.20 is a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl,
heteroaryl, 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.2NHNHR.sub.21,
SO.sub.2N(R.sub.21).sub.2, SO.sub.2N(R.sub.21)(R.sub.22), or
SO.sub.2R.sub.21, where R.sub.21 and R.sub.22 can be the same or
different and are 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, 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 also be an amino
acid, an amino acid salt, an amino acid ester residue, or an amino
acid amide residue; where R.sub.5 and R.sub.10 are aryl, heteroaryl
or substituted aryl or substituted heteroaryl, which may bear one
or more of the substituents 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, 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; M
is 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+, Y.sup.3+, Zn.sup.2+, Mg.sup.2+
wherein associated with the metal ion is the appropriate number of
physiologically acceptable charge balancing counter ions.
75. The method of claims 2 and 9 wherein the gallium azaporphyrin
is a compound of formula IV: 42wherein 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 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.9, where 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; (CH.sub.2).sub.nOH, or
(CH.sub.2).sub.nOR.sub.10, where R.sub.10 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.11,
(CHX).sub.nCO.sub.2R.sub.11, or (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,
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.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.nCONHNH(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, (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), or (CHX).sub.nCOR.sub.12, where
X is a halogen, and R.sub.12 and R.sub.13 can be the same or
different and are selected from H, 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, an amino acid, 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 (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, or a functional
group of less than about 100,000 daltons, 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).su- b.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, heterocycle, aryl, heteroaryl, 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.18 or (CH.sub.2).sub.nNHNHCOR.sub.18,
where R.sub.18 is a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl,
heteroaryl, 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.2NHNHR.sub.19,
SO.sub.2N(R.sub.19).sub.2, SO.sub.2N(R.sub.19)(R.sub.20), or
SO.sub.2R.sub.19, where R.sub.19 and R.sub.20 can be the same or
different and are 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, 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, 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 A, B, C, and D can be the same or
different and can be selected from N, CH, and CR.sub.20, where
R.sub.20 is selected from a halogen, aryl, substituted aryl,
heteroaryl, alkyl, haloalkyl, heterohaloalkyl, hydroxyalkyl,
hydroxyhaloalkyl, or a functional group of less than about 100,000
daltons; and wherein M is Ga.sup.3+, where associated with the
metal ion is the appropriate number of physiologically acceptable
charge balancing counter ions.
76. The method of claims 2 and 9 wherein the gallium azaporphyrin
is a compound of formula IV: 43wherein 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 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.9, where 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; (CH.sub.2).sub.nOH, or
(CH.sub.2).sub.nOR.sub.10, where R.sub.10 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.11,
(CHX).sub.nCO.sub.2R.sub.11, or (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,
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.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.nCONHNH(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, (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), or (CHX).sub.nCOR.sub.12, where
X is a halogen, and R.sub.12 and R.sub.13 can be the same or
different and are selected from H, 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, an amino acid, 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 (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, or a functional
group of less than about 100,000 daltons, 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).su- b.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, heterocycle, aryl, heteroaryl, 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.18 or (CH.sub.2).sub.nNHNHCOR.sub.18,
where R.sub.18 is a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl,
heteroaryl, 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.2NHNHR.sub.19,
SO.sub.2N(R.sub.19).sub.2, SO.sub.2N(R.sub.19)(R.sub.20), or
SO.sub.2R.sub.19, where R.sub.19 and R.sub.20 can be the same or
different and are 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, 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, 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; A, B, C, and D can be the same or different
and can be selected from N, CH, and CR.sub.20, where R.sub.20 is
selected from a halogen, aryl, substituted aryl, heteroaryl, alkyl,
haloalkyl, heterohaloalkyl, hydroxyalkyl, hydroxyhaloalkyl, or a
functional group of less than about 100,000 daltons; and wherein M
is 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+, Y.sup.3+, and
Mg.sup.2+, wherein associated with the metal ion is the appropriate
number of physiologically acceptable charge balancing counter
ions.
77. A compound of the following formula IV: 44wherein
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 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.9, where
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; (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.10,
where R.sub.10 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.11, (CHX).sub.nCO.sub.2R.sub.11, or
(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, 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.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.nCONHNH(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, (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), or (CHX).sub.nCOR.sub.12, where
X is a halogen, and R.sub.12 and R.sub.13 can be the same or
different and are selected from H, 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, an amino acid, 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 (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, or a functional
group of less than about 100,000 daltons, 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).su- b.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, heterocycle, aryl, heteroaryl, 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.18 or (CH.sub.2).sub.nNHNHCOR.sub.18,
where R.sub.18 is a straight or branched chain C.sub.1-C.sub.20
alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl,
heteroaryl, 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.2NHNHR.sub.19,
SO.sub.2N(R.sub.19).sub.2, SO.sub.2N(R.sub.19)(R.sub.20), or
SO.sub.2R.sub.19, where R.sub.19 and R.sub.20 can be the same or
different and are 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, 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, 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; A, B, C, and D can be the same or different
and can be selected from N, CH, and CR.sub.20, where R.sub.20 is
selected from a halogen, aryl, substituted aryl, heteroaryl, alkyl,
haloalkyl, heterohaloalkyl, hydroxyalkyl, hydroxyhaloalkyl, or a
functional group of less than about 100,000 daltons; and wherein M
is Ga.sup.3+ where associated with the metal ion is the appropriate
number of physiologically acceptable charge balancing counter ions;
with the proviso that where R.sub.1-R.sub.8 are all phenyl or H,
and A-D are N, M cannot be Ga.sup.3+.
78. The method of any of claims 55, 56, 59, 60, 64, 65, 67, 71, 72,
75 and 76, wherein a mammal is treated for disturbances of vascular
and perivascular cellular processes selected from proliferation,
replication, migration, necrosis, apoptosis, adhesion, matrix
deposition, signalling pathways, paracrine and autocrine functions,
mediator release, contraction, relaxation, shrinkage, phenotype
changes, angiogenesis, aggregation, healing, repair, regulation of
surrounding tissue, metabolism and matrices.
79. The method of claim 33, wherein said wavelength ranges between
about 350 to about 460 nm.
80. The method of claim 33, wherein said wavelength ranges between
about 500 to 600 nm.
81. The method of claim 79, wherein said energy source is visible
or UV light.
82. The method of claim 2, wherein said metallated azaporphyrin is
formulated by encapsulation in carriers selected from water,
deionized water, phosphate buffered saline, aqueous ethanol,
glucose, amino acids, vegetable oils, liposomes, immunoliposomes,
cyclodextrans, microspheres, nanoparticles, lipoproteins,
micellular systems or combinations thereof.
83. The method of claim 81, wherein said formulation is selected
from slow release, a prodrug, tablets, pills, solutions,
suspensions, emulsions, granules or capsules.
Description
DESCRIPTION OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to metallotetrapyrrolic compounds
having phototherapeutic properties utilizable in photodynamic
therapy for photodetection and phototherapy of target tissues.
[0003] 2. Background of the Invention
[0004] Photodynamic therapy ("PDT") is a new modality for the
treatment of malignancies, diseased tissue, hyperproliferating
tissues, normal tissues or pathogens. 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
exposure to the photoactivating light. The method of light delivery
is also an important therapeutic factor.
[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 at a
target site to a greater degree than other photosensitizers is not
well understood. In addition, the biological factors that result in
the preferential uptake of some photosensitizers in certain tissue
types compared to others is 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 drug 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 within the diseased or target tissues for an effective
therapy.
[0006] An emerging clinical role for photodynamic therapy is in the
treatment of proliferative cardiovascular diseases such as
atherosclerosis, restenosis and vein graft disease. Atherosclerosis
is a disease that causes thickening and hardening of the arteries,
particularly the larger artery walls. It is characterized by
lesions of raised fibrous plaque that form within the vessel lumen.
The plaques are most prevalent in, but not limited to, abdominal
aorta, coronary arteries and carotid arteries and increase
progressively with age. Intravascular ultrasound in man has shown
that the plaque has a dome-shaped, opaque, glistening surface that
protrudes into the lumen of the vessel. A lesion will typically
consist of a central core of lipid and necrotic cell debris, capped
by a collagen fibromuscular layer. Complicated lesions will also
include calcified deposits, necrotic tissue, thrombosis and fibrin.
The occlusion of vessel lumen caused by the plaque leads to reduced
blood flow, higher blood pressure and ultimately ischemic heart
disease, if untreated.
[0007] The treatment of coronary atherosclerosis presently consists
of pharmacological drug therapy, bypass surgery, percutaneous
angioplasty and/or stent deployment. Drug therapy is primarily
directed towards the control of hypertension (with vasodilators,
diuretics, anti-adrenergic agents, angiotensin converting enzyme
inhibitors etc) or stabilization of the plaque by lowering
circulating lipid levels (with statins). The goal of the drug
therapy is to return the patient's arterial blood pressure and
circulating cholesterol to normal levels and thereby reduce the
stress on the patient's heart, kidneys and other organs.
Unfortunately, in some cases drug therapy can have side effects and
does not control progressive or acute atherosclerosis.
[0008] In the more serious instances of coronary atherosclerosis, a
thoracic bypass surgery may be performed, where a vein, usually
from the patient's leg, is used to bypass the occluded coronary
artery. One end of the vein is attached to the aorta, and the other
end is attached to the occluded vessel just beyond the obstruction.
Although bypass surgery has become an accepted surgical procedure,
it can present substantial morbidity risks, is expensive and
generally requires extended hospital care. Moreover, the procedure
is often limited to proximal vessels to the heart and the long-term
prognosis is less than satisfactory. Roughly five percent of bypass
grafts can be expected to occlude each year following the operation
and the native vessel can also re-occlude as well, necessitating
repeat procedures.
[0009] Percutaneous transluminal angioplasty (PTA) consists of
balloon expansion of vessels to dilate areas of obstruction and has
been used since the late 1980's in the treatment of atherosclerotic
coronary and peripheral vascular occlusive disease. Advances in
catheter design have allowed more complex and distal stenoses and
occlusions of coronary vessels to be treated with PTA. While this
endovascular procedure displays excellent immediate
revascularization of treated vessels and has gained acceptance as a
less invasive alternative to bypass surgery, balloon angioplasty
simply redistributes the atherosclerotic stenoses. It has also been
determined that in some cases acute closure of the vessel after PTA
and accelerated arteriosclerosis, or restenosis (re-occlusion)
occurred as often as 40% within 6 months post-procedure. These
re-occlusions further increase both as a function of the number of
lesions treated and the time post-angioplasty.
[0010] Restenosis is the vessel's natural healing response that
typically occurs in direct proportion to the magnitude of the
balloon angioplasty injury. The exact mechanisms responsible for
the restenotic process are not fully understood and thus it is not
surprising that at present there are no proven clinical therapies
to prevent it. Nevertheless, recent studies in man and animals have
shown that two events, intimal thickening and abnormal geometric
remodeling, occur following PTA. Indeed, intravascular ultrasound
and pathologic studies suggest that, in man, intimal thickening and
vessel remodeling are responsible for approximately one-third and
two-thirds of the total lumen loss, respectively. Intimal
thickening involves the recruitment of vascular smooth muscle cells
(VSMC) and perhaps advential myofibroblasts to the intima, where
they proliferate and secrete an extracellular matrix. Stent
deployment (metal scaffolding used to open vessels) is the only
intervention that helps to reduce the effects of the vessel
remodelling component of restenosis. However, while stents hold an
artery open and significantly reduce acute closure--restenosis
rates have been reduced with stents from 40% to 20-35%--it is clear
that stents have not eliminated the problem.
[0011] Neointimal hyperplasia, i.e., new tissue growth through the
sides of the stents, has created a new problem, in-stent
restenosis. Interventional cardiologists have tried to remove this
proliferative tissue with rotational and directional atherectomy,
cutting balloons, eximer lasers, and deployment of another stent
(stent sandwich), but none of these has shown to be effective. It
is estimated that 1.8 million coronary interventions alone (0.36
million PTA and 1.45 million stent procedures) are performed
worldwide each year, so a method of reducing neointima formation
remains an important goal. Anti-restenosis treatments have focused
on arresting the cell replication cycle and the proliferation of
VSMC. A number of gene therapy approaches have been used
unsuccessfully to interfere with VSMC proliferation including the
use of antisense involved in cell proliferation (e.g. c-myc), and
the use of adenovirus to increase nitric oxide synthase and thereby
increase nitric oxide, an inhibitor of VSMC proliferation. Poor
delivery of the gene therapy to the target vessel and immune
reactions to some delivery vectors, however, have been major
drawbacks for this method.
[0012] Researchers have looked to cancer treatments for ideas and
ionizing radiation (brachytherapy) and stents coated with
anti-cancer drugs have recently been identified as treatment
options. At present, the use of drug coated stents has been
restricted to animal studies and the few reports of human therapy
appear to confirm the feasibility of the procedure. However, the
best way to truly understand the vascular effect of drug-coated
stents is to conduct long term studies well after the drug is
completely eluted from the stent because it may be associated with
inflammation and fibrin deposition, as seen in some animal models.
Several devices are now available for applying radiation to
recurrent narrowings within coronary stents or in-stent restenoses.
However, a study recently failed to show the effectiveness of beta
radiation (Beta-Cath system clinical trial; Novoste, 2001, Kuntz,
et al, J. American College of Cardiology, Feb, 2001) in preventing
renarrowing of de novo coronary lesions, i.e., lesions that have
not yet been treated with either PTA or stenting. Moreover, in
animal and human studies it has been found that if the dose of
radiation is too high, there is no healing of the lumenal
endothelial lining of the intima resulting in an increased risk of
late-onset thrombosis. Conversely, if the dose is too low, then
restenosis and arteriosclerosis could actually be accelerated.
Other technologies are being developed including cryotherapy using
hypothermia, for example. These products all have technical
challenges. The efficacy in animal models to date has been
unimpressive and each is still far from commercialization.
[0013] There exists a need for better methods for treatment of
atherosclerosis and restenosis. When considering a therapy to treat
or prevent restenosis, one must consider the steps in the
complicated biologic cascade with which the therapeutic agent
(e.g., photosensitizer) is designed to interfere, where the target
cells will be when the proposed treatment is to be applied, and
what the least traumatic and most efficient route of administration
of that agent is for the specific problem to be treated. The
ultimate objective of any therapy is to inhibit neointima formation
while also promoting the controlled healing of the vessel wall.
[0014] Recently, vascular photodynamic therapy has shown promise
for the prevention of injury-induced neointimal hyperplasia in
animal studies and has entered phase I/II clinical trials in man
(Lutetium texaphyrin; Pharmacyclics). In this study, a
photosensitizer was administered intravenously or locally to a
patient and, after a predetermined time that depends on the optimal
localization of the drug, the photosensitizer reached the target
vascular lesion and light of an appropriate wavelength was used to
activate the drug.
[0015] Several photosensitizers have been developed largely for use
in oncological applications, and have also been examined in the
cardiovascular field, mostly in preclinical animal models. Such
photosensitizers include Photofrin, 5-amino-levulinic acid
(protoporphyrin IX precursor), tin ethyl etiopurpurin (SnET2),
Visudyne.RTM. (Benzoporphyrin derivative), Antrin.RTM., Optrin.RTM.
(Lutetium texaphyrin), mono-aspartyl chlorin e6 (MACE), and
pheophorbide PH1126. All of these synthetic 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 in 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.
[0016] The excitation light source for PDT (usually diode lasers or
dye lasers) has historically been matched to the far-red absorption
bandwidth of the photosensitizer to maximize light penetration
through blood in the arteries. Indeed, the present inventors
believe that all the tetrapyrrolic photosensitizers used in
cardiovascular indications have been designed for long wavelength
absorption of light to address this perceived issue. The light is
then delivered to the treatment site via radially emitting fibers,
often enclosed in balloon catheters (with a variety of designs), to
exclude as much of the blood as possible.
[0017] Enthusiasm for photoangioplasty (PDT of vascular de novo
atherosclerotic, restenotic lesions and vein graft intimal
hyperplasia) is fueled by more effective second-generation
photosensitizers that are designed specifically for cardiovascular
indications and technological advances in endovascular light
delivery catheters. These molecules may be used adjunctively with
other debulking procedures. This enthusiasm revolves around at
least four significant attributes of light-activated therapy: a)
the putative selectivity and safety of photoangioplasty, b) the
potential for atraumatic and effective stabilization of
atheromatous plaque through a biological mechanism, c) the
postulated capability to reduce or inhibit restenosis using
minimally invasive clinically relevant interventional techniques,
and d) the potential to treat long segments of abnormal vessel by
simply using fibers with longer light-emitting regions.
[0018] 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.
[0019] 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.
[0020] 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 I
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, the present inventors have demonstrated in
pig arteries that effective treatment depths can be obtained with
shorter wavelengths of light, while sparing underlying tissue
damage.
[0021] Thus, in our opinion, 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 have
low energy "red" absorbtions by design (>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 to minimize tissue damage
due to the red light penetration 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.
[0022] Another important consideration in the design of
cardiovascular photosensitizers that absorb at shorter wavelengths
is that they must have absorptions at wavelengths where excitation
light devices emit maximally. At 532 nm, efficient inexpensive
diode lasers are available. At other wavelengths (besides blue)
<600 nm-only dye lasers exist to supply enough light power to
undertake a PDT treatment. These are particularly useful at 580 nm.
Blue lasers are available, and even though most of the
photosensitizers that have been used in cardiovascular diseases
have blue absorptions, the light output of these devices currently
limits their applicability to high power light treatments. Also,
blood attenuation of light in the blue region of the spectrum (350
to 460 nm) is significantly greater than in the green/yellow region
(500 to 600 nm). Thus, photosensitizers being activated in the blue
region may suffer larger therapeutic inconsistancies if small
amounts of blood are present within the vessel treatment area.
Should high power blue lasers come onto the market, it may be
possible (although difficult) to overcome significant blood
attenuation in the blue region, and perhaps effect a desired
therapy.
[0023] For these reasons, there is a real need for "shorter
wavelength" absorbing photosensitizer agents that do not display
red absorptions, that are cleared rapidly from normal tissues
(especially skin), and that are effective in the treatment of
intimal hyperplasia, atheromatous plaques, peripheral artery
disease, and vein graft hyperproliferation. 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
in hollow organ disease (for example, lung cancers and barrets
esophagus), and in diseases of the skin (for example, psoriasis,
actinic keratosis, and acne vulgaris).
[0024] The present invention is directed to certain metallated
photosensitizers 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.
These compounds are expected to be useful not only in
cardiovascular disease indications, but also for indications in
dermatology, oncology, ophthalmology, urology, and in
dentistry.
[0025] The present invention overcomes the disadvantages of the
prior art by providing novel metallated functionalized
phototherapeutic agents of the tetrapyrrolic type, which display
excellent uptake into cardiovascular tissues of interest, show low
systemic toxicity and low myocardial tissue toxicity on light
activation, and are cleared rapidly from skin and other tissues.
These phototherapeutic agents are based on tetrapyrrolic ring
systems such as the porphyrins.
[0026] We have additionally discovered that a single chemical
modification of tetrapyrrolic compounds involving the coordination
of a gallium ion into the central cavity of tetrapyrrolic compounds
to produce a gallium tetrapyrrolic complex, unexpectedly markedly
enhances the uptake and biological efficacy of the compounds as
photosensitizers for PDT of cardiovascular diseases when compared
to the corresponding tetrapyrrolic compounds having other metal
types coordinated to their central cavity. Additionally,
tetrapyrrolic macrocycles that coordinate gallium when administered
topically or systemically, show unexpected skin tissue responses,
such as hair growth stasis and positive skin remodelling
(deposition of collagen) following treatment with light. These
effects are not observed with other metallotetrapyrrolic
macrocycles. Therefore, a preferred embodiment of the invention is
directed to certain tetrapyrrolic compounds metallated with
gallium.
[0027] The invention also provides new methods of treating
cardiovascular diseases with PDT utilizing light at shorter
wavelengths with the new metallated porphyrins of the invention,
thus minimizing damage to the myocardial or muscle tissue.
[0028] The invention further provides new photosensitizers that may
be used in short wavelength applications in photodynamic therapy to
treat diseases other than cardiovascular diseases.
SUMMARY OF THE INVENTION
[0029] 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 in photodynamic therapy or in a
medicament for treatment of diseases such as cardiovascular
diseases: 1
[0030] In formula I, R.sub.1-R.sub.12 can be the same or different
and can be selected from:
[0031] 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.3.sup.+A,
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;
[0032] (CH.sub.2).sub.nO-alkoxy, or (CH.sub.2).sub.nO-alkyl; where
n is an integer from 0 to 8;
[0033] C(X).sub.2C(X).sub.3, where X is a halogen;
[0034] 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;
[0035] (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;
[0036] (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 0 and
4;
[0037] 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.1- 6),
(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 1 and 4;
[0038] 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, or a functional
group of less than about 100,000 daltons, 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;
[0039] (CH.sub.2).sub.nOPO.sub.2OR.sub.21,
(CH.sub.2).sub.nPO(OR.sub.21).s- ub.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, 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;
[0040] (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;
[0041] SO.sub.3R.sub.23, SO.sub.2NHR.sub.23,
SO.sub.2N(R.sub.23).sub.2, SO.sub.2NHNHR.sub.23,
SO.sub.2N(R.sub.23)(R.sub.24) or SO.sub.2R.sub.23, where R.sub.23
and R.sub.24 can be the same or different and are 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.22 can also be an amino acid, an amino acid salt, an amino
acid ester residue, and an amino acid amide residue;
[0042] 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
[0043] 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, 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.
[0044] In formula I, M is a diamagnetic or paramagnetic metal ion,
photoactive metal ions 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+, and Mg.sup.2+, wherein optionally associated
with the metal ion is the appropriate number of physiologically
acceptable charge balancing counter ions.
[0045] In a preferred embodiment of the invention, provided are
phototherapeutic compositions of metallo-tetrapyrrolic compounds of
formula IA: 2
[0046] In formula IA, R.sub.1 and R.sub.2 can be the same or
different and can be selected from:
[0047] CO.sub.2R.sub.3, where R.sub.3 is selected from H, a
physiologically acceptable salt, a straight or branched chain
C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl,
heteroaryl, heterocyclic, a mono-, di-, or polyhydroxyalkyl
residue, a mono-, di-, or polyhydroxyaryl residue, or a functional
group of less than about 100,000 daltons;
[0048] CONH(R.sub.4), CONHNH(R.sub.4), CON(R.sub.4).sub.2,
COR.sub.4, or CON(R.sub.4)(R.sub.5), where R.sub.4 and R.sub.5 can
be the same or different and are selected from H, NH.sub.2,
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocyclic, aryl, heteroaryl, 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 amide residue, or a functional
group of less than about 100,000 daltons;
[0049] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.6, where
R.sub.6 is selected from a C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocyclic, 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 0 and 4;
[0050] (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;
[0051] (CH.sub.2).sub.nCONH(R.sub.8), (CH.sub.2).sub.nCO(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.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)- .sub.t
(CHX).sub.nCONH(R.sub.9), (CHX).sub.nCONHNH(R.sub.9),
(CHX).sub.nCON(R.sub.9).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, heteroalkyl, haloalkyl, haloheteroalkyl,
heterocyclic, aryl, heteroaryl, an amino acid, an amino acid salt,
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, or a functional group of less than about
100,000 daltons, and n is an integer between 0 and 4;
[0052] 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, straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl,
heterocyclic, an amino acid or a salt, ester or amide thereof
(provided --NH(R.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, or a functional group of less than about
100,000 daltons, 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;
[0053] (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, 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, heterocycle, aryl, heteroaryl, 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;
[0054] (CH.sub.2).sub.nNHCOR.sub.14 or
(CH.sub.2).sub.nNHNHCOR.sub.14, where R.sub.14 is a straight or
branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0055] SO.sub.3R.sub.15, SO.sub.2NHR.sub.15,
SO.sub.2N(R.sub.15).sub.2, SO.sub.2NHNHR.sub.15,
SO.sub.2N(R.sub.15)(R.sub.16) or SO.sub.2R.sub.15, where R.sub.15
and R.sub.16 can be the same or different and are 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, 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; and
[0056] 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;
[0057] In formula IA, M is preferably Ga.sup.3+, wherein associated
with the co-ordinated gallium is a physiologically acceptable
charge balancing counter ion, but M in formula IA can also be
selected from Pt.sup.2+, Pd.sup.2+, Sn.sup.4+, In.sup.3+,
Ge.sup.4+, Si.sup.4+, Al.sup.3+, Mg.sup.2+, Zn.sup.2+ either with
or without a physiologically acceptable charge balancing counter
ion.
[0058] In another preferred embodiment of the invention, provided
are phototherapeutic compositions of metallo-tetrapyrrolic
compounds of formula IB: 3
[0059] In formula IB, R.sub.1 and R.sub.2 can be the same or
different and can be selected from H, CN, CO-alkyl, haloalkyl,
heteroalkyl, hydroxyhaloalkyl, ether haloalkyl, ester haloalkyl, a
C1-C20 alkyl, or a halogen;
[0060] R.sub.3 and R.sub.4 can be the same or different and are
selected from:
[0061] CO.sub.2R.sub.5, where R.sub.5 is selected from H, a
straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocyclic, aryl, 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;
[0062] CONH(R.sub.6), CONHNH(R.sub.6), CON(R.sub.6).sub.2, or
CON(R.sub.6)(R.sub.7), where R.sub.6 and R.sub.7 can be the same or
different and can be selected from H, a straight or branched chain
C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocyclic, aryl, heteroaryl, 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;
[0063] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.8, where
R.sub.8 is selected from a straight or branched chain C1-C20 alkyl,
haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, 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 0 and 4;
[0064] (CH.sub.2).sub.nCO.sub.2R.sub.9,
(CHX.sub.2).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, heterocyclic, 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;
[0065] (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.nCON(R.sub.10)(R.sub.- 11),
(CX.sub.2).sub.nCONH(R.sub.10), (CX.sub.2).sub.nCONHNH(R.sub.10),
(CX.sub.2).sub.nCON(R.sub.10).sub.2,
(CX.sub.2).sub.nCON(R.sub.10)(R.sub.- 11),
(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, straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, also
where NH(R.sub.10) is part of an amino acid, an amino acid salt, an
amino acid ester, or 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, or a functional group of less than about
100,000 daltons, and n is an integer between 0 and 4;
[0066] S(R.sub.12), (CH.sub.2).sub.nS(R.sub.12),
(CH.sub.2).sub.nNH(R.sub.- 12), (CH.sub.2).sub.nN(R.sub.12).sub.2,
(CH.sub.2).sub.nN(R.sub.12)(R.sub.- 13),
(CH.sub.2).sub.nN(R.sub.12)(R.sub.13)(R.sub.14).sup.+A, where
R.sub.12 and R.sub.13 can be the same or different and are selected
from H, straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an
amino acid or a salt, ester or amide thereof (provided
--NH(R.sub.12) 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
pclyetheraryl residue, or a functional group of less than about
100,000 daltons, where R.sub.12, R.sub.13 and R.sub.14 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;
[0067] (CH.sub.2).sub.nOPO.sub.2OR.sub.15,
(CH.sub.2).sub.nPO(OR.sub.15).s- ub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.15, or (CH.sub.2).sub.nPOR.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, heterocycle, aryl, heteroaryl, 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;
[0068] (CH.sub.2).sub.nNHCOR.sub.16 or
(CH.sub.2).sub.nNHNHCOR.sub.16, where R.sub.16 is a a straight or
branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0069] SO.sub.3R.sub.17, SO.sub.2NHR.sub.17,
SO.sub.2N(R.sub.17).sub.2, SO.sub.2NHNHR.sub.17,
SO.sub.2N(R.sub.17)(R.sub.18) or SO.sub.2R.sub.17, where R.sub.17
and R.sub.18 can be the same or different and are 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, 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; and
[0070] 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.
[0071] In formula 1B, M is Ga.sup.3+, wherein associated with the
co-ordinated gallium is a physiologically acceptable charge
balancing counter ion.
[0072] In another aspect of the invention, provided are
phototherapeutic compositions of metallo-tetrapyrrolic compounds of
formula 11 that may be useful as photosensitizers in photodynamic
therapy or in a medicament for treatment of diseases such as
cardiovascular diseases: 4
[0073] In formula II, R.sub.1 to R.sub.11 can be the same or
different and can be selected from:
[0074] 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 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;
[0075] (CH.sub.2).sub.nO-alkoxy, or (CH.sub.2).sub.nO-alkyl, where
n is an integer from 0 to 8;
[0076] C(X).sub.2C(X).sub.3, where X is a halogen;
[0077] CO.sub.2R.sub.12, where R.sub.12 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocyclic, 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;
[0078] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.13, where
R.sub.13 is selected from alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocyclic, 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;
[0079] (CH.sub.2).sub.nCO.sub.2R.sub.14,
(CX.sub.2).sub.nCO.sub.2R.sub.14, or (CHX).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,
heterocyclic, 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;
[0080] 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.nCONHNH(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, (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), or (CHX).sub.nCOR.sub.15, where
X is a halogen and R.sub.15 and R.sub.16 can be the same or
different and are selected from H, 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, 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;
[0081] S(R.sub.17), (CH.sub.2).sub.nS(R.sub.17),
(CH.sub.2).sub.nNH(R.sub.- 17), (CH.sub.2).sub.nNHNH(R.sub.17),
(CH.sub.2).sub.nN(R.sub.17).sub.2,
(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 (provided --NH(R.sub.17) 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, or a functional
group of less than about 100,000 daltons, where R.sub.17, R.sub.18
and R.sub.19 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;
[0082] (CH.sub.2).sub.nOPO.sub.2OR.sub.20,
(CH.sub.2).sub.nPO(OR.sub.20).s- ub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.20, or (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, heterocycle, aryl, heteroaryl, 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;
[0083] (CH.sub.2).sub.nNHCOR.sub.21 or
(CH.sub.2).sub.nNHNHCOR.sub.21, where R.sub.21 is a straight or
branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0084] SO.sub.3R.sub.22, SO.sub.2NHR.sub.22, SO.sub.2NHNHR.sub.22,
SO.sub.2N(R.sub.22).sub.2, SO.sub.2N(R.sub.22)(R.sub.23) or
SO.sub.2R.sub.22, where R.sub.22 and R.sub.23 can be the same or
different and are 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, a mono-, di-, or polyetheralkyl residue, a
mono-, di-, or polyetheraryl residue, or a functional group of less
than about 100,000 daltons, and NHA can also be an amino acid, an
amino acid salt, an amino acid ester residue, or an amino acid
amide residue, and n is an integer between 0 and 4;
[0085] 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
[0086] 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.8-R.sub.9, R.sub.9-R.sub.10, R.sub.11-R.sub.12 and
R.sub.12-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.
[0087] In formula II, M is a diamagnetic or paramagnetic
photoactive metal ion 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+ and Mg.sup.2+, wherein optionally associated
with the metal ion is the appropriate number of physiologically
acceptable charge balancing counter ions.
[0088] In a preferred embodiment of the invention, provided are
phototherapeutic compositions of metallo-tetrapyrrolic compounds of
formula IIA 5
[0089] In formula IIA, R.sub.1-R.sub.6 can be the same or different
and can be selected from:
[0090] 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 less
than about 100,000 daltons;
[0091] CH.dbd.CHCH.sub.2N.sup.+(CH.sub.3).sub.3.sup.+A,
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;
[0092] (CH.sub.2).sub.nO-alkoxy, or (CH.sub.2).sub.nO-alkyl, where
n is an integer from 0 to 8;
[0093] C(X).sub.2C(X).sub.3, where X is a halogen;
[0094] CO.sub.2R.sub.7, where 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;
[0095] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.8, where
R.sub.8 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;
[0096] (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;
[0097] 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,
(CH.sub.2).sub.nCON(R.sub.10)(R.sub.11)
(CX.sub.2).sub.nCONH(R.sub.10), (CX.sub.2).sub.nCONHNH(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, (CHX).sub.nCONH(R.sub.10),
(CHX).sub.nCONHNH(R.sub.10), (CHX).sub.nCON(R.sub.10).sub.2,
(CHX).sub.nCON(R.sub.10)(R.sub.11), or (CHX).sub.nCOR.sub.10, where
X is a halogen, and R.sub.10 and R.sup.11 can be the same or
different and are selected from H, 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, an amino acid, 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;
[0098] 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 (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, or a functional
group of less than about 100,000 daltons, 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;
[0099] (CH.sub.2).sub.nOPO.sub.2OR.sub.15,
(CH.sub.2).sub.nPO(OR.sub.15).s- ub.2,
(CH.sub.2).sub.nPO.sub.2R.sub.15, or (CH.sub.2).sub.nPOR.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, heterocycle, aryl, heteroaryl, 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;
[0100] (CH.sub.2).sub.nNHCOR.sub.16 or
(CH.sub.2).sub.nNHNHCOR.sub.16, where R.sub.16 is a straight or
branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0101] SO.sub.3R.sub.17, SO.sub.2NHR.sub.17, SO.sub.2NHNHR.sub.17,
SO.sub.2N(R.sub.17).sub.2, SO.sub.2N(R.sub.17)(R.sub.18) or
SO.sub.2R.sub.17, where R.sub.17 and R.sub.18 can be the same or
different and are selected from H, a physiologically acceptable
counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl,
heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, 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.17 can also be an amino
acid, an amino acid salt, an amino acid ester residue, or an amino
acid amide residue;
[0102] 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
[0103] R.sub.1-R.sub.2, 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.
[0104] In formula IIA, M is a diamagnetic or paramagnetic metal
ion, photoactive metal ions being preferably selected from
Ga.sup.3+, Pt.sup.+, Pd.sup.2+, Sn.sup.4+, In.sup.3+, Ge.sup.4+,
Si.sup.4+, Al.sup.3+, Zn.sup.2+, Mg.sup.2+ wherein optionally
associated with the metal ion is the appropriate number of
physiologically acceptable charge balancing counter ions.
Additionally, and in accordance with the present invention,
provided are phototherapeutic compositions of metallo-tetrapyrrolic
compounds of formula III which may be useful in photodynamic
therapy or in a medicament for treatment of diseases such as
cardiovascular diseases: 6
[0105] In formula III, R.sub.1 to R.sub.10 can be the same or
different and can be selected from:
[0106] 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 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;
[0107] (CH.sub.2).sub.nO-alkoxy, or (CH.sub.2).sub.nO-alkyl, where
n is an integer from 0 to 8;
[0108] C(X).sub.2C(X).sub.3, where X is a halogen;
[0109] CO.sub.2R.sub.11, where R.sub.11 is selected from H, a
physiologically acceptable counter ion, a straight or branched
chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl,
heterocyclic, 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;
[0110] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.12, where
R.sub.12 is selected from alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocyclic, 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;
[0111] (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,
heterocyclic, 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;
[0112] 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.nCONHNH(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, (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), or (CHX).sub.nCOR.sub.14, where
X is a halogen, and R.sub.14 and R.sub.15 can be the same or
different and are selected from H, 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, an amino acid, 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;
[0113] 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 (provided --NH(R.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, or a functional
group of less than about 100,000 daltons, where R.sub.16, R.sub.17
and R.sub.18 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;
[0114] (CH.sub.2).sub.nOPO.sub.2OR.sub.19,
(CH.sub.2).sub.nPO(OR.sub.19).s- ub.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, heterocycle, aryl, heteroaryl, 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;
[0115] (CH.sub.2).sub.nNHCOR.sub.20 or
(CH.sub.2).sub.nNHNHCOR.sub.20, where R.sub.20 is a straight or
branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0116] SO.sub.3R.sub.21, SO.sub.2NHR.sub.21, SO.sub.2NHNHR.sub.21,
SO.sub.2N(R.sub.21).sub.2, SO.sub.2N(R.sub.21)(R.sub.22) or
SO.sub.2R.sub.21, where R.sub.21 and R.sub.22 can be the same or
different and are 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, 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 also be an amino
acid, an amino acid salt, an amino acid ester residue, or an amino
acid amide residue;
[0117] 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
[0118] 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.
[0119] In formula III, M is a diamagnetic or paramagnetic metal
ion, photoactive metal ions 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+ wherein optionally
associated with the metal ion is the appropriate number of
physiologically acceptable charge balancing counter ions. In a
preferred embodiment of the invention, provided are
phototherapeutic compositions of metallo-tetrapyrrolic compounds of
formula IIIA: 7
[0120] In formula IIIA, R.sub.1, R.sub.2, R.sub.3, R.sub.4 can be
the same or different and can be selected from:
[0121] a functional group of less than about 100,000 daltons;
[0122] 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,
heterocyclic, 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;
[0123] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.6, where
R.sub.6 is selected from alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocyclic, 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;
[0124] (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;
[0125] 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.nCONHNH(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,
(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), or
(CHX).sub.nCOR.sub.8, where X is a halogen, and R.sub.8 and R.sub.9
can be the same or different and are selected from H, 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,
an amino acid, 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;
[0126] 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 (provided --NH(R.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, or a functional
group of less than about 100,000 daltons, 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;
[0127] (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, 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, heterocycle, aryl, heteroaryl, 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;
[0128] (CH.sub.2).sub.nNHCOR.sub.14 or
(CH.sub.2).sub.nNHNHCOR.sub.14, where R.sub.14 is a straight or
branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0129] SO.sub.3R.sub.15, SO.sub.2NHR.sub.15, SO.sub.2NHNHR.sub.15,
SO.sub.2N(R.sub.15).sub.2, SO.sub.2N(R.sub.15)(R.sub.16) or
SO.sub.2R.sub.15, where R.sub.15 and R.sub.16 can be the same or
different and are 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, 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.15 can also be an amino
acid, an amino acid salt, an amino acid ester residue, or an amino
acid amide residue;
[0130] 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.
[0131] In formula IIIA, M is a diamagnetic or paramagnetic metal
ion, photoactive metal ions 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+ wherein optionally
associated with the metal ion is the appropriate number of
physiologically acceptable charge balancing counter ions.
Additionally, and in accordance with the present invention,
provided are phototherapeutic compositions of metallo-tetrapyrrolic
compounds of formula IV which may be used in photodynamic therapy
or in a medicament for treatment of diseases such as cardiovascular
diseases: 8
[0132] In formula IV, R.sub.1-R.sub.8 can be the same or different
and are selected from:
[0133] 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 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,
[0134] CH(CH.sub.3)OH, CH(CH.sub.3)O-alkyl, CH(CH.sub.3)O-alkoxy,
or CH(CH.sub.3)O-aryl;
[0135] (CH.sub.2).sub.nO-alkoxy, or (CH.sub.2).sub.nO-alkyl, where
n is an integer from 0 to 8;
[0136] C(X).sub.2C(X).sub.3, where X is a halogen;
[0137] CO.sub.2R.sub.9, where 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;
[0138] (CH.sub.2).sub.nOH, or (CH.sub.2).sub.nOR.sub.10, where
R.sub.10 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;
[0139] (CH.sub.2).sub.nCO.sub.2R.sub.11,
(CHX).sub.nCO.sub.2R.sub.11, or (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,
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;
[0140] 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.nCONHNH(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, (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), or (CHX).sub.nCOR.sub.12, where
X is a halogen, and R.sub.12 and R.sub.13 can be the same or
different and are selected from H, 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, an amino acid, 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;
[0141] 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 (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, or a functional
group of less than about 100,000 daltons, 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;
[0142] (CH.sub.2).sub.nOPO.sub.2OR.sub.17,
(CH.sub.2).sub.nPO(OR.sub.17).s- ub.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, heterocycle, aryl, heteroaryl, 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;
[0143] (CH.sub.2).sub.nNHCOR.sub.18 or
(CH.sub.2).sub.nNHNHCOR.sub.18, where R.sub.18 is a straight or
branched chain C1-C20 alkyl, haloalkyl, heteroalkyl,
haloheteroalkyl, heterocyclic, aryl, heteroaryl, or a functional
group of less than about 100,000 daltons, and n is an integer
between 0 and 4;
[0144] SO.sub.3R.sub.19, SO.sub.2NHR.sub.19, SO.sub.2NHNHR.sub.19,
SO.sub.2N(R.sub.19).sub.2, SO.sub.2N(R.sub.19)(R.sub.20) or
SO.sub.2R.sub.19, where R.sub.19 and R.sub.20 can be the same or
different and are 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, a mono-, di-, or polyetheralkyl residue, a
mono-, di-, or polyetheraryl residue, or a functional group of less
than about 100,000 daltons, and NHA can also be an amino acid, an
amino acid salt, an amino acid ester residue;
[0145] 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
[0146] 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, substituted aryl, heteroaryl, alkyl, haloalkyl,
heterohaloalkyl, hydroxyalkyl, hydroxyhaloalkyl, or a functional
group of less than about 100,000 daltons.
[0147] In formula IV, M is a diamagnetic or paramagnetic metal ion,
photoactive metal ions 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+ wherein optionally associated with
the metal ion is the appropriate number of physiologically
acceptable charge balancing counter ions.
[0148] In accordance with a preferred embodiment of the invention,
the metallotetrapyrrolic compounds of the invention are derived by
various procedures from naturally occurring cyclic tetrapyrroles.
The naturally occuring cyclic tetrapyrrolic molecules have the
basic ring structure shown in Table 1 herein and are particularly
preferred as starting materials for the synthesis of compounds of
formula I.
[0149] In another preferred embodiment of the invention, the
metallotetrapyrrolic molecules of the invention are derived by the
coupling of suitably substituted dipyrromethane, dipyrromethenes,
biladienes, builirubins, pyrroles and functionalized aldehydes, or
functionalized maleonitriles. These cyclic tetrapyrroles have the
basic ring structure shown in Table 2, and are particularly
preferred as starting materials for the synthesis of the compounds
of formulae II-IV.
[0150] In accordance with another embodiment of this invention,
there is provided a method for detection and treatment of
cardiovascular tissue or other tissue abnormalities in a patient.
The method comprises administering to the patient an effective
amount of a metallotetrapyrrolic compound of the invention and
exposing the tissue to light within the photoactivating spectrum of
the particular tetrapyrrolic compound.
[0151] 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
[0152] The terms "tetrapyrrole", "tetrapyrrolic molecule," and
"porphyrin" are used herein to designate compounds having a cyclic
structure wherein four pyrrolic ring systems are linked via either
carbon or nitrogen atoms. Compounds within the scope of the
invention include porphyrins, mono-, di-, tri- and
tetra-azaporphyrins, and porphyrin isomers such as porphycenes,
isoporphycenes, hemiporphycenes, corroles, corrphycenes, and the
like, provided they are capable of coordinating a metal ion.
[0153] 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 of the invention
derived from blood derived porphyrins, for example hematoporphyrin
or hemin. Several porphyrin classes can be synthesized by the
routes shown. In these examples, hematoporphyrin can be modified by
those skilled in the art by well known methods to give compounds
(usually as their dimethyl esters) that possess defined
functionality at R (Scheme 1). The R substituents most commonly
utilized are vinyl (protoporphyrin IX) (2), ethyl (mesoporphyrin
IX) (3), hydrogen (deuteroporphyrin IX) (4), CH(Oalkyl)CH.sub.3
(hematoporphyrin ethers) (5), and halogens (halogenated
deuteroporphyrin IX) (6). Porphyrins that may be derived from
plants are shown in Scheme 2. Particularly advantageous are the
porphyrins such as 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 then modified according
to the invention to increase their biological activity. 9 10
[0154] While both blood and plant derived porphyrins are preferred
as starting materials due to their commercial availablity, a very
large number of synthetic porphyrins are generally applicable to
the invention. Such porphyrins may be made by synthetic methods
known to those skilled in the art, via coupling of pyrrolic
precursors, dipyrromethanes, dipyrromethenes and biladienes to give
the desired 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 1-3 in "The Porphyrin Handbook" Editors, K. M. Kadish, K.
M. Smith, R. Guilard, Volume 1, Academic press, 2000, pp. 1-148,
the disclosure of which is incorporated by reference herein. Such
functionality will be explained in detail shortly. This
functionality may be modified by further chemical reactions. Such
compounds may then be modified according to the invention to
produce metalloporphyrins that absorb light at or about 400, 532
and 575 nm. While these wavelengths are preferred, it is recognized
that other wavelengths >400 nm and less than 600 nm may be used
to excite compounds that absorb in this region. 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 11 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 dialkylether 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
[0155] A second preferred class of compounds according to the
invention are the mono-, di, -tri and tetra-azaporphyrins. Schemes
3-7 outlines the synthesis of mono-, di- and tetra-azaporphyrins,
examples of which are listed in Table 2.
2TABLE 2 12 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
[0156] Schemes 3-7 outline synthetic routes to novel tetrapyrrolic
molecules of interest in treating diseases of the cardiovascular
system and other diseases applicable to PDT. Such derivatives are
of particular interest because all display absorption maximas at
wavelengths at or near 400 nm, 532 nm and 575 nm.
[0157] 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 are obtained via the coupling of
5,5'-dibromopyrromethenes with sodium azide. Tetraazaporphyrins are
synthesized most efficiently via the treatment of substituted
maleonitriles with Mg powder or magnesium alcoxides. Such reactions
are well known in the art and are outlined in detail by N.
Kobayashi in "The Porphyrin Handbook" Editors, K. M. Kadish, K. M.
Smith, R. Guilard, Volume 2, Chapter 13, Academic press, 2000, p.
301-360, the disclosure of which is incorporated by reference
herein.
[0158] The peripheral functionality of these compounds is important
with respect to further derivatization to achieve the desired
therapeutic effect. 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. Some of these compounds for example, are shown in
Table 3.
[0159] 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 on which at least
one hydroxylated residue is present. The new porphyrins themselves
may be photodynamically active as metal free analogs and therefore
useful as PDT agents. However, metallated derivatives of these
compounds are of particular interest in treatment of 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 system; or olfactory system; where shorter
wavelengths of light are necessary or advantageous to effect a
desired therapy. In particular, porphyrin derivatives coordinating
gallium are very interesting as these have been demonstrated to
have greater uptake and efficacy in eliminating smooth muscle cells
from the media and intima portions of arteries in a variety of
animal models, than do other metalloporphyrins with different metal
centers. These findings are discussed in detail in the Biological
section.
[0160] 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 on which at least
one hydroxylated residue is present. The new porphyrins themselves
may be photodynamically active as metal free analogs and therefore
useful as PDT agents. However, metallated derivatives of these
compounds are of particular interest in treatment of 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 system; or olfactory system; where shorter
wavelengths of light are necessary or advantageous to effect a
desired therapy. In particular, porphyrin derivatives co-ordinating
gallium are very interesting as these have been demonstrated to
have greater uptake and efficacy in eliminating smooth muscle cells
from the media and intima portions of arteries in a variety of
animal models, than do other metalloporphyrins with different metal
centers. These findings are discussed in detail in the Biological
section.
[0161] Schemes 3-7 outline chemistry that has been undertaken to
produce photosensitizing agents according to the invention and are
not intended to limit the scope of 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 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. 1314 15 16 17 18
[0162] Synthesis of Metallotetrapyrroles
[0163] A) Acids and Salts of Metalloporphyrin and
Metalloazaporohyrins.
[0164] A number of metalloporphyrins and metallo azaporphyrin acids
and salts were synthesized. In general, a suitable free base
tetrapyrrole ester was metallated and the ester functionality
hydrolyzed using either basic or acidic conditions. Metal
incorporation followed standard procedures well known in the art
(see Johann Walter Buchler in "The Porphyrins", Ed. D. Dolphin,
Academic Press, Chapter 10, 389-483). Isolation of the
metallotetrapyrrolic acids was achieved by acidifying the
metallotetrapyrrolic salt with acetic acid after the ester
hydrolysis step, and the precipitated porphyrin collected.
Preparation of the corresponding salts was most readily achieved by
dissolution of the acid metalloporphyrin with a stoichiometric
amount of either KOH or NaOH.
[0165] B) Esters of Metalloporphyrins and Metalloazaporphyrins.
[0166] A large number of metalloporphyrins and metallo azaporphyrin
esters were synthesized. In general, a suitable free base
tetrapyrrole acid was esterified using the appropriate alcohol and
mineral acid (5%, H.sub.2SO.sub.4). Metallation of the ester
tetrapyrrole was achieved as described above.
[0167] C) Amide Derivatives of Metalloporphyrins and
Azaporphyrins.
[0168] Metallotetrapyrrolic amides were conveniently prepared using
the metal free tetrapyrrolic acids. The metal free tetrapyrrolic
acid compound was suspended or dissolved in dichloromethane and
subsequently refluxed after the addition of oxaylchloride for 1-2
hrs or less. Removal of the solvent under dry conditions, followed
by dissolution in dry dichloromethane and addition of the desired
amine, produced the corresponding amide. Metallation was then
achieved as described above. It was noted that in several instances
where alcohol moieties were present on the molecule, attempts to
metallate with gallium or indium or tin, using NaOAc as the proton
scavenger, resulted in acetylation of the alcohol moiety. It was
found convenient to hydrolyze the acetyl groups following the
metallation process using K.sub.2CO.sub.3/methanol/H.sub.2O or
dilute KOH/methanol/H.sub.2O.
[0169] Alternatively, ester functionalities on tetrapyrrolic
molecules may be reacted with amines at high temperature to produce
the corresponding amides. These, in turn, may be metallated to
produce metalloporphyrins with absorptions ranging between 500 and
600 nm.
[0170] Synthesis of Functionalized Metalloporphyrins and
Azaporphyrins.
[0171] The tetrapyrroles employed in the present invention to form
the aforementioned amide bond include two major classes that are
both well-known to those skilled in the art: 1) the carboxy or
amino-containing tetrapyrroles derived by various means
synthetically or from natural porphyrins; and 2) the
carboxy-containing meso-tetraphenylporphyrins. Exemplary
tetrapyrroles valuable for the preparation of the compounds
contemplated by the present invention are listed in Table 1.
[0172] A wide variety of functionality can be efficiently added to
the macrocycles by way of the amide bond. Of particular interest
are the tetrapyrrolic macrocycles bearing alkylamide
functionalities, amino acids or amides of amino alcohols. In the
latter instance, the amide bond is formed via coupling of a
tetrapyrrolic carbonyl moiety with an amino alcohol such that
mono-, di- or polyhydroxylated acyclic or cyclic, primary or
secondary amides are formed. Thus, various amino alcohols are
valuable for the present invention, including 2-aminoethanol,
2-amino-1,3-propanediol, 2-amino-2-(hydroxymethyl)-1,3-propanediol,
D-glucosamine and similar such amino alcohols. Alternatively, amine
containing tetrapyrroles may be coupled to carbonyl groups of a
second functionalized compound thus forming compounds that are
themselves amides.
[0173] A) Reduction of Ester Functionalities of Porphyrins and
Azaporphyrins.
[0174] In general, ester reduction of metal free tetrapyrroles with
lithium aluminium hydride produces the corresponding di-propyl
alcohol derivatives. These derivatives can then be directly
metallated to give metalloporphyrin di-alcohol complexes as
described above with due consideration given to the acetylation of
the alcohol. In some instances, for example with Pt tetrapyrroles,
it was found more convienient to metallate the tetrapyrrole first
then undertake the reduction of the ester.
[0175] B) Reaction of Di-Propyl Alcohol Tetrapyrrole
Derivatives
[0176] The di-alcohol porphyrins and azaporphyrins may be modified
in a number of ways. For example, they may be protected with
tosylchloride or a similar leaving group and reacted with amines to
give functionalized amino porphyrins, or reacted with salts of
alcohols, thiols or malonate esters to give functionalized esters,
ethers or functionalized thioethers which may be modified
accordingly. In addition, the alcohol moiety may be replaced by a
halogen (Scheme 3) and the subsequent mono or polyhalogenated
tetrapyrrole reacted with lithium reagents to form corresponding
adducts. Examples of lithium reagents are
Li(CH.sub.2).sub.nCO.sub.2alkyl (where n=1-4), and lithiated
aromatic reagents. In this way tetrapyrrolic molecules with longer
alkyl chain carboxylic acid or ester functionalities may be
produced and metallated.
[0177] Alternatively, the mono- or polyhalogenated tetrapyrrole can
be reacted with NaCN, which after treatment with HCl in methanol
gives the corresponding tetrapyrrolic molecule with longer alkyl
chain carboxylic acid or ester functionalities, which may be
metallated. Also, such longer chain tetrapyrrolic esters may be
made directly from biladienes routes.
[0178] In another alternative, the mono- or polyhalogenated
tetrapyrrole can be reacted with PO(O-alkyl.sub.3) producing
--CH.sub.2PO(O-alkyl).sub- .2 analogs that may be used directly or
further modified by standard techniques.
[0179] The dialcohol porphyrins and azaporphyrins can also be
modified by reaction with acid chlorides and the like to form
functionalized esters, by reaction with sulfonyl chlorides to
produce the corresponding esters, or by reaction with phosphoryl
chlorides to produce the corresponding phosphate esters or
acids.
[0180] Similar reactions may 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 as metallo-derivatives of such compounds
have larger molar extinction coefficients than the porphyrins in
the green and yellow region. Thus, these compounds theoretically
may be more efficient photosensitizers because a larger
cross-sectional area of light may be absorbed. While the above
examples list several chemical modifications to the tetrapyrrolic
compounds, other modifications known to those skilled in the art
could be made to the tetrapyrrolic ring systems without departing
from the spirit or scope of the invention.
[0181] Biological Evaluation of Photosensitizers
[0182] Metalloporphyrins were examined for biological efficacy in a
variety of in vitro and in vivo model systems.
[0183] In Vitro Cytotoxicity Assay
[0184] The in vitro biological evaluation of photosensitizers for
their ability to photosensitize cells was performed using standard
procedures. Using 5% FBS/DMEM phenol-free media, wells (180
.mu.l/well) were plated with 5.times.10.sup.4 V79 (Chinese Hamster
Lung Fibroblasts) cells/ml into two 96 well plates. Plate 1 was
light-treated and plate 2 served as a control. The plates were
Incubated at 37.degree. C., 5% CO.sub.2 for 3-5 hours. Standard
solutions of the photosensitizers were dissolved in pre-filtered
Dimethyl Sulfoxide (DMSO). Drug was diluted in 5% FBS DMEM phenol
free medium. Final drug concentrations for light and dark
experiments were 0.01, 0.1, 1.0, 3.0 and 5.0 .mu.M. Twenty
microliters of each concentration were added to six replicate wells
to the light and dark plate. The plates were wrapped in aluminum
foil to avoid photoactivation and mixed in a gyratory shaker for
approximately 2 minutes. Both plates were incubated for 24 hours at
37.degree. C., 5% CO.sub.2. After a 24 hour incubation,
drug-containing media was aspirated from the plates. Each well was
rinsed with 180 .mu.l Hepes buffer salt solution (HBSS) then
aspirated to remove the HBSS. 180 .mu.l of fresh media were added
(5% FBS/DMEM phenol-free) to each well. Plate 1 was immediately
light treated at a wavelength of 532 nm (metalloporphyrins and Pt
azaporphyrins) or 575 nm (metalloazaporphyrins) with a power
setting of 354 mW and a fluence of 1.25 J/cm.sup.2 for 7 min 22
seconds. Plate 2 was not light treated. Immediately after light
treatment, 20 .mu.l Alamar blue was added to each well in plate 1.
Alamar blue was added to plate 2 immediately after fresh media was
added. The plates were mixed on a gyratory shaker for 5 min.
[0185] Both plates were incubated under dark conditions for 24
hours at 37.degree. C, 5% CO.sub.2. After 24 hour incubation, the
plates were read on a plate reader spectrophotometer (Spectra Max
250) at wavelengths 570 and 600 nm. and the percentage of cell
survival recorded. Tables 3, 4, 5, and 6 contain in vitro light
EC50 data for the new photosensitizers. The Light EC50 data
compares photosensitizers for their ability to kill cells at
various concentrations. Photosensitizers that showed promise passed
into the in-vivo animal models.
[0186] In Vivo
[0187] Evaluation of Metallotetrapyrrolic Photosensitizers on
Skin
[0188] We tested metallo- and metal-free tetrapyrroles systemically
(see following section) for normal skin response in relation to the
pharmacodynamic distribution of the photosensitizers in CD hairless
rats. The skin of CD hairless rats are poorly developed, often
referred to as hyperkeratotic, with various sized cystic hair
follicles containing concentric lamellar accumulations of
keratinaceous material, which are often associated with enlarged
sebaceous glands. It quickly became apparent that gallium
tetrapyrroles induced a marked clearing of the hyperkeratotic
lesions in the treatment areas on the hairless rats. In fact, this
clearing could be induced without necrosis of the skin. No other
metallotetrapyrrole type produced such effects. This observation
led us to assess the metallotetrapyrrolic compounds for skin
restructuring effects both topically and systemically and for their
ability to reduce hair growth in the following animal models.
[0189] A) Systemic In-Vivo Normal Skin Response (CD Hairless
Rats)
[0190] Photosensitizer normal skin response as well as skin healing
response, was evaluated using CD Hairless male rats.
Photosensitizers were administered in an liposomal egg yolk
phospholipid formulation at 1, 1.5 and 2 .mu.mol/kg body weight
formulation per dose group as a single bolus intravenous injection
given through a marginal tail vein using a 27 gauge needle and a 1
cc tuberculin syringe. Normal skin responses were evaluated by
irradiating several spots on the skin of the rat with a 532 nm
laser (150 mW/cm.sup.2, 150J, 1 cm diameter) at 1, 6, 24, 48, and
96 hrs post injection. Normal skin responses were evaluated and
documented. The time at which the last spot is observed at the
concentration injected is reported in the far right hand column in
Tables 3, 4, 5 and 6. Skin samples were taken for histological
evaluation at days 1, 10, 20 and 22 post light treatment. Rats were
housed under normal lighting and all study procedures involving the
test article were conducted under light filtered through blue and
green Roscolox light filters to prevent photoactivation or
degradation of the drug.
[0191] Systemic Results
[0192] A total of 160 free base and metallotetrapyrrolic
photosensitizers were evaluated in the model and, surprisingly, the
only compounds that showed clearing of the hyperkeratotic lesions
without normal skin responses or necrosis were the
gallium-containing tetrapyrroles. Histologically, the skin
responses observed were identical to that induced topically, which
is explained in detail in the following section. Typically, in the
metallo or free base tetrapyrroles studied, at drug doses of 1.0,
1.5 or 2.0 .mu.mol/kg, there were skin responses with light
treatment over the range of 1 to 96 hours post drug administration,
depending on the skin pharmacokinetics of the molecules (see Tables
3, 4, 5, 6 for example). At the higher drug doses, indicated skin
responses, included moderate eschar, mild purpura and mild to
moderate halo with light treatment. In most instances, skin
responses resulted in the formation of an escar, which healed over
14-20 days to give an excellent cosmetic effect. In general,
optimal skin responses which included escar formation, resulted
histologically in full epidermal necrosis, extending in most cases
to 300 .mu.m into the dermis. Such destruction of the skin tissue
makes these gallium-containing tetrapyrroles very interesting with
respect to ablation of superficial diseases including superficial
cancers of the skin, barrets esophagus, early stage lung cancer,
actinic keratosis, basal cell carcinomas and the like. While many
tetrapyrrolic compounds are able to induce necrosis of the
epidermal layer, only the gallium tetrapyrrolic compounds under
specific drug/light and time dose combinations are able to induce
necrosis of the epidermal layer or alternatively cause clearing of
hyperkeratotic skin lesions with deposition of collagen formation
(see following section) without necrosis of the skin. Such skin
clearing is observed easily at lower drug doses (for example 1
.mu.mol/Kg) at treatment times of 24, 48 or 96 hrs post drug
injection, which failed to give escar, purpura or halo skin
responses.
[0193] B) Topical In-Vivo Normal Skin Response
[0194] Topically applied Gallium tetrapyrroles (3, 15 and 66)
dissolved at a concentration of 0.1-0.4% in several gel
formulations (formulation ingredients: benzylalcohol 0-30%, oleyl
alcohol 0-2%, hydroxypropylcellulose 0.5-2.0%, ethanol Qs (amount
required to make the formulation to 100%)) were assessed for their
ability to cause skin necrosis, hair removal and surface
remodelling in the rat and guinea pig models using the following
protocols. Data described below corresponds to a formulation where
the formulation excipients were benzylalcohol 19.6%, oleyl alcohol
2%, hydroxypropylcellulose 1.5%, ethanol Qs (amount required to
make the formulation to 100%).
[0195] Guinea Pigs (Single Topical Dermal Application):
[0196] 12 week old female albino Hartley guinea pigs (Simonsen:Sim
HA) (n=3) were used to assess the effects of photodynamic therapy
with the gallium tetrapyrroles in gel vehicle applied to the skin.
Gallium tetrapyrroles in gel vehicle were administered at 0.1
mg/cm.sup.2 (0.45% w/w) to a total of 3 guinea pigs as a single
application to 1 cm.sup.2 treatment areas (30 .mu.l vehicle gel or
formulated drug/spot) without subsequent occlusion. Light treatment
at 400 J/cm.sup.2 was administered 24 hours post drug application.
Skin responses were evaluated daily for 3 weeks after light
treatment. The test site was clipped one day prior to treatment and
as necessary for skin observations. Guinea pigs were housed and all
study procedures involving the test article were conducted under
light filtered through blue and green light filters to prevent
photoactivation or degradation of the drugs.
[0197] Sprague Dawley Rats (Single Topical Dermal Application):
[0198] 12 week old male Sprague Dawley rats (Harlan) (n=11) were
used to assess the effects of photodynamic therapy with gallium
tetrapyrroles (121, 15, 66) in gel vehicle applied to the skin.
Gallium tetrapyrroles in gel vehicle were administered at 0.14 (30
.mu.L), 0.28 (200 .mu.L), or 0.6 (30 .mu.L) mg/cm.sup.2 (0.45%,
0.45%, 2% w/w, respectively) to a total of 11 rats as a single
application to 1 cm.sup.2 treatment areas (30-200 .mu.l/treatment
spot) with semi-occlusion. Light treatment at 400 J/cm.sup.2 was
administered at 4 and 24 hours post drug application. Skin
responses were evaluated up to 3 months post light treatment. The
test site was clipped one day prior to treatment and as necessary
for skin observations. Skin samples were taken for histological
evaluation at days 1, 10, 20 and 28 post light treatment. Rats were
housed under normal lighting and all study procedures involving the
test article were conducted under light filtered through blue and
green filters to prevent photoactivation or degradation of the
drugs.
[0199] Histological Evaluation
[0200] The extent of epidermal and/or dermal involvement was
determined via histological evaluation. The grading parameters for
histological evaluation included the degree of epidermal/dermal
necrosis, the depth of necrosis, edema, and infiltration of
heterophils in the epidermis/dermis. Skin was also evaluated for
collage, elastin, fibronectin and immune cells via
immunohistochemistry. Tissues collected for histopathology were
placed in plastic embedding cassettes and immersed in 10% phosphate
buffered formalin. Fixed tissues were paraffin-embedded and
sectioned into approximately 4-8 .mu.m thickness slices using a
microtome. Slides were stained using hematoxylin and eosin or
collagen/elastin stains and interpreted by a qualified veterinary
pathologist blinded to the study groups.
[0201] Topical Results:
[0202] Guinea Pigs
[0203] All three gallium tetrapyrroles behaved similarly in the
topical animal models. Clearing (early scarring or extracellular
matrix deposition) with very mild eschar formation was seen in the
skin for approximately 7-14 days post light treatment. No other
skin responses were noted. Hair regrowth was not affected.
[0204] Hairless Rats
[0205] With the exception of clearing of the hyperkeratotic skin
(remodeling of epidermal/dermal skin) at 7 days post light
treatment, there was no skin response in animals that were light
treated 24 hours post drug administration topically. Clearing
(early scarring or extracellular matrix deposition) was seen for up
to 40 days post light treatment. Within the dermis at the
dermal/epidermal border, there was an approximately 75 .mu.m thick
zone of increased cellularity consisting of spindle to stellate
cells with oval nuclei consistent with fibroblasts. The stroma in
this area was pale and eosinophilic compared to the underlying
unaffected dermis. At the early light treatment time points, there
was mild serocellular crust indicating epidermal necrosis.
[0206] Sprague Dawley Rats
[0207] Using compound 3 topically, there was no skin response at
0.14 mg/cm.sup.2, however the time for hair regrowth was delayed
for approximately 21 days. At 0.28 mg/cm.sup.2, clearing formation
(early scarring or extracellular matrix deposition) of the skin was
seen at 7 days post light treatment and persisted for at least 28
days. There were no other skin responses observed in animals
treated at 0.28 mg/cm.sup.2. At 0.28 mg/cm.sup.2, hair regrowth was
delayed in the treatment site for approximately 38 days post light
treatment. At 0.6 mg/cm.sup.2, there were skin responses (small,
slight eschar) for up to approximately 10 days post light
treatment, followed by clearing formation (early scarring or
extracellular matrix deposition) for at least 30 days and with
variable clearing persisting for up to 3 months post light
treatment.
[0208] At 0.6 mg/cm.sup.2, hair did not regrow in the treatment
site for approximately 38 days post light treatment. Within the
dermis at the dermal/epidermal border, there was an approximately
75 .mu.m thick zone of increased cellularity consisting of spindle
to stellate cells with oval nuclei consistent with fibroblasts. The
stroma in this area was pale and eosinophilic compared to the
underlying unaffected dermis. At the higher drug doses, there was
mild serocellular crust indicating epidermal necrosis. There were
also scattered lymphocytes and neutrophils. No changes were noted
in the hair follicle.
[0209] The pale and fibrillar collagen was consistent with
remodeling of the epidermis and represents a more immature
connective tissue at the dermal/epidermal junction of the dermis.
There was no difference in elastin fibers in cases with the
previously described pale stroma at the dermal/epidermal junction
as compared to sections that did not have the pale zone. In all
sections examined, the dermis contained less than 5% elastin
stained fibers. Based on these findings, a change in elastin fibers
is not evident within the dermis.
[0210] The epidermal changes found in this study are consistent for
the three photosensitizers tested topically and for the
systemically administered gallium tetrapyrroles. These changes are
usually present following regrowth of the epidermis after necrosis
or ulceration. However, based on the lack of gross necrosis or
ulceration of the overlying epidermis in most cases, this change is
most likely a direct affect of the treatment. The replacement of
granulation tissue with scarring with no or minimal necrosis
involves transitions in the composition of the extracellular
matrix. Some of the growth factors that stimulate synthesis of
collagen and other connective tissue molecules also modulate the
synthesis and activation of metalloproteinases or other proteolytic
enzymes. The net result of extracellular matrix synthesis versus
degradation results in remodeling of the connective tissue
framework, an important feature of both chronic inflammation and
wound repair. Based on these observations, systemic or topical
application of gallium tetrapyrrolic compounds produces unique skin
restructuring processes that were not observed for any of the other
metal free or metallo tetrapyrrolic photosensitizers studied and
may be particularly valuable for the treatment of epithelial or
endothelial cell layers of tissues, scars, wound healing,
psoriasis, chronic inflammatory diseases, eczema, immune modulated
diseases, scleraderma, shingles, wrinkles, hair removal, actinic
keratosis, carcinomas or sarcoma of the skin or other tissues,
fungual infections, viral or bacterial infections, warts,
arthritis, port wine stains, birth marks, stretch marks, hyper
pigmentation, urticaria, allegenic reactions, chronic proliferative
dermatitis, chronic ulcerative dermatitis, disorders of hair or
hair follicles, disorders of skin pigmentation, acne, cutaneous
infections, skin tumors, seborrheic dermatitis, cutaneous
vasculitis, erythema multiforme and nodosum.
[0211] In Vivo Rat Corotid Artery
[0212] The acute effects of metallated photosensitizers, in
response to light activation, to cause depletion of cell
populations in the medial and adventitial layers of vessels was
measured in normal uninjured rat carotid arteries. Sprague Dawley
rats (Harlan, Ind., USA) received an intravenous injection of the
test substance (at doses typically 0.5-4 .mu.mol/kg body weight, in
a liposomal egg yolk phospholipid formulation), 120-240 min before
light delivery. Shortly before the light treatment, the rats were
anaesthetized with 3.5% isoflurane (Abbott Laboratories, Ill., USA)
and the femoral region of the right leg was shaved and cleaned. A
small midline incision was made and a 1 cm region of the right
femoral artery was surgically exposed and dissected from
surrounding tissues.
[0213] A direct arteriotomy was performed and a light balloon
catheter (Miravant Medical Technologies, Inc) was introduced into
the vessel and advanced retrogradely into a non-manipulated region
of the left common carotid artery via the abdominal aorta. The
light catheter was then inflated at 1 atmosphere, to the dimensions
of 2 mm.times.20 mm, and light was delivered to the carotid artery
via a diffuser centered within the catheter. The light dosimetry
was fixed at 50 J/cm.sup.2 fluence and 160 mW/cm.sup.2 irradiance.
After light treatment and removal of the catheter, the right
femoral artery was tied off and the skin wound was closed. Rats
were sacrificed three days post treatment as this corresponds to
the known peak time that vascular cells, e.g., VSMC and
myofibroblasts, proliferate and migrate in response to an
injury.
[0214] The area spanning both left and right carotid arteries and
surrounding tissue was harvested, fixed, embedded in paraffin and
sectioned. The tissues were stained with Hematoxylin and Eosin
(Fisher Scientific, Pa.) and examined by light microscopy to
histologically assess the cell population density in the medial and
adventitial layers of the PDT-treated vessel wall. Tables 3, 4, 5
and 6 contain results expressed as the % maximum accellularity
(depletion of cell population densities) for the molecules tested.
Metallo azaporphyrins with Ga, Zn, Al, Sn were excited at 575 nm,
while Pt azaporphyrins were excited at 532 nm.
3TABLE 3 Porphyrins (nd = not done) 19 In Vitro EC50 Drug Max % rat
Response Example Light dose Artery (1 .mu.mol) No M R1 R3 R4 R2
(.mu.M) .mu.Mol Accelularity in hrs. Ga Et Me Et CO.sub.2H 2.0 1 15
24 109 Ga Et Me Et CO.sub.2Na 2.4 1 10/4 hrs, none 100/24 hrs 110
In Et Me Et CO.sub.2Na 1.0 1 0 nd 111 Pt Et Me Et CO.sub.2Na 0.7 1
0 nd 112 In V Me V CO.sub.2Na 1.5 1 0 nd 113 In
(CH.sub.2).sub.2CO.sub.- 2Na Me (CH.sub.2).sub.2CO.sub.2Na
CO.sub.2Na 3.6 1 0 nd 114 Ga Et Me Et CH.sub.2CH.sub.2CO.sub.2Na
2.3 1 20 24 1 Ga Et Me Et CO.sub.2Me 0.2 1 95 48 115 Ga Et Et Me
CO.sub.2Me 0.3 1 10 6 32 Sn Et Me Et CO.sub.2Me 1.4 1 20 24 31 In
Et Me Et CO.sub.2Me 0.07 1 90 96 29 Pt Et Me Et CO.sub.2Me nd nd nd
nd 30 Al Et Me Et CO.sub.2Me 3.0 1 0 24 33 Zn Et Me Et CO.sub.2Me
4.0 1 0 24 2 Ga Et Me Et CO.sub.2Et 0.49 1 80 24 3 Ga Et Me Et
CO.sub.2Pr 0.06 1 85 6 34 Ga Et Me Et CO.sub.2CH.sub.2CH.sub.2F 0.4
1 80 24 35 Ga Et Me Et CO.sub.2(CH.sub.2).sub.2CH.sub.2Cl 0.4 1 80
96 4 Ga H Me H CO.sub.2Me 0.4 1 95 6 5 Ga H Me H CO.sub.2Et 0.4 1
80 48 122 Ga H Me H CO.sub.2Pr 0.35 1 95 6 38 Ga H Me H
CO.sub.2CH.sub.2CF.sub.3 0.4 1 80 24 36 Ga H Me H
CO.sub.2(CH.sub.2).sub.2CH.sub.2Cl 0.4 1 80 96 37 Ga H Me H
CO.sub.2CH.sub.2CH.sub.2F 0.4 1 80 48 39 Ga Br Me Br CO.sub.2Me 0.4
1 75 6 40 Ga CH.sub.2OH Me CH.sub.2OH CO.sub.2Me 0.6 1 5 6 12 Ga
CH.sub.2N(CH.sub.3).sub.2 Me CH.sub.2N(CH.sub.3).sub.2 CO.sub.2Me
0.5 1 50 None 41 Pt CH.sub.2N(CH.sub.3).sub.2 Me
CH.sub.2N(CH.sub.3).sub.2 CO.sub.2Me 0.2 1 0 48 42 Ga V Me V
CO.sub.2Me 0.48 1 70 6 Sn V Me V CO.sub.2Me 1.4 1 10 24 Al V Me V
CO.sub.2Me 3.5 1 0 6 43 Ga VCH.sub.2N(CH.sub.3).sub.2 Me
VCH.sub.2N(CH.sub.3).sub.2 CO.sub.2Me 2.45 nd nd None 44 Ga
CH(OMe)CH.sub.3 Me CH(OMe)CH.sub.3 CONHMe 0.6 nd nd nd 26 Ga Et Me
Et CH.sub.2CO.sub.2Me 0.37 1 75 24 45 Sn Et Me Et
CH.sub.2CO.sub.2Me 1.5 1 20 24 46 In Et Me Et CH.sub.2CO.sub.2Me
0.04 1 90 48 47 Pt Et Me Et CH.sub.2CO.sub.2Me 0.2 1 20 48 48 Al Et
Me Et CH.sub.2CO.sub.2Me 4.0 1 0 24 49 Zn Et Me Et
CH.sub.2CO.sub.2Me 4.0 1 0 24 Ga Et Me Et CH.sub.2CO.sub.2Et 0.4 1
80 24 Ga Et Me Et CH.sub.2CO.sub.2CH.sub.2CH.sub.2F 0.4 1 75 24 50
Ga Et Me Et CH.sub.2CO.sub.2Pr 0.4 1 80 48 28 Ga Et Me Et
CH.sub.2CH.sub.2CO.sub.2Et 0.4 1 80 6 51 Sn Et Me Et
CH.sub.2CH.sub.2CO.sub.2Et 1.7 1 20 24 52 In Et Me Et
CH.sub.2CH.sub.2CO.sub.2Et 0.05 1 75 48 53 Pt Et Me Et
CH.sub.2CH.sub.2CO.sub.2Et 0.1 1 20 nd 54 Al Et Me Et
CH.sub.2CH.sub.2CO.sub.2Et 4.0 1 0 24 55 Zn Et Me Et
CH.sub.2CH.sub.2CO.sub.2Et 4.0 1 0 24 57 Ga Et Me Et
CH.sub.2CH.sub.2CO.sub.2Me 0.46 1 80 6 56 Ga Et Me Et
CH.sub.2CH.sub.2CO.sub.2Pr 0.4 1 75 24 121 Ga Et Me Et CONHMe 0.4 1
60 6 Ga Et Me Et CONH(Hexyl) 0.4 1 60 96 58 Sn Et Me Et CONHMe 1.2
1 10 24 59 In Et Me Et CONHMe 0.17 1 60 48 60 Pt Et Me Et CONHMe
0.12 1 25 96 61 Al Et Me Et CONHMe 2.0 nd nd nd 15 Ga Et Me Et
CON(Et).sub.2 0.45 1 60 96 62 Zn Et Me Et CON(Et).sub.2 4 1 0 24 63
Zn Et Me Et CONH(CH.sub.2).sub.3--N(CH.sub.2CH.sub.2).sub.2O 0.025
nd nd None 64 Zn Et Me Et CONH(CH.sub.2).sub.2--(C.sub.5H.sub.4N)
nd nd nd nd 11 Ga Et Me Et CONH(CH.sub.2).sub.2OMe 1.9 1 30 6 65 Pt
Et Me Et CONH(CH.sub.2).sub.2OMe 0.05 nd nd nd 66 Ga Et Me Et
CONH(CH.sub.2).sub.3OH 0.2 nd nd None 67 Pt Et Me Et
CONH(CH.sub.2).sub.3OH 0.1 nd nd nd 68 Ga H Me H
CONH(CH.sub.2).sub.3OH 3 nd nd nd 6 Ga H Me H CONHMe 4.05 nd nd nd
16 Ga Et Me Et CONH(CH.sub.2).sub.2--O(CH.sub.2).sub.2OH 2.9 nd nd
nd 69 Pt Et Me Et CONH(CH.sub.2).sub.2--O(CH.sub.2).sub.2OH 0.5 nd
nd None 70 Ga Et Me Et CONH(CH.sub.2).sub.2--N(CH.sub.3).s- ub.2
1.7 nd nd None 71 Pt Et Me Et CONH(CH.sub.2).sub.3--N(CH.sub.-
2).sub.3 0.2 1 nd 96 7a H2 Et Me Et CH.sub.2OH 0.4 0.16 7 none 72
In Et Me Et CH.sub.2OH 0.04 0.5 40 96 73 Al Et Me Et CH.sub.2OH 3.6
1 0 nd 7 Ga Et Me Et CH.sub.2OH 0.55 1 95 48 74 Pt Et Me Et
CH.sub.2OH 0.1 1 25 24 10 Ga Et Me Et CH.sub.2Ome 0.4 1 75 48 75 In
Et Me Et CH.sub.2Ome 0.06 1 75 96 Ga Et Me Et
CH.sub.2O(CH.sub.2).sub.2OH 0.5 nd nd nd Ga Et Me Et
CH.sub.2O(CH.sub.2).sub.2OCH.sub.3 0.43 nd nd nd 76 In Et Me Et
CH.sub.2N(CH.sub.2).sub.4 0.02 1 nd 96 77 Pt Et Me Et
CH.sub.2N(CH.sub.2).sub.4 0.1 1 25 96 78 Ga Et Me Et
CH.sub.2NH(CH.sub.2).sub.3OH 1 2 10 6 79 Zn Et Me Et
CH.sub.2N(Et).sub.2 0.4 1 nd None 80 Ga H Me H
CH.sub.2PO(OEt).sub.3 2 nd nd nd 81 In H Me H CH.sub.2PO(OEt).sub.3
0.4 nd nd 48 8 Ga H Me H CH.sub.2OH 0.4 1 80 96
[0215] Compounds in Table with no example number were tested but
not synthesized in the Examples.
[0216] Some compounds in Table were synthesized in Examples but not
tested.
4TABLE 4 Azaporphyrins (nd = not done) 20 Normal In Vitro Drug Max
% Rat Response Example R1, R2, EC(50) dose Artery (1 .mu.mol) No M
R3 R4 R (.mu.Mol) (.mu.Mol) Accelulartiy in hrs. H2 Et Et CO.sub.2H
0.45 1 0 None 87 Ga Et Et CO.sub.2H 0.31 1 30 24 88 Ga Et Et
CO.sub.2Na 0.5 4 10 (4 hrs) None 100 (24 hrs) 21 Ga Et Et
CO.sub.2Me 0.4 1 60 24 82 Sn Et Et CO.sub.2Me 0.4 1 30 96 83 In Et
Et CO.sub.2Me 0.03 1 50 48 85 Pt Et Et CO.sub.2Me 4 nd nd nd 86 Pt
Et Et CO.sub.2K 0.4 1 nd 96 84 Al Et Et CO.sub.2Me 0.04 1 50 48 89
Ga Et Et CO.sub.2Et 0.4 1 60 24 22 Ga Et Et CONHMe 0.45 0.5 50 48
90 Sn Et Et CONHMe 0.5 1 30 96 91 In Et Et CONHMe 0.07 1 50 48 92
Pt Et Et CONHMe 2.3 nd nd nd 93 Al Et Et CONHMe 0.1 nd nd nd 19 Ga
Me V CO.sub.2Me 0.4 1 55 24 -- Ga Me V CONHMe 0.5 1 50 24 20 Ga Me
Et CO.sub.2Me 0.4 nd nd nd 94 Ga Me Et CONHMe 0.52 nd nd nd 95 Ga
Et Et CONH(CH.sub.2).sub.2OMe 2.0 nd nd nd 96 Pt Et Et
CONH(CH.sub.2).sub.2OMe 1.8 nd nd nd 97 Ga Et Et
CONH(CH.sub.2).sub.3OH 1.7 nd nd nd 98 Pt Et Et
CONH(CH.sub.2).sub.3OH 2.0 nd nd nd 99 Ga Me Et
CONH(CH.sub.2).sub.3OH 0.5 nd nd nd 100 Ga Et Et
CONH(CH.sub.2).sub.2O(CH.sub.2).sub.2OH 1.3 nd nd nd 101 Pt Et Et
CONH(CH.sub.2).sub.2O(CH.sub.2).sub.2OH 1.5 nd nd nd 102 Ga Et Et
CONH(CH.sub.2).sub.2N(CH.sub.3).sub.2 0.7 nd nd nd 103 Pt Et Et
CONH(CH.sub.2).sub.2N(CH.sub.3).sub.2 1.2 nd nd nd Ga Me
CH(OMe)CH.sub.3 CO.sub.2Me 1.0 nd nd nd 105 Pt Et Et CH.sub.2OH
0.04 nd nd 96 104 In Et Et CH.sub.2OH 0.03 nd nd 96 23 Ga Et Et
CH.sub.2OH 0.05 1 50 96 106 Ga Et Et CH.sub.2OMe 1.0 nd nd nd 107
In Et Et CH.sub.2OMe 0.05 nd nd 96 108 Ga Et Et CH.sub.2CO.sub.2Me
0.4 1 55 24
[0217]
5TABLE 5 Plant derived gallium porphyrins 21 Normal In Vitro Drug
Max % Rat Skin Example EC(50) dose Artery Response No M R1 R2 R3 R4
R5 (.mu.M) (.mu.Mol) Accelularity (1 .mu.mol) 13 Ga CO.sub.2Me Et
Et CO.sub.2Me CH.sub.2CO.sub.2Me 0.4 1 70 6 123 Ga CO.sub.2Me Et Et
CO.sub.2Me H 0.4 1 60 6 14 Ga CO.sub.2Me Et Et CONHMe
CH.sub.2CO.sub.2Me 0.29 1 65 6 Ga CO.sub.2H Et Et CONHMe H 0.5 1 50
6 Ga CONHMe Et Et CO.sub.2Me H 0.42 1 65 6 Ga CH.sub.2OH Et Et
CH.sub.2OH H 0.41 1 70 48
[0218]
6TABLE 6 Metallodiazaporphyrins 22 Normal In Vitro Drug Max % Rat
Skin Example EC(50) dose Artery Response No M R1 R2 R3 (.mu.M)
(.mu.Mol) Accelularity (1 .mu.mol) 116 Ga Me
(CH.sub.2).sub.2CO.sub.2Me H 0.35 1 55 24 118 Ga Me
(CH.sub.2).sub.2CH.sub.2OH H 0.3 nd nd nd 117 Ga Me
(CH.sub.2).sub.2CO.sub.2H H 0.6 nd nd nd 119 Pt Me
(CH.sub.2).sub.2CO.sub.2Me H 0.35 nd nd nd 120 Pt Me
(CH.sub.2).sub.2CH.sub.2OH H 0.06 nd nd nd Ga Et Et
p-(C.sub.6H.sub.4)OCH.sub.3 0.6 nd nd nd Pt Et Et
p-(C.sub.6H.sub.4)OCH.sub.3 0.3 nd nd nd
[0219] In Vivo Pig Coronary Artery Experiments
[0220] Those photosensitizers showing excellent efficacy in the rat
carotid artery model were evaluated in more detail in the pig
coronary artery model (Waksman, R., Rodriguez, J. C., Robinson, K.
A., Cipolla, G. D., Crocker, I. R., Scott, N. A., King, S. B.,
Wilcox, J. N., Circulation, 96, 1944-1952, 1997). If vascular PDT
is to be proposed as a therapy to prevent restenosis in humans due
to angioplasty or stenting, then it must first be shown to be
effective in a large animal model such as the swine. Porcine
coronary arteries are very similar to human coronary arteries with
regard to size, neointima formation, and thrombosis in response to
injury.
[0221] The swine model has been utilized in the preclinical
evaluation of interventions to reduce restenosis for several
reasons. Chief among these reasons are the similarities in (i) size
and anatomy of the swine arteries to human arteries, that permits
instrumentation and evaluation of results via catheters; and (ii)
histopathological characteristics of the proliferative response
following artery injury similar to that seen in humans.
Furthermore, large animals including the swine have proven to be
more predictive of success in reducing restenosis in humans than
have small animal models. An extensive literature search (e.g.,
Weiner, B. H., et al. Circulation. 72:1081-1086,1985; Schwartz, R.
S., et al. Circulation. 82:2190-2200, 1990; Vascular Brachytherapy,
Veenendaal, The Netherlands:Nucletron B.V. 1996 pp. 1-382) supports
the notion that restenosis after balloon injury in porcine
coronaries is the best model when compared to restenosis in humans.
Therapies investigated in other species still must be confirmed in
the porcine model. Several articles reviewing the relevant animal
models for the study of restenosis have concluded that although
imperfect, as are all animal models, the porcine model is still the
best from the standpoint of similarity to human disease, ease of
use, and cost (e.g., Schwartz, R. S., Murphy, J. G., Edwards, W.
D., Camrud, A. R., Vlietstra, R. E., and Holmes, D. R. Restenosis
after balloon angioplasty: A practical proliferative model in the
porcine coronary arteries. Circulation. 82:2190-2200, 1990; Karas,
S. P., Gravanis, M. B., Santoian, E. C., Robinson, K. A., and King,
S. B., 3d Coronary intimal proliferation after balloon injury and
stenting in swine: an animal model of restenosis. J. Am. Coll.
Cardiology 20:467-474, 1992).
[0222] Photosensitizers were administered systemically (at doses
typically 2-3.5 mg/kg body weight, in a soybean phospholipid
formulation) as a slow bolus injection in the ear vein. Drug
treatments were followed (1-4 hr later) by endovascular light
treatment (50-250 J/cm.sup.2 fluence and 100-300 mW/cm.sup.2
irradiance) in uninjured coronary (50-250 J/cm.sup.2 fluence and
100-300 mW/cm.sup.2 irradiance) and iliac (50-350 J/cm.sup.2
fluence and 100-450 mW/cm.sup.2 irradiance) arteries. In another
set of experiments, animals also received balloon injuries in the
coronary arteries at the time of PDT treatment. Angioplasty
injuries in 2 coronary arteries were performed. Vital signs and
cardiovascular parameters such as ECG, HR, BP, were monitored
together with arterio-angiograms for measurements of vessel
patency.
[0223] For acute experiments done in uninjured arteries, 3-5 days
after the PDT experiments, animals were sacrificed and serial
sections of all relevant arteries (iliacs, & coronaries) were
harvested in 10% formalin and processed for histological
assessment. Results of PDT at this timepoint give us an insight
into the selective cellular effects of PDT on VSMC and
myofibroblasts which are known to be maximally proliferating and
migrating at this same time in response to a vessel wall
injury--such as an angioplasty.
[0224] For longer term efficacy experiments (14 days after the PDT
experiments) animals were sacrificed and serial sections of all
relevant arteries (coronaries only) were harvested in 10% formalin
and processed for histological assessment. Representative arterial
segments underwent parafin embedding and sectioning for Hemoxylin
& Eosin and/or elastin staining. Slides were prepared for
microscopy histological analysis of the (i) acute cellular
responses and (ii) inhibition of neointima formation following
treatment. Once prepared, the slides were analyzed via microscopy
for histomorphometry and effects such as medial wall acellularity,
arterial wall and surrounding tissue cell death and proliferation.
The results of acellularity (depletion of cell population
densities) and inhibition of restenosis are shown in Table 7.
Control arteries that were subjected to angioplasty balloon injury
displayed extensive neointimal development at 14 days as typically
seen in this model. In contrast, coronary arteries subjected to
angioplasty balloon injury and treated with the test substances and
light activation at the time of injury, had markedly reduced
neointimal formation. The magnitude of the inhibition was greater
than any other photosensitizer drug currently used by other groups
in PDT (clinically or pre-clinically), and was on the order of that
only previously seen with radiation in this model. Inhibition data
is averaged over the injury length within the artery.
7TABLE 7 Pig coronary artery data Ex- Drug Light dose Acellularity
Intimal hyperplasia ample dose of (%) Inhibition (14 days) No mg/Kg
532 nm light (3 days) Av. over injury 1 1 55J, 125J/cm2, 50 nd 250
mW 1 2 55 J, 125 J/cm2, 70 nd 250 mW 1 3 55 J, 125 J/cm2, 100
>80% 250 mW 4 1 55 J, 125 J/cm2, 50 nd 250 mW 4 2 55 J, 125
J/cm2, 70 nd 250 mW 4 3 55 J, 125 J/cm2, 95 >70% 250 mW 121 1 55
J, 125 J/cm2, 45 nd 250 mW 121 2 55 J, 125 J/cm2, 75 nd 250 mW 121
3 55 J, 125 J/cm2, 95 >70% 250 mW
[0225] Biological Results of metalloporphyrins and
Metalloazaporphyrins In Vitro and in Restenosis Animal Models In
Vivo.
[0226] Before this study very little information was known about
the uptake and biodistribution of metallotetrapyrrolic compounds
biologically, either as their acids, salts, esters, amines or
amides. In particular, nothing is known about the distribution of
metalloporphyrins in cardiovascular diseases, nor has anyone
assessed structure-activity relationships. The following summary of
what has been determined is as follows.
[0227] A) Acids and Salts of Metalloporphyrin and
Metalloazaporphyrins.
[0228] A number of metalloporphyrins and metallo azaporphyrin acids
and salts were tested for efficacy. In vitro, several of these
compounds show the ability to kill cells. However, it appears that
the metallotetrapyrrolic salts at early treatment time points
post-administration are slightly less efficacious at the same drug
dose than the metallotetrapyrrolic acid compounds in vivo. For
example, as shown in Table 3, the disodium salt (109) shows 10%
accelularity at a four hour treatment point using the above
described protocol, whereas its acid derivative shows 15%
accelularity. A similar observation is seen between compounds 87
and 88 (30% and 10% respectively; Table 4). While this appears to
be a general observation, it is highly probable that water-soluble
compounds may be synthesized in accordance with the invention that,
given the correct pattern of peripheral substitution and functional
group selection, may show activity. Additionally, higher drug doses
may be required to effect a treatment. It is interesting to note
that the water soluble gallium porphyrins and azaporphyrins do not
display significant skin photosensitivity at the doses used, making
them potentially particularly interesting and valuable compounds.
For example, compounds 88 and 109 gave no observed normal skin
response at the drug doses used. It has also been noted that
significant acellularity occurs following PDT treatment of rat
arteries with water soluble gallium azaporphyrins and gallium
porphyrins at longer treatment times post injection (16, 24 hrs).
Examples of this are with compounds 109 and 88 (Table 4). It is
important to note that the metal-free azaporphyrin carboxylic acid
(first entry table 4) displays poor efficacy (0%, 4 hrs) in the
arterial rat model, even though in vitro it appeared to be a potent
molecule. We have investigated several other free base porphyrins
and all have poor efficacy in the arterial rat model at the time
point, drug and light dose parameters used (compound nos. (7a),
mesoporphyrin dimethyl ester, metal-free analogs of compounds (26)
and (28)). Thus it appears that metallation of tetrapyrrolic
macrocycles, especially with gallium, enhances efficacy
significantly.
[0229] B) Esters of Metalloporphyrins and Azaporphyrins.
[0230] The most active compounds tested for the elimination of
cells in the medial and adventitial layers of vascular vessels are
the esters (Tables 3 and 4). The nature of the ester functionality
has been shown to influence the biodistribution and skin
pharmacokinetic profile of the molecules. A surprising observation
is that in almost all of the cases, gallium tetrapyrrolic esters
are efficient at depleting cell population densities in the medial
and adventitial layers of vascular vessels, much more so than
almost all other metal types. For example, the superiority of the
gallium complexes over other metal types are shown with compound
(1) (Ga), as compared to compounds (31), (30), (33); compound
(12)(Ga), as compared to compound (41); compound (26)(Ga), as
compared to compounds (45), (47), (48), and (49) (the indium
complex (46) is more potent than the gallium complex (26), however
death occurs in the animals at 3.times. the therapeutic dose);
compound (28) (Ga), as compared to compounds (51), (52), (53),
(54), and (55); compound (121) (Ga), as compared to compounds (58),
(59), and (60); compound (7) (Ga), as compared to compounds (72),
(73), (7a), (74); and compound (21)(Ga), as compared to compounds
(82), (83), and (84). Additionally, in pig coronary artery models,
no cardiotoxicity was observed with compounds (1), (4) or (121) at
doses exceeding 20 mg/Kg. Among the other metal types that also
look promising are the indium tetrapyrrolic ester compounds;
however, we have found that there is significant toxicity with the
indium porphyrins studied at drug doses close to that of the
therapeutic dose. This may limit their usefulness as therapeutic
agents administered intravenously.
[0231] As would be expected, changing the peripheral functionality
on the gallium tetrapyrrolic macrocycles changes their
pharmacokinetic and distribution profiles in vivo. In some
derivatives changing the methyl esters to ethyl esters also reduces
the clearance time from the skin of the molecule by a factor of 2.
One such example where this is illustrated is a comparison of
normal skin responses between gallium mesoporphyrin dimethyl ester
(1) and gallium mesoporphyrin diethyl ester (2). The dimethyl ester
(1) at a drug dose of 1 .mu.mol/Kg shows normal skin responses to
48 hrs post drug injection in rats (Table 3). Its ethyl ester
derivative on the other hand at identical drug and light doses
shows normal skin responses up to 24 hrs and not beyond (Table 3).
Another example is gallium deuteroporphyrin ethyl ester (5) and
propyl ester (122). The propyl ester (122) at a drug dose of 1
.mu.mol/Kg shows normal skin responses only to 6 hrs post drug
injection in rats versus 48 hrs as seen for the ethyl ester
derivative (5).
[0232] Also surprising is that increasing the alkyl chain length of
R.sub.2 (Table 3), e.g., from 0 carbon CH.sub.2 units (i.e.,
compound (1) a propionic acid ester side chain) to 5-CH.sub.2 units
(compound (57)), also decreases the normal skin response by a
factor of 8 (6 hr spot only at 1 .mu.mol/Kg), without a significant
decrease in biological activity (1 .mu.mol/Kg gives 80%
acellularity), when compared to compound (1) (1 .mu.mol/Kg, 95%).
Another example of note is that gallium rhodoporphyrin dimethyl
ester (123) is cleared more rapidly from the skin (6 hrs) than is
gallium mesoporphyrin dimethyl ester (1) (48 hrs). Such changes in
biological responses in response to the functional modifications to
tetrapyrrolic compounds have not previously been recognized. Two
such gallium tetrapyrrolic esters, gallium mesoporphyrin dimethyl
ester (1) and gallium deuteroporphyrin dimethyl ester (4) have
shown >80% and >75% average inhibition of intimal hyperplasia
over the length of the injured artery in pig coronary arteries
(Table 7; many treated artery sections show 100% inhibition). The
results with these test substances are comparable to that observed
only with vascular brachytherapy and to our knowledge are
dramatically better than any other photosensitizers described to
date in vascular studies with PDT.
[0233] C) Amide Derivatives of Metalloporphyrins and
Azaporphyrins.
[0234] Very little is known about the uptake and biodistribution of
metallotetrapyrrolic amide molecules. Metallocomplexes of gallium
tetrapyrrolic amides vary in biological activity. Simple amides
such as --CONHCH.sub.3 and --CON(Et.sub.2) appear to generate
excellent responses in cardiovascular tissues. In particular, it
has been found that replacing the methyl ester functionality in
certain tetrapyrrolic molecules with a methyl amide group
(--CONHCH.sub.3) decreases the skin clearance of the new amide
derivative in animals by a factor of approximately eight when
compared to the parent ester tetrapyrrole. Longer amide alkyl
chains result in longer skin clearance times (for example the
dihexyl amide derivative shows a 96 hr normal skin spot table 3).
The shortening of the skin clearance time for a molecule will have
major clinical implications to patients, as long periods of
photosensitivity are particularly undesirable. One such example
where this is illustrated is a comparison of normal skin responses
between gallium mesoporphyrin dimethyl ester (1) and gallium
mesoporphyrin N-methylamide (121), Table 3. The ester compound at a
drug dose of 1 .mu.mol/Kg shows normal skin responses to 48 hrs
post drug injection in rats. Its methylamide derivative (121) on
the other hand at identical drug and light doses shows normal skin
responses up to 6 hrs and not beyond. Additionally the stability of
the methyl amide derivative and the diethylamide derivative in
liposomal formulations may be longer than the diester analog, which
may prove to be valuable in the pharmaceutical development of such
compounds. Notable also is the fact that some of the
metallotetrapyrrolic amides show no normal skin response at the
doses used, and do not appear to be efficient photosensitizers.
Such compounds may be of immense value as radiodiagnostics (where
radioactive gallium isotopes are used for example) or as
fluorescence diagnostic agents. It should be noted that the methyl
amide derivative (121) of gallium mesoporphyrin at 3 mg/Kg, and
light fluence of 125 J/cm.sup.2 shows >75% average inhibition of
intimal hyperplasia over the length of the injured artery in pig
coronary arteries (Table 7; Many treated artery sections show 100%
inhibition). These results are comparable to that observed only
with vascular brachytherapy and to our knowledge are dramatically
better than any other photosensitizer described to date in vascular
studies with PDT.
[0235] D) Metalloporphyrin and Metalloazaporphyrin Alcohols.
[0236] Very little is known about the uptake and biodistribution of
tetrapyrrolic alcohol molecules either, topically or in
cardiovascular diseases. Gallium derivatives of these compounds
(Table 3, (7), for example) are efficient at dramatically reducing
the number of smooth muscle cells in the media and myofibroblasts
in the adventitial layers of rat arteries, while other metal types
(for example (72), (73), (74) appear to be less efficacious or more
toxic). It is also interesting to note that the metal-free
mesoporphyrin propyl alcohol derivative (7a; Table 3, for example)
shows no efficacy in the rat arterial model at drug doses up to 2
.mu.mol/Kg.
[0237] E) Phosphate Tetrapyrrole Derivatives
[0238] Only two phosphonate analogs of metallotetrapyrrolic
complexes were synthesized and evaluated in vitro. Compared to the
ester tetrapyrrolic macrocycles, neither compound was particularly
outstanding, however the indium analog (81) is photodynamically
active in vivo, and hence has potential as a photosensitizer of
disease conditions.
[0239] In summary, the pharmacological properties of the novel
compounds according to the invention are substantially different
from those of existing photosensitizers described to date in the
literature; In particular, the compounds investigated possess the
following properties.
[0240] (I) They are distributed and localized to vascular vessels
following injections
[0241] (II) They are activated at wavelengths of 500-600 nm to
cause selective biological effects in the target vascular
tissue.
[0242] (III) Following light activation, they cause significant
depletions of medial wall vascular smooth muscle cells and
adventitial myofibroblast cells in the coronary and peripheral
vasculature at a time-point when these cell types are known to be
maximally proliferating and/or migrating in response to vessel wall
injury.
[0243] (IV) They demonstrate markedly reduced neointimal formation
in coronary arteries following angioplasty injury, the magnitude of
which has only previously been demonstrated with radiation
therapy.
[0244] (V) They have no adverse effects on heart rate, blood
pressure or electrocardiogram at doses that inhibit vascular injury
responses.
[0245] (VI) Upon light activation, the photodynamic effect is
localized to the treatment zone of the vascular vessel, while
sparing underlying tissue including the myocardium surrounding the
coronary arteries.
[0246] (VII) They show marked skin remodelling characteristics not
observed with other photosensitizers without necrosis of the skin,
depending on the time of treatment and dosimetry used.
[0247] (VIII) They are able to necrose skin or tissues at specific
treatment times and light dosimetry.
[0248] The scope of the present invention is not limited to the
examples provided herein. As shown by the above examples, 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. and "The Porphyrins", Ed D. Dolphin, Vol I-V, Academic Press,
1978; "The Porphyrin Handbook", Ed. K. Kadish, K. M. Smith, R.
Guilard, Academic Press, 1999 incorporated by reference). 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.
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 in nature. 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,
CH(CH.sub.3).sub.2, 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.s- ub.3)COOH,
--CH.sub.2CH.sub.2C(CH.sub.3).sub.2COOH,
--CH.sub.2CH.sub.2C(CH.sub.3).sub.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.2C- H.sub.3,
--CH.sub.2CH.sub.2COOCH.sub.2CH.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 and the like, 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) either
substituted or not, such as 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.
[0249] 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.
[0250] 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.
[0251] 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.
[0252] 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.
[0253] 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.
[0254] 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.
[0255] 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.
[0256] 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.
[0257] 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.
[0258] 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.
[0259] 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.
[0260] 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.
[0261] 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.
[0262] 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.
[0263] 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, and cancers in living subjects.
[0264] 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.
[0265] 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.
[0266] 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.
[0267] 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.
[0268] 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.
[0269] 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,
[0270] Adjunctive diagnostics may include, but are not limited to:
intra-vascular 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.
[0271] The method of the invention can include administration of
the particular metallotetrapyrrolic compound prior to, concomitant
with, or subsequent to a particular adjunctive therapy. A
particular regimen is employed for administration, where a single
bolus or plurality of doses may be administered to the patient. The
particular protocol will depend upon the nature of the tissue to be
treated, the particular compound that is employed and the severity
of the disease. Target tissue structure and function, carriers,
endocytosis, and other cellular transport mechanisms may be
important for particular compounds when determining the specific
mode of delivery. Administration will preferably be within about 3
days prior to vessel activation with an energy source, and
desirably will be the same day as the treatment of the target
vessel.
[0272] The compounds of the invention may be formulated in a
variety of ways, depending upon the manner of the administration,
the particular compound, the number of administrations, other
drugs, the presence of other active components and the like. The
formulation will generally be in a physiologically acceptable form,
using various carriers, such as water, deionized water, phosphate
buffered saline, aqueous ethanol, vegetable oils, liposomes,
emulsions, inclusion complex (cyclodextrans). In some instances the
formulation may be formulated as a slow release formulation, where
the subject compounds may be encapsulated in a wide variety of
carriers, may be administered as capsules, or as a prodrug.
[0273] Thus, for instance, when they are provided in the form of
tablets, pills, solutions, suspensions, emulsions, granules or
capsules, the preparations are typically administered orally.
Injectable solutions are usually administered intravenously, either
alone or in a mixture with conventional fluids for parenteral
infusion containing sugars, amino acids, saline and the like. Local
administration may be by injection at the site of the living cells,
by insertion or attachment of a solid carrier at the site, or by
direct, topical application of a viscous liquid. Specifically, when
necessary, solutions may be administered as is by the
intramuscular, intradermal, subcutaneous or intraperitoneal route.
Suppositories are administered rectally, and eye drops are
instilled into the eye. The delivery of the compounds of the
invention to living cells may be enhanced by the use of
controlled-release compositions.
[0274] The compounds of the invention may also be applied
externally by introducing them into a spray together with a
suitable propellant and, if desired, a solvent, as a fine powder
together with a suitable filler, and as a cream in combination with
known auxiliaries. Furthermore they may be used in the form of
suppositories. They may also contain the required auxiliaries, such
as fillers, lubricants, preservatives and emulsifying agents
prepared by any method known per se.
[0275] The pharmaceutical compositions of the invention may also
contain a pharmaceutically acceptable carrier, such as saline,
buffered saline, 5% dextrose in water, borate-buffered saline
containing trace metal, carboxymethyl cellulose, vegetable oil,
DMSO, ethanol, and the like. Formulations may further include one
or more excipients, preservatives, antioxidants, solubilizers,
buffering agents, albumin to prevent protein loss on vial surfaces,
lubricants, fillers, stabilizers, and the like. Methods of
formulation are well-known in the art and are disclosed, for
example, in Remington's Pharmaceutical Sciences, Mack Publishing
Co., Easton, Pa. (Gennaro, ed. 1990).
[0276] In preparing fluids for injection, the solutions or
suspensions are preferably sterilized and isotonic with blood. For
preparing such dosage forms, all the diluents in conventional use
in this field can be employed. Thus, for example, water, ethyl
alcohol, propylene glycol, ethoxylated isostearyl alcohol,
polyoxylated isostearyl alcohol, liposomes and polyoxyethylene
sorbitan fatty acid esters may be used. In this case, the
pharmaceutical preparations may contain sodium chloride, glucose,
lactose or glycerol in an amount sufficient to give isotonic
solutions. It is also possible to add conventional solubilizing
agents, buffers, soothing agents or local anesthetics, etc.
Further, when appropriate, the pharmaceutical preparations may
contain coloring materials, preservatives, perfumes, flavoring
agents, sweetening agents and the like.
[0277] The proportion of the active ingredient compound in the
pharmaceutical preparations of the invention is not critical, but
may suitably be selected from a wide range. Generally, however, the
proportion is preferably within the range of from about 0.01 to
about 70% by weight.
[0278] Depending upon the manner of administration, the frequency
of administration, as well the nature and the degree of the
biological activity, the dosage will generally be in the range of
about 0.01 to about 100 mg/kg. When administered parentally, the
total amount of the compound administered per day will generally be
in the range of 0.1 to 50 mg/kg/day, more usually in the range of
about 0.25 to 25 mg/kg/day. This dose may be in a single bolus or
be divided up to be administered in portions to provide the desired
level of the subject compound in the mammal.
[0279] Light doses appropriate to activate the compounds of the
invention can be administered externally or internally to the
target tissue. A particular regimen is employed for light
administration, where a single dose or plurality of dosimetries may
be administered to the patient. The particular protocol will depend
upon the nature of the tissue to be treated, the particular
compound that is employed and the severity of the disease. Light
delivery devices can be, for example, in the form of a balloon
catheter, bare tip diffuser and the like for endovascular delivery
of light to blood-carrying vessels.
[0280] As used herein, the term light is to be considered in its
broadest sense, encompassing all electromagnetic radiation. Light
suitable for use in activating the compounds of the invention will
typically be produced by, for example, arc lamps, LEDs or lasers at
a certain frequency in the visible spectrum or near infrared for
typical PDT treatments. In particular, wavelengths between 400 nm
and 900 nm, corresponding to laser diode activation, may also be
used. Additionally dual photon excitation may also be used.
[0281] Although it has been described primarily with reference to
presently preferred embodiments, one skilled in the art should
recognize that various modifications and improvements are within
the scope of this invention. It will be clearly understood that the
invention in its general aspects is not limited to the specific
details referred to herein.
Definitions
[0282] As used in the present application, the following
definitions apply:
[0283] 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.
[0284] 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.
[0285] 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 and the like.
[0286] The term "halogen" represents chlorine, fluorine, bromine or
iodine. The term "halocarbon" or "haloalkyl" represents one or more
halogens bonded to 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.
[0287] 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.
[0288] The term "electron withdrawing group" is intended to mean a
chemical group containing an electronegative element such as
halogen, sulfur, nitrogen or oxygen.
[0289] 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.
[0290] 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.
[0291] 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.
[0292] 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), the disclosure of which is incorporated herein by
reference in its entirety.
[0293] 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.
[0294] 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 groups.
[0295] 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)alkoxycarbonyl, 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 can be 1,
2, 3, 4, 5 and R.sub.7 can be 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.
[0296] 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.
[0297] 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.
[0298] 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.
[0299] 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.
[0300] 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.
[0301] 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 can
be 1, 2, 3, 4, 5 and R.sub.7 can be 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.
[0302] 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.
[0303] 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.
[0304] Examples of pharmaceutically acceptable solvates include,
but are not limited to, compounds prepared using water,
isopropanol, ethanol, DMSO, and other excipients generally referred
to as GRAS or likewise recognized by the food and Drug
administration as acceptable ingredients.
[0305] In the case of solid formulations, it is understood that the
compounds of the invention may exist in different polymorph forms,
such as stable and metastable crystalline forms (and solvates
thereof) and isotropic and amorphous forms, all of which are
intended to be within the scope of the present invention.
[0306] 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. 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.
[0307] 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.
[0308] 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.
EXAMPLES
[0309] 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
Gallium Chloride Mesoporphyrin Dimethyl Ester
[0310] Mesoporphyrin dimethyl ester (610 mg) was dissolved in
acetic acid (75 mL) and Gallium acetyl acetonate added (700 mg).
The solution was refluxed for 1 hr after which time a UV visible
analysis of the molecule showed the metallation to be complete. The
solvent was removed by rotary evaporation and the residue dissolved
in dichloromethane (100 mL). The dichloromethane layer was washed
repeatedly with 1N HCl and the organic layer collected and
evaporated. The crude reaction mixture was chromatographed on
silica (7.5% methanol/dichloromethane) and the major pink fraction
collected and evaporated. The compound was redissolved in
dichloromethane (100 mL), the organic layer was washed repeatedly
with 1N HCl, dried over sodium sulfate and evaporated to .about.10
mL. Hexane was added (7 mL) and the dichloromethane was removed by
rotary evaporation. The precipitated solid was collected by
filtration and dried. Yield of the title compound=650 mg.
Example 2
Gallium Chloride Mesoporphyrin Diethyl Ester
[0311] Mesoporphyrin dimethyl ester (200 mg) was refluxed in 5%
sulfuric acid in ethanol (25 ml) for 6 hrs. The reaction was cooled
to room temperature, diluted with water (100 ml) and solution
neutralized with sodium bicarbonate. The solid was filtered, dried
and crystallized from dichloromethane and ethanol. Yield of
mesoporphyrin diethyl ester=180 mg. This was then metallated as
described in example 1. Yield of the title compound=190 mg.
Example 3
Gallium Chloride Mesoporphyrin Dipropyl Ester
[0312] Mesoporphyrin dimethyl ester (150 mg) was refluxed in 2%
sulfuric acid in propanol (30 ml) for 6 hrs. The reaction was
cooled to room temperature, diluted with water (100 ml) and
solution neutralized with sodium bicarbonate. The solid was
filtered and dried. Yield of mesoporphyrin dipropyl ester=180 mg.
This was then metallated as described in example 1. Yield of the
title compound=190 mg.
Example 4
Gallium Chloride Deuteroporphyrin Dimethyl Ester
[0313] Deuteroporphyrin dimethyl ester (100 mg) was metallated as
described in example 1. Yield of the title compound=98 mg.
Example 5
Gallium Chloride Deuteroporphyrin Diethyl Ester
[0314] Deuteroporphyrin diethyl ester (100 mg) was metallated as
described in example 1. Yield of the title compound=100 mg.
Example 6
Gallium Chloride Deuteroporphyrin Methylamide
[0315] Deuteroporphyrin (100) mg was converted to its methyl amide
and metallated as described in example 121. Yield of the title
compound=98 mg.
Example 7
Gallium Chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(3'-hy-
droxypropyl)
[0316] a) Mesoporphyrin IX dimethyl ester (1 g) was dissolved in
THF (600 mL) and LiAlH.sub.4 (1 g) was added. The solution was
refluxed under argon for 1 hr, then cooled and the solution was
quenched by the addition of ethylacetate (50 mL). 3N HCl was added
to the solution and the crude porphyrin precipitated by removal of
the THF by rotary evaporation. The crude product was dissolved in
methanol/dichloromethane (10%) and chromatographed on silica
eluting with 10% methanol/dichloromethane. The major red fraction
was collected and evaporated to dryness. b) A small amount of the
product porphyrin (200 mg) was dissolved in acetic acid and gallium
acetyl acetonate added (200 mg). The solution was refluxed for 2
hrs after which time a UV visible analysis of the molecule showed
the metallation to be complete. The solvent was removed by rotary
evaporation and the residue dissolved in THF (100 mL). A solution
of sodium hydroxide (0.1 g) in water (2 mL) was added and the
solution warmed at 40.degree. C. until acetate hydrolysis was
complete by TLC. The solvent was removed by rotary evaporation and
the crude residue dissolved in dichloromethane. The crude reaction
mixture was chromatographed on silica (5% methanol/dichloromethane)
and the major pink fraction collected and evaporated. The compound
was redissolved in dichloromethane (100 mL), the organic layer was
washed repeatedly with 1N HCl, dried over sodium sulfate and
evaporated to .about.20 mL. Hexane was added (14 mL) and the
dichloromethane was removed by rotary evaporation. The precipitated
solid was collected by filtration and dried. Yield of the title
compound=180 mg.
Example 8
Gallium Chloride
8,13-desvinyl-3,7,12,17-tetramethylporphyrin-2,18-di(3'-h-
ydroxypropyl)
[0317] Deuteroporphyrin dimethyl ester (100 mg) was converted to
its propyl alcohol derivative according to example 7 and (70 mg)
was metallated and purified as described in example 7. Yield of the
title compound=65 mg.
Example 9
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(propyl-3'-p-toluenesul-
fonate)
[0318]
8,13-diethyl-3,7,12,17-tetramethylporphrine-2,18-di(3'-hydroxypropy-
l) (1 g) was dissolved in dichloromethane (200 mL) and pyridine (5
ml) was added. The solution was chilled in an ice bath and toluene
sulfonylchloride (3 g) was added and the solution stirred at
4.degree. C. overnight. Water (200 mL) was added and the organic
layer separated. The organic layer was washed with 1N HCl, followed
by water and separated. The solvent was dried over sodium sulfate,
filtered and the solvent removed by rotary evaporation. and the
crude residue dissolved in dichloromethane and washed with water
several times. The organic layer was collected and evaporated to
dryness. The crude porphyrin was pure enough to use without
additional purification. Yield of the title compound=800 mg.
Example 10
Gallium Chloride
8,13-diethyl-3.7,12,17-tetramethylporphyrin-2,18-di(3'-me-
thoxypropyl)
[0319] Sodium (200 mg) was added to a solution of methanol (dry, 10
mL). After all the sodium had dissolved, the ditosylate compound
produced in example 9 (120 mg) in dry dichloromethane (10 mL) was
added and the resulting solution refluxed overnight protected from
moisture. The solution was quenched with water (20 mL) and the
organic layer separated and washed with water (3.times.50 mL) with
back extraction with dichloromethane. The organic layer was dried,
filtered and the organic layer reduced in volume to .about.10 mL.
Methanol (10 mL) was added and the dichloromethane was removed by
rotary evaporation. The precipitated porphyrin was collected by
filtration and dried. This gave
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(propyl methyl
ether) with sufficient purity to be used in the metallation step.
Yield=80 mg.
[0320] To a solution of this porphyrin (80 mg) in acetic acid (20
mL) was added gallium acetoacetonate (80 mg). The solution was
refluxed for 1 hr after which the solvent was removed by rotary
evaporation. The resulting solid was dissolved in dichloromethane
and the crude reaction passed over silica, eluting with 5%
methanol/dichloromethane. The major pink fraction was collected and
the solvent removed by rotary evaporation. The solid was dissolved
in dichloromethane (5 mL) and hexane (5 mL) was added. The
dichloromethane was removed by rotary evaporation and the solid
precipitate collected by filtration and dried. Yield of the title
compound=75 mg.
Example 11
Gallium Chloride Mesoporphyrin Di-(2'-methoxyethyl Amide)
[0321] Mesoporphyrin (310 mg) was suspended in dichloromethane (20
mL) and oxaylchloride (3 mL) added to it. The solution was refluxed
for 1 hr. The solvent was removed by rotary evaporation and
dichloromethane (20 mL) added, followed by 2-methoxyethyl amine (1
mL). The reaction was stirred for 1 hr, diluted with
dichloromethane (50 mL), washed with water, dried and evaporated.
The residue was dissolved in dichloromethane (10 mL) and methanol
(10 mL) was added. The dichloromethane was removed by rotary
evaporation and the precipitated porphyrin collected by filtration
and dried. Yield of mesoporphyrin IX methoxyethylamide=300 mg.
[0322] Mesoporphyrin methoxyethylamide (150 mg) and gallium
acetylacetonate (130 mg) was heated in acetic acid (15 mL) for 1.5
hr. The solvent was removed by rotary evaporation, dissolved in
dichloromethane (100 mL) and washed with 1.2N HCl (2.times.50 mL),
dried and evaporated. The residue was dissolved in dichloromethane
(5 mL) and chromatographed on silica, eluting first with 2.5-7.5%
methanol/dichloromethane, followed by 10% methanol dichloromethane.
The major red fraction was collected and evaporated to dryness. The
solid was dissolved in dichloromethane (10 ml) and a 1:1 solution
of ether and hexane (10 mL) was added. The dichloromethane was
removed by rotary evaporation and the red precipitate of the title
compound collected by filtration and dried. Yield of the title
compound=155 mg.
Example 12
Gallium Hydroxy 3,8-N,N-dimethylaminomethyl Deuteroporphyrin
Dimethyl Ester
[0323] 3,8-N,N-dimethylaminomethyl deuteroporphyrin dimethyl ester
(100 mg) was prepared as described in the literature (Pandey, R. K.
et al, Tetrahedron 1992, 48, 7591) and metallated as described in
example 1, except that the final product was washed with 0.5% NaOH
solution and not 1N HCl. Yield of the title compound=100 mg.
Example 13
Gallium Chloride Chloroporphyrin E6 Trimethyl Ester
[0324] Chloroporphyrin e6 trimethyl ester (100 mg) was metallated
as described in example 1. Yield of the title compound=107 mg.
Example 14
Gallium Chloride Chloroporphyrin E6 Dimethyl Ester
12-methylamide
[0325] Meso-pheophorbide methyl ester (400 mg) was dissolved in a
solution of methyl amine in THF (2M, 100 mL). The resulting
solution was stirred at room temperature for 2 days. The solvent
was removed by rotary evaporation and the residue was dissolved in
dichloromethane (10 mL). Methanol was added and the dichloromethane
removed by rotary evaporation. The precipitated chlorin was
collected by filtration and dried (400 mg). The chlorin was
dissolved in chloroform (20 mL) and a methanolic solution of
saturated zinc acetate (2 ml) was added. The solution was heated
for 1 hr at reflux and the solution poured into water (100 ml). The
aqueous layer was extracted with dichloromethane (50 ml) and the
organic layer collected and evaporated to dryness. The residue was
dissolved in THF (20 mL) and a solution of DDQ (227 mg) in THF (10
mL) was added dropwise at room temperature. The solution was
stirred for 10 min at room temperature and the solution poured into
a saturated sodium bicarbonate solution. The resulting mixture was
extracted with dichloromethane (2.times.50 mL) and evaporated to
dryness. The crude residue was chromatographed on silica using 1%
acetone/dichloromethane as eluent and the major red porphyrin band
collected. The fraction was evaporated to dryness and precipitated
from dichloromethane/methanol. Yield of chloroporphyrin e6 dimethyl
ester 12-methyl amide=210 mg. The chloroporphyrin e6 dimethyl ester
12-methyl amide was metallated as described in example 1 to give
215 mg of gallium chloride chloroporphyrin e6 dimethyl ester
12-methyl amide.
Example 15
Gallium Chloride Mesoporphyrin N,N-diethylamide
[0326] Mesoporphyrin (148 mg) was converted to mesoporphyrin
N,N-diethyl amide as described in example 11, except that
N,N-diethyl amine was used in place of 2-methoxyethylamine.
Yield=0.242 mg. This material was metallated as described in
example 1 to give the title gallium compound. Yield=250 mg.
Example 16
Gallium Chloride Mesoporphyrin 2-Ethoxyethanol Amide
[0327] Mesoporphyrin dimethyl ester (200 mg) was dissolved in
dioxane (1 ml) and 2-(2-aminoethoxy)ethanol (3 ml) was added. The
solution was refluxed for 3 hrs at .about.120.degree. C. The
solution was poured into brine and extracted with
dichloromethane/5% methanol, dried and evaporated. The porphyrin
was TLC pure. The amide porphyrin was then refluxed for 45 min in
acetic acid (10 mL) containing gallium acetylacetonate (200 mg).
The acetic acid was evaporated and the residue dissolved in THF (50
mL) and a solution of KOH (1 g in 5 ml H.sub.2O/5 ml methanol) was
added. The solution was stirred for 2 hrs at room temperature. The
excess KOH was quenched with acetic acid and the solvent removed by
evaporation. The residue was dissolved in dichloromethane and
washed with 1N HCl (2.times.75 mL), dried and evaporated to
dryness. The product was pure by TLC (7% methanol/dichloromethane).
Yield of the title compound=210 mg.
Example 19
Gallium Chloride 5-azaprotoporphyrin IX Dimethyl Ester
[0328] 5-azaprotoporphyrin IX dimethyl ester (Monfforts, F-P., et
al, Tet. Lett. 1992, 33, 1985) (100 mg) was metallated as described
in example 1. Yield of the title compound=110 mg.
Example 20
Gallium Chloride 5-azamesoporphyrin IX Dimethyl Ester
[0329] 5-azamesoporphyrin IX dimethyl ester (Singh, J. P., et al,
Tet. Lett. 1995, 36, 1567) (100 mg) was metallated as described in
example 1. Yield of the title compound=107 mg.
Example 21
Gallium Chloride
78,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-d-
i(propionic Acid Methyl Ester)
[0330] 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) was added. The solution was stirred at
room temperature for 2 hrs after which time the solid
1,19-dibromobiladiene was filtered and dried. 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
7,8,12,13-tetraethyl-12,17-dimethyl-10--
azaporphyrin-2,18-di(propionic acid methyl ester)=1.7 g.
[0331] The azaporphyrin (100 mg) was metallated according to
example 1. Yield of the title compound=115 mg.
Example 22
Gallium Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18--
di(propionic Acid Methyl Amide)
[0332] The azaporphyrin synthesized in example 21 (150 mg) was
dissolved in THF (50 mL) and KOH (500 mg) in MeOH/water (5 mL:5 mL)
was added. The solution was refluxed for 2 hrs. The solvent was
evaporated and the residue dissolved in water (10 mL) and
neutralized with HCl. The precipitated solid was collected by
filtration and dried. Yield of dicarboxylic acid azaporphyrin=110
mg. The solid was suspended in dichloromethane (10 mL) and THF (100
mL). Triethylamine (2 mL) was added and the mixture stirred
overnight at room temprature. The solution was cooled to 0.degree.
C. and ethylchloroformate (1 mL) was added. The solution was
stirred for 30 min and then a solution of methylamine in THF (2M,
15 mL) was added. The solution was stirred at room temperature for
2 hrs and then the solvent was removed. The residue was dissolved
in dichloromethane/methanol (10%) and chromatographed on silica
eluting with 10% methanol/dichloromethane, followed by 15%
methanol/dichloromethane. The major fraction was collected and
evaporated to dryness. Yield of the
2,3,7,8-tetraethyl-12,13-dimethyl-5-azaporphyrin-13,17-propionic
acid dimethyl amide was 68 mg. The azaporphyrin was metallated as
shown in Example 1 purified by column chromatography eluting with
10% methanol/dichloromethane followed by 15%
methanol/dichloromethane. The title compound was precipitated from
dichloromethane/hexane, filtered and dried. Yield=72 mg.
Example 23
Gallium Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18--
di(3'-hydroxypropyl)
[0333] To a slurry of LiAlH.sub.4 (46 mg) in dry THF (3 mL) was
added a solution of azaporphyrin dimethyl ester (example 21) (150
mg) in dry THF (3 mL). The mixture was stirred at room temperature
for 15 min and excess LiALH.sub.4 decomposed with 0.2N HCl. The
solution was dissolved in dichloromethane (50 mL) and washed well
with water (2.times.50 mL). The organic layer was separated and
dried over sodium sulfate, filtered and evaporated to dryness. The
crude residue was chromatographed on silica using 5%
MeOH/dichloromethane and the major purple band collected. The
solvent was removed and the crude residue dried under vacuum. The
material was pure by TLC. Yield of
7,8,12,13-tetraethyl-12,17-dimethyl-10-
-azaporphyrin-2,18-di(3'-hydroxypropyl)=103 mg. The product was
dissolved in acetic acid (20 mL) and gallium acetylacetonate (125
mg) was added. The solution was refluxed for 15 min, cooled and the
solvent removed by rotary evaporation. The residue was dissolved in
dichloromethane (50 mL) and washed with water (50 ml). The organic
layer was collected and evaporated to dryness. The residue was
dissolved in methanol (7 mL) and K.sub.2CO.sub.3 (90 mg) was added.
The solution was stirred for 5 hrs at room temperature. The
solution was poured into water and extracted with dichloromethane.
The dichloromethane layer was washed with 1N HCl, dried over sodium
sulfate, filtered and the solvent removed. The product was
precipitated from dichloromethane/hexane to give the title
compound, 76 mg.
Example 24
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(3'-cyanopropyl)
[0334]
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(propyl-3'-tolue-
nesulfonate) (example 9) (150 mg) in DMSO (30 ml) was added to
sodium cyanide (100 mg). The mixture was warmed up slowly to just
refluxing (about 30 minutes) under argon. TLC of the reaction
solution indicated that the reaction was complete. Water (5 ml) was
added and the porphyrin precipitate was collected and washed with
water to remove any trace of DMSO. The solid was air dried to give
8,13-diethyl-3,7,12,17-tetramethylp-
orphyrin-2,18-di(3'-cyanopropyl) (84 mg, 85% yield).
Example 25
8,13-diethyl-3.7,12,17-tetramethylporphyrin-2,18-di(butanoic Acid
Methyl Ester)
[0335]
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(3'-cyanopropyl)
(50 mg) was dissolved in a solution of methanol (50 ml) saturated
with dry hydrogen chloride gas, the solution was stirred at room
temperature in the dark overnight. Water (100 ml) was added
followed by aqueous ammonia hydroxide to neutralize the solution.
The solution was then extracted with methylene chloride twice
(2.times.100 ml), and the combined methylene chloride was washed
with water, drained and dried over sodium sulfate. The crude
material was purified on a silica gel column, eluted with 1%
methanol/methylene chloride. The desired fraction was collected and
evaporated to dryness to give 8,13-diethyl-3,7,12,17-tetram-
ethylporphyrin-2,18-di(butanoic acid methyl ester) (47 mg, 84%
yield).
Example 26
Gallium Chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butan- oic Acid
Methyl Ester)
[0336] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic
acid methyl ester) (example 25) (47 mg) in AcOH (100 ml) was added
to Ga (acac).sub.3 (90 mg). The mixture was heated to reflux for
one hour, and then cooled to room temperature. AcOH was evaporated
to dryness and methylene chloride (100 ml) was added to dissolve
the solid. The methylene chloride solution was washed with 1N HCl
solution once (100 ml), drained and dried over sodium sulfate.
Methylene chloride was evaporated and the porphyrin was
precipitated from hexane. The precipitate was collected by
filtration and air dried to give 54 mg of gallium chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(buta- noic acid
methyl ester) (98% yield).
Example 27
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic Acid
Ethyl Ester)
[0337] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-dipropanol
di-tosylate ester (example 9) (150 mg) in anhydrous THF (30 ml) was
added to a solution of sodium hydride (150 mg)/diethyl malonate (1
g)/anhydrous THF (50 ml). The mixture was heated to reflux for 6
hours, and then cooled to room temperature. Aqueous HCl solution
was added, and the solution was extracted with methylene chloride
(3.times.100 ml). The combined methylene chloride layer was washed
once with water, drained, dried over sodium sulfate, and evaporated
to dryness. The crude material was precipitated from DMSO/water to
remove excess diethyl malonate. The porphyrin was dissolved in DMSO
and LiCl (200 mg) added. The solution was heated to 80.degree. C.
for 4 hrs, cooled and water was added to precipitate the porphyrin.
The crude porphyrin was purified on a silica gel column. The
desired fraction was collected by eluting 2% methanol/methylene
chloride, and then precipitated from hexane to give
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic acid
methyl ester) (118 mg, 98% yield).
Example 28
Gallium Chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(penta- noic
Acid Ethyl Ester)
[0338]
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic acid
methyl ester (example 27) (50 mg) in AcOH (100 ml) was added to
Ga(acac).sub.3 (50 mg). The mixture was heated to reflux for 40
minutes, and then cooled to room temperature. AcOH was evaporated
to dryness and methylene chloride was added to dissolve the solid.
The methylene chloride solution was washed with 1N HCl solution
twice (2.times.100 ml), drained and dried over sodium sulfate.
Methylene chloride was evaporated and the porphyrin was
precipitated from hexane. The precipitate was collected by
filtration and air dried to give Gallium chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic acid
methyl ester) (55 mg, 95% yield).
Example 29
Platinum Mesoporphyrin Dimethyl Ester
[0339] Platinum chloride (750 mg) and sodium chloride (750 mg) were
refluxed in propionic acid (300 ml) for 30 min. Mesoporphyrin
dimethyl ester (525 mg) and sodium acetate (550 mg) were added to
the solution and refluxing continued for 2 h after which time a UV
visible analysis of the molecule showed the metallation to be
complete. After cooling to room temperature, water (100 ml) was
added and the precipitate filtered over celite. The product was
recovered from celite by dissolving it in dichloromethane (100 ml).
Methanol (25 ml) was added. Dichloromethane was removed by rotary
evaporation. The precipitated solid was collected by filtration and
dried. Yield of the title compound=670 mg.
Example 30
Aluminum Chloride Mesoporphyrin Dimethyl Ester
[0340] Mesoporphyrin dimethylester (100 mg) was dissolved in
dichloromethane (20 mL) and cooled to -78.degree. C. in a
dry-ice/acetone bath. Trimethylaluminum in toluene (2 ml, 2 M) was
added slowly via syringe. The reaction was stirred at -78.degree.
C. for 30 min after which time a UV visible analysis of the
molecule showed the metallation to be complete. Excess
trimethylaluminum was decomposed by adding methanol (2 mL). The
reaction was allowed to warm to room temperature diluted with
dichloromethane (30 mL) and washed repeatedly with 1N HCl. The
organic layer was separated, dried over anhydrous sodium sulfate
and evaporated to dryness. The crude reaction product was
chromatographed on silica (5-10% methanol/dichloromethane) and the
major pink fraction collected and evaporated. The product was
dissolved in dichloromethane (50 mL), washed with 1N HCl, dried and
precipitated from hexane. The precipitate was collected by
filtration and air dried to give 0.092 g of Aluminum chloride
mesoporphyrin dimethyl ester.
Example 31
Indium Chloride Mesoporphyrin Dimethyl Ester
[0341] Mesoporphyrin dimethyl ester (150 mg), indium chloride (150
mg) and sodium acetate (200 mg) were refluxed in acetic acid (20
ml) for 3 hrs after which time a UV visible analysis of the
molecule showed the metallation to be complete. Acetic acid was
evaporated to dryness. The crude reaction product was
chromatographed on silica (5% methanol/dichloromethane) and the
major pink fraction collected and evaporated. Yield of the title
compound=139 mg.
Example 32
Tin (IV) Dichloride Mesoporphyrin Dimethyl Ester
[0342] Mesoporphyrin dimethyl ester (100 mg), tin (II) chloride
(100 mg) and sodium acetate (100 mg) were refluxed in the presence
of air in acetic acid (15 ml) for 2 hrs after which time a UV
visible analysis of the molecule showed the metallation to be
complete. The reaction was cooled to room temperature and diluted
with water (20 ml). The crude reaction product was filtered,
dissolved in dichloromethane and washed with 1N HCl, dried on
sodium sulfate and evaporated to dryness. The product was
precipitated from dichloromethane and hexane. Yield of the title
compound=100 mg.
Example 33
Zinc Mesoporphyrin Dimethyl Ester
[0343] Mesoporphyrin dimethyl ester (200 mg) was dissolved in
dichloromethane (50 ml). A solution of zinc acetate (250 mg) in
methanol (50 ml) was added and the reaction refluxed for 1 hr.
Dichloromethane was evaporated on a rotary evaporation and the
solid filtered and dried. Yield of the title compound=200 mg.
Example 34
Gallium Chloride Mesoporphyrin Di(2-fluoroethylester)
[0344] Mesoporphyrin dimethyl ester (150 mg) was transesterified as
described in example 3, except that 2-fluoroethanol was used
instead of propanol. The crude product was purified by
chromatography over silica gel (5% methanol/dichloromethane). This
was then metallated as described in example 1. Yield of the title
compound=140 mg.
Example 35
Gallium Chloride Mesoporphyrin Di(3-chloropropylester)
[0345] Mesoporphyrin dimethyl ester (150 mg) was transesterified as
described in example 3 except that 3-chloropropanol was used
instead of propanol. The crude product was purified by
chromatography over silica gel (5% methanol/dichloromethane). This
material was then metallated as described in example 1. Yield of
the title compound=150 mg.
Example 36
Gallium Chloride Deuteroporphyrin Di(3-chloropropylester)
[0346] Deuteroporphyrin dimethyl ester (150 mg) was transesterified
as described in example 3, except that 3-chloropropanol was used
instead of propanol. The crude product was purified by
chromatography over silica gel (2% methanol/dichloromethane). This
material was then metallated as described in example 1. Yield of
the title compound=150 mg.
Example 37
Gallium Chloride Deuteroporphyrin Di(2-fluoroethylester)
[0347] Deuteroporphyrin dimethyl ester (150 mg) was transesterified
as described in example 3, except that 2-fluoroethanol was used
instead of propanol. The crude product was purified by
chromatography over silica gel (5% methanol/dichloromethane). This
material was then metallated as described in example 1. Yield of
the title compound=140 mg.
Example 38
Gallium Chloride Deuteroporphyrin Di(2,2,2-trifluoroethylester)
[0348] Deuteroporphyrin dimethyl ester (120 mg) was transesterified
as described in example 3 except that 2,2,2-trifluoroethanol was
used instead of propanol. The crude product was purified by
chromatography over silica gel (5% methanol/dichloromethane). This
was then metallated as described in example 1. Yield of the title
compound=102 mg.
Example 39
Gallium Chloride 3,8-dibromodeuteroporphyrin Dimethyl Ester
[0349] 3,8-Dibromodeuteroporphyrin dimethyl ester was prepared from
deuteroporphyrin dimethylester (250 mg) according to literature
procedures (Bonnette, R. et al, J. Chem. Res (S), 1990, 138-139).
It was metallated as described in example 1. Yield of the title
compound=275 mg.
Example 40
Gallium Chloride 3,8-hydroxymethyl Deuteroporphyrin Dimethyl
Ester
[0350] 3,8-Dihydroxymethyl deuteroporphyrin dimethyl ester was
prepared following literature procedures (Kenner, G. W. et al. J.
Chem. Soc., Chem. Commun. 1987, 109-1347-1348). It was metallated
as described in example 23. Yield=60%
Example 41
Platinum 3,8-Bis(dimethylaminomethyl)deuteroporphyrin Dimethyl
Ester
[0351] Platinum deuteroporphyrin dimethyl ester (230 mg) and
eschenmoser's salt (1.5 g) were refluxed in chloroform (50 ml) for
36 hrs. The reaction mixture was diluted with dichloromethane (50
mL) and washed several times with 1% triethylamine/water, dried
over sodium sulfate and evaporated to dryness. The crude product
was chromatographed over silica gel (15% MeOH/2%
triethylamine/dichloromethane). The solvent was evaporated and the
product precipitated from dichloromethane and hexane. Yield of the
title compound=190 mg.
Example 42
Gallium Chloride Protoporphyrin Dimethyl Ester
[0352] Protoporphyrin dimethyl ester (100 mg) was metallated as
described in example 1. Yield of the title compound=100 mg.
Example 43
Gallium Hydroxy
3,8-Bis-(N,N-dimethylaminoprop-2-en-3-yl)deuteroporphyrin Dimethyl
Ester
[0353] 3,8-Bis (N,N-dimethylaminoprop-2-en-3-yl)deuteroporphyrin
dimethyl ester (120 mg) was prepared following literature
procedures (Pandey, R. K. et al, Tetrahedron 1992, 48, 7591) and
metallated according to example 12. The product was precipitated
from dichloromethane and hexane. Yield of the title compound=102
mg.
Example 44
Gallium Chloride Hematoporphyrin Dimethyl Ether Di(methyl
Amide)
[0354] Hematoporphyrin (1.0 g) was converted to hematoporphyrin
dimethyl ether dimethyl ester following literature procedures
(Byrne, C. J., et al, Tetrahedron Lett. 1988, 29, 1421).
Hematoporphyrin dimethyl ether dimethyl ester was dissolved in
tetrahydrofuran (100 ml). A solution of potassium hydroxide (2 g)
in methanol/water (5 ml/5 ml) was added. The reaction was stirred
overnight at room temperature. Tetrahydrofuran was evaporated and
residue dissolved in water (50 ml). The solution was neutralized by
1N HCl. The solid was filtered and dried to give hematoporphyrin
dimethyl ether. Hematoporphyrin dimethyl ether was dissolved in
tetrahydrofuran and cooled in an ice/water bath. Triethylamine (3
ml) was added followed by ethyl chloroformate (2 mL). The reaction
was stirred for 30 min then methylamine (10 ml, 2 M in THF) was
added. After 3 hours of stirring at room temperature,
tetrahydrofuran was evaporated. The residue was dissolved in
dichloromethane and the solution was washed with water, and dried
over sodium sulfate. The crude product was chromatographed on
silica gel (50-60% acetone/dichloromethane- ) to give
hematoporphyrin dimethyl ether di(methylamide). This material was
metallated as in example 1. Yield of the title compound=500 mg.
Example 45
Tin(IV) Dichloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(but- anoic Acid
Methyl Ester)
[0355] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic
acid methyl ester) (example 25) (100 mg) was metallated by the
procedure described in example 32. Yield of the title compound=107
mg.
Example 46
Indium Chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butano- ic Acid
Methyl Ester)
[0356] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic
acid methyl ester) (example 25) (100 mg) was metallated as
described in example 31. Yield of the title compound=95 mg.
Example 47
Platinum
8,13-diethyl-3.7,12,17-tetramethylporphyrin-2,18-di(butanoic Acid
Methyl Ester)
[0357] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic
acid methyl ester) (example 25)(100 mg) was metallated by the
procedure described in example 29. Yield of the title compound=110
mg.
Example 48
Aluminum Chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(buta- noic Acid
Methyl Ester)
[0358] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic
acid methyl ester) (example 25) (100 mg) was metallated by a
similar procedure as described in example 30. Yield of the title
compound=95 mg.
Example 49
Zinc 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic
Acid Methyl Ester)
[0359] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic
acid methyl ester) (example 25) (100 mg) was metallated by a
similar procedure (how different?) as described in example 33.
Yield of the title compound=105 mg.
Example 50
Gallium
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic Acid
Propyl Ester)
[0360] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic
acid methyl ester) (example 25) (150 mg) was transesterified using
1-propanol in the presence of concentrated sulfuric acid following
example 3. It was metallated as described in example 1. Yield of
the title compound=140 mg.
Example 51
Tin(IV)dichloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pent- anoic
Acid Ethyl Ester)
[0361]
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic acid
ethyl ester) (example 27) (100 mg) was metallated following the
procedure described in example 32. Yield of the title compound=95
mg.
Example 52
Indium Chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentan- oic
Acid Ethyl Ester)
[0362]
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic acid
ethyl ester) (example 27) (100 mg, example 26) was metallated
following the procedure described in example 31. Yield of the title
compound=100 mg.
Example 53
Platinum
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic Acid
Ethyl Ester)
[0363]
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic acid
ethyl ester) (example 27) (100 mg) was metallated following the
procedure described in example 29. Yield of the title compound=95
mg.
Example 54
Aluminum Chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pent- anoic
Acid Ethyl Ester)
[0364]
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic acid
ethyl ester) (example 27) (150 mg) was metallated following the
procedure described in example 30. Yield of the title compound=110
mg.
Example 55
Zinc 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic
Acid Ethyl Ester)
[0365]
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic acid
ethyl ester) (example 27) (100 mg) was metallated following the
procedure described in example 3. Yield of the title compound=95
mg.
Example 56
Gallium Chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(penta- noic
Acid Propyl Ester)
[0366]
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic acid
methyl ester) (example 27) (150 mg) was transesterified using
1-propanol in the presence of concentrated sulfuric acid as
described in example 3. It was metallated as described in example
1. Yield of the title compound=140 mg.
Example 57
Gallium Chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(penta- noic
Acid Methyl Ester)
[0367] Gallium
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentano- ic
acid methyl ester) was prepared as described in example 27 except
that dimethyl malonate was used instead of diethyl malonate. Yield
of the title compound=125 mg.
Example 58
Tin(IV)dichloride Mesoporphyrin N-methylamide
[0368] Mesoporphyrin N-methylamide (example 3) (425 mg) was
metallated as described in example 32. Yield of the title
compound=400 mg.
Example 59
Indium Chloride Mesoporphyrin N-methylamide
[0369] Mesoporphyrin N-methylamide (example 3) (150 mg) was
metallated as described in example 31. The crude product was
chromatographed over silica gel (10-15% methanol/dichlorometahne)
and precipitated from dichloromethane/hexane. Yield of the title
compound=108 mg.
Example 60
Platinum Mesoporphyrin N-methylamide
[0370] Mesoporphyrin N-methylamide (example 3) (100 mg) was
metallated as described in example 29. The crude product was
chromatographed over silica gel (10% methanol/dichloromethane) and
precipitated from dichloromethane/hexane. Yield of the title
compound=121 mg.
Example 61
Aluminum Chloride Mesoporphyrin N-methylamide
[0371] Mesoporphyrin N-methylamide (example 121) (150 mg) was
metallated as described in example 30. The crude product was
chromatographed over silica gel (10-15% methanol/dichloromethane)
and precipitated from dichloromethane/hexane. Yield of the title
compound=108 mg.
Example 62
Zinc Mesoporphyrin N,N-diethylamide
[0372] Mesoporphyrin (250 mg) was converted to mesoporphyrin
N,N-diethyl amide as described in example 121, except that
N,N-diethyl amine was used in place of methylamine. Yield=0.242 mg.
This material was metallated as described in example 1 to give the
title gallium compound. Yield=200 mg.
Example 63
Zinc Mesoporphyrin 3-(N-morpholino)propylamide
[0373] Mesoporphyrin (250 mg) was converted to mesoporphyrin
3-(N-morpholino)propylamide as outlined in example 121, except that
N-(3-aminopropyl)morpholine was used in place of methylamine,
Yield=275 mg. This material was metallated as described in example
33 to give the title zinc compound.
[0374] Yield of the title compound=250 mg.
Example 64
Zinc Mesoporphyrin 3-(4-pyridyl)propylamide
[0375] Mesoporphyrin (250 mg) was converted to Mesoporphyrin
3-(4-pyridyl)propylamide as outlined in example 121, except that
4-(3-aminopropyl)pyridine was used in place of methylamine,
Yield=200 mg. This material was metallated as described in example
33 to give the title zinc compound. Yield=175 mg.
Example 65
Platinum Mesoporphyrin di(2-methoxyethylamide)
[0376] Mesoporphyrin di(2-methoxyethylamide) (example 11, 150 mg)
was metallated as described in example 29. Yield of the title
compound=70 mg.
Example 66
Gallium Chloride Mesoporphyrin di(3-hydroxypropylamide)
[0377] Mesoporphyrin dimethylester (100 mg) was heated in
3-aminopropanol (5 ml) at 110.degree. C. for 2 hrs. The reaction
mixture was cooled to room temperature and diluted with water (25
mL). The solid was filtered and dried to give mesoporphyrin
di(3-hydroxypropylamide), 105 mg. This material was then metallated
as described in example 16. Yield of the title compound=80 mg.
Example 67
Platinum Mesoporphyrin di(3-hydroxypropylamide)
[0378] Platinum mesoporphyrin (125 mg) was heated in
3-aminopropanol (5 mL) at 120.degree. C. for 2 hrs. The reaction
mixture was cooled to room temperature and diluted with Water (25
mL). The solid was filtered and washed with water and dried to give
the title compound. Yield of the title compound=130 mg.
Example 68
Gallium Chloride Deuteroporphyrin di(3-hydroxypropylamide)
[0379] Deuteroporphyrin dimethylester (200 mg) was heated in
3-aminopropanol (6 ml) at 120.degree. C. for 2 hrs. The reaction
mixture was cooled to room temperature and diluted with water (25
mL). The solid was filtered and dried to give 200 mg of
deuteroporphrin di(3-hydroxypropylamide). This material was then
metallated as described in example 16. Yield of the title
compound=140 mg.
Example 69
Platinum Mesoporphyrin di(2-ethoxyethanolamide)
[0380] Platinum mesoporphyrin (125 mg) was heated in
((2-ethoxy)-2'-ethanol)amine (3 mL) and dioxane (1 ml) at
120.degree. C. for 3 hrs. The reaction mixture was cooled to room
temperature, diluted with water (25 mL) and extracted with
chloroform/methanol (3:1), dried and evaporated to dryness. The
crude product was chromatographed over silica gel (5%
methanol/dichloromethane). The product was precipitated from
dichloromethane/ether/hexane. Yield of the title compound=90
mg.
Example 70
Gallium Hydroxy Mesoporphyrin Di-(N,N-dimethylaminoethylamide)
[0381] Mesoporphyrin (315 mg) was converted to mesoporphyrin
di(N,N-dimethylaminoethyl amide) as described in example 121,
except that N,N-dimethylaminoethylamine was used in place of
methylamine. Yield=320 mg. This was metallated as described in
example 1, except that the product was not washed with 1N HCl but
with NaOH. Yield of the title compound=210 mg.
Example 71
Platinum Mesoporphyrin Di(N,N-dimethylaminoethylamide)
[0382] Platinum mesoporphyrin (100 mg) was refluxed in
N,N-dimethylaminoethylamine (5 mL) for 16 hrs. The reaction mixture
was cooled to room temperature and diluted with ether (25 mL). The
solid was filtered, dried and purified by chromatography over
alumina (grade III) (5% methanol/dichloromethane). The product was
precipitated using dichloromethane and hexane to give the title
compound. Yield=75 mg.
Example 72
Indium Chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(3'-hyd-
roxypropyl)
[0383] Mesoporphyrin dimethyl ester was reduced to the
corresponding diol as described in example 7. This compound (100
mg) was metallated as described in example 7, except that instead
of gallium acetylacetonate, indium chloride (100 mg) and sodium
acetate (80 mg) was used. Yield of the title compound=100 g.
Example 73
Aluminum Chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(3'-h-
ydroxypropyl)
[0384] Aluminum mesoporphyrin dimethyl ester (example 30) (92 mg)
was dissolved in dry tetrahydrofuran (50 ml). Lithium aluminum
hydride (75 mg) was added to the reaction and the reaction mixture
refluxed under an atmosphere of nitrogen for 1 hr. The reaction was
cooled to room temperature and 1N HCl was added slowly to destroy
excess LiAlH.sub.4. The solution was extracted with dichloromethane
(3.times.50 ml), dried over sodium sulfate and solvent evaporated
to dryness. The crude product was chromatographed on silica gel
(20% methanol/dichloromethane) to give the titled product. Yield=75
mg.
Example 74
Platinum
8,13-diethyl-3,7,12,17-tetramethylporphryin-2,18-di(3'-hydroxypro-
pyl)
[0385] Platinum mesoporphyrin dimethyl ester (example 29) (300 mg)
was dissolved in dry tetrahydrofuran (50 ml). Lithium aluminum
hydride (250 mg) was added to the reaction and the reaction mixture
refluxed for 1 hr. The reaction was cooled to room temperature and
methanol (1 ml) was added slowly to destroy excess LiAlH.sub.4. The
solution was diluted with 1N HCl (50 ml) and extracted with
dichloromethane (3.times.50 ml), dried over sodium sulfate and
solvent evaporated to dryness. The crude product was
chromatographed on silica gel (10% methanol/dichloromethane) to
give the title compound. Yield=250 mg.
Example 75
Indium Chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(3'-met-
hoxypropyl)
[0386]
8,13-diethyl-3,7,12,17-tetramethylporphyrine-2,18-di(3'-methoxyprop-
yl) (example 10) (100 mg) was refluxed for 2 hrs. in acetic acid
(15 ml) in the presence of indium chloride (100 mg) and sodium
acetate (100 mg) after which time the UV-Vis analysis of the
reaction indicated the metallation to be complete. Acetic acid was
evaporated by rotary evaporation. The residue was dissolved in
dichloromethane (25 ml) and washed with water followed by 1N HCl.
The dichloromethane layer was separated, dried over sodium sulfate
and evaporated to dryness. The product was precipitated from
dichloromethane/hexane. Yield of the title compound=70 mg.
Example 76
Indium Hydroxy
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(3-(N-py-
rrolidino)propyl)
[0387]
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(propyl-3'-p-tol-
uenesulfonate_(example 9) (140 mg) was dissolved in dichloromethane
(25 ml) and pyrrolidine (1 ml) was added. The reaction was stirred
at room temperature for 20 hrs. All the volatiles were removed by
rotary evaporation and the product precipitated from
dichloromethane and methanol. Yield of
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(3--
(N-pyrrolidino)propyl)=118 mg. This was then dissolved in acetic
acid (10 ml), and indium chloride (100 mg) and sodium acetate (100
mg) were added. The reaction mixture was heated at reflux for 2 hrs
after which time a UV visible analysis of the molecule showed the
metallation to be complete. Acetic acid was evaporated and the
residue dissolved in dichloromethane (50 ml). The solution was
washed with water followed by 1 N NaOH and again water, dried over
sodium sulfate and evaporated to dryness. The product was
precipitated from dichloromethane and hexane. Yield of the title
compound=90 mg.
Example 77
Platinum
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(3-(N-pyrrolid-
ino)propyl)
[0388] Platinum
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(3-hydr-
oxypropyl) (example 74) (200 mg) was converted to its corresponding
tosylate following the procedure in example 9. Yield=200 mg. This
was dissolved in chloroform (50 ml), pyrrolidine (2 ml) was added
and the reaction mixture was refluxed for 4 hrs. All the volatiles
were removed by rotoevaporation. The crude product was
chromatographed over silica gel (15%-25% methanol/1%
triethylamine/dichloromethane). The product precipitated when all
the dichloromethane was removed from the fractions. It was filtered
and dried to give the title compound. Yield=158 mg.
Example 78
Gallium Hydroxy 8,13-diethyl-3,7,12,17
tetramethylporphyrin-2,18-di((N-3'--
hydoxypropyl)-3-aminopropyl)
[0389]
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(propyl-3'-p-tol-
uenesulfonate_(example 9) (150 mg) and 3-aminopropanol were
refluxed in chloroform for 6 hrs. chloroform was evaporated and
water added to the residue. The solid was filtered, washed with
water and dried to give 2,7,12,18
tetramethyl-3,8-diethyl-13,17-di((N-3'-hydoxypropyl)-3-aminopro-
pyl)porphyrin. This was metallated with gallium acetylacetonate
(150 mg) in refluxing acetic acid (100 ml). Metallation was
complete after 1 hr. as evidenced by UV-Vis analysis. Acetic acid
was evaporated and the residue dissolved in THF (25 ml)/methanol
(25 ml). A solution of KOH (1 g/5 ml water) was added and the
reaction refluxed for 4 hrs. diluted with water (100 ml) and
extracted with dichloromethane. The dichloromethane layer was dried
and evaporated to dryness and the residue precipitated from
dichloromethane and hexane. Yield of the title compound=100 mg.
Example 79
Zinc 8,13-diethyl-3,7,12,17
tetramethylporphyrin-2,18-di((N,N-diethyl)-3-a- minopropyl)
[0390] Mesoporphyrin N,N-diethylamide (example 15) (350 mg) was
dissolved in THF (40 ml). Lithium aluminum hydride (1 g) was added
to the solution and the reaction stirred for 1 hr at room
temperature. Excess LiAlH.sub.4 was destroyed with methanol. The
reaction was diluted with water and extracted thoroughly with
dichloromethane, dried and evaporated to give
8,13-diethyl-3,7,12,17
tetramethylporphyrin-2,18-di((N,N-diethyl)-3-amino- propyl).
Yield=85 mg. This was dissolved in dichloromethane, a methanolic
solution of zinc acetate (5%, 5 ml) was added and the reaction
refluxed for 1 hr. The solution was washed with water, dried and
evaporated to dryness. The crude product was chromatographed over
silica gel (1% triethylamine/33% hexane/66% dichloromethane) to
give the titled compound. Yield=85 mg.
Example 80
Gallium Chloride
3,7,12,17-tetramethylporphyrin-2,18-di((3'-diethylphospho-
no)propyl)
[0391] Deuteroporphyrin dimethyl ester (1.0 g) was reduced to the
corresponding diol following example 7. The diol was dissolved in
pyridine (25 ml) and dichloromethane (100 ml) and cooled in an
ice-water bath. Methane sulfonyl chloride (5 ml) was added slowly
to the reaction. The reaction was stirred for 4 hrs and washed with
water and then 1N HCl until the organic layer was free of pyridine.
The organic layer was dried and evaporated to give the
deuteroporphyrin dimesylate. Yield=1.150 g. This was then suspended
in acetone (200 ml), and sodium iodide (2.5 g) was added and the
reaction refluxed for 3 hrs. Acetone was evaporated, and water (100
ml) was added to the residue and filtered. The solid was washed
with water and methanol and dried to give the deuteroporphyrin
diiodide. Yield=1.10 g.
[0392] Deuteroporphyrin diiodide (850 mg) was refluxed in
triethylphosphite (45 ml) for 3 hrs. Excess triethyphosphite was
evaporated under vacuum and the residue dissolved in
dichloromethane and chromatographed over silica gel (2%, 3%, 5%
methanol/dichloromethane). The major product was collected and
precipitated from dichloromethane/ether/hexane to give the
deuteroporphyrin diphosphonate. Yield=850 mg.
[0393] Deuteroporphyrin diphosphonate (700 mg) was metallated as
described in example 1. The crude product was purified by
chromatography on silica gel (5%, 10%, 15%
methanol/dichloromethane). The major product was collected and
crystallized from dichloromethane/ether/hexane to give the title
compound. Yield=492 mg.
Example 81
Indium Chloride
3,7,12,17-tetramethylporphyrin-2,18-di((3'-diethylphosphon-
o)propyl)
[0394]
3,7,12,17-tetramethylporphyrin-2,18-di((3'-diethylphosphono)propyl)
(example 80) (140 mg) was refluxed in acetic acid (10 ml) in the
presence of indium acetylacetone (140 mg) for 45 min. Acetic acid
was evaporated by rotary evaporation and the residue dissolved in
dichloromethane (75 mL). The dichloromethane solution was washed
with 1N HCl (2.times.50 ml), dried and evaporated. The crude
product was pure by TLC and was precipitated from
dichloromethane/ether/hexane to give the title compound. Yield=135
mg.
Example 82
Tin(IV)dichloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-
-di(propionic Acid Methyl Ester)
[0395] The metal free azaporphyrin (125 mg) synthesized in example
21 (prior to metallation) was metallated as described in example
32. Yield of the title compound=100 mg.
Example 83
Indium Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-d-
i(propionic Acid Methyl Ester)
[0396] The metal free azaporphyrin (125 mg) synthesized in example
21 (prior to metallation) was metallated as described in example
31. Yield of the title compound=125 mg.
Example 84
Aluminum Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-
-di(propionic Acid Methyl Ester)
[0397] The metal free azaporphyrin (125 mg) synthesized in example
21 (prior to metallation) was metallated as described in example
30. Yield of the title compound=125 mg.
Example 85
Platinum
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(propi-
onic Acid Methyl Ester)
[0398] The metal free azaporphyrin (100 mg) synthesized in example
21 (prior to metallation) was metallated as described in example
29. Yield of the title compound=110 mg.
Example 86
Platinum
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(propi-
onic Acid Potassium Salt)
[0399] The platinum azaporphyrin (example 85) (100 mg) was
dissolved in THF (25 ml), and KOH (100 mg) was dissolved in
methanol/water (1 ml/l ml) and added. The reaction was refluxed
until hydrolysis was complete, 2 hrs. THF was evaporated on a
rotoevaporator and the residue dissolved in water. The solution was
neutralized with 1N HCl, and the solid filtered and dried to give
the platinum azaporphyrin diacid. The diacid (100 mg) was dissolved
in methanol (25 ml) then treated with 2 equivalents of KOH in
methanol and stirred for 2 hrs. All the solvent was evaporated to
dryness to give the title compound. Yield of the title compound 90
mg.
Example 87
Gallium Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18--
di(propionic Acid)
[0400] Gallium azaporphyrin (example 21) (125 mg) was hydrolyzed to
the corresponding disodium salt as described in example 86. The
solution was neutralized with 1N HCl, and the solid filtered and
dried to give the gallium azaporphyrin diacid. Yield of the title
compound=100 mg.
Example 88
Gallium Hydroxy
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-d-
i(propionic Acid Sodium Salt)
[0401] Gallium azaporphyrin diacid (example 87) (100 mg) was
converted to its disodium salt as described in example 86, except
that NaOH was used instead of KOH. Yield of the title compound=100
mg.
Example 89
Gallium Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18--
di(propionic Acid Ethyl Ester)
[0402] Azaporphyrin (example 21) (100 mg) was transesterified as
described in example 2. Yield=90 mg. This was metallated as
described in example 1. Yield of the title compound=95 mg.
Example 90
Tin (IV) dichloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,-
18-di(propionic Acid Methyl Amide)
[0403] Azaporphyrin methylamide (example 22; prior to metallation)
(110 mg) was metallated as described in example 32. Yield of the
title compound=120 mg.
Example 91
Indium Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-d-
i(propionic Acid Methyl Amide)
[0404] Azaporphyrin methylamide (example 22; prior to metallation)
(100 mg) was metallated as described in example 31. Yield of the
title compound=120 mg.
Example 92
Platinum
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(propi-
onic Acid Methyl Amide)
[0405] Azaporphyrin methylamide (example 22; prior to metallation)
(110 mg) was metallated as described in example 29. Yield of the
title compound=120 mg.
Example 93
Aluminum Chloride
7.8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-
-di(propionic Acid Methyl Amide)
[0406] Azaporphyrin methylamide (example 22; prior to metallation)
(110 mg) was metallated as described in example 30. Yield of the
title compound=90 mg.
Example 94
Gallium Chloride 5-aza-mesoporphyrin IX Dimethyl Amide
[0407] 5-aza-mesoporphyrin IX (100 mg) was converted to its
methylamide and metallated as described in example 121. Yield of
the title compound=75 mg.
Example 95
Gallium Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18--
di(propionic Acid 2'-methoxyethyl Amide)
[0408] Azaporphyrin dimethyl ester (example 21; prior to
metallation) (100 mg) was converted to the amide as described in
example 66 except that 2-methoxyethylamine was used instead of
3-aminopropanol. Yield=110 mg. This material was metallated as
described in example 11. Yield of the title compound=95 mg.
Example 96
Platinum
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(propi-
onic Acid-2'-methoxyethyl Amide)
[0409]
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(propion-
ic acid 2'-methoxyethyl amide) (example 95) (100 mg) was metallated
as described in example 29. Yield=85%
Example 97
Gallium Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18--
di(propionic Acid-3'-hydroxypropyl Amide)
[0410] Azaporphyrin dimethyl ester (example 21) (100 mg) was
converted to the title compound as described in example 66.
Yield=110 mg.
Example 98
Platinum
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(propi-
onic Acid-3'-hydroxypropyl Amide Amide)
[0411] Platinum azaporphyrin dimethyl ester (example 85) (100 mg)
was converted to the title compound as described in example 67.
Yield=110 mg.
Example 99
Gallium Chloride 5-azamesoporphyrin IX di(3'-hydroxypropyl
Amide)
[0412] 5-azamesoporphyrin dimethyl ester (Singh, J. P., et al, Tet.
Lett. 1995, 36, 1567) (100 mg) was converted to the title compound
as described in example 66. Yield=110 mg.
Example 100
Gallium Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18--
di(propionic Acid-2-ethoxyethanol Amide)
[0413] Azaporphyrin dimethyl ester (example 21) (100 mg) was
converted to the title compound as described in example 16.
Yield=110 mg.
Example 101
Platinum
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(propi-
onic Acid-2-ethoxyethanol Amide)
[0414] Platinum azaporphyrin dimethyl ester (example 85) (100 mg)
was converted to the title compound as described in example 69.
Yield=100 mg.
Example 102
Gallium Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18--
di(propionic Acid-2'-N,N-dimethylaminoethyl Amide)
[0415] Azaporphyrin (example 21) (150 mg) was converted to the
titled compound as described in example 22 except that
2-N,N-dimethylaminoethyla- mine was used instead of methylamine.
Yield=100 mg.
Example 103
Platinum
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(propi-
onic Acid-2'-N,N-dimethylaminoethyl Amide)
[0416] Platinum azaporphyrin dimethyl ester (example 85) (100 mg)
was converted to the title compound as described in example 71.
Yield=100 mg.
Example 104
Indium Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-d-
i(3'-hyroxypropyl)
[0417]
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(3'-hyro-
xypropyl) (example 23) (125 mg) was metallated as described in
example 31. Yield of the title compound=100 mg.
Example 105
Platinum
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(3'-hy-
roxypropyl)
[0418] Platinum azaporphyrin dimethyl ester (150 mg) was reduced
using LiAlH.sub.4 as described in example 74. Yield of the title
compound=120 mg.
Example 106
Gallium Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18--
di(3'-methoxypropyl)
[0419] Azaporphyrin diol (example 23) (200 mg) was converted to its
methyl ether via the tosylate according to the procedure described
in examples 9 and 10. Yield=150 mg. This material was metallated
following the procedure described in example 10. Yield of the title
compound=120 mg.
Example 107
Indium Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-d-
i(3-methoxypropyl)
[0420] Azaporphyrin diol (example 23) (200 mg) was converted to its
methyl ether via the tosylate according to the procedure described
in examples 9 and 10. Yield=150 mg. This material was metallated
following the procedure described in example 31. Yield of the title
compound=120 mg.
Example 108
Gallium Chloride
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18--
di(butanoic Acid Methyl Ester)
[0421]
7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2,18-di(butanoi-
c acid methyl ester) was prepared from azaporphyrin dimethyl ester
(example 21) following the procedure described in examples 7, 9,
25, 26. Yield=500 mg.
Example 109
Gallium Hydroxy Mesoporphyrin Disodium Salt
[0422] Gallium chloride mesoporphyrin dimethyl ester (example 1)
(125 mg) was converted to its sodium salt as described in example
86, except that 3 equivalents of NaOH were used instead of KOH.
Yield of the title compound=100 mg.
Example 110
Indium Hydroxy Mesoporphyrin Disodium Salt
[0423] Indium chloride mesoporphyrin dimethyl ester (example 31)
(125 mg) was converted to its sodium salt as described in example
86, except that 3 equivalents of NaOH were used in the final step
instead of KOH. Yield of the title compound=100 mg.
Example 111
Platinum Mesoporphyrin Disodium Salt
[0424] Platinum mesoporphyrin dimethyl ester (example 29) (150 mg)
was converted to its sodium salt as described in example 86, except
that NaOH was used in the final step instead of KOH. Yield of the
title compound=100 mg.
Example 112
Indium Hydroxy Protoporphyrin Disodium Salt
[0425] Protoporphyrin dimethyl ester (150 mg) was metallated
following the procedure described in example 31. This material was
converted to the title compound as described in example 86, except
that 3 equivalents of NaOH were used in the final step instead of
KOH. Yield of the title compound=110 mg.
Example 113
Indium Hydroxy Coproporphyrin III Tetra Sodium Salt
[0426] Coproporphyrin III dimethyl ester (125 mg) was metallated
following the procedure described in example 31. This material was
converted to the title compound as described in example 110.
Yield=110 mg.
Example 114
Gallium Hydroxy
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(Pentan- oic
Acid Sodium Salt)
[0427] Gallium chloride
8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-d- i(pentanoic
acid methyl ester) (200 mg) (example 28) was converted to its
disodium salt following the procedure described in example 86,
except that 3 equivalents of NaOH were used in the final step
instead of KOH. Yield=180 mg.
Example 115
Gallium Chloride Mesoporphyrin III Dimethyl Ester
[0428] Mesoporphyrin III dimethyl ester was synthesized according
to literature procedures (Grigg, R., et al, J. Chem. Soc., C.,
1969, 176). This material (200 mg) was metallated as described in
example 1. Yield of the title compound=190 mg.
Example 116
Gallium Chloride
3,7,14,17-tetramethyl-5,10-diazaporphyrin-2,8,12,18-tetra-
(propionic Acid Methyl Ester)
[0429] 3,3'-dimethyl-4,4'-di(methyl propionate)dipyrromethane (1.05
g) was dissolved in ethyl acetate (25 ml) and bromine (1.5 g) was
added dropwise. A dark brown precipitate was formed. The reaction
was cooled and the solid filtered and dried. Yield of dibrominate
dipyrromethane=0.95 g. This material was dissolved in methanol (50
ml), and sodium azide (1 g) in water (5 mL) was added and the
reaction refluxed for 3 days. UV/Vis analysis of the reaction
showed the disappearance of the 429 nm peak (due to dipyrromethane)
and appearance of two peaks at 545 nm and 620 nm. The solvent was
evaporated and the residue chromatographed over silica gel (2-5%
methanol/dichloromethane). The fast running blue/purple band, which
was 3,7,14,17-tetramethyl-5,10-d-
iazaporphyrin-2,8,12,18-tetra(propionic acid methyl ester), was
isolated. Yield
3,7,14,17-tetramethyl-5,10-diazaporphyrin-2,8,12,18-tetra(propionic
acid methyl ester)=of 100 mg. This material was metallated as
described in example 21. Yield, 75 mg.
Example 117
Gallium Chloride
3,7,14,17-tetramethyl-5,10-diazaporphyrin-2,8,12,18-tetra Propionic
Acid
[0430] Gallium chloride
3,7,14,17-tetramethyl-5,10-diazaporphyrin-2,8,12,1-
8-tetra(propionic acid methyl ester) (example 116) (50 mg) was
hydrolyzed to the corresponding tetra acid as described in example
86. Yield of the title compound=45 mg.
Example 118
Gallium Chloride
3,7,14,17-tetramethyl-5,10-diazaporphyrin-2,8,12,18-tetra
(3'-hydroxypropyl)
[0431] Diazaporphyrin (synthesized in example 116) (50 mg) was
converted to the title compound following the procedure described
in example 23. Yield=30 mg.
Example 119
Platinum
3,7,14,17-tetramethyl-5,10-diazaporphyrin-2,8,12,18-tetra(propion-
ic acid methyl ester
[0432]
3,7,14,17-tetramethyl-5,10-diazaporphyrin-2,8,12,18-tetra(propionic
acid methyl ester) (synthesized in example 116) (50 mg) was
metallated as described in example 29. Yield, of the title
compound=50 mg.
Example 120
Platinum
3,7,14,17-tetramethyl-5,10-diazaporphyrin-2,8,12,18-tetra(3'-hydr-
oxypropyl)
[0433] Platinum
3,7,14,17-tetramethyl-5,10-diazaporphyrin-2,8,12,18-tetra(-
propionic acid methyl ester) (example 119) (50 mg) was reduced to
the corresponding tetraalcohol as described in example 74. Yield of
the title compound=35 mg.
Example 121
Gallium Chloride Mesoporphyrin N-methyl Amide
[0434] Mesoporphyrin (200 mg) was suspended/dissolved in
dichloromethane (25 mL) and oxalylchloride (5 mL) was added. The
solution was refluxed for 1 hr under argon. The excess
oxaylychloride and dichloromethane was removed by rotary
evaporation and dichloromethane (50 mL) was added, followed by a 2M
solution of methylamine in THF (40 mL). The solution was stirred
for 2 hrs after which the solvent was removed by rotary
evaporation. The residue was dissolved in 5%
methanol/dichloromethane and chromatographed on silica using 5%
methanol/dichloromethane as the eluent. The major red fraction
(mesoporphyrin dimethyl amide) was collected and evaporated to
.about.30 mL and methanol (20 mL) added. The dichloromethane was
removed by rotary evaporation and the precipitated solid collected
by filtration and dried. This compound was suspended in acetic acid
(25 mL) and gallium acetyl acetonate added (200 mg). The solution
was refluxed for 1.5 hrs after which time a UV/visible analysis of
the molecule showed the metallation to be complete. The solvent was
removed by rotary evaporation and the residue dissolved in
dichloromethane (100 mL). The dichloromethane layer was washed
repeatedly with 1N HCl and the organic layer collected and
evaporated. The crude reaction mixture was chromatographed on
silica (5% methanol/dichloromethane) and the major pink fraction
collected and evaporated. The compound was redissolved in
dichloromethane (100 mL), and the organic layer was washed
repeatedly with 1N HCl, dried over sodium sulfate and evaporated to
.about.20 mL. Hexane was added (14 mL) and the dichloromethane was
removed by rotary evaporation. The precipitated solid was collected
by filtration and dried. Yield of the title compound=200 mg.
Example 122
Gallium Chloride Deuteroporphyrin Di-propylester
[0435] Deuteroporphyrin dimethyl ester (200 mg) was refluxed in 5%
sulfuric acid in propanol (25 ml) for 6 hrs. The reaction was
cooled to room temperature, diluted with water (100 ml) and
solution neutralized with sodium bicarbonate. The solid was
filtered, dried and crystallized from dichloromethane and hexane.
Yield of deuterporphyrin dipropyl ester=180 mg. This was then
metallated as described in example 1. Yield of the title
compound=190 mg.
Example 123
Gallium Chloride Rhodoporphyrin Di-methylester
[0436] Rhodoporphryin dimethyl ester (200 mg) was synthesized
according to the method outlined in "The Porphyrins and
Metalloporphyrins" Ed. Kevin Smith, Chapter 19, Elsevier Scientific
Publishing Co., 1975, page 777, and metallated according to example
1. Yield=210 mg.
[0437] It will be apparent to those skilled in the art that various
modifications and variations can be made in the compounds and
methods of the present invetion without departing from the spirit
or scope of the invention. Thus, it is intended that the present
invention cover the modification and variations of this invention
provided they fall within the scope of the appended claims and the
equivalents.
* * * * *