JP2021528461A - 黒色腫の治療用放射性化合物およびこの用途 - Google Patents
黒色腫の治療用放射性化合物およびこの用途 Download PDFInfo
- Publication number
- JP2021528461A JP2021528461A JP2020572824A JP2020572824A JP2021528461A JP 2021528461 A JP2021528461 A JP 2021528461A JP 2020572824 A JP2020572824 A JP 2020572824A JP 2020572824 A JP2020572824 A JP 2020572824A JP 2021528461 A JP2021528461 A JP 2021528461A
- Authority
- JP
- Japan
- Prior art keywords
- chemical formula
- dota
- group
- ncs
- dmpy2
- 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.)
- Granted
Links
- 201000001441 melanoma Diseases 0.000 title claims abstract description 40
- 230000002285 radioactive effect Effects 0.000 title claims abstract description 40
- 150000001875 compounds Chemical class 0.000 title claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims description 89
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 24
- -1 alkylene glycol Chemical compound 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 claims description 9
- 125000005647 linker group Chemical group 0.000 claims description 8
- HHLZCENAOIROSL-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound OC(=O)CN1CCNCCN(CC(O)=O)CCN(CC(O)=O)CC1 HHLZCENAOIROSL-UHFFFAOYSA-N 0.000 claims description 6
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- XSVWFLQICKPQAA-UHFFFAOYSA-N 2-[4,10-bis(carboxymethyl)-7-[2-(2,5-dioxopyrrolidin-1-yl)oxy-2-oxoethyl]-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound C1CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CCN1CC(=O)ON1C(=O)CCC1=O XSVWFLQICKPQAA-UHFFFAOYSA-N 0.000 claims description 5
- JHALWMSZGCVVEM-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CC1 JHALWMSZGCVVEM-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical group CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000000524 functional group Chemical group 0.000 claims description 4
- ITWBWJFEJCHKSN-UHFFFAOYSA-N 1,4,7-triazonane Chemical compound C1CNCCNCCN1 ITWBWJFEJCHKSN-UHFFFAOYSA-N 0.000 claims description 3
- NXZALZWMPSMALQ-UHFFFAOYSA-N 2-[4,8-bis(carboxymethyl)-1,4,8,11-tetrazacyclotetradec-1-yl]acetic acid Chemical compound OC(=O)CN1CCCN(CC(O)=O)CCN(CC(O)=O)CCCNCC1 NXZALZWMPSMALQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000007983 Tris buffer Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004474 heteroalkylene group Chemical group 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 3
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical group CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 claims description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 3
- MRLKMCJVGAIGGE-UHFFFAOYSA-N 1,4,8,11-tetrazacyclotetradec-10-ene Chemical compound C1CNCCNCCCN=CCNC1 MRLKMCJVGAIGGE-UHFFFAOYSA-N 0.000 claims description 2
- LEPXTOQMJCRGCZ-UHFFFAOYSA-N 3-iodo-2-methoxybenzamide Chemical compound COC1=C(I)C=CC=C1C(N)=O LEPXTOQMJCRGCZ-UHFFFAOYSA-N 0.000 claims description 2
- XSRVEVDKKQCPBF-UHFFFAOYSA-N 3-iodopyridine-2-carboxamide Chemical compound IC=1C(=NC=CC=1)C(=O)N XSRVEVDKKQCPBF-UHFFFAOYSA-N 0.000 claims description 2
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 229960003966 nicotinamide Drugs 0.000 claims description 2
- 235000005152 nicotinamide Nutrition 0.000 claims description 2
- 239000011570 nicotinamide Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- NBIIXXVUZAFLBC-HOSYLAQJSA-K trioxido(oxo)-$l^{5}-phosphane Chemical compound [O-][32P]([O-])([O-])=O NBIIXXVUZAFLBC-HOSYLAQJSA-K 0.000 claims description 2
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 claims 2
- MDAXKAUIABOHTD-UHFFFAOYSA-N 1,4,8,11-tetraazacyclotetradecane Chemical compound C1CNCCNCCCNCCNC1 MDAXKAUIABOHTD-UHFFFAOYSA-N 0.000 claims 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 8
- 230000008685 targeting Effects 0.000 abstract description 8
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- 238000003384 imaging method Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 19
- 238000004519 manufacturing process Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 10
- 150000001345 alkine derivatives Chemical class 0.000 description 9
- 239000007974 sodium acetate buffer Substances 0.000 description 8
- 230000005855 radiation Effects 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 5
- 238000010171 animal model Methods 0.000 description 4
- 150000001540 azides Chemical class 0.000 description 4
- 239000002872 contrast media Substances 0.000 description 4
- 238000006352 cycloaddition reaction Methods 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 3
- 0 CC(*)=IC=CC(C(N*)=O)=** Chemical compound CC(*)=IC=CC(C(N*)=O)=** 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000012217 radiopharmaceutical Substances 0.000 description 3
- 229940121896 radiopharmaceutical Drugs 0.000 description 3
- 230000002799 radiopharmaceutical effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 150000003536 tetrazoles Chemical class 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- UDOPJKHABYSVIX-UHFFFAOYSA-N 2-[4,7,10-tris(carboxymethyl)-6-[(4-isothiocyanatophenyl)methyl]-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound C1N(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CCN(CC(O)=O)C1CC1=CC=C(N=C=S)C=C1 UDOPJKHABYSVIX-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- AOXIUIPADQFJLG-UHFFFAOYSA-N 4-amino-n-[2-(dimethylamino)ethyl]benzamide Chemical compound CN(C)CCNC(=O)C1=CC=C(N)C=C1 AOXIUIPADQFJLG-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- BDDLHHRCDSJVKV-UHFFFAOYSA-N 7028-40-2 Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O BDDLHHRCDSJVKV-UHFFFAOYSA-N 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 description 2
- 238000010958 [3+2] cycloaddition reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010461 azide-alkyne cycloaddition reaction Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- WDJARUKOMOGTHA-UHFFFAOYSA-N 5-aminopyridine-2-carboxylic acid Chemical compound NC1=CC=C(C(O)=O)N=C1 WDJARUKOMOGTHA-UHFFFAOYSA-N 0.000 description 1
- SKMOPPSRAHOLNC-UHFFFAOYSA-N 6-amino-n-[3-(dimethylamino)propyl]pyridine-3-carboxamide Chemical compound CN(C)CCCNC(=O)C1=CC=C(N)N=C1 SKMOPPSRAHOLNC-UHFFFAOYSA-N 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical group NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- MXHGHNIRTAFTLA-UHFFFAOYSA-N N-[(4-aminophenyl)methyl]-N',N'-dimethylpropane-1,3-diamine Chemical compound CN(C)CCCNCC1=CC=C(N)C=C1 MXHGHNIRTAFTLA-UHFFFAOYSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 230000005773 cancer-related death Effects 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- CTRVMZJBEVWFHM-UHFFFAOYSA-N cyclotetradecene Chemical compound C1CCCCCCC=CCCCCC1 CTRVMZJBEVWFHM-UHFFFAOYSA-N 0.000 description 1
- 230000002498 deadly effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229960003330 pentetic acid Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical group O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- LYRCQNDYYRPFMF-UHFFFAOYSA-N trimethyltin Chemical group C[Sn](C)C LYRCQNDYYRPFMF-UHFFFAOYSA-N 0.000 description 1
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
-
- 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
-
- C—CHEMISTRY; METALLURGY
- 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
-
- 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
- A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
- A61K51/0406—Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines
-
- 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
- A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- 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
-
- C—CHEMISTRY; METALLURGY
- 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
- C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Optics & Photonics (AREA)
- Physics & Mathematics (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
(前記化学式において、X1およびX2はそれぞれ独立して、炭素または窒素として、少なくとも二つのうち一つは窒素であり、L1はなかったり結合または炭素数1ないし20の置換または非置換アルキレン、炭素数6ないし14の置換または非置換アリルレン、炭素数1ないし20の置換または非置換ヘテロアルキレン、炭素数2ないし60の(ポリ)アルキレングリコール、
(前記化学式において、X1およびX2はそれぞれ独立して、炭素または窒素であって、少なくとも二つのうち一つは窒素であり、L1はなかったり結合または炭素数1ないし20の置換または非置換アルキレン、炭素数6ないし14の置換または非置換アリルレン、炭素数1ないし20の置換または非置換ヘテロアルキレン、炭素数2ないし60の(ポリ)アルキレングリコール、
前記化学式1の化合物は、下記のような反応式によって製造することができている:
(5−((2−(ジメチルアミノ)エチル)カルバモイル)ピリジン−2−イル)ヨウ化カルバミン酸[131I](carbamic[131I]iodide)
N−(2−(ジメチルアミノ)エチル)−6−([125I]ヨードメチル)ニコチンアミド
N−(2−(ジメチルアミノ)エチル)−5−([125I]ヨードメチル(iodomethyl))ピコリンアミド
N−(3−(ジメチルアミノ)プロピル)−5−[131I]ヨードピリジン(iodopyridine)−2−カルボキサミド
(S)−5−(2−アミノ−3−(4−ヒドロキシ−3−[131I]ヨードフェニル(iodophenyl))プロパンアミド)−N−(2−(ジメチルアミノ)エチル)ピコリンアミド
(S)−5−(4−(4−(2−(2−アミノ−3−(4−ヒドロキシ−3−[125I]ヨードフェニル)プロパンアミド)エチル)−1H−1,2,3−トリアゾール−1−イル)ブータンアミド)−N−(2−(ジメチルアミノ)エチル)ピコリンアミド
(S)−6−(6−(3−(3−(2−アミノ−3−(4−ヒドロキシ−3−[125I]ヨードフェニル)プロパンアミド)プロピル)−3H−ジベンゾ[b,f][1,2,3]トリアゾロ[4,5−d]アゾシン−8(9H)−イル)−6−オキソヘキサンアミド)−N−(2−(ジメチルアミノ)エチル)ニコチンアミド
(6−((2−(ジメチルアミノ)エチル)カルバモイル)ピリジン−3−イル)メチルジハイドロジェン[32P]ホスフェート)
4−アセトアミド−N−(2−(ジメチルアミノ)エチル)−5−[131I]ヨード−2−メトキシベンズアミド
177Lu−DOTA−DMP
177Lu−DOTA−DMPY2
177Lu−DOTA−NCS−DMP
177Lu−DOTA−NCS−DMPY2
177Lu−DOTA−NCS−トリアゾール−PEG−DMP
177Lu−DOTA−NCS−トリアゾール−PEG−DMPY2
177Lu−DOTA−NCS−ADIBO−DMP
177Lu−DOTA−NCS−ADIBO−DMPY2
177Lu−DOTA−トリアゾール−DMP
177Lu−DOTA−トリアゾール−DMPY2
177Lu−DOTA−トリアゾール−PEG−DMP
177Lu−DOTA−トリアゾール−PEG−DMPY2
177Lu−DOTA−ADIBO−DMP
177Lu−DOTA−ADIBO−DMPY2
1−1:DOTA−DMPの製造
4−アミノ安息香酸5gとN,N,N’,N’−テトラメチル−O−(N−スクシンイミジル)ウロニウムテトラフルオロボレート(TSTU)0.987gをN,N−ジメチルホルムアミド(DMF)に溶解しN,N−ジイソプロピルエチルアミン(DIPEA)1.72mLを添加した後、還流装置を用いて、60℃で3時間撹拌した。3時間攪拌した後N,N−ジメチルエチレンジアミン(DMEDA)0.612mLを添加した後、室温で2時間攪拌した。60mLのCH2Cl2と130mLのH2Oを利用して、生成物をCH2Cl2で抽出しMgSO4でCH2Cl2層の水分を除去し、フィルタリングした。フィルタしたろ液を蒸発乾燥した後、カラムクロマトグラフィーを用いて生成物である4−アミノ−N−(2−(ジメチルアミノ)エチル)ベンズアミドを分離精製した。
1H−NMR(300MHz,D2O):2.92(s,6H),3.13(br,16 H),3.33(t,2H),3.74(t,2H),3.87(br,8H),6.69(d,2H),7.66(d,2H).
5−アミノピリジン−2−カルボン酸0.6gとTSTU 1.308gをDMFに溶解させてDIPEA2.41mLを添加した後、還流装置を用いて、60℃で3時間撹拌した。3時間攪拌した後DMEDA0.808mLを添加した後、室温で2時間攪拌した。80mLのCH2Cl2および130mLのH2Oを利用して、生成物をCH2Cl2で抽出しMgSO4でCH2Cl2層の水分を除去し、フィルタリングした。フィルタしたろ液を蒸発乾燥した後、カラムクロマトグラフィーを用いて、5−アミノ−N−(2−(ジメチルアミノ)エチル)ピコリンアミド(NH2−DMPY2)を分離精製した。
1H−NMR(300MHz,D2O):2.99(s,6H),3.16(br,16H),3.41(t,2H),3.77(t,2H),3.85(br,8H),7.93(d,1H),8.35(m,1H),8.88(d,1H).
前記実施例1−1で製造されたNH2−DMFB 0.08gと2−(4−イソチオシアナトベンジル)−1,4,7,10−テトラアザシクロドデカン−1,4,7,10−四酢酸(p−SCN−Bn−DOTA)0.208gをCHCl3に溶解させ、トリエチルアミンを用いてpH9〜10に調整した後、24時間室温で攪拌した。減圧蒸留して溶媒を除去した後、準−精製カラムを用いて、前記化学式28の構造を有する2,2’,2’’,2’’’−(2−(4−(3−(4−((2−(ジメチルアミノ)エチル)カルバモイル)フェニル)チオウレイド)ベンジル)−1,4,7,10−テトラアザシクロドデカン−1,4,7,10−テトライル)四酢酸を分離し、これをDOTA−NCS−DMPと命名した。前記DOTA−NCS−DMPの1H−NMRデータは、下記の通りである。
1H−NMR(300MHz,D2O):2.92(s,6H),3.13(br,16H),3.33(t,2H),3.74(t,2H),3.87(br,8H),6.43(d,2H),6.69(d,2H),6.86(d,2H),7.66(d,2H).
前記実施例1−2で製造されたNH2−DMPY2 0.07gとp−SCN−Bn−DOTA0.181gをCHCl3に溶解させ、トリエチルアミンを用いてpH9〜10に調整した後、24時間室温で攪拌した。減圧蒸留して溶媒を除去した後、準−精製カラムを用いて、前記化学式29の構造を有する2,2’,2’’,2’’’−(2−(4−(3−(6−((2−(ジメチルアミノ)エチル)カルバモイル)ピリジン−3−イル)チオウレイド)ベンジル)−1,4,7,10−テトラアザシクロドデカン−1,4,7,10−テトライル)四酢酸を分離し、これをDOTA−NCS−DMPY2と命名した。前記DOTA−NCS−DMPY2の1H−NMRデータは、下記の通りである。
1H−NMR(300MHz,D2O):2.99(s,6H),3.16(br,16H),3.41(t,2H),3.77(t,2H),3.85(br,8H),6.42(d,2H),6.87(d,2H),7.93(d,1H),8.35(m,1H),8.88(d,1H).
2−1:Lu−DOTA−DMPの製造
前記実施例1−1で製造されたDOTA−DMP 5mgとLuCl3 5mgを0.2M酢酸ナトリウム緩衝液に溶解させ、95℃で1時間撹拌した。準−精製カラムを用いて、前記化学式30の構造を有するLu−DOTA−DMPを分離した。前記Lu−DOTA−DMPの1H−NMRデータは、下記の通りである。
1H−NMR(300MHz,D2O):2.94(s,6H),3.12(br,16H),3.34(t,2H),3.72(t,2H),3.85(br,8H),6.68(d,2H),7.65(d,2H).
前記実施例1−2で製造されたDOTA−DMPY2 7mgとLuCl3 7mgを0.2M酢酸ナトリウム緩衝液に溶解させ、95℃で1時間撹拌した。準−精製カラムを用いて、前記化学式31の構造を有するLu−DOTA−DMPY2を分離した。前記Lu−DOTA−DMPY2の1H−NMRデータは、下記の通りである。
1H−NMR(300MHz,D2O):2.98(s,6H),3.14(br,16H),3.38(t,2H),3.79(t,2H),3.88(br,8H),7.91(d,1H),8.38(m,1H),8.90(d,1H).
前記実施例1−3で製造されたDOTA−NCS−DMP 5mgとLuCl3 4mgを0.2M酢酸ナトリウム緩衝液に溶解させ、95℃で1時間撹拌した。準−精製カラムを用いて、前記化学式32の構造を有するLu−DOTA−NCS−DMPを分離した。前記Lu−DOTA−NCS−DMPの1H−NMRデータは、下記の通りである。
1H−NMR(300MHz,D2O):2.94(s,6H),3.12(br,16 H),3.34(t,2H),3.72(t,2H),3.85(br,8H),6.45(d,2H),6.68(d,2H),6.85(d,2H),7.65(d,2H).
前記実施例1−4で製造されたDOTA−NCS−DMPY2 7mgとLuCl3 6mgを0.2M酢酸ナトリウム緩衝液に溶解させ、95℃で1時間撹拌した。準−精製カラムを用いて、前記化学式33の構造を有するLu−DOTA−NCS−DMPY2を分離した。前記Lu−DOTA−NCS−DMPY2の1H−NMRデータは、下記の通りである。
1H−NMR(300MHz,D2O):2.98(s,6H),3.14(br,16H),3.38(t,2H),3.79(t,2H),3.88(br,8H),6.43(d,2H),6.89(d,2H),7.91(d,1H),8.38(m,1H),8.90(d,1H).
3−1:177Lu−DOTA−DMPの製造
前記実施例1−1で製造されたDOTA−DMP 30μgと177LuCl3(20mCi)を0.2M酢酸ナトリウム緩衝液に溶解させた後、90℃で1時間反応させて、前記化学式12の構造を有する177Lu−DOTA−DMPを合成した。反応混合物を室温で冷却した後準−精製カラムを用いて分離精製した。
前記実施例1−2で製造されたDOTA−DMPY2 30μgと177LuCl3(30mCi)を0.2M酢酸ナトリウム緩衝液に溶解させた後、90℃で1時間反応させて前記化学式13の構造を有する177Lu−DOTA−DMPY2を合成した。反応混合物を室温で冷却した後、準−精製カラムを用いて分離精製した。
前記実施例1−3で製造されたDOTA−NCS−DMP 30μgと177LuCl3(25mCi)を0.2M酢酸ナトリウム緩衝溶液に溶解させた後、90℃で1時間反応させて、前記化学式14の構造を有する177Lu−DOTA−NCS−DMPを合成した。反応混合物を室温で冷却した後、準−精製カラム)を用いて分離精製した。
前記実施例2−1−2で製造されたDOTA−NCS−DMPY2 30μgと177LuCl3(23mCi)を0.2M酢酸ナトリウム緩衝溶液に溶解させた後、90℃で1時間反応させて前記化学式15の構造を持つ177Lu−DOTA−NCS−DMPY2を合成した。反応混合物を室温で冷却した後、準−精製カラムを用いて分離精製した。
本発明者らは、前記の実施例3−1で製造された黒色腫のマウスモデルに静脈投与し、時間の経過に伴う腫瘍の体積と重量の変化を測定した。
具体的には、雄性BALB/c nu/nuマウス(6週齢)を利用し、全南大学校医科大学和順病院の施設で維持した。本研究のプロトコルは、全南大学校医科大学機関動物管理および使用委員会(IACUC)の承認を受けた。
腫瘍体積(mm3)=(幅)2x(長さ)x0.5
Claims (4)
- 下前記化学式1または2の構造を有する新規放射性化合物またはその許容可能な塩:
(前記化学式において、X1およびX2はそれぞれ独立して、炭素または窒素であって、少なくとも二つのうち一つは窒素であり、L1はなかったり結合または炭素数1ないし20の置換または非置換アルキレン、炭素数6ないし14の置換または非置換アリルレン、炭素数1ないし20の置換または非置換ヘテロアルキレン、炭素数2ないし60の(ポリ)アルキレングリコール、
- 前記結合は、エステル結合、アミド結合、エーテル結合、チオエーテル結合、チオエステル結合、またはジスルフィド結合である請求項1に記載の新規放射性化合物またはその許容可能な塩。
- (5−((2−(ジメチルアミノ)エチル)カルバモイル)ピリジン−2−イル)ヨウ化カルバミン酸[131I](carbamic[131I]iodide)
N−(2−(ジメチルアミノ)エチル)−6−([125I]ヨードメチル)ニコチンアミド
N−(2−(ジメチルアミノ)エチル)−5−([125I]ヨードメチル)ピコリンアミド
N−(3−(ジメチルアミノ)プロピル)−5−[131I]ヨードピリジン−2−カルボキサミド
(S)−5−(2−アミノ−3−(4−ヒドロキシ−3−[131I]ヨードフェニル)プロパンアミド)−N−(2−(ジメチルアミノ)エチル)ピコリンアミド
(S)−5−(4−(4−(2−(2−アミノ−3−(4−ヒドロキシ−3−[125I]ヨードフェニル)プロパンアミド)エチル)−1H−1,2,3−トリアゾール−1−イル)ブタンアミド)−N−(2−(ジメチルアミノ)エチル)ピコリンアミド
(S)−6−(6−(3−(3−(2−アミノ−3−(4−ヒドロキシ−3−[125I]ヨードフェニル)プロパンアミド)プロピル)−3H−ジベンゾ[b,f][1,2,3]トリアゾロ[4,5−d]アゾシン−8(9H)−イル)−6−オキソヘキサンアミド)−N−(2−(ジメチルアミノ)エチル)ニコチンアミド
(6−((2−(ジメチルアミノ)エチル)カルバモイル)ピリジン−3−イル)メチルジハイドロジェン[32P]ホスフェート)
4−アセトアミド−N−(2−(ジメチルアミノ)エチル)−5−[131I]ヨード−2−メトキシベンズアミド
177Lu−DOTA−DMP
177Lu−DOTA−DMPY2
177Lu−DOTA−NCS−DMP
177Lu−DOTA−NCS−DMPY2
177Lu−DOTA−NCS−トリアゾール−PEG−DMP
177Lu−DOTA−NCS−トリアゾール−PEG−DMPY2
177Lu−DOTA−NCS−ADIBO−DMP
177Lu−DOTA−NCS−ADIBO−DMPY2
177Lu−DOTA−トリアゾール−DMP
177Lu−DOTA−トリアゾール−DMPY2
177Lu−DOTA−トリアゾール−PEG−DMP
177Lu−DOTA−トリアゾール−PEG−DMPY2
177Lu−DOTA−ADIBO−DMP
177Lu−DOTA−ADIBO−DMPY2
から構成される群から選択される請求項1に記載の新規放射性化合物またはその許容可能な塩。 - 請求項1ないし請求項3のうちいずれか一項に記載の放射性化合物またはこの許容可能な塩を有効成分として含む黒色腫の治療用薬学的組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2018-0074766 | 2018-06-28 | ||
KR20180074766 | 2018-06-28 | ||
PCT/KR2019/004396 WO2020004785A1 (ko) | 2018-06-28 | 2019-04-11 | 흑색종 치료용 방사성 화합물 및 그의 용도 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2021528461A true JP2021528461A (ja) | 2021-10-21 |
JP7205930B2 JP7205930B2 (ja) | 2023-01-17 |
Family
ID=68987178
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020572824A Active JP7205930B2 (ja) | 2018-06-28 | 2019-04-11 | 黒色腫の治療用放射性化合物およびこの用途 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20210113719A1 (ja) |
EP (1) | EP3816156A4 (ja) |
JP (1) | JP7205930B2 (ja) |
KR (1) | KR102302065B1 (ja) |
CN (1) | CN112601740A (ja) |
WO (1) | WO2020004785A1 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102557303B1 (ko) | 2020-10-06 | 2023-07-18 | 전남대학교 산학협력단 | 인간 피브로넥틴 도메인 ⅲ 기본 골격의 신규 칼레티큘린 특이적 결합 단백질 및 그의 용도 |
CN113277989B (zh) * | 2021-04-27 | 2022-05-31 | 中南大学湘雅医院 | 一种68Ga标记的分子探针、制备方法及其应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19519508A1 (de) * | 1995-05-31 | 1996-12-05 | Eisenhut Michael Prof Dr | Radiohalogenierte Benzamidderivate, verwendbar zur Diagnose und Behandlung von Tumoren, insbesondere Melanomen |
WO2008012782A2 (en) * | 2006-07-27 | 2008-01-31 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Labelled analogues of halobenzamides as radiopharmaceuticals |
WO2009129573A1 (en) * | 2008-04-22 | 2009-10-29 | Australian Nuclear Science And Technology Organisation | Nicotinamide derivatives |
WO2018131911A1 (ko) * | 2017-01-13 | 2018-07-19 | 전남대학교 산학협력단 | 악성 흑색종 진단용 방사성 화합물 및 그의 용도 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19632052C2 (de) * | 1996-08-08 | 2003-05-28 | Michael Eisenhut | Benzamidderivate und deren Verwendung zur Diagnose und Behandlung von Tumoren, insbesondere Melanomen |
US20020002169A1 (en) * | 1999-12-08 | 2002-01-03 | Griffin John H. | Protein kinase inhibitors |
US20070202047A1 (en) * | 2006-01-05 | 2007-08-30 | Markus Wolf | Polyamine-substituted ligands for use as contrast agents |
EP2085390A1 (en) * | 2008-01-31 | 2009-08-05 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Labelled analogues of halobenzamides as multimodal radiopharmaceuticals and their precursors |
CA2736237A1 (en) * | 2008-09-05 | 2010-03-11 | Molecular Insight Pharmaceuticals, Inc. | Pharmaceutical composition of a radioiodinated benzamide derivative and methods of making the same |
KR101519006B1 (ko) * | 2013-03-26 | 2015-05-11 | 한국원자력연구원 | 신규한 벤즈아마이드 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 피부암 진단용 약학적 조성물 |
WO2017072909A1 (ja) | 2015-10-29 | 2017-05-04 | 日本たばこ産業株式会社 | 棒状たばこ物品における炭素熱源の燃え殻収容器、吸い殻入れ、及び棒状たばこ物品用パッケージ |
-
2019
- 2019-04-11 JP JP2020572824A patent/JP7205930B2/ja active Active
- 2019-04-11 WO PCT/KR2019/004396 patent/WO2020004785A1/ko unknown
- 2019-04-11 KR KR1020190042718A patent/KR102302065B1/ko active IP Right Grant
- 2019-04-11 CN CN201980055276.0A patent/CN112601740A/zh active Pending
- 2019-04-11 EP EP19827110.8A patent/EP3816156A4/en active Pending
-
2020
- 2020-12-28 US US17/134,709 patent/US20210113719A1/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19519508A1 (de) * | 1995-05-31 | 1996-12-05 | Eisenhut Michael Prof Dr | Radiohalogenierte Benzamidderivate, verwendbar zur Diagnose und Behandlung von Tumoren, insbesondere Melanomen |
WO2008012782A2 (en) * | 2006-07-27 | 2008-01-31 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Labelled analogues of halobenzamides as radiopharmaceuticals |
WO2009129573A1 (en) * | 2008-04-22 | 2009-10-29 | Australian Nuclear Science And Technology Organisation | Nicotinamide derivatives |
WO2018131911A1 (ko) * | 2017-01-13 | 2018-07-19 | 전남대학교 산학협력단 | 악성 흑색종 진단용 방사성 화합물 및 그의 용도 |
Non-Patent Citations (3)
Title |
---|
BILLAUD, EMILIE M. F.; VIDAL, AURELIEN; VINCENOT, AMELIE; BESSE, SOPHIE; ET AL: ""Development and Preliminary Evaluation of TFIB, a New Bimodal Prosthetic Group for Bioactive Molecu", ACS MEDICINAL CHEMISTRY LETTERS, vol. Vol.6(2), JPN6022003332, 2015, pages 168 - 172, ISSN: 0004697073 * |
DITTMANN, HELMUT; COENEN, HEINZ H.; ZOLZER, FRIEDO; ET AL: ""In vitro studies on the cellular uptake of melanoma imaging aminoalkyl-iodobenzamide derivatives (A", NUCLEAR MEDICINE AND BIOLOGY, vol. Vol.26(1), JPN6022003331, 1999, pages 51 - 56, ISSN: 0004697072 * |
LIU, HONGGUANG: ""Development of18F-Labeled Picolinamide Probes for PET Imaging of Malignant Melanoma"", JOURNAL OF MEDICINAL CHEMISTRY, vol. Vol.56(3), JPN6022003333, 2013, pages 895 - 901, ISSN: 0004697074 * |
Also Published As
Publication number | Publication date |
---|---|
KR102302065B1 (ko) | 2021-09-15 |
US20210113719A1 (en) | 2021-04-22 |
EP3816156A1 (en) | 2021-05-05 |
CN112601740A (zh) | 2021-04-02 |
EP3816156A4 (en) | 2022-04-27 |
WO2020004785A1 (ko) | 2020-01-02 |
JP7205930B2 (ja) | 2023-01-17 |
KR20200001971A (ko) | 2020-01-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7304588B2 (ja) | Psmaを標的としたイメージング及び放射線治療のための金属/放射性金属標識psma阻害剤 | |
US11661402B2 (en) | PSMA-targeting compounds and uses thereof | |
JP7449864B2 (ja) | エバンスブルー誘導体の化学結合体ならびに前立腺癌を標的とするための放射線療法および造影剤としてのその使用 | |
EP2170075B1 (en) | Labeled inhibitors of prostate specific membrane antigen (psma), biological evaluation, and use as imaging agents | |
US20220162241A1 (en) | Chelated PSMA Inhibitors | |
US9353120B2 (en) | Tetraaza macrocyclic compound, preparation method thereof and use thereof | |
WO2016062370A1 (en) | 18f-tagged inhibitors of prostate specific membrane antigen (psma), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer | |
JP5856982B2 (ja) | 二官能性キレート化剤 | |
US20210113719A1 (en) | Radioactive compound for treatment of melanoma and use thereof | |
US20150291538A1 (en) | Macrocyclic Compositions And Metal Complexes For Bioimaging And Biomedical Applications | |
EP2643301B1 (fr) | Complexe de technetium 99m en tant qu'outil de diagnostic in vivo des tumeurs cancereuses | |
EP3909944A1 (en) | Nuclide labelled h-tetrazines and use thereof for pet and spect pretargeted imaging and radionuclide therapy | |
AU2015203742A1 (en) | Labeled inhibitors of prostate specific membrane antigen (psma), biological evaluation, and use as imaging agents | |
JP5503149B2 (ja) | 二官能性ポリアザ大環状キレート剤 | |
Singh et al. | A homodimeric bivalent radioligand derived from 1-(2-methoxyphenyl) piperazine with high affinity for in vivo 5-HT1A receptor imaging | |
US11504439B2 (en) | Radioactive compound for diagnosis of malignant melanoma and use thereof | |
KR101920902B1 (ko) | 심혈관 질환 조기진단 pet 조영용 화합물 및 그의 용도 | |
CN116375709A (zh) | 一种叶酸受体靶向药物、金属络合物及其制备方法与用途 | |
CN116217505A (zh) | 用于诊断或治疗表达前列腺特异性膜抗原癌症的新型标记靶向剂 | |
WO2020045638A1 (ja) | 放射性イミダゾチアジアゾール誘導体化合物 | |
CA3205844A1 (en) | Ligands and their use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210225 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20220125 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220201 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20220428 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20220629 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220728 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20221122 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20221222 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7205930 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |