Claims for Patent: 8,540,967

Summary for Patent: 8,540,967

Title:	Porphyrazine optical and dual optical/MR contrast and therapeutic agents
Abstract:	Porphyrazines capable of localizing in a tumor of a mammal are disclosed. The porphyrazines are used in methods of imaging a tumor and in methods of treating tumors, either alone or in combination with a chemotherapeutic agent and/or radiation.
Inventor(s):	Barrett; Anthony G. M. (London, GB), Trivedi; Evan R. (Evanston, IL), Hoffman; Brian M. (Evanston, IL)
Assignee:	Hoffman/Barrett, L.L.C. (Evanston, IL)
Application Number:	13/062,031
Patent Claims:	1. A method of imaging a tumor comprising: a) administering a sufficient amount of a porphyrazine for visualization to a mammal suspected of having a tumor; and b) imaging the porphyrazine in the mammal, wherein the porphyrazine has a structure M[pz(A.sub.n;B.sub.4-n)] wherein pz is ##STR00037## M is 2H or a metal ion capable of complexing with pyrrole nitrogen atoms; n is 1-3; A is (--N(R.sup.1).sub.2).sub.2, (--OR.sup.1).sub.2, or (--SR.sup.1).sub.2; B is a benzo ring fused on the pz, substituted with one or more --XR.sup.2, group, wherein X is O or S; R.sup.1, independently, and R.sup.2, independently, are selected from the group consisting of C.sub.1-6alkyl optionally substituted with OH, OR.sup.3, N(R.sup.3).sub.2, CO.sub.2R.sup.3, or CON(R.sup.3).sub.2, C.sub.3-6cycloalkyl optionally substituted with OH, OR.sup.3, N(R.sup.3).sub.2, CO.sub.2R.sup.3, or CON(R.sup.3).sub.2, (CH.sub.2).sub.1-3C.sub.3-6cycloalkyl optionally substituted with OH, OR.sup.3, N(R.sup.3).sub.2, CO.sub.2R.sup.3, or CON(R.sup.3).sub.2, (CH.sub.2).sub.1-6C.sub.6H.sub.5, optionally substituted with OH, OR.sup.3, N(R.sup.3).sub.2, CO.sub.2R.sup.3, or CON(R.sup.3).sub.2, wherein each R.sup.3, independently is H, C.sub.1-6alkyl, C.sub.3-6cycloalkyl, or (CH.sub.2).sub.1-3C.sub.3-6cycloalkyl; ##STR00038## p is 0-10; TABLE-US-00003 E ##STR00039## ##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045## ##STR00046## G ##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053## L ##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058## ##STR00059## wherein at least one of the E, G, and L is ##STR00060## and ##STR00061## or two R.sup.1, groups can be taken together to form a 5- or 6- membered ring, and the porphyrazine localizes at a tumor in the mammal, and the porphyrazine comprises one to eight Gd chelates and the imaging is selected from the group consisting of optical imaging, visible or NIR imaging, PET imaging, nuclear imaging, and MR imaging. 2. The method of claim 1 wherein the porphyrazine is chiral. 3. The method of claim 1 wherein A is, independently, (--OR.sup.1).sub.2, or (--SR.sup.1).sub.2. 4. The method of claim 1 wherein the porphyrazine has a Structure M[pz(A.sub.2; B.sub.2)]. 5. The method of claim 4 wherein the porphyrazine has a structure M[pz(transA.sub.2; B.sub.2)]. 6. The method of claim 1 wherein M is selected from the group consisting of two hydrogen atoms, an alkali metal, an alkaline earth metal, a transition metal, a lanthanide,and an actinide. 7. The method of claim 1 wherein M is selected from the group consisting of nickel, copper, two hydrogen atoms, magnesium, iron, aluminum, manganese, gadolinium, rhodium, gold, cobalt, platinum, palladium, ruthenium, lead, lithium, zinc, chromium, technetium, silicon, indium, thallium, germanium, tin, tungsten, rhenium, zirconium, iridium, uranium, vanadium, titanium, molybdenum, gallium, neodymium, and ytterbium. 8. The method of claim 1 wherein said porphyrazine has the structure selected from the group consisting of ##STR00062## ##STR00063## ##STR00064## 9. The method of claim 1 wherein the porphyrazine kills cells in the tumor. 10. The method of claim 9 further comprising the step of light activation of the porphyrazine. 11. The method of claim 1 wherein two or more visualizing methods are jointly or simultaneously used after administration of a single porphyrazine. 12. The method of claim 11 wherein the two or more imaging methods are optical and MR imaging or optical and PET imaging. 13. The method of claim 1 wherein the mammal is a human. 14. A porphyrazine-chemotherapeutic agent conjugate comprising a porphyrazine compound having a structure M[pz(A.sub.n;B.sub.4-n)] wherein pz is ##STR00065## M is 2H or a metal ion capable of complexing with pyrrole nitrogen atoms; n is 1-3; A is (--N(R.sup.1).sub.2).sub.2, (--OR.sup.1).sub.2, or (--SR.sup.1).sub.2; B is a benzo ring fused on the pz, substituted with one or more --XR.sup.2, group, wherein X is O or S; R.sup.1, independently, and R.sup.2, independently, are selected from the group consisting of C.sub.1-6alkyl optionally substituted with OH, OR.sup.3, N(R.sup.3).sub.2, CO.sub.2R.sup.3, or CON(R.sup.3).sub.2, C.sub.3-6cycloalkyl optionally substituted with OH, OR.sup.3, N(R.sup.3).sub.2,CO.sub.2R.sup.3, or CON(R.sup.3).sub.2, (CH.sub.2).sub.1-3C.sub.3-6cycloalkyl optionally substituted with OH, OR.sup.3, N(R.sup.3).sub.2, CO.sub.2R.sup.3, or CON(R.sup.3).sub.2, (CH.sub.2).sub.1-6C.sub.6H.sub.5, optionally substituted with OH, OR.sup.3, N(R.sup.3).sub.2, CO.sub.2R.sup.3, or CON(R.sup.3).sub.2, wherein each R.sup.3, independently is H, C.sub.1-6alkyl, C.sub.3-6cycloalkyl, or (CH.sub.2).sub.1- 3C.sub.3-6cycloalkyl; ##STR00066## p is 0-10; TABLE-US-00004 E G L ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## wherein at least one of E, G, and L is ##STR00088## and ##STR00089## or two R.sup.1, groups can be taken together to form a 5- or 6- membered ring and the porphyrazine comprises one to eight Gd chelates, linked to a chemotherapeutic agent selected from the group consisting of gemcitabine, capecitabine, methotrexate, taxol, taxotere, mereaptopurine, thioguanine, hydroxyurea, ifosfamide, nitrosoureas, mitomycin, procarbizine, etoposide, teniposide, campatheeins, bleomycin, doxorubicin, idarubicin, daunorubicin, plicamycin, mitoxantrone, doxorubicin, epirubicin, leucovorin, levamisole, irinotecan, estramustine, etoposide, nitrogen mustards, topotecan, genistein, erbstatin, and lavendustin A, alkylating agents, nitrogen mustards, cyclophosphamide, trofosfamide, chlorambucil, nitrosoureas, treosulfan, plant alkaloids, vinca alkaloids, vineristine, vinblastine, vindesine, vinorelbine, epipodophyllins, 9-aminocamptothecin, camptothecin, crisnatol, mitomycins, mitomycin C, anti-metabolites, anti-folates, trimetrexate, mycophenolic acid, tiazofurin, ribavirin, ribonuclotide reductase inhibitors, hydroxyurea, deferoxamine, pyrimidine analogs, floxuridine, doxifluridine, ratitrexed, cytarabine (ara C), cytosine arabinoside, fludarabine, purine analogs, mercaptopurine, thioguanine, 3-HP, 2'-deoxy-5-fluorouridine, 5-HP, alpha-TGDR, aphidicolin glycinate, ara-C, 5-aza-2'-deoxycytidine, beta-TGDR, cyclocytidine, guanazole (inosine glycodialdehyde), macebecin II, receptor antagonists, anti-estrogen, raloxifene, megestrol, LHRH agonists, goserelin, leuprolide acetate, anti-androgens, flutamide, bicalutamide, retinoids/deltoids, cis-retinoic acid, all-trans retinoic acid (ATRA-IV), CB 1093, vertoporfin, phthalocyanine, photosensitizer Pc4, angiogenesis inhibitors, antiangiogenic antithrombin UI, angiozyme, ABT-627, Bay 12- 9566, bevacizumab, BMS-275291, CAI, CD59, complement fragment, CEP-7055, Col 3, combretastatin A-4, endostatin (collagen XVIII fragment), fibronectin fragment, halofuginone, heparin hexasaccharide fragment, HMV833, IM-862, marimastat, metalloproteinase inhibitors (UMPs), 2-methoxyestradiol, MMI 270, (CGS 27023A), NM-3, panzem, platelet factor-4, (PF4), prinomastat, prolactin 161(D fragment, proliferin-related protein (PRP), PTK 787/ZK 222594, retinoids, solimastat, squalamine, SS 3304, SU 5416, SU 6668, SU 11248, tetrahydrocortisol-S, thalidomide, thrombospondin-1, (TSP-1), TNP-470, antimitotic agents, halichondrin B, trityl cysteine, 1-methyl-4-phenylpyridinium ion, staurosporine, bleomycins, bleomycin A2, bleomycin B2, peplomycin, anthracycline, adriamycin, epirubicin, pirarnbicin, zorubicin, mitoxantrone, MDR inhibitors, Ca2'ATPase inhibitors, thapsigargin, acivicin; aclarubicin; acodazole hydrochloride; adozelesin; arnbomycin; ametantrone acetate; aminoglutethimide; amsacrine; anthramycin; azacitidine; azotomycin; batimastat; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelcsin; bleomycin sulfate; brequinar sodium; bropirimine; busul fan; cactinomycin; calusterone; carbetimer; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cladribine; crisnatol mesylate; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; diaziquone; docetaxel; doxorubicin hydrochloride; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide phosphate; etoprine; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; lometrexol sodium; losoxantrone hydrochloride; masoprocol; maytansine; mecchlorethamine hydrochloride; melphalan; menogaril; methotrexate sodium; metoprine; mitocarcin; mitocromin; mitogillin; mitomycin; mitoxantrone hydrochloride; mycophenolic acid; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfarnide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; sparfosate sodium; sparsornycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; teloxantrone hydrochloride; temoporfin; teroxirone; thiamiprine; thioguanine; tiazofurin; tirapazamine; toremifene citrate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracit mustard; vapreotide; verteporfln; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozolc; zeniplatin; zinostatin; zorubicin hydrochloride, 20-epi-1,25-dihydroxyvitamin D3; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL TK antagonists; altretamine; ambamustine; amidox; arnifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein 1; antiandrogen; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis regulators; apurinic acid; ara CDP DL PTBA; axinastatin 3; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; beta lactam derivatives; beta alethine; betaclarnycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylsperrnine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; buthionine sulfoximine; calcipotriol; calphostin C; canarypox IL- 2; carboxamide amino triazole; carboxyarnidotriazole; CaRest M3; CARN 700; carzelesin; castanospermine; cetrorelix; chlorins; cicaprost; cladribine; clomifene analogues; clotrimazole; combretastatin A4; conagenin; crambescidin 816; crisnatol; cyclopentanthraquinones; cytarabine ocfosfate; cytostatin; dacliximab; decitabine; deslorelin; dexamethasone; diaziquone; didemnin B; didox; diethylnorspermine; dihydro 5, azacytidine; dihydrotaxol, 9; dioxamycin; docetaxel; docosanol; doxifluridine; duocarmycin SA; ecomustine; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; fazarabine; fenretinide; finasteride; flavopiridol; fltidarabine; fluorodaunoruniein hydrochloride; forfenimex; formestane; fostriecin; galocitabine; ganirelix; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; iobenguane; iododoxorubiein; ipomeanol, 4; irsogladine; isobengazole; itasetron; jasplakinolide; kahalalide F; larnellarin N triacetate; lanreotide; leinamycin; leptolstatin; leuprolide+estrogen+progesterone; leuprorelin; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; metoclopramide; MIF inhibitor; mifepristone; mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor saporin; mitoxantrone; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; mustard anti-cancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N acetyldinaline; nafarelin; naloxone+pentazocine; napavin; naphterpin; nemorubicin; neridronic acid; nisamycin; nitrullyn; octreotide; okicenone; oligonucleotides; onapristone; oracin; osaterone; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; perfosfamide; perillyl alcohol; phenylacetate; phosphatase inhibitors; picibanil; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum triamine complex; porfimer sodium; porfiromycin; prednisone; propyl his acridone; prostaglandin J2; purpurins; pyrazoloaeridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; RH retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone BI; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; Sdi 1, mimetics; semustine; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stipiamide; sulfinosine; suradista; suramin; swainsonine; tallimustine; tauromustine; tazarotene; temoporfin; temozolomide; teniposide; tetrazomine; thiocoraline; tin ethyl etiopurpurin; tirapazamine; topsentin; toremifene; tretinoin; triciribine; trimetrexate; turosteride; ubenimex; vapreotide; variolin B; velaresol; veramine; verteporfin; vinorelbine; vinxaltine; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. 15. A method of treating a tumor comprising administering to an individual in need thereof a therapeutically effective amount of a porphyrazine-chemotherapeutic agent conjugate of claim 14. 16. The method of claim 15 wherein the chemotherapeutic agent is doxorubicin, methotrexate, tamoxifen, taxotere, or xeloda. 17. The method of claim 15 wherein the porphyrazine is ##STR00090## 18. The method of claim 17 wherein the chemotherapeutic agent is doxorubicin, methotrexate, tamoxifen, taxotere, or xeloda. 19. The porphyrazine-chemotherapeutic agent conjugate of claim 14 wherein the porphyrazine is ##STR00091## 20. The porphyrazine-chemotherapeutic agent conjugate of claim 19 wherein the chemotherapeutic agent is doxorubicin, methotrexate, tamoxifen, taxotere, or xeloda. 21. The porphyrazine-chemotherapeutic agent conjugate of claim 14 wherein the chemotherapeutic agent is doxorubicin, methotrexate, tamoxifen, taxotere, or xeloda.

Details for Patent 8,540,967

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Clinigen, Inc.	PROLEUKIN	aldesleukin	For Injection	103293	05/05/1992		2028-09-08
Servier Pharmaceuticals Llc	ONCASPAR	pegaspargase	Injection	103411	02/01/1994		2028-09-08
Hoffmann-la Roche Inc.	PEGASYS COPEGUS COMBINATION PACK	peginterferon alfa-2a and ribavirin		125083	06/04/2004		2028-09-08
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2028-09-08