JP2014240394A - テクネチウム及びレニウム−ビス(ヘテロアリール)錯体及びその使用方法 - Google Patents
テクネチウム及びレニウム−ビス(ヘテロアリール)錯体及びその使用方法 Download PDFInfo
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- JP2014240394A JP2014240394A JP2014145241A JP2014145241A JP2014240394A JP 2014240394 A JP2014240394 A JP 2014240394A JP 2014145241 A JP2014145241 A JP 2014145241A JP 2014145241 A JP2014145241 A JP 2014145241A JP 2014240394 A JP2014240394 A JP 2014240394A
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- 125000001072 heteroaryl group Chemical group 0.000 title claims description 94
- 238000000034 method Methods 0.000 title description 72
- -1 imidazoloyl Chemical group 0.000 claims abstract description 363
- 239000003446 ligand Substances 0.000 claims abstract description 87
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 43
- 229910052702 rhenium Inorganic materials 0.000 claims abstract description 28
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 27
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052713 technetium Inorganic materials 0.000 claims abstract description 15
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 claims abstract description 13
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract description 7
- 229910001413 alkali metal ion Inorganic materials 0.000 claims abstract description 7
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 339
- 125000003118 aryl group Chemical group 0.000 claims description 105
- 229910052739 hydrogen Inorganic materials 0.000 claims description 95
- 125000000217 alkyl group Chemical group 0.000 claims description 75
- 239000002253 acid Substances 0.000 claims description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 62
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 57
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 56
- 102000004169 proteins and genes Human genes 0.000 claims description 54
- 108090000623 proteins and genes Proteins 0.000 claims description 54
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 54
- 125000004001 thioalkyl group Chemical group 0.000 claims description 50
- 125000003342 alkenyl group Chemical group 0.000 claims description 49
- 150000007942 carboxylates Chemical class 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 48
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 46
- 102000003960 Ligases Human genes 0.000 claims description 45
- 108090000364 Ligases Proteins 0.000 claims description 45
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 44
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 claims description 43
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 claims description 43
- 125000000304 alkynyl group Chemical group 0.000 claims description 43
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 43
- 229920002477 rna polymer Polymers 0.000 claims description 43
- 125000002252 acyl group Chemical group 0.000 claims description 40
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 40
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 40
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 38
- 150000002431 hydrogen Chemical class 0.000 claims description 37
- 150000003573 thiols Chemical class 0.000 claims description 36
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 35
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 34
- 150000001412 amines Chemical class 0.000 claims description 34
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 33
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 claims description 32
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 32
- 150000001413 amino acids Chemical class 0.000 claims description 30
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 150000001720 carbohydrates Chemical class 0.000 claims description 26
- 150000002148 esters Chemical class 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 102000007399 Nuclear hormone receptor Human genes 0.000 claims description 23
- 108020005497 Nuclear hormone receptor Proteins 0.000 claims description 23
- 101710172711 Structural protein Proteins 0.000 claims description 23
- 102000040945 Transcription factor Human genes 0.000 claims description 23
- 108091023040 Transcription factor Proteins 0.000 claims description 23
- 102000004357 Transferases Human genes 0.000 claims description 23
- 108090000992 Transferases Proteins 0.000 claims description 23
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 23
- 125000004414 alkyl thio group Chemical group 0.000 claims description 23
- 102000003675 cytokine receptors Human genes 0.000 claims description 23
- 108010057085 cytokine receptors Proteins 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 23
- 108010044426 integrins Proteins 0.000 claims description 23
- 102000006495 integrins Human genes 0.000 claims description 23
- 125000003367 polycyclic group Polymers 0.000 claims description 23
- 102000027257 transmembrane receptors Human genes 0.000 claims description 23
- 108091008578 transmembrane receptors Proteins 0.000 claims description 23
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 claims description 22
- 150000001299 aldehydes Chemical class 0.000 claims description 22
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 22
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 22
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 22
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 21
- 102000004157 Hydrolases Human genes 0.000 claims description 21
- 108090000604 Hydrolases Proteins 0.000 claims description 21
- SOWBFZRMHSNYGE-UHFFFAOYSA-N Monoamide-Oxalic acid Natural products NC(=O)C(O)=O SOWBFZRMHSNYGE-UHFFFAOYSA-N 0.000 claims description 21
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 21
- 150000003949 imides Chemical class 0.000 claims description 21
- 150000002576 ketones Chemical class 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 108091006146 Channels Proteins 0.000 claims description 20
- 125000004442 acylamino group Chemical group 0.000 claims description 20
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 20
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 20
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 claims description 20
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 20
- 150000002923 oximes Chemical class 0.000 claims description 20
- 125000003441 thioacyl group Chemical group 0.000 claims description 20
- GNVMUORYQLCPJZ-UHFFFAOYSA-M Thiocarbamate Chemical compound NC([S-])=O GNVMUORYQLCPJZ-UHFFFAOYSA-M 0.000 claims description 19
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 19
- 125000004423 acyloxy group Chemical group 0.000 claims description 19
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 19
- 150000001409 amidines Chemical class 0.000 claims description 19
- 150000008064 anhydrides Chemical class 0.000 claims description 19
- 239000004202 carbamide Substances 0.000 claims description 19
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 19
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 claims description 19
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 claims description 19
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 19
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 19
- 229940124530 sulfonamide Drugs 0.000 claims description 19
- 150000003456 sulfonamides Chemical class 0.000 claims description 19
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 18
- VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 claims description 17
- 150000001408 amides Chemical class 0.000 claims description 17
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 claims description 17
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 17
- 229920001282 polysaccharide Polymers 0.000 claims description 17
- 239000005017 polysaccharide Substances 0.000 claims description 17
- 150000003568 thioethers Chemical class 0.000 claims description 17
- 108091034117 Oligonucleotide Proteins 0.000 claims description 16
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 16
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 16
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 16
- 239000002773 nucleotide Substances 0.000 claims description 16
- 125000003729 nucleotide group Chemical group 0.000 claims description 16
- 235000000346 sugar Nutrition 0.000 claims description 16
- 150000003536 tetrazoles Chemical class 0.000 claims description 16
- 150000003852 triazoles Chemical class 0.000 claims description 16
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 15
- 150000001540 azides Chemical class 0.000 claims description 15
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 claims description 13
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 229960000553 somatostatin Drugs 0.000 claims description 12
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 10
- 101001004391 Drosophila melanogaster Protein jim lovell Proteins 0.000 claims description 9
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 8
- 101150065749 Churc1 gene Proteins 0.000 claims description 8
- 102100038239 Protein Churchill Human genes 0.000 claims description 8
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 claims description 8
- 102000005157 Somatostatin Human genes 0.000 claims description 7
- 108010056088 Somatostatin Proteins 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 150000008378 aryl ethers Chemical class 0.000 claims description 7
- 230000014509 gene expression Effects 0.000 claims description 7
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims description 6
- 125000005600 alkyl phosphonate group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 229910052738 indium Inorganic materials 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 102000039446 nucleic acids Human genes 0.000 claims description 5
- 108020004707 nucleic acids Proteins 0.000 claims description 5
- 150000007523 nucleic acids Chemical class 0.000 claims description 5
- 229960002700 octreotide Drugs 0.000 claims description 5
- 229910052727 yttrium Inorganic materials 0.000 claims description 5
- 229910004013 NO 2 Inorganic materials 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 claims description 3
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052765 Lutetium Inorganic materials 0.000 claims description 3
- 108010016076 Octreotide Proteins 0.000 claims description 3
- 229910052733 gallium Inorganic materials 0.000 claims description 3
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 claims description 3
- OHSVLFRHMCKCQY-UHFFFAOYSA-N lutetium atom Chemical compound [Lu] OHSVLFRHMCKCQY-UHFFFAOYSA-N 0.000 claims description 3
- VEBQYHFHXCAREJ-UHFFFAOYSA-N pyrrolidin-2-ylboronic acid Chemical compound OB(O)C1CCCN1 VEBQYHFHXCAREJ-UHFFFAOYSA-N 0.000 claims description 3
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 claims description 3
- LHCIROHUTQLZCZ-UHFFFAOYSA-N 10-(4-aminobutyl)-19-[(2-amino-3-phenylpropanoyl)amino]-n-(1,3-dihydroxybutan-2-yl)-7-(1-hydroxyethyl)-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide Chemical compound O=C1NC(CC=2C=CC(O)=CC=2)C(=O)NC(CC=2C3=CC=CC=C3NC=2)C(=O)NC(CCCCN)C(=O)NC(C(C)O)C(=O)NC(C(=O)NC(CO)C(O)C)CSSCC1NC(=O)C(N)CC1=CC=CC=C1 LHCIROHUTQLZCZ-UHFFFAOYSA-N 0.000 claims description 2
- 108700014849 3-Tyr-octreotide Proteins 0.000 claims description 2
- LUZARLKNZGALGS-UHFFFAOYSA-N aziridin-1-yl(diazonio)azanide Chemical compound [N-]=[N+]=NN1CC1 LUZARLKNZGALGS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 6
- 150000002118 epoxides Chemical class 0.000 claims 6
- 150000004676 glycans Chemical class 0.000 claims 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims 2
- 239000012453 solvate Substances 0.000 claims 2
- IVHVNMLJNASKHW-UHFFFAOYSA-M Chlorphonium chloride Chemical compound [Cl-].CCCC[P+](CCCC)(CCCC)CC1=CC=C(Cl)C=C1Cl IVHVNMLJNASKHW-UHFFFAOYSA-M 0.000 claims 1
- NVGBPTNZLWRQSY-UWVGGRQHSA-N Lys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN NVGBPTNZLWRQSY-UWVGGRQHSA-N 0.000 claims 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims 1
- 229910017052 cobalt Inorganic materials 0.000 claims 1
- 239000010941 cobalt Substances 0.000 claims 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims 1
- 229910052742 iron Inorganic materials 0.000 claims 1
- 108010054155 lysyllysine Proteins 0.000 claims 1
- 229910052750 molybdenum Inorganic materials 0.000 claims 1
- 239000011733 molybdenum Substances 0.000 claims 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims 1
- 229910052707 ruthenium Inorganic materials 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 abstract description 10
- 239000012217 radiopharmaceutical Substances 0.000 abstract description 10
- 229940121896 radiopharmaceutical Drugs 0.000 abstract description 10
- 230000002799 radiopharmaceutical effect Effects 0.000 abstract description 10
- 230000001225 therapeutic effect Effects 0.000 abstract description 7
- 230000029142 excretion Effects 0.000 abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 150
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 146
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Abstract
Description
本出願は、2008年12月5日出願の米国仮特許出願第61/120,226号、2009年1月8日出願の米国特許出願第12/350,894号、及び2009年5月21日出願の米国仮特許出願第61/180,341号に対する優先権を主張し、この出願はあらゆる意味ですべて参照によりその全体を本明細書に組み込むものとする。
便宜上、本明細書及び添付の特許請求の範囲内で使用する特定の用語をここに集めた。
スキーム1:反応物/条件:(i)ジメチルアミンと110℃で反応、(ii)二酸化マンガン
スキーム2:保護されたリジン残基の還元アルキル化を介した4−ジメチルアミノピリジン−2−カルボキシアルデヒドの2つの等価物からのDPMA類似体の合成
スキーム3.反応物/条件:(iii)Pd(0)、NH(R90)2
スキーム4.ピリジン環構造のpKaに対する追加の環窒素及び窒素置換の効果
スキーム5:X’はII、IV又はVIで表された化合物で示すように、イミダゾリル又はピリジル基を表す
スキーム6:LIMES化合物の調製
スキーム7.
特定の実施形態を図示し、説明してきたが、添付の特許請求の範囲で定義されるようなより広義の態様における技術から逸脱することなく、当技術分野の通常の技術に従って、変更及び修正をできることを理解されたい。
なお、原出願(特願2011−539752号、PCT/US2009/066832)の出願当初の特許請求の範囲は以下の通りである。
〔請求項1〕(a)式(I)
Rは、H、アルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、チオアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アシル、アミノアシル、ヒドロキシアシル、チオアシル、−CO 2 H、−(CH 2 ) d −R 80 、又はアミノ酸ラジカルであり、
R 80 は、出現毎に独立にカルボキシアルデヒド、カルボン酸塩、カルボキシアミド、アルコキシカルボニル、アリールオキシカルボニル、アンモニウム、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクリル、ポリシクリル、アミノ酸、ペプチド、糖類、リボ核酸、(デオキシ)リボ核酸、又はGタンパク質共役型受容体、オキソ還元酵素、転移酵素、加水分解酵素、リガーゼ、オソメラーゼ、リガーゼ、GPCR、直接配位子ゲートチャネル受容体、サイトカイン受容体、インテグリン受容体、チロシンキナーゼ関連受容体、核受容体、ペプチド受容体、膜貫通型受容体、転写因子、骨格細胞タンパク質、構造タンパク質又は信号タンパク質の配位子であり、
dは、0〜12の範囲の整数(0と12を含む)であり、
mは、0〜6の範囲の整数(0と6を含む)であり、
nは、0〜6の範囲の整数(0と6を含む)であり、
R 70 、R 71 、R 72 、R 73 、R 74 、R 75 、R 76 及びR 77 は、それぞれ独立に水素、ハロゲン、アルキル、アルケニル、アルキニル、ヒドロキシル、アルコキシル、アシル、アシルオキシ、アシルアミノ、シリルオキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、ニトロ、スルフヒドリル、アルキルチオ、イミノ、アミド、ホスホリル、ホスホン酸塩、ホスフィン、カルボニル、カルボキシル、カルボキシアミド、無水物、シリル、チオアルキル、アルキルスルホニル、アリールスルホニル、セレノアルキル、ケトン、アルデヒド、エステル、ヘテロアルキル、シアノ、グアニジン、アミジン、アセタール、ケタール、アミンオキシド、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アジド、アジリジン、カルバモイル、エポキシド、ヒドロキサム酸、イミド、オキシム、スルホンアミド、チオアミド、チオカルバメート、尿素、チオ尿素、又は−(CH 2 ) d −R 80 であり、
但し、R 70 、R 71 、R 72 、又はR 73 のうち少なくとも1つは水素ではなく、R 74 、R 75 、R 76 又はR 77 のうち少なくとも1つは水素ではない。)、
(b)式(II)
Rは、H、アルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、チオアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アシル、アミノアシル、ヒドロキシアシル、チオアシル、−CO 2 H、−(CH 2 ) d −R 80 、又はアミノ酸ラジカルであり、
R 80 は、出現毎に独立にカルボキシアルデヒド、カルボン酸塩、カルボキシアミド、アルコキシカルボニル、アリールオキシカルボニル、アンモニウム、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクリル、ポリシクリル、アミノ酸、ペプチド、糖類、リボ核酸、(デオキシ)リボ核酸、又はGタンパク質共役型受容体、オキソ還元酵素、転移酵素、加水分解酵素、リガーゼ、オソメラーゼ、リガーゼ、GPCR、直接配位子ゲートチャネル受容体、サイトカイン受容体、インテグリン受容体、チロシンキナーゼ関連受容体、核受容体、ペプチド受容体、膜貫通型受容体、転写因子、骨格細胞タンパク質、構造タンパク質又は信号タンパク質の配位子であり、
dは、0〜12の範囲の整数(0と12を含む)であり、
mは、0〜6の範囲の整数(0と6を含む)であり、
nは、0〜6の範囲の整数(0と6を含む)であり、
Zは、チオアルキル、カルボン酸塩、2−(カルボキシ)アリール、2−(カルボキシ)ヘテロアリール、2−(ヒドロキシ)アリール、2−(ヒドロキシ)ヘテロアリール、2−(チオール)アリール、又は2−(チオール)ヘテロアリールであり、
R 70 、R 71 、R 72 及びR 73 は、それぞれ独立に水素、ハロゲン、アルキル、アルケニル、アルキニル、ヒドロキシル、アルコキシル、アシル、アシルオキシ、アシルアミノ、シリルオキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、ニトロ、スルフヒドリル、アルキルチオ、イミノ、アミド、ホスホリル、ホスホン酸塩、ホスフィン、カルボニル、カルボキシル、カルボキシアミド、無水物、シリル、チオアルキル、アルキルスルホニル、アリールスルホニル、セレノアルキル、ケトン、アルデヒド、エステル、ヘテロアルキル、シアノ、グアニジン、アミジン、アセタール、ケタール、アミンオキシド、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アジド、アジリジン、カルバモイル、エポキシド、ヒドロキサム酸、イミド、オキシム、スルホンアミド、チオアミド、チオカルバメート、尿素、チオ尿素、又は−(CH 2 ) d −R 80 であり、
但し、R 70 、R 71 、R 72 、及びR 73 のうち少なくとも1つは水素ではなく、R 74 、R 75 、R 76 及びR 77 のうち少なくとも1つは水素ではない。)、
(c)式(III)
Rは、H、アルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、チオアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アシル、アミノアシル、ヒドロキシアシル、チオアシル、CO 2 H、−(CH 2 ) d −R 80 、又はアミノ酸ラジカルであり、
R 80 は、出現毎に独立にカルボキシアルデヒド、カルボン酸塩、カルボキシアミド、アルコキシカルボニル、アリールオキシカルボニル、アンモニウム、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクリル、ポリシクリル、アミノ酸、ペプチド、糖類、リボ核酸、(デオキシ)リボ核酸、又はGタンパク質共役型受容体、オキソ還元酵素、転移酵素、加水分解酵素、リガーゼ、オソメラーゼ、リガーゼ、GPCR、直接配位子ゲートチャネル受容体、サイトカイン受容体、インテグリン受容体、チロシンキナーゼ関連受容体、核受容体、ペプチド受容体、膜貫通型受容体、転写因子、骨格細胞タンパク質、構造タンパク質又は信号タンパク質の配位子であり、
dは、0〜12の範囲の整数(0と12を含む)であり、
mは、0〜6の範囲の整数(0と6を含む)であり、
nは、0〜6の範囲の整数(0と6を含む)であり、
Dは、下式のいずれかであり、
(d)式(IV)
Rは、H、アルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、チオアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アシル、アミノアシル、ヒドロキシアシル、チオアシル、−CO 2 H、−(CH 2 ) d −R 80 、又はアミノ酸ラジカルであり、
R 80 は、出現毎に独立にカルボキシアルデヒド、カルボン酸塩、カルボキシアミド、アルコキシカルボニル、アリールオキシカルボニル、アンモニウム、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクリル、ポリシクリル、アミノ酸、ペプチド、糖類、リボ核酸、(デオキシ)リボ核酸、又はGタンパク質共役型受容体、オキソ還元酵素、転移酵素、加水分解酵素、リガーゼ、オソメラーゼ、リガーゼ、GPCR、直接配位子ゲートチャネル受容体、サイトカイン受容体、インテグリン受容体、チロシンキナーゼ関連受容体、核受容体、ペプチド受容体、膜貫通型受容体、転写因子、骨格細胞タンパク質、構造タンパク質又は信号タンパク質の配位子であり、
dは、0〜12の範囲の整数(0と12を含む)であり、
mは、0〜6の範囲の整数(0と6を含む)であり、
nは、0〜6の範囲の整数(0と6を含む)であり、
Zは、チオアルキル、カルボン酸塩、2−(カルボキシ)アリール、2−(カルボキシ)ヘテロアリール、2−(ヒドロキシ)アリール、2−(ヒドロキシ)ヘテロアリール、2−(チオール)アリール又は2−(チオール)ヘテロアリールであり、
Dは、下式のいずれかであり、
(e)式(V)
Rは、H、又は置換又は非置換アルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、チオアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アシル、アミノアシル、ヒドロキシアシル、チオアシル、アルキルケト、アミノアルコキシアルキル、ボラートアルキル、ホスホン酸アルキル、ホスフィン酸アルキル、(CH 2 ) 4 CH(NH 2 )CO 2 H、(CH 2 ) 3 CH(NH 2 )CO 2 H、(CH 2 ) 2 CH(NH 2 )CO 2 H、C(O)CH 2 (CH)NH 2 CO 2 H、C(O)(CH 2 ) 2 (CH)NH 2 CO 2 H、(CC)(CH 2 ) 2 CH(NH 2 )CO 2 H、(CHCH)(CH 2 ) 2 CHNH 2 CO 2 H、(CH 2 ) 2 (CHOH)(CH 2 )CHNH 2 CO 2 H又は(CH 2 )(CHOH)(CH 2 ) 2 CHNH 2 CO 2 H、(CO 2 H) 2 、−CO 2 H、−(CH 2 ) d −R 80 、−C(O)(CH 2 ) d −R 80 、又はアミノ酸ラジカルであり、
R 80 は、発現毎に独立にカルボキシアルデヒド、カルボン酸塩、カルボキシアミド、アルコキシカルボニル、アリールオキシカルボニル、アンモニウム、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクリル、ポリシクリル、アミノ酸、CH 2 CH 2 OCH 2 CH 3 、CH 2 C(OCH 3 ) 2 、(CH 2 CH 2 O) d CH 2 CH 3 、(CH 2 ) d NH 2 、CH 2 CH 2 C(O)NH 2 、(CH 2 ) d N(CH 3 ) 2 、CH 2 CH 2 OH、(CH 2 ) d C(CO 2 H) 2 、(CH 2 ) d P(O)(OH) 2 、(CH 2 ) d B(OH) 2 、ペプチド、糖類、リボ核酸、(デオキシ)リボ核酸、又はGタンパク質共役型受容体、オキソ還元酵素、転移酵素、加水分解酵素、リガーゼ、オソメラーゼ、リガーゼ、GPCR、直接配位子ゲートチャネル受容体、サイトカイン受容体、インテグリン受容体、チロシンキナーゼ関連受容体、核受容体、ペプチド受容体、膜貫通型受容体、転写因子、骨格細胞タンパク質、構造タンパク質又は信号タンパク質の配位子であり、
dは、0〜12の範囲の整数(0と12を含む)であり、
mは、0〜6の範囲の整数(0と6を含む)であり、
nは、0〜6の範囲の整数(0と6を含む)であり、
R 81 、R 82 、R 83 、R 84 、R 85 及びR 86 は、それぞれ独立に水素、ハロゲン、又は置換又は非置換アルキル、アルケニル、アルキニル、ヒドロキシル、アルコキシル、アシル、アシルオキシ、アシルアミノ、シリルオキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、ニトロ、スルフヒドリル、アルキルチオ、イミノ、アミド、ホスホリル、ホスホン酸塩、ホスフィン、カルボニル、カルボキシル、カルボキシアミド、無水物、シリル、チオアルキル、アルキルスルホニル、アリールスルホニル、セレノアルキル、ケトン、アルデヒド、エーテル、エステル、ヘテロアルキル、シアノ、グアニジン、アミジン、アセタール、ケタール、アミンオキシド、アリール、ヘテロアリール、アラルキル、アリールエーテル、ヘテロアラルキル、アジド、アジリジン、カルバモイル、エポキシド、ヒドロキサム酸、イミド、オキシム、スルホンアミド、チオアミド、チオカルバメート、尿素、チオ尿素、−(CH 2 ) d −R 80 、(CH 2 ) d (CO 2 H) 2 、CH 2 CH 2 OCH 2 CH 3 、CH 2 C(OCH 3 ) 2 、(CH 2 CH 2 O) d CH 2 CH 3 、(CH 2 ) d NH 2 、CH 2 CH 2 C(O)NH 2 、(CH 2 ) d N(CH 3 ) 2 、CH 2 CH 2 OH、(CH 2 ) n C(CO 2 H) 2 、(CH 2 ) d P(O)(OH) 2 、(CH 2 ) d B(OH) 2 、−(CH 2 ) d −R 80 、(CH 2 ) d R 87 又は−(CH 2 ) d −R 88 であり、
R 87 及びR 88 は、それぞれ独立に15−クラウン−5、18−クラウン−6、テトラゾール、オキサゾール、アジリジン、トリアゾール、イミダゾール、ピラゾール、チアゾール、ヒドロキサム酸、ホスホン酸塩、ホスフィン酸塩、チオール、チオエーテル、多糖類、糖類、ヌクレオチド又はオリゴヌクレオチドである。)又は
(f)式(VI)
Rは、H、アルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、チオアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アシル、アミノアシル、ヒドロキシアシル、チオアシル、アルキルケト、アミノアルコキシルアルキル、ボラートアルキル、ホスホン酸アルキル、ホスフィン酸アルキル、(CH 2 ) 4 CH(NH 2 )CO 2 H、(CH 2 ) 3 CH(NH 2 )CO 2 H、(CH 2 ) 2 CH(NH 2 )CO 2 H、C(O)CH 2 (CH)NH 2 CO 2 H、C(O)(CH 2 ) 2 (CH)NH 2 CO 2 H、(CC)(CH 2 ) 2 CH(NH 2 )CO 2 H、(CHCH)(CH 2 ) 2 CHNH 2 CO 2 H、(CH 2 ) 2 (CHOH)(CH 2 )CHNH 2 CO 2 H又は(CH 2 )(CHOH)(CH 2 ) 2 CHNH 2 CO 2 H、(CO 2 H) 2 、−CO 2 H、−(CH 2 ) d −R 80 、−C(O)(CH 2 ) d −R 80 又はアミノ酸ラジカルであり、
R 80 は、出現毎に独立にカルボキシアルデヒド、カルボン酸塩、カルボキシアミド、アルコキシカルボニル、アリールオキシカルボニル、アンモニウム、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクリル、ポリシクリル、アミノ酸、CH 2 CH 2 OCH 2 CH 3 、CH 2 C(OCH 3 ) 2 、(CH 2 CH 2 O) d CH 2 CH 3 、(CH 2 ) d NH 2 、CH 2 CH 2 C(O)NH 2 、(CH 2 ) d N(CH 3 ) 2 、CH 2 CH 2 OH、(CH 2 ) d C(CO 2 H) 2 、(CH 2 ) d P(O)(OH) 2 、(CH 2 ) d B(OH) 2 、ペプチド、糖類、リボ核酸、(デオキシ)リボ核酸、又はGタンパク質共役型受容体、オキソ還元酵素、転移酵素、加水分解酵素、リガーゼ、オソメラーゼ、リガーゼ、GPCR、直接配位子ゲートチャネル受容体、サイトカイン受容体、インテグリン受容体、チロシンキナーゼ関連受容体、核受容体、ペプチド受容体、膜貫通型受容体、転写因子、骨格細胞タンパク質、構造タンパク質又は信号タンパク質の配位子であり、
dは、0〜12の範囲の整数(0と12を含む)であり、
mは、0〜6の範囲の整数(0と6を含む)であり、
nは、0〜6の範囲の整数(0と6を含む)であり、
Zは、置換又は非置換チオアルキル、カルボン酸塩、カルボキシアルキル、アミノアルキル、ヘテロシクリル、(アミノ酸)、(アミノ酸)アルキル、ヒドロキシ、ヒドロキシアルキル、2−(カルボキシ)アリール、2−(カルボキシ)ヘテロアリール、2−(ヒドロキシ)アリール、2−(ヒドロキシ)ヘテロアリール、2−(チオール)アリール、2−ピロリジンボロン酸又は2−(チオール)ヘテロアリールであり、
R 81 、R 82 及びR 83 は、それぞれ独立に水素、ハロゲン、アルキル、アルケニル、アルキニル、ヒドロキシル、アルコキシル、アシル、アシルオキシ、アシルアミノ、シリルオキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、ニトロ、スルフヒドリル、アルキルチオ、イミノ、アミド、ホスホリル、ホスホン酸塩、ホスフィン、カルボニル、カルボキシル、カルボキシアミド、無水物、シリル、チオアルキル、アルキルスルホニル、アリールスルホニル、セレノアルキル、ケトン、アルデヒド、エーテル、エステル、ヘテロアルキル、シアノ、グアニジン、アミジン、アセタール、ケタール、アミンオキシド、アリール、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、アラルキル、アリールエーテル、ヘテロアラルキル、アジド、アジリジン、カルバモイル、エポキシド、ヒドロキサム酸、イミド、オキシム、スルホンアミド、チオアミド、チオカルバメート、尿素、チオ尿素、−(CH 2 ) d −R 80 、(CH 2 ) d (CO 2 H) 2 、CH 2 CH 2 OCH 2 CH 3 、CH 2 C(OCH 3 ) 2 、(CH 2 CH 2 O) d CH 2 CH 3 、(CH 2 ) d NH 2 、CH 2 CH 2 C(O)NH 2 、(CH 2 ) d N(CH 3 ) 2 、CH 2 CH 2 OH、(CH 2 ) d C(CO 2 H) 2 、(CH 2 ) d P(O)(OH) 2 、(CH 2 ) d B(OH) 2 、−(CH 2 ) d −R 80 、(CH 2 ) d R 87 又は−(CH 2 ) d R 88 であり、
R 87 及びR 88 は、それぞれ独立にヘテロアリール、ヘテロシクリル、15−クラウン−5、18−クラウン−6、テトラゾール、オキサゾール、アジリジン、トリアゾール、イミダゾール、ピラゾール、チアゾール、ヒドロキサム酸、ホスホン酸塩、ホスフィン酸塩、チオール、チオエーテル、多糖類、糖類、ヌクレオチド又はオリゴヌクレオチドである。)
で表される化合物。
〔請求項2〕式(I)又は(III)において、mが1であり、nが1である、請求項1に記載の化合物。
〔請求項3〕式(II)、(IV)又は(VI)において、Zがカルボン酸塩である、請求項1に記載の化合物。
〔請求項4〕Zがカルボン酸塩であり、mが1であり、nが1である、請求項3に記載の化合物。
〔請求項5〕式(I)において、R 70 、R 71 、R 72 又はR 73 のうち少なくとも1つがアミノであり、R 74 、R 75 、R 76 又はR 77 のうち少なくとも1つがアミノ基である、請求項1に記載の化合物。
〔請求項6〕前記アミノ基が−N(R 90 ) 2 である、請求項5に記載の化合物。
〔請求項7〕−N(R 90 ) 2 が下式のいずれかである、請求項6に記載の化合物。
〔請求項9〕式(I)、(II)、(III)、(IV)又は(VI)において、Rが−(CH 2 ) d −R 80 である、請求項1に記載の化合物。
〔請求項10〕前記式(I)又は(III)において、mが1であり、nが1であり、Rが−(CH 2 ) d −R 80 である、請求項1に記載の化合物。
〔請求項11〕式(I)、(III)又は(V)において、Rがアミノ酸ラジカルである、請求項1に記載の化合物。
〔請求項12〕前記アミノ酸ラジカルが、
−CH 2 CH 2 CH 2 CH 2 CH(NH 2 )CO 2 H、
−CH(CO 2 H)CH 2 CH 2 CH 2 CH 2 NH 2 、
−CH 2 CH 2 CH 2 CO 2 H、
−CH 2 (CH 2 ) x CO 2 H、
−CH 2 (CH 2 ) x CH(NH 2 )CO 2 H、又は
−CH(CO 2 H)(CH 2 ) x CH(NH 2 )CO 2 Hであり、
xが3〜9の整数(3と9を含む)である、
請求項11に記載の化合物。
〔請求項13〕R 81 、R 82 又はR 83 のうち少なくとも1つが親水基であるか、又はR 84 、R 85 又はR 86 のうち少なくとも1つが親水基であるか、又はR 81 、R 82 又はR 83 のうち少なくとも1つ及びR 84 、R 85 又はのうち少なくとも1つが親水基である、請求項1の式(V)に記載の化合物。
〔請求項14〕各親水基が、個々にエーテル、アルコキシアラルキル、カルボン酸塩、アルコール又はアミドである、請求項13に記載の化合物。
〔請求項15〕R 81 、R 82 又はR 83 のうち少なくとも1つが親水基である、請求項1の式(VI)に記載の化合物。
〔請求項16〕各親水基が、独立にエーテル、アルコキシアラルキル、カルボン酸塩、アルコール又はアミドである、請求項13に記載の化合物。
〔請求項17〕Rが、H、CH 3 、(CH 2 ) d CH 3 、CH 2 CH 2 OCH 2 CH 3 、CH 2 CH 2 C(O)NH 2 、CH 2 C(OCH 3 ) 2 、CH 2 (18−クラウン−6)、CH 2 (15−クラウン−5)、C(O)(CH 2 ) d (CH)(NH 2 )CO 2 H、(CH 2 CH 2 O) d CH 2 CH 3 、(CH 2 ) d Ph(SO 2 NH 2 )、(CH 2 ) d P(O)OH 2 、(CH 2 ) d OCH 2 NH 2 、(CH 2 ) d NHCH 2 NH 2 、(CH 2 ) d NHCH 2 CO 2 H、(CH 2 ) d NH 2 、(CH 2 ) d N(CH 3 ) 2 、(CH 2 ) d CO 2 H、(CH 2 ) d CO 2 H、(CH 2 ) d CH(CO 2 H)(NHC(S)NH)Ph(SO 2 NH 2 )、(CH 2 ) d C(CO 2 H) 2 、(CH 2 ) d B(OH) 3 、(CH 2 ) d (トリアゾール)、(CH 2 ) d (チオール)、(CH 2 ) d (チオエーテル)、(CH 2 ) d (チアゾール)、(CH 2 ) d (テトラゾール)、(CH 2 ) d (糖類)、(CH 2 ) d (ピラゾール)、(CH 2 ) d (多糖類)、(CH 2 ) d (ホスホン酸塩)、(CH 2 ) d (ホスフィン酸塩)、(CH 2 ) d (オキサゾール)、(CH 2 ) d (オリゴヌクレオチド)、(CH 2 ) d (ヌクレオチド)、(CH 2 ) d (イミダゾール)、(CH 2 ) d (ヒドロキサム酸)、(CH 2 ) d (CO 2 H) 2 、(CH 2 ) d (CHOH)(CH 2 ) d CH(NH 2 )CO 2 H、(CH 2 ) d (アジリジン)、(CH 2 ) d OH、(CH 2 ) d OCH 2 CO 2 H、(CH 2 ) d O(CH 2 ) n CH 3 、(CH 2 ) d NH 2 、(CH 2 ) d CH(NH 2 )CO 2 H、(CH 2 )(CHOH)(CH 2 ) d CH(NH 2 )CO 2 H、(CH=CH)(CH 2 ) d CH(NH 2 )CO 2 H、(C≡C)(CH 2 ) d CH(NH 2 )CO 2 Hであり、
R 81 、R 82 、R 83 、R 84 、R 85 及びR 86 が、それぞれ独立にH,F、Cl、Br、I、NO 2 、CH 3 、(CH 2 ) d CH 3 、CH 2 CH 2 OCH 2 CH 3 、CH 2 CH 2 C(O)NH 2 、CH 2 C(OCH 3 ) 2 、CH 2 (18−クラウン−6)、CH 2 (15−クラウン−5)、C(O)(CH 2 ) d (CH)(NH 2 )CO 2 H、(CH 2 CH 2 O) d CH 2 CH 3 、(CH 2 ) d Ph(SO 2 NH 2 )、(CH 2 ) d P(O)OH 2 、(CH 2 ) d OCH 2 NH 2 、(CH 2 ) d NHCH 2 NH 2 、(CH 2 ) d NHCH 2 CO 2 H、(CH 2 ) d NH 2 、(CH 2 ) d N(CH 3 ) 2 、(CH 2 ) d CO 2 H、(CH 2 ) d CO 2 H、(CH 2 ) d CH(CO 2 H)(NHC(S)NH)Ph(SO 2 NH 2 )、(CH 2 ) d C(CO 2 H) 2 、(CH 2 ) d B(OH) 3 、(CH 2 ) d (トリアゾール)、(CH 2 ) d (チオール)、(CH 2 ) d (チオエーテル)、(CH 2 ) d (チアゾール)、(CH 2 ) d (テトラゾール)、(CH 2 ) d (糖類)、(CH 2 ) d (ピラゾール)、(CH 2 ) d (多糖類)、(CH 2 ) d (ホスホン酸塩)、(CH 2 ) d (ホスフィン酸塩)、(CH 2 ) d (オキサゾール)、(CH 2 ) d (オリゴヌクレオチド)、(CH 2 ) d (ヌクレオチド)、(CH 2 ) d (イミダゾール)、(CH 2 ) d (ヒドロキサム酸)、(CH 2 ) d (CO 2 H) 2 、(CH 2 ) d (CHOH)(CH 2 ) d CH(NH 2 )CO 2 H、(CH 2 ) d (アジリジン)、(CH 2 ) d OH、(CH 2 ) d OCH 2 CO 2 H、(CH 2 ) d O(CH 2 ) n CH 3 、(CH 2 ) d NH 2 、(CH 2 ) d CH(NH 2 )CO 2 H、(CH 2 )(CHOH)(CH 2 ) d CH(NH 2 )CO 2 H、(CH=CH)(CH 2 ) d CH(NH 2 )CO 2 H、(C≡C)(CH 2 ) d CH(NH 2 )CO 2 Hであり、
dが、それぞれ独立に0〜6の範囲の整数(0と6を含む)である、
請求項1の式(V)に記載の化合物。
〔請求項18〕下式のいずれか、
式中、
R t が、H、C 1 −C 8 アルキル基、アンモニウムイオン、又はアルカリ又はアルカリ土類金属イオンであり、
R 84 が、アルキルである、
請求項1又は12の式(V)に記載の化合物。
〔請求項19〕下式のいずれか、
式中、
R t が、H、C 1 −C 8 アルキル基、アンモニウムイオン、又はアルカリ又はアルカリ土類金属イオンであり、
R 84 が、アルキルである、
請求項1又は12の式(V)に記載の化合物。
〔請求項20〕R 82 、R 83 、R 85 及びR 86 がHである、請求項19に記載の化合物。
〔請求項21〕R v が、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、イソブチル、又はtert−ブチルである、請求項20に記載の化合物。
〔請求項22〕各R t が、独立にH又はtert−ブチルである、請求項20に記載の化合物。
〔請求項23〕Yが請求項1の前記化合物のいずれか1つから誘導される、式Y−ソマトスタチンの化合物。
〔請求項24〕前記ソマトスタチンが、オクトレオチド又は3−Tyr−オクトレオチドである、請求項23に記載の化合物。
〔請求項25〕Rが−CH 2 CH 2 CH 2 CH 2 CH(NH 2 )CO 2 Hから誘導される、請求項23又は24に記載の化合物。
〔請求項26〕Yが下式のいずれかであり、
〔請求項27〕R 82 、R 83 、R 85 及びR 86 がHである、請求項26に記載の化合物。
〔請求項28〕放射性核種及び請求項1の前記化合物を含む錯体。
〔請求項29〕前記放射性核種が、テクネチウム、レニウム、コバルト、モリブデン、ルテニウム、インジウム、ルテチウム、ガリウム、イットリウム、又は鉄である、請求項28に記載の錯体。
〔請求項30〕前記放射性核種が、テクネチウム又はレニウムである、請求項29に記載の錯体。
Claims (30)
- (a)式(I)
Rは、H、アルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、チオアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アシル、アミノアシル、ヒドロキシアシル、チオアシル、−CO2H、−(CH2)d−R80、又はアミノ酸ラジカルであり、
R80は、出現毎に独立にカルボキシアルデヒド、カルボン酸塩、カルボキシアミド、アルコキシカルボニル、アリールオキシカルボニル、アンモニウム、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクリル、ポリシクリル、アミノ酸、ペプチド、糖類、リボ核酸、(デオキシ)リボ核酸、又はGタンパク質共役型受容体、オキソ還元酵素、転移酵素、加水分解酵素、リガーゼ、オソメラーゼ、リガーゼ、GPCR、直接配位子ゲートチャネル受容体、サイトカイン受容体、インテグリン受容体、チロシンキナーゼ関連受容体、核受容体、ペプチド受容体、膜貫通型受容体、転写因子、骨格細胞タンパク質、構造タンパク質又は信号タンパク質の配位子であり、
dは、0〜12の範囲の整数(0と12を含む)であり、
mは、0〜6の範囲の整数(0と6を含む)であり、
nは、0〜6の範囲の整数(0と6を含む)であり、
R70、R71、R72、R73、R74、R75、R76及びR77は、それぞれ独立に水素、ハロゲン、アルキル、アルケニル、アルキニル、ヒドロキシル、アルコキシル、アシル、アシルオキシ、アシルアミノ、シリルオキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、ニトロ、スルフヒドリル、アルキルチオ、イミノ、アミド、ホスホリル、ホスホン酸塩、ホスフィン、カルボニル、カルボキシル、カルボキシアミド、無水物、シリル、チオアルキル、アルキルスルホニル、アリールスルホニル、セレノアルキル、ケトン、アルデヒド、エステル、ヘテロアルキル、シアノ、グアニジン、アミジン、アセタール、ケタール、アミンオキシド、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アジド、アジリジン、カルバモイル、エポキシド、ヒドロキサム酸、イミド、オキシム、スルホンアミド、チオアミド、チオカルバメート、尿素、チオ尿素、又は−(CH2)d−R80であり、
但し、R70、R71、R72、又はR73のうち少なくとも1つは水素ではなく、R74、R75、R76又はR77のうち少なくとも1つは水素ではない。)、
(b)式(II)
Rは、H、アルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、チオアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アシル、アミノアシル、ヒドロキシアシル、チオアシル、−CO2H、−(CH2)d−R80、又はアミノ酸ラジカルであり、
R80は、出現毎に独立にカルボキシアルデヒド、カルボン酸塩、カルボキシアミド、アルコキシカルボニル、アリールオキシカルボニル、アンモニウム、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクリル、ポリシクリル、アミノ酸、ペプチド、糖類、リボ核酸、(デオキシ)リボ核酸、又はGタンパク質共役型受容体、オキソ還元酵素、転移酵素、加水分解酵素、リガーゼ、オソメラーゼ、リガーゼ、GPCR、直接配位子ゲートチャネル受容体、サイトカイン受容体、インテグリン受容体、チロシンキナーゼ関連受容体、核受容体、ペプチド受容体、膜貫通型受容体、転写因子、骨格細胞タンパク質、構造タンパク質又は信号タンパク質の配位子であり、
dは、0〜12の範囲の整数(0と12を含む)であり、
mは、0〜6の範囲の整数(0と6を含む)であり、
nは、0〜6の範囲の整数(0と6を含む)であり、
Zは、チオアルキル、カルボン酸塩、2−(カルボキシ)アリール、2−(カルボキシ)ヘテロアリール、2−(ヒドロキシ)アリール、2−(ヒドロキシ)ヘテロアリール、2−(チオール)アリール、又は2−(チオール)ヘテロアリールであり、
R70、R71、R72及びR73は、それぞれ独立に水素、ハロゲン、アルキル、アルケニル、アルキニル、ヒドロキシル、アルコキシル、アシル、アシルオキシ、アシルアミノ、シリルオキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、ニトロ、スルフヒドリル、アルキルチオ、イミノ、アミド、ホスホリル、ホスホン酸塩、ホスフィン、カルボニル、カルボキシル、カルボキシアミド、無水物、シリル、チオアルキル、アルキルスルホニル、アリールスルホニル、セレノアルキル、ケトン、アルデヒド、エステル、ヘテロアルキル、シアノ、グアニジン、アミジン、アセタール、ケタール、アミンオキシド、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アジド、アジリジン、カルバモイル、エポキシド、ヒドロキサム酸、イミド、オキシム、スルホンアミド、チオアミド、チオカルバメート、尿素、チオ尿素、又は−(CH2)d−R80であり、
但し、R70、R71、R72、及びR73のうち少なくとも1つは水素ではなく、R74、R75、R76及びR77のうち少なくとも1つは水素ではない。)、
(c)式(III)
Rは、H、アルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、チオアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アシル、アミノアシル、ヒドロキシアシル、チオアシル、CO2H、−(CH2)d−R80、又はアミノ酸ラジカルであり、
R80は、出現毎に独立にカルボキシアルデヒド、カルボン酸塩、カルボキシアミド、アルコキシカルボニル、アリールオキシカルボニル、アンモニウム、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクリル、ポリシクリル、アミノ酸、ペプチド、糖類、リボ核酸、(デオキシ)リボ核酸、又はGタンパク質共役型受容体、オキソ還元酵素、転移酵素、加水分解酵素、リガーゼ、オソメラーゼ、リガーゼ、GPCR、直接配位子ゲートチャネル受容体、サイトカイン受容体、インテグリン受容体、チロシンキナーゼ関連受容体、核受容体、ペプチド受容体、膜貫通型受容体、転写因子、骨格細胞タンパク質、構造タンパク質又は信号タンパク質の配位子であり、
dは、0〜12の範囲の整数(0と12を含む)であり、
mは、0〜6の範囲の整数(0と6を含む)であり、
nは、0〜6の範囲の整数(0と6を含む)であり、
Dは、下式のいずれかであり、
(d)式(IV)
Rは、H、アルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、チオアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アシル、アミノアシル、ヒドロキシアシル、チオアシル、−CO2H、−(CH2)d−R80、又はアミノ酸ラジカルであり、
R80は、出現毎に独立にカルボキシアルデヒド、カルボン酸塩、カルボキシアミド、アルコキシカルボニル、アリールオキシカルボニル、アンモニウム、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクリル、ポリシクリル、アミノ酸、ペプチド、糖類、リボ核酸、(デオキシ)リボ核酸、又はGタンパク質共役型受容体、オキソ還元酵素、転移酵素、加水分解酵素、リガーゼ、オソメラーゼ、リガーゼ、GPCR、直接配位子ゲートチャネル受容体、サイトカイン受容体、インテグリン受容体、チロシンキナーゼ関連受容体、核受容体、ペプチド受容体、膜貫通型受容体、転写因子、骨格細胞タンパク質、構造タンパク質又は信号タンパク質の配位子であり、
dは、0〜12の範囲の整数(0と12を含む)であり、
mは、0〜6の範囲の整数(0と6を含む)であり、
nは、0〜6の範囲の整数(0と6を含む)であり、
Zは、チオアルキル、カルボン酸塩、2−(カルボキシ)アリール、2−(カルボキシ)ヘテロアリール、2−(ヒドロキシ)アリール、2−(ヒドロキシ)ヘテロアリール、2−(チオール)アリール又は2−(チオール)ヘテロアリールであり、
Dは、下式のいずれかであり、
(e)式(V)
Rは、H、又は置換又は非置換アルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、チオアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アシル、アミノアシル、ヒドロキシアシル、チオアシル、アルキルケト、アミノアルコキシアルキル、ボラートアルキル、ホスホン酸アルキル、ホスフィン酸アルキル、(CH2)4CH(NH2)CO2H、(CH2)3CH(NH2)CO2H、(CH2)2CH(NH2)CO2H、C(O)CH2(CH)NH2CO2H、C(O)(CH2)2(CH)NH2CO2H、(CC)(CH2)2CH(NH2)CO2H、(CHCH)(CH2)2CHNH2CO2H、(CH2)2(CHOH)(CH2)CHNH2CO2H又は(CH2)(CHOH)(CH2)2CHNH2CO2H、(CO2H)2、−CO2H、−(CH2)d−R80、−C(O)(CH2)d−R80、又はアミノ酸ラジカルであり、
R80は、発現毎に独立にカルボキシアルデヒド、カルボン酸塩、カルボキシアミド、アルコキシカルボニル、アリールオキシカルボニル、アンモニウム、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクリル、ポリシクリル、アミノ酸、CH2CH2OCH2CH3、CH2C(OCH3)2、(CH2CH2O)dCH2CH3、(CH2)dNH2、CH2CH2C(O)NH2、(CH2)dN(CH3)2、CH2CH2OH、(CH2)dC(CO2H)2、(CH2)dP(O)(OH)2、(CH2)dB(OH)2、ペプチド、糖類、リボ核酸、(デオキシ)リボ核酸、又はGタンパク質共役型受容体、オキソ還元酵素、転移酵素、加水分解酵素、リガーゼ、オソメラーゼ、リガーゼ、GPCR、直接配位子ゲートチャネル受容体、サイトカイン受容体、インテグリン受容体、チロシンキナーゼ関連受容体、核受容体、ペプチド受容体、膜貫通型受容体、転写因子、骨格細胞タンパク質、構造タンパク質又は信号タンパク質の配位子であり、
dは、0〜12の範囲の整数(0と12を含む)であり、
mは、0〜6の範囲の整数(0と6を含む)であり、
nは、0〜6の範囲の整数(0と6を含む)であり、
R81、R82、R83、R84、R85及びR86は、それぞれ独立に水素、ハロゲン、又は置換又は非置換アルキル、アルケニル、アルキニル、ヒドロキシル、アルコキシル、アシル、アシルオキシ、アシルアミノ、シリルオキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、ニトロ、スルフヒドリル、アルキルチオ、イミノ、アミド、ホスホリル、ホスホン酸塩、ホスフィン、カルボニル、カルボキシル、カルボキシアミド、無水物、シリル、チオアルキル、アルキルスルホニル、アリールスルホニル、セレノアルキル、ケトン、アルデヒド、エーテル、エステル、ヘテロアルキル、シアノ、グアニジン、アミジン、アセタール、ケタール、アミンオキシド、アリール、ヘテロアリール、アラルキル、アリールエーテル、ヘテロアラルキル、アジド、アジリジン、カルバモイル、エポキシド、ヒドロキサム酸、イミド、オキシム、スルホンアミド、チオアミド、チオカルバメート、尿素、チオ尿素、−(CH2)d−R80、(CH2)d(CO2H)2、CH2CH2OCH2CH3、CH2C(OCH3)2、(CH2CH2O)dCH2CH3、(CH2)dNH2、CH2CH2C(O)NH2、(CH2)dN(CH3)2、CH2CH2OH、(CH2)nC(CO2H)2、(CH2)dP(O)(OH)2、(CH2)dB(OH)2、−(CH2)d−R80、(CH2)dR87又は−(CH2)d−R88であり、
R87及びR88は、それぞれ独立に15−クラウン−5、18−クラウン−6、テトラゾール、オキサゾール、アジリジン、トリアゾール、イミダゾール、ピラゾール、チアゾール、ヒドロキサム酸、ホスホン酸塩、ホスフィン酸塩、チオール、チオエーテル、多糖類、糖類、ヌクレオチド又はオリゴヌクレオチドである。)又は
(f)式(VI)
Rは、H、アルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、チオアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アシル、アミノアシル、ヒドロキシアシル、チオアシル、アルキルケト、アミノアルコキシルアルキル、ボラートアルキル、ホスホン酸アルキル、ホスフィン酸アルキル、(CH2)4CH(NH2)CO2H、(CH2)3CH(NH2)CO2H、(CH2)2CH(NH2)CO2H、C(O)CH2(CH)NH2CO2H、C(O)(CH2)2(CH)NH2CO2H、(CC)(CH2)2CH(NH2)CO2H、(CHCH)(CH2)2CHNH2CO2H、(CH2)2(CHOH)(CH2)CHNH2CO2H又は(CH2)(CHOH)(CH2)2CHNH2CO2H、(CO2H)2、−CO2H、−(CH2)d−R80、−C(O)(CH2)d−R80又はアミノ酸ラジカルであり、
R80は、出現毎に独立にカルボキシアルデヒド、カルボン酸塩、カルボキシアミド、アルコキシカルボニル、アリールオキシカルボニル、アンモニウム、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロシクリル、ポリシクリル、アミノ酸、CH2CH2OCH2CH3、CH2C(OCH3)2、(CH2CH2O)dCH2CH3、(CH2)dNH2、CH2CH2C(O)NH2、(CH2)dN(CH3)2、CH2CH2OH、(CH2)dC(CO2H)2、(CH2)dP(O)(OH)2、(CH2)dB(OH)2、ペプチド、糖類、リボ核酸、(デオキシ)リボ核酸、又はGタンパク質共役型受容体、オキソ還元酵素、転移酵素、加水分解酵素、リガーゼ、オソメラーゼ、リガーゼ、GPCR、直接配位子ゲートチャネル受容体、サイトカイン受容体、インテグリン受容体、チロシンキナーゼ関連受容体、核受容体、ペプチド受容体、膜貫通型受容体、転写因子、骨格細胞タンパク質、構造タンパク質又は信号タンパク質の配位子であり、
dは、0〜12の範囲の整数(0と12を含む)であり、
mは、0〜6の範囲の整数(0と6を含む)であり、
nは、0〜6の範囲の整数(0と6を含む)であり、
Zは、置換又は非置換チオアルキル、カルボン酸塩、カルボキシアルキル、アミノアルキル、ヘテロシクリル、(アミノ酸)、(アミノ酸)アルキル、ヒドロキシ、ヒドロキシアルキル、2−(カルボキシ)アリール、2−(カルボキシ)ヘテロアリール、2−(ヒドロキシ)アリール、2−(ヒドロキシ)ヘテロアリール、2−(チオール)アリール、2−ピロリジンボロン酸又は2−(チオール)ヘテロアリールであり、
R81、R82及びR83は、それぞれ独立に水素、ハロゲン、アルキル、アルケニル、アルキニル、ヒドロキシル、アルコキシル、アシル、アシルオキシ、アシルアミノ、シリルオキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、ニトロ、スルフヒドリル、アルキルチオ、イミノ、アミド、ホスホリル、ホスホン酸塩、ホスフィン、カルボニル、カルボキシル、カルボキシアミド、無水物、シリル、チオアルキル、アルキルスルホニル、アリールスルホニル、セレノアルキル、ケトン、アルデヒド、エーテル、エステル、ヘテロアルキル、シアノ、グアニジン、アミジン、アセタール、ケタール、アミンオキシド、アリール、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、アラルキル、アリールエーテル、ヘテロアラルキル、アジド、アジリジン、カルバモイル、エポキシド、ヒドロキサム酸、イミド、オキシム、スルホンアミド、チオアミド、チオカルバメート、尿素、チオ尿素、−(CH2)d−R80、(CH2)d(CO2H)2、CH2CH2OCH2CH3、CH2C(OCH3)2、(CH2CH2O)dCH2CH3、(CH2)dNH2、CH2CH2C(O)NH2、(CH2)dN(CH3)2、CH2CH2OH、(CH2)dC(CO2H)2、(CH2)dP(O)(OH)2、(CH2)dB(OH)2、−(CH2)d−R80、(CH2)dR87又は−(CH2)dR88であり、
R87及びR88は、それぞれ独立にヘテロアリール、ヘテロシクリル、15−クラウン−5、18−クラウン−6、テトラゾール、オキサゾール、アジリジン、トリアゾール、イミダゾール、ピラゾール、チアゾール、ヒドロキサム酸、ホスホン酸塩、ホスフィン酸塩、チオール、チオエーテル、多糖類、糖類、ヌクレオチド又はオリゴヌクレオチドである。)
で表される化合物。 - 式(I)又は(III)において、mが1であり、nが1である、請求項1に記載の化合物。
- 式(II)、(IV)又は(VI)において、Zがカルボン酸塩である、請求項1に記載の化合物。
- Zがカルボン酸塩であり、mが1であり、nが1である、請求項3に記載の化合物。
- 式(I)において、R70、R71、R72又はR73のうち少なくとも1つがアミノであり、R74、R75、R76又はR77のうち少なくとも1つがアミノ基である、請求項1に記載の化合物。
- 前記アミノ基が−N(R90)2である、請求項5に記載の化合物。
- 前記アミノ基が−N(CH3)2である、請求項5に記載の化合物。
- 式(I)、(II)、(III)、(IV)又は(VI)において、Rが−(CH2)d−R80である、請求項1に記載の化合物。
- 前記式(I)又は(III)において、mが1であり、nが1であり、Rが−(CH2)d−R80である、請求項1に記載の化合物。
- 式(I)、(III)又は(V)において、Rがアミノ酸ラジカルである、請求項1に記載の化合物。
- 前記アミノ酸ラジカルが、
−CH2CH2CH2CH2CH(NH2)CO2H、
−CH(CO2H)CH2CH2CH2CH2NH2、
−CH2CH2CH2CO2H、
−CH2(CH2)xCO2H、
−CH2(CH2)xCH(NH2)CO2H、又は
−CH(CO2H)(CH2)xCH(NH2)CO2Hであり、
xが3〜9の整数(3と9を含む)である、
請求項11に記載の化合物。 - R81、R82又はR83のうち少なくとも1つが親水基であるか、又はR84、R85又はR86のうち少なくとも1つが親水基であるか、又はR81、R82又はR83のうち少なくとも1つ及びR84、R85又はのうち少なくとも1つが親水基である、請求項1の式(V)に記載の化合物。
- 各親水基が、個々にエーテル、アルコキシアラルキル、カルボン酸塩、アルコール又はアミドである、請求項13に記載の化合物。
- R81、R82又はR83のうち少なくとも1つが親水基である、請求項1の式(VI)に記載の化合物。
- 各親水基が、独立にエーテル、アルコキシアラルキル、カルボン酸塩、アルコール又はアミドである、請求項13に記載の化合物。
- Rが、H、CH3、(CH2)dCH3、CH2CH2OCH2CH3、CH2CH2C(O)NH2、CH2C(OCH3)2、CH2(18−クラウン−6)、CH2(15−クラウン−5)、C(O)(CH2)d(CH)(NH2)CO2H、(CH2CH2O)dCH2CH3、(CH2)dPh(SO2NH2)、(CH2)dP(O)OH2、(CH2)dOCH2NH2、(CH2)dNHCH2NH2、(CH2)dNHCH2CO2H、(CH2)dNH2、(CH2)dN(CH3)2、(CH2)dCO2H、(CH2)dCO2H、(CH2)dCH(CO2H)(NHC(S)NH)Ph(SO2NH2)、(CH2)dC(CO2H)2、(CH2)dB(OH)3、(CH2)d(トリアゾール)、(CH2)d(チオール)、(CH2)d(チオエーテル)、(CH2)d(チアゾール)、(CH2)d(テトラゾール)、(CH2)d(糖類)、(CH2)d(ピラゾール)、(CH2)d(多糖類)、(CH2)d(ホスホン酸塩)、(CH2)d(ホスフィン酸塩)、(CH2)d(オキサゾール)、(CH2)d(オリゴヌクレオチド)、(CH2)d(ヌクレオチド)、(CH2)d(イミダゾール)、(CH2)d(ヒドロキサム酸)、(CH2)d(CO2H)2、(CH2)d(CHOH)(CH2)dCH(NH2)CO2H、(CH2)d(アジリジン)、(CH2)dOH、(CH2)dOCH2CO2H、(CH2)dO(CH2)nCH3、(CH2)dNH2、(CH2)dCH(NH2)CO2H、(CH2)(CHOH)(CH2)dCH(NH2)CO2H、(CH=CH)(CH2)dCH(NH2)CO2H、(C≡C)(CH2)dCH(NH2)CO2Hであり、
R81、R82、R83、R84、R85及びR86が、それぞれ独立にH,F、Cl、Br、I、NO2、CH3、(CH2)dCH3、CH2CH2OCH2CH3、CH2CH2C(O)NH2、CH2C(OCH3)2、CH2(18−クラウン−6)、CH2(15−クラウン−5)、C(O)(CH2)d(CH)(NH2)CO2H、(CH2CH2O)dCH2CH3、(CH2)dPh(SO2NH2)、(CH2)dP(O)OH2、(CH2)dOCH2NH2、(CH2)dNHCH2NH2、(CH2)dNHCH2CO2H、(CH2)dNH2、(CH2)dN(CH3)2、(CH2)dCO2H、(CH2)dCO2H、(CH2)dCH(CO2H)(NHC(S)NH)Ph(SO2NH2)、(CH2)dC(CO2H)2、(CH2)dB(OH)3、(CH2)d(トリアゾール)、(CH2)d(チオール)、(CH2)d(チオエーテル)、(CH2)d(チアゾール)、(CH2)d(テトラゾール)、(CH2)d(糖類)、(CH2)d(ピラゾール)、(CH2)d(多糖類)、(CH2)d(ホスホン酸塩)、(CH2)d(ホスフィン酸塩)、(CH2)d(オキサゾール)、(CH2)d(オリゴヌクレオチド)、(CH2)d(ヌクレオチド)、(CH2)d(イミダゾール)、(CH2)d(ヒドロキサム酸)、(CH2)d(CO2H)2、(CH2)d(CHOH)(CH2)dCH(NH2)CO2H、(CH2)d(アジリジン)、(CH2)dOH、(CH2)dOCH2CO2H、(CH2)dO(CH2)nCH3、(CH2)dNH2、(CH2)dCH(NH2)CO2H、(CH2)(CHOH)(CH2)dCH(NH2)CO2H、(CH=CH)(CH2)dCH(NH2)CO2H、(C≡C)(CH2)dCH(NH2)CO2Hであり、
dが、それぞれ独立に0〜6の範囲の整数(0と6を含む)である、
請求項1の式(V)に記載の化合物。 - R82、R83、R85及びR86がHである、請求項19に記載の化合物。
- Rvが、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、イソブチル、又はtert−ブチルである、請求項20に記載の化合物。
- 各Rtが、独立にH又はtert−ブチルである、請求項20に記載の化合物。
- Yが請求項1の前記化合物のいずれか1つから誘導される、式Y−ソマトスタチンの化合物。
- 前記ソマトスタチンが、オクトレオチド又は3−Tyr−オクトレオチドである、請求項23に記載の化合物。
- Rが−CH2CH2CH2CH2CH(NH2)CO2Hから誘導される、請求項23又は24に記載の化合物。
- R82、R83、R85及びR86がHである、請求項26に記載の化合物。
- 放射性核種及び請求項1の前記化合物を含む錯体。
- 前記放射性核種が、テクネチウム、レニウム、コバルト、モリブデン、ルテニウム、インジウム、ルテチウム、ガリウム、イットリウム、又は鉄である、請求項28に記載の錯体。
- 前記放射性核種が、テクネチウム又はレニウムである、請求項29に記載の錯体。
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