Metallotetrapyrrolic photosensitizing agents for use in photodynamic therapy

• US 20030105069A1
• Filed: 05/31/2002
• Published: 06/05/2003
• Est. Priority Date: 05/31/2001
• Status: Active Grant

• Current Assignee: Miravant Pharmaceuticals, Inc. (Miravant Medical Technologies)
• Original Assignee: Miravant Pharmaceuticals, Inc. (Miravant Medical Technologies)
• Inventors: Robinson, Byron C., Greene, Stephanie, Leitch, Ian M., Rychnovsky, Steve
• Granted Patent: US 6,827,926 B2
• Time in Patent Office: Days
• US Class Current: 514/185
• CPC Class Codes: A61K 41/0071 PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
• CPC Class Codes: A61K 49/0036 Porphyrins used in photodynamic therapy A61K41/0071 or A61K41/0076; used as targeting group or modifying agent for targeting a therapeutic compound A61K47/546
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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.

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.

12. The method of claim 1, wherein said porphyrin compound is selected from gallium (III) mesoporphyrin diacid, gallium (ill) 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 α

-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.

15. The method of any of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 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 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 wherein the cardiovascular disease is atherosclerosis, restenosis or graft disease.

31. The method of any of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 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.

55. The method of claim 1, wherein the gallium porphyrin is a compound of the following formula I:

56. The method of claim 1, wherein the gallium porphyrin is a compound of the following formula IA:

59. The method of claim 1, wherein the gallium porphyrin is a compound of the following formula IB:

60. The method of claim 1, wherein the gallium porphyrin is a compound of the following formula:

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.

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.

64. The method of claim 2, wherein said gallium azaporphyrin is a compound of the following formula II:

65. The method of claim 2, wherein the gallium azaporphyrin is a compound of the following formula:

67. The method of claim 2, wherein the gallium azaporphyin is a compound of the following formula IIA:

71. The method of claim 2, wherein the gallium azaporphyrin is a compound of formula III:

72. The method of claim 2, wherein the gallium azaporphyrin is a compound of formula IIIA:

75. The method of claim 2, wherein the gallium azaporphyrin is a compound of formula IV:

76. The method of claim 2, wherein the gallium azaporphyrin is a compound of formula IV:

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, Tl, 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.

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.

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. The method of claim 10, wherein said metal is Ga.

18. The method of claim 9 wherein said therapeutic effect is observed on the group consisting of normal contractile phenotype vascular smooth muscle cells (VS MC), non-contractile synthetic phenotype VS MC, 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.

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.

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.

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, sonotherapy, hyperthermia, cryotherapy, magnetic force, viral or 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, 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.

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 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.

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 coordinating 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 coordinating 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.

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.

57. A compound of the following formula IA:

58. A compound of the following formula:

61. A compound of the following formula:

62. A compound of the following formula IB:

63. Compounds according to claim 62 wherein M is Ga³⁺, where associated with the coordinated gallium is a physiologically acceptable charge balancing counter ion;

with the proviso that when R₁ and R₂═

H, R₅ cannot be CH₃, and when R₁ and R₂═

C1-C7 alkyl and n=2, R₁₀ or R₁₁ 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.

66. A metalloazaporphyrin of the following formula:

68. A compound of the following formula II:

69. A compound of the following formula:

70. A compound of the following formula IIA:

73. A compound of formula IIIA:

74. A compound of formula III:

77. A compound of the following formula IV: