JP5122964B2 - 新規テクネチウム及びレニウム錯体 - Google Patents
新規テクネチウム及びレニウム錯体 Download PDFInfo
- Publication number
- JP5122964B2 JP5122964B2 JP2007534091A JP2007534091A JP5122964B2 JP 5122964 B2 JP5122964 B2 JP 5122964B2 JP 2007534091 A JP2007534091 A JP 2007534091A JP 2007534091 A JP2007534091 A JP 2007534091A JP 5122964 B2 JP5122964 B2 JP 5122964B2
- Authority
- JP
- Japan
- Prior art keywords
- ligand
- formula
- complexes
- technetium
- metal
- 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.)
- Expired - Fee Related
Links
- 229910052713 technetium Inorganic materials 0.000 title claims abstract description 25
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 150000003281 rhenium Chemical class 0.000 title abstract description 5
- 239000003446 ligand Substances 0.000 claims abstract description 68
- 229910052751 metal Inorganic materials 0.000 claims description 28
- 239000002184 metal Substances 0.000 claims description 28
- 150000004696 coordination complex Chemical class 0.000 claims description 23
- 229910052702 rhenium Inorganic materials 0.000 claims description 14
- -1 2 -piperidinyl Chemical group 0.000 claims description 11
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 claims description 9
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 150000002527 isonitriles Chemical class 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 239000012217 radiopharmaceutical Substances 0.000 abstract description 26
- 229940121896 radiopharmaceutical Drugs 0.000 abstract description 25
- 230000002799 radiopharmaceutical effect Effects 0.000 abstract description 25
- 239000000203 mixture Substances 0.000 abstract description 17
- 230000002285 radioactive effect Effects 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 238000002360 preparation method Methods 0.000 abstract description 9
- 238000003384 imaging method Methods 0.000 abstract description 3
- 238000002603 single-photon emission computed tomography Methods 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 108090000765 processed proteins & peptides Proteins 0.000 description 19
- 239000000243 solution Substances 0.000 description 16
- 150000001413 amino acids Chemical class 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 235000001014 amino acid Nutrition 0.000 description 11
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 10
- 230000001588 bifunctional effect Effects 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000002202 Polyethylene glycol Substances 0.000 description 7
- 239000002738 chelating agent Substances 0.000 description 7
- 238000001819 mass spectrum Methods 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 239000012634 fragment Substances 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 125000005647 linker group Chemical group 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 4
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 4
- 101800000733 Angiotensin-2 Proteins 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 4
- 239000013522 chelant Substances 0.000 description 4
- 238000010668 complexation reaction Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 230000002335 preservative effect Effects 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102400000345 Angiotensin-2 Human genes 0.000 description 3
- 102000011632 Caseins Human genes 0.000 description 3
- 108010076119 Caseins Proteins 0.000 description 3
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000016359 Fibronectins Human genes 0.000 description 3
- 108010067306 Fibronectins Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 229950006323 angiotensin ii Drugs 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 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
- 239000002872 contrast media Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 229940050410 gluconate Drugs 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000009206 nuclear medicine Methods 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 150000003003 phosphines Chemical class 0.000 description 3
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YXTDAZMTQFUZHK-ZVGUSBNCSA-L (2r,3r)-2,3-dihydroxybutanedioate;tin(2+) Chemical compound [Sn+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O YXTDAZMTQFUZHK-ZVGUSBNCSA-L 0.000 description 2
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 108010069514 Cyclic Peptides Proteins 0.000 description 2
- 102000001189 Cyclic Peptides Human genes 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 101100208721 Mus musculus Usp5 gene Proteins 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 102000004211 Platelet factor 4 Human genes 0.000 description 2
- 108090000778 Platelet factor 4 Proteins 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 102000002938 Thrombospondin Human genes 0.000 description 2
- 108060008245 Thrombospondin Proteins 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 238000010976 amide bond formation reaction Methods 0.000 description 2
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000005018 casein Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 125000002993 cycloalkylene group Chemical group 0.000 description 2
- 238000002059 diagnostic imaging Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 150000003949 imides Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- MBKDYNNUVRNNRF-UHFFFAOYSA-N medronic acid Chemical compound OP(O)(=O)CP(O)(O)=O MBKDYNNUVRNNRF-UHFFFAOYSA-N 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 229960003742 phenol Drugs 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229940071643 prefilled syringe Drugs 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000000718 radiation-protective agent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 235000021247 β-casein Nutrition 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- XQQUSYWGKLRJRA-RABCQHRBSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-6-amino-2-[[(2s,3s)-2-amino-3-methylpentanoyl]amino]hexanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-3-methylbutanoic acid Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O XQQUSYWGKLRJRA-RABCQHRBSA-N 0.000 description 1
- MWOGMBZGFFZBMK-LJZWMIMPSA-N (2s)-2-[[(2s)-2-[[2-[[(2s,3s)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MWOGMBZGFFZBMK-LJZWMIMPSA-N 0.000 description 1
- 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 description 1
- LJJFNFYPZOHRHM-UHFFFAOYSA-N 1-isocyano-2-methoxy-2-methylpropane Chemical compound COC(C)(C)C[N+]#[C-] LJJFNFYPZOHRHM-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 description 1
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 1
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical class OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 1
- 150000003923 2,5-pyrrolediones Chemical class 0.000 description 1
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 1
- GNTIRRQEPHPUCI-UHFFFAOYSA-N 2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethylamino]-2-oxoethoxy]acetic acid Chemical compound NCCOCCOCCOCCNC(=O)COCC(O)=O GNTIRRQEPHPUCI-UHFFFAOYSA-N 0.000 description 1
- ZVUNAQTWOGAJRE-UHFFFAOYSA-N 2-[[1-[2-[[2-[[2-[[2-[[5-(diaminomethylideneamino)-2-[[2-(methylamino)acetyl]amino]pentanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylpentanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylpe Chemical compound CCC(C)C(C(O)=O)NC(=O)C1CCCN1C(=O)C(NC(=O)C(NC(=O)C(CC=1C=CC(O)=CC=1)NC(=O)C(NC(=O)C(CCCN=C(N)N)NC(=O)CNC)C(C)C)C(C)CC)CC1=CN=CN1 ZVUNAQTWOGAJRE-UHFFFAOYSA-N 0.000 description 1
- AOYNUTHNTBLRMT-SLPGGIOYSA-N 2-deoxy-2-fluoro-aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](F)C=O AOYNUTHNTBLRMT-SLPGGIOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- NYYSPVRERVXMLJ-UHFFFAOYSA-N 4,4-difluorocyclohexan-1-one Chemical compound FC1(F)CCC(=O)CC1 NYYSPVRERVXMLJ-UHFFFAOYSA-N 0.000 description 1
- BWRRWBIBNBVHQF-UHFFFAOYSA-N 4-(3-pyridin-2-yl-1,2,4-oxadiazol-5-yl)butanoic acid Chemical compound O1C(CCCC(=O)O)=NC(C=2N=CC=CC=2)=N1 BWRRWBIBNBVHQF-UHFFFAOYSA-N 0.000 description 1
- ROMPPAWVATWIKR-UHFFFAOYSA-N 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]butanoic acid Chemical compound O1C(CCCC(=O)O)=NC(C=2C=CC(Cl)=CC=2)=N1 ROMPPAWVATWIKR-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical group OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010031480 Artificial Receptors Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 101000702579 Crotalus durissus terrificus Snaclec crotocetin Proteins 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 108010002156 Depsipeptides Proteins 0.000 description 1
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 description 1
- 102000006441 Dopamine Plasma Membrane Transport Proteins Human genes 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical class ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000016387 Pancreatic elastase Human genes 0.000 description 1
- 108010067372 Pancreatic elastase Proteins 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- UZMAPBJVXOGOFT-UHFFFAOYSA-N Syringetin Natural products COC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UZMAPBJVXOGOFT-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000007614 Thrombospondin 1 Human genes 0.000 description 1
- 108010046722 Thrombospondin 1 Proteins 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical group [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 239000007997 Tricine buffer Substances 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- OEWPQSWDAXMHQG-UHFFFAOYSA-N [Tc+] Chemical compound [Tc+] OEWPQSWDAXMHQG-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 description 1
- 125000005333 aroyloxy group Chemical group 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 229940067596 butylparaben Drugs 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 229960002798 cetrimide Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 229940013361 cresol Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000004474 heteroalkylene group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 108010088381 isoleucyl-lysyl-valyl-alanyl-valine Proteins 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical group CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 1
- 229940031826 phenolate Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 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
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000004713 phosphodiesters Chemical class 0.000 description 1
- RDAVTSRGGPISMI-UHFFFAOYSA-N piperidin-1-yl acetate;hydrochloride Chemical compound Cl.CC(=O)ON1CCCCC1 RDAVTSRGGPISMI-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- PCTGJJZEWJRHFL-UHFFFAOYSA-N pyridin-3-yl acetate;hydrochloride Chemical compound Cl.CC(=O)OC1=CC=CN=C1 PCTGJJZEWJRHFL-UHFFFAOYSA-N 0.000 description 1
- OZWSIJLDYKHDND-UHFFFAOYSA-N pyridin-4-yl acetate;hydrochloride Chemical compound Cl.CC(=O)OC1=CC=NC=C1 OZWSIJLDYKHDND-UHFFFAOYSA-N 0.000 description 1
- 238000003608 radiolysis reaction Methods 0.000 description 1
- 230000003537 radioprotector Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 235000004400 serine Nutrition 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 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 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 229940007163 stannous tartrate Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- DIORMHZUUKOISG-UHFFFAOYSA-N sulfoformic acid Chemical compound OC(=O)S(O)(=O)=O DIORMHZUUKOISG-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003495 technetium Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 229960004906 thiomersal Drugs 0.000 description 1
- 229910001432 tin ion Inorganic materials 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- YUOWTJMRMWQJDA-UHFFFAOYSA-J tin(iv) fluoride Chemical compound [F-].[F-].[F-].[F-].[Sn+4] YUOWTJMRMWQJDA-UHFFFAOYSA-J 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 238000006478 transmetalation reaction Methods 0.000 description 1
- BOOZMUQOMHKQCS-UHFFFAOYSA-N tripyridin-2-ylmethanamine Chemical compound C=1C=CC=NC=1C(C=1N=CC=CC=1)(N)C1=CC=CC=N1 BOOZMUQOMHKQCS-UHFFFAOYSA-N 0.000 description 1
- XLRPYZSEQKXZAA-OCAPTIKFSA-N tropane Chemical compound C1CC[C@H]2CC[C@@H]1N2C XLRPYZSEQKXZAA-OCAPTIKFSA-N 0.000 description 1
- 229930004006 tropane Natural products 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 108010052768 tyrosyl-isoleucyl-glycyl-seryl-arginine Proteins 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
Classifications
-
- 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
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
-
- 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
- A61K51/0476—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 complexes from monodendate ligands, e.g. sestamibi
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Physics & Mathematics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Alberto et al, J.Am.Chem.Soc.120 pp7987−8(1998) Kothari et al, Appl.Rad.Isot.58 p543−9(2003) Arnold et al, JCS Dalton Trans.pp736−46(2001)
R1はE基又は−CH2(AR5)であり(AはS又はOであり、R5はH又はC1〜6アルキルである。)、
R2及びR3は各々独立にE基であり、
Eは適宜置換C3〜10窒素含有ヘテロアリール環であり、
R4は−(Z)q−Yであり
(式中、各Zは独立に、−CQ2−、−CQ=CQ−、−C≡C−、−CQ2CO2−、−CO2CQ2−、−NQ−、−NQCO−、−CONQ−、−NQ(C=O)NQ−、−NQ(C=S)NQ−、−SO2NQ−、−NQSO2−、−CQ2OCQ2−、−CQ2SCQ2−、−CQ2(NQ)CQ2−、C4〜8シクロヘテロアルキレン基、C4〜8シクロアルキレン基、C5〜12アリーレン基又はC3〜12ヘテロアリーレン基、アミノ酸若しくは単分散ポリエチレングリコール(PEG)構成ブロックであり、但し、各Qは独立に、H、C1〜4アルキル、C2〜4アルケニル、C2〜4アルキニル、C1〜4アルコキシアルキル又はC1〜4ヒドロキシアルキルから選択され、
qは0〜10の値の整数であり、
YはH、アミノ、C1〜10アルキル、C3〜20アルキルアリール、C6〜14アリール、C3〜12複素環、C2〜10アルコキシアルキル、C1〜10ヒドロキシアルキル、C1〜10アミノアルキル、C1〜10ヒドロキシアルキル、C1〜10アルコキシ、C1〜10アシルオキシ、C6〜10アリールオキシ又はC6〜10アロイルオキシであるか、或いはYは生体ターゲティング部分である。)、
上記金属がテクネチウム又はレニウムの放射性同位体であり、上記リガンドの5つの可能な原子のうちの3つ以下が錯化に関与する。
・ソマトスタチン、オクトレオチド及び類似体。
・ST受容体に結合するペプチド。ここで、STとは大腸菌その他の微生物の産生する熱安定性毒素をいう。
・ラミニン断片、例えばYIGSR、PDSGR、IKVAV、LRE及びKCQAGTFALRGDPQG。
・白血球集積のターゲティング部位用のN−ホルミルペプチド。
・血小板因子4(PF4)及びその断片。
・RGD(Arg−Gly−Asp)含有ペプチド。これは例えば血管新生をターゲティングし得る(R.Pasqualini et al., Nat Biotechnol.1997 Jun;15(6):542−6;E.Ruoslahti, Kidney Int. 1997 May;51(5):1413−7)。
・α2−抗プラスミン若しくはフィブロネクチン若しくはβ−カゼイン、フィブリノーゲン又はトロンボスポンジンのペプチド断片。α2−抗プラスミン、フィブロネクチン、β−カゼイン、フィブリノーゲン及びトロンボスポンジンのアミノ酸配列は以下の引用文献に記載されている:α2−抗プラスミン前駆体(M.Tone et al., J. Biochem,102,1033,(1987));β−カゼイン(L.Hansson et al, Gene,139,193,(1994));フィブロネクチン(A.Gutman et al, FEBS Lett.,207,145,(1996));トロンボスポンジン−1前駆体(V.Dixit et al, Proc. Natl. Acad. Sci.,USA,83,5449,(1986));R.F.Doolittle, Ann. Rev. Biochem.,53,195,(1984)。
・アンジオテンシンII:Asp−Arg−Val−Tyr−Ile−His−Pro−Phe(E.C.Jorgensen et al, J. Med. Chem.,1979,Vol 22,9,1038−1044)、[Sar,Ile]アンジオテンシンII:Sar−Arg−Val−Tyr−Ile−His−Pro−Ile(R.K.Turker et al, Science,1972,177,1203)のようなアンジオテンシンの基質又は阻害剤であるペプチド。
・アンジオテンシンI:Asp−Arg−Val−Tyr−Ile−His−Pro−Phe−His−Leu。
(i)α2−抗プラスミン
NH2−Asn−Gln−Glu−Gln−Val−Ser−Pro−Leu−Thr−Leu−Thr−Leu−Leu−Lys−OH、又はその変異体で1以上のアミノ酸が交換、付加又は除去されたもの、例えば、
NH2−Asn−Gln−Glu−Gln−Val−Ser−Pro−Leu−Thr−Leu−Thr−Leu−Leu−Lys−Gly−OH、
NH2−Asn−Gln−Glu−Ala−Val−Ser−Pro−Leu−Thr−Leu−Thr−Leu−Leu−Lys−Gly−OH、
NH2−Asn−Gln−Glu−Gln−Val−Gly−OHなど、或いは
(ii)カゼイン
Ac−Leu−Gly−Pro−Gly−Gln−Ser−Lys−Val−Ile−Gly。
式中、Lは第1の実施形態で定義した式Iのリガンドであり、
Mはテクネチウム又はレニウムの放射性同位体であり、
XはCO、ハロゲン、ホスフィン又はイソニトリルから選択され、
nは金属錯体の電荷であり、−1、0、+1又は+2であってよい。
式中、Mは式IIの定義と同様であり、
Lは上記定義と同様の式Iのリガンドであり、
但し、R1はE基又は−CH2(AR5)(R5はC1〜6アルキルである。)であり、
R4はアミノ又は−(Z)q−Y(Z、q及びYは請求項1で定義した通りである。)であり、
nは+1又は+2である。
式中、Mは式IIの定義と同様であり、
LはR1が−CH2SH又は−CH2OHである式Iのリガンドであり、
R2、R3及びR4は式Iで定義した通りである。
リガンド1[すなわち1,1,1−トリス(ピリジン−2−イル)メチルアミン]をArnold et al[JCS Dalton Trans.,736−746(2001)]の方法で調製した。
無水安息香酸(280mg、1.24ミリモル)を、CH2Cl2(2ml)中のリガンド1(250mg0.95ミリモル)の撹拌溶液に、室温で一括して加えた。撹拌を24時間続行し、反応混合物をCH2Cl2(18ml)で希釈した。この溶液を飽和重炭酸ナトリウム液(20ml×2)及び水(20ml×2)で洗浄し、次いで脱水し(MgSO4)、ろ過し、溶媒を蒸発させて黄色残留物を得た。この材料を、CH2Cl2/ペンタン混合液から再結晶化させて生成物(180mg、52%)を黄色粉末、mp233〜234℃として得た。
1H NMR(CDCl3):δH 7.10〜7.17(3H,m,5−H)、7.41〜7.51(3H,m,4−H)、7.59〜7.64(6H,m,3−H[x2],メタ−H[x2],パラ−H)、8.0(2H,dd,J=7及び2Hz,オルト−H[x2])、8.53(3H,br d,J=5Hz,6−H[x3])。
質量スペクトル(ES)m/e:C23H19N4O(M+H)の計算値:367 実測値:367
実施例2: リガンド3及び4の合成
塩化チオニル(5.0g、42ミリモル)とニコチン酸(620mg、5.0ミリモル)を還流下で3時間加熱し、次いで過剰の試薬を減圧下で除去して白色残留物を得た。この残留物を、減圧下でトルエン(25ml×2)と共蒸発させて白色粉末を得た。得られた固体を50mgに分割して、トリエチルアミン(1.10g、10.0ミリモル)を含むCH2Cl2(10ml)中のリガンド1(250mg、0.95ミリモル)の溶液に撹拌しながら加えた。室温で16時間撹拌した後、溶液を水(20ml×2)で洗浄し、脱水し(MgSO4)、ろ過し、溶媒を減圧下で除去して暗褐色の残留物を得た。この残留物を、シリカゲルを用いたクロマトグラフィーにより、CH2Cl2/MeOH混合液(20:1)で溶出させて精製した。所要の生成物を黄色固体(rf=0.25)として単離し、これをCH2Cl2/ペンタンから再結晶化して淡黄色粉末(収量210mg、60.0%)、mp206〜207℃を得た。
1H NMR(CDCl3):δH 7.14(3H,dt,J=5.0及び2.7Hz,5−H[x3],7.35(1H,dd,J=8.0及び5.0Hz,5’−H)、7.58〜7.61(3H,m 4−H[x3])、7.62(3H,dt,J=8.2及び1.5Hz,3−H[x3])、8.23(1H,dt,J=8.0及び2.0Hz,4’−H)、8.51(3H,br d,J=5Hz,6−H[x3])、8.71(1H,dd,J=5.0及び1.5Hz,6’−H)、9.25(1H,d,J=2.0Hz,2’−H)、10.4(1H,s,NH)。
質量スペクトル(ES)m/e:C22H18N5O(M+H)の計算値:368 実測値:368
リガンド4を出発材料として、同様の方法で、イソニコチン酸から調製して淡黄色粉末(140mg、40.0%)、mp183〜185℃を得た。
1H NMR(CDCl3):δH 7.15(3H,dt,J=5.0及び1.5Hz,5−H[x3],7.57〜7.66(6H,m 4−H[x3],3−H[x3],7.80(2H,d,J=5,9Hz,2’−H,6’−H)8.51(3H,d,J=5Hz,6−H[x3],8.74(2H,d,J=5.9Hz,3’−H,5’−H)、10.45(1H,bs,NH)。
質量スペクトル(ES)m/e:C22H18N5O(M+H)の計算値:368 実測値:368。
段階(a):エチル2−(ピペリジン−1−イル)−アセテート
ブロモ酢酸エチル(8.5g、50.9ミリモル)を、クロロホルム(20ml)中のピペリジン(4.3g、50.5ミリモル)とトリエチルアミン(5.5g、54.4ミリモル)の撹拌溶液に、弱い還流が維持される速度で滴下した。添加が完了したら撹拌を2時間続行し、反応混合物を水(20ml×3)で洗浄した。クロロホルム層を脱水し(MgSO4)、ろ過し、溶媒を蒸発させて黄色のオイル状物を得た。このオイル状物を、シリカの短いカラムにCH2Cl2/石油エーテル(Pet Ether)40:60混合液(1:1)で溶出させて通過させた。得られた溶液から溶媒を除去して所要の生成物を淡黄色オイル状物(収量5.5g、64%)として得た。
1H NMR(CDCl3):−δH 1.20(3H,t,J=7.0Hz,CH3)、1.40(2H,m,4’−H)、1.55(4H,m,3’−H 5’−H)、2,42(4H,m,2’−H 6’−H)、3.10(2H,s,NCH2CO)4.10(2H,q,J=7Hz,OCH2)。
エチル2−(ピペリジン−1−イル)−アセテート(5.5g、32.2ミリモル)、水(12ml)及びcHCl(3ml)を還流下で20時間加熱した。揮発性成分を減圧下で蒸発させて灰白色の固体を得た。この固体をトルエン(50ml×3)と共蒸発させ、真空下で乾燥して灰白色の粉末(収量4.8g、83%)を得た。
1H NMR(D2O);−δH 1.42〜1.46(1H,m,4’−H)、1.73〜1.86(5H,m,2’−H 3’−H 4’−H)、2.97〜3.05(2H,m,2’−H 6’−H)、3.52〜3.57(2H,m,2’−H 6’−H)、4.02(2H,s,NCH2CO)。
水酸化リチウム(85mg、3.5ミリモル)とピペリジン−1−イル酢酸ヒドロクロリド(300mg、1.68ミリモル)をメタノール(10ml)溶解して無色の溶液を得た。次いで、減圧下でメタノールを除去し、無色固体を、自由流動性の粉末が得られるまでトルエンと一緒に共蒸発させた。このリチウム塩に、無水DMF(10ml)、リガンド1(250mg、0.95ミリモル)、Pybop(510mg、0.98ミリモル)を加え、透明な溶液が得られるまで混合物を加温した。加熱を止め、撹拌を16時間続行した。減圧下で揮発性成分を除去して橙色残留物を得た。これをCH2Cl2(20ml)中に溶解し、水(20ml×3)で洗浄した。有機層を脱水し(MgSO4)、ろ過し、溶媒を蒸発させて橙色オイル状物を得た。この残留物を、シリカゲルを用いたクロマトグラフィーにより、CH3CN/MeOH混合液(200:5)で溶出させて精製した。所要の生成物を淡黄色のオイル状物として単離した(rf=0.2)。これは放置すると固化した(100mg27%)。mp123〜125℃。
1H NMR(CDCl3):−δ1.45〜1.50(2H,m,4’−H))、1.65〜1.63(4H,m,3’−H 5’−H)、2.54〜2.57(4H,m,2’−H 6’−H)、3.01(2H,s,NCH2CO)、7.12(3H,ddd,J=7.5,5.0及び1.0Hz,5−H,[x3])7.46〜7.50(3H,m,3−H[x3])、7.60(3H,dt,J=7.5及び5.0Hz,4−H[x3])、8.50〜8.53(3H,m,6−H[x3])、10.61(1H,s,NH)。
質量スペクトル(ES)m/e:C23H26N5O(M+H)の計算値:388 実測値:388
実施例4: リガンド6、7及び8の合成
1H−イミダゾール−4−カルボン酸(200mg、1.8ミリモル)と水酸化リチウム(45mg、1.9ミリモル)をメタノール(10ml)中に溶解して透明な溶液を得た。減圧下で揮発性成分を除去し、残留物を、自由流動性の粉末が得られるまでトルエンと一緒に共蒸発させた。リチウム塩に、無水DMF(10ml)、リガンド1(250mg、0.95ミリモル)及びPybop(510mg、0.98ミリモル)を加えた。透明な有機溶液が得られるまで混合物を加温した。次いで加熱を止め、溶液を16時間撹拌した。溶媒をロータリーエバポレータで除去して粘性の橙色残留物を得た。これを、シリカゲルを用いたクロマトグラフィーにより、CH3CN/MeOH(95:5)で溶出させて精製した。表記化合物(100mg、29%)を白色粉末mp>250℃として単離した(rf=0.3)。
1H NMR(d6 DMSO):−δH 5.76(1H,s,NHイミド)、7.23〜7.28(3H,m,5−H[x3],7.44〜7.47(3H,m,3−H[x3],7.53(1H,s,C−H,イミド)、7.72(3H,bt,J=7Hz,4−H[x3],7,82(1H,s,C−Hイミド)、8.50(3H,m,6−H[x3],)、10.46(1H,s,NH)。
質量スペクトル(ES)m/e:C20H17N6O(M+H)の計算値:357 実測値:357。
1H NMR(CDCl3):δH 3.70(2H,s,CH2)、7.13(3H,m,5−H[x3],7.26(2H,d,J=5.0 3−H,5−H)、7.43(3H,d,J=6Hz 3−H[x3],7.57(3H,t,J=6Hz 4−H[x3], 8.47(3H,d,J=5Hz,6−H[x3],8.53(2H,d,J=5.0Hz,2−H,6−H)、9.49(1H,bs,NH)。
質量スペクトル(ES)m/e:C23H20N5O(M+H)の計算値:382 実測値:382
同様の方法で、リガンド8を3−ピリジル酢酸ヒドロクロリドから調製して淡黄褐色の粉末(180mg、54%)、mp165〜166℃を得た。
1H NMR(CDCl3):δH 3.68(2H,s,CH2)7.08(3H,ddd,J=7.5,5.0及び1.0Hz,5−H[x3],7.19(1H dd,J=7.5及び5.0Hz 5’−H)、7.43(3H,m,3−H[x3])、7.53(3H,dt,J=7.5及び5.0 4−H[x3],7.64(1H,bd,J=7.5Hz 4’−H)、8.43(3H,m,6−H[x3],8.46(1H,dd,J=7.5及び1.5Hz,6’−H)、8.56(1H,d,J=1.5Hz,2’−H)、9.49(1H,s,NH)。
質量スペクトル(ES)m/e:C23H20N5O(M+H)の計算値:382 実測値:382。
ジェネレータから溶出した1mLのTcO4 −をTc−カルボニルキット(Isolink(商標),Mallinckrodt,Petten,Netherlands)に加えた。活性度を983MBqで測定した。バイアルから約4mLのヘッドスペースを取り出し、次いでこれを約100℃に30分間加熱した。バイアルを冷却し、抜出用ニードルで均圧化した。50〜100ugのリガンド6を加え、続いて4mLヘッドスペースを取り出した。バイアルを約100℃に30分間加熱し、次いで冷却し、抜出用ニードルでバイアルを均圧化した。pHは約11.5と測定された。高速液体クロマトグラフィー(HPLC)で測定した放射線化学的純度(RCP)は98%であった。
溶媒A=水の中に0.1%TFA、溶媒B=アセトニトリル中に0.1%TFA
方法B
溶媒A=0.2%880アンモニア溶液、溶媒B=アセトニトリル
両方の方法について以下の勾配を用いた。
ジェネレータから溶出した1mLのTcO4 −をTc−カルボニルキット(Isolink(商標),Mallinckrodt,Petten,Netherlands)に加えた。活性度の測定値は2.88Gqであった。バイアルから約4mLヘッドスペースを取り出し、次いでこれを約100℃に30分間加熱した。バイアルを冷却し、抜出用ニードルで均圧化した。
Claims (3)
- 次の式Iのリガンドの金属錯体。
R1〜R3は各々独立にピリジル、イミダゾイル及びピラゾイルから選択され、
R4は−NH(CO)Ph、−NH(CO)(CH2)3−(CO)NHCH2Ph、−NH(CO)(3−ピリジル)、−NH(CO)(4−ピリジル)、−NH(CO)CH2−ピペリジニル、−NH(CO)NH2及び−NH(CO)(2,4−イミダゾイル)から選択され、
上記金属がテクネチウム又はレニウムの放射性同位体であり、
R4位のアシル基が金属配位の際にR1、R2及びR3基の供与体原子と競合しない。 - 次の式IIの金属錯体。
[LMX3]n (II)
式中、
Lは請求項1記載の式Iのリガンドであり、
Mはテクネチウム又はレニウムの放射性同位体であり、
XはCO、ハロゲン、ホスフィン又はイソニトリルから選択され、
nは金属錯体の電荷であって、−1、0、+1又は+2である。 - 次の式IIaのものである、請求項2記載の金属錯体。
[LM(CO)3]n (IIa)
式中、Lは請求項1記載の式Iのリガンドであり、nは+1又は+2である。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0421987.9A GB0421987D0 (en) | 2004-10-04 | 2004-10-04 | Novel technetium and rhenium complexes |
GB0421987.9 | 2004-10-04 | ||
PCT/GB2005/003806 WO2006037988A2 (en) | 2004-10-04 | 2005-10-04 | Novel technetium and rhenium complexes, ligands used in their preparation and their use as radiopharmaceuticals |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2008515794A JP2008515794A (ja) | 2008-05-15 |
JP2008515794A5 JP2008515794A5 (ja) | 2008-11-20 |
JP5122964B2 true JP5122964B2 (ja) | 2013-01-16 |
Family
ID=33428024
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007534091A Expired - Fee Related JP5122964B2 (ja) | 2004-10-04 | 2005-10-04 | 新規テクネチウム及びレニウム錯体 |
Country Status (8)
Country | Link |
---|---|
US (2) | US8022211B2 (ja) |
EP (1) | EP1799274B1 (ja) |
JP (1) | JP5122964B2 (ja) |
CN (1) | CN101035567B (ja) |
AT (1) | ATE537849T1 (ja) |
ES (1) | ES2376902T3 (ja) |
GB (1) | GB0421987D0 (ja) |
WO (1) | WO2006037988A2 (ja) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0421987D0 (en) * | 2004-10-04 | 2004-11-03 | Amersham Plc | Novel technetium and rhenium complexes |
GB0518968D0 (en) * | 2005-09-16 | 2005-10-26 | Cdt Oxford Ltd | Organic light-emitting device |
KR101383655B1 (ko) | 2010-05-24 | 2014-04-10 | 주식회사 바이오이미징코리아 | 트리카르보닐 테크네슘-99m 또는 레늄-188 표지 고리 알지디 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 신생혈관 관련 질환의 진단 또는 치료용 약학적 조성물 |
US20130195756A1 (en) | 2012-01-31 | 2013-08-01 | General Electric Company | 99mTc IMAGING AGENTS AND METHODS OF USE |
CN106112699B (zh) * | 2016-06-24 | 2017-08-08 | 广汉快速铁路设备有限公司 | 不落轮车床轮对加工跟踪测量系统及其测量方法 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3826447B2 (ja) * | 1996-08-06 | 2006-09-27 | 住友化学株式会社 | フェノール縮合物の製造方法 |
US5824288A (en) | 1997-08-21 | 1998-10-20 | Hoechst Celanese Corporation | Thio-substituted pyridines as MRI ligand precursors |
US5869025A (en) | 1997-08-21 | 1999-02-09 | Hoechst Celanese Corporation | Tripodal aromatic heterocycle carboxamide MRI contrast agents |
AU2003213819C1 (en) | 2002-03-11 | 2010-03-04 | Molecular Insight Pharmaceuticals, Inc. | Technetium-dipyridine complexes, and methods of use thereof |
GB0421987D0 (en) * | 2004-10-04 | 2004-11-03 | Amersham Plc | Novel technetium and rhenium complexes |
-
2004
- 2004-10-04 GB GBGB0421987.9A patent/GB0421987D0/en not_active Ceased
-
2005
- 2005-10-04 ES ES05796769T patent/ES2376902T3/es active Active
- 2005-10-04 JP JP2007534091A patent/JP5122964B2/ja not_active Expired - Fee Related
- 2005-10-04 WO PCT/GB2005/003806 patent/WO2006037988A2/en active Application Filing
- 2005-10-04 CN CN2005800336647A patent/CN101035567B/zh not_active Expired - Fee Related
- 2005-10-04 EP EP05796769A patent/EP1799274B1/en not_active Not-in-force
- 2005-10-04 US US11/576,543 patent/US8022211B2/en not_active Expired - Fee Related
- 2005-10-04 AT AT05796769T patent/ATE537849T1/de active
-
2011
- 2011-09-14 US US13/232,255 patent/US8278448B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
JP2008515794A (ja) | 2008-05-15 |
ATE537849T1 (de) | 2012-01-15 |
GB0421987D0 (en) | 2004-11-03 |
WO2006037988A3 (en) | 2006-06-08 |
ES2376902T3 (es) | 2012-03-20 |
WO2006037988A2 (en) | 2006-04-13 |
EP1799274A2 (en) | 2007-06-27 |
EP1799274B1 (en) | 2011-12-21 |
US8022211B2 (en) | 2011-09-20 |
US20120077967A1 (en) | 2012-03-29 |
CN101035567A (zh) | 2007-09-12 |
US8278448B2 (en) | 2012-10-02 |
CN101035567B (zh) | 2012-10-10 |
US20080219921A1 (en) | 2008-09-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2170075B1 (en) | Labeled inhibitors of prostate specific membrane antigen (psma), biological evaluation, and use as imaging agents | |
US5753205A (en) | Radiolabelled peptide compounds | |
KR20050103221A (ko) | 개선된 방사성금속 착물 조성물 | |
CN116023429A (zh) | 一种含有与铅或钍放射性核素连接的psma靶向化合物的络合物 | |
KR101653182B1 (ko) | 세포 영상화 및 치료를 위한 조성물 및 방법 | |
JP5557425B2 (ja) | 改良n4キレーターコンジュゲート | |
JP2009518373A (ja) | 線維症用の新規造影剤 | |
US8278448B2 (en) | Technetium and rhenium complexes | |
KR20220063218A (ko) | 안정한 농축 방사성 약제학적 조성물 | |
EP2806901B1 (en) | Radiofluorination method | |
EP0888130B1 (en) | New ternary radiopharmaceutical complexes | |
JP6280507B2 (ja) | キレート剤 | |
EP1437145A1 (en) | Enhanced scintigraphic imaging agents for imaging of infection and inflammation | |
KR101551232B1 (ko) | N3s1형의 새로운 킬레이터가 접합된 폴레이트 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 암 진단 또는 치료용 조성물 | |
RU2799325C2 (ru) | ЛИОФИЛИЗАТ ДЛЯ ПОЛУЧЕНИЯ ДИАГНОСТИЧЕСКОГО РАДИОФАРМАЦЕВТИЧЕСКОГО ЛЕКАРСТВЕННОГО ПРЕПАРАТА НА ОСНОВЕ РАДИОНУКЛИДА 99mTc | |
CA3075958C (en) | Pharmaceutical composition comprising tetrofosmin and pharmaceutically acceptable salts thereof | |
NL8105845A (nl) | N-gesubstitueerde iminodiazijnzuren. | |
WO2019166537A1 (en) | Universal building blocks for radiolabeling | |
WO2014096191A1 (en) | Bis 2h-imidazole-2-thione chelating agents as ligands for radiopharmaceutical in vivo imaging | |
HRP970139A2 (en) | New ternary radiopharmaceutical complexes |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20081003 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20081003 |
|
RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20110114 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20110114 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20110810 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20110816 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20111116 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20111124 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120216 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20120313 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120712 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20120827 |
|
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: 20120925 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20121025 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20151102 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |