AU698824B2 - Technetium-sulphonamide complexes, their use, pharmaceutical agents containing the latter, as well as process for the production of the complexes and agents - Google Patents
Technetium-sulphonamide complexes, their use, pharmaceutical agents containing the latter, as well as process for the production of the complexes and agents Download PDFInfo
- Publication number
- AU698824B2 AU698824B2 AU28865/95A AU2886595A AU698824B2 AU 698824 B2 AU698824 B2 AU 698824B2 AU 28865/95 A AU28865/95 A AU 28865/95A AU 2886595 A AU2886595 A AU 2886595A AU 698824 B2 AU698824 B2 AU 698824B2
- Authority
- AU
- Australia
- Prior art keywords
- mmol
- group
- radical
- solution
- yield
- 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.)
- Ceased
Links
- 239000003795 chemical substances by application Substances 0.000 title claims description 20
- 238000004519 manufacturing process Methods 0.000 title claims description 15
- 238000000034 method Methods 0.000 title claims description 14
- 230000008569 process Effects 0.000 title claims description 11
- 239000008177 pharmaceutical agent Substances 0.000 title claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 258
- 229910052757 nitrogen Inorganic materials 0.000 claims description 245
- 229910052717 sulfur Inorganic materials 0.000 claims description 217
- 150000001875 compounds Chemical class 0.000 claims description 90
- -1 phenylene, phenylenoxy, phenylenamino, amide Chemical class 0.000 claims description 78
- 229910052760 oxygen Inorganic materials 0.000 claims description 42
- 239000000460 chlorine Substances 0.000 claims description 37
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 29
- 229910021645 metal ion Inorganic materials 0.000 claims description 25
- 229910052801 chlorine Inorganic materials 0.000 claims description 24
- 229910052751 metal Inorganic materials 0.000 claims description 21
- 239000002184 metal Substances 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 239000003446 ligand Substances 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 16
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 16
- 230000002285 radioactive effect Effects 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 14
- 239000002738 chelating agent Substances 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000003277 amino group Chemical group 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- 229910052713 technetium Inorganic materials 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 125000000524 functional group Chemical group 0.000 claims description 8
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M thiocyanate group Chemical group [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 8
- 235000001014 amino acid Nutrition 0.000 claims description 7
- 150000001413 amino acids Chemical class 0.000 claims description 7
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 102000040430 polynucleotide Human genes 0.000 claims description 6
- 108091033319 polynucleotide Proteins 0.000 claims description 6
- 239000002157 polynucleotide Substances 0.000 claims description 6
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 5
- 150000004696 coordination complex Chemical group 0.000 claims description 5
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 150000003431 steroids Chemical class 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 229960002317 succinimide Drugs 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 239000012736 aqueous medium Substances 0.000 claims description 3
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 229910044991 metal oxide Inorganic materials 0.000 claims description 3
- 150000004706 metal oxides Chemical class 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 230000003439 radiotherapeutic effect Effects 0.000 claims description 3
- 238000001959 radiotherapy Methods 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001491 aromatic compounds Chemical class 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000000350 glycoloyl group Chemical group O=C([*])C([H])([H])O[H] 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 claims description 2
- 238000011160 research Methods 0.000 claims description 2
- 125000000565 sulfonamide group Chemical group 0.000 claims description 2
- 238000012546 transfer Methods 0.000 claims description 2
- 102400000050 Oxytocin Human genes 0.000 claims 2
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 claims 2
- 101800000989 Oxytocin Proteins 0.000 claims 2
- 235000018417 cysteine Nutrition 0.000 claims 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims 2
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 claims 2
- 229960001723 oxytocin Drugs 0.000 claims 2
- 102000004877 Insulin Human genes 0.000 claims 1
- 108090001061 Insulin Proteins 0.000 claims 1
- 241000283986 Lepus Species 0.000 claims 1
- 150000001447 alkali salts Chemical class 0.000 claims 1
- 230000000845 anti-microbial effect Effects 0.000 claims 1
- UVXCXZBZPFCAAJ-UHFFFAOYSA-N arc-111 Chemical compound C1=C2OCOC2=CC2=C(N(CCN(C)C)C(=O)C3=C4C=C(C(=C3)OC)OC)C4=CN=C21 UVXCXZBZPFCAAJ-UHFFFAOYSA-N 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 229940125396 insulin Drugs 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 247
- 239000000243 solution Substances 0.000 description 156
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 89
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 78
- 238000001704 evaporation Methods 0.000 description 64
- 230000008020 evaporation Effects 0.000 description 64
- 239000002904 solvent Substances 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 52
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 52
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 48
- 239000000741 silica gel Substances 0.000 description 48
- 229910002027 silica gel Inorganic materials 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 41
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 235000019439 ethyl acetate Nutrition 0.000 description 33
- 239000012074 organic phase Substances 0.000 description 32
- 239000007787 solid Substances 0.000 description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- 150000001408 amides Chemical class 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 26
- 235000019341 magnesium sulphate Nutrition 0.000 description 26
- 239000008139 complexing agent Substances 0.000 description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 21
- 150000003254 radicals Chemical class 0.000 description 21
- 239000000706 filtrate Substances 0.000 description 19
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 18
- 150000001412 amines Chemical class 0.000 description 18
- 239000013078 crystal Substances 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 239000003054 catalyst Substances 0.000 description 15
- 238000002372 labelling Methods 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 229960002449 glycine Drugs 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 10
- 239000000284 extract Substances 0.000 description 10
- 239000005457 ice water Substances 0.000 description 10
- 229910052763 palladium Inorganic materials 0.000 description 10
- 239000008363 phosphate buffer Substances 0.000 description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 10
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 9
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 239000012217 radiopharmaceutical Substances 0.000 description 9
- AHTFMWCHTGEJHA-UHFFFAOYSA-N s-(2,5-dioxooxolan-3-yl) ethanethioate Chemical compound CC(=O)SC1CC(=O)OC1=O AHTFMWCHTGEJHA-UHFFFAOYSA-N 0.000 description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 description 9
- 229940056501 technetium 99m Drugs 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 230000007717 exclusion Effects 0.000 description 8
- 229910052731 fluorine Inorganic materials 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 8
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 7
- 229940050410 gluconate Drugs 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 235000011150 stannous chloride Nutrition 0.000 description 7
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 7
- 238000007098 aminolysis reaction Methods 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 5
- MTHSVFCYNBDYFN-UHFFFAOYSA-N anhydrous diethylene glycol Natural products OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- UIJGNTRUPZPVNG-UHFFFAOYSA-N benzenecarbothioic s-acid Chemical compound SC(=O)C1=CC=CC=C1 UIJGNTRUPZPVNG-UHFFFAOYSA-N 0.000 description 5
- 238000003745 diagnosis Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 230000000536 complexating effect Effects 0.000 description 4
- OOTFVKOQINZBBF-UHFFFAOYSA-N cystamine Chemical compound CCSSCCN OOTFVKOQINZBBF-UHFFFAOYSA-N 0.000 description 4
- 229940099500 cystamine Drugs 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 229910052702 rhenium Inorganic materials 0.000 description 4
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 4
- 239000001509 sodium citrate Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 4
- 229940038773 trisodium citrate Drugs 0.000 description 4
- VJRWULUDVUWCCQ-UHFFFAOYSA-N 2-benzoylsulfanylacetic acid Chemical compound OC(=O)CSC(=O)C1=CC=CC=C1 VJRWULUDVUWCCQ-UHFFFAOYSA-N 0.000 description 3
- OEDJQRXNDRUGEU-SRVKXCTJSA-N Asp-Leu-His Chemical compound N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)O OEDJQRXNDRUGEU-SRVKXCTJSA-N 0.000 description 3
- QHYSVLPJVYLGLX-UHFFFAOYSA-N C(C)(=O)SCC(NCCNC(C(NS(=O)(=O)C1=CC=C(C)C=C1)CC1=CC=C(C=C1)OCC(=O)O)=O)=O Chemical compound C(C)(=O)SCC(NCCNC(C(NS(=O)(=O)C1=CC=C(C)C=C1)CC1=CC=C(C=C1)OCC(=O)O)=O)=O QHYSVLPJVYLGLX-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 101100208721 Mus musculus Usp5 gene Proteins 0.000 description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000011097 chromatography purification Methods 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 230000009918 complex formation Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 229940124530 sulfonamide Drugs 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- XDFZUXHZXUFQOS-UHFFFAOYSA-N 1-chloro-2-(2-chloroethyldisulfanyl)ethane Chemical compound ClCCSSCCCl XDFZUXHZXUFQOS-UHFFFAOYSA-N 0.000 description 2
- ANOOTOPTCJRUPK-UHFFFAOYSA-N 1-iodohexane Chemical compound CCCCCCI ANOOTOPTCJRUPK-UHFFFAOYSA-N 0.000 description 2
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- RLWXZXYQGAZWDC-INIZCTEOSA-N COC([C@@H](N(S(=O)(=O)C1=CC=C(C=C1)C)C1=CC=C(C=C1)NC(=O)OC(C)(C)C)C)=O Chemical compound COC([C@@H](N(S(=O)(=O)C1=CC=C(C=C1)C)C1=CC=C(C=C1)NC(=O)OC(C)(C)C)C)=O RLWXZXYQGAZWDC-INIZCTEOSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000001351 alkyl iodides Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- JHVLLYQQQYIWKX-UHFFFAOYSA-N benzyl 2-bromoacetate Chemical compound BrCC(=O)OCC1=CC=CC=C1 JHVLLYQQQYIWKX-UHFFFAOYSA-N 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000001588 bifunctional effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- OVIISSOUXFJLSM-KPNWGBFJSA-N butanedioic acid;(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-ol Chemical compound OC(=O)CCC(O)=O.C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 OVIISSOUXFJLSM-KPNWGBFJSA-N 0.000 description 2
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- ZBKFYXZXZJPWNQ-UHFFFAOYSA-N isothiocyanate group Chemical group [N-]=C=S ZBKFYXZXZJPWNQ-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- HLXBVFXEKFMCOH-ZDUSSCGKSA-N methyl (2s)-2-(n-(4-methylphenyl)sulfonyl-4-nitroanilino)propanoate Chemical compound C=1C=C(C)C=CC=1S(=O)(=O)N([C@@H](C)C(=O)OC)C1=CC=C([N+]([O-])=O)C=C1 HLXBVFXEKFMCOH-ZDUSSCGKSA-N 0.000 description 2
- SLLMDHBKALJDBW-INIZCTEOSA-N methyl (2s)-3-(4-hydroxyphenyl)-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)OCC=1C=CC=CC=1)C1=CC=C(O)C=C1 SLLMDHBKALJDBW-INIZCTEOSA-N 0.000 description 2
- DDHAQDNXMUELPJ-UHFFFAOYSA-N methyl 2-[(3-aminophenyl)sulfonylamino]acetate Chemical compound COC(=O)CNS(=O)(=O)C1=CC=CC(N)=C1 DDHAQDNXMUELPJ-UHFFFAOYSA-N 0.000 description 2
- MWZPENIJLUWBSY-VIFPVBQESA-N methyl L-tyrosinate Chemical compound COC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MWZPENIJLUWBSY-VIFPVBQESA-N 0.000 description 2
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 238000009206 nuclear medicine Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- WUAPFZMCVAUBPE-IGMARMGPSA-N rhenium-186 Chemical compound [186Re] WUAPFZMCVAUBPE-IGMARMGPSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- BQHFYSWNHZMMDO-WDSKDSINSA-N (2r)-2-[2-[[(1r)-1-carboxy-2-sulfanylethyl]amino]ethylamino]-3-sulfanylpropanoic acid Chemical compound OC(=O)[C@H](CS)NCCN[C@@H](CS)C(O)=O BQHFYSWNHZMMDO-WDSKDSINSA-N 0.000 description 1
- 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 1
- YGFLNRUFVZPRST-VIFPVBQESA-N (2s)-2-amino-3-(4-hydroxyphenyl)-n-methylsulfonylpropanamide Chemical compound CS(=O)(=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 YGFLNRUFVZPRST-VIFPVBQESA-N 0.000 description 1
- MDSNZHSQCFCPOD-VIFPVBQESA-N (2s)-3-(4-hydroxyphenyl)-2-(methanesulfonamido)propanoic acid Chemical compound CS(=O)(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 MDSNZHSQCFCPOD-VIFPVBQESA-N 0.000 description 1
- AWNXKZVIZARMME-UHFFFAOYSA-N 1-[[5-[2-[(2-chloropyridin-4-yl)amino]pyrimidin-4-yl]-4-(cyclopropylmethyl)pyrimidin-2-yl]amino]-2-methylpropan-2-ol Chemical compound N=1C(NCC(C)(O)C)=NC=C(C=2N=C(NC=3C=C(Cl)N=CC=3)N=CC=2)C=1CC1CC1 AWNXKZVIZARMME-UHFFFAOYSA-N 0.000 description 1
- GCDPERPXPREHJF-UHFFFAOYSA-N 1-iodododecane Chemical compound CCCCCCCCCCCCI GCDPERPXPREHJF-UHFFFAOYSA-N 0.000 description 1
- BSOYWTITVKXHLM-UHFFFAOYSA-N 1-phenylmethoxycarbonyl-2,3-dihydroindole-2-carboxylic acid Chemical compound OC(=O)C1CC2=CC=CC=C2N1C(=O)OCC1=CC=CC=C1 BSOYWTITVKXHLM-UHFFFAOYSA-N 0.000 description 1
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 1
- QHQZEEGNGSZBOL-UHFFFAOYSA-N 2-(aminomethyl)-2-(hydroxymethyl)propane-1,3-diol Chemical compound NCC(CO)(CO)CO QHQZEEGNGSZBOL-UHFFFAOYSA-N 0.000 description 1
- DLLMHEDYJQACRM-UHFFFAOYSA-N 2-(carboxymethyldisulfanyl)acetic acid Chemical compound OC(=O)CSSCC(O)=O DLLMHEDYJQACRM-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- RJGBETJBXKQAHW-VWLOTQADSA-N 2-[[(2S)-1-[2-[[2-(1,3-benzodioxol-5-ylmethylsulfanyl)acetyl]amino]ethylamino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-benzylsulfonyloxyamino]acetic acid Chemical compound C(C1=CC=2OCOC=2C=C1)SCC(=O)NCCNC([C@@H](N(OS(=O)(=O)CC1=CC=CC=C1)CC(=O)O)CC1=CC=C(C=C1)O)=O RJGBETJBXKQAHW-VWLOTQADSA-N 0.000 description 1
- WPHUUIODWRNJLO-UHFFFAOYSA-N 2-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1S(Cl)(=O)=O WPHUUIODWRNJLO-UHFFFAOYSA-N 0.000 description 1
- ZAGWQJWRWKULDE-UHFFFAOYSA-N 3,3,3-trifluoropropanethioic s-acid Chemical compound OC(=S)CC(F)(F)F ZAGWQJWRWKULDE-UHFFFAOYSA-N 0.000 description 1
- HVYWMOMLDIMFJA-UHFFFAOYSA-N 3-cholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 HVYWMOMLDIMFJA-UHFFFAOYSA-N 0.000 description 1
- MWWNNNAOGWPTQY-UHFFFAOYSA-N 3-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC(S(Cl)(=O)=O)=C1 MWWNNNAOGWPTQY-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- PZASAAIJIFDWSB-CKPDSHCKSA-N 8-[(1S)-1-[8-(trifluoromethyl)-7-[4-(trifluoromethyl)cyclohexyl]oxynaphthalen-2-yl]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid Chemical compound FC(F)(F)C=1C2=CC([C@@H](N3C4CCC3CC(C4)C(O)=O)C)=CC=C2C=CC=1OC1CCC(C(F)(F)F)CC1 PZASAAIJIFDWSB-CKPDSHCKSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- RDWVVOTVINMEDX-UHFFFAOYSA-N C(C)(C)(C)OC(=O)NCCNC(C(NS(=O)(=O)C1=CC=C(C)C=C1)CC1=CC=C(C=C1)O)=O Chemical compound C(C)(C)(C)OC(=O)NCCNC(C(NS(=O)(=O)C1=CC=C(C)C=C1)CC1=CC=C(C=C1)O)=O RDWVVOTVINMEDX-UHFFFAOYSA-N 0.000 description 1
- DTLRCMIOCRDUMH-UHFFFAOYSA-N C(C)(C)(C)OC(=O)NCCNC(C(NS(=O)(=O)C1=CC=C(C)C=C1)CC1=CC=C(C=C1)OCC(=O)OCC1=CC=CC=C1)=O Chemical compound C(C)(C)(C)OC(=O)NCCNC(C(NS(=O)(=O)C1=CC=C(C)C=C1)CC1=CC=C(C=C1)OCC(=O)OCC1=CC=CC=C1)=O DTLRCMIOCRDUMH-UHFFFAOYSA-N 0.000 description 1
- QZPFUEGHGXLVEK-UHFFFAOYSA-N C(C)(C)(C)OC(=O)NCCNC(CNS(=O)(=O)C1=CC=C(C)C=C1)=O Chemical compound C(C)(C)(C)OC(=O)NCCNC(CNS(=O)(=O)C1=CC=C(C)C=C1)=O QZPFUEGHGXLVEK-UHFFFAOYSA-N 0.000 description 1
- KPVDFOOYRUQHGA-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)SCC(NCCNC(C(NS(=O)(=O)C)CC1=CC=C(C=C1)OCC1=CC=CC=C1)=O)=O Chemical compound C(C1=CC=CC=C1)(=O)SCC(NCCNC(C(NS(=O)(=O)C)CC1=CC=C(C=C1)OCC1=CC=CC=C1)=O)=O KPVDFOOYRUQHGA-UHFFFAOYSA-N 0.000 description 1
- RSWOTPMFWKDCPL-UHFFFAOYSA-N C(C1=CC=CC=C1)OC1=CC=C(CC(NS(=O)(=O)C)CNCCN)C=C1 Chemical compound C(C1=CC=CC=C1)OC1=CC=C(CC(NS(=O)(=O)C)CNCCN)C=C1 RSWOTPMFWKDCPL-UHFFFAOYSA-N 0.000 description 1
- QQXWMQLBQUOMJZ-UHFFFAOYSA-N CC(=O)SCC(=O)NCCNC(=O)CNS(=O)(=O)C1=CC=CC(=C1)N=C=S Chemical compound CC(=O)SCC(=O)NCCNC(=O)CNS(=O)(=O)C1=CC=CC(=C1)N=C=S QQXWMQLBQUOMJZ-UHFFFAOYSA-N 0.000 description 1
- CPBBEPNSIXDGCY-UHFFFAOYSA-N CC1=CC=C(C=C1)S(=O)(=O)NC(CC2=CC=C(C=C2)OCC3=CC=CC=C3)C(=O)NCCNC(=O)CSC(=O)C4=CC=CC=C4 Chemical compound CC1=CC=C(C=C1)S(=O)(=O)NC(CC2=CC=C(C=C2)OCC3=CC=CC=C3)C(=O)NCCNC(=O)CSC(=O)C4=CC=CC=C4 CPBBEPNSIXDGCY-UHFFFAOYSA-N 0.000 description 1
- UABDHHWIBMDQKN-UHFFFAOYSA-N CCCC(CC)OC(C1=CC=CC=C1)C(C(=O)OC)NC(=O)OCC2=CC=CC=C2 Chemical compound CCCC(CC)OC(C1=CC=CC=C1)C(C(=O)OC)NC(=O)OCC2=CC=CC=C2 UABDHHWIBMDQKN-UHFFFAOYSA-N 0.000 description 1
- QXFVQOGJCFAKGT-UHFFFAOYSA-N CCCCCCCCC(CCC)OC(C1=CC=CC=C1)C(C(=O)OC)NC(=O)OCC2=CC=CC=C2 Chemical compound CCCCCCCCC(CCC)OC(C1=CC=CC=C1)C(C(=O)OC)NC(=O)OCC2=CC=CC=C2 QXFVQOGJCFAKGT-UHFFFAOYSA-N 0.000 description 1
- MHFCCHDTRKMULS-UHFFFAOYSA-N CCCCCCCCC(CCC)OC(C1=CC=CC=C1)C(C(=O)OC)NS(=O)(=O)C2=CC=C(C=C2)C Chemical compound CCCCCCCCC(CCC)OC(C1=CC=CC=C1)C(C(=O)OC)NS(=O)(=O)C2=CC=C(C=C2)C MHFCCHDTRKMULS-UHFFFAOYSA-N 0.000 description 1
- WCYPEANLNHLKEU-UHFFFAOYSA-N COC(C(N)C(C1=CC=CC=C1)OC(CCC)CC)=O Chemical compound COC(C(N)C(C1=CC=CC=C1)OC(CCC)CC)=O WCYPEANLNHLKEU-UHFFFAOYSA-N 0.000 description 1
- ANRSPZPXKYMMOT-UHFFFAOYSA-N COC(C(N)C(C1=CC=CC=C1)OC(CCC)CCCCCCCC)=O Chemical compound COC(C(N)C(C1=CC=CC=C1)OC(CCC)CCCCCCCC)=O ANRSPZPXKYMMOT-UHFFFAOYSA-N 0.000 description 1
- IGBAKKLAGHWLTP-UHFFFAOYSA-N CS(=O)(=O)NC(CC1=CC=C(C=C1)OCC2=CC=CC=C2)CNC(=O)CNC(=O)CSC(=O)C3=CC=CC=C3 Chemical compound CS(=O)(=O)NC(CC1=CC=C(C=C1)OCC2=CC=CC=C2)CNC(=O)CNC(=O)CSC(=O)C3=CC=CC=C3 IGBAKKLAGHWLTP-UHFFFAOYSA-N 0.000 description 1
- LAZUGXVDCFAKSU-UHFFFAOYSA-N CS(=O)(=O)NC(CC1=CC=C(OCC2=CC=CC=C2)C=C1)C(=O)NCCNC(=O)CCl Chemical compound CS(=O)(=O)NC(CC1=CC=C(OCC2=CC=CC=C2)C=C1)C(=O)NCCNC(=O)CCl LAZUGXVDCFAKSU-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- VGXLHUCMBIRQHO-UHFFFAOYSA-N ClCC(NCC(NCC(NS(=O)(=O)C)CC1=CC=C(C=C1)OCC1=CC=CC=C1)=O)=O Chemical compound ClCC(NCC(NCC(NS(=O)(=O)C)CC1=CC=C(C=C1)OCC1=CC=CC=C1)=O)=O VGXLHUCMBIRQHO-UHFFFAOYSA-N 0.000 description 1
- AOUCHMZBNPIKKE-UHFFFAOYSA-N ClCC(NCCNC(C(NS(=O)(=O)C1=CC=C(C)C=C1)CC1=CC=C(C=C1)OC(CCCCCCCCCCCCCCC)=O)=O)=O Chemical compound ClCC(NCCNC(C(NS(=O)(=O)C1=CC=C(C)C=C1)CC1=CC=C(C=C1)OC(CCCCCCCCCCCCCCC)=O)=O)=O AOUCHMZBNPIKKE-UHFFFAOYSA-N 0.000 description 1
- SCOLHOIHQPEVFX-UHFFFAOYSA-N ClCC(NCCNC(C(NS(=O)(=O)C1=CC=C(C)C=C1)CC1=CC=C(C=C1)OCC(=O)OCC1=CC=CC=C1)=O)=O Chemical compound ClCC(NCCNC(C(NS(=O)(=O)C1=CC=C(C)C=C1)CC1=CC=C(C=C1)OCC(=O)OCC1=CC=CC=C1)=O)=O SCOLHOIHQPEVFX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- RBQXJFWNOMOAHE-UHFFFAOYSA-N FC(C(=O)SCC(NCCNC(C(NS(=O)(=O)C1=CC=C(C)C=C1)CC1=CC=C(C=C1)OCC1=CC=CC=C1)=O)=O)(F)F Chemical compound FC(C(=O)SCC(NCCNC(C(NS(=O)(=O)C1=CC=C(C)C=C1)CC1=CC=C(C=C1)OCC1=CC=CC=C1)=O)=O)(F)F RBQXJFWNOMOAHE-UHFFFAOYSA-N 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 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
- 241000562429 Jamides Species 0.000 description 1
- PQFMNVGMJJMLAE-QMMMGPOBSA-N L-tyrosinamide Chemical compound NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 PQFMNVGMJJMLAE-QMMMGPOBSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- DMBHUAZXPVQROR-UHFFFAOYSA-N S(=O)(=O)(C1=CC=C(C)C=C1)NCC(NCCN)=O Chemical compound S(=O)(=O)(C1=CC=C(C)C=C1)NCC(NCCN)=O DMBHUAZXPVQROR-UHFFFAOYSA-N 0.000 description 1
- MVGGNIOJHMIVRY-UHFFFAOYSA-N S-[2-[2-[[2-[(3-aminophenyl)sulfonylamino]acetyl]amino]ethylamino]-2-oxoethyl] ethanethioate Chemical compound CC(=O)SCC(=O)NCCNC(=O)CNS(=O)(=O)C1=CC=CC(=C1)N MVGGNIOJHMIVRY-UHFFFAOYSA-N 0.000 description 1
- 108091006629 SLC13A2 Proteins 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 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
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- TXWZIBMKHBHFTB-UHFFFAOYSA-N [(carbamothioylamino)sulfanylamino]urea Chemical compound C(=O)(N)NNSNC(=S)N TXWZIBMKHBHFTB-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- JCXGWMGPZLAOME-AKLPVKDBSA-N bismuth-212 Chemical compound [212Bi] JCXGWMGPZLAOME-AKLPVKDBSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229940107161 cholesterol Drugs 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical class C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 239000002812 cholic acid derivative Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000007819 coupling partner Substances 0.000 description 1
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- TWXWPPKDQOWNSX-UHFFFAOYSA-N dicyclohexylmethanone Chemical group C1CCCCC1C(=O)C1CCCCC1 TWXWPPKDQOWNSX-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- WABPQHHGFIMREM-BKFZFHPZSA-N lead-212 Chemical compound [212Pb] WABPQHHGFIMREM-BKFZFHPZSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- FUQCRIZLSCLPAV-ZDUSSCGKSA-N methyl (2s)-2-amino-3-[4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoate Chemical compound COC(=O)[C@@H](N)CC1=CC=C(OCC(=O)OC(C)(C)C)C=C1 FUQCRIZLSCLPAV-ZDUSSCGKSA-N 0.000 description 1
- UQSJOYDXZFRENM-UHFFFAOYSA-N methyl 2-[(3-nitrophenyl)sulfonylamino]acetate Chemical compound COC(=O)CNS(=O)(=O)C1=CC=CC([N+]([O-])=O)=C1 UQSJOYDXZFRENM-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- XMSCVBRMUJUIHE-UHFFFAOYSA-N n-(2-aminoethyl)-2-(methanesulfonamido)-3-(4-phenylmethoxyphenyl)propanamide Chemical compound C1=CC(CC(NS(=O)(=O)C)C(=O)NCCN)=CC=C1OCC1=CC=CC=C1 XMSCVBRMUJUIHE-UHFFFAOYSA-N 0.000 description 1
- NVIMASHGALOEEZ-UHFFFAOYSA-N n-(2-aminoethyl)-2-[(4-methylphenyl)sulfonylamino]-3-(4-phenylmethoxyphenyl)propanamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(C(=O)NCCN)CC(C=C1)=CC=C1OCC1=CC=CC=C1 NVIMASHGALOEEZ-UHFFFAOYSA-N 0.000 description 1
- JZFMCBRKVVLQEK-UHFFFAOYSA-N n-[2-[(2-chloroacetyl)amino]ethyl]-3-(4-hydroxyphenyl)-2-[(4-methylphenyl)sulfonylamino]propanamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(C(=O)NCCNC(=O)CCl)CC1=CC=C(O)C=C1 JZFMCBRKVVLQEK-UHFFFAOYSA-N 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 150000002829 nitrogen Chemical group 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- KDLHZDBZIXYQEI-AKLPVKDBSA-N palladium-109 Chemical compound [109Pd] KDLHZDBZIXYQEI-AKLPVKDBSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 150000003128 pregnanes Chemical class 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- ABYZQVVXGXLPCV-INIZCTEOSA-N s-[2-[2-[[(2s)-2-(4-amino-n-(4-methylphenyl)sulfonylanilino)propanoyl]amino]ethylamino]-2-oxoethyl] ethanethioate Chemical compound C=1C=C(C)C=CC=1S(=O)(=O)N([C@@H](C)C(=O)NCCNC(=O)CSC(C)=O)C1=CC=C(N)C=C1 ABYZQVVXGXLPCV-INIZCTEOSA-N 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- RBBWNXJFTBCLKT-UHFFFAOYSA-M sodium;ethanethioate Chemical compound [Na+].CC([S-])=O RBBWNXJFTBCLKT-UHFFFAOYSA-M 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- BYQTZCZJTJCFLF-NRFANRHFSA-N tert-butyl 2-[[(2S)-1-[2-aminoethyl(benzylsulfonyloxy)amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]acetate Chemical compound C(C1=CC=CC=C1)S(=O)(=O)ON(C([C@@H](NCC(=O)OC(C)(C)C)CC1=CC=C(C=C1)O)=O)CCN BYQTZCZJTJCFLF-NRFANRHFSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- CLUMXSRGYWVAAK-UHFFFAOYSA-N tert-butyl n-[2-[[2-(methanesulfonamido)-3-(4-phenylmethoxyphenyl)propanoyl]amino]ethyl]carbamate Chemical compound C1=CC(CC(C(=O)NCCNC(=O)OC(C)(C)C)NS(C)(=O)=O)=CC=C1OCC1=CC=CC=C1 CLUMXSRGYWVAAK-UHFFFAOYSA-N 0.000 description 1
- OTCIYKUORLUQOC-UHFFFAOYSA-N tert-butyl n-[2-[[3-(4-hydroxyphenyl)-2-(methanesulfonamido)propanoyl]amino]ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCNC(=O)C(NS(C)(=O)=O)CC1=CC=C(O)C=C1 OTCIYKUORLUQOC-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- IUTCEZPPWBHGIX-UHFFFAOYSA-N tin(2+) Chemical class [Sn+2] IUTCEZPPWBHGIX-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/20—Esters of monothiocarboxylic acids
- C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
- C07C331/16—Isothiocyanates
- C07C331/28—Isothiocyanates having isothiocyanate groups bound to carbon atoms of six-membered aromatic rings
-
- 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
-
- 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
- A61K51/0478—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 non-cyclic ligands, e.g. EDTA, MAG3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
-
- 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
- C07F13/005—Compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Optics & Photonics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
Technetium-Sulfonamide Complexes, Their Use, Pharmaceutical Agents Containing the Latter, as well as Process for the Production of the Complexes and Agents The invention relates to the object characterized in the claims, chelating agents containing new sulfonamide groups, their metal complexes, pharmaceutical agents containing these compounds, their use in radiodiagnosis and radiotherapy, process for the production of these compounds and agents, as well as conjugates of these compounds with substances, especially peptides, selectively accumulating in diseased tissue.
The use of radiopharmaceutical agents for diagnostic and therapeutic purposes has long been known in the area of biological and medical research. In particular, radiopharmaceutical agents are used to visualize certain structures such as, for example, the skeleton, organs or tissues.
The diagnostic application requires the use of such radioactive agents, which, after administration, accumulate specifically in the structures in patients which are to be examined. These locally accumulating radioactive agents can then be traced, plotted or scintiscanned with suitable detectors, such as, for example, scintillation cameras or other suitable imaging processes. The distribution and relative intensity of the detected radioactive agent identifies the point of a structure at which the radioactive agent is present and can display the presence of anomalies in structure and function, pathological changes, etc. In a similar way, radiopharmaceutical agents can *r be used as therapeutic agents to irradiate specific pathological tissues or areas. Such treatment requires the production of radioactive therapeutic agents, which accumulate in certain structures, tissues or organs. By concentration of these agents, the therapeutic radiation is brought directly to the pathological tissue.
Generally, metallic radionuclides are used as diagnostic agents or therapeutic agents, whereby the metal can be present in free form, as ions or in the form of a metal complex. Examples of metallic radionuclides, which can form complexes, are technetium-99m and various rhenium isotopes. The former is used in diagnosis, the latter in therapy. Besides the metal (complex), in general the radiopharmaceutical agents contain additional suitable vehicles and additives, which allow an injection, inhalation or ingestion by the patient, such as, e.g., physiological buffers, salts, etc.
The radionuclide most often used for nuclear-medicine problems is technetium-99m, which is especially well-suited as radioisotope for in vivo diagnosis because of its advantageous physical properties (no corpuscular radiation, 6 hours of physical half-life, 140 KeV of gamma radiation) and the small radiation exposure following from it. Technetium-99m can be obtained problem-free from nuclide generators as pertechnetate and can be used in this form directly for the production of kits for routine clinical demand.
The production of radiopharmaceutical agents first requires the synthesis of a suitable ligand. In clinical practice, the
J
complex is then produced immediately before use from the respective complexing agent (also named ligand or chelating agent below) and the desired radionuclide (labeling). In this respect, thi complexing agent, which is already present, in the form of a freeze-dried kit, is reacted under conditions of complex formation with a solution containing the radionuclide. If, for example, the production of technetium-99m radiopharmaceutical agent is desired, the ligand produced with addition of a suitable reducing agent is mixed with a pertechnetate solution, and the corresponding technetium complex is produced under suitable reaction conditions. These complexes are then administered to the patient in a suitable way by injection, inhalation or ingestion.
The solution containing the radionuclide can, as in the case of technetium-99m, be obtained from a commercially available Mo- 99/Tc-99m nuclide generator, or as in the case of rhenium- 186 be obtained directly from a manufacturer. The complexformation reaction is performed under suitable temperatures 20 0 -100 0 C) within a few minutes to several hours. To assure a complete complex formation, a larger excess (more than 100 times the excess) of the ligand produced and an amount of reducing agent SnC1 2 S204, etc.) sufficient for a complete reduction of the radionuclide used are necessary.
Since technetium can be present in a series of oxidation stages to which can greatly change the pharmacological properties by changes of the charge of a complex, it is necessary to provide chelating agents that can bond the technetium in a
I
stable manner in a defined oxidation stage to prevent an undesirable biodistribution from taking place by redox processes or technetium releases from the corresponding radiodiagnostic agents occurring in vivo, which makes more difficult a reliable diagnosis of corresponding diseases.
The efficiency of radionuclides in in vivo diagnosis and therapy depends on the specificity and the selectivity of the labeled chelates in the target cell. An improvement of these properties can be achieved by coupling chelates to biomolecules according to the "drug-targeting" principle. As biomolecules, antibodies, their fragments, hormones, growth factors and substrates of receptors and enzymes present themselves. Thus, in British Patent Application GB 2,109,407, the use of radioactively-labeled monoclonal antibodies to tumor-associated antigens is described for in vivo tumor diagnosis. Also, direct protein labeling with donor groups (amino, amide, thiol, etc.) of the protein (Rhodes, B. A. et al., J. Nukl. Med. 1986, 27, 685- 693) or by the introduction of complexing agents (US 4,479,930 and Fritzberg, A. R. et al., J. Nucl. Med. 1986, 27, 957) with technetium-99m is described. These experimental methods, however, are not available for clinical use, since, on the one hand, the selectivity is too low and, on the other hand, the "background activity" in the organism is too high to make possible an in vivo imaging.
As suitable complexing agents for technetium and rhenium isotopes, there are, cyclic amines, as they are described by Volkert et al. (Appl. Radiol. Isot. 1982, 33; 891) and I IU Troutner et al. Nucl. Med. 1980, 21; 443), but which have the drawback that starting from a pH 9, they are only able to bond technetium-99m in good yields.
N
2 0 2 systems are present in clinical use, but they are affected by the drawback that the corresponding metal complexes in vivo are not very stable. According to investigations of Pillai and Troutner, the complexes lose up to 30% of complexed metal in the plasma as early as after 1 hour (Pillai, M. R. A., Troutner, D. E. et al.; Inorg. Chem. 1990, 29; 1850).
Noncyclic N 4 systems, such as, the HM-PAO, have their low complex stability as a great drawback. Because of its instability (Ballinger, J. R. et al., Appl. Radiat. Isot. 1991, 42; 315), Billinghurst, M. W. et al., Appl. Radiat Isot. 1991, 42; 607), Tc-99m-HM-PAO must be administered within 30 minutes after its labeling, so that the portion of decomposition products, which have a different pharmacokinetics and precipitation, can be kept small. Such radiochemical'impurities make more difficult the detection of diseases to be diagnosed. A coupling of these chelates or chelating agents to other substances selectively accumulating in foci of disease cannot be achieved with simple means, so that the latter are generally dispersed unspecifically in the organism.
N
2
S
2 chelating agents (Bormans, G. et al.; Nucl. Med. Biol.
1990, 17; 499), such as, ethylene dicysteine (EC; Verbruggen, A. M. et al.; J. Nucl. Med. 1992, 33; 551), meet the requirement of sufficient stability of the corresponding technetium-99m complex, but radiodiagnostic agents with a purity
S.
I
of greater than 69% form first starting from a pH of the complexing medium 9.
The previously known N 3 S systems (Fritzburg, EP 0 173 424 and EP 0 250 013) form stable technetium-99m complexes, but they have to be heated to temperatures of about 100 0 C to form a homogeneous radiopharmaceutical agent.
In recent years, the need for radiodiagnostic agents accumulating specifically in diseased tissues has risen. This can be achieved if complexing agents can be coupled easily to selectively accumulating substances and in this case not lose their advantageous complexing properties. Since it very often results, however, that after coupling of a complexing agent with use of one of its functional groups to such a molecule, a weakening of the complex stability is observed, the present attempts to couple chelating agents to selectively accumulating substances appear hardly satisfactory, since a diagnostically intolerable portion of the isotope is released in vivo from the conjugate (Brechbiel, M. W. et al; Inorg. Chem. 1986, 25, 2772).
It is therefore necessary to produce bifunctional complexing agents that carry both functional groups for bonding the desired metal ion and a (different, several) functional group for bonding the selectively accumulating molecule. Such bifunctional ligands make possible a specific, chemically defined bond of technetium or rhenium isotopes to the most varied biological materials, even though a so-called pre-labeling is performed.
In EP 0 247 866, EP 0 188 256 and EP 0 200 492, several chelating agents, which are coupled to monoclonal antibodies or r i i- I I fatty acids, are described. As chelating agents, however, the already-mentioned N 2
S
2 systems are used, which are hardly suitable based on their low stability. Since both the selectively accumulating substances in their propertces and also the mechanisms, according to which they are concentrated, are very different, it is further necessary to vary the couplable chelating agents and to be able to adapt to the physiological requirements of the coupling partner with respect to its lipophilia, membrane permeability, etc.
The object of the invention is therefore to find complexes or complexing agents which overcome the drawbacks of the prior art, which can be produced at a physiological pH from the corresponding complexing agent and the respective metal oxide/salt, can be produced at low temperatures, preferably at room temperature, from the corresponding complexing agent and the respective metal oxide/salt, show a high complex stability even under in vivo conditions, show a high selectivity or tissue-/organ-specificity.
Furthermore, the complexes must meet the requirements which generally are to be imposed on pharmaceutical agents, such as, good compatibility no side effects), good solubility and complete precipitation.
The object is achieved by this invention.
C
I
_I
It has been found that compounds of general formula I 2 3
NX
1 N X X N. 4 V "V 1/ 1 S 4 R NX S CH2)--R 12 SO 2
R
R
P (I) in which
V
1
V
2
V
3
V
4 independently of one another, stand for a carbonyl, >CH(COOH) or -CH 2 group,
X
1 stands for a hydrogen atom, a C 1
-C
12 alkyl radical optionally substituted with a carboxyl, an amino or a thiocyanate group, or a metal ion equivalent of a radioactive metal ion of an element of atomic number 43, 45, 46, 75, 82 or 83,
X
2
,X
3 independently of one another, stand for a hydrogen atom or a metal ion equivalent of a radioactive metal ion of an element of the above-mentioned atomic numbers, n, m, p stand for numbers 0 or 1, whereby m n 1 holds true,
R
1 stands for a hydrogen atom, a carboxyl group or a group
-U-Z,
ij I'M 1mAl %ill( 16.,PJ ANtI- .7 SVS -9in which U stands for a direct bond, a straight-chain or branched, saturated or unsaturated C,-C 20 alkylene radical, which optionally contains a maleimide radical, a succinimide radical, a phenyl radical optionally S substituted by 1 to 5 fluorine atoms, an amino or nitro group, one or two imino, phenylene, phenylenoxy, phenylenamino, amide, hydrazide, carbonyl, uleido, thioureido, thioamide, ester group(s), 1 to 2 oxygen, sulfur and/or nitrogen atoms(s) as well as optionally 1 to 5 hydroxy, mercapto, oxo, thioxo, carboxy, alkylcarboxylic acid, ester, thiocyanate and/or amino groups, and Z stands for a hydrogen atom, a radical of an amino acid, a peptide, a polynucleotide or a steroid, or a functional group from the group which includes -COOH, -SCN, -OH, -Cl or -NH 2 with 15 which optionally the radical of an amino acid, a peptide, a polynucleotide or a steroid is bound, R' stands for a straight-chain or branched Ci-C,, alkyl radical, which optionally contains a -COOH group, a C 7
-C
12 aralkyl radical or an aromatic compound from the group 20 which includes -CoH 4 NCS, H 4 -COOH ur phenyl, which optionally is substituted with a chlorine or bromine atom; a thiocyanate, a methyl, ethyl, carbcxyl and/or methoxy group, R' stands for a hydrogen atom or a carboxyl group or if
R
1 means a hydrogen atom or a carboxyl group, it stands in addition for a group in which U and Z have the indicated meanings, Q L I i' WIVOl)(,o AI-SPI.C1621196 ANMI 26;V
R
3 stands for a hydrogen atom, a radioactive metal ion equivalent of an element of the above-mentioned atomic numbers; a trifluoroacetate, acetate, benzoate, Cl-C 6 acyl, a benzoyl, a hydroxyacetyl, an acetamidomethyl radical, a benzoic acid radical optionally substituted with a chlorine or bromine atom, a methyl, ethyl, carboxyl and/or methoxy group, a p-methoxybenzyl radical, an ethoxyethyl radical, an SH protective group, a
CH,
0 radical, or if X 2
X
3 stand for a hydrogen and X 1 stands for a hydrogen or an optionally substituted C 1
-C
12 alkyl 15 radical, for a radical of formula II so, SO 2 *CH2
R
NX XN \2 3 in which V 1 V, V 3 V, X 1
X
2 1 X 3 n, m, p, R and
R
4 have the indicated meanings,
,HA.
Iv whereby at least one and at most two radicals V 1
V
2
V
3
V
4 stand for a carbonyl group, are very well suited as radiodiagnostic agents and radiotherapeutic agents or for the production of radiodiagnostic agents and radiotherapeutic agents.
The complexing agents (chelating agents) according to the invention, compounds of general formula I with X 1
X
2
X
3 and R 3 in the indicated meanings with the exception of a metal ion equivalent, meet the above-mentioned requirement profile.
They are distinguished more particularly in that they complex the respectively desired metal quickly at the physiological pH and low temperatures. They are therefore especially suitable for routine use in clinical practice.
During the complexing process, monomeric metal complexes of formula I with R 3 meaning a metal ion equivalent are from the dimeric chelating agents with R 3 meaning a radical of general formula II.
As metal ions, radioactive metal ions of the elements of atomic numbers 43, 45, 46, 75, 82 or 83, such as, the radioisotopes technetium-99m, rhodium-103, palladium-109, rhenium-186, lead-212 and bismuth-212, are used, whereby the selection of the metal isotope depends on the desired field of use. According to the invention, metal complexes of the elements technetium and rhenium are preferred.
If the complexes of general formula I according to the invention contain isotopes that emit y-radiation, such as, e.g., Tc-99m, the latter can be used in single-photon emission tomography (SPECT).
O'
NEW
If the complexes of general formula I according to the invention contain isotopes that emit a-particles, such as, e.g., Bi-211, Bi-212, Bi-213, Bi-214 or 8-emitting isotopes, such as, Re-186 or Re-188, the latter can be used in radiotherapy.
According to the invention, compounds of formula I, in which
V
1 and V 4 each stand for a carbonyl group, V 2 and V 3 each for a
-CH
2 group and p for number 0, are preferred.
As radical R 1 hydrogen or a carboxylic acid group and especially a group -U-Z in which Z is a hydrogen atom are suitable, but it preferably stands for the radical of a biomolecule with tissue- or structure-specific properties or a functional group optionally present in activated form with which optionally such a biomolecule can be bound.
As examples of biomolecules, there can be mentioned radicals of an amino acid, a peptide, or a steroid, such as, the known steroid hormones (androgens, gestagens, estrogens, cholesterol, cholic acid derivatives, pregnanes, etc.) as well as polynucleotides such as RNA or DNA.
As examples of functional groups with which optionally the bond of a biomolecule can take place, a -COOH, an -SCN, an -OH, a -C1 or an -NH 2 group can be mentioned. Such groups can also be present in their activated form, as succinimide ester or acid chloride.
U can stand for a direct bond but preferably a straightchain or branched, saturated or unsaturated C 1
-C
20 alkylene radical, which optionally contains a succinimide radical, a phenyl radical optionally substituted by 1 to 5 fluorine atoms, an amino or a nitro group, one or two imino, phanylene, phenylenoxy, phenylenamino, amide, hydrazide, carbonyl, ureido, thioureido, thioamide, ester group(s), 1 to 2 oxygen, sulfur and/or nitrogen atom(s) as well as optionally I to 5 hydroxy, mercapto, oxo, thioxo, carboxy, alkylcarboxylic acid, ester, thiocyanate and/or amino groups.
As examples of U, if Z stands for a biomolecule, there can be mentioned a -CH 2
-C
6
H
4
-O-CH
2
-C
6
H
4
-CH
2 -0 6
H
4
-O-CO-C
1 5
H
30
-OH
2 0 6
H
4 -O-CO- (OH 2 2 -COO-, -CH 2 -0 6
H
4
-O-CH
2
-COO-C
6
H
4
-CH
2
-C
6
H
4
-O-CH
2 COO-, (OH 2 5-COO-, or a -CH 2 -0 6
H
4
(OH
2
(CH
2 group.
As radicals -U-Z with Z meaning hydrogen, there can be mentioned a -CH 2
-C
6
H
4
-O-CH
2
-OOO-
6
F
5
-CH
2
-C
6
H
4 -O-0H 2
-C
6
H
5
-CH
2
-C
6
H
4 0-OH 3
-CH
2
-C
6
H
4 -O-0 6
H
3 I -CH 2 -0 6
H
4
-OC
12
H
25 or a C2 0 6
H
4
-O-COC
5
H
31 group.
As radicals -U-Z with Z meaning an optionally activated functional group, there can be mentioned a -CH 2
-(CH
2 4 -NCS, -CH 2
C
6
H
4 -O-CO- (OH 2 2 -COOH, -CH 2
C
6
H
4
-O-CH
2 -COO-0 6
H
4
-NH
2 -0H 2 -0 6
H
4 -O-0H 2
COO-C
6
H
4 -N0 2
-CH
2
-C
6
H
4 -NCS,00 0 0 -0H 2 -0 6
H
4 (0H 2 2 (0H 2 2 -OH or a -CH 2 -0 6
H
4
-OCH-
2 -COOH group, i. e. 0 Z stands f or an -NOS, -COOH, -NH 2
-NO
2 -OH or a -COO-N group.0 As examples of radicals R 2 there can be mentioned a -C6
I
4- NCS or a -C 6
H
4 -COOH group, but especially a -C1 3 group or a phenyl ring.
As radicals R 3 there can be mentioned as examples, a) in the case of complexing agents: -SH protective
CH-
groups, such as, a -CO-CH 3 o -CO-C 6
-CO-CF
3 or a -C(C 6
H
5 3 group or a radical of general formula II, in which V 1
V
2
V
3
V
4
X
1
X
2
X
3 n, m, p, R 1
R
2 and R 4 have the indicated meanings, b) in the case of the complexes according to the invention: one of the previously mentioned radicals, with the exception of a radical of general formula II: but in addition,
R
3 can also stand for a metal ion equivalent of a radioactive metal ion of an element of the above-mentioned atomic numbers.
In the case of complexing agents, X 2
X
3 stand for a hydrogen atom and X 1 stands for a hydrogen atom or an optionally substituted C 1
-C
12 alkyl radical, in the case of complexes, depending on the oxidation stage of the metal in the complex, at least 2 of radicals X 1
X
2
X
3 or R 3 have the meaning of a metal ion equivalent.
R
4 stands for hydrogen or a carboxyl group, but R 4 can also stand for a group -U-Z with U and Z in the previously-indicated meanings, whereby it always holds true that at most one of two radicals R 1 or R 4 means a group According to the invention, compounds with R 4 meaning hydrogen are preferred.
Indices m and n stand for numbers 0 or 1. Since isomeric compounds can accumulate in the synthesis of complexing agents y.
according to the invention, it holds true that the sum of m and n is always 1.
The invention also relates to the process for the production of complexing agents and complexes according to the invention, whereby suitably different reaction paths are followed in the synthesis of the complexing agent as a function of the desired target structure. Some typical syntheses are described as examples below. Other complexing agents can be produced analogously to the synthesis methods described.
1. If ligands are to be produced, which contain an -O-C 6
H
4
CH
2 group in R 1 a start is advantageously made from a tyrosine ester, whose amino group first is protected in the way known to one skilled in the art by reaction with a reagent Z 1 -Cl, in which
Z
1 stands for any amino protective group, preferably for a benzyloxycarbonyl group (also named Z group below). Then, the phenolic hydroxyl group is alkylated with an alkyl iodide in a way known in the art, the amino protective group is cleaved off in acidic form and then tosylated, with toluenesulfonic acid chloride. The thus obtained intermediate product is reacted in an aminolysis of the ester function with ethylenediamine.
Then, it is reacted with 2-acetylmercaptosuccinic anhydride to the complexing agents according to the invention, whereby both isomers are always obtained in the last reaction step.
2. The production of ligands containing an -O-CO-CH 2 -O-C6H4-
CH
2 group in R 1 according to the invention is carried out by first, as described above, the corresponding Z-protected compound starting from tyrosine ester being produced. The phenolic hydroxyl group is then alkylated with bromoacetic acidt-butyl ester, and the amino protective group is cleaved off in a way known in the art. Tosylation and aminolysis of the ester function with ethylenediamine are carried out as described under 1, then it is reacted, however, with chloroacetyl chloride.
Chlorine is substituted in a way known in the art by reaction with potassium thioacetate or sodium thioacetate, and the t-butyl ester is acidically saponified. Optionally, the resulting carboxylic acid group can be activated with hydroxysuccinimide and then reacted with the respectively desired biomolecule.
3. Ligands according to the invention, in which R 1 stands for an SCN-C 6
H
4
-CH
2 radical, can be obtained by first the amino group of a p-nitrophenylalanine ester being tosylated in a way known in the art. Then, the nitro group is hydrogerated, and the resulting aromatic amino group is protected, o r3action with benzyl chloroformate. The aminolysis of the estor function with ethylenediamine follows this reaction step, as described in the preceding cases, followed by a reaction with S-protected mercaptoacetic acid. The cleavage of the benzyloxycarbonyl group follows the latter. The introduction of the isothiocyanate group is carried out by reaction with thiophosgene.
4. The production of the ligands according to the invention with X 1 meaning an alkyl radical is carried out by first the amino group of a glycine ester being tosylated with toluenesulfonyl chloride. Then, the ester function is reacted in an aminolysis with ethylenediamine. The resulting free amino group is protected with a tert-butoxycarbonyl group (designated below as a BOC group) and the nitrogen substituted with a tosyl radical is N-alkylated with an alkyl iodide in a way known in the art. After the cleavage of the BOC group, the reaction with 2acetylmercaptosuccinic anhydride follows, whereby again a mixture of isomers is obtained.
Ligands according to the invention with R 1 meaning an aminobutyl radical can be obtained by the BOC-protected lysine ester on a nitrogen atom first being tosylated on the remaining unprotected primary amino group and then being reacted with ethylenediamine in an aminolysis. Below, it is reacted with 2acetylmercaptosuccinic anhydride (whereby a mixture of isomers results) and the amino protective group is cleaved off according to known methods.
6. The production of ligands, according to the invention, that contain an isothiocyanatophenyl radical as R 2 is carried out by reaction of a glycine methyl ester with nitrobenzenesulfonyl chloride, subsequent reduction of the nitro group and protection of the resulting amino group. The thus obtained intermediate compound is reacted in an aminolysis with ethylenediamine and then with S-protected mercaptoacetic acid. The subsequent cleavage of the (BOC) protective group is carried out in a known way. The free amino group is then reacted with thiophosgene to the corresponding isothiocyanate group.
The production of the metal complexes of general formula I according to the invention with at least two radicals X 1
X
2
X
3 and/or R 3 in the meaning-of a metal ion equivalent is carried out in a way known in the art, by the complexing agents according to the invention (which can be obtained as previously described) being dissolved in aqueous medium with the addition of a reducing agent, prererably tin(II) salts, such as tin chloride or tin tartrate and optionally with the addition of the additives usual in galenicals, such as physiologically harmless buffers tromethamine), small additions of electrolytes sodium chloride), stabilizers gluconate, phosphates or phosphonates), etc. and then sterilized by filtration. In the case of short-lived metal isotopes, such as, Tc-99m, this solution is reacted immediately before administration with an aqueous solution of the respectively desired metal ion. In the case of long-lived isotopes, the reaction with the metal salt/oxide can even be performed by the manufacturer of radiopharmaceutical agents. To assure a complete complexing of the metal isotope, the complexing agent is generally added in at least a 100-fold excess, besides the desired metal complex, the agents according to the invention contain in addition the metal-free complexing agent, which is added advantageously in the form of its potassium salt.
Reaction solutions containing the above-mentioned described metal complex can basically be administered immediately without further working-up.
Since the technetium in particular can be present in a series of oxidation stages to it is advisable to attach stabilizers to the complexing agents. The latter keep the radionuclide in a stable form, until it has reacted completely with the complexing agent (ligand). The stabilizers, which are ('JjI known as transfer or auxiliary ligands, first complex the metal in an exactly defined oxidation stage and then provide it to the target ligands (complexing agents) in a ligand exchange reaction.
Examples of auxiliary ligands are gluconoheptonic acid, tartaric acid, citric acid (including their salts) or other substances known to one skilled in the art.
Optionally, the obtained metal complexes are mixed with pharmacologically acceptable radiological vehicles. This radiological vehicle should exhibit advantageous properties for the administration of the radiopharmaceutical agent in the form of an injection, inhalation or ingestion. As vehicles there can be mentioned as examples HSA, aqueous buffer solutions, such as, tris(hydroxymethyl)aminoethane (or their salts), phosphate, citrate, bicarbonate, etc., sterile water, physiological common salt solution, isotonic chloride or dicarbonation solutions or normal plasma ions such as Ca2+, Na and Mg2.
In nuclear-medicine in vivo use, the agents according to the invention are dosed in amounts of 10' 5 to 5 x 104 nmol/kg of body weight, preferably in amounts between 10-3 to 5 x 102 nmol/kg of body weight (relative to the metal complex). Starting from an average body weight of 70 kg, the required amount of radioactivity for diagnostic uses is between 1.85 MBq and 1.85 GBq per administration. The administration is carried out normally by intravenous, intraarterial, peritoneal or intratumoral injection of 0.1 to 2 ml of a solution of the agents according to the invention. Intravenous administration is preferred.
The metal complexes according to the invention with metal ions of the above-mentioned elements and the pharmaceutical agents prepared from them are distinguished by good compatibility and high stability in vivo. The complexing agents according to the invention are distinguished by an easy labeling capability, they complex the desired metals in high yields at room temperature and neutral pH.
The following examples are used for a more detailed explanation of the object of the invention, without intending that they be limited to this object.
Example 1 a) N-Benzyloxycarbonyl-tyrosine methyl ester A suspension of 97.6 g (0.5 mol) of tyrosine methyl ester in 500-1000 ml of dichloromethane is mixed at room temperature with a solution of 86 g of benzyl chloroformate in 100 ml of dichloromethane. Then, 51 g of triethylamine is slowly added in drops while being cooled, and it is stirred overnight. The mixture is concentrated by evaporation on a rotary evaporator at 0 C, the residue is taken up in 750 ml of EtOAc, and the undissolved material is filtered out. The filtrate is washed three times saturated common salt solution, dried and concentrated by evaporation and recrystallized.
Yield: 72% Cld: C 65.64% H 5.82% N 4.25% O 24.29% Fnd: C 65.47% H 5.98% N 4.02% b) N-Benzyloxycarbonyl-2-[(4-hexyloxy)benzyl]-2-aminoacetic acid methyl ester 1.12 g of potassium-tert-butylate (10 mmol) is added to a solution of 3.29 g of the compound produced according to Example la) (10 mmol) in 50 ml of DMF at room temperature, and then the solution of 2.12 g of hexyl iodide (10 mmol) in 10 ml of DMF is added in drops and heated for 3 hours to 110 0 C. After cooling to room temperature, it is poured onto ice, extracted with dichloromethane, washed several times with water, dried, filtered and concentrated by evaporation. After chromatography on a silica gel column (CH 2 C 2/EE 19:1), 1.8 g of a pale yellow oil remains.
Yield: 44% Cld: C 69.71% H 7.56% N 3.39% O 19.35% Fnd: C 69.54% H 7.69% N 3.13% c) 2-[(4-Hexyloxy)benzyl]-2-aminoacetic acid methyl ester 4.14 g (10 mmol) of the Z 1 -protected compound produced according to Example Ib) is hydrogenated with hydrogen in 50 ml of ethyl acetate in the presence of 1.5 g of palladium on activated carbon at 500C. After the reaction is completed, the catalyst is filtered out, and the solvent is drawn off. 2.7 g of colorless oil remains.
Yield: 97% Cld: C 68.79% H 9.02% N 5.01% O 17.18% Fnd: C 68.64% H 9.11% N 5.09% d) N-p-Toluenes'ulfonyl-2[(4-hexyloxy)benzyl]-2-aminoacetic acid methyl ester 8.38 g of the amine (30 mmol) produced according to Example Ic) is dissolved in 50 ml of dichloromethane and mixed at 0°C with 5.72 g of toluenesulfonic acid chloride in 30 ml of dichloromethane. While being stirred '-tensively, 3.0 g of triethylamine is added in drops at 0°C and stirred for 1 hour at room temperature. After the reaction is con '.Leted, it is mixed with ice water and extracted several times with dichloromethane.
The combined organic extracts are washed twice with cold 10% HC1, three times with 10% NaHCO 3 solution and twice with saturated Nacl solution. After drying, the solvent is drawn off and chromatographed (silica gel, CH 2 Cl 2 Yield: Cld: C 63.72% H 7.21% N 3.23% O 18.45% S 7.40% Fnd: C 63.48% H 7.52% N 3.02% S 7.25% e) N-p-Toluenesulfonyl-2[(4-hexyloxy)benzyl]-2-aminoacetic acid[N-(2-amino-ethyl)]amide A solution of 433 mg of tosyl glycine ester (1 mmol) p.-duced according to Example Id) in 1 ml of anhydrous dichloromethane is slowly added in drops to a solution of 1.2 g of ethylenediamine (20 mmol) in 1 ml of anhydrous dichloromethane and refluxed. After the reaction is completed, it is concentrated by evaporation in a vacuum, and the residue is chromatographed (silica gel, MeOH).
Yield: 42% Cld: C 62.45% H 7.64% N 9.10% O 13.864% S 6.95% Fnd: C 62.36% H 7.81% N 8.94% S 6.80% f) N-p-Toluenesulfonyl-2[(4-hexyloxy)benzyl]-2-aminoacetic acid-N-{2-N[(3-carboxy-2-mercaptoacetyl-l-oxopropyl)]aminoethyl}amide 0.38 g (2.2 mmol) of 2-acetylmercaptosuccinic anhydride is added to a solution of 1.00 g of the amine (2.2 mriol) produced according to Example le) in 10 ml of pyridine/DMF (50:50) and stirred for 4 hours at room temperature. Then, the solvent is drawr off, the residue is taken up in 0.5N HC1 and extracted with
CH
2 Cl 2 After flash chromatography, 420 mg of a yellow oil remains.
Yield: 31% Cld: C 56.67% H 6.50% N 6.61% 0 20.13% S 10.09% Fnd: C 56.41% H 7.01% N 6.43% S 9.90% g) Tc-99m complex of N-p-toluenesulfonyl-2[(4-hexyloxy)benzyl]- 2-aminoacetic acid-N-{2-N[(3-carboxy-2-mercaptoacetyl-1oxopropyl)]aminoethyl}amide 1 mg of the compound produced according to Example If) is dissolved in 100 gl of EtOH. 50 1 of this solution is added to 250 pg of a 0.1 M phosphate buffer of pH 8.5 and then mixed with 100 gl of a 99m-Tc-gluconate solution and allowed to stand for minutes. The labeling yield is determined with the aid of HPLC.
Example 2 a) N-Benzyloxycarbonyl-2-[(4-methyloxy)benzyl]-2-aminoacetic acid methyl ecter 1.12 g of potassium-tert-butylate (10 mmol) is added to a solution of 3.29 g of the alcohol (10 mmol) produced according to Example la) in 50 ml of DMF at room temperature and then the solution of 1.42 g of methyl iodide (10 mmol) in 10 ml of DMF is added in drops and heated to 11C C. After the reaction is completed, it is allowed to cool to room temperature, poured onto ice, extracted with dichloromethane, washed several times with water, dried, filtered and concentrated by evaporation. After v i column chromatography (silica gel, CH 2 C1 2 /EE 19:1), 1.92 g of an oil remains.
Yield: 56% Cld: C 66.46% H 6.16% N 4.08% 0 23.30% Fnd: C 66.18% H 6.41% N 3.97% b) 2-[(4-Methyloxy)benzyl]-2-aminoacetic acid methyl ester 3.43 g (10 mmol) of the Z 1 -protected c mpound produced according to Example 2a) is hydrogenated with hydrogen in 50 ml of ethyl acetate in the presence of 1.5 g of palladium on activated carbon at room temperature. After the reaction is completed, the catalyst is filtered out, and the solvent is drawn off.
Yield: 98% Cld: C 63.14% H 7.23% N 6.69% 0 22.94% Fnd: C 62.91% H 7.36% N 6.50% c) N-p-Toluenesulfonyl-2[(4-methyloxy)benzyl]-2-aminoacetic acid methyl ester 6.28 g of the amine (30 mmol) produced according to Example 2b) is dissolved in 50 ml of dichloromethane and mixed at 0 C with 5.72 g of toluenesulfonic acid chloride in 30 ml of dichloromethane. While being stirred intensively, 3.0 g of triethylamine is added in drops at 0 0 C and stirred for 1 hour at room temperature. After the reaction is completed, it is mixed with ice water and extracted several times with dichloromethane.
The combined organic extracts are washed twice with cold 10% HCl, three times with 10% NaHC03 solution and twice with saturated NaCl solution. After drying, the solvent is drawn off.
Yield: 76% Cld: C 59.49% H 5.82% N 3.85% O 22.01% S 8.82% Fnd: C 59.32% H 6.03% N 3.66% S 8.64% N-p-Toluenesulfonyl-2[(4-methyloxy)benzyl]-2 -aminoacetic acid-[N-(2-aminoethyl)]amide A solution of 363 mg of the ester (1 mmol) produced according to Example 2c) in 1 ml of anhydrous dichloromethane is slowly added in drops to a solution of 600 mg of ethylenediamine mmol) in 1 ml of anhydrous dichloromethane and refluxed.
After the reaction is completed, it is concentrated by evaporation in a vacuum, mixed with ethanolic HC1 and stirred for 2 hours at room temperature. The solvent is drawn off, and the residue is recrystallized.
Yield: 49% Cld: C 58.29% H 6.44% N 10.73% 0 16.35% S 8.19% Fnd: C 57.89% H 6.84% N 10.01% S 7.52% e) N-p-Toluenesulfonyl-2[(4-methyloxy)benzyl]-2-aminoacetic acid-N-{2-N[(3-carboxy-2-mercaptoacetyl-1oxopropyl)]aminoethyl}amide 0.38 g (2.2 mmol) of 2-acetylmercaptosuccinic anhydride is added to a solution of 941 mg of the amine (2.2 mmol) produced according to Example 2d) in 10 ml of pyridine/DMF (50:50), and it is stirred for 4 hours at room temperature. Then, the solvent is -i drawn off, the residue is taken up in 0.5N HC1 and extracted with
CH
2 Cl 2 After flash chromatography, 905 mg of a yellow oil remains.
Yield: 73% Cld: C 53.08% H 5.52% N 7.43% 0 22.63% S 11.34% Fnd: C 52.31% H 5.45% N 7.06% S 11.61% f) Tc-99m complex of N-p-toluenesulfonyl-2[(4methyloxy)benzyl]-2-aminoacetic acid-N-{2-N[(3-carboxy-2mercaptoacetyl-l-oxopropyl)]aminoethyl}amide 1 mg of the compound produced according to Example 2e) is dissolved in 100 il of EtOH. 50 ul of this solution is diluted with 250 .l of EtOH, mixed with 50 p, of a 0.1 M phosphate buffer of pH 8.5 and then mixed with 100 pl of a 99m-Tc-gluconate solution and allowed to stand for 15 minutes. After filtration, the labeling yield is determined with the aid of HPLC.
Example 3 a) N-Benzyloxycarbonyl-2-[ (4-dodecyloxy)benzyl]-2-aminoacetic acid methyl ester 1.12 g of potassium-tert-butylate (10 mmol) is added to a solution of 3.29 g of the alcohol (10 mmol) produced according to Example la) in 50 ml of DMF at room temperature, and then the solution of 3.55 g of dodecyl iodide (12 mmol) in 10 ml of DMF is added in drops and heated for 3 hours to 110 0 C. Then, it is allowed to cool to room temperature, poured onto ice, extracted with dichloromethane, washed several times with water, d.ied, filtered and concentrated by evaporation. After SC [column chromatography] (silica gel, CH 2 Clg/EE 19:1), 2.2 g of the desired substance remains.
Yield: 44% Cld: C 72.40% H 8.71% N 2.81% O 16.07% Fnd: C 72.08% H 8.85% N 2.68% b) 2-[(4-Dodecyloxy)benzyl]-2-aminoacetic acid methyl ester 4.98 g (10 mmol) of the Z 1 -protected compound produced according to Example 3a) is hydrogenated with hydrogen in 50 ml of ethyl acetate in the presence of 1.5 g of palladium on activated carbon at 500C. After the reaction is completed (4 hours), the catalyst is filtered out, and the solvent is drawn off.
Yield: 91% Cld: C 72.69% H 10.26% N 3.85% 0 13.20% Fnd: C 72.53% H 9.98% N 3.82% c) N-p-Toluenesulfonyl-2[(4-dodecyloxy)benzyl]-2-aminoacetic acid methyl ester 10.91 g of the amine (30 mmol) produced according to Example 3b) is dissolved in 50 ml of dichloromethane and mixed at 0°C with 5.72 g of toluenesulfonic acid chloride in 30 ml of dichloromethane. While being stirred intensively, 3.0 g of triethylamine is added in drops at 0°C and stirred for 1 hour at room temperature. After the reaction is completed, it is mixed with ice water and extracted several times with dichloromethane.
The combined organic extracts are washed twice with cold 10% HC1, three times with 10% NaHCO 3 solution and twice with saturated Naci solution. After drying, the solvent is drawn off and chromatographed (silica gel, CH2Cl 2 Yield: Cld: C 67.28% H 8.37% N 2.71% 0 15.45% S 6.19% Fnd: C 66.96% H 8.26% N 2.60% S 6.11% d) N-p-Toluenesulfonyl-2[(4-dodecyloxy)benzyl]-2-aminoacetic acid[N-(2-aminoethyl)]amide A solution of 3.3 g of the ester (6.38 mmol) produced according to Example 3c) in 10 ml of anhydrous dichloromethane is slowly added in drops to a solution of 1.92 g of ethylenediamine (31.9 mmol) in 20 ml of anhydrous dichloromethane and refluxed for 4 hours. After the reaction is completed, it is concentrated by evaporation in a vacuum, and the residue is recrystallized.
2.3 g of white crystals remains.
Yield: Cld: C 66.02% H 8.68% N 7.70% 0 11.73% S 5.86% Fnd: C 65.88% H 8.80% N 7.59% S 5.76% e) N-p-Toluenesulfonyl-2[(4-dodecyloxy)benzyl]-2-aminoacetic acid-N-{2-N[(3-carboxy-2-mercaptoacetyl-1-oxopropyl)]aminoethyl}amide 0.32 g (1.8 mmol) of 2-acetylmercaptosuccinic anhydride is added to a solution of 1.00 g of the amine (1.8 mmol) produced according to Example 3d) in 10 ml of pyridine/DMF (50:50), and it is stirred for 4 hours at room temperature. Then, the solvent is drawn off, the residue is taken up in 0.5N HC1 and extracted with
CH
2 Cl 2 After flash chromatography (silica gel, EtOAc/MeOH 9:1), 420 mg of a yellow oil remains.
Yield: 32% Cld: C 60.06% H 7.42% N 5.84% 0 17.78% S 8.91% Fnd: C 59.76% H 7.61% N 5.77% S 8.78% f) Tc-99m complex of N-p-toluenesulfonyl-2[(4dodecyloxy)benzyl]-2-aminoacetic acid-N-{2-N[(3-carboxy-2mercaptoacetyl-1-oxopropyl)]aminoethyl}amide 1 mg of the compound produced according to Example 3e) is dissolved in 100 Al of EtOH. 50 pl of this solution is added to 250 Al of a 0.1 M phosphate buffer of pH 8.5 and then mixed with 100 Al of a 99m-Tc-gluconate solution and allowed to stand for minutes. The labeling yield is determined with the aid of HPLC.
Example 4 a) N-p-Toluenesulfonyl-2[(4-benzyloxy)benzyl]-2-aminoacetic acid-N-{2-N[(3-carboxy-2-mercaptoacetyl-1oxopropyl)]aminoethyl}amide The solution of 4.68 g (10 mmol) of the amino compound produced according to Example 16b) in 150 ml of THF is slowly added in drops to a solution of 3.48 g of acetylmercaptosuccinic anhydride (20 mmol) in 50 ml of THF at room temperature and stirred overnight. Then, it is allowed to crystallize out at 0 C. 2.8 g of white crystals remains.
Yic d: 44% Cld: C 58.02% H 5.50% N 6.55% 0 19.95% S 9.99% Fnd: C 57.80% H 5.72% N 6.51% S 9.85% b) Tc-99m complex of N-p-toluenesulfonyl-2[(4benzyloxy)benzyl]-2-aminoacetic acid-N-{2-N[(3-carboxy-2mercaptoacetyl-1-oxopropyl)]aminoethyl}amide 1 mg produced according to Example 4a) is dissolved in 100 i. of EtOH. 50 pl of this solution is added to 250 Al of a 0.1 M phosphate buffer of pH 8.5 and then mixed with 100 Al of a 99m- Tc-gluconate solution and allowed to stand for 15 minutes. The labeling yield is determined with the aid of HPLC.
Example a) N-p-Toluenesulfonyl-(4-nitrophenyl)alanine methyl ester 7.56 g of 4-nitrophenylalanine methyl ester (30 mmol) is suspended in 30 ml of water and mixed at 0 C with 5.72 g of toluenesulfonic acid chloride in 20 ml of diethyl ether. While being stirred intensively, 3.0 g of anhydrous sodium carbonate is added in portions at 0 C within one hour, and it is stirred overnight at room temperature. It is mixed with water and extracted several times with ethyl acetate. The combined organic extracts are washed twice with cold 10% HC1, three times with NaHCO 3 solution and twice with saturated NaCI solution. After drying, the solvent is drawn off. 8.6 g of yellowish crystals remains.
Yield: 76% \j Cld: C 53.96% H 4.80% N 7.40% O 25.37% S 8.47% Fnd: C 53.79% H 4.99% N 7.29% S 8.30% b) N-p-Toluenesulfonyl-(4-aminophenyl)alanine methyl ester The solution of 2.0 g of N-p-toluenesulfonyl-(4nitrophenyl)alanine methyl ester in methanol is added to the suspension of 500 mg of Pd/C in 25 ml of methanol, and it is hydrogenated at 55 0 C with hydrogen. After filtration and concentration by evaporation, 1.4 g of whitish crystals remains.
Yield: 76% Cld: C 58.60% H 5.79% N 8.04% O 18.37% S 9.20% Fnd: C 58.09% H 5.99% N 8.80% S 9.01% c) N-p-Toluenesulfonyl-{4-[N-(tertbutyloxycarbonyl)]aminophenyl}-alanine methyl ester A solution of 3.78 g (10 mmol) of the amino compound produced according to Example 5b) and 3 g of triethylamine mmol) in 50 ml of dioxane is mixed in one portion with 7.4 g of di-tert-butyl-dicarbonate (34 mmol). (Gas generation!) The solution is stirred for 3 hours at room temperature, then poured onto ice water and extracted three times with ethyl acetate. The combined organic phases are washed three times with water and once with saturated common salt solution, dried (MgSO4), concentrated by evaporation and recrystallized.
Yield: 89% Cld: C 58.91% H 6.29% N 6.25% O 21.40 S 7.15% Fnd: C 58.12% H 6.69% N 6.21% S 6.59% d) N-p-Toluenesulfonyl-{4-[N-(tertbutyloxycarbonyl)]aminophenyl}-alanine[N-(2-aminoethyl)]amide The solution of 700 mg of N-p-toluenesulfonyl-{4-[N-(tertbutyloxycarbonyl)]aminophenyl}-alanine methyl ester (1.6 mmol) in 1 ml of anhydrous dichloromethane is added in drops to a solution of 450 mg of ethylenediamine (7.5 mmol) in 5 ml of anhydrous dichloromethane and refluxed for 8 hours. After the reaction is completed, it is concentrated by evaporation in a vacuum, and the residue is chromatographed (silica gel, ethyl acetate/MeOH 9:1).
Yield: Cld: C 57.97% H 6.77% N 11.76% O 16.79% S 6.73% Fnd: C 57.08% H 6.12% N 12.33% S 6.41% e) N-p-Toluenesulfonyl-{4-[N-(tertbutyloxycarbonyl)]aminophenyl}-alanine[N- (chloroacetylaminoethyl)]amide The solution of 1.24 g of chloroacetyl chloride (11 mmol) in ml of dichloromethane is added in drops to a solution of 4.77 g of the amine (10 mmol) produced according to Example 5d in 10 ml of dichloromethane at 0°C, then the solution of 2.02 g of triethylamine in 5 ml of dichloromethane is slowly added in drops (attention: strong heat build-up) and stirred overnight. Then, it is mixed with water, extracted with EtOAc, washed neutral with water, dried and concentrated by evaporation. 2.77 g of white crystals remains.
Yield: Cld: C 54.29% H 6.01% N 10.13% 0 17.38% S 5.80% Fnd: C 53.76% H 5.78% N 9.66% S 5.92% f) N-p-Toluenesulfonyl-{4-[N-(tertbutyloxycarbonyl)]aminophenyl}-alanine[N-(2- (acetylmercapto)acetylaminoethyl)]amide In 5 ml of anhydrous DMF under nitrogen atmosphere, a solution of 238 mg of potassium thioacetate (2 mmol) in anhydrous DMF is added in drops to a solution of 553 mg of the derivative (1 mmol) produced according to Example 5e and a catalytic amount of Nal and heated for 3 hours to 110 0 C. The hot solution is allowed to cool to room temperature, and it is poured into 1N HC1 ml). Then, it is extracted with EtOAc, washed neutral with water, dried, concentrated by evaporation and chromatographed (silica gel, EtOAc/MeOH 9:1).
Yield: Cld: C 54.71% H 6.12% N 9.45% O 18.90% S 10.82% Fnd: :4.40% H 6.45% N 9.25% S 10.04% g) N-p-Toluenesulfonyl-{4-aminophenyl}-alanine-[N-(2- (acetylmercapto)acetylaminoethyl)]amide, hydrochloride mg of N-p-toluenesulfonyl-{4-[N-(tertbutyloxycarbonyl)]aminophenyl}-alanine[N-(2- (acetylmercapto)acetylaminoethyl)]amide is dissolved in 2 ml of 3 M HC1 in ethyl acetate and stirred for 6 hours at room temperature. After the solvent is drawn off, 70 mg of white crystals remains.
Yield: 100% Cid: C 49.95% H 5.53% N 10.59% 0 15.12% S 12.12% Fnd: C 49.32% H 5.76% N 10.20% S 11.77% h) N-p-Toluenesulfonyl-{4-isothiocyanatophenyl-alalie- (2- (acetylmercapto) acetylaminoethyl)]Jamide The solution of 11.5 mg of thiophosgene in a little dichloromethane is added in drops with exclusion of moisture to a solution of 53 mg of N-p-toluenesulfonyl-{4-aminophenyl}-alanine- (acetylmercapto) acetylaminoethyl) ]amide, hydrochloride and A.l of triethylamine in 4 ml of dichioromethane, and it is stirred for 4 hours at room temperature. After the solvent is drawn off, 45 mg of yellowish crystals remains.
Yield: 84% Cld: C 51.67% H 4.90% N 10.48% 0 14.96% S 17.99% Fnd: C 50.99% H 5.15% N 10.21% S 18.56% Example 6 a) N-p-Toluenesulfonyl-{4- (tertbutyloxycarbonyl) Jaminophenyl}-alanine-i N- (2- (benzoylmercapto) acetylaminoethyl) ]amide 2 mmol of S-benzoyl-2-mercaptoacetic acid (394 mg) and 4 mmol of NEt 3 (560 tl) and 2 mmol of N-p--toluenesulfonyl-{4-[N- (tert-butyloxycarbonyl) aminophenyl}-alanine-[N- (2aminoethyl)]amide (953 mg) are mixed with 5 ml of dichloromethane and cooled to 10 0 C. Then, 2 mmol (509 mg) of 1benzotriazolyloxy-tris- (dimethylamino) -phosphoniumhexafluorophosphate-chloride (designated beloe- as BOP-C1) is added and stirred for 4 hours while being cooled in water, then it is mixed with water and brought to pH 1-1.5 with 4N HC1.
Then, it is extracted with dichloromethane, the combined organic extracts are washed with NaHCO 3 and water, dried, concentrated by evaporation and chromatographed.
Yield: Cld: C 58.70% H 5.85% N 8.56% 0 17.10% S 9.79% Fnd: C 58.04% H 6.03% N 8.39% S 9.30% b) N-p-Toluenesulfonyl-{4-aminophenyl}-alanine-[N-(2-(benzoylmercapto)acetyl-aminoethyl)]amide, hydrochloride A freshly produced solution of 3 M HC1 in EtOAc (10 ml, mmol) is added to a solution of 654 mg of the protected amine produced according to Example 6a) (1 mmol) in 5 ml of EtOAc. It is stirred for 30 minutes at room temperature. The solvent js drawn off, and the residue is dried in a vacuum at room temperature.
Yield: 98% Cld: C 54.86 H 5.29% N 9.48% O 13.53% S 10.85% Fnd: C 53.90% H 5.52% N 9.09% S 9.97% c) N-p-Toluenesulfonyl-{4-isothiocyanatophenyl}-alanine-[N-(2- (benzoylmercapto)-acetylaminoethyl)]amide The solution of 115 mg of thiophosgene in a little dichloromethane is added in drops with exclusion of moisture to a solution of 296 mg of the title compound of Example 6b) mmol) and 200 pl of triethylamine in 4 ml of dichloromethane, and it is stirred for 4 hours at room temperature. After tho solvent is drawn off, a residue remains, which is taken up in chloroform and washed with 0.1% citric acid, washed twice with NaHCO 3 solution and once with water. After drying and concentration by evaporation, 45 mg of yellowish crystals remains.
Yield: Cld: C 56.36 H 4.73% N 9.39% 0 13.14% S 16.12% Fnd: C 56.31% H 4.98% N 9.08% S 17.01% Example 7 a) N-(3-Nitrobenzenesulfonyl)glycine methyl ester 25.11 g of glycine methyl ester (0.2 mol) is dissolved in 500 ml of dichloromethane and mixed drop by drop with 44.32 g of 3-nitrobenzenesulfonic acid chloride in 100 ml of dichloromethane at 0 C. While being stirred intensively, 40 g of triethylamine, ml of dichloromethane are added in drops at 0 C and stirred for 1 hour at room temperature. After the reaction is completed (TLC control), it is mixed with ice water and extracted several times with dichloromethane. The combined organic extracts are washed twice with cold 10% HC1, three times with 10% NaHCO 3 solution and twice with saturated NaCI solution, After drying, the solvent is drawn off.
Yield: 82% Cld: C 39.42% H 3.68% N 10.22% 0 35.00% S 11.69% Fnd: C 40.31% H 3.37% N 9.89% S 11.0.4% N-(3-Aminobenzenesulfonyl)glycine methyl ester 2.74 g (10 mmol) of the nitro compound produced according to Example 7a) is hydrogenated with hydrogen in 50 ml of glacial acetic acid in the presence of 1.5 g of palladium on activated carbon at room temperature. After the reaction is completed, the catalyst is filtered out, and the solvent is drawn off.
Yield: Cld: C 44.26% H 4.95% N 11.47% O 26.20% S 13.13% Fnd: C 44.01% H 5.11% N 12.08% S 12.76% c) N-[(3-Aminobenzenesulfonyl)]glycyl-[N'-(2-aminoethyl)]amide A solution of 1 g of the N-(3-aminobenzenesulfonyl)-glycine methyl ester (3.6 mmol) in 2.5 ml of anhydrous dichloromethane is slowly added in drops, refluxed, to a solution of 2.2 g of ethylenediamine (36 mmol) in 2.5 ml of anhydrous dichloromethane.
After the reaction is completed, it is concentrated by evaporation in a vacuum, and the residue is chromatographed (silica gel, CH 2 Cl 2 /MeOH 9:1).
Yield: 76% Cld: C 44.11% H 5.92% N 20.57% O 17.63% S 11.78% Fnd: C 43.09% H 6.41% N 21.82% S 10.68% d) N-[(3-Aminobenzenesulfonyl)]glycyl-{N'- [(acetylmercapto)acetyl(2-aminoethyl)}amide 250 mg (1.08 mmol) of SATA (SIGMA Chemie [SIGMA Chemistry], 1994; A 9043) in THF is slowly added in drops under argon and iI with exclusion of moisture to a solution of 272 mg of amine (1 mmol) produced according to Example 7c) in anhydrous THF at 0 0
C,
and it is stirred for 2 hours at 0C, then for 12 hours at room temperature. The solvent is drawn off, and the residue is chromatographed (silica gel, CH 2 C1 2 /MeOH 9:1).
Yield: Cld: C 43.29% H 5.19% N 14.42% 0 20.59% S 16.51% Fnd: C 42.45% H 5.23% N 15.64% S 15.36% e) N-[(3-Isothiocyanatobenzenesulfonyl)]glycyl-{N'- [(acetylmercapto)acetyl]-(2-aminoethyl)}amide The solution of 65 mg of thiophosgene in a little dichloromethane is added in drops to a solution of 200 mg of N- [(3-aminobenzenesulfonyl)]glycyl-{N'-[(acetylmercapto)-acetyl]-- (2-aminoethyl)}amide and 20 pl of triethylamine in 4 ml of dichloromethane with exclusion of moisture, and it is stirred for 4 hours at room temperature. After the solvent is drawn off, a residue remains, which is taken up in chloroform and washed with 0.1% citric acid, washed twice with NaHCO 3 solution and once with water. After drying and concentration by evaporation, 197 mg of yellowish crystals remains.
Yield: 89% Cld: C 41.85% H 4.21% N 13.01% 0 18.58% S 22.35% Fnd: C 40.44% H 3.93% N 12.57% S 23.66% Example 8 a) N-Benzyloxycarbonyl-o-t-butyloxycarbonylmethyl-(tyrosine meihylester) 3.29 g of the Z 1 -protected tyrosine methyl ester produced according to Example la) is dissolved in anhydrous DMF and mixed with 1.12 g of potassium-t-butylate. After 30 minutes, the solution of 1.95 g of bromoacetic acid-t-butyl ester is added in drops and heated for 4 hours to 110 0 C, then it is stirred for 4 more hours at room temperature. The mixture is added to water, extracted with CH 2 C1 2 washed, dried and concentrated by evaporation. After column chromatography (silica gel, CH 2 C1 2
/EE
19:1), 2.5 g of yellow oil remains.
Yield: 57% Cld: C 65.00% H 6.59% N 3.16% 0 25.25% Fnd: C 64.65% H 6.82% N 3.09% b) O-(t-Butyloxycarbonylmethyl)-tyrosine methyl ester g (3.4 mmol) of the Z-protected compound produced according to Example 8a) is hydrogenated with hydrogen in 50 ml of ethyl acetate in the presence of 1.5 g of palladium on activated carbon at 50°C. After the reaction is completed, the catalyst is filtered out, and the solvent is drawn off. g of colorless oil remains.
Yield: 99% Cld: C 62.12% H 7.49% N 4.53% O 25.86% Fnd: C 61.88% H 7.67% N 4.47% c) N-Toluenesulfonyl-0-t-butyloxycarbonylmethyl-tyrosine methyl ester The solution of 570 mg of toluenesulfonyl chloride in CH2Cl 2 is added in drops to a solution of 920 mg of O-(tbutyloxycarbonylmethyl)-tyrosine methyl ester in CH 2 Cl 2 at 0°C, and it is then slowly mixed with 300 mg of triethylamine and stirred overnight. It is poured onto ice water, extracted with
CH
2 Cl 2 the organic phase is washed twice with 10% HC1, twice with 10% NaHCO 3 and twice with saturated common salt solution, dried and concentrated by evaporation. After treatment with ether, 900 mg of white crystals 's obtained.
Yield: Cld: C 59.60% H 6.31% N 3.02% O 24.16% S 6.92% Fnd: C 59.38% H 6.55% N 3.08% S 6.66% d) N-Toluenesulfonyl-O-t-butyloxycarbonylmethyl-N-(2aminoethyl)tyrosinamide The solution of 3.0 g of N-toluenesulfonyl-0-tbutyloxycarbonylmethyl-tyrosine methyl ester (6.5 mmol) in CH 2 Cl 2 is added in drops to a solution of 5 g of ethylenediamine in ml of CH 2 Cl 2 Then, it is refluxed for 4 hours. After cooling, it is mixed with water, the organic phase is separated and extracted several times with CH 2
CL
2 The combined organic extracts are washed, dried and concentrated by evaporation.
After column chromatography (silica gel MeOH), 1.5 g of colorless oil remains.
Yield: 47% Cld: C 58.64% H 6.77% N 8.55% 0 19.53% S 6.52% Fnd: C 58.39% H 6.91% N 8.38% S 6.56% e) N-Toluenesulfonyl-O-carboxymethyl[-N-(2aminoethyl)tyrosinamide] 2 ml of trifluoroacetic acid is added at room temperature to a solution of 491 mg of the tert-butyl ester (1 mmol) produced according to Example 8d) in 25 ml of dichloromethane, and it is stirred at room temperature. After the reaction is completed, the trifluoroacetic acid is drawn off in a vacuum, the residue is taken up in chloroform, washed with water, dried and concentrated by evaporation.
Yield: 83% Cld: C 55.16% H 5.79% N 9.65% 0 22.04% S 7.36% Fnd: C 53.88% H 5.64% N 10.02% S 7.44% f) N-Toluenesulfonyl-O-carboxymethyl-tyrosine-[N-(2- (piperonylmercapto)-acetylaminoethyl)]amide 350 mg of piperonylmercaptoacetic acid-Nhydroxysuccinimidoester (1.08 mmol) in THF is slowly added in drops under argon and with exclusion of moisture to a solution of 435 mg of amine (1 mmol) produced according to Example 8e) in anhydrous THF at 0 C, and it is stirred for 2 hours at 0°C, then for 12 hours at room temperature. The solvent is drawn off, and the residue is chromatographed (silica gel, CH 2 Cl 2 /MeOH/HOAC 9:1:0.1).
Yield: 58% Cld: C 55.98% H 5.17% N 6.53% 0 22.37% S 9.96% Fnd: C 55.38% H 5.04% N 6.68% S 9.09% g) N-Toluenesulfonyl-o-carboxymethyl-tyrosine-{N-[2- (mercaptoacetyl)-aminoethyl]}amide 644 mg of the protected S-compound (1 mmol) produced according to Example 8f) and a trace of anisole are added to ml of trifluoroacetic acid at room temperature and heated briefly to boiling. After the reaction is completed, the trifluoroacetic acid is drawn off in a vacuum, the residue is taken up in a suitable solvent, washed with water, dried and concentrated by evaporation and chromatographed.
Yield: 34% Cld: C 51.85% H 5.34% N 8.25% 0 21.98% S 12.59 Fnd: C 51.62% H 5.53% N 8.65% S 13.61% h) Tc-99m complex of N-toluenesulfonyl-0-carboxymethyltyrosine-{N-[2-(mercaptoacetyl)aminoethyl]}amide 1 mg of the compound produced according to Example 8g) is dissolved in 100 p1 of EtOH. 50 1l of this solution is added to 250 1l of a 0.1 M phosphate buffer of pH 8.5 and mixed with 50 1l of a citrate solution (50 ng of trisodium citrate in 1 ml of water) and 2.5 p1 of a tin(II) chloride solution (5.0 mg of tin(II) chloride in 1 ml of 0.1N HC1). Then, it is mixed with 100 1l of a 99m-Tc generator eluate and allowed to stand for minutes. The labeling yield is determined with the aid of HPLC.
Example 9 a) Cholesteryl diethylene glycol (DEG-cholesterol) A solution of 54.1 g of cholesteryl toluenesulfonate (100 mmol) and 106 g of diethylene glycol in 250 ml of anhydrous dioxane is refluxed under nitrogen atmosphere (TLC control).
After the reaction is completed, it is mixed with water and extracted with CH 2 Cl 2 After column chromatography (silica gel
CH
2 C1 2 /MeOH a colorless solid remains.
Yield: 81% Cld: C 78.43% H 11.46% O 10.11% Fnd: C 76.99% H 12.32% b) Cholesteryl-2-chloroethyl(ethylene glycol) A solution of 4.75 g of DEG-cholesterol (10 mmol) produced according to Example 9a) in 50 ml of anhydrous carbon tetrachloride is mixed under nitrogen atnosphere with 3.14 g of pulverized triphenylphosphine (12 mmol) and refluxed. After cooling, it is diluted with 50 ml of petroleum ether or hexane and stored for some time at -20 0 C. The precipitate is suctioned off, and the procedure is again as above until no more precipitate settles. Then, it is dried and concentrated by evaporation. After column chromatography (silica gel CH 2 Cl2/MeOH 3.70 g of an oil remains.
Yield: Cld: C 75.49% H 10.83% 0 6.49% Fnd: C 74.73% H 11.74% c) N-Benzyloxycarbonyl-2-[(4-cholesteryldiethyleneglycolyl)benzyl]-2-aminoacetic acid methyl ester The solution of 493 mg of the cholesterol derivative (1 mmol) (produced according to Example 9b) in 10 ml of toluene is added to a boiling solution of 295 mg of the N-benzyloxycarbonyltyrosine methyl ester (1 mmol) (produced according to Example la) and 183 mg of potassium carbonate (1 mmol) in 10 ml of toluene, and it is refluxed for 6 hours. After the reaction is completed, it is allowed to cool to room temperature, concentrated by evaporation and chromatographed (silica gel petroleum ether/ethyl acetate 1:1) Yield: 29% Cld: C 73.46% H 9.78% N 1.86% O 14.89% Fnd: C 73.28% H 10.01% N 1.70% d) 2-[(4-Cholesteryldiethyleneglycolyl)benzyl]-2-aminoacetic acid methyl ester hydrochloride 7.52 g (10 mmol) of the Z-protected compound produced according to Example 9c) iE solved in 50 ml of 3 M HCl in ethyl acetate and stirred for 1 hours at room temperature. After the solvent is drawn off, 6.02 g of white crystals remains.
Yield: 93% Cld: C 71.53% H 9.66% N 2.04% O 11.62% Fnd: C 71.82% H 9.39% N 2.01% e) N-p-Toluenesulfonyl-2[(4cholesteryldiethyleneglycolyl)benzyl]-2-aminoacetic acid methyl ester 19.53 g of the amine (30 mmol) produced according to Example 9d) is dissolved in 50 ml of dichloromethane and mixed at 0 C with 5.72 g of toluenesulfonic acid chloride in 30 ml of dichloromethane. While being stirred intensively, 3.0 g of triethylamine is added in drops at 0°C, and it is stirred for 1 hour at room temperature. After the reaction is completed, it is mixed with ice water and extracted several times with dichloromethane. The combined organic extracts are washed twice with cold 10% HC1, three times with 10% NaHCO 3 solution and twice with saturated NaC1 solution. After drying, the solvent is drawn off and chromatographed (silica gel, CH 2 C1 2 Yield: 77% Cld: C 71.52% H 8.88% N 1.74% O 13.89% S 3.98% Fnd: C 70.89% H 9.02% N 1.66% S 3.70% f) N-p-Toluenesulfonyl-2[(4cholesteryldiethyleneglycolyl)benzyl]-2-aminoacetic acid[N- (2-aminoethyl)]amide A solution of 806 mg of the tosylglycine ester (1 mmol) produced according to Example 9e in 1 ml of anhydrous dichloromethane is slowly added in drops to a solution of 1.2 g of ethylenediamine (20 mmol) in 1 ml of anhydrous dichloromethane, and it is refluxed. After the reaction is completed, it is concentrated by evaporation in a vacuum, and the residue is chromatographed (silica gel, MeOH).
Yield: Cld: C 70.55% H 9.06% N 5.04% 0 11.51% S 3.84% Fnd: C 69.24% H 9.31% N 4.83% S 3.71% g) N-p-Toluenesulfonyl-2 [(4-cholesteryldiethyleneglycolyl) benzyl] -2-aminoacetic acid-N-{2-N( (3-carboxy-2mercaptoacetyl-1-oxopropyl) ]aminoethyllamide 0.38 g (2.2 mmol) of 2-acetylmercaptosuccinic anhydride is added to a solution of 1.83 g of the amine (2.2 mmol) produced according to Example 9f) in 10 ml of pyridine/DMF (50:50), and it is stirred for 4 hours at room temperature. Then, the solvent is drawn off, the residue is taken up in 0.5N HCl and extracted with CH 2 C1 2 After flash chromatography, 887 mg of a yellow oil remains.
Yield: Old: C 65.51% H 8.10% N 4.17% 0 15.87% S 6.36% Fnd: C 63.66% H 7.58% N 3.99% S 7.41% h) Tc-99m. complex of N-p-toluenesulfonyl-2[(4cholesteryldiethyleneglycolyl) -benzyl] -2-aminoacetic acid-N- (3-carboxy-2-mercaptoacetyl-1-oxopropyl)]Jaminoethyllamide 1 mg of the ligand produced according to Example 9g is dissolved in 100 Mil of ethanol. 50 gl of this solution is added to 250 Ail of a 0.1 M phosphate buffer (pH 8.5) and then mixed with 50 pl of a citrate solution (50 mg of trisodium citrate in ml of water) and 2.5 1l of a tin(II) chloride solution mg of tin(IT) chloride in 1 ml of 0.1N HC1). Then, it is mixed with 50 Al of a Tc-99m generator eluate and allowed to stand for minutes. The labeling yield is determined with the aid of
HPLC.
Example a) 1-Tosyl-1,4,7-triazaheptan-3-one A solution of 25.73 g of tosylglycine methyl ester (0.1 mol) in anhydrous dichloromethane is slowly added in drops to a solution of 30 g of ethylenediamine (0.5 mol) in 50 ml of anhydrous dichloromethane. It is stirred for 12 hours at room temperature and then concentrated by evaporation in a vacuum. 24 g of a yellow oil remains.
Yield: 88% Cld: C 48.69% H 6.32% N 15.49% 0 17.69% S 11.82% Fnd: C 47.23% H 6.67% N 15.34% S 11.54% b) 7-N-tert-Butoxycarbonyl-l-tosyl-1,4,7-triazaheptan-3-one A solution of 27 g (100 mmol) of the amino compound produced according to Example 10a) in 500 ml of dioxane is mixed in one portion with 74 g of di-tert-butyl-dicarbonate (340 mmol). The solution is stirred for 3 hours at room temperature, then poured onto ice water and extracted three times with ethyl acetate. The combined organic phases are washed three times with water and once with saturated common salt solution, dried (MgSO 4 I r concentrated by evaporation and recrystallized. 27.9 g of white crystals remains.
Yield: Cld: C 51.74% H 6.78% N 11.31% O 21.54% S 8.63% Fnd: C 51.41% H 6.96% N 11.12% S 8.91% c) 7-N-t-Butyloxycarbonyl-l-r-hexyl-l-tosyl-1,4,7-triazaheptan- 3-one g of potassium carbonate is added to a solution of 3.71 g of the sulfonamide (10 mmol) produced according to Example in 50 ml of DMF at room temperature, and then the solution of 2.54 g of hexyl iodide (12 mmol) in 10 ml of DMF is added in drops and heated for 3 hours to 110 0 C. After the reaction is completed, it is allowed to cool to room temperature, poured onto ice, extracted with CH 2 C1 2 washed several times with water, dried, filtered and concentrated by evaporation. The residue is recrystallized from ethyl acetate.
Yield: 89% Cld: C 58.00% H 8.19% N 9.22% O 17.56% S 7.04% Fnd: C 57.37% H 7.87% N 9.01% S 6.95% d) l-n-Hexyl-l-tosyl-l,4,7-triazaheptan-3-one 456 mg of the sulfonamide (1 mmol) produced according to Example 10c) is added to 10 ml of trifluoroacetic acid at 0°C, and then it is stirred for 2 hours at room temperature. After the reaction is completed, it is poured onto ice, weakly alkalized (NaHCO 3 extracted, concentrated by evaporation and dried.
Yield: 94% Cld: C 57.44% H 8.22% N 11.82% 0 13.50% S 9.02% Fnd: C 57.96% H 8.01% N 11.63% S 8.75% e) 1O-Acetyl-9--carboxymethyl-l-n-hexyl-l-tosyl-1O-thia-1, 4,7triazadecane-3, 8-dione The solution of 3.55 g (10 mmol) of the amino compound in ml of DMF is slowly added in drops to a solution of 1.91 g of acetylmercaptosuccinic anhydride (20 mmol) in 20 ml of DMF at room temperature, and it is stirred overnight. Then, it is poured onto semiconcentrated HC1, extracted with CH 2 Cl 2 and chromatographed (silica gel, EtOAc/MeOH from 9:1 to 1:1).
Yield: 66% Old: C 52.16% H 6.66% N 7.93% 0 21.15% S 12.11% Fnd: C 52.85% H 6.87% N 7.52% S 11.66% f) Tc-99m. complex of lo-Acetyl-9-carboxymethyl-1-n-hexyl-ltosyl-lO-thia-1, 4, 7-triazadecane-3, 8-dione 1 mg of N,N [hexyl-p-toluenesulfonyl]glycyl-N-[(3-carboxy-2mercaptoacetyl-l-oxopropyl)]aminoethyllamide is dissolved in 100 4l of EtOH. 50 4l of this solution is diluted with 100 Al of EtOH and mixed with 100 Al of a 0. 1 M phosphate buffer at pH and 100 Al of a Tc-99m-gluconate solution. The labeling yield is 95% (silica gel, 95% EtOH)
I
IR BIC91~ I~-~II Example 11 a) N-a-Toluenesulfonyl-N- -tert-butyloxycarbonyllysine methyl ester 1.91 mg of toluenesulfonyl chloride is added in portions to a solution of 2.60 g of N-E-tert-butyloxycarbonyllysine methyl ester (10 mmol) in 50 ml of anhydrous pyridine at 0 C, and it is allowed to stand for 24 hours at 4 0 C. Then, it is poured onto ice water, and the precipitate is separated and recrystallized.
Yield: 78% Cld: C 55.05% H 7.30% N 6.76% O 23.16% S 7.74% Fnd: C 54.67% H 7.42% N 6.64% S 7.54% b) N-a-Toluenesulfonyl-N- -tert-butyloxycarbonyllysine-[N-(2aminoethyl)]amide A solution of 415 mg of the tosyllysine ester (1 mmol) produced according to Example lla) in 1 ml of anhydrous dichloromethane is slowly added in drops to a solution of 600 mg of ethylenediamine (10 mmol) in 1 ml of anhydrous dichloromethane and refluxed. After the reaction is completed, it is concentrated by evaporation in a vacuum, and the residue is recrystallized.
Yield: 59% Cld: C 54.28% H 7.74% N 12.66% O 18.08% S 7.25% Fnd: C 54.54% H 7.57% N 12.18% S 7.06%
I
c) N-a-Toluenesulfonyl-N- -tert-butyloxycarbonyllysine-[N-(2- (piperonylmercapto)-acetylaminoethyl)]amide 350 mg of piperonylmercaptoacetic acid-Nhydroxysuccinimidoester (1.08 mmol) in THF is slowly added in drops under argon and with exclusion of moisture to a solution of 443 mg of amine (1 mmol) produced according to Example 11b) in anhydrous THF at 0°C, and it is stirred for 2 hours at 0 C, then for 12 hours at room temperature. The solvent is drawn off, and the residue is chromatographed (silica gel, CH 2 Cl 2 /MeOH 9:1).
Yield: 54% Cld: C 55.37% H 6.51% N 8.61% O 19.67% S 9.85% Fnd: C 55.22% H 6.85% N 8.41% S 9.66% d) N-a-Toluenesulfonyl-lysine-[N-(2- (piperonylmercapto)acetylaminoethyl)]amide 651 mg of N-a-toluenesulfonyl-N-S-tertbutyloxycarbonyllysine-[N-(2-(piperonylmercapto)acetylaminoethyl)]amide is dissolved in 5 ml of 3 M HCl in ethyl acetate, and it is stirred for 6 hours at room temperature.
After the solvent is drawn off, 530 mg of white crystals remains.
Yield: 96% Cld: C 54.63% H 6.05% N 10.19% 0 17.46% S 11.67 Fnd: C 54.40% H 6.47% N 10.01% S 11.84% i I 3C I Example 12 a) N-a-Toluenesulfonyl-N- -tert-butyloxycarbonyllysine-[N-(2benzoylmercapto)-acetylaminoethyl)]amide 316 mg of benzoylmercaptoacetic acid-Nhydroxysuccinimidoester (1.08 mmol) in tetrahydrofuran is slowly added in drops under argon and with exclusion of moisture to a solution of 443 mg of amine produced according to Example 1ib) in anhydrous tetrahydrofuran at 0 C, and it is stirred for 2 hours at 0°C, then for 12 hours at room temperature. The solvent is drawn off, and the residue is chromatographed (silica gel,
CH
2 C1 2 /MeOH 9:1).
Yield: Cld: C 56.11% H 6.50% N 9.03% 0 18.04% S 10.33% Fnd: C 55.98% H 6.86% N 8.88% S 0.05% b) N-a-Toluenesulfonyl-lysine-[N-(2benzoylmercapto)acetylaminoethyl)]amide 621 mg of the title compound of Example 12a) is dissolved in ml of 3 M HC1 in ethyl acetate, and it is stirred for 6 hours at room temperature. After the solvent is drawn off, 500 mg of white crystals remains.
Yield: Cld: C 51.74% H 5.97% N 10.06% O 14.36% S 11.51% Fnd: C 51.40% H 6.14% N 10.10% S 11.48%
I-
I
c) Tc-99m complex of N-a-toluenesulfonyl-lysine-[N-(2- (benzoylmercapto)-acetylaminoethyl)]amide mg of the amide produced according to Example 12b) is mixed with 500 p1 of 1N NaOH and allowed to stand for 15 minutes.
p1 of this solution is added to 250 p1 of a 0.1 M phosphate buffer of pH 8.5 and mixed with 50 1l of a citrate solution mg of trisodium citrate in 1.0 ml of water) and 2.5 p1 of a tin(II) chloride solution (5.0 mg of tin(II) chloride in 1.0 ml of 0.1N HC1). Then, it is mixed with 50 p1 of a Tc-99m generator eluate and allowed to stand for 15 minutes. The labeling yield is determined with the aid of HPLC Example 13 a) N-[3-(N-tert-butyloxycarbonyl)aminobenzenesulfonyl]-glycine methyl ester A solution of 2.12 g (10 mmol) of the amino compound produced according to Example 7b) and 3 g of triethylamine mmol) in 50 ml of dioxane are mixed in one portion with 7.4 g of di-tert-butyldicarbonate (34 mmol). (Gas generation!) The solution is stirred for 30 minutes at room temperature, then poured onto ice water and extracted three times with ethyl acetate. The combined organic phases are washed three times with water and once with saturated common salt solution, dried (MgSO 4 concentrated by evaporation and recrystallized.
Yield: Cld: C 48.83% H 5.85% N 8.13% O 27.88% S 9.31% Fnd: C 47.44% H 5.93% N 8.57% S 9.66% b) (N-tert-butyloxycarbonyl)aminobenzenesulfonyl]-glycyl- [N'-(2-aminoethyl)amide A solution of 12.11 g of the glycine ester produced according to Example 13a) (35 mmol) in 250 ml of anhydrous toluene/dioxane or optionally only dioxane is slowly added in drops to a boiling solution of 42 g of ethylenediamine (700 mmol) in 100 ml of anhydrous toluene, and it is refluxed. After the reaction is completed, it is concentrated by evaporation in a vacuum, and the residue is taken up in chloroform and washed with water.
Yield: 78% Cld: C 44.06% H 6.16% N 13.70% O 19.56% S 7.84% Fnd: C 45.44% H 6.63% N 14.57% S 7.66% c) N-[3-(N-tert-Butyloxycarbonyl)aminobenzenesulfonyl]-glycyl- {N'-[(S-benzoylmercapto)acetyl]-(2-aminoethyl)}amide mmol of the S-benzoylmercaptoacetic acid (0.98 g) and mmol of NEt 3 (1.4 ml) and 5 mmol of the amine produced according to Example 13b) (1.86 g) are mixed with 50 ml of dichloromethane and cooled to 10 0 C. Then, 5.5 mmol (1.375 g) of BOP-C1 is added and stirred while being cooled in water. (After 10-20 minutes, a clear solution is obtained.) Then, it is stirred, stirred for 1 more hour, mixed with water and brought to pH 1-1.5 with 4N HC1.
Yield: 62% Cld: C 52.16% H 5.84% N 10.14% O 20.27% S 11.60% Fnd: C 53.44% H 6.63% N 10.57% S 11.66% II d) N-[3-Aminobenzenesulfonyl]-glycyl--,'-[(8benzoylmercapto)acetyl]-(2-aminoethyl)}amide A freshly prepared solution of 3 M HCl in EtOAc (10 ml, mmol) is added to a solution of 552 mg of the protected amine produced according to Example 13c) (1 mmol) in 5 ml of EtOAc. It is stirred for 30 minutes at room temperature. The solvent is drawn off, and the residue is dried in a vacuum at room temperature.
Yield: 93% Cld: C 46.86% H 4.76% N 11.51% O 16.43% S 13.17% Fnd: C 45.44% H 5.33% N 10.57% S 13.66% e) N-[3-Isothiocyanatobenzenesulfonyl]-glycyl-{N'-[(Sbenzoylmercapto)acetyl]-(2-aminoethyl)}amide The solution of 65 mg of thiophosgene in a little dichloromethane is added in drops with exclusion of moisture to a solution of 200 mg of N-[(3-aminosulfonyl)]glycyl-{N'- [(acetylmercapto)-acetyl](2-aminoethyl)}amide produced according to Example 13d) and 20 pL of triethylamine in 4 ml of dichloromethane, and it is stirred for 4 hours at room temperature. After the solvent is drawn off, a residue remains, which is taken up in chloroform and washed with 0.1% citric acid, washed twice with sodium chl*" ,de solution and once with water, dried, concentrated by evaporation and chromatographed.
Yield: 66% Cld: C 48.77% H 4.09% N 11.37% O 16.24% S 19.53% Fnd: C 48.44% H 4.63% N 11.75% S 20.06%
I
Example 14 a) N-Toluenesulfonyl-0-methoxycarbonylmethyl[-N-(2aminoethyl) tyrosinamide] HC1 gas is introduced until saturation in a solution of 4.35 g of amine produced according to Example 8e) (10 mmol) in 100 ml of anhydrous methanol, and it is stirred overnight. After the solvent is removed, a crystalline residue remains.
Yield: 92% Cld: C 51.90% H 5.81% N 8.65% O 19.75% S 6.60% Fnd: C 51.59% H 5.93% N 8.47% S 6.49% b) N-Toluenesulfonyl-O-methoxycarbonylmethyltyrosine-[N-(2tritylmercapto)-acetylaminoethyl)]amide 4.66 g of S-tritylmercaptoacetic acid-Nhydroxysuccinimidoester (10.8 mmol) in tetrahydrofuran is slowly added in drops under argon to a solution of 4.35 g of amine produced according to Example 14a) (10 mmol) and 2.02 g of triethylamine in tetrahydrofuran/water at 0 C, and it is stirred for 2 hours at 0 C, then for 12 hours at room temperature. The solvent is drawn off, and the residue is chromatographed (silica gel,
CH
2 C1 2 Yield: 68% Cld: C 65.86% H 5.66% N 5.49% O 14.62% S 8.37% Fnd: C 65.66% H 5.71% N 5.36% S 8.21%
I
c) N-Toluenesulfonyl-0-carboxymethyltyrosine-[N-(2tritylmercapto)acetylaminoethyl)]amide The solution of 766 mg of the methyl ester produced according to Example 14b) (1 mmol) in 2.5 ml of methanol is added to a methanolic KOH solution and stirred at room temperature.
After the reaction is completed, the solvent is drawn off, the potassium salt is taken up in water, weakly acidified and extracted with chloroform. The organic extract is washed with water, dried and concentrated by evaporation.
Yield: 63% Cld: C 65.49% H 5.50% N 5.59% 0 1490% S 8.53% Fnd: C 65.26% H 5.72% N 5.43% S 8.43% d) N-Toluenesulfonyl-[(HOOC-Trp-Ile-Ile Asp-Leu-His Gly-NH)carbonylmethyltyrosine-[N-(2tritylmercapto)acetylaminoethyl)]amide 206 mg of dicyclohexylcarbodiimide (1 mmol) dissolved in 2 ml of dimethylformamide is added in drops to a solution of 1 mmol of the acid (980 mg) produced according to Example 14c) and 115 mg of N-hydroxysuccinimide (1 mmol) in 2 ml of anhydrous dimethylformamide at 0C within 5 minutes. It is stirred first for another 30 minutes at 0°C, then the solution of 1 mmol of the peptide (853 mg) H 2 N-Gly-His-Leu-Asp-Ile-Ile-Trp (produced analogously to Barany and Merrifield, The Peptides: Analysis, Biology, Academic Press New York, 1980; Steward and Young, Solid Phase Peptides Syntheses, 2nd ed.; Pierce Chemical Rockford, II, 1984) and 304 mg (3 mmol) of triethylamine in 10 ml of
I
anhydrous dimethylformamide is added under argon atmosphere within 30 minutes. It is stirred for 12 more hours at room temperature, 200 pl of glacial acetic acid is added, stirred again for 30 minutes, the product is filtered off from N,N'dicyclohexylurea, and the residue is concentrated by evaporation.
After stirring up with diethyl ether, a white residue remains, which is recrystallized from dimethylformamide/ether.
Yield: Cld: C 62.07% H 6.29% N 4.04% O 16.13% S 4.04% Fnd: C 61.77% H 6.52% N 4.32% S 4.34% e) N-Toluenesulfonyl-[(HOOC-Trp-Ile-Ile Asp-Leu-His Gly- NH)carbonyl]-methyltyrosine-[N- (mercapto)acetylaminoethyl)]amide 530 mg of the protected S-compound produced according to Example 14d) (0.3 mmol) and a trace of anisole are added to 10 ml of trifluoroacetic acid under argon atmosphere at room temperature and heated briefly to boiling. Then, the trifluoroacetic acid is drawn off in a vacuum, the residue is taken up in tetrahydrofuran, concentrated by evaporation and chromatographed.
Yield: 59% Cld: C 56.67% H 6.32% N 13.42% O 18.87% S 4.73% Fnd: C 56.14% H 8% N 12.98% S 4.81% a
C
f) Tc-99m complex of N-toluenesulfonyl-[(HOOC-Trp-Ile-Ile Asp- Leu-His Gly-NH)carbonylmethyltyrosine-[N- (mercaptoacetyl)aminoethyl)]amide 1 mg of the above-named compound (Example 14e) is dissolved in 100 Al of EtOH/water 1:1. 50 Al of this solution is mixed with 100 Al of a 0.1 M phosphate buffer of pH 9.5 and 100 Al of a Tc-99m-gluconate solution. The labeling yield is 95% (HPLC, LiChrospher RP18, H 2 O/MeCN 0.1% TFA).
Example a) N-Toluenesulfonyl-0-t-butyloxycarbonylmethytyrosine-{N-(2benzoylmercapto)-acetylaminoethyl)]amide 2 mmol of S-benzoyl-2-mercaptoacetic acid (394 mg) and 4 mmol of NEt 3 (560 1l) and 2 mmol (982 mg) of the compound obtained according to Example 8d) are mixed with 5 ml of dichloromethane and cooled to 10 0 C. Then, 2 mmol (509 mg) of BOP-C1 is added and stirred for 12 hours while being cooled in water, then mixtd with water and brought to pH 1-1.5 with 4N HC1.
Then, it is extracted with dichloromethane, the combined organic extracts are washed with NaHCO 3 and water, dried, concentrated by evaporation and chromatographed.
Yield: 76% Cld: C 59.18% H 5.87% N 6.27% O 19.11% S 9.58% Fnd: C 60.88% H 5.89% N 5.63% S 8.74% b) N-Toluenesulfonyl-O-carboxymethyltyrosine-[N-(2benzoylmercapto)acetyl-aminoethyl)]amide 644 mg of the protected S-compound produced according to Example 15a) (1 mmol) is added to 10 ml of trifluoroacetic acid at room temperature, and it is stirred at room temperature.
After the reaction is completed, the trifluoroacetic acid is drawn off in a vacuum, the residue is taken up in ethyl acetate, washed with water, dried and concentrated by evaporation and chromatographed.
Yield: 77% Cld: C 56.76% H 5.09% N 6.85% O 20.86% S 10.45% Fnd: C 57.14% H 5.68% N 7.23% S 11.31% c) N-Toluenesulfonyl-[(HOOC-Trp-Ile-Ile Asp-Leu-(D-Trp)- NH)carbonylmethyl-tyrosine-[N-(2benzoylmercapto)acetylaminoethyl)]amide 206 mg of dicyclohexylcarbodiimide (1 mmol) dissolved in 2 ml of tetrahydrofuran is added in drops to a solution of 1 mmol of acid (614 mg) produced according to Example 15b) and 115 mg of N-hydroxysuccinimide (1 mmol) in 2 ml of anhydrous tetrahydrofuran at 0 C within 5 minutes. First, it is stirred for another 30 minutes at 0 C, then the solution of 1 mmol of the peptide (845 mg) of H 2 N-(D-Trp)-Leu-Asp-Ile-Ile-Trp (produced analogously to Barany and Merrifield, The Peptides: Analysis, Biology, Academic Press, New York, 1980; Steward and Young, Solid Phase Peptides Syntheses, 2nd ed.; Pierce Chemical Rockford, Il 1984) and 304 mg (3 mmol) of triethylamine in 10 ml of
I
I anhydrous dimethylformamide are added under argon atmosphere within 30 minutes. It is stirred for 12 more hours at room temperature, 200 .l of glacial acetic acid is added, stirred again for 30 minutes, the product is filtered off from N,N'dicyclohexylurea, and the residue is extracted twice with boiling tetrahydrofuran. The combined filtrates are evaporated to dryness and chromatographed (silica gel, CH 2 C12).
Yield: Cld: C 60.86% H 6.23% N 10.69% O 17.77% S 4.45% Fnd: C 60.77% H 6.42% N 10.32% S 4.65% d) Tc-99m complex of N-toluenesulfonyl-[(HOOC-Trp-Ile-Ile Asp- Leu-(D-Trp)-NH)carbonylmethyltyrosine-[N-(2mercaptoacetyl)aminoethyl)]aide 2 mg of the compound produced according to Example 15c) is dissolved in 100 Al of EtOH and mixed with 100 pl of IN NaOH.
After 15 minutes, 50 pl of this solution is added to 250 pl of a 0.1 M phosphate buffer of pH 8.5 and mixed with 50 Al of a citrate solution (50 mg of trisodium citrate in 1.0 ml of water) and 2.5 ~l of a tin(II) chloride solution (5.0 mg of tin(II) chloride in 1.0 ml of 0.1N HC1). Then, it is mixed with 50 Al of a Tc-99m generator eluate and allowed to stand again for minutes. The labeling yield 95%) is determined with the aid of HPLC.
I I Example 16 a) N-Tosyl-tyrosinemethylester-4-benzyl ttaer A solution of 32.58 g (171 mmol) of p-toluenesulfonic acid chloride in 100 ml of pyridine is added in drops to 50 g (155.37 mmol) of tyrosinemethylester-4-benzyl ether hydrochloride in 300 ml of pyridine at 0°C, and it is stirred for 3 hours at 0 C. It is evaporated to dryness in a vacuum, and the residue is dissolved in 500 ml of methylene chloride. The organic phase is shaken out twice with 300 ml of 5N hydrochloric acid. The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is recrystallized from a little methanol. 68.29 g of a colorless crystalline powder is obtained.
Yield: 93% Cld: C 65.58% H 5.73% N 3.19% S 7.29% Fnd: C 65.30% H 5.81% N 3.02% S 7.18% b) 2-(4-Benzyloxybenzyl)-l-tosyl-1,4,7-triazaheptan-3-one g (102.38 mmol) of the title substance of Example 16a) is introduced in 1 1 of 1,2-diaminoethane within 1 hour and then stirred for 3 hours at 80 0 C. The residue is evaporated to dryness, and the residue is absorptively precipitated in 200 ml of water. The precipitate is suctioned off and rewashed with a great deal of water. Then, it is dried overnight in a vacuum at 0 C. 46.91 g of a cream-colored, amorphous powder is obtained.
Yield: 98% Cld: C 64.22% H 6.25% N 8.95% S 6.86%
I
Fnd: C 64.05% H 6.17% N 9.05% S 6.78% c) 9-Chloro-2-(4-benzyloxybenzyl) -1-tosyl-l,4,7-triaza-nonane- 3,8-dione g (21.39 mmol) of the title compound of Example 16b) is dissolved in 100 ml of chloroform, and 2.38 g (23.53 mmol) of triethylamine is added. At 0 C, 2.66 g (23.53 mmol) of chloroacetyl chloride in 20 ml of chloroform is added in drops within 30 minutes. It is stirred for 30 minutes at 0 C. 200 ml of lN hydrochloric acid is added and shaken vigorously. The organic phase is separated, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is recrystallized from a little methanol. 10.36 g of a creamcolored, crystalline solid is obtained.
Yield: 89% Cld: C 59.61% H 5.56% N 7.72% S 5.89% Cl 6.52% Fnd: C 59.50% H 5.69% N 7.55% s 5.71% Cl 6.38% d) 10-Benzoyl-2-(4-benzyloxybenzyl)-l-tosyl-10-thia-1,4,7triazadecane-3,8-dione 9 g (16.54 mmol) of the title compound of Example 16c) is dissolved in 100 ml of chloroform, and 1.67 g (16.54 mmol) of triethylamine is added. Then, 2.29 g (16.54 mmol) of thiobenzoic acid is added and refluxed for 10 minutes. It is cooled to room temperature and shaken out once with 2N hydrochloric acid and once with a 5% sodium carbonate solution. The organic phase is dried on magnesium sulfate and concentrated by evaporation in a I" vacuum. The residue is recrystallized from a little methanol.
9.61 g of a colorless, crystalline powder is obtained.
Yield: Cld: C 63.24% H 5.46% N 6.51% S 9.93% Fnd: C 63.15% H 5.57% N 6.40% S 9.81% Example 17 a) 10-Acetyl-2-(4-benzyloxybenzyl)-l-tosyl-10-thia-l,4,7triazadecane-3,8-dione 9 g (16.54 mmol) of the title compound of Example 16c) is dissolved in 100 ml of chloroform, and 1.67 g (16.54 mmol) of triethylaiaine is added. Then, 1.28 g (16.54 mmol) of thioacetic acid is added and refluxed for 10 minutes. It is cooled to room temperature, shaken out with 2N hydrochloric acid and then with a sodium carbonate solution. The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum.
The residue is recrystallized from a little acetone. 8.20 g of cream-colored crystals is obtained.
Yield: Cld: C 59.67% H 5.70% N 7.20% S 10.98% Fnd: C 59.51% H 5.81% N 7.05% S 10.80% Example 18 a) 10-Trifluoroacetyl-2- (4-benzyloxybenzyl) -1-tosyl-10-thia- 1,4,7-triazadecane-3,8-dione 9 g (16.54 mmol) of the title compound of Example 16c) is dissolved in 100 ml of chloroform and 1.67 g (1654 mmol) of dL I I I I trifluoromethylthioacetic acid, and it is refluxed for minutes. It is cooled to room temperature, shaken out with 2N hydrochloric acid and then with a 1% sodium carbonate solution.
The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is recrystallized from a little acetone/ether. 8.75 g of colorless crystals is obtained.
Yield: 83% Cld: C 54.62% H 4.74% N 6.59% S 10.05% F 8.94% Fnd: C 54.47% H 4.61% N 6.50% S 9.90% F 8.81% Example 19 a) N-Mesyl-tyrosinemethylester-4-benzyl ether 19.58 g (171 mmol) of methanesulfonic acid chloride is added in drops to 50 g (155.37 mmol) of tyrosinemethylester-4-benzyl ether hydrochloride in 300 ml of pyridine at 0 0 C, and it is stirred for 3 hours at 0°C. It is evaporated to dryness in a vacuum, and the residue is dissolved in 500 ml of methylene chloride. The organic phase .s shaken out twice with 300 ml of hydrochloric acid. The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is recrystallized from a little methanol. 53.64 g of a colorless, crystalline powder is obtained.
Yield: Cld: C 59.49% H 5.82% N 3.85% S 8.82% Fnd: C 59.30% H 5.95% N 3.71% S 8.70% b) 2-(4-Benzyloxybenzyl)-l-mesyl-1,4,7-triazaheptan-3-one 37.2 g (102.38 mmrol) of the title substance of Example 19a) is introduced in 1 liter of 1,2-diaminoethane within 1 hour and then stirred for 3 hours at 80 0 C. The residue is evaporated to dryness, and the residue is absorptively precipitated in 200 ml of water. The precipitate is suctioned off and rewashed with a great deal of water. Then, it is dried overnight in a vacuum at 0 C. 37.68 g of a cream-colored, amorphous powder is obtained.
Yield: 97% Cld: C 56.97% H 6.64% N 11.07% S 8.45% Fnd: C 56.81% H 6.72% N 10.93% S 8.32% c) 9-Chloro-2-(4-benzyloxybenzyl)-l-mesyl-1,4,7-triaza-nonane- 3,8-dione g (26.35 mmol) of the title compound of Example 19b) is dissolved in 100 ml of chloroform, and 2.93 g (28.99 mmol) of triethylamine is added. At 0°C, 3.27 g (28.99 mmol) of chloroacetyl chloride in 20 ml of chloroform is added in drops within 30 minutes. It is stirred for 30 minutes at 0 C. 200 ml of 1N hydrochloric acid is added and vigorously shaken. The organic phase is separated, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is recrystallized from a little methanol. 10.93 g of a creamcolored, crystalline solid is obtained.
Yield: 91% Cld: C 52.68% H 5.75% N 9.22% S 7.03% Cl 7.78% Fnd: C 52.51% H 5.82% N 9.13% S 6.90% Cl 7.68%
~---~IIIPII
1 d) 10-Benzoyl-2-(4-benzyloxybenzyl)-1-mesyl-10-thia-1,4,7triaza-decane-3,8-dione 7.54 g (16.54 mmol) of the title compound of Example 16c) is dissolved in 100 ml of chloroform, and 1.67 g (16.54 mmol) of triethylamine is added. Then, 2.29 g (16.54 mmol) of thiobenzoic acid is added and refluxed for 10 minutes. It is cooled to room temperature and shaken out once with 2N hydrochloric acid and once with a 5% sodium carbonate solution. The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is recrystallized from a little methanol.
8.11 g of a colorless, crystalline powder is obtained.
Yield: 88% Cld: C 58.15% H 5.60% N 7.53% S 11.50% Fnd: C 58.03% H 5.71% N 7.61% S 11.38% Example a) 9-Chloro-2- (4-hydroxybenzyl) tosyl-, 4,7-triazanonane-3,8dione g (36.76 mmol) of the title compound of Example 16c) is dissolved in 200 ml of methylene chloride, and 2 ml of glacial acetic acid is added. Then, 3 g of palladium catalyst (10% Pd/C) is added and hydrogenated overnight. The catalyst is filtered out, and it is evaporated to dryness in a vacuum. 16.52 g of an amorphous solid is obtained.
Yield: 99% Cld: C 52.92% H 5.33% N 9.26% S 7.06% C1 7.81% Fnd: C 52.81% H 5.26% N 9.11% S 6.93% Cl 7.72%
~I~
b) 9-Chloro-2-(4-palmitoyloxybenzyl)-1-tosyl-1,4,7triazanonane-3,8-dione g (22.03 mmol) of the title compound of Example 20a) is dissolved in 100 ml of chloroform, and 2.45 g (23.53 mmol) of triethylamine is added. At 0 C, 6.66 g (24.23 mmol) of palmitic acid chloride is added in drops within 10 minutes, and it is stirred for 2 more hours at this temperature. It is shaken out with 200 ml of 2N hydrochloric acid, the organic phase is dried on magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/acetone 20:1). 11.90 g of a waxy solid is obtained.
Yield: 78% Cld: C 62.45% H 7.86% N 6.07% S 4.63% Cl 5.12% Fnd: C 62.28% H 7.70% N 5.89% S 4.54% Cl 4.98% c) 10-Benzoyl-2-(4-palmitoyloxybenzyl)-l-tosyl-10-thia-1,4,7triazadecane-3,8-dione 8 g (11.55 mmol) of the title compound of Example 20b) is dissolved in 100 ml of chloroform and 1.17 g (11.55 mmol) of triethylamine is added. Then, 1.60 g (11.55 mmol) of thiobenzoic acid is added and refluxed for 10 minutes. It is cooled to room temperature and shaken out once with 2N hydrochloric acid and once with a 5% sodium carbonate solution. After drying on magnesium sulfate, the organic phase is concentrated by evaporation in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/hexane/
M
I: acetone:20:10:1). 8.53 g of colorless flakes (of ether) is obtained.
Yield: 93% Cld: C 65.04% H 7.49% N 5.29% S 8.07% Fnd: C 64.90% H 7.55% N 5.17% S 7.91% Example 21 a) Phenolester of 3-cholesterol succinic acid semi-ester with 9-chloro-2-(4-hydroxybenzyl)-l-tosyl-1,4,7-triazanonane 3,8dione g (22.03 mmol) of the title compound of Example 20a) and 10.72 g (22.03 mmol) of cholesterol succinic acid semi-ester are dissolved in 49 ml of dimethylformamide and cooled to 0 0 C. Then, 300 mg of 4-dimethylaminopyridine and 5.45 g (26.44 mmol) of dicyclohexylcarbonyl are added and stirred for 3 hours at OOC.
It is allowed to stir at room temperature overnight. 50 ml of ether is added and precipitated urea is filtered out, the filtrate is diluted with 250 ml of ethyl acetate and shaken out times with 200 ml of water. The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum.
The residue is chromatographed on silica gel (mobile solvent: methylene chloride/hexane/ethyl acetate 10:5:1). 17.60 g of a waxy solid is obtained.
Yield: 78% Cld: C 66.39% H 7.87% N 4.55% S 3.48% Cl 3.84% Fnd: C 66.28% H 7.95% N 4.47% S 3.31% Cl 3.70%
I
I-a b) Phenolester of cholesterol succinic acid semi-ester with 10-benzoyl-2-(4-hydroxybenzyl)l-tosyl-lO-thia-1,4,7triazadecane-3,8-dione 6 g (6.50 mmol) of the title compound of Example 21a) is dissolved in 50 ml of chloroform and 0.66 g (6.50 mmol) of triethylamine is added. Then, 0.9 g (6.50 mmol) of thiobenzoic acid is added and refluxed for 10 minutes. It is cooled to room temperature and shaken out once with 2N hydrochloric acid and once with a 5% sodium carbonate solution. The organic phase is separated and dried on magnesium sulfate. After concentration by evaporation in a vacuum, the residue is recrystallized from methyl-tert-butyl ether. 6.06 g of waxy flakes is obtained.
Yield: 91% Cld: C 68.01% H 7.58% N 4.10% S 6.26% Fnd: C 67.85% H 7.43% N 3.98% S 6.17% Example 22 a) 7-N-(tert-Butoxycarbonyl)-2-(4-benzyloxybenzyl)-1-tosyl- 1,4,7-triazaheptan-3-one g (42.77 mmol) of the title compound of Example 16b) is dissolved in 200 ml of chloroform, and 4.76 g (47.05 mmol) of triethylamine is added. At 0 C, a solution of 10.27 g (47.05 mmol) of di-tert-butyl dicarbonate in 50 ml of chloroform is added in drops and stirred for 30 minutes at 0 C. Then, it is stirred for 5 hours at room temperature. It is shaken out three times with 5% sodium carbonate solution, the organic phase is dried on magnesium sulfate and concentrated by evaporation in a T I I I vacuum. The residue is recrystallized from a little methanol.
22.34 g of colorless crystals is obtained.
Yield: 92% Cld: C 63.47% H 6.57% N 7.40% S 5.65% Fnd: C 63.31% H 6.42% N 7.45% S 5.49% b) 7-N-tert-Butoxycarbonyl-2-(4-hydroxybenzyl)-1-tosyl-1,4,7triazaheptan-3-one 21 g (36.99 mmol) of the title compound of Example 22a) is dissolved in 300 ml of methylene chloride and 4 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated overnight. The catalyst is filtered out, and the filtrate is evaporated to dryness. 16.39 g of a vitreous foam is obtained, which solidifies after a short time.
Yield: 99% Cld: C 57.84% H 6.54% N 8.80% S 6.71% Fnd: C 57.70% H 6.61% N 8.69% S 6.54% c) 7-N-tert-Butoxycarbonyl-2-[4-(benzyloxycarbonylmethyloxy)benzyl]-i-tosyl-1,4,7-triazaheptan-3-one g (33.51 mmol) of the title compound of Example 22b), 7.68 g (33.51 mmol) of bromoacetic acid benzyl ester and 13.8 g (100 mmol) of potassium carbonate are refluxed in 300 ml of acetonitrile for 24 hours. The salts are filtered out, and the filtrate is evaporated to dryness. The residue is dissolved in 200 ml of methylene chloride and shaken out twice with 100 ml of water. The organic r' is dried on magnesium sulfate and I concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/hexane/acetone: 20/10/1). 10.69 g of a colorless oil is obtained.
Yield: 51% Cld: C 61.42% H 6.28% N 6.72% S 5.12% Fnd: C 61.27% H 6.09% N 6.68% S 5.03% d) l-Tosyl-2-(4-(benzyloxycarbonylmethyloxy)-benzyl)-1,4,7triazaheptan-3-one (as trifluoroacetate salt) g (15.98 mmol) of the title compound of Example 22c) is stirred for 1 hour in 100 ml of trifluoroacetic acid at room temperature. It is evaporated to dryness in a vacuum. 10.22 g of a vitreous foam is obtained, which solidifies with standing.
Yield: 100% Cld: C 54.45% H 5.04% N 6.57% S 5.01% F 8.91% Fnd: C 54.51% H 5.10% N 6.43% S 4.89% F 9.15% e) 9-Chloro-2-(4-(benzyloxycarbonylmethyloxy)-benzyl)-1-tosyl- 1,4,7-triazanonane-3,8-dione g (15.63 mmol) of the title compound of Example 22d) and 4.75 g (46.90 mmol) of triethylamine are dissolved in 200 ml of chloroform. At 0 C, 1.94 g (17.19 mmol) of chloroacetyl chloride is added in drops within 30 minutes and then stirred for 2 hours at 0 C. The organic phase is s aken out twice with hydrochloric acid and twice with water, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethyl acetate 20:1). 7.62 g of a waxy solid is obtained.
Yield: 81% Cld: C 57.85% H 5.36% N 6.98% S 5.32% Cl 5.89% Fnd: C 57.70% H 5.49% N 6.82% S 5.25% C1 5.78% f) 9-Chloro-2-(4-(carboxymethyloxy)-benzyl)-1-tosyl-1,4,7triazanonane-3,8-dione 7 g (11.63 mmol) of the title compound of Example 22e) is dissolved in 150 ml of methylene chloride and mixed with 2 g of palladium catalyst (10% Pd/C). It is hydrogenated overnight.
The catalyst is filtered out, and the filtrate is evaporated to dryness in a vacuum. 5.89 g of a vitreous solid is obtained.
Yield: 99% Cld: C 51.61% H 5.12% N 8.21% S 6.26% Cl 6.92% Fnd: C 51.45% H 5.03% N 8.13% S 6.11% Cl 6.79% g) 10-Acetyl-2-(4-(carboxymethyloxy)-benzyl)-l-tosyl-10-thia- 1,4,7-triazadecane-3,8-dione g (9.77 mmol) of the title compound of Example 22f) is dissolved in 80 ml of chloroform and 1.98 g (19.53 mmol) of trJethylamine is added. 0.74 g (9.77 mmol) of thioacetic acid is added and refluxed for 10 minutes. The solution is poured into 200 ml of ice-cooled 5% hydrochloric acid and stirred vigorously.
The organic phase is separated, dried on magnesium sulfate and evaporated to dryness in a vacuum. Chromatographic purification I I on silica gel (mobile solvent: hexane/ethyl acetate 3:1) yields 4.47 g of the title compound as vitreous solid.
Yield: 83% Cld: C 52.26% H 5.30% N 7.62% S 11.62% Fnd: C 52.11% H 5.39% N 7.50% S 11.49% h) N-Hydroxysuccinimidester of 10-acetyl-2-(4- (carboxymethyloxy)-benzyl)-l-tosyl-10-thia-1,4,7triazadecane-3,8-dione 4 g (7.25 mmol) of the title compound of Example 22g), 1.65 g (7.98 mmol) of dicyclohexylcarbodiimide, 30 mg of 4dimethylaminopyridine and 0.92 g (7.98 mmol) of Nhydroxysuccinimide are dissolved at 0°C in 20 ml of chloroform and stirred for 1 hour at this temperature. Then, stirring is continued for 24 hours at room temperature. 20 ml of ether is added, the precipitated dicyclohexylurea is suctioned off, and the filtrate is concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/dioxane 10:1). 4.09 g of a colorless solid is obtained.
Yield: 87% Cld: C 51.84% H 4.97% N 8.64% S 9.88% Fnd: C 51.68% H 4.80% N 8.53% S 9.68% Example 23 a) 4-Nitrophenolester of o0-acetyl-2-(4-(carboxymethyloxy)benzyl)-l-tosyl-10-thia-1,4,7-triazadecane-3,8-dione 4 g (7.25 mmol) of the title compound of Example 22g), 1.11 g (7.97 mmol) of 4-nitrophenol, 30 mg of 4-dimethylaminopyridine and 1.65 g (7.97 mmol) of dicyclohexylcarbodiimide are dissolved at 0°C in 20 ml of chloroform and stirred for 3 hours at this temperature. Then, it is stirred for 24 hours at room temperature. 20 ml of ether is added, settled precipitate is suctioned out, and the filtrate is concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/dioxane 15:1). 3.85 g of a creamcolored solid is obtained.
Yield: 79% Cld: C 53.56% H 4.79% N 8.33% S 9.53% Fnd: C 53.41% H 4.63% N 8.17% S 9.38% Example 24 a) Pentafluorophenolester of 10-acetyl-2-(4-(carboxymethyloxy)benzyl)-l-tosyl-10-thia-1,4,7-triazadecane-3,8-dione 4 g (7.25 mmol) of the title compound of Example 22g), 1.47 g (7.97 mmol) of pentafluorophenol, 30 mg of 4dimethylaminopyridine and 1.65 g (7.97 mmol) of dicyclohexylcarbodiimide are dissolved at 0 C in 20 ml of chloroform and stirred for 3 hours at this temperature. Then, it is stirred for 24 hours at room temperature. 20 ml of ether is added, settled precipitate is suctioned out, and the filtrate is concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/dioxane 15:1). 3.95 g of a colorless solid is obtained.
Yield: 76% Cld: C 50.20% H 3.93% N 5.85% S 8.93% F 13.24% Fnd: C 50.05% H 3.87% N 5.69% S 8.71% F 13.03% Example a) 7-N-tert-Butoxycarbonyl-2-(4-benzyloxybenzyl)-1-mesyl-1,4,7triazaheptan-3-one 16.23 g (42.77 mmol) of the title compound of Example 19b) is dissolved in 200 ml of chloroform and 4.76 g (47.05 mmol) of triethylamine is added. At 0 C, a solution of 10.27 g (47.05 mmol) of di-tert-butyldicarbonate in 50 ml of chloroform is added in drops and stirred for 30 minutes at 0 C. Then, it is stirred for 5 hours at room temperature. It is shaken out three times with 5% sodium carbonate solution, the organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum.
The residue is recrystallized from a little methanol. 20.19 g of a foamy solid is obtained.
Yield: 96% Cld: C 58.64% H 6.77% N 8.55% S 6.52% Fnd: C 58.48% H 6.59% N 8.41% S 6.42%
_M
b) 7-N-tert-Butoxycarbonyl-2- (4-hydroxybenzyl) mesyl-1,4,7triazaheptan-3-one g (40.68 mmol) of the title compound of Example 25a) is dissolved in 300 ml of methylene chloride, and 4 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated overnight. The catalyst is filtered out, and the filtrate is evaporated to dryness. 16.17 g of a vitreous foam is obtained, which solidifies after a short time.
Yield: 99% Cld: C 50.86% H 6.78% N 10.47% S 7.99% Fnd: C 50.70% H 6.69% N 10.31% S 7.78% c) 7-N-tert-Butoxycarbonyl-2-(4-benzyloxycarbonylmethyloxy)benzyl)-l-mesyl-1,4,7-triazaheptan-3-one g (37.36 mmol) of the title compound of Example 8.56 g (37.36 mmol) of bromoacetic acid benzyl ester and 13.8 g (100 mmol) of potassium carbonate are refluxed in 300 ml of acetonitrile for 24 hours. The salts are filtered out, and the filtrate is evaporated to dryness Vhe residue is dissolved in 200 ml of methylene chloride and shaken out twice with 100 ml of water. The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/hexane/acetone 20/10/1). 10.06 g of foamy solid is obtained.
Yield: 49% I- ~IC--u Cld: C 56.82% H 6.42% N 7.64% S 5.83% Fnd: C 56.65% H 6.35% N 7,51% S 5.72% d) 2-(4-(Benzyloxycarbonylmethyloxy)-benzyl)-l-mesyl-l,4,7triazaheptan-3-one (as trifluoroacetic acid salt) g (18.19 mmol) of the title compound of Example 25c) is stirred for 1 hour in 100 ml of trifluoroacetic acid at room temperature. It is evaporated to dryness in a vacuum. 9.95 g of a vitreous foam is obtained, which solidifies in the case of standing.
Yield: 97% Cld: C 49.02% H 5.01% N 7.46% S 5.69% F 10.11% Fnd: C 48.91% H 4.90% N 7.30% S 5.51% F 9.96% e) 9-Chloro-2-(4-(benzyloxycrbonylmethyloxy)-benzyl)-1-mesyl- 1,4,7-triazanonane-3,8-dione 9 g (15.97 mmol) of the title compound of Example 25d), 1.78 g (17.57 mmol) of triethylamine are dissolved in 200 ml of chloroform. At 0°C, 1.98 g (17.57 mmol) of chloroacetyl chloride is added in drops within 30 minutes and then stirrea for 2 hours at o°C. The organic phase is shaken out twice with hydrochloric acid and twice with water, dried on magnesium sulfate and evaporated co dryness in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethyl acetate 20:1).
Yield: 83% Cld: C 52.52% H 5.37% N 7.99% S 6.09% Cl 6.74% Fnd: C 52.37% H 5.43 N 7.81 S 5.93% C1 6.58% f) 9-Chloro-2-(4-(carboxymethyloxy)-benzyl)-l-meayl-1,4,7triazanonane-3,8-dione g (12.36 mmol) of the title compound of Example 25e) is dissolved in 150 ml of methylene chloride and mixed with 2 g of palladium catalyst (10% Pd/C). It is hydrogenated overnight.
The catalyst is filtered out, and the filtrate is evaporated to dryness in a vacuum. 5.33 g of a vitreous solid is obtained.
Yield: 99% Cld: C 44.09% H 5.09% N 9.64% S 7.36% C1 8.13% Fnd: C 43.93% H 4.95% N 9.52% S 7.22% Cl 8.03% g) 10-Acetyl-2-(4-(carboxymethyloxy)-benzyl) -1-esyl-10-thia- 1,4,7-triazadecane-3,8-dione g (11.47 mmol) of the title compound of Example 22f) is dissolved in 80 ml of chloroform, and 1.98 g (19.53 mmol) of triethylamine is added. 0.74 g (9.77 mmol) of thioacetic acid is added and refluxed for 10 minutes. The solution is poured into 200 ml of ice-cooled 5% hydrochloric acid and stirred vigorously.
The organic phase is separated, dried on magnesium sulfate and evaporated to dryness in a vacuum. Chromatographic purification on silica gel (mobile solvent: hexane/ethyl acetate 3:1) yields 4.64 g of the title compound as vitreous solid.
Yield: Cid: C 45.46% H 5.30% N 8.84% S 13.48% Fnd: C 45.28% H 5.17% N 8.61% S 13.38% h) N-Hydroxysuccinimidester of 1O-acetyl-2-(4- (carboxymethyloxy) -benzyl) -1-meeyl-iO-thia-i, 4,7triazadecane-3, 8-dione 4 g (8.41 mmol), 4 g (7.25 mmol) of the title compound of Example 25g), 1.91 g (9.25 mmcl) of dicyclohexylcarbodiimide, mg of 4-dimethylaminopyridine and 1.06 g (9.25 mmcl) of Nhydroxysuccinimide are dissolved at O 0 C in 20 ml of chloroform and stirred for 1 hour at this temperature. Then, stirring is continued for 24 hours at room temperature. 20 ml of ether is added, precipitated dicyclohexylurea is suctioned out, and the filtrate is concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/dioxane 10:1). 3.47 g of a cream-colored solid is obtained.
Yield: 72% Cld: C 46.15% H 4.93% N 9.78% S 11.20% Fnd: C 46.03% H 4.83% N 9.64% S 11.05% Example 26 a) 3-Glycerol-ester of lo-acetyl-2-(4-(carboxymethyloxy) benzyl) -l-mesyl-1O-thia-1,4,7-triazadecane-3,8-dione with glycerol-i, 2-dipalmitate 2 g (5.27 mmcl) of the title compound of Example 25g), 20 Mg of 4-dimethylaminopyridine, 3.30 g (5.80 mmol) of glycerol-1,2- 1__1 dipalmitic acid ester and 1.20 g (5.80 mmol) of dicyclohexylcarbodiimide are dissolved at O
O
C in 5 ml of chloroform and stirred for 3 hours at this temperature. Then, it is stirred for 24 hours at room temperature. 20 ml of ether is added, and precipitate is filtered out. The filtrate is evaporated to dryness in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: hexane/ethyl acetate 30:1). 3.35 g of a waxy solid is obtained.
Yield: 62% Cld: C 62.02% H 8.94% N 4.09% S 6.25% Fnd: C 61.91% H 8.75% N 3.91% S 6.18% Example 27 a) 4-Benzyl ether of N-mesyl-tyrosine g (27.5 mmol) of the title compound of Example 19a) and 5.50 g (137.6 mmol) of sodium hydroxide are refluxed in a mixture of 50 ml of water/150 ml of ethanol for 3 hours. It is evaporated to dryness, the residue is taken up in 200 ml of 3N hydrochloric acid, and it is stirred for 2 hours at room temperature. The precipitated acid is suctioned off, washed with water and dried in a vacuum at 70°C. 9.42 g of cream-colored solid is obtained.
Yield: 98% Cld: C 58.44% H 5.48% N 4.01% S 9.18% Fnd: C 58.28% H 5.37% N 3.91% S 9.02% i l r C.
b) 6,6 -Bis- l-N-tert-butoxycarbonyl-1,4-diaza-hexan-3-ono]disulfide g (65.67 mmol) of cystamine, 11.50 g (65.67 mmol) of Nboc-glycine and 14.90 g (72.24 mmol) of dicyclohoxylcarbodiimide are dissolved at 0 C in 50 ml of tetrahydrofuran and stirred for 2 hours at this temperature. Then, it is stirred for 12 hours at room temperature. 50 ml of ether is added, settled precipitate is suctioned out, and the filti j is evaporated to dryness. The residue is chromatographed on silica gel (mobile solvent: hexane/acetone 20.84 g of a vitreous solid is obtained.
Yield: 68% Cld: C 46.33% H 7.34% N 12.01% S 13.74% Fnd: C 46.15% H 7.28% N 11.93% S 13.67% S 6,6'-Bis-[l,4-diaza-hexan-3-one]-disulfide g (42.86 mmol) of the title compound of Example 27b) is dissolved in 100 ml of trifluoroacetic acid, and it is stirred for 2 hours at room temperature. It is evaporated to dryness, the residue is taken up with 300 ml of 10% sodium carbonate solution and extracted 6 times with 50 ml of chloroform. The combined chloroform phases are dried on magnesium sulfate and concentrated by evaporation in a vacuum. 10.96 g of a slightly yellow-colored solid is obtained.
Yield: 96% Cld: C 36.07% H 6.81% N 21.03% S 24.07% Fnd: C 35.91% H 6.90% N 20.89% S 23.89% d) 9,9'-Bis[2-(4-benzyloxybenzyl)-1-meoyl-1,4,7-triazanonane- 3,6-dione]disulfide 9 g (25.76 mmol) of the title compound of Example 27a), 3.43 g (12.87 mmol) of the title compound of Example 27c) and 6.19 g (30 mmol) of dicyclohexylcarbodiimide are dissolved at 0 C in 40 ml of tetrahydrofuran and stirred for 2 hours at this temperature. Then, it is stirred for 12 hours at room temperature. 30 ml of ether is added, and precipitate is suctioned out. The filtrate is evaporated to dryness in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/acetone 20:1). 5.59 g of a creamcolored solid is obtained.
Yield: 48% (relative to 27c)] Cld: C 53.08% H 5.79% N 9.28% S 14.17% Fnd: C 52.93% H 5.84% N 9.13 S 14.02% Example 28 a) 4-Benzyl ether of N-mesyl-tyrosinamide g (55.03 mmol) of the title compound of Example 19a) is dissolved in 300 ml of tetrahydrofuran, and an ammonia stream is introduced at 0 C for 3 hours. It is evaporated to dryness, and the residue is recrystallized from methanol. 18.6 g of colorless flakes is obtained.
Yield: 97% Cld: C 58.60% H 5.79% N 8.04% S 9.20% Fnd: C 58.47% H 5.88% N 7.91% S 9.05% b) 2- (4 -Dnyloxybenzyl) -1-mesyl-1, 4-diazabutane 18 g (51.66 mmoil) of the title compound of Example 28a) is di oolved in 200 ml of tetrahydrofuran, and 310 ml of 1 M dibcrane in THF is added under nitrogen atmosphere. It is roflgxed for 24 hours. It is cooled to 0 0 C in an ice bath, and rj. of concentrated hydrochloric acid is added. Then, it is refl 3ed for 5 hours. It is evaporated to dryness, and the rOidue is taken up with 300 ml of saturated sodium carbonate sol .ton. It is extracted 3 times with 100 ml of methylene chlorlde, the combined phases are dried on magnesium sulfate and evaDorated to dryness in a vacuum. The chromatographic purification is carried out on silica gel (mobile solvent: methylene chloride/othanol 10:1). 15.38 g of a cream-colored solid is obtained.
Yield: 89% Cld: C 61.05% H 6.63% N 8.38% S 9.59% fnd: C 60.91% H 6.54% N 8.27% S 9.41% c) 4-N-Butoxycarbonyl-2- (4-benzyloxybenzyl) -1-mesyl-1, 4,7g (44.85 mmol) of the title compound of Example 28b) is disolved in 200 ml of chloroform, and 5 g (49.34 mmol) of trietjYlamine and 12.84 g (49.34 mmol) of N-tert-butoxycarbonylglycire-N-hydroxysuccinimide ester are added at 0oC. It is stIrted for 12 hours at room temperature. It is extracted twice with cold 5% hydrochloric acid and once with water. The organic phase is dried on magnesium sulfate and evaporated to dryness in a vacuum. 20.51 g of an amorphous solid is obtained.
Yield: 93% Cld: C 58.64% H 6.77% N 8.55% S 6.52% Fnd: C 58.47% H 6.85% N d.43S S 6.41% d) 2-(4-Benzyloxybenzyl)-l-mesyl-1,4.,7-triazaheptan-5-one g (40.68 mmol) of the title compound of Example 28c) is dissolved in 100 ml of trifluoroacetic acid and dissolved for hours at room temperature. It is evaporated to dryness in a vacuum, the residue is taken up in 200 ml of saturated sodium carbonate solution and extracted 3 times with 100 ml of chloroform. The organic phases are dried on sodium sulfate and concentrated by evaporation in a vacuum. 15.61 g of a vitreous solid is obtained.
Yield: 98% Cld: C 58.29% H 6.44% N 10.73% S 8.19% Fnd: C 58.13% H 6.60% N 10.61% S 8.05% e) 9-Chloro-2-(4-benzyloxybenzyl) -mesyl-1,4,7-triazanonane- 5,8-dione g (25.54 mmo.) of the title compound of Example 28d) and 2.58 g (25.54 mmol) of triethylamine are dissolved in 200 ml of chloroform. 2.88 g (25.54 mmol) of chloroacetyl chloride is added in drops at 0C within 30 minutes. It is stirred for 3 hours at 0°C. It is poured onto 200 ml of 5% cold hydrochloric acid and stirred vigorously. The organic phase is separated, dried on magnesium and evaporated to dryness in a vacuum. The residue is recrystallized from methanol. 11.36 g of a creamcolored solid is obtained.
Yield: Cld: C 53.90% H 5.60% N 8.98% S 6.85% Cl 7.58% Fnd: C 53.80% H 5.71% N 8.91% S 6.73% Cl 7.44% f) 10-Benzoyl-2-(4-benzyloxybenzyl)-i-mesyl-1,4,7-triaza-10thiadecane-5,8-dione g (10.68 mmol) of the title compound of Example 28e), 1.08 g (10.68 mmol) of triethylamine and 1.48 g (10.68 mmol) of thiobenzoic acid are refluxed in 50 ml of chloroform for minutes. It is evaporated to dryness, and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/acetone 15:1). 4.93 g of a cream-colored, amorphous solid is obtained.
Yield: 81% Cld: C 59.03% H 5.48% N 7.38% S 11.26% Fnd: C 58.87% H 5.31% N 7.25% S 11.04% Example 29 a) 9,9'-Bis-[2-(4-benzyloxybenzyl)-l-mesyl-1,4,7-triazanonan-3one]-disulfide 2.00 g (13.17 mmol) of 1,6-dichloro-3,4-dithiahexane (dissolved in 20 ml of acetonitrile) is added in drops to 10 g (26.35 mmol) of the title compound of Example 19b) and 10.92 g (79 mmol) of potassium carbonate in 100 ml of acetonitrile in the c.
boiling leat within 1 hour. It is refluxed for 12 hours. The salts are filtered out, the filtrate is evaporated to dryness in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/isopropanol 10:1). 2.19 g of a slightly yellow-colored crystalline powder is obtained.
Yield: 19% (relative to 1,6-dichloro-3,4-dithiahexane) Cld: C 54.77% H 6.43% N 9.58% S 14.62% Fnd: C 54.61% H 6.53% N 9.41% S 14.51% Example a) 6-Chloro-2-(4-benzyloxybenzyl)-l-mesyl-1,4-diazahexan-5,one g (25.54 mmol) of the title compound of Example 28b) is dissolved together with 3.03 g (29.90 mmol) of triethylamine in 200 ml of chloroform. 3.38 g (29.90 mol) of chloroacetyl chloride is added in drops at 0°C, and it is stirred for 2 hours at this temperature. It is poured onto 200 ml of 5% cold hydrochloric acid and stirred well. The organic phase is separated, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from methanol. 11.67 g of colorless crystals is obtained.
Yield: Cld: C 55.54% H 5.64% N 6.82% S 7.80% Cl 8.63% Fnd: C 55.38% H 5.71% N 6.67% S 7.63% C1 8.51% b) 9,9'-Bis-[2-(4-benzyloxybenzyl)-l-mesyl-l,4,7-triazanonan-5one]-disulfide g (24.34 mmol) of the title compound of Example 1.52 g (10 mmol) of cystamine and 8.29 g (60 mol) of potassium carbonate are refluxed in 150 ml of tetrahydrofuran for 8 hours.
The salts are filtered out, the filtrate is evaporated to dryness in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol 15:1). 2.02 g of a slightly yellowish solid is obtained.
Yield: 23% (relative to cystamine) Cld: C 54.77% H 6.43% N 9.58% S 14.62% Fnd: C 54.61% H 6.52% N 9.47% S 14.48% Example 31 a) Cystamine-bis-(chloroacetamide) g (65.67 mmol) of cystamine and 13.29 g (131.34 mmol) of triethylamine are dissolved in 100 ml of chloroform at 0°C.
14.38 g (131.34 mol) of chloroacetyl chloride is added in drops, and it is stirred for 3 hours at 0 C. The solution is poured into 200 ml of cold 5% hydrochloric acid and stirred vigorously.
The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is recrystallized from a little acetone. 17.04 g of a cream-colored solid is obtained.
Yield: Cld: C 31.48% H 4.62% N 9.18% S 21.01% Cl 23.23% Fnd: C 31.27% H 4.51% N 9.09% S 20.93% Cl 23.12% r b) 9,9'-Bis[2-(4-benzyloxybenzyl)-l-mesyl-1,4,7-triazanonan-6.
one]-disulfide g (16.38 mmol) of the title compound of Example 31a), 13.69 g (40.95 mmol) of the title compound of Example 28b) and 20.73 g (150 mmol) of potassium carbonate are refluxed in 200 ml of ethanol for 8 hours. 200 ml of methylene chloride is added, salts are suctioned out, and the filtrate is concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol 15:1).
4.74 g of a vitreous solid is obtained.
Yield: 33% Cld: C 54.77% H 6.43% N 9.58% S 14.62% Fnd: C 54.65% H 6.37% N 9.41% S 14.53% Example 32 a) 2-[4-Benzyloxybenzyl]-l-mesyl-1,4,7-triazaheptane g (13.18 mmol) of the title compound of Example 19b) is dissolved in 50 ml of tetrahydrofuran, and 80 ml of 1 M diborane solution (1 M in THF) is added. It is refluxed for 24 hours. It is cooled to 0°C, and 20 ml of concentrated hydrochloric acid is added. Then, it is refluxed for 5 hours. The solution is evaporated to dryness and taken up with 200 ml of saturated sodium carbonate solution. Then, it is extracted 5 times with 100 ml of chloroform. The combined organic phases are dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/isopropanol 8:1, NHOH). 4.19 g of a vitreous solid is obtained.
Yield: 87% Cld: C 59.15% H 7.45% N 11.50% S 8.77% Fnd: C 59.03% H 7.28% N 11.37% S 8.61% b) 9,9'-Bis-[2-(4-benzyloxybenzyl)-l-mesyl-l,4,7-triazanonan-8one]-disulfide 4 g (10.94 mmol) of the title compound of Example 32a), 0.67 g (3.65 mmol) of 2,2'-dithiodiacetic acid and 2.48 g (12.04 mmol) of dicyclohexylcarbodiimide are dissolved at 0 C in 20 ml of tetrahydrofuran and stirred for 3 hours at this temperature.
Then, it is stirred for 24 hours at room temperature. 20 ml of ether is added, precipitate is filtered out, and the filtrate is concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol 15:1). 0.99 g of an amorphous solid is obtained.
Yield: 31% (relative to dicarboxylic acid) Cld: C 54.77% H 6.43% N 9.58% S 11.62% Fnd: C 54.58% H 6.38% N 9.47% S 14.51%
Claims (14)
1. Compounds of general formula I Vf- CH)--V /2 2 V NX X N 4 V I R NX S 2H )-R so2 R 1 2 R (I) in which V 1 V 2 V 3 V 4 independently of one another, stand for a carbonyl, >CH(COOH) or -CH 2 group, X 1 stands for a hydrogen atom, a C 1 -C 12 alkyl radical optionally substituted with a carboxyl, an amino or a thiocyanate group or a metal ion equivalent of a radioactive metal ion of an element of atomic number 43, 45, 46, 75, 82 or 83, X 2 ,X 3 independently of one another, stand for a hydrogen atom or a metal ion equivalent of a radioactive metal ion of an element of tha above-mentioned atomic numbers, n, m, p stand for numbers 0 or 1, whereby m n 1 holds true, I' WPjXDocS At I'I I 211196 ANhW 1i- 9 -93- R 1 stands for a hydrogen atom, a carboxyl group or a group -U- Z, in which U stands for a direct bond, a straight-chain or branched, saturated or unsaturated C 1 -C 20 alkylene radical, which optionally contains a maleimide radical, a succinimide radical, a phenyl radical optionally substituted by 1 to 5 fluorine atoms, an amino or nitro group, one or two imiro, phenylene, phenylenoxy, phenylenamino, amide, hydrazide, cabonyl, ureido, thioureido, chioamide, ester group(s), 1 to 2 oxygen, sulfur and/or nitrogen atom(s) as well as optionally 1 to hydroxy, mercapto, oxo, thioxo, carboxy, alkylcarboxylic acid, ester, thiocyanate and/or amino groups, and Z stands 15 for a hydrogen atom, a radical of an amino acid, a peptide, a polynucleotide or a steroid or a functional group from the group which includes -COOH, -SCN, -OH, -Cl or -NH 2 with e which optionally the radical of an amino acid, a peptide, a polynucleotide or a steroid is bound, R 2 stands for a straight-chain or branched C -Cio alkyl radical, which optionally contains a -COOH group, a C 7 -C 1 2 aralkyl radical or an aromatic compound from the group which includes -CbH 4 NCS, H4 -COOH or phenyl, which optionally is substituted with a chlorine or bromine atom, a thiocyanate, a methyl, ethyl, carboxyl and/or methoxy group, R 4 stands for a hydrogen atom or a carboxyl group or ifI R means a hydrogen atom or a carboxyl group, it stands in 94 addition for a group in which UI and Z have the indicated meanings, R3' stands for a hydrogen atom, a radioactive metal ion equivalent of an element of the above-mentioned atomic numbers; a trifluoroacetate, acetate, benzoate, CI-Cd acy., a benzoyl, a hydroxyacetyl, an acetamidomethyl radical, a benzoic acid radical optionally substituted with a chlorine or bromine atom, a methyl, ethyl, carboxyl and/or methoxy group, a p-methoxybenzyl radical, an ethoxyethyl radical, an SH protective group, a 0 1-0 radical, or if X 2 X 3 stand for a hydrogen and X 1 stands f or a hydrogen or an optionally substituted C -C 1 alkyl :radical, for a radical of formula II 2 R so 2. *R X S 2.2 14 2), NX X N 2 3 V- (H 2PP in which V 1 V 2 V 3 V'I X 1 X 2 X 3 n, im, p, R 1 R 2 and R' have the indicated meanings, whereby at least one and at most two radicals V 7 V 3 V 4 stand for a carbonyl group.
2. Compounds of general formula I according to claim 1, characterized in that at least two of radicals XI, X' or R' stand for a metal ion equivalent of a radioactive metal isotope of atomic numbers 43, 45, 46, 75, 82 or 83.
3. Compound according to one of the preceding claims, wherein Z stands for an amino acid or a peptide.
4. Compound according to one of the preceding claims, in which Z stands for a polynucleotide.
Compound according to one of the preceding claims, wherein V I and V4 each stand for a carbonyl group, V 2 and V 3 each for a -CH 2 group and p for number 0.
6. Compound according to one of the preceding claims, wherein a 99m-technetium is contained as a radioactive metal ion.
7. Compound according to one of the preceding claims, 9* wherein R 4 is hydrogen or a carboxylic acid group.
8. Compound according to one of the preceding claims, wherein R 2 is a p-CH 3 -C 6 H 4 radical.
9. Compound according to claim 1, wherein X 1 X 2 and X 3 sLand for a hydrogen atom and R 3 stands for a radical of formula II. Pharmaceutical agents, containing at least one metal complex of formula I according to claim 1, in which at least two of radicals X 1 X 2 X 3 and/or R 3 stand for a radioactive metal ion equivalent in combination with pharmacologically acceptable radiological vehicles.
A~r, o 2' 11 %WIIl)OC', %I)YSILCII.16201')6 NIfil 2119198 -96-
11. A method of radiodiagnostic or radiotherapeutic treatment which comprises administering to a subject in need of such treatment a radiodiagnostically or radiotherapeutically effective amount of a compound of the general formula according to any one claims 1 9 optionally in combination with one or more pharmacologically acceptable radiological vehicles.
12. A process for the production of a pharmaceutical agent according to claim 10 wherein a compound of formula I with X 2 and X 3 meaning a hydrogen atom and X' meaning hydrogen or a optionally substituted C 1 -C, 1 alkyl radical with a carboxyl, an amino or a S 10 thiocyanate group, and a reducing agent are dissolved in an aqueous medium with the addition of additives customary in galenicals and then reacted with a metal salt or metal oxide of the S" desired metal ion and mixed with a pharmacologically acceptable radiological vehicle, said Scompound of formula I being added in excess, 15
13. The process according to claim 12 wherein a transfer ligand is dissolved in said aqueous medium.
14. The process according to either claim 12 or claim 13 wherein the compound of formula I is present in the form of its alkali salt. Dated this 25th day of September, 1998 SCHERING AG By Its Patent Attorneys DAVIES COLLISON CAVE "7, 97 Abstract The invention relates to chelating agents containing new sulfonamide groups and their metal chelates of general formula I 2 3 V- H NX Np V X N"v I, 2 n I z o R NX S IH 2 )-R f2 R 2 R in which n, m, p, V 1 V 2 V 3 V 4 X 1 X 2 X 3 R 1 R 2 R 3 and R 4 have varying meanings, pharmaceutical agents containing these compounds, their use in :adiodiagnosis and radiotherapy, process for the production of these compounds and agents, as well as conjugates of these compounds with substances, especially peptides, selectively accumulating in diseased tissue. 1N'I'1FHNAT1O1NA1, SF A1ICII IUPO tm PCT/EP 95/02404 A~ t IAh%II 111 A110% 01 N 111(1 MA4 IlI It IPC 6 C07C327/32 C07C323/60 C07C331/28 C070317/68 CO7J41/0C C07K7/06 C070207/46 CO7K5/065 C07C323/25 C07C323/41 C07B59/00 C07F13/00 A61K51/04 A61K51/08 Acording Its Interrntionil I'atwnt laiition fII or I$ hsth naU;nal clasilication and ll'( 11Il l %I ARC 111) Mitnimum do'cumentation searched (Iailiitnmn %ytm fo'llowed hw laisilicallon symbhols) IPC 6 C07C IDocumencrtation searched othecr than minimum diieumcrntaton (is the extent that such docuiments are included in the licid icarchcd Ilctritnic data hase consulted during the international search (name til data base and, where practical, search terms tied) C. I)0(:(JMI 'IT. S :NIIR~110 111! IMINA N I' Category itation (if document, with indication, where appropriate. of thc relevant passages Rlevan5lt to claim No. A EP,A,0 250 013 (MALLINCKROOT) 23 December 1,10-12 1987 cited in the application see page 3 page A EP,A,0 173 424 (UNIVERSITY OF UTAH 1,10-12 RESEARCH) 5 March 1986 cited in the application see page 10 page 11 A JOURNAL OF THE INDIAN CHEMICAL SOCIETY, 1 vol. 60, no. 8, August 1983 CALCUTTA, IN, pages 762-765, A.M. EL-NAGGER, ET AL.: 'Synthesis and antimicrobial activity of some di-, tri- and tetrapeptides containing cysteine and cysti nel See compound XXXI lr7v 1urthcr dtieumcnta arc listed in ilhc cintinuauion of box C. Patenit famiuly membcrs are listed in annex. *Special categorics of cited documcnts later document published after the intcmaflona; filing datc *A dcumnt efiingUsc cncal tat ofihc rt hic isnotor pnonty datc and not in conflict with the application but ''dcund finid toh f nepartc l rtcl tevac ic s cited to undcrstantd the principlc or theory underlying ihc consdere tobe o paticuar elevnceinvention earlier documcnt hut publishcd on or aftcr the intcrnational W- documcnt of particular rclevancc; thc claimed invention filing date cannot he considcred n,)vcl or cannot he considered to ''documcnt which may throw doubts on prionity claim(s) iir involvc an inventve stcp whcn the documcnt is tAkcn alone which Is cited to estahlish the publicaioin date of inothcr i'document of particular relevance; the claimed Invention citation or tither special reason (a~s specified) cannot be considered to involve an inventive step when the document refernog to an oral diselosurc, use, exhihition or document is combined with one or more other such docti- other means mnrts, such combination being obvious to a person skilled document published pnor to the international filing date but in the ar-t, later than the priority date claimed document member of the same patent fanudl) lDate of the actual completion of the International search D~ate of mailing of the interniational search report 6 October 1995 1 7.1 9 Name and mailing address of the ISA Authonzed officer E~uropean I'atent Office, I'll. 5818 Platcntlaan 2 2280 1IIV Rilswijlc 'rel. (31.10) 340.2040, TX. 31 651 Ceii ol, Egi h I'axc 1 31.70) 340-30116 Eg ih Lrmr PCT ISA'liit (second sheet) (Juiy 1992) page 1 of 2 I NTF:UNA'rIONA1 4 $iAW('1 [W3LE010"I Ink ~ni lApiItutio PCT/EP 95/024C4 i.nunuati(np 1I00( 1%1 Ni Is 0%%11)I1 I 11) 1I I I II NVA., I McguY iIullon W' diguJmcnJt, lth Indlotion, WhrCC appirittirIat. 1 the relevant pwago Rtclofir oalm Iso A COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS, vol. 21, no, 1, 1956 PRAGUE, CS, pages 202-210, J. RUDINGER, ET AL.: 'Synthetic studies in the oxytocin field. III. An alternative synthesis of oxytocin' See compound XXXI A AUSTRALIAN JOURNAL OF CHEMISTRY, vol. 11, 1958 MELBOURNE, AU, pages 345-359, J.A. MACLAREN, ET AL.: 'Amino acids and peptides. IV. Intermediates for the synthesis of certain cysteine-containing peptide sequences in insulin' see page 354, paragraph 'rm PCT.ISA&2I (continuation ot second shee~t) (July 1992) page 2 of 2 I NTEM~NAIONAL S~EAR~CH RI-TO RT i nAl ApphitAtin PCT/EP 95/02404 [Inen duoumcnt Publication Patent family Vubi "uvin uwd in scsaroi rcrort date member(%)aat EP-A-250013 23-12-87 AU-B- 611854 27-06-91 AU-B- 7360587 01-12-88 CA-A- 1316296 13-04-93 JP-A- 62289596 16-12-87 US-A- 4849511 18-07-89 US-A- 5187264 16-02-93 EP-A-173424 05-03-86 US-A- 4980147 25-12-90 AU-B- 581003 09-02-89 AU-B- 4327085 02-01-86 CA-A- 1317066 27-04-93 JP-C- 1792970 14-10-93 JP-B- 4082159 25-12-92 JP-A- 61040295 26-02-86 JP-A- 7069935 14-03-95 JP-A- 5208986 20-08-93 JP-B- 7049406 31-05-95 US-A- 5322929 21-06-94 rorm PCT'ISA.1210 (patent family annex) (July 1992)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEP4425781 | 1994-07-14 | ||
DE4425781A DE4425781A1 (en) | 1994-07-14 | 1994-07-14 | Technetium sulfonamide complexes, their use, pharmaceutical compositions containing them, and processes for the preparation of the complexes and compositions |
PCT/EP1995/002404 WO1996002500A1 (en) | 1994-07-14 | 1995-06-22 | Technetium-sulphonamide complexes, their use, pharmaceutical agents containing them, and process for producing the complexes and agents |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2886595A AU2886595A (en) | 1996-02-16 |
AU698824B2 true AU698824B2 (en) | 1998-11-05 |
Family
ID=6523740
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU28865/95A Ceased AU698824B2 (en) | 1994-07-14 | 1995-06-22 | Technetium-sulphonamide complexes, their use, pharmaceutical agents containing the latter, as well as process for the production of the complexes and agents |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP0770063A1 (en) |
JP (1) | JPH10502648A (en) |
KR (1) | KR970704682A (en) |
CN (1) | CN1152914A (en) |
AU (1) | AU698824B2 (en) |
CA (1) | CA2194561A1 (en) |
DE (1) | DE4425781A1 (en) |
HU (1) | HUT76806A (en) |
NO (1) | NO970140L (en) |
WO (1) | WO1996002500A1 (en) |
ZA (1) | ZA955896B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5028422A (en) * | 1986-05-27 | 1991-07-02 | Schering Corporation | Treatment of basal cell carcinoma intralesionally with recombinant human alpha interferon |
ES2312461T3 (en) * | 2000-07-06 | 2009-03-01 | Array Biopharma Inc. | DERIVATIVES OF TYROSINE AS INHIBITORS OF PHOSPHATASE. |
KR100445971B1 (en) * | 2002-04-15 | 2004-08-25 | 한국원자력연구소 | Process for labeling technetium or rhenium using borohydride exchange resin |
DK2151250T3 (en) * | 2002-05-06 | 2013-12-16 | Endocyte Inc | Vitamin-targeted imaging agents |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4980147A (en) * | 1984-06-25 | 1990-12-25 | University Of Utah Research Foundation | Radiolabeled technetium chelates for use in renal function determinations |
EP0250013B1 (en) * | 1986-05-28 | 1990-05-09 | MALLINCKRODT, INC.(a Missouri corporation) | Technetium chelates to be used for determining the renal function |
-
1994
- 1994-07-14 DE DE4425781A patent/DE4425781A1/en not_active Withdrawn
-
1995
- 1995-06-22 HU HU9700101A patent/HUT76806A/en unknown
- 1995-06-22 AU AU28865/95A patent/AU698824B2/en not_active Ceased
- 1995-06-22 CN CN95194028A patent/CN1152914A/en active Pending
- 1995-06-22 EP EP95924304A patent/EP0770063A1/en not_active Withdrawn
- 1995-06-22 KR KR1019970700193A patent/KR970704682A/en not_active Application Discontinuation
- 1995-06-22 CA CA002194561A patent/CA2194561A1/en not_active Abandoned
- 1995-06-22 WO PCT/EP1995/002404 patent/WO1996002500A1/en not_active Application Discontinuation
- 1995-06-22 JP JP8504625A patent/JPH10502648A/en active Pending
- 1995-07-14 ZA ZA955896A patent/ZA955896B/en unknown
-
1997
- 1997-01-13 NO NO970140A patent/NO970140L/en unknown
Also Published As
Publication number | Publication date |
---|---|
CN1152914A (en) | 1997-06-25 |
NO970140D0 (en) | 1997-01-13 |
KR970704682A (en) | 1997-09-06 |
NO970140L (en) | 1997-03-13 |
WO1996002500A1 (en) | 1996-02-01 |
DE4425781A1 (en) | 1996-01-18 |
HUT76806A (en) | 1997-11-28 |
JPH10502648A (en) | 1998-03-10 |
ZA955896B (en) | 1996-02-19 |
EP0770063A1 (en) | 1997-05-02 |
AU2886595A (en) | 1996-02-16 |
CA2194561A1 (en) | 1996-02-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4897255A (en) | Metal radionuclide labeled proteins for diagnosis and therapy | |
CA2111863C (en) | Technetium-99m labeled peptides for imaging | |
US5175343A (en) | Metal radionuclide labeled proteins for diagnosis and therapy | |
DE69310733T2 (en) | TECHNETIUM-99M-MARKED PEPTIDES FOR IMAGE GENERATION | |
EP0975374B1 (en) | Radiometal-binding peptide analogues | |
US5037630A (en) | Metal radionuclide labeled proteins for diagnosis and therapy | |
US5242679A (en) | Metal radionuclide labeled proteins for diagnosis and therapy | |
JPH07103159B2 (en) | Radionuclide metal chelate | |
AU691806B2 (en) | Chelating agents of the type XN1S1O1 for radioactive isotopes, metal complexes thereof, and their use in diagnosis and therapy | |
US5120526A (en) | Method of producing metal radionuclide labeled proteins for diagnosis and therapy | |
Mach et al. | Synthesis and biodistribution of a new class of 99mTc-labeled fatty acid analogs for myocardial imaging | |
CA2156618A1 (en) | Bifunctional chelators and their use in radiopharmaceuticals | |
AU698824B2 (en) | Technetium-sulphonamide complexes, their use, pharmaceutical agents containing the latter, as well as process for the production of the complexes and agents | |
US6488909B1 (en) | Chelating agents as well as their tricarbonyl complexes with technetium and rhenium | |
CA3201655A1 (en) | Radiolabeled compounds targeting the prostate-specific membrane antigen | |
US5961954A (en) | Chealators of type XN1 S1 X1 for radioactive isotopes, their metal complexes and their diagnostic and therapeutical uses | |
US6143275A (en) | Type S3 N2 chelators for radioactive isotopes, their metal complexes and their diagnostic and therapeutical use | |
US6132697A (en) | Radiopharmaceutical compositions capable of localizing at sites of thrombus | |
HUT74881A (en) | N-alkyl peptide chelate formers, their metal comlexes with radionuclides, processes for producing them and radio-pharmaceutical compositions containing these compounds | |
WO1997047329A9 (en) | Radiopharmaceutical compositions capable of localizing at sites of thrombus | |
KR100567001B1 (en) | Cysteine derivatives and metal tricarbonyl complexes thereof, preparation thereof and contrast medium | |
JP2005509686A6 (en) | Technetium and rhenium complexes, radiopharmaceutical products comprising them | |
JP2005509686A (en) | Technetium and rhenium complexes, radiopharmaceutical products comprising them | |
CA2232620A1 (en) | Bifunctional sulfide-containing sulfonamide-chelating agents such as xsny for radioactive isotopes |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |