US20040131551A1 - Enhanced relaxivity monomeric and multimeric compounds - Google Patents
Enhanced relaxivity monomeric and multimeric compounds Download PDFInfo
- Publication number
- US20040131551A1 US20040131551A1 US10/741,872 US74187203A US2004131551A1 US 20040131551 A1 US20040131551 A1 US 20040131551A1 US 74187203 A US74187203 A US 74187203A US 2004131551 A1 US2004131551 A1 US 2004131551A1
- Authority
- US
- United States
- Prior art keywords
- compound
- chelate
- metal atom
- immobilized
- relaxivity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 100
- 229910052751 metal Inorganic materials 0.000 claims abstract description 79
- 239000002184 metal Substances 0.000 claims abstract description 79
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 52
- 239000001257 hydrogen Substances 0.000 claims abstract description 48
- 230000001747 exhibiting effect Effects 0.000 claims abstract description 31
- 125000000524 functional group Chemical group 0.000 claims abstract description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 15
- 125000003627 8 membered carbocyclic group Chemical group 0.000 claims abstract description 3
- 239000013522 chelant Substances 0.000 claims description 52
- 125000004429 atom Chemical group 0.000 claims description 48
- -1 1,2,4,5-Tetrahydroxy-1,4-cyclohexanediyl Chemical group 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- HHLZCENAOIROSL-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound OC(=O)CN1CCNCCN(CC(O)=O)CCN(CC(O)=O)CC1 HHLZCENAOIROSL-UHFFFAOYSA-N 0.000 claims description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 16
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 150000000921 Gadolinium Chemical class 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 229960000367 inositol Drugs 0.000 claims description 11
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 239000007983 Tris buffer Substances 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 230000005291 magnetic effect Effects 0.000 claims description 7
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- DRNKIOIJTYLTSS-UHFFFAOYSA-N 2-[4,10-bis(carboxymethyl)-7-(phosphonomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CP(O)(O)=O)CCN(CC(O)=O)CC1 DRNKIOIJTYLTSS-UHFFFAOYSA-N 0.000 claims description 5
- 125000002837 carbocyclic group Chemical group 0.000 claims description 5
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims description 5
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 5
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 238000002059 diagnostic imaging Methods 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- LGAILEFNHXWAJP-BMEPFDOTSA-N macrocycle Chemical group N([C@H]1[C@@H](C)CC)C(=O)C(N=2)=CSC=2CNC(=O)C(=C(O2)C)N=C2[C@H]([C@@H](C)CC)NC(=O)C2=CSC1=N2 LGAILEFNHXWAJP-BMEPFDOTSA-N 0.000 claims description 3
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 11
- 239000003446 ligand Substances 0.000 abstract description 31
- 238000002595 magnetic resonance imaging Methods 0.000 abstract description 6
- 239000012216 imaging agent Substances 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 105
- 229910001868 water Inorganic materials 0.000 description 94
- 239000000243 solution Substances 0.000 description 67
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 34
- 239000000047 product Substances 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 22
- 229940126062 Compound A Drugs 0.000 description 21
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 21
- 0 [13*]C1C([15*])N(CC)C([16*])C([14*])N(CC)C([17*])C([18*])N(CC)C([19*])C([20*])N1CC Chemical compound [13*]C1C([15*])N(CC)C([16*])C([14*])N(CC)C([17*])C([18*])N(CC)C([19*])C([20*])N1CC 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 16
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 16
- AFQIYTIJXGTIEY-UHFFFAOYSA-N hydrogen carbonate;triethylazanium Chemical compound OC(O)=O.CCN(CC)CC AFQIYTIJXGTIEY-UHFFFAOYSA-N 0.000 description 14
- 239000000376 reactant Substances 0.000 description 14
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 13
- 239000000523 sample Substances 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000008367 deionised water Substances 0.000 description 10
- 229910021641 deionized water Inorganic materials 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 238000000921 elemental analysis Methods 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- OTMSDBZUPAUEDD-UHFFFAOYSA-N CC Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000003384 imaging method Methods 0.000 description 7
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 7
- 239000000178 monomer Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 229940086542 triethylamine Drugs 0.000 description 7
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 239000002872 contrast media Substances 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 230000005298 paramagnetic effect Effects 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 229920005654 Sephadex Polymers 0.000 description 5
- 239000012507 Sephadex™ Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000010549 co-Evaporation Methods 0.000 description 5
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000012800 visualization Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 229910003317 GdCl3 Inorganic materials 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000009920 chelation Effects 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 238000003795 desorption Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 150000002118 epoxides Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- MEANOSLIBWSCIT-UHFFFAOYSA-K gadolinium trichloride Chemical compound Cl[Gd](Cl)Cl MEANOSLIBWSCIT-UHFFFAOYSA-K 0.000 description 4
- 229910021645 metal ion Inorganic materials 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 4
- 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 4
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 3
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000004423 acyloxy group Chemical group 0.000 description 3
- 125000005236 alkanoylamino group Chemical group 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 150000001356 alkyl thiols Chemical class 0.000 description 3
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 238000005349 anion exchange Methods 0.000 description 3
- 125000001589 carboacyl group Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 150000007942 carboxylates Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- DCZFGQYXRKMVFG-UHFFFAOYSA-N cyclohexane-1,4-dione Chemical compound O=C1CCC(=O)CC1 DCZFGQYXRKMVFG-UHFFFAOYSA-N 0.000 description 3
- 125000004663 dialkyl amino group Chemical group 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- LYQGMALGKYWNIU-UHFFFAOYSA-K gadolinium(3+);triacetate Chemical compound [Gd+3].CC([O-])=O.CC([O-])=O.CC([O-])=O LYQGMALGKYWNIU-UHFFFAOYSA-K 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 230000033001 locomotion Effects 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- JWCQGESWJBEJMA-UHFFFAOYSA-N CCN1CCN(C)CCN(CC)CCN(CC)CC1 Chemical compound CCN1CCN(C)CCN(CC)CCN(CC)CC1 JWCQGESWJBEJMA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- CDAISMWEOUEBRE-XCWYPRQJSA-N OC1C(O)[C@H](O)C(O)[C@H](O)C1O Chemical compound OC1C(O)[C@H](O)C(O)[C@H](O)C1O CDAISMWEOUEBRE-XCWYPRQJSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- PFOLQBJDGRRJKE-UHFFFAOYSA-N [1,3]dioxolo[4,5-f][1,3]benzodioxole Chemical compound C1=C2OCOC2=CC2=C1OCO2 PFOLQBJDGRRJKE-UHFFFAOYSA-N 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 150000004696 coordination complex Chemical class 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- 229940001584 sodium metabisulfite Drugs 0.000 description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- WLKSZYPZGAQRKF-OCAPTIKFSA-N (1r,4s)-2,5-dimethylidenecyclohexane-1,4-diol Chemical compound O[C@H]1CC(=C)[C@H](O)CC1=C WLKSZYPZGAQRKF-OCAPTIKFSA-N 0.000 description 1
- PJXWCRXOPLGFLX-VIFPVBQESA-N (2s)-2-(benzylamino)propan-1-ol Chemical compound OC[C@H](C)NCC1=CC=CC=C1 PJXWCRXOPLGFLX-VIFPVBQESA-N 0.000 description 1
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- IFZHGQSUNAKKSN-UHFFFAOYSA-N 1,1-diethylhydrazine Chemical compound CCN(N)CC IFZHGQSUNAKKSN-UHFFFAOYSA-N 0.000 description 1
- LDPFQVWIUACVFE-UHFFFAOYSA-N 1,2:4,5-Di-O-isopropylidene-myo-Inositol Natural products OC1C2OC(C)(C)OC2C(O)C2OC(C)(C)OC21 LDPFQVWIUACVFE-UHFFFAOYSA-N 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- CASDNPHWJOQUQX-UHFFFAOYSA-N 1-benzylaziridine Chemical compound C=1C=CC=CC=1CN1CC1 CASDNPHWJOQUQX-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- JKYSFPLAGCMMOI-UHFFFAOYSA-N 2,4-dichloro-7-(trifluoromethoxy)quinazoline Chemical compound ClC1=NC(Cl)=NC2=CC(OC(F)(F)F)=CC=C21 JKYSFPLAGCMMOI-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical class CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- LWURFTHWNQFWID-UHFFFAOYSA-N C.C.C.C1CO1.C=C.CCCO Chemical compound C.C.C.C1CO1.C=C.CCCO LWURFTHWNQFWID-UHFFFAOYSA-N 0.000 description 1
- VIFYQKMYLBZFQJ-VCDLGBMBSA-N C.C.CC1C(O)C(O)[C@@H](C)C(C)[C@H]1C.O=C1CCC(=O)CC1 Chemical compound C.C.CC1C(O)C(O)[C@@H](C)C(C)[C@H]1C.O=C1CCC(=O)CC1 VIFYQKMYLBZFQJ-VCDLGBMBSA-N 0.000 description 1
- MEKDPHXPVMKCON-UHFFFAOYSA-N C.CC Chemical compound C.CC MEKDPHXPVMKCON-UHFFFAOYSA-N 0.000 description 1
- FASUFOTUSHAIHG-UHFFFAOYSA-N C=CCOC Chemical compound C=CCOC FASUFOTUSHAIHG-UHFFFAOYSA-N 0.000 description 1
- TXYHYYWTSFYGNI-UHFFFAOYSA-K CC(C)N1CCN(CC(=O)[O-])CCN(CC(=O)[O-])CCN(CC(=O)[O-])CC1.[Gd+3] Chemical compound CC(C)N1CCN(CC(=O)[O-])CCN(CC(=O)[O-])CCN(CC(=O)[O-])CC1.[Gd+3] TXYHYYWTSFYGNI-UHFFFAOYSA-K 0.000 description 1
- YYJUKOILACGSCH-ITLKZVKHSA-N CC1C(O)C(O)[C@@H](C)C(C)[C@H]1C.CC1C(O)C(O)[C@@H](C)[C@@H](O)C1O.CC1C2OC(C)(C)OC2[C@@H](C)C(C)[C@H]1C.CC1C2OC3(CCC4(CC3)OC3C(O4)[C@@H](C)C(C)[C@@H](C)C3C)OC2[C@H](C)C(C)[C@@H]1C.CC1C[C@](C)(O)[C@H](C)C[C@@]1(C)O.C[C@]1(O)CC(O)[C@](C)(O)C[C@H]1O Chemical compound CC1C(O)C(O)[C@@H](C)C(C)[C@H]1C.CC1C(O)C(O)[C@@H](C)[C@@H](O)C1O.CC1C2OC(C)(C)OC2[C@@H](C)C(C)[C@H]1C.CC1C2OC3(CCC4(CC3)OC3C(O4)[C@@H](C)C(C)[C@@H](C)C3C)OC2[C@H](C)C(C)[C@@H]1C.CC1C[C@](C)(O)[C@H](C)C[C@@]1(C)O.C[C@]1(O)CC(O)[C@](C)(O)C[C@H]1O YYJUKOILACGSCH-ITLKZVKHSA-N 0.000 description 1
- JOCSUIHZPSDHRV-UHFFFAOYSA-N CC1CN(C(C)C(=O)O)C(C)CN(C(C)C(=O)O)C(C)CN(C(C)C(=O)O)C(C)CN1C(C)C(=O)O.[Gd] Chemical compound CC1CN(C(C)C(=O)O)C(C)CN(C(C)C(=O)O)C(C)CN(C(C)C(=O)O)C(C)CN1C(C)C(=O)O.[Gd] JOCSUIHZPSDHRV-UHFFFAOYSA-N 0.000 description 1
- PYENMVYXOFGWEG-UHFFFAOYSA-N CCC(O)COC.CCCO Chemical compound CCC(O)COC.CCCO PYENMVYXOFGWEG-UHFFFAOYSA-N 0.000 description 1
- BPGHSICRCLLYOK-UHFFFAOYSA-N CCC(O)COC.COCC1CO1 Chemical compound CCC(O)COC.COCC1CO1 BPGHSICRCLLYOK-UHFFFAOYSA-N 0.000 description 1
- FPGPMYCGQKZGLT-UHFFFAOYSA-N CCN1CC(C)N(CC(=O)O)CC(C)N(CC(=O)O)CC(C)N(CC(=O)O)CC1C.[Gd] Chemical compound CCN1CC(C)N(CC(=O)O)CC(C)N(CC(=O)O)CC(C)N(CC(=O)O)CC1C.[Gd] FPGPMYCGQKZGLT-UHFFFAOYSA-N 0.000 description 1
- 206010051290 Central nervous system lesion Diseases 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
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 description 1
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- UAQVHNZEONHPQG-ZETCQYMHSA-N N-benzoyl-L-alanine Chemical compound OC(=O)[C@H](C)NC(=O)C1=CC=CC=C1 UAQVHNZEONHPQG-ZETCQYMHSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- KTVCHLWQVVITIS-UHFFFAOYSA-N O=C(O)CN1CCN(CC(=O)O)CCN(CP(=O)(O)O)CCN(CC(=O)O)CC1.[Gd] Chemical compound O=C(O)CN1CCN(CC(=O)O)CCN(CP(=O)(O)O)CCN(CC(=O)O)CC1.[Gd] KTVCHLWQVVITIS-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 238000010477 Prilezhaev reaction Methods 0.000 description 1
- 229910006074 SO2NH2 Inorganic materials 0.000 description 1
- 238000010266 Sephadex chromatography Methods 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- OHHNDEMOKFHQMN-UHFFFAOYSA-N [Gd].[H]N1CC(C)N(CC(=O)O)CC(C)N(CC(=O)O)CC(C)N(CC(=O)O)CC1C Chemical compound [Gd].[H]N1CC(C)N(CC(=O)O)CC(C)N(CC(=O)O)CC(C)N(CC(=O)O)CC1C OHHNDEMOKFHQMN-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- LLQBBIIUROKJCG-UHFFFAOYSA-N benzyl 2-hydroxy-2-(trifluoromethylsulfonyloxy)propanoate Chemical compound FC(F)(F)S(=O)(=O)OC(O)(C)C(=O)OCC1=CC=CC=C1 LLQBBIIUROKJCG-UHFFFAOYSA-N 0.000 description 1
- ZYTLPUIDJRKAAM-UHFFFAOYSA-N benzyl 2-hydroxypropanoate Chemical compound CC(O)C(=O)OCC1=CC=CC=C1 ZYTLPUIDJRKAAM-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 230000003851 biochemical process Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 150000004697 chelate complex Chemical class 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- BFGKITSFLPAWGI-UHFFFAOYSA-N chromium(3+) Chemical compound [Cr+3] BFGKITSFLPAWGI-UHFFFAOYSA-N 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- KSKWGMNRWCYVAT-UHFFFAOYSA-N diethyl 2,5-dioxocyclohexane-1,4-dicarboxylate Chemical compound CCOC(=O)C1CC(=O)C(C(=O)OCC)CC1=O KSKWGMNRWCYVAT-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 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
- 230000002349 favourable effect Effects 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(III) oxide Inorganic materials [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- PYGSKMBEVAICCR-UHFFFAOYSA-N hexa-1,5-diene Chemical group C=CCCC=C PYGSKMBEVAICCR-UHFFFAOYSA-N 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000002075 inversion recovery Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000002405 nuclear magnetic resonance imaging agent Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000005408 paramagnetism Effects 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 229920003228 poly(4-vinyl pyridine) Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920002717 polyvinylpyridine Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- CSMWJXBSXGUPGY-UHFFFAOYSA-L sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000012799 strong cation exchange Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000012285 ultrasound imaging Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms
Definitions
- novel monomeric and multimeric compounds having enhanced relaxivities are provided. These compounds are useful, for example, as metal-chelating ligands.
- the compounds are also useful in the form of metal complexes as diagnostic contrast agents. When the metal in the complex is paramagnetic, the diagnostic contrast agents are especially suitable for magnetic resonance imaging (MRI).
- MRI magnetic resonance imaging
- certain specific compounds comprise a tetraazacyclododecane macrocycle, and are represented by the formula I: I
- each m, n, o and p is independently 1 or 2;
- each G is independently —COOR′′, —P(o)(OR′′) 2 , —P(O) (OR′′) (R′′) or —C(O)N(R′′) 2 ;
- each R′ is independently hydrogen or alkyl, alkoxy, cycloalkyl, hydroxyalkyl or aryl, each of which is optionally substituted, or a functional group capable of forming a conjugate with a biomolecule or of forming a multimer of said compound of formula I;
- each R′′ is hydrogen
- each R 13 through R 20 is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or a functional group capable of forming a conjugate with a biomolecule or of forming a multimer of said compound of the formula I;
- R 13 together with R 15 , and R 17 together with R 18 independently form, together with the carbon atoms in the tetraazacyclododecane macrocycle to which they are attached, a fused fully or partially saturated non-aromatic cyclohexyl ring which may be unsubstituted or substituted by one or more halogen, alkyl, ether, hydroxy or hydroxyalkyl groups, and which may be further fused to a carbocyclic ring, or R 13 and R 15 are each hydrogen and R 17 , together with R 18 , forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, or R 13 , together with R 15 , forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above and R 17 and R 18 are hydrogen; provided that (a.) when G is always —COOR′′ and (i.) R′, R′′, R 14 and R 16 through
- the expression “relaxivity” refers to the effectiveness of a metal chelate to reduce the relaxation time of bulk water in contact with the metal chelate.
- immobilized relaxivity refers to the relaxivity measured when a chelate moiety can undergo only slow molecular reorientation because of rigid attachment to a large moiety or a physiological surface, or because it is dissolved in a medium of high viscosity.
- water relaxivity refers to relaxivity in water where a chelate moiety possesses a relaxivity dominated by overall molecular reorientation.
- the expression “enhanced relaxivity” refers to relaxivity values made greater than those of well characterized prior art molecules by 1.) altering the electronic relaxation rate, ⁇ s , through modifications of the metal-donor atom bond vibration frequencies and/or amplitudes, (this being accomplished, for example, by increasing the steric bulk and/or orientation of organic elements bonded to the donor atoms and/or the macrocyclic carbon atoms), 2.) in a multimer by decreasing the internal molecular motion of one monomer unit relative to another (this being accomplished, for example, by increasing the steric bulk of the organic groups linking the monomer units) or 3.) by decreasing the molecular reorientation of a monomer or a multimer attached to a large moiety or a physiological surface.
- alkyl refers to both straight and branched, unsubstituted chains of carbon atoms. Those chains having 1 to 5 carbon atoms are preferred. Methyl is the most preferred alkyl group.
- cycloalkyl refers to cyclic hydrocarbon groups of 3 to 8 carbon atoms.
- the groups may be unsubstituted or substituted by, for example, alkyl, halogen, hydroxy, hydroxyalkyl, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthiol, nitro, cyano, carboxy, carbamoyl, alkoxycarbonyl, alkylsulfonyl, sulfonamido and the like.
- alkoxy refers to -alkyl(O). Methoxy is the most preferred alkoxy group.
- aryl refers to phenyl, pyridyl, furanyl, thiophenyl, pyrrolyl, imidazolyl and the like, all of which may be substituted.
- Preferred substituted aryl groups are those substituted with 1, 2 or 3 halogen, nitroamino, maleimido, isothiocyanato, hydroxy, hydroxyalkyl, alkyl, alkoxy, carbamoyl, carboxamide, acylamino or carboxy moieties.
- Haldroxyalkyl refers to straight and branched alkyl groups including one or more hydroxy radicals such as —CH 2 CH 2 OH, —CH 2 CH 2 OHCH 2 OH, —CH (CH 2 OH) 2 and the like. (See, for example, Sovak, M., Editor, Radiocontrast Agents , Springer-Verlag, 1984, pp. 1-125).
- aralkyl refers to an aryl group bonded through an alkyl group.
- carrier ring refers to a ring system in which all the ring atoms are carbon, e.g., phenyl or cyclohexyl.
- the ring may be unsubstituted or substituted by, for example, alkyl, halogen, hydroxy, hydroxyalkyl, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthiol, nitro, cyano, carboxy, carbamoyl, alkoxycarbonyl, alkylsulfonyl, sulfonamido and the like.
- halogen refers to bromo, chloro, fluoro or iodo.
- alkanoyl refers to the group alkyl-C(O)—.
- alkanoyloxy refers to the group alkyl-C(O)—O—.
- amino refers to the group —NH 2 .
- alkylamino refers to the group —NHR where R is alkyl.
- dialkylamino refers to the group —NRR′ where R and R′ are each, independently, alkyl.
- alkanoylamino refers to the group alkyl-C(O)—NH—.
- thiol refers to the group —SH.
- alkylthiol refers to the group —SR where R is alkyl.
- nitro refers to the group —NO 2 .
- cyano refers to the group —CN.
- carboxy refers to the group —C(O)OH or the group —C(O)OR where R is alkyl.
- alkoxycarbonyl refers to the group alkoxy—C—(O)—.
- alkylsulfonyl refers to the group alkyl-SO 2 .
- sulfonamido refers to the group —SO 2 NH 2, the group —SO 2 NHR or the group —SO 2 NRR′ where R and R′ are each, independently, alkyl, cycloalkyl or aryl.
- carbamoyl refers to the group —C(O)NH 2, the group —C(O)NHR or the group —C(O)NRR′ where R and R′ are each, independently, alkyl, alkoxy or hydroxyalkyl.
- carboxylate refers to the group —C(O)NH 2 , the group —C(O)NHR or the group —C(O)NRR′ where R and R′ are each, independently, alkyl.
- acylamino refers to the group —NH—C(O)—R where R is alkyl.
- bioactive group and “bioactive moiety” denote a group which is capable of functioning as a metabolic substrate, catalyst or inhibitor, or is capable of being preferentially taken up at a selected site of a subject, such as by possessing an affinity for a cellular recognition site.
- each monomer is preferably linked by a cyclic bridging group represented by the general formula II: II
- Q is a 4- to an 8-membered carbocyclic ring which may be fully or partially saturated;
- t is an integer from 2 to 16;
- each R group is independently hydrogen, —OH, —CH 2 -A, —OCH 2 CH(OH)CH 2 -A or a functional group capable of forming a conjugate with a biomolecule, provided that at least two of the R groups are selected from —CH 2 -A or —OCH 2 CH(OH)CH 2 -A; and
- A is the monomer of formula I.
- the cyclic bridging group may be used to link known moieties as well. Where it is a known moiety which is being linked by the cyclic bridging group of formula II, A is any moiety capable of chelating a metal atom.
- Preferred bridging groups of the formula II are those wherein
- each R 1 through R 12 group is independently hydrogen, —OH, —CH 2 -A, —OCH 2 CH(OH)CH 2 -A or a functional group capable of forming a conjugate with a biomolecule;
- At least two of R 1 through R 12 are selected from —CH 2 -A or —OCH 2 CH(OH)CH 2 -A;
- R 8 and R 9 taken together may additionally form the group —O—[C(RR)]—O— where each R is independently hydrogen or alkyl, or R 8 and R 9 taken together may form
- A is a moiety described above.
- A is a known monomer, for example, A is preferably
- each R′ is independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aryl, aralkyl or arylalkoxy;
- each R′′ is hydrogen
- each n is 1 or 2;
- Contrast agents with significantly enhanced relaxivities are of great interest, not only because they offer improved efficacy at reduced doses for current clinical applications, but also because they may provide the sensitivities needed for imaging various biochemical processes.
- Certain preferred compounds having enhanced relaxivities are (i.) chelates possessing a stability greater than or equal to 10 15 M ⁇ 1 and capable of exhibiting an immobilized relaxivity between about 60 and 200 mM ⁇ 1 s ⁇ 1 /metal atom, for example between about 70 and 150 mM ⁇ 1 s ⁇ 1 /metal atom, or between about 80 and 100 mM ⁇ 1 s ⁇ 1 /metal atom; and (ii.) multimeric chelates possessing monomer units with a stability greater than or equal to 10 15 M ⁇ 1 , and having relaxivity values (not immobilized) greater than 5 mM ⁇ 1 s ⁇ 1 /metal atom.
- immobilized relaxivity can depend strongly, for example, on the structure of the chelate. Without being bound by any particular theory, apparently a mechanism that involves rigidifying the chelate structures in solution with, for example, alkyl substitutions on the tetraaza ring of chelates, especially when the substitution is introduced into the carboxylate arms of the chelates, affects immobilized relaxivity.
- SBM Solomon-Bloembergen-Morgan
- ZFS transient zero-field splitting
- This transient ZFS is induced by the structural distortion of the metal complex from its ideal symmetry in solution which is thought to be caused by its collision with solvent molecules. Alkyl substitution on either the tetraaza ring or the carboxylate arms of a chelate is thought to reduce the flexibility of the chelate for structural distortion in solution. This in turn reduces the magnitude of ZFS, giving an increased immobilized relaxivity value.
- Water relaxivity is generally determined in aqueous Bis Tris buffer (pH 7) solutions by the standard inversion-recovery method (known to those in the art) at 20 MHz and 40° C. (See, e.g., X. Xhang, Inorganic Chemistry , 31, 1992, 5597, the entire contents of which are hereby incorporated by reference.) While a mathematical description of the relaxation mechanism at the presence of a paramagnetic species is provided by the classical SBM equations, it is experimentally difficult to explore the dependence of relaxivity on structure because the relaxivity values of most low-molecular weight chelates are often controlled by their rapid tumbling motions in regular aqueous solutions.
- the relaxivity of a chelate can be determined in aqueous sucrose solutions or other media that result in a reduction of molecular reorientation of any solute.
- the relaxivity values approximate, under optimal conditions, the relaxivities of chelates in biologically immobilized systems such as those covalently attached to cell surfaces.
- these values in sucrose solutions are defined as immobilized relaxivity.
- Immobilized relaxivity is generally determined under the same conditions as water relaxivity (see supra) except that the viscosity of the solutions is increased to 80 cp by the addition of solid sucrose to the aqueous solution of chelate, and the temperature is set at 20° C. In the calculation of relaxivity, one uses the concentration of the solute in the aqueous solution (before sucrose is added).
- this method serves as a simple screening technique for differentiating chelates designed for efficient biological targeting.
- the compounds of the invention may be complexed with a paramagnetic metal atom and used as relaxation enhancement agents for magnetic resonance imaging.
- a paramagnetic metal atom when administered to a mammalian host (e.g., a human) distribute in various concentrations to different tissues, and catalyze relaxation of protons (in the tissues) that have been excited by the absorption of radiofrequency energy from a magnetic resonance imager. This acceleration of the rate of relaxation of the excited protons provides for an image of different contrast when the host is scanned with a magnetic resonance imager.
- the magnetic resonance imager is used to record images at various times, generally either before and after administration of the agents, or after administration only, and the differences in the images created by the agents presence in tissues are used in diagnosis.
- paramagnetic metal atoms such as gadolinium(III), and manganese(II), chromium(III) and iron(III) (all are paramagnetic metal atoms with favorable electronic properties) are preferred as metals complexed by the ligands of the invention, including the ligands of formula I and formula II.
- Gadolinium(III) is the most preferred complexed metal due to the fact that it has the highest paramagnetism, it has low toxicity when complexed to a suitable ligand, and it has high lability of coordinated water. When the distance between the monomeric gadolinium chelate units in a complex is at least about 6 angstroms, the complexes tend to be sufficiently stable. Those compounds of formula II, when complexed with gadolinium (III) ions, are particularly useful.
- the distance between the monomeric gadolinium chelate units in these complexes is generally greater than 6 angstroms (although in certain circumstances a distance of 4.5 angstroms is sufficient), and the rigid bridges of these complexes assist in reducing independent motion of the gadolinium ions.
- the metal-chelating ligands of the present invention can also be complexed with a lanthanide (atomic number 58 to 71) and used as chemical shift or magnetic susceptibility agents in magnetic resonance imaging or in magnetic resonance in vivo spectroscopy.
- a lanthanide atomic number 58 to 71
- the metal-chelating ligands of the present invention are preferred, those working in the diagnostic arts will appreciate that the ligands can also be complexed with the appropriate metals and used as contrast agents in other imaging techniques such as x-ray imaging, radionuclide imaging and ultrasound imaging, and in radiotherapy.
- the ligands of the present invention are first complexed with an appropriate metal.
- the metal can be added to water in the form of an oxide or in the form of a halide or acetate and treated with an equimolar amount of a ligand of the present invention.
- the ligand can be added as an aqueous solution or suspension.
- Dilute acid or base can be added (where appropriate) to maintain a suitable pH. Heating at temperatures as high as 100° C. for periods of up to 24 hours or more may sometimes be employed to facilitate complexation, depending on the metal and the chelator, and their concentrations.
- compositions of the metal complexes of the ligands of this invention are also useful as imaging agents. They can be prepared by using a base (e.g., an alkali metal hydroxide, meglumine, arginine or lysine) to neutralize the above-prepared metal complexes while they are still in solution. Some of the metal complexes are formally uncharged and do not need cations as counterions. Such neutral complexes may be preferred in some situations as intravenously administered x-ray and NMR imaging agents over charged complexes because they may provide solutions of greater physiologic tolerance due to their lower osmolality.
- a base e.g., an alkali metal hydroxide, meglumine, arginine or lysine
- the present invention also provides pharmaceutical compositions comprising a compound of the invention, including a compound of the formula I or II, or a salt of one of these compounds, optionally complexed with a metal, and a pharmaceutically acceptable vehicle or diluent.
- the present invention further provides a method for diagnostic imaging comprising the steps of administering to a host a compound of the invention, or a salt thereof, which is complexed with a metal, and obtaining a diagnostic image, preferably a magnetic resonance image, of said host.
- Sterile aqueous solutions of the chelate complexes of the present invention are preferably administered to mammals (e.g., humans) orally, intrathecally and, especially, intravenously in concentrations of about 0.003 to 1.0 molar.
- the metal complexes of the present invention may be employed for visualization of various sites.
- a gadolinium complex of a ligand of the invention including a ligand of the formula I or formula II, may be administered intravenously at a dose of 0.001 to 0.5 millimoles of the complex per kilogram of body weight, preferably at a dose of 0.001 to 0.3 millimoles/kilogram.
- the dose is preferably 0.05 to 0.20 millimoles/kilogram.
- the dose is preferably 0.001 to 0.3 millimoles/kilogram.
- the dose is preferably 0.001 to 0.3 millimole/kilogram.
- the pH of the formulation of the present metal complexes is preferably between about 6.0 and 8.0, most preferably between about 6.5 and 7.5.
- Physiologically acceptable buffers e.g., tris(hydroxymethyl)-aminomethane
- other physiologically acceptable additives e.g., stabilizers such as parabens
- D and D′ are independently Ca or Zn
- L′ is an organic ligand which may be different from, or the same as, the ligand employed to complex the metal
- s and t are independently 1, 2 or 3.
- the present invention further includes multimeric forms of the compounds of the invention, including those of formula I and formula II, such as dimers, trimers, tetramers, etc.
- multimeric forms of the compounds of the invention including those of formula I and formula II, such as dimers, trimers, tetramers, etc.
- Known functional groups and technology are readily useable to provide such multimers.
- Compounds of the present invention may include those containing functional group(s) capable of forming a conjugate with a biomolecule. These compounds are preferably chelates, including a functional group, capable of exhibiting an immobilized relaxivity between about 60 and 200 mM ⁇ 1 s ⁇ 1 /metal atom, for example between about 70 and 150 mM ⁇ 1 s ⁇ 1 /metal atom, or between about 80 and 100 mM ⁇ 1 s ⁇ 1 /metal atom.
- the chelates once conjugated to a biomolecule of size greater than or equal to about 40,000 daltons, are also preferably capable of exhibiting a relaxivity between about 60 and 200 mM ⁇ 1 s ⁇ 1 /metal atom, for example between about 70 and 150 mM ⁇ 1 s ⁇ 1 /metal atom, or between about 80 and 100 mM ⁇ 1 s ⁇ 1 /metal atom.
- biomolecules are peptides, polypeptides and oligosaccharides or fragments thereof, although other biomolecules such as proteins, particularly monoclonal antibodies, lipids, sugars, alcohols, bile acids, fatty acids, receptor-binding ligands, amino acids and RNA, DNA or modified fragments of these may be conjugated to the compounds of the present invention.
- biomolecules such as proteins, particularly monoclonal antibodies, lipids, sugars, alcohols, bile acids, fatty acids, receptor-binding ligands, amino acids and RNA, DNA or modified fragments of these may be conjugated to the compounds of the present invention.
- the enhanced relaxivity afforded by the chelates of this invention may be more fully realized when the chelate-biomolecule conjugate becomes immobilized in vivo, such as by binding to a receptor on a cell surface or by binding to another biomolecule.
- Conjugates where a compound of the invention, or salt and/or multimer thereof, is linked to a biomolecule such as a protein, provided by the present invention are novel, as are metal complexes and pharmaceutical compositions containing, and methods of using (e.g., for imaging), the aforementioned conjugates. Conjugation may be achieved in vitro, such as by use of known conjugation methodologies, or in situ in a living subject by administration of a compound containing one or more of the aforementioned functional groups.
- the R groups may be reacted with a protein to produce a protein conjugate.
- Preferred proteins are those in serum, wherein the compound of the invention is directly injected and the conjugate is formed in situ. It is understood that other functional groups, as described above, may be used to link the bifunctional metal-chelating ligands of this invention to proteins such as monoclonal antibodies or fragments thereof.
- Ligands in which the aza macrocyclic ring carbon atoms are modified are built de novo from suitable aziridine precursors by cyclotetramerization.
- 1,4,7-tris-carboxymethyl-1,4,7,10-tetraazacyclododecane-10-yl (DO3A) units are attached to a bridging unit by two different methods.
- a spiro epoxide on the bridging unit is used to alkylate DO3A.
- a glycidyloxy moiety is attached to the bridging unit which then is used to alkylate DO3A.
- Epoxides of formula (9) are generated by the Prilezhaev Reaction in which olefins of formula (11) are treated with peracids such as m-chloroperbenzoic acid:
- Olefins of formula (11) are generated by the alkylation of alcohols of formula (12):
- DO3A Another mode of attachment of DO3A would be to epoxidize olefins of formula (13) to obtain epoxides of formula (14), and then alkylating DO3A with the epoxides to form ligands of formula (15):
- the bridging unit for formula 17 is generated from commercially available diethyl cyclohexane-1,4-dione-2,5-dicarboxylate by lithium aluminum hydride reduction as described in J. G. Murphy, J. Med. Chem., ( 1966), 9, 157.
- the bridging unit for formula (18) is generated by treating myo-inositol (25) with 2,2-dimethoxypropane in the presence of p-toluene sulfonic acid as descirbed by Giggs et al., Carbohydrate Res., 1985, 142, 132:
- the bridging unit (19) is made from (18) by acidic hydrolysis.
- the unit (20) is prepared from myo-inositol (25) by reaction with excess 2,2-dimethoxypropane in the presence of p-toluene-sulfonic acid.
- the unit (21) is made from the bis-epoxide precursor to the unit (17) by methods desribed above for functionalizing hydroxy groups.
- the paste was recrystallized from hot ethyl acetate; yield 4.39 g (31.3 mmol, 26.1%). A second recrystallization yielded 3.81 g (27.2 mmol, 22.6%). M.P. : 160-161.5° C., uncorrected (lit. 162.5 -163° C.).
- a solution of DO3A (17.3 g, 50 mmol) in water was made (80 ml) and the pH of the solution adjusted to 12 with 5 N sodium hydroxide solution.
- the solution was heated to 80° C. and a solution of compound B (1.42 g, 5 mmol) in dioxane (10 ml) was added dropwise.
- the mixture was stirred at this temperature for 82 hours.
- the pH of the reaction mixture was adjusted to 7 with acetic acid.
- the mixture was diluted and loaded on to a Sephadex G-25 column. The column was eluted first with 100-250 mM triethyl ammonium bicarbonate (TEAB) buffer and then with 250-500 mM TEAB buffer.
- TEAB triethyl ammonium bicarbonate
- TEAB triethyl-ammonium bicarbonate
- the hydrochloric solution was basified with 5N sodium hydroxide, extracted with ether (3 ⁇ 150 ml), dried and concentrated to afford the crude aziridine compound B as a yellow oily liquid. This was further purified by distillation under reduced pressure to afford pure compound B as a colorless liquid (24.3 g, yield 75%). b.p. 71-72° C. at 4 mm.
- Trifluoroacetic acid was removed in vacuo and anisole was removed by co-evaporation with water (6 ⁇ 50 mL) to afford the crude product.
- the residue was dissolved in water (100 mL) and purified by anion exchange column chromatography over AG1-X2 resin (150 mL). The column, after washing with water, was eluted with 1 M formic acid. The fractions containing the pure product were combined. Solvent removal afforded the pure product. A small amount of formic acid that remained in the sample was removed by co-evaporation with water (5 ⁇ 50 mL) to obtain pure title compound as a colorless glassy solid (550 mg, yield 87%).
- the excess metal ions were precipitated in the form of M(OH) 3 ⁇ H 2 O by raising solution pH to about 9.5 and incubating at both about 70° C. and room temperature for serveral hours. The precipitate was subsequently removed through centrifugation and filtration with a 0.22 ⁇ m membrane. The filtrate was finally condensed and neutralized to pH 7 in preparation for HPLC purification.
- Potassium carbonate was filtered off, acetonitrile removed in vacuo and the residue purified by column chromatography over silica gel (100 g) using chloroform and the methanol to afford a tetra benzyl ester (1.1 g).
- This material was dissolved in a mixture of ethanol (75 ml) and water (10 ml) and hydrogenated over 10% Pd/C (250 mg) for 18 hours.
- the catalyst was filtered off and solvent removal afforded the crude product. This was dissolved in water (100 ml) and purified by anion exchange column chromatography over AG1-X2 resin (150 ml). The column, after washing with water, was eluted with a gradient of 0-200 mM formic acid.
- the aqueous solution was applied to a strong cation exchange column of AG50WX8 (250 mL, flowrate, 12.5 mL/minute). Initially, water was used to remove any negatively charged inorganic species, and ammonium hydroxide (1.0 M) was employed to bring out the crude product. After removal of the ammonium hydroxide from the fractions containing the product, the residue dissolved in 5 mM TEAB (pH 7.5) was applied to a DEAE Sephadex ion exchange column (750 mL, flowrate, 4 mL/minute). The column was eluted with TEAB, whose concentration varied from 5 to 400 mM.
- the concentration of the buffer was doubled at every column volume (1L): 5, 10, 20, 40, 67, 80, 100, 125, 200 and 400 mM.
- Compound A required 400 mM TEAB to be brought out from the column.
- Evaporation of the buffer from the fractions containing Compound A gave a white residue (0.9 g).
- the solid, dissolved in water (35 mL) was loaded on a strongly basic anion column of Amberlite IRA 900 C (200 mL, flowrate, 14 mL/minute). Water was first used to remove triethylamine followed by sulfuric acid (1M) to elute Compound A from the column.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Electrochromic Elements, Electrophoresis, Or Variable Reflection Or Absorption Elements (AREA)
- Farming Of Fish And Shellfish (AREA)
- Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
Abstract
Metal chelates capable of exhibiting an immobilized relativity between about 60 and 200 mM−1s−1/metal atom are useful as magnetic resonance imaging agents. Additionally, a compound which is useful as a metal-chelating ligand has the following formula:
wherein
Q is a 4- to an 8-membered carbocyclic ring which may be fully or partially saturated;
t is an integer from 2 to 16;
each R group is independently hydrogen, —OH, —CH2-A, —OCH2CH(OH)CH2-A or a functional group capable of forming a conjugate with a biomolecule, provided that at least two of the R groups are selected from —CH2-A or —OCH2CH(OH)CH2-A; and
A is a moiety capable of chelating a metal atom.
Description
- In accordance with the present invention, novel monomeric and multimeric compounds having enhanced relaxivities are provided. These compounds are useful, for example, as metal-chelating ligands. The compounds are also useful in the form of metal complexes as diagnostic contrast agents. When the metal in the complex is paramagnetic, the diagnostic contrast agents are especially suitable for magnetic resonance imaging (MRI).
-
- wherein
- each m, n, o and p is independently 1 or 2;
- q is 0 or 1;
- each G is independently —COOR″, —P(o)(OR″)2, —P(O) (OR″) (R″) or —C(O)N(R″)2;
- each R′ is independently hydrogen or alkyl, alkoxy, cycloalkyl, hydroxyalkyl or aryl, each of which is optionally substituted, or a functional group capable of forming a conjugate with a biomolecule or of forming a multimer of said compound of formula I;
- each R″ is hydrogen;
- each R13 through R20 is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or a functional group capable of forming a conjugate with a biomolecule or of forming a multimer of said compound of the formula I;
- or R13 together with R15, and R17 together with R18, independently form, together with the carbon atoms in the tetraazacyclododecane macrocycle to which they are attached, a fused fully or partially saturated non-aromatic cyclohexyl ring which may be unsubstituted or substituted by one or more halogen, alkyl, ether, hydroxy or hydroxyalkyl groups, and which may be further fused to a carbocyclic ring, or R13 and R15 are each hydrogen and R17, together with R18, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, or R13, together with R15, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above and R17 and R18 are hydrogen; provided that (a.) when G is always —COOR″ and (i.) R′, R″, R14 and R16 through R20 are all hydrogen, then R13 and R15 are other than hydrogen; (ii.) R″ and R13 through R20 are all hydrogen, and m, n, o, p and q are each 1, then (CR′R′) is other than (CH2) and (CHCH3); (iii.) R′, R″, R13, R14, R17 and R20 are all hydrogen, then at least two of R15, R16, R18 and R19 are other than methyl; and (iv.) R″, R16, R19 and R20 are all hydrogen, and each (CR′R′) is independently (CHR′) or (CH2CHR′), then R13 and R15, and R17 and R18, are other than a fused ring; and (b.) when G is always —P (O)(OR″)2, —P(O)(OR″)(R″) or —C(O)N(R″)2, then at least one R′ or R13 through R20 is other than hydrogen;
- or a salt or multimeric form thereof.
- Listed below are definitions of various terms used in the description of this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
- The expression “relaxivity” refers to the effectiveness of a metal chelate to reduce the relaxation time of bulk water in contact with the metal chelate.
- The expression “immobilized relaxivity” refers to the relaxivity measured when a chelate moiety can undergo only slow molecular reorientation because of rigid attachment to a large moiety or a physiological surface, or because it is dissolved in a medium of high viscosity.
- The expression “water relaxivity” refers to relaxivity in water where a chelate moiety possesses a relaxivity dominated by overall molecular reorientation.
- The expression “enhanced relaxivity” refers to relaxivity values made greater than those of well characterized prior art molecules by 1.) altering the electronic relaxation rate, τs, through modifications of the metal-donor atom bond vibration frequencies and/or amplitudes, (this being accomplished, for example, by increasing the steric bulk and/or orientation of organic elements bonded to the donor atoms and/or the macrocyclic carbon atoms), 2.) in a multimer by decreasing the internal molecular motion of one monomer unit relative to another (this being accomplished, for example, by increasing the steric bulk of the organic groups linking the monomer units) or 3.) by decreasing the molecular reorientation of a monomer or a multimer attached to a large moiety or a physiological surface.
- The term “stability” refers to the equilibrium formation constant (K) of the reaction M+L→M(L) where K=[M(L))]/[M][L], M is a metal ion, L is a chelating ligand and M(L) is a chelate complex of a metal and a ligand.
- The term “alkyl” refers to both straight and branched, unsubstituted chains of carbon atoms. Those chains having 1 to 5 carbon atoms are preferred. Methyl is the most preferred alkyl group.
- The term “cycloalkyl” refers to cyclic hydrocarbon groups of 3 to 8 carbon atoms. The groups may be unsubstituted or substituted by, for example, alkyl, halogen, hydroxy, hydroxyalkyl, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthiol, nitro, cyano, carboxy, carbamoyl, alkoxycarbonyl, alkylsulfonyl, sulfonamido and the like.
- The term “alkoxy” refers to -alkyl(O). Methoxy is the most preferred alkoxy group.
- The term “aryl” refers to phenyl, pyridyl, furanyl, thiophenyl, pyrrolyl, imidazolyl and the like, all of which may be substituted. Preferred substituted aryl groups are those substituted with 1, 2 or 3 halogen, nitroamino, maleimido, isothiocyanato, hydroxy, hydroxyalkyl, alkyl, alkoxy, carbamoyl, carboxamide, acylamino or carboxy moieties.
- “Hydroxyalkyl” refers to straight and branched alkyl groups including one or more hydroxy radicals such as —CH2CH2OH, —CH2CH2OHCH2OH, —CH (CH2OH)2 and the like. (See, for example, Sovak, M., Editor, Radiocontrast Agents, Springer-Verlag, 1984, pp. 1-125).
- The term “aralkyl” refers to an aryl group bonded through an alkyl group.
- The term “carbocyclic ring” refers to a ring system in which all the ring atoms are carbon, e.g., phenyl or cyclohexyl. The ring may be unsubstituted or substituted by, for example, alkyl, halogen, hydroxy, hydroxyalkyl, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthiol, nitro, cyano, carboxy, carbamoyl, alkoxycarbonyl, alkylsulfonyl, sulfonamido and the like.
- The term “halogen” refers to bromo, chloro, fluoro or iodo.
- The term “alkanoyl” refers to the group alkyl-C(O)—.
- The term “alkanoyloxy” refers to the group alkyl-C(O)—O—.
- The term “amino” refers to the group —NH2.
- The term “alkylamino” refers to the group —NHR where R is alkyl.
- The term “dialkylamino” refers to the group —NRR′ where R and R′ are each, independently, alkyl.
- The term “alkanoylamino” refers to the group alkyl-C(O)—NH—.
- The term “thiol” refers to the group —SH.
- The term “alkylthiol” refers to the group —SR where R is alkyl.
- The term “nitro” refers to the group —NO2.
- The term “cyano” refers to the group —CN.
- The term “carboxy” refers to the group —C(O)OH or the group —C(O)OR where R is alkyl.
- The term “alkoxycarbonyl” refers to the group alkoxy—C—(O)—.
- The term “alkylsulfonyl” refers to the group alkyl-SO2.
- The term “sulfonamido” refers to the group —SO2NH2, the group —SO2NHR or the group —SO2NRR′ where R and R′ are each, independently, alkyl, cycloalkyl or aryl.
- The term “carbamoyl” refers to the group —C(O)NH2, the group —C(O)NHR or the group —C(O)NRR′ where R and R′ are each, independently, alkyl, alkoxy or hydroxyalkyl.
- The term “carboxamide” refers to the group —C(O)NH2, the group —C(O)NHR or the group —C(O)NRR′ where R and R′ are each, independently, alkyl.
- The term “acylamino” refers to the group —NH—C(O)—R where R is alkyl.
- The expressions “bioactive group” and “bioactive moiety” denote a group which is capable of functioning as a metabolic substrate, catalyst or inhibitor, or is capable of being preferentially taken up at a selected site of a subject, such as by possessing an affinity for a cellular recognition site.
-
- wherein
- Q is a 4- to an 8-membered carbocyclic ring which may be fully or partially saturated;
- t is an integer from 2 to 16;
- each R group is independently hydrogen, —OH, —CH2-A, —OCH2CH(OH)CH2-A or a functional group capable of forming a conjugate with a biomolecule, provided that at least two of the R groups are selected from —CH2-A or —OCH2CH(OH)CH2-A; and
- A is the monomer of formula I.
- Of course, the cyclic bridging group may be used to link known moieties as well. Where it is a known moiety which is being linked by the cyclic bridging group of formula II, A is any moiety capable of chelating a metal atom.
-
-
- wherein
- each R1 through R12 group is independently hydrogen, —OH, —CH2-A, —OCH2CH(OH)CH2-A or a functional group capable of forming a conjugate with a biomolecule;
- at least two of R1 through R12 are selected from —CH2-A or —OCH2CH(OH)CH2-A;
-
- and
- A is a moiety described above.
-
- wherein
- each R′ is independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aryl, aralkyl or arylalkoxy;
- each R″ is hydrogen; and
- each n is 1 or 2;
- or a salt thereof.
- Contrast agents with significantly enhanced relaxivities are of great interest, not only because they offer improved efficacy at reduced doses for current clinical applications, but also because they may provide the sensitivities needed for imaging various biochemical processes.
- Certain preferred compounds having enhanced relaxivities are (i.) chelates possessing a stability greater than or equal to 1015 M−1 and capable of exhibiting an immobilized relaxivity between about 60 and 200 mM−1s−1/metal atom, for example between about 70 and 150 mM−1s−1/metal atom, or between about 80 and 100 mM−1s−1/metal atom; and (ii.) multimeric chelates possessing monomer units with a stability greater than or equal to 1015 M−1, and having relaxivity values (not immobilized) greater than 5 mM−1s−1/metal atom.
- In designing new chelates with these elevated relaxivities, the inventors have noted that immobilized relaxivity can depend strongly, for example, on the structure of the chelate. Without being bound by any particular theory, apparently a mechanism that involves rigidifying the chelate structures in solution with, for example, alkyl substitutions on the tetraaza ring of chelates, especially when the substitution is introduced into the carboxylate arms of the chelates, affects immobilized relaxivity. In the Solomon-Bloembergen-Morgan (SBM) model, the electronic relaxation of a paramagnetic metal complex is viewed as occuring through a dynamic modulation process about the transient zero-field splitting (ZFS) of the metal's electronic spin levels. This transient ZFS is induced by the structural distortion of the metal complex from its ideal symmetry in solution which is thought to be caused by its collision with solvent molecules. Alkyl substitution on either the tetraaza ring or the carboxylate arms of a chelate is thought to reduce the flexibility of the chelate for structural distortion in solution. This in turn reduces the magnitude of ZFS, giving an increased immobilized relaxivity value.
- Water relaxivity is generally determined in aqueous Bis Tris buffer (pH 7) solutions by the standard inversion-recovery method (known to those in the art) at 20 MHz and 40° C. (See, e.g., X. Xhang,Inorganic Chemistry, 31, 1992, 5597, the entire contents of which are hereby incorporated by reference.) While a mathematical description of the relaxation mechanism at the presence of a paramagnetic species is provided by the classical SBM equations, it is experimentally difficult to explore the dependence of relaxivity on structure because the relaxivity values of most low-molecular weight chelates are often controlled by their rapid tumbling motions in regular aqueous solutions.
- To eliminate the overriding effect of molecular tumbling in regular aqueous solutions, the relaxivity of a chelate can be determined in aqueous sucrose solutions or other media that result in a reduction of molecular reorientation of any solute. In these solutions, the relaxivity values approximate, under optimal conditions, the relaxivities of chelates in biologically immobilized systems such as those covalently attached to cell surfaces. Hence, these values in sucrose solutions are defined as immobilized relaxivity. Immobilized relaxivity is generally determined under the same conditions as water relaxivity (see supra) except that the viscosity of the solutions is increased to 80 cp by the addition of solid sucrose to the aqueous solution of chelate, and the temperature is set at 20° C. In the calculation of relaxivity, one uses the concentration of the solute in the aqueous solution (before sucrose is added).
- When used for relative comparison, this method serves as a simple screening technique for differentiating chelates designed for efficient biological targeting.
- Thus, the compounds of the invention, including compounds of the formula I and formula II, and salts thereof, may be complexed with a paramagnetic metal atom and used as relaxation enhancement agents for magnetic resonance imaging. These agents, when administered to a mammalian host (e.g., a human) distribute in various concentrations to different tissues, and catalyze relaxation of protons (in the tissues) that have been excited by the absorption of radiofrequency energy from a magnetic resonance imager. This acceleration of the rate of relaxation of the excited protons provides for an image of different contrast when the host is scanned with a magnetic resonance imager. The magnetic resonance imager is used to record images at various times, generally either before and after administration of the agents, or after administration only, and the differences in the images created by the agents presence in tissues are used in diagnosis. In proton magnetic resonance imaging, paramagnetic metal atoms such as gadolinium(III), and manganese(II), chromium(III) and iron(III) (all are paramagnetic metal atoms with favorable electronic properties) are preferred as metals complexed by the ligands of the invention, including the ligands of formula I and formula II. Gadolinium(III) is the most preferred complexed metal due to the fact that it has the highest paramagnetism, it has low toxicity when complexed to a suitable ligand, and it has high lability of coordinated water. When the distance between the monomeric gadolinium chelate units in a complex is at least about 6 angstroms, the complexes tend to be sufficiently stable. Those compounds of formula II, when complexed with gadolinium (III) ions, are particularly useful. The distance between the monomeric gadolinium chelate units in these complexes is generally greater than 6 angstroms (although in certain circumstances a distance of 4.5 angstroms is sufficient), and the rigid bridges of these complexes assist in reducing independent motion of the gadolinium ions.
- The metal-chelating ligands of the present invention can also be complexed with a lanthanide (atomic number 58 to 71) and used as chemical shift or magnetic susceptibility agents in magnetic resonance imaging or in magnetic resonance in vivo spectroscopy.
- While the above-described uses for the metal-chelating ligands of the present invention are preferred, those working in the diagnostic arts will appreciate that the ligands can also be complexed with the appropriate metals and used as contrast agents in other imaging techniques such as x-ray imaging, radionuclide imaging and ultrasound imaging, and in radiotherapy.
- Use in Imaging
- To use the ligands of the present invention for imaging, they are first complexed with an appropriate metal. This may be accomplished by methodology known in the art. For example, the metal can be added to water in the form of an oxide or in the form of a halide or acetate and treated with an equimolar amount of a ligand of the present invention. The ligand can be added as an aqueous solution or suspension. Dilute acid or base can be added (where appropriate) to maintain a suitable pH. Heating at temperatures as high as 100° C. for periods of up to 24 hours or more may sometimes be employed to facilitate complexation, depending on the metal and the chelator, and their concentrations.
- Pharmaceutically acceptable salts of the metal complexes of the ligands of this invention are also useful as imaging agents. They can be prepared by using a base (e.g., an alkali metal hydroxide, meglumine, arginine or lysine) to neutralize the above-prepared metal complexes while they are still in solution. Some of the metal complexes are formally uncharged and do not need cations as counterions. Such neutral complexes may be preferred in some situations as intravenously administered x-ray and NMR imaging agents over charged complexes because they may provide solutions of greater physiologic tolerance due to their lower osmolality.
- The present invention also provides pharmaceutical compositions comprising a compound of the invention, including a compound of the formula I or II, or a salt of one of these compounds, optionally complexed with a metal, and a pharmaceutically acceptable vehicle or diluent. The present invention further provides a method for diagnostic imaging comprising the steps of administering to a host a compound of the invention, or a salt thereof, which is complexed with a metal, and obtaining a diagnostic image, preferably a magnetic resonance image, of said host.
- Sterile aqueous solutions of the chelate complexes of the present invention are preferably administered to mammals (e.g., humans) orally, intrathecally and, especially, intravenously in concentrations of about 0.003 to 1.0 molar. The metal complexes of the present invention may be employed for visualization of various sites. For example, for the visualization of brain lesions using magnetic resonance imaging, a gadolinium complex of a ligand of the invention, including a ligand of the formula I or formula II, may be administered intravenously at a dose of 0.001 to 0.5 millimoles of the complex per kilogram of body weight, preferably at a dose of 0.001 to 0.3 millimoles/kilogram. For visualization of the kidneys, the dose is preferably 0.05 to 0.20 millimoles/kilogram. For visualization of the heart, the dose is preferably 0.001 to 0.3 millimoles/kilogram. For visualization of the liver, the dose is preferably 0.001 to 0.3 millimole/kilogram.
- The pH of the formulation of the present metal complexes is preferably between about 6.0 and 8.0, most preferably between about 6.5 and 7.5. Physiologically acceptable buffers (e.g., tris(hydroxymethyl)-aminomethane) and other physiologically acceptable additives (e.g., stabilizers such as parabens) may also be present.
- It is also advantageous to employ dual scavenging excipients such as those described in copending application U.S. Ser. No. 032,763, filed Mar. 15, 1993, entitled “DUAL FUNCTIONING EXCIPIENT FOR METAL CHELATE CONTRAST AGENTS”, incorporated herein by reference. Those excipients have a general formula corresponding to:
- Ds[D′(L′)]t
- wherein D and D′ are independently Ca or Zn, L′ is an organic ligand which may be different from, or the same as, the ligand employed to complex the metal, and s and t are independently 1, 2 or 3.
- As already noted, the present invention further includes multimeric forms of the compounds of the invention, including those of formula I and formula II, such as dimers, trimers, tetramers, etc. Known functional groups and technology are readily useable to provide such multimers.
- Compounds of the present invention may include those containing functional group(s) capable of forming a conjugate with a biomolecule. These compounds are preferably chelates, including a functional group, capable of exhibiting an immobilized relaxivity between about 60 and 200 mM−1s−1/metal atom, for example between about 70 and 150 mM−1s−1/metal atom, or between about 80 and 100 mM−1s−1/metal atom. Similarly, the chelates, once conjugated to a biomolecule of size greater than or equal to about 40,000 daltons, are also preferably capable of exhibiting a relaxivity between about 60 and 200 mM−1s−1/metal atom, for example between about 70 and 150 mM−1s−1/metal atom, or between about 80 and 100 mM−1s−1/metal atom. Preferred biomolecules are peptides, polypeptides and oligosaccharides or fragments thereof, although other biomolecules such as proteins, particularly monoclonal antibodies, lipids, sugars, alcohols, bile acids, fatty acids, receptor-binding ligands, amino acids and RNA, DNA or modified fragments of these may be conjugated to the compounds of the present invention. For smaller biomolecules, the enhanced relaxivity afforded by the chelates of this invention may be more fully realized when the chelate-biomolecule conjugate becomes immobilized in vivo, such as by binding to a receptor on a cell surface or by binding to another biomolecule.
- Conjugates where a compound of the invention, or salt and/or multimer thereof, is linked to a biomolecule such as a protein, provided by the present invention, are novel, as are metal complexes and pharmaceutical compositions containing, and methods of using (e.g., for imaging), the aforementioned conjugates. Conjugation may be achieved in vitro, such as by use of known conjugation methodologies, or in situ in a living subject by administration of a compound containing one or more of the aforementioned functional groups.
- For linking the compounds of the present invention to a protein, the R groups may be reacted with a protein to produce a protein conjugate. Preferred proteins are those in serum, wherein the compound of the invention is directly injected and the conjugate is formed in situ. It is understood that other functional groups, as described above, may be used to link the bifunctional metal-chelating ligands of this invention to proteins such as monoclonal antibodies or fragments thereof.
- Compounds of the formula I can generally be prepared as follows:
- Ligands in which the aza macrocyclic ring carbon atoms are modified are built de novo from suitable aziridine precursors by cyclotetramerization.
-
- [S]-N-Benzoylalanine(1) is reduced with diborane to yield [S]-N-benzylalaninol(2). Under Mitsunobu conditions, compound (2) affords [S]-N-benzyl-2-methyl aziridine(3). Cyclotetramerization under p-toluene sulfonic acid catalysis in ethanol, followed by treatment with ammonium hydroxide (NH4OH), furnishes S,S,S,S-tetra-N-benzyl-tetramethyltetraazacyclododecane(4), which is debenzylated under transfer hydrogenolytic conditions to obtain S,S,S,S-tetramethyltetraaza-cyclododecane(5).
- Tetraalkylation of compound (5) with t-butyl bromoacetate in the presence of sodium carbonate, followed by deprotection with trifluoroacetic acid and anisole, affords the ligand (6).
- Tetraalkylation of compound (5) with benzyl 2-triflyloxylactate (prepared as described by S. I. Kang et al., Inorg. Chem., (1993), 3, 2912-2918) in the presence of sodium carbonate, followed by catalytic hydrogenolytic debenzylation furnishes the ligand (7).
- Tris-alkylation of compound (5) with t-butyl bromoacetate in the presence of sodium bicarbonate, followed by deprotection by treatment with trifluoroacetic acid and anisole, provides the ligand (8).
- For preparing multimeric ligands, 1,4,7-tris-carboxymethyl-1,4,7,10-tetraazacyclododecane-10-yl (DO3A) units, for example, are attached to a bridging unit by two different methods. In the first method, a spiro epoxide on the bridging unit is used to alkylate DO3A. In the second method, a glycidyloxy moiety is attached to the bridging unit which then is used to alkylate DO3A.
-
-
-
-
-
-
- The structures shown in formulas (17) to (22) are only by way of representative examples. They will, in actuality, be a mixture of all the possible diastereomers, if the attachment is through a 2-hydroxypropyloxy link. In the case of formula 22, for example, in addition to the presence of diastereomers, the product would also consist of the various geometric isomers that could result when the two myo-inositol molecules are coupled to each other. The coupling of the two myo-inositol units is achieved by reacting the compound of formula (23) with cyclohexane-1,4-dione (24):
- The bridging unit for formula 17 is generated from commercially available diethyl cyclohexane-1,4-dione-2,5-dicarboxylate by lithium aluminum hydride reduction as described in J. G. Murphy,J. Med. Chem., (1966), 9, 157.
-
- The bridging unit (19) is made from (18) by acidic hydrolysis. The unit (20) is prepared from myo-inositol (25) by reaction with excess 2,2-dimethoxypropane in the presence of p-toluene-sulfonic acid. The unit (21) is made from the bis-epoxide precursor to the unit (17) by methods desribed above for functionalizing hydroxy groups.
- The ligand of Example (10), below, bearing a phosphonomethyl arm, is made by treating DO3A with phosphorus acid and formaldehyde as described by M. Tazaki et al.,Chem, Lett., 1982, 571.
- All stereoisomers of the compounds and complexes of the present invention are contemplated herein, whether alone (that is substantially free of other isomers), in a mixture of certain stereoisomers (for example, as a racemate) or in any other mixture thereof.
-
-
- A. Trans-2,5-Dihydroxy-1,4-Dimethylene Cyclohexane
- A warm solution of dry, recrystallized diethyl 1,4-cyclohexanedione-2,5-dicarboxylate (30.75 g, 120 mmol) in 350 ml anhydrous tetrahydrofuran (THF) was added to a refluxing solution of 1.0 M LAH in THF (600 mL) over a 2 hour period. After an additional 1.5 hours at reflux and subsequent cooling, a saturated solution of aqueous Rochelles's salt (app. 73 mL) was added dropwise to the reaction mixture. The tartrate complex was filtered, washed with THF and the filtrate was concentrated to a paste. The paste was recrystallized from hot ethyl acetate; yield 4.39 g (31.3 mmol, 26.1%). A second recrystallization yielded 3.81 g (27.2 mmol, 22.6%). M.P. : 160-161.5° C., uncorrected (lit. 162.5 -163° C.).
- B. (3α,4α,6β,9β)-1,7-Dioxadispiro[2.2.2.2]-Decane-4,9-Diol
- A solution of wet, 80% m-chloroperoxybenzoic acid (mCPBA, 7.00 g, app. 30 mmol) in 30 mL dry dichloromethane (CH2Cl2) was dried over anhydrous magnesium sulfate (MgSO4). This solution was added to a solution of dry Compound A (1.40 g, 10.0 mmol) in 15 mL dry CH2Cl2). The mixture was stirred at room temperature under a dry nitrogen atmosphere for 16 hours. A second sample (550 mg) of mCPBA was added to ensure complete conversion of the dimethylene compound to the diepoxide. After 3 hours, the mixture was evaporated to dryness and excess mCPBA/m-chlorobenzoic acid was removed by treating the residue with diethyl ether. The ether-insoluble material was filtered, washed with ethyl ether (Et2O) and air dried to yield 1.35 g of crude Compound B. The crude material was recrystallized from a minimum of hot methanol; yield 967 mg (5.6 mmol, 56.1%). M.P.: 231-233° C.
- C. (1α,2α,4β,5β)-10,10′-[(1,2,4,5-Tetrahydroxy-1,4-Cyclohexanediyl)bis(Methylene)]bis[1,4,7,10-Tetraazacyclododecane-1,4,7-Triacetic Acid], Hexasodium Salt
- The pH of a suspension of 1,4,7,10-tetra-azacyclododecane-1,4,7-triacetic acid (DO3A)-H2SO4 (prepared as described in D. D. Dischino et al., Inorg. Chem., 1991, 30, 1265-69; 2.67 g, 6.0 mmol) in 2.0 mL water was adjusted to approximately pH 12.5 with 5.40 mL 5N sodium hydroxide. This solution was warmed to 50° C., and Compound B (517 mg, 3.0 mmol) was added portion-wise over 5.5 hours. Crystals developed overnight from the warm mixture. After cooling, the crude crystals (3.4 g) were isolated and were recrystallized from 20 mL hot water to yield 1.3 g (1.4 mmol, 45%) of Compound C. Mass Spectrum (FAB): (M−7H+8 Na)+ at 1040; (M−6H+7 Na)+ at 1019; (M−5H+6 Na)+ at 997; (M−4H+5 Na)+ at 975; (M−3H+4 Na)+ at 953; (M−2H+3 Na)+ at 931. Elemental analysis: Found: C 42.53, H 6.10, N 10.90. Calculated for: C36H58N8Na6O16·1.16 H2O: C 42.49, H 5.97, N 11.01.
- D. (1α,2α,4β,5β)-10,10′-[1,2,4,5-Tetrahydroxy-1,4-Cyclcohexanediyl)bis(Methylene)]bis[1,4,7,10-Tetraazacyclododecane-1,4,7-Triacetic Acid], Digadolinium Salt
- The pH of a solution of Compound C (760 mg, 762 μmol) in 5.0 mL deionized water was adjusted to pH 4.83 with 225 μL acetic acid (HOAc). A solution of Gd(OAc)3·4 H2O (680 mg, 1.67 mmol) in 5.0 mL warm deionized water was added to the ligand solution over a 10 minute period; final pH 4.73. After 1 minute of stirring at room temperature, a precipitate began to develop. The volume of the precipitate increased with time and the reaction was left to run overnight. The precipitate was filtered, extensively washed with water, and dried; yield 741 mg (631 μmol, 83%). An analytical sample was prepared by recrystallization from hot water. Mass spectrum: (FAB): (M+H)+ at 1169 through 1177. Elemental analysis: Found: C 35.93, H 5.50, N 8.84. Calculated for C36H58Gd2N8O16·2.5 H2O: C 35.49, H 5.21, N 9.20.
-
- A. (+)-1.2-O-Isopropylidene-Myo-Inositol
- A mixture of myo-inositol (25.0 g, 140 mmol), 2,2-dimethoxypropane (42.5 mL, 350 mmol) and p-toluenesulfonic acid (250 mg) in dimethylsulfoxide (80 mL) was stirred at 100° C. for 45 minutes until the solution became homogenous. After stirring the mixture at ambient temperature for 30 minutes, triethylamine (2.5 mL), ethanol (100 mL) and ether (500 mL) were introduced causing precipitation. The solid material was filtered, washed with ether-methanol (200 mL, 5:1) and ether, and dried to obtain the ketal compound A (9.72 g) as a white solid in 32% yield. m.p.: 182.4-182.9° C.
- B. (3aα,4α,5β, 6α,7aα,)-Hexahydro-2,2-Dimethyl-Tetra-Kis-4,5,6,7-(2-Propenyl-Oxy)-1,3-Benzodioxole
- To a suspension of sodium hydride (545 mmol) in dimethylformamide (50 mL) was added the ketal compound A (20.0 g, 90.8 mmol) dimethylformamide (20 mL) at ambient temperature under nitrogen. After stirring the suspension for 2 hours, allyl bromide (83.4 g, 689 mmol) in dimethylformamide (50 mL) was reacted for 18 hours. The unreacted sodium hydride was carefully quenched with water, and then the solvent was removed to obtain a dark brown oil. The residue was partitioned in water (100 mL) and dichloromethane (100 mL) and extracted with dichloromethane (100 mL×3). The combined organic layers were dried over sodium bisulfate and evaporated to obtain a brownish liquid (about 45 mL). The crude product was purified by silica gel flash chromatography (ethyl acetate and hexanes, 1:8) to afford compound B (26.2 g) as a pale yellow liquid in 76% yield.
- C. (3aα,4α,5β,6α,7aα)-Hexahydro-2,2-Dimethyl-Tetra-Kis-4,5,6,7-(Oxiranylmethoxy)-1,3-Benzodioxole
- To compound B (6.0 g, 15.8 mmol) in dichloromethane (10 mL) was added dropwise m-chloroperbenzoic acid (85% from ICN, 19.2 g, 94.6 mmol) dissolved in dichloromethane (100 mL). A homogeneous solution was initially obtained but a white solid, presumed to be m-chlorobenzoic acid, slowly precipitated out of the solution after about 15 minutes. After 24 hours, sodium metabisulfite (100 mL, 5% in water) and sodium bicarbonate (200 mL, 10% in water) were added and the resulting solution was extracted with dichloromethane (100 mL×3). The organic layers were combined and dried over sodium sulfate. The residue, obtained from removal of the solvent, was purified by flash silica gel chromatography to obtain compound C as a colorless liquid in 76% yield.
- D. (3aα,4α,5β, 6α, 7β,7aα,)-10,10′,10″,10′″-[[Hexahydro-2,2-Dimethyl-1,3-Benzodioxol-4,5,6,7-Tetrayl]-Tetra(Oxy)Tetra(2-Hydroxy-3,1-Propanediyl)]Tetrakis[1,4,7,10-Tetraazacyclo-Dodecane-1,4,7-Triacetic Acid], Triethylamine (1:4) Salt
- To a suspension of DO3A (9.77 g, 28.2 mmol) dissolved in alkaline water (6 mL, 10 N sodium hydroxide was used to obtain a pH 10 solution) at 40-50° C. was added the tetraepoxide compound C (1.54 g, 3.46 mmol) in acetonitrile (5 mL). The reaction mixture was stirred for 2 days maintaining the same pH. The crude product was purified by DEAE Sephadex chromatography using triethylammonium bicarbonate (pH 7.5) as the eluent. The buffer concentration to bring out the product compound D was 200 to 500 mM. Removal of the buffer gave compound D (7.8 g) in 58% yield. m.p.: 178° C. (decomp.)
- E. (3aα,4α,5β,6α,7β,7aα)-10,10′10″10″′-[[Hexahydro-2,2-Dimethyl-1,3-Benzodioxol-4,5,6,7-Tetrayl]Tetra(Oxy)Tetra(2-Hydroxy-3,1-Propanediyl)]Tetrakis[1,4,7,10-Tetraazacyclododecane-1,4,7-Triacetic Acid], Tetragadolinium Salt
- To compound D (216 mg, 96 μmol) dissolved in water (1 mL) was added gadolinium acetate (236 mg, 580 μmol) dissolved in water (2 mL). The solution was heated to 65° C. for 18 hours. The pH was maintained between 4.0 and 6.0 during the chelation reaction. The material was loaded to a CHP20P column and eluted with.water (1.9 L) followed by 10% ethanolic water (1 L). The product was eluted with 10% ethanol-containing fraction, as identified by HPLC, and evaporated to dryness to yield the title compound (283 mg) as a white crystalline solid in a quantitative yield. MS (FAB): m/z: 2447.8 [(M+H)+, base peak]. Analysis Calculated for C77H124N16O34Gd4·11.41H2O: C, 34.87; H, 5.58; N, 8.45. Found: C, 34.68; H, 5.98; N, 8.30; H2O, 7.75 (desorprtion KF).
-
- A. 3,4,5,6-Tetra-O-[2-Hydroxy-3-[4,7,10-Tris-(Carboxymethyl)-1,4,7,10-Tetraazacyclo-Dodecan-1-yl]Propyl]-Myo-Inositol, Tetratriethyl Ammonium Salt
- Compound D from Example 2 was treated with 1.0 N aqueous hydrochloric acid (10 mL) for 0.5 hours to remove the ketal group. The resulting-solution was applied to a polyvinylpyridine (PVP) column (2.5×30 cm) and eluted with water. Silver nitrate was given to test each fraction to detect any breakage of chloride ion. Removal of the water from the fractions containing the product gave the title compound (910 mg) in 80% yield. m.p.: 210° C. (decomp). MS (FAB): m/z: 1789.9 [(M+H)+, base peak]; 1811.9 [(M+Na)+]. Analysis Calculated for C74H132N16O34·11.0H2O: C, 44.63; H, 7.81; N, 11.27. Found: C, 44.63; H, 7.84; N, 11.41; H2O, 6.43 (desorption KF); ROI, 0.17.
- B. 3,4,5,6-Tetra-O-[2-Hydroxy-3-[4,7,10-Tris(Carboxymethyl)-1,4,7,10-Tetraazacyclo-Dodecan-1-yl]Propyl]-Myo-Inositol, Tetragadolinium Salt
- To gadolinium acetate (595 mg, 1.46 mmol) dissolved in water (1.5 mL) was added Compound A (550 mg, 0.246 mmol) dissolved in water (2 mL). The chelation mixture was kept overnight at 60° C. and the pH of the solution maintained between 4.0 and 5.0. The resulting mixture was loaded to a CHP20P column (2.5×25 cm) and eluted with water followed by 10% ethanol. The title compound was brought out by 10% ethanolic water. Removal of the solvents from the fractions containing the product gave the title compound as a white solid in 93% yield. MS (FAB): 2408.7[(M+H)+, 158Gd)]: Analysis Calculated for C74H120N16O34Gd4·4.86 H2O: C, 35.63; H, 5.24; N, 8.98. Found: C, 35.48; H, 5.74; N, 8.75; 3.51 H2O (desorption KF); ROI, 31.52.
-
- A. [3aR-(3aα,4α,4aα,7aα,8β,8b)]-Hexahydro-2,2,6,6-Tetramethyl-4,8-bis-(2-Propenyl-Oxy)Benzo[1,2-d:4,5-d′]bis [1,3]Dioxole
- A sample of sodium hydride (NaH)(8.31 g, 156 mmol; 45% in mineral oil) was added to an ice cold solution of dry 1,2:4,5-di-O-isopropylidene-myo-inositol (10.00 g, 38.4 mmol, prepared as indicated in Gigg et al.,Carbohyd. Res., 1985, 142, 132) in dry dimethylformamide (DMF) (80 ml). After stirring for 0.5 hours at room temperature, allyl bromide (8.31 mL, 96 mmol) was added dropwise over 5 minutes. During the addition, the temperature was maintained at 25° C. by cooling in a cold water bath. After 1.5 hours, the reaction was stopped by the careful addition of water and the mixture was evaporated to dryness in vacuo. The residue was dissolved in water, extracted with ethyl acetate (EtOAc) (4×50 ml), and washed with water (2×20 ml) and brine (1×20 ml). The organic layer was dried over sodium sulfate (Na2SO4) and evaporated to dryness under reduced pressure. The residue was recrystallized from hexane to give pure product as a colorless solid (12.88 g, yield 98.5%). M.P. 82-83° C., uncorrected.
- B. (3aα,4α,4aα,7aα,8β,8b)-Hexahydro-2,2,6,6-Tetramethyl-4,8-bis(Oxiranylmethoxy)Benzo [1,2-d:4,5-d′]bis[1,3]Dioxole
- A solution of 80% mCPBA (13.09 g, 60.7 mmol) in dry dichloromethane (CH2Cl2)(95 ml) was added to a cooled solution containing Compound A (5.11 g, 15.0 mmol) in dry CH2Cl2 (15 ml). After stirring at room temperature overnight, the mixture was treated with saturated aqueous sodium sulfite (Na2SO3) followed by saturated aqueous sodium bicarbonate (NaHCO3) until the aqueous layer was neutral. The organic layer was dried over sodium sulfate (Na2SO4) followed by evaporation to dryness in vacuo. The residue was recrystallized from hot ethanol to give the pure product (4.05 g, yield 72.4%). M.P. 103-105° C. (uncorrected)
- C. (1α,2α,3α,4β, 5α,6β)-10, 10′-[(2,3,5,6-Tetra-Hydroxy-1,4-Cyclohexanediyl)bis(2-Hydroxy-3,1-Propanediyl)]bis[1,4,7-10-Tetraazacyclodode-Cane-1,4,7-Triacetic Acid], Triethylamine (1:2) Salt
- A sample of crude (3aα,5α,5β,6α,7β,7aα)-10-10′-[[hexahydro-2,2-dimethylbenzol[1,2-d:4,5-d′]-bis[1,3]dioxol-4,8-diyl]di(oxy)di(2-hydroxy-3,1-propanediyl)]bis[1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid] was prepared by heating a solution of DO3A·H2SO4 (28.24 g, 63.5 mmol) and Compound B (5.92 g, 15.9 mmol) in 10 M sodium hydroxide (NaOH) (28.0 mL), H2O (20 mL) and 1,4-dioxane (17 mL) at 50° C. for 70 hours. The pH of the crude mixture was adjusted to pH 1 using 1N hydrochloric acid (HCl) and was heated at 55° C. for 1.5 hours. After the hydrolysis was complete, the pH of the solution was adjusted to 9 with dilute NaOH and the mixture was applied to a DEAE-Sephadex A-25 column (HCO3 − form, 2L). The column was washed with water, and the product was eluted with a linear gradient of 5-250 mM TEAB buffer (pH 7.5, 4 L each). The fractions which contained pure Compound C were combined, freed of TEAB, and lyophilized to give Compound C as the di(triethylammonium) salt (18.22 g, yield 97.2%). The mass spectral analysis of this product indicated the presence of chloride ion. A sample of the contaminated product (10.00 g) was dissolved in water and was applied onto a AG50W×8 column (H+ form , 500 ml). The column was washed with water, and the product was eluted with 0.5 M ammonium hydroxide (NH4OH). The fractions which contained Compound C were combined and evaporated to give the ammonium salt (2.91 g). The ammonium salt was dissolved in water, applied to a DEAE-Sephadex A-25 column (HCO3 − form, 2L). The column was washed with water and the product was eluted with 200 mM TEAB (pH 7.5, 5L). The fractions containing pure material were combined, freed of TEAB, and lyophilized to give pure Compound C as the di(triethylammonium) salt (2.86 g, theo. yeild 25.9%).
- D. (1α,2α,3α,4β,5α,6β)-10,10′-[(2,3,5,6-Tetrahydroxy-1,4-Cyclohexanediyl)]bis(2-Hydroxy-3,1-Propanediyl)]bis[1,4,7,10-Tetraazacyclododecane-1,4,7-Triacetic Acid], Digadolinium Salt
- A sample of Compound C (1.02 g) was dissolved in a solution containing Gd(OAc)3·4 H2O (1.219 g, 3 mmol) in water (10 mL) and was heated at 50° C. for 16 hours. The solution was applied onto a CHP20-P column (500 mL). The salt contaminants-were eluted with water, and the product was eluted with 10% ethanol in water. The appropriate fractions were combined and evaporated to dryness in vacuo. The glassy residue was dissolved in water, and lyophilized to give pure title compound (1.04 g, yield 80.5%). MS (FAB): (M+H)+ at 1295.2 (major isotope). Elemental analysis: Found: C, 36.83; H, 5.63; N, 8.46%. Calculated for C40H66Gd2N8O20·1.20 H2O: C, 36.53; H, 5.24; N, 8.52%.
-
- A. 1,7-Dioxadispiro [2,2,2,2]-Decane-4,9-Diallyldiol
- To a suspension of sodium hydride (432 mg, 18 mmol) in anhydrous dimethylformamide (15 ml), a solution of bisepoxydiol (1.0 g, 6 mmol) (described in Example 1B) in anhydrous dimethylformamide (60 ml) was added dropwise and the mixture was stirred at room temperature for 60 minutes. Allyl bromide (2.178 g, 18 mmol) was added and the mixture was stirred at room temperature for 18 hours. Excess of sodium hydride was decomposed with water (2 ml), dimethylformamide removed in vacuo and the residue extracted with ethyl acetate (2×100 ml), washed with water (2×50 ml) and dried. Solvent removal afforded the crude product. Silica gel (25 g) column chromatography using hexanes and ethyl acetate (2/1) as the eluent afforded the pure diallyl derivative compound A as a colorless solid (0.7 g, yield 48%). Melting point: 63.5-65.5° C. (uncorrected).
- B. (3α, 4α, 6β, 9β)-4,9-bis(Oxiranylmethoxy)-1,7-Dioxadispiror[2,2,2,2]Decane
- A solution of m-chloroperoxybenzoic acid (4.3 g, 80%, 18.5 mmol) in dichloromethane (30 ml) was dried over anhydrous magnesium sulfate. This solution was added dropwise to a solution of compound A (1.25 g, 5 mmol) in dry dichloromethane (25 ml). The reaction mixture was stirred at room temperature for 20 hours. Excess of m-chloroperoxybenzoic acid was decomposed with saturated aqueous sodium metabisulfate solution (15 ml). The organic layer was separated, washed with saturated sodium bicarbonate (2×50 ml), and with water (2×50 ml). The organic layer was dried over magnesium sulfate and evaporated to dryness. Recrystallization of the crude material from hot ether afforded the pure tetraepoxide compound B as white crystals (1.1 g, yield 77.5%). Melting point: 93.0-96.0° C. (uncorrected).
- C. 10-[[1,4-Dihydroxy-2,5-bis[2-Hydroxy-3-[4,7,10-Tris-(Carboxymethyl)-1,4,7-10-Tetraazacyclododecan-1-yl]-Propoxy]-4-[[4,7,10-Tris(Carboxymethyl)-1,4,7,10-Tetraazacyclododecan-1-yl]Methyl]cyclohexyllmethyl]-1,4,7,10-Tetraazacyclododecane-1,4,7-Triacetic Acid, Triethylamine (1:4) Salt
- A solution of DO3A (17.3 g, 50 mmol) in water was made (80 ml) and the pH of the solution adjusted to 12 with 5 N sodium hydroxide solution. The solution was heated to 80° C. and a solution of compound B (1.42 g, 5 mmol) in dioxane (10 ml) was added dropwise. The mixture was stirred at this temperature for 82 hours. At the end of 82 hours, the pH of the reaction mixture was adjusted to 7 with acetic acid. The mixture was diluted and loaded on to a Sephadex G-25 column. The column was eluted first with 100-250 mM triethyl ammonium bicarbonate (TEAB) buffer and then with 250-500 mM TEAB buffer. Fractions containing the pure tetrameric material were combined and solvent removal afforded the pure product as the tetra triethyl ammonium salt of the title compound as a colorless glassy solid (2.85 g, yield 35%). Mass Spectrum: 1670 (M+H)+. 102 (CH3CH2)3N+H Elemental Analysis: Found: C, 53.70; H, 9.15; N, 13.62; H2O, 0.58%. Calculated for C94H184N20O30·0.67 H2O: C, 54.11; H, 8.85; N. 13.42; O, 23.52%.
- D. 10-[[1,4-Dihydroxy-2,5-bis[2-Hydroxy-3-[4,7,10-Tris-(Carboxymethyl)-1,4,7,10-Tetraazacyclododecan-1-yl]-Propoxy]-4-[[4,7,10-Tris(Carboxymethyl)-1,4,7,10-Tetraazacyclododecan-1-yl]Methyl]Cyclohexyl]Methyl]-1,4,7,10-Tetraazacyclododecane-1,4,7-Triacetic Acid, Tetragadolinium Salt
- A sample of Compound C (0.2 g) was dissolved in 3 mL deinonized water (reactant I). In a separate vial, 0.18 g of GdCl3 powder was dissolved in 5 mL deionized water (reactant II). At about 70° C. and constant stirring, reactant I was added into reactant II dropwise over a time period of several hours. Meanwhile, 5N NaOH was pipetted into the solution from time to time to neutralize the protons released from chelation and maintain the reaction pH around 6. The excess metal ions were precipitated in the form of M(OH)3·×H2O by raising solution pH to about 9 and incubating at both about 70° C. and room temperature for several hours. The precipitate was subsequently removed through centrifugation and filtration with 0.22 μm membrane. The filtrate was finally condensed and neutralized to pH 7 in preparation for HPLC purification.
- The crude chelate product was purified by preparative HPLC, using mobile phase gradient (acetonitrile:water) and silica-based reverse phase column (YMC C18, 5μ, 200 A). The solvent was removed from the fractions containing the product. The residue was further dried in a vacuum oven at about 70° C. overnight. The yield of the desired chelate was 70%. Mass Spectrum (FAB, m/e):(Gd159+H)+ at 2287.5. Elemental Analysis (C,H,N): Calculated for C70H112N16O30Gd4·7.73 H2O: C34.66, H 5.30, N 9.24%. Found: C 34.26, H 5.36, N 9.08%.
-
- A. (+)-3,4,5,6-Tetra-O-Allyl-Myo-Inositol
- Compound B from Example 2 (15.3 g, 44.9 mmol) was dissolved in methanol (30 mL) and treated with 3N hydrochloric acid (30 mL), with constant stirring at room temperature for 13 hours. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with methylene chloride (50 mL×3). The dichloromethane layers were combined and dried with sodium sulfate, filtered, evaporated in vacuo and purified by column chromatography (silicon dioxide, ethyl acetate: hexanes (1:1 v/v)) to obtain 9.1 g (67%) of the desired product compound A.
- B. [3aR-(3aα,3″aα,4α,4″β,5β,5″α,6α,6″β,7β,7″α,7aα,7″aα)]-Dodecahydro-4,4″,5,-5″,6,6″,7,7″-Octakis-(2-Propenyloxy)-Dispiro[1,3-Benzo-Dioxole-2,1′-Cyclo-Hexane-4′,2″-[1,3]-Benzodioxole]
- A mixture of the diol compound A (1.0 g, 2.94 mmol), 1,4-cyclohexanedione (165 mg, 1.47 mmol) and p-toluenesulfonic acid (55 mg, 0.289 mmol) was heated in toluene (30 mL) at reflux for 19 hours. The crude reaction mixture was purified by flash silica gel column chromatography (about 200 g) using different eluents of hexane and ethyl acetate (2:1, 1:1 and 1:2, 500 mL each). Three to four spots that have the molecular ion peak at 757 (m/z) were pooled to afford an oil (520 mG) in 43% yield, and the resulting mixture used as a mixture of the isomers of the expected octa-allyl bis-ketal product. TLC: Rf 0.45, 0.37 and 0.32 in hexanes and : acetone (5:1, v/v)
- C. [3aR-(3aα,3″aα,4β,4″β,5α,5″α,6β,6″b,7α,7″α,7aα,7″aα)]-Dodecahydro-4,4″,5,5″,6,6″,7,7″-Octakis-(Oxyranylmethoxy)-Dispiro[1,3-Benzodioxole-2,1′-Cyclohexane-4′,2″-[1,3]-Benzodioxole]
- The oxidation of the octa-allyl compound B (1.13 g, 1.49 mmole) by m-chloroperoxybenzoic acid (3.0 g, 85%, 17.6 mmole) in dichloromethane (20 mL) was carried out at ambient temperature for 50 hours. The white solid, which precipitated out, during the oxidation was identified as m-chlorobenzoic acid by1H-NMR (CDCl3). After removal of the solid by filtration, the dichloromethane filtrate was treated with sodium metabisulfite and sodium hydroxide where the final pH of the aqueous layer was 11.7. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude solid product was purified by column chromatography (flash silica gel, 75 g) to obtain a white solid (670 mg) in 51% yield.
- D. (3aR-(3aα,3″α,4β,4″β,5α,5″α,6β,6″b,7α,7″α,7aα,7″aα)]-Dodecahydro-4,4″,5,5″,-6,6″,7,7″-Octakis-[[2-Hydroxy-3-[(4,7,10-Tricarboxymethyl)-1,4,7,10-Tetraazacyclo-Dodecan-1-yl]Propyl]Oxy]Dispiro-[1,3-Benzodioxole-2,1′-Cyclohexane-4′,2″-[1,3]-Benzodioxole]
- The octaepoxide Compound C (200 mg, 235 μmol) in acetonitrile (0.5 mL) was added to DO3A (2.41 g, 7.04 mmol) in water (4-5 mL) whose pH was adjusted to 9.6 by 10 N sodium hydroxide at 60° C. The resulting solution was kept for 48 hours and analyzed by PRP-X 100 HPLC column at desirable intervals. Two relatively pure fractions were obtained after two DEAE Sephadex A-25 ion exchange columns. One eluted by 300-400 mM triethyl-ammonium bicarbonate (TEAB) showed a peak at m/z 3328.0 corresponding to the heptamer, whereas-the other by 400 mM TEAB turned out to be the expected octamer with a peak at m/z 3656.6 (C154H268N32O68). 1H-NMR (D2O): d 1.15 (t, 106H, CH3CH2N); 1.7-1.9 (m, methylenes of the middle cyclohexane, 8H); 3.07 (q, 71H, CH3CH2N), 2.8-4.6 (m, 228H, all of methines and methylenes of the octamer ligand except the triethylamine and bridged cyclohexane). 13C-NMR (D2O): 8.10 and 46.29 (CH3CH2N of triethyl-amine); 41.88, 46.29, 49.25, 49.54, 49.62, 49.76, 50.04, 55.72, 56.43, 58.69, 172-175 (broad due to 24 carboxylate and/or carboxylic acid groups). MS (FAB): 3,328 (M+H)+. Analysis Calcualted for C154H268N32O68-8[N(C2H5)3]·17.20H2O: C, 50.81; H, 8.92; N, 11.73. Found: C, 50.33; H, 8.92; N, 11.75; H2O, 6.10 (desorption Karl-Fisher).
- E. [3aR-(3aα,3″aα,4β,4″β,5α,5″α,6β,6″b,7α,7″α,7aα,7″aα)]-Dodecahydro-4,4″,5,5″,6,6″,7,7″-Octakis[[2-Hydroxy-3-[(4,7,10-Tricarboxy-Methyl)-1,4,7,10-Tetraazacyclododecan-1-yl]Propyl]Oxy]Dispiro-[1,3-Benzodioxole-2,1′-Cyclo-Hexane-4′,2″-[1,3]Benzodioxole], Octagadolinium Salt
- Compound D (250 mg, 68.4 μmol as the octa-triethylammonium salt) in water (5 mL) at pH 6.0 was treated with tetrahydrated gadolinium acetate (222 mg, 546 μmol) at 60° C. for 5 hours. The pH of the aqueous reaction mixture was maintained at 7.0±1.0. The resulting solution was then applied to a CHP-20P column (2.5×20 cm). The column was eluted with water (750 mL), 2.5% (300 mL), 5% (300 mL) and 10% (300 mL) of ethanol. The fractions containing the desired compound, which were eluted by 10% ethanol, were combined and concentrated in vacuo to obtain the octameric gadolinium chelate (200 mg) as a white solid in 60% yield. Analysis Calculated for C154H244N32O68Gd8·19.58 H2O·2.0 C2H5OH: C, 35.57; H, 5.58; N, 8.40. Found: C, 35.06; H, 6.22; N, 8.42; H2O, 6.61% (desorption Karl-Fisher).
-
- A. L-2-Benzylamino Propanol
- To a solution of N-benzoyl-L-alanine (29.0 g, 150 mmol) in tetrahydrofuran (200 ml) at 0° C. was added a tetrahydrofuran solution of diborane (1 M solution, 800 ml) and the mixture was refluxed for 18 hours. Excess of diborane was decomposed with methanol and the solvents were removed under reduced pressure. The residue was dissolved in methanol (100 ml) and treated with 6 N hydrochloric acid (100 ml). The mixture was heated at 70° C. for 12 hours and the solvents were removed under reduced pressure. The residue was co-evaporated with methanol (5×150 ml) and the product was dissolved in water (50 ml), basified with 5 N sodium hydroxide to pH 12 and extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with saturated sodium chloride (150 ml), dried and concentrated to a final volume of 100 ml. 300 ml of hexane was added and the solution cooled in the refrigerator overnight. The white crystalline needles deposited were collected and dried to afford pure compound A (41.4 g, yield 87%). m.p. 46-48° C.
- B. (S)-1-Benzyl-2-Methyl-Ethyleneimine
- To a solution of Compound A (33.0 g, 200 mmol) and triphenyl phosphine (79.66 g, 300 mmol) in ether (500 ml) stirred under nitrogen in an ice bath, was slowly added diethyl azo-dicarboxylate (95%, 50 ml, 300 mmol). The solution was stirred at room temperature for 16 hours. A crystalline precipitate (triphenylphosphine/diethyl hydrazine carboxylate complex) was filtered off and washed with hexane/ether (1:1, 200 ml). The ether solution was extracted with 1 N hydrochloric (2×100 ml). The hydrochloric solution was basified with 5N sodium hydroxide, extracted with ether (3×150 ml), dried and concentrated to afford the crude aziridine compound B as a yellow oily liquid. This was further purified by distillation under reduced pressure to afford pure compound B as a colorless liquid (24.3 g, yield 75%). b.p. 71-72° C. at 4 mm.
- C. [2S-(2α,5α,8α,11α)]-2,5,8,11-Tetramethyl-1,4,7,10-Tetrakis(Phenylmethyl)-1,4,7,10-Tetraazacyclododecane
- To a solution of compound B (19.1 g, 130 mmol) in ethanol (250 ml) was added p-toluenesulfonic acid (PTSA, 1.1 g, 6.5 mmol) and the mixture was stirred at room temperature for 64 hours. At the end of this time, an additional 1.1 g (6.5 mmol) of PTSA was added and the mixture was stirred for 48 hours. Ethanol was removed in vacuo, and the product was purified by column chromatography over silica gel (400 g) using methanol as the eluent. Fractions containing the pure product were combined, and solvent removal afforded 5.8 g of a salt. This was dissolved in methanol (100 mL) and basified with concentrated ammonia solution. The precipitated solid was filtered, dried and recrystallized from absolute ethanol to afford pure compound C as a colorless microcrystalline solid (2.8 g, yield 14%). m.p.: 147-148° C.
- D. [2S-(2α,5α,8α,11α,)]-2,5,8,11-Tetramethyl-1,4,7,10-Tetraazacyclododecane
- To a solution of compound C (2.35 g, 4 mmol) in ethyl acetate (40 mL) and ethanol (400 mL) was added ammonium formate (2.52 g) and palladium acetate on Carbon (20%, 2.35 g). The mixture was stirred under reflux for 16 hours. The solution was filtered to remove the catalyst and the solvents were removed to afford pure Compound D as a light yellow solid (840 mg, yield 92%).
- E. [2S-(2α,5α,8α,11α)]-2,5,8,11-Tetramethyl-1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetraacetic Acid
- To a solution of compound D (570 mg, 2.5 mmol) in acetonitrile (200 mL) was added potassium carbonate (4.0 g) and t-butyl bromo acetate (2.34 g, 12 mmol). The mixture was stirred at room temperature for 18 hours. Potassium carbonate was filtered off, acetonitrile removed in vacuo and the residue purified by column chromatography over silica gel (50 g) using chloroform and methanol to afford the tetra butyl ester (1.6 g). This material was dissolved in trifluoroacetic acid (150 mL), anisole (10 mL) was added, and the mixture was stirred at room temperature for 16 hours. Trifluoroacetic acid was removed in vacuo and anisole was removed by co-evaporation with water (6×50 mL) to afford the crude product. The residue was dissolved in water (100 mL) and purified by anion exchange column chromatography over AG1-X2 resin (150 mL). The column, after washing with water, was eluted with 1 M formic acid. The fractions containing the pure product were combined. Solvent removal afforded the pure product. A small amount of formic acid that remained in the sample was removed by co-evaporation with water (5×50 mL) to obtain pure title compound as a colorless glassy solid (550 mg, yield 87%).
- F. [2S-(2α,5α,8α,11α,)]-2,5,8,11-Tetramethyl-1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetraacetic Acid, Gadolinium Salt
- A sample of Compound E (0.1 g) was dissolved in 8 mL deionized water. 0.04 mL 5N sodium hyroxide (NaOH) was added to convert the ligand into the monosodium salt (reactant I). In a separate vial, 0.08 g of GdCl3 powder was dissolved in 1 mL deionized water (reactant II). At about 70° C. and constant stirring, reactant II was added into reactant I dropwise over a time period of several hours. Meanwhile, 5N NaOH was pipetted into the solution from time to time to neutralize the protons released from chelation and maintain the reaction pH around 6. The excess metal ions were precipitated in the form of M(OH)3·H2O by raising solution pH to about 9.5 and incubating at both about 70° C. and room temperature for serveral hours. The precipitate was subsequently removed through centrifugation and filtration with a 0.22 μm membrane. The filtrate was finally condensed and neutralized to pH 7 in preparation for HPLC purification.
- The crude chelate product was purified by preparative HPLC, using mobile phase gradient (CH3CN:H20) and silica-based reversed phase column (YMC C18, 5μ,120 A). The solvent was removed from fractions containing the desired product. The residue was dried in a vacuum oven at about 70° C. overnight, furnishing the chelate in 65% yield. Mass Spectrum (FAB, m/e): Gd159+Na)+ at 638. Elemental Analysis (C, H, N): Calculated for C2OH33N4O8GdNa·5.01 H2O: C, 33.00; H, 5.96; N, 7.70%. Found: C, 32.94; H, 5.63; N, 7.75%
-
- A. [αR-(aR*,α′R*,α″R*,a′″R*,2S*,5S*,8S*,11S*)]-α,-α′,α″,a′″,2,5,8,11-Octamethyl-1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetraacetic Acid
- To a solution of compound D from Example 7 (570 mg, 2.5 mmol) in acetonitrile (200 ml) was added potassium carbonate followed by L-benzyl-2-trifluoromethanesufonyloxy-propionate (prepared fresh from benzyl lactate as described in S. I. Kang et al., Inorganic Chem., 1993, 32, 2912 -2918)(3.9 g, 12.5 mmol) and the mixture was stirred at room temperature for 48 hours. Potassium carbonate was filtered off, acetonitrile removed in vacuo and the residue purified by column chromatography over silica gel (100 g) using chloroform and the methanol to afford a tetra benzyl ester (1.1 g). This material was dissolved in a mixture of ethanol (75 ml) and water (10 ml) and hydrogenated over 10% Pd/C (250 mg) for 18 hours. The catalyst was filtered off and solvent removal afforded the crude product. This was dissolved in water (100 ml) and purified by anion exchange column chromatography over AG1-X2 resin (150 ml). The column, after washing with water, was eluted with a gradient of 0-200 mM formic acid. Fractions containing the pure product were combined. Solvent removal afforded the pure product. A small amount of formic acid that remained in the sample was removed by co-evaporation with water (5×50 ml) to obtain pure Compound A as a colorless glassy solid (340 mg, yield 26%).
- B. [αR-(aR*,α′R*,α″R*,α′″R*,2S*,5S*,8S*,11S*)]-α,-α′,α″,a′″,2,5,8,11-Octamethyl-1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetraacetic Acid, Gadolinium Salt
- A sample of Compound A (0.15 g) was dissolved in 8 mL deionized water. 0.056 mL 5N NaOH was added to convert the ligand into the monosodium salt (reactant I). In a separate vial, 0.11 g of GdCl3 powder was dissolved in 1 mL deionized water (reactant II). Reactants I and II were treated as described in the method of Example 7F to yield 74% of the title compound. Mass Spectrum (FAB, m/e): (Gd159+Na)+ at 694. Elemental alalysis: Calculated for C24H40N4O8GdNa·1.98 H2O: C, 39.57, H, 6.08, N, 7.69%. Found: C, 39.31, H, 6.19, N, 7.60%.
-
- A. [2S-(2R*, 5R*, 8R*,11R*)]-2,5,8,11-Tetramethyl-1,4,7,10-Tetraazacyclododecane-1,4,7-Triacetic Acid
- To a solution of Compound D (456 mg, 2 mmol) in acetonitrile (150 mL) was added sodium bicarbonate (4.0 g) and t-butyl bromo acetate (2.34 g, 12 mmol), and the mixture was stirred at room temperature for 48 hours. Sodium bicarbonate was filtered off, acetonitrile was removed in vacuo and the residue was dissolved in TFA (25 mL). Anisole (1 mL) was added and the mixture was stirred at room temperature for 12 hours. TFA was removed in vacuo and anisole was removed by co-evaporation with water (5×50 mL) to afford the crude product. The residue was dissolved in water (60 mL) and purified by anion exchange column chromatography over AG1-X2 resin (100 mL). The column, after washing with water, was eluted with a gradient of water to 50 mm M formic acid. The fractions were analyzed by HPLC and those containing the pure product were combined. Solvent removal afforded Compound A. A small amount of formic acid that remained in the sample was removed by co-evaporation with water (5×50 mL) to obtain pure Compound E as a colorless glassy solid (320 mg, yield 40%).
- B. [2S-(2R*,5R*,8R*,11R*)]-2,5,8,11,-Tetramethyl-1,4,7,10-Tetraazacylcododecane-1,4,7-Triacetic Acid, Gadolinium Salt
- A sample of Compound A (0.125 g) was dissolved in 9 mL deionized water (reactant I). In a separate vial, 0.129 g of GdCl3 powder was dissolved in 1.5 mL deionized water (reactant II). Reactants I and II were treated as described in the method of Example 7F to yield 80% of the title compound. Mass Spectrum (FAB, m/e): (Gd159+H)+ at 559. Elemental Analysis (C,H,N): Calculated for C18H31N4O6Gd·2.81 H2O: C 35.60, H 6.08, N 9.22%. Found: C 35.65, H 6.11, N 9.02%.
-
- A. 10-(Phosphonomethyl)-1,4,7,10-Tetraazacyclo-Dodecane-1,4,7-Triacetic Acid
- A mixture of DO3A (lg, 2.89 mmol), phosphorus acid (0.485 g, 5.91 mmol), concentrated hydrochloric acid (1.1 mL, 13.4 mmol) and formaldehyde (1.35 mL of 37% aqueous solution, 16.4 mmol) in water (2.5 mL) was refluxed for 27.5 hours. Removal of water from the reaction mixture in vacuo gave an off-white solid (1.74 g) as a crude product of Compound A. The solid was dissolved in water (50 mL), and the pH of the resulting solution was adjusted to 5.0 by addition of 1.0 N sodium hydroxide. The aqueous solution was applied to a strong cation exchange column of AG50WX8 (250 mL, flowrate, 12.5 mL/minute). Initially, water was used to remove any negatively charged inorganic species, and ammonium hydroxide (1.0 M) was employed to bring out the crude product. After removal of the ammonium hydroxide from the fractions containing the product, the residue dissolved in 5 mM TEAB (pH 7.5) was applied to a DEAE Sephadex ion exchange column (750 mL, flowrate, 4 mL/minute). The column was eluted with TEAB, whose concentration varied from 5 to 400 mM. The concentration of the buffer was doubled at every column volume (1L): 5, 10, 20, 40, 67, 80, 100, 125, 200 and 400 mM. Compound A required 400 mM TEAB to be brought out from the column. Evaporation of the buffer from the fractions containing Compound A gave a white residue (0.9 g). The solid, dissolved in water (35 mL) was loaded on a strongly basic anion column of Amberlite IRA 900 C (200 mL, flowrate, 14 mL/minute). Water was first used to remove triethylamine followed by sulfuric acid (1M) to elute Compound A from the column. The fractions containing the product were combined and applied to a column of Reillex 425 poly(4-vinyl)pyridine (PVP) 250 mL, 10 mL/minute). Water was used to elute the product free from sulfuric acid. Removal of water from the eluate (3.7 L) yielded Compound A (0.6 g, 47%) as a dense solid.
- B. 10-(Phosphonomethyl)-1,4,7,10-Tetraaza-Cyclododecane-1,4,7-Triacetic Acid, Gadolinium Salt
- A sample of Compound A (0.2 g) was dissolved in 5 mL deionized water and its pH was adjusted to 4 with dilute NaOH. 0.096 g of Gd2O3 powder was added slowly. The solution was refluxed overnight. The excess metal ions were precipitated in the form of M(OH)3·×H2O by raising solution pH to about 9.5 with 1N NaOH and incubating at both about 70° C. and room temperature for several hours. The precipitate was subsequently removed through centrifugation and filtration with 0.22 μm membrane. The filtrate was finally condensed and neutralized to pH 7 with 1N HCl in preparation for HPLC purification. HPLC purification was performed as in Example 7F to yield 64% of the title compound. Mass Spectrum (FAB, m/e): (Gd159+2 Na—H)+ at 640. Elemental Analysis (C,H,N): Calculated for C15H24N4O9PGdNa2·2.59 H2O: C 26.29, H 4.29, N 8.18%. Found: C 26.23, H 4.18, N 7.93%.
Claims (46)
1. A compound of the following formula I:
wherein
each m, n, o and p is independently 1 or 2;
q is 0 or 1;
each G is independently —COOR″, —P(O)(OR″)2, —P(O)(OR″)(R″) or —C(O)N(R″)2;
each R′ is independently hydrogen or alkyl, alkoxy, cycloalkyl, hydroxyalkyl or aryl, each of which is optionally substituted, or a functional group capable of forming a conjugate with a biomolecule or of forming a multimer of said compound of formula I;
each R″ is hydrogen;
each R13 through R20 is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or a functional group capable of forming a conjugate with a biomolecule or of forming a multimer of said compound of formula I;
or R13 together with R15, and R17 together with R18 , independently form, together with the carbon atoms in the tetraazacyclododecane macrocycle to which they are attached, a fused fully or partially saturated non-aromatic cyclohexyl ring which may be unsubstituted or substituted by one or more halogen, alkyl, ether, hydroxy or hydroxyalkyl groups, and which may be further fused to a carbocyclic ring, or R13 and R15, are each hydrogen and R17, together with R18, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, or R13, together with R15, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above and R17 and R18 are hydrogen; provided that (a.) when G is always —COOR″ and (i.) R′, R″, R14 and R16 through R20 are all hydrogen, then R13 and R15 are other than hydrogen; (ii.) R″ and R13 through R20 are all hydrogen, and m, n, o, p and q are each 1, then (CR′R′) is other than (CH2) and (CHCH3); (iii.) R′, R″, R13, R14, R17 and R20 are all hydrogen, then at least two of R15, R16, R18 and R19 are other than methyl; and (iv.) R″, R16, R19 and R20 are all hydrogen, and each (CR′R′) is independently (CHR′) or (CH2CHR′), then R13 and R15, and R17 and R18, are other than a fused ring; and (b.) when G is always —P(O)(OR″)2, —P(O)(OR″)(R″ ) or —C(O)N(R″)2, then at least one R′ or R13 through R20 is other than hydrogen;
or a salt or multimeric form thereof.
2. A metal chelate, comprising a compound of claim 1 complexed with a metal atom.
3. The chelate of claim 2 , wherein the metal is selected from atoms having an atomic number of 21 to 29, 42 or 57 to 83.
4. The chelate of claim 3 , wherein said metal is gadolinium.
5. A compound of the following formula II:
wherein
Q is a 4- to an 8-membered carbocyclic ring which may be fully or partially saturated;
t is an integer from 2 to 16;
each R group is independently hydrogen, —OH, —CH2-A, —OCH2CH(OH)CH2-A or a functional group capable of forming a conjugate with a biomolecule, provided that at least two of the R groups are selected from —CH2-A or —OCH2CH(OH)CH2-A; and
A is a moiety capable of chelating a metal atom.
6. A compound of claim 5 wherein A is
each m, n, o and p is independently 1 or 2;
q is 0 or 1;
each G is independently —COOR″, —P(O)(OR″)2, —P(O)(OR″)(R″) or —C(O)N(R″)2;
each R′ is independently hydrogen or alkyl, alkoxy, cycloalkyl, hydroxyalkyl or aryl, each of which is optionally substituted, or a functional group capable of forming a conjugate with a biomolecule or of forming a multimer;
each R″ is hydrogen;
each R13 through R20 is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or a functional group capable of forming a conjugate with a biomolecule or of forming a multimer of said compound of the formula I;
or R13 together with R15, and R17 together with R18, independently form, together with the carbon atoms in the tetraazacyclododecane macrocycle to which they are attached, a fused fully or partially saturated non-aromatic cyclohexyl ring which may be unsubstituted or substituted by one or more halogen, alkyl, ether, hydroxy or hydroxyalkyl groups, and which may be further fused to a carbocyclic ring, or R13 and R15 are each hydrogen and R17, together with R18, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, or R13, together with R15, forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above and R17 and R18 are hydrogen; provided that (a.) when G is always —COOR″ and (i.) R′, R″, R14 and R16 through R20 are all hydrogen, then R13 and R15 are other than hydrogen; (ii.) R″ and R13 through R20 are all hydrogen, and m, n, o, p and q are each 1, then (CR′R′) is other than (CH2) and (CHCH3); (iii.) R′, R″, R13, R14, R17 and R20 are all hydrogen, then at least two of R15, R16, R18 and R19 are other than methyl; and (iv.) R″, R16, R19 and R20 are all hydrogen, and each (CR′R′) is independently (CHR′) or (CH2CHR′), then R13 and R15, and R17 and R18, are other than a fused ring; and (b.) when G is always —P(O)(OR″)2, —P(O)(OR″)(R″) or —C(O)N(R″)2, then at least one R′ or R13 through R20 is other than hydrogen;
or a salt or multimeric form thereof.
8. A compound of claim 5 wherein
is
each R1 through R12 group is independently hydrogen, —OH, —CH2-A, —OCH2CH(OH)CH2-A or a functional group capable of forming a conjugate with a biomolecule;
at least two of R1 through R12 are selected from —CH2-A or —OCH2CH(OH)CH2-A; and
R8 and R9 taken together may additionally form the group —O—[C(RR)]—O— where each R is independently hydrogen or alkyl, or R8 and R9 taken together may form
9. A compound of claim 6 wherein
is a compound of the formula
wherein
each R1 through R12 group is independently hydrogen, —OH, —CH2-A, —OCH2CH(OH)CH2-A or a functional group capable of forming a conjugate with a biomolecule;
at least two of R1 through R12 are selected from —CH2-A or —OCH2CH(OH)CH2-A; and
R8 and R9 taken together may additionally form the group —O—[C(RR)]—O— where each R is independently hydrogen or alkyl, or R8 and R9 taken together may form
10. A compound of claim 7 , wherein
is
each R1 through R12 group is independently hydrogen, —OH, —CH2-A, —OCH2CH(OH)CH2-A or a functional group capable of forming a conjugate with a biomolecule;
at least two of R1 through R12 are selected from —CH2-A or —OCH2CH(OH)CH2-A; and
R8 and R9 taken together may additionally form the group —O—[C(RR)]—O— where each R is independently hydrogen or alkyl, or R8 and R9 taken together may form
11. A metal chelate, comprising a compound of claim 5 complexed with a metal atom.
12. A metal chelate, comprising a compound of claim 6 complexed with a metal atom.
13. A conjugate, comprising a compound of claim 5 conjugated with a biomolecule.
14. A metal chelate, comprising a conjugate of claim 13 complexed with a metal atom.
15. A method for diagnostic imaging, comprising the steps of administering to a host a compound of claim 5 , which compound is complexed with a metal, and obtaining a diagnostic image of said host.
16. The method of claim 15 , wherein said image is a magnetic resonance image.
17. A method for diagnostic imaging, comprising the steps of administering to a host a conjugate of claim 13 , which conjugate is complexed with a metal, and obtaining a diagnostic image of said host.
18. A compound selected from the group consisting of:
(1α,2α,4β,5β)-10,10′-[(1,2,4,5-Tetrahydroxy-1,4-cyclohexanediyl)bis(methylene)]bis[1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid];
(3aα,4α,5β,6α,7β,7aα)-10,10′10″,10″′-[[Hexahydro-2,2-dimethyl-1,3-benzodioxol-4,5,6,7-tetrayl]tetra(oxy)-tetra(2-hydroxy-3,1-propanediyl)]tetrakis[1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid];
3,4,5,6-Tetra-O-[2-hydroxy-3-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propyl]-myo-inositol;
(1α,2α,3α,4β,5α,6β)-10,10′-[(2,3,5,6-tetrahydroxy-1,4-cyclohexanediyl)bis(2-hydroxy-3,1-propanediyl)]-bis[1,4,7-10-tetraazacyclododecane-1,4,7-triacetic acid];
10 [[1,4-Dihydroxy-2,5-bis[2-hydroxy-3-[4,7,10-tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-propoxy]-4-[[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]methyl]cyclohexyl]methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid;
[3aR-(3aα,3″aα,4β,4″β,5α,5″α,6β,6″b,7α,-7″α,7aα,7″aα)]-dodecahydro-4,4″,5,5″,6,6″,7,7″-octakis-[[2-hydroxy-3-[(4,7,10-tricarboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propyl]-oxy]dispiro-[1,3-benzodioxole-2,1′-cyclo-hexane-4′,2″-[1,3]-benzodioxole];
[2S-(2α,5α,8α,11α)]-2,5,8,11-Tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid;
[aR-(αR*,α′R*,α″R*,α′″R*,2S*,5S*,8S*,11S*)]-α,-α′,α″,a′″,2,5,8,11-Octamethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid;
[2S-(2R*,5R*,8R*,11R*)]-2,5,8,11,-Tetramethyl-1,4,7,10-tetraazacylcododecane-1,4,7-triacetic acid; and
10-(Phosphonomethyl)-1,4,7,10-tetraaza-cyclododecane-1,4,7-triacetic acid.
19. A compound selected from the group consisting of:
(1α,2α,4β,5β)-10,10′-[(1,2,4,5-Tetrahydroxy-1,4-cyclohexanediyl)bis(methylene)]bis[1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid], digadolinium salt;
(3aα,4α,5β,6α,7β,7aα)-10,10′10″,10″′-[[Hexahydro-2,2-dimethyl-1,3-benzodioxol-4,5,6,7-tetrayl]tetra(oxy)-tetra(2-hydroxy-3,1-propanediyl)]tetrakis[1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid], tetragadolinium salt;
3,4,5,6-Tetra-O-[2-hydroxy-3-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propyl]-myo-inositol, tetragadolinium salt;
(1α,2α,3α,4β,5α,6β)-10,10′-[(2,3,5,6-tetrahydroxy-1,4-cyclohexanediyl)bis(2-hydroxy-3,1-propanediyl)]-bis[1,4,7-10-tetraazacyclododecane-1,4,7-triacetic acid], digadolinium salt;
10-[[1,4-Dihydroxy-2,5-bis[2-hydroxy-3-[4,7,10-tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-propoxy]-4-[[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]methyl]cyclohexyl]methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, tetragadolinium salt;
[3aR-(3aα,3″aα,4β,4″β,5α,5″α,6β,6″b,7α,-7″α,7aα,7″aα)]-dodecahydro-4,4″,5,5″,6,6″,7,7″-octakis-[[2-hydroxy-3-[(4,7,10-tricarboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propyl]-oxy]dispiro-[1,3-benzodioxole-2,1′-cyclo-hexane-4′,2″-[1,3]-benzodioxole], octagadolinium salt;
[2S- (2α,5α,8α,11α,)]-2,5,8,11-Tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, gadolinium salt;
[αR-(aR*,α′R*,α″R*,a′″R*,2S*,5S*,8S*,11S*)]-α, -α′,α″,a′″,2,5,8,11-Octamethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, gadolinium salt;
[2S-(2R*,5R*,8R*,11R*)]-2,5,8,11,-Tetramethyl-1,4,7,10-tetraazacylcododecane-1,4,7-triacetic acid, gadolinium salt; and
10-(Phosphonomethyl)-1,4,7,10-tetraaza-cyclododecane-1,4,7-triacetic acid, gadolinium salt.
20. A chelate other than [1R-(1R*,4R*,7R*,10R*)]-α,α′,α″,α′″-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid or [1R-(1R*,4R*,7R*)]-α,α′,α″-trimethyl-1,4,7 ,10-tetraazacyclododecane-1,4,7-triacetic acid possessing a stability greater than 1015 M−1 and capable of exhibiting an immobilized relaxivity between about 60 and 200 mM−1s−1/metal atom.
21. A chelate of claim 20 capable of exhibiting an immobilized relaxivity between about 70 and 150 mM−1s−1/metal atom.
22. A chelate of claim 20 capable of exhibiting an immobilized relaxivity between about 80 and 100 mM−1s−1/metal atom.
23. A chelate possessing a stability greater than 1015 M−1 and capable of exhibiting an immobilized relaxivity between about 60 and 200 mM−1s−1/metal atom comprising a compound of claim 1 .
24. A chelate possessing a stability greater than 1015 M−1 and capable of exhibiting an immobilized relaxivity between about 70 and 150 mM−1s−1/metal atom comprising a compound of claim 1 .
25. A chelate possessing a stability greater than 1015 M−1 and capable of exhibiting an immobilized relaxivity between about 80 and 100 mM−1s−1/metal atom comprising a compound of claim 1 .
26. A chelate possessing a stability greater than 1015 M−1 and capable of exhibiting an immobilized relaxivity between about 60 and 200 mM−1s−1/metal atom comprising a compound of claim 8 .
27. A chelate possessing a stability greater than 1015 M−1 and capable of exhibiting an immobilized relaxivity between about 70 and 150 mM−1s−1/metal atom comprising a compound of claim 8 .
28. A chelate possessing a stability greater than 1015 M−1 and capable of exhibiting an immobilized relaxivity between about 80 and 100 mM−1s−1/metal atom comprising a compound of claim 8 .
29. A chelate other than [1R-(1R*,4R*,7R*,10R*)]-α,α′,α″,α′″-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid or [1R*,4R*,7R *)]-α,α′,α″-trimethyl-1,4,7,10-tetraazcyclododecane-1,4,7-triacetic acid, including an immobilized functional group, capable of exhibiting an immobilized relaxivity between about 60 and 200 mM−1s−1/metal atom.
30. A chelate of claim 29 , capable of exhibiting an immobilized relaxivity between about 70 and 150 mM−1s−1/metal atom.
31. A chelate of claim 29 , capable of exhibiting an immobilized relaxivity between about 80 and 100 mM−1s−1/metal atom.
32. A chelate including a functional group, capable of exhibiting an immobilized relaxivity between about 60 and 200 mM−1s−1/metal atom comprising a compound of claim 1 .
33. A chelate including a functional group, capable of exhibiting an immobilized relaxivity between about 70 and 150 mM−1s−1/metal atom comprising a compound of claim 1 .
34. A chelate including a functional group, capable of exhibiting an immobilized relaxivity between about 80 and 100 mM−1s−1/metal atom comprising a compound of claim 1 .
35. A chelate including a functional group, capable of exhibiting an immobilized relaxivity between about 60 and 200 mM−1s−1/metal atom comprising a compound of claim 8 .
36. A chelate including a functional group, capable of exhibiting an immobilized relaxivity between about 70 and 150 mM−1s−1/metal atom comprising a compound of claim 8 .
37. A chelate including a functional group, capable of exhibiting an immobilized relaxivity between about 80 and 100 mM1s−1/metal atom comprising a compound of claim 8 .
38. A chelate other than [1R-(1R*,4R*,7R*,10R*)]-α,α′,α″,α′″-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, conjugated to a biomolecule, capable of exhibiting an immobilized relaxivity between about 60 and 200 mM−1s−1/metal atom.
39. A chelate of claim 38 , capable of exhibiting an immobilized relaxivity between about 70 and 150 mM−1s−1/metal atom.
40. A chelate of claim 38 , capable of exhibiting an immobilized relaxivity between about 80 and 100 mM−1s−1/metal atom.
41. A chelate conjugated to a biomolecule, capable of exhibiting an immobilized relaxivity between about 60 and 200 mM−1s−1/metal atom comprising a compound of claim 1 .
42. A chelate conjugated to a biomolecule, capable of exhibiting an immobilized relaxivity between about 70 and 150 mM−1s−1/metal atom comprising a compound of claim 1 .
43. A chelate conjugated to a biomolecule, capable of exhibiting an immobilized relaxivity between about 80 and 100 mM−1s−1/metal atom comprising a compound of claim 1 .
44. A chelate conjugated to a biomolecule, capable of exhibiting an immobilized relaxivity between about 60 and 200 mM−1s−1/metal atom comprising a compound of claim 8 .
45. A chelate conjugated to a biomolecule, capable of exhibiting an immobilized relativity between about 70 and 150 mM−1s−1/metal atom comprising a compound of claim 8 .
46. A chelate conjugated to a biomolecule, capable of exhibiting an immobilized relaxivity between about 80 and 100 mM−1s−1/metal atom comprising a compound of claim 8.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/741,872 US20040131551A1 (en) | 1994-05-11 | 2003-12-19 | Enhanced relaxivity monomeric and multimeric compounds |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/241,253 US6693190B1 (en) | 1994-05-11 | 1994-05-11 | Enhanced relaxivity monomeric and multimeric compounds |
US10/741,872 US20040131551A1 (en) | 1994-05-11 | 2003-12-19 | Enhanced relaxivity monomeric and multimeric compounds |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/241,253 Division US6693190B1 (en) | 1994-05-11 | 1994-05-11 | Enhanced relaxivity monomeric and multimeric compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
US20040131551A1 true US20040131551A1 (en) | 2004-07-08 |
Family
ID=22909910
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/241,253 Expired - Fee Related US6693190B1 (en) | 1994-05-11 | 1994-05-11 | Enhanced relaxivity monomeric and multimeric compounds |
US10/741,872 Abandoned US20040131551A1 (en) | 1994-05-11 | 2003-12-19 | Enhanced relaxivity monomeric and multimeric compounds |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/241,253 Expired - Fee Related US6693190B1 (en) | 1994-05-11 | 1994-05-11 | Enhanced relaxivity monomeric and multimeric compounds |
Country Status (11)
Country | Link |
---|---|
US (2) | US6693190B1 (en) |
EP (1) | EP0708761B1 (en) |
JP (1) | JPH09500660A (en) |
KR (1) | KR960703874A (en) |
CN (1) | CN1128534A (en) |
AT (1) | ATE222244T1 (en) |
CA (1) | CA2164944A1 (en) |
CZ (1) | CZ8596A3 (en) |
DE (1) | DE69527759T2 (en) |
NO (1) | NO306722B1 (en) |
WO (1) | WO1995031444A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080193384A1 (en) * | 2005-04-26 | 2008-08-14 | Koninklijke Philips Electronics, N.V. | Responsive Mri Contrast Agents |
Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6770261B2 (en) | 1995-06-02 | 2004-08-03 | Research Corporation Technologies | Magnetic resonance imaging agents for the detection of physiological agents |
US6713045B1 (en) | 1995-06-02 | 2004-03-30 | Research Corporation Technologies, Inc. | Targeted magnetic resonance imaging agents for the detection of physiological processes |
DE19608307C1 (en) * | 1996-02-26 | 1997-08-28 | Schering Ag | Process for the preparation of 1,4,7,10-tetraazacyclododecane and its derivatives |
US5744616A (en) * | 1996-02-26 | 1998-04-28 | Schering Aktiengesellschaft | Process for the production of 1,4,7,10-tetraazacyclododecane and its derivatives |
US6136311A (en) | 1996-05-06 | 2000-10-24 | Cornell Research Foundation, Inc. | Treatment and diagnosis of cancer |
US6107090A (en) | 1996-05-06 | 2000-08-22 | Cornell Research Foundation, Inc. | Treatment and diagnosis of prostate cancer with antibodies to extracellur PSMA domains |
US5900228A (en) | 1996-07-31 | 1999-05-04 | California Institute Of Technology | Bifunctional detection agents having a polymer covalently linked to an MRI agent and an optical dye |
US6713046B1 (en) | 1997-10-27 | 2004-03-30 | Research Corporation Technologies | Magnetic resonance imaging agents for the delivery of therapeutic agents |
CA2309749A1 (en) * | 1997-11-17 | 1999-05-27 | Research Corporation Technologies, Inc. | Magnetic resonance imaging agents for the detection of physiological agents |
US6565828B2 (en) | 2000-04-07 | 2003-05-20 | Bristol-Myers Squibb Company | Macrocyclic chelants for metallopharmaceuticals |
US6673333B1 (en) | 2000-05-04 | 2004-01-06 | Research Corporation Technologies, Inc. | Functional MRI agents for cancer imaging |
US6656450B2 (en) | 2000-07-17 | 2003-12-02 | California Institute Of Technology, Inc. | Macrocyclic magnetic resonance imaging contrast agents |
US7029655B2 (en) | 2000-10-04 | 2006-04-18 | California Institute Of Technology | Magnetic resonance imaging agents for in vivo labeling and detection of amyloid deposits |
WO2002098897A2 (en) | 2001-06-01 | 2002-12-12 | Cornell Research Foundation, Inc. | Modified antibodies to prostate-specific membrane antigen and uses thereof |
JP2005523235A (en) * | 2001-07-17 | 2005-08-04 | テラファルム ゲゼルシャフト ミット ベシュレンクテル ハフツング | Novel chelating agents and conjugates thereof, synthesis and use of the chelating agents and conjugates as diagnostic and therapeutic agents |
DE10135355C1 (en) * | 2001-07-20 | 2003-04-17 | Schering Ag | Conjugates of macrocyclic metal complexes with biomolecules and their use in the preparation of NMR and radiodiagnostic agents and radiotherapy |
DE10135356C1 (en) * | 2001-07-20 | 2003-04-17 | Schering Ag | Macrocyclic metal complexes and their use for the preparation of conjugates with biomolecules |
WO2003024388A2 (en) | 2001-09-20 | 2003-03-27 | Cornell Research Foundation, Inc. | Methods and compositions for treating and preventing skin disorders using binding agents specific for psma |
AU2003270347B2 (en) | 2002-09-06 | 2007-05-24 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Backbone-substituted bifunctional dota ligands, complexes and compositions thereof, and methods of using same |
WO2004063701A2 (en) | 2003-01-10 | 2004-07-29 | Millennium Pharmaceuticals, Inc. | Methods of diagnosing and treating cancer |
WO2005003105A1 (en) * | 2003-07-08 | 2005-01-13 | The University Of Hong Kong | Synthesis of tris n-alkylated 1,4,7,10-tetraazacyclododecanes |
US7012140B1 (en) * | 2003-07-14 | 2006-03-14 | Board Of Regents, The University Of Texas System | Selection of coordination geometry to adjust water exchange rates of paramagnetic metal ion-based macrocyclic contrast agents |
WO2005062828A2 (en) * | 2003-12-23 | 2005-07-14 | Bracco Imaging S.P.A. | New compounds useful as metal chelators |
US7804298B2 (en) * | 2004-07-29 | 2010-09-28 | Otsuka Pharmaceutical Co., Ltd. | Nuclear magnetic resonance measuring method for solid samples |
JP2008508333A (en) * | 2004-08-05 | 2008-03-21 | ヨハン ウォルフガング ゲーテ−ウニベルジテート フランクフルト アム マイン | Multivalent chelators for modification and organization of target molecules |
DE102004038134B4 (en) | 2004-08-05 | 2013-07-25 | Johann Wolfgang Goethe-Universität Frankfurt am Main | Multivalent chelators for modifying and organizing target molecules, methods for their preparation and their use |
EP1812453A1 (en) * | 2004-10-20 | 2007-08-01 | Therapharm GmbH | Method of preparing or synthesizing polyazamacrocycle derivatives |
CN101845112B (en) * | 2010-06-02 | 2011-09-14 | 华东理工大学 | Preparation method of high-flexibility nuclear magnetic resonance imaging contrast agents based on high molecular nanometer particles |
EP3101012A1 (en) | 2015-06-04 | 2016-12-07 | Bayer Pharma Aktiengesellschaft | New gadolinium chelate compounds for use in magnetic resonance imaging |
US11357873B2 (en) | 2016-09-19 | 2022-06-14 | The Hong Kong Polytechnic University | Chiral cyclen compounds and their uses |
KR102464647B1 (en) * | 2016-11-28 | 2022-11-08 | 바이엘 파마 악티엔게젤샤프트 | High Relaxation Gadolinium Chelate Compounds for Use in Magnetic Resonance Imaging |
BR112021007707A2 (en) | 2018-11-23 | 2021-07-27 | Bayer Aktiengesellschaft | formulation of contrast media and its preparation process |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4880008A (en) * | 1985-05-08 | 1989-11-14 | The General Hospital Corporation | Vivo enhancement of NMR relaxivity |
US6120768A (en) * | 1993-05-17 | 2000-09-19 | Immunomedics, Inc. | Dota-biotin derivatives |
Family Cites Families (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3129906C3 (en) | 1981-07-24 | 1996-12-19 | Schering Ag | Paramagnetic complex salts, their preparation and agents for use in NMR diagnostics |
SE465907B (en) | 1984-11-01 | 1991-11-18 | Nyegaard & Co As | DIAGNOSTIC AGENT CONTENT AND PARAMAGNETIC METAL |
US4899755A (en) | 1985-05-08 | 1990-02-13 | The General Hospital Corporation | Hepatobiliary NMR contrast agents |
US4678667A (en) | 1985-07-02 | 1987-07-07 | 501 Regents of the University of California | Macrocyclic bifunctional chelating agents |
US4885363A (en) * | 1987-04-24 | 1989-12-05 | E. R. Squibb & Sons, Inc. | 1-substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs |
US5271927A (en) | 1986-02-13 | 1993-12-21 | Celltech Limited | Antibody conjugates with macrocyclic ligands |
DE3625417C2 (en) | 1986-07-28 | 1998-10-08 | Schering Ag | Tetraazacyclododecane derivatives |
IT1224416B (en) | 1987-12-24 | 1990-10-04 | Bracco Ind Chimica Spa | MACROCYCLIC CHELANTS AND THEIR CHELATES |
US5049667A (en) | 1987-04-14 | 1991-09-17 | Guerbet S.A. | Nitrogen-containing cyclic ligands |
FR2637895B1 (en) | 1988-10-14 | 1992-11-06 | Guerbet Sa | NOVEL NITROGEN CYCLIC LIGANDS, METAL COMPLEXES FORMED BY THESE LIGANDS, DIAGNOSTIC COMPOSITIONS CONTAINING THESE COMPLEXES AND PROCESS FOR THE PREPARATION OF LIGANDS |
DE3855239T2 (en) | 1987-07-16 | 1996-10-31 | Nycomed Imaging As | Aminocarboxylic acid and derivatives |
GB8719041D0 (en) * | 1987-08-12 | 1987-09-16 | Parker D | Conjugate compounds |
US4923985A (en) | 1988-05-25 | 1990-05-08 | The United States Of America As Represented By The Department Of Health & Human Services | Process for synthesizing macrocyclic chelates |
JPH0720989B2 (en) | 1988-05-25 | 1995-03-08 | アメリカ合衆国 | Macrocyclic chelate conjugates and diagnostic test methods |
NZ229700A (en) | 1988-06-24 | 1993-01-27 | Dow Chemical Co | Tetraazacyclododecane derivatives containing a linker/spacer moiety capable of forming antibody conjugates; complexes with radionuclides and conjugates of such compounds and complexes with antibodies or antibody fragments |
WO1990007342A1 (en) | 1988-12-23 | 1990-07-12 | The Dow Chemical Company | Process for preparing isothiocyanato functionalized metal complexes |
ATE133165T1 (en) | 1989-02-10 | 1996-02-15 | Celltech Therapeutics Ltd | AZA MACROCYCLES AND METHOD FOR THE PRODUCTION THEREOF |
US5053503A (en) | 1989-02-17 | 1991-10-01 | Centocor | Chelating agents |
US5364613A (en) | 1989-04-07 | 1994-11-15 | Sieving Paul F | Polychelants containing macrocyclic chelant moieties |
DE3911816A1 (en) | 1989-04-11 | 1990-10-25 | Hoechst Ag | SUBSTITUTED 1,4,7,10-TETRAAZACYCLOTRIDECANE, METHOD FOR THE PRODUCTION THEREOF AND THE USE THEREOF FOR MARKING SUBSTANCES WITH RADIONUCLIDES |
IT1243801B (en) | 1990-08-29 | 1994-06-28 | Bracco Ind Chimica Spa | INTERMEDIATES FOR CHELATING AGENTS WITH PRE-FIXED SYMMETRY, AND PROCEDURES FOR THEIR PREPARATION |
US5162109A (en) | 1990-09-13 | 1992-11-10 | Mallinckrodt Medical, Inc. | Magnetic resonance imaging agents |
JPH04154729A (en) | 1990-10-16 | 1992-05-27 | Nippon Mejifuijitsukusu Kk | Contrast medium for nuclear magnetic resonance |
DE4035760A1 (en) | 1990-11-08 | 1992-05-14 | Schering Ag | MONO-N-SUBSTITUTED 1,4,7,10-TETRAAZACYCLODODECAN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM |
EP0660925A1 (en) | 1990-11-21 | 1995-07-05 | Mallinckrodt Medical, Inc. | Alkoxyamide derivatized chelates for mri |
FR2672051B1 (en) | 1991-01-24 | 1993-05-21 | Guerbet Sa | NOVEL NITROGEN MACROCYCLIC LIGANDS, PREPARATION METHOD, POLYMETALLIC COMPLEXES, DIAGNOSTIC AND THERAPEUTIC COMPOSITION. |
GB9115375D0 (en) | 1991-07-17 | 1991-09-04 | Salutar Inc | Compounds |
AU663572B2 (en) | 1992-03-27 | 1995-10-12 | Nihon Medi-Physics Co., Ltd. | Tetraazacyclododecane derivative and its use |
-
1994
- 1994-05-11 US US08/241,253 patent/US6693190B1/en not_active Expired - Fee Related
-
1995
- 1995-05-09 EP EP95915988A patent/EP0708761B1/en not_active Expired - Lifetime
- 1995-05-09 CA CA002164944A patent/CA2164944A1/en not_active Abandoned
- 1995-05-09 WO PCT/IB1995/000337 patent/WO1995031444A1/en active IP Right Grant
- 1995-05-09 CN CN95190415A patent/CN1128534A/en active Pending
- 1995-05-09 DE DE69527759T patent/DE69527759T2/en not_active Expired - Fee Related
- 1995-05-09 CZ CZ9685A patent/CZ8596A3/en unknown
- 1995-05-09 JP JP7529486A patent/JPH09500660A/en active Pending
- 1995-05-09 KR KR1019960700111A patent/KR960703874A/en not_active Application Discontinuation
- 1995-05-09 AT AT95915988T patent/ATE222244T1/en not_active IP Right Cessation
-
1996
- 1996-01-10 NO NO960115A patent/NO306722B1/en not_active IP Right Cessation
-
2003
- 2003-12-19 US US10/741,872 patent/US20040131551A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4880008A (en) * | 1985-05-08 | 1989-11-14 | The General Hospital Corporation | Vivo enhancement of NMR relaxivity |
US6120768A (en) * | 1993-05-17 | 2000-09-19 | Immunomedics, Inc. | Dota-biotin derivatives |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080193384A1 (en) * | 2005-04-26 | 2008-08-14 | Koninklijke Philips Electronics, N.V. | Responsive Mri Contrast Agents |
US8734761B2 (en) | 2005-04-26 | 2014-05-27 | Koninklijke Philips N.V. | Responsive MRI contrast agents |
Also Published As
Publication number | Publication date |
---|---|
KR960703874A (en) | 1996-08-31 |
CA2164944A1 (en) | 1995-11-23 |
WO1995031444A1 (en) | 1995-11-23 |
NO960115L (en) | 1996-03-05 |
ATE222244T1 (en) | 2002-08-15 |
NO960115D0 (en) | 1996-01-10 |
CZ8596A3 (en) | 1996-06-12 |
DE69527759T2 (en) | 2003-04-10 |
US6693190B1 (en) | 2004-02-17 |
JPH09500660A (en) | 1997-01-21 |
EP0708761A1 (en) | 1996-05-01 |
CN1128534A (en) | 1996-08-07 |
NO306722B1 (en) | 1999-12-13 |
DE69527759D1 (en) | 2002-09-19 |
EP0708761B1 (en) | 2002-08-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6693190B1 (en) | Enhanced relaxivity monomeric and multimeric compounds | |
US5480990A (en) | Bicyclopolyazamacrocyclocarboxylic acid complexes for use as contrast agents | |
US5750660A (en) | Bicyclopolyazamacrocyclophosphonic acid half esters | |
FI101378B (en) | Functionalized chelating polyamines and rhodium complexes thereof and process for the preparation of rhodium complexes | |
EP0670832B1 (en) | Hepatobiliary magnetic resonance contrast agents | |
JP3228296B2 (en) | β, β′-dihydroxymeso-substituted chlorins, isobacteriochlorins, bacteriochlorins, and methods for their preparation from β, β′-unsubstituted tetrapyrrole macrocycles | |
CN108368067B (en) | Dimeric contrast agents | |
US10179775B2 (en) | Cyclooctenes for bioorthogonol reactions | |
JPH03502575A (en) | Rare earth cryptates, their production methods, their synthetic intermediates, and their use as fluorescent tracers | |
US5945564A (en) | 2,2-dideutero-5-aminolevulinic acid | |
US11097017B2 (en) | Gadolinium-based contrast agents for sensitive detection of Zn2+with MRI | |
EP0579802B1 (en) | Bicycle-polyazamacrocyclocarboxylic acid complexes, conjugates, preparation and use as contrast agents | |
AU783640B2 (en) | Improvements in and relating to chromophores | |
RU2114115C1 (en) | Derivatives of bicyclopolyazamacrocyclophosphonic acids or their pharmaceutically acceptable salts and a method of their synthesis | |
US20080275232A1 (en) | Chlorins possessing fused ring systems useful as photoselective compounds for photodynamic therapy | |
EP3959208B1 (en) | Cyclen based compounds, coordination compounds, peptides, pharmaceutical preparation, and use thereof | |
US7582280B2 (en) | Conjugates of antioxidants with metal chelating ligands for use in diagnostic and therapeutic applications | |
US20030203888A1 (en) | Chromophores | |
JPH08509976A (en) | Bicyclopolyaza macrocyclophosphonic acids for use as contrast agents, complexes and composites thereof and processes for their preparation | |
WO1994026313A1 (en) | Bicyclopolyazamacrocyclocarboxylic acid complexes, their conjugates, processes for their preparation, and use as contrast agents | |
JPH03197468A (en) | Bifunctional large cyclic chelate ligand and its preparation | |
KR100306331B1 (en) | Bicyclo polyaza macrocyclocarboxylic acid complex, its conjugate, its preparation method and its use as contrast agent | |
CA2139738A1 (en) | Bicyclopolyazamacrocyclocarboxylic acid complexes, their conjugates, processes for their preparation, and use as contrast agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: BRISTOL-MYERS SQUIBB COMPANY, NEW JERSEY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:RANGANATHAN, RAMACHANDRAN S.;PILLAI, RADHAKRISHNA;RATSEP, PETER C.;AND OTHERS;REEL/FRAME:019513/0966;SIGNING DATES FROM 19940622 TO 19940708 Owner name: BRACCO INTERNATIONAL BV, NETHERLANDS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BRISTOL-MYERS SQUIBB COMPANY;REEL/FRAME:019513/0995 Effective date: 19940815 |
|
STCB | Information on status: application discontinuation |
Free format text: EXPRESSLY ABANDONED -- DURING EXAMINATION |