AU3275293A - Bicyclopolyazamacrocyclocarboxylic acid complexes, their conjugates processes for their preparation, and use as radiopharmaceuticals - Google Patents
Bicyclopolyazamacrocyclocarboxylic acid complexes, their conjugates processes for their preparation, and use as radiopharmaceuticalsInfo
- Publication number
- AU3275293A AU3275293A AU32752/93A AU3275293A AU3275293A AU 3275293 A AU3275293 A AU 3275293A AU 32752/93 A AU32752/93 A AU 32752/93A AU 3275293 A AU3275293 A AU 3275293A AU 3275293 A AU3275293 A AU 3275293A
- Authority
- AU
- Australia
- Prior art keywords
- conjugate
- complex
- alkyl
- metal ion
- antibody
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims description 21
- 239000002253 acid Substances 0.000 title claims description 14
- 239000012217 radiopharmaceutical Substances 0.000 title description 9
- 238000002360 preparation method Methods 0.000 title description 5
- 230000008569 process Effects 0.000 title description 5
- 229940121896 radiopharmaceutical Drugs 0.000 title description 5
- 230000002799 radiopharmaceutical effect Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 27
- -1 isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido Chemical group 0.000 claims description 24
- 229910021645 metal ion Inorganic materials 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- KZUNJOHGWZRPMI-AKLPVKDBSA-N samarium-153 Chemical compound [153Sm] KZUNJOHGWZRPMI-AKLPVKDBSA-N 0.000 claims description 19
- OHSVLFRHMCKCQY-NJFSPNSNSA-N lutetium-177 Chemical compound [177Lu] OHSVLFRHMCKCQY-NJFSPNSNSA-N 0.000 claims description 18
- 239000003446 ligand Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 11
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 11
- 239000011149 active material Substances 0.000 claims description 11
- 241001465754 Metazoa Species 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 238000003745 diagnosis Methods 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- WUAPFZMCVAUBPE-IGMARMGPSA-N rhenium-186 Chemical compound [186Re] WUAPFZMCVAUBPE-IGMARMGPSA-N 0.000 claims description 8
- 125000006416 CBr Chemical group BrC* 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims description 7
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 5
- GYHNNYVSQQEPJS-OIOBTWANSA-N Gallium-67 Chemical compound [67Ga] GYHNNYVSQQEPJS-OIOBTWANSA-N 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000012634 fragment Substances 0.000 claims description 4
- 229920002307 Dextran Polymers 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 125000006414 CCl Chemical group ClC* 0.000 claims 1
- 229920001184 polypeptide Polymers 0.000 claims 1
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- 230000001588 bifunctional effect Effects 0.000 description 20
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- 239000002738 chelating agent Substances 0.000 description 17
- 239000013522 chelant Substances 0.000 description 16
- 201000011510 cancer Diseases 0.000 description 11
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 10
- 238000002560 therapeutic procedure Methods 0.000 description 9
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- VWQVUPCCIRVNHF-OUBTZVSYSA-N Yttrium-90 Chemical compound [90Y] VWQVUPCCIRVNHF-OUBTZVSYSA-N 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 6
- 206010027452 Metastases to bone Diseases 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
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- 208000018084 Bone neoplasm Diseases 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 206010061289 metastatic neoplasm Diseases 0.000 description 4
- URDCARMUOSMFFI-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(2-hydroxyethyl)amino]acetic acid Chemical compound OCCN(CC(O)=O)CCN(CC(O)=O)CC(O)=O URDCARMUOSMFFI-UHFFFAOYSA-N 0.000 description 3
- 206010061728 Bone lesion Diseases 0.000 description 3
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- 241000124008 Mammalia Species 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 239000000032 diagnostic agent Substances 0.000 description 3
- 229940039227 diagnostic agent Drugs 0.000 description 3
- IFQUWYZCAGRUJN-UHFFFAOYSA-N ethylenediaminediacetic acid Chemical compound OC(=O)CNCCNCC(O)=O IFQUWYZCAGRUJN-UHFFFAOYSA-N 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 229910052738 indium Inorganic materials 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 230000001394 metastastic effect Effects 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229920000768 polyamine Polymers 0.000 description 3
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 206010005949 Bone cancer Diseases 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- FCKYPQBAHLOOJQ-UHFFFAOYSA-N Cyclohexane-1,2-diaminetetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)C1CCCCC1N(CC(O)=O)CC(O)=O FCKYPQBAHLOOJQ-UHFFFAOYSA-N 0.000 description 2
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 230000009920 chelation Effects 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000005881 detosylation reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000006159 dianhydride group Chemical group 0.000 description 2
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229960001484 edetic acid Drugs 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 229940127121 immunoconjugate Drugs 0.000 description 2
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 2
- APFVFJFRJDLVQX-AHCXROLUSA-N indium-111 Chemical compound [111In] APFVFJFRJDLVQX-AHCXROLUSA-N 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
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- 150000002739 metals Chemical class 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 description 1
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical group C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 description 1
- XNCSCQSQSGDGES-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]propyl-(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)C(C)CN(CC(O)=O)CC(O)=O XNCSCQSQSGDGES-UHFFFAOYSA-N 0.000 description 1
- CFEHQNGIUSNWQC-UHFFFAOYSA-N 2-[[2-(4-aminophenyl)-2-[bis(carboxymethyl)amino]ethyl]-(carboxymethyl)amino]acetic acid Chemical compound NC1=CC=C(C(CN(CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 CFEHQNGIUSNWQC-UHFFFAOYSA-N 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- WFFOZADOOUFBCT-UHFFFAOYSA-O 4-[1,2-bis[bis(carboxymethyl)amino]ethyl]benzenediazonium Chemical compound OC(=O)CN(CC(O)=O)CC(N(CC(O)=O)CC(O)=O)C1=CC=C([N+]#N)C=C1 WFFOZADOOUFBCT-UHFFFAOYSA-O 0.000 description 1
- BDDLHHRCDSJVKV-UHFFFAOYSA-N 7028-40-2 Chemical class CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O BDDLHHRCDSJVKV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
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- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
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- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
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- KWIARQFOOLCENU-UHFFFAOYSA-N [amino-(4-hydroxy-3-iodophenyl)-phosphonomethyl]phosphonic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(N)C1=CC=C(O)C(I)=C1 KWIARQFOOLCENU-UHFFFAOYSA-N 0.000 description 1
- GTDPSWPPOUPBNX-UHFFFAOYSA-N ac1mqpva Chemical compound CC12C(=O)OC(=O)C1(C)C1(C)C2(C)C(=O)OC1=O GTDPSWPPOUPBNX-UHFFFAOYSA-N 0.000 description 1
- HSANJBZMPJBTRT-UHFFFAOYSA-N acetic acid;1,4,7,10-tetrazacyclododecane Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.C1CNCCNCCNCCN1 HSANJBZMPJBTRT-UHFFFAOYSA-N 0.000 description 1
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- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical class NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- PUDIUYLPXJFUGB-UHFFFAOYSA-N praseodymium atom Chemical compound [Pr] PUDIUYLPXJFUGB-UHFFFAOYSA-N 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229910052761 rare earth metal Inorganic materials 0.000 description 1
- 150000002910 rare earth metals Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 1
- 229910052706 scandium Inorganic materials 0.000 description 1
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 description 1
- 238000003375 selectivity assay Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- XYITYKDGJLHYPW-UHFFFAOYSA-M sodium 2-iodohippurate Chemical class [Na+].[O-]C(=O)CNC(=O)C1=CC=CC=C1I XYITYKDGJLHYPW-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-N sorbic acid group Chemical group C(\C=C\C=C\C)(=O)O WSWCOQWTEOXDQX-MQQKCMAXSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 101150047061 tag-72 gene Proteins 0.000 description 1
- 229940056501 technetium 99m Drugs 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
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Description
BICYCLOPOLYAZAMACROCYCLOCARBOXYLIC ACID COMPLEXES, THEIR CONJUGATES, PROCESSES FOR THEIR PREPARATION, AND USE AS RADIOPHARMACEUTICALS
This invention concerns complexes that contain as the ligand bicyclopolyazamacrocyclocarboxylic acids complexed with metal ions, and comjugates thereof, for use as radiopharmaceuticals, especially for the treatment and/or diagnosis of cancer. The processes for their preparation are also provided.
The delivery of radionuclides to different organ and tissue targets has been the objective of many research efforts for both diagnostic and therapeutic purposes. Various molecules have been tried that would carry the active component to the desired site and yet be stable at least until the site has been reached by the delivery system. Halogenated (e g 131 l and 88mBr) organic molecules have been used. Thus iodinated hippuran has been used to study renal function, e.g. J. Nucl. Med. 23, 377-380 (1982). Also labelling a monoclonal antibody with 131l has been proposed for the detection and therapy of cancer, e.g. Cancer Res. 44, 5744-5751 (1984).
Metalic radionuclides offer a variety of nuclear properties and chemistries Thus, for example, 201Tl, 67Cu, 99mTc, 90Y and various isotopes of In and Ga are only a few examples of radioisotopes that have been used for disgnostic imaging and/or therpy. Of these metals, the chemistry of 99mTc has been explored the most for use as a radiopharmaceutical . For example, Tc-diphosphonates are used to image the skeletal system [see Subramanian et al., Radiology 149, 823-828 (1983)]. Loberg etal. [J. Nucl. Med. 16, 533 (1975)] were able to study liver function with lipophilic 99mTc complexes in which the Tc existed in a + 3 oxidation state and the overall charge of the iminodiacetic acid complex was -1. Deutsch etal. [Science 213, 85 (1981)] was able to prepare Tc complexes with As and P containing ligands that localized in the heart. These compounds contained a Tc(lll) core with an overall charge of the complex of + 1 Also Volkert et al. [Int'l. J Appl. Rad. Isotopes 35, 467-470 (1974)] were successful in delivering Tc(lll) to brain tissue
However, since 99mTc is a pure gamma emmiter , it is limited only to diagnostion applications. Therefore, there has been a need for particle emmiting radioisotope complexes
and/or conjugates which would be useful in therapy. Deutsch etal. [Corina Int'l. , Veronai and Raven Press, pp.733-740 (1990)] have used the combination of 186Re and a diphosphonate to treat bone tumors. Also Simon et al. (U.S. Patent 4,898,724) teach the use of 153Sm and other rare earth radionuclides ϊn combination with aminophosphonic acids for the treatment of bone pain and tumors.
The development of bone metastases is a common and often catastrophic event for a cancer patient. The pain, pathological fractures, frequent neurological deficits and forced immobility caused by these metastatic lesions significantly decrease the quality of life for the cancer patient. The number of patients that contract metastatic disease is large since nearly 50% of all patients who contract breast, lung or prostate carcinoma will eventually develop bone metastases. Bone metastases are also seen in patients with carcinoma of the kidney, thyroid, bladder, cervix and other tumors, but collectively, these represent less than 20% of patients who develop bone metastases. Metastatic bone cancer is rarely life threatening and occasionally patients live for years following the discovery of the bone lesions. Initially, treatment goals center on relieving pain, thus reducing requirements for narcotic medication and increasing ambulation. Clearly, it is hoped that some of the cancers can be cured.
The use of radionuclides for treatment of cancer metastaticto the bone dates back to the early 1950's. It has been proposed to inject a radioactive particle-emitting nuclide in a suitable form for the treatment of calcific lesions. It is desirable that such nuclides be concentrated in the area of the bone lesion with minimal amounts reaching the softtissue and normal bone. Radioactive phosphorus (P-32 and P-33) compounds have been proposed, but the nuclear and biolocafization properties limit the use of these compounds. (E. Kaplan, etal., J. Nucl. Med 1(1), 1, (I960); U.S. Patent 3,965,254).
Another attempt to treat bone cancer has been made using phosphorus compounds containing a boron residue. The compounds were injected into the body
(intravenously) and accumulated in the skeletal system. The treatment area was then irradiated with neutrons in order to activate the boron and give a therapeutic radiation dose (U.S. Patent 4,399,817).
The use of Re-186 complexed with a diphosphonate has also been proposed.
[L Mathϊeu et al.. Int. J. Applied Rad. & Isotopes, 30, 725-727 (1979); J. Weinenger, A. R.
Ketring et al., J. Nucl. Med., 24(5), P125 (1983)]. However, the preparation and purification needed forthis complex limits its utility and wide application.
Stron tϊum-89 has also been proposed for patients with metastatic bone lesions. However, the long half-life (50.4days), high blood levels and low lesion to normal bone ratios limit the utility. [N. Firusian, P. Mellin, C. G. Schmidt, J Urology, 116, 764 (1976); C G Schmidt, N Firusian, Int. J. Clin. Pharmacol., 93, 199-205, (1974)].
A palliative treatment of bone metastases has been reported wh;ch employed 1-131 labelled α-amino-(3-iodo-4-hydroxybenzylidene)diphosphonate [M. Eisenhut, J Nucl
Med., 25(12), 1356-1361 (1984)]. The use of radioiodine as a therapeutic radionudide is less than desirable due to the well known tendency of iodine to localize i n the thyroid. Eisenhut lists iodide as one of the possible metabolites of this compound.
The use of radionuclides for calific tumor therapy or relief of bone pain is discussed in published European patent application 176,288, where the use of Sm-153, Gd- 159, Ho-166, Lu-177 or Yb-175 complexed with a ligand such as ethylenediaminetetraacetic acid (EDTA) or hydroxyethylenediaminetriacetic acid (HEEDTA) is disclosed. A macrocyclic system having a 1,4,7,10-tetraazacyclododecane moiety complexed with Sm-153, Gd-159, Ho-166, Lu-177 or Yb-175 for calific tumor therapy or relief of bone pain is discussed in U.S. Patent 5,059,412 which complex is very stable and has a lower charge than the complex disclosed in published European patent application 176,288.
Functionalized chelants, or bifunctional coordinators, are known to be capable of being covalently attached to an antibody having specif icity for cancer or tumor cell epitopes or antigens. Radionudide complexes of such antibody/chelant conjugates are useful in diagnostic and/ortherapeutic applications as a means of conveying the radionuclidetoa cancer or tumor cell. See, for example, Meares et al., Anal. Biochem. 142, 68-78, (1984), and Krejcarek et al., Biochem. and Biophys. Res. Comm. 77, 581-585 (1977).
Aminocarboxylic acid chelating agents have been known and studied for many years. Typical of the aminocarboxylic acids are nitrilotriacetic acid (NTA), ethyl- enediaminetetraacetic acid (EDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), di- ethylenetriaminepentaacetic acid (DTPA), trans-1 ,2-diamino cyclohexanetetraacetic acid (CDTA) and 1, 4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) Numerous bifunctional chelating agents based on aminocarboxylic acids have been proposed and prepared. For example the cyclic dianhydride of DTPA [Hnatowich etal. Science 220, 613-615, (1983); U.S. Patent 4,479,930] and mixed carboxycarbonic anhydrides of DTPA [Gansow, U.S. Patents 4,454,106 and 4,472,509; Krejcarek et al., Biochem. and Biophys.Res. Comm. 77, 581-585, (1977)] have been reported. When the anhydrides are coupled to proteins the coupling proceeds via formation of an amide bond thus leaving four of the original five carboxymethyl groups on the diethylenetriamine (DETA) backbone [Hnatowich et al. Int. J. Appl. Isot 33, 327- 332, (1982)]. In addition, U.S. Patents 4,432,907 and 4,352,751 disclose bifunctional chelating agents useful for binding metal ions to "organic species such as organic target molecules or antibodies." As in the above, coupling is achieved via an amide group through the utilization of diaminotetraacetic acid dianhydrides. Examples of anhydrides include dianhydrides of EDTA, CDTA, propylenediaminetetraacetic acid and phenylene 1 ,2-diaminetetraacetic acid. A recent U S. Patent 4,647,447 discloses several complex salts formed from the anion of a complexing acid for use in various diagnostic techniques. Conjugation via a carboxyl group of the complexing acid is taught which gives a linkage through an amide bond.
Inthe J. Radioanal. Chem. 57(12), 553-564 (1980), Paiketal. disclose the use of p-nitrobenzylbromide in a reaction with a "blocked" diethylenetriamine, i.e. bis-(2- phthalimidoethyl)amϊne followed by deblocking procedures and carboxymethylation using chloroaceticacid, to give N'-p-nitrobenzyldiethylenetriamine N,N,N",N"-tetraaceticacid. Again, since the attachment is through a nitrogen, a tetraacetic acid derivative is obtained. Conjugation of the bifunctional chelating agent and chelation with indium is discussed. Substitution on the nitrogen atom is also taught by Eckelman, et al. in the J. Pharm. Sci. 64(4), 704-706 (1975) by reacting amines such as "ethylenediamine or diethylenetriamine with the appropriate alkyl bromide before carboxymethylation." The compounds are proposed as . potential radiopharmaceutical imaging agents.
Another class of bifunctional chelating agents based on aminocarboxylic acid functionality is also well documented in the literature. Thus, Sundberg, Meares, et al. in the J. Med. Chem. 17(12), 1304 (1974), disclosed bifunctional analogs of EDTA. Representative of these compounds are 1-(p-aminophenyl)-ethylenediaminetetraaceticacid and 1-(p- benzenediazonium)ethylenediaminetetraaceticacid. Coupling to proteins through the para- substϊtuent and the binding of radioactive metal ions to the chelating group is discussed. The compounds are also disclosed in Biochem. andBiophys. Res. Comm.75(1), 149 (1977), and in U.S. Patents 3,994,966 and 4,043,998. It is important to note thatthe attachment of the aromatic group to the EDTAstructure is through a carbon of the ethylenediamine backbone. Optically active bifunctional chelating agents based on EDTA, HEDTA and DTPA are disclosed in U.S.4,622,420. In these compounds an alkylene group links the aromatic group (which contains the functionality needed for attachment to the protein) to the carbon of the polyamine which contains the chelating functionality. Other references to such compounds include Brechbiel etal., Inorg. Chem. 25, 2772-2781 (1986), U.S. Patent 4,647,447 and international Patent Publication No. WO 86/06384.
More recently, certain macrocyclic bifunctional chelating agents and the use of their copper chelate conjugates for diagnostic or therapeutic applications have been disclosed in U S Patent 4,678,667 and by Moi et al., Inorg. Chem.26,3458-3463 (1987). Attachment of the aminocarboxylic acid functionality to the rest of the bifunctional chelating molecule is through a ring carbon of the cyclic polyamine backbone. Thus, a linker, attached atone end to a ring carbon of the cyclic polyamine, is also attached at its other end to a functional group capable of reacting with the protein.
Another class of bifunctional chelating agents, also worthy of note, consists of compounds wherein the chelating moiety, i.e. the aminocarboxylic acid, of the molecule is attached through a nitrogen to the functional group of the molecule containing the moiety capable of reacting with the protein. As an example, Mikola et al. in patent application (WO 84/03698, published 9/27/1984) disclose a bifunctional chelating agent prepared by reacting p- nitrobenzyl bromide with DETA followed by reaction with bromoacetic acid to make the
aminocarboxylic acid. The nitro groupis reduced to the corresponding amine group and is then converted to the isothiocyanate group by reaction with thiophosgene. These compounds are bifunctional chelating agents capable of chelating lanthanides which can be conjugated to bio-organic molecules for use as diagnostic agents. Since attachment of the linker portion of the molecule is through one of the nitrogens of the aminocarboxylic acid, then one potential aminocarboxyl group is lost for chelation. Thus, a DETA-based bifunctional chelant containing four (not five) acid groups is prepared. In this respect, this class of bifunctional chelant is similar to those where attachment to the protein is through an amide group with subsequent loss of a carboxyl chelating group.
Recently Carney, Rogers, and Johnson disclosed (3rd. Int'l. Conf. on Monoclonal
Antibodies For Cancer: San Diego, California - 2/4-6/88) abstracts entitled "Absence of
Intrinsically Higher Tissue Uptake from lndium-11 1 Labeled Antibodies: Co-administration of lndium-111 and lodine-125 Labeled B72.3 in a Nude Mouse Model" and "Influence of Chelator Denticity on the Biodistribution of lndium-1 1 1 Labeled B72.3 Immunoconjugates in Nude Mice". The biodistribution of indium-111 complexed with an EDTA and DTPA bifunctional chelating agent is disclosed. Attachment of the aromatic ring to the EDTA/DTPA moieties is through an acetate methylene. Also at a recent meeting D.K. Johnson et al. [Florida Conf. on Chem. in Biotechnology, April 26-29 (1988), Palm Coast, FL] disclosed bifunctional derivatives of EDTA and DTPA where a p-isothiocyanatobenzyl moiety is attached at the methylene carbon of one of the carboxymethyl groups. Previously Hunt et al. in U.S. Patents 4,088,747 and 4,091 ,088 (1978) disclosed ethylenediaminediacetic acid (EDDA) based chelating agents wherein attachment of an aromatic ring to the EDDA moiety isthrough the alkylene or acetate methylene. The compounds are taught to be useful as chelates for studying hepatobiliary function. The preferred metal is technetium-99m. lndium-111 and indium-1 13m are also taught as useful radionuclides for imaging.
Such uses of other complexes are known using radio frequency to induce hyperthermia (Japanese Kokai Tokkyo Koho JP 61 , 158,931) and fluorescent-lmmunoguided therapy (FIGS) [K. Pettersson et al., Clinical Chem. 29(1), 60-64 (1983) and C. Meares et al., Acc. Chem. Res. 17 , 202-209 (1984)].
Consequently, it would be advantageous to provide a complex that does not readily dissociate, that exhibits rapid whole body clearance except from the desired tissue, and conjugates with an antibody to produce the desired results.
Advantageously, the present invention provides a new type of a stable metal complex, especially with metals that are rare earths or pseudo-rare earths in their chemistry. This invention teaches the use of these complexes and that the variance of their charge and lipophilic character may favorably alter their biodistribution when introduced into an animal. The conjugates of these complexes with a biologically active material, such as an antibody, are
also a part of this invention. These complexes and conjugates may be formulated with suitable pharmaceutical carriers and administered to a mammal for disgnosis and/or therapy.
. The present invention is directed to novel complexes comprising a ligand that is a bicydopolyazamacrocyclocarboxylicacid of the formula
where: X and Y are independently H, OH, C1-C3 alkyl or COOH;
R7 is H or OH; and
R4 is H, NO2, NH2, isothiocyanato, semicarbazido,thiosemicarbazido, maleimido,
bromoacetamido or carboxyl;
with the proviso that at least two R terms must be
A = CH, N, C-Br, C-CI, C-OR1, C-OR2, N+-R3 X-, or
R1 = H, C1-C5 alkyl, benzyl, or benzyl substituted with at least one R4;
R2 is C1-C16 alkylamino;
R3 is C1- C16 alkyl, benzyl, or benzyl substituted with at least one R4;
R4 is defined as before;
X is Cl -, Br-, l- or H3CCO2-;
Q and Z independently are CH, N, N+-R3 X-, C-CH2-OR1 or C-C(O)-R5;
R3 is defined as above;
R5 is -O-(C1-C3 alkyl), OH or NHR6;
R6 is C1- C5 alkyl or a biologically active material;
X'is defined as above; and
with the proviso that:
a) when Q, A or Z is N or N +-R3X-, then the other two groups must be CH;
b) when A is C-Br, C-CI, C-OR1 or C-OR2, then both Q and Z must be CH;
c) thesum of the R2, R4and R6terms, when present, may not exceed one; and d) only one of Q or Z can be C-C(O)-R5 and when one of Q or Z is C-C(O)-R5, then A must be CH; and
complexed with a metal ion of 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 186Re, 188Re,
142Pr, 99mTc, 67Ga, 68Ga, 105Rh, 97Ru, 111ln, 113mln or 115mln; or
pharmaceutically-acceptabie salts thereof.
Bifunctional complexes of Formula (I) are desirable to prepare the conjugates of this invention. Such ligands must have:
one Rterm is
where R4 and R7 are defined as above; or A is C-OR1, C-OR2, where R1 and R2 are defined as above or
where R4 is defined as above; or
A is CH, and one of Q or Z is CH and the other is C-C(O)-R5 or C-CH2- OR1, where R1 and R5 are defined as above;
especially those ligands where R5 is NHR6, where R6 is a biologically active material.
The complexes of Formula (I) use various metal ions, usually in the +3 state, selected from: samarium (153Sm), lutetium (177Lu), holmium (166Ho), yttrium (90Y), scandium (47Sc), rhenium (186Re) or (188Re), praseodymium (142Pr),technetium (99mTc), gallium (67 Ga) or (68 Ga), or indium (111ln) or (115mIn); with 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 142Pr, 99mTc, 67 Ga, 68Ga, 11 1ln, 113mln or 115mln being preferred; with 153Sm, 177Lu, 166Ho, 90Y, 99mTc, 67 Ga, 68 Ga, 111In, 113mln or 115mln being especially preferred; and with 153Sm, 177Lu or 166Ho being most preferred. Complexes having gamma emissions, such as 99mTc, 68Ga, 67 Ga, 111ln, 113mln, or 97Ru, are useful as diagnostic agents. Complexes having particle emissions, such as 149Pm, 142Pr,90Y, or 175Yb, are useful as therapeutic agents. Complexes having both gamma and particle emissions, such as 153Sm, 177Lu, 159Gd, 140La, 166Ho, 47Sc, 186Re, 188Re, 105Rh, or 115mln, are useful as both diagnostic and therapeutic agents. The complexes so formed can be used by themselves or can be attached, by being covalently bonded, to an antibody or fragment thereof and used for diagnostic or therapeutic purposes. Such conjugates and complexes are useful as diagnostic and/ortherapeutic agents.
The complexes and conjugates of this invention can be modified to provide a specific overall charge. For example, when the metal ion is + 3 the following can be obtained:
(A) an overall neutral charge - when
Ris
and X and Y are all equal to H;
(B) an overall + 1 charge -when
one of A, Q or Z is N + -R3 X-, where R3 and X- are defined as above; and the three R terms are
Both the complexes and conjugates may be formulated to be in a pharmaceutically acceptable form for administration to an animal.
Use of the complexes or conjugates of this invention for diagnosis or therapy of disease states such as cancer is possible.
Use ofthe ligands of this invention with other metal ions for diagnosis of disease states such as cancer is possible. The use of those complexes and conjugates is discussed in another copending application.
The complex has the ligand of Formula (I) numbered for nomenclature purposes as follows:
The present invention concerns development of radiopharmaceutical agents having synthetic modifications to the chelate enabling site specific delivery of the
radiopharmaceutical agent to a desired tissue. The advantage being increased delivery of the radiopharmaceutical agent in the areas of interest based upon tissue affinity. The specificity of the complex of Formula (I) may be controlled by adjusting the total charge and lipophilic character ofthe complex. The overall range of the charge of the complex is from -3 to + 1. For example, for a complex having 2 or more PO3H2 groups, the overall charge is highly negative and bone uptake is expected; whereas when the overall charge of the complex is 0 (thus neutral), the com pi ex may have the ability to cross the blood brain barrier and normal brain uptake may be possible.
Tissue specificity may also be realized by ionic or covalent attachment of the chelate to a naturally occuring or synthetic molecule having specificity for a desired target tissue. One possible application of this approach is through the use of chelate conjugated monoclonal antibodies which would transport the radioactive chelate to diseased tissue enabling diagnosis and therapy.
Additionally, the present radiopharmaceutical agents of Formula (I) which are neutral in charge are particularly preferred for forming the conjugates of this invention since undersirable-ionic interactions between the chelate and protein are minimized which preserves the antibody immunoreactivity.
While notwϊshing to be bound by theory, it is believed thatwhen a charged complex of the invention is made (e.g. + 1 for heart), the variations in that chelate ionic charge can influence biolocalization. Thus, if the antibody or other directing moiety is also specific for the same site, then the conjugate displays two portions to aid in site specific delivery.
The terms used in Formula (I) and forthis invention are further defined as follows. "C1-C3 alkyl", "C1-C5 alkyl", "C1-C18 alkyl", include both straight and branched chain alkyl groups. An "animal" includes a warmblooded mammal, preferably a human being.
"Biologically active material" refers to, for example, a dextran, peptide, or molecules that have specific affinity for a receptor, or preferably antibodies or antibody fragments.
"Antibody" refers to any polyclonal, monoclonal, chimeric antibody or heteroantibody, preferably a monoclonal antibody; "antibody fragment" includes Fab fragments and F(ab')2 fragments, and any portion of an antibody having specificity toward a desired epitope orepϊtopes. When using the term "radioactive metal chelate/antibody conjugate" or "conjugate", the "antibody" is meant to include whole antibodies and/or antibody fragments, including semisynthetic or genetically engineered variants thereof.
Possible antibodies are 1116-NS-19-9 (anti-colorectal carcinoma), 1116-NS-3d (anti-CEA), 703D4 (anti-human lung cancer), 704A1 (anti-human lung cancer), CC49 (anti-TAG-72), CC83 (anti- TAG-72) and B72.3. The hybrϊdoma cell lines 1116-NS-19-9, 1116-NS-3d, 703D4, 704A1, CC49, CC83 and B72.3 are deposited with the American Type Culture Collection, having the accession numbers ATCC HB 8059, ATCC CRL 8019, ATCC HB 8301 , ATCC HB 8302, ATCC HB 9459, ATCC HB 9453 and ATCC HB 8108, respectively.
As used herein, "complex" refers to a complex ofthe compound ofthe invention, e.g. Formula (I), complexed with a metal ion, where at least one metal atom is chelated or sequestered; "conjugate" refers to a metal ion chelate that is covalently attached to an antibodyor antibody fragment. The terms "bifunctional coordinator", "bifunctional chelating agent" and "functionalized chelant" are used interchangeably and refer to com pounds that have a chelant moiety capable of chelating a metal ion and a moiety covalently bonded to the chelant moiety that is capable of serving as a means to covalently attach to an antibody or antibody fragment.
The bifunctional chelating agents described herein (represented by Formula I) can be used to chelate or sequester the metal ions so as to form metal ion chelates (also referred to herein as "complexes"). The complexes, because ofthe presence ofthe functionalizing moiety (represented by R2, R4 or R6 in Formula I), can be covalently attached to biologically active
materials, such as dextran, molecules that have specific affinity for a receptor, or preferably covalently attached to antibodies or antibody fragments. Thus the complexes described herein may be covalently attached to an antibody or antibody fragment or have specific affinity for a receptor and are referred to herein as "conjugates".
As used herein, "pharmaceutically-acceptable salt" means any salt or mixtures of salts of a complex or conjugate of formula (I) which is sufficiently non-toxic to be useful in therapy or diagnosis of animals, preferrably mammals. Thus, the salts are useful in accordance with this invention. Representative of those salts formed by standard reactions from both organic and inorganic sources include, for example, sulfuric, hydrochloric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, glutamic, gluconic, d- camphoric, glutaric, glycolic, phthalic, tartaric, formic, lauric, steric, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic and cinnamic acids and other suitable acids. Also included are salts formed by standard reactions from both organic and inorganic sources such as ammonium, alkali metal ions, alkaline earth metal ions, and other similar ions. Particularly preferred are the salts of the complexes or conjugates of formula (I) where the salt is potassium, sodium or ammonium. Also included are mixtures of the above salts.
The complexes or conjugates of the present invention contain a ligand of Formula (I). The ligands are prepared by various processes. Typical general synthetic approaches to such processes are provided by the reaction schemes given below
In Scheme 1 , the compounds of Formula (I) are prepared wherein Q, A and Z =
CH, and all three R =
X
|
-C-CO2H
|
Y
Scheme 2 prepares the compounds of Formula (I) wherein A = C-Br, and Q and Z = CH.
Scheme 3 prepares the compounds of Formula (I) wherein A =
R4 = H, NO2, NH2 or SCN; and Q and Z = CH.
Scheme 4 prepares the compounds of Formula (I) wherein A = C-OR2, where R2 = C1- C5 alkylamino; and
Q and Z = CH.
Scheme 5 prepares the compounds of Formula (I) wherein A = CH; and one of Q or Z = CH and the other Q or Z = C-C(O)-R6 or C-CH2-R6, where R6 is defined as before.
Scheme 6 prepares the compounds of Formula (I) wherein Z = C-CH2-OBz or C- C(O)-R5where R5 = -O-(C1-C3 alkyl), OH or NHR6, where is defined as before; and
Qand A = CH.
Scheme 7 prepares the compounds of Formula (I) wherein A = N or N +-R5X-; R5 = C1-C16 alkyl and is X- halide; and
Q and Z = CH.
Scheme 8 prepares the compounds of Formula (I) wherein Q = N+-R5X-, where R5 = C1-C16 alkyl and X- = halide; and
Aand Z = CH.
Scheme 9 prepares the compounds of Formula (I) wherein Q = N or N + -R5 X-, where R5 = C1-C16 alkyl and
X- = halide; and
Aand Z = CH.
Scheme 10 preparesthe compounds of Formula (I) wherein Rterm at the 6 position is
where R4 = NO2 or NH2; and
A. Q and Z = CH.
Scheme 11 prepares the compounds of Formula (I) wherein the Rterm at the 9 position is
where R4 = NO2 or NH2; and
A,Q and Z = CH.
In the above Schemes, the general process discription illustrates specific steps that may be used to accomplish a desired reaction step. The general description of these process steps follows.
The synthetic Scheme 1 begins with a halogeπation of commercially available bis- pyridyl alcohol (1) using thionyl chloride. Similar procedures for converting an alcohol to an electrophilic substrate, such as treatment with toluenesulfonyl chloride, HBr or HCI, should also result in a similarily reactive product which would work well in subsequent ring closure reactions. Macrocyclization procedures are numerous in the literature and the desired tetraazamacrocycle (3) was prepared according to the method of Stetter et al., Tetrahedron 37, 767-772 (1981). More general procedures have since been published which give good yields of similar macrocycies using milder conditions [A. D. Sherry etal., J. Org. Chem. 54, 2990-2992 (1989)]. Detosylation ofthe intermediate macrocycle [(3) to yield (4)] was accomplished under acidic conditions in good yield. Reductive detosylation procedures are also well known in the literature and can be adapted to the present reaction sequence.
Schemes 10 and 11 delinate a synthetic approach which introduces an aromatic nitrobenzyl substitutentatone ofthe macrocyclic nitrogen positions. Typically, the macrocyclic amine is mono-N-functioπalized in an organic solvent such as acetoπitrile or DMF at room temperature using a non-nudeophiltc base such as potassium carbonate. Additional functionalizatron ofthe remaining nitrogen positions is then preformed by methods and conditions described in previous Schemes. After the introduction ofthe desired chelating moieties, the πitro group isreduced using platinum oxide and hydrogen in water. In this form, the chelating agent is compatible with conjugation techniques which will enable attachment to larger synthetic or natural molecules.
The metal ions used to form the complexes of this invention are 153Sm, 177Lu, 159Gd, 149Pm, 14 0La, 175Yb, 166Ho, 90Y, 47Sc, 186Re, 188Re, 142Pr, 99mTc, 67 Ga, 68 Ga, 105Rh, 97Ru, 111 ln, 113mln or 115mln. The anion present is halide, preferrably chloride, or salt free (metal oxide).
The complexes are prepared by methods well known in the art. Thus, for example, see Chelating Agents and Metal Chelates, Dwyer & Mellor, Academic Press (1964), Chapter 7. See also methods for making amino acids in Synthetic Production and Utilization of Ami no Acids, (edited byKameko,etaI.) John Wiley & Sons (1974). An example ofthe preparation of a complex involves reacting a bϊcyclopolyazamacrocyclocarboxylicacid with the metal ion under aqueous conditions at a pH from 5 to 7. The complex formed is by a chemical bond and results in a stable radionudide composition, e.g. stable to the disassociation ofthe radionudide from the ligand.
The complexes ofthe present invention are administered at a ligand to metal molar ratio of at least about 1:1, preferably from 1 :1 to 3:1, more preferably from 1 : 1 to 1.5: 1.
A large excess of ligand is undesirable since uncomplexed ligand may be toxic to the animal or may result in cardiac arrest or hypocalcemic convulsions.
The antibodies or antibody fragments which may be used in the conjugates described herein can be prepared by techniques well known in the art. Highly specific monoclonal antibodies can be produced by hybridization techniques well known in the art, see for example, Kohler and Milstein [Nature, 256, 495-497 (1975); and fur. J. Immunol., 6, 51 1-519 (1976)]. Such antibodies normally have a highly specific reactivity. In the antibody targeted conjugates, antibodies directed against any desired antigen or hapten may be used. Preferably the antibodies which are used in the conjugates are monoclonal antibodies, or fragments thereof having high specificity for a desired epitope(s). Antibodies used in the present invention may be directed against, for example, tumors, bacteria, fungi, viruses, parasites, mycoplasma, differentiation and other cell membrane antigens, pathogen surface antigens, toxins, enzymes, allergens, drugs and any biologically active molecules. Some examples of antibodies or antibody fragraments are 1116-NS-19-9, 11 16-NS-3d, 703D4, 704A1 , CC49, CC83 and B72.3. All of these antibodies have been deposited in ATCC. A more complete list of antigens can be found in U.S. Patent 4, 193,983. The conjugates of the present invention are particularly preferred for the diagnosis of various cancers.
This invention is used with a physiologically acceptable carrier, excipient or vehicle therefor. The methods for preparing such formulations are well known. The formulations may be in the form of a suspension, injectable solution or other suitable formulations. Physiologically acceptable suspending media, with or without adjuvants, may be used.
An "effective amount" ofthe formulation is used for diagnosis. The dose will vary depending on the disease and physical parameters ofthe animal, such as weight. In vivo diagnostics are also contemplated using formulations of this invention.
Other embodiments ofthe invention will be apparent to those skilled in the art from a consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.
Claims (1)
- WHAT IS CLAIMED IS:1. Acomplexwhich comprises a bicyclopolyazamacrocyclocarboxylic acid compound of the formulawherein:R iswhere:X and Y are independently H, OH, C1-C3 alkyl or COOH;R7 is H or OH; andR4 is H, NO2, NH2, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or carboxyl;with the proviso that at least two R terms must beA = CH, N, C-Br, C-CI, C-OR1, C-OR2, N +-R3 X-, orwhere: R1 = H, C1-C5 alkyl, benzyl, or benzyl substituted with atleast one R4;R2is C1-C16alkylamino;R3 is C1-C16 alkyl, benzyl, or benzyl substituted with at least one R4;R4 is defined as before;X- is Cl-, Br-, |- or H3CCO2-;Q and Z independently are CH, N, N +-R3 X-, C-CH2-OR1 or C-C(O)-R5;R3 is defined as above;Rs is-O-(C1- C3 alkyl), OH or NHR6;R6is C1-C5 alkyl or a biologically active material;X- is defined as above; andwith the proviso that:a) when Q, A or Z is N or N +-R3 X-, then the other two groups must be CH;b) when A is C-Br, C-Cl, C-OR1 or C-OR2, then both Q and Z must be CH;c) the sum ofthe R2, R4and R6 terms, when present, may not exceed one; and d) only one of Q or Z can be C-C(O)-R5 and when one of Q or Z is C-C(O)-R5, then A must be CH;complexed with a metal ion of 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 186Re, 188Re,142Pr, 99mTc, 67 Ga, 68Ga, 105Rh, 97Ru, 111ln, 113mlnor 115mln; orpharmaceutically-acceptable salts thereof.2. A complex of Claim 1 wherein the metal ion is 153Sm, 177Lu, 159Gd, 149Pm,140La, 175Yb, 166Ho,90Y, 47Sc, 142Pr, 99mTc, 67 Ga, 68Ga, 111 In, 11 3mln or 115mln.3. A complex of Claim 2 wherein the metal ion is 153Sm, 177Lu, 166Ho, 90Y, 99mTc, 67Ga, 68 Ga, 11 1In, 113mIn or 11 5mln.4. A complex of Claim 3 wherein the metal ion is 153Sm, 177Lu or 166Ho.5. A complex of Claim 1 wherein X and Y are H.6. A complex of Claim 1 wherein A, Q and Z are CH.7. A complex of Claim 1 wherein Q, A and Z are CH; and one R term iswhere: X, Y, R2 and R4 are defined as in Claim 1.8. A complex of Claim 1 wherein A is C-OR1, C-OR2, where R1 and R2 are defined as in Claim 1 orwhere R4 is defined as in Claim 1.9. A complex of Claim 1 wherein A is CH, and one of Q or Z is CH and the other is C-C(O)-R5 or C-CH2-OR1, where R1 and R5 are defined as in Claim 1.10. A complex of Claim 9 wherein R5 is NHR6, where R6 is a biologically active material.11. A conjugate comprising a bicyclopolyazamacrocyclocarboxylic acid compound ofthe formulawherein:R iswhere:X and Y are independently H, OH, C1-C3 alkyl or COOH;R7 is H or OH; andR4 is H, NO2, NH2, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido,bromoacetamido or carboxyl;with the proviso that at two R terms areA = CH, N, C-Br, C-CI, C-OR', C-OR2, N +-R3 X-, orR1 = H, C1-C5 alkyl, benzyl, or benzyl substituted with at least one R4;R2 is C1- C16 alkylamino;R3 is C1-C16 alkyl, benzyl, or benzyl substituted with at least one R4;R4 is defined as before;χ-is Cl-, Br-, r- or H3CCO2- ;Q and Z independently are CH, N, N +-R3 X-, C-CH2-OR1 or C-C(O)-R5;R3 is defined as above;Rs is -O-(C1-C3 alkyl), OH or NHR6;R6 is C1-C5 alkyl ora biologically active material;X- is defined as above; andwith the proviso that:a) when Q, A or Z is N or N +-R3X-, then the other two groups must be CH;b) when A is C-Br, C-CI, C-OR1 or C-OR2, then both Q and Z must be CH;c) the sum ofthe R2, R4and R6 terms, when present, may not exceed one; and d) only one of Q or Z can be C-C(O)-Rs and when one of Q or Z is C-C(O)-R5, then A must be CH;complexed with a metal ion of 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 186Re, 188Re,142Pr,99mTc, 67 Ga, 68 Ga, 105Rh, 97Ru, 111ln, 11 3mln or 11 5mln; andcovalently attached to a biologically active material; orpharmaceuticaily-acceptable salts thereof.12. A conjugate of Claim 11 wherein the metal ion is 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 142Pr,99mTc, 67 Ga, 68Ga, 11 1In, 113mln or 11 5mln.13. A conjugate of Claim 11 wherein the biologically active material is a dextran, a polypeptide, a molecule that has specific affinity for a receptor, or an antibody or antibodyfragment.14. Aconjugate of Claim 13 wherein the antibody or antibody fragment is a monoclonal antibody or fragment thereof.15. A conjugate of Claim 14 wherein the antibody or antibody fragment is B72.3.16. A conjugate of any one of Claims 12-15 wherein the metal ion is 153Sm, 177Lu, 166Ho, 90Y, 99mTc, 67Ga, 68Ga, 111 In, 113mln or 11 5mln.17. A conjugate of Claim 16 wherein the metal ion is 153Sm, 177Lu or 166Ho.18. A conjugate of Claim 11 wherein X and Y are H.19. A conjugate of Claim 11 wherein A, Q and Z are CH.20. A conjugate of Claim 1 1 wherein Q, A and Z are CH; and one R term iswhere: X and R4 are defined as in Claim 11.21. A conjugate of Claim 1 1 wherein Q, A and Z are CH; and one Rterm iswhere: R4and R7 are defined as in Claim 11.22. A conjugate of Claim 11 wherein A is C-OR1, C-OR2, where R1 and R2 are defined as in Claim 1 1 , orwhere R4 is defined as in Claim 11.23. A conjugate of Claim 11 wherein A is CH, and one of Q or Z is CH and the other is C-C(O)-R6, where R6 is defined as in Claim 11.24. A conjugate of Claim 23 wherein R6 is NHR7, where R7 is a biologically active material25. A pharmaceutical formulation comprising a complex as claimed in any one of Claims 1-10 with a pharmaceuti cally-acceptable carrier.26. A pharmaceutical formulation comprising a conjugate as claimed in any one of Claims 1 1-24 with a pharmaceutically-acceptable carrier.27. A method forthe diagnosis of a disease state in an animal which comprises administering to said animal an effective amount of the formulation of Claim 25.28. A method forthe diagnosis of a disease state in an animal which comprises administering to said animal an effective amount ofthe formulation of Claim 26.29. The complex as claimed in any one of Claims 1-10for use asa pharmaceutϊcal.30. The conjugate as claimed in any one of Claims 11-24 for use as a pharmaceutical.31. A kit for use as a therapeutic agent which has as one component a ligand of Formula (I) as claimed in Claim 1, and as a second component a metal ion as claimed inClaim 1.32. A process for preparing the complex as claimed in any one of Claims 1-10, which comprises reacting a bicydopolyazamacrocydocarboxylic acid compound as claimed in Claim 1 with a metal ion of 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 186Re, 188Re, 142Pr, 99mTc, 67Ga, 68 Ga, 105Rh, 97Ru, 111 In, 113mln or 11 5mln under aqueous conditions at a pH from 5 to 7.
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US80539291A | 1991-12-10 | 1991-12-10 | |
US805392 | 1991-12-10 |
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KR (1) | KR930703331A (en) |
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US5385893A (en) * | 1993-05-06 | 1995-01-31 | The Dow Chemical Company | Tricyclopolyazamacrocyclophosphonic acids, complexes and derivatives thereof, for use as contrast agents |
CN102057054B (en) | 2008-04-11 | 2015-06-10 | 梅里麦克制药股份有限公司 | Human serum albumin linkers and conjugates thereof |
RU2505499C1 (en) * | 2012-10-08 | 2014-01-27 | Юлия Алексеевна Щепочкина | Raw material mixture for natural stone imitation |
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DE3825040A1 (en) * | 1988-07-20 | 1990-01-25 | Schering Ag | 5- OR 6-RING MACROCYCLIC POLYAZA COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM |
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US4940796A (en) * | 1989-03-17 | 1990-07-10 | The University Of Southern Mississippi | 2,6-substituted-4-aminopyridines and their corresponding intermediates |
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